Chapter 21
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The Total Synthesis of Paclitaxel Starting with Camphor Robert A. Holton, Carmen Somoza, Hyeong-Baik Kim, Feng Liang, Ronald J. Biediger, P. Douglas Boatman, Mitsuru Shindo, Chase C. Smith, Soekchan Kim, Hossain Nadizadeh, Yukio Suzuki, Chunlin Tao, Phong Vu, Suhan Tang, Pingsheng Zhang, Krishna K. Murthi, Lisa N . Gentile, and Jyanwei H . Liu Dittmer Laboratory of Chemistry, Florida State University, Tallahassee, FL 32306 Abstract: The first total synthesis of the potent anti-tumor agent taxol is described. The synthesis proceeds from the commodity chemical camphor, which is available in either enantiomeric form, and builds the taxol molecule in a linear fashion. An important feature of the synthetic route is the utilization of conformational control to enable the functionalization of the eight membered Β ring of taxol. 1
The total synthesis of the potent anti-tumor agent taxol (1), isolated by Wall and Wani in 1971, has stood for over twenty years as a major challenge for organic chemists. Taxol has been the subject of extensive chemical and biological studies, which have recently been summarized in several reviews, and many synthetic approaches have been described. « Until now, our taxane research program has produced a synthesis of the taxane ring system, a total synthesis of taxusin, and a (now commercialized) semisynthesis of taxol. Here we describe the first total synthesis of taxol. « The facile epimerization of taxol at C-7 is well documented, * and has been postulated to occur via a retroaldol-aldol process. We chose to pursue a synthetic strategy in which this stereocenter would be introduced at an early stage and carried throughout most of the synthesis in the absence of a C-9 carbonyl group, thereby avoiding the C-7 epimerization complication. Thus, our route to taxol proceeds retrosynthetically through C-7 protected baccatin ΙΠ (2) to the tricyclic ketone 3, which arises from Cringclosure of a precursor 4, properly functionalized at C - l , C-2, C-3, C-7, and C-8. Synthesis of this precursor would be made possible by conformational control of the eight membered Β ring, via ketone 5. Ketone 5 was projected to arise from an aldol condensation of the enolate of ketone 6, the formation of which would be made possible by the conformational control exerted by the C-10a substituent, with an aldehyde carrying the carbons necessary for the eventual construction of the taxane C ring. The synthesis begins with camphor, which is readily available in either enantiomeric form. Following the route provided by Buchi, camphor can be converted to β-patchouline and its epoxide, commercially available under the trade name "Patchino." Our synthetic studies had heretofore utilized the commercially available enantiomer of Patchino which leads ultimately to the unnatural enantiomers of 2
3
3e
5
4
6a
7
8a
b
9
3
5
10
11
NOTE:
Paclitaxel is the generic name for Taxol, which is now a registered trademark. 0097-6156/95/0583-0288$08.00/0 © 1995 American Chemical Society
In Taxane Anticancer Agents; Georg, G., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
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21.
HOLTON ET AL.
Total Synthesis of Paclitaxel front Camphor 289
the taxane natural products. To provide access to material in the enantiomeric series leading to natural taxanes, we have modified the synthesis reported by Buchi so that Patchino can be prepared in multigram quantities from camphor without the need for chromatographic separation at any stage. Patchino reacted, as reported by Buchi, in the presence of boron trifluoride etherate to give the rearranged homoallylic tertiary alcohol 7. This set the stage for discovery of the fragmentation of bicyclic epoxy alcohols pioneered in our laboratory nine years ago, ' known as the "epoxy alcohol fragmentation," and the cornerstone of our syntheses of the taxane skeleton, taxusin, and now taxol. The epoxy alcohol fragmentation has enabled the synthesis of a variety of molecules having different substitution patterns on the bicyclo [5.3.1] skeleton, e.g., ketone 8, generated in quantitative yield upon Sharpless epoxidation of alcohol 7. 10
5 12
camphor
. „ nno"
β-patchoulene
(IFF)
patchouli alcohol
epoxy alcohol fragmentation
In Taxane Anticancer Agents; Georg, G., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
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TAXANE ANTICANCER AGENTS
13
Spectroscopic studies of compounds having the the bicyclo [5.3.1] skeleton have demonstrated that there are four distinct conformations of this eight membered
ring, as shown in Scheme 1. For a given compound the equilibrium will shift to favor conformations which orient substituents toward the periphery of the Βringto minimize non-bonded interactions. The combination of a C-ΙΟβ alkoxyl group, a C-δβ methyl group, and a C-3 ketone in this ring system shifts the equilibrium to strongly favor the chair-boat conformation. For example, ketone 8a ^ was found to exist exclusively in the chairboat conformation, and calculations indicate that, in the case of 8a, this conformation is favored by ca. 7 kcal/mol. This ketone was projected to be an intermediate in the synthesis of taxusin and other taxanes until we discovered that it does not undergo deprotonation at C-8oc, presumably because of the approximately eclipsing alignment of the C-8a hydrogen and the C-3 carbonyl group. Therefore, to enable C-8a deprotonation (and subsequent aldol condensation), we chose to utilize a C-10a silyloxy substituent as a conformational control element. 1
14
6
As in the synthesis of taxusin, patchino was converted to epoxide 9 in 98% yield, and 9 then rearranged under very specific conditions to provide diol 10 in 93% yield at 75% conversion. Silylation (TESC1, pyridine) of 10 was followed by epoxy alcohol fragmentation and protection at C-13 to give 11 in 93% overall yield. Although 11 was found to be in the chair-boat conformation, calculations indicate that, while the chair-boat conformer is lowest in energy, the chair-chair and boat-chair conformers are only ca. 2.5 kcal/mol less stable. Presumably deprotonation of one of these other conformers at C-8 is facile. The magnesium enolate of ketone 11 (HN(iPr) , THF, MeMgBr, 25 °C, 3 h, then 11, 1.5 h) underwent aldol condensation with 4-pentenal (THF, -23 °C, 1.5 h), and the crude product was directly protected (Cl CO, pyridine, C H a , -10 °C, 0.5 h, then ethanol, 0.5 h) to give ethyl carbonate 12, a ca. 6:1 mixture of chair-chair and boat-chair conformers (CDC1 ), slowly interconverting on the NMR time scale, in 75% yield. Hydroxylation at C-2 (12, LDA, THF, -35 °C, 0.5 h, then -78 °C, 1.0 mol equiv of (+)-camphorsulfonyl oxaziridine (for the enantiomer leading to taxol; (-)camphorsulfonyl oxaziridine for the enantiomer leading to ent-taxol), 0.5 h) gave 14
15
2
2
2
2
16
3
17
In Taxane Anticancer Agents; Georg, G., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
Downloaded by UNIV OF CALIFORNIA SANTA BARBARA on November 24, 2014 | http://pubs.acs.org Publication Date: December 7, 1994 | doi: 10.1021/bk-1995-0583.ch021
21.
Total Synthesis of Paclitaxel front Camphor
HOLTON ET AL.
291
hydroxy carbonate 13 (chair-chair conformation) in 85% yield. Reduction of 13 from the periphery of the molecule (20 mol equiv of RedAl, toluene, -78 °C, 6 h, then warm to 25 °C over 6 h) gave a triol which, without isolation, was converted to carbonate 14 (Cl CO, pyridine, CH C1 .> " ° » > 0 · Carbonate 14 could be obtained directlyfromRedAl reduction of 13, but complete reduction followed by regeneration of the cyclic carbonate was operationally easier and more efficient. 18
7 8 t o 2 5
2
2
c
1 h
97
