Radical cyclization cascades are powerful tools used to construct the complex three-dimensional structures of some of society’s most prized molecules. Since its first use 40 years ago, SmI2 has been used extensively for reductive radical cyclizations. Unfortunately, SmI2 must almost always be used in significant excess, thus raising issues of cost and waste. Here, we have developed radical cyclization cascades that are catalysed by SmI2 and exploit a radical relay/electron-catalysis strategy. The approach negates the need for a super-stoichiometric co-reductant and requires no additives. Complex cyclic products, including products of dearomatization, containing up to four contiguous stereocentres are obtained in excellent yield. Mechanistic studies support a single-electron-transfer radical mechanism. Our strategy provides a long-awaited solution to the problem of how to avoid the need for stoichiometric amounts of SmI2 and establishes a conceptual platform on which other catalytic radical processes using the ubiquitous reducing agent can be built.
Subscribe to Journal
Get full journal access for 1 year
We are sorry, but there is no personal subscription option available for your country.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Data relating to the materials and methods, optimization studies, experimental procedures, mechanistic studies, EPR spectra, NMR spectra and mass spectrometry are available in the Supplementary Information. Crystallographic data for compounds 2k, 2m, 2o, 4n, 4o, 6k and 6l are available free of charge from the Cambridge Crystallographic Data Centre under reference numbers CCDC 1866917–1866923. All other data are available from the authors upon reasonable request.
Wender, P. A. & Miller, B. L. Synthesis at the molecular frontier. Nature 460, 197–201 (2009).
Newhouse, T., Baran, P. S. & Hoffmann, R. W. The economies of synthesis. Chem. Soc. Rev. 38, 3010–3021 (2009).
Nicolaou, K. C. & Chen, J. S. The art of total synthesis through cascade reactions. Chem. Soc. Rev. 38, 2993–3009 (2009).
Walji, A. & MacMillan, D. Strategies to bypass the taxol problem. Enantioselective cascade catalysis, a new approach for the efficient construction of molecular complexity. Synlett 2007, 1477–1489 (2007).
Yan, M., Lo, J. C., Edwards, J. T. & Baran, P. S. Radicals: reactive intermediates with translational potential. J. Am. Chem. Soc. 138, 12692–12714 (2016).
Studer, A. & Curran, D. P. Catalysis of radical reactions: a radical chemistry perspective. Angew. Chem. Int. Ed. 55, 58–102 (2016).
Hung, K., Hu, X. & Maimone, T. J. Total synthesis of complex terpenoids employing radical cascade processes. Nat. Prod. Rep. 35, 174–202 (2018).
Kärkäs, M. D., Porco, J. A. & Stephenson, C. R. J. Photochemical approaches to complex chemotypes: applications in natural product synthesis. Chem. Rev. 116, 9683–9747 (2016).
Ardkhean, R. et al. Cascade polycyclizations in natural product synthesis. Chem. Soc. Rev. 45, 1557–1569 (2016).
Girard, P., Namy, J. L. & Kagan, H. B. Divalent lanthanide derivatives in organic synthesis. 1. Mild preparation of SmI2 and YbI2 and their use as reducing or coupling agents. J. Am. Chem. Soc. 102, 2693–2698 (1980).
Szostak, M., Fazakerley, N. J., Parmar, D. & Procter, D. J. Cross-coupling reactions using samarium(ii) iodide. Chem. Rev. 114, 5959–6039 (2014).
Molander, G. A. & Harris, C. R. Sequencing reactions with samarium(ii) iodide. Chem. Rev. 96, 307–338 (1996).
Nicolaou, K. C., Ellery, S. P. & Chen, J. S. Samarium diiodide mediated reactions in total synthesis. Angew. Chem. Int. Ed. 48, 7140–7165 (2009).
Edmonds, D. J., Johnston, D. & Procter, D. J. Samarium(ii)-iodide-mediated cyclizations in natural product synthesis. Chem. Rev. 104, 3371–3403 (2004).
Mukaiyama, T. et al. Asymmetric total synthesis of taxol®. Chem. Eur. J. 5, 121–161 (1999).
Cha, J. Y., Yeoman, J. T. S. & Reisman, S. E. A concise total synthesis of (−)-maoecrystal Z. J. Am. Chem. Soc. 133, 14964–14967 (2011).
Beemelmanns, C. & Reissig, H.-U. A short formal total synthesis of strychnine with a samarium diiodide induced cascade reaction as the key step. Angew. Chem. Int. Ed. 49, 8021–8025 (2010).
Fazakerley, N. J., Helm, M. D. & Procter, D. J. Total synthesis of (+)-pleuromutilin. Chem. Eur. J. 19, 6718–6723 (2013).
Corey, E. J. & Zheng, G. Z. Catalytic reactions of samarium (ii) iodide. Tetrahedron Lett. 38, 2045–2048 (1997).
Nomura, R., Matsuno, T. & Endo, T. Samarium iodide-catalyzed pinacol coupling of carbonyl compounds. J. Am. Chem. Soc. 118, 11666–11667 (1996).
Hélion, F. & Namy, J.-L. Mischmetall: an efficient and low cost coreductant for catalytic reactions of samarium diiodide. J. Org. Chem. 64, 2944–2946 (1999).
Zhang, Y. F. & Mellah, M. Convenient electrocatalytic synthesis of azobenzenes from nitroaromatic derivatives using SmI2. ACS Catal. 7, 8480–8486 (2017).
Trost, B. The atom economy—a search for synthetic efficiency. Science 254, 1471–1477 (1991).
Okada, Y. & Chiba, K. Redox-tag processes: intramolecular electron transfer and its broad relationship to redox reactions in general. Chem. Rev. 118, 4592–4630 (2018).
Gansäuer, A., Hildebrandt, S., Vogelsang, E. & Flowers, R. A. II. Tuning the redox properties of the titanocene(iii)/(iv)-couple for atom-economical catalysis in single electron steps. Dalton Trans. 45, 448–452 (2016).
Lu, Z., Shen, M. & Yoon, T. P. [3+2] cycloadditions of aryl cyclopropyl ketones by visible light photocatalysis. J. Am. Chem. Soc. 133, 1162–1164 (2011).
Amador, A. G., Sherbrook, E. M. & Yoon, T. P. Enantioselective photocatalytic [3+2] cycloadditions of aryl cyclopropyl ketones. J. Am. Chem. Soc. 138, 4722–4725 (2016).
Amador, A. G., Sherbrook, E. M., Lu, Z. & Yoon, T. P. A general protocol for radical anion [3+2] cycloaddition enabled by tandem Lewis acid photoredox catalysis. Synthesis 50, 539–547 (2018).
Hao, W. et al. Radical redox-relay catalysis: formal [3+2] cycloaddition of N-acylaziridines and alkenes. J. Am. Chem. Soc. 139, 12141–12144 (2017).
Hao, W., Harenberg, J. H., Wu, X., MacMillan, S. N. & Lin, S. Diastereo- and enantioselective formal [3+2] cycloaddition of cyclopropyl ketones and alkenes via Ti-catalyzed radical redox relay. J. Am. Chem. Soc. 140, 3514–3517 (2018).
Huang, X. et al. Asymmetric [3+2] photocycloadditions of cyclopropanes with alkenes or alkynes through visible-light excitation of catalyst-bound substrates. Angew. Chem. Int. Ed. 57, 5454–5458 (2018).
Molander, G. A. & Alonso-Alija, C. Opening of cyclopropyl ketones with SmI2. Synthesis of spirocyclic and bicyclic ketones by intramolecular trapping of an electrophile. Tetrahedron 53, 8067–8084 (1997).
Luo, Z., Zhou, B. & Li, Y. Total synthesis of (−)-(α)-kainic acid via a diastereoselective intramolecular [3+2] cycloaddition reaction of an aryl cyclopropyl ketone with an alkyne. Org. Lett. 14, 2540–2543 (2012).
Mainetti, E., Fensterbank, L. & Malacria, M. New elements in the reactivity of α-cyclopropyl vinyl radicals. Synlett 2002, 0923–0926 (2002).
Pape, A. R., Kaliappan, K. P. & Kündig, E. P. Transition-metal-mediated dearomatization reactions. Chem. Rev. 100, 2917–2940 (2000).
Roche, S. P. & Porco, J. A. Jr. Dearomatization strategies in the synthesis of complex natural products. Angew. Chem. Int. Ed. 50, 4068–4093 (2011).
Zhuo, C. X. et al. Catalytic asymmetric dearomatization reactions. Angew. Chem. Int. Ed. 51, 12662–12686 (2012).
Beemelmanns, C. & Reissig, H.-U. Samarium diiodide induced ketyl-(het)arene cyclisations towards novel N-heterocycles. Chem. Soc. Rev. 40, 2199–2210 (2011).
Reissig, H.-U. & Zimmer, R. Donor−acceptor-substituted cyclopropane derivatives and their application in organic synthesis. Chem. Rev. 103, 1151–1196 (2003).
Studer, A. & Curran, D. P. The electron is a catalyst. Nat. Chem. 6, 765–773 (2014).
We thank B. Wang, A. Baldansuren and D. Collison for assistance with the EPR studies. We gratefully acknowledge funding from the UK Engineering and Physical Sciences Research Council (Postdoctoral Fellowship EP/M005062/01 to H.-M.H. and an Established Career Fellowship to D.J.P.). We also acknowledge the Engineering and Physical Sciences Research Council UK National EPR Facility and Service at the University of Manchester (NS/A000055/1)
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Methods, Supplementary Figures 1–23, Supplementary Tables 1–7, Supplementary References
Optimized structures corresponding to Supplementary Table 7
Crystallographic data for compound 2k
Crystallographic data for compound 2m
Crystallographic data for compound 2o
Crystallographic data for compound 4n
Crystallographic data for compound 4o
Crystallographic data for compound 6k
Crystallographic data for compound 6l
About this article
Cite this article
Huang, H., McDouall, J.J.W. & Procter, D.J. SmI2-catalysed cyclization cascades by radical relay. Nat Catal 2, 211–218 (2019). https://doi.org/10.1038/s41929-018-0219-x
Organic Letters (2019)
Nature Reviews Chemistry (2019)
Enantioselective Radical Construction of 5-Membered Cyclic Sulfonamides by Metalloradical C–H Amination
Journal of the American Chemical Society (2019)
Chemical Society Reviews (2019)