148914-67-4Relevant academic research and scientific papers
Total synthesis of the didemnins; IV. Synthesis of the peptolide ring and construction of the side chain
Schmidt,Kroner,Griesser
, p. 294 - 300 (2007/10/02)
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 β-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 β-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.
TOTAL SYNTHESIS OF THE DIDEMNINS - 1. SYNTHESIS OF THE PEPTOLIDE RING
Schmidt, U.,Kroner, M.,Griesser, H.
, p. 3057 - 3060 (2007/10/02)
The 23-membered peptolide ring of the didemnins is formed in a two phase cyclization of a linear ω-amino-pentafluorophenyl ester in 70percent yield without high dilution. (2RS,4S)-2,5-dimethyl-4-hydroxy-3-oxohexanoic acid (Hip) and (3S,4R,5S)-isostatine are synthesized by acylations of trimethylsilyl malonates.
