Chemoenzymatic synthesis of statine side chain building blocks and application in the total synthesis of the cholesterol-lowering compound solistatin

•Regio- and enantioselective (ee > 91%) enzymatic reduction of diverse diketones.•Protecting group-free chain elongation of a complex chlorohydrine by cyanide addition.•Access to well-established statine side-chain building blocks by Julia-Kocienski olefination.•Total synthesis of the cholesterol-lowering natural compound solistatin.

The synthesis and enzymatic reduction of several 6-substituted dioxohexanoates are presented. Two-step syntheses of tert-butyl 6-bromo-3,5-dioxohexanoate and the corresponding 6-hydroxy compound have been achieved in 89% and 59% yield, respectively. Regio- and enantioselective reduction of these diketones and of the 6-chloro derivative with alcohol dehydrogenase from Lactobacillus brevis (LBADH) gave the (5S)-5-hydroxy-3-oxo products with enantiomeric excesses of 91%, 98.4%, and >99.5%, respectively. Chain elongation of the reduction products by one carbon via cyanide addition, and by more than one carbon by Julia-Kocienski olefination, gave access to well-established statine side-chain building blocks. Application in the synthesis of the cholesterol-lowering natural compound solistatin is given.