Synthesis and Conformational Preferences of a Potential β-Sheet Nucleator Based on the 9,9-Dimethylxanthene Skeleton

A 4,5-disubstituted-9,9-dimethylxanthene-based amino acid (10) has been synthesized for incorporation into peptide sequences which have a propensity to adopt beta-sheet structure. Molecular dynamics studies support the FT-IR and NMR results which demonstrate that amides based on this residue utilize the NH and the C=O from the xanthene residue to form an intramolecular hydrogen bond (13-membered ring), unlike the previously studied dibenzofuran-based amino acid residues in which the NH and the C=O of the attached amide groups participate in intramolecular hydrogen bonding (15-membered ring). Interestingly, residue 10 derivatized as a simple amide prefers to adopt a trans conformation where the aliphatic side chains are placed on opposite sides of the plane of the 9,9-dimethylxanthene ring system. This is different than the conformational preferences of the dibenzofuran-based amino acids which adopt a cis conformation that is preorganized to nucleate beta-sheet formation. It will be interesting to see how these conformational differences effect nucleation in aqueous solution.