Unique Remote Regiocontrol by an N-Oxide Group in the Synthesis of Isocaulibugulones A, B, C, and D

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.

Automated summary

The elongated resonance with the N-oxide group and the vinylogous effect of the oxoammonium group enabled a regioselection switch in the oxidative amination reaction of an isoquinolinedione, leading to the straightforward synthesis of isocaulibugulones A, B, C, and D. Alkaloid counterparts A and D were synthesized in 4 steps with 11-36% global yield. Further late-stage halogenation of isocaulibugulone A resulted in the synthesis of counterparts B and C with 83-94% yield. Density Functional Theory (DFT) calculations predicted the aforementioned effects and the disruptive action of hydrogen bonding, which were experimentally observed in the synthesis of isocaulibugulone D due to partial loss of regioselectivity.