Computationally Guided Development of an Alkene Aminocarboxylation with CO2: Synthesis of a β-Amino Acid Derivative

Abstract

β-Amino acids are important structural motifs in synthetic organic chemistry owing to their applications as components in artificial peptides, which are intensively studied in pharmaceutical science. While various strategies exist for synthesizing α- and γ-amino acids from CO₂ via α-amino carbanion or α-aminoalkyl radical intermediates, direct and concise routes to β-amino acids remain rare. Herein, we report the computationally guided development of a photoredox-catalyzed aminocarboxylation of an aminoalkene with CO₂, affording a β-amino acid derivative under mild conditions. Although the demonstrated scope is currently limited, this transformation showcases a mechanistically distinct reactivity pattern enabled by photoredox catalysis. The reaction was inspired by our previous multistate reaction path network explored for Knowles’ hydroamination, where we found that a seam of crossing (SX) point for the potential energy surface involving a CH₃OH molecule facilitates product formation via proton-coupled electron transfer. Upon substituting CH₃OH with CO₂, the corresponding SX calculations indicated that the energetically concerted reduction–carboxylation mechanism is feasible. Indeed, cyclic β-amino acids were obtained from amino alkenes using [Ir(ppy)₂(dtbbpy)]PF₆ as a photoredox catalyst under irradiation with blue LEDs (440 nm). The developed photoreaction was successfully applied to a gas–liquid flow system under CO₂ pressure (1.0 MPa), in which the blue LEDs irradiated the tube line (total volume: 4.6 mL) for merely 3.2 min to afford the desired β-amino acids in good yield.