Total Synthesis of the Marine Natural Product Leiodelide A

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DESCRIPTION (provided by applicant): Leiodelide A is a naturally occurring compound that possesses biological activity against cancer. This natural product, which was obtained from the rare deep sea sponge leiodermatium off the coast of Palau, exhibits impressive activity against the human colon carcinoma cell line HCT-116, with IC50 values of 1.4 ¿g/mL (2.5 ¿M) and 3.8 ¿g/mL (5.6¿M), for leiodolides A and B respectively (J. Org. Chem. 2006, 71, 7245-7251). The depth at which the sponge lives makes harvesting it a difficult, expensive, and dangerous proposition. Therefore, the low natural supply of this compound, combined with its interesting activity and intriguing structure, make it an attractive target for total synthesis. This compound presents opportunities to exploit techniques familiar to the Smith laboratory and to develop new methods, while increasing the supply of material for further testing towards development for human therapy. A synthetic route to leiodelide A has been developed which exploits a Suzuki-Miyaura cross-coupling as a key step, and which makes use of the pool of chiral material as well as catalytic, asymmetric techniques to construct this complex molecule. The synthesis is 18 steps (longest linear sequence) from simple starting materials. This total synthesis effort may also point the way to analogs which could be superior to the natural product itself. Nature provides us with many complex natural products that have interesting medicinal properties. Unfortunately, the amounts of these materials that is isolated is usually quite low, making their development into useful medicinal agents very difficult. The total chemical synthesis of these compounds is therefore an important and crucial part of expanding the lexicon of drugs that are available to us for the treatment of disease. The goal of this project will be to achieve the total synthesis of a naturally occurring compound that posesses biological activity against against cancer, namely, leiodelide A. In doing so, the project will bolster the NIH's mission of sponsoring research that can be applied to expanding the nation's ability to protect and improve public health.