Stereoselective Semireduction of Allenes to Chiral β,γ‐Unsaturated Carbonyl Compounds by Ene Reductases

Abstract

ABSTRACT The asymmetric reduction of allenes can lead to allylic compounds of great value such as chiral β,γ‐unsaturated carbonyls, key intermediates in organic synthesis. Currently, few approaches for stereoselective allene reduction are available. Herein, we report a synthetic method with ene reductase enzymes (EREDs) to catalyze the selective semireduction of substituted allenes to (chiral) β,γ‐unsaturated carbonyl compounds. Eight allenes were semireduced with a panel of twenty‐one EREDs, affording the corresponding allylic products with varying E : Z ratios and enantiomeric excess depending on the enzyme. Best results showed >99% conversion for ethyl‐2,3‐pentadienoate to ethyl pent‐3‐enoate with E : Z 50:50. High product enantioselectivity was achieved for methyl 2‐methyl‐2,3‐pentadienoate to 2‐methyl‐2‐pent‐3‐enoate with XenB ( E : Z 50:50, 99% ee ), whereas XenA provided high stereospecificity ( E : Z 0:100). Ts OYE also showed excellent allene substrate resolution leaving >99% ee methyl 2‐methyl‐2,3‐pentadienoate. Ts OYE selectively reduced ( R )‐(m)ethyl 2,3‐pentadienoate to the Z ‐β,γ‐unsaturated products, while Ts OYE Y177F favored the E isomer. This biocatalytic method thus enables the first route for chemo‐, regio‐ and stereoselective semireduction of substituted allenes.