Photoredox Fe-Catalyzed Aminoalkylation toward Sterically Hindered Chiral β-Amino Acids.

Abstract

β-Amino acids represent a vital class of structural motifs in natural products and pharmaceuticals, motivating sustained research efforts in organic synthesis and peptidomimetics. Despite the development of numerous methods for the preparation of β-amino acids, sterically hindered variants continue to pose challenges for their synthesis. In this context, an alternative approach via carboxyalkylation of prevalent tertiary amine scaffolds offers a promising yet underexplored strategy for the streamlined synthesis of β-amino acid derivatives. Herein, we report the development of an iron-porphyrin/photoredox dual catalytic system for the C(sp3)-C(sp3) cross-coupling of tertiary amines and α-halo acyl compounds, enabling the efficient assembly of sterically hindered β-amino acid frameworks. Mechanistic studies disclosed that the iron catalyst participates in the single-electron oxidation with α-carbonyl radical to generate a ferric enolate intermediate, thereby facilitating Mannich-type addition to afford the desired β-amino acid derivatives. Furthermore, the utilization of chiral auxiliaries enabled efficient stereocontrol over the aminoalkylation process, providing a platform for synthesizing a broad array of chiral β-amino acid derivatives.