The first total synthesis of potent antitumoral (±)-mafaicheenamine A, unnatural 6-fluoromafaicheenamine A and expedient synthesis of clausine E

Abstract

The first total synthesis of potent antitumoral mafaicheenamine A (1) and its unnatural analogue, 6-fluoromafaicheenamine A (2) have been accomplished. An expedient synthesis of clausine E, a key intermediate in the course of synthesis of 1 and 2, was achieved in three steps from commercially available methyl 4-amino-3-(benzyloxy)benzoate (10) by copper-catalyzed N-arylation with aryllead triacetate, followed by cyclodehydrogenation of the resultant diarylamine under palladium(II) acetate catalysis. Moreover, palladium-catalyzed O-prenylation of clausine E and subsequent o-Claisen rearrangement under microwave irradiation rendered the advanced intermediate, C-prenylated phenol, which was eventually subjected to oxidative cyclization to construct the dihydroisocoumarin unit, leading to the synthesis of 1 and 2 in 12% and 15% overall yield, respectively, from 10.