Eleutherobin is diterpenoid isolated from a soft coral which potent anti-cancer activity in vitro against breast, kidney, a lung and ovarian cancer cell lines. It's biological activity is due to it's ability to stabilize microtubules and thus prevent cell division, a mechanism it shares with the sarcodictyins, taxol, discodermolide and epothilone. Eleutherobin is also a member of a growing class of structurally related compounds isolated from marine sources which display a range of biological activities, including astrogorgin, and inhibitor of cell division in fertilized starfish eggs, and litophynol B, a hemolytic agent. Eleutherobin, astrogorgin and oxidation, and the in the location and stereochemistry of a furanoid ring. The highly promising biological activities of these and other eunicellin diterpenes demands a concise yet general approach to synthesis of this class of molecules. Complementary approaches to eleutherobin, astrogorgin and litophynol B are detailed herein which employ an Ireland Claisen rearrangement or an aldol reaction to establish the relative stereochemistry between the cyclohexane and the cyclodecane rings. The synthesis employ regio- and stereocontrolled functionalization of an alkylidene cyclohexene as a means of installing the requisite oxidation patterns for each of the natural products. The proposed synthesis of syntheses of eleutherobin, astrogorgin and litophynol B highlight the conciseness of the synthetic strategies: the natural products may be prepared in as fe as fourteen to fifteen steps from commercially available (S)-carvone. The Claisen rearrangement will also be employed in the synthesis of the diterpene infuscatrienol to establish the relative stereochemistry between the ring and side chain, which is currently unknown. An approach to the lignan eupomatilone-2 is proposed which will use the Claisen rearrangement to install the requisite stereochemistry of the natural product, as well as generating a reactive quinone methide which will allow for in situ formation of the butyrolactone ring.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Medicinal Chemistry Study Section (MCHA)
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Schwab, John M
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University of Arkansas at Fayetteville
Schools of Arts and Sciences
United States
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