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.