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.

  • Protocol
  • Published:

Highly enantioselective rhodium-catalyzed cross-coupling of boronic acids and racemic allyl halides

Nature Protocols volume 14, pages 2972–2985 (2019)Cite this article

Subjects

Abstract

Although Csp2–Csp2 Suzuki–Miyaura couplings (SMCs) are widely used in small-molecule synthesis, related methods that allow the incorporation of Csp3-hybridized coupling partners, particularly in an asymmetric manner, are less developed. This protocol describes catalytic asymmetric SMC reactions that provide access to enantiomerically enriched cyclic allylic products. The method couples racemic allyl halide starting materials with sp2-hybridized boronic acid derivatives and is compatible with heterocyclic coupling partners. These reactions are catalyzed by a rhodium–ligand complex and typically display very high levels of enantioselectivity (>95% enantiomeric excess (ee)). In this protocol, we detail a procedure using a dihydropyridine-derived allyl chloride for the synthesis of (−)-(S)-tert-butyl-3-(4-bromophenyl)-3,6-dihydropyridine-1(2H)-carboxylate, an intermediate in the synthesis of the anticancer drug niraparib. This procedure affords 1.17 g (86% yield) of the coupling product with 96% ee. The initial experimental setup of the reaction takes 45–50 min, and the reaction is complete within 4–5 h.

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

Fig. 1: SMC: from flat to 3D molecules.
Fig. 2: Application of the Rh-catalyzed asymmetric SMC in drug synthesis.
Fig. 3
Fig. 4: Rh complex.
Fig. 5: Preparation of the boronic ester and allyl halide solutions.
Fig. 6: Reaction setup.
Fig. 7: View of the KMNO4-stained TLC plate used to examine fractions obtained by silica gel flash column chromatography.

Similar content being viewed by others

Data availability

All data supporting this protocol are available within the article and in the Supplementary Information file.

References

  1. Armin, D. M., Stefan, B. & Martin, O. (eds) Metal-Catalyzed Cross-Coupling Reactions and More (Wiley-VCH, 2014).

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

    Article  CAS  Google Scholar 

  3. Suzuki, A. Recent advances in the cross-coupling reactions of organoboron derivatives with organic electrophiles, 1995–1998. J. Organomet. Chem. 576, 147–168 (1999).

    Article  CAS  Google Scholar 

  4. Blakemore, D. C., Doyle, P. M. & Fobian, Y. M. (eds) Synthetic Methods in Drug Discovery Vol 1, 1–69 (Royal Society of Chemistry, 2016).

  5. D. G. Hall, Boronic Acids: Preparation, Applications in Organic Synthesis and Medicine (John Wiley & Sons, 2006).

  6. Lovering, F., Bikker, J. & Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 (2009).

    Article  CAS  Google Scholar 

  7. Lovering, F. Escape from Flatland 2: complexity and promiscuity. MedChemComm 4, 515–519 (2013).

    Article  CAS  Google Scholar 

  8. Brown, D. G. & Boström, J. Analysis of past and present synthetic methodologies on medicinal chemistry: where have all the new reactions gone? J. Med. Chem. 59, 4443–4458 (2016).

    Article  CAS  Google Scholar 

  9. Blakemore, D. C. et al. Organic synthesis provides opportunities to transform drug discovery. Nat. Chem. 10, 383–394 (2018).

    Article  CAS  Google Scholar 

  10. Cammidge, A. N. & Crepy, K. V. L. The first asymmetric Suzuki cross-coupling reaction. Chem. Commun. 18, 1723–1724 (2000).

    Article  Google Scholar 

  11. Yin, J. & Buchwald, S. L. A catalytic asymmetric Suzuki coupling for the synthesis of axially chiral biaryl compounds. J. Am. Chem. Soc. 122, 12051–12052 (2000).

    Article  CAS  Google Scholar 

  12. Baudoin, O. The asymmetric Suzuki coupling route to axially chiral biaryls. Eur. J. Org. Chem. 2005, 4223–4229 (2005).

    Article  Google Scholar 

  13. Zhou, Y. et al. Enantioselective synthesis of axially chiral multifunctionalized biaryls via asymmetric Suzuki-Miyaura coupling. Org. Lett. 15, 5508–5511 (2013).

    Article  CAS  Google Scholar 

  14. Ros, A. et al. Dynamic kinetic cross-coupling strategy for the asymmetric synthesis of axially chiral heterobiaryls. J. Am. Chem. Soc. 135, 15730–15733 (2013).

    Article  CAS  Google Scholar 

  15. Willis, M. C., Powell, L. H. W., Claverie, C. K. & Watson, S. J. Enantioselective Suzuki reactions: catalytic asymmetric synthesis of compounds containing quaternary carbon centers. Angew. Chem. Int. Ed. 43, 1249–1251 (2004).

    Article  CAS  Google Scholar 

  16. Jana, R., Pathak, T. P. & Sigman, M. S. Advances in transition metal (Pd,Ni,Fe)-catalyzed cross-coupling reactions using alkyl-organometallics as reaction partners. Chem. Rev. 111, 1417–1492 (2011).

    Article  CAS  Google Scholar 

  17. Rygus, J. P. G. & Crudden, C. M. Enantiospecific and iterative Suzuki-Miyaura cross-couplings. J. Am. Chem. Soc. 139, 18124–18137 (2017).

    Article  CAS  Google Scholar 

  18. Cherney, A. H., Kadunce, N. T. & Reisman, S. E. Enantioselective and enantiospecific transition-metal-catalyzed cross-coupling reactions of organometallic reagents to construct C–C bonds. Chem. Rev. 115, 9587–9652 (2015).

    Article  CAS  Google Scholar 

  19. Lundin, P. M. & Fu, G. C. Asymmetric Suzuki cross-couplings of activated secondary alkyl electrophiles: arylations of racemic α-chloroamides. J. Am. Chem. Soc. 132, 11027–11029 (2010).

    Article  CAS  Google Scholar 

  20. Huang, W., Wan, X. & Shen, Q. Enantioselective construction of trifluoromethoxylated stereogenic centers by a nickel-catalyzed asymmetric Suzuki-Miyaura coupling of secondary benzyl bromides. Angew. Chem. Int. Ed. 56, 11986–11989 (2017).

    Article  CAS  Google Scholar 

  21. Almond-Thynne, J., Blakemore, D. C., Pryde, D. C. & Spivey, A. C. Site-selective Suzuki–Miyaura coupling of heteroaryl halides—understanding the trends for pharmaceutically important classes. Chem. Sci. 8, 40–62 (2017).

    Article  CAS  Google Scholar 

  22. Nadin, A., Hattotuwagama, C. & Churcher, I. Lead-oriented synthesis: a new opportunity for synthetic chemistry. Angew. Chem. Int. Ed. 51, 1114–1122 (2012).

    Article  CAS  Google Scholar 

  23. Huang, L. et al. Highly enantioselective rhodium-catalyzed addition of arylboroxines to simple aryl ketones: efficient synthesis of escitalopram. Angew. Chem. Int. Ed. 55, 4527–4531 (2016).

    Article  CAS  Google Scholar 

  24. Zhu, T. S., Jin, S. S. & Xu, M. H. Rhodium-catalyzed, highly enantioselective 1,2-addition of aryl boronic acids to α-ketoesters and α-diketones using simple, chiral sulfur-olefin ligands. Angew. Chem. Int. Ed. 51, 780–783 (2012).

    Article  CAS  Google Scholar 

  25. Kuriyama, M., Soeta, T., Hao, X., Chen, Q. & Tomioka, K. N-Boc-l-valine-connected amidomonophosphane rhodium(I) catalyst for asymmetric arylation of N-tosylarylimines with arylboroxines. J. Am. Chem. Soc. 126, 8128–8129 (2004).

    Article  CAS  Google Scholar 

  26. Burns, A. R., Lam, H. W. & Roy, I. D. Organic Reactions Vol. 93, 1–686 (John Wiley & Sons, 2017).

  27. Heravi, M. M., Dehghani, M. & Zadsirjan, V. Rh-catalyzed asymmetric 1,4-addition reactions to α,β-unsaturated carbonyl and related compounds: an update. Tetrahedron Asymmetry 27, 513–588 (2016).

    Article  CAS  Google Scholar 

  28. Tian, P., Dong, H. Q. & Lin, G. Q. Rhodium-catalyzed asymmetric arylation. ACS Catal. 2, 95–119 (2012).

    Article  CAS  Google Scholar 

  29. Hayashi, T. & Yamasaki, K. Rhodium-catalyzed asymmetric 1,4-addition and its related asymmetric reactions. Chem. Rev. 103, 2829–2844 (2003).

    Article  CAS  Google Scholar 

  30. Kiuchi, H., Takahashi, D., Funaki, K., Sato, T. & Oi, S. Rhodium-catalyzed asymmetric coupling reaction of allylic ethers with arylboronic acids. Org. Lett. 14, 4502–4505 (2012).

    Article  CAS  Google Scholar 

  31. Hamilton, J. Y., Sarlah, D. & Carreira, E. M. Iridium-catalyzed enantioselective allylic vinylation. J. Am. Chem. Soc. 135, 994–997 (2013).

    Article  CAS  Google Scholar 

  32. Miura, T., Takahashi, Y. & Murakami, M. Rhodium-catalysed substitutive arylation of cis-allylic diols with arylboroxines. Chem. Commun. 6, 595–597 (2007).

    Article  Google Scholar 

  33. Yu, B., Menard, F., Isono, N. & Lautens, M. Synthesis of homoallylic alcohols via Lewis acid assisted enantioselective desymmetrization. Synthesis 2009, 853–859 (2009).

    Article  Google Scholar 

  34. Menard, F., Perez, D., Sustac Roman, D., Chapman, T. M. & Lautens, M. Ligand-controlled selectivity in the desymmetrization of meso cyclopenten-1,4-diols via rhodium(I)-catalyzed addition of arylboronic acids. J. Org. Chem. 75, 4056–4068 (2010).

    Article  CAS  Google Scholar 

  35. Menard, F., Chapman, T. M., Dockendorff, C. & Lautens, M. Rhodium-catalyzed asymmetric allylic substitution with boronic acid nucleophiles. Org. Lett. 8, 4569–4572 (2006).

    Article  CAS  Google Scholar 

  36. Sidera, M. & Fletcher, S. P. Rhodium-catalysed asymmetric allylic arylation of racemic halides with arylboronic acids. Nat. Chem. 7, 935–939 (2015).

    Article  CAS  Google Scholar 

  37. Schäfer, P., Palacin, T., Sidera, M. & Fletcher, S. P. Asymmetric Suzuki-Miyaura coupling of heterocycles via rhodium-catalysed allylic arylation of racemates. Nat. Commun. 8, 15762 (2017).

    Article  Google Scholar 

  38. Schäfer, P., Sidera, M., Palacin, T. & Fletcher, S. P. Asymmetric cross-coupling of alkyl, alkenyl and (hetero)aryl nucleophiles with racemic allyl halides. Chem. Commun. 53, 12499–12511 (2017).

    Article  Google Scholar 

  39. Steinreiber, J., Faber, K. & Griengl, H. De-racemization of enantiomers versus de-epimerization of diastereomers—classification of dynamic kinetic asymmetric transformations (DYKAT). Chem. A Eur. J. 14, 8060–8072 (2008).

    Article  CAS  Google Scholar 

  40. Vo, C. V. T. & Bode, J. W. Synthesis of saturated N-heterocycles. J. Org. Chem. 79, 2809–2815 (2014).

    Article  CAS  Google Scholar 

  41. Källström, S. & Leino, R. Synthesis of pharmaceutically active compounds containing a disubstituted piperidine framework. Bioorg. Med. Chem. 16, 601–635 (2008).

    Article  Google Scholar 

  42. Cox, P. A., Leach, A. G., Campbell, A. D. & Lloyd-Jones, G. C. Protodeboronation of heteroaromatic, vinyl, and cyclopropyl boronic acids: pH-rate profiles, autocatalysis, and disproportionation. J. Am. Chem. Soc. 138, 9145–9157 (2016).

    Article  CAS  Google Scholar 

  43. Macchia, M. et al. New N-n-propyl-substituted 3-aryl- and 3-cyclohexylpiperidines as partial agonists at the D4 dopamine receptor. J. Med. Chem. 46, 161–168 (2003).

    Article  CAS  Google Scholar 

  44. Wikstrom, H. et al. Resolved 3-(3-hydroxypheny1)-N-n-propylpiperidine and its analogues: central dopamine receptor activity. J. Med. Chem. 27, 1030–1036 (1984).

    Article  CAS  Google Scholar 

  45. Kang, C.-Q., Cheng, Y.-Q., Guo, H.-Q., Qiu, X.-P. & Gao, L.-X. The natural alkaloid isoanabasine: synthesis from 2,30-bipyridine, efficient resolution with BINOL, and assignment of absolute configuration by Mosher’s method. Tetrahedron Asymmetry 16, 2141–2147 (2005).

    Article  CAS  Google Scholar 

  46. Wallace, D. J. et al. Development of a fit-for-purpose large-scale synthesis of an oral PARP inhibitor. Org. Process Res. Dev. 15, 831–840 (2011).

    Article  CAS  Google Scholar 

  47. Chung, C. K. et al. Process development of C–N cross-coupling and enantioselective biocatalytic reactions for the asymmetric synthesis of niraparib. Org. Process Res. Dev. 18, 215–227 (2014).

    Article  CAS  Google Scholar 

  48. Hughes, D. L. Patent review of manufacturing routes to recently approved PARP inhibitors: olaparib, rucaparib, and niraparib. Org. Process Res. Dev. 21, 1227–1244 (2017).

    Article  CAS  Google Scholar 

  49. Uson, R., Oro, L. A., Cabeza, J. A., Bryndza, H. E. & Stepro, M. P. in Inorganic Syntheses Vol 23 (ed. Kirschner, S.) 126−130 (John Wiley & Sons, 2007)

Download references

Acknowledgements

Financial support from the UK Engineering and Physical Sciences Research Council (EP/N022246/1) is gratefully acknowledged. J.G. thanks the European Union’s Horizon 2020 research and innovation program for a Marie Skłodowska-Curie Fellowship (GA 700108). L.v.D. is grateful to the Engineering and Physical Sciences Research Council (EPSRC) Centre for Doctoral Training in Synthesis for Biology and Medicine (EP/L015838/1) for a studentship, generously supported by AstraZeneca, Diamond Light Source, Defence Science and Technology Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta, Takeda, UCB and Vertex. F.W.G. is grateful to the National Research Fund, Luxembourg, for an AFR PhD grant (11588566), the EPSRC Doctoral Training Partnership (DTP) for a studentship (EP/N509711/1) and Vertex Pharmaceuticals for financial support.

Author information

Authors and Affiliations

  1. Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK

    Jesús González, Lucy van Dijk, F. Wieland Goetzke & Stephen P. Fletcher

Authors
  1. Jesús González
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lucy van Dijk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F. Wieland Goetzke
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stephen P. Fletcher
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.G., L.v.D. and F.W.G. conducted the experiments. All authors designed the experiments, analyzed the data and edited the manuscript. S.P.F. guided the research. J.G. wrote the manuscript. All authors contributed to discussions.

Corresponding author

Correspondence to Stephen P. Fletcher.

Ethics declarations

Competing interests

Oxford University Innovation has filed a patent application (PCT/GB2016/051612) with S.P.F. named as an inventor. The remaining authors declare no competing interests.

Additional information

Peer review information Nature Protocols thanks David Blakemore and Choonhong Tan for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

Key references using this protocol

Sidera, M. & Fletcher, S. P. Nat. Chem. 7, 935–939 (2015): https://www.nature.com/articles/nchem.2360

Schäfer, P., Palacin, T., Sidera, M. & Fletcher, S. P. Nat. Commun. 8, 15762 (2017): https://www.nature.com/articles/ncomms15762

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

González, J., van Dijk, L., Goetzke, F.W. et al. Highly enantioselective rhodium-catalyzed cross-coupling of boronic acids and racemic allyl halides. Nat Protoc 14, 2972–2985 (2019). https://doi.org/10.1038/s41596-019-0209-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41596-019-0209-8

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

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