Highly Antiplasmodial Non-Natural Oxidative Products of Dioncophylline A: Synthesis, Absolute Configuration, and Conformational Stability

• Published in: Chemistry : a European journal Vol. 21; no. 41; pp. 14507 - 14518
• Main Authors: Hemberger, Yasmin, Zhang, Guoliang, Brun, Reto, Kaiser, Marcel, Bringmann, Gerhard
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 05.10.2015; WILEY‐VCH Verlag; Wiley
• Subjects: Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; aromaticity; Biological Products - chemistry; Chemistry; Chemistry, Multidisciplinary; chirality; Circular Dichroism; conformation analysis; Isoquinolines - chemical synthesis; Isoquinolines - chemistry; Magnetic Resonance Spectroscopy; Molecular Conformation; Naphthalenes - chemistry; Oxidative Coupling; Physical Sciences; Science & Technology; Stereoisomerism; structure elucidation; conformation analysis; CD CALCULATIONS; chirality; NATURAL-PRODUCTS; DIMERIC NAPHTHYLISOQUINOLINE ALKALOIDS; CIRCULAR-DICHROISM SPECTRA; oxidative coupling; PERTURBATION-THEORY; ACETOGENIC ISOQUINOLINE ALKALOIDS; ZETA VALENCE QUALITY; ANTI-HIV MICHELLAMINES; structure elucidation; DENSITY-FUNCTIONAL THEORY; GAUSSIAN-BASIS SETS; aromaticity
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201501657

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 sp3–sp2 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. A new twist: Dioncotetralones A and B possess an unprecedented Z‐configured double bond with a helical distorted conformation and a new stereogenic center at the C2′ atom. Dioncotetralone A shows highly selective activity against Plasmodium falciparum. The stereochemistry and the conformational stability of these structures was thoroughly investigated and their absolute configurations successfully elucidated by the fruitful interplay of spectroscopic methods and quantum‐chemical calculations (DFT, coupled cluster).