Metal-Bronsted Acid Cooperative Catalysis for Asymmetric Direct Reductive Amination

金属-布朗台德酸协同催化不对称直接还原胺化

• 批准号: EP/G031444/1
• 负责人: Jianliang Xiao
• 金额: $ 57.83万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FG031444%2F1
• 关键词: Metal; Bronsted; Acid; Cooperative; Catalysis

Chiral amines are ubiquitous in nature and are the most common functionalities in drug molecules, fine chemicals and new materials. They can be prepared by a number of methods; but the simplest, most efficient and eco-benign preparation is asymmetric direct reductive amination (ADRA) of ketones with hydrogen, which produces chiral amines in one pot. However, this reaction has not found applications in commercial synthesis, because literally no good catalysts are yet available. This proposal attempts to address this Holy Gail problem facing chemical synthesis and asymmetric catalysis by exploiting a novel strategy, Metal-Bronsted Acid Cooperative Catalysis (MBCC). Unlike traditional chemistry developed for ADRA, our approach incorporates three new elements: ionic catalysis, electrophilic activation, and counter anion-directed chiral induction. Under MBCC, an amine condenses with a ketone, forming an imine; this is catalyzed by the Bronsted acid. More importantly, the Bronsted acid then protonates, and thereby activates, the resulting imine by converting it into a highly electrophilic iminium ion. Subsequent hydride transfer, now with a lower barrier, from the metal centre to the iminium carbon atom reduces the C=N double bond. Last not the least, the hydride transfer to which enantiotopic face of the C=N double bond is aided by the conjugate base of the acid through ion-pairing. Clearly, the acid will play a key role in the operation of MBCC, which we believe stands for the most promising approach thus far for developing ADAR. Whilst the concept is designed for ADRA, its potential utility is expected to be much wider. The proposal builds on our recent highly successful studies of asymmetric hydrogenation of imines, key intermediates in ADRA, where unprecedented enantioselectivities have been recorded for a wide range of imines. A key discovery is the use of both hydrogenating metal catalyst and Bronsted acids. Our preliminary results indicate that MBCC drives the reaction and dictates the face selection, pointing to the potential of tackling ADRA via MBCC. However, we have not been able to carry out any mechanistic investigations yet. In order to most efficiently develop catalysts for ADAR by rational design, this project will be built on our preliminary results informed by mechanistic studies. The project will be divided into two synergistic parts, experimental exploration of MBCC for ADRA, and mechanistic and theoretical investigations. We believe experiments alone cannot answer key mechanistic questions, while mechanistic studies can only aid, but not replace, the discovery process

手性胺在自然界中普遍存在，是药物分子、精细化学品和新材料中最常见的功能。它们可以通过多种方法制备；但最简单、最有效且对生态有益的制备方法是酮与氢的不对称直接还原胺化（ADRA），一锅即可产生手性胺。然而，该反应尚未在商业合成中得到应用，因​​为实际上还没有好的催化剂可用。该提案试图通过利用一种新的策略——金属-布朗斯台德酸协同催化（MBCC）来解决化学合成和不对称催化面临的这一神圣盖尔问题。与 ADRA 开发的传统化学不同，我们的方法结合了三个新元素：离子催化、亲电子活化和反阴离子引导的手性诱导。在 MBCC 下，胺与酮缩合，形成亚胺；这是由布朗斯台德酸催化的。更重要的是，布朗斯台德酸随后质子化，从而通过将所得亚胺转化为高亲电子的亚胺离子来将其活化。随后的氢化物转移（现在具有较低的势垒）从金属中心到亚胺碳原子减少了 C=N 双键。最后，酸的共轭碱通过离子对帮助氢化物转移至 C=N 双键的对映体面。显然，酸将在 MBCC 的运行中发挥关键作用，我们相信这是迄今为止开发 ADAR 最有前途的方法。虽然这个概念是为 ADRA 设计的，但其潜在用途预计会更广泛。该提案建立在我们最近对亚胺（ADRA 的关键中间体）不对称氢化的高度成功研究的基础上，其中多种亚胺都记录了前所未有的对映选择性。一个关键的发现是氢化金属催化剂和布朗斯台德酸的使用。我们的初步结果表明，MBCC 驱动反应并决定面孔选择，表明通过 MBCC 解决 ADRA 的潜力。然而，我们还无法进行任何机制研究。为了通过合理设计最有效地开发 ADAR 催化剂，该项目将建立在我们通过机理研究获得的初步结果的基础上。该项目将分为两个协同部分，即针对 ADRA 的 MBCC 实验探索以及机理和理论研究。我们相信仅靠实验无法回答关键的机制问题，而机制研究只能帮助但不能取代发现过程

项目成果

Cyclometalated Iridium Complexes as Highly Active Catalysts for the Hydrogenation of Imines

环金属化铱配合物作为亚胺加氢的高活性催化剂

• DOI: 10.1055/s-0033-1340086
• 发表时间: 2013
• 期刊: Synlett
• 影响因子: 2
• 作者: Xiao J

Cooperative catalysis through noncovalent interactions.

• DOI: 10.1002/anie.201208774
• 发表时间: 2013-02
• 期刊: Angewandte Chemie
• 作者: Weijun Tang;S. Johnston;J. Iggo;N. Berry;M. Phelan;Lu-Yun Lian;J. Bacsa;Jianliang Xiao

Efficient and Chemoselective Reduction of Pyridines to Tetrahydropyridines and Piperidines via Rhodium-Catalyzed Transfer Hydrogenation

• DOI: 10.1002/adsc.201201034
• 发表时间: 2013-01-01
• 期刊: ADVANCED SYNTHESIS & CATALYSIS
• 影响因子: 5.4
• 作者: Wu, Jianjun;Tang, Weijun;Xiao, Jianliang
• 通讯作者: Xiao, Jianliang