Organocatalytic Asymmetric [5 + 3] Domino Annulation: Direct Access to Enantioenriched Eight-Membered Bridged Dihydroazocino[4,5- <i>b</i> ]indolizines

We present here a chiral phosphoric acid (CPA)-catalyzed formal [5 + 3] annulation reaction of <i>ortho</i>-indolizinyl anilines with chalcones. This intriguing Schiff-base/Friedel-Crafts domino cyclization enabled the direct and efficient synthesis of enantioenriched eight-membered bridged heterocycles with good to high yields and excellent stereoselectivities (up to 98% yield, 99% ee). The mild reaction conditions, excellent enantioselectivity, broad substrate tolerance, and diverse product transformations demonstrated the practical synthetic utility of this method. Detailed mechanistic investigations have elucidated that the catalytic cycle operates via an ion pair mechanism involving a chiral phosphoric acid (CPA) catalyst, which facilitates a domino reaction sequence comprised of initial Schiff-base formation followed by a stereoselective Friedel-Crafts reaction.