Asymmetric synthesis of unnatural α-amino acids through photoredox-mediated C-O bond activation of aliphatic alcohols

• Published in: Chemical science (Cambridge) 2024-05, Vol.15 (19), p.7316-7323
• Main Authors: Alvey, Gregory R, Stepanova, Elena V, Shatskiy, Andrey, Lantz, Josefin, Willemsen, Rachel, Munoz, Alix, Dinér, Peter, Kärkäs, Markus D
• Format: Article
• Language: English
• Subjects: Aliphatic alcohols; Amino acids; Asymmetry; Chemistry; Esters; Reagents; Stoichiometry; Substrates; Synthesis
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/d4sc00403e

Unnatural α-amino acids constitute a fundamental class of biologically relevant compounds. However, despite the interest in these motifs, synthetic strategies have traditionally employed polar retrosynthetic disconnections. These methods typically entail the use of stoichiometric amounts of toxic and highly sensitive reagents, thereby limiting the substrate scope and practicality for scale up. In this work, an efficient protocol for the asymmetric synthesis of unnatural α-amino acids is realized through photoredox-mediated C-O bond activation in oxalate esters of aliphatic alcohols as radical precursors. The developed system uses a chiral glyoxylate-derived N -sulfinyl imine as the radical acceptor and allows facile access to a range of functionalized unnatural α-amino acids through an atom-economical redox-neutral process with CO 2 as the only stoichiometric byproduct. A practical protocol for the stereoselective synthesis of unnatural α-amino acids is disclosed, using ubiquitous aliphatic alcohols as radical precursors to form the α-amino acid backbone under redox-neutral photoredox-mediated conditions.