Terpene cyclization catalysed inside a self-assembled cavity

Journal name:
Nature Chemistry
Volume:
7,
Pages:
197–202
Year published:
DOI:
doi:10.1038/nchem.2181
Received
Accepted
Published online

Abstract

In nature, complex terpene natural products are formed by the so-called tail-to-head terpene (THT) cyclization. The cationic reaction cascade is promoted efficiently in complex enzyme pockets, in which cationic intermediates and transition states are stabilized. In solution, the reaction is hard to control and man-made catalysts able to perform selective THT cyclizations are lacking. We herein report the first example of a successful THT cyclization inside a supramolecular structure. The basic mode of operation in cyclase enzymes was mimicked successfully and a catalytic non-stop THT was achieved with ​geranyl acetate as the substrate. The results presented have implications for the postulated reaction mechanism in cyclase enzymes. Evidence indicates that the direct isomerization of a geranyl cation to the cisoid isomer, which so far was considered unlikely, is feasible.

At a glance

Figures

  1. Biosynthesis of cyclic terpene natural products.
    Figure 1: Biosynthesis of cyclic terpene natural products.

    a, Structures of the natural terpene substrates. These are converted into cyclic monoterpenes (​geranyl-PP), sesquiterpenes (​farnesyl-PP) and diterpenes (​geranylgeranyl-PP). b, Reaction pathways for the biosynthesis of a selection of monoterpene natural products via THT cyclization. Cleavage of the PP-leaving group forms the transoid cation 4a, which has to isomerize to the cisoid form 4b before cyclization can occur. A direct isomerization is considered unlikely in the literature and therefore a step-wise isomerization that involves reattachment of the pyrophosphate group was proposed. After cyclization to the ​α-terpinyl cation (6), a variety of different reaction paths are available. An attack of water forms ​α-terpineol (7), which can further cyclize to ​eucalyptol (8). Alternatively, elimination delivers ​terpinolene (9) or ​limonene (10). Rearrangements can also occur. A hydride shift, for instance, delivers cation 11, which yields ​α-terpinene (12) after elimination.

  2. Structure of the resorcinarene capsule I.
    Figure 2: Structure of the resorcinarene capsule I.

    This self-assembles via a hydrogen-bond network from six monomer units of 13 and eight water molecules in apolar solvents and encloses a volume of ~1,400 Å3. Cationic guests, such as alkylammonium ions, are bound inside the cavity via cation–π interactions. Guest exchange is facile and probably occurs via dissociation of one monomer unit. Capsule I is a mild Brønsted acid (pKa ~5.5–6).

  3. Results of the THT cyclizations with catalyst I for the alcohol substrates.
    Figure 3: Results of the THT cyclizations with catalyst I for the alcohol substrates.

    Products were identified by gas chromatography and 1H NMR spectroscopy and quantified by gas chromatography. a, The cyclization of ​GOH (14) is rather unselective. Initially, in analogy to the proposed biosynthesis, ​LOH (15) was formed. The other main products formed within the first ten hours were ​α-terpinene (12) and ​α-terpineol (7). With progressing reaction time, the concentrations of ​LOH (15) and ​α-terpineol (7) decreased as ​eucalyptol (8) started to form. b, ​NOH (16) is first cyclized mainly to ​α-terpineol (7), which is then converted into ​eucalyptol (8). c, The reaction profile of ​LOH (15) appears to be a composite of the results from ​GOH (14) and ​NOH (16), and gives a less-pronounced initial maximum of ​α-terpineol (7) and a better selectivity of ​α-terpinene (12) over ​terpinolene (9) than in the case of ​NOH (16). Error bars indicate typical maximal errors (±5%) as evidenced by the experiment, which was run in triplicate (Fig. 4a).

  4. Results of the THT cyclizations with catalyst I for the acetate substrates.
    Figure 4: Results of the THT cyclizations with catalyst I for the acetate substrates.

    a, The cyclization of ​GOAc (14a) led to ​α-terpinene (12) in good selectivity. It represents a ‘non-stop’ THT cyclization because the cationic intermediates were not quenched by nucleophiles or elimination—as evidenced by the disappearance of ​LOH and ​α-terpineol derivatives. b, ​NOAc (16a) cyclized mainly to ​α-terpinene (12) and ​terpinolene (9), with the latter dominating in the first 36 hours. c, The product profile of ​LOAc (15a) appears to be a composite of the results from ​GOAc (14a) and ​NOAc (16a). Initially, ​GOAc was formed, which could indicate an equilibration to the thermodynamically more stable isomer. d, The extended geranyl substrate 19 used for the control experiments. e,f, Fluoro derivatives explored in the cyclization. 2-Fluorogeranyl acetate (F-14a) did not undergo cyclization within I (e). 2-Fluoroneryl acetate (F-16a) produced fluoroterpinolene (F-9) and fluorolimonene (F-10) as the only main products (f), which indicates that these products are formed predominantly via a concerted (SN2) mechanism, whereas ​α-terpinene (12) is formed predominantly via an SN1-mechanism within I. Error bars in a represent the standard deviation from the mean value (the experiment was run in triplicate). Error bars in b and c indicate typical maximal errors (±5%), as evidenced by the results in a.

Compounds

29 compounds View all compounds
  1. Geranyl pyrophosphate
    Compound 1 Geranyl pyrophosphate
  2. Farnesyl pyrophosphate
    Compound 2 Farnesyl pyrophosphate
  3. Geranylgeranyl pyrophosphate
    Compound 3 Geranylgeranyl pyrophosphate
  4. transoid 3,7-dimethylocta-1,6-dien-3-ylium
    Compound 4a transoid 3,7-dimethylocta-1,6-dien-3-ylium
  5. cisoid 3,7-dimethylocta-1,6-dien-3-ylium
    Compound 4b cisoid 3,7-dimethylocta-1,6-dien-3-ylium
  6. transoid 3,7-dimethylocta-1,6-dien-3-yl diphosphate
    Compound 5a transoid 3,7-dimethylocta-1,6-dien-3-yl diphosphate
  7. cisoid 3,7-dimethylocta-1,6-dien-3-yl diphosphate
    Compound 5b cisoid 3,7-dimethylocta-1,6-dien-3-yl diphosphate
  8. 2-(4-Methylcyclohex-3-en-1-yl)propan-2-ylium
    Compound 6 2-(4-Methylcyclohex-3-en-1-yl)propan-2-ylium
  9. α-Terpineol
    Compound 7 α-Terpineol
  10. α-Terpinyl acetate
    Compound 7a α-Terpinyl acetate
  11. Eucalyptol
    Compound 8 Eucalyptol
  12. Terpinolene
    Compound 9 Terpinolene
  13. Limonene
    Compound 10 Limonene
  14. 1-Isopropyl-4-methylcyclohex-3-en-1-ylium
    Compound 11 1-Isopropyl-4-methylcyclohex-3-en-1-ylium
  15. α-Terpinene
    Compound 12 α-Terpinene
  16. 2,8,14,20-Tetra(n-undecyl)resorcin[4]arene
    Compound 13 2,8,14,20-Tetra(n-undecyl)resorcin[4]arene
  17. Geraniol
    Compound 14 Geraniol
  18. Geranyl acetate
    Compound 14a Geranyl acetate
  19. Linalool
    Compound 15 Linalool
  20. Linalyl acetate
    Compound 15a Linalyl acetate
  21. Nerol
    Compound 16 Nerol
  22. Neryl acetate
    Compound 16a Neryl acetate
  23. γ-Terpinene
    Compound 17 γ-Terpinene
  24. Isoterpinolene
    Compound 18 Isoterpinolene
  25. (2E,6Z)-3,7-Dimethyloctadeca-2,6-dien-1-yl acetate
    Compound 19 (2E,6Z)-3,7-Dimethyloctadeca-2,6-dien-1-yl acetate
  26. 2-Fluoro-1-methyl-4-(propan-2-ylidene)cyclohex-1-ene
    Compound F-9 2-Fluoro-1-methyl-4-(propan-2-ylidene)cyclohex-1-ene
  27. 2-Fluoro-1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene
    Compound F-10 2-Fluoro-1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene
  28. (Z)-2-Fluoro-3,7-dimethylocta-2,6-dien-1-yl acetate
    Compound F-14a (Z)-2-Fluoro-3,7-dimethylocta-2,6-dien-1-yl acetate
  29. (E)-2-Fluoro-3,7-dimethylocta-2,6-dien-1-yl acetate
    Compound F-16a (E)-2-Fluoro-3,7-dimethylocta-2,6-dien-1-yl acetate

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Affiliations

  1. Department Chemie, Technische Universität München, Lichtenbergstraße 4, D-85747 Garching, Germany

    • Q. Zhang &
    • K. Tiefenbacher

Contributions

K.T. conceived the project and wrote the manuscript with Q.Z. Q.Z. planned and carried out the experiments. K.T. and Q.Z. discussed the experiments and results.

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The authors declare no competing financial interests.

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