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Stereoinversion of tertiary alcohols to tertiary-alkyl isonitriles and amines

Nature volume 501, pages 195–199 (2013)Cite this article

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A Corrigendum to this article was published on 13 November 2013

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Abstract

The SN2 reaction (bimolecular nucleophilic substitution) is a well-known chemical transformation that can be used to join two smaller molecules together into a larger molecule or to exchange one functional group for another. The SN2 reaction proceeds in a very predictable manner: substitution occurs with inversion of stereochemistry, resulting from the ‘backside attack’ of the electrophilic carbon by the nucleophile. A significant limitation of the SN2 reaction is its intolerance for tertiary carbon atoms: whereas primary and secondary alcohols are viable precursor substrates, tertiary alcohols and their derivatives usually either fail to react or produce stereochemical mixtures of products1,2,3. Here we report the stereochemical inversion of chiral tertiary alcohols with a nitrogenous nucleophile facilitated by a Lewis-acid-catalysed solvolysis. The method is chemoselective against secondary and primary alcohols, thereby complementing the selectivity of the SN2 reaction. Furthermore, this method for carbon–nitrogen bond formation mimics a putative biosynthetic step in the synthesis of marine terpenoids4 and enables their preparation from the corresponding terrestrial terpenes. We expect that the general attributes of the methodology will allow chiral tertiary alcohols to be considered viable substrates for stereoinversion reactions.

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Figure 1: Nitrogenous marine terpenoids derived from inorganic cyanide.
Figure 2: Development of a stereoselective Ritter-type reaction through tertiary alcohol inversion.
Figure 3: Probing the selectivity and functional group tolerance of isocyanation.
Figure 4: Amines, amides and isothiocyanates synthesized from the corresponding isonitriles.
Figure 5: Limitations of tertiary alcohol stereoinversion.
Figure 6: Possible reaction pathways.

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Data deposits

Crystallographic data are deposited with the Cambridge Crystallographic Data Centre under accession numbers CCDC 949094 (25) and CCDC 948968 (26).

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Acknowledgements

We thank C. Moore and A. L. Rheingold for X-ray crystallographic analysis. We thank the Yu laboratory for the use of their liquid chromatography–mass spectrometry equipment, the Boger laboratory for the use of their polarimeter, the Baran laboratory for the use of their cold room. Financial support for this work was provided by Eli Lilly, Boehringer Ingelheim and the Scripps Research Institute.

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  1. Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA,

    Sergey V. Pronin, Christopher A. Reiher & Ryan A. Shenvi

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Contributions

S.V.P. and R.A.S. conceived the work. S.V.P. and C.A.R. performed the experiments. S.V.P., C.A.R. and R.A.S. designed the experiments and analysed the data. R.A.S. wrote the manuscript.

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Correspondence to Ryan A. Shenvi.

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The authors declare no competing financial interests.

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This file contains Supplementary Text and Supplementary Data – see contents page for details. This file was replaced on 13 November 2013. (PDF 14777 kb)

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Pronin, S., Reiher, C. & Shenvi, R. Stereoinversion of tertiary alcohols to tertiary-alkyl isonitriles and amines. Nature 501, 195–199 (2013). https://doi.org/10.1038/nature12472

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