Research into macrocycles as an emerging class of pharmaceutically relevant molecules has increased in recent years. Advances in combinatorial chemistry and screening have yielded a number of potent macrocycles against challenging protein targets. Although they often exhibit favorable target binding characteristics, with long off rates and high specificity, they generally tend to suffer from an inability to cross cellular membranes and are thus limited to extracellular targets. By contrast, some cyclic peptide natural products or derivatives thereof are cell permeable. This observation has led to a surge of interest in understanding the factors that govern ADME characteristics such as cell permeability, solubility and plasma stability, in medium- and large-ring macrocycles. Additionally, new synthetic strategies that allow for the synthesis of more diverse macrocycles, especially those mimicking natural products, are desired. First we investigate a cyclic peptide scaffold able to undergo an N-to-O acyl rearrangement. Despite the prevalence of head-to-side chain threonine linkages in natural products, their incorporation has been underexplored in synthetic cyclic peptides. Upon acylation of the amine with diverse carboxylic acids, the resulting cyclic depsipeptides displayed favorable cellular permeability and a conformation similar to the parent peptide. The rearrangement was found to be scaffold and conformation dependent as evidenced by molecular dynamics experiments. Additionally, we report on the effect of peptide-to-peptoid substitutions on the passive membrane permeability of an N-methylated cyclic hexapeptide. In general, substitutions maintained permeability but increased conformational heterogeneity. Diversification with nonproteinogenic side chains increased permeability up to 3-fold. Additionally, the conformational impact of peptoid substitutions within a beta-turn are explored. Based on these results, the strategic incorporation of peptoid residues into cyclic peptides can maintain or improve cell permeability, while increasing access to diverse side-chain functionality. Finally, we identified the phepropeptins as natural product cyclic peptides with potential cell permeability. Synthesis of the phepropeptins and epimeric analogues revealed much more rapid cellular permeability for the natural stereochemical pattern. Despite being more cell permeable, the natural compounds exhibited similar aqueous solubility as the corresponding epimers, a phenomenon explained by solvent-dependent conformational flexibility among the natural compounds. When analyzing the polarity of the solution structures we found that neither the number of hydrogen bonds nor the total polar surface area accurately represents the solvation energies of the high and low dielectric conformations. This work adds to a growing number of natural cyclic peptides whose solvent-dependent conformational behavior allows for a balance between aqueous solubility and cell permeability, highlighting structural flexibility as an important consideration in the design of molecules in bRo5 chemical space.