Theoretical Study of Mechanism and Stereoselectivity of Catalytic Kinugasa Reaction

Abstract

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 β-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.

Catalytic mechanism of human glyoxalase I studied by quantum-mechanical cluster calculations

“…In this paper, we investigate all proposed mechanisms for both the S and R substrates on an equal footing. We have used the quantum mechanical (QM) cluster approach, which has extensively been used to study catalytic mechanisms and structures of enzymes [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] . In this approach, the most important residues are cut out from the active site of the enzyme.…”

Hollow Nanospheres Constructed by CoS2 Nanosheets with a Nitrogen‐Doped‐Carbon Coating for Energy‐Storage and Photocatalysis

“…In both cases, the initial steps involve the formation of a metalated isoxazoline intermediate and subsequent ring contraction to form the β‐lactam (Scheme ). Very recently, the mechanism of the catalytic Kinugasa reaction has been investigated by means of DFT calculations 10…”

Metal Acetylides in Cycloaddition Reactions

“…In Himo's work, both the noncatalysed and the copper-promoted reaction were analysed in depth using DFT methods. A key finding in this report was the discovery of the participation of a two copper centre based acetylide, 56 a species that had also been identified in the past in the CuAAC reaction. 10,[57][58][59][60] Interestingly, the proposed mechanism that arose from this investigation merged aspects of the two previous schemes (the six-membered ring 3 and the ketene intermediate 4), in order to produce a viable overall reaction profile (Scheme 18).…”