Progress and challenges in the synthesis of sequence controlled polysaccharides

• Giulio Fittolani,
• Theodore Tyrikos-Ergas,
• Denisa Vargová,
• Manishkumar A. Chaube and
• Martina Delbianco

Beilstein J. Org. Chem. 2021, 17, 1981–2025, doi:10.3762/bjoc.17.129

• β-linkages are still considered a major challenge in carbohydrate chemistry (Figure 5). While long α-mannosides could be accessed either by chemical synthesis or by polymerization approaches, only relatively short β-mannan analogues could be synthesized to date. In addition, limited enzymatic

• ). No enzyme has been reported for the synthesis of α-mannosides. Similarly, polymerization approaches remain to date underrepresented. α-Mannosides can be reliably prepared through chemical glycosylation, which is in general highly α-stereoselective. Construction of the 1,2-trans linkage of α

• -mannosides is conventionally achieved with [142][157][269], or even without [270], neighboring group participation (e.g., Ac, Bz). The favorable anomeric effect ensures efficient glycosylation reactions. The synthesis of α-mannosides is widely established, allowing the chemical synthesis of the longest

Metal-free glycosylation with glycosyl fluorides in liquid SO₂

• Krista Gulbe,
• Jevgeņija Lugiņina,
• Edijs Jansons,
• Artis Kinens and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 964–976, doi:10.3762/bjoc.17.78

• armed and disarmed glucose and mannose-derived glycosyl fluorides in moderate to excellent yields. A series of pivaloyl-protected O- and S-mannosides, as well as one example of a C-mannoside, are synthesized to demonstrate the scope of the glycosyl acceptors. The formation of the fluorosulfite species

• mixture of mannosides α-3r and α-3s was obtained when cyclopropylmethanol (2r) was applied. The cyclopropylmethyl carbocation (C4H7+), which is generated in liquid SO2 medium, can undergo a rearrangement to form a cyclobutyl carbocation [68]. The latter can be trapped by a water molecule forming

• fluoride α-1a to form bis-mannosides α-8 in good yields (Scheme 2). In a series of pivaloyl-protected mannosides 3 a substrate-controlled α-selectivity due to the favoring effect of both neighboring ester-type protecting groups and the anomeric effect was observed [3]. On the other hand, mixing of glycosyl

Automated glycan assembly of arabinomannan oligosaccharides from Mycobacterium tuberculosis

• Alonso Pardo-Vargas,
• Priya Bharate,
• Martina Delbianco and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2019, 15, 2936–2940, doi:10.3762/bjoc.15.288

• essential, as an early diagnosis would help to prevent most deaths from tuberculosis [1]. AMs, one of the main components of the mycobacterial cell wall [2], are composed of α-(1,5)-, α-(1,3)- and β-(1,2)-arabinoses as well as α-(1,6)- and α-(1,2)-mannosides [3][4][5]. AMs are potential clinical biomarkers

• methanolysis, followed by Pd/C-catalyzed hydrogenolysis of the carboxybenzyl group and the benzyl ethers. Mannosides 4–6 were deprotected and purified using reversed-phase HPLC to obtain fully deprotected mannosides 10–12 (Figure 2). For the arabinomannosides 7–9, the acid-labile arabinose chain was cleaved

Design, synthesis and biological evaluation of immunostimulating mannosylated desmuramyl peptides

• Rosana Ribić,
• Ranko Stojković,
• Lidija Milković,
• Mariastefania Antica,
• Marko Cigler and
• Srđanka Tomić

Beilstein J. Org. Chem. 2019, 15, 1805–1814, doi:10.3762/bjoc.15.174

• condensation reactions with hydroxyisobutyryl and glycolyl mannosides. The synthesis of desmuramyl peptide 7 with an adamantane moiety bound at C-terminus is presented in Scheme 2. After hydrogenolysis of the starting dipeptide, condensation of free carboxyl group with adamant-1-ylamine hydrochloride was

• described [34]. Condensations of peptides 1, 4 and 7 with carboxy-functionalized mannosides containing a (R)-hydroxyisobutyryl and glycolyl linker are shown in Scheme 4 and Scheme 5, respectively. For the amide bond formation between mannose and peptide part, an optimized EDC/HOBt method was used in each

Influence of per-O-sulfation upon the conformational behaviour of common furanosides

• Alexey G. Gerbst,
• Vadim B. Krylov,
• Dmitry A. Argunov,
• Maksim I. Petruk,
• Arsenii S. Solovev,
• Andrey S. Dmitrenok and
• Nikolay E. Nifantiev

Beilstein J. Org. Chem. 2019, 15, 685–694, doi:10.3762/bjoc.15.63

• conformation of the furanoside ring and thus the intraring couplings, the additional conformations were considered for mannosides 1 and 1s (Table 7). The previously found conformers (A and B for the free mannoside 1 and C and D for its sulfated counter-part 1s) had the C5–C6 bond in gauche-trans orientation

Lectins of Mycobacterium tuberculosis – rarely studied proteins

• Katharina Kolbe,
• Sri Kumar Veleti,
• Norbert Reiling and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2019, 15, 1–15, doi:10.3762/bjoc.15.1

• connected to colonization of the kidney [64][65]. Inhibition of carbohydrate–lectin interactions by antiadhesive drugs is an emerging anti-infective therapeutic approach, particularly in light of increasing rates of bacterial resistance to traditional antibiotics. α-D-Mannosides containing aromatic aglycons

• calcium-dependent manner. The ligand specificity is highly diverse, including fucosides, mannosides, glucosides, N-acetylglucosamines, galactosides, and N-acetylgalactosamines. While some of the C-type lectins are known to be secreted, others are membrane-associated proteins. They often oligomerize into

Pathoblockers or antivirulence drugs as a new option for the treatment of bacterial infections

• Matthew B. Calvert,
• Varsha R. Jumde and
• Alexander Titz

Beilstein J. Org. Chem. 2018, 14, 2607–2617, doi:10.3762/bjoc.14.239

• aglycon part of the mannosides. The attachment of lipophilic aglycons to an α-linked mannose residue was identified to increase the binding potency tremendously due to the opening of a lipophilic cleft on FimH, the tyrosine gate [15]. Various alkyl mannosides 1 (Figure 1) were analyzed and n-heptyl

• mannoside (1b) revealed the highest potency, as a result of it having the optimal length to bind to the tyrosine gate. Lindhorst and co-workers have demonstrated that mannosides with an extended aromatic aglycon could further improve the interaction as shown for compounds 2 and 3. Their relative inhibitory

• potential (RIP), which is benchmarked with the reference methyl α-D-mannoside (1a) defined as RIP = 1, was increased up to 6900-fold [17]. The biphenyl mannosides (e.g., 4, 5) have subsequently been identified by the Ernst and Hultgren/Janetka groups as promising inhibitors of FimH-mediated bacterial

Diazirine-functionalized mannosides for photoaffinity labeling: trouble with FimH

• Femke Beiroth,
• Tomas Koudelka,
• Thorsten Overath,
• Stefan D. Knight,
• Andreas Tholey and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1890–1900, doi:10.3762/bjoc.14.163

• -functionalized mannosides as high-affinity FimH ligands and performed an extensive study on photo-crosslinking of the best ligand (mannoside 3) with a series of model peptides and FimH. Notably, we have employed high-performance mass spectrometry to be able to detect radiation results with the highest possible

• accuracy. We are concluding from this study that photolabeling of FimH with sugar diazirines has only very limited success and cannot be regarded a facile approach for covalent modification of FimH. Keywords: diazirines; docking; FimH; lectin ligands; mannosides; mass spectrometry; photoaffinity labelling

• . Finally, back in 2010, we analyzed photolabeling of the octapeptide angiotensin II with three different sugar diazirines using mass spectrometry and then also detected photolabeling of FimH with the same three mannosides. However, we could not measure the labeling product with full accuracy [11]. Although

Anomeric modification of carbohydrates using the Mitsunobu reaction

• Julia Hain,
• Patrick Rollin,
• Werner Klaffke and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1619–1636, doi:10.3762/bjoc.14.138

• , they can also be manipulated to one’s advantage, for example for the stereoselective formation of β-mannosides [28]. Reactions with protic acids to achieve anomeric esters The first application of the Mitsunobu reaction involved esterification of a secondary alcohol. Although an anomeric OH group

• otherwise difficult to synthesize β-mannosides using the Mitsunobu procedure. This approach to 1,2-cis-mannosides is equally effective when cyclohexylidene protecting groups are used [28][47][62]. Mitsunobu glycosylation was also a successful method in total synthesis. In the course of a 17-step synthesis

• sugars representing the alcohol component of the reaction. The stereochemical outcome of a Mitsunobu glycosylation is often advantageous such as in the synthesis of β-D-mannosides, which are otherwise difficult to prepare. However, often, the stereoselectivity of the reaction is less definite than our

What contributes to an effective mannose recognition domain?

• Christoph P. Sager,
• Deniz Eriş,
• Martin Smieško,
• Rachel Hevey and
• Beat Ernst

Beilstein J. Org. Chem. 2017, 13, 2584–2595, doi:10.3762/bjoc.13.255

• glycosides on mammalian cell surfaces. After this initial contact, they can infect host cells and form biofilms, both of which are key factors for their survival [9][27][28]. Examples of such opportunistic bacterial species binding to mannosides on host cells include Pseudomonas aeruginosa with its membrane

• exhibit short residence times in the low picosecond range [52]. Whereas E-selectin in complex with sLex is an excellent example of a solvent exposed interaction [12][53], the interaction of FimHLD with mannosides well illustrates the counter situation for a deep CRD [36] (Figure 2A and B, respectively

Electron-deficient pyridinium salts/thiourea cooperative catalyzed O-glycosylation via activation of O-glycosyl trichloroacetimidate donors

• Mukta Shaw,
• Yogesh Kumar,
• Rima Thakur and
• Amit Kumar

Beilstein J. Org. Chem. 2017, 13, 2385–2395, doi:10.3762/bjoc.13.236

• glycosyl acceptors 2c, 2g, 2h, and 2n produces their corresponding mannosides 14–18 (61–78% yields) with moderate selectivity (Table 3, entries 6–10) [40][41]. Gratifyingly, the highest stereoselective outcome was observed when 4,6-O-benzylidine-2,3-di-O-benzyl-α-D-glucopyranosyl trichloroacetimidate 8α

Intramolecular glycosylation

• Xiao G. Jia and
• Alexei V. Demchenko

Beilstein J. Org. Chem. 2017, 13, 2028–2048, doi:10.3762/bjoc.13.201

• complete stereoselectivities: α- for glucosides and β- for mannosides. Another direction in the development of the IAD method emerged with the introduction of the allyl-mediated strategy by Fairbanks and co-workers who achieved improved yields and complete stereoselectivity in α-glucosylations and β

• synthesis of a variety of oligosaccharides and glycoconjugates containing challenging β-mannosides [95][96]. A very impressive application of the IAD in polymer-supported reactions has also emerged [97]. Interestingly, the PMB tether was although used as the linker for the attachment to the polymer support

• % and complete β-selectivity [100]. Initially investigated for the synthesis of β-mannosides, α-glucosides, and β-arabinofuranosides [100], this approach was extended to the synthesis of β-rhamnosides [101] and many other challenging linkages and targets [41][102][103][104][105][106][107][108

Silyl-protective groups influencing the reactivity and selectivity in glycosylations

• Mikael Bols and
• Christian Marcus Pedersen

Beilstein J. Org. Chem. 2017, 13, 93–105, doi:10.3762/bjoc.13.12

• . This approach works for glucosides, mannosides, and galactosides and both, α- and β-thioglycosides [40]. It was shown by competition experiments that these tethered donors were even more reactive than the TBS-protected donors such as 20. This was particularly the case for the α-anomers as a

Are D-manno-configured Amadori products ligands of the bacterial lectin FimH?

• Tobias-Elias Gloe,
• Insa Stamer,
• Cornelia Hojnik,
• Tanja M. Wrodnigg and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2015, 11, 1096–1104, doi:10.3762/bjoc.11.123

• site of the type 1-fimbrial lectin FimH. Keywords: Amadori rearrangement; bacterial adhesion; C-mannosides; docking studies; FimH ligands; Introduction The Amadori rearrangement (AR) is the reaction in which aldohexoses react with suitable amines under acidic catalysis to 1-amino-1-deoxyketohexoses

• ]. Obviously, FimH binds α-D-mannosides such as simple methyl α-D-mannoside (MeMan, 1) but not β-mannosides. Mannosides with an aromatic aglycone, such as p-nitrophenyl α-D-mannoside (pNPMan) and 4-methylumbelliferyl α-D-mannoside (3) show an improved affinity to FimH due to π–π-stacking interactions of the

• for this type of reaction. Analogous observations have been made in previous studies [20]. Rearrangement products 9 and 10 exist in their 5C2 pyranoid conformation as determined by NMR analysis and can thus indeed be regarded as analogues of α-D-mannosides. The N-alkyl/aryl aminomethyl substituent at

DNA display of glycoconjugates to emulate oligomeric interactions of glycans

• Alexandre Novoa and
• Nicolas Winssinger

Beilstein J. Org. Chem. 2015, 11, 707–719, doi:10.3762/bjoc.11.81

• binding sites for glucosides and mannosides (preferred) spaced by 72 Å. Titration studies showed a clear dependence on the functionalization of each arm in the 3-way junction consistent with a synergistic interaction of each arm with a binding site. However, the number of glycan units (on each arm 3, 6 or

Synthesis of carbohydrate-scaffolded thymine glycoconjugates to organize multivalency

• Anna K. Ciuk and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2015, 11, 668–674, doi:10.3762/bjoc.11.75

• used as scaffold molecule, and α-D-mannosides as specific carbohydrate ligands for the fabrication of the envisaged divalent glycoconjugate (Figure 1C). In the following, we report the synthesis of the divalent glycoconjugates outlined in Figure 1 and their [2 + 2] photocycloaddition. Results and

Synthesis and solvodynamic diameter measurements of closely related mannodendrimers for the study of multivalent carbohydrate–protein interactions

• Yoann M. Chabre,
• Alex Papadopoulos,
• Alexandre A. Arnold and
• René Roy

Beilstein J. Org. Chem. 2014, 10, 1524–1535, doi:10.3762/bjoc.10.157

• studies To accurately estimate the various structural factors involved in the intricate binding interactions between our synthetic multimeric mannosides and ConA, we determined their relative diffusivity measurements by NMR spectroscopy. In fact, diffusion NMR spectroscopy has recently become a method of

Why a diaminopyrrolic tripodal receptor binds mannosides in acetonitrile but not in water?

• Diogo Vila-Viçosa,
• Oscar Francesconi and
• Miguel Machuqueiro

Beilstein J. Org. Chem. 2014, 10, 1513–1523, doi:10.3762/bjoc.10.156

• processes. Recently, it was synthetized a diaminopyrrolic tripodal receptor that is selective for mannosides, which are obtained from mannose, a sugar with significant relevance in living systems. However, this receptor is significantly more active in acetonitrile than in water. In this work, we performed

• of the most abundant sugars in glycoconjugates [9][10]. In 2011, Roelens’ group [11][12][13] synthetized and tested a chiral diaminopyrrolic tripodal receptor that showed high binding affinities to mannosides (Figure 1). This particular receptor is significantly more active in acetonitrile (ACN) than

• . There are several works, both theoretical [38][39][40] and experimental [1][2][3][4][5][6][37][41][42], showing that the interaction between sugars and their receptors is mainly driven by hydrogen bonds. In fact, there are several experimental structures of mannosides similar to the one used in this

Gold-catalyzed glycosidation for the synthesis of trisaccharides by applying the armed–disarmed strategy

• Abhijeet K. Kayastha and
• Srinivas Hotha

Beilstein J. Org. Chem. 2013, 9, 2147–2155, doi:10.3762/bjoc.9.252

• the more acid-sensitive p-methoxybenzyl derivative 12 underwent deprotection of the p-methoxybenzyl moiety to give alcohol 13 with 88% yield. The deprotection of the p-methoxybenzyl moiety can be utilized for the one-pot synthesis of glycerol mannosides from mannosyl donor 1 and compound 12 in 67

Synthesis and testing of the first azobenzene mannobioside as photoswitchable ligand for the bacterial lectin FimH

• Vijayanand Chandrasekaran,
• Katharina Kolbe,
• Femke Beiroth and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2013, 9, 223–233, doi:10.3762/bjoc.9.26

• control of carbohydrate-specific bacterial adhesion, it has become our goal to synthesise azobenzene mannosides as photoswitchable inhibitors of type 1 fimbriae-mediated adhesion of E. coli. An azobenzene mannobioside 2 was prepared and its photochromic properties were investigated. The E→Z isomerisation

• azobenzene mannoside 6 was prepared first. Thus, mannosylation of the hydroxy-functionalised azobenzene 4 by using the mannosyl trichlororacetimidate 3 [19] led to the respective azobenzene α-mannosides 5 in 81% yield (Scheme 1). Treatment of 5 under Zemplén conditions [20] furnished the deprotected

• of the mannobioside is important both to mediate hydrophilicity and to intensify the steric effect that photoswitching has on the exposition of the terminal mannoside. Conclusion The azobenzene mannosides presented herein resemble a structure quite similar to biaryl mannosides, which have been

2-Allylphenyl glycosides as complementary building blocks for oligosaccharide and glycoconjugate synthesis

• Hemali D. Premathilake and
• Alexei V. Demchenko

Beilstein J. Org. Chem. 2012, 8, 597–605, doi:10.3762/bjoc.8.66

• a more flexible approach for oligosaccharide synthesis. Concomitantly with our studies, Hung et al. came up with essentially the same idea and reported the synthesis of AP mannosides and their activation for O-mannosylation in the presence of ICl/AgOTf [27]. The following considerations driving our

Dependency of the regio- and stereoselectivity of intramolecular, ring-closing glycosylations upon the ring size

• Patrick Claude,
• Christian Lehmann and
• Thomas Ziegler

Beilstein J. Org. Chem. 2011, 7, 1609–1619, doi:10.3762/bjoc.7.189

• glycosylations. Schematic representation of the “prearranged-glycoside concept” for intramolecular, ring-closing glycosylation. Structures of compounds 1–5. Intramolecular glycosylation of peptide-tethered mannosides according to Fairbanks [38][39][40]. Isolated β(1→3)-glycosidic linkage favored by triad

Synthesis of glycoconjugate fragments of mycobacterial phosphatidylinositol mannosides and lipomannan

• Benjamin Cao,
• Jonathan M. White and
• Spencer J. Williams

Beilstein J. Org. Chem. 2011, 7, 369–377, doi:10.3762/bjoc.7.47

• agent of tuberculosis (TB), possesses a complex cell wall containing mannose-rich glycophospholids termed phosphatidylinositol mannosides (PIMs), lipomannan (LM), and lipoarabinomannan (LAM). These glycophospholipids play important roles in cell wall function and host–pathogen interactions. Synthetic

• provided diacetate 19 in 60% yield. Compound 19 was converted into the trichloroacetimidate 16 following the approach of Kong and coworkers [38] or to the thioglycoside 17 by treatment with p-thiocresol and BF3·Et2O in toluene. Assembly of mannosides 1–4 Synthesis of the protected disaccharide 20 was

En route to photoaffinity labeling of the bacterial lectin FimH

• Thisbe K. Lindhorst,
• Michaela Märten,
• Andreas Fuchs and
• Stefan D. Knight

Beilstein J. Org. Chem. 2010, 6, 810–822, doi:10.3762/bjoc.6.91

• FimH that can complex α-D-mannosides. However, as the precise nature of the ligand–receptor interactions in mannose-specific adhesion is not yet fully understood, it is of interest to identify carbohydrate recognition domains on the fimbrial lectin also in solution. Photoaffinity labeling serves as an

• appropriate methodology in this endeavour and hence biotin-labeled photoactive mannosides were designed and synthesized for photoaffinity labeling of FimH. So far, the photo-crosslinking properties of the new photoactive mannosides could be detailed with the peptide angiotensin II and labeling of FimH was

• X-ray studies a carbohydrate recognition domain (CRD), which can complex one α-D-mannosyl residue, has been clearly identified [6][7][8]. However, other binding experiments performed with a multitude of synthetic as well as natural mannosides and oligomannosides are not in complete agreement with