Scalable enantioselective total synthesis of taxanes

Journal name:
Nature Chemistry
Volume:
4,
Pages:
21–25
Year published:
DOI:
doi:10.1038/nchem.1196
Received
Accepted
Published online

Abstract

Taxanes form a large family of terpenes comprising over 350 members, the most famous of which is Taxol (paclitaxel), a billion-dollar anticancer drug. Here, we describe the first practical and scalable synthetic entry to these natural products via a concise preparation of (+)-taxa-4(5),11(12)-dien-2-one, which has a suitable functional handle with which to access more oxidized members of its family. This route enables a gram-scale preparation of the ‘parent’ taxane—taxadiene—which is the largest quantity of this naturally occurring terpene ever isolated or prepared in pure form. The characteristic 6-8-6 tricyclic system of the taxane family, containing a bridgehead alkene, is forged via a vicinal difunctionalization/Diels–Alder strategy. Asymmetry is introduced by means of an enantioselective conjugate addition that forms an all-carbon quaternary centre, from which all other stereocentres are fixed through substrate control. This study lays a critical foundation for a planned access to minimally oxidized taxane analogues and a scalable laboratory preparation of Taxol itself.

At a glance

Figures

  1. Retrosynthetic analysis of Taxol (1) and other members of the taxane family.
    Figure 1: Retrosynthetic analysis of Taxol (1) and other members of the taxane family.

    a, Partial ‘oxidase phase pyramid’ for the retrosynthetic planning of the taxane family, including its key member, Taxol (1). b, Representative taxanes of varying oxidation states, sharing a C2-hydroxyl group. c, Synthetic design for ‘taxadienone’ (6) and reduction to generate taxadiene (7). Sites of oxidation installed onto taxadiene (7) are indicated in red. The ‘oxidation level’ of taxanes is defined as the number of C=C and C–O bonds installed onto the taxane carbon skeleton33.

  2. Enantioselective synthesis of key taxane 6.
    Figure 2: Enantioselective synthesis of key taxane 6.

    Conditions: a. 2,3-dimethyl-2-butene, CHBr3, potassium tert-butoxide, hexanes, 2 h; evaporate volatile materials, then N,N-dimethylaniline, 150 °C, 30 min (67%); a′. 3-ethoxy-2-cyclohexen-1-one, vinylmagnesium bromide, Et2O, 16 h (75%)45; b. 10, sec-butyllithium, Et2O, –78 °C, 15 min; then CuBr·SMe2, 30 min; then TMSCl, 5 min; then 11, 2 h; warm to room temperature, 8 h; then AcOH, 30 min; then 3 M HCl, 30 min (86%); c. CuTC (2 mol%), phosphoramidite 13 (4 mol%), Et2O, room temperature, 30 min; then 2.0 M Me3Al, enone 12, –30 °C, 24 h; then THF, TMSCl, 0 °C to room temperature, 8 h; then Et3N, Florisil, 2 h (89%, 93% e.e.); d. Gd(OTf)3 (10 mol%), acrolein, 1:10:4 H2O:EtOH:PhMe, 4 °C, 24 h; then evaporate volatiles, then Jones’ reagent, acetone, 10 min (85% over two steps, 2:1 d.r. at C3, inseparable mixture of diastereomers); e. BF3·OEt2, CH2Cl2, 0 °C, 6 h (47% 17 + 29% undesired diketone); f. 0.4 M KHMDS, PhNTf2, THF, 0 °C, 1 h; g. 1.2 M Me2Zn, Pd(PPh3)4 (5 mol %), THF, 0 °C to room temperature, 5 h (84% over two steps). TMSCl, trimethylsilyl chloride; CuTC, copper(I) thiophene-2-carboxylate; PhNTf2, N-phenylbis(trifluoromethanesulfonimide); KHMDS, potassium hexamethyldisilazide; Pd(PPh3)4, tetrakis(triphenylphosphine)palladium.

  3. Elaboration of (+)-taxadienone (6) to (+)-taxadiene (7) by a three-step reduction–deoxygenation sequence.
    Figure 3: Elaboration of (+)-taxadienone (6) to (+)-taxadiene (7) by a three-step reduction–deoxygenation sequence.

    Conditions: a. LiAlH4 (3.0 equiv.), Et2O, –78 °C to room temperature, 12 h (72 %); b. KH (7 equiv.), acetyl chloride (4 equiv.), THF, 60 °C, 18 h (89%); c. Na (18 equiv.), Et2O, HMPA, tBuOH, room temperature, 40 min (82%)48. Sites of oxidation installed onto taxadiene (7) are indicated in red.

  4. Initial synthetic investigations towards the synthesis of taxadienone (6).
    Figure 4: Initial synthetic investigations towards the synthesis of taxadienone (6).

    Disconnection A: an RCM approach would require many more steps in building the taxane framework. Disconnection B: the required aldol closure simply did not proceed. Disconnection C: a Shapiro reaction, followed by aldol and Diels–Alder reactions, is strategically similar to the successful synthetic route, but the stereochemistry at C8 could not be set stereoselectively. Disconnection D: conjugate addition at C8 to install the methyl unit did not proceed, because only the undesired conjugate addition onto C14 occurred.

Compounds

21 compounds View all compounds
  1. Taxol®
    Compound 1 Taxol®
  2. 2-Debenzoyl-4,10-bis(deacetyl)-baccatin III
    Compound 2 2-Debenzoyl-4,10-bis(deacetyl)-baccatin III
  3. (1S,2S,3R,5S,7S,8S,9R,10R,13S)-1,2,5,7,9,10,13-Heptahydroxy-8,12,15,15-tetramethyl-4-methylene-tricyclo[9.3.1.03,8]pentadec-11-ene
    Compound 3 (1S,2S,3R,5S,7S,8S,9R,10R,13S)-1,2,5,7,9,10,13-Heptahydroxy-8,12,15,15-tetramethyl-4-methylene-tricyclo[9.3.1.03,8]pentadec-11-ene
  4. (1R,2R,3R,5S,8R,9R,10R,13S)-2,5,9,10,13-Pentahydroxy-8,12,15,15-tetramethyl-4-methylene-tricyclo[9.3.1.03,8]pentadec-11-ene
    Compound 4 (1R,2R,3R,5S,8R,9R,10R,13S)-2,5,9,10,13-Pentahydroxy-8,12,15,15-tetramethyl-4-methylene-tricyclo[9.3.1.03,8]pentadec-11-ene
  5. (1R,2R,3S,5S,8S,10S,13S)-2,5,10,13-Tetrahydroxy-8,12,15,15-tetramethyl-4-methylene-tricyclo[9.3.1.03,8]pentadec-11-ene
    Compound 5 (1R,2R,3S,5S,8S,10S,13S)-2,5,10,13-Tetrahydroxy-8,12,15,15-tetramethyl-4-methylene-tricyclo[9.3.1.03,8]pentadec-11-ene
  6. (+)-Taxa-4(5),11(12)-dien-2-one
    Compound (+)-6 (+)-Taxa-4(5),11(12)-dien-2-one
  7. (+)-Taxa-4(5),11(12)-diene
    Compound (+)-7 (+)-Taxa-4(5),11(12)-diene
  8. 2,3-Dimethylbut-2-ene
    Compound 8 2,3-Dimethylbut-2-ene
  9. 3-Ethoxycyclohex-2-enone
    Compound 9 3-Ethoxycyclohex-2-enone
  10. 3-Bromo-2,4-dimethylpenta-1,3-diene
    Compound 10 3-Bromo-2,4-dimethylpenta-1,3-diene
  11. 3-Vinylcyclohex-2-enone
    Compound 11 3-Vinylcyclohex-2-enone
  12. 3-[4-Methyl-3-(prop-1-en-2-yl)pent-3-en-1-yl]cyclohex-2-enone
    Compound 12 3-[4-Methyl-3-(prop-1-en-2-yl)pent-3-en-1-yl]cyclohex-2-enone
  13. 2,4,8,10-Tetramethyl-N,N-bis[(S)-1-phenylethyl]dibenzo[d,f][1,3,2]dioxaphosphepin-6-amine
    Compound (–)-13 2,4,8,10-Tetramethyl-N,N-bis[(S)-1-phenylethyl]dibenzo[d,f][1,3,2]dioxaphosphepin-6-amine
  14. (S)-Trimethyl{{3-methyl-3-[4-methyl-3-(prop-1-en-2-yl)pent-3-en-1-yl]cyclohex-1-en-1-yl}oxy}silane
    Compound (–)-14 (S)-Trimethyl{{3-methyl-3-[4-methyl-3-(prop-1-en-2-yl)pent-3-en-1-yl]cyclohex-1-en-1-yl}oxy}silane
  15. (S)-3-Methyl-3-[4-methyl-3-(prop-1-en-2-yl)pent-3-en-1-yl]cyclohexanone
    Compound (+)-15 (S)-3-Methyl-3-[4-methyl-3-(prop-1-en-2-yl)pent-3-en-1-yl]cyclohexanone
  16. (2S,3S)-2-Acryloyl-3-methyl-3-[4-methyl-3-(prop-1-en-2-yl)pent-3-en-1-yl]cyclohexanone
    Compound 16 (2S,3S)-2-Acryloyl-3-methyl-3-[4-methyl-3-(prop-1-en-2-yl)pent-3-en-1-yl]cyclohexanone
  17. (1R,3S,8S)-8,12,15,15-Tetramethyl-tricyclo[9.3.1.03,8]pentadec-11-en-2,4-dione
    Compound (+)-17 (1R,3S,8S)-8,12,15,15-Tetramethyl-tricyclo[9.3.1.03,8]pentadec-11-en-2,4-dione
  18. (2S,3S)-3-Methyl-2-[(R)-2,2,4-trimethyl-3-vinylcyclohex-3-enecarbonyl]-3-vinylcyclohexanone
    Compound 18 (2S,3S)-3-Methyl-2-[(R)-2,2,4-trimethyl-3-vinylcyclohex-3-enecarbonyl]-3-vinylcyclohexanone
  19. 2,2,4-Trimethyl-3-{2-[(S)-1-methyl-3-oxocyclohexyl]ethyl}cyclohex-3-enecarbaldehyde
    Compound 19 2,2,4-Trimethyl-3-{2-[(S)-1-methyl-3-oxocyclohexyl]ethyl}cyclohex-3-enecarbaldehyde
  20. (2S)-2,6-Dimethyl-2-[4-methyl-3-(prop-1-en-2-yl)pent-3-en-1-yl]cyclohexanone
    Compound 20 (2S)-2,6-Dimethyl-2-[4-methyl-3-(prop-1-en-2-yl)pent-3-en-1-yl]cyclohexanone
  21. 1-{2-[4-Methyl-3-(prop-1-en-2-yl)pent-3-en-1-yl]-6-methylenecyclohex-1-en-1-yl}prop-2-en-1-one
    Compound 21 1-{2-[4-Methyl-3-(prop-1-en-2-yl)pent-3-en-1-yl]-6-methylenecyclohex-1-en-1-yl}prop-2-en-1-one

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Author information

  1. These authors contributed equally to this manuscript

    • Abraham Mendoza &
    • Yoshihiro Ishihara

Affiliations

  1. Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California, 92037, USA

    • Abraham Mendoza,
    • Yoshihiro Ishihara &
    • Phil S. Baran

Contributions

A.M., Y.I. and P.S.B. conceived the synthetic route, conducted the experimental work, analysed the results and wrote the manuscript.

Competing financial interests

The authors declare no competing financial interests.

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    Supplementary information, NMR spectra

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    Crystallographic data for compound (+)-6

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    Crystallographic data for compound S2

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