Regioselection Switch in Nucleophilic Addition to Isoquinolinequinones: Mechanism and Origin of the Regioselectivity in the Total Synthesis of Ellipticine

Ellipticine was synthesized in six steps and 20% global yield starting from the readily available 2,5-dimethoxy isoquinoline. Unprecedented regioselective control of the nucleophilic attack on the isoquinoline-5,8-dione is first described. Investigation of the possible pathways of this transformatio...

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Published inJournal of organic chemistry Vol. 87; no. 12; pp. 7610 - 7617
Main Authors Castro, Joaquim A. M., Serikava, Bruno K., Maior, Christian R. S., Naciuk, Fabrício F., Rocco, Silvana A., Ligiéro, Carolina B. P., Morgon, Nelson H., Miranda, Paulo C. M. L.
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 17.06.2022
Amer Chemical Soc
Subjects
Chemistry
Chemistry, Organic
Physical Sciences
Science & Technology
QUINONES
REACTIVITY
DIRECT ARYLATION
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Summary:Ellipticine was synthesized in six steps and 20% global yield starting from the readily available 2,5-dimethoxy isoquinoline. Unprecedented regioselective control of the nucleophilic attack on the isoquinoline-5,8-dione is first described. Investigation of the possible pathways of this transformation through density functional theory calculations reveals unexpected N-oxide assistance in cascade tautomerizations, which was crucial for directing the nucleophilic attack and hastening the overall process. Using this strategy, we prepared the aniline-isoquinolinedione adduct and submitted it to an intramolecular double C–H cross-coupling activation to furnish ellipticinequinone, which gave ellipticine after a MeLi addition/BH3 reduction sequence.
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ISSN:0022-3263
1520-6904
DOI:10.1021/acs.joc.1c02952