Amyloids DOI: 10.1002/anie.200802587 A Fiberlike Peptide Material Stabilized by Single Intermolecular Hydrogen Bonds** Gaetano Angelici, Giuseppe Falini, Hans-Jörg Hofmann, Daniel Huster, Magda Monari, and Claudia Tomasini* Aggregation and disaggregation are central phenomena in nature. [1] In this context, formation of fibers through self- assembly is of particular interest, as protein fibers are involved in intra- and extracellular functions. Moreover, several diseases such as Alzheimer)s or prion diseases are characterized by extracellular protein depositions. [1–4] Recently, it was demonstrated that b-sheet layers are the most stable superstructure, although an exact explanation for the existence of this “dead-end” structure cannot yet be given. [5] To understand aggregation phenomena, oligopeptides that interfere with [6–8] or mimick [9–14] these processes may be designed and prepared. Indeed, the potential applications of such supramolecular assemblies exceed those of synthetic polymers since the building blocks may introduce biological function in addition to mechanical properties. [15] All reported examples show fiber-forming peptides that are stabilized in the solid state by at least two N À H···O = C hydrogen bonds. Herein, we present a fiberlike material that is stabilized by only single hydrogen bonds between dipeptide units. Such an assembly represents the absolute borderline case of a sheet structure. The fiberlike material was obtained by aggregation of Boc-l-Phe-d-Oxd-OBn (1; Boc = tert-butoxycarbonyl; Phe = phenylalanine; Oxd = 4-methyl-5-carboxy oxazolidin-2-one; Bn = benzyl), [16, 17] which can be easily synthesized by coupling of Boc-l-Phe-OH with H-d-Oxd-OBn (for details, see the Supporting Information). Compound 1 was purified by flash chromatography using a 1:1 mixture of cyclohexane and ethyl acetate as the eluting solvent. The formation of a fiberlike white solid was detected after evaporation of the mixture overnight. Moreover, a 20– 25 mm solution of 1 in the same solvent mixture forms a gel, which becomes a white solid after slow solvent evaporation (Figure 1 a). The molecule also shows good solubility in polar solvents, such as acetonitrile, methanol, diethyl ether, and ethyl acetate, but is not soluble in water. It assembles to form a fiberlike material under a wide variety of solution con- ditions. This material shows strong birefringence and has defined edges. It is made of bundles of crystalline-shaped filaments clustered and aligned along the main bundle direction (Figure 1 b). The IR spectra of 1 in dichloromethane and of a 1 % mixture of solid 1 with KBr showed very different results. Hydrogen bonding is clearly present in the solid but is distinctly diminished in solution, indicating its intermolecular character. The analysis of the C =O region (1600–1850 cm À1 ) confirms this conclusion (Figure 2). A small fragment of 1 was examined by scanning electron microscopy (SEM; Figure 3 a). Interestingly, the thickness and width of the mature filaments are almost constant, regardless of the solvent conditions for assembly, whereas their length varies widely even under a single set of experimental conditions. The material is stable. Its overall shape was conserved in the precipitation media for several months and even after it was air-dried. Only strong thermal Figure 1. Boc-l-Phe-d-Oxd-OBn (1) after slow evaporation of a 1:1 mixture of cyclohexane/ethyl acetate. a) String of pure 1 after slow evaporation of the solvent from a 25 mm solution. b) Optical micro- graph obtained through crossed polarizers of fiberlike material. Scale bar:0.3mm. [*] Dr. G. Angelici, Prof.Dr. G. Falini, Prof.Dr. M. Monari, Prof.Dr. C. Tomasini Dipartimento di Chimica “G. Ciamician”, Alma Mater Studiorum Università di Bologna Via Selmi 21, 40126 Bologna (Italy) Fax:(+ 39)051-209-9456 E-mail: claudia.tomasini@unibo.it Prof.Dr. H.-J. Hofmann Institute of Biochemistry, University of Leipzig Brüderstraße 34, 04103 Leipzig (Germany) Prof.Dr. D. Huster Institute of Medical Physics and Biophysics, University of Leipzig Härtelstrasse 16–18, 04107 Leipzig (Germany) [**] G.A., G.F., M.M., and C.T. thank the Ministero dell’Università e della Ricerca Scientifica (PRIN 2006) and Università di Bologna (Funds for selected topics) for financial support. H.-J.H. and D.H. are obliged to the DFG (SFB 610, HO 2346/1-3) for funding. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.200802587. Angewandte Chemie 8075 Angew. Chem. Int. Ed. 2008, 47, 8075 –8078 # 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim