1. Field of the Invention
This invention relates to novel intermediates for the preparation of taxol and its congeners, a process for their preparation, and a process for the preparation of taxol involving the use of such intermediates or their functionally equivalent molecules.
2. Description of Related Art
Taxol was first isolated in 1971 from the western yew, Taxus brevifolia by Wani et al. (J. Am. Chem. Soc., 1971, 93, 2325), who characterized its structure by chemical and X-ray crystallographic methods.
Taxol is a member of the taxane family of diterpenes having the following structure: ##STR2## Taxol and various taxane derivatives (collectively herein referred to as "taxols") are highly cytotoxic and possess strong in vivo activities in a number of leukemic and tumor systems. Especially, taxol (1) is considered an exceptionally promising cancer chemotherapeutic agent, and is currently in phase II clinical trials in the United States. Equally important is taxotere (2), a semisynthetic analog of taxol which is also undergoing clinical trials with impressive results.
Clinical results have demonstrated high efficacy against such cancer types as ovarian, lung, gastric, breast, colon and cervical carcinomas. However, the major problem with the ongoing clinical trial is the limited availability of the compound. Various techniques for securing a sufficient supply of taxol are the subject of active research. Strategies being studied include total synthesis, partial synthesis (from readily available taxol precursors), extraction from Taxus needles, cultivation of Taxus plants, identification of structurally simpler taxols, and cell culture production.
The only available natural source of taxol to date is several species of very slowgrowing yew (genus Taxus, family Taxaceae). The isolation procedures currently in use are very difficult, low-yielding, and obviously fatal to the source. For example, C.H.O. Huang et al. (J. Nat. Prod., 1986, 49, 665) reported a 0.01% yield from a large scale isolation starting with 806 lbs. or more of Taxus brevifolia bark. Other reported yields of taxol from various species of yew range from 50 mg/kg to 165 mg/kg (i.e., 0.005-0.017%).
Because of the structural complexity of taxol, partial synthesis is considered a viable approach to providing adequate supplies of taxol. The first successful partial synthesis of taxol was developed by J. N. Denis et al. in J. Am. Chem. Soc., 1988, 110, 5917; J. Am. Chem. Soc., 1988, 110, 5417; U.S. Pat. No. 4,924,011. The starting materials for the partial synthesis, 10-deacetylbaccatin III (3) or baccatin III (4), can be extracted in relatively high yield from the leaves of Taxus baccata. However, this approach still relies upon the supply of yew leaves, although they are renewable resources, unlike yew bark.
The total synthesis of taxols may provide practical solutions to the problems associated with the isolation method or the partial synthesis. Thus, the total synthesis of taxol has attracted much interest among synthetic organic chemists worldwide. So far, the results have not been entirely satisfactory. One successful example is the work of Holton et al. (J. Am. Chem. Soc., 1988, 110, 6558), wherein a synthesis of the taxol congener-taxusin- is reported. Despite the progress made in this and numerous other synthetic approaches, the final total synthesis of taxol is likely to be a multi-step, tedious and costly process.
The major difficulty involved in the synthesis of taxols resides in the construction of the tricyclic carbon frame, pentadecene, which is shown below: ##STR3## Another difficulty with the synthesis of taxols is the incorporation of abundant oxygen functionalities at positions 1, 2, 4, 5, 7, 9, 10 and 13 of the ring system.
Based on a rational retrosynthetic analysis, the present investigators have identified two key ring units which are provided with oxygen substituents having proper (natural stereochemistry) and which could be easily coupled to form a basic skeleton of taxols. The use of such versatile intermediates allows the synthesis of not only taxol, but also other potential antitumor agents having the pentadecene ring with an array of oxygenated functionalities at various positions.
Consequently, the present invention addresses the much-sought need of availability of key intermediates for the synthesis of taxols, and leads to the ultimate total synthesis of taxol itself.