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.

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.

Supporters like you are critical to our success by providing the resources necessary to advance the rights of transgender and gender nonconforming people, defend our victories, and ensure our movement's strength. Thank you!

The administration has circulated a list that includes nine other campuses, accusing them of failure to address antisemitism.