Our novel synthetic route to isoellipticine featured palladium‐catalyzed intramolecular reactions for the construction of the B ring of the pyridocarbazole nucleus. The adequate palladium‐catalyzed reaction depended upon the oxidation conditions that were applied in order to prepare the immediate synthetic precursor. When CAN was used to make the quinone intermediate, an oxidative cyclization through a double C−H bond activation was applied. Conversely, when the oxidation condition involved TCCA as oxidant, a direct C−H arylation was employed. Both approaches showed similar efficiencies in order to construct the pyridocarbazole nucleus. Isoellipticine was prepared in only 5 steps with a 21%–23% overall yield.

Ellipticine was synthesized in six steps and 20% global yield starting from the readily available 2,5-dimethoxy isoquinoline. Unprecedented regioselective control of the nucleophilic attack on the isoquinoline-5,8-dione is first described. Investigation of the possible pathways of this transformation through density functional theory calculations reveals unexpected N-oxide assistance in cascade tautomerizations, which was crucial for directing the nucleophilic attack and hastening the overall process. Using this strategy, we prepared the aniline-isoquinolinedione adduct and submitted it to an intramolecular double C−H cross-coupling activation to furnish ellipticinequinone, which gave ellipticine after a MeLi addition/BH 3 reduction sequence.

An elongated resonance with the N‐oxide group and the vinylogous effect of the oxoammonium group allowed the regioselection switch during an oxidative amination reaction of an isoquinolinedione, permitting us to prepare isocaulibugulones A, B, C, and D in a straightforward approach. The alkaloid counterparts A and D were synthesized in 4 steps with 11–36 % global yield. A further late‐stage halogenation step at isocaulibugulone A led to preparing counterparts B and C with 83–94 % yield. Density Functional Theory (DFT) calculations anticipate the effects mentioned above and the disruptive action of hydrogen bonding in the process, which were observed experimentally in the synthesis of isocaulibugulone D due to the partial loss of regioselectivity.

The cover picture shows a switch between two reaction mechanisms. An elongated resonance with the N‐oxide group and the vinylogous effect of the oxoammonium group allowed a regioselection switch during an oxidative amination reaction, permitting the preparation of isocaulibugulones A, B, C, and D in a straightforward approach. Isocaulibugulones A and D were synthesized in four steps and 11‐36% global yield. A further late‐stage halogenation step at isocaulibugulone A led to counterparts B and C with 83‐94% yield. More information can be found in the Research Article by Paulo C. M. L. Miranda et al. (DOI: 10.1002/slct.202300347).

Foi desenvolvido uma rota sintética para síntese total da elipticina através de uma reação de ciclização intermolecular envolvendo ativação C-H catalisada por paládio. O método envolve a formação de uma isoquinolina a partir de 2,5-dimetoxibenzaldeído seguido de uma reação de adição nucleofílica enantiosseletiva de uma anilina.