Pharmacophore-Directed Retrosynthesis Applied to Rameswaralide: Synthesis and Bioactivity of Sinularia Natural Product Tricyclic Cores

A pharmacophore-directed retrosynthesis strategy applied to rameswaralide provided simplified precursors bearing the common 5,5,6 (red) and 5,5,7 (blue) skeleton present in several cembranoid and norcembranoids from Sinularia soft corals. Key steps include a Diels–Alder lactonization organocascade delivering the common 5,5,6 core and a subsequent ring expansion affording a 5,5,7 core serviceable for the synthesis of rameswaralide. Initial structure–activity relationships of intermediates en route to the natural product have revealed interesting differential and selective cytotoxicity.