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PART I: THE STEREOSELECTIVE SYNTHESIS OFCANNABINOIDS

PART II: THE TOTAL SYNTHESIS OF SARCOPHYTOL AAND ITS ANALOGS

A DISSERTAnON SUBlVtITIED TO THE GRADUATE DIVISION OF THEUNIVERSITY OF HAWAII IN PARTIAL FULFILLMENT OF THE

REQUIREMENTS FOR TIlE DEGREE OF

DOCTOR OF PHILOSOPHY

IN

CHElVtISTRY

DECEMBER 1995

By

Xianglong Zou

Dissertation Committee:Marcus A. Tius, Chairman

Charles F. HayesCraig M. JensenEdgar F. KieferRobert S. H. Liu

UMI Number: 9615565

UMI Microform 9615565Copyright 1996, by UMI Company. All rights reserved.

This microform edition is protected against unauthorizedcopying under Title 17, United States Code.

UMI300 North Zeeb RoadAnn Arbor, MI 48103

iii

ACKNOWLEDGEMENTS

I would like to thank my advisor, Professor Marcus A. Tius, not

only for guidance but also for his patience and encouragement during

the completion or. this work. I also wish to thank the other members

of my dissertation committee for their assistan~e and

encouragement.

I thank members of the Tius group, past and present, for being

helpful and understanding. Many thanks to Dr. David Drake for

proofreading this dissertation and Dr. Walter Niemczura, Mike Burger

and Wesley Yoshida for their valuable help in obtaining NMR and

mass spectral data.

I would like to thank my wife Ling Cui and my daughter Susan

fer their love and support.

Finally, I would like to thank Professor Marcus A. Tius for his

support in the form of research assistantship and the Department of

Chemistry of the University of Hawaii for support in the form of a

teaching assistantship.

IV

ABSTRACT

Part I: The stereoselective total synthesis of each of the two

diastereomeric C6-hydroxyhexahydrocannabinols is described. The

extension of isopropenyl to hydroxymethyl was accomplished by the

use of an ene reaction with formaldehyde in the presence of

methylalurninum bis(2,6-diphenylphenoxide). Stereochemistry of the

two final products was controlled by an intramolecular mercuration.

Biological testing showed that the analogs exhibit different degrees

of binding to the CB1 cannabinoid receptor.

Part II: The total synthesis of a dienone precursor of sarcophytol A

is described. The conversion of dienone to sarcophytol A has been

reported. Hence, this is the formal total synthesis of sarcophytol A.

Interesting features of this synthesis include an alkynylation of an

allylic halide, macrocyclization, and C-alkylation of a 1,3-diketone

with isopropyl iodide. Selective reduction of diketone to dienone was

accomplished with DIBAL. It is noteworthy that conversion of

sulfoxide directly to the corresponding enone did not succeed

through a Pummerer rearrangement. Attempted conversion of

sulfone to dienone in the target molecule was not successful and

eliminated product was obtained. A synthesis of canventol is also

described. Biological testing has shown that canventol is a more

potent antitumor promotor than sarcophytol A even though

canventol is structurally simpler.

v

TABLE OF CONTENTS

ACKNOWLEDGEMENTS .iiiABSTRACT .i vLIST OF ABBREVIATIONS viii

PART ISTEREOSELECTIVE SYNTHESIS OF CANNABINOIDS

INTRODUCTION 1

1. Background 12. The Structural and Stereochemical Requirements forBiological Activity 33. Previous Synthetic Approaches towards Cannabinoids 7

RESULTS AND DISCUSSION 1 4

1. Retrosynthesis of 1213-Hydroxymethyl-9-nor-913-Hydroxyhexahydrocannabinol. 142. Stereospecific Ring Opening of Cuprate Adduct.. l 53. Formation of Tetraol l 84. Stereoselective Synthesis of 12p-Hydroxymethyl-9-nor-913-Hydroxyhexahydrocannabinol.. 195. Stereoselective Synthesis of 14a-Hydroxymethyl-9-nor-9p-Hydroxyhexahydrocannabinol.. 2 16. Biological Activities of the Synthetic Compounds 2 4

CONCLUSION 2 6EXPERIMENTAL 2 7REFERENCES : 5 2

vi

PART IITOTAL SYNTHESIS OF SARCOPHYTOL A AND ITS ANALOGS

A. SYNTHESIS OF CANVENTOL AND ITS ANALOGS .5 6

INTRODUCTION 5 6

1. Background 5 62. Synthesis of Canventol and Its Analogs 5 63. Biological Activity 60

EXPERIMENTAL 6 1REFERENCES 7 3

B. THE TOTAL SYNTHESIS OF SARCOPHYTOL A 7 4

INTRODUCTION 74

1. Background 742. Previous Approaches to Macrocyclization 75

a. Stabilized Anion Additions 75b. Alkynyl Anion Addition 76

3. Previous Synthetic Approaches to Sarcophytol A 77a. Takayanagi et. al. 77b. Takahashi et. al. 79c. Kodama et. al. 8 0d. Li et. al. 8 0

RESULTS AND DISCUSSION 8 2

1. Retrosynthesis of Sarcophytol A 8 22. Synthesis of Alkynyl Acetate 8 33. Formation of Cyclic Alkynyl Alcohol.. 8 54. Synthesis of Alkylated Sulfoxide 8 8

vii

'5. Pummerer Rearrangement of Alkylated Sulfoxide.Attempted Synthesis of Enone 9 0

a. Model Study 90b. Attempted Conversion of Sulfoxide to Enone 92c. Attempted Synthesis of Ester 93

6. Reevalu,ation of Retrosynthesis 967. Synthesis of Alkylated Diketone 968. Selective Reduction of 1,3-Diketone. Synthesis ofDienone 99

CONCLUSION 10 1EXPERIMENTAL 102REF'ERENCE:S 124

Ac

Ar

br

C

c

cat.

CBD

a:JN

CSCM

6 8­

6 9-

d

DBA

DBU

dd

ddd

DIBAL

DMAP

DME

DMF

DMSO

dt

FE

LIST OF ABBREVIATIONS

acetyl

aromatic

broad

Celsius

concentration

catalytic

Cannabidiol

Correlated Spectroscopy

Chemical Shift Correlation Map

Delta-8-

Delta-9-

doublet

Dibenzyl acetone

l,8-diazabicyclo[5.4.0]JJnctec-7 -ene

doublet of doublets

doublet of doublet of doublets

diisobutylaluminum hydride

4-(dimethylamino)pyridine

1,2-dimethoxyethane

N ,N-dimethylformamide

dimethyl sulfoxide

doublet of triplets

ethoxyethyl

VUl

Et

Et20

eV

EVE

g

h

Hz

HHC

HMBC

HMPA

HMQC

HPLC

HRMS

IR

J

KHMDS

LAH

LDA

m

M

mg

MHz

ethyl

diethyl ether

electron volt

ethyl vinyl ether

gram

hour

Hertz

Hydroxyhexahydrocannabinol

Heteronuclear Multiple Bond Correlation

Hexamethylphosphoramide

Heteronuclear Multiple Quantum Correlation

High Pressure Liquid Chromatography

high resolution mass spectrum

infrared

coupling constant

potassium bis(trimethylsilyl)amide

lithium aluminum hydride

lithium diisopropylamide

multiplet

Molar

milligram

megahertz

ix

min

mL

mmol

n-Bu

NMR

nOe

Oxaziridine

Ph

PPTS

p-TSA

pyr.

q

Rf

s

SAR

sat'd

t

tert-B u

TBDM

TEA

TFA

TFAA

me

minutes

milliliter

millimole

normal butyl

nuclear magnetic resonance

nuclear Overhauser effect

2 -(p-toluenesu lfony1)-3 -ary loxaziridine

phenyl

pyridium para-toluenesulfonate

para-toluenesulfonic acid

pyridine

quartet

retention factor

singlet

Structure Activity Relationship

saturated

triplet

tertiary butyl

tertiary-bu tyld imethy Is ilyl

triethylamine

trifluoroacetic acid

trifluoroacetic anhydride

tetrahydrocannabinol

x

THF

TMS

Ts

tetrahydrofuran

trimethylsilyl

toluenesulfonyl

Xl

PART I: THE STEREOSELECTIVE SYNTHESIS OF CANNABINOIDS

INTRODUCTION

1. Background

Cannabis sativa L. was one of the first plants to be used for

fiber, food, medicine and in social and religious rituals.! Its medical

properties have been recognized for thousands of years in different

societies. In Assyria, cannabis, known as azallu, was used for pain

alleviation and its seed was prescribed for treatment of depression,

"evil eye", and kidney stones.2 The medical applications of cannabis

were also well recognized by Chinese in their traditional folk

medicine formulations, some of which are still followed today.

Cannabis was used for alleviation of pain, clearing blood and

treatment of hyperthermia.3 Externally, cannabis was used as a

poultice, or as a constituent of various ointments for swellings and

bruises. The plant ex.tracts were used in Europe for a long time for

treatment of chronic headaches and certain psychosomatic

disorders.4 ,5 Although cannabis has its origins in folk medicine.

considerable interest for its use in standard medical practice was

generated in the early 19th century when the British scientist

O'Shaugnessy applied various cannabis preparations to animal and

human clinical experiments.6 The most important observation made

by O'Shaugnessy was that cannabis was a potent antinauseant agent.

Since then various medical potentials were observed.7•8 Despite these

observations of potential medicinal uses, little progress was made

1

toward practical medical use. The main reason was that no pure

constituents of cannabis had been isolated and the variety of crude

plant preparations made it difficult to obtain reproducible clinical

results. The situation was dramatically changed after a series of

compounds with cannabimimetic activity were synthesized by

Adams and Todd9. 10 and subjected to biological tests)l The most

widely tested compound was parahexyl, ~6a.lOa-THC 1.

2

1 Parahexyl

In 1964, the isolation and elucidation of the major

psychotropically active constituent, ~9-tetrahydrocannabinol, (-)_~9_

THe 2, by Mechoulam12 indicated that the modern era of cannabis

chemistry had arrived for synthesis, pharmacology, metabolism and

clinical investigation. For convenience, the following dibenzopyran

numbering system will be used throughout this dissertation.

3

2. T~e Structural and Stereochemical Requirements for

Biological Activity

Previous studies have shown that alteration of the basic

cannabinoid structure dramatically altered the biological activity.I3

Although the structure activity relationships (SAR) for cannabinoids

are relatively well established, some observations still need to be

clarified. Generally, a classical cannabinoid contains three major

parts: (a) a phenol (A ring) with C-3 side chain, (b) a six-membered

ring (B ring) with oxygen substitution, (c) a six-membered C ring. In

the early 1940's, the SAR of several synthetic cannabinoids were

investigated by Loewe. 14 Since the identification of the structure of

(-)-69-THC in the 1960's, a large amount of biological data has been

recorded for both natural and synthetic cannabinoids. Much of this

data comes from whole animal bioassays, and the methods for

assessment of activities include the overt behavior test in rhesus

monkeys or baboons,14 dog ataxia test,15 spontaneous activity test 10

rats and mice,16 drug discrimination test.!7 Limited data is available

from humafls, for a small number of cannabinoids. Some tentative

rules for SARs formulated by Mechoulam 18 in the early 1970's are

still consistent with what has been observed for newly synthesized

cannabinoids. Most of the active cannabinoids, including (-)_~9_THC,

have a benzopyran structure and cannabinoids in which the pyran

ring has been cleaved, e.g. cannabidiol (CBD, 3), show complete loss of

activity. Although a pyran ring is a requirement for activity. the

4

benzopyran itself does not confer activity. Substitution of oxygen

with nitrogen retains the activity, as illustrated by levonantradol 4.

Surprisingly, some cannabinoids which do not contain the

OH

/'N (CH2bCsHsH

4 Levonantradol

~ "'OH

3 Cannabidiol (CBD)

benzopyran structure, referred to as non-classical cannabinoids, are

more potent than (-)-~9-THC. For example, CP-47,497 Sand CP­

55,940 6 are ten times more potent than (-)-~9-THC itself. This

indicates that the benzopyran ring may not be an absolute

requirement for activity ,19

OH (NAH)

OH

5 CP-47,947

OH

(CH20H (SAH)

6 CP·55,940

Furthermore, SAR studies have also shown that the hydroxyl at C-l

has to be free or esterified. Etherification of the phenol led to either

complete loss or reduction in activity, whereas the phenolic ester

5

retains the activity.20 The replacement of hydroxyl by amino or

other ·heteroatoms eliminates the activity. It is also known that the

side chain at C-3 is of considerable importance for cannabinoid

activity. In general, elongation and branching of the side chain

increase the activity . Johnson and Melvin21 reported that compounds

7 and 8 are analgesically more active than (-)-9-nor-9~-

hydroxyhexahydrocannabinol (HHC. 9) and (-)-.19-THC. The most

OH

R

7 A =CH(CH3)(CH2)4CSHS8 A = CH (CH3)CH(CH3)(CH2)4CH3

OH

9 HHC

active side chains identified thus far are l,l-dimethylheptyl and 1,2­

dimethylheptyl. It is interesting to note that substitution of an all­

carbon chain by one containing oxygen at different positions does not

considerably influence the activity.22...... ,"1'•••

In contrast to the well established structural requirements for

activity, stereochemical aspects of the SAR need more investigation

due to the difficulties in purification of cannabinoids in large

amounts and enantiomeric contamination of cannabinoids used In

early in vivo testing. 23 Considerable efforts have been made to

establish stereochemical SARs. It was found that the stereochemistry

at C-6a, C-IOa should be trans (6aR, IOaR) and that an equatorial

6

substituent at C-9 was more active than an axial one. Molecular

shape:"plays an important part in determining the pharmacology of

cannabinoids. Recently, Makriyannis24 suggested that cannabinoids

with all three rings coplanar are inactive, or have very low activity,

and analogs in which the C-ring deviates from planarity are

pharmacologically' active. Enormous differences in activity between

enantiomeric pairs have been observed. Mechoulam25 reported that

(-)-1l-0H-~8_THC-DMH (HU210) was about 87 times more active

than (-)-~9-THC. Its (+)-enantiomer was inactive in the pigeon drug

discrimination test. Similar results were demonstrated by Johnson

and Melvin26 on other enantiomeric pairs. For example,

levonantradol 4 was active in a series of tests for analgetic and other

natural cannabimimetic responses (spontaneous activity,

hypothermia and catalepsy), however, its enantiomer was inactive in

these tests.

10 HU 210

OH

CH20H

11 CP-55,244

It should be emphasized that the stereospecificity for classical or

synthetic cannabinoids is consistent with the results for non-classical

cannabinoids. Generally, a conformation in which the southern

7

aliphatic hydroxyl (SAH) is syn to the northern aliphatic hydroxyl

(NAH), is required for activity. The non-classical analog, CP-47,497 5,

includes the minimal structural requirements for activity and is

approximately 10-fold more potent than naturally occurring (_)_.6,9-

THC with respect to analgesic activity. Conversely, CP-55,244 11

which contains a: conformationally more defined sy n SAH group is

50-fold more potent than its simpler congener and shows a high

degree of enantioselectivity.27

3. Previous Synthetic Approaches towards Cannabinoids

Since the isolation and elucidation of the structure of (_)_.6,9 -T HC

in 1964, several hundred papers related to the synthesis of

cannabinoids and their analogs have appeared.28 The main reason for

early synthetic afforts was to understand whether the parent

cannabinoids themselves were biologically active or whether the

activity was derived from one or more biologically active

metabolites. Recently, the interest in these compounds was driven by

the commercial need for metabolites of (_)_.6,9-THC as analytical

standards in the calibration of assays for the accurate detection of

cannabinoids in urine. Further, much effort has been devoted to the

design of analogs that may serve as probes in order to increase the

understanding of the mechanism responsible for cannabinoid

pharmacology in man and also as potential therapeutic agents.29

Several syntheses directed toward .6,9_, .6,8-THC and their analogs have

been reported.3 0 Generally, chiral cyclic monoterpenoids and olivetol

8

were the key starting materials In these syntheses. A facile and

practi~al method to (-)-L\9-THe was developed by Mechoulam and co-

workers in 1972 (scheme 1).31 Therein, (- )-verbenol 12, which itself

SCHEME 1

OH

0 a ..~ +

OH HO

12 13 14

b

d

16

Reagents: (a) p-toluenesulfonic acid. CHZC1Z; (b) BF3·EtZO, room temperature;(c) ZnClz. HCl (g); (d) potassium tert-amylate.

was prepared from p-pinene, was condensed with olivetol 13 in

methylene chloride in the presence of p-toluenesulfonic acid to

produce condensation adduct 14 which was obtained in 60% yield

9

after chromatography. The treatment of adduct 14 with boron

trifluoride etherate in methylene chloride at room temperature for

10 min gave ~8-THC 15 in 80% yield. It should be pointed out that in

the p-toluenesulfonic acid catalyzed condensation, 4-(2­

olivetyl)pinene 14 was the only product isolated. No abnormal

isomers were obtained. In 14 the C-6a and C-I0a hydrogens are

trans, presumably due to steric factors. The conversion of 15 to 16

was accomplished in quantitative yield by adding gaseous

hydrochloric acid at low temperature with catalytic zinc chloride.

Treatment of 16 with potassium tert-amylate led to (_)_~9-THC 2 in

90% yield. The overall yield of (_)_~9-THC (2) from (-)-verbenol 12

was ca. 43%. The advantages of the synthesis were the ready

availability of starting materials and the reasonable yields.

The major urinary metabolite of ~9_THC, Il-nor-~9-THC-9-

carboxylic acid 22, has received much attention as an internal

reference in a number of immunological screening tests which have

been developed to ascertain whether an individual has used

marijuana. In the synthesis of (-)_~9_THC metabolites, the principle

was to indentify an available terpene which would provide the

carbon atoms for the C-ring and also establish the absolute sense of

asymmetry of the final product, for example, (-)-1l-nor-~9-THC-9-

carboxylic acid 22. Although a number of synthetic approaches to 22

have been reported,32.33 the shortcomings of these syntheses were

either that they were long, produced racemic product or were low

yielding. A novel, efficient synthesis was reported in our laboratory

(scheme 2),34 Therein, the starting material, monoacetate 18, was

10

SCHEME 2

..OH

b ..~o

I20

COOH

d, e ..~O

I

22

~18

OOCOCH3

HO

I +4 steps

~O I1 9

OH

c

a

~17

CHO

6

Reagents: (a) BF3·Et20; (b) TBSCI. CH2CI2; (c) LAH. THF; (d) Swern oxidation; (e)Sodium chlorite, 2-methylbut-2-ene, CH2 C12.

prepared from R -(+)-perillaldehyde34 17 in 4 steps. The conversion

of 18 to 19 was accomplished by exposure of a dichloromethane

solution of olivetol 13 and 18 to freshly distilled boron trifluoride

etherate at ooC for 2 h. The yield of 19 was ca. 30% and it was

11

subsequently converted to final product 22 by protection as sHyl

ether ~O, reduction to 21, oxidation and deprotection in good yield.

Recently, a convenient synthesis of ~8_THC metabolites was

reported in our labaratory (scheme 3),35 wherein (+)-apoverbenone

SCHEME 3

o

29

HO27

COOCH3

OH

c

0 OEE

8 +~

23 24

OS02CF3

OEEb

•

EEO26

OS02CF3

~ OHd ..

~OI

28

Reagents: (a) Mixed higher-order cuprate; (b) KN(TMS)2 or LOA, thenPhN(S02CF3)2; (c) PPTS, methanol; (d) BF3"Et20. CH2Cl2; (e) PdCI2(PPh3)2,K2C03. CO, THF. methanol.

23, which was prepared from (-)-J3-pinene, was used as a starting

12

material. Olivetol 13 was converted to its bis(ethoxyethyl)ether 24

in 77% yield by treatment in diethyl ether with a small excess of

ethyl vinyl ether in the presence of p-toluenesulfonic acid. The

lithiated olivetol derivative was transferred to 1 equivalent of

lithium 2-thiophenecyanocuprate in THF. The mixed, higher order

cuprate was treat.ed with a THF solution of apoverbenone and boron

trifluoride etherate (1/1) at -780C for 2 h and cuprate adduct 25 was

obtained in 66% yield. Consecutive treatment of adduct 25 with

potassium hexamethyldisilylamide followed by

bis«(trifluoromethyl)sulfonyl)oxy)aniline in THF at OOC led to enol

triflate 26. Exposure enol triflate 26 to pyridinium tosylate in

methanol gave the dihydroxy compound 27 in 65% yield from 26. A

solution of 27 in anhydrous dichloromethane was treated at 25°C

with an excess of boron trifluoride etherate for 8 h and cyclic vinyl

triflate was obtained in 87% yield. Transposition of the double bond

during cyclization leads specifically to the ~8-series. The

stereochemistry of the ring junction was determined by the trans

cuprate addition to the geminal dimethyl bearing bridge. Treatment

of a solution of 28 in methanolic THF with 10% mol PdCI2(PPh3h,

potassium carbonate and a static atmosphere of CO at 250C led to

methyl ester 29 in 72% yield. Although all these syntheses are for

classical cannabinoids, some of these synthetic methods could be

applied to non-classical cannabinoids. For example, the cuprate

addition which forms the trans ring junction and the cleavage of the

ring. Since non-classical cannabinoid CP-55,940 was more active as

an analgesic than morphine, its increase in potency was attributed in

13

part to the introduction of the new hydroxypropyl binding

component in the southern portion of the molecule. Significantly,

both the arylcyclohexyl bond and the hydroxypropyl groups are not

conformationally restricted.

14

RESULTS AND DISCUSSION

The aim of this work was to synthesize non-classical

cannabinoids which combine the structural elements of CP-55,940 6

and HHC 9 and to study the relationships between stereochemistry

and their activity.

1. Retrosynthesis of 1213- H yd roxy m et hyl- 9- nor - 9 ~­

hydroxyhexahydrocannabinol

In order to synthesize compound 30, intermediate 32 was

envisioned as a potential precursor to the product 30, because it is

possible to convert 32 to 30 by an ene reaction followed by

stereoselective cyclization (scheme 4).

SCHEME 4

OHOH

:> :>I

HO~OH~

HO 31

0 0

>

RO33

15

Compound 31 would be prepared through an ene reaction on the

intermediate 32. The compound 32 could be obtained from a two­

step procedure involving the ring opening of compound 33.

2. Stereospecific Ring Opening of Cuprate Adduct

The starting· material for the synthesis, (+)-apoverbenone 23,

was prepared from cheap and readily available (-)-13-pinene 34

according to Huffman's method36 via ozonolysis of (-)-~-pinene 34 to

nopinone 35, followed by lead tetraacetate oxidation and acetic acid

hydrolysis (scheme 5). Olivetol 13 was converted to its bis-2-

SCHEME 5

80 0

a ~ b, C G.. • /1'

34 35 23

Reagents: (a) 03; (b) isopropenyl acetate; then Pb(OAc)4; (c) aq. HOAc, roomtemperature.

HO

OH

13

a ..EEO

OEE

24

Reagents: (a) p-toluenesulfonic acid, ethyl vinyl ether, CH2 CIZ 00 C.

16

ethoxyethyl ether 24 in 75% yield by treatment with a small excess

of EVE in the presence of a catalytic amount of PPTS.

The cuprate addition was carried out according to a published

procedure37 (scheme 6): Bis-2-ethoxyethyl ether 24 can be

Reagents: (a) Mixed high-order cuprate. BF3·EtZO. THF, -78°C; (b). PPTS,methanol; (c) TBSCI. DMAP; (d) TMSI. CCI4. OOC; (e) DBU. benzene.

deprotonated selectively using n-butyllithium in THF at 25°C. The

lithiated bis-2-ethoxyethyl ether of olivetol was converted to the

17

mixed higher-order cuprate by transferring to a solution of lithium­

2-thiophenecyanocuprate in THF at -78°C which was prepared

according to the procedure published by Lipshutz.3 8 The mixed

higher-order cuprate solution was then treated with a THF solution

of (+)-apoverbenone 23 and boron trifluoride etherate (I/l) at

-780C. The progress of the reaction can be monitored by tIc. After 30

min. the reaction was quenched with a solution of saturated

NH4CI/NH40H (9/1) and the product was purified by silica gel column

chromatography. The yield of cuprate adduct 2S was 70-80%.

Treatment of 25 with PPTS in methanol at 250C led to 36 in

quantitative yield. Exposure of resorcinol 36 to

tert-butyldimethylsilyl chloride and imidazole in DMF at 230C

produced bis-tert-butyldimethylsilyl ether 37 in 85% yield. Cleavage

of the cyclobutane ring in adduct 37 under the influence of

trimethylsilyl iodide (generated in situ from allyltrimethylsilane and

iodine) at OOC gave rise to tertiary iodide 38 which was immediately

converted to 39 by treatment with DBU in benzene at 23°C. It should

be emphasized that the regiospecific elimination which forms the

388 3ab

18

isopropenyl substituent of 39 is due to a stereoelectronic effect39

caused by the aryl substituent at C-5: The steric bulk of the aryl

group prevents iodine and H-6a from adopting a trans-anti

conformation which would lead to the undesired elimination product.

3. Formation of Tetraol

The next task was to append a hydroxymethyl group to the

isopropenyl methyl of 39. An obvious approach was to make use of

an acid catalyzed ene reaction with formaldehyde (scheme 7).

SCHEME 7

o

~ ~OTBS

39

OH

- I ~HO~OTBS

41

a

c

o

: I ~HO~OTBS

40

OH

b

Reagents: (a) Trioxane. Me3A1, 2.6-diphenylphenol; (b) NaBH4.THF/isopropanol; (c) n-Bu4N+F-, THF. aoc.

19

Dimethylaluminum chloride was initially used as the Lewis acid, but

the yield of 40 was too low (ca. 20%) and the reaction did not

proceed to completion. A very efficient reagent, methylaluminum

bis(2,6-diphenylphenoxide)formaldehyde, which was prepared from

trimethylaluminum, 2,6-diphenylphenol and trioxane In

dichloromethane at DoC, has been reported by Yamamoto,39a

Exposure of 39 to Yamamoto's reagent in dichloromethane at room

temperature for 1 h followed by quenching with sodium bicarbonate

led to 40 in 55% yield. Treatment of 40 with sodium borohydride in

THF/isopropanol (9/1) at 230C led to equatorial alcohol 41 in 88%

yield. Removal of both TBS protecting groups was accomplished to

produce tetraol 42 in 90-96% yield by simply exposing diol 41 to

tetra-n-butylammonium fluoride in THF at room temperature.

Compound 42 was envisioned as a potential precursor in the

synthesis of both the target molecules 30 and 43.

4. Stereoselective Synthesis of 12~·Hydroxymethyl·9·nor·

9~·Hydroxyhexahydrocannabinol

Several methods for the non-stereoselective cyclization of

tetraol 42 can be imagined. However, control of the stereochemistry

at C-6 posed a difficult challenge, since cyclization of 42a leads to 43

whereas, 42b leads to 30. Also, there was no reason a priori to

expect any conformational preference between 42a and 42 b. In fact,

H

..

HO

20

OH428 42b

treatment of tetraol 42 with p-toluenesulfonic acid in refluxing

toluene led to 1:1 diastereoisomeric mixture of 30 and 43. The

protonation of the isopropenyl group presumably led to a tertiary

planar carbocation which was attacked by the phenolic hydroxyl

OH

30

OH

with a complete lack of stereochemical bias. This result with proton

as the electrophile was disheartening, but it suggested that the

OH

- I ~. ~ A'

HO OH42

a ..

OH

30

Reagents: (a) Hg(OAc)2. NaOH; NaBH4. room temperature,

21

problem might be overcome by altering the mechanism, through the

use of an alternative electrophile. Treatment of tetraol 42 with

mercuric acetate39b in THF at OOC for 30 min, followed by reductive

demercuration with sodium borohydride in aqueous sodium

hydroxide led to a 86: 14 (hplc: 25cm, 10 ~ Econosil column; 80/20

ethyl acetate/heximes) mixture of compounds 30 and 43 in 75%

yield. The determination of stereochemistry in compound 30 was

based on nOe analysis: irradiation of the pseudoaxial methyl group (0

= 1.10 ppm) led to enhancement of the C-I0a benzylic methine signal

(0 = 2.52 ppm). The assignment of stereochemistry is also supported

by the IH-NMR data of various THe derivatives in which the 6a­

methyl is always at higher field (1.10 ppm) than that of the 6~­

methyl.39 This approach provided the stereoselective route to

compound 30.

5. Stereoselective Synthesis of 14a.-Hydroxymethyl-9.nor­9~-Hydroxyhexahydrocannabinol

In order to prepare compound 43, the Swern oxidation of 40

presumably gave the ~,.y·unsaturated aldehyde 44 which underwent

spontaneous isomerization to a single conjugated aldehyde 45

(scheme 8). The E-geometry of the double bond of aldehyde 45 was

determined by examination in 1H-NMR spectrum at 300 MHz: no

coupling between the vinylic methyl and vinylic hydrogen was

observed. Reduction of both carbonyl groups in 4S with sodium

borohydride in a mixed solvent (THF/isopropanol) led to 46 in 80%

yield. Cleavage of the phenolic protecting groups with t etra -n-

22

SCHEME 8

o

..

o

o44

OH

b .. ..

OH

e

OH

..I

)HOHO 47

d

Reagents: (a) Swern oxidation; (b) room temperature 30 h: (c) NaBH4.methanol; (d) n-Bu4N+F-, THF; (e) Hg(OAc)2, NaOH: NaBH4.

butylammonium fluoride led to tetraol 47. Mercuration­

demercuration of 47 with sodium borohydride led to a 15:85

mixture of 30 and 43 in 80% yield. The stereochemistry was

23

assigned by nOe analysis: irradiation of the C-14 methylene group m

isomer 43 led to enhancement of the C-IOa benzylic methine signal

(0 = 2.52 ppm).

The results from the above syntheses demonstrated that each of

the two diastereomers was available selectively, however the origin

of the stereoselectivity was not easily rationalized. Some of the

results in this area are contradictory. For example, Sinay40 has shown

that intramolecular oxymercuration of 48 produces 49, in which the

-CH2HgCI group is axial. The stereochemistry in this case was

attributed to coordination by the adjacent benzyloxy group to

~\_O~~BnO~~BnOBnO

48~

Bn

BnO 0

BnO OBn49 HgCI

the incoming mercurio species. On the other hand, Ganem41 reported

only equatorial product 51 from the intramolecular

aminomercuration of 50, even though an adjacent benzyloxy group

was present to direct the axial stereochemistry. In Kozikowski's42

synthesis of dactylomelynes, the high degree of stereoselectivity

~ NHBnBnO~~BnO OBn

50

.. ~~~~rBno~~nBnOBnO

51

24

during the cyclization of 48 was attributed to the equatorial

preference of the bulky alkylmercurial group in a chair-like

transition state. It is perhaps significant that in the solid state of the

HrrHm

~ ·~OH.;

MeO'"! O! ! OHHHH

52

..

product, rotation about the CI-C3 bond in 53 places the

chloromercury group syn to the C7 hydroxyl, suggesting that in this

case, the stereoselectivity may in fact be traced to a directing effect

by hydroxyl. In the case of both 42 and 47, oxymercuration took

place so as to place the alkylmercurial group axial in the developing

dihydrobenzopyran ring. In the absence of any heteroatomic

directing effect, the stereochemical preference may be due to the

anomeric effect of the positively charge mercurio species43 in the

transition state. The mercury is clearly exercising a profound effect

on the stereochemistry, as shown by the observation that

fluorodesilylation of compound 45, followed by reduction with

sodium borohydride, produced a I: I mixture of 30 and 43.

6. Biological Activities of the Synthetic Compounds

Compounds 30 and 43 as well as their uncyclized precursor 42,

were tested for their affinities for the cannabinoid CB 1 receptor

25

using rat brain membranes and [3H]-CP-55,940 as the radioligand.44

Of tht:se, compound 30, in which the hydroxyethyl group has a /3­

equatorial relative configuration, was shown to possess considerable

affinity for the CB 1 receptor (ICSO = 100 nM), while compounds 43

and 42 exhibited much weaker affinities (ICSO =3.2 IJ.M; 0.10 IJ.M,

respectively). The above biochemical data demonstrates the strict

stereochemical requirements for a favorable ligand/receptor

interaction imposed by the cannabinoid receptor on the

hydroxypropyl pharmacophore.

26

CONCLUSION

In conclusion, the design and stereoselective synthesis of two

cannabinoids from 39 in high yield have been described.

Several features are noteworthy: (1) compound 39 is a versatile

precursor for the synthesis of other cannabinoids. (2) Stereoselective

cyclization was achieved by intramolecular oxymercuration.

Biological testing has shown that compound 30 had very good

activity whereas compound 43 showed much weaker binding to the

CB 1 receptor than 30. These results showed that the stereochemistry

of the hydroxyethyl sidechain effects activity significantly.

27

EXPERIMENTAL

General:

IH-NMR and 13C NMR spectra were recorded at 300 MHz IH

(75.5 MHz 13C) or 500 Hz IH (125.8 MHz BC) in either

deuteriochloroform (CDCI3) with chloroform (7.26 ppm, 77.00 ppm

13C) or deuteriobenzene (C6D6) with benzene (7.15 ppm IH, 128.00

ppm 13C) as an internal reference. Chemical shifts are given in 0;

multiplicities are indicated as br (broadened), s (singlet), d (doublet),

t (triplet), q (quartet), m (multiplet); coupling constants (1) are

reported in hertz (Hz). Infrared spectra were recorded on a Perkin­

Elmer IR 1430 spectrometer. Electron impact mass spectra were

recorded on a VG-70 SE mass spectrometer.

Thin-layer chromatography (tic) was performed on EM Reagents

precoated silica gel 60 F-254 analytical plates (0.25 mm). Flash

column chromatography was performed on Brinkmann silica gel

(0.040-0.063 mm). Tetrahydrofuran (THF), diethyl ether, 1,2­

dimethoxyethane (DME) were distilled from sodium-benzophenone

ketyl, N,N-dimethylformamide (DMF), triethylamine (Et3N), and

boron trifluoride-etherate (BF3·Et20) from calcium hydride, carbon

tetrachloride (CCI4), dichloromethane (CH2CI2) from phosphorus

pentoxide. Other reagents were obtained commercially and used as

received unless otherwise specified.

All moisture sensitive reactions were performed under a static

nitrogen or argon atmosphere in flame-dried glassware. The purity

28

and homogeneity of the products on which the high resolution mass

spectr~l data are reported were determined on the basis of 300 MHz

IH-NMR (>94%) and multiple elution tic analysis, respectively.

OH OEE

29

EEO

Procedure:

13· 24

To a solution of olivetol 13 (lg, 5.55 mmol) in dichloromethane

(20 ml) at 230C was added ethyl vinyl ether (1.35 ml, 13.88 mmol),

followed by a catalytic amount (ca. 50 mg) of PPTS in

dichloromethane. The reaction mixture was stirred at 230C and the

progress of the reaction was monitored by tIc. After 7 h, the reaction

mixture was diluted with ether, washed with sat'd aqueous NaHC03,

followed by brine, and was dried (NaZS04). Solvent evaporation in

vacuo gave the crude bis-2-ethoxyethyl olivetol which was purified

by flash chromatography on silica gel eluting with 5% ethyl acetate in

hexanes. The yield of the reaction was 70-85%.

30

OEE

EEO

24

Bis-2-ethoxyethyl olivetol 24:

IH-NMR (CDC13, 300 MHz, ppm): a 6.49-6.47 (br s, 2H), 5.35 (q, J = 5.1

Hz, 2H), 3.81-3.73 (m, 2H), 3.59-3.49 (m, 2H), 2.52 (t, J = 7.5 Hz, 2H),

1.61-1.56 (m, 2H), 1.49 (d, J = 5.4 Hz, 6H), 1.33-1.27 (m, 4H), 1.21 (t, J

= 6.9, 6H), 0.89 (t, J =6.3 Hz, 3H).

13C-NMR (CDC13, 75 MHz, ppm): a 157.8, 145.3, nO.8, 103.8, 99.5,

61.5, 36.1, 31.4. 30.9, 22.5, 20.3, 15.2, 13.9.

IR (neat, em- l ): 2990, 2920, 2850, 1590, 1450, 1380, 1150, lll0,

1080, 1050.

31

0

0 OEE

~..

+EEO

23 24 25

Procedure:

To a solution of 311 mg (0.956 mmol) of bis-2-ethoxyethyl

olivetol 24 in THF (IS ml) at OOC was added n-butyllithium solution

in hexane (0.85 ml, 1.150 mmol) during 20 min. The mixture was

stirred at OOC for 10 min and then at 250C for 2.5 h. In a separate

flask 3.85 ml (0.956 mmol) of a solution of lithium 2­

thienylcyanocuprate in THF was cooled to -78°C. The lithiated

olivetol ether was transferred by cannula to the cuprate solution

over a 20 min period. Following addition, the reaction mixture was

placed in an ice bath for 10 min, cooled to -78°C, and stirred for 1.5

h. To the pale yellow cuprate solution was added a mixture of 200

mg (1.470 mmol mmol) of (+)-apoverbenone (23) and 0.20 ml (1.470

mmol) of BF3.Et20 in 1.5 ml of THF at -78°C. The mixture was stirred

at -780C until tic (5% ethyl actate in hexane) showed the

disappearance of the starting material (lh). The reaction was diluted

with ether (30 ml), washed with concentrated NH40H/saturated

32

NH4CI (1/9) solution, extracted with ether, and dried (MgS04).

Evapo~ation of the solvent in vacuo and purification of the crude

product by flash chromatography on silica gel eluting with 5% ethyl

acetate in hexane produced 225 mg (70% yield) as a mixture of

diastereomers due to the asymmetric center on each of the two

ethoxyethyl protecting group.

4 - [4 - n - pentyl- 2,6- bis (2 -ethoxyethyl) phenyl] - 6,6 -d im ethyl­

2-nopinone 25:

!H-NMR (CDCI3, 300 MHz, ppm): d 6.59 (s, IH), 6.55 (s, IH), 5.46-5.39

(m, 2H), 4.16-4.09 (m, IH), 3.74-3.64 (m, 2H), 3.38-3.29 (m, IH),

2.56-2.45 (m, 6H), 2.22 (br s, IH), 1.61-1.56 (m, 4H), 1.48 (d, J = 5.1

Hz, 6H), 1.35 (s, 3H), 1.33-1.31 (m, 2H), 1.22-1.16 (m, 6H), 0.98 (s,

3H), 0.89 (t, J = 6.7 Hz, 3H).

IR (neat, cm-!): 2975, 2925, 2860, 1710, 1605, 1570, 1430, 1380,

1070, 1050.

,.

a

25

Procedure:

a

36

33

To a solution of compound 2S (150 mg, 0.33 mmol) in 25 ml of

methanol was added ca. 25 mg of PPTS. The reaction mixture was

stirred at 25°C until tic indicated that both ethoxyethyl groups had

been removed (ca. 5 h). The reaction mixture was diluted with ether,

washed with brine and was dried over MgS04. Evaporation of the

solvent followed by flash chromatography eluting with 15% ethyl

acetate in hexane produced 80 mg (78% yield) of resorcinol 36 as

single isomer.

34

o

36

Resorcinol 36 :

IH-NMR (CDCI3, 300 MHz, ppm): 0 6.17 (s, 2H), 5.13 (s, 2H,

exchangeable with D20), 3.95 (t, J =8.1 Hz, IH), 3.47 (dd, J = 18.9, 7.8

Hz, IH), 2.68-2.39 (m, 5H), 2.30 (t, J = 5.4 Hz, IH), 1.36 (s, 3H), 1.31­

1.26 (m, 4H), 0.99 (s, 3H), 0.89 (t, J = 6.9 Hz, 3H).

I3C-NMR (CDC13, 75 MHz, ppm): 0 217.2, 155.3, 142.6, 113.7, 108.6,

57.9, 46.8, 42.3, 37.9, 35.2, 31.5, 30.6, 29.5, 26.2, 24.4, 22.5, 22.1,

14.0.

IR (CC4, em-I): 3350, 2950, 2850, 1680, 1620, 1590, 1430, 1265,

1020.

Mass spectrum (70 eV, m/e): 316 (M+), 310, 273, 247, 233, 219, 206,

193, 150, 83, 69, 57.

o

36

Procedure:

•

o

37

35

To a solution of resorcinol 36 (158 mg. 0.50 mmol) and tert­

butydimethylsilyl chloride (453 mg. 3.00 mmol) in 10 ml N.N­

dimethylformamide (DMF) at 230C was added imidazole (410 mg.

6.00 mmol). The mixture was stirred at 230C for 16 hand 50 ml

ether was added. The organic phase was washed with water. dried

(MgS04) and evaporated. The crude product was purified by flash

column chromatography on silica gel (5% ethyl acetate in hexane) to

give 231 mg (85% yield) of 37.

36

o

37

Ketone 37:

IH-NMR (CDCI3, 300 MHz, ppm): a 6.27(s, 2H), 3.98 (m, IH), 3.75 (d, J

= 6.9 Hz, IH), 3.68 (d, J = 6.9 Hz, IH), 2.56-2.36 (m, 6H), 2.21 (m, IH),

1.56-1.30 (m, 2H), 1.55 (s, 3H), 1.32 (s, 3H), 0.98 (s, 6H), 0.86 (s,

18H), 0.02 (s, 12H).

IR (neat, em-I): 2960, 2860,1710,1600,1560,1460,1420,1150,

1050.

Mass spectrum (70 eV, role): 544 (M+), 487, 377, 215, 168, 73.

Calculated mass for C32Hs603Si2: 544.3767, found: 544.3748.

o

T880

37

Procdure:

..

o

39

37

A solution of iodine (343 mg, 1.35 mmol) and

allyltrimethylsilane (156 mg, 1.37 mmol) in 5 ml CCl4 was stirred at

DoC for 2 h. Ketone 37 (480 mg, 0.88 mmol) in 3 ml CCl4 was added.

The reaction mixture was stirred at DoC for 30 min, then quenched

by adding aqueous sat'd Na2S203. The mixture was extracted with

ether. The organic solution was dried (MgS04) and evaporated. The

crude product 38 was dissolved in 5 ml benzene at 23°C and excess

DBU (ca. 4 mmol) was added. The solution was stirred for 2 h at 230C

and diluted with 20 ml ether. The organic solution was washed with

water, dried (MgS04) and evaporated. The residue was purified by

flash chromatography (10% ethyl acetate in hexane) on silica gel to

give 250 mg (52% over yield) of 39.

38

a

39

Ketone 39:

IH-NMR (CDCI3, 300 MHz, ppm): () 6.22 (s, IH), 6.20 (s, IH), 4.66 (d, J

= 0.3 Hz, IH), 3.47 (td, J = 12.0, 3.0 Hz, IH), 3.17 (dd, J = 14.1, 13.5 Hz,

IH), 2.48 (m, 3H), 2.33-1.67 (m, 6H), 1.56 (s, 3H), 1.32 (m, 4H), 1.06

(s, 9H), 0.98 (s, 9H), 0.88 (dd, J = 6.9, 6.6 Hz), 0.35 (s, 3H), 0.32 (s, 3H),

0.23 (s, 3H), 0.16 (s, 3H).

IR (neat, em-I): 3010, 2960, 1720, 1610, 1560, 1470.

Mass spectrum (70 eV, role): 544 (M+), 487, 379, 258, 194, 110, 73.

Calculated mass for C32HS603Si2: 544.3767, found: 544.3794.

o

Procedure:

o

~ I ~HO~OTBS

40

39

To a solution of 2,6-diphenylphenol (134 mg, 0.55 mmol) in 2 ml

CH2Clz was added 0.17 ml of a 1.6 M solution of trimethylaluminum

in toluene (0.27 mmol) at 230C. The solution turned light brown and

was stirred for 1 h at 230C, cooled to DoC, and trioxane (11 mg, 0.12

mmol) in 1 ml CHZClz was added. The mixture was stirred for 1 h at

DoC. Ketone 39 in 2 ml CH2CIZ was added and the solution was stirred

for additional 2 h. Sat'd aqueous NaHC03 was used quench the

reaction. The reaction mixture was extracted with CHzClz and the

organic phase was dried (MgS04) and evaporated. The residue was

purified by flash column chromatography on silica gel (20% ethyl

acetate in hexane) to give 58 mg (50-55% yield) of 40.

-- ~--~. -~ ..._ ..

40

o

Compound 40:

IH-NMR (CDCI3, 300 MHz, ppm): a 6.24 (s, IH), 6.20 (s, IH), 4.97 (s,

IH), 4.68 (s, IH), 3.75 (m, IH), 3.58 (q, J = 12.3, 12.0 Hz, 2H), 3.36 (m,

2H), 2.48-2.05 (m, 6H), 1.71-1.50 (m, 3H), 1.55 (s, 3H), 1.30-1.25 (m,

3H), 1.05 (s, 9H), 0.88 (dd, J = 6.9, 6.6 Hz, 3H), 0.36 (s, 3H), 0.32 (s,

3H), 0.24 (s, 3H), 0.16 (s, 3H).

IR (neat, em-I): 3450, 2980,1710,1570,1420,1100.

Mass spectrum (70 eV, m/e): 574 (M+), 487, 379, 73, 69.

Calculated mass for C33HSS04Si2: 574.3957, found: 574.3915.

..

a

40

Procedure:

OH

- I ~HO~OTBS

41

41

To a solution of ketone 40 (80 mg, 0.14 mmol) in 10 ml of a

mixture of THF and isopropanol (9:1) at 230C was added sodium

borohydride (8 mg, 0.21 mmol) portionwise, and the mixture was

stirred for 30 min. The reaction was quenched with water and the

mixture was extracted with ether. The organic layer was dried

(MgS04) and evaporated. The crude product was purified by flash

column chromatography (20% ethyl in hexane) on silica gel to give 70

mg (85-88% yield) of alcohol 41.

42

OH

41

Diol 41:

IH-NMR (CDCh, 300 Hz, ppm): d 6.22 (s, 1H), 6.18 (s, 1H), 4.91 (s, 1H),

4.61 (s, IH), 3.69 (m, IH), 3.54 (tt, 5.7, 5.7 Hz, 2H), 3.35 (m, IH), 2.89

(m, IH), 2.41 (dd, 7.8, 7.5 Hz, 2H), 2.09 (m, 3H), 1.86 (m, 1H), 1.55 (s,

3H), 1.57-1.24 (m, 7H), 1.06 (s, 9H), 1.02 (s, 9H), 0.88 (dd, J = 6.0, 5.7

Hz, 3H), 0.33 (s, 3H), 0.32 (s, 3H), 0.25 (s, 3H), 0.17 (s, 3H).

IR (neat, em-I): 3340, 2970, 2880, 1600, 1420, 1050.

OH

Procedure:

OH

42

43

-- - ---- - ------

To a solution of 41 (40 mg, 0.07 mmol) in 6 ml THF at 23°C was

added tetra-n-butylammonium fluoride hydrate (73 mg, 0.28 mmol)

portionwise. The mixture was stirred for 1 hand 30 ml ether was

added. The organic phase was washed with water, dried (MgS04) and

evaporated. The residue was purified by flash column

chromatography (80% ethyl acetate In hexane) on silica gel to give 23

mg (90-96% yield) of tetraol 42.

44

OH

42

TetraoI 42:

lH-NMR (CD3COCD3, 300 MHz, ppm): 0 8.00 (br, IH, exchangeable with

D20), 6.16 (s, IH), 6.14 (s, IH), 5.61 (s, IH, exchangeable with D20),

4.84 (d, J = 1.5 Hz, IH), 4.47 (s, IH), 3.64 (m, IH), 3.54-3.31 (m, 3H),

3.03 (m, IH), 2.33 (dd, J = 8.1, 6.9 Hz, 2H), 2.15 (m, 2H), 1.79 (m,

2H), 1.55-1.19 (m, 10H), 0.86 (dd, J = 6.9, 6.6 Hz, 3H).

l3C-NMR (CD3COCD3, 75 MHz, ppm): 0 157.6, 156.0, 151.1, 141.7,

115.8, 109.8, 108.5, 107.6, 71.1, 61.6, 46.4, 40.4, 38.6, 37.1, 36.7,

36.0, 32.9, 32.2, 31.5, 23.1, 14.2.

IR (neat, cm- l ): 3350, 2960, 2880, 1620, 1590, 1420, 1040.

Mass spectrum (70 eV, role) 572 (M+): 516, 515, 445, 405, 377, 100,

95, 73.

Calculated mass for C33HS604Sh: 572.3717, found: 572.3741.

o

~I#HO OTBS

40

Procedure:

o

45

Dimethylsulfoxide (0.52 mmol) was added to the solution of

oxalyl chloride (0.35 mmol) in 2 ml CH2Cl2 at -780C. After 8 min, 48

mg of 40 (0.08 mmol) in 1 ml CH2C12 was added slowly. The mixture

was stirred for 15 min, then triethylamine (0.22 mmol) was added at

-780C. The mixture was warmed to 230C and stirring was continued

for 12 h. The reaction was quenched with water. The organic layer

was washed with brine, dried (MgS04) and evaporated. The crude

product was purified by flash column chromatography 20% ethyl

acetate in hexane) on silica gel to give 41 mg in 85% yield of

ketoaldehyde 45.

46

o

Ketonealdehyde 45:

IH-NMR (CDC13, 300 MHz, ppm): B9.82 (d, J =7.9 Hz, IH), 6.22 (s, IH),

6.18 (s, IH), 5.86 (d, J = 7.9 Hz, IH), 3.76 (m, IH), 3.56 (m, IH), 3.20

(dd, J = 13.5, 11.2 Hz, IH), 2.41 (m, 3H), 2.05 (m, IH), 1.99 (s, 3H),

1.80-1.57 (m, 5H), 1.25 (m, 4H), 1.06 (s, 9H), 0.99 (s, 9H), 0.88 (t, J =

6.9, 6.6 Hz, 3H), 0.36 (s, 3H), 0.25 (s, 3H), 0.17 (s, 3H).

IR (neat, em-I): 2980,2880,1720,1680,1605,1570,1100.

Mass spectrum (70 eV, role) 572 (M+): 515, 445, 405, 377, 100, 95,

73.

Calculated mass for C33HS604Si2: 572.3717, found: 572.3741.

47

OH

I)'HO

HO47

Tetraol 47:

The same procedure was followed as in the conversion of (41) to

(42). Ketoaldehyde 4S (25 mg) was converted to diol 4S (18 mg,

72% yield). Desilylation produced 10 mg of tetraol 47 in 92% yield.

IH-NMR (CD3COCD3, 300 MHz, ppm): 07.60 (br d, exchangeable with

DzO, 1H), 6.15 (s, 1H), 6.12 (s, 1H), 5.34 (dd, J = 6.6, 6.0 Hz, 1H), 3.88

(m, 1H), 3.76 (m, 1H), 3.64 (m, 1H), 3.33 (td, J = 11.7, 3.3 Hz, 1H), 2.33

(dd, J = 7.8, 7.5 Hz, 2H), 2.17-1.96 (m, 3H), 1.84 (m, 1H), 1.65-1.23

(m, 9H), 1.48 (s, 3H), 0.86 (dd, J = 7.2, 6.6 Hz 3H).

IR (neat, cm- 1): 3400, 3010, 2980, 1600, 1420, 1100.

Mass spectrum (70 eV, m/e) (no M+): 330 (M+-HzO), 312, 217, 194,

193, 150, 79.

OH

42

Procedure:

OH

30

48

Mercuric acetate (28 mg, 0.06 mmol) was added to a solution of

tetraol 42 (20 mg, 0.06 mmol) in 3 ml THF in one portion at 23 0C.

The mixture was stirred for 18 h. Excess sodium borohydride (0.12

mmol) in 0.5 ml 2.5 M aqueous NaOH (0.5 ml) was added, and the

mixture was stirred for additional 10 h. Sat'd aqueous Na2C03 (0.5

ml) was added and the mixture was stirred for another 4 h. The

reaction mixture was decanted from metallic mercury and was

partitioned between water and ether. The organic phase was dried

(MgS04) and evaporated. The residue was purified by flash

chromatography on silica gel to give 15 mg (75% yield) of a 86:14

mixture of products 30 and 43. The pure product was purified by

hplc (80% ethyl acetate in hexane).

49

OH

30

1213- Hydroxym ethyl-9 -nor-9 ~ -hydroxyahydrocannabinol 30:

IH-NMR (CDC13, 500 MHz, ppm): 0 6.21 (d, J = 1.5 Hz, IH), 6.11 (br, IH,

exchangeable with DzO), 6.10 (d, J = 1.5 Hz, IH), 3.97-3.81 (m, 3H),

3.55-3.52 (m, IH), 2.86 (br, 1H, exchangeable with D20), 2.52 (td, J =

11.1, 2.1 Hz, IH), 2.41 (dd, J = 8.5, 7.0 Hz, 2H), 2.16 (m, IH), 1.95 (t,

5.8 Hz, 2H), 1.84 (m, IH), 1.66-1.53 (m, 4H), 1.40-1.26 (m, 5H), 1.14­

1.01 (m, IH), 1.10 (s, 3H), 0.88 (t, J = 7.2 Hz, 3H).

13C-NMR (CDC13, 125 MHz, ppm): 0 155.1, 153.9, 142.9, 109.6, 109.0,

108.2, 79.9, 70.9, 58.9, 46.3, 41.1, 38.6, 35.5, 35.4, 33.2, 31.6, 30.6,

25.7, 22.5, 17.8, 14.0.

IR (neat, em-I): 3400, 2980, 1600, 1480, 1350, 1050.

Mass spectrum (70 eV, m/e) 348 (M+): 257, 193, 167, 150, 149.

Calculated mass for C2IH3204: 348.2300, found: 348.2308.

50

~I) HO

HO47

Procedure:

OH

43

Compound 43 (8 mg) was prepared in 80% yield from 10 mg of

47 by the same procedure for 30. The ratio of 43:30 was 85:15.

51

OH

43

14cx- Hyd roxymethyl-9-nor-9~-Hydroxyhexahyd rocanna binol

43:

IH-NMR (CDCI3, 500 MHz, ppm): 0 6.20 (d, J = 0.9 Hz, IH), 6.09 (d, 0.9

Hz, IH), 5.97 (br, IH, exchangeable with DzO), 3.87 (m, 2H), 3.73 (m,

IH), 3.48 (m, IH), 2.53 (td, J = 11.4, 2.0 Hz, IH), 2.44 (m, 2H), 2.18 (m,

IH), 1.97-1.83 (m, 4H), 1.58-1.33 (m, 8H), 1.42 (s, 3H), 1.05 (q, J =

7.2, 6.9 Hz, IH), 0.87 (dd, J = 7.2, 6.9 Hz, 3R).

13C-NMR (CDCI3, 125 MHz, ppm): 0 155.1, 154.2, 143.2, 109.2 (2C),

108.3, 78.5, 70.8, 59.1, 49.7, 38.8, 35.7, 35.4, 32.8, 32.7, 31.5, 30.6,

25.7, 24.7, 22.5, 14.0.

IR (neat, cm- 1): 3400, 2980, 1610, 1450, 1350, 1100.

Mass spectrum (70 eV, m/e) 348 (M+): 285, 257, 231, 217, 193, 149.

Calculated mass for CZIH3204: 348.2300, found: 348.2295.

REFERENCES

1. Schultes, R. E.; Hofmann, A. The Botany and Chemistry of

Halucinogens, 2nd ed., Charles C Thomas, Springfield, 111.,

1980.

2. Campbell Thompson, R. A Dictionary of Assyrian Botany, the

British Academy, London, 1949.

3. (a) Touw, M. J. Psychoactive Drugs, 1981, 13, 23.

(b) Li, C. P. Chinese Herbal Medicine, Pub!. No. 75-732, U. S.

Department of Health, Education and Welfare, Washington,

D. C., 1974.

4. Mechoulam, R. The Pharmacohistory of Cannabis sativa. In:

Cannabinoids as Therapeutic Agents, Mechoulam, R. ed., CRC

Press, Boca Raton, FL, 1986, pp. 1-19.

5. Kabelik, J.; Krejci, S,; Santavy, F. Bull Narc. 1960, 12, 5.

6. O'Shaugnessy, W. B.; Trans. Med. Phys. Soc. Bombay 1839, 8,

421.

7. O'Shaugnessy, W. B. Pharmacol. J. Trans. 1843,2, 594.

8. O'Shaugnessy, W. B. Cannabis. In: The Bengal Dispensatory and

Pharmacopoeia, Bishop's College Press, Calcutta, 1841, 579.

9. Adams, R. Harvey Lect. 1941·1942,37, 168.

10. Todd, A. R. Experientia 1946, 2, 55.

11. Loewe, S. Arch. Exp. Pathol. Pharmacol. 1950,211, 175.

12. Gaoni, Y.; Mechoulam, R. J. Am. Chern. Soc. 1964,86, 1646.

13. Mechoulam, R.; Edery, H. Structure-activity relationships in the

52

53

cannabinoid series, in Marijuana: Chemistry, Pharmacology,

Metabolism and Clinical Effects, Mechoulam, R., Ed., Academic

Press, New york, 1073.

14. Dewey, W. L.; Martin, B. R.; May, E. L. Cannabinoid

stereoisomers: Pharmacological effects, in Handbook of

Stereoisomers: Drugs in Psychopharmacology, Smith, D. F. ed.,

CRC press, boca Raton, FL. 1984, 317.

15. Razdan, R. K. Pharmacol. Rev. 1986,38, 75.

16. Little, P. J.; Compton, D. R.; Martin, B. R. J. Pharmacol. Exp. Ther.

1988, 247, 1046.

17. Jarbe, T. U. C.; Hituene, A. J.; Mechoulam, R., Srebnik, M.; Breuer,

A. Eur. J. Pharmacol. 1988, 156, 361.

18. Mechoulam, R.; Devane, W. A.; Glaser, R. Cannabinoid geometry

and biological activity in Marijuana/Cannabinoids

Neurobiology and Neurophysiology, Murphy & Bartke, Ed., CRC

Press, Boca Raton, FL, 1992, 1.

19. (a) Houry, S.; Mechoulam, R.; Fowler, P. J.; Macko, E.; Loev, B. J.

Med. Chem. 1974,17, 287.

(b) Houry, S.; Mechoulam, R.; Loev, B. J. Med. Chern. 1975, 18,

951.

20. Banerjee, S. P.; Mechoulam, R.; Snyder, S. H. J. Pharmacol. Exp.

Ther. 1975,194, 75.

21. Johnson, M. R.; Althuis, T. H.; Bindra, J. S.; Harbert, C. A.; Melvin,

L. S.; Milne, G. M. NIDA Res. Monogr. Ser., 1981,34, 68.

22. Johnson, M. R.; Melvin, L. S.; Althius, T. H.; Bindra, J. S.; Harbert,

C. A.; Milne, G. M.; Weissman, A., J. Clin. Pharmacol. 1981,271s,

54

21.

23. Matsumoto, K.; Stark, P.; Meister, R. G. J. Med. Chem. 1977,20,

17.24. Makriyannis, A.; Rapaka, R. S. Life Science 1990,47, 2173.

25. Mechoulam, R.; Feigenbaum, J. J.; Lander, N.; Segal, M.; Jarbe, T.

U. C.; Hiltuene, A. J.; Consore, P. Experientia 1988,44, 762.

26. Johnson, M. R.; Milne, G. M. J. Clin. Pharmacol. 1981,21, 367.

27. Charalambous, A.; Marciniak, G.; Lin, S. Y.; Friend, F. L.; Compton,

D. R.; Martin, B. R.; Wang, C. L. J.; Makriyannis, A. Neurosci.

Biobehav. Rev. 1991, 40, 471.

28. Kannangara, G. C. K. Ph. D. Dissertation, University of Hawaii,

1994.

29. Razdan, R. K.; Dalzell, H. C.; Handrick, G. R. J. Am. Chem. Soc.

1974, 96, 5860.

30. Tius, M. A.; Kannangara, G. S. K. Tetrahedron 1992,48, 9173.

31. Mechoulam, R.; Braun, P.; Gaoni, Y. J. Am. Chem. Soc. 1972, 94,

6159.

32. Fahrenholtz, K. E.; Lurie, M.; Kierstead, R. W. J. Am. Chem. Soc.

1967, 89, 5934.

33. Pitt, C. G.; Fowler, M. S.; Sathe, S.; Srivastava, S. C.; Williams, D. L.

J. Am. Chem. Soc. 1975,97, 3798.

34. (a) Tius, M. A.; Gu, X. Q..; Kerr, M. A. J. Chem. Soc., Chem.

Commun. 1989, 62. (b) Tius, M. A.; Kerr, M. A. Synth. Commun.

1988, 1905. (c) Tius, M. A.; Gu, X. Q. J. Chem. Soc., Chem.

Commun. 1989, 1171.

35. Tius, M. A.; Kannangara, G. S. K. J. Org. Chem. 1990,51, 5463.

55

36. Huffman, J. W.; Joyner, H. H.; Lee, M. D.; Jordan, R. D.;

pennington, W. T. J. Org. Chern. 1991,56, 2081.

37. Tius, M. A.; Kannangara, G. S. K.; Kerr, M. A.; Grace, K. J. S.

Tetrahedron, 1993,49, 3291.

38. Lipshutz, B. H.; Kozlowski, J. A.; Parker, D. A.; Nguyen, S. L.;

McCarthy, K. E. J. Organornet. Chem. 1985,285, 437.

39. (a) Maruoka, K.; Concepcion, A. B.; Hirayama, N.; Yamamoto, H. J.

Am. Chem. Soc. 1990,112,7422. (b) Brown, H. C.; Geoghegan, P.

J. Jr. J. Org. Chern. 1975,35, 1844.

40. (a) Uliss, D. B.; Razdan. R. K.; Dalzell, H. C. J. Am. Chern. Soc.

1974,96, 7372. (b) Archer, R. A.; Boyd, D. B.; Demarco, P. V.;

Tyminski, I. J.; Allinger, N. L. J. Am. Chem. Soc. 1970,92, 5200.

41. (a) Pougny, J. R.; Nassr, M. A. M.; Sinay, P. J. Chem. Soc., Chern.

Commun. 1981, 375. (b) Bernotas, R. C.; Ganem, B. Tetrahedron

Lett. 1985,26, 4981.

42. Kozikowski, A. P.; Lee, J. J. Org. Chern. 1990,55, 863.

43. Tius, M. A.; Busch-Petersen, J. Tetrahedron Lett. 1994,35,

5181.

44. Tius, M. A.; Makriyannis, A.; Zou, X. L.; Abadji, V. Tetrahedron,

1994,50, 2671.

-- - ---.-._- --

PART II: THE TOTAL SYNTHESIS OF SARCOPHYTOL A AND ITSANALOGS

56

A. SYNTHESIS OF CANVENTOL AND ITS ANALOGS

INTRODUCTION

1. Background

The aim of this project was to synthesize some structurally

simplified analogs of the natural product sarcophytol A 55 and to

subject them to biological testing for cancer preventative activity.

The analogs 56-59, which are structurally related to sarcophytol A,

were designed by Professor Tius and their biological activity was

evaluated in Professor Hirota Fujiki's laboratory.l

55 sarcophytol A 56 canventol

OHR

57

2. Synthesis of Canventol and Its Analogs

The synthesis of analog 56, which has been named canventol by

Dr. Fujiki, was accomplished by following the synthetic route outlined

57

below (scheme 1). The conversion of compound 60 to enone 62 was

carried out by following the published procedure:2 Birch reduction

SCHEME 1

OCH3 cey; if&COOH a.,~ COOLi b

I~ .. III

60 61 62

c ™CY d e ... 65III ...

OMe63 64

g f.. ..

57 65 56

Reagents; (a) Li/NH3, THF. -78°C; (b) isopropyl iodide; aqueous HCI. 600C; (c)FeCI3/CH3MgBr. TMSCI. Et3N. HMPA; (d) 2,2-dimethoxypropane. TiCI4, OOC; (e)HCI04; (t) NaBH4. CeCI3. methanol; (g) MeLi. Et20. OOC.

of anisic acid 60, followed by alkylation with isopropyl

iodide led to carboxylic acid 61. Hydrolysis of 61 in aqueous Hel

produced enone 62 in 45% overall yield. Formation of the

thermodynamic enolate of 62 and trapping with

58

chlorotrimethylsilane led to enol ether 63 which was exposed to 2,2­

dimethoxypropane and titanium tetrachloride at OOC to give enone

64 in 49% overall yield.4 ,5 Elimination of methanol from enone 64 in

the presence of perchloric acid produced dienone 65 in 51 % yield.

The reduction of dienone 65 with sodium borohydride and cerous

chloride gave crystalline (d, l)-canventol (56) in 96% yield.

Treatment of dienone 65 with methyllithium led to analog 57 in

quantitative yield. The overall yield in this synthesis of canventol

was 24% from enone 62. Its shortcomings are the use of HMPA and

the low yield for the elimination of methanol from enone 64.

These problems were largely overcome during a novel, efficient

synthesis of analogs S8 and 59 (scheme 2). Nopinone 35, which was

SCHEME 2

R

58 R = CH359 R = C2 Hs

67

OH

o 0

O~

e

6968

0 0 0

GJ a Gt°~ b.. /i'. •I

35 66

0 0 0

O~R

c d.. R •

Reagents: (a) Diallyl carbonate, NaH, DME; (b) TMSI, CCI4; (c) RX, acetone,K2C03; (d) Pd(OAc)2, THF, 800C; (e) NaBH4, methanol.

59

prepared from (-)-f3-pinene,6 was converted to ketoester 66 in 80%

yield by treatment of 35 with diallyl carbonate in DME. Ring

cleavage of 66 was achieved by treatment with TMSI in CCl4 at OOC

led to tertiary iodide 67 in 60-70% yield.7 Alkylation of 67 with

iodomethane or iodoethane followed by elimination produced ketone

68 in 50-60% yield respectively. Treatment of 68 with catalytic

palladium acetate led to dienone 69 in 80% yield.8 Reduction of

dienone 69 gave products 58 and 59 in 90% yield.9 The advantages

of this synthesis were the cheap, available starting material and its

applicability for larger scale.

This method was applied to the synthesis of canventol. It was

shown that alkylation of 66 with isopropyl iodide led to a (3:2)

mixture of O-alkylated 70 and C-alkylated 71 products. Starting

material 66 was recovered by hydrolysis of 70 under acidic

condition.

0 0 Jo~o~~o~ a GY'0~

~ ... ~ + ~I I I 0

66 70 71

Reagents: (a) acetone, K2C03, isopropyl iodide.

Recently, a novel synthetic method to canventol was developed

by our laboratory 10 and it provides the possibility of production on

kilogram scale. Further investigation of this synthesis will be

undertaken by our group.

60

3. Biological Activity

The testing which was performed in Professor Fujiki's laboratory

in Japan showed that canventol inhibited tumor promotion induced

by okadaic acid on mouse skin initiated with 7,12­

dimethylbenz(a)anthracene in the two stage carcinogenesis

experiment. Canventol inhibited tumor promotion more strongly than

sarcophytol A, even though canventol has a simpler structure than

sarcophytol A.II

--- .-------- ...

61

EXPERIMENTAL

Procedure:

OCH3&COOH _60 62

A three-neck flask was charged with 15.2 g (100 mmol) of 0­

methoxybenzoic acid and 100 ml of THF. The solution was stirred and

ammonia (400 ml) was distilled in to give a thick white suspension.

The reaction mixture was maintained at reflux under a nitrogen

atmosphere and lithium wire (washed sequentially with hexane,

ethyl ether) was added in 2 cm pieces until a blue solution was

maintained. The reaction vessel was cooled in a dry ice-acetone bath

and 1,2-dibromoethane (2 ml) added, followed by 2-iodopropane 12

ml (120 mmol). The reaction mixture was warmed to room

temperature under nitrogen and the resultant yellow slurry diluted

with 100 ml water, then acidified with 100 ml concentrated aqueous

HCl. Hydroquinone (200 mg) was added and the solution refluxed for

30 min. The solution was cooled to room temperature and extracted

with CH2C12. The solvent was removed and the residue purified by

chromatography to give 3.84 g of enone 62 in 50% yield.

-- - ---------

62

Enone 62:

IH-NMR (CDCI3, 300 MHz, ppm): 6.21 (dd, J =7.2, 6.9 Hz, IH), 2.87­

2.78 (sept, IH), 2.40-2.29 (m, 4H), 1.96-1.87 (m, 2H), 0.97-0.96 (d,

6.9 Hz, 6H).

IR (neat, em-I): 3050, 2960, 1660, 1440, 1380, 1100.

62

Procedure:

62if

63

63

To a solution of anhydrous ferric chloride (257 mg, 2.2 mmol) in

15 ml of anhydrous ether at OOC under an atmosphere of N2 was

slowly added an ethereal solution of methylmagnesium bromide (2.2

ml, 6.6 mmol). The resulting slurry was stirred for 1 h at 25°C, then

enone 62 (276 mg, 2.0 mmol) dissolved in 5 ml ethyl ether was

slowly added over a period of 10 min. After 30 min, Me3SiCI (0.84

ml, 6.6 mmol), Et3N (0.95 ml, 6.8 mmol), HMPA (0.38 ml, 2.2 mmol)

were added in that order. The solution was stirred overnight, diluted

with 10 ml ethyl ether and poured into cold saturated NaHC03

solution. The aqueous layer was extracted with 15 ml ether. The

organic layer was dried over anhydrous sodium sulfate, filtered and

concentrated. The resulting colorless oil was filtered through a plug

of silica gel (5% EtOAc/Hexanes) to remove HMPA and Et3N. The

eluant was concentrated to give a colorless oil 63 which was used in

the subsequent reaction without further purification.

Procedure:

6"-----.....63

OMe

64

64

Under nitrogen, 2,2-dimethoxypropane (0.12 ml, 1.0 mmol) was

added slowly to a solution of TiC4 (1.0 mmol) in 10 ml anhydrous

CHzCl2 at -780 C. After 5 min, compound 63 (210 mg, 1.0 mmol)

dissolved in 5 ml CHzCl2 was added. The deep red solution was

stirred for 30 min at -780C and then 5 ml water added and the

mixture was warmed to room temperature. The aqueous layer was

extracted with 10 ml CH2CIZ. The organic layer was dried over

anhydrous MgS04, filtered and concentrated. The residue was

purified by silica gel chromatography to give 126 mg of the desired

product 64 in 60% yield.

Methoxyketone 64:

IH-NMR (CDCI3, 300 MHz, ppm): 6.75 (s, IH), 3.25 (s, 3H), 2.63-2.50

(m, 2H), 2.38-2.26 (m, IH), 2.03-1.96 (m, IH), 1.71-1.56 (m, IH), 1.17

(s, 3H), 1.10 (s, 3H), 1.02 (d, J = 3.0 Hz, 3H), 0.99 (d, J = 2.7 Hz, 3H).

IR (neat, cm- 1): 3050, 2960, 1680, 1450, 1380, 1050.

Procedure:

OMe

64 65

65

To a solution of compound 64 (294 mg, 1.4 mmol) in 12 ml

CF3CH20H, excess perchloric acid was added slowly at 250C. The

solution was heated to 400C for 30 h and then 10 ml water added.

The mixture was extracted with 10 ml ether and the organic layer

dried over anhydrous MgS04, filtered and concentrated. The oily

residue was purified by silica gel chromatography to give 120 mg of

the desired product 65 in 50% yield.

Dienone 65:

IH-NMR (CDC13, 300 MHz, ppm): 7.25 (s, IH), 2.97 (sept, IH), 2.66 (t, J

= 6.9 Hz, 2H), 2.46 (dd, J = 7.5 Hz, J = 6.6 Hz, 2H), 1.93 (s, 3H), 1.07 (s,

3H), 1.04 (s, 3H).

IR (neat, cm- 1): 3050, 2940, 1670, 1450, 1380, 1050.

Procedure:

65 56

66

To a stirring solution of compound 65 (100 mg, 0.56 mmol mg)

in 5 ml CH30H at 25°C, CeC13 (138 mg, 0.56 mmol) was added. After 5

min, NaBH4 (22 mg, 0.56 mmol) was added, the solution was stirred

for 2 min and water added. The mixture was extracted with 10 ml

ethyl ether. The organic layer was dried over anhydrous MgS04,

filtered and concentrated. The residue was purified by

chromatography to give 98 mg crystalline desired product 56 in 95%

yield.

Canventol 56:

IH-NMR (CDCI3, 300 MHz, ppm): 6.32 (s, IH), 4.24 (dd, J =6.9, 6.6 Hz,

IH), 2.52 (sept, IH), 2.37 (m, 2H), 1.81-1.76 (m, 8H), 1.11 (t, J = 7.2

Hz,6H).

13CNMR (CDCI3, 75 MHz, ppm): 127.5, 126.8, 120.9, 66.0, 32.4, 31.79,

22.59, 21.64, 21.32, 20.86, 19.68.

IR (neat, em-I): 3500, 3030, 2980, 1620, 1450, 1380, 1100, 1050.

Procedure:

65 57

67

To a solution of dienone 65 (45 mg, 0.25 mmol) in 10 ml ethyl

ether was added CH3Li (0.3 mmol) at OOC. The mixture was stirred

for 5 min at OOC and 10 ml water was added. The organic layer was

dried over anhydrous MgS04 and solvent removed. The residue was

purified by flash chromatography to give 40 mg of the desired

product 57 in 89% yield.

Alcohol 57:

IH-NMR (CDC13, 300 MHz, ppm): 6.37 (s, 1H), 2.80-2.67 (m, 1H), 2.35­

2.26 (m, 1H), 2.15-2.04 (m, 1H), 1.71 (s, 3H), 1.66-1.62 (m, 2H), 1.60

(s, 3H), 1.21-1.19 (d, J = 6.9 Hz, 3H), 1.13 (d, J = 6.9 Hz, 3H).

IR (neat, em-I): 3350, 2980, 1480, 1350. 1100, 1050.

o 0

~.. O~)t'-.. ----i.._

I

66

Procedure:

o 0

O~

I

67

68

To a solution of allyltrimethylsilane (684 mg, 6.0 mmol) in 5 ml

CCl4 at OOC was added iodine (762 mg, 6.0 mmol). The mixture was

stirred for 1 h at ooC. The starting material 66 (1.11 g, 5.0 mmol) in

5 ml CCl4 was added and the solution was stirred for 30 min at OOC.

The solution was washed with sat'd aqueous NazSz03 solution. The

solvent was removed and the residue purified by flash

chromatography to give 950 mg of the desired product 67 in 55%

yield (the compound was not isolated).

o 0

O~

67

Procedure:

o 0

O~R

68 R = CH369 R = C2Hs

69

A mixture of compound 67 (0.68 mmol), 2 ml acetone,

potassium carbonate (280 mg, 2.03 mmol) and 0.5 ml alkyl iodide

was refluxed in a sealed tube for 10 h. The solution was cooled to

room temperature and filtered. The acetone was removed under

reduced pressure. The residue was purified by flash chromatography

to give 120 mg of compounds 68 or 69 in 75-80% yield.

Compound 69:

IH-NMR (CDCI3, 300 MHz, ppm): 5.92-5.72 (m, 1H), 5.31 (d, J = 17.1

Hz, 1H), 5.24 (d, J = 10.5 Hz, 1H), 4.65-4.51 (m, 2H), 3.23 (d, J = 14.4

Hz, 1H), 2.73-2.30 (m, 4H), 2.21 (d, J = 14.4 Hz, 1H), 1.74 (s, 3H), 1.70

(s, 3H), 1.33 (s, 3H).

IR (neat, em-I): 3040, 2980, 1730, 1710, 1640, 1460, 1380, 1140.

o 0

o~

oA

70

Procedure:

68 R=CH369 Ro=C2Hs

A mixture of compound 68 or 69 (0.48 mmol), Pd(OAch (0.1

mmol), diphenylphosphinoethane (dppe) (0.05 mmol), in 5 ml

acetonitrile was refluxed for 1h. The solution was cooled to room

temperature, filtered, and 20 ml water was added. The mixture was

extracted with ethyl ether and the organic layer was dried over

anhydrous MgS04. The crude product was purified by flash

chromatography to give 45 mg of the desired product dienone in 57­

60% yield.

Dienone 72:

IH-NMR (CDCI3, 300 MHz, ppm): 7.26 (s, 1H), 2.70 (d, J = 6.9 Hz, 1H),

2.65 (d, J =7.2 Hz, 1H), 2.49-2.44 (m, 2H), 2.32-2.24 (dd, J = 15.0,

14.7 Hz, 1H), 1.92 (s, 3H), 1.87 (s, 3H), 1.05 (t, J = 7.5 Hz, 3H).

IR (neat, cm- l ): 3030, 2980, 1680, 1640, 1450, 1380, 1100.

o OH

71

RII'

R

Procedure:

58 R = CH359 R = C2Hs

To a stirring solution of dienone (0.27 mmol), CeCl3 (0.27 mmol)

in 5 ml CH30H at room temperature was added NaB14 (0.27 mmol).

After 5 min, 20 ml water was added and the mixture was extracted

with ethyl ether. The organic layer was dried over anhydrous MgS04

and the solvent was removed. The crude product was purified by

chromatography to give 10 mg desired products 58 or 59 in 88-90%

yield.

Compound 58:

IH-NMR (CDCI3, 300 MHz, ppm): 6.29 (s, IH), 4.10 (d, J = 2.1 Hz, IH),

2.32 (t, J = 6.3 Hz, 2H), 1.89 (s, 3H), 1.85-1.70 (m, 2H), 1.78 (s, 3H),

1.74 (s, 3H).

IR (neat, cm- l ): 3350, 2980, 1640, 1450, 1380, 1200, 1050.

72

Compound 59:

IH-NMR (CDC13, 300 MHz, ppm): 6.29 (s, IH), 4.18 (m, IH), 2.35 (t, J =

5.1 Hz, 2H), 2.28-2.21 (dd, J = 14.7, 15.0 Hz, 2H), 1.83-1.78 (m, 2H),

1.80 (s, 3H), 1.75 (s, 3H), 1.10 (dd, J = 7.5, 7.2 Hz, 3H).

13C-NMR (CDCh, 75 MHz, ppm): 140.3, 127.0, 126.8, 122.1, 67.2, 31.8,

27.4, 21.7, 20.7, 19.6, 12.7.

IR (neat, em-I): 3350, 2980, 1640, 1450, 1380, 1100, 1050.

73

REFERENCES

1. Professor H. Fujiki, Cancer Prevention Division, National Cancer

Center Research Institute, Tokyo 104, Japan.

2. (a) Taber, D. ,F. J. Org. Chern. 1976,41, 2649.

3. (a) Zank, G. A.; Rauchfuss, T. B.; Wilson, S. R. J. Am. Chem. Soc.

1984, 106, 7620.

4. Mukaiyama, T.; Hayashi, M. Chem. Lett. 1974, 15.

5. (a) Coxon, J. M.; Hydes, G. J.; Steel, P. J. Tetrahedron, 1985,42,

5213. (b) Luche, J. L.; Gemal, A. L. J. Am. Chem. Soc. 1981,103,

5454.

6. Grimshaw, J.; Grimshaw, J. T.; Juneja, H. R. J. Chem. Soc. Perkin

Trans. 1 1972, 50.

7. (a) Kato, M.; Kamat, Y. P.; Tooyama, Y., Yoshikoshi, A. J. Org.

Chem. 1989,54, 1536. (b) Jung, M. E.; Blumenkopf, T. A.

Tetrahedron Lett. 1978,29, 3657.

8. (a) Wilhelm, F. Newer Methods of Preparative Organic chemistry

Vol 2, 1963, Academic Press, New York. (b) Fatiadi, A. J.

Synthesis 1987, 85.

9. Minami, I.; Nisar, M.; Yuhara, M.; Shimizu, I.; Tsuji, J. Synthesis

1987, 992.

10. Tius, M. A.; Zhuo, J. C. Unpublished Result.

11. Komori, A.; Suganuma, Okabe, S.; ZOll, X. L.; Tius, M. A.; Fujiki, H.

Cancer Res. 1993,53, 3462.

74B. THE TOTAL SYNTHESIS OF SARCOPHYTOL A

INTRODUCTION

1. Background

Cembranes are fourteen membered, diterpenoid natural

products which were isolated from terrestrial and marine sources in

the 1970's.1 The structures range from the simple hydrocarbon

cembrane 73, found in pine 0leoresins,2 to those containing highly

oxygenated stereocenters such as sinularin 74.3 The biological

activities in the cembrane series have been found to be diverse: from

cytotoxins4-6 to termite allomones.7-9 For example, sarcophytol ASS,

which was isolated from Sarcophyton glaucum,lO inhibits tumor

promotion by teleocidin in the two-stage carcinogenesis model in

73 cembrane 74 sinularin

55 sarcophytol A

75

mouse skin. I I Due to the biological activities and interesting

structu.ral features, cembranes have become attractive targets for

total synthesis. 12 The major obstacles for synthesis are

macrocyclization, the introduction of functionality and asymmetric

centers on the fourteen membered ring.

2. Previous Approaches to Macrocyclization

The development of an efficient method of macrocyclization is

the key step for a successful cembrane synthesis. Unlike small nngs

(e.g. 5, 6), the number of degrees of freedom is much larger in the

open-chain precursor for larger ring (e.g. 14). Therefore, the entropy

barrier can become a problem, and bimolecular reaction can

predominate over the intramolecular cyclization. The bimolecular

processes, which lead to dimeric or oligomeric products, can be

suppressed at high dilution. There are several general methods of

macrocyclization that have been successfully used for cembrane

synthesis which will be discussed next.

a. Stabilized Anion Additions

Sulfur and cyanohydrin stabilized anions have been used for

direct cyclization. For example, a sulfone stabilized carbanion was

reported by Marshall I3 in the synthesis of dl-7(8)-deoxyasperdiol in

which a sulfone iodide 7S was cyclized to 76 in 53% yield by

treatment with KN(TMSh in THF in the presence of 18-crown-6. An

76

ethoxyethyl-protected cyanohydrin-derived anion 77 also

under~ent cyclization to 78 in 83% yield in the synthesis of mukulol

by Takahashi. 14

7877

a ...

I S02Ph

75 R = CH2Ph 76NC 0

OEEb

Reagents: (a) KN(TMS)2. THF. 18-crown-6; (b) NaN(TMS)2. THF, Hel.

b. Alkynyl Anion Addition

The most recent method of cyclization is that of direct addition

of an alkynyl anion to aldehydes (e.g. 79) or allylic halides (e.g. 81).

This method was previously developed for the formation of ten

membered rings 15 and was first used for cembrane synthesis in our

laboratory.16 The yields of the reaction were 30-60%. There are

several other methods for cyclization e.g. intramolecular Horner­

Emmons reaction,17 and radical cyclization18 all of which have been

used in the synthesis of cembranes.

77

a

Br

'---====--H b

- HCHO -----1-._

81

Reagents: (a) LiN(TMS)2, THF. 50°C; (b) LiN(TMS)2, LiI, THF.

3. Previous Synthetic Approaches to Sarcophytol A

The geometrical structure and absolute configuration of

sarcophytol A were confirmed to be 2Z, 4£, 8£, 12£ and IS,

respectively.19 So far, several methods have been developed to the

synthesis of sarcophytol A.

a. Takayanagi et. al.

The first total synthesis of sarcophytol A was accomplished by

Takayanagi et. al. in 1990 (scheme 1).20 Therein trans, trans-farnesal

was converted to nitrile 83 by a Wittig reaction. Sharpless oxidation

of compound 83 led to allylic alcohol 84 in 52% yield (based on the

78

consumed starting material 83, which was converted to the chloride

8S by treatment with PPh3 and CC4. Treatment of 8S with DIBAL at

Doe followed by hydrolysis of the intermediate imine led to dienal

86. The unstable conjugated dienal 86 was converted to the

SCHEME 1

,a b

eN .. ..X

83 84 X = OH85 X = CI

, dc ..

CHO..

CI CI

86 87

e .. 55

88

Reagents: (a) SeOz, t-BuOOH, CH2CIZ, OOC; then CCI4, PPh3; (b) DIBAL, THF, OOC;(c) TMSCN; (d) LiN(TMS)Z, THF, 550C; n-Bu4NF, THF, OOC; (e) (S)-Z-(2,6­xylidinomethyl)pyrrolidine, LAH, EtZ 0, -78°C.

cyanohydrin trimethysilyl ether 87. The macrocyclization of 87 was

immediately carried out by adding a solution of LiN(TMSh in the

presence of 18-crown-6, followed by n-Bu4NF to give dienone 88 in

79

60% yield. Treatment of 88 with the asymmetric reducing reagent

prepar~d by mixing LAH in ether with (S)-2-(2,6-xylidinomethyl)

pyrrolidine at -78°C led to optically active 55 of 93% ee in 88% yield.

b. Takahashi et. al.

Another new synthesis of sarcophytol A was developed by

Takahashi et. al. (scheme 2).21 Therein compound 89 was prepared

SCHEME 2

89

b

88

a

90

Reagents: (a) LiN(TMS)2, THF, 50°C; (b) LiCu(CH3)2. THF, DoC.

from trans, trans-farnesol in seven steps. Macrocyclization of 89

with NaN(TMSh in THF, followed by deprotection, led to enone 90 in

45% yield. Methyl cuprate addition to the conjugated exocyclic

double bond of 90 was followed by spontaneous 13-elimination of

alkoxide from the cuprate adduct to produce dienone 88 in 50%

yield.

80

c. Kodama et. al.

Recently, a novel synthesis to sarcophytol A was achieved by a

[2,3] Wittig rearrangement (scheme 3).22 Alcohol 92 was prepared

from geranial 91 in seven steps. Cyclization of 92 led to cyclic ether

93 in 9% yield. Rearrangement of 93 with n-BuLi at -78°C produced

sarcophytol A 55· in 90% yield. Obviously, the defect of this synthesis

was the poor yield (9%) of cyclization of 92.

SCHEME 3

91

7 steps...

92

a ...

93

b----1..._ 55

Reagents: (a) CC13CN, NaH; p-toluenesulfonic acid; (b) n-BuLi, THF.

d. Li et. al.

Macrocyclization by titanium-induced coupling of a dicarbonyl

compound was also achieved in the synthesis of sarcophytol A23.

Compound 94 was prepared from acetone in eight steps and

macrocyclization was carried out by treatment of 94 with TiCI3-AICI3

81

(1/3) and Cu-Zn alloy at 55°C in THF. Sarcophytol A SS was obtained

in 63% yield (scheme 4).

SCHEME 4

oA

8 steps ..

94

a---I"~ 55

Reagents: (a) TiCI3-AICI3 (1/3), Cu-Zn alloy, THF, 550 C.

The development of a novel and efficient method of the

synthesis of sarcophytol A will be disussed in the following chapter.

82

RESULTS AND DISCUSSION

1. Retrosynthesis of Sarcophytol A

Sarcophytol A SS was envisioned as being prepared from cyclic

alkynyl alcohol 96 (scheme 5). Our strategy and key steps are: (1)

the preparation of precursor acyclic alkynyl aldehyde 97 for

macrocyclization. (2) the introduction of isopropyl (C-2) and sulfoxide

(C-l) groups on the 14-membered ring (3) the conversion of

sulfoxide 9S to enone 88. The advantages of starting the synthesis

with trans, trans-farnesol are that it contains three trisubstituted

alkenes which fit the pattern for sarcophytol A.

SCHEME S

55

96

88

OH

===>

97

95

CHO

H,

83

2. Synthesis of Alkynyl Acetate

Starting material trans, trans-farnesol 98 was converted to

farnesyl acetate 99 in the presence of acetic anhydride and pyridine

in quantitative yield. Sharpless oxidation24 of 99 led to allylic alcohol

SCHEME 6

98 R= H99 R = Ae

101

a

c ..

100

102

OAe b

OH

OAe

H

Reagents: (a) (CH3CO)20, pyridine, CH2CI2; then Se02, t-BuOOH, DOC; (b) MsCI,LiBr, THF; (c) Acetylene, K2C03, NaI, CuI, acetone.

100 in 25% yield (scheme 6). There are several features of the

Sharpless oxidation which are noteworthy: (l) the regiochemical

preference of the oxidation made it possible to oxidize the E-terminal

CH3 (2) the methylene (-CHZ-) which IS next to the acetyl group was

not oxidized (3) the low yield (25%) of the reaction and the tedious

column chromatography in the initial step made the reaction very

difficult to perform on large scale. Treatment of allylic alcohol 100

with MsCI, NEt3 and lithium bromide at DOC led to allylic bromide

84

101 in 85% yield.25 Because of the instability of this allylic bromide,

101 was purified by short flash chromatography and used for

subsequent acetylene displacement immediately. To complete the

conversion from 101 to 102, acetylene gas was bubbled into a

mixture of CuI, K2C03, NaI and acetone at room temperature for 2 h

and then 101 was added dropwise.26 The mixture was stirred for 2

days and 102 was isolated in 60% yield. Several other conditions

were also examined. Replacement of acetone by DMF led to 102 in

very poor yield (20-30%), even though the reaction time was short (5

h). Direct displacement of bromide 101 with sodium acetylide or

lithium acetylide in THF at OOC did not succeed, the reaction did not

take place and only starting material 101 was isolated. It has to be

pointed out that acetylene displacement of 101 led to some dimeric

and SN2' byproducts (103 and 104 30% yield). The probable

mechanism of dimerization might be as follows:

SN2'

I ~

V~~r102 SN2 100

S~103

y~

104

85

Byproducts 103 and 104 were inseparable from desired product

102. Optimization of the reaction conditions did not give rise to a

yield better than 60%. The reaction was repeated at high dilution

(e.g. 0.005, 0.003, 0.001 M), but this led to no improvement of the

yield.

3. Formation of Cyclic Alkynyl Alcohol

Hydrolysis of 102 with KzC03 in methanol produced 105 in 85%

yield. Swern oxidationZ7 of 105 led to aldehyde 97. The overall yield

SCHEME 7

-::::-- CHO

H,a102

105 97

Reagents: (a) KZC03, methanol, Z30C; (b) DMSO, (COCI)Z, Et3N, CHZCIZ,-78°C.

from 102 to 97 was 60% (scheme 7). Although several methods for

macrocyclization have been applied to cembrane synthesis, only a

few cases of macrocyclization by direct addition of an alkynyl anion

to an aldehyde exist. The method was first used in the synthesis of

sinularin 74 in our laboratory, but the yield was very poor (30%).16

86

As mentioned above, several factors also affect the macrocyclization,

e.g. te"mperature, base and concentration. What we did first was the

use of different bases at the same temperature and highly dilute

concentration. When NaN(TMS)z was used at room temperature in

THF, the reaction proceeded well. Product 96 was obtained in 50­

60% yield. Use of LiN(TMS)z resulted in incomplete reaction (10%

yield). When the stronger base KN(TMS)z was used, the cyclic allenic

a ..OH

96

97

106

Reagents: (a) NaN(TMS)2, THF, room temperature; (b) KN(TMS)2, THF, roomtemperature.

alcohol 106 was obtained in 60% yield. A possible mechanism to

account for the formation of allene 106 was by attack of cyclic

alcohol 96 by KN(TMS)z, so that the allene was formed after

cyclization. But when KN(TMSh was added to the solution of 96 in

87

...00

106

THF at room temperature, no allene 106 was isolated. Another

possibility was that the allene 106 was formed from 107 before

SCHEME 8

97 ...~ CHO

107

---.......-106

cyclization (scheme 8), although no evidence has been obtained to

confirm this assumption. Further work needs to be done on this

reaction. Allenic alcohol 106 was characterized by IH-NMR, IR and

mass spectrometry: IR showed a strong allene absorption band at

1960 em-I. Also, the appearance of the allenic protons (5.6-5.8 ppm)

on allene 106 in the IH-NMR spectrum and the exact mass matched

the proposed structure.

88

4. Synthesis of Alkylated Sulfoxide

To prepare the allenic sulfoxide 111, the following conditions

were examined in a model reaction in order to develop optimal

conditions for the real system (scheme 9).28 Compound 108 was

prepared from I-hexyn-3-01. The solution of compound 108 was

added dropwise to the mixture of CuI and isopropyllithium

SCHEME 9

OH a H>=C~ b

~H.. ...

SOPh H

1-Hexyn-3-ol 108 109

Reagents: (a) PhSCI, Et3N, Et20, -78°C; (b) isopropyllithium. lithium-2­thienylcyanocuprate. THF, -780C or CuI. isopropylmagnesium chloride, THF.aoc.

or isopropylmagnesium bromide in THF at -780C. The mixture was

stirred for 2 h, the reaction was worked up with saturated NH4CI and

adduct 109 was obtained in 50% yield. Mixed higher-order cuprate

with lithium-2-thienylcyanocuprate led to the same adduct in 58%

yield. For the real system, allenic sulfoxide 111 was prepared by

[2,3] sigmatropic rearrangement of sulfenate ester 110 derived from

alkynol 96. Treatment of 96 with PhSCI at -78°C in diethyl ether led

to 111 in 80% yield (scheme 10).28 The reaction was quenched at

89

-78°C and compound 111 was purified by flash chromatography.

The el.ectrophilicity of the sp carbon (C-2) of the allene III allowed

the use of a cuprate to introduce the isopropyl appendage at C-2. For

the real system, the cuprate addition to the allene 111 did not work

with CuI and isopropyllithium or isopropylmagnesium bromide and

the reaction was· messy. Thus, an alternative mixed higher-order

reagent was examined. Isopropyllithium was prepared from

SCHEME 10

96

OHa

110

111

SOPh

b

95

Reagents: (a) PhSCI. Et3N. Et20, -780C; (b) isopropyllithium. lithium-2­thienylcyanocuprate. THF. -78°C.

isopropyl chloride and lithium sand according to the published

procedure: isopropyl chloride and lithium sand were refluxed in

pentane for 10 h.29 The solution was transferred to another flask to

get it away from the excess lithium sand and was titrated under

90

nitrogen. The mixed higher-order cuprate reagent was prepared by

addition of isopropyllithium to a solution of lithium-2­

thienylcyanocuprate30 in THF at -780C. The mixture was stirred for

10 min and then the solution of 111 in THF was added. The mixture

was stirred for 2 h and the reaction was worked up with saturated

NH4Cl. The crude mixture was purified by flash chromatography.

Alkylated sulfoxide 95 was isolated in 60% yield as a diastereomeric

mixture. Sulfoxide 95 was characterized by JR, IH-NMR and HRMS.

The chemical shift of the methine proton at C-I was 3.5 ppm in the

1H-NMR spectrum.

5. Pummerer Rearrangement of Alkylated Sulfoxide.Attempted Synthesis of Enone

a. Model Study

The Pummerer rearrangement, the conversion of a sulfoxide to

the carbonyl group of aldehyde, is well known,31 but very few

reactions have been carried out for conversion to a ketone. The

reason is not clear. It might be due to elimination during

rearrangement or during hydrolysis. Before we worked on the real

system, several conditions were examined in the following model

system (scheme 11). Sulfoxide 113 was prepared from

perillaldehyde 112 in 5 steps. Treatment of 113 with trifluoroacetic

anhydride at -78°C followed by hydrolysis with aqueous NaHC03 did

not give ketone 115 and the reaction was messy. Oxidation of

compound 114 with m-CPBA led to sulfoxide 116 followed by

hydrolysis in aqueous NaHC03 and no ketone 115 was isolated. An

9 1

SCHEME 11

CHO

112

117

5 steps ..

d

115

OCOCF3

SPh~

116

Reagents: (a) TFAA. CH2CI2. -780C; (b) aqueous NaHC03, room temperature; (c)H202. THF. room temperature; (d) n-BuLi, then TMSOOTMS. THF. -78°C; (e) m­

CPBA. CH2CI2. (lOC.

alternative method which oxidizes the carbon next to the sulfoxide

group was also considered. Treatment of 113 with different bases

(e.g. LDA, n-BuLi, KN(TMSh, Na(TMSh, sec-BuLi etc.) in THF at -780C,

followed by oxidants (e.g. TMSOOTMS. oxaziridine, H20Z, Oz etc.) did

not produce the desired ketone 115. Since the conversion of sulfone

to the corresponding ketone by oxidation was previously reported,32

sulfoxide 113 was oxidized to sulfone 117 with H20Z in 40% yield in

THF at room temperature. Treatment of 117 with n-BuLi in THF at

92

-78°C followed by TMSOOTMS or oxaziridine led to ketone in 40% and

20% yield respectively. Replacement of n-BuLi with other different

bases (e.g. LDA, KN(TMS)2) did not improve the yield.

b. Attempted Conversion of Sulfoxide to Enone

Since there were significant structural differences between the

real and model systems, direct conversion of sulfoxide 95 to the

corresponding ketone 88 was attempted~ even though the model

reaction did not work well. Treatment of sulfoxide 95 with

trifluoroacetic anhydride at -780C followed by hydrolysis with

aqueous NaHC03 led to several compounds and the reaction was

messy (scheme 12). The crude compounds were characterized by

SCHEME 12

c ..

88

119

Reagents: (a) TFAA, ·78oC; aq. NaHC03; (b) 30% H202, THF, 23°C; (c) n-BuLi,(TMSO)2, THF, -780C.

93

IR. IR did not show any evidence of carbonyl group absorption. The

difficu~ty of this Pummerer rearrangement made us consider an

alternative approach. Compound 9S was oxidized to sulfone 118

with HZ02 in 40% yield. Attempted optimization of the reaction

conditions did not increase the yield. The conversion of 118 to

ketone 88 with n-BuLi/ TMSOOTMS did not succeed. Only compound

119 was isolated due to elimination. ~-Elimination probably took

place under the influence of the strong base (n-BuLi) and compound

119 was formed. Compound 119 was characterized by IR and 1H ­

NMR. There was no sulfoxide absorption in IR. Disappearance of the

methine proton at C-I (3.8 ppm) and the appearance of vinylic

protons (5.6-5.8 ppm) matched the structure of compound 119.

Other conditions were also attempted: When NaN(TMS)z and

TMSOOTMS were used, only starting material 118 was isolated. The

formation of the anion of compound 118 from deprotection by

Na(TMS)z was confirmed by trapping with D20. Different oxidants

(e.g. 02, oxizaridine) were also tried with NaN(TMS)z; none of these

conditions gave the desired dienone 88. These results made

necessary a change in strategy, therefore, substituents other than

sulfoxide and sulfone were considered.

c. Attempted Synthesis of Ester

The conversion of alkynyl carbonate to allenic ester has been

reported by Tsuji in good yield.33 The model study was carried out in

the following system (scheme 13). Compound 120 was prepared

94

from l-hexyn-3-01. Allenic ester 121 was obtained In 80% yield

SCHEME 13

OCOOCH3

~H

120

a ~ ~C=<OO_C_H_b.--1.._H~H7 'cOaCH.

121 122

Reagents: (a) Pd2(DBA)3. PPh3. CO. CH30H. 40oC; (b) isopropyllithium. lithium­2-thienylcyanocuprate. THF. -780C.

by treatment of 120 with a catalytic amount of Pd2(DBAh and CO in

methanol. Cuprate addition to 121 with the mixed higher-order

reagent led to ester 122 in 55% yield. It was hoped that the same

chemistry could be applied to our system. Therefore, cyclic alcohol

96 was converted to carbonate 123 by treatment with methyl

chloroformate and DMAP at room temperature (scheme 14).

Compound 123 was treated with the conditions which were

developed for the model reaction, but the reaction only gave the

isomerized ester 125 in 20% yield rather than allenic ester 124.43

Compound 125 was characterized by IH-NMR, IR and HRMS. A

possible mechanism for the formation of 125 from 124 was by a

[1,5] sigmatropic rearrangement. The ease with which 124

rearranged to 125 suggests that the conjugated triene 125 is

thermodynamically more stable than allene 124. These results made

it very difficult to continue our synthesis using the current route,

althou~h enone 88 might be prepared from intermediate 125 by

SCHEME 14

95

96a

125

OCOOCH3

b

c._------

126

d-------

e._----- .....

127

f._------ .....

88

Reagents: (a) CH30COCI, DMAP. El20, DoC; (b) Pd2(DBA)3. PPh3. CO. CH30H. 4QoC;(c) cuprale; (d) hydrolysis; (e) oxidation; (0 isomerization.

cuprate addition, hydrolysis, oxidation and isomerization. Therefore,

on the basis of all of these results, we decided on a more reliable

alternative route.

96

6. Reevaluation of Retrosynthesis

We considered that the difficulties encountered in the above

synthetic routes might be avoided by the following the pathway

which is summarized in scheme 15. The key steps are: (1) selective

reduction of 128 followed by dehydration to enone 88 (2) C­

alkylation of diketone 129 with isopropyl iodide

(3) conversion of cyclic alkynyl alcohol 96 to diketone 129. The

reactivity difference between the conjugated carbonyl and

nonconjugated carbonyl groups is well-documented.3 4

SCHEME 15

88

128

7. Synthesis of Alkylated Diketone

129

Oxidation of the cyclic alkynyl alcohol 96 with manganese

dioxide in CH2Cl2 at room temperature led to alkynyl ketone 130 in

60% yield (scheme 16). Compound 130 was characterized by IR, IH­

NMR, 13C-NMR, and HRMS. Conjugate addition of methanol to 130,

97

SCHEME 16

OH

ao

b ...

96 130

129

mediated by K2C03, followed by hydrolysis with concentrated

CF3COOH in acetone, produced diketone 129 in 50-60% overall yield

from 130.35 It should be pointed out that the yield for the conjugate

addition of methanol depends on the reaction temperature. The

reaction produced the desired product at ooC. But at higher

temperature (e.g. room temperature) the reaction resulted in several

uncharacterized compounds. To perform the alkylation step, several

conditions in a model system were examined. Generally, alkylation of

a 1,3-diketone with a secondary halide produces both 0- and C­

alkylated products.36 For the model system, 5,5-dimethyl-l,3-

+ 133

98

o o-lJio--a·~o

132 133

~

134

Reagents: (a) NaN(TMS)2. THF. 2-iodopropane; (b) DMSO. K2C03. 2-iodopropane.40°C.

cyclohexanedione 132 was chosen as the starting material. When

strong base (e.g. LOA, NaH, KN(TMS)2, Na(TMS)z, LiN(TMSh) was

used, reaction led to either O-alkylated product 133 or some

uncharacterized compounds regardless of solvent. Based on these

results, a weak base (e.g. K2C03) and a more polar solvent (e.g. DMF,

DMSO) were considered. It was found that only DMSO was the solvent

which gave minor C-alkylation 134 and major O-alkylated products

133. The ratio of C-alkylated to O-alkylated product was 2:8. Other

solvents (acetone, THF, DMF) led only to O-alkylated products. Thus,

OMSO was our first choice for the real reaction.

99

a ..

128

Reagent: (a) K2C03, DMSO, 2-iodopropane, 40°C.

Treatment of diketone 129 with isopropyl iodide in DMSO at

400C only produced C-alkylated diketone 128 in 50% yield without

any O-alkylated product, and this material was used for the

subsequent selective reduction step. The problem of the alkylation

was that we were unable to reproduce this reaction and got 50%

yield only three times. Attempted optimization of the conditions of

the reaction with other solvents was not successful.

8. Selective Reduction of 1,3·Diketone. Synthesis ofDienone

A reactivity difference between the two carbonyl groups (C-l &

C-4) of compound 128 was predicted. It has been reported that a

conjugated ketone could be selectively reduced by sodium

borohydride and cerium(lIl) chloride in the presence of a saturated

ketone in good yield.34 Treatment of diketone 128 with sodium

borohydride and cerium (III) chloride produced diol 135 in 65%

100

128

a

135

..

88

Reagents: (a) DIBAL, OOC, CHZC1Z; (b) NaBH4, CeC13, CH30H.

yield. Other reducing reagents (e.g. L-selectride, LAH) were also

tried. None of these reagents gave the desired product. Addition of

DIBAL to a solution of 117 at DOC in CHzClz produced dienone 88 in

20% yield. Enone 88 was characterized by IR, 1H-NMR and mass

spectrometry. The spectral data were identical to the published data

for 88.z0 Reduction of dienone 88 to 55 has been accomplished in

previous syntheses,ZO,21 hence our methodology represents an

effective synthetic pathway to sarcophytol A.

101

CONCLUSION

The total synthesis of dienone 88 has been accomplished in ten

steps from farnesol. The conversion of 88 to sarcophytol A has been

reported during previous syntheses. Hence, this work provides a

formal total synthesis of sarcophytol A.

There are several reactions which are noteworthy:

1. Acetylene displacement of 101 produced 102 10 60% yield.

The polarity of the solvent affects the yield of the reaction and so far

acetone has proved to be the best solvent for the reaction.

2. The macrocyclization of 97 to 96 took place in 50-60% yield.

When KN(TMSh was used, allenic product 106 was isolated in 60%

yield. The mechanism for formation of allene 104 is not clear at this

time.

3. Alkylation of 1,3-diketone 129 with a secondary halide in

DMSO only gave C-alkylated product 128 in 50% yield, without any

observed O-alkylated product.

4. Selective reduction of 128 to dienone 88 was achieved by

DIBAL in moderate yield.

102

EXPERIMENTAL

Procedure:

99

OAe .. OAe

OH

100

To stirred a mixture of 1 mi CHZCIZ, SeOz (5 mg, 0.05 mmol) and

salicylic acid (32 mg, 0.23 mmol) was added TBHP (0.82 mI, 8.2

mmol) at OOC. Farnesyl acetate 99 (600 mg, 2.14 mmol) in 2 ml

CHzClz was added dropwise. After 4 h, the mixture was washed with

NaOH followed by brine. The crude product was purified by column

chromatography in 20% EtOAc/hexanes to give 174 mg of the desired

product 100 in 27% yield.

103

OAe

OH

100

Allylic alcohol 100:

IH-NMR (CDC13, 300 MHz, ppm): 5.34 (m, 2H), 5.10 (dd, J =6.0, 5.4 Hz,

IH), 4.57 (d, J = 7.2 Hz, 2H), 3.97 (s, 2H), 2.10-2.00 (m, 8H), 2.05 (s,

3H), 1.70 (s, 3H), 1.61 (s, 3H), 1.60 (s, 3H).

IR (neat, em-I): 3030, 2980,1740,1620,1450,1380,1100,1050.

Mass spectrum (70 eV, m/e): 280 (M+), 262, 237, 220, 189, 135, 121,

93, 81, 68.

Calculated mass for CI7H2803: 280.2039, found: 280.2050.

Procedure:

100·

OAe ..

101

Br

OAe

104

To alcohol 100 (28 mg, 0.10 mmol) in 5 ml THF was added NEt3

(0.04 ml, 0.29 mmo!) and the mixture was brought to OOC. MsCI (0.02

ml, 0.21 mmol) and LiBr (67 mg, 0.77 mmol) were added. The

solution was warmed to room temperature. Sat'd NaHC03 solution

was added and the mixture was extracted with Et20. The solvent was

dried and removed in vacuo. The crude product was purified by

chromatography to give 31 mg bromide 101 in 90% yield.

105

OAe

101

Bromide 101:

IH-NMR (CDCI3, 300 MHz, ppm): 5.6-5.5 (dd, J = 7.2, 6.9 Hz, IH), 5.34­

5.32 (dd, J = 7.2, 6.9 Hz, IH), 5.10-5.08 (dd, J = 6.6, 5.4 Hz, IH), 4.60­

4.58 (d, J = 7.2 Hz, 2H), 3.97 (s, 2H), 2.20-2.00 (m, 8H), 2.05 (s, 3H),

1.75 (s, 3H), 1.70 (s, 3H), 1.60 (s, 3H).

IR (neat, cm- 1): 2950, 1740, 1620, 1450, 1380, 1100, 1050.

Mass spectrum (70 eV, m/e): 263, 203, 187, 159, 135, 119, 107, 93,

79.

106

101

Procedure:

OAc ...

H105

Acetylene was passed through a mixture of 5 ml acetone, KzC03

(28 mg, 0.20 mmol), CuI (21 mg, 0.22 mmol) and NaI (30 mg, 0.20

mmol) at room temprature. Allylic bromide 101 (34 mg, 0.1 mmol)

was added to the mixture and stirred at room temperature for 48 h.

The mixture was filtered and the solvent removed. The residue was

added to a mixture of K2 CO 3 and methanol, stirred for 1 h at room

temperature, then water was added and the mixture was extracted

with EtzO. The solvent was dried and removed. The crude product

was purified by chromatography to give 12 mg of lOS in 50% overall

yield.

107

H105

Alcohol lOS:

IH-NMR (CDC13, 300 MHz, ppm): 5.44-5.37 (m, 2H), 5.17 (dd, J =6.9,

6.6 Hz, IH), 4.15 (d, J = 6.6 Hz, 2H), 2.87 (s, 2H), 2.10-2.00 (m, 9H),

1.68 (s, 3H), 1.60 (s, 3H), 1.55 (s, 3H).

IR (neat, cm- 1): 3350, 3300, 2980, 2100, 1630, 1450, 1380, 1100.

Mass spectrum (70 eV, m/e): 246 (M+), 231, 213, 199, 189, 171, 159,

119, 91, 77.

105

Procedure:

97

108

To oxalyl chloride (0.69 ml, 0.79 mmol) in 1.0 ml CH2C12 at -78°C

was added DMSO (0.065 ml, 0.92 mmol). The solution was stirred for

5-8 min and alcohol 105 (60 mg, 0.26 mmol) in 2.0 ml CH2CIZ was

added over a period of 5 min. After 15 min, Et3N (0.18 ml, 1.32

mmol) was added and the solution was allowed to warm to room

temperature. The solution was extracted with CH2Ch. The crude

product was purified by chromatography to give 50 mg of aldehyde

97 in 80% yield.

109

97

Aldehyde 97:

IH-NMR (CDCI3, 300 MHz, ppm): 10.00 (d, J = 8.1 Hz, IH), 5.90 (m,

1H), 5.40 (m, IH), 5.10 (m, IH), 2.80 (s, 2H), 2.40-2.00 (m, 9H), 1.68

(s, 3H), 1.60 (s, 3H), 1.57 (s, 3H).

IR (neat, cm- l ): 3300, 2980, 2960, 2100, 1670, 1630, 1450, 1380.

Mass spectrum (70 eV, m/e): 244, 229, 215, 211, 205, 201, 197, 145,

119, 91, 77.

Calculated mass for C17H240: 244.1850, found: 244.1838.

Procedure:

97

CHO

Ha ..

96

OH

110

To a solution of aldehyde 97 (30 mg, 0.12 mmol) in 20 ml THF

was added 0.37 ml, 1.0 N, NaN(TMSh in a :;iugie porLion at room

temperature. After 5 min, IN Hel was added and the solution was

extracted with Et20. The combined ethereal extracts were washed

with brine dried and solvent was removed in vacuo. The crude

product was purified by chromatography to give 18 mg of alkynyl

alcohol 96 in 50-60% yield.

111

OH

96

Alkynyl alcohol 96:

IH-NMR (CDCI3, 300 MHz, ppm): 5.61 (m, 1H), 5.40 (d, J = 8.4 Hz, 1H),

5.10-5.00 (m, 2H), 2.83 (s, 2H), 2.40-2.00 (m, 8H), 1.65 (s, 3H), 1.59

(s, 3H), 1.58 (s, 3H).

I3C-NMR (CDCI3, 125 MHz, ppm): 136.8, 133.9, 128.8, 126.7, 125.7,

123.3, 85.1, 82.5, 59.3, 38.7, 38.4, 27.4, 24.6, 23.4, 17.5, 15.8, 15.0.

IR (neat, em-I): 3350, 3010, 2960, 2210, 1620, 1480, 1350, 1200.

Mass spectrum (70 eV, m/e): 244, 226, 211, 205, 197, 183, 169, 157.

Calculated mass for C17H240: 244.1827, found: 244.1849.

112

OH

SOPh

11196

Procedure:

To a solution of alkynyl alcohol 96 (20 mg, 0.08 mmol) and

(0.04 ml, 5.6 mmol) Et3N in 3 ml EtzO at -780C was added very

slowly PhSCI (25 mg, 0.16 mmol) in 2 ml EtzO. The solution was

stirred for 5 min at -78°C. Water was added and the reaction mixture

was warmed to room temperature. The solution was extracted with

EtzO and the organic layer was dried over MgS04. The solvent was

removed and the residue was purified by chromatography to give 23

mg of desired product sulfoxide 111 in 80% yield.

113

SOPh

111

Sulfoxide 111:

lH-NMR (CDCI3, 300MHz, ppm): 7.50-7.27 (m, 5H), 6.40-6.35 (m, IH),

5.57-5.53 (d, J = 10.8 Hz, IH), 5.16-5.11 (ro, IH), 4.98-4.94 (m, IH),

2.90-2.84 (d, J = 16.8 Hz, IH), 2.50-2.45 (d, J = 16.8 Hz, IH), 2.19-2.11

(ro, 8H), 1.74 (d, J = 0.9 Hz, 3H), 1.52 (s, 3H), 1.48 (s, 3H).

IR (neat, cm- l ): 3030, 1940, 1640, 1560, 1440, 1380, 1080, 1050.

Mass spectrum (70 eV, role): 352 (M+), 336, 275, 267, 243, 236, 226,

185, 143, 109.

Calculated mass for C23H2SS0: 352.1869, found: 352.1841.

114

111'

Procedure:

SOPh

95

To 2.8 ml of a 0.1 M solution of Cu(CN)(Th)Li in THF was added

0.78 ml of a 0.36 M solution of isopropyllithium in pentane dropwise

at -780C. The mixture was stirred for 5 min and sulfoxide 111 (20

mg. 0.057 mmol) in 2 ml THF was added. The mixture was further

stirred for 1 h and the sat'd NH4CI was added. The mixture was

extracted with Et20. The solvent was dried and removed in vacuo.

The crude product was purified by chromatography to give 12 mg of

alkylated sulfoxide 9S in 57% yield.

115

95

Alkylated sulfoxide 95:

IH-NMR (CDC13, 300 MHz, ppm): 7.66-7.42 (m, 5H), 6.32 (d, J = 11.7

Hz, 1H), 5.64 (d, J = 11.7 Hz, IH), 4.97-4.87 (m, 2H), 4.21 (dd. J = 10.8,

3.0 Hz, IH). 2.50-2.45 (m, 2H), 2.18-1.83 (m, 9H), 1.67 (s, 3H), 1.54 (s,

3H), 1.35 (s, 3H), 1.12 (d, J =6.6 Hz, 3H), 0.97 (d, J = 6.9 Hz, 3H).

IR (neat. cm- 1): 3030, 2980, 1600, 1580, 1450, 1380, 1280, 1050.

Mass spectrum (70 eV, m/e): 270, 255, 227, 187, 159, 120, 105, 84.

96

Procedure:

OH

130

o

116

To a solution of alkynyl alcohol 96 (12 mg, 0.05 mmol) in 5 ml

CH2Cl2 at OOC was added 90 mg (3x30 mg, 1.03 mmol) manganese

dioxide in 15 min. The mixture was stirred until tic showed no

starting material remaining. The mixture was filtered and the CH2Cl2

was removed in vacuo. The crude product was purified by

chromatography to give 7 mg of desired product ketone 130 in 50­

60% yield.

1 17

o

130

Ketone 130:

IH-NMR (CDC13, 300 MHz, ppm): 6.29 (s, lH), 5.72 (dd, J = 5.7, 5.1 Hz,

IH), 5.11 (d, J = 0.9 Hz, lH), 2.97 (s, 2H), 2.31 (s, 4H), 2.23-2.18 (m,

4H), 2.06 (s, 3H), 1.60 (s, 3H), 1.57 (s, 3H).

13C-NMR (CDC13, 125 MHz, ppm): 177.9, 155.7, 134.8, 128.3, 127.3,

126.1, 124.0,93.1, 87.6, 38.4, 38.3, 27.5, 24.3, 23.6, 19.7, 17.7, 14.8.

IR (neat, em-I): 3030, 2970, 2250, 1660, 1620, 1450, 1380, 1200.

Mass spectrum (70 eV, m/e): 242 (M+), 227, 199, 173, 159, 145, 115,

91, 77.

Calculated mass for C17H2Z0: 242.1646, found: 242.1658.

118

Procedure:

130

o

129

A mixture of (10 mg, 0.04 mmol) ketone 130 and 1 mg K2C03 in

2 ml methanol was stirred at OOC for 30 min and then warmed to

room temperature for 1 h. The mixture was filtered and the

methanol was removed in vacuo. The residue was dissolved in 5 ml

acetone and 2 drops of CF3COOH was added. The solution was stirred

for 3 h and water was added. The mixture was extracted with Et20

and dried over anhydrous MgS04. The solvent was removed and the

crude product was purified by chromatography to give 6 mg of

desired product diketone 129 in 60% overall yield.

119

129

Diketone 129:

lH-NMR (CDCI3, 300 MHz, ppm): 5.97 (s, IH), 5.06 (t, J =6.3 Hz, 1H),

4.91 (t, J = 6.0 Hz, IH), 3.50 (s, 2H), 3.20 (s, 2H), 2.28-2.14 (m, 8H),

2.11 (s, 3H), 1.66 (s, 3H), 1.57 (s, 3H).

IR (neat, cm- l ): 3030, 2950, 1720, 1680, 1440, 1380, 1150, 1050.

Mass spectrum (70 eV, m/e): 260 (M+), 192, 163, 134, 121, 107, 95,

82.

Calculated mass for Cl7H2402: 260.1772, found: 260.1783.

129

Procedure:

128

120

A mixture of (10 mg, 0.04 mmol) diketone 129 and 30 mg K2C03

in 2 ml DMSO was heated to 400C in a sealed tube. The color of the

solution changed to yellow in 10 min and (0.05 ml, 5.00 mmol)

isopropyl iodide was added. The mixture was stirred for 1 hand

cooled down to room temperature. Water was added, the solution

was extracted with Et20 and the organic layer was dried over

anhydrous MgS04. The solvent was removed and the residue was

purified by chromatography to give 6 mg of desired product 128 in

50% yield.

------ --- ----_.- ~.-.-_.._-

121

128

Alkylated diketone 128:

IH-NMR (CDCI3, 300 MHz, ppm): 5.96 (s, IH), 4.98 (dd, J = 6.9, 6.3 Hz,

IH), 4.86 (dd, J = 6.4, 5.4 Hz, IH), 3.40 (d, J = 10.2 Hz, IH), 2.96 (s,

2H), 2.51-2.23 (m, 9H), 2.11 (s, 3H), 1.65 (s, 3H), 1.56 (s, 3H), 0.89­

0.84 (dd, J = 6.6, 6.0 Hz, 6H).

I3C-NMR (CDCI3, 125 MHz, ppm): 205.4, 194.9, 160.7, 134.6, 129.0,

128.6, 123.9, 123.7, 76.3, 52.0, 40.5, 38.8, 28.1, 24.8, 24.3, 21.2, 20.4,

19.3, 17.3, 15.4.

IR (neat, em-I): 3030, 2950, 1720, 1680, 1440, 1380, 1150, 1050.

Mass spectrum (70 eV, m/e): 302 (M+), 259, 234, 203, 163, 150, 135,

121, 95, 82.

Calculated mass for C20H3002: 302.2232, found 302.2238.

128

Procedure:

88

122

To a solution of alkylated diketone 128 (15 mg 0.05 mmol) in

2 ml CHzC1z was added highly dilute DIBAL solution (0.5 eq, 0.025

mmol, 0.3 rol) in CHzClz at aoc. The mixture wqS stirred for 10 min

and IN HCI was added. The solution was extracted with CHzClz and

dried over anhydrous MgS04. The solvent was removed and the

residue was purified by chromatography to give 4 mg of desired

dienone 88 in 30% yield.

123

88

Dienone 88:

IH-NMR (CDCI3, 300 MHz, ppm): 6.23-6.20 (dd, ] = 12.0, 1.5 Hz, IH),

5.90-5.88 (d, ] = 11.5 Hz, IH), 5.02-4.99 (td, ] = 5.5, 1.0 Hz, IH), 4.96­

4.93 (t, 6.5 Hz, IH), 3.15 (s, 2H), 2.70-2.65 (sept, IH), 2.20-2.07 (m,

8H), 1.75 (d, ] = 1.0 Hz, 3H), 1.72 (s, 3H), 1.47 (s, 3H), 1.08 (d, ] = 7.0

Hz,6H).

IR (neat, em-I): 3030, 3010, 2980, 1680, 1620, 1380, 1250.

Mass spectrum (70 eV, m/e): 286 (M+), 271, 243, 203, 175, 150, 135,

121, 107, 91, 81.

Calculated mass for C20H300: 286.2334, found: 286.2316.

124

REFERENCES

1. (a) Weinheimer, A. J.; Chang, C. W.; Matson, J. A. Fortschr. Chern.

Org. Naturst. 1979,36, 285.

2. Tursch, B.; Braeckman, J. C.; Daloze, D.; Kaisin, M. In Marine

Natural Products; Scheuer, P. J., Ed.; Academic: New York,

1978; Vol. II, p 247.

3. (a) Kobayashi, H.; Akiyoshi, S. Bull. Chern. Soc. lpn. 1962,35,

1044. (b) Scheuer, P. J. Bioorganic Marine Chemistry, Springer

Verlag, Berlin, 1987, Vol. III, p 99. (c) Takashi, M.; Niwa, M.;

Fukaura, Y.; Fujiki H. Cancer Res. 1989,49, 3287.

4. Weinheimer, A. J.; Matson, J. A.; Hossain, M. B.; Van der Helm, D.

Tetrahedron Lett. 1977,28,34, 2923.

5. Tursch, B.; Braekman, J. C.; Daloze, D.; Herin, M.; Karlsson, R.;

Losman, D. Tetrahedron 1975,31, 129.

6. Culver, P.; Burch, M.; Potenza, C.; Wasserman, L.; Fenical, W.;

Taylor, P. Mol. Pharrnacol. 1985,28, 436.

7. Kobayashi, M.; Nakagawa, T.; Mitsuhashi, H. Chern. Pharm.

Bull. 1979,27, 2382.

8. (a) Fujiki, H.; Suganuma, M.; SU5ud, R.; Yoshizawa, S.; Takagi, K.;

Kobayashi, M. l. Cancer Res. Clin. Oncol. 1989,115, 25.

9. Fujiki, H.; Sugimura, T. Cancer Surveys 1983,2, 539.

10. Fujiki, H.; Suganuma, M.; Takagi, K.; Nishiwaki, S.; Yoshizawa, S.;

Okabe, S.; Yatsunami, J.; Frenkel, K.; Troll, W.; Marshall, J. A.;

125

Tius, M. A. In Phenolic Compounds in Food and Their Effects on

Health II; Huang, M.; Ho. C.; Lee, C. Eds.; ACS Symposiurn Series

507; ACS: Washington, DC, 1992, 380.

11. Narisawa, T.; Takahashi, M.; Niwa, M.; Fukaura, Y.; Fujiki, H.

Cancer Res. 1989, 49, 3287.

12. Tius, M. A:. Chern. Rev. 1988,88, 719.

13. Marshall, J. A.; Cleary, D. G. J. Org. Chern. 1986,51,858.

14. (a) Takahashi, T.; Nemoto, H.; Tsuji, J.; Miura, I. Tetrahedron

Lett. 1983,24, 3485.

(b) Takahashi, T.; Nagashima, T.; Tsuji, J. Tetrahedron Lett.

1981,22, 1359.

15. (a) Danishefsky, S.; Mantlo, N. B.; Yamashita, D. S.; Schulte, G. J.

Arn. Chern. Soc. 1988, 110, 6890. (b) Kende, A. S.; Smith, C. A.;

Tetrahedron Lett. 1988,29, 4217.

16. (a) Tius, M. A.; Cullingham, J. M. Tetrahedron Lett. 1989,30,

3749. (b) Tius, M. A.; Reddy, K. Tetrahedron Lett. 1991,32,

3605.

17. (a) Tius, M. A.; Fauq, A. H. J. Arn. Chern. Soc. 1986, 108, 1035.

(b) Nicolaou, K. C.; Seitz, S. P.; Pavia, M. R.; Petasis, N. A. J. Org.

Chern. 1979,44, 4011. (b) Crombie, L.; Kneen, G.; Pattenden, G.;

Whybrow, D. J. Chern. Soc. Perkin Trans. 1 1980, 1711. (b)

Crombie, L.; Kneen, G.; Pattenden, G. J. Chern. Soc., Chern.

Cornrnun. 1976, 66.

18. (a) Wender, P. A.; Holt, D. A. J. Am. Chern. Soc. 1985, 107,

7771. (b) Marshall, J. A.; Jenson, T. M.; DeHoff, B. S. J. Org. Chern.

1986,51, 4316.

126

20. Takayanagi, H.; Kitano, Y.; Morinaka, Y. Tetrahedron Lett. 1990,

31,3317.

21. Takahashi, T.; Yokoyama, H.; Haino, T.; Yamada, H. J. Org. Chem.

1992,57, 3521.

22. Kodama, M.; Yoshio, S.; Yamaguchi, S.; Fukuyama, Y.;

Takayanagi,.. H.; Morinaka, Y.; Usui, S.; Fukazawa, Y. Tetrahedron

Lett. 1993,34, 8453.

23. Li,W.; Li, Y.; Li, Y. Chin. Chem. Lett. 1994,5, 101.

24. Sharpless, K. B.; Umbreit, M. A. J. Am. Chem. Soc. 1977,99,

5526.

25. Collington, E. W.; Meyers, A. I. J. Org. Chem. 1976,36, 3044.

26. Bumagin, N. A. Bull. Acad. Sci. USSR Engl. (Transl.) 1987,36,

1445.

27. Swern, D.; Mancuso, A. J.; Huang, S. J. Org. Chem. 1978,43,

2480.

28. (a) Van Kruchten, E. M. G. A.; Okamura, W. H. Tetrahedron Lett.

1982,23, 1019. (b) Bulter, P. E.; Mueller, W. H.; J. Am. Chem.

Soc. 1968, 90, 2075. (c) Seliger, H.; Gortz, H. Syn. Comm. 1980,

10, 175.

29. (a) Gilman, H.; Langham, W.; Moore, F. W.; Sugihara, H.;

Tanikaga, R.; Kaji, A. J. Am. Chem. Soc. 1940, 62, 2334. (b)

Luche, J.; Damiano, J. J. Am. Chern. Soc. 1980,102, 7926.

30. Lipshutz, B. H.; Koerner, M.; Parker, D. A. Tetrahedron Lett.

1987,28,945.

127

31. Lucchi, O. D.; Miotti, U.; Modena, G. Organic Reactions 1991,40,

157.

32. (a) Hwu, J. R. J. Org. Chern. 1983,48, 4432. (b) Babin, P.;

Bennetau, B.; Dunogues, J. Syn. Cornm. 1992,22, 2849.

33. Tsuji, J.; Sugiura, T.; Minami, I. Tetrahedron Lett. 1986,27,

731.

34. (a) Paradisi, M. P.; Zecchini, G. P.; Romo, A. Tetrahedron Lett.

1977, 18, 2369. (b) Gemal, A. L.; Luche, J. L. J. Org. Chern.

1979,44, 4187.

35. Walia, J. S.; Walia, A. S. J. Org. Chem. 1976,41, 3765.

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