The Takahashi Taxol total synthesis published by Takashi Takahashi in 2006 is one of several methods in taxol total synthesis. [1] The method starts from geraniol and differs from the other 6 published methods that it is a formal synthesis (the final product is baccatin III which lacks the amide tail found in taxol itself) and that it is racemic (the product baccatin III is optically inactive). A key feature of the published procedure is that several synthetic steps (construction of rings A, B and C) 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 ( acetic anhydride, DMAP, Et3N) to 2, epoxidation ( N-bromosuccinimide, tBuOH/ H2O then triethylamine) to 3, radical cyclisation ( titanocene dichloride, manganese, triethylborane, 2,6-lutidine) to 4, alcohol protection ( ethyl vinyl ether, camphorsulfonic acid) to 5, alcohol deprotection (NaOH, MeOH/THF/H2O) to alcohol 6, Parikh-Doering oxidation to aldehyde 7, isomerization ( DBU) to enone 8, organic reduction ( sodium borohydride) to alcohol 9, alcohol protection ( TBSCl, Et3N) to TBS ether 10, hydrazone formation ( H2NNHTs) to 11 and finally vinyl bromide formation ( tBuLi, 1,2-Dibromoethane) 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 ( SeO2, tBuO2H, salicylic acid) to aldehyde 13, then carbonyl reduction ( NaBH4) to alcohol 14, then epoxidation ( VO(acac)2, tBuO2H) to 15, then alcohol protection ( MPM trichloroacetimidate) to MPM ether 16, then radical cyclisation ( titanocene dichloride, manganese, triethylborane, TMSCl, K2CO3) to alcohol 17, alcohol protection ( BOMCl, DIPEA) to benzyloxymethyl ether 18, acetate hydrolysis ( NaOH) and Ley oxidation to aldehyde 19.
 |
| Scheme 2. C ring synthesis |
|---|
Ring B synthesis
Ring A (12) and ring C (19) reacted together to alcohol 20 in a Shapiro reaction ( tBuLi, CeCl3) in a similar way as in the Nicolaou Taxol total synthesis. Subsequent steps were epoxidation ( VO(acac)2, tBuO2H) to 21, reduction ( LiAlH4) to the diol and alcohol protection (aqueous KOH, BnBr, Bu4NHSO4) to benzyl ether 22, alcohol protection ( Me2SiHCl, imidazole) and oxidation ( DDQ) to DMS ether 23, tosylation ( TsCl, DMAP) to 24, deprotection to diol ( TBAF) and reprotection ( TMSOTf, 2,6-lutidine, DIPEA) as TMS ether 25, Ley oxidation to aldehyde 26, cyanohydrin formation ( TMSCN, 18-crown-6, KCN) and alcohol protection ( ethyl vinyl ether, camphorsulfonic acid) to EE ether 27.
 |
| Scheme 3. B ring synthesis |
|---|
Ring D synthesis
Cyclisation of 27 took place by alkylation ( LiN(TMS)2, dioxane, microwave irradiation) to tricycle 28. Subsequent steps were cyanohydrin hydrolysis ( camphorsulfonic acid), TMS deprotection ( KOH) and allylic oxidation ( SeO2, tBuO2H, salicylic acid) to ketone 29, then Upjohn dihydroxylation to triol 30, then acylation ( AcCl, DMAP) and mesitylation ( MsCl, DMAP) to 31, then benzyl group and benzyloxy group removal ( hydrogenation / Palladium on carbon) followed by carbonate protection ( triphosgene, pyridine) to 32, then secondary alcohol protection ( TESCl, pyridine) and primary alcohol deprotection ( potassium carbonate) to diol 33, then oxetane formation ( DIPEA, HMPA) to 34, then acylation ( Ac2O, DMAP), then benzoylation ( phenyllithium) to 35, then oxidation ( tBuOK, (PhSeO)2O, THF) to the acyloin 36, then isomerisation ( tBuOK) and acylation ( Ac2O, DMAP, pyr) to 37, then oxidation at the allylic position ( PCC, celite, NaOAc, benzene), ketone group oxidation ( NaBH4) and TES protecting group removal ( HF· pyr) to baccatin III (38).
 |
| Scheme 4. D ring synthesis |
|---|