Theoretical study of mechanism and stereoselectivity of catalytic Kinugasa reaction.

The mechanism of the catalytic Kinugasa reaction is investigated by means of density functional theory calculations. Different possible mechanistic scenarios are presented using phenanthroline as a ligand, and it is shown that the most reasonable one in terms of energy barriers involves two copper ions. The reaction starts with the formation of a dicopper-acetylide that undergoes a stepwise cycloaddition with the nitrone, generating a five-membered ring intermediate. Protonation of the nitrogen of the metalated isoxazoline intermediate results in ring opening and the formation of a ketene intermediate. This then undergoes a copper-catalyzed cyclization by an intramolecular nucleophilic attack of the nitrogen on the ketene, affording a cyclic copper enolate. Catalyst release and tautomerization gives the final ß-lactamic product. A comprehensive study of the enantioselective reaction was also performed with a chiral bis(azaferrocene) ligand. In this case, two different reaction mechanisms, involving either the scenario with the two copper ions or a direct cycloaddition of the parent alkyne using one copper ion, were found to have quite similar barriers. Both mechanisms reproduced the experimental enantioselectivity, and the current calculations can therefore not distinguish between the two possibilities.

Theoretical mechanistic study of the TBD-catalyzed intramolecular aldol reaction of ketoaldehydes.

The intramolecular aldol reaction of acyclic ketoaldehydes catalyzed by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) is investigated using density functional theory calculations. Compared to the proline-catalyzed aldol reaction, the use of TBD provides a unique and unusual complete switch of product selectivity. Three mechanistic pathways are proposed and evaluated. The calculations provide new insights into the activation mode of bifunctional guanidine catalysts. In the favored mechanism, TBD first catalyzes the enolization of the substrate and then the C-C bond formation through two concerted proton transfers. In addition, the computationally predicted stereochemical outcome of the reaction is in agreement with the experimental findings.

Phosphoric acid catalyzed enantioselective transfer hydrogenation of imines: a density functional theory study of reaction mechanism and the origins of enantioselectivity.

The phosphoric acid catalyzed reaction of 1,4-dihydropyridines with N-arylimines has been investigated by using density functional theory. We first considered the reaction of acetophenone PMP-imine (PMP=p-methoxyphenyl) with the dimethyl Hantzsch ester catalyzed by diphenyl phosphate. Our study showed that, in agreement with what has previously been postulated for other reactions, diphenyl phosphate acts as a Lewis base/Brønsted acid bifunctional catalyst in this transformation, simultaneously activating both reaction partners. The calculations also showed that the hydride transfer transition states for the E and Z isomers of the iminium ion have comparable energies. This observation turned out to be crucial to the understanding of the enantioselectivity of the process. Our results indicate that when using a chiral 3,3'-disubstituted biaryl phosphoric acid, hydride transfer to the Re face of the (Z)-iminium is energetically more favorable and is responsible for the enantioselectivity, whereas the corresponding transition states for nucleophilic attack on the two faces of the (E)-iminium are virtually degenerate. Moreover, model calculations predict the reversal in enantioselectivity observed in the hydrogenation of 2-arylquinolines, which during the catalytic cycle are converted into (E)-iminium ions that lack the flexibility of those derived from acyclic N-arylimines. In this respect, the conformational rigidity of the dihydroquinolinium cation imposes an unfavorable binding geometry on the transition state for hydride transfer on the Re face and is therefore responsible for the high enantioselectivity.