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.
Institute of Organic Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg (Germany).
Yasmin
Y
Hemberger
Institute of Organic Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg (Germany).
Guoliang
G
Zhang
Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel (Switzerland) and University of Basel, Petersplatz 1, 4003 Basel (Switzerland).
Reto
R
Brun
Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel (Switzerland) and University of Basel, Petersplatz 1, 4003 Basel (Switzerland).
Marcel
M
Kaiser
Institute of Organic Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg (Germany). bringman@chemie.uni-wuerzburg.de.
Gerhard
G
Bringmann
D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry*; D002942:Circular Dichroism; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D009281:Naphthalenes / Q000737:chemistry*; D058451:Oxidative Coupling; D013237:Stereoisomerism
D000962:Antimalarials; D001688:Biological Products; D007546:Isoquinolines; D009281:Naphthalenes; C402882:dioncophylline B; C581448:jozimine A2; C104320:dioncophylline A
aromaticity; chirality; conformation analysis; oxidative coupling; structure elucidation