Total Synthesis of Otteliones Possessing Powerful Tubulin Polymerization Inhibitory Activity

Otteliones A and B, isolated from the fleshwater plant Ottelia alismoides, were found to exhibit extremely potent growth-inhibitory activity against human cancer cell lines. Structurally, these small-molecule natural products possess a novel bicyclic hydrindane skeleton with four contiguous asymmetric carbon centers, in which the rare and sensitive 4-methylene-2-cyclohexenone substructure is a special characteristic feature. When these natural products were isolated, the relative configuration of ottelione B was determined; however, ottelione A could not been assigned unambiguously. In this article, we describe the first enantioselective total synthesis of (+)-ottelione A, (-)-ottelione B, and (+)-3-epi-ottelione A (the earlier proposed stereostructure of ottelione A) using a flexible synthetic scheme that allows an access to all possible stereostructures of ottelione A. The present total synthesis has fully established the absolute configuration of these natural products. In addition, the cell growth inhibition analysis and tubulin polymerization assay of the synthesized otteliones are also described.