Taxol Distributed Development

There are several books on the history of the development of taxol, which is one of the most remarkable stories in product development. In fact, it inspired the 1992 motion picture Medicine Man, starring Sean Connery as a research botanist looking for a cancer cure in the Brazilian rain forest. For a time, it became a moral drama pitting the needs of patients of intractable ovarian and breast cancer against the passions of environmentalists to preserve an obscure Pacific yew tree. Suffness and Wall are two of the principals in this story, and they wrote (1995) It [Taxol] is not an obvious winner till the very end, and there were a number of times till the very end when it seemed highly likely that it would not be put into development at all, or that once it had been accepted, it would be dropped. More than 30 years passed between the discovery of taxol, with its potential as an anticancer drug, and its approval by the Food and Drug Administration (FDA) for clinical use. 

The discovery of penicillin and its successful application in World War II inspired the antibiotic era, and a broad search for other cures for infectious diseases. Cancer has a totally different cause, as it arises through the malignant mutation of normal cells instead of from the actions of bacterial or other outside organisms. Penicillin destroys the bacteria cell walls, but not the mammalian cell membranes. Unless a dmg could be found that could tell the difference between a normal cell and a cancer cell, then it was not clear that there would be an effective cancer drug, that is until the first report by Goodman in 1946 that nitrogen mustard, developed as a war gas, was an effective chemotherapeutic for human leukemia. 

This led to cooperation between the Army Chemical Warfare Service and Sloan-Kettering Cancer Institute to concentrate on the organization of industrial techniques 

Monroe Wall of the USDA Eastern Regional Research Laboratory had been collecting plants for steroids that are oxygenated at positions 11 or 12, which could be converted into cortisone and related compounds. The search for a cancer cure led Wall to move to the Research Triangle Institute in 1960, to work on the isolation of plant-derived antitumor agents. Wall requested specimens of plants showing KB activity, and worked with a 30 lbs shipment of bark in late 1964. The procedure included extraction by ethanol, followed by concentration and partition between water and an organic solvent. He found that fractions from this extract were active in vivo for mice with 

P-1534 leukemia, the Walker 256 carcinosarcoma, and the P388 leukemia. He also worked on isolation by extraction of 12 kg of Pacific yew bark with ethanol, followed by partition of the ethanol extract between chloroform and water. In his first publication in 1967, about 0.5 g of taxol was isolated from 12 kg of air-dried stem and bark from T. brevifolia, and the yield was about 0.004%, or 40 ppm. 

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Photocycloaddition of allene to the cyclopentenone derivative (6) in methylene chloride solution at — 78°C afforded a cycloadduct (7) in 84% yield, which was a key intermediate for the construction of the AB ring core of Taxol (Shimada et al, Chapter 2). Similarly, photocycloadditions of ethene to enan-tiopure butenolides (8) at — 78°C have been studied by de March et al. (Chapter 2). The product distribution was found to depend on the protecting group R, but with R = TMS, the product stereoisomer (9) was obtained in 83% yield, and an efficient synthesis of (-I- )-grandisol was developed. 

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