Total synthesis of rameswaralide utilizing a pharmacophore directed retrosynthetic approach.


A pharmacophore-directed retrosynthesis strategy was applied to rameswaralide which simultaneously allowed the total synthesis of rameswaralide and the identification of simplified analogs containing the common 5,5,6 and 5,5,7 skeleton present in several cembranoid and norcembranoids from Sinularia soft corals. The common cores not only serve as starting points for the synthesis of related natural products, but have also provided intriguing initial structure–activity relationships of intermediates en route to rameswaralide revealing differential and selective cytotoxicity. Our route intersects a versatile ⍺-bromo enone resulting in multiple possible endgame strategies, one of which lead to the first total synthesis of rameswaralide. Key steps include a kinetic resolution Diels–Alder lactonization organocascade delivering the common 5,5,6 core, followed by subsequent ring expansion to a 5,5,7 core serviceable for Stille cross coupling and an intra-molecular pyrrolidine catalyzed Michael addition providing access to rameswaralide.