A Crown Ether-Derived Chiral Phosphoric Acid for Catalytic Asymmetric Synthesis of 3,4-Dihydro-2 H -1,2,4-benzothiadiazine-1,1-dioxides

-1,2,4-benzothiadiazine-1,1-dioxides (DHBDs) are core structural units in numerous biologically active molecules and chiral drug molecules. However, current catalytic synthetic methods for chiral DHBDs exhibit limitations, including limited substrate versatility and relatively unsatisfactory stereocontrol efficiency. This study has successfully developed a novel crown ether-derived chiral phosphoric acid catalyst, which can effectively catalyze the asymmetric tandem acetalization reaction between 2-aminobenzenesulfonamides and aldehydes, affording 36 chiral DHBDs under optimized conditions in 63-91% yield and 82-99% ee. Notably, this catalytic system exhibits broad substrate applicability, demonstrating high catalytic activity and excellent enantioselectivity toward both aromatic and aliphatic aldehydes, featuring simple operation and enabling gram-scale preparation. It is evidenced that the electron-rich, flexible structural features of crown ethers allow them to adaptively accommodate substrates through noncovalent interactions and therefore effectively promote the reactions in high reactivity and stereoselectivity.