α-Amino acid and peptide synthesis using catalytic cross-dehydrogenative coupling

Ionic or radical α-amino Schiff base methods are well known for the synthesis of α,α-disubstituted α-amino acids. However, the incorporation of sterically demanding groups is challenging with ionic methods, and radical methods require prefunctionalization of the substrates. Now we have developed a dehydrogenative coupling process of α-amino acid Schiff bases with hydrocarbon feedstocks for the synthesis of α,α-disubstituted α-amino acid derivatives. These α-amino acid derivatives were transformed into C- and N-protected amino acids, which could be easily incorporated into peptide synthesis. A range of α-amino acid derivatives could be readily accessed, which includes, notably, those that bear contiguous quaternary centres. Circular dichroism measurements show that the helical peptide structure is stabilized by the highly sterically congested unnatural α-amino acid. Mechanistic studies revealed that deprotonation of the α-amino acid Schiff base is a turnover-limiting step and the use of an enhanced Brønsted basic copper(I) tert-butoxide complex produced a superior catalytic performance. Photoinduction of the catalytic reaction, using blue light-emitting diode radiation, allowed the reaction to proceed without external heating.