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  • Late-stage C-H functionalization of complex alkaloids and drug molecules via intermolecular rhodium-carbenoid insertion.

Late-stage C-H functionalization of complex alkaloids and drug molecules via intermolecular rhodium-carbenoid insertion.

Nature communications (2015-01-13)
Jing He, Lawrence G Hamann, Huw M L Davies, Rohan E J Beckwith
ABSTRACT

Alkaloids constitute a large family of natural products possessing diverse biological properties. Their unique and complex structures have inspired numerous innovations in synthetic chemistry. In the realm of late-stage C-H functionalization, alkaloids remain a significant challenge due to the presence of the basic amine and a variety of other functional groups. Herein we report the first examples of dirhodium(II)-catalysed intermolecular C-H insertion into complex natural products containing nucleophilic tertiary amines to generate a C-C bond. The application to a diverse range of alkaloids and drug molecules demonstrates remarkable chemoselectivity and predictable regioselectivity. The capacity for late-stage diversification is highlighted in the catalyst-controlled selective functionalizations of the alkaloid brucine. The remarkable selectivity observed, particularly for site-specific C-H insertion at N-methyl functionalities, offers utility in a range of applications where efficient installation of synthetic handles on complex alkaloids is desired.

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Thebaine, European Pharmacopoeia (EP) Reference Standard
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