Selective Reduction of α,β-Unsaturated Carbonyls with Ketoreductase.

Enzymatic catalysis promises the achievement of functional group reactivity selectivity with the conjunctional expansive acquirement of reactivity diversity through the conformal mutagenesis tuning of catalytic cavity. However, essentially all of the functional group reactivity diversification systems demonstrated thus far are centered on the intersubstrate-shift regime, with the enzymatic catalysis adapted to alternative substrate and associated target functional group in totality. Herein, we report an enzymatic stringency-relaxation strategy for effecting reactivity diversification into the intrasubstrate orthogonal functional group reactivity selectivity regime. The stringency-relaxation strategy operates in either the amino acid relaxation or functional group relaxation format by a working sequence of initial stringency amino acid catalytic access to the catalytically most demanding functional group and subsequent relaxation amino acid catalytic access to the catalytically less demanding functional group. In particular, herein, through this strategy, α,β-unsaturated carbonyls have been reduced with ketoreductase, in a selective manner, at either the carbonyl group site or the alkenyl group site. A broad substrate scope has been established for the alkenyl reduction of α-cyano-α,β-unsaturated esters, showcasing enzymatic stringency-relaxation as a prospective platform for programming reactivity diversification and reaction development.