SmI2-catalysed cyclization cascades by radical relay

Abstract

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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Fig. 1: Importance of stoichiometric SmI2-mediated cyclizations and the challenge of catalysis using SmI2.
Fig. 2: Substrate scope for alkynes.
Fig. 3: Substrate scope for alkenes.
Fig. 4: SmI2-catalysed dearomatizing cyclization cascades.
Fig. 5: Preliminary mechanistic studies.
Fig. 6: Computational studies.

Data availability

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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Acknowledgements

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)

Author information

H.-M.H. and D.J.P. conceived and directed the project. H.-M.H. and D.J.P. designed the experiments. H.-M.H. performed and analysed all of the reactions. J.J.W.M. performed all of the computational studies. H.-M.H. and D.J.P. wrote the manuscript.

Correspondence to David J. Procter.

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The authors declare no competing interests.

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Supplementary information

Supplementary Information

Supplementary Methods, Supplementary Figures 1–23, Supplementary Tables 1–7, Supplementary References

Supplementary Data 1

Optimized structures corresponding to Supplementary Table 7

Compound 2k

Crystallographic data for compound 2k

Compound 2n

Crystallographic data for compound 2m

Compound 2o

Crystallographic data for compound 2o

Compound 4n

Crystallographic data for compound 4n

Compound 4o

Crystallographic data for compound 4o

Compound 6k

Crystallographic data for compound 6k

Compound 6l

Crystallographic data for compound 6l

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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

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