An efficient enantioselective reductive amination and amidation cascade reaction has been developed. Catalyzed by iridium or rhodium complexes and with the help of sets of additives, the coupling of simple alkyl diamines and α-ketoesters occurs smoothly to afford the chiral cyclic piperazinone products. For disubstituted and monosubstituted alkyl diamine substrates, the corresponding reactions proceed through distinctive types of intermediates and thus require different transition metals to achieve high enantioselectivity, namely, iridium for the former and rhodium for the latter. In this transformation, the applied highly modular phosphoramidite-phosphine hybrid ligands displayed preeminent versatility and tunability.