In seminal work conducted 35-40 years ago, Stammer and co-workers established that ,dehydroamino acids (AAs) such as Ala, Z-Phe, and Z-Leu could improve the proteolytic stability of the enkephalin peptide hormones. This phenomenon can be attributed to the A1,3 strain caused by the alkene, which limits the conformational freedom of AAs and increases the rigidity of peptides that contain them. This rigidity favors folded states instead of random coil conformations and leads to greater stability since folded peptides undergo proteolysis more slowly than unfolded peptides. Subsequent to Stammer's pioneering investigations, Chauhan and others 19 studied the impact of AAs containing trisubstituted alkenes (e.g., Phe, Leu) on peptide structure. In general, these residues promote the formation of -turns or 310 helices (Figure ). In fact, Dong and co-workers recently exploited the turninducing properties of Phe as an aid to cyclizing pentapeptides. This AA and its analogs have been inserted into the backbones of bioactive peptides with promising results. Phe and other AAs that incorporate trisubstituted alkenes are typically encountered as the more stable Z-isomers due to challenges in constructing the E-isomers and E-to-Z isomerization that often occurs during peptide coupling reactions. Despite their presence in bioactive peptides including the yaku'amides, phomopsins, and myxovalargin A, bulky dehydroamino acids such as Val and Ile that contain tetrasubstituted alkenes have been less studied than their counterparts with trisubstituted Z-alkenes (Figure ). We hypothesized that the elevated A1,3 strain characteristic of bulky AAs would render them more effective than smaller AAs at rigidifying peptides and increasing their proteolytic stability. However, this strain also makes them more difficult to incorporate into peptides than their smaller relatives. A few years ago, we developed a protocol for synthesizing peptides containing Val and its bis-homolog dehydroethylnorvaline (Env) via solid-phase peptide synthesis. We applied this method to the construction of -hairpins and demonstrated that inserting bulky AAs into these peptides leads to an increased preference for the folded state as well as substantially higher proteolytic stability. The synthetic challenges that we faced during this endeavor, which included construction of congested azlactone dipeptides and sluggish couplings of these species, caused us to wonder how the effect of bulky AAs on peptide structure and stability compared to that of medium-sized AAs with trisubstituted alkenes. Specifically, we were unsure if the extra effort required to furnish peptides containing bulky AAs was worthwhile. Comparisons of these two types of AAs in the literature have been limited to studies of individual amino acids 27f-h or dipeptides 27a that are too small to exhibit secondary structure.