Synthesis p. 294 - 300 (1991)
Update date:2022-08-04
Topics:
Schmidt
Kroner
Griesser
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.
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Doi:10.1038/s41467-019-09387-4
(2019)Doi:10.1021/jo01069a062
(1961)Doi:10.1002/ardp.200600111
(2006)Doi:10.1021/acs.orglett.8b00139
(2018)Doi:10.1021/om020260k
(2002)Doi:10.1007/BF00776786
(1984)