Synthesis of taxol

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). 

One method of synthesis of taxol analogues starts with a-pinene (8), the readily available and inexpensive monoterpene derived from the processing of turpentine from the pine tree (200). The a-pinene is oxidized to verbenone, which is then alkylated and converted to taxol analogues in a multistep process. 

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,... 

Kusama, H., Hara, R., Kawahara, S. et al. (2000) Enantioselective Total Synthesis of (—)-Taxol. Journalof the American Chemical Society, 122, 3811-3820. 

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 first synthesis of Taxol was completed by Robert Holton and co-workers and is outlined in Scheme 13.53. One of the key steps occurs early in the synthesis in sequence A and effects fragmentation of 4 to 5. The intermediate epoxide 4 was prepared from a sesquiterpene alcohol called patchino. 35 The epoxide was then converted to 5 by a BF3-mediated rearrangement. 

During the total synthesis of taxol the oxirane C-O bond was selectively ruptured on 10% Pd/C in EtOH for 1.25 hours at -5°C (Scheme 4.65),287... 

In the meantime, the race toward the total synthesis of Taxol and the synthesis of Taxol-like compounds started. It was announced in February 1994... 

Finally, this chapter discusses the synthesis of two taxol components bac-catin III, the polycyclic part of taxol and the side chain of taxol. Although several groups have completed the total synthesis of taxol, work on taxol synthesis is still far from over. Chemists working in the area of asymmetric synthesis will find challenge and opportunity in Section 7.5 of this chapter. 

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

As this synthesis started from an achiral starting material, compound 199 must be resolved to secure enantiomerically pure intermediates for the synthesis of taxol. Treatment of (+ )-diol 199 with excess ( lA)-( )-camphanic chloride in methylene chloride in the presence of Et3N forms two diastereomeric monoesters for chromatographic separation. Enantiomerically pure diol 199 can be regenerated from the ester in 90% yield with a specific rotation of +187 (c = 0.5, CHC13). 

Phenyl lithium attack on the cyclic carbonate convertes 202 to C-2 benzoate compound 203. PCC oxidation and subsequent NaBH4 reduction then furnishes the final baccatin III for the total synthesis of taxol (Scheme 7-65). 

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

The semisynthesis of taxol [1], as well as the synthesis of taxoid model systems have been the focus of extensive research efforts in many laboratories, all over the world, which have greatly simplified the total synthesis of taxol itself. An excellent review by Nicolaou et al. has recently been published in Angewandte Chemie [2]. 

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). 

A total synthesis following this route would be highly convergent bearing all the advantages that this type of synthesis offers. One could expect, therefore, that a short and efficient, as well as stereocontrolled, synthesis of taxol could be worked up starting from simple precursors. 

The total synthesis of taxol (1) by Holton and his associates [4] is based in the retrosynthetic analysis outlined in Scheme 13.6.7. 

With the structure of 53a securely stablished, the synthesis of taxol proceeded as outlined in Scheme 13.6.12. 

The synthesis of Taxol completed by a group led by the Japanese chemist Teruaki Mukaiyama and shown in Scheme 13.46 takes a rather different approach. Much of the stereochemistry is built into the B ring by a series of acyclic aldol condensations in steps A-D. The ring is closed by a samarium-mediated cyclization at step E-3. 

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. 

Partial hydrolysis of an oxazoline to produce the hydroxy amide was used extensively in the synthesis of Taxol analogues (Table 8.24 Scheme It is noteworthy that a solution of the amino... 

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