Enantioselective Synthesis of Isocarbostyril Alkaloids and Analogs Using Catalytic Dearomative Functionalization of Benzene

J Am Chem Soc. 2019 Jan 9;141(1):657-670. doi: 10.1021/jacs.8b12123. Epub 2018 Dec 20.


Enantioselective total syntheses of the anticancer isocarbostyril alkaloids (+)-7-deoxypancratistatin, (+)-pancratistatin, (+)-lycoricidine, and (+)-narciclasine are described. Our strategy for accessing this unique class of natural products is based on the development of a Ni-catalyzed dearomative trans-1,2-carboamination of benzene. The effectiveness of this dearomatization approach is notable, as only two additional olefin functionalizations are needed to construct the fully decorated aminocyclitol cores of these alkaloids. Installation of the lactam ring has been achieved through several pathways and a direct interconversion between natural products was established via a late-stage C-7 cupration. Using this synthetic blueprint, we were able to produce natural products on a gram scale and provide tailored analogs with improved activity, solubility, and metabolic stability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alkaloids / chemical synthesis*
  • Alkaloids / chemistry*
  • Alkaloids / metabolism
  • Benzene / chemistry*
  • Catalysis
  • Cell Line, Tumor
  • Chemistry Techniques, Synthetic
  • Drug Stability
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Solubility
  • Stereoisomerism


  • Alkaloids
  • Benzene