The first transition-metal-free catalytic protocol for controlled reduction of amide functions using cheap and bench-stable hydrosilanes as reducing agents has been established. By altering the hydrosilane and solvent, the new method enables the selective cleavage of unactivated C–O bonds in amides and allows the C–N bonds to selectively break via the deacylated cleavage. Overall, this novel process may offer a versatile alternative to current methodologies employing stoichiometric metal systems for the controlled reduction of carboxamides.
Using organosilicon compounds of the type Me 3 SiX (X = CN, N 3 , C n F 2n+1 , and halogens) and an amine base, alkylsilyl peroxides were generated in situ from the corresponding alkyl hydroperoxides . Subsequent in situ copper-catalyzed homolytic cleavage of the alkylsilyl peroxides afforded alkyl radicals, which were then trapped with a nucleophile X (X = CN, N 3 , C n F 2n+1 , and halogens) to furnish coupling products with new carbon–carbon, carbon–nitrogen, or carbon–halogen bonds in good to high yields. In addition, 1-(trimethylsilyl)morpholine can also be employed for the in-situ-generation of alkylsilyl peroxides, which are subsequently utilized for N-alkylation of amides, arylations , and borylations with high efficiency.
Non-canonical amino acids (ncAAs) bearing diverse functional groups hold transformative potential in drug discovery, protein engineering, and biomaterial science. However, their industrial-scale production remains constrained by the inefficiency, high cost, and environmental burden of conventional chemical and enzymatic methods. Here, we present a modular multi-enzyme cascade platform that leverages glycerol—an abundant and sustainable byproduct of biodiesel production—as a low-cost substrate for ncAAs synthesis. Directed evolution of O -phospho- l -serine sulfhydrylase (OPSS) enhances the catalytic efficiency of C–N bond formation by 5.6-fold, enabling the efficient synthesis of triazole-functionalized ncAAs. By integrating a plug-and-play enzymatic strategy, our system enables gram- to decagram-scale production of 22 ncAAs with C–S, C–Se, and C–N side chains and can be readily scaled up to a 2 liter reaction system. Notably, water is the sole byproduct, and all products exhibit an atomic economy of >75%, highlighting the environmental compatibility of this platform. This work establishes a green, cost-effective, and industrially viable approach to expanding amino acid diversity, providing a versatile toolkit for applications in pharmaceuticals, synthetic biology, and next-generation biomaterials.
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