Chiral gamma-lactams are effective structural motifs found in numerous pharmaceutical agents. Despite their importance, current approaches mostly necessitate laborious synthetic steps employing pre-functionalized starting materials under demanding conditions. In this regard, asymmetric C-H amidation can provide an ideal platform for rapid construction of this valuable scaffold from unactivated materials, but unsolved issues have hampered the strategy. Here, we report iridium catalysts that overcome these challenges by utilizing chiral hydrogen-bond-donor ligands. The protocol makes use of easily accessible substrates derived from carboxylic acid, which display excellent efficiency and enantioselectivity towards direct amidation of prochiral sp(3) C-H bonds. Desymmetrization of meso-substrates is also achieved, where two consecutive stereogenic centres are selectively introduced in a single transformation. Computational investigations reveal the presence of crucial hydrogen bonding in the stereo-determining transition states and spectroscopic analysis of the structural analogues further corroborate this non-covalent interaction.