Study Toward The Total Synthesis Of Clionastatin B

As the secondary metabolites from marine organism,marine halogenated natural products contain novel chemical structures and exhibit unique biological activities including anti-tumor and anti-cancer activities.Our group has been focusing on total syntheses of marine halogenated natural products and has completed the total syntheses of Aplydactone and asymmetric total synthesis of(+)-Majusculoic Acid.In this thesis,the synthetic studies toward polychlorinated marine steroid natural product Clionastatin B were described.Clionastatin B was isolated from the burrowing sponge Cliona nigricans collected from the coast of Gallinara,Italy,in the fall of 2004.It was the first polyhalogenated androstane which has ever been separated from nature.Clionastatin B features a 6/6/6/5 tetracyclic core framework,an α,β-unsaturated enone and a dienone,and four chloride atoms.And the construction of diequatorial trans-dichloride of C1 and C2 stereocenters and introduction of C19 methylene chloride group could be a great challenge in the way of the total synthesis of Clionastatin B.Given the high oxidation state of Clionastatin B,we decided to construct the α,β-unsaturated dienone system via dearomative cyclization of phenol compound.We have designed three different synthetic strategies and tried two different types of dearomati reaction including hypervalent iodine-mediated oxidative dearomatization and Pd-catalyzed dearomative cyclization.Finally,we have realized the synthesis of 6/6/6/5 tetracyclic dienone structure from commercial available 3-bromo-4-methylphenol via Robinson annulation and Pd-catalyzed dearomative cyclization.As for the construction of the trans-dichloride functionality at C1 and C2,we are now working it through by the addition of in-situ-formed chlorine to the corresponding double bond.All these progress will facilitate the total synthesis of halogenated steroid Clionastatin B.