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

• Published in: Nature communications Vol. 6; no. 1; p. 5943
• Main Authors: He, Jing, Hamann, Lawrence G., Davies, Huw M. L., Beckwith, Rohan E. J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.01.2015; Nature Publishing Group
• Subjects: 140/131; 639/638/309/436; 639/638/403/349; Alkaloids - chemistry; Amines - chemistry; Biological Products - chemistry; Carbon - chemistry; Catalysis; Chemistry, Pharmaceutical - methods; Drug Design; Humanities and Social Sciences; Hydrogen - chemistry; Magnetic Resonance Spectroscopy; multidisciplinary; Rhodium - chemistry; Science; Science (multidisciplinary); Strychnine - analogs & derivatives; Strychnine - chemistry
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms6943

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. The ability to functionalize a C–H bond is useful in complex organic syntheses, but the scope of this approach is sometimes limited by its sensitivity to basic amines. Here, the authors achieve functionalization of amine-containing natural products by site-selective rhodium-carbene-mediated C–H insertion.