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DEVELOPMENT OF CATALYSTS FOR ASYMMETRIC SYNTHESIS

不对称合成催化剂的开发

基本信息

批准号：
8652467
负责人：
VIRESH H. RAWAL
金额：
$ 31.83万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-01 至 2015-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The development of effective methods for the selective synthesis of compounds having mirror asymmetry (chirality) is of significant economic and biomedical importance. In the pharmaceutical industry, single chiral-form (enantiomer) drugs constitute over half of the total drug market, and the key components in 9 of the top 10 drugs are chiral. The biomedical importance of chiral compounds has spurred intense research efforts from leading laboratories-indeed the founding of several companies. Moreover, the societal and scientific importance of this endeavor has been recognized through two separate Nobel prizes. In this renewal proposal, we outline plans for the development and use of novel catalysts for enantioselective synthesis of chiral compounds. Unlike traditional metal-based catalysts, the catalysts being developed and studied in this program are organic molecules that, like enzymes, are capable of activating a reactant through the formation of one or more hydrogen bonds. This metal-free acceleration of reactions is not only of fundamental interest, but is also of industrial importance, since metal impurities, especially transition metals, are undesirable in pharmaceutical drugs. The research efforts will focus on three major areas: (a) development, application, and mechanistic studies of chiral taddols and related compounds as enantioselective catalysts, (b) the development and application of chiral squaramides and related compounds, and (c) the design and study of novel hydrogen bond donor scaffolds. The central hypothesis driving this work is that the development of new and distinct classes of hydrogen bond donor scaffolds is expected to greatly expand the classes of reactions that can be rendered enantioselective and lead to improvements in the effectiveness and substrate-scope of existing reactions. The range of projects that have been selected for the next funding period represents a balance between feasibility and novelty. Some known reactions will be examined using the newly developed catalysts so as to allow calibration of these catalysts with established methodology. Much of the effort, however, will be on the discovery of new enantioselective reactions using the newly developed catalysts. Many of the subprojects are supported by promising preliminary results, whereas others represent new directions in either catalyst or methodology development. Mechanistic, crystallographic, and computational studies will provide an understanding of the catalytic processes and steer the development of more effective catalysts. Overall, the investigations proposed for the next funding period are expected to lead to the development of broadly useful asymmetric catalysis methodologies that will impact many facets of chemical synthesis, including the synthesis of biologically active natural products and pharmaceutical drugs. Additionally, the effort will provide excellent training in synthetic methodology development to undergraduate, graduate and postdoctoral students interested in a research career in the pharmaceutical industry or academia.

描述（由申请人提供）：开发具有镜像不对称（手性）的化合物的选择性合成的有效方法具有重要的经济和生物医学意义。在制药行业，单手性（对映体）药物占整个药品市场的一半以上，前10名药物中有9种的关键成分是手性。手性化合物在生物医学上的重要性激发了领先实验室的强烈研究努力——实际上是几家公司的成立。此外，这一努力的社会和科学重要性已经通过两个独立的诺贝尔奖得到认可。在这一更新建议中，我们概述了用于手性化合物对映选择性合成的新型催化剂的开发和使用计划。与传统的金属基催化剂不同，本项目正在开发和研究的催化剂是有机分子，像酶一样，能够通过形成一个或多个氢键来激活反应物。这种不含金属的加速反应不仅具有根本意义，而且在工业上也具有重要意义，因为金属杂质，特别是过渡金属，在药物中是不受欢迎的。研究工作将集中在三个主要领域：(a)手性角酰胺及其相关化合物作为对端选择性催化剂的开发、应用和机理研究；(b)手性角酰胺及其相关化合物的开发和应用；(c)新型氢键供体支架的设计和研究。推动这项工作的中心假设是，开发新的和独特类型的氢键供体支架有望极大地扩展可以呈现对映选择性的反应类别，并导致现有反应的有效性和底物范围的改进。为下一个资助期选定的项目范围在可行性和新颖性之间取得了平衡。一些已知的反应将使用新开发的催化剂进行检验，以便用既定的方法对这些催化剂进行校准。然而，大部分的努力将是利用新开发的催化剂发现新的对映选择性反应。许多子项目得到了有希望的初步结果的支持，而其他子项目则代表了催化剂或方法开发的新方向。机械、晶体学和计算研究将提供对催化过程的理解，并指导更有效催化剂的开发。总的来说，为下一个资助期提出的调查预计将导致广泛有用的不对称催化方法的发展，这将影响化学合成的许多方面，包括生物活性天然产物和药物的合成。此外，该项目还将为有意在制药行业或学术界从事研究工作的本科生、研究生和博士后提供合成方法学开发方面的优秀培训。