Kopar Merve, Senyurt Tuzun Nurcan
Department of Chemistry, Faculty of Science and Letters, Istanbul Technical University, Maslak, İstanbul34469, Turkey.
Chempluschem. 2025 Jan;90(1):e202400606. doi: 10.1002/cplu.202400606. Epub 2024 Nov 15.
The asymmetric synthesis of tetrahydroisoquinolines (THIQs) has gained importance in recent years due to their significant potential in drug development studies. In this study, the conversion of 1-methyl-3,4-dihydroisoquinoline substrate to a chiral amine, 1-methyl-1,2,3,4-tetrahydroisoquinoline, under the catalysis of the stereoselective imine reductase enzyme from Stackebrandtia nassauensis (SnIR) was investigated in detail to elucidate the mechanism and explain the experimental enantioselectivity. The results were found to be in agreement with the experimental data. To elucidate the reaction mechanism, quantum mechanical calculations were performed by considering a large cluster of the active site of the enzyme. In this regard, possible reaction pathways leading to both R- and S-products with the corresponding intermediates and the transition states for the hydride transfer from the cofactor to the substrate were considered by density functional theory (DFT) calculations, and the factors contributing to the observed stereoselectivity were sought. The calculations supported a stepwise mechanism rather than the concerted protonation and the hydride transfer steps. The stereoselectivity in the hydride transfer was found to be due not only to the stability of the enzyme-subtrate complex but also to the corresponding reaction barriers. The calculations were performed at the wB97XD/6-311+G(2df,2p)//B3LYP/6-31G(d,p) level of theory using the PCM approach.
近年来，由于四氢异喹啉（THIQs）在药物开发研究中具有巨大潜力，其不对称合成受到了广泛关注。在本研究中，详细研究了在来自纳氏堆囊菌的立体选择性亚胺还原酶（SnIR）催化下，1-甲基-3,4-二氢异喹啉底物转化为手性胺1-甲基-1,2,3,4-四氢异喹啉的过程，以阐明反应机理并解释实验中的对映选择性。计算结果与实验数据相符。为了阐明反应机理，通过考虑酶活性位点的一个大簇进行了量子力学计算。在这方面，利用密度泛函理论（DFT）计算考虑了导致R-和S-产物以及相应中间体的可能反应途径，以及从辅因子到底物的氢化物转移的过渡态，并寻找影响观察到的立体选择性的因素。计算结果支持分步反应机理，而非协同质子化和氢化物转移步骤。发现氢化物转移中的立体选择性不仅归因于酶-底物复合物的稳定性，还归因于相应的反应势垒。计算在理论水平wB97XD/6-311+G(2df,2p)//B3LYP/6-31G(d,p)下采用PCM方法进行。
