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Final Report Summary - FLUCYC (Asymmetric Fluorocyclisations)

Fluorinated organic molecules have found great utility in the pharmaceutical, agrochemical and material science industries. This is in large part due to the unique properties the incorporation of fluorine into a molecule can impart. The small size and high electronegativity of fluorine and the strong bonds it forms with carbon mean that the replacement of a hydrogen atom or hydroxy group can have a profound effect on a molecule. The influence of fluorine on conformation, log D, pKa, protein-ligand interactions and the metabolic stability of compounds has been extensively reviewed. With this in mind, new methodologies that allow for the regio- and stereoselective introduction of fluorine into organic compounds, with the use of safe and easy to handle fluorinating reagents are highly sought-after. Heterocycles are ubiquitous motifs in medicinal chemistry and as such fluorinated heterocycles are becoming a key sub-class of synthetic drug molecule; necessitating the development of novel methodologies for their preparation. Current methods to access fluoroheterocycles rely on the fluorination of already constructed heterocycles or through the cyclisation of fluorinated building blocks. One complementary and attractive route for the preparation of fluorinated heterocycles is by fluorocyclisation, a reaction in which both the fluorination and the cyclisation occur in a one-pot procedure. This area of research continues to attract attention especially the validation of asymmetric variants for the construction of halogenated natural products. Despite the emergence of novel chiral fluorinating reagents, asymmetric fluorocyclisations have not been explored with the exception of a Nazarov-fluorination process. In essence this process features a catalytic asymmetric cyclisation followed by a diastereoselective fluorination. The reverse process, a catalytic asymmetric fluorination followed by cyclisation has not been reported to date, despite significant progress made in developing of asymmetric fluorination methodologies.
Our research group recently developed a novel asymmetric fluoroetherification reaction using chiral N-F reagents generated in situ by treatment of cinchona alkaloids with Selectfluor. We had for the first time validated feasibility of an asymmetric fluorocyclisation with the fluoroetherification of allylsilanes for the synthesis of enantioenriched fluorinated tetrahydrofurans with up to 45% ee (Scheme 3).
Building on this preliminary result, we have now investigated in more detail asymmetric fluorocyclisation reactions using chiral N-F reagents generated in situ by treatment of cinchona alkaloids with Selectfluor. Our studies indicate that high level of enantioselectivities can be obtained for the preparation of new spirocyclic derivatives (for details see Mid-Term Report).
During the past thirteen months of this IEF funded project, we have completed most of its objectives with only minor deviations from the proposed research project. The proposal was based on two key approaches for the preparation of enantioenriched fluorinated heterocycles: fluorocyclisation using in situ prepared chiral N-F reagents derived from Selectfluor and cinchona alkaloids and fluorocyclisation based on the use of novel chiral N-F reagents. The first aim was achieved with success. The fluorocyclisations under investigation have been validated in both racemic series asymmetric series probing on a range of new substrates both their reactivity profile and the level of stereoselectivity achievable. Our best results are summarized hereafter.

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THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
United Kingdom
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