Taxol Analogs

Because the reaction of an amine with an acyl chloride is much faster than the hydrolysis of the acyl chloride, the reaction can usually be carried out in an aqueous alkali solution. This is well known as the Schotten-Baumann procedure.6 For example, a number of N-acyl taxol analogs have been prepared under Schotten-Baumann conditions by the reaction of A-debenzoyltaxol with various acid chlorides (Eq. 9.4).7 Highly purified /V-long-chain-acyl neutral amino acids such as potassium AMauroyTy-aminobutyrate, useful as surfactants for detergent... 

Taxol has received considerable competitive challenge from taxotere, officially named docetaxel, a patented taxol analog developed by Rh6ne-Poulenc, based on the 1981 first successful semi-synthesis by Gueritte-Voegelein from 10-DAB. In 1987, Rh6ne-Poulenc selected taxotere for clinical development, and it is now used clinically in the United States. 

TABLE 8.24 UNMASKING THE SIDE-CHAIN OE TAXOL ANALOGS BY ACID HYDROLYSIS,... 

Additional examples of selenophene ring-formation reaction that result from the treatment of 1,4-dienes with selenium dioxide have been reported. For example, treatment of verbenone derivative 116 with selenium dioxide in the presence of pyridine gave fused selenophene 117 in 92% yield (Equation 19) <20010L3161, 2002JOC6553>. Additional applications of this reaction include taxol analog 150 <1997BML1941> and a [l]benzopyrano[3,2-/ ]-selenophene-9-one derivative <2001SAA1427>. 

Gueritte-Voegelein, R Guenard, D. Lavelle, R Le Goff, M.-T. Mangatal, L. Potier, P. Relationships between the structure of taxol analogs and their antimitotic activity. J. Med. Chem., 1991, 34 992-998. 

Chen, S.-H. Huang, S. Wei, J. Farina, V. Serendipitous synthesis of a cyclopropane-containing taxol analog via anchimeric participation of an unexpected angular methyl group. J. Org. Chem., 1993, 58 4520-4521. 

Such fingerprints of mass spectral fragmentation have been useful in dereplication and in identification of family similarities. For instance, a family of 18 different naturally occurring taxol analogs were each identified from crude extracts of Taxus brevifolia and Taxus baccata by a procedure primarily based on analysis of their behavior under LC-MS-MS conditions (33). Fourteen different molecular ions were obtained for the eighteen compounds, but after the four or five fragmentations depicted in Fig. 4, each compound exhibited an identical template ion of 327 m/z, representing the ionized taxol core. 

Taxol Analogs with Modified N-Acyl and 3 -Aryl Groups. 131... 

Taxol Analogs Modified Both on the Side Chain and the... 

Synthesis of Taxol Analogs with Highly Modified Side Chains. . 133... 

Taxol Analogs with Polymeric Acyl Substitutions. 140... 

The Synthesis of Taxol and Taxol Analogs from Precursors... 

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. 

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)... 

Various C-seco analogs have been prepared in addition to 4.2.2.6 described above. Thus treatment of 10-deacetylbaccatin III with cupric acetate gave the 10-oxo derivative as described previously 42), and treatment of this compound with sodium borohydride and ceric chloride gave a mixture of the lO-e/ /-10-deacetylbaccatin III and the D-seco product 4.2.2.9 182). In a later publication the taxol analogs 4.2.2.10-4.2.2.13 were prepared by standard methods from 4.2.2.9 183). 

Reacylation at the C-4 position is also difficult because of the hindered nature of this position, but various methods have been developed to overcome this problem. The first C-4 analog of taxol was reported by Georg, who converted a 2, 7-protected taxol to its 2,4-dideacyl derivative and thence to the cyclic carbonate 4.3.2.I. Esterification at C-4 was achieved with excess isobutyric anhydride and DMAP to give the 4-isobutyrate derivative 4.3.2.2, which was converted to the taxol analog 4.3.2.3 with phenyllithium followed by deprotection. The corresponding docetaxel analog was also prepared (190). 

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