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


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.

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Figure 1
Figure 2: Synthesis of diketone 6.
Figure 3: Synthesis of cyanthiwigin F.


  1. Masamune, S., Choy, W., Petersen, J. & Sita, L. Double asymmetric synthesis and a new strategy for stereocontrol in organic synthesis. Angew. Chem. Int. Edn Engl. 24, 1–30 (1985)

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Google Scholar 

  4. Vigneron, J. P., Dhaenens, M. & Horeau, A. 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)

    Article  CAS  Google Scholar 

  5. Rautenstrauch, V. 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)

    CAS  Google Scholar 

  6. Baba, S. E., Sartor, K., Poulin, J. & Kagan, H. Tandem asymmetric syntheses from achiral precursors – asymmetric homogeneous reduction of bisdehydrodipeptides. Bull. Soc. Chim. Fr. 131, 525–533 (1994)

    Google Scholar 

  7. Mohr, J. T., Ebner, D. C. & Stoltz, B. M. Catalytic enantioselective stereoablative reactions: an unexploited approach to enantioselective catalysis. Org. Biomol. Chem. 5, 3571–3576 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  9. Sennett, S. H., Pomponi, S. A. & Wright, A. E. Diterpene metabolites from two chemotypes of the marine sponge Myrmekioderma styx . J. Nat. Prod. 55, 1421–1429 (1992)

    Article  CAS  PubMed  Google Scholar 

  10. Peng, J., Avery, M. A. & Hamann, M. T. Cyanthiwigin AC and AD, two novel diterpene skeletons from the Jamaican sponge Myrmekioderma styx . Org. Lett. 5, 4575–4578 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Saito, T. 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)

    Article  CAS  Google Scholar 

  12. Cozzi, P. G., Hlgraf, R. & Zimmermann, N. Enantioselective catalytic formation of quaternary stereogenic centers. Eur. J. Org. Chem. 2007, 5969–5994 (2007)

    Article  Google Scholar 

  13. Trost, B. M. & Jiang, C. Catalytic enantioselective construction of all-carbon quaternary stereocenters. Synthesis 369–396 (2006)

  14. Pfeiffer, M. W. B. & Phillips, A. J. Total synthesis of (+)-cyanthiwigin U. J. Am. Chem. Soc. 127, 5334–5335 (2005)

    Article  CAS  PubMed  Google Scholar 

  15. Reddy, J. T., Bordeau, G. & Trimble, L. Total synthesis of (+)-cyanthiwigin AC. Org. Lett. 8, 5585–5588 (2006)

    Article  CAS  PubMed  Google Scholar 

  16. Poss, C. S. & Schreiber, S. L. Two-directional chain synthesis and terminus differentiation. Acc. Chem. Res. 27, 9–17 (1994)

    Article  CAS  Google Scholar 

  17. Behenna, D. C. & Stoltz, B. M. The enantioselective Tsuji allylation. J. Am. Chem. Soc. 126, 15044–15045 (2004)

    Article  CAS  PubMed  Google Scholar 

  18. Mohr, J. T., Behenna, D. C., Harned, A. M. & Stoltz, B. M. Deracemization of quaternary stereocenters by Pd-catalyzed enantioconvergent decarboxylative allylation of racemic β-ketoesters. Angew. Chem. Int. Edn Engl. 44, 6924–6927 (2005)

    Article  CAS  Google Scholar 

  19. Greene, T. & Wuts, P. Protective Groups in Organic Synthesis. (Wiley, New York, 1999)

    Book  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. Hoffmann, R. W. Protecting-group-free synthesis. Synthesis 3531–3541 (2006)

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  23. Baran, P. S., Maimone, T. J. & Richter, J. M. Total synthesis of marine natural products without using protecting groups. Nature 446, 404–408 (2007)

    Article  ADS  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  26. Eliel, E. L. & Wilen, S. H. Stereochemistry of Organic Compounds 965–971 (Wiley, New York, 1994)

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  28. Taishi, T., Takechi, S. & Mori, S. First total synthesis of (±)-stachyflin. Tetrahedr. Lett. 39, 4347–4350 (1998)

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  30. Yoshikai, K., Hayama, T., Nishimura, K., Yamada, K. & Tomioka, K. Thiol-catalyzed acyl radical cyclization of alkenals. J. Org. Chem. 70, 681–683 (2005)

    Article  CAS  PubMed  Google Scholar 

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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.

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Correspondence to Brian M. Stoltz.

Additional information

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

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. (PDF 1503 kb)

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. (ZIP 5 kb)

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Enquist Jr, J., Stoltz, B. The total synthesis of (-)-cyanthiwigin F by means of double catalytic enantioselective alkylation. Nature 453, 1228–1231 (2008).

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