Asymmetric total synthesis of Taxol®

The asymmetric total synthesis of Taxol was achieved by way of B to BC to ABC to ABCD ring construction. Optically active 8-membered ring enones 1 and 2 corresponding to the B ring of Taxol have been synthesized in high yields from the linear precursors 28 and 32, respectively, by intramolecular aldol cyclization using SmI2. The optically active linear polyoxy compounds 28 and 32 were obtained by way of diastereoselective aldol reaction between aldehyde 4 and ketene silyl acetal 8 catalyzed by MgBr2. OEt2. The chiral pentanal 4 was synthesized either by asymmetric aldol reaction of achiral aldehyde 7 and ketene silyl acetal 8 by means of a chiral Lewis acid or by diastereoselective aldol reaction between the chiral aldehyde 16, derived from L-serine, and the lithium enolate derived from methyl isobutyrate. Optically active bicyclo[6.4.0]dodecanone 38 beta, corresponding to the BC ring system of Taxol, was prepared from 8-membered ring enone 2 in high yield by stereoselective Michael addition and successive intramolecular aldol cyclization. Furthermore, baccatin III, the ABCD ring system of Taxol, was efficiently synthesized from the BC ring system 38 beta by successive construction of the A and D rings by intramolecular pinacol coupling cyclization, introduction of the C-13 hydroxyl group and an oxetane-forming reaction. Finally, the total synthesis of Taxol was accomplished by dehydration condensation between a protected N-benzoylphenylisoserine 70 or 75 and 7-TES baccatin III, prepared from baccatin III. Taxol side chains 70, 73, 75, and 77 optically active protected N-benzoylphenylisoserines, were synthesized by enantioselective aldol reaction from two achiral starting materials, benzaldehyde and an enol silyl ether 65 derived from S-ethyl benzyloxyethanethioate.