I. Formal Synthesis of SCH 351448. II. Synthesis and

I Formal Synthesis of SCH 351448 II Synthesis and Characterization of Largazole Analogues

by

Heekwang Park

Department of Chemistry Duke University

Date_______________________

Approved

___________________________

Jiyong Hong Supervisor

___________________________

Steven W Baldwin

___________________________

Barbara R Shaw

___________________________

Don M Coltart

Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of

Chemistry in the Graduate School of Duke University

2012

ABSTRACT


by

Heekwang Park


Date_______________________

Approved

___________________________


___________________________

Steven W Baldwin

___________________________

Barbara R Shaw

___________________________

Don M Coltart

An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of


2012

Copyright by Heekwang Park

2012

iv

Abstract

Part I Extensive studies for treating hypercholesterolemia one of the major causes of

human morbidity throughout the world have led to the development of statin drugsndashthe most

prevalent drug prescribed today In addition to statins SCH 351448 has attracted considerable

interest from many synthetic groups as it is the only selective activator of low-density lipoprotein

receptor (LDL-R) containing structural features such as a C2-symmetry and 26-cis-

tetrahydropyrans Even though direct dimerization has been the most efficient method for the

construction of C2-symmetric macrodiolides total syntheses of SCH 351448 were only achived

by stepwise dimerizations In this chapter attempts were made to exploit the inherent C2-

symmetric macrodioloide via direct dimerization using various single monomeric units but they

did not prove to be viable Therefore formal synthesis of SCH 351448 was accomplished through

two tandem sequences cross-metathesisconjugate addition and allylic oxidationconjugate

addition reactions to stereoselectively construct 26-cis-tetrahydropyrans embedded in SCH

351448 The 14-syn aldol and the Suzuki coupling reactions were effective for the construction

of the monomeric units This convergent route should be broadly applicable to the synthesis of a

diverse set of analogues of SCH 351448 for further biological studies

Part II Histone deacetylases (HDACs) play a significant role in tumorigenesis and have

been recognized as one of the target enzymes for cancer therapy Extensive studies in small

molecules inhibiting HDAC enzymes have resulted in pan-HDAC inhibitor suberoylanilide

hydroxamic acid (SAHA) and class I HDAC inhibitor FK228 approved by FDA in 2006 and

2009 respectively Recently largazole a natural product was isolated from Symploca sp

v

presented HDAC inhibitory activity Due to its unique differential cytotoxicity potency and class

selectivity structure-activity relationship (SAR) studies of largazole have been achieved to

improve the potency and class selectivity In addition to such biological activities

pharmacokinetic characteristics and isoform selectivity should be improved for the therapeutic

potential of cancer therapy In this chapter two types of largazole analogues were synthesized by

a convergent route that involved an efficient and high yielding multistep sequence The synthesis

of three disulfide analogues to improve pharmacokinetics and five linker analogues to enhance

HDAC isoform selectivity is disclosed The evaluation of biological studies is in progress

vi

Dedication

To my parents wife daughter and son for love support and encouragement

vii

Contents

Abstract iv

List of Tables x

List of Figures xi

Acknowledgements xx

1 Introduction 1

11 Drug Discovery from Natural Products 1

12 Goal of Dissertation 5

2 Formal Synthesis of SCH 351448 6

21 Introduction 6

211 Hypercholesterolemia 6

212 C2-Symmetric Macrodiolides 9

213 Direct Dimerization 10

214 Stepwise Dimerization 13

215 Background and Isolation of SCH 351448 17

216 Previous Syntheses 19

2161 Leersquos Total Synthesis 19

2162 Leightonrsquos Total Synthesis 23

22 Result and Discussion 26

221 The First Approach to SCH 351448 26

2211 Retrosynthetic Analysis 26

2212 Synthesis of 26-cis-Tetrahydropyrans 27

2213 Asymmetric Aldol Reaction 31

222 The Second Approach to SCH 351448 36

viii

2221 Revised Retrosynthetic Analysis 36



2224 Synthesis of Monomeric Unit 39

2225 Attempts for Direct Dimerization 43


23 Conclusion 51

24 Experimental Section 52

3 Synthesis and Characterization of Largazole Analogues 74

31 Introduction 74

311 Histone Deacetylase Enzymes 74

312 Acyclic Histone Deacetylase Inhibitors 79

313 Cyclic Tetrapeptide Histone Deacetylase Inhibitors 80

314 Sulfur-Containing Histone Deacetylase Inhibitors 83

315 Background of Largazole 89

3151 Discovery and Biological Activities of Largazole 89

3152 Total Syntheses of Largazole 93

3153 Mode of Action of Largazole 98

3154 Syntheses of Largazole Analogues 99


321 Synthetic Goals 102


323 Synthesis of Disulfide Analogues 105

324 Synthesis of Phenyl and Triazolyl Analogues 108

3241 Synthesis of Phenyl Analogues 108

ix

3242 Synthesis of Triazolyl Analogues 112

33 Conclusion 115


References 161

Biography 172

x

List of Tables Chapter 2

Table 21 Boron mediated asymmetric aldol reaction 32

Table 22 Alkali metal mediated asymmetric aldol reaction 32

Table 23 Other asymmetric aldol reaction 33

Table 24 Model test of aldol reaction with propionaldehyde 34

Table 25 Model test of aldol reaction with simple methyl ketone 34

Table 26 14-syn-Aldol reaction of 8 and 9 38

Table 27 Dimerization with diol monomer 44

Table 28 Dimerization with alkyne monomer 45

Table 29 Comparison of 1H NMR data for 2124 (CDCl3) 49

Table 210 Comparison of 13C NMR data for 2124 (CDCl3) 50

Table 211 Chemical shift of (R) and (S)-MTPA ester of 2114 61

Chapter 3

Table 31 Functions of members of the HDAC family 78

Table 32 Growth inhibitory activity (GI50) of natural products 90

Table 33 GI50 and IC50 values for largazole and largazole free thiol (nM) 92

xi

List of Figures Chapter 1

Figure 11 Structure of penicillin and taxol 1

Figure 12 All new chemical entities by source (N = 1184) 2

Figure 13 All new chemical entities by source and year (N = 1184) 3

Figure 14 Representative natural products 4

Chapter 2

Figure 21 Mevalonate pathway 7

Figure 22 Representative statin drugs marketed 8

Figure 23 Reresentative C2-symmetric macrodiolide natural products 10

Figure 24 The structure of SCH 351448 17

Figure 25 Single crystal X-ray structure of SCH 351448 18

Figure 26 Retrosynthetic analysis by other groups 19

Figure 27 The first retrosynthetic analysis of SCH 351448 26

Figure 28 Asymmetric aldol reaction with 14-syn induction 31

Figure 29 The second retrosynthetic analysis of SCH 351448 36

Chapter 3

Figure 31 Role of HAT and HDAC in transcriptional regulation 75

Figure 32 Classification of classes I II and IV HDACs 76

Figure 33 Representative acyclic HDAC inhibitors 79

Figure 34 Representative cyclic tetrapeptide HDAC inhibitors 81

Figure 35 Structure of azumamide AndashE 82

Figure 36 Representative sulfur-containing macrocyclic HDAC inhibitors 84

Figure 37 The structure of largazole 89

xii

Figure 38 Structural similarity between FK228 and largazole and modes of activation 91

Figure 39 Cellular activity of largazole in HCT-116 cells 92

Figure 310 Synthetic plans to largazole 94

Figure 311 Molecular docking of largazole thiol into an HDAC1 homology model 98

Figure 312 Co-crystal structure of HDAC8ndashlargazole thiol complex 99

Figure 313 Structurendashactivity relationship of largazole 100

Figure 314 Schematic representation of HDLPndashTSA interaction 103

Figure 315 Retrosynthetic analysis of disulfide analogues 104

Figure 316 Retrosynthetic analysis of phenyl and triazolyl analogues 105

xiii

List of Schemes

Chapter 2

Scheme 21 Synthesis of cycloviracin B1 by Fuumlrstner 11

Scheme 22 Synthesis of elaiolide by Paterson 12

Scheme 23 Synthesis of swinholide A by Nicolaou 14

Scheme 24 Synthesis of tartrolon B by Mulzer 16

Scheme 25 Synthesis of 26-cis-tetrahydropyrans by Lee 20

Scheme 26 Synthesis of monomeric unit by Lee 21

Scheme 27 Synthesis of SCH 351448 by Lee 22

Scheme 28 Synthesis of monomeric unit by Leighton 23

Scheme 29 Synthesis SCH 351448 by Leighton 25

Scheme 210 Synthesis of two epoxides 27

Scheme 211 Synthesis of two 26-cis-tetrahydropyrans 28

Scheme 212 Synthesis of methyl ketone 30

Scheme 213 Model test of aldol reaction with simple methyl ketone and propionaldehyde 35

Scheme 214 Synthesis of 26-cis-tetrahydropyran and methyl ketone 37

Scheme 215 Synthesis of diol monomeric unit 40

Scheme 216 Synthesis of PMB monomeric unit 41

Scheme 217 Synthesis of alkyne monomeric unit 42

Scheme 218 Dimerization with PMB monomer 45

Scheme 219 Synthesis of epoxide 46

Scheme 220 Formal synthesis of SCH 351448 47

Chapter 3

Scheme 31 Synthesis of FK228 by Simon 85

xiv

Scheme 32 Synthesis of FR901375 by Janda 86

Scheme 33 Synthesis of spiruchostatin A by Ganesan 88

Scheme 34 Synthesis of largazole by HongLuesch 96

Scheme 35 Synthesis of largazole by Williams 97

Scheme 36 Synthesis of common macrocycle core 106

Scheme 37 Synthesis of disulfide analogues 107

Scheme 38 Synthesis of aldehyde 345a and 345b 108

Scheme 39 Synthesis of aldehyde 345c 109

Scheme 310 Inital attempt for the synthesis of aldehyde 345d 110

Scheme 311 Second attempt for the synthesis of aldehyde 345d 110

Scheme 312 Synthesis of phenyl macrocycle 371 111

Scheme 313 Completion of largazole phenyl analogues 112

Scheme 314 Attempt to the synthesis of triazolyl aldehyde 379 113

Scheme 315 Synthesis of triazolyl β-hydroxy ester 114

Scheme 316 Completion of the triazolyl analogue 115

xv

List of Abbreviations

acac acetylacetonate

AIBN azobisisobutyronitrile

aq aqueous

Asp aspartic acid

br s broad singlet

Bn benzyl

BnBr benzyl bromide

B-OMe-9-BBN 9-methoxy-9-borabicyclo[331]nonane

BRSM based upon recovered starting material

t-Bu tert-butyl

n-BuLi n-butyllithium

t-BuLi t-butyllithium

CH2Cl2DCM methylene chloride

CM cross metathesis

COSY correlation spectroscopy

CTCL cutaneous T cell lymphoma

Cu copper

CuTC copper (I) thiophene-2-carboxylate

d doublet

DABCO 14-diazabicyclo[222]octane

dd doublet of doublets

DBU 18-diazabicyclo[540]undec-7-ene

DCC dicyclohexylcarbodiimide

xvi

DDQ 23-dichloro-56-dicyano-14-benzoquinone

DEAD diethyl azodicarboxylate

DIAD diisopropyl azodicarboxylate

DMAP 4-(NN-dimethylamino)-pyridine

DMF NN-dimethylformamide

DMSO dimethylsulfoxide

DNA deoxyribonucleic acid

dppf 11-bis(diphenylphosphino)ferrocene

dr diastereomeric ratio

ED50 the concentration exhibited 50 of its maximum activity

EDCEDCI 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride

ent enantiomer

eq equivalent

Et2O diethyl ether

EtOAc ethyl acetate

FDA food and drug administration

GABA γ-aminobutyric acid

GI50 the concentration required 50 growth inhibition

HATU O-(7-azabenzotriazo-1-yl)-1133-tetramethyluronium

HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A

c-Hex cyclohexane

HAT histone acetyl transferase

HDAC histone deacetylase

His histidine

xvii

HMPA hexamethylphosphoramide

HRMS high-resolution mass spectrometry

IC50 inhibitory concentration 50

Ipc diisopinocampheyl

KHMDS potassium bis(trimethylsilyl)amide

LAH lithium aluminium hydride

LDL low-density lipoprotein

LDL-R low-density lipoprotein receptor

LiHMDS lithium bis(trimethylsilyl)amide

Lys lysine

m multiplet

m-CPBA meta-chloroperoxybenzoic acid

MeCN acetonitrile

MeOH methanol

MIC minimum inhibitory concentration

min minute

MnO2 manganese dioxide

MOM methoxyl-O-methyl

NAD nicotinamide adenine dinucleotide

NOESY nuclear Overhauser effect spectroscopy

NMM N-methylmorpholine

NMO N-methylmorpholine-N-oxide

NMR nuclear magnetic resonance

NEt3TEA triethylamine

xviii

pH negative logarithium of hydrogen ion concentration

PPh3 triphenylphosphine

ppm parts per million

PPTS pyridinium p-toluenesulfonate

i-Pr2NEt diisopropylethylamine

q quartet

RCM ring-closing metathesis

Rf retention factor

rt room temperature

s singlet

sat saturated

SEM [2-(trimethylsilyl)ethoxy]methyl

SO3middotPyr sulfur trioxide pyridine complex

t triplet

TBAF tetra-n-butylammonium fluoride

TBAI tetra-n-butylammonium iodide

TBS tert-butyldimethylsilyl

Tf trifluoromethanesulfonyl

TFA trifluoroacetic acid

THF tetrahydrofuran

TIPS triisopropylsilyl

TLC thin layer chromatography

TMS trimethylsilyl

TMSE trimethylsilylethyl

xix

TsTosyl para-toluenesulfonyl

p-TsOH para-toluenesulfonic acid

Tyr tyrosine

TrTrt trhphenylmethyl

UV ultraviolet

1H NMR proton nuclear magnetic resonance

13C NMR carbon 13 nuclear magnetic resonance

δ chemical shift (ppm)

4Aring MS 4Aring molecular sieves

xx

Acknowledgements

I would like to thank my graduate research advisor Prof Jiyong Hong for his assistance

guidance constant enthusiasm and intellectual support in my chemistry world I am very grateful

for his continued encouragement and very fortunate to do my research under his supervision I

would also like to thank my committee members Prof Steven W Baldwin Prof Barbara R

Shaw and Prof Don M Coltart for their excellent teaching and their time as well as the effort

they have put on my research and career in chemistry

I also thank all of the individuals at Duke who helped my research and life Specifically I

would like to thank Dr George Dubay for his helpful mass spectroscopy assistance and Duke

University and National Institutes of Health for their financial support I also sincerely thank my

former and current lab colleagues Dr Hyoungsu Kim Dr Seongrim Byeon Dr Yongcheng

Ying Dr Joseph Baker Dr Amanda Kasper Kiyoun Lee Tesia Stephenson Doyeon Kwon

Megan Lanier and Bumki Kim for their help with all kinds of research assistance insightful

discussion and friendship

Finally I would like to express my deepest gratitude to my parents for their constant

support and love without which I would not be here I sincerely thank my fantastic wife Hyesun

Jung She is always at my side willing to share my frustrations chemistry career and our

wonderful life In addition I would like to give a special thank you to my daughter Seohyun and

son Jayden who have been always my hope and motivation in my life Lastly I would like to give

my special appreciation to my father who passed away during the study and had supported

constantly in all aspects

1

1 Introduction

11 Drug Discovery from Natural Products

In 1804 pharmacist Friedrich Sertuumlrner first isolated the biologically active small

molecule morphine from the plant opium produced by cut seed pods of the poppy Papaver

somniferum1 Since this discovery the majority of new drugs have historically originated from

natural products or their derivatives As of 1990 approximately 80 of drugs were inspired by

natural products antibiotics (penicillin erythromycin) antimalarials (quinine artemisinin)

hypocholesterolmics (lovastatin) and anticancers (taxol doxorubicin)2

Figure 11 Structure of penicillin and taxol

For instance penicillin is one of the earliest discovered and widely used antibiotic agents

against many previously serious diseases derived from the Penicillium fungi even though many

types of bacteria are now resistant to it More recently taxol (paclitaxel) a molecule that received

much attention in the early 1990s was isolated from the bark of the Pacific Yew tree Taxus

brevifolia in 1962 by Wall and co-workers2b However one 100-year-old yew tree would provide

approximately 300 mg of taxol just enough for one single dose for a cancer patient Following

2

studies of semi-2c and total synthesis2d of it as well as its clinical studies it was approved for the

treatment of ovarian cancer by FDA in 1992 Through this drug discovery process natural

sources have been essential for drug development

Figure 12 All new chemical entities by source (N = 1184)3

Recently Newman and co-workers summarized sources of new drugs from 1981 to

20063 They categorized the sources of new chemical entities covering all diseases countries and

sources biological (B) natural product (N) derived from natural product usually semisynthetic

modification (ND) totally synthetic drug (S) made by total synthesis (S) natural product mimic

(NM) and vaccine (V) As shown in Figure 12 approximately 58 (N ND and S) of 1184 new

chemical entities originated from natural sources In addition 24 (SNM NM and SNM)

have been related to natural products Another investigation by source and year showed that there

has been a sharp decrease in the number of N and ND starting in 1997 (Figure 13) As such a

trend toward natural product-based drug discovery has been descending only 13 natural product-

based drugs were approved by FDA in the United States between 2005 and 2007 with the

proportion also decreasing to below 502

3

Figure 13 All new chemical entities by source and year (N = 1184)3

Due to the prevailing paradigm in the pharmaceutical industries and difficulties to finding

new chemical entities with desirable activities the effort and outcome of drug discovery based on

natural sources has declined in both industries and academia However we should not overlook

beneficial aspects from this research field Although the practice of isolation and total synthesis

of natural products have changed throughout the course of its history its fundamentals have

continued regardless of the change in scientific environment Specifically total synthesis of

natural products not only provides various research opportunities to study further biological

mechanisms but also elicits the discovery of new chemical reactions or organic theories In the

industrial point of view it should be noted that in 2008 the best-selling drug was a

hypocholesterolemic atorvastatin (Lipitor) which sold over $124 billion worldwide and $59

4

billion in the US and its origin derived from natural sources During the search for potent and

efficacious inhibitors of the enzyme HMG-CoA reductase in the 1980s compactin was first

isolated from the microorganism Penicillium brevicompactum by Beecham and co-workers3b

Although it was a potent and competitive HMG-CoA reductase inhibitor safety concerns

resulting from preclinical toxicology studies led to development of novel inhibitors based on the

structural modification Among many synthetic molecules derived through structurendashactivity

relationship atorvastatin showed the outstanding potency and efficacy at lowering cholesterol

levels

In the field of academia prostaglandin F2a4 a subclass of eicosanoids found in most

tissues and organs served as the inspiration for E J Corey to discover chiral catalysts to enable

asymmetric DielsndashAlder reactions in the 1970s56 In addition synthesis of cobyric acid (vitamin

B12)7 and its derivatives also served as the basis for new reactions and physical organic principles8

such as the Eschenmoser corrin synthesis9 and the WoodwardndashHoffman rules10 (Figure 14)

Figure 14 Representative natural products

5

Consequently in spite of the current low level of natural product-based drug discovery

programs in major pharmaceuticals and academia natural products must still be playing a highly

significant role in drug discovery and organic chemistry Therefore it is impossible to

overestimate the importance of natural products toward drug discovery as well as chemical

development

12 Goal of Dissertation

The reminder of this dissertation will be focused on my studies towards total or formal

syntheses of biologically active natural products and their analogues To provide context for all

the work the biological background as well as the previous synthetic works from other groups

will be introduced in each chapter

In chapter 2 the formal synthesis of SCH 351448 and the attempt of direct dimerization

toward the total synthesis will be discussed Chapter 3 will focus on the synthesis of two different

types of largazole analogues their biological studies including pharmacokinetic characteristics

and histone deacetylase (HDAC) isoform profiling

6

2 Formal Synthesis of SCH 351448

21 Introduction

211 Hypercholesterolemia

Hypercholesterolemia refers to elevated levels of lipid and cholesterol in the blood serum

and is also identified as dyslipidemia to describe the manifestations of different disorders of

lipoprotein metabolism11 Cholesterol is mainly produced in the endoplasmic reticulum of

mammalian cells via the mevalonate pathway12 (Figure 21) and supplemented from dietary fat

sources Total fat intake plays an important role in the regulation of cholesterol levels In

particular while saturated fats have been shown to increase low-density lipoprotein (LDL)

cholesterol levels cis-unsaturated fats have been shown to lower levels of total cholesterol and

LDL in the bloodstream Although cholesterol is important and necessary for biological processes

high levels of cholesterol in the blood have been associated with artery and cardiovascular

diseases Due to dietary changes in the past a few decades occurrences of hypercholesterolemia

have been rising leading it to be one of the major causes to human morbidity throughout the

world

7

Figure 21 Mevalonate pathway

Among the chemotherapies for treating hypercholesterolemia statins are the most

prevalent drugs prescribed today As shown in Figure 22 representative statins have common

structural motifs including carboxylate diol and hetero- and carbocycles Such statins

commonly act as competitive inhibitors of HMG-CoA reductase in the mevalonate pathway

8

(Figure 21) The inhibition results in the cessation of cholesterol biosynthesis and subsequent

overexpression of low density lipoprotein receptor (LDL-R) to intake cholesterol from

extracellular sources Eventually the level of LDL is decreased in the blood serum

N O

OOHOH

NH

O

F 2

Ca2+

atorvastatin (Lipitor)

O

OOHOH

2

Ca2+

rosuvastatin (Crestor)

N

NNSO2Me

F

OH

OOHOHN

Ffluvastatin (Lescol)

O

O

HO O

O

H

H

lovastatin (Mevacor)

O

OHCO2Na

HO

O

H

pravastatin (Pravachol)

O

O

HO O

O

H

H

simvastatin (Zocor)

OH

OOHOH

pitavastatin (Livalo)

N

F

3H2O

Figure 22 Representative statin drugs marketed

Since HMG-CoA reductase catalyzes the primary rate-limiting step in the hepatic

biosynthesis of cholesterol enzyme inhibitors effectively regulate the synthesis of cholesterol

The HMG-CoA reductase inhibitors statin drugs (Figure 22) have been successfully used to

treat hypercholesterolemia Despite their efficiencies the statin drugs have been reported to be

associated with side effects such as hepatotoxicity and myotoxicity13 The problem may be caused

9

by the suppression of the formation of mevalonate which is not only the first intermediate in

cholesterol biosynthesis but also a precursor of other vital products such as dolichol and

ubiquinone Alternatively since bile acids are biosynthesized from cholesterol the bile acid

sequestrants (colesevelam cholestyramine and colestipol) decrease the cholesterol levels by

disruption of bile acid reabsorption However they are not more efficacious to lower cholesterol

levels than the statin drugs In addition the fibrates (bezafibrate ciprofibrate clofibrate

gemfibrozil and fenofibrate) a class of amphipathic carboxylic acids are used to treat

hypercholesterolemia but usually in combination with the statin drugs Therefore there have been

constant studies and efforts by academia and pharmaceutical industries to develop new classes of

drugs

212 C2-Symmetric Macrodiolides

There have been several natural products that belong to the C2-symmetric macrodiolide

class which are characterized by the presence of a bislactone in a C2-symmetric fashion14 This

class of macrodiolides consists of a single and common monomeric structure and has typically

been isolated from natural sources Some of the most well-known C2-symmetric macrodiolides

with tetrahydropyrans are swinholide A1516 tartrolon B1718 elaiolideelaiophylin19 and

cycloviracin B12021 (Figure 23) Their biological activities vary widely including anticancer

antibiotic antiviral and hypercholesterolemia activity Among the various approaches for their

syntheses the stepwise and direct dimerization have mainly been attempted based on the dimeric

nature inspired by biosynthetic pathways to construct C2-symmetric macrodiolide core22

10

O

O

OH

Me

O

Me

Me

OH OH

MeO

O

O

OH

Me

O

Me

Me

HOHO

OMe

MeOH

MeO

OMe

Me

Me

Me

HO

OMe

OMeswinholide A

tartrolon B

O

Me

Me O

Me

O

O

MeOOH

O

Me

O

OHO

Me

OO

OO

O

HOOH

OH

OO

R

OOO

HOOH

OH

O

R

O

O

OHOH

OH

OH

O

OH

4

10

R =

cycloviracin B1

BNa

RO O

O

HO

OH O O

OOH

O

OR

elaiophylinelaiolide

R = 2-deoxy- -L-fucoseR = H

Figure 23 Reresentative C2-symmetric macrodiolide natural products

213 Direct Dimerization

The actinomycete strain Kibdelosporangium albatum so nov (R761-7) isolated from a

soil sample collected on Mindanao Island Philippines was found to produce a complex

glycolipid cycloviracin B1 which exhibited pronounced antiviral activity against the human

pathogens herpes simplex virus type 1 (HSV-1) influenza A virus varicella-zoster virus and

human immunodeficiency virus type 1 (HIV-1)2324

11

Scheme 21 Synthesis of cycloviracin B1 by Fuumlrstner

In the total synthesis of cycloviracin B1 by Fuumlrstner and co-workers the key step of

template-directed macrodilactonization is outlined in Scheme 21 Although preliminary

experiments using DCCDMAP as the activating agents were unsuccessful the original plan was

pursued further in the hope that a more efficient activator than DCC would allow to enable the

desired macrodilactonization Encouraging observations were made when compound 21 was

exposed to 2-chloro-13-dimethylimidazolinium chloride Specifically reaction of 21 with 22 in

the presence of DMAP at 0 degC afforded a separable mixture of cyclic monomer 24 (20) the

desired cyclic dimer 23 (75) and several oligomeric byproducts (combined yield ca 5)

Since the effect exerted by Na+ or Cs+ was much less pronounced the optimal outcome was

deemed to reflect the ability of the K+ cation to preorganize the cyclization precursor 21 for

directed macrodilactonization Even though the cyclic monomer was produced as a minor product

it was remarkable that the cyclodimer could be formed in a single step with a common monomer

12

Scheme 22 Synthesis of elaiolide by Paterson

Elaiophylin a sixteen-membered macrolide first isolated from cultures of Streptomyces

melanosporus by Arcamone and co-workers25 and displayed antimicrobial activity against several

strains of gram-positive bacteria26ndash28 Elaiophylin also had anthelmintic activity against

Trichonomonas Vaginalis29 as well as inhibitory activity against K+-dependent adenosine

triphosphatases30 The elaiophylin aglycon elaiolide has been obtained through acidic

deglycosylation of elaiophylin31

Paterson and co-workers envisioned a novel cyclodimerization process involving the

Stille cross-coupling reaction32 to construct the macrocyclic core The key cyclodimerization

reaction was performed on the vinylstannane 25 with copper(I) thiophene-2-carboxylate

(CuTC)33 under mild conditions in the absence of Pd catalyst to produce the required sixteen-

membered macrocycle 26 as a white crystalline solid in 80 yield accompanied by traces of

other macrocycles The reaction led to clean formation of 26 without the isolation of the open-

chain intermediate suggesting the occurrence of a rapid Cu(I)-mediated cyclization without

competing oligomerization (Scheme 22)

13

214 Stepwise Dimerization

One of the most common methods for C2-symmetric macrodiolide synthesis is the

stepwise dimerization This initiates intermolecular esterification between two different

monomeric units one of which protects the alcohol or carboxylic acid Then following the

deprotection the macrolactonization proceeds intramolecularly to construct the macrodiolide For

example swinholide A and tartrolon B were synthesized in this manner

Swinholide A is a marine natural product isolated from the sponge Theonella swinhoei34

It was demonstrated that the producer organisms of this natural product are heterotrophic

unicellular bacteria35ndash39 It displayed impressive biological properties including antifungal activity

and potent cytotoxicity against a number of tumor cells Its cytotoxicity has been attributed to its

ability to dimerize actin and disrupt the actin cytoskeleton40 Swinholide A is a C2-symmetric

forty-membered macrodiolide which consists of two conjugated diene two trisubstituted oxane

and two disubstituted oxene systems

14

O

O

OTBS

Me

O

Me

Me

O O

MeO

O

OHMe

Me

OO

OMe

MeOTBS

MeO

OMe

Me

Me

Me

TBSO

OMe

OMe

OTBS

Me

O

MeO

PMP

PMP

O

HO

OTBS

Me

O

Me

Me

O O

MeO

O

OTMSMe

Me

OO

OMe

MeOTBS

MeO

OMe

Me

Me

Me

TBSO

OMe

OMe

OTBS

Me

O

MeO

PMP

PMP

OH

O

O

OTBS

Me

O

Me

Me

O O

MeO

O

O

TBSO

Me

O

Me

Me

OO

OMe

MeOTBS

MeO

OMe

Me

Me

Me

TBSO

OMe

OMe

swinholide A

PMP

PMP

ab

27

28 29

210

cd e

Reagents and conditions (a) 27 246-trichlorobenzoyl chloride Et3N toluene 25 degC (b) 28 DMAP toluene 105 degC 46 (c) Ba(OH)2middotH2O MeOH 25 degC 83 (d) 246-trichlrobenzoyl chloride Et3N toluene 25 degC then DMAP toluene 110 degC 38 (e) HF MeCN 0 degC 60

Scheme 23 Synthesis of swinholide A by Nicolaou

In the total synthesis of swinholide A by Nicolaou and co-workers15 stepwise

dimerization is outlined in Scheme 23 Esterification of carboxylic acid 27 with alcohol 28

under the Yamaguchi procedure41 (246-trichlorobenzoyl chloride Et3N DMAP) was employed

15

affording hydroxy ester 29 in 46 yield which had suffered concomitant TMS removal

Selective saponification42 of the ester 29 by Ba(OH)2 followed by macrolactonization of the

resultant hydroxy acid using Yamaguchi protocol (05 mM in toluene) gave the protected

swinholide A 210 (38 yield based on 75 conversion) Finally concurrent removal of all the

protecting groups from 210 with aqueous HF in acetonitrile liberated swinholide A in 60 yield

Despite the low yield in esterification and macrolactonization steps it provided only

macrodiolide without any monolide formation issue

The tartrolons were first isolated in 1994 by Hӧfle and Reichenbach from

Myxobacterium Sorangium cellulosum strain So ce6784344 The fermentation furnished tartrolon

A or B depending on the fermentation vessel Glass vessels provided boron and hence allowed the

formation of tartrolon B whereas in steel fermenters the boron-free compounds tartrolon A was

formed as diastereomeric mixtures Alternatively the boron could be incorporated into tartrolon

A chemically This leads to a fixation of the variable stereogenic center at C2 and forces tartrolon

B into a C2-symmetrical structure Both tartrolon A and B act as ion carriers and they are both

active against gram-positive bacteria with MIC values of 1 microgmL

16

Reagents and conditions (a) Ba(OH)2middotH2O MeOH 1 h (b) 246-trichlorobenzoyl chloride Et3N DMAP toluene then 211 74 (c) HFpyridine THF 25 degC 24 h 96 (d) Ba(OH)2middotH2O MeOH 15 min (e) 246-trichlorobenzoyl chloride Et3N DMAP toluene 35 degC 82 (f) (COCl)2 DMSO Et3N CH2Cl2 ndash78 degC 89 (g) Me2BBr CH2Cl2 ndash78 degC 65 (h) Na2B4H7middot10H2O MeOH 60 degC 41

Scheme 24 Synthesis of tartrolon B by Mulzer

Mulzer and co-workers reported the total synthesis of tartrolon B in 1999 via both direct

and stepwise dimerization as key steps17 They first attempted the direct dimerization with a

single monomeric unit in one operation However Yamaguchi lactonization45 resulted in a 19

mixture of the desired diolide 213 together with the monolide in 89 combined yield Therefore

turning to the stepwise manner the hydroxy ester 211 was divided in two portions one of which

was desilylated to the diol while the other one was saponified Yamaguchi esterification of diol

and the free acid of 211 gave the desired ester 212 Desilylation and selective saponification46 of

17

the methyl ester furnished the dimeric seco acid which was smoothly cyclized to the 42-

membered lactone 213 as a mixture of diastereomers under Yamaguchi conditions in 82 yield

Reoxidation of the 9-OH and removal of the MOM and the acetonide group in one step with

Me2BBr47 delivered tartrolon A as a diastereomeric mixture Treatment with Na2B4O7 in methanol

at 50 degC completed the synthesis of tartrolon B In this report even though they showed both

direct and stepwise dimerization the latter was more effective (Scheme 24)

215 Background and Isolation of SCH 351448

In 2000 Hedge and co-workers screened microbial fermentation broths and reported the

isolation and structure elucidation of SCH 351448 (214 Figure 24) an activator of low-density

lipoprotein receptor (LDL-R) The ethyl acetate extract obtained from a microorganism belonging

to Micromonospora sp displayed distinct activity in the LDL-R assay and subsequent bioassay-

guided fractionation of this extract led to the isolation of 21448 It is the first and only natural

product acting as an activator of LDL-R promoter and therefore has been attracted as a potential

therapeutic for controlling cholesterol levels49

Figure 24 The structure of SCH 351448

18

SCH 351448 showed an ED50 of 25 microM in the LDL-R promoter transcription assay using

hGH as a reporter gene but it did not activate transcription of hGH from the SRα promoter Thus

214 selectively activates transcription from the LDL-R promoter and was the only selective

activator of LDL-R transcription in natural product libraries Therefore 214 is the first small

molecule activator of the LDL-R promoter identified to date and may be able to decrease LDL

levels in serum by increasing LDL uptake by the LDL-R

Figure 25 Single crystal X-ray structure of SCH 35144848

After the isolation of SCH 351448 its structure and relative configuration were

determined by extensive NMR studies and single crystal X-ray analysis which revealed that the

structure consists of a 28-membered pseudo-C2-symmetric dimeric macrodiolide (Figure 25) In

addition 214 is composed of four 26-cis-tetrahydropyrans and two salicylates including 14

stereogenic centers In 2008 Rychnovsky and co-workers established its absolute stereochemistry

via total synthesis in which both natural and synthetic 214 had positive specific optical rotation

values (synthetic [α]23D +80 c 10 CHCl3 and natural [α]23

D +26 c 10 CHCl3)50

19

216 Previous Syntheses

Since SCH 351448 was isolated in 2000 there have been five total syntheses reported by

Lee5152 De Brabander53 Leighton54 Crimmins55 and Rychnovsky50 They all disconnected two

ester bonds to give monomeric units but used different protecting groups at C1 and C11 positions

as shown in Figure 26 From these monomeric units they synthesized 214 in a stepwise fashion

using coupling macrolactonization cross-metathesis andor photochemical reaction For the

synthesis of 26-cis-tetrahydropyrans they utilized radical cyclization base-catalyzed conjugate

addition reaction diastereoselective reduction ring closing metathesis or Prins reaction

O

R1

OO

O O

OHOR2

O

NaO2C

OOH

O O O

CO2H

O O

HOO

HO

OH

H

H

H

H

H

H

H

Hcis

cis

cis

cis

Lee CO2TMSEDe Brabander CO2BnLeighton CO2BnCrimins CH2OTIPSRychnovsky CO2TMSE

BnMOMBnMOMSEM

R1 R2

H

H

H

H

SCH 351448 (214)

11

Figure 26 Retrosynthetic analysis by other groups

2161 Leersquos Total Synthesis5152

The synthesis of one of the two 26-cis-tetrahydropyrans by the Lee group started from an

20

aldehyde with Mukaiyama aldol reaction of the aldehyde 21556 mediated by a chiral borane

reagent57 The secondary alcohol obtained was converted into the α-alkoxyacrylate 216 via

reaction with methyl propiolate TBS deprotection and iodide substitution Radical cyclization58

in the presence of hypophosphite and triethylborane in ethanol59 proceeded efficiently to yield

26-cis-tetrahydropyran 217 For the other 26-cis-tetrahydropyran the selenide obtained from

218 was converted into 219 via regioselective benzylation and reaction with methyl propiolate

Radical cyclization of 219 proceeded smoothly in the presence of tributylstannane and AIBN to

provide 26-cis-tetrahydropyran 220 in good yield (Scheme 25)

Reagents and conditions (a) N-tosyl-(S)-valine BH3middotTHF 215 Me2CC(OMe)(OTMS) CH2Cl2 ndash78 degC 94 (b) CHCCO2Me NMM MeCN (c) c-HCl MeOH (d) I2 PPh3 imidazole THF 0 degC 71 for three steps (e) H3PO2 1-ethylpiperidine Et3B EtOH 99 (f) TsCl Et3N CH2Cl2 0 degC (g) PhSeSePh NaBH4 EtOH (h) c-HCl MeOH 81 for three steps (i) Bu2SnO benzene reflux BnBr TBAI benzene reflux (j) CHCCO2Me NMM MeCN 61 for two steps (k) n-Bu3SnH AIBN benzene reflux 98

Scheme 25 Synthesis of 26-cis-tetrahydropyrans by Lee

Basic hydrolysis of 217 provided a monocarboxylic acid and followed by reduction and

oxidation gave the aldehyde which was converted into the correct homoallylic alcohol (dr =

961) via Brown allylation Benzyl protection and transesterification with TMSE-OH led to a

21

new ester 221 The aldehyde obtained via oxidative cleavage was converted into the homoallylic

alcohol 222 (dr=1411) via Brown crotylation60 A five-step sequence converted the homoallylic

alcohol 222 into the sulfone 223 which was efficiently coupled with the aldehyde 226 to

generate the olefin The monomeric unit 224 was obtained from the olefin via diimide reduction

(Scheme 26)

Reagents and conditions (a) KOH THFH2OMeOH (311) (b) BH3middotDMS B(OMe)3 THF 0 degC (c) SO3middotPyr Et3N DMSOCH2Cl2 (11) 0 degC (d) CH2CHCH2B(lIpc)2 ether ndash78 degC NaOH H2O2 reflux (e) NaHMDS BnBr THFDMF (41) 0 degC to 25 degC (f) Ti(Oi-Pr)4 TMSCH2CH2OH DME 120 degC 55 for six steps (g) OsO4 NMO acetoneH2O (31) NaIO4 (h) (E)-CH3CHCHCH2B(dIpc)2 THF ndash78 degC NaOH H2O2 ndash78 degC to 25 degC 69 for two steps (i) TBSOTf 26-lutidine CH2Cl2 0 degC (j) OsO4 NMO acetoneH2O (31) NaIO4 (k) NaBH4 EtOH (l) 225 DIAD PPh3 THF 0 degC (m) (NH4)6Mo7O24middot4H2O H2O2 EtOH 0 degC to 25 degC 84 for five steps (n) NaHMDS ether ndash78 degC 226 ndash78 degC to 25 degC (o) TsNHNH2 NaOAc DMEH2O (11) reflux 79 for two steps

Scheme 26 Synthesis of monomeric unit by Lee

The final assembly of the fragments was initiated by reacting the sodium alkoxide

derived from 222 with 227 The coupled product was then converted into another alkoxide after

22

TBS-deprotection which was used for the coupling with 230 to produce the diester 228

Intramolecular olefin metathesis of 228 mediated by Grubbsrsquo 2nd generation catalyst proceeded

smoothly and subsequent hydrogenationndashhydrogenolysis afforded the macrodiolide 229 TMSE

ester functionalities in 229 were removed by reaction with TBAF and the monosodium salt 214

was obtained when the reaction mixture was equilibrated with 4 N HCl saturated with sodium

chloride (Scheme 27)

O

TMSEO2C

OO

O O

OTBSOBn O

TMSEO2C

OOH

O O O

CO2TMSE

O O

HOO

BnO

OBn

H

H

H

H

H

H

H

H

H

H

H

H

O

TMSEO2C

OOH

O O O

CO2TMSE

O O

HOO

HO

OH

H

H

H

H

H

H

H

H

SCH 351448

a c

de f

2 27 2 28

2 29

2 22 +

OO

O O

2 30

Reagents and conditions (a) NaHMDS THF 0 degC 227 (b) c-HCl MeOH (c) NaHMDS THF 0 degC 230 0 degC 77 for three steps (d) 10 mol Grubbsrsquo 2nd generation catalyst CH2Cl2 (3 mM) 80 degC (e) H2 PdC MeOHEtOAc (31) 70 for two steps (f) TBAF THF 4 N HCl (saturated with NaCl) 91

Scheme 27 Synthesis of SCH 351448 by Lee

23

2162 Leightonrsquos Total Synthesis54

O

BnO2C

OO

O O

OTBSOBn

ab cd

i k l o

O

BnO2C

OH

OHOBn

O

BnO2C

OOBnO

BnO2C

O

OCO2

tBu

CHOe h

NSi

Np-Br-C6H4

p-Br-C6H4

ClR

237 R= H238 R=Me

2 312 32

2 33 2 34

2 35 2 36

O

O O

O

2 39

+

Reagents and conditions (a) ent-237 CH2Cl2 ndash10 degC (b) p-TsOH benzene reflux 72 for two steps (c) BnO2CCH(CH3)2 LDA THF 0 degC (d) BF3middotOEt2 Et3SiH CH2Cl2 ndash78 degC 68 for two steps (e) OsO4 NMO acetone H2O NaIO4 THF H2O (f) (+)-B-methoxyldiisopino-campheylborane AllylMgBr Et2O ndash100 degC 80 for six steps (g) NaH BnBr DMF 0 degC (h) OsO4 NMO acetone H2O NaIO4 THF H2O 89 for two steps (i) 238 CH2Cl2 0 degC 80 (j) (Allyl)2Si(NEt2)H CH2Cl2 (k) i) 5 mol Rh(acac)(CO)2 900 psi CO PhH 65 degC ii) n-Bu4NF THF reflux 69 for two steps (l) 239 10 mol Grubbsrsquo 2nd generation catalyst CH2Cl2 reflux 85 (m) Lindlar catalyst H2 MeOH (n) BF3middotOEt2 Et3SiH CH2Cl2 ndash78 degC 68 for two steps (o) TBSOTf Et3N CH2Cl2 99

Scheme 28 Synthesis of monomeric unit by Leighton

Asymmetric allylation of aldehyde 231 using silane reagent ent-23761 followed by

lactonization with p-TsOH provided lactone 232 in 72 yield (93 ee) Addition of the lithium

enolate derived from benzyl isobutyrate to lactone 232 and cis diastereoselective (gt201)

reduction of the resulting lactol62 gave tetrahydropyran 233 in 68 yield for two steps Oxidative

cleavage of the alkene to the corresponding aldehyde was followed by asymmetric Brown

allylation63 (dr ge101) to give the alcohol in 80 yield for two steps Protection of alcohol as a

24

benzyl ether and oxidative cleavage of the alkene gave aldehyde 234 in 89 yield for two steps

Asymmetric crotylation employing the enantiomer of crotylsilane 23864 gave the alcohol as a

single diastereomer (drge201) in 80 yield Treatment of alcohol with diallyl-diethylaminosilane

provided silyl ether which was immediately subjected to the rhodium-catalyzed tandem

silylformylationndashallylsilylation reaction (5 mol Rh(acac)(CO)2 900 psi CO PhH 65 degC)6566

Upon ventilation of the high-pressure reaction apparatus the residue was treated with n-Bu4NF in

refluxing THF to provide diol 235 as a single diastereomer in 69 yield for two steps Cross

metathesis67 between 235 and enone 239 proceeded smoothly using the Grubbsrsquo 2nd generation

catalyst6869 to deliver the enone in 85 yield Conjugate reduction was accomplished by

hydrogenation over Lindlarrsquos catalyst and the resulting lactol was reduced with Et3SiH and

BF3middotOEt2 to give monomeric unit as a single diastereomer (drgt201) in 91 yield for two steps

Protection of the alcohol with TBS proceeded to give 236 in 99 yield (Scheme 28)

25

Reagents and conditions (a) 240 NaHMDS THF 0 degC then 236 (b) HCl Et2O MeOH 66 for two steps (c) NaHMDS THF 0 degC then 242 63 (d) 10 mol Grubbsrsquo 2nd generation catalyst CH2Cl2 reflux (e) PdC H2 MeOH EtOAc 57 for two steps

Scheme 29 Synthesis SCH 351448 by Leighton

With fragments 236 and 240 in hand they were positioned to investigate their coupling

Thus deprotonation of alcohol 240 with NaHMDS and addition of acetonide 236 led to the

desired ester product and methanolysis of the TBS ether then produced alcohol 241 in 66 yield

for two steps Deprotonation of 241 with NaHMDS and treatment with acetonide 242 provided

bis-benzoyl ester 243 in 63 yield RCM then proceeded smoothly using the Grubbsrsquo 2nd

generation catalyst and the macrocycle product was subjected to hydrogenation over PdC

resulting in reduction of the alkene both benzyl ethers and both benzyl esters After workup with

4 N HCl saturated with NaCl SCH 351448 was obtained in 57 yield (Scheme 29)

26

22 Result and Discussion

221 The First Approach to SCH 351448

2211 Retrosynthetic Analysis

14-syn-Aldol

O

O

Sonogashira Coupling

O

TfO

O

O

O

O

O OHSS

O

HO

OH

OH

O

+ +

+ +

SS SS

TIPSO

TIPSO PMBO

OH

SS

PMBO

Tandem Oxidation Conjugate Addition

OH

OSS

TIPSO

O

13-Dithiane Coupling

OAc OTBS

O

O

O O

H

H

OH H

TIPSOSS

S

SO

NaO2C

OOH

O O O

CO2H

O O

HOO

HO

OH

H

H

H

H

H

H

H

Hcis

cis

cis

cis

214 244

245 246 247

248 249 250

251252

253

Figure 27 The first retrosynthetic analysis of SCH 351448

27

Our retrosynthetic plan for SCH 351448 relies on the tandem allylic oxidationconjugate

addition reaction for the synthesis of the 26-cis-tetrahydropyrans embedded in 214 (Figure 27)

We envisioned that C2-symmetric dimer 214 would be dissected to the monomeric unit 244 and

the Sonogashira coupling reaction and asymmetric aldol reaction of 245 246 and 247 would

complete the monomeric unit 244 The tandem allylic oxidationconjugate addition reaction in

conjuction with the dithiane coupling reaction was expected to afford 26-cis-tetrahydropyran

245 and 246 with excellent yield and diastereoselectivity The requisite epoxide 251 and 253

could be readily prepared from commerially available (R)-pantolactone and L-aspartic acid

respectively

2212 Synthesis of 26-cis-Tetrahydropyrans

Reagents and conditions (a) NaNO2 KBr H2SO4 H2O 0 degC 3 h 91 (b) BH3middotTHF THF 25 degC 4 h 90 (c) NaH THF ndash10 degC 05 h (d) PMBCl TBAI THF 25 degC 14 h 74 for 2 steps (e) TsCl DMAP pyridine CH2Cl2 25 degC 18 h 83 (f) DIBALH THF 0 degC 12 h 76 (g) TIPSCl TBAI THF 25 degC 16 h 75 for 2 steps

Scheme 210 Synthesis of two epoxides

28

The synthesis of the two epoxides commenced from L-aspartic acid and (R)-pantolactone

which are commercially available L-Aspartic acid 254 was converted into bromosuccinic acid

255 by treatment of sodium nitrite and potassium bromide under aqueous sulfuric acid in 91

The diacid 255 was reduced into the bromodiol 256 in 90 yield70 Then epoxidation under

sodium hydride followed by PMB protection provided epoxide 253 in 74 yield for two steps

Tosylation of (R)-pantolactone 258 and followed by reduction by DIBALH gave diol 260 in

83 and 76 respectively71 Then epoxidation and TIPS protection provided epoxide 251 in

75 yield in two steps (Scheme 210)72

Reagents and conditions (a) t-BuLi HMPATHF (110) ndash78 degC 1 h 78 (b) MnO2 CH2Cl2 25 degC 16 h 82 (c) t-BuLi HMPATHF (15) ndash78 degC 1 h 77 (d) MnO2 CH2Cl2 25 degC 24 h 62

Scheme 211 Synthesis of two 26-cis-tetrahydropyrans

To construct 26-cis-tetrahydropyrans dithiane coupling73 and subsequent tandem allylic

oxidation and conjugate addition reaction was utilized which was developed by our group7374

29

Dithiane coupling with epoxide 253 provided diol 262 in 78 yield which was subjected to

tandem reaction using MnO2 to smoothly yield 26-cis-tetrahydropyranyl aldehyde 263 with

excellent yield and stereoselectivity (82 dr gt201) In similar fashion epoxide 251 was coupled

with dithane 252 However a higher ratio of HMPA (HMPATHF =15) was required

presumably due to the steric congestion of the adjacent dimethyl group The diol 264 was

smoothly converted into 26-cis-tetrahydropyranyl aldehyde 245 in 62 yield and excellent

diastereoselectivity (dr gt201) to set the stage for the asymmetric aldol reaction The relative

stereochemistry was determined to be cis configuration by extensive 2D NMR studies (Scheme

211)

30

MsO O

SS

PMBO O

SSO

PMBO O

SS

HO O

SS

TIPS TIPS

PMBO O

SS

TIPS

I O

SS

TIPS

a b c

d e

N O

OSS

OH

TIPS

H3C O

OSS

TIPS

N O

SS

CH3

TIPSO

H3C

Ph

OTf

f

g

h

263 265 266

267 268 269

270 271

272

Reagents and conditions (a) p-TsN3 (MeO)2P(O)CHCOCH3 MeCN MeOH 25 degC 16 h 82 (b) NaHMDS TIPSCl THF 0 degC 1 h 88 (c) DDQ CH2Cl2H2O (101) 25 degC 1 h 90 (d) MsCl Et3N CH2Cl2 25 degC 05 h (e) NaI acetone reflux 16 h 81 for 2 steps (f) LDA LiCl THF MeOH 25 degC 36 h 95 (g) Tf2O pyridine CH2Cl2 0 degC 05 h (h) MeMgBr THF 0 degC 1 h then 01 N HCl TFA 50 degC 2 h 95 for 2 steps

Scheme 212 Synthesis of methyl ketone

To construct the central piece one-carbon homologation of 263 was achieved using the

Bestmann reagent75 Then TIPS protection and PMB deprotection gave alcohol 267 in 88 and

90 respectively Alcohol 267 was converted into iodide 269 through the mesylate

intermediate 268 in 81 for two steps The Myersrsquo asymmetric alkylation reaction76 of 269 and

(RR)-pseudoephedrine propionamide afforded the desired alkylation product 270 as a single

disastereomer in 95 yield Treatment of 270 with CH3Li directly afforded the corresponding

31

methyl ketone 272 in 33 yield along with several byproducts which presumably come from

deprotonation at the propargyl position in 270 by MeLi followed by ring opening Alternatively

the formation of oxazolium triflate 271 and Grignard addition under mild conditions provided

methyl ketone 272 in 95 for two steps (Scheme 212)77

2213 Asymmetric Aldol Reaction

Figure 28 Asymmetric aldol reaction with 14-syn induction

With aldehyde 245 and methyl ketone 272 in hand asymmetric aldol reaction78 was

attempted using boron reagents to give an aldol adduct with 14-syn induction in substrate-

controlled manner under the various conditions as shown in Table 21 However all reactions

resulted in no reaction or decomposition of aldehyde 245 So we assumed that boron could not

form the boron enolate to facilitate a rigid cyclic transition state but preferably coordinated with

sulfur atoms in the dithiane group Therefore we decided to attempt alkali metal mediated

conditions

32

Table 21 Boron mediated asymmetric aldol reaction

entry reagents conditions yield (dr) 1 c-Hex2BCl Et3N Et2O ndash78 ordmC (1 h) ndash20 ordmC (3 h) Deca 2 c-Hex2BCl Et3N THF ndash78 ordmC (1 h) ndash20 ordmC (2 h) 0 ordmC (12 h) NRb 3 c-Hex2BCl i-Pr2NEt Et2O ndash78 ordmC (1 h) ndash20 ordmC (2 h) 0 ordmC (12 h) NRb 4 c-Hex2BCl i-Pr2NEt THF ndash78 ordmC (1 h) ndash20 ordmC (2 h) 0 ordmC (12 h) NRb 5 n-Bu2BOTf Et3N Et2O ndash78 ordmC (1 h) ndash20 ordmC (3 h) Deca 6 n-Bu2BOTf Et3N THF ndash78 ordmC (1 h) ndash20 ordmC (2 h) 0 ordmC (12 h) NRb 7 n-Bu2BOTf i-Pr2NEt Et2O ndash78 ordmC (1 h) ndash20 ordmC (2 h) 0 ordmC (12 h) NRb 8 n-Bu2BOTf i-Pr2NEt THF ndash78 ordmC (1 h) ndash20 ordmC (3 h) NRb

aDec decomposition bNR no reaction

As shown in Table 22 Li Na and K metal using various sources were tried for aldol

reactions in Figure 28 Unsuccessfully we could only obtain aldol adduct with low yield and

poor diastereoselectivity Furthermore the minor diastereomer was the desired product which

was proved via Mosher ester analysis79 From these results we assumed that those bases

abstracted the propargyl proton in methyl ketone 272 andor α-proton in aldehyde 245 to induce

retro conjugate addition reaction to open the tetrahydropyran rings Alternatively various aldol

conditions were attempted but we could not get a successful result (Table 23)

Table 22 Alkali metal mediated asymmetric aldol reaction

entry reagents conditions yieldb (drc) 1 LiHMDS THF ndash78 ordmC (1 h) ndash20 ordmC (2 h) 30 (12) 2 NaHMDS THF ndash78 ordmC (05 h) ndash20 ordmC (1 h) 16 (124) 3 NaHMDS THF ndash78 ordmC (05 h) ndash20 ordmC (10 min) Deca 4 KHMDS THF ndash78 ordmC (05 h) ndash20 ordmC (1 h) 30 (125) 5 t-BuOK THF ndash78 ordmC (1 h) ndash20 ordmC (2 h) Deca 6 LDA THF ndash78 ordmC (05 h) ndash20 ordmC (1 h) Deca

aDec decomposition bcombined yield cthe diastereomeric ratio was determined by integration of the 1H NMR of the mixture

33

Table 23 Other asymmetric aldol reaction

entry reagents conditions yieldc (drd) 1 TiCl4 i-Pr2NEt CH2Cl2 ndash78 ordmC (05 h) ndash20 ordmC (1 h) 23 (112) 2 MBDA THF ndash78 ordmC (05 h) ndash20 ordmC (1 h) Deca 3 LiHMDS MgBr2middotOEt2 THF ndash78 ordmC (05 h) ndash20 ordmC (1 h) 40 (12) 4 LiHMDS MgBr2middotOEt2 THF ndash78 ordmC (05 h) ndash20 ordmC (1 h) 55 (111) 5 LiHMDS HMPA THF ndash78 ordmC (05 h) ndash20 ordmC (1 h) 14 (12) 6 LiHMDS c-Hex2BCl THF ndash78 ordmC (05 h) ndash20 ordmC (1 h) low yield 7 DBU c-Hex2BCl Et2O 0 ordmC (1 h) ndash78 ordmC (1 h) ndash20 ordmC (1 h) NRb 8 DBU n-Bu2BOTf Et2O 0 ordmC (1 h) ndash78 ordmC (1 h) ndash20 ordmC (1 h) NRb 9 Chiral Li amidee THF ndash78 ordmC (05 h) ndash20 ordmC (1 h) 53 (125) 10 MgBr2middotOEt2 CH2Cl2 0 ordmC (15 h) 25 ordmC (12 h) NRb 11 TiCl4 CH2Cl2 ndash78 ordmC (1 h) ndash20 ordmC (14 h) NRb

aDec decomposition bNR no reaction ccombined yield dthe diastereomeric ratio was determined by integration of the 1H NMR of the mixture ebenzenemethanamine α-methyl-N-[(1R)-1-phenylethyl]- lithium salt

To prove the above assumptions we tested aldol reactions with or without the dithiane

group Aldol reactions of 274 with 272 and 245 with 276 resulted in low yield and poor

diastereoselectivity similar to the real substrate with both dithiane functionals (Table 24 and 25)

As expected the substrate without the dithiane group could form the boron enolate to give high

yield (82) and moderate diastereoselectivity (251) (Scheme 213) Consequently we needed to

revise the retrosynthetic analysis to bring about aldol substrates without the dithiane functional on

both the aldehyde and methyl ketone

34

Table 24 Model test of aldol reaction with propionaldehyde

OH O

OH

HTIPS

S

S

H3C

O

OH

HTIPS

S

S

+

conditions

O

274

272 275

entry reagents conditions yielda 1 LiHMDS THF ndash78 ordmC (05 h) ndash78 ordmC (05 h) 34 2 MgBr2middotOEt2 CH2Cl2 0 ordmC (16 h) NRb 3 c-Hex2BCl Et3N Et2O ndash78 ordmC (1 h) ndash20 ordmC (14 h) Decc

acombined yield bNR no reaction cDec decomposition

Table 25 Model test of aldol reaction with simple methyl ketone

entry reagents conditions yieldb (drc) 1 LiHMDS THF ndash78 ordmC (05 h) ndash78 ordmC (05 h) 23 (127) 2 MgBr2middotOEt2 CH2Cl2 0 ordmC (16 h) NRa 3 TiCl4 i-Pr2NEt CH2Cl2 ndash78 ordmC (05 h) ndash78 ordmC (05 h) 15 (111) 4 c-Hex2BCl Et3N Et2O ndash78 ordmC (1 h) ndash20 ordmC (14 h) NRa

aNR no reaction bcombined yield cthe diastereomeric ratio was determined by integration of the 1H NMR of the mixture

35

Scheme 213 Model test of aldol reaction with simple methyl ketone and propionaldehyde

36

222 The Second Approach to SCH 351448

2221 Revised Retrosynthetic Analysis

Figure 29 The second retrosynthetic analysis of SCH 351448

Our second retrosynthetic plan for SCH 351448 relied on the tandem cross-

metathesisconjugate addition reaction and the tandem allylic oxidationconjugate addition

reaction for the synthesis of the 26-cis-tetrahydropyrans embedded in 214 (Figure 29) We

envisioned that the Suzuki coupling reaction of 247 and 280 would complete the monomeric

37

unit 279 which would constitute a formal synthesis of 214 The tandem allylic

oxidationconjugate addition reaction in conjuction with the dithiane coupling reaction was

expected to afford 26-cis-tetrahydropyran 280 with excellent stereoselectivity The requisite

epoxide 282 could be prepared by the 14-syn aldol reaction of tetrahydropyran aldehyde 283

and ketone 276 We envisioned that the tandem CMconjugate addition reaction of hydroxy

alkene 284 and (E)-crotonaldehyde would smoothly proceed to provide 26-cis-tetrahydropyran

aldehyde 283 under mild thermal conditions


Reagents and conditions (a) 3-butenylmagnesium bromide CuI THF ndash20 degC 1 h 71 (b) (E)-crotonaldehyde HoveydandashGrubbsrsquo 2nd generation catalyst toluene 110 degC 18 h 60ndash77 (c) LDA LiCl THF ndash78 degC 1 h then 287 25 degC 3 h 97 (d) CH3Li THF 0 degC 05 h 89

Scheme 214 Synthesis of 26-cis-tetrahydropyran and methyl ketone

The synthesis of SCH 351448 started with the preparation of 26-cis-tetrahydropyran

aldehyde 283 and ketone 276 (Scheme 214) Opening of the chiral epoxide 28580 with 3-

butenylmagnesium bromide provided hydroxy alkene 284 The CM reaction of 284 and (E)-

crotonaldehyde in the presence of HoveydandashGrubbsrsquo 2nd generation catalyst8182 and the

38

subsequent conjugate addition reaction smoothly proceeded to provide the desired 26-cis-

tetrahydropyran aldehyde 283 (60ndash77 dr = 4ndash51)83ndash88 The conjugate addition step required no

activation by base or microwave83 and proceeded under mild thermal conditions To the best of

our knowledge this is the first successful example of the tandem CMconjugate addition reaction

with aldehyde substrates The Myersrsquo asymmetric alkylation reaction76 of 287 and 288 afforded

the desired alkylation product 289 as a single disastereomer in 97 yield Treatment of 289 with

CH3Li afforded the corresponding methyl ketone 276 in 89 yield


Table 26 14-syn-Aldol reaction of 8 and 9

entry reagents enolization conditions reaction conditions yield ()a drb

1 c-Hex2BCl Et3N Et2O 0 degC 1 h ndash78 degC 1 h ndash20 degC 14 h 55 151

2 (ndash)-Ipc2BCl Et3N Et2O 0 degC 2 h ndash78 degC 5 h 70 31

3 (ndash)-Ipc2BCl Et3N Et2O 0 degC 1 h ndash78 degC 1 h ndash20 degC 3 h 62 41


acombined yield of the isolated 290 and 290ʹ bthe diastereomeric ratio (290290ʹ) was determined by integration of the 1H NMR of the mixture

With efficient routes to 285 and 276 in hand we next examined the coupling of 285 and

276 through the 14-syn aldol reaction78 (Table 26) The aldol addition of 276 to 285 (c-

39

Hex2BCl Et3N Et2O) provided the desired β-hydroxy ketone 290 (55) but with poor

stereoselectivity (dr = 151 entry 1) The 14-syn aldol reaction of 285 and 276 at minus78 degC in the

presence of (ndash)-Ipc2BCl78 improved the stereoselectivity of the reaction (dr = 31 entry 2)

Surprisingly higher reaction temperature and prolonged reaction time further improved the

stereoselectivity of the 14-syn aldol reaction (dr = 91 entry 4) Despite its broad utility the 14-

syn aldol reaction has rarely been applied in the stereoselective synthesis of natural products8990

2224 Synthesis of Monomeric Unit

From 14-syn aldol adduct 290 13-anti reduction91 TBS protection selective acetonide

deprotection using Zn(NO3)292 and epoxide formation93 set the stage for the installation of the

second 26-cis-tetrahydropyran moiety The coupling reaction of epoxide and dithiane proceeded

smoothly to provide allyl alcohol 293 in 80 yield Subsequent tandem allylic

oxidationconjugate addition reaction stereoselectively provided the desired 26-cis-

tetrahydropyran aldehyde 294 with excellent stereoselectivity (dr gt201) One-carbon

homologation of aldehyde 294 was achieved using the Bestmann reagent The Suzuki coupling

reaction94ndash97 of alkyne 295 with triflate 247 and TBS deprotection set the stage for the

dimerization of monomeric unit 297 In such a spndashsp2 coupling reaction the Sonogashira

reaction98 of alkyne 295 and triflate 247 provided only the homo-coupling product of 295

Other coupling reactions (the Negishi the Stille and the Heck reaction) were not effective in

providing the desired coupling product (Scheme 215)

40

292 R = TBS

OR OR

OO

O

OBn

H H

OR OR

O

OBn

H H

OH

OH O

OO

O

OBn

H Hab

291 R = TBS

cd

OR OR

OH

S

S

HO

OR OR

O

O

H

H

S

S

OH H

OBn

cis

OR OR

OH

H

S

S

gt201

H

OH H

OBn

OH H

OBn

OH

OR

H

OROBn

OO

O O

H

H

S

S

f g

h i

293 R = TBS 294 R = TBS

e

296 R = TBS

OH

OH

H

OHOBn

OO

O O

H

H

S

S

290

295 R = TBS

297

O

O O

OTf

247

Reagents and conditions (a) Me4NBH(OAc)3 MeCN HOAc 25 degC 4 h 75 (b) TBSCl Et3N DMAP DMF 25 degC 24 h 93 (c) Zn(NO3)2 MeCN 50 degC 4 h 62 (d) NaH 1-tosylimidazole THF 25 degC 4 h 91 (e) 252 t-BuLi THFHMPA (41) ndash78 degC 5 min then 292 ndash78 degC 1 h 70 (f) MnO2 CH2Cl2 25 degC 16 h 82 (g) p-TsN3 K2CO3 (MeO)2P(O)CH2COCH3 MeCN MeOH 25 degC 6 h 90 (h) 247 NaHMDS B-OMe-9-BBN KBr PdCl2(dppf) THF reflux 12 h 60 (i) HFmiddotpyridine THF 25 degC 12 h 95

Scheme 215 Synthesis of diol monomeric unit

41

Reagents and conditions (a) HFmiddotpyridine THF 25 degC 12 h 92 (b) p-anisaldehyde dimethyl acetal PPTS CH2Cl2 25 degC 2 h (c) NaBH3CN TFA DMF 0 degC 15 min then 25 degC 2 h 67 for 2 steps (2992100 = 32) (d) TBSCl Et3N DMAP DMF 25 degC 14 h 99 (e) 247 NaHMDS B-OMe-9-BBN KBr PdCl2(dppf) THF reflux 16 h 87 (h) HFmiddotpyridine THF 25 degC 9 h 35

Scheme 216 Synthesis of PMB monomeric unit

To differentiate the two hydroxy functional groups TBS deprotection of 295 PMB

acetal formation and regioselective cleavage of acetal provided two regioisomers (2992100 =

32) in 62 for three steps one of which 299 proceeded to TBS protection The Suzuki

coupling reaction of alkyne 2101 with triflate 247 and TBS deprotection set the stage for the

direct dimerization of monomeric unit 2103 with only one hydroxy group (Scheme 216)

42

OH

OR1

H

OR2OBn

OH

H

S

S

b

OH H

OBn OR1 OR2

OH

H

S

S

OH H

OBn OR1 OR2

OH

H

S

S

a

d

2100 R1 = H R2 = PMB 2104 R1 = Bn R2 = PMB 2105 R1 = Bn R2 = H

OH

OR

H

OOBn

OH

H

S

S

O

HO OTf

OH

OR

H

OOBn

OH

H

S

S

O

BnO OTf

c

2106 R = Bn 2107 R = Bn

Reagents and conditions (a) NaH BnBr TBAI DMF 25 degC 18 h 91 (b) DDQ CH2Cl2H2O 25 degC 1 h 71 (c) NaHMDS 247 THF 0 degC 2 h 45 (d) BnBr K2CO3 DMF 25 degC 1 h 99

Scheme 217 Synthesis of alkyne monomeric unit

While all precedents disassembled SCH 351448 at both internal lactone bonds to give a

monomeric unit we attempted to disconnect 214 via two inter- and intramolecular Suzuki

coupling reactions Based on this retrosynthetic analysis one of two regioisomers in acetal

cleavage 2100 proceeded to benzyl protection and PMB deprotection in 91 and 71

respectively The coupling of alcohol 2105 with triflate 247 and benzyl protection set the stage

for the direct dimerization of monomeric unit 2107 using the Suzuki coupling reaction (Scheme

217)

43

2225 Attempts for Direct Dimerization

We hypothesized that the internal triple bond in the monomeric unit might reduce the

tendency to cyclize intramolecularly due to two linear sp orbitals with 180deg angles Based on this

postulation we attempted the direct dimerization with diol monomeric unit 297 as shown in

Table 27 While NaHMDS decomposed the substrate NaH washed with hexane gave two

undesired products The one was intramolecularly lactonized to give 14-membered cyclic

monomer 2108 (14) confirmed by MS and the other was intermolecularly cyclized to give

unsymmetric dimer 2109 (13) which was confirmed by 1HndashNMR At this point we were

looking forward to the direct dimerization if the substrate contained only one hydroxy group to

react with acetonide

44

Table 27 Dimerization with diol monomer

entry conditions results 1 NaHMDS THF 25 degC 24 h Deca 2 NaH THF 25 degC 4 h 2108 (8) and 2109 (12) 3 NaHb THF 25 degC 4 h 2108 (14) and 2109 (13)

aDec decomposition of 297 bwashed with hexanes twice and dried under reduced pressure

Second we attempted the direct dimerization again with PMB protected alcohol 2103

under the condition on entry 3 in Table 27 However the only isolated product was the

intramolecularly cyclized macrolactone 2110 in 71 yield Consequently we concluded that the

direct dimerization under the coupling condition did not work favorably in an intermolecular

fashion (Scheme 218)

45

Reagents and conditions (a) NaH THF 25 degC 4 h 71

Scheme 218 Dimerization with PMB monomer

Lastly spndashsp2 coupling dimerization was attempted as shown in Table 28

Unsuccessfully the Suzuki coupling and the Sonogashira coupling did not work but decomposed

the substrate in all cases

Table 28 Dimerization with alkyne monomer

entry conditions results

1 NaHMDS B-OMe-9-BBN KBr PdCl2(dppf) reflux 1 h Deca 2 NaHMDS B-OMe-9-BBN KBr PdCl2(dppf) reflux 12 h Deca 3 Et2NH CuI Pd(PPh3)4 THF 25 ordmC 5 h Deca

aDec decomposition of 2107

46

Even though we attempted two different types of direct dimerizations such conditions

were not effective to give the desired C2-symmetric macrodiolide Therefore the aim of this

project was changed to the formal synthesis of the known monomeric unit from which the final

SCH 351448 would be achieved by stepwise dimerization


Reagents and conditions (a) Me4NBH(OAc)3 MeCN HOAc 25 degC 4 h 75 (b) p-anisaldehyde dimethyl acetal PPTS CH2Cl2 25 degC 2 h 85 (c) DIBALH toluene ndash20 degC 1 h 72 (d) MOMCl i-Pr2NEt CH2Cl2 25 degC 24 h 92 (e) PPTS CHCl3MeOH 25 degC 48 h 91 (f) NaH 1-tosylimidazole THF 25 degC 6 h 90

Scheme 219 Synthesis of epoxide

From 14-syn aldol adduct 289 13-anti reduction91 PMB-acetal protection and DIBAL-

reduction provided a mixture of 2114 and 2115 (31) MOM-protection acetonide-deprotection

47

and epoxide formation93 set the stage for the installation of the second 26-cis-tetrahydropyran

moiety (Scheme 219)

O OPMB

OH

S

S

HO

O OPMB

O

O

H

H

S

S

OH H

OBn

cis

O OPMB

OH

H

S

S

gt201

H

OH H

OBn

OH H

OBn

MOM

MOMMOMO OPMB

OH

OH H

OBnMOM

SS

OH

+

OTfO

O O

OH

O

H

OPMBOBn

OO

O O

H

H

S

S

MOM

OH

O

H

OPMBOH

O

O

O O

H

H

MOM

O OPMB

O

O

O O

H

H

OBnO2C

H H

MOM

a b c

+d e

fgh i

2117

252

2118 2119

2120

247 2121 2122

2123 2124

ref 53 SCH 351448

BnO2CO

H

O

H

OH

O

O

O O

H

H

MOM

13 7

9 11

15

192229

Reagents and conditions (a) 252 t-BuLi THFHMPA (41) ndash78 degC 5 min then 2117 ndash78 degC 1 h 80 (b) MnO2 CH2Cl2 25 degC 8 h 90 (c) p-TsN3 K2CO3 (MeO)2P(O)CH2COCH3 MeCN MeOH 25 degC 18 h 89 (d) NaHMDS B-OMe-9-BBN KBr PdCl2(dppf) THF reflux 3 h 73 (e) H2 Raney-Ni EtOH 50 degC 40 h 50 (f) DessndashMartin periodinane pyridine CH2Cl2 25 degC 5 h 93 (g) NaClO2 NaH2PO4middotH2O 2-methyl-2-butene t-BuOHH2O (11) 25 degC 4 h (h) BnBr Cs2CO3 MeCN 25 degC 2 h 84 for 2 steps (i) DDQ CH2Cl2H2O 25 degC 1 h 98

Scheme 220 Formal synthesis of SCH 351448

48

The coupling reaction of epoxide 2117 and dithiane 252 proceeded smoothly to provide

allyl alcohol 2118 for the key tandem allylic oxidationconjugate addition reaction The tandem

allylic oxidationconjugate addition reaction of 2118 (MnO2 CH2Cl2 25 degC 8 h)

stereoselectively provided the desired 26-cis-tetrahydropyran aldehyde 2119 with excellent yield

and stereoselectivity (90 dr gt201) One-carbon homologation of aldehyde 2119 was achieved

by the Bestmann reagent

Having successfully assembled both the 26-cis-tetrahydropyran moieties in 214 we

embarked on the final stage of the synthesis of 214 The Suzuki coupling94ndash97 reaction of alkyne

2120 with triflate 24799 provided the corresponding coupling product 2121 Simultaneous Bn-

deprotection desulfurization and reduction of alkyne 2121 were accomplished by treatment with

Raney-Ni Oxidation of alcohol 2122 to the corresponding carboxylic acid was achieved in a

two-step sequence (Scheme 220) Formation of Bn ester and PMB-deprotection completed the

synthesis of 2124 which proved identical in all respects with the known synthetic 2124 reported

by De Brabander and co-workers (Table 210 and 211)53

49

Table 29 Comparison of 1H NMR data for 2124 (CDCl3)a

Carbon

chemical shifts (δ) Carbon

chemical shifts (δ) De Brabander

(400 MHz) Hong

(500 MHz) De Brabander

(400 MHz) Hong

(500 MHz) 1 ndash ndash 20 139ndash165 (m) 138ndash165 (m)

2 ndash ndash 21 174ndash188 (m) 174ndash188 (m)

3 351 (d) 350 (d) 107ndash128 (m) 106ndash128 (m)

4 139ndash165 (m) 138ndash165 (m) 22 306-313 (m) 306-313 (m)

5 174ndash188 (m) 174ndash188 (m) 23 ndash ndash

139ndash165 (m) 138ndash165 (m) 24 678 (d) 678 (d)

6 139ndash165 (m) 138ndash165 (m) 25 728 (t) 738 (t)

107ndash128 (m) 106ndash128 (m) 26 693 (d) 693 (d)





11 363ndash369 (m) 363ndash368 (m) 1-OCH2Ph 727ndash740 (m) 727ndash735 (m)

12 139ndash165 (m) 138ndash165 (m) 1-OCH2Ph 458 (d) 458 (d)


107ndash128 (m) 106ndash128 (m) 2-Me 112 (s) 112 (s)

14 107ndash128 (m) 106ndash128 (m) 2-Me 120 (s) 120 (s)

15 317ndash340 (m) 317ndash337 (m) 9-OCH2OCH3 512 (s) 512 (s)


17 139ndash165 (m) 138ndash165 (m) 11-OH 295 (m) 294 (d)

174ndash188 (m) 174ndash188 (m) 12-Me 086 (d) 086 (d)



19 317ndash340 (m) 317ndash337 (m) a Chemical shifts of methylenes in the upfield region may be interchangeable

50

Table 210 Comparison of 13C NMR data for 2124 (CDCl3)

Carbon


chemical shifts (δ)

De Brabander

(100 MHz) Hong


(100 MHz) Hong

(125 MHz) 1 1769 1769 22 344 344

2 469 469 23 1484 1484

3 824 824 24 1254 1254

4 366 366 25 1353 1352

5 238 238 26 1153 1153

6 320 320 27 1122 1122

7 a 752 751 28 1604 1604

8 414 413 29 1573 1573

9 736 736 30 1051 1051

10 391 391 1-OCH2Ph 1366 1366

11 717 717 1286 1286

12 372 372 1281 1281

13 273 273 1279 1279

14 253 253 1-OCH2Ph 663 663

15 a 778 778 2-Me 214 213

16 319 319 2-Me 207 207

17 239 239 9-OCH2OCH3 962 962

18 317 317 9-OCH2OCH3 560 559

191 785 784 12-Me 153 153

20 343 343 30-Me 259 259

21 284 283 30-Me 258 258 a Chemical shifts may be interchangeable

51

23 Conclusion

In summary we explored the feasibility of direct dimerization with various single

monomeric units We expected the gem-disubstituent effect of dithianes and the reduced

flexibility by alkyne would facilitate the formation of the C2-symmetric macrodiloides If this

hypothesis had worked well it could be the first successful total synthesis of SCH 351448 by

direct dimerization Despite our best efforts direct dimerization was not successful Therefore

efforts toward the total synthesis of SCH 351448 culminated in the formal synthesis of the

monomeric unit 2117 which proved identical in all respects with the known synthetic monomer

reported by De Brabander and co-workers

In this formal synthesis the utility of the tandem CMconjugate addition reaction and the

tandem allylic oxidationconjugate addition reaction was demonstrated for the efficient formal

synthesis of SCH 351448 The tandem reactions proceeded under mild reaction conditions and

required no activation of oxygen nucleophiles andor aldehydes It was also shown that the 14-

syn aldol reaction and the Suzuki coupling reaction were effective for the efficient construction of

the monomeric unit of 214 It is noteworthy that all seven of the stereogenic centers in 2117

were derived from three simple fragments 285ndash87 and substrate-controlled reactions The

convergent route should be broadly applicable to the synthesis of a diverse set of analogues of

SCH 351448 for further biological studies

52

24 Experimental Section

Preparation of Hydroxy Alkene 284

To a cooled (ndash78 degC) solution of 3-butenylmagnesium bromide (163 mg 3636 mmol) in THF

(10 mL) were added CuI (93 mg 0485 mmol) and epoxide 285 (500 mg 2424 mmol) in THF

(5 mL) After stirred for 1 h at ndash20 degC the reaction mixture was quenched with addition of

saturated aqueous NH4Cl solution The layers were separated and the aqueous layer was

extracted with EtOAc The combined organic layers were dried over anhydrous Na2SO4 and

concentrated in vacuo The residue was purified by column chromatography (silica gel

EtOAchexanes 120) to afford hydroxy alkene 284 (450 mg 71) [α]25D= +299 (c 10

CHCl3) 1H NMR (500 MHz CDCl3) δ 726ndash737 (m 5H) 583 (dddd J = 170 100 65 65 Hz

1H) 502 (dd J = 170 15 Hz 1H) 495 (dd J = 105 10 Hz 1H) 451 (d J = 40 Hz 2H)

342ndash345 (m 1H) 340 (d J = 85 Hz 1H) 329 (d J = 90 Hz 1H) 320 (d J = 40 Hz 1H)

204ndash214 (m 2H) 169ndash179 (m 1H) 138ndash150 (m 2H) 126ndash134 (m 1H) 092 (s 3H) 091

(s 3H) 13C NMR (125 MHz CDCl3) δ 1391 1379 1285 12776 12756 1144 800 785

736 384 339 311 260 229 198 IR (neat) 3500 1098 910 738 698 cmndash1 HRMS (ESI)

mz 2632004 [(M+H)+ C17H26O2 requires 2632006]

53

Preparation of 26-cis-Tetrahydropyran 283 by Tandem CMConjugate Addition Reaction

To a solution of hydroxy alkene 284 (50ndash200 mg 0191ndash0762 mmol) in toluene (3ndash10 mL)

were added (E)-crotonaldehyde (008ndash032 mL 0955ndash3811 mmol) and Grubbsrsquo 2nd generation

catalyst (5 mol ) at 25 degC After refluxed for 18 h the reaction mixture was concentrated in

vacuo The residue was purified by column chromatography (silica gel EtOAchexanes 140 to

120) to afford 26-cis-tetrahydropyran 283 (29ndash113 mg 49ndash51) and 26-trans-tetrahydropyran

286 (6ndash29 mg 10ndash13) [For 26-cis-tetrahydropyran 283] [α]25D= ndash99 (c 10 CHCl3) 1H

NMR (500 MHz CDCl3) δ 997 (dd J = 30 20 Hz 1H) 725ndash738 (m 5H) 448 (s 2H) 379ndash

385 (m 1H) 333 (dd J = 110 15 Hz 1H) 332 (d J = 85 Hz 1H) 315 (d J = 85 Hz 1H)

246 (ddd J = 160 80 30 Hz 1H) 239 (ddd J = 160 45 20 Hz 1H) 185ndash191 (m 1H)

148ndash160 (m 3H) 117ndash131 (m 2H) 089 (s 3H) 088 (s 3H) 13C NMR (125 MHz CDCl3) δ

2023 1391 1283 12741 12737 814 769 735 732 500 385 315 246 238 215

203 IR (neat) 1725 1090 1048 734 cmndash1 HRMS (ESI) mz 2911954 [(M+H)+ C18H26O3

requires 2911955] [For 26-trans-tetrahydropyran 286] [α]25D= ndash333 (c 10 CHCl3) 1H

NMR (500 MHz CDCl3) δ 977 (dd J = 25 20 Hz 1H) 727ndash740 (m 5H) 459ndash463 (m 1H)

453 (d J = 125 Hz 1H) 444 (d J = 120 Hz 1H) 353 (dd J = 115 20 Hz 1H) 329 (d J =

85 Hz 1H) 314 (d J = 90 Hz 1H) 306 (ddd J = 160 100 30 Hz 1H) 237 (ddd J = 160

105 20 Hz 1H) 178ndash186 (m 1H) 170ndash176 (m 1H) 155ndash166 (m 2H) 142ndash146 (m 1H)

134 (ddd J = 245 125 40 Hz 1H) 090 (s 3H) 089 (s 3H) 13C NMR (125 MHz CDCl3) δ

2018 1390 1282 12743 12734 767 731 728 685 444 383 283 249 215 201 188

54

Preparation of Methyl Ketone 276 by Myersrsquo Asymmetric Alkylation

To a cooled (ndash78 degC) suspension of lithium chloride (153 mg 3616 mmol) in THF (2

mL) were added LDA (10 M 14 mL 14 mmol) and amide 287 (100 mg 0452 mmol) in THF

(5 mL) The reaction mixture was stirred at ndash78 degC for 1 h at 0 degC for 15 min at 25 degC for 5 min

and then cooled to 0 degC and iodide 288 (310 mg 1356 mmol) was added After stirred for 3 h

at 25 degC the reaction mixture was quenched with addition of saturated aqueous NH4Cl solution

The layers were separated and the aqueous layer was extracted with EtOAc The combined

organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo The residue was

purified by column chromatography (silica gel EtOAchexanes 11 to 21) to afford amide 289

(153 mg 97 ) [α]25D= ndash696 (c 10 CHCl3) 1H NMR (21 rotamer ratio denotes minor

rotamer peaks 500 MHz C6H6) δ 705ndash735 (m 5H) 512 (br 1H) 456 (dd J = 60 Hz 1H)

438ndash445 (m 1H) 434ndash440 (m 1H) 427 (s 1H) 407ndash413 (m 1H) 390ndash396 (m 1H)

387 (dd J = 70 Hz 1H) 378ndash383 (m 1H) 376 (dd J = 70 Hz 1H) 342 (dd J = 70 Hz

1H) 332 (dd J = 70 Hz 1H) 282ndash289 (m 1H) 284 (s 3H) 235 (s 3H) 223ndash228 (m 1H)

204ndash211 (m 1H) 162ndash185 (m 1H) 102ndash153 (m 2H) 142 (s 3H) 139 (s 3H) 134 (s

3H) 129 (s 3H) 099 (d J = 65 Hz 3H) 096 (d J = 70 Hz 3H) 091 (d J = 65 Hz 3H)

071 (d J = 65 Hz 3H) 13C NMR (21 rotamer ratio denotes minor rotamer peaks 125 MHz

C6H6) δ 1772 1765 1433 1429 1283 1280 1270 1265 1084 760 7574 7565

749 694 692 578 361 353 3114 3111 300 297 2697 2694 2577 2560

55

181 171 153 140 IR (neat) 3389 1615 1214 1050 701 cmndash1 HRMS (ESI) mz 3502326

[(M+H)+ C20H31NO4 requires 3502326]

To a cooled (ndash78 degC) solution of 289 (80 mg 0229 mmol) in THF (5 mL) was added

methyllithium in diethyl ether (16 M 072 mL 1145 mmol) The resulting mixture was warmed

to 0 degC and stirred for 15 min at 0 degC Excess methyllithium was scavenged by the addition of

diisopropylamine (013 mL 0916 mmol) at 0 degC The reaction mixture was quenched by addition

of acetic acid in diethyl ether (10 vv 2 mL) After stirred for 15 min at 25 degC the reaction

mixture was neutralized with addition of saturated aqueous NaHCO3 solution The layers were

separated and the aqueous layer was extracted with EtOAc The combined organic layers were

dried over anhydrous Na2SO4 and concentrated in vacuo The residue was purified by column

chromatography (silica gel EtOAchexanes 110) to afford methyl ketone 276 (41 mg 89 )

[α]25D= ndash67 (c 10 CHCl3) 1H NMR (500 MHz CDCl3) δ 390ndash397 (m 2H) 339 (t J = 70 Hz

1H) 241ndash246 (m 1H) 203 (s 3H) 165ndash173 (m 1H) 135ndash147 (m 2H) 128 (s 3H) 122ndash

128 (m 1H) 122 (s 3H) 100 (d J = 70 Hz 3H) 13C NMR (125 MHz CDCl3) δ 2121 1087

757 692 458 311 286 279 269 256 162 IR (neat) 1713 1057 668 cmndash1 HRMS (ESI)

mz 2231305 [(M+Na)+ C11H20O3 requires 2231305]

56

Preparation of β-Hydroxy Ketone 290

A flask charged with (ndash)-Ipc2BCl (29 g 909 mmol) was further dried under high

vacuum for 2 h to remove traces of HCl To a cooled (0 degC) solution of dried (ndash)-Ipc2Cl in Et2O

(40 mL) were added methyl ketone 276 (910 mg 454 mmol) in Et2O (20 mL) and triethylamine

(19 mL 1363 mmol) and the resulting white suspension was stirred for 1 h at 0 degC The mixture

was cooled to ndash78 degC and aldehyde 283 (18 g 619 mmol) in Et2O (30 mL) was added slowly

The reaction mixture was stirred for 2 h at ndash78 degC and for additional 2 h at ndash20 degC The reaction

mixture was kept in ndash20degC refrigerator for 14 h The resulting mixture was stirred at 0 degC and pH

7 Phosphate buffer solution (8 mL) MeOH (2 mL) and 50 H2O2 (5 mL) were added to the

reaction mixture at 0 degC and the resulting mixture was stirred for 1 h at 25 degC The layers were

separated and the aqueous layer was extracted with Et2O The combined organic layers were


chromatography (silica gel EtOAchexanes 15) to afford an inseparable 91 mixture of 290 and

2125 (16 g 72) [For 290] [α]25D= ndash07 (c 10 CHCl3) 1H NMR (500 MHz CDCl3) δ 725ndash

738 (m 5H) 448 (AB ∆υ = 325 Hz JAB = 125 Hz 2H) 426ndash431 (m 1H) 398ndash407 (m 3H)

357ndash362 (m 1H) 350 (dd J = 70 65 Hz 1H) 335 (d J = 55 Hz 1H) 325 (d J = 90 Hz

1H) 318 (d J = 90 Hz 1H) 271 (dd J = 165 65 Hz 1H) 256 (dd J = 70 Hz 1H) 250 (dd

57

J = 165 50 Hz 1H) 176ndash186 (m 2H) 144ndash165 (m 7H) 140 (s 3H) 134 (s 3H) 119ndash

133 (m 3H) 109 (d J = 70 Hz 3H) 092 (s 3H) 088 (s 3H) 13C NMR (125 MHz CDCl3) δ

2135 1389 1283 12742 12736 1088 821 788 772 758 732 693 679 481 466

427 383 321 311 284 269 257 249 236 216 210 162 IR (neat) 3478 1709 1368

1046 735 cmndash1 HRMS (ESI) mz 5133189 [(M+Na)+ C29H46O6 requires 5133187]

Preparation of 13-anti-Diol 2112

To a cooled (ndash20 degC) solution of Me4NBH(OAc)3 (37 g 14265 mmol) in MeCNHOAc

(11 70 mL) was added 290 (14 g 2853 mmol) in MeCN (5 mL) After stirred for 4 h at 25 degC

the reaction mixture was quenched with addition of saturated aqueous NaHCO3 solution The

layers were separated and the aqueous layer was extracted with CH2Cl2 The combined organic

layers were dried over anhydrous Na2SO4 and concentrated in vacuo The residue was purified by

column chromatography (silica gel EtOAchexanes 17 to 12) to afford 13-anti-diol 2112 (105

g 75) [α]25D= ndash43 (c 05 CHCl3) 1H NMR (500 MHz CDCl3) δ 725ndash738 (m 5H) 448 (AB

∆υ = 310 Hz JAB = 125 Hz 2H) 440 (s 1H) 415ndash419 (m 1H) 401ndash409 (m 2H) 371ndash374

(m 1H) 360 (dd J = 105 Hz 1H) 350 (dd J = 70 Hz 1H) 337ndash339 (m 2H) 323 (d J =

95 Hz 1H) 317 (d J = 90 Hz 1H) 173ndash186 (m 2H) 144ndash168 (m 10H) 140 (s 3H) 134

(s 3H) 119ndash133 (m 2H) 105ndash113 (m 1H) 091 (s 3H) 087 (d J = 60 Hz 3H) 087 (s

3H) 13C NMR (125 MHz CDCl3) δ 1389 1283 12752 12748 1086 823 8014 773 765

732 723 708 696 424 3895 3881 3834 324 312 283 270 258 249 236 218 211

58


requires 4932524]

Preparation of Acetal 2113

To a cooled (0 degC) solution of 13-anti-diol 2112 (10 g 2029 mmol) in CH2Cl2 (100

mL) were added p-anisaldehyde dimethyl acetal (11 g 6089 mmol) and PPTS (102 mg 0406

mmol) After stirred for 2 h at 25 degC the reaction mixture was quenched with addition of


extracted with CH2Cl2 The combined organic layers were dried over anhydrous Na2SO4 and

concentrated in vacuo The residue was purified by column chromatography (silica gel EtOAc

hexanes 110) to afford 32 mixture of acetal 2113 (105 g 85) [α]25D= ndash43 (c 05 CHCl3)

1H NMR (500 MHz CDCl3 32 mixture denotes minor peaks) δ 742 (d J = 90 Hz 2H)

740 (d J = 90 Hz 2H) 726ndash735 (m 5H) 688 (d J = 80 Hz 2H) 687 (d J = 80 Hz 2H)

572 (s 1H) 567 (s 1H) 445ndash453 (m 2H) 416ndash442 (m 1H) 401ndash409 (m 2H) 379 (s

3H) 372ndash376 (m 1H) 345ndash352 (m 1H) 333ndash340 (m 1H) 336 (d J = 90 Hz 1H) 326ndash

330 (m 2H) 325 (d J = 90 Hz 1H) 320 (d J = 115 Hz 1H) 316 (d J = 90 Hz 1H)

230ndash238 (m 1H) 210ndash216 (m 1H) 177ndash198 (m 4H) 145ndash171 (m 7H) 142 (s 3H)

141 (s 3H) 137 (s 3H) 136 (s 3H) 110ndash130 (m 3H) 096 (s 3H) 090ndash091 (m 9H)

59

IR (neat) 1516 1246 1048 669 cmndash1 HRMS (ESI) mz 6333754 [(M+Na)+ C37H54O7 requires

6333762]

Preparation of Alcohol 2114

OH

O

H

OOBn

PMP

OO2113

OH

O

H

OHOBn

DIBALtoluene

+

OH

OH

H

OPMBOBn

2114 2115O

OO

O

PMB

ndash20 degC 1 h72

[21142115 = 31]

To a cooled (ndash20 degC) solution of acetal 2113 (50 mg 0081 mmol) in toluene (2 mL) was

added diisobutylaluminum hydride (10 M 04 mL 0405 mmol) After stirred for 1 h at the same

temperature the reaction mixture was quenched with addition of saturated aqueous potassium

sodium tartate solution and diluted with EtOAc The layers were separated and the aqueous layer

was extracted with EtOAc The combined organic layers were dried over anhydrous Na2SO4 and


EtOAchexanes 110) to afford 2114 (27 mg 54) and 2115 (9 mg 18) [For 2114] [α]25D=

+86 (c 05 CHCl3) 1H NMR (500 MHz CDCl3) δ 727ndash737 (m 5H) 724 (d J = 85 Hz 2H)

683 (d J = 80 Hz 2H) 454 (d J = 120 Hz 1H) 452 (d J = 110 Hz 1H) 445 (d J = 110

Hz 1H) 444 (d J = 125 Hz 1H) 400ndash411 (m 4H) 377 (s 3H) 364 (ddd J = 55 50 50

Hz 1H) 358 (dd J = 105 100 Hz 1H) 349 (dd J = 70 Hz 1H) 339 (d J = 110 Hz 1H)

329 (d J = 90 Hz 1H) 321 (d J = 85 Hz 1H) 179ndash186 (m 2H) 145ndash166 (m 10H) 141

60

(s 3H) 135 (s 3H) 118ndash132 (m 2H) 104ndash113 (m 1H) 095 (s 3H) 087 (d J = 55 Hz

3H) 089 (s 3H) 13C NMR (125 MHz CDCl3) δ 1591 1389 1313 1294 1283 12748

12742 1138 1086 821 798 793 773 763 733 720 695 688 553 439 3845 3838

358 324 317 290 270 258 249 237 216 211 143 IR (neat) 3501 1516 1250 cmndash1

HRMS (ESI) mz 6353910 [(M+Na)+ C37H56O7 requires 6353918]

[For 2115] [α]25D= +36 (c 02 CHCl3) 1H NMR (500 MHz CDCl3) δ 726ndash736 (m

5H) 725 (d J = 85 Hz 2H) 686 (d J = 85 Hz 2H) 450 (d J = 115 Hz 1H) 447 (d J =

100 Hz 1H) 442 (d J = 115 Hz 1H) 440 (d J = 110 Hz 1H) 401ndash407 (m 2H) 388ndash394

(m 1H) 378 (s 3H) 361ndash366 (m 1H) 348 (dd J = 70 60 Hz 1H) 328 (d J = 85 Hz 1H)

324ndash330 (m 1H) 318 (d J = 115 Hz 1H) 316 (d J = 85 Hz 1H) 305 (s 1H) 192ndash199

(m 1H) 181ndash187 (m 1H) 168ndash174 (m 1H) 145ndash164 (m 9H) 140 (s 3H) 135 (s 3H)

115ndash132 (m 2H) 102ndash109 (m 1H) 090 (s 3H) 088 (s 3H) 082 (d J = 70 Hz 3H) 13C

NMR (125 MHz CDCl3) δ 1593 1392 1305 1296 1283 12742 12736 1139 1087 816

772 766 747 739 733 722 704 696 554 396 3891 3868 356 323 312 283 271

259 250 240 216 207 154

Determination of Absolute Stereochemistry of C9

OH

OH

H

OPMBOBn

2114O

O

(R) or (S)-MTPA-Cl

Et3N DMAPCH2Cl2

OH

O

H

OPMBOBn(R)(S)-MTPA

1

2 2

39

12

16

1717

OO

25 degC 2 h

[(R)-MTPA ester of 2114] 1H NMR (500 MHz CDCl3) δ 754ndash756 (m 2H) 734ndash739

(m 3H) 722ndash733 (m 7H) 686 (d J = 90 Hz 2H) 555ndash561 (m 1H) 442 (d J = 125 Hz

61

1H) 437 (d J = 110 Hz 1H) 432 (d J = 125 Hz 1H) 420 (d J = 105 Hz 1H) 392ndash399

(m 2H) 378 (s 3H) 355 (s 3H) 340ndash345 (m 1H) 326ndash333 (m 1H) 324 (d J = 90 Hz

1H) 314 (d J = 110 Hz 1H) 311 (d J = 85 Hz 1H) 309ndash313 (m 1H) 191ndash198 (m 1H)


(s 3H) 108ndash124 (m 3H) 092ndash101 (m 1H) 089 (s 3H) 083 (s 3H) 079 (d J = 65 Hz

3H)

[(S)-MTPA ester of 2114] 1H NMR (500 MHz CDCl3) δ 752ndash755 (m 2H) 734ndash739





140 (s 3H) 136 (s 3H) 100ndash124 (m 4H) 089 (s 3H) 084 (d J = 65 Hz 3H) 083 (s 3H)

Table 211 Chemical shift of (R) and (S)-MTPA ester of 2114

H-1A H-2ʹ H-2ʹ H-3 H-16A H-16B H-17ʹ H-17ʹ H-12ʹ(S)ndash ester 3237 0888 0828 3092 3448 3991 1403 1355 0845

(R)ndash ester 3244 0892 0829 3140 3429 3965 1401 1353 0795

δSndashδR (ppm) ndash0007 ndash0004 ndash0001 ndash0048 +0019 +0026 +0002 +0002 +0050

Preparation of 2116

62

To a solution of alcohol 2114 (300 mg 0489 mmol) in CH2Cl2 (15 mL) were added

NN-diisopropylethylamine (17 mL 9790 mmol) and chloromethyl methyl ether (037 mL

4895 mmol) at 25 degC After stirred for 24 h at the same temperature the reaction mixture was

quenched with addition of saturated aqueous NH4Cl solution The layers were separated and the

aqueous layer was extracted with CH2Cl2 The combined organic layers were dried over

anhydrous Na2SO4 and concentrated in vacuo The residue was purified by column

chromatography (silica gel EtOAchexanes 15) to afford 2116 (299 mg 92) [α]25D= +112 (c

05 CHCl3) 1H NMR (500 MHz CDCl3) δ 725ndash736 (m 7H) 687 (d J = 85 Hz 2H) 467 (d

J = 70 Hz 1H) 457 (d J = 65 Hz 1H) 453 (d J = 105 Hz 1H) 447 (d J = 120 Hz 1H)


(s 3H) 357ndash360 (m 1H) 351 (dd J = 55 Hz 1H) 339 (s 3H) 336ndash342 (m 1H) 329 (d J

= 85 Hz 1H) 321 (d J = 90 Hz 1H) 320 (d J = 105 Hz 1H) 182ndash196 (m 3H) 145ndash169

(m 8H) 144 (s 3H) 138 (s 3H) 108ndash130 (m 4H) 095 (s 3H) 091 (d J = 65 Hz 3H)

088 (s 3H) 13C NMR (125 MHz CDCl3) δ 1591 1393 1314 1293 1282 12733 12726

1137 1087 962 817 791 772 764 745 7322 7318 709 696 558 553 428 386

358 349 323 319 293 271 258 250 241 2145 2127 139 IR (neat) 1514 1246 1034

697 cmndash1 HRMS (ESI) mz 6794170 [(M+Na)+ C39H60O8 requires 6794180]

63

Preparation of Diol 2126

To a solution of 2116 (295 mg 0449 mmol) in CHCl3MeOH (11 14 mL) was added

PPTS (113 mg 0449 mmol) at 25 degC After stirred for 48 h at the same temperature the reaction

mixture was quenched with addition of saturated aqueous NaHCO3 solution The layers were

separated and the aqueous layer was extracted with CH2Cl2 The combined organic layers were


chromatography (silica gel EtOAchexanes 13 to 21) to afford diol 2126 (249 mg 91)

[α]25D= +153 (c 05 CHCl3) 1H NMR (500 MHz CDCl3) δ 725ndash736 (m 7H) 687 (d J = 85

Hz 2H) 466 (d J = 65 Hz 1H) 457 (d J = 65 Hz 1H) 452 (d J = 105 Hz 1H) 447 (d J

= 120 Hz 1H) 439 (d J = 125 Hz 1H) 438 (d J = 115 Hz 1H) 395ndash405 (m 1H) 380 (s

3H) 363ndash368 (m 2H) 357ndash361 (m 1H) 335ndash345 (m 2H) 339 (s 3H) 329 (d J = 90 Hz

1H) 321 (d J = 90 Hz 1H) 320 (d J = 105 Hz 1H) 256 (br s 1H) 241 (br s 1H) 181ndash

196 (m 3H) 163ndash170 (m 1H) 141ndash159 (m 8H) 112ndash129 (m 3H) 095 (s 3H) 091 (d J

= 70 Hz 3H) 088 (s 3H) 13C NMR (125 MHz CDCl3) δ 1590 1393 1313 1293 1282

12734 12727 1137 961 817 789 772 745 7331 7319 726 708 668 558 553 428

386 357 349 323 314 291 250 241 2143 2124 141 IR (neat) 3418 1456 1250 739

cmndash1 HRMS (ESI) mz 6393851 [(M+Na)+ C36H56O8 requires 6393867]

64

Preparation of Epoxide 2117

To a cooled (0 degC) solution of diol 2126 (245 mg 0397 mmol) in THF (10 mL) was

added NaH (60 dispersion in mineral oil 48 mg 1192 mmol) and the resulting mixture was

stirred for 20 min before 1-tosylimidazole (1060 mg 0476 mmol) was added After stirred for 6

h at 25 degC the reaction mixture was quenched with addition of saturated aqueous NH4Cl solution

and diluted with EtOAc The layers were separated and the aqueous layer was extracted with

EtOAc The combined organic layers were dried over anhydrous Na2SO4 and concentrated in

vacuo The residue was purified by column chromatography (silica gel EtOAchexanes 15) to

afford epoxide 2117 (214 mg 90) [α]25D= +227 (c 05 CHCl3) 1H NMR (500 MHz CDCl3)

δ 725ndash733 (m 7H) 685 (d J = 90 Hz 2H) 465 (d J = 65 Hz 1H) 455 (d J = 65 Hz 1H)


Hz 1H) 393ndash399 (m 1H) 378 (s 3H) 354ndash359 (m 1H) 333ndash340 (m 1H) 337 (s 3H)

327 (d J = 85 Hz 1H) 319 (d J = 90 Hz 1H) 318 (d J = 130 Hz 1H) 287ndash291 (m 1H)

274 (dd J = 45 40 Hz 1H) 246 (dd J = 50 30 Hz 1H) 190ndash196 (m 1H) 179ndash186 (m

2H) 141ndash171 (m 9H) 112ndash131 (m 3H) 093 (s 3H) 089 (d J = 70 Hz 3H) 086 (s 3H)

13C NMR (125 MHz CDCl3) δ 1591 1393 1314 1293 1282 12733 12725 1138 962

817 791 772 745 7324 7317 709 558 553 526 471 428 386 358 347 323 308

294 250 241 2144 2125 139 IR (neat) 1513 1247 1035 668 cmndash1 HRMS (ESI) mz

6213753 [(M+Na)+ C36H54O7 requires 6213762]

65

Preparation of Allyl Alcohol 2118

To a cooled (ndash78 ordmC) solution of 252 (405 mg 2138 mmol) in THFHMPA (41 125

mL) was added dropwise t-BuLi (25 mL 17 M in pentane 4276 mmol) and the resulting

mixture was stirred for 5 min before epoxide 2117 (160 mg 0267 mmol) was added After

stirred for 1 h at ndash78 ordmC the reaction mixture was quenched with addition of saturated aqueous

NH4Cl solution and diluted with EtOAc The layers were separated and the aqueous layer was

extracted with EtOAc The combined organic layers were washed with brine dried over


chromatography (silica gel EtOAchexanes 12) to afford allyl alcohol 2118 (168 mg 80)


Hz 2H) 581ndash586 (m 1H) 569ndash574 (m 1H) 466 (d J = 70 Hz 1H) 456 (d J = 60 Hz 1H)

453 (d J = 105 Hz 1H) 447 (d J = 125 Hz 1H) 439 (d J = 100 Hz 1H) 437 (d J = 80 Hz

1H) 424 (dd J = 125 65 Hz 1H) 416 (dd J = 125 65 Hz 1H) 394ndash405 (m 2H) 379 (s

3H) 356ndash360 (m 1H) 338 (s 3H) 334ndash342 (m 1H) 328 (d J = 85 Hz 1H) 321 (d J =

90 Hz 1H) 319 (d J = 90 Hz 1H) 279ndash300 (m 5H) 273 (dd J = 150 70 Hz 1H) 219ndash

226 (m 2H) 180ndash209 (m 7H) 162ndash170 (m 1H) 142ndash159 (m 8H) 112ndash129 (m 3H) 095

(s 3H) 091 (d J = 60 Hz 3H) 088 (s 3H) 13C NMR (125 MHz CDCl3) δ 1590 1393 1320

1314 1293 1282 12732 12722 1262 1137 961 817 790 772 745 7325 7314 707

691 584 558 553 519 447 428 386 373 362 356 347 323 290 2646 2625 2503

66

2489 241 2141 2119 139 IR (neat) 3445 1516 1249 1039 739 cmndash1 HRMS (ESI) mz

8114242 [(M+Na)+ C44H68O8S2 requires 8114248]

Preparation of 26-cis-Tetrahydropyran Aldehyde 2119 by Tandem OxidationConjugate

Addition Reaction

To a stirred solution of allyl alcohol 2118 (128 mg 0162 mmol) in CH2Cl2 (10 mL) was

added MnO2 (212 mg 2433 mmol) at 25 degC After stirred for 8 h at the same temperature the

reaction mixture was filtered through celite with EtOAc and concentrated in vacuo The residue

was purified by column chromatography (silica gel EtOAchexanes 15 to 13) to afford 26-cis-

tetrahydropyran aldehyde 2119 (115 mg 90) [α]25D= +151 (c 05 CHCl3) 1H NMR (500

MHz CDCl3) δ 980 (s 1H) 725ndash735 (m 7H) 686 (d J = 50 Hz 2H) 467 (d J = 70 Hz


90 Hz 1H) 437 (d J = 75 Hz 1H) 430ndash435 (m 1H) 394ndash405 (m 1H) 379 (s 3H) 373ndash

382 (m 1H) 354ndash358 (m 1H) 339 (s 3H) 334ndash342 (m 1H) 328 (d J = 85 Hz 1H) 321

(d J = 90 Hz 1H) 319 (d J = 105 Hz 1H) 273ndash300 (m 4H) 262 (ddd J = 165 80 25 Hz

1H) 247 (ddd J = 165 45 25 Hz 1H) 237 (d J = 135 Hz 1H) 220 (d J = 135 Hz 1H)


(d J = 80 Hz 3H) 088 (s 3H) 13C NMR (125 MHz CDCl3) δ 2009 1590 1393 1314

1293 1282 12731 12721 1137 962 817 792 772 745 7321 7314 7303 708 685

67

558 553 491 478 4320 4290 4278 386 358 348 339 323 288 2600 2593 2581

250 241 214 212 139 IR (neat) 1725 1512 1035 668 cmndash1 HRMS (ESI) mz 8094087

[(M+Na)+ C44H66O8S2 requires 8094081]

Preparation of Alkyne 2120

To a suspension of K2CO3 (351 mg 2541 mmol) and p-toluenesulfonyl azide (10 M

102 mL 1016 mmol) in MeCN (7 mL) was added dimethyl-2-oxopropylphosphonate (169 mg

1016 mmol) at 25 degC The resulting suspension was stirred for 2 h at the same temperature and

then the aldehyde 2119 (160 mg 0203 mmol) in MeOH (5 mL) was added After stirred for 18 h

at the same temperature the solvents were removed in vacuo and the residue was dissolved in

EtOAcH2O (11 30 mL) The layers were separated and the aqueous layer was extracted with



afford alkyne 2120 (141 mg 89) [α]25D= +162 (c 05 CHCl3) 1H NMR (500 MHz CDCl3) δ



Hz 1H) 395ndash405 (m 1H) 389ndash395 (m 1H) 380 (s 3H) 374ndash381 (m 1H) 355ndash359 (m

1H) 339 (s 3H) 335ndash342 (m 1H) 329 (d J = 90 Hz 1H) 321 (d J = 90 Hz 1H) 320 (d J

= 95 Hz 1H) 273ndash302 (m 4H) 257 (d J = 135 Hz 1H) 252 (ddd J = 165 55 30 Hz

68

1H) 234 (ddd J = 165 75 25 Hz 1H) 221 (d J = 140 Hz 1H) 195ndash210 (m 3H) 181ndash

194 (m 3H) 144ndash170 (m 11H) 112ndash129 (m 3H) 095 (s 3H) 089 (d J = 75 Hz 3H) 088

(s 3H) 13C NMR (125 MHz CDCl3) δ 1590 1394 1315 1293 1282 12734 12723 1137

962 817 805 793 772 745 7322 7317 7315 712 708 705 558 553 480 432 429

421 386 358 348 340 323 289 2603 2593 (2 carbons) 255 250 241 214 212

138 IR (neat) 3304 1514 1248 1038 738 cmndash1 HRMS (ESI) mz 8054136 [(M+Na)+

C45H66O7S2 requires 8054142]

Preparation of 2121

To a cooled (ndash78 ordmC) solution of alkyne 2120 (117 mg 0149 mmol) in THF (10 mL)

was added NaHMDS (10 M 030 mL 0299 mmol) After stirred for 30 min at the same

temperature B-OMe-9-BBN (10 M 037 mL 0374 mmol) was added and the resulting mixture

was then warmed to 25 ordmC After stirred for 30 min KBr (36 mg 0299 mmol) PdCl2(dppf) (22

mg 0030 mmol) and triflate 247 (98 mg 0299 mmol) were added After refluxed for 3 h the

reaction mixture was cooled to 25 ordmC and quenched with addition of saturated aqueous NH4Cl

solution The layers were separated and the aqueous layer was extracted with EtOAc The

combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo The

residue was purified by column chromatography (silica gel EtOAchexanes 110 to 15) to afford

2121 (122 mg 73) [α]25D= +16 (c 02 CHCl3) 1H NMR (500 MHz CDCl3) δ 742 (dd J =

69

85 75 Hz 1H) 721ndash733 (m 8H) 688 (d J = 80 Hz 1H) 684 (d J = 85 Hz 2H) 464 (d J

= 70 Hz 1H) 455 (d J = 60 Hz 1H) 450 (d J = 115 Hz 1H) 445 (d J = 130 Hz 1H) 436

(d J = 125 Hz 1H) 434 (d J = 105 Hz 1H) 401ndash407 (m 1H) 392ndash399 (m 1H) 377 (s

3H) 373ndash382 (m 1H) 352ndash358 (m 1H) 336 (s 3H) 331ndash340 (m 1H) 315ndash327 (m 4H)

274ndash305 (m 2H) 285 (dd J = 170 50 Hz 1H) 273ndash279 (m 1H) 263ndash268 (m 1H) 263

(dd J = 170 90 Hz 1H) 205ndash213 (m 2H) 179ndash197 (m 4H) 171 (s 6H) 141ndash169 (m

11H) 110ndash123 (m 3H) 092 (s 3H) 086 (d J = 80 Hz 3H) 086 (s 3H) 13C NMR (125

MHz CDCl3) δ 1590 1589 1566 1394 1349 1315 1294 1291 1282 12737 12725

1259 1169 1143 1138 1056 962 939 818 806 792 772 746 7325 7320 727 719

708 558 554 482 436 429 422 386 358 348 341 323 289 269 2608 2602 2586

2585 2576 251 241 215 212 138 IR (neat) 2232 1738 1271 1036 734cmndash1 HRMS

(ESI) mz 9814615 [(M+Na)+ C55H74O10S2 requires 9814616]


To a stirred solution of coupling product 2121 (40 mg 0042 mmol) in EtOH (05 mL)

was added Raneyreg 2400 nickel slurry in EtOH (2 pipets) After stirred under H2 atmosphere for

40 h at 50 degC the reaction mixture was then filtered through celite with EtOAc and concentrated

in vacuo The residue was purified by column chromatography (silica gel EtOAchexanes 15 to

21) to afford alcohol 2122 (16 mg 50) [α]25D= +266 (c 02 CHCl3) 1H NMR (500 MHz

70

CDCl3) δ 738 (dd J = 75 Hz 1H) 727 (d J = 85 Hz 2H) 692 (d J = 75 Hz 1H) 686 (d J =

85 Hz 2H) 679 (d J = 75 Hz 1H) 459 (d J = 70 Hz 1H) 450 (d J = 115 Hz 1H) 449 (d

J = 70 Hz 1H) 431 (d J = 110 Hz 1H) 387ndash393 (m 1H) 379 (s 3H) 356 (dd J = 100

30 Hz 1H) 347 (dd J = 105 55 Hz 1H) 331 (s 3H) 317ndash336 (m 5H) 309 (dd J = 70 Hz

2H) 295 (dd J = 100 40 Hz 1H) 175ndash195 (m 5H) 168 (s 6H) 154ndash167 (m 6H) 136ndash


(s 3H) 13C NMR (125 MHz CDCl3) δ 1602 1591 1571 1483 1351 1308 1298 1252

1151 1137 1120 1049 963 837 789 780 777 754 732 707 702 556 553 422

380 364 3481 (2 carbons) 3427 3424 320 3169 (2 carbons) 291 271 2572 2562 250


[(M+Na)+ C45H68O10 requires 7914705]

Preparation of Benzyl Ester 2123

71

[DessminusMartin Oxidation] To a stirred solution of alcohol 2122 (16 mg 0021 mmol) in

CH2Cl2 (1 mL) were added pyridine (34 microL 0042 mmol) and DessminusMartin periodinane (13 mg

0032 mmol) at 25 ordmC After stirred for 5 h the reaction mixture was quenched with addition of

saturated aqueous Na2S2O3 and saturated aqueous NaHCO3 The layers were separated and the



chromatography (silica gel EtOAchexanes 12) to afford aldehyde 2127 (15 mg 93) 1H

NMR (500 MHz CDCl3) δ 953 (s 1H) 738 (dd J = 75 Hz 1H) 726 (d J = 90 Hz 2H) 693

(d J = 70 Hz 1H) 686 (d J = 90 Hz 2H) 679 (dd J = 80 10 Hz 1H) 458 (d J = 60 Hz

1H) 450 (d J = 105 Hz 1H) 448 (d J = 80 Hz 1H) 430 (d J = 115 Hz 1H) 383ndash389 (m

1H) 379 (s 3H) 348ndash353 (m 1H) 332 (s 3H) 324ndash340 (m 3H) 317ndash323 (m 1H) 309

(dd J = 70 Hz 2H) 171ndash194 (m 5H) 169 (s 3H) 168 (s 3H) 154ndash167 (m 4H) 136ndash152

(m 11H) 108ndash123 (m 5H) 100 (s 3H) 099 (s 3H) 087 (d J = 70 Hz 3H)

[Oxidation to Carboxylic Acid] To a solution of aldehyde 2127 (15 mg 0019 mmol)

in t-BuOH H2O (11 2 mL) were added 2-methyl-2-butene (83 microL 0782 mmol) sodium

phosphate monobasic monohydrate (52 mg 0038 mmol) and sodium chlorite (35 mg 0038

mmol) at 25 degC After stirred for 4 h at 25 degC the reaction mixture was diluted with EtOAc and

H2O The layers were separated and the aqueous layer was extracted with EtOAc The combined

organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to afford the crude

carboxylic acid 2128 which was employed in the next step without further purification

[Esterification] To a solution of carboxylic acid 2128 in MeCN (1 mL) were added

Cs2CO3 (31 mg 0095 mmol) and benzyl bromide (23 microL 0190 mmol) at 25 degC After stirred for

2 h at 25 degC the reaction mixture was quenched with addition of saturated aqueous NH4Cl

solution and diluted with EtOAc The layers were separated and the aqueous layer was extracted

72

with EtOAc The combined organic layers were dried over anhydrous Na2SO4 and concentrated

in vacuo The residue was purified by column chromatography (silica gel EtOAchexanes 15) to

afford benzyl ester 2123 (14 mg 84 for two steps) [α]25D= +141 (c 015 CHCl3) 1H NMR

(500 MHz CDCl3) δ 737 (dd J = 75 Hz 1H) 728ndash735 (m 5H) 724 (d J = 80 Hz 2H) 692

(d J = 75 Hz 1H) 686 (d J = 85 Hz 2H) 678 (d J = 75 Hz 1H) 507 (s 2H) 458 (d J =

70 Hz 1H) 450 (d J = 65 Hz 1H) 448 (d J = 125 Hz 1H) 430 (d J = 115 Hz 1H) 385ndash

391 (m 1H) 377 (s 3H) 349ndash354 (m 1H) 345 (dd J = 110 15 Hz 1H) 335ndash341 (m 1H)

332 (s 3H) 324ndash329 (m 1H) 317ndash322 (m 1H) 309 (dd J = 70 Hz 2H) 185ndash192 (m 1H)

174ndash182 (m 3H) 169 (s 6H) 132ndash164 (m 16H) 108ndash124 (m 5H) 119 (s 3H) 111 (s

3H) 086 (d J = 70 Hz 3H) 13C NMR (125 MHz CDCl3) δ 1767 1604 1591 1573 1483

1367 1353 1315 1294 1286 12800 12791 1253 1153 1138 1122 1051 963 821

793 782 779 750 732 707 661 558 554 469 429 366 359 350 347 344 3201

3182 (2 carbons) 292 273 2585 2576 2570 2390 2382 222 203 138 IR (neat) 1737

1513 1389 1039 669 cmndash1 HRMS (ESI) mz 8954966 [(M+Na)+ C52H72O11 requires 8954967]

Preparation of 2124

To a cooled (0 degC) solution of benzyl ester 2123 (14 mg 0016 mmol) in CH2Cl2H2O

(101 11 mL) was added DDQ (11 mg 0048 mmol) After stirred for 1 h at 25 degC the reaction


73



chromatography (silica gel EtOAchexanes 15) to 2124 (12 mg 98) [α]25D= +79 (c 007

CHCl3) 1H NMR (500 MHz CDCl3) δ 738 (t J = 80 Hz 1H) 727ndash735 (m 5H) 693 (d J =

75 Hz 1H) 678 (d J = 85 Hz 1H) 512 (s 2H) 461 (d J = 60 Hz 1H) 458 (d J = 65 Hz

1H) 392ndash398 (m 1H) 363ndash368 (m 1H) 350 (d J = 100 Hz 1H) 317ndash337 (m 3H) 335 (s

3H) 306ndash313 (m 2H) 294 (d J = 40 Hz 1H) 174ndash188 (m 3H) 169 (s 6H) 138ndash165 (m

16H) 107ndash128 (m 6H) 120 (s 3H) 112 (s 3H) 086 (d J = 65 Hz 3H) 13C NMR (125

MHz CDCl3) δ 1769 1604 1573 1484 1366 1352 1286 1281 1279 1254 1153 1122

1051 962 824 784 778 751 736 717 663 559 469 413 391 372 366 344 343

320 319 317 283 273 259 258 253 239 238 213 207 153 IR (neat) 3521 1733

1456 1038 734 cmndash1 HRMS (ESI) mz 7754390 [(M+Na)+ C44H64O10 requires 7754392]

74

3 Synthesis and Characterization of Largazole Analogues

31 Introduction

311 Histone Deacetylase Enzymes

Core histones have been known for decades to undergo extensive post-translational

modifications such as acetylation methylation and phosphorylation as well as ubiquitination

sumoylation and ADP-ribosylation100 Among them Alfrey and co-workers100c proposed that

acetylation could have significant roles on the transcriptional response of the cell in 1964

Thereafter extensive studies on histone deacetylase (HDAC) revealed that HDAC plays a

significant role in carcinogenesis and has been recognized as one of the target enzymes for cancer

therapy100 In addition to the transcriptional regulation in carcinogenesis HDAC plays an

important role in several interactions such as proteinndashDNA interaction proteinndashprotein

interaction and protein stability by changing the acetylation levels of proteins including p53

transcription factor and tubulin100b Together with histone acetyl transferases (HATs) HDACs

are responsible for chromatin packaging which regulates the transcriptional process High levels

of HATs is associated with increased transcriptional activity whereas high levels of HDACs

decreases acetylation levels to suppress transcriptional activity101 Deacetylation of a lysine

residue on the histone tail results in a positively charged ammonium residue which complexes

with negatively charged DNA102 This condensed chromatin causes cessation of the

transcriptional process and represses the expression of the target gene In this manner reversible

acetylation of histones is catalyzed by two key enzymes HAT and HDAC (Figure 31)

75

Figure 31 Role of HAT and HDAC in transcriptional regulation (A) Histone modification by HAT and HDAC (B) Regulation of gene-expression switch by co-activator or co-repressor complex100b

HDACs are classified into four major classes based on the their homology to yeast

proteins class I (HADCs 1238) class IIa (HDACs 4579) class IIb (HDACs 610) class IV

(HDAC 11) and class III (Figure 32)104 While class I has homology to yeast RPD3 class IIa has

homology to yeast HDA1 Class IIb uniquely contains two catalytic sites whereas class IV has

conserved residues in its catalytic center that are shared by both class I and II Remarkably while

class III is a structurally distinct group of NAD-dependent deacetylases105ndash107 class I II and IV

are Zn2+-dependent histone deacetylases sharing a common enzymatic mechanism of

deacetylation

76

Figure 32 Classification of classes I II and IV HDACs104

Structurally class I HDACs are smaller have fewer domains and share similar

sequences in the catalytic domain close to the C-terminus Class I HDACs are mostly localized

within the nucleus whereas class II HDACs shuttle between the nucleus and the cytoplasm

Specifically HDACs 1 2 and 3 are ubiquitously expressed and function to complex with other

proteins whereas HDAC8 is mainly expressed in the liver (Figure 32)108

Targeting of HDACs for therapeutic purposes requires knowledge of their function in

normal tissues in order to understand the potential side effects of their inhibitors Several

knockout mice targeting HDAC family members have been generated providing valuable

insights into their physiological function108b In general class I HDACs plays a role in cell

survival and proliferation For instance HDAC1 knockout has a wide range of proliferation and

survival defect despite compensatory upregulation of HDAC2 and HDAC3 Expression of the

77

cyclin-dependent kinase (CDK) inhibitors p21 and p27 is upregulated and global HDAC activity

is downregulated HDAC2 modulates transcriptional activity through the regulation of p53

binding affinity because its silencing resulted in neonatal lethality accompanied by cardiac

arrhythmias and dilated cardiomyopathy Deletion of HDAC3 led to a delay in cell cycle

progression cell cycle-dependent DNA damage and apoptosis in mouse embryonic fibroblasts

Liver specific knockout of HDAC3 resulted in an enlarged organ hepatocyte hypertrophy and

disturbed fat metabolism In the class II HDACs HDAC4 knockout mice displayed premature

ossification of developing bones and hence is a central regulator of chondrocyte hypertrophy and

endochondral bone formation Deletion of HDAC5 and HDAC9 developed spontaneous cardiac

hypertrophy in response to pressure overload resulting from aortic constriction or consititutive

activation of cardiac stress signals Disruption of HDAC7 resulted in embryonic lethality due to a

failure in endothelial cellndashcell adhesion and consequent dilatation and rupture of blood vessels

Mice lacking HDAC6 known as a tubulin deacetylase were viable despite highly elevated

tubulin acetylation and changes in bone mineral density and immune response (Table 31)108b

Silencing of HDAC8 10 11 have not yet been reported These knockout studies demonstrated

that the function of individual HDACs cannot be compensated by other members of the HDAC

family and the use of pan-HDAC inhibitors can produce significant side effects

78

Table 31 Functions of members of the HDAC family

classes members knockout phenotype I HDAC1 embryonic lethal p21 and p27 upregulation reduced overall HDAC

activity HDAC2 viable until perinatal period fatal multiple cardiac defects excessive

hyperplasia of heart muscle arrythmia HDAC3 embryonic lethal defective cell cycle DNA repair and apoptosis in

embryonic fibroblasts conditional liver knock out results in hepatocyte hypertrophy and induction of metabolic genes

HDAC8 unknown IIa HDAC4 viable premature and ectopic ossification chondrocyte hypertrophy

HDAC5 myocardial hypertrophy abnormal cardiac stress response HDAC7 embryonic lethal lack of endothelial cell-cell adhesion HDAC9 viable at birth spontaneous myocardial hypertrophy

IIb HDAC6 viable no significant defects increase in global tubulin acetylation MEFs fail to recover from oxidative stress

HDAC10 unknown IV HDAC11 unknown

Although knowledge about HDAC functions has been well-established a single HDAC

isoform specific inhibitor has never been reported Most HDAC inhibitors reported so far

displayed only class-selective inhibition Even suberoylanilide hydroxamic acid (SAHA) which

was approved by the FDA for the treatment of cutaneous T cell lymphoma in 2006 is a pan-

HDAC inhibitor and demonstrates numorous side effects such as bone marrow depression

diarrhea weight loss taste disturbances electrolyte changes disordered clotting fatigue and

cardiac arrhythmias Despite these disadvantages these pan-HDAC inhibitors not only play a

significant role in understanding the mode of action in cellular or molecular levels but also serve

as potential drugs in cancer therapy

79

312 Acyclic Histone Deacetylase Inhibitors

Figure 33 shows the representative acyclic HDAC inhibitors Trichostatin A (TSA) was

obtained from a natural source and SAHA was discovered by small molecule screening TSA was

isolated from a culture broth of Streptomyces platensis as a fungal antibiotic in 1976110

Thereafter TSA was found to cause an accumulation of acetylated histones in a variety of

mammalian tumor cell lines in 1990111 Following this discovery Yoshida and co-workers

reported its potent inhibitory effect upon HDACs in 1995 (IC50 = 20 nM against HDAC 1 3 4 6

and 10)111112 In addition its X-ray co-crystal structure with HDAC-like protein (HDLP) has

shown that terminal hydroxamic acid functions to coordinate Zn2+ ion in the active pocket site of

the enzyme while the aliphatic chain reaches through a long narrow binding cavity and

dimethylaniline interacts with amino acids on the surface of the enzyme113 So far its

pharmacological activity is now found to affect both gene expression of tumor cells and to be a

profound therapeutic agent in several non-cancer diseases

Figure 33 Representative acyclic HDAC inhibitors

Among the acyclic HDAC inhibitors as cancer therapeutics SAHA (Zolinzareg by Merck)

was the most extensively studied and first approved by FDA for the treatment of cutaneous T cell

lymphoma (CTCL) in 2006114 It was developed through the screening of numerous small

molecules115 Its biological activity has been shown to potently inhibit HDAC1 (IC50 = 10 nM)

and HDAC3 (IC50 = 20 nM) resulting in induction of cell differentiation cell growth arrest and

80

apoptosis in various cell lines In animal studies it inhibited solid tumor growth such as breast

prostate lung and gastric cancers as well as hematological malignancies with little toxicity Even

though it is the first therapeutically approved HDAC inhibitor it functions like a pan-HDAC

inhibitor and lacks the specificity which means it inhibits all HDAC isoforms in class I and II116

Due to this limitation it is proposed that adverse effects such as cardiac complications may

occur117

VPA was first synthesized in 1882 as an analogue of valeric acid naturally originated

from Valeriana officinalis118 Since valeric acid has a similar structure to both γ-hydroxybutyric

acid (GHB) and the neurotransmitter γ-aminobutyric acid (GABA) in the human brain VPA and

valeric acid function as an antagonist inhibiting GABA transaminase and increasing the level of

GABA119 Therefore its semisodium salt formulation was approved by FDA for the treatment of

the manic episodes of bipolar disorder Recently its anticancer activity has been revealed

through HDAC inhibition and its magnesium salt is in phase III clinical trials for cervical cancer

and ovarian cancer

313 Cyclic Tetrapeptide Histone Deacetylase Inhibitors

Due to the lack of potency and HDAC specificity macrocyclic peptides have attracted a

great deal of attention to enhance degrees of class selectivity120 Also this group of HDAC

inhibitors possesses more potent biological activity than acyclic HDAC inhibitors Those

different biological features between the two classes might arise from the different Zn2+ binding

moiety and the greater complexity of the cap region Figure 34 shows the representative two

classes of cyclic tetrapeptide HDAC inhibitors reversible and irreversible While the α-epoxy

ketone containing inhibitors are typically classified as irreversible HDAC inhibitors those

without the α-epoxy ketone moiety are reversible inhibitors

81

Figure 34 Representative cyclic tetrapeptide HDAC inhibitors

One of the first cyclic tetrapeptide HDAC inhibitors bearing (S)-2-amino-910-epoxy-8-

oxodecanoic acid (L-Aoe) was HC-toxin which was isolated from Helminthosporium carbonum

in 1970120b All this class of inhibitors possess a cyclic tetrapeptide containing hydrophobic amino

acids in the cap region saturated alkyl chain in the linker region and α-epoxy ketone (red) in the

Zn2+ binding region L-Aoe side chain is essentially isosteric with an acetylated lysine residue

suggesting that this class of inhibitors acts as substrate mimics And they typically displayed

nanomolar levels of HDAC inhibitory activity Interestingly Cyl-2 showed the greater potency

(IC50=075 nM against HDAC1) and the impressive selectivity for class I HDAC1 (IC50 = 070 plusmn

045 nM) over class II HDAC6 (IC50 = 40000 plusmn 11000 nM)121a

82

Within the subclass of cyclic tetrapeptide ketones are one of the active variants of L-Aoe

moiety Studies on this subclass have demonstrated that the hydrate form of the ketone acts as a

transition-state analogue and coordinates the Zn2+ ion in the active site Apicidin which was

isolated from cultures of Fusarium pallidoroseum in 1996121b contains an (S)-2-amino-8-

oxodecanoyl side chain lacking an epoxide It displays broad spectrum activity ranging from 4ndash

125 ngmL against the apicomplexan family of parasites presumably via inhibition of protozoan

histone deacetylases (IC50 = 1ndash2 nM) and demonstrates efficacy against Plasmodium berghei

malaria in mice121c

Figure 35 Structure of azumamide AndashE

Azumamides was isolated from the marine sponge Mycale izuensis by Nakao and co-

workers in 2006193a Structurally azumamides include three D-α-amino acids (D-Phe D-Tyr D-

Ala D-Val) and a unique β-amino acid assigned as (Z2S3R)-3-amino-2-methyl-5-nonenedioic

acid 9-amide (amnaa) in azumamides A B and D and (Z2S3R)-3-amino-2-methyl-5-

nonenedioic acid (amnda) in azumamides C and E (Figure 35) Azumamides show an unusual

stereochemical arrangement displaying an inverse direction of the amide bonds and opposite

absolute configuration at C3 position Although azumamides present relatively weak Zn2+ ion

83

binding moieties carboxamides (A B and D) and carboxylic acids (C and E) they showed a

high degree of HDAC inhibitory potency against the crude enzymes extracted from K562 cells

with IC50 values ranging from 45 nM (azumamide A) to 13 microM (azumamide D)193a

314 Sulfur-Containing Histone Deacetylase Inhibitors

One of the class of HDAC inhibitors which are studied extensively and approved by the

FDA are macrocyclic depsipeptides bearing sulfur atom in the Zn2+ ion binding domain This

group of HDAC inhibitors displays the greater HDAC inhibitory activity than acyclic and cyclic

tetrapeptide HDAC inhibitors and possesses structurally unique Zn2+ binding moieties free thiols

Figure 36 shows the representative macrocyclic HDAC inhibitors FK228 (romidepsin)

FR901375 spiruchostatins AB and largazole In addition to the Zn2+ binding moiety they

structurally consist of a larger cap region (the macrocycle) to interact with the surface of the

enzyme These more extensive interactions between the inhibitor and enzyme may explain the

higher degree of class selectivity121 Also while FK228 FR901375 and spiruchostatins

commonly contain disulfide linkages connecting a β-hydroxy mercaptoheptenoic acid residue and

a cysteine residue largazole uniquely holds a thioester bond

84

Figure 36 Representative sulfur-containing macrocyclic HDAC inhibitors

FK228 (Romidepsin or FR901228) is the FDA-approved drug for the treatment of

cutaneous T cell lymphoma (CTCL) in 2009 and was isolated from a culture of Chromobacterium

violaceum from a soil sample in Japan by Ueda and co-workers at Fujisawa Pharmaceuticals in

1994122 Structurally FK228 consists of a sixteen-membered macrocyclic ring as the cap group

and a β-hydroxy mercaptoheptenoic acid in the conjunction with internal cysteine residue Under

the reductive conditions within the cell FK228 releases a free thiol to tightly bind to Zn2+ ion in

the narrow binding pocket of HDAC enzyme Thus the disulfide molecule acts as a prodrug

Biologically it showed potent antitumor activity with little effect on normal cells In addition it

presented class I HDAC1 (IC50 = 30 nM) selectivity over class II HDAC6 (IC50 = 14000 nM)123

85

Reagents and conditions (a) Ti(IV) catalyst toluene 99 (b) LiOH MeOH 100 (c) Fmoc-L-Thr BOP i-Pr2NEt 95 (d) Et2NH (e) Fmoc-D-Cys(Trt) BOP i-Pr2NEt 97 (f) Et2NH (g) Fmoc-D-Val BOP i-Pr2NEt 86 (h) Tos2O 97 (i) DABCO (j) Et2NH (k) BOP i-Pr2NEt 95 (l) LiOH MeOH 98 (m) DIAD PPh3 62 (n) I2 MeOH 84

Scheme 31 Synthesis of FK228 by Simon

To date there have been three total syntheses of FK228 reported first by Simon and co-

workers124 in 1996 followed by Williams and co-workers125 and Ganesan and co-workers126 in

2008 Simon and co-workers utilized a titanium-mediated asymmetric aldol reaction to synthesize

the β-hydroxy mercaptoheptenoic acid 34 with great yield and enantioselectivity (gt95 yield

and gt98 ee)127 The peptide bond was assembled by standard Fmoc peptide synthetic methods

using the BOP coupling reagent128 In macrocyclization under the Mitsunobu conditions (DIAD

and PPh3) with the additive TsOH to suppress elimination of the activated allylic alcohol

86

hydroxy acid 38 afforded macrocycle 39 in 62 yield Oxidation of 39 with iodine in dilute

MeOH solution129 provided FK228 in 84 yield (Scheme 31)

FR901375

O O O

NHHN

OTBS

ONH

O

NHO

STr

STr

O OHCO2H

NHHN

OTBS

ONH

O

NHO

STr

STr

CO2MeNH2

HNOTBS

ONH

O

NHO

STr

O

O

Bn

O

Cl

H

O STr

O

O

Bn

O

Cl

OH STrOH STr

HO2C

CO2Me

HNOTBS

OFmocHN

STr

CO2H

HNOH

310

312 313

310 315 316

317 318

311

h k

bc

d g

a+

opn

lm

Reagents and conditions (a) (n-Bu)2BOTf i-Pr2NEt then 311 69 (b) AlndashHg (c) LiOH 78 (d) HCl(g) MeOH (e) NH3(g) Et2O (f) Fmoc-D-Cys(Trt) EDCI HOBt (g) TBSCl imidazole 83 (h) Et2NH (i) Fmoc-D-Val EDCI HOBt 97 (j) Et2NH (k) Fmoc-D-Val EDCI HOBt 71 (l) BOP i-Pr2NEt (m) LiOH 79 (n) DIAD PPh3 TsOH 58 (o) I2 MeOH (p) 5 HF MeCN 63

Scheme 32 Synthesis of FR901375 by Janda

FR901375 was discovered by Fujisawa Pharmaceuticals in the fermentation broth of

Pseudomonas chloroaphis (No 2522) is a member of a rare and structurally elegant family of

macrocyclic depsipeptides130 Like FK228 this natural product possesses potent antitumor

activity against a range of murine and human solid tumors and its mode of action has been linked

87

to the reversal of prodifferentiation effects of the ras oncogene pathway via blockade of p21

protein-mediated signal transduction131ndash134 FR901375 reveals several unique structural aspects a

tetrapeptide framework H2N-D-Val-D-Val-D-Cys-L-Thr-OH consisting of a sixteen-membered

macrocyclic ring β-hydroxy mercaptoheptenoic acid and an internal disulfide linkage There has

been only one total synthesis reported by Janda and co-workers in 2003135 They utilized Evanrsquos

aldol reaction136 for the construction of β-hydroxy mercaptoheptenoic acid and the Mitsunobu

conditions (DIAD and PPh3) with additive TsOH for macrocyclization (Scheme 32)

Spiruchostatins A and B were isolated from a culture broth of a Pseudomonas sp in

2001137 showing gene expressionndashenhancement properties Structurally while spiruchostatin A

contains a valine residue at C-4 position spiruchostatin B bears an isoleucine residue

Biologically both exhibited extremely potent inhibitory activity against HDAC1 (IC50 = 22ndash33

nM) whereas both were essentially inactive for HDAC6 (IC50 = 1400ndash1600 nM) There have

been three total syntheses of spiruchostatin A by Ganesan and co-workers in 2004138 Doi and co-

workers in 2006139 and Miller and co-workers in 2009140 The only one total synthesis of

spiruchostatin B was reported by Katoh and co-workers in 2009141

Scheme 33 representatively shows Ganesanrsquos total synthesis of spiruchostatin A138 They

synthesized β-hydroxy mercaptoheptenoic acid 320 using with the Nagaorsquos N-

acetylthiazolidinethione auxiliary under Vilarrasarsquos TiCl4 conditions142 with high

diastereoselectivity (synanti = 951) which was readily coupled with the free amine of the

peptide framework 323 In macrocyclization Yamaguchi macrolactonization proceeded in 53

yield Finally oxidation and TIPS deprotection completed the total synthesis of spiruchostatin A

88

Reagents and conditions (a) TiCl4 i-Pr2NEt CH2Cl2 ndash78 degC 30 min 84 (b) PfpOH EDACmiddotHCl DMAP CH2Cl2 0 degC 30 min 20 degC 4 h (c) LiCH2CO2CH3 THF ndash78 degC 45 min 66 (d) KBH4 MeOH ndash78 to 0 degC 50 min 70 (e) LiOH THFH2O (41) 0 degC 1 h (f) TceOH DCC DMAP CH2Cl2 0 degC to 25 degC 18 h 95 (g) TFA CH2Cl2 25 degC 3 h (h) Fmoc-D-Cys(STrt) PyBOP i-Pr2NEt MeCN 20 degC 20 min 74 (i) TIPSOTf 26-lutidine CH2Cl2 25 degC 3 h 93 (j) 5 Et2NHMeCN 20 degC 3 h (k) Fmoc-D-Ala PyBOP i-Pr2NEt MeCN 20 degC 1 h 82 (l) 323 5 Et2NHMeCN 20 degC 5 h (m) 320 DMAP CH2Cl2 0 degC then 20 degC 7 h 84 (n) Zn NH4OAcTHF 20 degC 5 h 71 (o) 246-trichlorobenzoyl chloride Et3N MeCNTHF 0 degC then 20 degC 1 h (p) DMAP toluene 50 degC 4 h 53 (q) I2 10 MeOHCH2Cl2 20 min 84 (r) HCl EtOAc ndash30 to 0 degC 3 h 77

Scheme 33 Synthesis of spiruchostatin A by Ganesan

89

315 Background of Largazole

3151 Discovery and Biological Activities of Largazole

The most recent sulfur-containing macrocyclic depsipeptide HDAC inhibitor largazole

was isolated from the marine cyanobacterium of Symploca sp from coastal Florida by Luesch

and co-workers in 2008143 From one Symploca extract from Key Largo Florida possessing

potent antiproliferative activity they isolated a new chemical entity termed as largazole for its

collection site (Key Largo) and structural feature (thiazole) using bioassay-guided fractionation

and HPLC (Figure 37)144145 The structural elucidation was confirmed by extensive 1D and 2D

NMR analysis and high-resolution and tandem mass spectroscopy Consequently Luesch and co-

workers could clearly establish its structure and absolute configuration through the degradation

analysis Largazole contains only one natural amino acid L-valine (black) one thiazole linearly

fused to a 4-methylthiazoline (blue) and 3-hydroxy-7-mercapto-hept-4-enoic acid capped as an

octanoyl thioester (red)146

Figure 37 The structure of largazole

With largazole from natural source in hand Luesch and co-workers attempted to assess if

it had any selectivity towards certain cancer cell types and any selectivity for cancer cells over

non-transformed cells because they reasoned that these would be the first differentiating factors

90

when assessing the compoundrsquos therapeutic potential as an anticancer agent146 As shown in

Table 32 it potently inhibited the growth of highly invasive transformed human mammary

epithelial cells (MDA-MB-231) in a dose-dependent manner (GI50 = 77 nM) and induced

cytotoxicity at a higher concentration (LC50 = 117 nM) while not being potent for nontransformed

murine mammary epithelial cells (NMuMG) and differentication (GI50 = 122 nM and LC50 = 272

nM) Compared with other natural products or drugs (paclitaxel actinomycin D and doxorubicin)

largazole might have a greater selectivity and was worthy of further study In addition it similarly

showed a selective tendency for transformed firoblastic osteosarcoma U2OS cells (GI50 = 55 nM

and LC50 = 94 nM) over nontransformed fibroblasts NIH3T3 (GI50 = 480 nM and LC50 gt 8 microM)

This promising result suggested that largazole preferentially targeted cancer cells over normal

cells145

Table 32 Growth inhibitory activity (GI50) of natural products145

MDA-MB-231 NMuMG U2OS NIH3T3

Largazole 77 nM 122 nM 55 nM 480 nM

Paclitaxel 70 nM 59 nM 12 nM 64 nM

Actinomycin D 05 nM 03 nM 08 nM 04 nM

Doxorubicin 310 nM 63 nM 220 nM 47 nM

Due to the limited amount of material from natural sources synthetic studies to provide

sufficient amounts of largazole were required for extensive biological studies including its mode

of action and target identification These efforts culminated in the first total synthesis by the

HongLuesch group150 followed by ten other total syntheses151ndash160 which will be discussed in

more detail later

91

Although the thioester functionality in largazole is unusual in the HDAC inhibitory

natural products such a thioester linkage could be hydrolyzed under the normal cellular

metabolism to release the thiol functionality suggesting that largazole is a prodrug Based on the

structural similarity between largazole and FK228 which is an already established HDAC

inhibitor largazole was hypothesized to be a HDAC inhibitor Figure 38 shows the structural

similarities between largazole and FK228 especially after the reduction of the disulfide bond in

FK228 and the hydrolysis of the thioester in largazole

Figure 38 Structural similarity between FK228 and largazole and modes of activation146

To prove the hypothesis of its mode of action HongLuesch and co-workers150 first

assessed the cellular HDAC activity upon treatment with largazole in HCT-116 cells found to

possess high intrinsic HDAC activity The result showed a decrease of HDAC activity in a dosendash

response manner and the IC50 for HDAC inhibition was closely corresponded with the GI50 of

92

largazole (Figure 39 Table 33) This correlation suggested that HDAC is the relevant target

responsible for its antiproliferative effect Additionally largazole showed 10-fold lower potency

(IC50 = 25 plusmn 11 nM) than largazole thiol (IC50 = 25 plusmn 14 nM) against HDAC1 in the in vitro

enzymatic assay supporting the hypothesis of prodrug activation of largazole150 This

comparative decrease in potency between largazole and largazole thiol was also reported by

Williams and co-workers152

Figure 39 Cellular activity of largazole in HCT-116 cells150

Table 33 GI50 and IC50 values for largazole and largazole free thiol (nM)150

HCT-116 growth inhibition

HCT-116 HDAC cellular assay

HeLa nuclear extract HDACs

largazole 44 plusmn 10 51 plusmn 3 37 plusmn 11 largazole thiol 38 plusmn 5 209 plusmn 15 42 plusmn 29

93

3152 Total Syntheses of Largazole

The remarkable potency and selectivity of largazole against cancer cells has prompted its

biological studies and total syntheses To date there have been eleven total syntheses of natural

largazole reported150ndash160 which have been extensively reviewed146148 The synthetic challenges

included enantioselective synthesis of the β-hydroxy acid subunit macrocylization of the sixteen-

membered cyclic core and formation of the thioester functionality Two main synthetic strategies

for the total synthesis of largazole are illustrated in Figure 310 macrolactamization III followed

by installation of the thioester side chain via cross-metathesis and incorporation of the S-protected

precursors to the linker chain followed by macrolactamization III andor acylation146

94

N S

BocHN

SN

MeO2C

OHO

NH2

OH

OOH

S NH

O O OSN

SNNH

O

O

Macrolactamization IHong de Lera XieTillekeratne Doi

Macrolactamization IICramer Williams Phillips JiangGanesan Ye Ghosh Forsyth

Cross-MetathesisHong Cramer Phillips Ghosh de LeraJulia Kocienski Olef inationJiang

Thiol DeprotectionAcylationWilliams Doi Ganesan YeXie Tillekeratne

OH

OOH

RSL-valine 4-methylthiazoline-thiazole-hydroxy acid

or+ +

H

O

RS OHHO

OOH

O

OOtBu

OOH

Aux

OO

R+ or or or

Asymmetr ic Aldol ReactionHong Williams Doi Ye XieEnzymatic ResolutionCramer Phillips GhoshNHC-mediated Acylation Forsyth

Figure 310 Strategies for the total synthesis of largazole146

For the synthesis of the β-hydroxy acid HongLuesch Williams Doi Ye and Xie used

Nagao asymmetric aldol reaction whereas Phillips Cramer and Ghosh took advantage of an

enzymatic resolution of t-butyl-3-hydroxypent-4-enoate Forsyth uniquely synthesized a fully

elaborated derivative of 3-hydroxy-7-(octanoylthio)hept-4-enoic acid using acylation of αβ-

epoxy-aldehyde via the mediation of an N-heterocyclic carbene (NHC) With all three subunits

each group combined them together to prepare macrocyclic core in two different sequences

95

macrolactamization I and II While HongLuesch de Lera Xie Tillekeratne and Doi prepared

largazole through the macrolactamization I the other groups synthesized it through the

macrolactamization II Although HongLuesch and Forsyth attempted the macrolactonization

reaction for the macrocyclic core this approach failed due to ring strain and possible elimination

of the β-hydroxy acid to a conjugated diene

For the installation of the thioester during the synthesis of largazole HongLuesch

Cramer Phillips Ghosh and de Lera utilized the cross-metathesis reaction using a higher ratio

(50 mol) of Grubbsrsquo 2nd generation catalyst because of the possible coordination of the sulfur

atom with the ruthenium catalyst Since Williams Doi Ganesan Ye Xie and Tillekeratne

incorporated the side chain as a thiotrityl or a thioester at the early stage removal of the trityl

group and acylation completed the synthesis of largazole

HongLuesch and co-workers completed the first total synthesis of largazole as shown in

Scheme 34 using the strategy of macrolactamization I and cross-metathesis150 Condensation of

nitrile 326 with (R)-2-methyl cysteine methyl ester 327161 gave the thiazoline-thiazole subunit

328 Removal of Boc protecting group followed by coupling with β-hydroxy acid 329162163

which came from Nagao asymmetric aldol reaction provided 330 in 94 yield Yamaguchi

esterification with N-Boc-L-valine set the stage for macrolactamization Subsequent hydrolysis

Boc deprotection and macrolactamization164ndash167 using HATUndashHOAt coupling reagents provided

macrocycle 332 in 64 yield for three steps The cross-metathesis in the presence of Grubbsrsquo 2nd

generation catalyst (50 mol) gave largazole in 41 yield

96

Reagents and conditions (a) 327 Et3N EtOH 50 degC 72 h 51 (b) TFA CH2Cl2 25 degC 1 h (c) 329 DMAP CH2Cl2 25 degC 1 h 94 for 2 steps (d) 246-trichlorobenzoyl chloride Et3N THF 0 degC 1 h then 330 DMAP 25 degC 10 h 99 (e) 05 N LiOH THF H2O 0 degC 3 h (f) TFA CH2Cl2 25 degC 2 h (g) HATU HOAt i-Pr2NEt CH2Cl2 25 degC 24 h 64 for 3 steps (h) Grubbsrsquo 2nd generation catalyst (50 mol ) toluene reflux 4 h 41 (64 BRSM)

Scheme 34 Synthesis of largazole by HongLuesch

Williams and co-workers utilized the macrolactamization II and thiol deprotection

acylation strategies which began with thiazolidinethione 334168 containing thiotrityl side chain

Substitution of auxiliary with TMSE ester followed by esterification with N-Fmoc-L-valine

provided diester 335 Deprotection of Fmoc protecting group and subsequent coupling with

thiazoline-thiazole subunit 336 gave 337 for the macrolactamization Removal of Boc and

TMSE protecting groups and macrolactamization using HATU coupling reagent provided the

macrocycle 338 in 77 yield For the formation of thioester removal of trityl group and

acylation with octanoyl chloride under standard conditions completed the synthesis of largazole

in 89 yield (Scheme 35)152

97

largazole

BocHN

SN

SN

HO2C

N

OH O S

S

Bn

TrtS

OTMSE

O O

TrtS

O

NHFmoc

NH

O OSN

SNNH

O

O

TrtS

OSN

SNNH

O

O

TrtS NHBoc

O OTMSE

334 335

336

337338

ab cd

ef gh

Reagents and conditions (a) TMSEOH imidazole CH2Cl2 83 (b) Fmoc-L-Val EDCI DMAP CH2Cl2 (c) Et2NH MeCN (d) 336 PyBOP i-Pr2NEt CH2Cl2 73 for 3 steps (e) TFA CH2Cl2 (f) HATU HOBt i-Pr2NEt CH2Cl2 77 for 2 steps (g) TFA i-Pr3SiH CH2Cl2 (h) octanoyl chloride Et3N CH2Cl2 89

Scheme 35 Synthesis of largazole by Williams

98

3153 Mode of Action of Largazole

Figure 311 Molecular docking of largazole thiol into an HDAC1 homology model146

As described in section 3151 mechanism of action of largazole is mediated by the

inhibition of HDAC enzymes and in the presence of plasma or cellular proteins largazole is

rapidly hydrolyzed to release largazole thiol a reactive species through a general protein-assisted

mechanism To figure out the interaction between largazole thiol and the HDAC enzymes several

groups have used molecular docking of largazole thiol into an HDAC1 homology modeling

(Figure 311)171174175 However to support this prediction reliably a real visualization of the

interaction between HDAC enzyme and largazole thiol should be required Recently

Christianson and co-workers reported the X-ray crystal structure of HDAC8 complexed with

largazole free thiol at 214 Aring resolution (Figure 312)149 It was the first structure of an HDAC

complex with a macrocyclic depsipeptide inhibitor It revealed that ideal thiolate-zinc

coordination geometry is the requisite chemical feature responsible for its exceptional affinity and

99

biological activity While the macrocyclic core underwent minimal conformational changes upon

binding to HDAC8 the enzyme required remarkable conformational changes to accommodate the

binding of largazole free thiol Then the side chain with a thiol functionality extended into the

active pocket site The overall metal coordination geometry was nearly tetrahedral with ligandndash

Zn2+ndashligand angles ranging between 1076ordm and 1118ordm This co-crystal structure of the HDAC8ndash

largazole free thiol complex provided a foundation for understanding structurendashactivity

relationships in a number of largazole analogues synthesized so far

Figure 312 Co-crystal structure of HDAC8ndashlargazole thiol complex149

3154 Syntheses of Largazole Analogues

In addition to eleven total syntheses reported to date numerous largazole analogues have

been synthesized to enhance potency and isoform selectivity based on structurendashactivity

relationship studies Structural substitutions took place at variable positions L-valine amino acid

100

NH of amide bond C9 methyl thiazoline thiazole (17R)-configuration (E)-geometry number

of carbons in the liker region ester bond and thioester (Figure 313)146

Figure 313 Structurendashactivity relationship studies of largazole146

The L-valine subunit of largazole could be substituted with various amino acids as in

Figure 313151155169 However they did not show any drastic change of activity which was

rationalized by the co-crystal structure of HDAC8ndashlargazole complex Since L-valine side chain

faces toward the solvent other amino acids and epimer (D-valine) does not affect on the

interactions between the enzyme and largazole so variability might be tolerated at this position149

Interestingly 2-epi-largazole presented more potency to inhibit prostate cancer cells (LNCaP and

PC-3)170

The thioester linker region has been one of the most extensively studied including Zn2+

binding moierty length of side chain olefin geometry or configuration at C17 Alteration of the

length cis configuration or (17S) stereochemistry resulted in significant loss of activity169171

Each modification would compromise the ideal zinc coordination geometry in the complex

Replacement of zinc binding moieties with thioacetyl aminobenzamide thioamide 2-thiomethyl

pyridine 2-thiomethyl thiophene 2-thiomethyl phenol or carboxylic acid did not enhance the

potency170172

101

It has been shown that the replacement of the methyl group of the 4-methylthiazoline

moiety with a hydrogen atom an ethyl or a benzyl group did not significantly affect its

activity170173 The HDAC8ndashlargazole complex proved that this methyl group is oriented parallel

to the protein surface However Christianson and co-workers suggested that longer and larger

substituents would possibly allow for the capture of additional interaction In addition structural

modification of 4-methylthiazoline might change the conformation of the macrocycle to affect its

binding affinity because the strained bithiazole analogue by Williams170 was 25ndash145 times less

active than largazole and the simplified dehydrobutyrine analogue by Ganesan155 showed

nanomolar HDAC inhibition (IC50 = 099 nM) Williams and co-workers reported the pyridine

analogue instead of the thiazole leading to 3ndash4 fold enhanced potency (IC50 = 032 nM)170 Also

they reported methyloxazolinendashoxazole analogue which showed slightly more potency (IC50 =

069 nM)170 Even though the crystal structure showed that the methylthiazoline-thiazole ring is

oriented away from the protein structure and faced toward the solvent it is possible that this

position could tolerate additional substitution and conformational change in macrocycle core

might have an effect on affinity

The rest of the analogues were the amide isostere174 and N-methyl analogues175 Although

the replacement of an oxygen with nitrogen had minimal effect such an analogue showed 4ndash9

times less potency against HDAC 1ndash3 N-methylated analogues were 100- to 1000-fold less

active which was explained by loss of a possible hydrogen bonding between the amide and the

thiazoline substructure leading to a conformational change

102


321 Synthetic Goals

The therapeutic potential of largazole is determined by its potency and selectivity as well

as pharmacokinetic properties However there have been only a few reports about its stability

HongLuesch and co-workers reported that gt99 of largazole is rapidly hydrolyzed to largazole

thiol in mouse serum within 5 min175 Ganesan and co-workers investigated that the largazole

thiol is relatively stable in murine liver homogenate with a half-life of 51 min at 37 degC155 These

results reveal the potential disadvantage of thioester prodrugs compared to disulfide prodrugs

such as FK228 approved by the FDA It has been reported that the half-lives of FK228 and

redFK228 were gt12 h and 054 h respectively in growth medium and 47 h and lt03 h in

serum147 Therefore we envisioned that the incorporation of a disulfide linkage in largazole would

improve the pharmacokinetic characteristics without the compromise of the potency and

selectivity

103

Figure 314 Schematic representation of HDLPndashTSA interaction113

Given that most HDAC inhibitors lack isoform selectivity we have been pursuing new

analogues which could display more isoform-selectivity To do this we focused on the linker

region without altering the macrocyclic core based on the co-crystal structure of HDLPndashTSA

which was reported by Pavletich and co-workers They presented that the walls of the enzyme

pocket are covered with hydrophobic and aromatic residues that are identical in HDAC1 such as

P22 G140 F141 F198 L265 and Y297 (Figure 314)113 Particularly phenyl groups of F141

and F198 face each other in parallel at a distance of 75 Aring making the narrowest portion of the

pocket Therefore we planned to substitute the olefin of the linker region with aromatic or

heteroaromatic rings because πndashπ stacking interaction would facilitate the enzymendashinhibitor

binding

104


Based on the rationale and goals mentioned earlier we attempted to synthesize two

different sets of largazole analogues to enhance pharmacokinetics and isoform-selectivity For the

first purpose we planned to synthesize both a disulfide homodimer and a hetero disulfide with

cysteine (Figure 315) We envisioned that those three analogues could be prepared from the

common macrocycle 338 using the standard oxidation conditions as shown in the synthesis of

FK228 FR901375 and spiruchostatins AB

Figure 315 Retrosynthetic analysis of disulfide analogues

Aiming for the isoform-selective analogues we designed phenyl and triazolyl analogues

in collaboration with the Luesch group based on the πndashπ stacking interaction between the enzyme

105

and inhibitors (Figure 316) Our common retrosynthetic analysis relies on the total synthesis of

natural largazole Thioester could be incorporated by trityl deprotection and acylation of

macrocylic core 342 Then we envisioned disconnection of the macrocycle 342 into the two

common units and one variable unit methylthiazoline-thiazole 328 L-valine 344 and various

hydroxy acids 343 Given the methylthiazoline-thiazole synthesis from prior efforts the

underlying synthetic challenge turned out to be the preparation of several aldehydes 345 for the

asymmetric aldol reaction

Figure 316 Retrosynthetic analysis of phenyl and triazolyl analogues

323 Synthesis of Disulfide Analogues

The synthesis commenced with the coupling of the Nagao aldol product 347138 with

methylthiazoline-thiazole 328176 to afford 348 in 91 yield Yamaguchi esterification of 348

106

and Fmoc-L-valine 344 provided the linear depsipeptide 349 Hydrolysis of 349 under basic

conditions (12 equiv 025 N LiOH THF 0 degC 2 h) followed by the deprotection of Fmoc group

and subsequent macrolactamization using HATU coupling reagent to afford macrocycle 338 in

60 for three steps (Scheme 36) This convergent route (51 overall yield for 6 steps) should be

broadly applicable to the large scale synthesis of natural largazole as well as its disulfide

analogues for further biological studies

def

N S

BocHN

NS

MeO2C

SN

SOOH

N S

NH

NS

MeO2C

OOHTrtS

TrtS

N S

NH

NS

OOO

R2R1

349 R1 = CO2Me R2 = NHFmoc

TrtS

N S

NH

NSO

OOO

NH

TrtS

ab

c

+

347328

348

338

Reagents and conditions (a) 328 TFA CH2Cl2 25 ordmC 2 h (b) 347 DMAP CH2Cl2 25 ordmC 3 h 91 for three steps (c) N-Fmoc-L-Valine 246-trichlorobenzoyl chloride Et3N 0 ordmC 1 h and then 348 DMAP THF 25 ordmC 2 h 94 (d) LiOH THFH2O 0 ordmC 15 h (e) Et2NH MeCN 25 ordmC 3 h (f) HATU i-Pr2NEt CH2Cl2 25 ordmC 18 h 60 for three steps

Scheme 36 Synthesis of common macrocycle core

As shown in Scheme 37 for the synthesis of largazole disulfide analogues (339 340

341) we utilized standard iodine oxidation conditions129 from a common macrocylic core

withwithout cysteine amino acids All three cases smoothly provided the desired disulfide

linkage in excellent yield (88ndash93) We expect that homodimer 339 would show very similar

potency in cellular assay with greater bioavailability Simultaneously we attempted to prepare

107

hetero disulfide analogue 340 with cysteine amino acid In addition free carboxylic acid

analogue 341 was synthesized to improve the water-solubility The evaluation of their biological

activities and pharmacokinetic characteristics are in progress by our collaborator the Luesch

group at Univ of Florida

a

S NH

O OSN

SN

O

NH

O

SNH

OOS N

SN

O

HN

O

b

NH

O OSN

SN

O

NH

O

SS

BocHN CO2tBu

c

NH

O OSN

SN

O

NH

O

SS

BocHN CO2H

NH

O OSN

SN

O

NH

O

TrtS

338

339

340

341

Reagents and conditions (a) I2 CH2Cl2MeOH (91) 25 ordmC 05 h 88 (b) Boc-Cys(Trt)-OtBu I2 CH2Cl2MeOH (91) 25 ordmC 05 h 93 (c) Boc-Cys(Trt)-OH I2 CH2Cl2MeOH (91) 25 ordmC 05 h 89

Scheme 37 Synthesis of disulfide analogues

108

324 Synthesis of Phenyl and Triazolyl Analogues

3241 Synthesis of Phenyl Analogues

To prepare various phenyl analogues the respective aldehydes are required First trityl

protection of 350 followed by the reduction of nitrile 351 provided aldehyde 345a in 91 for

two steps For the preparation of 345b three step sequence from 352 bromination trityl

protection and nitrile reduction afforded aldehyde 345b in 96 (Scheme 38)

Reagents and conditions (a) LiOH TrtSH EtOHH2O (31) 25 degC 5 h (b) DIBALH toluene 0 degC 1 h 91 for two steps (c) CBr4 PPh3 CH2Cl2 25 degC 15 h (d) LiOH TrtSH EtOHH2OTHF (311) 25 degC 2 h (e) DIBALH toluene 0 degC 2 h 96 for three steps

Scheme 38 Synthesis of aldehyde 345a and 345b

The synthesis of m-mercaptoethyl benzaldehyde 345c required a few more steps from

the commercially available 354 Stille coupling177178 of 3-bromobenzonitrile 354 with

tributylvinyltin in the presence of Pd(PPh3)4 and LiCl followed by hydroborationndashoxidation179

provided alcohol 356 along with a byproduct from partial reduction of nitrile 356180 Then

mesylation tritylation and reduction of nitrile 358 provided aldehyde 345c in 50 for three

steps (Scheme 39)

109

Reagents and conditions (a) tributylvinyltin LiCl Pd(PPh3)4 THF 70 degC 14 h 96 (b) BH3middotTHF THF 0 degC 1 h then 4 N NaOH 50 H2O2 25 degC 40 min 45 (c) MsCl Et3N CH2Cl2 0 degC 05 h (d) NaH TrtSH THFDMF 25 degC 16 h (e) DIBALH toluene 0 degC 1 h 50 for three steps

Scheme 39 Synthesis of aldehyde 345c

The last phenyl aldehyde 345d required for the aldol reaction is benzacetaldehyde

Initially we attempted the fourndashstep sequence as outlined in Scheme 310 Bromination of 359

and subsequent tritylation and reduction smoothly provided alcohol 362 The oxidation of

alcohol 362 to aldehyde 345d was thought to be trivial However various oxidation conditions

(DessndashMartin periodinane181 ParikhndashDoering oxidation182 and TPAP183) did not work well

Additionally we observed that some amount of benzaldehyde was formed due to oxidative

cleavage of carbonndashcarbon bond similar to the oxidation of substituted phenylethanol184

Simultaneously we also suspected that sulfur might be oxidized to sulfone or sulfoxide Due to

these reasons we planned to introduce other precursors for this aldehyde (Scheme 310)

110

Reagents and conditions (a) NBS (BzO)2 CCl4 reflux 4 h 52 (b) TrtSH LiOH EtOHTHFH2O (311) 25 ordmC 2 h 78 (c) LiAlH4 THF 0 ordmC 2 h 71

Scheme 310 Inital attempt for the synthesis of aldehyde 345d

Based on the previous results we envisioned that a nitrile would be one of the possible

precursors of the aldehyde Esterification of 363 and subsequent bromination and cyanation

afforded the nitrile 365 in 83 yield185 Then chemoselective reduction of ester 365 by

NaBH4186 bromination and tritylation smoothly proceeded to provide the nitrile 367 in 81

yield for three steps Then DIBALH reduction clearly and quantitatively converted nitrile 367 to

aldehyde 345d (Scheme 311) However it decomposed during column chromatography on silica

gel Therefore aldehyde 345d was used in the next step without purification

Reagents and conditions (a) SOCl2 MeOH reflux 1 h (b) NBS (BzO)2 MeCN reflux 5 h 90 for two steps (c) KCN MeOHH2O reflux 6 h 92 (d) NaBH4 MeOH THF 80 degC 16 h 88 (e) CBr4 PPh3 CH2Cl2 0 degC 05 h (f) LiOH TrtSH EtOHH2OTHF (311) 25 degC 2 h 92 for two steps (g) DIBALH toluene 0 degC 1 h

Scheme 311 Second attempt for the synthesis of aldehyde 345d

111

With the four phenyl aldehydes 345andashd and N-acetyl-thiazolidinethione 346 in hand

asymmetric aldol reaction provided the syn products 343andashd as the major products under

Vilarrasarsquos TiCl4 conditions142 For the benzacetaldehyde 334d the yield was not as great as the

others due to the instability of aldehyde 334d Then the coupling of the aldol products 343andashd

with methylthiazoline-thiazole 368 smoothly afforded amides 369andashd which were esterified

with Fmoc-L-valine under the Yamaguchi conditions to provide the linear depsipeptides 370andashd

Subsequent hydrolysis of 370andashd under basic condition (12 equiv 025 N LiOH THF 0 degC 2

h) deprotection of the Fmoc group and macrolactamization using HATU coupling reagent

afforded macrocycles 371andashd (Scheme 312)

Reagents and conditions (a) 346 TiCl4 i-Pr2NEt CH2Cl2 ndash78 ordmC 1 h then 345 ndash78 ordmC 1 h 39 (343a) 65 (343b) 70 (343c) 18 (343d) (b) 368 CH2Cl2 DMAP 25 ordmC 2 h 87 (343a) 94 (343b) 87 (343c) 85 (343d) (c) N-Fmoc-L-valine 246-trichlorobenzoyl chloride NEt3 0 ordmC 1 h and then 369 DMAP THF 25 ordmC 2 h 99 (343a) 83 (343b) 85 (343c) 93 (343d) (d) LiOH THFH2O (41) 0 ordmC 15 h (e) Et2NH MeCN 25 ordmC 3 h (f) HATU i-Pr2NEt CH2Cl2 25 ordmC 18 h 42 (343a) 48 (343b) 23 (343c) 39 (343d)

Scheme 312 Synthesis of phenyl macrocycle 371

112

With the macrocycles 371andashd in hand trityl deprotection and subsequent acylation with

octanoyl chloride successfully completed the synthesis of 373andashd (Scheme 313) The evaluation

of biological activities and HDAC isoform profiling of 373andashd are in progress in collaboration

with the Luesch group

N S

NH

NSO

OOO

NH

R1

N S

NH

NSO

OOO

NH

R2

a

XS XS

XS

XS

a b c d

R1 =R2 =R3 =

N S

NH

NSO

OOO

NH

R3

b

X = Trt

371a d 372a d 373a d

X = HX = n-C7H17CO

Reagents and conditions (a) TFA i-Pr3SiH CH2Cl2 25 ordmC 1 h 76 (343a) 83 (343b) 55 (343c) 84 (343d) (b) octanoyl chloride i-Pr2NEt CH2Cl2 0 ordmC 30 min 81 (343a) 91 (343b) 70 (343c) 98 (343d)

Scheme 313 Completion of largazole phenyl analogues

3242 Synthesis of Triazolyl Analogues

The synthesis of triazolyl aldehyde 379 commenced with the azidendashalkyne

cycloaddition187188 of 374 with 375 using a ruthenium catalyst189190 to afford the desired 15-

adduct 376 Then we attempted to oxidize alcohol 376 to aldehyde 379 under various oxidation

conditions (DessndashMartin periodinane ParikhndashDoering oxidation and TPAP) However all

attempts were not effective in providing the aldehyde 379 presumably due to the possible

oxidation of the sulfur atom Alternatively dimethyl acetal 378 was synthesized which would be

113

converted to aldehyde 379 by hydrolysis However standard hydrolysis conditions failed to give

the desired aldehyde 379 (Scheme 114)

Reagents and conditions (a) CpRuCl(PPh3)2 THF reflux 12 h 46 (376) and 64 (378)

Scheme 314 Attempt to the synthesis of triazolyl aldehyde 379

Since the oxidation and hydrolysis of triazolyl substrates turned out to be challenging the

synthesis of β-hydroxy acid commenced with chiral L-malic acid 380 Esterification and

regioselective reduction191 (BH3middotSMe2 and NaBH4) provided diol 382 which was followed by

selective tosylation and azidation to afford azide 384192 Ruthenium catalyzed azidendashalkyne

cycloaddition of 384 with alkyne 375 gave the 15-adduct 385 in 56 yield

114

a b

d e

cOH

O

MeO

NN

N

OH

TrtS

OMe

O

HO2C

OHOMe

O

CO2H

OH

OMe

O

OH

OH

OMe

O

OTs

OH

OMe

O

N3NN

N

OH

HS

OMe

O

AB

NOEH

NOE

f

380 381 382 383

384 385

386

Reagents and conditions (a) SOCl2 MeOH reflux 0 degC 1 h 84 (b) BH3middotSMe2 NaBH4 THF 0 deg 1 h (c) p-TsCl pyridine 0 degC 1 h (d) NaN3 DMF 80 degC 1 h 36 for three steps (e) 375 CpRuCl(PPh3)2 benzene reflux 12 h 56 (f) TFA i-Pr3SiH CH2Cl2 25 ordmC 1 h 89

Scheme 315 Synthesis of triazolyl β-hydroxy ester

With β-hydroxy ester 385 and methylthiazoline-thiazole 368 in hand hydrolysis of 385

followed by coupling with amine 368 afforded amide 388 in 85 yield for two steps

Subsequent Yamaguchi esterification hydrolysis Fmoc deprotection and macrolactamziation

which were already optimized for the synthesis of phenyl analogues afforded the macrocycle

core 391 in very low yield possibly due to the non-selective hydrolysis of the two ester group in

394 Therefore we considered an alternative ester to avoid the hydrolysis step using the 9-

fluorenylmethyl (Fm) protecting group which could readily be cleaved under mild conditions

(Et2NH or piperidine) As expected hydrolysis of 385 and coupling with Fm ester 387 smoothly

provided amide 389 in 89 yield for two steps Then Yamaguchi esterification (93 yield)

cleavage of Fm and Fmoc groups and macrolactamization using HATU coupling reagent

afforded macrocycle 391 in 27 yield for two steps Finally trityl deprotection of 391 and

subsequent acylation with octanoyl chloride successfully completed the synthesis of thioester

392 (Scheme 316)

115

ab c

de fg

NN

N

OH

TrtS

OMe

O

N S

NH

NS

RO2C

OOH

N

NNTrtS

N S

NH

NS

R

OO

N

NNTrtS

O

NHFmocN S

NH

NSO

OOO

NH

N

NNTrtS

N S

NH

NSO

OOO

NH

N

NNS

N S

TFA H2N

NS

RO2C

392

385

388 R = Me389 R = Fm

368 R = Me387 R = Fm

394 R = CO2Me390 R = CO2Fm

391

n-C7H15

O

Reagents and conditions (a) LiOH THFH2O (41) 25 degC 3 h (b) 387 PyBOP DMAP MeCN 25 degC 4 h 89 for two steps (c) N-Fmoc-L-Valine 246-trichlorobenzoyl chloride NEt3 0 ordmC 1 h and then alcohol DMAP THF 25 ordmC 2 h 93 (d) Et2NH MeCN 25 ordmC 3 h (e) HATU i-Pr2NEt CH2Cl2 25 ordmC 12 h 27 (f) TFA Et3SiH CH2Cl2 25 ordmC 1 h 72 (g) octanoyl chloride i-Pr2NEt CH2Cl2 0 ordmC 30 min 63

Scheme 316 Completion of the triazolyl analogue

33 Conclusion

In summary we investigated the synthesis of numerous largazole analogues in the pursuit

of improved pharmacokinetic characteristics and isoform-selectivity For the first goal we

synthesized three disulfide analogues because this disulfide linkage was expected to improve the

half-lives of the inhibitor in growth medium or serum as observed in pharmacokinetic studies of

FK228 The hydrophilic cysteine disulfide analogue 341 shows great promise to present similar

116

potency but greater bioavailability and water-solubility Currently pharmacokinetic studies are

underway in collaboration with the Luesch group at Univ of Florida

In order to improve the HDAC isoform-selectivity we designed and prepared four phenyl

and one triazolyl analogue based on the hypothesis of πndashπ stacking interaction between the

enzyme and the inhibitor During the synthesis of the triazolyl analogue we modified the route to

avoid the regioselective hydrolysis of the methyl ester by using the Fm ester This Fm protecting

group should be applicable to the synthesis of a diverse set of largazole analogues with increased

overall yield Further biological evaluations including HDAC isoform profiling with these

analogues are currently underway in collaboration with the Luesch group

117


Preparation of Amide 348

[Boc Deprotection] To a cooled (0 degC) solution of 328 (950 mg 2557 mmol) in CH2Cl2

(16 mL) was added dropwise TFA (40 mL) After stirring for 2 h at 25 degC the reaction mixture

was concentrated and washed with Et2O to afford the crude amine which was employed in the

next step without further purification

[Coupling] To a solution of crude amine in CH2Cl2 (50 mL) were added 347 (11 g

1957 mmol) in CH2Cl2 (10 mL) and DMAP (12 g 9785 mmol) After stirring for 3 h at 25 degC

the reaction mixture was quenched by the addition of H2O The layers were separated and the



chromatography (silica gel EtOAchexanesMeOH 10101) to afford 348 (12 g 91) 1H NMR

(500 MHz CDCl3) δ 791 (s 1 H) 740ndash741 (m 6 H) 726ndash729 (m 6 H) 719ndash722 (m 3 H)

555 (ddd J = 70 70 150 Hz 1 H) 542 (dd J = 55 150 Hz 1 H) 468 (dd J = 55 55 Hz 1

H) 445 (m 1 H) 386 (d J = 110 Hz 1 H) 379 (s 3 H) 326 (d J = 115 Hz 1 H) 244 (dd J

= 45 150 Hz 1 H) 238 (dd J = 80 150 Hz 1 H) 221 (dd J = 70 70 Hz 2 H) 206 (ddd J

= 70 70 70 Hz 2 H) 164 (s 3 H)

118

Preparation of Ester 349

To a cooled (0 degC) solution of Fmoc-L-Val-OH (919 mg 2709 mmol) in THF (50 mL)

were added dropwise 246-trichlorobenzoyl chloride (045 mL 2902 mmol) and Et3N (043 mL

3096 mmol) After stirring for 1 h at 0 degC 348 (13 g 1935 mmol) in THF (10 mL) and DMAP

(284 mg 2322 mmol) were added at 0 degC After stirring for 2 h at 25 degC the reaction mixture

was quenched by the addition of saturated NH4Cl solution The layers were separated and the

aqueous layer was extracted with EtOAc The combined organic layers were dried over


chromatography (silica gel EtOAchexanesMeOH 210 to 10101) to afford 349 (18 g 94)

1H NMR (500 MHz CDCl3) δ 788 (s 1 H) 775 (d J = 80 Hz 2 H) 757 (d J = 75 Hz 2 H)

738ndash739 (m 8 H) 726ndash732 (m 8 H) 719ndash722 (m 3 H) 683 (dd J = 60 60 Hz 1 H) 568

(ddd J = 70 70 150 Hz 1 H) 562 (m 1 H) 542 (dd J = 75 155 Hz 1 H) 527 (d J = 75

Hz 1 H) 469 (d J = 55 Hz 2 H) 435 (m 2 H) 419 (m 1 H) 407 (m 1 H) 385 (d J = 110

Hz 1 H) 377 (s 3 H) 323 (d J = 115 Hz 1 H) 257 (d J = 60 Hz 2 H) 218 (m 2 H) 204

(m 3 H) 163 (s 3 H) 090 (d J = 60 Hz 3 H) 085 (d J = 70 Hz 3 H)

119

Preparation of Macrocycle 338

[Hydrolysis] To a cooled (0 degC) solution of 349 (10 g 1007 mmol) in THFH2O (50

mL 41 002M) was added LiOH (025 M 483 mL 1208 mmol) After stirring for 15 h at 0 degC

the reaction mixture was acidified by KHSO4 solution (10 M) and diluted with EtOAc The

layers were separated and the aqueous layer was extracted with EtOAc The combined organic

layers were dried over anhydrous Na2SO4 and concentrated in vacuo to afford the crude

carboxylic acid which was employed in the next step without further purification

[Fmoc Deprotection] To a solution of crude carboxylic acid in MeCN (55 mL) was

added Et2NH (40 mL) at 25 degC After stirring for 3 h at 25 degC the reaction mixture was

concentrated in vacuo to afford the crude amine which was employed in the next step without

further purification

[Macrocyclization] To a solution of crude amine in CH2Cl2 (114 L 088 mM) were

added HATU (765 mg 2012 mmol) and i-Pr2NEt (053 mL 3018 mmol) at 25 degC After stirring

for 18 h at 25 degC the reaction mixture was concentrated The residue was dissolved in EtOAc and



purified by column chromatography (silica gel EtOAchexanesMeOH 10101) to afford 338

(450 mg 60 for 3 steps) 1H NMR (500 MHz CDCl3) δ 773 (s 1 H) 736ndash738 (m 6 H)

725ndash728 (m 6 H) 718ndash721 (m 4 H) 653 (dd J = 90 30 Hz 1 H) 571 (ddd J = 70 70

120

150 Hz 1 H) 562 (m 1 H) 540 (dd J = 70 155 Hz 1 H) 519 (dd J = 90 175 Hz 1 H)

456 (dd J = 35 90 Hz 1 H) 410 (dd J = 30 175 Hz 1 H) 402 (d J = 110 Hz 1 H) 326 (d

J = 110 Hz 1 H) 277 (dd J = 95 160 Hz 1 H) 265 (dd J = 30 160 Hz 1 H) 220 (m 2 H)

205 (m 3 H) 183 (s 3 H) 068 (d J = 65 Hz 3 H) 052 (d J = 65 Hz 3 H)

Preparation of Homodimer 339

N S

NH

NSO

OOO

NH

TrtS S NH

O OSN

SN

O

NH

O

SNH

OOS N

SN

O

HN

OI2

CH2Cl2MeOH(91)25 degC30 min

88

338 339

To a solution of 338 (110 mg 0149 mmol) in CH2Cl2MeOH (15 mL 91) was added I2

(76 mg 0298 mmol) at 25 degC After stirring for 30 min at 25 degC the reaction mixture was

quenched by the addition of saturated Na2S2O3 solution The layers were separated and the



chromatography (silica gel EtOAchexanesMeOH 551) to afford 339 (135 mg 88) [α]25D=

+231 (c 01 CHCl3) 1H NMR (500 MHz CDCl3) δ 776 (s 2 H) 717 (d J = 95 Hz 2 H) 640

(dd J = 90 30 Hz 2 H) 589 (ddd J = 160 75 70 Hz 2 H) 569 (m 2 H) 554 (dd J = 155

70 Hz 2 H) 524 (dd J = 175 95 Hz 2 H) 461 (dd J = 95 35 Hz 2 H) 421 (dd J = 175

35 Hz 2 H) 402 (d J = 115 Hz 2 H) 327 (d J = 110 Hz 2 H) 288 (dd J = 165 105 Hz 2

H) 272 (m 2 H) 271 (dd J = 70 70 Hz 4 H) 243 (m 4 H) 210 (m 2 H) 186 (s 6 H) 070

(d J = 70 Hz 6 H) 053 (d J = 70 Hz 6 H) 13C NMR (125 MHz CDCl3) δ 1737 16941

121

16907 16817 1647 1476 1329 1285 1243 846 721 579 434 412 406 378 343

319 244 190 168 HRMS (ESI) mz 9912456 [(M+H)+ C42H54N8O8S6 requires 9912462]

Preparation of Disulfide 340

To a solution of 338 (32 mg 0043 mmol) in CH2Cl2MeOH (4 mL 91) was added N-

Boc-Cys(STrt)-OtBu (223 mg 043 mmol) and I2 (220 mg 087 mmol) at 25 degC After stirring for

30 min at 25 degC the reaction mixture was quenched by the addition of saturated Na2S2O3 solution

The layers were separated and the aqueous layer was extracted with CH2Cl2 The combined



(31 mg 93) [α]25D= ndash97 (c 15 CHCl3) 1H NMR (400 MHz CDCl3) δ 776 (s 1 H) 716 (d J

= 92 Hz 1 H) 651 (d J = 72 Hz 1 H) 586 (ddd J = 152 72 70 Hz 1 H) 566 (m 1 H)

553 (dd J = 156 68 Hz 1 H) 530 (m 1 H) 527 (dd J = 176 92 Hz 1 H) 458 (dd J = 92

32 Hz 1 H) 443 (m 1 H) 426 (dd J = 176 28 Hz 1 H) 402 (d J = 112 Hz 1 H) 326 (d J

= 116 Hz 1 H) 315 (dd J = 136 48 Hz 1 H) 306 (dd J = 136 48 Hz 1 H) 285 (dd J =

164 100 Hz 1 H) 272 (dd J = 64 64 Hz 2 H) 268 (dd J = 136 24 Hz 1 H) 242 (ddd J

= 72 72 72 Hz 2 H) 208 (m 1 H) 185 (s 3 H) 146 (s 9 H) 143 (s 9 H) 068 (d J = 68

Hz 3 H) 050 (d J = 68 Hz 3 H) 13C NMR (100 MHz CDCl3) δ 1736 1697 1693 1689

1680 1646 1151 475 1325 1285 1243 844 827 799 720 578 538 433 418 411

122

404 376 342 317 284 280 243 189 167 HRMS (ESI) mz 7722537 [(M+H)+

C33H49N5O8S4 requires 7722537]



Boc-Cys(STrt)-OH (138 mg 0298 mmol) and I2 (151 mg 0596 mmol) at 25 degC After stirring

for 30 min at 25 degC the reaction mixture was quenched by the addition of saturated Na2S2O3

solution The layers were separated and the aqueous layer was extracted with CH2Cl2 The


residue was purified by column chromatography (silica gel EtOAchexanesMeOH 10101) to

afford 341 (19 mg 89) [α]25D= ndash3751 (c 08 CHCl3) 1H NMR (400 MHz CDCl3) δ 781 (s 1

H) 765 (dd J = 82 28 Hz 1 H) 706 (d J = 96 Hz 1 H) 578 (dd J = 160 36 Hz 1 H)

560 (m 2 H) 525 (dd J = 176 92 Hz 1 H) 500 (d J = 72 Hz 1 H) 471 (m 1 H) 464 (dd

J = 92 32 Hz 1 H) 416 (dd J = 176 36 Hz 1 H) 404 (d J = 112 Hz 1 H) 333 (d J =


257 (m 3 H) 218 (m 2 H) 183 (s 3 H) 141 (s 9 H) 075 (d J = 72 Hz 3 H) 053 (d J =

72 Hz 3 H) 13C NMR (100 MHz CD3OD) δ 1758 1746 1722 1703 1700 1682 1579

1480 1335 1300 1269 850 806 795 739 590 543 437 418 415 406 386 354

327 288 243 197 171 HRMS (ESI) mz 7161927 [(M+H)+ C29H41N5O8S4 requires

7161911]

123

Preparation of Aldehyde 345a

[Tritylation] To a solution of 350 (300 mg 1530 mmol) in EtOHH2O (100 mL 31)

were added TrtSH (846 mg 3060 mmol) and LiOH (74 mg 3060 mmol) at 25 degC After stirring

for 5 h at 25 degC the reaction mixture was concentrated The residue was dissolved in CH2Cl2 and

H2O The layers were separated and the aqueous layer was extracted with CH2Cl2 The combined


purified by column chromatography (silica gel EtOAchexanes 120) to afford 351 1H NMR

(400 MHz CDCl3) δ 744ndash747 (m 6H) 730ndash734 (m 9H) 724ndash728 (m 4H) 337 (s 2 H)

[Reduction] To a cooled (0 degC) solution of 351 in toluene (10 mL) was added DIBALH

(10M 30 mL 3060 mmol) After stirring for 1 h at 0 degC the reaction mixture was quenched by

the addition of HCl solution (10 M) and diluted with CH2Cl2 and H2O The layers were separated

and the aqueous layer was extracted with CH2Cl2 The combined organic layers were dried over


chromatography (silica gel EtOAchexanes 120) to afford 345a (550 mg 91 for 2 steps) 1H

NMR (500 MHz CDCl3) δ 993 (s 1 H) 769 (d J = 65 Hz 1 H) 757 (s 1 H) 746ndash748 (m 6

H) 736ndash740 (m 2 H) 727ndash732 (m 6 H) 722ndash725 (m 3 H) 341 (s 2 H)

Preparation of β-Hydroxy Amide 343a

124

To a cooled (ndash78 degC) solution of 346 (300 mg 1475 mmol) in CH2Cl2 (15 mL) was

added TiCl4 (10 M 16 mL 1622 mmol) After stirring for 5 min at ndash78 degC i-Pr2NEt (028 mL

1622 mmol) was added slowly The resulting mixture was stirred for 1 h at ndash78 degC before the

addition of 345a (514 mg 1302 mmol) in CH2Cl2 (5 mL) After stirring for 1 h at ndash78 degC the

reaction was quenched by the addition of saturated NH4Cl solution The layers were separated



chromatography (silica gel EtOAchexanes 15 to 13) to afford 343a (301 mg 39) 1H NMR

(500 MHz CDCl3) δ 749ndash750 (m 6 H) 733 (dd J = 75 75 Hz 1 H) 724ndash727 (m 5 H) 716

(s 1 H) 710 (m 1 H) 522 (m 1 H) 510 (dd J = 70 70 Hz 1 H) 372 (dd J = 25 175 Hz 1

H) 363 (dd J = 90 175 Hz 1 H) 344 (dd J = 80 115 Hz 1 H) 335 (s 2 H) 318 (d J =

40 Hz 1 H) 298 (d J = 110 Hz 1 H) 237 (m 1 H) 107 (d J = 70 Hz 3 H) 100 (d J = 65

Hz 3 H)

Preparation of Amide 369a

N S

BocHN

NS

MeO2C 1) TFA CH2Cl225 degC 2 h

N S

NH

NS

MeO2C

OOH2) DMAP CH2Cl2

25 degC 2 h87 for 2 steps

SN

SOOH

TrtS

TrtS

343a

328369a



125



[Coupling] To a solution of crude amine in CH2Cl2 (15 mL) were added 343a (300 mg

0502 mmol) in CH2Cl2 (10 mL) and DMAP (313 mg 2560 mmol) After stirring for 2 h at 25 degC




chromatography (silica gel EtOAchexanesMeOH 10101) to afford 369a (310 mg 87) 1H

NMR (500 MHz CDCl3) δ 786 (s 1 H) 744 (d J = 80 Hz 6 H) 729 (dd J = 80 80 Hz 6 H)

713ndash723 (m 5 H) 710 (s 1 H) 703 (d J = 65 Hz 1 H) 504 (dd J = 30 95 Hz 1 H) 469

(dd J = 60 160 Hz 1 H) 464 (dd J = 60 160 Hz 1 H) 418 (br s 1 H) 383 (d J = 150 Hz

1 H) 375 (s 3 H) 329 (s 2 H) 323 (d J = 110 Hz 1 H) 259 (dd J = 80 150 Hz 1 H) 253

(dd J = 45 150 Hz 1 H) 161 (s 3 H) 13C NMR (125 MHz CDCl3) δ 1736 1720 1680

1629 1482 1447 1434 1373 1296 12875 12856 1280 1268 1264 1244 1225 845

706 675 530 448 415 408 370 240

Preparation of Ester 370a


were added dropwise 246-trichlorobenzoyl chloride (63 microL 0403 mmol) and Et3N (60 microL

126

0429 mmol) After stirring for 1 h at 0 degC 369a (190 mg 0268 mmol) in THF (5 mL) and

DMAP (39 mg 0322 mmol) were added at 0 degC After stirring for 2 h at 25 degC the reaction

mixture was quenched by the addition of saturated NH4Cl solution The layers were separated

and the aqueous layer was extracted with EtOAc The combined organic layers were dried over


chromatography (silica gel EtOAchexanesMeOH 210 to 10101) to afford 370a (290 mg

99) 1H NMR (500 MHz CDCl3) δ 788 (s 1 H) 775 (d J = 70 Hz 2 H) 757 (m 2 H) 745

(d J = 75 Hz 6 H) 739 (m 2 H) 731 (dd J = 75 75 Hz 8 H) 718ndash725 (m 5 H) 713 (s 1

H) 707 (m 1 H) 652 (dd J = 55 55 Hz 1 H) 617 (dd J = 45 85 Hz 1 H) 522 (d J = 90

Hz 1 H) 470 (d J = 60 Hz 1 H) 438 (m 2 H) 420 (m 2 H) 385 (d J = 120 Hz 1 H) 378

(s 3 H) 328 (d J = 95 Hz 2 H) 324 (d J = 105 Hz 1 H) 289 (dd J = 85 150 Hz 1 H)

267 (dd J = 45 150 Hz 1 H) 163 (s 3 H) 084 (d J = 60 Hz 3 H) 070 (d J = 70 Hz 3 H)

Preparation of Macrocycle 371a

[Hydrolysis] To a cooled (0 degC) solution of 370a (230 mg 0223 mmol) in THFH2O

(11 mL 41 002 M) was added LiOH (025 M 107 mL 0268 mmol) After stirring for 15 h at

0 degC the reaction mixture was acidified by KHSO4 solution (10 M) and diluted with EtOAc The


127







[Macrocyclization] To a solution of crude amine in CH2Cl2 (253 mL 088 mM) were





purified by column chromatography (silica gel EtOAchexanesMeOH 10101) to afford 371a

(73 mg 42 for 3 steps) 1H NMR (500 MHz CDCl3) δ 777 (s 1 H) 744 (d J = 80 Hz 6 H)

730 (dd J = 80 80 Hz 6 H) 720ndash723 (m 4 H) 715 (s 1 H) 714 (d J = 80 Hz 1 H) 706

(d J = 75 Hz 1 H) 633 (dd J = 95 30 Hz 1 H) 607 (dd J = 75 25 Hz 1 H) 531 (dd J =

175 100 Hz 1 H) 455 (dd J = 90 30 Hz 1 H) 423 (dd J = 175 30 Hz 1 H) 406 (d J =


210 (m 1 H) 187 (s 3 H) 069 (d J = 70 Hz 3 H) 055 (d J = 70 Hz 3 H)

Preparation of Thiol 372a

128

To a cooled (0 degC) solution of 371a (21 mg 0027 mmol) in CH2Cl2 (10 mL) were added

TFA (015 mL) and i-Pr3SiH (12 microL 0054 mmol) After stirring for 2 h at 25 degC the reaction

mixture was concentrated in vacuo The residue was purified by column chromatography (silica

gel EtOAchexanesMeOH 15151) to afford 372a (11 mg 76) 1H NMR (500 MHz CDCl3)

δ 779 (s 1 H) 738 (s 1 H) 730 (m 3 H) 719 (d J = 80 Hz 1 H) 634 (dd J = 95 30 Hz 1

H) 614 (dd J = 115 25 Hz 1 H) 531 (dd J = 175 90 Hz 1 H) 457 (dd J = 90 35 Hz 1


330 (d J = 120 Hz 1 H) 309 (dd J = 160 105 Hz 1 H) 280 (dd J = 160 25 Hz 1 H) 206

(m 1 H) 191 (s 3 H) 177 (dd J = 80 80 Hz 1 H) 070 (d J = 65 Hz 3 H) 056 (d J = 70

Hz 3 H)

Preparation of Thioester 373a


octanoyl chloride (51 microL 0300 mmol) and i-Pr2NEt (105 microL 0600 mmol) After stirring for 05

h at 25 degC the reaction mixture was quenched by the addition of saturated NaHCO3 solution The


layers were dried over anhydrous Na2SO4 and concentrated in vacuo The residue was purified

by column chromatography (silica gel EtOAchexanesMeOH 10101) to afford 73a (32 mg

81) 1H NMR (500 MHz CDCl3) δ 778 (s 1 H) 717ndash729 (m 5 H) 640 (dd J = 95 30 Hz

1 H) 610 (dd J = 110 25 Hz 1 H) 531 (dd J = 175 100 Hz 1 H) 456 (dd J = 90 30 Hz

129

1 H) 424 (dd J = 175 30 Hz 1 H) 408 (s 2 H) 405 (d J = 110 Hz 1 H) 329 (d J = 115

Hz 1 H) 307 (dd J = 165 115 Hz 1 H) 277 (dd J = 165 25 Hz 1 H) 254 (dd J = 75 75

Hz 2 H) 209 (m 1 H) 190 (s 3 H) 165 (m 2 H) 127 (m 8 H) 086 (dd J = 65 65 Hz 3

H) 069 (d J = 65 Hz 3 H) 054 (d J = 70 Hz 3 H) 13C NMR (125 MHz CDCl3) δ 1989

1738 1696 1689 1681 1647 1476 1400 1386 12918 12887 1265 12478 12446

845 739 578 440 434 429 413 344 330 317 2902 2901 257 245 227 189 168

142 344 330 317 2902 2901

Preparation of Aldehyde 45b

[Bromination] To a solution of 352 (300 mg 2038 mmol) in CH2Cl2 (15 mL) were

added CBr4 (743 mg 2242 mmol) and PPh3 (588 mg 2242 mmol) at 25 degC After stirring for 15

h at 25 degC the reaction mixture was concentrated The residue was purified by column

chromatography (silica gel EtOAchexanes 120) to afford 353 1H NMR (500 MHz CDCl3) δ

761 (d J = 80 Hz 2 H) 733 (d J = 80 Hz 2 H) 358 (dd J = 75 75 Hz 2 H) 323 (dd J =

75 75 Hz 2 H)

[Tritylation] To a solution of 353 in EtOHTHFH2O (20 mL 311) were added TrtSH

(845 mg 3057 mmol) and LiOH (98 mg 4076 mmol) at 25 degC After stirring for 2 h at 25 degC

the reaction mixture was concentrated The residue was dissolved in CH2Cl2 and H2O The layers

were separated and the aqueous layer was extracted with CH2Cl2 The combined organic layers

were dried over anhydrous Na2SO4 and concentrated in vacuo to afford nitrile which was

employed in the next step without further purification

130

[Reduction] To a cooled (0 degC) solution of the crude nitrile in toluene (10 mL) was

added DIBALH (10M 30 mL 3057 mmol) After stirring for 2 h at 0 degC the reaction mixture

was quenched by the addition of HCl solution (10 M) and diluted with CH2Cl2 and H2O The



by column chromatography (silica gel EtOAchexanes 110) to afford 345b (800 mg 96 for 3

steps) 1H NMR (400 MHz CDCl3) δ 998 (s 1 H) 779 (d J = 80 Hz 2 H) 746ndash749 (m 6 H)

731ndash737 (m 6 H) 725ndash729 (m 3 H) 719 (d J = 80 Hz 2 H) 269 (dd J = 80 80Hz 2 H)

254 (dd J = 80 80 Hz 2 H)

Preparation of β-Hydroxy Amide 343b




addition of 345b (505 mg 1239 mmol) in CH2Cl2 (5 mL) After stirring for 1 h at ndash78 degC the




chromatography (silica gel EtOAchexanes 15 to 13) to afford 343b (490 mg 65) 1H NMR

(500 MHz CDCl3) δ 740 (d J = 75 Hz 6 H) 720ndash729 (m 11 H) 698 (d J = 75 Hz 2 H)

521 (dd J = 85 15 Hz 1 H) 510 (dd J = 70 70 Hz 1 H) 373 (dd J = 25 175 Hz 1 H)

131

359 (dd J = 90 175 Hz 1 H) 344 (dd J = 75 115 Hz 1 H) 309 (br s 1 H) 297 (d J =

115 Hz 1 H) 257 (dd J = 75 75 Hz 2 H) 244 (dd J = 80 80 Hz 2 H) 235 (m 1 H) 105

(d J = 70 Hz 3 H) 098 (d J = 70 Hz 3 H)

Preparation of Amide 369b





[Coupling] To a solution of crude amine in CH2Cl2 (5 mL) were added 343b (29 mg





chromatography (silica gel EtOAchexanesMeOH 10101) to afford 369b (32 mg 94) 1H


719ndash722 (m 5 H) 699 (dd J = 60 60 Hz 1 H) 694 (d J = 80 Hz 2 H) 506 (dd J = 100

30 Hz 1 H) 474 (dd J = 160 60 Hz 1 H) 468 (dd J = 160 55 Hz 1 H) 386 (d J = 115

132

Hz 1 H) 377 (s 3 H) 326 (d J = 115 Hz 1 H) 259 (dd J = 150 95 Hz 1 H) 256 (m 3 H)

242 (dd J = 75 75 Hz 2 H) 163 (s 3 H)

Preparation of Ester 370b

N S

NH

NS

OOO

R2R1

370b R1 = CO2MeR2 = NHFmoc

1) Fmoc-L-Val-OHEt3N246-trichlorobenozyl chlorideTHF 0 degC 1 h

2) 369b DMAP25 degC 2 h83

N S

NH

NS

MeO2C

OOH

TrtS TrtS369b



0687 mmol) After stirring for 1 h at 0 degC 369b (310 mg 0429 mmol) in THF (5 mL) and





chromatography (silica gel EtOAchexanesMeOH 210 to 10101) to afford 370b (370 mg

83) 1H NMR (500 MHz CDCl3) δ 788 (s 1 H) 775 (d J = 70 Hz 2 H) 757 (d J = 75 Hz

2 H) 738 (d J = 75 Hz 8 H) 725ndash731 (m 8 H) 720ndash722 (m 5 H) 694 (d J = 80 Hz 2 H)

662 (dd J = 60 60 Hz 1 H) 618 (dd J = 45 85 Hz 1 H) 525 (d J = 85 Hz 1 H) 469 (m

2 H) 438 (m 2 H) 420 (dd J = 70 70 Hz 2 H) 385 (d J = 110 Hz 1 H) 378 (s 3 H) 324

(d J = 115 Hz 1 H) 290 (dd J = 85 150 Hz 1 H) 270 (dd J = 45 150 Hz 1 H) 253 (dd J

= 75 75 Hz 2 H) 241 (m 2 H) 205 (m 1 H) 163 (s 3 H) 083 (d J = 70 Hz 3 H) 069 (d

J = 70 Hz 3 H)

133

Preparation of Macrocycle 371b

[Hydrolysis] To a cooled (0 degC) solution of 370b (370 mg 0354 mmol) in THFH2O






[Fmoc Deprotection] To a solution of the crude carboxylic acid in MeCN (15 mL) was




[Macrocyclization] To a solution of the crude amine in CH2Cl2 (400 mL 088 mM) were





purified by column chromatography (silica gel EtOAchexanesMeOH 10101) to afford 371b


723ndash727 (m 6 H) 714ndash721 (m 5 H) 692 (d J = 80 Hz 1 H) 643 (dd J = 96 32 Hz 1 H)

134


420 (dd J = 175 32 Hz 1 H) 403 (d J = 116 Hz 1 H) 327 (d J = 112 Hz 1 H) 305 (dd J

= 164 116 Hz 1 H) 268ndash273 (m 1 H) 250 (m 2 H) 240 (m 2 H) 208 (m 1 H) 188 (s 3

H) 066 (d J = 68 Hz 3 H) 051 (d J = 68 Hz 3 H)

Preparation of Thiol 372b

TFA i-Pr3SiHCH2Cl2 25 degC 2 h

83

N S

NH

NSO

OOO

NH

TrtS

N S

NH

NSO

OOO

NH

HS371b 372b

To a cooled (0 degC) solution of 371b (133 mg 0169 mmol) in CH2Cl2 (10 mL) were

added TFA (10 mL) and i-Pr3SiH (69 microL 0338 mmol) After stirring for 2 h at 25 degC the

reaction mixture was concentrated in vacuo The residue was purified by column chromatography

(silica gel EtOAchexanesMeOH 15151) to afford 372b (76 mg 83) 1H NMR (500 MHz

CDCl3) δ 779 (s 1 H) 727 (d J = 80 Hz 2 H) 717 (d J = 80 Hz 2 H) 633 (dd J = 95 30


Hz 1 H) 425 (dd J = 175 35 Hz 1 H) 407 (d J = 115 Hz 1 H) 330 (d J = 115 Hz 1 H)

310 (dd J = 165 110 Hz 1 H) 290 (dd J = 75 75 Hz 2 H) 277 (m 3 H) 210 (m 1 H)

191 (s 3 H) 139 (dd J = 80 80 Hz 1 H) 068 (d J = 70 Hz 3 H) 054 (d J = 65 Hz 3 H)

135

Preparation of Thioester 373b

To a cooled (0 degC) solution of 372b (60 mg 0109 mmol) in CH2Cl2 (10 mL) were added





by column chromatography (silica gel EtOAchexanesMeOH 10101) to afford 373b (67 mg



1 H) 456 (dd J = 95 30 Hz 1 H) 424 (dd J = 175 35 Hz 1 H) 406 (d J = 110 Hz 1 H)

329 (d J = 115 Hz 1 H) 307ndash313 (m 3 H) 284 (dd J = 75 75 Hz 2 H) 276 (dd J = 165

25 Hz 1 H) 255 (dd J = 75 75 Hz 2 H) 210 (m 1 H) 190 (s 3 H) 165 (m 2 H) 127 (m

8 H) 086 (dd J = 70 70 Hz 3 H) 068 (d J = 70 Hz 3 H) 054 (d J = 70 Hz 3 H) 13C

NMR (125 MHz CDCl3) δ 1995 1737 1696 1689 1681 1647 1475 1402 1347 1290

1262 1245 844 740 577 442 434 427 412 357 343 317 301 289 257 244 226

189 167 141

136

Preparation of Nitrile 355

To a suspension of 354 (500 mg 2746 mmol) and LiCl (835 mg 1970 mmol) in THF

(12 mL) was added Pd(PPh3)4 (50 mg 0043 mmol) at 25 degC After stirring for 1 h at 25 degC

tributylvinyltin (088 mL 3021 mmol) was added After heating at 70 degC for 14 h the reaction

mixture was diluted with EtOAc and filtered The filtrate was washed with 10 NaOH solution

twice The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo The

residue was purified by column chromatography (silica gel EtOAchexanes 130) to afford 355

(340 mg 96) 1H NMR (500 MHz CDCl3) δ 763 (s 1 H) 759 (d J = 80 Hz 1 H) 749 (d J

= 70 Hz 1 H) 740 (dd J = 75 75 Hz 1 H) 665 (dd J = 175 110 Hz 1 H) 579 (d J =

175 Hz 1 H) 536 (d J = 105 Hz 1 H)


To a cooled (0 degC) solution of 355 (330 mg 2555 mmol) in THF (12 mL) was added

BH3THF (10 M 31 mL 3066 mmol) After stirring for 1 h at 0 degC H2O (20 mL) was added

After stirring for 10 min NaOH (40 M 26 mL) and H2O2 (50 20 mL) were added After

stirring for 40 min the reaction mixture was diluted with EtOAc and H2O The layers were


137


chromatography (silica gel EtOAchexanes 12) to afford 356 (168 mg 45)

Preparation of Aldehyde 345c

CNHODIBALH toluene

0 degC 1 h TrtSO

50 for 3 steps

CN

1) MsCl Et3NCH2Cl20 degC 30 min TrtS

2) TrtSH NaHTHFDMF25 degC 16 h356 358 345c

[Mesylation] To a cooled (0 degC) solution of 356 (150 mg 1019 mmol) in CH2Cl2 (8

mL) were added MsCl (016 mL 2038 mmol) and Et3N (043 mL 3057 mmol) After stirring

for 05 h at 0 degC brine was added The layers were separated and the aqueous layer was


concentrated in vacuo to afford 357 which was employed in the next step without further

purification

[Tritylation] To a cooled (0 degC) solution of 357 in THFDMF (15 mL 41) were added

TrtSH (113 g 4076 mmol) and NaH (60 dispersion in mineral oil 163 mg 4076 mmol)

After stirring for 16 h at 25 degC the reaction mixture was quenched by the addition of saturated

NH4Cl solution The layers were separated and the aqueous layer was extracted with EtOAc The



(18 g 94) 1H NMR (400 MHz CDCl3) δ 745ndash769 (m 19 H) 280 (dd J = 76 76 Hz 2 H)

268 (dd J = 76 76 Hz 2 H)




138



chromatography (silica gel EtOAchexanes 130) to afford 345c (208 mg 50 for 3 steps) 1H

NMR (400 MHz CDCl3) δ 995 (s 1 H) 769 (d J = 76 Hz 1 H) 749 (s 1 H) 719ndash741 (m

17 H) 263 (dd J = 76 76 Hz 2 H) 247 (dd J = 76 76 Hz 2 H)

Preparation of β-Hydroxy Amide 343c




addition of 345c (61 mg 0149 mmol) in CH2Cl2 (3 mL) After stirring for 1 h at ndash78 degC the




chromatography (silica gel EtOAchexanes 15 to 13) to afford 343c (64 mg 70) 1H NMR

(400 MHz CDCl3) δ 740 (d J = 76 Hz 6 H) 724ndash731 (m 6 H) 717ndash723 (m 5 H) 702 (s 1

H) 691 (d J = 64 Hz 1 H) 521 (dd J = 92 24 Hz 1 H) 512 (dd J = 68 68 Hz 1 H) 373

(dd J = 28 172 Hz 1 H) 356 (dd J = 92 172 Hz 1 H) 346 (dd J = 80 116 Hz 1 H) 311

(br s 1 H) 301 (dd J = 116 08 Hz 1 H) 258 (m 2 H) 245 (m 2 H) 239 (m 1 H) 106 (d J

= 68 Hz 3 H) 099 (d J = 68 Hz 3 H)

139

Preparation of Amide 369c





[Coupling] To a solution of the crude amine in CH2Cl2 (10 mL) were added 343c (64 mg





chromatography (silica gel EtOAchexanesMeOH 10101) to afford 369c (65 mg 87) 1H

NMR (400 MHz CDCl3) δ 788 (s 1 H) 735ndash738 (m 6 H) 705ndash726 (m 12 H) 696 (s 1 H)

685 (d J = 72 Hz 1 H) 503 (dd J = 92 32 Hz 1 H) 466 (m 2 H) 383 (d J = 112 Hz 1 H)

374 (s 3 H) 323 (d J = 112 Hz 1 H) 255 (m 4 H) 240 (dd J = 76 76 Hz 2 H) 160 (s 3

H)

140

Preparation of Ester 370c

N S

NH

NS

OOO

R2R1

370c R1 = CO2MeR2 = NHFmoc


2) 3-69c DMAP25 degC 2 h85

N S

NH

NS

MeO2C

OOHTrtS TrtS

369c



0144 mmol) After stirring for 1 h at 0 degC 369c (65 mg 0090 mmol) in THF (5 mL) and





chromatography (silica gel EtOAchexanesMeOH 210 to 10101) to afford 370c (80 mg


2 H) 717ndash743 (m 21 H) 701 (s 1 H) 692 (m 1 H) 685 (m 1 H) 621 (dd J = 48 84 Hz 1

H) 538 (d J = 88 Hz 1 H) 468 (d J = 56 Hz 2 H) 430 (m 2 H) 423 (m 2 H) 387 (d J =

112 Hz 1 H) 380 (s 3 H) 326 (d J = 116 Hz 1 H) 293 (dd J = 88 148 Hz 1 H) 271 (dd

J = 48 152 Hz 1 H) 256 (m 2 H) 244 (m 2 H) 205 (m 1 H) 166 (s 3 H) 083 (d J = 68

Hz 3 H) 069 (d J = 64 Hz 3 H)

141

Preparation of Macrocycle 371c

[Hydrolysis] To a cooled (0 degC) solution of 370c (80 mg 0076 mmol) in THFH2O (4

mL 41 002 M) was added LiOH (025 M 036 mL 0091 mmol) After stirring for 2 h at 0 degC










added HATU (58 mg 0152 mmol) and i-Pr2NEt (40 microL 0228 mmol) at 25 degC After stirring for

24 h at 25 degC the reaction mixture was concentrated The residue was dissolved in EtOAc and



purified by column chromatography (silica gel EtOAchexanesMeOH 10101) to afford 371c

(14 mg 23 for 3 steps) 1H NMR (400 MHz CDCl3) δ 775 (s 1 H) 732ndash734 (m 6 H) 712ndash

727 (m 11 H) 705 (d J = 76 Hz 1 H) 697 (s 1 H) 682 (d J = 76 Hz 1 H) 625 (m 1 H)

142



= 160 116 Hz 1 H) 268 (dd J = 164 24 Hz 1 H) 249 (m 2 H) 237 (m 2 H) 206 (m 1

H) 184 (s 3 H) 063 (d J = 72 Hz 3 H) 049 (d J = 68 Hz 3 H)

Preparation of Thiol 372c

To a cooled (0 degC) solution of 371c (13 mg 0017 mmol) in CH2Cl2 (3 mL) were added



gel EtOAchexanesMeOH 20201) to afford 372c (5 mg 55) 1H NMR (500 MHz CDCl3) δ

780 (s 1 H) 728ndash732 (m 2 H) 724 (s 1 H) 718 (d J = 80 Hz 1 H) 713 (d J = 75 Hz 1

H) 633 (d J = 60 Hz 1 H) 615 (dd J = 105 20 Hz 1 H) 531 (dd J = 175 95 Hz 1 H)


J = 115 Hz 1 H) 310 (dd J = 165 100 Hz 1 H) 290 (dd J = 80 80 Hz 2 H) 280 (dd J =

165 25 Hz 1 H) 276 (ddd J = 80 80 80 Hz 2 H) 211 (m 1 H) 191 (s 3 H) 134 (dd J =

80 80 Hz 1 H) 070 (d J = 65 Hz 3 H) 057 (d J = 65 Hz 3 H)

143

Preparation of Thioester 373c

To a cooled (0 degC) solution of 372c (28 mg 00051 mmol) in CH2Cl2 (2 mL) were

added octanoyl chloride (5 microL 0026 mmol) and i-Pr2NEt (9 microL 0051 mmol) After stirring for

05 h at 25 degC the reaction mixture was quenched by the addition of saturated NaHCO3 solution




(24 mg 70) 1H NMR (500 MHz CDCl3) δ 779 (s 1 H) 732 (m 2 H) 728 (s 1 H) 716 (d



110 Hz 1 H) 330 (d J = 115 Hz 1 H) 306ndash312 (m 3 H) 282ndash288 (m 2 H) 276 (dd J =

165 30 Hz 1 H) 253 (dd J = 75 75 Hz 2 H) 211 (m 1 H) 191 (s 3 H) 164 (m 2 H)

127 (m 8 H) 088 (dd J = 70 70 Hz 3 H) 071 (d J = 65 Hz 3 H) 057 (d J = 70 Hz 3 H)

Preparation of Bromide 364

[Esterification] To a cooled (0 degC) solution of m-toluic acid (10 g 7345 mmol) in

MeOH (30 mL) was added SOCl2 (107 mL 1469 mmol) After refluxing for 1 h the reaction

144

mixture was concentrated The resulting mixture was diluted with H2O and CH2Cl2 The layers


were dried over anhydrous Na2SO4 and concentrated in vacuo to afford 3631 which was


[Bromination] To a solution of 3631 in MeCN (30 mL) were added NBS (196 g 1102

mmol) and Bz2O2 (178 mg 0735 mmol) After refluxing for 5 h the reaction mixture was

concentrated The resulting mixture was diluted with H2O and CH2Cl2 The layers were separated



chromatography (silica gel EtOAchexanes 130) to afford 364 (151 g 90 for 2 steps) 1H

NMR (400 MHz CDCl3) δ 805 (s 1 H) 795 (d J = 76 Hz 1 H) 757 (d J = 80 Hz 1 H) 741

(dd J = 76 76 Hz 1 H) 450 (s 2 H) 391 (s 3 H)


To a solution of 364 (570 mg 2488 mmol) in MeOHH2O (20 mL 31) was added KCN

(810 mg 1244 mmol) After refluxing for 5 h the reaction mixture was concentrated The

resulting mixture was diluted with H2O and CH2Cl2 The layers were separated and the aqueous

layer was extracted with CH2Cl2 The combined organic layers were dried over anhydrous

Na2SO4 and concentrated in vacuo The residue was purified by column chromatography (silica

gel EtOAchexanes 110) to afford 365 (366 mg 84) 1H NMR (400 MHz CDCl3) δ 797 (m

145

2 H) 752 (d J = 80 Hz 1 H) 744 (dd J = 80 80 Hz 1 H) 390 (s 3 H) 379 (s 2 H) 13C

NMR (100 MHz CDCl3) δ 1663 1323 1311 1305 12931 12927 12907 1175 523 234


To a solution of 365 (220 mg 1256 mmol) in THF (20 mL) was added NaBH4 (285 mg

7536 mmol) After stirring for 15 min MeOH (5 mL) was added The resulting mixture was

heated at 80 degC for 1 h then the reaction mixture was quenched by the addition of saturated




(163 mg 88) 1H NMR (500 MHz CDCl3) δ 735 (dd J = 75 75 Hz 1 H) 729 (s 1 H) 728

(d J = 80 Hz 1 H) 721 (d J = 80 Hz 1 H) 463 (s 2 H) 371 (s 2 H) 323 (br s 1 H)


[Bromination] To a cooled (0 degC) solution of 366 (450 mg 3058 mmol) in CH2Cl2 (30

mL) were added CBr4 (112 g 3363 mmol) and PPh3 (882 mg 3363 mmol) After stirring for 1

h at 0 degC the reaction mixture was diluted with H2O and CH2Cl2 The layers were separated and

the aqueous layer was extracted with CH2Cl2 The combined organic layers were dried over

146


chromatography (silica gel EtOAchexanes 110) to afford 366-1 1H NMR (500 MHz CDCl3)

δ 726ndash739 (m 4 H) 449 (s 2 H) 375 (s 2 H)

[Tritylation] To a solution of 366-1 in EtOHTHFH2O (30 mL 311) were added

TrtSH (127 g 4587 mmol) and LiOH (110 mg 4587 mmol) at 25 degC After stirring for 2 h at

25 degC the reaction mixture was concentrated The residue was dissolved in CH2Cl2 and H2O The



by column chromatography (silica gel EtOAchexanes 110) to afford 367 (114 g 92 for 2

steps) 1H NMR (400 MHz CDCl3) δ 748ndash751 (m 6 H) 731ndash736 (m 6 H) 724ndash728 (m 4 H)

716 (d J = 76 Hz 1 H) 712 (d J = 76 Hz 1 H) 704 (s 1 H) 367 (s 2 H) 336 (s 2 H)

Preparation of Aldehyde 345d

To a cooled (0 degC) solution of 367 (792 mg 1953 mmol) in toluene (20 mL) was added

DIBALH (10 M 29 mL 2930 mmol) After stirring for 1 h at 0 degC the reaction mixture was

quenched by the addition of HCl solution (10 M) and diluted with CH2Cl2 and H2O The layers


were dried over anhydrous Na2SO4 and concentrated in vacuo which was employed in the next

step without further purification due to the instability For the spectral analysis the residue was

purified by column chromatography (silica gel EtOAchexanes 110) to afford 345d 1H NMR

(400 MHz CDCl3) δ 969 (dd J = 24 Hz 1 H) 745ndash748 (m 6 H) 728ndash733 (m 6 H) 721ndash

147

726 (m 4 H) 708 (d J = 80 Hz 1 H) 705 (d J = 76 Hz 1 H) 693 (s 1 H) 361 (d J = 24

Hz 2 H) 332 (s 2 H)

Preparation of β-Hydroxy Amide 343d




addition of crude 345d (280 mg 0685 mmol) in CH2Cl2 (5 mL) After stirring for 1 h at ndash78 degC

the reaction was quenched by the addition of saturated NH4Cl solution The layers were separated



chromatography (silica gel EtOAchexanes 15 to 13) to afford 343d (77 mg 18 for 2 steps)

1H NMR (500 MHz CDCl3) δ 746ndash749 (m 6 H) 727ndash733 (m 6 H) 721ndash725 (m 3 H) 720

(dd J = 76 76 Hz 1 H) 707 (d J = 76 Hz 1 H) 703 (d J = 76 Hz 1 H) 698 (s 1 H) 514

(dd J = 68 68 Hz 1 H) 433 (m 2 H) 360 (dd J = 24 176 Hz 1 H) 349 (dd J = 80 112

Hz 1 H) 330 (s 2 H) 316 (dd J = 116 92 Hz 1 H) 300 (d J = 112 Hz 1 H) 279 (m 3 H)

233 (m 1 H) 104 (d J = 68 Hz 3 H) 096 (d J = 68 Hz 3 H)

148

Preparation of Amide 369d





[Coupling] To a solution of the crude amine in CH2Cl2 (10 mL) were added 343d (77

mg 0125 mmol) in CH2Cl2 (5 mL) and DMAP (76 mg 0625 mmol) After stirring for 2 h at

25 degC the reaction mixture was quenched by the addition of H2O The layers were separated and



chromatography (silica gel EtOAchexanesMeOH 10101) to afford 369d (78 mg 85) 1H

NMR (400 MHz CDCl3) δ 790 (s 1 H) 744ndash748 (m 6 H) 727ndash732 (m 6 H) 720ndash725 (m

3 H) 717 (dd J = 76 76 Hz 1 H) 698ndash703 (m 3 H) 694 (s 1 H) 472 (dd J = 160 60 Hz

1 H) 465 (dd J = 160 60 Hz 1 H) 419 (m 1 H) 384 (d J = 112 Hz 1 H) 379 (s 3 H)

329 (s 2 H) 324 (d J = 112 Hz 1 H) 277 (dd J = 132 76 Hz 1 H) 269 (dd J = 136 60

Hz 1 H) 241 (dd J = 152 28 Hz 1 H) 231 (dd J = 152 48 Hz 1 H) 161 (s 3 H)

149

Preparation of Ester 70d

N S

NH

NS

OOO

R2R1

370d R1 = CO2MeR2 = NHFmoc


2) 369d DMAP25 degC 2 h93

N S

NH

NS

MeO2C

OOH

TrtS TrtS

369d



0173mmol) After stirring for 1 h at 0 degC 369d (78 mg 0108 mmol) in THF (5 mL) and DMAP

(13 mg 0108 mmol) were added at 0 degC After stirring for 2 h at 25 degC the reaction mixture was

quenched by the addition of saturated NH4Cl solution The layers were separated and the



chromatography (silica gel EtOAchexanesMeOH 210 to 10101) to afford 370d (105 mg


2 H) 744ndash748 (m 6 H) 719ndash733 (m 14 H) 716 (dd J = 76 76 Hz 1 H) 698ndash703 (m 3

H) 693 (s 1 H) 621 (m 1 H) 541 (m 1 H) 470 (d J = 60 Hz 2 H) 430 (m 2 H) 423 (m 2

H) 387 (d J = 112 Hz 1 H) 378 (s 3 H) 331 (s 2 H) 325 (d J = 116 Hz 1 H) 277 (dd J

= 132 76 Hz 1 H) 269 (dd J = 136 60 Hz 1 H) 241 (dd J = 152 28 Hz 1 H) 231 (dd J

= 152 48 Hz 1 H) 206 (m 1 H) 167 (s 3 H) 084 (d J = 68 Hz 3 H) 067 (d J = 68 Hz 3

H)

150

Preparation of Macrocycle 371d

[Hydrolysis] To a cooled (0 degC) solution of 370d (105 mg 0101 mmol) in THFH2O (5















purified by column chromatography (silica gel EtOAchexanesMeOH 10101) to afford 371d

(31 mg 39 for 3 steps) 1H NMR (400 MHz CDCl3) δ 775 (s 1 H) 745ndash748 (m 6 H) 731

151

(dd J = 76 76 Hz 6 H) 719ndash725 (m 3 H) 718 (dd J = 76 76 Hz 1 H) 711 (d J = 96 Hz

1 H) 702ndash705 (m 2 H) 690 (s 1 H) 624 (dd J = 92 32 Hz 1 H) 542 (m 1 H) 521 (dd J

= 176 92 Hz 1 H) 468 (dd J = 92 32 Hz 1 H) 419 (dd J = 176 32 Hz 1 H) 405 (d J =


J = 128 92 Hz 1 H) 262 (dd J = 164 108 Hz 1 H) 253 (dd J = 164 28 Hz 1 H) 219 (m

1 H) 185 (s 3 H) 071 (d J = 72 Hz 3 H) 050 (d J = 68 Hz 3 H)

Preparation of Thiol 372d

To a cooled (0 degC) solution of 371d (19 mg 0024 mmol) in CH2Cl2 (3 mL) were added



gel EtOAchexanesMeOH 15151) to afford 372d (11 mg 84) 1H NMR (400 MHz CDCl3)

δ 776 (s 1 H) 719ndash725 (m 2 H) 716 (s 1 H) 707ndash712 (m 2 H) 627 (dd J = 96 28 Hz 1

H) 546 (m 1 H) 522 (dd J = 176 96 Hz 1 H) 469 (dd J = 96 32 Hz 1 H) 422 (dd J =

176 36 Hz 1 H) 405 (d J = 112 Hz 1 H) 371 (d J = 76 Hz 2 H) 327 (d J = 112 Hz 1 H)


260 (dd J = 164 32 Hz 1 H) 217 (m 1 H) 186 (s 3 H) 177 (dd J = 76 76 Hz 1 H) 070

(d J = 68 Hz 3 H) 050 (d J = 72 Hz 3 H)

152

Preparation of Thioester 373d

To a cooled (0 degC) solution of 372d (50 mg 00091 mmol) in CH2Cl2 (2 mL) were






(60 mg 98) 1H NMR (500 MHz CDCl3) δ 775 (s 1 H) 722 (dd J = 75 75 Hz 1 H) 716

(d J = 75 Hz 1 H) 708ndash712 (m 3 H) 628 (dd J = 90 35 Hz 1 H) 545 (m 1 H) 523 (dd J



H) 276 (dd J = 135 90 Hz 1 H) 267 (dd J = 170 105 Hz 1 H) 259 (dd J = 170 35 Hz

1 H) 256 (dd J = 75 75 Hz 2 H) 217 (m 1 H) 186 (s 3 H) 166 (m 2 H) 129 (m 8 H)

087 (dd J = 70 70 Hz 3 H) 071 (d J = 65 Hz 3 H) 051 (d J = 70 Hz 3 H)

153

Preparation of Azide 384

[Esterification] To a cooled (0 degC) solution of (L)-(ndash)-malic acid (20 g 1492 mmol) in

MeOH (30 mL) was added SOCl2 (217 mL 2983 mmol) After stirring for 1 h the reaction



were dried over anhydrous Na2SO4 and concentrated in vacuo The residue was purified by

column chromatography (silica gel EtOAchexanes 110) to afford 381 (203 g 84)

[Reduction] To a solution of 381 (203 g 1253 mmol) in THF (30 mL) was added

BH3middotSMe2 (131 mL 1379 mmol) at 25 degC After cooling to 0 degC NaBH4 (47 mg 1253 mmol)

was added to the reaction mixture After stirring for 1 h at 25 degC the reaction mixture was

quenched by the addition of MeOH (10 mL) and PTSA (238 mg 1253 mmol) The crude was

diluted with H2O and EtOAc The layers were separated and the aqueous layer was extracted


in vacuo to afford the crude 382 which was employed in the next step without further

purification

[Tosylation] To a cooled (0 degC) solution of 382 in pyridine (25 mL) was added p-TsCl

(263 g 1378 mmol) After stirring for 1 h at 25 degC the reaction mixture was quenched by the

addition of 1 N HCl and extracted with EtOAc The organic layer was dried over anhydrous

Na2SO4 and concentrated in vacuo to afford the crude 383 which was employed in the next step

without further purification

154

[Azidation] To a solution of 383 in DMF (15 mL) was added NaN3 (163 g 2506

mmol) After heating for 1 h at 80 degC the reaction mixture was concentrated and diluted with

EtOAc and H2O The layers were separated and the aqueous layer was extracted with EtOAc

The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo The


(108 g 30 for 3 steps) 1H NMR (400 MHz CDCl3) δ 418 (m 1 H) 369 (s 3 H) 331 (m 3

H) 251 (m 2 H) 13C NMR (100 MHz CDCl3) δ 1725 673 556 521 383

Preparation of Triazole 385

To a solution of 384 (280 mg 1759 mmol) and 375 (867 mg 2639 mmol) in benzene

(20 mL) was added CpRuCl(PPh3)2 (28 mg 0035 mmol) at 25 degC After refluxing for 12 h the


(silica gel EtOAchexanesMeOH 15151) to afford 385 (484 mg 56) 1H NMR (400 MHz

CDCl3) δ 740ndash742 (m 6 H) 721ndash732 (m 10 H) 443 (m 1 H) 423 (dd J = 140 36 Hz 1

H) 409 (dd J = 140 72 Hz 1 H) 370 (s 3 H) 259ndash266 (m 2 H) 246ndash266 (m 4 H) 13C

NMR (100 MHz CDCl3) δ 1720 1445 1368 1322 1296 1281 1269 6724 6708 5219

5206 385 304 228

155

Preparation of Thiol 386

To a cooled (0 degC) solution of 385 (47 mg 0096 mmol) in CH2Cl2 (6 mL) were added



gel EtOAchexanesMeOH 10101) to afford 386 (21 mg 89) 1H NMR (400 MHz CDCl3) δ

748 (s 1 H) 450 (m 1 H) 444 (dd J = 140 30 Hz 1 H) 430 (dd J = 140 70 Hz 1 H)

397 (br s 1 H) 370 (s 3 H) 304 (dd J = 65 65 Hz 2 H) 281 (ddd J = 75 75 75 Hz 2 H)

264 (dd J = 170 50 Hz 1 H) 255 (dd J = 170 80 Hz 1 H)


[Hydrolysis] To a solution of 385 (90 mg 0185 mmol) in THFH2O (6 mL 41) was

added LiOH (10 M 037 mL 0370 mmol) After stirring for 2 h at 25 degC the reaction mixture

was acidified by KHSO4 solution (10 M) and diluted with EtOAc The layers were separated and

the aqueous layer was extracted with EtOAc The combined organic layers were dried over

156

anhydrous Na2SO4 and concentrated in vacuo to afford the crude carboxylic acid which was


[Coupling] To a solution of the crude carboxylic acid and 387 (132 mg 0241 mmol) in

MeCN (15 mL) were added PyBOP (193 mg 0370 mmol) and DMAP (90 mg 0740 mmol) at

25 degC After stirring for 4 h at 25 degC the reaction mixture was concentrated The residue was

dissolved in EtOAc and the saturated NH4Cl solution The layers were separated and the aqueous

layer was extracted with EtOAc The combined organic layers were dried over anhydrous Na2SO4

and concentrated in vacuo The residue was purified by column chromatography (silica gel

EtOAchexanesMeOH 10101) to afford 389 (147 mg 89 for 2 steps) 1H NMR (400 MHz

CDCl3) δ 784 (s 1 H) 772 (dd J = 76 44 Hz 2 H) 758 (dd J = 76 32 Hz 2 H) 752 (dd J

= 56 56 Hz 1 H) 715ndash743 (m 19 H) 473 (dd J = 160 60 Hz 1 H) 467 (dd J = 168 60

Hz 1 H) 450 (d J = 64 Hz 2 H) 434 (m 1 H) 423 (dd J = 64 64 Hz 1 H) 369 (d J =

112 Hz 1 H) 320 (d J = 112 Hz 1 H) 258 (dd J = 76 76 Hz 2 H) 250 (dd J = 156 40





157

0251 mmol) After stirring for 1 h at 0 degC 389 (140 mg 0157 mmol) in THF (5 mL) and





chromatography (silica gel EtOAchexanesMeOH 15151 to 10101) to afford 390 (177 mg

93) 1H NMR (400 MHz CDCl3) δ 793 (s 1 H) 773 (dd J = 64 64 Hz 4 H) 761 (d J =

72 Hz 2 H) 754 (d J = 72 Hz 2 H) 719ndash741 (m 24 H) 559 (m 1 H) 529 (d J = 76 Hz 1

H) 477 (dd J = 60 60 Hz 2 H) 443ndash453 (m 4 H) 439 (dd J = 104 68 Hz 1 H) 433 (dd

J = 104 68 Hz 1 H) 424 (dd J = 68 68 Hz 1 H) 417 (dd J = 68 68 Hz 1 H) 393 (dd J

= 64 64 Hz 1 H) 374 (d J = 116 Hz 1 H) 319 (d J = 112 Hz 1 H) 274 (dd J = 148 60

Hz 1 H) 245ndash266 (m 6 H) 188 (m 1 H) 164 (s 3 H) 319 (d J = 64 Hz 6 H) 13C NMR

(100 MHz CDCl3) δ 1730 1714 1687 1685 1630 1566 1485 1444 14367 14361

14352 14139 14136 1365 1324 1296 1281 12791 12787 12719 12713 12695

12530 12521 12511 12505 1221 12010 12007 846 702 6748 6736 6724 599 489

471 468 417 413 381 3026 3019 241 227 189 180


1) Et2NH CH3CN25 degC 2 h

2) HATU i-Pr2NEtCH2Cl2 25 degC 12 h27 for 2 steps

390 R1 = CO2FmR2 = NHFmoc

N S

NH

NS

R1

OO

N

NNTrtS

O

R2

N S

NH

NS

OO

N

NNTrtS

O

NH

O

391

158

[Deprotection] To a solution of 390 (79 mg 0065 mmol) in MeCN (8 mL) was added

Et2NH (15 mL) at 25 degC After stirring for 2 h at 25 degC the reaction mixture was concentrated in

vacuo to afford the crude acid amine which was employed in the next step without further

purification

[Macrocyclization] To a solution of the crude acid amine in CH2Cl2 (74 mL 088 mM)

were added HATU (49 mg 0130 mmol) and i-Pr2NEt (34 microL 0195 mmol) at 25 degC After

stirring for 12 h at 25 degC the reaction mixture was concentrated The residue was dissolved in




afford 391 (14 mg 27 for 2 steps) 1H NMR (500 MHz CDCl3) δ 774 (s 1 H) 738 (d J = 75

Hz 6 H) 734 (s 1 H) 728 (dd J = 75 75 Hz 6 H) 721 (dd J = 70 70 Hz 3 H) 706 (d J =

100 Hz 1 H) 672 (dd J = 90 35 Hz 1 H) 531 (m 1 H) 521 (dd J = 175 90 Hz 1 H) 466


(dd J = 175 90 Hz 1 H) 401 (d J = 120 Hz 1 H) 328 (d J = 110 Hz 1 H) 278 (dd J =

160 30 Hz 1 H) 272 (dd J = 165 100 Hz 1 H) 268 (m 1 H) 258 (m 1 H) 246 (dd J =

70 70 Hz 2 H) 214 (m 1 H) 182 (s 3 H) 073 (d J = 70 Hz 3 H) 054 (d J = 65 Hz 3 H)


159





776 (s 1 H) 758 (s 1 H) 707 (d J = 96 Hz 1 H) 660 (dd J = 92 32 Hz 1 H) 543 (m 1


H) 463 (dd J = 148 36 Hz 1 H) 426 (dd J = 176 36 Hz 1 H) 401 (d J = 112 Hz 1 H)

329 (d J = 116 Hz 1 H) 303 (ddd J = 72 72 28 Hz 2 H) 289 (dd J = 168 32 Hz 1 H)

283 (m 2 H) 279 (dd J = 168 104 Hz 1 H) 216 (m 1 H) 184 (s 3 H) 158 (dd J = 76 76

Hz 1 H) 073 (d J = 68 Hz 3 H) 052 (d J = 68 Hz 3 H)

Preparation of Thioester 392


octanoyl chloride (4 microL 0024 mmol) and i-Pr2NEt (8 microL 0047 mmol) After stirring for 05 h at

25 degC the reaction mixture was quenched by the addition of saturated NaHCO3 solution The



by column chromatography (silica gel EtOAchexanesMeOH 10101) to afford 392 (20 mg

63) 1H NMR (500 MHz CDCl3) δ 775 (s 1 H) 755 (s 1 H) 709 (d J = 100 Hz 1 H) 671

160



Hz 1 H) 401 (d J = 115 Hz 1 H) 328 (d J = 110 Hz 1 H) 311 (m 2 H) 299 (m 2 H) 287


(m 1 H) 184 (s 3 H) 162 (m 2 H) 128 (m 8 H) 088 (dd J = 70 70 Hz 3 H) 074 (d J =

70 Hz 3 H) 055 (d J = 70 Hz 3 H)

161

References

1 Luch A Molecular Clinical and Environmental Toxicology Volume 1 Molecular Toxicology 2009 p 20

2 (a) Li J W-H Vederas J C Science 2009 325 161ndash165 (b) Nicolaou K C Sorensen E J Classics in Total Synthesis 1996 p 655 (c) Denis J -N Correa A Green A E J Org Chem 1990 55 1957ndash1959 (d) Nicolaou K C Guy R K Angew Chem Int Ed 1995 34 2079ndash2090

3 (a) Newman D J Cragg G M J Nat Prod 2007 70 461ndash477 (b) Roth B D Prog Med Chem 2002 40 1ndash22

4 Collins P W Djuric S W Chem Rev 1993 93 1533ndash1564

5 Corey E J Ann NY Acad Sci 1971 180 24ndash37

6 Corey E J Weinshenker N M Schaaf T K Huber W J Am Chem Soc 1969 91 5675ndash5677

7 Bonnett R Chem Rev 1963 63 573ndash605

8 Nicolaou K C Snyder S A P Natl Acad Sci USA 2004 101 11929ndash11936

9 Goumltschi E Hunkeler W Wild H-J Schneider P Fuhrer W Gleason J Eschenmoser A Angew Chem Int Ed 1973 12 910ndash912

10 Benfey O T Morris P J T Robert Burns Woodward Artist and Architect in the World of Molecules 2001 p 470

11 Paul D Lancet 2003 362 717ndash731

12 Thompson P D Clarkson P Karas R H JAMAndashJ Am Med Assoc 2003 289 1681ndash1690

13 Golomb B A Evans M A Am J Cardiovasc Drug 2008 8 373ndash418

14 Kang E J Lee E Chem Rev 2005 105 4348ndash4378

15 Nicolaou K C Ajito K Patron A P Khatuya H Richter P K Bertinato P J Am Chem Soc 1996 118 3059ndash3060

16 Nicolaou K C Patron A P Ajito K Richter P K Khatuya H Bertinato P Miller R A Tomaszewski M J ChemndashEur J 1996 2 847ndash868

17 Berger M Mulzer J J Am Chem Soc 1999 121 8393ndash8394

162

18 Mulzer J Berger M J Org Chem 2004 69 891ndash898

19 Paterson I Lombart H-G Allerton C Org Lett 1999 1 19ndash22

20 Fuumlrstner A Albert M Mlynarski J Matheu M J Am Chem Soc 2002 124 1168ndash1169

21 Fuumlrstner A Albert M Mlynarski J Matheu M DeClercq E J Am Chem Soc 2003 125 13132ndash13142

22 Poss C S Schreiber S L Acc Chem Res 1994 27 9ndash17

23 Tsunakawa M Komiyama N Tenmyo O Tomita K Kawano K Kotake C Konishi M Oki T J Antibiot 1992 45 1467ndash1471

24 Tsunakawa M Kotake C Yamasaki T Moriyama T Konishi M Oki T J Anitbiot 1992 45 1472

25 Arcamone F M Bertazzoli C Ghione M Scotti T G Microbiol 1959 7 207ndash216

26 Hammann P Kretzschmar G Tetrahedron 1990 46 5603ndash5608

27 Hammann P Kretzschmar G Seibert G J Antibiot 1990 43 1431ndash1440

28 Liu C M Jensen L Westley J W Siegel D J Antibiot 1993 46 350ndash352

29 Takahashi S Arai M Ohki E Chem Pharm Bull 1967 15 1651ndash1656

30 Drose S Bindseil K U Bowman E J Siebers A Zeek A Altendorf K Biochemistry 1993 32 3902ndash3906

31 Bindseil K U Zeeck A J Org Chem 1993 58 5487ndash5492

32 Stille J K Angew Chem Int Ed 1986 25 508ndash524

33 Allred G D Liebeskind L S J Am Chem Soc 1996 118 2748ndash2749

34 Carmely S Kashman Y Tetrahedron Lett 1985 26 511ndash514

35 Doi M Ishida T Kobayashi M Kitagawa I J Org Chem 1991 56 3629ndash3632

36 Kitagawa I Kobayashi M Katori T Yamashita M J Am Chem Soc 1990 112 3710ndash3712

37 Kobayashi M Tanaka J Katori T Kitagawa I Chem Pharm Bull 1990 38 2960ndash2966

38 Kobayashi M Tanaka J Katori T Matsura M Kitagawa I Tetrahedron Lett 1989 30 2963ndash2966

163

39 Kobayashi M Tanaka J Katori T Yamashita M Matsuura M Kitagawa I Chem Pharm Bull 1990 38 2409ndash2418

40 Bubb M R Spector I Bershadsky A D Korn E D J Biol Chem 1995 270 3463ndash3466

41 Inanaga J Hirata K Saeki H Katsuki T Yamaguchi M Bull Chem Soc Jpn 1979 52 1989ndash1993

42 Paterson I Yeung K Ward R A Smith J D Cumming J G Lamboley S Tetrahedron 1995 51 9467ndash9486

43 Irschik H Schummer D Gerth K Houmlfle G Reichenbach H J Antibiot 1995 48 26ndash30

44 Schummer D Irschik H Reichenbach H Houmlfle G Liebigs Ann Chem 1994 283ndash289

45 Inanaga I Hirata K Saeki H Katsuki T Yamaguchi M Bull Chem Soc Jpn 1979 52 1989ndash1993

46 Paterson I Yeung K S Ward J D Cumming J G Smith J D J Am Chem Soc 1994 116 9391ndash9392

47 Guindon Y Yoakim C Morton H E J Org Chem 1984 49 3912ndash3920

48 Hegde V R Puar M S Dai P Patel M Gullo V P Das P R Bond R W McPhail A T Tetrahedron Lett 2000 41 1351ndash1354

49 Goldstein J L Brown M S Arterioscler Thromb Vasc Biol 2009 29 431ndash438

50 Cheung L L Marumoto S Anderson C D Rychnovsky S D Org Lett 2008 10 3101ndash3104

51 Kang E J Cho E J Lee Y E Ji M K Shin D M Chung Y K Lee E J Am Chem Soc 2004 126 2680ndash2681

52 Kang E J Cho E J Ji M K Lee Y E Shin D M Choi S Y Chung Y K Kim J S Kim H J Lee S G Lah M S Lee E J Org Chem 2005 70 6321ndash6329

53 Soltani O De Brabander J K Org Lett 2005 7 2791ndash2793

54 Bolshakov S Leighton J L Org Lett 2005 7 3809ndash3812

55 Crimmins M T Vanier G S Org Lett 2006 8 2887ndash2890

56 Danishefsky S J Pearson W H J Org Chem 1983 48 3865ndash3866

164

57 Drouet K E Theodorakis E A J Am Chem Soc 1999 121 456ndash457

58 Song H Y Joo J M Kang J W Kim D S Jung C K Kwak H S Park J H Lee E Hong C Y Jeong S Jeon K J Org Chem 2003 68 8080ndash8087

59 Lee E Han H O Tetrahedron Lett 2002 43 7295ndash7296

60 Brown H C Bhat K S J Am Chem Soc 1986 108 5919ndash5923

61 Kubota K Leighton J L Angew Chem Int Ed 2003 42 946ndash948

62 Lewis M D Cha K C Kishi Y J Am Chem Soc 1982 104 4976ndash4978

63 Brown H C Jadhav P K J Am Chem Soc 1983 105 2092ndash2093

64 Hackman B M Lombardi P J Leighton J L Org Lett 2004 6 4375ndash4377

65 Zacuto M J Leighton J L J Am Chem Soc 2000 122 8587ndash8588

66 Zacuto M J OMalley S J Leighton J L Tetrahedron 2003 59 8889ndash8900

67 Chatterjee A K Choi T L Sanders D P Grubbs R H J Am Chem Soc 2003 125 11360ndash11370

68 Sanford M S Love J A Grubbs R H J Am Chem Soc 2001 123 6543ndash6544

69 Scholl M Ding S Lee C W Grubbs R H Org Lett 1999 1 953ndash956

70 Frick J A Klassen J B Bathe A Abramson J M Rapoport H Synthesis 1992 621ndash623

71 Akbutina F A Sadretdinov I F Vasileva E V Miftakhov M S Russ J Org Chem 2001 37 695ndash699

72 Lavalleacutee P Ruel R Grenier L Bissonnette M Tetrahedron Lett 1986 27 679ndash682

73 Kim H Park Y Hong J Angew Chem Int Ed 2009 48 7577ndash4581

74 Lee K Kim H Hong J Org Lett 2011 13 2722ndash2725

75 Roth G J Liepold B Muumlller S G Bestmann H J Synthesis 2004 59ndash62

76 Myers A G Yang B H Chen H McKinstry L Kopecky D J Gleason J L J Am Chem Soc 1997 119 6496ndash6511

77 Chain W J Myers A G Org Lett 2006 9 355ndash357

78 Paterson I Goodman J M Isaka M Tetrahedron Lett 1989 30 7121ndash7124

165

79 Ohtani I Kusumi T Kashman Y Kakisawa H J Am Chem Soc 1991 113 4092ndash4096

80 Nakata T Matsukura H Jian D Nagashima H Tetrahedron Lett 1994 35 8229ndash8232

81 Garber S B Kingsbury J S Gray B L Hoveyda A H J Am Chem Soc 2000 122 8168ndash8179

82 Gessler S Randl S Blechert S Tetrahedron Lett 2000 41 9973ndash9976

83 Fuwa H Noto K Sasaki M Org Lett 2010 12 1636ndash1639

84 Fustero S Jimenez D Sanchez-Rosello M del Pozo C J Am Chem Soc 2007 129 6700ndash6701

85 Legeay J C Lewis W Stockman R A Chem Commun 2009 2207ndash2209

86 Cai Q Zheng C You S L Angew Chem Int Ed 2010 49 8666ndash8669

87 Fustero S Monteagudo S Sanchez-Rosello M Flores S Barrio P del Pozo C ChemmdashEur J 2010 16 9835ndash9845


89 Paterson I Oballa R M Tetrahedron Lett 1997 38 8241ndash8244

90 Evans D A Ripin D H B Halstead D P Campos K R J Am Chem Soc 1999 121 6816ndash6826

91 Evans D A Chapman K T Carreira E H J Am Chem Soc 1988 110 3560ndash3578

92 Vijayasaradhi S Singh J Singh Aidhen I Synlett 2000 110ndash112

93 Hicks D R Fraser-Reid B Synthesis 1974 203

94 Miyaura N Suzuki A Chem Rev 1995 95 2457ndash2483

95 Soderquist J A Matos K Rane A Ramos J Tetrahedron Lett 1995 36 2401ndash2402

96 Fuumlrstner A Seidel G Tetrahedron 1995 51 11165ndash11176

97 Fuumlrstner A Nikolakis K Liebigs Ann 1996 2107ndash2113

98 Kenkichi S J Organomet Chem 2002 653 46ndash49

99 Uchiyama M Ozawa H Takuma K Matsumoto Y Yonehara M Hiroya K Sakamoto T Org Lett 2006 8 5517ndash5520

166

100 (a) Lin H Y Chen C S Lin S P Weng J R Med Res Rev 2006 26 397ndash413 (b) Kim D H Kim M Kwon H J J Biochem Mol Biol 2003 31 110ndash119 (c) Allfrey A G Faulkner R Mirsky A E P Natl Acad Sci USA 1964 51 786ndash794

101 Wade P A Hu Mol Genet 2001 10 693ndash698

102 Saha R N Pahan K Cell Death Differ 2005 13 539ndash550

103 Barnes P J Reduced Histone Deacetylase Activity in Chronic Obstructive Pulmonary Disease 2005 Chapter 242

104 Lucio-Eterovic A Cortez M Valera E Motta F Queiroz R Machado H Carlotti C Neder L Scrideli C Tone L BMC Cancer 2008 8 243ndash252

105 Blander G Guarente L Annu Rev Biochem 2004 73 417ndash435

106 Imai S Armstrong C M Kaeberlein M Guarente L Nature 2000 403 795ndash800

107 Marmorstein R Biochem Soc T 2004 32 904ndash909

108 (a) Annemieke JM Biochem J 2003 370 737ndash749 (b) Witt O Deubzer H E Milde T Oehme I Cancer Lett 2009 277 8ndash21

109 Wilson A J Byun D S Popova N Murray L B LItalien K Sowa Y Arango D Velcich A Augenlicht L H Mariadason J M J Biol Chem 2006 281 13548ndash13558

110 Tsuji N Nagashima K Wakisawa Y Koizumi K J Antibiot 1976 29 1ndash6

111 Yoshida M Kijima M Akita M Beppu T J Biol Chem 1990 265 17174ndash17179

112 Maier T S Beckers T Hummel R Feth M Muller M Bar T Volz J Novel Sulphonylpyrroles as Inhibitors of Hdac S Novel Sulphonylpyrroles 2009

113 Finnin M S Donigian J R Cohen A Richon V M Rifkind R A Marks P A Breslow R Pavletich N P Nature 1999 401 188ndash193

114 Duvic M Vu J Expert Opin Inv Drug 2007 16 1111ndash1120

115 Marks P A Breslow R Nat Biotech 2007 25 84ndash90

116 Garber K Nat Biotech 2007 25 17ndash19

117 Piekarz R L Frye A R Wright J J Steinberg S M Liewehr D J Rosing D R Sachdev V Fojo T Bates S E Clin Cancer Res 2006 12 3762ndash3773

118 Burton B S Am Chem J 1882 3 385ndash395

167

119 Rosenberg G CMLSndashCell Mol Life Sci 2007 64 2090ndash2103

120 (a) Crabb S J Howell M Rogers H Ishfaq M Yurek-George A Carey K Pickering B M East P Mitter R Maeda S Johnson P W M Townsend P Shin-ya K Yoshida M Ganesan A Packham G Biochem Pharm 2008 76 463ndash475 (b) Pringle R B Plant Physiol 1970 46 45ndash49

121 (a) Furumai R Komatsu Y Nishino N Khochbin S Yoshida M Horinouchi S P Natl Acad Sci USA 2001 98 87ndash92 (b) Singh S B Zink D L Polishook J D Dombrowski A W Darkin-Rattray S J Schmatz D M Goetz M A Tetrahedron Lett 1996 37 8077ndash8880

122 Ueda H Nakajima H Hori Y Fujita T Nishimura M Goto T Okuhara M J Antibiot 1994 47 301ndash310

123 Brownell J E Sintchak M D Gavin J M Liao H Bruzzese F J Bump N J Soucy T A Milhollen M A Yang X Burkhardt A L Ma J Loke H-K Lingaraj T Wu D Hamman K B Spelman J J Cullis C A Langston S P Vyskocil S Sells T B Mallender W D Visiers I Li P Claiborne C F Rolfe M Bolen J B Dick L R Mol Cell 2010 37 102ndash111

124 Li K W Wu J Xing W Simon J A J Am Chem Soc 1996 118 7237ndash7238

125 Greshock T J Johns D M Noguchi Y Williams R M Org Lett 2008 10 613ndash616

126 Wen S Packham G Ganesan A J Org Chem 2008 73 9353ndash9361

127 Carreira E M Singer R A Lee W J Am Chem Soc 1994 116 8837ndash8838

128 Castro B Dormoy J R Evin G Selve C Tetrahedron Lett 1975 14 1219ndash1222

129 Kamber B Hartmann A Eisler K Riniker B Rink H Sieber P Rittel W Helv Chim Acta 1980 63 899ndash915

130 Fujisawa Pharmaceutical Co Ltd Japan Jpn Kokai Tokkyo Koho JP 03141296 1991

131 Shigematsu N Ueda H Takase S Tanaka H Yamamoto K Tada T J Antibiot 1994 47 311ndash314

132 Ueda H Manda T Matsumoto S Mukumoto S Nishigaki F Kawamura I Shimomura K J Antibiot 1994 47 315ndash323

133 Blanchard F Kinzie E Wang Y Duplomb L Godard A Held W A Asch B B Baumann H Oncogene 2002 21 6264ndash6277

134 Nakajima H Kim Y B Terano H Yoshida M Horinouchi S Exp Cell Res 1998 241 126ndash133

168

135 Chen Y Gambs C Abe Y Wentworth P Janda K D J Org Chem 2003 68 8902ndash8905

136 Evans D A Sjogren E B Weber A E Conn R E Tetrahedron Lett 1987 28 39ndash42

137 Shin n Masuoka Y Nagai A Furihata K Nagai K Suzuki K Hayakawa Y Seto Y Tetrahedron Lett 2001 42 41ndash44

138 Yurek-George A Habens F Brimmell M Packham G Ganesan A J Am Chem Soc 2004 126 1030ndash1031

139 Doi T Iijima Y Shin-ya K Ganesan A Takahashi T Tetrahedron Lett 2006 47 1177ndash1180

140 Calandra N A Cheng Y L Kocak K A Miller J S Org Lett 2009 11 1971ndash1974

141 Takizawa T Watanabe K Narita K Oguchi T Abe H Katoh T Chem Commun 2008 1677ndash1679

142 Aiguadeacute J Gonzaacutelez A Urpiacute F Vilarrasa J Tetrahedron Lett 1996 37 8949ndash8952

143 Luesch H Moore R E Paul V J Mooberry S L Corbett T H J Nat Prod 2001 64 907ndash910

144 Montaser R Luesch H Future Med Chem 2011 3 1475ndash1489

145 Taori K Paul V J Luesch H J Am Chem Soc 2008 130 1806ndash1807

146 Hong J Luesch H Nat Prod Rep 2012 29 449ndash456

147 Furumai R Matsuyama A Kobashi N Lee K H Nishiyama N Nakajima H Tanaka A Komatsu Y Nishino N Yoshida M Horinouchi S Cancer Res 2002 62 4916ndash4921

148 (a) Li S Yao H Xu J Jiang S Molecules 2011 16 4681-4694 (b) Newkirk T L Bowers A A Williams R M Nat Prod Rep 2009 60 1293ndash1320

149 Cole K E Dowling D P Boone M A Phillips A J Christianson D W J Am Chem Soc 2011 133 12474ndash12477

150 Ying Y Taori K Kim H Hong J Luesch H J Am Chem Soc 2008 130 8455ndash8459

151 Zeng X Yin B Hu Z Liao C Liu J Li S Li Z Nicklaus M C Zhou G Jiang S Org Lett 2010 12 1368ndash1371

169

152 Bowers A West N Taunton J Schreiber S L Bradner J E Williams R M J Am Chem Soc 2008 130 11219ndash11222

153 Seiser T Kamena F Cramer N Angew Chem Int Ed 2008 47 6483ndash6485

154 Nasveschuk C G Ungermannova D Liu X Phillips A J Org Lett 2008 10 3595ndash3598

155 Benelkebir H Marie S Hayden A L Lyle J Loadman P M Crabb S J Packham G Ganesan A Bioorg Med Chem 2011 15 3650ndash3658

156 Ren Q Dai L Zhang H Tan W Xu Z Ye T Synlett 2008 2379ndash2383

157 Numajiri Y Takahashi T Takagi M Shin-ya K Doi T Synlett 2008 2483ndash2486

158 Wang B Forsyth C J Synthesis 2009 2873ndash2880

159 Ghosh A K Kulkarni S Org Lett 2008 10 3907ndash3909

160 Xiao Q Wang L-P Jiao X-Z Liu X-Y Wu Q Xie P J Asian Nat Prod Res 2010 12 940ndash949

161 Pattenden G Thom S M Jones M F Tetrahedron 1993 49 2131ndash2138

162 Nagao Y Hagiwara Y Kumagai T Ochiai M Inoue T Hashimoto K Fujita E J Org Chem 1986 51 2391ndash2393

163 Hodge M B Olivo H F Tetrahedron 2004 60 9397ndash9403

164 Hamada Y Shioiri T Chem Rev 2005 105 4441ndash4482

165 Li W R Ewing W R Harris B D Joullie M M J Am Chem Soc 1990 112 7659ndash7672

166 Jiang W Wanner J Lee R J Bounaud P Y Boger D L J Am Chem Soc 2002 124 5288ndash5290

167 Chen J Forsyth C J J Am Chem Soc 2003 125 8734ndash8735

168 Johns D M Greshock T J Noguchi Y Williams R M Org Lett 2008 10 613ndash616

169 Ying Y Liu Y Byeon S R Kim H Luesch H Hong J Org Lett 2008 10 4021ndash4024

170 Bowers A A West N Newkirk T L Troutman-Youngman A E Schreiber S L Wiest O Bradner J E Williams R M Org Lett 2009 11 1301ndash1304

170


172 Bhansali P Hanigan C L Casero R A Tillekeratne L M V J Med Chem 2011 54 7453ndash7463

173 Souto J A Vaz E Lepore I Poppler A C Franci G Alvarez R Altucci L de Lera A R J Med Chem 2010 53 4654ndash4667

174 Bowers A A Greshock T J West N Estiu G Schreiber S L Wiest O Williams R M Bradner J E J Am Chem Soc 2009 131 2900ndash2905

175 Liu Y Salvador L A Byeon S Ying Y Kwan J C Law B K Hong J Luesch H J Pharmacol and Exp Ther 2010 335 351ndash361


177 Milstein D Stille J K J Am Chem Soc 1978 100 3636ndash3638

178 Scott W J Crisp G T Still J K J Am Chem Soc 1984 106 4630ndash4632

179 Brown H C Unni M K J Am Chem Soc 1968 90 2902ndash2905

180 Lee B C Paik J-Y Chi D Y Lee K-H Choe Y S Bioconjugate Chem 2003 15 104ndash111

181 Dess D B Martin J C J Org Chem 1983 48 4155ndash4156

182 Tidwell T T Org React John Wiley amp Sons Inc 2004

183 Ley S V Norman J Griffith W P Marsden S P Synthesis 1994 639ndash666

184 Li M Johnson M E Synthetic Commun 1995 25 533ndash537

185 Pignataro L Carboni S Civera M Colombo R Piarulli U Gennari C Angew Chem Int Ed 2010 49 6633ndash6637

186 Poverenov E Gandelman M Shimon L J W Rozenberg H Ben-David Y Milstein D ChemndashEur J 2004 10 4673ndash4684

187 Tornoslashe C W Christensen C Meldal M J Org Chem 2002 67 3057ndash3064

188 Rostovtsev V V Green L G Fokin V V Sharpless K B Angew Chem Int Ed 2002 41 2596ndash2599

189 Zhang L Chen X Xue P Sun H H Y Williams I D Sharpless K B Fokin V V Jia G J Am Chem Soc 2005 127 15998ndash15999

171

190 Boren B C Narayan S Rasmussen L K Zhang L Zhao H Lin Z Jia G Fokin V V J Am Chem Soc 2008 130 8923ndash8930

191 Saito S Inaba T H Moriwake T Nishida R Fujii T Nomizu S Moriwake T Chem Lett 1984 1389ndash1392

192 Nakatani S Ikura M Yamamoto S Nishita Y Itadani S Habashita H Sugiura T Ogawa K Ohno H Takahashi K Nakai H Toda M Bioorg Med Chem 2006 14 5402ndash5422

193 (a) Nakao Y Yoshida S Matsunaga S Shindoh N Terada Y Nagai K Yamashita

J K Ganesan A van Soest R W M Fusetani N Angew Chem Int Ed 2006 45 7553ndash7557 (b) Maulucci N Chini M G MiccoS D Izzo I Cafaro E Russo A Gallinari P Paolini C Nardi M C Casapullo A Riccio R Bifulco G Riccardis F D J Am Chem Soc 2007 129 3007ndash3012

172

Biography

Heekwang Park was born on December 23 1976 in Seoul South Korea and spent most

of his childhood living in Seoul Following graduation from high school He received his

Bachelor of Science degree in Chemistry in February of 1999 and Master of Science degree in

analytical chemistry from Chung-Ang University South Korea in February of 2002 Then he had

worked as a junior research scientist at Bukwang Pharmaceuticals in South Korea in which his

major responsibility was drug discovery including small molecule synthesis analytical studies

and process development In the fall of 2007 he began his graduate career at Duke University and

received his Doctor of Philosophy in organic chemistry in May of 2012

Honors amp Awards

Duke University Graduate School Travel Grant 2011 Pelham Wilder Teaching Award 2008 Kathleen Zielek Fellowship Duke University 2011 University Award Chung-Ang University 1995 Departmental Merit Scholarship Chung-Ang University 1995

Publications

1 Byeon S B Park H Kim H Hong J Stereoselective synthesis of 26-trans-tetrahydropyrans via the primary amine-catalyzed oxa-conjugate addition reaction total synthesis of psymberin Org Lett 2011 13 5816ndash5819

2 Park H Kim H Hong J A formal synthesis of SCH 351448 Org Lett 2011 13 3742ndash3745

3 Harrington J M Park H Ying Y Hong J Crumbliss A L Characterization of iron(III) sequestration by an analog of the cytotoxic siderophore brasilibactin A Implications for the iron transport mechanism in mycobacteria Metallomics 2011 3 464ndash471

173

4 Woo S J Park H K Song K H Han T H Koo C H Improved process for the preparation of Clevudine as anti-HBV agent PCT publication WO2008069451 2008

5 Chung H J Lee J H Woo S J Park H K Koo C H Lee M G Pharmacokinetics of L-FMAUS a new antiviral agent after intravenous and oral administration to rats Contribution of gastrointestinal first-pass effect to low bioavailability Biopharm Drug Dispos 2007 28 187

6 Park H K Chang S K Selective Transport of Hg2+ Ions by Kemps Triacid-based Cleft Type Ionophores Bull Korean Chem Soc 2000 21 1052

Presentations

1 Park H Byeon S Hong J Total synthesis of Irciniastatin A (Psymberin) 242th ACS NC Local Meeting Raleigh NC United States September 30 2011

2 Park H Kim H Hong J synthesis of SCH 351448 242th ACS National Meeting Denver Colorado United States August 28-September 01 2011

3 Harrington J M Park H Ying Y Hong J Crumbliss A L Thermodynamic characterization of iron(III) and zinc binding by Brasilibactin A 238th ACS National Meeting Washington DC United States August 16-20 2009

4 Woo S J Park H K Koo C H Development of new nucleoside analog as anti-HBV agent 2002 Health Industry Technologies Exposition Korea Seoul December 13 2002

ABSTRACT


by

Heekwang Park


Date_______________________

Approved

___________________________


___________________________

Steven W Baldwin

___________________________

Barbara R Shaw

___________________________

Don M Coltart

An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of


2012


2012

iv

Abstract





















v









vi

Dedication


vii

Contents

Abstract iv

List of Tables x

List of Figures xi

Acknowledgements xx

1 Introduction 1




21 Introduction 6















viii







23 Conclusion 51



31 Introduction 74
















ix


33 Conclusion 115


References 161

Biography 172

x













Chapter 3




xi






Chapter 2










Chapter 3








xii










xiii

List of Schemes

Chapter 2





















Chapter 3


xiv
















xv




aq aqueous

Asp aspartic acid

br s broad singlet

Bn benzyl

BnBr benzyl bromide



t-Bu tert-butyl




CM cross metathesis



Cu copper


d doublet





xvi












ent enantiomer

eq equivalent

Et2O diethyl ether

EtOAc ethyl acetate






c-Hex cyclohexane



His histidine

xvii










Lys lysine

m multiplet


MeCN acetonitrile

MeOH methanol


min minute









xviii






q quartet


Rf retention factor

rt room temperature

s singlet

sat saturated



t triplet






THF tetrahydrofuran



TMS trimethylsilyl


xix



Tyr tyrosine


UV ultraviolet





xx

Acknowledgements





















1

1 Introduction















2
















3












4








levels







5





development










6


21 Introduction













world

7






8




N O

OOHOH

NH

O

F 2

Ca2+


O

OOHOH

2

Ca2+


N

NNSO2Me

F

OH

OOHOHN


O

O

HO O

O

H

H


O

OHCO2Na

HO

O

H


O

O

HO O

O

H

H

simvastatin (Zocor)

OH

OOHOH


N

F

3H2O







9










drugs











10

O

O

OH

Me

O

Me

Me

OH OH

MeO

O

O

OH

Me

O

Me

Me

HOHO

OMe

MeOH

MeO

OMe

Me

Me

Me

HO

OMe

OMeswinholide A

tartrolon B

O

Me

Me O

Me

O

O

MeOOH

O

Me

O

OHO

Me

OO

OO

O

HOOH

OH

OO

R

OOO

HOOH

OH

O

R

O

O

OHOH

OH

OH

O

OH

4

10

R =

cycloviracin B1

BNa

RO O

O

HO

OH O O

OOH

O

OR










11














12
















13














14

O

O

OTBS

Me

O

Me

Me

O O

MeO

O

OHMe

Me

OO

OMe

MeOTBS

MeO

OMe

Me

Me

Me

TBSO

OMe

OMe

OTBS

Me

O

MeO

PMP

PMP

O

HO

OTBS

Me

O

Me

Me

O O

MeO

O

OTMSMe

Me

OO

OMe

MeOTBS

MeO

OMe

Me

Me

Me

TBSO

OMe

OMe

OTBS

Me

O

MeO

PMP

PMP

OH

O

O

OTBS

Me

O

Me

Me

O O

MeO

O

O

TBSO

Me

O

Me

Me

OO

OMe

MeOTBS

MeO

OMe

Me

Me

Me

TBSO

OMe

OMe

swinholide A

PMP

PMP

ab

27

28 29

210

cd e






15
















16










17
















18















D +26 c 10 CHCl3)50

19









O

R1

OO

O O

OHOR2

O

NaO2C

OOH

O O O

CO2H

O O

HOO

HO

OH

H

H

H

H

H

H

H

Hcis

cis

cis

cis


BnMOMBnMOMSEM

R1 R2

H

H

H

H

SCH 351448 (214)

11




20














21





(Scheme 26)





22







O

TMSEO2C

OO

O O

OTBSOBn O

TMSEO2C

OOH

O O O

CO2TMSE

O O

HOO

BnO

OBn

H

H

H

H

H

H

H

H

H

H

H

H

O

TMSEO2C

OOH

O O O

CO2TMSE

O O

HOO

HO

OH

H

H

H

H

H

H

H

H

SCH 351448

a c

de f

2 27 2 28

2 29

2 22 +

OO

O O

2 30



23


O

BnO2C

OO

O O

OTBSOBn

ab cd

i k l o

O

BnO2C

OH

OHOBn

O

BnO2C

OOBnO

BnO2C

O

OCO2

tBu

CHOe h

NSi

Np-Br-C6H4

p-Br-C6H4

ClR

237 R= H238 R=Me

2 312 32

2 33 2 34

2 35 2 36

O

O O

O

2 39

+









24













25











26




14-syn-Aldol

O

O


O

TfO

O

O

O

O

O OHSS

O

HO

OH

OH

O

+ +

+ +

SS SS

TIPSO

TIPSO PMBO

OH

SS

PMBO


OH

OSS

TIPSO

O


OAc OTBS

O

O

O O

H

H

OH H

TIPSOSS

S

SO

NaO2C

OOH

O O O

CO2H

O O

HOO

HO

OH

H

H

H

H

H

H

H

Hcis

cis

cis

cis

214 244

245 246 247

248 249 250

251252

253


27









respectively




28













29









211)

30

MsO O

SS

PMBO O

SSO

PMBO O

SS

HO O

SS

TIPS TIPS

PMBO O

SS

TIPS

I O

SS

TIPS

a b c

d e

N O

OSS

OH

TIPS

H3C O

OSS

TIPS

N O

SS

CH3

TIPSO

H3C

Ph

OTf

f

g

h

263 265 266

267 268 269

270 271

272









31













conditions

32














33











34


OH O

OH

HTIPS

S

S

H3C

O

OH

HTIPS

S

S

+

conditions

O

274

272 275






35


36








37















38


















39




















40

292 R = TBS

OR OR

OO

O

OBn

H H

OR OR

O

OBn

H H

OH

OH O

OO

O

OBn

H Hab

291 R = TBS

cd

OR OR

OH

S

S

HO

OR OR

O

O

H

H

S

S

OH H

OBn

cis

OR OR

OH

H

S

S

gt201

H

OH H

OBn

OH H

OBn

OH

OR

H

OROBn

OO

O O

H

H

S

S

f g

h i

293 R = TBS 294 R = TBS

e

296 R = TBS

OH

OH

H

OHOBn

OO

O O

H

H

S

S

290

295 R = TBS

297

O

O O

OTf

247



41








42

OH

OR1

H

OR2OBn

OH

H

S

S

b

OH H

OBn OR1 OR2

OH

H

S

S

OH H

OBn OR1 OR2

OH

H

S

S

a

d


OH

OR

H

OOBn

OH

H

S

S

O

HO OTf

OH

OR

H

OOBn

OH

H

S

S

O

BnO OTf

c

2106 R = Bn 2107 R = Bn









217)

43











44









45










46










47


moiety (Scheme 219)

O OPMB

OH

S

S

HO

O OPMB

O

O

H

H

S

S

OH H

OBn

cis

O OPMB

OH

H

S

S

gt201

H

OH H

OBn

OH H

OBn

MOM

MOMMOMO OPMB

OH

OH H

OBnMOM

SS

OH

+

OTfO

O O

OH

O

H

OPMBOBn

OO

O O

H

H

S

S

MOM

OH

O

H

OPMBOH

O

O

O O

H

H

MOM

O OPMB

O

O

O O

H

H

OBnO2C

H H

MOM

a b c

+d e

fgh i

2117

252

2118 2119

2120

247 2121 2122

2123 2124

ref 53 SCH 351448

BnO2CO

H

O

H

OH

O

O

O O

H

H

MOM

13 7

9 11

15

192229



48















49


Carbon



(400 MHz) Hong


(400 MHz) Hong



3 351 (d) 350 (d) 107ndash128 (m) 106ndash128 (m)

4 139ndash165 (m) 138ndash165 (m) 22 306-313 (m) 306-313 (m)


139ndash165 (m) 138ndash165 (m) 24 678 (d) 678 (d)

6 139ndash165 (m) 138ndash165 (m) 25 728 (t) 738 (t)

107ndash128 (m) 106ndash128 (m) 26 693 (d) 693 (d)

















50


Carbon



De Brabander

(100 MHz) Hong


(100 MHz) Hong

(125 MHz) 1 1769 1769 22 344 344

2 469 469 23 1484 1484

3 824 824 24 1254 1254

4 366 366 25 1353 1352

5 238 238 26 1153 1153

6 320 320 27 1122 1122

7 a 752 751 28 1604 1604

8 414 413 29 1573 1573

9 736 736 30 1051 1051

10 391 391 1-OCH2Ph 1366 1366

11 717 717 1286 1286

12 372 372 1281 1281

13 273 273 1279 1279

14 253 253 1-OCH2Ph 663 663

15 a 778 778 2-Me 214 213

16 319 319 2-Me 207 207

17 239 239 9-OCH2OCH3 962 962

18 317 317 9-OCH2OCH3 560 559

191 785 784 12-Me 153 153

20 343 343 30-Me 259 259


51

23 Conclusion


















52














(s 3H) 13C NMR (125 MHz CDCl3) δ 1391 1379 1285 12776 12756 1144 800 785



53












2023 1391 1283 12741 12737 814 769 735 732 500 385 315 246 238 215








2018 1390 1282 12743 12734 767 731 728 685 444 383 283 249 215 201 188

54


















C6H6) δ 1772 1765 1433 1429 1283 1280 1270 1265 1084 760 7574 7565

749 694 692 578 361 353 3114 3111 300 297 2697 2694 2577 2560

55

















56


















57



2135 1389 1283 12742 12736 1088 821 788 772 758 732 693 679 481 466

427 383 321 311 284 269 257 249 236 216 210 162 IR (neat) 3478 1709 1368














3H) 13C NMR (125 MHz CDCl3) δ 1389 1283 12752 12748 1086 823 8014 773 765

732 723 708 696 424 3895 3881 3834 324 312 283 270 258 249 236 218 211

58


requires 4932524]
















59


6333762]


OH

O

H

OOBn

PMP

OO2113

OH

O

H

OHOBn

DIBALtoluene

+

OH

OH

H

OPMBOBn

2114 2115O

OO

O

PMB

ndash20 degC 1 h72

[21142115 = 31]













60



12742 1138 1086 821 798 793 773 763 733 720 695 688 553 439 3845 3838

358 324 317 290 270 258 249 237 216 211 143 IR (neat) 3501 1516 1250 cmndash1









NMR (125 MHz CDCl3) δ 1593 1392 1305 1296 1283 12742 12736 1139 1087 816

772 766 747 739 733 722 704 696 554 396 3891 3868 356 323 312 283 271

259 250 240 216 207 154


OH

OH

H

OPMBOBn

2114O

O

(R) or (S)-MTPA-Cl

Et3N DMAPCH2Cl2

OH

O

H

OPMBOBn(R)(S)-MTPA

1

2 2

39

12

16

1717

OO

25 degC 2 h



61






3H)









(R)ndash ester 3244 0892 0829 3140 3429 3965 1401 1353 0795


Preparation of 2116

62














088 (s 3H) 13C NMR (125 MHz CDCl3) δ 1591 1393 1314 1293 1282 12733 12726

1137 1087 962 817 791 772 764 745 7322 7318 709 696 558 553 428 386

358 349 323 319 293 271 258 250 241 2145 2127 139 IR (neat) 1514 1246 1034


63















12734 12727 1137 961 817 789 772 745 7331 7319 726 708 668 558 553 428

386 357 349 323 314 291 250 241 2143 2124 141 IR (neat) 3418 1456 1250 739


64
















13C NMR (125 MHz CDCl3) δ 1591 1393 1314 1293 1282 12733 12725 1138 962

817 791 772 745 7324 7317 709 558 553 526 471 428 386 358 347 323 308


6213753 [(M+Na)+ C36H54O7 requires 6213762]

65


















1314 1293 1282 12732 12722 1262 1137 961 817 790 772 745 7325 7314 707

691 584 558 553 519 447 428 386 373 362 356 347 323 290 2646 2625 2503

66




Addition Reaction














1293 1282 12731 12721 1137 962 817 792 772 745 7321 7314 7303 708 685

67

558 553 491 478 4320 4290 4278 386 358 348 339 323 288 2600 2593 2581


















68



(s 3H) 13C NMR (125 MHz CDCl3) δ 1590 1394 1315 1293 1282 12734 12723 1137

962 817 805 793 772 745 7322 7317 7315 712 708 705 558 553 480 432 429

421 386 358 348 340 323 289 2603 2593 (2 carbons) 255 250 241 214 212



Preparation of 2121











69








MHz CDCl3) δ 1590 1589 1566 1394 1349 1315 1294 1291 1282 12737 12725

1259 1169 1143 1138 1056 962 939 818 806 792 772 746 7325 7320 727 719

708 558 554 482 436 429 422 386 358 348 341 323 289 269 2608 2602 2586









70







(s 3H) 13C NMR (125 MHz CDCl3) δ 1602 1591 1571 1483 1351 1308 1298 1252

1151 1137 1120 1049 963 837 789 780 777 754 732 707 702 556 553 422

380 364 3481 (2 carbons) 3427 3424 320 3169 (2 carbons) 291 271 2572 2562 250


[(M+Na)+ C45H68O10 requires 7914705]


71

























72











1367 1353 1315 1294 1286 12800 12791 1253 1153 1138 1122 1051 963 821

793 782 779 750 732 707 661 558 554 469 429 366 359 350 347 344 3201

3182 (2 carbons) 292 273 2585 2576 2570 2390 2382 222 203 138 IR (neat) 1737


Preparation of 2124




73









MHz CDCl3) δ 1769 1604 1573 1484 1366 1352 1286 1281 1279 1254 1153 1122

1051 962 824 784 778 751 736 717 663 559 469 413 391 372 366 344 343

320 319 317 283 273 259 258 253 239 238 213 207 153 IR (neat) 3521 1733


74


31 Introduction



















75









deacetylation

76













77


















78



















79




















80






occur117








and ovarian cancer










81











82








malaria in mice121c









83
















84











85










86



FR901375

O O O

NHHN

OTBS

ONH

O

NHO

STr

STr

O OHCO2H

NHHN

OTBS

ONH

O

NHO

STr

STr

CO2MeNH2

HNOTBS

ONH

O

NHO

STr

O

O

Bn

O

Cl

H

O STr

O

O

Bn

O

Cl

OH STrOH STr

HO2C

CO2Me

HNOTBS

OFmocHN

STr

CO2H

HNOH

310

312 313

310 315 316

317 318

311

h k

bc

d g

a+

opn

lm







87






















88



89


















90











cells145











more detail later

91













92













93










94

N S

BocHN

SN

MeO2C

OHO

NH2

OH

OOH

S NH

O O OSN

SNNH

O

O





OH

OOH


or+ +

H

O

RS OHHO

OOH

O

OOtBu

OOH

Aux

OO

R+ or or or









95





















96












97

largazole

BocHN

SN

SN

HO2C

N

OH O S

S

Bn

TrtS

OTMSE

O O

TrtS

O

NHFmoc

NH

O OSN

SNNH

O

O

TrtS

OSN

SNNH

O

O

TrtS NHBoc

O OTMSE

334 335

336

337338

ab cd

ef gh



98














99













100










PC-3)170







potency170172

101





















102


321 Synthetic Goals











selectivity

103











binding

104











105












106







def

N S

BocHN

NS

MeO2C

SN

SOOH

N S

NH

NS

MeO2C

OOHTrtS

TrtS

N S

NH

NS

OOO

R2R1


TrtS

N S

NH

NSO

OOO

NH

TrtS

ab

c

+

347328

348

338








107





a

S NH

O OSN

SN

O

NH

O

SNH

OOS N

SN

O

HN

O

b

NH

O OSN

SN

O

NH

O

SS

BocHN CO2tBu

c

NH

O OSN

SN

O

NH

O

SS

BocHN CO2H

NH

O OSN

SN

O

NH

O

TrtS

338

339

340

341



108














steps (Scheme 39)

109












110












111












112





N S

NH

NSO

OOO

NH

R1

N S

NH

NSO

OOO

NH

R2

a

XS XS

XS

XS

a b c d

R1 =R2 =R3 =

N S

NH

NSO

OOO

NH

R3

b

X = Trt

371a d 372a d 373a d

X = HX = n-C7H17CO










113










114

a b

d e

cOH

O

MeO

NN

N

OH

TrtS

OMe

O

HO2C

OHOMe

O

CO2H

OH

OMe

O

OH

OH

OMe

O

OTs

OH

OMe

O

N3NN

N

OH

HS

OMe

O

AB

NOEH

NOE

f

380 381 382 383

384 385

386















392 (Scheme 316)

115

ab c

de fg

NN

N

OH

TrtS

OMe

O

N S

NH

NS

RO2C

OOH

N

NNTrtS

N S

NH

NS

R

OO

N

NNTrtS

O

NHFmocN S

NH

NSO

OOO

NH

N

NNTrtS

N S

NH

NSO

OOO

NH

N

NNS

N S

TFA H2N

NS

RO2C

392

385

388 R = Me389 R = Fm

368 R = Me387 R = Fm

394 R = CO2Me390 R = CO2Fm

391

n-C7H15

O



33 Conclusion






116










117

















= 70 70 70 Hz 2 H) 164 (s 3 H)

118















(m 3 H) 163 (s 3 H) 090 (d J = 60 Hz 3 H) 085 (d J = 70 Hz 3 H)

119




















120




205 (m 3 H) 183 (s 3 H) 068 (d J = 65 Hz 3 H) 052 (d J = 65 Hz 3 H)


N S

NH

NSO

OOO

NH

TrtS S NH

O OSN

SN

O

NH

O

SNH

OOS N

SN

O

HN

OI2


88

338 339













121

16907 16817 1647 1476 1329 1285 1243 846 721 579 434 412 406 378 343















= 72 72 72 Hz 2 H) 208 (m 1 H) 185 (s 3 H) 146 (s 9 H) 143 (s 9 H) 068 (d J = 68


1680 1646 1151 475 1325 1285 1243 844 827 799 720 578 538 433 418 411

122

404 376 342 317 284 280 243 189 167 HRMS (ESI) mz 7722537 [(M+H)+
















1480 1335 1300 1269 850 806 795 739 590 543 437 418 415 406 386 354


7161911]

123


















124













Hz 3 H)


N S

BocHN

NS


N S

NH

NS

MeO2C

OOH2) DMAP CH2Cl2


SN

SOOH

TrtS

TrtS

343a

328369a



125














1629 1482 1447 1434 1373 1296 12875 12856 1280 1268 1264 1244 1225 845

706 675 530 448 415 408 370 240




126


















127


















210 (m 1 H) 187 (s 3 H) 069 (d J = 70 Hz 3 H) 055 (d J = 70 Hz 3 H)


128










Hz 3 H)










129





1738 1696 1689 1681 1647 1476 1400 1386 12918 12887 1265 12478 12446

845 739 578 440 434 429 413 344 330 317 2902 2901 257 245 227 189 168

142 344 330 317 2902 2901







75 75 Hz 2 H)







130









254 (dd J = 80 80 Hz 2 H)












131



(d J = 70 Hz 3 H) 098 (d J = 70 Hz 3 H)















132


242 (dd J = 75 75 Hz 2 H) 163 (s 3 H)


N S

NH

NS

OOO

R2R1




N S

NH

NS

MeO2C

OOH

TrtS TrtS369b















J = 70 Hz 3 H)

133




















134




H) 066 (d J = 68 Hz 3 H) 051 (d J = 68 Hz 3 H)



83

N S

NH

NSO

OOO

NH

TrtS

N S

NH

NSO

OOO

NH

HS371b 372b










135














NMR (125 MHz CDCl3) δ 1995 1737 1696 1689 1681 1647 1475 1402 1347 1290

1262 1245 844 740 577 442 434 427 412 357 343 317 301 289 257 244 226

189 167 141

136










175 Hz 1 H) 536 (d J = 105 Hz 1 H)







137




CNHODIBALH toluene

0 degC 1 h TrtSO

50 for 3 steps

CN








purification








268 (dd J = 76 76 Hz 2 H)




138





17 H) 263 (dd J = 76 76 Hz 2 H) 247 (dd J = 76 76 Hz 2 H)














= 68 Hz 3 H) 099 (d J = 68 Hz 3 H)

139















H)

140


N S

NH

NS

OOO

R2R1



2) 3-69c DMAP25 degC 2 h85

N S

NH

NS

MeO2C

OOHTrtS TrtS

369c













J = 48 152 Hz 1 H) 256 (m 2 H) 244 (m 2 H) 205 (m 1 H) 166 (s 3 H) 083 (d J = 68

Hz 3 H) 069 (d J = 64 Hz 3 H)

141




















142



= 160 116 Hz 1 H) 268 (dd J = 164 24 Hz 1 H) 249 (m 2 H) 237 (m 2 H) 206 (m 1

H) 184 (s 3 H) 063 (d J = 72 Hz 3 H) 049 (d J = 68 Hz 3 H)











80 80 Hz 1 H) 070 (d J = 65 Hz 3 H) 057 (d J = 65 Hz 3 H)

143

















144












(dd J = 76 76 Hz 1 H) 450 (s 2 H) 391 (s 3 H)








145


NMR (100 MHz CDCl3) δ 1663 1323 1311 1305 12931 12927 12907 1175 523 234















146



δ 726ndash739 (m 4 H) 449 (s 2 H) 375 (s 2 H)


















147


Hz 2 H) 332 (s 2 H)














233 (m 1 H) 104 (d J = 68 Hz 3 H) 096 (d J = 68 Hz 3 H)

148

















149


N S

NH

NS

OOO

R2R1




N S

NH

NS

MeO2C

OOH

TrtS TrtS

369d















H)

150



















151






1 H) 185 (s 3 H) 071 (d J = 72 Hz 3 H) 050 (d J = 68 Hz 3 H)











(d J = 68 Hz 3 H) 050 (d J = 72 Hz 3 H)

152















153















purification






154















NMR (100 MHz CDCl3) δ 1720 1445 1368 1322 1296 1281 1269 6724 6708 5219

5206 385 304 228

155








264 (dd J = 170 50 Hz 1 H) 255 (dd J = 170 80 Hz 1 H)






156


















157













(100 MHz CDCl3) δ 1730 1714 1687 1685 1630 1566 1485 1444 14367 14361

14352 14139 14136 1365 1324 1296 1281 12791 12787 12719 12713 12695

12530 12521 12511 12505 1221 12010 12007 846 702 6748 6736 6724 599 489

471 468 417 413 381 3026 3019 241 227 189 180





N S

NH

NS

R1

OO

N

NNTrtS

O

R2

N S

NH

NS

OO

N

NNTrtS

O

NH

O

391

158




purification















159










Hz 1 H) 073 (d J = 68 Hz 3 H) 052 (d J = 68 Hz 3 H)









160






70 Hz 3 H) 055 (d J = 70 Hz 3 H)

161

References


















162






















163



















164























165






















166




















167

















168


















169




















170




















171






172

Biography









Honors amp Awards


Publications




173




Presentations






2012

iv

Abstract





















v









vi

Dedication


vii

Contents

Abstract iv

List of Tables x

List of Figures xi

Acknowledgements xx

1 Introduction 1




21 Introduction 6















viii







23 Conclusion 51



31 Introduction 74
















ix


33 Conclusion 115


References 161

Biography 172

x













Chapter 3




xi






Chapter 2










Chapter 3








xii










xiii

List of Schemes

Chapter 2





















Chapter 3


xiv
















xv




aq aqueous

Asp aspartic acid

br s broad singlet

Bn benzyl

BnBr benzyl bromide



t-Bu tert-butyl




CM cross metathesis



Cu copper


d doublet





xvi












ent enantiomer

eq equivalent

Et2O diethyl ether

EtOAc ethyl acetate






c-Hex cyclohexane



His histidine

xvii










Lys lysine

m multiplet


MeCN acetonitrile

MeOH methanol


min minute









xviii






q quartet


Rf retention factor

rt room temperature

s singlet

sat saturated



t triplet






THF tetrahydrofuran



TMS trimethylsilyl


xix



Tyr tyrosine


UV ultraviolet





xx

Acknowledgements





















1

1 Introduction















2
















3












4








levels







5





development










6


21 Introduction













world

7






8




N O

OOHOH

NH

O

F 2

Ca2+


O

OOHOH

2

Ca2+


N

NNSO2Me

F

OH

OOHOHN


O

O

HO O

O

H

H


O

OHCO2Na

HO

O

H


O

O

HO O

O

H

H

simvastatin (Zocor)

OH

OOHOH


N

F

3H2O







9










drugs











10

O

O

OH

Me

O

Me

Me

OH OH

MeO

O

O

OH

Me

O

Me

Me

HOHO

OMe

MeOH

MeO

OMe

Me

Me

Me

HO

OMe

OMeswinholide A

tartrolon B

O

Me

Me O

Me

O

O

MeOOH

O

Me

O

OHO

Me

OO

OO

O

HOOH

OH

OO

R

OOO

HOOH

OH

O

R

O

O

OHOH

OH

OH

O

OH

4

10

R =

cycloviracin B1

BNa

RO O

O

HO

OH O O

OOH

O

OR










11














12
















13














14

O

O

OTBS

Me

O

Me

Me

O O

MeO

O

OHMe

Me

OO

OMe

MeOTBS

MeO

OMe

Me

Me

Me

TBSO

OMe

OMe

OTBS

Me

O

MeO

PMP

PMP

O

HO

OTBS

Me

O

Me

Me

O O

MeO

O

OTMSMe

Me

OO

OMe

MeOTBS

MeO

OMe

Me

Me

Me

TBSO

OMe

OMe

OTBS

Me

O

MeO

PMP

PMP

OH

O

O

OTBS

Me

O

Me

Me

O O

MeO

O

O

TBSO

Me

O

Me

Me

OO

OMe

MeOTBS

MeO

OMe

Me

Me

Me

TBSO

OMe

OMe

swinholide A

PMP

PMP

ab

27

28 29

210

cd e






15
















16










17
















18















D +26 c 10 CHCl3)50

19









O

R1

OO

O O

OHOR2

O

NaO2C

OOH

O O O

CO2H

O O

HOO

HO

OH

H

H

H

H

H

H

H

Hcis

cis

cis

cis


BnMOMBnMOMSEM

R1 R2

H

H

H

H

SCH 351448 (214)

11




20














21





(Scheme 26)





22







O

TMSEO2C

OO

O O

OTBSOBn O

TMSEO2C

OOH

O O O

CO2TMSE

O O

HOO

BnO

OBn

H

H

H

H

H

H

H

H

H

H

H

H

O

TMSEO2C

OOH

O O O

CO2TMSE

O O

HOO

HO

OH

H

H

H

H

H

H

H

H

SCH 351448

a c

de f

2 27 2 28

2 29

2 22 +

OO

O O

2 30



23


O

BnO2C

OO

O O

OTBSOBn

ab cd

i k l o

O

BnO2C

OH

OHOBn

O

BnO2C

OOBnO

BnO2C

O

OCO2

tBu

CHOe h

NSi

Np-Br-C6H4

p-Br-C6H4

ClR

237 R= H238 R=Me

2 312 32

2 33 2 34

2 35 2 36

O

O O

O

2 39

+









24













25











26




14-syn-Aldol

O

O


O

TfO

O

O

O

O

O OHSS

O

HO

OH

OH

O

+ +

+ +

SS SS

TIPSO

TIPSO PMBO

OH

SS

PMBO


OH

OSS

TIPSO

O


OAc OTBS

O

O

O O

H

H

OH H

TIPSOSS

S

SO

NaO2C

OOH

O O O

CO2H

O O

HOO

HO

OH

H

H

H

H

H

H

H

Hcis

cis

cis

cis

214 244

245 246 247

248 249 250

251252

253


27









respectively




28













29









211)

30

MsO O

SS

PMBO O

SSO

PMBO O

SS

HO O

SS

TIPS TIPS

PMBO O

SS

TIPS

I O

SS

TIPS

a b c

d e

N O

OSS

OH

TIPS

H3C O

OSS

TIPS

N O

SS

CH3

TIPSO

H3C

Ph

OTf

f

g

h

263 265 266

267 268 269

270 271

272









31













conditions

32














33











34


OH O

OH

HTIPS

S

S

H3C

O

OH

HTIPS

S

S

+

conditions

O

274

272 275






35


36








37















38


















39




















40

292 R = TBS

OR OR

OO

O

OBn

H H

OR OR

O

OBn

H H

OH

OH O

OO

O

OBn

H Hab

291 R = TBS

cd

OR OR

OH

S

S

HO

OR OR

O

O

H

H

S

S

OH H

OBn

cis

OR OR

OH

H

S

S

gt201

H

OH H

OBn

OH H

OBn

OH

OR

H

OROBn

OO

O O

H

H

S

S

f g

h i

293 R = TBS 294 R = TBS

e

296 R = TBS

OH

OH

H

OHOBn

OO

O O

H

H

S

S

290

295 R = TBS

297

O

O O

OTf

247



41








42

OH

OR1

H

OR2OBn

OH

H

S

S

b

OH H

OBn OR1 OR2

OH

H

S

S

OH H

OBn OR1 OR2

OH

H

S

S

a

d


OH

OR

H

OOBn

OH

H

S

S

O

HO OTf

OH

OR

H

OOBn

OH

H

S

S

O

BnO OTf

c

2106 R = Bn 2107 R = Bn









217)

43











44









45










46










47


moiety (Scheme 219)

O OPMB

OH

S

S

HO

O OPMB

O

O

H

H

S

S

OH H

OBn

cis

O OPMB

OH

H

S

S

gt201

H

OH H

OBn

OH H

OBn

MOM

MOMMOMO OPMB

OH

OH H

OBnMOM

SS

OH

+

OTfO

O O

OH

O

H

OPMBOBn

OO

O O

H

H

S

S

MOM

OH

O

H

OPMBOH

O

O

O O

H

H

MOM

O OPMB

O

O

O O

H

H

OBnO2C

H H

MOM

a b c

+d e

fgh i

2117

252

2118 2119

2120

247 2121 2122

2123 2124

ref 53 SCH 351448

BnO2CO

H

O

H

OH

O

O

O O

H

H

MOM

13 7

9 11

15

192229



48















49


Carbon



(400 MHz) Hong


(400 MHz) Hong



3 351 (d) 350 (d) 107ndash128 (m) 106ndash128 (m)

4 139ndash165 (m) 138ndash165 (m) 22 306-313 (m) 306-313 (m)


139ndash165 (m) 138ndash165 (m) 24 678 (d) 678 (d)

6 139ndash165 (m) 138ndash165 (m) 25 728 (t) 738 (t)

107ndash128 (m) 106ndash128 (m) 26 693 (d) 693 (d)

















50


Carbon



De Brabander

(100 MHz) Hong


(100 MHz) Hong

(125 MHz) 1 1769 1769 22 344 344

2 469 469 23 1484 1484

3 824 824 24 1254 1254

4 366 366 25 1353 1352

5 238 238 26 1153 1153

6 320 320 27 1122 1122

7 a 752 751 28 1604 1604

8 414 413 29 1573 1573

9 736 736 30 1051 1051

10 391 391 1-OCH2Ph 1366 1366

11 717 717 1286 1286

12 372 372 1281 1281

13 273 273 1279 1279

14 253 253 1-OCH2Ph 663 663

15 a 778 778 2-Me 214 213

16 319 319 2-Me 207 207

17 239 239 9-OCH2OCH3 962 962

18 317 317 9-OCH2OCH3 560 559

191 785 784 12-Me 153 153

20 343 343 30-Me 259 259


51

23 Conclusion


















52














(s 3H) 13C NMR (125 MHz CDCl3) δ 1391 1379 1285 12776 12756 1144 800 785



53












2023 1391 1283 12741 12737 814 769 735 732 500 385 315 246 238 215








2018 1390 1282 12743 12734 767 731 728 685 444 383 283 249 215 201 188

54


















C6H6) δ 1772 1765 1433 1429 1283 1280 1270 1265 1084 760 7574 7565

749 694 692 578 361 353 3114 3111 300 297 2697 2694 2577 2560

55

















56


















57



2135 1389 1283 12742 12736 1088 821 788 772 758 732 693 679 481 466

427 383 321 311 284 269 257 249 236 216 210 162 IR (neat) 3478 1709 1368














3H) 13C NMR (125 MHz CDCl3) δ 1389 1283 12752 12748 1086 823 8014 773 765

732 723 708 696 424 3895 3881 3834 324 312 283 270 258 249 236 218 211

58


requires 4932524]
















59


6333762]


OH

O

H

OOBn

PMP

OO2113

OH

O

H

OHOBn

DIBALtoluene

+

OH

OH

H

OPMBOBn

2114 2115O

OO

O

PMB

ndash20 degC 1 h72

[21142115 = 31]













60



12742 1138 1086 821 798 793 773 763 733 720 695 688 553 439 3845 3838

358 324 317 290 270 258 249 237 216 211 143 IR (neat) 3501 1516 1250 cmndash1









NMR (125 MHz CDCl3) δ 1593 1392 1305 1296 1283 12742 12736 1139 1087 816

772 766 747 739 733 722 704 696 554 396 3891 3868 356 323 312 283 271

259 250 240 216 207 154


OH

OH

H

OPMBOBn

2114O

O

(R) or (S)-MTPA-Cl

Et3N DMAPCH2Cl2

OH

O

H

OPMBOBn(R)(S)-MTPA

1

2 2

39

12

16

1717

OO

25 degC 2 h



61






3H)









(R)ndash ester 3244 0892 0829 3140 3429 3965 1401 1353 0795


Preparation of 2116

62














088 (s 3H) 13C NMR (125 MHz CDCl3) δ 1591 1393 1314 1293 1282 12733 12726

1137 1087 962 817 791 772 764 745 7322 7318 709 696 558 553 428 386

358 349 323 319 293 271 258 250 241 2145 2127 139 IR (neat) 1514 1246 1034


63















12734 12727 1137 961 817 789 772 745 7331 7319 726 708 668 558 553 428

386 357 349 323 314 291 250 241 2143 2124 141 IR (neat) 3418 1456 1250 739


64
















13C NMR (125 MHz CDCl3) δ 1591 1393 1314 1293 1282 12733 12725 1138 962

817 791 772 745 7324 7317 709 558 553 526 471 428 386 358 347 323 308


6213753 [(M+Na)+ C36H54O7 requires 6213762]

65


















1314 1293 1282 12732 12722 1262 1137 961 817 790 772 745 7325 7314 707

691 584 558 553 519 447 428 386 373 362 356 347 323 290 2646 2625 2503

66




Addition Reaction














1293 1282 12731 12721 1137 962 817 792 772 745 7321 7314 7303 708 685

67

558 553 491 478 4320 4290 4278 386 358 348 339 323 288 2600 2593 2581


















68



(s 3H) 13C NMR (125 MHz CDCl3) δ 1590 1394 1315 1293 1282 12734 12723 1137

962 817 805 793 772 745 7322 7317 7315 712 708 705 558 553 480 432 429

421 386 358 348 340 323 289 2603 2593 (2 carbons) 255 250 241 214 212



Preparation of 2121











69








MHz CDCl3) δ 1590 1589 1566 1394 1349 1315 1294 1291 1282 12737 12725

1259 1169 1143 1138 1056 962 939 818 806 792 772 746 7325 7320 727 719

708 558 554 482 436 429 422 386 358 348 341 323 289 269 2608 2602 2586









70







(s 3H) 13C NMR (125 MHz CDCl3) δ 1602 1591 1571 1483 1351 1308 1298 1252

1151 1137 1120 1049 963 837 789 780 777 754 732 707 702 556 553 422

380 364 3481 (2 carbons) 3427 3424 320 3169 (2 carbons) 291 271 2572 2562 250


[(M+Na)+ C45H68O10 requires 7914705]


71

























72











1367 1353 1315 1294 1286 12800 12791 1253 1153 1138 1122 1051 963 821

793 782 779 750 732 707 661 558 554 469 429 366 359 350 347 344 3201

3182 (2 carbons) 292 273 2585 2576 2570 2390 2382 222 203 138 IR (neat) 1737


Preparation of 2124




73









MHz CDCl3) δ 1769 1604 1573 1484 1366 1352 1286 1281 1279 1254 1153 1122

1051 962 824 784 778 751 736 717 663 559 469 413 391 372 366 344 343

320 319 317 283 273 259 258 253 239 238 213 207 153 IR (neat) 3521 1733


74


31 Introduction



















75









deacetylation

76













77


















78



















79




















80






occur117








and ovarian cancer










81











82








malaria in mice121c









83
















84











85










86



FR901375

O O O

NHHN

OTBS

ONH

O

NHO

STr

STr

O OHCO2H

NHHN

OTBS

ONH

O

NHO

STr

STr

CO2MeNH2

HNOTBS

ONH

O

NHO

STr

O

O

Bn

O

Cl

H

O STr

O

O

Bn

O

Cl

OH STrOH STr

HO2C

CO2Me

HNOTBS

OFmocHN

STr

CO2H

HNOH

310

312 313

310 315 316

317 318

311

h k

bc

d g

a+

opn

lm







87






















88



89


















90











cells145











more detail later

91













92













93










94

N S

BocHN

SN

MeO2C

OHO

NH2

OH

OOH

S NH

O O OSN

SNNH

O

O





OH

OOH


or+ +

H

O

RS OHHO

OOH

O

OOtBu

OOH

Aux

OO

R+ or or or









95





















96












97

largazole

BocHN

SN

SN

HO2C

N

OH O S

S

Bn

TrtS

OTMSE

O O

TrtS

O

NHFmoc

NH

O OSN

SNNH

O

O

TrtS

OSN

SNNH

O

O

TrtS NHBoc

O OTMSE

334 335

336

337338

ab cd

ef gh



98














99













100










PC-3)170







potency170172

101





















102


321 Synthetic Goals











selectivity

103











binding

104











105












106







def

N S

BocHN

NS

MeO2C

SN

SOOH

N S

NH

NS

MeO2C

OOHTrtS

TrtS

N S

NH

NS

OOO

R2R1


TrtS

N S

NH

NSO

OOO

NH

TrtS

ab

c

+

347328

348

338








107





a

S NH

O OSN

SN

O

NH

O

SNH

OOS N

SN

O

HN

O

b

NH

O OSN

SN

O

NH

O

SS

BocHN CO2tBu

c

NH

O OSN

SN

O

NH

O

SS

BocHN CO2H

NH

O OSN

SN

O

NH

O

TrtS

338

339

340

341



108














steps (Scheme 39)

109












110












111












112





N S

NH

NSO

OOO

NH

R1

N S

NH

NSO

OOO

NH

R2

a

XS XS

XS

XS

a b c d

R1 =R2 =R3 =

N S

NH

NSO

OOO

NH

R3

b

X = Trt

371a d 372a d 373a d

X = HX = n-C7H17CO










113










114

a b

d e

cOH

O

MeO

NN

N

OH

TrtS

OMe

O

HO2C

OHOMe

O

CO2H

OH

OMe

O

OH

OH

OMe

O

OTs

OH

OMe

O

N3NN

N

OH

HS

OMe

O

AB

NOEH

NOE

f

380 381 382 383

384 385

386















392 (Scheme 316)

115

ab c

de fg

NN

N

OH

TrtS

OMe

O

N S

NH

NS

RO2C

OOH

N

NNTrtS

N S

NH

NS

R

OO

N

NNTrtS

O

NHFmocN S

NH

NSO

OOO

NH

N

NNTrtS

N S

NH

NSO

OOO

NH

N

NNS

N S

TFA H2N

NS

RO2C

392

385

388 R = Me389 R = Fm

368 R = Me387 R = Fm

394 R = CO2Me390 R = CO2Fm

391

n-C7H15

O



33 Conclusion






116










117

















= 70 70 70 Hz 2 H) 164 (s 3 H)

118















(m 3 H) 163 (s 3 H) 090 (d J = 60 Hz 3 H) 085 (d J = 70 Hz 3 H)

119




















120




205 (m 3 H) 183 (s 3 H) 068 (d J = 65 Hz 3 H) 052 (d J = 65 Hz 3 H)


N S

NH

NSO

OOO

NH

TrtS S NH

O OSN

SN

O

NH

O

SNH

OOS N

SN

O

HN

OI2


88

338 339













121

16907 16817 1647 1476 1329 1285 1243 846 721 579 434 412 406 378 343















= 72 72 72 Hz 2 H) 208 (m 1 H) 185 (s 3 H) 146 (s 9 H) 143 (s 9 H) 068 (d J = 68


1680 1646 1151 475 1325 1285 1243 844 827 799 720 578 538 433 418 411

122

404 376 342 317 284 280 243 189 167 HRMS (ESI) mz 7722537 [(M+H)+
















1480 1335 1300 1269 850 806 795 739 590 543 437 418 415 406 386 354


7161911]

123


















124













Hz 3 H)


N S

BocHN

NS


N S

NH

NS

MeO2C

OOH2) DMAP CH2Cl2


SN

SOOH

TrtS

TrtS

343a

328369a



125














1629 1482 1447 1434 1373 1296 12875 12856 1280 1268 1264 1244 1225 845

706 675 530 448 415 408 370 240




126


















127


















210 (m 1 H) 187 (s 3 H) 069 (d J = 70 Hz 3 H) 055 (d J = 70 Hz 3 H)


128










Hz 3 H)










129





1738 1696 1689 1681 1647 1476 1400 1386 12918 12887 1265 12478 12446

845 739 578 440 434 429 413 344 330 317 2902 2901 257 245 227 189 168

142 344 330 317 2902 2901







75 75 Hz 2 H)







130









254 (dd J = 80 80 Hz 2 H)












131



(d J = 70 Hz 3 H) 098 (d J = 70 Hz 3 H)















132


242 (dd J = 75 75 Hz 2 H) 163 (s 3 H)


N S

NH

NS

OOO

R2R1




N S

NH

NS

MeO2C

OOH

TrtS TrtS369b















J = 70 Hz 3 H)

133




















134




H) 066 (d J = 68 Hz 3 H) 051 (d J = 68 Hz 3 H)



83

N S

NH

NSO

OOO

NH

TrtS

N S

NH

NSO

OOO

NH

HS371b 372b










135














NMR (125 MHz CDCl3) δ 1995 1737 1696 1689 1681 1647 1475 1402 1347 1290

1262 1245 844 740 577 442 434 427 412 357 343 317 301 289 257 244 226

189 167 141

136










175 Hz 1 H) 536 (d J = 105 Hz 1 H)







137




CNHODIBALH toluene

0 degC 1 h TrtSO

50 for 3 steps

CN








purification








268 (dd J = 76 76 Hz 2 H)




138





17 H) 263 (dd J = 76 76 Hz 2 H) 247 (dd J = 76 76 Hz 2 H)














= 68 Hz 3 H) 099 (d J = 68 Hz 3 H)

139















H)

140


N S

NH

NS

OOO

R2R1



2) 3-69c DMAP25 degC 2 h85

N S

NH

NS

MeO2C

OOHTrtS TrtS

369c













J = 48 152 Hz 1 H) 256 (m 2 H) 244 (m 2 H) 205 (m 1 H) 166 (s 3 H) 083 (d J = 68

Hz 3 H) 069 (d J = 64 Hz 3 H)

141




















142



= 160 116 Hz 1 H) 268 (dd J = 164 24 Hz 1 H) 249 (m 2 H) 237 (m 2 H) 206 (m 1

H) 184 (s 3 H) 063 (d J = 72 Hz 3 H) 049 (d J = 68 Hz 3 H)











80 80 Hz 1 H) 070 (d J = 65 Hz 3 H) 057 (d J = 65 Hz 3 H)

143

















144












(dd J = 76 76 Hz 1 H) 450 (s 2 H) 391 (s 3 H)








145


NMR (100 MHz CDCl3) δ 1663 1323 1311 1305 12931 12927 12907 1175 523 234















146



δ 726ndash739 (m 4 H) 449 (s 2 H) 375 (s 2 H)


















147


Hz 2 H) 332 (s 2 H)














233 (m 1 H) 104 (d J = 68 Hz 3 H) 096 (d J = 68 Hz 3 H)

148

















149


N S

NH

NS

OOO

R2R1




N S

NH

NS

MeO2C

OOH

TrtS TrtS

369d















H)

150



















151






1 H) 185 (s 3 H) 071 (d J = 72 Hz 3 H) 050 (d J = 68 Hz 3 H)











(d J = 68 Hz 3 H) 050 (d J = 72 Hz 3 H)

152















153















purification






154















NMR (100 MHz CDCl3) δ 1720 1445 1368 1322 1296 1281 1269 6724 6708 5219

5206 385 304 228

155








264 (dd J = 170 50 Hz 1 H) 255 (dd J = 170 80 Hz 1 H)






156


















157













(100 MHz CDCl3) δ 1730 1714 1687 1685 1630 1566 1485 1444 14367 14361

14352 14139 14136 1365 1324 1296 1281 12791 12787 12719 12713 12695

12530 12521 12511 12505 1221 12010 12007 846 702 6748 6736 6724 599 489

471 468 417 413 381 3026 3019 241 227 189 180





N S

NH

NS

R1

OO

N

NNTrtS

O

R2

N S

NH

NS

OO

N

NNTrtS

O

NH

O

391

158




purification















159










Hz 1 H) 073 (d J = 68 Hz 3 H) 052 (d J = 68 Hz 3 H)









160






70 Hz 3 H) 055 (d J = 70 Hz 3 H)

161

References


















162






















163



















164























165






















166




















167

















168


















169




















170




















171






172

Biography









Honors amp Awards


Publications




173




Presentations





iv

Abstract





















v









vi

Dedication


vii

Contents

Abstract iv

List of Tables x

List of Figures xi

Acknowledgements xx

1 Introduction 1




21 Introduction 6















viii







23 Conclusion 51



31 Introduction 74
















ix


33 Conclusion 115


References 161

Biography 172

x













Chapter 3




xi






Chapter 2










Chapter 3








xii










xiii

List of Schemes

Chapter 2





















Chapter 3


xiv
















xv




aq aqueous

Asp aspartic acid

br s broad singlet

Bn benzyl

BnBr benzyl bromide



t-Bu tert-butyl




CM cross metathesis



Cu copper


d doublet





xvi












ent enantiomer

eq equivalent

Et2O diethyl ether

EtOAc ethyl acetate






c-Hex cyclohexane



His histidine

xvii










Lys lysine

m multiplet


MeCN acetonitrile

MeOH methanol


min minute









xviii






q quartet


Rf retention factor

rt room temperature

s singlet

sat saturated



t triplet






THF tetrahydrofuran



TMS trimethylsilyl


xix



Tyr tyrosine


UV ultraviolet





xx

Acknowledgements





















1

1 Introduction















2
















3












4








levels







5





development










6


21 Introduction













world

7






8




N O

OOHOH

NH

O

F 2

Ca2+


O

OOHOH

2

Ca2+


N

NNSO2Me

F

OH

OOHOHN


O

O

HO O

O

H

H


O

OHCO2Na

HO

O

H


O

O

HO O

O

H

H

simvastatin (Zocor)

OH

OOHOH


N

F

3H2O







9










drugs











10

O

O

OH

Me

O

Me

Me

OH OH

MeO

O

O

OH

Me

O

Me

Me

HOHO

OMe

MeOH

MeO

OMe

Me

Me

Me

HO

OMe

OMeswinholide A

tartrolon B

O

Me

Me O

Me

O

O

MeOOH

O

Me

O

OHO

Me

OO

OO

O

HOOH

OH

OO

R

OOO

HOOH

OH

O

R

O

O

OHOH

OH

OH

O

OH

4

10

R =

cycloviracin B1

BNa

RO O

O

HO

OH O O

OOH

O

OR










11














12
















13














14

O

O

OTBS

Me

O

Me

Me

O O

MeO

O

OHMe

Me

OO

OMe

MeOTBS

MeO

OMe

Me

Me

Me

TBSO

OMe

OMe

OTBS

Me

O

MeO

PMP

PMP

O

HO

OTBS

Me

O

Me

Me

O O

MeO

O

OTMSMe

Me

OO

OMe

MeOTBS

MeO

OMe

Me

Me

Me

TBSO

OMe

OMe

OTBS

Me

O

MeO

PMP

PMP

OH

O

O

OTBS

Me

O

Me

Me

O O

MeO

O

O

TBSO

Me

O

Me

Me

OO

OMe

MeOTBS

MeO

OMe

Me

Me

Me

TBSO

OMe

OMe

swinholide A

PMP

PMP

ab

27

28 29

210

cd e






15
















16










17
















18















D +26 c 10 CHCl3)50

19









O

R1

OO

O O

OHOR2

O

NaO2C

OOH

O O O

CO2H

O O

HOO

HO

OH

H

H

H

H

H

H

H

Hcis

cis

cis

cis


BnMOMBnMOMSEM

R1 R2

H

H

H

H

SCH 351448 (214)

11




20














21





(Scheme 26)





22







O

TMSEO2C

OO

O O

OTBSOBn O

TMSEO2C

OOH

O O O

CO2TMSE

O O

HOO

BnO

OBn

H

H

H

H

H

H

H

H

H

H

H

H

O

TMSEO2C

OOH

O O O

CO2TMSE

O O

HOO

HO

OH

H

H

H

H

H

H

H

H

SCH 351448

a c

de f

2 27 2 28

2 29

2 22 +

OO

O O

2 30



23


O

BnO2C

OO

O O

OTBSOBn

ab cd

i k l o

O

BnO2C

OH

OHOBn

O

BnO2C

OOBnO

BnO2C

O

OCO2

tBu

CHOe h

NSi

Np-Br-C6H4

p-Br-C6H4

ClR

237 R= H238 R=Me

2 312 32

2 33 2 34

2 35 2 36

O

O O

O

2 39

+









24













25











26




14-syn-Aldol

O

O


O

TfO

O

O

O

O

O OHSS

O

HO

OH

OH

O

+ +

+ +

SS SS

TIPSO

TIPSO PMBO

OH

SS

PMBO


OH

OSS

TIPSO

O


OAc OTBS

O

O

O O

H

H

OH H

TIPSOSS

S

SO

NaO2C

OOH

O O O

CO2H

O O

HOO

HO

OH

H

H

H

H

H

H

H

Hcis

cis

cis

cis

214 244

245 246 247

248 249 250

251252

253


27









respectively




28













29









211)

30

MsO O

SS

PMBO O

SSO

PMBO O

SS

HO O

SS

TIPS TIPS

PMBO O

SS

TIPS

I O

SS

TIPS

a b c

d e

N O

OSS

OH

TIPS

H3C O

OSS

TIPS

N O

SS

CH3

TIPSO

H3C

Ph

OTf

f

g

h

263 265 266

267 268 269

270 271

272









31













conditions

32














33











34


OH O

OH

HTIPS

S

S

H3C

O

OH

HTIPS

S

S

+

conditions

O

274

272 275






35


36








37















38


















39




















40

292 R = TBS

OR OR

OO

O

OBn

H H

OR OR

O

OBn

H H

OH

OH O

OO

O

OBn

H Hab

291 R = TBS

cd

OR OR

OH

S

S

HO

OR OR

O

O

H

H

S

S

OH H

OBn

cis

OR OR

OH

H

S

S

gt201

H

OH H

OBn

OH H

OBn

OH

OR

H

OROBn

OO

O O

H

H

S

S

f g

h i

293 R = TBS 294 R = TBS

e

296 R = TBS

OH

OH

H

OHOBn

OO

O O

H

H

S

S

290

295 R = TBS

297

O

O O

OTf

247



41








42

OH

OR1

H

OR2OBn

OH

H

S

S

b

OH H

OBn OR1 OR2

OH

H

S

S

OH H

OBn OR1 OR2

OH

H

S

S

a

d


OH

OR

H

OOBn

OH

H

S

S

O

HO OTf

OH

OR

H

OOBn

OH

H

S

S

O

BnO OTf

c

2106 R = Bn 2107 R = Bn









217)

43











44









45










46










47


moiety (Scheme 219)

O OPMB

OH

S

S

HO

O OPMB

O

O

H

H

S

S

OH H

OBn

cis

O OPMB

OH

H

S

S

gt201

H

OH H

OBn

OH H

OBn

MOM

MOMMOMO OPMB

OH

OH H

OBnMOM

SS

OH

+

OTfO

O O

OH

O

H

OPMBOBn

OO

O O

H

H

S

S

MOM

OH

O

H

OPMBOH

O

O

O O

H

H

MOM

O OPMB

O

O

O O

H

H

OBnO2C

H H

MOM

a b c

+d e

fgh i

2117

252

2118 2119

2120

247 2121 2122

2123 2124

ref 53 SCH 351448

BnO2CO

H

O

H

OH

O

O

O O

H

H

MOM

13 7

9 11

15

192229



48















49


Carbon



(400 MHz) Hong


(400 MHz) Hong



3 351 (d) 350 (d) 107ndash128 (m) 106ndash128 (m)

4 139ndash165 (m) 138ndash165 (m) 22 306-313 (m) 306-313 (m)


139ndash165 (m) 138ndash165 (m) 24 678 (d) 678 (d)

6 139ndash165 (m) 138ndash165 (m) 25 728 (t) 738 (t)

107ndash128 (m) 106ndash128 (m) 26 693 (d) 693 (d)

















50


Carbon



De Brabander

(100 MHz) Hong


(100 MHz) Hong

(125 MHz) 1 1769 1769 22 344 344

2 469 469 23 1484 1484

3 824 824 24 1254 1254

4 366 366 25 1353 1352

5 238 238 26 1153 1153

6 320 320 27 1122 1122

7 a 752 751 28 1604 1604

8 414 413 29 1573 1573

9 736 736 30 1051 1051

10 391 391 1-OCH2Ph 1366 1366

11 717 717 1286 1286

12 372 372 1281 1281

13 273 273 1279 1279

14 253 253 1-OCH2Ph 663 663

15 a 778 778 2-Me 214 213

16 319 319 2-Me 207 207

17 239 239 9-OCH2OCH3 962 962

18 317 317 9-OCH2OCH3 560 559

191 785 784 12-Me 153 153

20 343 343 30-Me 259 259


51

23 Conclusion


















52














(s 3H) 13C NMR (125 MHz CDCl3) δ 1391 1379 1285 12776 12756 1144 800 785



53












2023 1391 1283 12741 12737 814 769 735 732 500 385 315 246 238 215








2018 1390 1282 12743 12734 767 731 728 685 444 383 283 249 215 201 188

54


















C6H6) δ 1772 1765 1433 1429 1283 1280 1270 1265 1084 760 7574 7565

749 694 692 578 361 353 3114 3111 300 297 2697 2694 2577 2560

55

















56


















57



2135 1389 1283 12742 12736 1088 821 788 772 758 732 693 679 481 466

427 383 321 311 284 269 257 249 236 216 210 162 IR (neat) 3478 1709 1368














3H) 13C NMR (125 MHz CDCl3) δ 1389 1283 12752 12748 1086 823 8014 773 765

732 723 708 696 424 3895 3881 3834 324 312 283 270 258 249 236 218 211

58


requires 4932524]
















59


6333762]


OH

O

H

OOBn

PMP

OO2113

OH

O

H

OHOBn

DIBALtoluene

+

OH

OH

H

OPMBOBn

2114 2115O

OO

O

PMB

ndash20 degC 1 h72

[21142115 = 31]













60



12742 1138 1086 821 798 793 773 763 733 720 695 688 553 439 3845 3838

358 324 317 290 270 258 249 237 216 211 143 IR (neat) 3501 1516 1250 cmndash1









NMR (125 MHz CDCl3) δ 1593 1392 1305 1296 1283 12742 12736 1139 1087 816

772 766 747 739 733 722 704 696 554 396 3891 3868 356 323 312 283 271

259 250 240 216 207 154


OH

OH

H

OPMBOBn

2114O

O

(R) or (S)-MTPA-Cl

Et3N DMAPCH2Cl2

OH

O

H

OPMBOBn(R)(S)-MTPA

1

2 2

39

12

16

1717

OO

25 degC 2 h



61






3H)









(R)ndash ester 3244 0892 0829 3140 3429 3965 1401 1353 0795


Preparation of 2116

62














088 (s 3H) 13C NMR (125 MHz CDCl3) δ 1591 1393 1314 1293 1282 12733 12726

1137 1087 962 817 791 772 764 745 7322 7318 709 696 558 553 428 386

358 349 323 319 293 271 258 250 241 2145 2127 139 IR (neat) 1514 1246 1034


63















12734 12727 1137 961 817 789 772 745 7331 7319 726 708 668 558 553 428

386 357 349 323 314 291 250 241 2143 2124 141 IR (neat) 3418 1456 1250 739


64
















13C NMR (125 MHz CDCl3) δ 1591 1393 1314 1293 1282 12733 12725 1138 962

817 791 772 745 7324 7317 709 558 553 526 471 428 386 358 347 323 308


6213753 [(M+Na)+ C36H54O7 requires 6213762]

65


















1314 1293 1282 12732 12722 1262 1137 961 817 790 772 745 7325 7314 707

691 584 558 553 519 447 428 386 373 362 356 347 323 290 2646 2625 2503

66




Addition Reaction














1293 1282 12731 12721 1137 962 817 792 772 745 7321 7314 7303 708 685

67

558 553 491 478 4320 4290 4278 386 358 348 339 323 288 2600 2593 2581


















68



(s 3H) 13C NMR (125 MHz CDCl3) δ 1590 1394 1315 1293 1282 12734 12723 1137

962 817 805 793 772 745 7322 7317 7315 712 708 705 558 553 480 432 429

421 386 358 348 340 323 289 2603 2593 (2 carbons) 255 250 241 214 212



Preparation of 2121











69








MHz CDCl3) δ 1590 1589 1566 1394 1349 1315 1294 1291 1282 12737 12725

1259 1169 1143 1138 1056 962 939 818 806 792 772 746 7325 7320 727 719

708 558 554 482 436 429 422 386 358 348 341 323 289 269 2608 2602 2586









70







(s 3H) 13C NMR (125 MHz CDCl3) δ 1602 1591 1571 1483 1351 1308 1298 1252

1151 1137 1120 1049 963 837 789 780 777 754 732 707 702 556 553 422

380 364 3481 (2 carbons) 3427 3424 320 3169 (2 carbons) 291 271 2572 2562 250


[(M+Na)+ C45H68O10 requires 7914705]


71

























72











1367 1353 1315 1294 1286 12800 12791 1253 1153 1138 1122 1051 963 821

793 782 779 750 732 707 661 558 554 469 429 366 359 350 347 344 3201

3182 (2 carbons) 292 273 2585 2576 2570 2390 2382 222 203 138 IR (neat) 1737


Preparation of 2124




73









MHz CDCl3) δ 1769 1604 1573 1484 1366 1352 1286 1281 1279 1254 1153 1122

1051 962 824 784 778 751 736 717 663 559 469 413 391 372 366 344 343

320 319 317 283 273 259 258 253 239 238 213 207 153 IR (neat) 3521 1733


74


31 Introduction



















75









deacetylation

76













77


















78



















79




















80






occur117








and ovarian cancer










81











82








malaria in mice121c









83
















84











85










86



FR901375

O O O

NHHN

OTBS

ONH

O

NHO

STr

STr

O OHCO2H

NHHN

OTBS

ONH

O

NHO

STr

STr

CO2MeNH2

HNOTBS

ONH

O

NHO

STr

O

O

Bn

O

Cl

H

O STr

O

O

Bn

O

Cl

OH STrOH STr

HO2C

CO2Me

HNOTBS

OFmocHN

STr

CO2H

HNOH

310

312 313

310 315 316

317 318

311

h k

bc

d g

a+

opn

lm







87






















88



89


















90











cells145











more detail later

91













92













93










94

N S

BocHN

SN

MeO2C

OHO

NH2

OH

OOH

S NH

O O OSN

SNNH

O

O





OH

OOH


or+ +

H

O

RS OHHO

OOH

O

OOtBu

OOH

Aux

OO

R+ or or or









95





















96












97

largazole

BocHN

SN

SN

HO2C

N

OH O S

S

Bn

TrtS

OTMSE

O O

TrtS

O

NHFmoc

NH

O OSN

SNNH

O

O

TrtS

OSN

SNNH

O

O

TrtS NHBoc

O OTMSE

334 335

336

337338

ab cd

ef gh



98














99













100










PC-3)170







potency170172

101





















102


321 Synthetic Goals











selectivity

103











binding

104











105












106







def

N S

BocHN

NS

MeO2C

SN

SOOH

N S

NH

NS

MeO2C

OOHTrtS

TrtS

N S

NH

NS

OOO

R2R1


TrtS

N S

NH

NSO

OOO

NH

TrtS

ab

c

+

347328

348

338








107





a

S NH

O OSN

SN

O

NH

O

SNH

OOS N

SN

O

HN

O

b

NH

O OSN

SN

O

NH

O

SS

BocHN CO2tBu

c

NH

O OSN

SN

O

NH

O

SS

BocHN CO2H

NH

O OSN

SN

O

NH

O

TrtS

338

339

340

341



108














steps (Scheme 39)

109












110












111












112





N S

NH

NSO

OOO

NH

R1

N S

NH

NSO

OOO

NH

R2

a

XS XS

XS

XS

a b c d

R1 =R2 =R3 =

N S

NH

NSO

OOO

NH

R3

b

X = Trt

371a d 372a d 373a d

X = HX = n-C7H17CO










113










114

a b

d e

cOH

O

MeO

NN

N

OH

TrtS

OMe

O

HO2C

OHOMe

O

CO2H

OH

OMe

O

OH

OH

OMe

O

OTs

OH

OMe

O

N3NN

N

OH

HS

OMe

O

AB

NOEH

NOE

f

380 381 382 383

384 385

386















392 (Scheme 316)

115

ab c

de fg

NN

N

OH

TrtS

OMe

O

N S

NH

NS

RO2C

OOH

N

NNTrtS

N S

NH

NS

R

OO

N

NNTrtS

O

NHFmocN S

NH

NSO

OOO

NH

N

NNTrtS

N S

NH

NSO

OOO

NH

N

NNS

N S

TFA H2N

NS

RO2C

392

385

388 R = Me389 R = Fm

368 R = Me387 R = Fm

394 R = CO2Me390 R = CO2Fm

391

n-C7H15

O



33 Conclusion






116










117

















= 70 70 70 Hz 2 H) 164 (s 3 H)

118















(m 3 H) 163 (s 3 H) 090 (d J = 60 Hz 3 H) 085 (d J = 70 Hz 3 H)

119




















120




205 (m 3 H) 183 (s 3 H) 068 (d J = 65 Hz 3 H) 052 (d J = 65 Hz 3 H)


N S

NH

NSO

OOO

NH

TrtS S NH

O OSN

SN

O

NH

O

SNH

OOS N

SN

O

HN

OI2


88

338 339













121

16907 16817 1647 1476 1329 1285 1243 846 721 579 434 412 406 378 343















= 72 72 72 Hz 2 H) 208 (m 1 H) 185 (s 3 H) 146 (s 9 H) 143 (s 9 H) 068 (d J = 68


1680 1646 1151 475 1325 1285 1243 844 827 799 720 578 538 433 418 411

122

404 376 342 317 284 280 243 189 167 HRMS (ESI) mz 7722537 [(M+H)+
















1480 1335 1300 1269 850 806 795 739 590 543 437 418 415 406 386 354


7161911]

123


















124













Hz 3 H)


N S

BocHN

NS


N S

NH

NS

MeO2C

OOH2) DMAP CH2Cl2


SN

SOOH

TrtS

TrtS

343a

328369a



125














1629 1482 1447 1434 1373 1296 12875 12856 1280 1268 1264 1244 1225 845

706 675 530 448 415 408 370 240




126


















127


















210 (m 1 H) 187 (s 3 H) 069 (d J = 70 Hz 3 H) 055 (d J = 70 Hz 3 H)


128










Hz 3 H)










129





1738 1696 1689 1681 1647 1476 1400 1386 12918 12887 1265 12478 12446

845 739 578 440 434 429 413 344 330 317 2902 2901 257 245 227 189 168

142 344 330 317 2902 2901







75 75 Hz 2 H)







130









254 (dd J = 80 80 Hz 2 H)












131



(d J = 70 Hz 3 H) 098 (d J = 70 Hz 3 H)















132


242 (dd J = 75 75 Hz 2 H) 163 (s 3 H)


N S

NH

NS

OOO

R2R1




N S

NH

NS

MeO2C

OOH

TrtS TrtS369b















J = 70 Hz 3 H)

133




















134




H) 066 (d J = 68 Hz 3 H) 051 (d J = 68 Hz 3 H)



83

N S

NH

NSO

OOO

NH

TrtS

N S

NH

NSO

OOO

NH

HS371b 372b










135














NMR (125 MHz CDCl3) δ 1995 1737 1696 1689 1681 1647 1475 1402 1347 1290

1262 1245 844 740 577 442 434 427 412 357 343 317 301 289 257 244 226

189 167 141

136










175 Hz 1 H) 536 (d J = 105 Hz 1 H)







137




CNHODIBALH toluene

0 degC 1 h TrtSO

50 for 3 steps

CN








purification








268 (dd J = 76 76 Hz 2 H)




138





17 H) 263 (dd J = 76 76 Hz 2 H) 247 (dd J = 76 76 Hz 2 H)














= 68 Hz 3 H) 099 (d J = 68 Hz 3 H)

139















H)

140


N S

NH

NS

OOO

R2R1



2) 3-69c DMAP25 degC 2 h85

N S

NH

NS

MeO2C

OOHTrtS TrtS

369c













J = 48 152 Hz 1 H) 256 (m 2 H) 244 (m 2 H) 205 (m 1 H) 166 (s 3 H) 083 (d J = 68

Hz 3 H) 069 (d J = 64 Hz 3 H)

141




















142



= 160 116 Hz 1 H) 268 (dd J = 164 24 Hz 1 H) 249 (m 2 H) 237 (m 2 H) 206 (m 1

H) 184 (s 3 H) 063 (d J = 72 Hz 3 H) 049 (d J = 68 Hz 3 H)











80 80 Hz 1 H) 070 (d J = 65 Hz 3 H) 057 (d J = 65 Hz 3 H)

143

















144












(dd J = 76 76 Hz 1 H) 450 (s 2 H) 391 (s 3 H)








145


NMR (100 MHz CDCl3) δ 1663 1323 1311 1305 12931 12927 12907 1175 523 234















146



δ 726ndash739 (m 4 H) 449 (s 2 H) 375 (s 2 H)


















147


Hz 2 H) 332 (s 2 H)














233 (m 1 H) 104 (d J = 68 Hz 3 H) 096 (d J = 68 Hz 3 H)

148

















149


N S

NH

NS

OOO

R2R1




N S

NH

NS

MeO2C

OOH

TrtS TrtS

369d















H)

150



















151






1 H) 185 (s 3 H) 071 (d J = 72 Hz 3 H) 050 (d J = 68 Hz 3 H)











(d J = 68 Hz 3 H) 050 (d J = 72 Hz 3 H)

152















153















purification






154















NMR (100 MHz CDCl3) δ 1720 1445 1368 1322 1296 1281 1269 6724 6708 5219

5206 385 304 228

155








264 (dd J = 170 50 Hz 1 H) 255 (dd J = 170 80 Hz 1 H)






156


















157













(100 MHz CDCl3) δ 1730 1714 1687 1685 1630 1566 1485 1444 14367 14361

14352 14139 14136 1365 1324 1296 1281 12791 12787 12719 12713 12695

12530 12521 12511 12505 1221 12010 12007 846 702 6748 6736 6724 599 489

471 468 417 413 381 3026 3019 241 227 189 180





N S

NH

NS

R1

OO

N

NNTrtS

O

R2

N S

NH

NS

OO

N

NNTrtS

O

NH

O

391

158




purification















159










Hz 1 H) 073 (d J = 68 Hz 3 H) 052 (d J = 68 Hz 3 H)









160






70 Hz 3 H) 055 (d J = 70 Hz 3 H)

161

References


















162






















163



















164























165






















166




















167

















168


















169




















170




















171






172

Biography









Honors amp Awards


Publications




173




Presentations





v









vi

Dedication


vii

Contents

Abstract iv

List of Tables x

List of Figures xi

Acknowledgements xx

1 Introduction 1




21 Introduction 6















viii







23 Conclusion 51



31 Introduction 74
















ix


33 Conclusion 115


References 161

Biography 172

x













Chapter 3




xi






Chapter 2










Chapter 3








xii










xiii

List of Schemes

Chapter 2





















Chapter 3


xiv
















xv




aq aqueous

Asp aspartic acid

br s broad singlet

Bn benzyl

BnBr benzyl bromide



t-Bu tert-butyl




CM cross metathesis



Cu copper


d doublet





xvi












ent enantiomer

eq equivalent

Et2O diethyl ether

EtOAc ethyl acetate






c-Hex cyclohexane



His histidine

xvii










Lys lysine

m multiplet


MeCN acetonitrile

MeOH methanol


min minute









xviii






q quartet


Rf retention factor

rt room temperature

s singlet

sat saturated



t triplet






THF tetrahydrofuran



TMS trimethylsilyl


xix



Tyr tyrosine


UV ultraviolet





xx

Acknowledgements





















1

1 Introduction















2
















3












4








levels







5





development










6


21 Introduction













world

7






8




N O

OOHOH

NH

O

F 2

Ca2+


O

OOHOH

2

Ca2+


N

NNSO2Me

F

OH

OOHOHN


O

O

HO O

O

H

H


O

OHCO2Na

HO

O

H


O

O

HO O

O

H

H

simvastatin (Zocor)

OH

OOHOH


N

F

3H2O







9










drugs











10

O

O

OH

Me

O

Me

Me

OH OH

MeO

O

O

OH

Me

O

Me

Me

HOHO

OMe

MeOH

MeO

OMe

Me

Me

Me

HO

OMe

OMeswinholide A

tartrolon B

O

Me

Me O

Me

O

O

MeOOH

O

Me

O

OHO

Me

OO

OO

O

HOOH

OH

OO

R

OOO

HOOH

OH

O

R

O

O

OHOH

OH

OH

O

OH

4

10

R =

cycloviracin B1

BNa

RO O

O

HO

OH O O

OOH

O

OR










11














12
















13














14

O

O

OTBS

Me

O

Me

Me

O O

MeO

O

OHMe

Me

OO

OMe

MeOTBS

MeO

OMe

Me

Me

Me

TBSO

OMe

OMe

OTBS

Me

O

MeO

PMP

PMP

O

HO

OTBS

Me

O

Me

Me

O O

MeO

O

OTMSMe

Me

OO

OMe

MeOTBS

MeO

OMe

Me

Me

Me

TBSO

OMe

OMe

OTBS

Me

O

MeO

PMP

PMP

OH

O

O

OTBS

Me

O

Me

Me

O O

MeO

O

O

TBSO

Me

O

Me

Me

OO

OMe

MeOTBS

MeO

OMe

Me

Me

Me

TBSO

OMe

OMe

swinholide A

PMP

PMP

ab

27

28 29

210

cd e






15
















16










17
















18















D +26 c 10 CHCl3)50

19









O

R1

OO

O O

OHOR2

O

NaO2C

OOH

O O O

CO2H

O O

HOO

HO

OH

H

H

H

H

H

H

H

Hcis

cis

cis

cis


BnMOMBnMOMSEM

R1 R2

H

H

H

H

SCH 351448 (214)

11




20














21





(Scheme 26)





22







O

TMSEO2C

OO

O O

OTBSOBn O

TMSEO2C

OOH

O O O

CO2TMSE

O O

HOO

BnO

OBn

H

H

H

H

H

H

H

H

H

H

H

H

O

TMSEO2C

OOH

O O O

CO2TMSE

O O

HOO

HO

OH

H

H

H

H

H

H

H

H

SCH 351448

a c

de f

2 27 2 28

2 29

2 22 +

OO

O O

2 30



23


O

BnO2C

OO

O O

OTBSOBn

ab cd

i k l o

O

BnO2C

OH

OHOBn

O

BnO2C

OOBnO

BnO2C

O

OCO2

tBu

CHOe h

NSi

Np-Br-C6H4

p-Br-C6H4

ClR

237 R= H238 R=Me

2 312 32

2 33 2 34

2 35 2 36

O

O O

O

2 39

+









24













25











26




14-syn-Aldol

O

O


O

TfO

O

O

O

O

O OHSS

O

HO

OH

OH

O

+ +

+ +

SS SS

TIPSO

TIPSO PMBO

OH

SS

PMBO


OH

OSS

TIPSO

O


OAc OTBS

O

O

O O

H

H

OH H

TIPSOSS

S

SO

NaO2C

OOH

O O O

CO2H

O O

HOO

HO

OH

H

H

H

H

H

H

H

Hcis

cis

cis

cis

214 244

245 246 247

248 249 250

251252

253


27









respectively




28













29









211)

30

MsO O

SS

PMBO O

SSO

PMBO O

SS

HO O

SS

TIPS TIPS

PMBO O

SS

TIPS

I O

SS

TIPS

a b c

d e

N O

OSS

OH

TIPS

H3C O

OSS

TIPS

N O

SS

CH3

TIPSO

H3C

Ph

OTf

f

g

h

263 265 266

267 268 269

270 271

272









31













conditions

32














33











34


OH O

OH

HTIPS

S

S

H3C

O

OH

HTIPS

S

S

+

conditions

O

274

272 275






35


36








37















38


















39




















40

292 R = TBS

OR OR

OO

O

OBn

H H

OR OR

O

OBn

H H

OH

OH O

OO

O

OBn

H Hab

291 R = TBS

cd

OR OR

OH

S

S

HO

OR OR

O

O

H

H

S

S

OH H

OBn

cis

OR OR

OH

H

S

S

gt201

H

OH H

OBn

OH H

OBn

OH

OR

H

OROBn

OO

O O

H

H

S

S

f g

h i

293 R = TBS 294 R = TBS

e

296 R = TBS

OH

OH

H

OHOBn

OO

O O

H

H

S

S

290

295 R = TBS

297

O

O O

OTf

247



41








42

OH

OR1

H

OR2OBn

OH

H

S

S

b

OH H

OBn OR1 OR2

OH

H

S

S

OH H

OBn OR1 OR2

OH

H

S

S

a

d


OH

OR

H

OOBn

OH

H

S

S

O

HO OTf

OH

OR

H

OOBn

OH

H

S

S

O

BnO OTf

c

2106 R = Bn 2107 R = Bn









217)

43











44









45










46










47


moiety (Scheme 219)

O OPMB

OH

S

S

HO

O OPMB

O

O

H

H

S

S

OH H

OBn

cis

O OPMB

OH

H

S

S

gt201

H

OH H

OBn

OH H

OBn

MOM

MOMMOMO OPMB

OH

OH H

OBnMOM

SS

OH

+

OTfO

O O

OH

O

H

OPMBOBn

OO

O O

H

H

S

S

MOM

OH

O

H

OPMBOH

O

O

O O

H

H

MOM

O OPMB

O

O

O O

H

H

OBnO2C

H H

MOM

a b c

+d e

fgh i

2117

252

2118 2119

2120

247 2121 2122

2123 2124

ref 53 SCH 351448

BnO2CO

H

O

H

OH

O

O

O O

H

H

MOM

13 7

9 11

15

192229



48















49


Carbon



(400 MHz) Hong


(400 MHz) Hong



3 351 (d) 350 (d) 107ndash128 (m) 106ndash128 (m)

4 139ndash165 (m) 138ndash165 (m) 22 306-313 (m) 306-313 (m)


139ndash165 (m) 138ndash165 (m) 24 678 (d) 678 (d)

6 139ndash165 (m) 138ndash165 (m) 25 728 (t) 738 (t)

107ndash128 (m) 106ndash128 (m) 26 693 (d) 693 (d)

















50


Carbon



De Brabander

(100 MHz) Hong


(100 MHz) Hong

(125 MHz) 1 1769 1769 22 344 344

2 469 469 23 1484 1484

3 824 824 24 1254 1254

4 366 366 25 1353 1352

5 238 238 26 1153 1153

6 320 320 27 1122 1122

7 a 752 751 28 1604 1604

8 414 413 29 1573 1573

9 736 736 30 1051 1051

10 391 391 1-OCH2Ph 1366 1366

11 717 717 1286 1286

12 372 372 1281 1281

13 273 273 1279 1279

14 253 253 1-OCH2Ph 663 663

15 a 778 778 2-Me 214 213

16 319 319 2-Me 207 207

17 239 239 9-OCH2OCH3 962 962

18 317 317 9-OCH2OCH3 560 559

191 785 784 12-Me 153 153

20 343 343 30-Me 259 259


51

23 Conclusion


















52














(s 3H) 13C NMR (125 MHz CDCl3) δ 1391 1379 1285 12776 12756 1144 800 785



53












2023 1391 1283 12741 12737 814 769 735 732 500 385 315 246 238 215








2018 1390 1282 12743 12734 767 731 728 685 444 383 283 249 215 201 188

54


















C6H6) δ 1772 1765 1433 1429 1283 1280 1270 1265 1084 760 7574 7565

749 694 692 578 361 353 3114 3111 300 297 2697 2694 2577 2560

55

















56


















57



2135 1389 1283 12742 12736 1088 821 788 772 758 732 693 679 481 466

427 383 321 311 284 269 257 249 236 216 210 162 IR (neat) 3478 1709 1368














3H) 13C NMR (125 MHz CDCl3) δ 1389 1283 12752 12748 1086 823 8014 773 765

732 723 708 696 424 3895 3881 3834 324 312 283 270 258 249 236 218 211

58


requires 4932524]
















59


6333762]


OH

O

H

OOBn

PMP

OO2113

OH

O

H

OHOBn

DIBALtoluene

+

OH

OH

H

OPMBOBn

2114 2115O

OO

O

PMB

ndash20 degC 1 h72

[21142115 = 31]













60



12742 1138 1086 821 798 793 773 763 733 720 695 688 553 439 3845 3838

358 324 317 290 270 258 249 237 216 211 143 IR (neat) 3501 1516 1250 cmndash1









NMR (125 MHz CDCl3) δ 1593 1392 1305 1296 1283 12742 12736 1139 1087 816

772 766 747 739 733 722 704 696 554 396 3891 3868 356 323 312 283 271

259 250 240 216 207 154


OH

OH

H

OPMBOBn

2114O

O

(R) or (S)-MTPA-Cl

Et3N DMAPCH2Cl2

OH

O

H

OPMBOBn(R)(S)-MTPA

1

2 2

39

12

16

1717

OO

25 degC 2 h



61






3H)









(R)ndash ester 3244 0892 0829 3140 3429 3965 1401 1353 0795


Preparation of 2116

62














088 (s 3H) 13C NMR (125 MHz CDCl3) δ 1591 1393 1314 1293 1282 12733 12726

1137 1087 962 817 791 772 764 745 7322 7318 709 696 558 553 428 386

358 349 323 319 293 271 258 250 241 2145 2127 139 IR (neat) 1514 1246 1034


63















12734 12727 1137 961 817 789 772 745 7331 7319 726 708 668 558 553 428

386 357 349 323 314 291 250 241 2143 2124 141 IR (neat) 3418 1456 1250 739


64
















13C NMR (125 MHz CDCl3) δ 1591 1393 1314 1293 1282 12733 12725 1138 962

817 791 772 745 7324 7317 709 558 553 526 471 428 386 358 347 323 308


6213753 [(M+Na)+ C36H54O7 requires 6213762]

65


















1314 1293 1282 12732 12722 1262 1137 961 817 790 772 745 7325 7314 707

691 584 558 553 519 447 428 386 373 362 356 347 323 290 2646 2625 2503

66




Addition Reaction














1293 1282 12731 12721 1137 962 817 792 772 745 7321 7314 7303 708 685

67

558 553 491 478 4320 4290 4278 386 358 348 339 323 288 2600 2593 2581


















68



(s 3H) 13C NMR (125 MHz CDCl3) δ 1590 1394 1315 1293 1282 12734 12723 1137

962 817 805 793 772 745 7322 7317 7315 712 708 705 558 553 480 432 429

421 386 358 348 340 323 289 2603 2593 (2 carbons) 255 250 241 214 212



Preparation of 2121











69








MHz CDCl3) δ 1590 1589 1566 1394 1349 1315 1294 1291 1282 12737 12725

1259 1169 1143 1138 1056 962 939 818 806 792 772 746 7325 7320 727 719

708 558 554 482 436 429 422 386 358 348 341 323 289 269 2608 2602 2586









70







(s 3H) 13C NMR (125 MHz CDCl3) δ 1602 1591 1571 1483 1351 1308 1298 1252

1151 1137 1120 1049 963 837 789 780 777 754 732 707 702 556 553 422

380 364 3481 (2 carbons) 3427 3424 320 3169 (2 carbons) 291 271 2572 2562 250


[(M+Na)+ C45H68O10 requires 7914705]


71

























72











1367 1353 1315 1294 1286 12800 12791 1253 1153 1138 1122 1051 963 821

793 782 779 750 732 707 661 558 554 469 429 366 359 350 347 344 3201

3182 (2 carbons) 292 273 2585 2576 2570 2390 2382 222 203 138 IR (neat) 1737


Preparation of 2124




73









MHz CDCl3) δ 1769 1604 1573 1484 1366 1352 1286 1281 1279 1254 1153 1122

1051 962 824 784 778 751 736 717 663 559 469 413 391 372 366 344 343

320 319 317 283 273 259 258 253 239 238 213 207 153 IR (neat) 3521 1733


74


31 Introduction



















75









deacetylation

76













77


















78



















79




















80






occur117








and ovarian cancer










81











82








malaria in mice121c









83
















84











85










86



FR901375

O O O

NHHN

OTBS

ONH

O

NHO

STr

STr

O OHCO2H

NHHN

OTBS

ONH

O

NHO

STr

STr

CO2MeNH2

HNOTBS

ONH

O

NHO

STr

O

O

Bn

O

Cl

H

O STr

O

O

Bn

O

Cl

OH STrOH STr

HO2C

CO2Me

HNOTBS

OFmocHN

STr

CO2H

HNOH

310

312 313

310 315 316

317 318

311

h k

bc

d g

a+

opn

lm







87






















88



89


















90











cells145











more detail later

91













92













93










94

N S

BocHN

SN

MeO2C

OHO

NH2

OH

OOH

S NH

O O OSN

SNNH

O

O





OH

OOH


or+ +

H

O

RS OHHO

OOH

O

OOtBu

OOH

Aux

OO

R+ or or or









95





















96












97

largazole

BocHN

SN

SN

HO2C

N

OH O S

S

Bn

TrtS

OTMSE

O O

TrtS

O

NHFmoc

NH

O OSN

SNNH

O

O

TrtS

OSN

SNNH

O

O

TrtS NHBoc

O OTMSE

334 335

336

337338

ab cd

ef gh



98














99













100










PC-3)170







potency170172

101





















102


321 Synthetic Goals











selectivity

103











binding

104











105












106







def

N S

BocHN

NS

MeO2C

SN

SOOH

N S

NH

NS

MeO2C

OOHTrtS

TrtS

N S

NH

NS

OOO

R2R1


TrtS

N S

NH

NSO

OOO

NH

TrtS

ab

c

+

347328

348

338








107





a

S NH

O OSN

SN

O

NH

O

SNH

OOS N

SN

O

HN

O

b

NH

O OSN

SN

O

NH

O

SS

BocHN CO2tBu

c

NH

O OSN

SN

O

NH

O

SS

BocHN CO2H

NH

O OSN

SN

O

NH

O

TrtS

338

339

340

341



108














steps (Scheme 39)

109












110












111












112





N S

NH

NSO

OOO

NH

R1

N S

NH

NSO

OOO

NH

R2

a

XS XS

XS

XS

a b c d

R1 =R2 =R3 =

N S

NH

NSO

OOO

NH

R3

b

X = Trt

371a d 372a d 373a d

X = HX = n-C7H17CO










113










114

a b

d e

cOH

O

MeO

NN

N

OH

TrtS

OMe

O

HO2C

OHOMe

O

CO2H

OH

OMe

O

OH

OH

OMe

O

OTs

OH

OMe

O

N3NN

N

OH

HS

OMe

O

AB

NOEH

NOE

f

380 381 382 383

384 385

386















392 (Scheme 316)

115

ab c

de fg

NN

N

OH

TrtS

OMe

O

N S

NH

NS

RO2C

OOH

N

NNTrtS

N S

NH

NS

R

OO

N

NNTrtS

O

NHFmocN S

NH

NSO

OOO

NH

N

NNTrtS

N S

NH

NSO

OOO

NH

N

NNS

N S

TFA H2N

NS

RO2C

392

385

388 R = Me389 R = Fm

368 R = Me387 R = Fm

394 R = CO2Me390 R = CO2Fm

391

n-C7H15

O



33 Conclusion






116










117

















= 70 70 70 Hz 2 H) 164 (s 3 H)

118















(m 3 H) 163 (s 3 H) 090 (d J = 60 Hz 3 H) 085 (d J = 70 Hz 3 H)

119




















120




205 (m 3 H) 183 (s 3 H) 068 (d J = 65 Hz 3 H) 052 (d J = 65 Hz 3 H)


N S

NH

NSO

OOO

NH

TrtS S NH

O OSN

SN

O

NH

O

SNH

OOS N

SN

O

HN

OI2


88

338 339













121

16907 16817 1647 1476 1329 1285 1243 846 721 579 434 412 406 378 343















= 72 72 72 Hz 2 H) 208 (m 1 H) 185 (s 3 H) 146 (s 9 H) 143 (s 9 H) 068 (d J = 68


1680 1646 1151 475 1325 1285 1243 844 827 799 720 578 538 433 418 411

122

404 376 342 317 284 280 243 189 167 HRMS (ESI) mz 7722537 [(M+H)+
















1480 1335 1300 1269 850 806 795 739 590 543 437 418 415 406 386 354


7161911]

123


















124













Hz 3 H)


N S

BocHN

NS


N S

NH

NS

MeO2C

OOH2) DMAP CH2Cl2


SN

SOOH

TrtS

TrtS

343a

328369a



125














1629 1482 1447 1434 1373 1296 12875 12856 1280 1268 1264 1244 1225 845

706 675 530 448 415 408 370 240




126


















127


















210 (m 1 H) 187 (s 3 H) 069 (d J = 70 Hz 3 H) 055 (d J = 70 Hz 3 H)


128










Hz 3 H)










129





1738 1696 1689 1681 1647 1476 1400 1386 12918 12887 1265 12478 12446

845 739 578 440 434 429 413 344 330 317 2902 2901 257 245 227 189 168

142 344 330 317 2902 2901







75 75 Hz 2 H)







130









254 (dd J = 80 80 Hz 2 H)












131



(d J = 70 Hz 3 H) 098 (d J = 70 Hz 3 H)















132


242 (dd J = 75 75 Hz 2 H) 163 (s 3 H)


N S

NH

NS

OOO

R2R1




N S

NH

NS

MeO2C

OOH

TrtS TrtS369b















J = 70 Hz 3 H)

133




















134




H) 066 (d J = 68 Hz 3 H) 051 (d J = 68 Hz 3 H)



83

N S

NH

NSO

OOO

NH

TrtS

N S

NH

NSO

OOO

NH

HS371b 372b










135














NMR (125 MHz CDCl3) δ 1995 1737 1696 1689 1681 1647 1475 1402 1347 1290

1262 1245 844 740 577 442 434 427 412 357 343 317 301 289 257 244 226

189 167 141

136










175 Hz 1 H) 536 (d J = 105 Hz 1 H)







137




CNHODIBALH toluene

0 degC 1 h TrtSO

50 for 3 steps

CN








purification








268 (dd J = 76 76 Hz 2 H)




138





17 H) 263 (dd J = 76 76 Hz 2 H) 247 (dd J = 76 76 Hz 2 H)














= 68 Hz 3 H) 099 (d J = 68 Hz 3 H)

139















H)

140


N S

NH

NS

OOO

R2R1



2) 3-69c DMAP25 degC 2 h85

N S

NH

NS

MeO2C

OOHTrtS TrtS

369c













J = 48 152 Hz 1 H) 256 (m 2 H) 244 (m 2 H) 205 (m 1 H) 166 (s 3 H) 083 (d J = 68

Hz 3 H) 069 (d J = 64 Hz 3 H)

141




















142



= 160 116 Hz 1 H) 268 (dd J = 164 24 Hz 1 H) 249 (m 2 H) 237 (m 2 H) 206 (m 1

H) 184 (s 3 H) 063 (d J = 72 Hz 3 H) 049 (d J = 68 Hz 3 H)











80 80 Hz 1 H) 070 (d J = 65 Hz 3 H) 057 (d J = 65 Hz 3 H)

143

















144












(dd J = 76 76 Hz 1 H) 450 (s 2 H) 391 (s 3 H)








145


NMR (100 MHz CDCl3) δ 1663 1323 1311 1305 12931 12927 12907 1175 523 234















146



δ 726ndash739 (m 4 H) 449 (s 2 H) 375 (s 2 H)


















147


Hz 2 H) 332 (s 2 H)














233 (m 1 H) 104 (d J = 68 Hz 3 H) 096 (d J = 68 Hz 3 H)

148

















149


N S

NH

NS

OOO

R2R1




N S

NH

NS

MeO2C

OOH

TrtS TrtS

369d















H)

150



















151






1 H) 185 (s 3 H) 071 (d J = 72 Hz 3 H) 050 (d J = 68 Hz 3 H)











(d J = 68 Hz 3 H) 050 (d J = 72 Hz 3 H)

152















153















purification






154















NMR (100 MHz CDCl3) δ 1720 1445 1368 1322 1296 1281 1269 6724 6708 5219

5206 385 304 228

155








264 (dd J = 170 50 Hz 1 H) 255 (dd J = 170 80 Hz 1 H)






156


















157













(100 MHz CDCl3) δ 1730 1714 1687 1685 1630 1566 1485 1444 14367 14361

14352 14139 14136 1365 1324 1296 1281 12791 12787 12719 12713 12695

12530 12521 12511 12505 1221 12010 12007 846 702 6748 6736 6724 599 489

471 468 417 413 381 3026 3019 241 227 189 180





N S

NH

NS

R1

OO

N

NNTrtS

O

R2

N S

NH

NS

OO

N

NNTrtS

O

NH

O

391

158




purification















159










Hz 1 H) 073 (d J = 68 Hz 3 H) 052 (d J = 68 Hz 3 H)









160






70 Hz 3 H) 055 (d J = 70 Hz 3 H)

161

References


















162






















163



















164























165






















166




















167

















168


















169




















170




















171






172

Biography









Honors amp Awards


Publications




173




Presentations





vi

Dedication


vii

Contents

Abstract iv

List of Tables x

List of Figures xi

Acknowledgements xx

1 Introduction 1




21 Introduction 6















viii







23 Conclusion 51



31 Introduction 74
















ix


33 Conclusion 115


References 161

Biography 172

x













Chapter 3




xi






Chapter 2










Chapter 3








xii










xiii

List of Schemes

Chapter 2





















Chapter 3


xiv
















xv




aq aqueous

Asp aspartic acid

br s broad singlet

Bn benzyl

BnBr benzyl bromide



t-Bu tert-butyl




CM cross metathesis



Cu copper


d doublet





xvi












ent enantiomer

eq equivalent

Et2O diethyl ether

EtOAc ethyl acetate






c-Hex cyclohexane



His histidine

xvii










Lys lysine

m multiplet


MeCN acetonitrile

MeOH methanol


min minute









xviii






q quartet


Rf retention factor

rt room temperature

s singlet

sat saturated



t triplet






THF tetrahydrofuran



TMS trimethylsilyl


xix



Tyr tyrosine


UV ultraviolet





xx

Acknowledgements





















1

1 Introduction















2
















3












4








levels







5





development










6


21 Introduction













world

7






8




N O

OOHOH

NH

O

F 2

Ca2+


O

OOHOH

2

Ca2+


N

NNSO2Me

F

OH

OOHOHN


O

O

HO O

O

H

H


O

OHCO2Na

HO

O

H


O

O

HO O

O

H

H

simvastatin (Zocor)

OH

OOHOH


N

F

3H2O







9










drugs











10

O

O

OH

Me

O

Me

Me

OH OH

MeO

O

O

OH

Me

O

Me

Me

HOHO

OMe

MeOH

MeO

OMe

Me

Me

Me

HO

OMe

OMeswinholide A

tartrolon B

O

Me

Me O

Me

O

O

MeOOH

O

Me

O

OHO

Me

OO

OO

O

HOOH

OH

OO

R

OOO

HOOH

OH

O

R

O

O

OHOH

OH

OH

O

OH

4

10

R =

cycloviracin B1

BNa

RO O

O

HO

OH O O

OOH

O

OR










11














12
















13














14

O

O

OTBS

Me

O

Me

Me

O O

MeO

O

OHMe

Me

OO

OMe

MeOTBS

MeO

OMe

Me

Me

Me

TBSO

OMe

OMe

OTBS

Me

O

MeO

PMP

PMP

O

HO

OTBS

Me

O

Me

Me

O O

MeO

O

OTMSMe

Me

OO

OMe

MeOTBS

MeO

OMe

Me

Me

Me

TBSO

OMe

OMe

OTBS

Me

O

MeO

PMP

PMP

OH

O

O

OTBS

Me

O

Me

Me

O O

MeO

O

O

TBSO

Me

O

Me

Me

OO

OMe

MeOTBS

MeO

OMe

Me

Me

Me

TBSO

OMe

OMe

swinholide A

PMP

PMP

ab

27

28 29

210

cd e






15
















16










17
















18















D +26 c 10 CHCl3)50

19









O

R1

OO

O O

OHOR2

O

NaO2C

OOH

O O O

CO2H

O O

HOO

HO

OH

H

H

H

H

H

H

H

Hcis

cis

cis

cis


BnMOMBnMOMSEM

R1 R2

H

H

H

H

SCH 351448 (214)

11




20














21





(Scheme 26)





22







O

TMSEO2C

OO

O O

OTBSOBn O

TMSEO2C

OOH

O O O

CO2TMSE

O O

HOO

BnO

OBn

H

H

H

H

H

H

H

H

H

H

H

H

O

TMSEO2C

OOH

O O O

CO2TMSE

O O

HOO

HO

OH

H

H

H

H

H

H

H

H

SCH 351448

a c

de f

2 27 2 28

2 29

2 22 +

OO

O O

2 30



23


O

BnO2C

OO

O O

OTBSOBn

ab cd

i k l o

O

BnO2C

OH

OHOBn

O

BnO2C

OOBnO

BnO2C

O

OCO2

tBu

CHOe h

NSi

Np-Br-C6H4

p-Br-C6H4

ClR

237 R= H238 R=Me

2 312 32

2 33 2 34

2 35 2 36

O

O O

O

2 39

+









24













25











26




14-syn-Aldol

O

O


O

TfO

O

O

O

O

O OHSS

O

HO

OH

OH

O

+ +

+ +

SS SS

TIPSO

TIPSO PMBO

OH

SS

PMBO


OH

OSS

TIPSO

O


OAc OTBS

O

O

O O

H

H

OH H

TIPSOSS

S

SO

NaO2C

OOH

O O O

CO2H

O O

HOO

HO

OH

H

H

H

H

H

H

H

Hcis

cis

cis

cis

214 244

245 246 247

248 249 250

251252

253


27









respectively




28













29









211)

30

MsO O

SS

PMBO O

SSO

PMBO O

SS

HO O

SS

TIPS TIPS

PMBO O

SS

TIPS

I O

SS

TIPS

a b c

d e

N O

OSS

OH

TIPS

H3C O

OSS

TIPS

N O

SS

CH3

TIPSO

H3C

Ph

OTf

f

g

h

263 265 266

267 268 269

270 271

272









31













conditions

32














33











34


OH O

OH

HTIPS

S

S

H3C

O

OH

HTIPS

S

S

+

conditions

O

274

272 275






35


36








37















38


















39




















40

292 R = TBS

OR OR

OO

O

OBn

H H

OR OR

O

OBn

H H

OH

OH O

OO

O

OBn

H Hab

291 R = TBS

cd

OR OR

OH

S

S

HO

OR OR

O

O

H

H

S

S

OH H

OBn

cis

OR OR

OH

H

S

S

gt201

H

OH H

OBn

OH H

OBn

OH

OR

H

OROBn

OO

O O

H

H

S

S

f g

h i

293 R = TBS 294 R = TBS

e

296 R = TBS

OH

OH

H

OHOBn

OO

O O

H

H

S

S

290

295 R = TBS

297

O

O O

OTf

247



41








42

OH

OR1

H

OR2OBn

OH

H

S

S

b

OH H

OBn OR1 OR2

OH

H

S

S

OH H

OBn OR1 OR2

OH

H

S

S

a

d


OH

OR

H

OOBn

OH

H

S

S

O

HO OTf

OH

OR

H

OOBn

OH

H

S

S

O

BnO OTf

c

2106 R = Bn 2107 R = Bn









217)

43











44









45










46










47


moiety (Scheme 219)

O OPMB

OH

S

S

HO

O OPMB

O

O

H

H

S

S

OH H

OBn

cis

O OPMB

OH

H

S

S

gt201

H

OH H

OBn

OH H

OBn

MOM

MOMMOMO OPMB

OH

OH H

OBnMOM

SS

OH

+

OTfO

O O

OH

O

H

OPMBOBn

OO

O O

H

H

S

S

MOM

OH

O

H

OPMBOH

O

O

O O

H

H

MOM

O OPMB

O

O

O O

H

H

OBnO2C

H H

MOM

a b c

+d e

fgh i

2117

252

2118 2119

2120

247 2121 2122

2123 2124

ref 53 SCH 351448

BnO2CO

H

O

H

OH

O

O

O O

H

H

MOM

13 7

9 11

15

192229



48















49


Carbon



(400 MHz) Hong


(400 MHz) Hong



3 351 (d) 350 (d) 107ndash128 (m) 106ndash128 (m)

4 139ndash165 (m) 138ndash165 (m) 22 306-313 (m) 306-313 (m)


139ndash165 (m) 138ndash165 (m) 24 678 (d) 678 (d)

6 139ndash165 (m) 138ndash165 (m) 25 728 (t) 738 (t)

107ndash128 (m) 106ndash128 (m) 26 693 (d) 693 (d)

















50


Carbon



De Brabander

(100 MHz) Hong


(100 MHz) Hong

(125 MHz) 1 1769 1769 22 344 344

2 469 469 23 1484 1484

3 824 824 24 1254 1254

4 366 366 25 1353 1352

5 238 238 26 1153 1153

6 320 320 27 1122 1122

7 a 752 751 28 1604 1604

8 414 413 29 1573 1573

9 736 736 30 1051 1051

10 391 391 1-OCH2Ph 1366 1366

11 717 717 1286 1286

12 372 372 1281 1281

13 273 273 1279 1279

14 253 253 1-OCH2Ph 663 663

15 a 778 778 2-Me 214 213

16 319 319 2-Me 207 207

17 239 239 9-OCH2OCH3 962 962

18 317 317 9-OCH2OCH3 560 559

191 785 784 12-Me 153 153

20 343 343 30-Me 259 259


51

23 Conclusion


















52














(s 3H) 13C NMR (125 MHz CDCl3) δ 1391 1379 1285 12776 12756 1144 800 785



53












2023 1391 1283 12741 12737 814 769 735 732 500 385 315 246 238 215








2018 1390 1282 12743 12734 767 731 728 685 444 383 283 249 215 201 188

54


















C6H6) δ 1772 1765 1433 1429 1283 1280 1270 1265 1084 760 7574 7565

749 694 692 578 361 353 3114 3111 300 297 2697 2694 2577 2560

55

















56


















57



2135 1389 1283 12742 12736 1088 821 788 772 758 732 693 679 481 466

427 383 321 311 284 269 257 249 236 216 210 162 IR (neat) 3478 1709 1368














3H) 13C NMR (125 MHz CDCl3) δ 1389 1283 12752 12748 1086 823 8014 773 765

732 723 708 696 424 3895 3881 3834 324 312 283 270 258 249 236 218 211

58


requires 4932524]
















59


6333762]


OH

O

H

OOBn

PMP

OO2113

OH

O

H

OHOBn

DIBALtoluene

+

OH

OH

H

OPMBOBn

2114 2115O

OO

O

PMB

ndash20 degC 1 h72

[21142115 = 31]













60



12742 1138 1086 821 798 793 773 763 733 720 695 688 553 439 3845 3838

358 324 317 290 270 258 249 237 216 211 143 IR (neat) 3501 1516 1250 cmndash1









NMR (125 MHz CDCl3) δ 1593 1392 1305 1296 1283 12742 12736 1139 1087 816

772 766 747 739 733 722 704 696 554 396 3891 3868 356 323 312 283 271

259 250 240 216 207 154


OH

OH

H

OPMBOBn

2114O

O

(R) or (S)-MTPA-Cl

Et3N DMAPCH2Cl2

OH

O

H

OPMBOBn(R)(S)-MTPA

1

2 2

39

12

16

1717

OO

25 degC 2 h



61






3H)









(R)ndash ester 3244 0892 0829 3140 3429 3965 1401 1353 0795


Preparation of 2116

62














088 (s 3H) 13C NMR (125 MHz CDCl3) δ 1591 1393 1314 1293 1282 12733 12726

1137 1087 962 817 791 772 764 745 7322 7318 709 696 558 553 428 386

358 349 323 319 293 271 258 250 241 2145 2127 139 IR (neat) 1514 1246 1034


63















12734 12727 1137 961 817 789 772 745 7331 7319 726 708 668 558 553 428

386 357 349 323 314 291 250 241 2143 2124 141 IR (neat) 3418 1456 1250 739


64
















13C NMR (125 MHz CDCl3) δ 1591 1393 1314 1293 1282 12733 12725 1138 962

817 791 772 745 7324 7317 709 558 553 526 471 428 386 358 347 323 308


6213753 [(M+Na)+ C36H54O7 requires 6213762]

65


















1314 1293 1282 12732 12722 1262 1137 961 817 790 772 745 7325 7314 707

691 584 558 553 519 447 428 386 373 362 356 347 323 290 2646 2625 2503

66




Addition Reaction














1293 1282 12731 12721 1137 962 817 792 772 745 7321 7314 7303 708 685

67

558 553 491 478 4320 4290 4278 386 358 348 339 323 288 2600 2593 2581


















68



(s 3H) 13C NMR (125 MHz CDCl3) δ 1590 1394 1315 1293 1282 12734 12723 1137

962 817 805 793 772 745 7322 7317 7315 712 708 705 558 553 480 432 429

421 386 358 348 340 323 289 2603 2593 (2 carbons) 255 250 241 214 212



Preparation of 2121











69








MHz CDCl3) δ 1590 1589 1566 1394 1349 1315 1294 1291 1282 12737 12725

1259 1169 1143 1138 1056 962 939 818 806 792 772 746 7325 7320 727 719

708 558 554 482 436 429 422 386 358 348 341 323 289 269 2608 2602 2586









70







(s 3H) 13C NMR (125 MHz CDCl3) δ 1602 1591 1571 1483 1351 1308 1298 1252

1151 1137 1120 1049 963 837 789 780 777 754 732 707 702 556 553 422

380 364 3481 (2 carbons) 3427 3424 320 3169 (2 carbons) 291 271 2572 2562 250


[(M+Na)+ C45H68O10 requires 7914705]


71

























72











1367 1353 1315 1294 1286 12800 12791 1253 1153 1138 1122 1051 963 821

793 782 779 750 732 707 661 558 554 469 429 366 359 350 347 344 3201

3182 (2 carbons) 292 273 2585 2576 2570 2390 2382 222 203 138 IR (neat) 1737


Preparation of 2124




73









MHz CDCl3) δ 1769 1604 1573 1484 1366 1352 1286 1281 1279 1254 1153 1122

1051 962 824 784 778 751 736 717 663 559 469 413 391 372 366 344 343

320 319 317 283 273 259 258 253 239 238 213 207 153 IR (neat) 3521 1733


74


31 Introduction



















75









deacetylation

76













77


















78



















79




















80






occur117








and ovarian cancer










81











82








malaria in mice121c









83
















84











85










86



FR901375

O O O

NHHN

OTBS

ONH

O

NHO

STr

STr

O OHCO2H

NHHN

OTBS

ONH

O

NHO

STr

STr

CO2MeNH2

HNOTBS

ONH

O

NHO

STr

O

O

Bn

O

Cl

H

O STr

O

O

Bn

O

Cl

OH STrOH STr

HO2C

CO2Me

HNOTBS

OFmocHN

STr

CO2H

HNOH

310

312 313

310 315 316

317 318

311

h k

bc

d g

a+

opn

lm







87






















88



89


















90











cells145











more detail later

91













92













93










94

N S

BocHN

SN

MeO2C

OHO

NH2

OH

OOH

S NH

O O OSN

SNNH

O

O





OH

OOH


or+ +

H

O

RS OHHO

OOH

O

OOtBu

OOH

Aux

OO

R+ or or or









95





















96












97

largazole

BocHN

SN

SN

HO2C

N

OH O S

S

Bn

TrtS

OTMSE

O O

TrtS

O

NHFmoc

NH

O OSN

SNNH

O

O

TrtS

OSN

SNNH

O

O

TrtS NHBoc

O OTMSE

334 335

336

337338

ab cd

ef gh



98














99













100










PC-3)170







potency170172

101





















102


321 Synthetic Goals











selectivity

103











binding

104











105












106







def

N S

BocHN

NS

MeO2C

SN

SOOH

N S

NH

NS

MeO2C

OOHTrtS

TrtS

N S

NH

NS

OOO

R2R1


TrtS

N S

NH

NSO

OOO

NH

TrtS

ab

c

+

347328

348

338








107





a

S NH

O OSN

SN

O

NH

O

SNH

OOS N

SN

O

HN

O

b

NH

O OSN

SN

O

NH

O

SS

BocHN CO2tBu

c

NH

O OSN

SN

O

NH

O

SS

BocHN CO2H

NH

O OSN

SN

O

NH

O

TrtS

338

339

340

341



108














steps (Scheme 39)

109












110












111












112





N S

NH

NSO

OOO

NH

R1

N S

NH

NSO

OOO

NH

R2

a

XS XS

XS

XS

a b c d

R1 =R2 =R3 =

N S

NH

NSO

OOO

NH

R3

b

X = Trt

371a d 372a d 373a d

X = HX = n-C7H17CO










113










114

a b

d e

cOH

O

MeO

NN

N

OH

TrtS

OMe

O

HO2C

OHOMe

O

CO2H

OH

OMe

O

OH

OH

OMe

O

OTs

OH

OMe

O

N3NN

N

OH

HS

OMe

O

AB

NOEH

NOE

f

380 381 382 383

384 385

386















392 (Scheme 316)

115

ab c

de fg

NN

N

OH

TrtS

OMe

O

N S

NH

NS

RO2C

OOH

N

NNTrtS

N S

NH

NS

R

OO

N

NNTrtS

O

NHFmocN S

NH

NSO

OOO

NH

N

NNTrtS

N S

NH

NSO

OOO

NH

N

NNS

N S

TFA H2N

NS

RO2C

392

385

388 R = Me389 R = Fm

368 R = Me387 R = Fm

394 R = CO2Me390 R = CO2Fm

391

n-C7H15

O



33 Conclusion






116










117

















= 70 70 70 Hz 2 H) 164 (s 3 H)

118















(m 3 H) 163 (s 3 H) 090 (d J = 60 Hz 3 H) 085 (d J = 70 Hz 3 H)

119




















120




205 (m 3 H) 183 (s 3 H) 068 (d J = 65 Hz 3 H) 052 (d J = 65 Hz 3 H)


N S

NH

NSO

OOO

NH

TrtS S NH

O OSN

SN

O

NH

O

SNH

OOS N

SN

O

HN

OI2


88

338 339













121

16907 16817 1647 1476 1329 1285 1243 846 721 579 434 412 406 378 343















= 72 72 72 Hz 2 H) 208 (m 1 H) 185 (s 3 H) 146 (s 9 H) 143 (s 9 H) 068 (d J = 68


1680 1646 1151 475 1325 1285 1243 844 827 799 720 578 538 433 418 411

122

404 376 342 317 284 280 243 189 167 HRMS (ESI) mz 7722537 [(M+H)+
















1480 1335 1300 1269 850 806 795 739 590 543 437 418 415 406 386 354


7161911]

123


















124













Hz 3 H)


N S

BocHN

NS


N S

NH

NS

MeO2C

OOH2) DMAP CH2Cl2


SN

SOOH

TrtS

TrtS

343a

328369a



125














1629 1482 1447 1434 1373 1296 12875 12856 1280 1268 1264 1244 1225 845

706 675 530 448 415 408 370 240




126


















127


















210 (m 1 H) 187 (s 3 H) 069 (d J = 70 Hz 3 H) 055 (d J = 70 Hz 3 H)


128










Hz 3 H)










129





1738 1696 1689 1681 1647 1476 1400 1386 12918 12887 1265 12478 12446

845 739 578 440 434 429 413 344 330 317 2902 2901 257 245 227 189 168

142 344 330 317 2902 2901







75 75 Hz 2 H)







130









254 (dd J = 80 80 Hz 2 H)












131



(d J = 70 Hz 3 H) 098 (d J = 70 Hz 3 H)















132


242 (dd J = 75 75 Hz 2 H) 163 (s 3 H)


N S

NH

NS

OOO

R2R1




N S

NH

NS

MeO2C

OOH

TrtS TrtS369b















J = 70 Hz 3 H)

133




















134




H) 066 (d J = 68 Hz 3 H) 051 (d J = 68 Hz 3 H)



83

N S

NH

NSO

OOO

NH

TrtS

N S

NH

NSO

OOO

NH

HS371b 372b










135














NMR (125 MHz CDCl3) δ 1995 1737 1696 1689 1681 1647 1475 1402 1347 1290

1262 1245 844 740 577 442 434 427 412 357 343 317 301 289 257 244 226

189 167 141

136










175 Hz 1 H) 536 (d J = 105 Hz 1 H)







137




CNHODIBALH toluene

0 degC 1 h TrtSO

50 for 3 steps

CN








purification








268 (dd J = 76 76 Hz 2 H)




138





17 H) 263 (dd J = 76 76 Hz 2 H) 247 (dd J = 76 76 Hz 2 H)














= 68 Hz 3 H) 099 (d J = 68 Hz 3 H)

139















H)

140


N S

NH

NS

OOO

R2R1



2) 3-69c DMAP25 degC 2 h85

N S

NH

NS

MeO2C

OOHTrtS TrtS

369c













J = 48 152 Hz 1 H) 256 (m 2 H) 244 (m 2 H) 205 (m 1 H) 166 (s 3 H) 083 (d J = 68

Hz 3 H) 069 (d J = 64 Hz 3 H)

141




















142



= 160 116 Hz 1 H) 268 (dd J = 164 24 Hz 1 H) 249 (m 2 H) 237 (m 2 H) 206 (m 1

H) 184 (s 3 H) 063 (d J = 72 Hz 3 H) 049 (d J = 68 Hz 3 H)











80 80 Hz 1 H) 070 (d J = 65 Hz 3 H) 057 (d J = 65 Hz 3 H)

143

















144












(dd J = 76 76 Hz 1 H) 450 (s 2 H) 391 (s 3 H)








145


NMR (100 MHz CDCl3) δ 1663 1323 1311 1305 12931 12927 12907 1175 523 234















146



δ 726ndash739 (m 4 H) 449 (s 2 H) 375 (s 2 H)


















147


Hz 2 H) 332 (s 2 H)














233 (m 1 H) 104 (d J = 68 Hz 3 H) 096 (d J = 68 Hz 3 H)

148

















149


N S

NH

NS

OOO

R2R1




N S

NH

NS

MeO2C

OOH

TrtS TrtS

369d















H)

150



















151






1 H) 185 (s 3 H) 071 (d J = 72 Hz 3 H) 050 (d J = 68 Hz 3 H)











(d J = 68 Hz 3 H) 050 (d J = 72 Hz 3 H)

152















153















purification






154















NMR (100 MHz CDCl3) δ 1720 1445 1368 1322 1296 1281 1269 6724 6708 5219

5206 385 304 228

155








264 (dd J = 170 50 Hz 1 H) 255 (dd J = 170 80 Hz 1 H)






156


















157













(100 MHz CDCl3) δ 1730 1714 1687 1685 1630 1566 1485 1444 14367 14361

14352 14139 14136 1365 1324 1296 1281 12791 12787 12719 12713 12695

12530 12521 12511 12505 1221 12010 12007 846 702 6748 6736 6724 599 489

471 468 417 413 381 3026 3019 241 227 189 180





N S

NH

NS

R1

OO

N

NNTrtS

O

R2

N S

NH

NS

OO

N

NNTrtS

O

NH

O

391

158




purification















159










Hz 1 H) 073 (d J = 68 Hz 3 H) 052 (d J = 68 Hz 3 H)









160






70 Hz 3 H) 055 (d J = 70 Hz 3 H)

161

References


















162






















163



















164























165






















166




















167

















168


















169




















170




















171






172

Biography









Honors amp Awards


Publications




173




Presentations





vii

Contents

Abstract iv

List of Tables x

List of Figures xi

Acknowledgements xx

1 Introduction 1




21 Introduction 6















viii







23 Conclusion 51



31 Introduction 74
















ix


33 Conclusion 115


References 161

Biography 172

x













Chapter 3




xi






Chapter 2










Chapter 3








xii










xiii

List of Schemes

Chapter 2





















Chapter 3


xiv
















xv




aq aqueous

Asp aspartic acid

br s broad singlet

Bn benzyl

BnBr benzyl bromide



t-Bu tert-butyl




CM cross metathesis



Cu copper


d doublet





xvi












ent enantiomer

eq equivalent

Et2O diethyl ether

EtOAc ethyl acetate






c-Hex cyclohexane



His histidine

xvii










Lys lysine

m multiplet


MeCN acetonitrile

MeOH methanol


min minute









xviii






q quartet


Rf retention factor

rt room temperature

s singlet

sat saturated



t triplet






THF tetrahydrofuran



TMS trimethylsilyl


xix



Tyr tyrosine


UV ultraviolet





xx

Acknowledgements





















1

1 Introduction















2
















3












4








levels







5





development










6


21 Introduction













world

7






8




N O

OOHOH

NH

O

F 2

Ca2+


O

OOHOH

2

Ca2+


N

NNSO2Me

F

OH

OOHOHN


O

O

HO O

O

H

H


O

OHCO2Na

HO

O

H


O

O

HO O

O

H

H

simvastatin (Zocor)

OH

OOHOH


N

F

3H2O







9










drugs











10

O

O

OH

Me

O

Me

Me

OH OH

MeO

O

O

OH

Me

O

Me

Me

HOHO

OMe

MeOH

MeO

OMe

Me

Me

Me

HO

OMe

OMeswinholide A

tartrolon B

O

Me

Me O

Me

O

O

MeOOH

O

Me

O

OHO

Me

OO

OO

O

HOOH

OH

OO

R

OOO

HOOH

OH

O

R

O

O

OHOH

OH

OH

O

OH

4

10

R =

cycloviracin B1

BNa

RO O

O

HO

OH O O

OOH

O

OR










11














12
















13














14

O

O

OTBS

Me

O

Me

Me

O O

MeO

O

OHMe

Me

OO

OMe

MeOTBS

MeO

OMe

Me

Me

Me

TBSO

OMe

OMe

OTBS

Me

O

MeO

PMP

PMP

O

HO

OTBS

Me

O

Me

Me

O O

MeO

O

OTMSMe

Me

OO

OMe

MeOTBS

MeO

OMe

Me

Me

Me

TBSO

OMe

OMe

OTBS

Me

O

MeO

PMP

PMP

OH

O

O

OTBS

Me

O

Me

Me

O O

MeO

O

O

TBSO

Me

O

Me

Me

OO

OMe

MeOTBS

MeO

OMe

Me

Me

Me

TBSO

OMe

OMe

swinholide A

PMP

PMP

ab

27

28 29

210

cd e






15
















16










17
















18















D +26 c 10 CHCl3)50

19









O

R1

OO

O O

OHOR2

O

NaO2C

OOH

O O O

CO2H

O O

HOO

HO

OH

H

H

H

H

H

H

H

Hcis

cis

cis

cis


BnMOMBnMOMSEM

R1 R2

H

H

H

H

SCH 351448 (214)

11




20














21





(Scheme 26)





22







O

TMSEO2C

OO

O O

OTBSOBn O

TMSEO2C

OOH

O O O

CO2TMSE

O O

HOO

BnO

OBn

H

H

H

H

H

H

H

H

H

H

H

H

O

TMSEO2C

OOH

O O O

CO2TMSE

O O

HOO

HO

OH

H

H

H

H

H

H

H

H

SCH 351448

a c

de f

2 27 2 28

2 29

2 22 +

OO

O O

2 30



23


O

BnO2C

OO

O O

OTBSOBn

ab cd

i k l o

O

BnO2C

OH

OHOBn

O

BnO2C

OOBnO

BnO2C

O

OCO2

tBu

CHOe h

NSi

Np-Br-C6H4

p-Br-C6H4

ClR

237 R= H238 R=Me

2 312 32

2 33 2 34

2 35 2 36

O

O O

O

2 39

+









24













25











26




14-syn-Aldol

O

O


O

TfO

O

O

O

O

O OHSS

O

HO

OH

OH

O

+ +

+ +

SS SS

TIPSO

TIPSO PMBO

OH

SS

PMBO


OH

OSS

TIPSO

O


OAc OTBS

O

O

O O

H

H

OH H

TIPSOSS

S

SO

NaO2C

OOH

O O O

CO2H

O O

HOO

HO

OH

H

H

H

H

H

H

H

Hcis

cis

cis

cis

214 244

245 246 247

248 249 250

251252

253


27









respectively




28













29









211)

30

MsO O

SS

PMBO O

SSO

PMBO O

SS

HO O

SS

TIPS TIPS

PMBO O

SS

TIPS

I O

SS

TIPS

a b c

d e

N O

OSS

OH

TIPS

H3C O

OSS

TIPS

N O

SS

CH3

TIPSO

H3C

Ph

OTf

f

g

h

263 265 266

267 268 269

270 271

272









31













conditions

32














33











34


OH O

OH

HTIPS

S

S

H3C

O

OH

HTIPS

S

S

+

conditions

O

274

272 275






35


36








37















38


















39




















40

292 R = TBS

OR OR

OO

O

OBn

H H

OR OR

O

OBn

H H

OH

OH O

OO

O

OBn

H Hab

291 R = TBS

cd

OR OR

OH

S

S

HO

OR OR

O

O

H

H

S

S

OH H

OBn

cis

OR OR

OH

H

S

S

gt201

H

OH H

OBn

OH H

OBn

OH

OR

H

OROBn

OO

O O

H

H

S

S

f g

h i

293 R = TBS 294 R = TBS

e

296 R = TBS

OH

OH

H

OHOBn

OO

O O

H

H

S

S

290

295 R = TBS

297

O

O O

OTf

247



41








42

OH

OR1

H

OR2OBn

OH

H

S

S

b

OH H

OBn OR1 OR2

OH

H

S

S

OH H

OBn OR1 OR2

OH

H

S

S

a

d


OH

OR

H

OOBn

OH

H

S

S

O

HO OTf

OH

OR

H

OOBn

OH

H

S

S

O

BnO OTf

c

2106 R = Bn 2107 R = Bn









217)

43











44









45










46










47


moiety (Scheme 219)

O OPMB

OH

S

S

HO

O OPMB

O

O

H

H

S

S

OH H

OBn

cis

O OPMB

OH

H

S

S

gt201

H

OH H

OBn

OH H

OBn

MOM

MOMMOMO OPMB

OH

OH H

OBnMOM

SS

OH

+

OTfO

O O

OH

O

H

OPMBOBn

OO

O O

H

H

S

S

MOM

OH

O

H

OPMBOH

O

O

O O

H

H

MOM

O OPMB

O

O

O O

H

H

OBnO2C

H H

MOM

a b c

+d e

fgh i

2117

252

2118 2119

2120

247 2121 2122

2123 2124

ref 53 SCH 351448

BnO2CO

H

O

H

OH

O

O

O O

H

H

MOM

13 7

9 11

15

192229



48















49


Carbon



(400 MHz) Hong


(400 MHz) Hong



3 351 (d) 350 (d) 107ndash128 (m) 106ndash128 (m)

4 139ndash165 (m) 138ndash165 (m) 22 306-313 (m) 306-313 (m)


139ndash165 (m) 138ndash165 (m) 24 678 (d) 678 (d)

6 139ndash165 (m) 138ndash165 (m) 25 728 (t) 738 (t)

107ndash128 (m) 106ndash128 (m) 26 693 (d) 693 (d)

















50


Carbon



De Brabander

(100 MHz) Hong


(100 MHz) Hong

(125 MHz) 1 1769 1769 22 344 344

2 469 469 23 1484 1484

3 824 824 24 1254 1254

4 366 366 25 1353 1352

5 238 238 26 1153 1153

6 320 320 27 1122 1122

7 a 752 751 28 1604 1604

8 414 413 29 1573 1573

9 736 736 30 1051 1051

10 391 391 1-OCH2Ph 1366 1366

11 717 717 1286 1286

12 372 372 1281 1281

13 273 273 1279 1279

14 253 253 1-OCH2Ph 663 663

15 a 778 778 2-Me 214 213

16 319 319 2-Me 207 207

17 239 239 9-OCH2OCH3 962 962

18 317 317 9-OCH2OCH3 560 559

191 785 784 12-Me 153 153

20 343 343 30-Me 259 259


51

23 Conclusion


















52














(s 3H) 13C NMR (125 MHz CDCl3) δ 1391 1379 1285 12776 12756 1144 800 785



53












2023 1391 1283 12741 12737 814 769 735 732 500 385 315 246 238 215








2018 1390 1282 12743 12734 767 731 728 685 444 383 283 249 215 201 188

54


















C6H6) δ 1772 1765 1433 1429 1283 1280 1270 1265 1084 760 7574 7565

749 694 692 578 361 353 3114 3111 300 297 2697 2694 2577 2560

55

















56


















57



2135 1389 1283 12742 12736 1088 821 788 772 758 732 693 679 481 466

427 383 321 311 284 269 257 249 236 216 210 162 IR (neat) 3478 1709 1368














3H) 13C NMR (125 MHz CDCl3) δ 1389 1283 12752 12748 1086 823 8014 773 765

732 723 708 696 424 3895 3881 3834 324 312 283 270 258 249 236 218 211

58


requires 4932524]
















59


6333762]


OH

O

H

OOBn

PMP

OO2113

OH

O

H

OHOBn

DIBALtoluene

+

OH

OH

H

OPMBOBn

2114 2115O

OO

O

PMB

ndash20 degC 1 h72

[21142115 = 31]













60



12742 1138 1086 821 798 793 773 763 733 720 695 688 553 439 3845 3838

358 324 317 290 270 258 249 237 216 211 143 IR (neat) 3501 1516 1250 cmndash1









NMR (125 MHz CDCl3) δ 1593 1392 1305 1296 1283 12742 12736 1139 1087 816

772 766 747 739 733 722 704 696 554 396 3891 3868 356 323 312 283 271

259 250 240 216 207 154


OH

OH

H

OPMBOBn

2114O

O

(R) or (S)-MTPA-Cl

Et3N DMAPCH2Cl2

OH

O

H

OPMBOBn(R)(S)-MTPA

1

2 2

39

12

16

1717

OO

25 degC 2 h



61






3H)









(R)ndash ester 3244 0892 0829 3140 3429 3965 1401 1353 0795


Preparation of 2116

62














088 (s 3H) 13C NMR (125 MHz CDCl3) δ 1591 1393 1314 1293 1282 12733 12726

1137 1087 962 817 791 772 764 745 7322 7318 709 696 558 553 428 386

358 349 323 319 293 271 258 250 241 2145 2127 139 IR (neat) 1514 1246 1034


63















12734 12727 1137 961 817 789 772 745 7331 7319 726 708 668 558 553 428

386 357 349 323 314 291 250 241 2143 2124 141 IR (neat) 3418 1456 1250 739


64
















13C NMR (125 MHz CDCl3) δ 1591 1393 1314 1293 1282 12733 12725 1138 962

817 791 772 745 7324 7317 709 558 553 526 471 428 386 358 347 323 308


6213753 [(M+Na)+ C36H54O7 requires 6213762]

65


















1314 1293 1282 12732 12722 1262 1137 961 817 790 772 745 7325 7314 707

691 584 558 553 519 447 428 386 373 362 356 347 323 290 2646 2625 2503

66




Addition Reaction














1293 1282 12731 12721 1137 962 817 792 772 745 7321 7314 7303 708 685

67

558 553 491 478 4320 4290 4278 386 358 348 339 323 288 2600 2593 2581


















68



(s 3H) 13C NMR (125 MHz CDCl3) δ 1590 1394 1315 1293 1282 12734 12723 1137

962 817 805 793 772 745 7322 7317 7315 712 708 705 558 553 480 432 429

421 386 358 348 340 323 289 2603 2593 (2 carbons) 255 250 241 214 212



Preparation of 2121











69








MHz CDCl3) δ 1590 1589 1566 1394 1349 1315 1294 1291 1282 12737 12725

1259 1169 1143 1138 1056 962 939 818 806 792 772 746 7325 7320 727 719

708 558 554 482 436 429 422 386 358 348 341 323 289 269 2608 2602 2586









70







(s 3H) 13C NMR (125 MHz CDCl3) δ 1602 1591 1571 1483 1351 1308 1298 1252

1151 1137 1120 1049 963 837 789 780 777 754 732 707 702 556 553 422

380 364 3481 (2 carbons) 3427 3424 320 3169 (2 carbons) 291 271 2572 2562 250


[(M+Na)+ C45H68O10 requires 7914705]


71

























72











1367 1353 1315 1294 1286 12800 12791 1253 1153 1138 1122 1051 963 821

793 782 779 750 732 707 661 558 554 469 429 366 359 350 347 344 3201

3182 (2 carbons) 292 273 2585 2576 2570 2390 2382 222 203 138 IR (neat) 1737


Preparation of 2124




73









MHz CDCl3) δ 1769 1604 1573 1484 1366 1352 1286 1281 1279 1254 1153 1122

1051 962 824 784 778 751 736 717 663 559 469 413 391 372 366 344 343

320 319 317 283 273 259 258 253 239 238 213 207 153 IR (neat) 3521 1733


74


31 Introduction



















75









deacetylation

76













77


















78



















79




















80






occur117








and ovarian cancer










81











82








malaria in mice121c









83
















84











85










86



FR901375

O O O

NHHN

OTBS

ONH

O

NHO

STr

STr

O OHCO2H

NHHN

OTBS

ONH

O

NHO

STr

STr

CO2MeNH2

HNOTBS

ONH

O

NHO

STr

O

O

Bn

O

Cl

H

O STr

O

O

Bn

O

Cl

OH STrOH STr

HO2C

CO2Me

HNOTBS

OFmocHN

STr

CO2H

HNOH

310

312 313

310 315 316

317 318

311

h k

bc

d g

a+

opn

lm







87






















88



89


















90











cells145











more detail later

91













92













93










94

N S

BocHN

SN

MeO2C

OHO

NH2

OH

OOH

S NH

O O OSN

SNNH

O

O





OH

OOH


or+ +

H

O

RS OHHO

OOH

O

OOtBu

OOH

Aux

OO

R+ or or or









95





















96












97

largazole

BocHN

SN

SN

HO2C

N

OH O S

S

Bn

TrtS

OTMSE

O O

TrtS

O

NHFmoc

NH

O OSN

SNNH

O

O

TrtS

OSN

SNNH

O

O

TrtS NHBoc

O OTMSE

334 335

336

337338

ab cd

ef gh



98














99













100










PC-3)170







potency170172

101





















102


321 Synthetic Goals











selectivity

103











binding

104











105












106







def

N S

BocHN

NS

MeO2C

SN

SOOH

N S

NH

NS

MeO2C

OOHTrtS

TrtS

N S

NH

NS

OOO

R2R1


TrtS

N S

NH

NSO

OOO

NH

TrtS

ab

c

+

347328

348

338








107





a

S NH

O OSN

SN

O

NH

O

SNH

OOS N

SN

O

HN

O

b

NH

O OSN

SN

O

NH

O

SS

BocHN CO2tBu

c

NH

O OSN

SN

O

NH

O

SS

BocHN CO2H

NH

O OSN

SN

O

NH

O

TrtS

338

339

340

341



108














steps (Scheme 39)

109












110












111












112





N S

NH

NSO

OOO

NH

R1

N S

NH

NSO

OOO

NH

R2

a

XS XS

XS

XS

a b c d

R1 =R2 =R3 =

N S

NH

NSO

OOO

NH

R3

b

X = Trt

371a d 372a d 373a d

X = HX = n-C7H17CO










113










114

a b

d e

cOH

O

MeO

NN

N

OH

TrtS

OMe

O

HO2C

OHOMe

O

CO2H

OH

OMe

O

OH

OH

OMe

O

OTs

OH

OMe

O

N3NN

N

OH

HS

OMe

O

AB

NOEH

NOE

f

380 381 382 383

384 385

386















392 (Scheme 316)

115

ab c

de fg

NN

N

OH

TrtS

OMe

O

N S

NH

NS

RO2C

OOH

N

NNTrtS

N S

NH

NS

R

OO

N

NNTrtS

O

NHFmocN S

NH

NSO

OOO

NH

N

NNTrtS

N S

NH

NSO

OOO

NH

N

NNS

N S

TFA H2N

NS

RO2C

392

385

388 R = Me389 R = Fm

368 R = Me387 R = Fm

394 R = CO2Me390 R = CO2Fm

391

n-C7H15

O



33 Conclusion






116










117

















= 70 70 70 Hz 2 H) 164 (s 3 H)

118















(m 3 H) 163 (s 3 H) 090 (d J = 60 Hz 3 H) 085 (d J = 70 Hz 3 H)

119




















120




205 (m 3 H) 183 (s 3 H) 068 (d J = 65 Hz 3 H) 052 (d J = 65 Hz 3 H)


N S

NH

NSO

OOO

NH

TrtS S NH

O OSN

SN

O

NH

O

SNH

OOS N

SN

O

HN

OI2


88

338 339













121

16907 16817 1647 1476 1329 1285 1243 846 721 579 434 412 406 378 343















= 72 72 72 Hz 2 H) 208 (m 1 H) 185 (s 3 H) 146 (s 9 H) 143 (s 9 H) 068 (d J = 68


1680 1646 1151 475 1325 1285 1243 844 827 799 720 578 538 433 418 411

122

404 376 342 317 284 280 243 189 167 HRMS (ESI) mz 7722537 [(M+H)+
















1480 1335 1300 1269 850 806 795 739 590 543 437 418 415 406 386 354


7161911]

123


















124













Hz 3 H)


N S

BocHN

NS


N S

NH

NS

MeO2C

OOH2) DMAP CH2Cl2


SN

SOOH

TrtS

TrtS

343a

328369a



125














1629 1482 1447 1434 1373 1296 12875 12856 1280 1268 1264 1244 1225 845

706 675 530 448 415 408 370 240




126


















127


















210 (m 1 H) 187 (s 3 H) 069 (d J = 70 Hz 3 H) 055 (d J = 70 Hz 3 H)


128










Hz 3 H)










129





1738 1696 1689 1681 1647 1476 1400 1386 12918 12887 1265 12478 12446

845 739 578 440 434 429 413 344 330 317 2902 2901 257 245 227 189 168

142 344 330 317 2902 2901







75 75 Hz 2 H)







130









254 (dd J = 80 80 Hz 2 H)












131



(d J = 70 Hz 3 H) 098 (d J = 70 Hz 3 H)















132


242 (dd J = 75 75 Hz 2 H) 163 (s 3 H)


N S

NH

NS

OOO

R2R1




N S

NH

NS

MeO2C

OOH

TrtS TrtS369b















J = 70 Hz 3 H)

133




















134




H) 066 (d J = 68 Hz 3 H) 051 (d J = 68 Hz 3 H)



83

N S

NH

NSO

OOO

NH

TrtS

N S

NH

NSO

OOO

NH

HS371b 372b










135














NMR (125 MHz CDCl3) δ 1995 1737 1696 1689 1681 1647 1475 1402 1347 1290

1262 1245 844 740 577 442 434 427 412 357 343 317 301 289 257 244 226

189 167 141

136










175 Hz 1 H) 536 (d J = 105 Hz 1 H)







137




CNHODIBALH toluene

0 degC 1 h TrtSO

50 for 3 steps

CN








purification








268 (dd J = 76 76 Hz 2 H)




138





17 H) 263 (dd J = 76 76 Hz 2 H) 247 (dd J = 76 76 Hz 2 H)














= 68 Hz 3 H) 099 (d J = 68 Hz 3 H)

139















H)

140


N S

NH

NS

OOO

R2R1



2) 3-69c DMAP25 degC 2 h85

N S

NH

NS

MeO2C

OOHTrtS TrtS

369c













J = 48 152 Hz 1 H) 256 (m 2 H) 244 (m 2 H) 205 (m 1 H) 166 (s 3 H) 083 (d J = 68

Hz 3 H) 069 (d J = 64 Hz 3 H)

141




















142



= 160 116 Hz 1 H) 268 (dd J = 164 24 Hz 1 H) 249 (m 2 H) 237 (m 2 H) 206 (m 1

H) 184 (s 3 H) 063 (d J = 72 Hz 3 H) 049 (d J = 68 Hz 3 H)











80 80 Hz 1 H) 070 (d J = 65 Hz 3 H) 057 (d J = 65 Hz 3 H)

143

















144












(dd J = 76 76 Hz 1 H) 450 (s 2 H) 391 (s 3 H)








145


NMR (100 MHz CDCl3) δ 1663 1323 1311 1305 12931 12927 12907 1175 523 234















146



δ 726ndash739 (m 4 H) 449 (s 2 H) 375 (s 2 H)


















147


Hz 2 H) 332 (s 2 H)














233 (m 1 H) 104 (d J = 68 Hz 3 H) 096 (d J = 68 Hz 3 H)

148

















149


N S

NH

NS

OOO

R2R1




N S

NH

NS

MeO2C

OOH

TrtS TrtS

369d















H)

150



















151






1 H) 185 (s 3 H) 071 (d J = 72 Hz 3 H) 050 (d J = 68 Hz 3 H)











(d J = 68 Hz 3 H) 050 (d J = 72 Hz 3 H)

152















153















purification






154















NMR (100 MHz CDCl3) δ 1720 1445 1368 1322 1296 1281 1269 6724 6708 5219

5206 385 304 228

155








264 (dd J = 170 50 Hz 1 H) 255 (dd J = 170 80 Hz 1 H)






156


















157













(100 MHz CDCl3) δ 1730 1714 1687 1685 1630 1566 1485 1444 14367 14361

14352 14139 14136 1365 1324 1296 1281 12791 12787 12719 12713 12695

12530 12521 12511 12505 1221 12010 12007 846 702 6748 6736 6724 599 489

471 468 417 413 381 3026 3019 241 227 189 180





N S

NH

NS

R1

OO

N

NNTrtS

O

R2

N S

NH

NS

OO

N

NNTrtS

O

NH

O

391

158




purification















159










Hz 1 H) 073 (d J = 68 Hz 3 H) 052 (d J = 68 Hz 3 H)









160






70 Hz 3 H) 055 (d J = 70 Hz 3 H)

161

References


















162






















163



















164























165






















166




















167

















168


















169




















170




















171






172

Biography









Honors amp Awards


Publications




173




Presentations





viii







23 Conclusion 51



31 Introduction 74
















ix


33 Conclusion 115


References 161

Biography 172

x













Chapter 3




xi






Chapter 2










Chapter 3








xii










xiii

List of Schemes

Chapter 2





















Chapter 3


xiv
















xv




aq aqueous

Asp aspartic acid

br s broad singlet

Bn benzyl

BnBr benzyl bromide



t-Bu tert-butyl




CM cross metathesis



Cu copper


d doublet





xvi












ent enantiomer

eq equivalent

Et2O diethyl ether

EtOAc ethyl acetate






c-Hex cyclohexane



His histidine

xvii










Lys lysine

m multiplet


MeCN acetonitrile

MeOH methanol


min minute









xviii






q quartet


Rf retention factor

rt room temperature

s singlet

sat saturated



t triplet






THF tetrahydrofuran



TMS trimethylsilyl


xix



Tyr tyrosine


UV ultraviolet





xx

Acknowledgements





















1

1 Introduction















2
















3












4








levels







5





development










6


21 Introduction













world

7






8




N O

OOHOH

NH

O

F 2

Ca2+


O

OOHOH

2

Ca2+


N

NNSO2Me

F

OH

OOHOHN


O

O

HO O

O

H

H


O

OHCO2Na

HO

O

H


O

O

HO O

O

H

H

simvastatin (Zocor)

OH

OOHOH


N

F

3H2O







9










drugs











10

O

O

OH

Me

O

Me

Me

OH OH

MeO

O

O

OH

Me

O

Me

Me

HOHO

OMe

MeOH

MeO

OMe

Me

Me

Me

HO

OMe

OMeswinholide A

tartrolon B

O

Me

Me O

Me

O

O

MeOOH

O

Me

O

OHO

Me

OO

OO

O

HOOH

OH

OO

R

OOO

HOOH

OH

O

R

O

O

OHOH

OH

OH

O

OH

4

10

R =

cycloviracin B1

BNa

RO O

O

HO

OH O O

OOH

O

OR










11














12
















13














14

O

O

OTBS

Me

O

Me

Me

O O

MeO

O

OHMe

Me

OO

OMe

MeOTBS

MeO

OMe

Me

Me

Me

TBSO

OMe

OMe

OTBS

Me

O

MeO

PMP

PMP

O

HO

OTBS

Me

O

Me

Me

O O

MeO

O

OTMSMe

Me

OO

OMe

MeOTBS

MeO

OMe

Me

Me

Me

TBSO

OMe

OMe

OTBS

Me

O

MeO

PMP

PMP

OH

O

O

OTBS

Me

O

Me

Me

O O

MeO

O

O

TBSO

Me

O

Me

Me

OO

OMe

MeOTBS

MeO

OMe

Me

Me

Me

TBSO

OMe

OMe

swinholide A

PMP

PMP

ab

27

28 29

210

cd e






15
















16










17
















18















D +26 c 10 CHCl3)50

19









O

R1

OO

O O

OHOR2

O

NaO2C

OOH

O O O

CO2H

O O

HOO

HO

OH

H

H

H

H

H

H

H

Hcis

cis

cis

cis


BnMOMBnMOMSEM

R1 R2

H

H

H

H

SCH 351448 (214)

11




20














21





(Scheme 26)





22







O

TMSEO2C

OO

O O

OTBSOBn O

TMSEO2C

OOH

O O O

CO2TMSE

O O

HOO

BnO

OBn

H

H

H

H

H

H

H

H

H

H

H

H

O

TMSEO2C

OOH

O O O

CO2TMSE

O O

HOO

HO

OH

H

H

H

H

H

H

H

H

SCH 351448

a c

de f

2 27 2 28

2 29

2 22 +

OO

O O

2 30



23


O

BnO2C

OO

O O

OTBSOBn

ab cd

i k l o

O

BnO2C

OH

OHOBn

O

BnO2C

OOBnO

BnO2C

O

OCO2

tBu

CHOe h

NSi

Np-Br-C6H4

p-Br-C6H4

ClR

237 R= H238 R=Me

2 312 32

2 33 2 34

2 35 2 36

O

O O

O

2 39

+









24













25











26




14-syn-Aldol

O

O


O

TfO

O

O

O

O

O OHSS

O

HO

OH

OH

O

+ +

+ +

SS SS

TIPSO

TIPSO PMBO

OH

SS

PMBO


OH

OSS

TIPSO

O


OAc OTBS

O

O

O O

H

H

OH H

TIPSOSS

S

SO

NaO2C

OOH

O O O

CO2H

O O

HOO

HO

OH

H

H

H

H

H

H

H

Hcis

cis

cis

cis

214 244

245 246 247

248 249 250

251252

253


27









respectively




28













29









211)

30

MsO O

SS

PMBO O

SSO

PMBO O

SS

HO O

SS

TIPS TIPS

PMBO O

SS

TIPS

I O

SS

TIPS

a b c

d e

N O

OSS

OH

TIPS

H3C O

OSS

TIPS

N O

SS

CH3

TIPSO

H3C

Ph

OTf

f

g

h

263 265 266

267 268 269

270 271

272









31













conditions

32














33











34


OH O

OH

HTIPS

S

S

H3C

O

OH

HTIPS

S

S

+

conditions

O

274

272 275






35


36








37















38


















39




















40

292 R = TBS

OR OR

OO

O

OBn

H H

OR OR

O

OBn

H H

OH

OH O

OO

O

OBn

H Hab

291 R = TBS

cd

OR OR

OH

S

S

HO

OR OR

O

O

H

H

S

S

OH H

OBn

cis

OR OR

OH

H

S

S

gt201

H

OH H

OBn

OH H

OBn

OH

OR

H

OROBn

OO

O O

H

H

S

S

f g

h i

293 R = TBS 294 R = TBS

e

296 R = TBS

OH

OH

H

OHOBn

OO

O O

H

H

S

S

290

295 R = TBS

297

O

O O

OTf

247



41








42

OH

OR1

H

OR2OBn

OH

H

S

S

b

OH H

OBn OR1 OR2

OH

H

S

S

OH H

OBn OR1 OR2

OH

H

S

S

a

d


OH

OR

H

OOBn

OH

H

S

S

O

HO OTf

OH

OR

H

OOBn

OH

H

S

S

O

BnO OTf

c

2106 R = Bn 2107 R = Bn









217)

43











44









45










46










47


moiety (Scheme 219)

O OPMB

OH

S

S

HO

O OPMB

O

O

H

H

S

S

OH H

OBn

cis

O OPMB

OH

H

S

S

gt201

H

OH H

OBn

OH H

OBn

MOM

MOMMOMO OPMB

OH

OH H

OBnMOM

SS

OH

+

OTfO

O O

OH

O

H

OPMBOBn

OO

O O

H

H

S

S

MOM

OH

O

H

OPMBOH

O

O

O O

H

H

MOM

O OPMB

O

O

O O

H

H

OBnO2C

H H

MOM

a b c

+d e

fgh i

2117

252

2118 2119

2120

247 2121 2122

2123 2124

ref 53 SCH 351448

BnO2CO

H

O

H

OH

O

O

O O

H

H

MOM

13 7

9 11

15

192229



48















49


Carbon



(400 MHz) Hong


(400 MHz) Hong



3 351 (d) 350 (d) 107ndash128 (m) 106ndash128 (m)

4 139ndash165 (m) 138ndash165 (m) 22 306-313 (m) 306-313 (m)


139ndash165 (m) 138ndash165 (m) 24 678 (d) 678 (d)

6 139ndash165 (m) 138ndash165 (m) 25 728 (t) 738 (t)

107ndash128 (m) 106ndash128 (m) 26 693 (d) 693 (d)

















50


Carbon



De Brabander

(100 MHz) Hong


(100 MHz) Hong

(125 MHz) 1 1769 1769 22 344 344

2 469 469 23 1484 1484

3 824 824 24 1254 1254

4 366 366 25 1353 1352

5 238 238 26 1153 1153

6 320 320 27 1122 1122

7 a 752 751 28 1604 1604

8 414 413 29 1573 1573

9 736 736 30 1051 1051

10 391 391 1-OCH2Ph 1366 1366

11 717 717 1286 1286

12 372 372 1281 1281

13 273 273 1279 1279

14 253 253 1-OCH2Ph 663 663

15 a 778 778 2-Me 214 213

16 319 319 2-Me 207 207

17 239 239 9-OCH2OCH3 962 962

18 317 317 9-OCH2OCH3 560 559

191 785 784 12-Me 153 153

20 343 343 30-Me 259 259


51

23 Conclusion


















52














(s 3H) 13C NMR (125 MHz CDCl3) δ 1391 1379 1285 12776 12756 1144 800 785



53












2023 1391 1283 12741 12737 814 769 735 732 500 385 315 246 238 215








2018 1390 1282 12743 12734 767 731 728 685 444 383 283 249 215 201 188

54


















C6H6) δ 1772 1765 1433 1429 1283 1280 1270 1265 1084 760 7574 7565

749 694 692 578 361 353 3114 3111 300 297 2697 2694 2577 2560

55

















56


















57



2135 1389 1283 12742 12736 1088 821 788 772 758 732 693 679 481 466

427 383 321 311 284 269 257 249 236 216 210 162 IR (neat) 3478 1709 1368














3H) 13C NMR (125 MHz CDCl3) δ 1389 1283 12752 12748 1086 823 8014 773 765

732 723 708 696 424 3895 3881 3834 324 312 283 270 258 249 236 218 211

58


requires 4932524]
















59


6333762]


OH

O

H

OOBn

PMP

OO2113

OH

O

H

OHOBn

DIBALtoluene

+

OH

OH

H

OPMBOBn

2114 2115O

OO

O

PMB

ndash20 degC 1 h72

[21142115 = 31]













60



12742 1138 1086 821 798 793 773 763 733 720 695 688 553 439 3845 3838

358 324 317 290 270 258 249 237 216 211 143 IR (neat) 3501 1516 1250 cmndash1









NMR (125 MHz CDCl3) δ 1593 1392 1305 1296 1283 12742 12736 1139 1087 816

772 766 747 739 733 722 704 696 554 396 3891 3868 356 323 312 283 271

259 250 240 216 207 154


OH

OH

H

OPMBOBn

2114O

O

(R) or (S)-MTPA-Cl

Et3N DMAPCH2Cl2

OH

O

H

OPMBOBn(R)(S)-MTPA

1

2 2

39

12

16

1717

OO

25 degC 2 h



61






3H)









(R)ndash ester 3244 0892 0829 3140 3429 3965 1401 1353 0795


Preparation of 2116

62














088 (s 3H) 13C NMR (125 MHz CDCl3) δ 1591 1393 1314 1293 1282 12733 12726

1137 1087 962 817 791 772 764 745 7322 7318 709 696 558 553 428 386

358 349 323 319 293 271 258 250 241 2145 2127 139 IR (neat) 1514 1246 1034


63















12734 12727 1137 961 817 789 772 745 7331 7319 726 708 668 558 553 428

386 357 349 323 314 291 250 241 2143 2124 141 IR (neat) 3418 1456 1250 739


64
















13C NMR (125 MHz CDCl3) δ 1591 1393 1314 1293 1282 12733 12725 1138 962

817 791 772 745 7324 7317 709 558 553 526 471 428 386 358 347 323 308


6213753 [(M+Na)+ C36H54O7 requires 6213762]

65


















1314 1293 1282 12732 12722 1262 1137 961 817 790 772 745 7325 7314 707

691 584 558 553 519 447 428 386 373 362 356 347 323 290 2646 2625 2503

66




Addition Reaction














1293 1282 12731 12721 1137 962 817 792 772 745 7321 7314 7303 708 685

67

558 553 491 478 4320 4290 4278 386 358 348 339 323 288 2600 2593 2581


















68



(s 3H) 13C NMR (125 MHz CDCl3) δ 1590 1394 1315 1293 1282 12734 12723 1137

962 817 805 793 772 745 7322 7317 7315 712 708 705 558 553 480 432 429

421 386 358 348 340 323 289 2603 2593 (2 carbons) 255 250 241 214 212



Preparation of 2121











69








MHz CDCl3) δ 1590 1589 1566 1394 1349 1315 1294 1291 1282 12737 12725

1259 1169 1143 1138 1056 962 939 818 806 792 772 746 7325 7320 727 719

708 558 554 482 436 429 422 386 358 348 341 323 289 269 2608 2602 2586









70







(s 3H) 13C NMR (125 MHz CDCl3) δ 1602 1591 1571 1483 1351 1308 1298 1252

1151 1137 1120 1049 963 837 789 780 777 754 732 707 702 556 553 422

380 364 3481 (2 carbons) 3427 3424 320 3169 (2 carbons) 291 271 2572 2562 250


[(M+Na)+ C45H68O10 requires 7914705]


71

























72











1367 1353 1315 1294 1286 12800 12791 1253 1153 1138 1122 1051 963 821

793 782 779 750 732 707 661 558 554 469 429 366 359 350 347 344 3201

3182 (2 carbons) 292 273 2585 2576 2570 2390 2382 222 203 138 IR (neat) 1737


Preparation of 2124




73









MHz CDCl3) δ 1769 1604 1573 1484 1366 1352 1286 1281 1279 1254 1153 1122

1051 962 824 784 778 751 736 717 663 559 469 413 391 372 366 344 343

320 319 317 283 273 259 258 253 239 238 213 207 153 IR (neat) 3521 1733


74


31 Introduction



















75









deacetylation

76













77


















78



















79




















80






occur117








and ovarian cancer










81











82








malaria in mice121c









83
















84











85










86



FR901375

O O O

NHHN

OTBS

ONH

O

NHO

STr

STr

O OHCO2H

NHHN

OTBS

ONH

O

NHO

STr

STr

CO2MeNH2

HNOTBS

ONH

O

NHO

STr

O

O

Bn

O

Cl

H

O STr

O

O

Bn

O

Cl

OH STrOH STr

HO2C

CO2Me

HNOTBS

OFmocHN

STr

CO2H

HNOH

310

312 313

310 315 316

317 318

311

h k

bc

d g

a+

opn

lm







87






















88



89


















90











cells145











more detail later

91













92













93










94

N S

BocHN

SN

MeO2C

OHO

NH2

OH

OOH

S NH

O O OSN

SNNH

O

O





OH

OOH


or+ +

H

O

RS OHHO

OOH

O

OOtBu

OOH

Aux

OO

R+ or or or









95





















96












97

largazole

BocHN

SN

SN

HO2C

N

OH O S

S

Bn

TrtS

OTMSE

O O

TrtS

O

NHFmoc

NH

O OSN

SNNH

O

O

TrtS

OSN

SNNH

O

O

TrtS NHBoc

O OTMSE

334 335

336

337338

ab cd

ef gh



98














99













100










PC-3)170







potency170172

101





















102


321 Synthetic Goals











selectivity

103











binding

104











105












106







def

N S

BocHN

NS

MeO2C

SN

SOOH

N S

NH

NS

MeO2C

OOHTrtS

TrtS

N S

NH

NS

OOO

R2R1


TrtS

N S

NH

NSO

OOO

NH

TrtS

ab

c

+

347328

348

338








107





a

S NH

O OSN

SN

O

NH

O

SNH

OOS N

SN

O

HN

O

b

NH

O OSN

SN

O

NH

O

SS

BocHN CO2tBu

c

NH

O OSN

SN

O

NH

O

SS

BocHN CO2H

NH

O OSN

SN

O

NH

O

TrtS

338

339

340

341



108














steps (Scheme 39)

109












110












111












112





N S

NH

NSO

OOO

NH

R1

N S

NH

NSO

OOO

NH

R2

a

XS XS

XS

XS

a b c d

R1 =R2 =R3 =

N S

NH

NSO

OOO

NH

R3

b

X = Trt

371a d 372a d 373a d

X = HX = n-C7H17CO










113










114

a b

d e

cOH

O

MeO

NN

N

OH

TrtS

OMe

O

HO2C

OHOMe

O

CO2H

OH

OMe

O

OH

OH

OMe

O

OTs

OH

OMe

O

N3NN

N

OH

HS

OMe

O

AB

NOEH

NOE

f

380 381 382 383

384 385

386















392 (Scheme 316)

115

ab c

de fg

NN

N

OH

TrtS

OMe

O

N S

NH

NS

RO2C

OOH

N

NNTrtS

N S

NH

NS

R

OO

N

NNTrtS

O

NHFmocN S

NH

NSO

OOO

NH

N

NNTrtS

N S

NH

NSO

OOO

NH

N

NNS

N S

TFA H2N

NS

RO2C

392

385

388 R = Me389 R = Fm

368 R = Me387 R = Fm

394 R = CO2Me390 R = CO2Fm

391

n-C7H15

O



33 Conclusion






116










117

















= 70 70 70 Hz 2 H) 164 (s 3 H)

118















(m 3 H) 163 (s 3 H) 090 (d J = 60 Hz 3 H) 085 (d J = 70 Hz 3 H)

119




















120




205 (m 3 H) 183 (s 3 H) 068 (d J = 65 Hz 3 H) 052 (d J = 65 Hz 3 H)


N S

NH

NSO

OOO

NH

TrtS S NH

O OSN

SN

O

NH

O

SNH

OOS N

SN

O

HN

OI2


88

338 339













121

16907 16817 1647 1476 1329 1285 1243 846 721 579 434 412 406 378 343















= 72 72 72 Hz 2 H) 208 (m 1 H) 185 (s 3 H) 146 (s 9 H) 143 (s 9 H) 068 (d J = 68


1680 1646 1151 475 1325 1285 1243 844 827 799 720 578 538 433 418 411

122

404 376 342 317 284 280 243 189 167 HRMS (ESI) mz 7722537 [(M+H)+
















1480 1335 1300 1269 850 806 795 739 590 543 437 418 415 406 386 354


7161911]

123


















124













Hz 3 H)


N S

BocHN

NS


N S

NH

NS

MeO2C

OOH2) DMAP CH2Cl2


SN

SOOH

TrtS

TrtS

343a

328369a



125














1629 1482 1447 1434 1373 1296 12875 12856 1280 1268 1264 1244 1225 845

706 675 530 448 415 408 370 240




126


















127


















210 (m 1 H) 187 (s 3 H) 069 (d J = 70 Hz 3 H) 055 (d J = 70 Hz 3 H)


128










Hz 3 H)










129





1738 1696 1689 1681 1647 1476 1400 1386 12918 12887 1265 12478 12446

845 739 578 440 434 429 413 344 330 317 2902 2901 257 245 227 189 168

142 344 330 317 2902 2901







75 75 Hz 2 H)







130









254 (dd J = 80 80 Hz 2 H)












131



(d J = 70 Hz 3 H) 098 (d J = 70 Hz 3 H)















132


242 (dd J = 75 75 Hz 2 H) 163 (s 3 H)


N S

NH

NS

OOO

R2R1




N S

NH

NS

MeO2C

OOH

TrtS TrtS369b















J = 70 Hz 3 H)

133




















134




H) 066 (d J = 68 Hz 3 H) 051 (d J = 68 Hz 3 H)



83

N S

NH

NSO

OOO

NH

TrtS

N S

NH

NSO

OOO

NH

HS371b 372b










135














NMR (125 MHz CDCl3) δ 1995 1737 1696 1689 1681 1647 1475 1402 1347 1290

1262 1245 844 740 577 442 434 427 412 357 343 317 301 289 257 244 226

189 167 141

136










175 Hz 1 H) 536 (d J = 105 Hz 1 H)







137




CNHODIBALH toluene

0 degC 1 h TrtSO

50 for 3 steps

CN








purification








268 (dd J = 76 76 Hz 2 H)




138





17 H) 263 (dd J = 76 76 Hz 2 H) 247 (dd J = 76 76 Hz 2 H)














= 68 Hz 3 H) 099 (d J = 68 Hz 3 H)

139















H)

140


N S

NH

NS

OOO

R2R1



2) 3-69c DMAP25 degC 2 h85

N S

NH

NS

MeO2C

OOHTrtS TrtS

369c













J = 48 152 Hz 1 H) 256 (m 2 H) 244 (m 2 H) 205 (m 1 H) 166 (s 3 H) 083 (d J = 68

Hz 3 H) 069 (d J = 64 Hz 3 H)

141




















142



= 160 116 Hz 1 H) 268 (dd J = 164 24 Hz 1 H) 249 (m 2 H) 237 (m 2 H) 206 (m 1

H) 184 (s 3 H) 063 (d J = 72 Hz 3 H) 049 (d J = 68 Hz 3 H)











80 80 Hz 1 H) 070 (d J = 65 Hz 3 H) 057 (d J = 65 Hz 3 H)

143

















144












(dd J = 76 76 Hz 1 H) 450 (s 2 H) 391 (s 3 H)








145


NMR (100 MHz CDCl3) δ 1663 1323 1311 1305 12931 12927 12907 1175 523 234















146



δ 726ndash739 (m 4 H) 449 (s 2 H) 375 (s 2 H)


















147


Hz 2 H) 332 (s 2 H)














233 (m 1 H) 104 (d J = 68 Hz 3 H) 096 (d J = 68 Hz 3 H)

148

















149


N S

NH

NS

OOO

R2R1




N S

NH

NS

MeO2C

OOH

TrtS TrtS

369d















H)

150



















151






1 H) 185 (s 3 H) 071 (d J = 72 Hz 3 H) 050 (d J = 68 Hz 3 H)











(d J = 68 Hz 3 H) 050 (d J = 72 Hz 3 H)

152















153















purification






154















NMR (100 MHz CDCl3) δ 1720 1445 1368 1322 1296 1281 1269 6724 6708 5219

5206 385 304 228

155








264 (dd J = 170 50 Hz 1 H) 255 (dd J = 170 80 Hz 1 H)






156


















157













(100 MHz CDCl3) δ 1730 1714 1687 1685 1630 1566 1485 1444 14367 14361

14352 14139 14136 1365 1324 1296 1281 12791 12787 12719 12713 12695

12530 12521 12511 12505 1221 12010 12007 846 702 6748 6736 6724 599 489

471 468 417 413 381 3026 3019 241 227 189 180





N S

NH

NS

R1

OO

N

NNTrtS

O

R2

N S

NH

NS

OO

N

NNTrtS

O

NH

O

391

158




purification















159










Hz 1 H) 073 (d J = 68 Hz 3 H) 052 (d J = 68 Hz 3 H)









160






70 Hz 3 H) 055 (d J = 70 Hz 3 H)

161

References


















162






















163



















164























165






















166




















167

















168


















169




















170




















171






172

Biography









Honors amp Awards


Publications




173




Presentations





Documents

I. Formal Synthesis of SCH 351448. II. Synthesis and