Direct synthesis of diastereomerically pure glycosyl sulfonium salts

It is reported that stable glycosyl sulfonium salts can be generated via direct anomeric S-methylation of ethylthioglycosides. Mechanistically, this pathway represents the first step in the activation of thioglycosides for glycosidation; however, it can further allow for the synthesis and isolation of quasi-stable sulfonium ions, representing a new approach for studying these key intermediates.     

α‐ and β‐Glycosyl Sulfonium Ions: Generation and Reactivity

Low‐temperature electrochemical oxidation of thioglycosides gave glycosyl triflates from which glycosyl sulfonium ions were produced (see scheme). The latter were characterized by NMR spectroscopy and cold‐spray mass spectrometry as a mixture of α‐ and β‐isomers (45:55). The α‐glycosyl sulfonium ion exhibited higher reactivity than the β‐glycosyl sulfonium ion in the reaction with methanol, which gave a mixture of α‐ and β‐methyl glycosides (41:59).

     

Mechanistic Investigations into the Application of Sulfoxides in Carbohydrate Synthesis

The utility of sulfoxides in a diverse range of transformations in the field of carbohydrate chemistry has seen rapid growth since the first introduction of a sulfoxide as a glycosyl donor in 1989. Sulfoxides have since developed into more than just anomeric leaving groups, and today have multiple roles in glycosylation reactions. These include as activators for thioglycosides, hemiacetals, and glycals, and as precursors to glycosyl triflates, which are essential for stereoselective β‐mannoside synthesis, and bicyclic sulfonium ions that facilitate the stereoselective synthesis of α‐glycosides. In this review we highlight the mechanistic investigations undertaken in this area, often outlining strategies employed to differentiate between multiple proposed reaction pathways, and how the conclusions of these investigations have and continue to inform upon the development of more efficient transformations in sulfoxide‐based carbohydrate synthesis.     

Stereoselective assembly of complex oligosaccharides using anomeric sulfonium ions as glycosyl donors

The development of selectively protected monosaccharide building blocks that can reliably be glycosylated with a wide variety of acceptors is expected to make oligosaccharide synthesis a more routine operation. In particular, there is an urgent need for the development of modular building blocks that can readily be converted into glycosyl donors for glycosylations that give reliably high 1,2-cis-anomeric selectivity. We report here that 1,2-oxathiane ethers are stable under acidic, basic, and reductive conditions making it possible to conduct a wide range of protecting group manipulations and install selectively removable protecting groups such as levulinoyl (Lev) ester, fluorenylmethyloxy (Fmoc)- and allyloxy (Alloc)-carbonates, and 2-methyl naphthyl ethers (Nap). The 1,2-oxathiane ethers could easily be converted into bicyclic anomeric sulfonium ions by oxidization to sulfoxides and arylated with 1,3,5-trimethoxybenzene. The resulting sulfonium ions gave high 1,2-cis-anomeric selectivity when glycosylated with a wide variety of glycosyl acceptors including properly protected amino acids, primary and secondary sugar alcohols and partially protected thioglycosides. The selective protected 1,2-oxathianes were successfully employed in the preparation of a branched glucoside derived from a glycogen-like polysaccharide isolated form the fungus Pseudallescheria boydii , which is involved in fungal phagocytosis and activation of innate immune responses. The compound was assembled by a latent-active glycosylation strategy in which an oxathiane was employed as an acceptor in a glycosylation with a sulfoxide donor. The product of such a glycosylation was oxidized to a sulfoxide for a subsequent glycosylation. The use of Nap and Fmoc as temporary protecting groups made it possible to install branching points.     

Sulfide-mediated dehydrative glycosylation

The development of a new method for glycosylation with 1-hydroxy glycosyl donors employing dialkyl sulfonium reagents is described. The process employs the reagent combination of a dialkyl sulfide and triflic anhydride to effect anomeric bond constructions. This controlled dehydrative coupling of various C(1)-hemiacetal glycosyl donors and nucleophilic acceptors proceeds by way of a sulfide-to-sulfoxide oxidation process in which triflic anhydride serves as the oxidant.     

Do Glycosyl Sulfonium Ions Engage in Neighbouring‐Group Participation? A Study of Oxathiane Glycosyl Donors and the Basis for their Stereoselectivity

Neighbouring‐group participation has long been used to control the synthesis of 1,2‐trans‐glycosides. More recently there has been a growing interest in the development of similar strategies for the synthesis of 1,2‐cis‐glycosides, in particular the use of auxiliary groups that generate sulfonium ion intermediates. However, there has been some debate over the role of sulfonium ion intermediates in these reactions: do sulfonium ions actually engage in neighbouring‐group participation, or are they a resting state of the system prior to reaction through an oxacarbenium ion intermediate? Herein, we describe the reactivities and stereoselectivities of a family of bicyclic thioglycosides in which an oxathiane ring is fused to the sugar to form a trans‐decalin‐like structure. A methyl sulfonium ion derived from one such glycosyl donor is so stable that it can be crystallised from ethanol, yet it reacts with complete stereoselectivity at high temperature. The importance of a ketal group in the oxathiane ring for maintaining this high stereoselectivity is investigated using a combination of experiment and ab initio calculations. The data are discussed in terms of S_N1 and S_N2 type mechanisms. Trends in stereoselectivity across a series of compounds are more consistent with selective addition to oxacarbenium ions rather than a shift between S_N1 and S_N2 mechanisms.     

Communication: Synthetic Studies on Sialoglycoconjugates 25: Reactivity of Glycosyl Promoters in α-Glycosylation of N-Acetyl-Neuraminic Acid with the Primary and Secondary Hydroxyl Groups in the Suitably Protected Galactose and Lactose Derivatives

Development of an efficient α-glycoside synthesis of sialic acids is critically significant for the syntheses of sialoglycoconjugates, especially gangliosides which carry important biological functions¹ in biological systems. Previously, we demonstrated² a new α-glycosylation of sialic acids by use of dimethyl(methylthio)sulfonium triflate (DMTST)³ as the glycosyl promoter, the suitably protected glycosyl acceptors and the methyl 2-thioglycoside 1 of N-acetylneuraminic acid (Neu5Ac) as the donor in acetonitrile under kinetically controlled conditions, and accomplished⁴ the syntheses of a variety of gangliosides and their analogs.     

Directional Preferences of Approach of Nucleophiles to Sulfonium Ions

An analysis of the crystal environments of sulfonium ions shows that short nonbonded contacts (secondary bonds) to sulfur tend to occur along the extensions of the C-S primary bonds. Non-bonded contacts to the C (a)-atoms of sulfonium ions are not especially short and do not show any striking directional preference, except in sulfonium ions derived from methionine where a specific intramolecular interaction between a carboxyl O-atom and the C (γ)-atom may represent an incipient stage of the internal nucleophilic displacement leading to formation of homoserine and mercaptan.     

A general strategy for stereoselective glycosylations

The principal challenge that the synthesis of oligosaccharides of biological importance presents is the development of a general approach for the stereoselective introduction of a glycosidic linkage. It is shown here that a (1S)-phenyl-2-(phenylsulfanyl)ethyl moiety at C-2 of a glycosyl donor can perform neighboring group participation to give a quasi-stable anomeric sulfonium ion. Due to steric and electronic factors, the sulfonium ion is formed as a trans-decalin ring system. Displacement of the sulfonium ion by a hydroxyl leads to the stereoselective formation of alpha-glycosides. NMR experiments were employed to show convincingly the presence of the beta-linked sulfonium ion intermediate. The (1S)-phenyl-2-(phenylsulfanyl)ethyl moiety could be introduced by reaction of a sugar alcohol with acetic acid (1S)-phenyl-2-(phenylsulfanyl)ethyl ester in the presence of BF(3)-OEt(2). Furthermore, it could be removed by conversion into acetate by treatment with BF(3)-OEt(2) in acetic anhydride. The introduction as well as the cleavage reaction proceeds through the formation of an intermediate episulfonium ion. The use of the new methodology in combination with traditional neighboring group participation by esters to introduce beta-glycosides makes it possible, for the first time, to synthesize a wide variety of oligosaccharides by routine procedures. The latter was demonstrated by the synthesis of the Galili trisaccharide, which has been identified as an epitope that can trigger acute rejections in xeno-transplantations, by the one-pot two-step glycosylation sequence.     

Probing the mechanism of sulfoxide-catalyzed hemiacetal activation in dehydrative glycosylation

The concept of sulfoxide-covalent catalysis has been established in the context of a versatile hemiacetal hydroxyl activation/substitution reaction for the formation of anomeric linkages. Mechanistic studies focused on the hemiacetal activation process show that this transformation proceeds in the presence of a sulfonic anhydride and an acid scavenger through the intermediacy of a glycosyl sulfonate species (10), which serves as a resting state prior to the addition of an external nucleophile and subsequent glycosidic bond formation. Successful determination of the proportion of (18)O incorporation in 10 as a function of its formation, via the technique of dynamic monitoring of (13)C-(16/18)O isotopic chemical shift perturbations, provides strong evidence that hemiacetal activation proceeds through initial nucleophilic addition of the hemiacetal hydroxyl to the S(IV)-center of putative sulfonium sulfonate 6. Further confirmation was obtained through the independent synthesis, structure verification, and (1)H NMR detection of glycosyl oxosulfonium 11 during the sulfoxide-catalyzed conversion of hemiacetal 3 to glycosyl sulfonate 10.     

Synthetic Studies on Sialoglycoconjugates 16: α-Predominant Glycoside Synthesis of N-Acetylneuraminic Acid With the Primary Hydroxyl Group in Carbohydrates Using Dimethyl(Methylthio)Sulfonium Triflate as a Glycosyl Promoter

ABSTRACT

Coupling of the primary hydroxyl group in the suitably protected 2-(trimethylsilyl)ethyl glycosides of D-glucopyranose (3), N-acetyl-D-glucosamine (7), N-acetyl-D-galactosamine (9), D-lactose (10), and N-acetylneuraminic acid (11), with methyl (methyl 5-acetamido-4, 7,8, 9-tetra-O-acetyl-3, 5-dideoxy-2-thio-D-glycero-α-D-galacto-2-nonulopyranosid)onate (12) as the glycosyl donor in acetonitrile in the presence of dimethyl(methylthio)sulfonium triflate (DMTST) as a glycosyl promoter and molecular sieves 3A, gave predominantly the corresponding α-glycosides 13, 15, 17, 25, and 29 of N-acetylneuraminic acid in 43-71% yields, respectively, together with the ß-glycosides (13-24%).     

Tris(trimethylsilyl)sulfonium and methylbis(trimethylsilyl)sulfonium ions: preparation, NMR spectroscopy, and theoretical studies(1)

Tris(trimethylsilyl)sulfonium 1 and methylbis(trimethylsilyl)sulfonium 2 ions were prepared as long-lived species by reacting trimethylsilane and trityl tetrakis(pentafluorophenyl)borate (Ph(3)C(+) TPFPB) in the presence of precursor sulfides and characterized by (1)H, (13)C, and (29)Si NMR spectroscopy at -78 degrees C. Attempted preparation of dimethyl(trimethylsilyl)sulfonium ion under similar conditions failed as a result of the formation of the more stabilized trimethylsulfonium ion. Structures, and (13)C and (29)Si NMR chemical shifts were calculated by density functional theory (DFT)/IGLO methods. The calculated results agree well with the experimental data.     

Ion chromatographic analysis of the purity and synthesis of sulfonium and selenonium ions.

The use of single-column ion chromatography with conductometric detection was shown to be useful for the analysis of sulfonium and selenonium ions. A Hamilton PRP X-200 cation column was eluted with either solvent A (5 mM nitric acid in 30% methanol) or solvent B (4 mM nitric acid). With solvent B, trimethylsulfonium ion was separated from trimethylselenonium ion. With solvent A, amounts of trimethylsulfonium ion from 2 to 250 nmol were detected with a linear response. The retention times and response factors for a series of sulfonium ions with various organic groups were determined. In general the ions with more hydrophobic groups eluted later, but all had similar response factors. The method was shown to be useful for optimizing conditions for the synthesis of methylsulfonium ions, specifically the reaction of methyl iodide with diallyl sulfide.     

Single-Step Glycosylations with 13C-Labelled Sulfoxide Donors: A Low-Temperature NMR Cartography of the Distinguishing Mechanistic Intermediates

Glycosyl sulfoxides have gained recognition in the total synthesis of complex oligosaccharides and as model substrates for dissecting the mechanisms involved. Reactions of these donors are usually performed under pre-activation conditions, but an experimentally more convenient single-step protocol has also been reported, whereby activation is performed in the presence of the acceptor alcohol; yet, the nature and prevalence of the reaction intermediates formed in this more complex scenario have comparatively received minimal attention. Herein, a systematic NMR-based study employing both ¹³C-labelled and unlabelled glycosyl sulfoxide donors for the detection and monitoring of marginally populated intermediates is reported. The results conclusively show that glycosyl triflates play a key role in these glycosylations despite the presence of the acceptor alcohol. Importantly, the formation of covalent donor/acceptor sulfonium adducts was identified as the main competing reaction, and thus a non-productive consumption of the acceptor that could limit the reaction yield was revealed.     

Synthesis of Oligosaccharide Structures from the Lipopolysaccharide of Moraxella catarrhalis

The synthesis of the octasaccharide [p-(trifluoroacetamido)phenyl]ethyl 4-O-[2-O-(2-acetamido-2-deoxy-alpha-D-glucopyranosyl)-beta-D-glucopyranosyl]-6-O-[2-O-[4-O-(4-O-alpha-D-galactopyranosyl-beta-D-galactopyranosyl)-alpha-D-glucopyranosyl]-beta-D-glucopyranosyl]-3-O-beta-D-glucopyranosyl-alpha-D-glucopyranoside, representing the outer part of the lipooligosaccharide from Moraxella catarrhalis serotype A, is described, together with a hepta-, a hexa-, and a pentasaccaride, composing parts thereof with shorter oligosaccharide chains substituted in the 6-position of the central 3,4,6-branched glucose moiety. The versatility of the use of thioglycosides in oligosaccharide synthesis is shown, since throughout the synthesis thioglycosides are used as glycosyl donor precursors, either directly in dimethyl(methylthio)sulfonium triflate (DMTST)-promoted coupling reactions or after conversion to the corresponding glycosyl bromide in silver triflate-promoted couplings. The effects of different protecting groups, anomeric leaving groups, and solvents used in the various coupling reactions are often substantial, which necessitates the use of easily convertible intermediates.     

Generation of alkoxycarbenium ion pools from thioacetals and applications to glycosylation chemistry

[reaction: see text] Alkoxycarbenium ions have been generated and accumulated as "cation pools" by the low-temperature electrochemical oxidation of alpha-phenylthioethers. Although an unsuccessful attempt to accumulate glycosyl cations was made, a one-pot method for electrochemical glycosylation, which involves anodic oxidation of thioglycosides to generate glycosyl cation equivalents followed by their reactions with glycosyl acceptors, has been developed.     

Cationic Polymerization of Cyclic Sulfides

Abstract

The mechanism of the cationic polymerization of several thietanes and of propylene sulfide under the influence of triethyloxonium tetrafluoroborate in methylene chloride is described. The thietane polymerizations stop at limited conversions because of a termination reaction occurring between the reactive chain ends (cyclic sulfonium salts) and the sulfur atoms of the polymer chain. The maximum conversions obtained under identical conditions differ markedly for the different monomers. Ratios of rate constants of propagation (k_p) to rate constants of termination (k_t) have been calculated. The differences in k _p/k_t. values for the different monomers are explained in terms of differences in basicity and differences in steric hindrance of the monomers compared to the corresponding polymers. In the case of propylene sulfide it is proposed that the main termination reaction is the formation of 12-membered ring sulfonium salts by an intramolecular reaction of the third sulfur of the growing polymer chain with the reactive chain end (three-membered ring sulfonium salt). This terminated polymer is able to reinitiate the polymerization, for example, by reaction of a monomer molecule at the exocyclic carbon atom of the sulfonium salt function. The cyclic tetramer of propylene sulfide is formed in this reaction. After complete polymerization, formation of cyclic tetramer continues, probably via a backbiting mechanism. In methylene chloride as solvent, the absolute value of the rate constant of propagation for 3,3-dimethylthietane changes with changing concentration of initiator and by adding different amounts of indifferent electrolyte to the reaction mixture. From these changes, and assuming that the value of the dissociation constant of the growing chain-ends is close to values of dissociation constants of low molecular weight sulfonium salts, separate rate constants for propagation via free ions and ion-pairs were calculated. The propagation constant of free ions is about 70 times higher than that of ion pairs in methylene chloride at 20°C. Free ions and ion pairs are nearly equally reactive in nitrobenzene.     

Electrophilic substitution reactions using an electrogenerated ArS(ArSSAr)+ cation pool as an ArS+ equivalent

Arylbis(arylthio)sulfonium ions (ArS(ArSSAr)⁺), which were generated and accumulated by the low-temperature electrolysis of diaryl disulfide (ArSSAr), were found to serve as ArS⁺ equivalent in electrophilic substitution reactions of aromatic compounds, enolizable ketones, enol acetates, ketene silyl acetals and allylsilanes to give the corresponding arylthiolated products.     

Molecular orbital calculations relating to the mechanism of the reactions of sugar orthoesters: 1,2,4-orthoacetyl-α-D-xylopyranose

Quantum chemical studies of 1,2,4-orthoacetyl-α-D-xylopyranose and three protonated forms, four acyloxonium ions, and the glycosyl cation by means of the MINDO/2 method are reported. The protonated forms (oxonium ions) should not be considered as product-determining intermediates in acid-catalysed reactions of ortho-esters due to their fast rearrangement into isomeric acyloxonium ions. Of the latter, only 1,2- and 1,4-acyloxoniums, adopting a conformation close to that of starting orthoester (i.e. a distorted boat), were found to be relatively stable and reactive and so are considered to be the main product-determining intermediates. The distribution of the positive charge in these ions was interpreted as evidence of preferred nucleophilic attack on C-1 rather than on other centres of these ions. The isomerisation of the 1,2-acyloxonium ion into the glycosyl cation was found to be energetically very unlikely and so would be product determining only in fast, especially intramolecular, reactions. The results obtained were in good agreement with qualitative data on the chemistry of sugar orthoesters.     

Über die Anlagerung von Thioäthern an Chinone und Chinonimine in stark sauren Medien

By adding thioethers to protonated quinones or quinone imines, hydroquinone sulfonium compounds are prepared in good yields. A mechanism running over carbenium ions is proposed.