Prindl Martha I, Westwood Matthew T, Goodfellow Alister S, McKay Aidan P, Cordes David B, Bühl Michael, Smith Andrew D
EaStCHEM, School of Chemistry, University of St Andrews, St Andrews, Fife, KY16 9ST, UK.
Angew Chem Int Ed Engl. 2025 May;64(19):e202425305. doi: 10.1002/anie.202425305. Epub 2025 Mar 31.
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.
吡唑杂环广泛存在于各种医药和农用化学品中，因此，非常需要开发将它们对映选择性引入分子骨架的方法。本论文描述了通过异硒脲（HyperSe）催化的对映选择性[3 + 3]-迈克尔加成环化过程，以易得的吡唑基磺酰胺或吡唑酮作为亲核试剂前体，α,β-不饱和酸酐作为起始原料，高效地形成具有高对映选择性（高达>99:1 er）的稠合吡唑并吡啶酮和吡喃酮。机理分析表明存在一条不寻常的自我校正反应途径，涉及亲核试剂前体优先进行[1,2]-加成以最初生成一种中间体酰胺或酯，该中间体可被异硒脲酰化作用截获，从而导致以高对映体控制高效形成稠合杂环产物。通过一系列实例研究了该过程的适用范围和局限性，并通过密度泛函理论（DFT）分析深入了解了导致观察到的对映选择性的因素。
