Total synthesis of the isoquinolinium metabolite ETM-204 of Trabectidin

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

A new route for the synthesis of 1-deazaguanine and 1-deazahypoxanthine

“…At this point, we note that N9-tert-butyloxycarbonyl-protected 6-iodo-1-deazapurine was successfully synthesized but not stable during the cross coupling reaction. We also mention that we did not decide for a direct transformation [27,28] of 6-iodo-1-deazapurine into 6-hydroxy-1-deazapurine for reasons of solubility and desired regioselectivity of the subsequent nitration reaction.…”