TY - JOUR
T1 - Toward the Total Synthesis of Alpkinidine
T2 - Michael Addition to Isoquinolinetrione CE Ring-System Synthons
AU - Buccini, Marco
AU - Dhoro, Francis
AU - Tham, Louisa
AU - Skelton, Brian W.
AU - Williams, Craig M.
AU - Piggott, Matthew J.
N1 - Funding Information:
We thank the UWA Centre for Characterisation, Microscopy and Analysis, in particular Drs. Lindsay Byrne and Gareth Nealon for assistance with NMR spectroscopy and Drs. Anthony Reeder and Michael Clarke for help with mass spectrometry. The Australian Government is gratefully acknowledged for an Australian Postgraduate Award (M.B.) and Research Training Program (RTP) Scholarships (F.D. and L.T.). Waiver of tuition fees (F.D.) and a UWA–UQ Bilateral Research Collaboration Award from the University of Western Australia facilitated this work. C.M.W. thanks the University of Queensland for financial support. a
Publisher Copyright:
© 2022 The Authors. Published by American Chemical Society.
PY - 2022/6/14
Y1 - 2022/6/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85132017986&partnerID=8YFLogxK
U2 - 10.1021/acsomega.2c02117
DO - 10.1021/acsomega.2c02117
M3 - Article
C2 - 35722017
AN - SCOPUS:85132017986
SN - 2470-1343
VL - 7
SP - 19093
EP - 19105
JO - ACS Omega
JF - ACS Omega
IS - 23
ER -
