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Mechanistic, crystallographic, and computational studies on the catalytic, enantioselective sulfenofunctionalization of alkenes

Nature Chemistry volume 6, pages 1056–1064 (2014)Cite this article

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Abstract

The stereocontrolled introduction of vicinal heteroatomic substituents into organic molecules is one of the most powerful ways of adding value and function. Although many methods exist for the introduction of oxygen- and nitrogen-containing substituents, the number of stereocontrolled methods for the introduction of sulfur-containing substituents pales by comparison. Previous reports from our laboratories have described sulfenofunctionalizations of alkenes that construct carbon–sulfur bonds vicinal to carbon–oxygen, carbon–nitrogen or carbon–carbon bonds with high levels of diastereospecificity and enantioselectivity. This process is enabled by the concept of Lewis-base activation of Lewis acids, which provides activation of Group 16 electrophiles. To provide a foundation for the expansion of substrate scope and improved selectivities, we have undertaken a comprehensive study of the catalytically active species. Insights gleaned from kinetic, crystallographic and computational methods have led to the introduction of a new family of sulfenylating agents that provide significantly enhanced selectivities.

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Figure 1: Lewis-base catalysed, enantioselective sulfenofunctionalization of unactivated alkenes.
Figure 2: Synthesis of catalytically active species (±)-5b and its X-ray crystal structure.
Figure 3: Proposed catalytic cycle of Lewis-base catalysed sulfenofunctionalization.
Figure 4: Calculations of transition states leading to formation of the thiiranium ion.

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Acknowledgements

The authors acknowledge financial support from the National Institutes of Health (GM R01-085235). E.H. thanks the Deutscher Akademischer Austauschdienst for a postdoctoral fellowship. D.J-P.K. thanks the University of Illinois for a Seemon H. Pines Graduate Fellowship in Synthetic Organic Chemistry. The authors thank L.M. Wolf (MPI-Mühlheim) for assistance with the computational analysis.

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Authors and Affiliations

  1. Department of Chemistry, Roger Adams Laboratory, University of Illinois, Urbana, 61801, Illinois, USA

    Scott E. Denmark, Eduard Hartmann, David J. P. Kornfilt & Hao Wang

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  1. Scott E. Denmark
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Contributions

E.H. planned and carried out the experimental work and obtained the X-ray structure of 5b. D.J-P.K. carried out the kinetic analysis and H.W. performed the transition state calculations. S.E.D. initiated and directed the project. E.H. wrote the manuscript with the assistance of the other authors.

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Correspondence to Scott E. Denmark.

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The authors declare no competing financial interests.

Supplementary information

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Supplementary information (PDF 4612 kb)

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Crystallographic data for compound (±)-5b (CIF 56 kb)

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Crystallographic data for compound S5 (CIF 36 kb)

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Denmark, S., Hartmann, E., Kornfilt, D. et al. Mechanistic, crystallographic, and computational studies on the catalytic, enantioselective sulfenofunctionalization of alkenes. Nature Chem 6, 1056–1064 (2014). https://doi.org/10.1038/nchem.2109

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