Synthesis of optically active cyanohydrins from aromatic ketones: evidence of an increased substrate range and inverted stereoselectivity for the hydroxynitrile lyase from Linum usitatissimum

Abstract

The synthesis of ( R)- and ( S)-cyanohydrins from a range of aromatic methyl and ethyl ketones, including the first examples from substituted variants of phenylacetone, benzylacetone and propiophenone, is described. Commercially available hydroxynitrile lyase (HNL) enzymes were used to catalyze the asymmetric addition of cyanide to the ketones, including the first successful application of the flax HNL (LuHNL) to the synthesis of any aromatic ( S)-cyanohydrin. Both reaction yields and stereoselectivities were shown to be influenced by the carbon chain length between the ketone and phenyl functional groups, and the type of aromatic substitution present on the starting material. Substrates converted with the greatest degree of productivity and selectivity were phenylacetones with large, electron withdrawing meta-substituents, such as 3-Cl, 3-Br and 3-CF 3 phenylacetones, from which cyanohydrins are formed with 93–99% ee and 61–71% yield.