Search for: All records

Nitrogen‐containing compounds are valuable synthetic intermediates and targets in nearly every chemical industry. While methods for nitrogen‐carbon and nitrogen‐heteroatom bond formation have primarily relied on nucleophilic nitrogen atom reactivity, molecules containing nitrogen‐halogen bonds allow for electrophilic or radical reactivity modes at the nitrogen center. Despite the growing synthetic utility of nitrogen‐halogen bond‐containing compounds, selective catalytic strategies for their synthesis are largely underexplored. We recently discovered that the vanadium‐dependent haloperoxidase (VHPO) class of enzymes are a suitable biocatalyst platform for nitrogen‐halogen bond formation. Herein, we show that VHPOs perform selective halogenation of a range of substituted benzamidine hydrochlorides to produce the corresponding N’‐halobenzimidamides. This biocatalytic platform is applied to the synthesis of 1,2,4‐oxadiazoles from the corresponding N‐acylbenzamidines in high yield and with excellent chemoselectivity. Finally, the synthetic applicability of this biotechnology is demonstrated in an extension to nitrogen‐nitrogen bond formation and the chemoenzymatic synthesis of the Duchenne muscular dystrophy drug, ataluren. 

Abstract Flavin‐dependent ‘ene’‐reductases (EREDs) are highly selective catalysts for the asymmetric reduction of activated alkenes. This function is, however, limited to enones, enoates, and nitroalkenes using the native hydride transfer mechanism. Here we demonstrate that EREDs can reduce vinyl pyridines when irradiated with visible light in the presence of a photoredox catalyst. Experimental evidence suggests the reaction proceeds via a radical mechanism where the vinyl pyridine is reduced to the corresponding neutral benzylic radical in solution. DFT calculations reveal this radical to be “dynamically stable”, suggesting it is sufficiently long‐lived to diffuse into the enzyme active site for stereoselective hydrogen atom transfer. This reduction mechanism is distinct from the native one, highlighting the opportunity to expand the synthetic capabilities of existing enzyme platforms by exploiting new mechanistic models.