Lysine (Lys) residues undergoe a variety of post-translational modifications at the e-amine:  e.g., methylation,  acetylation,  propionylation, butyrylation, succinylation, ubiquitination,  and SUMOylation. These modifications can regulate diverse biological processes such as gene transcription, DNA repair and chromosome condensation. Considering that synthetic methods for making constrained lysine mimics offer potential for exploring and modulating such physiological processes, we have pursued routes to prepare aza-lysine peptides by elaborating the sub monomer synthesis of azapeptides.[1]  The copper-catalyzed reaction of Mannich reagents and aza-propargylglycine residues has now been achieved and employed to introduce a variety of alkyl substituents to the e-amine of a series of aza-lysine peptides.[2]  Employing growth hormone releasing peptide-6 (GHRP-6) to examine this method, we have produced eighteen [aza-Lys]GHRP-6 analogs in which sets of aza-Lys residues were introduced at the 3-, 4- and 5-positions.  Our presentation will focus on the solution- and solid-phase chemistry developed for this method.[1] Sabatino, D.; Proulx, C.; Klocek, S.; Bourguet, C. B.; Boeglin, D.; Ong, H.; Lubell, W. D. Org. Lett. 2009, 11, 3650�3653.[2] Peshkov, V. A.; Pereshivko, O. P.; Van der Eycken, E. V. Chem. Soc. Rev. 2012, 41, 3790�3807.

Aza-lysine peptide synthesis by copper-catalyzed reaction of Mannich reagents and aza-propargylglycines

247th National Meeting (2014)

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