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.
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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.
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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.
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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
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Huang, HM., 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
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