Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences , Magyar tudósok körútja 2, H-1117 Budapest, Hungary.
MTA-BME Lendület Quantum Chemistry Research Group, Department of Physical Chemistry and Materials Science, Budapest University of Technology and Economics , P.O. Box 91, H-1521 Budapest, Hungary.
J Am Chem Soc. 2017 Nov 29;139(47):17052-17063. doi: 10.1021/jacs.7b07097. Epub 2017 Nov 13.
The enantioselectivity of amine-catalyzed reactions of aldehydes with electrophiles is often explained by simple steric arguments emphasizing the role of the bulky group of the catalyst that prevents the approach of the electrophile from the more hindered side. This standard steric shielding model has recently been challenged by the discovery of stable downstream intermediates, which appear to be involved in the rate-determining step of the catalytic cycle. The alternative model, referred to as the Curtin-Hammett scenario of stereocontrol, assumes that the enantioselectivity is related to the stability and reactivity of downstream intermediates. In our present computational study, we examine the two key processes of the catalytic Michael reaction between propanal and β-nitrostyrene that are relevant to the proposed stereoselectivity models, namely the C-C bond formation and the protonation steps. The free energy profiles obtained for the pathways leading to the enantiomeric products suggest that the rate- and stereodetermining steps are not identical as implied by the previous models. The stereoselectivity can be primarily controlled by C-C bond formation even though the reaction rate is dictated by the protonation step. This kinetic scheme is consistent with all observations of experimental mechanistic studies including those of mass spectrometric back reaction screening experiments, which reveal a mismatch between the stereoselectivity of the back and the forward reactions.
手性胺催化醛与亲电试剂反应的对映选择性通常可以用简单的空间位阻论点来解释，这些论点强调了催化剂的庞大基团的作用，该基团阻止亲电试剂从更受阻的一侧接近。这种标准的空间位阻屏蔽模型最近受到了稳定的下游中间体的发现的挑战，这些中间体似乎参与了催化循环的速率决定步骤。替代模型，称为立体控制的 Curtin-Hammett 情景，假设对映选择性与下游中间体的稳定性和反应性有关。在我们目前的计算研究中，我们研究了丙醛和β-硝基苯乙烯之间的催化迈克尔反应的两个关键过程，这些过程与所提出的立体选择性模型相关，即 C-C 键形成和质子化步骤。对于导致对映异构体产物的途径的自由能曲线表明，速率和立体决定步骤与先前的模型所暗示的并不相同。立体选择性可以主要通过 C-C 键形成来控制，尽管反应速率由质子化步骤决定。这种动力学方案与包括质谱反反应筛选实验在内的所有实验机理研究的观察结果一致，这些观察结果揭示了反反应和前反应的立体选择性之间的不匹配。
