Design, synthesis, and characterization of biomimetic oligomers

The first synthesis of functionalized ! -peptoid macrocycles is reported. X-ray crystallographic structure of tetramer 9 reveals a C2-symmetrical derivative with unexpected all-cis-amide bonds and spatial disposition of the appendages toward the two opposite faces of the ring. Quantum calculations suggest that 9 is locked in this layout. These macrocycles constitute novel promising templates for multimeric ligation of biologically active ligands. The concept was exemplified by chemical decoration of tetramer 9 via “click” reactions. The development of oligomers with artificial backbones carrying diverse side chains, capable of mimicking bioactive peptides, is an area of intense research activity.1 These socalled peptidomimetics can be designed for conformational rigidity of the backbone, their resistance to hydrolytic peptidases and proteases,2 and their folding properties.3 Oligoureas,4 azapeptides,5 peptoids,6 γ-peptides,7 and "-peptides8 are representative oligomers that belong to this class of peptidomimetic. Among them, "-peptides have been particularly studied in this regard as "-peptides can adopt a large variety of secondary structures from very short sequences.9 This unique feature makes them not only interesting oligomers as peptidomimetics but also as foldamers for multimeric attachment of biologically active pharmacophoric groups.10 "-Peptoids represent a new class † Université Blaise Pascal Clermont-Ferrand II. ‡ Nancy Université. (1) (a) Barron, A. E. ; Zuckermann, R. N. Curr. Opin. Chem. 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(7) Pseudo-Peptides in Drug DiscoVery; Nielsen, P. E. , Ed.; WileyVCH: Weinheim, 2004; pp 33-120. (8) (a) Seebach, D. ; Matthews, J. L. Chem. Commun. 1997, 2015-2022. (b) Seebach, D. ; Beck, A. K. ; Bierbaum, D. J. Chem. BiodiVersity 2004, 1, 1111-1239. (9) (a) Martinek, T. A. ; Fülöp, F. Eur. J. Biochem. 2003, 270, 36573666. (b) Seebach, D. ; Hook, D. F. ; Glattli, A. Biopolymers 2006, 84, 2337. ORGANIC LETTERS 2008 Vol. 10, No. 5 921-924 10.1021/ol7030763 CCC: $40.75 © 2008 American Chemical Society Published on Web 02/06/2008 47 the amount of α-chiral side chains from 50% to 75% did not have a pronounced effect of the conformational preference. However, when the pattern of the side chains where shifted so that the α-chiral side chains resided on the peptoid residue (60) rather than the β-peptoid (59), the NMR-spectrum revealed a more homogeneous distribution of the cisand trans-conformations (Figure 2.2). Figure 2.2. Structures of cyclic α-/β-hybrid peptoids with different side chain distributions, and X-ray crystal structure of 60. Further, the X-ray crystal structure was solved for this compound revealing four cisamides and four trans-amides. These are distributed in pairs, giving rise to a twisted rectangular shape of the backbone, with the cis-amide pairs located at the corners. The β-peptoid with propargyl side chains has also been used in cyclic scaffolds of mixed α− and β-peptoids. An X-ray crystal structure of a tetramer, with a sequence of alternating αand β-peptoid residues, revealed all β-peptoids to be in a cisconformation while the α-peptoids where in the trans-conformation. The existing literature on linear oligomers of β-peptoids or β-peptoid-hybrids shows ambiguities concerning their foldameric properties. To obtain experimental data regarding the folding propensities of β-peptoids, we designed a series of monomers, inspired by the studies of peptoids. These monomers were designed to test the influence of steric bulk and stereo-electronic effects on the cis–trans ratio. Ultimately we hope that knowledge on how the individual residues behave, would result in guidelines to rationally design oligomers with defined structures. 2.2 Design and synthesis of monomeric β-peptoid model systems First it was decided that all model compounds should be based on acetylated βpeptoid model. This design was chosen as it was thought to mimic the local interactions encountered in an oligomer structure. In this way the effect of the side chains can be investigated with regard to steric bulk and stereoelectronic properties. Since a study has shown that the capping of these compounds are influencing on the CD-spectrum of oligomers, we decided to prepare series of both C-terminal tert-butyl