Taxol®, chemical synthesis

Besides their essential roles in nature, isoprenoids are of commercial importance in industry. Some isoprenoids have been used as flavors, fragrances, spices, and food additives, while many are used as pharmaceuticals to treat an array of human diseases, such as cancer (Taxol), malaria (artemisinin), and HIV (coumarins). In contrast to the huge market demand, isoprenoids are present only in low abundance in their host organisms. Thus, isolation of the required isoprenoids consumes a large quantity of natural resources. Furthermore, owing to their structural complexity, total chemical synthesis is often not commercially feasible. For these reasons, metabolic engineering may provide an alternative to produce these valuable isoprenoids [88,89]. 

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. 

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... 

Since its discovery in 1907, the Staudinger reaction is one of the most useful methods for the synthesis of p-lactams (2-oxazetidinones) [77,78]. The importance of these strained heterocycles relies not only on the chemical synthesis of 3-lactam antibiotics [79] but also on other valuable compounds in medicinal chemistry [80] such as the acyclic chain of taxol and bestatin [81] or ecteinascidin-743 (Scheme 2.4) [82]. 

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. 

It turned out that yew trees not only of the Pacific coast but of other species contain a compound called 10-deacetylbaccatin III (see Fig. 7.6) this is a precursor of taxol. You see in Fig. 7.6 that taxol consists of two portions A and B, and that this precursor provides the portion A. Now, to make another compound starting with a simpler compound is called Chemical Synthesis, and this is what chemists excel at. Some people even say that this, chemical synthesis, is the only thing that is a proper chemistry. In this case, you have to add portion B on to the existing portion A. Robert A. Holton of Horida State University succeeded in synthesizing taxol from 10-deacetylbaccatin III. 

Camptothecin was discovered as an active anticancer drug isolated from the bark of Camptotheca acuminata. The anticancer activity of camptothecin was discovered in the 1960s by the National Cancer Institute (NCI) as part of a systematic effort to screen for novel anticancer agents derived from natural products. Monroe Wall and Mansuhk Wani identified the chemical structure of camptothecin. They also identified the chemical structure of taxol, again under the auspices of the NCI. Susan Hoiwitz was contracted by the NCI to elucidate the anticancer mechanisms of camptothecin. She found in the early 1970s that camptothecin induced DNA breaks and attested DNA and RNA synthesis. However, it is approximately 12 years later, only after DNA topo-isomerase I (Topi) had been identified in human cells, that Leroy Liu and his coworkers found that Topi was the cellular target of camptothecin [reviewed in [1]. 

Kusama, H., Hara, R., Kawahara, S. et al. (2000) Enantioselective Total Synthesis of (—)-Taxol. Journalof the American Chemical Society, 122, 3811-3820. 

Nicolaou, K.C., Liu, J.J., Yang, Z. et al. (1995) Total Synthesis of Taxol. 2. Construction of A and C Ring Intermediates and Initial Attempts to Construct the ABC Ring System. Journal of the American Chemical Society, 117, 634-644. 

Danishefsky S.J., Masters, J.J., Young, W.B. etal. (1996) Total Synthesis ofBaccatin III and Taxol. Journal of the American Chemical Society, 118, 2843-2859. 

Holton, R.A., Somoza, C., Kim, H.B. etal. (1994) First Total Synthesis of Taxol. 1. Functionalization ofthe B Ring. Journal of the American Chemical Society, 116, 1597-1598. 

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. 

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... 

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