10-deacetyl taxol

The first, reported in 1986 (46) utilizes Sharpless oxyamination of the C-13 cinnamate derivative (25), leading in one step to both the correct substitutions at C-2 and C-3 and to the threo configuration present in taxol. This reaction yields 10-deacetyl taxol (23f), after deprotection and benzoylation of the oxyamination product, in five steps starting from 13a with an overall yield of about 10% and to taxol (1) itself starting from 13b. When the standard conditions described for oxyamination are used, the reaction is nonspecific and leads to two regioisomers and their associated diastereoisomers (27a-d). Use of asymmetric catalysts (50) in the reaction leads to an improvement in the yield of the desired isomer 27a, the precursor of natural deacetyltaxol. 

Zheng QY, Murray CK (1995). Preparation of 10-deacetylbaccatin III and 7-pro-tected-lO-deacetylbaccatin III Derivatives from 10-deacetyltaxol A, 10-deacetyl taxol B, and 10-deacetyltaxol C. US Patent 5,449,790 Chem Abstr 132 340476e... 

R,3S)-N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl-2-(1 -ethoxyethyl)-7,10-bis-(triethylsilyl)taxol (XXIII)... 

Chemical Name 10-Deacetyl-N-debenzoyl-N-[(l,l-dimethylethoxy)carbonyl] taxol... 

Under oxidizing conditions (Jones reagent), taxol is converted to the 7-keto derivatives 20a and 20b (43) (see Scheme 3). Under these same conditions (2,11,28), the free 13-hydroxyl group of baccatin III (13b) and 10-deacetyl baccatin III (13a) is oxidized to form 13-oxobaccatin III (21b) and the deacetyl derivative (21a), respectively. Treatment of compound 20c, derived from the oxidation product 20a after protection of its 2 -hydroxyl group, with base leads to rearrangement products such as D-seco taxane 22. 

For centuries, plants have been a unique source of therapeutically significant alkaloids and they continue to be excellent sources of drugs. Furthermore, alkaloids of natural origin serve as a model for the semisynthesis or the synthesis of derivatives which have improved pharmacokinetic properties, a higher efficacy and/or less toxicity. One of the most recent examples is the isolation of the anticancer agent, called taxol, from the stem bark Of the Pacific yew tree Taxus brevifolia in 1971 by Wani and co-workers [1] and the development, a few years later, of docetaxel, a semisynthetic derivative obtained from 10-deacetyl-baccatin III [2]. 

Some more significant changes at C-13 have also been made. Thus Georg and her coworkers prepared 13-epitaxol from baccatin III (43). The key to their strategy was the stereoselective reduction of 4-deacetyl-13-oxo-7-(triethylsilyl)baccatin III (2.2.1) with tetramethylammonium triacetoxyborohydride, which gave a 13-epibaccatin derivative which was converted to the taxol analog 2.2.2. This product was essentially inactive in a tubulin-assembly assay. 

Modifications at the C-9 position of taxol were initially facilitated by the isolation of 9-dihydrobaccatin (3.2.1) from T. canadensis, the Canadian yew (97). The availability of this compound was then used to advantage by Klein, who converted it into 9-dihydrotaxol. Protection of 3.2.1 as its 7,9-acetonide 3.2.2, selective deacetylation at C-13 to give 3.2.3, addition of the side chain to give 3.2.4, and deprotection gave the (9i )-dihydrotaxol 3.2.5 98). 

The only reported taxol analog modified at C-19 was prepared from the naturally occurring 10-deacetyl-19-hydroxybaccatin III (3.3.1), Protection of 3.3.1 as its 7,10,19-tri(trichloroethoxycarbonate), followed by coupling with a protected side chain and appropriate deprotection gave the 19-hydroxy docetaxel analog 3.3.2 (103)... 

Selective deacetylation of the C-4 acetate of taxol or baccatin III proved to be a challenging task because this acetate group is in a very hindered location. The first clue to a method for selective deacetylation came in studies of the hydrolysis of hexahydrobaccatin III 58) in which it was found that hexahydrobaccatin III itself underwent reasonably selective deacylation at C-10 and C-4 to give the 4,10-bis-deacetyl derivative. A 13-(triethylsilyl)-analog, however, underwent selective hydrolysis at the C-10 and C-2 positions. These results were explained by a neighboring group effect, with intramolecular transfer of the C-4 acetate to the C-13 position. 

The synthesis of taxol and taxol analogs from baccatin III and its precursor 10-deacetyl baccatin III was described in section 8 above, and this approach constitutes the current commercial synthesis of taxol and docetaxel. The concept of converting other taxoid precursors into taxol or bioactive taxol analogs continues to intrigue chemists, however, and several groups have investigated such conversions. 

A semisynthesis of the 19-hydroxy taxol derivative, 19-hydroxy docetaxd 869, was accomplished by semisynthesis of a new baccatin derivative, lO-deacetyl-19-hydroxybaccatin III 866, which, after temporary protection at positions C-7, C-10, and C-19 with Troc groups using 2,2,2-trichloroethyl chloroformate (Troc-Cl) (to give 867), was coupled with N-Boc-N,0-isopropylidene-phenylisoserine 868 to yield 869 [629]. Analogue 869 exhibits a high level of in vitro cytotoxicity and thus the results demonstrate that chemical modifications at C-19 can be made without significant loss of biological activity. 

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