Coupling of Peptides using Ethyl Propiolate

23 May 2005

The coupling of protected amino-acids remains a challenging reaction, despite the plethora of new reagents introduced in the last few years such as EDC/HOBt, PyBOP, PyBroP, HATU and FDPP. It has now been found that ethyl propiolate reacts with protected amino acids in the presence of a catalytic amount of nucleophile (e.g. tertiary amine) to give an active ester, which can be aminolysed to give a depeptide and ethyl formylacetate (Iorga B et al, Synlett, 2004, 1826). Use of 1.5eq base allows the amine hydrochloride salt of one component to be used. The usual protecting
groups (Boc, Cbz, Fmoc) are well tolerated. Reactions with hydroxylamine and Weinreb amine were also successful. Unfortunately, the authors use chloroform as solvent and it would be desirable to replace this with something else, preferable a nonchlorinated solvent. Using the catalytic procedure (NMM as base) 3% racemisation was observed – the same as with PyBOP, but with stoichiometric base 30% racemisation is observed.