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Enantioselective silyl protection of alcohols promoted by a combination of chiral and achiral Lewis basic catalysts

Nature Chemistry volume 5, pages 768–774 (2013)Cite this article

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Abstract

Catalytic enantioselective monosilylations of diols and polyols furnish valuable alcohol-containing molecules in high enantiomeric purity. These transformations, however, require high catalyst loadings (20–30 mol%) and long reaction times (2–5 days). Here, we report that a counterintuitive strategy involving the use of an achiral co-catalyst structurally similar to the chiral catalyst provides an effective solution to this problem. A combination of seemingly competitive Lewis basic molecules can function in concert such that one serves as an achiral nucleophilic promoter and the other performs as a chiral Brønsted base. On the addition of 7.5–20 mol% of a commercially available N-heterocycle (5-ethylthiotetrazole), reactions typically proceed within one hour, and deliver the desired products in high yields and enantiomeric ratios. In some instances, there is no reaction in the absence of the achiral base, yet the presence of the achiral co-catalyst gives rise to facile formation of products in high enantiomeric purity.

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Figure 1: Previously reported enantioselective alcohol silylations, the initially proposed model and the results of initial theoretical studies.
Figure 2: Examples of the catalytic system.
Figure 3: Mechanistic models to account for the observed sense and levels of enantioselectivity (deprotonated 13 serves as the nucleophilic co-catalyst).

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Acknowledgements

This research was supported by the US National Institutes of Health, Institute of General Medical Sciences (Grant GM-57212). We thank D. Silverio, V. Rendina and B. Potter for many helpful discussions and experimental assistance and Boston College for providing access to computational facilities.

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Authors and Affiliations

  1. Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, 02467, Massachusetts, USA

    Nathan Manville, Hekla Alite, Fredrik Haeffner, Amir H. Hoveyda & Marc L. Snapper

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  1. Nathan Manville
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  2. Hekla Alite
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  3. Fredrik Haeffner
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  4. Amir H. Hoveyda
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Contributions

N.M. and H.A. were involved in the development of the catalytic protocol. F.H. designed and performed the theoretical studies. M.L.S. and A.H.H. directed the investigations. A.H.H. wrote the manuscript with revisions provided by the other authors.

Corresponding authors

Correspondence to Amir H. Hoveyda or Marc L. Snapper.

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The authors declare no competing financial interests.

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Manville, N., Alite, H., Haeffner, F. et al. Enantioselective silyl protection of alcohols promoted by a combination of chiral and achiral Lewis basic catalysts. Nature Chem 5, 768–774 (2013). https://doi.org/10.1038/nchem.1708

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