Scharf Manuel J, Tsuji Nobuya, Lindner Monika M, Leutzsch Markus, Lõkov Märt, Parman Elisabeth, Leito Ivo, List Benjamin
Max-Planck-Institut für Kohlenforschung, Mülheim an der Ruhr 45470, Germany.
Institute for Chemical Reaction Design and Discovery, Hokkaido University, Sapporo 001-0021, Japan.
J Am Chem Soc. 2024 Oct 3;146(41):28339-49. doi: 10.1021/jacs.4c09421.
Electron-rich heteroaromatic imidodiphosphorimidates (IDPis) catalyze the asymmetric Pictet-Spengler reaction of -carbamoyl-β-arylethylamines with high stereochemical precision. This particular class of catalysts furthermore provides a vital rate enhancement compared to related Brønsted acids. Here we present experimental studies on the underlying reaction kinetics that shed light on the specific origins of rate acceleration. Analysis of Hammett plots, kinetic isotope effects, reaction orders, Eyring plots, and isotopic scrambling experiments, allowed us to gather insights into the molecular interactions between the chiral Brønsted acid and catalytically formed intermediates. Based on rigorously determined p values as well as the experimental evidence, we propose that attractive intermolecular forces offered by electron-rich π-surfaces of the chiral counteranion enthalpically stabilize cationic intermediates and transition states by way of cation-π interactions. This view is furthermore supported by in-depth density functional theory calculations. Our deepened understanding of the reaction mechanism allowed us to develop a method for accessing 1-aryltetrahydroisoquinolines from aromatic dimethyl acetals, a substrate class that was thus far inaccessible via catalytic asymmetric Pictet-Spengler reactions.
富电子杂芳族亚氨基二磷亚胺（IDPis）能以高立体化学精度催化氨基甲酰基-β-芳基乙胺的不对称Pictet-Spengler反应。与相关的布朗斯特酸相比，这类特殊的催化剂还能显著提高反应速率。在此，我们展示了关于潜在反应动力学的实验研究，这些研究揭示了速率加速的具体来源。通过对哈米特图、动力学同位素效应、反应级数、艾林图和同位素重排实验的分析，我们得以深入了解手性布朗斯特酸与催化形成的中间体之间的分子相互作用。基于严格测定的p值以及实验证据，我们提出，手性抗衡阴离子富电子的π表面通过阳离子-π相互作用提供的有吸引力的分子间力，在焓上稳定了阳离子中间体和过渡态。深入的密度泛函理论计算进一步支持了这一观点。我们对反应机理的深入理解使我们能够开发出一种从芳族二甲基缩醛制备1-芳基四氢异喹啉的方法，而芳族二甲基缩醛是迄今为止通过催化不对称Pictet-Spengler反应无法获得的一类底物。
