A practical large-scale synthesis of cyclic RGD pentapeptides suitable for further functionalization through click' chemistry

A multigram batch of the cyclo[Arg-Gly-Asp-d-Phe-Lys] and its N - azido derivative was accomplished via solution-phase synthesis using an epimerization-free fragment condensation. The C-terminus of d-Phe was protected as its tert-butyl ester. Fmoc (Arg, Gly, Asp, d-Phe) and Boc (Lys) groups were used to protect all N - termini. The Ts and NO² groups, respectively were chosen to protect the guanidine group. The macrocyclization step (between d-Phe and l-Lys) was carried out under TBTU/HOBt or DPPA condensation conditions. Finally, the -amino group of the lysine residue was selectively converted into the azido group by a diazo-transfer reaction.