Department of Chemistry, Aarhus University , DK-8000 Aarhus C, Denmark.
Acc Chem Res. 2016 May 17;49(5):974-86. doi: 10.1021/acs.accounts.6b00008. Epub 2016 Apr 29.
Asymmetric organocatalysis has witnessed a remarkable development since its "re-birth" in the beginning of the millenium. In this rapidly growing field, computational investigations have proven to be an important contribution for the elucidation of mechanisms and rationalizations of the stereochemical outcomes of many of the reaction concepts developed. The improved understanding of mechanistic details has facilitated the further advancement of the field. The diarylprolinol-silyl ethers have since their introduction been one of the most applied catalysts in asymmetric aminocatalysis due to their robustness and generality. Although aminocatalytic methods at first glance appear to follow relatively simple mechanistic principles, more comprehensive computational studies have shown that this notion in some cases is deceiving and that more complex pathways might be operating. In this Account, the application of density functional theory (DFT) and other computational methods on systems catalyzed by the diarylprolinol-silyl ethers is described. It will be illustrated how computational investigations have shed light on the structure and reactivity of important intermediates in aminocatalysis, such as enamines and iminium ions formed from aldehydes and α,β-unsaturated aldehydes, respectively. Enamine and iminium ion catalysis can be classified as HOMO-raising and LUMO-lowering activation modes. In these systems, the exclusive reactivity through one of the possible intermediates is often a requisite for achieving high stereoselectivity; therefore, the appreciation of subtle energy differences has been vital for the efficient development of new stereoselective reactions. The diarylprolinol-silyl ethers have also allowed for novel activation modes for unsaturated aldehydes, which have opened up avenues for the development of new remote functionalization reactions of poly-unsaturated carbonyl compounds via di-, tri-, and tetraenamine intermediates and vinylogous iminium ions. Computational studies have played a pivotal role in the elucidation of the regioselectivities observed for such systems because these pose a challenge due to the presence of multiple reactive sites in these intermediates. Charge distribution and π-orbital coefficient calculations have been applied to explain the observed regioselectivity of the given reactions. The calculation of more elaborate energetic pathways has allowed for in silico identification of high-energy intermediates, such as zwitterions, and transition-state structures, which have also provided information on the driving force controlling the reaction course and outcome.
自千禧年初“重生”以来，不对称有机催化取得了显著发展。在这个快速发展的领域中，计算研究已被证明是阐明许多反应概念的机制和立体化学结果的重要贡献。对机制细节的深入理解促进了该领域的进一步发展。自引入以来，二芳基脯氨醇硅醚因其稳定性和通用性而成为不对称氨基催化中应用最广泛的催化剂之一。尽管氨基催化方法乍一看似乎遵循相对简单的机制原理，但更全面的计算研究表明，在某些情况下，这种概念具有欺骗性，可能存在更复杂的途径。在本报告中，描述了二芳基脯氨醇硅醚催化体系中应用密度泛函理论（DFT）和其他计算方法的情况。将说明计算研究如何阐明氨基催化中重要中间体的结构和反应性，例如分别由醛和α,β-不饱和醛形成的烯胺和亚胺离子。烯胺和亚胺离子催化可以归类为 HOMO-raising 和 LUMO-lowering 活化模式。在这些系统中，通过其中一种可能的中间体进行的排他性反应通常是实现高立体选择性的必要条件；因此，对微妙能量差异的理解对于高效开发新的立体选择性反应至关重要。二芳基脯氨醇硅醚还允许不饱和醛具有新的活化模式，这为通过二烯、三烯和四烯胺中间体以及乙烯基亚胺离子发展多不饱和羰基化合物的新远程官能化反应开辟了途径。计算研究在阐明观察到的此类系统的区域选择性方面发挥了关键作用，因为由于这些中间体中存在多个反应性位点，因此这构成了挑战。电荷分布和π-轨道系数计算已被应用于解释给定反应观察到的区域选择性。更精细的能量途径的计算允许在计算机上识别高能中间体，如两性离子和过渡态结构，这也提供了有关控制反应过程和结果的驱动力的信息。
