Paclitaxel synthesizing

Summary of Green Metrics Parameters for Paclitaxel Syntheses... 

Docetaxel is a water-soluble, semisynthetic analogue of paclitaxel, synthesized from the... 

There are natural targets whose syntheses have important practical applications. For example, paclitaxel (marketed as Taxol by Bristol-Myers Squibb) is an anticancer compound originally isolated from the bark of a species of yew tree, but for a long time it seemed that natural sources would not be sufficient to meet the need. Consequently, many chemists developed synthetic approaches to paclitaxel from readily available materials, although these are not yet fully practical for manufacturing. The quest continues, and a semisynthetic route has been developed starting with a compound isolated from yew needles that can be harvested without destroying the tree. An alternative approach has employed plantcell cultures in bioreactors to produce paclitaxel from yew needles (see Chapter 7 for discussion of related matters). 

The molecular complexity of paclitaxel created enormous barriers to a complete synthetic solution to this supply issue. Although some researchers did make headway in the race toward a total synthesis, their efforts proved non-viable commercially, with published reports from successful research laboratories describing 40-step syntheses with overall yields of about 2% [11, 12]. 

Paclitaxel (Taxot ) Paclitaxel (85) is one of the most promising compounds against several types of cancer, and a number of elegant total syntheses have been reported in recent years [99], It is produced by the slow growing pacific yew tree, and therefore its availability is limited. By partial synthesis, it is best prepared from 10-deacetylbaccatin III, a derivative lacking the C-10 acetoxy fragment as well as the C-l 3 side chain. Therefore, many efforts have been focused on... 

Taxol (paclitaxel) is a cytotoxic drug that has been shown to have potent antileukemic and tumor inhibitory properties. Taxol suffers from very poor water solubility (0.25 pg/mL), and hence, a few phosphate ester prodrugs of taxol have been synthesized. While great improvement of water solubility was achieved (>10 mg/mL), these prodrugs were resistant to degradation by alkaline phosphatase, probably due to hindered enzyme access, and no free taxol was formed [50],... 

Paclitaxel (Taxol) is a diterpenoid compound that contains a complex taxane ring as its nucleus (Figure 62.1). The side chain linked to the taxane ring at carbon 13 is essential for its antitumor activity. Modification of the side chain has led to identification of a more potent analogue, docetaxel (Taxotere), which has clinical activity against breast and ovarian cancers. Originally purified as the parent molecule from yew bark, paclitaxel can now be obtained for commercial purposes by semisynthesis from 10-desacetylbaccatin, a precursor found in yew leaves. It also has been successfully synthesized from simple off-the-shelf reagents in a complex series of reactions. 

Holton claimed in a patent application that (3/ ,45)-A-benzoyl-3-0-EE-(3-lactam 11 (5 equiv), obtained through tedious classical optical resolution of racemic t (. -3-hydroxy-4-phenylazetidin-2-one, could be directly coupled with 7-TES-bac-catin III (8) in the presence of 4-dimethylaminopyridine (DMAP) and pyridine and the subsequent deprotection afforded paclitaxel in ca. 82% yield.54 Although this procedure was proved to work by us and by others, the use of a large excess of (3-lactam is obviously inefficient. Moreover, the Holton procedure did not work at all when /V-f-Boc-(3-lactam 12 was used for our attempted syntheses of docetaxel and its 10-acetyl analogue. This is due to the lack of reactivity of the A-r-Boc-(3-lactam 12 toward the C-13 hydroxyl group of a protected baccatin III under the Holton conditions. The lack of reactivity is ascribed to the substantially weaker... 

It is very important to clarify the minimum structural requirements for paclitaxel and taxoids to exhibit anticancer activity by looking at simplified structure analogues. Along this line, we have investigated the role of the A ring by synthesizing novel nor-seco analogues of paclitaxel and docetaxel.37,96... 

We have developed a new photoreactive analogue of paclitaxel, 3 -N-BzDC-3 -N-debenzoylpaclitaxel (109) and its ditritiated derivative ([3H]-109) has been evaluated for its ability to photolabel tubulin and P-glycoprotein.66 Radiolabeled photoreactive analogue [3H]-109 was synthesized by N-acylation of 3 -N-deben-zoyl-2, 7-bis(0-TES)paclitaxel (108) with N-(2,3-ditritio-3-(4-benzoyl-phenyl)propanoyloxy)succinimide ([3H]-107), followed by purification on a reversed phase semipreparative HPLC using a C-18 column (Scheme 21).66 Photoaffinity label [3H]-109 was assessed to possess >99.9% radiochemical purity and a high specific radioactivity (34 Ci/mmol). 

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