Synthesis of the Antimicrobial S‐Linked Glycopeptide,Glycocin F

The first total synthesis of glycocin F, a uniquely diglycosylated antimicrobial peptide bearing a rare S‐linked N‐acetylglucosamine (GlcNAc) moiety in addition to an O‐linked GlcNAc, has been accomplished using a native chemical ligation strategy. The synthetic and naturally occurring peptides were compared by HPLC, mass spectrometry, NMR and CD spectroscopy, and their stability towards chymotrypsin digestion and antimicrobial activity were measured. This is the first comprehensive structural and functional comparison of a naturally occurring glycocin with an active synthetic analogue.     

Transition-Metal-Mediated Glycosylation with Thioglycosides

Thioglycosides are among the most common glycosyl donors that find broad application in the synthesis of glycans and glycoconjugates. However, the requirement for toxic and/or large access of activators needed for common glycosylations with thioglycosides remains a notable drawback. Due to the increased awareness of the chemical waste impact on the environment, synthetic studies have been driven by the goal of finding non-toxic reagents. The main focus of this review is to highlight recent methods for thioglycoside activation that rely on transition metal catalysis.     

Defining the Scope of the Acid-Catalyzed Glycosidation of Glycosyl Bromides

Following the recent discovery that traditional silver(I) oxide-promoted glycosidations of glycosyl bromides (Koenigs–Knorr reaction) can be greatly accelerated in the presence of catalytic TMSOTf, reported herein is a dedicated study of all major aspects of this reaction. A thorough investigation of numerous silver salts and careful refinement of the reaction conditions led to an improved mechanistic understanding. This, in turn, led to a significant reduction in the amount of silver salt required for these glycosylations. The progress of this reaction can be monitored by naked eye, and the completion of the reaction can be judged by the disappearance of characteristic dark color of Ag₂O. Further evidence on higher reactivity of benzoylated α-bromides in comparison to that of their benzylated counterparts has been acquired.     

Total Synthesis of Terpioside B

The first total synthesis of terpioside B ( 1 ) has been accomplished. Key steps include the stereoselective installments of a set of challenging 1,2-cis-glycosidic linkages. Thus, α(1,4)-linked d -galactoside was effectively constructed from a 1,2-anhydrogalactose donor and an unprotected 1,6-anhydrogalactose acceptor by using a boron-mediated aglycon delivery (BMAD) method. In addition, α-l -fucofuranosides were stereoselectively and simultaneously constructed by remote group-assisted 1,2-cis-α-stereoselective glycosylations.     

Highly Stereoselective β‐Mannopyranosylation via the 1‐α‐Glycosyloxy‐isochromenylium‐4‐gold(I) Intermediates

While the gold(I)‐catalyzed glycosylation reaction with 4,6‐O‐benzylidene tethered mannosyl ortho‐alkynylbenzoates as donors falls squarely into the category of the Crich‐type β‐selective mannosylation when Ph₃PAuOTf is used as the catalyst, in that the mannosyl α‐triflates are invoked, replacement of the ^?OTf in the gold(I) complex with less nucleophilic counter anions (i.e., ^?NTf₂, ^?SbF₆, ^?BF₄, and ^?BAr₄^F) leads to complete loss of β‐selectivity with the mannosyl ortho‐alkynylbenzoate β‐donors. Nevertheless, with the α‐donors, the mannosylation reactions under the catalysis of Ph₃PAuBAr₄^F (BAr₄^F=tetrakis[3,5‐bis(trifluoromethyl)phenyl]borate) are especially highly β‐selective and accommodate a broad scope of substrates; these include glycosylation with mannosyl donors installed with a bulky TBS group at O3, donors bearing 4,6‐di‐O‐benzoyl groups, and acceptors known as sterically unmatched or hindered. For the ortho‐alkynylbenzoate β‐donors, an anomerization and glycosylation sequence can also ensure the highly β‐selective mannosylation. The 1‐α‐mannosyloxy‐isochromenylium‐4‐gold(I) complex ( Cα ), readily generated upon activation of the α‐mannosyl ortho‐alkynylbenzoate ( 1 α ) with Ph₃PAuBAr₄^F at ?35 °C, was well characterized by NMR spectroscopy; the occurrence of this species accounts for the high β‐selectivity in the present mannosylation.     

Reversing the Stereoselectivity of a Palladium‐Catalyzed O‐Glycosylation through an Inner‐Sphere or Outer‐Sphere Pathway

An efficient and concise method for the construction of various O‐glycosidic bonds by a palladium‐catalyzed reaction with a 3‐O‐picoloyl glucal has been developed. The stereochemistry of the anomeric center derives from either an inner‐sphere or outer‐sphere pathway. Harder nucleophiles, such as aliphatic alcohols and sodium phenoxides give β‐products, and α products result from using softer nucleophiles, such as phenol.     

Structural Characterization of O‐ and C‐Glycosylating Variants of the Landomycin Glycosyltransferase LanGT2

The structures of the O‐glycosyltransferase LanGT2 and the engineered, C? C bond‐forming variant LanGT2S8Ac show how the replacement of a single loop can change the functionality of the enzyme. Crystal structures of the enzymes in complex with a nonhydrolyzable nucleotide‐sugar analogue revealed that there is a conformational transition to create the binding sites for the aglycon substrate. This induced‐fit transition was explored by molecular docking experiments with various aglycon substrates.     

A PEGylated Photocleavable Auxiliary Mediates the Sequential Enzymatic Glycosylation and Native Chemical Ligation of Peptides

Research aimed at understanding the specific role of glycosylation patterns in protein function would greatly benefit from additional approaches allowing direct access to homogeneous glycoproteins. Herein the development and application of an efficient approach for the synthesis of complex homogenously glycosylated peptides based on a multifunctional photocleavable auxiliary is described. The presence of a PEG polymer within the auxiliary enables sequential enzymatic glycosylation and straightforward isolation in excellent yields. The auxiliary‐modified peptides can be directly used in native chemical ligations with peptide thioesters easily obtained by direct hydrazinolysis of the respective glycosylated peptidyl resins and subsequent oxidation. The ligated glycopeptides can be smoothly deprotected by UV irradiation. We apply this approach to the preparation of variants of the epithelial tumor marker MUC1 carrying one or more Tn, T, or sialyl‐T antigens.     

Creating Space for Large Acceptors: Rational Biocatalyst Design for Resveratrol Glycosylation in an Aqueous System

Polyphenols display a number of interesting properties but their low solubility limits practical applications. In that respect, glycosylation offers a solution for which sucrose phosphorylase has been proposed as a cost‐effective biocatalyst. However, its activity on alternative acceptor substrates is too low for synthetic purposes and typically requires the addition of organic (co‐)solvents. Here, we describe the engineering of the enzyme from Thermoanaerobacterium thermosaccharolyticum to enable glycosylation of resveratrol as test case. Based on docking and modeling studies, an active‐site loop was predicted to hinder binding. Indeed, the unbolted loop variant R134A showed useful affinity for resveratrol (K_m=185 mM ) and could be used for the quantitative production of resveratrol 3‐α‐glucoside in an aqueous system. Improved activity was also shown for other acceptors, introducing variant R134A as promising new biocatalyst for glycosylation reactions on bulky phenolic acceptors.     

Synthesis of Disaccharide Nucleosides by the O‐Glycosylation of Natural Nucleosides with Thioglycoside Donors

Disaccharide nucleosides constitute an important group of naturally‐occurring sugar derivatives. In this study, we report on the synthesis of disaccharide nucleosides by the direct O‐glycosylation of nucleoside acceptors, such as adenosine, guanosine, thymidine, and cytidine, with glycosyl donors. Among the glycosyl donors tested, thioglycosides were found to give the corresponding disaccharide nucleosides in moderate to high chemical yields with the above nucleoside acceptors using p‐toluenesulfenyl chloride (TolSCl) and silver triflate (AgOTf) as promoters. The interaction of these promoters with nucleoside acceptors was examined by ¹H NMR spectroscopic experiments.