The Use of Aryl Hydrazide Linkers for the Solid‐Phase Synthesis of Chemically Modified Peptides

Abstract

Since Merrifield introduced the concept of solid phase synthesis in 1963 for the rapid preparation of peptides, a large variety of different supports and resin-linkers have been developed that improve the efficiency of peptide assembly and expand the myriad of synthetically feasible peptides. The aryl hydrazide is one of the most useful resin-linkers for the synthesis of chemically modified peptides. This linker is completely stable during Boc-and Fmoc-based solid phase synthesis and yet it can be cleaved under very mild oxidative conditions. The present article reviews the use of this valuable linker for the rapid and efficient synthesis of C-terminal modified peptides, head-to-tail cyclic peptides and lipidated peptides.

Improved Total Synthesis and Biological Evaluation of Coibamide A Analogues

“…First our efforts were focused on determining the optimal resin for the solid-phase peptide synthesis (SPPS) and thus the cyclization point. In our previous total synthesis of coibamide A, aryl hydrazide resin was chosen because the aryl hydrazide linker is stable in both strongly basic and acidic conditions, 19 thus allowing the use of an Fmoc-based solid-phase method that is also compatible with trifluoroacetic acid (TFA) deprotection. 17 Therefore, the commercially available amino acid, Fmoc-Nmethyl-O-tert-butyl-L-threonine could be applied for successive solid-phase assembly of the main peptidyl chain followed by removal of the tert-butyl ( t Bu) group with TFA and introduction of MeAla via the ester bond formation for elongation of the branched chain.…”

Chemical Synthesis, Backbone Cyclization and Oxidative Folding of Cystine-knot Peptides — Promising Scaffolds for Applications in Drug Design

“…Interestingly, it has not been checked so far, whether 2-methylpiperidine could solve these problems as its utility for the synthesis of peptides with piperidine-labile tyrosine sulfate esters was demonstrated [ 91 ]. The third possibility, though not yet elaborated, might be the usage of safety-catch linkers (e.g., hydrazinobenzoyl) which can be cleaved by a respective nucleophile after suitable activation [ 92 , 93 ].…”