Glycosyl Halides Research Articles

Thermal decomposition study of 4-methyloxybenzyl-glycoside by TG/DTA and on-line pyrolysis-photoionization mass spectrometry

A flavor precursor of 4-methyloxybenzyl-2, 3, 4, 6-tetra-O-acetyl-β-d-glucopyranoside (MBGL) was synthesized via a modified Koenigs–Knorr reaction. The thermal decomposition behaviour and pyrolysis intermediate products of the glycoside were studied by simultaneous thermogravimetric/differential thermal analysis (TG/DTA) and synchrotron vacuum ultraviolet (VUV) photoionization mass spectrometry (PIMS). TG/DTA results showed that the largest mass loss rate appeared at a Tp of 246.7 °C. PIMS was used to identify the pyrolysis products of MBGL at 300 °C, 500 °C and 700 °C, respectively. The experimental apparatus had some advantages in real-time analysis and fewer secondary reactions. Some important pyrolysis intermediates, such as the ions of the 4-methyloxybenzyl group at m/z 121 and the glycone moiety at m/z 347, were detected by PIMS. The results indicate that the MBGL was probably showed a different pyrolysis way compared with the other glycosides. This work reports a useful application of synchrotron VUV PIMS in a thermal decomposition study of glycoside flavor precursors.

Synthesis of sialyl halides with various acyl protective groups

Glycosyl halides are historically one of the first glycosyl donors used in glycosylation reactions, and interest in glycosylation reactions involving this class of glycosyl donors is currently increasing. New methods for their activation have been proposed and effective syntheses of oligosaccharides with their participation have been developed. At the same time, the possibilities of using these approaches to the synthesis of sialosides are restricted by the limited diversity of known sialyl halides (previously, mainly sialyl chlorides, less often sialyl bromides and sialyl fluorides, with acetyl (Ac) groups at the oxygen atoms and AcNH, Ac2N and N3 groups at C-5 were used). This work describes the synthesis of six new N-acetyl- and N-trifluoroacetyl-sialyl chlorides and bromides with O-chloroacetyl and O-trifluoroacetyl protective groups. Preparation of N,O-trifluoroacetyl protected derivatives was made possible due to development of the synthesis of sialic acid methyl ester pentaol with N-trifluoroacetyl group.

Urea-catalyzed N-Glycosylation of Amides/Azacycles with Glycosyl Halides.

The efficient synthesis of N-glycosides via direct N-glycosylation of amides/azacycles has been reported. The glycosylation of amides/azacycles with glycosyl halides in the presence of a catalytic amount of urea proceeded smoothly to provide the corresponding N-glycosylated amides or nucleosides in good to excellent yields with 1,2-trans-stereoselectivity. Moreover, by the addition of terpyridine, the 1,2-cis-stereoselectivity was achieved.

Cooperatively Catalyzed Activation of Thioglycosides That Bypasses Intermediacy of Glycosyl Halides.

Reported herein is the development of a novel method for activating thioglycosides without a glycosyl halide intermediate. This has been achieved through the use of a silver salt coupled with an acid additive and molecular iodine. The enhanced stereocontrol was achieved via the H-bond mediated aglycone delivery (HAD) method, and the extended trisaccharide synthesis was achieved via iteration of deprotection and glycosylation steps.

A Photoinduced, Nickel-Catalyzed Reaction for the Stereoselective Assembly of C-Linked Glycosides and Glycopeptides.

C-Alkyl glycosides and glycoproteins exist in natural products and are prized for their role as carbohydrate mimics in drug design. However, a practical strategy that merges glycosyl donors with readily accessible reagents, derived from abundant carboxylic acid and amine feedstocks, is yet to be conceived. Herein, we show that a nickel catalyst promotes C-C coupling between glycosyl halides and aliphatic acids or primary amines (converted into redox-active electrophiles in one step), in the presence of Hantzsch ester and LiI (or Et3 N) under blue LED illumination to deliver C-alkyl glycosides with high diastereoselectivity. Mechanistic studies support the photoinduced formation of alkyl radicals that react with a glycosyl nickel species generated in situ to facilitate cross-coupling. Through this manifold, innate CO2 H and NH2 motifs embedded within amino acids and oligopeptides are selectively capped and functionalized to afford glycopeptide conjugates through late-stage glycosylation.

A Photoinduced, Nickel‐Catalyzed Reaction for the Stereoselective Assembly of C‐Linked Glycosides and Glycopeptides

AbstractC‐Alkyl glycosides and glycoproteins exist in natural products and are prized for their role as carbohydrate mimics in drug design. However, a practical strategy that merges glycosyl donors with readily accessible reagents, derived from abundant carboxylic acid and amine feedstocks, is yet to be conceived. Herein, we show that a nickel catalyst promotes C−C coupling between glycosyl halides and aliphatic acids or primary amines (converted into redox‐active electrophiles in one step), in the presence of Hantzsch ester and LiI (or Et3N) under blue LED illumination to deliver C‐alkyl glycosides with high diastereoselectivity. Mechanistic studies support the photoinduced formation of alkyl radicals that react with a glycosyl nickel species generated in situ to facilitate cross‐coupling. Through this manifold, innate CO2H and NH2 motifs embedded within amino acids and oligopeptides are selectively capped and functionalized to afford glycopeptide conjugates through late‐stage glycosylation.

Synthesis of selenium linked disaccharides using glycosyl selenocyanates as selenium precursors

A library of selenium linked pseudodisaccharide derivatives has been prepared in very good yield in one-pot by the hydrolysis of glycosyl selenocyanate derivatives using sodium borohydride followed by treatment of the in situ generated glycosyl selenols with anomeric glycosyl halides. Stable glycosyl selenocyanate derivative were used as selenium precursors. Exclusive formation of β-linked selenoglycoside derivatives was observed under the reaction conditions.

Catalytic Multicomponent Synthesis ofC‐Acyl Glycosides by Consecutive Cross‐Electrophile Couplings

AbstractC‐Acyl glycosides are versatile intermediates to natural products and medicinally relevant entities. Conventional cross‐coupling strategies to secure these molecules often relied on two‐component manifolds in which a glycosyl precursor is coupled with an acyl donor (pre‐synthesized or generated in situ) under transition metal or dual catalysis to forge a C−C bond. Here, we disclose a three‐component Ni‐catalyzed reductive regime that facilitates the chemoselective union of glycosyl halides, organoiodides and commercially available isobutyl chloroformate as a CO surrogate. The method tolerates multiple functionalities and the resulting products are obtained in high diastereoselectivities. Theoretical calculations provide a mechanistic rationale for the unexpectedly high chemoselectivity of sequential cross‐electrophile couplings. This approach enables the expeditious assembly of difficult‐to‐synthesizeC‐acyl glycosides, as well as late‐stage keto‐glycosylation of oligopeptides.

Catalytic Multicomponent Synthesis of C-Acyl Glycosides by Consecutive Cross-Electrophile Couplings.

C-Acyl glycosides are versatile intermediates to natural products and medicinally relevant entities. Conventional cross-coupling strategies to secure these molecules often relied on two-component manifolds in which a glycosyl precursor is coupled with an acyl donor (pre-synthesized or generated in situ) under transition metal or dual catalysis to forge a C-C bond. Here, we disclose a three-component Ni-catalyzed reductive regime that facilitates the chemoselective union of glycosyl halides, organoiodides and commercially available isobutyl chloroformate as a CO surrogate. The method tolerates multiple functionalities and the resulting products are obtained in high diastereoselectivities. Theoretical calculations provide a mechanistic rationale for the unexpectedly high chemoselectivity of sequential cross-electrophile couplings. This approach enables the expeditious assembly of difficult-to-synthesize C-acyl glycosides, as well as late-stage keto-glycosylation of oligopeptides.

Zinc Acetate Catalyzed Stereoselective 1,2-trans-Glycosylation Using Glycosyl Chlorides

AbstractWe report a strategy for the stereoselective synthesis of 1,2-trans-glycosides in the absence of neighboring group participation. The present protocol for the selective glycosylation mainly relies on catalyst control rather than protecting group selection. By using this protocol, several glycosides were prepared. Zinc acetate was found to be the optimal catalyst, providing the desired 1,2-trans-glycosides from glucose- and mannose-derived glycosyl halides at room temperature instead of low-temperature conditions.

Remote C-H Glycosylation by Ruthenium(II) Catalysis: Modular Assembly of meta-C-Aryl Glycosides.

The prevalence of C-aryl glycosides in biologically active natural products and approved drugs has long motivated the development of efficient strategies for their selective synthesis. Cross-couplings have been frequently used, but largely relied on palladium catalyst with prefunctionalized substrates, while ruthenium-catalyzed C-aryl glycoside preparation has thus far proven elusive. Herein, we disclose a versatile ruthenium(II)-catalyzed meta-C-H glycosylation to access meta-C-aryl glycosides from readily available glycosyl halide donors. The robustness of the ruthenium catalysis was reflected by mild reaction conditions, outstanding levels of anomeric selectivity and exclusive meta-site-selectivity.

Synthesis and Glycosidation of Anomeric Halides: Evolution from Early Studies to Modern Methods of the 21st Century.

Advances in synthetic carbohydrate chemistry have dramatically improved access to common glycans. However, many novel methods still fail to adequately address challenges associated with chemical glycosylation and glycan synthesis. Since a challenge of glycosylation has remained, scientists have been frequently returning to the traditional glycosyl donors. This review is dedicated to glycosyl halides that have played crucial roles in shaping the field of glycosciences and continue to pave the way toward our understanding of chemical glycosylation.

Convenient synthesis of mixed S–Se-linked pseudodisaccharides by sulfur and selenium exchange

A one-pot reaction methodology has been developed for the preparation of mixed S–Se-linked pseudodisaccharides by the treatment of glycosyl halides with a combination sodium sulfide nonahydrate (Na2S⋅9H2O) and carbon disulfide (CS2) in the presence of alkyl and glycosyl diselenides. The reaction condition is fast, odourless, high yielding and suitable for scale-up synthesis. Exclusive formation of anomerically beta-linked products was obtained from anomeric glycosyl bromides.

Synthesis of selenoglycosides and selenium linked disaccharides using reductive cleavage of diselenides

Reduction of diselenides using a combination of hydrazine monohydrate and potassium hydroxide (KOH) followed by the treatment of the selenolate ions generated in situ with glycosyl halides under a one-pot, two-step phase transfer reaction condition resulted in the formation of beta-selenoglycosides in excellent yield. In addition, selenium linked disaccharide derivatives with beta-glycosidic linkages were also prepared by the reductive cleavage of diglycosyl diselenide derivatives in very good yield. The reaction condition is non-hazardous and high yielding for scaling up.

Black Swan in Phase Transfer Catalysis: Influence of Mixing Mode on the Stereoselectivity of Glycosylation

AbstractPhase transfer catalysis (PTC) is widely used for the preparation of anomerically pure aryl glycosides by glycosylation of phenols with glycosyl halides. Here, we attempted to synthesize 4‐(3‐chloropropoxy)phenyl (CPP) sialoside – a useful Janus glycoside for neoglycoconjugate synthesis. A batch glycosylation reaction under typical PTC conditions (N‐acetylsialyl chloride, 4‐(3‐chloropropoxy)phenol, Bu4NHSO4, AcOEt, 10 % aq Na2CO3) resulted in formation of CPP sialoside as a single anomer, albeit in low yield. Conversely, the PTC glycosylation in flow using Comet X‐01 micromixer doubled the yield of CPP sialoside, which was obtained as a mixture of anomers suggesting the change in the reaction mechanism apparently induced by the change in mixing mode. An increase in flow rate led to further loss of stereoselectivity while the use of T‐shaped mixer increased stereoselectivity. Similar results were obtained for N,N‐diacetylsialyl chloride and two other para‐alkoxy‐substituted phenols suggesting generality of the discovered phenomenon.

Pathways in the synthesis of functionalized glycolipids for liposomal preparations

We describe in this paper the synthesis of two glycolipids containing a mannosyl residue functionalized with malonic acid and azide groups at the C6 position. Two synthetic routes have been successfully implemented: the first one involves Schmidt’s glycosylation procedure using functionalized carbohydrates, whereas the second one involves nucleophilic substitutions in the C6 position of an iodinated intermediate obtained using Koenigs-Knorr reaction. A comparative discussion of reactions and yields is realized. The two glycolipids served as material for the preparation of liposomes.

Synthesis of C-Mannosylated Glycopeptides Enabled by Ni-Catalyzed Photoreductive Cross-Coupling Reactions.

The biological functions of tryptophan C-mannosylation are poorly understood, in part, due to a dearth of methods for preparing pure glycopeptides and glycoproteins with this modification. To address this issue, efficient and scalable methods are required for installing this protein modification. Here, we describe unique Ni-catalyzed cross-coupling conditions that utilize photocatalysis or a Hantzsch ester photoreductant to couple glycosyl halides with (hetero)aryl bromides, thereby enabling the α-C-mannosylation of 2-bromo-tryptophan, peptides thereof, and (hetero)aryl bromides more generally. We also report that 2-(α-d-mannopyranosyl)-L-tryptophan undergoes facile anomerization in the presence of acid: something that must be considered when preparing and handling peptides with this modification. These developments enabled the first automated solid-phase peptide syntheses of C-mannosylated glycopeptides, which we used to map the epitope of an antibody, as well as providing the first verified synthesis of Carmo-HrTH-I, a C-mannosylated insect hormone. To complement this approach, we also performed late-stage tryptophan C-mannosylation on a diverse array of peptides, demonstrating the broad scope and utility of this methodology for preparing glycopeptides.

Improved Synthesis of 1‐Glycosyl Thioacetates and Its Application in the Synthesis of Thioglucoside Gliflozin Analogues

AbstractAn improved method to synthesize 1‐glycosyl thioacetates was developed, where per‐O‐acetylated glycoses were allowed to directly react with potassium thioacetate (KSAc) in the presence of BF3 ⋅ Et2O in ethyl acetate under mild conditions. This method not only overcomes the disadvantage of the traditional one‐step method, which is that the odorous and toxic thioacetic acid has to be used, but also overcomes the disadvantage of the traditional two‐step method, which is that the unstable intermediate, glycosyl halide, has to be synthesized from the per‐O‐acetylated glycose in advance. Based on this, the per‐O‐acetylated glucosyl disulfide and the per‐O‐acetylated glucosyl 1‐thiol were efficiently synthesized in high yields (91 % and 90 % respectively) starting from per‐O‐acetylated glycoses in two‐step without the need to isolate intermediate products. Through metal‐catalyzed cross‐coupling of per‐O‐acetylated glucosyl 1‐thiol with aryl‐iodide under very mild conditions, two thioglucoside gliflozin analogues were efficiently synthesized in high yields for the first time. These two thioglucoside gliflozin analogues were further confirmed to be stable to hydrolysis of β‐glucosidase.

Boronic Acid-Catalyzed Regioselective Koenigs-Knorr-Type Glycosylation.

Boronic acid-catalyzed regioselective Koenigs-Knorr-type glycosylation is presented. The reaction of an unprotected or partially protected glycosyl acceptor with a glycosyl halide donor in the presence of silver oxide and a low catalytic amount of imidazole-containing boronic acid was found to proceed smoothly, which enables construction of a 1,2-trans glycosidic linkage with high regioselectivities. This is the first example of the use of a boronic acid catalyst to initiate regioselective glycosylation via the activation of cis-vicinal diols in glycosyl acceptors.

Phenanthroline-Catalyzed Stereoselective Formation of α-1,2-cis 2-Deoxy-2-Fluoro Glycosides.

Phenanthroline is a heterocyclic aromatic organic compound and commonly used in coordination chemistry acting as a bidentate ligand. The C4 and C7 positions of phenanthroline can often be substituted to change the binding capabilities of the ligand. Recently, there has been a push in the field of chemistry to create environmental-friendly chemical methodologies by utilizing catalysts and minimizing solvent. Herein, we have illustrated how, at high concentrations with minimal use of solvent, the C4 and C7 positions of phenanthroline can be tuned to develop an efficient and stereoselective catalyst for the formation of α-1,2-cis-fluorinated glycosides. By activating 2-deoxy-2-fluoro glycosyl halides with phenanthroline-based catalysts, we have been able to achieve glycosylations with high levels of α-selectivities and moderate to high yields. The catalytic system has been applied to several glycosyl halide electrophiles with a range of glycosyl nucleophilic acceptors. The proposed mechanism for this catalytic glycosylation system has been investigated by density functional theory calculations, indicating that the double SN2 displacement pathways with phenanthroline catalysts have lower barriers and ensure stereoselective formation of α-1,2-cis-2-fluoro glycosides.