Anhydro Ring Research Articles

Aldehydic nature and conformation of 3,6-anhydro-L-galactose monomer

We investigated the aldehydic nature and conformation of 3,6-anhydro-L-galactose (L-AnG) by using enzymes that bind L-AnG in a reactive conformation. We found that L-AnG, but not L-galactose, can be oxidized by E. coli L-lactaldehyde dehydrogenase (Ec_LADH); this observation suggests that L-AnG is an aldehyde belonging to the a-hydroxyaldehyde family. Because the native enzyme that catalyzes oxidation of L-AnG to its carboxylate is LAnG dehydrogenase (L-AnGDH), we compared the crystal structure and amino-acid sequences of Ec_LADH with those of L-AnGDHs. This analysis revealed that the two oxygen atoms in the a-hydroxyaldehyde moiety of L-AnG are essential for the reactions of Ec_LADH and LAnGDHs. A chemical database search indicated that two configurations of L-AnG are possible: a trans arrangement in which C-2 and C-5 hydroxyl groups are on the opposite side and a cis arrangement in which these groups are on the same side. Manual docking of the two forms of L-AnG into the active site of Pseudoalteromonas atlantica LAnGDH (Pa_L-AnGDH) revealed that only the trans LAnG configuration can be fitted into the active site of Pa_L-AnGDH. The identification of trans L-AnG suggests the existence of three L-AnG conformations: bicyclic pyranose, opened pyranose, and open-chain aldehyde. The conformation of L-AnG monomer (open-chain aldehyde) differs from that in agarose (bicyclic pyranose) or agarobiose (opened pyranose) because a five-membered anhydro ring is free to move and can find its most stable conformation. This study validates the assumption of trans-type open-chain aldehyde conformation of L-AnG that was applied in our previous studies.

(1R*,2S*,4S*,5R*)-Cyclohexane-1,2:4,5-tetracarboxylic dianhydride

The title compound, C10H8O6, a promising raw material to obtain colorless polyimides which are applied to microelectronic and optoelectronic devices, adopts a folded conformation in which the dihedral angle between the two anhydro rings is 55.15 (8)°. The central six-membered ring assumes a conformation inter­mediate between boat and twist-boat. In the crystal, mol­ecules are linked by weak C—H⋯O inter­actions, forming a layer parallel to the bc plane.

Structural Determinants of Enoxaparin Oligosaccharides for the Down-Regulation of Tissue Factor Induced Factor VIIa Generation In Human Plasma.

AbstractAbstract 1106 Introduction.Low molecular weight heparins are multitargeted drugs that exert their antithrombotic effect primarily via the binding of pentasaccharide domain on antithrombin. The structural and functional fingerprint of enoxaparin regarding the affinity for AT and the inhibition of FXa and thrombin has been extensively studied. The depolymerization process used for manufacturing enoxaparin results in the formation of a 1,6 anhydro ring (bicyclic) structure at the reducing end of all oligosaccharides bearing 6-0-sulfo-groups on the glucosamine moiety. The influence of this particular structure on the antithrombotic activity of enoxaparin is not known. In previous studies our group demonstrated that enoxaparin and the synthetic pentasaccharide inhibit factor VIIa generation after triggering tissue factor pathway in human plasma. In patients suffering from acute coronary syndromes treatment with enoxaparin induces inhibition of FVIIa in plasma. Aim.We investigated the effect of structural characteristics of enoxaparin oligosaccharide on the generation of FVIIa. Methods.Oligosaccharides (hexa- octa- dodeca- saccharides) with the 1,6 anhydro ring structure (40%-50%) or without it (<7%) and one octasaccharide with high affinity for antithrombin (AT) were provided by Sanofi-Aventis France. Normal platelet poor plasma (PPP) from 5 healthy donors was spiked with increasing concentrations of the studied oligosaccharides (0.625 to 10 μg/ml) or enoxaparin or saline (control). Factor VIIa generation was studied after TF pathway activation in PPP according to previously described assay sensitive to detect the inhibitory effect of low concentrations of enoxaparin and pentasaccharide (Gerotziafas et al Blood Coagul Fibrinolysis. 2003;14:633-8). Briefly in polystyrene tubes containing one volume of normal human PPP was added one volume of diluted (1:250) non calcified thromboplastin (Recombiplastin). After a 3 min incubation, coagulation was triggered by adding one volume of CaCl2 solution (0.025 M). FVIIa levels were determined with the one-stage clotting assay using recombinant thromboplastin (TF1–218) truncated to interact only with FVIIa (Staclot FVIIa-rTF; Diagnostica Stago, Asnières, France), with clotting times determined by chronometric method. Results.At 2.5 μg/ml enoxaparin all studied oligosaccharide significantly inhibited FVIIa generation. The octasaccharide with the higher affinity for AT inhibited FVIIa generation significantly more than enoxaparin or the other oligosaccharides. Oligosaccharides possessing the 1,6 anhydro ring structure induced more pronounced inhibition of FVIIa generation compared to those without this structure. Octa- and dodeca- saccharides induced higher inhibition of FVIIa generation compared to the hexasaccharide. This difference was not influenced by the presence of the 1,6 anhydro ring structure. Conclusion.The FVIIa generation in PPP is a sensitive experimental system for the evaluation of structural/functional relationships in oligosaccharides contained in LMWH preparations. The present study is the first to report that the length of the oligosaccharide chain the affinity to AT and the presence of the 1,6 anhydro ring structure are structural characteristics enoxaparin which in addition to the pentasaccharide domain dowregulate TF triggered factor VIIa generation. Disclosures:No relevant conflicts of interest to declare.

ChemInform Abstract: Novel Carbocyclization of a D-Glucose-Derived Alkene.

Cyclopentadiene reacts with a D-glucose-derived hex-3-enose derivative to give norbornene derivatives attached at the 2,3-position of a 1,6-anhydrohexose skeleton; although the bicyclic enone isolevoglucosenone is a plausible intermediate in this reaction, the products actually appear to arise through initial cycloaddition to a rearranged acyclic sugar derivative with subsequent generation of the anhydro ring.

The Cyclization of the 3,6-Anhydro-Galactose Ring of ι-Carrageenan Is Catalyzed by Two d-Galactose-2,6-Sulfurylases in the Red Alga Chondrus crispus

Carrageenans are sulfated galactans found in the cell walls of numerous red seaweeds (Rhodophyta). They are classified according to the number and the position of sulfate ester groups and the occurrence of 3,6-anhydro-galactose. Although the carrageenan biosynthesis pathway is not fully understood, it is usually accepted that the last step consists of the formation of a 3,6-anhydro ring found in kappa- and iota-carrageenans through the enzymatic conversion of d-galactose-6-sulfate or d-galactose-2,6-disulfate occurring in mu- and nu-carrageenan, respectively. We purified two enzymes, sulfurylase I (65 kD) and sulfurylase II (32 kD), that are able to catalyze the conversion of nu- into iota-carrageenan. We compared their sulfate release rates (i.e. arising from the formation of the anhydro ring) with the viscosity of the solution and demonstrated two distinct modes of action. In addition, we found that some mixtures of sulfurylase I and II lead to the formation of carrageenan solutions with unexpectedly low viscosities. We discuss the implication of these findings for the assembly of a densely aggregated matrix in red algal cell walls.

1,6-anhydro-N-acetyl-β-D-glucosamine in oligosaccharide synthesis: II. The synthesis of the spacered Ley tetrasaccharide

3-Aminopropyl glycoside of 3,2'-di-O-alpha-L-fucosyl-N-acetyllactosamine (Ley tetrasaccharide) was synthesized. The glycosyl donor, 2-O-acetyl-3,4,6-tri-O-benzoyl-alpha-D-galactopyranosyl bromide, was coupled with glycosyl acceptor, 1,6-anhydro-2-acetamido-2-deoxy-beta-D-glucopyranose or its 3-O-acetyl derivative, to give the corresponding N-acetyllactosamine derivatives in 20 and 71% yields, respectively. The glycosyl donor was synthesized from 1,2-di-O-acetyl-3,4,6-tri-O-benzoyl-D-galactopyranose, which was obtained by the treatment of benzobromogalactose with sodium borohydride to yield 1,2-O-benzylidene derivative and subsequent removal of benzylidene group and acetylation. Acidic methanolysis of the disaccharide derivatives resulted in the selective removal of one or both acetyl groups to give the disaccharide acceptor bearing hydroxy groups at C3 of the glucosamine residue and C2 of the galactose residue. The introduction of fucose residues in these positions by the treatment with tetrabenzylfucopyranosyl bromide resulted in a tetrasaccharide derivative, which was converted into 3,2'-di-O-alphha-L-fucopuranosyl- 1,6-anhydro-N-acetyllactosamine peracetate after substitution of acetyl groups for benzoyl and benzyl groups. Opening of the anhydro ring by acetolysis resulted in peracetate, which was then converted into the corresponding oxazoline derivative in two steps. Glycosylation of the oxazoline derivative with 3-trifluoroacetamidopropan-1-ol and removal of O-acetyl and N-trifluoroacetyl protective groups resulted in a free spacered Ley tetrasaccharide.

Cis,cis,cis-1,2,4,5-cyclohexanetetracarboxylic acid and its dianhydride.

cis,cis,cis-1,2,4,5-Cyclohexanetetracarboxylic acid, C(10)H(12)O(8), (I), contains a mirror plane and the cyclohexane ring exhibits a chair conformation. Two crystallographically independent hydrogen bonds form R(2)(2)(14), R(2)(2)(16) and R(4)(4)(16) ring motifs, and propagation of these two hydrogen bonds along the c and b axes generates C(2)(2)(16) and C(2)(2)(7) chains. cis,cis,cis-1,2:4,5-Cyclohexanetetracarboxylic dianhydride, C(10)H(8)O(6), (II), was prepared by the reaction of (I) with acetic anhydride. The cyclohexane ring of (II) exhibits a boat conformation and the dihedral angle between the two anhydro rings is 117.5 (1) degrees.

Methyl 2,21-Anhydro-4,6-O-benzylidene-3-deoxy-3-C-[(R)-2-hydroxyethyl]-α-D-allo-pyranoside at 173 K

The 1,3-dioxane ring in the title compound, C 16 H 20 O 5 , has an almost undistorted α4 C α1 conformation, while the pyranose ring has a more distorted 4 C 1 conformation. The five-membered C(2,2 1 ) anhydro ring has an envelope conformation, with C(3) lying out of the plane formed by the other four atoms.

Structure and taste of 3,6:3′,6′-dianhydro-α,α-trehalose monohydrate

The X-ray diffraction structure of 3,6: 3′,6′-dianhydro-α,α-trehalose (3,6-anhydro-α- d-glucopyranosyl 3,6-anhydro-α- d-glucopyranoside) monohydrate is described. The molecule has exact two-fold symmetry through the anomeric oxygen atom. The pyranosyl ring has a slightly distorted 1C 4 chair conformation and the cis-fused five-membered anhydro ring has a near perfect 4E envelope conformation. X-ray crystal data show an absence of a sweet AH,B glucophore, which would explain the absence of sweetness. Evidence indicating the importance of hydrophobic character to bitterness is presented.

2,2'-Di-O-acetyl-3,6;3',6'-dianhydro-4,4'-dideoxy-α,α-trehalose

The structure of 2,2'-di-O-acetyl-3,6;3',6'-dianhydro-4,4'-dideoxy-α,α-trehalose (2-O-acetyl-3,6-anhydro-4-deoxy-α-D-xylo-hexopyranosyl 2-O-acetyl-3,6-anhydro-4-deoxy-α-D-xylo-hexopyranoside), C 16 H 22 O 9 is described. The molecule has approximate twofold symmetry through O(1). Both pyranoid rings have distorted 1 C 4 chair conformations and the five-membered anhydro rings have distorted 4 E conformations. The structure of the compound appears to show the absence of a sweet AH,B glucophore, which would explain the absence of sweetness in the unsubstituted derivative

Synthesis of 1-(3-Azido-2,3-dideoxy-4-C-hydroxymethyl-α-L-threo-pentofuranosyl)thymine, 1-(2,3-Dideoxy-4-C-hydroxymethyl-α-L-glycero-pentofuranosyl)thymine and 1-(2,3-Dideoxy-4-C-hydroxymethyl-α-L-glycero-pent-2-enofuranosyl)thymine

1-(2-O-Acetyl-3,5-di-O-benzoyl-4-C-benzoyloxymethyl-α-L-arabinofuranosyl)thymine (II) was converted to 2,2'-anhydro derivative V by selective deacetylation, mesylation and treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene. Cleavage of 2,2'-anhydro ring in compound V with hydrogen chloride or bromide afforded the respective 2'-chloro and 2'-bromo derivatives VI and VII. Reaction of compound VII with Cu/Zn couple and subsequent debenzoylation led to 1-(2,3-dideoxy-4-C-hydroxymethyl-α-L-pent-2-enofuranosyl)thymine (IX). Catalytic hydrogenation of IX gave 1-(2,3-dideoxy-4-C-hydroxymethyl-α-L-glycero-pentofuranosyl)thymine (X). Dehalogenation of compound VI with tributyltin hydride and debenzoylation afforded 1-(2-deoxy-4-C-hydroxymethyl-α-L-erythro-pentofuranosyl)thymine (XII). Tritylation of compound XII, followed by mesylation, detritylation and nucleophilic substitution with azide furnished 1-(3-azido-2,3-dideoxy-4-C-hydroxymethyl-α-L-threo-pentofuranosyl)thymine (XXII).

Synthesis of 1-(3-azido-2,3-dideoxy-β-d-allofuranosyl)thymine, 1-(2,3-dideoxy-β-d-allofuranosyl)thymine, and 1-(2,3-dideoxy-β-d-erythro-hex-2-enofuranosyl)thymine

1-(2-O-Acetyl-3,5,6-tri-O-benzoyl-β-d-glucofuranosyl)thymine (1) was converted into the 2,2′-anhydro derivative 4 by selective deacetylation, mesylation, and treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene. Cleavage of the 2,2′-anhydro ring in 4 with hydrogen bromide or hydrogen chloride led to the 2′-bromo (5) or 2′-chloro (6) derivative, respectively. Dehalogenation of 6 with tributylstannane and then debenzoylation gave 1-(2-deoxy-β-d-arabino-hexofuranosyl)thymine (8). Isopropylidenation of 8 followed by mesylation, azide displacement, and deprotection gave 1-(3-azido-2,3-dideoxy-β-d-ribo-hexofuranosyl)-thymine (12). Oxidation of 12 with Dowex 1 (IO4−) resin followed by reduction with Dowex 1 (BH4−) resin gave 1-(3-azido-2,3-dideoxy-β-d-erythro-pentofuranosyl)thymine (AZT). Catalytic hydrogenation of 5 afforded a mixture of 1-(5,6-di-O-benzoyl-2,3-dideoxy-β-d-erythro-hexofuranosyl)thymine (13) and 1-(3,5,6-tri-O-benzoyl-2-deoxy- β-d-arabino-hexofuranosyl)thymine (7). Reaction of 5 with a Cu/Zn couple gave 1-(5,6-di-O-benzoyl-2,3-dideoxy-β-d-erythro-hex-2-enofuranosyl)thymine (15). 1-(2,3-Dideoxy-β-d- erythro-hexofuranosyl)thymine (14) and 1-(2,3-dideoxy-β-d-erythro-hex-2-enofuranosyl)thymine (16) were obtained by debenzoylation.

Synthesis of Four Spacer-Containing Trisaccharides with the 4-0-(β-L-Rhamnopyranosyl)-D-glucopyranose Unit in Common, Representing Fragments of Capsular Polysaccharides fromStreptococcus PneumoniaeTypes 2, 7F, 22F, and 23F

Abstract The synthesis is reported of 3-aminopropyl 3-O-[4-O(β-L-rhamnopyranosyl)-β-D-glucopyranosyl]-α-L-rhamnopyranoside (34), 3-aminopropyl 2-acetamido-3-O-[4-0-(β-L-rhamnopyranosyl)-β-D-glucopyranosyl]-2-deoxy-β-D-galactopyranoside (37), 3-aminopropyl 3-O-[4-O-(β-L-rhamnopyranosyl)-α-D-glucopyranosyl]-α-D-galactofuranoside (41), and 3-aminopropyl 4-O-[4-O-(β-L-rhamnopyranosyl)-β-D-glucopyranosyl]-β-D-galactopyranoside (45). These are spacer-containing fragments of the capsular polysaccharides of Streptococcus pneumoniae type 2, 7F, 22F, and 23F, respectively, which are constituents of Pneumovax© 23. 2,3,4-Tri-O-benzyl-α-L-rhamnopyranosyl bromide was coupled to l,6-anhydro-2,3-di-(O-benzyl-β-D-glucopyranose (3). Opening of the anhydro ring, removal of AcO-1, and imidation of l,6-anhydro-2,3-di- O-benzyl-4-O-(2,3,4-tri-O-benzyl-β-L-rhamnopyranosyl)-β-D-glucopyranose (4β) afforded 6-O-acetyl-2,3-di-O-ben-zyl-4-O-(2,3,4-tri- O-benzyl-β-L-rhamnopyranosyl)-αβ-D-glucopyranosyl trichloroacet-imidate (7αβ). Condensation of 7αβ with 3-N-benzyloxycarbonylaminopropyl 2-O-ben-zyl-5,6-O-isopropylidene-α-D-galactofuranoside (26), followed by deprotection gave 41 Opening of the anhydro ring of 4 p followed by debenzylation, acerylauon, removal of AcO-1, and imidation yielded 2,3,6-tri-(9-aceryl-4-O-(2,3,4-tri-0-acetyl-P-L-rharnnopyran-.-osyl)-α-D-glucopyranosyl trichloroacetimidate (11). Condensation of 11 with 3-N-bcn-zyloxycarbonylaminopropyl 2,4-di-O-benzyl-α-L-rhamnopyranoside (18), with 3-N-bcn-zyloxycarbonylaminopropyl 2-acetamido-4,6-O-benzylidene-2-deoxy-β-D-galactopyran-oside (21), or with 3-N -benzyloxycarbonylaminopropyl 2-O-acetyl-3-O-allyl-6-O-benzyl-β-D-galactopyranoside (31), followed by deprotection afforded 34, 37, and 45, respectively.

Selective protections on 2-allyloxycarbonylamino-1,6-anhydro-2-deoxy-β- d-glucopyranose

Regioselective monoacetylation of 2-allyloxycarbonylamino-1,6-anhydro-2-deoxy-β- d-glucopyranose ( 1) gave a mixture of 3- O-acetyl and 4- O-acetyl derivatives, the structures of which were estabished by two-dimensional, phase-sensitive NOESY and confirmed by chemical proofs. The benzylation of 1, on the other hand, led to 2-allyloxycarbonylamino-1,6-anhydro-3,4-di- ( 5) or 2-allyloxycarbonylamino-1,6-anhydro-2 - N-benzyl-3,4-di- O-benzyl-2-deoxy-β- d-glucopyranose ( 10). The regioselective cleavage of 5 with titanium tetrachloride gave the expected 3- O-benzyl derivative, the structure of which was ascertained by chemical proofs; the same reaction performed on 10 led to the opening of the anhydro ring to afford 3-benzyl-[3,4-di- O-benzyl-1,2-dideoxy-α- d-glucopyrano]-[2,1-d]-2-oxazolidone.

Lanthanide‐induced shifts in the 17O NMR spectra of 1,6‐anhydro‐β‐D‐hexopyranoses. Evidence for tridentate complexing

AbstractThe complexation of four 1,6‐anhydro‐β‐D‐hexopyranoses with europium(III) was studied in aqueous solution by natural abundance 17O NMR. The paramagnetic ion induced contact shifts of individual hydroxy and ether resonances to low frequency. A clear indication of tridentate complexes was obtained, proving the involvement of the oxygen atom of the anhydro ring in talosan and mannosan and that of the pyranose ring in glucosan.

Novel carbocyclization of a D-glucose-derived alkene

Cyclopentadiene reacts with a D-glucose-derived hex-3-enose derivative to give norbornene derivatives attached at the 2,3-position of a 1,6-anhydrohexose skeleton; although the bicyclic enone isolevoglucosenone is a plausible intermediate in this reaction, the products actually appear to arise through initial cycloaddition to a rearranged acyclic sugar derivative with subsequent generation of the anhydro ring.

ChemInform Abstract: Synthesis of (.+‐.)‐3‐Amino‐2,4‐dihydroxy‐6‐hydroxymethyl‐8‐oxabicyclo‐(3.2.1)octane Derivatives and Their Anhydro Ring Migration with Hydrogen Bromide‐Acetic Acid.

AbstractThe triacetate of the bicyclic triol (I) is deacetylated and subsequently oxidized with NaIO4 to give the dialdehyde (II) which is coupled with nitromethane (III) to produce the three diastereomeric nitro derivatives (IV) ‐ (VI).

Base-catalyzed conversion of the a- l-iduronic acid 2-sulfate unit of heparin into a unit of a- l-galacturonic acid, and related reactions

Residues of a- l-idopyranosyluronic acid 2-sulfate in heparin undergo a loss of the sulfate group, by intramolecular displacement in sodium carbonate solution at 100°, leading to the formation of a heparin analog containing residues of a- l-galactopyranosyluronic acid ( 4). The configuration of these latter residues, which was determined by chemical evidence in combination with n.m.r. and c.d. spectroscopic data, is accounted for by selective hydrolysis of the oxirane ring of 2,3-anhydro- a- l-guluronic acid ( 3), a transient intermediate formed during the desulfation step. Regio- and stereo-selective aspects of ring-opening reactions of 3 are described. Several observations suggest that the reaction temperature is critical in determining whether the nucleophilic attack on the anhydro ring occurs at C-2 or C-3. Among these is the finding that, in contrast to the conditions used in the formation of the a- l- agalacto diastereomer ( 4), ammonolysis of 3 at room temperature gives rise to a 2-amino-2-deoxyaldohexuronic acid having the a- l- ido configuration.

Synthesis of (±)-3-amino-2,4-dihydroxy-6-hydroxymethyl-8-oxabicyclo[3.2.1]octane derivatives, and their anhydroring-migration with hydrogen bromide-acetic acid

Nitromethane-mediated cyclization of the dialdehyde generated by periodate oxidation of (±)-2 exo,3 exo-dihydroxy-5 endo-hydroxymethyl-7-oxabicyclo[2.2.1]-heptane ( 2) in methanolic sodium methoxide afforded, after neutralisation, three diastereoisomers ( 4a–6a) of (±)-2,4-dihydroxy-6-hydroxymethyl-3-nitro-8-oxabicyclo[3.2.1]octane in 52% combined yield. Their structures were assigned on the basis of 1H-n.m.r. spectra of the respective triacetates ( 4b–6b). Hydrogenation of the nitro compounds in methanol-acetic anhydride with Raney nickel followed by acetylation gave the corresponding N-acetyl derivatives ( 4c–6c), treatment of which with 15% hydrogen bromide-acetic acid at 80° replaced the primary acetoxyl group with bromine, giving the monobromo derivatives 4d–6d. Migration of the anhydro rings also occurred with 4c and 6c, yielding the respective isomers (1 RS,2 RS,4 SR, 5 RS,6 RS,7 SR)-7-acetamido-2,6-diacetoxy-4-bromomethyl-8-oxabicyclo[3.2.1]octane ( 7) and (1 RS,2 RS,4 SR,5 RS,6 SR,7 SR)-6-acetamido-4,7-diacetoxy-2-bromo-methyl-8-oxabicyclo[3.2.1]octane ( 8a). The mechanism of these reactions is considered.

Synthesis of l-fructose

l-Sorbose ( 1) was converted into methyl 4,6- O-isopropylidene-α- l-sorbofuranoside, which was tosylated to give methyl 4,6- O-isopropylidene-1,3-di- O- p-tolylsulfonyl-α- l-sorbofuranoside. Removal of the isopropylidene protecting group and formation of a 3,4-anhydro-ring afforded methyl 3,4-anhydro-1- O- p-tolyl-sulfonyl-α- l-tagatofuranoside, which was converted into l-fructose ( 7) by acid hydrolysis. In an alternative, facile synthesis, 1 was converted, in the presence of tin(II) chloride as a catalyst, into 1,2:4,6-di- O-isopropylidene-α- l-sorbofuranose. Selective removal of the 4,6- O-isopropylidene group, followed by formation of a 3,4-anhydro ring afforded 3,4-anhydro-1,2- O-isopropylidene-α- l-tagatofuranose. Opening of the anhydro ring by base catalysis and removal of the 1,2- O-isopropylidene group yielded 7.