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-epsilon-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-alpha-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 e-amino group of the lysine residue was selectively converted into the azido group by a diazo-transfer reaction.