Chiral Brønsted Acid Catalyzed Pinacol Rearrangement

The privileged spiro[pyrrolidin-3,3'-oxindole] derivatives exhibit important biological activities. An enantioselective organocatalytic approach to the rapid synthesis of spiro[pyrrolidin-3,3'-oxindole] derivatives with high enantiopurity and structural diversity is described. The asymmetric catalytic three-component 1,3-dipolar cycloaddition of a broad range of methyleneindolinones with aldehydes and amino esters in the presence of chiral phosphoric acid provides spirooxindole derivatives in high yield with unusual regiochemistry and excellent stereoselectivities (up to 98% ee) under mild conditions. The straightforward construction of spirooxindole skeletons with high stereo- and regioselectivity suggests a new avenue to medicinal chemistry and diversity-oriented synthesis. Theoretical calculations disclosed that both the azomethine ylide and the methyleneindolinone are hydrogen-bonded with the phosphoric acid, which accounted for the high enantio- and regioselectivity and indicated that the unusual regioselectivity results from the stabilization stemming from the favorable pi-pi stacking interaction between the oxo-indole ring and the conjugated esters.