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

Rezgui, Samir P.; Farhi, Jonathan; Yu, Hao; Sercel, Zachary P.; Virgil, Scott C.; Stoltz, Brian M.

doi:10.1039/d4sc02981j

Chem. Sci.

2024

DOI: 10.1039/d4sc02981j

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

Samir P. Rezgui,

Jonathan Farhi,

Hao Yu

et al.

Abstract: 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...

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A Divergent Synthesis of Numerous Pyrroloiminoquinone Alkaloids Identifies Promising Antiprotozoal Agents

Barnes,

Magann,

Perrotta

et al. 2024

J. Am. Chem. Soc.

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On the basis of a streamlined route to the pyrroloiminoquinone (PIQ) core, we made 16 natural products spread across four classes of biosynthetically related alkaloid natural products, and multiple structural analogs, all in ≤8 steps longest linear sequence (LLS). The strategy features a Larock indole synthesis as the key operation in a five-step synthesis of a key methoxy-PIQ intermediate. Critically, this compound was readily diverged via selective methylation of either (or both) of the imine-like or pyrrole nitrogens, which then permitted further divergence by either Odemethylation to o-quinone natural products or displacement of the methoxy group with a range of amine nucleophiles. Based on a single, early report of their potential utility against the malaria parasite, we assayed these compounds against several strains of Plasmodium falciparum, as well as two species of the related protozoan parasite Babesia. In combination with evaluations of their human cytotoxicity, we identified several compounds with potent (low-nM IC 50 ) antimalarial and antibabesial activities that are much less toxic toward mammalian cells and are therefore promising lead compounds for antiprotozoal drug discovery.

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A Divergent Synthesis of Numerous Pyrroloiminoquinone Alkaloids Identifies Promising Antiprotozoal Agents

Barnes,

Magann,

Perrotta

et al. 2024

J. Am. Chem. Soc.

View full text Add to dashboard Cite

show abstract

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

Abstract: 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...

Cited by 1 publication

References 52 publications

A Divergent Synthesis of Numerous Pyrroloiminoquinone Alkaloids Identifies Promising Antiprotozoal Agents

A Divergent Synthesis of Numerous Pyrroloiminoquinone Alkaloids Identifies Promising Antiprotozoal Agents

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