Products Derived from 6,7-Dehydrotaxol

The availability of the 6,7-dehydro derivative 4.1.3.7 opened up routes to analogs derivatized at C-6 as well as to analogs with other modifications. Hydroxylation of 4.1.3.7 gave the a-diol 4.2.1.1 (167) while treatment with dimethyldioxirane gave the a-epoxide 4.2.1.2 (167, 168) a conflict between the / -stereochemistry (167) and the a-stereo-chemistry was resolved in favor of the latter by an x-ray crystal structure determination (175). 

Treatment of 6,7-dehydro derivative 4.1.3.7 with bromine in chloroform did not give any addition product, but led instead to the D-seco product 4.2.1.3 (168). 

The epoxide 4.2.1.2 proved resistant to nucleophilic attack, but the diol 4.2.1.1 could be converted into a number of new analogs. These included simple analogs such as various C-6 acyl derivatives 4.2.1.4 (167) but also various derivatives produced by deoxygenation at C-7. Thus diol 4.2.1.1 could be protected as its 2 -(triethylsilyl)ether, converted to its cyclic 6,7-a-thiocarbonate, and deoxygenated to the 7-deoxyanalog 4.2.I.5. Analog 4.2.1.5 can be oxidized to the ketone 4.2.1.6, which can then be reduced to the /5-alcohol 4.2.1.7 (176). Both compounds 4.2.1.5 and 4.2.1.7 were as active as taxol in a tubulin-assembly assay, but were 4 and 10 times less potent than taxol in a cytotoxicity assay with the HCT-116 human colon tumor cell line (176). 

The diol 4.2.1.1 has also been converted into 6-a-hydroxytaxol 4.2.1.8, the major human metabolite of taxol. In the first approach, direct treatment of diol 4.2.1.1 (protected as its 2 -f rr-butyldimethylsilyl derivative) with DBU in xylene at 80°C gave 4.2.1.8 in 15% yield after 

A recent publication gives an improved method by which the diol 4.2.1.1 (as its 2 -triethylsilylether) is oxidized selectively to its 6-oxo derivative, which was then epimerized to the 7/ -hydroxy derivative 4.2.I.9. Reduction of 4.2.1.9 with sodium triacetoxyborohydride gave the 6/3,7/3-diol, and this was converted to the a-nitrate 4.2.1 10 by treatment with thionyl chloride and then sodium periodate to give a cyclic sulfate, followed by tetrabutyl ammonium nitrate. Hydrogenolysis of 4.2.1.10 and deprotection gave the metabolite 4.2.1.8 in 37% overall yield from 4.2.1.1 (178). 

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