Synthesis of Aib- and Phe(2Me)-Containing Cyclopentapeptides

Abstract

Some recently described pentapeptides containing the alpha,alpha-disubstituted alpha-amino acids Aib and Phe(2Me) have been cyclized in DMF solution using diphenyl phosphorazidate (DPPA), O-(1H-benzotriazol-1-yl)-N,N,N’,N’-tetamethyluronium tetrafluoroborate/1-hydroxybenzotriazole (TBTU/HOBt), and diethyl phosphorocyanidate (DEPC), respectively, to give the corresponding cyclopentapeptides in fair-to-good yields. In the case of peptides with L-amino acids, and (R)- and (S)-Phe(2Me), the yields differed significantly in favor of the L/(R) combination. The conformations in the crystals of cyclo(Gly-Aib-(R,S)-Phe(2Me)-Aib-Gly) and cyclo(Gly-(R)-Phe(2Me)-Pro-Aib-Gly) have been determined by X-ray crystallography, leading to quite different results. In the latter case, the conformation in solution has been elucidated by NMR studies.