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 (À)-epineoclausenamide and (+)-epineoclausenamide were 1.3(+):98.7(À) and 99.3(+):0.7(À), 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.

A new method for the synthesis of (-)-clausenamide was reported. (-)-Clausenamide was synthesized starting from the inexpensive trans-cinnamic acid. The synthesis was carried out over five steps, and the overall yields were 8.9% (99.9% ee). Compared with the multi-step asymmetric synthesis methods reported in the literature, the raw materials used in this method are inexpensive. The overall method is easy to carry out. Furthermore, the reaction takes place under very mild reaction conditions (25 °C). Anhydrous and very low temperature (-78 °C) conditions can be avoided. The column chromatography technique need not be conducted after each reaction step. Hence, this is a suitable method to carry out the large-scale synthesis of (-)-clausenamide. The structures were confirmed using the 1 H NMR, 13 C NMR, and MS techniques.