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-Δ1,10-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 bicyclo3.2.1octane 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.