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))(2) 7, which was then converted to cyclic hexapeptide cyclo(GPE)(2) 2. Cyclization at higher temperature induced racemization and gave cyclic tripeptide cyclo(GP(D)E(OBn)) 9. Structure characteristics of the newly synthesized cyclopeptides were determined using (1)H-NMR, (13)C-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.