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 E-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.