Baccatin III and Taxol

Multistep Syntheses natural substances,32 and it is currently an important drug in cancer chemotherapy. 

Another epoxidation, followed by fragmentation gave the bicyclic intermediate that contains the eight-membered ring and bridgehead double bond properly positioned for conversion to Taxol (Steps B-2 and B-3). 

31- Taxol is a registered trade name of Bristol-Myers Squibb. The generic name is paclitaxel. 

Stiffness, ed., Taxol Science and Applications, CRC Press, Boca Raton, FL, 1995. 

The next phase of the synthesis was construction of the C-ring. An aldol addition was used to introduce a 3-butenyl group at C(8) and the product was trapped as a carbonate ester. The Davis oxaziridine was then used to introduce an oxygen at C(2). After reduction of the C(3) oxygen, a cyclic carbonate was formed, and C(2) was converted 

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A new total synthesis of Baccatin III and Taxol including a new method for the introduction of the phenylisoserine side chain was published after the typesetting for this book I. Shiina,... 

Danishefsky SJ, Masters JJ, Young WB, Link JT, Snyder LB, Magee TV, Jung DK, Isaacs RCA, Bommann WG, Alaimo CA, Coburn CA, Di Grandi MJ (1996) Total Synthesis of Baccatin III and Taxol. J Am Chem Soc 118 2843... 

The structures of taxol and its polycyclic part baccatin III are shown in Figure 7-2, and the numbering of these two compounds is extensively used throughout the rest of this chapter. Because connecting the side chain to baccatin HI is just routine chemistry, we introduce only the synthesis of baccatin III and the taxol side chain. 

PG Grothaus, et al. Taxane-specific monoclonal antibodies Measurement of taxol, baccatin III, and total laxanes in Taxus brevifolia extracts by enzyme immunoassay. J Natural Products, 1995 58 1003. 

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... 

The metabolites 9.1 and 9.2 were both synthesized by Georg and her collaborators by standard methods, using an appropriate / -lactam to prepare 9.1 from baccatin III and converting taxol to a protected 2-debenzoyltaxol and then acylating it to prepare 9.2 347). The 3 -metabolite 9.1 was about twice as active as taxol in a tubulin-assembly assay, but was sevenfold less cytotoxic than taxol to B-1 melanoma cells. The metabolite 9.2 was about 40 times less cytotoxic than taxol to LI210 leukemia cells. The synthesis of the major human metabolite 9.3 was described earlier in section 4.2.1. 

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. 

Shiina I, Saitoh K, Frechard-Ortuno I, Mukaiyama T (1998) Total Asymmetric Synthesis of Taxol by Dehydration Condensation between 7-TES Baccatin III and Protected N-Benzoylphenylisoserines Prepared by Enantioselective Aldol Reaction. Chem Lett 3... 

The total synthesis of taxol (52) has been described in Chapter 34. Clearly, total synthesis cannot hope to meet the demand for taxol at the present time, and supplies are currently procured by semisynthesis. This approach uses baccatin III (derived from yew tree needles) and the C-13 side chain 51, made synthetically (Scheme 13). A practical synthesis of the side chain is necessary,... 

Phenyl lithium attack on the cyclic carbonate convertes 202 to C-2 benzoate compound 203. PCC oxidation and subsequent NaBH4 reduction then furnishes the final baccatin III for the total synthesis of taxol (Scheme 7-65). 

This chapter has introduced the asymmetric synthesis of several types of natural products erythronolide A, 6-deoxyerythronolide, rifamycin S, prostaglandins and baccatin III, the polycyclic part of taxol, as well as the taxol side chain. The... 

The last steps of the synthesis involved i) removal of the TBS group with TASF [21], to give 7-BOM baccatin III (64b) ii) reaction of the corresponding lithium alkoxide with P-lactam 34 from Scheme 13.6.6 iii) desilylation of the resulting product and iv) removal of the C(7) BOM group by hydrogenolysis (H2, Pd/C, EtOH, reflux, Ih) to give taxol in 93% yield from 64b. The synthesis produces (-)-taxol from (-)-bomeol and enr-(+)-taxol from (-)-patchino. The overall yield from 40a is ca. 4-5%. 

Taxol (Paclitaxel) 137, a natural product derived from the bark of the Pacific yew, Taxus brevifolia [213-215], and the hemisynthetic analogue Docetaxel (Taxotere) 138, two recent and promising antitumour agents, have been the matter of extensive in vivo and in vitro animal metabolic studies. The major metabolites of taxol excreted in rat bile [216] were identified as a C-4 hydroxylated derivative on the phenyl group of the acyl side chain at C-13 (139), another aromatic hydroxylation product at the mefa-position on the benzoate group at C-2 (140) and a C-13 deacylated metabolite (baccatin III, 142) the structure of six minor metabolites could not be determined. The major human liver microsomal metabolite, apparently different from those formed in rat [217], has been identified as the 6a-hydroxytaxol (141) [218, 219]. A very similar metabolic pattern was... 

Taxol is derived from GGPP via cyclization reactions, employing the same mechanistic principles as in mono- and sesquiterpenes. Baccatin III (2), another taxane derivative, has been found (up to 0.2%) in the bark. A number of other taxane derivatives were isolated and characterized as 10 - deacetyltaxol, 10 - deacetylbaccatin III (3), cephalomannine (4) and 10 - deacetylcephalomannine (5) while some of them have been microbiologically transformed into taxol, Fig. (6). 

There has been intense interest in recent years in selective modification of functionality in baccatin III, 1, the basic diterpenoid core of paclitaxel (Taxol ) which is now established as a clinically active antitumour drug. Given the complexity of 1, rearrangements are common even under mild conditions and attempts to carry out apparently simple transformations are frequently frustrated, as shown by the following example. The 13p-chloro derivative 2 was prepared and fully characterised, then treated with sodium azide in aqueous DMF at 60°C in the expectation that the 13 a azide would be obtained. The product, however, was shown to be the ring cleaved compound 3 (71% yield). 

Esterification.1 This reagent in combination with a catalytic amount of 4-dimethylaminopyridine (DMAP) is very effective for esterification of carboxylic acids with alcohols or thiols at room temperatures. However, reaction of aromatic and hindered acids requires several days at room temperature. French chemists report that only this method is useful for esterification of the protected baccatin III derivative (2) with (2R,3S)-N-benzoyl-0-(l-ethoxyethyl)-3-phenylisoserine (3) to provide the protected taxol derivative (4). A reaction conducted at 73° for 100 hours with 6 equiv. of 1 and 2 equiv. of DMAP produced 4 in 80% yield. Natural taxol, a cancer chemotherapeutic agent, is obtained by removal of the protective groups at C2 and C7 of 4. 

Scientists from Bristol-Myers Squibb developed a new side chain for Taxol, making it water-soluble. A kinetic resolution with Pseudomonas cepacia lipase (lipase PS-30 from Amano) was applied to obtain the desired material enantiopure (Scheme 6.10). After the lipase-catalysed hydrolysis of the wrong enantiomer (49% conversion) the ester was obtained with an ee of >99%. Separation and subsequent chemical cleavage of the ester yielded the desired enantiomer of the lactame, which could then be coupled to baccatin III [44]. 

In cases where an isopropytidene acetal resists hydrolysis, the more labile p-methoxybenzylidene acetal can be used. The final steps of Mukaiyama s synthesis of Taxo 346 were impeded by difficulties associated with the esterification reaction by which the N-benzoylphenylisoserine side chain was attached to the Baccatin III core [Scheme 8.159]. Side chains protected as cyclic N 0-acetals were more reactive because of lower steric hindrance even so, the isopropyli-dene derivative of N-benzoylphenylisoserine (159.1) gave incomplete conversion (64%). Moreover, the isopropylidene group was resistant to hydrolysis. However, the corresponding p-methoxybenzylidene derivative (159.2) esterified the Baccatin III core (1593) in 95% yield and 93% conversion and it hydrolysed with aqueous trifluoroacetic acid at 0 cC to give Taxol in 93% yield. 

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