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

• compounds have been attracting attention due to their broad spectrum of biological activities [6]. A number of synthetic and naturally occurring iminosugars are able to inhibit various enzymes of medicinal interest including glycosidases, glycosyltransferases and many other carbohydrate processing enzymes

• (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

• alcohol 66 can be lithitated and reacted with a range of electrophiles, even without the need for a Lewis acid catalyst, and good levels of stereoinduction can be achieved. The method was used for the synthesis of a range of hexose sugars, as well as iminosugars (viz 66 → 67 → 68), wherein the piperidine

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

• products. Finally, some surprising observations regarding the mechanism of their formation were made. Keywords: amide functionalization; iminosugars; Schwartz’s reagent; tetrazole; Introduction The transformation of an amide into another chemical moiety in a controlled manner is not a trivial task

• suspect that the low stability of imines of type 2 may be the reason for this behavior. The established optimal conditions were applied for the synthesis of selected examples of various 2-(1H-tetrazol-5-yl)-iminosugars (Table 2). Attempts at using this methodology to synthesize pentose-derived 2-(tetrazol

• -5-yl)-iminosugars, using 2,3,5-tri-O-benzyl-ᴅ-ribofuranose- and -arabinofuranose-derived lactams as substrates were made. Very unexpectedly, we failed to isolate such products although we did observe their formation via mass spectrometry of the reaction mixtures. Employing alternative procedures did

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

• ], disaccharides or higher oligosaccharides [5][6] as well as multivalent [7][8] carbohydrate units have been developed. These glycomimetics and glycopeptides have also found applications as bioactive compounds [9][10]. One group of the scaffolds includes iminosugars [11][12] as analogues of the monosaccharides

• wherein the endocyclic oxygen atom is replaced by a nitrogen atom. An additional feature of iminosugars, in comparison with their parent oxygen containing counterparts, is a protonation of the ring nitrogen under physiological pH. The protonation of the amine is often important for the inhibition

• properties of these compounds [13][14]. Another advantage of the iminosugars is a possibility to introduce a functional group onto the nitrogen atom. The importance of iminosugars is documented by a number of reports dealing with the synthesis of polyhydroxylated piperidines, pyrrolidines, pyrolizidines

Synthesis of polyhydroxylated decalins via two consecutive one-pot reactions: 1,4-addition/aldol reaction followed by RCM/syn-dihydroxylation

• Michał Malik and
• Sławomir Jarosz

Beilstein J. Org. Chem. 2016, 12, 2602–2608, doi:10.3762/bjoc.12.255

• Snapper [41][42]. Both groups described a methodology, in which the ring-closing metathesis (RCM) reaction is followed by the reuse of the Ru catalyst in the syn-dihydroxylation step. In our recent papers [43][44], we extended this concise and effective approach to the synthesis of bicyclic iminosugars

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

• glycosidases. Keywords: dendrimers; glycosidase inhibitors; iminosugars; multivalency; piperidine alkaloids; Introduction Iminosugars are well-known naturally occurring glycomimetics with a nitrogen atom replacing the endocyclic oxygen, mainly recognized as inhibitors of carbohydrate-processing enzymes

• (glycosidases) [1][2]. In quite sharp contrast the multivalent effect, widely investigated in the field of carbohydrate–lectin interactions [3], has remained essentially unexplored concerning glycosidase inhibition up to 2010. Indeed, the first examples of multivalent iminosugars gave disappointing results in

• high multivalent effects towards jack-bean α-mannosidase were reported for fullerene- [11], cyclodextrin- [12][13] and porphyrin- [14] based scaffolds decorated with 1-deoxynojirimycin (DNJ) or 1-deoxymannojirimycin as the bioactive iminosugars. Self-assembled DNJ-based glycopeptides also experienced a

Multivalency as a chemical organization and action principle

• Rainer Haag

Beilstein J. Org. Chem. 2015, 11, 848–849, doi:10.3762/bjoc.11.94

• [8][9][10][11][12] and studies the scope of multivalent lectin-glycointeractions in galectins [13], with iminosugars [14] and carbohydrate mimetics [15]. This Thematic Series in the Beilstein Journal of Organic Chemistry also investigates the enhanced multivalent binding of protein scaffolds [16

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

• ; fluorescent probes; iminosugars; 4-methylumbelliferone; multivalency; pyrene; Introduction Since the isolation in the 1970’s of 1-deoxynojirimycin (DNJ) from natural sources and the finding of its biological activity as an α-glucosidase inhibitor, thousands of sugar mimetics with a nitrogen atom replacing

• the endocyclic oxygen have been reported in the literature [1][2]. Iminosugars are mainly known to be inhibitors of a number of carbohydrate-processing enzymes with an emphasis on glycosidases [1][2]. In the early 2000’s, iminosugars were, remarkably, found to inhibit metalloproteinases [3], protein

• kinases [4] and cholinesterases [5], which are enzymes that act on non-sugar substrates. The versatility of iminosugars as inhibitors of enzymes of therapeutic interest has been harnessed to cure a diversity of diseases including diabetes, viral infection, lysosomal storage disorders, tumour metastasis

The Shono-type electroorganic oxidation of unfunctionalised amides. Carbon–carbon bond formation via electrogenerated N-acyliminium ions

• Alan M. Jones and
• Craig E. Banks

Beilstein J. Org. Chem. 2014, 10, 3056–3072, doi:10.3762/bjoc.10.323

• intermediate 73 (Scheme 16) [80]. 195C had never before been prepared enantioselectively and the first total synthesis of 195C utilised a key asymmetric Shono oxidation step. Electrosynthesis using anodic oxidation has also been applied to the α-methylene of an amide for the preparation of iminosugars [81][82

• ]. Iminosugars have shown a variety of biological effects including inhibiting glycosidases and glycoprotein-processing enzymes. Onomura and Matsumura and colleagues have used the anodic methoxylation and mild acid treatment strategy to prepare the initial starting materials in the synthetic campaign (Scheme 17

• ). The Shono-type oxidation of unfunctionalised amides has been applied to the synthesis of inhibitors of a variety of biological targets [83], in particular α-L-fucosidase [84][85]. Toyooka and co-workers also applied anodic methoxylation to prepare iminosugars as potent inhibitors of α-L-fucosidase, an

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

• ketones affording the corresponding hydantoins (precursors of amino acids) via the Bucherer–Bergs reaction in the next step, which were finally transformed into sugar amino acids (precursors of biologicaly active iminosugars). Thus, using methylmagnesium iodide, some alanine-branched sugars were obtained

• sugar aldehydes. The structures of o-tolyl and benzyl derivatives 8 and 9 were unambiguously confirmed by X-ray crystallographic analysis. Compounds 8 and 9 represent profitable synthetic blocks for the synthesis of structurally modified iminosugars and sugar moiety-containing heterocycles, amino acids

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

• . Keywords: cyclopeptoids; glycosidases; iminosugars; inhibitors; multivalency; mutivalent glycosystems; Introduction Within a few years, the field of multivalent glycosidase inhibitors has witnessed tremendous advancement. Since the report in 2009 of the first quantifiable multivalent effect in glycosidase

• iminosugars 5 onto polyalkyne “clickable” scaffolds 2–4 by Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reactions [40][41] (Figure 1). N-alkyl derivatives of DNJ were logically chosen as the peripheral ligands because of the therapeutic relevance of these compounds [42]. In addition, most of the

• stages of the DNJ cluster synthesis were based on a robust two-step process, recently developed in our group for the preparation of iminosugar click clusters [4][5][9][10][11]. The first step of the process involved the attachment of peracetylated azido iminosugars 5 [4] onto polyalkyne scaffolds 2–4 by

Synthesis of (2S,3R)-3-amino-2-hydroxydecanoic acid and its enantiomer: a non-proteinogenic amino acid segment of the linear pentapeptide microginin

• Rajendra S. Rohokale and
• Dilip D. Dhavale

Beilstein J. Org. Chem. 2014, 10, 667–671, doi:10.3762/bjoc.10.59

• enantiomer (2R,3S)-AHDA (2b). As a part of our continuous interest in the synthesis of chiral amino acids [22][23] and their utility in the synthesis of iminosugars [24][25][26][27][28][29], we report here an efficient and practical approach for the synthesis of both enantiomers of AHDA (2a and 2b) from 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

• , their hydrogen bonding ability, and their basicity. Finally, some methods for the synthesis of stereoselectively fluorinated N-heterocycles will also be reviewed. Keywords: conformation; fluorine; N-heterocycles; iminosugars; medicinal chemistry; organo-fluorine; Review 1. Introduction A cursory

• group in a bioactive molecule with a fluorine atom can cause the loss of hydrogen bond donor ability, which may have profound effects on the ligand–receptor interaction. The study of fluorinated iminosugars serves as a good platform to discuss this issue. Naturally occurring iminosugars, also referred

• as polyhydroxylated alkaloids or azasugars, are sugar mimics in which a nitrogen atom replaces the ring oxygen of the corresponding monosaccharide (Figure 8) [31][32][33][34][35][36]. Iminosugars can competitively bind to glycosidase enzymes because of their structural resemblance to the terminal

Garner’s aldehyde as a versatile intermediate in the synthesis of enantiopure natural products

• Mikko Passiniemi and
• Ari M.P. Koskinen

Beilstein J. Org. Chem. 2013, 9, 2641–2659, doi:10.3762/bjoc.9.300

• substructures. This structural motif can be found in many natural products, such as iminosugars (7 and 9), peptide antibiotics (8), sphingosines and their derivatives (10 and 11, Figure 3). These naturally occurring polyhydroxylated compounds have attracted increasing interest from synthetic chemists, because

• six-membered rings. Five-membered dihydrofuran rings lead to the synthesis of furanomycin D [35][36], norfuranomycin E [37], and the polyoxin family F [38]. The six-membered tetrahydropyridine G synthesized via this route can be used as an intermediate in the synthesis of iminosugars, e.g., of the

• of Garner’s aldehyde. Structures of some iminosugars (7, 9), peptide antibiotics (8) and sphingosine (10) and pachastrissamine (11). (a) i) Boc2O, 1.0 N NaOH (pH >10), dioxane, +5 °C → rt; ii) MeI, K2CO3, DMF, 0 °C → rt (86% over two steps); (b) Me2C(OMe)2, cat. p-TsOH, benzene, reflux (70–89%); (c

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

• ; L-pyroglutamic acid; total synthesis; Introduction Iminosugars, monosaccharide analogues in which the endocyclic oxygen has been replaced by nitrogen, display beneficial therapeutic activity as sugar-mimicking glycosidase inhibitors [1][2][3][4]. Since the discovery of nojirimycin (Figure 1), which

• a sponge Batzella sp. collected off the west coast of Madagascar, represent the first example of iminosugars from a marine organism [11]. These naturally occurring products have been demonstrated to retain a remarkably high degree of potency against Staphylococcus epidermidis with MICs of ≤6.3 μg/mL

• class of biologically potent piperidine alkaloids and related analogues. Examples of naturally occurring iminosugars. The chemical structures of (+)-batzellasides A–C (1a–c). Our previous approach to (+)-batzellaside B and retrosynthetic analysis for the new synthetic strategy. Reagents and conditions

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

• with more complex and/or biologically relevant iminosugars. Keywords: calixarenes; cation-responsive system; dendrimers; iminosugars; multivalency; Introduction Polyhydroxylated pyrrolidines are one of the main classes of naturally occurring sugar mimics [1][2] and belong to the so-called iminosugars

• [3]. Several iminosugars have shown potential as therapeutics due to the ability to inhibit glycosidases and other enzymes associated with the metabolism of polysaccharides and the processing of glycoproteins [3]. Conjugation of iminosugars onto a polyvalent skeleton has been investigated only

• , blocks the calixarene in a “rigid cone” structure [34], also controlling the convergence of the iminosugars. The ability of first-generation calixarene dendrimer 2 to bind alkali-metal cations was tested by means of NMR, by solid–liquid extraction of solid alkali picrate salts into a CDCl3 solution of

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

• scarcely characterised. Keywords: glycosidases inhibitors; iminosugars; nojirimycins; pyrrolidines; trehalases; Introduction Trehalase (EC3.2.1.28) is a glycosidase that catalyses trehalose (α-D-glucopyranosyl-α-D-glucopyranoside 1, Figure 1) [1][2][3] hydrolysis. It was found initially at the end of the

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

• ; iminocyclitols; natural products; olefin metathesis; Ru-alkylidene catalysts; Review Introduction Synthetic and natural polyhydroxylated N-heterocyclic compounds (pyrrolidines, piperidines, piperazines, indolizines, etc., and higher homologues), commonly referred to as azasugars, iminosugars or iminocyclitols

• number of excellent books and reviews [1][2][3][4][5][6][7][8][9][10][11][12]. Natural iminosugars (i.e., alkaloids mimicking the structures of sugars, widespread in many plants or microorganisms) [12][13][14][15], as well as non-natural counterparts, are becoming important leads for drug development in

• differing from that of other standard iminosugars such as DNJ. In the majority of the broussonetines (54, Scheme 10), a common polyhydroxylated pyrrolidine building block (possibly prepared via protocols including RCM) is bound to a side chain fragment of 13 C-atoms, diversely functionalized. For the

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

• related β-galactosidase mutants. Keywords: chemical chaperones; 1-deoxy-D-galactonojirimycin; iminosugars; lipophilic galactosidase inhibitor; N-modified iminosugars; Introduction Iminosugars such as compounds 1–4 (Figure 1) have been shown to be potent glycosidase inhibitors and useful tools for the

• study of glycoside-hydrolysing enzymes. These sugar mimetics have been found to have anti-viral, anti-cancer, anti-diabetes, anti-infective, as well as insect anti-feedant and plant growth regulatory effects. Because of their diverse properties, iminosugars have enjoyed continuous interest since their

• discovery in the 1960s. Consequently, many different derivatives have been prepared for biological evaluations via a wide range of synthetic approaches and have been used for various medicinal and biomolecular applications [1][2][3][4][5][6][7][8][9]. Recently, iminosugars were found to have potential to

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

• glycosidases have been carried out. For these C8-glycomimetics, weak activities were observed, which can probably be explained by a too high conformational flexibility of such structures. Experimental See Supporting Information File 1. Sugars, iminosugars and carbasugars. Retrosynthetic analysis. 1D proton NMR