One-pot synthesis of alternating peptides exploiting a new polymerization technique based on Ugi's 4CC reaction

Abstract

We developed a one-pot synthetic technique for alternating peptides. Central to this technique is a new, catalyst-free polymerization based on Ugi's 4CC reaction. The treatment of imines with the ambident molecules bearing both an isocyanide and a carboxylic acid afforded alternating peptides.

Synthetic Approach of Thermally Tunable Nature‐Mimetic Polypeptides from N‐Protected Alternating Peptoids

“…The polymer structure was confirmed by 1 H NMR, 13 C NMR, and IR spectra (see Supporting Information). It is noted that the broadenings in the 1 H NMR spectrum are attributed to the proximity of noncontrolled chiral centers and the existence of cis‐trans rotamers of the amide bonds . We found that the reactivity of the benzyl group was quite low.…”

“…Table 1 shows the screening of benzylic‐protecting group and the results of deprotection reactions. We started from N ‐benzyl‐protected Poly(Gly‐Val) (entries 1 and 2), because we have already developed the synthetic method of the polymer . The polymer structure was confirmed by 1 H NMR, 13 C NMR, and IR spectra (see Supporting Information).…”

“…The addition of methanesulfonic acid (MsOH) as a stronger acid than TFA afforded 60% deprotection ratio (entry 12). Although the precise reason for the moderate conversion was not clear at this moment, we made a working hypothesis that one of cis‐trans rotamers of N , N ‐disubstituted amides might exhibit low reactivity owing to the steric electron effect . Considering the thermal isomerization of unreactive rotamer, the reaction in MsOH was carried out at 100 °C, which resulted in the perfect removal of MPE to afford Poly(Gly‐Val) skeleton in a quantitative conversion (entry 13).…”

“…We sought to exploit an imine as an equivalent of III and an ambident molecule consisting of both isonitrile and carboxylic acid as IV. In fact, we found that the reaction of imine with the ambident molecule proceeded catalyst‐free polymerization to give the alternating peptoids in one‐pot . Therefore, the remaining challenge toward the synthesis of I is the elimination step of R 3 group from II.…”

“…In a recent publication, we reported a one‐pot synthetic technique for synthesizing alternating peptoids . The technique involves catalyst‐free polymerization analogous to the Ugi’s four‐component condensation (Ugi’s 4CC).…”