First stereoselective approach for structure revision of nagiol and syntheses of 2,3-dihydroxyferruginol and ferruginol

We report the first enantioselective total synthesis of nagiol, accompanied by a revision of its previously proposed structure. This synthetic strategy has been successfully extended to the total synthesis of (+)-ferruginol as well as to the 2,3-dihydroxyferruginol. Enantiomerically enriched 8,11,13-podocarpatriene-3-ol was utilized as a versatile and efficient precursor to access the abietane diterpenoid framework. Functionalization of the aromatic C-ring on podocarpatriene was achieved through regioselective Friedel-Crafts acylation and further modification. Two distinct strategies were employed to install the 2,3-dihydroxy functionality on the A-ring: (i) selective elimination followed by <i>syn</i>-stereoselective dihydroxylation, and (ii) α-oxygenation of the ketone followed by highly diastereoselective reduction of the diketone intermediates. These methods allowed access to possible C-2/C-3 <i>syn</i>-isomers for comparative spectroscopic analysis. Careful comparison of the NMR data of the synthetic products with the reported values, in conjunction with single-crystal X-ray diffraction studies, led to a revision of the originally proposed structure of nagiol. Furthermore, this study presents the first enantioselective synthesis of 2,3-dihydroxyferruginol, revealing certain structural discrepancies among the isolation reports.