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

Abstract

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.

o-Nitrophenylacetonitrile Michael additions and cyclocondensations: a novel quinoline synthesis

“…o-Nitrophenylacetonitriles, e.g., the parent 1, are valuable and versatile precursors to a variety of benzo-fused heterocycles, including indoles 2, 1-10 N-hydroxyindoles 3, [11][12][13][14][15] quinoline-N-oxides 4, [16][17][18][19][20][21] quinolines 5, [22][23][24][25][26] cinnoline-1-oxides 6, [27][28][29] and 2,1-benzisoxazoles (anthranils) 7 20,30,31 (Figure 1). As part of efforts to achieve the total synthesis of the marine pyrroloacridine natural product alpkinidine, [32][33][34] we investigated Michael addition of 1 to quinones. Somewhat surprisingly, these reactions were unsuccessful.…”