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

The new thiazole amino acid (gln)Thz, found to occur as one unit of the marine sea hare cyclic pentapeptide dolastatin 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 °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.