synthesis
Efficient synthesis of amide and peptide bonds remains a central objective in organic and medicinal chemistry, particularly in natural product synthesis. There are many different types of conventional coupling reagents such as carbodiimides, uranium salts, and phosphonium-based activators which frequently generate stoichiometric waste, induce racemization, and require extensive purification. In this study, we report a rapid, metal-free, and operationally simple precursor (highly reactive allene intermediates) for the synthesis of substituted amides and dipeptides employing prop-2-ynyl-triphenylphosphonium bromide. In the presence of triethylamine, prop-2-ynyl-triphenylphosphonium bromide undergoes base-promoted isomerization to generate an allene species in situ, which reacts with N-protected amino acids to provide activated ester intermediates. Subsequent coupling with C-protected amino acid esters affords the corresponding amides and dipeptides through clean –CONH– bond formation, enabling efficient amino acid conjugation. The method was successfully applied to prepare a series of many different substituted dipeptides in a very effective way while isolated yields were up to 85% without chromatographic purification. The present synthesis protocol offers significant advantages such as operational simplicity, waste minimization, broad substrate scope, and so on, which lead a better efficiency to facilitate peptide coupling processes.
