Total syntheses of (-)-Scabrolide B and related marine natural products

Abstract

The furanobutenolide-derived norcembranoid diterpenes are a rare family of natural products isolated mainly in Sinularia-type soft coral. Among these molecules, it was discovered in 2022 that scabrolide B possesses a 6/7/5/5 carbocyclic core, instead of the initially postulated 7/6/5/5 core. The objective of this thesis is to accomplish a total synthesis of that natural product. Two convergent approaches to scabrolide B were investigated, each relying on a ring-closure of the central seven-membered ring: one by ring closing metathesis and one via intramolecular enolate alkenylation. In both approaches, the precursors required for ring-closure were synthesized by a 1,4 addition between a protected bicyclic lactone and a (R)-carvone derivative. If both approaches converge on a common intermediate en route to the total synthesis of scabrolide B, only the alkenylation route afforded a reliable supply of the natural product, providing 110 mg in a single run over 19 steps (longest linear sequence) and 1.2% overall yield. Scabrolide B was subsequently transformed into the sister norcembranoids fragilolide A, sinuscalide C and ineleganolide, the latter could further be converted into horiolide and kavaranolide, supporting the biosynthetic sequence proposed in the literature. Overall, a series of polycyclic norcembranoids and their derivatives were synthesized, providing valuable material and insight for future studies on the biological activity of this rare family of molecules.