Cover Picture: Regioselective and Stereospecific β-Arabinofuranosylation by Boron-Mediated Aglycon Delivery (Angew. Chem. Int. Ed. 46/2023)

Regio- and stereoselective formation of the 1,2-cis-furanosidic linkage has been in great demand for efficient synthesis of biologically active natural glycosides. In this study, we developed a regioselective and β-stereospecific d -/l -arabinofuranosylation promoted by a boronic acid catalyst under mild conditions. The glycosylations proceeded smoothly for a variety of diols, triols, and unprotected sugar acceptors to give the corresponding β-arabinofuranosides (β-Arbf) in high yields with complete β-stereoselectivity and high regioselectivity. The regioselectivity was completely reversed depending on the optical isomerism of the donor used and was predictable a priori using predictive models. Mechanistic studies based on DFT calculations revealed that the present glycosylation occurs through a highly dissociative concerted S_Ni mechanism. The usefulness of the glycosylation method was demonstrated by the chemical synthesis of trisaccharide structures of arabinogalactan fragments.     

Utilization of Donor–Acceptor Interactions for the Catalytic Acceleration of Nucleophilic Additions to Aromatic Carbonyl Compounds

A conceptually new method for the catalytic electrophilic activation of aromatic carbonyl substrates, by utilizing donor–acceptor interactions between an electron‐deficient macrocyclic boronic ester host ( [2+2] _BTH‐F ) and an aromatic carbonyl guest substrate, was realized. In the presence of a catalytic amount of [2+2] _BTH‐F , dramatic acceleration of the nucleophilic addition of a ketene silyl acetal towards either electron‐rich aromatic aldehydes or ketones was achieved. Several control experiments confirmed that inclusion of the aromatic substrates within [2+2] _BTH‐F , through efficient donor–acceptor interactions, is essential for the acceleration of the reaction.     

Regioselective and 1,2‐cis‐α‐Stereoselective Glycosylation Utilizing Glycosyl‐Acceptor‐Derived Boronic Ester Catalyst

Regioselective and 1,2‐cis‐α‐stereoselective glycosylations using 1α,2α‐anhydro glycosyl donors and diol glycosyl acceptors in the presence of a glycosyl‐acceptor‐derived boronic ester catalyst. The reactions proceed smoothly to give the corresponding 1,2‐cis‐α‐glycosides with high stereo‐ and regioselectivities in high yields without any further additives under mild reaction conditions. In addition, the present glycosylation method was successfully applied to the synthesis of an isoflavone glycoside.     

Stereoselective Synthesis of the Hexasaccharide Repeating Unit of the Cell Wall Polysaccharide from Kineosporia aurantiaca VKM Ac-720T Employing the Direct Glycosylation with Anomeric Hydroxy Sugars Involving Glycosyl Phthalate Intermediates

Synthesis of a suitably protected form of the hexasaccharide repeating unit of the cell wall polymer from Kineosporia aurantiaca VKM Ac-720 ^T has been achieved by the stereoselective direct glycosylation of a trisaccharide acceptor with a trisaccharide donor having an anomeric hydroxy group involving a glycosyl phthalate intermediate. Both the trisaccharide acceptor and the trisaccharide donor were obtained from a common trisaccharide, of which two β-mannopyranosyl linkages were constructed stereoselectively by employing the direct glycosylation method with the anomeric hydroxy sugar involving a glycosyl phthalate intermediate and the 2′-carboxybenzyl glycoside method, respectively.     

Chemical Glycosylations for the Synthesis of Building Units of Post‐Translational Modifications

In chemical glycosylation reactions, a glycosyl donor couples with a glycosyl acceptor through glycosidic linkage. Most of the products end up with a mixture due to the formation of a stereogenic center at the anomeric carbon. Activation with a suitable Lewis acid and introduction of the non‐participating protecting group on donor and acceptor results in a selective product. Herein, we used a suitably protected donor and acceptor which produced an orthogonally protected building block with α‐selectivity. We used also a donor for the synthesis of modified phosphoribosylated amino acid. The formation of glycoside products can be used to synthesize complex biologically important organic molecules.     

First Total Synthesis of Trehalose‐Containing Branched Oligosaccharide OSE‐1 of Mycobacterium gordonae (Strain 990)

The first total synthesis of the branched oligosaccharide OSE‐1 of Mycobacterium gordonae (strain 990) is reported. An intramolecular aglycon delivery approach was used for constructing the desymmetrized 1,1′‐α,α‐linked trehalose moiety. A [3+2] glycosylation of the trisaccharide donor and trehalose acceptor furnished the right hand side pentasaccharide. Regioselective O3 glycosylation of L ‐rhamnosyl 2,3‐diol allowed expedient synthesis of the left hand side tetrasaccharide. The nonasaccharide was assembled in a highly convergent fashion through a [4+5] glycosylation.     

The Total Synthesis of Starfish Ganglioside GP3 Bearing a Unique Sialyl Glycan Architecture

The total synthesis of ganglioside GP3, which is found in the starfish Asterina pectinifera, has been accomplished through stereoselective and effective glycosylation reactions. The sialic acid embedded octasaccharide moiety of the target compound was constructed by [4+4] convergent coupling. A tetrasaccharyl donor and acceptor that contained internal sialic acid residues were synthesized with an orthogonally protected N‐Troc sialic acid donor as the key common synthetic unit, and they underwent highly stereoselective glycosidation. The resulting sialosides were subsequently transformed into reactive glycosyl acceptors. [4+4] coupling furnished the octasaccharide framework in 91 % yield as a single stereoisomer. Final conjugation of the octasaccharyl donor and glucosyl ceramide acceptor produced the protected target compound in high yield, which underwent global deprotection to successfully deliver ganglioside GP3.     

Self-Promoted N-Glycosylation: Extended Substrate Scope and Substituent Effects

A self-promoted glycosylation method for the stereoselective formation of β-glucosides from a substrate library of glycosyl trichloroacetimidate glycosyl donors and glycosyl acceptors is presented. The simple two-component reaction takes place at elevated temperatures, without the addition of any additives or catalysts. After a simple basic workup, N-glycosides were obtained in good yields and with high β-selectivity and hence this method allows for easy access to glycoconjugates under very mild conditions. The influences of neighboring group participation and substituents, in both the glycosyl donor and acceptor, were studied. Kinetic data were obtained from in situ IR and these were used for a Hammett study. A connection between the pK_a of the acceptor and reaction rate was found and new mechanistic insight in self-promoted glycosylations gained.     

Mapping the Relationship between Glycosyl Acceptor Reactivity and Glycosylation Stereoselectivity

The reactivity of both coupling partners—the glycosyl donor and acceptor—is decisive for the outcome of a glycosylation reaction, in terms of both yield and stereoselectivity. Where the reactivity of glycosyl donors is well understood and can be controlled through manipulation of the functional/protecting‐group pattern, the reactivity of glycosyl acceptor alcohols is poorly understood. We here present an operationally simple system to gauge glycosyl acceptor reactivity, which employs two conformationally locked donors with stereoselectivity that critically depends on the reactivity of the nucleophile. A wide array of acceptors was screened and their structure–reactivity/stereoselectivity relationships established. By systematically varying the protecting groups, the reactivity of glycosyl acceptors can be adjusted to attain stereoselective cis‐glucosylations.     

Stereoselective Synthesis of the O-antigen of A. baumannii ATCC 17961 Using Long-Range Levulinoyl Group Participation

Herein, we described the first synthesis of the pentasaccharide and decasaccharide of the A. baumannii ATCC 17961 O-antigen for developing a synthetic carbohydrate-based vaccine against A. baumannii infection. The efficient synthesis of the rare sugar 2,3-diacetamido-glucuronate was achieved using our recently introduced organocatalytic glycosylation method. We found, for the first time, that long-range levulinoyl group participation via a hydrogen bond can result in a significantly improved β-selectivity in glycosylations. This solves the stereoselectivity problem of highly branched galactose acceptors. The proposed mechanism was supported by control experiments and DFT computations. Benefiting from the long-range levulinoyl group participation strategy, the pentasaccharide donor and acceptor were obtained via an efficient [2+1+2] one-pot glycosylation method and were used for the target decasaccharide synthesis.     

Total synthesis of the heptasaccharide repeating unit of the iron-binding exopolysaccharide secreted by Klebsiella oxytoca BAS-10

The first total synthesis of a heptasaccharide found in the iron-binding exopolysaccharide produced by Klebsiella oxytoca BAS-10 has been achieved in excellent yield using a block synthetic strategy. A trisaccharide glycosyl donor was stereoselectively coupled with a tetrasaccharide glycosyl acceptor using the trichloroacetimidate activation procedure. The yields and stereo outcome were excellent in each step of glycosylation. A late stage oxidation protocol was adopted for the oxidation of the primary hydroxyl group to the carboxylic functionality while keeping a secondary hydroxyl group unaffected.     

Regio/Stereoselective Glycosylation of Diol and Polyol Acceptors in Efficient Synthesis of Neu5Ac‐α‐2,3‐LacNPhth Trisaccharide

A concise approach to a Neu5Ac‐α‐2,3‐LacNPhth trisaccharide derivative was developed. First, the regio/stereoselective glycosylation between glycoside donors and glucoNPhth diol acceptors was investigated. It was found that the regioselectivity depends not only on the steric hindrance of the C2‐NPhth group and the C6‐OH protecting group of the glucosamine acceptors, but also on the leaving group and protecting group of the glycoside donors. Under optimized conditions, LacNPhth derivatives were synthesized in up to 92 % yield through a regio/stereoselective glycosylation between peracetylated‐α‐galactopyranosyl trichloroacetimidate and p‐methoxyphenyl 6‐O‐tert‐butyldiphenylsilyl‐2‐deoxy‐2‐phthalimido‐β‐d ‐glucopyranoside, avoiding the formation of glycosylated orthoesters and anomeric aglycon transfer. Then, the LacNPhth derivative was deacylated and then protected on the primary position by TBDPS to form a LacNPhth polyol acceptor. Finally, the Neu5Ac‐α‐2,3‐LacNPhth derivative was synthesized in 48 % yield through the regio/stereoselective glycosylation between the LacNPhth polyol acceptor and a sialyl phosphite donor. Starting from d ‐glucosamine hydrochloride, the target Neu5Ac‐α‐2,3‐LacNPhth derivative was synthesized in a total yield of 18.5 % over only 10 steps.     

α:β Selectivity in the synthesis of 3-substituted, 4-methyl umbelliferone glycosides of N-acetyl glucosamine and chitobiose

The influence of phenolic acceptor nucleophilicity; for example, 3-substituted, 4-methylumbelliferones, and glycosyl donor electrophilicity; for example, 3- and 4-substituted N-acetylglucosamines, on glycosylation stereochemistry has been evaluated. In a systematic comparison, the stereochemical outcome as well as the reaction yield appeared to be influenced by the 3- and 4-substituents of the donor as well as the 3-substituent of the aryl acceptor. In the context of synthesizing a fluorogenic substrate for oligosaccharyltransferase, an α-glycoside was desired. Although most acceptor–donor pairs led to predominantly or exclusively the β-glycoside, reaction of the most activated (3,4-di-O-benzyl) donor and the least nucleophilic acceptor (3-Br), resulted in a 1:1 ratio of α,β arylglycosides.     

Bimolecular nature of boron trifluoride catalyzed glycosylation of a galactosyl donor: The role of the acceptor

Density functional theory (DFT) computations disclose the mechanism of a crucial neighboring participation step in BF₃ catalyzed stereoselective glycosylation of 1,2‐cyclopropaneacetylated galactosyl donor. Two tandem S_N2 displacements comprise this step: first, the glycosyl acceptor attacks the BF₃‐activated donor to break the donor's 1,2‐cyclopropane ring; then, the donor's 2‐acetyl oxygen substitutes the acceptor to accomplish the neighboring participation. A donor–acceptor hydrogen bond has been found to lower the overall activation free energy. This mechanism is preferred over a 2‐acetyl oxygen coface S_N2 displacement mechanism, in which no glycosyl acceptor is involved. © 2013 Wiley Periodicals, Inc.     

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.     

Hydroxynorleucine as a glycosyl acceptor is an efficient means for introducing amino acid functionality into complex carbohydrates

A new approach to the synthesis of biologically relevant glycosyl amino acids using a non-natural amino acid as the glycosyl acceptor is described. The procedure involves a glycosylation reaction of a suitable carbohydrate donor with Fmoc-l-hydroxynorleucine benzyl ester. This reaction results in the direct incorporation of the amino acid moiety. The acceptor can be used for the preparation of α- or β-O-linked glycosides depending upon the nature of the glycosyl donor. This method has been applied in the synthesis of six different tumor-associated carbohydrate antigens.     

Synthesis Of Isomaltose Analogues

ABSTRACT

Preparation of the α-glucosides 11, 12, 13 and 14 were accomplished through glycosylation of racemic trans-1-hydroxy-2-(hydroxymethyl)cyclohexane using 2-thiopyridyl tetra-O-benzyl-glucoside as the glycosyl donor in acceptable overall yield for α-selectivity, but with poor regioselectivity. Glycosylation under thermodynamic control using tetrabenzyl glucopyranose acetate and trimethylsilyl triflate as the promotor gave similar results. The unprotected glucosides 12 and 13 were separated and characterized by NMR spectroscopy. Similarly methyl 4-deoxy-α-isomaltoside (5a) was prepared through halide catalyzed glycosylation of methyl 2,3-di-O-benzoyl-4-deoxy-α-D-glucopyranoside (15) in acceptable yield and the unprotected compound characterized by NMR spectroscopy. Compounds 5a, 12a, 13a and the mixture 11a and 14a were all tested as substrates for the enzyme glucoamylase from Aspergillus niger and proved to be very poor substrates for the enzymic hydrolysis.     

Acceptor Reactivity in the Total Synthesis of Alginate Fragments Containing α‐L‐Guluronic Acid and β‐D‐Mannuronic Acid

The total synthesis of mixed‐sequence alginate oligosaccharides, featuring both β‐D ‐mannuronic acid (M) and α‐L ‐guluronic acid (G), is reported for the first time. A set of GM, GMG, GMGM, GMGMG, GMGMGM, GMGMGMG, and GMGGMG alginates was assembled using GM building blocks, having a guluronic acid acceptor part and a mannuronic acid donor side to allow the fully stereoselective construction of the cis‐glycosidic linkages. It was found that the nature of the reducing‐end anomeric center, which is ten atoms away from the reacting alcohol group in the key disaccharide acceptor, had a tremendous effect on the efficiency with which the building blocks were united. This chiral center determines the overall shape of the acceptor and it is revealed that the conformational flexibility of the acceptor is an all‐important factor in determining the outcome of a glycosylation reaction.     

Prearranged Glycosides,Part 12, Intramolecular Mannosylations of Glucose Derivatives via Prearranged Glycosides

A series of prearranged glycosides 5 , 17 , 23 , 28 , 37 , and 41 , having a benzyl‐protected 1‐thiomannosyl donor linked through its positions 2, 3, 4, and 6 via succinate and malonate tethers, respectively, to positions 2, 3, and 6 of a benzyl glucopyranoside acceptor, were prepared by condensation of the respective mannosyl succinates and malonates with suitably protected benzyl glucopyranosides. The prearranged glycosides were intramolecularly coupled under various conditions to give the corresponding tethered (1→4)‐linked disaccharides. The yields and anomer ratios of the products of these couplings were interpreted in terms of the thermodynamic stability of the resulting disaccharides. In the case of prearranged glycoside 17 , having positions 3 of both the donor and the acceptor linked by a succinate tether, a strong dependence of the diastereoselectivity of the intramolecular glycosylation on the activation procedure was observed. All other cases did not show a significant dependence of the outcome of the anomeric configuration in intramolecular glycosylation on the activation procedure or the solvent.     

Novel Selectivity in Carbohydrate Reactions Ii. Selective 6-O-Glycosylation of a Partially Protected Lactoside 1 2

Abstract

A novel regioselectivity was observed in the silver salt promoted glycosylation of 2-(trimethylsilyl)ethyl 3′-O-benzyl-β-D-lactoside using acetobromogalactose as the glycosyl donor. The resulting trisaccharide, obtained in 67% yield, was shown to have the newly formed β-glycosidic linkage at the O-6 position of the lactoside. This was confirmed by synthesis of the authentic product by an alternate route. The novel regioselectivity observed is attributed to the presence of the axially disposed 4′-OH group in the lactoside acceptor.