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.