Triphosgene: an efficient carbonylating agent for liquid and solid-phase aza-peptide synthesis. Application to the synthesis of two aza-analogues of the AChR MIR decapeptide

Abstract

The N alpha/C alphaH exchange in aza-peptides has the advantage of preserving the side chain. Bis(trichloromethyl)carbonate or triphosgene is a solid, stable phosgene substitute which retains its high reactivity. Temperature and coupling times are greatly reduced with reference to other usually recommended carbonylating agents, while purity and yield are increased. It has been used, in both liquid- and solid-phase procedures, for the synthesis of various aza-analogues of dipeptides, tripeptides and decapeptides containing the alanine, aspartic acid and asparagine aza-residue.

Novel Solid-Phase Synthesis of Azapeptides and Azapeptoides via Fmoc-Strategy and Its Application in the Synthesis of RGD-Mimetics

“…Instead of the expected reaction, compound 4 was converted quantitatively into the bis-Fmoc-carbonic dihydrazide, whereas 6 afforded impure carbazic acid chloride 7 . The in situ activation of Boc-protected hydrazines with triphosgene in the presence of N -methylmorpholine was reported by Marraud et al , Unfortunately, our attempts to activate 4 with phosgene in the presence of tertiary bases such as Et 3 N, DIEA, pyridine, collidine, or N -methylmorpholine afforded a mixture of side products. In contrast to the activation of Boc-protected hydrazines, we did not need to neutralize the hydrogen chloride formed during the reaction, since the Fmoc-protected hydrazines are stable under acidic conditions.…”

Access to N -Fluorinated Azapeptides and Azapeptoids as Peptidomimetic Scaffolds

“…In order to introduce the carbonyl group, compound 11a was treated with triphosgene (bis (trichloromethyl) carbonate/BTC), at 0 °C in the presence of DIPEA in dichloromethane. − After 30 min, a solution of L -Leu methyl ester hydrochloride and DIPEA in DCM was added in one portion. Unfortunately, instead of obtaining the desired azapeptide, the reaction yielded a very stable oxadiazolone intermediate due to an undesired intramolecular cyclization, already observed in the literature.…”

Aza-Amino Acid Scanning of Secondary Structure Suited for Solid-Phase Peptide Synthesis with Fmoc Chemistry and Aza-Amino Acids with Heteroatomic Side Chains

“…With N ‘-alkyl carbazates 3a − j in hand, we examined next their incorporation into peptides as activated aza-amino acids. Carbonyl activation reagents that have been successful for forming aza-peptide bonds in solution include carbonyldiimidazole, bis(pentafluorophenyl)carbonate, ,, bis(trichloromethyl)carbonate (BTC), ,, p -nitrophenylchloroformate, , as well as phosgene 44 in toluene solution. In our hands, activation of the N ‘-alkyl carbazate was achieved conveniently by treating carbazates 3a − j in DCM with a 2-fold excess of a phosgene solution in toluene at room temperature.…”