Theoretical Study on Cooperation Catalysis of Chiral Guanidine/ Copper(I) in Asymmetric Azide-Alkyne Cycloaddition/[2...

Density functional theory (DFT) calculations with BP86-D3(BJ) functionals were employed to reveal the mechanism and stereoselectivity of chiral guanidine/copper(I) salt-catalyzed stereoselective three-component reaction among N-sulfonyl azide, terminal alkyne, and isatin-imine for spiroazetidinimines that was first reported by Feng and Liu (Angew. Chem. Int. Ed. 2018, 57, 16852-16856). For the noncatalytic cascade reaction, the denitrogenation to generate ketenimine species was the rate-determining step, with an activation barrier of 25.8-34.8 kcal mol^-1. Chiral guanidine-amide promoted the deprotonation of phenylacetylene, generating guanidine-Cu(I) acetylide complexes as active species. In azide-alkyne cycloaddition, copper acetylene coordinated to the O atom of the amide moiety in guanidium, and TsN₃ was activated by hydrogen bonding, affording the Cu(I)-ketenimine species with an energy barrier of 3.5∼9.4 kcal mol^-1. The optically active spiroazetidinimine oxindole was constructed via a stepwise four-membered ring formation, followed by deprotonation of guanidium moieties for C-H bonding in a stereoselective way. The steric effect of the bulky CHPh₂ group and chiral backbone in the guanidine, combined with the coordination between the Boc group in isatin-imine with a copper center, played important roles in controlling the stereoselectivity of the reaction. The major spiroazetidinimine oxindole product with an SS configuration was formed in a kinetically more favored way, which was consistent with the experimental observation.