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Synthetic miracle: Why was the race to synthesize taxol so intense in the 1990s?
Paclitaxel, also known as Taxol, is an important anti-cancer drug that is expensive to make because it is made from the rare Pacific yew (Taxus brevifolia). As the scientific community's demand for this highly effective compound continued to increase, researchers launched a fierce synthetic race in the 1990s to achieve the total synthesis of tyxol and to search for new derivatives.
The four-ring core structure required for the synthesis of tyxol is called baccatin III and is attached to an amide tail. This complex structure has always been a research hotspot in organic chemistry.
The anti-tumor activity of tyxol was first discovered in the 1940s, but real research began in 1963 under the U.S. government's plant screening program. In 1969, researchers identified its main active ingredient and completed its structural analysis in 1971. Subsequently, Robert A. Holton from Florida State University successfully achieved the first total synthesis of tyxol in 1994, having begun this research in 1982. The success of this research not only marks a milestone in synthetic chemistry, but also a major breakthrough in the commercial world.
What these synthetic strategies have in common is that baccatin III is synthesized first, followed by the final-stage amide tail addition, a process usually based on Ojima's lactone ring.
By 1992, approximately 30 research teams had entered the competition. In the end, 11 research teams reported their total synthesis results. The Holden research group and the Nicolaou group succeeded almost simultaneously in the so-called "photo finish".
In 1994, Holden used Patchoulol as a precursor to synthesize Tyxol in a step-by-step linear synthesis. Nicolao chose to use Mucic acid and adopted a convergent synthesis strategy to finally synthesize Tyxol by merging the A and C rings. In addition, Danishefsky used Wieland-Miescher ketone as a precursor in 1996, and Wender used conifer resin in 1997.
Many researchers also explored semisynthetic methods during this period, such as the semisynthesis of 10-deacetylbaccatin III by Bristol-Myers Squibb and the semisynthesis of 10-deacetylbaccatin III by Ojima The free hydroxyl groups of the lactone are tail-added to obtain tyxol. Central to the success of this approach is the extraction and utilization of improved compounds from the more generalized European yew.
Although the natural synthesis pathway of taxo has not yet been fully revealed, researchers have reported the benefits of using genetically engineered E. coli to produce taxadiene in 2001. This new development has paved the way for the commercialization of taxo Production has developed new ideas.The natural pathway for making tyroxine involves about 20 enzymatic steps, but these processes are difficult to replicate in the lab, largely because nature has better control over stereochemistry than artificial synthesis.
As research into the synthesis of tyxol continued in the 1990s, competition around it intensified, promoting not only advances in organic chemistry but also hope for its potential in cancer treatment. The race to synthesize Tyxol became a common goal for both the scientific and commercial communities, inspiring countless research ideas.
So, is this synthesis race truly pushing the boundaries of chemical science, or is it simply driven by commercial interests?
