Enzymatic enantiotopic differentiation

In the 1980 s there was a great increase in the development and use of enzymatic procedures by synthetic chemists.6 Previously regarded more as scientific curiosities of limited scope than of practical utility, biological-chemical transformations are now used regularly by synthetic chemists. The ability to induce optical activity in molecules where none existed before is the most useful property of these chiral catalysts. Hydrolase enzymes are generally preferred over other kinds of enzymes for transformations of this nature because they are more easily handled and do not require cofactors for activity. In cases where enantiotopic differentiation between ester functions is desired, prochiral meso diesters are more efficient substrates than racemic esters. In the former case it is possible for all starting material to be converted into a single enantiomer, whereas in the latter example only enzymatic resolution is possible. 

EEAC has been used successfully in other enantiotopic differentiations. Johnson, et al.17 have reported that diester 3 can be readily transformed into hydroxy acetate 4 via this enzymatic process in 98% e.e. and an 80% chemical yield. Similarly, hydroxy acetate 6 was prepared from its parent diester 5 by Pearson, et al.18 in 100% e.e., although 39% yield (50-55% recovered starting material). The enzyme also appears effective on 4-substituted cis-3,5-diacetoxycyclopentenes as Danishefsky19 demonstrated with the conversion of 7 into 8 in 95% yield and 95% e.e. Finally, the successful enantioselective hydrolysis of 9 into 10 (77%, 92% e.e.) extends the range of useful EEAC substrates to acyclic cases.20... 

Polypropionate chains with alternating methyl and hydroxy substituents are structural elements of many natural products with a broad spectrum of biological activities (e.g. antibiotic, antitumor). The anti-anti stereotriad is symmetric but is the most elusive one. Harada and Oku described the synthesis and the chemical desymmetrization of meso-polypropionates [152]. More recently, the problem of enantiotopic group differentiation was solved by enzymatic transesterification. The synthesis of the acid moiety of the marine polypropionate dolabriferol (Figure 6.58a) and the elaboration of the C(19)-C(27) segment of the antibiotic rifamycin S (Figure 6.58b) involved desymmetrization of meso-polypropionates [153,154]. 

Enzyme-catalyzed reactions can provide a rich source of chiral starting materials for organic synthesis.2 Enzymes are capable of differentiating the enantiotopic groups of prochiral and mew-compounds. The theoretical conversion for enzymatic desymmetrization of mew-compounds is 100% therefore enzymatic desymmetrization of mew-compounds has gained much attention and constitutes an effective entry to the synthesis of enantiomerically pure compounds. 

Desymmetrization of an achiral, symmetrical molecule through a catalytic process is a potentially powerful but relatively unexplored concept for asymmetric synthesis. Whereas the ability of enzymes to differentiate enantiotopic functional groups is well-known [27], little has been explored on a similar ability of non-enzymatic catalysts, particularly for C-C bond-forming processes. The asymmetric desymmetrization through the catalytic glyoxylate-ene reaction of prochiral ene substrates with planar symmetry provides an efficient access to remote [28] and internal [29] asymmetric induction (Scheme 8C.10) [30]. The (2/ ,5S)-s> i-product is obtained with >99% ee and >99% diastereoselectivity. The diene thus obtained can be transformed to a more functionalized compound in a regioselective and diastereoselective manner. 

D. Breitgoff, K. Laumen, M.P. Schneider, Enzymatic differentiation of the enantiotopic hydroxymethyl groups of glycerol synthesis of chiral building blocks, 1. Chem. Soc. Chem. Commun. (1986) 1523-1524. 

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