Studies on discovery and synthesis of bioactive marine organic molecules

Abstract

This paper describes the discovery and total synthesis of bioactive marine natural products conducted in our laboratory. Clavulone, chlorovulone, bromovulone, and iodovulone are antitumor marine prostanoids isolated from the Okinawan soft coral Clavularia viridis. The synthesis of clavulone and chlorovulone was achieved from chiral 4-hydroxy-2-cyclopentenone. Marine prostanoid punaglandins 3 and 4 were synthesized via similar methodology. The chemical structures of punaglandins 3 and 4 were revised by these syntheses. Dollaberane-type diterpenoid stolonidiol and claenone were isolated from Okinawan soft coral Clavularia sp. Stolonidiol showed potent choline acetyltransferase-inducible activity in cultured basal forebrain cells. The synthesis of stolondiol and claenone was conducted via sequential Michael reaction and retro-aldol reaction. Aragusterols, isolated from the Okinawan marine sponge Xestospongia sp., are structurally unique steroids possessing a rare 26,27-cyclo structure in the side chain. Aragusterols express potent in vivo antitumor activity against L1210 leukemia in mice. The synthesis of aragusterols was carried out via steroselective construction of the side chain and stereocontrolled coupling reaction with the steroid skeleton. Kalihinane-type diterpenoid kalihinol A, isolated by Scheuer, has remarkable in vitro antimalarial activity. The absolute configuration of kalihinol A was determined by applying the CD exciton chiral method. Synthesis of kalihinene X, a kalihinane-type diterpenoid, was achieved. This synthesis involves the regioselective coupling reaction of carbanion of alkyl sulfone with epoxyalcohol and construction of cis-decalin by an intramolecular Diels-Alder reaction.