Isoselenourea‐Catalyzed Enantioselective Pyrazolo‐Heterocycle Synthesis Enabled by Self‐Correcting Amide and Ester Acylation

Pyrazole heterocycles are prevalent in a wide range of medicinal and agrochemical compounds, and as such, the development of methods for their enantioselective incorporation into molecular scaffolds is highly desirable. This manuscript describes the effective formation of fused pyrazolo-pyridones and -pyranones in high enantioselectivity (up to >99:1 er) via an isoselenourea (HyperSe) catalyzed enantioselective [3 + 3]-Michael addition-cyclization process using readily available pyrazolylsulfonamides or pyrazolones as pronucleophiles and α,β-unsaturated anhydrides as starting materials. Mechanistic analysis indicates an unusual self-correcting reaction pathway involving preferential [1,2]-addition of the pronucleophile to initially generate an intermediate amide or ester that can be intercepted by isoselenourea acylation, leading to productive formation of the fused heterocyclic products with high enantiocontrol. The scope and limitations of this process are developed across a range of examples, with insight into the factors leading to the observed enantioselectivity provided by density functional theory (DFT) analysis.