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.

Automated summary

Strategies for the total synthesis of alpkinidine, a marine pyrroloacridine alkaloid, were explored. While advanced intermediates with the complete carbon skeleton of alpkinidine were obtained, the attempted closure of the D and B rings was unsuccessful. The novel isoquinolinetriones and the general strategy of linking CE- and A-ring synthons through Michael additions may find applications in the synthesis of other pyrrolo- and pyridoacridines.