Radical‐Mediated C−H Alkylation of Glycine Derivatives: A Straightforward Strategy for Diverse α‐Unnatural Amino Acids

Abstract

Jaehoon Sim was nominated to be part of this collection by EurJOC Board Member Sungwoo HongUnnatural amino acids are important scaffolds for novel drug candidates, and especially α-alkyl amino acids have emerged as a valuable variant. This is due to the ubiquity of alkyl groups, which are pervasive as key motifs in natural products, biological and pharmaceutical molecules. The development of radicalbased approaches in organic synthesis has expanded dramatically in recent years. It has enabled site-and region-specific installation of a variety of functionalities in small molecules, which has been spontaneously applied in the preparation of versatile amino acid building blocks. The glycine motif in the backbone of amino acids has gained significant attention for allowing access to a variety of complex α-unnatural amino acids via radical-mediated α-CÀ H alkylation. This review summarizes the last decade's development of radical-based α-CÀ H alkylation of glycine derivatives to provide unnatural α-amino acids. The advantages, current limitations, and perspectives of glycine-based unnatural amino acid synthesis are also discussed.

Direct Alkylation of Glycine Derivatives via Photoinduced Palladium Catalysis, Utilizing Intermolecular Hydrogen Atom Transfer Mediated by Alkyl Radicals

“…This choice is driven by two factors: first, these derivatives possess activated α-sp3 C–H bonds, and second amino acids have found wide-ranging applications in the synthesis of biologically active compounds and peptide mimetic drugs . Glycine, serving as the fundamental scaffold for all α-amino acids, allows for the direct functionalization of α-sp3 C–H bonds, providing the most straightforward route to the preparation of unnatural α-amino acids …”

Visible Light-Driven Flexible Synthesis of α-Alkylated Glycine Derivatives Catalyzed by Reusable Covalent Organic Frameworks

“…Glycine is the most elementary α-amino acid. Its direct derivatization and modification hold significant relevance in synthesizing unnatural amino acid-containing bioactive peptides and pharmaceuticals. , Past decades have witnessed a booming interest in functionalizing glycine derivatives. − Among them, visible light-driven α-C­(sp 3 )–H bond alkylation of glycine derivatives is outstanding as it could deliver diverse alkylated glycine derivatives precisely and efficiently in a green and sustainable manner. − Regarding the photocatalysts involved in initiating the reaction, reported visible light-driven approaches toward this objective can be categorized into the following three types (Scheme a): (1) the external photocatalyst (PC) needed visible light-driven C­(sp 3 )–H bond alkylation, in which transition-metal complexes, organic dyes, or quantum dots acted as photocatalysts to absorb visible light and initiate the reaction. − (2) photocatalyst-free visible light-driven C­(sp 3 )–H bond alkylation, in which electron donor–acceptor (EDA) complexes always formed and served as internal photocatalysts. − (3) visible light-driven C­(sp 3 )–H bond asymmetric alkylation, in which transition-metal asymmetric catalysis and photocatalysis merged to fulfill the synthesis of C­(sp 3 )-alkylated glycine derivatives stereo selectively. − The protocols above have demonstrated significant advancements concerning reaction efficiency, selectivity, and the range of applicable substrates. Nevertheless, substantial room exists for further enhancement in various facets of environmentally benign characteristics, including but not limited to catalyst reusability, reaction flexibility, and simplification of postreaction workup procedures.…”

Photoinduced C(sp3)–H Functionalization of Glycine Derivatives: Preparation of Unnatural α-Amino Acids and Late-Stage Modification of Peptides

“…For example, this strategy has been utilized for stereoselective functionalization of glycine derivatives to prepare unnatural chiral α-amino acids (Scheme B) . Notably, the C α -radical intermediate generated through the single-electron oxidation of the glycine α-C­(sp 3 )–H bond is an important coupling partner; however, its applications for synthesizing unnatural α-amino acids and modifying peptides are still limited …”