Silver- and gold-catalyzed divergent cascade cycloisomerization/[3 + 2] <i>versus</i> [2 + 2 + 1] cycloaddition towards a stereoselective access to heterohexacyclic derivatives

A divergent cascade cycloisomerization/[3 + 2] <i>vs.</i> [2 + 2 + 1]-cycloaddition <i>via</i> 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 <i>N</i>-oxo-indolinone pattern. The unique influence of HFIP was demonstrated <i>via</i> 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 and interest of these catalytic transformations. DFT calculations were performed to rationalize the proposed mechanism of this cascade reaction.