Biocatalytic asymmetric ring-opening of dihydroisoxazoles: a cyanide-free route to complementary enantiomers of β-hydroxy nitriles from olefins

Abstract

By combination of the cyanide-free synthesis of chiral nitriles and the Kemp elimination reaction catalyzed by aldoxime dehydratases, we herein report a new application of aldoxime dehydratase in the asymmetric ring-opening of 5-sub-4,5-dihydroisoxazoles to synthesize chiral β-hydroxy nitriles with broad substrate scope, excellent enantioselectivity (up to 99% ee), and good turnover number (up to 11 s⁻¹). Upon simple isolation and treatment with an alkaline reagent, the remaining chiral 5-sub-4,5-dihydroisoxazoles can be easily transformed into their corresponding β-hydroxy nitriles. Using site-directed mutagenesis, a ferrous Heme-containing active site was confirmed and two possible deprotonation pathways were proposed. To the best of our knowledge, this is the first enzymatic reaction used to construct a chiral hydroxyl group and nitrile group in one-step starting from a simple alkene, which provides a novel and useful strategy for the synthesis of complementary enantiomers of β-hydroxy nitriles.