Journal of Peptide Science, Vol. 3, 110–122 (1997) Conformational Characterization of the 1-Aminocyclobutane-1-carboxylic Acid Residue in Model Peptides MADDALENA GATOS 1 , FERNANDO FORMAGGIO 1 , MARCO CRISMA 1 , CLAUDIO TONIOLO 1 , GIAN MARIA BONORA, ZETTORE BENEDETTI 3 , BENEDETTO DI BLASIO 3,4 , ROSA IACOVINO 3 , ANTONELLO SANTINI 3 , MICHELE SAVIANO 3 and JOHAN KAMPHUIS 5 1 Biopolymer Research Centre, University of Padova, Padova, Italy 2 Pharmaco-, Chemico-, Technological Department, University of Cagliari, Cagliari, Italy 3 Biocrystallography Research Centre, University of Naples "Federico II", Napoli, Italy 4 Facolta ` di Scienze Ambientali, Seconda Universita ` di Napoli, Caserta, Italy 5 DSM Research, Bioorganic Chemistry Section, 6160 MD Geleen, The Netherlands Received 18 March 1996 Accepted 13 May 1996 Abstract: A series of N- and C-protected, monodispersed homo-oligopeptides (to the dodecamer level) from the small-ring alicyclic C , -dialkylated glycine 1-aminocyclobutane-1-carboxylic acid (Ac 4 c) and two Ala/Ac 4 c tripeptides were synthesized by solution methods and fully characterized. The conformational preferences of all the model peptides were determined in deuterochloroform solution by FT-IR absorption and 1 H-NMR. The molecular structures of the amino acid derivatives Z-Ac 4 c-OH and Z 2 -Ac 4 c-OH, the tripeptides Z-(Ac 4 c) 3 - OtBu, Z-Ac 4 c-(L-Ala) 2 -OMe and Z-L-Ala-Ac 4 c-L-Ala-OMe, and the tetrapeptide Z-(Ac 4 c) 4 -OtBu were deter- mined in the crystal state by X-ray diffraction. The average geometry of the cyclobutyl moiety of the Ac 4 c residue was assessed and the (N–C –C ) bond angle was found to be significantly expanded from the regular tetrahedral value. The conformational data are strongly in favour of the conclusion that the Ac 4 c residue is an effective -turn and helix former. A comparison with the structural propensities of -aminoisobutyric acid, the prototype of C , -dialkylated glycines, and the other extensively investigated members of the family of 1- aminocycloalkane-1-carboxylic acids (Ac n c, with n 3, 5–8) is made and the implications for the use of the Ac 4 c residue in conformationally constrained peptide analogues are briefly examined. 1997 European Peptide Society and John Wiley & Sons, Ltd Keywords: -bend; cyclic amino acid; 3 10 -helix; peptide conformation, X-ray diffraction INTRODUCTION Many experimental observations have provided a firm foundation for the incorporation into peptides of -amino acids in which the C -proton has been replaced with an alkyl group as a means of restrict- ing backbone conformations as well as a tool for inhibiting biodegration [1–5]. In this regard the family of the cycloaliphatic residues Ac n c (n 3, 5–8) is valuable in the design of conformationally constrained peptides [3–5]. More specifically, the three-membered ring Ac 3 c residue shows significant preference for the ‘bridge’ region of the conformational space [6], in particular for the backbone torsion angles , 90 , 0 , that is for the position i 2 of type I(I ) and type II(II ) - turns [7–9]. This small-ring residue can also be accommodated in distorted type III(III ) -turns and Abbreviations: Ac n c, 1-aminocycloalkane-1-carboxylic acid; Ac 4 c, 1-aminocyclobutane-1-carboxylic acid; Aib, -aminoisobutyric acid or C , -dimethylglycine; TEMPO, 2,2,6,6-tetramethylpiperidinyl-1- oxy. Address for correspondence: Prof. Claudio Toniolo, Department of Organic Chemistry, University of Padova, Via Marzolo 1, 35131 Padova, Italy. Tel. (39) 49-827-5247; fax. (39) 49-827-5239. 1997 European Peptide Society and John Wiley & Sons, Ltd. CCC 1075-2617/97/020110-13 $17.50