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Stereodefined alkenes with a fluoro-chloro terminus as a uniquely enabling compound class

A Publisher Correction to this article was published on 24 March 2022

This article has been updated

Abstract

Trisubstituted alkenyl fluorides are important compounds for drug discovery, agrochemical development and materials science. Despite notable progress, however, many stereochemically defined trisubstituted fluoroalkenes either cannot be prepared efficiently or can only be accessed in one isomeric form. Here we outline a general solution to this problem by first unveiling a practical, widely applicable and catalytic strategy for stereodivergent synthesis of olefins bearing a fluoro-chloro terminus. This has been accomplished by cross-metathesis between two trisubstituted olefins, one of which is a purchasable but scarcely utilized trihaloalkene. Subsequent cross-coupling can then be used to generate an assortment of trisubstituted alkenyl fluorides. The importance of the advance is highlighted by syntheses of, among others, a fluoronematic liquid-crystal component, peptide analogues bearing an E- or a Z-amide bond mimic, and all four stereoisomers of difluororumenic ester (an anti-cancer compound).

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Fig. 1: The importance of trisubstituted alkenyl fluorides and existing approaches to their stereoselective synthesis.
Fig. 2: The adopted strategy and its mechanistic basis.
Fig. 3: Mechanism-based development of the cross-metathesis approach.
Fig. 4: The catalytic method is broadly applicable, practical and cost-effective.
Fig. 5: Site-selective cross-coupling, and site-selective and regiodivergent fluoro-labelling.
Fig. 6: Diastereodivergent synthesis of monofluoro- and difluoro-labelled bioactive compounds.

Data availability

All data in support of the findings of this study are available within the article and its Supplementary Information.

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Acknowledgements

Financial support was provided by the NIH (grants GM-59426 to A.H.H. and R.R.S. and GM-130395 to A.H.H.) and the Shanghai Institute of Organic Chemistry (postdoctoral fellowship to Q.L.). We thank F. Romiti, P. H. S. Paioti, X. Li and C. Qin for valuable discussions.

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Q.L., Y.M. and T.K. developed the methodology and designed and carried out the applications. R.R.S. and A.H.H. developed the catalyst systems used. A.H.H. directed the studies and wrote the manuscript.

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Correspondence to Amir H. Hoveyda.

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Optimization studies, criteria for additive selection, experimental procedures, analytical data for all cross-metathesis products and related derivatives, and Supplementary Figs. 1–3.

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Liu, Q., Mu, Y., Koengeter, T. et al. Stereodefined alkenes with a fluoro-chloro terminus as a uniquely enabling compound class. Nat. Chem. 14, 463–473 (2022). https://doi.org/10.1038/s41557-022-00893-5

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