Tuning of the prolyl trans/cis-amide rotamer population by use of C-glucosylproline hybrids

摘要

We describe the synthesis of a fused bicyclic C-glucosylproline hybrid (GlcProH) from commercially available 2,3,4,6-tetra-O-benzyl-D-glucopyranose. The GlcProH was incorporated into the model peptides Ac-GlcProH-NHMe and Ac-Gly-GlcProH-NHMe. Postsynthetic modifications can be introduced via derivatization of the carbohydrate scaffold. Conformational analysis of the GlcProH-modified model peptides shows that while the conformation of GlcProH remains fixed, the prolyl N-terminal amide equilibrium (K-t/c) can be varied with different modifications of the carbohydrate scaffold. Simple N-acyl derivatives studied by NMR spectroscopy showed that in CD3OD there was an increase in the cis-amide content as the sugar substituents changed from benzyl (10%) to hydroxyl (22%) to acetate (36%). Similar effects were observed in DMSO-d(6). The exact nature of the influence is unclear, but it most likely arises through intramolecular interactions between sugar groups and the peptidic amide backbone. Overall, our GlcProH demonstrates variation in K-t/c through tuning of the carbohydrate scaffold: a new concept in proline peptidomimetics.