TAXOL SEMISYNTHESIS - A HIGHLY ENANTIOSELECTIVE AND DIASTEREOSELECTIVE SYNTHESIS OF THE SIDE-CHAIN AND A NEW METHOD FOR ESTER FORMATION AT C-13 USING THIOESTERS

A very simple, new, and straightforward approach to the Paclitaxel (Ta xol) and Docetaxel (Taxotere) side chains has been developed using the imine addition reaction of thioester-derived boron enolates bearing c hiral ligands. The addition reaction was studied extensively, using a combination of different thioesters (ROCH2COSPh, ROCH(2)60St-Bu), oxyg en protecting groups (R = Bn, TBDMS, COPh, EE, TMS), chiral boron liga nds [derived from both (-) and (+)-menthone], imines (PhCH=NSiMe3, PhC H=NCOPh), and in the presence or in the absence of additional Lewis ac ids (BF3-OEt2, Et2AlCl, TiCl4). The side chain was assembled in a few steps with the correct relative (syn) and absolute stereochemistry (2R ,3S). The stereochemical outcome of the boron-mediated reaction was ra tionalized using chair vs boat transition state structures. A new dire ct route for attachment of the side chains to the baccatin nucleus usi ng thioester chemistry has also been developed. By treatment of a mixt ure of a thioester (8, 12, or 17) and protected baccatin III (2b, 2c) with LHMDS, the 13-O acylated compounds were obtained in high yield (u p to 90%). Hydrolysis of 18b gave Paclitaxel (1a) in 80% yield.