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An organic thiyl radical catalyst for enantioselective cyclization


A diverse array of chiral organocatalysts have been developed that rely on acid–base interactions to promote enantioselective ionic reactions via the movement of electron pairs. The stereocontrol of radical reactions using organocatalysts is an alternative approach, and several studies have shown that synthetically useful reactivity can result by controlling the movement of single electrons. However, in these studies, it is still an acid–based organocatalyst which forms a closed-shell intermediate with substrate prior to the radical reaction and imparts chiral information, and use of a chiral organic radical directly as catalyst has only rarely been explored. Here, we report the design of an organic thiyl radical catalyst with a carefully designed chiral pocket constructed around a chiral thiol precatalyst. The resulting catalyst was used to effect highly diastereo- and enantioselective C–C bond-forming radical cyclizations.

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Figure 1: Initial foray into the development of the chiral organic radical catalyst.
Figure 2: Design of a new scaffold for enantioselective radical cyclization.
Figure 3: Synthesis of a new chiral thiol.

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  1. Dalko, P. I. Comprehensive Enantioselective Organocatalysis: Catalysts, Reactions, and Applications (Wiley-VCH, 2013).

  2. Mukherjee, S., Yang, J. W., Hoffmann, S. & List, B. Asymmetric enamine catalysis. Chem. Rev. 107, 5471–5569 (2007).

    Article  CAS  Google Scholar 

  3. 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 

  4. Akiyama, T. Stronger Brønsted acids. Chem. Rev. 107, 5744–5758 (2007).

    Article  CAS  Google Scholar 

  5. Terada, M. Chiral phosphoric acids as versatile catalysts for enantioselective transformations. Synthesis 2010, 1929–1982 (2010).

    Article  Google Scholar 

  6. Taylor, M. S. & Jacobsen, E. N. Asymmetric catalysis by chiral hydrogen-bond donors. Angew. Chem. Int. Ed. 45, 1520–1543 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Chatgilialoglu, C. & Studer, A. Encyclopedia of Radicals in Chemistry, Biology and Materials (Wiley, 2012).

  9. Frey, P. A., Hegeman, A. D. & Reed, G. H. Free radical mechanisms in enzymology. Chem. Rev. 106, 3302–3316 (2006).

    Article  CAS  Google Scholar 

  10. Sibi, M. P., Manyem, S. & Zimmerman, J. Enantioselective radical processes. Chem. Rev. 103, 3263–3296 (2003).

    Article  CAS  Google Scholar 

  11. Bauer, A., Westkämper, F., Grimme, S. & Bach, T. Catalytic enantioselective reactions driven by photoinduced electron transfer. Nature 436, 1139–1140 (2005).

    Article  CAS  Google Scholar 

  12. Beeson, T. D., Mastracchio, A., Hong, J-B., Ashton, K. & MacMillan, D. W. C. Enantioselective organocatalysis using SOMO activation. Science 316, 582–585 (2007).

    Article  CAS  Google Scholar 

  13. Sibi, M. P. & Hasegawa, M. Organocatalysis in radical chemistry. Enantioselective α-oxyamination of aldehydes. J. Am. Chem. Soc. 129, 4124–4125 (2007).

    Article  CAS  Google Scholar 

  14. Nicewicz, D. A. & MacMillan, D. W. C. Merging photoredox catalysis with organocatalysis: the direct asymmetric alkylation of aldehydes. Science 322, 77–80 (2008).

    Article  CAS  Google Scholar 

  15. Arceo, E., Jurberg, I. D., Álvarez-Fernández, A. & Melchiorre, P. Photochemical activity of a key donor–acceptor complex can drive stereoselective catalytic α-alkylation of aldehydes. Nature Chem. 5, 750–756 (2013).

    Article  CAS  Google Scholar 

  16. Rono, L. J., Yayla, H. G., Wang, D. Y., Armstrong, M. F. & Knowles, R. R. Enantioselective photoredox catalysis enabled by proton-coupled electron transfer: development of an asymmetric aza-pinacol cyclization. J. Am. Chem. Soc. 135, 17735–17738 (2013).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. Dénès, F., Pichowicz, M., Povie, G. & Renaud, P. Thiyl radicals in organic synthesis. Chem. Rev. 114, 2587–2693 (2014).

    Article  Google Scholar 

  19. Roberts, B. P. Polarity-reversal catalysis of hydrogen-atom abstraction reactions: concepts and applications in organic chemistry. Chem. Soc. Rev. 28, 25–35 (1999).

    Article  CAS  Google Scholar 

  20. Haque, M. B. & Roberts, B. P. Enantioselective radical-chain hydrosilylation of prochiral alkenes using optically active thiol catalysts. Tetrahedron Lett. 37, 9123–9126 (1996).

    Article  CAS  Google Scholar 

  21. Cai, Y., Roberts, B. P. & Tocher, D. A. Carbohydrate-derived thiols as protic polarity-reversal catalysts for enantioselective radical-chain reactions. J. Chem. Soc. Perkin Trans. 1, 1376–1386 (2002).

  22. Qiao, C. & Marsh, E. N. G. Mechanism of benzylsuccinate synthase: stereochemistry of toluene addition to fumarate and maleate. J. Am. Chem. Soc. 127, 8608–8609 (2005).

    Article  CAS  Google Scholar 

  23. Miura, K., Fugami, K., Oshima, K. & Utimoto, K. Synthesis of vinylcyclopentanes from vinylcyclopropanes and alkenes promoted by benzenethiyl radical. Tetrahedron Lett. 29, 5135–5138 (1988).

    Article  CAS  Google Scholar 

  24. Feldman, K. S., Romanelli, A. L., Ruckle, R. E. & Miller, R. F. Cyclopentane synthesis via free radical mediated addition of functionalized alkenes to substituted vinyl cyclopropanes. J. Am. Chem. Soc. 110, 3300–3302 (1988).

    Article  CAS  Google Scholar 

  25. Hancock, A. N. & Schiesser, C. H. Guidelines for radical reactions: some thirty years on. Chem. Commun. 49, 9892–9895 (2013).

    Article  CAS  Google Scholar 

  26. Jiao, L. & Yu, Z-X. Vinylcyclopropane derivatives in transition-metal-catalyzed cycloadditions for the synthesis of carbocyclic compounds. J. Org. Chem. 78, 6842–6848 (2013).

    Article  CAS  Google Scholar 

  27. Xu, H., Qu, J-P., Liao, S., Xiong, H. & Tang, Y. Highly enantioselective [3+2] annulation of cyclic enol silyl ethers with donor–acceptor cyclopropanes: accessing 3a-hydroxy [n.3.0]carbobicycles. Angew. Chem. Int. Ed. 52, 4004–4007 (2013).

    Article  CAS  Google Scholar 

  28. Giacalone, F., Gruttadauria, M., Agrigento, P. & Noto, R. Low-loading asymmetric organocatalysis. Chem. Soc. Rev. 41, 2406–2447 (2012).

    Article  CAS  Google Scholar 

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This work was partially supported by a Grant-in-Aid for Scientific Research from the MEXT (Japan). Y.K. acknowledges a Grant-in-Aid for the Research Fellowship of JSPS for Young Scientists.

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T.H. conceived the study and wrote the manuscript. T.H. and Y.K. designed experiments and Y.K. performed experiments. K.M. organized the research.

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Correspondence to Keiji Maruoka.

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The authors declare no competing financial interests.

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Crystallographic data for compound 2a' (CIF 30 kb)

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Crystallographic data for compound (S)-5b (CIF 50 kb)

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Hashimoto, T., Kawamata, Y. & Maruoka, K. An organic thiyl radical catalyst for enantioselective cyclization. Nature Chem 6, 702–705 (2014).

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