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. 2017 Aug 2;139(30):10196-10199.
doi: 10.1021/jacs.7b05196. Epub 2017 Jul 24.

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

Steven A Loskot  1 , David K Romney  1 , Frances H Arnold  1 , Brian M Stoltz  1
Affiliations

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

Steven A Loskot et al. J Am Chem Soc. .

Abstract

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.

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Figures

Figure 1
Figure 1
Structures of nigelladines A–C and nigel-laquinomine.
Figure 2
Figure 2
Retrosynthetic analysis of nigelladine A (1).
Scheme 1
Scheme 1
Synthesis of dienone 13
Scheme 2
Scheme 2
Condensation of imine 5
Scheme 3
Scheme 3
Completion of the synthesis of nigelladine Aa aADH, alcohol dehydrogenase; KPi, potassium phosphate; DMP, Dess-Martin periodinane.
See this image and copyright information in PMC

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