Highly antiplasmodial non-natural oxidative products of dioncophylline A: synthesis, absolute configuration, and conformational stability

Four new compounds, the monomeric dioncotetralones A (6 a) and B (6 b) and the dimeric compounds jozimine A3 (7) and jozimine A4 (9), were semi-synthesized from the natural product dioncophylline A (4) and its 5'-O-demethylated derivative (5), respectively, under phenol oxidative reaction conditions. Dioncotetralones A (6 a) and B (6 b) possess an unprecedented Z-configured double bond, in contrast to the classic biaryl axis that is present in the precursor dioncophylline A (4), and an additional stereogenic center at the C2' atom was generated due to the dearomatization. The resulting steric repulsion forced the expected planar double bond into a helical distorted conformation. The homocoupling of 5 yielded compounds 7 and 9, the latter of which is the first sp(3) -sp(2) coupled product of a monomeric naphthylisoquinoline with a reduced one and, thus, contains a newly generated stereogenic center. The full stereostructures of 6 a, 6 b, 7, and 9 were successfully elucidated by the interplay of spectroscopic methods (1D/2D NMR and electronic circular-dichroism spectroscopy) in combination with quantum-chemical calculations. In addition, compounds 6 a and 7 exhibited high antiplasmodial activities with excellent half-maximal inhibitory concentration values.