ChemInform Abstract: Review: Backbone N‐Modified Peptides: How to Meet the Challenge of Secondary Amine Acylation

Abstract

Backbone N‐substitution of peptides (N‐Me and N‐alkyl) has become of special interest as a chemical tool for peptide lead modification, either to improve biological activity or to optimize key pharmacokinetic characteristics. For the synthesis of backbone N‐methylated peptides, many protocols have been developed already, yet some effort often has to be made to find appropriate conditions for the acylation of N‐Me residues. Fewer examples are reported of peptides with other backbone N‐substituents different than N‐Me, and their synthesis is frequently reported as difficult. The synthesis of such peptides becomes more difficult as the size of the N‐substituent increases. Coupling methods that work for the synthesis of N‐methylated peptides were often found to fail when applied to peptides with larger N‐substituents. This review addresses the challenges of the synthesis of backbone N‐modified peptides, focusing on N‐substituents larger than the N‐Me group. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 104: 435–452, 2015.

Site-selective modification of peptide backbones

“…The traditional way to introduce N-alkylated amino acids in a peptide is troublesome, with poor reaction rates and many side-reactions (Scheme 32, conversion 122→123). [106][107][108] An exception is the coupling of cyclic aminoacids, such as proline and hydroxyproline. Therefore, Boto and al have suggested an alternative route (Scheme 32, conversions 124→125→123) where hydroxyproline is introduced first in the desired position, and then its scission and functionalization would readily give the desired N-alkylated peptides.…”

“…Other residues are less frequent, since the steric hindrance created by both the lateral chain and the Nsubstituents hinder peptide coupling. 106,107 The use of backbone protecting groups to enhance solubility was originally put forward with the dimethoxybenzyl (Dmb) group (Figure 1, structure 137). 111 The introduction of Dmb disrupted the hydrogen bonding that generated scarcely-soluble secondary structures, such as β-sheets, and inhibited interchain aggregation.…”