A Convergent Approach to Phragmalin-Type Limonoids: Total Synthesis of Thaigranatin P

Abstract

Herein, we report the total synthesis of erythrocarpines M and L and thaigranatin P, topologically complex phragmalin-type limonoids, the latter exhibiting potent agonism on the human pregnane X receptor (hPXR). A key transformation is a SmI₂-mediated reductive coupling of an aldehyde and an alkene, which constructs the signature tricyclo[3.3.1^2,10.1^1,4]decane framework characteristic of phragmalin natural products. The synthesis features a strategically convergent construction of the phragmalin core structure via a cuprate addition, triflation, and intramolecular Heck reaction sequence. This route offers a versatile platform for the synthesis of structurally diverse phragmalin analogs for future biological investigation.