Asymmetric Synthesis of Macrolide Antibiotics

大环内酯类抗生素的不对称合成

• 批准号: 7654416
• 负责人: JAMES L LEIGHTON
• 金额: $ 33.67万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7654416
• 关键词: Alkenes; Alkynes; Antibiotics; Antineoplastic Agents; Antiviral Agents; Arts; Benchmarking; Biological; Biological Factors; Cancer Cell Growth; Complex; Development; Effectiveness; Epothilones; Evaluation; Family; Fermentation; Foundations; Goals; Hydrocarbons; Hydroxyl Radical; Ionophores; Ketones; Macrolide Antibiotics; Macrolides; Marines; Methodology; Methods; Microtubules; Polyketide Macrolides; Process; Reaction; Route; Silanes; Source; Spongistatin; Structure; Time; Work; analog; bryostatin; design; dictyostatin; discodermolide; improved; interest; marine natural product; novel; public health relevance; research study; silane; sound; spongistatin 1; success; zincophorin

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.

描述（由申请人提供）：在过去的十年中，人们对聚酮化合物/大环内酯类天然产物如苔藓抑素、discodermolides、spongistatins、埃博霉素等作为非常有效的抗癌剂的表征、合成和药物开发产生了浓厚的兴趣。在许多情况下，这些（通常是海洋）天然产品只能从天然来源/发酵中获得非常有限的数量，这极大地阻碍了更全面地评估其生物/医学特性的努力。最近由大量诺华化学家花费巨大的努力、时间和费用合成了约60 g的discodermolide，这既强调了对大量这些化合物的需求，又提供了关于合成可及性方面的现有技术的有用基准。因此，合成有机化学家必须继续提供更简单的方法来合成这些化合物。实现这一雄心勃勃的目标的成功不仅会影响这些化合物的供应，还会影响开发具有改善药理学特征的类似物的努力。本提案详细介绍了反应的发展，将建立高水平的结构和立体化学复杂性的操作琐碎，环境友好，可扩展的过程。这将通过串联反应的编排来实现，串联反应将简单的主要是烃片段组装成含有多达三个立体中心的目标天然产物的大片段。重要的是，这些方法的概念基础涉及使用刘易斯酸性硅烷，这种化合物非常简单，大规模合成成本低廉。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蛋白、网抑素和海绵抑素的C（1）-C（28）ABCD片段和C（29）-C（51）EF片段的简单而有效的合成来证明它们的有效性。选择这些靶点是因为它们的生物学重要性，并且因为我们的目标是提高制备这种结构的步骤经济性。 公共卫生相关性：聚酮化合物天然产物是生物活性化合物的丰富来源，具有作为抗生素和抗癌剂的非凡药用潜力。然而，从自然资源中获得的此类物质往往数量极少，不足以对其全部生物特征进行调查。该提案旨在开发用于合成克级量的此类化合物的有效方法，以帮助其生物学评价和开发。