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.
Additional Information© 2017 American Chemical Society. Received: May 19, 2017; Published: July 19, 2017. This work was supported by the NSF under the CCI Center for Selective C–H Functionalization (CHE-1205646). D.K.R. was supported by a Ruth Kirschstein NIH Postdoctoral Fellowship (F32GM117635). Additional financial support was provided by Caltech and Novartis. We thank Dr. Scott Virgil (CIT) and the Caltech 3CS for access to analytical equipment. The authors gratefully acknowledge Larry Henling and Dr. Michael Takase (CIT) for X-ray crystallographic structural determination, Dr. Mona Shahgholi and Naseem Torian (CIT) for mass spectrometry assistance, and Dr. David VanderVelde (CIT) for NMR experimental assistance and helpful discussions. The authors also acknowledge Dr. Sabine Brinkmann-Chen and Dr. Stephan Hammer (CIT) for helpful discussions regarding the enzymatic oxidation system.
Accepted Version - nihms915344.pdf
Supplemental Material - ja7b05196_si_001.pdf
Supplemental Material - ja7b05196_si_002.cif