Enzymes in organic synthesis. 14. Stereoselective horse liver alcohol dehydrogenase catalyzed oxidations of diols containing a prochiral centre and of related hemiacetals

Abstract

The asymmetric synthetic potential of horse liver alcohol dehydrogenase catalyzed oxidations of variously 3-substituted pentane-1,5-diols has been further delineated. The oxidations proceed with enantiotopic selectivity to give the corresponding (3S)-3-substituted valerolactones of up to 78% ee. The reactions occur via initial oxidation of the pro-S hydroxyethyl group, with the initially-formed hydroxyaldehydes undergoing further in situ enzyme-catalyzed oxidation in their hemiacetal forms to give the (3S)-lactones directly. The hemiacetal oxidation step is also stereoselective, with oxidation of the (4S)-enantiomer being much preferred. The size of the substituent at C-3 in the diols (C-4 in the hemiacetals) affects both the enantiotopic and enantiomeric specificity of the enzyme. Both types of stereospecificity are highest when the substituents are smallest, such as methyl or ethyl, and diminish progressively for diol or hemiacetal substrates bearing large aliphatic or aromatic substituents. All reactions were carried out on a preparative (up to 2 g) scale.