Total Synthesis of the Marine Natural Product Leiodelide A

描述（由申请人提供）：Leiodelide A是一种天然存在的化合物，具有抗癌生物活性。这种天然产物是从帕劳海岸稀有的深海海绵leiodermatium中获得的，对人结肠癌细胞系HCT-116表现出令人印象深刻的活性，对leiodolides A和B的IC50值分别为1.4¿g/mL（2.5¿M）和3.8¿g/mL（5.6¿M）。化学，2006,71,7245-7251)。海绵生活的深度使得收获它是一件困难、昂贵和危险的事情。因此，该化合物的天然供应量低，加上其有趣的活性和有趣的结构，使其成为全合成的一个有吸引力的目标。这种化合物提供了利用史密斯实验室熟悉的技术和开发新方法的机会，同时增加了进一步测试人类治疗发展的材料供应。以Suzuki-Miyaura交叉偶联为关键步骤，利用大量的手性材料和催化、不对称技术构建了一种合成碘酰A的方法。从简单的起始材料开始，合成有18个步骤（最长的线性序列）。这种全面合成的努力也可能指向可能优于天然产物本身的类似物。

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.