chiral auxiliaries – principles and recent applications · key words: asymmetric synthesis,...

REVIEW 1899

Chiral Auxiliaries – Principles and Recent ApplicationsChiral Auxiliaries – Principles and Recent ApplicationsYvonne Gnas, Frank Glorius*Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Straße, 35032 Marburg, GermanyFax +49(6421)2825629; E-mail: [email protected] 6 January 2006; revised 17 February 2006Dedicated to David A. Evans on the occasion of his 65th birthday

SYNTHESIS 2006, No. 12, pp 1899–1930xx.xx.2006Advanced online publication: 17.05.2006DOI: 10.1055/s-2006-942399; Art ID: E15206SS© Georg Thieme Verlag Stuttgart · New York

Abstract: With modern methods for asymmetric catalysis breakingground, the use of chiral auxiliaries seems to be old-fashioned andrather inefficient. However, for many transformations, chiral auxil-iaries often represent the only selective method available. In addi-tion, high levels of selectivity and reliability are often attractivecharacteristics of chiral auxiliaries and allow for the efficient andrapid synthesis of desired chiral compounds. In addition, even incases with imperfect selectivity, the use of an attached chiral auxil-iary allows the enrichment of diastereoselectivity, and hence enan-tioselectivity after removal of the auxiliary, by many standardseparation techniques. This article gives an overview on the mostimportant classes of chiral auxiliaries, discussing the mode of actionand highlighting some recent applications. It does not deal with theuse of chiral catalysts, chiral reagents or achiral auxiliaries.

1 Introduction2 Sulfinamides, Sulfoxides, Bis(sulfoxides)3 Camphor-Derived Auxiliaries4 Carbohydrate-Derived Auxiliaries5 RAMP, SAMP6 Alcohols, Amines, Amino Alcohols7 Oxazolidinones, Oxazolines, Oxazolidines8 Conclusion

Key words: asymmetric synthesis, chiral auxiliary, diastereoselec-tivity, sulfoxides, oxazolidinones, SAMP

1 Introduction

The increasing demand in the life sciences for enantio-merically pure compounds has led to a wealth of methodsfor asymmetric synthesis. Although asymmetric catalysisand biocatalytic methods increasingly allow for the effi-cient synthesis of many enantiomerically pure com-pounds,1 chiral auxiliaries remain to be the workhorses ofasymmetric synthesis.2 Chiral auxiliaries (XC) are enan-tiomerically pure compounds that are linked to a substrateand influence the stereochemical course of a reaction. Acertain functional group is needed in the substrate to se-lectively bind the auxiliary. In most cases the auxiliary isintroduced prior to the stereoselective reaction and re-moved afterwards. These additional synthetic steps andthe cost of stoichiometric amounts of auxiliary seem torender this approach rather unattractive.

Can chiral auxiliaries compete with methods like asym-metric catalysis? For many applications, no enantioselec-

tive catalytic method exists, and chiral auxiliaries are theonly available stereoselective method. Furthermore, aux-iliaries are generally reliable and the great knowledge ofchiral auxiliaries allows a high level of predictability, en-abling the synthesis of a plethora of enantiomerically purecompounds in a time-efficient manner. Most importantly,even in cases with imperfect selectivity, the use of an at-tached chiral auxiliary allows the enrichment of diaste-reoselectivity, and hence enantioselectivity after removalof the auxiliary, by many standard separation techniques.As a consequence, chiral auxiliaries are often the methodof choice in, for example, the early phases of drug devel-opment.3

With respect to the vast number and diverse nature of ap-plications of chiral auxiliaries in asymmetric synthesis2

this review cannot be a comprehensive treatment of chiralauxiliaries. Rather, it gives an update on some of the mostimportant classes of chiral auxiliaries, discussing theirmode of action and highlighting some recent applications.Each section begins with general information on the aux-iliary itself and methods for its incorporation. After thediscussion of a couple of insightful recent applications,each section ends with information about the cleavage ofthe particular auxiliary class. Chiral catalysts, chiral re-agents or achiral auxiliaries are not included in this re-view.

2 Sulfinamides, Sulfoxides, Bis(sulfoxides)

2.1 Sulfinamides

Three different substituents and an additional lone pairrender the sulfur atom of sulfinamides and sulfoxideschiral. Sulfinamides 1 are often employed in asymmetricsynthesis in the form of their N-sulfinimines. They areversatile precursors for a variety of chiral nitrogen-con-taining molecules. Commonly used chiral auxiliaries likep-toluenesulfinyl imines 2a and N-tert-butanesulfinylimines 2b can easily be derived by condensation of theenantiopure, commercially available (R)- or (S)-p-tolu-enesulfinamide or tert-butanesufinamide with an appro-priate aldehyde or ketone, mediated by, for example,Ti(Oi-Pr)4 (Scheme 1).4

The most important applications of these chiral auxiliariesare the synthesis of a- and b-aminoacids and 1,2- and 1,3-aminoalcohols.4 Typically, these chiral sulfinimines areemployed in nucleophilic addition reactions of C- and P-

1900 Y. Gnas, F. Glorius REVIEW

Synthesis 2006, No. 12, 1899–1930 © Thieme Stuttgart · New York

nucleophiles as well as [2+1] and [3+2] cycloadditions. Inaddition the C=N moiety is activated electronically by theN-sulfinyl group to such an extent that the addition of or-ganometallic reagents becomes a facile process. Since theN-sulfinyl group stabilizes anions at nitrogen, epimeriza-tion of the newly formed carbon stereocenter in the result-ing sulfinamide is prevented. Presumably, thestereochemistry is controlled by a cyclic transition state.In the presence of smaller and more covalently boundmetals, higher diastereoselectivities are obtained.5

A recent example for the innovative application of sulfin-imines was reported by Ellman and co-workers.6 Deproto-nation (possibly followed by transmetallation) of the tert-butanesulfinyl ketimine 3 forms an N-sulfinyl metallo-enamine 4. Addition of nitroalkenes or a,b-unsaturatedketones to the thus-formed electrophile led to Michael ad-ditions, wherein the additions to a,b-unsaturated ketonesproceeded with very high diastereoselectivities(Scheme 2). The obtained N-sulfinylamino ketones 5could be easily converted to piperidines 6 by stereoselec-tive reduction of 5 and subsequent cyclization. This se-quence represents the first asymmetric synthesis of 2,4,6-trialkyl-substituted piperidines.6 A similar example for

stereoselective reduction of sulfinimides is given inScheme 4.

The addition of N-sulfinyl metalloenamines 8 to alde-hydes were reported by Ellman and co-workers resultingin the asymmetric synthesis of syn- and anti-1,3-amino al-cohols.7 Deprotonation of the tert-butanesulfinyl ketimine7 occurs with LDA and is followed by addition of an alde-hyde resulting in the formation of 9 (Scheme 3). Additionof metal salts like MgBr2 or ZnBr2 gave higher diastereo-selectivities which have been attributed to a six-mem-bered transition state, depicted in 8a.

Furthermore, careful choice of the reducing agent allowsfor a highly diastereoselective syn or anti reduction of theb-hydroxy-N-sulfinyl imines 10 (Scheme 4).7

Scheme 1 Introduction of the chiral auxiliary.

R2 R3

NS

O

R1

S

O

R1H2N

R2 R3

O

R2 = alkyl, aryl R3 = alkyl, aryl, H

1 2a: R1 = p-Tolb: R1 = t-Bu

Yvonne Gnas was born inMarburg (Germany) in1981. She studied chemistryat the Philipps-University in

Marburg and obtained herdiploma in 2005. She is cur-rently working as a Ph.D.student in the group of Prof.

Glorius on asymmetric hy-drogenation reactions.

Frank Glorius was educat-ed in chemistry at the Uni-versität Hannover, StanfordUniversity (Prof. Paul A.Wender), Max-Planck-In-stitut für Kohlenforschungand Universität Basel (Prof.Andreas Pfaltz), and Har-vard University (Prof.David A. Evans). In 2001 he

began his independent re-search career at the Max-Planck-Institut für Kohlen-forschung in Mülheim/Ruhr(Germany). Since 2004 he isa Professor of OrganicChemistry at the Philipps-Universität Marburg. Thepurpose of his research pro-gram is to significantly fa-

cilitate organic synthesis bydeveloping new conceptsfor catalysis. At present hisgroup focuses on the designof new N-heterocyclic car-benes, challenging cross-coupling reactions, asym-metric hydrogenations, andorganocatalyzed umpolungreactions.

Biographical Sketches

Scheme 2 Diastereoselective addition of N-sulfinyl metallo-enamines to a,b-unsaturated ketones.

(R)

R1

N R2 R3

O

NH

R3R1

Me

R1

S

t-Bu

O R2

R3

ON

LDA (1.1 equiv);

5, 60–84%, >98% de

1) LiAlH4

2) Dess–Martin periodinane

S

43

R1

NS

ZnBr

ZnBr2

(1.2 equiv)

O O

t-Bu

6a, R1 = Ph; R3 = Me: 51%, 94% de6d, R1 = i-Pr; R3 = Ph: 55%, 92% de

a, R1 = Ph; R2 = Me; R3 = Me (94% de)b, R1 = Ph; R2 = Ph; R3 = Mec, R1 = t-Bu; R2 = Me; R3 = Phd, R1 = i-Pr; R2 = Me; R3 = Ph

3) HCl, dioxane MeOH4) DIBAL-H

REVIEW Chiral Auxiliaries – Principles and Recent Applications 1901


Scheme 4 Diastereoselective reduction of b-hydroxy-N-sulfinylimines 9.

In the synthesis of amino alcohols, chiral sulfinimines canalso act as electrophiles. A recent example for nucleo-philic addition of Grignard reagents to sulfinimines is thesynthesis of 1,2-disubstituted b-amino alcohols describedby Ellman and Evans.8 The diastereofacial selectivity ofthe N-sulfinyl group overrides the inherent preference ofthe a-stereocenter of the imine 11, resulting in the highlyselective formation of the syn and anti products. Changingthe alcohol protecting group of sulfinimine 11 or the reac-tion conditions favors or disfavors a Cram-type chelateand thus allows the optimization of the syn/anti selectivity(Scheme 5). Deprotection of the resulting sulfinamine 12is carried out with HCl/MeOH or HF/pyridine, affordingthe b-amino alcohol in high yields.

Scheme 5 Diastereoselective nucleophilic addition of Grignardreagents.

Recently, Xu and co-workers reported the reductive ho-mocoupling of N-tert-butanesulfinyl imines to C2-sym-metrical vicinal diamines.9 An extension of this work isthe cross-coupling of N-tert-butanesulfinyl imines 13with nitrones or aldehydes affording unsymmetrical vici-nal diamines and anti-b-amino alcohols 14 (Scheme 6).10

Due to competitive imine homocoupling and pinacol cou-pling of the aldehyde substrates, only aliphatic aldehydescan be successfully employed in this challenging SmI2-mediated reaction. Remarkably, the free b-amino alcoholwas obtained after final acidic hydrolysis of 14 with enan-tiomeric excesses of greater than 94% for all substitutionpatterns shown in Scheme 6.

Scheme 6 Asymmetric reductive cross-coupling of N-tert-butane-sulfinyl imines with aldehydes.

The cleavage of the auxiliaries under acidic conditions(HCl–MeOH or HCl–dioxane) generally provides the cor-responding amines in high yields and high enantiomericexcess (>95%). This method provides a very efficientroute to b-amino alcohols, as demonstrated by the rapidpreparation of D-erythro-sphinganine and (3R,4S)-statine(15) (Scheme 7).10b

Scheme 7 Synthesis of (3R,4S)-statine by asymmetric reductivecross-coupling.

Viso et al. investigated a highly diastereoselective 1,3-di-polar cycloaddition of p-toluenesulfinyl imines 16 withazomethine ylides 17 yielding enantiopure imidazolines18 (Scheme 8).11 Interestingly, only two out of eight pos-sible 1,3-imidazoline diastereomers are formed, and in a95:5 ratio. The [3+2] cycloaddition products can beopened to the corresponding vicinal diaminoalcohols bytreatment of cycloadduct 18 with LiAlH4 and TFA/MeOH.11

Scheme 3 Diastereoselective addition of N-sulfinyl metallo-enamines to some aldehydes.

(R)

R1

NS

O NM

H

R2

OS

R1

R1

NS

R1

NS O

R2

OH

1) LDA (1.1 equiv) THF, –78 °C, 45 min

2) MBr2 (2.0 equiv) –78 °C, 45 min

R2CHO (1.3 equiv)

–78 °C, 3 h

7 8

950–92%

76:24 to 99:1 dr

8a

MBr

R1 = Ph, t-Bu, i-Pr, EtR2 = Et, i-Bu, t-Bu, i-Pr, PhM = Zn, Mg

O O

reductant

R1

NH

R2

OHS

O

syn-10 anti-10

9

R1

NH

R2

OHS

O

catecholborane: 84–94%, >95:5 drLiBHEt3: 69–91%, 1:>99 dr

R1 = Ph, t-Bu, i-Pr, Et; R2 = Et, i-Bu, t-Bu, i-Pr, Ph

H

OBn

NS

ORMgBr

R

OBn

HNS

O

R

OBn

HNS

O

tolueneor

THF, TMEDA–78 °C syn-12 anti-1211

(R) or (S)

(R)-auxiliary: R = Ph: 80%, 5:95 R = Et: 86%, 2:98(S)-auxiliary: R = Ph: 94%, 99:1 R = Et: 75%, 91:9

SmI2, t-BuOH

THF, 4 h, –78 °C

NH

R1

S

O

1470–95%

76% to >99% de

R1 = 4-CH3C6H4, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 4-AcOC6H4, 4-CH3OC6H4, 3,4-(MeO)2C6H3, 2,4-(MeO)2C6H3, PhC2H4, CH3(CH2)4, BnOCH2, i-Pr, PhR2 = i-Pr, C6H11, (C2H5)2CH, n-C5H11, PhC2H4

R2 H

O

R1 H

NS

O

13

(R)R2

HO

NH

OH

H

NS

O

NH2

OH

15

SmI2, t-BuOH

THF, –78 °C

1) HCl–dioxane

2) NH3.H2O

80%

(3R,4S)-statine

S

O

t-Bu

34

O

Ot-Bu

O

OH

O

O

Ot-Bu

H

58%, 99% de



Scheme 8 Asymmetric [3+2] cycloaddition.

In general, the sulfinamide auxiliary can be removed eas-ily. Typically, imine-type substrates like 9 can be convert-ed to ketones 19 by hydrolysis with acetic acid in MeOH–H2O.7 In the case of sulfinamides 12, cleavage by treat-ment with acid generates the corresponding amines 20upon decomposition of the auxiliary (Scheme 9).4b,12

Scheme 9 Typical conditions for cleavage of the sulfinamide auxi-liary.

2.2 Sulfoxides

Enantiomerically pure sulfoxides can be efficient chiralcontrollers – cheap and easy to both introduce and func-tionalize. Therefore, they are versatile intermediates for anumber of organic reactions. Introduction of the sulfinylgroup mostly occurs by nucleophilic addition of thedeprotonated sulfoxide 21 to an ester to form b-keto sul-foxides 22 (Scheme 10).13 Another entry to sulfoxides is

the nucleophilic substitution of diastereomerically purementhyl-p-toluenesulfinates 23 with Grignard reagentsoccurring with complete inversion of the configuration atsulfur. This method, forming alkyl or aryl sulfoxides 24,is also known as the Andersen synthesis (Scheme 10).14

Furthermore, the asymmetric oxidation of sulfides alsoprovides easy access to the desired sulfoxides.15a In anal-ogy to the sulfinamides, p-tolyl or tert-butyl groups are of-ten the substituents of choice at sulfur.15

Sulfoxides have been mostly employed in asymmetric re-ductions of b-keto sulfoxides, carbon–carbon and carbon–heteroatom bond formation, cycloadditions and othermetal-catalyzed reactions. Moreover, chiral sulfoxideshave found numerous applications in natural product syn-thesis.15–17 The stereoinduction can be explained by thecoordination of the auxiliary oxygen to a Lewis acid ortransition metal, resulting in highly ordered transitionstates. As a consequence, the bulky substituents at sulfurare either placed in an equatorial position or shield onediastereotopic face of the substrate, allowing for highlystereoselective reactions.

A recent example for the well-known highly selectiveasymmetric reduction of b-keto sulfoxides 25 to giveproducts 27 was reported by Carreno et al. (Scheme 11).18

NS

R1

O

p-Tol

OMe

N

Ph

R2Li

O

NNH

Ph

MeO2C R2R1

Sp-Tol

1837–80%

90–98% de

THF, 20 h

–78 to 4 °C

O

R1 = Ph, p-(NO2)C6H4, 3-pyridyl, 2-furylR2 = CH2Ph, Me, i-Bu

16 17

R

NS O

R

OH AcOH

OR

HNS

O

OR

NH2⋅HCl

R

O

R

OH

HCl, MeOH

MeOH–H2O

19

20

9

12

Scheme 10 General methods for the introduction of a chiral sulf-oxide auxiliary.

S

O

R1Me R2 CO2Et

S

O

R1 ClS

O

OMentR1

S

O

OMentR1

R2MgX

R2

O

S

O

R1

S

O

OMentR1

S

O

R1R2

2)

1) LDA, THF, –78 °C

21 22

(–)-mentholpy, Et2O

r.t.

crystallization inacetone–HCl

23 24R1 = p-Tol, t-Bu; R2 = substrate

Scheme 11 Stereocomplementary diastereoselective reductions of b-keto sulfoxides 25.

O OMeO

Sp-TolO

O HOMeO

Sp-TolO

DIBAL-H

–78 °C, 1 h

25a 27a, 73%, >98% de

DIBAL-H, ZnBr2

–78 °C, 1 h

S

H

AlO

O HOEtO

SpTolO

27b, 88%, >98% de

O n-Prn-Hex

2826a

26b

i-Bu

i-BuO

R

p-Tol

S

O

ZnO

Br

Br

R

p-Tol

H(+)-isolaurepan

O OEtO

Sp-TolO

25b



In the cyclic transition state (26a) an intramolecular hy-dride transfer takes place. This reaction was used as a keystep in the asymmetric synthesis of (+)-isolaurepan 28. IfZnBr2 is added, a zinc chelate is formed and the hydridetransfer proceeds in an intermolecular fashion (26b).19

In addition, chiral sulfoxides are becoming ever more im-portant in the area of transition-metal-catalyzed reactions,like Pauson–Khand (PKR)20 and Heck reactions.21 Asym-metric intra- and intermolecular PKRs were reported byCarretero and co-workers.22,23 The more demanding inter-molecular version of this cyclopentenone synthesis (30)proceeds completely regioselectively and with very highdiastereoselectivities when an a,b-unsaturated chiral sul-foxide 29 is used (Scheme 12).22 However, only with ter-minal alkynes were acceptable yields (49–74%) and highdiastereoselectivities (93:7 to >98:2) obtained; with inter-nal alkynes the yields were low (0–33%).

Scheme 12 Diastereoselective Pauson–Khand reaction.

Intriguingly, chiral sulfoxides can even be used as tempo-rary chiral auxiliaries, as demonstrated by Malacria andco-workers in an intramolecular radical vinylation.24,25

Starting with auxiliary-substituted substrates 31, alkyl-idenecyclopentanes 32 were synthesized in a tandem reac-tion by a radical 5-exo-cyclization followed by b-elimination of the chiral auxiliary (Scheme 13).24 Interest-ingly, in these cyclization reactions, the addition of sever-al Lewis acids like methylaluminum bis(2,6-di-tert-butyl-4-methylphenoxide) (MAD) to 33 reversed the selectivityto preferentially give enantiomer 34 (Scheme 13).24

Scheme 13 Asymmetric radical cyclization reactions.

If cleavage of the auxiliary is not part of the reaction, sev-eral methods for desulfinylation exist. Traceless cleavagecan be accomplished with Zn/NH4Cl in H2O/THF,23 or bygeneration of a double bond by sulfoxide pyrolysis in re-fluxing toluene.22 Cleavage of the auxiliary by a Pummer-er reaction unveils an aldehyde group (e.g. 35) and allowsfor further functionalization (Scheme 14).16,26

In addition, asymmetric epoxidations,27 intramolecularasymmetric [4+2] cycloadditions28 and other reactions29–31

are taking advantage of chiral sulfoxides as chiral auxilia-ries.

Scheme 14 Representative methods for auxiliary cleavage.

2.3 Bis(sulfoxides)

An important class of sulfoxide auxiliaries are C2-sym-metric bis(sulfoxides) with 1,1-bis-p-toluene derivatives36 and cyclic dithioacetal dioxides 37 being commonlyused (Figure 1). These compounds can be synthesized fol-lowing Andersen’s approach,32,33 asymmetric oxidationmethods34 or with the assistance of chiral auxiliaries.32

Figure 1 C2-symmetric bis(sulfoxides).

Bis(sulfoxides) 36 and 37 have been used mainly as chiralketene equivalents in epoxidation reactions or cycloaddi-tions, extensively studied by Aggarwal et al.35–37 Exam-ples are the asymmetric [3+2] cycloadditions of nitroneswith thioacetal 38 that can be accomplished intra- or inter-molecularly to give isoxazolidine 39 in good yield andhigh diastereoselectivity (Scheme 15).35,36,38

Another recent application of chiral bis(sulfoxides) wasreported by Fensterbank, Malacria and co-workers.39 Us-ing 40 as a Michael acceptor for a diastereoselective con-jugate addition, only a single diastereomeric product, 42a,was obtained in near quantitative yield (Scheme 16). An

TMS

H

MeCNCo2(CO)6

O

TMS

H

H

S

O

ArS

NMe2

NMO, 0 °C

29 30, 74%, >96% de

O

MeO

EE

SR2

R1

O

p-Tol

PhSe

Bu3SnHAIBN, hν

31

EE

R1

R2MeO

32, 52–93%73% to >98%

ee

33

Bu3SnH, AIBN,toluene, 0 °C

hν, MAD

E = CO2MeR1 = H, Me, -(CH2)5-; R2 = Me, i-Pr, c-Pr, -(CH2)5-

34, 52–89%76–95% ee

R3

EE

SO

pTol

PhSe

E = CO2MeR3 = C(CH3)2OMe, CH2OH, CH2OTBS, CH2OEt, n-Bu, c-C6H11,nCH(OMe)2, OEt (35%, 52% ee)

EE

R3

toluene–78 °C,

–40 °C or0 °C

O

H SHt-Bu

O

Zn, NH4Cl

Sp-Tol

O

O

R

O TFAA

O

TIPSO S

H O

p-Tol

r.t., 96%

OO

R

O

O

H

O

TIPSO

73%

toluene

reflux 72%

H2O, THF

35H

S S

R

Op-Tol

O

p-TolS S

R

36 37

O

O



X-ray structural analysis of 40 (with R = Ph) revealed thatthe preferred conformation is the one shown in the transi-tion state 41a.

Addition of Lewis acids can reverse the diastereoselectionthrough a complexation of the two sulfoxide oxygen at-oms. In a cyclic transition state (41b), attack of the nu-cleophile occurs from the opposite side and product 42bis formed in excellent yield and diastereoselectivity.

Podlech and Wedel used bis(sulfoxides) for the asymmet-ric addition of enolates to a bis(sulfoxide)-derived Micha-el acceptor (Scheme 17).40 Beside enolates prepared bydeprotonation with BuLi oder NaHMDS, silyl enoleethers can also be added to bis(sulfoxides) 43. In general,yields and diastereoselectivities of these reactions lie be-tween 66–94% and 72–92%, respectively.

Finally, cleavage of the auxiliary of 44 in two steps releas-es the original aldehyde or ketone functional group ingood yield (Scheme 18).40 Alternatively, a Pummerer re-action can be used to remove or transform the auxiliaryvia intermediate 45 to an alcohol 46 (Scheme 18). Insteadof a reduction with LiAlH4, Hg(OAc)2 in MeOH can beemployed to yield the corresponding ester.39,41

3 Camphor-Derived Auxiliaries

Both enantiomeric forms of camphor are commerciallyavailable and inexpensive. Its rigid backbone is an attrac-tive structural element for chiral auxiliaries. As a conse-quence, many structurally diverse camphor-derivedauxiliaries (Figure 2) have been prepared in only a few

steps as well as successfully employed in a variety of dif-ferent reactions.42

As shown in Scheme 19, the camphor-derived auxiliariescan often be readily incorporated into the substrate.42b,43

The broad variety of organic reactions stereochemicallycontrolled by camphor auxiliaries is impressive: amongothers are Michael additions,44 Baylis–Hillman reac-tions,45,46 Darzens reactions,43 cyclopropanations,47

Pauson–Khand reactions,48 cyclopentannelations,49,50

enantioselective epoxidations51 and reductions.52

Arguably, the most prominent camphor-derived auxiliaryis Oppolzer’s sultam (47).53 Very recently, an asymmetric[2,3] rearrangement of allyldimethyl ammonium sultamylides 55 to allyl glycine derivatives 56 was reported bySweeney and co-workers in good yield and excellent se-lectivities (Scheme 20).54

Scheme 15 Diastereoselective [3+2] cycloaddition with a bis(sulf-oxide) auxiliary.

N

Ph

Me O

O

NMe

PhCH2Cl2, r.t.

13 h

5 equiv38 39, 86%, >98% de

SS

O

O

SSO

O

Scheme 16 Application of bis(sulfoxides) in asymmetric synthesis.

HNu

R

S

S

O

p-Tolp-Tol

O

R

S

S

p-Tol

p-Tol

O

OLA

Nu

NuLi CuI(2 equiv)

S S

Op-Tol

O

p-Tol

RHNu

S S

OpTol

O

pTol

R HNu

40 41a

41b

42a94–100%

single diastereomer

42b77–98%, >96% de

40THF

–78 to –30 °C

HNu (2 equiv)

THF, –60 °C

Nu = Me, n-BuR = Ph, i-Pr, t-Bu, m-(PhO)C6H4

HNu =

R = Ph, 4-NO2C6H4

S S

Op-Tol

O

p-Tol

R

HN

Scheme 17 Asymmetric enolate addition to bis(sulfoxides).

SSO

O R1

O

NaHMDS

43 44, 75–82%72–92% deR1 = Ph, p-(MeO)C6H4, Me, OEt

Ph

SSO

O

Ph

O R1

Scheme 18 Conversion of bis(sulfoxides) to aldehydes or alcohols.

TFAAO S

PhHNR2

p-Tol

THF

THF

OH

PhHNR2

42apy

46, 56%45

44TiCl4, In S S

Ph

O Ph

PhI(O2CCF3)2

MeCN–H2O

O

Ph

Ph

O

76%

H

LiAlH4



Moreover, the auxiliary can also be attached to the otherend of the substrate (57); this also results in high stereose-lectivities (Scheme 21).54 To underline the versatility ofthis methodology, an efficient asymmetric synthesis of(R)-(+)-allylglycine was carried out with good overallyield (86%) and very high diastereoselectivity (>95:5dr).54,55

Scheme 21 Camphorsultam-controlled asymmetric [2,3] rearrange-ment.

Oppolzer’s sultam 47 is also known to be a powerful aux-iliary in the asymmetric Baylis–Hillman reaction. The useof one equivalent of aldehyde leads to the formation of theexpected chiral allylic alcohols. Intriguingly, Leahy andco-workers reported that the use of two equivalents of al-dehyde results in the direct cleavage of the auxiliary andthus in the formation of the cyclic products 58 with excel-lent selectivities (Scheme 22).45 Aliphatic aldehydes canbe employed in this reaction, however, aromatic alde-hydes like benzaldehyde are not sufficiently reactive. Theobtained 1,3-dioxan-4-ones 58 can be easily convertedinto versatile products such as a-methylene-b-hydroxy es-ters.45

Scheme 22 Asymmetric Baylis–Hillman reaction with direct cleav-age of the auxiliary.

More recently, Chen and Yang developed another bicycliccamphor-derived auxiliary 48 for the Baylis–Hillman re-action.46 Interestingly, the solvent severely influences theselectivity of this reaction. Whereas in DMSO diastereo-mer 59a is formed predominantly, in a THF–H2O solventsystem the selectivity is completely reversed and 59b isformed selectively (Scheme 23). The stabilization of thezwitterion intermediate by intermolecular hydrogen bond-ing with the solvent might be important for the stereo-chemical outcome, but more information is needed for adefinite analysis. It is also important to note that the reac-tion time for different substrates and solvents varies great-ly. For example, the reaction of benzaldehyde in DMSOtakes 7 days to reach completion, whereas in THF–H2O asthe solvent, no isolable product formed even after 21 days.

Figure 2 Camphor and some camphor-derived auxiliaries.

S

O

S

NH

O O

S

O

SMe

SH

50

SH

OH

51

OO

(+)-camphor

49

53

O

54

O

OH

N

NH

O

Ph

48

52

1 2

345

6

10

789

(–)-D-(2R)-10,2-camphorsultam (47)

Scheme 19 Representative incorporation of camphor-derived aux-iliaries into substrates.

47

S

NH

O O

S

O

Cl

O

NEt2Br

O

49

S

N

OO O

S NEt2

O

OBr

base

Scheme 20 Camphorsultam-controlled asymmetric [2,3] rearrange-ment.

R3N

O

R2R1

R4

Br

NaH, DME, 0 °C

N

S

OO

Xc =

Xc

O

N

R1

R2

R4

R3

H

Xc

55

56a (2'R)

Xc

O

N

R1

R2

R4

R3

H

56b (2'S)

R1 = H, Me, CO2MeR2 = H, MeR3 = Me, allyl, BnR4 = Me, allyl

64–99%97:3 to >99:1 (2'R:2'S)

(anti:syn >99:1for R1 = Me, CO2Me; R2 = H)

+2' 2'

57

DME, 0 °C

Xc

O

NOMe

OH

R

S

94%(2'S,3'R):(2'R,3'S) = 96:4

anti:syn 96:3

N

O

BrOMe

O

Xc

NaH

S

N

O

O O

R H

O

58, 67–98%>99% ee

O

O

O

RRDABCO, CH2Cl2

0 °C

(2 equiv)

R = CH3, CH2CH3, (CH2)2CH3, i-Bu PhC2H4, AcOCH2



Scheme 23 Asymmetric Baylis–Hillman reaction.

Substrate 60 can easily be prepared in multigram quanti-ties from d-lactol auxiliary 54, which is available in twosteps from (+)-camphor. The Michael addition of the cor-responding amide enolate to a,b-unsaturated esters, lac-tones or ketones (chalcone, 78% de) leads to the highlyselective formation of a variety of amino acid derivatives61 with two newly formed stereocenters (Scheme 24).44

Dixon et al. rationalize the stereochemical outcome in thefollowing way. First, the lithium amide enolate of 60forms, in which the inner si face is shielded by the auxil-iary. As a consequence, the Michael acceptor attacks theless-shielded re face in a synclinal manner, resulting in theformation of the observed diastereomer 61.

Camphor-derived sulfides and sulfur ylides are also versa-tile chiral substrates, suitable for a number of asymmetricreactions. A recent example is the highly enantioselectiveDarzens reaction of sulfonium amide 62 (derived from 49)reported by Aggarwal et al.43a After deprotonation, thesulfur ylide adds to the aldehyde and the resulting betaineeliminates the auxiliary while closing the epoxide ring togive 63 (Scheme 25).

Notably, the auxiliary fulfills three different tasks in thissequence: it facilitates the formation of the nucleophile bymeans of acidification, efficiently controls the stereo-chemistry of the nucleophilic attack, and finally, acts as aleaving group. Many aromatic aldehydes lead to the for-mation of epoxides 63 in high yields and very good enan-tioselectivities. Aliphatic aldehydes like tridecanal and 2-

methyl propanal gave much lower enantioselectivities(63% and 10%, respectively).43

Even more impressively, the auxiliary can be successfullyused catalytically in a related epoxidation reaction(Scheme 26).56–58 The phase-transfer catalyst (PTC) al-lows for the in situ formation of the diazo compound un-der mild conditions starting from tosyl hydrazone 64. Thisdiazo compound reacts with the rhodium catalyst to givea metal carbenoid 67 that reacts subsequently with theauxiliary 52 to form the sulfur ylide 66 (Scheme 27).56 Asin the non-catalytic variant, this ylide adds to the aldehydeand the successive formation of epoxide 65 liberates theauxiliary 52.59

Scheme 26 Catalytic use of auxiliary 52 in an asymmetric epoxida-tion.

In a process related to the aforementioned epoxidation ofaldehydes, sulfur ylides can also be used for a cyclopropa-nation of terminal 1,2-disubstituted and 1,2,3-trisubsti-tuted electron-deficient olefins.47,60 A representative

XC

O

R H

O

DABCO2–7 d

59a

XC

O OH

R

DMSO: 75–88%, 97:3 to 99:1 drTHF–H2O: 73–85%, 3:97 to 1:99 dr

R = CH3, CH3CH2, Ph(CH2)2, (CH3)2CHCH2, Ph

59b

XC

O OH

R+

N

N

O

Ph

= XC

Scheme 24 Asymmetric Michael addition.

O N

O

NMe2

Cbz

O N

O

NMe2

Cbz

R

EWG

EWG

R

EWG

R O

LiON

Cbz

NMe2 H

CamTHP*N

EWG

Cbz OLi

NMe2

1) LHMDS (2 equiv) THF, –78 °C

2)

–78 °C to –20 °C60

6176–100%, >95% de

H

R

R = Me, n-Pr, i-Pr, n-pentyl, Ph, MeOC6H4, naphthyl EWG = NO2, CO2t-Bu, CO2Et

O O

Michael acceptor:

blocked inner si-face synclinal approach

Scheme 25 Darzens reaction of sulfonium amide 62.

S

ONEt2

O

RCHO

62Br

O HR

H CONEt2KOH, EtOH

–50 °C63

84–93%92–99% ee

R = Ph, p-MeOC6H4, p-ClC6H4, p-MeC6H4, p-FC6H4, p-CF3C6H4, p-NO2C6H4, 3-pyridyl, t-Bu

R H

O Rh2(OAc)4

(1 mol%)

BnEt3N+Cl– (5 mol%)

MeCN

N

Ph

N

Ts

O

Ph H

RHNa 52

65 58%–82%

76 to >96% de87 to 94% ee

R = Ph, p-NO2C6H4, p-ClC6H4, p-MeOC6H4, p-MeC6H4, o-MeC6H4, CHCH2C6H5, C6H11CO, 2-furyl, 3-furyl

(5 mol%)

64(2 equiv)



example is the cyclopropanation of electron-poor alkeneslike vinylesters or acrylonitrile with the sulfonium salt 68reported by Huang and Huang (Scheme 28).47 Again, theauxiliary is removed in the course of the reaction. Interest-ingly, the stereoselectivity of this reaction can be reversedby simply changing the base. Whereas KOt-Bu leads tothe selective formation of cyclopropane 69, the use ofNaH gives rise to ent-69.61

Scheme 28 Asymmetric cyclopropanation.

A proposed transition state for the formation of 69 isshown in Figure 3.60 However, the impact of the base onthe enantioselectivity cannot yet be sufficiently explained.

Figure 3 Reasonable transition state for cyclopropanation of acry-lates.

Camphor-derived thiols like 50 are used as chiral control-lers in an asymmetric PKR reported by Riera and co-workers.48 Alkynes 70 react with both norbornene andnorbornadiene in moderate yields and good to excellentdiastereoselectivities (30–96% de), forming bicyclic cy-clopentenones 71 (Scheme 29).

Scheme 29 Asymmetric Pauson–Khand reaction.

A tandem Michael addition and Meerwein–Ponndorf–Verley (MPV) reduction of auxiliary 51 and the a,b-un-saturated ketone 72 was reported by Node and co-work-ers.62 This sequence allows the impressive construction ofthree contiguous stereocenters in an acyclic compound(Scheme 30). The MPV reduction occurs intramolecular-ly between the alcohol group of the auxiliary and the ke-tone. The cyclic transition state leads to the predominantformation of diastereomer 73. Destructive cleavage of theauxiliary associated with transfer of the sulfur atom to theproduct results in the formation of product 74.

Scheme 30 Tandem Michael–MPV reaction.

Another camphor-derived auxiliary was synthesized fromcamphoric acid and used in an asymmetric cyclopentan-nelation by Tius and co-workers (Scheme 31).49,50 Addi-tion of substrate 75 (derived from 53) to a,b-unsaturatedamide 76 under acidic conditions led to the formation of77 in good yields and enantioselectivities. In these trans-formations, the chiral allene moiety is essential for highselectivities and ee values of up to 96% were obtained inthe matched case.49a Cleavage of the auxiliary is carriedout in situ to release the corresponding alcohol 77. Thisreaction sequence gives ready access to an importantbuilding block for the synthesis of roseophilin.63

Closely related to camphor, though much less commonlyused, are derivatives of pinene or myrtenal.64 A recent ex-ample for asymmetric aldol reactions with (–)-b-pineneauxiliaries was reported by Pinheiro et al.65 The reactionof pinene-substituted esters with aldehydes led to chiral

Scheme 27 Proposed catalytic cycle of the sulfide-catalyzed asym-metric epoxidation reaction.

PhCHO

O R

Ph

N2

RCHN2

Rh2(OAc)4

Rh=CHR

52

R'2S-CHR

R'2S

65

66

67

R

68R

HPh

H R

S

O

Ph

RH

Ph H

68

Brt-BuOK, THF

–50 °C69 (R,R)

NaH, THF–10 °C

75–91%trans:cis 97:3 to 100:0

90–95% ee

ent-69 (S,S)76–80%

trans:cis 98:2 to 99:172–85% ee

R = CO2Et, CO2Me, CO2n-Bu, CO2CH2Ph, CN

R = CO2Et, CO2Me, CO2n-Bu, CO2CH2Ph

O MS

OOR

HPh

SR

SNMO

1) Co2(CO)8

SR

S

O H

H

71a, 31–66%, 34–90% de71b, 28–60%, 30–96% de

2)

70a, R = Me 70b, R = CH2Mes

SH

OH R1 Ph

O

R2

Me2AlCl (1.5 equiv)

72

R1 Ph

OH

R2

Cam-S

O

51

R1 Ph

OH

R2

SH

CH2Cl2, r.t.

73, 37–92%, 92:8 to 100:0 dr

Cam =

1) LiAlH4

2) BF3 OEt2 CH2Cl2

Dodec-SH

74, 92%

R1 = Ph (E/Z), p-MeC6H4, p-MeOC6H4, p-ClC6H4

R2 = Me, Et, Pr, Bn



alcohols in good yields (70–90%) and moderate selectivi-ties (anti/syn = 64:36 to 80:20). Costa and co-workersused pinene-derived auxiliaries for asymmetric Friedel–Crafts reactions with greatly varying stereoselectivi-ties.66,67

In some cases presented in this section, the auxiliary actsas a leaving group and is removed under the reaction con-ditions. On one hand, this is elegant and advantageoussince no additional cleavage step is needed in these cases.On the other hand, the loss of an enantiopure chiral auxil-iary also has undesirable consequences: the determinationof the enantiomeric purity of the product and the purifica-tion of the stereoisomers (enantiomers vs. diastereomers)by crystallization or chromatography both become moredifficult.

In the majority of cases, auxiliary-substituted products areisolated. The cleavage conditions for these compoundsdepend on the nature of the auxiliary attachment. In addi-tion to the reductive elimination with SmI2,

49,50 LiOH52 orLiAlH4,

53 hydrolytic cleavage procedures are often themethod of choice.44,68,69

4 Carbohydrate-Derived Auxiliaries

The attractiveness of carbohydrate-derived auxiliaries re-sults from the fact that they bear many stereocenters andare often commercially available and reasonably priced.They have been successfully employed in numerous or-ganic reactions, such as cycloadditions (Diels–Alder reac-tions,70 [2+2] cycloadditions71), cyclopropanations,72

alkylations,73 and Mannich reactions.74–76

Pyranosides like 78 or 79 derived from a-D-gluco-, a-D-galacto- or a-D-mannopyranosides are commonly usedauxiliaries. The alcohol functionalities of the sugar servetwo purposes: first, they are ideal anchoring groups for at-tachment of the auxiliary to the substrate, and second,they allow for the tuning of the steric bulk of the auxiliary

by protection with a variety of groups with different stericdemands.76a Furanosides like L-sorbide-derived 8077 or bi-cyclic sugars like isomannide (81) and isosorbide (82)78

are somewhat less popular than pyranoside auxiliaries(Figure 4).

Figure 4 Carbohydrate-derived chiral auxiliaries.

Auxiliaries like 78 or 79 can easily react with nucleophilicsubstrates to form enamides 83 or esters 84 (Scheme 32).

Scheme 32 Formation of carbohydrate-auxiliary-bearing sub-strates.

A 6-deoxy-D-glucopyranoside derivative 85 can be usedfor several asymmetric reactions. Tadano et al. reported ahighly diastereoselective a-alkylation of ester 85 thatgave rise to products 87. Deprotonation with NaHMDSresulted in the formation of the metal-associated Z-enolate86, which attacked the electrophile with its unhinderedback face (Scheme 33).79–81 Interestingly, the use of otherbases like LDA or n-BuLi resulted in a reversal of stereo-selectivity and rather low selectivities (46–68% de).79 Inorder to explain these latter results, the authors proposedthat as a consequence of the bulky substituents on Li, the180° rotamer around the former ester C–O bond (curvedarrow in 86) is more stable. Attack of the electrophile bythis rotamer would then lead to formation of the oppositediastereomer.

The glycopyranoside auxiliary 79 can also be incorporat-ed into a,b-unsaturated esters 88 to influence the 1,4-ad-dition of organocuprates that forms products 90(Scheme 34).80,81 The choice of the nucleophile severely

Scheme 31 Asymmetric cyclopentannelation reported by Tius.HFIP = hexafluoro-2-propanol.

OOLi

R2

O

N

O

76

O

HO

R3R2

R1

77a, 34%–84%, 55 to 87% ee 77b, 42%–80%, 92 to 96% ee

1) –78 to –30 °C, 1 h

2) HCl, HFIP/TFE (1:1) –78 °C

75a, R1 = H75b, R1 = t-Bu

R3

R2, R3 = Me, Ph, p-MeOC6H4, F, Br, Et, n-Bu, t-Bu, c-C6H11, TMS, n-Pent, CH2OTBS, i-Pr, -(CH2)4-, -(CH2)5-, -(CH2)6-

HR1

HO OTBSO

TBSOOMe

79

O

PivOOPiv

PivO

PivOF

78

HO

OH

HO

OH

82(+)-isosorbide

HO

OH

HO

OH

81(+)-isomannide

O OBnHO

O O

80

R O

O

OTBSO

TBSOOMe

83

R OH

O

79

N

OTMS

O

PivOOPiv

NPivOO

OPiv78

84



influences the stereoselectivity, since different conforma-tions of the resulting crotyl ester moiety are preferred.Whereas organocopper reagents are capable of coordina-tion with the crotyl carbonyl, the organolithium nucleo-phile is not.80

Scheme 34 Asymmetric 1,4-addition of cuprates and organolithiumcompounds to an a,b-unsaturated ester.

The asymmetric 1,4-addition can be successfully com-bined with an a-alkylation reaction of the resulting eno-late leading to a,b-dialkylated esters 91 with highdiastereoselectivities (98% de). Again, the nature of theorganometallic reagent determines the observed selectivi-

ties, with cuprates giving the syn product and PhLi givingthe anti product (Scheme 35).80,81

Scheme 35 Tandem 1,4-addition and a-alkylation.

O-Pivaloylated pyranosides like 78 are rather popularauxiliaries. Kunz and co-workers reported the synthesis ofenantiomerically pure piperidines starting from N-galac-tosylated pyridones 83. In the key step, the silylated trif-late salt of 83 was treated with a variety of Grignardreagents to give differently substituted dehydropiperidin-ones 93 (Scheme 36).82 It is reasonable to assume that thepivaloyl group next to the anomeric center shields thefront of the heterocycle in 92. Consequently, the Grignardreagent attacks from the back to form stereoisomer 93 thatcan be used for the asymmetric synthesis of natural prod-ucts such as coniine (94) (Scheme 36).82,83

The asymmetric Mannich reaction of O-pivaloylated ga-lactosyl substituted imines 95 with bis-O-trimethylsi-lylketeneacetals 96 leads to the selective formation of b-amino acids 97 or esters 98. In general, of the four possi-ble diastereomers only the two threo-isomers were ob-served (Scheme 37).74

The galactosyl auxiliaries can often be recovered as galac-tosylalcohols 99 in quantitative yields after cleavage bytreatment with dilute HCl in methanol (Scheme 38).74

Cleavage of an ester-bound auxiliary under alkaline hy-drolysis results in the formation of carboxylic acids like101 and auxiliary 79 in high yields, allowing a recyclingof the chiral auxiliary.84–86

Scheme 33 Asymmetric a-alkylation of an ester.

R1

O

O

XcNaHMDS

R2X, THFR1

O

O

Xc

R2

8780–97%

90–96% de

85R1 = Me, CH2Ph

R2X = BnBr, MeI, n-BuI, allylBr

OTBSO

TBSOOMe

Xc =O

TBSOOMe

OO

ONa

R1

Si

R2X

86

O

O R O

OXc

R2CuMgXTHF, Me2S

88 8958–85%

84–90% deR = Et, t-Bu, Ph

88RLi, THF

–78 to 0 °C

9092–95%

92–96% deOTBSO

TBSOOMe

Xc =

–78 °C

Xc

R O

OXc

881) 1,4-addition

2) α-alkylation O

O

Me

Ph

Xc

anti-91 syn-91

Method a: Ph2CuMgBr, THF-Me2S (2:1), –18 to 0 °C, then MeI: syn:anti 96:4, 98% de (syn)

O

O

Me

Ph

Xc

Method b: PhLi, THF, –78 °C, then MeI: 92%, anti:syn 95:5, 98% de (anti)

+

Scheme 36 Asymmetric alkylation of pyridones.

O

PivOOPiv

NPivOO

OPiv

O

PivOOPiv

NPivOOTMS

OPiv

TMSOTf

CH2Cl2, 1 h

2,6-lutidineR1MgX

CH2Cl2, 1–2 h

O

PivOOPiv

NPivOO

OPivR

R1 = Me, n-Pr, i-Pr, n-Bu, n-Dec, vinyl, 1-butenyl, Ph, m-MeOC6H4, -(CH2)3SiPhMe2 and R1MgX = ClMg(CH2)3OMgClX = Cl, Br

83 92

93, 19–89%, 58% to >98% de

OTf

O

PivOOPiv

NPivOOTMS

O

O

RMgX

backsideattack

NH HCl

coniine (94)

52% over four steps



Scheme 38 Typical conditions for cleavage of the auxiliary.

5 RAMP, SAMP

First introduced by Enders and Eichenauer87 in 1976, (S)-1-amino-2-methoxymethylpyrrolidine (SAMP) and (R)-1-amino-2-methoxymethylpyrrolidine (RAMP) have be-come commonly used chiral auxiliaries for organic syn-thesis.88 The auxiliary SAMP is available in four stepsstarting from (S)-proline, RAMP can be synthesized in sixsteps from glutamic acid.88 Both enantiomeric forms ofthe auxiliary are also commercially available. Moreover,a number of related, albeit sterically more demanding,auxiliaries like SADP, SAEP, SAPP and RAMBO havebeen developed (Figure 5).

Figure 5 RAMP, SAMP and some useful analogues.

SAMP- or RAMP-containing hydrazone substrates like104 are easily prepared by condensation of SAMP/RAMPwith the appropriate aldehyde or ketone under rather mildreaction conditions (Scheme 39).88a

Scheme 39 Synthesis of RAMP-hydrazones.

a-Alkylations of chiral hydrazones still represent the mostpopular application of these auxiliaries.88 Deprotonationof the hydrazone substrates with lithium bases results inan enamine forming a six-membered chelate (e.g. 105). Inthis rigid structure, the auxiliary shields the enamine topface and as a consequence, alkylation from the bottomface is favored (Scheme 40).88a In addition, these hydra-zine auxiliaries can be used in various organic reactionssuch as aldol reactions,89 Michael additions,90 rearrange-ments,91 nucleophilic addition reactions to the C=N dou-ble bond,92 Diels–Alder reactions93 and synthesis oforganometallic substrates like substituted ferrocenes.94,95

Some important recent advances are presented in the fol-lowing paragraphs.

Scheme 40 Proposed mechanism for a-alkylations of SAMP-hydrazones.

Ferrocenyl ligands are of increasing interest for asymmet-ric catalysis in academia and industry.95 Therefore, theasymmetric synthesis of planar- or central chiral ferro-cenes with phosphorus, sulfur and nitrogen substituents isan important goal. Starting from SAMP-derived hydra-zones 106, Enders et al. successfully used the auxiliary tocontrol central as well as planar chirality in the synthesisof ferrocenes 109 (Scheme 41).95

Subsequent functionalization of the side chain of 107 andof the ortho-position in 108 can be executed with severalelectrophiles. The first deprotonation is carried out withLDA, whereas a stronger lithium base has to be used forthe directed ortho-metallation. High yields and stereose-

Scheme 37 Asymmetric Mannich reaction.

O

PivOOPiv

PivO

OPiv

NR1

H

OTMS

OTMSH

R2

9695

ZnCl2

THFO

PivOOPiv

PivO

OPiv

HN

R1

COOH

R2

97, 45–97%, 50% to >90% deR1 = Ph, m-ClC6H4, p-ClC6H4, p-FC6H4, p-MeC6H4, 2-naphthyl, n-pentylR2 = Me, Et, Ph

1) 4 M KOH/ MeOH, reflux

2) 1M HClR

OH

O

R

101

RO

O

OTBSO

TBSOOMe

100

R

98

1) 0.01 M HCl aq MeOH

2) aq NaHCO3CO2t-Bu

H2N

R

R

97O

PivOOPiv

PivO

OPiv

99

OH

79

N

NH2

OCH3

SADP

NOCH3

N

NH2

OCH3

SAPP

N

NH2

OCH3

RAMBOSAEP

NH2

N

OCH3

NH2

SAMP(102)

RAMP(103)

N

OCH3

NH2

Ph Ph

103R1 R2

O

R1 R2

NN

OCH3

R1, R2 = alkyl, aryl, H 104

74–96%

0–80 °C

R1

R2

NN

OMe R2R1

NN

Li

MeO

ROR

RO

R

1) LDA

EX

EX105

2) EX

R1

R2

NN

OMeE

R1 = H, Me, Et, PrR2 = Me, Et, Pr, i-Pr, Hex, PhR1/R2 = -(CH2)n-, -CH=CH(CH2)2-, n = 3–6R = Et, -(CH2)4-E = Me, Et, Pr, Bn, allylX = Br, I



lectivities were obtained with nine different substrates. Fi-nally, reductive cleavage of the auxiliary in two stepsliberated the ferrocenyl ligand 109 in moderate yield andhigh enantioselectivity.

More recently, SAMP was employed by Enders et al. inthe synthesis of the planar chiral 2-monosubstituted difer-rocenylketones 110 (Scheme 42).96 For all reported elec-trophiles the alkylation step proceeds with 96% de. Thissequence provides ready access to a novel class of planarchiral ferrocenyl ligands containing a diferrocenyl ketonebackbone.

Scheme 42 Planar chiral 2-monosubstituted diferrocenyl ketones.

Dihydroxyacetone phosphates (DHAP) are used in natureas C3-building blocks for enzyme-catalyzed asymmetricaldol reactions leading to carbohydrates.97 Hydrazoneslike 111 are currently of interest as chiral dihydroxyace-tone synthons in organic synthesis. With the SAMP-hydrazone 111, high selectivities can be achieved inasymmetric a-alkylations forming 112 (Scheme 43).98 Anaziridine, Michael acceptors, alkyl halides and a silyl tri-flate were successfully employed as electrophiles in thesereactions. In addition, a bisalkylation using the same ordifferent electrophiles proceeded with impressive selec-tivities to yield 113.

The versatility of these hydrazine auxiliaries is reflectedin applications in the asymmetric synthesis of importantbuilding blocks such as aza- or deoxysugars99 or the totalsynthesis of natural products like (+)-aspicillin.100 The de-mand for enantiomerically pure fluorinated compoundsfor medicinal chemistry, crop science or materials scienceis constantly increasing. In 1998 the asymmetric inductionreported for the synthesis of a-alkoxy-a-trifluoromethylaldehydes using the RAMP/SAMP methodology was stilllow (51:49 to 81:19 dr).101 More recently, Enders and co-workers published an efficient synthesis of a-trifluoro-methyl-substituted primary amines using a highly diaste-reoselective nucleophilic 1,2-addition of alkyllithiumreagents to SAMP-hydrazone 114.102 Under optimized re-action conditions, 115 was obtained in moderate yieldsbut with very high diastereoselectivities (>96% de)(Scheme 44). Purification by column chromatography in-creased the diastereomeric purity even further (>98% de).Only the addition of phenyllithium remains unsatisfacto-ry, giving the desired product in a disappointingly lowyield of 15%. Benzoylation of 115 provided hydrazides116, which could be converted to the corresponding enan-tiomerically pure a-trifluoromethyl substituted amides117 by reductive cleavage with SmI2 in THF(Scheme 44).102–105

In general, oxidative, hydrolytic and reductive cleavageconditions allow the synthesis of the corresponding ke-tones or aldehydes from the hydrazones 118. Oxidativecleavage is normally accomplished by ozonolysis, withsinglet oxygen, aqueous sodium periodate, sodium perbo-rate or other oxidizing agents releasing the ketone or alde-hyde products. Often, the auxiliary can be isolated as thenitrosamine and easily transformed back to the hydrazineauxiliary.106 Oxidative cleavage with H2O2 or with per-

Scheme 41 Synthesis of planar chiral ferrocenyl ligands.

R

N N

OMe

R

N N

OMe

R1

R

N N

OMe

R2

R1

R

R2

R1

Fe

106

Fe

Fe

108, 65–98%, >90% de

Fe

107

1) LDA LiClO4

2) R1X –100 °C

E/Z 9:1–50:1, >96% de

1) t-BuLi, LiClO4

–70 °C

2) R2X

R = Me, EtR1 = Ph2P BH3, SMe, Si-PrR2 = Ph2P BH3, SMe, STol, SPh, P(i-Pr)2, BH3

109, 51–88%94 to >96% de96 to >99% ee

Fe Fe

O

E

11020–94%

97 to >99% eeE = Me, SiMe3, Ph2COH, Ph2CH, SMe, STol, Si-Pr, Ph2P, i-Pr2P

Fe Fe

O 1) hydrazone formation with SAMP2) alkylation

3) cleavage of the auxiliary

Scheme 43 Stereoselective alkylation and bisalkylation of the chi-ral dihydroxyacetone synthon 111.

O O

H3C CH3

NN

OCH3

111

111

O O

H3C CH3

O

R1

112, 25–90%89 to >98% ee

O O

H3C CH3

O

R1R2

113, 40–83%>95% de>97% ee

1) t-BuLi, THF, –78 °C, 2 h; R1X, –100 °C, 2 h; warm to r.t. over 15 h

2) auxiliary cleavage using O3, aq CuCl2 or aq oxalic acid

1) t-BuLi, THF, –78 °C, 2 h; R1X, –100 °C, 2 h; warm to r.t. over 15 h

2) t-BuLi, THF, –78 °C, 2 h; R2X, –100 °C, 2 h; warm to r.t. over 15 h3) O3, CH2Cl2, –78 °C, 15 min

R1 = R2 = Pr, i-Pr, Bn, Et, (CH2)2Ph;R1 = Me, R2 = i-Pr, CH2OBn, Bn, CH(Me)Ph, c-Pent, c-Hex, CH2CO2CH3

R1 = (CH2)2NHTs, CH(Me)CH2CO2t-Bu (96% de), Me, i-Pr, (CH2)2Ph, CH2OBn, (CH2)2OTBS, (CH2)3OTBS, CH2CH=CH2, (CH2)2CH=CH2, (CH2)3CH=CH2, SiMe2t-Hex, CH2CO2CH3



acids like m-chloroperoxybenzoic acid (MCPBA) orMeCO3H, leads to the formation of the corresponding ni-triles. Hydrolysis can be achieved with CuCl2, Cu(OAc)2,oxalic acid, methyl iodide/HCl (salt method) or(NH4)H2PO4. Finally, the reductive cleavage with TiCl3,SnCl2 or Cr(OAc)2 was reported in some cases(Scheme 45).106

Scheme 45 Conditions for cleavage of the hydrazine auxiliaries.

6 Alcohols, Amines, Amino Alcohols

Alcohols, amines and amino alcohols are versatile chiralauxiliaries that have been successfully applied in numer-ous reactions.107–109 Although chiral alcohols can easily beattached to suitable substrates by esterification, their useas chiral auxiliaries is mainly limited to a few nucleophilicaddition reactions,110,111 cycloadditions112 or radical reac-tions.113 Typically, alcohols such as pantolactone 119a,107

pantolactam 119b (Scheme 46),114 cyclohexanols,113 anddiphenylethanediol110 have been used successfully.

Much more frequently used auxiliaries are the readilyavailable chiral amines such as phenylglycine amide orphenylethylamine 120.108 Most often, they are introducedinto the substrate as imines (Scheme 46). Chiral amineauxiliaries have been successfully applied in nucleophilic

addition reactions to C=N double bonds,115

hydrogenations116,117 and Michael addition reactions.118

In general, chelating auxiliaries allow the formation ofhighly ordered, cyclic transition states often resulting inhigh levels of stereocontrol. Therefore, it does not comeas a surprise that chiral amino alcohols are especially use-ful auxiliaries.109,119 In this respect, ephedrine is an espe-cially important amino alcohol. Ephedrine andpseudoephedrine 121 are commercially available, cheapand no further modification is needed prior to their use.However, legislative restrictions may apply since they arepossible drug precursors. Incorporation of the aminoalco-hol into the substrate by imine or amide formation(Scheme 46) allows for an easy introduction, non-destruc-tive cleavage, and reuse of the auxiliary. Successful appli-cations of ephedrine auxiliaries120 can be found in theareas of Mannich reactions,121 alkylations122 and aldol re-actions.123

Scheme 46 Typical methods for introduction of alcohol, amine, oramino alcohol auxiliaries.

6.1 Alcohols as Auxiliaries

Numerous applications of pantolactone (119a) in asym-metric synthesis have been reported.107 An industriallyrelevant application is the highly selective Lewis acid cat-alyzed Diels–Alder reaction of D-pantolactone-substitut-ed substrate 122 originally developed by Helmchen andco-workers.124a Treatment with cyclopentadiene and a cat-alytic amount of TiCl4 in CH2Cl2–petroleum ether led tothe highly stereoselective formation of the correspondingDiels–Alder product. The diastereomeric excess of theproduct was significantly increased to >99.8% by crystal-lization. For the scale-up to kilogram scale and in order toreduce the cost of this process, conditions were developedby Chang et al. to allow for the recovery of the chiral aux-iliary.124b Saponification and acidification of the solutionresulted in the precipitation and isolation of the desiredproduct (1S,2S)-5-norbornene-2-carboxylic acid. The fil-trate contained the ring-opened, water-soluble D-pantoicacid, which was formed under these reaction conditionsfrom D-pantolactone. Fortunately, heating of the acidic

Scheme 44 Stereoselective nucleophilic 1,2-addition to SAMP-hydrazones.

SmI2, THFDMPU, r.t.

N

F3C

N

OMe

114

N

F3C

N

OMeR1

O

Ph

HN

F3C

N

OMeR1

11548–79%

R1Li (3 equiv)–78 °C

PhCOClcat. DMAPEt3N, r.t.

116, 62–97%unchanged de

R1 = Et, n-Pr, n-Bu, t-Bu, n-Hex

NHBz

F3C R1

117, 71–97% 97% to >99% ee

>96% de (R1 = t-Bu: 72% de)>98% de after column chromatography

118R1 R2

NNR2

R1 = alkyl, arylR2 = alkyl, aryl, H

R1 R2

Oa) hydrolytic cleavage

b) reductive cleavage

R1118d) oxidative cleavage

c) oxidative cleavage

a) CuCl2, Cu(OAc)2, oxalic acid or MeI/HClb) TiCl3, SnCl2 or Cr(OAc)2

c) O3, O2, NaIO4 or NaBO3

d) mCPBA, H2O2 or MeCO3H with R2 = H

or

or

CN

OHY

119a: Y = O119b: Y = NPh

O

OY

O

R

O

PhN

OH

H X

O

R PhN

OH

O

R

121

Ph NH2

R

O

H N Ph

R H120

R

O

X



filtrate resulted in lactonization and provided the enantio-merically pure D-pantolactone auxiliary in good yield,thus allowing for the recycling of the auxiliary. Overall,this represents a highly stereoselective, cost-efficient ap-plication of pantolactone.124

Scheme 47 Asymmetric Diels–Alder reaction, product isolation byprecipitation, and efficient recovery of the chiral auxiliary.

An innovative application of a chiral C2-symmetric diolfor the asymmetric synthesis of amines was reported byCharette and co-workers.125 Starting from (R,R)-1,2-diphenylethylene-1,2-diol (123), orthoacylimines 124were prepared in two steps. Addition of organolithium re-agents to 124 followed by removal of the auxiliary byacidic hydrolysis in a one-pot procedure revealed thechiral amine 125 and auxiliary diol 123(Scheme 48).110,125 It was shown that an appropriatelysubstituted 125 (R1 = t-Bu, R2 = Ph) can be transformedinto precious enantiomerically pure tert-leucine in threesimple steps. High selectivities, mild conditions for auxil-iary cleavage, and recovery of the auxiliary render thismethod attractive.

Scheme 48 Nucleophilic addition to chiral orthoacylimines.

An efficient application of a lactol as a chiral reagent hasrecently been reported by Dixon and co-workers.126,127

Therein, highly diastereoselective oxy-Michael additionsare accomplished, resulting in chiral tetrahydropyranolethers.128,129

6.2 Amines as Auxiliaries

D’Angelo and co-workers developed a highly stereoselec-tive Michael addition using (R)-phenylethylamine130 de-rived imine 126 (Scheme 49).131–133 Intriguingly, whereasthermal activation of these reactions fails, activation byhigh pressure overcomes the steric hindrance that arises inthe course of the addition process. The high selectivitiesobtained are a result of an energetic preference for confor-mations with minimized 1,3-allylic strain in theintermediate enamine moiety. Interestingly, with phenyl-crotonates, a product of type 127 is not observed; instead,the reaction affords bicyclic lactams by N-heterocycliza-tion of the transient Michael adduct.134,135

Scheme 49 Asymmetric Michael addition under high pressure.

Sato and co-workers reported another very efficient appli-cation of enantiomerically pure (S)-phenylethylamine inthe asymmetric synthesis of allenylamines 130(Scheme 50). Impressively, reaction of enyne–titaniumcomplexes 128 with chiral imines 129 resulted in the for-mation of a chiral allene and two stereocenters in a singlestep with high diastereoselectivities.136,137

Scheme 50 Asymmetric synthesis of allenylamines.

In a more recent publication, Sato and co-workers de-scribed a related carbon–carbon coupling reaction. Addi-tion of a chiral (h2-imine)Ti(Oi-Pr)2 complex 131 toterminal or substituted alkynes led to allyl- or a-allenyl-amines (Scheme 51).138 b-Elimination of an intermediate

OO

OO

OO

OO

OHOHO

OHO

OH

TiCl4

94% de(81%, >99.8% de

after crystallization)

aq NaOHTHFMeOH

+

89% >99.9 ee(135 g)

H+

90 °C 119a

85%>99.9% ee

(122 g)

solvent

(water-soluble)

122

recovery of chiral auxiliary

Ph

OH

OH

Ph

1) HC(OMe3) p-TsOH; TMSN3

2) RCHO PMe3, THF

Ph

Ph O

ON

R1

H

1) R2Li, DME, –78 °C

2) HCl, H2O, MeOH

123 124

R2

NH2

R1

12533% to >98%70–98% ee

R1 = Ph, PhCH=CH-, t-Bu, furanylR2 = Me, Bu, Ph

123

NH

MePh

CO2Me

NH

MePh

CO2Me

126

12770–78%, >98% de, 94–96% ee

Me

THF, 12000 bar20 h, 20 °C

20% aq AcOH

O

CO2Me

Me

n

n n

n = 0, 1

Me

Me3Si

Ti

R1

Oi-Pri-PrO

N

H

E+

.•Me3Si

E

R2

NH

R1

128

13045–67%, 84–94% de

R1 = Me, C6H13R2 = Et, Me, i-BuE+ = H+, Me2C=OE = H, Me2(HO)C

129

R2

H

PhMe

H

PhMe



azatitanacyclopentene resulted in synthetically usefulproducts 132 or 133. In these reactions, an amine auxiliarywith a second coordination site (2-methoxy-1-phenyleth-ylamine) was essential for obtaining high enantiomericexcess. The authors proposed that the reaction proceedsthrough the chelated, six-membered chair-like titanacycle134 to result in the high selectivities (Scheme 52).138

Scheme 51 Asymmetric synthesis of allyl- and allenylamines.

Scheme 52 Formation of an azatitanacyclopropane complex.

The asymmetric synthesis using (S)-valinol or (S)-tert-leucinol derived methyl- or TMS-protected amino ethersas chiral auxiliaries also profits from the capacity to forma chelate with zinc chloride (135 and 136, Scheme 53).139

This reaction proceeded in high yields and selectivitieswith a series of cyclic imines. The use of a sterically more-demanding TBDMS protecting group on the alcohol moi-ety decreased both the yield (14%) and stereoselectivity(55% ee) significantly.

In addition to ethylene, other alkenes like propene and sty-rene can also be employed with good results. Further-more, treatment of the g-zincoimine intermediates 136with electrophiles other than H+ allowed for an interestingfunctionalization and resulted in products 137–139(Figure 6).140–143

Chelation also plays an important role in the mode of ac-tion of chiral amino acid amide auxiliaries. (R)-phenyl-glycine amide is an efficient auxiliary for the asymmetricallylation of auxiliary-derived imines 140 developed byKellogg and co-workers (Scheme 54).144 Many different-ly substituted imine substrates 140 result in highly selec-tive transformations. In the proposed six-membered chairtransition state 141, the organozinc reagent is chelated by

the C=O function of the amide and the N-atom of the imi-ne. This leads to the highly selective formation of the ob-served product. The diastereomeric chair transition state isless favorable, since the phenyl substituent of the auxilia-ry would interact unfavorably with the allyl group(Scheme 54). Related auxiliary-modified imines can beused in asymmetric Strecker reactions with good yields(76–93%) and excellent diastereoselectivities (de >98%).145

R1

N PhTi(Oi-Pr)2

131

OMe

R21)

2) H2O

HN Ph

OMe

R1

HR1

13228–84%

88 to >96% deR1 = Ph, o-IC6H4

R2 = SiMe3, n-Hex, Ph, CO2Et, SO2Tol

131

R2

R4

R3

–35 °C

HN Ph

OMe

R1

H

• R3

R2

13345–74%,

86% to >96% de

R1 = Ph, o-IC6H4, C10H7, p-TBSOC6H4, MesR2/R3 = H, n-Hex, PhR4 = Br, OAc, OP(O)(OEt)2

Ti ON

Me

H

Ph

H

Ari-PrO

Oi-Pr

134

N

Ar

Ph

OMe

Ti(Oi-Pr)4, 2 i-PrMgCl

–35 °C, 2.5 h;0 °C, 0.5 h

Scheme 53 Asymmetric alkylation of zinc enamides with ethylene.

N

OR2

R1 1) MesLi2) ZnCl2

3) R3Li

N

O

R1

R2

ZnR3

N

O

R1

R2

Zn

CH2

CH2

R3

ethylene

O

135

136

R1 = i-Pr, t-Bu, PhR2 = Me, TMSR3 = Me, t-Bu, Mes

H3O+

73–91%77–95% ee

Figure 6 Functionalized products.

O

13789%, 97% ee

O

13890%, 97% ee, >99% E

O

13984%, 97% ee

Ph EtO2C

Scheme 54 Asymmetric allylation reaction.

R1 H

N

Ph

CONH2

R1

HN

Ph

CONH2

H

BrZn

THF, 0 °C to r.t.

R1 = Ph, p-MeC6H4, p-MeOC6H4, p-FC6H4, p-ClC6H4, p-BrC6H4, p-PhC6H4, p-NO2C6H4, 3-piperonyl, p-HOC6H4, 2,5-(MeO)2C6H4, 3-pyridyl, 2-furyl, 2-thiophene, t-Bu, i-Pr, i-Bu

140

77 to >99%92 to >98% de

N

NH2

O

R1

H

Ph

BrZn

141



More recently, an impressive asymmetric hydrogenationusing (S)-phenylglycine amide as chiral auxiliary was re-ported by Ikemoto, Tellers, Rivera and co-workers.116,117

The substrates 142 can easily be prepared from the corre-sponding b-keto esters or amides. The amine of the result-ing Z-enamine 142 acts as a hydrogen-bond donor andforms hydrogen bonds with both carbonyl groups, result-ing in a rigid, mostly planar structure. As a consequence,the phenyl substituent of the auxiliary shields one of thetwo diastereomeric p-faces of the enamine (top face inScheme 55). Diastereoselective hydrogenation of the dou-ble bond from the less-hindered face resulted in the for-mation of precious optically active b-amino acidderivatives 143 (Scheme 55).116,146

Scheme 55 Asymmetric hydrogenation of chiral enamines.

A further noteworthy application of chelating amine aux-iliaries is the copper-catalyzed Michael addition of chiralenamines 144 to electron-deficient alkenes developed byChristoffers and Mann.147 In this highly asymmetric syn-thesis of chiral cyclohexanone derivatives 145, valine- ortert-leucine-derived amides were used as chiral auxilia-ries (Scheme 56). Interestingly, the auxiliary is hydrolyti-cally cleaved under the reaction conditions, making anadditional cleavage step unnecessary. More recent reportsfrom Christoffers and co-workers dealt with the synthesisand application of exocyclic enamines, resulting in aswitch of configuration of the resulting product stereo-centers.148,149 However, the yields and stereoselectivitiesobtained in this process were only moderate.

Scheme 56 Enantioselective synthesis of cyclohexanone deriva-tives.

6.3 Amino Alcohols as Auxiliaries

Another class of important chiral auxiliaries capable offorming chelates are the amino alcohols. Ephedrine deriv-atives are especially popular in this respect. The asymmet-ric alkylation of substrates attached to pseudoephedrine is

a very efficient method for the synthesis of optically ac-tive carboxylic acids or amino acids. Myers developed ahigh-yielding and highly stereoselective alkylation ofamides 146 with alkyl halides RX (Scheme 57). Thebroad scope renders this reaction to be of great syntheticinterest. Of the examples given in Scheme 57, only the re-action with BOMCl results in a low diastereomeric excess(33%) of product 147.150 This method also gives ready ac-cess to D- and L-amino acids of high optical purity – up to>99% de (Scheme 57, b).151 Organofluorine compounds,especially those that are enantiomerically pure, are in-creasingly important for many areas of chemistry andtheir synthesis using this auxiliary-based method was in-vestigated. The use of pseudoephedrine-derived a-fluoro-acetamides as starting materials resulted in the highlystereoselective formation of chiral organofluorine com-pounds (Scheme 57, c).152

Scheme 57 Asymmetric alkylation of various substrates 146.

An efficient asymmetric synthesis of a-methyl-b-aminoesters by stereoselective Mannich reaction was reportedby Badía and co-workers applying (S,S)-(+)-pseudoephe-drine as the chiral auxiliary (Scheme 58).153 Non-enoliz-able as well as enolizable imines can be successfullyemployed in this transformation, and in all cases excellentstereoselectivities were obtained. A six-membered che-late transition state 148 formed by the amide enolate andthe imine is proposed and, in addition, the alcohol of pseu-doephedrine is thought to coordinate to the lithium re-agent. Finally, the products 149a can be easily convertedto a,b-disubstituted aminoesters or b-lactams in goodyields and with enantiomeric excesses of >99% in all re-ported cases.

Whereas the auxiliary-bearing chiral amide enolate wasused as the nucleophile, the pseudoephedrine-derived a,b-unsaturated amide 150 was employed as the electrophilein an aza-Michael reaction (Scheme 59). This aza-Michaelreaction leads to the formation of b-amino amides 151.

R1 R2

N OPh

R1 R2

NH O

CONH2

Ph6.2 bar H2

PtO2 (2.5–10 mol%)THF

R1 = Me, i-Pr, Bn, p-CH3OC6H4, p-CF3C6H4R2 = OMe, NH2, N-piperidyl

142 14387–99%

70–99% de

H

H2N O

CO2Et

NH

NR12O

i-PrMe

O

Cu(OAc)2 H2O(2.5–20 mol%)23 °C

O

CO2Et

O

Me

R1 = Et, Me, allyl, (CH2)5

144 145, 65–90%, 83–98% ee

PhN

OH

O

R1 1) LDA or n-BuLi

2) R2X

PhN

OH

O

R1

R2

R1 = Me, Bn, n-Bu, Ph, CH2Bn, i-Pr, t-Bu, Cl, 3-pyridyl, 2-thiopheneR2X = BnBr, n-BuI, BOMBr, Ph(CH2)2I, BrCH2CO2t-Bu, MeI, EtI, CH2=CHCH2I, I(CH2)2OTIPS, I(CH2)2OTBS, BOMCl (77%, 33% de)

146

a)151 78–99%, 94 to >99% de

b)152 57–96%, 75 to >99% de

c)153 54–97%, 93 to >99% de

147

R1 = NH2R2X = MeI, EtI, EtBr, H2C=CHCH2Br, H2C=CH-CH2I, i-PrCH2I, i-PrCH2Mes, i-PrCH2OTf, c-C3H5CH2I, BnCl, BnBr, BnI, TMSCH2Br, o-MeOBnBr (43%)

R1 = FR2X = MeI, H2C=CHCH2I, H2C=C(CH3)CH2Br, BnBr, EtOTf, EtI (29%)



Rather reactive lithium benzylamides had to be used asnucleophiles since simple amines, like benzylamine, re-sulted in the recovery of starting material(Scheme 59).120,154 Some more recent examples for theuse of ephedrine derivatives as chiral auxiliaries in asym-metric synthesis, for example in aldol reactions, have beenreported.123,155,156

Scheme 59 Asymmetric aza-Michael reaction.

Another related class of chiral auxiliaries are amino acidsand amino acid esters.119 Most often, however, cyclic de-rivatives of these compounds are used and these are dis-cussed elsewhere in this review.

6.4 Cleavage

In most cases, the auxiliaries are attached to the productby an ether, amide or imine bond and hydrolysis underacidic conditions proceeds smoothly. For example, imine152 or amide 147 can be converted into the correspondingketone 153 or carboxylic acid 154 by hydrolysis(Scheme 60). Under these conditions, the auxiliaries canoften be recovered. Alternatively, reductive cleavage ofamides with borane–lithium pyrrolidide or LiAlH(OEt)3

yields the desired alcohol or aldehyde, respectively.122

7 Oxazolidinones, Oxazolines and Oxazo-lidines

Amino alcohol derived oxazolidinones 155, oxazolines156 and oxazolidines 157 are members of arguably one ofthe most commonly used classes of chiral auxiliaries inorganic synthesis (Figure 7).110,157–160

The popularity of these auxiliaries relies on their readyavailability, the generally high diastereoselectivities ob-tained for many transformations and the rather facile in-

troduction and cleavage of the auxiliary. Oxazolidinonesare linked to the substrate through their N atom, most of-ten by an N-acylation resulting in N-acyl oxazolidinoneproducts 164.157,158 On the contrary, the oxazolines 165are generally connected to the substrate by their 2-position(Rsubstrate in Figure 7). Meyers has popularized the use ofoxazolines in organic synthesis and many routes for thesynthesis of enantiomerically pure oxazolines exist.159 Ingeneral, they can be prepared from a carboxylic acid de-rivative of the substrate and the appropriate amino alcohol(route 1). Alternatively, a preformed oxazoline can belinked to the substrate (route 2). Oxazolidines 166 can bebound to the substrate at the N atom or at the 2-position.In the latter case, the oxazolidine ring is readily preparedby reaction of the substrate aldehyde with an appropriateamino alcohol (Scheme 61).160

7.1 Oxazolidinones

Oxazolidin-2-ones, first introduced by Evans et al. in1981,161 have found widespread applications and a greatwealth of structural modification of these auxiliaries has

Scheme 58 Asymmetric Mannich reaction using (S,S)-pseudoephedrine.

N

O

Ph

OH

N

HR1

PMPN

O

Ph

OH

R1

NHPMP

1) LDA, LiCl, THF –78 °C

2)

THF, 0 °C

R1 = Ph, m,p-(MeO)2C6H3, 2-furyl, 2-thienyl, t-Bu

LnLi

NO

R1NMe

OLnLi

Me

HH

(X)n

PMP

N

O

Ph

OH

R1

NHPMP

149b149a

69–86%149a:149b >99:1

anti/syn >99:1

148, X = THF

R1

O

NPh

OH

R1

O

NPh

OH

NR2 Bn

R2BnNLi

R1 = Et, i-Pr, t-Bu, PhR2 = Bn, Me

150 15115–94%

30% to >98% de

Scheme 60 Cleavage of amine or amino alcohol auxiliaries.

PhN

OH

O

R

R

147

H2SO4

dioxane

O

R

R

HO

154

NH

MePh

R

152

aq AcOH

O

R

153

Figure 7 Oxazolidinones, oxazolidines and oxazolines.

O N

O

R1

O N

Rsubstrate

R1

155 156

NO R3/Rsubstrate

R1R2

Rsubstrate/R3

157

Oxazolidinones Oxazolines Oxazolidines

Rsubstrate



been reported.162–165 Representative oxazolidinones (alsocommonly called Evans auxiliary) are the very popularmonosubstituted oxazolidinones 158 [for example (S)-4-benzyl-2-oxazolidinone 158a] and the more highly substi-tuted oxazolidinones 159, 160, camphor-derived 161,166

carbohydrate-derived 162,167 or SuperQuats 163162,163

(Figure 8). Furthermore, related auxiliaries using otherheteroatoms like imidazolidinones,168,169 thiazolidinethiones170–173 or oxazolidinethiones170,174,175 have alsobeen successfully used.

Figure 8 Differently substituted oxazolidinone auxiliaries.

Even though oxazolidinones are linked to the substrate viaa single bond only, additional factors like chelation(167)176 or dipole-moment minimization (168,169)161,177,178 often lead to preferred conformations(Scheme 62) in which the substituent R1 of the oxazolidi-none efficiently shields one of the molecule’s diaste-reotopic faces. As a consequence of this type of energeticpreference for certain rotamers, in many cases very highstereoselectivities are obtained. Asymmetric aldol reac-tions, alkylations and pericyclic reactions are traditionally

the most important areas of usage for these auxilia-ries.110,157–160

The versatility of oxazolidinone auxiliaries is nicely dem-onstrated by their numerous applications in aldol reac-tions (Scheme 63).110,157,158 Proper choice of reagents andreaction conditions allows access to all four diastereo-mers. In this respect, boron enolates are very popularsince, as a result of short B–C and B–O bonds, they formtighter transition states, generally leading to higher selec-tivities. As a consequence, the reaction of Z-boron eno-lates of the acyl oxazolidinones with an aldehydegenerally leads to the highly selective formation of synproducts 170 (also called ‘Evans syn’ aldol product).178

Arguably, this represents one of the most popular applica-tions of acyl oxazolidinones. In some cases, the additionaluse of a large Lewis acid like Et2AlCl allows the forma-tion of anti products 172.176

Chelate-controlled methods usually result in the forma-tion of ‘non-Evans’ products. The use of titanium enolates(also Li, Zn or Sn)176 gives rise to ‘non-Evans syn’ prod-ucts 171.170b The synthesis of ‘non-Evans anti’ products173 (Scheme 63) was recently reported in a MgCl2-cata-lyzed aldol reaction by Evans et al. (Scheme 64).179 Theuse of TMSCl allowed the turnover of the metal complexby silylation of the anti-aldol products. It appears thatthere is a delicate balance between silylation of the aldo-late and the retro-aldol reaction and that the anti diaste-reomer is silylated in preference to the syn isomer.Cleavage of the silyl protection group results in the forma-tion of the unprotected products 176. Instead of oxazolid-inones, the reaction can also be run with related N-acylthiazolidinethiones,173 the advantage of these sulfur-containing oxazolidinones being the milder cleavage con-ditions.170b

Modification of the acyl substituents of substrate 175 overa wide range does not result in a deterioration of yieldsand diastereoselectivities as long as no b-branched sub-stituents are used. However, only non-enolizable alde-hydes can be successfully used, whereas enolizablealdehydes result in their own undesired self-condensation.Mechanistic studies show that no enolsilane is formed andthat the reaction does not proceed by a Mukaiyama aldol

Scheme 61 Preparation of oxazolidinone, oxazoline and oxazolidi-ne substituted substrates.

O NH

O

R1

Cl R2

O

cat. DMAPEt3N

O N

O

R1

O

R2

O N

OEt

i-Pr

158

H+, BnNHMeO N

R

i-Pr

HNHO Ts

MePh

RCHO NO Ts

MePh

R

164

166

165

HO NH2

R

i-Pr

XO

R = NBnMe

Route 2Route 1

O NH

O

R1R2

R2

O NH

O

O NH

O

Ph Me

ONH

OOO

ONH

163

160159

161 162O O

O NH

O

R1

158a

SuperQuatR1 = i-Pr, Ph, BnR2 = Me, Ph

5

32

1

R = i-Pr, t-Bu, Ph, Bn

O NH

O

R1

158b

5

32

1

R = Ph, Bn

4S 4R

Scheme 62 Alternative modes of action of the oxazolidinone auxi-liaries: chelation vs. dipole minimization.

155O N

O

R1

O

167

LnM

chelate formation

minimization of dipole moment

O

N

O

R2

O

R

O

N

OMLn

O

R

R3

R3 or168

169



pathway. Silylation of the metal aldolate is essential forthe catalytic process, since the equilibrium of the revers-ible aldol reaction is shifted towards the silylated aldolproducts.173,179

Scheme 64 Asymmetric magnesium halide catalyzed aldol reac-tion.

Optically active polyhydroxylated products can be ob-tained by an oxy-aldol reaction wherein the substituent R2

of the oxazolidinone substrate 164 contains an a-alkoxysubstituent.180–182 This oxy-aldol methodology has foundmany applications in the synthesis of natural products. Forexample, it allowed for the asymmetric synthesis of inter-esting seven-, eight- and nine-membered rings by Crim-mins and co-workers.181,182 Originally, an auxiliary-controlled aldol reaction was used to build precursors fora metathesis reaction leading to up to nine-memberedrings.182 Recently, the total syntheses of a number of nat-ural products like (+)-prelaureatin, (+)-laurallene and (–)-isolaurallene were completed using this aldol technolo-gy.183,184

It is important to note that the recent developments in thearea of organocatalysis and especially enamine catalysisusing proline have resulted in powerful methods for enan-tioselective aldol reactions for many different classes ofsubstrates.185,186

A recent example for an asymmetric alkylation utilizingan oxazolidinone auxiliary is part of the synthesis of bicy-clooctanone 179, a useful building block for the synthesisof the diterpenoid vinigrol.187 Conversion of 177 withLDA and allylbromide leads to 178 in excellent yield anddiastereoselectivity (Scheme 65).

Scheme 65 Oxazolidinone-mediated asymmetric alkylation reac-tion.

The stereochemical outcome of pericyclic reactions canalso be efficiently controlled by oxazolidinone auxiliaries.Diels–Alder reactions, especially those that are intramo-lecular, lead to a significant increase in structural com-plexity.188–190 Quite recently, Evans et al. reported on auseful aldol/Diels–Alder reaction sequence.188 Enantio-merically pure 180 was prepared by an Evans syn aldol re-action, followed by a Parikh–Doering oxidation.Intriguingly, the cycloaddition of oxazolidinone-substi-tuted substrate 180 leads to the bicyclic product 181 inhigh diastereomeric excess. Subsequent conversion of theacyloxazolidinone to a thioester, followed by decarboxy-lation, removed the auxiliary and the initially created ringstereocenter. Finally, treatment with the Tebbe reagentgave rise to enantiomerically pure a-himachalene (182)(Scheme 66).188,189

Scheme 63 Possible formation of stereocomplementary aldol products.

O N

R1

O O

R2

R3CHO

O N

R1

O O

R2

164

R3

OH

O N

R1

O O

R2

R3

OH

O N

R1

O O

R2

R3

OH

O N

R1

O O

OR4

R3

OH

oxy-aldolR2 = OR4

anti-aldolsyn-aldol

"Evans syn"

"non-Evans syn" "non-Evans anti"

O N

R1

O O

R2

R3

OH

"Evans anti"TiCl4base

Bu2BOTfbase

Bu2BOTfEt2AlCl

170

171

172

173

174

MgCl2base, TMSCl

X N

Bn

X O

R1

PhCHO

1) MgCl2 (10 mol%) Et3N, TMSCl, EtOAc, 23 °C

2) MeOH, TFA

X N

Bn

X O

R1

175

Ph

OH

17688–94%, >90:10 dr

X = O, SR1 = Me, Et, Bn, CH2CHMe2, CH2CH=CH2, p-MeC6H4, p-MeOC6H4, Ph, CH=CHPh

O N

O O

O N

O O

17893%, >99% de

BrLDA

THF, –78 °C

O

H

177

179

BnO

H



An asymmetric samarium diiodide mediated Reformatskyreaction of a-bromoacetyloxazolidinones 183 was recent-ly reported by Fukuzawa et al.191 A variety of differentlysubstituted oxazolidinones lead to the desired products ingood to excellent yields and high diastereoselectivities.The use of 5,5-disubstituted oxazolidinone 163 (Super-Quat, R2 = Me or Ph) resulted in lower yields but slightlyimproved diastereoselectivities (Scheme 67).191,192

Scheme 67 Oxazolidinone auxiliaries in asymmetric Reformatskyreactions.

Steric control of reactions with singlet oxygen is a chal-lenging problem. Wirth, Adam, and co-workers reportedon the successful use of oxazoline auxiliaries in diaste-reoselective [4+2] cycloadditions with singlet oxygen asdienophile in 1998.193 More recently, oxazolidinone-func-tionalized enecarbamates 184 were used in [2+2] cycload-ditions with 1O2 by Bosio, Adam, and Turro(Scheme 68).194 The high levels of diastereoselectivitywere explained to be a result of steric repulsion caused bythe R1 substituent of the auxiliary. The other stereocenterat C3 is without any significant influence, as can be seenby the fact that the use of an achiral oxazolidione (R1 = H)leads to an unselective formation of the two diastereomersof 185. In addition, switching from the R- to the S-config-ured auxiliary leads to the highly selective formation ofthe corresponding diastereomeric product.194,195

Scheme 68 [2+2] cycloaddition of singlet oxygen and oxazolidin-one-functionalized enecarbamates; TPFPP = 5,10,15,20-tetrakis(pen-tafluorophenyl)porphine (sensitizer).

The combination of multiple transformations in a singlestep is highly desirable, since it often rapidly increases thestructural complexity of the substrate. This kind of tan-dem reaction can also benefit from oxazolidinone auxilia-ries, as showcased by Hsung and co-workers. A tandemepoxidation, epoxide opening and [4+3] cycloaddition ofchiral allenamide 186 led to product 187 with high diaste-reoselectivity (Scheme 69).196 The intermolecular variantof this reaction resulted in good stereoselectivities aswell.197 This method might become an important tool forthe synthesis of complex natural products.198

Scheme 69 Tandem epoxidation, epoxide opening and subsequentcycloaddition reaction.

Although examples of selective free radical reactionshave been reported in recent years,199 stereoselective rad-ical reactions are still a great challenge in organic synthe-sis. Pioneering work by Sibi and co-workers dealt with theapplication of oxazolidinone auxiliaries in conjugate b-radical additions (Scheme 70).200,201 Rare-earth Lewis ac-ids and especially Yb(OTf)3 provided the best results interms of diastereoselectivity. It turned out that a large sub-stituent (i.e. diphenylmethyl) on the oxazolidinone of sub-strate 188 resulted in much higher diastereoselectivitiesthan smaller substituents like phenyl, isopropyl or ben-zyl.202–208

Oxazolidinone-substituted substrates have also success-fully been employed in heterogeneous catalysis. Prashadet al. developed a stereoselective synthesis of (2S,3R)-erythro-methyl phenidate 189, the key step being an ox-azolidinone-controlled hydrogenation of a tetrasubstitut-ed double bond.209 The excellent diastereoselectivityobtained in this reaction is a result of an energetically pre-

Scheme 66 Asymmetric Diels–Alder reaction; Xc = 4-(S)-benzyl-2-oxazolidinone.

Xc

O

180

18178%, 94% de(after column

chromatography: 100% de)

OO

Xc

182α-himachalene

Xc

O O

ZnBr2

0 °C

1) Bu2BOTf, i-Pr2NEt isoprene, 0 °C; acrolein, –78 °C2) SO3⋅pyridine DMSO–CH2Cl2 i-Pr2NEt, –10 °C

1) LiSEt; AgNO3

lutidine THF–H2O 70 °C

2) Tebbe reagent –40 °C

71%

Br

O

N O

O

R1R2

R2

R3CHOSmI2

THF, –78°C

R1 = i-Pr, Bn, PhR2 = H, Me, PhR3 = i-Pr (78–98% de), Et2CH (76% de), c-Hex (84% de), t-Bu (96–99% de), n-C7H15 (70–94% de), Ph (49–99% de), PhCH2CH2 (86% de)

O

N O

O

R1R2

R2

R3

OH

183 32–92%, 49% to >99% de

O N

O

Ph

Ph

R1

O N

O

R1

OO

PhPh

1O2, TPFPP

CDCl3, –35 °C

184R1 = Me, i-Pr

185>95%, >95:5 dr

ODMDO

(2–5 equiv)

O

ON

OO

Ph

CH2Cl2–78 °C

186

187, 75%, 95:5 dr

N

OO

Ph

O

N

OO

PhO



ferred conformation caused by a hydrogen bond and by aminimization of the molecule’s overall dipole moment.As a consequence, the benzyl substituent of the oxazolid-inone moiety shields the bottom face of the molecule andhydrogenation takes place from the opposite top face(Scheme 71).

Scheme 71 Asymmetric hydrogenation of a highly substituteddouble bond.

Another recent application of oxazolidinones in heteroge-neous catalysis is instructive, too. A variety of 2-oxazoli-dinone-substituted pyridines was selectively hydro-genated to enantiomerically pure piperidines by Glorius etal. This method represents the first auxiliary-mediatedhighly stereoselective pyridine hydrogenation. Pyridines190 (4-, 5- or 6-substituted) as well as multiply substitutedderivatives lead to products 193 in high yields and highenantiomeric excess. Up to three ring stereocenters ofcompound 193 and four ring stereocenters of compound192 were selectively generated in a single step(Scheme 72).177 The proposed mechanism starts off withthe protonation of 190. As a consequence of a hydrogenbond formed in pyridinium salt 191, the i-Pr group of theauxiliary shields the top face, whereas the unhindered bot-tom face of the molecule is available for attack by the het-erogeneous hydrogenation catalyst and the successivehydrogenation. Cleavage of the resulting aminal 192 un-der slightly acidic conditions (AcOH) and hydrogenationof the imine/enamine intermediates gave product 193.Many attractive features, like high yields and selectivities,traceless cleavage of the oxazolidinone auxiliary underthe reaction conditions, and facile separation and purifica-tion of the piperidine products, arguably render this reac-

tion to be one of the most efficient applications of chiralauxiliaries.

7.2 Oxazolines

2-Oxazolines (also called 4,5-dihydrooxazoles) have lessoften been used as chiral auxiliaries. Exciting recent ap-plications can be found in the area of C–H bond activa-tion, which is a powerful method for the functionalizationof organic molecules. However, it is often limited by lowtolerance for functional groups, restriction to aryl groupsand other activated C–H bonds, and stereoselectivity is asyet an untackled problem. An important step towards thisgoal is an exciting asymmetric C–H bond activation withthe help of an oxazoline auxiliary reported by Sames andco-workers. Preformed platinum complexes 194 alloweda stereoselective dehydrogenation, giving rise to products195 (Scheme 73).210 A delicate temperature dependenceof the diastereoselectivity of this C–H bond activation wasobserved. The highest stereoselectivity was obtained withthe tert-butyl-substituted oxazoline (>90% de), howeverthe product could not be isolated (conversion <10%). Ithas to be noted that, even though stoichiometric amountsof a noble metal had to be used for this step and only mod-erate selectivities and yields were obtained, this is atrendsetting transformation. Two more steps completedthe short synthesis of the natural product (–)-rhazinil-am.210

Another stereoselective C–H bond activation has very re-cently been reported by Yu and co-workers. The asym-metric palladium-catalyzed iodination of unactivated C–H bonds occurred with high diastereoselectivities andgood yields, forming products 197 and 199(Scheme 74).211 Both sp3- and sp2-hybridized carbons canbe functionalized in this reaction. Interestingly, a second-ary C–H bond of a cyclopropane can be iodinated in thepresence of a methyl group in reasonable yield (65%) andvery high diastereoselectivity (98% de).159,211,212

Scheme 70 Diastereoselective radical addition. Reagents and con-ditions: a) Yb(OTf)3 (1 equiv), R2X (5 equiv), Bu3SnH (2 equiv),CH2Cl2–THF (4:1), Et3B, O2, 3 h, –78 °C.

O N

O

R1

O

CHPh2

O N

O

R1

O

CHPh2

R2

188 81–94%76% to 96% de

R1 = Me, PhR2 = i-Pr, Et, c-Hex, t-Bu, MeOCH2, MeCO

a)

NH

O

Ph

N

OO

Ph

Pd/C, H2

EtOAc, r.t.

NH

Ph

O

OMe

95%, 94% de

189

NH

O

Ph

N

OO

Ph

MeOH, LnI3

THF, r.t.

1. H-bond formation

2. minimization of dipole moment

3. steric shielding of the molecule's lower faceby the Bn group

Scheme 72 Plausible mechanism for the asymmetric heterogeneoushydrogenation of pyridines.

N N O

O

i-Pr

1) H2, AcOH, catalyst

2) HCl

R3

R2

R1

190

NH

R3

R2

R1

HCl

193, 64–95%85–98% ee

H+

N

R3

R2

R1 N

OO

i-Pr

H

191

H2, catalyst

NH2

R3

R2

R1 N

OO

i-Pr

R1, R2, R3 = Me, n-Pr, CHO (substrate) to CH2OH (product), CF3, CONMe2catalysts: Pd(OH)2/C, PtO2, Rh/Pd/C, Rh/C

192

HN O

O

i-Pr

+6

45

3

2



Scheme 74 Asymmetric C–H bond activation and iodination.

7.3 Oxazolidines

Oxazolidines have found a number of applications aschiral auxiliaries. Some impressive results have been ob-tained and should be highlighted. However, it is importantto note that oxazolidines are rather acid-sensitive and in

some cases exist in equilibrium with the open-chain iminealcohol.213

Clayden and co-workers showed that a chiral oxazolidinecan influence the conformation of a long carbon chain andfinally control the addition to an aldehyde group at the op-posite end of the molecule (Scheme 75).214–216 Most im-pressively, the auxiliary and the electrophilic aldehydecan be separated by more than 20 C–C bonds, and never-theless, the Grignard addition to 200 still is highly diaste-reoselective (>90% de) (Scheme 75).214 Once again,minimization of the overall dipole moment is key to thesuccess of this transformation. The auxiliary influencesthe amide next to it and leads to a preferred conformation.The following amides are alternatingly pointing to theback and to the front in order to minimize the dipole mo-ment. Finally, the last one shields one of the aldehyde p-faces (see 200 and 201).

An insightful synthesis of 1,4-dihydropyridines by a face-selective addition to a cation-p complex was reported byYamada and Morita (Scheme 76).217 Addition of silylketene acetals to auxiliary-substituted pyridine 202 in thepresence of methyl chloroformate resulted in the highlyselective formation of 1,4-dihydropyridine adducts 203.By careful choice of the appropriate solvent, the forma-tion of the undesired 1,6-adduct could be strongly sup-pressed (Scheme 76).

X-ray analysis of 202 showed no intramolecular interac-tion of the two aromatic rings. However, X-ray analysis ofthe corresponding N-methylated pyridinium derivative of202 unambiguously showed that a cation-p interaction de-termines the conformation to be 204a (R = Me). The au-thors postulate that for R = CO2Me, rotamer 204b isenergetically favored over 204a, as indicated by ab initiocalculations (Figure 9). Addition of the nucleophile to theless-shielded si face of 204b would result in the observedhighly selective formation of 203.217

Scheme 73 Stereoselective dehydrogenation by C–H bond activati-on.

N

OH3CO

N

Ph

O

N

R

1) TfOH, CH2Cl22) CF3CH2OH heat, 72 h3) KCN

194 (R)-195

N

OH3CO

N

Ph

O

N

R

Pt

Me

Me

R = Ph: 15%, 72% deR = i-Pr: 10%, 70% deR = c-Hex: 20%, 76% deR = t-Bu, <10% conversion, >90% de

R = Ph: 40%, 50% deR = i-Pr: 40%, 50% deR = c-Hex: 42%, 63% de

@ 60 °C: @ 70 °C:

Me

Me R1

O

Nt-Bu

Me R1

O

Nt-Bu

I

Ph

Ph Me

O

Nt-Bu

Ph Me

O

Nt-Bu

196 19762–83%

82–86% de

198 199, 98%, 98% de

Pd(OAc)2

(10 mol%)I2 (1 equiv)

PhI(OAc)2, CH2Cl2

Pd(OAc)2

(10 mol%)I2 (1 equiv)

PhI(OAc)2, CH2Cl2 I

R1 = t-Bu, OTBS

Scheme 75 Ultra-remote stereocontrol along a carbon chain.

O

N O

ON

Me

PhMe

ON

O

ON

ON

O

O ON N

O

H

RMgBr

THF, –78 °C

O

N O

ON

Me

PhMe

ON

O

ON

ON

O

O ON N

H

200

201, 58–77%, >90% de

R = Me, Ph

i-Pri-Pr i-Pr

i-Pr i-Pri-Pr i-Pr

i-Pr

i-Pri-Pr i-Pr i-Pr

i-Pri-Pr i-Pr

i-Pr i-Pri-Pr i-Pr

i-Pr

i-Pri-Pri-Pr

i-Pr

OHR



Scheme 76 Asymmetric synthesis of 1,4-dihydropyridines.

Figure 9 Working model for nucleophilic addition to cation-p com-plex 204b.

Another recent example for the use of oxazolidine auxil-iaries is the asymmetric epoxidation of acetylated or car-bamoyl-substituted oxazolidines 205 reported bySchambony and co-workers.218,219 A hydrogen bond be-tween the urea functionality NH and the oxidant seems tobe important for high stereoselectivities. This can be de-duced from a reversal in stereoselectivity in the casewhere the substrate with R4 = Me is employed (26:74 dr).The epoxidation reaction can be run with dimethyldiox-irane (DMD) (Scheme 77) or alternatively with m-chlo-roperbenzoic acid, resulting in slightly lower yields anddiastereoselectivities of products 206.219–223

Scheme 77 Asymmetric epoxidation of oxazolidine-substituteddouble bonds.

7.4 Cleavage

Cleavage of the oxazoline211 and oxazolidineauxiliaries219 is generally achieved by simple acid- orbase-catalyzed hydrolysis. For the cleavage of oxazolid-inones, a variety of efficient procedures has been devel-

oped, such as reductive cleavage with NaBH4 or LiBH4

leading to the corresponding alcohol 208.184,224 Anotherexemplary transformation is the transamidation of 207 toWeinreb amide 209.225 In addition, hydrolysis withLiOOH under basic conditions provides the correspond-ing carboxylic acid 210226 and an alternative decarboxyla-tion results in 211 (Scheme 78).188 In most cases, theauxiliary can be recovered and recycled.

Scheme 78 Cleavage of oxazolidinone auxiliaries.

8 Conclusion

The recent applications of chiral auxiliaries presented inthis review show a high level of sophistication. Low costand ready availability, ease of introduction and cleavageof the auxiliaries, as well as high levels of predictability,reliability, time-efficiency and stereoinduction, often ren-der auxiliaries an attractive method in asymmetric synthe-sis. In addition, and contrary to other methods ofasymmetric synthesis, facile purification of the auxiliary-substituted product diastereomers allows for very highenantiomeric purities of the final products after removalof the auxiliary. Future research will most likely focus onthe application of auxiliaries in challenging transforma-tions and increasingly efficient methods. In this context,processes using temporary24,25,45,47,60,61,147,177 or catalyticauxiliaries56,57 might become role models for future devel-opments.

Acknowledgment

Generous financial support by the Deutsche Forschungsgemein-schaft, the Fonds der Chemischen Industrie (Dozentenstipendium),Lilly Germany (Lilly Lecture Award) and the BASF AG (BASFCatalysis Award) is gratefully acknowledged. In addition, we thanka number of distinguished experts of the field for their support ofthis work.

N

O

N O

Bn

202

N

O

N O

BnCO2Me

203

R1 R2CO2Me

MeO

R2R1

OSiMe3

ClCO2Me;

R1, R2 = Me: 70%, 97:3 (1,4:1,6), >99% de in tolueneR1 = H, R2 = Ph: 61%, 93:7 (1,4:1,6), >99% de, 94:6 (syn:anti) in CH2Cl2

O

NO

Re

Si

O

NO

Nu

Re

SiNR

NR

204a 204b

203

O N

R3

R1

R2

NAr

O

R4

Ph

O N

R3

R1

R2

NAr

O

R4

Ph

DMD, acetone

20 °C, 5 h

205

H H

O

R1/R2 = Me, Et, HR3 = H, MeR4 = HAr = Ph, p-NO2Ph

206>90%

48% to >90% de

MeONHMe HCl

AlMe3

O

RN

Me

MeO

O N

R

O O

R LiAlH4 O NH

R

O

R

207

207

158a

158a

208

209

207LiOOH

158a

O

HO R

210

207 R-H1) EtSH, KH

2) AgNO3, H2O 2,6-lutidine 211

OH

158a



References

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(54) Workman, J. A.; Garrido, N. P.; Sancon, J.; Roberts, E.; Wessel, H. P.; Sweeney, J. B. J. Am. Chem. Soc. 2005, 127, 1066.

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(56) Aggarwal, V. K.; Alonso, E.; Hynd, G.; Lydon, K. M.; Palmer, M. J.; Porcelloni, M.; Studley, J. R. Angew. Chem. Int. Ed. 2001, 40, 1430.

(57) Aggarwal, V. K.; Harvey, J. N.; Richardson, J. J. Am. Chem. Soc. 2002, 124, 5747.

(58) Aggarwal, V. K.; Bae, I.; Lee, H.-Y.; Richardson, J.; Williams, D. T. Angew. Chem. Int. Ed. 2003, 42, 3274.

(59) For more information on the catalytic asymmetric epoxidation, see: (a) Aggarwal, V. K.; Vasse, J.-L. Org. Lett. 2003, 5, 3987. (b) Aggarwal, V. K.; Richardson, J. Chem. Commun. 2003, 2644. (c) Aggarwal, V. K.; Alonso, E.; Bae, I.; Hynd, G.; Lydon, K. M.; Palmer, M. J.; Patel, M.; Porcelloni, M.; Richardson, J.; Stenson, R. A.; Studley, J. R.; Vasse, J.-L.; Winn, C. L. J. Am. Chem. Soc. 200, 125, 10926. (d) Aggarwal, V. K.; Bae, I.; Lee, H.-Y. Tetrahedron 2004, 60, 9725. (e) Aggarwal, V. K.; Hebach, C. Org. Biomol. Chem. 2005, 3, 1419.

(60) Ye, S.; Huang, Z.-Z.; Xia, C.-A.; Tang, Y.; Dai, L.-X. J. Am. Chem. Soc. 2002, 124, 2432.

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(63) Harrington, P. E.; Tius, M. A. J. Am. Chem. Soc. 2001, 123, 8509.

(64) For applications of myrtenal-derived auxiliaries, see: (a) Pérez-Estrada, S.; Lagunas-Rivera, S.; Vargas-Díaz, M. E.; Velázquez-Ponce, P.; Joseph-Nathan, P.; Zepeda, L. G. Tetrahedron: Asymmetry 2005, 16, 1837. (b) Chacón-García, L.; Lagunas-Rivera, S.; Pérez-Estrada, S.; Vargas-Díaz, M. E.; Joseph-Nathan, P.; Tamariz, J.; Zepeda, L. G. Tetrahedron Lett. 2004, 45, 2141. (c) Solladié-Cavallo, A.; Balaz, M.; Salisova, M.; Welter, R. J. Org. Chem. 2003, 68, 6619. (d) Vargas-Díaz, M. E.; Chacón-García, L.; Velázquez, P.; Tamariz, J.; Joseph-Nathan, P.; Zepeda, L. G. Tetrahedron: Asymmetry 2003, 14, 3225.

(65) Pinheiro, S.; Goncalves, C. B. S. S.; de Lima, M. B.; de Farias, F. M. C. Tetrahedron: Asymmetry 2000, 11, 3495.

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(67) Dumas, F.; Alencar, K.; Mahuteau, J.; Barbero, M. J. L.; Miet, C.; Gérard, F.; Vasconcellos, M. L. A. A.; Costa, P. R. R. Tetrahedron: Asymmetry 1997, 8, 579.

(68) For additional recent applications of camphor-derived chiral auxiliaries in organic synthesis, see: (a) Dixon, D. J.; Horan, R. A. J.; Monck, N. J. T. Org. Lett. 2004, 6, 4423. (b) Voituriez, A.; Moulinas, J.; Kouklovsky, C.; Langlois, Y. Synthesis 2003, 1419. (c) Gawley, R. E.; Campagna, S. A.; Santiago, M.; Ren, T. Tetrahedron: Asymmetry 2002, 13, 29. (d) Boeckman, R. K. Jr.; Laci, M. A.; Johnson, A. T. Tetrahedron: Asymmetry 2001, 12, 205. (e) Ref. 55c. (f) Aggarwal, V. K.; Lattanzi, A.; Fuentes, D. Chem. Commun. 2002, 2534. (g) Fringuelli, F.; Matteucci, M.; Piermatti, O.; Pizzo, F.; Burla, M. C. J. Org. Chem. 2001, 66, 4661. (h) Lin, J.; Chan, W. H.; Lee, A. W. M.; Wong, W. Y. Tetrahedron 1999, 55, 13983.

(69) For the application of sultam auxiliaries in asymmetric Diels–Alder reactions, see: (a) Chan, W. H.; Lee, A. W. M.; Jiang, L. S.; Mak, T. C. W. Tetrahedron: Asymmetry 1997, 8, 2501. (b) Ho, K. F.; Fung, D. C. W.; Wong, W. Y.; Chan, W. H.; Lee, A. W. M. Tetrahedron Lett. 2001, 42, 3121.

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(71) (a) Borer, B. C.; Balogh, D. W. Tetrahedron Lett. 1991, 32, 1039. (b) Ganz, I.; Kunz, H. Synthesis 1994, 1353.

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(76) For excellent reviews on the application of carbohydrates in asymmetric synthesis, see: (a) Hultin, P. G.; Earle, M. A.; Sudharshan, M. Tetrahedron 1997, 53, 14823. (b) Kunz, H.; Rück, K. Angew. Chem., Int. Ed. Engl. 1993, 32, 336. (c) Kunz, H. Pure Appl. Chem. 1995, 67, 1627. (d) Knauer, S.; Kranke, B.; Krause, L.; Kunz, H. Curr. Org. Chem. 2004, 8, 1739.

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(79) Totani, K.; Takao, K.; Tadano, K. Synlett 2004, 2066.(80) Totani, K.; Asano, S.; Takao, K.; Tadano, K. Synlett 2001,

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(82) Klegraf, E.; Follmann, M.; Schollmeyer, D.; Kunz, H. Eur. J. Org. Chem. 2004, 3346.

(83) For more information about this asymmetric piperidine synthesis, see: (a) Follmann, M.; Rösch, A.; Klegraf, E.; Kunz, H. Synlett 2001, 1569. (b) Follmann, M.; Kunz, H. Synlett 1998, 989. (c) Kranke, B.; Hebrault, D.; Schultz-Kukala, M.; Kunz, H. Synlett 2004, 671.

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(85) For more examples of cycloaddition reactions with carbohydrate auxiliaries, see: (a) Ferreira, M. L. G.; Pinheiro, S.; Perrone, C. C.; Costa, P. R. R.; Ferreira, V. F. Tetrahedron: Asymmetry 1998, 9, 2671. (b) Weyershausen, B.; Nieger, M.; Dötz, K. H. J. Org. Chem. 1999, 64, 4206. (c) Nouguier, R.; Mignon, V.; Gras, J.-L. J. Org. Chem. 1999, 64, 1412. (d) Hall, A.; Bailey, P. D.; Rees, D. C.; Wightman, R. H. Chem. Commun. 1998, 2251.

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(87) (a) Enders, D.; Eichenauer, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 549. (b) Enders, D.; Eichenauer, H. Tetrahedron Lett. 1977, 18, 191.

(88) For excellent reviews on the application of RAMP-/SAMP-auxiliaries in organic synthesis, see: (a) Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D. Tetrahedron 2002, 58, 2253. (b) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895. (c) Bloch, R. Chem. Rev. 1998, 98, 1407. (d) Enders, D. In Asymmetric Synthesis, Vol. 3; Morrison, J. D., Ed.; Academic Press: Orlando, 1984, 275–339.

(89) Enders, D. Chem. Scr. 1985, 25, 139.(90) Enders, D.; Papadopoulos, K.; Herdtweck, E. Tetrahedron

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(b) Enders, D.; Lochtman, R. Eur. J. Org. Chem. 1998, 689.(95) Enders, D.; Peters, R.; Lochtman, P.; Raabe, G. Angew.

Chem. Int. Ed. 1999, 38, 2421; and references cited therein.(96) Enders, D.; Klumpen, T.; Raabe, G. Synlett 2003, 1198.(97) For a review on the dihydroxyacetone unit as a versatile C3

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(98) (a) Enders, D.; Voith, M.; Ince, S. J. Synthesis 2002, 1775. (b) Enders, D.; Prokopenko, O. F.; Raabe, G.; Runsink, J. Synthesis 1996, 1095.

(99) (a) Enders, D.; Jegelka, U. Synlett 1992, 999. (b) Enders, D.; Jegelka, U. Tetrahedron Lett. 1993, 34, 2453.

(100) (a) Enders, D.; Hundertmark, T. Eur. J. Org. Chem. 1999, 751. (b) Enders, D.; Prokopenko, O. F. Liebigs Ann. Chem. 1995, 1185. (c) Enders, D.; Whitehouse, D.; Runsink, J. Chem. Eur. J. 1995, 1, 382. (d) Majewski, M.; Nowak, P. Tetrahedron: Asymmetry 1998, 9, 2611.

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(102) Enders, D.; Funabiki, K. Org. Lett. 2001, 3, 1575.(103) For recent applications of the RAMP-/SAMP-methodology

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(104) For the synthesis of sulfones, sufanyl amines, sulfonates, sultames and sultones utilizing RAMP-/SAMP-hydrazones, see: (a) Enders, D.; Müller, S. F.; Raabe, G. Angew. Chem. Int. Ed. 1999, 38, 195. (b) Enders, D.; Moll, A.; Schaadt, A.; Raabe, G.; Runsink, J. Eur. J. Org. Chem. 2003, 2923. (c) Enders, D.; Wallert, S.; Runsink, J. Synthesis 2003, 1856. (d) Enders, D.; Moll, A. Synthesis 2005, 1807.



(105) For additonal interesting examples of applications of RAMP-/SAMP-hydrazones, see: (a) Enders, D.; Müller, P.; Klein, D. Synlett 1998, 43. (b) Enders, D.; Gries, J.; Kim, Z.-S. Eur. J. Org. Chem. 2004, 4471. (c) Enders, D.; Meiers, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2261. (d) Enders, D.; Knopp, M.; Runsink, J.; Raabe, G. Angew. Chem., Int. Ed. Engl. 1995, 34, 2278. (e) Enders, D.; Janeck, C. F.; Raabe, G. Eur. J. Org. Chem. 2000, 3337. (f) Funabiki, K.; Nagamori, M.; Matsui, M.; Enders, D. Synthesis 2002, 2585. (g) Enders, D.; Vázquez, J.; Raabe, G. Eur. J. Org. Chem. 2000, 893. (h) Lassaletta, J.-M.; Fernández, R.; Martín-Zamora, E.; Díez, E. J. Am. Chem. Soc. 1996, 118, 7002.

(106) For an excellent review describing several cleavage methods, see: Enders, D.; Wortmann, L.; Peters, R. Acc. Chem. Res. 2000, 33, 157.

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(122) (a) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem. Soc. 1994, 116, 9361. (b) Myers, A. G.; Gleason, J. L.; Yoon, T. J. Am. Chem. Soc. 1995, 117, 8488.

(123) For an asymmetric aldol reaction with ephedrine auxiliaries, see: Vicario, J. L.; Badía, D.; Carrillo, L. Tetrahedron: Asymmetry 2003, 14, 489.

(124) (a) Poll, T.; Sobczak, A.; Hartmann, H.; Helmchen, G. Tetrahedron Lett. 1985, 26, 3095. (b) Chang, H. X.; Zhou, L.; McCargar, R. D.; Mahmud, T.; Hirst, I. Org. Process Res. Dev. 1999, 3, 289. For another industrial application of pantolactone see: (c) Cannizzaro, C. E.; Strassner, T.; Houk, K. N. J. Am. Chem. Soc. 2001, 123, 2668. (d) Larsen, R. D.; Corley, E. G.; Davis, P.; Reider, P. J.; Grabowski, E. J. J. J. Am. Chem. Soc. 1989, 111, 7650.

(125) Boezio, A. A.; Solberghe, G.; Lauzon, C.; Charette, A. B. J. Org. Chem. 2003, 68, 3241.

(126) Dixon, D. J.; Horan, R. A. J.; Monck, N. J. T. Tetrahedron: Asymmetry 2004, 15, 913.

(127) (a) Adderley, N. J.; Buchanan, D. J.; Dixon, D. J.; Lainé, D. I. Angew. Chem. Int. Ed. 2003, 42, 4241. (b) Buchanan, D. J.; Dixon, D. J.; Hernandez-Juan, F. A. Org. Lett. 2004, 6, 1357. (c) Buchanan, D. J.; Dixon, D. J.; Hernandez-Juan, F. A. Org. Biomol. Chem. 2004, 2, 2932.

(128) For some more examples of chiral alcohol auxiliaries, see: (a) Kim, J.-H.; Yang, H.; Boons, G.-J. Angew. Chem. Int. Ed. 2005, 44, 947. (b) Gurskii, M. E.; Karionova, A. L.; Ignatenko, A. V.; Lyssenko, K. A.; Antipin, M. Y.; Bubnov, Y. N. J. Organomet. Chem. 2005, 690, 2840. (c) Koshiishi, E.; Hattori, T.; Ichihara, N.; Miyano, S. J. Chem. Soc., Perkin Trans. 1 2002, 377. (d) Guarna, A.; Occhiato, E. G.; Pizzetti, M.; Scarpi, D.; Sisi, S.; van Sterkenburg, M. Tetrahedron: Asymmetry 2000, 11, 4227. (e) Funk, R. L.; Yang, G. Tetrahedron Lett. 1999, 40, 1073. (f) Basavaiah, D.; Pandiaraju, S.; Bakthadoss, M.; Muthukumaran, K. Tetrahedron: Asymmetry 1996, 7, 997.

(129) For examples of chiral cyclohexyl-based alcohol auxiliaries, see: (a) Nishida, M.; Nobuta, M.; Nakaoka, K.; Nishida, A.; Kawahara, N. Tetrahedron: Asymmetry 1995, 6, 2657. (b) Sarakinos, G.; Corey, E. J. Org. Lett. 1999, 1, 1741. (c) Nishida, A.; Shirato, F.; Nakagawa, M. Tetrahedron: Asymmetry 2000, 11, 3789. (d) Garner, P.; Anderson, J. T.; Turske, R. A. Chem. Commun. 2000, 1579. (e) D’Oca, M. G. M.; Pilli, R. A.; Vencato, I. Tetrahedron Lett. 2000, 41, 9709. (f) Yang, D.; Xu, M.; Bian, M.-Y. Org. Lett. 2001, 3, 111. (g) For a review on the use of 8-phenylmenthol as an auxiliary in enantioselective syntheses, see: Whitesell, J. K. Chem. Rev. 1992, 92, 953.

(130) For some selected applications of enantiomerically pure phenylethylamine not covered in this review, see: (a) Tori, M.; Miyake, T.; Hamaguchi, T.; Sono, M. Tetrahedron: Asymmetry 1997, 8, 2731. (b) Tori, M.; Hisazumi, K.; Wada, T.; Sono, M.; Nakashima, K. Tetrahedron: Asymmetry 1999, 10, 961. (c) Bandini, M.; Cozzi, P. G.; Umani-Ronchi, A.; Villa, M. Tetrahedron 1999, 55, 8103. (d) Jabin, I.; Revial, G.; Pfau, M.; Netchitailo, P. Tetrahedron: Asymmetry 2002, 13, 563. (e) Funabiki, K.; Honma, N.; Hashimoto, W.; Matsui, M. Org. Lett. 2003, 5, 2059. (f) Funabiki, K.; Hashimoto, W.; Matsui, M. Chem. Commun. 2004, 2056. (g) Hazelard, D.; Fadel, A. Tetrahedron: Asymmetry 2005, 16, 2067. (h) Torssell, S.; Kienle, M.; Somfai, P. Angew. Chem. Int. Ed. 2005, 44, 3096. (i) O’Malley, S. J.; Tan, K. L.; Watzke, A.; Bergmann, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 13496.

(131) Camara, C.; Joseph, D.; Dumas, F.; d’Angelo, J.; Chiaroni, A. Tetrahedron Lett. 2002, 43, 1445.

(132) Keller, L.; Camara, C.; Pinheiro, A.; Dumas, F.; d’Angelo, J. Tetrahedron Lett. 2001, 42, 381.

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(135) An excellent theoretical approach to explain the origin of chirality transfer in this Michael additions can be found in: Lucero, M. J.; Houk, K. N. J. Am. Chem. Soc. 1997, 119, 826.

(136) Hamada, T.; Mizojiri, R.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 2000, 122, 7138.

(137) For more information on reactions of titanium compounds with chiral amines, see: (a) Gao, Y.; Sato, F. J. Org. Chem. 1995, 60, 8136. (b) Okamoto, S.; Fukuhara, K.; Sato, F. Tetrahedron Lett. 2000, 41, 5561.

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(141) For applications of aminoindanol as chiral auxiliary, see: (a) Ghosh, A. K.; Chen, Y. Tetrahedron Lett. 1995, 36, 6811. (b) Ghosh, A. K.; Mathivanan, P. Tetrahedron: Asymmetry 1996, 7, 375. (c) Larrow, J. F.; Roberts, E.; Verhoeven, T. R.; Ryan, K. M.; Senanayake, C. H.; Reider, P. J.; Jacabson, E. N. Org. Synth. 1999, 76, 46. (d) Jones, S.; Atherton, J. C. C. Tetrahedron: Asymmetry 2000, 11, 4543. (e) Tanaka, K.; Katsumura, S. J. Am. Chem. Soc. 2002, 124, 9660. (f) Kobayashi, T.; Tanaka, K.; Miwa, J.; Katsumura, S. Tetrahedron: Asymmetry 2004, 15, 185.

(142) For reviews on aminoindanol derivatives in asymmetric synthesis, see: (a) Ghosh, A. K.; Fidanze, S.; Senanayake, C. H. Synthesis 1998, 937. (b) Senanayake, C. H. Aldrichimica Acta 1998, 31, 3.

(143) Orsini, F.; Sello, G.; Manzo, A. M.; Lucci, E. M. Tetrahedron: Asymmetry 2005, 16, 1913.

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(148) Kreidler, B.; Baro, A.; Frey, W.; Christoffers, J. Chem. Eur. J. 2005, 11, 2660.

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(152) (a) Myers, A. G.; McKinstry, L.; Gleason, J. L. Tetrahedron Lett. 1997, 38, 7037. (b) Myers, A. G.; McKinstry, L.; Barbay, J. K.; Gleason, J. L. Tetrahedron Lett. 1998, 39, 1335. (c) Myers, A. G.; Barbay, J. K.; Zhong, B. J. Am. Chem. Soc. 2001, 123, 7207.

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(158) For an inspiring update on chiral imide auxiliaries, see: Evans, D. A.; Shaw, J. T. Actual. Chim. 2003, 35.

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(166) (a) Banks, M. R.; Blake, A. J.; Cadogan, J. I. G.; Dawson, I. M.; Gosney, I.; Grant, K. J.; Gaur, S.; Hodgson, P. K.;



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(168) For a review on imidazolidinones, see: Roos, G. H. P.; Balasubramaniam, S. Synth. Commun. 1998, 28, 3877.

(169) For applications of imidazolidinones in asymmetric synthesis, see: (a) Chun, C. C.; Lee, G.-J.; Kim, J. N.; Kim, T. H. Tetrahedron: Asymmetry 2005, 16, 2989. (b) Kim, T. H.; Lee, G.-J. Tetrahedron Lett. 2000, 41, 1505. (c) Abdel-Aziz, A. A.-M.; Okuno, J.; Tanaka, S.; Ishizuka, T.; Matsunaga, H.; Kunieda, T. Tetrahedron Lett. 2000, 41, 8533. (d) Roos, G. H. P.; Balasubramaniam, S. Tetrahedron: Asymmetry 1998, 9, 923. (e) Königsberger, K.; Prasad, K.; Repic, O.; Blacklock, T. J. Tetrahedron: Asymmetry 1997, 8, 2347.

(170) For information on both oxazolidinethiones and thiazolidinethiones, see: (a) Velazquez, F.; Olivo, H. F. Curr. Org. Chem. 2002, 6, 303. (b) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem. 2001, 66, 894.

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(173) For the magnesium bromide catalyzed aldol reaction carried out with thiazolidine thione, see: Evans, D. A.; Downey, C. W.; Shaw, J. T.; Tedrow, J. S. Org. Lett. 2002, 4, 1127.

(174) For some applications of oxazolidinethiones in total synthesis, see: (a) Crimmins, M. T.; King, B. W. J. Am. Chem. Soc. 1998, 120, 9084. (b) Crimmins, M. T.; McDougall, P. J.; Emmitte, K. A. Org. Lett. 2005, 7, 4033.

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