Mechanistic Insights on Organocatalytic Enantioselective Decarboxylative Protonation by Epicinchona-Thiourea Hybrid Derivatives

摘要

Mechanism and the origin of enantioselectivity in the decarboxylativenprotonation of α-amino malonate hemiester promoted by epicinchona−thiourea hybridnorganocatalyst is established by using the DFT(M06-2X/6-311+G**//ONIOM2)ncomputational methods. The origin of stereoselectivity rendered by this hybridnbifunctional catalyst in asymmetric protonation is investigated for the first time usingnsuitable transition-state models. A detailed conformational analysis of N-[3,5-nbis(trifluoromethyl)]phenylthiourea-based epicinchonidine reveals the potential for anbifunctional mode of activation of the substrate α-amino malonate hemiester throughnhydrogen bonding. Six different conformer families differing in characteristic dihedralnangles are identified within a range of 16 kcal/mol with respect to the lowest energynconformer. Different likely mechanistic pathways obtained through detailed analysis ofnthe transition states and intermediates are compared. It is identified that in the preferrednpathway, the decarboxylation is followed by a direct proton transfer from the chiralnquinuclidinium moiety to the enolate carbon as opposed to a conventional protonation at the enolate oxygen followed by anketo−enol tautomerization. The factors responsible for high levels of observed stereoselectivity are traced to interestingnhydrogen-bonding interactions offered by the thiourea−cinchona bifunctional framework. The predicted stereoselectivities usingncomputed Gibbs free energies of diastereomeric transition states are in fair agreement with the experimental stereoselectivities.