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Holton Taxol total synthesis


The Holton Taxol total synthesis, published by Robert A. Holton and his group at Florida State University in 1994 was the first total synthesis of Taxol [1] [2] [3]. The Holton Taxol total synthesis is a good example of a linear synthesis starting from commercially available natural compound patchoulene oxide. This epoxide can be obtained in two steps from the terpene patchoulol and also from borneol. The reaction sequence is also enantioselective, synthesizing (+)-Taxol from (-)-patchoulene oxide or (-)-Taxol from (-)-borneol with a reported specific rotation of +- 47° (c=0.19 / MeOH). The Holton sequence to Taxol is relatively short compared to that of the other groups with an estimated 37 step not counting the addition of the amide tail. One of the reasons is that the patchoulol starting compound already contains 15 of the 20 carbon atoms required for the Taxol ABCD ring framework.

Other raw materials besides the already mentioned patchoulene oxide required for this synthesis are 4-pentenal ,m-CPBA,methyl magnesium bromide and phosgene. Two key chemical transformations in this sequence are a Chan rearrangement and a sulfonyloxaziridine enolate oxidation.

Additional recommended knowledge


Synthesis AB ring

Starting from patchoulene oxide 1 in scheme 1 the first part is the creation of the fused 6 and 8 membered AB ring system through a sequence of rearrangement reactions. Reaction of 1 with tert-butyllithium removes the acidic α-epoxide proton leading to an elimination reaction and ring-opening of the epoxide to the allyl alcohol 2. the thus created alkene group is oxidized to an epoxide group in 3 with tert-butylperoxide and tin tetraisopropoxide. In the subsequent reaction the lewis acid boron trifluoride catalyses the ring opening of the epoxide followed by a skeletal rearrangement of the isopropyl bridge and a second elimination reaction to the diol 4. The newly created hydroxyl group is protected as the TES silyl ether 5 by reaction with triethylsilylchloride, DMAP and pyridine. The also newly created alkene group is epoxidized by reaction with m-CPBA. The epoxide 6 is unstable and an epoxy alcohol Grob fragmentation reaction follows whereby driven by the oxidation of the alcohol group to a ketone group a carbon-carbon bond gives way to the desired AB ring in 7. The hydroxyde group is protected as the TBS silyl ether. In the next phase the required carbon atoms are added for the formation of the C ring through the available ketone group. The ketone group in 7 is converted into the magnesium bromide enolate 8 by action of LDA and methyl magnesium bromide to which is added 4-pentenal in an aldol reaction to the secondary alcohol 9. This group is protected as the asymmetric carbonate ester 10 by reaction first with phosgene, pyridine in dichloromethane and then with ethanol. The introduction of the acyloin group in 11 is with stereochemical control, enolate formation by action of LDA is followed by its oxidation with (+)-camphorsulfonyl oxaziridine for the enantiomer leading to Taxol. Reduction of the ketone group with Red-Al to an alcohol with basic workup is accompanied with a carbonate rearrangement to the new cyclic carbonate ester 12 with elimination of ethanol.

Synthesis C ring

It takes two carbon carbon bond formation steps to create the cyclohexane C ring. The alcohol 12 in scheme 2 is converted to the ketone 13 in a Swern oxidation. The first carbon carbon bond formation in this sequence is a Chan rearrangement of the carbonate ester with lithium tetramethylpiperidide to a α-hydroxy ester 14. The hydroxyl group is reduced in two steps to the enol 15 with Samarium(II) iodide followed by acidic workup with silica gel (in chromatography) to the ketone 16. This compound is obtained as a cis-trans mixture but the undesired trans isomer (the fused B ring and lactone C ring in a boat-boat conformation) can be recycled back to the cis isomer by reverting back to the enolate with base and additional acidic workup. The placement of an α-keto hydroxyl group with lithium tetramethylpiperidide and (+)-camphorsulfonyl oxaziridine to the acyloin 17 is the second sulfonyloxaziridine enolate oxidation in the Holton sequence and occurs exclusively (trans) at the C1 position on the A ring although the C3 position located on the C ring is more acidic. The newly formed ketone group is converted to the hydroxyl group in 18 by Red-Al.

In scheme 3 the diol in 18 is protected as a carbonate ester 19 with phosgene. The terminal alkene group is next converted to a methyl ester in 20 by ozonolysis, followed by oxidation by potassium permanganate and esterification with diazomethane. The second C-C bond formation step in the cyclohexane C ring synthesis is a Dieckman condensation of 20 to the enol ester 21 initialized by LDA at -78°C in THF followed by workup with acetic acid. Decarboxylation of the ester group requires protection of the hydroxyl group as an alkoxy ether (22) (MOP) by reaction with p-toluenesulfonic acid and 2-methoxypropene. With the protective group in place the carboxyl group is removed in 23 by reaction with potassium thiophenolate in DMF in a modified Barton decarboxylation. In the next two steps the MOP ether is removed by acid to the alcohol 24 and reprotected with another more robust alkoxy ether protecting group in 25 (a benzyloxymethyl ether or BOM ether) by reaction with the corresponding BOM chloride, N,N-diisopropylethylamine and a quat. The ketone is converted into the TMS enol ether 26 with LDA and trimethylsilylchloride and subsequently oxidized with m-CPBA to the TMS protected acyloin 27. At this stage the final missing carbon atom in the Taxol ring framework is introduced in a Grignard reaction of the ketone with a 10 fold excess of methyl magnesium bromide to the tertiary alcohol 28. This carbon atom will become part of the oxetane D ring. The Burgess reagent brings about an elimination reaction of the alcohol to an exocyclic alkene and acidic workup provides the free allyl alcohol 29.

Synthesis D ring

In this section of the Holton Taxol synthesis the oxetane D ring is completed and ring B is functionalized with the correct substituents. The allyl alcohol 29 in scheme 4 is oxidized with osmium tetroxide in pyridine to the triol 30. The three alcohol groups are modified in the next 5 reaction steps. The primary alcohol is protected by reaction with trimethylsilylchloride as the TSM ether 31 and this makes it possible to turn the secondary alcohol into a tosylate leaving group in 32 by reaction with tosyl chloride. The TMS group no longer needed is removed in 33 with acetic acid. The next step is the actual oxetane formation (34) by nucleophilic displacement with inversion of the tosyl group on C5 by the hydroxyl nucleophile on C20. The remaining tertiary alcohol is acylated with acetic anhydride, DMAP and pyridine (35) and then the C10 hydroxyl group is reintroduced in 36 by cleavage of the TES silyl ether with hydrogen fluoride pyridine complex in acetonitrile. The carbonate ester is cleaved by reaction with phenyllithium in THF at -78°C to the hydroxy benzoate 37 completing the lower part of the B ring. In the upper part of the same ring the hydroxyl group is oxidized to a ketone in 38 with a TPAP / NMO system, turned into the enolate with potassium tert-butoxide in THF at low temperatures and further oxidized by reaction with a suspension of benzeneseleninic anhydride to the acyloin 39 which is subsequently acylated to the acylketone 40.

Tail addition

The tail addition step in this synthesis (scheme 5) is identical to that in the Nicolaou tail addition and based on the Ojima lactam. The C13 hydroxyl group in 40 is deprotected by silyl ether cleavage with the TASF reagent. Reaction of the lithium alkoxide of 41 with the Ojima lactam 42 adds the tail in 43. A silyl deprotection step at the TES position (44) and a BOM deprotection step with hydrogen and palladium on carbon gives (-)-Taxol 45.

Precursor synthesis

The synthesis of patchoulene oxide starts from patchoulol. Patchoulol (45) is a tricyclic compound which gives a carbocationic rearrangement reaction followed by an elimination reaction in presence of a protic acid. The driving force for the rearrangement is relief of ring strain. Zaitsev's rule applies in the elimination. In the second step the newly formed double bond in 46 is epoxidized to patchoulene oxide 1.

See also


  1. ^ First total synthesis of taxol 1. Functionalization of the B ring Robert A. Holton, Carmen Somoza, Hyeong Baik Kim, Feng Liang, Ronald J. Biediger, P. Douglas Boatman, Mitsuru Shindo, Chase C. Smith, Soekchan Kim, et al.; J. Am. Chem. Soc.; 1994; 116(4); 1597-1598. DOI Abstract
  2. ^ First total synthesis of taxol. 2. Completion of the C and D rings Robert A. Holton, Hyeong Baik Kim, Carmen Somoza, Feng Liang, Ronald J. Biediger, P. Douglas Boatman, Mitsuru Shindo, Chase C. Smith, Soekchan Kim, and et al. J. Am. Chem. Soc.; 1994; 116(4) pp 1599 - 1600 DOI Abstract
  3. ^ A synthesis of taxusin Robert A. Holton, R. R. Juo, Hyeong B. Kim, Andrew D. Williams, Shinya Harusawa, Richard E. Lowenthal, Sadamu Yogai J. Am. Chem. Soc.; 1988; 110(19); 6558-6560. Abstract
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Holton_Taxol_total_synthesis". A list of authors is available in Wikipedia.
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