Bakers' yeast reduction of alkyl 6-chloro-3-oxohexanoates: synthesis of (R)-(+)-α-lipoic acid

A number of alkyl 6-chloro-3-oxohexanoates were synthesized and their reduction with bakers' yeast studied. The enantioselectivity of these reductions was found to be influenced by the nature of the ester alkoxy substituent. The ethyl ester was reduced to the (3R)-6-chloro-3-hydroxy-hexanoate (49% yield, 30% e.e.) while the octyl ester gave the (3S)-6-chloro-3-hydroxyhexanoate (62% yield, 90% e.e.). The latter product was then converted into (R)-(+)-α-lipoic acid, a cofactor in the biochemical decarboxylation of α-keto acids, via a sequence of seven steps.