ChemInform Abstract: Stereoselective Construction of 1,1‐α,α‐Glycosidic Bonds

Chaube, Manishkumar A.; Kulkarni, Suvarn S.

doi:10.1002/chin.201241251

Cited by 5 publications

(11 citation statements)

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“…Typically, approaches involving conventional glycosylation procedures for the synthesis of trehalose provide moderate stereoselectivity and low yields. 38 Since we aimed to establish the α,α-(1↔1) glycosidic linkage between an amino sugar and a manno -configured monosaccharide, we could hardly rely on the intramolecular aglycon delivery approach 39 or on the versatile synthetic desymmetrization of the natural trehalose. 40 …”

Section: Resultsmentioning

confidence: 99%

Development of αGlcN(1↔1)αMan-Based Lipid A Mimetics as a Novel Class of Potent Toll-like Receptor 4 Agonists

et al. 2014

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The endotoxic portion of lipopolysaccharide (LPS), a glycophospholipid Lipid A, initiates the activation of the Toll-like Receptor 4 (TLR4)–myeloid differentiation factor 2 (MD-2) complex, which results in pro-inflammatory immune signaling. To unveil the structural requirements for TLR4·MD-2-specific ligands, we have developed conformationally restricted Lipid A mimetics wherein the flexible βGlcN(1→6)GlcN backbone of Lipid A is exchanged for a rigid trehalose-like αGlcN(1↔1)αMan scaffold resembling the molecular shape of TLR4·MD-2-bound E. coli Lipid A disclosed in the X-ray structure. A convergent synthetic route toward orthogonally protected αGlcN(1↔1)αMan disaccharide has been elaborated. The α,α-(1↔1) linkage was attained by the glycosylation of 2-N-carbamate-protected α-GlcN-lactol with N-phenyl-trifluoroacetimidate of 2-O-methylated mannose. Regioselective acylation with (R)-3-acyloxyacyl fatty acids and successive phosphorylation followed by global deprotection afforded bis- and monophosphorylated hexaacylated Lipid A mimetics. αGlcN(1↔1)αMan-based Lipid A mimetics (α,α-GM-LAM) induced potent activation of NF-κB signaling in hTLR4/hMD-2/CD14-transfected HEK293 cells and robust LPS-like cytokines expression in macrophages and dendritic cells. Thus, restricting the conformational flexibility of Lipid A by fixing the molecular shape of its carbohydrate backbone in the “agonistic” conformation attained by a rigid αGlcN(1↔1)αMan scaffold represents an efficient approach toward powerful and adjustable TLR4 activation.

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Section: Resultsmentioning

confidence: 99%

Development of αGlcN(1↔1)αMan-Based Lipid A Mimetics as a Novel Class of Potent Toll-like Receptor 4 Agonists

et al. 2014

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“…Existing multistep chemical synthesis methods are useful for producing complex trehalose analogues with multiple sites of modification (e.g., naturally occurring complex mycobacterial glycolipids). However, these methods are invariably lengthy and inefficient, even when applied to the synthesis of comparatively simple monosubstituted trehalose analogues 9, 13, 14 . Alternative synthetic approaches are needed to rapidly and efficiently produce various types of trehalose analogues that may have value in the aforementioned areas.…”

Section: Discussionmentioning

confidence: 99%

“…One route involves desymmetrization/modification of natural trehalose, while the other involves starting with properly functionalized monosaccharide building blocks and performing chemical glycosylation to forge the 1,1-α,α-glycosidic bond. These approaches, which have recently been discussed in review articles 13, 14 , have proven useful for accomplishing multistep synthesis of small quantities of complex trehalose-containing natural products, such as sulfolipid-1 from M. tuberculosis 15 . However, both approaches are generally inefficient, time-consuming, inaccessible to non-chemists, and, additionally, are not considered to be environmentally friendly.…”

Section: Introductionmentioning

confidence: 99%

Rapid One-step Enzymatic Synthesis and All-aqueous Purification of Trehalose Analogues

Meints

Poston

Piligian

et al. 2017

JoVE

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Chemically modified versions of trehalose, or trehalose analogues, have applications in biology, biotechnology, and pharmaceutical science, among other fields. For instance, trehalose analogues bearing detectable tags have been used to detect Mycobacterium tuberculosis and may have applications as tuberculosis diagnostic imaging agents. Hydrolytically stable versions of trehalose are also being pursued due to their potential for use as non-caloric sweeteners and bioprotective agents. Despite the appeal of this class of compounds for various applications, their potential remains unfulfilled due to the lack of a robust route for their production. Here, we report a detailed protocol for the rapid and efficient one-step biocatalytic synthesis of trehalose analogues that bypasses the problems associated with chemical synthesis. By utilizing the thermostable trehalose synthase (TreT) enzyme from Thermoproteus tenax, trehalose analogues can be generated in a single step from glucose analogues and uridine diphosphate glucose in high yield (up to quantitative conversion) in 15–60 min. A simple and rapid non-chromatographic purification protocol, which consists of spin dialysis and ion exchange, can deliver many trehalose analogues of known concentration in aqueous solution in as little as 45 min. In cases where unreacted glucose analogue still remains, chromatographic purification of the trehalose analogue product can be performed. Overall, this method provides a “green” biocatalytic platform for the expedited synthesis and purification of trehalose analogues that is efficient and accessible to non-chemists. To exemplify the applicability of this method, we describe a protocol for the synthesis, all-aqueous purification, and administration of a trehalose-based click chemistry probe to mycobacteria, all of which took less than 1 hour and enabled fluorescence detection of mycobacteria. In the future, we envision that, among other applications, this protocol may be applied to the rapid synthesis of trehalose-based probes for tuberculosis diagnostics. For instance, short-lived radionuclide-modified trehalose analogues (e.g., 18F-modified trehalose) could be used for advanced clinical imaging modalities such as positron emission tomography-computed tomography (PET-CT).

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“…However, this approach requires custom building block preparation, and, moreover, the glycosylation reaction typically generates 4 difficult-to-separate stereoisomers (α,α; α,β; β,α; and β,β) with low selectivity. 15 Even when a specialized glycosylation method featuring excellent α,α-stereoselectivity was elegantly used to synthesize FITC-Tre ( 4 ), building block preparation and protecting group manipulations made the longest linear sequence of this convergent synthesis 8 steps with an overall yield of ˂ 10%, and the product 4 contained a non-native anomeric methyl group. 10 An alternative approach that sidesteps the challenging 1,1-α,α-glycosylation is to modify native trehalose through regioselective manipulations.…”

mentioning

confidence: 99%

“…Isolation of trehalosamine from natural sources is arduous and may not provide material in sufficient quantity and purity. , Chemical synthesis offers flexibility, but to date, the reported routes to trehalosamine and its analogues are relatively lengthy and low yielding. ,− One approach to trehalose analogue synthesis is to perform a chemical glycosylation reaction between protected acceptor and donor monosaccharides. However, this approach requires custom building block preparation, and moreover, the glycosylation reaction typically generates four difficult-to-separate stereoisomers (α,α; α,β; β,α; and β,β) with low selectivity . Even when a specialized glycosylation method featuring excellent α,α-stereoselectivity was elegantly used to synthesize FITC-Tre ( 4 ), building block preparation and protecting group manipulations made the longest linear sequence of this convergent synthesis eight steps with an overall yield of <10%, and the product 4 contained a non-native anomeric methyl group .…”

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confidence: 99%

Chemoenzymatic Synthesis of Trehalosamine, an Aminoglycoside Antibiotic and Precursor to Mycobacterial Imaging Probes

et al. 2018

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Trehalosamine (2-amino-2-deoxy-α,α-d-trehalose) is an aminoglycoside with antimicrobial activity against Mycobacterium tuberculosis, and it is also a versatile synthetic intermediate used to access imaging probes for mycobacteria. To overcome inefficient chemical synthesis approaches, we report a two-step chemoenzymatic synthesis of trehalosamine that features trehalose synthase (TreT)-catalyzed glycosylation as the key transformation. Soluble and recyclable immobilized forms of TreT were successfully employed. We demonstrate that chemoenzymatically synthesized trehalosamine can be elaborated to two complementary imaging probes, which label mycobacteria via distinct pathways.

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ChemInform Abstract: Stereoselective Construction of 1,1‐α,α‐Glycosidic Bonds

Abstract: Review: 57 refs.

Cited by 5 publications

References 0 publications

Development of αGlcN(1↔1)αMan-Based Lipid A Mimetics as a Novel Class of Potent Toll-like Receptor 4 Agonists

Development of αGlcN(1↔1)αMan-Based Lipid A Mimetics as a Novel Class of Potent Toll-like Receptor 4 Agonists

Rapid One-step Enzymatic Synthesis and All-aqueous Purification of Trehalose Analogues

Chemoenzymatic Synthesis of Trehalosamine, an Aminoglycoside Antibiotic and Precursor to Mycobacterial Imaging Probes

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