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Nicolaou Taxol total synthesis


The Nicolaou taxol total synthesis, published by Kyriacos Costa Nicolaou and his group in 1994 concerns the total synthesis of Taxol. This organic synthesis is considered a classic in organic chemistry.[1] Taxol is an important drug in the treatment of cancer but also expensive because the compound is harvested from a scarce resource, namely the pacific yew. This synthetic route to Taxol is by no means the only one, other groups have presented their own solutions, notably the group of Holton with a linear synthesis starting from Borneol, the Danishefsky group starting from the Wieland-Miescher ketone and the Wender group from Pinene. The Nicolaou synthesis is a good example of convergent synthesis because the molecule is assembled from 3 pre-assembled chunks. Two major parts are cyclohexene rings A and C that are connected by two short bridges creating an 8 membered ring in the middle (ring B). The third pre-assembled part is an amide tail. Ring D is an oxetane ring fused to ring C.

Based on the molecular makeup of this Taxol synthesis the compound is compiled from mucic acid, 2-chloro-acrylonitrile, lithium aluminium hydride, phosgene, glycolic acid, benzaldehyde, HMPA, ethyl propionate, allyl alcohol, acetone, Acetylacetonate, methyl bromide, acetic acid, phenyllithium and pyridinium chlorochromate. Two key chemical transformations are the Shapiro reaction and the pinacol coupling reaction.

Additional recommended knowledge


Synthesis C ring

The ring synthesis of ring C starts with a condensation reaction of phenylboronic acid 1.2 with the diene 3-hydroxy-2-pyrone 1.3 and dienophile 1.2 to the boronic ester 1.4. Boron serves as a template (or molecular tether) and aligns both diene and dienophile for an endo Diels-Alder cycloaddition to a bicyclic[2.2.2]lactone (1.5). The boronate ester is cleaved again in neopentyl glycol to the diol 1.6. A lactone rearrangement reaction takes place to a Bicyclo[4.2.0]lactone 1.7 with the formation of a 5-membered lactone and ring-opening of 6-membered lactone. With t-butyldimethylsilyltriflate and DMAP a silylation to 1.9 takes place preceded by the formation of an acetal protecting group in 1.8. All sensitive groups now protected for an ester reduction with lithium aluminium hydride to 1.10. Finally the protecting groups are removed by camphorsulfonic acid to 1.11

In the next series of steps 4 hydroxyl group are protected leaving one remaining hydroxyl group exposed for oxidation to an aldehyde. In preparation to a lactone reduction, the protection of the primary alcohol 2.1 with TPSCl or t-butyldiphenylsilyl chloride with imidazole as a base is performed to a TBDPS silyl ether 2.2 followed by protection of the secondary alcohol group by benzylbromide with potassium hydride as a base and tetra(n-butyl)ammonium iodine as a phase transfer catalyst to a benzyl protecting group 2.3. Reduction of the lactone takes place with lithium aluminium hydride, liberating two additional hydroxyl groups. The compound 2.4 now contains 5 hydroxyl groups two of which protected as a silyl ether. The vicinal diol group is protected by transacetalization with 2,2-dimethoxypropane to 2.5. The final remaining primary alcohol group is selectively oxidized to the aldehyde by TPAP and N-methylmorpholine N-oxide. This aldehyde (2.6) is the terminus for docking with the vinyllithium group in ring part A.

Synthesis A ring

The A ring synthesis in scheme 3 starts with a Diels-Alder reaction of the diene 3.1 with the commercially available dienophile 2-chloroacrylonitrile 3.2 to the DA product 3.3 with complete regioselectivity. Gem halide hydrolysis of the gem cyanochloro group to a ketone and simultaneous hydrolysis of the acetate group to the alcohol leads to the hydroxy ketone 3.4. The hydroxyl group is protected by silylation with tert-butyldimethylsilylchloride (TBSCl) to the silyl ether 3.5. A Shapiro reaction of the ketone group with p-toluenesulfonylhydrazide and n-butyllithium leads through the hydrazone 3.6 to the viyllithium compound 3.7. This nucleophile reacts with the aldehyde group present in ring C in scheme 4.

Synthesis B ring

 The coupling of ring A and ring C creates the 8 membered B ring. One connection is made via a nucleophilic addition of a vinyllithium compound to an aldehyde and the other connection through a pinacol coupling reaction of two aldehydes (scheme 4).

The nucleophilic addition of the vinyllithium compound 4.1 to aldehyde 4.2 is the first part in the ring closure. The control of stereochemistry in 4.3 is assured because the lithium atom coordinates with the two oxygen atoms in the dioxolane ring and the nucleophile has a hindered Si face approach due to the proximity of the axial methyl group. A peroxidation with vanadyl(acetylacetate) converts the alkene bond into the epoxide 4.4 which is in turn reduced to the vicinal diol 4.5 with lithium aluminium hydride. This diol is then protected as the carbonate ester 4.6 by reaction with phosgene and potassium hydride. The carbonate group also serves to create rigidity in the ring structure for the imminent pinacol coupling reaction. The two silyl ether groups are removed by the fluoride source tetra-n-butylammonium fluoride and the diol 4.7 is formed. The two free hydroxyl groups (out of the total of 7 hydroxyl groups) are now oxidized by the TPAP / NMO combination to the dialdehyde 4.8 and the final step is the pinacol coupling reaction in a McMurry fashion with Titanium(III) chloride and a zinc / copper alloy to the diol 4.9.

Preparation for D ring

At this point in the synthesis of taxol chirality can be introduced by reaction of the diol 5.1 with DMAP and (1S)-(−)-Camphanic chloride as a chiral auxiliary. This reaction converts the pair of alcohol enantiomers into a pair of ester diastereoisomers which can be separated by conventional column chromatography. The thus purified esters are then hydrolyzed back to the enantiomeric diols. This chirality however, is only temporary because the alcohol group is converted into a ketone later on in the reaction sequence.

The allylic alcohol group in 5.1 (scheme 5) is acylated with acetic anhydride and DMAP to 5.2. It is noteworthy that while this reaction is exclusive for the allylic alcohol, the adjacent alcohol group is not responsive to this acylation. oxidation with TPAP and NMO gives the ketone 5.3. The next series of reaction steps activate new alcohol groups on ring C in preparation of the formation of the oxetane ring D. This involves coupled deprotection and reprotection steps.

A new hydroxyl group is introduced in the allyl ether group in ring C by hydroboration with borane and hydrogen peroxide. This reaction step to 5.4 suffers from poor regioselectivity because both alkene positions can be hydroxylated. The acetal group that has thus far protected two hydroxyl groups is now removed by hydrochloric acid to the diol 5.5. The new primary hydroxyl group is esterified to 5.6 with an acetyl group (Ac) by reaction with acetic anhydride and DMAP. The protective benzyl group is now removed by organic reduction with hydrogen gas and a palladium catalyst. The alcohol 5.7 is protected again to the TES silyl ether 5.8 by reaction with triethylsilyl chloride. Finally the secondary hydroxyl group is converted into a leaving group by derivatization with mesyl chloride and DMAP to the MES mesylate 5.9.

Synthesis D ring

The acetyl group in 6.1 (scheme 6) is removed by potassium carbonate and liberates the primary alcohol in 6.2. The Taxol oxetane ring D is added by an intramolecular nucleophilic aliphatic substitution of the mesylate by this hydroxyl group in 6.3 with the aid of a tetrabutyl ammonium acetate. For this reaction to be a success the alcohol and mesylate group have the correct Trans configuration. The only remaining tertiary alcohol group is acetylated (6.4) which step enables phenyllithium to ring open the carbonate ester ring to the α-hydroxybenzoate ester 6.5. The other three carbonyl groups present at this stage are impervious to this reagent. In the next step the allylic methylene position in the A ring is oxidized by pyridinium chlorochromate, sodium acatate and celite to the ketone 6.6 which is subsequently reduced to the alcohol group with sodium borohydride. The A ring hydroxyl group in 6.7 is the anchor point for the amide tail in the next step.

Tail addition

The Ojima lactam 7.1 reacts with alcohol 7.2 with sodium bis(trimethylsilyl)amide as a base. This alcohol (10-deacetylbaccatinIII) is a naturally occurring compound found in Taxus baccata also known as the European Yew in concentrations of 1 gram per kilogram leaves. Therefore this reaction step is also a semi-synthesis. The final step in this reaction sequence is the hydrolysis of the remaining silyl ether with hydrofluoric acid and pyridine. The Taxol molecule is often displayed with an additional benzoyl group in the amide tail. This modification can be included by reaction of 7.4 with benzoyl chloride in the Schotten-Baumann reaction.

Precursor synthesis

Synthesis of the diene precursor in ring C: The ethyl ester of propionic acid 1 is brominated (2) and then converted to the Wittig reagent 3 with triphenylphosphine. This compound reacts with the aldehyde 6 in a Wittig reaction. This aldehyde is obtained from allyl alcohol 4, with the alcohol group protected as a silyl ether 5 with tert-butyldiphenylsiliyl chloride and the allyl group oxidized by ozonolysis (6). The Wittig reaction product 7 is deprotected to the allyl alcohol 8

Synthesis of the diene precursor in ring A: acetone 1 and acetylacetonate 2 react in an aldol condensation to the β-keto-ester 3. The ketone group is reacted with methylmagnesium bromide derived from methyl bromide in a Grignard reaction to the alcohol 4. The final three steps are an acid catalyzed elimination reaction to the diene 5 , ester reduction to 6 and acylation to 7

See also


  1. ^  Total synthesis of taxol K. C. Nicolaou, Z. Yang, J. J. Liu, H. Ueno, P. G. Nantermet, R. K. Guy, C. F. Claiborne, J. Renaud, E. A. Couladouros, K. Paulvannan & E. J. Sorensen Nature 367, 630 - 634 (17 February 1994) Abstract Pubmed
  2. ^  Synthesis of C-2 Taxol Analogues Kyriacos Costa Nicolaou, Elias A. Couladouros, Phillipe G. Nantermet, Joanne Renaud, Rodney Kiplin Guy, Wolfgang Wrasidlo Angewandte Chemie International Edition Volume 33, Issue 15-16 , Pages 1581 - 1583 1994 Abstract
  3. ^  Synthesis of a fully functionalized CD ring system of taxol K. C. Nicolaou, J. J. Liu, C.-K. Hwang, W.-M. Dai and R. K. Guy Journal of the Chemical Society, Chemical Communications, 1992, (16), 1118 - 1120 DOI Abstract
  4. ^  A convergent strategy towards taxol. A facile enantioselective entry into a fully functionalized ring A system K. C. Nicolaou, C.-K. Hwang, E. J. Soresen and C. F. Clairborne Journal of the Chemical Society, Chemical Communications, 1992, (16), 1117 - 1118 DOI Abstract
  5. ^  Novel chemistry of taxol. Retrosynthetic and synthetic studies K. C. Nicolaou, P. G. Nantermet, H. Ueno and R. K. Guy Journal of the Chemical Society, Chemical Communications, 1994, (3), 295 - 296 DOI Abstract
  6. ^  Synthesis of ABCtaxoid ring systems via a convergent strategy K. C. Nicolaou, Zhen Yang, Erik J. Sorensen and Masahisa Nakada Journal of the Chemical Society, Chemical Communications, 1993, (12), 1024 - 1026 [2]
  7. ^  Synthesis of Novel Taxoids K. C. Nicolaou, Christopher F. Claiborne, Philippe G. Nantermet, Elias A. Couladouros, and Erik J. Sorensen J. Am. Chem. Soc.; 1994; 116(4) pp 1591 - 1592; DOI Abstract
  8. ^  New and efficient approaches to the semisynthesis of taxol and its C-13 side chain analogs by means of lactam synthon method Iwao Ojima, Ivan Habus, Mangzhu Zhao, Martine Zucco, Young Hoon Park, Chung Ming Sun and Thierry Brigaud Tetrahedron Volume 48, Issue 34 , 1992, Pages 6985-7012 Abstract
  9. ^  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
  10. ^  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
  11. ^  Total Synthesis of Baccatin III and Taxol Samuel J. Danishefsky, John J. Masters, Wendy B. Young, J. T. Link, Lawrence B. Snyder, Thomas V. Magee, David K. Jung, Richard C. A. Isaacs, William G. Bornmann, Cheryl A. Alaimo, Craig A. Coburn, and Martin J. Di Grandi J. Am. Chem. Soc.; 1996; 118(12) pp 2843 - 2859 DOI Abstract
  12. ^  Classics in Total Synthesis: Targets, Strategies, Methods K. C. Nicolaou, E. J. Sorensen ISBN 3-527-29231-4
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Nicolaou_Taxol_total_synthesis". A list of authors is available in Wikipedia.
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