1,4-Dioxane-2,5-dione-type monomers derived from l-ascorbic and d-isoascorbic acids. Synthesis and polymerisation

l-Ascorbic and d-isoascorbic acids have been used as the starting materials for the preparation of (3R,4′S)-3-(2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)-1,4-dioxane-2,5-dione (IPTA), (3R and S, 4′S,6R)-3-methyl-6-(2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)-1,4-dioxane-2,5-dione (IPTP) and (3R,4′R)-3-(2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)-1,4-dioxane-2,5-dione (IPEA), three novel 1,4-dioxane-2,5-dione-type monomers. Ring-opening homopolymerisation and copolymerisation of the IPTA monomer, derived from l-ascorbic acid, with d,l-lactide have been performed. The polymers were characterised by elemental microanalysis, as well as IR and ¹H and ¹³C NMR spectroscopies. GPC was used to estimate product molecular weights, and thermal studies (DSC and TGA) revealed that all the polymers were amorphous, being stable up to 250 °C under nitrogen.     

Substitution of 1,4:3,6-dianhydro-D-mannitol derivatives by reactions with iodide

Reaction of 1,4:3,6-dianhydro-2,5-di-O-mesyl- and -tosyl-D-mannitol with sodium iodide gave a 1:1 mixture of 2,5-dideoxy-2,5-diiodo-D-glucitol (12) and -L-iditol (22). 1,4:3,6-Dianhydro-2-deoxy-2-iodo-5-O-mesyl-D-glucitol (13) and the corresponding D-mannitol derivative (9) are formed as intermediates. Both 9 and 13, as well as 12 and 22, are rapidly isomerized to a mixture of the two in the presence of iodide, proving a fast iodo-iodo substitution reaction. This is restricted to starting materials having the mannitol configuration, as the corresponding 2,5-di-O-mesyl-D-glucitol derivative gives only the known 5-deoxy-5-iodo-L-iditol derivative. The possible mechanism of the unusual isomerization reactions is discussed.     

Stereoselective entry into the d-GalNAc series starting from the d-Gal one: a new access to N-acetyl-d-galactosamine and derivatives thereof

A new stereoselective preparation of N-aceyl-d-galactosamine (1b) starting from the known p-methoxyphenyl 3,4-O-isopropylidene-6-O-(1-methoxy-1-methylethyl)-β-d-galactopyranoside (10) is described using a simple strategy based on (a) epimerization at C-2 of 10 via oxidation-reduction to give the talo derivative 11, (b) amination with configurational inversion at C-2 of 11 via a S_N2-type reaction on its 2-imidazylate, (c) anomeric deprotection of the p-methoxyphenyl β-d-galactosamine glycoside 14, (d) complete deprotection. Applying the same protocol to 2,3:5,6:3′,4′-tri-O-isopropylidene-6′-O-(1-methoxy-1-methylethyl)-lactose dimethyl acetal (4), directly obtained through acetonation of lactose, the disaccharide β-d-GalNAcp-(1→4)-d-Glcp (1a) was obtained with complete stereoselectivity in good (40%) overall yield from lactose.     

Toward the synthesis of fine chemicals from lactose: preparation of d-xylo and l-lyxo-aldohexos-5-ulose derivatives

The transformation of (5R)-2,6-di-O-benzyl-5-C-methoxy-β-d-galactopyranosyl-(1→4)-2,3:5,6-di-O-isopropylidene-aldehydo-d-glucose dimethyl acetal (8) into partially protected derivatives of d-xylo- and l-lyxo-aldohexos-5-ulose has been reported, applying appropriate epimerisation methods to its 3′-O- and 4′-O-protected alcoholic derivatives.     

Synthesis,crystal structure,and conformation of 1(S)-acetoxy-3-[6(R)-O-benzyl-1,2:3,4-di-O-isopropylidene-α-d-galactopyranos-6-yl]-1-(methyl 2,3,4-tri-O-benzyl-6-deoxy-β-d-galactopyranosid-6-yl)propyne

Condensation of 6-O-benzyl-7,8-dideoxy-1,2:3,4-di-O-isopropylidene-d-glycero-α-d-galacto-oct-7-ynopyranose with methyl 2,3,4-tri-O-benzyl-6-deoxy-β-d-galacto-heptodialdo-1,5-pyranoside afforded a 2:1 mixture of the 1S and 1R isomers (1a and 1b) of 3-[6(R)-O-benzyl-1,2:3,4-di-O-isopropylidene-α-d-galactopyranos-6-yl]-1-hydroxy-1-(methyl 2,3,4-tri-O-benzyl-6-deoxy-β-d-galactopyranosid-6-yl)propyne. A single crystal of the 1-O-acetyl derivative (1c) of 1a was investigated by X-ray diffraction methods in a four-circle diffractometer. Compound 1c crystallises in the monoclinic system, space group P2₁ (Z = 2) with cell dimensions a = 14.896(2), b = 8.295(1), c = 20.547(3) Å, and β = 102.66(1)°. The structure was solved by direct methods and refined by a full-matrix, least-squares procedure against 3839 unique reflections (F > 2σ_F), resulting in a final R = 0.045 (unit weights). The configuration at the new chiral center (C-1) was established as S(d). The galactopyranose rings have conformations ⁴C₁ (tri-O-benzylated moiety) and °S₅ + °T₂ (di-O-isopropylidenated moiety). The 1,2- and 3,4-O-isopropylidene rings have ³T₂ and ²E conformations, respectively.     

Synthesis and characterization of propyl O-β-d-galactopyranosyl-(1→4)-O-β-d-galactopyranosyl-(1→4)-α-d-galactopyranoside

Allyl 4-O-(4-O-acetyl-2-O-benzoyl-3,6-di-O-benzyl-β-d-galactopyranosyl)-2-O-benzoyl-3,6-di-O-benzyl-α-d- galactopyranoside was O-deallylated to give the 1-hydroxy derivative, and this was converted into the corresponding 1-O-(N-phenylcarbamoyl) derivative, treatment of which with dry HCl produced the α-d-galactopyranosyl chloride. This was converted into the corresponding 2,2,2-trifluoroethanesulfonate, which was coupled to allyl 2-O-benzoyl-3,6-di-O-benzyl-α-d-galactopyranoside, to give crystalline allyl 4-O-[4-O-(4-O-acetyl-2-O-benzoyl-3,6-di-O-benzyl-β-d-galactopyranosyl)-2-O-benzoyl-3,6-di- O-benzyl-β-d-galactopyranosyl]-2-O-benzoyl-3,6-di-O-benzyl-α-d-galactopyranoside (15) in 85% yield, no trace of the α anomer being found. The trisaccharide derivative 15 was de-esterified with 2% KCN in 95% ethanol, and the product O-debenzylated with H₂-Pd, to give the unprotected trisaccharide. Alternative sequences are discussed.     

Dehydration of 2-(d-arabino-tetrahydroxybutyl)furans : Part II. The steric course and mechanism of the reaction

Acid-catalyzed dehydration of methyl and ethyl 2-methyl-5-(d-arabino-tetrahydroxybutyl)-3-furoate (4a, b) takes place preferentially with inversion of configuration at C-1′, yielding the corresponding 5-(1,4-anhydro-d-ribo-tetrahydroxybutyl)-2-methyl-3-furoate (6a, b), and, to a much smaller extent, with retention of configuration giving the isomeric d-arabino anhydro-derivative (5a, b). The reaction is reversible, the equilibrium being set up when there is a high concentration of the thermodynamically more-stable d-ribo anhydro-derivative in the presence of the d-arabino isomer, the starting (d-arabino-tetrahydroxybutyl)furan (4a, db), and a compound thought to be methyl (or ethyl) 2-methyl-5-(d-ribo-tetrahydroxybutyl)-3-furoate (13). A mechanism is proposed for this reaction which involves the C-1′ carbonium ion 15 as the key intermediate. The anhydro derivatives of the d-ribo and d-arabino configurations can be distinguished by their optical rotations, the chemical shifts of H-1′, and the J_1′,2′ coupling constants.     

Stereosensitive formation and interconversion of sulfur-bridged cobalt(III)-mercury(II) polynuclear complexes with d- and/or l-penicillaminates

The reaction of trans(N)-[Co(d-pen)₂]⁻ (pen = penicillaminate) with HgCl₂ or HgBr₂ in the molar ratios of 1:1 gave the sulfur-bridged heterodinuclear complex, [HgX(OH₂){Co(d-pen)₂}] (X = Cl (1a) or Br (1b)). A similar reaction in the ratio of 2:1 produced the trinuclear complex, [Hg{Co(d-pen)₂}₂] (1c). The enantiomers of 1a and 1c, [HgCl(OH₂){Co(l-pen)₂}] (1a′) and [Hg{Co(l-pen)₂}₂] (1c′), were also obtained by using trans(N)-[Co(l-pen)₂]⁻ instead of trans(N)-[Co(d-pen)₂]⁻. Further, the reaction of cis · cis · cis-[Co(d-pen)(l-pen)]⁻ with HgCl₂ in the molar ratio of 1:1 resulted in the formation of [HgCl(OH₂){Co(d-pen)(l-pen)}] (2a). During the formations of the above six complexes, 1a, 1b, 1c, 1a′, 1c′, and 2a, the octahedral Co(III) units retain their configurations. On the other hand, the reaction of cis · cis · cis-[Co(d-pen)(l-pen)]⁻ with HgCl₂ in the molar ratio of 2:1 gave not [Hg{Co(d-pen)(l-pen}₂] but [Hg{Co(d-pen)₂}{Co(l-pen)₂}] (2c), accompanied by the ligand-exchange on the terminal Co(III) units. The X-ray crystal structural analyses show that the central Hg(II) atom in 1c takes a considerably distorted tetrahedral geometry, whereas that in 2c is of an ideal tetrahedron. The interconversion between the complexes is also examined. The electronic absorption, CD, and NMR spectral behavior of the complexes is discussed in relation to the crystal structures of 1c and 2c.     

Facile route for the synthesis of the iminosugar nucleoside (3R,4R)-1-(pyren-1-yl)-4-(hydroxymethyl)pyrrolidin-3-ol

N-(Pyren-1-yl)-(3R,4S)-4-[(1S,2R)-1,2,3-trihydroxypropyl]pyrrolidin-3-ol (4) was obtained in 36% yield from 3-deoxy-3-C-formyl-1,2:5,6-di-O-isopropylidene-α-d-allofuranose (3) by combined hydrolysis and aminoalkylation reactions with 1-aminopyrene in a one-pot reaction. Cleavage reactions of the exocyclic triol chain in 4 with NaIO₄ and NaBH₄ resulted in iminosugars 7 and 8, which are analogues of the furanose forms of 2-deoxy-d-allose and of 2-deoxy-d-ribose, the latter analogue N-(pyren-1-yl)-(3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol (8) being formed in 83% yield.     

A chiron approach to the total synthesis of cytotoxic (+)-muricatacin and (+)-5-epi-muricatacin from d-ribose

A chiron approach strategy toward the total synthesis of (+)-muricatacin and (+)-5-epi-muricatacin starting from commercially available and inexpensive d-ribose through the key intermediate (S)-5-((R)-1-hydroxyallyl)furan-2(5H)-one has been disclosed.     

Syntheses of 2-acetamido-2-deoxy-4-O-α-D-glucopyranosyl-α-d-glucopyranose (n-acetylmaltosamine) and 2-acetamido-2-deoxy-4-O-β-d-glucopyranosyl-α-d-glucopyranose

Condensation of benzyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-α-D-glucopyranoside with 2,3,4,6-tetra-O-benzyl-1-O-(N-methyl)acetimidoyl-β-D-glucopyranose gave benzyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-4-O-(2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl)-α-D-glucopyranoside which was catalytically hydrogenolysed to crystalline 2-acetamido-2-deoxy-4-O-α-D-glucopyranosyl-α-D-glucopyranose (N-acetylmaltosamine). In an alternative route, the aforementioned imidate was condensed with 2-acetamido-3-O-acetyl-1,6-anhydro-2-deoxy-β-D-glucopyranose, and the resulting disaccharide was catalytically hydrogenolysed, acetylated, and acetolysed to give 2-acetamido-1,3,6-tri-O-acetyl-2-deoxy-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-α-D-glucopyranose Deacetylation gave N-acetylmaltosamine. The synthesis of 2-acetamido-2-deoxy-4-O-β-D-glucopyranosyl-α-D-glucopyranose involved condensation of benzyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-α-D-glucopyranoside with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide in the presence of mercuric bromide, followed by deacetylation and catalytic hydrogenolysis of the condensation product.     

A short semi-synthesis and complete NMR-spectroscopic characterization of the naturally occurring lignan glycoside matairesinol 4,4′-di-O-β-d-diglucoside

A convenient semi-synthesis of (8R,8′R)-matairesinol 4,4′-di-O-β-d-glucopyranoside (MDG), found in the stems of Trachelospermum asiaticum var. intermedium, is described starting from the readily available starting materials d-glucose and hydroxymatairesinol. By this approach the synthesis of MDG can be accomplished in six steps with an overall yield of 28%. In addition, the first complete NMR-spectroscopic characterization of MDG was accomplished by the combination of standard NMR techniques and spectral simulations performed with the PERCH NMR simulation software.     

α,β-dicarbonyl reduction by Saccharomycesd-arabinose dehydrogenase

An α,β-dicarbonyl reductase activity was purified from Saccharomyces cerevisiae and identified as the cytosolic enzyme d-Arabinose dehydrogenase (ARA1) by MALDI-TOF/TOF. Size exclusion chromatography analysis of recombinant Ara1p revealed that this protein formed a homodimer. Ara1p catalyzed the reduction of the reactive α,β-dicarbonyl compounds methylglyoxal, diacetyl, and pentanedione in a NADPH dependant manner. Ara1p had apparent K_m values of ∼ 14 mM, 7 mM and 4 mM for methylglyoxal, diacetyl and pentanedione respectively, with corresponding turnover rates of 4.4, 6.9 and 5.9 s^− 1 at pH 7.0. pH profiling showed that Ara1p had a pH optimum of 4.5 for the diacetyl reduction reaction. Ara1p also catalyzed the NADP⁺ dependant oxidation of acetoin; however this back reaction only occurred at alkaline pH values. That Ara1p was important for degradation of α,β-dicarbonyl substrates was further supported by the observation that ara1-Δ knockout yeast mutants exhibited a decreased growth rate phenotype in media containing diacetyl.     

Acetalation of d-glucitol: 2,3:5,6-Di-O-isopropylidene-d-glucitol

The reaction of d-glucitol with acetone-zinc chloride gave a mixture of isopropylidene derivatives, from which the 2,3:5,6-diacetal (12) could be separated as its 1,4-dimesylate (13) or 1,4-ditosylate (14). The structure of 12 was proved by converting 14, via the 1-mono-iodide, into the known 1-deoxy-d-glucitol, and by mass-spectrometric investigation of the 1-deoxy-4-O-methyl diacetal. The terminally situated acetal group in 12 can be selectively hydrolyzed, and, on treatment with base, the 5,6-dihydroxy derivative obtained gives a d-galactitol 4,5-epoxide derivative.     

Neuroprotective Activity of (+)-(S)-2-[(1S,5R)-(3,7-Dioxo-2,4,6,8-Tetraazabicyclo[3.3.0]oct-2-yl)]-4-methylthiobutanoic acid

A study of the neurotropic, neuroprotective, and antioxidant action of the enantiomers and racemate of 2-[(3,7-dioxo-2,4,6,8-tetraazabicyclo[3.3.0]oct-2-yl)]-4-methylthiobutanoic acid synthesized in a stereoselective reaction of (R)-, (S)-, or (R,S)-N-carbamoylmethionine with 4,5-dihydroxyimidazolidine-2-one showed that only (+)-(S)-2-[(1S,5R)-(3,7-dioxo-2,4,6,8-tetraazabicyclo[3.3.0]oct-2-yl)]-4-methylthiobutanoic acid had neuroprotective properties. X-ray structure analysis showed that the predominating racemate of glycolurils is crystallized from aqueous solutions as a conglomerate. Antioxidant activity was not detected.     

Synthesis of 2- (and 6-) -dithian-2-yluracil nucleosides and their conversion into nucleoside derivatives

Addition of 2,2′-anhydro-[1-(3-O-acetyl-5-O-trityl-β-D-arabinofuranosyl)uracil] (1) to excess 2-litho-1,3-dithiane (2)in oxolane at ?78° gave 2-(1,3-dithian-2-yl)-1-(5-O-trityl-β-D-arabinofuranosyl)-4(1H)pyrimidinone (3), O²,2′-anhydro-5,6-di-hydro-6-(S)-(1,3-dithian-2-yl)-5′-O-trityluridine (4), and 2-(1,4-dihydroxybutyl)-1,3-dithiane (5) in yields of 15, 30, and 10% respectively. The structure of 3 was proved by its hydrolysis in acid to give 2-(1,3-dithian-2-yl)-4-pyrimidinone (6) and arabinose, and by desulfurization with Raney nickel to yield the known 2-methyl-1-(5-O-trityl-β-D-arabinofuranosyl)-4(1H)-pyrimidinone (7). Detritylation of 3 without glycosidic cleavage could only be effected by prior acetylation to 1-(2,3-di-O-acetyl-5-O-trityl-β-D-arabinofuranosyl)-2-(1,3-dithian-2-yl)-4(1H)-pyrimidinone (8) which, after treatment with acetic acid at room temperature for 65 h followed by the action of sodium methoxide gave 2-(1,3-dithian-2-yl)-1-β-D-arabinofuranosyl-4(1H)-pyrimidinone (10) in 45% yield. Detritylation of 4 in boiling acetic acid gave 5,6-dihydro-6-(S)-(1,3-dithian-2-yl)-1-β-D-arabinofuranosyluracil (12) and 3-[(S)-1-(1,3-dithian-2-yl)]propionamido-(1,2-dideoxy-β-D-arabinofurano)-[1,2-d]-2-oxazolidinone (13) in 10 and 90% yields, respectively. When 12 was kept in water or methanol for 7 days, quantitative conversion into 13 occurred. Acid hydrolysis of 12 afforded arabinose and 5,6-di-hydro-6-(1,3-dithian-2-yl)uracil (14), which was desulfurized with Raney nickel to the known 5,6-dihydro-6-methyluracil (15). Treatment of 13 with trifluoroacetic anhydride-pyridine yielded 77% of the cyano derivative 17. Similar dehydration of 3-(R)-1-methylpropionamido-(1,2-dideoxy-β-D-arabinofurano)-[1,2-d]-2-oxalidinone (18), obtained by desulfurization of 13, gave 60% of the nitrile 19. Hydrogenation of 19 over platinum oxide in acetic anhydride gave the acetamide derivative 20 in 95% yield. Nitrobenzoylation of 13 gave 3-[(S)-1-(1,3-dithian-2-yl)]cyanomethyl-3,5-di-O-p-nitrobenzoyl-(1,2-dideoxy-β-D-arabinofurano)-[1,2-d]-2-oxazolidinone (22), which was converted in 37% yield by treatment with methyl iodide in dimethyl sulfoxide into the aldehyde 24, characterized as the semicarbazone 25. The purification of 5 and its characterization as 2-(1,4-di-O-p-nitrobenzoylbutyl)-1,3-dithiane (27) is described.     

An enzymic synthesis of purine d-Arabinonucleosides

A method is described for the synthesis of purine d-arabinonucleosides that uses purine bases and 2,2′-anhydro-(1-β-d-arabinofuranosylcytosine), AraC-an, as the starting materials. AraC-an was chosen as the precursor to the d-arabinosyl donor, because it is more readily available than any of the products that may be sequentially derived from it, namely, 1-β-d-arabinofuranosylcytosine (AraC), 1-β-d-arabinofuranosyluracil (AraU), and α-d-arabinofuranosyl-1-phosphate (Araf 1-P), a d-arabinofuranosyl donor. Four reactions were involved in the overall process; (a) AraC-an was nonenzymically hydrolyzed at alkaline pH to AraC which was then (b) deaminated by cytidine deaminase to AraU, a nucleoside, (c) phosphorylyzed by uridine phosphorylase to Araf 1-P, and (d) this ester caused to react with a purine base to afford a purine d-arabinonucleoside, the reaction being catalyzed by purine nucleoside phosphorylase. All four reactions occurred in situ, the first and second being performed sequentially, whereas the third and fourth were combined in a single step. The three enzyme catalysts were purified from Escherichia coli. The efficiency of the method is exemplified by the synthesis of the d-arabinonucleosides of 2,6-diaminopurine and adenine; the overall yields, based on AraC-an, were 60 and 80%, respectively.     

Synthesis and glycosidase inhibitory activity of 1-amino-3,6-anhydro-1-deoxy-d-sorbitol derivatives

3,6-Anhydro-1-(aryl or alkylamino)-1-deoxy-d-sorbitol derivatives have been prepared in four steps from isosorbide, a by-product from the starch industry. The inhibitory activities of these new compounds have been evaluated towards 13 glycosidases. A first lead-compound was identified, which inhibited β-N-acetylglucosaminidase from bovine kidney (82% inhibition at 1 mM).     

High-performance liquid chromatography separation of the (S,S)- and (R,S)-forms of S-adenosyl-l-methionine

S-adenosyl-l-methionine (AdoMet), an important biological cofactor, exists in two chiral forms, (S,S)- and (R,S)-, only the former of which is biologically active. Here, we have developed a chromatographic method to obtain pure (S,S)-AdoMet using a single C18 column.     

Synthesis of 4-O-glycosylated 1,5-anhydro-d-fructose and of 1,5-anhydro-d-tagatose from a common intermediate 2,3-O-isopropylidene-d-fructose

Four novel disaccharides of glycosylated 1,5-anhydro-d-ketoses have been prepared: 1,5-anhydro-4-O-β-d-glucopyranosyl-d-fructose, 1,5-anhydro-4-O-β-d-galactopyranosyl-d-fructose, 1,5-anhydro-4-O-β-d-glucopyranosyl-d-tagatose, and 1,5-anhydro-4-O-β-d-galactopyranosyl-d-tagatose. The common intermediate, 1,5-anhydro-2,3-O-isopropylidene-β-d-fructopyranose, was prepared from d-fructose and was converted into the d-tagatose derivative by oxidation followed by stereoselective reduction to the 4-epimer. The anhydroketoses thus prepared were glycosylated and deprotected to give the disaccharides.