Concise Total Syntheses of Phleghenrines A and C

The phleghenrine alkaloids were isolated from Phlegmariurus henryi Ching in scare amount and have shown potent and selective acetylcholinesterase inhibition activity. Structurally, they have a distinct and complex tetracyclic skeleton featuring a bicyclo[3.2.2]nonene core fused with a 2-pyridone or its derivative. Herein, we report concise total syntheses of phleghenrines A and C from commercially available starting materials in only 7 and 8 steps, respectively. The key steps in our approach include an inverse electron-demand Diels-Alder reaction between a masked o-benzoquinone and a N-protected enamine to prepare one key intermediate with a bicyclo[2.2.2]octenone core, a Büchner–Curtius–Schlotterbeck one-carbon insertion to expand the bicyclo[2.2.2]octenone to a bicyclo[3.2.2]nonenone, and the Trauner’s modified 2-pyridone synthesis to install the 2-pyridone moiety.