The preparation of optically active epineoclausenamide and enantiomeric separation of its racemate

• Published in: Chirality (New York, N.Y.) N.Y.), 2021-10, Vol.33 (10), p.643-651
• Main Authors: Yan, Yixiao, Zhu, Senmei, Luo, Xuna, Rao, Yu, Su, Jinlong, He, Guantao, Lin, Hansen
• Format: Article
• Language: English
• Subjects: (+)‐epineoclausenamide; (−)‐epineoclausenamide; asymmetric synthesis; chemical resolution; enantiomeric resolution; Enantiomers; Flow rates; Flow velocity; Hexanes; High performance liquid chromatography; HPLC; Isomers; Liquid chromatography; Optical activity; Quality control; Reagents; Reduction; Separation
• ISSN: 0899-0042; 1520-636X
• DOI: 10.1002/chir.23341

We synthesized the optically active epineoclausenamide by utilizing chiral reagents, such as R‐α‐methylbenzylamine and S‐α‐methylbenzylamine, for the resolution of the intermediate (trans‐3‐phenyl‐oxiranecarboxylic acid 12), followed by amide exchange, cyclization, and reduction, unlike previously reported methods. The Meerwein–Ponndorf–Verley reduction was used to asymmetrically reduce neoclausenamidone. A plausible reduction mechanism of this method was elucidated. Thereafter, high‐performance liquid chromatography (HPLC) was investigated for the resolution of the epineoclausenamide enantiomers. HPLC was also used to determine the optical purity of these isomers. Two chiral stationary phases (CSPs) for separating the enantiomers were compared. Different mobile phase compositions were tested at 298.15 K. The results showed that the best separation was obtained when the mobile phase was composed of n‐hexane and isopropanol (IPA) (75/25, v/v), the racemate was separated on a Chiralcel OJ‐H column, and the flow rate was 1.0 mL/min at a wavelength of 210 nm and a temperature of 25°C. The enantiomeric ratio (e.r.) values of both the synthetic (−)‐epineoclausenamide and (+)‐epineoclausenamide were 1.3(+):98.7(−) and 99.3(+):0.7(−), respectively. In this study, a new synthetic route was designed with a yield of 12.3–14.1%, and a quick (8 min) effective separation method was obtained. This provides basis for pharmacological research and quality control of clausenamide analogues. We synthesized the optically active epineoclausenamide by utilizing chiral reagents, such as R‐α‐methylbenzylamine and S‐α‐methylbenzylamine, for the resolution of the intermediate (trans‐3‐phenyl‐oxiranecarboxylic acid 12), followed by amide exchange, cyclization, and reduction, unlike previously reported methods. This new synthetic route was designed with a yield of 12.3–14.1%. Thereafter, HPLC was investigated for the resolution of the epineoclausenamide enantiomers. A quick (8 min) effective separation method was obtained.