Synthesis of Furan and Thiophene Analogs of Duocarmycin SA.

Abstract

Total synthesis of furan and thiophene analogs 6 and 7 of duocarmycin SA was achieved in racemic forms, starting from methyl 4, 5-dibromo-2-furan- and thiophenecarboxylates (15a and 15b). Lithio derivatives 12a (a series : X=O) and 12b (b serie : X=S) were reacted with the aldehyde 22 for preparation of 25a and 25b, and successive synthetic operations, including Heck reaction of 25a and 25b to obtain 26a+27a and 26b+27b, and B ring aromatization, 28a and 28n→31a and 31b, based on our previous total synthesis of duocarmycin SA, afforded 36a and 36b. Treatment of 36a and 36b with potassium carbonate in methanol directly afforded cyclopropapyrroloindole derivatives 38a and 38b, whose condensation with the 5, 6, 7-trimethoxy-2-indolecarbonyl unit completed the synthesis of (±)-6 and (±)-7.