Enantiotopic ester groups

PLE) transforms the meso substrate into chiral compound 5 with >98% te. This en/yme is capable of differendating between the two enantiotopic ester groups on the prochiral carbon atom and hydrolyzing only one of them to a carboxylic acid. Maximum enan-tioselectivity is achieved by carrying out the reaction in 25% aqueous DMSO solution at 35 C. 

Many developments have come from Corey s laboratories in the lactacystin area since the synthesis described above.24 One strategy we have not mentioned before is the use of an enzyme, pig liver esterase (chapter 29) in the selective hydrolysis of one of two enantiotopic ester groups in the malonate 161. An MeS group is used to block enolisation and prevent racemisation of the product 162. The mono ester 162 is initially formed in 67% ee improved by one crystallisation of the quinine salt to 95% ee. The pyrrolidine ring 164 is made in an unusual way by first forming the amide 163 and then cyclising the diester by carbonyl condensation. The new chiral centre in 164 is not controlled but disappears in the next step. 

I, 2-position, seem to be less appropriate substrates for pig liver esterase (33-39 and 41-43). Finally, it seems noteworthy that transition metal complexes containing enantiotopic esters groups are also amenable to a highly selective pig liver esterase-catalyzed hydrolysis (71). Cyclic monoesters of Table 11.1-1, which can be obtained with other hydrolases as such or of opposite configuration, are contained in Tables... 

Hydrolytic enzymes such as esterases and Upases have proven particularly useful for asymmetric synthesis because of their abiUties to discriminate between enantiotopic ester and hydroxyl groups. A large number of esterases and Upases are commercially available in large quantities many are inexpensive and accept a broad range of substrates. 

Desymmetrization of prochiral cyclic anhydrides In the presence of the chiral nucleophilic catalyst (e.g. A, Scheme 13.1, top) one of the enantiotopic carbonyl groups of the prochiral (usually meso) cyclic anhydride substrate is selectively converted into an ester. Application of catalyst B (usually the enantiomer or a pseudoenantiomer of A) results in generation of the enantiomeric product ester. Ideally, 100% of one enantiomerically pure product can be generated from the starting anhydride. No reports of desymmetrizing alcoholyses of acyclic meso anhydrides appear to exist in the literature. 

As exemplified in Scheme 13.4, attack of the nucleophile methanol occurs uniformly at one or the other of the two enantiotopic carbonyl groups of the meso-anhydride (affording the hemi-esters 10 and mt-10, respectively), depending on whether (—)-quinine (2) or (+)-quinidine (3) is employed as catalyst. 

Enantiotopically selective ester hydrolysis can also be achieved enzymatically (Table 8). Eiflier one ester group in a me.ro-diester (103)-(1(M>) or one acetate in a me.m-diacetate (107) 111) are saponified with PLE or other lipases. In favorable cases enzymatic acylation and deacylation are stereochemically complementary and may thus be combined to gain access to bodi enantiomers, as illustrated by the example in Table 9. ... 

Construction of the enantiomerically pure cyclopentane unit for 161 hinged on the ability of an enzyme to react preferentially with one of two enantiotopically related functional groups. To this end, the reaction of the meso diester 261 with commercially available pig liver esterase resulted in almost exclusive hydrolysis at the 1/ ester group to afford the mono ester 262 in 92% yield and >99% ee. Reduction to the alcohol was accomplished via the intermediate acid chloride, which was then cyclized to the lactone 263. Oxidative ring opening followed... 

Identify relationships within the molecule. For example, once you have identified a plane of symmetry in a molecule, you might decide that two ester groups are enantiotopic. Enantiotopic is... 

Reduction of the achiral ketodiester 139 gives the racemic lactone 140. Hydrolysis of both ester groups then gives the again achiral hydroxydicarboxylate 141. This compound is prochiral and the two C02 groups are enantiotopic. If one could be protonated selectively by an enantiomerically pure acid, one enantiomer of the monoacid would be formed. This sounds like an improbable event. 

Intramolecular cyclopropanations with unsaturated diazo ketones have also been reported. Furthermore, enantioselective cyclopropanation with diazomethane can be achieved in up to 75% ee. In detailed mechanistic discussions, a copper(I) species, complexed with only one semicorrin ligand, and formed by reduction and decomplcxation, is suggested as the catalytical-ly active species, cisjtrans Stereoselection and discrimination of enantiotopic alkene faces should take place within a copper-carbene-alkene complex25-54"56. According to these interpretations, cisjtrans selectivity is determined solely by the substituents of the alkene and of the diazo compound (especially the ester group in diazoacetates) and is independent of the chiral ligand structure (salicylaldimine or semicorrin)25. 

In a second set of examples, cyclic substrates containing two enantiotopic allylic acetates imdergo enantioselective substitution (Equations 20.51 and 20.52). Tliese reactions have been conducted with palladium catalysts, particularly those of Trost. In this case, the palladium catalyst selects for reaction at one of two ester groups of an achiral meso substrate. Reaction at the two esters generates enantiomeric products. This approach has been used to generate many natural products (for one example, see Equation 20.52), carbonucleosides (for one example, see Equation 20.53), and other optically active cyclic materials for further synthetic applications. 

A variant on this approach is to incorporate the enantiotopic alkenes into a five-membered ring such as a cyclopentadiene. 3-Hydride elimination is then obviated, as a if-allyl complex 5.130 is formed after insertion, which may be intercepted by an added nucleophile, such as acetate (Scheme 5.39). Other nucleophiles, including carbon nucleophiles can also be used to intercept the tt -allyl intermediate (see Section 9.2.9). This chemistry was used in a synthesis of capnellene 5.137 (Scheme 5.40). The T]p-allyl intermediate 5.130 was intercepted with a functionalized malonate nucleophile 5.132. The malonate was used to construct the third five-membered ring of the natural product while one ester group was removed by Krapcho... 

The most important technical applications of catalytic hydrolysis and acylation involve technical enzymes, as used in food processing, washing powders, or derace-misations. Especially the latter application has also found significant application in chemical synthesis. The kinetic resolution of chiral, racemic esters, anhydrides, or alcohols relies on the faster conversion of only one substrate enantiomer by the chiral catalyst, whereas the other enantiomer ideally remains unchanged. A special case within kinetic resolutions is the desymmetrization of prochiral mexo-compounds like mera-anhydrides (2) or meso-diols, (5) that requires a selective conversion of one of the two enantiotopic functional groups (carbonyl or OH-group, Scheme 7.1). 

One can also compare faces of a molecule in the same way as groups, since the comparison actually applies to environments. Thus, the two faces of the carbonyl groups of aldehydes, unsymmetrical ketones, esters, and other acid derivatives are enantiotopic. Reaction at the two faces by a chiral nucleophile will take place at different rates, resulting in asymmetric induction. 

The most common types of lipids are esters of glycerol. Glycerol is just propane-1,2,3-triol but it has interesting stereochemistry. It is not chiral as it has a plane of symmetry, but the two primary Oh[ groups are enantiotopic (Chapter 16), If one of them is changed—hy esterification, for example—the molecule becomes chiral. Natural glycerol phosphate is such an ester and it is optically active. 

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