Aldrichimica Acta Vol 32 N°3

7/28/2019 Aldrichimica Acta Vol 32 N3

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Volume 32, Number 3, 1999 (Last issue in 1999)

Ring-Closing Metathesis of Nitrogen-Containing Compounds: Applicationsto Heterocycles, Alkaloids, and Peptidomimetics

Are Two Phenyls Better than One? Synthesis and Applicationsof (R)-4-Diphenylmethyl-2-oxazolidinone

ALDRICH

chemists helping chemists in research and industry


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This benzophenone has been usedto prepare several photoinitiators,including tetraalkylammoniumsalts, for acrylate polymerization.1

It is also used to prepare photo-cleavable protein cross-linkingagents.2

(1) Zhang, W. et al. J. Org. Chem. 1999, 64, 458. (2) Oatis, J.E., Jr.; Knapp, D.R.Tetrahedron Lett. 1998, 39, 1665.

44,938-5 4-(Bromomethyl)benzophenone, 97%

Oligothiophenes, with nonlinear

optic and electrochemical applica-tions, have been prepared from thisbrominated bithiophene.1,2

(1) Nakanishi, H. et al.J. Org. Chem. 1998, 63, 8632. (2) Roncali, J. Chem. Rev. 1992,92, 711.

51,549-3 5,5-Dibromo-2,2-bithiophene, 99%

A variety of organometal-lic complexes have beenprepared from thesebipyridines. Compounds

1 and 2 are useful for thepreparation of rutheniumcomplexes with increasedsolubility in organicsolvents and modifiedredox properties relativeto those of the complexes with unsubstituted bipyridineanalogs.1,2 Compound 3 has been utilized to prepare highlyfunctionalized bipyridines.3

(1) Hadda, T.B.; Bozec, H.L. Polyhedron 1988, 575. (2) Fabian, R.H. et al.Inorg. Chem.1980, 19, 1977. (3) Penicaud, V. et al. Tetrahedron Lett. 1998, 39, 3689.

51,547-7 4,4-Di-tert-butyl-2,2-dipyridyl, 98% (1)

51,614-7 6-Methyl-2,2-dipyridyl, 97% (2)51,776-3 2,2-Bipyridine-5,5-dicarboxylic acid, 97% (3)

This compound is readily lithiated atC-7 using sec-butyllithium, and hasbeen used to prepare a variety of 7-substituted indolines.Meyers, A.I.; Milot, G.J. Org. Chem. 1993, 58, 6538.

51,014-9 tert-Butyl indoline-1-carboxylate, 98%

I m p o r t a n t s t a r t i n g m a t e r i a l f o r t h epreparation of cyclopropane-substitutedheterocycles.1,2

(1) Li, Q. et al.J. Med. Chem. 1996, 39, 3070. (2) Kim, D.-K. et al. ibid. 1997, 40, 2363.

51,611-2 Cyclopropylacetonitrile, 97%

Useful synthon for the synthesis ofbiologically active quinolones1 and fibrinogenreceptor antagonists.2

(1) Cooper, C.S. et al.J. Med. Chem. 1992, 35, 1392. (2) Alig, L.et al. ibid. 1992, 35, 4393.

51,390-3 Benzyl 4-hydroxy-1-piperidinecar-

boxylate, 97%

This cyclopentadiene has been used as a diene inDielsAlder reactions,1 and for the preparation offulvenes2 and metallocenes.3

(1) Riemshneider, R.; Nehring, R. Monatsh. Chem. 1959, 90, 568.(2) Miyake, S. et al.Macromolecules 1995, 28, 3074. (3) Drewitt, M.J. Chem. Commun.1996, 2153.

49,498-4 tert-Butylcyclopentadiene, mixture of isomers

A number of anthraquinones and naphtho-quinones have been prepared from thiscompound.1,2

(1) Kesteleyn, B. et al. J. Org. Chem. 1999, 64, 1173. (2)Joshi, B.S. et al. ibid. 1994, 59, 8220.

51,030-0 2-Bromo-1,4-naphthoquinone, 98%

These heterocyclic syn-thons are widely used start-ing materials in medicinalchemistry.1-4

(1) Tucker, T.J. et al. J. Med. Chem.1994, 37, 2437. (2) Moltzen, E.K. et al.ibid. 1994, 37, 4085. (3) Zhang, H. etal. J. Org. Chem . 1998, 63, 6886. (4)Hoffman, J.M. et al. J. Med. Chem.1992, 35, 3784.

51,811-5 3-(2-Aminoethyl)pyridine dihydrobromide, 98%

15,674-4 1-Chloroisoquinoline, 95%

52,044-6 3-Ethynylpyridine, 98%

O

Br

SBr

SBr

CN

N

OH

OO Ph

N

O

O

O

O

Br

N N1

N N2

N N

HO2C CO2H

3

N

NH2

2HBr

N

Cl N

H

51,811-5

15,674-4 52,044-6


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Volume 32, Number 3, 1999

A publication of ALDRICH. Aldrich is a member of the Sigma-Aldrich family. 1999 by Sigma-Aldrich Co. Printed in the United States.

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For worldwide mailing/contact information, please seethe inside back cover.

About Our CoverJan Davidsz. de Heems Vase of Flowers (oil on canvas,27L in. x 22I in.), painted about 1660, is a beautifulexample of the delight that Dutch and Flemish seventeenth-century artists took in the natural world. The brilliant color, thesoft texture of flower petals, the moist gleam of dew on leaves,and the detailed delineation of insects and small animals allcontribute to the extraordinary illusionism of the painting.Moreover, the dynamic rhythms of the leaves, wheat stalks,peas, and flowers, and the small creatures crawling andfluttering in the air surpass mere description to make theobjects represented seem almost to break through the surface

of the picture. One can almost imagine the sweet scents ofthe flowers. The painting is far more than simply an extraordi-nary literal record of reality, however. It is an important expression of the imagination of theartist, who has overcome the laws of nature. Normally, this combination of flowers, fruits,and vegetables could not be in the same bouquet because they mature at different seasonsof the year. Furthermore, these flowers will continue to bloom long after those in nature havewithered and died. Ars longa, vita brevis. The painting is also filled with symbolic associa-tions that would have been well understood in the seventeenth century. Insects and snailsrepresent forces that are destructive of the beauties of nature. The transient loveliness offlowers is a reminder of the temporality of life.The morning glory, which opens at dawn andcloses at dusk, symbolizes the light of truth.

This painting is part of the Andrew W. Mellon Collection at the National Gallery of Art,Washington, D. C.

PleaseBotherUs.

Dr. Martin J. ODonnell (IUPUI,Indianapolis) kindly suggested that wemake O-allyl-N-(9-anthracenylmethyl)-

cinchonidinium bromide. This phase-transfer catalyst is useful for theenantioselective synthesis of -amino

acid derivatives.1-3 A key step in the syn-thesis is the enantioselective alkylationof the enolate derived from N-(diphenyl-methylene)glycine tert-butyl ester.(1) ODonnel l , M.J. et al . Tetrahedron1999 , 55, 6347.(2) ODonnell, M.J. et al. Tetrahedron Lett. 1998, 39, 8775.(3) Corey, E.J. et al. J.Am. Chem. Soc. 1997, 119, 12414.

Naturally, we made this useful catalyst.It was no bother at all, just a pleasure tobe able to help.

Do you have a compound that you wish Aldrichcould list, and that would help you in your research bysaving you time and money? If so, please send us yoursuggestion; we will be delighted to give it carefulconsideration. You can contact us in any one of theways shown on this page or on the inside back cover.

N+H

H

O

N

Br-

49,961-7 O-Allyl-N-(9-anthracenyl-methyl)cinchonidiniumbromide, 95%

36,448-7 N-(Diphenylmethylene)-glycine tert-butyl ester, 98%

Vol. 32, No. 3, 1999 73
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A Simple, Inexpensive

Apparatus for ParallelSynthesis

In recent years, combinatorial chemistry1 has

emerged as an important component in drugdiscovery and as a technology that can increasethe productivity of pharmaceutical researchtremendously. Numerous synthesizers withvarying degrees of automation are availablecommercially, both for solution- and solid-phasesynthesis. Moreover, synthesis carried out inmultiwell plates requires a liquid handling systemand generates only a few milligrams of products.

In an attempt to increase the number of

compounds synthesized, keeping in mind thecost, we designed a simple piece of equipmentthat is a modification of a vacuum manifold.Initially, we used a manifold with five arms(Figure A). Each arm is about 7 inches in length

and serves as an air condenser; a refluxcondenser is attached to the top of the manifold.The apparatus can be comfortably used for higher

boiling solvents, especially when a commonsolvent is in use, with no overflow or drying of anyflask. Later on, this apparatus was modified toaccommodate a larger number (10) of reactionvessels (Figure B). Using this apparatus in an oilbath heated on a laboratory stirrer/hotplate, wecarried out a series of solution-phase ester,amide, and guanidine syntheses in both10-mL and 15-mL flasks. Each of the reactionflasks was charged with only 57 mL of reactionsolution, and rigorous reflux was avoided to permitthe refluxing solvent (e.g., xylenes) to condensecompletely in the 7-in. arm and thus avoid cross-contamination. We isolated a few hundred

milligrams of each product in a relatively pure form(HPLC purity of guanidine derivatives >93%) withno cross-contamination. In the absence of fancierand more costly equipment, this apparatus can beused effectively for the synthesis of analogs with acommon chemistry. It does not require anyadditional laboratory space and may also besuitable for solid-phase synthesis.

References: (1) Combinatorial Chemistry: Synthesis andApplication; Wilson, S.R., Czarnik, A.W., Eds.; John Wiley &Sons, Inc.: New York, NY, 1997 (Z28,759-8).

Seetharamaiyer Padmanabhan, Ph.D.Cambridge NeuroScienceOne Kendall Square, Bldg. 700Cambridge, MA 02139, U.S.A.E-mail: [email protected]

A Simple and Efficient

Apparatus for GrowingCrystals by Diffusion of

Reacting Solutions

Growing crystals for X-ray diffraction analysis isoften a challenging task. Several methodsand techniques have been developed to growgood-quality crystals. Among them are the slowevaporation of saturated solutions,1 cooling ofsaturated solutions, liquid diffusion, vapor diffu-sion, diffusion of reacting solutions,2 and othermore sophisticated methods such as crystalgrowing in gels.3 In our research, we encountered

difficulties growing suitable crystals of an organichostguest complex using conventional methods.Layering one reacting solution on the other in atube2 gave crystals of some quality, but were toosmall for X-ray diffraction analysis. To overcomethis problem, we designed a simple apparatus,which allows growing crystals of the complexduring its formation reaction.

If compound A readily forms a crystallinecomplex with compound B, the size and quality ofthe crystals of the complex AB can be significantlyimproved by performing the reaction slowly.The apparatus shown in Figure 1 is capableof extending the reaction time up to several

weeks. The whole system is an easily made,single-piece glassware consisting of several parts:

Lab Notes

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Teflon is a registered trademark of E.I. du Pont de Nemours & Co., Inc.

74 Vol. 32, No. 3, 1999

Continued on page 90.Figure A Figure B

Aldrich Addition Funnelswith Teflon Needle Valve

With pressure-equalization arm, Teflon needle valvefor precise addition-rate control, and B 24/40 joints.

Cap. (mL) Cat. No.Jacketed100 Z41,993-1250 Z41,995-8500 Z41,996-6

Unjacketed100 Z41,997-4250 Z41,998-2500 Z41,999-0
mailto:[email protected]:[email protected]


5/40Vol. 32, No. 3, 1999 75

Outline

1. Introduction2. Catalysts and Mechanism3. Scope and Functionality Tolerance4. Applications to the Synthesis of Nitrogen-

Containing Systems4.1. Cyclizations Leading to

Heterocycles: Pyrrolidines,Piperidines, Lactams,Azasugars,Alkaloids, and Related Compounds

4.2. Cyclizations Leading to Carbocycles4.3. Miscellaneous Cyclizations:

Macrocyclic Peptides, Solid-Phase

Methods, and Other Applications5. Conclusions6. Acknowledgments7. References and Notes

1. Introduction

Olefin metathesis, a process by whichalkylidene groups on alkenes are exchanged(Figure 1), was first reported in 1955 byAnderson and Merckling. Their seminalreport described the polymerization ofnorbornene by titanium(II) species.1 Despiteits widespread use in industry as a method for

producing higher olefins and polymers, it isonly in recent times that the process hasbecome more generally utilized. The general-ization into synthetic organic chemistry hasbeen driven primarily by the discovery ofwell-defined and functional-group-tolerantcatalysts independently by Schrock andGrubbs.2,3 The functional-group tolerance andreasonable stability of these catalysts haveallowed their widespread use for ring forma-tion. This review describes the applications ofolefin metathesis to systems containingnitrogen functionality such as peptides,

peptidomimetics, and azasugars, and coversthe literature from January 1990 to December1998. Recent reviews by Blechert,Armstrong,and Grubbs have surveyed other aspects ofolefin metathesis in synthesis.3

2. Catalysts and Mechanism

At the present time there are two maintypes of catalyst in use (Figure 2). These are

the molybdenum-based complex 1, developedby Schrock and co-workers,2 and the ruthen-ium-based complexes 2, and in particular 3,developed by Grubbs and co-workers.4

Complex 1 has the major disadvantage ofbeing particularly air- and moisture-sensitive,whereas 3 is not significantly affected by air,moisture, or other reaction impurities. Bothcatalysts are commercially available anddetails for their synthesis have been reported.4d

It is worth noting that complex 3 is readilyprepared by a short, one-pot sequence that isreadily scalable to amounts as large as

10 g.5 A number of other catalysts are alsoillustrated in Figure 2. Titanium carbenessuch as 4 (presumably formed under the reac-tion conditions), which are more commonlyutilized in olefination reactions, findoccasional use.6 Hoveyda and co-workershave recently reported the synthesis and someapplications of ruthenium alkylidene 5.7

Although its scope has yet to be defined, thiscatalyst may well offer some advantages since

it is stable to silica chromatography and thuscan be recycled. It is worth noting that,although its rate of initiation is some 30-foldslower than that of carbene 3, its rate ofpropagation is fourfold faster. Furtherinvestigations of carbenes that contain othernonphosphine ligands may yield even moreuseful catalysts.8 In a similar vein, Grubbs andNguyen have also reported the preparation ofpolystyrenedivinylbenzene-supportedruthenium carbenes and examined theiractivity and reuse.9

Ring-Closing Metathesis of

Nitrogen-Containing Compounds:

Applications to Heterocycles, Alkaloids,

and Peptidomimetics

Andrew J. Phillips and Andrew D. Abell

Department of Chemistry, University of Canterbury, Private Bag 4800

Christchurch, New Zealand

Current Address: Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA

E-mail: [email protected]

[email protected]
mailto:[email protected]:[email protected]:[email protected]:[email protected]


6/4076 Vol. 32, No. 3, 1999

Catalysts that allow ring-closing metathe-sis (RCM) in methanol and water (complexes6 and 7) have recently been reported byGrubbs and co-workers.10 The phosphineligands of these catalysts contain quaternaryammonium salts, which confer enhancedsolubility (and hence activity) in proticsolvents. This study also revealed that thenature of the substrate has an important influ-

ence on the ease of cyclization. Phenyl-substituted substrates are claimed to be thebest suited to cyclizations, since, as opposedto simple alkylidenes, they yield more stablebenzylidene systems upon turnover. Theexceptional activity of these catalysts in proticsolvents should allow their ready applicationto systems of biological significance.Asymmetric ring-closing metathesis withchiral molybdenum carbenes 811 and 912 hasbeen described but has yet to see widespreaduse. Several tungsten-based catalysts havealso been described but have not been widelyapplied.13 The preparation of imines by

molybdenum-mediated metathesis has beenreported recently.14

Most of the early work in olefin metathesiswas performed using poorly defined catalystsystems and, even today, mechanistic studieson the ring-closing metathesis reaction remainscarce. This is primarily because of the diffi-culties involved in characterizing the speciesin these classical metathesis systems.However, there is some evidence that thereaction proceeds via metallacyclobutanes(Figure 3).15 With the availability of well-defined catalysts, progress should now bemore rapid on this front. In light of this,

Grubbs has recently investigated the ring-closure of diethyl diallylmalonate byH2C=Ru(PCy3)2Cl2.16 This study revealed thatthe major mechanistic pathway for thiscatalyst was via phosphine loss beforemetallacyclobutane formation.17 Althoughthis report is informative, care must beexercised in extending the results of this studyto other catalyst systems. For the purpose ofthis review, the general mechanism illustratedin Figure 3 is adequate.

3. Scope and Functionality

Tolerance

The body of literature that has emergedover the past three years has provided enoughinformation to allow some guidelines to beformulated with respect to both ring size andcompatible functionality. Catalysts 13 are allcapable of catalyzing the formation of simplefive-, six-, and seven-membered mono- andbicyclic rings. Eight-membered rings, as isthe case for so many methods, remain moredifficult to access by metathesis chemistry.18

Nonetheless, examples do exist.19 Theformation of macrocycles is facile, and

Ring-closingmetathesis

Ring-openingmetathesis

R' R"+

Acyclic cross metathesis

R'R"

Ring-closing enyne metathesis

( ) n

Mo

N

OO

PriPri

F3CCF3

CF3F3C

Ph

1

Ru

PCy3

PCy3Cl

Cl

Ph

Ph

Ru

PCy3

PCy3Cl

Cl

Ph

Ti CH22

3

4

O RuClCl

PCy3

5

RuP

PCl

Cl

Ph

CyCy

CyCy

NMe3+Cl -

NMe3+Cl -

Ru

P

PCl

Cl

Ph

Cy Cy

Cy Cy

N+

N+

Cl -

Cl -

Mo

N

OO

PriPri

CF3F3C

CF3

CF3

Ph

6 7 8

Mo

N

OO

PriPri

Ph

But

But

9

Figure 1. General types of olefin metathesis reactions.

Figure 2. Catalysts used for olefin metathesis.

CH2H2C

LnM CH2

( )m

( )m

MLn

MLn

( )m

( )m

MLn

( )m

Figure 3. Schematic mechanism for ring-closing metathesis of acyclic dienes.


7/40Vol. 32, No. 3, 1999 77

catalysts 13 have all been utilized in totalsyntheses of macrolides. Examples include

the Hoveyda synthesis of fluvirucin (eq 1)20and the Danishefsky,21 Nicolaou,22 orSchinzer23 syntheses of epothilones. In gener-al, ruthenium alkylidenes 2 and 3 are lessactive than 1 with respect to the formation oftrisubstituted alkenes, and incapable ofcyclizations that form tetrasubstitutedalkenes.24 In contrast, 1 is capable of catalyz-ing the formation of tri- and tetrasubstitutedbonds. Although appreciably sensitive tooxygen and water, molybdenum catalyst 1 isrelatively tolerant of functionality in the

substrate. At least in simple systems, this cat-alyst will tolerate ketones, esters, amides,

epoxides, acetals, silyl ethers, some amines,and sulfides. Ruthenium catalysts 2 and 3 areremarkably tolerant of oxygen and moisture,and they will also tolerate substrates contain-ing free alcohols, as well as the functionalgroups listed above for 1. With catalysts 2 and3, some authors have noted difficulties incyclizing substrates in which functionalgroups, that can potentially coordinate themetal center, are adjacent to the initiallymetathesized alkene. As a solution to thisproblem, Frstner and Langemann have

reported a procedure that involves the additionof Ti(i-PrO)4 to these reactions.25 Significant

differences in the rates and yields of thesereactions were noted.

The functional-group tolerance and abilityof catalysts 58 to form cyclic structures ofvarious sizes have yet to be fully explored. Itis reasonable to assume that their compatibili-ty with various functional groups will besimilar to those of the original ruthenium andmolybdenum catalysts. Their ability to formrings of various sizes is also expected to besimilar, although the asymmetric processesmay prove less efficient with some substrates.

HN

OTBS

O

HN

OTBS

O

25 mol% 1

( )n

NPh

R1

( )n

NPh ( )nNPh

OO

R1

( )n

R2

R2R1

N

R1

Ph R2 4 mol% 1, PhH

20 C, 40 min3 h

4 mol% 1, PhH

20 C or 50 C

R3

N

O

X

N

O

X

+N

Ph

Cl -N

Ph

N

O

PhN

O

( )nPh2-4 mol% 2, PhH

20 C, 640 h

2-4 mol% 2, PhH

20 C, 1 h

X = CF3, 93%X = t-BuO, 91%

(i) 4 mol% 2, CH2Cl2

20 C, 36 h

79%

( )n

(ii) NaOHH

40 min3 h

n = 0, 1, 2; 78-93%

n

1123

R1

HMeMeMe

R2

HHEtH

Yield (%)

86858673

n

00122

R1

HHHHMe

R2

HMeHHH

Yield (%)

7477808781

R3

MeMeEtHH

eq 1

eq 2

eq 3

eq 4

eq 5

eq 6


8/4078 Vol. 32, No. 3, 1999

4. Applications to the Synthesis

of Nitrogen-Containing

Systems

Due to their high catalytic activity andfunctional-group tolerance, catalysts 19seem ideally suited to applications involvingnitrogen. Many reports have appearedrecently detailing ready access to a diverse

range of compounds including peptido-mimetics, peptide tertiary structure mimics,and azasugars. This growth of ring-closingmetathesis (RCM) as a synthetic method forthe preparation of nitrogen-containingcompounds can probably be traced to 1992and 1993 when several papers were publishedby Grubbs and co-workers on the synthesis ofheterocycles by RCM.26 In these papers, Fu,Grubbs, and Nguyen delineated the nitrogen-functional-group compatibility of catalysts 1and 2, along with their ability to form five-,six-, and seven-membered rings (eq 26). Theremainder of this review will be devoted topresenting illustrative examples of theapplication of RCM to a number of these andrelated classes of compounds. For organiza-tional purposes, we have classed the examplesinto three main groups that are defined bywhat the dienes are attached to:

(i) Cyclizations leading to heterocyclic

structures. Here, the diene chain containsone or more nitrogen atom(s) such thatcyclization gives rise to heterocycles,including pyrrolidines, piperidines,

lac tams, azasugars , and a lkaloids .Systems that contain rings of 10 or moreatoms are discussed under macrocyclicsystems in part (iii).

(ii) Cyclizations leading to carbocycles.Examples in this class give rise to carbo-cycles that contain a pendant nitrogenfunctionality.

(iii) Miscellaneous cyclizations. Thissection includes macrocyclizations,solid-phase methods, and various otherapplications.

For some examples of peptidomimetics,we have tried to point out the relationship ofthe peptidomimetic to the peptide by denotingthe atoms between which cyclization occursrelative to those of a simple peptidesubstrate.27 This approach should prove usefulto researchers working with peptidomimetics,whereby it is important to have systematic anddocumented methods for restraining theconformations of peptides and pseudo-peptides. The nomenclature used is illustratedin Figure 4.

HN

HN

NH

R1

R2

R3O

C to C

C to NC to C'

O

HN

O R3

CO to N

C''C'

C

Figure 4. Nomenclature used todescribe the cyclizations of peptidomimetics.

N

4 mol% 2

PhH, rt, 32 h

BOC

N

BOC

NH

HO OH

NH

HO OH

OHOH OH OH

95%

N

Tfa OTBS

N

Tfa OTBS

NH

HO OH

OHOH

10 mol% 3

PhH, rt, 48 h

88% at 25% conversion

+ other examples

C to N

eq 7

eq 8

NOR1

ON

OR1

O7.510 mol% 2

R1 = Tr; R 2 = H rt, 48h, 76%R1 = H; R2 = Bn rt, 3d, then 65C, 1d, 41%R1 = TBS; R2 = Bn rt, 1d, then 80C, 2d, 62%

R2R2

PhH

NH

O

ORNH

O

OR

10 mol% 2

PhH

NPh

O

Fcm

NPh

O

Fcm

NH2CO2HPh

510 mol% 2

PhH, rt (R = H)reflux (R = Bn)

C to N

C to N

CO to N

RR

R

R = H 40C, 32h, 52%R = Bn rt, 31h, 75%R = Tr rt, 60h, 95%

eq 9

eq 10

eq 11


9/40Vol. 32, No. 3, 1999 79

4.1.Cyclizations Leading to

Heterocycles: Pyrrolidines,

Piperidines, Lactams,

Azasugars, Alkaloids, and

Related Compounds

There are a large number of examples of

RCM involving substrates in which the dienelinker contains a nitrogen atom. These typesof cyclizations give access to a number of use-ful classes of compounds such as mono- andbicyclic pyrrolidine, pyrrolidinone, piperidine,and piperidinone ring systems. Many of theseheterocycles are derived from amino acids,and offer a significant potential as peptido-mimetics in which the torsion angle betweenthe carbon and the nitrogen of the aminoacid is defined by the ring size and the positionof the alkene. Some of these compounds are

also important intermediates for the synthesisof azasugars and alkaloids.

A flexible synthesis of azasugars andhomoazasugars has been reported by Blechertand Huwe (eq 7 and 8).28 RCM of a vinylglycine methyl ester derived diene, followedby stereoselective functionalization of thedouble bond, gave the desired sugar deriva-

tives in good yields. The same group hasalso synthesized a number of five- andsix-membered lactams using carbene 2 (eq 9and 10).29 Like many examples of metathesiscyclizations of this type, the yield of the cyclicproduct is dependent on the nature of theprotecting group on nitrogen. In some cases,however, protection of the nitrogen is notnecessary (eq 10). It is also interesting to notethat increasing steric demand of theoxygen substituent in the example shown ineq 10 led to a marked increase in yield of the

cyclic product (compare R = H, Bn, and Tr).The precursors in the pyrrolidinone series(eq 9) and the piperidinone series (eq 10) weresynthesized from vinylglycine and allyl-glycine, respectively. Garro-Hlion andGuib have reported an efficient sequence toZ-ethylenic peptidomimetics based on arelated RCM chemistry.30 Treatment of the

acyclic dienes with 2 resulted in a smoothcyclization to the desired piperidinones;however, reflux in benzene was required in thecase where R = Bn (eq 11). These compoundswere then hydrolyzed to give the deprotectedpeptide isosteres.

Related work by Rutjes and Schoemakerhas also resulted in the synthesis of a series ofsix- and seven-membered lactams and hetero-cycles (eq 1216).31 The yields of theRCM-derived tetrahydropyridines shown ineq 12 were dependent on the nature of the

N CO2Me

RN CO2Me

R

N CO2MeR

N CO2MeR

N CO2MeOPMB

N CO2MeOPMB

5 mol% 3, CH2Cl2

reflux

5 mol% 3, CH2Cl2

reflux

5 mol% 3, CH2Cl2

reflux

65%

R = H 0%R = PMB 54%R = CH2Fer 18%R = BOC 93%

N CO2Me

RN CO2Me

R

5 mol% 3, CH2Cl2

refluxOO

R = PMB 93%R = CH2Fer 89%

N CO2Me

PMBN CO2Me

PMB

5 mol% 3, CH2Cl2

refluxXX

X = H,H 82%X = O 95%

R = PMB 94%R = CH2Fer 87%

C to N

C to N

C to N

C to N

C to N

eq 15

eq 16

eq 14

eq 13

eq 12


10/4080 Vol. 32, No. 3, 1999

protecting group (R) on nitrogen. Withoutprotection (R = H), ring closure was notobserved, while BOC protection resulted in anexcellent yield. The ease of cyclization of theacyclic amides shown in eq 13 also proved tobe dependent on the nature of the protectinggroup. The free amide (R = H) wassluggish, while the N-protected counterpartscyclized readily and in excellent yields. It hasbeen suggested that an increase in steric bulk

around the nitrogen leads to a more favorabletransition state for ring closure.31 Theintroduction of a methyl substituent to thecarboxyl group resulted in a marked increasein the ease of RCM (eq 14). The trifluo-romethyl analogs have also been reportedrecently by Osipov,Dixneuf, and co-workers.32

The homoallylglycine-derived acyclic sys-tems shown in eq 15 and 16 gave thecorresponding seven-membered-ring hetero-cycles. The nature of N-protection proved tobe less critical in these examples. A sequence

based on the IrelandClaisen rearrangement,followed by RCM, has been reported as aconvenient means to construct similarsystems.33 The products shown in equations1216 are non-natural cyclic amino acidderivatives that deserve further study becauseof their interesting properties.

Grubbs and co-workers have also reporteda number of applications of their Ru carbenesto peptide and heterocyclic chemistry. In a

seminal paper, the application of carbene 2 tothe synthesis of cyclic amino acids wasreported (eq 1720).34 While six- and seven-membered cyclic amino acids were readilysynthesized (eq 17 and 18), attempts toprepare a dehydroproline system wereunsuccessful (eq 19). This was attributed tothe acidity of the hydrogen, althoughconformational effects and/or internalcomplexation of the carbene by the carbonylgroup may also play a role. Recent work byCampagne and Ghosez35 has shown that

dehydroproline systems can be prepared,provided a triphenylmethyl (trityl) group isused as the protecting group on the nitrogen(eq 21). The original report by Grubbs andco-workers also included the synthesis of aneight-membered AlaGly dipeptide (eq 20).

The chemistry shown in eq 12 and eq 17was recently extended by Abell and co-workers, who used a combination ofSeebachs oxazolidinone chemistry and RCM

in the synthesis of a phenylalanine mimic(eq 22).36 This tetrahydropyridine system wasdesigned to probe the constraints imposed bythe six-membered ring on the torsion anglebetween the carbon and the nitrogen. X-rayanalysis demonstrated that this type of systemhas potential as a -turn mimic.

A number of groups have investigated theuse of metathesis chemistry to form bicyclicsystems. Martin and co-workers have shownthe potential of RCM to form the ring systemsfound in a number of alkaloids (eq 23 and

N CO2Me

BOC

N CO2Me

BOC

NNHBOC

O

MeO2CN

NHBOCO

MeO2C

5 mol% 2, 0.2M

C6H6, 25C, 91%

5 mol% 2, 0.2M

CHCl3, 25C, 52%

5 mol% 2, 0.2M

CHCl3, 25CNO REACTION

N

BOC

CO2Me

N

OO

PhO

Ph

PhN

CO2Me

Ph O

N

CO2Me

Ph O

10 mol% 3

CH2Cl2, 25C, 2h,

86%

N NBOC

O

MeO2C N N BOC

O

MeO2C5 mol% 2, 0.2M

C6H6, 25C, 51%

R

Ph PhR = HR = allyl

5 mol% 2

CH2Cl2, reflux, 70%N

Tr

CO2Me N

Tr

CO2Me

C to N

C to N

C to N

N to N'

C to N

C to N

eq 17

eq 18

eq 19

eq 20

eq 21

eq 22


11/40

24).37 This work has demonstrated that anumber of fused nitrogen heterocycles, includ-ing pyrrolizidines, indolizidines, and quino-lizidines, can be readily prepared. Furtherexamples of related bicyclic systems that havebeen synthesized using RCM are shown ineq 2527.38 Several of these examples havebeen used in the synthesis of simple alkaloids.

A number of medium-sized rings havebeen synthesized by RCM (eq 2830). Seven-membered heterocyclic rings can be readilyformed by RCM (see for example eq 1516).However, reported syntheses of eight-mem-bered rings tend to be on dienes attached orfused to other ring systems, i.e., the acyclicprecursor is pre-organized into a conforma-tion that favors cyclization.39 Early studies inthis area by Grubbs and co-workers demon-strated the application of RCM to structuressuitable for mitomycin and FR-900482

synthesis.40 As part of studies directed towardthe manzamine class of alkaloids, Winkler andco-workers investigated the synthesis ofazocine rings by RCM (eq 28).41 Advancedintermediates en route to manzamine A havebeen similarly cyclized by Martins groupusing Mo carbene 1, and by Pandit andco-workers using Ru carbene 2 (eq 28).42

Magnier and Langlois have recently reportedsimilar results.43 An elegant synthesis of(+)-australine, utilizing RCM as the key step toform an eight-membered ring, has been report-ed by White and co-workers (eq 29).44 As afurther example, ring-closing enyne metathesishas been employed with impressive strategicgain in a concise synthesis of a key intermedi-ate en route to ()-stemoamide (eq 30).45

Some examples of diastereoselective RCMhave recently been reported by Blechert andco-workers (eq 3133).46 The existing stereo-

genic center is used to control the cyclizationof a diastereotopic diene. Control of whichalkene is metathesized first is important, andthe use of trans-disubstituted alkenes allowsthe initial reaction to be directed to themonosubstituted alkene. Levels of diastereo-selection are modest when formingsix-membered rings (eq 31 and 32), but are>70% with five-membered rings (eq 33).Interestingly, changing the catalyst from Mocarbene 1 to Ru carbene 3 allows some controlof the relative diastereoselection (eq 33). Thisis probably related to the different spatialarrangements of various ligands around thedifferent metal centers.

Pandit and co-workers have explored theapplications of RCM of dienes appendedto polysubstituted pyrrolidinones and piperidi-nones (eq 34 and 35).47 In one such case(eq 34), a demanding five-membered-ring

N

O

( )nm( )

N

O

( )nm( )

N

O( )n

N

On( )

1, PhH, rt or 50 C

n = 1,2 and m = 035095%

1, DME, rt

n = 0,1; R=H, Me7395%

R

R

R1

R

N

N

O

O

R1

R2

N

N

O

O

R1

R2

N

O

OBn

OBnH

N

O

OBn

OBnH

N

O ( )n R

N

O ( )n

R2

R

R3n = 04; R = H, Me093%

510 mol% 2 or 3

PhH, rt or 80CN

O

N

O

(S)-pyrrolam A()-coniceine

4 mol% 3, PhH

NOH

OHH

()-1,2-dihydroxyindolizidine

reflux, 80%

10 mol% 3

CH2Cl2, reflux

R1 = Ph, p-MeOBn, Cy, t-BuR2 = Bn, i-Pr, i-Bu, allyl, Me,

N-allyl-3-indolylmethyl

4574%C to N

or

Vol. 32, No. 3, 1999 81

eq 23

eq 24

eq 25

eq 26

eq 27


12/40

cyclization was performed by using 50 mol%of catalyst 2. These studies have expanded onan earlier report by the same group ona concise synthesis of castanospermine(eq 36), which demonstrated that, in somesystems, ,-unsaturated esters may besuitable substrates for metathesis.48

A number of other substrates, such as-lactam-based dienes, have also been usedto prepare interesting heterocycles by RCM(eq 37 and 38).49

4.2.Cyclizations Leading to

Carbocycles

Although widely utilized for the synthesisof heterocycles, RCM has only been appliedto a handful of systems that lead to carbocy-cles. This will undoubtedly be an area of

growth over the next few years as moreresearch groups employ RCM in carbocyclesynthesis.

Hammer and Undheim have appliedRCM to the synthesis of a number of five-,six-, and seven-membered carbocyclesderived from (2R)-2,5-dihydro-3,6-dimeth-

oxy-2-isopropylpyrazine (enantiomer ofSchllkopfs bislactim ether; see eq 39 and40).50,51 The results detailed in eq 39indicate that, not surprisingly, the reaction issensitive to steric interaction between theisopropyl group and the alkylidene. Forexample, the authors note that an allyl groupsyn to the isopropyl group is less reactivethan when it is in the anti position. It is alsoworth noting that in these studies, five-membered rings were more difficult to formthan either six- or seven-membered rings.

The bislactims are readily hydrolyzed bydilute acid (0.2 M TFA, MeCN) to give anamino ester, where the carbon is incorpor-ated into a five-, six-, or seven-memberedring. Two recent reports have demonstratedthe use of enones and hydroxymethylateddienes related to those in eq 39 and 40 as

suitable RCM substrates within thisstrategy.52 Further studies by Hammer andUndheim have also explored the applicationsof ruthenium-catalyzed, ring-closing enynemetathesis to systems derived fromSchllkopfs bislactim ether (eq 41).53

Kotha and Sreenivasachary have appliedRCM to the synthesis of simple carbocyclicamino acids (eq 42 and 43).54 Recently,Maier and Lapeva reported a synthesis ofcyclohexenylamines that relies on RCM asthe key step (eq 44).55

82 Vol. 32, No. 3, 1999

N

N

N NHH

OH

H

manzamine A

(Winkler and coworkers)

N

N

O

H

OH

H

MEMO

ON

N

O

H

H

CO2Me

OBn

RCM RCM

RCM

(Martin and coworkers) (Pandit and coworkers)

N

O

O

H

N

O

O

H

3, 75%

NO

H N

O

H

MeO2CCO2Me

N

O

H

O

O

H

H4 mol% 3

CH2Cl2, rt, 5h

87% ()-stemoamide

N

OO

O

O

N

OO

O

O

N

CH2OH

OHH

OH

(+)-australine

3, CH2Cl2

rt, 97%

HO

eq 28

eq 29

eq 30


13/40

4.3.Miscellaneous Cyclizations:

Macrocyclic Peptides, Solid-Phase Methods, and Other

Applications

Miller, Blackwell, and Grubbs havedescribed a number of applications of RCM to

give rigid amino acids and macrocyclic pep-tides.34 In this work (eq 45 and 46), a numberof acyclic polypeptides were cyclized underhigh dilution to give 14- and 20-memberedmacrocycles. Several other polypeptides werecyclized, including a 14-membered tetrapep-tide designed as a dicarba analog of adisulfide -turn motif (eq 47).34 Initially, ithad been thought that pre-existing conforma-tional restrictions in the peptide backbonewould be necessary to induce RCMcyclization.56 However, the success of the

cyclization shown in eq 47 demonstrates thatthis may not strictly be the case.

Williams and Liu have reported relatedstudies in which a differentially protected2,7-diaminosuberic acid derivative wasprepared by RCM (eq 48).57 Vederas andcoworkers concurrently developed a similar

route (eq 49).58

2,7-Diaminosuberic acidshave been utilized in the synthesis of dicarbaanalogs of naturally occurring biologicallyactive peptides.59

Several other research groups have utilizedRCM in the synthesis of macrocyclic peptides.Katzenellenbogen and co-workers employedRCM as part of studies on a proposed Type 1-turn mimic (eq 50).60 Here, the use of RCMon a dipeptide allowed the convenientsynthesis of the 10-membered lactam in sixsteps. By comparison, a more traditional

macrolactamization route to this compoundrequired nine steps, and the RCM route hadthe added advantage of providing access to the(3S,10S) diastereoisomer, which was unob-tainable by the original route.

Rich and co-workers have also reported arelated synthesis of a macrocyclic pepsin

inhibitor by RCM of a tripeptide-deriveddiene (eq 51).61 The macrocyclic alkene andthe fully saturated analog (derived from thiscompound by reduction) proved to be goodinhibitors of Rhizopus chinensis pepsin(Ki 1.31 M and 0.34 M, respectively).

Acyclic dienes that are not derived fromamino acids have also been shown to undergomacrocyclization by RCM. For example,Fuchs and co-workers reported such a macro-cyclization in their synthesis of the tricyclicansa-bridged core of roseophilin (eq 52).62

Vol. 32, No. 3, 1999 83

TfaN

OTBS

TfaN

OTBS

N

O

ON

O

O

1 or 3

10 mol% 1, 80C, 20 h, 95%, syn:anti 26:74

5 mol% 3, 80C, 1 h, 98%, syn:anti 48:52

1 or 3

PhH

5 mol% 1, rt, 24h, 88%, syn:anti 36:645 mol% 3, rt, 2h, 90%, syn:anti 50:50

N

F3C O

OTBS

N

F3C O

OTBS

N

F3C O

OTBS

10 mol% 1 PhH, 80C, 3d

10 mol% 3

PhH, 80C, 4d

88%, syn:anti 4:96

97%, syn:anti 86:14

C to N

C to N

C to N

eq 31

eq 32

eq 33


14/40

This reaction required very dilute conditions(0.5 mM) to avoid the formation ofmacrocyclic dimers.

In an impressive example of what the

authors describe as supramolecular design bycovalent capture, Clark and Ghadiri havesynthesized a macromolecular peptide by anintermolecular RCM (eq 53).63 Here, the twoprecursors are held in close proximity byhydrogen bonding between the amino acidside chains of the N-methyl cyclic peptidessuch that intermolecular RCM gives themacrocycle in an impressive yield of 65%.Another example of the use of RCM to givepeptidic supramolecular structures was recent-ly provided by Blackwell and Grubbs with the

preparation of helical polypeptides.64 Here,carbene 3 was used to prepare examples ofheptapeptides in which the i and (i + 4)residues of the peptide are linked by RCM

(eq 54). As noted by the authors, "The relativeease of introducing carboncarbon bonds intopeptide secondary structures by RCM and thepredicted metabolic stability of the bondsrenders olefin metathesis an exceptionalmethodology for the synthesis of rigidifiedpeptide architectures". This area is one ofexceptional promise given the compatibility of3 with functional groups and solventscommonly found in peptide chemistry.

The products of RCM of amino acid basedsubstrates have also been reported as key

intermediates of important isosteric units. Forexample, Ghosh and co-workers have reportedthe cyclization of amino acid derived acrylateesters as part of a synthesis of hydroxyethyl-ene isosteres that form the core units of animportant class of HIV protease inhibitors(eq 55).65 This work further demonstrates theusefulness of Frstner and Langemannsprocedure, which involves the addition of

Ti(i-PrO)4, in the case of substrates that mayform stable, chelated carbene intermediates.

Although yet to be clearly defined, asubstantial amount of the chemistry describedin this review is applicable to solid-phasemethods. Amongst the most impressiveexamples of the potential of this adaptation isthe recent report by Nicolaou and co-workersof the synthesis of a library of epothiloneanalogs by a solid-phase RCMcleavagestrategy.66 In the area of nitrogen-containingsubstrates, a number of groups have reportedsolid-phase adaptations of their synthesesusing RCM. Blechert and co-workers have

reported that their previous synthesis of five-and six-membered nitrogen heterocycles(eq 911) can be performed on solid-phaseresins, such as Tentagel S and tritylpolystyrol(eq 5659).67 Examples have been reportedwhere the resin is attached through eithernitrogen or carbon, and, in all cases, thecyclizations appear to be slower than thecorresponding solution-phase cyclizations.

An RCMcleavage strategy for the synthe-sis of cyclic lactams has also been reported byvan Maarseveen and co-workers (eq 60).68 Anessential feature of this work is the cleaving ofthe lactams from the resin in the course of

RCM. The rate of RCM is, however, slowunder relatively standard reaction conditions,a feature that the authors attribute to theimmobilization of the carbene on the resin.This problem can be partly overcome by theaddition of a terminal olefin such as 1-octene,although the yields are still modest. Piscopioand co-workers have reported a similarRCMcleavage strategy for the solid-phasesynthesis of pipecolinic acids and Freidingerlactams (eq 61).69 In this report, the use of acinnamyl alcohol resin appears to aid thecyclizationcleavage reaction. Further devel-opments of this work have recently been

reported.70The synthesis of hexahydroisoindoles has

been carried out on solid phase using Wangresin (eq 62).71 Although no yields werereported, the authors described the synthesisof a library of 4200 (theoretical) compoundsby this methodology. The equivalent solution-phase chemistry was also reported.

Grubbs and co-workers have demonstratedthat RCM cyclization of polypeptides can alsobe performed on solid phase.34 As noted bythe authors, peptides of >5 residues in length

84 Vol. 32, No. 3, 1999

N O

OBnBnO

H

N O

OBnBnO

H

N

H

O

BnO

BnO

RON

H

O

BnO

BnO

RO

50 mol% 2, 50C

PhH, 24h, 66%

R = Ac 2.5 mol% 3, CH2Cl2, 25C, 95%R = Bn 1 mol% 2, PhMe, 25C, 74%

NO

OBn

BnOBnO

NO

OBn

BnOBnO

MeO2C

N

OHHO

HO

HO

castanospermine

3 mol% 2, PhMe

110C, 48h, 70%

N

N

X

O

O

OTBS

NO

OTBS

N

X

O

5 mol% 3, CH2Cl2

rt, 6h, 78%

5 mol% 3, CH2Cl2( )n ( )n

rt, 26h

n = 0, X = CH2, 81%n = 1, X = NTs, 91%n = 1, X = S, 78%

1 or

eq 34

eq 35

eq 36

eq 37

eq 38


15/40

usually suffer from low solubility in solventscommonly used for RCM. However, thesynthesis and RCM of these substrates wasreadily performed on a PEG/PS resin (eq 63).

5. Conclusions

Ring-closing metathesis has clearlyreached the point where it is a reliable and

relatively mature technique for the formationof a diverse range of ring structures. The mildconditions under which most reactions can beperformed, along with the high functional-group tolerance of the current catalysts, meanthat it is clearly of immense value in manyareas of chemistry. The synthesis ofN-containing compounds such as heterocyclesand peptides has benefited from thesefeatures. Ring-closing metathesis also offers anew potential for strategic disconnections as isclearly evidenced by the synthesis ofmacrolides, where it provides a powerfulalternative to traditional macrocyclization

techniques. The future of ring-closingmetathesis can almost certainly be bright asnew catalysts and applications are discovered.

6. Acknowledgments

We thank the Marsden Fund of NewZealand (ADA), the New Zealand PublicGood Science Fund (ADA), and theUniversity of Canterbury (DoctoralScholarship to AJP) for support of ourresearch, and Professor Robert Grubbs forgenerous advice on RCM chemistry.

7. References and Notes Abbreviations: Ac, acetyl; BOC, tert-butoxy-

carbonyl; Bn, benzyl; Cbz, benzyloxycarbonyl;DCE, dichloroethane; Fcm, ferrocenylmethyl;Fer, ferrocenyl; FMOC, 9-fluorenylmethoxy-carbonyl; MEM, (2-methoxyethoxy)methyl;PCy3, tricyclohexylphosphine; PMB, 4-methoxybenzyl; TBS, tert-butyldimethylsilyl;TFA, trifluoroacetic acid; Tfa, trifluoroacetyl;TIPS, triisopropylsilyl; Tr, triphenylmethyl;Ts, 4-methylphenylsulfonyl.

(1) Anderson, A.W.; Merckling, N.G. U.S. Patent2,721,189, 1955; Chem. Abstr. 1956, 50,3008i.

(2) (a) Schrock, R.R.; Murdzek, J.S.; Bazan,G.C.; Robbins, J.; DiMare, M.; ORegan, M.J. Am. Chem. Soc. 1990, 112, 3875.(b) Bazan, G.C.; Khosravi, E.; Schrock, R.R.;Feast, W.J.; Gibson, V.C.; ORegan, M.B.;Thomas, J.K.; Davis, W.M.J. Am. Chem. Soc.1990, 112, 8378. (c) Bazan, G.C.; Oskam,J.H.; Cho, H.-N.; Park, L.Y.; Schrock, R.R.J. Am. Chem. Soc. 1991, 113, 6899.

(3) (a) Schuster, M.; Blechert, S.Angew. Chem.,Int. Ed. Engl. 1997, 37, 2036. (b) Armstrong,S.K.J. Chem. Soc., Perkin Trans.1 1998, 371.(c) Grubbs, R.H.; Chang, S. Tetrahedron1998, 54, 4413. (d) Grubbs, R.H.; Miller,

S.J.; Fu, G.C.Acc. Chem. Res. 1995, 28, 446.(4) (a) Nguyen, S.T.; Johnson, L.K.; Grubbs,

R.H.; Ziller, J.W. J. Am. Chem. Soc. 1992,114, 3974. (b) Nguyen, S.T.; Grubbs, R.H.;Ziller, J.W. J. Am. Chem. Soc. 1993, 115,9858. (c) Schwab, P.; France, M.B.; Ziller,

J.W.; Grubbs, R.H. Angew. Chem., Int. Ed.Engl. 1995, 34, 2039. (d) Schwab, P.; Grubbs,R.H.; Ziller, J.W. J. Am. Chem. Soc. 1996,118, 100.

(5) Grubbs, R. H. Personal communication.(6) See for example: Nicolaou, K.C.; Postema,

M.H.D.; Yue, E.W.; Nadin, A. J. Am. Chem.Soc. 1996, 118, 10335.

(7) Kingsbury, J.S.; Harrity, J.P.A.; Bonitatebus,P.J., Jr.; Hoveyda, A.H. J. Am. Chem. Soc.1999, 121, 791.

(8) For recent investigations, see: (a) Frstner, A.;Picquet, M.; Bruneau, C.; Dixneuf, P.H.

Chem. Commun. 1998, 1315. (b) Dias, E.L.;Grubbs, R.H. Organometallics 1998, 17,2758.

(9) Nguyen, S.T.; Grubbs, R.H. J. Organomet.Chem. 1995, 497, 195.

(10) Kirkland, T.A.; Lynn, D.M.; Grubbs, R.H.J. Org. Chem. 1998, 63, 9904.

(11) (a) Fujimura, O.; Grubbs, R.H.J. Am. Chem.Soc. 1996, 118, 2499. (b) Fujimura, O.;Grubbs, R.H.J. Org. Chem. 1998, 63, 824.

(12) (a) Alexander, J.B.; La, D.S.; Cefalo, D.R.;Hoveyda, A.H.; Schrock, R.R.J. Am. Chem.Soc. 1998, 120, 4041. (b) La, D.S.;Alexander, J.B.; Cefalo, D.R.; Graf, D.D.;Hoveyda, A.H.; Schrock, R.R.J. Am. Chem.Soc. 1998, 120, 9720.

(13) (a) Couturier, J.L.; Paillet, C.; Leconte, M.;Basset, J.M. Angew. Chem., Int. Ed. Engl.1993, 32, 112. (b) Nugent, W.A.; Feldman, J.;

Vol. 32, No. 3, 1999 85

N

N

MeO

OMe

N

N

MeO

OMe( )m

( )mn( )

n( )

2 mol% 3

PhH or PhMe25100C

N

N

MeO

OMe

N

N

MeO

OMe( )n ( )n

HOHO

2 mol% 3

PhH, 20C (n =2)DCE, 80C (n= 3)

n = 2, 88%n = 3, 63%

N

N

MeO

OMe

N

N

MeO

OMe

( )n ( )n

RR

5 mol% 3

PhH, reflux, 14h

H2N

O OMe

( )m

n( )

C to C

C to C

C to C

n = m = 1, 53%n = 1, m = 2, 99%n = 1, m = 3, 60%

n = 2, m = 1, 95%n = 2, m = 2, 90%n = 2, m = 3, 0%

n = 1 or 27186%R = H, Me, CH2OAc

NHAc

CO2Et

NHAc

CO2Et

NHAc

CO2Et

NHAc

CO2Et

cat 3, PhMe

reflux, 90%

cat 3

92%

NR2

R1

NR2

R13 mol% 3

CH2Cl2, rt, 24h

C to C

C to C

R1 = H, R2 = Cbz, 95%

R1 = H, R2 = BOC, 91%

R1 = Bn, R2 = H, 0%

R1 = Bn, R2 = Tfa, 98%

eq 39

eq 40

eq 41

eq 42

eq 43

eq 44


16/4086 Vol. 32, No. 3, 1999

HN

N

NH

ONH

O

O

CO2Me

O

BOCN

CbzO

HN

N

NH

ONH

O

O

CO2Me

O

BOCN

CbzO

BOCHNNH

CO2MeO

O

O

BOCHNNH

O

O

O

CO2Me

30 mol% 3

CH2Cl2, 40C

30 mol% 3

CH2Cl2, 50C

HN

HN

NH

OOBn

O

O

O

BOCHN

HN

HN

NH

OOBn

O

O

O

BOCHN

30 mol% 3

CH2Cl2, 40C

O

O

O

HN

O

BOCHN

PhO2C

O

O

O

HN

O

BOCHN

PhO2C

42 mol% 3

CH2Cl2, reflux

OH

O

BOCHN

PhO2C NH2

O

O

NHBOC

NHCbz

O

O

O

O

NHBOC

NHCbz

O

O

20 mol% 3, CH2Cl2

rt, 1.5 h, 35%

H H

C to C'''

C to C'

C to C'''

80%

56%

80%

66 h, 83%

N

O

NHBOC

MeO2C

N

O

NHBOC

MeO2C

10 mol% 3, 0.2 mM

CH2Cl2, reflux,18h

BOCHN

HN

NH

O

O

OBn BOCHN

HN

NH

O

O

OBn

3, slow addition

24 h, 88%

HH

C to C'

C to C'''

65%

eq 45

eq 46

eq 47

eq 48

eq 49

eq 50

eq 51


17/40

Calabrese, J.C.J. Am. Chem. Soc. 1995, 117,8992.

(14) Cantrell, G.K.; Meyer, T.Y.J. Am. Chem. Soc.1998, 120, 8035.

(15) Hrrison, J.P.; Chauvin,Y.Makromol. Chem.1970, 141, 161.

(16) Dias, E.L.; Nguyen, S.T.; Grubbs, R.H.J. Am.Chem. Soc. 1997, 119, 3887.

(17) An X-ray structure of a reaction intermedi-ate obtained recently by Snapper and

co-workers supports this postulate. Tallarico,J.A.; Bonitatebus, P.J., Jr.; Snapper, M.L.J. Am. Chem. Soc. 1997, 119, 7157.

(18) Phillips, A.J.; Abell, A.D. Unpublished resultsdirected towards taxane synthesis, Universityof Canterbury, 19971998.

(19) (a) Miller, S.J.; Kim, S.H.; Chen, Z.-R.;Grubbs, R.H. J. Am. Chem. Soc. 1995, 117,2108. (b) Frstner, A.; Langemann, K.J. Org.Chem. 1996, 61, 8746.

(20) Houri, A.F.; Xu, Z.; Cogan, D.A.; Hoveyda,A.H.J. Am. Chem. Soc. 1995, 117, 2943.

(21)Balog, A.; Meng, D.; Kamenecka, T.;Bertinato, P.; Su, D.S.; Sorensen, E.J.;Danishefsky, S.J. Angew. Chem., Int. Ed.Engl. 1996, 35, 2801.

(22) Yang, Z.; He, Y.; Vourloumis, D.; Vallberg, H.;Nicolaou, K.C.Angew. Chem., Int. Ed. Engl.1997, 36, 166.

(23)Schinzer, D.; Limberg, A.; Bhm, O.M.Chem.Eur. J. 1996, 2, 1477.

(24) Kirkland, T.A.; Grubbs, R.H. J. Org. Chem.1997, 62, 7310. For further examples oftrisubstituted systems, see: (a) Maier, M.E.;Langenbacher, D.; Rebien, F. Liebigs Ann.Chem. 1995, 1843. (b) Hlder, S.; Blechert,S. Synlett1996, 505. (c) Chang, S.; Grubbs,R.H.J. Org. Chem. 1998, 63, 864.

(25) Frstner, A.; Langemann, K. J. Am. Chem.Soc. 1997, 119, 9130.

(26) (a) Fu, G.C.; Grubbs, R.H.J. Am. Chem. Soc.1992, 114, 5426. (b) Fu, G.C.; Grubbs, R.H.J. Am. Chem. Soc . 1992, 114, 7324. (c) Fu,G.C.; Nguyen, S.T.; Grubbs, R.H. J. Am.Chem. Soc. 1993, 115, 9856.

(27) For the genesis of this nomenclature system,see Toniolo, C. Int. J. Peptide Protein Res.1990, 35, 287.

(28) (a) Huwe, C.M.; Blechert, S. TetrahedronLett. 1995, 36, 1621. (b) Huwe, C.M.;Blechert, S. Synthesis 1997, 61.

(29) Huwe, C.M.; Kiehl, O.C.; Blechert, S. Synlett1996, 65.

(30)(a) Garro-Hlion, F.; Guib, F. Chem.Commun. 1996, 641. (b) Sauriat-Dorizon, H.;Guib, F. Tetrahedron Lett. 1998, 39, 6711.

(31) R u t j es , F. P. J . T. ; S c h oe m a ke r, H . E .

Tetrahedron Lett. 1997, 38, 677.(32)Osipov, S.N.; Bruneau, C.; Picquet, M.;Kolomiets, A.F.; Dixneuf, P.H. Chem.Commun. 1998, 2053.

(33) Miller, J.F.; Termin, A.; Koch, K.; Piscopio,A.D.J. Org. Chem. 1998, 63, 3158.

(34) Miller, S.J.; Blackwell, H.E.; Grubbs, R.H.J. Am. Chem. Soc. 1996, 118, 9606.

(35) Campagne, J.-M.; Ghosez, L. TetrahedronLett. 1998, 39, 6175.

(36)Abell, A.D.; Gardiner, J.; Phillips, A.J.;Robinson, W.T. Tetrahedron Lett. 1998, 39,9563.

(37) Martin, S.F.; Chen, H.-J.; Courtney, A.K.;

Vol. 32, No. 3, 1999 87

NTs

TIPSO

H

ONTs

TIPSO

H

O

30 mol% 3

CH2Cl2, 40C, 25 h

60%

roseophilin

NN

NN

O

OH

O

O

N

N

N

O O

O H

N

OH

NN

NNN

N

N

N

O

O

H O

O

H O

O

O

O

H

H

NN

NN

O

OH

O

O

N

N

N

O O

O H

N

OH

NN

NNN

N

N

N

O

O

H O

O

H O

O

O

O

H

H

2025 mol% 2, 5.0 mMCDCl3, 25C, 48h, 65%

N

H

BOC

MeO2C

OO

i

i+ 4

( )n

( )n

N

H

BOC

MeO2C

OO

( )n

( )n

BocValSerLeuAibValSerLeuOMe (n = 1)or BocValHseLeu-AibValHseLeuOMe (n = 2)

85%or 90%

20 mol% 3

25C, CHCl3

C to Cintermolecular

H

H

O

O

BOCN

Ph

( )n

HO

O

BOCN

Ph

( )n

H 10 mol% 3, CH2Cl2

30 mol% Ti(i-PrO)4,reflux, 515h

8284%

OH

BOCN

Ph

H

O

HN Ph

Ph

n = 0

HIV ProteaseInhibitors

n = 0, 1

eq 52

eq 53

eq 54

eq 55


18/40

Liao,Y.; Ptzel, M.; Ramser, M.N.; Wagman,A.S. Tetrahedron 1996, 52, 7251.

(38) (a) Arisawa, M.; Takezawa, E.; Nishida, A.;Mori, M.; Nakagawa, M. Synlett1997, 1179.(b) Paolucci, C.; Musiani, L.; Venturelli, F.;Fava, A. Synthesis 1997, 1415. (c) Dyatkin,A.B. Tetrahedron Lett. 1997, 38, 2065.

(39) Illuminati, G.; Mandolini, L.Acc. Chem. Res.1981, 14, 95.

(40) Miller, S.J.; Kim., S.-H.; Chen, Z.-R.; Grubbs,R.H. J. Am. Chem. Soc. 1995, 117, 2108.Related concurrent studies have been reportedby Martin and co-workers. See reference 37.

(41)Winkler, J.D.; Stelmach, J.E.; Axten, J.Tetrahedron Lett. 1996, 37, 4317.

(42) (a) Martin, S.F.; Liao, Y.; Wong, Y.; Rein, T.Tetrahedron Lett. 1994, 35, 691. (b) Pandit,U.K.; Borer, B.C.; Bierugel, H. Pure Appl.Chem. 1996, 68, 659.

(43) Magnier, E.; Langlois, Y. Tetrahedron Lett.1998, 39, 837.

(44) White, J.D.; Hrnciar, P.; Yokochi, A.F.T.J. Am. Chem. Soc. 1998, 120, 7359.

(45) Kinoshita, A.; Mori, M.J. Org. Chem. 1996,61, 8356.

(46) Huwe, C.M.; Velder, J.; Blechert, S. Angew.Chem., Int. Ed. Engl. 1996, 35, 2376.

(47) Overkleeft, H.S.; Bruggeman, P.; Pandit, U.K.Tetrahedron Lett. 1998, 39, 3869.

(48) Overkleeft, H.S.; Pandit, U.K. TetrahedronLett. 1996, 37, 547.

(49) Barrett, A.G.M.; Baugh, S.P.D.; Gibson, V.C.;Giles, M.R.; Marshall, E.L.; Procopiou, P.A.Chem. Commun. 1997, 155.

(50) Hammer, K.; Undheim, K. Tetrahedron 1997,53, 2309.


(52) (a) Krikstolaityt, S.; Hammer, K.; Undheim,K. Tetrahedron Lett. 1998, 39, 7595.(b) Hammer, K.; Undheim, K. Tetrahedron:Asymmetry 1998, 9, 2359.


(54) Kotha, S.; Sreenivasachary, N. Bioorg. Med.Chem. Lett. 1998, 8, 257.

(55) Maier, M.E.; Lapeva, T. Synlett1998, 891.

(56) Miller, S.J.; Grubbs, R.H. J. Am. Chem. Soc.1995, 117, 5855.(57) Williams, R.M.; Liu, J.J. Org. Chem. 1998,

63, 2130.(58) Gao, Y.; Lane-Bell, P.; Vederas, J.C. J. Org.

Chem. 1998, 63, 2133.(59) See for example: (a) Walker, R.; Yamanaka,

T.; Sakakibara, S. Proc. Natl. Acad. Sci.U.S.A. 1974, 71, 1901. (b) Veber, D.F.;Strachan, R.G.; Bergstrand, S.J.; Holly, F.W.;Homnick, C.F.; Hirschmann, R.; Torchiana,M.; Saperstein, R. J. Am. Chem. Soc. 1976,98, 2367.

(60) Fink, B.E.; Kym,P.R.; Katzenellenbogen, J.A.J. Am. Chem. Soc. 1998, 120, 4334.

(61)Ripka, A.S.; Bohacek, R.S.; Rich, D.H.Bioorg. Med. Chem. Lett. 1998, 8, 357.

(62) Kim, S.H.; Figueroa, I .; Fuchs, P.L.Tetrahedron Lett. 1997, 38, 2601.

(63) Clark, T.D.; Ghadiri, M.R.J. Am. Chem. Soc.1995, 117, 12364.

(64) Blackwell, H.E.; Grubbs, R.H.Angew. Chem.,Int. Ed. Engl. 1998, 37, 3281.

(65) Ghosh, A.K.; Cappiel lo, J .; Shin, D.Tetrahedron Lett. 1998, 39, 4651.

(66) Nicolaou, K.C.; Winssinger, N.; Pastor, J.;Ninkovic, S.; Sarabia, F.; He, Y.; Vourloumis,D.; Yang, Z.; Li, T.; Giannakakou, P.; Hamel,E.Nature 1997, 387, 268.

(67) Schuster, M.; Pernerstorfer, J.; Blechert, S.Angew. Chem., Int. Ed. Engl. 1996, 35, 1979.

(68) van Maarseveen, J.H.; den Hartog, J.A.J.;Engelen, V.; Finner, E.; Visser, G.; Kruse, C.G. Tetrahedron Lett. 1996, 37, 8249.

(69)Piscopio, A.D.; Miller, J.F.; Koch, K.Tetrahedron Lett. 1997, 38, 7143.

(70)Piscopio, A.D.; Miller, J.F.; Koch, K.Tetrahedron Lett. 1998, 39, 2667.

(71) Heerding, D.A.; Takata, D.T.; Kwon, C.;Huffman, W.F.; Samanen, J. Tetrahedron Lett.1998, 39, 6815.

88 Vol. 32, No. 3, 1999

N N10 mol% 2, PhH

25C, 72 h

>90%Tentagel S

N 15 mol% 2, PhH

30C, 120 h

83%tritylpolystyrol

O

Ts N

O

Ts

15 mol% 2, PhH

30C, 120 h

tritylpolystyrol

N

O

R

X

N

O

R

X

R = Ts, X=H,H; 83%R = H, X=O; 91%

13 mol% 2, PhH

reflux, 12 h

tritylpolystyrol

N

O

Tfa N

O

Tfa

70%

Ph Ph

eq 56

eq 57

eq 58

eq 59

New Fluorinating ReagentAldrich has recently added fluoro-N,N,N,N-tetramethylformamidinium hexafluorophosphate(TFFH) to our library of fluorinating agents. TFFH is an excellent reagent for peptidecoupling and the in situ formation of acyl fluoridesstable and powerful acylating agentsused in both solution- and solid-phase peptide synthesis, including the coupling of hinderedamino acids.1 In addition, TFFH is a useful reagent for the rapid and mild synthesis ofisothiocyanates from primary amines and carbon disulfide.2

Licensed from Perseptive Biosystems.

52,033-0 Fluoro-N,N,N,N-tetramethylformamidinium hexafluorophosphate (TFFH), 97% . . . . . . 1g; 5g

References: (1) Carpino, L.A.; El-Faham, A. J. Am. Chem. Soc. 1995, 117, 5401. (2) Boas, U. et al. Synth. Commun. 1998, 28, 1223.

New Fluorinating Reagent

N N

F

PF6


19/40

About the Authors

Dr. Andrew Abell was born in 1960 inAdelaide, South Australia. He obtained a

Bachelor of Science with First Class Honoursin Organic Chemistry from the University ofAdelaide in 1982. Dr. Abell received hisPh.D. from the same university in 1986 work-ing with Dr. Ralph Massy-Westropp onaspects of terpenoid chemistry. Two yearswere then spent working as a postdoctoralfellow with Professor Sir Alan Battersby at theUniversity of Cambridge, Cambridge, UK. In1987, he took a position as a lecturer inchemistry at the University of Canterbury,where he is currently employed as a senior

lecturer. Dr. Abell was awarded the NewZealand Institute of Chemistry EasterfieldMedal in 1995 and a Senior Fulbright

Fellowship in 1994, which was spent workingat SmithKline Beecham Pharmaceuticals,King of Prussia, USA. He is also a recentrecipient of a Royal Society of ChemistryTravel award for international authors. Dr.Abell has authored more than sixty publica-tions and trained 15 Ph.D. students and 6 M.S.students. His current research interestsinclude the design, synthesis, and biologicalproperties of peptidomimetics.

Dr. Andrew Phillips was born in 1970 inKawerau, New Zealand. In 1995, he obtained

a Bachelor of Science with First ClassHonours in Biochemistry from the Universityof Canterbury. The following year, he began a

Ph.D. research program with Andrew Abell onthe possible applications of ring-closingmetathesis to the synthesis of the taxanediterpenoids. He is presently a postdoctoralassociate with Professor Peter Wipf at theUniversity of Pittsburgh. His current researchinterests include the applications of transitionmetals in organic synthesis, the synthesis ofnatural products, and the applications oforganic synthesis to the investigation ofbiological processes such as cell signaling.

Vol. 32, No. 3, 1999 89

methylene polystyrene1% DVB

N

NHBOC

O

12 mol% 3

CH2Cl2, reflux, 2h

ON

NHBOC

OO

+

BnBn

37%

OO

1-octene

N

NHBOC

O5 mol% 3

DCE, reflux, 16h16%

N

NHBOC

O

CO2Me

Ph

H

H

CO2Me

Ph

N to C

N to C

O

N

O

R2

R1

O

N

O R1

R2

Wang resin

3 mol% 3, PhH

reflux, 18h

R1, R2 = H, 90%

R1 = Pri, R2 = Me, 96%

O

N

O R1

NH

R2

O

O

H

N Val NH

Tyr

O

Pro NH

Gly

O

Fmoc

N ValNH

Tyr

O

ProNH

Gly

O

Fmoc

50 mol% 3, CH2Cl240C, 22h, 65%

C to C'''

H

H

eq 60

eq 61

eq 62

eq 63


20/4090 Vol. 32, No. 3, 1999

(1) a crystallization chamber where crystal growthoccurs; (2) curved tubes, which serve as gatesthat prevent the free flow of solutions into thecrystallization chamber (as a result of the densitydifference between the two solutions and the puresolvent); and (3) side arms, which serve as reser-voirs for the reacting solutions. Best results are

obtained by using a seed crystal of the complexas follows: A small crystal seed is placed into thecrystallization chamber. This chamber and thecurved tubes are then filled with the pure solventused in the reaction. The pure solvent serves as abuffer layer preventing the immediate mixing ofthe two reacting solutions. Separately preparedsolutions of reactants A and B are carefully andsimultaneously poured into the correspondingside arms. A smooth addition can be accom-plished with the aid of disposable pipettes. Theside arms are closed with rubber or plasticstoppers and the system is kept undisturbed forthe period of time required for the complete

mixing of the two components.Thus, mixing of the

solutions occurs slowly in the reaction chamberonly due to diffusion.

We used this system to prepare crystals ofseveral complexes of organic hosts with guani-dinium and alkylguanidinium salts.4 The crystalsgrown in our apparatus, even without crystal seed,were about ten times larger in the edge dimen-sions (0.3 mm the smallest edge) than thecrystals obtained in the vertical tube by layering

the reacting solutions. For the apparatus withinner diameters of side arms and curved tubes of12 mm and 4 mm, respectively, and a total volumeof 7 mL, the whole crystal growing process takesabout 2 to 3 weeks. After crystal growth hasstopped, the stoppers are removed, and thecrystals collected by pouring the solution into abeaker. If some crystals remain attached to theglass surface, they can be detached by gentletapping with a piece of wood.

Our design can be very useful for growingcrystals by diffusion of reacting solutions.Compared to the simple layering technique, it pro-vides several advanced features such as smooth

and independent-of-density gradient diffusion of

the solutions leading to the formation of largercrystals, and the ability to use a crystal seed,since it can be simply placed into the crystalliza-tion chamber without special attachmenttechniques. The crystal growth and the major dif-fusion interface occur in the same chamberproviding the shortest path between regions oflocal supersaturation and crystallization, thusminimizing the undesired spontaneous formation

of many other nucleation sites.

References: (1) Fischinger, A.J.A Flotation Method for GrowingLarge Single Crystals. J.Chem. Ed. 1969, 46, 486. (2) Jones,P.G. Crystal Growing. Chem. Br. 1981, 17, 222. (3) Suib, S.L.Crystal Growth in Gels. J.Chem.Ed. 1985, 62, 81. (4) Bell, T.W.;Khasanov, A.B.; Drew, M.G.B.; Filikov, A.; James, T.L. A Small-Molecule Guanidinium Receptor: The Arginine Cork. Angew.Chem., Int. Ed. Engl. 1999, 38, 2543.

Alisher B. Khasanov, Graduate StudentDepartment of Chemistry, MS 216University of NevadaReno, NV 89557-0020E-mail: [email protected]

Editor's Note: Following publication of the labnote, Maintaining a Constant Water Level in anOpen, Warm-Water Bath(Aldrichimica Acta1999,32(2), 34), we received other suggestions onaccomplishing the same thing. Chester J. Opalkaof Albany Molecular Research, Inc. wrote torecommend the use of paraffin wax (e.g.,32,720-4), which, he states, is easier to separatefrom the water after the bath has cooled. JimBrien of Aldrich Techware recommends the use ofpolypropylene floating balls (Z37,593-4). Each ofthese three ideas, as well as the one recom-mending the use of polystyrene chips (Stronski,

R.E. J.Chem. Educ. 1967, 44, 767), has its meritsand drawbacks; for example the paraffin wax can-not be used if the bath temperature is lower than5680 C. However, each is a lot simpler to carry

out than some of the more complicated setupsand devices recommended elsewhere in theliterature.

Lab Notes (continued from page 74).

The Inauguration of the Herbert C. Brown Center for Borane ResearchMarch 31, 2000

~Invited Speakers~

For more information, please contact Professor P. V. Ramachandran [email protected].

Figure 1

Herbert C. Brown (Purdue) Bakthan Singaram (UCSC, CA)R. W. Hoffmann (Marburg) Kung K. Wang (WVU, Morgantown)Don Matteson (WSU, Pullman) Hisashi Yamamoto (Nagoya)

Ian Paterson (Cambridge) Marek Zaidllewicz (NCU, Torun)Nicos Petasis (USC, CA)
mailto:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]


21/40

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22/4092 Vol. 32, No. 3, 1999

Purdue University

Saturday, April 1, 2000

Modern Trends in Organic ChemistryRonald BreslowThe Chelate Effect in Binding, Catalysis, and Chemotherapy

Toyoki Kunitake

Molecular Imprinting in Ultrathin Metal Oxide Films

Akira Suzuki

Cross-Coupling Reactions of Organoboron Compounds with Organic Electrophiles

Barry Trost

On Designing Chiral Space for Molecular Recognition in an Asymmetric CatalyticReaction

For more information, please contact Professor P. V. Ramachandran at

[email protected]

alHerbertC.BrownLectures

Ye ar 20 00 AC S Award Re ci pi en tsYe ar 20 00 AC S Awar d Recip ie nt s

Aldrich, a proud sponsor of three separate ACS awards, congratulates the followingyear 2000 recipients for their outstanding contributions to chemistry.

AC S Aw ar d for Cr eat iv e Wo rk inAC S Aw ar d fo r Cr ea tiv e Wo rk in

Synthetic Organic ChemistrySynthetic Organic Chemistry

Professor Dennis P. CurranUniversity of Pittsburgh

Professor Curran has been selected to receivethis award in recognition of his lasting impactand outstanding pioneering contributions tosuch wide-ranging research areas as syntheticradical chemistry, natural product synthesis,stereoselective organic reactions, fluorous

chemistry, and others. To paraphrase a recentstatement by an admiring colleague, Dennis isone of the most prominent synthetic organicchemists not only in the US, but also in therest of the world. His loyalty to the Universityof Pittsburgh has given its chemistrydepartment a top ranking.

AC S Aw ar d in In or gan ic Ch emi st ryAC S Aw ar d in In or ga nic Ch emi st ry

Dr. Edward I. StiefelExxon Research and Engineering Co.

This award is a fitting tribute to Dr. Stiefelspioneering research and outstanding achieve-ments in Inorganic Chemistry. In the words of anenthusiastic colleague, Ed has made "significantand original contributions to Co-ordinationChemistry, Bioinorganic Chemistry, InorganicMaterials, and Catalysis", and is regarded as a"leading international authority" in these areas.Most noteworthy are his studies of transitionmetal sulfide complexes that have importantbiological and industrial applications, his synthe-sis of the first isolated metal complexes of theanti-Parkinsonism drugL-DOPA, and his discoveryand development of the remarkable "inducedinternal electron transfer reactions" in which theaddition of an external oxidant leads to reductionof the metal center.

Herbert C. Brown Award for CreativeHerbert C. Brown Award for Creative

Research in Synthetic MethodsResearch in Synthetic Methods

Professor Samuel J. DanishefskySloanKettering Institute for Cancer

Research and Columbia University

One of the leading synthetic organic chemistsof the twentieth century, ProfessorDanishefsky was chosen for this award on thebasis of his seminal contributions to the twinareas of synthetic methodology and total

synthesis of complex molecules of biologicalsignificance. Notable examples of the formerinclude the glycal assembly method for thesynthesis of oligosaccharides and glycoconju-gates, the DielsAlder reaction of siloxydienes,and Lewis acid catalyzed cyclocondensationreactions. His accomplishments in the latterarea include the total synthesis of paclitaxel,camptothecin, coriolin, and pancratistatin, toname only a few.

Congratulations to each and all!Congratulations to each and all!


23/40

Outline

1. Introduction

2. Synthesis of (R)-4-Diphenylmethyl-2-oxazolidinone3. Alkylation Reactions

3.1. Synthesis of-Amino Acids3.2. Radical Allylations

4. Aldol Reactions4.1. Synthesis of Butyrolactone Natural

Products4.2. Synthesis of Paraconic Acid Natural

Products4.3. Synthesis of Amino Sugars

5. Conjugate Additions5.1. Radical Conjugate Additions5.2. Synthesis of Paraconic Acid Natural

Products5.3. Conjugate Addition of Copper

Reagents5.4. Synthesis of Peperomins

6. DielsAlder Reactions7. Conclusions8. Acknowledgements9. References and Notes

1. Introduction

Chiral auxiliaries have played a key role inthe development of efficient and elegantroutes to a variety of enantiomerically purecompounds (Figure 1).1 Academics as well asthe chemical industry have made extensive useof chiral auxiliaries in the synthesis of targetmolecules. The more commonly usedauxiliaries are derived from either amino acidsor terpenes. The availability of these natural-ly occurring materials in both enantiomericforms makes them ideal starting materials.Oxazolidinones, readily available from chiralamino alcohols, have been the more popularauxiliaries.2 Pioneering work from ProfessorDavid Evans's group has firmly established

the utility of oxazolidinones as superiorauxiliaries for a variety of bond constructions.3

Compounds 25 are generally successful

in providing high levels of selectivity in alarge number of transformations (alkylation,aldol, DielsAlder, etc.). However, there arereactions in which they do not provideadequate selectivity. A notable transformationin this category is the conjugate additionreaction. While working on the preparation ofunnatural amino acids from serine, we cameupon an oxazolidinone which, we thought,was worth looking into as a chiral auxiliary.Our hypothesis was that, by placing a largegroup at the oxazolidinone 4 position, whichextends its bulk to the carbon in enoates,there was the potential for achieving a higher

selectivity in transformations in which thetraditional chiral auxiliaries did not performsatisfactorily. This account describes thepreparation and utilization of a new oxazo-lidinone auxiliary, 1, that is derived fromdiphenylalaninol. The chemistry describedhere is work from our laboratory only.Wherever possible, the advantages anddisadvantages of the new auxiliary and itsefficiency, as compared to that of thetraditional compounds, will be highlighted.

2. Synthesis of (R)-4-Diphenyl-

methyl-2-oxazolidinone

Chiral oxazolidinones can be readilyprepared from the corresponding aminoalcohols. However, there are only a few enan-tioselective routes to the parent amino acid,diphenylalanine,4 and most of these requireseveral steps. We have prepared 1 in threesteps from serine methyl ester hydrochloride(Scheme 1). Treatment of12 with triphosgeneand triethylamine provides oxazolidinone 13in 95% yield. The desired aryl groups areintroduced by reaction of13 with phenylmag-nesium bromide to furnish tertiary alcohol 14,

which is then deoxygenated with Na/NH3.The synthesis of 1 {mp: 135137 C,[]20D = +37.1 (c = 1.0, CH2Cl2)} is amenableto scaleup, and we have typically prepared 1 in2550-g quantities.5 Having reasonablequantities of the auxiliary on hand, we set outto evaluate its utility by examining three majortypes of reactions: alkylation, aldol condensa-tion, and conjugate addition.

3. Alkylation Reactions

The synthetic utility of oxazolidinone 1 instereoselective alkylations was explored first

(eq 1).6 Thus, treatment of157 with NaHMDSin THF at -78 C produced an enolate, which,upon quenching with reactive alkyl bromides,furnished the alkylated products 16 inmoderate-to-good yields and excellentdiastereofacial selectivity. The stereochemicalcourse of these reactions was established forone of the examples by LiOH/H2O2 hydrolysisof 16 (R = CH2Ph) to afford a knowncarboxylic acid. In comparison, alkylationwith benzyl bromide of the lithium enolatederived from the N-propionyl derivative of2proceeds in 92% yield and >99% de.8

Are Two Phenyls Better than One?

Synthesis and Applications of

(R)-4-Diphenylmethyl-2-oxazolidinone

Mukund P. Sibi

Department of Chemistry

North Dakota State University

Fargo, ND 58105, USA

E-mail: [email protected]

Vol. 32, No. 3, 1999 93


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3.1.Synthesis of-Amino Acids

Naturally occurring -amino acids arecompounds with an interesting pharmaco-logical profile.9 They are also found ascomponents in a wide variety of biologicallyactive compounds,10 including peptides suchas pepstatin.11 -Amino acids are also usefulprecursors in the synthesis of -lactams.12

Recently, -substituted -amino acids havereceived greater scrutiny, since they areimportant segments of bioactive moleculessuch as paclitaxel.13

We have evaluated the synthesis of-amino acids in the context of a generalmethodology involving functionalization oflinear dicarboxylic acid derivatives in aregio- and stereoselective manner. Thesuccinate unit is an ideal fragment for thesynthesis of a variety of natural products ifsubstituents can be introduced regio- andstereoselectively onto the carbon framework.14

Further selective conversion of one of thecarboxyl groups to an amino functionality bya Curtius rearrangement provides access to-amino acids. Alternatively, the lactoniza-tion strategy provides butyrolactone naturalproducts (vide infra).

Scheme 2 illustrates our approach to-amino acids wherein the starting material isa readily available succinate, 17. The twocarboxyl groups are differentiated by formingan ester at one end and attaching a chiralauxiliary to the other. With the two endsdifferentiated, the first step is a regio- andstereoselective alkylation at the carbon tothe imide functionality to furnish 18. Thesecond step involves the selective removal ofeither the imide or the ester functionality; thisis then followed by a Curtius rearrangement ofthe free carboxyl group with retention ofstereochemistry (if applicable). Thus, inter-mediate 18 serves as a common precursor fortwo different -amino acids, 19 and 20.15

Our methodology began with the attach-ment16 of the mono-tert-butyl succinate17 tooxazolidinone 1 (Scheme 3). Treatment of21with one equivalent of NaHMDS, followed byquenching with a reactive alkyl bromide,furnished 22 in good yield and diastereo-selectivity.18 In this reaction step, temperatureand counterion played an important role in thegeneration of the enolate. When the reactionmixtures were warmed to above -48 C, aftersodium enolate generation, cleavage of thechiral auxiliary was observed. The regioselec-tivity observed for the enolate generated from21 may be attributed to the higher acidity ofthe hydrogens to the imide as comparedwith those to the ester group.19 The next stepinvolved the selective hydrolysis of the imidefunctionality. This was accomplished bytreating 22 with LiOH/H2O2 to furnish 23.20

The key step in our methodology was the use

94 Vol. 32, No. 3, 1999

NHO

O

Ph

Ph

NHO

O

R

NHO

O

MePh

2, R = CH(CH3)2

3, R = CH2Ph

4, R = Ph

SO O

NHOH

Ph

N

Me2N

t-BuO

NOMe

NH2

1 5 6

7 8 11

NH

HN

R

9

O

O

RO2C CO2R

HO OH

10

Figure 1. Some Commonly Used Chiral Auxiliaries.

HONH3Cl

O

OCH3NHO

O

O

OCH3

NHO

O

12 13 14

OH

NHO

O

1

Triphosgene

CH2Cl2, Et3N, -78 C

95%

5 eq PhMgBr

80%

Na, NH3

80%

Scheme 1. Synthesis of the Chiral Auxiliary.

1. NaHMDS

2. RBr, THF-78 to 0 C

16

NO

O

R

O

Me

Ph

Ph

NO

O O

Ph

Ph

R Yield, % de, %

PhCH2

t-BuOCOCH2

C3H5

81

86

61

>98

>99

>9915

eq 1

XcOR

O

O

XcOR

O

OR1

PHN OR

OR1

NHP

R1

O

RO17 18

19

20Xc = Chiral auxiliary; P = Protecting group

Scheme 2. Outline for the Synthesis of -Amino Acids.


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of the Curtius rearrangement to effect theone-pot conversion of the carboxylic acidgroup to the protected amino group withretention of stereochemistry (23 to 24).21,22

Thus, the synthesis of -amino acids wasaccomplished in four steps in good overallyields and high optical purities.

Intermediate 22 also served as a usefulprecursor for the synthesis of isomeric

-amino acids (Scheme 4). Selective depro-tection of the tert-butyl ester functionality wasachieved in high yields using trifluoroaceticacid. Curtius rearrangement followed bycleavage of the imide provided the isomeric-amino acids in good yields (26 27).

3.2.Radical Allylations

The stereoselective introduction offunctional groups into acyclic systems by freeradical methods is often a challenge.23 As has

been amply demonstrated in the literature, aswell as by the chemistry illustrated above,oxazolidinones provide high stereoselectivi-ties in enolate alkylations. We were intriguedby the potential of oxazolidinones in radicalchemistry, and wondered whether they wouldbe equally suited for the introduction of theallyl group under a radical chain process.However, the use of oxazol id inone

auxiliaries24 in radical reactions has beenhampered by the limited rotamer controlthat is available in the absence of Lewis acidadditives.25 Based on literature precedents forDielsAlder reactions using oxazolidinoneauxiliaries, we surmised that a proper combin-ation of a chelating Lewis acid and the Rgroup in the chiral auxiliary would allow forhighly diastereoselective radical reactions.This would require that the radical react froma single rotamer (28) out of several possiblerotamers (2831) (Figure 2).

Radical allylations using several mono-and multidentate Lewis acids were tested(Table 1).26 As expected, poor selectivity wasobserved with single-point-binding Lewisacids, such as BF3OEt2. Of the Lewis acidsexamined, scandium and magnesium reagentsresulted in the highest selectivities.27 Thesense of stereoinduction in the Lewis acidmediated radical allylation was the same as

that of the enolate allylation, with the tworeactions providing comparable diastereo-selectivities.

The effect of the substituent at C-4 of theoxazolidinone ring was also examined. Theresults shown in Table 1 indicate that

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Aldrichimica Acta Vol 32 N°3