Of taxol

Many notable examples of the synthesis of complex natural products from optically pure starting materials have been reported (70). One synthesis of considerable interest is that of taxol [33069-62-4] (74), a potent antitumor agent used clinically. The starting material (73) used ia the first total synthesis of taxol is produced ia enantiomericaHy pure form from inexpensive and readily available /-camphor [464-48-2] (72) (73). 

One method of synthesis of taxol analogues starts with a-pinene (8), the readily available and inexpensive monoterpene derived from the processing of turpentine from the pine tree (200). The a-pinene is oxidized to verbenone, which is then alkylated and converted to taxol analogues in a multistep process. 

Another monoterpene used as a starting material for taxol analogues is camphor (43), which is readily available naturally or can be produced synthetically (201,202). Total synthesis of taxol analogues may be the answer toward finding new compounds for the treatment of many types of cancer. 

The remarkable success of taxol in treatment of breast and ovarian cancers stimulated research efforts to synthesize taxol directly and to identify new antimitotic agents that, like taxol, stimulate microtubule polymerization. 

Chemistry of taxol, anticancer diterpenoid with oxethane cycle as a part of fused system 98PAC331. 

Taxol s journey to the clinic was slow and arduous. Initial difficulties with aqueous solubility and lack of knowledge regarding its mechanism, of action delayed its development until 1979 when, in another seminal paper in the field, S.B.Horwitz and her collaborators disclosed their findings on the interaction of taxol with microtubules.4 Taxol s unique biological action, which includes promotion of microtubule formation and microtubule stabilization, stimulated a renewed interest in taxol as a potential drug candidate. The problem of procuring adequate supplies of taxol became even... 

Scheme 1. Strategic bond disconnections and retrosynthetic analysis of taxol (1).

All that remains before the final destination is reached is the introduction of the C-l3 oxygen and attachment of the side chain. A simple oxidation of compound 4 with pyridinium chlorochro-mate (PCC) provides the desired A-ring enone in 75 % yield via a regioselective allylic oxidation. Sodium borohydride reduction of the latter compound then leads to the desired 13a-hydroxy compound 2 (83% yield). Sequential treatment of 2 with sodium bis(trimethylsilyl)amide and /(-lactam 3 according to the Ojima-Holton method36 provides taxol bis(triethylsilyl ether) (86 % yield, based on 89% conversion) from which taxol (1) can be liberated, in 80 % yield, by exposure to HF pyridine in THF at room temperature. Thus the total synthesis of (-)-taxol (1) was accomplished. 

The total synthesis of taxol (52) has been described in Chapter 34. Clearly, total synthesis cannot hope to meet the demand for taxol at the present time, and supplies are currently procured by semisynthesis. This approach uses baccatin III (derived from yew tree needles) and the C-13 side chain 51, made synthetically (Scheme 13). A practical synthesis of the side chain is necessary,... 

Scheme 13. Sharpless s asymmetric synthesis of the C-13 side chain 51 of taxol (52).

Camptothecin was discovered as an active anticancer drug isolated from the bark of Camptotheca acuminata. The anticancer activity of camptothecin was discovered in the 1960s by the National Cancer Institute (NCI) as part of a systematic effort to screen for novel anticancer agents derived from natural products. Monroe Wall and Mansuhk Wani identified the chemical structure of camptothecin. They also identified the chemical structure of taxol, again under the auspices of the NCI. Susan Hoiwitz was contracted by the NCI to elucidate the anticancer mechanisms of camptothecin. She found in the early 1970s that camptothecin induced DNA breaks and attested DNA and RNA synthesis. However, it is approximately 12 years later, only after DNA topo-isomerase I (Topi) had been identified in human cells, that Leroy Liu and his coworkers found that Topi was the cellular target of camptothecin [reviewed in [1]. 

Another drug is taxol, which is extracted from the bark of the Pacific yew tree, Taxus brevijolia. Unlike colchicine and the vinca alkaloids, taxol binds tightly to microtubules and stabilizes them against depolymerization by Ca. It also enhances the rate and yield of microtubule assembly, thereby decreasing the amount of soluble tubulin in the cytosol pool. Again, the overall effect of taxol is to arrest dividing cells in mitosis. Taxol is used in cancer chemotherapy. 

Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT. Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc 1971 93 2325-7. 

Kusama, H., Hara, R., Kawahara, S. et al. (2000) Enantioselective Total Synthesis of (—)-Taxol. Journalof the American Chemical Society, 122, 3811-3820. 

Nicolaou, K.C., Liu, J.J., Yang, Z. et al. (1995) Total Synthesis of Taxol. 2. Construction of A and C Ring Intermediates and Initial Attempts to Construct the ABC Ring System. Journal of the American Chemical Society, 117, 634-644. 

Mukaiyama, T., Shiina, J., Jwadare, H. et al. (1999) Asymmetric Total Synthesis of Taxol. Chemistry A European Journal, 5, 121-161. 

Holton, R.A., Somoza, C., Kim, H.B. etal. (1994) First Total Synthesis of Taxol. 1. Functionalization ofthe B Ring. Journal of the American Chemical Society, 116, 1597-1598. 

In another example, a sequence of methylation-elimination-hydroxymethylation was used to install the functionality pattern found in the A-ring of taxol. The hydrazone dianion was generated and methylated at low temperature. The hydrazone was then deprotonated again using excess n-butyllithium and allowed to warm to room temperature, at which point formation of the vinyllithium occurred. Reaction with paraformaldehyde generated the desired product.290... 

The first synthesis of Taxol was completed by Robert Holton and co-workers and is outlined in Scheme 13.53. One of the key steps occurs early in the synthesis in sequence A and effects fragmentation of 4 to 5. The intermediate epoxide 4 was prepared from a sesquiterpene alcohol called patchino. 35 The epoxide was then converted to 5 by a BF3-mediated rearrangement. 

Amino-Hydroxylation. A related reaction to asymmetric dihydroxylation is the asymmetric amino-hydroxylation of olefins, forming v/c-ami noalcohols. The vic-hydroxyamino group is found in many biologically important molecules, such as the (3-amino acid 3.10 (the side-chain of taxol). In the mid-1970s, Sharpless76 reported that the trihydrate of N-chloro-p-toluenesulfonamide sodium salt (chloramine-T) reacts with olefins in the presence of a catalytic amount of osmium tetroxide to produce vicinal hydroxyl p-toluenesulfonamides (Eq. 3.16). Aminohydroxylation was also promoted by palladium.77... 

A Sparreboom, J van Asperen, U Mayer, AH Schinkel, JW Smit, DKF Meijer, P Borst, WJ Nooijen, JH Beijnen, O van Tillingen. Limited oral bioavailability of taxol and active epithelial secretion of pa-clitaxel (Taxol) caused by -glycoprotein in the intestine. Proc Nat Acad Sci USA 94 2031-2035, 1997. 

The chromatid separation process has also remained mysterious. It is an autonomous process that does not direcdy depend on the mitotic spindle (Wilson 1925, Mazia 1961). This is most vividly seen in cells whose spindles have been destroyed by spindle poisons such as colchicine. In many organisms, in particular in plant cells, the cell cycle delay induced by colchicine is only transient and chromatids eventually split apart in the complete absence of a mitotic spindle (Mole-Bajer 1958, Rieder Palazzo 1992) (Fig. 2). Mitosis in the presence of colchicine or colcemid (known as c-mitosis) leads to the production of daughter cells with twice the normal complement of chromosomes. This process is routinely used for manipulating plant genomes and may contribute to the therapeutic effects of taxol in treating breast cancer. 

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