Access to N-α-deuterated amino acids and DNA conjugates via Ca(II)-HFIP-mediated reductive deutero-amination of α-oxo-carbonyl compounds
Haoran Li, Yuwei Liu, Silin Zhang, Lei Ma, Zhongyi Zeng, Zhi Zhou, Vincent Gandon, Hongtao Xu, Wei Yi, Shengdong Wang
Abstract
The development of practical and selective strategies for deuterium incorporation to construct deuterated molecules, particularly deuterium-labeled amino acids, has become as a growing focus of basic research, yet it remains a formidable challenge. Herein, we present a bioinspired calcium-HFIP-mediated site-selective reductive deutero-amination of α-oxo-carbonyl compounds with amines. Utilizing d2-Hantzsch ester as the deuterium source, this reaction attains remarkable deuteration efficiency (> 99% deuteration). It enables the synthesis of N-α-deuterated amino acid motifs with a wide range of functionality, as evidenced by over 130 examples. The method exhibits compatibility with diverse substrates, such as amino acids, peptides, drug molecules, and natural products bearing different substituents. Moreover, the application of this strategy in the synthesis of DNA-tagged N-α-deuterated amino acids/peptides has been demonstrated. This work offers an efficient and innovative solution for deuterated amino acid chemistry and holds substantial application potential in organic synthesis, medicinal chemistry, and chemical biology. The development of practical and selective strategies for deuterium incorporation to construct deuterium-labeled amino acids remains a challenge. Here, the authors report a bioinspired calcium-HFIP-mediated site-selective reductive deutero-amination of α-oxo-carbonyl compounds with amines.