Concise Enantioselective Total Synthesis of Daphenylline Enabled by an Intramolecular Oxidative Dearomatization

J Am Chem Soc. 2022 Apr 6;144(13):5750-5755. doi: 10.1021/jacs.2c01674. Epub 2022 Mar 15.

Abstract

Daphenylline is a structurally unique member of the triterpenoid Daphniphyllum natural alkaloids, which exhibit intriguing biological activities. Six total syntheses have been reported, five of which utilize aromatization approaches. Herein, we report a concise protecting-group-free total synthesis by means of a novel intramolecular oxidative dearomatization reaction, which concurrently generates the critical seven-membered ring and the quaternary-containing vicinal stereocenters. Other notable transformations include a tandem reductive amination/amidation double cyclization reaction, to assemble the cage-like architecture, and installation of the other two chiral stereocenters via a highly enantioselective rhodium-catalyzed challenging hydrogenation of the diene intermediate (90% e.e.) and an unprecedented remote acid-directed Mukaiyama-Michael reaction of the complex benzofused cyclohexanone (13:1 d.r.).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids*
  • Cyclization
  • Oxidative Stress
  • Stereoisomerism

Substances

  • Alkaloids
  • daphenylline