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Cascade CuH-catalysed conversion of alkynes into enantioenriched 1,1-disubstituted products

Abstract

Enantioenriched α-aminoboronic acids play a unique role in medicinal chemistry and have emerged as privileged pharmacophores in proteasome inhibitors. Additionally, they represent synthetically useful chiral building blocks in organic synthesis. Recently, CuH-catalysed asymmetric alkene hydrofunctionalization has become a powerful tool to construct stereogenic carbon centres. By contrast, applying CuH cascade catalysis to achieve the reductive 1,1-difunctionalization of alkynes remains an important, but largely unaddressed, synthetic challenge. Herein, we report an efficient strategy to synthesize α-aminoboron compounds by a CuH-catalysed hydroboration/hydroamination cascade of readily available alkynes. Notably, this transformation selectively delivers the desired 1,1-heterodifunctionalized product rather than the alternative homodifunctionalized, 1,2-heterodifunctionalized or reductively monofunctionalized by-products, thereby offering rapid access to these privileged scaffolds with high chemo-, regio- and enantioselectivity.

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Fig. 1: Overview of the proposed approach to CuH-catalysed cascade reductive difunctionalization of alkynes.
Fig. 2: Discovery and evaluation of the CuH cascade process.
Fig. 3: Synthetic applications of the enantioselective 1,1-aminoboration method.
Fig. 4: Mechanistic overview.

Data availability

Most of the data that support the findings of this study are available within the article and its Supplementary Information. Additional data are available from the corresponding author upon reasonable request.

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Acknowledgements

D. G. Blackmond, D. E. Hill and J. S. Bandar are acknowledged for helpful discussions regarding the reaction mechanism. This work was financially supported by The Scripps Research Institute, Pfizer, Bristol-Myers Squibb (unrestricted grant) and the National Institutes of Health (5R35GM125052-02, R35GM128779). We gratefully acknowledge the Nankai University College of Chemistry for a Summer Project Scholarship (T.-Z.Q.) and the China Scholarship Council for supporting a visiting studentship (X.W.). Calculations were performed at the Center for Research Computing at the University of Pittsburgh and the Extreme Science and Engineering Discovery Environment (XSEDE) supported by the NSF.

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D.-W.G. and K.M.E. conceived the project. D.-W.G. optimized the reaction conditions. D.-W.G., Y.G., T.-Z.Q. and X.W. prepared substrates and examined the substrate scope. D.-W.G. and Y.G. studied the mechanism and explored the synthetic applications. H.S. and P.L. carried out DFT studies. B.B.S. and J.S.C. assisted with analytical aspects of the project. P.L. and K.M.E. directed the project. D.-W.G., Y.G., H.S., P.L. and K.M.E. wrote the manuscript with input from all authors.

Corresponding authors

Correspondence to Peng Liu or Keary M. Engle.

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Supplementary information

Supplementary Information

Supplementary Methods, Figures 1–13 and references.

Supplementary Data 1

Coordinates of optimized structures.

NMR data

NMR data.

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Gao, DW., Gao, Y., Shao, H. et al. Cascade CuH-catalysed conversion of alkynes into enantioenriched 1,1-disubstituted products. Nat Catal 3, 23–29 (2020). https://doi.org/10.1038/s41929-019-0384-6

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