As of that date, all strategies had aimed to prepare a 10-deacetylbaccatin-type core containing the ABCD ring system, followed generally by last stage addition of the "tail" to the 13-hydroxyl group.While the "political climate surrounding [paclitaxel] and [the Pacific yew] in the early 1990s ... helped bolster [a] link between total synthesis and the [paclitaxel] supply problem," and though total synthesis activities were a requisite to explore the structure-activity relationships of paclitaxel via generation of analogs for testing, the total synthesis efforts were never seen "as a serious commercial route" to provide significant quantities of the natural product for medical testing or therapeutic use. History
The discovery of paclitaxel began in 1962 as a result of a NCI-funded screening program. A number of years later it was isolated from the bark of the Pacific yew, Taxus brevifolia, hence its name "taxol".The discovery was made by Monroe E. Wall and Mansukh C. Wani at the Research Triangle Institute, Research Triangle Park, North Carolina, in 1971. These scientists isolated the natural product from the bark of the Pacific yew tree, determined its structure and named it "taxol", and arranged for its first biological testing. The compound was then developed commercially by BMS, who had the generic name assigned as "paclitaxel". Plant screening program
In 1955, the NCI in the United States set up the Cancer Chemotherapy National Service Center (CCNSC) to act as a public screening center for anticancer activity in compounds submitted by external institutions and companies.
Later in the pathway, an oxidation at C9 forms a ketone functional group and an oxetane, forming the intermediate baccatin III. The final steps of the pathway include the formation of a C13-side chain which is attached to baccatin III. The biosynthesis of Taxol is illustrated in more detail in the figure, with steps 1-7 all occurring in the enzyme taxadiene synthase (TS on the figure). Taxols biosynthesis begins with E,E,E-GGPP losing pyrophosphate via an SN1 mechanism (step 1 in the figure). The double-bond attacks the cation via electrophilic addition, yielding a tertiary cation and creating the first ring closure (step 2). Another electrophilic attack occurs, further cyclizing the structure by creating the first 6-membered ring and creating another tertiary cation (step 3). An intramolecular proton transfer occurs, attacking the verticillyl cation (step 4) and creating a double bond, yielding a tertiary cation. An electrophilic cyclization occurs in step 5, and an intramolecular proton transfer attacks the taxenyl cation (step 6). This forms the fused ring structure intermediate known as taxadiene. Taxadiene then undergoes a series of 10 oxidations via NADPH, forming the intermediate taxadiene-5α-acetoxy-10β-ol (multiple steps later in the figure). A series of hydroxylations and esterficiations occur, forming the intermediate 10-deacetyl-baccatin III, which undergoes a further series of esterifications and a side-chain hydroxylation. This finally yields the product taxol. Total synthesis
By 1992, at least thirty academic research teams globally were working to achieve a total synthesis of this natural product, with the synthesis proceeding from simple natural products and other readily available starting materials.