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Nature Chemistry | Article

An efficient synthesis of loline alkaloids

Journal name:
Nature Chemistry
Volume:
3,
Pages:
543–545
Year published:
DOI:
doi:10.1038/nchem.1072
Received
Accepted
Published online

Abstract

Loline (1) is a small alkaloid that, in spite of its simple-looking structure, has posed surprising challenges to synthetic chemists. It has been known for more than a century and has been the subject of extensive biological investigations, but only two total syntheses have been achieved to date. Here, we report an asymmetric total synthesis of loline that, with less then ten steps, is remarkably short. Our synthesis incorporates a Sharpless epoxidation, a Grubbs olefin metathesis and an unprecedented transannular aminobromination, which converts an eight-membered cyclic carbamate into a bromopyrrolizidine. The synthesis is marked by a high degree of chemo- and stereoselectivity and gives access to several members of the loline alkaloid family. It delivers sufficient material to support a programme aimed at studying the complex interactions between plants, fungi, insects and bacteria brokered by loline alkaloids.

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  1. Loline alkaloids.
    Figure 1: Loline alkaloids.

    Members of the loline family of alkaloids have a common heterotricyclic core and are distinguished by the substitution pattern at the nitrogen in position 1.

  2. Short total synthesis of loline alkaloids.
    Figure 2: Short total synthesis of loline alkaloids.

    a, Synthesis starts with an achiral alcohol 7 that can be easily desymmetrized to give epoxide 8 and then diene 10. A ring-closing metathesis converts this compound into the eight-membered heterocycle 11, which is further processed to yield azidoalcohol 13. In the key step, this compound is transformed into the bicyclic pyrrolizidine 14. Establishment of the oxygen bridge then yields an azide (16), a branching point of the synthesis. b, Azide 16 can be converted to temuline 2 by reduction of the azide. Alternatively, reduction of the azide in the presence of di-tert-butyldicarbonate gives the N-Boc protected compound, which can be further transformed into N-methyl compound loline 1 and N-formyl loline 4. c, X-ray crystal structure of the key intermediate pyrrolizidine 14. AFA, acetic formic anhydride.

  3. Mechanism of the key step.
    Figure 3: Mechanism of the key step.

    a, Electrophilic activation of 13 with bromine affords bromonium ion 18, which presumably undergoes transannular attack of the carbamate nitrogen to yield N-acylammonium ion 19. Subsequent cleavage by methanol affords a carbonate by-product (21) and the pyrrolizidine core of the loline alkaloids (14). b, X-ray crystal structure of 20, a sulfonate ester of 13, which shows that the nitrogen is essentially in van der Waals contact with the carbon with which it eventually forms a bond.

  4. Synthesis and X-ray structure of temuline carbamate.
    Figure 4: Synthesis and X-ray structure of temuline carbamate.

    Exposure of temuline to CO2 yields a zwitterionic carbamate. Also shown is the X-ray crystal structure, a rare example of a solid-state structure bearing a free carbamate.

Compounds

22 compounds View all compounds
  1. (1S,6R,7R,7aS)-N-Methylhexahydro-1H-1,6-epoxypyrrolizin-7-amine
    Compound 1 (1S,6R,7R,7aS)-N-Methylhexahydro-1H-1,6-epoxypyrrolizin-7-amine
    View:
  2. (1S,6R,7R,7aS)-Hexahydro-1H-1,6-epoxypyrrolizin-7-amine
    Compound 2 (1S,6R,7R,7aS)-Hexahydro-1H-1,6-epoxypyrrolizin-7-amine
    View:
  3. (1S,6R,7R,7aS)-N,N-Dimethylhexahydro-1H-1,6-epoxypyrrolizin-7-amine
    Compound 3 (1S,6R,7R,7aS)-N,N-Dimethylhexahydro-1H-1,6-epoxypyrrolizin-7-amine
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  4. N-((1S,6R,7R,7aS)-Hexahydro-1H-1,6-epoxypyrrolizin-7-yl)-N-methylformamide
    Compound 4 N-((1S,6R,7R,7aS)-Hexahydro-1H-1,6-epoxypyrrolizin-7-yl)-N-methylformamide
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  5. N-((1S,6R,7R,7aS)-Hexahydro-1H-1,6-epoxypyrrolizin-7-yl)-3-methylbut-2-enamide
    Compound 5 N-((1S,6R,7R,7aS)-Hexahydro-1H-1,6-epoxypyrrolizin-7-yl)-3-methylbut-2-enamide
    View:
  6. (1R,2R,7R,7aS)-1-Acetamido-7-chlorohexahydro-1H-pyrrolizin-2-yl ((1S,6R,7R,7aS)-hexahydro-1H-1,6-epoxypyrrolizin-7-yl)(methyl)carbamate
    Compound 6 (1R,2R,7R,7aS)-1-Acetamido-7-chlorohexahydro-1H-pyrrolizin-2-yl ((1S,6R,7R,7aS)-hexahydro-1H-1,6-epoxypyrrolizin-7-yl)(methyl)carbamate
    View:
  7. Penta-1,4-dien-3-ol
    Compound 7 Penta-1,4-dien-3-ol
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  8. (S)-1-((R)-Oxiran-2-yl)prop-2-en-1-ol
    Compound 8 (S)-1-((R)-Oxiran-2-yl)prop-2-en-1-ol
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  9. But-3-en-1-amine hydrochloride
    Compound 9 But-3-en-1-amine hydrochloride
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  10. Benzyl but-3-en-1-yl((2R,3S)-2,3-dihydroxypent-4-en-1-yl)carbamate
    Compound 10 Benzyl but-3-en-1-yl((2R,3S)-2,3-dihydroxypent-4-en-1-yl)carbamate
    View:
  11. (3R,4S,Z)-Benzyl 3,4-dihydroxy-3,4,7,8-tetrahydroazocine-1(2H)-carboxylate
    Compound 11 (3R,4S,Z)-Benzyl 3,4-dihydroxy-3,4,7,8-tetrahydroazocine-1(2H)-carboxylate
    View:
  12. (3aR,9aS,Z)-Benzyl 3a,4,6,7-tetrahydro-[1,3,2]dioxathiolo[4,5-c]azocine-5(9aH)-carboxylate 2-oxide
    Compound 12 (3aR,9aS,Z)-Benzyl 3a,4,6,7-tetrahydro-[1,3,2]dioxathiolo[4,5-c]azocine-5(9aH)-carboxylate 2-oxide
    View:
  13. (3R,4R,Z)-Benzyl 4-azido-3-hydroxy-3,4,7,8-tetrahydroazocine-1(2H)-carboxylate
    Compound 13 (3R,4R,Z)-Benzyl 4-azido-3-hydroxy-3,4,7,8-tetrahydroazocine-1(2H)-carboxylate
    View:
  14. (1R,2R,7S,7aS)-1-Azido-7-bromohexahydro-1H-pyrrolizin-2-ol hydrobromide
    Compound 14 (1R,2R,7S,7aS)-1-Azido-7-bromohexahydro-1H-pyrrolizin-2-ol hydrobromide
    View:
  15. (1R,2R,7R,7aS)-1-Azido-7-chlorohexahydro-1H-pyrrolizin-2-ol
    Compound 15 (1R,2R,7R,7aS)-1-Azido-7-chlorohexahydro-1H-pyrrolizin-2-ol
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  16. (1S,6R,7R,7aS)-7-Azidohexahydro-1H-1,6-epoxypyrrolizine
    Compound 16 (1S,6R,7R,7aS)-7-Azidohexahydro-1H-1,6-epoxypyrrolizine
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  17. tert-Butyl ((1S,6R,7R,7aS)-hexahydro-1H-1,6-epoxypyrrolizin-7-yl)carbamate
    Compound 17 tert-Butyl ((1S,6R,7R,7aS)-hexahydro-1H-1,6-epoxypyrrolizin-7-yl)carbamate
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  18. (1R,6R,7S,8S)-7-Azido-4-((benzyloxy)carbonyl)-6-hydroxy-9-boranylia-4-azabicyclo[6.1.0]nonan-9-ium bromide
    Compound 18 (1R,6R,7S,8S)-7-Azido-4-((benzyloxy)carbonyl)-6-hydroxy-9-boranylia-4-azabicyclo[6.1.0]nonan-9-ium bromide
    View:
  19. (1R,2R,4R,7S,7aS)-1-Azido-4-((benzyloxy)carbonyl)-7-bromo-2-hydroxyoctahydropyrrolizin-4-ium bromide
    Compound 19 (1R,2R,4R,7S,7aS)-1-Azido-4-((benzyloxy)carbonyl)-7-bromo-2-hydroxyoctahydropyrrolizin-4-ium bromide
    View:
  20. (3R,4R,Z)-Benzyl 4-azido-3-((methylsulfonyl)oxy)-3,4,7,8-tetrahydroazocine-1(2H)-carboxylate
    Compound 20 (3R,4R,Z)-Benzyl 4-azido-3-((methylsulfonyl)oxy)-3,4,7,8-tetrahydroazocine-1(2H)-carboxylate
    View:
  21. Benzyl methyl carbonate
    Compound 21 Benzyl methyl carbonate
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  22. (Octahydro-1,6-epoxypyrrolizin-4-ium-7-yl)carbamate
    Compound 22 (Octahydro-1,6-epoxypyrrolizin-4-ium-7-yl)carbamate
    View:

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Author information

Affiliations

  1. Department of Chemistry and Pharmacology, Ludwig-Maximilians-Universität, München, and Center for Integrated Protein Science, 81377 Munich, Germany

    • Mesut Cakmak,
    • Peter Mayer &
    • Dirk Trauner

Contributions

M.C. and D.T. conceived the synthetic route and wrote the manuscript. M.C. conducted the experimental work, analysed the results and wrote the Supplementary Information. P.M. solved the crystal structures.

Competing financial interests

The authors declare no competing financial interests.

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Supplementary information

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    Supplementary information

Crystallographic information files

  1. Supplementary information (16 KB)

    Crystallographic data for compound 14

  2. Supplementary information (20 KB)

    Crystallographic data for compound 20

  3. Supplementary information (16 KB)

    Crystallographic data for compound 22

Additional data