Synthesis of 5-chloro-1- (2,3-dideoxy-3-fluoro-β-D-glycero-HEX-2-enopyranose-4-ulosyl)uracil as potential anticancer/antiviral agent

Article abstract of DOI:10.1081/NCN-100002424

Peracetylated α-D-glucose was coupled with silylated 5-chlorouracil. The product (2) was deacetylated and 4′,6′-hydroxyls were then protected with 4′,6′-O-isopropylidene group. Fluorine was introduced at the 3′-position, followed by acetylation, deprotect

Full text of DOI:10.1081/NCN-100002424

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SYNTHESIS OF 5-CHLORO-1-(2,3-DIDEOXY-3-
FLUORO-β-D-GLYCERO-HEX-2-ENOPYRANOSE-4-
ULOSYL)URACIL AS POTENTIAL ANTICANCER/
ANTIVIRAL AGENT
Abdul R. Khan a , Kimberly X. Mulligan* a & Abraham P. Ollapally b
a Department of Chemistry , Florida A & M University , Tallahassee, Florida, 32307,
U.S.A.
b Department of Chemistry , Florida A & M University , Tallahassee, Florida, 32307,
U.S.A.
Published online: 07 Feb 2007.
To cite this article: Abdul R. Khan , Kimberly X. Mulligan* & Abraham P. Ollapally (2001) SYNTHESIS OF 5-CHLORO-1-(2,3-
DIDEOXY-3-FLUORO-β-D-GLYCERO-HEX-2-ENOPYRANOSE-4-ULOSYL)URACIL AS POTENTIAL ANTICANCER/ANTIVIRAL AGENT,
Nucleosides, Nucleotides and Nucleic Acids, 20:4-7, 759-762, DOI: 10.1081/NCN-100002424
To link to this article: http://dx.doi.org/10.1081/NCN-100002424
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 759–762 (2001)
SYNTHESIS OF 5-CHLORO-1-(2,3-DIDEOXY-3-
FLUORO-β-D-GLYCERO-HEX-2-ENOPYRANOSE-
4-ULOSYL)URACIL AS POTENTIAL
ANTICANCER/ANTIVIRAL AGENT
Abdul R. Khan, Kimberly X. Mulligan,∗
and Abraham P. Ollapally†
Department of Chemistry, Florida A & M University,
Tallahassee, Florida 32307
ABSTRACT
Peracetylated α-D-glucose was coupled with silylated 5-chlorouracil. The prod-
uct (2) was deacetylated and 4ꢀ,6ꢀ-hydroxyls were then protected with 4ꢀ,6ꢀ-O-
isopropylidene group. Fluorine was introduced at the 3ꢀ-position, followed by
acetylation, deprotection, tritylation, oxidation and deritylation of subsequent
compounds gave the target compound (10).
INTRODUCTION
As an extension of our studies on the unique class of fluoroenone hexopy-
ranose nucleosides with 5-fluorouracil, which showed both anticancer as well as
antiviral activities (1–3), we decided to synthesize another ketounsaturated nucleo-
side with the nucleobase 5-chlorouracil, to study any variation in biological activity.
In addition, we are reporting here an alternative method for synthesizing the title
compound.
∗Undergraduate student sponsored by the Minority Biomedical Research Support Program.
†Corresponding author.
759
ꢁ
C
Copyright 2001 by Marcel Dekker, Inc.
www.dekker.com

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KHAN, MULLIGAN, AND OLLAPALLY
CHEMISTRY
The strategy initially attempted to successfully synthesize the title compound
was based on the synthesis of 1,2,4,6-tetra-O-acetyl-3-deoxy-3-fluoro-D-glucose
using 3-deoxy-3-fluoro-1,2:5,6-di-O-ispropylidene-α-D-glucofuranose as an inter-
mediate (4–6). But due to high cost, instability and arduous method, we synthesized
the title compound through an alternative method based on the previous reported
preparation of 7-(3-deoxy-3-fluoro-4,6-O-isopropylidene-β-D-allopyranosyl) the-
ophylline (7).
To this end, we first coupled the α-D-glucose pentaacetate with silylated 5-
chlorouracil in the presence of TMS-triflate to get the nucleoside 2. Deacetylation
of 2 in methanolic ammonia gave 3 in quantitative yield. 3 was then reacted with
2,2-dimethoxypropane in presence of pTSA in anhydrous DMF (7) in order to pro-
tect 4ꢀ,6ꢀ-hydroxyls to give 4. Direct and selective fluorination (7) of 3ꢀ-OH in 4 was
done with DAST in presence of DMAP in anhydrous CH2Cl2 to get 5. It was then
acetylated with acetic anhydride in pyridine to give 6. 4ꢀ,6ꢀ-O-isopropylidene pro-
tective group was then cleaved with 40% aq. trifluoroacetic acid in a small amount
of ethanol to afford 7, which was dried well overnight and treated with well dried
triphenylmethyl chloride in presence of DMAP in pyridine giving the 6ꢀ-O-trityl
nucleoside 8. Oxidation (8) of 8 with pyridinium dichromate in presence of molec-
❛
ular sieves (3 A) in anhydrous CH2Cl2 afforded 9. Finally, detritylation with 1.0
eq of boron trichloride (9) in anhydrous CH2Cl2 at −30 to 40◦C gave the ketoun-
saturated nucleoside 10, the target compound. The structure of the compound was
determined by its 1H NMR, 19F NMR and IR spectra.
EXPERIMENTAL
Acetonitrile, DMF, and methylene chloride are of anhydrous grade (sure/
sealTM) and all chemicals unless otherwise stated were purchased from Aldrich
Chemical Co. Thin layer chromatography (TLC) was performed on precoated silica
gel plastic sheets 60F254 (0.2 mm) EM. Compounds were detected under short
wavelength UV light and also by heating after spraying with 3% sulfuric acid
in methanol (v/v). Silica gel 60 (70–230 mesh ASTM) EM science was used for
column chromatography. Duration of the reactions was monitered by TLC. All
reaction were carried out under N2 atmosphere.
Melting points (uncorrected) were recorded using a MEL-Temp apparatus. 1H
NMR and 19F NMR spectra were recorded on a Bruker/IBM-SY200 spectrometer
at 270 MHz using tetramethylsilane as an internal standard and trifluoroacetic acid
as an external standard respectively. The chemical shifts of NMR spectra were
❛
expressed in parts per million (ppm). Molecular sieves (3 A), used for oxidation,
was finely powdered, and then heated for 30 min. on a flame in vacuo in the vicinity
of P2O5 in a specially designed vessel just before the oxidation and cooled to room
temprature in vacuo.

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5-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-hexopyranosyl)uracil(2):
A mixture of 5-chlorouracil (10 g, 68.24 mmol), HMDS (14.45 ml, 89.75 mmol)
and saccharine (50 mg) was refluxed in anhydrous acetonitrile (20 ml) for 3 hr to
get a clear solution. Excess solvent was removed by evaporation under vacuum.
A solution of 1 (9.12 g, 23.61 mmol) in anhydrous acetonitrile (30 ml) was then
added to the silylated base. The reaction mixture was then cooled to 0◦C in an ice
bath. The stirred, cooled reaction mixture was finally treated dropwise with TMS-
triflate (5.39 ml, 24.28 mmol) in anhydrous acetonitrile (3.0 ml). After complete
addition, the reaction mixture was stirred at room temperature for 30 min and at
85◦C for 3 hr. After being stirred overnight at room temperature the reaction was
neutralized with MeOH/NH3 at below 5◦C. Solvent was evaporated and the residue
obtained was mixed with ethyl acetate. The precipitate that separated was filtered
and washed with excess ethyl acetate. The combined filtrate was concentrated and
purified by column chromatography (silica gel) using hexane:ethyl acetate (3:2)
1
as eluant. Yield 90%; M.P. 218–220◦C; H NMR (CDCl3): δ 8.59 (bs, 1H, NH
proton); 7.15 (s, 1H, H-6); 5.89 & 5.86 (dd, 1H, J = 10 Hz & 7 Hz, H-1ꢀ); 5.56 (m,
1H, H-4ꢀ); 5.16 (m, 1H, H-3ꢀ); 4.28 & 4.26 (dd, J = 12 Hz & 4 Hz, 1H, H-6ꢀa); 4.10
& 4.06 (dd, J = 12 Hz & 4.5 Hz, 1H, H-6ꢀb); 3.80 (m, 1H, H-5ꢀ); 2.12, 2.11, 2.03
& 2.01 (4s, 12H, 4 × COCH3).
5-Chloro-1-(3-deoxy-3-fluoro-4,6-O-isopropylidene-β-D-allopyranosyl)-
uracil (5). A stirred solution of 4 (1.55 g, 4.45 mmol) and 4-dimethylaminopyri-
dine (1 g, 8.00 mmol) in dry CH2Cl2 (10 ml) at −60◦C was treated with DAST
(1.0 ml, 8.5 mmol) during 15 min under nitrogen. The mixture was then allowed to
attain room temperature. After 24–28 hr, the mixture was cooled to 0◦C, methanol
was added, solvents were removed under vacuum and the resulting oil was purified
by column chromatography (ethyl acetate-hexane, 3:1) give 5. Yield 42%; 1H NMR
(CDCl3): δ 8.68 (bs, 1H, NH proton); 7.64 (s, 1H, H-5); 5.91 (d, 1H, J = 12 Hz,
H-1ꢀ); 5.36 (t, 1/2H, J = 3.5 Hz, H-3ꢀ); 5.18 (t, 1/2H, J = 3.5 Hz, H-3ꢀ); 4.98 (m,
1H, H-2ꢀ); 4.24 (m, 1H, H- 4ꢀ); 3.98 (m, 2H, H-6ꢀ); 3.74 (m, 1H, H-5ꢀ); 1.58 & 1.56
(2s, 6H, 2 × CH3). 19F NMR (CDCl3): −78.38.
5-Chloro-1-(2,3-dideoxy-3-fluoro-6-O-trityl-β-D-glycero-hex-2-enopyr-
anosyl-4-ulose)uracil(9). 1.10 g (2.05 mmol) of 8 and (2.50 g, 5.50 mmol) of
PDC were reacted in anhydrous CH2Cl2 (35 ml) in the presence of freshly activated
❛
room temperature molecular sieves (3 A) under N2 atmosphere. After 6–8 hr of stir-
ring at room temperature the mixture was diluted with an equal amount of ethyl
acetate and stirred further for 30 min. It was then filtered over a bed of silica gel and
celite and washed copiously with methylene chloride. The combined filtrate was
concentrated and purified by column chromatography using hexane:ethyl acetate
(3:2) as eluant to obtain pure compound 9. Yield 44%; sirup; 1H NMR (CDCl3):
δ 7.58 (s, 1H, H-6); 7.22–7.50 (m, 15H, 3 × C6H5); 5.58 (d, 1H, J = 10 Hz, H-1ꢀ);
5.28 (m, 1H, H-2ꢀ); 4.12 (m, 1H, H-5ꢀ); 3.58 (dd, 1H, J = 8.0 Hz & 5.4 Hz, H-6ꢀa);

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KHAN, MULLIGAN, AND OLLAPALLY
3.36 (dd, 1H, J = 8.2 Hz & 5.5 Hz, H-6ꢀb). 19F NMR (CD3OD): δ−78.42; IR (Neat):
1720 cm−1.
ACKNOWLEDGMENT
Financial support from NIGMS through Minority Biomedical Research Sup-
port Program grant number SO6 GM 08111 is gratefully acknowledged.
REFERENCES
1: Komiotis, D.; Delatre, S.; Holt, L.; Ollapally, A.P.; Balzarini, J.; De Clercq, E.; Iigo,
M. Nucleosides and Nucleotides, 1991, 10, 431–455.
2: Akhtar, M.S.; Carthy, M.; De Clercq, E.; Balzarini, J.; Ollapally, A.P. Communicated
to J. Med. Chem.
3: Ollapally, A.P.; Bennouna-Dorange, I.; Whitaker, T.L. Nucleosides and Nucleotides,
1999, 18 (4&5), 703–705.
4: Tewson, T.J.; Welch, M.J. J. Org. Chem., 1978, 43, 1090–1092.
5: Lemieux, R.U.; Driguez, H. J. Am. Chem. Soc., 1975, 97, 4069–4075.
6: Stevens, J.D. Methods in Carbohydrate Chemistry, 1972, VI, 123–125.
7: Leclercq, F.; Antonakis, K. Carbohydrate Research., 1989, 193, 307–313.
8: Herscovici, J.; Antonakis, K. J. Chem. Soc., Chem. Commun., 1980, 561–563.
9: Jones, G.B.; Hynd, G.; Wright, J.M.; Sharma, A., J. Org. Chem., 2000, 65, 263–265.

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