Abstract
Catalytic reactions that enable access to different diastereoisomers are important but often difficult to achieve. One long-standing unsolved challenge is the anti-selective conjugate addition reaction between aldehydes and nitroolefins. This organocatalytic transformation is a versatile method for the synthesis of γ-nitroaldehydes and downstream compounds such as pyrrolidines and γ-butyrolactams, which are key moieties in bioactive molecules. Numerous amine catalysts have been developed for this transformation, but all provide syn-configured products. Here, we present a tripeptide as a general catalyst for the synthesis of anti-configured γ-nitroaldehydes. Key to the anti selectivity is the installation of substituents at Cδ of the reactive pyrrolidine of proline to enable the formation of s-cis enamine intermediates. The peptidic catalyst converts different aldehyde and nitroolefin combinations into the products in high yields and stereoselectivities. Conformational and mechanistic studies revealed a Curtin–Hammett scenario for the catalytic system. The strategy provides long-sought-after access to anti-configured γ-nitroaldehydes and a guide for reversing the diastereoselectivity of amine-based organocatalysts.
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Acknowledgements
We thank the Fonds der Chemischen Industrie (Germany) for a Kekulé Fellowship for T.S., the Alfred Werner Fund of the Swiss Chemical Society Foundation for an MSc scholarship for A.B. and the Swiss National Science Foundation (grant no. 200020_169423).
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T.S. and A.B. conducted the experiments. T.S. and H.W. conceived and designed the project, analysed the data and prepared this manuscript.
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Supplementary methods, Tables 1–5, Figs. 1 and 2 and references.
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Coordinates of the calculated lowest-energy structures.
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Schnitzer, T., Budinská, A. & Wennemers, H. Organocatalysed conjugate addition reactions of aldehydes to nitroolefins with anti selectivity. Nat Catal 3, 143–147 (2020). https://doi.org/10.1038/s41929-019-0406-4
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DOI: https://doi.org/10.1038/s41929-019-0406-4
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