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.

Tuning conformation and properties of peptidomimetic backbones through dual N/Cα-substitution

“…A strong reagent such as triphosgene was utilized for the sterically demanding DS-peptoid monomers (see SI for detailed synthesis procedures). 17 All nine constructs were functionalized with a nitroxide radical spin-label on both termini. The nitroxide spin label was chosen to be minimally disturbing: it is small compared to commonly used fluorescent labels, and is chemically benign given the lack of charge and its “neutral” chemical property that is neither strongly hydrophobic nor hydrophilic.…”

Total Syntheses of Cathepsin D Inhibitory Izenamides A, B, and C and Structural Confirmation of Izenamide B

“…Tripeptides 24 and 25 were subjected to hydrolysis and then amidation with l -proline methyl ester hydrochloride to afford tetrapeptides 4 and 5 in 84 and 81% yield over two steps, respectively. In general, the N -Me peptide backbone near the C -terminal is prone to α-epimerization upon carboxy activation due to steric hindrance and electronic effects [28]. However, we could obtain the desired tetrapeptides without epimerization under the optimized conditions (DEPBT, CH 2 Cl 2 , 0 °C).…”

N‐methylation in amino acids and peptides: Scope and limitations

“…NMAA‐rich peptides undergo deletion of some residues during the coupling process, even when HATU, PyAOP or COMU is used, thereby leading to low yield for the target peptide …”

“…N ‐methylation affects not only the conformation of the modified amino acid but also the preceding residue. In addition, it facilitates the formation of a cis ‐peptide bond, which is thermodynamically less favored compared to the corresponding normal peptide bond …”