Conformational restriction through C-i(alpha)<->C-i(alpha) cyclization: 1-aminocycloheptane-1-carboxylic acid (Ac(7)c)

A complete series of N-and C-blocked, monodispersed homo-oligopeptides to the pentamer level from 1-aminocycloheptane-1-carboxylic acid (Ac(7)c), an alpha-amino add conformationally restricted through C-1(alpha)<->C-1(alpha) cyclization, and three tripeptides with Ac(7)c combined with Ala, Leu, and Val residues have been synthesized by solution methods and fully characterized. The solution conformational preferences I have been determined by IR absorption and H-1 NMR spectroscopy, In addition, the molecular structures of three derivatives (Ac(7)c hydantoin, ClCH2CO-Ac7Ac-OH, and Z-Ac(7)c-OH; Z=benzyloxycarbonyl) and four peptides [the dipeptide ZAc(7)c-L-Ala-OMe, the tripeptides Z-Ac(7)c-(L-Ala)(2)OMe and Z-(Ac(7)c)(3)OBut, the tetrapeptide Z-(Ac(7)c)(4)-OBut, and the pentapeptide Z(Ac(7)c)(5)-OBut] have been assessed in the crystal state by X-ray diffraction. The results obtained confirm the tentative conclusions put forward on the basis of our previous preliminary study, namely that beta-bends and 3(10)-helices are preferentially adopted by Ac(7)c-based peptides. A comparison with the structural tendencies extracted from Published work on peptides from alpha-aminoisobutyric acid, the prototype of C(alpha,alpha)4-dialkylated glycines, and the other extensively investigated members of the class of 1-aminocycloalkane-1-carboxylic acids (Ac(n)c, with n = 3-6, 8, 9) is made and the implications for the use of the Ac(7)c residue in conformationally constrained analogues of bioactive peptides are briefly dicussed.