Synthesis of chondramide A analogues with modified β-tyrosine and their biological evaluation.
Starting from cinnamates 9, obtained by Wittig reaction or Heck coupling, the diols 17 were prepared by asymmetric dihydroxylation. This was followed by a regioselective substitution of the 3-OH group with hydrazoic acid under Mitsunobu conditions. Methylation of the 2-OH group and reduction of the azide group led to the β-tyrosine derivatives 8. Condensation with the dipeptide acid 6 furnished the tripeptide part of the chondramides. The derived acids 21 were combined with the hydroxy ester 7 to the esters 22. Cleavage of the tert-butyl groups and intramolecular lactam formation gave rise to the chondramide A analogues 2 b-k. Growth inhibition assays showed most of the analogues to be biologically active. Some of them even reach the activity of jasplakinolide. It can be concluded that the 4-position of the aryl ring in the β-tyrosine of chondramide A tolerates structural modifications quite well.
Institut für Organische Chemie, Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany.
Alexander
A
Zhdanko
Anke
A
Schmauder
Christopher I
CI
Ma
L David
LD
Sibley
David
D
Sept
Florenz
F
Sasse
Martin E
ME
Maier
D001426:Bacterial Proteins / Q000138:chemical synthesis* / Q000737:chemistry*; D001685:Biological Factors / Q000737:chemistry*; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry*; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry*; D013237:Stereoisomerism; D014443:Tyrosine / Q000737:chemistry*
D001426:Bacterial Proteins; D001685:Biological Factors; D047630:Depsipeptides; D009842:Oligopeptides; C097819:chondramide A; D014443:Tyrosine