title: Origins of enantioselectivity in the chiral Brønsted acid catalyzed hydrophosphonylation of imines.
abstract: The results of an experimental and ONIOM-based computational investigation of the mechanism and the origins of enantioselectivity in the asymmetric synthesis of alpha-amino phosphonates by an enantioselective hydrophosphonylation of imines catalyzed by chiral Brønsted acids are reported. It was found that the enantioselectivity observed in the enantioselective hydrophosphonylation of the imine with a benzothiazole moiety was poor. A detailed computational study with a two-layer ONIOM (B3LYP/6-31G(d)/AM1) method on the mechanism of the investigated reaction was carried out to explore the origins of the enantioselectivity. Calculations indicate that the investigated reaction is a two-step process involving proton-transfer and nucleophilic addition, which is the stereo-controlling step. The investigated reaction prefers a di-coordination pathway to a mono-coordination pathway. The different enantioselectivities exhibited by three kinds of catalyst and two kinds of nucleophile were rationalized. Calculations indicate that si-facial attack is higher in energy than re-facial attack by only 0.1 kcal/mol, which accounts well for the low ee value observed in the enantioselective hydrophosphonylation of the imine with a benzothiazole moiety. The energy barrier for phosphonate-phosphite tautomerism catalyzed by chiral Brønsted acid in toluene is only 1.8 kcal/mol, which could explain why the investigated reaction can take place at room temperature.
authors.affiliation: Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Center for Research and Development of Fine Chemicals, Guizhou University, Huaxi District, Guiyang 550025, PR China. fcc.fqshi@gzu.edu.cn
authors.forename: Fu-Qiang
authors.initials: FQ
authors.lastname: Shi
authors.forename: Bao-An
authors.initials: BA
authors.lastname: Song
mesh_terms: D000143:Acids / Q000737:chemistry*; D002384:Catalysis; D003198:Computer Simulation; D007097:Imines / Q000737:chemistry*; D008956:Models, Chemical; D015394:Molecular Structure; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry; D010766:Phosphorylation; D013237:Stereoisomerism
chemical_list: D000143:Acids; D007097:Imines; D063065:Organophosphonates