Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, October 5, 2015
Douglass F. Taber
University of Delaware

The Sato/Chida Synthesis of Paclitaxel (TaxolŽ)

Paclitaxel (TaxolŽ) (3) is widely used in the clinical treatment of a variety of cancers. Takaaki Sato and Noritaka Chida of Keio University envisioned (Org. Lett. 2015, 17, 2570, DOI: 10.1021/acs.orglett.5b01173; 2574, DOI: 10.1021/acs.orglett.5b01174) establishing the central eight-membered ring of 3 by the SmI2-mediated cyclization of 1 to 2.

The starting point for the synthesis was the enantiomerically-pure cyclohexenone 5, prepared from the carbohydrate precursor 4. Conjugate addition to 5 proceeded anti to the benzyloxy substituent to give, after trapping with formaldehyde and protection, the ketone 6. Reduction and protection followed by hydroboration led to 7, that was, after protection and deprotection, oxidized to 8.

The second ring of 3 was added in the form of the alkenyl lithium derivative 9, prepared from the trisylhydrazone of the corresponding ketone. Hydroxyl-directed epoxidation of 10 proceeded with high facial selectivity, leading, after reduction and protection, to the cyclic carbonate 11. Allylic oxidation converted the alkene into the enone, while at the same time oxidizing the benzyl protecting group to the benzoate, to give 12. Reduction of the ketone 12 lead to a mixture of diastereomers. In practice, only one of the diastereomers of 1 cyclized cleanly to 2, as illustrated, so the undesired diastereomer from the NaBH4 reduction was oxidized back to the enone for recycling. For convenience, only one of the diastereomers of 2 was carried forward.

To establish the tetrasubstituted alkene of 3, the alkene of 2 was converted to the cis diol and on to the bis xanthate 13. Warming to 50°C led to the desired tetrasubstituted alkene, sparing the oxygenation that is eventually required for 3. For convenience, to intercept 16, the intermediate in the Takahashi total synthesis, both xanthates were eliminated to give 14. Hydrogenation removed the disubstituted alkene, and also deprotected the benzyl ether. Oxidation followed by Peterson alkene formation led to 15, that was carried on to the Takahashi intermediate 16 using the now standard protocol for oxetane construction.

It is a measure of the strength of the science of organic synthesis that Masahisa Nakada of Waseda University also reported (Chem. Eur. J. 2015, 21, 355, DOI: 10.1002/chem.201404295; not illustrated) an elegant synthesis of 3. These two approaches are well worth studying side by side, for the complementary way they addressed the several challenges inherent in the structure of 3.

D. F. Taber, Org. Chem. Highlights 2015, October 5.