Biocatalytic Strategies for the Preparation of Chiral Building Blocks in 100% Chemical and Optical Yield from Racemates

Abstract

Driven by the increased demand for chiral drugs in enantiomerically pure form following the release of new FDA´s marketing guidelines, the search for novel methods for EPC-syntheses is a major topic in contemporary organic synthesis [ 1 ]. In this context, the use of biocatalysts has found widespread application in preparative organic chemistry over the last decade [ 2 ]. From the two principles of biocatalytic reactions where chiral molecules are involved, i.e. (i) desymmetrization of meso- and prochiral compounds [ 3 , 4 ] and (ii) kinetic resolution of racemates [ 5 ], the latter is astonishingly dominant in number of applications (~1:4) [ 6 ], which is probably due to the fact that meso- and prochiral substrates are less easily synthesized than racemates. Despite its widespread application, kinetic resolution is impeded by several inherent disadvantages for practical applications, in particular on an industrial scale. After all, it should be kept in mind that an ideal resolution process should provide a single enantiomeric product in 100 % yield. The most obvious drawbacks are as follows: (i) The theoretical yield of each enantiomer can never exceed a limit of 50 %, (ii) separation of the formed product from the remaining substrate may be laborious, in particular for those cases, where simple extraction or distillation fails and chromatographic methods are required [ 7 ]. (iii) In the majority of processes, only one stereoisomer is desired and there is little or no use for the other. In some rare cases, the unwanted isomer may be used through a separate pathway in an enantio-convergent fashion, but this requires additional labour and a highly flexible synthetic strategy [ 8 ]. (iv) For kinetic reasons, the optical purity of substrate and/or product is depleted at the point, where separation of product and substrate is most desirable from a preparative standpoint - i.e. 50 % conversion