Solid-Phase Synthesis of Hybrid 2,5-Diketopiperazines Using Acylhydrazide, Carbazate, Semicarbazide, Amino Acid, and Primary Amine Submonomers

Abstract

We report the solid-phase synthesis of N,N′-di­(acylamino)-2,5-diketopiperazine, an acylhydrazide-based conformationally rigid 2,5-DKP scaffold having exocyclic N–N bonds. We also show that different combinations of acylhydrazides, carbazates, semicarbazides, amino acids, and primary amines can be used to synthesize a highly diverse collection of hybrid DKP molecules via the solid-phase submonomer synthesis route. Finally, we show incorporation of a methyl substituent in one of the carbon atoms of the DKP ring to generate chiral daa- and hybrid-DKPs without compromising the synthetic efficiency.

Sidechain‐Backbone Tetrel Bonding Interactions Provide a General Mechanism for trans‐Peptoid Stabilization

“…To incorporate backbone chirality, we synthesized chiral azapeptoid monomers 19 – 23 (Figure 3) by following a method previously developed in our group [64] . 1 H and 2D‐NOESY NMR studies showed the presence of only the trans amide isomer of 19 – 23 in CDCl 3 and C 6 D 6 .…”

“…To incorporate backbone chirality, we synthesized chiral azapeptoid monomers 19-23 (Figure 3) by following a method previously developed in our group. [64] 1 H and 2D-NOESY NMR studies showed the presence of only the trans amide isomer of 19-23 in CDCl 3 and C 6 D 6 . We could crystallize compounds 19 and 20, which also confirmed backbone trans amide geometries of these molecules.…”

Diketopiperazine Gels: New Horizons from the Self-Assembly of Cyclic Dipeptides

“…Solid-phase synthesis of CDPs [ 77 , 78 ] offers the possibility to rapidly gain access to a plethora of structurally complex products [ 79 ]. Solid-phase methods can be very convenient for the rapid screening of arrays of libraries obtained through the parallel synthesis of CDPs, for instance via the SPOT method on cellulose membranes ( Scheme 2 ) [ 80 ].…”