While remarkable progress has been made over the past decade, new design strategies for chiral catalysts in enantioselective C(sp(3))-H functionalization reactions are still highly desirable. In particular, the ability to use attractive noncovalent interactions for rate acceleration and enantiocontrol would significantly expand the current arsenal for asymmetric metal catalysis. Herein, we report the development of a highly enantioselective Ir(III)-catalyzed intramolecular C(sp(3))-H amidation reaction of dioxazolone substrates for synthesis of optically enriched gamma-lactams using a newly designed alpha-amino-acid-based chiral ligand. This Ir-catalyzed reaction proceeds with excellent efficiency and with outstanding enantioselectivity for both activated and unactivated alkyl C(sp(3))-H bonds under very mild conditions. It offers the first general route for asymmetric synthesis of gamma-alkyl gamma-lactams. Water was found to be a unique cosolvent to achieve excellent enantioselectivity for gamma-aryl lactam production. Mechanistic studies revealed that the ligands form a well-defined groove-type chiral pocket around the Ir center. The hydrophobic effect of this pocket allows facile stereocontrolled binding of substrates in polar or aqueous media. Instead of capitalizing on steric repulsions as in the conventional approaches, this new Ir catalyst operates through an unprecedented enantiocontrol mechanism for intramolecular nitrenoid C-H insertion featuring multiple attractive noncovalent interactions.