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Switchable selectivity in an NHC-catalysed dearomatizing annulation reaction

Abstract

The development of general catalytic methods for the regio- and stereoselective construction of chiral N-heterocycles in a diversity-oriented fashion remains a formidable challenge in organic synthesis. N-heterocyclic carbene (NHC) catalysis has been shown to produce a variety of outcomes, but control of the reactivity has rarely been demonstrated. Here we report a switchable catalytic activation of enals with aromatic azomethine imines that provides high selectivity using NHC organocatalysts. The original selectivity corresponds to the acidity of the base used in the reaction. The catalytically generated chiral homoenolate or enol intermediate undergoes enantioselective annulation with electrophiles such as N-iminoquinolinium ylides, N-iminoisoquinolinium ylides and β-N-iminocarboline ylides. The good-to-high overall yields, high regioselectivities and excellent enantioselectivities observed are controlled by the catalyst and reaction conditions.

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Figure 1: Overview of polycyclic indolizidine alkaloids and a strategy for their preparation.
Figure 2: Influence of effective proton concentration on the homoenolate- and enol-derived product ratios.
Figure 3: Synthetic versatility of the catalytic system.
Figure 4: Mechanistic proposal for asymmetric catalytic switchable annulation reactions.

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Acknowledgements

The authors acknowledge financial support from the Alexander von Humboldt Foundation (C.G.), the Deutsche Forschungsgemeinschaft IRTG 2027 (M.F.) and the Deutsche Forschungsgemeinschaft (SPP 1179, Leibniz award; F.G.). The authors also thank M.N. Hopkinson, K. Chepiga and J. Neugebauer for discussions and corrections during the preparation of the manuscript. This work is dedicated to the memory of C. Djerassi.

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C.G. and F.G. conceived and designed the study, and co-wrote the paper. C.G. and M.F. performed the experiments and analysed the data. C.G., M.F. and D.J.-M. performed the mechanism study. C.G.D. performed the crystallographic studies. All the authors discussed the results and commented on the manuscript.

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Correspondence to Frank Glorius.

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The authors declare no competing financial interests.

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Crystallographic data for compound 3k. (CIF 330 kb)

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Structure factors for compound 3k. (CIF 203 kb)

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Crystallographic data for compound 3l. (CIF 35 kb)

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Structure factors for compound 3l. (CIF 421 kb)

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Guo, C., Fleige, M., Janssen-Müller, D. et al. Switchable selectivity in an NHC-catalysed dearomatizing annulation reaction. Nature Chem 7, 842–847 (2015). https://doi.org/10.1038/nchem.2337

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