Abstract
Ecteinascidin-743 (Trabectidin, Trabectedin®, Yondelis®) is a synthetically obtained pharmaceutical drug originally isolated from a marine tunicate. Trabectedin is used for the chemotherapy of soft-tissue sarcoma and ovarian cancer. The isoquinolinium metabolite ETM-204 has been found in biotransformation and degradation studies of Trabectedin. We report the first total synthesis of ETM-204 and its full spectroscopic characterization confirming the postulated structure. Central elements of the 12-step synthesis starting from 2-methyl-6-nitrophenol are a Cu-mediated conversion of an iodoarene to a phenol, a Skattebøl-formylation, and a modified Pomeranz–Fritsch cyclization to assemble the isoquinoline ring. The pH-dependence of its visual absorbance could be clarified.Graphic abstract
Highlights
Ecteicinascidin-743 (ET-743) is a marine alkaloid originally isolated from the Caribbean tunicate Ecteinascidia turbinata
To verify and characterize ETM-204, one of the main degradation products, sufficient amounts of this substance needed to be isolated from a stressed Trabectedin solution
We have successfully synthesized the central Trabectedin metabolite ETM-204 in a 12-step synthesis, assigned its structure via NMR spectroscopy and confirmed it with authentic material resulting from degradation studies
Summary
Ecteicinascidin-743 (ET-743) is a marine alkaloid originally isolated from the Caribbean tunicate Ecteinascidia turbinata. Scheme 2 Synthetic route towards Trabectedin degradation product ETM-204 phase separation during aqueous workup took some time because of formation of an emulsion, the reaction provided 98% of the desired compound 2 as a red-brown oil, which was already pure according to NMR and used without further treatment.
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