Conformational and Configurational Analysis in the Study and Synthesis of Chlorinated Natural Products

The first detailed study of the J-based configuration analysis method in chlorinated hydrocarbons and chlorohydrins is presented along with the development of a spectroscopic database that facilitates configurational assignment of these structures. The data are generated through the investigation of model structures in solution by NMR spectroscopic methods and in the solid state by X-ray crystallography. Consequently, complete conformational analysis of trichlorinated hexane-1,2- and -1,3-diols is presented. The investigations in chlorinated systems for the first time attest to the relevance, reliability, and accuracy of the spectroscopic approach in configurational assignment, which had been otherwise developed for polyketides. During the synthesis of the various molecules that constitute the database and exemplify the various possible stereochemical patterns, a number of observations were made that underscore the unique features of these chlorinated systems. Thus, certain diastereomeric subclasses of 4,5-dichloro-2,3-epoxyhexane-1-ols display a propensity to undergo ring-opening reactions at C-3 with concomitant inversion of configuration at the neighboring C−Cl at C4, implicating the intermediacy of chloronium ions. The observations of positional and stereochemical scrambling in polychlorinated hydrocarbons underscore the necessity of a spectroscopic database that enables rapid, reliable configurational assignment of chlorinated natural products and intermediates en route to these.

本文针对氯代烃与氯代醇中的J基构型分析方法（J-based configuration analysis method）开展了首项详尽研究，并同步构建了可助力该类结构完成构型归属的光谱数据库。本数据集通过以下方式获取：利用核磁共振波谱法对溶液中的模型结构进行表征，并借助X射线晶体学对固态模型结构开展分析。据此，本文完成了三氯代己烷-1,2-二醇与己烷-1,3-二醇的完整构象分析。此前该光谱分析方法仅针对聚酮类化合物（polyketides）开发，而本次针对氯代体系的研究首次证实了该方法在构型归属中的适用性、可靠性与准确性。在构建该数据库、并通过各类分子展现所有可能立体化学模式的合成过程中，本文得到了多项观测结果，这些结果凸显了此类氯代体系的独特性质。例如，4,5-二氯-2,3-环氧己烷-1-醇的部分非对映异构子类，表现出在C3位发生开环反应、并伴随相邻C4位C-Cl键所在手性中心构型翻转的倾向，这暗示了氯鎓离子（chloronium ions）作为反应中间体的存在。针对多氯代烃中观测到的位置与立体化学混杂现象，本文进一步凸显了构建专属光谱数据库的必要性——该数据库可快速、可靠地完成氯代天然产物及其合成此类天然产物过程中所涉及中间体的构型归属工作。