A Monocationic Zn(II) Acetate Complex of a Chiral Bisamidine Dioxolane Ligand, Naph-diPIM-dioxo-R, for the Asymmetric 1,3-Dipolar Cycloaddition of Tridentate α-Substituted α-Imino Esters and Acrylates to Multi-Substituted Prolines: Importance of an n-π* Interaction for High Enantioselectivity

A monocationic Zn(II) acetate complex of a C-2-chiral bisamidine-type sp(2)N bidentate ligand (L-R) possessing two dioxolane oxygen n orbitals in the reaction site catalyzes, without the use of an external base, a highly efficient asymmetric 1,3-dipolar cycloaddition (1,3-DC) of tridentate alpha-substituted alpha-imino esters with acrylates, attaining up to >99:1 enantiomeric ratio with perfect regio- and diastereo-selectivities. A catalyst loading of 0.1 mol% is generally acceptable to furnish various chiral multi-substituted prolines. Both (S)-alpha-imino ester and the R enantiomer show a high level of enantioselectivity. An overall picture of the present 1,3-DC has been revealed via analyses of substrate structure/reactivity/selectivity relationships, NMR, MS, X-ray diffraction, C-12/C-13 isotope effects, rate law, and kinetics. The first success in the high performance 1,3-DC is ascribed to i) a Bronsted base/Lewis acid synergistic effect of [Zn(OAc)L-R]OTf (R cat); ii) the existence of the n orbital, which determines the position of the intermediary N,O-cis-Zn enolate (dipole) by an n-pi* non-bonding attractive interaction between the oxygen atom in L-R and the C=N moiety of the dipole; and iii) utilization of chelatable alpha-imino esters capturing Zn(II) as a tridentate ligand. A C-12/C-13 analysis has clarified that a stepwise 1,3-DC mechanism is operating.

Automated summary

A monocationic Zn(II) acetate complex has been found to catalyze a highly efficient asymmetric 1,3-dipolar cycloaddition reaction without the need for an external base. Through detailed analyses of substrate structure, reactivity, and reaction mechanism, the success of the reaction has been explained.