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Alkyl sulfinates as cross-coupling partners for programmable and stereospecific installation of C(sp3) bioisosteres

Nature Chemistry volume 15, pages 550–559 (2023)Cite this article

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Abstract

In recent years, a variety of cycloalkyl groups with quaternary carbons, in particular cyclopropyl and cyclobutyl trifluoromethyl groups, have emerged as promising bioisosteres in drug-like molecules. The modular installation of such bioisosteres remains challenging to synthetic chemists. Alkyl sulfinate reagents have been developed as radical precursors to prepare functionalized heterocycles with the desired alkyl bioisosteres. However, the innate (radical) reactivity of this transformation poses reactivity and regioselectivity challenges for the functionalization of any aromatic or heteroaromatic scaffold. Here we showcase the ability of alkyl sulfinates to engage in sulfurane-mediated C(sp3)–C(sp2) cross-coupling, thereby allowing for programmable and stereospecific installation of these alkyl bioisosteres. The ability of this method to simplify retrosynthetic analysis is exemplified by the improved synthesis of multiple medicinally relevant scaffolds. Experimental studies and theoretical calculations for the mechanism of this sulfur chemistry reveal a ligand-coupling trend under alkyl Grignard activation via the sulfurane intermediate, stabilized by solvation of tetrahydrofuran.

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Fig. 1: Alkyl sulfinates as programmable and modular coupling reagents.
Fig. 2: Synthetic applications.
Fig. 3: Experimental studies on the mechanism of sulfinate coupling.
Fig. 4: Reaction coordinate diagram of direct C(sp2)–C(sp3) cross-coupling.

Data availability

Experimental data, as well as characterization data for all compounds prepared in the course of these studies, are provided in the Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2086919 (40), 2086920 (41), 2172148 (74) and 2172149 (116) (see 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 to T.Q. and A-2102-20220331 to O.G.), the National Institutes of Health (R01GM141088 to T.Q. and R35GM137797 to O.G.), the Camille and Henry Dreyfus Foundation (to O.G.), the American Chemistry Society Petroleum Research Fund (62223-DNI1 to T.Q.) and a UT Southwestern Eugene McDermott Scholarship (to T.Q.). 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 at UTSW for generous access to equipment and helpful discussions. We are grateful to E. Wappes, K. McClymont and C. Hethcox (Merck and Co., Inc.) for feedback on this manuscript.

Author information

Author notes

  1. These authors contributed equally: Min Zhou, Jet Tsien.

Authors and Affiliations

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

    Min Zhou, Jet Tsien & Tian Qin

  2. Department of Chemistry and Biochemistry, University of Maryland, College Park, MD, USA

    Ryan Dykstra & Osvaldo Gutierrez

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

    Jonathan M. E. Hughes & Byron K. Peters

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

    Rohan R. Merchant

  5. Department of Chemistry, Texas A&M University, College Station, TX, USA

    Osvaldo Gutierrez

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Contributions

M.Z., J.T. and T.Q. performed experiments. R.D. and O.G. performed DFT theoretical studies. J.M.E.H., B.K.P., R.R.M. and T.Q. designed and supervised the project; M.Z., J.T., R.D., J.M.E.H., B.K.P., R.R.M., O.G. and T.Q. wrote the paper.

Corresponding authors

Correspondence to Osvaldo Gutierrez or Tian Qin.

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Nature Chemistry thanks Georg Manolikakes, Raju Reddy 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, optimization studies, general procedures, reaction guidelines and troubleshooting, experimental procedures and characterization data of starting materials, experimental procedures and characterization data of substrates, control experiments, capture of sulfur part by-product, control experiments on stereochemistry fidelity, VT 19F-NMR experiment, ReactIR experiment, computer investigation, X-ray crystallographic data, references and NMR spectra.

Supplementary Data 1

Crystallographic data for compound 40; CCDC no. 2086919.

Supplementary Data 2

Crystallographic data for compound 41; CCDC no. 2086920.

Supplementary Data 3

Crystallographic data for compound 74; CCDC no. 2172148.

Supplementary Data 4

Crystallographic data for compound 116; CCDC no. 2172149.

Supplementary Data 5

Coordinates and energies of calculated structures.

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Zhou, M., Tsien, J., Dykstra, R. et al. Alkyl sulfinates as cross-coupling partners for programmable and stereospecific installation of C(sp3) bioisosteres. Nat. Chem. 15, 550–559 (2023). https://doi.org/10.1038/s41557-023-01150-z

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