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

Abstract

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.