The Effect of Backbone‐Heteroatom Substitution on the Folding of Peptides – A Single Fluorine Substituent Prevents a β‐Heptapeptide from Folding into a 314‐Helix (NMR Analysis)

The β‐heptapeptides H‐βhVal‐βhAla‐βhLeu‐βhAla(X_n)‐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(X_n)) 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 F? C and the C?O 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).