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Enantioselective organocatalytic cycloadditions for the synthesis of medium-sized rings

Nature Synthesis volume 2, pages 1142–1158 (2023)Cite this article

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Abstract

Optically active medium-sized cyclic compounds are often found in natural products and are therefore attractive targets in organic synthesis. However, generating these cyclic entities with specific stereochemistry is far from trivial owing to unfavourable entropic factors and competing pathways that favour the formation of rings of lesser size. As a result, conventional ring-forming strategies can be challenging, and alternative methods, such as organocatalytic cycloadditions, have emerged to address these issues. Enantioselective synthesis of medium-sized rings by organocatalytic cycloadditions is a rapidly growing field of research offering opportunities that are complementary to metal-catalysed cycloadditions. Several organocatalytic approaches are available, including enamine/iminium-ion activation, along with catalysis using Lewis and Brønsted acids, hydrogen-bond donors, N-heterocyclic carbenes, and nucleophilic phosphines and amines. Here we discuss the ability of organocatalytic cycloadditions to synthesize stereodefined medium-sized ring architectures, critically evaluate current synthetic strategies, and highlight avenues for further development.

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Fig. 1: Enantioselective cycloadditions organocatalysed by chiral primary amines.
Fig. 2: Enantioselective cycloadditions organocatalysed by chiral pyrrolidines.
Fig. 3: Enantioselective cycloadditions organocatalysed by chiral imidazolidinones.
Fig. 4: Enantioselective cycloadditions organocatalysed by chiral oxazaborolidinium-based Lewis acids.
Fig. 5: Enantioselective cycloadditions organocatalysed by chiral Brønsted acids.
Fig. 6: Enantioselective cycloadditions organocatalysed by chiral HBDs.
Fig. 7: Enantioselective cycloadditions organocatalysed by chiral NHCs.
Fig. 8: Enantioselective cycloadditions organocatalysed by chiral nucleophilic phosphines and amines.

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References

  1. Morrison, K. C. & Hergenrother, P. J. Natural products as starting points for the synthesis of complex and diverse compounds. Nat. Prod. Rep. 31, 6–14 (2014).

    CAS  PubMed  Google Scholar 

  2. Newman, D. J. & Cragg, G. M. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J. Nat. Prod. 83, 770–803 (2020).

    CAS  PubMed  Google Scholar 

  3. Atanasov, A. G., Zotchev, S. B., Dirsch, V. M. & Supuran, C. T. Natural products in drug discovery: advances and opportunities. Nat. Rev. Drug Discov. 20, 200–216 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Li, J. W.-H. & Vederas, J. C. Drug discovery and natural products: end of an era or an endless frontier? Science 325, 161–165 (2009).

    PubMed  Google Scholar 

  5. Rosén, J., Gottfries, J., Muresan, S., Backlund, A. & Oprea, T. I. Novel chemical space exploration via natural products. J. Med. Chem. 52, 1953–1962 (2009).

    PubMed Central  Google Scholar 

  6. Harvey, A. L. Natural products in drug discovery. Drug Discov. Today 13, 894–901 (2008).

    CAS  PubMed  Google Scholar 

  7. Grigalunas, M., Brakmann, S. & Waldmann, H. Chemical evolution of natural product structure. J. Am. Chem. Soc. 144, 3314–3329 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Karageorgis, G., Foley, D. J., Laraia, L., Brakmann, S. & Waldmann, H. Pseudo natural products—chemical evolution of natural product structure. Angew. Chem. Int. Ed. 60, 15705–15723 (2021).

    CAS  Google Scholar 

  9. Karageorgis, G., Foley, D. J., Laraia, L. & Waldmann, H. Principle and design of pseudo-natural products. Nat. Chem. 12, 227–235 (2020).

    CAS  PubMed  Google Scholar 

  10. Hu, Y.-J., Li, L.-X., Han, J.-C., Min, L. & Li, C.-C. Recent advances in the total synthesis of natural products containing eight-membered carbocycles (2009–2019). Chem. Rev. 120, 5910–5953 (2020).

    CAS  PubMed  Google Scholar 

  11. de Oliveira, K. T., Servilha, B. M., de C. Alves, L., Desiderá, A. L. & Brocksom, T. J. in Studies in Natural Products Chemistry Vol. 42 (ed. Rahman, A.) 421–463 (Elsevier, 2014).

  12. Kaur, N. 8-Membered Heterocycle Synthesis (Elsevier, 2023).

  13. Chen, Y., Rosenkranz, C., Hirte, S. & Kirchmair, J. Ring systems in natural products: structural diversity, physicochemical properties and coverage by synthetic compounds. Nat. Prod. Rep. 39, 1544–1556 (2022).

    CAS  PubMed  Google Scholar 

  14. Yet, L. Metal-mediated synthesis of medium-sized rings. Chem. Rev. 100, 2963–3008 (2000).

    CAS  PubMed  Google Scholar 

  15. Engler, E. M., Andose, J. D. & Schleyer, P. V. R. Critical evaluation of molecular mechanics. J. Am. Chem. Soc. 95, 8005–8025 (1973).

    CAS  Google Scholar 

  16. Galli, C. & Mandolini, L. The role of ring strain on the ease of ring closure of bifunctional chain molecules. Eur. J. Org. Chem. 2000, 3117–3125 (2000).

    Google Scholar 

  17. Illuminati, G. & Mandolini, L. Ring closure reactions of bifunctional chain molecules. Acc. Chem. Res. 14, 95–102 (1981).

    CAS  Google Scholar 

  18. Hendrickson, J. B. Molecular geometry. V. Evaluation of functions and conformations of medium rings. J. Am. Chem. Soc. 89, 7036–7043 (1967).

    CAS  Google Scholar 

  19. Winnik, M. A. Cyclization and the conformation of hydrocarbon chains. Chem. Rev. 81, 491–524 (1981).

    CAS  Google Scholar 

  20. Wiberg, K. B. The C7−C10 cycloalkanes revisited. J. Org. Chem. 68, 9322–9329 (2003).

    CAS  Google Scholar 

  21. Anet, F. A. L. & Krane, J. Strain energy calculation of conformations and conformational changes in cyclooctane. Tetrahedron Lett. 14, 5029–5032 (1973).

    Google Scholar 

  22. Saunders, M. Searching for conformers of nine- to twelve-ring hydrocarbons on the MM2 and MM3 energy surfaces: stochastic search for interconversion pathways. J. Comput. Chem. 12, 645–663 (1991).

    CAS  Google Scholar 

  23. Toromanoff, E. Dynamic stereochemistry of the 5-, 6- and 7-membered rings using the torsion angle notation. Tetrahedron 36, 2809–2931 (1980).

    CAS  Google Scholar 

  24. Zhang, Z. et al. Construction of bridged polycycles through dearomatization strategies. Org. Biomol. Chem. 19, 3960–3982 (2021).

    CAS  PubMed  Google Scholar 

  25. Liu, J., Liu, X., Wu, J. & Li, C.-C. Total synthesis of natural products containing a bridgehead double bond. Chem 6, 579–615 (2020).

    CAS  Google Scholar 

  26. Min, L., Liu, X. & Li, C.-C. Total synthesis of natural products with bridged bicyclo[m.n.1] ring systems via type II [5 + 2] cycloaddition. Acc. Chem. Res. 53, 703–718 (2020).

    CAS  PubMed  Google Scholar 

  27. Presset, M., Coquerel, Y. & Rodriguez, J. Syntheses and applications of functionalized bicyclo[3.2.1]octanes: thirteen years of progress. Chem. Rev. 113, 525–595 (2013).

    CAS  Google Scholar 

  28. Ruiz, M., López-Alvarado, P., Giorgi, G. & Menéndez, J. C. Domino reactions for the synthesis of bridged bicyclic frameworks: fast access to bicyclo[n.3.1]alkanes. Chem. Soc. Rev. 40, 3445–3454 (2011).

    PubMed  Google Scholar 

  29. Narayan, R., Potowski, M., Jia, Z.-J., Antonchick, A. P. & Waldmann, H. Catalytic enantioselective 1,3-dipolar cycloadditions of azomethine ylides for biology-oriented synthesis. Acc. Chem. Res. 47, 1296–1310 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Held, F. E. & Tsogoeva, S. B. Asymmetric cycloaddition reactions catalyzed by bifunctional thiourea and squaramide organocatalysts: recent advances. Catal. Sci. Technol. 6, 645–667 (2016).

    CAS  Google Scholar 

  31. Harmata, M. Fun with (4 + 3)-cycloadditions. Synlett 30, 532–541 (2019).

    CAS  Google Scholar 

  32. Min, L., Hu, Y.-J., Fan, J.-H., Zhang, W. & Li, C.-C. Synthetic applications of type II intramolecular cycloadditions. Chem. Soc. Rev. 49, 7015–7043 (2020).

    CAS  PubMed  Google Scholar 

  33. Bejcek, L. P. & Murelli, R. P. Oxidopyrylium [5 + 2] cycloaddition chemistry: historical perspective and recent advances (2008–2018). Tetrahedron 74, 2501–2521 (2018).

    CAS  PubMed Central  Google Scholar 

  34. Wang, N., Wu, Z., Wang, J., Ullah, N. & Lu, Y. Recent applications of asymmetric organocatalytic annulation reactions in natural product synthesis. Chem. Soc. Rev. 50, 9766–9793 (2021).

    CAS  PubMed  Google Scholar 

  35. Moyano, A. & Rios, R. Asymmetric organocatalytic cyclization and cycloaddition reactions. Chem. Rev. 111, 4703–4832 (2011).

    CAS  PubMed  Google Scholar 

  36. Yao, T., Li, J., Jiang, C. & Zhao, C. Recent advances for the catalytic asymmetric construction of medium-sized rings. J. Catal. 2, 2929–2964 (2022).

    CAS  Google Scholar 

  37. Tan, W., Zhang, J.-Y., Gao, C.-H. & Shi, F. Progress in organocatalytic asymmetric (4 + 3) cycloadditions for the enantioselective construction of seven-membered rings. Sci. China Chem. 66, 966–992 (2023).

    CAS  Google Scholar 

  38. Wei, Y. & Shi, M. Organocatalytic Cycloadditions for Synthesis of Carbo‐ and Heterocycles (Wiley, 2018).

  39. McNaught, A. D. & Wilkinson, A. Compendium of Chemical Terminology. Vol. 1669 (Blackwell Science, 1997).

  40. Jessen, N. I., McLeod, D. & Jørgensen, K. A. Higher-order cycloadditions in the age of catalysis. Chem 8, 20–30 (2022).

    CAS  Google Scholar 

  41. Palazzo, T. A., Mose, R. & Jørgensen, K. A. Cycloaddition reactions: why is it so challenging to move from six to ten electrons? Angew. Chem. Int. Ed. 56, 10033–10038 (2017).

    CAS  Google Scholar 

  42. McLeod, D. et al. Expanding the frontiers of higher-order cycloadditions. Acc. Chem. Res. 52, 3488–3501 (2019).

    CAS  Google Scholar 

  43. Frankowski, S., Romaniszyn, M., Skrzyńska, A. & Albrecht, Ł. The game of electrons: organocatalytic higher-order cycloadditions involving fulvene- and tropone-derived systems. Chem. Eur. J. 26, 2120–2132 (2020).

    CAS  PubMed  Google Scholar 

  44. MacMillan, D. W. C. The advent and development of organocatalysis. Nature 455, 304–308 (2008).

    CAS  PubMed  Google Scholar 

  45. Abbasov, M. E. & Romo, D. The ever-expanding role of asymmetric covalent organocatalysis in scalable, natural product synthesis. Nat. Prod. Rep. 31, 1318–1327 (2014).

    CAS  PubMed Central  Google Scholar 

  46. Reyes-Rodríguez, G. J., Rezayee, N. M., Vidal-Albalat, A. & Jørgensen, K. A. Prevalence of diarylprolinol silyl ethers as catalysts in total synthesis and patents. Chem. Rev. 119, 4221–4260 (2019).

    PubMed  Google Scholar 

  47. Gaunt, M. J., Johansson, C. C. C., McNally, A. & Vo, N. T. Enantioselective organocatalysis. Drug Discov. Today 12, 8–27 (2007).

    CAS  PubMed  Google Scholar 

  48. Yao, T., Li, J., Jiang, C. & Zhao, C. Recent advances for the catalytic asymmetric construction of medium-sized rings. Chem Catal. 2, 2929–2964 (2022).

    CAS  Google Scholar 

  49. Lelais, G. & MacMillan, D. W. C. Modern strategies in organic catalysis: the advent and development of iminium activation. Aldrichim. Acta 39, 79–87 (2006).

    CAS  Google Scholar 

  50. List, B. Enamine catalysis is a powerful strategy for the catalytic generation and use of carbanion equivalents. Acc. Chem. Res. 37, 548–557 (2004).

    CAS  PubMed  Google Scholar 

  51. Jensen, K. L., Dickmeiss, G., Jiang, H., Albrecht, Ł. & Jørgensen, K. A. The diarylprolinol silyl ether system: a general organocatalyst. Acc. Chem. Res. 45, 248–264 (2012).

    CAS  PubMed  Google Scholar 

  52. Burns, N. Z., Witten, M. R. & Jacobsen, E. N. Dual catalysis in enantioselective oxidopyrylium-based [5 + 2] cycloadditions. J. Am. Chem. Soc. 133, 14578–14581 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Witten, M. R. & Jacobsen, E. N. Catalytic asymmetric synthesis of 8-oxabicyclooctanes by intermolecular [5 + 2] pyrylium cycloadditions. Angew. Chem. Int. Ed. 53, 5912–5916 (2014).

    CAS  Google Scholar 

  54. McLeod, D. et al. Enantioselective 1,3-dipolar [6 + 4] cycloaddition of pyrylium ions and fulvenes towards cyclooctanoids. Chem. Eur. J. 26, 11417–11422 (2020).

    CAS  PubMed  Google Scholar 

  55. Mose, R. et al. Organocatalytic stereoselective [8 + 2] and [6 + 4] cycloadditions. Nat. Chem. 9, 487–492 (2017).

    CAS  PubMed  Google Scholar 

  56. Yu, P. et al. Organocatalytic [6 + 4] cycloadditions via zwitterionic intermediates: chemo-, regio- and stereoselectivities. J. Am. Chem. Soc. 140, 13726–13735 (2018).

    CAS  PubMed  Google Scholar 

  57. Chen, X. et al. [8 + 2] versus [4 + 2] cycloadditions of cyclohexadienamines to tropone and heptafulvenes—mechanisms and selectivities. J. Am. Chem. Soc. 143, 934–944 (2021).

    CAS  PubMed  Google Scholar 

  58. Donslund, B. S., Johansen, T. K., Poulsen, P. H., Halskov, K. S. & Jørgensen, K. A. The diarylprolinol silyl ethers: ten years after. Angew. Chem. Int. Ed. 54, 13860–13874 (2015).

    CAS  Google Scholar 

  59. Orue, A., Uria, U., Reyes, E., Carrillo, L. & Vicario, J. L. Catalytic enantioselective [5 + 2] cycloaddition between oxidopyrylium ylides and enals under dienamine activation. Angew. Chem. Int. Ed. 54, 3043–3046 (2015).

    CAS  Google Scholar 

  60. Gao, Y., Song, X., Yan, R.-J., Du, W. & Chen, Y.-C. Asymmetric β,γ′-regioselective [4 + 3] and [4 + 2] annulations of α-vinylenals via cascade iminium ion-dienamine catalysis. Org. Biomol. Chem. 19, 151–155 (2021).

    CAS  PubMed  Google Scholar 

  61. Donslund, B. S. et al. Organocatalytic enantioselective higher-order cycloadditions of in situ generated amino isobenzofulvenes. Angew. Chem. Int. Ed. 57, 1246–1250 (2018).

    CAS  Google Scholar 

  62. Donslund, B. S. et al. Catalytic enantioselective [10 + 4] cycloadditions. Angew. Chem. Int. Ed. 57, 13182–13186 (2018).

    CAS  Google Scholar 

  63. Bertuzzi, G. et al. Catalytic enantioselective hetero-[6+4] and -[6+2] cycloadditions for the construction of condensed polycyclic pyrroles, imidazoles and pyrazoles. J. Am. Chem. Soc. 141, 3288–3297 (2019).

    CAS  PubMed  Google Scholar 

  64. Woodward, R. B. & Hoffmann, R. The conservation of orbital symmetry. Angew. Chem. Int. Ed. 8, 781–853 (1969).

    CAS  Google Scholar 

  65. Corti, V. et al. Organocatalytic enantioselective thermal [4 + 4] cycloadditions. J. Am. Chem. Soc. 145, 1448–1459 (2023).

    CAS  PubMed  Google Scholar 

  66. Harmata, M., Ghosh, S. K., Hong, X., Wacharasindhu, S. & Kirchhoefer, P. Asymmetric organocatalysis of 4 + 3 cycloaddition reactions. J. Am. Chem. Soc. 125, 2058–2059 (2003).

    CAS  PubMed  Google Scholar 

  67. Sun, W.-B., Wang, X., Sun, B.-F., Zou, J.-P. & Lin, G.-Q. Catalytic asymmetric total synthesis of hedyosumins A, B and C. Org. Lett. 18, 1219–1221 (2016).

    CAS  PubMed  Google Scholar 

  68. Wang, J., Chen, S.-G., Sun, B.-F., Lin, G.-Q. & Shang, Y.-J. Collective total synthesis of englerin A and B, orientalol E and F, and oxyphyllol: application of the organocatalytic [4 + 3] cycloaddition reaction. Chem. Eur. J. 19, 2539–2547 (2013).

    CAS  Google Scholar 

  69. 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 

  70. Corey, E. J., Shibata, T. & Lee, T. W. Asymmetric Diels-Alder reactions catalyzed by a triflic acid activated chiral oxazaborolidine. J. Am. Chem. Soc. 124, 3808–3809 (2002).

    CAS  PubMed  Google Scholar 

  71. Corey, E. J. Enantioselective catalysis based on cationic oxazaborolidines. Angew. Chem. Int. Ed. 48, 2100–2117 (2009).

    CAS  Google Scholar 

  72. Mukherjee, S. & Corey, E. Enantioselective synthesis based on catalysis by chiral oxazaborolidinium cations. Aldrichim. Acta 43, 49–59 (2010).

    CAS  Google Scholar 

  73. Brimioulle, R. & Bach, T. Enantioselective Lewis acid catalysis of intramolecular enone [2 + 2] photocycloaddition reactions. Science 342, 840–843 (2013).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  75. 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  Google Scholar 

  76. Parmar, D., Sugiono, E., Raja, S. & Rueping, M. Complete field guide to asymmetric binol-phosphate derived Brønsted acid and metal catalysis: history and classification by mode of activation; Brønsted acidity, hydrogen bonding, ion pairing and metal phosphates. Chem. Rev. 114, 9047–9153 (2014).

    CAS  PubMed  Google Scholar 

  77. Del Corte, X., Martínez De Marigorta, E., Palacios, F., Vicario, J. & Maestro, A. An overview of the applications of chiral phosphoric acid organocatalysts in enantioselective additions to C–O and C–N bonds. Org. Chem. Front. 9, 6331–6399 (2022).

    Google Scholar 

  78. Jiménez, E. I. An update on chiral phosphoric acid organocatalyzed stereoselective reactions. Org. Biomol. Chem. 21, 3477–3502 (2023).

    PubMed  Google Scholar 

  79. Rueping, M., Parmar, D. & Sugiono, E. Asymmetric Brønsted Acid Catalysis (Wiley, 2016).

  80. Dorsch, C. & Schneider, C. in Asymmetric Organocatalysis. Ch. 1 (Wiley, 2023).

  81. Mei, G.-J. et al. Brønsted acid-catalyzed stereoselective [4 + 3] cycloadditions of ortho-hydroxybenzyl alcohols with N,N′-cyclic azomethine imines. Chem. Commun. 53, 2768–2771 (2017).

    CAS  Google Scholar 

  82. Villar, L. et al. Enantioselective oxidative (4 + 3) cycloadditions between allenamides and furans through bifunctional hydrogen-bonding/ion-pairing interactions. Angew. Chem. Int. Ed. 56, 10535–10538 (2017).

    CAS  Google Scholar 

  83. Gelis, C. et al. Highly diastereo- and enantioselective synthesis of cyclohepta[b]indoles by chiral-phosphoric-acid-catalyzed (4 + 3) cycloaddition. Angew. Chem. Int. Ed. 57, 12121–12125 (2018).

    CAS  Google Scholar 

  84. Sun, M. et al. Catalytic asymmetric (4 + 3) cyclizations of in situ generated ortho-quinone methides with 2‐indolylmethanols. Angew. Chem. Int. Ed. 131, 8795–8800 (2019).

    Google Scholar 

  85. Mahlau, M. & List, B. Asymmetric counteranion-directed catalysis (ACDC): a remarkably general approach to enantioselective synthesis. Isr. J. Chem. 52, 630–638 (2012).

    CAS  Google Scholar 

  86. Mahlau, M. & List, B. Asymmetric counteranion-directed catalysis: concept, definition and applications. Angew. Chem. Int. Ed. 52, 518–533 (2013).

    CAS  Google Scholar 

  87. Schreyer, L., Properzi, R. & List, B. IDPi catalysis. Angew. Chem. Int. Ed. 58, 12761–12777 (2019).

    CAS  Google Scholar 

  88. Ouyang, J., Maji, R., Leutzsch, M., Mitschke, B. & List, B. Design of an organocatalytic asymmetric (4 + 3) cycloaddition of 2-indolylalcohols with dienolsilanes. J. Am. Chem. Soc. 144, 8460–8466 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Gribble, G. W. Heterocyclic Scaffolds II: Reactions and Applications of Indoles. Vol. 26 (Springer Science & Business Media, 2010).

  90. Huber, T., Wildermuth, R. E. & Magauer, T. 9-membered carbocycles: strategies and tactics for their synthesis. Chem. Eur. J. 24, 12107–12120 (2018).

    CAS  PubMed  Google Scholar 

  91. Bertuzzi, G., McLeod, D., Mohr, L.-M. & Jørgensen, K. A. Organocatalytic enantioselective 1,3-dipolar [6 + 4] cycloadditions of tropone. Chem. Eur. J. 26, 15491–15496 (2020).

    CAS  PubMed  Google Scholar 

  92. Doyle, A. G. & Jacobsen, E. N. Small-molecule H-bond donors in asymmetric catalysis. Chem. Rev. 107, 5713–5743 (2007).

    CAS  PubMed  Google Scholar 

  93. Brak, K. & Jacobsen, E. N. Asymmetric ion-pairing catalysis. Angew. Chem. Int. Ed. 52, 534–561 (2013).

    CAS  Google Scholar 

  94. Garcia-Mancheno, O. Anion-Binding Catalysis (Wiley, 2022).

  95. Matador, E., Fernández, R., Lassaletta, J. M. & Monge, D. in Asymmetric Organocatalysis. Ch. 4 (Wiley, 2023).

  96. Banik, S. M., Levina, A., Hyde, A. M. & Jacobsen, E. N. Lewis acid enhancement by hydrogen-bond donors for asymmetric catalysis. Science 358, 761–764 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Jeyaraman, R. & Avila, S. Chemistry of 3-azabicyclo[3.3.1]nonanes. Chem. Rev. 81, 149–174 (1981).

    CAS  Google Scholar 

  98. Tan, J.-P. et al. Asymmetric synthesis of N-bridged [3.3.1] ring systems by phosphonium salt/Lewis acid relay catalysis. Nat. Commun. 13, 357 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Qi, S.-S. et al. Catalytic asymmetric conjugate addition/hydroalkoxylation sequence: expeditious access to enantioenriched eight-membered cyclic ether derivatives. Org. Lett. 23, 2471–2476 (2021).

    CAS  PubMed  Google Scholar 

  100. Breslow, R. On the mechanism of thiamine action. IV. Evidence from studies on model systems. J. Am. Chem. Soc. 80, 3719–3726 (1958).

    CAS  Google Scholar 

  101. Ryan, S. J., Candish, L. & Lupton, D. W. Acyl anion free N-heterocyclic carbene organocatalysis. Chem. Soc. Rev. 42, 4906–4917 (2013).

    CAS  PubMed  Google Scholar 

  102. Enders, D., Niemeier, O. & Henseler, A. Organocatalysis by N-heterocyclic carbenes. Chem. Rev. 107, 5606–5655 (2007).

    CAS  Google Scholar 

  103. Flanigan, D. M., Romanov-Michailidis, F., White, N. A. & Rovis, T. Organocatalytic reactions enabled by N-heterocyclic carbenes. Chem. Rev. 115, 9307–9387 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Chen, X.-Y., Gao, Z.-H. & Ye, S. Bifunctional N-heterocyclic carbenes derived from l-pyroglutamic acid and their applications in enantioselective organocatalysis. Acc. Chem. Res. 53, 690–702 (2020).

    CAS  PubMed  Google Scholar 

  105. Hong, L., Liu, J.-Y., Hong-Yu, L. & Peng-Fei, X. Recent developments in N-heterocyclic carbene and transition-metal cooperative catalysis. Acta Chim. Sin. 76, 831–837 (2018).

    Google Scholar 

  106. Dhayalan, V., Dandela, R., Sharma, D. & Chatterjee, R. Recent advances in enantioselective organocatalytic reactions enabled by N-heterocyclic carbenes (NHCs) containing triazolium motifs. Synthesis 54, 4129–4166 (2022).

    Google Scholar 

  107. Chen, X., Wang, H., Jin, Z. & Chi, Y. R. N-heterocyclic carbene organocatalysis: activation modes and typical reactive intermediates. Chin. J. Chem. 38, 1167–1202 (2020).

    CAS  Google Scholar 

  108. Reyes, E., Uria, U., Carrillo, L. & Vicario, J. L. Enantioselective cascade reactions under N-heterocyclic carbene catalysis. Synthesis 49, 451–471 (2017).

    CAS  Google Scholar 

  109. Yao, T., Li, J., Wang, L. & Zhao, C. Recent advances for the construction of seven-membered ring catalyzed by N-heterocyclic carbenes. Chin. J. Org. Chem. 42, 925–944 (2022).

    CAS  Google Scholar 

  110. Izquierdo, J., Orue, A. & Scheidt, K. A. A dual Lewis base activation strategy for enantioselective carbene-catalyzed annulations. J. Am. Chem. Soc. 135, 10634–10637 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Lv, H., Jia, W.-Q., Sun, L.-H. & Ye, S. N-heterocyclic carbene catalyzed [4 + 3] annulation of enals and o-quinone methides: highly enantioselective synthesis of benzo-ε-lactones. Angew. Chem. Int. Ed. 125, 8769–8772 (2013).

    Google Scholar 

  112. Wang, M., Huang, Z., Xu, J. & Chi, Y. R. N-heterocyclic carbene-catalyzed [3 + 4] cycloaddition and kinetic resolution of azomethine imines. J. Am. Chem. Soc. 136, 1214–1217 (2014).

    CAS  PubMed  Google Scholar 

  113. Guo, C., Sahoo, B., Daniliuc, C. G. & Glorius, F. N-heterocyclic carbene catalyzed switchable reactions of enals with azoalkenes: formal [4 + 3] and [4 + 1] annulations for the synthesis of 1,2-diazepines and pyrazoles. J. Am. Chem. Soc. 136, 17402–17405 (2014).

    CAS  PubMed  Google Scholar 

  114. Wang, M., Rong, Z.-Q. & Zhao, Y. Stereoselective synthesis of ε-lactones or spiro-heterocycles through NHC-catalyzed annulation: divergent reactivity by catalyst control. Chem. Commun. 50, 15309–15312 (2014).

    CAS  Google Scholar 

  115. Liang, Z.-Q., Gao, Z.-H., Jia, W.-Q. & Ye, S. Bifunctional N-heterocyclic carbene catalyzed [3 + 4] annulation of enals and aurones. Chem. Eur. J. 21, 1868–1872 (2015).

    CAS  PubMed  Google Scholar 

  116. Liang, Z.-Q., Yi, L., Chen, K.-Q. & Ye, S. N-heterocyclic carbene-catalyzed [3 + 4] annulation of enals and alkenyl thiazolones: enantioselective synthesis of thiazole-fused ε-lactones. J. Org. Chem. 81, 4841–4846 (2016).

    CAS  PubMed  Google Scholar 

  117. Wang, L. et al. Asymmetric synthesis of spirobenzazepinones with atroposelectivity and spiro-1,2-diazepinones by NHC-catalyzed [3 + 4] annulation reactions. Angew. Chem. Int. Ed. 128, 11276–11280 (2016).

    Google Scholar 

  118. Liu, Q., Li, S., Chen, X.-Y., Rissanen, K. & Enders, D. Asymmetric synthesis of spiro-oxindole-ε-lactones through N-heterocyclic carbene catalysis. Org. Lett. 20, 3622–3626 (2018).

    CAS  PubMed  Google Scholar 

  119. Li, W. et al. NHC-catalyzed enantioselective [4 + 3] cycloaddition of ortho-hydroxyphenyl substituted para-quinone methides with isatin-derived enals. Adv. Synth. Catal. 360, 2460–2464 (2018).

    CAS  Google Scholar 

  120. Gao, Z.-H. et al. Enantioselective N-heterocyclic carbene-catalyzed synthesis of spirocyclic oxindole-benzofuroazepinones. J. Org. Chem. 83, 15225–15235 (2018).

    CAS  PubMed  Google Scholar 

  121. Chen, K.-Q., Gao, Z.-H. & Ye, S. Bifunctional N-heterocyclic carbene catalyzed [3 + 4] annulation of enals with azadienes: enantioselective synthesis of benzofuroazepinones. Org. Chem. Front. 6, 405–409 (2019).

    CAS  Google Scholar 

  122. Wang, Z., Xu, X. & Kwon, O. Phosphine catalysis of allenes with electrophiles. Chem. Soc. Rev. 43, 2927–2940 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Guo, H., Fan, Y. C., Sun, Z., Wu, Y. & Kwon, O. Phosphine organocatalysis. Chem. Rev. 118, 10049–10293 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. France, S., Guerin, D. J., Miller, S. J. & Lectka, T. Nucleophilic chiral amines as catalysts in asymmetric synthesis. Chem. Rev. 103, 2985–3012 (2003).

    CAS  PubMed  Google Scholar 

  125. Yan, R.-J., Liu, B.-X., Xiao, B.-X., Du, W. & Chen, Y.-C. Asymmetric (4 + 3) and (4 + 1) annulations of isatin-derived Morita-Baylis-Hillman carbonates to construct diverse chiral heterocyclic frameworks. Org. Lett. 22, 4240–4244 (2020).

    CAS  PubMed  Google Scholar 

  126. Yuan, C. et al. Phosphine-catalyzed enantioselective [4 + 3] annulation of allenoates with C,N-cyclic azomethine imines: synthesis of quinazoline-based tricyclic heterocycles. Org. Lett. 18, 5644–5647 (2016).

    CAS  Google Scholar 

  127. Ni, H. et al. Enantioselective phosphine-catalyzed formal [4 + 4] annulation of α,β-unsaturated imines and allene ketones: construction of eight-membered rings. Angew. Chem. Int. Ed. 56, 14222–14226 (2017).

    CAS  Google Scholar 

  128. Jia, R.-L., Liu, Q.-L., Yang, L.-W., Deng, S. & Song, Y. [6 + 3] annulations of Morita-Baylis-Hillman carbonates and dicyanoheptafulvene. Org. Biomol. Chem. 19, 9867–9871 (2021).

    CAS  PubMed  Google Scholar 

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Acknowledgements

K.A.J. acknowledges a Villum Investigator grant (no. 25867), the Novo Nordisk Foundation, FNU and Aarhus University. J.O. acknowledges support from MUNI/A/1096/2022 (MUNI Brno – Specific research) and the Erasmus+ programme of the European Union. M.E. acknowledges the support of MOV_CA_2021_1_171965 and MIA-322.

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  1. These authors contributed equally: Jan Otevrel, Macarena Eugui, Sebastijan Ričko.

Authors and Affiliations

  1. Department of Chemistry, Aarhus University, Aarhus, Denmark

    Jan Otevrel, Macarena Eugui, Sebastijan Ričko & Karl Anker Jørgensen

  2. Department of Chemical Drugs, Masaryk University, Brno, Czechia

    Jan Otevrel

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K.A.J. supervised the process. All authors analysed the topic, contributed to the discussions and wrote the manuscript.

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Otevrel, J., Eugui, M., Ričko, S. et al. Enantioselective organocatalytic cycloadditions for the synthesis of medium-sized rings. Nat. Synth 2, 1142–1158 (2023). https://doi.org/10.1038/s44160-023-00416-1

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