Alkylation Of Glycine Derivatives Research Articles

Alkylation of Glycine Derivatives through a Synergistic Single-Electron Transfer and Halogen-Atom Transfer Process.

Here, we present a versatile method for forming C(sp3)-C(sp3) bonds, enabling the synthesis of a range of natural and non-natural amino acids. This approach utilizes readily available glycine derivatives and alkyl iodides, combining single-electron transfer and halogen-atom transfer processes. The utility of this step-economic and redox-economic C(sp3)-C(sp3) bond formation is further highlighted in the late-stage site-selective modifications of the glycine residue in short peptides.

Copper-Catalyzed C(sp3)–H Alkylation of Glycine Derivatives

Copper-Catalyzed C(sp3)–H Alkylation of Glycine Derivatives

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

ConspectusPeptides are essential components of living systems and contribute to critical biological processes, such as cell proliferation, immune defense, tumor formation, and differentiation. Therefore, peptides have attracted considerable attention as targets for the development of therapeutic products. The incorporation of unnatural amino acid residues into peptides can considerably impact peptide immunogenicity, toxicity, side effects, water solubility, action duration, and distribution and enhance the peptides' druggability. Typically, the direct modification of natural amino acids is a practical and effective approach for promptly obtaining unnatural amino acids. However, selective functionalization of multiple C(sp3)-H bonds with comparable chemical reactivities in the peptide side chains remains a formidable challenge. Furthermore, chemical modifications aimed at highly reactive (nucleophilic and aromatic) groups on peptide side chains can interfere with the biological activity of peptides.In recent years, the rapid advancement of photoinduced radical reactions has made photoredox radical-radical cross-coupling a practical approach for constructing C(sp3)-C(sp3) bonds under mild conditions. Glycine, a naturally occurring amino acid and the fundamental skeleton of all α-amino acids, provides a basis for the alkylated modification of its own α-C(sp3)-H bond under mild conditions. This Account describes our recent research endeavors for systematically investigating the photocatalytic α-C(sp3)-H alkylation of glycine derivatives via radical-radical coupling between N-aryl glycinate-derived radicals and various alkyl radicals. In 2018, we disclosed the photoinduced Cu-catalyzed decarboxylative α-C(sp3)-H alkylation of glycine derivatives. Subsequently, we developed a catalyst-free method for alkylating glycine derivatives and glycine residues in peptides via electron donor-acceptor (EDA)-complex-promoted single electron transfer. Moreover, we developed a photoinduced method for the radical alkylation of N-aryl glycinate α-C(sp3)-H bonds using unactivated alkyl chlorides (iodides) under photocatalyst-free conditions. Notably, by building on racemic alkylations of glycine derivatives and glycine-residue-containing peptides, we recently stereoselectively alkylated the N-aryl glycinate α-C(sp3)-H bond using a dual-functional Cu catalyst generated in situ for synthesizing a series of unnatural chiral α-amino and C-glycoamino acids.We have developed a series of methods for synthesizing unnatural amino acids through the α-C(sp3)-H alkylation of glycine derivatives using photoredox-promoted radical coupling as a key strategy. These methods are efficient and versatile and can be used for the late-stage modification of peptides in various contexts. Our work builds on the fundamental importance of glycine as the basic scaffold of all α-amino acids and highlights the potential of radical-based chemistry for developing chemical transformations in peptide synthesis. These findings have broad implications for chemical biology and may open doors for discovering peptide drugs and developing therapeutics.

Amide-Based Cinchona Alkaloids as Phase-Transfer Catalysts: Synthesis and Potential Application.

Herein we present a library of simple amide derivatives of Cinchona alkaloids in the form of quaternary ammonium salts. The obtained derivatives can be generated very easily and efficiently from inexpensive and commercially available substrates. We tested this class of alkaloids in the alkylation of glycine derivative, carried out under phase-transfer catalyst conditions. The presented hybrid catalysts offer both high reaction yields (up to 97%) and high enantioselectivities of the obtained product (up to 94% ee).

Copper-Catalyzed Asymmetric Alkylation of Glycine Derivatives

Copper-Catalyzed Asymmetric Alkylation of Glycine Derivatives

両親媒性高分子を利用する高分子固定化型不斉触媒の創製

The heterogeneous chiral catalysts for the synthesis of optically active compounds have been energetically developed mainly due to their easy separation and recycle use. However, the supported catalysts sometimes lead to negative effects both on the reactivity and the enantioselectivity. Design of the polymer–support is important issue to develop essentially useful polymeric chiral catalyst. We have designed novel polymer–immobilized chiral catalysts based on the use of amphiphilic polymer support. For example, polymers having quaternary ammonium sulfonate pendant groups were efficiently used as suitable polymer support of the chiral catalyst for the reactions in aqueous solution. By using of the amphiphilic polymer–immobilized chiral catalyst, asymmetric transfer hydrogenation in water smoothly occurred to give the corresponding optically active alcohol with positive effect on the enantioselectivity. When the enantiopure quaternary ammonium sulfonate was introduced into polymer, asymmetric alkylation of glycine derivatives can be catalyzed by the chiral ammonium polymer. Chiral quaternary ammonium cation was attached to polymeric sulfonate anion through ionic bonding. This immobilization method using ionic bond is substantially useful since any type of chiral quaternary ammonium structure can be immobilized into polymer without any additional chemical modification on the catalyst molecule.

Alkylation of Glycine Derivatives in Liquid Ammonia. Ill. Dephthaloylation and N-Benzylation of Phthaloylglycine in Liquid Ammonia

フタロイルグリシン, フタロイルグリシンエステルおよびフタロイルグリシンアミドのメタル置換を液安中金属アルカリまたはアルカリアミドを用いて行ない, そのアルカリ置換体と塩化ベンジルとの反応を行なった結果, 室温ではいずれも脱フタロイルを起し, N-ベンジルフタルイミドと N,N'- ジベンジルフタルアミドを生成した。しかしこの反応を -40°～-50℃ の低温で行なうときは, N-ベンジル-o-カルバモイル馬尿酸アミドがえられた。