Development of method for assignment of absolute configuration based on an induced axial chirality and its application to natural products

在本研究中，我们开发了一种新的绝对构型分配方法，该方法适用于具有单一官能团的化合物，例如手性单醇。设计了一种新的CD显色试剂和一种测定手性单醇绝对构型的新方法：3-氰羰基-3′-甲氧羰基-2,2′-二萘，它是一种易于引入醇的独特显色试剂。衍生物的CD谱呈现双叉形CD曲线，表明醇的手性信息被传递到二萘基发色团中，并诱导了轴向手性。通过对激子手性与绝对构型关系的分析，发现所采用的醇可分为A和B两类，这两类醇在很大程度上取决于相邻碳上的结构。A族化合物在邻碳上缺少不饱和或氧原子，而B族c…More化合物在邻碳上具有不饱和或氧原子。A组(R)-醇激子手性为负，(S)-醇激子手性为正。而b组的激子手性符号则相反。基于以上结果，我们提出了一种确定手性单醇绝对构型的新方法。诱导轴向手性的起源：通过核磁共振实验和分子力学计算，证明了衍生物中观察到的手性的传递是以热力学控制的方式发生的。诱导激子耦合CD （ECCD）方法的发展：通过分子力学计算发现，在最稳定的二萘基衍生物的构象中，激子手性的符号与2-萘酸基团的两个纵向^1B_b电跃迁矩之间的螺旋意义密切相关：具有正激子手性的酯呈顺时针(C)转，而具有负激子手性的酯呈逆时针（CC）转。在此基础上，提出了一种利用诱导CD法和分子力学计算确定绝对构型的改进方法。该方法在天然产物中的应用：将该方法应用于育亨宾，一种重要的吲哚类生物碱，以证明其对绝对构型赋值的有效性。盐酸育亨宾（C17: S）的绝对构型已通过单晶x射线分析确定。育亨宾衍生物的CD谱显示出正的激子手性。根据17s衍生物的分子力学计算数据，发现17s异构体优先表现为顺时针旋感（C/CC=56/44）。育亨宾在C17处的绝对构型为S. Less

In the present study, we developed a novel method for assignment of absolute configuration, which is applicable to compounds having a single functional group, ex. chiral mono-alcohol.Novel CD chromophoric reagent and a new procedure to determine the absolute configuration of chiral mono-alcohols : 3-cyanocarbonyl-3'-methoxycarbonyl-2,2'-binaphthalene, which can be easily introduced to alcohols, was designed as a unique chromophoric reagent. The CD spectra of the derivatives exhibited bisignate CD curves, indicating that chiral information of the alcohol was definitely transmitted to the binaphthyl chromophore and induced axial chirality. According to the analysis of the relationship between exciton chirality and absolute configuration, the alcohols employed were found to be classified into two groups, A and B, which depend strongly upon the structure on the vicinal carbons. Group A constitutes compounds lacking an unsaturation or an oxygen atom on the vicinal carbons, whereas group B c … More onstitutes compounds possessing either an unsaturation or an oxygen atom at the vicinal position. In group A, exciton chirality of (R)-alcohols was negative and that of (S)-alcohols was positive. On the contrary, the signs of exciton chirality were opposite in group B. On the basis of the above results, we proposed a new method to determine the absolute configuration of chiral mono-aicohols.Origin of the induced axial chirality : the transmission of the chirality observed in the derivatives was proved to occur in a thermodynamicaly controlled fashion based on the NMR experiments and molecular mechanics calculations.Development of induced exciton-coupled CD (ECCD) method : it was found that a close relationship between the sign of exciton chirality and the screw sense between the two longitudinal ^1B_b electric transition moments of 2-naphthoate groups in the most stable conformer of the binaphthyl derivative calculated by molecular mechanics : the esters showing positive exciton chirality had a clockwise (C) turn, whereas those with negative exciton chirality show a counterclockwise (CC) turn. Based on the results, a modified procedure for determining absolute configurations using an induced CD method and molecular mechanics calculations was proposed.Application of the method to natural products : the method was applied to yohimbine, an important indole alkaloid in order to prove its usefulness for the assignment of absolute configuration. The absolute configuration has already been determined by a single-crystal X-ray analysis of yohimbine hydrochloride (C17 : S). The CD spectrum of the derivative from yohimbine showed a positive exciton chirality. On the basis of the data from the molecular mechanics calculation of the 17S-derivative, it was found that 17S-isomer preferentially exhibits a clockwise screw sense (C/CC=56/44). The absolute configuration of yohimbine at C17 was thus S. Less