Solution-phase combinatorial synthesis of (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxamides was studied. First, di-tert-butyl (2S,4S)-4-amino-5-oxopyrrolidine-1,2-dicarboxylate hydrochloride was prepared as the key intermediate in five steps from (S)-pyroglutamic acid. Acylation of the amino group followed by acidolytic deprotection gave (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxylic acids, which were then coupled with amines to furnish a library of (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxamides. Four coupling reagents, BPC, EEDQ, TBTU, and PFTU, were tested for the amidation reactions in the final step. Amidations with EEDQ and TBTU led to the desired carboxamides. On the other hand, BPC and PFTU were not suited, since diketopiperazines were sometimes obtained instead of the desired carboxamides.

Homopolypeptides of linear and star‐like architectures were prepared by polymerizing benzylic‐protected L‐glutamic acid and L‐aspartic acid N‐carboxyanhydrides (Glu NCA, Asp NCA) in DMF. The polymerization rate of the Glu NCA is faster than that of Asp NCA. Using a simple monoamino initiator, its hydrochloride, di‐, tri‐, and tetraamino functional initiators, homopolypeptides with well‐defined structures and molar masses were obtained. The molar‐mass averages of the poly(γ‐benzyl‐L‐glutamate)s lie very close to calculated values, according to the initial [M]:[I] ratios, while those of the linear poly(β‐benzyl‐L‐aspartate)s were lower than the predicted ones. PBAs had somewhat broader molar‐mass distributions than PBGs. magnified image