Synthesis of the Dolastatin Thiazole Amino Acid Component (gln)Thz

Article abstract of DOI:10.1021/jo00213a024

The new thiazole amino acid (gln)Thz, found to occur as one unit of the marine sea hare cyclic pentapeptide dolastin 3, has been synthesized from L-glutamic acid by the route 2 -> 10e.The synthesis of Z-L-isoglutamine (4) was improved by selective ammonolysis of anhydride 3 at -60 deg C.A variety of reaction conditions were found to cause complete racemization during the Hantzsch thiazole synthesis step (9 -> 10).Deuterium labeling experiments indicated loss of the chiral center prior to formation of the thiazole system and suggested an imine-enamine type equilibration involving intermediates A <*> B (Scheme II).The N-benzyloxycarbonyl derivative (10d) of (gln)Thz was partially resolved by employing brucine.