Chemoenzymatic synthesis of the cardenolide rhodexin A and its aglycone sarmentogenin

• Fuzhen Song,
• Mengmeng Zheng,
• Dongkai Wang,
• Xudong Qu and
• Qianghui Zhou

Beilstein J. Org. Chem. 2025, 21, 2637–2644, doi:10.3762/bjoc.21.204

• donor, through a late-stage glycosylation. The aglycon 2 can be derived from the Δ14 olefin intermediate 3 via Mukaiyama hydration and several functional group transformations. In turn, 3 would be generated from the key C14α-hydroxylated intermediate 4 via an elimination process. For the synthesis of 4

• hand, we first tried the synthesis of rhodexin A through direct glycosylation of 2 by the ʟ-rhamnose donor 2,3,4-tri-O-benzoyl-α-ʟ-rhamnopyranosyl trichloroacetimidate (14). However, the selective glycosylation at the C3-hydroxy group of 2 was a formidable challenge since competitive glycosylations of

• the other hydroxy groups of 2 could not be avoided, resulting in a complex mixture including mono-, di-, and triglycosylated products (Scheme 3A). Thus, both C11–OH and C14–OH needed to be masked before glycosylation. Based on this thought, we selected intermediate 11 as a suitable substrate for

Ex-situ generation of gaseous nitriles in two-chamber glassware for facile haloacetimidate synthesis

• Nikolai B. Akselvoll,
• Jonas T. Larsen and
• Christian M. Pedersen

Beilstein J. Org. Chem. 2025, 21, 2465–2469, doi:10.3762/bjoc.21.188

• trifluoroacetimidates to be more stable than their trichloroacetimidate counterparts [25]. Since these early examples trichloroacetimidates have become one of the most common glycosyl donors used in catalytic glycosylation, whereas the trifluoroacetimidates have received much less attention. Results and Discussion We

Enantioselective desymmetrization strategy of prochiral 1,3-diols in natural product synthesis

• Lihua Wei,
• Rui Yang,
• Zhifeng Shi and
• Zhiqiang Ma

Beilstein J. Org. Chem. 2025, 21, 1932–1963, doi:10.3762/bjoc.21.151

• monobenzoate 142 in 94% yield along with 4% yield of its diastereomer (dr = 24:1). Following a four-step conversion of 142 to epoxide 143, reductive cleavage produced a diol intermediate, which was subjected to chemoselective glycosylation with compound 144 to provide compound 145. After a four-step

• two steps. Macrocyclization of 147, followed by glycosylation with 135, gave compound 148, which was converted into azithromycin (149) upon desilylation. This desymmetrization strategy was also employed in the synthesis of (−)-dysiherbaine reported by Kang and co-workers in 2012 (Scheme 21) [61

Approaches to stereoselective 1,1'-glycosylation

• Daniele Zucchetta and
• Alla Zamyatina

Beilstein J. Org. Chem. 2025, 21, 1700–1718, doi:10.3762/bjoc.21.133

• are involved. Consequently, approaches to 1,1′-glycosylation for the synthesis of nonreducing disaccharides with defined anomeric configurations are essential for the development of 1,1′-disaccharide-containing biomolecules used in vaccine research, as well as for therapeutic and diagnostic

• applications. The assembly of nonreducing 1,1′-linked disaccharides presents greater challenges than conventional chemical glycosylation due to the need for simultaneous control of stereochemistry at two anomeric centers. The structural complexity of natural biomolecules entailing 1,1′-disaccharides, which

• advances in 1,1′-glycosylation and provides an overview of selected glycosylation strategies, including those aimed at forming α,β-, β,β-, and α,α-1,1′-glycosidic linkages. Particular emphasis is placed on the challenges of achieving stereoselectivity with lactol glycosyl acceptors, which commonly exist as

Structural analysis of stereoselective galactose pyruvylation toward the synthesis of bacterial capsular polysaccharides

• Tsun-Yi Chiang,
• Mei-Huei Lin,
• Chun-Wei Chang,
• Jinq-Chyi Lee and
• Cheng-Chung Wang

Beilstein J. Org. Chem. 2025, 21, 1671–1677, doi:10.3762/bjoc.21.131

• successfully obtained. Subsequently, the compound was used for the synthesis of zwitterionic polysaccharide A1 (PS A1) precursor, and a clear structural elucidation was applied by using nuclear magnetic resonance and X-ray. Keywords: carbohydrates; capsular polysaccharides; diastereochemistry; glycosylation

• derivatives, enabling the exploration of the practical applications of PSA1 while simultaneously enhancing our understanding of synthetic chemistry. To simplify the synthetic process, glycosylation was facilitated by employing preactivation and the differences in acceptor reactivity. Using the p

• same reaction mixture, in situ activation of disaccharide donor 8 and acceptor 9 using TolSCl/AgOTf reagent combination was introduced. This two-step, one-pot glycosylation gave a 42% yield of disaccharide 10, maintaining good β-stereoselectivity at the galactosyl linkage (α/β = 1:5.8). The 2

Chemical synthesis of glycan motifs from the antitumor agent PI-88 through an orthogonal one-pot glycosylation strategy

• Shaokang Yang,
• Xingchun Sun,
• Hanyingzi Fan and
• Guozhi Xiao

Beilstein J. Org. Chem. 2025, 21, 1587–1594, doi:10.3762/bjoc.21.122

• Academy of Sciences, Kunming 650201, China 10.3762/bjoc.21.122 Abstract Chemical synthesis of monophosphorylated glycan motifs from the antitumor agent PI-88 has been achieved through an orthogonal one-pot glycosylation strategy on the basis of glycosyl ortho-(1-phenylvinyl)benzoates, which not only

• glycosylation, respectively; 2) synthesis of PI-88 glycan motif pentasaccharide via [1 + 1 + 1] and [1 + 1 + 3] one-pot orthogonal glycosylation; 3) synthesis of hexasaccharide via [1 + 1 + 1] and [1 + 1 + 1 + 3] one-pot assembly. Keywords: carbohydrates; chemical synthesis; glycosyl ortho-(1-phenylvinyl

• )benzoates; one-pot glycosylation; PI-88; Introduction Carbohydrates as one of four essential biomolecules have been widely recognized as important targets for the development of carbohydrate-based therapeutics [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. The example in point is the

Oxetanes: formation, reactivity and total syntheses of natural products

• Peter Gabko,
• Martin Kalník and
• Maroš Bella

Beilstein J. Org. Chem. 2025, 21, 1324–1373, doi:10.3762/bjoc.21.101

• that this synthesis is easily scalable up to a 100 g scale. In the same year, Zhang et al. developed another highly modular route to 3,3-disubstituted oxetanes 173 via derivatization of oxetanyl trichloroacetimidates (Scheme 43) [95]. This method, inspired by a Schmidt glycosylation, provides easy

Recent advances in synthetic approaches for bioactive cinnamic acid derivatives

• Betty A. Kustiana,
• Galuh Widiyarti and
• Teni Ernawati

Beilstein J. Org. Chem. 2025, 21, 1031–1086, doi:10.3762/bjoc.21.85

• (Scheme 21C) [55]. Kawabata and co-workers (2020) prepared the β-glycoside 66 from α-ᴅ-glucose and cinnamic acid (7) in good yield through the Mitsunobu reaction (Scheme 22) [56]. The 13C kinetic isotope effect experiment (KIE = 1.028) showed that the glycosylation proceeded via SN2 substitution (67). Sun

Origami with small molecules: exploiting the C–F bond as a conformational tool

• Patrick Ryan,
• Ramsha Iftikhar and
• Luke Hunter

Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54

• -membered ring of pyranoses. However, it must be remembered that pyranoses are reactive molecules that can undergo, e.g., glycosylation, and it emerges that fluorine can play a much more significant conformational role during the dynamics of such chemical reactions [125][126][127][128][129][130

• ]. Glycosylation reactions (e.g., 63 → 65 and 64 → 66, Figure 9) proceed via an oxocarbenium intermediate. If fluorine is located at C-2, an electrostatic attraction might be expected between the partially negative fluorine and the positively charged C=O+ moiety, and this interaction would favour one of the half

• rate and the β-stereoselectivity of the glycosylation reaction (e.g., 63 → 65 vs 64 → 66, Figure 9) [129]. Of course, the fluorine substituent remains in the product, which may or may not be advantageous depending on the particular biological context. Let us now consider furanoses (i.e., five-membered

Beyond symmetric self-assembly and effective molarity: unlocking functional enzyme mimics with robust organic cages

• Keith G. Andrews

Beilstein J. Org. Chem. 2025, 21, 421–443, doi:10.3762/bjoc.21.30

• nucleophile and electrophile in a glycosylation reaction [105]. (D) An externally charged cavitand promotes charge-stabilized nucleophilic substitution reactions of hydrophobically encapsulated substrates [136][137]. (A) Metal-organic cages and key modes in catalysis. (B) Charged metals or ligands can result

The effect of neighbouring group participation and possible long range remote group participation in O-glycosylation

• Rituparna Das and
• Balaram Mukhopadhyay

Beilstein J. Org. Chem. 2025, 21, 369–406, doi:10.3762/bjoc.21.27

• multistep synthesis of complex oligosaccharides and in turn, standardise the process of the glycosylation towards a particular stereochemical output. While neighbouring group participation has been quite effective in achieving the required stereochemistry of the produced glycosides, remote participation

• exhibits comparatively less efficacy in achieving complete stereoselectivity in the glycosylation reactions. Remote participation is a still highly debated topic in the scientific community. However, implementing the participating role of the remote groups in glycosylation reactions is widely practised to

• achieve better stereocontrol and to facilitate the formation of synthetically challenging glycosidic linkages. Keywords: chemical O-glycosylation; neighbouring group participation; remote group participation; solvent effect; stereocontrol; Introduction Cell surface glycans in living cells have

N-Glycosides of indigo, indirubin, and isoindigo: blue, red, and yellow sugars and their cancerostatic activity

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 2840–2869, doi:10.3762/bjoc.20.240

• (4a) initially resulted in the glycosylation of the oxygen atom to give intermediate A (−20 °C, 1.5 h). Extension of the reaction time (20 °C, 12 h) afforded N-indigoglycoside 5a which was isolated in 35% yield. The product contained an α-rhamnosyl moiety with 4C1 conformation. The formation of the

• (Scheme 4) [20]. The reaction of 1b with 3,4,6-tri-O-acetyl-2-O-benzoyl-α-ᴅ-glucosyl trichloroacetimidate (6a) afforded indigo-N-glycoside 7a. The benzoyl group located at OH-2 seemed to be unreactive enough to avoid formation of orthoester-like amide acetals during the N-glycosylation with 1b. Oxidative

• sodium tert-butanolate afforded the desired deprotected indigo-N-rhamnoside 5d (α/β = 2:1). In contrast to the antiproliferative properties of the akashins, 5d showed no significant activity against human cancer cell lines. The glycosylation of 13 can be explained as follows (Scheme 9): Reaction of tetra

Improved deconvolution of natural products’ protein targets using diagnostic ions from chemical proteomics linkers

• Andreas Wiest and
• Pavel Kielkowski

Beilstein J. Org. Chem. 2024, 20, 2323–2341, doi:10.3762/bjoc.20.199

• -step synthesis. However, in comparison to the DMP-tag or AzidoTMT the release of the reporter ion from the SOX-tag has somewhat lower intensity. Calle et al. designed, synthesized, and validated a series of ‘clickable’ linkers for characterization of protein O-glycosylation containing positively

Computational toolbox for the analysis of protein–glycan interactions

• Ferran Nieto-Fabregat,
• Maria Pia Lenza,
• Angela Marseglia,
• Cristina Di Carluccio,
• Antonio Molinaro,
• Alba Silipo and
• Roberta Marchetti

Beilstein J. Org. Chem. 2024, 20, 2084–2107, doi:10.3762/bjoc.20.180

• -translational modifications, including glycosylation, in which a carbohydrate chain is directly attached to a specific amino acid to generate glycoproteins and proteoglycans [27]. Based on the amino acid involved in the link with the carbohydrates chain, it is possible to classify different types of

• glycosylation: i) N-glycosylation, where a N-acetylglucosamine (GlcNAc) is linked to the nitrogen atom of an asparagine side chain [28]; ii) O-glycosylation, where a GlcNAc or N-acetylgalactosamine (GalNAc) is linked to the hydroxy group of a serine or threonine residue [29]; iii) C-glycosylation, where a

• , flexibility, and heterogeneity. In particular, the Re-glyco tool allows the user to restore the missing glycosylation on glycoproteins deposited in the RCSB PDB or in the EBI-EMBL AlphaFold protein structure database (https://glycoshape.org/). The quality of the generated protein model is contingent on

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• catalysis with chemical synthesis [86]. By taking advantage of the chemo-enzymatically accessible 4, Sherman and co-workers further implemented the systematic total synthesis of juvenimicins and the M-4365 series via enzymatic and chemical late-stage modifications (Scheme 8B) [68]. In vivo glycosylation

Photoswitchable glycoligands targeting Pseudomonas aeruginosa LecA

• Yu Fan,
• Ahmed El Rhaz,
• Stéphane Maisonneuve,
• Emilie Gillon,
• Maha Fatthalla,
• Franck Le Bideau,
• Guillaume Laurent,
• Samir Messaoudi,
• Anne Imberty and
• Juan Xie

Beilstein J. Org. Chem. 2024, 20, 1486–1496, doi:10.3762/bjoc.20.132

• commercially available p,p’-dihydroxyazobenzene (6), by using our recently developed DMC (2-chloro-1,3-dimethylimidazolinium chloride)-mediated one-pot glycosylation method in water [28], followed by O-alkylation of the remaining hydroxy group with BrCH2CH2NHBoc and acidic deprotection (Scheme 1). Three

• equivalents of dihydroxyazobenzene 6 were used for the selective monoglycosylation step, with the excess of azobenene being recovered after column chromatography. Under these conditions, no bisglycosylated azobenzene was observed [28]. The observed 1,2-trans glycosylation could be explained either by the

• β-O-galactoside [36]. The same strategy was applied for the m,m’-substituted derivative 2, starting from the glycosylation of m,m’-dihydroxyazobenzene (9) [37], followed by O-alkylation and Boc deprotection to afford the galacoside 2 in 19% total yield. Unfortunately, all our attempts to synthesize

Synthesis of cyclic β-1,6-oligosaccharides from glucosamine monomers by electrochemical polyglycosylation

• Md Azadur Rahman,
• Hirofumi Endo,
• Takashi Yamamoto,
• Shoma Okushiba,
• Norihiko Sasaki and
• Toshiki Nokami

Beilstein J. Org. Chem. 2024, 20, 1421–1427, doi:10.3762/bjoc.20.124

• protecting group afforded the cyclic disaccharide exclusively. Cyclic oligosaccharides up to the trisaccharide were obtained using the monomer with a 2-azido-2-deoxy group. Keywords: cyclic oligosaccharide; electrochemical glycosylation; glucosamine; polyglycosylation; Introduction Electrochemical

• ][7][8][9][10]. Thus, chemical glycosylation has to be improved to be able to synthesize complex oligosaccharides, including cyclic oligosaccharides. In this context, electrochemical glycosylation is an important alternative to conventional chemical glycosylations because the precise control of

• intramolecular glycosylation (Scheme 1a) [14]. One-pot two-step synthesis via electrochemical polyglycosylation and intramolecular glycosylation has also been achieved in order to synthesize unnatural cyclic oligosaccharides of glucosamine (Scheme 1b) [15]. Here, we report the direct synthesis of cyclic

Monitoring carbohydrate 3D structure quality with the Privateer database

• Jordan S. Dialpuri,
• Haroldas Bagdonas,
• Lucy C. Schofield,
• Phuong Thao Pham,
• Lou Holland and
• Jon Agirre

Beilstein J. Org. Chem. 2024, 20, 931–939, doi:10.3762/bjoc.20.83

• complement the growing glycan content of the PDB. Keywords: carbohydrates; database; N-glycans; N-glycosylation; polysaccharides; validation; website; Introduction Carbohydrate modelling is an important but often cumbersome stage in the macromolecular X-ray structure solution workflow. The accurate

• calculated by Privateer and, most importantly, the diagnostic provided by Privateer (Figure 4). A ‘yes’ diagnostic indicates the conformation is correct for the glycosylation type (e.g., 4C1 for GlcNAc in an N-glycan, 1C4 for mannose in a C-glycan), has the correct anomer, and has an acceptable fit to

• interface on the Privateer database homepage, carbohydrate-containing PDB entries can easily be found and filtered. Privateer database entries for specific glycosylation types, namely, N-glycosylation, O-glycosylation, S-glycosylation, or C-glycosylation can be filtered quickly and easily. Additional

Research progress on the pharmacological activity, biosynthetic pathways, and biosynthesis of crocins

• Zhongwei Hua,
• Nan Liu and
• Xiaohui Yan

Beilstein J. Org. Chem. 2024, 20, 741–752, doi:10.3762/bjoc.20.68

• ), or zeaxanthin (7) by a carotenoid cleavage dioxygenase (CCD) to form crocetin aldehyde (8) and, after oxidation, 1, and 3) glycosylation of 1 to generate crocins (Figure 3). Since the biosynthetic pathways of 5 in plants and microorganisms have been elucidated and reviewed, we will only elaborate the

• crocins The late steps in crocin biosynthesis are the glycosylation of crocetin (1) by various UGTs [86]. The crocin biosynthetic pathways in G. jasminoides have been characterized in detail, and several GjUGTs were identified. Attributed to different substrate specificities, the glucose or gentiobiose

• that it was able to convert crocetin dialdehyde (8) into crocetin (1) in vitro [100]. BdALDH and CsALDH3I1 belong to the ALDH3 family, one of the most diverse groups of the ALDH superfamily. UGTs: Glycosylation of crocetin (1) improves the solubility significantly [101][102]. Moraga et al. cloned two

Chemoenzymatic synthesis of macrocyclic peptides and polyketides via thioesterase-catalyzed macrocyclization

• Senze Qiao,
• Zhongyu Cheng and
• Fuzhuo Li

Beilstein J. Org. Chem. 2024, 20, 721–733, doi:10.3762/bjoc.20.66

• overall yield. According to the biosynthetic approach, these macrolides are produced by the type I PKS system, including thioesterase (TE)-catalyzed cyclization of the linear hexa- and heptaketide intermediates, post-PKS oxidation, and glycosylation [67]. Cane and co-workers reported that Pik TE, the TE

• macrolactonization, leading to the formation of tylactone (39) in 69% yield. Furthermore, the Streptomyces strain S. venezuelae DHS316 [76] performed an in vivo glycosylation resulting in M-4365 G1 (50) in 15 linear steps and 4.6% overall yield from commercial resources. With regio- and stereoselective C–H

Introduction of a human- and keyboard-friendly N-glycan nomenclature

• Friedrich Altmann,
• Johannes Helm,
• Martin Pabst and
• Johannes Stadlmann

Beilstein J. Org. Chem. 2024, 20, 607–620, doi:10.3762/bjoc.20.53

• greatly facilitate keyboard-based mining for glycan substructures in glycan repositories. Keywords: N-glycans; nomenclature; structural features; Introduction Virtually any article on protein glycosylation starts with imposing assurances about the biological significance of the various structures. This

• “proglycan” nomenclature, an acronym derived from our then nom de guerre “protein-glycosylation analysis” group. By the way, glycan analysis also funneled in activities in the area of allergy diagnosis, where the term MUXF3 enjoys widespread use [38][39][40]. Finally, our work on the isomer-specific analysis

Elucidating the glycan-binding specificity and structure of Cucumis melo agglutinin, a new R-type lectin

• Jon Lundstrøm,
• Emilie Gillon,
• Valérie Chazalet,
• Nicole Kerekes,
• Antonio Di Maio,
• Ten Feizi,
• Yan Liu,
• Annabelle Varrot and
• Daniel Bojar

Beilstein J. Org. Chem. 2024, 20, 306–320, doi:10.3762/bjoc.20.31

• profiling, thereby advancing both diagnostic methods and biomarker discovery. Examples include arrays that can rapidly profile alterations in glycosylation patterns, pivotal in many diseases and inflammatory changes [10][11]. Traditionally, lectins are divided into classes based on structural similarity and

• ). In parallel, we also expressed CMA1 in a bacterial expression system, which allowed us to ascertain whether binding was influenced by lectin glycosylation. The full-length mature protein (6–264) and individual N- or C-terminal domains were expressed using a N-terminal fusion comprising DsbC and a

• binding in solution and a further confirmation of the binding specificity obtained by the array experiments. We note that the functional activity of bacterially produced CMA1 indicates that potential modification by glycosylation is not required for ligand binding. Next, we set out to quantify the binding

Optimizations of lipid II synthesis: an essential glycolipid precursor in bacterial cell wall synthesis and a validated antibiotic target

• Milandip Karak,
• Cian R. Cloonan,
• Brad R. Baker,
• Rachel V. K. Cochrane and
• Stephen A. Cochrane

Beilstein J. Org. Chem. 2024, 20, 220–227, doi:10.3762/bjoc.20.22

• bacteria. Accessing this valuable cell wall precursor is important both for studying cell wall synthesis and for studying/identifying novel antimicrobial compounds. Herein, we describe optimizations to the modular chemical synthesis of lipid II and unnatural analogues. In particular, the glycosylation step

• analogues through the incorporation of alternative building blocks at different stages of synthesis. Keywords: chemical glycosylation; lipid II; peptidoglycan; polyprenyls; total synthesis; Introduction Lipid II (Figure 1) is an essential bacterial glycolipid involved in peptidoglycan biosynthesis [1]. It

• describe herein. The base lipid II syntheses upon which optimizations were made are our previously reported syntheses of Gram-negative lipid II in 2016 [20] and Gram-positive lipid II (11) in 2018 [23]. Building upon these synthetic strategies we have achieved noteworthy enhancements in glycosylation

Comparison of glycosyl donors: a supramer approach

• Anna V. Orlova,
• Nelly N. Malysheva,
• Maria V. Panova,
• Nikita M. Podvalnyy,
• Michael G. Medvedev and
• Leonid O. Kononov

Beilstein J. Org. Chem. 2024, 20, 181–192, doi:10.3762/bjoc.20.18

• , Russian Federation 10.3762/bjoc.20.18 Abstract The development of new methods for chemical glycosylation commonly includes comparison of various glycosyl donors. An attempted comparison of chemical properties of two sialic acid-based thioglycoside glycosyl donors, differing only in the substituent at O-9

• (trifluoroacetyl vs chloroacetyl), at different concentrations (0.05 and 0.15 mol·L−1) led to mutually excluding conclusions concerning their relative reactivity and selectivity, which prevented us from revealing a possible influence of remote protective groups at O-9 on glycosylation outcome. According to the

• and straightforward as it is usually considered. Keywords: concentration; glycosylation; protecting groups; reactivity; sialic acids; stereoselectivity; Introduction Glycoconjugates containing sialic acid occur on the surface of all cell types in a variety of organisms. They participate in a broad

Synthesis of the 3’-O-sulfated TF antigen with a TEG-N₃ linker for glycodendrimersomes preparation to study lectin binding

• Mark Reihill,
• Hanyue Ma,
• Dennis Bengtsson and
• Stefan Oscarson

Beilstein J. Org. Chem. 2024, 20, 173–180, doi:10.3762/bjoc.20.17

• glycosylation reactions. The 3’-sulfate was finally introduced through tin activation in benzene/DMF followed by treatment with a sulfur trioxide–trimethylamine complex in a 66% yield. Keywords: regioselective sulfation; thioglycoside donors; Thomsen–Friedenreich antigen; Introduction In a collaboration

• at this stage was predicted to be problematic. Therefore, the azido functionality was installed in the spacer before the glycosylation. Donor 3 underwent an NIS/AgOTf-promoted glycosylation with the TEG-N3 acceptor [18], furnishing α-linked 4 in an 85% yield (Scheme 1). H-1 appeared as a doublet at

• choice [12], surprisingly better than a benzoylated donor [19], why this donor was the first one tested also with the quite different acceptor 5. An NIS/AgOTf-promoted glycosylation with donor 6 [20] yielded 79% of disaccharide 7. Due to the presence of rotamers, NMR spectra of 7 proved to be difficult