N-Halogenation by Vanadium-Dependent Haloperoxidases Enables 1,2,4-Oxadiazole Synthesis

Area of Science:

• Biocatalysis
• Organic Synthesis
• Medicinal Chemistry

Background:

• Nitrogen-containing compounds are crucial in chemical industries.
• Existing methods for nitrogen bond formation often rely on nucleophilic nitrogen reactivity.
• Selective catalytic strategies for synthesizing nitrogen-halogen compounds are underdeveloped.

Purpose of the Study:

• To explore the use of vanadium-dependent haloperoxidase (VHPO) enzymes for nitrogen-halogen bond formation.
• To demonstrate the biocatalytic synthesis of N'-halobenzimidamides and their application in synthesizing 1,2,4-oxadiazoles.
• To showcase the chemoenzymatic synthesis of ataluren, a drug for Duchenne muscular dystrophy.

Main Methods:

• Utilized VHPO enzymes for the selective halogenation of benzamidine hydrochlorides.
• Applied the biocatalytic platform to synthesize 1,2,4-oxadiazoles from N-acylbenzamidines.
• Extended the methodology to nitrogen-nitrogen bond formation and chemoenzymatic synthesis of ataluren.

Main Results:

• VHPOs selectively halogenated substituted benzamidine hydrochlorides to N'-halobenzimidamides.
• Achieved high yield and excellent chemoselectivity in the synthesis of 1,2,4-oxadiazoles.
• Successfully demonstrated the chemoenzymatic synthesis of ataluren.

Conclusions:

• VHPO enzymes provide a versatile biocatalytic platform for nitrogen-halogen bond formation.
• This enzymatic approach offers a selective and efficient route to valuable chemical intermediates and pharmaceuticals.
• The methodology holds promise for broader applications in synthetic chemistry and drug development.