Activation of carboxyl group with cyanate: peptide bond formation from dicarboxylic acids

Abstract

The reaction of cyanate with C-terminal carboxyl groups of peptides in aqueous solution was considered as a potential pathway for the abiotic formation of peptide bonds under the condition of the primitive Earth. The catalytic effect of dicarboxylic acids on cyanate hydrolysis was definitely attributed to intramolecular nucleophilic catalysis by the observation of the 1H-NMR signal of succinic anhydride when reacting succinic acid with KOCN in aqueous solution (pH 2.2-5.5). The formation of amide bonds was noticed when adding amino acids or amino acid derivatives into the solution. The reaction of N-acyl aspartic acid derivatives was observed to proceed similarly and the scope of the cyanate-promoted reaction was analyzed from the standpoint of prebiotic peptide formation. The role of cyanate in activating peptide C-terminus constitutes a proof of principle that intramolecular reactions of adducts of peptides C-terminal carboxyl groups with activating agents represent a pathway for peptide activation in aqueous solution, the relevance of which is discussed in connexion with the issue of the emergence of homochirality.

The Activation of Free Dipeptides Promoted by Strong Activating Agents in Water Does not Yield Diketopiperazines

“…By contrast, no epimerization was observed using cyanate as a potrential activating agent and the only product was the N-carbamoylated product (14.1 min, ESI-MS positive mode m/z 332.12 [M+Na + ]). This observation confirms the absence of reactivity of this reagent for the activation of protected peptides except C-terminal aspartyl peptides (Danger et al 2012a). As regards pre-activated substrates, the reactivity of the methyl ester was sluggish at room temperature and yielded mostly the hydrolysis product.…”

Systems chemistry of α-amino acids and peptides

“…But it was observed that succinic anhydride could be formed intramolecularly from succinic acid in the presence of cyanate. In the same way, peptides having a C-terminal aspartyl residue were observed to undergo coupling with cyanate as an activating agent (Figure 3) [20]. This possibility is enabled by the neighbouring group participation of the β-carboxyl group leading to a five-membered cyclic anhydride (Figure 3).…”

“…However, we observed that the degree of activation of cyanate is usually not sufficient to activate carboxylic acids, and no reaction occurred when attempting to couple acetyl alanine with glycine or glycine derivatives in water at pH values close to neutrality in the presence of cyanate [20]. But it was observed that succinic anhydride could be formed intramolecularly from succinic acid in the presence of cyanate.…”

“…The new and improbable properties emerging this kind of processes are the object of study of Systems Chemistry [16,17]. We report here on the conceptual background leading our studies [18] and on the results of studies carried out to assess the possibilities of a potential Systems Chemistry of α-amino acids and peptides [19][20][21].…”

5(4H)‐Oxazolones as Intermediates in the Carbodiimide‐ and Cyanamide‐Promoted Peptide Activations in Aqueous Solution

“…However, alternative explanations could be proposed. [8a] The cyanate-mediated activation of peptides with a C-terminal aspartyl residue [9] proceeds similarly by cyclization, and amino acid N-carboxyanhydrides are involved when activated a-amino acids are coupled at the N terminus. [5a] The formation of 5(4H)-oxazolones has exhaustively been studied owing to its importance for the chiral integrity of synthetic peptides, [7] a result of the fast proton exchange at the a-carbon atom in the presence of bases.…”