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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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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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.
The authors declare no competing interests.
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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
Nature Catalysis (2019)