the growing synthetic utility of the weinreb amide...dehyde group. these two aspects have been...

REVIEW 3707

The Growing Synthetic Utility of the Weinreb AmideThe Growing Synthetic Utility of the Weinreb AmideSivaraman Balasubramaniam, Indrapal Singh Aidhen*Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, India Fax +91(44)22574202; E-mail: [email protected] 8 April 2008; revised 16 June 2008Dedicated to Professor M. S. Wadia

SYNTHESIS 2008, No. 23, pp 3707–3738xx.xx.2008Advanced online publication: 14.11.2008DOI: 10.1055/s-0028-1083226; Art ID: E22008SS© Georg Thieme Verlag Stuttgart · New York

Abstract: N-Methoxy-N-methylamide, popularly addressed as theWeinreb amide, has surfaced as an amide with a difference. Thisamide has served as an excellent acylating agent for organolithiumor organomagnesium reagents and as a robust equivalent for an al-dehyde group. These two aspects have been exploited exhaustivelyin various synthetic endeavors. This review presents the growingsynthetic utility of the Weinreb amide not only in academic circles,but also its popular use on kilogram scale by various pharmaceuticalindustries across the globe.

1 Introduction1.1 Limitations2 Methods for Preparation3 Applications3.1 Use in Heterocyclic Chemistry3.2 Use in Total Synthesis3.3 Use in Industry on Kilogram Scale 3.4 Synthetic Equivalents and Building Blocks 4 Miscellaneous5 Conclusion

Key words: Weinreb amide, Grignard addition, ketones, alde-hydes, acylation

1 Introduction

N-Methoxy-N-methylamides (1; Scheme 1), now popu-larly called Weinreb amides (WAs) after their discoverer,1

have reached a center stage for clean and effective acyla-tions of organolithium and organomagnesium reagents.The emerging interest and confidence in the use of thisfunctionality in the synthetic organic chemistry domain isclearly substantiated by the surge in the number of publi-cations over recent years. A quick search on Scifinder®

under the phrase ‘Weinreb amide’ reflects this fact(Figure 1). Our continued interest since the late 1990s to-wards developing small building blocks based on the WAfunctionality for use in organic synthesis and its growinguse on kilogram scale by industry is the trigger for this re-view. Given the recent rise in the number of publicationsthat invoke the use of WA functionality, the earlier re-views by Sibi,2a Hoffmann2b and by us,2c that foresaw thepotential and promise then, despite the field’s infancy,were appropriate, succinct and justified. Another reviewby Khlestkin3 discussed, in general, the advances of theapplication of N,O-dialkylhydroxylamines in organic

chemistry, and thereby did survey some part of Weinrebamide chemistry, because N,O-dimethylhydroxylamine(DMHA; also named N-methoxy-N-methylamine) is usedfor installing the WA functionality. The present reviewpredominantly covers the literature published during theperiod of 2000 to 2008. Occasional reference to the workpreceding this period is included only for the sake of rele-vance and completeness of discussion.

Figure 1 The growing use of WAs based on a Scifinder® literaturesearch

The successful acylation by a variety of organolithiumand organomagnesium reagents or reductions by lithiumaluminum hydride or diisobutylaluminum hydride is dueto the putative and stable tetrahedral intermediate4 2 or 3formed upon addition of the first equivalent of the organo-metallic species or reducing agent (Scheme 1). This sta-bility precludes the collapse to a ketone or aldehyde underthe reaction conditions and thus prevents the formationand subsequent possibility of addition to the ketone or al-dehyde.

The aqueous workup not only facilitates the collapse oftetrahedral intermediate 2 or 3 to furnish the respectiveketone or aldehyde, but also ensures simultaneous

Scheme 1

R1 N

O

OMe

Me

R1 N

OOMe

Me

M

R2

R1 R2

O

R1 = alkyl, alkenyl, alkynyl aryl or heteroaryl[plain or functionalized]

M = Li, Mg1 2

R1 N

OOMe

Me

M

H

R1 H

O

LAH orDIBAL-H

3

or Vitride®

M = Li, Al

R2 = alkyl, alkenyl, alkynyl aryl or heteroaryl

R2M

3708 S. Balasubramaniam, I. S. Aidhen REVIEW

Synthesis 2008, No. 23, 3707–3738 © Thieme Stuttgart · New York

quenching of all the excess equivalents of organometallicspecies or reducing agent, thereby explaining why noover-addition product is formed despite the use of a largeexcess of reagents. Recent investigations into themechanism5 of acylating the phenylacetylide with WA,which clearly indicate no detectable IR stretching fre-quency for carbonyl until the reaction is quenched, sub-stantiate this rationale.

The growing synthetic utility of the WA stems from fourattractive features associated with this functionality. Theyare summarized as the four S’s: (i) Simplicity associatedwith its preparation by in situ activation of the carboxylgroup or through its stable ester derivative, even in a high-ly functionalized molecule; (ii) the Success it has met asan effective acylating agent for organometallics, facilitat-ing convenient access to highly functionalized ketones,particularly in the total synthesis of complex natural prod-ucts; (iii) Scale-up through which these amides have beenprepared and routinely used; and finally, (iv) the Stabilityand hence easy storability. Their facile reduction to alde-hydes with hydride reducing agents, coupled with all theabove attractive features makes them serve as an excellentprecursor to sensitive aldehyde in the masked form. A fewexamples from the literature, presented in Scheme 2,6

demonstrate these facts.

1.1 Limitations

Given the fact that it is the N-methoxyl-N-methyl part ofthe WA which makes it different from other amides, anyperturbation in it would result in the loss of its signifi-

cance. With certain inherent structural features embeddedin the compound containing the WA, two observationshave been mentioned as being the only apparentlimitations7 associated with WA functionality(Scheme 3). Gratifyingly, one of these has been recentlyaddressed with a simple and convenient solution. The firstobservation was made by Graham and Scholz.7a The WA4, when treated with lithium diisopropylamide at –78 °C,resulted in demethoxylation and formation of 5 as the ma-jor product (73%). This decomposition, with concomitantrelease of formaldehyde, was shown to take place throughan E2 elimination mechanism as depicted. A similar ob-servation was made when 6 was added to 7a with a viewto effect Michael addition; it resulted only in the forma-tion of 7b.7b

Such observation of demethoxylation with the release offormaldehyde is not restricted to the nitrogen-centeredbase alone. Carbon-centered nucleophiles, such as organ-olithiums which normally undergo clean acylation withWA, fail to add to the carbonyl carbon at an appreciablerate, for steric reasons, and instead act as a base and effectdemethoxylation. The addition of octyllithium to WA 8during the synthesis of isoavenaciolide serves to illustratethe point. Despite several changes in the reaction condi-tions (solvent, temperature and number of equivalents ofoctyllithium), the desired ketone 9a was always obtainedin 5–24% yield, whereas the demethoxylated compound9b remained the major product (36–63%). It was reasonedthat the gem-dimethylallyl moiety at the a-position in WA8, being sterically more demanding, impeded the attack ofoctyllithium and hence diverted its course to that of an in-

Sivaraman Balasubrama-niam (1981) was born inChennai, India and receivedhis B.Sc. and M.Sc. degreesfrom Loyola College

Chennai (2003). In 2005, hejoined Professor IndrapalSingh Aidhen’s group at IITMadras. His Ph.D. researchfocuses on the development

of new synthetic equivalentsbased on the Weinreb amidefunctionality, and their usesin synthetic organic chemis-try.

Indrapal Singh Aidhen(1960) was born in Pune,India and received his Ph.D.degree (1990) from theDepartment of Chemistry,University of Pune under theguidance of Professor N. S.Narasimhan. He undertookhis first postdoctoral studiesat the University of Califor-nia, Santa Cruz, with Pro-fessor Rebecca Braslau. Hewas awarded an AlexanderVon Humboldt fellowship(1993) to work with Profes-

sor R. R. Schmidt at Univer-sität Konstanz, Germany onthe synthesis of the chal-lenging targets, C-glyco-sides of neuraminic acid. In1995, he was appointed asan Assistant Professor ofOrganic Chemistry at theDepartment of Chemistry,IIT-Madras, India and iscurrently a Full Professorthere. In 2003, he wasawarded a JSPS InvitationFellowship to work in thelaboratories of Professor

Shoichi Kusumoto at theUniversity of Osaka, Japanon the synthesis of immunoadjuvants. Besides the syn-thesis of important mole-cules, his research interestsinclude both the develop-ment of new syntheticequivalents based on theWeinreb amide functional-ity and synthesis of biologi-cally important C-glyco-sides in particular.

Biographical Sketches

REVIEW The Growing Synthetic Utility of the Weinreb Amide 3709


evitable base for demethoxylation.7c The successful addi-tion of octyllithium in high yield (85%), when the a-position had an allyl moiety, supported the author’s argu-ment. Intentional reductive cleavage of the N–O bond inthe WA at room temperature, leading to demethoxylation,has been achieved using lithium powder in presence of4,4¢-di(tert-butyl)biphenyl as a catalyst in 10 mol%.7d

An elegant solution to this problem of demethoxylationhas been provided by Genet and Phansavath with the ad-vent of N-(tert-butoxy)-N-methylamides.7e For the conve-nient synthesis of these amides, the authors developed apractical multi-gram scale procedure for access to therequisite amine, N-methyl-O-(tert-butyl)hydroxylamine,

as its hydrochloride salt 10 (Scheme 4). The amide 11, ob-tained using this amine 10, behaved identically to WA inits reactivity towards organolithiums and organomagne-siums, as well as diisobutylaluminum hydride. A clean re-action ensued with octyllithium and furnished the desiredketone 9a in 73% isolated yield. With the replacement ofN-methoxy group in 8 with N-(tert-butoxy) as in 11, theelimination possibility was completely excluded andhence only nucleophilic addition occurred, however slowthis addition may have been because of steric reasons.

Keck independently reported the formation of demethox-ylated product 12 and rearranged product 12a, when WA13 was exposed to tert-butyldimethylsilyl triflate in thepresence of triethylamine or collidine as a base7f

(Figure 2). The formation of these products has been ra-

Scheme 2 Representative examples illustrating the four S’s [Simplicity, Success in acylation, Scale, Stability/Storability]

OMeN

MeO O O O

TMS TMS TBS

O

O O O OTMS TMS TBS

O

Br

t-BuLi, Et2O–78 °C, 87%

OH

OBocHN

ClCOOEtDMHA⋅HCl

N

OBocHN

OMe

MeEt3N, 91% H

OBocHN

Vitride®

100%

33 kg

Me3Si

O OTBSO

Me3Si

OTBSO O

NOMe

Me

TBS(MeO)MeNAl(Cl)Me

TBSOTf, 2,6-lutidine

86%

O

OO

O

OTBS

O O

O

OO

HO

O

BnO

OO

OTBS

HH

H

H

SEM

DMHA⋅HClEDCI, HOBt

ref. 6a

ref. 6b

ref. 6c

ref. 6d

N

OMeO

Me

Scheme 3

ON

MeO

O

Me

HNH

MeO

O

Me

NOMe

Me

O

7a

Ph N

Ph

Li

Li NH(i-Pr)2

BnOZ

OOH

8: Z = N(OMe)Me

4 5

6

7b

NH

Me

O

BnOZ

OOH

9a: Z = (CH2)7Me9b: Z = NHMe

n-C8H17Li

THF

Scheme 4

BnON

OOHO

Me

BnO(CH2)7Me

OOH

HN

OH

Me

H

ClN

OH

Me

Cbz

NO

Me

CbzHNO

Me

HCl

9a11

benzylchloroformate

NaHCO3, CH2Cl2

t-BuOAcHClO4

H2, Pd/C

MeOH

n-C8H17Li

THF, 72%

10



tionalized through a retro-ene reaction on the initiallyformed enol derivative 14 resulting in the formation of 15and monomeric formaldehyde. Quenching of the interme-diate 15 during aqueous workup would explain the forma-tion of 12. However the formation of product 12anecessitates the reaction of 15 at nitrogen with the TBS-activated formaldehyde, before aqueous workup. The ra-tio of these products was found to be a function of stoichi-ometry of tert-butyldimethylsilyl triflate and the baseused. Excess triethylamine consumed the liberated form-aldehyde by reacting with it or with TBS-activated form-aldehyde; hence the exclusive formation of 12 observedwith triethylamine as base. Collidine fails to do so andhence allows the reaction between 15 and TBS-activatedformaldehyde; this explains the formation of the rear-ranged product 12a when collidine is used as a base.

Figure 2 Role of the base in explaining the unusual reactivity ofWA

2 Methods for Preparation

These amides have been prepared from either the acid orits derivatives (Scheme 5). The amine DMHA is commer-cially available in the form of its hydrochloride salt. Thehydrochloride salt 16 can also be conveniently preparedon large scale starting from the inexpensive hydroxyl-amine hydrochloride (17; Scheme 6).8 In most of the syn-thetic operations, largely because of convenience, theamine is generated in situ, with the help of one equivalentof a base. Occasional reports of preparing free amineDMHA as a distillable liquid (bp 47–50 °C) from the hy-drochloride salt 16 do exist.9 Among the various methods,the direct conversion of the acid into the WA is the mostprominent and attractive, as it obviates the need to firstconvert the acid into one of its derivatives. This directconversion relies on in situ activation of the carboxyl car-bon for attack by DMHA.

To this end, several acid activating agents have been suc-cessful.10,11 These include DCC,12 DEPC,13 HOBT/DCC,14 HOBT/EDCI,15 BOP·PF6,

16 CDI,17 alkyl chloro-formates,18 CBr4/TPP,19 2-halo-1-alkylpyridinium salts,20

py·BOP,21 EDCI,22 PPA.23 During recent times, develop-ment of new methods that are less expensive, operational-

ly simple and also allow easy removal of excess reagentsfrom the products have been the focus. New additions tothe list of reagents24 for carboxyl activation are (2-pyri-dine-N-oxide) disulfide with tri(n-butyl)phosphine,25

CDMT,26 TOTT,27 HOTT,27 TODT,27 HODT,27 CPMA,28

and DMT-MM29 (Figure 3).

The reagents N-methoxy-N-methylcarbamoyl chloride1830 and N-methoxy-N-methylcarbamoylimidazolium io-dide 1931 (Figure 3) are distinct and interesting because oftheir dual role. Along with their activation of the carboxylcarbon, they also provide the DMHA moiety for the con-version of the acid into the WA. Reagent 18 is a colorlessdistillable liquid (bp 67–73 °C/8.0 mm Hg) readily pre-pared by treating DMHA hydrochloride with bis(trichlo-romethyl) carbonate in presence of two equivalents oftriethylamine. Sequential treatment of DMHA with com-mercially available N,N¢-carbonyldiimidazole (CDI) and

PhN

OOMe

Me

PhNH

O

Me

PhN

O

MeOTBS

PhN

OTBS

Me

OH

PhN

OTBS

MeH H

O

H H

O TBS OTf

12 12a

13

14

15

Scheme 5 Various substrates from which the WA is prepared

R1 OH

O

R1 N

OOMe

Me

R1 X

O

X = F, Cl, BrX = OMe, OEtX = OCOR2

R1 N

O

O

O

R1 H

O

Scheme 6

NH3Cl NOH

O

EtOHO

HN

OMeO

EtOMe

H2NOMe

Me

Cl

17

16

HNOMe

MeDMHA

(liquid; bp 47–50 °C)

EtO2CCl

NaOH

Me2SO4 NaOH

HCl16

ref. 9

Figure 3 Various acid activating agents

N

N

N

MeO N

Me

O

OMe

N

N

N

OMe

ClMeO

CDMT

NMe

Me

Cl

S MeCl

CPMA

N S

NMe2

ONMe2

X

N S

O

X

N

N

Me

Me

X = BF4 (TOTT)X = PF6 (HOTT)

X = BF4 (TODT)X = PF6 (HODT)

Me

NMeO

Cl

O

MeN

MeON

O

N Me

I

DMT-MM

1819

NN

NSMe

O O

BtMs



iodomethane furnishes 19 as a crystalline solid. Becauseof the N-methylation in the imidazole ring, these saltshave enhanced reactivity over the corresponding carbam-oylimidazoles. The salt, 19, is more readily handled than18, and its preparation also precludes the direct use ofphosgene or triphosgene.

With both these reagents 18 and 19, the conversion of theacid into the WA in the presence of triethylamine pro-ceeds through the mixed anhydride 20 (Scheme 7). In thecase of the former, the added DMAP results in theformation of acylpyridinium species 21 through attackon the activated carbon, whereas in the latter, the expelledN-methylimidazole during the first step furnishes acylimidazolium species 22. Both of these attacks concomi-tantly release carbon dioxide and free DMHA, attack ofthe released DMHA on the activated intermediates 21 and22 results in the formation of the WA.

Scheme 7

Besides the popular use of alkyl chloroformates for in situgeneration of mixed anhydride of carbonic acid whereinthe carbonyl groups differ electronically, use of othermixed anhydrides wherein the carbonyl groups differ ei-ther sterically or electronically have also been made.32 Tothis end, use of simple pivaloyl chloride,32a,b methane-sulfonyl chloride32c or 1- (methanesulfonyl)benzotriazole(BtMs)32d have been equally successful (Scheme 8). The

mixed anhydride 23 resulting from the use of pivaloylchoride is attacked by DMHA at –5 to 0 °C furnishing theWA 2432b in good yield. The attack of DMHA on the piv-aloyl carbonyl carbon in the mixed anhydride 23 is pre-cluded due to steric factors. Similarly, the mixedanhydride 25, formed during the reaction of carboxylicacid with 1.1 equivalents of methanesulfonyl chloride inthe presence of 3 equivalents of triethylamine, has also en-abled the formation of WA. This method has been veryuseful with hindered carboxylic acids, where several otherprocedures for the construction of WA 26 gave disap-pointing results. The possible byproduct, N-methoxy-N-methylmethanesulfonamide, formed by the attack ofDMHA on the sulfur in the mixed anhydride 25, isclaimed to be easily removed by gentle warming undervacuum overnight. The use of 1-(methanesulfonyl)benzo-triazole was developed by Katritzky.32d The mixed anhy-dride 27 formed by the reaction of carboxylic acid and 1-(methanesulfonyl)benzotriazole in presence of 1.0 equiv-alent of triethylamine is attacked by the liberated benzo-triazole (Bt) to give the activated acid as acyl-benzotriazoles 28. This, on refluxing with DMHA hydro-chloride in tetrahydrofuran with 2.2 equivalents of tri-ethylamine, afforded the WA 29. The benzotriazole by-product formed in the reaction can be easily removed andrecovered by washing with saturated sodium carbonatesolution.

Conversions into acid halides (Scheme 9) in situ or other-wise have been used to arrive at functionalized WAs.33

The use of bis(2-methoxyethyl)aminosulfur trifluoride 30(Deoxo-Fluor reagent) as a reagent for the conversion ofcarboxylic acids into the corresponding acid fluorides 31and subsequent reaction with DMHA have been made forthe synthesis of N-Boc a-amino WA 32.33a The acid fluor-ides react more like active esters than any other acid ha-lides, their stability is much higher than that of acidchlorides towards water and methanol, and they reactsmoothly with amines and anionic species.33b It is also ofnote that no significant loss of optical purity is observedduring the conversion of acid fluorides into amides. The

R N

OOMe

Me

R O NOMe

O O

Me

R N

O

N MeR N

O

NMe

Me

CO2

DMHA

20

2122

DMAP

75–99% 75–97%

N N Me

Scheme 8

OH

O

PMBO

O

O

PMBO

SO2MeN

O

PMBO

OMe

Me84%DMHAMsCl

S S

HO

OH

n

S S

H

n

O

O O

S SH

O

N

n OMe

Me

DMHA⋅HCl

Et3N, 80%

PivCl

25 26

R OH

O

R O

OSO2MeBtMs, THF

R Bt

O

R N

OOMe

MeR = aryl, heteroaryl functionalized

27 28 29

Et3N, reflux

DMHA⋅HCl THF

Et3N, reflux

n = 0, 1 23 n = 0, 1 24 n = 0, 1

Bt

71–89%

Et3N

Et3N



combination of effective fluorination properties, en-hanced safety features over those of DAST, and commer-cial availability will make this reagent a cost-effectivealternative for many uses. In fact, the successful activationwith Deoxo-Fluor and formation of WA have been ap-plied to the one-pot synthesis of aldehydes and ketones,specifically for long-chain fatty ketones.33c As an alterna-tive to the use of the expensive Deoxo-Fluor reagent,Sureshbabu et al. recently claimed the successful conver-sion of various N-Fmoc-protected amino acids into thecorresponding acid chlorides using conventional thionylchloride as the reagent.33d The N-Fmoc-protected aminoacid chlorides 33 react with DMHA, itself derived fromthe hydrochloride salt, in the presence of N-methylmor-pholine to yield the corresponding WA 34 in excellentyields.

Scheme 9

Esters and lactones (Scheme 10) have been converted intotheir WAs by the combined use of two to five equivalentsof trimethylaluminum, or dimethylaluminum chloride, ordiisobutylaluminum hydride, with DMHA hydrochlo-ride.34–37 As the aluminum reagents are air sensitive, theymust be used under strictly inert conditions. The use ofMe3Al in conjunction with DMHA hydrochloride for con-verting esters into WAs was originally developed byWeinreb34a himself, and the method continues to enjoy theconfidence of synthetic chemists in various endeavors. Itworks exceedingly well even in highly functionalized keyintermediates encountered during long synthetic schemesaimed at the total synthesis of challenging targets.34b–g Asan illustrative example, this combination has been usedfor converting a-hydroxy esters 35a or a-hydroxy-pro-tected esters 35b into the corresponding WAs 36a and36b.35a Although no rationale has been proposed, aryl es-ters furnished better yields of the corresponding WAs thando the alkyl esters.35b Shimizu et al. observed some unsat-isfactory results while attempting the conversion of steri-cally crowded lactones with the trimethylaluminum andDMHA hydrochloride combination. This led to the devel-opment of an alternative combination of dimethylalumi-num chloride and DMHA hydrochloride for the samepurpose.36a Substantial improvement in the yields and re-action time were observed with this combination. Thiscombination has been also used for converting esters intoWAs in various total syntheses of natural products.36b–e

The real species formed in situ by the combination of this

reagent is Cl2Al·NMe(OMe), with concomitant evolutionof two equivalents of methane. As the handling of di-isobutylaluminum hydride is comparatively easier thanthat of trimethylaluminum, the only report of using di-isobutylaluminum hydride as a source of aluminum re-agent along with DMHA or DMHA hydrochloride forconverting ester 37 or lactone 38 into their correspondingWA, in excellent yield,37 should hold significant promisefor further use in other synthetic endeavors.

Scheme 10

Although less used, the prominence of the DMHA hydro-chloride with aluminum reagent combination should notovershadow the importance of another procedure devel-oped by Williams et al.38a Interestingly, when trimethylalu-minum-based conversion of esters into amides failed,probably due to the steric crowding around the carbonylcarbon of the ester, it was observed that magnesium amide[Me(MeO)N-MgCl], obtained by reaction betweenDMHA hydrochloride and a non-nucleophilic organo-magnesium reagent such as isopropylmagnesium chlo-ride, had the necessary Lewis acidity and nucleophilicityto attack the carbonyl carbon of the ester. Using this ap-proach, ester 41 has been converted into WA 42.38b Thismethod has been used in a few other cases, also with goodsuccess.38c,d Akin to this method, an isolated report of(MeO)MeN-Sn-Cl being used for the conversion of estersinto WAs was disclosed by Roskamp.39 The species isconveniently prepared by treating Sn[N(TMS)2]2 withDMHA hydrochloride.

In contrast to the popular use of the ester functionality foreffecting conversion into the WA, use of imides, fuelledby the other objectives of the given synthetic scheme, hasalso been made, but only rarely. The oxazolidinone-basedimide scaffold, known for its synthetic potential, has beenconverted into WA by Reinhart,15 Sibi,40 Evans,41a,b

Martin,41c and Schreiber41d using a combination of Me3Aland DMHA hydrochloride in dichloromethane or tetrahy-drofuran at –20 to 0 °C. An illustrative example is theconversion of imide 43 into WA 44 (Scheme 11).

OH

O MeO

NO

Me

SF3

DIPEA,0 °C, CH2Cl2

73–92%

DMHAR

NHBocF

OR

NHBoc

N

OR

BocHN

OMe

Me

R = MeR = i-Bu

30

31 32

OH

OR

NHFmoc

SOCl2

76–90%

DMHA⋅HClCl

OR

NHBoc

N

OR

FmocHN

OMe

Me3433

NMMCH2Cl2

O ODIBAL-H, HNMe(OMe)

HO

O

NOMeMe

MeCOOBu-n

DIBAL-H,HNMe(OMe)

r.t., 2 h, 91%

THF, r.t., 0.5 h, 92%

N

H

COOMe

Boc

Br

N

H

CON(OMe)Me

Boc

Br

i-PrMgCl, DMHA⋅HCl

THF –20 to –10 °C

83%

37

38

39

40

41 42

POOP

O

OMe

POOP

O

NOMe

Me

35a: P = H 35b: P = protection

36a or 36b

Me3Al, DMHA⋅HCl

78%

N

O

OMe

Me



Scheme 11

Incorporation of WA functionality through the disconnec-tion shown in Scheme 12 was accomplished under palla-dium catalysis in cases where the residue R was alkenyl,alkynyl or aryl.42 N-Methoxy-N-methylcarbamoyl chlo-ride 18 has been used under Stille-type cross-couplingconditions with vinyl, alkynyl and aryl stannanes 45 forthe synthesis of WA 46 through the proposed disconnec-tion. The coupling was effected with catalytic amounts ofbis(triphenylphosphine)palladium(II) dichloride in tet-rahydrofuran at 60 °C and in yields ranging from 60 to90%. Another useful method based on the aforementioneddisconnection was developed by Buchwald.43a It compris-es the aminocarbonylation of aryl bromides with DMHAhydrochloride and carbon monoxide at atmospheric pres-sure under Heck coupling conditions [2 mol% Pd(OAc)2

with 2 mol% Xantphos as ligand in toluene at 100 °C].This method has been used for the coupling of ketone-,lactone-, lactam- and thiolactone-derived triflates 47a–dfor the synthesis of alicyclic 48a and heterocyclic WAs48b–d.43b

Scheme 12

The cyanohydrins available from aldehydes, in principleafter oxidation and subsequent treatment with DMHA,should afford the corresponding WAs through the inter-mediacy of the acyl cyanides.44 The successful formationof WA 49 based on this concept was observed during thesynthesis of phomactin D (Scheme 13).44a Very recently,Nemoto et al. developed an attractive procedure, based onthe intermediacy of an acyl cyanide, for converting aro-matic and aliphatic aldehydes into the corresponding a-si-

lyloxy WAs 50.44b The conversion proceeds through theaddition of carbanion 51a, generated from 51 under the re-action conditions, to the aldehyde, followed by silyl mi-gration, collapse to acyl cyanide 52 and attack of DMHA.For high yields and efficiency, for aromatic aldehydes,DMAP and acetonitrile were the best choices of base andsolvent, whereas for nonaromatic aldehydes, it was imida-zole and diethyl ether.

Scheme 13

3 Applications

The major application of WA functionality in organic syn-thesis centers on its facile conversion into ketones and al-dehydes. For the formation of ketones, invariably thenucleophilic species have been in the form of either orga-nolithium or organomagnesium reagents, and for the for-mation of aldehydes the hydride source has been eitherlithium aluminum hydride or diisobutylaluminum hy-dride. Very rarely have nucleophiles other than organo-lithium or organomagnesium species been used.45 Withthe first disclosure from Murphy’s research group thatalkylidenetriphenylphosphoranes 53 also react with WAas nucleophiles,46a yet another synthetic potential of WAwas uncovered. It is presumably a case of successful Wit-tig reaction on the amide carbonyl, wherein the oxaphos-phetane intermediate 54, upon cycloreversion andextrusion of triphenylphosphine oxide, afforded the puta-tive enamine 55, which on hydrolysis furnished the ketoneas the final product of the reaction. Importantly, the phos-phonates react in a completely different way. The phos-phonate anion 56 does not lead to olefination of the amidecarbonyl, but instead leads to b-ketophosphonates 57 withthe expulsion of an amine residue. The extension ofMurphy’s successful addition of alkylidenetriphenylphos-phoranes onto WA 58, derived from formic acid, resultedin formylation46b of phosphoranes (Scheme 14).

N

O

O

O

BnO

OH

N

O

Me

OMe

OH

OBn OBn

Me3Al

DMHA⋅HCl89%

43 44

R N

O

Me

OMeCl N

O

Me

OMeRSn(Bu)3

R = alkenyl, aryl alkynyl

Pd(OAc)2 (2 mol%)ligand (2 mol%)

O

PPh2 PPh2

Br

O

N

OMe

O ligand: [Xantphos]Me

+ CO + DMHA⋅HCl (1 atm)

OMe

Me

X OTf

a: X = CH2b: X = O c: X = Sd: X = NCOOMe, NTs, NBoc

XN

OMe

OMe CO (1 atm) DMHA⋅HCl

45 18

48a–d

ligand (2 mol%)Pd(OAc)2 (2 mol%)

46

47

CNH

I

OHNC

CN

O

NH

I

ONC

Me

OMe

R H

O

R = alkyl, aryl

HC(CN)2-OTBS

CN

O

R

OTBS

R

OTBSCN

OCN

RN

O

Me

OMe

TBSO

C(CN)2-OTBS

49

50

DMHA

51

52

51a

phomactin D



Scheme 14

For the reader to gauge the confidence that the WA func-tionality enjoys in various organic synthetic endeavors,the broad-ranging applications have been classified underthe following four categories: (a) use in heterocyclicchemistry; (b) use in total synthesis of natural products;(c) use on kilogram scale in industry; and (d) syntheticequivalents and building blocks based on the WA func-tionality, and its uses in synthesis.

3.1 Use in Heterocyclic Chemistry

The alkynones 59 (Scheme 15), anticipated as productsthrough the nucleophilic addition of alkynyl lithium ormagnesium derivatives, appear to be reactive enough fora facile Michael reaction. The extruded DMHA, during orafter the workup, simply adds in a Michael fashion, there-by furnishing N-methoxy-N-methyl-b-enamino ketones60.47 These have become versatile building blocks and theversatility arises from the fact that the DMHA unit doesnot remain as an imposing structural feature in the b-enamino ketones, but can be readily exchanged with anyamine to afford novel amine segments on the vinylic sys-tem of b-enamino ketones for further synthetic endeavors.With the choice of appropriate amine, diverse and highlyfunctionalized heterocycles have been synthesized.47a TheWAs 61a and 61b obtained from N-protected L-phenyl-alanine and L-threonine, respectively, when treated withethynylmagnesium bromide, afforded through corre-sponding ynones the N-methoxy-N-methyl-b-enaminoketones 60a and 60b. To demonstrate the significance ofthese enamino ketones, compound 60b, when reactedwith phenylhydrazine or 62 as an amine, not only dis-places the DMHA residue, but also undergoes further cy-clocondensation to furnish functionalized heterocycles 63and 64 respectively.

Acetylenic keto esters 65, apparently attractive scaffoldsfor condensation with hydrazine for 3-carboxy-function-alized pyrazoles (Scheme 16), are rare synthetic interme-

diates as they are available only through thecorresponding aldehydes.48 Despite the well-documentedsuccessful addition of alkynyl residues to activated ac-ids,49 the addition of alkyl propynoates has been restrictedto potentially explosive silver acetylide alone.50 Interest-ingly, the addition of lithium or sodium acetylide of ethylpropynoate, on N-methoxy-N-methylacetamide (66) as arepresentative WA, again did not furnish the expected eth-yl-4-oxopent-2-ynoate framework 65a, but led instead tothe formation of enaminones 67 and 68.

Scheme 16

The facile conjugate addition of the liberated DMHA onthe acetylenic keto ester at two possible sites, followingcollapse of the initial tetrahedral complex, explains theformation of enaminones 67 and 68. The DMHA group inthe b-enaminoketo ester 67 could be exchanged by ami-nolysis and with hydrazine as aminating agent, to furnish

NOMe

O

MeX

X = Cl or F or H

Ph3P=CHC3H7

NOMe

MeX

C3H7

O

X

3

aq hydrolysis

PPh3Br10

HCONMe(OMe)CHO

10

PPh3O

NAr

OMeMeC3H7

R NOMe

O

Me

PCH2MeO

O

MeO

RP

O O

OMeOMe

BuLi

53 54

55

56

58

aq hydrolysis

57

Scheme 15

R1

O

NOMe

Me

R1

O

R2

HN(OMe)Me

R1 NOMe

O

Me

R2Li

R1 NOMe

OLi

Me

[during workup]

R2

R2

PhNHBoc

b: R1 = ON

Me

COOBn

a: R1 =

R2 = H

NN

Ph

BnOOCHN

HO

N

HNH2N

NC N

NN

CN

HO

BnOOCHN

phenyl hydrazine

NHNH2

59 60a,b

61a,b

62

63

64

60b +

60b +

O COOEt

NOMe

Me

O COOEt

NMeO Me+

O

COOEt

HN(OMe)Me

NOMe

O

Me OEt

OLi N

OMeO

Me

OEt

O

NNR

COOEt

RNHNH2

[during workup]

+

R

O

COOEt65

66

6768

Li

pyrazoles

65a



an elegant route toward 3-carboxy-functionalized pyra-zoles.51

The Michael addition of DMHA to alkynones only duringor after the workup is not a rule, since successful forma-tion of alkynones for further synthetic endeavors has alsobeen achieved (Scheme 17).52 Couty and co-workers havesuccessfully prepared and used N-Boc-oxazolidine-basedalkynones 69a52a as valuable building blocks, obtainedfrom the corresponding WA 69b, for various synthetictargets.52b,c Similarly, Cox and co-workers, in their effortstowards 3,5-diaryl-5-alkyl-4,5-dihydropyrazole throughcyclocondensation of hydrazine with b-alkyl chalcones70, have synthesized the requisite chalcones through 1,4-addition of the alkyl residue as organocuprate on thereadily obtained alkynones 71.52d These alkynones weresimply prepared by addition of the lithium salt of the ter-minal alkyne onto the WA, whereupon during workup noMichael addition of liberated DMHA was observed.

Scheme 17

Recently, the reliability of WA–alkynylide coupling forthe synthesis of the alkynone functionality has been ex-ploited by Williams for the synthesis of macrolide pect-enotoxin-4 which is discussed in the application of WAsin natural product synthesis (vide infra).

The building block 72 has paved the way for an efficientand novel synthetic route to 3,4-disubstituted pyrrole-2-carboxaldehyde 73 and 3-pyrrolidin-2-one 74(Scheme 18). The key reaction is the cyclocondensationbetween the a-nitroalkene or b-nitroacetate and the acti-vated isocyanide functionality in 75.53

3-Acylindazoles and 3-formylindazoles are valuablebuilding blocks in medicinal chemistry54 for wide range ofapplications, particularly in the development of serotoninreceptor ligands (5HT).55 In the context of low-yieldingroutes reported in the literature for this class of com-pounds, the recently disclosed strategy invoking the use ofWA-based building block 76 constitutes the most efficientand flexible route for 3-acylindazole libraries (Figure 4).56

Multigram quantities of 76 and 77 were conveniently pre-pared in good yields by condensation of the correspondingindazole acid with DMHA liberated from its salt, in thepresence of dicyclohexylcarbodiimide or N¢-(3-dimethyl-aminopropyl)-N-ethylcarbodiimide.

The Parham cyclization process, which hinges upon lithi-ation followed by attack of the generated aryl- or hetero-aryllithium on the tethered internal electrophile, hasoccupied a place of choice in the arsenal of synthetic tac-tics for the assembly of carbo- and heterocyclic systems(Figure 5).57 With the use of the WA functionality as theinternal electrophile, the strength of the Parham cycliza-tion process has increased manifold. Initial exploration in-cluded successful reaction of organolithiums derivedfrom alkyliodides with tethered WA for access to cyclicketones.58 This is interesting in light of the fact that metal–halogen exchange must be extremely fast and the lithiat-ing agent should not directly add to the carbonyl carbon ofWA as a nucleophile. Application of the same concept us-ing heteroaryl- or aryllithium has led to the synthesis ofthieno[2,3-b]thiophenes,59 benzocyclobutenones,60 andmethylideneindanones.61 Applications of this concept inthe syntheses of (–)-brunsvigine,62 the hexahydrobenzofu-ran subunit of avermectin,63 and fused indolizinonesystems64 have been the most important and interestingcontributions.

Liebscher treated the WA of oxiranecarboxylic acid 78and the corresponding aziridinecarboxylic acids 79a and79b with ortho-lithiated O-MOM-protected phenol 80 asa nucleophilic reagent to furnish a novel route to the 3-hy-droxychromanone 8165 and 3-amino-2,3-dihydrobenzo-pyran-4-one 82b66 heterocyclic systems (Scheme 19).The aziridine carboxamides 79a and 79b are easily pre-pared from the corresponding aziridine-2-carboxylate es-ters and are convenient equivalents for aziridinealdehydes and 2-keto aziridines.67 Aziridine aldehydes 83

NN

H

R1

Ar1

O

R1 Ar2

Ar2

Ar1

Ar2Li, CuBr⋅DMS THF, –78 °CAr1

O

R1

NH2NH2⋅H2ON

O

R2PhBoc

O

69b: R2 = N(OMe)Me

OTBS

69a: R2 =

7071Ar1 = Ph, 4-BrC6H4

R1 = alkyl Ar2 = Ph, 3-HOC6H4

Scheme 18

OH

O

NHBoc

1. HCOOH, 80 °C

R1 R2

O2N OAc

R1 R2

O2Nor

POCl3, Et3NTHF, 70%

NH

R1 R2

NOMe

MeO

NH

R1 R2

H

ONH

R1 R2

O

2. HCOOEt, Et3N∆, 65% (2 steps)

DBU, THF, 0 °C–r.t.

LAH, THF, 0 °C

H2O2, NaHCO3 MeOH, r.t.

50–80%

72

73 74

75

DMHA

DCC

O

H NH

O

NOMe

MeBocHNO

NOMe

Me

NCO

N

OMe

Me

59–84%

R1, R2 = Me, Et, Ph

Figure 4 Flexible route for 3-acylindazole libraries

NN

R2

NOMeO

NN

R3O

MeR1 R1

R1 = MeO or HR2 = H or BocR3 = alkyl or aryl

7776R2



and 2-keto aziridines 84 are fine examples of compoundsdisplaying amphoterism,68 wherein amine and carbonylfunctionalities are kinetically stabilized against inter- orintramolecular reactions and thereby orthogonal (noamine protection is required).

Scheme 19

Franck et al., for their neoglycopeptide program, envi-sioned isooxazoles 85 and 86 as valuable synthons forpeptidomimetics (Scheme 20).69 The simplicity of prepar-ing the five-membered heterocycle via a 1,3-dipolar cy-cloaddition and effective use of WA functionality formedthe basis of their vision. The nitrile oxide 87 and nitrones88 were prepared using aldehyde 89, the ozonolysis prod-uct of cinnamic acid derived WA.70

A variety of substituted pyrroles 90 and pyrroles fusedwith diverse carbo- or heterocycles 91 have been preparedby the Knorr approach that takes advantage of the WAfunctionality (Scheme 21).71 The developed strategy re-

moves the severe limitation of auto-condensation of a-amino ketones usually encountered in the Knorr approach.The N-vinyl-a-amino ketones for fused pyrroles wereconveniently prepared from scaffold 92, which carries theWA functionality, by addition of R3MgX. Reaction be-tween b-chlorocycloalkenyl ketones 93 and the amine lib-erated from the hydrobromide salt of N-methoxy-N-methyl-a-amino carboxamides 9472 provided the requisitestarting substrates 92.

Scheme 21

For pyridone annulation through [4+2] coupling of dieno-lates with nitriles, the reaction between the dienolate 95and acetonitrile and benzonitrile simply failed.73 Even thezinc enolate in the vinylogous Blaise reaction74 failed toafford pyridone 96. However, reaction of the same dieno-late 95 with WA 97 as acylating agent afforded the d-ketoacrylates 98, which were easily transformed into the de-sired pyridone heterocycle (Scheme 22).

Scheme 22

Conceptually, 2-acyl oxazoles 99 should be directly avail-able through the reaction of 2-metallated oxazole 100 anda suitable acylating agent (Scheme 23). The reported in-stability of 2-lithio oxazoles 100a in tetrahydrofuranabove –40 °C,75 coupled with their known propensity toring-open and exist predominantly as the thermodynami-cally more stable enolate isonitrile species 101, hasmarred their apparent attractiveness for the direct use inthe synthesis of 2-acyl oxazoles 99. However, researchers

Figure 5 Pictorial representation of Parham cyclizations

N

OOMe

Me

Li

R N

(CH2)nLi

N

O

OMe

Li

ON

OMeMe

SS

O

NMe

MeOR

R1

Li Li

O

NMe

MeO

NTs

O

NOMe

MeLi

X

O

NOMe

MeLi

X = N, O

Me

ref. 58 ref. 59 ref. 60 ref. 61

ref. 62 ref. 63 ref. 64

N

O

OMe

MeX

R1

R2

78: X = O79a: X = NTs79b: X = NH

MOMOO

X

R1

R2

81: X = O82a: X = NHTs82b: X = NH2

MOMO

Li

X = O or NH or NTs

O

O

R2

R1

X

R

O

HN

R1

R2

83: R = H84: R = alkyl or aryl

80

R1 = R2

= H or alkyl

Scheme 20

MeN

OMe

O

NO

MeN

OMe

OH

O

MeN

MeO

OH

NBnO

MeN

OMe

O

ON

R

MeN

MeO

O

OBnN

Z

R

Z

Z = OEt, COOEt

85

86

87

88

89

N

Me

Me R1

Z R2

N R2

R3O

X

R1

N

O

X

R1

O N

R2

Me

OMe

Z = CN, COOEt, COMe, COPhR1 = R2 = H, alkyl

Cl

O

X H3N

ON

R2

Me

MeO

Br93 94 92

90

91

R3MgX

+

X = C or O

EtOH

N

O

X

R1

O R3

R2

R3 = alkyl or aryl

Et3N

O

OMeR1 N

OMe

O

MeO

OMe

R1 O

NH

O

R1

R2CNO

OMe

R2 N

Li

Li95

96

97

98

X

X

R2 = Ph or MeR1 = n-Bu, Me

NH3, EtOH



at Eli Lilly75a,b have observed that at –70 °C, the initiallyformed 2-lithio oxazoles can be transmetallated to the zin-cate 100b using two equivalents of zinc chloride and thesezincates are resistant to the ring-opening phenomenon.They conveniently react with aroyl, alkenoyl and alkanoylchlorides as acylating agents to furnish 2-acyl oxazoles 99in good yields. Despite the predominant existence of 2-magnesio oxazoles 100c in the ring-opened form at 0 °Cin tetrahydrofuran solution, Pippel et al.75c were success-ful in obtaining 2-acyl oxazoles by using the attenuatedreactivity of WAs as acylating agents. The slow rate of re-action between 100c and the acylating agent, against thefaster equilibration between 100c and 101c, was used torationalize the success observed with the WA-based acy-lating agents.

Scheme 23

Among the a-keto heterocycles that represent a broadclass of fatty acid amide hydrolase (FAAH) inhibitors,Boger’s (Z)-1-oxo-1-(3-pyridazinyl)octadec-9-ene 102stands out as one of the most potent.76a The addition of py-ridazinyllithium 103 to the WA of oleic acid furnishedproduct 102, albeit in a low yield of 11%. It wasrecently76b observed that the four-fold excess of lithium2,2,6,6-tetramethylpiperidine for lithiating the pyridazinewas deleterious and also the reason for poor yield. How-ever, four-fold excess of pyridazinyllithium with respectto the WA significantly improved the yields of 102 andalso provided generality for various other acylpyridazines(Scheme 24).

Scheme 24

During an attempt to synthesize the therapeutically impor-tant phosphorothioates 104, ketone 105, with both indoleand imidazole moieties, was postulated as an elegant aux-iliary (Scheme 25).77 These moieties would not only reactwith dichloro(methoxy)phosphine through their respec-tive nitrogen centers, but would also serve as leavinggroups on subsequent treatment with nucleosides R1OHas nucleophiles. The indole WA 106, readily availablefrom the corresponding acid, was responsible for the con-venient access to 105, through reaction with two equiva-lents of N-tritylimidazole anion and followed by de-tritylation. The same target could not be obtained throughthe coupling of N-tritylimidazole anion and 1-(phenylsul-fonyl)-2-indolecarboxaldehyde.

Scheme 25

3.2 Use in Total Synthesis

Cyclic peptides that provide rigid scaffolds for lockingshort peptides into specific configurations are potentialdrug candidates in medicinal chemistry. The C-terminusfunctionalized cyclic peptides such as 107 (Scheme 26)have been one of the important synthetic targets at Bristol-Myers Squibb.78

A number of cyclic peptides, wherein (i) and (i + 1) resi-due side chains are joined by an alkyl linker, have beensynthesized. Although the synthetic scheme starts withamino acid building block 108 that already contains theWA moiety, its utility for enabling functionalization at theC-terminus is employed only towards the end of the syn-thesis (Scheme 26). This is important because formationof an activated carbonyl at an early stage could be prob-lematic, owing to potential epimerization at the corre-sponding a-position.

Among the marine natural product macrolides, spongi-statins, altohyrtins and cinachyrolides, isolated respec-tively by Pettit,79a Kitagawa79b and Fusetani,79c constitutethe most potent antitumor agents (Scheme 27). The novelarchitectures stimulated widespread interest in the syn-thetic community. Nakata’s research group, in their pro-gram towards the total synthesis of altohyrtins, achieved a

O

N

MOM

N C

a: M = Lib: M = ZnClc: M = MgCl

100b

O

N

O

R

R NOMe

O

Me

R Cl

O

–15 °C

100101

100c

–70 °C

99

NNLi

NOMe

O

Me7

O

7

NN

+

THF–75 °C 30 min

102

103

NLi

LiTMP

LiTMP

NH HN

N

O

NN

N

O

PMeO

OTBSO

N

HO

HNO

O

R1OP OR1

MeO

R1OH

105

MeOPCl2

R1OH

R1OP OR1

MeO

S

NH Me

N

O

OMe

106

104



stereocontrolled synthesis of the C29–C44 portion of thetarget through the coupling of highly functionalized vinyl-lithium reagent 109 with the WA moiety in 110 as the keyreaction.79d The successful coupling and obtainment ofcompound 111 in good yield (77%) as a key buildingblock midway through the synthetic scheme demonstratesthe significance of this approach for carbon–carbon bondformation. Given that 111 had to undergo several func-

tional group manipulations spread over ten subsequentsteps to furnish the target 112, its obtainment on a multi-gram scale reflects the confidence invoked by this cou-pling procedure during earlier stages of the synthesis.

The tricyclic pyrrolo[2,1-c][1,4]benzodiazepine (PBD;113), a nitrogen-containing heterocyclic system, repre-sents one of the most promising classes of compounds ca-pable of binding to DNA in a highly sequence-selectivemanner. Among the many synthetic analogues, the C8-linked dimers of PBD, represented here by DSB-120(Scheme 28), have surfaced as one of the most efficientinterstrand DNA cross-linkers.80 DSB-120 is approxi-mately 300- and 50-fold more efficient than the clinicallyused cross-linking agents melphalan and cisplatin, respec-

Scheme 26

NH

HN

NH

ZO

S

O

OS

O

cyclic

Z = H, heterocycle

PHNN

Me

TrS

O

OMe i. Et2NH, CH2Cl2ii. Fmoc-Ala-OH⋅H2O DIPEA (3.0 equiv)

HBTU, BtOH⋅H2O, DMA

PHNNH

N

OTrS

O

OMe

Me

i. Et2NH, CH2Cl2ii. Fmoc-Cys(St-Bu)OH⋅H2O DIPEA (3.0 equiv) HBTU, BtOH⋅H2O, DMA

Ph NH

HN

NH

NO

S-St-Bu

O

OTrS

O

OMe

MeBu3P; THF–H2OI(CH2)4I, DBU

Ph NH

HN

NH

OS

O

OS

O

(CH2)4

N

S2-Li-thiazole (8.0 equiv)LiCl (5.0 equiv)

107

108

Ph NH

HN

NH

NO

S

O

OS

O

(CH2)4

OMe

Me

P = Fmoc

Scheme 27

OO

OR2

O

OO

O O

O

O

OHOH

OH

HO

HO

R1O

OMe

HO

H

OH

X

altohyrtin A (spongistatin 1): X = Cl, R1 = R2 = Acaltohyrtin B: X = Br, R1 = R2 = Acaltohyrtin C (spongistatin 2): X = H, R1 = R2 = Accinachyrolide A (spongistatin 4): X = Cl, R1 = Ac, R2 = H

A

B C

D

ONOMe

OBn

BnO

HO

Me

TBSO

Li OTrMe

OMPMOTBS

29

37

3844

O

OBnBnO

HOTBSO

44 OTrMe

OMPMOTBS

29

O

OBnBnO

HTBSO

3844

OTBS

O

OMeOTBS

OTBDPS

29

29

44

10 steps

109

110

111112

+

3

15

1

Scheme 28

OMe

ON3

N

O

ON

MeO

Me

MeO

N3

N

O

ON

OMe

MeO

n

OMe

O

MeO

On

N

N

H

N

N

OO

H

n = 1–3

n = 1–3 when n = 1 DSB-120

LiAlH4 or LiBH4in THF50–68%

N

N

O

H1

23

4567

8

9 1011

113

114



tively. Continued efforts in Kamal’s research group insynthesizing PBD heterocycles have led to a versatile andinexpensive strategy that involves reduction of the aro-matic azides and the WAs of 114 in one step; this providesan efficient and convenient intramolecular reductive cy-clization route to DSB-120.

In Danishefsky’s group, the success in arriving at the re-sorcinylic scaffold present in various natural products re-lied on a Diels–Alder reaction between dimedone-derived1,3-dioxygenated diene 115 and ynolide 116 and a subse-quent retro-Diels–Alder reaction of the adduct 117 withthe loss of isobutylene. The concept has been applied tothe total synthesis of xestodecalactone A (Scheme 29).81

The requisite dienophile, alkynyl ketone 118, was ob-tained in good yield (84%) by coupling of alkynyllithium119 and WA 120.

The straightforward synthesis of commercially important,g-bicyclohomofarnesal 121 and 121a, as strong ambergrisodorants from Torre’s research group, substantiates onceagain the importance of the WA functionality(Scheme 30).82 Compound 121 and its endo isomer, 121a,equally important as key synthetic intermediates, wereeasily prepared in 47 and 26% overall yields from com-

mercial starting material (R)-(+)-sclareolide (122). Acid-catalyzed alcoholysis of (R)-(+)-sclareolide for lactone-ring opening led to an inseparable mixture of all three pos-sible unsaturated isomers, deceivingly homogeneous un-der all TLC conditions explored. However, in sharpcontrast, the lactone ring in 122 was easily opened withDMHA in presence of trimethylaluminum at room tem-perature. WA 123 was thus obtained in 88% yield andcontained the sensitive tertiary hydroxy group intact. De-hydration in the presence of thionyl chloride and pyridineafforded an easily separated mixture of 124 and 124a in60 and 32% yield. Independent reduction of the WAs us-ing lithium aluminum hydride in anhydrous tetrahydrofu-ran gave the desired targets 121 and 121a in high isolatedyields of 89 and 91%, respectively.

Dias et al., while working towards the total synthesis ofdolabriferol, the first natural product from the molluskfamily Dolabriferidae, relied on the WA-containing start-ing material 125 as a valuable building block that wouldserve as a common precursor for both the C1–C9 and theC10–C21 fragments.83 It was easily obtained through twoconvenient and high-yielding steps from the known acyl-oxazolidinone 126. A highly stereoselective asymmetric

Scheme 29

OR

RO

OOOR

RO

O

O

OR

RO

O

O

O

OH

HO

O

O

OMe

AcO

O

OP

OO O

OMe

AcO

O

OP

OO O

N

O

OP

OO O MeO

Me

Li

+

neat, heat

180 °C

79%

heat

heat

115 116 117

118

119 120

+

+

xestodecalactone A

R

P = TBDPS

Scheme 30

O

H

O

H

OMe

O

178

OH

H

O

N

H

O

N

H

O

N

H

O

H

H

O

H

122

121 121a124 124a

LAHTHFLAH

THF

DMHAMeOHH2SO4

reflux20 h

Me3Al

OMe

Me

OMe

Me

OMe

Me

123



aldol reaction constituted the first step, and the subsequentreaction with DMHA in presence of trimethylaluminumwas the second step in furnishing the requisite WA build-ing block (Scheme 31).

Scheme 31

Compounds 127 and 127a, isolated first as a mixture oftwo stereoisomers from iron-deficient cultures ofPseudomonas aeruginosa ATCC 15692 by Liu and Shok-rani,84a and named then as pyochelin, presented a syntheticchallenge. Pyochelin 127 is a hydroxyphenylthiazolinylthiazolidine-type of siderophore produced by a large num-ber of Pseudomonas aeruginosa strains and by manystrains of Burkholderia (ex Pseudomonas) cepacia, thespecies known to be involved in severe lung infections oc-curring in cystic fibrosis patients. The condensation of(R)-N-methylcysteine (128a) with aldehyde 129 consti-tutes the most attractive and direct approach to arrive at127 (Scheme 32).84b Although in principle the thiazolinealdehyde 129 should be easily accessible from the reduc-tion of the carboxylic acid or ester group in thiazoline130a or 130b respectively, this was, however, not thecase. Reduction of acid 130a with thexylborane gave apoor yield of aldehyde 129 (15%), owing to the formationof a stable boron–thiazoline complex. Reduction of ester130b at –78 °C with diisobutylaluminum hydride (2equiv) furnished the aldehyde 129 in 61% yield, but in an8:2 ratio along with starting material. Attempts to improvethe yield by using more than two equivalents of diisobu-tylaluminum hydride and raising the temperature above–50 °C resulted in considerable over-reduction of theester to the alcohol. Finally, the method developed byFehrentz and Castro16a for the preparation of aldehydesderived from protected amino acids based on the reduc-tion of the corresponding WA using excess lithium alumi-num hydride (5 equiv) at 0 °C paved the way for thesuccessful obtainment of the aldehyde 129. The thiazolineacid 130a was coupled with DMHA using diethyl cyano-phosphonate (DECP) as a coupling agent. Reduction ofthiazoline WA 130c with three equivalents of lithium alu-minum hydride at –20 °C was complete within 20 min-utes, yielding aldehyde 129 in 94% yield with no trace ofstarting material, epimerization, or over-reduced prod-uct.84b The availability of aldehyde 129 has enabled thesynthesis of pyochelin and analogues.84c

WA alkynylation has proven itself as a reliable and con-vergent way to establish new carbon connectivity in theassembly of ynones late in a synthetic scheme. In Ghosh’sconvergent approach85 to the synthesis of the antitumormacrolide laulimalide, the stereocontrolled synthesis ofthe C17–C28 was centered on two key steps. These werea ring-closing olefin metathesis for the construction of thedihydropyran unit in 131, and a carbon–carbon connectiv-ity through addition of alkynyl anion 132 to WA 133(Scheme 33). The WA 133 not only facilitated the car-bon–carbon connection but also enabled the setting up ofthe stereochemistry of the C20 hydroxy group and con-struction of the E-geometry of the C21–C22 double bond.

Scheme 33

Recently this WA–alkynylide coupling, reliable for thesynthesis of alkynones, was used in tackling the syntheticchallenge posed by the macrolide pectenotoxin-4(Figure 6). The synthesis of the C21–C28 segment con-taining WA 134 and its facile coupling with 135 is a sig-nificant contribution made by Williams.86

O N

O

Bn

O

O N

O

Bn

O OH

MeON

O OTBS

Me

n-Bu2BOTf

Et3NEtCHO

Me3AlDMHA⋅HCl

TBSClimidazole

O OTBS OTBS

O

EtO

6 43

2 116

1311

10

fragment C10–C21

fragment C1–C9

125

126

Scheme 32

CN

OH

HSNHR1

COOHH

OH

S

NCOX

130a: X = OH130b: X = OMe130c: X = N(OMe)Me

OH

S

N

CHO

128a: R1 = Me128b: R1 = H

2'4'

5'

OH

S

N

S

N

H

Me COOH

H

127

129

OH

S

N

S

N

H

Me COOH

H127a

O

O O

HH

OH

OH

HOOH

H

PMBO

OHPhO2S

OLi

N

Me

OMe

OOTHP

HO

THPO

H

20

19

20

17

17

21

22

281

131

132133



Koert’s stereoselective synthesis of compound 136, theC18–C28 segment of apoptolidin, an important naturalproduct used for cancer treatment, is a fine example thatsubstantiates the ease of incorporating the WA moietyinto a multifunctional molecule and its use as a valuablehandle for synthetic operations on a key and major build-ing block6a (Scheme 34). Transamidation using a combi-nation of trimethylaluminum and DMHA hydrochlorideafforded WA 137 in 81% yields at –10 °C. As a truncatedmodel for the apoptolidin skeleton, the three-carbon orga-nolithium generated from (E)-1-bromoprop-1-ene wasmade to react with WA 137 to obtain propenyl ketone 138in 87% yield. This then allowed for the facile introductionof a vicinal diol moiety at C19 and C20 through Sharplessdihydroxylation using AD-mix a, and was followed byacid-catalyzed ring closure to yield the pyranoid ketal oftarget 136.

The central 6,6-spiroacetal segment of spirofungin A, anantifungal antibiotic isolated from Streptomyces viola-ceusniger, was envisaged to arise through an intramolec-ular acetalization of ketone 139 (Scheme 35). Shimizu’sefficient synthesis of the spiroacetal fragment through thisapproach became a reality only because of successful syn-thesis of ketone 140 via coupling of WA 141 with alky-

nyllithium 142.87 This coupling proceeded without anydifficulty at –78 °C and furnished the desired ketone in anisolated yield of 81%. Reaction of the same alkynyllithi-um, but with lactone 143 instead, furnished the requisiteketone 140 (without TES protection) only in 23% yield.

Scheme 35

An economical synthesis of a number of racemic diketidethioesters,88a through genetic manipulations of the organ-isms that synthesize these natural products, was used atKosan Biosciences in the search for possible intermedi-ates that would lead to (+)-discodermolide, a polyketidenatural product.88b Burlingame, using 144, targeted thesynthesis of WA 145 (Scheme 36), which itself hadserved as the key building block for three major substruc-tures in Smith’s total synthesis of discodermolide.88c Allthe structural features required in 145 were present in thevinyl lactone 146, but the vinyl group had to be removedthrough ozonolysis and decarbonylation. Attempted ozo-nolysis of the double bond in the unprotected vinyl lac-tone 146a led to spontaneous formation of the bicyclicacetal 147, which refused decarbonylation. However, thesilyl ether 146b underwent ozonolysis and subsequent de-carbonylation with Wilkinson’s catalyst to furnish the de-sired lactone 148. Ring opening with DMHA andtrimethylaluminum and protection of the primary hydroxyas the the p-methoxybenzyl ether afforded the requiredWA 145 for the synthesis of discodermolide.

The synthesis of macrosphelide 149, a novel 16-mem-bered macrolide containing three ester linkages, whichhad shown interesting and diverse biological activities,banked on the lactic acid derived WA 150 as the startingmaterial (Scheme 37).89 This building block enabled con-venient synthesis of 151, an important common interme-diate for fragments 152 and 153. The direct addition oftrans-vinylogous 2,6,7-trioxabicyclo[2,2,2]octane (OBO)

Figure 6 WA–alkynylide coupling for macrolide pectenotoxin-4

OO

O

O

O

HO

OH O

O

O

OO

OHO

HO

H

ON

OOMe

Me

TBDPSO

HOTES

R2

R1

2128

28

21

18

18

135

pectenotoxin-4

R1 = CH2CH(Me)2

R2 = Me

134

Scheme 34

NOMe

O

O

Bn

O OH OH OTBS

NOMe

O O O OTBS

Me

OMe

TMS TMS

OMeO O O OTBS

TMS TMS

OMe

O O O OTBSTMS TMS

OH

OH

OOMe

OH

OTBS

HOMeHO

OH

18

19

20

21

22 23

25

2627

28

24

136

137

138

1. DMHA⋅HCl Me3Al

Br

t-BuLi

Sharplessconditions

18 2821 25

2. TMSCl imidazole

O

OCOOH

HOOC

H

H OH

OHHO

MPMOH

H

CO

OOMPMMPMO

O

OTBS

TES

O NOMPMMPMO

O

OTBS

TES

OMe

Me

Li

MPMOO O

139

140

141142

+

143

spirofungin A



ester anion 154 to the PMB-protected WA 150 furnishedketone 155. Highly stereoselective reduction with lithiumtriethylborohydride, followed by MEM protection and hy-drolysis afforded the acid 151. It is the simplicity of eachstep, the higher overall yield, and the high enantiomericpurity of the intermediates that lead to 149, that attest tothe efficiency and conciseness of this methodology usingWA functionality.

Scheme 37

3.3 Use in Industry on Kilogram Scale

Prominent attention has been paid to the advantages asso-ciated with the WA by industry. Several syntheticschemes aiming at large-scale operation have made gooduse of the WA in one form or another.90–93 Merck’s con-tinuous interest in compound 156, and the synthetic ef-forts towards this product in the last few years, finelyillustrate the confidence that industry has in the use of theWA functionality on a multi-kilogram scale(Scheme 38).90 Compound 156, which surfaced as a de-velopmental candidate for HIV protease inhibition, wastargeted for synthesis through two disconnections, A andB, in the oxazole segment of the molecule. For disconnec-tion A, the Boc-protected a-aminoketone 157 was re-quired as one of the basic building blocks along with 158.

Scheme 38

Realizing that, because of the presence of an exchange-able amino proton in the starting WA, the use of Boc- orCbz-protected amino WA 159, en route to the synthesis ofthe a-protected aminoketone 157 (as a representative ex-ample) would necessitate the use of at least two equiva-lents of Grignard or organolithium reagent, the Merckgroup systematically developed a very practical solutionthat completely prevented the waste of expensive and dif-ficult-to-obtain nucleophiles.90a Various a-Boc-aminoWAs were treated with a little less than one equivalent ofisopropylmagnesium chloride for removal of the acidic N-H proton prior to the reaction with one equivalent of thedesired Grignard reagent. This pre-deprotonation strategyallowed for a convenient and practical synthesis of theamino ketone 157 that was required for the synthesis oftarget compound 156. This was achieved on a nine-kilo-gram scale and hence accelerated their synthetic pro-gram.90b The strategy is general and not restricted tosynthesis of 157 alone, as various other a-Boc-amino ke-tones have also been synthesized on a multi-kilogramscale.90c

The stereoselective synthesis of taranabant (160;Scheme 39), a drug targeted at Merck for the treatment ofobesity, serves as a second example to illustrate the use ofthe WA functionality on a multi-kilogram scale.91 For thesynthesis of taranabant, envisaged to take place throughthe coupling of an amine and a carboxylic acid fragment,the convenient availability of the amine 161 became im-perative. Methyl ketone 162 was prepared in nearly quan-titative yield on an 11.5 kilogram scale from acid 163a viaWA 163b. The enantioselective reduction of ketone 162via dynamic kinetic resolution under basic conditions at

Scheme 36

O

PMBO

O

NMe

OMe

TBS

Me3Al, DMHA

PMBOC(=NH)CCl3O

OTBS

O

O

SNAC

OHO

OR

O146a: R = H146b: R = TBS

fermentation

CSA, 90%

OO

HOO

144

145 148

147

O

O

O

OHO

O

OH

OH O

OPMB

MEMO

HO

HO

AllylO OO O

OHOMEM

PMBO

O

NOMe

Me

OPMB

O

O

O

O

LiO

O

O

OPMB

OMEMOH

O

149

150

151

152 153

154

155

N

MeO O

N

N

N

HN

NCF3

O OH

O

O

OHH

N

N

NH

alloc

CF3O

O

HO

N

MeO

NHBoc

O

N

MeO

NHP

OMgBr

N

Me

MeO

i-PrMgCl

N

MeO

NHBoc

O

(9 kg scale)

156

158

a: P = Boc b: P = Cbz

157

159a

157

RMgX

BrMg

NO

NOMe

Me

Boc

RMgX 159

A B



room temperature using Noyori’s catalyst [(xyl-BI-NAP)(DAIPEN)RuCl2] afforded the desired diastereoiso-mer of the alcohol 164 in 94% ee and 8:1 dr.

The commendable task of synthesizing sixty grams of dis-codermolide,92a an anticancer compound produced by therare Caribbean sponge Discodermia dissolute, through 39steps by the Novartis team over a period of two years pre-sents yet another fine example wherein the WA function-ality has been used in a multi-kilogram productsynthesis.92b The synthetic scheme adopted by Mickel’steam at Novartis incorporated the best features of the syn-theses reported for discodermolide by Smith88c and Patter-son.92c The cornerstone of the hybrid approach was theWA building block 165 (Scheme 40). It allowed for thesynthesis of three major fragments: C1–C6, C9–C14 andC15–C21. Smith’s approach to 165 from Roche ester 166was optimized by Mickel et al.92b into a more efficientroute capable of delivering 28 kilograms of 165.

To avoid workup problems, lithium borohydride was usedinstead of lithium aluminum hydride for reducing the con-veniently available PMB-protected derivative 167 ofRoche ester 166, to arrive at alcohol 168. A two-phase2,2,6,6-tetramethylpiperidine N-oxyl and bleach oxida-tion of 168 in dichloromethane furnished the requisite al-dehyde 169 in quantitative yield for a subsequent Evanssyn-aldol reaction. It was directly used without purifica-tion, to avoid possible racemization at the stereogeniccenter. Enolization of 170 with dibutylboron triflate in thepresence of triethylamine at 0 °C followed by treatment ofthe resulting enolate with aldehyde 169 at –78 °C fur-nished alcohol 171 in 46–55% yield on a 20–25 kilogramscale. As trimethyl aluminum is pyrophoric, its use inlarge plant-scale operations was avoided despite its greatsuccess in transamidation on such scales.

Scheme 40

Although use of triisobutylaluminum in conjunction withDMHA hydrochloride was safe for effecting the conver-sion of 171 into the desired WA 165 on a multi-gramscale, the high exothermicity of the reaction, coupled withthe fear of any accidental cooling failure, remained a ma-jor safety concern. Finally, cleavage of the oxazolidinonewith hydrogen peroxide and lithium hydroxide affordedthe corresponding acid 172, isolated as its crystalline (R)-2-phenylethylamine salt. Starting with 34 kilograms ofthis salt, 28 kilograms of WA 165 were obtained throughactivation of the acid with isobutylchloroformate and re-action with DMHA.

The large-scale synthesis of the lactone 173, an immediateprecursor for the hydroxyethylene dipeptide isotere 174,by Urban et al. at Pfizer tops the list of examples demon-strating the scalability of reactions that involve the use ofthe WA (Figure 7).93a The targeted synthesis of the de-sired lactone 173 was envisaged to take place through theuse of ketone 175a as a key building block, because of theavailability of a successful and convenient procedure forthe analogues ketone 175b in the literature, based on theuse of WA functionality. Diederich and Ryckmann93b hadaccomplished the synthesis of 175b by the coupling of

Scheme 39

NH

ONC

Cl

ON

CF3

(MK-0364, taranabant)

NH2NC

Cl

Br

Cl

OH Br

Cl

O

Br

Cl

Z

O

163a: Z = OH163b: Z = N(OMe)Me

160

161

162164

Noyoriconditions

O

OH

OH OO

OH

HO

NH2

O

OH

PMBO

O

NMe

OMe

OTBS

PMBOI

O O

I

OTBSO O

NMe

OMe

OTBS

ROZ

166: R = H, Z = COOMe167: R = PMB, Z = COOMe168: R = PMB, Z = CH2OH169: R = PMB, Z = CHO

O

N O

O

Ph

O

N O

O

Ph

PMBO

OH

n-Bu2BOTf Et3N

O

OPMBO

OH

H3N

OH

PMBO

O

NMe

OMe

DMHA⋅HClMe3Al,THF

1. LiOH, H2O2, MeOH, r.t.2. (R)-phenylethylamine toluene

165

+

170

171

165

172

C1–C6

C9–C14

C15–C21

1521

9 14

16

1

8

13

22



WA 176b derived from N,N-dibenzylphenylalanine with2-(1,3-dioxanyl)ethylmagnesium bromide 177b. Al-though the initial attempts to combine WA 176a with thepreformed Grignard reagent 177b in tetrahydrofuran gaveat best traces of the desired ketone 175a, their switchingto a Barbier-type procedure and prior deprotonation of theamide N-H, using either methylmagnesium bromide orbenzylmagnesium chloride as a sacrificial base, enabledpreparation of this ketone 175a on a scale of more than200 kilograms. The Barbier-type procedure involved ad-dition of 2-(2-bromoethyl)-1,3-dioxane (177a) to a stirredmixture of WA 176a and magnesium turnings in tetrahy-drofuran at –10 °C. Addition of one equivalent of methyl-magnesium bromide prior to the addition of 177a effectedthe necessary deprotonation.

Figure 7 Pfizer’s use of WA on a scale of more than 200 kg

3.4 Synthetic Equivalents and Building Blocks

a,b-Unsaturated WA structural units, which allow notonly the synthetic manipulations associated with a,b-un-saturated systems but also those innate to the WA, havebeen easily assembled using Wittig,94a Horner–Wad-sworth–Emmons94b,c or Julia-based94d synthetic equiva-lents 178, 179 and 180 respectively (Scheme 41). In analternative approach, alkyl halides have been convertedinto the a,b-unsaturated WAs using N-methoxy-N-meth-yl-2-(phenylsufinyl)acetamide (181)94e as the reagent.The obtained a,b-unsaturated WA is predominantly or ex-clusively E-configured. For the dominant formation of Z-configured a,b-unsaturated WA units, Ando’s N-meth-oxy-N-methyl(diphenylphosphono)acetamide (179b)94f

and Deslongchamps’ N-methoxy-N-methyl[bis(2,2,2-tri-fluoroethyl)phosphono]acetamide (179c)94g have beenvery useful. Both 179b and the sterically more demandinganalogue 179d94h are very useful with alkyl aldehydes,whereas with aromatic aldehydes, reagent 179c is superi-or.

The incorporation of a,b-unsaturated WA structural unitsusing the synthetic equivalents mentioned in Scheme 41has been exploited in many synthetic endeavors.95 Recentefforts by Chida’s group towards A-315675, an anti-influ-

enza agent from the Abbott Laboratories, serve as a repre-sentative example (Scheme 42).96 This target compoundcontains a highly functionalized pyrrolidine core with acis-propenyl group as well as four contiguous stereogeniccenters including a vicinal diamino moiety and a tertiaryether function. These unique structural features are notonly crucial for A-315675’s biological activity as an anti-influenza agent, but also offer a great synthetic challenge.The vicinal diamino moiety was stereoselectively con-structed by a cascade Overman rearrangement in 182. TheZ-selective Horner–Wadsworth–Emmons olefination en-visaged for incorporating the a,b-unsaturated WA struc-tural unit in the key building block 183 relied upon the useof Ando’s reagent, 179b.

Scheme 42

Recently, olefin cross-metathesis using ruthenium car-bene complex 184 developed by Grubbs was also found toenable access to the a,b-unsaturated WA structural unit(Scheme 43).97a Terminal alkenes with N-methoxy-N-methylacrylamide (185) under the influence of Grubbs’

F

NH

OH

O

OH

O

R

P2P1NO

F

BocHNO

O O

O

R

P2P1NN

O

OMe

Me

Z O

O

a: R = F; P1 = Boc; P2 = Hb: R = H; P1 = P2 = Bn

a: Z = Brb: Z = MgBr

173174

175 176

177S

Scheme 41 Various reagents for a,b-unsaturated WAs

RO PN

OMeO

MeOR

O

Ph3PN

OMe

O

Me

SN

OMeO

Me

O

179a: R = Et [Boumendjel, 1989]179b: R = Ph [Ando, 2001]179c: R = CF3CH2 [Deslongchamps, 2002]179d: R = o-tolyl

SN

OMeO

Me

N

S

O O

[Evans, 1990]

[Boumendjel, 1998]

[Aidhen, 2006]

R NOMe

O

Me

RCHO RX

178 180

181

OTBDPS

MeO

OHN

CCl3

OHN

CCl3

n-PrOTBDPS

MeO

NHCOCCl3

NHCOCCl3

OTBDPS

MeO OH

OH

NH

OMeH

AcHNCOOH

OTBDPSN

O

O

O

OMe

Me

OTBDPSO

O

O

NaH, THF–78 °C82% (Z-isomer)

A-315675

182

183

179b



catalyst 184 and a boron-based Lewis acid as additive fur-nished the a,b-unsaturated WA in low to moderate yields(24–53%). This approach has been used for the prepara-tion of starting substrate 187b from 187a for the synthesisof substituted benzoxacycles 186 via a domino ortho-alkylation–Heck-coupling sequence.97b

Scheme 43

The a,b-unsaturated WA structural unit has shown uniquereactivity in two ways. In light of the fact that a,b-unsat-urated aldehydes and ketones are poor substrates forasymmetric dihydroxylation (AD) processes, the facileand convenient AD of a,b-unsaturated WAs has allowedfor an indirect access to these functionalities(Scheme 44).98a The modified AD-mix-a containing(DHQ)2PHAL was required to achieve good turnoverrates.

The concept has been used for the gram-scale synthesis ofenantiomerically pure 2-methylglycerol acetonide build-ing blocks (S)-188 and (R)-189 using 2-methylprop-2-enoic acid WA 190 as the starting substrate.98b These

building blocks further enabled convenient access to theO-benzyl-2-methylglycidol derivatives (S)-191 and (R)-192.

A similar advantage was observed during cyclopropana-tion of a,b-unsaturated WA (Scheme 45) for indirect ac-cess to a,b-cyclopropyl ketones, particularly when well-documented direct cyclopropanation of a,b-unsaturatedketones failed.99 It is believed that the oxygen atom of themethoxy group in the WA, through its inductive effect, isthe key to the facile Michael addition of dimethylsulfoxo-nium ylide 193 onto 194a that took place in one hour at50 °C to yield 90% of 195, because similar attempts of cy-clopropanation on the dimethyl analogue substrate 194bunder the same conditions resulted in only 76% conver-sion, even after 48 hours. In addition, no cyclopropanationoccurred with the N-hydroxy analogue 194c when it wastreated with two equivalents of 193. Presumably, this wasbecause the first equivalent of 193 abstracts the protonfrom the hydroxy, thereby increasing the electron densityon nitrogen and decreasing the electron-deficient natureof the double bond.

Scheme 45

The a,b-unsaturated WA structural unit allows for Micha-el addition with nitrogen-centered nucleophiles. From thesuccessful diastereoselective hetero-Michael addition oflithium (S)- or (R)-N-allyl-N-a-methylbenzylamide toa,b-unsaturated WA disclosed by the Davies researchgroup,100 the product b-aminoamide 196 has opened upmany possibilities for chiral b-amino ketones and alde-hydes (Figure 8).

In the first report,100a lithium (S)-N-allyl-N-a-methylben-zylamide was added to 197 to obtain (3S,aS)-hexanamide

R NOMe

O

MeR

O

R

187a: R = H187b: R = CON(OMe)Me

O

PhO

NOMe

Me

Ru O

N

N

Mes

Mes Cl Cl

184

184, 185

186

NOMe

O

Me

185

Scheme 44

RN

O

OMe

Me

n

n = 0, 1R = alkyl, Ph

RN

OOMe

Me

n

OH

OH

AD-mix-α

MeSO2NH2

t-BuOH–H2O

NOMe

O

Me

NOMe

O

MeHO

HON

OMe

O

MeHO

HO

OHOO

OHOO

OBnO

OBnO

AD-mix β AD-mix α

MeSO2NH2t-BuOH–H2O

MeSO2NH2t-BuOH–H2O

188 189

191 192

190

Ph N

O

Z

Me

Ph N

OOMe

Me

194a: Z = OMe194b: Z = Me194c: Z = OH

H2CS

MeMe

O

193

195

Figure 8 Products of Michael addition on a,b-unsaturated WA

NOMe

O

Me

N Ph

Li

N Ph

Li

NOMe

O

Me

NPh NPh

NPh H2NCl

196

197

198

199 200



196 in 65% yield and greater than 95% de. Reduction ofWA 196 with diisobutylaluminum hydride to the alde-hyde and subsequent Wittig reaction furnished diene 198in 62% yield over two steps, in greater than 95% de. Fi-nally, ring-closing metathesis produced the N-protectedcyclic amine 199 in 91% yield, which, after hydrogena-tion and treatment with hydrochloric acid furnished (S)-coniine hydrochloride (200) in 95% yield.

Troin, while exploring the addition of 201 on cinnamicacid derived WA 202a, observed some major difficul-ties.101a It failed to furnish any product arising fromMichael reaction. Instead, being a strong base, 201 effect-ed demethoxylation of WA 202a, presumably by an E2pathway, to afford 202b in an isolated yield of 71%. Anextra step in Figure 9 not only allowed circumvention ofthis difficulty, but also ensured immediate and convenientaccess to the WA group. The diastereoselective conjugateaddition of 201 onto 202c in tetrahydrofuran at –78 °C af-forded ester 203a in an excellent yield of 94% (de >94%).The ester functionality was converted into WA 203b, us-ing a combination of DMHA hydrochloride and trimeth-ylaluminum, in high yield (90%). The Cbz-protected WA204 served as a building block for the asymmetric synthe-sis of 1,3-aminoketals 205, and 2-monosubstituted and2,6-disubstituted piperidines 206.101b

Figure 9

An alternative approach to b-amino ketones using the WAfunctionality stemmed from an observation made duringthe addition of vinylmagnesium bromide to a WA(Scheme 46).101c,d In the anticipated a,b-unsaturated ke-tone, the reactive acryloyl unit could not possibly evadethe facile Michael addition of the liberated DMHA, andhence furnished b-N-methoxy-N-methylamino ketones207. This observation, made by Gomtsyan101c and others,has thus enabled the development of a direct route to b-amino ketones.101d In the developed route, after the initialaddition of vinylmagnesium halide, a secondary amine isdeliberately added; this amine successfully competes withDMHA, or the corresponding magnesium amide 208, dur-ing Michael addition to furnish b-amino ketones 209.

However, successful incorporation of the acryloyl unitthrough the addition of vinylmagnesium bromide ontoWA 210, without any Michael addition problem from theliberated DMHA, is also possible; this was accomplishedduring the synthesis of compound 211 en route to the totalsynthesis of lasonolide.101e

Scheme 46

The successful addition of the N-methoxy-N-methylacet-amide potassium enolate (212) onto N-sulfinyl imines 213by the Davis research group is another approach taken toincorporate WA functionality and thereby assemble theimportant scaffold, N-protected b-amino WA 214, whichitself is capable of delivering N-protected b-amino ke-tones or aldehydes (Scheme 47).102a N-Sulfinyl b-aminoWA 214, despite the presence of the acidic sulfonamideproton, reacts with various organometallic reagents to af-ford the corresponding N-protected b-amino carbonylcompounds in good yields. The utility of these new b-ami-no carbonyl compounds has been illustrated by the con-

R X

O

N PhPh

Li

202a: X = N(OMe)Me 202b: X = NHMe202c: X = OMe

R X

ON

Ph

Ph

203a: X = OMe203b: X = N(OMe)Me

R = Ph, Me, Pr

R N

ONHCbz

OMe

Me

R2 = H, Ph, Pr

R1

NH2

OO

R2

NH

R2 R1

201

204

205206

R1 NOMe

O

Me

MgBr

HNR2R3

R1

O

R1

O

NR2R3

BrMgN(OMe)Me

R1 = alkyl, arylR2, R3 = alkyl, benzylR2, R3 = -(CH2)5- or -(CH2)2O(CH2)2-

MeON

OBnO

Me

OH

OBn

O OH

MgBr

R1

O

NOMe

Me207

208

209

210

DMHA or

211

Scheme 47

R2 H

NS

R1

O NMe

O K

OMe

R2 N

NH O

Me

OMe

SR1

O

R2 H

NS

R1

O

(S)-(+)-213 (R1 = p-tol or t-Bu)

THF, –78 °C

[R2 = Ph, Me, n-Pr, t-Bu, Cl(CH2)4-, (E)-MeCH=CH-]

52–82%

NMe

O Li

OMeTHF, –78 °C

H

R2 N

NH O

Me

OMe

SR1

O

R2 N

NH O

Me

OMe

SR1

O

67–99% (R2 = Ph, Et)

R1 = 2,4,6,-i-Pr3C6H2

212

214

215

216a (major) 216b (minor)

+



cise asymmetric synthesis of the sedum alkaloids (+)-sedridine and (–)-allosedridine.102b Replacement of theenolate of N-methoxy-N-methylacetamide 212 with thatof N-methoxy-N-methylpropylamide 215 brings to lightthe additional possibilities of synthesizing a-substitutedb-amino WAs 216.

Recent studies by Davis and co-workers have shown thatof the four possible diastereoisomers, the syn-a-substitut-ed b-aminoWA 216a is the major product.102c Althoughthe E-geometry of the enolate and chair-like transitionstate accounts for the preponderance of the syn-product,the geometry of the enolate during the reaction conditionscould not be independently confirmed.

Building block 217, easily available by a simple syntheticscheme starting with fumaroyl chloride (218a), attemptsto combine the strengths of N-acyliminium chemistry andWA functionality (Scheme 48). It contains the requisiteprecursor moiety for generating an N-acyliminium ionand thereby allowing addition of a variety of p-nucleo-philes as illustrated here by the use of allyltrimethylsilane.Subsequent diastereoselective double addition of a varietyof Grignard reagents furnishes a new strategy for the syn-thesis of the b-amino alcohol structural scaffold 219.103

The WA-based building block 220a was obtained fromthe corresponding acid, a-(tert-butyl) (S)-N-(tert-but-oxy)carbonylaspartate, using the Wernic procedure16b

involving activation with (benzotriazol-1-yloxy)tris(dimeth-ylamino)phosphonium hexafluorophosphate (BOP·PF6)and subsequent reaction with DMHA in presence of tri-ethylamine. WA 220a has been the most practical and im-mediate source for (S)-aspartate semi-aldehyde 220c viathe protected precursor 220b (Scheme 49). This aldehyde220c, which exists in the hydrated form, has a prominentrole in a variety of biochemical studies.104a,b Aldehyde220b and its higher homologue 221b, obtained from theglutamyl WA 221a in a similar manner, have been sub-jected to the Wittig reaction for stereoselective synthesisof allyl and homoallyl glycines 222 (n = 1 and n = 2) re-spectively.104c The side-chain modification in the aspartyland glutamyl residues through the aldehyde has been alsoachieved on solid support.104d Similarly, the N- and side-chain-protected aspartyl and glutamyl WAs have servedas convenient building blocks for the corresponding alde-hydes. Reduction of the amides with bulky hydrides suchas lithium tri-tert-butoxyaluminum hydride or lithiumtris[(3-ethylpent-3-yl)oxy]aluminum hydride (LTEPA)proceeded better than reduction with the conventionallithium aluminum hydride.104e Various Boc-protected nat-ural and unnatural a-amino acids have been convertedinto the corresponding aldehydes using this approach.104f

Another WA-based building block from the domain of a-amino acids is that derived from serine a-amino acid 223a(Scheme 50). Three N-protected serine derivatives 223b–d have been converted into the corresponding WAs 224b–d by standard protocols.105 The lowered acidity of the a-proton enabled convenient displacement of the b-hydroxygroup by the azide nucleophile through the mesylate inter-mediate, whereas a similar attempt on the ester led to theexclusive formation of eliminated product 225. The avail-ability of b-azido-substituted WA derivatives 226b–d ona multi-gram scale opened up avenues for successful nu-cleophilic addition that had not been possible until then.Utilization of this short reaction sequence now allows forthe synthesis of a,b-diamino acids.

Scheme 48

HNN

Me

OMe

O

OMe

Cbz

XX

O

O218a: X = Cl218b: X = NMe(OMe)

MeON

Me

OMe

O

OH

BnO NH2

OO3

4 Å MS, CH2Cl2, reflux

i.

ii. p-TsOH, MeOH

BF3⋅OEt2 CH2Cl2HN

NMe

OMe

OCbz

TMS

HNN

Me

OMe

OCbz

HNR1

OHCbzMe

R1 = Et, allyl

217

219

Scheme 49

221

CH2=PPh3O

NH

O

OO

H

222

R2

NH

OR1Z

O

OH

220

O

NH

N(OMe)Me

O

O

OO

H

n

N- and side-chain-protectedaspartyl/glutamyl WA

a: Z = N(OMe)Me, R1 = t-Bu, R2 = Bocb: Z = H, R1 = t-Bu, R2 = Bocc: Z = H, R1 = R2 = H

R2

NH

OR1Z

O

OH

n

a: Z = N(OMe)Me, R1 = t-Bu, R2 = Bocb: Z = H, R1 = t-Bu, R2 = Boc

n

Scheme 50

PHNN

OMeO

OHMe

PHNOMe

O

OH

PHNN

OMeO

N3Me PHN

OMeO

PHNOH

O

OH

a: P = H b: P = Boc c: P = Cbz d: P = Fmoc

224

223a

226 225



The use of 224b as a template has paved the way for anelegant and straightforward synthesis of sphinganines,represented here by compound 227; further protection of224b presented two other serine-derived WAs, 228 and229, as valuable building blocks (Scheme 51).106 Use ofall three of these was explored in the synthesis of 227. Itis obvious that 224b, with its two exchangeable protons,would necessitate the use of multiple equivalents of tet-radecyllithium, and would thus be unacceptable when theorganolithium reagent is expensive or difficult to prepare.Use of two equivalents of either n- or sec-butylmagne-sium chloride, as a sacrificial base prior to the addition oftetradecyllithium, circumvented the excess use of the lat-ter and furnished the desired ketone 230 in yields rangingfrom 63 to 78%. Unfortunately, despite the advantage thatWA 228 is easily available from 224b, and its use for thesame objective requires only one equivalent of sacrificialbase, the obtained ketone 230 was contaminated with in-separable and unidentified impurity. Also, since 229 doesnot react with long-chain organometallic reagents, the ap-proach starting from 224b is the most practical.

Scheme 51

Given the importance of the fluoro analogues and in a bidto increase the potency of molecules important in biology,regioselective aldol reaction of fluoroacetone with alde-hydes has been visualized as an effective technique, inprinciple, to introduce fluorine into the molecule(Scheme 52).107 The aldol reaction of fluoroacetone(231a) with aldehyde 232 under basic conditions usinglithium diisopropylamide, or sodium or potassium hexa-methyldisilazide, however, is not trivial and has failed tofurnish any of the aldol product 233 or 234. In and indirectand interesting pathway, the carbanion obtained from a-fluoro WA 231b using lithium diisopropylamide reactedcleanly with 232, furnishing the intermediate 235 in highyields. Further addition of methylmagnesium bromideprovided easy access to the aldol product 234. The otherregioisomer, 233, was obtained through the addition ofboron enolate of fluoroacetone (231a) onto aldehyde 232.The formation of boron enolate involved the use of dibu-

tylboron triflate in the presence of Hünig’s base (diisopro-pylethylamine, DIPEA).

In an attempt to obtain pharmacologically important g-alkylidenebutenolides 236 through an approach based oncondensing dicarbanion of 1,3-dicarbonyl compoundswith simple oxalic acid dielectrophiles (Scheme 53), thereactions of 237 with oxalyl chloride 238a, diethyl oxalate238b and 1,4-dimethylpiperazine-2,3-dione 238d failedto furnish the desired product. However, the dianion 237from ethyl acetoacetate reacted cleanly with the bis-WAof oxalic acid (238c) and afforded the desired product 236in 75% yield.108 This clear success and the observed regio-selectivity were rationalized through the possible forma-tion of the chelated intermediate 239, which could bepossible only with 238c.

Scheme 53

The bromoalkanoic acid derived WAs represent yet an-other small building block capable of appending the WAfunctionality as part of a synthetic objective. The bro-moacetic acid WA 240a, readily available from the a-bro-moacetyl bromide, has been used by Palomo109a andothers109b as a nucleophilic synthon, through a Refor-matsky addition procedure under zinc-mediated condi-tions (Scheme 54).

The b-hydroxy WA 241 and its b-trimethylsilyloxy coun-terpart are masked aldol products capable of further de-rivatization into b-hydroxy aldehydes and ketones. Anattempt to obtain nonracemic aldol product 241, throughthe influence of chiral 1,2-amino alcohols as ligands un-

TBSO NOMe

BocHN

O

Me

NOMe

O

MeO

NBoc

NOMe

BocHN

O

Me

RBocHN

O

R = -(CH2)13Me

s-BuMgCl (2 equiv)

OH OH

n-C14H29Li

R

BocHN

OH

TBSOR

H2N

OBn

HO

228 229

227

224b230

Scheme 52

N

S

OH O

N

S

H

O

F

N

S

R

OH O

F

235: R = N(OMe)Me

234: R = Me

MeMgBr 0 °C

R

OF

231a: R = Me231b: R = N(OMe)Me 232

233

231a

1. n-Bu2BOTf DIPEA

2. 232

O

OX

X

238a: X = Cl238b: X = OEt238c: X = N(OMe)Me

OEt

O O

N

N

O

O

ON

OLi

O

NMeO

LiO

Me

Me

Me

OOEt

O

OOEt

O

HO

237

238d: X =

236

239



der zinc-mediated reaction conditions, met with limitedsuccess.

The 3-bromopropanoic acid, 5-bromopentanoic acid and6-bromohexanoic acid derived WAs 240b–d have beenused as electrophilic synthons. WA 240b was used in thesynthesis of unsymmetrical 1,4-diketones 242109c and b-(N,N-disubstituted)amino ketones 243109d (Scheme 55).For the synthesis of the former, the key step involvedalkylation of various aryl and heteroaryl a-aminonitrileswith 240b followed by addition of the Grignard reagent tothe alkylated product 244 and unmasking of the carbonylgroup under acidic hydrolytic conditions. For the latter,various secondary amines were first alkylated with 240b,then subsequent Grignard addition onto 245 furnished theb-amino ketones 243.

Scheme 55

The WAs 240c and 240d have served as valuable startingsubstrates enabling convenient synthesis of pyrimidin-ones 246a and 246b that contain the WA functionality(Scheme 56).109e

Alkylation of the potassium salt of ethyl cyanoacetate(247) with 240c and 240d and subsequent reaction withthe free base of guanidine (248) under basic conditionsgave the desired pyrimidinones 246a and 246b, respec-tively. The protection of the amine groups, followed byreaction with aryl- or heteroaryllithiums, furnished a con-

venient access to a series of simplified a-keto heterocy-cles 249 for glycinamide ribonucleotide transformylase(GARTfase) inhibition studies.

One of the most extensively used building blocks contain-ing the WA functionality is that derived from tartaric acid(Figure 10). The 2,3-O-isopropylidene-1,4-bis-WAs 250and 251 are extremely important, particularly when the1,4-carboxylate residues on the tartaric acid are to be dif-ferentiated.

Figure 10 Tartaric acid derived WA

The conveniently accessible diester, (–)-dialkyl 2,3-O-isopropylidene-L-tartrate 252110 and its enantiomer 253111

from D-(–)-tartaric acid have been converted into the cor-responding bis-WAs 250112 and 251113on treatment withDMHA hydrochloride in presence of trimethylaluminum.

Although convenient access to C2-symmetric 1,4-dike-tones was known to be possible through the addition ofGrignard reagents onto WA 250,112 it was the systematicstudy by McNulty that unraveled the importance of exper-imental conditions and the potential of 250 for furthersynthetic exploitation (Scheme 57).114

Mono-addition of simple alkyl groups through Grignardreagents furnished the ketoamide 254 in good isolatedyields when the bis-amide 250 was treated with oneequivalent of R1MgX at temperatures ranging from –78 to22 °C. Use of large excess of R1MgX led to a straightfor-

Scheme 54

BrN

OOMe

Men

R H

O Zn, Me3SiCl

THF N

OOMe

MeR

OH

a: n = 1; b: n = 2c: n = 4; d: n = 5

R = phenyl 241

240

240a

N

O

R1 CN

N

O

R1CN

N

O

OMe

Me

R2MgX

N

O

R1CN

R2

O

240b

R1 R2O

O242

244R1 = aryl or heteroaryl

R2 = alkyl or aryl

N

O

R3

R4N N

O

R3

R4

Me

OMeR2MgX

245 243

R2

Scheme 56

MeONMe

On

OEt

N

O

NH2

HN NH2

MeONMe

On

NH

N

O

NH2H2N

MeONMe

On

NBoc

N

O

NHBocBocHN

Ar

On

NH

N

O

NH2H2N

TFA

Ar =S

N

S

N N NN

N

N

(Boc)2OOEtNC

O K240c240d

247

246a: n = 3246b: n = 4

248

249

Et3N

ArLi

ROOR

O

OO

O

ROOR

O

OO

O

MeON

NOMe

O

OO

OMe

Me

MeON

NOMe

O

OO

OMe

Me

R = Me or Et

250 251

252 253



ward synthesis of symmetrical diketone 255, and stepwiseaddition of Grignard reagents led to unsymmetrical dike-tone 256.

Using this precedence, various ketoamides 254 were re-cently prepared by Prasad and co-workers and these prod-ucts were subjected to stereoselective reduction for anefficient entry into the synthesis of various classes of nat-ural products.115a–f Representative examples of the ketoa-mides prepared and used, along with the targeted naturalproduct, are depicted in Scheme 58. In the targeted syn-theses, the first operation on the keto amide was the stere-oselective reduction of the keto group using either L- orK-Selectride and subsequent protection of the resultinghydroxy group. Alternatively, stereoselective reduction ofthe keto group in the ketoamide 254, followed by ace-tonide removal and concomitant cyclization, has pavedthe way for an efficient strategy to g-alkyl(aryl)-a,b-dihy-droxybutyrolactones 263.115f

Scheme 58 Use of ketoamide 254 in the synthesis of various natu-ral products

Bruckner et al.116 used the keto amide 258 (Scheme 59) ona multi-gram scale for Wittig olefinations with stabilizedylides 264 and 265 in their novel strategy towards thebutenolide moiety of peridinin. The WA functionality ap-parently should afford direct access to the requisite alde-hyde 266 and 267 needed for the synthetic endeavor, but

the presence of the a,b-unsaturated ester probably de-terred direct reduction with lithium aluminum hydride.

The authors used eight equivalents of sodium borohydrideto selectively reduce the WA functionality in 268 and 269to obtain the corresponding alcohols 270 and 271; theseproducts were then re-oxidized under Swern conditions toarrive at 266 and 267. It is worth noting that reduction ofthe WA to the alcohol in the presence of the ester seemsto be the first such observation.

In contrast to the formation of keto amides, the formationof C2-symmetric ketones 255 using excess amounts ofRMgX or RLi was simple and straightforward(Scheme 60). Excellent use of various C2-symmetric 1,4-diketones 255 has been made in variety of synthetic en-deavors and the most prominent and extensive amongthem originates from Prasad’s laboratory.117a–e A varietyof C2-symmetric 1,4-diketones, obtained from buildingblock 250, provided an efficient strategy for the enantio-selective synthesis of a-O-benzylated aldehydes 272.

Scheme 60

The highly stereoselective reduction of the C2-symmetricdiketone 255 at low temperatures using L- or K-Selectridewas the key reaction in the strategy for the synthesis of a-O-protected aldehydes. The a-O-benzylated aldehydes272a–d (Scheme 61) have served as a building block forthe synthesis of (+)-exo-brevicomin,117a (–)-muricata-cin,117b the (–)-acid fragment of (–)-microcarpalide117c and(–)-disparlure.117d Stereoselective reduction of the dike-

Scheme 57

R1MgCl

THF, 0 °C250 R1 N

OMe

O

OO

O

Me

R1 R1

O

OO

OR1 R2

O

OO

O

255 256

254 R2MgClTHF, 0 °C

R1MgCl(excess)

(+)-hydroxy-exo-brevicomin

(–)-hydroxy-exo-brevicomin

(+)-2-hydroxy-exo-brevicomin

(–)-2-hydroxy-exo-brevicominboronolide

Guggul tetrol

γ-alkyl(aryl)-α,β-dihydroxy-γ-butyrolactone

257

258 R = Me

259 R = Et

260261

262

263

254

RN

OMeO

OO

O

Me

ref.115a

ref.115b

ref.115c

ref.115d

ref.115e

ref.115f

ref.115f

R = (CH2)2CH=CH2

R = n-Bu

R = (CH2)3CH=CH2

R = C14H29

R = Me, Et, n-Bu

Scheme 59

P(Ph3)3MeOOC

toluene, reflux, 27 h

(2 equiv)

toluene, reflux, 30 h(2 equiv)265264

266: Z = CHO268: Z = CON(OMe)Me270: Z = CH2OH

258

NOMe

O

OO

O

Me

ZO

O

MeOOCZ

O

OMeOOC

Ph3P COOMe

267: Z = CHO269: Z = CON(OMe)Me271: Z = CH2OH

RO

OR

O

O

ROH

HOR

O

O

ROBn

OBn

R

OH

OH

R

OBn

O

H

K-Selectride

THF, –78 °C 2.5 h

1. NaH, DMF, BnBr 0 °C, 2 h2. FeCl3⋅6H2O, CH2Cl2 r.t., 2 h

Pb(OAc)4

C6H6, r.t., 1.5 h

272

255



tone 273, followed by protection of the resulting hydroxygroups and functionalization of the alkenyl residues, ledto a new strategy for preparing the tetrahydropyran frame-work of (–)-centrolobine (274; Scheme 62) through aniron(III) chloride mediated cyclization of the 1,5-diolunit.117e

Scheme 61 Utility of C2-symmetric diketone 255

Scheme 62

The symmetrical diketone 275, prepared by the additionof the magnesium salt of THP-protected propargylic alco-hol to 250, has provided convenient access to the tetra-hydroxy-substituted ten-membered cyclic enediynestructure 276118 (Scheme 63) through a series of function-al group manipulations and a pinacol-type ring closure onthe bis-aldehyde 277 using Pederson’s vanadium(II) re-agent.

Strategies involving oxidative cleavage of the diol unit af-ter synthetic operations on the carbonyl groups have alsoyielded valuable building blocks. C2-Symmetric 1,4-diar-yl diketones 278 have been used for the synthesis of a-methoxyarylacetic acids,119a a-methyl-a-methoxyarylace-tic acids119b and TADDOL analogues119c (Scheme 64). Itis important to note that one can also use bis(N,N-dimeth-ylamide) 279 instead of 250 for the convenient synthesisof 280 and 281.120

Hydrolysis of the acetal unit in C2-symmetric 1,4-dike-tones 282, followed by dioxolane protection of the carbo-nyl groups and subsequent oxidative cleavage, provides aconvenient route to protected a-keto aldehydes 283(Scheme 65).121

OR

HOBn

(+)-exo-brevicomin

(–)-muricatacin

(–)-disparlure

(–)-microcarpalide

272a: R = (CH2)3CH=CH2 272b: R = C12H25272c: R = C10H21 272d: R = (CH2)2CH=CH2

272

a

b

c

d

O

O3

3

O

O

O

O3

3

OTBS

OTBS

1. L-Selectride2.TBSCl

O

O

Ar

3

3

TBSO

TBSO

Ar

OH

OH

1. ozonolysis2. 4-MeOC6H4MgBr

OO

Ar

Ar

HO

HO

+other isomer

OH

OH

ArH

advanced precursor for (–)-centrolobine

Pb(OAc)4

273

274

FeCl3

Scheme 63

O

O

O

O

OTHP

OTHP

O

O

OTBS

OTBS O

H

O

H O

O

TBSO

TBSO

OH

OH

HO

HO

TBSO

TBSO

1. DIBAL-H2.TBSCl

O

O

OTBS

OTBS

OTHP

OTHP

1. MgBr22. DMP

[V2Cl3(THF)6]2 Zn2Cl6

275

276

277

Scheme 64

O

O

OH

OOMe

Ar

OMe

O

O

Ar

OMe

ArMe

Me

OMe

HO

HO

Ar

OMe

ArMe

MeOH

OOMe

ArMe

O

Ar

O

Ar

1. MeMgBr2. NaH, MeI

FeCl3⋅6H2O

278

MeN

NMe

O

OO

OMe

Me

279

OMe

HO

HO

Ar

OMe

Ar

1. K-Selectride2. NaH, MeI3. FeCl3⋅6H2O

Pb(OAc)4

Pb(OAc)4

280 281

Scheme 65

RO

OR

O

O

RR

HO

OHOO

O O

RO

OOH

2. (CH2OH)2

282Pb(OAc)4

R = Ph, n-C7H15

PTSA, C6H6

283

1. TFA, H2O



Finally, in our own research, we have developed severalWA-based synthetic equivalents for specific objectives.Although the initial development of these was driven by aspecific objective, their use is wide open to the imagina-tion. Among those developed, two – 180 and 240b – havealready been discussed; the others are shown in Figure 11.

Figure 11 Various WA-based synthetic equivalents developed inour research program

N-Methoxy-N-methyl-2-phenylsulfonylacetamide (284),easily obtained by the reaction of the sodium salt of phe-nylsulfinic acid with a-chloro-N-methoxy-N-methylacet-amide,122a was developed for use in the two-carbonhomologation of alkyl halides.122b Successful alkylationof 284 with various alkyl halides under the mild condi-tions of potassium carbonate in N,N-dimethylformamide,followed by reductive desulfonylation with sodium amal-gam and reduction of the WA to the aldehyde, renders 284equivalent to an acetaldehyde carbanion. Given the factthat aldehydes with a-stereocenters do have the potentialto epimerize while effecting two-carbon homologationwith Wittig-based reagents, the approach with 284 is im-portant and necessary in the domain of carbohydrates.Two-carbon homologations of various iodides(Scheme 66) have been realized. That of the threo-config-ured iodide 291 enabled the efficient synthesis of 4,5-O-isopropylidine-protected L-rhodinose,123 an importanttrideoxy sugar, and that of arabino-configured iodide 292furnished the C3–C9 fragment of the natural product (+)-aspicillin.122b The erythro-configured iodides 293 and 294have been used in the synthesis of another trideoxy sugar,D-amicetose.124

The dithiolane- and dithiane-based carboxamides 285 and286 derived from glyoxalic acid represent novel syntheticequivalents for an a-dicarbonyl unit with opposing polar-ities (Scheme 67).32b They have been conveniently pre-pared on gram-scale as crystalline solids through an initialacid-catalyzed thioketalization of the aldehyde group inglyoxalic acid with ethane-1,2-dithiol or propane-1,3-dithiol and subsequent conversion of the carboxyl groupinto the WA. Nucleophilic addition onto the WA in 285 or286 followed by alkylation provided a new strategy forthe synthesis of the targeted mono-protected b-diketonesin moderate to good yields. An interesting application ofthis new protocol was the successful synthesis of 6-(2-methyl-1,3-dithiolan-2-yl)-2,3,4,5-tetrahydropyridine (295),a dithioacetal-protected derivative of the important targetmolecule 296, a tautomer of a compound responsible forthe bread flavor. The requisite carbon skeleton to arrive atcompound 295 was easily assembled in good yields bynucleophilic addition of 4-(2-tetrahydropyranyloxy)bu-tylmagnesium bromide on 285 followed by methylation atC2 position to furnish 297. Further functional group inter-conversion gave convenient access to the azido ketone298 as a key intermediate which underwent phosphine-mediated cyclization affording the target 295.

Scheme 67

Recently, the development by our research group of thethree synthetic equivalents 287, 288 and 289 using com-mercially available p-toluic acid was triggered by the im-portance of FTY-720 (299) as an immunosuppressant,currently in phase III clinical trials (Scheme 68).125

These synthetic equivalents for the central core of 299have enabled incorporation of the polar head groupthrough Julia, Wittig and Horner–Wadsworth–Emmonsreactions and also provided an excellent handle, in theform of the WA functionality, for complete control overthe length of the lipophilic side chain. All the reactionsand conditions en route to the target molecule are simple

PhO2SO

NMe

OMe

284

S Sn

HO

NOMe

Me

285: n = 0 286: n = 1

N

OOMe

Me

289: X = SN

S

288: X = -P(O)(OEt)2

287: X = -P(Ph)3BrX

O O

OHN

PhO2S

290

NOMe

Me

Scheme 66 Alkylation of sulfone 284 with various sugar halides

284 N

OOMe

Me

R

I

O

OI

O

O

I

OTBS

OBn

IO

O

O

O

291 292 293 294

S Sn

HO

NOMe

Me

O

O285: n = 0 286: n = 1

285S S

HO

R

RMgX R1XS S

R1

O

R

S S

MeO

OTHP3

S S

MeO

S SMe

N

MeN

O

295296

297 298

1. THPO(CH2)4 MgBr, THF2. MeI, NaH, DMF

Ph3P

N3

H COOH

O



and good-yielding and therefore hold significant promisefor industrial application. The olefination of protectedtris-aldehyde 300 with either 288 or 289 using threeequivalents of potassium carbonate in a 1:3 mixture ofN,N-dimethylformamide and tetrahydrofuran at 70 °Cyielded product 301 as the E-isomer in 70 or 60% yield,respectively. The same reaction using Wittig salt 287 af-forded the desired product 301 accompanied by its Z-iso-mer (E/Z = 1:3) in 70% yield. However, a simplehydrogenation of the E/Z-product mixture makes the for-mation of geometrical isomer with 287 inconsequential.The addition of n-heptylmagnesium bromide onto 301and 302 furnished the ketones 303 and 304 in 70% yields,which on reduction using sodium borohydride and subse-quent hydrogenolysis afforded the target compound 299in good yields.

The reagent N-methoxy-N-methyl-N¢-phenylsulfonylgly-cinamide 290, derived from glycine (305) in two steps isa crystalline solid with unlimited shelf-life. It has servedas a useful template for the general synthesis of 4-aryl-1,2,3,4-tetrahydroisoquinoline derivatives 306(Scheme 69).126 N-Benzylation, followed by nucleophilicaddition of ArMgX onto the WA group furnished the pen-ultimate precursor 307 for derivatives 306. Although theN-phenylsulfonyl group in 290 offers a robust protectionand also facilitates the desired alkylation, the use of othereasily removable protecting groups on nitrogen shouldfurther enhance the significance and the potential of thisglycine-derived WA building block.

4 Miscellaneous

The successful synthesis of resin-bound amines 308,127a

309,127b and 310127c equivalent to DMHA (Figure 12) hasmade available all the convenience and advantages asso-ciated with solid-phase synthesis. In amine 308, the solidsupport is anchored to the oxygen, whereas in amines 309and 310, the solid support is tethered to the nitrogen.

Figure 12 Resin-bound amines

N-Acylation on amines 308–310 affords the correspond-ing solid-supported WAs 311–313 (Figure 13). These an-chored WAs have enabled convenient access to N-Boc-amino aldehydes 314, from a-amino acids, and a-acyl-amino-a,a-disubstituted ketones 315. Until the synthesisof 316 by Tanner et al., there were no examples in the lit-erature of using lithiated alkynes and heterocyclic com-pounds as nucleophiles in the reaction with solid-supported WAs.

Very recently, an unusual and interesting product arisingfrom the sequential treatment of the glycine-based WA317a with lithium diisopropylamide and phenylmagne-sium bromide led to an efficient protocol for the a-aryl-ation of glycine (Scheme 70).128 The observation of the

Scheme 68

NH2⋅HCl

HO

HO

299

6

288 or 289

OO O

NHBoc

K2CO3, DMF

O

NOMe

Me

n-C7H15MgBr

NHBoc

6O

O

H2, Pd/C

O

300

301

301+ Z-isomer

304

NHBoc

6O

O

O

303

O

ONHBoc

O

NOMe

Me

302O

ONHBoc

299

300

n-C7H15MgBr303

287

Scheme 69

ArMgBr–40 °C

NaBH4MeOH

N

Ar

SO2Ph

TFAconcd H2SO4

307

30668–82%

OHN

PhO2S290

NOMe

Me

OH2N

305

OH

NSO2Ph

CON(OMe)Me

NSO2Ph

OAr

NSO2Ph

HOAr

BnBr

MeHN

OMe

HNO

Ph

O

HNO

Me

O

HNO

Me

OHN

A: support tethered through OB: support tethered through N

B

B

A

308

309 310



demethoxylated product 318a is not surprising as it arisesmerely from an E2 elimination reaction, as observed byGraham.7a It was the formation of 318b that hinted to-wards the possibility of a-arylation. With the use of O-(tert-butyl) WA 317b, wherein the elimination reaction iscompletely circumvented, similar sequential treatmentwith lithium diisopropylamide and phenylmagnesiumbromide furnished a-arylated amide 319 as the exclusiveproduct in 86% isolated yield. Expulsion of the tert-but-oxide anion from the initially formed enolate 320 seems tobe the key step which generates the iminium ion 321 andallows for the facile addition of various aryl residues asnucleophiles. This new chemistry of the WA functionalityis likely to bring a new dimension to its further explora-tion.

Scheme 70

Another important and interesting functional group inter-conversion effected using the WA functionality is its one-pot conversion into a terminal alkyne (Scheme 71) withthe use of the Bestmann–Ohira reagent (322).129 The WAis first reduced to the aldehyde using diisobutylaluminum

hydride, which in the same pot reacts with 322 under mildconditions (K2CO3, MeOH, r.t.). The reaction affords thecorresponding terminal alkynes 323 in good yields, rang-ing from 71 to 88%, and with complete preservation ofstereochemical integrity at the a-stereocenter.

Scheme 71

From Pohl’s research group, the synthesis of (R)-3-hy-droxyalkanoic acids 324, an important class of biological-ly active compounds, using (S)-3-hydroxy-b-butyrolactone as the starting building block, illustrates theonly use of the WA functionality as a protecting group(Scheme 72).130 The benzyl-protected lactone ring 325b,when opened using DMHA, afforded WA 326 in 87%yield. The amide functionality served as masked carboxygroup during the Parikh–Doering oxidation of the primaryhydroxy, the Wittig reaction on the aldehyde, and finallythe hydrogenation. Although the WA served as a ruggedprotection during these three steps, its hydrolysis and sub-sequent release of the free carboxy group was not all thatstraightforward. Conventional heating of 327 in aqueousmethanol (1:1) in the presence of potassium hydroxide (2N) failed to furnish the product; however, under micro-wave irradiation at 130 °C and 90 psi, the product was ob-tained in 20 minutes and in 87% yield.

Scheme 72

5 Conclusion

The stability of the WA functionality, its ease of prepara-tion, the scalability of its reactions and its predictable re-activity are the four main reasons for the increasingconfidence that synthetic organic chemists have with re-gard to the use of the WA in various synthetic endeavors.The development of new building blocks and synthetic

Figure 13 Resin-bound WAs

BnN

O

O

NO

Me

OR1

O

NO

Me

OHN

R2

O

R3

O

R1 =Me

NHBoc

Bn

NHBoc

R2 = -C(Me)2NHCOPh

R3 = PhR4 = Ph

or

O

R5 = Ph or Et

311 312 313

314: R1CHO315: R2COR5

316: R3COR4

or

BnNN

OR

O

Me

317a: R = Me317b: R = t-Bu

BnNNH

O

Me

LDA

PhMgBr R1

318a: R1 = H318b: R1 = Ph

BnNN

Ot-Bu

O

MeBnN

NOt-Bu

Me

O LiLDA

BnNNMe

O LiBnNNH

Me

O

Ar

ArMgX

–78 °C

–78 to 25 °C

317b

319 321

320

BocHNN

OMe

O

Me

P

O

N2

O

OMeOMe

DIBAL-H–78 °C

BocHNH

O

BocHN

H

r.t.

4 examples

322

323

322

O

O

RO

325a: R = H325b: R = Bn

MeON

OH

O

Me

OBn

MeON

O

Me

OH

HO

O OH

5 4324 327

326

DMHA

1. [O]2. Wittig3. hydrogenation

90 psi, 87%MW



equivalents based on the WA functionality will providesolutions to the existing problems or hurdles in syntheticschemes that aim at large and important objectives ofgreat significance in any field of science. The use of theWA in functional materials has yet to be explored, but thefour aspects mentioned above are bound to further inspireand motivate.

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the growing synthetic utility of the weinreb amide...dehyde group. these two aspects have been...

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