New Strategy for Determining the Absolute Stereochemistry of Mono-Functional Natural Products by the CD Exciton Chirality Method

1.我们发展了一种用CD激子手性方法确定单官能团化合物绝对构型的新策略。这种方法对于包括天然产物在内的手性化合物的绝对构型研究是非常有效的。我们最近开发了两种“强大的手性酸”，用于在硅胶上用高效液相色谱拆分各种醇，并用X射线结晶学和/或~1H核磁共振各向异性方法确定它们的绝对构型。第一种是手性二氯邻苯二甲酸(-)-1，它与外消旋醇反应得到了非对映异构酯混合物。得到的混合酯在硅胶上用高效液相色谱分离，两个分离的酯分别结晶，得到适合于X射线分析的单晶。用X-射线单晶衍射法确定了醇组分的绝对构型，用K2CO3在甲醇中溶解可以很容易地回收对映体醇类化合物。第二种手性酸是2-甲氧基-2-(1-萘基)丙酸(M-αNP酸，S)-(+)-2或R-(-)-2，用于测定手性醇的绝对构型。M-αNP酸(S)-(+)-2可以与外消旋醇类化合物反应，生成非对映异构体的酯类混合物。得到的非对映异构酯的核磁共振信号被各种二维方法完全赋值，从而计算出Δδ值(Δδ=δ(R，X)-δ(S，X))。通过应用MαNP扇形规则，确定了绝对构型X。分离出的酯用KOH/EtOH水解法回收对映体醇类。以M-αNP酸(S)-(+)-2及其氚标记的对映体R-(-)-2-D6为原料，建立了一种用MS测定手性醇对映体过量(%ee)的新方法。

1. We have developed a new strategy for determining the absolute configuration of mono-fucntional compounds by the CD exciton chirality method. This method is powerful for the absolute configurational studies of chiral compounds including natural products.2. We have recently developed two "powerful chiral acids" for enantioresolution of various alcohols by HPLC on silica gel and also for determination of their absolute configurations by X-ray crystallography and/or by the 1H NMR anisotropy method. The first is the chiral dichlorophthalic acid (-)-1, which was reacted with racemic alcohol to give a diastereomeric mixture of esters. The mixture of esters obtained was separated by HPLC on silica gel, and two separated esters were crystallized respectively to afford single crystals suitable for X-ray analysis. The absolute configuration of the alcohol part was determined by X-ray crystallography of the esters, and enantiopure alcohols were easily recovered by solvolysis with K_2CO_3 in methanol.3. The second powerful chiral acid is 2-methoxy-2-(1-naphthyl)propionic acid (MαNP acid, (S)-(+)-2 or R-(-)-2) for determining the absolute configuration of chiral alcohols by the 1H NMR anisotropy method.The enantiopure MαNP acid (S)-(+)-2 was allowed to react with racemic alcohols yielding diastereomeric mixtures of esters, which were easily separated by HPLC on silica gel. The NMR signals of diastereomeric esters obtained were fully assigned by the various two-dimensional methods leading to the calculation of Δδ values (Δδ = δ(R,X)-δ(S,X)). By applying the MαNP sector rule, the absolute configuration X was determined. Separated esters were hydrolyzed with KOH/EtOH to recover enantiopure alcohols.4. Using MαNP acid, (S)-(+)-2 and its deuterium labeled enantiomer R-(-)-2-d_6, we have developed a new diastereomer method for determining enantiomeric excess (% ee) of chiral alcohols by MS spectrometry.