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Nat Commun. 2015 Jan 12;6:5943. doi: 10.1038/ncomms6943.

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

Author information

1
Department of Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
2
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, USA.

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.

PMID:
25581471
DOI:
10.1038/ncomms6943
[Indexed for MEDLINE]

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