Enantioselective Synthesis of Fluorinated Carbon Compounds

Fluorinated carbon compounds occupy a central role in medicinal chemistry, agrochemicals and advanced materials owing to the unique physicochemical properties imparted by the C–F bond, including enhanced metabolic stability, lipophilicity and bioavailability. Enantioselective methods for their construction enable the precise installation of stereocentres adjacent to fluorine atoms, a longstanding challenge due to the strong electronegativity and steric effects of fluorinated substituents. Contemporary strategies employ chiral metal catalysts, organocatalysts and relay catalysis to generate and control difluoroenolate and related intermediates under mild conditions. Key approaches include asymmetric aldol and Mannich reactions of in situ-derived α,α-difluoroenol species, transition-metal-catalysed fluorine transfer and chiral auxiliary–mediated protocols. Recent advances have demonstrated the ability to forge quaternary stereocentres bearing CF2 motifs, streamline reaction sequences through one-pot processes and integrate sustainable reagents to minimise environmental impact. This field continues to evolve towards broad substrate scope, high enantiomeric excess, and operational simplicity, paving the way for the rapid synthesis of complex fluorinated building blocks for drug discovery and functional materials.

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Enantioselective Synthesis of Fluorinated Carbon Compounds publication trend

The graph below shows the total number of articles in enantioselective synthesis of fluorinated carbon compounds across all publications each year (not limited to Nature Index journals).

Technical terms

Enantioselectivity: The preferential formation of one enantiomer over its mirror image in a chiral reaction.

Difluoroenolate: A reactive anion generated from a carbonyl compound bearing two fluorine atoms at the α-position, used in carbon–carbon bond formation.

Relay catalysis: A sequential catalytic process in which two or more catalysts operate cooperatively to achieve multi-step transformations in a single vessel.

Reformatsky reaction: A carbon–carbon bond-forming reaction between α-halo carbonyl compounds and aldehydes or ketones mediated by a metal, yielding β-hydroxy carbonyl products.

Chiral phosphoric acid: An organocatalyst derived from BINOL or related scaffolds, featuring a phosphate moiety that induces asymmetry in a variety of transformations.

References

1. Catalytic Asymmetric Difluoroalkylation Using In Situ Generated Difluoroenol Species as the Privileged Synthon. Advanced Science (2024).
2. Recent developments in the asymmetric Reformatsky-type reaction. Beilstein Journal of Organic Chemistry (2018).