A practical method for the synthesis of small peptides using DCC and HOBt as activators in H2O–THF while avoiding the use of protecting groups†

The synthesis of peptides in solution proceeds through successive steps involving the removal of a protecting group and the formation of the peptide bond. While most methodological efforts have focused on the development of new protecting groups and coupling agents, methodologies based on minimal protecting groups have been less explored. In this research, a peptide synthesis methodology was developed using DCC and HOBt in THF–H₂O, avoiding the use of protecting groups, reducing reaction times, and reusing HOBt during successive couplings. The reaction conditions allow the production of peptides that can directly serve as the starting material for the next coupling, leading to the creation of small peptide sequences, which in turn are precursors to biologically important molecules. Here we explore the example of Sansalvamide as a template for other active peptides. Unlike SPPS, our methodology constructs the sequence from the N-terminus to C-terminus. This unique approach could streamline peptide synthesis and facilitate the development of complex peptides efficiently.