REVIEW J. Chem. Soc. Perkin Trans. 1 1999 357–373 357 Stoichiometric asymmetric processes Andrew C. Regan Department of Chemistry University of Manchester Manchester UK M13 9PL Received (in Cambridge) 7th September 1998 Covering April 1996 to March 1997 Previous review J. Chem. Soc. Perkin Trans. 1 1998 1151 1 Introduction 2 Chiral auxiliaries 2.1 Reactions of chiral enolates 2.1.1 Alkylation 2.1.2 Aldol reactions 2.1.3 Miscellaneous reactions of chiral enolates 2.2 Reactions of carbanions 2.2.1 SAMP hydrazones 2.2.2 Other carbanions 2.3 Michael addition reactions 2.3.1 Michael addition reactions of chiral nucleophiles 2.3.2 Michael addition reactions to chiral electrophiles 2.4 Additions to C]] N double bonds 2.5 Addition to C]] O double bonds 2.6 Cycloaddition reactions 2.7 Other addition reactions 2.8 Radical reactions 2.9 Miscellaneous uses of chiral auxiliaries 3 Chiral reagents 3.1 Chiral bases 3.2 Miscellaneous uses of chiral reagents 4 Miscellaneous asymmetric processes 1 Introduction This article covers the literature from April 1996 to March 1997 and continues the coverage of the previous review.Since the field of asymmetric processes is such a large one this review covers stoichiometric processes only and asymmetric catalytic processes are now the subject of a separate review. 2 Chiral auxiliaries 2.1 Reactions of chiral enolates 2.1.1 Alkylation One of the most well-established and widely used types of auxiliary for asymmetric reactions of enolates is the oxazolidinone class developed by Evans. A new procedure for the N-acylation of the parent oxazolidinones with either acid chlorides or symmetrical or mixed anhydrides uses catalytic 4-(N,N-dimethylamino) pyridine (DMAP) in the presence of triethylamine at room temperature rather than deprotonation of the oxazolidinone with strong bases such as butyllithium.1 Alkylation of the lithium enolates of the N-acyl oxazolidinones 1 with dibromodifluoromethane gives the a-(bromodifluoromethyl) products 2 in 68% de for the N-propionyl case (R1=Me) improving to 92% de when R1 = But (Scheme 1).2 An ionic chain mechanism is proposed involving formation of difluorocarbene and similar results are obtained using bromodifluoromethane.An Evans-type oxazolidinone has been attached to a Merrifield polystyrene resin as in 3 and the lithium enolate alkylated with benzyl bromide (Scheme 2).3 After hydrolysis the polymer bound auxiliary can be reisolated by simple filtration and the a-benzylated acid is formed in 96% ee.The tricyclic oxazolidinone 4 is prepared from a chiral aminoindanol which is fully synthetic and resolved using mandelic acid rather than being derived from natural amino acids.4 Enolates of N-acyl-4 undergo alkylation acylation bromination and hydroxylation all with high diastereoselectivities. Another tricyclic oxazolidinone 5 has a rigid bridged ring system where the bulky silyl-protected alcohol is essential in order to obtain very high diastereoselectivities in alkylation reactions of enolates of the corresponding N-acyl compounds (dr = 300 1 to >500 1).5 The corresponding Nalkenoyl oxazolidinones have also been used both as dienophiles in Diels–Alder reactions and as Michael acceptors for conjugate additions of cuprates.The N-acylcamphor-derived auxiliary 6 also has a rigid bridged ring system but has a cyclic urea ring in the exo-orientation as compared with the endooxazolidinone in 5.6 Alkylation reactions of the sodium enolate of the N-propionyl derivative of 6 give uniformly high diastereoselectivities of >99 1 even with the small electrophile methyl iodide. The N-propionylanilide 7 possesses axial chirality with enantiomeric atropisomers.7 Diastereoselective alkylation of the lithium enolate of 7 occurs with good selectivity (15 1 to >25 1) for a range of alkyl halides. Aldol reactions of the lithium enolate are also highly stereoselective for one of the syn-isomers. The N-MEM group in 7 appears to enhance the stereoselectivity of reactions of the enolate since the corresponding N-methyl analogue gives rather low selectivities.Only racemic 7 has so far been used but some progress has been made towards its kinetic resolution using a chiral lithium amide base. Pseudoephedrine has been developed as an eVective practical chiral auxiliary by Myers for the alkylation of its amides 8 and an extension of this is the use of epoxides as the electrophiles. 8 Ethylene oxide gives moderate diastereoselectivities (49–59% de) however the use of the “matched” enantiomer of a monosubstituted epoxide gives double-diastereoselective reactions of 93 to �99% de. Hydrolysis of the g-hydroxyacyl products also results in cyclisation to g-lactones. Scheme 1 O N O Pri R1 O O N O Pri R1 O CF2Br 1. LDA THF 2. remove THF 3.DME 4. CBr2F2 –20 °C 1 2 68% de (R1 = Me) 92% de (R1 = But) Scheme 2 N O O Me O O polymer N O O Me O O polymer Ph 1. LDA THF 0 °C 2. PhCH2Br 3 96% de 358 J. Chem. Soc. Perkin Trans. 1 1999 357–373 The binaphthol mono-ester 9 has been used as a chiral glycine equivalent 9 alkylation of the lithium enolate followed by hydrolysis of the imine and benzoylation gives the protected a-aminoesters 10 in 69–86% de (Scheme 3). The planar-chiral h2-manganese complex 11 has previously been used for diastereoselective alkylation and aldol reactions but only in a racemic form. By forming the complex from optically active cyclopentenol followed by oxidation of the alcohol to give 11 alkylation and aldol reactions of the optically active lithium enolate give products (e.g. 12) in 85–88% ee after oxidative removal of the manganese (Scheme 4).10 An asymmetric allylation–Cope rearrangement sequence has been developed by Nakai and co-workers 11 using the enolate of the b,g-unsaturated acyl Oppolzer auxiliary 13 (Scheme 5).Good diastereoselectivity in the allylation reaction to give 14 is observed (>99%) together with complete retention of the (E)- stereochemistry of the alkene. Interestingly the corresponding a,b-unsaturated isomer of 13 gives mostly the (Z)-isomer of 14 and use of the Evans’ auxiliary gives much lower selectivity in the allylation (48% de). The Cope rearrangement of 14 at 220 8C is highly stereoselective giving 15 as the sole product whereas the (Z)-isomer of 14 rearranges with lower selectivity (85 15 dr) to give the epimer of 15. A similar sequence involving an aldol reaction followed by Cope rearrangement is also possible,12 by initial aldol reaction of the enolate of 13 with crotonaldehyde in the first step rather than alkylation with allyl bromide.a-Cyanoesters 16 of Helmchen’s chiral auxiliary can be alkylated under mild conditions with allyl bromide (Scheme 6).13 Hydrolytic removal of the auxiliary followed by Curtius HN O O O NH O O SiMe2Ph N NH O Ph But N MEM O Me Ph N R OH Me Me O 4 5 6 7 8 Scheme 3 OH O N O Ph Ph R*O NHBz O R 1. LDA THF-HMPA 2. H+ H2O 3. BzCl R-X 69-86% de 9 10 Scheme 4 O Mn OC CO O R 1. LDA THF –78 °C 2. RCHO 3. D MeCN air 11 12 R = Me allyl Bn 85% ee rearrangement gives optically active protected a-aminonitriles 17 which can be converted into a-aminoacid derivatives. Chiral N-dialkylaminolactams 18 are alkylated in fairly good diastereoselectivity which can be improved to >96% after chromatography (Scheme 7).14 Reductive removal of the auxiliary provides a route to optically active 2-substituted lactams containing 5- to 7-membered rings.Enolates of menthyl arylacetates can be formed by vicarious nucleophilic substitution of hydrogen in 1-chloro-3-nitrobenzene 19 (Scheme 8); alkylation in the same reaction vessel gives the products 20 in up to 8 1 dr.15 2.1.2 Aldol reactions One of the problems in the area of asymmetric aldol reactions has been to find eVective methods for acetate enolates since Scheme 5 N SO2 O Xc Br O Xc O Xc Xc = 13 LiHMDS THF-HMPA –78 °C 87% 14 >99% de 15 >99% de 220 °C Scheme 6 R CO2R* CN R CO2R* CN Br R NHBoc CN SO2N(C6H11)2 OH 1. KOH 2.SOCl2 3. NaN3 4. ButOH K2CO3 acetone 17 dr 75:25 to 92:8 R*OH = 16 Scheme 7 N O N N O R Et Et OMe N Et Et OMe n 1. LDA THF –78 °C 2. R-X –100 °C 69-87% de crude >98% de after chromatography 18 n = 0 1 2 Scheme 8 Cl O2N CO2R* PhS O2N CO2R* Bn HO Pri Me 19 1. NaH 2. BnBr R*OH = 70% dr 8:1 20 J. Chem. Soc. Perkin Trans. 1 1999 357–373 359 these often react relatively unselectively compared to the corresponding propionate enolates. One solution to this problem is to use a chromium–Reformatsky species prepared from an (a-bromoacetyl) Evans’ auxiliary 21 (Scheme 9).16 The aldol product 22 is formed with good diasteroselectivity (92 8) in the opposite sense to more usual methods. The N-acetyl analogue of the cyclic urea 6 has also been used for lithium and titanium aldol reactions with useful diastereoselectivities for aromatic aldehydes.Aliphatic aldehydes react rather less selectively and the titanium and lithium mediated reactions give selectivities in the opposite sense to each other. Asymmetric aldol reactions of acetate enolate equivalents have also been achieved using chiral reagents (see below). New designs of chiral auxiliary for the aldol reaction continue to appear. The N-propionyloxazolidinone 23 is prepared from 2-aminocyclopentanol which is itself formed by bakers’ yeast reduction of ethyl 2-oxocyclopentanecarboxylate followed by Curtius rearrangement.17 Boron aldol reactions of 23 under the usual conditions give uniformly high diastereoselectivities (>99%) for one of the syn-aldol products. The N-propionyl “quat”-type lactam 24 gives similarly high selectivities for the same syn-aldol isomer.18 The 1,3-benzoxazinone 25 is derived from menthone and aldol reactions of its sodium and titanium enolates with benzaldehyde give the two alternative syn-diastereoisomers in 91 2 and 2 96 dr respectively.19 The standard combination of a dialkylboron triflate and a tertiary amine base widely used for aldol reactions of ketones thioesters and N-acyl chiral imides has also been shown to be eVective for esters,20 contrary to widespread assumption.As well as simple achiral esters 8-phenylmenthyl propionate 26 is converted into its enol borinate with dicyclohexylboron triflate and following equilibration of the geometical isomers aldol reaction with isobutyraldehyde gives a 98 2 ratio for the two possible syn-isomers. Aldol reaction of the kinetic enol borinate is very selective for the two anti-aldol products but both are formed in almost equal amounts (48 52).The vinylogous urethane 27 contains a pyrrolidine auxiliary which has been reported as a more accessible replacement for 2,5-dimethylpyrrolidine (Scheme 10).21 Aldol reactions of the extended lithium enolate of 27 give syn-lactones 28 followed by a two-step removal of the auxiliary to give the unsaturated lactones 29. Some interesting new applications of established asymmetric Scheme 9 N O O Br O Bn OHC O Xc O OH O dr 92:8 22 21 CrCl2 LiI (cat.) THF RT 5 h 63% O N H H O N O CO2Et O N O Pri Me O O Ph O O O 24 23 25 26 aldol reactions include Oppolzer’s use of his N-propionyl sultam auxiliary 30 for the desymmetrisation of the mesodialdehyde 31 (Scheme 11).22 Oxidation of the lactol product 32 gives the lactones 33 and 34 in a dr of 7 to 8 1 and hydrolytic removal of the auxiliary results in a short synthesis of the Prelog–Djerassi lactonic acid.An approach to the iterative construction of polyketide chains involves aldol reaction of an acylated Evans’ oxazolidinone auxiliary with a polymer supported aldehyde.23 Removal of the auxiliary and transformation of the imide into an aldehyde group via a Weinreb amide allows the asymmetric aldol reaction to be repeated building up the chain on the polymer support. Evans’ auxiliaries have also been used in aldol reactions with the ketone group of pyruvates resulting in the construction of tertiary alcohol centres during the aldol step.24 Complete control over the stereochemistry at the a-carbon is achieved but the control over the new tertiary alcohol centre is less selective resulting in a syn anti mixture of diastereoisomers in up to 83 17 dr.The lithium enolate of the chiral amide 35 can be homologated to the zinc homoenolate 36 and combined with a titanium homoaldol reaction to give a-alkyl-g-hydroxyamides 37 in 64–86% de (Scheme 12).25 The auxiliary can be removed with tosic acid causing cyclisation of the products to a,gdisubstituted g-lactones. 2.1.3 Miscellaneous reactions of chiral enolates Halogenation of chiral enol borinates using N-halosuccinimides has been applied to the xylose-derived N-acyloxazolidin- Scheme 10 OMe O N H MeO Et Et O O N H MeO Et Et R O O R 1. LDA THF –78 °C 2. RCHO 2. MCPBA 92-99% de 95-97% ee 27 28 1. NaBH3CN 29 Scheme 11 SO2 N OHC CHO Me Me O Me OH Xc Me O O Me O Me O Xc Me O Me O Me O Xc Me O Me TPAP NMO 1.Et2BOTf Pri 2NEt CH2Cl2 2. 32 30 31 95% + 33 34 7 to 8 1 TPAP = tetra- n-propylammonium perruthenate NMO = 4-methylmorpholine N-oxide 360 J. Chem. Soc. Perkin Trans. 1 1999 357–373 one 38 to give a-bromo and a-chloro products 39 in up to 4 1 dr (Scheme 13).26 Acylation of the lithium enolate of 38 is more selective giving the b-ketoacyl oxazolidinones in up to 12 1 dr. Bromination (with NBS) of an Evans’ acyloxazolidinone containing an o-carborane cage has been followed by azide displacement and reduction of the azide to the amine aVording a route to both enantiomers of carboranylalanine a compound useful in boron neutron capture therapy.27 The a,b-unsaturated acyloxazolidinone 40 has been converted into the lithium and sodium extended enolates which are fluorinated with N-fluoro- (N-phenylsulfonyl)benzenesulfonamide 41 at the a-position to give 42 as a single diastereoisomer (Scheme 14).28 The product 42 was then used as an intermediate in the preparation of 2-deoxy-2-fluoro sugars.The asymmetric Darzens reaction of 8-phenylmenthyl chloroacetate 43 with ketones gives glycidic esters in 77–94% de (Scheme 15).29 With unsymmetrical ketones there is also good selectivity in favour of the (Z)-epoxide (4.5 1 to 7.6 1). Asymmetric aza-Darzens reactions have also been achieved using the lithium enolate of a bromoacetyl Oppolzer sultam and N-(diphenylphosphinyl)imines giving cis-disubstituted aziridines with >95% face selectivity.30 2.2 Reactions of carbanions 2.2.1 SAMP hydrazones Enders and Klatt have reviewed the uses of 1-amino-2- Scheme 12 Xc O R Xc O R (ICH2)Zn OBn Xc O R R' OH O N H H 1.BuLi 2. (ICH2)2Zn LiOBn 1. PriOTiCl3 2. R'CHO 37 35 36 64-86% de Xc = R = Me Bn Scheme 13 O N O O O O O O Xc Br (Cl) 1. R2BOTf 2. NBS or NCS 4:1 dr 38 39 Scheme 14 O N O Xc BnO O Xc O BnO F Me Ph N F PhSO2 PhSO2 Xc = 40 41 1. LiHMDS 2. 100% de 42 Scheme 15 Cl O O Me Ph O CO2R* Ph H Me ButOK CH2Cl2 93% de Z:E = 7.6:1 43 PhCOMe (methoxymethyl)pyrrolidine (SAMP) hydrazones of aldehydes and ketones 44 in asymmetric synthesis.31 In general these involve creation of a new stereogenic centre a to the hydrazone group by deprotonation followed by reaction with an electrophile. The diethyl (SAEP) analogues 45 often give improved diastereoselection. New examples include the use of a-(phenylselanyl) aldehydes as electrophiles which give hydroxyselenides 46.32 After removal of the auxiliary and elimination of the hydroxyselenide chiral b,g-unsaturated aldehydes and ketones 47 are formed with very little racemisation at the a-centre.Chiral 2-phosphinoalcohols can be prepared by reaction of SAMP or SAEP hydrazone anions with chlorodialkylphosphines to give 48 followed by removal of the auxiliary and reduction of the aldehyde.33 The lithiated SAMP hydrazone of cyclohexanone can be transmetallated to an organozinc reagent which then adds to the alkene double bond of a cyclopropenone acetal giving the cyclopropane 49 in 96% de.34 The SAEP hydrazone 50 undergoes regioselective lithiation and [2,3]-Wittig rearrangement to give the a-hydroxycyclohexanone derivatives 51 containing adjacent quaternary and tertiary stereogenic centres (Scheme 16).35 Enantioselective Mannich reactions can be performed in an indirect way starting from SAMP hydrazones which are used to prepare a-silylketones 52.This is followed by formation of the a9-silylenol ether and reaction with an iminium salt. The second stereogenic centre is controlled by the a-silyl group which is then finally removed to give the chiral b-(dialkylamino) ketones 53 (Scheme 17).36 2.2.2 Other carbanions 2-(Aminomethyl)thiazole 54 can be converted into imines (e.g. R1 N N OMe R2 R R R1 N Xc R2 R3 SePh OH R1 O R2 R3 H N Xc R1 PR2 2 O O N Xc H H 44 R=H 45 R=Et 46 47 (89 - 94% ee) 48 (50 - 87% de) 49 (96% de) Scheme 16 N N Et Et OMe O R N OH R N Et Et OMe ButLi THF –100 to 0 °C 50 51 74-91% anti �96% de Scheme 17 R Me O R O Me NBn2 1.LDA TMSCl 2.Bn2NCH2OMe 3. TBAF 52 53 91-97% ee C6H13 tMe2Si J. Chem. Soc. Perkin Trans. 1 1999 357–373 361 56) by reaction with camphor or a hydroxypinanone 55 (Scheme 18).37 Alkylation of the carbanion formed by deprotonation of 56 followed by cleavage of the imine and protection aVords the N-Boc-protected aminoalkylthiazoles 57 which can serve as precursors to chiral a-aminoaldehydes. The hydroxypinanone imines show better selectivities (mostly >98 2 dr) in the alkylations than do those derived from camphor. An enantioselective preparaton of allenecarboxylate esters 60 relies upon an asymmetric Wadsworth–Emmons reaction of the phosphonoacetate 59 containing a substituted binaphthol auxiliary with ketenes which are generated in situ by treatment of the aryl esters 58 with BuLi and ZnCl2 (Scheme 19).38 The allenes 60 are mostly formed in 61–84% ee and the unsubstituted binaphthol analogue of 59 shows much lower enantioselectivity.An asymmetric synthesis of the b-ketophosphonate 64 starts with treatment of the achiral cyclohexanone 61 with LDA to give a racemic chiral enolate which reacts with an optically pure phosphorochloridate 62 to give the vinyl phosphates 63 as a mixture of diastereoisomers (Scheme 20).39 Deprotonation of 63 with LiTMP gives a delocalised allyl anion which is now a single stereoisomer and which rearranges stereoselectively to 64 with a dr of 2.5 1 at the 5-position. The C2-symmetric cyclic bis-sulfoxide 65 has been used to desymmetrise meso-1,2-diols (Scheme 21).40 Formation of the acetal 65 from the meso-diol followed by asymmetric deprotonation elimination and acetylation gives the desymmetrised product 66 in >96% de.The selectivity is very dependent on the metal counter-ion since only 8% de is obtained using LiHMDS and 12-crown-4. The reactions of chiral allyl organometallic species with aldehydes has been a very active area for some years. The metallated sulfoximines 67 and 68 containing 5- and 6-membered rings show very high levels of stereocontrol even when combined with a chiral aldehyde in a mismatched sense (Scheme 22).41 Analogous acyclic sulfoximines show good stereocontrol with achiral aldehydes and also with chiral aldehydes in matched pairs but less control using mismatched pairs. Scheme 18 N N S OH NH2 N S O OH NHBoc N S R 54 TiCl3 PhMe reflux 1.LDA 2. R-X 3. NH2OH AcOH 4. Boc2O 55 56 >96% ee 57 Scheme 19 R1 R2 CO2Ar R1 R2 · H CO2Me O O P O CO2Me Me Me 2. 58 59 60 1. BuLi ZnCl2 THF –78 °C mostly 61-84% ee – 2.3 Michael addition reactions 2.3.1 Michael addition reactions of chiral nucleophiles Conjugate additions of chiral enamines e.g. 69 formed from a cyclic ketone and 1-phenylethylamine have been extended to the study of the formation of a second stereogenic centre by using a- or b-substituted Michael acceptors (Scheme 23).42 Use of methyl methacrylate gives 70 as a single diastereoisomer and although there is no reaction with methyl crotonate some other more reactive b-substituted acceptors react successfully. A model is proposed for the transition state and the face selectivity of this type of reaction has been interpreted as the chiral amine causing one cyclohexene chair conformation to be preferred over the other in the enamine intermediate.43 The SAMP-hydrazone of formaldehyde 71 undergoes Michael addition to enones as a neutral nucleophile (in contrast Scheme 20 O O O P O Cl O O O P O O O O O O P O O O 1.LDA 2. LiTMP 62 63 64 dr = 2.5:1 61 LiTMP = lithium 2,2,6,6-tetramethylpiperidide Scheme 21 S+ S+ O– O– O O S+ S+ O– O– O AcO 1. KHMDS 18-crown-6 2. Ac2O 65 66 >96% de Scheme 22 S O p-Tol N Pri OTBDMS S O p-Tol N Pri OTBDMS H H OH OTBDMS CHO OTBDMS n n 1. BuLI 2. ClTi(OPri)3 3. 67 ( n=1) 68 ( n=2) 96 to 98% de Scheme 23 CO2Me N H Ph Me CO2Me Me CO2Me O CO2Me Me 2. AcOH-H2O MgBr2 1. 72% 100% de 69 70 362 J. Chem. Soc. Perkin Trans. 1 1999 357–373 to the more usual carbanions discussed in section 2.2.1) in 85 to �98% de to give adducts 72 which can be transformed into either 4-ketoaldehydes 73 or 4-ketonitriles 74 (Scheme 24).44 The same hydrazone 71 also reacts with 1-nitroalkenes derived from sugars without any base or additive in diastereoselectivities which are >96% for matched pairs of reagents but 38–68% for mismatched pairs.45 Conjugate addition of chiral lithium amides to a,b-unsaturated esters has been discussed in previous reports in this series and Davies has extended this work by incorporating a subsequent stereoselective aldol reaction at the a-carbon atom as a key step in the synthesis of a thienamycin intermediate.46 Stereoselective reaction of the enolate with trisyl azide followed by reduction of the azide gives anti-2,3-diaminobutanoic acid.47 The syn-diastereoisomer can also be prepared by an inversion at the a-carbon atom.The anion of chromium carbene complex 75 containing an imidazolidinone chiral auxiliary acts as an acetate equivalent in the conjugate addition to a,b-unsaturated ketones and generally shows a selectivity of at least 96 4 dr with one exception. (Scheme 25).48 Interestingly the stereoselectivity reaches a maximum at 220 8C and is reduced at both higher and lower temperatures. Oxidation of the carbene and removal of the auxiliary gives chiral b-alkyl-d-oxoesters. 2.3.2 Michael addition reactions to chiral electrophiles The conjugate addition of organometallic reagents to crotonyl derivatives of a variety of chiral auxiliaries has been a theme for some years now. New examples include the conjugate addition of Grignard reagents to the imidazolidinone 76 (using the same auxiliary as in 75) where the presence of Me2AlCl as a Lewis acid improves diastereoselectivity to 90 10 via a proposed chelated intermediate.49 Copper(I)-catalysed asymmetric additions of organozirconocenes to the crotonyl Evans-type auxilary 77 have been reported for the first time.50 The intermediate zirconium enolate formed during the conjugate addition can also be trapped with benzaldehyde in an aldol step to give a product with three new stereogenic centres in >97% de.Use of the more common benzyl or isopropyl-substituted oxazolidinones is less selective as is the Oppolzer sultam auxiliary. The iodotrimethylsilane promoted addition of monocopper Scheme 24 N N OMe R4 O R3 R2 R1 N N MeO O R1 R3 R4 R2 NC O R1 R3 R4 R2 OHC O R1 R3 R4 R2 + 1.TDSOTf THF –78 °C 2. TBAF 85 - 98% de magnesium monoperoxyperphthalate O3–DMS 71 72 73 74 85 - 98% ee 85 - 98% ee TDS = tert-hexyldimethylsilyl Scheme 25 N N Ph Me Me O Me Cr R2 R1 O Xc Cr R2 O R1 de 88:12 to >97:3 (CO)4 75 (CO)4 1. BuLi THF –78 °C 2. 3. AcOH reagents to the bornyl crotonate 78 has been extended to the use of a farnesyl-derived homoallylic copper reagent in the synthesis of geranylcitronellol † in 99% ee.51 Replacement of the naphthyl group in 78 with a phenyl group reduces the stereoselectivity in the conjugate addition step to 73% de. The high pressure induced conjugate addition of amines to a variety of “arylmenthyl” crotonates 79 has been studied together with crotonates of some chiral cyclohexanols.52 Very high selectivities are obtained in additions to 79 where Ar = 2-methoxyphenyl 4-phenoxyphenyl or 2-naphthyl whereas only moderate selectivities are observed for trans-2-arylcyclohexanol esters.This diVerence is interpreted in terms of improved p-stacking in 79. 8-Arylmenthols have also been studied as auxiliaries in the conjugate addition of allyltrimethylsilane to the dihydropyridones 80 (Scheme 26).53 Again Ar = 2-naphthyl is particularly eVective (30 1 and the use of menthol itself (Ar = H) results in an almost completely unselective reaction. The monoesters 81 of 1,19-binaphthalene-8,89-diol undergo conjugate addition reactions of lithium dialkylcuprates followed by 1,2-addition of the same reagent at the ester and elimination of the chiral auxiliary all in one process to give ketones 82 in 96–100% ee (Scheme 27).54 Previously the corresponding esters of the widely used 1,19-binaphthalene-2,29-diol auxiliary had shown rather less stereoselectivity.Asymmetric conjugate addition reactions of radicals to chiral a,b-unsaturated acyloxazolidinones have been previously reported but new examples include conjugate addition of an N N Me Ph O Me Me O O N Ph O Me O O Me O R O Me O Ar 76 79 78 77 R = naphthyl Scheme 26 O N O R O SiMe3 O N O R O TiCl4 80 dr = 30:1 (R = 2-naphthyl) Scheme 27 O O Ar OH R Ar O R R2 CuLi R = Me Bu 81 82 96-100% ee † IUPAC name 8-geranyl-3,7-dimethyloct-6-en-1-ol. J. Chem. Soc. Perkin Trans. 1 1999 357–373 363 ethyl radical to 83 followed by trapping of the intermediate radical with an allyl stannane generating the new stereocentre during the trapping step only.55 Related to this is the radical addition of tributyltin hydride to the a-methyl substituted acceptor 84; here the stereogenic a-centre is created during hydrogen atom transfer in 92 18 dr.56 Addition of an isopropyl radical to the fumaryl oxazolidinone 85 is both highly regioand stereoselective in the presence of the correct choice of lanthanide triflate as a Lewis acid; 57 the saturated acyl oxazolidinone products can then be used in standard asymmetric aldol reactions resulting in the creation of three contiguous stereogenic centres.2.4 Additions to C]] N double bonds A contribution to the well-studied field of addition of nucleophiles to imines derived from 1-phenylethylamine is the investigation of the addition of allyl organometallic compounds looking at the dependence of diasteroselectivity upon the allyl reagent used and also the structure of the imine 86 (Scheme 28).58 Allyl-BBN and diallylcuprate give the best results with both aliphatic and aromatic imines (up to 98% de) although with imines derived from pyridine-2-carbaldehyde allylzinc bromide and allyl(dichloro)iodotin are better.Additions to imines derived from chiral sulfinamides are represented by the addition of Grignard reagents to toluenesulfinamides 87 in 60–74% de,59 and hydride reduction of imines 88 in up to 86% de using DIBALH.60 Addition of ZnBr2 to the DIBALH reduction gives the opposite sense of diastereoselectivity in up to 92% de. Addition of methyl and ethyl Grignard reagents to the analogous aldehyde imines is also stereoselective in 79–85% de and the sense of the stereoselectivity is as expected from the results using DIBALH without ZnBr2.Asymmetric synthesis of b-amino acids has been achieved by additions to N-galactosylimines 89 (Scheme 29).61 Addition of bis-silyl ketene acetals 90 gives only the two possible erythro (syn) isomers and usually in >20 1 dr whereas addition of the lithium enolate of tert-butyl phenylacetate gives exclusively the two threo isomers but in a lower 3 1 ratio. The addition of organolithium reagents to the C]] N double bond of SAMP-hydrazones has been extended to the indoline- 2-carboxylic acid derived hydrazones 91 (Scheme 30).62 Uniformly high diastereoselectivities are observed (>93 7) even with imines which could be deprotonated at the a-position by the basic organolithium reagents.The same types of chiral N O O O Ph Ph N O O O Ph Ph N O Ph O O Me CO2Et 85 84 83 Scheme 28 R N Ph Me M R N H Ph Me + 86 p-Tol S N Ar O NH But O S+ N O– Ar R 87 88 imines also undergo addition of trimethylsilyl cyanide in the presence of Et2AlCl in up to 96% de.63 Dehydromorpholines 92 prepared from (R)-phenylglycinol and a-ketoesters undergo addition of Grignard reagents to the C]] N bond in the presence of a Lewis acid with complete diastereoselectivity (Scheme 31).64 Destructive removal of the chiral auxiliary by catalytic hydrogenation then results in optically pure a-methyl-a-amino acids. Enantiomerically pure 1,2-diamines have been prepared by a symmetrical pinacol-type coupling of optically pure chromium tricarbonyl complexes of benzaldehyde imines.65 The reaction is promoted by SmI2 and is an example of the formation of both stereogenic centres in a 1,2-difunctionalised compound as well as the C–C bond connecting them in a single step.Hanessian has reported that the addition of allylzinc reagents to oximes of glyoxylic acid attached to Oppolzer’s camphor-derived sultam gives a-allylglycines.66 However a more direct approach from the same group uses an external chiral ligand for the same type of reaction (see Section 3.2). An unusual asymmetric addition to C]] N bonds involves the addition of Grignard reagents to the 2-position of pyridinium salts with N-alkoxycarbonyl groups formed from chiral alchohols as the chiral auxiliaries.67 8-Phenylmenthol and closely related derivatives were found to be the best auxiliaries with diastereoselectivities of up to 95%.2.5 Addition to C]] O double bonds This section covers additions of nucleophilic species to carbonyl groups which have not already been covered in section 2.1.1. Scheme 32 shows the addition of Grignard reagents to a ketone 93 bearing a chiral auxiliary which is of the now standard trans-2-substituted cyclohexyl ester type but is novel in that the 2-substituent is a nitroxy group.68 The aminoalcohol derived auxiliary 94 is not initially attached to the ketone substrate but becomes covalently bonded during the reaction with the allylsilane (Scheme 33).69 The auxiliary can be reductively cleaved using sodium in liquid ammonia and gives improved selectivity over an earlier reagent. Some of the most eVective neutral chiral nucleophiles for Scheme 29 OPiv PivO PivO OPiv N R H OPiv PivO PivO OPiv HN R CO2H R1 OTMS OTMS H R1 + ZnCl2 THF 89 90 dr = 3:1 to >20:1 + other syn-isomer Scheme 30 N OMe N R1 H N OMe N R1 H R2 THF or Et2O R2Li –78 °C 91 dr 93:7 Scheme 31 O N O Ph H Me O N O Ph H Me R 1.BF3·OEt2 –78 °C 2. RMgX 2 equiv. 100% de 92 364 J. Chem. Soc. Perkin Trans. 1 1999 357–373 asymmetric addition to carbonyl groups are allyl boronates. The g,g-disubstituted allyl boronates 95 can be formed in situ from tartrate esters of either enantiomer and add to aldehydes to give homoallylic alcohols with a quaternary stereogenic centre (Scheme 34).70 Allyltrichlorosilane also reacts with tartrate esters to give a pentacoordinate allyl silicate which undergoes similar asymmetric addition of the allyl group to aldehydes in up to 71% ee.71 Very similar work has also been reported by Kira and co-workers.72 Tartrate esters are also used in the in situ formation of a pentacoordinate chiral allyltin species which transfers the allyl group to aromatic aldehydes in the presence of catalytic amounts of copper salts in 89–94% ee.73 Diisopinocampheylallylboranes have also been extensively investigated for asymmetric addition of allyl groups to aldehydes; incorporation of a g-aminoallyl group results in the formation of unsaturated 1,2-aminoalcohols and use of an imine as the protecting group on nitrogen is important to allow easy deprotection.74 Masked a-hydroxyketones are formed by reduction of a 2- acyldithiane-1-oxide 96 (Scheme 35) where the chiral auxiliary is formed by Kagan oxidation of the corresponding dithiane after incorporation into the substrate.Other examples related to 96 can also be prepared by acylation and methylation of the parent chiral 1,3-dithiane-1-oxide.75 Reduction of ketone groups which are remote from the chiral auxiliary has been achieved using 4- and 5-oxoesters of anhydroglucose derivatives. 76 Use of ZnCl2 in the reduction with sodium borohydride is essential for high selectivity and chiral lactones are formed in up to 93% ee after removal of the auxiliary. b-Ketophosphine oxides containing a chiral oxazolidine auxiliary adjacent to the ketone have been reduced to the corresponding b-hydroxyphosphine oxides in 95 5 dr and the auxiliary can be removed using ethane-1,2-dithiol.77 An intramolecular Meerwein–Ponndorf–Verley reduction is shown in Scheme 36 where the auxiliary 97 first undergoes Michael addition to the a,b-unsaturated ketones followed by highly diastereoselective 1,7-hydride transfer to give 98.78 Destructive removal of the auxiliary by reductive cleavage with Raney nickel then gives secondary alchohols in 96–98% ee with overall reduction of both alkene and ketone groups.Scheme 32 O ONO2 Ph O O O ONO2 Ph O HO R Et2O –78 °C 93 RMgBr ZnCl2 82-86% de Scheme 33 Me3SiO NHCOCF3 Ph Ph O NHCOCF3 Ph Ph SiMe3 O + + TfOH TMSOTf CH2Cl2 –78 °C dr = 18:1 94 Scheme 34 R1 B R2 O O CO2Pri CO2Pri R4 OH R2 R1 dr 96:4 major isomer 62-85% ee R3CHO 95 2.6 Cycloaddition reactions The majority of asymmetric Diels–Alder reactions employing chiral auxiliaries have the auxiliary attached to the dienophile and there are several new examples of these. The aminoindanolderived oxazolidinones 99 have a gem-dimethyl group to increase steric shielding on one face of the alkene and give selectivities of 96 4 to >99 1 in reactions with both cyclic and acyclic dienes using Et2AlCl as a Lewis acid.79 The acrylate ester 100 has been investigated because the parent chiral diol isosorbide is readily available in large quantities at low cost.80 Using SnCl4 as the Lewis Acid Diels–Alder reaction of 100 with cyclopentadiene gives the (S)-endo product in 96 4 dr.However the closely related epimeric isomannide acrylate 101 gives the (R)-endo adduct in 95 5 dr using EtAlCl2 as the Lewis acid. The dienophile 102 is the monoacrylate monopivalate diester of a chiral spiro-fused diol and reacts also with cyclopentadiene to give the endo-adduct in >97% de using BCl3 as the Lewis acid.81 A chiral sulfoxide is the auxiliary in the N-acylated pyrrole 103,82 which gives >99% de in the endo adduct with cyclopentadiene with AlCl3 as the Lewis acid and is one of the few examples of a dienophile with a sulfoxide auxiliary which is recoverable.The N-methacryloyl bicyclic lactam 104 shows complete diastereofacial selectivity in addition to an acyclic silyloxy-activated triene and this was used as a key step in the synthesis of (2)-cassioside.83 In the Diels– Alder addition of the a-methylene-b-ketoester of 8-phenylmenthol 105 with cyclopentadiene either the ketone or the ester group of the dienophile could become the endo-substituent.84 Using FeCl2I as the Lewis acid results in an endo exo ratio of >99 1 for the ester group and also complete diastereoselectivity.Asymmetric Diels–Alder reactions using furan as the dienophile are usually diYcult because furan is sensitive to many Lewis acids chiral acrylate esters often react slowly with furan and the adducts often readily undergo the reverse reaction precluding kinetic control of the diastereoselectivity. However 8-phenylmenthyl acrylate 106 has been found to react with furan using titanium or zinc halides supported on silica gel as Lewis acids giving mixtures of endo and exo adducts with reasonable diastereoselecitivities (up to 70% de).85 Hetero-Diels–Alder reactions between the N-glyoxyloyl Oppolzer sultam 107 and either 1-methoxybutadiene or Danishefsky-type 1-methoxy-3-silyloxydienes have been found to be highly diastereoselective when promoted by catalytic Eu(fod)3 (Scheme 37).86,87 However when the diene is changed to 2-(trimethylsilyloxy)furan a Diels–Alder reaction does not Scheme 35 S S+ Ph O– O S S+ Ph O– OH S S+ Ph O– OH THF –78 °C 100% de ZnCl2 DIBAL-H THF –78 °C 100% de 96 DIBAL-H Scheme 36 S OH SH O H OH R3 R2 R1 R1 R3 R2 O Me2AlCl RT 97 98 J.Chem. Soc. Perkin Trans. 1 1999 357–373 365 occur; instead there is addition of the furan to the aldehyde to give a g-substituted butenolide in 90% de.88 In the tandem reaction shown in Scheme 38 the vinyl ether of 2-phenylcyclohexanol 109 first acts as a dienophile in an intermolecular hetero-Diels–Alder reaction with the unsaturated nitroalkene 108 and this is followed by an intramolecular [312] cycloaddition of the adduct with the unsaturated ester portion which is held by a temporary silicon tether.89 The product 110 formed in >25 1 dr is the key intermediate in a synthesis of (2)-detoxinine and the same strategy has also been used for a synthesis of (2)-mesembrine.90 Chiral auxiliaries attached to the diene component in Diels– Alder reactions are rather less common.A tartrate-derived dienyl boronate adds to methyl crotonate to give a cyclohexenyl boronate which is then employed in a tandem addition to an aldehyde in 70% ee.91 Dienes with a camphor-derived sulfinyl group at the 2-position give excellent selectivity (>99 1) in addition to N-phenylmaleimide as the dienophile provided that LiClO4 is used as a catalyst however the auxiliary has not been removed from the products.92 An interesting intramolecular Diels–Alder reaction of 111 allows reaction between a furan as the diene and acrylic acid as N O O R O H H O O O OBn O O O O OBn O O H O O O But N S+ O O– Tol Ph N O O O Ph O Ph O O Ph O 99 100 101 102 105 103 104 106 Scheme 37 SO2 N O H O OMe H OMe O Xc + + isomers dr = 91:5:4 Eu(fod)3 CH2Cl2 107 Scheme 38 N+ O Si MeO2C Pri Pri –O O N O Si MeO2C Pri Pri O O OR* Ph O MeAl(OAr)2 –85 °C 59% Ar=2,6-dimethylphenyl dr > 25:1 108 109 110 the dienophile tethered together using 8-aminomenthol as the auxiliary (Scheme 39).93 The reaction proceeds under very mild conditions and by changing the solvent either of the two exoisomers can be produced selectively.These can be separated and give enantiomeric products after cleavage of the auxiliary. The SAMP auxiliary which has already been discussed in Section 2.2.1 has also been used as a chiral auxiliary attached to C-2 of a diene in a hetero-Diels–Alder reaction with N-silylimines giving piperidine-4-ones after hydrolytic workup in moderate to very high enantiomeric excesses.94 a,b-Unsaturated N-acyloxazolidinones which have previously been used as dienophiles can also serve as dipolarophiles in [312] cycloaddition reactions with azomethine ylides.95 The products are chiral disubstituted pyrrolidines and are formed in 56 44 to 80 20 dr.Vinyl sulfoxides are also eVective chiral dipolarophiles in [312] cycloadditions to cyclic nitrones 112 (Scheme 40),96 with the best selectivity being achieved using the (Z)-vinyl sulfoxide 113. The six-membered ring homologue of 112 is also eVective giving products which can be transformed into piperidine alkaloids.The cyclic nitrone 112 also reacts with acrylates of chiral 9-anthrylalcohols as the dipolarophiles,97 but this gives all four possible isomers (two regioisomers each formed as two diastereoisomers) with the best ratio being 70:11:15:4. The [212] cycloaddition of ketenes to imines (the Staudinger reaction) is an important method for the construction of b-lactams and use of either the ketene or the imine as a chiral component has already been extensively investigated. Recent developments include a study of double diastereodiVerentiating reactions where both components are chiral.98 Use of an Evans’ oxazolidinone auxiliary in the ketene component usually dominates the eVect of a stereogenic centre in the imine even when mismatched but its influence can be overcome by using two stereogenic centres in the imine.Use of an N-[bis- (trimethylsilyl)methyl] protecting group on the imine component of this type of reaction has proved beneficial in supressing deprotonation at the a-position.99 Intramolecular [212]-photocycloadditions have been investigated using a chiral auxiliary to form a removable tether between the two components.100 For example the 3-hydroxybutyrate- derived diester 114 undergoes only one regioisomeric mode of cycloaddition (Scheme 41) and the tether can subsequently be removed with sodium methoxide. Intramolecular [212]-photocycloadditions using chiral trimethylsilylallenes as one component result in chirality transfer from the allene to the newly formed cyclobutane in a “self-immolative” fashion,101 Scheme 39 N O O O N O O O H CH2Cl2 23 °C 15 h 96% + other exo-isomer dr = 69:31 hexane 23 °C 15 h 96% dr = 22:78 111 Scheme 40 N+ O– Ph S O p-Tol N O S Ph H H O p-Tol H + Et2O RT 17 days dr = 99:1 112 113 366 J.Chem. Soc. Perkin Trans. 1 1999 357–373 where the silyl group is designed to be easily removed afterwards. The Pauson–Khand reaction is one of the most widely used transition metal mediated cycloaddition reactions and asymmetric versions have been developed using chiral alkoxy groups on either the alkene or alkyne component. By using a cleavable sulfide tether the resulting cyclopentenones can undergo conjugate addition and reductive cleavage to generate quaternary stereogenic centres exemplified by a synthesis of (1)-bcuparenone. 102 (Z)-Enol ethers e.g. 116 have been formed using a wide variety of diVerent chiral alcohols as possible auxiliaries and then used in Bradsher cycloaddition reactions to the naphthyridinium salt 115 (Scheme 42).103 Best results are obtained using isosorbide and isomannide enol ethers which give the bridged isoquinoline derivatives 117 in 80% de.2.7 Other addition reactions The reaction shown in Scheme 43 is interesting in that the acetal chiral auxiliary first directs the formation of one stereogenic centre during the haloetherification step and then the resulting oxonium ion undergoes stereoselective addition of an alcohol to give 118.104 The iodide in 118 can be replaced by a nucleophile and this can then be followed by Grignard reaction at the acetal carbon with retention of stereochemistry giving chiral 1,4- and 1,5-diols after reductive cleavage of the auxiliary.Electrophile-induced cyclisation of alkenes can also be achieved by the reaction with chiral selenyl chlorides in up to 93 7 dr.105 Chiral 1,4-diols have also been prepared with complete stereoselectivity by hydrogenation of exo-alkylidenebutyrolactones containing a menthyl auxiliary followed by hydride reduction.106 Hydrogenation of glucose-derived enol ethers conjugated to a carbonyl group shows diastereoselectivities ranging from 85:15 to 67 33 but the ratios can be improved by fractional crystallisation.107 Scheme 41 O O O O O O O H O O O hn CH2Cl2 RT + isomers dr = 62:16:<1 114 Scheme 42 N N+ OH N N O Me R*O O O OBn O H H Me 80% de 115 116 117 X– Scheme 43 O O Ph Ph O O O Ph Ph I OMe OH OMe 85% dr = 80:6:12:2 I(coll)2PF6 coll = sym-collidine or 2,4,6-collidine 118 Chiral acetals of cyclic a,b-unsaturated ketones undergo Simmons–Smith cyclopropanation with a stereoselectivity which can be tuned up to >98% de by varying the size of alkoxy substituents on the acetal.108 Two groups have reported the asymmetric addition of lithiated 2-methylpropionitrile to chiral alkoxyarene–chromium tricarbonyl complexes in up to 76% de (Scheme 44).109,110 The chiral ether is rather remote for control of the new stereogenic centre but the reactions appear to be under thermodynamic control and so simply reflect the relative stability of the two diasteroisomeric products.Enantiopure arene chromium tricarbonyl complexes are also used in the first synthesis of chiral acetals e.g. 120 in which the acetal carbon is the only stereogenic centre (Scheme 45).111 The chromium tricarbonyl unit in 119 eVectively shields one face of an intermediate oxocarbenium ion during nucleophilic addition of the alcohol.Chiral acetals of unsubstituted benzaldehyde can also be prepared by using a trimethylsilyl group in place of the o-methoxy group and removing it with TBAF as the final step. A more complex example also containing an acetal carbon as the stereogenic centre involves reaction of an alcohol with an a-bromoether attached to Boeckman’s camphorderived lactam auxiliary and gives the acetal in 96 4 dr.112 A novel synthesis of biologically important chiral a-aminophosphonates 122 involves the insertion of trimethyl phosphite into the C–O bond of oxazolidines 121 (Scheme 46).113 Inversion of configuration at C-2 suggests that the reaction proceeds via ring opening formation of a mixed phosphite ester followed by addition of the phosphorus atom to an iminium species.2.8 Radical reactions Radical cyclisation of the dehydroalanine derivatives 123 uses ester-based chiral auxiliaries to control the stereoselectivity Scheme 44 O Me Cr(CO)3 fenchyl O Me fenchyl CN 1. Me2C(Li)CN THF –78 °C 2. TFA –78 °C 3. aq. NH3 59% 76% de Scheme 45 Cr(CO)3 OMe OMe OMe Cr(CO)3 OMe OPri OMe H OPri OMe H OMe 1. TiCl4 2. Et3N PriOH 70% 94% de Et2O air hn 100% >95% ee 119 120 Scheme 46 N O Ph R Bn N P O Ph R Bn O OMe H2N P(OH)2 R O 3 P(OMe)3 SnCl4 1. H2 Pd 2. HCl 3 S:3 R = 86:14 to 100:0 121 122 2 J. Chem. Soc. Perkin Trans. 1 1999 357–373 367 (Scheme 47).114 The best diastereoselectivity of 4 1 is obtained using 8-phenylmenthyl esters with the menthyl esters being less eVective (1.75 1).An alternative approach to the synthesis of similar chiral 2-pyrrolidinones is an intermolecular allylation of a pyrrolidinone radical containing a substituted 1-phenylethyl group on the nitrogen atom as the chiral auxiliary; however the selectivities obtained so far are rather low.115 Radical cyclisation of acyl radical equivalents has been achieved using the vinyl bromides 124 shown in Scheme 48 where hydrogen atom transfer to the initially formed vinyl radical creates an acetal-carbon-centred radical which subsequently undergoes cyclisation onto the alkene.116,117 Rigid dioxanyl radicals (e.g. from 124) which are constrained to a chair conformation give high diastereoselectivities whereas simple chiral dioxanes formed from C2-symmetric diols are ineVective.Aldol-type products can be formed by the intermolecular addition of an alkoxy-centred radical (in a Barton-type procedure) bearing a glucal-derived chiral auxiliary to 2-nitropropene followed by hydrolysis of the resulting nitro thioether group.118 A particularly simple synthesis of chiral g-butyrolactones 126 involves reaction of acrylate or crotonate esters of N-methylephedrine 125 with ketones mediated by SmI2 (Scheme 49).119 Initial formation of a ketyl radical by oneelectron transfer to the ketone is followed by coupling with the ester 125 and cleavage of the auxiliary to give the chiral products 126 in one step and in high enantioselectivities (mostly 93–99% ee). An unusual approach to asymmetric synthesis involves the intermolecular reaction of a long-lived chiral radical with another radical (Scheme 50).120 Here the conformationally rigid nitroxyl radical 127 reacts with the benzylic radical generated from the hydrazine 128 to give 129 in 92 8 dr.Nitroxyl radicals with greater conformational mobility were initially studied but they are much less selective. Scheme 47 N O Br Bn O OR* N O Bn CO2R* Bu3SnH AIBN PhH 80 °C * dr = 4:1 69% 123 R* = 8-phenylmenthyl Scheme 48 O O H Ph EtO2C EtO2C Br O O EtO2C EtO2C H Ph hn 100% de 124 Scheme 49 R3 O Me O Ph NMe2 O O R1 R2 R3 O R1 R2 2 SmI2 ButOH + THF 126 mostly 93-99% ee 125 2.9 Miscellaneous uses of chiral auxiliaries The use of amino acids and their derivatives as chiral auxiliaries in a wide variety of asymmetric reactions has been reviewed.121 Synthesis of a-amino acids using reaction of a chiral electrophilic glycine equivalent with Grignard reagents has been reported with moderate diastereoselectivities ranging from 2.8 1 to 5.5 1.122 a-Aryloxyesters 131 can be prepared by substitution reaction of esters 130 formed from racemic a-haloacids and a lactate-derived auxiliary (Scheme 51).123 The two diastereoisomers of 130 (or a corresponding intermediate) react with the aryloxide at very diVerent rates with epimerisation of the slower reacting isomer.The allyl selenenimides 133 prepared by nucleophilic substitution of the chloroselenuranes 132 with protected lithium amides undergo a highly selective [2,3]sigmatropic rearrangement with chirality transfer from the stereogenic selenium atom to give the chiral protected allylic amines 134 via an endo transition state (Scheme 52).124 Enantiomerically pure allyl sulfoximines do not undergo significant rearrangement at room temperature however SN29 reaction with butylcopper gives alkenes in high enantioselectivity from the (Z)-sulfoximines where the stereoselectivity is controlled by a chiral leaving group.125 The corresponding (E)-isomers react much less selectively.Other rearrangements controlled by chiral auxiliaries include a vinyl epoxide attached to an Evans’ acyl oxazolidinone which rearranges to the dihydrofuran on heating to 180 8C.126 The stereoselectivity is modest (e.g. 57:33:6:4) but the diastereoisomers can be separated by flash chromatography. Enolate Claisen rearrangements can be controlled by an h4-diene iron- (tricarbonyl) unit as the chiral auxiliary with the newly formed C–C bond developing anti to the Fe(CO)3 substituent.127 Formation of enantiomerically pure 1,3-dithiane 1-oxide by Scheme 50 OH N O NHNH2 OH N O + PbO2 PhMe –78 °C 80% 127 128 129 dr 92:8 Scheme 51 R O N O X O Me R O N O OAr O Me ArO–Li+ THF RT 76-88% dr 95:5 to 99:1 130 131 Scheme 52 O Se R Cl OH Se R R NHR1 R1N R1NHLi [2,3] THF 0 °C 90-93% ee (R1 = Ts Ph2PO) 132 133 134 368 J.Chem. Soc. Perkin Trans. 1 1999 357–373 direct asymmetric oxidation of 1,3-dithiane itself occurs with low selectivity however attachment of a chiral auxiliary derived from camphor or diacetone glucose at the 2-position allows highly diastereoselective oxidations.128 Interestingly the best selectivities are observed using Sharpless oxidation conditions but the same isomer is obtained irrespective of which enantiomer of diethyl tartrate is used.The auxiliary is then removed by base-catalysed hydrolysis. Preparation of the chiral phosphinate ester 137 which has a stereogenic phosphorus atom can be achieved with complete diastereoselectivity by reaction of diacetone glucose 136 with the racemic chloride 135 (Scheme 53).129 Chiral phosphinous esters can be formed similarly and phosphines and phosphine oxides can be formed from the products with inversion of con- figuration by displacement of the auxiliary with organolithium reagents. 3 Chiral reagents 3.1 Chiral bases The asymmetric deprotonation of cyclohexene oxide 138 was one of the first examples of the use of chiral lithium amide bases and Singh and co-workers have revisited this reaction comparing a variety of bases derived from phenylglycine (e.g.139) which is available as both enantiomers at similar cost (Scheme 54).130 This work has also been extended to the enantioselective deprotonation of 4-substituted cyclopentene oxides in order to prepare prostaglandin intermediates. O’Brien and Poumellec have also used the base 139 for the deprotonation of dioxygenated cyclohexene oxides in up to 92% ee.131 exo- Norbornene oxide 140 undergoes deprotonation–rearrangement to give 141 in up to 52% ee using chiral lithium amide bases or an organolithium in the presence of (2)-sparteine (Scheme 55).132 If the two endo-protons are replaced by methyl groups then rearrangement of the epoxide to a ketone occurs instead in 35% ee.133 Enantioselective deprotonation of medium ring meso-epoxides using organolithium reagents and (2)- sparteine results in bicyclic alcohols rather than simple ring opening of the epoxide in up to 83% ee for the nine-membered ring.134 The asymmetric deprotonation of 4-substituted cyclohexanones has been previously studied by several groups and by Scheme 53 O O O OH O O P Ph Bn O Cl P Ph Bn O OR* DABCO PhMe (±)- + –20 to +20 °C 135 136 137 100% de Scheme 54 O OH N MeN Li Ph THF 0 °C to RT 80% ee 138 139 Scheme 55 O OH R2NLi or 24-52% ee RLi–(–)-sparteine 140 141 examining the NMR spectra of several analogues of a phenylalanine derived lithium amide base together with a comparison of their enantioselectivities Koga and co-workers have proposed an eight-membered cyclic transition state for this reaction.135 Several groups have reported on the asymmetric deprotonations of various arene chromium tricarbonyl complexes.Deprotonation at the benzylic position of the isobenzofuran complex 142 using the lithium amide 143 followed by reaction with benzophenone occurs in 99% ee (Scheme 56),136 and in 75–80% ee using a simpler base and several diVerent electrophiles. 137 Chromium tricarbonyl complexes of benzyl ethers are also deprotonated using 143 with very high enantioselectivities. 138 Benzaldehyde acetal complexes can be deprotonated at the ortho-position using either a chiral lithium amide 136 or a chiral organolithium reagent prepared from 8-phenylmenthyl chloride.139 Beak and co-workers have extended their work on the enantioselective deprotonation of N-Boc-benzylamines using organolithium reagents in the presence of (2)-sparteine to the p-methoxyphenyl-protected example 144 shown in Scheme 57.140 Alkyl triflates give higher enantioselectivities than alkyl halides and the p-methoxyphenyl group can then be removed oxidatively to give the N-Boc-protected primary amines 145.By reacting with Me3SnCl as the electrophile followed by transmetallation of the product with BuLi products with the opposite configuration can also be accessed. Carboxylation of deprotonated benzylamine 144 with carbon dioxide gives an a-amino acid derivative in 96 4 er whereas changing the electrophile to methyl chloroformate gives the corresponding methyl ester of the opposite enantiomer.141 Alternative electrophiles can also be used to give b- and g-amino acid derivatives. The cinnamylamine derivative 146 undergoes a similar enantioselective deprotonation and reaction with electrophiles usually occurs at the g-position to give the enecarbamates 147 (Scheme 58).142 Again the opposite enantiomer of 147 is accessible via the intermediate g-stannylated compound.Enantioselectivities of these types of reactions involving chiral benzyllithium species complexed with sparteine can be aVected by equilibration and also by kinetic resolution in reactions with limiting quantities of the electrophile.143 Alternatives to the naturally-occurring sparteine as a chiral Scheme 56 Cr(CO)3 O NLi LiN Ph Me Ph Me Ph Ph Cr(CO)3 O CH(OH)Ph2 2. Ph2CO LiCl THF –100 °C 1. 70% 99% ee 142 143 Scheme 57 N Boc Ph p-MeOC6H4 HN Boc Ph R 1. BuLi–(–)-sparteine 2. ROTf 3. ceric ammonium nitrate 144 145 93-96% ee Scheme 58 Ph N p-MeOC6H4 Boc Ph N Ar Boc E 1. BuLi–(–)-sparteine 2.E+ (= MeOTf R-X Me2C=O TMSOTf) 92-98% ee 146 147 J. Chem. Soc. Perkin Trans. 1 1999 357–373 369 solvating agent are the synthetic cyclic ureas (e.g. 149) prepared by Koga and co-workers.144 Reaction of the lithium enolate of tetralone 148 with methyl iodide in the presence of 149 gives 150 in 92% ee (Scheme 59). The enantioselectivity is aVected by the base used to generate the enolate being higher for LiHMDS than LDA or LiTMP and it is also improved by the addition of HMDS. The deprotonation–cyclisation of O-tosylketoximes using chiral amine bases has been reported.145 The O-tosylketoximes are formed from b-ketoesters which allows the doubly-activated a-position to be deprotonated by tertiary amine bases. 2HAzirines are formed in up to 80% ee using quinidine as the chiral base which was found to be the most eVective among several naturally occurring chiral amines tested.3.2 Miscellaneous uses of chiral reagents Asymmetric aldol reactions of acetate enolate equivalents attached to chiral auxiliaries often use alkylthio groups as “dummy” substituents at the a-position to enhance stereoselectivity and the same strategy has been used for aldol reactions using chiral reagents. In Scheme 60 an achiral dithiolane ketene acetal 151 undergoes an aldol reaction promoted by the oxazaborolidine 152 and subsequent reductive removal of the dithiolane gives the acetate aldol 153.146 A similar strategy can be applied to (methylthio)acetic acid involving formation of an intermediate chiral boron enolate with terpene-derived ligands on the boron atoms.147 Addition of lithium enolates of esters to imines mediated by a chiral C2-symmetric ether 154 results in b-lactams 155 in up to 90% ee (Scheme 61).148 Addition of extra lithium amide base over that required to generate the enolate improves the enantioselectivity and the chiral ligand 154 also enhances the reactivity of the enolate complex at low temperatures.Another addition to imines involves chiral menthone-derived boron enolates of a-halothioesters where the products can subsequently be cyclised to give aziridines in 94–99% ee.149 Lithium enolates this time of aryl methyl ketones are also involved in asymmetric Michael addition to doubly-activated electrophiles promoted by a chiral chelating amine in up to 94% ee.150 Scheme 59 O O Me N N Me BnO Ph Me OBn Ph O 1. LHMDS PhMe 2.Ligand 149 HMDS (4 equiv.) 3. Me-I (10 equiv.) 48 h 148 150 149 = 92% ee Scheme 60 S S OTMS OEt TsN B H O Pri R OEt OH O RCHO 151 152 (1 equiv.) CH2Cl2 –78 °C + 83-99% ee 1. 2. Ni2B - H2 153 Scheme 61 R R O OLi Et Et N R1 PMP N R R PMP O R1 Ph OMe MeO Ph + PMP = p-MeOC6H4 lithium amide PhMe 75-90% ee 154 155 Addition of organolithium reagents to carbonyl groups in the presence of chiral ligands has been one of the longeststudied processes in asymmetric synthesis. New examples include the addition of lithium trimethylsilylacetylide to cyclohexanones using proline-derived chelating amines.151 The chiral ether 154 (which was used above for addition of an enolate to an imine) has also been used to control the ring opening of cyclohexene oxide by phenyllithium in moderate enantioselectivity of 43%.152 A more unusual reaction of organolithium reagents is the addition to styrenes e.g.2-methoxystyrene 156 (Scheme 62) in the presence of (2)-sparteine where the electrophilic trapping with CO2 is the enantioselective process.153 Other 2-substituted styrenes and styrene itself are less eVective. Addition of organolithium reagents to prochiral arene chromium tricarbonyl complexes is mediated by chiral ligands and is followed by electrophilic trapping to give substituted cyclohexadienes (Scheme 63).154 The chiral ether 154 again features and is the best ligand among four that were investigated. Other types of organometallic reagents used with chiral ligands include organocerium reagents in the presence of TADDOLs (tetraaryl-1,3-dioxolane-4,5-dimethanols) which add to aldehydes in up to 92% ee.155,156 Asymmetric reactions of diethylzinc are usually additions to aldehyes with catalytic amounts of chiral ligands.However the addition of diethylzinc to imine 155 shown in Scheme 64 uses a stoichiometric amount of the chiral aziridine 156 as the ligand forming the amine 157 in 94% ee.157 Another addition of organozinc reagents to imines (Scheme 65) uses an allylzinc reagent and a lithiated bis-oxazoline ligand 158 (R = Pri) previously used by the same group for addition of allylzinc reagents to cyclopropenone acetals.158 Addition to the acyclic (E)-N-phenyl benzaldehyde imine gives little enantioselectivity but much better results are obtained with cyclic imines which are geometrically constrained to the (Z)-geometry. A very similar lithiated bis-oxazoline ligand to 158 (R = Ph) has also been used by Hanessian and Yang for the addition of allylzinc reagents to oximes of a-ketoesters.159 The bis-oxazoline 159 (which is lithiated to form 158) has also been used as a chiral ligand for a zinc Lewis acid in the radical allyl transfer reaction shown in Scheme 66.160 Better enantioselectivities are observed in this reaction when the intermediate radical is generated by Michael addition rather than bromine atom abstraction.An intermediate N-sulfonylimine undergoes addition of organoaluminium reagents formed from trimethyl- or triethylaluminium and binaphthol in 52–62% ee.161 Six diVerent ligands have been investigated for the asymmetric addition of lithium dimethylcuprate to chalcone in order to tune the enantioselectivity which is 90% in the best case.162 The same Scheme 62 OMe OMe Bu CO2H 1.BuLi (–)-sparteine cumene –95 °C 2. CO2 then H+ 72% ee 156 Scheme 63 Cr(CO)3 O N Ph OMe MeO Ph N O R RLi PhMe –78 °C 1. 2. propargyl bromide HMPA 154 65-93% ee 370 J. Chem. Soc. Perkin Trans. 1 1999 357–373 ligand also mediates the addition of magnesium dibutylcuprate to cyclohexenone in 96% ee. The use of metal hydride reagents bearing a chiral ligand for the asymmetric reduction of ketones has been a popular approach for many years however reduction of simple straightchain aliphatic ketones is often diYcult. A new chiral borohydride reagent 160 where the ligand is derived from b-pinene shows better selectivity for the reduction of octan-2-one than Midland’s similar benzyloxy reagent.163 The neutral borane (1)-B-chlorodiisopinocampheylborane (Ipc2BCl) 161 gives poor selectivities in the reduction of unhindered dialkyl ketones; however reduction of a- and b-hydroxyketones with this reagent is much better (84–92% ee) since initial formation of a borinate allows reduction to occur in an intramolecular fashion.164 The same reagent 161 also reduces diacylaromatic compounds to chiral C2-symmetric diols in >99% ee with only small amounts of the meso-diols being formed.165 Asymmetric reduction using borane together with a chiral oxazaborolidine has previously been applied to many ketones and has been extended to the case of a-alkynylketones which are reduced in 71–98% ee using an excess of the chiral ligand.166 Asymmetric reduction of a C]] N bond in oxime ethers can also be achieved using a chiral borane reagent 162 which is prepared in situ from borane and norephedrine.167 Asymmetric hydroboration of alkenes using pinene-derived reagents has been studied extensively and Brown and coworkers have now reported on a comparison of methods for the synthesis of optically pure isopinocampheylchloroborane (IpcBHCl) and have also compared IpcBHCl with IpcBH2 for the hydroboration of representative alkenes.168 The corresponding bromo-compound IpcBHBr has also been prepared and Scheme 64 Ph N PPh2 O N Bn Me OH Ph HN PPh2 O Et Et2Zn (3 equiv.) 63% 94% ee 155 156 157 Scheme 65 N Li N O O R R N NH + allylZnBr (premixed) 95% ee 158 (R=Pri) Scheme 66 O N R O O Br O N R O O N N O O Ph Ph allylSnBu3 Zn(OTf)2 67-90 % ee 159 B– H NEt2 )2BCl O B H N+ Ph Me BH3 – H Li+ 160 161 162 reacts with alkenes at lower temperatures than does IpcBHCl and often with higher enantioselectivities.169 Asymmetric hydrogen transfer from a chiral tin hydride to a prochiral radical has been achieved using the stannane 163 which incorporates a binaphthyl unit (Scheme 67).170 Although the enantioselectivity is modest the tin hydride 163 can be regenerated with sodium cyanoborohydride with retention of configuration allowing it to be used catalytically and with the same enantioselectivity as for the stoichiometric reaction.The asymmetric a-hydroxylation of 29,49-difluoropropiophenone using a camphorsulfonyl oxaziridine has been optimised from previously used literature conditions including eYcient recycling of the oxaziridine reagent and this has allowed scale-up to the multi-kilo level for the preparation of potential antifungal drugs.171 A new method for asymmetric epoxidation of a,bunsaturated ketones uses molecular oxygen as the oxidant together with diethylzinc and N-methylpseudoephedrine 164 (Scheme 68).172 In order to arrive at the use of 164 35 chiral alcohols were screened together with 8 solvents.The enantioselectivities are mostly good (82–92%) except when the b-substituent on the enone is phenyl (61% ee). A chiral (ethylperoxy) alkoxyzinc species is proposed as the reactive intermediate. The asymmetric aziridination of b-trimethylsilylstyrene using the chiral acetoxyaminoquinazolinone 165 is much more selective than with the analogous reagent where the chiral centre has a bulky alkyl (But) substituent instead of the silyloxy substituent (Scheme 69).173 This diVerence has been accounted for in terms of a preference for the C–O bond to eclipse the C]] N bond of the heterocycle and this is supported by a crystal structure.Asymmetric cyclopropanation of allylic alcohols using a chiral dioxaborolane and Zn(CH2I)2 has been extended to cases where the substrate also contains other alkene double bonds.174 Scheme 67 Sn But H But CO2Me Ph Br H MeO2C Ph But Et3B Et2O –78 °C 52% ee 163 93% Scheme 68 R1 R2 O Ph Me OH NMe2 R1 R2 O O O2 Et2Zn PhMe 0 °C 94-99% >99% de 61-92% ee 164 Scheme 69 N N O Me OTBDMS AcON Ph SiMe3 Ph SiMe3 N Q* H + 165 (= Q*NHOAc) dr = 11:1 J. Chem. Soc. Perkin Trans. 1 1999 357–373 371 In most cases high chemoselectivity for the allylic alcohol is observed with both conjugated and isolated polyenes and in one problematic case a glucose-derived auxiliary was superior to the chiral reagent.Formation of optically active 1,3-diene irontricarbonyl complexes 167 directly from the corresponding prochiral dienes is possible using a chiral irontricarbonyl transfer reagent (Scheme 70).175 The structure of the reagent is presumed to be 166 although it has not been characterised because of its air sensitivity and low stability. Desymmetrisation of meso-substrates is a useful approach to chiral products since unlike resolution of racemic compounds 100% conversion to a single enantiomer is possible at least in principle. The meso-diketone 168 actually exists as a rapidlyequilibrating mixture of enols and formation of the enamine 169 with prolinol occurs with a dr of 3 1 (Scheme 71).176 The mixture can be enriched in the major diastereoisomer by fractional crystallisation or alternatively complete separation is possible by chromatography of the acetates.Tricyclic norbornane-derived meso-anhydrides have previously been desymmetrised by amide formation with methyl prolinate and this approach has been extended to bicyclic anhydrides.177 tert- Butyl prolinate has some practical advantages in this case facilitating separation of the diastereoisomeric products and in the case of a bridged bicyclic anhydride complete diastereoselectivity is observed. Kinetic resolution of secondary alcohols using the chiral acylating agent 171 gives widely varying enantioselectivities (19–84% ee) with diVerent alcohols (Scheme 72) and the alcohol 170 gives much the best results.178 In some cases addition of MeMgBr as a base reverses the enantioselectivity.5 Miscellaneous asymmetric processes An unusual example of absolute asymmetric synthesis (no chiral reagent or catalyst) is shown in Scheme 73 and relies on a Scheme 70 N OMe Ph Fe(CO)3 R2 R1 R2 R1 Fe(CO)3 166 33-64% ee 167 Scheme 71 O O O N OH ( S)-(+)-prolinol PhMe heat dr = 3:1 168 169 Scheme 72 S N S But O But OH OCOBut (±)- hexane Et3N RT 84% ee 171 170 two-component molecular crystal 172.179 Diphenylacetic acid forms achiral crystals but when crystallised with acridine the two-component molecular crystal 172 is chiral and can be produced in either enantiomeric form by seeding methods. 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Engl. 1996 35 1725. 173 R. S. Atkinson M. P. Coogan and I. S. T. Lochrie Tetrahedron Lett. 1996 37 5179. 174 A. B. Charette H. Juteau H. Lebel and D. Deschenes Tetrahedron Lett. 1996 37 7925. 175 F. Maywald and P. Eilbracht Synlett 1996 380. 176 F. J. A. D. Bakkeren N. G. Ramesh D. Degroot A. J. H. Klunder and B. Zwanenburg Tetrahedron Lett. 1996 37 8003. 177 I. G. Jones W. Jones M. North M. Teijeira and E. Uriarte Tetrahedron Lett. 1997 38 889. 178 S. Yamada and T. Ohe Tetrahedron Lett. 1996 37 6777. 179 H.Koshima K. L. Ding Y. Chisaka and T. Matsuura J. Am. Chem. Soc. 1996 118 12059. 180 Y. Shimizu and S. Kawanishi Chem. Commun. 1996 819. Review 7/06651A REVIEW J. Chem. Soc. Perkin Trans. 1 1999 357–373 357 Stoichiometric asymmetric processes Andrew C. Regan Department of Chemistry University of Manchester Manchester UK M13 9PL Received (in Cambridge) 7th September 1998 Covering April 1996 to March 1997 Previous review J. Chem. Soc. Perkin Trans. 1 1998 1151 1 Introduction 2 Chiral auxiliaries 2.1 Reactions of chiral enolates 2.1.1 Alkylation 2.1.2 Aldol reactions 2.1.3 Miscellaneous reactions of chiral enolates 2.2 Reactions of carbanions 2.2.1 SAMP hydrazones 2.2.2 Other carbanions 2.3 Michael addition reactions 2.3.1 Michael addition reactions of chiral nucleophiles 2.3.2 Michael addition reactions to chiral electrophiles 2.4 Additions to C]] N double bonds 2.5 Addition to C]] O double bonds 2.6 Cycloaddition reactions 2.7 Other addition reactions 2.8 Radical reactions 2.9 Miscellaneous uses of chiral auxiliaries 3 Chiral reagents 3.1 Chiral bases 3.2 Miscellaneous uses of chiral reagents 4 Miscellaneous asymmetric processes 1 Introduction This article covers the literature from April 1996 to March 1997 and continues the coverage of the previous review.Since the field of asymmetric processes is such a large one this review covers stoichiometric processes only and asymmetric catalytic processes are now the subject of a separate review. 2 Chiral auxiliaries 2.1 Reactions of chiral enolates 2.1.1 Alkylation One of the most well-established and widely used types of auxiliary for asymmetric reactions of enolates is the oxazolidinone class developed by Evans.A new procedure for the N-acylation of the parent oxazolidinones with either acid chlorides or symmetrical or mixed anhydrides uses catalytic 4-(N,N-dimethylamino) pyridine (DMAP) in the presence of triethylamine at room temperature rather than deprotonation of the oxazolidinone with strong bases such as butyllithium.1 Alkylation of the lithium enolates of the N-acyl oxazolidinones 1 with dibromodifluoromethane gives the a-(bromodifluoromethyl) products 2 in 68% de for the N-propionyl case (R1=Me) improving to 92% de when R1 = But (Scheme 1).2 An ionic chain mechanism is proposed involving formation of difluorocarbene and similar results are obtained using bromodifluoromethane.An Evans-type oxazolidinone has been attached to a Merrifield polystyrene resin as in 3 and the lithium enolate alkylated with benzyl bromide (Scheme 2).3 After hydrolysis the polymer bound auxiliary can be reisolated by simple filtration and the a-benzylated acid is formed in 96% ee. The tricyclic oxazolidinone 4 is prepared from a chiral aminoindanol which is fully synthetic and resolved using mandelic acid rather than being derived from natural amino acids.4 Enolates of N-acyl-4 undergo alkylation acylation bromination and hydroxylation all with high diastereoselectivities. Another tricyclic oxazolidinone 5 has a rigid bridged ring system where the bulky silyl-protected alcohol is essential in order to obtain very high diastereoselectivities in alkylation reactions of enolates of the corresponding N-acyl compounds (dr = 300 1 to >500 1).5 The corresponding Nalkenoyl oxazolidinones have also been used both as dienophiles in Diels–Alder reactions and as Michael acceptors for conjugate additions of cuprates.The N-acylcamphor-derived auxiliary 6 also has a rigid bridged ring system but has a cyclic urea ring in the exo-orientation as compared with the endooxazolidinone in 5.6 Alkylation reactions of the sodium enolate of the N-propionyl derivative of 6 give uniformly high diastereoselectivities of >99 1 even with the small electrophile methyl iodide. The N-propionylanilide 7 possesses axial chirality with enantiomeric atropisomers.7 Diastereoselective alkylation of the lithium enolate of 7 occurs with good selectivity (15 1 to >25 1) for a range of alkyl halides.Aldol reactions of the lithium enolate are also highly stereoselective for one of the syn-isomers. The N-MEM group in 7 appears to enhance the stereoselectivity of reactions of the enolate since the corresponding N-methyl analogue gives rather low selectivities. Only racemic 7 has so far been used but some progress has been made towards its kinetic resolution using a chiral lithium amide base. Pseudoephedrine has been developed as an eVective practical chiral auxiliary by Myers for the alkylation of its amides 8 and an extension of this is the use of epoxides as the electrophiles. 8 Ethylene oxide gives moderate diastereoselectivities (49–59% de) however the use of the “matched” enantiomer of a monosubstituted epoxide gives double-diastereoselective reactions of 93 to �99% de.Hydrolysis of the g-hydroxyacyl products also results in cyclisation to g-lactones. Scheme 1 O N O Pri R1 O O N O Pri R1 O CF2Br 1. LDA THF 2. remove THF 3. DME 4. CBr2F2 –20 °C 1 2 68% de (R1 = Me) 92% de (R1 = But) Scheme 2 N O O Me O O polymer N O O Me O O polymer Ph 1. LDA THF 0 °C 2. PhCH2Br 3 96% de 358 J. Chem. Soc. Perkin Trans. 1 1999 357–373 The binaphthol mono-ester 9 has been used as a chiral glycine equivalent 9 alkylation of the lithium enolate followed by hydrolysis of the imine and benzoylation gives the protected a-aminoesters 10 in 69–86% de (Scheme 3). The planar-chiral h2-manganese complex 11 has previously been used for diastereoselective alkylation and aldol reactions but only in a racemic form. By forming the complex from optically active cyclopentenol followed by oxidation of the alcohol to give 11 alkylation and aldol reactions of the optically active lithium enolate give products (e.g.12) in 85–88% ee after oxidative removal of the manganese (Scheme 4).10 An asymmetric allylation–Cope rearrangement sequence has been developed by Nakai and co-workers 11 using the enolate of the b,g-unsaturated acyl Oppolzer auxiliary 13 (Scheme 5). Good diastereoselectivity in the allylation reaction to give 14 is observed (>99%) together with complete retention of the (E)- stereochemistry of the alkene. Interestingly the corresponding a,b-unsaturated isomer of 13 gives mostly the (Z)-isomer of 14 and use of the Evans’ auxiliary gives much lower selectivity in the allylation (48% de). The Cope rearrangement of 14 at 220 8C is highly stereoselective giving 15 as the sole product whereas the (Z)-isomer of 14 rearranges with lower selectivity (85 15 dr) to give the epimer of 15.A similar sequence involving an aldol reaction followed by Cope rearrangement is also possible,12 by initial aldol reaction of the enolate of 13 with crotonaldehyde in the first step rather than alkylation with allyl bromide. a-Cyanoesters 16 of Helmchen’s chiral auxiliary can be alkylated under mild conditions with allyl bromide (Scheme 6).13 Hydrolytic removal of the auxiliary followed by Curtius HN O O O NH O O SiMe2Ph N NH O Ph But N MEM O Me Ph N R OH Me Me O 4 5 6 7 8 Scheme 3 OH O N O Ph Ph R*O NHBz O R 1. LDA THF-HMPA 2. H+ H2O 3. BzCl R-X 69-86% de 9 10 Scheme 4 O Mn OC CO O R 1. LDA THF –78 °C 2. RCHO 3. D MeCN air 11 12 R = Me allyl Bn 85% ee rearrangement gives optically active protected a-aminonitriles 17 which can be converted into a-aminoacid derivatives.Chiral N-dialkylaminolactams 18 are alkylated in fairly good diastereoselectivity which can be improved to >96% after chromatography (Scheme 7).14 Reductive removal of the auxiliary provides a route to optically active 2-substituted laams containing 5- to 7-membered rings. Enolates of menthyl arylacetates can be formed by vicarious nucleophilic substitution of hydrogen in 1-chloro-3-nitrobenzene 19 (Scheme 8); alkylation in the same reaction vessel gives the products 20 in up to 8 1 dr.15 2.1.2 Aldol reactions One of the problems in the area of asymmetric aldol reactions has been to find eVective methods for acetate enolates since Scheme 5 N SO2 O Xc Br O Xc O Xc Xc = 13 LiHMDS THF-HMPA –78 °C 87% 14 >99% de 15 >99% de 220 °C Scheme 6 R CO2R* CN R CO2R* CN Br R NHBoc CN SO2N(C6H11)2 OH 1.KOH 2. SOCl2 3. NaN3 4. ButOH K2CO3 acetone 17 dr 75:25 to 92:8 R*OH = 16 Scheme 7 N O N N O R Et Et OMe N Et Et OMe n 1. LDA THF –78 °C 2. R-X –100 °C n 69-87% de crude >98% de after chromatography 18 n = 0 1 2 Scheme 8 Cl O2N CO2R* PhS O2N CO2R* Bn HO Pri Me 19 1. NaH 2. BnBr R*OH = 70% dr 8:1 20 J. Chem. Soc. Perkin Trans. 1 1999 357–373 359 these often react relatively unselectively compared to the corresponding propionate enolates. One solution to this problem is to use a chromium–Reformatsky species prepared from an (a-bromoacetyl) Evans’ auxiliary 21 (Scheme 9).16 The aldol product 22 is formed with good diasteroselectivity (92 8) in the opposite sense to more usual methods.The N-acetyl analogue of the cyclic urea 6 has also been used for lithium and titanium aldol reactions with useful diastereoselectivities for aromatic aldehydes. Aliphatic aldehydes react rather less selectively and the titanium and lithium mediated reactions give selectivities in the opposite sense to each other. Asymmetric aldol reactions of acetate enolate equivalents have also been achieved using chiral reagents (see below). New designs of chiral auxiliary for the aldol reaction continue to appear. The N-propionyloxazolidinone 23 is prepared from 2-aminocyclopentanol which is itself formed by bakers’ yeast reduction of ethyl 2-oxocyclopentanecarboxylate followed by Curtius rearrangement.17 Boron aldol reactions of 23 under the usual conditions give uniformly high diastereoselectivities (>99%) for one of the syn-aldol products.The N-propionyl “quat”-type lactam 24 gives similarly high selectivities for the same syn-aldol isomer.18 The 1,3-benzoxazinone 25 is derived from menthone and aldol reactions of its sodium and titanium enolates with benzaldehyde give the two alternative syn-diastereoisomers in 91 2 and 2 96 dr respectively.19 The standard combination of a dialkylboron triflate and a tertiary amine base widely used for aldol reactions of ketones thioesters and N-acyl chiral imides has also been shown to be eVective for esters,20 contrary to widespread assumption. As well as simple achiral esters 8-phenylmenthyl propionate 26 is converted into its enol borinate with dicyclohexylboron triflate and following equilibration of the geometical isomers aldol reaction with isobutyraldehyde gives a 98 2 ratio for the two possible syn-isomers.Aldol reaction of the kinetic enol borinate is very selective for the two anti-aldol products but both are formed in almost equal amounts (48 52). The vinylogous urethane 27 contains a pyrrolidine auxiliary which has been reported as a more accessible replacement for 2,5-dimethylpyrrolidine (Scheme 10).21 Aldol reactions of the extended lithium enolate of 27 give syn-lactones 28 followed by a two-step removal of the auxiliary to give the unsaturated lactones 29. Some interesting new applications of established asymmetric Scheme 9 N O O Br O Bn OHC O Xc O OH O dr 92:8 22 21 CrCl2 LiI (cat.) THF RT 5 h 63% O N H H O N O CO2Et O N O Pri Me O O Ph O O O 24 23 25 26 aldol reactions include Oppolzer’s use of his N-propionyl sultam auxiliary 30 for the desymmetrisation of the mesodialdehyde 31 (Scheme 11).22 Oxidation of the lactol product 32 gives the lactones 33 and 34 in a dr of 7 to 8 1 and hydrolytic removal of the auxiliary results in a short synthesis of the Prelog–Djerassi lactonic acid.An approach to the iterative construction of polyketide chains involves aldol reaction of an acylated Evans’ oxazolidinone auxiliary with a polymer supported aldehyde.23 Removal of the auxiliary and transformation of the imide into an aldehyde group via a Weinreb amide allows the asymmetric aldol reaction to be repeated building up the chain on the polymer support. Evans’ auxiliaries have also been used in aldol reactions with the ketone group of pyruvates resulting in the construction of tertiary alcohol centres during the aldol step.24 Complete control over the stereochemistry at the a-carbon is achieved but the control over the new tertiary alcohol centre is less selective resulting in a syn anti mixture of diastereoisomers in up to 83 17 dr.The lithium enolate of the chiral amide 35 can be homologated to the zinc homoenolate 36 and combined with a titanium homoaldol reaction to give a-alkyl-g-hydroxyamides 37 in 64–86% de (Scheme 12).25 The auxiliary can be removed with tosic acid causing cyclisation of the products to a,gdisubstituted g-lactones. 2.1.3 Miscellaneous reactions of chiral enolates Halogenation of chiral enol borinates using N-halosuccinimides has been applied to the xylose-derived N-acyloxazolidin- Scheme 10 OMe O N H MeO Et Et O O N H MeO Et Et R O O R 1.LDA THF –78 °C 2. RCHO 2. MCPBA 92-99% de 95-97% ee 27 28 1. NaBH3CN 29 Scheme 11 SO2 N OHC CHO Me Me O Me OH Xc Me O O Me O Me O Xc Me O Me O Me O Xc Me O Me TPAP NMO 1. Et2BOTf Pri 2NEt CH2Cl2 2. 32 30 31 95% + 33 34 7 to 8 1 TPAP = tetra- n-propylammonium perruthenate NMO = 4-methylmorpholine N-oxide 360 J. Chem. Soc. Perkin Trans. 1 1999 357–373 one 38 to give a-bromo and a-chloro products 39 in up to 4 1 dr (Scheme 13).26 Acylation of the lithium enolate of 38 is more selective giving the b-ketoacyl oxazolidinones in up to 12 1 dr. Bromination (with NBS) of an Evans’ acyloxazolidinone containing an o-carborane cage has been followed by azide displacement and reduction of the azide to the amine aVording a route to both enantiomers of carboranylalanine a compound useful in boron neutron capture therapy.27 The a,b-unsaturated acyloxazolidinone 40 has been converted into the lithium and sodium extended enolates which are fluorinated with N-fluoro- (N-phenylsulfonyl)benzenesulfonamide 41 at the a-position to give 42 as a single diastereoisomer (Scheme 14).28 The product 42 was then used as an intermediate in the preparation of 2-deoxy-2-fluoro sugars.The asymmetric Darzens reaction of 8-phenylmenthyl chloroacetate 43 with ketones gives glycidic esters in 77–94% de (Scheme 15).29 With unsymmetrical ketones there is also good selectivity in favour of the (Z)-epoxide (4.5 1 to 7.6 1). Asymmetric aza-Darzens reactions have also been achieved using the lithium enolate of a bromoacetyl Oppolzer sultam and N-(diphenylphosphinyl)imines giving cis-disubstituted aziridines with >95% face selectivity.30 2.2 Reactions of carbanions 2.2.1 SAMP hydrazones Enders and Klatt have reviewed the uses of 1-amino-2- Scheme 12 Xc O R Xc O R (ICH2)Zn OBn Xc O R R' OH O N H H 1.BuLi 2. (ICH2)2Zn LiOBn 1. PriOTiCl3 2. R'CHO 37 35 36 64-86% de Xc = R = Me Bn Scheme 13 O N O O O O O O Xc Br (Cl) 1. R2BOTf 2. NBS or NCS 4:1 dr 38 39 Scheme 14 O N O Xc BnO O Xc O BnO F Me Ph N F PhSO2 PhSO2 Xc = 40 41 1. LiHMDS 2. 100% de 42 Scheme 15 Cl O O Me Ph O CO2R* Ph H Me ButOK CH2Cl2 93% de Z:E = 7.6:1 43 PhCOMe (methoxymethyl)pyrrolidine (SAMP) hydrazones of aldehydes and ketones 44 in asymmetric synthesis.31 In general these involve creation of a new stereogenic centre a to the hydrazone group by deprotonation followed by reaction with an electrophile.The diethyl (SAEP) analogues 45 often give improved diastereoselection. New examples include the use of a-(phenylselanyl) aldehydes as electrophiles which give hydroxyselenides 46.32 After removal of the auxiliary and elimination of the hydroxyselenide chiral b,g-unsaturated aldehydes and ketones 47 are formed with very little racemisation at the a-centre. Chiral 2-phosphinoalcohols can be prepared by reaction of SAMP or SAEP hydrazone anions with chlorodialkylphosphines to give 48 followed by removal of the auxiliary and reduction of the aldehyde.33 The lithiated SAMP hydrazone of cyclohexanone can be transmetallated to an organozinc reagent which then adds to the alkene double bond of a cyclopropenone acetal giving the cyclopropane 49 in 96% de.34 The SAEP hydrazone 50 undergoes regioselective lithiation and [2,3]-Wittig rearrangement to give the a-hydroxycyclohexanone derivatives 51 containing adjacent quaternary and tertiary stereogenic centres (Scheme 16).35 Enantioselective Mannich reactions can be performed in an indirect way starting from SAMP hydrazones which are used to prepare a-silylketones 52.This is followed by formation of the a9-silylenol ether and reaction with an iminium salt. The second stereogenic centre is controlled by the a-silyl group which is then finally removed to give the chiral b-(dialkylamino) ketones 53 (Scheme 17).36 2.2.2 Other carbanions 2-(Aminomethyl)thiazole 54 can be converted into imines (e.g. R1 N N OMe R2 R R R1 N Xc R2 R3 SePh OH R1 O R2 R3 H N Xc R1 PR2 2 O O N Xc H H 44 R=H 45 R=Et 46 47 (89 - 94% ee) 48 (50 - 87% de) 49 (96% de) Scheme 16 N N Et Et OMe O R N OH R N Et Et OMe ButLi THF –100 to 0 °C 50 51 74-91% anti �96% de Scheme 17 R Me O R O Me NBn2 1.LDA TMSCl 2.Bn2NCH2OMe 3. TBAF 52 53 91-97% ee C6H13 tMe2Si J. Chem. Soc. Perkin Trans. 1 1999 357–373 361 56) by reaction with camphor or a hydroxypinanone 55 (Scheme 18).37 Alkylation of the carbanion formed by deprotonation of 56 followed by cleavage of the imine and protection aVords the N-Boc-protected aminoalkylthiazoles 57 which can serve as precursors to chiral a-aminoaldehydes. The hydroxypinanone imines show better selectivities (mostly >98 2 dr) in the alkylations than do those derived from camphor. An enantioselective preparaton of allenecarboxylate esters 60 relies upon an asymmetric Wadsworth–Emmons reaction of the phosphonoacetate 59 containing a substituted binaphthol auxiliary with ketenes which are generated in situ by treatment of the aryl esters 58 with BuLi and ZnCl2 (Scheme 19).38 The allenes 60 are mostly formed in 61–84% ee and the unsubstituted binaphthol analogue of 59 shows much lower enantioselectivity.An asymmetric synthesis of the b-ketophosphonate 64 starts with treatment of the achiral cyclohexanone 61 with LDA to give a racemic chiral enolate which reacts with an optically pure phosphorochloridate 62 to give the vinyl phosphates 63 as a mixture of diastereoisomers (Scheme 20).39 Deprotonation of 63 with LiTMP gives a delocalised allyl anion which is now a single stereoisomer and which rearranges stereoselectively to 64 with a dr of 2.5 1 at the 5-position.The C2-symmetric cyclic bis-sulfoxide 65 has been used to desymmetrise meso-1,2-diols (Scheme 21).40 Formation of the acetal 65 from the meso-diol followed by asymmetric deprotonation elimination and acetylation gives the desymmetrised product 66 in >96% de. The selectivity is very dependent on the metal counter-ion since only 8% de is obtained using LiHMDS and 12-crown-4. The reactions of chiral allyl organometallic species with aldehydes has been a very active area for some years. The metallated sulfoximines 67 and 68 containing 5- and 6-membered rings show very high levels of stereocontrol even when combined with a chiral aldehyde in a mismatched sense (Scheme 22).41 Analogous acyclic sulfoximines show good stereocontrol with achiral aldehydes and also with chiral aldehydes in matched pairs but less control using mismatched pairs.Scheme 18 N N S OH NH2 N S O OH NHBoc N S R 54 TiCl3 PhMe reflux 1. LDA 2. R-X 3. NH2OH AcOH 4. Boc2O 55 56 >96% ee 57 Scheme 19 R1 R2 CO2Ar R1 R2 · H CO2Me O O P O CO2Me Me Me 2. 58 59 60 1. BuLi ZnCl2 THF –78 °C mostly 61-84% ee – 2.3 Michael addition reactions 2.3.1 Michael addition reactions of chiral nucleophiles Conjugate additions of chiral enamines e.g. 69 formed from a cyclic ketone and 1-phenylethylamine have been extended to the study of the formation of a second stereogenic centre by using a- or b-substituted Michael acceptors (Scheme 23).42 Use of methyl methacrylate gives 70 as a single diastereoisomer and although there is no reaction with methyl crotonate some other more reactive b-substituted acceptors react successfully.A model is proposed for the transition state and the face selectivity of this type of reaction has been interpreted as the chiral amine causing one cyclohexene chair conformation to be preferred over the other in the enamine intermediate.43 The SAMP-hydrazone of formaldehyde 71 undergoes Michael addition to enones as a neutral nucleophile (in contrast Scheme 20 O O O P O Cl O O O P O O O O O O P O O O 1. LDA 2. LiTMP 62 63 64 dr = 2.5:1 61 LiTMP = lithium 2,2,6,6-tetramethylpiperidide Scheme 21 S+ S+ O– O– O O S+ S+ O– O– O AcO 1. KHMDS 18-crown-6 2. Ac2O 65 66 >96% de Scheme 22 S O p-Tol N Pri OTBDMS S O p-Tol N Pri OTBDMS H H OH OTBDMS CHO OTBDMS n n 1. BuLI 2. ClTi(OPri)3 3. 67 ( n=1) 68 ( n=2) 96 to 98% de Scheme 23 CO2Me N H Ph Me CO2Me Me CO2Me O CO2Me Me 2.AcOH-H2O MgBr2 1. 72% 100% de 69 70 362 J. Chem. Soc. Perkin Trans. 1 1999 357–373 to the more usual carbanions discussed in section 2.2.1) in 85 to �98% de to give adducts 72 which can be transformed into either 4-ketoaldehydes 73 or 4-ketonitriles 74 (Scheme 24).44 The same hydrazone 71 also reacts with 1-nitroalkenes derived from sugars without any base or additive in diastereoselectivities which are >96% for matched pairs of reagents but 38–68% for mismatched pairs.45 Conjugate addition of chiral lithium amides to a,b-unsaturated esters has been discussed in previous reports in this series and Davies has extended this work by incorporating a subsequent stereoselective aldol reaction at the a-carbon atom as a key step in the synthesis of a thienamycin intermediate.46 Stereoselective reaction of the enolate with trisyl azide followed by reduction of the azide gives anti-2,3-diaminobutanoic acid.47 The syn-diastereoisomer can also be prepared by an inversion at the a-carbon atom.The anion of chromium carbene complex 75 containing an imidazolidinone chiral auxiliary acts as an acetate equivalent in the conjugate addition to a,b-unsaturated ketones and generally shows a selectivity of at least 96 4 dr with one exception. (Scheme 25).48 Interestingly the stereoselectivity reaches a maximum at 220 8C and is reduced at both higher and lower temperatures. Oxidation of the carbene and removal of the auxiliary gives chiral b-alkyl-d-oxoesters. 2.3.2 Michael addition reactions to chiral electrophiles The conjugate addition of organometallic reagents to crotonyl derivatives of a variety of chiral auxiliaries has been a theme for some years now.New examples include the conjugate addition of Grignard reagents to the imidazolidinone 76 (using the same auxiliary as in 75) where the presence of Me2AlCl as a Lewis acid improves diastereoselectivity to 90 10 via a proposed chelated intermediate.49 Copper(I)-catalysed asymmetric additions of organozirconocenes to the crotonyl Evans-type auxilary 77 have been reported for the first time.50 The intermediate zirconium enolate formed during the conjugate addition can also be trapped with benzaldehyde in an aldol step to give a product with three new stereogenic centres in >97% de. Use of the more common benzyl or isopropyl-substituted oxazolidinones is less selective as is the Oppolzer sultam auxiliary.The iodotrimethylsilane promoted addition of monocopper Scheme 24 N N OMe R4 O R3 R2 R1 N N MeO O R1 R3 R4 R2 NC O R1 R3 R4 R2 OHC O R1 R3 R4 R2 + 1. TDSOTf THF –78 °C 2. TBAF 85 - 98% de magnesium monoperoxyperphthalate O3–DMS 71 72 73 74 85 - 98% ee 85 - 98% ee TDS = tert-hexyldimethylsilyl Scheme 25 N N Ph Me Me O Me Cr R2 R1 O Xc Cr R2 O R1 de 88:12 to >97:3 (CO)4 75 (CO)4 1. BuLi THF –78 °C 2. 3. AcOH reagents to the bornyl crotonate 78 has been extended to the use of a farnesyl-derived homoallylic copper reagent in the synthesis of geranylcitronellol † in 99% ee.51 Replacement of the naphtgroup in 78 with a phenyl group reduces the stereoselectivity in the conjugate addition step to 73% de.The high pressure induced conjugate addition of amines to a variety of “arylmenthyl” crotonates 79 has been studied together with crotonates of some chiral cyclohexanols.52 Very high selectivities are obtained in additions to 79 where Ar = 2-methoxyphenyl 4-phenoxyphenyl or 2-naphthyl whereas only moderate selectivities are observed for trans-2-arylcyclohexanol esters. This diVerence is interpreted in terms of improved p-stacking in 79. 8-Arylmenthols have also been studied as auxiliaries in the conjugate addition of allyltrimethylsilane to the dihydropyridones 80 (Scheme 26).53 Again Ar = 2-naphthyl is particularly eVective (30 1 dr) and the use of menthol itself (Ar = H) results in an almost completely unselective reaction. The monoesters 81 of 1,19-binaphthalene-8,89-diol undergo conjugate addition reactions of lithium dialkylcuprates followed by 1,2-addition of the same reagent at the ester and elimination of the chiral auxiliary all in one process to give ketones 82 in 96–100% ee (Scheme 27).54 Previously the corresponding esters of the widely used 1,19-binaphthalene-2,29-diol auxiliary had shown rather less stereoselectivity.Asymmetric conjugate addition reactions of radicals to chiral a,b-unsaturated acyloxazolidinones have been previously reported but new examples include conjugate addition of an N N Me Ph O Me Me O O N Ph O Me O O Me O R O Me O Ar 76 79 78 77 R = naphthyl Scheme 26 O N O R O SiMe3 O N O R O TiCl4 80 dr = 30:1 (R = 2-naphthyl) Scheme 27 O O Ar OH R Ar O R R2 CuLi R = Me Bu 81 82 96-100% ee † IUPAC name 8-geranyl-3,7-dimethyloct-6-en-1-ol.J. Chem. Soc. Perkin Trans. 1 1999 357–373 363 ethyl radical to 83 followed by trapping of the intermediate radical with an allyl stannane generating the new stereocentre during the trapping step only.55 Related to this is the radical addition of tributyltin hydride to the a-methyl substituted acceptor 84; here the stereogenic a-centre is created during hydrogen atom transfer in 92 18 dr.56 Addition of an isopropyl radical to the fumaryl oxazolidinone 85 is both highly regioand stereoselective in the presence of the correct choice of lanthanide triflate as a Lewis acid; 57 the saturated acyl oxazolidinone products can then be used in standard asymmetric aldol reactions resulting in the creation of three contiguous stereogenic centres. 2.4 Additions to C]] N double bonds A contribution to the well-studied field of addition of nucleophiles to imines derived from 1-phenylethylamine is the investigation of the addition of allyl organometallic compounds looking at the dependence of diasteroselectivity upon the allyl reagent used and also the structure of the imine 86 (Scheme 28).58 Allyl-BBN and diallylcuprate give the best results with both aliphatic and aromatic imines (up to 98% de) although with imines derived from pyridine-2-carbaldehyde allylzinc bromide and allyl(dichloro)iodotin are better.Additions to imines derived from chiral sulfinamides are represented by the addition of Grignard reagents to toluenesulfinamides 87 in 60–74% de,59 and hydride reduction of imines 88 in up to 86% de using DIBALH.60 Addition of ZnBr2 to the DIBALH reduction gives the opposite sense of diastereoselectivity in up to 92% de.Addition of methyl and ethyl Grignard reagents to the analogous aldehyde imines is also stereoselective in 79–85% de and the sense of the stereoselectivity is as expected from the results using DIBALH without ZnBr2. Asymmetric synthesis of b-amino acids has been achieved by additions to N-galactosylimines 89 (Scheme 29).61 Addition of bis-silyl ketene acetals 90 gives only the two possible erythro (syn) isomers and usually in >20 1 dr whereas addition of the lithium enolate of tert-butyl phenylacetate gives exclusively the two threo isomers but in a lower 3 1 ratio. The addition of organolithium reagents to the C]] N double bond of SAMP-hydrazones has been extended to the indoline- 2-carboxylic acid derived hydrazones 91 (Scheme 30).62 Uniformly high diastereoselectivities are observed (>93 7) even with imines which could be deprotonated at the a-position by the basic organolithium reagents.The same types of chiral N O O O Ph Ph N O O O Ph Ph N O Ph O O Me CO2Et 85 84 83 Scheme 28 R N Ph Me M R N H Ph Me + 86 p-Tol S N Ar O NH But O S+ N O– Ar R 87 88 imines also undergo addition of trimethylsilyl cyanide in the presence of Et2AlCl in up to 96% de.63 Dehydromorpholines 92 prepared from (R)-phenylglycinol and a-ketoesters undergo addition of Grignard reagents to the C]] N bond in the presence of a Lewis acid with complete diastereoselectivity (Scheme 31).64 Destructive removal of the chiral auxiliary by catalytic hydrogenation then results in optically pure a-methyl-a-amino acids.Enantiomerically pure 1,2-diamines have been prepared by a symmetrical pinacol-type coupling of optically pure chromium tricarbonyl complexes of benzaldehyde imines.65 The reaction is promoted by SmI2 and is an example of the formation of both stereogenic centres in a 1,2-difunctionalised compound as well as the C–C bond connecting them in a single step. Hanessian has reported that the addition of allylzinc reagents to oximes of glyoxylic acid attached to Oppolzer’s camphor-derived sultam gives a-allylglycines.66 However a more direct approach from the same group uses an external chiral ligand for the same type of reaction (see Section 3.2). An unusual asymmetric addition to C]] N bonds involves the addition of Grignard reagents to the 2-position of pyridinium salts with N-alkoxycarbonyl groups formed from chiral alchohols as the chiral auxiliaries.67 8-Phenylmenthol and closely related derivatives were found to be the best auxiliaries with diastereoselectivities of up to 95%.2.5 Addition to C]] O double bonds This section covers additions of nucleophilic species to carbonyl groups which have not already been covered in section 2.1.1. Scheme 32 shows the addition of Grignard reagents to a ketone 93 bearing a chiral auxiliary which is of the now standard trans-2-substituted cyclohexyl ester type but is novel in that the 2-substituent is a nitroxy group.68 The aminoalcohol derived auxiliary 94 is not initially attached to the ketone substrate but becomes covalently bonded during the reaction with the allylsilane (Scheme 33).69 The auxiliary can be reductively cleaved using sodium in liquid ammonia and gives improved selectivity over an earlier reagent.Some of the most eVective neutral chiral nucleophiles for Scheme 29 OPiv PivO PivO OPiv N R H OPiv PivO PivO OPiv HN R CO2H R1 OTMS OTMS H R1 + ZnCl2 THF 89 90 dr = 3:1 to >20:1 + other syn-isomer Scheme 30 N OMe N R1 H N OMe N R1 H R2 THF or Et2O R2Li –78 °C 91 dr 93:7 Scheme 31 O N O Ph H Me O N O Ph H Me R 1. BF3·OEt2 –78 °C 2. RMgX 2 equiv. 100% de 92 364 J. Chem. Soc. Perkin Trans. 1 1999 357–373 asymmetric addition to carbonyl groups are allyl boronates. The g,g-disubstituted allyl boronates 95 can be formed in situ from tartrate esters of either enantiomer and add to aldehydes to give homoallylic alcohols with a quaternary stereogenic centre (Scheme 34).70 Allyltrichlorosilane also reacts with tartrate esters to give a pentacoordinate allyl silicate which undergoes similar asymmetric addition of the allyl group to aldehydes in up to 71% ee.71 Very similar work has also been reported by Kira and co-workers.72 Tartrate esters are also used in the in situ formation of a pentacoordinate chiral allyltin species which transfers the allyl group to aromatic aldehydes in the presence of catalytic amounts of copper salts in 89–94% ee.73 Diisopinocampheylallylboranes have also been extensively investigated for asymmetric addition of allyl groups to aldehydes; incorporation of a g-aminoallyl group results in the formation of unsaturated 1,2-aminoalcohols and use of an imine as the protecting group on nitrogen is important to allow easy deprotection.74 Masked a-hydroxyketones are formed by reduction of a 2- acyldithiane-1-oxide 96 (Scheme 35) where the chiral auxiliary is formed by Kagan oxidation of the corresponding dithiane after incorporation into the substrate.Other examples related to 96 can also be prepared by acylation and methylation of the parent chiral 1,3-dithiane-1-oxide.75 Reduction of ketone groups which are remote from the chiral auxiliary has been achieved using 4- and 5-oxoesters of anhydroglucose derivatives. 76 Use of ZnCl2 in the reduction with sodium borohydride is essential for high selectivity and chiral lactones are formed in up to 93% ee after removal of the auxiliary. b-Ketophosphine oxides containing a chiral oxazolidine auxiliary adjacent to the ketone have been reduced to the corresponding b-hydroxyphosphine oxides in 95 5 dr and the auxiliary can be removed using ethane-1,2-dithiol.77 An intramolecular Meerwein–Ponndorf–Verley reduction is shown in Scheme 36 where the auxiliary 97 first undergoes Michael addition to the a,b-unsaturated ketones followed by highly diastereoselective 1,7-hydride transfer to give 98.78 Destructive removal of the auxiliary by reductive cleavage with Raney nickel then gives secondary alchohols in 96–98% ee with overall reduction of both alkene and ketone groups.Scheme 32 O ONO2 Ph O O O ONO2 Ph O HO R Et2O –78 °C 93 RMgBr ZnCl2 82-86% de Scheme 33 Me3SiO NHCOCF3 Ph Ph O NHCOCF3 Ph Ph SiMe3 O + + TfOH TMSOTf CH2Cl2 –78 °C dr = 18:1 94 Scheme 34 R1 B R2 O O CO2Pri CO2Pri R4 OH R2 R1 dr 96:4 major isomer 62-85% ee R3CHO 95 2.6 Cycloaddition reactions The majority of asymmetric Diels–Alder reactions employing chiral auxiliaries have the auxiliary attached to the dienophile and there are several new examples of these.The aminoindanolderived oxazolidinones 99 have a gem-dimethyl group to increase steric shielding on one face of the alkene and give selectivities of 96 4 to >99 1 in reactions with both cyclic and acyclic dienes using Et2AlCl as a Lewis acid.79 The acrylate ester 100 has been investigated because the parent chiral diol isosorbide is readily available in large quantities at low cost.80 Using SnCl4 as the Lewis Acid Diels–Alder reaction of 100 with cyclopentadiene gives the (S)-endo product in 96 4 dr. However the closely related epimeric isomannide acrylate 101 gives the (R)-endo adduct in 95 5 dr using EtAlCl2 as the Lewis acid.The dienophile 102 is the monoacrylate monopivalate diester of a chiral spiro-fused diol and reacts also with cyclopentadiene to give the endo-adduct in >97% de using BCl3 as the Lewis acid.81 A chiral sulfoxide is the auxiliary in the N-acylated pyrrole 103,82 which gives >99% de in the endo adduct with cyclopentadiene with AlCl3 as the Lewis acid and is one of the few examples of a dienophile with a sulfoxide auxiliary which is recoverable. The N-methacryloyl bicyclic lactam 104 shows complete diastereofacial selectivity in addition to an acyclic silyloxy-activated triene and this was used as a key step in the synthesis of (2)-cassioside.83 In the Diels– Alder addition of the a-methylene-b-ketoester of 8-phenylmenthol 105 with cyclopentadiene either the ketone or the ester group of the dienophile could become the endo-substituent.84 Using FeCl2I as the Lewis acid results in an endo exo ratio of >99 1 for the ester group and also complete diastereoselectivity.Asymmetric Diels–Alder reactions using furan as the dienophile are usually diYcult because furan is sensitive to many Lewis acids chiral acrylate esters often react slowly with furan and the adducts often readily undergo the reverse reaction precluding kinetic control of the diastereoselectivity. However 8-phenylmenthyl acrylate 106 has been found to react with furan using titanium or zinc halides supported on silica gel as Lewis acids giving mixtures of endo and exo adducts with reasonable diastereoselecitivities (up to 70% de).85 Hetero-Diels–Alder reactions between the N-glyoxyloyl Oppolzer sultam 107 and either 1-methoxybutadiene or Danishefsky-type 1-methoxy-3-silyloxydienes have been found to be highly diastereoselective when promoted by catalytic Eu(fod)3 (Scheme 37).86,87 However when the diene is changed to 2-(trimethylsilyloxy)furan a Diels–Alder reaction does not Scheme 35 S S+ Ph O– O S S+ Ph O– OH S S+ Ph O– OH THF –78 °C 100% de ZnCl2 DIBAL-H THF –78 °C 100% de 96 DIBAL-H Scheme 36 S OH SH O H OH R3 R2 R1 R1 R3 R2 O Me2AlCl RT 97 98 J.Chem. Soc. Perkin Trans. 1 1999 357–373 365 occur; instead there is addition of the furan to the aldehyde to give a g-substituted butenolide in 90% de.88 In the tandem reaction shown in Scheme 38 the vinyl ether of 2-phenylcyclohexanol 109 first acts as a dienophile in an intermolecular hetero-Diels–Alder reaction with the unsaturated nitroalkene 108 and this is followed by an intramolecular [312] cycloaddition of the adduct with the unsaturated ester portion which is held by a temporary silicon tether.89 The product 110 formed in >25 1 dr is the key intermediate in a synthesis of (2)-detoxinine and the same strategy has also been used for a synthesis of (2)-mesembrine.90 Chiral auxiliaries attached to the diene component in Diels– Alder reactions are rather less common.A tartrate-derived dienyl boronate adds to methyl crotonate to give a cyclohexenyl boronate which is then employed in a tandem addition to an aldehyde in 70% ee.91 Dienes with a camphor-derived sulfinyl group at the 2-position give excellent selectivity (>99 1) in addition to N-phenylmaleimide as the dienophile provided that LiClO4 is used as a catalyst however the auxiliary has not been removed from the products.92 An interesting intramolecular Diels–Alder reaction of 111 allows reaction between a furan as the diene and acrylic acid as N O O R O H H O O O OBn O O O O OBn O O H O O O But N S+ O O– Tol Ph N O O O Ph O Ph O O Ph O 99 100 101 102 105 103 104 106 Scheme 37 SO2 N O H O OMe H OMe O Xc + + isomers dr = 91:5:4 Eu(fod)3 CH2Cl2 107 Scheme 38 N+ O Si MeO2C Pri Pri –O O N O Si MeO2C Pri Pri O O OR* Ph O MeAl(OAr)2 –85 °C 59% Ar=2,6-dimethylphenyl dr > 25:1 108 109 110 the dienophile tethered together using 8-aminomenthol as the auxiliary (Scheme 39).93 The reaction proceeds under very mild conditions and by changing the solvent either of the two exoisomers can be produced selectively.These can be separated and give enantiomeric products after cleavage of the auxiliary. The SAMP auxiliary which has already been discussed in Section 2.2.1 has also been used as a chiral auxiliary attached to C-2 of a diene in a hetero-Diels–Alder reaction with N-silylimines giving piperidine-4-ones after hydrolytic workup in moderate to very high enantiomeric excesses.94 a,b-Unsaturated N-acyloxazolidinones which have previously been used as dienophiles can also serve as dipolarophiles in [312] cycloaddition reactions with azomethine ylides.95 The products are chiral disubstituted pyrrolidines and are formed in 56 44 to 80 20 dr. Vinyl sulfoxides are also eVective chiral dipolarophiles in [312] cycloadditions to cyclic nitrones 112 (Scheme 40),96 with the best selectivity being achieved using the (Z)-vinyl sulfoxide 113.The six-membered ring homologue of 112 is also eVective giving products which can be transformed into piperidine alkaloids. The cyclic nitrone 112 also reacts with acrylates of chiral 9-anthrylalcohols as the dipolarophiles,97 but this gives all four possible isomers (two regioisomers each formed as two diastereoisomers) with the best ratio being 70:11:15:4. The [212] cycloaddition of ketenes to imines (the Staudinger reaction) is an important method for the construction of b-lactams and use of either the ketene or the imine as a chiral component has already been extensively investigated. Recent developments include a study of double diastereodiVerentiating reactions where both components are chiral.98 Use of an Evans’ oxazolidinone auxiliary in the ketene component usually dominates the eVect of a stereogenic centre in the imine even when mismatched but its influence can be overcome by using two stereogenic centres in the imine.Use of an N-[bis- (trimethylsilyl)methyl] protecting group on the imine component of this type of reaction has proved beneficial in supressing deprotonation at the a-position.99 Intramolecular [212]-photocycloadditions have been investigated using a chiral auxiliary to form a removable tether between the two components.100 For example the 3-hydroxybutyrate- derived diester 114 undergoes only one regioisomeric mode of cycloaddition (Scheme 41) and the tether can subsequently be removed with sodium methoxide. Intramolecular [212]-photocycloadditions using chiral trimethylsilylallenes as one component result in chirality transfer from the allene to the newly formed cyclobutane in a “self-immolative” fashion,101 Scheme 39 N O O O N O O O H CH2Cl2 23 °C 15 h 96% + other exo-isomer dr = 69:31 hexane 23 °C 15 h 96% dr = 22:78 111 Scheme 40 N+ O– Ph S O p-Tol N O S Ph H H O p-Tol H + Et2O RT 17 days dr = 99:1 112 113 366 J.Chem. Soc. Perkin Trans. 1 1999 357–373 where the silyl group is designed to be easily removed afterwards. The Pauson–Khand reaction is one of the most widely used transition metal mediated cycloaddition reactions and asymmetric versions have been developed using chiral alkoxy groups on either the alkene or alkyne component. By using a cleavable sulfide tether the resulting cyclopentenones can undergo conjugate addition and reductive cleavage to generate quaternary stereogenic centres exemplified by a synthesis of (1)-bcuparenone.102 (Z)-Enol ethers e.g. 116 have been formed using a wide variety of diVerent chiral alcohols as possible auxiliaries and then used in Bradsher cycloaddition reactions to the naphthyridinium salt 115 (Scheme 42).103 Best results are obtained using isosorbide and isomannide enol ethers which give the bridged isoquinoline derivatives 117 in 80% de. 2.7 Other addition reactions The reaction shown in Scheme 43 is interesting in that the acetal chiral auxiliary first directs the formation of one stereogenic centre during the haloetherification step and then the resulting oxonium ion undergoes stereoselective addition of an alcohol to give 118.104 The iodide in 118 can be replaced by a nucleophile and this can then be followed by Grignard reaction at the acetal carbon with retention of stereochemistry giving chiral 1,4- and 1,5-diols after reductive cleavage of the auxiliary.Electrophile-induced cyclisation of alkenes can also be achieved by the reaction with chiral selenyl chlorides in up to 93 7 dr.105 Chiral 1,4-diols have also been prepared with complete stereoselectivity by hydrogenation of exo-alkylidenebutyrolactones containing a menthyl auxiliary followed by hydride reduction.106 Hydrogenation of glucose-derived enol ethers conjugated to a carbonyl group shows diastereoselectivities ranging from 85:15 to 67 33 but the ratios can be improved by fractional crystallisation.107 Scheme 41 O O O O O O O H O O O hn CH2Cl2 RT + isomers dr = 62:16:<1 114 Scheme 42 N N+ OH N N O Me R*O O O OBn O H H Me 80% de 115 116 117 X– Scheme 43 O O Ph Ph O O O Ph Ph I OMe OH OMe 85% dr = 80:6:12:2 I(coll)2PF6 coll = sym-collidine or 2,4,6-collidine 118 Chiral acetals of cyclic a,b-unsaturated ketones undergo Simmons–Smith cyclopropanation with a stereoselectivity which can be tuned up to >98% de by varying the size of alkoxy substituents on the acetal.108 Two groups have reported the asymmetric addition of lithiated 2-methylpropionitrile to chiral alkoxyarene–chromium tricarbonyl complexes in up to 76% de (Scheme 44).109,110 The chiral ether is rather remote for control of the new stereogenic centre but the reactions appear to be under thermodynamic control and so simply reflect the relative stability of the two diasteroisomeric products.Enantiopure arene chromium tricarbonyl complexes are also used in the first synthesis of chiral acetals e.g.120 in which the acetal carbon is the only stereogenic centre (Scheme 45).111 The chromium tricarbonyl unit in 119 eVectively shields one face of an intermediate oxocarbenium ion during nucleophilic addition of the alcohol. Chiral acetals of unsubstituted benzaldehyde can also be prepared by using a trimethylsilyl group in place of the o-methoxy group and removing it with TBAF as the final step. A more complex example also containing an acetal carbon as the stereogenic centre involves reaction of an alcohol with an a-bromoether attached to Boeckman’s camphorderived lactam auxiliary and gives the acetal in 96 4 dr.112 A novel synthesis of biologically important chiral a-aminophosphonates 122 involves the insertion of trimethyl phosphite into the C–O bond of oxazolidines 121 (Scheme 46).113 Inversion of configuration at C-2 suggests that the reaction proceeds via ring opening formation of a mixed phosphite ester followed by addition of the phosphorus atom to an iminium species.2.8 Radical reactions Radical cyclisation of the dehydroalanine derivatives 123 uses ester-based chiral auxiliaries to control the stereoselectivity Scheme 44 O Me Cr(CO)3 fenchyl O Me fenchyl CN 1. Me2C(Li)CN THF –78 °C 2. TFA –78 °C 3. aq. NH3 59% 76% de Scheme 45 Cr(CO)3 OMe OMe OMe Cr(CO)3 OMe OPri OMe H OPri OMe H OMe 1. TiCl4 2. Et3N PriOH 70% 94% de Et2O air hn 100% >95% ee 119 120 Scheme 46 N O Ph R Bn N P O Ph R Bn O OMe H2N P(OH)2 R O 3 P(OMe)3 SnCl4 1. H2 Pd 2. HCl 3 S:3 R = 86:14 to 100:0 121 122 2 J.Chem. Soc. Perkin Trans. 1 1999 357–373 367 (Scheme 47).114 The best diastereoselectivity of 4 1 is obtained using 8-phenylmenthyl esters with the menthyl esters being less eVective (1.75 1). An alternative approach to the synthesis of similar chiral 2-pyrrolidinones is an intermolecular allylation of a pyrrolidinone radical containing a substituted 1-phenylethyl group on the nitrogen atom as the chiral auxiliary; however the selectivities obtained so far are rather low.115 Radical cyclisation of acyl radical equivalents has been achieved using the vinyl bromides 124 shown in Scheme 48 where hydrogen atom transfer to the initially formed vinyl radical creates an acetal-carbon-centred radical which subsequently undergoes cyclisation onto the alkene.116,117 Rigid dioxanyl radicals (e.g.from 124) which are constrained to a chair conformation give high diastereoselectivities whereas simple chiral dioxanes formed from C2-symmetric diols are ineVective. Aldol-type products can be formed by the intermolecular addition of an alkoxy-centred radical (in a Barton-type procedure) bearing a glucal-derived chiral auxiliary to 2-nitropropene followed by hydrolysis of the resulting nitro thioether group.118 A particularly simple synthesis of chiral g-butyrolactones 126 involves reaction of acrylate or crotonate esters of N-methylephedrine 125 with ketones mediated by SmI2 (Scheme 49).119 Initial formation of a ketyl radical by oneelectron transfer to the ketone is followed by coupling with the ester 125 and cleavage of the auxiliary to give the chiral products 126 in one step and in high enantioselectivities (mostly 93–99% ee).An unusual approach to asymmetric synthesis involves the intermolecular reaction of a long-lived chiral radical with another radical (Scheme 50).120 Here the conformationally rigid nitroxyl radical 127 reacts with the benzylic radical generated from the hydrazine 128 to give 129 in 92 8 dr. Nitroxyl radicals with greater conformational mobility were initially studied but they are much less selective. Scheme 47 N O Br Bn O OR* N O Bn CO2R* Bu3SnH AIBN PhH 80 °C * dr = 4:1 69% 123 R* = 8-phenylmenthyl Scheme 48 O O H Ph EtO2C EtO2C Br O O EtO2C EtO2C H Ph hn 100% de 124 Scheme 49 R3 O Me O Ph NMe2 O O R1 R2 R3 O R1 R2 2 SmI2 ButOH + THF 126 mostly 93-99% ee 125 2.9 Miscellaneous uses of chiral auxiliaries The use of amino acids and their derivatives as chiral auxiliaries in a wide variety of asymmetric reactions has been reviewed.121 Synthesis of a-amino acids using reaction of a chiral electrophilic glycine equivalent with Grignard reagents has been reported with moderate diastereoselectivities ranging from 2.8 1 to 5.5 1.122 a-Aryloxyesters 131 can be prepared by substitution reaction of esters 130 formed from racemic a-haloacids and a lactate-derived auxiliary (Scheme 51).123 The two diastereoisomers of 130 (or a corresponding intermediate) react with the aryloxide at very diVerent rates with epimerisation of the slower reacting isomer.The allyl selenenimides 133 prepared by nucleophilic substitution of the chloroselenuranes 132 with protected lithium amides undergo a highly selective [2,3]sigmatropic rearrangement with chirality transfer from the stereogenic selenium atom to give the chiral protected allylic amines 134 via an endo transition state (Scheme 52).124 Enantiomerically pure allyl sulfoximines do not undergo significant rearrangement at room temperature however SN29 reaction with butylcopper gives alkenes in high enantioselectivity from the (Z)-sulfoximines where the stereoselectivity is controlled by a chiral leaving group.125 The corresponding (E)-isomers react much less selectively.Other rearrangements controlled by chiral auxiliaries include a vinyl epoxide attached to an Evans’ acyl oxazolidinone which rearranges to the dihydrofuran on heating to 180 8C.126 The stereoselectivity is modest (e.g. 57:33:6:4) but the diastereoisomers can be separated by flash chromatography.Enolate Claisen rearrangements can be controlled by an h4-diene iron- (tricarbonyl) unit as the chiral auxiliary with the newly formed C–C bond developing anti to the Fe(CO)3 substituent.127 Formation of enantiomerically pure 1,3-dithiane 1-oxide by Scheme 50 OH N O NHNH2 OH N O + PbO2 PhMe –78 °C 80% 127 128 129 dr 92:8 Scheme 51 R O N O X O Me R O N O OAr O Me ArO–Li+ THF RT 76-88% dr 95:5 to 99:1 130 131 Scheme 52 O Se R Cl OH Se R R NHR1 R1N R1NHLi [2,3] THF 0 °C 90-93% ee (R1 = Ts Ph2PO) 132 133 134 368 J. Chem. Soc. Perkin Trans. 1 1999 357–373 direct asymmetric oxidation of 1,3-dithiane itself occurs with low selectivity however attachment of a chiral auxiliary derived from camphor or diacetone glucose at the 2-position allows highly diastereoselective oxidations.128 Interestingly the best selectivities are observed using Sharpless oxidation conditions but the same isomer is obtained irrespective of which enantiomer of diethyl tartrate is used.The auxiliary is then removed by base-catalysed hydrolysis. Preparation of the chiral phosphinate ester 137 which has a stereogenic phosphorus atom can be achieved with complete diastereoselectivity by reaction of diacetone glucose 136 with the racemic chloride 135 (Scheme 53).129 Chiral phosphinous esters can be formed similarly and phosphines and phosphine oxides can be formed from the products with inversion of con- figuration by displacement of the auxiliary with organolithium reagents. 3 Chiral reagents 3.1 Chiral bases The asymmetric deprotonation of cyclohexene oxide 138 was one of the first examples of the use of chiral lithium amide bases and Singh and co-workers have revisited this reaction comparing a variety of bases derived from phenylglycine (e.g.139) which is available as both enantiomers at similar cost (Scheme 54).130 This work has also been extended to the enantioselective deprotonation of 4-substituted cyclopentene oxides in order to prepare prostaglandin intermediates. O’Brien and Poumellec have also used the base 139 for the deprotonation of dioxygenated cyclohexene oxides in up to 92% ee.131 exo- Norbornene oxide 140 undergoes deprotonation–rearrangement to give 141 in up to 52% ee using chiral lithium amide bases or an organolithium in the presence of (2)-sparteine (Scheme 55).132 If the two endo-protons are replaced by methyl groups then rearrangement of the epoxide to a ketone occurs instead in 35% ee.133 Enantioselective deprotonation of medium ring meso-epoxides using organolithium reagents and (2)- sparteine results in bicyclic alcohols rather than simple ring opening of the epoxide in up to 83% ee for the nine-membered ring.134 The asymmetric deprotonation of 4-substituted cyclohexanones has been previously studied by several groups and by Scheme 53 O O O OH O O P Ph Bn O Cl P Ph Bn O OR* DABCO PhMe (±)- + –20 to +20 °C 135 136 137 100% de Scheme 54 O OH N MeN Li Ph THF 0 °C to RT 80% ee 138 139 Scheme 55 O OH R2NLi or 24-52% ee RLi–(–)-sparteine 140 141 examining the NMR spectra of several analogues of a phenylalanine derived lithium amide base together with a comparison of their enantioselectivities Koga and co-workers have proposed an eight-membered cyclic transition state for this reaction.135 Several groups have reported on the asymmetric deprotonations of various arene chromium tricarbonyl complexes.Deprotonation at the benzylic position of the isobenzofuran complex 142 using the lithium amide 143 followed by reaction with benzophenone occurs in 99% ee (Scheme 56),136 and in 75–80% ee using a simpler base and several diVerent electrophiles. 137 Chromium tricarbonyl complexes of benzyl ethers are also deprotonated using 143 with very high enantioselectivities. 138 Benzaldehyde acetal complexes can be deprotonated at the ortho-position using either a chiral lithium amide 136 or a chiral organolithium reagent prepared from 8-phenylmenthyl chloride.139 Beak and co-workers have extended their work on the enantioselective deprotonation of N-Boc-benzylamines using organolithium reagents in the presence of (2)-sparteine to the p-methoxyphenyl-protected example 144 shown in Scheme 57.140 Alkyl triflates give higher enantioselectivities than alkyl halides and the p-methoxyphenyl group can then be removed oxidatively to give the N-Boc-protected primary amines 145.By reacting with Me3SnCl as the electrophile followed by transmetallation of the product with BuLi products with the opposite configuration can also be accessed. Carboxylation of deprotonated benzylamine 144 with carbon dioxide gives an a-amino acid derivative in 96 4 er whereas changing the electrophile to methyl chloroformate gives the corresponding methyl ester of the opposite enantiomer.141 Alternative electrophiles can also be used to give b- and g-amino acid derivatives.The cinnamylamine derivative 146 undergoes a similar enantioselective deprotonation and reaction with electrophiles usually occurs at the g-position to give the enecarbamates 147 (Scheme 58).142 Again the opposite enantiomer of 147 is accessible via the intermediate g-stannylated compound. Enantioselectivities of these types of reactions involving chiral benzyllithium species complexed with sparteine can be aVected by equilibration and also by kinetic resolution in reactions with limiting quantities of the electrophile.143 Alternatives to the naturally-occurring sparteine as a chiral Scheme 56 Cr(CO)3 O NLi LiN Ph Me Ph Me Ph Ph Cr(CO)3 O CH(OH)Ph2 2. Ph2CO LiCl THF –100 °C 1. 70% 99% ee 142 143 Scheme 57 N Boc Ph p-MeOC6H4 HN Boc Ph R 1.BuLi–(–)-sparteine 2. ROTf 3. ceric ammonium nitrate 144 145 93-96% ee Scheme 58 Ph N p-MeOC6H4 Boc Ph N Ar Boc E 1. BuLi–(–)-sparteine 2. E+ (= MeOTf R-X Me2C=O TMSOTf) 92-98% ee 146 147 J. Chem. Soc. Perkin Trans. 1 1999 357–373 369 solvating agent are the synthetic cyclic ureas (e.g. 149) prepared by Koga and co-workers.144 Reaction of the lithium enolate of tetralone 148 with methyl iodide in the presence of 149 gives 150 in 92% ee (Scheme 59). The enantioselectivity is aVected by the base used to generate the enolate being higher for LiHMDS than LDA or LiTMP and it is also improved by the addition of HMDS. The deprotonation–cyclisation of O-tosylketoximes using chiral amine bases has been reported.145 The O-tosylketoximes are formed from b-ketoesters which allows the doubly-activated a-position to be deprotonated by tertiary amine bases.2HAzirines are formed in up to 80% ee using quinidine as the chiral base which was found to be the most eVective among several naturally occurring chiral amines tested. 3.2 Miscellaneous uses of chiral reagents Asymmetric aldol reactions of acetate enolate equivalents attached to chiral auxiliaries often use alkylthio groups as “dummy” substituents at the a-position to enhance stereoselectivity and the same strategy has been used for aldol reactions using chiral reagents. In Scheme 60 an achiral dithiolane ketene acetal 151 undergoes an aldol reaction promoted by the oxazaborolidine 152 and subsequent reductive removal of the dithiolane gives the acetate aldol 153.146 A similar strategy can be applied to (methylthio)acetic acid involving formation of an intermediate chiral boron enolate with terpene-derived ligands on the boron atoms.147 Addition of lithium enolates of esters to imines mediated by a chiral C2-symmetric ether 154 results in b-lactams 155 in up to 90% ee (Scheme 61).148 Addition of extra lithium amide base over that required to generate the enolate improves the enantioselectivity and the chiral ligand 154 also enhances the reactivity of the enolate complex at low temperatures.Another addition to imines involves chiral menthone-derived boron enolates of a-halothioesters where the products can subsequently be cyclised to give aziridines in 94–99% ee.149 Lithium enolates this time of aryl methyl ketones are also involved in asymmetric Michael addition to doubly-activated electrophiles promoted by a chiral chelating amine in up to 94% ee.150 Scheme 59 O O Me N N Me BnO Ph Me OBn Ph O 1.LHMDS PhMe 2. Ligand 149 HMDS (4 equiv.) 3. Me-I (10 equiv.) 48 h 148 150 149 = 92% ee Scheme 60 S S OTMS OEt TsN B H O Pri R OEt OH O RCHO 151 152 (1 equiv.) CH2Cl2 –78 °C + 83-99% ee 1. 2. Ni2B - H2 153 Scheme 61 R R O OLi Et Et N R1 PMP N R R PMP O R1 Ph OMe MeO Ph + PMP = p-MeOC6H4 lithium amide PhMe 75-90% ee 154 155 Addition of organolithium reagents to carbonyl groups in the presence of chiral ligands has been one of the longeststudied processes in asymmetric synthesis. New examples include the addition of lithium trimethylsilylacetylide to cyclohexanones using proline-derived chelating amines.151 The chiral ether 154 (which was used above for addition of an enolate to an imine) has also been used to control the ring opening of cyclohexene oxide by phenyllithium in moderate enantioselectivity of 43%.152 A more unusual reaction of organolithium reagents is the addition to styrenes e.g.2-methoxystyrene 156 (Scheme 62) in the presence of (2)-sparteine where the electrophilic trapping with CO2 is the enantioselective process.153 Other 2-substituted styrenes and styrene itself are less eVective. Addition of organolithium reagents to prochiral arene chromium tricarbonyl complexes is mediated by chiral ligands and is followed by electrophilic trapping to give substituted cyclohexadienes (Scheme 63).154 The chiral ether 154 again features and is the best ligand among four that were investigated. Other types of organometallic reagents used with chiral ligands include organocerium reagents in the presence of TADDOLs (tetraaryl-1,3-dioxolane-4,5-dimethanols) which add to aldehydes in up to 92% ee.155,156 Asymmetric reactions of diethylzinc are usually additions to aldehyes with catalytic amounts of chiral ligands.However the addition of diethylzinc to imine 155 shown in Scheme 64 uses a stoichiometric amount of the chiral aziridine 156 as the ligand forming the amine 157 in 94% ee.157 Another addition of organozinc reagents to imines (Scheme 65) uses an allylzinc reagent and a lithiated bis-oxazoline ligand 158 (R = Pri) previously used by the same group for addition of allylzinc reagents to cyclopropenone acetals.158 Addition to the acyclic (E)-N-phenyl benzaldehyde imine gives little enantioselectivity but much better results are obtained with cyclic imines which are geometrically constrained to the (Z)-geometry.A very similar lithiated bis-oxazoline ligand to 158 (R = Ph) has also been used by Hanessian and Yang for the addition of allylzinc reagents to oximes of a-ketoesters.159 The bis-oxazoline 159 (which is lithiated to form 158) has also been used as a chiral ligand for a zinc Lewis acid in the radical allyl transfer reaction shown in Scheme 66.160 Better enantioselectivities are observed in this reaction when the intermediate radical is generated by Michael addition rather than bromine atom abstraction. An intermediate N-sulfonylimine undergoes addition of organoaluminium reagents formed from trimethyl- or triethylaluminium and binaphthol in 52–62% ee.161 Six diVerent ligands have been investigated for the asymmetric addition of lithium dimethylcuprate to chalcone in order to tune the enantioselectivity which is 90% in the best case.162 The same Scheme 62 OMe OMe Bu CO2H 1.BuLi (–)-sparteine cumene –95 °C 2. CO2 then H+ 72% ee 156 Scheme 63 Cr(CO)3 O N Ph OMe MeO Ph N O R RLi PhMe –78 °C 1. 2. propargyl bromide HMPA 154 65-93% ee 370 J. Chem. Soc. Perkin Trans. 1 1999 357–373 ligand also mediates the addition of magnesium dibutylcuprate to cyclohexenone in 96% ee. The use of metal hydride reagents bearing a chiral ligand for the asymmetric reduction of ketones has been a popular approach for many years however reduction of simple straightchain aliphatic ketones is often diYcult. A new chiral borohydride reagent 160 where the ligand is derived from b-pinene shows better selectivity for the reduction of octan-2-one than Midland’s similar benzyloxy reagent.163 The neutral borane (1)-B-chlorodiisopinocampheylborane (Ipc2BCl) 161 gives poor selectivities in the reduction of unhindered dialkyl ketones; however reduction of a- and b-hydroxyketones with this reagent is much better (84–92% ee) since initial formation of a borinate allows reduction to occur in an intramolecular fashion.164 The same reagent 161 also reduces diacylaromatic compounds to chiral C2-symmetric diols in >99% ee with only small amounts of the meso-diols being formed.165 Asymmetric reduction using borane together with a chiral oxazaborolidine has previously been applied to many ketones and has been extended to the case of a-alkynylketones which are reduced in 71–98% ee using an excess of the chiral ligand.166 Asymmetric reduction of a C]] N bond in oxime ethers can also be achieved using a chiral borane reagent 162 which is prepared in situ from borane and norephedrine.167 Asymmetric hydroboration of alkenes using pinene-derived reagents has been studied extensively and Brown and coworkers have now reported on a comparison of methods for the synthesis of optically pure isopinocampheylchloroborane (IpcBHCl) and have also compared IpcBHCl with IpcBH2 for the hydroboration of representative alkenes.168 The corresponding bromo-compound IpcBHBr has also been prepared and Scheme 64 Ph N PPh2 O N Bn Me OH Ph HN PPh2 O Et Et2Zn (3 equiv.) 63% 94% ee 155 156 157 Scheme 65 N Li N O O R R N NH + allylZnBr (premixed) 95% ee 158 (R=Pri) Scheme 66 O N R O O Br O N R O O N N O O Ph Ph allylSnBu3 Zn(OTf)2 67-90 % ee 159 B– H NEt2 )2BCl O B H N+ Ph Me BH3 – H Li+ 160 161 162 reacts with alkenes at lower temperatures than does IpcBHCl and often with higher enantioselectivities.169 Asymmetric hydrogen transfer from a chiral tin hydride to a prochiral radical has been achieved using the stannane 163 which incorporates a binaphthyl unit (Scheme 67).170 Although the enantioselectivity is modest the tin hydride 163 can be regenerated with sodium cyanoborohydride with retention of configuration allowing it to be used catalytically and with the same enantioselectivity as for the stoichiometric reaction.The asymmetric a-hydroxylation of 29,49-difluoropropiophenone using a camphorsulfonyl oxaziridine has been optimised from previously used literature conditions including eYcient recycling of the oxaziridine reagent and this has allowed scale-up to the multi-kilo level for the preparation of potential antifungal drugs.171 A new method for asymmetric epoxidation of a,bunsaturated ketones uses molecular oxygen as the oxidant together with diethylzinc and N-methylpseudoephedrine 164 (Scheme 68).172 In order to arrive at the use of 164 35 chiral alcohols were screened together with 8 solvents.The enantioselectivities are mostly good (82–92%) except when the b-substituent on the enone is phenyl (61% ee). A chiral (ethylperoxy) alkoxyzinc species is proposed as the reactive intermediate. The asymmetric aziridination of b-trimethylsilylstyrene using the chiral acetoxyaminoquinazolinone 165 is much more selective than with the analogous reagent where the chiral centre has a bulky alkyl (But) substituent instead of the silyloxy substituent (Scheme 69).173 This diVerence has been accounted for in terms of a preference for the C–O bond to eclipse the C]] N bond of the heterocycle and this is supported by a crystal structure.Asymmetric cyclopropanation of allylic alcohols using a chiral dioxaborolane and Zn(CH2I)2 has been extended to cases where the substrate also contains other alkene double bonds.174 Scheme 67 Sn But H But CO2Me Ph Br H MeO2C Ph But Et3B Et2O –78 °C 52% ee 163 93% Scheme 68 R1 R2 O Ph Me OH NMe2 R1 R2 O O O2 Et2Zn PhMe 0 °C 94-99% >99% de 61-92% ee 164 Scheme 69 N N O Me OTBDMS AcON Ph SiMe3 Ph SiMe3 N Q* H + 165 (= Q*NHOAc) dr = 11:1 J. Chem. Soc.Perkin Trans. 1 1999 357–373 371 In most cases high chemoselectivity for the allylic alcohol is observed with both conjugated and isolated polyenes and in one problematic case a glucose-derived auxiliary was superior to the chiral reagent. Formation of optically active 1,3-diene irontricarbonyl complexes 167 directly from the corresponding prochiral dienes is possible using a chiral irontricarbonyl transfer reagent (Scheme 70).175 The structure of the reagent is presumed to be 166 although it has not been characterised because of its air sensitivity and low stability. Desymmetrisation of meso-substrates is a useful approach to chiral products since unlike resolution of racemic compounds 100% conversion to a single enantiomer is possible at least in principle. The meso-diketone 168 actually exists as a rapidlyequilibrating mixture of enols and formation of the enamine 169 with prolinol occurs with a dr of 3 1 (Scheme 71).176 The mixture can be enriched in the major diastereoisomer by fractional crystallisation or alternatively complete separation is possible by chromatography of the acetates.Tricyclic norbornane-derived meso-anhydrides have previously been desymmetrised by amide formation with methyl prolinate and this approach has been extended to bicyclic anhydrides.177 tert- Butyl prolinate has some practical advantages in this case facilitating separation of the diastereoisomeric products and in the case of a bridged bicyclic anhydride complete diastereoselectivity is observed. Kinetic resolution of secondary alcohols using the chiral acylating agent 171 gives widely varying enantioselectivities (19–84% ee) with diVerent alcohols (Scheme 72) and the alcohol 170 gives much the best results.178 In some cases addition of MeMgBr as a base reverses the enantioselectivity.5 Miscellaneous asymmetric processes An unusual example of absolute asymmetric synthesis (no chiral reagent or catalyst) is shown in Scheme 73 and relies on a Scheme 70 N OMe Ph Fe(CO)3 R2 R1 R2 R1 Fe(CO)3 166 33-64% ee 167 Scheme 71 O O O N OH ( S)-(+)-prolinol PhMe heat dr = 3:1 168 169 Scheme 72 S N S But O But OH OCOBut (±)- hexane Et3N RT 84% ee 171 170 two-component molecular crystal 172.179 Diphenylacetic acid forms achiral crystals but when crystallised with acridine the two-component molecular crystal 172 is chiral and can be produced in either enantiomeric form by seeding methods.Photolysis of a pulverised single crystal of one enantiomeric form then causes decarboxylation and formation of 173 in about 35% ee. 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