Toward the Total Synthesis of Alpkinidine: Synthesis of Haloquinone CE Ring System Synthons and Attempted Nucleophilic Bisannulation.

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(2H)-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(2H)-trione afforded an adduct sharing the complete carbon skeleton of alpkinidine, but this could not be elaborated to the natural product.

Toward the Total Synthesis of Alpkinidine: Michael Addition to Isoquinolinetrione CE Ring-System Synthons.

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(2H)-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.