Exploitation of a Tuned Oxidation with N‑Haloimides in the Synthesis of Caulibugulones A–D

Marine alkaloids caulibugulones A–D were synthesized in six steps starting from the readily available 2,5-dimethoxybenzaldehyde. Pomeranz–Fritsch reaction of N-(2,5-dimethoxybenzyl)-N-(2,2-dimethoxyethyl)-2-nitrobenzenesulfonamide proceeded smoothly to give 5,8-dimethoxyisoquinoline, which was oxidized to isoquinolinediones by a tunable oxidation reaction with N-haloimides. Therefore, NBS furnished direct conversion to the isoquinoline-5,8-dione; alternatively, N-haloimides of cyanuric acid provided both oxidation and halogenation generating 6,7-dihaloisoquinoline-5,8-diones. Aminolyses of these isoquinolinediones with methylamine or ethanolamine produced the isoquinolinedione alkaloids caulibugulones A–D in 24–57% overall yield.