Elucidation of the Atroposelectivity in the Synthesis of Axially Chiral Thiohydantoin Derivatives

Recently, Sarigul and Dogan have synthesized a number of enantiomerically enriched axially chiral atropoisomeric 2-thiohydantoins by the reaction of L-amino acid ester salts and o-aryl isothiocyanates in the presence of triethyl amine (TEA) in dichloromethane. The nonaxially chiral derivative 5-methyl-3-phenyl-2-thiohydantoin gave a racemic product whereas the axially chiral 5-methyl-3-o-bromophenyl-2-thiohydantoin was less prone to racemize at C5 of the heterocyclic ring. In this study, we present a computational study (M06-2X/6-311+G(d,p) for C, H, O, N and S; M06-2X/6-311++G(3df,3pd) for Br) in order to propose plausible mechanisms for the racemization and cyclization steps for 2-thiohydantoin derivatives. The study includes rationalization based on steric as well as the electrostatic effects to elucidate the epimerization differences at C5.

近期，Sarigul与Dogan通过L-氨基酸酯盐与邻芳基异硫氰酸酯在三乙胺(TEA)与二氯甲烷体系中反应，合成了一系列对映体富集的轴手性阻转异构2-硫代海因(2-thiohydantoins)。非轴手性衍生物5-甲基-3-苯基-2-硫代海因反应后得到外消旋产物，而轴手性的5-甲基-3-邻溴苯基-2-硫代海因则不易在其杂环的C5位发生外消旋化。本研究开展了一项计算化学研究，针对C、H、O、N和S元素采用M06-2X/6-311+G(d,p)基组，针对Br元素采用M06-2X/6-311++G(3df,3pd)基组，旨在阐明2-硫代海因衍生物外消旋化与环化步骤的合理反应机理。本研究通过空间位阻与静电效应开展合理化分析，以阐明C5位的差向异构化差异。