Synthesis of Z-Protected Aib- and Phe(2Me)-Containing Pentapeptides and Their Crystal Structures

A series of pentapeptide derivatives containing alpha,alpha-disubstituted alpha-amino acids have been prepared by a combination of the 'azirine/oxazolone method' and segment condensations. X-Ray crystal-structure determinations of the molecular structures confirmed the presence of helical conformations stabilized by beta-turns of type III or III’. Pentapeptides containing (R)-Phe(2Me) form a right-handed helix, whereas those containing (S)-Phe(2Me) adopt a left-handed helical structure

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

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

Synthesis of Cyclopentapeptides with Three to Five Aib Units

Four new Aib-containing cyclopentapeptides have been synthesized by cyclization of the corresponding linear pentapeptides using the diethyl phosphorocyanidate (DEPC)/EtN(iPr)2 method. The linear precursors were prepared via the 'azirine/oxazolone method', i.e., the Aib units were introduced by the reaction of amino acids or peptide acids with a 2,2-dimethyl-2H-azirin-3-amine, followed by selective hydrolysis of the terminal amide function. Most remarkably, cyclo[(Aib)5] exists in CDCl3 solution in a symmetrical conformation, i.e., no intramolecular H-bonds are detectable