Paclitaxel, chemical synthesis

Kanazawa, A.M., Denis, J.N., Greene, A.E. (1994) Direct, Stereoselective Synthesis ofthe Protected Paclitaxel (Taxol) Side Chain and High-Yield Transformation to Paclitaxel. Chemical Communications, 2591-2592. 

Paclitaxel (Taxol ) is an anti-cancer agent originally obtained from Pacific yew tree bark. The complexity of the molecule makes chemical synthesis from simple compounds economically unfeasible. For instance, one of the most efficient semisyntheses starts from 10-deacetylbaccatin III, a more abundant taxoid obtained from needles of the European yew tree (Scheme 8.16) [67,68], However, the process is still long, requiring 11 chemical transformations. 

Figure 1 Bulk drugs from natural sources Paclitaxel (antileukemic and antitumor) and lovastatin (inhibitor of cholesterol biosynthesis) are examples of the diverse and complex structures made by plant and microbial cell biosyntheses, respectively. In most instances of such compounds having desirable biological activities, their structural and chiral complexities make chemical synthesis not competitive with isolation from biosynthesis.

One example of the use of renewable feedstocks is the extraction of a precursor of the anticancer compound paclitaxel (Taxol) from the needles of English yew shrubs. Taxol was originally discovered in the bark of Pacific yew trees, but in quantities so small that large amounts of bark would have to be stripped, killing trees the replacements for which require 200 years to grow and mature. A published 40-step chemical synthesis of taxol was also not practical commercially. The needles of the English yew shrub are rapidly renewable. Bristol-Meyers Squibb, partnering with the National Cancer Institute in 1991, developed a semisynthetic process based upon the paclitaxel precursor and put it into... 

Compound C is a key intermediate in a chemical synthesis of paclitaxel, a drug used to treat breast, ovarian, and lung cancer. It is prepared by a reaction between compounds A and B. What is the structure of compound B ... 

To obtain paclitaxel, total chemical synthesis, semi-synthesis, and extraction methods have been employed by excellent synthetic chemists. Total synthesis, however, has not been practically applied in the industry because of the too complex structure. A semi-synthetic method employing precursors such as 10-deacetylbaccatin III is now used in industry to obtain paclitaxel and has revealed some drawbacks since 10-deacetylbaccatin III is extracted from a large number of yew trees (Figure 6.8), and mass deforestation has led to serious environmental destruction. 

The complexity of the paclitaxel molecule makes commercial production by chemical synthesis from simple compounds impractical. Published syntheses involve about 40 steps with an overall yield of approximately 2%. In 1991, NCI signed a Collaborative Research and Development Agreement with Bristol-Myers Squibb (BMS) in which BMS agreed to ensure supply of paclitaxel from yew bark while it developed a semisynthetic route (semisynthesis) to paclitaxel from the naturally occurring compound 10-deacetylbaccatin III (lO-DAB). 

Because of the limited natural availability of the compound, as discussed in Sect. 14.3, and despite the complexity of the molecule, huge synthetic efforts have been made to achieve the total synthesis of pachtaxel. These endeavours have resulted in many elegant partial or total synthetic approaches [1-3], and these have been reviewed repeatedly [4, 5]. Numerically, by 2010, there were 156 citations in SciFinder related to the synthesis of taxol and 7,875 citations related to the general terms, taxol and synthesis. In addition to total chemical synthesis, the strategy of site-selective transformation of the complex mixture in the natural taxanes, together with enantio- and diastereo-selective transformation of paclitaxel molecular fragments, complete the pallette of selective transformations that have been studied. 

Paclitaxel is prepared in a convergent synthesis starting from 10-DAB and hydrobenzamide and entails 11 chemical transformations and 7 isolations. Issues arising from this process include ... 

The decision by RPR to patent the method came about when one of the discoverer s of the method sent RPR s patent counsel a draft publication that described the synthesis of paclitaxel from 10-DAB that they intended to submit for publication to the Journal of the American Chemical Society (JACS). Of particular note, the draft publication explained that the conversion of 10-DAB to taxol could be... 

Testa B, Jenner P (1976) Drug metabolism chemical and biochemical aspects. Part II Biochemical aspects of drug oxidation. In Swarbrick J (ed) Drug and the pharmaceutical science. Marcel Dekker, New York, pp 271-312 Wittman MD, Kadow JK, Vyas DM (2000) Stereospecific synthesis of the major human metabolite of paclitaxel. Tetrahedron Lett 41 4729... 

The success of paclitaxel spurred an enormous amount of work on the synthesis of analogs, and this work has been summarized in several reviews. The first analog to be developed is the close chemical relative, docetaxel (Taxotere Figure 8.13). The new albumin-bound formulation of paclitaxel known as Abraxane has also been approved for clinical use and launched in 2005 this formulation offers some important clinical advantages compared with the original Cremophor formulation. The reviews cited above should be consulted for information on new agents in development, such as BMS-184776, BMS-188797, and larotaxel (Figure 8.13). 

Natural products are generally complex chemical structures, whether they are cyclic peptides like cyclosporin A, or complex diterpenes like paclitaxel. Inspection of the structures that are discussed in Section IV is usually enough to convince any skeptic that few of them would have been discovered without application of natural products chemistry. Recognition and appreciation of the value of natural product-like models in improving efficiency in so-called diversity-oriented synthesis has already been mentioned. ... 

Further research has continued into the development of drug eluting coronary stents for the treatment of cardiovascular restenosis. Because the miscibility of paclitaxel with SIBS as demonstrated by the previous authors [33] is low as measured by DSC, Sipos et al. [34] have reported on the synthesis of poly (p-tertbutyldimethylsiloxy)styrene (TBDMS)-P-isobutylene (IB)-PTBDMS), which can be hydrolysed to poly(PHOS-P-PIB-P-PHOS) in order to modulate the solubility of PTx in the polymer, which, in turn, affects its release from the polymer. Further chemical modification of the polymer can be undertaken to effect changes in the polarity of the polymer, including acetylation, which gives rise to PAcOS-P-PIB-p-PAcOS. 

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