Photoinduced C–H Bond Activation Involving Alkoxy Radicals for the Synthesis of Non-Canonical Amino Acid Derivatives

Abstract

Non-canonical amino acids (ncAAs) are key privileged structural motifs in drug discovery. However, their synthesis via C–H functionalization is often hampered by poor functional group tolerance and narrow substrate scope, and largely restricted to activated ethereal or benzylic C–H bonds. Herein, we report a green photoredox strategy that enables direct C(sp3)–C(sp3) cross-coupling between N-phenylglycine esters and unactivated alkanes (including cyclohexane, methylcyclohexane, ethylcyclohexane, cyclopentane, and adamantane) under mild conditions. Using copper(II) acetate (Cu(OAc)2) as the catalyst and tert-butyl hydroperoxide (TBHP) as the oxidant, the reaction proceeds under 390 nm LED irradiation at room temperature, affording a series of α-alkylated glycine derivatives in moderate to excellent yields, up to 89%. This protocol features a broad substrate scope and good compatibility with diverse functional groups, including halogens, alkyl, and aryl groups, and can be scaled up to gram-scale synthesis, delivering the product in 69% yield. Mechanistic studies reveal that the reaction follows a radical pathway involving single-electron transfer (SET) and hydrogen atom transfer (HAT): the tert-butoxyl radical abstracts a hydrogen atom from the alkane, generating an alkyl radical, which subsequently couples with the glycine Cα radical. Featuring operational simplicity and high atom economy, this method provides a practical and sustainable complement to existing approaches for constructing non-canonical amino acid scaffolds.