Synthesis of the Aminovinylcysteine-Containing C-Terminal Macrocycle of the Linaridins.

N-Phthalimido-d-cysteine allyl ester was S-alkylated with 2-iodoethanol. The derived β-thioaldehyde was condensed with Nα-tetrachlorophthalimidovalinamide to afford a Z-thioenamide. Removal of the tetrachlorophthalimido protecting group and homologation with N-Boc-l-leucine afforded the linear tripeptide. Removal of the Boc and allyl protecting groups, followed by carbodiimide-mediated cyclization, led to the 13-membered ring with the aminovinylcysteine moiety embedded. This constitutes the C-terminal macrocycle of all known members of the linardin family of peptides, including the antileukemia agent, cypemycin.