Three-Component C -Glycosylation of Amino Acids and Peptides Enabled by Photoinduced Palladium Catalysis

Key words manganese catalysis - glycopeptides - C–H glycosylation - C–H activation

C ‐glycosylation is a well‐established strategy for improving the pharmacokinetic properties of peptides; however, the influence of chiral C ‐glycosyl amino acid incorporation on peptide conformation remains insufficiently explored. Most existing synthetic approaches restrict C ‐glycosyl amino acid placement to the N ‐terminus, C ‐terminus, or specific residues containing pre‐installed reactive groups. Here, we present a more versatile strategy based on the design and synthesis of customized C ‐glycosyl amino acids. Four variants bearing protected galactopyranose, ribofuranose, sorbofuranose, or allofuranose side chains were synthesized and incorporated into peptides using a solid‐phase methodology, enabling substitution at diverse sequence positions. Detailed NMR analyses revealed that each C ‐glycosyl α‐amino acid promotes distinct conformational preferences, primarily stabilized by hydrogen‐bonding networks between backbone amides and carbohydrate side chains. These findings uncover conformational information encoded within four non‐canonical C ‐glycosyl α‐amino acids, offering new molecular tools for catalysis, materials development and drug discovery.

Effect of the roasting process on the flavor formation of Tibetan pork: Matrices oxidation dependence on temperature or time.

Until recently, investigations on the glycosylation of amino acids during the Maillard reaction, on the formation of advanced glycation endproducts (AGE) and the postranslational modification of proteins mainly concentrated on the amino acids lysine, arginine, asparagine, serine and threonine whereas the significance of tryptophan remained largely unnoticed. While studying occurrence and relevance of novel tryptophan metabolites in biological systems, our attention on tryptophan glycosylation was attracted by reports on mannosylated tryptophan residues in proteins [1-6]. In this contribution, we describe the characterization and structure elucidation of novel tryptophan glycoconjugates resulting from the chemical condensation of tryptophan and aldohexoses and demonstrate their occurrence in food samples [7]. In addition, we report on the identification of tryptophan-N- and -C-glycoconjugates, namely N1-(b-D-glucopyranosyl-4C1)-L-tryptophan and 2-(a -manno-pyranosyl-1C4)-L-tryptophan, formed enzymatically as novel tryptophan metabolites in plants [8] and man [7].

Synthesis of novel triazole-derived glycopeptides as analogs of α-dystroglycan mucins

A new affinity chromatography system that selectively retains glycosylated amino acids has been utilized to determine the amount of nonenzymatic glycosylation present in peripheral nerve from diabetic and control rats and dogs. The mean value for glycosylated amino acids in diabetic rats was 2.8 times greater than the mean value in normal rats (P less than 0.001). In diabetic dogs, mean values were 2.15 times greater than normal values (P less than 0.05). Amino acid analysis of reduced, glycosylated amino acids previously isolated by affinity chromatography showed that glycosylated lysine and its hydrolysis rearrangement products were the major borohydride-reducible adduct present. In addition, another glycosylated product was noted to be present in major proportions. This radioactive product did not chromatograph with any of the available glycosylated amino acid standards. The finding that diabetes results in a nearly 3-fold increase of peripheral nerve glycosylation is consistent with a number of previous investigations in which glycosylation was measured in hemoglobin, serum albumin, and urinary amino acids and peptides from diabetics and normals. The results reported here provide evidence that increased nonenzymatic glycosylation is occurring in a tissue where physiological, morphological, and clinical degeneration characteristically develop as a result of diabetes mellitus.

C-glycosides are widely distributed structural motifs found in natural products and commercially available drug molecules. Due to the stability of glycosidic C-C bonds against chemical and enzymatic hydrolysis, only C-glycosides have been used and synthesized as synthetic substitutes for O-glycosides. Research into the development of stereoselective C-glycosylation for accessing carbohydrate analogs has gained significant importance. However, the precise construction of glycosidic C-C bonds has long been a major challenge in the stereocontrolled synthesis of carbohydrates. In recent years, transition metal-catalyzed glycosylation reactions have established themselves for the synthesis of various C-glycosides and glycoconjugates due to their versatility, efficiency, and stereoselectivity. Nevertheless, the laborious synthesis of glycosyl donors and the need for toxic and sensitive organometallic reagents limit the broad applicability of these reactions. Hence, late-stage C-H glycosylation was developed. Initially, a palladium-catalyzed C(sp3)-H glycosylation of amino acids using triazole as an isostere for peptides was established. This allowed for the versatile synthesis of glycoamino acids, glycopeptides, and BODIPY-labeled glycoamino acids. Furthermore, a conceptually new C-glycosyl acceptor was designed through palladium-catalyzed C-H activation of glycosides. Equipped with glycal iodide donors, the selective palladium-catalyzed C-H glycosylation of glycosides was explored for the efficient assembly of oligosaccharides. Additionally, the method for the selective C(sp2)-H glycosylation of arenes using a stable glycosyl bromide donor via ruthenium catalysis was developed. Remarkably, the remote meta-C(sp2)-H glycosylation enabled the efficient construction of biologically important meta-C-aryl glycosides. Furthermore, a domino reaction for the construction of meta-C-alkyl glycosides in a single catalytic reaction with readily available starting materials was developed. Finally, the rhodium-catalyzed position-selective tryptophan peptide C7 amidation was achieved using easily accessible dioxazolones.

Glycosylation and functionalization of native amino acids with azido uronic acids

α-Selective glycosylation affords mucin-related GalNAc amino acids and diketopiperazines active on Trypanosoma cruzi

A highly stereoselective strategy to facilitate the synthesis of 1,2-cis-O-linked glycosyl amino acids was established via a additive-modulated trichloroacetimidate glycosylation approach. This mild and practical protocol demonstrates broad applicability with diverse glycosyl donors, including D-gluco-, D-galacto-, 2-deoxy-2-azido-D-gluco-, 2-deoxy-2-azido-D-galacto-, D-xylo-, L-fuco-pyranosyl and L-arabinofuranosyl trichloroacetimidates, and orthogonally protected amino acids such as Ser, Thr, Tyr, and 4-hydroxyproline (Hyp) as acceptors. These 1,2-cis linked glycosyl amino acids serve as valuable building blocks for glycopeptide synthesis via solid-phase peptide synthesis (SPPS), offering significant potential for advancing glycoprotein research.

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We describe an efficient synthesis of 2,6- and 2,3-sialyl T antigens linked to serine in a one-pot glycosylation. We first investigated the glycosidation of thiosialosides by varying the N-protecting group. Modification of the C-5 amino group of beta-thiosialosides into the N-9-fluorenylmethoxycarbonyl, N-2,2,2-trichloroethoxycarbonyl (N-Troc), and N-trichloroacetyl derivatives enhanced the reactivity of these compounds towards glycosidation. Addition of a minimum amount of 3 A molecular sieves was also effective in improving the yield of alpha-linked sialosides. Next, we conducted one-pot syntheses of the glycosyl amino acids by using the N-Troc sialyl donor. The N-Troc derivative can be converted into the N-acetyl derivative without racemization of the amino acids. Branched-type one-pot glycosylation, initiated by regioselective glycosylation of the 3,6-dihydroxy galactoside with the N-Troc-beta-thiophenyl sialoside, provided the protected 2,6-sialyl T antigen in good yield. Linear-type one-pot glycosylation, initiated by chemoselective glycosylation of galactosyl fluoride with the N-Troc-beta-thiophenyl sialoside, afforded the protected 2,3-sialyl T antigen in excellent yield. Both protected glycosyl amino acids were converted into the fully deprotected 2,6- and 2,3-sialyl T antigens linked to serine in good yields.

A convergent total synthesis of F1α antigen, a member of the tumor-associated O-linked mucin glycosyl amino acid, was tried by one-pot sequential glycosylation. Highly α-selective glycosylation of amino acid 7 with thioglycoside 6 was successfully carried out by combining trityl trifluoromethanesulfonate (TrOTf) and N-iodosuccimide (NIS) which gave glycosyl amino acid 21 in high yield (97%, α/β = 83⁄17). Next, the glycosylation of thioglycoside 4 with galactosyl phenyl carbonate 2 or fluoride 3 was tried by the promotion of trityl tetrakis(pentafluorophenyl)borate [TrB(C6F5)4] or trifluoromethanesulfonic acid (TfOH); protected F1α 25 was afforded in 80 or 89% overall yield, respectively, by the further addition of glycosyl amino acid 5 and NIS. The desired trisaccharide was obtained in high yield after removal of the protecting groups. Next, a convergent total synthesis of branched hepta-β-glucoside 30 having phytoalexin-elicitor activity was efficiently performed by way of two one-pot sequential glycosylation reactions: that is, trisaccharide 34 was synthesized in high yield by TfOH-catalyzed one-pot glycosylation using three given monosaccharides (31, 35, and 36) as shown in Scheme 12 and by subsequent selective deprotection of 6′-O-TBDPS group. The second one-pot glycosylation of trisaccharide 34 with three monosaccharides (31, 32, and 33d) also proceeded smoothly to afford heptaglucoside 43 stereoselectively in 48% total yield based on monosaccharide 32. Phytoalexin-elicitor active branched hepta-β-glucoside 30 was afforded by the sequential deprotection.

Construction of carbohydrate-based antitumor vaccines: synthesis of glycosyl amino acids by olefin cross-metathesis

Syntheses of α-dystroglycan derived sialylated glycosyl amino acids carrying a novel mannosyl serine/threonine linkage