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:

Synthetic nat- or ent-steroids in as few as five chemical steps from epichlorohydrin

Nature Chemistry volume 10, pages 70–77 (2018)Cite this article

Subjects

Abstract

Today, more than 100 Food and Drug Administration-approved steroidal agents are prescribed daily for indications including heart failure, inflammation, pain and cancer. While triumphs in organic chemistry have enabled the establishment and sustained growth of the steroid pharmaceutical industry, the production of highly functionalized synthetic steroids of varying substitution and stereochemistry remains challenging, despite the numerous reports of elegant strategies for their de novo synthesis. Here, we describe an advance in chemical synthesis that has established an enantiospecific means to access novel steroids with unprecedented facility and flexibility through the sequential use of two powerful ring-forming reactions: a modern metallacycle-mediated annulative cross-coupling and a new acid-catalysed vinylcyclopropane rearrangement cascade. In addition to accessing synthetic steroids of either enantiomeric series, these steroidal products have been selectively functionalized within each of the four carbocyclic rings, a synthetic ent-steroid has been prepared on a multigram scale, the enantiomer of a selective oestrogen has been synthesized, and a novel ent-steroid with growth inhibitory properties in three cancer cell lines has been discovered.

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: Introduction to steroid structure and synthesis.
Figure 2
Figure 3: Establishment of a new chemical pathway for the enantiospecific synthesis of steroids.
Figure 4
Figure 5: Exploring utility of this new strategy for steroid synthesis.

Similar content being viewed by others

References

  1. Windaus, A. Concerning the constitution of cholesterol and biliary acid. Z. Physiol. Chem. 213, 147–187 (1932).

    Article  CAS  Google Scholar 

  2. Bachmann, W. E., Cole, W. & Wilds, A. L. The total synthesis of the sex hormone equilenin. J. Am. Chem. Soc. 61, 974–975 (1939).

    Article  CAS  Google Scholar 

  3. Lednicer, D. Steroid Chemistry at a Glance (Wiley, 2011).

    Google Scholar 

  4. Pines, S. H. The Merck bile acid cortisone process: the next-to-last word. Org. Proc. Res. Dev. 8, 708–724 (2004).

    Article  CAS  Google Scholar 

  5. Marker, R. E., Tsukamoto, T., Turner, D. L. & Sterols, C. Diosgenin. J. Am. Chem. Soc. 62, 2525–2532 (1940).

    Article  CAS  Google Scholar 

  6. Renneberg, R. Mexico, the father of the pill and the race for cortisone. Biotechnol. J. 3, 449–451 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Hanson, J. R. Steroids: partial synthesis in medicinal chemistry. Nat. Prod. Rep. 27, 887–899 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Biellmann, J. F. Enantiomeric steroids: synthesis, physical, and biological properties. Chem. Rev. 103, 2019–2033 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Covey, D. F. ent-Steroids: novel tools for studies of signaling pathways. Steroids 74, 577–585 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Green, P. S. et al. The nonfeminizing enantiomer of 17β-estradiol exerts protective effects in neuronal cultures and a rat model of cerebral ischemia. Endocrinology 142, 400–406 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Akwa, Y., Ladurelle, N., Covey, D. F. & Baulieu, E. E. The synthetic enantiomer of pregnenolone sulfate is very active on memory in rats and mice, even more so than its physiological neurosteroid counterpart: distinct mechanisms? Proc. Natl Acad. Sci. USA 98, 14033–14037 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Petit, G. H. et al. Pregnenolone sulfate and its enantiomer differential modulation of memory in a spatial discrimination task using forebrain NMDA receptor deficient mice. Eur. Neuropsychopharmacol. 21, 211–215 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. Yeung, Y.-Y., Chein, R.-J. & Corey, E. J. Conversion of Torgov's synthesis of estrone into a highly enantioselective and efficient process. J. Am. Chem. Soc. 129, 10346–10347 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Yoder, R. A. & Johnston, J. N. A case study in biomimetic total synthesis: polyolefin carbocyclizations to terpenes and sterols. Chem. Rev. 105, 4730–4756 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zeelen, F. J. Steroid total synthesis. Nat. Prod. Rep. 11, 607–612 (1994).

    Article  CAS  PubMed  Google Scholar 

  16. Chapelon, A., Moraléda, D., Rodriguez, R., Ollivier, C. & Santelli, M. Enantioselective synthesis of steroids. Tetrahedron 63, 11511–11616 (2007).

    Article  CAS  Google Scholar 

  17. Mackay, E. G. & Sherburn, M. S. The Diels–Alder reaction in steroid synthesis. Synthesis 47, 1–21 (2015).

    Article  CAS  Google Scholar 

  18. Funk, R. L. & Vollhardt, K. P. C. A cobalt-catalyzed steroid synthesis. J. Am. Chem. Soc. 99, 5483–5484 (1977).

    Article  CAS  PubMed  Google Scholar 

  19. Funk, R. L. & Vollhardt, K. P. C. The cobalt way to dl-estrone. A highly regiospecific functionalization of 2,3-bis(trimethylsilyl)extratrien-17-one. J. Am. Chem. Soc. 101, 215–217 (1979).

    Article  CAS  Google Scholar 

  20. Vollhardt, K. P. C. Cobalt-mediated steroid synthesis. Pure Appl. Chem. 57, 1819–1826 (1985).

    Article  Google Scholar 

  21. Kaplan, W., Khatri, H. R. & Nagorny, P. Concise enantioselective total synthesis of cardiotonic steroids 19-hydroxysarmentogenin and trewianin aglycone. J. Am. Chem. Soc. 138, 7194–7198 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nising, C. F. & Bräse, S. Highlights in steroid chemistry: total synthesis versus semisynthesis. Angew. Chem. Int. Ed. 47, 9389–9391 (2008).

    Article  CAS  Google Scholar 

  23. Wender, P. A. et al. Function-oriented synthesis, step economy, and drug design. Acc. Chem. Res. 41, 40–49 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Jeso, V. et al. Synthesis of angularly substituted trans-fused hydroindanes by convergent coupling of acyclic precursors. J. Am. Chem. Soc. 136, 8209–8212 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Reichard, H. A., McLaughlin, M., Chen, M. Z. & Micalizio, G. C. Regioselective reductive cross-coupling reations of unsymmetrical alkynes. Eur. J. Org. Chem. 2010, 391–409 (2010).

    Article  CAS  Google Scholar 

  26. Reichard, H. A. & Micalizio, G. C. Metallacycle-mediated cross-coupling with substituted and electronically unactivated alkenes. Chem. Sci. 2, 573–589 (2011).

    Article  CAS  Google Scholar 

  27. Micalizio, G. C. & Mizoguchi, H. The development of alkoxide-directed metallacycle-mediated annulative cross-coupling chemistry. Isr. J. Chem. 57, 228–238 (2017).

    Article  CAS  PubMed  Google Scholar 

  28. Micalizio, G. C., O'Rourke, N. F. & Kier, M. J. Metallacycle-mediated cross-coupling in natural product synthesis. Tetrahedron 72, 7093–7123 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Ryan, J. & Micalizio, G. C. An alkoxide-directed carbometalation of internal alkynes. J. Am. Chem. Soc. 128, 2764–2765 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Makosza, M. & Wawrzyniewicz, M. Reactions of organic anions. XXIV. Catalytic method for preparation of dichlorocyclopropane derivatives in aqueous medium. Tetrahedron Lett. 10, 4659–4662 (1969).

    Article  Google Scholar 

  31. Fedorynski, M. Synthesis of gem-dihalocyclopropanes and their use in organic synthesis. Chem. Rev. 103, 1099–1132 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Sasaki, T., Eguchi, S. & Kiriyama, T. Studies on heterocage compounds. V. Reaction of 5-hydroxymethyl-2-norbornene with dihalocarbene. Novel synthesis of some oxa-modified adamantane analogs. J. Org. Chem. 38, 2230–2234 (1973).

    Article  CAS  Google Scholar 

  33. Danheiser, R. L., Morin, J. M. Jr, Yu, M. & Basak, A. Cationic cyclizations initiated by electrocyclic cleavage of cyclopropanes. Synthesis of lactones, tetrahydropyrans, and tetrahydrofurans. Tetrahedron Lett. 22, 4205–4208 (1981).

    Article  CAS  Google Scholar 

  34. Gassman, P. G., Tan, L. & Hoye, T. R. Intramolecular cationic cyclizations initiated by electrocyclic cleavage of cyclopropanes. Synthesis of trienic cyclopentane derivatives. Tetrahedron Lett. 37, 439–442 (1996).

    Article  CAS  Google Scholar 

  35. Banwell, M. G., Harvey, J. E., Hockless, D. C. R. & Wu, A. W. Electrocyclic ring-opening/π-allyl cation cyclization reaction sequences involving gem-dihalocyclopropanes as substrates: application to syntheses of (±)-, (+)-, and (–)-γ-lycorane. J. Org. Chem. 65, 4241–4250 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Olah, G. A. & Bollinger, J. M. Stable carbonium ions. LXVIII. Protonation and ionization of cyclopropyl halides. Measurement of rotational barriers in substituted allyl cations. J. Am. Chem. Soc. 90, 6082–6086 (1968).

    Article  CAS  Google Scholar 

  37. Poulter, C. D. & Winstein, S. The cyclopropylcarbinyl–allyl rearrangement of a hexamethylcyclopropylcarbinyl system. J. Am. Chem. Soc. 91, 3649–3650 (1969).

    Article  CAS  Google Scholar 

  38. Poulter, C. D. & Winstein, S. Solvolysis and degenerate cyclopropylcarbinyl–cyclopropylcarbinyl rearrangement of a hexamethylcyclopropylcarbinyl system. J. Am. Chem. Soc. 91, 3650–3652 (1969).

    Article  CAS  Google Scholar 

  39. Sorensen, T. S. & Ranganayakulu, K. Cyclopropylcarbinyl–allylcarbinyl–allyl cation rearrangements. Tetrahedron Lett. 11, 659–662 (1970).

    Article  Google Scholar 

  40. Seko, S., Tanabe, Y. & Suzukamo, G. A novel synthesis of α- and β-halonaphthalenes via regioselective ring cleavage of aryl(gem-dihalocyclopropyl)methanols and its application to total synthesis of lignan lactones, justicidin E and taiwanin C. Tetrahedron Lett. 31, 6883–6886 (1990).

    Article  CAS  Google Scholar 

  41. Tanabe, Y. et al. Novel method for the synthesis of α- and β-halogenonaphthalenes by regioselective benzannulation of aryl(gem-dihalogenocyclopropyl)methanols application to the total synthesis of the lignan lactones, justicidin E and taiwanin C. J. Chem. Soc. Perkin Trans. 1, 2157–2165 (1996).

    Article  Google Scholar 

  42. Kim, W. S., Aquino, C., Mizoguchi, H. & Micalizio, G. C. LiOOt-Bu as a terminal oxidant in a titanium alkoxide-mediated [2+2+2] reaction cascade. Tetrahedron Lett. 56, 3557–3559 (2015).

    Article  CAS  Google Scholar 

  43. Rabideau, P. W. The metal–ammonia reduction of aromatic compounds. Tetrahedron 45, 1579–1603 (1989).

    Article  CAS  Google Scholar 

  44. Rabideau, P. W. & Marcinow, Z. The Birch reduction of aromatic compounds. Org. React. 42, 1–334 (1992).

    CAS  Google Scholar 

  45. Pellissier, H. & Santelli, M. The Birch reduction of steroids. A review. Org. Prep. Proc. Int. 34, 609–642 (2002).

    Article  CAS  Google Scholar 

  46. Subba Rao, G. S. R. Birch reduction and its application in the total synthesis of natural products. Pure Appl. Chem. 75, 1443–1451 (2003).

    Article  CAS  Google Scholar 

  47. Fajkoš, J. & Joska, J. On steroids. LV. Bromination of 3β-acetoxy-5α-androstan-16-one. Collect. Czech. Chem. Commun. 25, 2863–2877 (1960).

    Article  Google Scholar 

  48. Miyaura, N. & Suzuki, A. Palladium-catalyzed cross-coupling reactions of organoboron compounds. Chem. Rev. 95, 2457–2483 (1995).

    Article  CAS  Google Scholar 

  49. Sawyer, J. S. Recent advances in diaryl ether synthesis. Tetrahedron 56, 5045–5065 (2000).

    Article  Google Scholar 

  50. Syper, L. Partial oxidation of aliphatic side chains with cerium(IV). Tetrahedron Lett. 7, 4493–4498 (1966).

    Article  Google Scholar 

  51. Kuenzer, H. et al. 16-Hydroxyestratrienes as selectively active estrogens. US patent 7,109,360 B1 (2006).

  52. Eastgate, M. D., Schmidt, M. A. & Fandrick, K. R. On the design of complex drug candidate syntheses in the pharmaceutical industry. Nat. Rev. Chem. 1, 0016 (2017).

    Article  CAS  Google Scholar 

  53. Montano, R., Chung, I., Garner, K. M., Parry, D. & Eastman, A. Preclinical development of the novel Chk1 inhibitor SCH900776 in combination with DNA damaging agents and antimetabolites. Mol. Cancer Ther. 11, 427–438 (2012).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge financial support of this work by the National Institutes of Health NIGMS (GM80266). The authors also thank G. Gribble, P. Jacobi, J. Wu and B. Heasley for discussions.

Author information

Author notes

  1. Wan Shin Kim and Kang Du: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry, Dartmouth College, Burke Laboratory, Hanover, 03755, New Hampshire, USA

    Wan Shin Kim, Kang Du, Russell P. Hughes & Glenn C. Micalizio

  2. Department of Molecular and Systems Biology, Dartmouth College, Geisel School of Medicine, The Norris Cotton Cancer Center, Lebanon, 03756, New Hampshire, USA

    Alan Eastman

Authors
  1. Wan Shin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kang Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alan Eastman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Russell P. Hughes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Glenn C. Micalizio
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

W.S.K., K.D., R.P.H. and G.C.M. contributed to the chemical experiments. R.P.H performed in silico experiments to explore the mechanism of the vinylcyclopropane rearrangement. W.S.K. and K.D. performed all chemical reactions reported. A.E. performed the in vitro evaluation of ent-steroid 39, and G.C.M. wrote the manuscript with contributions from all authors.

Corresponding author

Correspondence to Glenn C. Micalizio.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 5481 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, W., Du, K., Eastman, A. et al. Synthetic nat- or ent-steroids in as few as five chemical steps from epichlorohydrin. Nature Chem 10, 70–77 (2018). https://doi.org/10.1038/nchem.2865

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchem.2865

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