Aminosugar-based immunomodulator lipid A: synthetic approaches

• Alla Zamyatina

Beilstein J. Org. Chem. 2018, 14, 25–53, doi:10.3762/bjoc.14.3

Preactivation-based chemoselective glycosylations: A powerful strategy for oligosaccharide assembly

• Weizhun Yang,
• Bo Yang,
• Sherif Ramadan and
• Xuefei Huang

Beilstein J. Org. Chem. 2017, 13, 2094–2114, doi:10.3762/bjoc.13.207

• thioglycosyl building blocks as illustrated in Scheme 9 [38]. The hemiacetal donor 38 was preactivated with Ph2SO and Tf2O, and reacted with a bifunctional thioglycosyl acceptor 39 to form disaccharide 40. Interestingly, thioglycoside 40 could also be activated by Ph2SO/Tf2O. The subsequent addition of

• transformations commonly encountered in building block preparation [41]. At the same time, mild promoters are available for thioglycoside activation. The anomeric reactivities of thioglycosides towards glycosylation can be significantly influenced by the protective groups on the glycan ring as well as the size

• thioglycoside with even lower anomeric reactivity. When building blocks with suitable anomeric reactivities are selected, multiple glycosylation reactions can be carried out in one pot without the need for synthetic manipulations or purification of the advanced oligosaccharide intermediates. This strategy

Intramolecular glycosylation

• Xiao G. Jia and
• Alexei V. Demchenko

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

• conformations and energies chose the latter linker [55]. To apply the remote glycosidation methodology to the synthesis of the 4,6-branched trisaccharide, phthaloylated thioglycoside 17 was coupled with the 6-hydroxy group of the acceptor precursor 16 in the presence of DCC and DMAP (Scheme 5). The tethering

• introduced by Schmidt [68], was successfully applied to the intramolecular synthesis of 1,2-cis glycosides with complete selectivity (Scheme 7) [69]. Thus, thioglycoside 25 is first alkylated at C-3 position. The resulting intermediate 26 is then used as the alkylating reagent to create a tether to acceptor

• size of the macrocycle formed during the glycosylation (Scheme 12) [80][81]. Thioglycoside donor 45 containing a 2-O-propargyl group and acceptor 46 with an azide-containing protecting group were connected using a click reaction to afford the tethered intermediate 47. Upon treatment with NIS/TfOH

1,3-Dibromo-5,5-dimethylhydantoin as promoter for glycosylations using thioglycosides

• Fei-Fei Xu,
• Claney L. Pereira and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2017, 13, 1994–1998, doi:10.3762/bjoc.13.195

• agents that are commonly used in oligosaccharide synthesis due to their accessibility, stability, compatibility with various reaction conditions, and orthogonality to other donors [1][2][3][4][5]. Different electrophilic/thiophilic reagents have been developed as promoters to activate thioglycoside

• thioglycosides. Results and Discussion Initially, the capability of DBDMH to activate thioglycoside 1 [32] in order to glycosylate the primary hydroxy group present in D-glucose acceptor 2 [33] was explored without any additives (Table 1, entry 1). This initial experiment furnished disaccharide 3, albeit in

Urea–hydrogen peroxide prompted the selective and controlled oxidation of thioglycosides into sulfoxides and sulfones

• Adesh Kumar Singh,
• Varsha Tiwari,
• Kunj Bihari Mishra,
• Surabhi Gupta and
• Jeyakumar Kandasamy

Beilstein J. Org. Chem. 2017, 13, 1139–1144, doi:10.3762/bjoc.13.113

• controlled oxidation of thioglycosides to glycosyl sulfoxides and sulfones selectively by altering the reaction conditions. It is also observed that thioglycoside oxidation suffers from low yields, poor selectivity (i.e., sulfoxide vs sulfone), use of inconvenient reaction conditions and expensive oxidants

• deficient thioglucopyranosides, we further investigated the oxidation of O-benzyl protected 4-methylphenyl thioglycoside 13 under optimized conditions (Table 2, entry 13). This substrate was found to be more reactive than O-acetylated and benzoylated thioglycosides and gave the sulfoxide in a good yield

• .) [34]. Therefore, the scope of this methodology was further investigated with oxidation of allyl group protected thioglycoside 14 (Table 2, entry 14). Remarkably, allyl groups were found to be very stable during the oxidation while sulfide underwent selective oxidation to corresponding sulfoxide and

Total synthesis of TMG-chitotriomycin based on an automated electrochemical assembly of a disaccharide building block

• Yuta Isoda,
• Norihiko Sasaki,
• Kei Kitamura,
• Shuji Takahashi,
• Sujit Manmode,
• Naoko Takeda-Okuda,
• Jun-ichi Tamura,
• Toshiki Nokami and
• Toshiyuki Itoh

Beilstein J. Org. Chem. 2017, 13, 919–924, doi:10.3762/bjoc.13.93

• β-glycosyl triflate intermediates 3 might determine the observed selectivity (Figure 2). We previously established that glycosyl triflate 3a was derived from thioglycoside 2a by an NMR study under low-temperature conditions, in which the glycosyl triflate α-isomer 3aα was confirmed as an exclusive

• an equilibrium between the α-isomer and the β-isomer of 3a. To the contrary, glycosyl triflate 3b, derived from thioglycoside 2b, might be more reactive and affords the β-product 5bβ before isomerization from the α-isomer 3bα to the β-isomer 3bβ. In this case, glycosylation via 3bα becomes the major

• potential precursor 7 of TMG-chitotriomycin (1) using disaccharide 5bβ as a building block as illustrated in Figure 3. The automated electrochemical assembly of building blocks was initiated by the anodic oxidation of 5bβ and the subsequent coupling with thioglycoside 4 afforded the corresponding

Total synthesis of a Streptococcus pneumoniae serotype 12F CPS repeating unit hexasaccharide

• Peter H. Seeberger,
• Claney L. Pereira and
• Subramanian Govindan

Beilstein J. Org. Chem. 2017, 13, 164–173, doi:10.3762/bjoc.13.19

• , which was to be carried forward into the C2 inversion step. Conversion of 13 to the corresponding C2 triflate upon treatment with triflic anhydride in pyridine was not successful. Even model thioglycoside 10 failed to react to the corresponding glycosyl triflate under similar conditions (Scheme 2). The

• problems associated with the lengthy and low yielding synthetic sequence prompted us to explore a different approach to obtain the key mannosazide building block (Scheme 3). Partially protected mannosazide thioglycoside 16 was prepared in seven steps from α-O-methylglucose following a published procedure

• [25]. Silylation of the C3 hydroxy group furnished thioglycoside 17. Glycosylation of the C5 linker by activation of 17 using NIS/TfOH as the promoter at −20 °C produced mainly β-mannoside 15 (4:1 β:α) [26]. The identity of the β-isomer was confirmed by NMR analysis (1JCH β = 159.0 Hz, see Supporting

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

• the galactose derivative 2 (Scheme 1). The reaction gave a 56% yield of 3 as a 1:1 mixture of α- and β-glucosides. Migration of a TBS group to the acceptor alcohol 2 was observed as a byproduct (10%). Attempts of glycosylating 2 with the thioglycoside or the corresponding glycosyl halides were

• been applied to prepare partially acylated cholestan glycosides. In this case an imidate with a 2-O-acetate and 3,4-O-TES protection was used, which ensured stereoselectivity by neighboring-group participation [11]. For similar reasons the per-TES-protected thioglycoside 7 was employed to prepare the

• acetyl and benzoyl are among the most electron-withdrawing of the common protective groups, whereas benzyl (or methyl) groups are less so, which is reflected in the reactivity of glycosyl donors carrying these groups. As shown in Figure 2, the thioglycoside with benzyl ethers 13 is about 40 times more

Mycothiol synthesis by an anomerization reaction through endocyclic cleavage

• Shino Manabe and
• Yukishige Ito

Beilstein J. Org. Chem. 2016, 12, 328–333, doi:10.3762/bjoc.12.35

• phthalimide group in the 2-position, was converted to α-glycoside 4, by introducing an N-acetyl 2,3-trans-carbamate group (Scheme 3) and by conducting an anomerization reaction. The glycosylation reaction of phthalimido-protected glucosamine thioglycoside 5 with inositol 6 [24] afforded β-linked pseudo

Synthesis of D-fructose-derived spirocyclic 2-substituted-2-oxazoline ribosides

• Madhuri Vangala and
• Ganesh P. Shinde

Beilstein J. Org. Chem. 2015, 11, 2289–2296, doi:10.3762/bjoc.11.249

• were eventually found to be unstable. Later in 2004, García Fernández and co-workers elegantly showed the formation of fused and spiroglycooxazolines from D-fructose [37]. More recently, Mong and co-workers synthesized fused glucopyranose oxazolines in nitrile solvents from thioglycoside donors and

Automated solid-phase synthesis of oligosaccharides containing sialic acids

• Chian-Hui Lai,
• Heung Sik Hahm,
• Chien-Fu Liang and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2015, 11, 617–621, doi:10.3762/bjoc.11.69

• these considerations sialyl phosphate building blocks 4 and 5 [14] were selected for automated glycan assembly using monosaccharides (Scheme 1). The synthesis of building block 4 commenced with the placement of a C-9 Fmoc protecting group on thioglycoside 1 [14] to produce 2. Installation of O

Synthesis of a hexasaccharide partial sequence of hyaluronan for click chemistry and more

• Marina Bantzi,
• Stephan Rigol and
• Athanassios Giannis

Beilstein J. Org. Chem. 2015, 11, 604–607, doi:10.3762/bjoc.11.67

• TBS group at O-4''' in 59% yield [22]. The excess amount of pyridine is necessary in order to avoid cleavage of the benzylidene acetals. Following the same concept, fully protected hexasaccharide 7 was synthesized. Therefore, thioglycoside 4 was activated with NIS and TfOH and subsequently combined

Synthesis of the pentasaccharide repeating unit of the O-antigen of E. coli O117:K98:H4

• Pintu Kumar Mandal

Beilstein J. Org. Chem. 2014, 10, 2724–2728, doi:10.3762/bjoc.10.287

• following the reaction pathway depicted in Scheme 2. Glycosylation of 3-azidopropyl 2,3,6-tri-O-benzyl-β-D-galactopyranoside (2) with the thioglycoside donor 3 in the presence of N-iodosuccinimide (NIS) and trimethylsilyl trifluoromethanesulfonate (TMSOTf) [26][27] gave disaccharide derivative 8 in 72

Galactan synthesis in a single step via oligomerization of monosaccharides

• Marius Dräger and
• Amit Basu

Beilstein J. Org. Chem. 2014, 10, 2658–2663, doi:10.3762/bjoc.10.279

• earlier attempt at the oligomerization of a 6-hydroxyglucosamine thioglycoside donor in the presence of an initiating primary alcohol resulted in a single glycosylation of the initiating alcohol to provide a glycoside product, and trace amounts of further oligomerization were detected in some cases [15

Efficient routes toward the synthesis of the D-rhamno-trisaccharide related to the A-band polysaccharide of Pseudomonas aeruginosa

• Aritra Chaudhury,
• Sajal K. Maity and
• Rina Ghosh

Beilstein J. Org. Chem. 2014, 10, 1488–1494, doi:10.3762/bjoc.10.153

• -rhamno-trisaccharide. The application of the reported regioselective radical-mediated deoxygenation on 4,6-O-benzylidene D-manno thioglycoside (hitherto unexplored) has potential for ramification in the field of synthesis of oligosaccharides based on 6-deoxy hexoses. Keywords: A-band polysaccharide; D

• -rhamno-trisaccharide; deoxygenation on thioglycoside; multivalent glycosystems; one-pot sequential glycosylation; Pseudomonas aeruginosa; Introduction With the firm establishment of the critical roles played by oligosaccharides in diverse biological processes [1][2][3][4], the field of oligosaccharide

• by the selective cleavage of the same with 80% aq AcOH. Compound 3a which is the phenyl thioglycoside analogue of 4 was also accessed similarly. Both the compounds were next converted to their rhamnoside counterparts 6 and 7 [44], respectively by treatment with di-tert-butyl peroxide (DTBP) and

Convergent synthesis of a tetrasaccharide repeating unit of the O-specific polysaccharide from the cell wall lipopolysaccharide of Azospirillum brasilense strain Sp7

• Pintu Kumar Mandal,
• Debashis Dhara and
• Anup Kumar Misra

Beilstein J. Org. Chem. 2014, 10, 293–299, doi:10.3762/bjoc.10.26

• (e.g. a protein, a lipid or another aglycone) for biochemical applications. A stereoselective [2 + 2] block glycosylation of the disaccharide derivative 8 with the disaccharide thioglycoside 9 led to the formation of tetrasaccharide 10, which was finally deprotected to give the desired tetrasaccharide

• in 77% yield. The formation of compound 8 was confirmed by NMR analysis (signals at δ 4.80 (br s, H-1B), 4.44 (d, J = 8.0 Hz, H-1A) and at δ 101.0 (C-1A), 99.4 (C-1B) in the 1H and 13C NMR spectra respectively) (Scheme 2). The 1,2-cis-glycosylation of thioglycoside 4 with thioglycoside 5 in the

• presence of a combination of NIS–TfOH [39][40] in the mixed solvent CH2Cl2/Et2O 1:1 furnished disaccharide thioglycoside derivative 9 in 75% yield. A minor quantity (~8%) of the 1,2-trans-glycosylated product was also formed under the reaction conditions but could be removed by column chromatography. The

Synthesis of homo- and heteromultivalent carbohydrate-functionalized oligo(amidoamines) using novel glyco-building blocks

• Felix Wojcik,
• Sinaida Lel,
• Alexander G. O’Brien,
• Peter H. Seeberger and
• Laura Hartmann

Beilstein J. Org. Chem. 2013, 9, 2395–2403, doi:10.3762/bjoc.9.276

• reaction of several thioglycosides and the double bond presenting diethylenetriamine succinic acid building block (DDS) 1, giving access to a small alphabet of carbohydrate-functionalized building blocks. TEC in flow enabled determining the reactivity of each thioglycoside at >275 nm, leading to optimized

• conditions. Integration of the HPLC UV-signals at 254 nm was used to establish residence time versus conversion plots (Figure 2). The plots showed close to complete conversion within 30 min residence time and 1.5 equiv of thioglycoside β-Glc(OAc)4-SH 2 (95%) or β-Gal(OAc)4-SH 3 (94%) (Figure 2; Glc and Gal

• established conditions (30 min; 1.5 equiv thioglycoside; 0.1 M). Although the reactivity of aminoglycosides 5 and 6 is in the same range as that of glycosides 2–4, we chose a higher excess of thiol component (2 equiv) for the production of glycosylated building blocks 11 and 12, resulting in >95% conversion

Synthesis of mucin-type O-glycan probes as aminopropyl glycosides

• David Benito-Alifonso,
• Rachel A. Jones,
• Anh-Tuan Tran,
• Hannah Woodward,
• Nichola Smith and
• M. Carmen Galan

Beilstein J. Org. Chem. 2013, 9, 1867–1872, doi:10.3762/bjoc.9.218

• thioglycoside donor. The NMR data of 22a unambiguously confirmed the presence of α-sialyl linkage (Δδ [H-9’a–H-9’b] = 0.62 ppm and J7’,8’ = 4.8 Hz) [24]. Acetal deprotection was subsequently carried out using p-TsOH in MeOH and the α-anomer of disaccharide 22b was isolated by silica gel column chromatography in

• and acceptors that both have a free hydroxy group [27]. In this report, we employed the difference in reactivity of trichloroacetimidates and thioglycoside donors. In general, trichloroacetimidates are activated by strong Lewis acids such as TMSOTf [28], while the more stable thioglycosides require

• the presence of a more electrophilic species such as N-iodosuccinimide/TMSOTf combinations [29][30]. To that end, thioglycoside building block 23 bearing a free OH at C-3 was synthesized following reported procedures [16] and subjected to a chemo- and stereoselective glycosylation reaction with

Straightforward synthesis of a tetrasaccharide repeating unit corresponding to the O-antigen of Escherichia coli O16

• Manas Jana and
• Anup Kumar Misra

Beilstein J. Org. Chem. 2013, 9, 1757–1762, doi:10.3762/bjoc.9.203

• iodonium ion mediated glycosylation conditions; (c) the use of p-methoxybenzyl (PMB) ether protection as an in situ removable protecting group in a one-pot glycosylation reaction and its removal [17] and (d) the use of galactofuranosidic thioglycoside as a glycosyl donor. The iodonium ion promoted

• the 1H and 13C NMR spectra respectively). The coupling of compound 6 with thioglycoside 4 in the presence of a combination of NIS and TfOH [18][19] in CH2Cl2/Et2O (1:3, v/v) furnished the 1,2-cis glycosylated compound 7 in 73% yield together with a minor quantity (~8%) of its other isomer, which was

• using sodium methoxide furnished the trisaccharide acceptor 8 in 94% yield. The stereoselective glycosylation of compound 8 with D-galactofuranosyl thioglycoside 5 by using a combination of NIS/TfOH furnished the tetrasaccharide derivative 9 in 72% yield. The formation of compound 9 was supported by its

Appel-reagent-mediated transformation of glycosyl hemiacetal derivatives into thioglycosides and glycosyl thiols

• Tamashree Ghosh,
• Abhishek Santra and
• Anup Kumar Misra

Beilstein J. Org. Chem. 2013, 9, 974–982, doi:10.3762/bjoc.9.112

• carbonotrithioate. The reaction conditions are reasonably simple and yields were very good. Keywords: Appel reagent; carbon tetrabromide; glycosyl hemiacetal; glycosyl thiol; thioglycoside; triphenylphosphine; Introduction Thioglycosides (1-thiosugar) are widely used glycosyl donors in glycosylation reactions [1

• -glycosyl bromide to the reactive β-glycosyl bromide in the presence of a catalytic bromide ion derived from TBAB, led to the formation of a 1,2-oxocarbonium ion by participation of the neighboring group, which finally furnished 1,2-trans-thioglycoside by the reaction of thiols under reasonably slow

• biphasic reaction conditions. The thioglycoside formation became very slow without the addition of TBAB and the same product was obtained in a poor yield over a much longer period of time. In contrast, rapid SN2-substitution of the bromide ion at the anomeric center in α-glycosyl bromide with a

Glycosylation efficiencies on different solid supports using a hydrogenolysis-labile linker

• Mayeul Collot,
• Steffen Eller,
• Markus Weishaupt and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2013, 9, 97–105, doi:10.3762/bjoc.9.13

• toluene. Thioglycoside 35 was activated with N-iodosuccinimide (NIS) and triflic acid (TfOH) in dichloromethane and dioxane. In order to establish optimal reaction conditions, temperatures ranging from −40 °C to 25 °C were screened and the reaction time was varied between 15 and 45 minutes. After

Acylsulfonamide safety-catch linker: promise and limitations for solid–phase oligosaccharide synthesis

• Jian Yin,
• Steffen Eller,
• Mayeul Collot and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2012, 8, 2067–2071, doi:10.3762/bjoc.8.232

• with either glucosamine thioglycoside 17 and glucosamine trichloroacetimidate 18 or perbenzylated thioglycoside 19, which are both important building blocks for the synthesis of heparin and heparan sulfate. Three repetitions of a glycosylation using each three equivalents trichloroacetimidate 18

• reactions result in the preactivation of the safety-catch linker, which can lead to cleavage in presence of nucleophiles. Similar results were observed when the experiments were repeated. The desired product 22 was detected in trace amounts only in the case of the coupling of thioglycoside 17 activated by

• in the production of glycosylated linker 21, implied that sodium methoxide may directly cleave safety-catch linkers without prior activation. To examine linker reactivity in more detail, additional automated glycosylations were performed by using thioglycoside 19 activated with NIS/TfOH, on

Convergent synthesis of the tetrasaccharide repeating unit of the cell wall lipopolysaccharide of Escherichia coli O40

• Abhijit Sau and
• Anup Kumar Misra

Beilstein J. Org. Chem. 2012, 8, 2053–2059, doi:10.3762/bjoc.8.230

• strategy. Results and Discussion The target tetrasaccharide 1 as its 2-aminoethyl glycoside was synthesized by a stereoselective glycosylation of a disaccharide acceptor 8 and a disaccharide thioglycoside donor 9 using a [2 + 2] block synthetic strategy. The disaccharide intermediates were synthesized from

• ) exploitation of the armed–disarmed glycosylation concept for the orthogonal activation of thioglycoside during the synthesis of disaccharide derivative 9 [19]; (d) use of aminoethyl linker as the anomeric protecting group; (e) removal of benzyl groups using a combination of triethylsilane and Pd(OH)2–C [20

• -benzylidene acetal with triethylsilane and iodine [22] furnished compound 6 in 82% yield. Stereoselective glycosylation of compound 6 with thioglycoside derivative 3 in the presence of a combination of N-iodosuccinimide (NIS) and HClO4–SiO2 [17] gave disaccharide derivative 7 in a 77% yield. Formation of

Automated synthesis of sialylated oligosaccharides

• Davide Esposito,
• Mattan Hurevich,
• Bastien Castagner,
• Cheng-Chung Wang and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2012, 8, 1601–1609, doi:10.3762/bjoc.8.183

• were applied to the synthesis of GM3 trisaccharide 16 previously prepared in solution phase (see above). Glucose thioglycoside building block 21 and disaccharide building block 4 served for the assembly of 16 (Scheme 4). Final saponification afforded the partially protected glycan 22 in 40% overall

• hydroxy nucleophile on the central glucosamine. Our first attempt to glycosylate using fucose thioglycoside building block 25 afforded the product in low yield and as a mixture of anomers as confirmed by LC–MS analysis. The use of N-phenyl trifluoroacetimidate building block 24 proved more efficient

Studies on the substrate specificity of a GDP-mannose pyrophosphorylase from Salmonella enterica

• Lu Zou,
• Ruixiang Blake Zheng and
• Todd L. Lowary

Beilstein J. Org. Chem. 2012, 8, 1219–1226, doi:10.3762/bjoc.8.136

• affording 15. The benzylidene protecting group was cleaved, together with the methyl glycoside, by acetolysis giving the tetra-O-acetylated compound 16 in 81% yield. This glycosyl acetate was converted to the corresponding thioglycoside (17), which was, in turn, coupled with dibenzyl phosphate under NIS

• % yield. Acetolysis of 27 to the corresponding glycosyl acetate 28, followed by reaction with ethanethiol and BF3·OEt2, yielded thioglycoside 29, in a modest 39% yield from 27 over two steps. This compound was then converted to 11, in 56% yield, as outlined above, by successive phosphorylation and

• the other they were protected with benzoyl esters. The overall yields of these two methods were 30% and 17%, respectively. In the first method (Scheme 4), the initial step was the conversion, in 78% yield, of the fully acetylated thioglycoside 31 [28] into silyl ether 32 by treatment with sodium