Total Synthesis of the Marine Natural Product Leiodelide A

说明（由申请人提供）：莱奥德利特A是一种天然存在的化合物，具有抗癌生物活性。从帕劳海岸外的稀有深海海绵leiodermatium获得的这种天然产物对人结肠癌细胞系HCT-116表现出令人印象深刻的活性，对于leiodolides A和B，IC 50值分别为1.4 μ g/mL（2.5 μ M）和3.8 μ g/mL（5.6 μ M）（J. Org. Chem. 2006，71，7245-7251）。海绵生活的深度使收获它成为一个困难，昂贵和危险的提议。因此，这种化合物的低天然供应，结合其有趣的活性和有趣的结构，使其成为全合成的有吸引力的目标。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开发的材料供应。Leiodelide A的合成路线已经开发，其利用Suzuki-Miyaura交叉偶联作为关键步骤，并且其利用手性材料池以及催化、不对称技术来构建该复杂分子。合成是18个步骤（最长的线性序列）从简单的起始材料。这种全合成的努力也可能指向类似物的方式，这可能是上级天然产品本身。 大自然为我们提供了许多复杂的天然产品，这些产品具有有趣的药用特性。 不幸的是，这些材料的分离量通常很低，使得它们很难发展成有用的药物。因此，这些化合物的全化学合成是扩大我们可用于治疗疾病的药物词汇的重要和关键部分。本项目的目标是实现一种具有抗癌生物活性的天然化合物，即leiodelide A的全合成。在这样做的过程中，该项目将支持国家卫生研究院的使命，赞助研究，可用于扩大国家的能力，以保护和改善公共卫生。

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.