Controversy of Peptide Cyclization from Tripeptide

The present investigation reports an attempt to synthesize naturally occurring α-cyclic tripeptide cyclo(Gly-l-Pro-l-Glu) 1, [cyclo(GPE)], previously isolated from the Ruegeria strain of bacteria with marine sponge Suberites domuncula. Three linear precursors, Boc-GPE(OBn)₂, Boc-PE(OBn)G and Boc-E(OBn)GP, were synthesized using a solution phase peptide coupling protocol. Although cyclo(GPE) 1 was our original target, all precursors were dimerized and cyclized at 0 °C with high dilution to form corresponding α-cyclic hexapeptide, cyclo(GPE(OBn))₂7, which was then converted to cyclic hexapeptide cyclo(GPE)₂2. Cyclization at higher temperature induced racemization and gave cyclic tripeptide cyclo(GP_DE(OBn)) 9. Structure characteristics of the newly synthesized cyclopeptides were determined using ¹H-NMR, ¹³C-NMR and high-resolution mass spectrometry. The chemical shift values of carbonyls of 2 and 7 are larger than 170 ppm, indicating the formation of a cyclic hexapeptide.