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

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.