Takahashi Taxol total synthesis
The Takahashi Taxol total synthesis published by Takashi Takahashi in 2006 is one of several successful methods in taxol total synthesis. The method starts from geraniol and differs from the other 6 published methods that it is a formal synthesis and that it is racemic. A key feature of the published procedure is that several synthetic steps were performed in an automated synthesizer on a scale up to 300 gram and that purification steps were also automated.
A ring synthesis
Ring A was synthesised starting from geraniol 1 and involved acylation to 2, epoxidation to 3, radical cyclisation to 4, alcohol protection to 5, alcohol deprotection to alcohol 6, Parikh-Doering oxidation to aldehyde 7, isomerization to enone 8, organic reduction to alcohol 9, alcohol protection to TBS ether 10, hydrazone formation to 11 and finally vinyl bromide formation in 12.| Scheme 1. A ring synthesis |
Ring C synthesis
The synthesis of ring C also required hydroxygeranyl acetate 2. Subsequent steps were Allylic oxidation to aldehyde 13, then carbonyl reduction to alcohol 14, then epoxidation to 15, then alcohol protection to MPM ether 16, then radical cyclisation to alcohol 17, alcohol protection to BOM ether 18, acetate hydrolysis and Ley oxidation to aldehyde 19.| Scheme 2. C ring synthesis |
Ring B synthesis
Ring A and ring C reacted together to alcohol 20 in a Shapiro reaction in a similar way as in the Nicolaou Taxol total synthesis. Subsequent steps were epoxidation to 21, reduction to the diol and alcohol protection to benzyl ether 22, alcohol protection and oxidation to DMS ether 23, tosylation to 24, deprotection to diol and reprotection as TMS ether 25, Ley oxidation to aldehyde 26, cyanohydrin formation and alcohol protection to EE ether 27.| Scheme 3. B ring synthesis |
Ring D synthesis
Cyclisation of 27 took place by alkylation to tricycle 28. Subsequent steps were cyanohydrin hydrolysis, TMS deprotection and allylic oxidation to ketone 29, then Upjohn dihydroxylation to triol 30, then acylation and mesitylation to 31, then benzyl group and benzyloxy group removal followed by carbonate protection to 32, then secondary alcohol protection and primary alcohol deprotection to diol 33, then oxetane formation to 34, then acylation, then benzoylation to 35, then oxidation to the acyloin 36, then isomerisation and acylation to 37, then oxidation at the allylic position, ketone group oxidation and TES protecting group removal to baccatin III.| Scheme 4. D ring synthesis |