Novel Concepts and Mechanistic Probes in Catalysis

项目摘要：本提案概述了针对以下目标的系统、持续努力的愿景 对催化不对称反应的基本认识及其在More开发中的应用 不对称有机催化中的选择性催化剂和新概念的发现。我们的研究项目，自从 它成立于2013年9月，已经积累了大量的机械信息，包括实验 几种重要有机催化反应的动力学同位素效应研究和过渡态分析 并特别强调了脯氨酸-烯胺催化。这份提案描述了我们目前在利用这一点方面所做的努力 为设计更具选择性的催化剂和开发烯胺催化的新概念提供信息。 这些努力取得了一些初步成功，我们成功地制定了一项总体战略，以 获得合成上有用的对映体发散-使用其获得目标分子的两个对极 手性催化剂对映体--在脯氨酸-烯胺催化中的应用。在这项建议中，我们扩大了 这一概念在脯氨酸-烯胺催化中发展了两个新概念--化学发散和 非对映发散烯胺催化。后一个概念，非对映发散催化，提供了 使用相同手性催化剂的高对映纯度手性分子的互补非对映异构体-a 在不对称催化中没有先例的现象。 最后，我们正在寻求扩大合成有机社区可用的物理有机工具包 通过开发用于快速阐明反应机理的探针。我们开发了一种新的方法 -分子内设计反应物(IDR)-用于在自然丰度下快速测定13C Kies。我们 建议应用IDR方法对几种钯催化的高通量机理进行研究 交叉偶联反应。交叉偶联反应是最常用的碳-碳键形成策略 从这项研究中收集的药物化学和机理信息预计将具有重要的 对制药业工艺发展的影响。

Project Summary: This proposal outlines the vision of a systematic, ongoing effort directed towards the fundamental understanding of catalytic asymmetric reactions and its application to the development of more selective catalysts and discovery of novel concepts in asymmetric organocatalysis. Our research program, since its inception in September 2013, has accumulated a vast body of mechanistic information including experimental kinetic isotope effect (KIE) studies and transition state analysis of several important organocatalytic reactions with a special emphasis on proline-enamine catalysis. This proposal describes our current efforts in utilizing this information to design more selective catalysts and to develop novel concepts in enamine catalysis. These efforts have met with some initial success and we have successfully developed a general strategy to obtain synthetically useful enantiodivergence – access to both antipodes of a target molecule using the same enantiomer of chiral catalyst – in proline-enamine catalysis. In this proposal, we are extending the application of this concept to develop two novel concepts in proline-enamine catalysis – chemodivergent and diastereodivergent enamine catalysis. The latter concept, diastereodivergent catalysis, provides access to complementary diastereomers of a chiral molecule in high enantiopurity using the same chiral catalyst – a phenomenon that has no precedent in asymmetric catalysis. Finally, we are seeking to expand the physical organic toolkit available to the synthetic organic community by developing probes for the rapid elucidation of reaction mechanisms. We have developed a novel methodology – intramolecular designed reactant (IDR) – for the rapid determination of 13C KIEs at natural abundance. We propose to apply the IDR method to conduct a high-throughput mechanistic study of several palladium catalyzed cross-coupling reactions. Cross-coupling reactions are the most-utilized carbon-carbon bond-forming strategy in medicinal chemistry and the mechanistic information gleaned from this study is expected to have a significant impact on process development in the pharmaceutical industry.