Conformational restriction through C^α_i ←→ C^α_i cyclization: 1-aminocycloheptane-1-carboxylic acid (Ac₇c)

Abstract

A complete series of N- and C-blocked, monodispersed homo-oligopeptides to the pentamer level from 1-aminocycloheptane-1-carboxylic acid (Ac₇c), an α-amino acid conformationally restricted through C_i^α ←→ C_i^α cyclization, and three tripeptides with Ac₇c combined with Ala, Leu, and Val residues have been synthesized by solution methods and fully characterized. The solution conformational preferences have been determined by IR absorption and ¹H NMR spectroscopy. In addition, the molecular structures of three derivatives (Ac₇c hydantoin, ClCH₂CO-Ac₇c-OH, and Z-Ac₇c-OH; Z = benzyloxycarbonyl) and four peptides [the dipeptide Z-Ac₇c-L-Ala-OMe, the tripeptides Z-Ac₇c-(L-Ala)₂-OMe and Z-(Ac₇c)₃-OBu^t, the tetrapeptide Z-(Ac₇c)₄-OBu^t, and the pentapeptide Z-(Ac₇c)₅-OBu^t] 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 β-bends and 3₁₀-helices are preferentially adopted by Ac₇c-based peptides. A comparison with the structural tendencies extracted from published work on peptides from α-aminoisobutyric acid, the prototype of C^α,α-dialkylated glycines, and the other extensively investigated members of the class of 1-aminocycloalkane-1-carboxylic acids (Ac_nc, with n = 3–6, 8, 9) is made and the implications for the use of the Ac₇c residue in conformationally constrained analogues of bioactive peptides are briefly discussed.

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