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Correlating the Effects of the N-Substituent Sizes of Chiral 1,2-Amino Phosphinamide Ligands on Enantioselectivities in Catalytic Asymmetric Henry Reaction Using Physical Steric Parameters

Huang, Huayin, Zong, Hua, Bian, Guangling, Yue, Huifeng, Song, Ling
Journal of organic chemistry 2014 v.79 no.20 pp. 9455-9464
alcohols, benzaldehyde, enantioselectivity, ligands, mathematical models, organic chemistry, quantitative structure-activity relationships
In this study, a series of mono- and dialkylated chiral 1,2-amino phosphinamide ligands derived from modular (1R,2R)-diphenylethylenediamine were successfully applied in the chiral 1,2-amino phosphinamide-Zn(II) catalyzed asymmetric Henry reaction between benzaldehyde and nitromethane. Although the chiral N-monosubstituted and N,N-disubstituted 1,2-amino phosphinamide ligands gave the main alcohol products with opposite configurations, a validated quantitative structure–activity relationship (QSAR) mathematical model could be constructed between the physical Sterimol steric parameters of the N-substituents of the chiral ligands and the enantiomeric ratios of the alcohol products produced in the asymmetric Henry reaction. Since two sets of N-substituents are involved in the QSAR model construction, the key factor to succesfully construct a highly correlative and predictive model is to appropriately assign the N-substitutents. Ligand optimization based on the established QSAR model led to chiral 1,2-amino phosphinamide ligand 2r, which produced (R)-β-nitroalcohol in excellent yield and enantioselectivity (99% yield and 92% ee). In addition, a quantitative correlation could also be established with the use of subtractive Sterimol parameters.