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.     

2,5:3,4-Dianhydro-1,6-dideoxy-6-(trimethylamino)-d-allitol and -d-galactitol

A new, four-step synthesis of 2,5:3,6-dianhydro-1-deoxy-d-glucitol 16 was worked out, starting from 1,6-dibromo-1,6-dideoxy-d-mannitol. Compound 16 was converted into different 4-O-acyl derivatives, the 3,6-anhydro rings of which where opened with hydrogen bromide, yielding the corresponding 6-bromo compounds. These were converted, via the 6-azides, into the 6-(dimethylamino) derivatives, the sulfonic esters of which gave, on treatment with base, the 2,5:3,4-dianhydro-d-allitol and -d-galactitol derivatives. These were converted with methyl iodide into the corresponding quaternary salts. On biological testing, only the d-allitol derivative showed weak, muscarine-like activity.     

1,6-diamino-2,5-anhydro-1,6-dideoxy-l-iditol and some derivatives thereof

1,6-Diamino-2,5-anhydro-1,6-dideoxy-l-iditol (31) and its derivatives were synthesized, starting from 2,4-O-benzylidene-1,6-di-O-tosyl-d-glucitol. The 1,6-bis-(acetamido)-l-talo epoxide was readily hydrolyzed to the corresponding l-iditol derivative under anchimeric assistance of the 1-acetamido group. On treatment with formaldehyde-formic acid, diamine 31 gave a tricyclic, 1,4:3,6-bis(N,O-methylene) derivative which was stable under acidic conditions but, according to ¹³C-n.m.r. spectroscopy, was readily hydrolyzed to an equilibrium mixture in neutral, aqueous solution. The corresponding 1,6-bis(dimethylamino) derivative could be obtained by reducing this equilibrium mixture with borohydride. The different, quaternary salts obtained on methylation of the corresponding 1,6-bis(dimethylamino) derivatives with methyl iodide (aiming at the structure of epi-allo-muscarine) showed no muscarine-like, biological activity.     

Nitrous acid deamination of conformationally inverted aminodeoxyhexopyranoses

Nitrous acid deamination of 2-amino-1,6-anhydro-2-deoxy-β-D-glucopyranose (1) in the presence of weakly acidic, cation-exchange resin gave 1,6:2,3-dianhydro-β-D-mannopyranose (3) and 2,6-anhydro-D-mannose (6), characterized, respectively, as the 4-acetate of 3 and the per-O-acetylated reduction product of 6, namely 2,3,4,6- tetra-O-acetyl-1,5-anhydro-D-mannitol, obtained in the ratio of 7:13. Comparative deaminatior of the 4-O-benzyl derivative of 1 led to similar qualitative results. Deamination of 3-amino-1,6-anhydro-3-deoxy-β-D-glucopyranose gave 1,6:2,3- and 1,6:3,4-dianhydro-β-D-allopyranose (13 and 16), characterized as the corresponding acetates, obtained in the ratio of 31:69, as well as the corresponding p-toluenesulfonates. Deamination of 4-amino-1,6-anhydro-4-deoxy-β-D-glucopyranose and of its 2-O-benzyl derivative gave the corresponding 1,6:3,4-D-galacto dianhydrides as the only detectable products. 2,5-Anhydro-D-glucose, characterized as the 1,3,4,6-tetra-O- acetyl derivative of the corresponding anhydropolyol, was obtained in 39% yield from the same deamination reaction performed on 2-amino-1,6-anhydro-2-deoxy-β-D- mannopyranose (24). In 90% acetic acid, the nitrous acid deamination of 24, followed by per-O-acetylation, gave only 1,3-4-tri-O-acetyl-2,5-anhydro-α-D-glucoseptanose. In the case of 1,6-anhydro-3,4-dideoxy-3,4-epimino-β-D-altropyranose, only the corresponding glycosene was formed, namely, 1,6-anhydro-3,4-dideoxy-β-D-threo--hex-3-enopyranose.     

Acid-catalyzed pyrolytic synthesis and decomposition of 1,4:3,6-dianhydro-α-d-glucopyranose

1,4:3,6-dianhydro-α-d-glucopyranose (1) was formed, together with 1,6-anhydro-3,4-dideoxy-β-d-glycero-hex-3-enopyranos-2-ulose (levoglycosenone, 2) and levoglucosan (4), on acid-catalyzed pyrolysis of d-glucose, amylopectin, and cellulose. Pyrolysis of 1 in the presence of acid provided significant quantities of 2, indicating that 1 can act as a pyrolytic precursor of 2. A pyrolysis product from cellulose previously considered to be 1,6-anhydro-3-deoxy-β-d-erythro-hex-3-enopyranose (12) was shown to be dianhydride 1.     

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.     

Synthesis of derivatives of methyl β-sophoroside

Selective tritylation of methyl β-sophoroside (1) and subsequent acetylation gave the 3,4,2′,3′,4′-penta-O-acetyl-6,6′-di-O-trityl derivative, which was O-detritylated, and the product p-toluenesulfonylated, to give methyl 3,4,2′,3′,4′-penta-O-acetyl-6,6′-di-O-p-tolylsulfonyl-β-sophoroside (4) in 63% net yield. Compound 4 was also obtained in 69% yield by p-toluenesulfonylation of 1, followed by acetylation. Several, 6,6′-disubstituted derivatives of 1 were synthesized by displacement reactions of 4 with various nucleophiles. Treatment of 4 with sodium methoxide afforded methyl 3,6:3′,6′-dianhydro-β-sophoroside. Several 6- and 6′-monosubstituted derivatives of 1 were prepared, starting from the 4,6-O-benzylidene derivative of 1.     

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.     

Synthesis of 4-cyano- and 4-nitrophenyl 2,5-anhydro- 1,6-dithio-alpha-D-gluco- and -alpha-L-guloseptanosides carrying different substituents at C-3 and C-4

Treatment of 1,6:2,5-dianhydro-3,4-di-O-methanesulfonyl-1-thio-D-glucitol in methanol with sodium hydroxide afforded 1,6:2,5:3,4-trianhydro-1-thio-allitol, 1,4:2,5-dianhydro-6-methoxy-1-thio-D-galactitol, 1,6:2,5-dianhydro-4-O-methyl-1 -thio-D-glucitol, 1 ,6:2,5-dianhydro-3-O-methanesulfonyl-1 -thio-D-glucitol and 1 ,6:2,5-dianhydro-4-deoxy-1-thio-D-erythro-hex-3-ulose (14) in 5, 4, 28, 5.5 and 41% yield, respectively. Formation of these derivatives can be explained via a common sulfonium intermediate. Reduction of 14 with sodium borohydride and subsequent acetylation afforded 3-O-acetyl-1,6:2,5-dianhydro-4-deoxy-1-thio-D-xylo-hexitol, the absolute configuration of which was proved by X-ray crystallography. The 1,6:2,5-dianhydro-1-thio-D-hexitol derivatives in which the free OH groups were protected by acetylation, methylation or mesylation were converted by a Pummerer reaction of their sulfoxides into the corresponding 1-O-acetyl hexoseptanose derivatives which were used as donors for the glycosidation of 4-cyano- and 4-nitrobenzenethiol, respectively. The Pummerer reaction of 1,6:2,5-dianhydro-4-deoxy-3-O-methyl-1-thio-D-xylo-hexitol S-oxide gave, besides 1-O-acetyl-2,5-anhydro-3-deoxy-4-O-methyl-6-thio-alpha-L- (23) and 1-O-acetyl-2,5-anhydro-4-deoxy-3-O-methyl-6-thio-alpha-D-xylo-hexoseptanose (25), 1-O-acetyl-4-deoxy-2,6-thioanhydro-D-lyxo-hexopyranose, formed in a rearrangement reaction. The same rearrangement took place, when a mixture of 23 and 25 was used as donor in the glycosidation reaction with 4-cyanobenzenethiol, applying trimethylsilyl triflate as promoter. The oral antithrombotic activity of the obtained alpha-thioglycosides was determined in rats, using Pescador's model.     

Monodeoxy-1,4:3,6-dianhydrohexitol nitrates

Monodeoxy-1,4:3,6-dianhydrohexitol nitrates with (5) or without (6) an additional chloro substituent were synthesized, starting from 1,4:3,6-dianhydrohexitol-monoacetates, via 3 as key intermediates. Attempts to generate an unsaturated nitrate ester resulted in a DBN alkylation product (9).Both the endo- and exo-configurated monodeoxy-1,4:3,6-dianhydrohexitol nitrates have been prepared. Attempts to generate an unsaturated nitrate ester resulted in a DBN alkylation produkt.     

Synthesis of a 2-acetamido-5-amino-2,5-dideoxy-d-xylopyranosyl derivative

2-Acetamido-5-amino-2,5-dideoxy-d-xylopyranosyl hydrogensulfite (11) has been synthesized from benzyl 2-(benzyloxycarbonylamino)-2-deoxy-5,6-O-isopro-pylidene-β-d-glucofuranoside (1). O-Deisopropylidenation of 1 gave the triol 2, which was converted, via oxidative cleavage at C-5-C-6 and subsequent reduction, into the related benzyl β-d-xylofuranoside derivative (3). Catalytic reduction of benzyl 2-(benzyloxycarbonylamino)-2-deoxy-5-O-tosyl-β-d-xylofuranoside, derived from 3 by selective tosylation, and subsequent N-acetylation, afforded benzyl 2-acetamido-2-deoxy-5-O-tosyl-β-d-xylofuranoside, which was treated with sodium azide to give the corresponding 5-azido derivative (6). (Tetrahydropyran-2-yl)ation of the product formed by hydrolysis of 6 gave 2-acetamido-5-azido-2,5-dideoxy-1,3- di-O-(tetrahydropyran-2-yl)-d-xylofuranose (9). Treatment of 2-acetamido-5-amino-2,5-dideoxy-1,3-di-O-(tetrahydropyran-2-yl)-d-xylofuranose, derived from 9 by reduction, with sulfur dioxide in water gave 11. Hydrogenation of 6 and subsequent acetylation yielded 3-acetamido-4,5-diacetoxy-1-acetyl-xylo-piperidine. Evidence in support of the structures assigned to the new derivatives is presented.     

Derivatives of 2,5-anhydroallitol and 2,5-anhydroaltritol

Two routes to protected derivatives of 2,5-anhydroallitol were investigated. The first route, involving a two-step reduction of 2,5-anhydro-6-O-benzoyl-3,4-O-isopropylidene-D-allonitrile (4), gave a mixture of 2,5-anhydro-6-O-benzoyl-3,4-O-isopropylidene-D-altritol (7) and a lesser amount of the desired 2,5-anhydro-6-O-benzoyl-3,4-O-isopropylidene-D-allitol (6). Isomerization was shown to occur in the first reduction step—treatment of the nitrile 4 with Raney nickel, sodium hypophosphite, and acetic acid. The second route gave isomerically pure 2,5-anhydro-3,4,6-tri-O-benzyl-D-allitol (21) via reduction of the corresponding ethyl allonate (18).     

New monoterpenoid by biotransformation of thymoquinone using Aspergillus niger

Microbial transformation of thymoquinone (5-isopropyl-2-methyl-cyclohexa-2,5-diene-1,4-dione) (1) by suspended cell-cultures of the plant pathogenic fungus Aspergillus niger resulted in the production of three metabolites. These metabolites were identified as 5-isopropyl-2-methyloxepin-1-one (2), 3-hydroxy-5-isopropyl-2-methylcyclohexa-2,5-diene-1,4-dione (3), and 5-isopropyl-2-methylbenzene-1,4-diol (4) by different spectroscopic methods. Metabolite 2 was found to be a new compound. Compound 4 showed a potent antioxidant activity.     

Studies on dextranases. 3. Insolubilization of a bacterial dextranase

Ammonium hydroxide treatment of 1,6:2,3-dianhydro-4-O-benzyl-β-D-mannopyranose, followed by acetylation, gave 2-acetamido-3-O-acetyl-1,6-anhydro-4-O-benzyl-2-deoxy-β-D-glucopyranose which was catalytically reduced to give 2-acetamido-3-O-acetyl-1,6-anhydro-2-deoxy-β-D-glucopyranose (6), the starting material for the synthesis of (1→4)-linked disaccharides bearing a 2-acetamido-2-deoxy-D-glucopyranose reducing residue. Selective benzylation of 2-acetamido-1,6-anhydro-2-deoxy-β-D-glucopyranose gave a mixture of the 3,4-di-O-benzyl derivative and the two mono-O-benzyl derivatives, the 4-O-benzyl being preponderant. The latter derivative was acetylated, to give a compound identical with that just described. For the purpose of comparison, 2-acetamido-4-O-acetyl-1,6-anhydro-2-deoxy-β-D-glucopyranose has been prepared by selective acetylation of 2-acetamido-1,6-anhydro-2-deoxy-β-D-glucopyranose.Condensation between 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide and 6 gave, after acetolysis of the anhydro ring, the peracetylated derivative (17) of 2-acetamido-2-deoxy-4-O-β-D-glucopyranosyl-α-D-glucopyranose. A condensation of 6 with 3,4,6-tri-O-acetyl-2-deoxy-2-diphenoxyphosphorylamino-α-D-glucopyranosyl bromide likewise gave, after catalytic hydrogenation, acetylation, and acetolysis, the peracylated derivative (21) of di-N-acetylchitobiose.     

Selektive monotosylierung von 1,6-anhydro-β-D-glucofuranose und darstellung der 1,6:3,5-dianhydro-α-L-idofuranose,des ersten vertreters einer neuen klasse von dianhydrohexosen

Monotosylation of 1,6-anhydro-β-D-glucofuranose is a highly selective process, which yields the 5-O-tosyl derivative 2 preferentially (77%). By-products of the reaction are the 2-O-monotosyl derivative (6%) and the 2,5- and 3,5-di-O-tosyl derivatives (both 5%). The substitution pattern of all compounds was derived from n.m.r. spectra, especially from those of the acetylated compounds. Attempts to use 2 in the synthesis of 1,6-anhydro-α-L-idofuranose by intermolecular nucleophilic substitution failed, but instead yielded 1,6:3,5-dianhydro-α-L-idofuranose. This first representative of a new class of dianhydrohexoses was characterized by n.m.r. and m.s. Acetylation gave the 2-monoacetate showing an n.m.r. spectrum in agreement with the proposed structure. This tricyclic structure is expected to be very rigid and is composed of four-, five-, six-, seven-, and eight-membered rings.     

Structure and anomeric configuration of the 3,6-anhydro-osazone derivatives obtained from d-altro-2-heptulose phenylosazone

Dehydration of d-altro-2-heptulose phenylosazone with methanolic sulfuric acid afforded two 3,6-anhydro-osazone derivatives (2 and 3). Compound 3 was obtained as the preponderant isomer, with inversion at C-1 (C-3 of the starting osazone), and 2 was obtained without inversion. Refluxing of 3 with copper sulfate afforded the C-nucleoside analog, namely, 2-phenyl-4-β-d-ribofuranosyl-1,2,3-osotriazole (4). Acetylation of 4 afforded the tri-O-acetyl derivative 5. The anomeric configuration was determined by c.d. and n.m.r. spectroscopy. The mass spectra of compounds 2–5 are discussed.     

Reduced perylenequinone derivatives from an endophytic Alternaria sp. isolated from Pinus ponderosa

The consecutive solvent extraction of endophytic Alternaria sp. (DC401) isolated from Pinus ponderosa followed by chromatographic techniques led to the isolation of five perylenequinone compounds and one dihydronaphthaquinone derivative, which include three new perylenequinones (1–3). The compounds were identified as 6-methoxy-3,6a,7,10-tetrahydroxy-4,9-dioxo-4,5,6,6a,6b,7,8,9-octahydroperylene (1), 3,6a,9,10-tetrahydroxy-7,8-epoxy-4-oxo-4,5,6,6a,6b,7,8,9-octahydroperylene (2), 6-methoxy-3,6a,9,10-tetrahydroxy-7,8-epoxy-4-oxo-4,5,6,6a,6b,7,8,9-octahydroperylene (3), 3,6a,7,10-tetrahydroxy-4,9-dioxo-4,5,6,6a,6b,7,8,9-octahydroperylene (altertoxin I) (4), 3,6a,7,10-tetrahydroxy-4,9-dioxo-4,6a,6b,7,8,9-hexahydroperylene (dehydroaltertoxin I) (5), and 7-chloroscytalone (6). Structure of compounds 1–6 was determined on the basis of detailed spectroscopic analysis, as well as by comparison with literature reports. The antileismanial, antimicrobial, antimalarial and in vitro cytotoxic activities of compounds 1–6 were evaluated.     

Camphor Pathway Redux: Functional Recombinant Expression of 2,5- and 3,6-Diketocamphane Monooxygenases of Pseudomonas putida ATCC 17453 with Their Cognate Flavin Reductase Catalyzing Baeyer-Villiger Reactions

Whereas the biochemical properties of the monooxygenase components that catalyze the oxidation of 2,5-diketocamphane and 3,6-diketocamphane (2,5-DKCMO and 3,6-DKCMO, respectively) in the initial catabolic steps of (+) and (−) isomeric forms of camphor (CAM) metabolism in Pseudomonas putida ATCC 17453 are relatively well characterized, the actual identity of the flavin reductase (Fred) component that provides the reduced flavin to the oxygenases has hitherto been ill defined. In this study, a 37-kDa Fred was purified from a camphor-induced culture of P. putida ATCC 17453 and this facilitated cloning and characterization of the requisite protein. The active Fred is a homodimer with a subunit molecular weight of 18,000 that uses NADH as an electron donor (K_m = 32 μM), and it catalyzes the reduction of flavin mononucleotide (FMN) (K_m = 3.6 μM; k_cat = 283 s⁻¹) in preference to flavin adenine dinucleotide (FAD) (K_m = 19 μM; k_cat = 128 s⁻¹). Sequence determination of ∼40 kb of the CAM degradation plasmid revealed the locations of two isofunctional 2,5-DKCMO genes (camE_25–1 for 2,5-DKCMO-1 and camE_25–2 for 2,5-DKCMO-2) as well as that of a 3,6-DKCMO-encoding gene (camE₃₆). In addition, by pulsed-field gel electrophoresis, the CAM plasmid was established to be linear and ∼533 kb in length. To enable functional assessment of the two-component monooxygenase system in Baeyer-Villiger oxidations, recombinant plasmids expressing Fred in tandem with the respective 2,5-DKCMO- and 3,6-DKCMO-encoding genes in Escherichia coli were constructed. Comparative substrate profiling of the isofunctional 2,5-DCKMOs did not yield obvious differences in Baeyer-Villiger biooxidations, but they are distinct from 3,6-DKCMO in the stereoselective oxygenations with various mono- and bicyclic ketone substrates.     

]Hexitol derivatives containing a 1,4-oxathiane ring

The synthesis of 2,5-anhydro-3-O-methylsulfonyl-6-thio-1,4-thioanhydro-D-galactitol (4; type A structure) and 2,5-anhydro-3,4-di-O-methylsulfonyl-1,6-thioanhydro-D-glucitol (10, type B structure), starting from 2,5-anhydro-1,6-dibromo-1,6-dideoxy-3,4-di-O-methylsulfonyl-D-glucitol (1) is described. The 4-O-methyl-sulfonyl group of 10 can be displaced by nucleophiles with retention of configuration. In this reaction, a cyclic sulfonium intermediate 21 is involved, which, depending on the nucleophilicity of the anion, leads to different ratios of type A and B compounds. Introduction of a three-membered ring into the 3,4-position of type B compounds yielded tricyclic derivatives of allitol.     

The preparation of some bromodeoxy- and dibromodideoxy-pentonolactones

Treatment of ammonium d-xylonate with hydrogen bromide in acetic acid yields 2,5-dibromo-2,5-dideoxy-d-lyxono-1,4-lactone (2a), whereas similar treatment of potassium d-arabinonate gives 5-bromo-5-deoxy-d-arabinono-1,4-lactone (8a) as the main product. Two isomeric 2,5-dibromo-2,5-dideoxy-1,4-lactones are also formed in minor amounts. Selective hydrogenolysis of 2a affords 5-bromo-2,5-dideoxy-d-threo-pentono-1,4-lactone, while prolonged treatment results in the formation of 3-hydroxypentanoic acid. Similarly, hydrogenolysis of 8a produces a 2,3-dihydroxypentanoic acid together with smaller amounts of 5-deoxy-d-arabinono-1,4-lactone; the latter also results from hydrogenolysis of 5-deoxy-5-iodo-d-arabinono-1,4-lactone with Raney nickel.