Diastereodivergent synthesis of enantioenriched α,β-disubstituted γ-butyrolactones via cooperative N-heterocyclic carbene and Ir catalysis

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Abstract

The stereodivergent synthesis of natural product frameworks via a single transformation using simple starting materials is a significant challenge. The prevalence of γ-butyrolactones in biologically active natural products has long motivated the development of enantioselective strategies towards their synthesis. Herein, we report an enantio- and diastereodivergent [3 + 2] annulation reaction for the synthesis of α,β-disubstituted γ-butyrolactones through cooperative N-heterocyclic carbene organocatalysis and iridium catalysis. This method overcomes the challenges of merging N-heterocyclic carbene organocatalysis with iridium catalysis by the appropriate choice of ligands. The use of two chiral catalysts allowed control over the relative and absolute configuration of the two formed stereocentres, thereby providing selective access to all four possible stereoisomers of the γ-lactone products. The transformation could be extended to the synthesis of δ-lactams via [4 + 2] annulation. The synthetic utility of this methodology was illustrated in the concise synthesis of the naturally occurring lignan (−)-hinokinin.

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Fig. 1: Examples of γ-butyrolactones and their synthesis by NHC organocatalysis.
Fig. 2: Scope of the cis-selective [3 + 2] annulation reaction.
Fig. 3: Diastereodivergent synthesis of all four isomers of γ-butyrolactone 3a.
Fig. 4: Diastereodivergent [3 + 2] annulation reaction and isomerization of cis-lactones.
Fig. 5: Scope of the [4 + 2] annulation for the formation of cis-δ-lactams.
Fig. 6: Application of the [3 + 2] annulation to the synthesis of (−)-hinokinin.
Fig. 7: Mechanistic insights into the [3 + 2] annulation.

Data availability

Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers 1907670 ((R,S)-3c′) and 1907671 ((R,S)-6ab). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All other data supporting the findings of this study are available within the article and its Supplementary Information, or from the corresponding author upon reasonable request.

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Acknowledgements

Support for this work was generously provided by the Deutsche Forschungsgemeinschaft (Leibniz Award) and the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement number 843349-H2020-MSCA-IF-2018 (E.S.). We also thank M. J. James, M. van Gemmeren, T. Patra and Z. Nairoukh (University of Münster) for helpful discussions and corrections during the preparation of the manuscript. M. Wollenburg, M. Wiesenfeldt, T. Wagener, K. Kronenberg and N. Radhoff (University of Münster) are acknowledged for experimental support.

Author information

S.S., E.S., S.M. and F.G. designed, performed and analysed the experiments. C.G.D. performed the crystallographic studies. S.S., E.S. and F.G. co-wrote the manuscript. All authors contributed to discussions.

Correspondence to Frank Glorius.

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Supplementary information

Supplementary information

Supplementary methods, Tables 1–7, Figures 1–8, references

Compound (R,S)-3c

Crystallographic data for compound (R,S)-3c′

Compound (R,S)-6ab

Crystallographic data for compound (R,S)-6ab

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Singha, S., Serrano, E., Mondal, S. et al. Diastereodivergent synthesis of enantioenriched α,β-disubstituted γ-butyrolactones via cooperative N-heterocyclic carbene and Ir catalysis. Nat Catal (2019) doi:10.1038/s41929-019-0387-3

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