DEVELOPMENT OF CATALYSTS FOR ASYMMETRIC SYNTHESIS

不对称合成催化剂的开发

• 批准号: 8109428
• 负责人: VIRESH H. RAWAL
• 金额: $ 27.87万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8109428
• 关键词: 3-hydroxybutanal; Academia; Acceleration; Acetals; Alcohols; Aldehydes; Area; Automobile Driving; Biological Factors; Calibration; Catalysis; Cyanides; Development; Development Plans; Diels Alder reaction; Drug Industry; Economics; Effectiveness; Electrons; Enzymes; Equilibrium; Funding; Glycols; Goals; Hydrogen Bonding; Image; Indoles; Investigation; Laboratories; Lead; Literature; Masks; Metals; Methodology; Methods; Nobel Prize; Pharmaceutical Preparations; Pharmacologic Substance; Preparation; Process; Reaction; Research; Research Design; Salts; Students; Training; Transition Elements; Work; base; career; catalyst; chemical synthesis; chiral molecule; computer studies; cycloaddition; design; dibenzofuran; drug market; enantiomer; interest; ketene; nitroalkene; novel; programs; salen; scaffold

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. PUBLIC HEALTH RELEVANCE: Most new pharmaceutical drugs are chiral compounds-that is, they are produced in one of two possible mirror image forms. The chemical synthesis of chiral intermediates to these drugs presents a significant scientific challenge. The overall goal of this project is to develop new catalysts and new methods-based on environmentally-friendly hydrogen bond-based activation-for the synthesis of diverse classes of chiral molecules, many of which could prove useful for the development of pharmaceutical drugs.

描述（由申请人提供）：开发用于选择性合成具有镜像不对称性（手性）的化合物的有效方法具有显着的经济和生物医学重要性。在医药行业，单一手性（对映体）药物占整个药物市场的一半以上，前10名药物中有9个关键成分是手性的。手性化合物在生物医学上的重要性激发了领先实验室的大量研究工作——实际上还成立了多家公司。此外，这项努力的社会和科学重要性已通过两项单独的诺贝尔奖得到认可。在这份更新提案中，我们概述了开发和使用新型催化剂用于手性化合物对映选择性合成的计划。与传统的金属催化剂不同，该项目中正在开发和研究的催化剂是有机分子，它们像酶一样，能够通过形成一个或多个氢键来激活反应物。这种无金属的反应加速不仅具有根本意义，而且具有工业重要性，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taddols及相关化合物作为对映选择性催化剂的开发、应用和机理研究，（b）手性方酰胺及相关化合物的开发和应用，以及（c）设计新型氢键供体支架的研究。推动这项工作的中心假设是，新型和独特类型的氢键供体支架的开发预计将极大地扩展可以实现对映选择性的反应类型，并导致现有反应的有效性和底物范围的改进。为下一个资助期选择的项目范围体现了可行性和新颖性之间的平衡。将使用新开发的催化剂来检查一些已知的反应，以便能够用既定的方法来校准这些催化剂。然而，大部分努力将集中在使用新开发的催化剂发现新的对映选择性反应上。许多子项目都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。机理、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。 总体而言，下一个资助期提出的研究预计将导致广泛有用的不对称催化方法的开发，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，这项工作还将为对制药行业或学术界研究职业感兴趣的本科生、研究生和博士后提供合成方法开发方面的优秀培训。 公共卫生相关性：大多数新药物都是手性化合物，也就是说，它们以两种可能的镜像形式之一生产。这些药物的手性中间体的化学合成提出了重大的科学挑战。该项目的总体目标是开发基于环保氢键活化的新催化剂和新方法，用于合成不同类别的手性分子，其中许多可用于药物的开发。