Asymmetric Synthesis of Macrolide Antibiotics

描述（由申请人提供）：在过去的十年中，人们对聚酮类/大环内酯类天然产物的表征、合成和药物开发产生了浓厚的兴趣，这些天然产物如苔藓虫抑素、苯德莫里酯、海绵抑素、埃波霉素等，它们是非常有效的抗癌药物。在许多情况下，从天然来源/发酵中获得的这些（通常是海洋）天然产物的数量非常有限，这极大地阻碍了更充分地评估其生物/药用特性的努力。最近，诺华公司的一大批化学家花费了巨大的精力、时间和费用合成了约60克的迪德莫里特，这既强调了对大量这些化合物的需求，也为合成可及性方面的最新技术状况提供了一个有用的基准。因此，合成有机化学家必须继续为这类化合物的合成提供更简单的方法。成功实现这一雄心勃勃的目标不仅会影响这些化合物的供应，还会影响开发具有改进药理特征的类似物的努力。本提案详细介绍了反应的发展，这些反应将在操作琐碎，环境无害和可扩展的过程中建立高水平的结构和立体化学复杂性。这将通过串联反应的编排来实现，这些反应将简单的，主要是碳氢化合物片段组装成含有多达三个立体中心的目标天然产物的大块。重要的是，这些方法的概念基础涉及到路易斯酸性硅烷的使用，这种化合物非常简单，而且在大规模合成时成本低廉。随着这些方法的发展，我们将通过完成重要的天然产物，如锌磷素、dictyostatin和海绵抑素的C(1)-C(28) ABCD片段和C(29)-C(51) EF片段的简短而高效的合成来证明它们的有效性。选择目标是因为它们的生物学重要性，因为我们的目标是改进制备这种结构的步骤经济。

DESCRIPTION (provided by applicant): The past decade has seen intense interest in the characterization, synthesis and medicinal development of polyketide/macrolide natural products such as the bryostatins, discodermolides, spongistatins, epothilones, etc. as extraordinarily potent anti-cancer agents. In many cases, only exceedingly limited quantities of these (often marine) natural products are available from natural sources/fermentation, and this has greatly hampered efforts to more fully evaluate their biological/medicinal profile. The recent synthesis of ~60 g of discodermolide by a large group of Novartis chemists with enormous effort, time, and expense both underscores the need for large amounts of these compounds and provides a useful benchmark as to the state of the art in terms of synthetic accessibility. It is imperative, therefore, that synthetic organic chemists continue to provide significantly simpler methods for the synthesis of such compounds. Success toward this ambitious goal would impact not just the supply of these compounds, but efforts to develop analogs with improved pharmacological profiles as well. The present proposal details the development of reactions that will establish high levels of structural and stereochemical complexity in operationally trivial, environmentally sound, and scalable processes. This will be achieved through the orchestration of tandem reactions that assemble simple, principally hydrocarbon fragments into large segments of the target natural products that contain as many as three stereocenters. Importantly, the conceptual foundation for these methods involves the use of Lewis acidic silanes, compounds that are extraordinarily straightforward and inexpensive to synthesize on large scales. Following the development of these methodologies, we will demonstrate their effectiveness by accomplishing brief and efficient syntheses of important natural products such as zincophorin, dictyostatin, and the C(1)-C(28) ABCD fragment and the C(29)-C(51) EF fragment of the spongistatins. The targets have been selected for their biological importance and because it is our goal to improve the step economy with which such structures may be prepared. PUBLIC HEALTH RELEVANCE: Polyketide natural products are a rich source of biologically active compounds with extraordinary medicinal potential as antibiotics and as anti-cancer agents. However, very often they are available from natural sources in only minute quantities, insufficient for their full biological profile to be investigated. This proposal seeks to develop efficient methods for the synthesis of gram-scale quantities of such compounds to aid in their biological evaluation and development.