Advances in Fmoc solid-phase peptide synthesis.

Raymond Behrendt,Peter White,John Offer

doi:10.1002/psc.2836

Raymond Behrendt, Peter White + Show 1 more

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https://doi.org/10.1002/psc.2836

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Abstract

Today, Fmoc SPPS is the method of choice for peptide synthesis. Very‐high‐quality Fmoc building blocks are available at low cost because of the economies of scale arising from current multiton production of therapeutic peptides by Fmoc SPPS. Many modified derivatives are commercially available as Fmoc building blocks, making synthetic access to a broad range of peptide derivatives straightforward. The number of synthetic peptides entering clinical trials has grown continuously over the last decade, and recent advances in the Fmoc SPPS technology are a response to the growing demand from medicinal chemistry and pharmacology. Improvements are being continually reported for peptide quality, synthesis time and novel synthetic targets. Topical peptide research has contributed to a continuous improvement and expansion of Fmoc SPPS applications. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.

Highlights

The success of peptide drugs, notably glucagon-like peptide 1 receptor agonists, and a promising pipeline of peptide drugs has renewed interest in synthetic peptides [1,2]
The majority of synthetic peptides are prepared by Fmoc solid-phase peptide synthesis (SPPS) [4]
Fmoc SPPS was easy to automate because there was no need for corrosive TFA in the synthetic cycles and because deprotection released a fluorene group with strong UV absorption properties that gave a useful indicator of synthesis success [6]

Summary

Introduction

Neopentyl ester is stable to TFA; cleaved with sodium azide/DMSO or aq. ammonium acetate. N-alkylated cysteine underwent this reaction [265], and this observation was extended to other tertiary amides bearing a C-terminal δ- or ε-thio akyl or aryl group [266] Many of these linkers are converted to a thioester in a two-step reaction, rearrangement occurs irreversibly under strong acidic conditions followed by exchange to give a peptide thioester suitable for use in ligation. Its lack of N-substitution made it compatible with standard linkers as it was less susceptible to diketopiperazine formation [128] These N,S-acyl transfer methods are currently limited by slow-ligation kinetics in comparison with safety-catch or Boc methods and require careful control of pH and reaction conditions to achieve good results. Despite these measures, aspartimide formation is still evident [57,285]

Findings

Conclusion