Biocatalytic, stereoconvergent alkylation of (Z/E)-trisubstituted silyl enol ethers

The selective conversion of mixtures of Z/E alkenes into chiral products is a synthetic challenge. Biocatalytic strategies can transform isomeric alkenes into stereopure compounds, but enzymes typically convert only one alkene isomer, limiting the overall yield. Additional strategies have been used to interconvert alkene isomers, often at the cost of increasing energy consumption and chemical waste. Here we present engineered haemoproteins derived from a bacterial cytochrome P450 that efficiently catalyse alpha-carbonyl alkylation of isomeric silyl enol ethers, producing stereopure products. Through screening and directed evolution, we generated P450(BM3) variant P411-SCA-5188, which catalyses stereoconvergent carbene transfer in Escherichia coli with high efficiency and stereoselectivity to various Z/E mixtures of silyl enol ethers. In contrast to established stereospecific transformations that leave one isomer unreacted, P411-SCA-5188 converts both isomers to a stereopure product. This biocatalytic approach simplifies the synthesis of chiral alpha-branched ketones by eliminating the need for stoichiometric chiral auxiliaries, strongly basic alkali-metal enolates and harsh conditions, delivering products with high efficiency and excellent chemo- and stereoselectivities.