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首页> 外文期刊>Chirality: The pharmacological, biological, and chemical consequences of molecular asymmetry >Application of chiral technology in a pharmaceutical company. Enantiomeric separation and spectroscopic studies of key asymmetric intermediates using a combination of techniques. Phenylglycidols
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Application of chiral technology in a pharmaceutical company. Enantiomeric separation and spectroscopic studies of key asymmetric intermediates using a combination of techniques. Phenylglycidols

机译：手性技术在制药公司中的应用。结合使用多种技术，对主要不对称中间体进行对映体分离和光谱研究。苯基糖苷

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摘要

Phenylglycidols substituted in the 2-, 3-, and 4- positions with fluorine, chlorine, and trifluoromethyl, and with methoxy in the 3- position, were synthesized from the corresponding E-cinnamic acids and separated into their (RR)- and (SS)- enantiomers using subcritical fluid chromatography with mixtures of MeOH in CO2, on either a Chiralpak AD or AS chiral stationary phase. These compounds and commercially-available (RR)- and (S,S)-phenylglycidol were analyzed for their vibrational circular dichroism (VCD), electronic circular dichroism (ECD), and optical rotation (OR) properties to exemplify a strategy whereby the absolute stereochemistry of common and key chiral intermediates is established early in the structure-activity and structure-property relationship phase of a drug discovery program in a pharmaceutical company. From this study, substituents in the phenyl group of the synthesized molecules were found not to grossly alter spectroscopic features, and therefore, diagnostic absorption bands in the respective VCD spectra, and the sign and shape of the measured ECD curves could be used to determine and track the absolute stereochemistry of analogs without necessarily requiring time-consuming ab initio calculations of all low energy conformers for all compounds. VCD, OF, and ECD calculations for the determination of absolute configuration carried out at the DFT level with the hybrid B3PW91 functional and the TZVP basis set were found to be especially useful in this study. Chirality 19:716-730, 2007. (c) 2007 Wiley-Liss, Inc.
机译：由相应的E-肉桂酸合成在2-，3-和4-位被氟，氯和三氟甲基以及在3-位被甲氧基取代的苯甲基缩水甘油，并将其分离为（RR）-和（在Chiralpak AD或AS手性固定相上使用亚临界流体色谱法和MeOH在CO2中的混合物进行SS）-对映异构体。分析了这些化合物以及市售的（RR）-和（S，S）-苯基缩水甘油的振动圆二色性（VCD），电子圆二色性（ECD）和旋光性（OR）性质，以举例说明采用绝对常见和关键手性中间体的立体化学是在制药公司的药物发现计划的结构-活性和结构-性质关系阶段早期建立的。通过这项研究，发现合成分子的苯基中的取代基不会显着改变光谱特征，因此，相应VCD光谱中的诊断吸收带以及测得的ECD曲线的符号和形状可用于确定和跟踪类似物的绝对立体化学，而不必对所有化合物的所有低能构象异构体进行耗时的从头算。发现利用混合B3PW91功能和TZVP基础集在DFT级别上进行的VCD，OF和ECD计算对于确定绝对构型特别有用。手性19：716-730，2007.（c）2007 Wiley-Liss，Inc.

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