Novel Concepts and Mechanistic Probes in Catalysis

催化中的新概念和机理探索

• 批准号: 10304174
• 负责人: Mathew J Vetticatt
• 金额: $ 30.08万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-10 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304174
• 关键词: Acids; Address; Aldehydes; Amination; Area; Carbon; Catalysis; Communities; Complex; Coupling; Data; Development; Drug Industry; Elements; Generations; Glean; Goals; Industry; Isotopes; Kinetics; Methodology; Methods; Palladium; Pharmaceutical Chemistry; Process; Proline; Reaction; Research; Structure; Thiourea; Vision; base; carbene; catalyst; chiral molecule; density; design; enantiomer; high throughput screening; method development; novel; novel strategies; programs; stereochemistry; success; theories; tool

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.

项目摘要：本提案概述了系统、持续努力的愿景， 对催化不对称反应的基本理解及其在开发更多 选择性催化剂和不对称有机催化新概念的发现。我们的研究计划，自 它于2013年9月成立，积累了大量的机械信息，包括实验 几个重要有机催化反应动力学同位素效应（KIE）研究和过渡态分析 特别强调脯氨酸-烯胺催化。本提案介绍了我们目前在利用这一 设计更有选择性的催化剂和开发烯胺催化新概念的信息。 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， 获得合成上有用的对映异构性-使用相同的对映异构体获得靶分子的两个对映体 手性催化剂的对映体-脯氨酸-烯胺催化。在这项建议中，我们扩大了 这一概念发展了脯氨酸-烯胺催化中的两个新概念-化学分散剂和 非对映异构烯胺催化。后一个概念，非对映异构体催化，提供了获得 使用相同的手性催化剂，以高对映纯度制备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）-用于快速测定天然丰度的13 C KIE。我们 建议应用IDR方法对几种钯催化的化合物进行高通量机理研究 交叉偶联反应交叉偶联反应是合成中最常用的碳-碳键形成策略。 药物化学和从这项研究中收集的机制信息预计将有一个显着的 对制药行业工艺开发的影响。

项目成果

Isotope Effects Reveal the Catalytic Mechanism of the Archetypical Suzuki-Miyaura Reaction.

• DOI: 10.1021/acscatal.1c05802
• 发表时间: 2022-03-04
• 期刊: ACS CATALYSIS
• 影响因子: 12.9
• 作者: Joshi, Chetan;Macharia, Juliet M.;Izzo, Joseph A.;Wambua, Victor;Kim, Sungjin;Hirschi, Jennifer S.;Vetticatt, Mathew J.
• 通讯作者: Vetticatt, Mathew J.

A Selenourea-Thiourea Brønsted Acid Catalyst Facilitates Asymmetric Conjugate Additions of Amines to α,β-Unsaturated Esters.

• DOI: 10.1021/jacs.9b12457
• 发表时间: 2020-03-25
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Lin Y;Hirschi WJ;Kunadia A;Paul A;Ghiviriga I;Abboud KA;Karugu RW;Vetticatt MJ;Hirschi JS;Seidel D
• 通讯作者: Seidel D

Isotope Effects Reveal an Alternative Mechanism for "Iminium-Ion" Catalysis.

同位素效应揭示了“亚胺离子”催化的替代机制。

• DOI: 10.1021/jacs.8b04856
• 发表时间: 2018
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Izzo,JosephA;Poulsen,PernilleH;Intrator,JeremyA;Jørgensen,KarlAnker;Vetticatt,MathewJ
• 通讯作者: Vetticatt,MathewJ