The Synthesis of Taxol

Since the emphasis of this review is on the chemistry of taxol itself, the many approaches to the synthesis of taxol are outside its scope and will not be discussed here. Instead the six completed total syntheses will be described briefly, primarily in the form of reaction flow charts. Since baccatin III can readily be converted to taxol by the chemistry described in Section 8.1, the total synthesis of baccatin III constitutes a formal synthesis of taxol, and thus the synthetic routes described will stop at baccatin III, although the authors did in each case convert this to taxol. 

The synthesis of baccatin III presents a formidable challenge, because the molecule contains an unusual and distorted ABCD ring 

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In the meantime, the race toward the total synthesis of Taxol and the synthesis of Taxol-like compounds started. It was announced in February 1994... 

As this synthesis started from an achiral starting material, compound 199 must be resolved to secure enantiomerically pure intermediates for the synthesis of taxol. Treatment of (+ )-diol 199 with excess ( lA)-( )-camphanic chloride in methylene chloride in the presence of Et3N forms two diastereomeric monoesters for chromatographic separation. Enantiomerically pure diol 199 can be regenerated from the ester in 90% yield with a specific rotation of +187 (c = 0.5, CHC13). 

With the structure of 53a securely stablished, the synthesis of taxol proceeded as outlined in Scheme 13.6.12. 

The synthesis of Taxol completed by a group led by the Japanese chemist Teruaki Mukaiyama and shown in Scheme 13.46 takes a rather different approach. Much of the stereochemistry is built into the B ring by a series of acyclic aldol condensations in steps A-D. The ring is closed by a samarium-mediated cyclization at step E-3. 

Partial hydrolysis of an oxazoline to produce the hydroxy amide was used extensively in the synthesis of Taxol analogues (Table 8.24 Scheme It is noteworthy that a solution of the amino... 

As well as being applicable to the glycosylation of monohydroxy compounds, the reaction has been used to disubstitute diols such as chloramphenicol (84), to give products of sequential substitution such as 86, and hence saturated glycosylated compounds. In a different type of application, the resolution of the racemate of compound 85 can be accomplished by glycosylation and separation of the diastereomers to afford the illustrated enantiomer which was required for work on the synthesis of taxol. 

Oxirane taxol derivatives have also been found to be convenient starting materials for the synthesis of taxols fused with a thietane ring. The oxirane-derived taxine B derivatives 118 and 119 have undergone reaction with potassium thioacetate in dimethylformamide (DMF) at 60°C <2000TL4891, 2001JOC5058>, leading to the formation of thietane-derived taxine B derivatives 57 and 121. In the case of the bromine derivative 118, the thietane-taxol 57 was not the exclusive product and the 1,2-dithiolane derivative 120 occurred as the major product (Equations 35 and 36). 

The asymmetric oxidation of indene to the corresponding epoxide (Equation 24) is carried out commercially by Sepracor on a small scale. Chiral indene oxide is an intermediate in the synthesis of crixivan (an HIV protease inhibitor). Reaction is carried out at 5°C with moderately high turnover numbers in the presence of an exotic donor ligand ( P3NO , 3-phenylpropylpyridine N oxide) and sodium hypochlorite as the terminal oxidant. A similar epoxidation of a simple cis olefin (Equation 25) leads to an enantiomerically pure amino-alcohol used in the synthesis of taxol, a potent anticancer drug. 

Ermolenko, M S, Shekharam, T, Lukacs, G, Potier, P, A convergent carbohydrate approach to the synthesis of taxol 1. Ring A subunit. Tetrahedron Lett, 36, 2461-2464, 1995. 

Several approaches to the synthesis of taxol and the taxane skeleton have employed Shapiro reactions.25 An interesting route to the taxol A-ring that illustrates the utility of dianion functionalization prior to alkene generation was recently described by Koskinen.256 As shown below, treatment of tosylhydrazone 48 with 2.2 equiv of n-BuLi... 

What was it that made the synthesis of taxol so difficult For a while, the assertion that every molecule that can exist can today be made, given enough manpower, [9] was almost called into question. To analyse the synthetic problem, it is useful to concentrate on the tricyclic A/B/C ring system of baccatin... 

An isomerization reaction at an ot-position with superbase was also applied in the synthesis of taxol (157) by Kusama et al. [48]. C 10a-Acetate 210, obtained from the enol... 

The Synthesis of Taxol and Taxol Analogs from Precursors... 

Studies of the chemistry of the phenylisoserine side chain of taxol continue to be made, reflecting the importance of this structural unit for the synthesis of taxol from baccatin III and the potential of preparing improved analogs of taxol by modification of the side chain. Synthetic... 

Early on in the study of the synthesis of taxol from baccatin III it was realized that the C-13 hydroxyl group of baccatin III is very hindered, so that acylation by a bulky protected side chain is difficult. One of the favored approaches to overcoming this problem is to protect the 2 -hydroxyl group through a cyclic structure, usually as an oxazolidine or an oxazoline. The synthesis of these protected side chains thus becomes an important goal. 

Several microbial processes have been applied to the synthesis of taxol side chain. Thus Patel et al demonstrated that racemic a-keto-y0-amino esters such as 7.6.4 can be reduced by enzymes isolated from Hansenula species to give the side chain ester 7.6.5 in 80-85% yield and 90-98% enantiomeric excess 288). 

The synthesis of taxol or docetaxel requires the coupling of a protected side chain with a protected baccatin III. The procedures for this have not changed significantly since the previous review in this series, but some points of interest have emerged. The semisynthesis of taxol has been reviewed relatively recently (295), and the first section has thus been abbreviated. In addition, since the focus of this review is on the chemistry of taxol rather than its medicinal chemistry and structure-activity relationships, the sections dealing with the syntheses of taxol analogs will present illustrative rather than exhaustive examples. 

In a series of reports Gennari et al. demonstrated the synthesis of taxol side chain thioesters protected as oxazolines and oxazolidines. Thus reaction of the enolate of thioester 8.1.8 and TMS-imine 8.1.9 in the presence of chiral borate 8.1.10 gave the side chain thioester 8.1.11 in 60% yield. Compound 8.1.11 was then protected as its acetonide 8.1.12. The oxazoline analog 8.1.13 was synthesized by a similar strategy with an inversion to achieve the desired stereochemistry at C-2 during the formation of the oxazoline ring (299). 

Chen et al. reported the synthesis of taxol analogs which were isomeric with docetaxel by virtue of having a 3 -f-butylaminocarbonyl-oxy group in place of the normal 3 -r-butoxycarbonylamino group... 

The metabolism of taxol and other taxoid drugs has been reviewed (341-343), and this section will thus primarily cover the synthesis of taxol metabolites. The major identified metabolites of taxol in the rat were found in the bile, and two of these were the phenolic metabolites... 

The synthesis of taxol and taxol analogs from baccatin III and its precursor 10-deacetyl baccatin III was described in section 8 above, and this approach constitutes the current commercial synthesis of taxol and docetaxel. The concept of converting other taxoid precursors into taxol or bioactive taxol analogs continues to intrigue chemists, however, and several groups have investigated such conversions. 

Two different groups have reported the synthesis of taxol analogs with a basic group at C-10. In an extension of work reported in section 3.1.3 (79, 80), Soga and his collaborators modified their C-10 analogs by preparing various ethers at C-7. The methyl ether A3.1.1 showed the best cytotoxicity, and was active against the B16 melanoma in mice both intravenously and orally (578). 

Work continues seemingly unabated on the synthesis of taxols with various substituents, either as prodrugs or as analogs with modified properties. 

Taxol is a powerful anti-cancer drug with a versatile and widespread medical application. In the synthesis of taxol, cydocarhonates are sometimes useful tools in functionalizing the taxol rings. An intermediate protective group is introduced by cyclocarbonylation of the 1,2-diol of 10-TES baccatin III 890 with phosgene, furnishing 891 in 95% yield [648] (see also Section 4.3.3.5). 

Alkene metathesis catalysts are also capable of undergoing reaction with aUene and alkyne functionality, which can lead to the synthesis of polyene compounds. For example. Diver has explored the use of alkene/alkyne CM, which leads to 2-substituted 1,3-dienes (Scheme 2.11). Prunet has recently disclosed an elegant metathesis cascade sequence towards the synthesis of Taxol, involving two alkenes and one alkyne functional group (Scheme 2.12) the desired product was accompanied by small quantities of a side product that resulted from metathesis of the two alkenes. 

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