Gold-catalyzed domino cyclization enabling construction of diverse fused azaspiro tetracyclic scaffolds: a cascade catalysis mechanism due to a substrate and counterion

• Published in: Catalysis science & technology Vol. 1; no. 8; pp. 2415 - 2426
• Main Authors: Li, Yunhe, Zhao, Xiang
• Format: Journal Article
• Language: English
• Published: Cambridge Royal Society of Chemistry 01.01.2020
• Subjects: Activation energy; Alkaloids; Catalysis; Catalysts; Gold; Hydrogen bonding; Scaffolds; Selectivity; Substrates
• ISSN: 2044-4753; 2044-4761
• DOI: 10.1039/d0cy00120a

The detailed mechanism and origins of gold-catalyzed domino cyclization to diverse fused azaspiro tetracyclic scaffolds by cooperative dual catalysis and cascade catalysis are systematically studied. Unexpectedly, the results showed that the reaction order of the cooperative and cascade catalysis mechanisms was divergent. Specifically, the gold-counterion cascade catalysis mechanism was the most plausible mechanism for domino cyclization because of its hydrogen bonding bridge, small activation energy, and favorable coordination mode in the transition states (TS) and intermediates. Based on the Curtin-Hammett principle, the calculated activation energy of 28.0 kcal mol −1 was the rate-determining step for the overall reaction. Besides, the energy profiles for three different models, i.e. catalysts without an OTf − counterion, a phenolic Ugi adduct as a substrate, and a NTfc 2 − counterion, were investigated to compare the cooperative dual catalysis and cascade dual catalysis mechanisms. The calculations revealed that the selectivity for tetracyclic alkaloids versus spirocarbocyclic products was determined by the thermodynamic stability of the tetracyclic TS. This research not only highlights the balance of periplanar conformation and activation mode in cascade catalysis but also provides valuable guidance for catalyst design in domino cyclization. The detailed mechanism and origins of gold-catalyzed domino cyclization to diverse fused azaspiro tetracyclic scaffolds by cooperative dual catalysis and cascade catalysis are systematically studied.