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

Abstract

The detailed mechanism and origins of gold-catalyzed domino cyclization to diverse fused azaspiro tetracyclic scafffolds 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 was the rate-determining step for the overall reaction. Besides, the energy profiles for three different models, i.e. catalysts without OTfˉcounterion, the use of phenolic Ugi adduct as substrate, and NTf2ˉcounterion, were investigated to compare the cooperative dual catalysis and cascade dual catalysis mechanisms. The calculations revealed that the selectivity of tetracyclic alkaloid versus spirocarbocyclic product 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 a valuable guidance to catalyst design in domino cyclization.

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Supplementary files

Article information


Submitted
20 Jan 2020
Accepted
18 Mar 2020
First published
19 Mar 2020

Catal. Sci. Technol., 2020, Accepted Manuscript
Article type
Paper

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

Y. Li and X. Zhao, Catal. Sci. Technol., 2020, Accepted Manuscript , DOI: 10.1039/D0CY00120A

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