Abstract
The acidity of the α-proton in peptides has an essential role in numerous biochemical reactions and underpins their stereochemical integrity, which is critical to their biological function. We report a detailed kinetic and computational study of the acidity of the α-proton in two cyclic peptide systems: diketopiperazine (DKP) and triketopiperazine (TKP). The kinetic acidity (protofugality) of the α-protons were determined though hydrogen deuterium exchange studies in aqueous solutions. The acidities of the α-proton in prolyl residues were increased by 3–89 fold relative to other amino acid residues (prolyl > glycyl ≫ alanyl > tyrosyl). Experimental and computational evidence for the stereoelectronic origins of this enhanced prolyl reactivity is presented. TKPs were 106-fold more reactive than their DKP analogues towards deprotonation, which we attribute to the advanced development of aromaticity in the earlier transition state for proton transfer in these cases. A Brønsted linear free energy analysis of the reaction data was conducted to provide estimates of α-proton pKas.
Highlights
Proline is unique amongst the proteinogenic amino acids in its ability to induce structural and conformational modi cations in proteins.[1]
The acidities of the a-proton in prolyl residues were increased by 3–89 fold relative to other amino acid residues
Our new data highlights that cyclisation of a peptide substantially increases the labilities of the a-protons, which can be further enhanced by stereoelectronic factors especially in the case of Pro residues
Summary
Proline is unique amongst the proteinogenic amino acids in its ability to induce structural and conformational modi cations in proteins.[1]. Proline and smallmolecule derivatives have been widely shown to be efficient, stereoselective catalysts for a range of (bio)organic transformations.[12,13,14,15,16,17] The superior abilities of proline derivatives as organocatalysts compared with other amino acids is o en ascribed to the increased nucleophilicity of the prolyl secondary amine and in uence on cis/trans isomerism in enamine intermediates.[18,19,20,21,22,23,24] Mayr and co-workers have demonstrated a 100fold increased nucleophilicity of the secondary amino group of proline towards reaction with diarylcarbenium ions relative to the primary amino groups of other amino acids.[25] Myers and Raines recently reported a detailed kinetic study of the hydrogen–deuterium exchange reactions of cyclohexanone catalysed by proline derivatives in aqueous solution Their kinetic structure–activity analysis demonstrated that inter- and intramolecular electrostatic interactions involving charged and electron-rich atoms derived from the proline catalyst, cyclohexanone substrate and buffer can have dramatic in uences on catalytic activity.[26] Xaa-Pro bonds are a highly. The slopes of linear ts of the H/D-exchange kinetic data are the
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