Divergent total syntheses of pyrroloiminoquinone alkaloids enabled by the development of a Larock/Buchwald-Hartwig annulation/cyclization

• Published in: Chemical science (Cambridge) Vol. 15; no. 31; pp. 12284 - 12290
• Main Authors: Rezgui, Samir P, Farhi, Jonathan, Yu, Hao, Sercel, Zachary P, Virgil, Scott C, Stoltz, Brian M
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 07-08-2024; The Royal Society of Chemistry
• Subjects: Alkaloids; Chemical reactions; Chemistry; Natural products; Organic chemistry; Sequences
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/d4sc02981j

Pyrroloiminoquinone alkaloids are a large class of natural products that display a wide range of biological activities. Synthetic approaches to these natural products typically rely on a common late-stage C10-oxygenated pyrroloiminoquinone intermediate, but these strategies often lead to lengthy synthetic sequences that are not amenable to divergent syntheses. We devised an alternative approach aimed at the early introduction of the C10 nitrogen, which we hypothesized would enable late-stage diversification. This strategy hinged upon a Larock/Buchwald-Hartwig annulation/cyclization to quickly access the core of these alkaloids. We report the development of this cascade process, which was facilitated by a dual ligand system in addition to selective functionalization of the key intermediate, to provide efficient syntheses of makaluvamines A, C, and D and isobatzelline B, and the first total synthesis of makaluvamine N.