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Regiodivergent enantioselective C–H functionalization of Boc-1,3-oxazinanes for the synthesis of β2- and β3-amino acids

Nature Catalysis volume 2, pages 882–888 (2019)Cite this article

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Abstract

β2- and β3-amino acids are important chiral building blocks for the design of new pharmaceuticals and peptidomimetics. Here, we report a straightforward regio- and enantiodivergent access to these compounds using a one-pot reaction composed of sparteine-mediated enantioselective lithiation of a Boc-1,3-oxazinane, transmetallation to zinc and direct or migratory Negishi coupling with an organic electrophile. The regioselectivity of the Negishi coupling was highly ligand-controlled and switchable to obtain the C4- or the C5-functionalized product exclusively. High enantioselectivities were achieved on a broad range of examples, and a catalytic version in chiral diamine was developed using the (+)-sparteine surrogate. Selected C4- and C5-functionalized Boc-1,3-oxazinanes were subsequently converted to highly enantioenriched β2- and β3-amino acids with the (R) or (S) configuration, depending on the sparteine enantiomer employed in the lithiation step.

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Fig. 1
Fig. 2: Lithiation/Negishi coupling of cyclic Boc-amines.
Fig. 3: Trapping experiments.
Fig. 4: Scope of the C4 and C5 functionalization of Boc-1,3-oxazinanes.
Fig. 5: Development of proof-of-concept catalytic enantioselective C4 and C5 arylations.
Fig. 6: Application to the synthesis of β2- and β3-amino acids.

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Data availability

Data supporting the findings of this study are available in the Supplementary Information or from the corresponding author upon request. The Supplementary Information contains full details on the synthesis and characterization of compounds. CCDC 1913804 (compound (R)-11a) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

This work was financially supported by the Swiss National Science Foundation (grant no. 200021_165987) and the University of Basel. We thank A. Prescimone, University of Basel, for X-ray diffraction analysis, D. Häussinger, University of Basel, for NMR experiments, S. Mittelheisser and M. Pfeffer, University of Basel, for mass spectrometry analysis and J. Rotzler and F. Bächle (Solvias AG), for fruitful discussions.

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  1. These authors contributed equally: Weilong Lin, Ke-Feng Zhang.

Authors and Affiliations

  1. Department of Chemistry, University of Basel, Basel, Switzerland

    Weilong Lin, Ke-Feng Zhang & Olivier Baudoin

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  1. Weilong Lin
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Contributions

W.L. and K.-F.Z. designed and performed the experiments, analysed the experimental data and prepared the Supplementary Information. O.B. directed the investigations and prepared the manuscript.

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Correspondence to Olivier Baudoin.

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Supplementary information

Supplementary Information

Supplementary Methods, Supplementary Table 1, Supplementary Figures 1–2, Supplementary References

Compound (R)-11a

Crystallographic data for compound (R)-11a

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Lin, W., Zhang, KF. & Baudoin, O. Regiodivergent enantioselective C–H functionalization of Boc-1,3-oxazinanes for the synthesis of β2- and β3-amino acids. Nat Catal 2, 882–888 (2019). https://doi.org/10.1038/s41929-019-0336-1

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