Divergent Synthetic Approach to Grayanane Diterpenoids.

The total syntheses of nine grayanane diterpenoids, namely, GTX-II ( 1 ), GTX-III ( 2 ), rhodojaponin III ( 3 ), GTX-XV ( 4 ), principinol D ( 5 ), iso-GTX-II ( 6 ), 1,5-seco-GTX-Δ 1,10 -ene (7), and leucothols B ( 8 ) and D ( 9 ), that belong to five distinct subtypes, were disclosed in a divergent manner. Among them, six members were accomplished for the first time. The concise synthetic approach features three key transformations: (1) an oxidative dearomatization-induced [5 + 2] cycloaddition/pinacol rearrangement cascade to assemble the bicyclo[3.2.1]octane carbon framework (CD rings); (2) a photosantonin rearrangement to build up the 5/7 bicycle (AB rings) of 1- epi -grayanoids; and (3) a Grob fragmentation/carbonyl-ene process to access four additional subtypes of grayanane skeletons. Density functional theory calculations were performed to elucidate the mechanistic origins of the crucial divergent transformation, which combined with late-stage synthetic findings provided insights into the biosynthetic relationships between these diverse skeletons.