Since the advent of native chemical ligation, broadening the scope beyond cysteine-site ligations has been actively studied in peptide chemistry. Proline-site ligation, owing to intrinsic electronic properties, is putatively the most challenging site, indicated both by the longest reaction times and the paucity of methodologies to address this problem. In this study, salicylaldehyde is first installed at phenolic site, furnishing the aldehyde for capture of 4-hydroxyproline’s amine. Upon capture, through a Schiff’s base-type mechanism, an iminium species is formed, inducing the 4-hydroxyl group to attack. This frees the amine to attack the N-term carboxyl, brought into proximity by the phenolically attached salicylaldehyde. The hemiaminal reforms the aldehyde of salicylaldehyde, liberating the amine of hydroxyproline and the newly ligated fragments. Salicylaldehyde is acidolyzed from the 4-hydroxyl position, yielding native peptide product.<br/>This approached was successfully demonstrated on various syntheses of oligopeptides, as verified by NMR, elemental analysis, and mass spectrometry.<br/>

Novel hydroxyproline methodology involving an auxiliary salicylaldehyde capture followed by imine-induced intramolecular rearrangement to achieve chemoselective ligations at difficult proline site<br />
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249th National Meeting (2015)

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Novel hydroxyproline methodology involving an auxiliary salicylaldehyde capture followed by imine-induced intramolecular rearrangement to achieve chemoselective ligations at difficult proline site<br /> <br />