Late-Stage N-Alkylation of Azapeptides

Abstract

Azapeptides undergo on-resin, late-stage N-alkylations to install side chains with high chemoselectivity for the hydrazide nitrogen atoms. The major product is the N1-alkylated “azapeptoid”, with only small amounts (<10%) of alkylation occurring at the other aza-amino acid nitrogen (N2). Dialkylations are also possible and afford highly functionalized, disubstituted azapeptides with side chains installed on both aza-amino acid nitrogen atoms. The site-selectivity was determined using Edman degradation, MS/MS sequencing, and comparative LCMS and NMR analyses.

Synthesis and biological evaluation of novel all-hydrocarbon cross-linked aza-stapled peptides

“…The second alkenyl aza-amino acid residue could not however be introduced using the same protocol, due to the risk of alkylation of the β-NH of the aza-residue within the sequence. 24 The second alkenyl aza-amino acid residue was therefore introduced by employing an azadipeptide building block. The final ring-closing olefin metathesis between two alkenyl aza-amino acid residues would provide the designed all-hydrocarbon aza-stapled peptides.…”

Chemical Tagging of Bioactive Amides by Cooperative Catalysis: Applications in the Syntheses of Drug Conjugates

“…The late-stage functionalization of bioactive organic molecules permits facile access to drug analogues while omitting the need for potentially cumbersome total syntheses. − Protocols for the chemical tagging of natural products and pharmaceuticals are central to drug discovery as they expand the scope of small-molecule drugs that can be linked to biomolecules or other therapeutic reagents. − Processes of particular importance are those that incorporate chemical handles for azide–alkyne cycloaddition, − ,− ,− thiol-Michael addition (e.g., maleimide), ,,,− hetero Diels–Alder reaction (e.g., tetrazine), ,,− …”

Stapling of leu-enkephalin analogs with bifunctional reagents for prolonged analgesic activity

“…11–13 Therefore, the synthesis of conformationally constrained leu-enkephalin analogs has been developed over many decades in the search for new peptidomimetics with improved stability and biological activity. Numerous analogs were obtained by cyclization, 14 substitution of single amino acid residues with natural or unnatural amino acids, 15 incorporation of cyclopropane-based scaffolds, 16 introduction of linear and oligoheterocyclic motifs, 17 introduction of amide bond isosters (ester, N -methylamide, triazole, alkene, trifluoroethylamine, azapeptide and fluoroalkene), 18 introduction of sugar moieties, 19 β-turn mimetic synthesis 20 and retropeptide synthesis. 21…”