Iridium-catalysed enantioselective formal deoxygenation of racemic alcohols via asymmetric hydrogenation

Abstract

Asymmetric hydrogenation of alkenes is one of the most powerful tools for the preparation of optically active compounds. However, to achieve high enantioselectivity, the starting olefin in most cases needs to be isomerically pure in either the cis or the trans form. Generally, most olefination protocols provide olefins as isomeric mixtures that are difficult to separate, and in many cases also generate lots of waste. In contrast, the synthesis of racemic alcohols is straightforward and highly atom-efficient, with products that are easier to purify. Here, we describe a strategy that enables rapid access to chiral alkanes via enantioconvergent formal deoxygenation of racemic alcohols. Mechanistic studies indicate an Ir-mediated elimination of water and subsequent in situ hydrogenation. This approach allows rapid and efficient assembly of chiral intermediates and is exemplified in the total synthesis of antidepressant sertraline and σ2 receptor PB 28.

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Fig. 1: Different preparative routes from ketones to chiral alkanes.
Fig. 2: Initial studies of Ir-catalysed deoxygenation.
Fig. 3: Substrate scope of linear tertiary alcohols.
Fig. 4: Substrate scope of cyclic tertiary alcohols and applications.
Fig. 5: Mechanistic studies.
Fig. 6: Computational studies of c1c6.

Data availability

All data is available from the authors on reasonable request.

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Acknowledgements

The Swedish Research Council (VR), Stiftelsen Olle Engkvist Byggmästare, the Carl Tryggers Stiftelse, Knut and Alice Wallenberg foundation (KAW 2016.0072 and KAW 2018:0066) supported this work. J.J. thanks the Scientist Development Project Commemorating His Majesty the King’s 84th Birthday Anniversary, Chulabhorn Graduate Institute. We are also thankful to D.A. Tanner and M. Nolan for proofreading the manuscript.

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P.G.A. conceived and designed the experiments. J.Z., J.J., B.B.C.P., J.G. and S.P. performed experiments and prepared the Supplementary Information. M.S.G.A. performed the computational studies. P.G.A. and J.Z. wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Pher G. Andersson.

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Supplementary Information

Supplementary Figs. 1–5, Tables 1–6, discussion, methods and references.

Supplementary Data 1

Cartesian coordinates of optimized structures.

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Zheng, J., Jongcharoenkamol, J., Peters, B.B.C. et al. Iridium-catalysed enantioselective formal deoxygenation of racemic alcohols via asymmetric hydrogenation. Nat Catal 2, 1093–1100 (2019). https://doi.org/10.1038/s41929-019-0375-7

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