- Wender Taxol total synthesis
starting from a naturally occurring compound with ring construction in the order A,B,C,D. The Wender effort is shorter by approximately 10 steps.
Raw materials for the preparation of Taxol by this route include
verbenone , prenyl bromine,allyl bromide ,propiolic acid ,Gilman reagent andEschenmoser's salt .ynthesis AB ring
The taxol synthesis starts from the terpene
verbenone 1.1 in "scheme 1", which is the oxidation product of naturally occurring α-pinene and forming ring A. Construction of ring B starts with abstraction of the vinylicenone proton bypotassium tert-butoxide followed bynucleophilic displacement of thebromine atom in prenyl bromide 1.2 to formdiene 1.3.Ozonolysis of the prenyl group (more electron-rich than the internal double bond) formsaldehyde 1.4 which afterisomerization orphotorearrangement to theChrysanthenone 1.5 reacts with the lithium salt (via LDA) of the ethylester ofPropiolic acid 1.6 in anucleophilic addition to thealcohol 1.7. This compound is not isolated but trappedin situ withtrimethylsilyl chloride to thesilyl ether 1.8. In the next stepGilman reagent 1.9 is a methylating reagent innucleophilic conjugate addition through thealkyne group to theketone group forming thealcohol 1.10. The silyl etherprotective group is removed by reaction withacetic acid to alcohol 1.11 which is then oxidized to theketone 1.12 with RuCl2(PPh3)3 and NMO as thesacrificial catalyst . Theacyloin group in 1.13 is introduced by KHMDS and Davis’ oxaziridine (seeHolton Taxol total synthesis for another use of this system) and its hydroxyl group together with the ester group are reduced bylithium aluminium hydride to tetrol 1.14. Finally the primary alcohol group is protected as a tert-butyldimethylsilyl ether by the corresponding silylchloride andimidazole in triol 1.15.In the second part ("scheme 2") the procedures are still confined to rings A and B. More protective groups are added to triol 2.1 as reaction with PPTS and
2-methoxypropene gives theacetonide 2.2. At this point the double bond in ring A is epoxidized withm-CPBA andsodium carbonate toepoxide 2.3 and aGrob fragmentation (also present in the Holton effort) initiated byDABCO opens up the AB ring system in alcohol 2.4 which is not isolated but protected as a TIPSsilyl ether 2.5 withtriisopropylsilyl triflate and2,6-lutidine . The C1 position in next oxidized by thephosphite ester , P(OEt)3 and the strong base KOt-Bu, and oxygen to alcohol 2.6 (the stereochemistry controlled by bowl-shaped AB ring with hydroxylation from unhinderedconvex direction), the primary alcohol group is deprotected withammonium chloride inmethanol todiol 2.7 and two reductions first with NaBH4 to triol 2.8 and then hydrogen gas andCrabtree's catalyst give triol 2.9. These positions are protected bytrimethylsilyl chloride andpyridine to 2.10 and thentriphosgene to 2.11 in order to facilitate the oxidation of the primary alcohol group to thealdehyde 2.12 by PCC.ynthesis C ring
The next part constructs the C ring starting from aldehyde 3.1 which is extended by one carbon atom to homologue 3.2 in a
Wittig reaction withMethoxymethylenetriphenylphosphine . The acetonide group is removed by dilutehydrochloric acid andsodium iodide indioxane and one hydroxyl group in the resulting diol 3.3 is protected as thetriethylsilyl ether (TES) 3.4 with the corresponding silyl chloride andpyridine enabling oxidation of the remaining hydroxyl group to theketone 3.5 with theDess-Martin periodinane . Reaction withEschenmoser's salt places amethylene group (C20 in the Taxol framework) in the alpha position of the aldehyde to 3.6 and the next reaction introduces (the still lacking) C6 and C7 as theGrignard reagent ofallyl bromide in anucleophilic addition aided byzinc(II) chloride which blocks the Grignard from attack on carbonate group, to alcohol 3.7. The newly formed alcohol is protected as the BOM ether 3.8 with BOMCl and N,N-diisopropylethylamine. After removal of the TES protecting group withammonium fluoride , the carbonate group in 3.9 is converted to a hydroxybenzoate group by action ofphenyllithium and the secondary alcohol to theacetate 3.10 byin situ reaction withacetic anhydride andDMAP . In the next step theacyloin group has its positions swapped by reaction withtriazabicyclodecene (other amine bases fail) forming 3.11 and in the final steps ring closure of ring C is accomplished byozonolysis at the allyl group to 3.12 andAldol reaction with 4-pyrrolidinopyridine to 3.13.ynthesis D ring
The final part deals with the construction of
oxetane ring D starting with protection of the alcohol group in 4.1 in "scheme 4". as aTROC alcohol 4.2 with2,2,2-trichloroethyl chloroformate andpyridine . The OBOM group is replaced by abromine group in three steps: deprotection to 4.3 withhydrochloric acid andsodium iodide ,mesylation to 4.4 withmesyl chloride ,DMAP andpyridine andnucleophilic substitution withinversion of configuration withlithium bromide to bromide 4.5. Because the oxidation of thealkene group to thediol 4.6 withosmium tetroxide is accompanied by the undesired migration of thebenzoate group, this step is taken to completion withimidazole as 4.7. Two additional countermeasures are required: reprotection of the diol as thecarbonate ester 4.8 withtriphosgene and removal of the benzoate group (KCN) to alcohol 4.9 in preparation of the actual ring closure to the oxetane 4.10 with N,N-diisopropylethylamine. In the final steps the tertiary alcohol is acylated in 4.11, the TIPS group removed in 4.12 and the benzoate group re-introduced in 4.13.Tail addition of the
Ojima lactam was not disclosed in detail but finally taxol 4.14 is formed in several steps similar to the other efforts.External links
* The Wender Taxol Mug: [http://thechemblog.com Link]
References
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