Chiral esters, formation

The first attempt to effect the asymmetric cw-dihydroxylation of olefins with osmium tetroxide was reported in 1980 by Hentges and Sharpless.54 Taking into consideration that the rate of osmium(VI) ester formation can be accelerated by nucleophilic ligands such as pyridine, Hentges and Sharpless used 1-2-(2-menthyl)-pyridine as a chiral ligand. However, the diols obtained in this way were of low enantiomeric excess (3-18% ee only). The low ee was attributed to the instability of the osmium tetroxide chiral pyridine complexes. As a result, the naturally occurring cinchona alkaloids quinine and quinidine were derived to dihydroquinine and dihydroquinidine acetate and were selected as chiral... 

In addition, three types of lipophilic conjugates have been found in pyrethroid metabolism studies (Fig. 4). They are cholesterol ester (fenvalerate) [15], glyceride (3-PBacid, a common metabolite of several pyrethroids) [16], and bile acid conjugates (fluvalinate) [17]. It is noteworthy that one isomer out of the four chiral isomers of fenvalerate yields a cholesterol ester conjugate from its acid moiety [15]. This chiral-specific formation of the cholesterol ester has been demonstrated to be mediated by transesterification reactions of carboxylesterase(s) in microsomes, not by any of the three known biosynthetic pathways of endogenous cholesterol esters... 

Perlmutter used an oxymercuration/demercuration of a y-hydroxy alkene as the key transformation in an enantioselective synthesis of the C(8 ) epimeric smaller fragment of lb (and many more pamamycin homologs cf. Fig. 1) [36]. Preparation of substrate 164 for the crucial cyclization event commenced with silylation and reduction of hydroxy ester 158 (85-89% ee) [37] to give aldehyde 159, which was converted to alkenal 162 by (Z)-selective olefination with ylide 160 (dr=89 l 1) and another diisobutylaluminum hydride reduction (Scheme 22). An Oppolzer aldol reaction with boron enolate 163 then provided 164 as the major product. Upon successive treatment of 164 with mercury(II) acetate and sodium chloride, organomercurial compound 165 and a second minor diastereomer (dr=6 l) were formed, which could be easily separated. Reductive demercuration, hydrolytic cleavage of the chiral auxiliary, methyl ester formation, and desilylation eventually led to 166, the C(8 ) epimer of the... 

Abstract It is well known that spontaneous deracemization or spontaneous chiral resolution occasionally occurs when racemic molecules are crystallized. However, it is not easy to believe such phenomenon will occur when forming liquid crystal phases. Spontaneous chiral domain formation is introduced, when molecules form particular liquid crystal phases. Such molecules possess no chiral carbon but may have axial chirality. However, the potential barrier between two chiral states is low enough to allow mutual transformation even at room temperature. Therefore the systems are essentially not racemic but nonchiral or achiral. First, enhanced chirality by doping chiral nematic liquid crystals with nonchiral molecules is described. Emphasis is made on ester molecules for their anomalous behavior. Second, spontaneous chiral resolution is discussed. Three examples with rod-, bent-, and diskshaped molecules are shown to give such phenomena. Particular attention will be paid to controlling enantiomeric excess (ee). Actually, almost 100% ee was obtained by applying some external chiral stimuli. This is very noteworthy in the sense that we can create chiral molecules (chiral field) without using any chiral species. 

Kinetic resolution of chiral, racemic anhydrides In this process the racemic mixture of a chiral anhydride is exposed to the alcohol nucleophile in the presence of a chiral catalyst such as A (Scheme 13.2, middle). Under these conditions, one substrate enantiomer is converted to a mono-ester whereas the other remains unchanged. Application of catalyst B (usually the enantiomer or a pseudo-enantiomer of A) results in transformation/non-transformation of the enantiomeric starting anhydride ). As usual for kinetic resolution, substrate conversion/product yield(s) are intrinsically limited to a maximum of 50%. For normal anhydrides (X = CR2), both carbonyl groups can engage in ester formation, and the product formulas in Scheme 13.1 are drawn arbitrarily. This section also covers the catalytic asymmetric alcoholysis of a-hydroxy acid O-carboxy anhydrides (X = O) and of a-amino acid N-carboxy anhydrides (X = NR). In these reactions the electrophilicity of the carbonyl groups flanking X is reduced and regioselective attack of the alcohol nucleophile on the other carbonyl function results. 

Fig. 14.49. Trans-selective Iretand-Claisen rearrangements with 1,3-chirality transfer. (DMAP refers to 4-dimethyl-aminopyridine see Figure 6.9 on DHAP-catalyzed ester formation.)...

Oxidation of chiral esters of phenylacetic acids. These esters can be converted into acetates of mandelic esters by oxidation with DDQ in acetic acid. The reaction is diastereoselective when carried out on esters of chiral alcohols, of which 8-phenylmenthol is the most useful. The presence of substituents on the phenyl group has slight effect on the diastereoselectivity, which depends on formation of a donor-acceptor complex between the substrate and the quinone with removal of a hydrogen atom. The acetoxy group then enters from the opposite, more bulky face. 

A new diastereoselective and enantioselective synthesis of a-amino-y-oxo acid esters has been reported involving the alkylation of enamines with acyliminoacetates (78). The stereocontrol is attributed to formation of a Diels-Alder like transition state (79). Ring opening of the adduct leads to a zwitterion or alkylated enamine, hydrolysis of which gives the single diastereoisomer (80 de > 96%)174 (Scheme 71). The use of a chiral ester [R = ( + )- or ( —)-menthyl or (—)-8-phenylmenthyl] converted this process into an enantioselective reaction (de and ee 24-67%). Since the reaction proceeds with complete anti-diastereoselectivity the two stereoisomers, enantiomeric at the two new stereogenic centres, could readily be separated by fractional crystallization. The main isomer of 80 (X = CH2), obtained in 80% yield, was shown to have the (l S, 2R)-configuration174. 

Asymmetric alkylation of esters. HMPT tias a marked influence on the asymmetric alkylation of enolates of chiral esters, such as the propionates 1, where R is a derivative of (+ )-camphor. A typical example is shown in equation (I). The esters are deprotonated with lithium cyclohexylisopropylamide (LICA) cither in THE (A) or in THF/HMPT (B). In the first case, alkylation with benzyl bromide results mainly in (2S)-2 in the second case, formation of (2R)-2 is markedly favored The effect of HMPT is considered to result, at least in part, from preferential formation of the (E)-enolate of 1. 

Of great importance in peptide chemistry are the f-butyl, benzyl and substituted benzyl es-ters. 226 They are more stable to acids than the corresponding urethanes. Benzyl and substituted benzyl esters can be prepared by azeotropic esterification with the respective benzyl alcohol, by activating the carboxy group, e.g. with dicyclohexylcarbodiimide (DCC) or by reacting a carboxylate with a benzyl halide (Scheme 65). The latter 5N2-type ester formation is particularly efficient if cesium carbox-ylates are employed. Under the conditions required for this reaction the racemization of a-chiral car-... 

Notably, this latter reaction proceeded with 92% ds and tolerates the ketone functionality at C5 of the aldehyde. An alternative approach to C2-C3 bond formation hoped for substrate control in uniting chiral ester enolate 207 with chiral aldehydes 208 and 209. However, this led to a non-selective reaction in each case... 

New asymmetric reactions utilizing tartaric acid esters as chiral auxiliaries (formation of N- and A,0-heteroeyeles by nucleophilic addition of iminoderivatives or 1,3-dipolar cycloaddition of nitrile oxides and nitrones) 03SL1075. 

By far the commonest reaction used in kinetic resolution by enzymes is ester formation or hydrolysis. Normally one enantiomer of the ester is formed or hydrolysed leaving the other untouched so one has the easy job of separating an ester from either an acid or an alcohol. There are broadly two kinds of enzymes that do this job. Lipases hydrolyse esters of chiral alcohols with achiral acids such as 119 while esterases hydrolyse esters of chiral acids and achiral alcohols such as 122. Be warned this definition is by no mans hard and fast If the unreacted component (120 or 123) is wanted, the reaction is run to just over 50% completion, to ensure complete destruction of the unwanted enantiomer, while if the reacted component (121 or 124) is wanted it is best to stop short of 50% completion so that little of the unwanted enantiomer reacts. 

A general synthesis of a-chiral ketones with essentially 100% ee is based on the utilization of boronic esters. These esters can be prepared by asymmetric hydroboration of prostereogenic olefins and subsequent removal of the chiral auxiliary. Two approaches to a-chiral ketone formation are known ... 

Both enantiomers of binaphthol have found many uses as chiral reagents and catalysts. Thus, they modify reducing agents (e.g., lithium aluminum hydride) for the reduction of ketones to chiral secondary alcohols (Section D.2.3.3.2.) or react with aluminum, titanium or boron compounds to give chiral Lewis acids for asymmetric Diels-Alder reactions (Section D. 1.6.1.1.1.3.) and ene reactions (Section D.I.6.2.). They have also been used as chiral leaving groups in the rearrangement of allyl ethers (Section D.l.1.2.2.) and for the formation of chiral esters with a-oxo acids (Section D. 1.3.1.4.1, and many other purposes. 

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