Analogues of taxol with a modified phenylisoserine side chain were synthesised and evaluated as potential cytotoxic agents. Taxol (1), a complex antineoplastic diterpene isolated from Taxus brevifolia,1 has recently been approved for the treatment of metastatic carcinoma of the ovary.2 The cytotoxicity of taxol is related to microtubule-mediated interruption of mitosis which occurs by inducing tubulin polymerization and forming extremely stable and nonfunctional microtubules abnormally resistant to depolymerization.3 Study of natural and semisynthetic congeners of taxol has demonstrated that an intact taxane ring and an ester C-13 side chain are required for cytotoxicity as Baccatin III and N-benzoyl-(2R, 3S)-3-phenylisoserine are devoid of significant antitumor activity.4 Taxol derivatives with simplified side chains displayed no cytotoxicity or significantly lower biological activity than taxol and the stereochemistry 2'R and 3'S was also found to be critical for optimal activity.5a-d Derivatives with substituted phenyl rings at the 3'-position displayed cytotoxicity comparable to taxol.6 Interestingly, replacing the N-benzoyl group with a tert-butyloxycarbonyl group at the C-3 position of the C-10 desacetyl derivative of taxol has resulted in an analogue, Taxotere® (2), which is currently undergoing clinical trials in the United States and Europe.6 In order to better define the structure-activity relationships of taxol for the design of more effective drugs and to understand the features of the taxol binding site on microtubules, we were interested in the role of the 2' hydroxyl group. Based upon the X-ray structure of Taxotere® 7, Swindell has suggested that the 2'-hydroxyl is stabilizing the amino acid side chain conformation for proper binding to the receptor via intramolecular hydrogen bonding between the ester carbonyl, the 2'-hydroxyl, and the 3'-NH groups.7a,b However, we cannot rule out the possibility of direct participation of the 2'-OH group in intermolecular hydrogen bonding at the receptor site. So far, modifications at the C-2' position have only included prodrugs of taxol.8 Simple analogues like 2'-desoxytaxol or the 2'-methyl ether have not been reported in the literature. We felt that the biological properties of these compounds might lead to some insight into the role of the 2'-hydroxyl group; therefore, we decided to synthesize 2'-methoxytaxol (3) and 2'-desoxytaxol (4). Furthermore, we were also interested in synthesizing and evaluating 2'-fluorotaxol (5) as a potential cytotoxic agent. Isosteric groups are often applied extensively in drug design9 and 5 can be viewed as an isostere of taxol. Herein, we describe the synthesis and cytotoxicity results of these new 2'-modified analogues of taxol.