Development of Catalysts for Asymmetric Synthesis

不对称合成催化剂的开发

• 批准号: 6836563
• 负责人: VIRESH H. RAWAL
• 金额: $ 22.42万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6836563
• 关键词: Diels Alder reaction; alcohols; carbonyl group; catalyst; chemical reaction; chemical structure; chemical synthesis; chromium; cobalt; drug design /synthesis /production; electron crystallography; heavy metals; hydrogen bond; stereoisomer; technology /technique development

DESCRIPTION (provided by applicant): The importance of methods for the synthesis of chiral compounds in high enantiomeric purity cannot be overstated. In 2001, single enantiomer drugs comprised 36% ($147 billion) of the total market of $410 billion. This number is projected to increase steadily, such that chiral drugs will constitute a market of over $200 billion by 2008. The growing economic importance of chiral compounds has spurred major research efforts from many laboratories, academic and industrial, directed at the selective preparation of chiral compounds. A recent report from the PI's laboratory described the development of chiral metal-salen complexes that are exceptional catalysts for enantioselective Diels-AIder (DA) reactions, one of the most useful reactions for organic synthesis. A major focus of the proposed activity will be to investigate these catalysts and to develop related complexes for use in DA and other C-C bond forming reactions. The high efficiency of these catalysts (record low catalyst loading) makes them attractive for various applications in complex molecule synthesis, even for industrial uses. In conjunction with this work, additional heteroatom-substituted dienes will be developed for use in DA reactions. Also presented in the proposal are plans for the development of metal-free catalysts that use hydrogen bonding rather than Lewis acids to promote the enantioselective process. This metal-free acceleration of reactions is not only of fundamental interest, but is also of potential industrial importance, since metal impurities, especially transition metals, are undesirable in precious chemicals such as pharmaceutical drugs. Effort will be directed at the use of hydrogen bonding for the enantioselective catalysis of various C-C bond-forming reactions. The asymmetric catalysis capabilities of numerous chiral alcohols as well as other hydrogen bond donors will be examined. Both of the major subprojects (metal salen complexes and hydrogen bonding catalysis) will integrate crystallographic studies and computational modeling in order to develop models to rationalize the observed enantioselectivities. Overall, the investigations described in this proposal are expected to lead to useful new methodology advances for the asymmetric synthesis of complex molecules. The projects described herein will provide excellent training for undergraduate students, graduate students, and postdoctoral associates in asymmetric catalysis methodology development and complex molecule synthesis, experience that will prepare them well for independent research careers, either in industry or academics.

描述（由申请人提供）：高对映体纯度手性化合物合成方法的重要性怎么强调都不过分。2001年，单一对映体药物占4100亿美元总市场的36%（1470亿美元）。这一数字预计将稳步增长，到2008年，手性药物将构成一个超过2000亿美元的市场。手性化合物日益增长的经济重要性促使许多实验室，学术和工业，致力于手性化合物的选择性制备。PI实验室最近的一份报告描述了手性金属-salen配合物的发展，这种配合物是对映选择性Diels-AIder （DA）反应的特殊催化剂，DA是有机合成中最有用的反应之一。该活动的主要重点将是研究这些催化剂并开发用于DA和其他C-C键形成反应的相关配合物。这些催化剂的高效率（创纪录的低催化剂负载）使它们在复杂分子合成的各种应用中具有吸引力，甚至用于工业用途。结合这项工作，将开发更多的杂原子取代二烯用于DA反应。提案中还提出了开发无金属催化剂的计划，该催化剂使用氢键而不是路易斯酸来促进对映选择过程。这种不含金属的加速反应不仅具有根本意义，而且具有潜在的工业重要性，因为金属杂质，特别是过渡金属，在诸如药物之类的贵重化学品中是不受欢迎的。我们将致力于利用氢键对各种C-C键形成反应进行对映选择性催化。许多手性醇以及其他氢键供体的不对称催化能力将被检查。两个主要子项目（金属salen配合物和氢键催化）将结合晶体学研究和计算建模，以建立模型来合理化观察到的对映选择性。总的来说，本提案中描述的研究有望为复杂分子的不对称合成带来有用的新方法进展。本文所述的项目将为本科生、研究生和博士后在不对称催化方法开发和复杂分子合成方面提供良好的培训，为他们在工业界或学术界的独立研究生涯做好准备。