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Enantioselective construction of remote quaternary stereocentres


Small molecules that contain all-carbon quaternary stereocentres—carbon atoms bonded to four distinct carbon substituents—are found in many secondary metabolites and some pharmaceutical agents. The construction of such compounds in an enantioselective fashion remains a long-standing challenge to synthetic organic chemists. In particular, methods for synthesizing quaternary stereocentres that are remote from other functional groups are underdeveloped. Here we report a catalytic and enantioselective intermolecular Heck-type reaction of trisubstituted-alkenyl alcohols with aryl boronic acids. This method provides direct access to quaternary all-carbon-substituted β-, γ-, δ-, ε- or ζ-aryl carbonyl compounds, because the unsaturation of the alkene is relayed to the alcohol, resulting in the formation of a carbonyl group. The scope of the process also includes incorporation of pre-existing stereocentres along the alkyl chain, which links the alkene and the alcohol, in which the stereocentre is preserved. The method described allows access to diverse molecular building blocks containing an enantiomerically enriched quaternary centre.

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Figure 1: Approaches to constructing acyclic all-carbon quaternary stereocentres.
Figure 2: Enantioselective construction of remote quaternary stereocentres.
Figure 3: Evaluation of alkene substrates containing a branch point.

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Data deposits

Data for the crystallized product (a derivative of 2f) have been deposited in the Cambridge Crystallographic Data Centre under accession number CCDC 988090.


  1. Trost, B. M. & Jiang, C. Catalytic enantioselective construction of all-carbon quaternary stereocenters. Synthesis 369–396 (2006)

  2. Douglas, C. J. & Overman, L. E. Catalytic asymmetric synthesis of all-carbon quaternary stereocenters. Proc. Natl Acad. Sci. USA 101, 5363–5367 (2004)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  3. Christoffers, J. & Mann, A. Enantioselective construction of quaternary stereocenters. Angew. Chem. Int. Ed. 40, 4591–4597 (2001)

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  5. Marek, I. et al. All-carbon quaternary stereogenic centers in acyclic systems through the creation of several C–C bonds per chemical step. J. Am. Chem. Soc. 136, 2682–2694 (2014)

    CAS  PubMed  Google Scholar 

  6. Masarwa, A. et al. Merging allylic carbon-hydrogen and selective carbon-carbon bond activation. Nature 505, 199–203 (2014)

    ADS  CAS  PubMed  Google Scholar 

  7. Liu, W.-B., Reeves, C. M. & Stoltz, B. M. Enantio-, diastereo-, and regioselective iridium-catalyzed asymmetric allylic alkylation of acyclic β-ketoesters. J. Am. Chem. Soc. 135, 17298–17301 (2013)

    CAS  PubMed  Google Scholar 

  8. Krautwald, S., Sarlah, D., Schafroth, M. A. & Carreira, E. M. Enantio- and diastereodivergent dual catalysis: α-allylation of branched aldehydes. Science 340, 1065–1068 (2013)

    ADS  CAS  PubMed  Google Scholar 

  9. Taylor, M. S. & Jacobsen, E. N. Enantioselective Michael additions to α,β-unsaturated imides catalyzed by a salen-Al complex. J. Am. Chem. Soc. 125, 11204–11205 (2003)

    CAS  PubMed  Google Scholar 

  10. Mermerian, A. H. & Fu, G. C. Catalytic enantioselective synthesis of quaternary stereocenters via intermolecular C-acylation of silyl ketene acetals: dual activation of the electrophile and the nucleophile. J. Am. Chem. Soc. 125, 4050–4051 (2003)

    CAS  PubMed  Google Scholar 

  11. Sawamura, M., Hamashima, H. & Ito, Y. Catalytic asymmetric synthesis with trans-chelating chiral diphosphine ligand TRAP: rhodium-catalyzed asymmetric Michael addition of α-cyano carboxylates. J. Am. Chem. Soc. 114, 8295–8296 (1992)

    CAS  Google Scholar 

  12. Mauleón, P. & Carretero, J. C. Enantioselective construction of stereogenic quaternary centers via Rh-catalyzed asymmetric addition of alkenylboronic acids to α,β-unsaturated pyridylsulfones. Chem. Commun. 4961–4963 (2005)

  13. Wu, J., Mampreian, D. M. & Hoveyda, A. H. Enantioselective synthesis of nitroalkanes bearing all-carbon quaternary stereogenic centers through Cu-catalyzed asymmetric conjugate additions. J. Am. Chem. Soc. 127, 4584–4585 (2005)

    CAS  PubMed  Google Scholar 

  14. Hawner, C. et al. Rhodium-catalyzed asymmetric 1,4-addition of aryl alanes to trisubstituted enones: BINAP as an effective ligand in the formation of quaternary stereocenters. Angew. Chem. Int. Ed. 49, 7769–7772 (2010)

    CAS  Google Scholar 

  15. Shintani, R., Takeda, M., Nishimura, T. & Hayashi, T. Chiral tetrafluorobenzobarrelenes as effective ligands for rhodium-catalyzed asymmetric 1,4-addition of arylboroxines to β,β-disubstituted α,β-unsaturated ketones. Angew. Chem. Int. Ed. 49, 3969–3971 (2010)

    CAS  Google Scholar 

  16. Dabrowski, J. A., Villaume, M. T. & Hoveyda, A. H. Enantioselective synthesis of quaternary carbon stereogenic centers through copper-catalyzed conjugate additions of aryl- and alkylaluminum reagents to acyclic trisubstituted enones. Angew. Chem. Int. Ed. 52, 8156–8159 (2013)

    CAS  Google Scholar 

  17. Jung, B. & Hoveyda, A. H. Site- and enantioselective formation of allene-bearing tertiary or quaternary carbon stereogenic centers through NHC–Cu-catalyzed allylic substitution. J. Am. Chem. Soc. 134, 1490–1493 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Lee, Y. & Hoveyda, A. H. Lewis base activation of Grignard reagents with N-heterocyclic carbenes. Cu-free catalytic enantioselective additions to γ-chloro-α,β-unsaturated esters. J. Am. Chem. Soc. 128, 15604–15605 (2006)

    CAS  PubMed  Google Scholar 

  19. Luchaco-Cullis, C. A., Mizutani, H., Murphy, K. E. & Hoveyda, A. H. Modular pyridinyl peptide ligands in asymmetric catalysis: enantioselective synthesis of quaternary carbon atoms through copper-catalyzed allylic substitutions. Angew. Chem. Int. Ed. 40, 1456–1460 (2001)

    CAS  Google Scholar 

  20. Denmark, S. E. & Fu, J. Catalytic, enantioselective addition of substituted allylic trichlorosilanes using a rationally-designed 2,2′-bispyrrolidine-based bisphosphoramide. J. Am. Chem. Soc. 123, 9488–9489 (2001)

    CAS  PubMed  Google Scholar 

  21. Shi, W.-J. et al. Highly enantioselective hydrovinylation of α-alkyl vinylarenes. An approach to the construction of all-carbon quaternary stereocenters. J. Am. Chem. Soc. 128, 2780–2781 (2006)

    CAS  PubMed  Google Scholar 

  22. Zhang, A. &. RajanBabu, T. V. All-carbon quaternary centers via catalytic asymmetric hydrovinylation. New approaches to the exocyclic side chain stereochemistry problem. J. Am. Chem. Soc. 128, 5620–5621 (2006)

    CAS  PubMed  Google Scholar 

  23. Zhang, P., Le, H., Kyne, R. E. & Morken, J. P. Enantioselective construction of all-carbon quaternary centers by branch-selective Pd-catalyzed allyl-allyl cross-coupling. J. Am. Chem. Soc. 133, 9716–9719 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Mei, T.-S., Werner, E. W., Burckle, A. J. & Sigman, M. S. Enantioselective redox-relay oxidative Heck arylations of acyclic alkenyl alcohols using boronic acids. J. Am. Chem. Soc. 135, 6830–6833 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Werner, E. W., Mei, T.-S., Burckle, A. J. & Sigman, M. S. Enantioselective Heck arylations of acyclic alkenyl alcohols using a redox-relay strategy. Science 338, 1455–1458 (2012)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sigman, M. S. & Werner, E. W. Imparting catalyst control upon classical palladium-catalyzed alkenyl C–H bond functionalization reactions. Acc. Chem. Res. 45, 874–884 (2012)

    CAS  PubMed  Google Scholar 

  27. Beletskaya, I. P. & Cheprakov, A. V. The Heck reaction as a sharpening stone of palladium catalysis. Chem. Rev. 100, 3009–3066 (2000)

    CAS  PubMed  Google Scholar 

  28. Calò, V., Nacci, A., Monopoli, A. & Ferola, V. Palladium-catalyzed Heck arylations of allyl alcohols in ionic liquids: remarkable base effect on the selectivity. J. Org. Chem. 72, 2596–2601 (2007)

    PubMed  Google Scholar 

  29. Bouquillon, S., Ganchegui, B., Estrine, B., Hénin, F. & Muzart, J. Heck arylation of allylic alcohols in molten salts. J. Organomet. Chem. 634, 153–156 (2001)

    CAS  Google Scholar 

  30. Dounay, A. B. & Overman, L. E. The asymmetric intramolecular Heck reaction in natural product total synthesis. Chem. Rev. 103, 2945–2964 (2003)

    CAS  PubMed  Google Scholar 

  31. Shibasaki, M., Vogl, E. M. & Ohshima, T. Asymmetric Heck reaction. Adv. Synth. Catal. 346, 1533–1552 (2004)

    CAS  Google Scholar 

  32. Mc Cartney, D. & Guiry, P. J. The asymmetric Heck and related reactions. Chem. Soc. Rev. 40, 5122–5150 (2011)

    CAS  PubMed  Google Scholar 

  33. Melpolder, J. B. & Heck, R. F. Palladium-catalyzed arylation of allylic alcohols with aryl halides. J. Org. Chem. 41, 265–272 (1976)

    CAS  Google Scholar 

  34. Dang, Y., Qu, S., Wang, Z.-X. & Wang, X. A Computational mechanistic study of an unprecedented Heck-type relay reaction: insight into the origins of regio- and enantioselectivities. J. Am. Chem. Soc. 136, 986–998 (2014)

    CAS  PubMed  Google Scholar 

  35. Xu, L. et al. Mechanism, reactivity, and selectivity in palladium-catalyzed redox-relay Heck arylations of alkenyl alcohols. J. Am. Chem. Soc. 136, 1960–1967 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Oliveira, C. C., Angnes, R. A. & Correia, C. R. D. Intermolecular enantioselective Heck–Matsuda arylations of acyclic olefins: application to the synthesis of β-aryl-γ-lactones and β-aryl aldehydes. J. Org. Chem. 78, 4373–4385 (2013)

    CAS  PubMed  Google Scholar 

  37. Kikushima, K., Holder, J. C., Gatti, M. & Stoltz, B. M. Palladium-catalyzed asymmetric conjugate addition of arylboronic acids to five-, six-, and seven-membered β-substituted cyclic enones: enantioselective construction of all-carbon quaternary stereocenters. J. Am. Chem. Soc. 133, 6902–6905 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Yoo, K. S. et al. Asymmetric intermolecular boron Heck-type reactions via oxidative palladium(II) catalysis with chiral tridentate NHC-amidate-alkoxide ligands. J. Org. Chem. 75, 95–101 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Yoo, K. S. et al. Asymmetric intermolecular Heck-type reaction of acyclic alkenes via oxidative palladium(II) catalysis. Org. Lett. 9, 3933–3935 (2007)

    CAS  PubMed  Google Scholar 

  40. Yonehara, K. et al. Palladium-catalyzed asymmetric intermolecular arylation of cyclic or acyclic alkenes using phosphinite-oxazoline ligands derived from d-glucosamine. J. Organomet. Chem. 603, 40–49 (2000)

    CAS  Google Scholar 

  41. Werner, E. W. & Sigman, M. S. A highly selective and general palladium catalyst for the oxidative Heck reaction of electronically nonbiased olefins. J. Am. Chem. Soc. 132, 13981–13983 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Yoo, K. S., Yoon, C. H. & Jung, K. W. Oxidative palladium(II) catalysis: a highly efficient and chemoselective cross-coupling method for carbon−carbon bond formation under base-free and nitrogenous-ligand conditions. J. Am. Chem. Soc. 128, 16384–16393 (2006)

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Du, X. et al. Mizoroki−Heck type reaction of organoboron reagents with alkenes and alkynes. A Pd(II)-catalyzed pathway with Cu(OAc)2 as an oxidant. Org. Lett. 3, 3313–3316 (2001)

    CAS  PubMed  Google Scholar 

  44. Gligorich, K. M. & Sigman, M. S. Recent advancements and challenges of palladiumII-catalyzed oxidation reactions with molecular oxygen as the sole oxidant. Chem. Commun. 3854–3867 (2009)

  45. Steinhoff, B. A., King, A. E. & Stahl, S. S. Unexpected roles of molecular sieves in palladium-catalyzed aerobic alcohol oxidation. J. Org. Chem. 71, 1861–1868 (2006)

    CAS  PubMed  Google Scholar 

  46. Kochi, T., Hamasaki, T., Aoyama, Y., Kawasaki, J. & Kakiuchi, F. Chain-walking strategy for organic synthesis: catalytic cycloisomerization of 1,N-dienes. J. Am. Chem. Soc. 134, 16544–16547 (2012)

    CAS  PubMed  Google Scholar 

  47. Johnson, L. K., Killian, C. M. & Brookhart, M. New Pd(II)- and Ni(II)-based catalysts for polymerization of ethylene and α-olefins. J. Am. Chem. Soc. 117, 6414–6415 (1995)

    CAS  Google Scholar 

  48. Larock, R. C., Leung, W.-Y. & Stolz-Dunn, S. Synthesis of aryl-substituted aldehydes and ketones via palladium-catalyzed coupling of aryl halides and non-allylic unsaturated alcohols. Tetrahedr. Lett. 30, 6629–6632 (1989)

    CAS  Google Scholar 

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We thank the US National Institutes of Health (NIGMS GM063540) for financial support.

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T.-S.M. and H.H.P. performed the experiments and analysed the data. T.-S.M. and M.S.S. designed the experiments. T.-S.M. and M.S.S. prepared this manuscript with feedback from H.H.P.

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Correspondence to Matthew S. Sigman.

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The authors declare no competing financial interests.

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Mei, TS., Patel, H. & Sigman, M. Enantioselective construction of remote quaternary stereocentres. Nature 508, 340–344 (2014).

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