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Sugars
Sugars Patent:
Heavily Fluorinated Sugar Analogues S.G. Dimagno, US Patent 6,392,032 (May 21, 2002) Assignee: Board of Regents University of Nebraska-Lincoln Utility: Anti-Neoplastic Agents Reaction
CO2H
C02Et
F
F
F F
F Note 1
F
CO2H
11
Note 2
C02Et
^ F2C-C-^
F 2 C - C ^ F 2 ' b ^ 0
O
OH
F2'c-^0
O
584
ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY i- Ethyl alcohol, sulfuric acid ii- Butyllithium, THF, furan, hexane iii- Sodium borohydride, methyl alcohol iv- Benzoyl chloride, triethylamine, CH2CI2 V- Ruthenium(IV)oxide, acetonitrile, water, carbontetrachloride, sodium periodate vi- THF, boronhydride • THF, diisobutylaluminum hydride vii- Potassium carbonate, trifluoroethyl alcohol
Experimental 1. Diethyl 2,2,3,3,4,4-hexafluoropentanoate 2,2,3,3,4,4-Hexafluoropentanoate (0.47 mmol) was dissolved in 250 ml ethyl alcohol containing 5 ml concentrated H2SO4 and refluxed 7 days using a soxlet extractor and 65 pellets 1.4 A molecular sieves. Ethyl alcohol was then removed and the residue neutralized to pH 7 using NaHC03 before adding water. The product was extracted 3 times with 100 ml diethyl ether, washed, and the product isolated in 81% yield. ^H-NMR data supplied. 2. Ethyl-(2-furyl)-5-oxo-2,2,3,3,4,4-hexafluoropentanoate In the absence of Hght, furan (12.4 mmol) was dissolved in 30 ml THF cooled to - 7 8 °C, 3 ml 2.5 M n-butyllithium added, and the mixture stirred 3 hours. The product from Step 1 (13.8 mmol) dissolved in 100 ml THF was added over 15 minutes and then stirred 30 minutes. The solvent was removed at ambient temperature, the mixture purified by chromatography on silica gel using hexanes/EtOAc, 9:1, and the product isolated in 39% yield. ^H- and ^^F-NMR and elemental analysis data supplied. 3. l-Hydroxyl-5-(2-furyl)-2,2,3?3,4,4-hexafluorooxetane NaBH4 (9.25 mmol) was added to a solution of the product from Step 2 (4.81 mmol) dissolved in 100ml methyl alcohol at 0°C. After 3 hours, the solvent was removed and the residue acidified to pH 2 using 2 M HCl. The mixture was then neutralized with NaHC03 and the product extracted 3 times with 50 ml diethyl ether. The product was isolated as an oil, re-crystallized in hexane/chloroform, 3:1, and isolated in 96% yield as 1:1 trans/cis isomers, mp = 89-90°C. ^H- and '^F-NMR and elemental analysis data supplied. 4. l-0-Benzyloxy-5-(2-furyl)-2,2,3,3,4,4-hexafluorooxetane Benzoyl chloride (10.0 mmol) and TEA (20 mmol) were added to a solution of the product from Step 3 (8.41 mmol) dissolved in 50 ml CH2CI2 at ambient temperature. The solution was stirred 15 minutes, then quenched with excess TEA, and stirred an additional 15 minutes. The solvent was removed and the residue purified by chromatography on silica gel using hexane/EtOAc, 9:1, and the product isolated as 15:1 trans/cis isomers, respectively, in 97% yield. ^H- and ^^ F-NMR and elemental analysis data supplied.
SUGARS
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5. 5-0-Benzyloxy-2,2,353,4,4-hexafluorooxetanic add RUO2 (5 mol) was added to the product from Step 4 (2.93 mmol) in a biphase solution of 180 ml water, 60 ml acetonitrile and 120 ml CCI4 containing NaI04 (116 mmol) and the mixture stirred vigorously 5 days. The volatile solvents were removed, the mixture extracted 3 times with 150 ml EtOAc, dried, and the product isolated in 96% yield. ^Hand ^^F-NMR and elemental analysis data supplied. 6. l-0-Benzyloxy-5-(5'-hydroxymethyl)-2,2,3,3,4,4-hexafluorooxetane The product from Step 5 (6.42 mmol) was dissolved in 20 ml THF and treated with 39 ml 1M BH3 THF. The mixture was stirred 20 minutes at 0°C, 19 ml 1M diisobutylaluminum hydride in THF added, and the mixture stirred an additional 30 minutes at ambient temperature. Thereafter, the reaction was quenched with 20 ml water at 0°C, neutralized to pH 2 with 20 ml I M HCl, and further neutraHzed to pH 7 with NaHCOg before extracting 3 times with 150 ml EtOAc. The mixture was purified by flash chromatography with silica gel using hexane/EtOAc, 10:1, and the product isolated in 82% yield. ^H- and ^^F-NMR and elemental analysis data supplied. 7. l-Hydroxyl-5-(5'-hydroxymethyl)-2,2,3,3,4,4-hexafluorooxetane The product from Step 6 (1.44 mmol) and K2CO3 (0.47 mmol) dissolved in 20 ml trifluoroethyl alcohol were stirred at ambient temperature 12 hours. The solvent was removed and NaHC03 solution added to the residue. The mixture was extracted 3 times with 50 ml pentane, neutralized to pH 2 using 2M HCl, re-extracted 3 times with 60 ml HO Ac, and the product isolated in 99% yield. ^H- and ^^F-NMR and elemental analysis data supplied.
Notes 1. Steps 2-5 were conducted in the absence of light. 2. In a previous investigation by the author (1) fluoro analogues of the current invention were prepared using 2,2,3,3-tetrafluorodiethyl butanedioate in Step 1 and the corresponding 2,2,3,3-tetrafluorofuran, (I), -ribofuranose, (II), and nucleoside derivatives, (III), respectively, were prepared. HO
^O^X
/"'/OH
F2C-CF2
(I)
X
/"'/OH
F2G-CF2
(II)
Fi-cV-r^N <^
(III)
I
J
586
ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY
3. 2,3,7,8,12,13,17,18-Octafluoro-5,10,15,20-tetrakis(pentafluorophenyl) porphyrin has also been prepared by the author (1) by reacting pentafluorobenzaldehyde with 3,4difluoropyrrole (2). Other preparations are described (3). 4. Electron-deficient porphyrins have been prepared using 2-(2,2,3,3,4,4,4-heptafluoro-lhydroxybutyl)pyrrole. The pyrrole intermediate was prepared using heptafluorobutyraldehyde hydrate and is described (4).
References 1. 2. 3. 4.
S.G. Dimagno, US Patent 6,013,790 (January 11, 2000) S.G. Dimagno, US Patent 6,455,510 (September 26, 2000) T. Wijesekera etal, US Patent 5,571,908 (November 6, 1996) M.J. Therien etal US Patent 5,599,924 (February 4, 1997)
SUGARS Patent: Assignee: Utility:
587 Preparation of Thioarabinofuranosyl Compounds and Use Thereof J.A. Secrist, III etaU US Patent 6,576,621 (June 10, 2003) Southern Research Institute Anti-Neoplastic Agent Inhibitor of DNA Replication
Reaction /-O
/Ov-OMe
HO^^OH
^Ov^OMe
HO^>^^^)H
CeHsO-^^^^jCgHs
o ^ ^,
CeHsO-^V^S^^G
^ _ ^
GeHsO-^V^S^SCeHs
^^^^
Note 1 /.SCeH^ 1^ 2 Q,y^,0H OCeHs -H SCeHs
0<5N^N
NH2
0
"°
°"
HC?
• ^
" ^
"OH
^
H G - V ^ N ^
I X
Notes 2,3
HdX)H
i- Hydrochloric acid, AmberHte IRA-400 anion exchange resin ii- THF, sodium hydride, tetrabutylammonium iodide, benzyl bromide iii- CH2CI2, benzyl mercaptan, tin(IV)chloride iv- Toluene, acetonitrile, triphenylphosphine, iodine, imidazole V- Mercury(II)acetate, acetic acid vi- Cytosine, acetonitrile, hexamethyldisilazane, chlorotrimethylsilane, trimethylsilyltrifluoromethane sulfonate vii- Boron trifluoride, CH2CI2 viii- Pyridine, 4,4^-dimethoxytritylchloride ix- Trifluoroacetic, chloroform Experimental 1. a-and j8-MethyI L-xylofuranoside L-Xylose (167 mmol) was stirred 5 hours in 675 ml 0.5% HCl in methyl alcohol at ambient temperature and neutralized with Amberlite IRA-400 OH anion exchange resin. The
588
ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY
combined filtrates were purified by chromatography on silica using chloroform/methyl alcohol, 2:8, and the products isolated in 95% yield as a 1:1 a,l3 mixture. MS data supplied. 2. Methyl-2,3,5-Tri-0-benzyl-L-xylofuranoside The product from Step 1 (60.9 mmol) dissolved in 350 ml THF was treated with NaH (370mmol) and then stirred 15 minutes at 0°C. Thereafter, benzyl bromide (214mmol) and solid NBU4I (0.96 mmol) were added and the mixture stirred 3 days at ambient temperature. It was quenched with 25 ml methyl alcohol, concentrated, purified by chromatography on silica gel with cyclohexane/EtOAc, 9:1, and the product isolated in 87% yield. ^H-NMR and MS data suppHed. 3. 2,3,5-Tri-O-benzyl-L-xylose dibenzyl dithioacetal The product from Step 2 (97 mmol) was dissolved in 1 L CH2CI2 and benzyl mercaptan (400 mmol) and tin(IV)chloride (18.9 mmol) added. The mixture stirred overnight at ambient temperature and was then neutralized with 750 ml 5% NaHCOg. The phases were separated, concentrated, purified by chromatography on silica gel using cyclohexane/EtOAc, 99:1, and the product isolated in 57% yield. ^H-NMR and MS data supplied. 4. 2,3,5-Tri-0-benzyl-l-acetyl-4-thio-D-arabinofuranose The product from Step 3 (20 mmol) was dissolved in 200 ml toluene and acetonitrile, 2:1, added to triphenylphosphine (60 mmol), iodine (50 mmol) and imidazole (80 mmol) and the mixture stirred at 90 °C 24 hours. It was concentrated, purified by chromatography on by silica gel with cyclohexane/EtOAc, 4:1, and the product isolated in 83% yield. ^H-NMR, elemental analysis, and MS data supplied. 5. 2,3,5-Tri-0-benzyl-l-0-acetyl-4-thio-D-arabinofuranose The product from Step 4 (10 mmol) was added to a suspension of mercuric acetate (22.9 mmol) in HO Ac (96 g) and the mixture stirred at ambient temperature 2 hours. It was then diluted with 200ml CH2CI2, washed with NaHC03 and KCl solutions, dried, and concentrated. The mixture was purified by chromatography using cyclohexane/EtOAc, 98:2, and a 1:1 mixture of a and (3 anomers isolated in 78% yield. ^H-NMR, elemental analysis, and MS data supplied. 6. l-(2,3,5-Tri-0-benzyl-4-thio-a- and j8-D-arabinofuranosyl)cytosine The product from Step 5(1 mmol) and cytosine (1 mmol) were dissolved in acetonitrile (25 mmol), hexamethyldisilazane (Immol) and chlorotrimethylsilane (4 mmol) added, and the mixture stirred at ambient temperature 30 minutes. The solution was cooled to —78°C, trimethylsilyltrifluoromethane sulfonate (1.2 mmol) added, and the solution stirred 2.5 hours. Thereafter, the mixture was warmed to ambient temperature, concentrated to 5 ml, diluted with 50 ml CH2CI2, washed with 20 ml water, dried, and concentrated. The residue was purified by chromatography over silica gel using chloroform/methyl alcohol, 98:2, and the product isolated in 77.5% yield. ^H-NMR, elemental analysis, and MS data supplied.
SUGARS
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7. l-(4-Thio-a- and j8-D-arabinofuranosyl)cytosine A solution of 1 ml M BF3 in 7 ml CH2CI2 was cooled to —78°C, the product from Step 6 (O.Smmol) dissolved in 10ml CH2CI2 added, the mixture stirred overnight at —20°C, and concentrated. The residue was co-evaporated 4 times with 20 ml CH2CI2, neutralized with NaHCOg, purified using an H+ cation exchange column with water to remove salts and then with NH4OH, and the product isolated 85% yield. ^H-NMR, elemental analysis, and MS data supplied. 8. l-(5-0-Dimethoxytrityl-4-thio-j8-D-arabinofuranosyl)cytosme The product from Step 7 (0.38nmiol) was dissolved in 10 ml pyridine, added to 4,4dimethoxytritylchloride (0.6 mmol), and the mixture stirred 2 hours at ambient temperature. Thereafter it was concentrated, dissolved in 20 ml EtOAc, washed with water, and re-concentrated. It was purified as in Step 6 and the product isolated in 90% yield. ^H-NMR and MS data supplied. 9. l-(4-Thio-)8-D-arabinofuranosyl)cytosine The product from Step 8 (0.16 mmol) was mixed with trifluoroacetic acid (22 mg) dissolved in 5 ml chloroform at ambient temperature for 10 minutes, neutralized with NaHC03, purified as in Step 6, and the product isolated in 85% yield, mp = 218-220°C. ^H-NMR, elemental analysis, and MS data supplied.
Notes 1. The products from Step 3 and Step 9 were previously prepared by the author and are discussed (1). 2. 5^ Deoxy-5^-guanidine adenosines derivatives, (I), were previously prepared by the author (2) and others (3). In an earlier investigation 2-fluoro-9-(2-deoxy-2-fluoro-j8D-arabinofuranosyl)-9H-purin-6-amine, (II), and derivatives were also prepared by the author and are discussed (4).
O )
/
/ HO
K(
\
V
^NH2
N^/'^
OH
HN
n
/
HO-XiT
VX Nw^
m
.^^ (I)
V
(11)
NH,
590
ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY
3. The Step 9 analogue, l-(2-deoxy-2-fluoro-4-thio-/3-D-arabinofuranosyl)-cytosine, (III), has been prepared and is described (4).
(Ill)
4. l-(4-Thio-^-D-arabinofuranosyl) cytosine derivatives have been prepared on a controlglass pore silica gel substrate (5).
References 1. J.A. Secrist, III etal. Nucleosides Nucleotides, 14, 3, 675 (1995) 2. J.A. Secrist, III, US Patent 4,794,174 (December 27, 1988) 3. M. Manoharan etal US Patent 6,593,466 (July 15, 2003) and US Patent 6,534,639 (March 18, 2003) 4. J.A. Secrist, III, US Patent 5,384,310 (January 24, 1995) 5. Y. Yoshimura etal US Patent 6,147,058 (November 14, 2000)
591
SUGARS
Patent:
Process for the Alkaline Oxidative Degradation of Reducing Sugars G. Fleche etaU US Patent 5,817,780 (October 6, 1998) Assignee: Roquette Freres Utility: Industrial Processing of Reducing Sugars Reaction HO-m HO...?
O
Notes 1,2 HO
OH
i- Sodium hydroxide, water, sodium anthraquinone 2-sulfonate, hydrogen peroxide
Experimental 1. Arabinonic acid Dextrose monohydrate (1.71 mol glucose) was dissolved in 7.0 liters water and introduced into a Biolafitte glass fermenter tank having a working capacity of 15 liters. The solution was aerated with an air flow rate of 20 liters/minute while stirring 650 rev/minute at 40 °C. Three additional solutions are also prepared. The first was a glucose solution containing 50% solids, prepared using 1443.4 g dextrose monohydrate and 1181 g water, thus containing 7.92 mol of glucose. The second was a 50% NaOH solution consisting of 840 g NaOH and 840 g water. The third was sodium anthraquinone 2-sulfonate (24 g) dissolved in 110 volumes of 30% H2O2.
Procedure When dextrose monohydrate had been aerating for 30 minutes in the Biolafitte fermenter, sodium hydroxide and anthraquinone 2-sulfonate dissolved in hydrogen peroxide was added (Note 1). Stirring speed was then increased to 800 rev/min and the solution becames clear, characteristic of the oxidixed form of sodium anthraquinone 2-sulfonate. The 50% glucose solution was gradually added and the stirring speed adjusted so that the solution had a very light pink color. After 2 hours the reducing sugar content has fallen to lOg/1 and the temperature was gradually raised to 60 °C. Thereafter the solution was cooled and arabinonic acid isolated in 84.7%.
592
ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY
Derivatives Sugar Glucose syrup
Yield (%) 100
Oxidation Products Sodium arabinonate Sodium dextrose-arabinonate Sodium xylonate Carboxymethyl starch
Ketose Carboxymethyl-wheat starch
75 —
Notes 1 Sodium anthraquinone 2-sulfonate (SAM) is the reaction indicator. In the oxidized form it causes the solution to become deep red; it is colorless in the reduced state. This oxidative method is a modified Spengler-Pfannenstiel (1) reaction (1). This reaction is illustrated in Eq. 1 and described for the preparation of 3-(a-D-glucosido)-D-arabonic acid below. .OH
.OH
HO-'-'V^L^
Eq. 1
^^"tloOH^
HO O H > OH
OH
O OH
O
OH
i- Barium hydroxide, oxygen, water ii- Carbon dioxide Procedure A solution of maltose (53mmol) dissolved in 200 ml water was added dropwise to a stirred suspension of Ba(OH)2 crystals (20 g) in 150 water under a flow of oxygen. In 22 hours the reaction consumed 1.25 L O2. Thereafter, the mixture was saturated with CO2 and the product quantitatively isolated. 3. Sodium hypochlorite in the presence of the catalyst 2,2,6,6-tetra-methylpiperidin-l-oxyl (TEMPO) has been used to oxidize sugars to the corresponding di-acids without oxidative degradation. This is illustrated in Eq. 2 where sorbitol is oxidized to glucaric acid (2). HOyO pOH k-OH
Eq. 2
HO-
koH h-OH
I—OH
UoH HOH HOH OH
A.
HO
i-Demineralized water, 2,2,6,6-tetramethylpiperidin-l-oxyl, sodium hypochlorite
SUGARS
593
4. A novel clothing detergent was obtained when glucose syrup was oxidized in tandem by sodium anthraquinone 2-sulfonate/H202 and then NaOCl/TEMPO and is described (2). 5. A single-pot method for oxidizing sodium arabinonate using molecular oxygen in the presence NaOH followed by subsequent lactonization is described (3).
References 1. E. Hardegger, Helv. Chim. Acta, 35, 618 (1952) 2. G. Fleche, US Patent 5,831,043 (November 3, 1998) 3. T. Vuorinen, US Patent 5,563,303 (October 8, 1996)
594
Patent:
Assignee: Utility:
ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY
Sugar Derivatives of Hydromorphorine, Dihydromorphorine and Dihydroisomorphorine Compositions Thereof and Uses for Treating or Preventing Pain F. Gao etaU US Patent 6,740,641 (May 25, 2004) Euro-Celtique, S.A. Analgesic
OH
OH
OH
OH
i- Mercuric(Il)cyanide, acetonitrile ii- Methyl alcohol, sodium methoxide Experimental 1. 3-Acetyl-6-O-glucosyldihydromorphorine A mixture of 3-acetyl-dihydromorphorine (Immol), drierite (Ig) and Hg(0Ac)2 (0.75 mmol) in 5 ml acetonitrile were stirred at room temperature 1 hour. Thereafter, 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide (1.5 mmol) was added and the mixture stirred 4 days. The mixture was filtered, concentrated, washed with 1M KOH, and diluted with CH2CI2. The product was isolated after chromatographic purification. 2. 6-j8-0-Glucosyldihydromorphorine The product from Step 1 was dissolved in 5 ml methyl alcohol and the solution made alkaline by the addition of 1M sodium methoxide. The solution stood 3 hours and was neutralized with Amberlite IR 120 exchange resin. The solvent was removed, the residue purified by column chromatography, and the product isolated. Derivatives Opioid 3 -0-/3-Glucosy Idihy droisomorphine 3-^-O-Glucosyldihydromorphine
Yield (%) (Second Step) 45 30
SUGARS
595
Notes 1. This is an example of the Koenings-Kjiorr glucosidation reaction where glucoside derivatives are prepared using halo- or acetoxysugars in the presence of Lewis acids such as Ag"^ or Hg"^^. Glycosidations can also occur using NaOH-NBu40H as the catalyst (1). 2. 3-0-Glucosylhydromorphorine, (I), and 3-0-j8-0-glucosyldihydro-isomorphorine, (II), were also prepared by the author as illustrated in Eq. 1 and Eq. 2, respectively: AcO lOAc ^Br
JLP-; OAc OAc
(I) i- Lithium hydroxide, water AcO,
AcO
|0Ac/Br
OAc OAc
i- Lithium hydroxide, water 3. The preparation of 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide and derivatives is described (2). 4. The preparation of glucosylhydromorphorine derivatives containing N-alkyl, -acyl, or -oxides is provided (3). 5. Nordihydroisomorphine-3-glucuronide, (III), has been prepared and is described (4). HO HO^/
OH )—O
HOOC
(III)
596
ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY
References 1. S. Gabrey, Synthesis, 1078 (1992); A. Knochel, Tetrahedron Lett., 551 (1974); CM. Ice, J. Am. Chem. Soc, 74, 4606 (1952) 2. R.R. Tuttle etal, US Patent 4,774,230 (September 27, 1988) 3. F. Scheinmann, US Patent 6,046,313 (April 4, 2000) 4. K. Rice, J. Org. Chem., 40, 1850 (1975)
Heavily Fluorinated Sugar Analogues S.G. Dimagno, US Patent 6,392,032 (May 21, 2002) Assignee: Board of Regents University of Nebraska-Lincoln Utility: Anti-Neoplastic Agents Reaction
CO2H
C02Et
F
F
F F
F Note 1
F
CO2H
11
Note 2
C02Et
^ F2C-C-^
F 2 C - C ^ F 2 ' b ^ 0
O
OH
F2'c-^0
O
584
ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY i- Ethyl alcohol, sulfuric acid ii- Butyllithium, THF, furan, hexane iii- Sodium borohydride, methyl alcohol iv- Benzoyl chloride, triethylamine, CH2CI2 V- Ruthenium(IV)oxide, acetonitrile, water, carbontetrachloride, sodium periodate vi- THF, boronhydride • THF, diisobutylaluminum hydride vii- Potassium carbonate, trifluoroethyl alcohol
Experimental 1. Diethyl 2,2,3,3,4,4-hexafluoropentanoate 2,2,3,3,4,4-Hexafluoropentanoate (0.47 mmol) was dissolved in 250 ml ethyl alcohol containing 5 ml concentrated H2SO4 and refluxed 7 days using a soxlet extractor and 65 pellets 1.4 A molecular sieves. Ethyl alcohol was then removed and the residue neutralized to pH 7 using NaHC03 before adding water. The product was extracted 3 times with 100 ml diethyl ether, washed, and the product isolated in 81% yield. ^H-NMR data supplied. 2. Ethyl-(2-furyl)-5-oxo-2,2,3,3,4,4-hexafluoropentanoate In the absence of Hght, furan (12.4 mmol) was dissolved in 30 ml THF cooled to - 7 8 °C, 3 ml 2.5 M n-butyllithium added, and the mixture stirred 3 hours. The product from Step 1 (13.8 mmol) dissolved in 100 ml THF was added over 15 minutes and then stirred 30 minutes. The solvent was removed at ambient temperature, the mixture purified by chromatography on silica gel using hexanes/EtOAc, 9:1, and the product isolated in 39% yield. ^H- and ^^F-NMR and elemental analysis data supplied. 3. l-Hydroxyl-5-(2-furyl)-2,2,3?3,4,4-hexafluorooxetane NaBH4 (9.25 mmol) was added to a solution of the product from Step 2 (4.81 mmol) dissolved in 100ml methyl alcohol at 0°C. After 3 hours, the solvent was removed and the residue acidified to pH 2 using 2 M HCl. The mixture was then neutralized with NaHC03 and the product extracted 3 times with 50 ml diethyl ether. The product was isolated as an oil, re-crystallized in hexane/chloroform, 3:1, and isolated in 96% yield as 1:1 trans/cis isomers, mp = 89-90°C. ^H- and '^F-NMR and elemental analysis data supplied. 4. l-0-Benzyloxy-5-(2-furyl)-2,2,3,3,4,4-hexafluorooxetane Benzoyl chloride (10.0 mmol) and TEA (20 mmol) were added to a solution of the product from Step 3 (8.41 mmol) dissolved in 50 ml CH2CI2 at ambient temperature. The solution was stirred 15 minutes, then quenched with excess TEA, and stirred an additional 15 minutes. The solvent was removed and the residue purified by chromatography on silica gel using hexane/EtOAc, 9:1, and the product isolated as 15:1 trans/cis isomers, respectively, in 97% yield. ^H- and ^^ F-NMR and elemental analysis data supplied.
SUGARS
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5. 5-0-Benzyloxy-2,2,353,4,4-hexafluorooxetanic add RUO2 (5 mol) was added to the product from Step 4 (2.93 mmol) in a biphase solution of 180 ml water, 60 ml acetonitrile and 120 ml CCI4 containing NaI04 (116 mmol) and the mixture stirred vigorously 5 days. The volatile solvents were removed, the mixture extracted 3 times with 150 ml EtOAc, dried, and the product isolated in 96% yield. ^Hand ^^F-NMR and elemental analysis data supplied. 6. l-0-Benzyloxy-5-(5'-hydroxymethyl)-2,2,3,3,4,4-hexafluorooxetane The product from Step 5 (6.42 mmol) was dissolved in 20 ml THF and treated with 39 ml 1M BH3 THF. The mixture was stirred 20 minutes at 0°C, 19 ml 1M diisobutylaluminum hydride in THF added, and the mixture stirred an additional 30 minutes at ambient temperature. Thereafter, the reaction was quenched with 20 ml water at 0°C, neutralized to pH 2 with 20 ml I M HCl, and further neutraHzed to pH 7 with NaHCOg before extracting 3 times with 150 ml EtOAc. The mixture was purified by flash chromatography with silica gel using hexane/EtOAc, 10:1, and the product isolated in 82% yield. ^H- and ^^F-NMR and elemental analysis data supplied. 7. l-Hydroxyl-5-(5'-hydroxymethyl)-2,2,3,3,4,4-hexafluorooxetane The product from Step 6 (1.44 mmol) and K2CO3 (0.47 mmol) dissolved in 20 ml trifluoroethyl alcohol were stirred at ambient temperature 12 hours. The solvent was removed and NaHC03 solution added to the residue. The mixture was extracted 3 times with 50 ml pentane, neutralized to pH 2 using 2M HCl, re-extracted 3 times with 60 ml HO Ac, and the product isolated in 99% yield. ^H- and ^^F-NMR and elemental analysis data supplied.
Notes 1. Steps 2-5 were conducted in the absence of light. 2. In a previous investigation by the author (1) fluoro analogues of the current invention were prepared using 2,2,3,3-tetrafluorodiethyl butanedioate in Step 1 and the corresponding 2,2,3,3-tetrafluorofuran, (I), -ribofuranose, (II), and nucleoside derivatives, (III), respectively, were prepared. HO
^O^X
/"'/OH
F2C-CF2
(I)
X
/"'/OH
F2G-CF2
(II)
Fi-cV-r^N <^
(III)
I
J
586
ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY
3. 2,3,7,8,12,13,17,18-Octafluoro-5,10,15,20-tetrakis(pentafluorophenyl) porphyrin has also been prepared by the author (1) by reacting pentafluorobenzaldehyde with 3,4difluoropyrrole (2). Other preparations are described (3). 4. Electron-deficient porphyrins have been prepared using 2-(2,2,3,3,4,4,4-heptafluoro-lhydroxybutyl)pyrrole. The pyrrole intermediate was prepared using heptafluorobutyraldehyde hydrate and is described (4).
References 1. 2. 3. 4.
S.G. Dimagno, US Patent 6,013,790 (January 11, 2000) S.G. Dimagno, US Patent 6,455,510 (September 26, 2000) T. Wijesekera etal, US Patent 5,571,908 (November 6, 1996) M.J. Therien etal US Patent 5,599,924 (February 4, 1997)
SUGARS Patent: Assignee: Utility:
587 Preparation of Thioarabinofuranosyl Compounds and Use Thereof J.A. Secrist, III etaU US Patent 6,576,621 (June 10, 2003) Southern Research Institute Anti-Neoplastic Agent Inhibitor of DNA Replication
Reaction /-O
/Ov-OMe
HO^^OH
^Ov^OMe
HO^>^^^)H
CeHsO-^^^^jCgHs
o ^ ^,
CeHsO-^V^S^^G
^ _ ^
GeHsO-^V^S^SCeHs
^^^^
Note 1 /.SCeH^ 1^ 2 Q,y^,0H OCeHs -H SCeHs
0<5N^N
NH2
0
"°
°"
HC?
• ^
" ^
"OH
^
H G - V ^ N ^
I X
Notes 2,3
HdX)H
i- Hydrochloric acid, AmberHte IRA-400 anion exchange resin ii- THF, sodium hydride, tetrabutylammonium iodide, benzyl bromide iii- CH2CI2, benzyl mercaptan, tin(IV)chloride iv- Toluene, acetonitrile, triphenylphosphine, iodine, imidazole V- Mercury(II)acetate, acetic acid vi- Cytosine, acetonitrile, hexamethyldisilazane, chlorotrimethylsilane, trimethylsilyltrifluoromethane sulfonate vii- Boron trifluoride, CH2CI2 viii- Pyridine, 4,4^-dimethoxytritylchloride ix- Trifluoroacetic, chloroform Experimental 1. a-and j8-MethyI L-xylofuranoside L-Xylose (167 mmol) was stirred 5 hours in 675 ml 0.5% HCl in methyl alcohol at ambient temperature and neutralized with Amberlite IRA-400 OH anion exchange resin. The
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ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY
combined filtrates were purified by chromatography on silica using chloroform/methyl alcohol, 2:8, and the products isolated in 95% yield as a 1:1 a,l3 mixture. MS data supplied. 2. Methyl-2,3,5-Tri-0-benzyl-L-xylofuranoside The product from Step 1 (60.9 mmol) dissolved in 350 ml THF was treated with NaH (370mmol) and then stirred 15 minutes at 0°C. Thereafter, benzyl bromide (214mmol) and solid NBU4I (0.96 mmol) were added and the mixture stirred 3 days at ambient temperature. It was quenched with 25 ml methyl alcohol, concentrated, purified by chromatography on silica gel with cyclohexane/EtOAc, 9:1, and the product isolated in 87% yield. ^H-NMR and MS data suppHed. 3. 2,3,5-Tri-O-benzyl-L-xylose dibenzyl dithioacetal The product from Step 2 (97 mmol) was dissolved in 1 L CH2CI2 and benzyl mercaptan (400 mmol) and tin(IV)chloride (18.9 mmol) added. The mixture stirred overnight at ambient temperature and was then neutralized with 750 ml 5% NaHCOg. The phases were separated, concentrated, purified by chromatography on silica gel using cyclohexane/EtOAc, 99:1, and the product isolated in 57% yield. ^H-NMR and MS data supplied. 4. 2,3,5-Tri-0-benzyl-l-acetyl-4-thio-D-arabinofuranose The product from Step 3 (20 mmol) was dissolved in 200 ml toluene and acetonitrile, 2:1, added to triphenylphosphine (60 mmol), iodine (50 mmol) and imidazole (80 mmol) and the mixture stirred at 90 °C 24 hours. It was concentrated, purified by chromatography on by silica gel with cyclohexane/EtOAc, 4:1, and the product isolated in 83% yield. ^H-NMR, elemental analysis, and MS data supplied. 5. 2,3,5-Tri-0-benzyl-l-0-acetyl-4-thio-D-arabinofuranose The product from Step 4 (10 mmol) was added to a suspension of mercuric acetate (22.9 mmol) in HO Ac (96 g) and the mixture stirred at ambient temperature 2 hours. It was then diluted with 200ml CH2CI2, washed with NaHC03 and KCl solutions, dried, and concentrated. The mixture was purified by chromatography using cyclohexane/EtOAc, 98:2, and a 1:1 mixture of a and (3 anomers isolated in 78% yield. ^H-NMR, elemental analysis, and MS data supplied. 6. l-(2,3,5-Tri-0-benzyl-4-thio-a- and j8-D-arabinofuranosyl)cytosine The product from Step 5(1 mmol) and cytosine (1 mmol) were dissolved in acetonitrile (25 mmol), hexamethyldisilazane (Immol) and chlorotrimethylsilane (4 mmol) added, and the mixture stirred at ambient temperature 30 minutes. The solution was cooled to —78°C, trimethylsilyltrifluoromethane sulfonate (1.2 mmol) added, and the solution stirred 2.5 hours. Thereafter, the mixture was warmed to ambient temperature, concentrated to 5 ml, diluted with 50 ml CH2CI2, washed with 20 ml water, dried, and concentrated. The residue was purified by chromatography over silica gel using chloroform/methyl alcohol, 98:2, and the product isolated in 77.5% yield. ^H-NMR, elemental analysis, and MS data supplied.
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7. l-(4-Thio-a- and j8-D-arabinofuranosyl)cytosine A solution of 1 ml M BF3 in 7 ml CH2CI2 was cooled to —78°C, the product from Step 6 (O.Smmol) dissolved in 10ml CH2CI2 added, the mixture stirred overnight at —20°C, and concentrated. The residue was co-evaporated 4 times with 20 ml CH2CI2, neutralized with NaHCOg, purified using an H+ cation exchange column with water to remove salts and then with NH4OH, and the product isolated 85% yield. ^H-NMR, elemental analysis, and MS data supplied. 8. l-(5-0-Dimethoxytrityl-4-thio-j8-D-arabinofuranosyl)cytosme The product from Step 7 (0.38nmiol) was dissolved in 10 ml pyridine, added to 4,4dimethoxytritylchloride (0.6 mmol), and the mixture stirred 2 hours at ambient temperature. Thereafter it was concentrated, dissolved in 20 ml EtOAc, washed with water, and re-concentrated. It was purified as in Step 6 and the product isolated in 90% yield. ^H-NMR and MS data supplied. 9. l-(4-Thio-)8-D-arabinofuranosyl)cytosine The product from Step 8 (0.16 mmol) was mixed with trifluoroacetic acid (22 mg) dissolved in 5 ml chloroform at ambient temperature for 10 minutes, neutralized with NaHC03, purified as in Step 6, and the product isolated in 85% yield, mp = 218-220°C. ^H-NMR, elemental analysis, and MS data supplied.
Notes 1. The products from Step 3 and Step 9 were previously prepared by the author and are discussed (1). 2. 5^ Deoxy-5^-guanidine adenosines derivatives, (I), were previously prepared by the author (2) and others (3). In an earlier investigation 2-fluoro-9-(2-deoxy-2-fluoro-j8D-arabinofuranosyl)-9H-purin-6-amine, (II), and derivatives were also prepared by the author and are discussed (4).
O )
/
/ HO
K(
\
V
^NH2
N^/'^
OH
HN
n
/
HO-XiT
VX Nw^
m
.^^ (I)
V
(11)
NH,
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ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY
3. The Step 9 analogue, l-(2-deoxy-2-fluoro-4-thio-/3-D-arabinofuranosyl)-cytosine, (III), has been prepared and is described (4).
(Ill)
4. l-(4-Thio-^-D-arabinofuranosyl) cytosine derivatives have been prepared on a controlglass pore silica gel substrate (5).
References 1. J.A. Secrist, III etal. Nucleosides Nucleotides, 14, 3, 675 (1995) 2. J.A. Secrist, III, US Patent 4,794,174 (December 27, 1988) 3. M. Manoharan etal US Patent 6,593,466 (July 15, 2003) and US Patent 6,534,639 (March 18, 2003) 4. J.A. Secrist, III, US Patent 5,384,310 (January 24, 1995) 5. Y. Yoshimura etal US Patent 6,147,058 (November 14, 2000)
591
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Patent:
Process for the Alkaline Oxidative Degradation of Reducing Sugars G. Fleche etaU US Patent 5,817,780 (October 6, 1998) Assignee: Roquette Freres Utility: Industrial Processing of Reducing Sugars Reaction HO-m HO...?
O
Notes 1,2 HO
OH
i- Sodium hydroxide, water, sodium anthraquinone 2-sulfonate, hydrogen peroxide
Experimental 1. Arabinonic acid Dextrose monohydrate (1.71 mol glucose) was dissolved in 7.0 liters water and introduced into a Biolafitte glass fermenter tank having a working capacity of 15 liters. The solution was aerated with an air flow rate of 20 liters/minute while stirring 650 rev/minute at 40 °C. Three additional solutions are also prepared. The first was a glucose solution containing 50% solids, prepared using 1443.4 g dextrose monohydrate and 1181 g water, thus containing 7.92 mol of glucose. The second was a 50% NaOH solution consisting of 840 g NaOH and 840 g water. The third was sodium anthraquinone 2-sulfonate (24 g) dissolved in 110 volumes of 30% H2O2.
Procedure When dextrose monohydrate had been aerating for 30 minutes in the Biolafitte fermenter, sodium hydroxide and anthraquinone 2-sulfonate dissolved in hydrogen peroxide was added (Note 1). Stirring speed was then increased to 800 rev/min and the solution becames clear, characteristic of the oxidixed form of sodium anthraquinone 2-sulfonate. The 50% glucose solution was gradually added and the stirring speed adjusted so that the solution had a very light pink color. After 2 hours the reducing sugar content has fallen to lOg/1 and the temperature was gradually raised to 60 °C. Thereafter the solution was cooled and arabinonic acid isolated in 84.7%.
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ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY
Derivatives Sugar Glucose syrup
Yield (%) 100
Oxidation Products Sodium arabinonate Sodium dextrose-arabinonate Sodium xylonate Carboxymethyl starch
Ketose Carboxymethyl-wheat starch
75 —
Notes 1 Sodium anthraquinone 2-sulfonate (SAM) is the reaction indicator. In the oxidized form it causes the solution to become deep red; it is colorless in the reduced state. This oxidative method is a modified Spengler-Pfannenstiel (1) reaction (1). This reaction is illustrated in Eq. 1 and described for the preparation of 3-(a-D-glucosido)-D-arabonic acid below. .OH
.OH
HO-'-'V^L^
Eq. 1
^^"tloOH^
HO O H > OH
OH
O OH
O
OH
i- Barium hydroxide, oxygen, water ii- Carbon dioxide Procedure A solution of maltose (53mmol) dissolved in 200 ml water was added dropwise to a stirred suspension of Ba(OH)2 crystals (20 g) in 150 water under a flow of oxygen. In 22 hours the reaction consumed 1.25 L O2. Thereafter, the mixture was saturated with CO2 and the product quantitatively isolated. 3. Sodium hypochlorite in the presence of the catalyst 2,2,6,6-tetra-methylpiperidin-l-oxyl (TEMPO) has been used to oxidize sugars to the corresponding di-acids without oxidative degradation. This is illustrated in Eq. 2 where sorbitol is oxidized to glucaric acid (2). HOyO pOH k-OH
Eq. 2
HO-
koH h-OH
I—OH
UoH HOH HOH OH
A.
HO
i-Demineralized water, 2,2,6,6-tetramethylpiperidin-l-oxyl, sodium hypochlorite
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593
4. A novel clothing detergent was obtained when glucose syrup was oxidized in tandem by sodium anthraquinone 2-sulfonate/H202 and then NaOCl/TEMPO and is described (2). 5. A single-pot method for oxidizing sodium arabinonate using molecular oxygen in the presence NaOH followed by subsequent lactonization is described (3).
References 1. E. Hardegger, Helv. Chim. Acta, 35, 618 (1952) 2. G. Fleche, US Patent 5,831,043 (November 3, 1998) 3. T. Vuorinen, US Patent 5,563,303 (October 8, 1996)
594
Patent:
Assignee: Utility:
ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY
Sugar Derivatives of Hydromorphorine, Dihydromorphorine and Dihydroisomorphorine Compositions Thereof and Uses for Treating or Preventing Pain F. Gao etaU US Patent 6,740,641 (May 25, 2004) Euro-Celtique, S.A. Analgesic
OH
OH
OH
OH
i- Mercuric(Il)cyanide, acetonitrile ii- Methyl alcohol, sodium methoxide Experimental 1. 3-Acetyl-6-O-glucosyldihydromorphorine A mixture of 3-acetyl-dihydromorphorine (Immol), drierite (Ig) and Hg(0Ac)2 (0.75 mmol) in 5 ml acetonitrile were stirred at room temperature 1 hour. Thereafter, 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide (1.5 mmol) was added and the mixture stirred 4 days. The mixture was filtered, concentrated, washed with 1M KOH, and diluted with CH2CI2. The product was isolated after chromatographic purification. 2. 6-j8-0-Glucosyldihydromorphorine The product from Step 1 was dissolved in 5 ml methyl alcohol and the solution made alkaline by the addition of 1M sodium methoxide. The solution stood 3 hours and was neutralized with Amberlite IR 120 exchange resin. The solvent was removed, the residue purified by column chromatography, and the product isolated. Derivatives Opioid 3 -0-/3-Glucosy Idihy droisomorphine 3-^-O-Glucosyldihydromorphine
Yield (%) (Second Step) 45 30
SUGARS
595
Notes 1. This is an example of the Koenings-Kjiorr glucosidation reaction where glucoside derivatives are prepared using halo- or acetoxysugars in the presence of Lewis acids such as Ag"^ or Hg"^^. Glycosidations can also occur using NaOH-NBu40H as the catalyst (1). 2. 3-0-Glucosylhydromorphorine, (I), and 3-0-j8-0-glucosyldihydro-isomorphorine, (II), were also prepared by the author as illustrated in Eq. 1 and Eq. 2, respectively: AcO lOAc ^Br
JLP-; OAc OAc
(I) i- Lithium hydroxide, water AcO,
AcO
|0Ac/Br
OAc OAc
i- Lithium hydroxide, water 3. The preparation of 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide and derivatives is described (2). 4. The preparation of glucosylhydromorphorine derivatives containing N-alkyl, -acyl, or -oxides is provided (3). 5. Nordihydroisomorphine-3-glucuronide, (III), has been prepared and is described (4). HO HO^/
OH )—O
HOOC
(III)
596
ADVANCES IN SYNTHETIC ORGANIC CHEMISTRY
References 1. S. Gabrey, Synthesis, 1078 (1992); A. Knochel, Tetrahedron Lett., 551 (1974); CM. Ice, J. Am. Chem. Soc, 74, 4606 (1952) 2. R.R. Tuttle etal, US Patent 4,774,230 (September 27, 1988) 3. F. Scheinmann, US Patent 6,046,313 (April 4, 2000) 4. K. Rice, J. Org. Chem., 40, 1850 (1975)