Semi-synthesis, taxol

A fine example of such a semi-synthesis is the preparation of the anti-cancer drug paclitaxel (Taxol ), a relatively scarce compound from Taxus brevifolia. Here, the natural and better accessible 10-deacetylbaccatin III, isolated from the leaves of Taxus baccata, provides the complicated ring system of paclitaxel, including all substituents with the right stereostructure (Scheme 5.1). In just four reaction steps [5] paclitaxel is obtained from 10-deacetylbaccatin III. 

Taxol has received considerable competitive challenge from taxotere, officially named docetaxel, a patented taxol analog developed by Rh6ne-Poulenc, based on the 1981 first successful semi-synthesis by Gueritte-Voegelein from 10-DAB. In 1987, Rh6ne-Poulenc selected taxotere for clinical development, and it is now used clinically in the United States. 

Plant-based products obtained by direct extraction from a native producer, or by semi-synthesis (e.g. taxol) No Yes No... 

Deacetylbaccatin III could be turned into taxol in only four steps (a process called semi-synthesis )- Molecules like this are responsible for the resistance of yew to woodworm and insects in general - yew isn t just poisonous to humans ... 

Table 4.22 Summary of reaction metrics and synthesis tree parameters for paclitaxel (taxol) semi plans ranked according to overall kernel (maximum) RME. -synthesis...

Much of the basis of the BMS CRADA proposal was built on the ability of BMS to tap into the tremendous synthetic knowledge contained in Robert Holton s research group at Florida State University (FSU). This research group had been actively studying the chemistry of Taxol and had made significant strides toward a total synthesis and a viable semi-synthetic pathway from 10-DAB. A licensing agreement between BMS and FSU was created, and in 1992 the first commercially viable semi-synthetic route from 10-DAB to Taxol was discovered [13]. 

Plants have also provided a key source of potential cancer treatments. A well-known example is paclitaxel (Taxol ), isolated from the bark of the Pacific yew tree, which has become a blockbuster drug and analogues have also been approved for use that demonstrate improved efficacy (Fig. 1.4) [6]. Taxol also provides an excellent example to illustrate the challenges that remain in total synthesis. Numerous examples of the total synthesis of Taxol have been reported [7-13]. However, the overall yield and the number of steps required means it is not economically viable to synthesise the quantities required for its medicinal application. It is therefore obtained industrially via a semi-synthetic route starting from 10-deacetylbaccatin HI, a biosynthetic precursor, which can be isolated, in much larger quantities than Taxol itself, from the leaves of a different species of yew tree. More recently however, a plant cell fermentation approach has been developed for the industrial production of Taxol. 

As mentioned before, the market demand of the anticancer drug, paclitaxel (15, Taxol ) was threatened initially by an unsustainable natural supply, which relied mainly on extracting this compound from the bark of the slow-growing Pacific yew tree, from which it is produced only in a very low yield [57]. Although the total synthesis of paclitaxel has been described, this is still inefficient when considered the extensive market need [58-60]. 10-Deacetylbaccatin El (22), which is available with a relatively high yield from the leaves of other renewable yew species, such as Taxus baccata L., was introduced as a semi-synthetic precursor compound of paclitaxel by the major pharmaceutical manufacturer, Bristol-Myers Squibb (B-MS) [61]. Docetaxel (23), a related taxane anticancer drug can also prepared from 10-deacetylbaccatin El (22) [62]. 

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