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Synthesis and structural analysis of 2-quinuclidonium tetrafluoroborate

Naturevolume 441pages731734 (2006) | Download Citation

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Abstract

The amide functional group is one of the most fundamental motifs found in chemistry and biology, and it has been studied extensively for the past century1. Typical acyclic amides are planar. But the amide groups of bicyclic bridgehead lactams1,2 are highly twisted, and this distortion from planarity can dramatically affect the stability and reactivity of these amides; it also increases the basicity of the nitrogen so that it often behaves more like an amine than a typical planar amide. As a result, the structures and reactivity profiles of these ‘anti-Bredt’ amides3 differ significantly from those of planar amides. It is possible that this twisting phenomenon is not exclusive to cyclic systems—non-planarity may also be a critical biological design element that leads to amide ground-state destabilization and alters the reactivity, selectivity and mechanism of various protein and enzymatic processes (such as amide hydrolysis1,4,5,6,7,8,9,10). The intriguing qualities of these twisted amides were first recognized in 1938 (ref. 11), wherein one of the simplest families was introduced—molecules containing the 1-azabicyclo[2.2.2]octan-2-one system. But the parent member of this group, 2-quinuclidone (molecule 1 in this paper), has not yet been unambiguously synthesized. Here, we report the chemical synthesis, isolation and full characterization of the HBF4 salt of 1. Critical to the success of the synthesis and isolation was the decision to generate 1 by a route other than classical amide bond formation. We anticipate that these results will provide a greater understanding of the properties of amide bonds.

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Acknowledgements

We thank H. H. Wasserman, E. J. Corey, and N. J. Leonard for discussions. We thank Ono Pharmaceutical Co. Ltd (for a postdoctoral fellowship to K.T.), the Research Corporation, the Camille and Henry Dreyfus Foundation, Merck, Pfizer, Lilly, Amgen and Bristol-Myers Squibb for financial support. We also thank M. W. Day and L. M. Henling for their X-ray crystallographic expertise.

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  1. Laboratories of Chemical Synthesis, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, 1200 E. California Boulevard, M/C 164-30, California, 91125, USA

    • Kousuke Tani
    •  & Brian M. Stoltz

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Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. Crystallographic data have been deposited at the CCDC (12 Union Road, Cambridge CB2 1EZ, UK) and copies can be obtained on request, free of charge, by quoting the publication citation and the deposition number 296767. The authors declare no competing financial interests.

Corresponding author

Correspondence to Brian M. Stoltz.

Supplementary information

  1. Supplementary Notes

    This file provides the full experimental details for the preparation of all new compounds and their characterization (PDF 1376 kb)

  2. Supplementary Data

    This file provides the X-ray data for 1•HBF4. (PDF 34 kb)

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https://doi.org/10.1038/nature04842

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