Synthesis of Monodehydro-Diketopiperazines Enabled by Cp*Rh(III)-Catalyzed Amine-Directed N–H Functionalization

A two-step, diversity-building sequence to prepare monodehydro-diketopiperazines from readily accessible materials is reported. Rh(III)-catalyzed, amine-directed N-H functionalization of a variety of α-amino amides with a diazophosphonate ester and subsequent cyclization gives phosphonate-substituted diketopiperazines. A Horner-Wadsworth-Emmons reaction then provides monodehydro-diketopiperazines with high <i>E</i>-alkene selectivity. This transformation was used to incorporate a variety of groups originating from diverse aldehydes and ketones with different steric and electronic properties. Face-selective hydrogenation to diketopiperazines is also disclosed.