Stereoconvergent reduction of alkenes using a repurposed iron-based dioxygenase

Abstract

The stereoconvergent reduction of alkenes for efficient synthesis of chiral compounds is a challenge in synthetic chemistry, even for exquisite enzymes in nature. Natural ene-reductases for example generally catalyse the reduction of alkenes in an enantiodivergent or resolution fashion. Here we report the repurposing of non-haem iron-based dioxygenases to catalyse the stereoconvergent reduction of alkenes through an iron hydride intermediate, by introducing silanes to the biocatalytic system. Directed evolution of gentisate 1,2-dioxygenase led to iron-based ene-reductases with high efficiency (up to 99% yield), excellent enantioselectivity (23 examples with >99% e.e.) and compatibility with a structurally diverse range of substrates. Experimental studies suggest the formation of iron hydride species in the enzyme and support the divalency of iron during the catalytic process. Computational studies show that the reaction is energetically feasible through an iron hydride mechanism and reveal the molecular mechanism of stereoconvergence. A repurposed non-haem, iron-based dioxygenase enables the stereoconvergent reduction of alkenes with excellent selectivity. Mechanistic studies support an iron hydride pathway and reveal the molecular mechanism of stereoconvergence.