A Brønsted acid catalyzed aza-Friedel-Crafts reaction of indolizines with 3-hydroxyisoindolinones has been established, which constructs isoindolinone derivatives bearing a tetrasubstituted stereocenter in good to high yields and enantioselectivities. Notably, this strategy provides a new access to C1-functionalization of indolizines with excellent regioselectivities. Moreover, this intriguing C1-regioselective transformation was induced under thermodynamic control.