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.     

Stereoselectivity investigation on glycosylation of oxazolidinone protected 2-amino-2-deoxy-d-glucose donors based on pre-activation protocol

Diverse 2,3-oxazolidinone protected 2-amino-2-deoxy-d-glucose thioglycosides were prepared and studied as glycosyl donors at low temperature by BSM/Tf₂O pre-activation protocol before the addition of glycosyl acceptors. The stereochemistry outcomes of a series of glycosylations were investigated. Different stereoselectivities of the coupling reactions were obtained, arising from the different protecting groups in the oxazolidinone donors. 4,6-Di-O-benzyl-N-benzyl-oxazolidinone protected thioglycoside donor 1c underwent glycosylation with general β-anomeric selectivity and the stereoselectivity could be also affected by glycosylation conditions.     

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.     

Relevance of the glycosyl donor to the regioselectivity of glycosidation of primary-secondary diol acceptors and application of these ideas to in situ three-component double differential glycosidation

[reaction: see text] Three pairs of primary-secondary diol acceptors have been exposed to armed, disarmed, and n-pentenyl ortho ester glycosyl donors in glycosidation reactions. It is shown that the regioselectivity of those glycosylations is greatly influenced by the armed, disarmed, or ortho ester nature of the glycosyl donors. The selectivities observed have been used to devise efficient in situ three-component glycosylations involving two donors and one acceptor.     

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.     

Synthesis of a pentasaccharide repeating unit of the O-antigen of enteroadherent Escherichia coli O154 strain

A straightforward linear synthetic strategy has been developed for the synthesis of the pentasaccharide repeating unit of the cell wall O-antigenic polysaccharide of enteroadherent Escherichia coli O154 strain. Newly developed glycosylation conditions using glycosyl trichloroacetimidate derivatives as glycosyl donors and nitrosyl tetrafluoroborate as the glycosylation activator have been used in all of the glycosylation reactions throughout the synthetic scheme. The stereochemical outcomes of the glycosylations were excellent and the yields were very good.     

S-Benzoxazolyl (SBox) glycosides as novel,versatile glycosyl donors for stereoselective 1,2-cis glycosylation

[reaction: see text] Novel glycosyl donors, S-benzoxazolyl (SBox) glycosides, have been synthesized, tested toward various protecting group manipulations, and applied to the highly stereoselective 1,2-cis glycosylation. These compounds fulfill the requirements for a modern glycosyl donor such as accessibility, high stability toward protecting group manipulations, and mild activation conditions. It was also demonstrated that SBox glycosides withstand other glycosyl donor activation conditions and therefore allow selective glycosylations of O-pentenyl and thioglycosides.     

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.     

Towards the preparation of 2″-deoxy-2″-fluoro-adenophostin A. Study of the glycosylation reaction

The synthesis of 2″-deoxy-2″-fluoro-adenophostin A framework starting from tri-O-acetylglucal and adenosine is described. The key steps are the formation of the 2-deoxy-2-fluoroglycosyl donor by electrophilic fluorination of tri-O-acetylglucal and the stereoselective glycosylation of a suitable adenosine derivative. The glycosylation reaction was optimized affording the desired 2″-deoxy-2″-fluoroglycoside with excellent α-stereoselectivity and in good yields, taking into account that glycosylations using nucleosides as glycosyl acceptors do not usually give excellent results. In that sense, an improvement of the glycosylation step with respect to that of the reported adenophostin synthesis, using adenosine derivatives as glycosyl donors, has been made.     

Expanding the scope of aminosugars: synthesis of 2-amino septanosyl glycoconjugates using septanosyl fluoride donors

A general strategy amenable to the strerocontrolled synthesis of complex, ring-expanded analogues of natural aminoglycosides has been developed. Central to the method is the utilization of septanosyl fluorides as glycosyl donors in facile and selective glycosylation reactions. The septanosyl fluorides proved to be the best choice for the glycosylations because of their accessibility and the scope of aglycones that they could glycosylate. Moreover, a high degree of stereoselectivity was observed in the glycosylations, exclusively giving 1,2-trans-glycosides. 2-Amino septanosyl fluorides were prepared from D-glucose, D-galactose, and D-mannose. Other routes to the septanosyl glyconjugates, especially with regard to alternate donor types, were systematically investigated. Since routes to the individual donor types were being explored, factors that exert a controlling influence on the acid-mediated cyclization of 1,6-hydroxy-aldehydes were determined. The newly prepared 2-amino septanosyl glycoconjugates illustrate the scope of the reaction and how it may be utilized for the preparation of other ring-expanded analogues of glycosylated natural products.     

Stereoselective 1,2-cis glycosylation of 2-O-allyl protected thioglycosides

The technique of intramolecular aglycon delivery (IAD), whereby a glycosyl acceptor is temporarily appended to a hydroxyl group of a glycosyl donor is an attractive method that can allow the synthesis of 1,2-cis glycosides in an entirely stereoselective fashion. 2-O-Allyl protected thioglycoside donors are excellent substrates for IAD, and may be glycosylated stereoselectively through a three-step reaction sequence. This sequence consists of quantitative yielding allyl bond isomerisation, to produce vinyl ethers that can then undergo N-iodosuccinimide mediated tethering of the desired glycosyl acceptor, and subsequent intramolecular glycosylation, to yield either alpha-glucosides or beta-mannosides accordingly. Although attempted one-pot tethering and glycosylation is hampered by competitive intermolecular reaction with excess glycosyl acceptor, this problem can be simply overcome by the use of excess glycosyl donor. Allyl mediated IAD is a widely applicable practical alternative to other IAD approaches for the synthesis of beta-mannosides, that is equally applicable for alpha-gluco linkages. It is advantageous in terms of both simplicity of application and yield, and in addition has no requirement for cyclic 4,6-protection of the glycosyl donor.     

Matched/Mismatched Interactions in Chiral Brønsted Acid-Catalyzed Glycosylation Reactions with 2-Deoxy-Sugar Trichloroacetimidate Donors

The stereochemical outcome of glycosylation reactions of 2-deoxy-sugar trichloroacetimidates promoted by chiral Brønsted acids is shown to be dependent on both the chirality of the catalyst and the configuration of the leaving group. High levels of selectivity (1:16 α:β) can be obtained with (S)-catalysts and an α-trichloroacetimidate donor. Conversely, (R)-catalysts require longer reaction times and provide the product in much lower selectivity (6.6:1 α:β). These observations demonstrate that stereochemical “match” and “mismatch” between donor and acceptor are important factors in chiral Brønsted acid-promoted glycosylations.     

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.     

Factors affecting stereocontrol during glycosidation of 2,3-oxazolidinone-protected 1-tolylthio-N-acetyl-D-glucosamine

[reaction: see text] It is demonstrated that a ring-fused 2,3-oxazolidinone-protected derivative of 1-tolylthio-N-acetyl-D-glucosamine undergoes high-yield glycosidation under mild donor activation conditions. Stereoselective formation of alpha-linked or beta-linked glycosides is dependent on reactivity of acceptor alcohols, where rate of glycosidation correlates to stereochemical outcome. Evidence for the role of glycosyl triflate intermediates and the N-acetyl substituent of the 2N,3O-oxazolidinone ring in stereochemical control is presented.     

Studies on the Selectivity Between Nickel-Catalyzed 1,2-cis-2-Amino Glycosylation of Hydroxyl Groups of Thioglycoside Acceptors with C(2)-Substituted Benzylidene N-Phenyl Trifluoroacetimidates and Intermolecular Aglycon Transfer of the Sulfide Group

The stereoselective synthesis of saccharide thioglycosides containing 1,2-cis-2-amino glycosidic linkages is challenging. In addition to the difficulties associated with achieving high α-selectivity in the formation of 1,2-cis-2-amino glycosidic bonds, the glycosylation reaction is hampered by undesired transfer of the anomeric sulfide group from the glycosyl acceptor to the glycosyl donor. Overcoming these obstacles will pave the way for the preparation of oligosaccharides and glycoconjugates bearing the 1,2-cis-2-amino glycosidic linkages because the saccharide thioglycosides obtained can serve as donors for another coupling iteration. This approach streamlines selective deprotection and anomeric derivatization steps prior to the subsequent coupling event. We have developed an efficient approach for the synthesis of highly yielding and α-selective saccharide thioglycosides containing 1,2-cis-2-amino glycosidic bonds, via cationic nickel-catalyzed glycosylation of thioglycoside acceptors bearing the 2-trifluoromethylphenyl aglycon with N-phenyl trifluoroacetimidate donors. The 2-trifluoromethylphenyl group effectively blocks transfer of the anomeric sulfide group from the glycosyl acceptor to the C(2)-benzylidene donor and can be easily installed and activated. The current method also highlights the efficacy of the nickel catalyst selectively activating the C(2)-benzylidene imidate group in the presence of the anomeric sulfide group on the glycosyl acceptors.     

Stereoselective Synthesis of 1,1′-Disaccharides by Organoboron Catalysis

The highly stereoselective synthesis of 1,1′-disaccharides was achieved by using 1,2-dihydroxyglycosyl acceptors and glycosyl donors in the presence of a tricyclic borinic acid catalyst. In this reaction, the complexation of the diols and the catalyst is crucial for the activation of glycosyl donors, as well as for the 1,2-cis-configuration of the products. The anomeric stereochemistry of the glycosyl donor depends on the employed glycosyl donor. Applications of the produced 1,1′-disaccharides are also described.     

Stereoselective Synthesis of 1,1′‐Disaccharides by Organoboron Catalysis

The highly stereoselective synthesis of 1,1′‐disaccharides was achieved by using 1,2‐dihydroxyglycosyl acceptors and glycosyl donors in the presence of a tricyclic borinic acid catalyst. In this reaction, the complexation of the diols and the catalyst is crucial for the activation of glycosyl donors, as well as for the 1,2‐cis‐configuration of the products. The anomeric stereochemistry of the glycosyl donor depends on the employed glycosyl donor. Applications of the produced 1,1′‐disaccharides are also described.     

Installation of electron-donating protective groups, a strategy for glycosylating unreactive thioglycosyl acceptors using the preactivation-based glycosylation method

Preactivation-based chemoselective glycosylation is a powerful strategy for oligosaccharide synthesis with its successful application in assemblies of many complex oligosaccharides. However, difficulties were encountered in reactions where glycosyl donors bearing multiple electron-withdrawing groups failed to glycosylate hindered unreactive acceptors. In order to overcome this problem, it was discovered that the introduction of electron-donating protective groups onto the glycosyl donors can considerably enhance their glycosylating power, leading to productive glycosylations even with unreactive acceptors. This observation is quite general and can be extended to a wide range of glycosylation reactions, including one-pot syntheses of chondroitin and heparin trisaccharides. The structures of the reactive intermediates formed upon preactivation were determined through low-temperature NMR studies. It was found that for a donor with multiple electron-withdrawing groups, the glycosyl triflate was formed following preactivation, while the dioxalenium ion was the major intermediate with a donor bearing electron-donating protective groups. As donors were all cleanly preactivated prior to the addition of the acceptors, the observed reactivity difference between these donors was not due to selective activation encountered in the traditional armed-disarmed strategy. Rather, it was rationalized by the inherent internal energy difference between the reactive intermediates and associated oxacarbenium ion like transition states during nucleophilic attack by the acceptor.     

Semisynthesis of fuscoside B analogues and eunicosides, and analysis of anti-inflammatory activity

A small library of semisynthetic analogues of fuscol and eunicol have been prepared and evaluated for in vivo topical anti-inflammatory activity using the mouse-ear edema assay. The first glycosylation of fuscol and eunicol has been achieved using a modified Koenigs-Knorr glycosylation to synthesize new fuscosides and eunicosides, a novel structural class of diterpene glycosides. The availability of adequate glycosylation methods for this synthesis was limited owing to the instability of the glycosyl acceptors. Glycosyl donor protecting group type had a pronounced effect on overall glycosylation yields of a model glycosyl acceptor. This synthesis provided access to the unnatural β-glycosides allowing for an evaluation of the effect of differing anomeric stereochemistry on anti-inflammatory activity. The PEGylated derivatives of fuscol and eunicol were also synthesized by a convenient acid-promoted solvolysis of the natural product aglycones. This work highlights the importance of the glycan portion of fuscoside B, notably the stereochemical configuration of the glycosidic linkage, in the observed anti-inflammatory activity.     

Synthesis of β-Glucosides with 3-O-Picoloyl-Protected Glycosyl Donors in the Presence of Excess Triflic Acid: A Mechanistic Study

Our previous study showed that picoloylated donors are capable of providing excellent facial stereoselectivity through the H-bond-mediated aglycone delivery (HAD) pathway. Presented herein is a detailed mechanistic study of stereoselective glycosylation with 3-O-picoloylated glucosyl donors. While reactions of glycosyl donors equipped with the 3-O-benzoyl group are typically non-stereoselective because these reactions proceed via the oxacarbenium intermediate, 3-O-picoloylated donors are capable of providing enhanced, but somewhat relaxed, β-stereoselectivity by the HAD pathway. In an attempt to refine this reaction, we noticed that glycosylations are highly β-stereoselective in the presence of NIS and stoichiometric TfOH. The HAD pathway is highly unlikely because the picoloyl nitrogen is protonated under these reaction conditions. The protonation and glycosylation were studied by low-temperature NMR, and the intermediacy of the glycosyl triflate has been observed. This article is dedicated to broadening the scope of this reaction in application to a variety of substrates and targets.