Metal-Bronsted Acid Cooperative Catalysis for Asymmetric Direct Reductive Amination

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官能团。它们可以通过多种方法制备；但最简单、最有效和最环保的制备方法是酮与氢的不对称直接还原胺化（ADRA），它在一个锅中产生手性胺。然而，由于没有好的催化剂，这种反应还没有在商业合成中得到应用。本提案试图通过开发一种新的策略，金属- bronsted酸协同催化（MBCC）来解决化学合成和不对称催化所面临的这个难题。与传统的ADRA化学不同，我们的方法结合了三个新的元素：离子催化、亲电活化和反阴离子定向手性诱导。在MBCC下，胺与酮缩合形成亚胺；这是由Bronsted酸催化的。更重要的是，Bronsted酸然后质子化，从而激活生成的亚胺，将其转化为高度亲电的亚胺离子。随后的氢化物转移，现在以较低的势垒，从金属中心转移到碳原子，减少了C=N双键。最后，C=N双键的对映面氢化物的转移是由酸的共轭碱通过离子配对辅助的。显然，酸将在MBCC的运行中发挥关键作用，我们认为这是迄今为止开发ADAR最有前途的方法。虽然这个概念是为ADRA设计的，但它的潜在用途预计会更广泛。该建议建立在我们最近非常成功的亚胺不对称氢化研究的基础上，亚胺是ADRA的关键中间体，其中亚胺具有前所未有的对映选择性。一个关键的发现是同时使用氢化金属催化剂和布朗斯特酸。我们的初步结果表明，MBCC驱动反应并决定了面部选择，指出了通过MBCC解决ADRA的潜力。然而，我们还无法进行任何机械调查。为了通过合理的设计最有效地开发ADAR催化剂，本项目将建立在我们的初步研究结果的基础上。该项目将分为两个协同部分，即MBCC对ADRA的实验探索，以及机理和理论研究。我们相信实验本身不能回答关键的机械问题，而机械研究只能帮助而不能取代发现过程

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