A Comprehensive Mechanistic Scenario for Asymmetric Cross-Coupling Reaction of Diazoacetate and Terminal Alkyne under Copper Catalysis

Terminal alkynes have emerged as highly versatile building blocks for constructing C-C bonds. These compounds are thought to undergo conversion to acetylide intermediates before further transformation. In the present work, the possible reaction mechanisms of the cross-coupling reaction of diazoacetate with alkyne under copper catalysis are investigated using the M06-L method. Two different reaction pathways including a copper-acetylide mechanism and a copper-carbene mechanism are investigated and comparatively analyzed. Computational results demonstrate that the energetically favored pathway follows a copper-acetylide mechanism, comprising alkynation of the terminal alkyne, carbenation, carbene insertion, Aldol reaction, and catalyst regeneration. In contrast, the alternative pathway involving a carbenation-alkynation sequence is found to be less favorable. The rate-determining step is verified by the carbenation process, which also determines the stereoselectivity. Noncovalent interaction (NCI) analysis reveals that noncovalent interactions between the diazo and indane groups of the bisoxazoline ligand are important in controlling stereoselectivity. Calculations involving a series of chiral ligands further demonstrate that the bulky indane moiety in the bisoxazoline ligand is essential for achieving stereoselectivity, consistent with experimental observations.