The Inoue Synthesis of 1-Hydroxytaxinine

1-Hydroxytaxinine (3), isolated from the Japanese yew Taxus cuspidata, shows modest cytotoxicity. Masayuki Inoue of the University of Tokyo envisioned a route to 3 based on the diastereoselective reductive cyclization of 1 to 2 (Angew. Chem. Int. Ed. 2019, 58, 12159. DOI: 10.1002/anie.201906872).

The starting material for the preparation of 1 was commercial 2,2-dimethylcyclohexane-1,3-dione, that was readily converted to 4 by monoketalization followed by methylation. Conversion of the ketone to the iodoalkene followed by Heck coupling with 5 led to 6. Sharpless asymmetric dihydroxylation followed by protection delivered 8 in 96% ee. The α-alkoxy radical derived from the telluride 9 was added in a conjugate sense to 10 to give an intermediate that was oxidized to the enone 11.

Conjugate addition to 11 proceeded with a remarkable 7:1 diastereomeric preference. Subsequent reduction of the ketone and dehydration, followed by Dibal reduction of the nitrile and acid hydrolysis completed the assembly of 1.

Despite encouraging literature reports, the pinacol cyclization of 1 with SmI₂ was not satisfactory. Eventually, a Ti-based protocol was developed that delivered 2 as the major diastereomer. The minor diastereomer 12 was readily converted back to 1.

Oxidation of the monoacetate derived from 2 led to the bis-enone 13. Fortunately, the tosylhydrazone could be formed selectively from the less hindered of the two ketones. Reduction by the Kabalka protocol then proceeded with a sufficient preference for the desired diastereomer 14. Osmylation followed by esterification with 15 led to 16.

The alcohol 16 could be oxidized to the corresponding ketone, but attempts at methylenation failed. Instead, methyl Grignard was added, and the acetonide was removed. Acetylation then gave 17. Direct dehydration of the diol led predominantly to rearrangement, so the more exposed tertiary alcohol was protected. Dehydration followed by deprotection then delivered 1-hydroxytaxinine (3).