Ligand-controlled chemoselectivity in gold-catalyzed cascade cyclization of 1,4-diene-tethered 2-alkynylbenzaldehydes

A method to chemo- and stereoselectively assemble polycyclic bridged pyrrolidines and azepines which relies on the gold(i)-catalyzed cascade annulation of skipped 1,4-diene-tethered 2-alkynylbenzaldehydes is described. The divergence in product selectivity was accomplished by controlling the reaction pathway of the surmised Au-bound benzopyrylium species, generated from 6-endo-dig oxycyclization of the substrate, and by changing the steric nature of the ligand of the metal complex. With BrettPhosAuNTf(2) (BrettPhos = dicyclohexyl(2 ',4 ',6 '-triisopropyl-3,6-dimethoxy-[1,1 '-biphenyl]-2-yl)phosphine) as the catalyst, the ensuing [3 + 2] cycloaddition/cyclopropanation cascade of the metal-bound cyclic oxonium intermediate was found to occur to afford the cyclopropane-fused bridged-pyrrolidine product. The presence of SIMesAuNTf(2) (SIMes = 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene) as the catalyst, on the other hand, was observed to result in an Au-bound benzopyrylium intermediate undergoing a sequential [3 + 2] cycloaddition followed by selective C(sp(3))-H bond insertion in the ensuing gold carbenoid species to give the cyclopropane-bridged-azepine ring system. The synthetic utility of the divergent catalytic protocol was demonstrated by the late-stage modification of a series of structurally complex natural products and drug molecules under mild reaction conditions.

Automated summary

This study presents a method to selectively assemble polycyclic bridged pyrrolidines and azepines using gold(I)-catalyzed cascade annulation, showcasing the divergent product selectivity by controlling the reaction pathway and ligand steric nature of the metal complex. The synthetic utility of this divergent catalytic protocol was demonstrated by modifying structurally complex natural products and drug molecules under mild reaction conditions, highlighting its potential applications in drug synthesis and natural product modification.