Oxime Carbonates: Novel Reagents for the Introduction of Fmoc and Alloc Protecting Groups, Free of Side Reactions

Abstract

Fmoc and Alloc protecting groups represent a consistent alternative to classical Boc protection in peptide chemistry. The former was established in the last decades as the α‐amino protecting group of choice, whereas the latter allows a fully orthogonal protection strategy with Fmoc and Boc. Usually, the introduction of the Fmoc and Alloc moieties takes place through their halogenoformates, azides, or activated carbonates. This rather simple reaction is accompanied by several side reactions, specially the formation of Fmoc/Alloc dipeptides and even tripeptides. The present work describes new promising Fmoc/Alloc‐oxime reagents, which are easy to prepare, stable, and highly reactive crystalline materials that afford almost contaminant‐free Fmoc/Alloc‐amino acids in high yields by following a conventional procedure. Amongst the Fmoc‐oxime derivatives, the N‐hydroxypicolinimidoyl cyanide derivative (N‐{[(9H‐fluoren‐9‐yl)methoxy]carbonyloxy}picolinimidoyl cyanide) gave the best results for the preparation of Fmoc‐Gly‐OH, which is the most predisposed to give side reactions. The same Alloc‐oxime analogue afforded the preparation of Alloc‐Gly‐OH in good yield, purity, and extremely low dipeptide formation, as analyzed by reverse‐phase HPLC and NMR spectroscopy.

Advances in Fmoc solid‐phase peptide synthesis

“…To prevent this, an intermediate silylation with chlorotrimethylsilane has been proposed to protect the carboxylic acid and prevent amino acid oligomerisation during Fmoc protection . The requirements for improved oxime base reagents have been developed for the clean introduction of the N α ‐Fmoc protecting group aiming to replace the N ‐hydroxysuccinimide activation .…”

K‐Oxyma: a Strong Acylation‐Promoting, 2‐CTC Resin‐Friendly Coupling Additive

“…In fact, the isolation and use of other oxime potassium salts had been previously reported by our group. The solid nature of such compounds simplifies the handling of such materials and helps to preserve their reactivity 20. In the case of OxymaPure ( 4 ), there is no record of the use of the OxymaPure potassium salt as an additive to carbodiimide for peptide synthesis.…”

OxymaPure Coupling Reagents: Beyond Solid-Phase Peptide Synthesis

“…In 2010, our group synthesized Fmoc/Alloc-oxime reagents and examined their efficiency for the introduction of the Fmoc/Alloc group. 72 Most commonly, Fmoc/Alloc-Cl, 73,74 Fmoc/Alloc-OSu, 75,76 and Fmoc/Alloc-N 3 77 reagents were used to synthesize Fmoc/Alloc-protected amino acids. However, these reagents have several drawbacks, for exam-ple, highly reactive chlorides may lead to the formation of dipeptide and tripeptide impurities along with the desired N-protected amino acids.…”