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 A 3 ( 7 ) and jozimine A 4 ( 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.