NaOH Bartfield (@naohbartfield.bsky.social)

Total Synthesis of Chartelline C Chartellines are cytotoxic marine alkaloids that were isolated in the late 1980s. Their unique, heavily oxidized structures, comprising a spirocyclic β-lactam, a halogenated indolenine, a chloroenamide, and a 2-haloimidazole, have motivated extensive efforts toward their synthesis. However, only a single synthesis of any chartelline has been reported in the nearly 40 years since their isolation. Here, we describe a route to chartelline C (3) from the macrolactam 21, an intermediate we employed en route to the related securine and securamine alkaloids. The key challenges in converting macrolactam 21 to chartelline C (3) involve stereocontrolled construction of the C2–C3 enamide, isomerization of the trans-C10–C11 alkene, formation of the strained spirocyclic β-lactam, and chlorination of the enamide. Each of these challenges was addressed by an unconventional approach. The macrolactam 21 was converted to cis-enamide (2Z,10E)-24 by in situ masking of the C12 ketone, followed by stereoselective acid-catalyzed elimination of the C2 carbinolamide. The C10–C11 trans-alkene was isomerized by a photolytic process; control experiments suggest that this isomerization occurs by energy transfer. The β-lactam was constructed by a solid-state reaction involving the adsorption of the bromoindolenine 26 onto activated basic alumina. Late-stage enamide chlorination, which had been an obstacle in prior approaches, was accomplished by a novel photoredox-mediated halogenation. These latter studies suggest that N-haloanomeric amides and N-haloguanidines may act as halogen atom transfer agents under thermal or photolytic conditions. Finally, we show that chartelline C (3) reacts with sulfur-based nucleophiles, suggesting that further studies of their biological activity may be warranted. https://pubs.acs.org/doi/10.1021/jacs.5c07148