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.
Davy Sébastien Lin (Wed,) studied this question.