DEVELOPMENT OF CATALYSTS FOR ASYMMETRIC SYNTHESIS

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著的经济和生物医学重要性。在医药工业中，单一手性形式（对映异构体）药物占药物市场的一半以上，前10种药物中有9种的关键成分是手性药物。手性化合物在生物医学上的重要性促使了领先的实验室进行了大量的研究，甚至成立了几家公司。此外，这一奋进的社会和科学重要性已经通过两个独立的诺贝尔奖得到了认可。在这个更新的建议，我们概述了计划的发展和使用的新型催化剂的手性化合物的不对称合成。与传统的金属基催化剂不同，该计划正在开发和研究的催化剂是有机分子，与酶一样，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，在药物中是不希望的。研究工作将集中在三个主要领域：（a）手性taddol及其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）手性方酰胺及其相关化合物的开发和应用;以及（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，新的和不同类别的氢键供体支架的发展，预计将大大扩大类的反应，可以呈现对映选择性，并导致现有反应的有效性和基板范围的改善。为下一个供资期选定的项目范围在可行性和新奇之间取得了平衡。一些已知的反应将使用新开发的催化剂进行检查，以便允许用已建立的方法校准这些催化剂。然而，大部分的努力将是在使用新开发的催化剂发现新的对映选择性反应。许多分项目都得到了有希望的初步结果的支持，而其他分项目则代表了催化剂或方法开发的新方向。机制，晶体学和计算研究将提供对催化过程的理解，并指导更有效的催化剂的开发。 总体而言，下一个供资期拟议的研究预计将导致开发广泛有用的不对称催化方法，这将影响化学合成的许多方面，包括生物活性天然产品和药物的合成。此外，这项工作将为对制药行业或学术界的研究生涯感兴趣的本科生、研究生和博士后学生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。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新的催化剂和新的方法-基于环境友好的基于氢键的活化-用于合成不同类别的手性分子，其中许多可以证明对药物开发有用。

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.