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Hindered dialkyl ether synthesis with electrogenerated carbocations

Nature volume 573, pages 398–402 (2019)Cite this article

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Abstract

Hindered ethers are of high value for various applications; however, they remain an underexplored area of chemical space because they are difficult to synthesize via conventional reactions1,2. Such motifs are highly coveted in medicinal chemistry, because extensive substitution about the ether bond prevents unwanted metabolic processes that can lead to rapid degradation in vivo. Here we report a simple route towards the synthesis of hindered ethers, in which electrochemical oxidation is used to liberate high-energy carbocations from simple carboxylic acids. These reactive carbocation intermediates, which are generated with low electrochemical potentials, capture an alcohol donor under non-acidic conditions; this enables the formation of a range of ethers (more than 80 have been prepared here) that would otherwise be difficult to access. The carbocations can also be intercepted by simple nucleophiles, leading to the formation of hindered alcohols and even alkyl fluorides. This method was evaluated for its ability to circumvent the synthetic bottlenecks encountered in the preparation of 12 chemical scaffolds, leading to higher yields of the required products, in addition to substantial reductions in the number of steps and the amount of labour required to prepare them. The use of molecular probes and the results of kinetic studies support the proposed mechanism and the role of additives under the conditions examined. The reaction manifold that we report here demonstrates the power of electrochemistry to access highly reactive intermediates under mild conditions and, in turn, the substantial improvements in efficiency that can be achieved with these otherwise-inaccessible intermediates.

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Fig. 1: Background and reaction development.
Fig. 2: Applications, and partial scope of hindered ether synthesis via electrochemical decarboxylation.
Fig. 3: Applications and partial scope of trapping electrogenerated carbocations with other nucleophiles along with scalability demonstration.

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Data availability

The data that support the findings of this study are available within the paper and its Supplementary Information. Metrical parameters for the structures of (2R)-77 and (11R)-138 are available free of charge from the Cambridge Crystallographic Data Centre (https://www.ccdc.cam.ac.uk/) under reference numbers 1918528 and 1903823, respectively.

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Acknowledgements

Financial support for this work was provided by Pfizer, Inc., the National Science Foundation (CCI Phase 1 grant 1740656), and the National Institutes of Health (grant number GM-118176). China Scholarship Council and Jilin University supported a fellowship to J.X., Zhejiang Yuanhong Medicine Technology Co. Ltd supported a fellowship to M.S., The Hewitt Foundation supported a fellowship to Y.K., The Swedish Research Council supported a fellowship to H.L., Fulbright Fellowship supported a fellowship to P.M., and S.H.R. acknowledges an NSF Graduate Research Fellowship Program (no. 2017237151) and a Donald and Delia Baxter Fellowship. We thank D.-H. Huang and L. Pasternack for assistance with NMR spectroscopy; J. Chen for measuring the high-resolution mass spectroscopy data, and A. Rheingold, C. E. Moore and M. A. Galella for X-ray crystallographic analysis.

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Author notes

  1. These authors contributed equally: Jinbao Xiang, Ming Shang

Authors and Affiliations

  1. Department of Chemistry, Scripps Research, La Jolla, CA, USA

    Jinbao Xiang, Ming Shang, Yu Kawamata, Helena Lundberg, Solomon H. Reisberg, Miao Chen, Pavel Mykhailiuk, Donna G. Blackmond & Phil S. Baran

  2. The Center for Combinatorial Chemistry and Drug Discovery of Jilin University, The School of Pharmaceutical Sciences, Jilin University, Jilin, People’s Republic of China

    Jinbao Xiang

  3. Department of Chemistry, KTH Royal Institute of Technology, Stockholm, Sweden

    Helena Lundberg

  4. Enamine Ltd, Kiev, Ukraine

    Pavel Mykhailiuk

  5. Chemistry Department, Taras Shevchenko National University of Kyiv, Kiev, Ukraine

    Pavel Mykhailiuk

  6. Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, NJ, USA

    Gregory Beutner

  7. Department of Chemistry, La Jolla Laboratories, Pfizer Inc, San Diego, CA, USA

    Michael R. Collins, Matthew Del Bel, Gary M. Gallego, Jillian E. Spangler & Shouliang Yang

  8. Pfizer Medicinal Sciences, Groton, CT, USA

    Alyn Davies & Jeremy Starr

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Contributions

J.X., M.S. and P.S.B. conceived the project. J.X., M.S., Y.K., H.L., D.G.B. and P.S.B. designed the experiments and analysed the data. J.X. and M.S. developed the electrochemical decarboxylative methods and performed their applications. H.L. and Y.K. carried out the mechanistic study. J.X., M.S., S.H.R., M.C., P.M., G.B., M.R.C., A.D., M.D.B., G.M.G., J.E.S., J.S. and S.Y. conducted experiments to demonstrate the substrate scope. P.S.B. wrote the manuscript. J.X., M.S., Y.K., S.H.R., P.M., H.L. and D.G.B. assisted in writing and editing the manuscript.

Corresponding author

Correspondence to Phil S. Baran.

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The authors declare no competing interests.

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Supplementary information

Supplementary Information

Supplementary Data 1

Cif file of (2R)-77

Supplementary Data 2

Cif file of (11R)-138

Supplementary Data 3

Checkcif of (2R)-77

Supplementary Data 4

Checkcif of (11R)-138

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Xiang, J., Shang, M., Kawamata, Y. et al. Hindered dialkyl ether synthesis with electrogenerated carbocations. Nature 573, 398–402 (2019). https://doi.org/10.1038/s41586-019-1539-y

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