Enantiospecific sp2sp3 coupling of secondary and tertiary boronic esters

Abstract

The cross-coupling of boronic acids and related derivatives with sp2 electrophiles (the Suzuki–Miyaura reaction) is one of the most powerful C–C bond formation reactions in synthesis, with applications that span pharmaceuticals, agrochemicals and high-tech materials. Despite the breadth of its utility, the scope of this Nobel prize-winning reaction is rather limited when applied to aliphatic boronic esters. Primary organoboron reagents work well, but secondary and tertiary boronic esters do not (apart from a few specific and isolated examples). Through an alternative strategy, which does not involve using transition metals, we have discovered that enantioenriched secondary and tertiary boronic esters can be coupled to electron-rich aromatics with essentially complete enantiospecificity. As the enantioenriched boronic esters are easily accessible, this reaction should find considerable application, particularly in the pharmaceutical industry where there is growing awareness of the importance of, and greater clinical success in, creating biomolecules with three-dimensional architectures.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Proposed method for stereospecific coupling of boronic esters with an illustration of previous literature and key results.
Figure 2: Range of secondary and tertiary boronic esters tested in this study.
Figure 3: Possible reaction pathways for the reactions of aryl–boronate complexes with electrophiles, illustrated with [Br+].

References

  1. 1

    Suzuki, A. Cross-coupling reactions of organoboranes: an easy way to construct C–C bonds (Nobel Lecture). Angew. Chem. Int. Ed. 50, 6722–6737 (2011).

    CAS  Article  Google Scholar 

  2. 2

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

    CAS  Article  Google Scholar 

  3. 3

    Molander, G. A. & Wisniewski, S. R. Stereospecific cross-coupling of secondary organotrifluoroborates: potassium 1-(benzyloxy)alkyltrifluoroborates. J. Am. Chem. Soc. 134, 16856–16868 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4

    Awano, T., Ohmura, T. & Suginome, M. Inversion or retention? Effects of acidic additives on the stereochemical course in enantiospecific Suzuki–Miyaura coupling of α-(acetylamino)benzylboronic esters. J. Am. Chem. Soc. 133, 20738–20741 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5

    Ohmura, T., Awano, T. & Suginome, M. Stereospecific Suzuki−Miyaura coupling of chiral α-(acylamino)benzylboronic esters with inversion of configuration. J. Am. Chem. Soc. 132, 13191–13193 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  6. 6

    Sandrock, D. L., Jean-Gérard, L., Chen, C-Y., Dreher, S. D. & Molander, G. A. Stereospecific cross-coupling of secondary alkyl β-trifluoroboratoamides. J. Am. Chem. Soc. 132, 17108–17110 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7

    Imao, D., Glasspoole, B. W., Laberge, V. S. & Crudden, C. M. Cross coupling reactions of chiral secondary organoboronic esters with retention of configuration. J. Am. Chem. Soc. 131, 5024–5025 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. 8

    Lee, J. C. H., McDonald, R. & Hall, D. G. Enantioselective preparation and chemoselective cross-coupling of 1,1-diboron compounds. Nature Chem. 3, 894–899 (2011).

    CAS  Article  Google Scholar 

  9. 9

    Zhou, S-M., Deng, M-Z., Xia, L-J. & Tang, M-H. Efficient Suzuki-type cross-coupling of enantiomerically pure cyclopropylboronic acids. Angew. Chem. Int. Ed. 37, 2845–2847 (1998).

    CAS  Article  Google Scholar 

  10. 10

    Partridge, B. M., Chausset-Boissarie, L., Burns, M., Pulis, A. P. & Aggarwal, V. K. Enantioselective synthesis and cross-coupling of tertiary propargylic boronic esters using lithiation–borylation of propargylic carbamates. Angew. Chem. Int. Ed. 51, 11795–11799 (2012).

    CAS  Article  Google Scholar 

  11. 11

    Chausset-Boissarie, L. et al. Enantiospecific, regioselective cross-coupling reactions of secondary allylic boronic esters. Chem. Eur. J. 19, 17698–17701 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. 12

    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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  13. 13

    Dreher, S. D., Dormer, P. G., Sandrock, D. L. & Molander, G. A. Efficient cross-coupling of secondary alkyltrifluoroborates with aryl chlorides—reaction discovery using parallel microscale experimentation. J. Am. Chem. Soc. 130, 9257–9259 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14

    Kataoka, N., Shelby, Q., Stambuli, J. P. & Hartwig, J. F. Air stable, sterically hindered ferrocenyl dialkylphosphines for palladium-catalyzed C–C, C–N, and C–O bond-forming cross-couplings. J. Org. Chem. 67, 5553–5566 (2002).

    CAS  PubMed  Article  Google Scholar 

  15. 15

    Swift, E. C. & Jarvo, E. R. Asymmetric transition metal-catalyzed cross-coupling reactions for the construction of tertiary stereocenters. Tetrahedron 69, 5799–5817 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16

    Saito, B. & Fu, G. C. Enantioselective alkyl–alkyl Suzuki cross-couplings of unactivated homobenzylic halides. J. Am. Chem. Soc. 130, 6694–6695 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  17. 17

    Zhou, J. & Fu, G. C. Cross-couplings of unactivated secondary alkyl halides: room-temperature nickel-catalyzed Negishi reactions of alkyl bromides and iodides. J. Am. Chem. Soc. 125, 14726–14727 (2003).

    CAS  PubMed  Article  Google Scholar 

  18. 18

    Son, S. & Fu, G. C. Nickel-catalyzed asymmetric Negishi cross-couplings of secondary allylic chlorides with alkylzincs. J. Am. Chem. Soc. 130, 2756–2757 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 19

    Cordier, C-J., Lundgren, R. J. & Fu, G. C. Enantioconvergent cross-couplings of racemic alkylmetal reagents with unactivated secondary alkyl electrophiles: catalytic asymmetric Negishi α-alkylations of N-Boc-pyrrolidine. J. Am. Chem. Soc. 135, 10946–10949 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20

    Li, L., Wang, C-Y., Huang, R. & Biscoe, M. R. Stereoretentive Pd-catalysed Stille cross-coupling reactions of secondary alkyl azastannatranes and aryl halides. Nature Chem. 5, 607–612 (2013).

    CAS  Article  Google Scholar 

  21. 21

    Kalkofen, R. & Hoppe, D. First example of an enantiospecific sp3sp2 Stille coupling of a chiral allylstannane with aryl halides. Synlett 12, 1959–1961 (2006).

    Google Scholar 

  22. 22

    Falk, J. R., Patel, P. K. & Bandyopadhyay, A. Stereospecific cross-coupling of alpha-(thiocarbamoyl)organostannanes with alkenyl, aryl, and heteroaryl iodides. J. Am. Chem. Soc. 129, 790–793 (2007).

    Article  CAS  Google Scholar 

  23. 23

    Yonova, I. M. et al. Stereospecific nickel-catalyzed cross-coupling reactions of alkyl Grignard reagents and identification of selective anti-breast-cancer agents. Angew. Chem. Int. Ed. 129, 2454–2459 (2014).

    Article  Google Scholar 

  24. 24

    Zhou, Q., Srinivas, H. D., Dasgupta, S. & Watson, M. P. Nickel-catalyzed cross-couplings of benzylic pivalates with arylboroxines: stereospecific formation of diarylalkanes and triarylmethanes. J. Am. Chem. Soc. 135, 3307–3310 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25

    Levy, A. B. Aromatic substitution via organoboranes. Regiospecific formation of 2-alkylindoles. J. Org. Chem. 43, 4684–4685 (1978).

    CAS  Article  Google Scholar 

  26. 26

    Ishikura, M. & Kato, M. A synthetic use of the intramolecular alkyl migration process in indolylborates for intramolecular cyclization: a novel construction of carbazole derivatives. Tetrahedron 58, 9827–9838 (2002).

    CAS  Article  Google Scholar 

  27. 27

    Akimoto, I. & Suzuki, A. Synthesis of 2-alkylfurans via the reaction of iodine with the ate-complexes obtained from 2-furyllithium and trialkylboranes. Synthesis 146–148 (1979).

  28. 28

    Pelter, A., Williamson, H. & Davies, G. M. Aryl coupling through borate complexes with ethanolamine. Tetrahedron Lett. 25, 453–456 (1984).

    CAS  Article  Google Scholar 

  29. 29

    Marinelli, E. R. & Levy, A. B. Aromatic substitution via organoboranes 2. Regiospecific alkylation of the furan and pyrrole nucleus. Tetrahedron Lett. 20, 2313–2316 (1979).

    Article  Google Scholar 

  30. 30

    Ishikura, M., Kato, M. & Ohnuki, N. A novel C–C bond formation reaction with 1-methoxymethylindolylborate. Chem. Commun. 220–221 (2002).

  31. 31

    Kagan, J. & Arora, S. K. The synthesis of alpha-thiophene oligomers via organoboranes. Tetrahedron Lett. 24, 4043–4046 (1983).

    CAS  Article  Google Scholar 

  32. 32

    Davies, G. M., Davies, P. S., Paget, W. E. & Wardleworth, J. M. Borinic acids: novel intermediates in regiospecific synthesis of biaryls. Tetrahedron Lett. 17, 795–798 (1976).

    Article  Google Scholar 

  33. 33

    Labadie, S. S. & Teng, E. Indol-2-yltributylstannane: a versatile reagent for 2-substituted indoles. J. Org. Chem. 59, 4250–4254 (1994).

    CAS  Article  Google Scholar 

  34. 34

    Levy, A. B. Aromatic substitution via organoboranes. 3. Simultaneous regiospecific functionalization of the indole nucleus at the 2- and 3-positions. Tetrahedron Lett. 20, 4021–4024 (1979).

    Article  Google Scholar 

  35. 35

    Brown, H. C., De Lue, N. R., Kabalka, G. W. & Hedgecock, H. C. J. Consistent inversion in the base-induced reaction of iodine with organoboranes. A convenient procedure for the synthesis of optically active iodides. J. Am. Chem. Soc. 98, 1290–1291 (1976).

    CAS  Article  Google Scholar 

  36. 36

    Kabalka, G. W. & Gooch, E. E. I. A mild and convenient procedure for conversion of alkenes into alkyl iodides via reaction of iodine monochloride with organoboranes. J. Org. Chem. 45, 3578–3580 (1980).

    CAS  Article  Google Scholar 

  37. 37

    Brown, H. C. & Lane, C. F. Base-induced bromination of tri-exo-norbornylborane: an electrophilic substitution with predominant inversion of configuration. J. Chem. Soc. Chem. Commun. 521–522 (1971).

  38. 38

    Larouche-Gauthier, R., Elford, T. G. & Aggarwal, V. K. Ate complexes of secondary boronic esters as chiral organometallic-type nucleophiles for asymmetric synthesis. J. Am. Chem. Soc. 133, 16794–16797 (2011).

    CAS  PubMed  Article  Google Scholar 

  39. 39

    Stymiest, J. L., Dutheuil, D., Mohmood, E. & Aggarwal, V. K. Lithiated carbamates: chiral carbenoids for iterative homologation of boranes and boronic esters. Angew. Chem. Int. Ed. 46, 7491–7494 (2007).

    CAS  Article  Google Scholar 

  40. 40

    Stymiest, J. L., Bagutski, V., French, R. M. & Aggarwal, V. K. Enantiodivergent conversion of chiral secondary alcohols into tertiary alcohols. Nature 456, 778–782 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41

    Bagutski, V., French, R. M. & Aggarwal, V. K. Full chirality transfer in the conversion of secondary alcohols into tertiary boronic esters and alcohols using lithiation–borylation reactions. Angew. Chem. Int. Ed. 49, 5142–5145 (2010).

    CAS  Article  Google Scholar 

  42. 42

    Pulis, A. P., Blair, D. J., Torres, E. & Aggarwal, V. K. Synthesis of enantioenriched tertiary boronic esters by the lithiation/borylation of secondary alkyl benzoates. J. Am. Chem. Soc. 135, 16054–16057 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. 43

    Batsanov, A. S., Grosjean, C., Schultz, T. & Whiting, A. A (–)-Sparteine-directed highly enantioselective synthesis of boroproline. Solid- and solution-state structure and properties. J. Org. Chem. 72, 6276–6279 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  44. 44

    Villa, G., Povie, G. & Renaud, P. Radical chain reduction of alkylboron compounds with catechols. J. Am. Chem. Soc. 133, 5913–5920 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. 45

    Paras, N., Simmons, B. & MacMillan, D. W. C. A process for the rapid removal of dialkylamino-substituents from aromatic rings. Application to the expedient synthesis of (R)-tolterodine. Tetrahedron 65, 3232–3238 (2009).

    CAS  Article  Google Scholar 

  46. 46

    Blakey, S. B. & MacMillan, D. W. C. The first Suzuki cross-coupling of aryltrimethylammonium ions. J. Am. Chem. Soc. 125, 6046–6047 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. 47

    Koehn, F. E. & Carter, G. T. The evolving role of natural products in drug discovery. Nature Rev. 4, 206–220 (2005).

    CAS  Google Scholar 

  48. 48

    Mohiti, M., Rampalakos, C., Feeney, K., Leonori, D. & Aggarwal, V. K. Asymmetric addition of chiral boron-ate complexes to cyclic iminium ions. Chem. Sci. 5, 602–607 (2013).

    Article  Google Scholar 

  49. 49

    Berionni, G., Maji, B., Knochel, P. & Mayr, H. Nucleophilicity parameters for designing transition metal-free C–C bond forming reactions of organoboron compounds. Chem. Sci. 3, 878–882 (2012).

    CAS  Article  Google Scholar 

  50. 50

    Reichardt, C. & Welton, T. E. Solvents and Solvent Effects in Organic Chemistry 4th edn (Wiley, 2010).

    Google Scholar 

Download references

Acknowledgements

We thank the Engineering and Physical Sciences Research Council (EP/I038071/1) and the European Research Council (FP7/2007-2013, ERC grant no. 246785) for financial support. A.B. thanks the Marie Curie Fellowship program (EC FP7 No 329578). We thank H. Mayr, V. Rawal and J. N. Harvey for useful discussions.

Author information

Affiliations

Authors

Contributions

D.L. and V.K.A. designed the project and wrote the manuscript. A.B. and M.O. contributed intellectually and practically to the laboratory experiments, S.E. performed preliminary computational studies and was involved in the mechanistic discussions.

Corresponding author

Correspondence to Varinder K. Aggarwal.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 8606 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bonet, A., Odachowski, M., Leonori, D. et al. Enantiospecific sp2sp3 coupling of secondary and tertiary boronic esters. Nature Chem 6, 584–589 (2014). https://doi.org/10.1038/nchem.1971

Download citation

Further reading

Search

Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing