Synthesis of 3′-azido-2′,3′Dideoxy-4′-ketohexopyranoid analogues as possible antiviral nucleosides

Article abstract of DOI:10.1081/SCC-120003150

Peracetylated 2-deoxy-D-glucose was coupled with silylated bases. The product was deacetylated and the 4′,6′-hydroxy groups were then protected. An azido group was introduced at the 3′-carbon via tosylation, followed by deprotection, tritylation, and oxid

Full text of DOI:10.1081/SCC-120003150

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SYNTHESIS OF 3′-AZIDO-2′,3′- DIDEOXY-4′-
KETOHEXOPYRANOID ANALOGUES AS POSSIBLE
ANTIVIRAL NUCLEOSIDES
Abdul R. Khan a , Kimberly X. Mulligan a , Kinfe K. Redda b & Abraham P. Ollapally a
a Department of Chemistry , Florida Agricultural and Mechanical University , Tallahassee, FL,
32307, U.S.A.
b College of Pharmacy and Pharmaceutical Sciences , Florida Agricultural and Mechanical
University , Tallahassee, FL, 32307, U.S.A.
Published online: 21 Aug 2006.
To cite this article: Abdul R. Khan , Kimberly X. Mulligan , Kinfe K. Redda & Abraham P. Ollapally (2002) SYNTHESIS OF 3′-
AZIDO-2′,3′- DIDEOXY-4′-KETOHEXOPYRANOID ANALOGUES AS POSSIBLE ANTIVIRAL NUCLEOSIDES, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:7, 1023-1030, DOI: 10.1081/
SCC-120003150
To link to this article: http://dx.doi.org/10.1081/SCC-120003150
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SYNTHETIC COMMUNICATIONS, 32(7), 1023–1030 (2002)
SYNTHESIS OF 30-AZIDO-20,30-
DIDEOXY-40-KETOHEXOPYRANOID
ANALOGUES AS POSSIBLE
ANTIVIRAL NUCLEOSIDES
1
Abdul R.Khan, Kimberly X.Mulligan,
1,
*
2
Kinfe K.Redda, and Abraham P.Ollapally
1,y
1Department of Chemistry and
2College of Pharmacy and Pharmaceutical Sciences,
Florida Agricultural and Mechanical University,
Tallahassee, FL 32307
ABSTRACT
Peracetylated 2-deoxy-D-glucose was coupled with silylated
bases. The product was deacetylated and the 40,60-hydroxy
groups were then protected. An azido group was introduced
at the 30-carbon via tosylation, followed by deprotection,
tritylation, and oxidation to give the final compound.
INTRODUCTION
Azidothymidine (AZT),1 is the first clinically approved drug for treat-
ing acquired immunodeficiency syndrome (AIDS).2 However, serious side
*Undergraduate student supported by Minority Biomedical Research Support
Program.
yCorresponding author.
1023
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

1024
KHAN ET AL.
effects, such as short plasma half life3 and bone marrow suppression,4
were reported on clinical administration. In order to increase its therapeutic
efficacy, several analogues of AZTwere synthesized 5,6 and various steroidal
carboxylic ester7 and phosphotriester8 conjugates of AZTwere synthesized
in our laboratory.
Recent synthesis in our laboratory and others of some pyrimidine
nucleosides with unsaturated ketohexopyranosyl moiety,9–12 which showed
significant in vitro and in vivo anti-cancer and antiviral activities, stimulated
our quest for more analogues of these compounds.
The study of the structure–activity relationship of unsaturated
ketohexopyranosyl nucleosides has shown that the presence of an
a,b-unsaturated keto system in the sugar ring plays a very important role
for the biological activities13 of these nucleosides.
Considering all these factors, we report here the synthesis of
pyranoid analogues having an azido (N3) group at the 30-carbon and
a keto group at the 40-carbon with different pyrimidine bases in order
to examine whether there is any potential for biological activity.
While the evaluation of the biological activity of these compounds is in
progress, the synthesis of other compounds in this series is continuing in
our laboratory.
Reagent and Conditions: (a) Ac2O, Pyridine (b) TMS-triflate, CH3CN,
0ꢀC
reflux (85ꢀC), 3 h (c) NH3/MeOH (d) C6H5CH(OCH3)2, HBF4, DMF,
18–24 h, 75–80% (e) Tosyl chloride, DMAP, Pyridine, 32 h, 80% (f) NaN3, DMF,
135ꢀC, reflux, 4 h, 75–80% (g) 40% aq. trifluoroacetic acid, 4 h (h) Triphenylmethyl
chloride, DMAP, Pyridine, 18–24 h, 62% (i) PDC, molecular sieves 3 A, CH2Cl2,
room temp., 6 h, 42%.

POSSIBLE ANTIVIRAL NUCLEOSIDES
CHEMISTRY
1025
Acetylated a-2-deoxy-D-glucose 2 was coupled with silylated bases in
the presence of TMS-triflate to yield the b-isomer of tri-o-acetylated nucleo-
sides 3, 4, 5.6
Deacetylation of 3, 4, 5 in methanolic ammonia gave compounds 6, 7, 8
in quantitative yield. These compounds were then treated with benz-
aldehydedimethyl acetal and tetrafluoroboric acid14 in anhydrous DMF to
protect 40,60-hydroxyl groups to give 9, 10 and 11. The protected benzylidene
nucleosides were treated with tosyl chloride in pyridine with DMAP to give
12, 13 and 14. These then reacted with NaN3 in DMF to afford compounds
15, 16 and 17. The 40,60-benzylidene groups of these nucleosides were cleaved
in 40% aq. trifluoroacetic acid in a small amount of ethanol to afford 18, 19
and 20 which were then dried well overnight and treated with well-dried
triphenylmethyl chloride in pyridine in the presence of DMAP, giving the
60-o-trityl nucleosides 21, 22 and 23. Finally, oxidation of 21, 22 and 23 with
pyridinium dichromate in the presence of molecular sieves (3A) in dry
CH2Cl2 gave the target compounds 24, 25 and 26 which were characterized
by the absence of the H-40 proton in their NMR and by IR spectrum.
EXPERIMENTAL SECTION
a-2-Deoxy-glucose, nucleobases, DMF, acetonitrile of anhydrous
grade, and all other chemicals used were purchased from Adrich Chemical
Co. THF and CH2Cl2 were distilled from Na/benzophenone and CaH
respectively under N2 atmosphere. Melting point (uncorrected) was recorded
using Mel-Temp apparatus. Thin layer chromatography (TLC) was
performed on precoated silica gel plastic TLC sheets 60F254 (0.2 mm) EM
reagents. Compound visualization was effected with a UV lamp (254 nm) and
confirmed by spraying a 5% solution of H2SO4 in EtOH, followed by heating.
1H NMR spectra were recorded on a Brucker/IBM-5Y2000 spectrometer at
300 MHz with Me4Si as internal standard and are expressed in ppm. Silica gel
60 (70–230 mesh ASTM) was used for column chromatography. Molecular
sieves (3 A) used for oxidation was finely powdered, heated to about
375–400ꢀC just before the experiment in a vacuum system (specially designed)
in the vicinity of P2O5 and then cooled to room temperature. All the reactions
were carried out under N2 atmosphere.
1-(2,3-Dideoxy-3,4,6-tri-o-acetyl-b-D-glycero-hexopyranosyl)thymine 3:
A mixture of thymine (17.0 g, 134.79 mmol) and saccharine (50 mg) in
hexamethyldisilazane (HMDS) (30 ml) and 1,2-dichloroethane (20 ml) was

1026
KHAN ET AL.
heated under reflux for 3 h to get a clear solution. Excess HMDS
was removed by evaporation under vacuum and the reaction assembly
was flushed with dry N2 gas. A solution of 2 (17.76 g, 53.49 mmol) in dry
CH3CN (50 ml) was then added to the silylated base. The reaction mixture
was then cooled to 0ꢀC in an ice bath. The stirred, cooled reaction mixture
was finally treated dropwise with TMS-triflate (10 ml, 44.99 mmol). After
complete addition, the reaction mixture was stirred at room temperature for
30 min and then heated at 85ꢀC for 3 h. Later, it was cooled in an ice bath
(below 5ꢀC) and neutralized with methanolic ammonia solution. The solvent
was evaporated and the residue obtained was mixed with EtOAc. The
precipitate separated was filtered and washed with excess of ethyl acetate.
The combined filtrate was concentrated and purified by column chromato-
graphy (silica gel) using hexane : EtOAc (3 : 2) as eluant. Yield, 92%, m.p.
188ꢀC. H NMR (CDCl3): d 8.59 (s, 1H,-NH proton); 7.15 (brs, 1H, H-6);
1
5.88 and 5.84 (dd, 1H, H-10, J ¼ 10 Hz and 7 Hz); 5.15 (m, 1H, H-30); 5.02
(m, 1H, H-40); 4.28 and 4.24 (dd, 1H, H-60b, J ¼ 12 Hz and 4 Hz); 4.10 and
4.06 (dd, 1H, H-60a, J ¼ 12 Hz and 4.5 Hz); 3.80 (m, 1H, H-50); 2.42 (m, 2H,
H-20); 2.08, 2.05, 2.01 (each s, each 3H, 3 ꢁOAc); 1.93 (s, 3H,-CH3). Anal.
calcd for C17H22O9N2: C, 51.25; H, 5.53; N, 7.04. Found: C, 51.82; H, 5.06;
N, 7.18.
5-Fluoro-1-(2,3-dideoxy-3,4,6-tri-o-acetyl-b-D-glycero-hexopyranosyl)ura-
cil 4: Following the procedure as described for the synthesis of 3, 5-fluoro-
uracil (10 g, 76.88 mmol) was silylated with HMDS (22 ml) and saccharine
(30 mg), and then silylated base was condensed with 2 (9.2 g, 27.71 mmol) in
presence of TMS-triflate (6.0 ml, 26.99 mmol) in dry acetonitrile (40 ml).
Worked up followed by column chromatography (3 : 2, hexane : ethyl
acetate) of the reaction mixture afforded compound 4 as crystalline solid.
1
Yield 88%. H NMR (CDCl3): d 8.68 (s, 1H,-NH proton); 7.25 (brs, 1H,
H-6); 5.78 and 5.75 (dd, 1H, H-10, J ¼ 12 Hz and 8 Hz); 5.15–5.08 (m, 2H,
H-30 and H-40); 4.26 and 4.21 (dd, 1H, H-60b, J ¼ 12 Hz and 6 Hz); 4.12 and
4.05 (dd, 1H, H-60a, J ¼ 10 Hz and 4.5 Hz); 3.76 (m, 1H, H-50); 2.45 (m, 2H,
H-20); 2.06, 2.04, 2.01 (each s, each 3H, 3 ꢁ OAc). 19F NMR (CDCl3):
ꢂ116.35. Anal. calcd for C16H19O9N2F: C, 47.76; H, 4.73; N, 6.97.
Found: C, 47.02; H, 4.73; N, 6.82.
5-Chloro-1-(2,3-dideoxy-3,4,6-tri-o-acetyl-b-D-glycero-hexopyranosyl)ura-
cil 5: Following the procedure as described for the synthesis of 3, 5-chloro-
uracil (8.0 g, 54.60 mmol) was silylated with HMDS (12 ml) and saccharine
(20 mg), and then silylated base was condensed with 2 (7.0 g, 21.08 mmol) in
the presence of TMS-triflate (4.5 ml, 20.25 mmol) in dry acetonitrile (40 ml).
Worked up followed by column chromatography (3 : 2, hexane : ethyl
acetate) of the reaction mixture afforded compound 5 as crystalline solid.
Yield 89%. m.p. 132–135ꢀC. 1H NMR was in accordance with the structure

POSSIBLE ANTIVIRAL NUCLEOSIDES
1027
of the compound. Anal. calcd for C16H19O9N2Cl: C, 45.93; H, 4.55; N, 6.70.
Found: C, 45.81; H, 4.53; N, 6.06.
1-(2,3-Dideoxy-b-D-glycero-hexopyranosyl)thymine 6: Yield 95%; m.p.
218–220ꢀC; H NMR (CD3OD): d 8.88 (brs, 1H, -NH proton); 7.18 (brs,
1
1H, H-6); 5.88 and 5.84 (dd, 1H, H-10, J ¼ 10 Hz and 7 Hz); 5.15 (m, 1H,
H-30); 5.02 (m, 1H, H-40); 4.28 and 4.19 (dd, 2H, H-6, J ¼ 12 Hz and 6 Hz);
3.80 (m, 1H, H-50); 2.42 (m, 2H, H-20); 1.93 (s, 3H, -CH3).
Compound 7: Yield 94%; m.p. 215–219ꢀC.
Compound 8: Yield 93%; m.p. 220–222ꢀC.
1-(2,3-Dideoxy-4,6-o-benzylidene-b-D-glycero-hexopyranosyl)thymine 9:
Yield 75%; m.p. 149–152ꢀC; 1H NMR (CDCl3): d 8.65 (brs, 1H, -NH
proton); 7.23–7.16 (m, 6H, -C6H5 and H-6); 6.68 (d, 1H, H-10, J ¼ 10 Hz);
5.51 (m, 1H, H-30); 5.12 (m, 1H, H-40); 4.48 and 4.32 (two dd, 2H, H-60,
J ¼ 12 Hz and 4 Hz); 3.51 (m, 1H, H-50); 2.46 and 2.40 (two m, 2H,
Jgem ¼ 12.7 Hz, Jvic ¼ 3.05, 1.65 Hz, H-20); 1.92 (s, 3H, CH3).
Compound 10: Yield 72%; m.p. 154–155ꢀC.
Compound 11: Yield 71%; m.p. 158–161ꢀC.
1-(2,3-Dideoxy-4,6-o-benzylidene-3-o-tosyl-b-D-glycero-hexopyranosyl)-
1
thymine 12: Yield 75%; H NMR (CDCl3): d 8.70 (brs, 1H,-NH proton);
7.28–7.17 (m, 11H, 2x-C6H5 and H-6); 5.98 (d, 1H, H-10, J ¼ 12 Hz);
5.52–5.33 (m, 2H, H-30 and H-40); 4.46 and 4.31 (two dd, 2H, H-60,
J ¼ 12 Hz and 4 Hz); 3.60 (m, 1H, H-50); 2.45 and 2.41 (two m, 2H,
Jgem ¼ 12.7 Hz, Jvic ¼ 3.05, 1.65 Hz, H-20); 1.91 and 1.93 (two s, 6H, 2ꢁ- CH3).
Compound 13: Yield 75–78%; Syrup.
Compound 14: Yield 76–80%; Syrup.
1-(3-Azido-2,3-dideoxy-4,6-o-benzylidene-b-D-glycero-hexopyranosyl)thy-
mine 15: Yield 75%; m.p. 110–112ꢀC; H NMR (CDCl3): d 8.63 (brs, 1H,
1
-NH proton); 7.48–7.22 (m, 6H, -C6H5 and H-6); 6.65 (d, 1H, H-10,
J ¼ 12 Hz); 5.65–5.51 (m, 2H, H-30 and H-40); 4.58 and 4.41 (two dd, 2H,
H-60, J ¼ 10 Hz and 4 Hz); 3.54 (m, 1H, H-50); 2.46 and 2.40 (two m, 2H,
Jgem ¼ 12.8 Hz, Jvic ¼ 3.08, 1.80 Hz, H-20); 1.93 (s, 3H, CH3). IR (KBr):
2125 cmꢂ1 (N3 group).
Compound 16: Yield 72–78%; IR(Neat): 2120 cmꢂ1 (N3 group).
Compound 17: Yield 75–80%; IR(Neat): 2122 cmꢂ1 (N3 group).
1-(3-Azido-2,3-dideoxy-b-D-glycero-hexopyranosyl)thymine 18: Yield
90%; m.p. 182–185ꢀC; H NMR (CDCl3): d 8.62 (brs, 1H, -NH proton);
1
7.50 (brs, 1H, H-6); 6.68 (d, 1H, H-10, J ¼ 10 Hz); 5.64–5.46 (m, 2H, H-30
and H-40); 4.52 and 4.38 (two dd, 2H, H-60, J ¼ 12 Hz and 4 Hz); 3.62 (m,
1H, H-50); 2.48 and 2.32 (two m, 2H, H-20); 1.92 (s, 3H, CH3). IR (KBr):
2125 cmꢂ1 (N3 group).
Compound 19: Yield 85–90%; IR(Neat): 2120 cmꢂ1 (N3 group);
19F NMR (CDCl3): ꢂ 117.65.

1028
KHAN ET AL.
Compound 20: Yield 85%; IR(Neat): 2122 cmꢂ1 (N3 group).
1-(3-Azido-2,3-dideoxy-6-o-trityl-b-D-glycero-hexopyranosyl)thymine 21:
Yield 55–60%; 1H NMR (CDCl3): d 8.60 (brs, 1H, -NH proton);
7.58–7.18 (m, 16H, 3x-C6H5 and H-6); 6.62 (d, 1H, H-10, J ¼ 10 Hz);
4.92–4.72 (m, 2H, H-30 and H-40); 4.46 and 4.31 (two dd, 2H, H-60,
J ¼ 10 Hz and 4 Hz); 3.55 (m, 1H, H-50); 2.43 and 2.38 (two m, 2H, H-20);
1.91 (s, 3H, -CH3). IR (KBr): 2122 cmꢂ1 (N3 group).
Compound 22: Yield 60–62%; IR(Neat): 2125 cmꢂ1 (N3 group).
Compound 23: Yield 58–60%; IR(Neat): 2124 cmꢂ1 (N3 group).
1-(3-Azido-2,3-dideoxy-6-o-trityl-b-D-glycero-hexopyranose-4-ulosyl)thy-
mine 24: 1.0 gm (1.90 mmol) of 21 and (1.78 g, 4.73 mmol) of PDC were dried
with THF. 4.0 g of molecular seive (3A), freshly activated at 375ꢀC over
P2O5 in vacuum, was cooled and added to the flask, followed by 40 ml of
anhyd. CH2Cl2. After 6 h stirring at room temperature, the mixture was
diluted with equal volume of EtOAc and stirred further for 30 min. It was
then filtered over a bed of silica gel and celite and washed copiously with
CH2Cl2. Combined filterate was concentrated and purified by column
chromatography using hexane : EtOAc (3 : 2) as eluant to obtain pure com-
pound. Yield: 42%; m.p. 145ꢀC; H NMR (CDCl3): d 8.62 (brs, 1H, -NH
1
proton); 7.50–7.20 (m, 16H, 3 ꢁ -C6H5 and H-6); 6.68 (d, 1H, H-10,
J ¼ 10 Hz); 5.51 (m, 1H, H-30); 4.48 and 4.32 (two dd, 2H, H-60, J ¼ 12 Hz
and 4 Hz); 3.51 (m, 1H, H-50); 2.46 and 2.40 (two m, 2H, Jgem ¼ 12.7 Hz,
Jvic ¼ 3.05, 1.65 Hz, H-20); 1.92 (s, 3H, CH3). IR (KBr): 2125 cmꢂ1 (N3
group), 1720 cmꢂ1 (keto group). Anal. calcd for C30H27O5N5: C, 67.04,;
H, 5.03; N, 13.04. Found: C, 67.31; H, 5.08; N, 13.21.
5-Fluoro-1-(3-azido-2,3-dideoxy-6-o-trityl-b-D-glycero-hexopyranose-4-
ulosyl)uracil 25: Following the procedure as described for the synthesis of
24, 1.10 g (2.02 mmol) of 22 and (2.05 mg, 5.45 mmol) of PDC were reacted
in anhydrous dichloromethane (45 ml) in presence of 3.0 gm of cooled
molecular seive (3A), freshly activated at 375ꢀC over P2O5 in vacuum.
Worked up and purified by column chromatography using hexane : EtOAc
(3 : 2) as eluant to obtain pure compound. Yield: 45%; 1H NMR (CDCl3): d
8.80 (brs, 1H,-NH proton); 7.55–7.21 (m, 16H, 3 ꢁ C6H5 and H-6); 5.58 (d,
1H, H-10, J ¼ 10 Hz); 5.32 (m, 1H, H-30); 4.38 and 4.25 (two dd, 2H, H-60,
J ¼ 11 Hz and 4.5 Hz); 3.48 (m, 1H, H-50); 2.44 and 2.42 (two m, 2H,
Jgem ¼ 11 Hz, Jvic ¼ 3.00, 1.66 Hz, H-20); 19F NMR (CDCl3) : ꢂ 117.60. IR
(Neat): 2126 cmꢂ1 (N3 group), 1722 cmꢂ1 (keto group). Anal. calcd for
C29H24O5N5F: C, 64.33; H, 4.45; N, 12.94. Found: C, 64.89; H, 4.42; N,
12.94.
5-Chloro-1-(3-azido-2,3-dideoxy-6-o-trityl-b-D-glycero-hexopyranose-4-
ulosyl)uracil 26: Following the procedure as described for the synthesis of
24, 0.98 g (1.75 mmol) of 23 and (1.68 g, 4.46 mmol) of PDC were reacted in

POSSIBLE ANTIVIRAL NUCLEOSIDES
1029
anhydrous dichloromethane (45 ml) in presence of 3.0 g of cooled molecular
seive (3 A), freshly activated at 375ꢀC over P2O5 in vacuum. Worked up and
purified by column chromatography using hexane : EtOAc (3 : 2) as eluant to
obtain pure compound. Yield: 44%; 1H NMR (CDCl3): d 8.75 (brs, 1H,-NH
proton); 7.48–7.00 (m, 16H, 3 ꢁ C6H5 and H-6); 6.12 (d, 1H, H-10); 5.48 (m,
1H, H-30); 4.58 and 4.37 (m, 2H, H-60); 3.36 (m, 1H, H-50); 2.46 and 2.41
(two m, 2H, Jgem ¼ 12 Hz, Jvic ¼ 3.06, H-20); IR (Neat): 2124 cmꢂ1 (N3
group), 1719 cmꢂ1 (keto group). Anal. calcd for C29H24O5N5Cl: C, 62.48;
H, 4.31; N, 12.57. Found: C, 61.98; H, 4.31; N, 12.21.
ACKNOWLEDGMENT
We are thankful to Dr. Ralph W. Turner, Chairman, Department of
Chemistry for his encouragement and interest. Financial support from
NIGMS through Minority Biomedical Research Support Program grant
number SO6 GM 08111 is gratefully acknowledged.
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Received in the USA March 27, 2001