Short synthesis of hydroxylated thiolane and selenolane rings from mono-benzylated pentitols and aldoses dithioacetals bis-thionocarbonates as bis-electrophilic substrates

1-O-Benzylpentitols (with d-arabino, d-lyxo, d,l-xylo and d,l-ribo configurations) and aldoses dibenzyldithioacetals (with l-arabino, d-lyxo, d-xylo, d-ribo, d-galacto, d-gluco and d-manno configurations) were directly and efficiently transformed into their cyclic bis-thionocarbonate derivatives (61-73%) by reaction with diimidazolyl thione (Im₂CS) in 1,4-dioxane. These bis-electrophilic adducts react regioselectively with Na₂S·9H₂O or Se/NaBH₄ to lead regioselectively to the corresponding thiolane and selenolane rings in good yields for a short synthesis (47-65%).     

Stereoselective synthesis of C-glycosylphosphonates from their ketols. Reconsideration of an abandoned route

Isosteric phosphonate analogues of glycosyl 1-phosphates have been obtained by addition of LiCH₂P(O)(OMe)₂ to glyconolactones followed by Et₃SiH–TMSOTf reductive dehydroxylation of the resultant ketols. The compounds prepared include four β-linked pyranose derivatives (d-galacto, 2-azido-2-deoxy-d-galacto, d-gluco, d-manno) and one β-linked furanose derivative (d-manno). In the latter case the ketol was activated as its 2-acetate. In agreement with an observation in another laboratory, the dehydroxylation of a model ketol phosphonate failed with the use of Et₃SiH–BF₃·Et₂O.     

Synthesis and glycosidase inhibitory activity of aminocyclitols with a C6- or a C7-ring

The synthesis of carbasugars and various aminocyclitols, related to voglibose and acarbose used in the treatment of non-insulino-dependant diabetes, is described from C₂-symmetrical bis-epoxides derived from d-mannitol. The methodology involves two key steps: a domino alkylation-cyclization with 2-lithio-1,3-dithiane derivatives, and reduction or reductive amination with a primary amine. These compounds have been evaluated as inhibitors of several glycosidases, and this study indicates notably that the l-ido or d-manno 1-aminocycloheptane-3,4,5,6-tetrol are inhibitors of α-d-glucosidase with K_i in the micromolar range.     

Short synthesis of new salacinol analogues and their evaluation as glycosidase inhibitors

Versatile synthesis of some analogues of the naturally-occurring α-glucosidase inhibitor salacinol (1), involving thioanhydro alditol moieties with erythro, d,l-threo, xylo, ribo, d-arabino and d-manno configurations is described. Nucleophilic attack at the least-hindered carbon atom of an l- or d-protected erythritol cyclic sulfate by the thioanhydro alditol sulfur atom yielded the desired zwitterionic compounds. In addition, the preparation of the cyclic sulfates of 2,4-O-benzylidene-d-erythritol and 2,4-O-isopropylidene-l-erythritol was improved. Enzyme inhibition tests showed that most of the new compounds were weak but specific inhibitors, while good inhibitory activity was found for a six-membered ring analogue (β-glucosidase: K_i=16 μM).     

Synthesis of d-gluco-, l-ido-, d-galacto-, and l-altro-configured glycaro-1,5-lactams from tartaric acid

The d-gluco-, l-ido-, d-galacto-, and l-altro-configured glycaro-1,5-lactams 1-4 were prepared from the known tartaric anhydride 5 via the aldehyde 6. These lactams are known (1) or potential (2-4) inhibitors of β-d-glucuronidases and α-l-iduronidases. Olefination of 6 to the (E)- and (Z)-alkenes 7 or 8, followed by reagent or substrate controlled dihydroxylation, lactonization, azidation, reduction, and deprotection led in 10 steps and in overall yields of 11-20% to the title lactams.     

Expedious synthesis of polyhydroxylated selena and thia-heterocycles via Se and S-ring closure of α,ω-dibromoalditols

The selena and thiaanhydro alditols (with xylo, ribo, d-arabino, erythro, d,l-threo and d-manno configuration) were easily and expeditiously synthesized in good to excellent yields by reaction of selenure and sulfur ions as binucleophiles with α,ω-dibromoalditols as bis-electrophilic substrates. With the 1,6-dibromo-d-glucitol derivative as substrate, only the corresponding thiepane derivative was obtained while the selenaheterocyclistation attempte led to complex mixture.     

Anomeric spiroannelated 1,4-diazepine 2,5-diones from furano exo-glycals: towards a new class of spironucleosides

The first synthesis of 1,4-diazepine 2,5-dione peptides containing a β-amino acid in which the β carbon is also the anomeric carbon of a furanoid sugar is described. These new anomeric spirosugars obtained with a stereoselective control in the d-gulo, d-manno, d-allo and d-ribo series can be regarded as the first members of a new class of spironucleosides. In the course of our study, two symmetrical tetrameric cyclopeptides comprising two identical sugar β-amino acid and α-amino acid residues were also isolated, these structures could be of interest as new potential host molecules.     

Synthesis of O-[4,6-Di-O-Acetyl-4-O-(2,3,4,6-Tetra-O-Acetyl-β-D-Galactopyranosyl)-2-Deoxy-2-Hydroxyimino-D-Arabino-Hexopyranosyl]-N-Benzyloxycarbonyl-L-Serine Methyl Esters And Their Transformations

ABSTRACT

3,6-Di-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-2-deoxy-2-hydroxyimino-α- and -β-D-arabino-hexopyranosides of N-benzyloxycarbonyl-L-serine methyl ester as well as of ethanol have been synthesised from D-lactal hexaacetate via nitrosyl chloride, followed by condensation with L-serine derivatives and ethanol, respectively. The compounds of L-serine thus obtained were modified at C-2 and C-3 to afford L-serine derivatives attached to disaccharides containing terminal α-D-gluco-, 2-acetamido-α-D-gluco-, β-D-manno, 2-acetamido-β-D-manno-pyranosyl, 3-azido-2-hydroxyimino-α-D-arabino-, and α-D-ribo-hexopyranosyl residues.     

Synthesis and glycosidase inhibitory activity of pseudo-di-(or tri-)saccharides

The synthesis of pseudo-di-(or tri-)saccharides with a d-mannoazepane or a l-gulopiperidine skeleton either N-linked to a d-gluco-C-furanoside or to d-mannitol, and evaluation of their inhibitory activities against α- or β-d-glucosidase, α-d-mannosidase and α-l-fucosidase are described.     

Synthesis of eight-membered iminocyclitols from d-glucose

The Baylis-Hillman reaction of 3-O-benzyl-α-d-xylo-pentodialdo-1,4-furanose 2 afforded a diastereomeric mixture of l-ido- and d-gluco-configurated α-methylene-β-hydroxy esters 3a and 3b, respectively, in 1:1 ratio. Conjugate addition of benzyl amine on 3a gave adduct 4a as a major product while, addition of benzyl amine to 3b gave only one diastereomer 4b. Reduction of ester functionality in 4a/4b, opening of 1,2-acetonide functionality followed by reductive amino-cyclization under hydrogenation condition afforded azocanes 1c/1d in good yield.     

Synthesis of C-glycosidically linked ADP glycero-β-d-manno-heptose analogues

C-Glycosides of l-glycero-d-manno- and d-glycero-d-manno-heptose containing either (S)- or (R)-2-hydroxypropyl aglycons are easily accessible compounds via condensation of reducing heptoses with pentane-2,4-dione. 2′,3′-Di-O-acetyl adenosine was transformed into the corresponding 5′-O-cyanoethyl N,N-diisopropylaminophosphoramidite derivative, which was coupled in fair yields to the O-acetylated diastereoisomeric C-glycosidic alcohols. Oxidation of the phosphite triesters followed by deprotection furnished four ADP-heptose analogues, wherein the heptosyl phosphate moiety had been replaced by a three carbon-skeleton. The compounds serving as substrate analogues will be used for co-crystallization experiments with ADP heptosyl transferases.     

An efficient approach to d-threo-3-hydroxyaspartic acid for the synthesis of novel l-threo-oxazolines as selective blockers of glutamate reversed uptake

An efficient, stereoselective synthetic strategy to d-threo-3-hydroxyaspartic acid was developed. Starting from l-(2S,3S)-N-benzoyl-3-hydroxyaspartic acid dimethyl ester by a Deoxo-fluor-catalyzed cyclization reaction, an inversion of configuration at the β-center (erythro isomer), was observed. A base-induced epimerization reaction led to the d-trans-isomer, which was hydrolyzed to give d-threo-3-hydroxyaspartic acid with excellent stereoselectivity and overall yield. Starting from d-threo-3-hydroxyaspartic acid, l-threo-oxazolines can be stereoselectively synthesized.     

Chiral 1,4-morpholin-2,5-dione derivatives as α-glucosidase inhibitors: Part 2

A series of chiral 1,4-morpholin-2,5-dione derivatives were synthesized starting from chiral synthons 1 and 2, diastereomeric monolactim ethers derived from l-valine. The compounds investigated, were inactive toward β-glucosidase, α-mannosidase and α-galactosidase but behave as noncompetitive inhibitors against the α-glucosidase (from Saccharomices cervisiae) with some showing a good inhibition ability (0.05 < K_i < 0.18 mM).     

Fluorinated piperidine iminosugars and their N-alkylated derivatives: Synthesis,conformational analysis,immunosuppressive and glycosidase inhibitory activity studies

The fluorinated piperidine iminosugars 2a-4a and their N-octyl and N-decyl derivatives 2b,c-4b,c were synthesized from d-mannose/d-xylose using nucleophilic fluorination as the key step. The conformation of iminosugars 2/3, either ²C₅ or ⁵C₂, was assigned based on the ¹H NMR studies at different pH. Immunomodulatory activity of 2a,c-4a,c was examined using Mixed Lymphocyte Reaction (MLR) and B-cell assay. The N-alkylated fluorinated d-manno-iminosugars 3b/4b were found to be better immunosuppressive agents (IC₅₀?=?5–6?μM) on T-cells. The fluorinated iminosugar 3a/4a act as potent and selective inhibitors of β-glucosidase (IC₅₀?=?4–8?μM). The N-alkyl-iminosugars 4b-c were found to be moderate inhibitors of α-glucosidase (yeast) and α-galactosidase (coffee beans), respectively.     

Synthesis of hybrids of d-glucose and d-galactose with 1-deoxynojirimycin analogues using ring-closing metathesis

Four hybrids of azasugars with d-glucose and d-galactose have been synthesized from 3-nitro-2,3-unsaturated-O-glycosides. All the hybrid molecules showed moderate activity against β-galactosidase, the one derived from d-glucose and 1,4-dideoxygulonojirimycin 18, and 26, which is a hybrid of d-glucose and 1,4-dideoxymannohomonojrimycin, showed selectivity toward α-glucosidase and β-galactosidase, respectively.     

Structure of C-1 substituted glycopyranosyl azides: new insights based on CD measurements

CD spectra have been recorded for a series of peracetylated d-glycopyranosyl azides (d-gluco, d-galacto, d-xylo, d-arabino configuration) substituted at the anomeric position by various groups: amido, azido, cyano, ethoxy, methoxy. Application of the azide octant rule for the interpretation of the sign for the long-wavelength azide band allowed conformation of the azido group in each mono azido derivative investigated to be established. In each 1-cyano derivative, the azido group was in a gauche-like arrangement with respect to the C-1–O^ring bond, which is considered as a manifestation of the exo-anomeric effect of the azido group. For the 1-alkoxy derivatives, an antiparallel orientation of the azido group with respect to the C-1–O^ring bond was found in solution by CD measurement analysis, as already observed for methoxyazide 5 in the solid state. For azidoamide derivatives, intramolecularly (N–H–N^x_azide) H-bonded conformers are believed to prevail in methanol, in contrast to the situation in DMSO.     

Synthesis of New C(2)‐Substituted gluco‐Configured Tetrahydroimidazopyridines and Their Evaluation as Glucosidase Inhibitors

The gluco‐configured C(2)‐substituted tetrahydroimidazopyridines 8 – 14 were prepared and tested as inhibitors of the β‐glucosidases from Caldocellum saccharolyticum and from sweet almonds, and of the α‐glucosidase from brewer's yeast. All new imidazopyridines are nanomolar inhibitors of the β‐glucosidases and micromolar inhibitors of the α‐glucosidase. The 3‐phenylpropyl derivative 14 proved the strongest inhibitor of the Caldocellum β‐glucosidase (K_i = 0.9 nM ), only slightly weaker than the known 2‐phenylethyl analogue 7 , and the propyl derivative 13 is the strongest inhibitor of the sweet almond β‐glucosidases (K_i = 3.2 nM ), again slightly weaker than 7 . There is no strong dependence of the inhibition on the nature of the C(2)‐substituent and no clear correlation between the inhibitory strength of the known manno‐configured imidazopyridines 2 – 6 and the gluco‐analogues 8 – 12 . While most manno‐imidazopyridines are competitive inhibitors, the gluco‐analogues proved non‐competitive inhibitors of the Caldocellum β‐glucosidase and mixed‐type or partial mixed‐type inhibitors of the sweet almond β‐glucosidases.     

Chemical synthesis of the innate immune modulator – bacterial d-glycero-β-d-manno-heptose-1,7-bisphosphate (HBP)

The bacterial metabolite and potent innate immune modulator d-glycero-β-d-manno-heptose-1,7-bisphosphate (HBP) and its α-configured counterpart d-glycero-α-d-manno-heptose-1,7-bisphosphate were synthesized via stereoselective anomeric phosphorylation of the peracetylated d,d-heptose 7-dibenzylphosphate by exploiting different nucleophilicity of equatorial and axial lactols in the d-manno-series. We also report a novel approach for anomeric phosphorylation using modified Mitsunobu reaction conditions and provide the first full structural characterization of HBP. The first chemical synthesis of HBP offers access to an anomerically pure structurally defined probe for biological studies and to a lead compound operating as a powerful stimulator of intracellular signaling for possible therapeutic immunomodulation.     

Highly diastereoselective 1,2-dichlorination of glycals using NCS/PPh3: study of substituent and solvent effects

Highly diastereoselective 1,2-dichlorination of glycals has been achieved at room temperature conditions in good to excellent yields using a milder, more convenient, less hazardous reagent combination NCS/PPh₃ giving only one major product out of four possible diastereomers [either α-gluco (2) or α-manno (4)] depending upon the substituents. The diastereoselectivity is maximum (100% α/β-selectivity as well as cis/trans selectivity) for d-galactal and l-rhamnal derivatives. Detailed studies showed that solvent and substituent effects play a significant role in determining the product distribution.     

Fragmentation of carbohydrate anomeric alkoxyl radicals. Synthesis of highly functionalized chiral vinyl sulfones

The reaction of derivatives of 3-acetyl-d-glucal, 3-acetyl-l-rhamnal, 3-acetyl-d-galactal, and 3-acetyl-d-lactal with sodium benzenesulfinate in acid medium catalyzed by HgSO₄ afforded diastereoisomeric mixtures of the corresponding 2,3-dideoxy-3-(phenylsulfonyl)-hexopyranoses through a Ferrier rearrangement. The anomeric alkoxyl radical fragmentation of these γ-hydroxy sulfones using the system (diacetoxyiodo)benzene and iodine gave vinyl sulfones with structures of 1,2-dideoxy-4-O-formyl-2-(phenylsulfonyl)-pent-1-enitol and configurations d-erythro, l-erythro, and d-threo at the two stereogenic centers.