Electrostatic versus Steric Effects in Peptidomimicry: Synthesis and Secondary Structure Analysis of Gramicidin S Analogues with (<i>E</i>)-Alkene Peptide Isosteres

A concise synthetic strategy was used for the first preparation of GS analogues with trisubstituted (E)-alkene peptide bond replacements. Solution and solid state conformational analysis demonstrated that the bistrifluoromethylated analogue was a superior mimic of the natural product, whereas the incorporation of methyl groups into the alkene peptide isostere led to a far greater perturbation of the secondary structure features of GS. The difference between CF3- and CH3-substitution can be explained by the superior electrostatic carbonyl group mimicry of the former function.