Synthesis of Chondramide A Analogues with Modified β‐Tyrosine and Their Biological Evaluation

Abstract

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. SUB ‐ units : Ten different chondramide A analogues were prepared with different substituents at the 3‐amino‐2‐methoxy‐propanoate subunit. The modified β‐tyrosines were obtained from the corresponding cinnamates. From Mitsunobu esterification, acyclic depsipeptides were obtained that were cyclized by macrolactam formation. Almost all analogues were at least as active as chondramide A itself. However, an amide group reduced the cytotoxicity significantly.