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

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.