ao2c02117_si_001.pdf (1.71 MB)
Toward the Total Synthesis of Alpkinidine: Michael Addition to Isoquinolinetrione CE Ring-System Synthons
journal contributionposted on 2022-06-01, 12:37 authored by Marco Buccini, Francis Dhoro, Louisa Tham, Brian W. Skelton, Craig M. Williams, Matthew J. Piggott
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.
novel isoquinolinetriones reportedester enolate derivedcomplete carbon skeletonanticancer lead neoamphimedine>)- trione proceeded8 ( 2key michael additionisoquinolinetrione ce ringmichael additionconnecting cemichael additionswrong regiochemistrysystem synthonsring synthonsring nitrogengeneral strategyearlier stage>- nitrophenylacetate