DEVELOPMENT OF CATALYSTS FOR ASYMMETRIC SYNTHESIS

不对称合成催化剂的开发

• 批准号: 8525855
• 负责人: VIRESH H. RAWAL
• 金额: $ 5.53万
• 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/8525855
• 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; public health relevance; 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）：开发有效合成具有反镜不对称（手性）的化合物的有效方法具有重要的经济和生物医学重要性。在制药行业中，单手性形式（对映异构体）药物占药物总市场的一半，而前十种药物中有9种的关键组成部分是手性的。手性化合物的生物医学重要性刺激了领先的实验室的激烈研究工作 - 几家公司的成立。此外，这项努力的社会和科学重要性通过两个独立的诺贝尔奖得到认可。在这项续签建议中，我们概述了开发和使用新型催化剂来对映选择性化合物合成的计划。与传统的基于金属的催化剂不同，在该程序中开发和研究的催化剂是有机分子，就像酶一样，能够通过形成一个或多个氢键来激活反应物。这种无金属反应的加速不仅具有根本利益，而且具有工业意义，因为金属杂质（尤其是过渡金属）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和相关化合物作为对映选择性催化剂的开发，应用和机械研究，（b）手性方形胺和相关化合物的开发和应用，以及（c）新型Hydrogen Bond Donor donor scaffolds的设计和研究。推动这项工作的中心假设是，新的和不同类别的氢键供体支架的发展有望大大扩大可以对映选择性的反应类别，并改善现有反应的有效性和底物。在下一个资金期间选择的项目范围代表了可行性和新颖性之间的平衡。将使用新开发的催化剂检查一些已知的反应，以允许用既定方法对这些催化剂进行校准。然而，大部分努力将在使用新开发的催化剂发现新的对映选择性反应上。许多次要投影都得到了有希望的初步结果的支持，而其他则代表了催化剂或方法论开发中的新方向。机械，晶体学和计算研究将提供对催化过程的理解，并引导更有效的催化剂的发展。 总体而言，预计在下一个资金期间提出的研究将导致开发广泛有用的不对称催化方法，这些方法将影响化学合成的许多方面，包括合成生物活性的天然产物和药物。此外，这项努力将为对制药行业或学术界研究职业感兴趣的本科，研究生和博士后学生提供出色的综合方法发展培训。 公共卫生相关性：大多数新的药物都是手性化合物，也就是说，它们是以两种可能的镜像形式之一生产的。手性中间体的化学合成对这些药物提出了重大的科学挑战。该项目的总体目标是开发新的催化剂和基于环境友好的氢键基于基于环保的氢键的激活，以合成各种手性分子的综合，其中许多分子可能被证明可用于开发药物。