Asymmetric Ring Contraction of 2-Hydroxypyranones by Borrowing Hydrogen Biocatalysis

Ring contraction reactions facilitate easy access to carbo- and heterocyclic scaffolds from readily available precursors and have therefore enjoyed great popularity as a strategy in organic synthesis for a long time. By repurposing commercial alcohol dehydrogenases as borrowing hydrogen biocatalysts, we were able to develop a rare example of an enzymatic ring contraction methodology, where racemic 2-hydroxypyranones can be converted in an enantioconvergent manner to the corresponding 5-membered butenolides. The redox self-sufficient transformation delivers gamma-lactones in excellent optical purities and was successfully employed in the total synthesis of an Osmunda metabolite. Moreover, the biocatalytic tool was incorporated into a multi-step cascade consisting of six enzymes, achieving the formal enantioselective dearomatization of a furfuryl alcohol to deliver the corresponding saturated gamma-lactone in >99% ee.