Synthesis, Crystal Structures, and Modelling ofβ-Oligopeptides Consisting of 1-(Aminomethyl)cyclopropanecarboxylic Acid: Ribbon-Type Arrangement of Eight-Membered H-Bonded Rings

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Partially and fully protected, and unprotected β-oligopeptides (3 – 9) were prepared from 1-(aminomethyl)cyclopropanecarboxylic acid, which, in turn, is readily available from cyanoacetate and dibromoethane. N-Boc and C-OMe protection were applied for the fragment-coupling (1-hydroxy-1H-benzotriazole (HOBt)/1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC)) solution synthesis. X-Ray crystal structures of the dimer (3), trimer (5), and tetramer (6) are described, and compared with those of the Boc-protected building blocks (2) and of the corresponding trimer (10) consisting of 1-(aminomethyl)cyclohexanecarbonyl residues (cf. Figs. 1 and 2). While the cyclohexane derivative forms ten-membered hydrogen-bonded rings, the characteristic secondary-structural motif in the cyclopropane derivatives is an eight-membered ring with H-bonding between next neighbors (Fig. 1). All cyclopropanecarbonyl moieties in the reported structures have the – generally more stable – s-cis (`bisected') conformation of the C=O groups on the three-membered rings (not preferred with the cyclohexane analog, the exocyclic CO group of which may be in an s-trans, a perpendicular, an axial, or an equatorial position). The bisecting effect and the large exocyclic bond angle (120°) in the cyclopropane units are proposed to provide the `ordering' elements – on top of the staggering effect of the C(2)−C(3) ethane bond in all β-peptides – which lead to the observed substituent-induced turn formation. A high degree of intramolecular H-bonding is evident also from IR spectroscopy (Fig. 3), and concentration- and temperature-dependent NMR measurements (Fig. 4) of CHCl3 and CD2Cl2 solutions, indicating that the boat-type arrangement of the eight-membered rings with their unusual H-bonding geometry (Fig. 1, f ) is also present in solution. A possible structure of a poly[1-(aminomethyl)cyclopropane-carboxylic acid] consisting of a flight of stairs formed by folded H-bonded eight-membered rings is modelled, using the oligomer X-ray data (Fig. 5). The type of secondary structure found in the solid state of the β2,2-peptides reported here is unprecedented in the realm of α-peptides and proteins.