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Direct functionalization of the C(O)–N amide bond is one of the most high-profile research directions in the last few decades; however oxidative couplings involving amide bonds and functionalization of thioamide C(S)–N analogues remain an unsolved challenge. Herein, a novel hypervalent iodine-induced twofold oxidative coupling of amines with amides and thioamides has been established. The protocol accomplishes divergent C(O)–N and C(S)–N disconnection by the previously unknown Ar–O and Ar–S oxidative coupling and highly chemoselectively assembles the versatile yet synthetically challenging oxazoles and thiazoles. Employing amides instead of thioamides affords an alternative bond cleavage pattern, which is a result of the higher conjugation in thioamides. Mechanistic investigations indicate ureas and thioureas generated in the first oxidation as pivotal intermediates to realize the oxidative coupling. These findings open up new avenues for exploring oxidative amide and thioamide bond chemistry in various synthetic contexts. 

Abstract Microbial lipid metabolism is an attractive route for producing oleochemicals. The predominant strategy centers on heterologous thioesterases to synthesize desired chain-length fatty acids. To convert acids to oleochemicals (e.g., fatty alcohols, ketones), the narrowed fatty acid pool needs to be reactivated as coenzyme A thioesters at cost of one ATP per reactivation - an expense that could be saved if the acyl-chain was directly transferred from ACP- to CoA-thioester. Here, we demonstrate such an alternative acyl-transferase strategy by heterologous expression of PhaG, an enzyme first identified inPseudomonads, that transfers 3-hydroxy acyl-chains between acyl-carrier protein and coenzyme A thioester forms for creating polyhydroxyalkanoate monomers. We use it to create a pool of acyl-CoA’s that can be redirected to oleochemical products. Through bioprospecting, mutagenesis, and metabolic engineering, we develop three strains ofEscherichia colicapable of producing over 1 g/L of medium-chain free fatty acids, fatty alcohols, and methyl ketones.