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.

Catalytic enantioselective synthesis of quaternary carbon stereocentres

Abstract

Quaternary carbon stereocentres—carbon atoms to which four distinct carbon substituents are attached—are common features of molecules found in nature. However, before recent advances in chemical catalysis, there were few methods of constructing single stereoisomers of this important structural motif. Here we discuss the many catalytic enantioselective reactions developed during the past decade for the synthesis of single stereoisomers of such organic molecules. This progress now makes it possible to incorporate quaternary stereocentres selectively in many organic molecules that are useful in medicine, agriculture and potentially other areas such as flavouring, fragrances and materials.

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: Quaternary stereocentres are important structural features of many biologically active molecules, as exemplified by the natural products cortisone and morphine.
Figure 2: The use of catalytic enantioselective Diels–Alder reactions to synthesize natural products containing quaternary stereocentres.
Figure 3: Examples of other catalytic enantioselective cycloaddition reactions used to prepare products containing quaternary stereocentres.
Figure 4: Catalytic enantioselective polyene cyclizations to construct polycyclic products having quaternary stereocentres.
Figure 5: Transition metal-catalysed insertion reactions that form quaternary stereocentres.
Figure 6: Enantioselective copper-catalysed conjugate additions to construct quaternary stereocentres.
Figure 7: Use of the enantioselective intramolecular Stetter reaction and allylic alkylation reactions to construct quaternary stereocentres.
Figure 8: Use of palladium-catalysed asymmetric allylic alkylation reactions for constructing quaternary centres in alkaloid and terpenoid natural products.
Figure 9: Miscellaneous methods involving the union of a catalytically generated chiral carbon electrophile with a carbon nucleophile.
Figure 10: Enantioselective desymmetrization reactions of precursors containing prochiral quaternary carbons.

References

  1. Bartholow, M. Top 200 drugs of 2011. Pharm. Times 48–51 (10 July 2012)

  2. Ding, H. X., Liu, K. K.-C., Sakya, S. M., Flick, A. C. & O’Donnell, C. J. Synthetic approaches to the 2011 new drugs. Bioorg. Med. Chem. 21, 2795–2825 (2013)

    CAS  PubMed  Google Scholar 

  3. Christoffers J., Baro A., eds. Quaternary Stereocenters — Challenges and Solutions for Organic Synthesis (Wiley-VCH, 2005)

  4. Hong, A. Y. & Stoltz, B. M. The construction of all-carbon quaternary stereocenters by use of Pd-catalyzed asymmetric allylic alkylation reactions in total synthesis. Eur. J. Org. Chem. 2745–2759 (2013)

  5. 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  Google Scholar 

  6. Wilson, R. M., Jen, W. S. & MacMillan, D. W. C. Enantioselective organocatalytic intramolecular Diels–Alder reactions. The asymmetric synthesis of solanapyrone D. J. Am. Chem. Soc. 127, 11616–11617 (2005)

    CAS  PubMed  Google Scholar 

  7. Jones, S. B., Simmons, B., Mastracchio, A. & MacMillan, D. W. C. Collective synthesis of natural products by means of organocascade catalysis. Nature 475, 183–188 (2011)A highlight of the use of iminium activation and cascade catalysis in the synthesis of alkaloid natural products.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Laforteza, B. N., Pickworth, M. & MacMillan, D. W. C. Enantioselective total synthesis of (–)-minovincine in nine chemical steps: an approach to ketone activation in cascade catalysis. Angew. Chem. Int. Edn 52, 11269–11272 (2013)

    CAS  Google Scholar 

  9. Liu, Y., Nappi, M., Arceo, E., Vera, S. & Melchiorre, P. Asymmetric catalysis of Diels–Alder reactions with in situ generated heterocyclic ortho-quinodimethanes. J. Am. Chem. Soc. 133, 15212–15218 (2011)

    CAS  PubMed  Google Scholar 

  10. Tan, B., Hernández-Torres, G. & Barbas, C. F., III Highly efficient hydrogen-bonding catalysis of the Diels–Alder reaction of 3-vinylindoles and methyleneindolinones provides carbazolespirooxindole skeletons. J. Am. Chem. Soc. 133, 12354–12357 (2011)

    CAS  PubMed  Google Scholar 

  11. Shimizu, Y., Shi, S.-L., Usuda, H., Kanai, M. & Shibasaki, M. Catalytic asymmetric total synthesis of ent-hyperforin. Angew. Chem. Int. Edn 49, 1103–1106 (2010)

    CAS  Google Scholar 

  12. Snyder, S. A. & Corey, E. J. Concise total syntheses of palominol, dolabellatrienone, β-araneosene, and isoedunol via an enantioselective Diels–Alder macrobicyclization. J. Am. Chem. Soc. 128, 740–742 (2006)

    CAS  PubMed  Google Scholar 

  13. Balskus, E. P. & Jacobsen, E. N. Asymmetric catalysis of the transannular Diels–Alder reaction. Science 317, 1736–1740 (2007)

    ADS  CAS  PubMed  Google Scholar 

  14. Lian, Y. & Davies, H. M. L. Rhodium-catalyzed [3 + 2] annulation of indoles. J. Am. Chem. Soc. 132, 440–441 (2010)

    CAS  PubMed  Google Scholar 

  15. Trost, B. M., Silverman, S. M. & Stambuli, J. P. Development of an asymmetric trimethylenemethane cycloaddition reaction: application in the enantioselective synthesis of highly substituted carbocycles. J. Am. Chem. Soc. 133, 19483–19497 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Trost, B. M., Bringley, D. A., Zhang, T. & Cramer, N. Rapid access to spirocyclic oxindole alkaloids: application of the asymmetric palladium-catalyzed [3 + 2] trimethylenemethane cycloaddition. J. Am. Chem. Soc. 135, 16720–16735 (2013)An informative discussion of development of the TMM reaction for the synthesis of spirocyclic oxindoles.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Ohmatsu, K., Imagawa, N. & Ooi, T. Ligand-enabled multiple absolute stereocontrol in metal-catalysed cycloaddition for construction of contiguous all-carbon quaternary stereocentres. Nature Chem. 6, 47–51 (2014)

    ADS  CAS  Google Scholar 

  18. Chen, X.-H., Wei, Q., Luo, S.-W., Xiao, H. & Gong, L.-Z. Organocatalytic synthesis of spiro[pyrrolidin-3,3-oxindoles] with high enantiopurity and structural diversity. J. Am. Chem. Soc. 131, 13819–13825 (2009)

    CAS  PubMed  Google Scholar 

  19. Martínez, A., Webber, M. J., Müller, S. & List, B. Versatile access to chiral indolines by catalytic asymmetric Fischer indolization. Angew. Chem. Int. Edn 52, 9486–9490 (2013)

    Google Scholar 

  20. Pellissier, H. Recent developments in asymmetric cyclopropanation. Tetrahedron 64, 7041–7095 (2008)

    CAS  Google Scholar 

  21. Schwartz, B. D., Denton, J. R., Lian, Y., Davies, H. M. L. & Williams, C. M. Asymmetric [4 + 3] cycloadditions between vinylcarbenoids and dienes: application to the total synthesis of the natural product (–)-5-epi-vibsanin E. J. Am. Chem. Soc. 131, 8329–8332 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Ishibashi, H., Ishihara, K. & Yamamoto, H. A new artificial cyclase for polyprenoids: enantioselective total synthesis of (–)-chromazonarol, (+)-8-epi-puupehedione, and (–)-11′-deoxytaondiol methyl ether. J. Am. Chem. Soc. 126, 11122–11123 (2004)

    CAS  PubMed  Google Scholar 

  23. Surendra, K. & Corey, E. J. Highly enantioselective proton-initiated polycyclization of polyenes. J. Am. Chem. Soc. 134, 11992–11994 (2012)

    CAS  PubMed  Google Scholar 

  24. Surendra, K., Rajendar, G. & Corey, E. J. Useful catalytic enantioselective cationic double annulation reactions initiated at an internal π-bond: method and applications. J. Am. Chem. Soc. 136, 642–645 (2014)

    CAS  PubMed  Google Scholar 

  25. Schafroth, M. A., Sarlah, D., Krautwald, S. & Carreira, E. M. Iridium-catalyzed enantioselective polyene cyclization. J. Am. Chem. Soc. 134, 20276–20278 (2012)A potentially broadly applicable approach for orchestrating enantioselective polyene cyclizations.

    CAS  PubMed  Google Scholar 

  26. Jeker, O. F., Kravina, A. G. & Carreira, E. M. Total synthesis of (+)-asperolide C by iridium-catalyzed enantioselective polyene cyclization. Angew. Chem. Int. Edn 52, 12166–12169 (2013)

    CAS  Google Scholar 

  27. Sethofer, S. G., Mayer, T. & Toste, F. D. Gold(I)-catalyzed enantioselective polycyclization reactions. J. Am. Chem. Soc. 132, 8276–8277 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Brazeau, J.-F., Zhang, S., Colomer, I., Corkey, B. K. & Toste, F. D. Enantioselective cyclizations of silyloxyenynes catalyzed by cationic metal phosphine complexes. J. Am. Chem. Soc. 134, 2742–2749 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Corkey, B. K. & Toste, F. D. Catalytic enantioselective Conia-ene reaction. J. Am. Chem. Soc. 127, 17168–17169 (2005)

    CAS  PubMed  Google Scholar 

  30. Shibata, T., Tahara, Y.-K., Tamura, K. & Endo, K. Enantioselective syntheses of various chiral multicyclic compounds with quaternary carbon stereocenters by catalytic intramolecular cycloaddition. J. Am. Chem. Soc. 130, 3451–3457 (2008)

    CAS  PubMed  Google Scholar 

  31. Knowles, R. R., Lin, S. & Jacobsen, E. N. Enantioselective thiourea-catalyzed cationic polycyclizations. J. Am. Chem. Soc. 132, 5030–5032 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Rendler, S. & MacMillan, D. W. C. Enantioselective polyene cyclization via organo-SOMO catalysis. J. Am. Chem. Soc. 132, 5027–5029 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Dounay, A. B., Humphreys, P. G., Overman, L. E. & Wrobleski, A. D. Total synthesis of the strychnos alkaloid (+)-minfiensine: tandem enantioselective intramolecular Heck–iminium ion cyclization. J. Am. Chem. Soc. 130, 5368–5377 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Watson, M. P. & Jacobsen, E. N. Asymmetric intramolecular arylcyanation of unactivated olefins via C–CN bond activation. J. Am. Chem. Soc. 130, 12594–12595 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Nakao, Y. et al. Intramolecular arylcyanation of alkenes catalyzed by nickel/AlMe2Cl. J. Am. Chem. Soc. 130, 12874–12875 (2008)

    CAS  PubMed  Google Scholar 

  36. García-Fortanet, J., Kessler, F. & Buchwald, S. L. Palladium-catalyzed asymmetric dearomatization of naphthalene derivatives. J. Am. Chem. Soc. 131, 6676–6677 (2009)

    PubMed  PubMed Central  Google Scholar 

  37. Xu, T., Ko, H. M., Savage, N. A. & Dong, G. Highly enantioselective Rh-catalyzed carboacylation of olefins: efficient syntheses of chiral poly-fused rings. J. Am. Chem. Soc. 134, 20005–20008 (2012)

    CAS  PubMed  Google Scholar 

  38. Mei, T.-S., Patel, H. H. & Sigman, M. S. Enantioselective construction of remote quaternary stereocentres. Nature 508, 340–344 (2014)A pioneering method for constructing remote stereocentres in acyclic substrates by enantioselective Heck reactions.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  39. Vuagnoux-d’Augustin, M. & Alexakis, A. Copper-catalyzed asymmetric conjugate addition of trialkylaluminium reagents to trisubstituted enones: construction of chiral quaternary centers. Chem. Eur. J. 13, 9647–9662 (2007)

    PubMed  Google Scholar 

  40. Müller, D. & Alexakis, A. Formation of quaternary stereogenic centers by copper-catalyzed asymmetric conjugate addition reactions of alkenylaluminums to trisubstituted enones. Chem. Eur. J. 19, 15226–15239 (2013)

    PubMed  Google Scholar 

  41. Hawner, C., Li, K., Cirriez, V. & Alexakis, A. Copper-catalyzed asymmetric conjugate addition of aryl aluminum reagents to trisubstituted enones: construction of aryl-substituted quaternary centers. Angew. Chem. Int. Edn 47, 8211–8214 (2008)

    CAS  Google Scholar 

  42. May, T. L., Brown, M. K. & Hoveyda, A. H. Enantioselective synthesis of all-carbon quaternary stereogenic centers by catalytic asymmetric conjugate additions of alkyl and aryl aluminum reagents to five-, six-, and seven-membered-ring β-substituted cyclic enones. Angew. Chem. Int. Edn 47, 7358–7362 (2008)

    CAS  Google Scholar 

  43. May, T. L., Dabrowski, J. A. & Hoveyda, A. H. Formation of vinyl-, vinylhalide- or acyl-substituted quaternary carbon stereogenic centers through NHC–Cu-catalyzed enantioselective conjugate additions of Si-containing vinylaluminums to β-substituted cyclic enones. J. Am. Chem. Soc. 133, 736–739 (2011)

    CAS  PubMed  Google Scholar 

  44. Lee, K.-S., Brown, M. K., Hird, A. W. & Hoveyda, A. H. A practical method for enantioselective synthesis of all-carbon quaternary stereogenic centers through NHC-Cu-catalyzed conjugate additions of alkyl and arylzinc reagents to β-substituted cyclic enones. J. Am. Chem. Soc. 128, 7182–7184 (2006)

    CAS  PubMed  Google Scholar 

  45. Martin, D. et al. Copper-catalyzed asymmetric conjugate addition of Grignard reagents to trisubstituted enones. Construction of all-carbon quaternary chiral centers. J. Am. Chem. Soc. 128, 8416–8417 (2006)

    CAS  PubMed  Google Scholar 

  46. Sidera, M., Roth, P. M. C., Maksymowicz, R. M. & Fletcher, S. P. Formation of quaternary carbon centers by copper-catalyzed asymmetric conjugate addition of alkylzirconium reagents. Angew. Chem. Int. Edn 52, 7995–7999 (2013)

    CAS  Google Scholar 

  47. Shintani, R., Duan, W.-L. & Hayashi, T. Rhodium-catalyzed asymmetric construction of quaternary stereocenters: ligand-dependent regiocontrol in the 1,4-addition to substituted maleimides. J. Am. Chem. Soc. 128, 5628–5629 (2006)

    CAS  PubMed  Google Scholar 

  48. Shintani, R., Tsutsumi, Y., Nagaosa, M., Nishimura, T. & Hayashi, T. Sodium tetraarylborates as effective nucleophiles in rhodium/diene-catalyzed 1,4-addition to β,β-disubstituted α,β-unsaturated ketones: catalytic asymmetric construction of quaternary carbon stereocenters. J. Am. Chem. Soc. 131, 13588–13589 (2009)

    CAS  PubMed  Google Scholar 

  49. 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. Edn 49, 7769–7772 (2010)

    CAS  Google Scholar 

  50. Holder, J. C. et al. Mechanism and enantioselectivity in palladium-catalyzed conjugate addition of arylboronic acids to β-substituted cyclic enones: insights from computation and experiment. J. Am. Chem. Soc. 135, 14996–15007 (2013)

    CAS  PubMed  Google Scholar 

  51. Mendoza, A., Ishihara, Y. & Baran, P. S. Scalable enantioselective total synthesis of taxanes. Nature Chem. 4, 21–25 (2012)

    ADS  CAS  Google Scholar 

  52. Brown, M. K. & Hoveyda, A. H. Enantioselective total synthesis of clavirolide C. Applications of Cu-catalyzed asymmetric conjugate additions and Ru-catalyzed ring-closing metathesis. J. Am. Chem. Soc. 130, 12904–12906 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Wu, F., Li, H., Hong, R. & Deng, L. Construction of quaternary stereocenters by efficient and practical conjugate additions to α,β-unsaturated ketones with a chiral organic catalyst. Angew. Chem. Int. Edn 45, 947–950 (2006)

    CAS  Google Scholar 

  54. Poulsen, T. B., Bernardi, L., Alemán, J., Overgaard, J. & Jørgensen, K. A. Organocatalytic asymmetric direct α-alkynylation of cyclic β-ketoesters. J. Am. Chem. Soc. 129, 441–449 (2007)

    CAS  PubMed  Google Scholar 

  55. Penon, O. et al. Quaternary stereogenic carbon atoms in complex molecules by an asymmetric, organocatalytic, triple-cascade reaction. Chemistry 14, 4788–4791 (2008)

    CAS  PubMed  Google Scholar 

  56. Mase, N., Thayumanavan, R., Tanaka, F. & Barbas, C. F., III Direct asymmetric organocatalytic Michael reactions of α,α-disubstituted aldehydes with β-nitrostyrenes for the synthesis of quaternary carbon-containing products. Org. Lett. 6, 2527–2530 (2004)

    CAS  PubMed  Google Scholar 

  57. Kerr, M. S. & Rovis, T. Enantioselective synthesis of quaternary stereocenters via a catalytic asymmetric Stetter reaction. J. Am. Chem. Soc. 126, 8876–8877 (2004)

    CAS  PubMed  Google Scholar 

  58. Gao, L., Kang, B. C. & Ryu, D. H. Catalytic asymmetric insertion of diazoesters into aryl-CHO bonds: highly enantioselective construction of chiral all-carbon quaternary centers. J. Am. Chem. Soc. 135, 14556–14559 (2013)

    CAS  PubMed  Google Scholar 

  59. Doyle, A. G. & Jacobsen, E. N. Enantioselective alkylation of acyclic α,α-disubstituted tributyltin enolates catalyzed by a {Cr(salen)} complex. Angew. Chem. Int. Edn 46, 3701–3705 (2007)

    CAS  Google Scholar 

  60. 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 

  61. Gao, F., Carr, J. L. & Hoveyda, A. H. Copper-catalyzed enantioselective allylic substitution with readily accessible carbonyl- and acetal-containing vinylboron reagents. Angew. Chem. Int. Edn 51, 6613–6617 (2012)

    CAS  Google Scholar 

  62. Van Veldhuizen, J. J., Campbell, J. E., Giudici, R. E. & Hoveyda, A. H. A readily available chiral Ag-based N-heterocyclic carbene complex for use in efficient and highly enantioselective Ru-catalyzed olefin metathesis and Cu-catalyzed allylic alkylation reactions. J. Am. Chem. Soc. 127, 6877–6882 (2005)

    CAS  PubMed  Google Scholar 

  63. Dabrowski, J. A., Gao, F. & Hoveyda, A. H. Enantioselective synthesis of alkyne-substituted quaternary carbon stereogenic centers through NHC-Cu-catalyzed allylic substitution reactions with (i-Bu)2(alkynylaluminum reagents. J. Am. Chem. Soc. 133, 4778–4781 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Feng, J., Garza, V. J. & Krische, M. J. Redox-triggered C−C coupling of alcohols and vinyl epoxides: diastereo- and enantioselective formation of all-carbon quaternary centers via tert-(hydroxy)-prenylation. J. Am. Chem. Soc. 136, 8911–8914 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Behenna, D. C. & Stoltz, B. M. The enantioselective Tsuji allylation. J. Am. Chem. Soc. 126, 15044–15045 (2004)

    CAS  PubMed  Google Scholar 

  66. Trost, B. M. & Xu, J. Regio- and enantioselective Pd-catalyzed allylic alkylation of ketones through allyl enol carbonates. J. Am. Chem. Soc. 127, 2846–2847 (2005)An excellent synopsis of the development of the asymmetric allylic alkylation reaction.

    CAS  PubMed  Google Scholar 

  67. Trost, B. M. & Frederiksen, M. U. Palladium-catalyzed asymmetric allylation of prochiral nucleophiles: synthesis of 3-allyl-3-aryl oxindoles. Angew. Chem. Int. Edn 44, 308–310 (2005)

    CAS  Google Scholar 

  68. Trost, B. M., Xie, J. & Sieber, J. D. The palladium catalyzed asymmetric addition of oxindoles and allenes: an atom-economical versatile method for the construction of chiral indole alkaloids. J. Am. Chem. Soc. 133, 20611–20622 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Trost, B. M., Malhotra, S. & Chan, W. H. Exercising regiocontrol in palladium-catalyzed asymmetric prenylations and geranylation: unifying strategy toward flustramines A and B. J. Am. Chem. Soc. 133, 7328–7331 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Enquist, J. A., Jr & Stoltz, B. M. The total synthesis of (–)-cyanthiwigin F by means of double catalytic enantioselective alkylation. Nature 453, 1228–1231 (2008)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  71. Du, C., Li, L., Li, Y. & Xie, Z. Construction of two vicinal quaternary carbons by asymmetric allylic alkylation: total synthesis of hyperolactone C and (–)-biyouyanagin A. Angew. Chem. Int. Edn 48, 7853–7856 (2009)

    CAS  Google Scholar 

  72. Trost, B. M., Miller, J. R. & Hoffman, C. M., Jr A highly enantio- and diastereoselective molybdenum-catalyzed asymmetric allylic alkylation of cyanoesters. J. Am. Chem. Soc. 133, 8165–8167 (2011)

    CAS  PubMed  Google Scholar 

  73. Liu, W.-B., Reeves, C. M., Virgil, S. C. & Stoltz, B. M. Construction of vicinal tertiary and all-carbon quaternary stereocenters via Ir-catalyzed regio-, diastereo-, and enantioselective allylic alkylation and applications in sequential Pd catalysis. J. Am. Chem. Soc. 135, 10626–10629 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Trost, B. M. & Quancard, J. Palladium-catalyzed enantioselective C-3 allylation of 3-substituted-1H-indoles using trialkylboranes. J. Am. Chem. Soc. 128, 6314–6315 (2006)

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Hills, I. D. & Fu, G. C. Catalytic enantioselective synthesis of oxindoles and benzofuranones that bear a quaternary stereocenter. Angew. Chem. Int. Edn 42, 3921–3924 (2003)

    CAS  Google Scholar 

  76. Shaw, S. A. et al. Enantioselective TADMAP-catalyzed carboxyl migration reactions for the synthesis of stereogenic quaternary carbon. J. Am. Chem. Soc. 128, 925–934 (2006)

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Mermerian, A. H. & Fu, G. C. Nucleophile-catalyzed asymmetric acylations of silyl ketene imines: application to the enantioselective synthesis of verapamil. Angew. Chem. Int. Edn 44, 949–952 (2005)

    CAS  Google Scholar 

  78. DeLorbe, J. E., Jabri, S. Y., Mennen, S. M., Overman, L. E. & Zhang, F.-L. Enantioselective total synthesis of (+)-gliocladine C: convergent construction of cyclotryptamine-fused polyoxopiperazines and a general approach for preparing epidithiodioxopiperazines from trioxopiperazine precursors. J. Am. Chem. Soc. 133, 6549–6552 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Austin, J. F., Kim, S.-G., Sinz, C. J., Xiao, W.-J. & MacMillan, D. W. C. Enantioselective organocatalytic construction of pyrroloindolines by a cascade addition–cyclization strategy: synthesis of (–) flustramine B. Proc. Natl Acad. Sci. USA 101, 5482–5487 (2004)

    ADS  CAS  PubMed  Google Scholar 

  80. Zhu, S. & MacMillan, D. W. C. Enantioselective copper-catalyzed construction of aryl pyrroloindolines via an arylation−cyclization cascade. J. Am. Chem. Soc. 134, 10815–10818 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Xie, X., Chen, Y. & Ma, D. Enantioselective arylation of 2-methylacetoacetates catalyzed by CuI/trans-4-hydroxy-L-proline at low reaction temperatures. J. Am. Chem. Soc. 128, 16050–16051 (2006)

    CAS  PubMed  Google Scholar 

  82. García-Fortanet, J. & Buchwald, S. L. Asymmetric palladium-catalyzed intramolecular α-arylation of aldehydes. Angew. Chem. Int. Edn 47, 8108–8111 (2008)

    Google Scholar 

  83. Taylor, A. M., Altman, R. A. & Buchwald, S. L. Palladium-catalyzed enantioselective α-arylation and α-vinylation of oxindoles facilitated by an axially chiral P-stereogenic ligand. J. Am. Chem. Soc. 131, 9900–9901 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Mitsunuma, H., Shibasaki, M., Kanai, M. & Matsunaga, S. Catalytic asymmetric total synthesis of chimonanthine, folicanthine, and calycanthine through double Michael reaction of bisoxindole. Angew. Chem. Int. Edn 51, 5217–5221 (2012)

    CAS  Google Scholar 

  85. Zhang, H., Hong, L., Kang, H. & Wang, R. Construction of vicinal all-carbon quaternary stereocenters by catalytic asymmetric alkylation reaction of 3-bromooxindoles with 3-substituted indoles: total synthesis of (+)-perophoramidine. J. Am. Chem. Soc. 135, 14098–14101 (2013)

    CAS  PubMed  Google Scholar 

  86. Malcolmson, S. J., Meek, S. J., Sattely, E. S., Schrock, R. R. & Hoveyda, A. H. Highly efficient molybdenum-based catalysts for enantioselective alkene metathesis. Nature 456, 933–937 (2008)An excellent example of using desymmetrization to install a key quaternary stereocentre in a structurally complex natural product.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  87. Giudici, R. E. & Hoveyda, A. H. Directed catalytic asymmetric olefin metathesis. Selectivity control by enoate and ynoate groups in Ru-catalyzed asymmetric ring-opening/cross-metathesis. J. Am. Chem. Soc. 129, 3824–3825 (2007)

    CAS  PubMed  Google Scholar 

  88. Kleinbeck, F. & Toste, F. D. Gold(I)-catalyzed enantioselective ring expansion of allenylcyclopropanols. J. Am. Chem. Soc. 131, 9178–9179 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Phan, D. H. T., Kou, K. G. M. & Dong, V. M. Enantioselective desymmetrization of cyclopropenes by hydroacylation. J. Am. Chem. Soc. 132, 16354–16355 (2010)

    CAS  PubMed  Google Scholar 

  90. Souillart, L., Parker, E. & Cramer, N. Highly enantioselective rhodium(I)-catalyzed activation of enantiotopic cyclobutanone C–C bonds. Angew. Chem. Int. Edn 53, 3001–3005 (2014)

    CAS  Google Scholar 

  91. Shi, B.-F., Zhang, Y.-H., Lam, J. K., Wang, D.-H. & Yu, J.-Q. Pd(II)-catalyzed enantioselective C-H olefination of diphenylacetic acids. J. Am. Chem. Soc. 132, 460–461 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Aikawa, K., Okamoto, T. & Mikami, K. Copper(I)-catalyzed asymmetric desymmetrization: synthesis of five-membered-ring compounds containing all-carbon quaternary stereocenters. J. Am. Chem. Soc. 134, 10329–10332 (2012)

    CAS  PubMed  Google Scholar 

  93. Zhang, E., Fan, C.-A., Tu, Y.-Q., Zhang, F.-M. & Song, Y.-L. Organocatalytic asymmetric vinylogous α-ketol rearrangement: enantioselective construction of chiral all-carbon quaternary stereocenters in spirocyclic diketones via semipinacol-type 1,2-carbon migration. J. Am. Chem. Soc. 131, 14626–14627 (2009)

    CAS  PubMed  Google Scholar 

  94. Wadamoto, M., Phillips, E. M., Reynolds, T. E. & Scheidt, K. A. Enantioselective synthesis of α,α-disubstituted cyclopentenes by an N-heterocyclic carbene-catalyzed desymmetrization of 1,3-diketones. J. Am. Chem. Soc. 129, 10098–10099 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 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 

  96. Xiao, K.-J. et al. Palladium(II)-catalyzed enantioselective C(sp3)–H activation using a chiral hydroxamic acid ligand. J. Am. Chem. Soc. 136, 8138–8142 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Notte, G. T. New chemical entities entering phase III trials in 2012. Annu. Rep. Med. Chem. 48, 451–469 (2013)

    CAS  Google Scholar 

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

    CAS  Google Scholar 

Download references

Acknowledgements

Our research in this area was supported by the US National Institutes of Health (R01 GM030859 and GM098601).

Author information

Authors and Affiliations

Authors

Contributions

Both K.W.Q. and L.E.O. prepared the manuscript.

Corresponding author

Correspondence to Larry E. Overman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Quasdorf, K., Overman, L. Catalytic enantioselective synthesis of quaternary carbon stereocentres. Nature 516, 181–191 (2014). https://doi.org/10.1038/nature14007

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature14007

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