A divergent cascade cycloisomerization / [3 + 2] vs [2+2+1]-cycloaddition via gold or silver catalysis has been reported in 1,1,1,3,3,3-hexafluoroisopropan-2-ol (HFIP). The reaction was independently optimized for both metals leading to two hexacyclic derivatives comprising a bicyclo[3.2.1]octane unit and respectively a benzoxazinone or a N-oxo-indolinone pattern. The unique influence of HFIP was demonstrated via 19F and 31P NMR analyses. This process, involving the formation of C-C, C-O, and C-N bonds and of three stereogenic centers led to privileged scaffolds in a context of the search for increased molecular diversity of drug-candidate libraries. The versatility of this methodology was demonstrated by the synthesis of 25 different hexacyclic scaffolds (yields up to 98%). Gram-scale synthesis as well as post-functionalization reactions illustrated the versatility an interest of these catalytic transformations. DFT calculations were performed to rationalize the proposed mechanism of this cascade reaction.
