Electrosynthesis of ¹⁵N-labeled amino acids from ¹⁵N-nitrite and ketonic acids

Abstract

¹⁵N isotope-labeled amino acids (¹⁵N-amino acids) are crucial in the fields of biology, medicine, and chemistry. ¹⁵N-amino acids are conventionally synthesized through microbial fermentation and chemical reductive amination of ketonic acids methodologies, which usually require complicated procedures, high temperatures, or toxic cyanide usage, causing energy and environmental concerns. Here, we report a sustainable pathway to synthesize ¹⁵N-amino acids from readily available ¹⁵N-nitrite (¹⁵NO₂) and biomass-derived ketonic acids under ambient conditions driven by renewable electricity. A mechanistic study demonstrates a ¹⁵N-nitrite→¹⁵NH₂OH→¹⁵N-pyruvate oxime→¹⁵N-alanine reaction pathway for ¹⁵N-alanine synthesis. Moreover, this electro-chemical strategy can synthesize six ¹⁵N-amino acids with 68%-95% yields. Furthermore, a ¹⁵N-labeled drug of ¹⁵N-tiopronin, the most commonly used hepatitis treatment drug, is fabricated using ¹⁵N-glycine as the building block. Impressively, ¹⁵N sources can be recycled by the electrooxidation of ¹⁵NH₄⁺ to ¹⁵NO₂ with a method economy. This work opens a venue for the green synthesis of ¹⁵N-labeled compounds or drugs.