Taxol structure

Entry 4 involves nitrogen participation and formation of an iminium ion that is reduced by NaBH4. The reaction in Entry 5 creates an 11-methylenebicyclo[4.3.1]undecen-3-one structure found in a biologically active natural product. Note that this fragmentation creates a bridgehead double bond. Entry 6 involves construction of a portion of the taxol structure. The reaction in Entry 7 is stereospecific, leading to the E-double bond. 

Chen, S.-H. Fairchild, C. Mamber, S. W. Farina, V. Taxol structure-activity relationships synthesis and biological evaluation of 10-deox3daxol. J. Org. Chem., 1993, 58 2927-2928. 

Chen S-H, Fairchild C, Mamber SW, Farina V (1993) Taxol Structure-Activity Relationships Synthesis and Biological Evaluation of 10-Deoxytaxol. J Org Chem 58 2927... 

The second example shows an unexpected evolution of the intermediate ketyL The interest in this reaction is based on the possible easy access to a part of the Taxol structure. 

Several different synthesis routes of paclitaxel have been published. The total synthesis has been first achieved independently by two teams in 1994, the Holton s and the Nicolaou s [41-43]. The third synthetic route was accomplished by Danishefsky s group in 1996 [44]. Total synthesis of Taxol is a complex task for chemists given the fact that the molecule consists of four complicated rings (A, B, C rings and the oxetane ring) and has 11 chiral centers. The synthesis processed more than 20 steps, and only 0.07% and 2.7% production rates for the Holton s and Nicolaou s routes were obtained, respectively [41, 42]. Mukaiyama et al. have proposed an improved method for the asymmetric total synthesis of Taxol by a different way [45]. An automated synthesizer with a 36-step synthesis sequences for intermediate of Taxol was developed by Doi et al. (2006) [46]. Due to the complexity of Taxol structure, the expensive chemical reagents, and the strict requirement for reaction, the process of the total synthesis of Taxol is multiple-step, costly, and commercially unfeasible for industrial application for Taxol manufacture. 

The. structure.s of vinbla.stine, vincri.stine, colchicine, and taxol. 

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]. 

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. 

The epothilones are natural products containing a 16-membered lactone ring that are isolated from mycobacteria. Epothilones A-D differ in the presence of the C(12)-C(13) epoxide and in the C(12) methyl group. Although structurally very different from Taxol, they have a similar mechanism of anticancer action and epothilone A and its analogs are of substantial current interest as chemotherapeutic agents.36 Schemes 13.59 to 13.66 summarize eight syntheses of epothilone A. Several syntheses of epothilone B have also been completed.37... 

One of the most interesting structures of the past decade has been Taxol [25]. This compound is important in the treatment of cancer, and has stimulated many... 

Besides their essential roles in nature, isoprenoids are of commercial importance in industry. Some isoprenoids have been used as flavors, fragrances, spices, and food additives, while many are used as pharmaceuticals to treat an array of human diseases, such as cancer (Taxol), malaria (artemisinin), and HIV (coumarins). In contrast to the huge market demand, isoprenoids are present only in low abundance in their host organisms. Thus, isolation of the required isoprenoids consumes a large quantity of natural resources. Furthermore, owing to their structural complexity, total chemical synthesis is often not commercially feasible. For these reasons, metabolic engineering may provide an alternative to produce these valuable isoprenoids [88,89]. 

Figure 12.4 The molecular structure of a taxane [114]. Taxotere is the semi-synthetic congener of Taxol. (Reproduced by permission from Macmillan Publishers Ltd Susan C. Roberts. Production and engineering of terpenoids in plant cell culture. Nature Chemical Biology 3 (7) 387-395. London Nature Publishing Group. 2007 Macmillan)...

By using an elegant 13C-labeling study that involved incubation of Phoma sp. with 1-13C and 1,2-13C acetate, Oikawa et al. [9], were able to isolate the proposed biosynthetic intermediate phomactatriene (or Sch 49026), with 13C incorporation from singly labeled acetate units as indicated by in Fig. 8.3. Phomactatriene is strikingly reminiscent of taxadiene, a biosynthetic intermediate for Taxol . The net biosynthesis for both involves geranylgeranyl diphosphate (GGDP) cyclization [9]. It is noteworthy that prior to isolation of phomactins, the only known related structure is cleomeolide, a diterpene from the herb Cleome viscosa [10] that remarkably resembles phomactin H. 

Structure 1 vinblastine, 2 vincristine, 3 maytansine, 4 rhizoxin and 5 paclitaxel (Taxol)... 

Epothilones A, B and E (4,5 and 6) (Fig. 2) are representative members of a new class of bacterially derived natural products which exhibit potent biological activity. Isolated by Hofle and coworkers [6] from a soil sample collected near the Zambesi river, the compounds have provided a great deal of excitement in the scientific community due to their potent cytotoxicity against a number of multiple drug-resistant tumor cell lines and because of the mechanism by which they exert this effect. Like Taxol [7], the epothilones promote the combination of a- and 3-tubulin subunits and stabilize the resulting microtubule structures. This mode of action inhibits the cell division process and is, therefore, an attractive strategy for cancer chemotherapy [7,8]. 

The structures of taxol and its polycyclic part baccatin III are shown in Figure 7-2, and the numbering of these two compounds is extensively used throughout the rest of this chapter. Because connecting the side chain to baccatin HI is just routine chemistry, we introduce only the synthesis of baccatin III and the taxol side chain. 

Wang et al.36 have used the chiral catalyst (DHQ)2 PHAL (see Chapter 4 for the structure) for the asymmetric synthesis of the taxol side chain. Optically enriched diol was obtained at 99% ee via asymmetric dihydroxylation. Sub-... 

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