NOVEL CYTOTOXIC 3'-(TERT-BUTYL) 3'-DEPHENYL ANALOGS OF PACLITAXEL ANDDOCETAXEL

3'-(tert-Butyl) 3'-dephenyl analogs of paclitaxel were synthesized fro m 10-deacetylbaccatin III and oxazolidinecarboxylic acid 7 followed by acylation of intermediate amines 10 and 11. Oxazolidinecarboxylic aci d 7 was prepared in five steps and in good overall yield from L-tert-l eucine. Twelve analogs were synthesized and evaluated for their in vit ro ability to stimulate the formation of microtubules and for their cy totoxicity against B16 melanoma cells. Amide, carbamate, urea, and thi ourea congeners were prepared. The most potent derivatives found in th is study are the docetaxel analog 13, the N-[(tert-amyloxy)carbonyl] a nalog 17, and the 3'-phenylurea and 3'-tert-butylurea derivatives 20 a nd 23. Six of these analogs were shown to be ca. 90 times more soluble in water than paclitaxel and ca. 4-5 times more water-soluble than do cetaxel.