Synthesis of Taxol and Docetaxel

The /3-lactam synthon approach pioneered by Holton, Ojima, and Georg remains the most widely used method, and is the method currently used by Bristol-Myers Squibb for the commercial synthesis of taxol. 

The oxazolidine approach has undergone some refinement, particularly in the nature of the protecting groups used. Thus trichloromethyl-substituted oxazolidines 8.1.2 and 8.1.3 could be prepared from the debenzoyl side chain 8.1.1 and coupled directly with 7,10-ditroc-baccatin III (without the necessity of protecting the nitrogen). The resulting oxazoline was converted to the open-chain product with zinc and acetic acid and acylated to give docetaxel (296). 

In another approach, Greene et al. found that compounds such as 8.1.4, which had the wrong stereochemistry at the C-2 position, gave a product 8.1.5 with the taxol configuration at C-2 when coupled with 7,10-bis-troc-10-deacetylbaccatin III under DCC/DMAP conditions (297). 

As noted earlier, the oxazoline 7.5.12 can serve as an excellent side chain precursor. It can be coupled with protected baccatin III in good yield, and the resulting cyclic product 8.1.6 can be converted to taxol under mild conditions. An attempt to modify this approach by the use of dioxo-oxathiazolidine 8.1.7 came to a surprising conclusion, in that coupling of 8.1.7 with protected baccatin III gave the same product 8.1.6 as had previously been prepared. Subsequent studies showed that the oxathiazolidine 8.1.7 was unstable and rearranged to the oxazoline 7.5.12 under the conditions of the reaction 298). 

In a series of reports Gennari et al. demonstrated the synthesis of taxol side chain thioesters protected as oxazolines and oxazolidines. Thus reaction of the enolate of thioester 8.1.8 and TMS-imine 8.1.9 in the presence of chiral borate 8.1.10 gave the side chain thioester 8.1.11 in 60% yield. Compound 8.1.11 was then protected as its acetonide 8.1.12. The oxazoline analog 8.1.13 was synthesized by a similar strategy with an inversion to achieve the desired stereochemistry at C-2 during the formation of the oxazoline ring (299). 

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The synthesis of taxol and taxol analogs from baccatin III and its precursor 10-deacetyl baccatin III was described in section 8 above, and this approach constitutes the current commercial synthesis of taxol and docetaxel. The concept of converting other taxoid precursors into taxol or bioactive taxol analogs continues to intrigue chemists, however, and several groups have investigated such conversions. 

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