Update 1 of: Enantioselective enzymatic desymmetrizations in organic synthesis.

Abstract

During the recent past years, tremendous efforts have been made to establish enantioselective routes for the preparation of enantiomerically pure compounds due to their importance in the pharmaceutical, agricultural, and food industries. This is reflected in the fact that the sales of single-enantiomer small-molecule drugs has reached c. US $10 billion in 2002.1 Moreover, the FDA has become increasingly reluctant to permit the introduction of additional racemic drugs, as these therapies are by definition saddled with 50% of chemical ballast.2 Enzymes are nowadays widely recognized among the most active and selective catalysts for the preparation of optically active compounds.3 Some of the factors that account for this popularity are (1) They are chemo-, regio-, and stereoselective, and environmentally friendly. (2) Because of the mild conditions under which they operate, enzymatic reactions are affected to a lesser extent by side reactions (viz. isomerization, racemization, epimerization, and rearrangement of molecules) as compared to nonenzymatic processes. Nevertheless, organic chemists have been traditionally reluctant to employ biocatalysts in their syntheses. This is mainly because, in their natural form, most of the enzymes are very sensitive catalysts that exert their activity mainly in aqueous solution. Moreover, their handling requires some biochemistry knowledge. However, some recent advances carried out in the biocatalysis field have “approached” enzymes to organic synthesis: (a) They can operate in nonaqueous media accepting a broad range of substrates;4 (b) immobilization techniques increase their stability and simplify their handling.5 Thus, many enzymes can now be acquired and used as any other chemical.

Stereoselective biotransformations can be grouped into two main different classes: asymmetric synthesis and kinetic resolution of racemic mixtures (KR). Conceptually, they differ from each other in the fact that while asymmetric synthesis implies the formation of one or more chirality elements in a substrate, a KR is based on a transformation, which, subsequently, makes easier the separation of the two enantiomers of the racemic substrate. This fact involves a practical difference: in a kinetic resolution only half of the starting material is used. When only one enantiomer of a substrate is required this fact constitutes a disadvantage of KRs and different approaches have been developed to overcome this limitation.6 The one on which more attention has been recently paid is the dynamic KR7 and consists of carrying out an in situ continuous racemization of the substrate, so that, theoretically, all of the racemic starting material can be used for transformation into one enantiomer. Nevertheless, many substrates employed in enzyme-catalyzed kinetic resolutions are not liable to undergo racemization.

The desymmetrization of symmetric compounds consists of a modification that eliminates one or more elements of symmetry of the substrate. If the symmetry elements that preclude chirality are eliminated, enantioselectivity can be achieved.8 Enantioselective enzymatic desymmetrizations (EEDs) belong to the field of asymmetric synthesis and, accordingly, a maximum yield of 100% can be attained.9 For this reason, they constitute a very interesting alternative to KRs for the preparation of optically active compounds, which is reflected in the increasing number of enzymatic desymmetrizations applied to synthesis published in the literature during the recent past years. This review deals with the developments made in the use of biocatalysts for the desymmetrization of meso and prochiral compounds, especially from 1999 on. It is structured according to a synthetic rather than a biocatalytic point of view and, as a rule of thumb, only those examples useful from a synthetic point of view are included, i.e., EEDs that constitute or can constitute a key step in a synthetic route, or aid to rationalize either the substrate specificity of an enzyme or the desymmetrization of a certain class of compounds. Accordingly, important parameters to which attention has been paid are enantioselectivity and the yield of the EED, which should be higher than 50% so that the desymmetrization implies a clear advantage over KRs. Nevertheless, exceptions can be made on the basis of novelty and difficulty of obtaining a compound by other means.