Methodology for the Absolute Configuration Determination of Epoxythymols Using the Constituents of Ageratina glabrata

• Published in: Journal of natural products (Washington, D.C.) Vol. 81; no. 1; pp. 63 - 71
• Main Authors: Arreaga-González, Héctor M, Pardo-Novoa, Julio C, del Río, Rosa E, Rodríguez-García, Gabriela, Torres-Valencia, J. Martín, Manríquez-Torres, J. Jesús, Cerda-García-Rojas, Carlos M, Joseph-Nathan, Pedro, Gómez-Hurtado, Mario A
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society and American Society of Pharmacognosy 26.01.2018
• DOI: 10.1021/acs.jnatprod.7b00637
• ISSN: 0163-3864

A methodology to determine the enantiomeric excess and the absolute configuration (AC) of natural epoxythymols was developed and tested using five constituents of Ageratina glabrata. The methodology is based on enantiomeric purity determination employing 1,1′-bi-2-naphthol (BINOL) as a chiral solvating agent combined with vibrational circular dichroism (VCD) measurements and calculations. The conformational searching included an extensive Monte Carlo protocol that considered the rotational barriers to cover the whole conformational spaces. (+)-(8S)-10-Benzoyloxy-6-hydroxy-8,9-epoxythymol isobutyrate (1), (+)-(8S)-10-acetoxy-6-methoxy-8,9-epoxythymol isobutyrate (4), and (+)-(8S)-10-benzoyloxy-6-methoxy-8,9-epoxythymol isobutyrate (5) were isolated as enantiomerically pure constituents, while 10-isobutyryloxy-8,9-epoxythymol isobutyrate (2) was obtained as a 75:25 (8S)/(8R) scalemic mixture. In the case of 10-benzoyloxy-8,9-epoxythymol isobutyrate (3), the BINOL methodology revealed a 56:44 scalemic mixture and the VCD measurement was beyond the limit of sensitivity since the enantiomeric excess is only 12%. The racemization process of epoxythymol derivatives was studied using compound 1 and allowed the clarification of some stereochemical aspects of epoxythymol derivatives since their ACs have been scarcely analyzed and a particular behavior in their specific rotations was detected. In more than 30 oxygenated thymol derivatives, including some epoxythymols, the reported specific rotation values fluctuate from −1.6 to +1.4 passing through zero, suggesting the presence of scalemic and close to racemic mixtures, since enantiomerically pure natural constituents showed positive or negative specific rotations greater than 10 units.