Synthesis, α-mannosidase inhibition studies and molecular modeling of 1,4-imino-ᴅ-lyxitols and their C-5-altered N-arylalkyl derivatives

• Martin Kalník,
• Sergej Šesták,
• Juraj Kóňa,
• Maroš Bella and
• Monika Poláková

Beilstein J. Org. Chem. 2023, 19, 282–293, doi:10.3762/bjoc.19.24

• inhibitor:enzyme complexes were analyzed by molecular modeling. Keywords: glycosidase inhibitor; Golgi mannosidase II; iminosugar; inhibition; molecular modeling; Introduction Iminosugars are analogs of monosaccharides in which the endocyclic oxygen atom is replaced with a nitrogen atom [1][2][3][4][5]. These

• that are involved in diseases such as viral infections, diabetes or cancer and lysosomal storage disorders [7][8][9]. Thus, iminosugar derivatives are promising candidates for pharmaceuticals, and many of them have already been approved for treatments, for example miglitol (type 2 diabetes), miglustat

• (lysosomal storage disorders, e.g., Gaucher disease) and migalstat (Fabry disease, an orphan drug) [8][10]. Natural iminosugars can be monocyclic or bicyclic compounds since the presence of the nitrogen atom allows for a formation of an additional cycle. In synthetic iminosugar analogs, various structural

1,4-Dithianes: attractive C2-building blocks for the synthesis of complex molecular architectures

• Bram Ryckaert,
• Ellen Demeyere,
• Frederick Degroote,
• Hilde Janssens and
• Johan M. Winne

Beilstein J. Org. Chem. 2023, 19, 115–132, doi:10.3762/bjoc.19.12

• used dihydrodithiin-scaffolding is tentatively indicated on the target structures 70–81 [62][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80]. D’Alonzo, Palumbo, Guaranga and co-workers also developed a de novo synthesis of the unnatural enantiomer of the iminosugar drug miglustat

Direct synthesis of anomeric tetrazolyl iminosugars from sugar-derived lactams

• Michał M. Więcław and
• Bartłomiej Furman

Beilstein J. Org. Chem. 2021, 17, 115–123, doi:10.3762/bjoc.17.12

• molecule incorporating both an iminosugar and a tetrazole fragment is of particular interest, due to the interesting properties of both moieties (Figure 1). It is probably hard to overestimate the importance of sugar scaffolds in nature, and we believe that it speaks for itself, however, a significance of

• iminosugar derivatives may be less obvious. Several pharmaceuticals are based on this scaffold including the glucose-derived nojirimycin, an antibiotic and glycosidase inhibitor [26] and 1-deoxygalactonojirimycin, known under the trade name Galafold®, which is utilized for the treatment of the Fabry disease

• ones in this work – fused iminosugar-tetrazoles – which have shown inhibition properties against bovine liver α-ᴅ-glucuronidase and human β-ʟ-iduronidase [29]. Moreover, there are numerous reports of the organocatalytic activity of chiral aminotriazoles and aminotetrazoles in number of reactions, such

N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds

• Iwona E. Głowacka,
• Aleksandra Trocha,
• Andrzej E. Wróblewski and
• Dorota G. Piotrowska

Beilstein J. Org. Chem. 2019, 15, 1722–1757, doi:10.3762/bjoc.15.168

• hydrogenation followed by saponification converted 178 into (2S,3S)-N-Boc-3-hydroxy-2-hydroxymethylpyrrolidine (2S,3S)-179, one of the simplest members of the iminosugar family. Reaction of aziridine 4-methoxyphenyl esters either (2R,1′S)-5e or (2S,1′S)-5e with vinylene carbonate at 280 °C gave a mixture of

• ), respectively. Their enantiomers were prepared from the aziridine aldehyde (2S,1'R)-6 in an analogous manner. 2,5-Imino-2,5,6-trideoxy-ʟ-gulo-heptitol ((2S,3R,4R,5R)-184) an iminosugar isolated from Hyacintus orientalis was recognized as inhibitor of glycosidases [104]. The efficient syntheses of (2S,3R,4R,5R

Synthesis of pyrrolidine-based hamamelitannin analogues as quorum sensing inhibitors in Staphylococcus aureus

• Jakob Bouton,
• Kristof Van Hecke,
• Reuven Rasooly and
• Serge Van Calenbergh

Beilstein J. Org. Chem. 2018, 14, 2822–2828, doi:10.3762/bjoc.14.260

• developed and delivered the pyrrolidine analogue in 17 steps in high yield. Chemoselective derivatization of the pyrrolidine nitrogen atom resulted in 6 more compounds. The synthesized compounds were evaluated in a biofilm model, but were all inactive. Keywords: hamamelitannin; iminosugar; pyrrolidine

• pyrrolidine-based hamamelitannin analogues is depicted in Scheme 1. The synthesis of 4 as a key intermediate allows to gain access to a diverse set of analogues by chemoselective late-stage derivatization of the pyrrolidine nitrogen. Previously, we used the iminosugar 5 to prepare a series of 2

• ’-homoazanucleosides. This possible precursor was synthesized convergently in 12 steps [20]. The pyrrolidine ring was constructed via alkylation of 6 and 7, followed by ring-closing metathesis. Stereoselective dihydroxylation of the resulting alkene then furnished the protected iminosugar 5. However, using

Synthesis of 1,4-imino-L-lyxitols modified at C-5 and their evaluation as inhibitors of GH38 α-mannosidases

• Maroš Bella,
• Sergej Šesták,
• Ján Moncoľ,
• Miroslav Koóš and
• Monika Poláková

Beilstein J. Org. Chem. 2018, 14, 2156–2162, doi:10.3762/bjoc.14.189

• , indolizidines etc. which exhibited remarkable biological activities and are highly interesting as pharmaceutical agents [15][16][17][18][19]. In addition, iminosugars exhibited a powerful inhibitory activity against a wide range of glycoside hydrolases [20][21][22]. One naturally occurring iminosugar, alkaloid

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

• -dialkoxycarbonylhydrazines [84]. This anomeric N-phthalimidation was later implemented by Nishimura et al. for the iminosugar 114 with phthalimide to give 115 in a high yield, en route to a new family of α-L-fucosidase inhibitors (Scheme 21) [85]. More generally, the preparation of modified glycosylamines under Mitsunobu

Enabling technologies and green processes in cyclodextrin chemistry

• Giancarlo Cravotto,
• Marina Caporaso,
• Laszlo Jicsinszky and
• Katia Martina

Beilstein J. Org. Chem. 2016, 12, 278–294, doi:10.3762/bjoc.12.30

• in Scheme 10: CD-acryloyl derivative [60][61], β-CD/dye derivatives [31][62][63][64], CD-ionic liquid hybrids [65][66], CD-based iminosugar conjugates [67], water-soluble CD homo- and heterodimers [68][69], trimers [70][71] and oligomers [72] of α-, β- and γ-CD have all been successfully produced

Exploring architectures displaying multimeric presentations of a trihydroxypiperidine iminosugar

• Camilla Matassini,
• Stefania Mirabella,
• Andrea Goti,
• Inmaculada Robina,
• Antonio J. Moreno-Vargas and
• Francesca Cardona

Beilstein J. Org. Chem. 2015, 11, 2631–2640, doi:10.3762/bjoc.11.282

• multimerization of compound ent-1 with the aim of studying its inhibitory activity when the molecule decorates a multivalent scaffold. Herein we report the synthesis of a tetra- and a nonavalent polyhydroxypiperidine iminosugar, by exploiting the CuI-catalyzed azide-alkyne cycloadditions (CuAAC) [29][30][31][32

• synthesis of two different scaffolds bearing terminal alkyne moieties suitable for conjugation to compound 4. A preliminary evaluation of the role of the valency in enhancing the inhibitory activity of the iminosugar was investigated by synthesizing a tetravalent and a nonavalent scaffold. The tetravalent

• trimesoyl chloride, as we recently reported [21]. The CuAAC reaction of the azido derivative 4 (4.0 equivalents) with scaffold 5 was performed with CuSO4/sodium ascorbate in THF/H2O 2:1 in a MW reactor at 80 °C for 45 minutes, affording the expected tetravalent iminosugar derivative 7 in 88% yield after

Design, synthesis and photochemical properties of the first examples of iminosugar clusters based on fluorescent cores

• Mathieu L. Lepage,
• Antoine Mirloup,
• Manon Ripoll,
• Fabien Stauffert,
• Anne Bodlenner,
• Raymond Ziessel and
• Philippe Compain

Beilstein J. Org. Chem. 2015, 11, 659–667, doi:10.3762/bjoc.11.74

• Strasbourg, France Institut Universitaire de France, 103 Bd Saint-Michel, 75005 Paris, France 10.3762/bjoc.11.74 Abstract The synthesis and photophysical properties of the first examples of iminosugar clusters based on a BODIPY or a pyrene core are reported. The tri- and tetravalent systems designed as

• carefully degassed conditions and the desired protected cluster 12b could be obtained in 56% yield after purification on silica gel (Scheme 2). The major side-product observed which could not be isolated in pure form may correspond to CuAAC reaction of the azido iminosugar 4a with the terminal alkyne

• -methylumbelliferone or other coumarine derivatives has thus to be taken into account during the quantitative analyses of dedicated biological processes. Conclusion We have reported the preparation of multivalent iminosugar clusters based on two fluorescent cores by way of Cu(I)-catalysed azide–alkyne cycloadditions

Reaction of selected carbohydrate aldehydes with benzylmagnesium halides: benzyl versus o-tolyl rearrangement

• Maroš Bella,
• Bohumil Steiner,
• Vratislav Langer and
• Miroslav Koóš

Beilstein J. Org. Chem. 2014, 10, 1942–1950, doi:10.3762/bjoc.10.202

• carbohydrates. In the context of our studies on the synthesis of sugar amino acids structurally related to iminosugar mannojirimycin (a strong inhibitor of α-mannosidase), we have recently prepared, by applying the Grignard reaction, several branched sugar carbinols as intermediates for subsequent oxidation to

Synthesis of the first examples of iminosugar clusters based on cyclopeptoid cores

• Mathieu L. Lepage,
• Alessandra Meli,
• Anne Bodlenner,
• Céline Tarnus,
• Francesco De Riccardis,
• Irene Izzo and
• Philippe Compain

Beilstein J. Org. Chem. 2014, 10, 1406–1412, doi:10.3762/bjoc.10.144

• France, 103 Bd Saint-Michel, 75005 Paris, France 10.3762/bjoc.10.144 Abstract Cyclic N-propargyl α-peptoids of various sizes were prepared by way of macrocyclizations of linear N-substituted oligoglycines. These compounds were used as molecular platforms to synthesize a series of iminosugar clusters

• inhibition [1][2], the pace of progress has been breath-taking with the discovery of iminosugar clusters showing outstanding affinity enhancements of up to four orders of magnitude over the parent monovalent analogues [3][4][5][6][7]. The best results were obtained with multivalent systems based on C60 [3

• ], β-cyclodextrin [4][5] and porphyrin [7] cores, and with nanoparticles prepared by self-assembly of iminosugar-based glycopolypetides [6]. So far, the largest multivalent effect (up to 610-fold relative inhibition potency increase on a valency-corrected basis) has been achieved on jack bean α

Concise, stereodivergent and highly stereoselective synthesis of cis- and trans-2-substituted 3-hydroxypiperidines – development of a phosphite-driven cyclodehydration

• Peter H. Huy,
• Julia C. Westphal and
• Ari M. P. Koskinen

Beilstein J. Org. Chem. 2014, 10, 369–383, doi:10.3762/bjoc.10.35

• the iminosugar swainsonine, a new potential chemotherapeutic agent [27][28]. Recently, analogs of halofuginone were discovered as inhibitors of tRNA synthetases [29][30][31]. The majority of the reported syntheses [2][3][4][32][33][34][35] are elaborate (far more than 10 steps), specific on one of the

Stereoselectively fluorinated N-heterocycles: a brief survey

• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2013, 9, 2696–2708, doi:10.3762/bjoc.9.306

• ]. Fluorinated analogues of several of these privileged structures have been prepared, in order to probe the importance of hydrogen bonding in these systems [38][39][40][41][42][43]. For example, 1-deoxynojirimycin (28) is the C1-deoxy product of nojirimycin, the first iminosugar isolated from Nature. Iminosugar

• not [46][47]. The fluorinated analogue 37 is particularly worthy of note, since this compound is five times more potent than the existing drug 30, and exhibits no toxicity in human cells. However, a word of warning: in the fluorinated iminosugar examples discussed above (Figure 9 and Figure 10) the

• -membered N-heterocycle 24 prefers an axial orientation of the fluorine substituent, giving two C–F…N+ interactions. Some iminosugars are “privileged structures” that serve as valuable drug leads. Fluorinated iminosugar analogues 32–34 illuminate the binding interactions of the α-glycosidase inhibitor 28

A new approach toward the total synthesis of (+)-batzellaside B

• Jolanta Wierzejska,
• Shin-ichi Motogoe,
• Yuto Makino,
• Tetsuya Sengoku,
• Masaki Takahashi and
• Hidemi Yoda

Beilstein J. Org. Chem. 2012, 8, 1831–1838, doi:10.3762/bjoc.8.210

• hemiaminal 4, which could be converted from the resulting product, was found to provide stereospecific access to enantiomerically enriched allylated intermediate, offering better prospects for the total synthesis of this natural product. Keywords: asymmetric dihydroxylation; (+)-batzellaside B; iminosugar

• of iminosugar alkaloids. In a previous publication, we communicated the first total synthesis of (+)-batzellaside B (1b) by the use of L-arabinose, wherein the absolute stereochemistry of this natural product was completely established by the modified Mosher analysis of a synthetic intermediate

Low-generation dendrimers with a calixarene core and based on a chiral C₂-symmetric pyrrolidine as iminosugar mimics

• Marco Marradi,
• Stefano Cicchi,
• Francesco Sansone,
• Alessandro Casnati and
• Andrea Goti

Beilstein J. Org. Chem. 2012, 8, 951–957, doi:10.3762/bjoc.8.107

• , Parco Area delle Scienze 17/A, I-43124 Parma, Italy 10.3762/bjoc.8.107 Abstract The preparation of low-generation dendrimers based on a simple calix[4]arene scaffold by insertion of the iminosugar-analogue C2-symmetric 3,4-dihydroxypyrrolidine is described. This methodology allows a rapid incorporation

• of a considerable number of iminosugar-like moieties in a reduced volume and in a well-defined geometry. The inclusion of alkali-metal ions (sodium and potassium) in the polar cavity defined by the acetamide moieties at the lower rim of the calixarene was demonstrated, which allows also the

• rigidification of the dendrimer structure and the iminosugar presentation in the clusters. The combination of the supramolecular properties of calixarenes with the advantage of a dendrimeric presentation of repetitive units opens up the possibility of generating well-defined multivalent and multifaceted systems

Synthesis and biological evaluation of nojirimycin- and pyrrolidine-based trehalase inhibitors

• Davide Bini,
• Francesca Cardona,
• Matilde Forcella,
• Camilla Parmeggiani,
• Paolo Parenti,
• Francesco Nicotra and
• Laura Cipolla

Beilstein J. Org. Chem. 2012, 8, 514–521, doi:10.3762/bjoc.8.58

• 10.3762/bjoc.8.58 Abstract A small set of nojirimycin- and pyrrolidine-based iminosugar derivatives has been synthesized and evaluated as potential inhibitors of porcine and insect trehalases. Compounds 12, 13 and 20 proved to be active against both insect and porcine trehalases with selectivity towards

• potential fungicides or antibiotics [13], such as trehalostatin (4) [1][14] and some iminosugar glycoconjugates, e.g., 5 or MDL 25,637 (6) [1][15][16] (Figure 1). In this work we report the synthesis and the biological activity of a small set of nojirimycin- and pyrrolidine-based iminosugar derivatives and

• possibility to synthesize a few nojirimycin and pyrrolidine derivatives bearing a benzyl urea moiety and a different alkyl substituent on the adjacent carbon (10, 11, 15 and 18, Figure 3). Thus the presence of a benzyl urea moiety was expected to be a common feature of the majority of the iminosugar

Metathesis access to monocyclic iminocyclitol-based therapeutic agents

• Ileana Dragutan,
• Valerian Dragutan,
• Carmen Mitan,
• Hermanus C.M. Vosloo,
• Lionel Delaude and
• Albert Demonceau

Beilstein J. Org. Chem. 2011, 7, 699–716, doi:10.3762/bjoc.7.81

• ) (129) a natural iminosugar present in buckwheat (widely used in traditional recipes) is an efficient agent for preventing sharp blood glucose peaks after the intake of refined carbohydrates and for positively influencing intestinal microbiota by favouring adhesion of probiotics. It is supposed that

Synthesis of lipophilic 1-deoxygalactonojirimycin derivatives as D-galactosidase inhibitors

• Georg Schitter,
• Elisabeth Scheucher,
• Andreas J. Steiner,
• Arnold E. Stütz,
• Martin Thonhofer,
• Chris A. Tarling,
• Stephen G. Withers,
• Jacqueline Wicki,
• Katrin Fantur,
• Eduard Paschke,
• Don J. Mahuran,
• Brigitte A. Rigat,
• Michael Tropak and
• Tanja M. Wrodnigg

Beilstein J. Org. Chem. 2010, 6, No. 21, doi:10.3762/bjoc.6.21

• disease, an X-linked inherited lysosomal storage disorder caused by the deficiency of α-galactosidase A activity resulting in the accumulation of globotriaosylceramide, thereby affecting the lysosomes of vascular endothelial cells. Iminosugar 4 can increase α-galactosidase A levels 1.5 to 28 fold in

• to compare the different aromatic substituents. Additionally, Wong [15] as well as Suzuki [23] have shown from computational studies, that in case of N-substitution on compounds 8b and 10, the iminosugar and carbasugar units respectively, were found to interact with the active site of the

• -isopropylidene iminosugar 12. Starting from enol ether 10 [26][27], treatment with m-chloroperbenzoic acid gave the 5-O-chlorobenzoic ester via the corresponding 5,6-epoxide. This ester underwent hydrolysis under basic conditions to afford the L-arabino-hexos-5-ulose 11, which was immediately used for the next

Synthesis and glycosidase inhibitory activity of new hexa- substituted C8-glycomimetics

• Olivia Andriuzzi,
• Christine Gravier-Pelletier,
• Gildas Bertho,
• Thierry Prangé and
• Yves Le Merrer

Beilstein J. Org. Chem. 2005, 1, No. 12, doi:10.1186/1860-5397-1-12

• adhesion, cell growth and differentiation.[1][2][3][4][5][6][7][8][9] In this context, the goal is to obtain new compounds with improved efficacy, stability and specificity. Thus, a change from an aldopyranoside to a 1-deoxy-iminosugar (Figure 1) decreases the vulnerability of the resulting glycomimetic