Challenges and recent advancements in the synthesis of α,α-disubstituted α-amino acids

Abstract

Abstractα,α-Disubstituted α-amino acids (α-AAs) have improved properties compared to other types of amino acids. They serve as modifiers of peptide conformation and as precursors of bioactive compounds. Therefore, it has been a long-standing goal to construct this highly valuable scaffold efficiently in organic synthesis and drug discovery. However, access to α,α-disubstituted α-AAs is highly challenging and largely unexplored due to their steric constraints. To overcome these, remarkable advances have been made in the last decades. Emerging strategies such as synergistic enantioselective catalysis, visible-light-mediated photocatalysis, metal-free methodologies and CO2 fixation offer new avenues to access the challenging synthesis of α,α-disubstituted α-AAs and continuously bring additional contributions to this field. This review article aims to provide an overview of the recent advancements since 2015 and discuss existing challenges for the synthesis of α,α-disubstituted α-AAs and their derivatives.

Synergistic Photoenzymatic Catalysis Enables Synthesis of a-Tertiary Amino Acids Using Threonine Aldolases

“…Catalytic asymmetric syntheses of a -tertiary amino acids are challenging because of the inherent reactivity of the amino acid motif . For a -alkylation reactions, the amine and carboxylic acid must be masked to enable enolization, requiring the subsequent removal of the two protecting groups to form the desired ncAA. , Alternative synthetic strategies, such as nucleophilic addition to a -iminoesters, also require protection of both the acid and imine to enable a selective synthesis (Figure B) − Nature avoids these tedious protection and deprotection steps by transiently activating the amino acid for functionalization using pyridoxal 5-phosphate (PLP). , This cofactor reacts with the amino moiety to form an aldimine, which both protects the amine functional group and acidifies the α-protons, while electrostatic and hydrogen-bonding interactions with the protein temper the reactivity of the carboxylate.…”