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Capturing primary ozonides for a syn-dihydroxylation of olefins

Abstract

Ozonolysis is a widely used and practical synthetic technique for the deconstructive oxidation of olefins using ozone. While there are numerous ozonolysis reactions that give a myriad of products and functionalities, almost all of them involve scission at the olefin double bond. Using ozone as a constructive reagent rather than a deconstructive one would open new domains of chemical reactivity and amplify molecular complexity in synthetic methodology. Here we report the use of primary ozonides as preparative synthetic intermediates for a safe and green olefin syn-dihydroxylation reaction. Furthermore, we have demonstrated this method using a continuous flow reactor that virtually eliminates peroxide accumulation and extended these applications towards the synthesis of pharmaceutically relevant small molecules such as guaifenesin, the active ingredient in Mucinex, and a precursor to ponesimod, a drug to treat multiple sclerosis.

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Fig. 1: Applications of olefin ozonolysis.
Fig. 2: Reactivity studies of POZs at synthetically useful temperatures.
Fig. 3: Constructive ozonolysis in flow.

Data availability

All data are available in the main text or the Supplementary Information.

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Acknowledgements

A.A.T. and D.K.A. are grateful for the generous financial support from Texas A&M University and the Welch Foundation (grant no. A-2081-20210327). A.A.T. and D.K.A. thank M. Garcia for his preliminary experiments performed before the research described here.

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A.A.T. conceived the work. A.A.T. and D.K.A. designed the experiments. D.K.A. conducted the synthetic experiments including NMR experiments, synthesis of starting materials, titrations, purifications and flow experiments. A.A.T. and D.K.A. wrote the manuscript.

Corresponding author

Correspondence to Andy A. Thomas.

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Nature Chemistry thanks Patrick Dussault, Christopher Hone and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Information

Supplementary Figs. 1–80, Tables 1–17 and Experimental procedures and spectra.

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Arriaga, D.K., Thomas, A.A. Capturing primary ozonides for a syn-dihydroxylation of olefins. Nat. Chem. 15, 1262–1266 (2023). https://doi.org/10.1038/s41557-023-01247-5

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