Biocatalytic, Stereoconvergent Alkylation of ()-Trisubstituted Silyl Enol Ethers.

Alkene functionalization has garnered significant attention due to the versatile reactivity of C=C bonds. A major challenge is the selective conversion of isomeric alkenes into chiral products. Researchers have devised various biocatalytic strategies to transform isomeric alkenes into stereopure compounds; while selective, the enzymes often specifically convert one alkene isomer, thereby diminishing overall yield. To increase the overall yield, scientists have introduced additional driving forces to interconvert alkene isomers. This improves the yield of biocatalytic alkene functionalization at the cost of increased energy consumption and chemical waste. Developing a stereoconvergent enzyme for alkene functionalization offers an ideal solution, although such catalysts are rarely reported. Here we present engineered hemoproteins derived from a bacterial cytochrome P450 that efficiently catalyze the stereoconvergent -carbonyl alkylation of isomeric silyl enol ethers, producing stereopure products. Through screening and directed evolution, we generated P450 variant , which catalyzes stereoconvergent carbene transfer in , with high efficiency and stereoselectivity toward various mixtures of silyl enol ethers. In contrast to established transformations that leave one isomer unreacted, converts both isomers to a stereopure product. This biocatalytic approach simplifies the synthesis of chiral -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.