Mechanism of 4,6‐<i>O</i>‐Benzylidene‐Directed β‐Mannosylation as Determined by α‐Deuterium Kinetic Isotope Effects

Crich, David; Chandrasekera, N. Susantha

doi:10.1002/ange.200453688

Cited by 37 publications

(32 citation statements)

References 41 publications

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“…4A) (36). For the β-products, the SDKIEs at the anomeric C-H bond were determined to be normal (k H /k D > 1) and increased with the Lewis basicity of the catalyst, reflecting an increase in the forming carbon-oxygen bond distance in the transition state as the reactivity of the nucleophile increases (37). In contrast, no such trend is observed in the case of the minor α-diastereomers.…”

Section: Main Textmentioning

confidence: 99%

Macrocyclic bis-thioureas catalyze stereospecific glycosylation reactions

Park

Harper

Kuhl

et al. 2017

Science

253

144

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Carbohydrates are involved in nearly all aspects of biochemistry, but their complex chemical structures present long-standing practical challenges to their synthesis. In particular, stereochemical outcomes in glycosylation reactions are highly dependent on the steric and electronic properties of coupling partners, and thus, carbohydrate synthesis is not easily predictable. Here, we report the discovery of a macrocyclic bis-thiourea derivative that catalyzes stereospecific invertive substitution pathways of glycosyl chlorides. The utility of the catalyst is demonstrated in the synthesis of 1,2-trans-, 1,2-cis-, and 2-deoxy-β-glycosides. Mechanistic studies are consistent with a cooperative mechanism in which an electrophile and a nucleophile are simultaneously activated to effect a stereospecific substitution reaction.

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Section: Main Textmentioning

confidence: 99%

Macrocyclic bis-thioureas catalyze stereospecific glycosylation reactions

Park

Harper

Kuhl

et al. 2017

Science

253

144

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“…This observation is perhaps not surprising when one considers that models of the S N 2 transition states have considerable oxacarbenium ion character. [16,22,51] Factors that destabilise an oxacarbenium ion intermediate would thus also destabilise the S N 2 transition state. The modelling results summarised in Figure 3 do indicate that ester protecting groups should increase the probability of an S N 2-like mechanism.…”

Section: Wwwchemeurjorgmentioning

confidence: 99%

“…The identification of glycosyl triflate intermediates (or contact/solvent separated ion pairs) has also provided substantial insight into the stereoselectivity of glycosylation. [15][16][17] Recently, Boons and co-workers introduced a participating group that could provide 1,2-cis-a-glycosides (Scheme 1a). [18] A glycosyl donor 1 bearing a modified benzyl ether on O2 generates a bicyclic sulfonium ion 2 upon activation of the imidate leaving group.…”

Section: Introductionmentioning

confidence: 99%

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

Fascione

Kilner

Leach

et al. 2011

Chemistry A European J

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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(N)1 and S(N)2 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(N)1 and S(N)2 mechanisms.

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“…More subtle roles for α− and β−mannosides are found in the glycans of higher organisms, where oligosaccharide diversity affords cell signaling and recognition events that lead oligosaccharides to play the role of “glycocode”; the language of cellular communication [1]. Furthermore, mannose chemistry itself is extremely challenging, demanding inspired solutions to the problem of synthesis at its occluded anomeric centre [2], [3], [4]. Not surprisingly, therefore, there is considerable interest in the enzymatic synthesis and degradation of mannosides.…”

Section: Introductionmentioning

confidence: 99%

Structure and Kinetic Investigation of Streptococcus pyogenes Family GH38 α-Mannosidase

et al. 2010

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BackgroundThe enzymatic hydrolysis of α−mannosides is catalyzed by glycoside hydrolases (GH), termed α−mannosidases. These enzymes are found in different GH sequence–based families. Considerable research has probed the role of higher eukaryotic “GH38” α−mannosides that play a key role in the modification and diversification of hybrid N-glycans; processes with strong cellular links to cancer and autoimmune disease. The most extensively studied of these enzymes is the Drosophila GH38 α−mannosidase II, which has been shown to be a retaining α−mannosidase that targets both α−1,3 and α−1,6 mannosyl linkages, an activity that enables the enzyme to process GlcNAc(Man)5(GlcNAc)2 hybrid N-glycans to GlcNAc(Man)3(GlcNAc)2. Far less well understood is the observation that many bacterial species, predominantly but not exclusively pathogens and symbionts, also possess putative GH38 α−mannosidases whose activity and specificity is unknown.Methodology/Principal FindingsHere we show that the Streptococcus pyogenes (M1 GAS SF370) GH38 enzyme (Spy1604; hereafter SpGH38) is an α−mannosidase with specificity for α−1,3 mannosidic linkages. The 3D X-ray structure of SpGH38, obtained in native form at 1.9 Å resolution and in complex with the inhibitor swainsonine (K i 18 µM) at 2.6 Å, reveals a canonical GH38 five-domain structure in which the catalytic “–1” subsite shows high similarity with the Drosophila enzyme, including the catalytic Zn2+ ion. In contrast, the “leaving group” subsites of SpGH38 display considerable differences to the higher eukaryotic GH38s; features that contribute to their apparent specificity.Conclusions/SignificanceAlthough the in vivo function of this streptococcal GH38 α−mannosidase remains unknown, it is shown to be an α−mannosidase active on N-glycans. SpGH38 lies on an operon that also contains the GH84 hexosaminidase (Spy1600) and an additional putative glycosidase. The activity of SpGH38, together with its genomic context, strongly hints at a function in the degradation of host N- or possibly O-glycans. The absence of any classical signal peptide further suggests that SpGH38 may be intracellular, perhaps functioning in the subsequent degradation of extracellular host glycans following their initial digestion by secreted glycosidases.

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Mechanism of 4,6‐O‐Benzylidene‐Directed β‐Mannosylation as Determined by α‐Deuterium Kinetic Isotope Effects

Cited by 37 publications

References 41 publications

Macrocyclic bis-thioureas catalyze stereospecific glycosylation reactions

Macrocyclic bis-thioureas catalyze stereospecific glycosylation reactions

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

Structure and Kinetic Investigation of Streptococcus pyogenes Family GH38 α-Mannosidase

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