Next Generation Chiral Fluorine Groups for Molecular Design
Fluorinated motifs have enormous societal relevance due to their ubiquity across the pharmaceutical, agrochemical and materials science sectors. These essential structural components feature prominently in the World Health Organization’s (WHO) list of essential medicines, and contribute to global food supplies by optimising the performance of many key agrochemicals. Similarly, our reliance on (polyfluorinated) materials ranging from non-stick Teflon® through to smart materials underscores the versatility of fluorinated groups in functional small molecule design.
The historic success of fluorinated groups in societally-important molecules, coupled with scarcity of organofluorine building blocks in nature, continues to create a powerful impetus to develop more efficient and sustainable methods to facilitate their construction. However, the environmental impact of perfluorinated materials has come under scrutiny due to the persistence of the materials in the environment. The recent proposal by the European Parliament to address the persistence of perfluoroalkyl and polyfluoroalkyl (PFAS-type molecules) in water supplies covers "any substance that contains at least one fully fluorinated methyl (CF3) or methylene (CF2) without any H, Cl, Br, or I attached to it."
Fluorinated groups that simultaneously conform to new legislative guidance, no longer pose an environmental threat and open up new areas of space for discovery will be generated efficiently. Through the intervention of ChiroFluor, unique structural entities will be forged in both enantiomeric forms (handedness) to push chemical space beyond the existing boundaries. This project will simultaneously address a pressing environmental and legislative issue in a sustainable manner using an organocatalytic I(I)/I(III) platform based on data generated in ERC Consolidator RECON (818949), and validated with key industrial partners.
Using an operationally simple I(I)/I(III) organocatalysis platform, an alternative motif can be generated that occupies chemical space that is not affected by the EU REACH Restriction Proposal. Since the fluorine-bearing carbon atoms also contain a hydrogen substituent, these new structural units are no longer environmentally persistent. Starting from simple alkene precursors, and using inexpensive reagent and organocatalyst combinations, it is possible to generate hybrids of -CF3 and ethyl groups to create a scaffold containing F, H and CH2F units. This so-called “BITE group” (Bioisostere of Trifluoromethyl and Ethyl) can be appended to alkyl and aryl groups alike. Not only can these materials be generated enantioselectively, but in the case of aryl derivatives, a handle for subsequent coupling can be installed to allow facile derivatisation. Most importantly, this general platform is expansive and so whilst the initial phase will be to commercialise BITE-containing discovery modules, slight adjustments to the starting material will allow a larger area of chemical space to be investigated.
