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Asymmetric spiroacetalization catalysed by confined Brønsted acids

Abstract

Acetals are molecular substructures that contain two oxygen–carbon single bonds at the same carbon atom, and are used in cells to construct carbohydrates and numerous other molecules. A distinctive subgroup are spiroacetals, acetals joining two rings, which occur in a broad range of biologically active compounds, including small insect pheromones and more complex macrocycles1,2. Despite numerous methods for the catalytic asymmetric formation of other commonly occurring stereocentres, there are few approaches that exclusively target the chiral acetal centre and none for spiroacetals3,4. Here we report the design and synthesis of confined Brønsted acids based on a C2-symmetric imidodiphosphoric acid motif, enabling a catalytic enantioselective spiroacetalization reaction. These rationally constructed Brønsted acids possess an extremely sterically demanding chiral microenvironment, with a single catalytically relevant and geometrically constrained bifunctional active site. Our catalyst design is expected to be of broad utility in catalytic asymmetric reactions involving small and structurally or functionally unbiased substrates.

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Figure 1: Towards catalytic asymmetric synthesis of olean.
Figure 2: Development of C 2 -symmetric imidodiphosphoric acids.
Figure 3: Comparison of crystal structures of anions of 6a (6 with R = 2,4,6-Et 3 C 6 H 2 ) and TRIP.

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Data deposits

X-ray crystallographic data have been deposited in the Cambridge Crystallographic Data Centre database (http://www.ccdc.cam.ac.uk/) under accession code CCDC 864762.

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Acknowledgements

We thank A. Dreier and R. Goddard for crystal structure analysis of catalyst 6a. S. Vellalath and S. Müller are acknowledged for donating several previously described catalysts, and N. Wippich and S. Dehn for technical assistance. We gratefully acknowledge support from the Max Planck Sociey and the European Research Council.

Author information

Authors and Affiliations

Authors

Contributions

I.Č. and B.L. jointly designed and developed C2-symmetric imidodiphosphoric acids, developed the spiroacetalization reaction, and wrote the manuscript. I.Č. conducted the laboratory experiments. B.L. initiated and oversaw the project.

Corresponding author

Correspondence to Benjamin List.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-4, Supplementary Tables 1-6, Supplementary Methods, Supplementary References and Supplementary Data. The figures in the Supplementary Data show synthetic routes used and crystal structure of the catalyst 6a with probability ellipsoids. (PDF 4230 kb)

Supplementary Data

This file contains the crystallographic information for catalyst 6a. (ZIP 17 kb)

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Čorić, I., List, B. Asymmetric spiroacetalization catalysed by confined Brønsted acids. Nature 483, 315–319 (2012). https://doi.org/10.1038/nature10932

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