From Polyesters to Polyamides Via ON Acyl Migration: An Original Multi‐Transfer Reaction

Abstract

A new strategy for the synthesis of polyamides from polyesters of hydroxyl-containing amino acids using a multi O-N acyl transfer reaction was developed. This original approach allowed the synthesis of three generations of polymers from the same starting monomer. The polymerization of N-benzyloxycarbonyl-serine and its γ-homologated derivative provided the Z-protected polyesters; then the water-soluble polycationic polyesters were obtained by removal of the Z-protecting group; and finally the polyamides were obtained by a base-induced multi O-N acyl transfer, both in aqueous or organic medium. The key step transfer reaction was monitored by the disappearance and appearance of characteristic NMR proton signals and IR bands of polyesters and polyamides.

Synthesis and mechanistic investigations of pH-responsive cationic poly(aminoester)s

“…33 The proposed 1,5-O/N acyl shi has been reported for related processes in poly(aminoesters) (PAEs) containing side-chain amines. 25,69,70 The proposed 1,6-O/N acyl shi is analogous to that reported by Almutairi and coworkers for 6-and 7-membered acyl shis in PAEs featuring side chain nucleophiles. 23,26,27,30 However, the rapid and highly selective sequence of alternating 1,5-and 1,6-cyclizations to generate diketopiperazine 5 is a novel and characteristic feature for the degradation of the poly(a-amino esters) such as P1 + .…”

“…14) and literature precedent [59][60][61][62][63][64] also indicate that the rapid rate at P1 + degradation can be in part attributed to the activating effect of the aammonium substituent, which predisposes the adjacent ester for nucleophilic attack. 33 As the pH increases, more of the ammonium groups are deprotonated, facilitating cyclization by a 1,5-O/N acyl shi 25,53,62,64,72,73 to generate an N-hydroxyethylamide intermediate A (Fig. 16).…”

“…The potential toxicity of the (aza)quinone methide byproducts 15 has stimulated research into alternative chemistries for stimuli-sensitive degradation processes, 16 including disuldebased self-immolative systems that degrade upon reduction, 17,18 acid-labile polymers, [19][20][21][22] or amine-functionalized polyesters and polycarbonates that degrade either through intramolecular nucleophilic attack or by hydrolysis. 11,[23][24][25][26][27][28][29][30][31] Cationic poly(aminoester)s are an attractive class of materials due to the tunable lability of the ester linkage 32 and the functional cationic ammonium repeat units that can bind appropriate polyanionic cargoes and then become neutral, enabling cargo release. Several classes of cationic poly(aminoester)s have been shown to undergo pHsensitive degradation resulting from deprotonation of embedded ammonium groups, which leads to nucleophilic attack on the ester backbone.…”

“…Several classes of cationic poly(aminoester)s have been shown to undergo pHsensitive degradation resulting from deprotonation of embedded ammonium groups, which leads to nucleophilic attack on the ester backbone. [23][24][25]30,33 Cationic poly(b-aminoester)s have demonstrated good biocompatibility and are used in a wide range of biomedical applications, 34,35 highlighted by recent advances in gene delivery vehicles for a variety of therapeutic indications. [36][37][38][39][40][41][42][43] We recently reported a novel class of materials based on cationic poly(a-aminoester) backbones that undergo a pHsensitive rapid and selective degradation to neutral amide and amino acid byproducts in water.…”

The Application of Isoacyl Structural Motifs in Prodrug Design and Peptide Chemistry

“…The same group also reported an interesting application of isoacyl motifs in the biodegradable polymer.T he polyesterm aterial, consisting of multiple isoacyl motifs, was water soluble;h owever,o nce exposed to physiological conditions, it was converted into an insoluble polyamide. [64]…”