In 1979, Balaram and co-workers synthesized tetrapeptide 1 (Figure ) and studied its structure using X-ray crystallography and NMR spectroscopy. They determined that 1 forms two overlapping -turns in solution and in the solid state, representing an incipient 310 helix due to the presence of consecutive (i  i + 3) hydrogen bonds. This compound is well-suited as a system for studying the impacts of different AAs on peptide structure and stability, as the turn-inducing properties of these residues should cause subtle yet measurable perturbations to its secondary structure. Moreover, the short and simple sequence of 1 should render its AA-containing variants synthetically accessible and relatively straightforward to study via NMR spectroscopy. Thus, we targeted peptides 2 (Figure ) in which the Aib-1 residue is replaced by Val (2a), Ala (2b), or Z-Abu (2c) in order to probe the impact of these AAs when they are inserted at the (i + 1) position of one of the -turns contained in the incipient 310 helix. Similarly, peptides 3 would permit evaluation of the effect of AAs when placed at the (i + 2) position. The synthesis of analog 2a incorporating a bulky AA in place of the Aib-1 residue in 1 commenced with the construction of tripeptide 5 via coupling of Aib-Ala-OMe ( ) and Cbz-Pro (Scheme 1). The moderate yield is presumably due to the steric hindrance of the two coupling partners. Val derivative 7 was generated in good yield by using Martin sulfurane to dehydrate -OHVal derivative 6, which is readily available via OsO4-catalyzed aminohydroxylation. Saponification of 7 was sluggish owing to the A1,3 strain caused by the -methyl groups, with two days required to obtain complete conversion to acid 8. Coupling of this acid with the amine derived from hydrogenolysis of tripeptide 5 furnished the targeted tetrapeptide 2a in reasonable yield considering bulkiness of the reactants.