Three bisannulation strategies have been used to rapidly construct pentacyclic benzo‐fused pyrrolo[4,3,2‐mn]acridines, similar to several biologically active natural products. The key steps involve Michael substitution of 2,3‐dichloro‐1,4‐naphthoquinone with o‐nitrophenylacetic acid derivatives, followed by domino amino‐Michael substitutions/cyclisations. The most efficient of these syntheses provided a model compound (1) including the ABCD ring‐system of alpkinidine, in just three steps and 55 % overall yield.

Radermachol has been synthesized in four steps and an overall yield of 22% via key ytterbium triflate catalyzed furannulation and intramolecular nucleophilic acylation reactions.

An improved synthesis of the anti-inflammatory natural product antrocamphin A (2), involving a key Castro-Stephens reaction, is presented, along with the first total synthesis of its congener antrocamphin B (3). Approaches towards the more complex co-metabolite antrodioxolanone (4) were unsuccessful, but a samarium diiodide-mediated pinacol coupling of antrocamphin B did provide the chiral epimers (51). Antrocamphin A (2) inhibits Tumour Necrosis Factor (TNF) reporter gene expression, but its development as an anti-inflammatory agent may be limited by cytotoxicity.

Model chemistry involving the bisannulation of 2,3-dichloro-1,4-naphthoquinone with the ester enolate derived from ethyl o -nitrophenylacetic acid, which rapid assembled the ABCD ring system of a pentacyclic pyrroloacridine, has been applied to the attempted synthesis of the marine natural product alpkinidine. The reaction of ethyl o -nitrophenylacetic acid with 6,7-dichloro-2-methylisoquinoline-1,5,8(2 H )-trione, required to extend the model strategy to alpkinidine, was unfruitful, giving only complex mixtures. Efforts to direct the regiochemistry of the key Michael substitution step using 6-bromo-2-methylisoquinoline-1,5,8(2 H )-trione afforded an adduct sharing the complete carbon skeleton of alpkinidine, but this could not be elaborated to the natural product.

Strategies toward the total synthesis of the marine pyrroloacridine alkaloid alpkinidine have been explored, focusing on linking quinonoid CE ring-system synthons with the A ring, followed by condensation to form the B and D rings. The key Michael addition of the ester enolate derived from ethyl o -nitrophenylacetate to 2-methylisoquinoline-1,5,8(2 H )-trione proceeded with the wrong regiochemistry. This issue was addressed by incorporating the D-ring nitrogen at an earlier stage, affording advanced intermediates possessing the complete carbon skeleton of alpkinidine. However, attempts to close the D and B rings were unsuccessful. The novel isoquinolinetriones reported here, and the general strategy of connecting CE- and A-ring synthons through Michael additions, may be useful in the synthesis of other pyrrolo- and pyridoacridines, in particular the anticancer lead neoamphimedine and analogues.