- 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 reagentand Eschenmoser's salt.
ynthesis AB ring
The taxol synthesis starts from the terpene
verbenone1.1 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 vinylic enoneproton by potassium tert-butoxidefollowed by nucleophilic displacementof the bromineatom in prenyl bromide 1.2 to form diene1.3. Ozonolysisof the prenyl group (more electron-rich than the internal double bond) forms aldehyde1.4 which after isomerizationor photorearrangementto the Chrysanthenone1.5 reacts with the lithium salt (via LDA) of the ethyl esterof Propiolic acid1.6 in a nucleophilic additionto the alcohol1.7. This compound is not isolated but trapped in situwith trimethylsilyl chlorideto the silyl ether1.8. In the next step Gilman reagent1.9 is a methylating reagent in nucleophilic conjugate additionthrough the alkynegroup to the ketonegroup forming the alcohol1.10. The silyl ether protective groupis removed by reaction with acetic acidto alcohol 1.11 which is then oxidized to the ketone1.12 with RuCl2(PPh3)3 and NMO as the sacrificial catalyst. The acyloingroup in 1.13 is introduced by KHMDS and Davis’ oxaziridine (see Holton Taxol total synthesisfor another use of this system) and its hydroxyl group together with the ester group are reduced by lithium aluminium hydrideto tetrol 1.14. Finally the primary alcohol group is protected as a tert-butyldimethylsilyl ether by the corresponding silylchloride and imidazolein 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-methoxypropenegives the acetonide2.2. At this point the double bond in ring A is epoxidized with m-CPBAand sodium carbonateto epoxide2.3 and a Grob fragmentation(also present in the Holton effort) initiated by DABCOopens up the AB ring system in alcohol 2.4 which is not isolated but protected as a TIPS silyl ether2.5 with triisopropylsilyl triflateand 2,6-lutidine. The C1 position in next oxidized by the phosphite 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 unhindered convexdirection), the primary alcohol group is deprotected with ammonium chloridein methanolto diol2.7 and two reductions first with NaBH4 to triol 2.8 and then hydrogen gas and Crabtree's catalystgive triol 2.9. These positions are protected by trimethylsilyl chlorideand pyridineto 2.10 and then triphosgeneto 2.11 in order to facilitate the oxidation of the primary alcohol group to the aldehyde2.12 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 reactionwith Methoxymethylenetriphenylphosphine. The acetonide group is removed by dilute hydrochloric acidand sodium iodidein dioxaneand one hydroxyl group in the resulting diol 3.3 is protected as the triethylsilyl ether(TES) 3.4 with the corresponding silyl chloride and pyridineenabling oxidation of the remaining hydroxyl group to the ketone3.5 with the Dess-Martin periodinane. Reaction with Eschenmoser's saltplaces a methylenegroup (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 the Grignard reagentof allyl bromidein a nucleophilic additionaided by zinc(II) chloridewhich 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 with ammonium fluoride, the carbonate group in 3.9 is converted to a hydroxybenzoate group by action of phenyllithiumand the secondary alcohol to the acetate3.10 by in situreaction with acetic anhydrideand DMAP. In the next step the acyloingroup has its positions swapped by reaction with triazabicyclodecene(other amine bases fail) forming 3.11 and in the final steps ring closure of ring C is accomplished by ozonolysisat the allyl group to 3.12 and Aldol reactionwith 4-pyrrolidinopyridine to 3.13.
ynthesis D ring
The final part deals with the construction of
oxetanering D starting with protection of the alcohol group in 4.1 in "scheme 4". as a TROCalcohol 4.2 with 2,2,2-trichloroethyl chloroformateand pyridine. The OBOM group is replaced by a brominegroup in three steps: deprotection to 4.3 with hydrochloric acidand sodium iodide, mesylationto 4.4 with mesyl chloride, DMAPand pyridineand nucleophilic substitutionwith inversion of configurationwith lithium bromideto bromide 4.5. Because the oxidation of the alkenegroup to the diol4.6 with osmium tetroxideis accompanied by the undesired migration of the benzoategroup, this step is taken to completion with imidazoleas 4.7. Two additional countermeasures are required: reprotection of the diol as the carbonate ester4.8 with triphosgeneand 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 lactamwas not disclosed in detail but finally taxol 4.14 is formed in several steps similar to the other efforts.
* The Wender Taxol Mug: [http://thechemblog.com Link]
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