Anti-Markovnikov alkene oxidation by metal-oxo–mediated enzyme catalysis

• Published in: Science (American Association for the Advancement of Science) Vol. 358; no. 6360; pp. 215 - 218
• Main Authors: Hammer, Stephan C., Kubik, Grzegorz, Watkins, Ella, Huang, Shan, Minges, Hannah, Arnold, Frances H.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 13-10-2017; The American Association for the Advancement of Science
• Subjects: Alkenes; Alkenes - chemistry; Biocatalysis; Catalysis; Catalysts; Chemical reactions; Cytochrome; Cytochrome P-450 Enzyme System - chemistry; Cytochrome P-450 Enzyme System - genetics; Cytochrome P450; Directed evolution; Directed Molecular Evolution; Enantiomers; Enzymes; Epoxidation; Evolution; Intermediates; Metabolic pathways; Metals; Migration; Organic Chemistry; Oxidation; Oxidation-Reduction; Oxygenase; Palladium; Protein Engineering; Selectivity; Styrenes
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aao1482

Catalytic anti-Markovnikov oxidation of alkene feedstocks could simplify synthetic routes to many important molecules and solve a long-standing challenge in chemistry. Here we report the engineering of a cytochrome P450 enzyme by directed evolution to catalyze metal-oxo–mediated anti-Markovnikov oxidation of styrenes with high efficiency. The enzyme uses dioxygen as the terminal oxidant and achieves selectivity for anti-Markovnikov oxidation over the kinetically favored alkene epoxidation by trapping high-energy intermediates and catalyzing an oxo transfer, including an enantioselective 1,2-hydride migration. The anti-Markovnikov oxygenase can be combined with other catalysts in synthetic metabolic pathways to access a variety of challenging anti-Markovnikov functionalization reactions.