A Total Synthesis of Taxol

Abstracted with permission from Angew. Chem., Int. Ed Engl., 1995,34, 1723 1995 VCH Verlaggesellschaft 

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Scheme 3-52 A total synthesis of taxol employing the Heck reaction in a key step [162],...

Mukaiyama has described a total synthesis of taxol wherein pinacol cyclization of a diketone was employed to construct the A ring in good yield (Eq. 3.13) [31J. In this work, partially reduced alcohols and rearranged compounds were the major side products of the titanium-mediated coupling process. 

The Corey-Winter reaction has found use in complex natural product synthesis. In one example, treatment of thionocarbonate 26 with diazaphospholidine 21 afforded diene 27 in 82% yield. This diene was ultimately used in a total synthesis of (-)-taxol.14... 

Many notable examples of the synthesis of complex natural products from optically pure starting materials have been reported (70). One synthesis of considerable interest is that of taxol [33069-62-4] (74), a potent antitumor agent used clinically. The starting material (73) used ia the first total synthesis of taxol is produced ia enantiomericaHy pure form from inexpensive and readily available /-camphor [464-48-2] (72) (73). 

Another monoterpene used as a starting material for taxol analogues is camphor (43), which is readily available naturally or can be produced synthetically (201,202). Total synthesis of taxol analogues may be the answer toward finding new compounds for the treatment of many types of cancer. 

All that remains before the final destination is reached is the introduction of the C-l3 oxygen and attachment of the side chain. A simple oxidation of compound 4 with pyridinium chlorochro-mate (PCC) provides the desired A-ring enone in 75 % yield via a regioselective allylic oxidation. Sodium borohydride reduction of the latter compound then leads to the desired 13a-hydroxy compound 2 (83% yield). Sequential treatment of 2 with sodium bis(trimethylsilyl)amide and /(-lactam 3 according to the Ojima-Holton method36 provides taxol bis(triethylsilyl ether) (86 % yield, based on 89% conversion) from which taxol (1) can be liberated, in 80 % yield, by exposure to HF pyridine in THF at room temperature. Thus the total synthesis of (-)-taxol (1) was accomplished. 

The total synthesis of taxol (52) has been described in Chapter 34. Clearly, total synthesis cannot hope to meet the demand for taxol at the present time, and supplies are currently procured by semisynthesis. This approach uses baccatin III (derived from yew tree needles) and the C-13 side chain 51, made synthetically (Scheme 13). A practical synthesis of the side chain is necessary,... 

Nicolaou, K.C., Liu, J.J., Yang, Z. et al. (1995) Total Synthesis of Taxol. 2. Construction of A and C Ring Intermediates and Initial Attempts to Construct the ABC Ring System. Journal of the American Chemical Society, 117, 634-644. 

Mukaiyama, T., Shiina, J., Jwadare, H. et al. (1999) Asymmetric Total Synthesis of Taxol. Chemistry A European Journal, 5, 121-161. 

Holton, R.A., Somoza, C., Kim, H.B. etal. (1994) First Total Synthesis of Taxol. 1. Functionalization ofthe B Ring. Journal of the American Chemical Society, 116, 1597-1598. 

THE TOTAL SYNTHESIS OF TAXOL—A CHALLENGE AND OPPORTUNITY FOR CHEMISTS WORKING IN THE AREA OF ASYMMETRIC SYNTHESIS... 

The Total Synthesis of Taxol—A Challenge and Opportunity for Chemists Working in the Area of... 

The strategy followed by Nicolaou and his group for the total synthesis of taxol was based on a retrosynthetic analysis already devised by the author in 1992 [6], which implies a convergent synthesis (Scheme 13.6.1). 

Taxol is the showcase for the billions spent by the NCI over many decades. But there has not yet been a dramatic decrease in the death rate from cancer in the United States. Future challenges include discovering whether some derivatives of taxol would be even more effective than taxol, more easy to administer, and could be made at lower cost. The total synthesis of taxol also gives us the tool to investigate numerous alternatives. Another challenge is whether we can go beyond ovarian and breast cancer to treat the big killers of lung and stomach cancer. 

During the first total synthesis of taxol , R. Holton and co-workers installed an exo-methylene group on the C ring in order to set the stage for the D ring (oxetane) formation. The Burgess dehydration reaction was applied to a complex tricyclic tertiary alcohol intermediate (ABC rings) and the desired exocyclic alkene was isolated in 63% yield. 

Narasaka and coworkers have reported the IMDA reaction of 3-hydroxy-2-pyrone 34 (Scheme 36) with 4-hydroxy-2-butenoate 144, which was temporarily tethered with phenylboronic acid, to provide a single cycloadduct 147 in 75% yield <91S1171>. This elegant strategy was further elaborated by Nicolaou and coworkers for the synthesis of 151 as the C-ring intermediate in their initial synthetic endeavors towards the total synthesis of taxol <92JCS(CC)1118 95JACS624>. 

In their studies toward the total synthesis of Taxol , Danishefsky and co-workers have focused their attention on the formation of eight-membered rings by an intramolecular Heck reaction proceeding by an -exo-trig cyclization of a 2-halo-1,8-decadiene system (Scheme 19, Table 14). 

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