To investigate the effect of aromatic backbone modifications we looked for a model peptide that had several desirable properties. First, a peptide already containing an aromatic group was prioritized so that it was clear where to install the modification. Second, we looked for a peptide for which a robust total synthesis had been described. Various natural product peptides could satisfy these criteria but we found Sanguinamide A (Fig. ) to be particularly suitable. Although no biological function has been described, the peptide has been shown to have a medium degree of cell permeability and even bioavailability (F = 7 %). The total synthesis was described by the Fairlie group and consists of the assembly of a leucine modified thiazole building block which is installed into the peptide using standard Fmoc-based solid phase peptide synthesis (SPPS). After linear assembly, the peptide is cyclized in solution in good yields. However, what attracted our attention the most about Sanguinamide A, was a second report by the Fairlie group where it was demonstrated that the cellular uptake as well as bioavailability could be improved by exchanging the alanine residue for a tert-butyl glycine (Danamide F, F = 51%, Fig. ). Further work by the Lokey group also demonstrated that subtle modifications to side chains or by backbone N-methylation lead to significant changes in the membrane permeability. These reports clearly indicated that cellular uptake of this scaffold could be modulated and set the stage for our work to study the effect of backbone aromatics.