Search

A new synthetic strategy for C7-carbasugars is developed via an intramolecular Morita-Baylis-Hillman reaction, in which a substituted dial precursor prepared from d-mannose cyclizes smoothly in the presence of DMAP to afford polyhydroxylated cyclohex-1-enecarbaldehyde with good yield. By employment of the cyclization products as key intermediates, the first syntheses of carbasugar ester

A broadly applicable diastereo- and enantioselective inverse-electron-demand Diels-Alder reaction of 2-pyrones and acyclic enol ethers is reported herein. Using a copper(II)-BOX catalytic system, bridged bicyclic lactones are obtained in very high yields (up to 99 % yield) and enantioselectivities (up to 99 % ee) from diversely substituted 2-pyrones and acyclic enol ethers. Mechanistic experiments as well as DFT calculations indicate the occurrence of a stepwise mechanism. The synthetic potential of the bridged bicyclic lactones is showcased by the enantioselective synthesis of polyfunctional cyclohexenes and cyclohexadienes, as well as a carbasugar unit.

Here, we report the synthesis of five novel seven-membered carbasugar analogs. We adopted a chiral-pool strategy starting from the cheap and readily available D-mannitol to synthesize these ring-expanded carbasugars. Apart from several regioselective protecting group manipulations, these syntheses involved Wittig olefination and ring-closing metathesis as the key steps. We observed an unprecedented deoxygenation reaction of an allylic benzyl ether upon treatment with H2/Pd during the synthesis. Preliminary biological evaluation of the carbasugars revealed that these ring expanded carbasugars act as inhibitors of various glycosidases. This study highlights the importance of the synthesis of novel ring expanded carbasugars and their biological exploration.

Glycans are well established to play important roles at various stages of infection and disease, and ways to modulate these interactions have been sought as novel therapies. The use of native glycan structures has met with limited success, which can be attributed to their characteristic high polarity (e.g., low binding affinities) and inherently poor pharmacokinetic properties (e.g., short drug-target residence times, rapid renal excretion), leading to the development of 'glycomimetics'. Fluorinated drugs have become increasingly common over recent decades, with fluorinated glycomimetics offering some unique advantages. Deoxyfluorination maintains certain electrostatic interactions, while concomitantly reducing net polarity through 'polar hydrophobicity', improving residence times and binding affinities. Fluorination destabilizes the oxocarbenium transition state associated with metabolic degradation, and can restore exo- and endo-anomeric effects in C-glycosides and carbasugars. Lastly, it has shown great utility in radiotracer development and enhancement of antigenicity in glycan-based vaccines. Owing to synthetic challenges, fluorinated glycomimetics have been somewhat underutilized to date, but methodological improvements will advance their use in glycomimetic drugs.

The synthesis of the carbasugar of β-galactosamine-(1,4)-3-O-methyl-D-chiro-inositol (INS-2), a potential tool for studying glucose metabolism, is described. The synthetic strategy, entails an oxocarbenium ion cyclization on a chiro-inositol derived, thioacetal-enol ether to give a carbocyclic enol ether, which is elaborated to the 2-amino-2-deoxy carbasugar framework via a 2-oximo derivative.

The widespread use of antibiotics in recent decades has been a major factor in the emergence of antibiotic resistances. Antibiotic-resistant pathogens pose increasing challenges to healthcare systems in both developing and developed countries. To counteract this, the development of new antibiotics or adjuvants to combat existing resistance to antibiotics is crucial. Glycomimetics, for example carbasugars, offer high potential as adjuvants, as they can inhibit metabolic pathways or biofilm formation due to their similarity to natural substrates. Here, we demonstrate the synthesis of carbasugar precursors (CSPs) and their application as biofilm inhibitors for E. coli and MRSA, as well as their synergistic effect in combination with antibiotics to circumvent biofilm-induced antibiotic resistances. This results in a biofilm reduction of up to 70% for the CSP rac-7 and a reduction in bacterial viability of MRSA by approximately 45% when combined with the otherwise ineffective antibiotic mixture of penicillin and streptomycin.

Carbasugars are a group of carbohydrate derivatives in which the ring oxygen is replaced by a methylene group, producing a molecule with a nearly identical structure but highly different behavior. Over time, this definition has been extended to include other unsaturated cyclohexenols and carba-, di-, and polysaccharides. Such molecules can be found in bacterial strains and the human body, acting as neurotransmitters (e.g., inositol trisphosphate). In science, there are a wide range of research areas that are affected by, and involve, carbasugars, such as studies on enzyme inhibition, lectin-binding, and even HIV and cancer treatment. In this review article, different methods for synthesizing carbasugars, their derivatives, and similar cyclohexanes presenting comparable characteristics are summarized and evaluated, utilizing diverse starting materials and synthetic procedures.

Glycomimetics are structural mimics of naturally occurring carbohydrates and represent important therapeutic leads in several disease treatments. However, the structural and stereochemical complexity inherent to glycomimetics often challenges medicinal chemistry efforts and is incompatible with diversity-oriented synthesis approaches. Here, we describe a one-pot proline-catalyzed aldehyde α-functionalization/aldol reaction that produces an array of stereochemically well-defined glycomimetic building blocks containing fluoro, chloro, bromo, trifluoromethylthio and azodicarboxylate functional groups. Using density functional theory calculations, we demonstrate both steric and electrostatic interactions play key diastereodiscriminating roles in the dynamic kinetic resolution. The utility of this simple process for generating large and diverse libraries of glycomimetics is demonstrated in the rapid production of iminosugars, nucleoside analogues, carbasugars and carbohydrates from common intermediates. Glycomimetics are structural mimics of carbohydrates that can replicate their biological activity but have improved drug-like properties. Here, using proline-catalysed α-halogenation/aldol cascades, carbohydrate building blocks are readily assembled and then diversified into glycomimetics including imino- and carbasugars.

There is a vast genomic resource for enzymes active on carbohydrates. Lagging far behind, however, are functional chemical tools for the rapid characterization of carbohydrate‐active enzymes. Activity‐based probes (ABPs) offer one chemical solution to these issues with ABPs based upon cyclophellitol epoxide and aziridine covalent and irreversible inhibitors representing a potent and widespread approach. Such inhibitors for enzymes active on polysaccharides are potentially limited by the requirement for several glycosidic bonds, themselves substrates for the enzyme targets. Here, it is shown that non‐hydrolysable trisaccharide can be synthesized and applied even to enzymes with challenging subsite requirements. It was found that incorporation of carbasugar moieties, which was accomplished by cuprate‐assisted regioselective trans‐diaxial epoxide opening of carba‐mannal synthesised for this purpose, yields inactivators that act as powerful activity‐based inhibitors for α‐1,6 endo‐mannanases. 3‐D structures at 1.35–1.47 Å resolutions confirm the design rationale and binding to the enzymatic nucleophile. Carbasugar oligosaccharide cyclophellitols offer a powerful new approach for the design of robust endoglycosidase inhibitors, while the synthesis procedures presented here should allow adaptation towards activity‐based endoglycosidase probes as well as configurational isosteres targeting other endoglycosidase families., Carba‐trisaccharide cyclophellitols are potent GH76 α‐1,6 endo‐mannanase inactivators and resistant to endoglycosidic bond cleavage.

A convenient synthesis of novel 3-deoxy-5-hydroxy-1-aminocarbasugars was developed here. The benzyl-protected glucose-derived ketone 12 was selectively converted in high yield to enone 13via retro-Michael elimination of BnOH. The double bond of 13 was regio- and stereo-selectively reduced by the induction of C4-α-OBn to the multi-functionalized 15. 15 contained all the functionalities with similar configurations to carbasugars but with 3-H and 5-OH in the ring, and it would be a very interesting building block for organic synthesis or for bioactive compounds. As one application, 15 was further transformed into 1-amino-carbasugars by the reductive amination and final deprotection of benzyls. The targets were subjected to the in vitro inhibitory activity test against sucrase or maltase. The inhibitory activity of 17b, 17h or 17j against sucrase was nearly similar to that of voglibose. In comparison with voglibose, in vivo results similarly showed that 17b, 17h or 17j could lower the post-prandial blood glucose level after sucrose loading in healthy male ICR mice, while miglitol or acarbose was less effective. The molecular modeling study of some targets or voglibose with human sucrase could explain the inhibiting action.

Gabosines and their natural analogues, belonging to C7 carbasugars, have attracted great attention in synthesis due to their rich structural variety and promising biological activities. A new diversity-oriented approach for the gabosine-type carbasugars based on a tunable regioselective aldol cyclization of flexible precursor 2 is explored. Two cyclization modes (A and B) of the precursor can be well controlled by switching promoters to selectively produce two resulting cyclohexa(e)nones 3 and 10, both of which are versatile intermediates for various C7 carbasugars. After the conversion of 3 to eight natural carbasugars, the utility of intermediate 10 is illustrated by the first synthesis of (-)-gabosine L, as well as the new synthesis of (-)-gabosine A, (-)-gabosine B, (-)-gabosine N and (-)-gabosine O. The chemical structure and the absolute configuration of (-)-gabosine L are confirmed by its total synthesis.

Two new carbasugar-type metabolites, (1 S,2 R,3 R,4 R,5 R)-2,3,4-trihydroxy-5-methylcyclohexyl-2',5'-dihydroxybenzoate (1) and (1 S,2 S,3 S,4 R,5 R)-4-[(2',5'-dihydroxybenzyl)oxy]-5-methylcyclohexane-1,2,3-triol (2), were isolated from the filamentous fungus Geosmithia langdonii isolated from cotton textiles from Assiut, Egypt. The structures of 1 and 2 were elucidated based on comprehensive 1D and 2D NMR and MS data. Compounds 1 and 2 showed antileishmanial activity against Leishmania donovani with IC50 values of 100 and 57 μM, respectively. The (1 S,2 R,3 R,4 R,5 R) absolute configuration of carbasugar 1 was assigned via 2D NMR and experimental and calculated electronic circular dichroism (ECD) data. Similarly, the tentative structure of compound 2 was shown to possess a (1 S,2 S,3 S,4 R,5 R) absolute configuration via comparing its experimental ECD data and the specific rotation with 1 as well as examining the energy-minimized 3D computational models of compounds 1 and 2.

Carbasugars are a wide group of carbohydrate mimetics in which the ring oxygen is replaced by a methylene group. The high importance of these compounds is related to their interesting biological and pharmacological properties which are the matter of current studies. In our work, a concise synthesis of carbasugars from naturally occurring D-pentoses is presented. The one-pot seleno-Michael reaction connected with intramolecular aldol reaction is a key step of the carbasugar core asymmetric synthesis. Further transformation of obtained carbasugar moiety led to different bioactive compounds. Tandem seleno-Michael reaction conjugated with oxidation/elimination step of in situ generated nucleophile was described a few years ago in the intermolecular variant. In our work, we present the first example of this reaction in an intramolecular way which leads to a previously inaccessible cyclic product of Morita–Baylis–Hillman reaction. Conducted experiments allowed us to obtain cyclic products with high yields and good diastereoisomeric excesses.

Carbasugars are important carbohydrate analogs in which the ring oxygen is replaced with a methylene group. This change has no significant impact on structure (bonds length, torsion angles, conformation) but strongly affects biological activity (pharmacokinetics, molecule-enzyme interactions).1 The therapeutic potential of some carbasugars has led to a growing interest in their development and identification. In our work, we present our recent studies of the application of the tandem seleno-Michael/aldol process in carbasugar synthesis involving D-ribose as a readily available and cheap starting material. An intramolecular seleno-Michael/aldol reaction turned out to be a key step in the asymmetric synthesis of the carbasugar core. In situ generated lithium n-butylselenolate was used as the initiator in the reaction.2,3 Regioselective Steglich esterification or methylation of the secondary hydroxyl and deprotection of benzyl ethers groups gave three known carbasugars (+)-COTC, (+)-Pericosine B and (+)-Pericosine C and a new 7-chloro-analogue of (+)-Gabosine C in satisfactory yields.3 This work was financed by the Polish National Science Center: Grant No. 2015/17/D/ST5/01334 [1] O. Arjona, A.M. Gomez, J.C. Lopez, J. Plumet, Chem. Rev. 107 (2007) 1919-2036 [2] P. Banachowicz; J. Mlynarski ; S.Buda , J. Org. Chem., 2018, 83, 11269-11277. [3] N. Biduś; P. Banachowicz; S. Buda, Tetrahedron, 2020, doi.org/10.1016/j.tet.2020.131397.

2,3,4-Tri-O-benzyl-D-xylopyranose was used as a starting material in the preparation of the corresponding triene, which underwent smooth cyclization to a polyhydroxylated hydrindane, as a single diastereoisomer. The analogous triene prepared from D-glucose did not undergo any cyclization even under high pressure.

Glycoside hydrolases (GHs) catalyze hydrolyses of glycoconjugates in which the enzyme choreographs a series of conformational changes during the catalytic cycle. As a result, some GH families, including α-amylases (GH13), have their chemical steps concealed kinetically. To address this issue for a GH13 enzyme, we prepared seven cyclohexenyl-based carbasugars of α-d-glucopyranoside that we show are good covalent inhibitors of a GH13 yeast α-glucosidase. The linear free energy relationships between rate constants and p

The natural occurrence of enantiomers and diastereomers is often encountered. In addition, the synthesis of these stereoisomers is important for structure determination and for the study of structure–activity relationships. Stereodivergent routes simplify the access to these molecules starting from a common material. This review is focused on the synthesis of carbohydrates, amino acids, alkaloids and terpenes using this efficient strategy. In the case of carbohydrates, such as monosaccharides, carbasugars, aminosugars and azasugars, carbohydrates are usually employed as common starting materials. As a very common strategy, configurations of hydroxy groups are inverted by SN2 methods playing with protection and deprotection processes. For the synthesis of acyclic α-AAs, diastereoselective methods using mainly Garner's aldehyde have been described. Diastereodivergent routes allowed the synthesis of β-hydroxy- and β-amino-α-amino acids, as well as of β- and γ-amino acids. Heterocyclic and cyclic amino phosphonic acids were synthesized using diastereodivergent routes. Alkaloids containing five- and six-membered saturated azaheterocycles needed multistep stereodivergent routes and other alkaloids, such as enantiomers of balanol, vincamine, anatoxin and codeine, and diastereomeric isochaetominines C and galanthamines. In the terpene field, sesquiterpenes β-santalene, α-curcumene and α-cuparenone and the diterpene scopadulcic acid A have been synthesized using enantiodivergent routes. We thank the Spanish Ministerio de Economía, Industria y Competitividad, Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER, EU) (projects CTQ2016-76782-P, CTQ2016-81797-REDC, and CTQ2017-85093-P), the Generalitat Valenciana (PROMETEOII/2014/017) and the University of Alicante for financial support.

Sugar mimics are a large class of compounds mainly constituting iminosugars, thiosugars, and carbasugars. They are transition state analogs of sugar substrates catalyzed by various glucosidases that help understand the mechanism of inhibition of glucosidases, and provide structural clues to developing new inhibitors. In fact, acarbose, voglibose, and miglitol are all sugar mimics developed decades ago. Sugar mimics are still a promising class of α-glucosidase inhibitors with potential for treatment of diabetes mellitus and other diseases. Since the discovery of acarbose, voglibose, and miglitol, a significant number of clinically promising sugar mimics have been reported to date. These include various aminosugars, thiosugars, carbasugars and iminosugars such as pyrrolidines, piperidines, azepanes, pyrrolizidines, indolizidines, and nortropanes. Research on sugar-mimicking α-glucosidase inhibitors has been progressing at a fast pace which has witnessed the identification of diverse inhibitors exhibiting excellent in vitro and in vivo activities which exceed that of acarbose, voglibose, and miglitol. These include but not limited to chemically diverse derivatives of nojirimycin, salacinol, ponkoranol, casuarine, and pericosine. The field of sugar-mimicking α-glucosidase inhibitors is rich in new avenues and opportunities that warrant further progress to development of new α-glucosidase inhibitors as antidiabetic drugs.

Carbasugars are structural mimics of naturally occurring carbohydrates that can interact with and inhibit enzymes involved in carbohydrate processing. In particular, carbasugars have attracted attention as inhibitors of glycoside hydrolases (GHs) and as therapeutic leads in several disease areas. However, it is unclear how the carbasugars are recognized and processed by GHs. Here, we report the synthesis of three carbasugar isotopologues and provide a detailed transition state (TS) analysis for the formation of the initial GH-carbasugar covalent intermediate, as well as for hydrolysis of this intermediate, using a combination of experimentally measured kinetic isotope effects and hybrid QM/MM calculations. We find that the α-galactosidase from Thermotoga maritima effectively stabilizes TS charge development on a remote C5-allylic center acting in concert with the reacting carbasugar, and catalysis proceeds via an exploded, or loose, SN2 transition state with no discrete enzyme-bound cationic intermediate. We conclude that, in complement to what we know about the TS structures of enzyme-natural substrate complexes, knowledge of the TS structures of enzymes reacting with non-natural carbasugar substrates shows that GHs can stabilize a wider range of positively charged TS structures than previously thought. Furthermore, this enhanced understanding will enable the design of new carbasugar GH transition state analogues to be used as, for example, chemical biology tools and pharmaceutical lead compounds., Positive charge stabilized on remote C5-allylic center with catalysis occurring via a loose SN2 transition state.

In the present study, (3aR,7aS)-1,3,3a,4,7,7a-hexahydroisobenzofuran was submitted to photooxygenation and two isomeric hydroperoxides were successfully obtained. Without any further purification, reduction of the hydroperoxides with titanium tetraisopropoxide catalyzed by dimethyl sulfide gave two alcohol isomers in high yields. After acetylation of alcohol with Ac2O in pyridine, epoxidation reaction of formed monoacetates with m-CPBA, then chromatographed and followed by hydrolysis of the acetate groups with NH3 in CH3OH resulted in the formation of epoxy alcohol isomers respectively. These epoxy alcohol isomers were subjected to trans-dihydroxylation reaction with acid (H2SO4) in the presence of water to afford triols. Acetylation of the free hydroxyl groups produced benzofuran triacetates in high yields. Ring-opening reaction of furan triacetates with sulfamic acid catalyzed in the presence of acetic acid/acetic anhydrate and subsequently hydrolysis of the acetate groups with ammonia gave the targeted cyclohexane carbasugar-based pentols. All products were separated and purified by chromatographic and crystallographic methods. Structural analyses of all compounds were conducted by spectral techniques including NMR and X-ray analyses. The biological inhibition activity of the target compounds was tested against glycosidase enzymes, α- and β-glucosidase.

In the recent decades, the interest on glycosidases has dramatically increased, mainly because these enzymes play a vital role in many biological processes. Based on the biological potential associated to these enzymes, several glycosidase inhibitors have been developed. In this review, the most important inhibitors targeting these enzymes, including the disaccharides, iminosugars, monocyclic iminosugars, bicyclic iminosugars, thiosugars and carbasugars will be discussed and special attention will be given to the ones that are currently used clinically. This review summarizes and characterizes the current knowledge regarding the classes of glycosidase inhibitors that have therapeutic potential in a wide range of diseases. It highlights the patents, relevant research and patent applications filed in the past years in the field. Since the glycosidase inhibitors are involved in several chronic diseases and possibly pandemic, the pharmaceutical research towards developing new generations of these molecules is very important to public health. Most of the glycosidase inhibitors mimics the structures of monosaccharides or oligosaccharides and are well accepted by the organisms since they benefit from privileged drug-like properties. Disaccharides, iminosugars, carbasugars and thiosugars derivatives are the most popular inhibitors among the glycosidase inhibitors.

An efficient synthesis of new six-membered carbasugars in both L-form and D-form starting from N–acetylglucosamine is described. The key synthetic steps involved regioselective protection and deprotection, Ferrier carbocyclization, Peterson olefination, hydroboration and stereoselective epoxidation followed by regioselective epoxide ring opening reactions. These six-membered carbasugars showed moderate glycosidase inhibitory activity and one of the compounds was found selective towards β-galactosidase inhibitory activity.

A common, divergent, efficient, and stereoselective approach to the total syntheses of four carbasugars, namely, (–)-zeylenol, (+)-6-O-benzoylzeylenol, (+)-uvarigranol E and (+)-uvarigranol F from d -mannose derived key intermediate 14 is described. This intermediate was synthesized using mixed aldol condensation, Grignard reaction and ring closing metathesis as key steps by our previous method in nine steps from d -mannose. From this intermediate, we achieved the syntheses of (+)-6-O-benzoylzeylenol, (+)-uvarigranol F in three steps, (+)-uvarigranol E in four steps and improved synthesis of (–)-zeylenol.