Total synthesis of motuporin and 5-[L-Ala]-motuporin

Total synthesis of the cyclic peptide hepatotoxin motuporin is described, i ncluding an efficient synthesis of the constituent amino acid Adda. Three s trategies to motuporin are outlined with their relative strengths and weakn esses. Cyclization of the linear peptide precursor was found to proceed mod erately well for peptides containing the N-methyldehydrobutyrine residue ma sked as a threonine, but significant C-terminal epimerization occurred in t he presence of the dehydroamino acid. Replacement of the N-methyldehydrobut yrine residue by L-alanine was explored to assess the contribution of this dehydroamino acid to the biochemical activity of motuporin. Some epimerizat ion also was observed during cyclization of the alanine-containing peptide. Synthetic motuporin and both isomers of 5-[L-Ala]-motuporin inhibit the ac tivity of protein phosphatase-l (PP1) in rat adipocyte lysates with compara ble IC50 values. These results indicate that the N-methyldehydrobutyrine re sidue is not essential for PP1 inhibition.