Nickel-photocatalytic deoxygenative arylation efficiently synthesizes diverse β-methyl-branched α-amino acids from threonine.

β-Methyl-branched α-amino acids are crucial building blocks in peptide therapeutics, often enhancing metabolic stability or receptor affinity. Current synthetic methods for these noncanonical amino acids are limited, posing a bottleneck for drug discovery and development. This study addresses the need for efficient, diverse synthetic routes to incorporate these motifs into novel peptide structures, thereby expanding the chemical space for peptide drug design.

Researchers developed a novel nickel-photocatalytic deoxygenative arylation protocol for amino acid synthesis. They utilized threonine and 3-hydroxyproline as starting materials, subjecting them to specific photocatalytic reaction conditions involving a nickel catalyst and light activation. The study focused on achieving a one-step transformation that simultaneously deoxygenates the β-hydroxyl group and introduces an aryl moiety, aiming for broad functional group tolerance and diverse product scope.

The developed method achieved an efficient, one-step synthesis of β-methyl-branched α-amino acids from threonine. This protocol demonstrated good functional group tolerance, successfully yielding a diverse scope of noncanonical α-amino acids.

The method was also successfully extended to the deoxygenative arylation of 3-hydroxyproline, providing access to various therapeutically relevant arylated amino acids. This approach represents a significant advancement by enabling the direct incorporation of aryl groups while simultaneously deoxygenating the β-hydroxyl group, simplifying the creation of complex amino acid structures. The broad diversity of accessible products highlights its potential for modifying peptide backbones.