title: Chemo-enzymatic asymmetric synthesis of S-citalopram by lipase-catalyzed cyclic resolution and stereoinversion of quaternary stereogenic center.
abstract: A chemo-enzymatic synthesis method of S-citalopram was developed to overcome the disadvantage of relatively low selectivity of enzyme towards tertiary alcohols. The combination of kinetic resolution, cyclic resolution and stereoinversion synthesis was successfully applied in the asymmetric synthesis of the S-citalopram. Using the kinetic model to predict the cyclic resolution, R-diol with high ee value was obtained by controlling the conversion rate. Subsequently, the unwanted R-diol was inverted to S-citalopram by stereoinversion of chiral quaternary center with 98.0% yield and ee value of 91.0%. Based on dynamic simulation and experiments, the kinetic resolution was scaled up from 10 mL to 1 L and 14 L, gradually. There was no significant scale-up effect and the dynamic simulation result fitted the experimental data well, with an error of 12.5 and 14.0%, respectively. This chemo-enzymatic synthesis route is a promising model system for the production of pharmaceuticals with the chiral tertiary alcohols intermediate.
authors.affiliation: Department of Chemical and Biochemical Engineering, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China. szwang@xmu.edu.cn
authors.forename: Shi-Zhen
authors.initials: SZ
authors.lastname: Wang
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Wu
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
authors.forename: Li-Rong
authors.initials: LR
authors.lastname: Yang
mesh_terms: D000438:Alcohols / Q000737:chemistry; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D015283:Citalopram / Q000138:chemical synthesis* / Q000737:chemistry*; D015195:Drug Design; D008049:Lipase / Q000737:chemistry*; D015203:Reproducibility of Results; D012997:Solvents / Q000737:chemistry; D013237:Stereoisomerism; D013997:Time Factors
chemical_list: D000438:Alcohols; D012997:Solvents; D015283:Citalopram; D008049:Lipase