The Effect of Backbone-Heteroatom Substitution on the Folding of Peptides - A Single Fluorine Substituent Prevents a?-Heptapeptide from Folding into a314-Helix (NMR Analysis)

The β-heptapeptides H-βhVal-βhAla-βhLeu-βhAla(Xn)-βhVal-βhAla-βhLeu-OH 3–7 with central 3-amino-2-fluoro-, 3-amino-2,2-difluoro-, or 3-amino-2-hydroxybutanoic acid residues (βhAla(Xn)) of like and unlike configuration were subjected to a detailed NMR analysis in MeOH solution. For the geminal difluoro and for the F- and OH-substituted derivatives of u-configuration (see 5, 4, and 7, resp.), 14-helices were found, i.e., with axial disposition of the hetero atoms on the helix. The two compounds containing the central l-configured β-amino acid moieties (see 3 and 6) are not helical over the full lengths of the chains; they have ‘quasi-helical’ termini and a central turn consisting of a ten-membered H-bonded ring (Fig. 2, d and e). Quantum-mechanical calculations with l- and u-AcNH-CHMe-CHF-CONH2 confirm the observed preference for a conformation with antiperiplanar arrangement of the FC and the CO bond. The calculated energy difference between the observed ‘non-helical’ geometry of this moiety and a hypothetical helical one is 6.4 kcal/mol (Fig. 3).