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 overall transformation is redox self-sufficient without the need for cofactor recycling systems and delivers γ-lactones in excellent optical purities. To underline the synthetic value of this ring contraction, the methodology was successfully applied in the preparation of an <i>Osmunda butenolide</i> and in the formal total synthesis of <i>threo</i>-cavernosine. 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 γ-lactone in >99% <i>ee</i>.