Chiral Phosphoric Acid-Catalyzed Enantioselective Higher-Order Cycloadditions: Temperature-Dependent Periselectivity

Higher-order cycloadditions (HOCs) are powerful tools for constructing complex cyclic structures, but their synthetic utility is often limited by poor periselectivity and challenges in achieving high diastereo- and enantioselectivity. Herein, we report a chiral phosphoric acid-catalyzed reaction between tropones and trifluoroacetamido-1,3-dienes that proceeds efficiently at room temperature, delivering bicyclo[4.4.1]undecatrienones in high yields with excellent peri-, diastereo-, and enantioselectivities. Without isolation, these (6 + 4) cycloadducts undergo a regioselective Cope rearrangement at 100 °C, yielding bicyclo[3.2.2]nonadienones─products of formal (4 + 2) cycloaddition. Remarkably, 7-alkyl-substituted analogues undergo a distinct transformation at 150 °C, producing tetracyclic products featuring a unique decahydro-1,5-methanoazulene motif. The presence of multiple functional groups in these adducts provides versatile synthetic handles for the further derivatization of these structurally intricate bridged polycyclic molecules.