Chiral π–Cu(ii)-catalyzed site-, exo/endo-, and enantioselective dearomative (3 + 2) cycloadditions of isoquinolinium ylides with enamides, dienamides, and a trienamide

Abstract

Here, we report a highly effective dearomative (3 + 2) cycloaddition reaction between isoquinolinium ylides and α,β-enamides, α,β–γ,δ-dienamides, or an α,β–γ,δ–ε,ζ-trienamide, which is catalyzed by a chiral π–Cu(II) complex (1–10 mol%) and proceeds in a site-selective, exo/endo-selective, and enantioselective manner. The (3 + 2) cycloaddition involving the α,β-enamides proceeds with high exo-selectivity and enantioselectivity. This method is applicable to various substrates including α-substituted, α,β-disubstituted, or β,β-disubstituted α,β-enamides, which are compounds with an intrinsically low reactivity. This method provides synthetic access to pyrroloisoquinoline derivatives with up to three chiral carbon centers, including those featuring fluorine and trifluoromethyl groups, as well as quaternary carbon centers. The (3 + 2) cycloaddition involving α,β–γ,δ-dienamides proceeds with high γ,δ-site-selectivity and enantioselectivity, whereby the exo/endo-selectivity depends on the substrates and ligands. Remarkably, the (3 + 2) cycloaddition of δ-phenyl-α,β–γ,δ-dienamide proceeds with high α,β-site-selectivity, exo-selectivity, and enantioselectivity. In a manner similar to the reaction with the α,β–γ,δ-dienamides, α,β–γ,δ–ε,ζ-trienamide furnishes a (3 + 2) cycloadduct with good ε,ζ-site-selectivity, endo-selectivity, and enantioselectivity.