title: Late-stage C-H functionalization of complex alkaloids and drug molecules via intermolecular rhodium-carbenoid insertion.
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.
authors.affiliation: Department of Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors.forename: Lawrence G
authors.initials: LG
authors.lastname: Hamann
authors.affiliation: Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, USA.
authors.forename: Huw M L
authors.initials: HM
authors.lastname: Davies
authors.affiliation: Department of Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors.forename: Rohan E J
authors.initials: RE
authors.lastname: Beckwith
mesh_terms: D000470:Alkaloids / Q000737:chemistry*; D000588:Amines / Q000737:chemistry; D001688:Biological Products / Q000737:chemistry; D002244:Carbon / Q000737:chemistry*; D002384:Catalysis; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D006859:Hydrogen / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D012238:Rhodium / Q000737:chemistry*; D013331:Strychnine / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D000470:Alkaloids; D000588:Amines; D001688:Biological Products; C083806:brucine; D002244:Carbon; D006859:Hydrogen; D012238:Rhodium; D013331:Strychnine