Total Synthesis of the Didemnins; IV.1Synthesis of the Peptolide Ring and Construction of the Side Chain

All articles of this category A total synthesis of didemnins A, B, and C ( 1-3 ) which enables these highly cytotoxic cyclopeptides to be prepared in decigram amounts is described. The ß-keto acid unit (hydroxyisovaleryl)propionic acid derivative (Hip, 6 ) was prepared by acylation of dibenzyl methylmalonate and subsequent cleavage of the benzyl groups by the action of boron trichloride. The free ß-keto acid 6 was activated by the DCC method and allowed to react with the leucine ester 7 to furnish the amide 8 . Activation, deprotection, and ring closure of the linear peptide 19 by means of the pentafluorophenyl ester method in a two-phase system gave rise to the didemnin ring skeleton in 75% yield within a few minutes. The respective side chains were then attached to the didemnin ring easily and in high yields by activation of Z-( R )- N -methylleucine as its 3-cyano-2-pyridylthiol ester followed by reaction with Z-lactylproline chloride and Z-lactic acid chloride.