Wender Taxol total synthesis
From Wikipedia, the free encyclopedia
The Wender Taxol total synthesis in organic chemistry describes a Taxol total synthesis (one of six to date) by the group of Paul A. Wender at Stanford University published in 1997 [1] [2]. This synthesis has much in common with the Holton Taxol total synthesis in that it is a linear 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 and Eschenmoser's salt.
Contents |
[edit] Synthesis 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 vinylic enone proton by potassium tert-butoxide followed by nucleophilic displacement of the bromine atom in prenyl bromide 1.2 to formdiene 1.3. Ozonolysis of the prenyl group (more electron-rich than the internal double bond) forms aldehyde 1.4 which after isomerization or photorearrangement to the Chrysanthenone 1.5 reacts with the lithium salt (via LDA) of the ethyl ester of Propiolic acid 1.6 in a nucleophilic addition to the alcohol 1.7. This compound is not isolated but trapped in situ with trimethylsilyl chloride to the silyl ether 1.8. In the next step Gilman reagent 1.9 is a methylating reagent in nucleophilic conjugate addition through the alkyne group to the ketone group forming the alcohol 1.10. The silyl ether protective group is removed by reaction with acetic acid to alcohol 1.11 which is then oxidized to the ketone 1.12 with RuCl2(PPh3)3 and NMO as the sacrificial catalyst. The acyloin group in 1.13 is introduced by KHMDS and Davis’ oxaziridine (see Holton Taxol total synthesis for another use of this system) and its hydroxyl group together with the ester group are reduced by lithium aluminium hydride to tetrol 1.14. Finally the primary alcohol group is protected as a tert-butyldimethylsilyl ether by the corresponding silylchloride and imidazole 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 the acetonide 2.2. At this point the double bond in ring A is epoxidized with m-CPBA and sodium carbonate to epoxide 2.3 and a Grob fragmentation (also present in the Holton effort) initiated by DABCO opens up the AB ring system in alcohol 2.4 which is not isolated but protected as a TIPS silyl ether 2.5 with triisopropylsilyl triflate and 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 convex direction), the primary alcohol group is deprotected with ammonium chloride in methanol to diol 2.7 and two reductions first with NaBH4 to triol 2.8 and then hydrogen gas and Crabtree's catalyst give triol 2.9. These positions are protected by trimethylsilyl chloride and pyridine to 2.10 and then triphosgene to 2.11 in order to facilitate the oxidation of the primary alcohol group to the aldehyde 2.12 by PCC.
[edit] Synthesis 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 with Methoxymethylenetriphenylphosphine. The acetonide group is removed by dilute hydrochloric acid and sodium iodide in dioxane and one hydroxyl group in the resulting diol 3.3 is protected as the triethylsilyl ether (TES) 3.4 with the corresponding silyl chloride and pyridine enabling oxidation of the remaining hydroxyl group to the ketone 3.5 with the Dess-Martin periodinane. Reaction with Eschenmoser's salt places a methylene 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 the Grignard reagent of allyl bromide in a nucleophilic addition aided by zinc(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 with ammonium fluoride, the carbonate group in 3.9 is converted to a hydroxybenzoate group by action of phenyllithium and the secondary alcohol to the acetate 3.10 by in situ reaction with acetic anhydride and DMAP. In the next step the acyloin group 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 ozonolysis at the allyl group to 3.12 and Aldol reaction with 4-pyrrolidinopyridine to 3.13.
[edit] Synthesis 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 a TROC alcohol 4.2 with 2,2,2-trichloroethyl chloroformate and pyridine. The OBOM group is replaced by a bromine group in three steps: deprotection to 4.3 with hydrochloric acid and sodium iodide , mesylation to 4.4 with mesyl chloride, DMAP and pyridine and nucleophilic substitution with inversion of configuration with lithium bromide to bromide 4.5. Because the oxidation of the alkene group to the diol 4.6 with osmium tetroxide is accompanied by the undesired migration of the benzoate group, this step is taken to completion with imidazole as 4.7. Two additional countermeasures are required: reprotection of the diol as the carbonate ester 4.8 with triphosgene 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.
[edit] External links
- The Wender Taxol Mug: Link
[edit] References
- ^ The Pinene Path to Taxanes. 5. Stereocontrolled Synthesis of a Versatile Taxane Precursor Paul A. Wender et al.J. Am. Chem. Soc.; 1997; 119(11) pp 2755 - 2756; (Communication) DOI: 10.1021/ja9635387
- ^ The Pinene Path to Taxanes. 6. A Concise Stereocontrolled Synthesis of Taxol Wender, P. A. et al. J. Am. Chem. Soc.; (Communication); 1997; 119(11); 2757-2758. DOI: 10.1021/ja963539z
