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Enantioselective preparation and chemoselective cross-coupling of 1,1-diboron compounds

A Corrigendum to this article was published on 20 June 2013

This article has been updated


The simplicity, efficiency and generality of the transition-metal-catalysed Suzuki–Miyaura cross-coupling reaction has led to its application in the preparation of a wide variety of organic compounds. Cross-coupling of alkylboron derivatives, however, remains a major challenge, in particular with regard to stereochemical control. Here, we describe the preparation and reaction of highly optically enriched 1,1-diboron compounds. A catalytic asymmetric conjugate borylation of β-boronylacrylates provided geminal diboronate products that feature two distinct boronyl units, in 99% enantiomeric excess. Chemoselective cross-coupling of one-boronyl unit, a trifluoroborate salt, occurred stereospecifically via inversion of its configuration to generate enantioenriched benzylic or allylic boronates. The difficult transmetallation in the Suzuki–Miyaura catalytic reaction cycle is believed to be facilitated by a stabilization effect from the second boronyl unit, and internal coordination by the oxygen of the proximal carboxyester. We also explored subsequent functionalization of the second boronyl unit.

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Figure 1: Suzuki–Miyaura cross-coupling reactions with enantioenriched secondary alkyl boronate derivatives.
Figure 2
Figure 3: Proposed transition state for the stereospecific cross-coupling reaction of 3,3-diboronyl carboxyester 9 and applications of mono cross-coupled products 10.

Change history

  • 10 May 2013

    In the version of this Article originally published, in Table 1, the ferrocene-based ligands 4, 5, 7 and 8 should have had 1,2-substituted cyclopentadienyl rings rather than 1,3-substituted. This error has been corrected in the HTML and PDF versions of this Article.


  1. 1

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

    CAS  Google Scholar 

  2. 2

    Bellina, F., Carpita, A. & Rossi, R. Palladium catalysts for the Suzuki cross-coupling reaction: an overview of recent advances. Synthesis 15, 2419–2440 (2004).

    Google Scholar 

  3. 3

    Rudolph, A. & Lautens, M. Secondary alkyl halides in transition-metal-catalyzed cross-coupling reactions. Angew. Chem. Int. Ed. 48, 2656–2670 (2009).

    CAS  Google Scholar 

  4. 4

    Molander, G. A. & Canturk, B. Organotrifluoroborates and monocoordinated palladium complexes as catalysts—a perfect combination for Suzuki–Miyaura coupling. Angew. Chem. Int. Ed. 48, 9240–9261 (2009).

    CAS  Google Scholar 

  5. 5

    Chemler, S. R., Trauner, D. & Danishefsky, S. J. The β-alkyl Suzuki–Miyaura cross-coupling reaction: development, mechanistic study, and applications in natural product synthesis. Angew. Chem. Int. Ed. 40, 4544–4568 (2001).

    CAS  Google Scholar 

  6. 6

    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  Google Scholar 

  7. 7

    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  Google Scholar 

  8. 8

    Sandrock, D., 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, 17109–17110 (2010).

    Google Scholar 

  9. 9

    Zou, G. & Falck, J. R. Suzuki–Miyaura cross-coupling of lithium n-alkylborates. Tetrahedron Lett. 42, 5817–5819 (2001).

    CAS  Google Scholar 

  10. 10

    Zhou, J. R. & 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  Google Scholar 

  11. 11

    Zhou, J. R. & Fu, G. C. Palladium-catalyzed Negishi cross-coupling reactions of unactivated alkyl iodides, bromides, chlorides, and tosylates. J. Am. Chem. Soc. 125, 12527–12530 (2003).

    CAS  PubMed  Google Scholar 

  12. 12

    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  Google Scholar 

  13. 13

    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  Google Scholar 

  14. 14

    He, A. & Falck, J. R. Stereospecific Suzuki cross-coupling of alkyl α-cyanohydrin triflates. J. Am. Chem. Soc. 132, 2524–2525 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Endo, K., Ohkubo, T., Hirokami, M. & Shibata, T. Chemoselective and regiospecific Suzuki coupling on a multisubstituted sp3-carbon in 1,1-diborylalkanes at room temperature. J. Am. Chem. Soc. 132, 11033–11035 (2010).

    CAS  PubMed  Google Scholar 

  16. 16

    Lee, J. C. H. & Hall, D. G. Chiral boronate derivatives via catalytic enantioselective conjugate addition of Grignard reagents on 3-boronyl unsaturated esters and thioesters. J. Am. Chem. Soc. 132, 5544–5545 (2010).

    CAS  PubMed  Google Scholar 

  17. 17

    Gao, M., Thorpe, S. B. & Santos, W. L. sp2sp3 hybridized mixed diboron: synthesis, characterization, and copper-catalyzed β-boration of α,β-unsaturated conjugated compounds. Org. Lett. 11, 3478–3481 (2009).

    CAS  PubMed  Google Scholar 

  18. 18

    Lee, J. E. & Yun, J. Catalytic asymmetric boration of acyclic α,β-unsaturated esters and nitriles. Angew. Chem. Int. Ed. 47, 145–147 (2008).

    CAS  Google Scholar 

  19. 19

    Sim, H. S., Feng, X. & Yun, J. Copper-catalyzed enantioselective β-boration of acyclic enones. Chem. Eur. J. 15, 1939–1943 (2009).

    CAS  PubMed  Google Scholar 

  20. 20

    Feng, X. & Yun, J. Conjugate boration of β,β-disubstituted unsaturated esters: asymmetric synthesis of functionalized chiral tertiary organoboronic esters. Chem. Eur. J. 16, 13609–13612 (2010).

    CAS  PubMed  Google Scholar 

  21. 21

    Flack, H. D. On enantiomorph-polarity estimation. Acta. Crystallogr. A39, 876–881 (1983).

    CAS  Google Scholar 

  22. 22

    Flack, H. D. & Bernardinelli, G. Absolute structure and absolute configuration. Acta. Crystallogr. A55, 908–915 (1999).

    CAS  Google Scholar 

  23. 23

    Flack, H. D. & Bernardinelli, G. Reporting and evaluating absolute-structure and absolute-configuration determinations. J. Appl. Cryst. 33, 1143–1148 (2000).

    CAS  Google Scholar 

  24. 24

    Ho, O. C. et al. ((Trityloxy)methyl)boronic esters. Organometallics 14, 2855–2860 (1995).

    CAS  Google Scholar 

  25. 25

    Noguchi, H., Hojo, K. & Suginome, M. Boron-masking strategy for the selective synthesis of oligoarenes via iterative Suzuki−Miyaura coupling. J. Am. Chem. Soc. 129, 758–759 (2007).

    CAS  PubMed  Google Scholar 

  26. 26

    Noguchi, H., Shilda, T., Chou, C-M. & Suginome, M. Differentially protected benzenediboronic acids: divalent cross-coupling modules for the efficient synthesis of boron-substituted oligoarenes. Org. Lett. 10, 377–380 (2008).

    CAS  PubMed  Google Scholar 

  27. 27

    Xu, C. & Yuan, C. Candida Rugosa lipase-catalyzed kinetic resolution of β-hydroxy-β-arylpropionates and δ-hydroxy-δ-aryl-β-oxo-pentanoates. Tetrahedron 61, 2169–2186 (2005).

    CAS  Google Scholar 

  28. 28

    Gao, X. & Hall, D. G. 3-Boronoacrolein as an exceptional heterodiene in the highly enantio- and diastereoselective Cr(III)-catalyzed three-component [4+2]/allylboration. J. Am. Chem. Soc. 125, 9308–9309 (2003).

    CAS  PubMed  Google Scholar 

  29. 29

    Carosi, L. & Hall, D. G. Catalytic enantioselective preparation of α-substituted allylboronates: one-pot addition to functionalized aldehydes and a route to chiral allylic trifluoroborate reagents. Angew. Chem. Int. Ed. 46, 5913–5915 (2007).

    CAS  Google Scholar 

  30. 30

    Lessard, S., Peng, F. & Hall, D. G. α-Hydroxyalkyl heterocycles via chiral allylic boronates: Pd-catalyzed borylation leading to a formal enantioselective isomerization of allylic ether and amine. J. Am. Chem. Soc. 131, 9612–9613 (2009).

    CAS  PubMed  Google Scholar 

  31. 31

    Ito, H., Ito, S., Sasaki, Y., Matsuura, K. & Sawamura, M. Copper-catalyzed enantioselective substitution of allylic carbonates with diboron: an efficient route to optically active α-chiral allylboronates. J. Am. Chem. Soc. 129, 14856–14857 (2007).

    CAS  PubMed  Google Scholar 

  32. 32

    Guzman-Martinez, A. & Hoveyda, A. H. Enantioselective synthesis of allylboronates bearing a tertiary or quaternary β-substituted stereogenic carbon by NHC-Cu-catalyzed substitution reactions. J. Am. Chem. Soc. 132, 10634–10637 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Denmark, S. E. & Fu, J. Catalytic enantioselective addition of allylic organometallic reagents to aldehydes and ketones. Chem. Rev. 103, 2763–2793 (2003).

    CAS  PubMed  Google Scholar 

  34. 34

    Hall, D. G. Lewis and Brønsted acid catalyzed allylboration of carbonyl compounds: from discovery to mechanism and applications. Synlett 11, 1644–1655 (2007).

    Google Scholar 

  35. 35

    Lachance, H. & Hall, D. G. Allylboration of Carbonyl Compounds. Organic Reactions 1–574 (Wiley, 2008).

    Google Scholar 

  36. 36

    Roush, W. R. & Grover, P. T. Diisopropyl tartrate (ɛ)-γ-(dimethylphenylsilyl)allylboronate, a chiral allylic alcohol β-carbanion equivalent for the enantioselective synthesis of 2-butene-1,4-diols from aldehydes. Tetrahedron Lett. 31, 7567–7570 (1990).

    CAS  Google Scholar 

  37. 37

    Hunt, J. A. & Roush, W. R. 4,5-Diisopropyl-β-[(ɛ)-[(3′-menthofuryl)dimethylsilyl]allyl]-1,3,2- dioxaborolane, an improved chiral reagent for the anti α-hydroxyallylation of aldehydes: application to the enantioselective synthesis of (−)-swainsonine. J. Org. Chem. 62, 1112–1124 (1997).

    CAS  Google Scholar 

  38. 38

    Flamme, E. M. & Roush, W. R. Enantioselective synthesis of 1,5-anti- and 1,5-syn-diols using a highly diastereoselective one-pot double allylboration reaction sequence. J. Am. Chem. Soc. 124, 13644–13645 (2002).

    CAS  PubMed  Google Scholar 

  39. 39

    Binanzer, M., Fang, G. Y. & Aggarwal, V. K. Asymmetric synthesis of allylsilanes by the borylation of lithiated carbamates: formal total synthesis of (–)-decarestrictine D. Angew. Chem. Int. Ed. 49, 4264–4268 (2010).

    CAS  Google Scholar 

  40. 40

    Butters, M., Harvey, J., Jover, J., Lennox, A., Lloyd-Jones, G. & Murray, P. Aryl trifluoroborates in Suzuki–Miyaura coupling: the roles of endogenous aryl boronic acid and fluoride. Angew. Chem. Int. Ed. 49, 5156–5160 (2010).

    CAS  Google Scholar 

  41. 41

    Yang, X. & Birman, V. B. Acyl transfer catalysis with 1,2,4-triazole anion. Org. Lett. 11, 1499–1502 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Fessard, T. C., Andrews, S. P., Motoyoshi, H. & Carreira, E. M. Enantioselective preparation of 1,1-diarylethanes: aldehydes as removable steering groups for asymmetric synthesis. Angew. Chem. Int. Ed. 46, 9331–9334 (2007) and references therein.

    CAS  Google Scholar 

  43. 43

    Yu, S. H., Ferguson, M. J., McDonald, R. & Hall, D. G. Brønsted acid-catalyzed allylboration: short and stereodivergent synthesis of all four eupomatilone diastereomers with crystallographic assignments. J. Am. Chem. Soc. 127, 12808–12809 (2005).

    CAS  PubMed  Google Scholar 

  44. 44

    Elford, T., Yu, S. H., Arimura, Y. & Hall, D. G. Triflic acid-catalyzed additions of 2-alkoxycarbonyl allylboronates to aldehydes. Study of scope and mechanistic investigation of the reaction stereochemistry. J. Org. Chem. 72, 1276–1277 (2007).

    CAS  PubMed  Google Scholar 

  45. 45

    Li, Y. & Houk, K. N. Transition structures for the allylboration reactions of formaldehyde by allylborane and allylboronic acid. J. Am. Chem. Soc. 111, 1236–1240 (1989).

    CAS  Google Scholar 

  46. 46

    Kennedy, J. W. J. & Hall, D. G. Dramatic rate enhancement with preservation of stereospecificity in the first metal-catalyzed additions of allylboronates. J. Am. Chem. Soc. 124, 11586–11587 (2002).

    CAS  PubMed  Google Scholar 

  47. 47

    Carosi, L. & Hall, D. G. Catalytic enantioselective preparation of alpha-substituted allylboronates. One-pot addition to functionalized aldehydes and a route to chiral allylic trifluoroborate salts. Angew. Chem. Int. Ed. 46, 5913–5915 (2007).

    CAS  Google Scholar 

  48. 48

    Althaus, M., Mahmood, A., Ramón Suárez, J., Thomas, S. P. & Aggarwal, V. K. Application of the lithiation-borylation reaction to the preparation of enantioenriched allylic boron reagents and subsequent in situ conversion into 1,2,4-trisubstituted homoallylic alcohols with complete control over all elements of stereochemistry. J. Am. Chem. Soc. 132, 4025–4028 (2010).

    CAS  PubMed  Google Scholar 

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This research was generously funded by the Natural Sciences and Engineering Research Council (NSERC) of Canada, and the University of Alberta. J.C.H.L. thanks the University of Alberta for a Queen Elizabeth II Graduate Scholarship. The authors are grateful to M. Ferguson of the X-ray Crystallographic Laboratory (analysis of 2a) and to the Spectral Services staff at the University of Alberta, Department of Chemistry. The authors thank Solvias AG (H. Steiner and H.-U. Blaser) for a generous gift of chiral ligands.

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J.C.H.L. performed the experiments. R.M. performed the X-ray crystallographic analysis of 2b. D.G.H. directed the project. The manuscript was co-written by J.C.H.L. and D.G.H.

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Correspondence to Dennis G. Hall.

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The authors declare no competing financial interests.

Supplementary information

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Crystallographic data for compound 2a (CIF 17 kb)

Supplementary information

Crystallographic data for compound 2b (CIF 32 kb)

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

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