Semisynthesis taxol

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,... 

The semisynthesis of taxol [1], as well as the synthesis of taxoid model systems have been the focus of extensive research efforts in many laboratories, all over the world, which have greatly simplified the total synthesis of taxol itself. An excellent review by Nicolaou et al. has recently been published in Angewandte Chemie [2]. 

A common strategy to invert the stereochemistry at the hydroxyl bearing carbon of an amino alcohol involves oxazoline formation with inversion followed by hydrolysis. This strategy has been applied to Taxol resulting in a practical semisynthesis of 2 -epi-Taxol 44 from Taxol 42 (Scheme 8.17). ... 

Paclitaxel (Taxol) is a diterpenoid compound that contains a complex taxane ring as its nucleus (Figure 62.1). The side chain linked to the taxane ring at carbon 13 is essential for its antitumor activity. Modification of the side chain has led to identification of a more potent analogue, docetaxel (Taxotere), which has clinical activity against breast and ovarian cancers. Originally purified as the parent molecule from yew bark, paclitaxel can now be obtained for commercial purposes by semisynthesis from 10-desacetylbaccatin, a precursor found in yew leaves. It also has been successfully synthesized from simple off-the-shelf reagents in a complex series of reactions. 

In this chapter, we describe an account of our research on the chemistry and biology of paclitaxel and taxoid anticancer agents (taxoid = taxol-like compound). The topics covered in this chapter include (i) the development of a practical and efficient method for the semisynthesis of paclitaxel and docetaxel using chiral 3-hydroxy-P-lactams as synthetic intermediates, (ii) structure-activity relationship (SAR) studies of various taxoids that led to the discovery of the extremely potent second-generation taxoids, and (iii) biological and conformational studies with the use of fluorine-containing taxoids as probes. ... 

Scheme 3-2. Selective protection of hydroxyls in 10-DAB (3) for the semisynthesis of Taxol.

Holton RA, Biediger RJ, Boatman PD. Semisynthesis of taxol and taxotere. In Taxol Science and Apphcations. Stiffness M, ed. 1995. CRC Press, Inc., Boca Raton, FL. pp. 97-121. 

Ojima, I., Habus, I., Zhao, M., et al. (1992) New and efficient approaches to the semisynthesis of taxol and its C-13 side-chain analogs by means of beta-lactam synthon method. Tetrahedron, 48, 6985-7012. 

TAXOL (Paclitaxel) was first isolated from the bark of the Pacific Yew, Taxus brevifolm Nutt., family Taxaceae. Because of its value, supplies were difficult to obtain. Attempts to address the supply issue have involved semisynthesis from baccatin III or 10-deacetylbaccatin III which are taxanes found in the needles of the common European Yew Taxus baccMa L. Other approaches have involved the use of fungal and tissue culture. 

R. A. Hoiton R. J. Biediger P. D. Boatman, Semisynthesis of Taxol and Taxotere. In Taxol Science and Applications, ... 

For centuries, plants have been a unique source of therapeutically significant alkaloids and they continue to be excellent sources of drugs. Furthermore, alkaloids of natural origin serve as a model for the semisynthesis or the synthesis of derivatives which have improved pharmacokinetic properties, a higher efficacy and/or less toxicity. One of the most recent examples is the isolation of the anticancer agent, called taxol, from the stem bark Of the Pacific yew tree Taxus brevifolia in 1971 by Wani and co-workers [1] and the development, a few years later, of docetaxel, a semisynthetic derivative obtained from 10-deacetyl-baccatin III [2]. 

Most studies of structure activity relationships (SAR) rely on degradations of baccatin and semisynthesis. [1, 3, 4] First insights into the SAR of taxol derivatives have been summerized in a recent article on C ring aryl derivatives, [4] and more can be expected in the near future as patented information becomes released. Total synthesis, especially in preparing the way for the synthesis of derivatives, will be of great importance to elucidate the relationship between structure, microtubuli stabilization and anticancer activity more thoroughly. This impact of total syn-... 

Scheme 1. Semisynthesis of taxol (paclitaxel) and taxotere from protected baccatin III according to Holton and Ojima (cf. [la-d]) strategic bond cleavages for the syntheses of Holton et al., [5] Nicolaou et al.,...

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. 

Georg GI, Cheruvallath ZS, Harriman GCB, Hepperle M, Park H (1993) An Efficient Semisynthesis of Taxol from (3R,4S)-N-Benzoyl-3-[(t-butyldimethylsilyl)oxy]-4-phenyl-2-azetidinone and 7-(Triethylsilyl)baccatin III. Bioorg Med Chem Lett 3 2467... 

Wroblewski AE, Piotrowska DG (2000) Enantiomeric Phosphonate Analogs of the Docetaxel C-13 Side Chain. Tetrahedron Asymmetry 11 2615 Wuts PGM (1998) Semisynthesis of Taxol. Curr Opin Drug Disc Devel 1 329 Didier E, Fouque E, Commer on A (1994) Expeditious Semisynthesis of Docetaxel Using 2-Trichloromethyl-l,3-Oxazolidine as Side-Chain Protection. Tetrahedron Lett 35 3063... 

Gennari C, Carcano M, Donghi M, Mongelli N, Vanotti E, Vulpetti A (1997) Taxol Semisynthesis A Highly Enantio- and Diastereoselective Synthesis of the Side Chain and a New Method for Ester Formation at C-13 Using Thioesters. J Org Chem 62 4746... 

U.S. government s war on cancer led to a massive screening program by the National Cancer Institute, which yielded important chemotherapeutic agents such as Taxol , vinblastine, and camp-tothecin. Moreover, the cytotoxicity screens developed remain the most common primary assay for evaluating crude natural product extracts. At the same time, natural products were heavily exploited outside the antimicrobial and anticancer areas. Two classic examples are the medicinal chemistry endeavors devoted to the total and semisynthesis of thousands of compounds based on opium alkaloids as analgesics and steroids as hormones. 

A semisynthesis of the 19-hydroxy taxol derivative, 19-hydroxy docetaxd 869, was accomplished by semisynthesis of a new baccatin derivative, lO-deacetyl-19-hydroxybaccatin III 866, which, after temporary protection at positions C-7, C-10, and C-19 with Troc groups using 2,2,2-trichloroethyl chloroformate (Troc-Cl) (to give 867), was coupled with N-Boc-N,0-isopropylidene-phenylisoserine 868 to yield 869 [629]. Analogue 869 exhibits a high level of in vitro cytotoxicity and thus the results demonstrate that chemical modifications at C-19 can be made without significant loss of biological activity. 

Some approaches for the semisynthesis of taxol are based on relatively economically priced 10-deacetylbaccatin III, obtained from leaves of the European yew Taxus baccata. The leaves are able to regenerate by growing again, whereas removal of the bark of the Pacific yew Taxus brevijblia, which contains taxol, kills the tree. The semisyntheses of Denis and Greene from 1988 [190] and 1994 [191] are discussed here. 10-Deacetylbaccatin III 257 is first protected at the 7-position with a triethyl-silyl residue and acetylated at the 10-position with acetyl chloride. The resulting 7-TES-baccatin III 258 is coupled with O-protected N-benzoyl-3-phenylisoserine using a sixfold excess of dipyridyl carbonate (DPC) to afford 2 -0-ethoxyethyl-7-TES-taxol 259, which is deprotected with 0.5% hydrochloric acid to afford taxol 241 [190]. 

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