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Flow chemistry and polymer-supported pseudoenantiomeric acylating agents enable parallel kinetic resolution of chiral saturated N-heterocycles

Nature Chemistry volume 9, pages 446–452 (2017)Cite this article

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Abstract

Kinetic resolution is a common method to obtain enantioenriched material from a racemic mixture. This process will deliver enantiopure unreacted material when the selectivity factor of the process, s, is greater than 1; however, the scalemic reaction product is often discarded. Parallel kinetic resolution, on the other hand, provides access to two enantioenriched products from a single racemic starting material, but suffers from a variety of practical challenges regarding experimental design that limit its applications. Here, we describe the development of a flow-based system that enables practical parallel kinetic resolution of saturated N-heterocycles. This process provides access to both enantiomers of the starting material in good yield and high enantiopurity; similar results with classical kinetic resolution would require selectivity factors in the range of s = 100. To achieve this, two immobilized quasienantiomeric acylating agents were designed for the asymmetric acylation of racemic saturated N-heterocycles. Using the flow-based system we could efficiently separate, recover and reuse the polymer-supported reagents. The amide products could be readily separated and hydrolysed to the corresponding amines without detectable epimerization.

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Figure 1: Principles of kinetic and parallel kinetic resolution.
Figure 2: Acylating agents and s factors afforded in kinetic resolution.
Figure 3: Amide product hydrolysis.

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Acknowledgements

This work was supported by the European Research Council (ERC Starting Grant no. 306793-CASAA) and the Swiss Federal Commission for Technology and Innovation (CTI 15523.1). S.-Y. Hsieh, B. Wanner and K.-Y. Chen (all ETH) are thanked for helpful discussions and advice with flow-based systems.

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  1. Department of Chemistry and Applied Biosciences, Laboratorium für Organische Chemie, ETH-Zürich, Zürich, 8093, Switzerland

    Imants Kreituss & Jeffrey W. Bode

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Contributions

J.W.B. and I.K. contributed equally to the design of the study. J.W.B. and I.K. co-wrote the paper. I.K. performed the experiments and wrote the Supplementary Information.

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Correspondence to Jeffrey W. Bode.

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Kreituss, I., Bode, J. Flow chemistry and polymer-supported pseudoenantiomeric acylating agents enable parallel kinetic resolution of chiral saturated N-heterocycles. Nature Chem 9, 446–452 (2017). https://doi.org/10.1038/nchem.2681

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