Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Biogenetically inspired synthesis and skeletal diversification of indole alkaloids

Nature Chemistry volume 6, pages 57–64 (2014)Cite this article

Subjects

Abstract

To access architecturally complex natural products, chemists usually devise a customized synthetic strategy for constructing a single target skeleton. In contrast, biosynthetic assembly lines often employ divergent intramolecular cyclizations of a polyunsaturated common intermediate to produce diverse arrays of scaffolds. With the aim of integrating such biogenetic strategies, we show the development of an artificial divergent assembly line generating unprecedented numbers of scaffold variations of terpenoid indole alkaloids. This approach not only allows practical access to multipotent intermediates, but also enables systematic diversification of skeletal, stereochemical and functional group properties without structural simplification of naturally occurring alkaloids. Three distinct modes of [4+2] cyclizations and two types of redox-mediated annulations provided divergent access to five skeletally distinct scaffolds involving iboga-, aspidosperma-, andranginine- and ngouniensine-type skeletons and a non-natural variant within six to nine steps from tryptamine. The efficiency of our approach was demonstrated by successful total syntheses of (±)-vincadifformine, (±)-andranginine and (−)-catharanthine.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Proposed biogenesis of indole alkaloids 5–7 and structure of ngouniensine 8.
Figure 2: Outline of a biogenetically inspired synthetic process to furnish alkaloidal scaffolds.
Figure 3: Unified synthetic process for divergent access to 23, 25 and 27 through distinct [4+2] cyclization reactions.
Figure 4: Redox-mediated activation of the DHP–diene 14a leading to tetracyclic 28 and 29, which contain a DHP ring.
Figure 5: Total synthesis of three natural products.

Similar content being viewed by others

References

  1. Ganesan, A. The impact of natural products upon modern drug discovery. Curr. Opin. Chem. Biol. 12, 306–317 (2008).

    Article  CAS  Google Scholar 

  2. Nielsen, T. E. & Schreiber, S. L. Towards the optimal screening collection. A synthesis strategy. Angew. Chem. Int. Ed. 47, 48–56 (2008).

    Article  CAS  Google Scholar 

  3. Lachance, H., Wetzel, S., Kumar, K. & Waldmann, H. Charting, navigating, and populating natural product chemical space for drug discovery. J. Med. Chem. 55, 5989–6001 (2012).

    Article  CAS  Google Scholar 

  4. Young, I. S. & Baran, P. S. Protecting-group-free synthesis as an opportunity for invention. Nature Chem. 1, 193–205 (2009).

    Article  CAS  Google Scholar 

  5. Jones, S. B., Simmons, B., Mastracchio, A. & MacMillan, D. W. C. Collective synthesis of natural products by means of organocascade catalysis. Nature 475, 183–188 (2011).

    Article  CAS  Google Scholar 

  6. Snyder, S. A., Gollner, A. & Chiriac, M. I. Regioselective reactions for programmable resveratrol oligomer synthesis. Nature 474, 461–465 (2011).

    Article  CAS  Google Scholar 

  7. Oguri, H. et al. Generation of anti-trypanosomal agents through concise synthesis and structural diversification of sesquiterpene analogs. J. Am. Chem. Soc. 133, 7096–7105 (2011).

    Article  CAS  Google Scholar 

  8. Balthaser, B. R., Maloney, M. C., Beeler, A. B., Porco, J. A. & Snyder, J. K. Remodelling of the natural product fumagillol employing a reaction discovery approach. Nature Chem. 3, 969–973 (2011).

    Article  CAS  Google Scholar 

  9. Aquino, C. et al. A biomimetic polyketide-inspired approach to small-molecule ligand discovery. Nature Chem. 4, 99–104 (2012).

    Article  CAS  Google Scholar 

  10. Bauer, R. A., Wenderski, T. A. & Tan, D. S. Biomimetic diversity-oriented synthesis of benzannulated medium rings via ring expansion. Nature Chem. Biol. 9, 21–29 (2013).

    Article  CAS  Google Scholar 

  11. Huigens III, R. W. et al. A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products. Nature Chem. 5, 195–202 (2013).

    Article  Google Scholar 

  12. O'Connor, S. E. & Maresh, J. J. Chemistry and biology of monoterpene indole alkaloid biosynthesis. Nat. Prod. Rep. 23, 532–547 (2006).

    Article  CAS  Google Scholar 

  13. Stocking, E. M. & Williams, R. M. Chemistry and biology of biosynthetic Diels–Alder reactions. Angew. Chem. Int. Ed. 42, 3078–3115 (2003).

    Article  CAS  Google Scholar 

  14. Danieli, B., Lesma, G., Martinelli, M., Passarella, D. & Silvani, A. Diastereoselective synthesis of 3-oxo-14,15-dihydroandranginine. J. Org. Chem. 62, 6519–6523 (1997).

    Article  CAS  Google Scholar 

  15. Finefield, J. M., Sherman, D. H., Kreitman, M. & Williams, R. M. Enantiomeric natural products: occurrence and biogenesis. Angew. Chem. Int. Ed. 51, 4802–4836 (2012).

    Article  CAS  Google Scholar 

  16. Oikawa, H. & Tokiwano, T. Enzymatic catalysis of the Diels–Alder reaction in the biosynthesis of natural products. Nat. Prod. Rep. 21, 321–352 (2004).

    Article  CAS  Google Scholar 

  17. Kim, J. & Movassaghi, M. Biogenetically inspired syntheses of alkaloid natural products. Chem. Soc. Rev. 38, 3035–3050 (2009).

    Article  CAS  Google Scholar 

  18. Massiot, G. et al. Structures of ngouniensine: an indole alkaloid of a new type from Strychnos ngouniensis. J. Chem. Soc. Chem. Commun. 768–769 (1982).

  19. Abbiati, G. et al. Sequential amination/annulation/aromatization reaction of carbonyl compounds and propargylamine: a new one-pot approach to functionalized pyridines. J. Org. Chem. 68, 6959–6966 (2003).

    Article  CAS  Google Scholar 

  20. Cacchi, S., Fabrizi, G. & Filisti, E. N-Propargylic β-enaminones: common intermediates for the synthesis of polysubstituted pyrroles and pyridines. Org. Lett. 10, 2629–2632 (2008).

    Google Scholar 

  21. Colby, D. A., Bergman, R. G. & Ellman, J. A. Synthesis of dihydropyridines and pyridines from imines and alkynes via C–H activation. J. Am. Chem. Soc. 130, 3645–3651 (2008).

    Article  CAS  Google Scholar 

  22. Kim, H. & Lee, C. Rhodium-catalyzed cycloisomerization of N-propargyl enamine derivatives. J. Am. Chem. Soc. 128, 6336–6337 (2006).

    Article  CAS  Google Scholar 

  23. Martins, M. A. P. et al. Intramolecular cyclization of N-propargylic β-enaminones catalyzed by silver. Tetrahedron Lett. 54, 847–849 (2013).

    Article  CAS  Google Scholar 

  24. Kim, H-S., Kim, J-W., Kwon, S-C., Shim, S-C. & Kim, T-J. Catalytic formation of carbamates and cyclic carbonates by copper complex of 2,5,19,22-tetraaza[6,6](1,1′)ferrocenophane-1,5-diene X-ray crystal structure of [Cu(I)]PF6 . J. Organomet. Chem. 545–546, 337–344 (1997).

    Article  Google Scholar 

  25. Chen, P., Cao, L. & Li, C. Protecting-group-free total synthesis of (±)-subincanadine F. J. Org. Chem. 74, 7533–7535 (2009).

    Article  CAS  Google Scholar 

  26. Kuehne, M. E., Bornmann, W. G., Earley, W. G. & Marko, I. Studies in biomimetic alkaloid syntheses. 14. Controlled, selective syntheses of catharanthine and tabersonine, and related desethyl compounds, through generation of 15-oxosecodine intermediates. J. Org. Chem. 51, 2913–2927 (1986).

    Article  CAS  Google Scholar 

  27. Passarella, D., Martinelli, M., Llor, N., Amat, M. & Bosch, J. Biomimetic construction of the tetracyclic ring system of ngouniensine. Tetrahedron 55, 14995–15000 (1999).

    Article  CAS  Google Scholar 

  28. Wilson, R. M., Farr, R. A. & Burlett, D. J. Synthesis and chemistry of a stabilized dehydrosecodine model system. J. Org. Chem. 46, 3293–3302 (1981).

    Article  CAS  Google Scholar 

  29. Yoon, T. P., Ischay, M. A. & Du, J. Visible light photocatalysis as a greener approach to photochemical synthesis. Nature Chem. 2, 527–532 (2010).

    Article  CAS  Google Scholar 

  30. Tucker, J. W. & Stephenson, C. R. J. Shining light on photoredox catalysis: theory and synthetic applications. J. Org. Chem. 77, 1617–1622 (2012).

    Article  CAS  Google Scholar 

  31. Prier, C. K., Rankic, D. A. & MacMillan, D. W. C. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem. Rev. 113, 5322–5363 (2013).

    Article  CAS  Google Scholar 

  32. Kutney, J. P. et al. The total synthesis of some monomeric Vinca alkaloids: dl-vincadine, dl-vincaminoreine, dl-vincaminorine, dl-vincadifformine, dl-minovine, and dl-vincaminoridine. J. Am. Chem. Soc. 90, 3891–3893 (1968).

    Article  CAS  Google Scholar 

  33. Kuehne, M. E., Wang, T. & Seaton, P. J. Total syntheses of vincadifformine, 3-oxovincadifformine, pseudo-and-20-epi-pseudo-vincadifformine, tabersonine, and Δ18-tabersonine through radical reactions and Heck reactions. J. Org. Chem. 61, 6001–6008 (1996).

    Article  CAS  Google Scholar 

  34. Kobayashi, S., Peng, G. & Fukuyama, T. Efficient total syntheses of (±)-vincadifformine and (−)-tabersonine. Tetrahedron Lett. 40, 1519–1522 (1999).

    Article  CAS  Google Scholar 

  35. Pandey, G. & Kumara, C. P. Iminium ion cascade reaction in the total synthesis of (+)-vincadifformine. Org. Lett. 13, 4672–4675 (2011).

    Article  CAS  Google Scholar 

  36. Mi, Y., Schreiber, J. V. & Corey, E. J. Total synthesis of (+)-α-onocerin in four steps via four-component coupling and tetracyclization steps. J. Am. Chem. Soc. 124, 11290–11291 (2002).

    Article  CAS  Google Scholar 

  37. Riche, C. & Pascard-Billy, C. Structure and stereochemistry of indole alkaloids. IV. Structure of andranginine. Acta Crystallogr. B B35, 666–669 (1979).

    Article  Google Scholar 

  38. Kan-Fan, C. et al. Structure and biogenetic-type synthesis of andranginine: an indole alkaloid of a new type. J. Chem. Soc. Chem. Commun. 164–165 (1974).

  39. Yanagisawa, A., Nomura, N. & Yamamoto, H. Transition metal-catalyzed substitution reaction of allylic phosphates with Grignard reagents. Tetrahedron 50, 6017–6028 (1994).

    Article  CAS  Google Scholar 

  40. Büchi, G., Kulsa, P., Ogasawara, K. & Rosati, R. L. Syntheses of velbanamine and catharanthine. J. Am. Chem. Soc. 92, 999–1005 (1970).

    Article  Google Scholar 

  41. Kutney, J. P. & Bylsma, F. Synthesis of monomeric and dimeric vinca alkaloids. The total synthesis of isovelbanamine, velbanamine, cleavamine, 18β-carbomethoxycleavamine, and catharanthine. J. Am. Chem. Soc. 92, 6090–6092 (1970).

    Article  CAS  Google Scholar 

  42. Trost, B. M., Godleski, S. A. & Belletire, J. L. Synthesis of (±)-catharanthine via organopalladium chemistry. J. Org. Chem. 44, 2052–2054 (1979).

    Article  CAS  Google Scholar 

  43. Atta-ur-Rahman, Beisler J. A. & Harley-Mason, J. The total syntheses of (±)-α- and β-dihydrocleavamines, (±)-16-methoxycarbonyldihydrocleavamine, (±)-coronaridine, (±)-dihydrocatharanthine, (±)-ibogamine, (±)-epi-ibogamine, and (±)-catharanthine. Tetrahedron 36, 1063–1070 (1980).

    Article  CAS  Google Scholar 

  44. Marazano, C., Le, G. M. T., Fourrey, J. L. & Das, B. C. An unequivocal synthesis of 1-benzyl-3-ethyl-1,6-dihydropyridine and its use for a biogenetically modeled synthesis of (±)-catharanthine. J. Chem. Soc. Chem. Commun. 389–391 (1981).

  45. Imanishi, T., Yagi, N., Shin, H. & Hanaoka, M. 1,6-Dihydro-3(2H)-pyridinones. III. A formal synthesis of (±)-catharanthine. Chem. Pharm. Bull. 30, 4052–4059 (1982).

    Article  CAS  Google Scholar 

  46. Raucher, S. & Bray, B. L. Total synthesis of (±)-catharanthine. J. Org. Chem. 50, 3236–3237 (1985).

    Article  CAS  Google Scholar 

  47. Raucher, S., Bray, B. L. & Lawrence, R. F. Synthesis of (±)-catharanthine, (+)-anhydrovinblastine, and (−)-anhydrovincovaline. J. Am. Chem. Soc. 109, 442–446 (1987).

    Article  CAS  Google Scholar 

  48. Szántay, C., Bölcskei, H. & Gács-Baitz, E. Synthesis of vinca alkaloids and related compounds XLVIII synthesis of (+)-catharanthine and (±)-allocatharanthine. Tetrahedron 46, 1711–1732 (1990).

    Article  Google Scholar 

  49. Reding, M. T., Kaburagi, Y., Tokuyama, H. & Fukuyama, T. Synthesis of 2,3-disubstituted indoles by radical cyclization with hypophosphorous acid and its application to total synthesis of (±)-catharanthine. Heterocycles 56, 313–330 (2002).

    Article  CAS  Google Scholar 

  50. Moisan, L., Thuery, P., Nicolas, M., Doris, E. & Rousseau, B. Formal synthesis of (+)-catharanthine. Angew. Chem. Int. Ed. 45, 5334–5336 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors dedicate this manuscript to Masahiro Hirama on the occasion of his 65th birthday. The authors thank Y. Fujimura (Shionogi & Co.) and T. Matsumoto (Rigaku Corporation) for performing X-ray analyses. This work was supported by JSPS KAKENHI (grant no. 23310156 to H. Oguri) and in part by the Naito Foundation and the Science and Technology Research Partnership for Sustainable Development Program (SATREPS) of the Japan Science and Technology Agency (JST). The authors acknowledge a fellowship for H.M. from the JSPS.

Author information

Authors and Affiliations

  1. Division of Chemistry, Graduate School of Science, Hokkaido University, North 10, West 8, Kita-ku, Sapporo, 060-0810, Japan

    Haruki Mizoguchi, Hideaki Oikawa & Hiroki Oguri

  2. Japan Science and Technology Agency (JST) PRESTO, 4-1-8 Honcho, Kawaguchi, 332-0012, Saitama, Japan

    Hiroki Oguri

Authors
  1. Haruki Mizoguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hideaki Oikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroki Oguri
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.M. carried out the experimental work. H.M. and H. Oguri conceived the projects, analysed the experimental results and wrote the manuscript. H. Oikawa discussed the results and provided oversight.

Corresponding author

Correspondence to Hiroki Oguri.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 4657 kb)

Supplementary information

Crystallographic data for compound 7 (CIF 35 kb)

Supplementary information

Crystallographic data for compound 48 (CIF 18 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mizoguchi, H., Oikawa, H. & Oguri, H. Biogenetically inspired synthesis and skeletal diversification of indole alkaloids. Nature Chem 6, 57–64 (2014). https://doi.org/10.1038/nchem.1798

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchem.1798

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing