Synthesis of (–)-Ophiodilactones A and B

Significance

In 2009, (–)-ophiodilactones A and B were isolated from the brittle star Ophiocoma scolopendrina (R. Ueoka, T. Fujita, S. Matsunaga J. Org. Chem. 2009, 74, 4396). These natural products are characterized by a fused γ,δ-dilactone core. Both natural products exhibit moderate cytotoxicity against leukemia cell lines. In the isolation report, Matsunaga and co-workers hypothesize that ophiodilactone B is directly biosynthesized from ophiodilactone A via a C–C bond-forming reaction between C-6 and C-6b. In the present work, Hatakeyama and co-workers report a reaction which allowed them to mimic this transformation in the laboratory.

Comment

The synthetic sequence commences with an enantioselective epoxidation of allylic alcohol A, a reaction developed by Yamamoto and co-workers (Angew. Chem. Int. Ed. 2005, 44, 4389). After oxidation to the carboxylic acid, the γ-lactone is generated by a diastereoselective iodo­lactonization (dr = 15:1). Hydrolysis of the corresponding primary iodide provides alcohol E in 65% yield from epoxide C. The δ-lactone is introduced by an intramolecular epoxide-opening reaction. After some experimentation, the authors found that heating F in a protic solvent efficiently generates (–)-ophiodilactone A. The crucial biomimetic coupling between the phenyl ring and the δ-lactone is achieved in an impressive 75% yield in the presence of catalytic amounts of copper(II) under an oxygen atmosphere to give (–)-ophiodilactone B.