Design, synthesis, and NMR structure of linear and cyclic oligomers containing novel furanoid sugar amino acids

Sugar Amino Acids (SAAs) are sugar moieties containing at least one amino and one carboxyl group. The straightforward synthesis of two furanoid SAAs, 3-amino-3-deoxy-1,2-isopropylidene-α-D-ribofuranoic acid (f-SAA1) and 3-amino-3-deoxy-1,2-isopropylidene-α-D-allofuranoic acid (f-SAA2) starting from diacetone glucose, is described. These SAAs were used as structural templates aiming at new structures for peptidomimetic drug design, f-SAA1 resembles a β-amino acid, whereas f-SAA2 is a γ-amino acid mimetic. Thus, for the synthesis of the mixed, linear and cyclic oligomers of f-SAA1, β-homoglycine (β-hGly, also called β-alanine) was chosen as an amino acid counterpart, while for the oligomer of f-SAA2 γ-amino butyric acid (GABA) was chosen. Fmoc-[f-SAA1-β-hGly]₃-OH (3) and cyclo[f-SAA1-β-hGly]₃ (5) resemble linear and cyclic β-peptides with a very different substitution pattern, compared with the β-peptides known so far in the literature, whereas Fmoc-[f-SAA2-GABA]₃-OH (4) resembles a γ-peptide. The linear f-SAA oligomers 3 and 4 were synthesized on the solid-phase using Fmoc strategy. 23 unambiguous interresidue NOE contacts (from a total of 76 NOE values), obtained from extensive NMR studies in C₃CN, were used in subsequent simulated annealing and MD calculations, to elucidate the 12/10/12-helical structure of oligomer 3 in CH₃CN. The results indicate that f-SAA1 strongly induces a secondary structure. A characteristic CD curve for the linear oligomer 3 is observed up to 75 °C in both CH₃CN and CH₃CN/H₂O, even though 3 contains β-hGly, which is known to destabilize helices. By contrast, 4 does not seem to form a stable conformation in solution. The cyclic SAA containing oligomer cyclo [f-SAA1-β-hGly]₃ (5) exhibits a C₃ symmetric conformation on the NMR chemical shift time scale.