Electrochemical Synthesis of Unnatural Amino Acids Embedding 5- and 6-Membered Heteroaromatics

Abstract

Using a commercially available potentiostat, the electrochemical synthesis of unnatural amino acids bearing heteroaromatics on the lateral chain has been accomplished. This strategy exploits the side-chain decarboxylative arylation of aspartic/glutamic acid, a reaction that becomes challenging with electron-rich coupling partners such as 5-and 6-membered heteroaromatics. These rings are underrepresented in unnatural amino acids, therefore allowing a wider exploration of the chemical space, given the abundance of the aryl bromides employable in this reaction.

Electrochemical Synthesis of a Sitagliptin Precursor

“…Overview of the electrochemical Ni-catalyzed cross-coupling reaction conditions by Baran compared to our work.…”

“…More details on this reaction type and mechanism were recently reviewed by Oderinde . Meanwhile this methodology has led to the synthesis of novel, unnatural α- and β-amino acid derivatives featuring 5- and 6-membered heterocycles as substituents . We decided to employ a design of experiment (DoE) approach for better understanding of the electrochemical synthesis to the sitagliptin precursor ( 3 ).…”