The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

• , reported that, by using hexafluoroisopropanol (HFIP) as the solvent, GBB adducts derived from glycal aldehydes could be isolated without additional catalysts in a few hours at 25–50 °C [10]. In this case, however, the role of the solvent as a Brønsted acid cannot be ruled out (this article will be

• (Scheme 13). Glycal aldehydes 32 were synthetized starting from ᴅ-glucose and ᴅ-galactose, following an established procedure [40]. The scope of the reaction was evaluated using differently substituted amidines, and 9 different 2-(β-ᴅ-glycal-1-yl-)-3-N-alkylamino-1-azaindolizines 33 were synthesized in

Synthesis, docking study and biological evaluation of ᴅ-fructofuranosyl and ᴅ-tagatofuranosyl sulfones as potential inhibitors of the mycobacterial galactan synthesis targeting the galactofuranosyltransferase GlfT2

• Marek Baráth,
• Jana Jakubčinová,
• Zuzana Konyariková,
• Stanislav Kozmon,
• Katarína Mikušová and
• Maroš Bella

Beilstein J. Org. Chem. 2020, 16, 1853–1862, doi:10.3762/bjoc.16.152

• fluorinated exo-glycal analogue of UDP-Galf in a radiometric assay with a glycolipid acceptor substrate and crude mycobacterial enzymes [31]. Therefore, we decided to examine compounds 1bα and 3a, representing the best and the worst inhibitors, respectively, according to the docking study, in the range of 1

Synthesis of C-glycosyl phosphonate derivatives of 4-amino-4-deoxy-α-ʟ-arabinose

• Lukáš Kerner and
• Paul Kosma

Beilstein J. Org. Chem. 2020, 16, 9–14, doi:10.3762/bjoc.16.2

• lactone with the lithium salt of dimethyl methylphosphonate followed by an elimination step of the resulting hemiketal, leading to the corresponding exo- and endo-glycal derivatives. The ensuing selective monodemethylation and hydrogenolysis of the benzyl groups and reduction of the 4-azido group gave the

• α-ʟ-anomeric arabino- and ribo-configured methyl phosphonate esters. In addition, the monomethyl phosphonate glycal intermediates were converted into n-octyl derivatives followed by subsequent selective removal of the methyl phosphonate ester group and hydrogenation to give the octylphosphono

• compounds to allow for future incorporation of different lipid chains and options towards glycal analogues as potential transition state analogues to inhibit 4-amino-4-deoxy-ʟ-arabinose transfer to bacterial LPS. Results and Discussion The previously synthesized [14] methyl 4-azido-4-deoxy-α-ʟ

SnCl₄-catalyzed solvent-free acetolysis of 2,7-anhydrosialic acid derivatives

• Kesatebrhan Haile Asressu and
• Cheng-Chung Wang

Beilstein J. Org. Chem. 2019, 15, 2990–2999, doi:10.3762/bjoc.15.295

• Ac2O afforded glycal 13 (Table 1, entries 1–4). None of these conditions were successful for the acetolysis of these 2,7-anhydro derivatives, although they worked for the 1,6-anhydro sugars [29][32][33]. Adding 10 equiv of acetic acid to suppress the 2,3-elimination reaction failed to give the desired

• compound 12. Due to the absence of a hydrogen bond, azido-protected glycal 13 could be used as acceptor for reactions at its OH-4 and OH-8 group [36][37]. Moreover, it was used as sialyl donor in α-selective glycosylation reactions [35]. Next, acetolysis of 2,7-anhydro derivative 6 was examined with SnCl4

• optimized conditions and gave the desired acetolysis products 22 and 26. While ring opening of the triacetylated 6 and trimethylated 21 were accompanied by competitive 2,3-elimination, yielding products 13 (34%) and 23 (27%), respectively (Table 2, entries 1 and 2), the formation of glycal 28 from substate

Robust perfluorophenylboronic acid-catalyzed stereoselective synthesis of 2,3-unsaturated O-, C-, N- and S-linked glycosides

• Madhu Babu Tatina,
• Xia Mengxin,
• Rao Peilin and
• Zaher M. A. Judeh

Beilstein J. Org. Chem. 2019, 15, 1275–1280, doi:10.3762/bjoc.15.125

• -acetyl-D-glucal 4a and O- and S-nucleophiles. Perfluorophenylboronic-acid-catalyzed reaction between 3,4-di-O-acetyl-L-rhamnal (6a) and O- and S-nucleophiles. Plausible perfluorophenylboronic acid-catalyzed activation of glycal 1a. Optimization of the arylboronic acid-catalyzed reaction of 3,4,6-tri-O

Synthesis, biophysical properties, and RNase H activity of 6’-difluoro[4.3.0]bicyclo-DNA

• Sibylle Frei,
• Adam K. Katolik and
• Christian J. Leumann

Beilstein J. Org. Chem. 2019, 15, 79–88, doi:10.3762/bjoc.15.9

• -DNA (6’-diF-bc4,3-DNA). The difluorinated thymidine phosphoramidite building block was synthesized starting from an already known gem-difluorinated tricyclic glycal. This tricyclic siloxydifluorocyclopropane was converted into the [4.3.0]bicyclic nucleoside via cyclopropane ring-opening through the

• corresponding siloxydifluorocyclopropane [38][39][40]. However, based on previous observations in the nucleoside synthesis of the 6’F-bc4,3-T [37] we thought to construct the 6’-diF-bc4,3 building block in utilizing this methodology. Along this synthesis, the glycal 1 was treated with N-iodosuccinimide (NIS) in

6’-Fluoro[4.3.0]bicyclo nucleic acid: synthesis, biophysical properties and molecular dynamics simulations

• Sibylle Frei,
• Andrei Istrate and
• Christian J. Leumann

Beilstein J. Org. Chem. 2018, 14, 3088–3097, doi:10.3762/bjoc.14.288

• spectra (Supporting Information File 1). The plan for the pyrimidine nucleoside synthesis comprised the use of the meanwhile well-established β-selective N-iodosuccinimide (NIS)-mediated addition of a persilylated nucleobase to a tricyclic glycal [43][45][53][54]. Therefore, the gem-difluorinated

• tricyclic sugars 3α/β were individually reacted with trimethylsilyl trifluoromethanesulfonate (TMSOTf) in order to produce the corresponding glycal 4. Surprisingly, apart from the desired glycal 4 its hydrolysis products 5α/β were produced as main side products. In the case of the α-tricyclic sugar 3α the

• ratio of products 4 to 5α/β could be influenced by the reaction time. A shorter reaction time furnished the tricyclic alcohols 5α/β as major product, while prolongation of the reaction time produced the glycal 4 as main component (Table S1, Supporting Information File 1). Treatment of the glycal 4 with

Stereodivergent approach in the protected glycal synthesis of L-vancosamine, L-saccharosamine, L-daunosamine and L-ristosamine involving a ring-closing metathesis step

• Pierre-Antoine Nocquet,
• Aurélie Macé,
• Frédéric Legros,
• Jacques Lebreton,
• Gilles Dujardin,
• Sylvain Collet,
• Arnaud Martel,
• Bertrand Carboni and
• François Carreaux

Beilstein J. Org. Chem. 2018, 14, 2949–2955, doi:10.3762/bjoc.14.274

• structures 3-amino-2-deoxy sugars [1]. For instance, N,N-dimethyl-L-vancosamine is an essential component of pluramycin antibiotics such as kidamycin and pluramycin A via a C-glycosidic linkage (Figure 1). For constructing aryl C-glycoside bonds, glycal derivatives are versatile synthetic intermediates

• glycal scaffolds are versatile building blocks with multiple applications in the field of natural product synthesis [6], the development of new asymmetric synthetic sequences with stereochemical diversity is still of high interest. Different approaches have been reported for the asymmetric synthesis of

• protected 3-aminoglycals from non-carbohydrate precursors. Most of them used a common methodology for the construction of the pyranosyl glycal ring which is based on a cycloisomerization reaction of chiral homopropargylic alcohols [7][8][9][10]. In some cases, the strategy used for the preparation of the

Glycosylation reactions mediated by hypervalent iodine: application to the synthesis of nucleosides and carbohydrates

• Yuichi Yoshimura,
• Hideaki Wakamatsu,
• Yoshihiro Natori,
• Yukako Saito and
• Noriaki Minakawa

Beilstein J. Org. Chem. 2018, 14, 1595–1618, doi:10.3762/bjoc.14.137

• well. The extension of hypervalent iodine-mediated glycosylation allowed us to couple a nucleobase with cyclic allylsilanes and glycal derivatives to yield carbocyclic nucleosides and 2’,3’-unsaturated nucleosides, respectively. In addition, the combination of hypervalent iodine and Lewis acid could be

• synthesize new carbocyclic nucleosides. Synthesis of dihydropyranonucleosides The success of the oxidative coupling reaction for constructing a carbocyclic nucleoside skeleton led us to develop a glycosylation reaction applicable to glycal derivatives. Since an electron-rich enol ether unit of glycal could

• oxidation of an allylsilane 86 with PhI(OAc)2 and TMSOTf, and 2) the subsequent nucleophilic attack of the persilylated base to 87 as shown in Figure 5. Therefore, we expected that subjecting the electron-rich glycal 100 to the hypervalent iodine-mediated reaction described above would generate an

Synthetic and semi-synthetic approaches to unprotected N-glycan oxazolines

• Antony J. Fairbanks

Beilstein J. Org. Chem. 2018, 14, 416–429, doi:10.3762/bjoc.14.30

• % overall yield, Scheme 8). In the key transformation, the mannose residue at the reducing terminus was then converted into a glucosamine derivative (in fact possessing an azide at C2) first by conversion to the glycal and then an azido nitration reaction. This innovative method is considerably shorter than

Intramolecular glycosylation

• Xiao G. Jia and
• Alexei V. Demchenko

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

• technique to glycosidic bond formation has been hampered by the difficulty in the formation of the palladium π-allyl intermediates and their poor reactivity in the electron-rich glycal systems [120]. To overcome this challenge the Liu group explored the application of palladium π-allyl intermediates to O

Orthogonal protection of saccharide polyols through solvent-free one-pot sequences based on regioselective silylations

• Serena Traboni,
• Emiliano Bedini and
• Alfonso Iadonisi

Beilstein J. Org. Chem. 2016, 12, 2748–2756, doi:10.3762/bjoc.12.271

• amount of TBAB, pyridine and TBDMSCl, the regioselective synthesis of di-O-TBDMS derivatives was achieved at 50 °C in satisfying yields from glycosides 1 and 3 (Table 3, entries 1 and 2), and glycal 8 (entry 3). Double silylation at primary positions of the disaccharide lactoside 20 [60] also proved

• benzylation step (Table 4, entry 8). In the case of glycal 8, the application of a benzylation/silylation sequence resulted in very good yields with both silylating agents (Table 4, entries 7 and 8), although the 6-O-silylation alone had been low yielding in the initial set of experiments (Table 2, entries 6

TMSBr-mediated solvent- and work-up-free synthesis of α-2-deoxyglycosides from glycals

• Mei-Yuan Hsu,
• Yi-Pei Liu,
• Sarah Lam,
• Su-Ching Lin and
• Cheng-Chung Wang

Beilstein J. Org. Chem. 2016, 12, 1758–1764, doi:10.3762/bjoc.12.164

• that the acid-catalysed nucleophilic addition of an alcohol to a glycal is likely to proceed through the formation of an oxocarbenium ion via the protonation at C2 [6][63]. In the presence of TPPO, the oxocarbenium cation is stabilized by the ion–dipole interaction with TPPO oriented preferably at the

A general metal-free approach for the stereoselective synthesis of C-glycals from unactivated alkynes

• Shekaraiah Devari,
• Manjeet Kumar,
• Ramesh Deshidi,
• Masood Rizvi and
• Bhahwal Ali Shah

Beilstein J. Org. Chem. 2014, 10, 2649–2653, doi:10.3762/bjoc.10.277

• single step from a variety of acetylenes , i.e., arylacetylenes and most importantly aliphatic alkynes. Keywords: α-selective; C-alkynylation; glycal; metal free; TMSOTf; Introduction C-Glycosides represent an important class of carbohydrate mimics, owing to their presence in a large number of

Design and synthesis of multivalent neoglycoconjugates by click conjugations

• Feiqing Ding,
• Li Ji,
• Ronny William,
• Hua Chai and
• Xue-Wei Liu

Beilstein J. Org. Chem. 2014, 10, 1325–1332, doi:10.3762/bjoc.10.134

• hydroamination/glycosylation on glycal scaffolds has been developed to form propargyl 3-tosylamino-2,3-dideoxysugars in a one-pot manner. Subsequent construction of multivalent 3-tosylamino-2,3-dideoxyneoglycoconjugates with potential biochemical applications was presented herein involving click conjugations as

• /glycosylation of the glycal shown in Figure 1 [49][50][51][52][53]. Extending the synthetic utility of this protocol, herein, we wish to report the synthetic modification of α-GalNAc-linked glycopeptides to 3-tosylamino-2,3-dideoxyneoglycoconjugates via click conjugations (Figure 2). Given the success in using

• , entry 7). Next, the required α-propargyl 3-tosylamino-2,3-dideoxyglycosides 2 were synthesized by BF3∙OEt2-promoted one-pot three-component tandem hydroamination/glycosylation reaction on a glycal scaffold including tri-O-acetyl-D-glucal (1a), tri-O-acetyl-D-allal (1b), tri-O-acetyl-D-galactal (1c), di

Olefin cross metathesis based de novo synthesis of a partially protected L-amicetose and a fully protected L-cinerulose derivative

• Bernd Schmidt and
• Sylvia Hauke

Beilstein J. Org. Chem. 2014, 10, 1023–1031, doi:10.3762/bjoc.10.102

• sugar biosynthesis genes [5]. Comparatively few transition metal mediated or -catalyzed reactions have hitherto been used for the synthesis of 2,3,6-tridesoxy sugars such as amicetose. An example is the W-promoted cycloisomerization of lactaldehyde derived alkynols, which yields the glycal of amicetose

Efficient carbon-Ferrier rearrangement on glycals mediated by ceric ammonium nitrate: Application to the synthesis of 2-deoxy-2-amino-C-glycoside

• Alafia A. Ansari,
• Y. Suman Reddy and
• Yashwant D. Vankar

Beilstein J. Org. Chem. 2014, 10, 300–306, doi:10.3762/bjoc.10.27

• the poor solubility of CAN, whereas in acetone the reaction gave lower yields. After several optimization experiments, the reaction was observed to be most efficient when 2 equivalents of silane and one equivalent of CAN, with respect to the glycal, was used in acetonitrile. The reaction was then

• Information File 1) and 2k [42], respectively. These findings indicate that the protecting groups were not affected by this reagent system. D-rhamnal 1j and D-ribose derived glycal 1l [46] yielded hitherto unknown C-allyl glycosides 2j and 2l, respectively (see Supporting Information File 1). However, the

Synthesis and antifungal properties of papulacandin derivatives

• Marjolein van der Kaaden,
• Eefjan Breukink and
• Roland J. Pieters

Beilstein J. Org. Chem. 2012, 8, 732–737, doi:10.3762/bjoc.8.82

• spiroketal unit, which is introduced in a palladium-catalyzed cross-coupling reaction of a glycal silanolate and an aryl iodide followed by an oxidative spiroketalization. Four different variants were made, differing in the nature of the acyl side chain with respect to the length, and in the number and

• the core of the structure, as present in papulacandin D, was approached from glycal 15. The aim was to obtain a silanol such as 22 for coupling to an aryl iodide in the palladium-catalyzed cross-coupling reactions of silanolates, as pioneered and applied by the Denmark group (Scheme 2) [48]. The

• acid derivative 50 was measured as 100 μg/mL. The saturated palmitic acid derivative 49 was slightly more potent with an MIC of 88 μg/mL. Discussion Starting from glycal the synthesis of papulacandin D derivatives was undertaken with an initial focus on the acyl side chain, a clearly sensitive area for

Sonogashira–Hagihara reactions of halogenated glycals

• Dennis C. Koester and
• Daniel B. Werz

Beilstein J. Org. Chem. 2012, 8, 675–682, doi:10.3762/bjoc.8.75

• cross-coupling reaction with iodoarenes. However, it is not only metalated sugar derivatives that have prevailed in the synthesis of C-glycosides, but also some electrophilic coupling reagents, such as glycalyl phosphates, and bromo- and iodoglycals. Glycal phosphates of type 5 were employed as

• of the sugar core is particularly high, rendering the 2-palladated glycal a bad electrophile towards electron-poor or electron-neutral alkynes. To push the reaction an elevated temperature was necessary, and only moderate yields were obtained. Efforts to react perbenzylated 2-chloro-1-iodoglucal 12

Acid- mediated reactions under microfluidic conditions: A new strategy for practical synthesis of biofunctional natural products

• Katsunori Tanaka and
• Koichi Fukase

Beilstein J. Org. Chem. 2009, 5, No. 40, doi:10.3762/bjoc.5.40

• only 60% of α-sialoside accompanied by a significant amount of a glycal by-product. The decrease in sialylation efficiency might be due to the high reactivity of the donor 1a. For such a case, precise reaction control is very difficult under the conventional batch process conditions, especially when

• the reaction is scaled-up. Thus, the disorder of the reaction factors in the scaled-up batch reaction, i.e., (i) precise temperature control, (ii) mixing efficiency between acceptor, donor, and Lewis acid, and (iii) reaction time, might lead to the glycal production. In order to circumvent these

• severe problem under such drastic conditions [41]. The use of excess amounts of donor 1a and/or TMSOTf in batch reaction did not improve the sialylation yield, but rather resulted in a large amount of glycal production. Apparently, the efficient micromixing between substrates and the high concentration

Study of thioglycosylation in ionic liquids

• Jianguo Zhang and
• Arthur Ragauskas

Beilstein J. Org. Chem. 2006, 2, No. 12, doi:10.1186/1860-5397-2-12

• ionic liquids for the synthesis of alkyl glycoside and disaccharides via coupling of thioalkyl glycosyl donors with glycal acceptors. Alkyl glycosides and oligosaccharides are important intermediates and products in the synthesis of biologically active natural compounds and mimics. For example, tetra-O