Radical Fluoromethylation Enabled by Cobalamin-Dependent Radical SAM Enzymes

Area of Science:

• Medicinal Chemistry
• Organic Chemistry
• Biocatalysis

Background:

• Fluorine incorporation enhances drug efficacy and metabolic stability.
• Monofluoromethylation strategies are less developed than di- or trifluoromethylation.
• Existing enzymatic methods rely on nucleophilic attack (S_N2), limiting substrate scope.

Purpose of the Study:

• To develop a novel enzymatic strategy for monofluoromethylation of unactivated carbon atoms.
• To overcome the limitations of S_N2-based enzymatic fluoromethylation.
• To enable derivatization of molecules previously inaccessible to monofluoromethylation.

Main Methods:

• Utilized radical S-adenosylmethionine (SAM) superfamily enzymes.
• Developed a fluoromethyl-containing SAM analog (S-adenosyl-L-(fluoromethyl)-methionine).
• Employed reductive cleavage and radical initiation for C-H bond functionalization.

Main Results:

• Demonstrated enzymatic transfer of fluoromethyl groups to unactivated C-H bonds.
• Established a radical-dependent mechanism involving hydrogen-atom abstraction.
• Successfully derivatized molecules where S_N2 fluoromethylation was not feasible.

Conclusions:

• Radical SAM enzymes offer a powerful new route for monofluoromethylation.
• This method significantly broadens the scope of fluorinated drug candidates.
• Enables the modification of inert carbon centers, previously a major challenge in medicinal chemistry.