Controlling the chemical glycosylation reaction remains the major challenge in the synthesis of oligosaccharides. Though 1,2-trans glycosidic linkages can be installed using neighboring group ...participation, the construction of 1,2-cis linkages is difficult and has no general solution. Long-range participation (LRP) by distal acyl groups may steer the stereoselectivity, but contradictory results have been reported on the role and strength of this stereoelectronic effect. It has been exceedingly difficult to study the bridging dioxolenium ion intermediates because of their high reactivity and fleeting nature. Here we report an integrated approach, using infrared ion spectroscopy, DFT computations, and a systematic series of glycosylation reactions to probe these ions in detail. Our study reveals how distal acyl groups can play a decisive role in shaping the stereochemical outcome of a glycosylation reaction, and opens new avenues to exploit these species in the assembly of oligosaccharides and glycoconjugates to fuel biological research.
Acceptor reactivity in glycosylation reactions van der Vorm, Stefan; Hansen, Thomas; van Hengst, Jacob M. A ...
Chemical Society reviews,
08/2019, Volume:
48, Issue:
17
Journal Article
Peer reviewed
Open access
The outcome of a glycosylation reaction critically depends on the reactivity of all reaction partners involved: the donor glycoside (the electrophile), the activator (that generally provides the ...leaving group on the activated donor species) and the glycosyl acceptor (the nucleophile). The influence of the donor on the outcome of a glycosylation reaction is well appreciated and documented. Differences in donor reactivity have led to the development of chemoselective glycosylation reactions and the reactivity of donor glycosides has been tuned to affect stereoselective glycosylation reactions. The quantification of donor reactivity has enabled the conception of streamlined one-pot glycosylation sequences. In contrast, although it has long been known that the nature and the reactivity of the nucleophile influence the outcome of a glycosylation, the knowledge of acceptor reactivity and insight into the consequences thereof are often circumstantial or anecdotal. This review documents how the reactivity impacts the glycosylation reaction outcome both in terms of chemical yield and stereoselectivity. The effect of acceptor nucleophilicity on the reaction mechanism is described and steric, conformational and electronic influences are outlined. Quantitative and computational approaches to comprehend acceptor nucleophilicity are assessed. The increasing insight into the stereoelectronic effects governing glycoside reactivity will eventually enable the conception of effective stereoselective glycosylation methodology that can be tuned to the reaction partners at hand.
The effect of the reactivity of the glycosyl acceptor on the outcome of glycosylation reactions is reviewed.
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.
The sweet spot: An operationally simple system to gauge glycosyl acceptor reactivity is presented that employs two conformationally locked donors with stereoselectivity that critically depends on the reactivity of the acceptor. The structure–reactivity/stereoselectivity relationships of a wide array of acceptors were established. The reactivity of glycosyl acceptors can be adjusted by systematically varying the protecting groups to attain stereoselective cis‐glucosylations.
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Glycosylations of 4,6-tethered glucosazide donors with a panel of model acceptors revealed the effect of acceptor nucleophilicity on the stereoselectivity of these donors. The differences in ...reactivity among the donors were evaluated in competitive glycosylation reactions, and their relative reactivities were found to be reflected in the stereoselectivity in glycosylations with a set of fluorinated alcohols as well as carbohydrate acceptors. We found that the 2-azido-2-deoxy moiety is more β-directing than its C-2-O-benzyl counterpart, as a consequence of increased destabilization of anomeric charge development by the electron-withdrawing azide. Additional disarming groups further decreased the α-selectivity of the studied donors, whereas substitution of the 4,6-benzylidene acetal with a 4,6-di-tert-butyl silylidene led to a slight increase in α-selectivity. The C-2-dinitropyridone group was also explored as an alternative for the nonparticipating azide group, but this protecting group significantly increased β-selectivity. All studied donors exhibited the same acceptor-dependent selectivity trend, and good α-selectivity could be obtained with the weakest acceptors and most reactive donors.
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The 3D shape of glycosyl oxocarbenium ions determines their stability and reactivity and the stereochemical course of SN1 reactions taking place on these reactive intermediates is dictated by the ...conformation of these species. The nature and configuration of functional groups on the carbohydrate ring affect the stability of glycosyl oxocarbenium ions and control the overall shape of the cations. We herein map the stereoelectronic substituent effects of the C2‐azide, C2‐fluoride and C4‐carboxylic acid ester on the stability and reactivity of the complete suite of diastereoisomeric furanoses by using a combined computational and experimental approach. Surprisingly, all furanosyl donors studied react in a highly stereoselective manner to provide the 1,2‐cis products, except for the reactions in the xylose series. The 1,2‐cis selectivity for the ribo‐, arabino‐ and lyxo‐configured furanosides can be traced back to the lowest‐energy 3E or E3 conformers of the intermediate oxocarbenium ions. The lack of selectivity for the xylosyl donors is related to the occurrence of oxocarbenium ions adopting other conformations.
Explaining selectivity: A combined experimental and computational approach is used to investigate the stereoselective outcome of glycosylation reactions of differentially substituted furanoses. A high 1,2‐cis selectivity was found for the ribo‐, arabino‐ and lyxo‐configured furanosides, whereas the xylosyl derivatives show a lack of selectivity (see figure).
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The broad application of well-defined synthetic oligosaccharides in glycobiology and glycobiotechnology is largely hampered by the lack of sufficient amounts of synthetic carbohydrate specimens. ...Insufficient knowledge of the glycosylation reaction mechanism thwarts the routine assembly of these materials. Glycosyl cations are key reactive intermediates in the glycosylation reaction, but their high reactivity and fleeting nature have precluded the determination of clear structure–reactivity-stereoselectivity principles for these species. We report a combined experimental and computational method that connects the stereoselectivity of oxocarbenium ions to the full ensemble of conformations these species can adopt, mapped in conformational energy landscapes (CEL), in a quantitative manner. The detailed description of stereoselective SN1-type glycosylation reactions firmly establishes glycosyl cations as true reaction intermediates and will enable the generation of new stereoselective glycosylation methodology.
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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.
Feinabstimmung: Ein einfaches System für die Feinabstimmung der Reaktivität von Glykosylakzeptoren nutzt zwei konformativ fixierte Donoren, deren Stereoselektivität von der Reaktivität des Akzeptors abhängt. Die Struktur‐Reaktivitäts/Stereoselektivitäts‐Beziehungen eines breiten Spektrums von Akzeptoren wurden erforscht. Die Reaktivität der Glykosylakzeptoren kann durch Variieren der Schutzgruppen so abgestimmt werden, dass stereoselektive cis‐Glukosylierungen resultieren.
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Die Stereoselektivität von Glykosylierungen kann ganz zentral von der Reaktivität des Akzeptor‐Glykosids (des Nukleophils in der Reaktion) abhängen. J. D. Codée et al. berichten in ihrer Zuschrift ...auf S. 8372 ff. über ein einfaches System, um die Beziehung zwischen der Reaktivität des Glykosyl‐Akzeptors und der Stereoselektivität der Glykosylierung zu kartieren. Die Feinabstimmung der Reaktivität des Nukleophils durch sorgfältige Wahl der Schutzgruppen ermöglicht stereoselektive 1,2‐cis‐Glykosylierungen.
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A library of positional isomers of d-glucose (O-1–O-6) as ligands and their 11 light-active ruthenium conjugates has been synthesized. A protecting group strategy without the necessity of using ...palladium on carbon for the modification for the 2-O and 4-O position allows for the incorporation of sulfur donor atoms as ligands for transition metal complexes.
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Minimal structural differences in the structure of glycosyl donors can have a tremendous impact on their reactivity and the stereochemical outcome of their glycosylation reactions. Here, we used a ...combination of systematic glycosylation reactions, the characterization of potential reactive intermediates, and in-depth computational studies to study the disparate behavior of glycosylation systems involving benzylidene glucosyl and mannosyl donors. While these systems have been studied extensively, no satisfactory explanations are available for the differences observed between the 3-O-benzyl/benzoyl mannose and glucose donor systems. The potential energy surfaces of the different reaction pathways available for these donors provide an explanation for the contrasting behavior of seemingly very similar systems. Evidence has been provided for the intermediacy of benzylidene mannosyl 1,3-dioxanium ions, while the formation of the analogous 1,3-glucosyl dioxanium ions is thwarted by a prohibitively strong flagpole interaction of the C-2-O-benzyl group with the C-5 proton in moving toward the transition state, in which the glucose ring adopts a B 2,5-conformation. This study provides an explanation for the intermediacy of 1,3-dioxanium ions in the mannosyl system and an answer to why these do not form from analogous glucosyl donors.
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