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Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme

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journal contribution
posted on 19.07.2017, 00:00 authored by Steven A. Loskot, David K. Romney, Frances H. Arnold, Brian M. Stoltz
An enantio­selective total synthesis of the nor­di­terp­enoid alkaloid nigella­dine A is described. Strategically, the synthesis relies on a late-stage C–H oxidation of an advanced intermediate. While traditional chemical methods failed to deliver the desired outcome, an engineered cyto­chrome P450 enzyme was employed to effect a chemo- and regio­selective allylic C–H oxidation in the presence of four oxidizable positions. The enzyme variant was readily identified from a focused library of three enzymes, allowing for completion of the synthesis without the need for extensive screening.