Investigation of a strategy to streamline the synthesis of peptides containing α,β-dehydroamino acids (ΔAAs) is reported. The key step involves generating the alkene moiety via elimination of a suitable precursor after it has been inserted into a peptide chain. This process obviates the need to prepare ΔAA-containing azlactone dipeptides to facilitate coupling of these residues. Z-dehydroaminobutyric acid (Z-ΔAbu) could be constructed most efficiently via EDC/CuCl-mediated dehydration of Thr. Formation of Z-ΔPhe by this or other dehydration methods was unsuccessful. Production of the bulky ΔVal residue could be accomplished by DAST-promoted dehydrations of β-OHVal or by DBU-triggered eliminations of sulfonium ions derived from penicillamine derivatives. However, competitive formation of an oxazoline byproduct remains problematic.
Keywords: Dehydration; Dehydroamino acids; Peptide synthesis; Proteolytic stability; Sulfonium elimination.