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By-design enantioselective self-amplification based on non-covalent product–catalyst interactions

Abstract

The synthesis of enantiomerically pure compounds is of great importance in pharmaceuticals, fragrances and biological applications, and functions as a key to many processes in nature. Asymmetric catalysis using enantiomerically pure catalysts represents an efficient synthetic method to achieve this goal. The enantiomeric excess of the reaction product correlates with the enantiomeric purity of the catalysts, except for nonlinear behaviour, therefore the use of stereochemically flexible catalysts seems to complicate the control of stereoselectivity. Self-amplifying catalytic reactions are attractive, but a general rational design is highly challenging. Here we show that product interaction with chiral recognition sites attached to structurally flexible phoshoramidite-type catalysts can sense the chirality and induce enantioselectivity in the catalyst. Structural flexibility along with sensing of the chirality of the product molecules results in a rapid increase of enantioselectivity of the dynamic catalysts (Δe.e. of up to 76%) and a shift out of equilibrium. In contrast to stereodynamic catalysts controlled with cleavable chiral auxiliaries, the enantioselectivity does not decrease.

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Figure 1: Schematic overview of the key steps of enantioselective self-amplifying catalysis.
Figure 2: Non-covalent binding model, design of the structurally flexible ligand and the catalysis product, and synthesis of the ligand and catalysts.
Figure 3: Investigation of the non-covalent interactions of 4 and 5 with 10 equiv. 7, (R)-8 or (S)-8 and 20 equiv. rac-8 in solution via 13C{1H} and 31P{1H} NMR spectroscopy.
Figure 4: Investigation of the influence of non-covalent interaction additives on the enantioselectivity of catalyst 6.
Figure 5: Enantioselectivity of rhodium catalyst 6 in the hydrogenation of 3,5-DNB-ΔAla-OEt (7).
Figure 6: Hydrogenations of dehydroamino acid derivatives with non-covalent binding sites.

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Acknowledgements

Generous financial support by the European Research Council for a Starting Grant (no. 258740, AMPCAT) is gratefully acknowledged. G.S. acknowledges the Fonds der Chemischen Industrie for a PhD fellowship. We thank. F. Rominger (Institut für Organische Chemie, Ruprecht-Karls-Universität Heidelberg) for X-ray crystallographic investigations.

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G.S. synthesized and characterized the compounds and performed catalytic investigations. O.T. and G.S. conceived and designed the experiments, analysed data and prepared the manuscript. Both authors discussed the results and commented on the manuscript.

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Correspondence to Oliver Trapp.

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Crystallographic data for compound 3. (CIF 366 kb)

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Crystallographic data for compound 11. (CIF 495 kb)

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Crystallographic data for compound 16. (CIF 1128 kb)

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Storch, G., Trapp, O. By-design enantioselective self-amplification based on non-covalent product–catalyst interactions. Nature Chem 9, 179–187 (2017). https://doi.org/10.1038/nchem.2638

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