Cobalt‐Catalyzed Enantioselective Reductive α‐Chloro‐Carbonyl Addition of Ketimine to Construct the β‐Tertiary Amino Acid Analogues

Abstract

β‐Tertiary amino acid derivatives constitute one of the most frequently occurring units in natural products and bioactive molecules. However, the efficient asymmetric synthesis of this motif still remains a significant challenge. Herein, we disclose a cobalt‐catalyzed enantioselective reductive addition reaction of ketimine using α‐chloro carbonyl compound as a radical precursor, providing expedient access to a diverse array of enantioenriched β‐quaternary amino acid analogues. This protocol exhibits outstanding enantioselectivity and broad substrate scope with excellent functional group tolerance. Preliminary mechanism studies rule out the possibility of Reformatsky‐type addition and confirm the involvement of radical species in stereoselective addition process. The synthetic utility has been demonstrated through the rapid assembly of iterative amino acid units and oligopeptide, showcasing its versatile platform for late‐stage modification of drug candidates.

Regio- and Enantioselective Hydromethylation of 3-Pyrrolines and Glycals Enabled by Cobalt Catalysis

“…In this context, the choice of the transition metal is paramount. Cobalt, being one of the most promising earth-abundant transition metals, has been successfully employed in catalytic alkene hydrofunctionalization reactions owing to its unique characteristics and prominent catalytic properties. ,,− ,,,− In this work, we utilized unsaturated nitrogen heterocyclic olefins with a weak directing group as substrates, and the reaction was catalyzed by a system based on cobalt catalysts and chiral bisoxazoline ligands. This strategic approach effectively prevents β-H elimination due to the introduction of a cobalt catalyst.…”

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. We hypothesized that repurposing native PLP-dependent enzymes might provide an attractive strategy for synthesizing a -tertiary amino acids.…”