Letter | Published:

The total synthesis of (-)-cyanthiwigin F by means of double catalytic enantioselective alkylation

Nature volume 453, pages 12281231 (26 June 2008) | Download Citation

Abstract

Double catalytic enantioselective transformations are powerful synthetic methods that can facilitate the construction of stereochemically complex molecules in a single operation1,2. In addition to generating two or more stereocentres in a single reaction, multiple asymmetric reactions also impart increased enantiomeric excess to the final product in comparison with the analogous single transformation3,4,5,6. Furthermore, multiple asymmetric operations have the potential to independently construct several stereocentres at remote points within the same molecular scaffold, rather than relying on pre-existing chiral centres that are proximal to the reactive site1. Despite the inherent benefits of multiple catalytic enantioselective reactions, their application to natural product total synthesis remains largely underutilized2. Here we report the use of a double stereoablative7 enantioselective alkylation reaction in a concise synthesis of the marine diterpenoid (-)-cyanthiwigin F (ref. 8). By employing a technique for independent, selective formation of two stereocentres in a single stereoconvergent operation, we demonstrate that a complicated mixture of racemic and meso diastereomers may be smoothly converted to a synthetically useful intermediate with exceptional enantiomeric excess. The stereochemical information generated by means of this catalytic transformation facilitates the easy and rapid completion of the total synthesis of this marine natural product.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , , & Double asymmetric synthesis and a new strategy for stereocontrol in organic synthesis. Angew. Chem. Int. Edn Engl. 24, 1–30 (1985)

  2. 2.

    Multiple stereoselectivity and its applications in organic synthesis. Tetrahedron 59, 5953–6018 (2003)

  3. 3.

    & Zur Theorie der Erhaltung und Entstehung optischer Aktivität in der Natur. Z. Phys. Chem. A 117, 401–409 (1936)

  4. 4.

    , & Nouvelle méthode pour porter au maximum la pureté optique d’un produit partiellement dédoublé sans l’aide d’aucune substance chirale. Tetrahedron 29, 1055–1059 (1973)

  5. 5.

    The two expressions of the Horeau principle, nth-order Horeau amplifications, and scales for the resulting very high enantiopurities. Bull. Soc. Chim. Fr. 131, 515–524 (1994)

  6. 6.

    , , & Tandem asymmetric syntheses from achiral precursors – asymmetric homogeneous reduction of bisdehydrodipeptides. Bull. Soc. Chim. Fr. 131, 525–533 (1994)

  7. 7.

    , & Catalytic enantioselective stereoablative reactions: an unexploited approach to enantioselective catalysis. Org. Biomol. Chem. 5, 3571–3576 (2007)

  8. 8.

    et al. The new bioactive diterpenes cyanthiwigin E-AA from the Jamaican sponge Myrmekioderma styx. Tetrahedron 58, 7809–7819 (2002)

  9. 9.

    , & Diterpene metabolites from two chemotypes of the marine sponge Myrmekioderma styx. J. Nat. Prod. 55, 1421–1429 (1992)

  10. 10.

    , & Cyanthiwigin AC and AD, two novel diterpene skeletons from the Jamaican sponge Myrmekioderma styx. Org. Lett. 5, 4575–4578 (2003)

  11. 11.

    et al. Erinacine E as a kappa opioid receptor agonist and its new analogs from a basidiomycete, Hericium ramosum. J. Antibiot. (Tokyo) 51, 983–990 (1998)

  12. 12.

    , & Enantioselective catalytic formation of quaternary stereogenic centers. Eur. J. Org. Chem. 2007, 5969–5994 (2007)

  13. 13.

    & Catalytic enantioselective construction of all-carbon quaternary stereocenters. Synthesis 369–396 (2006)

  14. 14.

    & Total synthesis of (+)-cyanthiwigin U. J. Am. Chem. Soc. 127, 5334–5335 (2005)

  15. 15.

    , & Total synthesis of (+)-cyanthiwigin AC. Org. Lett. 8, 5585–5588 (2006)

  16. 16.

    & Two-directional chain synthesis and terminus differentiation. Acc. Chem. Res. 27, 9–17 (1994)

  17. 17.

    & The enantioselective Tsuji allylation. J. Am. Chem. Soc. 126, 15044–15045 (2004)

  18. 18.

    , , & Deracemization of quaternary stereocenters by Pd-catalyzed enantioconvergent decarboxylative allylation of racemic β-ketoesters. Angew. Chem. Int. Edn Engl. 44, 6924–6927 (2005)

  19. 19.

    & Protective Groups in Organic Synthesis. (Wiley, New York, 1999)

  20. 20.

    A synthesis of tropinone. J. Chem. Soc. 111, 762–768 (1917)

  21. 21.

    Protecting-group-free synthesis. Synthesis 3531–3541 (2006)

  22. 22.

    & The catalytic enantioselective, protecting group-free total synthesis of (+)-dichroanone. J. Am. Chem. Soc. 128, 7738–7739 (2006)

  23. 23.

    , & Total synthesis of marine natural products without using protecting groups. Nature 446, 404–408 (2007)

  24. 24.

    Zur Constitution des Succinylobernsteinsäureäthers. Liebigs Ann. Chem. 229, 45–88 (1885)

  25. 25.

    Various aspects of the reaction of a chiral catalyst or reagent with a racemic or enantiopure substrate. Tetrahedron 57, 2449–2468 (2001)

  26. 26.

    & Stereochemistry of Organic Compounds 965–971 (Wiley, New York, 1994)

  27. 27.

    & Phosphinooxazolines-a new class of versatile, modular P,N-ligands for asymmetric catalysis. Acc. Chem. Res. 33, 336–345 (2000)

  28. 28.

    , & First total synthesis of (±)-stachyflin. Tetrahedr. Lett. 39, 4347–4350 (1998)

  29. 29.

    et al. Highly efficient ruthenium catalysts for the formation of tetrasubstituted olefins via ring-closing metathesis. Org. Lett. 9, 1589–1592 (2007)

  30. 30.

    , , , & Thiol-catalyzed acyl radical cyclization of alkenals. J. Org. Chem. 70, 681–683 (2005)

Download references

Acknowledgements

The authors wish to thank NIH-NIGMS (R01GM080269-01), Amgen, Abbott, Boehringer Ingelheim, Merck and Bristol-Myers Squibb for financial support. We also wish to thank M. W. Day and L. M. Henling for X-ray crystallographic expertise, S. Virgil, A. Harned, D. White, D. Caspi and J. T. Mohr for helpful discussions, and M. T. Hamann for an authentic sample and spectra of cyanthiwigin F. We thank E. J. Corey for guidance and mentorship, on the occasion of his 80th birthday.

Author information

Affiliations

  1. The Arnold and Mabel Beckman Laboratories of Chemical Synthesis, Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Boulevard, MC164-30, Pasadena, California 91125, USA

    • John A. Enquist Jr
    •  & Brian M. Stoltz

Authors

  1. Search for John A. Enquist Jr in:

  2. Search for Brian M. Stoltz in:

Corresponding author

Correspondence to Brian M. Stoltz.

Crystallographic data have been deposited at the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK, and copies can be obtained on request, free of charge, by quoting the publication citation and the deposition number 664430.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    The file contains Supplementary Methods, Supplementary Tables 1 – 7, Supplementary Figures 1 – 5, and Supplementary Notes. This file contains detailed data on experimental procedures, characterization of new chemical compounds, X-ray crystal structure, and comparisons between synthetic and natural samples of cyanthiwigin F.

Zip files

  1. 1.

    Supplementary Zip file

    This folder contains Crystal Structure CIF File. This file is a properly formatted representation of the crystal structure data reported in the Supplementary Information.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature07046

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.