Conventional wisdom indicates that AAs are reactive electrophiles that undergo conjugate additions by biological nucleophiles such as thiols. In fact, enzyme-catalyzed conjugate additions of thiols to Ala and Abu are involved in the biosynthesis of lantibiotics. However, a close look at the literature reveals that uncatalyzed conjugate additions of thiols to AAs larger than Ala typically require large excesses of thiol to proceed. Alternatively, placement of the AA at the C-terminus of a peptide instead of embedded within the backbone can increase its electrophilicity. Based on these prior results, we postulated that steric hindrance at the -carbon atom would significantly attenuate the reactivity of medium-sized and bulky AAs to thiols in the absence of enzymes. We probed this hypothesis by exposing solutions of 2a-c and 3a-c in DMSO-d6 to ca. 2 equiv of cysteamine, a highly nucleophilic thiol. As anticipated, Ala-containing peptides 2b and 3b were steadily consumed under these conditions. The decomposition of cysteamine in DMSO solution complicated our efforts to calculate halflives for these reactions. Nonetheless, it was clear that 3b was consumed more rapidly than 2b, as 65% of the former and 93% of the latter remained after 40 minutes of incubation at room temperature.