Concise Enantioselective Total Synthesis of Daphenylline Enabledby an Intramolecular Oxidative Dearomatization

Daphenylline is a structurally unique member of the triterpenoidDaphniphyllumnatural alkaloids, which exhibitintriguing biological activities. Six total syntheses have been reported,five of which utilize aromatization approaches. Herein, wereport a concise protecting-group-free total synthesis by means of a novel intramolecular oxidative dearomatization reaction, whichconcurrently generates the critical seven-membered ring and the quaternary-containing vicinal stereocenters. Other notabletransformations 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 ofthe diene intermediate (90% e.e.) and an unprecedented remote acid-directed Mukaiyama-Michael reaction of the complexbenzofused cyclohexanone (13:1 d.r.)

Automated summary

This paper reports a concise protecting-group-free total synthesis of Daphenylline, a structurally unique member of the triterpenoid Daphniphyllum natural alkaloids. Key reactions include an intramolecular oxidative dearomatization reaction, a tandem reductive amination/amidation double cyclization reaction, and a highly enantioselective rhodium-catalyzed hydrogenation reaction.