Enzymatic diastereo- and enantioselective synthesis of α-alkyl-α,β-dihydroxyketones

Enantiopure tertiary alcohols are very valuable building blocks for the synthesis of many different natural products and pharmaceuticals. Recently we reported the syntheses of chiral and prochiral α-alkyl-α-hydroxy-β-diketones catalyzed by acetylacetoin synthase (AAS) from Bacillus stearothermophilus.1 This approach, together with the recently proposed use of YerE,2 represents the first example of an asymmetric aldehyde-ketone carboligation reaction catalyzed by a ThDP-dependent enzyme affording chiral tertiary alcohols. In this communication a fully enzymatic strategy for the preparation of optically pure α-alkyl-α,β-dihydroxyketones is reported. A set of α-alkyl-α-hydroxy-β-diketones 2a-g and 3b-d, obtained by acetylacetoin synthase (AAS) catalyzed homo- and cross-coupling of α-diketones 1a-f, have been regio- and enatioselectively reduced with diacetyl(acetoin)reductase (DR) to α-alkyl-α,β-dihydroxy ketones 4a-e and 4g. AAS and DR have been obtained from the same bacterial source and used in a crude form.