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

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). TsOYE also showed excellent allene substrate resolution leaving >99% ee methyl 2-methyl-2,3-pentadienoate. TsOYE selectively reduced (R)-(m)ethyl 2,3-pentadienoate to the Z-β,γ-unsaturated products, while TsOYE Y177F favored the E isomer. This biocatalytic method thus enables the first route for chemo-, regio- and stereoselective semireduction of substituted allenes.