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An intramolecular coupling approach to alkyl bioisosteres for the synthesis of multisubstituted bicycloalkyl boronates

Nature Chemistry volume 13, pages 950–955 (2021)Cite this article

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Abstract

Bicyclic hydrocarbons, and bicyclo[1.1.1]pentanes (BCPs) in particular, are playing an emerging role as saturated bioisosteres in pharmaceutical, agrochemical and materials chemistry. Taking advantage of strain-release strategies, prior synthetic studies have featured the synthesis of bridgehead-substituted (C1, C3) BCPs from [1.1.1]propellane. Here, we describe an approach to access multisubstituted BCPs via intramolecular cyclization. In addition to C1,C3-disubstituted BCPs, this method also enables the construction of underexplored multisubstituted (C1, C2 and C3) BCPs from readily accessible cyclobutanones. The broad generality of this method has also been examined through the synthesis of a variety of other caged bicyclic molecules, ranging from [2.1.1] to [3.2.1] scaffolds. The modularity afforded by the pendant bridgehead boron pinacol esters generated during the cyclization reaction has been demonstrated through several downstream functionalizations, highlighting the ability of this approach to enable the programmed and divergent synthesis of multisubstituted bicyclic hydrocarbons.

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Fig. 1: Bridged hydrocarbons and BCP syntheses.
Fig. 2: Derivatization and synthetic application of BCP boronates.

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Data availability

The experimental data as well as the characterization data for all the compounds prepared in the course of these studies are provided in the Supplementary Information. The crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2062923 (16), 2062924 (20), 2062925 (26) and 2081087 (40-ester; see the X-ray crystallographic data in the Supplementary Information). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

Financial support for this work was provided by the Welch Foundation (I-2010-20190330), the National Institutes of Health (R01GM141088) and UT Southwestern Eugene McDermott Endowed Scholarship. We thank F. Lin (UTSW) for assistance with NMR spectroscopy, H. Baniasadi (UTSW) for HRMS and V. Lynch (UT-Austin) for X-ray crystallographic analysis. We thank the Chen, Tambar, Ready, De Brabander, Smith and Falck groups (UTSW) for generous access to equipment, and helpful discussions. We are grateful to K. Campos, L.-C. Campeau, P. Fier, C. Zarate Saez and K. McClymont (Merck & Co., Inc., Kenilworth, NJ, USA) for feedback on this manuscript.

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  1. These authors contributed equally: Yangyang Yang, Jet Tsien.

Authors and Affiliations

  1. Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX, USA

    Yangyang Yang, Jet Tsien & Tian Qin

  2. Department of Process Research and Development, Merck & Co., Inc., Rahway, NJ, USA

    Jonathan M. E. Hughes & Byron K. Peters

  3. Department of Discovery Chemistry, Merck & Co., Inc., South San Francisco, CA, USA

    Rohan R. Merchant

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Contributions

Y.Y., J.T. and T.Q. performed the experiments; J.M.E.H., B.K.P., R.R.M. and T.Q. designed and supervised the project; J.M.E.H. and B.K.P. performed the DSC experiments; Y.Y., J.T., J.M.E.H., R.R.M. and T.Q. wrote the paper.

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Correspondence to Tian Qin.

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Competing interests

A provisional patent application naming T.Q., Y.Y. and J.T. as inventors has been filed by the Board of Regents of the University of Texas System, which covers the synthetic method and structural motifs described in this manuscript. The remaining authors declare no competing interests.

Additional information

Peer review information Nature Chemistry thanks Varinder Aggarwal, Cara Brocklehurst and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary information

General experimental, general procedures, additional optimization of cyclizations, Suzuki cross-couplings and aminations, limitations, troubleshooting, experimental procedures and characterization data of starting materials, substrate precursors and substrates, DSC experiments, X-ray crystallographic data and NMR spectra.

Supplementary Data 1

Crystallographic data for compound 16; CCDC reference 2062923.

Supplementary Data 2

Crystallographic data for compound 20; CCDC reference 2062924.

Supplementary Data 3

Crystallographic data for compound 26; CCDC reference 2062925.

Supplementary Data 4

Crystallographic data for compound 40-ester; CCDC reference 2081087.

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Yang, Y., Tsien, J., Hughes, J.M.E. et al. An intramolecular coupling approach to alkyl bioisosteres for the synthesis of multisubstituted bicycloalkyl boronates. Nat. Chem. 13, 950–955 (2021). https://doi.org/10.1038/s41557-021-00786-z

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