Asymmetric Synthesis of Macrolide Antibiotics

描述(申请人提供)：在过去的十年里，人们对聚酮/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，如苔藓他汀类、盘状内酯、海绵他汀类、埃普西酮等，这些都是非常有效的抗癌药物。在许多情况下，从自然来源/发酵中获得的这些天然产品(通常是海洋产品)的数量非常有限，这极大地阻碍了更充分地评估其生物学/药用概况的努力。诺华公司的一大批化学家最近花费了巨大的精力、时间和费用合成了~60克的盘状莫立德，这既突显了对大量这些化合物的需求，也为合成可及性方面的最先进水平提供了一个有用的基准。因此，合成有机化学家必须继续提供简单得多的方法来合成这类化合物。实现这一雄心勃勃的目标的成功不仅将影响这些化合物的供应，还将影响开发具有更好药理特征的类似物的努力。本提案详细说明了将在操作琐碎、无害环境和可扩展的过程中建立高度结构和立体化学复杂性的反应的发展。这将通过串联反应的协调实现，这些反应将简单的、主要是碳氢化合物片段组装成目标天然产品的大片段，其中包含多达三个立体中心。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，而且大规模合成成本低廉。随着这些方法学的发展，我们将通过简单有效地合成重要的天然产物来证明它们的有效性，例如津科普林、百代他汀、海绵抑素的C(1)-C(28)ABCD片段和C(29)-C(51)EF片段。选择靶标是因为它们具有生物学意义，也是因为我们的目标是提高制备此类结构所需的步骤经济性。 公共卫生相关性：聚酮类天然产物是生物活性化合物的丰富来源，具有非凡的药用潜力，可用作抗生素和抗癌剂。然而，它们往往只能从自然来源获得极少量的物质，不足以对它们的全部生物学特征进行调查。这项建议寻求开发有效的方法来合成克级数量的这类化合物，以帮助它们的生物评估和开发。

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.