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Diastereo- and enantioselective synthesis of compounds with a trifluoromethyl- and fluoro-substituted carbon centre

Nature Chemistry volume 14, pages 1459–1469 (2022)Cite this article

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Abstract

Molecules that contain one or more fluorine atoms are crucial to drug discovery. There are protocols available for the selective synthesis of different organofluorine compounds, including those with a fluoro-substituted or a trifluoromethyl-substituted stereogenic carbon centre. However, approaches for synthesizing compounds with a trifluoromethyl- and fluoro-substituent stereogenic carbon centre are far less common. This potentially impactful set of molecules thus remains severely underdeveloped. Here we introduce a catalytic regio-, diastereo- and enantioselective strategy for the preparation of homoallylic alcohols bearing a stereogenic carbon centre bound to a trifluoromethyl group and a fluorine atom. The process, which involves a polyfluoroallyl boronate and is catalysed by an in situ-formed organozinc complex, can be used for diastereodivergent preparation of tetrafluoro-monosaccharides, including ribose core analogues of the antiviral drug sofosbuvir (Sovaldi). Unexpected reactivity/selectivity profiles, probably originating from the trifluoromethyl- and fluoro-substituted carbon site, are discovered, foreshadowing other unique chemistries that remain unknown.

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Fig. 1: Notable nucleosides, the initial approach and the state of the art in catalytic allyl additions to aldehydes.
Fig. 2: Diastereoconvergent and enantioselective synthesis of polyfluoro monosaccharides.
Fig. 3: Computational and experimental studies reveal that the active catalyst is probably an organozinc compound.
Fig. 4: Mechanistic proposal based on experimental and computational studies.
Fig. 5: Regarding how and why a CF3- and F-substituted carbon gives rise to unusual reactivity/selectivity profiles.

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Data availability

All data in support of the findings of this study are available within the Article and its Supplementary Information. X-ray crystallographic data for compounds R,R,S-3a, 3j, 5a, the p-nitrobenzoyl derivative of R,R,S-10, (ap)2Zn2, and the p-nitrobenzoyl derivative of R,R,R-13 are freely available from the Cambridge Crystallographic Data Center ((CCDC 2113846), (2113843), (2113794), (2113845), (2113842) and (2113792), respectively).

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Acknowledgements

This research was supported by a grant from the National Institutes of Health (R35 GM-130395 to A.H.H. and R35 GM-128779 to P.L.). S.X. and M.J.K. were supported as LaMattina Family and Bristol-Myers Squibb Graduate Fellows, respectively. DFT calculations were performed at the Center for Research Computing at the University of Pittsburgh, the Frontera supercomputer at the Texas Advanced Computing Center, and the Extreme Science and Engineering Discovery Environment (XSEDE) supported by the National Science Foundation.

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Author notes

  1. These authors contributed equally: Shibo Xu, Juan del Pozo.

Authors and Affiliations

  1. Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, MA, USA

    Shibo Xu, Juan del Pozo, Ryan J. Morrison, KyungA Lee, Shaowei Hu, Ming Joo Koh, Jaehee Lee & Amir H. Hoveyda

  2. Supramolecular Science and Engineering Institute, University of Strasbourg, CNRS, Strasbourg, France

    Filippo Romiti, Xinghan Li & Amir H. Hoveyda

  3. Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA

    Yue Fu, Binh Khanh Mai & Peng Liu

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Contributions

S.X., J.d.P., F.R., R.J.M., K.L., S.H., M.J.K. and J.L. developed the catalytic method and carried out the applications to the synthesis of polyfluoro monosaccharides. F.R. designed the applications to polyfluoro monosaccharide syntheses. S.X., J.d.P., Y.F., B.K.M. and X.L. designed and performed the mechanistic and DFT studies. The investigations were directed by A.H.H. DFT studies were directed by P.L. A.H.H. wrote the manuscript with revisions provided by the other authors.

Corresponding authors

Correspondence to Peng Liu or Amir H. Hoveyda.

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Nature Chemistry thanks A. Boese and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

All experimental, analytical, crystallographic and computational data. The methods by which various starting materials were prepared are presented. The 1H and 13C NMR spectra for each compound are reproduced (one per page). This document also contains the source for each reagent used, as well as an extended bibliography. There are a total of 18 tables and 20 figures.

Supplementary Data 1

Crystallographic data for compound 3j; CCDC reference 2113843.

Supplementary Data 2

Crystallographic data for compound (R,R,S)-3a; CCDC reference 2113846.

Supplementary Data 3

Crystallographic data for compound 5a; CCDC reference 2113794.

Supplementary Data 4

Crystallographic data for p-nitro-benozoate derivative of (R,R,R)-13; CCDC reference 2113792.

Supplementary Data 5

Data for X-ray structure of p-nitro-benozoate derivative of (R,R,S)-10; CCDC reference 2113845.

Supplementary Data 6

Data for X-ray structure of compound (ap)2Zn2; CCDC reference 2113842.

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Xu, S., del Pozo, J., Romiti, F. et al. Diastereo- and enantioselective synthesis of compounds with a trifluoromethyl- and fluoro-substituted carbon centre. Nat. Chem. 14, 1459–1469 (2022). https://doi.org/10.1038/s41557-022-01054-4

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