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Thiourea-catalysed ring opening of episulfonium ions with indole derivatives by means of stabilizing non-covalent interactions

Nature Chemistry volume 4, pages 817–824 (2012)Cite this article

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Abstract

Small organic and metal-containing molecules (molecular mass <1,000) can catalyse synthetically useful reactions with the high levels of stereoselectivity typically associated with macromolecular enzymatic catalysts. Whereas enzymes are generally understood to accelerate reactions and impart selectivity as they stabilize specific transition structures through networks of cooperative interactions, enantioselectivity with chiral, small-molecule catalysts is rationalized typically by the steric destabilization of all but one dominant pathway. However, it is increasingly apparent that stabilizing effects also play an important role in small-molecule catalysis, although the mechanistic characterization of such systems is rare. Here, we show that arylpyrrolidino amido thiourea catalysts catalyse the enantioselective nucleophilic ring opening of episulfonium ions by indoles. Evidence is provided for the selective transition-state stabilization of the major pathway by the thiourea catalyst in the rate- and selectivity-determining step. Enantioselectivity is achieved through a network of attractive anion binding, cation-π and hydrogen-bond interactions between the catalyst and the reacting components in the transition-structure assembly.

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Figure 1
Figure 2: Proposed catalytic cycle for thiourea-catalysed ring-opening of episulfonium ions with indole.
Figure 3: Rate acceleration by 3e and acidity of the N–H motif of the 5-indole derivatives.
Figure 4: Enantio-induction with thiourea catalysts through a selective, attractive cation-π interaction between the extended aromatic residue on the catalyst and the acidic α-protons in the episulfonium ion.
Figure 5: Proposed transition-structure model.

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Acknowledgements

This work was supported by the National Institute of General Medical Sciences (NIGMS) (P50 GM-69721 and RO1 GM-43214) and by a predoctoral fellowship to S.L. from Eli Lilly. We thank R. Knowles, K. Brak and H. Mayr for helpful discussions, A. Brown, D. Lehnherr and A. Hyde for the use of catalysts, and S-L. Zheng for crystal structure determinations.

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  1. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, 02138, Massachusetts, USA

    Song Lin & Eric N. Jacobsen

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  1. Song Lin
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S.L. conducted the experiments, S.L. and E.N.J. co-wrote the manuscript and E.N.J. guided the research.

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Correspondence to Eric N. Jacobsen.

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Lin, S., Jacobsen, E. Thiourea-catalysed ring opening of episulfonium ions with indole derivatives by means of stabilizing non-covalent interactions. Nature Chem 4, 817–824 (2012). https://doi.org/10.1038/nchem.1450

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