Deoxyfluoroketohexoses: 4-deoxy-4-fluoro- -sorbose and -tagatose and 5-deoxy-5-fluoro- -sorbose

4-Deoxy-4-fluoro-α- -sorbose (6) was prepared in crystalline form by the action of potassium hydrogen fluoride on 3,4-anhydro-1,2-O-isopropylidene-β- -psicopyranose (3) followed by deacetonation. Under identical conditions 3,4-anhydro-1,2-O-isopropylidene-β- -tagatopyranose (7) underwent epoxide migration to give 4,5-anhydro- 1,2-O-isopropylidene-β- -fructopyranose (12), which after deacetonation yielded 4-deoxy-4-fluoro- -tagatose (15) 5-deoxy-5-fluoro-α- -sorbopyranose (16) the latter as the crystalline free sugar. The action of glycol-cleavage reagents on the isopropylidene acetals of the deoxyfluoro sugars was consistent with the assigned structures. The structures were established by ¹³C n.m.r. studies of the free deoxyfluoro sugars 6 and 16 of the isopropylidene acetal 13, and by ¹H n.m.r. studies on the acetylated isopropylidene acetals 5 diacetate, 13 diacetate, and 14 diacetate. 5-Deoxy-5-fluoro- -sorbose (16) was biologically active producing in mice effects characteristic of deoxyfluorotrioses and of fluoroacetate. 4-Deoxy-4-fluoro- -tagatose (15) and 4-deoxy-4-fluoro- -sorbose (6) produced no apparent effects in mice up to a dose of 500 mg/kg. The implications of these findings with respect to transport phosphorylation, and the action of aldolase on ketohexoses are discussed.     

Deoxyfluoroketohexoses: 4-deoxy-4-fluoro-D-sorbose and -tagatose and 5-deoxy-5-fluoro-L-sorbose.

4-Deoxy-4-fluoro-alpha-D-sorbose (6) was prepared in crystalline form by the action of potassium hydrogen fluoride on 3,4-anhydro-1,2-O-isopropylidene-beta-D-psicopyranose (3) followed by deacetonation. Under identical conditions, 3,4-anhydro-1,2-O-isopropylidene-beta-D-tagatopyranose (7) underwent epoxide migration to give 4,5-anhydro-1,2-O-isopropylidene-beta-D-fructopyranose (12), which after deacetonation yielded 4-deoxy-4-fluoro-D-tagatose (15) and 5-deoxy-5-fluoro-alpha-L-sorbopyranose (16), the latter as the crystalline, free sugar. The action of glycol-cleavage reagents on the isopropylidene acetals of the deoxyfluoro sugars was consistent with the assigned structures. The structures were established by 13-C n.m.r. studies of the free deoxyfluoro sugars 6 and 16 and of the isopropylidene acetal 13, and by 1-H n.m.r. studies on the acetylated isopropylidene acetals 5 diacetate, 13 diacetate, and 14 diacetate. 5-Deoxy-5-fluoro-L-sorbose (16) was biologically active, producing in mice effects characteristic of deoxyfluorotrioses and of fluoroacetate. 4-Deoxy-4-fluoro-D-tagatose (15) and 4-deoxy-4-fluoro-D-sorbose (6) produced no apparent effects in mice up to a dose of 500mg/kg. The implications of these findings with respect to transport, phosphorylation, and the action of aldolase on ketohexoses are discussed.     

4-deoxy-4-fluoro-xyloside derivatives as inhibitors of glycosaminoglycan biosynthesis

Various 4-deoxy-4-fluoro-xylosides were prepared using click chemistry for evaluating their potential utility as inhibitors of glycosaminoglycan biosynthesis. 2,3-Di-O-benzoyl-4-deoxy-4-fluoro-β-D-xylopyranosylazide, obtained from L-arabinopyranose by six steps, was treated with a wide variety of azide-reactive triple bond-containing hydrophobic agents in the presence of Cu(2+) salt/ascorbic acid, a step known as click chemistry. After click chemistry, benzoylated derivatives were deprotected under Zemplén conditions to obtain 4-deoxy-4-fluoro-xyloside derivatives. A mixture of α:β-isomers of twelve derivatives were then separated on a reverse phase C18 column using HPLC and the resulting twenty four 4-deoxy-4-fluoro-xylosides were evaluated for their ability to inhibit glycosaminoglycan biosynthesis in endothelial cells. We identified two xyloside derivatives that selectively inhibit heparan sulfate and chondroitin sulfate/derman sulfate biosynthesis without affecting cell viability. These novel derivatives can potentially be used to define the biological actions of proteoglycans in model organisms and also as therapeutic agents to combat various human diseases in which glycosaminoglycans participate.     

Synthesis and antibacterial activity of 5-deoxy-5-episubstituted arbekacin derivatives

5-Deoxy-5-episubstituted arbekacin derivatives have been designed and efficiently synthesized. The synthetic compounds showed potent antibacterial activity against both Staphylococcus aureus, including methicillin-resistant S. aureus, and Pseudomonas aeruginosa. In particular, these derivatives were superior to arbekacin against MRSA strains expressing the bifunctional aminoglycoside-modifying enzyme AAC(6')-APH(2'). The antibacterial activity of the 5-deoxy-5-episubstituted arbekacin derivatives against Pseudomonas aeruginosa was markedly influenced by the efflux system of MexXY/OprM. The 6'-N-methyl derivative of the 5-epi arbekacin was effective against Pseudomonas aeruginosa expressing the aminoglycoside-modifying enzyme AAC(6').     

Synthesis and antitumor activity of 7-O-[2,6-dideoxy-2-fluoro-5-C-(trifluoromethyl)-alpha-L-talopyranosyl]- daunomycinone and -adriamycinone.

7-O-[2,6-Dideoxy-2-fluoro-5-C-(trifluoromethyl)-alpha-L-talopyranosyl]- daunomycinone and -adriamycinone have been prepared by the coupling of 3,4-di-O-acetyl-2,6-dideoxy-2-fluoro-5-C-(trifluoromethyl)-alpha-L- talopyranosyl iodide with daunomycinone. The key steps in this synthesis are the regioselective fluorination of methyl alpha-D-lyxopyranoside to give the 4-deoxy-4-fluoro-beta-L-ribopyranoside and the C-trifluoromethylation of the aldehydo-L-ribose derivative to give the 1,1,1-trifluoro-5-monofluoro-L-altritol derivative. Antitumor activities of the synthetic products were compared with those for the 2'-deoxy-2'-fluoro and 2',6'-dideoxy-5'-C-trifluoromethyl analogs.     

Cyclic acetals of 4,1',6'-trichloro-4,1',6'-trideoxy-galacto-sucrose and their conversion into methyl ether derivatives

The acid-catalysed reaction of 4,1',6'-trichloro-4,1',6'-trideoxy-galacto- sucrose (1) with 5.5 equiv. of 2-methoxypropene in N,N-dimethylformamide followed by acetylation gave 3',4'-di-O-acetyl-4,1',6'-trichloro-4,1',6'-trideoxy-2,3-O- isopropylidene-6-O-(1-methoxy-1-methylethyl)-galacto-sucrose (2, 2%), 6,3',4'- tri- O-acetyl-4,1',6'-trichloro-4,1',6'-trideoxy-2,3-O-isopropylidene-galacto -sucrose (3, 31%), 3',4'-di-O-acetyl-4,1',6'-trichloro-4,1',6'-trideoxy-2,3-O- isopropylidene- galacto-sucrose (4, 38%), 3'-O-acetyl-4,1',6'-trichloro-4,1',6'-trideoxy-2,3-O- isopropylidene- galacto-sucrose (5, 13%), and 2,3',4'-tri-O-acetyl-4,1',6'-trichloro- 4,1',6'-trideoxy-galacto-sucrose (6, 13%). Methylation of 4 followed by removal of the protecting groups gave 4,1',6'-trichloro-4,1',6'-trideoxy-6-O-methyl- galacto- sucrose (8). 4,1',6'-Trichloro-4,1',6'-trideoxy-3-O-methyl-galacto-sucrose (11) was synthesised from 6 by preferential tert-butyldiphenylsilylation of HO-6 followed by methylation and removal of the protecting groups. Likewise, 4,1',6'-trichloro- 4,1',6'-trideoxy-4'-O-methyl-galacto-sucrose (14) was synthesised from 5. Treatment of 3 with aqueous acetic acid followed by methylation and removal of the protecting groups afforded 4,1',6'-trichloro-4,1'6'-trideoxy-2,3-di-O-methyl- galacto-sucrose (17).     

Synthesis of 3'-substituted-2',3'-deoxy-2'-methylidenepyrimidine nucleosides.

2'-deoxy-2'-methylideneuridine derivative 9 was converted into 2',3'-didehydro-2',3'-dideoxy-2'-phenyl-selenomethyl derivative 16, which was treated with NCS and tert-butyl carbamate to afford 3'-amino derivative 18 via a [2,3]-sigmatropic rearrangement. Treatment of 9 with DAST gave a mixture of 2',3'-didehydro-2', 3'-dideoxy-2'-fluoromethyl derivative 19 and 3'-"up"-fluoro-2'-methylidene derivative 20 in a ratio of 1.5 : 1. On the other hand, when 12 was treated with DAST, 19 and 3'-"down"-fluoro-2'-methylidene derivative 21 were obtained in a ratio of 1 : 1.6. These nucleosides were converted into the corresponding cytidine derivatives 4, 6, and 8, respectively. The reaction mechanisms as well as biological activity of these compounds will also be discussed.     

Synthesis of methyl 6'-deoxy-6'-fluoro-alpha-isomaltoside and of the corresponding trisaccharide

Methyl 6-O-(6-O-acetyl-2,3,4-tri-O-benzyl-alpha-D-glucopyranosyl)-2,3,4-tri- O-benzyl-alpha-D-glucopyranoside (5) was formed with high stereoselectivity when the condensation of methyl 2,3,4-tri-O-benzyl-alpha-D-glucopyranosyl (1) with 6-O-acetyl-2,3,4-tri-O-benzyl-alpha-D-glucopyranosyl chloride in ether was promoted with silver perchlorate in the presence of 2,4,6-trimethylpyridine. O-Deacetylation of 5, followed by treatment of the formed 6, containing only HO-6' unsubstituted, with diethylaminosulfur trifluoride (DAST) or dimethylaminosulfur trifluoride (methyl DAST) gave the per-O-benzyl derivative (9) of methyl 6'-deoxy-6'-fluoro-alpha-isomaltoside. Compound 9 was also obtained by condensation of 1 with 2,3,4-tri-O-benzyl-6-deoxy-6-fluoro-beta-D-glucopyranosyl fluoride (4) in the presence of silver perchlorate and anhydrous stannous chloride. The fully benzylated methyl alpha-glycoside (15) of 6-deoxy-6-fluoro-isomaltotriose, was obtained by condensation of 6 with 4. Hydrogenolysis of 9 and 15 gave the methyl alpha-glycosides of isomaltose and isomaltotriose fluorinated at C-6 of their (nonreducing) D-glucosyl group. Fluoride-ion displacements involving DAST and methyl DAST gave practically identical results, but mixtures arising from reactions involving the latter reagent were lighter-colored and easier to resolve by chromatography. The isolation of methyl alpha-glycosides of 6'-deoxy-6'-fluorogentiobiose and of 6'-O-(6-deoxy-6-fluoro-beta-D-glucopyranosyl) isomaltose is also described.     

Synthetic explorations towards 3-deoxy-3-fluoro derivatives of D-perosamine

Based on a literature precedent, preparation of methyl 4-azido-3,4,6-trideoxy-3-fluoro-alpha-D-mannopyranoside (18) was attempted via fluorination of methyl 4-azido-2-O-benzyl-4,6-dideoxy-alpha-D-altropyranoside with diethylaminosulfur trifluoride (DAST). Contrary to expectations, the reaction took place with retention of configuration at the site of the fluorination yielding methyl 4-azido-2-O-benzyl-3,4,6-trideoxy-3-fluoro-alpha-D-altropyranoside. Treatment with DAST of methyl 4-azido-2-O-benzyl-4,6-dideoxy-alpha-D-allopyranoside (8), or its 2-(p-methoxybenzyl) analog 9 resulted in fluorination with inversion of configuration at position 3, to give the corresponding 3-deoxy-3-fluoro glucopyranosides 10 and 11, respectively. Accordingly, compound 18 was prepared from 11, by de-p-methoxybenzylation at O-2, followed by inversion of configuration at C-2 in the resulting methyl 4-azido-3,4,6-trideoxy-3-fluoro-alpha-D-glucopyranoside. The 2-O-methyl analog of 18 (19) was prepared by methylation of 18. Compounds 18 and 19 were converted, conventionally, into the 3-fluoro analogs of the terminal determinants of the O-PS of Vibrio cholerae O:1, serotype Inaba and Ogawa, respectively.     

Identification of some metabolic products of 5' -deoxy-5' -S-isobutylthioadenosine, an inhibitor of virus-induced cell transformation.

5' -Deoxy-5' -S-isobutylthioadenosine (iBuS)5' Ado has been shown to be rapidly degraded to 5-deoxy-5-S-isobutylthioribose and adenine in procaryotes. In chick embryo fibroblasts there are two metabolic pathways for (iBuS)5' Ado degradation: (a) oxidative deamination into 5' -deoxy-5'-S-isobutylthioinosine (the main product) and (b) hydrolysis into 5-deoxy-5-S-isobutylthioribose plus adenine. The latter reaction is not due to bacterial contamination, since the same results were obtained under sterile conditions and in chick embryo fibroblasts in culture. The inhibition of the virus-induced cell transformation reported by us previously was due to (iBuS)5' Ado rather than to the main metabolic product of this molecule in chick embryo fibroblasts.     

An efficient synthesis of 3-fluoro-5-thio-xylofuranosyl nucleosides of thymine, uracil, and 5-fluorouracil as potential antitumor or/and antiviral agents

1,2:5,6-Di-O-isopropylidene-alpha-D-glucofuranose by the sequence of mild oxidation, reduction, fluorination, periodate oxidation, borohydride reduction, and sulfonylation gave 3-deoxy-3-fluoro-1,2-O-isopropylidene-5-O-p-toluenesulfonyl-alpha-D-xylofuranose (5). Tosylate 5 was converted to thioacetate derivative 6, which after acetolysis gave 1,2-di-O-acetyl-5-S-acetyl-3-deoxy-3-fluoro-5-thio-D-xylofuranose (7). Condensation of 7 with silylated thymine, uracil, and 5-fluorouracil afforded nucleosides 1-(5-S-acetyl-3-deoxy-3-fluoro-5-thio-beta-D-xylofuranosyl) thymine (8), 1-(5-S-acetyl-3-deoxy-3-fluoro-5-thio-beta-D-xylofuranosyl) uracil (9), and 1-(5-S-acetyl-3-deoxy-3-fluoro-5-thio-beta-D-xylofuranosyl) 5-fluorouracil (10). Compounds 8, 9, and 10 are biologically active against rotavirus infection and the growth of tumor cells.     

Nucleosides and Nucleotides. 125. Synthesis and Biological Evaluation of 2′,3′-Dideoxy-3′-fluoro-2′-methylidene Pyrimidine Nucleosides

Abstract

Reaction of 2′-deoxy-2′-methylidene-5′-O-trityluridine (1) with diethylamino-sulfur trifluoride (DAST) in CH₂Cl₂ resulted in the formation of a mixture of (3′R)-2′,3′-dideoxy-3′-fluoro-2′-methylidene derivative 3 and 2′,3′-didehydro-2′,3′-dideoxy-2′-fluoromethyl derivative 4 (3:4 = 1:1.5) in 65% yield. A similar treatment of 1-(2-deoxy-2-methylidene-5-O-trityl-β-D-threo-pentofuranosyl)uracil (19) with DAST in CH₂Cl₂ afforded (3′S)-2′,3′-dideoxy-3′-fluoro-2′-methylidene derivatives 20 and 4 in 38% and 17% yields respectively. Transformation of the uracil nucleosides 4, 12, and 20 into cytosines followed by deprotection furnished the corresponding cytidine derivatives 29, 18, and 25, respectively. The corresponding thymidine congener 27 was also synthesized in a similar manner. All of the newly synthesized nucleosides were evaluated for their inhibitory activities against HIV and for their antiproliferative activities against L1210 and KB cells.     

A practical synthesis of 2-deoxy-2-fluoro-D-arabinofuranose derivatives.

A seven-step synthesis of 1,3-di-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranose, a versatile intermediate in the synthesis of chemotherapeutically important nucleosides, was achieved from 1,2:5,6-di-O-isopropylidene-3-O-tosyl-alpha-D-allofuranose. The crucial steps were the fluorination by use of potassium fluoride in acetamide and the conversion of 6-O-benzoyl-3-deoxy-3-fluoro-D-glucofuranose into 5-O-benzoyl-2-deoxy-2-fluoro-3-O-formyl-D-arabinofuranose by periodate oxidation. Also described is the synthesis of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)cytosine. This procedure affords good overall yields of products without formation of undesirable, isomeric intermediates and is suitable for large-scale preparations.     

5-Fluorouracil derivatives. III. A simple method to prepare 5-fluoro-2'-deoxyuridine derivatives

3',5'-Diacyl-2'-bromo-5-fluoro-2'-deoxyuridine (4) was obtained by the reaction of 5, 6-dihydro-6-hydroxy-5-fluorouridine (2) and acyl bromide. Because the route from uridine (1) to 2, the route from 4 to 3',5'-diacyl-5-fluoro-2'-deoxyuridine (5), and the route from 5 to 5-fluoro-2'-deoxyuridine (FUDR, 6) are known reactions, the three step synthesis from uridine to 5 and four step synthesis from uridine to FUDR have been accomplished.     

Fluorinated carbohydrates as potential plasma membrane modifiers. Synthesis of 4- and 6-fluoro derivatives of 2-acetamido-2-deoxy-D-hexopyranoses

2-Amino-2,4-dideoxy-4-fluoro- and 2-amino-2,4,6-trideoxy-4, 6-difluoro-D-galactose, and 2-amino-2,4-dideoxy-4-fluoro- and 2-amino-4-deoxy-4, 4-difluoro-D-xylo-hexose were synthesized, as potential modifiers of tumor cell-surface glyco-conjugate, from benzyl 2-acetamido-3-O-benzyl-2-deoxy-4, 6-di-O-mesyl-alpha-D-glucopyranoside and benzyl 2-acetamido-3, 6-di-O-benzyl-2-deoxy-4-O-mesyl-alpha-D-glucopyranoside, which were converted into the corresponding 4,6-difluoro-2,4, 6-trideoxy and 2,4-dideoxy-4-fluoro derivatives. Benzyl 2-acetamido-2-deoxy-4-O-mesyl-alpha-D-galactopyranoside and benzyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-alpha-D-xylo-hexo-4-ulopyra noside were treated with diethylaminosulfur trifluoride to give 2-amino-2,4-dideoxy-4-fluoro-D-glucose and 2-amino-2,4-dideoxy-4, 4-di-fluoro-D-xylo-hexose derivatives, respectively, to give after deprotection the target compounds. Several of the peracetylated sugar derivatives inhibited L1210 tumor-cell growth in vitro at concentrations of 1-5 10(-5) M. The peracetylated derivative of 2-amino-2,4-dideoxy-4-fluoro-D-galactose inhibited protein and glycoconjugate biosynthesis, and also exhibited antitumor activity in mice with L1210 leukemia.     

A concise synthesis of 3-fluoro-5-thio-xylo- and glucopyranoses, useful precursors towards their corresponding pyranonucleoside derivatives

The chemical synthesis of 1,2,4-tri-O-acetyl-3-deoxy-3-fluoro-5-thio-D-xylopyranose, 1,2,4,6-tetra-O-acetyl-3-deoxy-3-fluoro-5-thio-alpha-D-glucopyranose and their corresponding nucleosides of thymine is described. Treatment of 3-fluoro-5-S-acetyl-5-thio-D-xylofuranose, obtained by hydrolysis of the isopropylidene group of 3-fluoro-1,2-O-isopropylidene-5-S-acetyl-5-thio-D-xylofuranose, with methanolic ammonia and direct acetylation, led to triacetylated 3-deoxy-3-fluoro-5-thio-D-xylopyranose. Condensation of acetylated 3-fluoro-5-thio-D-xylopyranose with silylated thymine afforded the corresponding nucleoside. Selective benzoylation and direct methanesulfonylation of 3-fluoro-1,2-O-isopropylidene-alpha-D-glucofuranose gave the 6-O-benzoyl-5-O-methylsulfonyl derivative, which on treatment with sodium methoxide afforded the 5,6-anhydro derivative. Treatment of the latter with thiourea, followed by acetolysis, gave the 3-fluoro-5-S-acetyl-6-O-acetyl-1,2-O-isopropylidene-5-thio-alpha-D-glucofuranose. 3-fluoro-5-S-acetyl-6-O-acetyl-5-thio-D-glucofuranose, obtained after hydrolysis of 5-thiofuranose isopropylidene, was treated with ammonia in methanol and directly acetylated, giving tetraacetylated 3-deoxy-3-fluoro-5-thio-alpha-D-glucopyranose. Condensation of the latter with silylated thymine afforded the desired 3-deoxy-3-fluoro-5-thio-beta-D-glucopyranonucleoside analogue.     

Synthesis and glycosidase inhibitory activity of some N-substituted 6-deoxy-5a-carba-beta-DL- and L-galactopyranosylamines

Chemical modification of 5a-carba-beta-DL-fucopyranosylamine (3) generated six N-substituted derivatives 9a-f, among which N-octyl 9b, decyl 9c, and phenylbutyl ones 9f were found to be very strong beta-galactosidase as well as beta-glucosidase inhibitors. The inhibitory activity appeared attributable to D-enantiomers from biological assays of prepared L-enantiomers. Therefore, 6-deoxy-5a-carba-beta-D-galactopyranosylamine (D-3) might be a promising lead compound for further design of new carba sugar-type beta-galactosidase inhibitors.     

Fluorinated carbohydrates : Part XIII. 2-deoxy-2-fluoro-D-galactose

Reaction of trifluoro(fluoroxy)methane at ca. −80° with 3,4,6-tri-O-acetyl-D-galactal affords trifluoromethyl 3,4,6-tri-O-acetyl-2-deoxy-2-fluoro-α-D-galactopyranoside (2, 39%), 3,4,6-tri-O-acetyl-2-deoxy-2-fluoro-α-D-galactopyranosyl fluoride (3, 37%), trifluoromethyl 3,4,6-tri-O-acetyl-2-deoxy-2-fluoro-α-D-talopyranoside (4, 3%), and 3,4,6-tri-O-acetyl-2-deoxy-2-fluor-α-D-talopyranosyl fluoride (5, 2%). The structures of compounds 2–5 have been established by n.m.r. spectroscopy. Acid hydrolysis of 2 or 3 allords 2-deoxy-2-fluoro-D-galactose.     

Access to tetrachlorophthalimide-protected ethyl 2-amino-2-deoxy-1-thio-beta-D-glucopyranosides.

Ethyl 2-deoxy-2-tetrachlorophthalimido-1-thio-beta-D-glucopyranoside (7) was prepared from glucosamine hydrochloride in four steps with a 20-25% overall yield. Formation of 1,3,4,6-tetra-O-acetyl-2-deoxy-2-tetrachlorophthalimido-beta-D- glucopyranoside (5) was found to be crucial for this reaction sequence since the corresponding alpha-1-acetate did not react in Lewis-acid-catalyzed ethylthio glycosidations. Formation of the beta-1-acetate (5) was achieved by treatment of 3,4,6-tri-O-acetyl-2-deoxy-2-tetrachlorophthalimido-alpha-D-glucop yranosyl bromide (4) with acetic acid under silver zeolite promotion. This was necessary because conditions normally used for beta-1-acetate formation were not tolerated by the tetrachlorophthalimido (TCP) group.     

The synthesis of some fluoro derivatives of sucrose

2,3,1',3'4',6'-Hexa-O-benzylsucrose was obtained by mild acid-catalysed hydrolysis of the 4,6-O-isopropylidene derivative and then converted into its 4,6-di-O-mesyl derivative. Selective displacement of this disulphonate with fluoride anion (from tetrabutylammonium fluoride) then afforded the 6-fluoro-4-mesylate. Removal of the protecting groups yielded 6-deoxy-6-fluorosucrose, which was characterised as its crystalline hepta-acetate. A derivative of 6-deoxy-6-fluoro-galacto-sucrose was formed when the above 6-fluoro-4-mesylate was subjected to nucleophilic displacement with benzoate anion.