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.

Forming all-carbon quaternary stereogenic centres in acyclic systems from alkynes

Subjects

Abstract

The formation of all-carbon quaternary stereocentres in acyclic systems is one of the most difficult contemporary challenges in modern synthetic organic chemistry1,2. Particularly challenging is the preparation of all-carbon quaternary stereocentres in aldol adducts3; this difficulty is problematic because the aldol reaction represents one of the most valuable chemical transformations in organic synthesis4. The main problem that limits the formation of these stereocentres is the absence of an efficient method of preparing stereodefined trisubstituted enolates in acyclic systems5,6,7,8. Here we describe a different approach that involves the formation of two new stereogenic centres—including the all-carbon quaternary one—via a combined carbometalation–oxidation reaction of an organocuprate to give a stereodefined trisubstituted enolate. We use this method to generate a series of aldol and Mannich products from ynamides with excellent diastereomeric and enantiomeric ratios and moderate yields.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: General strategies for the formation of stereodefined enolates.
Figure 2: Proposed approach.
Figure 3: Combined carbometalation-oxidation sequence.
Figure 4: Application to the aldol and Mannich reactions.
Figure 5: Cleavage of the auxiliaries.

Accession codes

Data deposits

Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre, accession numbers CCDC 881250 (8), CCDC 881248 (5a) and CCDC 881249 (6a).

References

  1. Hawner, C. & Alexakis, A. Metal-catalyzed asymmetric conjugate addition reaction: formation of quaternary stereocenters. Chem. Commun. 46, 7295–7306 (2010)

    Article  CAS  Google Scholar 

  2. Das, J. P. & Marek, I. Enantioselective synthesis of all-carbon quaternary stereogenic centers in acyclic systems. Chem. Commun. 47, 4593–4623 (2011)

    Article  CAS  Google Scholar 

  3. Das, J. P., Chechik, H. & Marek, I. A unique approach to aldol products for the creation of all-carbon quaternary stereocentres. Nature Chem. 1, 128–132 (2009)

    Article  ADS  CAS  Google Scholar 

  4. Carreira, E. M. in Modern Carbonyl Chemistry (ed. Otera, J. ) Ch. 8 227–248 (Wiley-VCH, 2001)

    Google Scholar 

  5. Manthorpe, J. M. & Gleason, J. L. Stereoselective generation of E- and Z-disubstituted amide enolates. Reductive enolate formation from bicyclic thioglycolate lactams. J. Am. Chem. Soc. 123, 2091–2092 (2001)

    Article  CAS  Google Scholar 

  6. Kummer, D. A., Chain, W. J., Morales, M. R., Quiroga, O. & Myers, A. G. Stereocontrolled alkylative construction of quaternary carbon centers. J. Am. Chem. Soc. 130, 13231–13233 (2008)

    Article  CAS  Google Scholar 

  7. Qin, Y.-C., Stivala, C. E. & Zakarian, A. Acyclic stereocontrol in the Ireland-Claisen rearrangement of α-branched esters. Angew. Chem. Int. Edn 46, 7466–7469 (2007)

    Article  CAS  Google Scholar 

  8. Gu, Z., Herrmann, A. T., Stivala, C. E. & Zakarian, A. Stereoselective construction of adjacent quaternary chiral centers by the Ireland-Claisen rearrangement: stereoselection with esters of cyclic alcohols. Synlett 1717–1722 (2010)

  9. Newhouse, T., Baran, P. S. & Hoffmann, R. W. The economies of synthesis. Chem. Soc. Rev. 38, 3010–3021 (2009)

    Article  CAS  Google Scholar 

  10. 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  Google Scholar 

  11. Seebach, D. Organic synthesis — where now? Angew. Chem. Int. Edn Engl. 29, 1320–1367 (1990)

    Article  Google Scholar 

  12. Wender, P. A. & Miller, B. L. Synthesis at the molecular frontier. Nature 460, 197–201 (2009)

    Article  ADS  CAS  Google Scholar 

  13. Scott, H. K. &. Aggarwal, V. K. Highly enantioselective synthesis of tertiary boronic esters and their stereospecific conversion to other functional groups and quaternary stereocentres. Chem. Eur. J. 17, 13124–13132 (2011)

    Article  CAS  Google Scholar 

  14. Marek, I. A shift in retrosynthetic paradigm. Chem. Eur. J. 14, 7460–7468 (2008)

    Article  CAS  Google Scholar 

  15. Sklute, G. & Marek, I. Multicomponent approach for the creation of chiral quaternary centers in the carbonyl allylation reactions. J. Am. Chem. Soc. 128, 4642–4649 (2006)

    Article  CAS  Google Scholar 

  16. Dutta, B., Gilboa, N. & Marek, I. Highly diastereoselective preparation of homoallylic alcohols containing two contiguous quaternary stereocenters in acyclic systems from simple terminal alkynes. J. Am. Chem. Soc. 132, 5588–5589 (2010)

    Article  CAS  Google Scholar 

  17. Gilboa, N., Wang, H., Houk, K. N. & Marek, I. Axial preferences in allylation via the Zimmerman-Traxler transition state. Chem. Eur. J. 17, 8000–8004 (2011)

    Article  CAS  Google Scholar 

  18. Yamago, S., Machii, D. & Nakamura, E. Simple diastereoselectivity of the aldol reaction of persubstituted enolates. Stereoselective construction of quaternary centers. J. Org. Chem. 56, 2098–2106 (1991)

    Article  CAS  Google Scholar 

  19. Häner, R., Laube, T. & Seebach, D. Regio- and diastereoselective preparation of aldols from α-branched ketone enolates generated from BHT ester enolates and organolithium reagents: in-situ generation and trapping of ketenes from ester enolates. J. Am. Chem. Soc. 107, 5396–5403 (1985)

    Article  Google Scholar 

  20. Mase, N., Tanaka, F. & Barbas, C. F., III Synthesis of β-hydroxyaldehydes with stereogenic quaternary carbon centers by direct organocatalytic asymmetric aldol reactions. Angew. Chem. Int. Edn 43, 2420–2423 (2004)

    Article  CAS  Google Scholar 

  21. Denmark, S. E., Wilson, T. W., Burk, M. T. & Heemstra, J. R., Jr Enantioselective construction of quaternary stereogenic centers by the Lewis base catalyzed additions of silyl imines to aldehydes. J. Am. Chem. Soc. 129, 14864–14865 (2007)

    Article  CAS  Google Scholar 

  22. Evans, D. A., Bartroli, J. & Shih, T. L. Enantioselective aldol condensations. Erythro-selective chiral aldol condensations via boron enolates. J. Am. Chem. Soc. 103, 2127–2129 (1981)

    Article  CAS  Google Scholar 

  23. Chechik-Lankin, H. Livshin, S. & Marek, I. Regiocontrolled carbometalation reactions of ynamides. Synlett 2239–2241 (2005)

  24. Evano, G., Coste, A. & Jouvin, K. Ynamides: versatile tools in organic synthesis. Angew. Chem. Int. Edn 49, 2840–2859 (2010)

    Article  CAS  Google Scholar 

  25. Wendlandt, A. E., Suess, A. M. & Stahl, S. S. Copper-catalyzed aerobic oxidative C-H functionalizations: trends and mechanistic insights. Angew. Chem. Int. Edn 50, 11062–11087 (2011)

    Article  CAS  Google Scholar 

  26. Panek, E. J., Kaiser, L. R. & Whitesides, G. M. Vinylic radicals are intermediates in the oxidation of vinylic lithium reagents to lithium enolates by dioxygen, but not by lithium tert-butyl peroxide. J. Am. Chem. Soc. 99, 3708–3713 (1977)

    Article  CAS  Google Scholar 

  27. Zhang, D. & Ready, J. M. Tandem carbocupration/oxygenation of terminal alkynes. Org. Lett. 7, 5681–5683 (2005)

    Article  CAS  Google Scholar 

  28. DeBergh, J. R., Spivey, K. M. & Ready, J. M. Preparation of substituted enol derivatives from terminal alkynes and their synthetic utility. J. Am. Chem. Soc. 130, 7828–7829 (2008)

    Article  CAS  Google Scholar 

  29. Tiong, E. A. & Gleason, J. L. Stereoselective formation of α-quaternary stereocenters in Mannich reaction. Org. Lett. 11, 1725–1728 (2009)

    Article  CAS  Google Scholar 

  30. Stivala, C. E. & Zakarian, A. Total synthesis of (+)-pinnatoxin A. J. Am. Chem. Soc. 130, 3774–3776 (2008)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by the Israel Science Foundation administrated by the Israel Academy of Sciences and Humanities (140/12), and by the Fund for Promotion of Research at the Technion. L.L. thanks the Bayer-Stiftung for financial support. I.M. is holder of the Sir Michael and Lady Sobell Academic Chair.

Author information

Authors and Affiliations

Authors

Contributions

Y.M., M.P. and L.L. planned, conducted and analysed experiments. I.M. conceived and directed the project and wrote the manuscript with contributions from Y.M. and M.P. X-ray structures were resolved by M.B. All authors contributed to discussions.

Corresponding author

Correspondence to Ilan Marek.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Methods, Supplementary Text and Data and additional references – see Contents for details. (PDF 10000 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Minko, Y., Pasco, M., Lercher, L. et al. Forming all-carbon quaternary stereogenic centres in acyclic systems from alkynes. Nature 490, 522–526 (2012). https://doi.org/10.1038/nature11569

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11569

This article is cited by

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.

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