- Holton Taxol total synthesis
The Holton Taxol total synthesis, published by
Robert A. Holton and his group atFlorida State University in 1994 was the firsttotal synthesis ofTaxol (generic name: paclitaxel) ["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. [http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/ja00083a066 DOI Abstract] ] ["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 [http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/ja00083a067 DOI Abstract] ] ["A synthesis of taxusin" Robert A. Holton, R. R. Juo, Hyeong B. Kim, Andrew D. Williams, Shinya Harusawa, Richard E. Lowenthal, Sadamu YogaiJ. Am. Chem. Soc. ; 1988; 110(19); 6558-6560. [http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/1988/110/i19/f_ja00227a043.pdf Abstract] ] .The Holton
Taxol total synthesis is a good example of alinear synthesis starting from commercially available natural compoundpatchoulene oxide . Thisepoxide can be obtained in two steps from the terpenepatchoulol and also fromborneol . The reaction sequence is alsoenantioselective , synthesizing (+)-Taxol from (-)-patchoulene oxide or (-)-Taxol from (-)-borneol with a reportedspecific 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-chloroperoxybenzoic acid, methyl magnesium bromide andphosgene . Two key chemical transformations in this sequence are aChan rearrangement and asulfonyloxaziridine enolate oxidation .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 reaction s. Reaction of 1 with tert-butyllithium removes the acidic α-epoxide proton leading to anelimination reaction and ring-opening of the epoxide to theallyl alcohol 2. The resultantalkene group is oxidized to anepoxide group in 3 withtert-butylperoxide andtin tetraisopropoxide . In the subsequent reaction thelewis 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 thediol 4. The newly createdhydroxyl group is protected as the TESsilyl ether 5 by reaction withtriethylsilylchloride ,DMAP andpyridine . The also newly created alkene group is epoxidized by reaction withm-CPBA . The epoxide 6 is unstable and an epoxy alcoholGrob fragmentation reaction follows whereby driven by the oxidation of the alcohol group to aketone group acarbon-carbon bond gives way to the desired AB ring in 7. The hydroxyde group is protected as the TBSsilyl 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 bromideenolate 8 by action of LDA and methyl magnesium bromide to which is added 4-pentenal in analdol reaction to the secondaryalcohol 9. This group is protected as the asymmetriccarbonate ester 10 by reaction first withphosgene ,pyridine indichloromethane and then with ethanol. The introduction of theacyloin group in 11 is with stereochemical control,enolate formation by action of LDA is followed by its oxidation with (+)-camphorsulfonyl oxaziridine for theenantiomer leading to Taxol. Reduction of the ketone group withRed-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 theketone 13 in aSwern oxidation . The first carbon carbon bond formation in this sequence is aChan rearrangement of thecarbonate ester withlithium tetramethylpiperidide to a α-hydroxy ester 14. The hydroxyl group is reduced in two steps to theenol 15 withSamarium(II) iodide followed by acidic workup withsilica 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 withlithium tetramethylpiperidide and (+)-camphorsulfonyl oxaziridine to theacyloin 17 is the secondsulfonyloxaziridine 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 byRed-Al .In "scheme 3" the diol in 18 is protected as a
carbonate ester 19 withphosgene . The terminal alkene group is next converted to a methylester in 20 byozonolysis , followed by oxidation by potassium permanganate and esterification with diazomethane. The second C-C bond formation step in the cyclohexane C ring synthesis is aDieckman condensation of 20 to the enol ester 21 initialized by LDA at -78°C in THF followed by workup withacetic 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 withpotassium thiophenolate in DMF in a modifiedBarton 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 aquat .The ketone is converted into the TMSenol ether 26 with LDA and trimethylsilylchloride and subsequently oxidized withm-CPBA to the TMS protectedacyloin 27. At this stage the final missing carbon atom in the Taxol ring framework is introduced in aGrignard 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 theoxetane D ring. TheBurgess reagent brings about anelimination 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 inpyridine 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 atosylate leaving group in 32 by reaction with tosyl chloride. The TMS group no longer needed is removed in 33 withacetic acid . The next step is the actual oxetane formation (34) bynucleophilic displacement with inversion of the tosyl group on C5 by the hydroxylnucleophile on C20. The remaining tertiary alcohol is acylated withacetic anhydride ,DMAP andpyridine (35) and then the C10 hydroxyl group is reintroduced in 36 by cleavage of the TESsilyl ether withhydrogen fluoride pyridine complex inacetonitrile . The carbonate ester is cleaved by reaction withphenyllithium 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 aTPAP / 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 theacyloin 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 theTASF reagent . Reaction of the lithium alkoxide of 41 with theOjima lactam 42 adds the tail in 43. A silyl deprotection step at the TES position (44) and a BOM deprotection step with hydrogen andpalladium on carbon gives (-)-Taxol 45.Precursor synthesis
The synthesis of patchoulene oxide starts from
patchoulol . Patchoulol (45) is a tricyclic compound which gives acarbocation icrearrangement reaction followed by anelimination reaction in presence of a protic acid. The driving force for the rearrangement is relief ofring 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
*
Nicolaou Taxol total synthesis
*Danishefsky Taxol total synthesis References
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