The Effect of Backbone‐Heteroatom Substitution on the Folding of Peptides – A Single Fluorine Substituent Prevents a β ‐Heptapeptide from Folding into a 3 14 ‐Helix (NMR Analysis)

The β ‐heptapeptides H‐ β hVal‐ β hAla‐ β hLeu‐ β hAla(X n )‐ β hVal‐ β hAla‐ β hLeu‐OH 3 – 7 with central 3‐amino‐2‐fluoro‐, 3‐amino‐2,2‐difluoro‐, or 3‐amino‐2‐hydroxybutanoic acid residues ( β hAla(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‐CONH 2 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 ).