Synthesis of some monocyclic-N-acetyl 4′-aza-D-nucleosides

Article abstract of DOI:10.1002/jhet.5570430212

1,2,3,5-Tetra-O-acetyl-4-deoxy-4-(acetamido)-β-D-ribofuranose 5 was prepared from L-lyxose, which on condensation with silylated nucleoside bases gave the corresponding protected 4′-azanucleosides. The protecting groups were removed using methanolic ammon

Full text of DOI:10.1002/jhet.5570430212

Mar-Apr 2006
325
Synthesis of Some Monocyclic-N-acetyl 4'-Aza-D-nucleosides
Chamakura V. N. S. Varaprasad*, Kanda S. Ramasamy, Zhi Hong
Drug Discovery, Valeant Pharmaceuticals Research & Development,
3300 Hyland Avenue, Costa Mesa, CA 92626
Received June 13, 2005
1,2,3,5-Tetra-O-acetyl-4-deoxy-4-(acetamido)-ꢀ-D-ribofuranose 5 was prepared from L-lyxose, which
on condensation with silylated nucleoside bases gave the corresponding protected 4'-azanucleosides. The
protecting groups were removed using methanolic ammonia to afford the N-acetyl-4'-azanucleosides,
wherein the sugar ring oxygen is replaced with a substituted nitrogen atom, in good yields. Further, the 1-
(4-deoxy-4-acetamido-ꢀ-D-ribofuranosyl)thymine 16 was transformed to the corresponding 2'-deoxy, 2',3'-
dideoxy derivatives. The stereochemical assignments of the synthesized nucleosides were established
based on NMR and X-ray studies.
J. Heterocyclic Chem., 43, 325 (2006).
Introduction.
efficacy in treating viral disease as monotherapy
(respiratory syncytial virus) [14] or in combination with
interferon-alpha (hepatitis C) [15]. Recent collective
studies have shown that the in vivo utility of ribavirin may
be ascribed to more than the direct reduction in levels of
circulating virus. The promotion of T-cell mediated
immunity against viral infection has been shown to be a
possible additional mechanism of antiviral activity by this
nucleoside analog [16-18]. The central focus of this
immunomodulatory effect of ribavirin is the augmentation
of antiviral Type 1 cytokine expression (IL-2, IFN-ꢀ,
TNF-ꢁ) and concomitant suppression of Type 2 cytokine
levels (IL-4, IL-5, IL-10) by activated T cells. The
induction of a Type 1 cytokine bias by ribavirin, which
was first demonstrated in humans in vitro [19], was
shown to be functionally significant in vivo [20a] through
the enhancement of a Type 1 cytokine-mediated contact
hypersensitivity responses in BALB/c mice. Whereas L-
ribavirin, wherein the ribose moiety was derived from
unnatural sugar L-ribose, was shown [20b] to retain Type
Modulation of the immune system offers an important
paradigm in the control of diseases. Central to the
balance between protection from disease versus
mediating the pathophysiologic events of diseases [1] is
the control of the levels of cytokines secreted by Th1/Th2
subsets of T helper (Th) cells [2]. Th-1 derived cytokines
(IL-2, IFN-ꢀ, TNF-ꢁ) are responsible primarily for cell-
mediated immunity such as delayed hypersensitivity,
whereas the Th-2 cytokines (IL-4, IL-5, IL-6, IL-9, IL-
10, IL-13) are primarily involved in providing optimal
help for humoral immune responses such as IgE and
IgG4 antibody isotype switching [3]. Th1 and Th2
responses not only play different roles in protection but
also promote different immunopathological reactions.
Th1-type responses are involved in organ specific
autoimmunity such as experimental autoimmune
uveoretinitis [4] and experimental autoimmune
encephalitis (EAE) [5], insulin dependent diabetes
mellitus [6], in contact dermatitis [7] and in some chronic
inflammatory disorders. In contrast, Th2-type responses
are responsible for triggering allergic atopic disorders
(against common environmental allergens) such as
asthma [8]. They are thought to exacerbate infection with
tissue-dwelling protozoa such as helminthes [9] and
Leishmania major [10] and are preferentially induced in
certain immunodeficiencies such as hpyer-IgE syndrome
[11] and Omenn's syndrome [12] and are also associated
with reduced ability to suppress HIV replication [13].
Thus, modulation of the cytokine profile of the
aforementioned disease states would be of therapeutic
benefit.
1
cytokine enhancing activity similar to ribavirin.
However these isomers differ markedly with respect to
other biological properties [20c]. Thus the modification of
ribose moiety selectively modulates ribavirin properties.
Our interest in 4'-azasugar nucleosides [21] coupled
with the immunomodulatory properties of ribavirin
prompted us to prepare ribavirin analogs and other
monocyclic nucleosides containing azasugar 5.
Previously, a few groups have reported the synthesis of
nucleosides having 4'-azasugar from different starting
materials [22-26]. We now describe an improved method
for the synthesis of 1,2,3,5-tetra-O-acetyl-4-deoxy-4-
(acetamido)-ꢀ-D-ribofuranose
5
from commercially
Ribavirin (1-ꢀ-D-ribofuranosyl-1,2,4-triazole-3-carbox-
amide) is a nucleoside analog that has demonstrated
available L-lyxose and certain monocyclic nucleosides
derived from 5.

326
C. V. N. S. Varaprasad, K. S. Ramasamy, Z. Hong
Vol 43
Results and Discussion.
methane to obtain the desired deoxy-4'-aza-ribavirin 11 in
good yield.
The desired protected aza-D-sugar 5 is synthesized as
shown in Scheme 1 following the procedure developed
earlier [21]. The key step involves the conversion of C4
free hydroxyl group of 1 to a protected amino function
with inversion of configuration to afford the desired D
configuration. Then the pyranose derivative 4 was
rearranged to the intermediate 4-aza-D-ribofuranose under
aqueous acetic acid conditions with concomitant cleavage
of acetonide. The azaribofuranose was then protected in
presence of acetic acid, acetic anhydride and conc. H2SO4
to afford the target 1,2,3,5-tetra-O-acetyl-4-deoxy-4-
1
(acetamido)-ꢀ-D-ribofuranose 5. The H NMR spectrum
of 5 showed the presence of ꢁ and ꢀ anomers in a ratio of
25:75 and correlated with 1,2,3,5-tetra-O-acetyl-4-deoxy-
4-(acetamido)-ꢀ-L-ribofuranose [21].
After successfully accomplishing the synthesis of 11,
we turned our attention to the coupling of 5 with thymine
using Vorbrüggen glycosylation conditions. Accordingly,
thymine was per-silylated with hexamethyldisilazane
under reflux to give the corresponding silylated derivative
which on treatment with 5 in the presence of SnCl4 at –5
to 0 °C afforded 1-(2,3,5-tri-O-acetyl-4-deoxy-4-aceta-
mido-ꢀ-D-ribofuranosyl)thymine 12 in 87% yield.
Exposure of 12 to methanolic ammonia at room
temperature provided the target product viz., 1-(4-deoxy-
4-acetamido-ꢀ-D-ribofuranosyl)thymine 17 in 79% yield.
Utilization of the similar coupling procedure for the
preparation of a few other monocyclic 4'-aza-D-nucleosides
(13-16) was found to be remarkably successful. In all these
cases, ꢀ-isomers were obtained as the predominant
products. These protected nucleosides upon deprotection
afforded the corresponding deblocked nucleosides (18-21)
in good yield. However, in general ꢀ isomers were also
obtained as minor products during coupling but no further
After accomplishing the synthesis of desired sugar 5, it
was then coupled to the triazole of ribavirin under
Vorbrüggen conditions [27]. Accordingly the silylated
methyl-1,2,4-triazole-3-carboxylate was reacted with 5 in
presence of tin(IV) chloride to obtain the corresponding
nucleoside 6 in moderate yield (51%). The ester 6 upon
reaction with methanolic ammonia at room temperature
for 16 h furnished the 4'-aza-D-ribavirin 7 in excellent
yield.
The deoxy analog 11 of 4'-aza-ribavirin 7 was
synthesized as follows. Thus reaction of 3' and 5'
hydroxyl groups with Markiewicz reagent [28] readily
gave the required cyclic silyl ether 8. The corresponding
2' thiocarbonate 9, obtained by reacting ether 8 with p-
tolylthionochloroformate, upon exposure to tributyltin
hydride [29] in presence of 2,2'-azobisisobutyronitrile
(AIBN) in refluxing toluene afforded the protected deoxy-
4'-aza-ribavirin 10. The silyl groups of product 10 were
removed with triethylamine trihydroflouride in dichloro-
effort was made to deprotect
them to obtain the
corresponding ꢀ isomers of 4'-aza-ribonucleosides.
After accomplishing the synthesis of selected 4'-aza-D-
ribonucleosides, we were interested in converting 17 to

Mar-Apr 2006
Synthesis of Some Monocyclic-N-acetyl 4'-Aza-D-nucleosides
327
the corresponding 2'-deoxy and 2',3'-dideoxy nucleosides.
Thus, treatment of 17 with Markiewicz reagent
(TPDSiCl2) afforded an inseparable mixture of silyl ether
derivatives 22a and 22b. The mixture on further reaction
with p-tolyl chlorothionoformate and pyridine in CH2Cl2
afforded a readily separable mixture of thionoformate
esters 23 and 24. Radical mediated deoxygenation of 23
and 24 with tri-n-butyltin hydride in presence of AIBN in
toluene under reflux furnished silyl-protected 4'-aza-D-
thymidine 25 and 5'-deoxy-4'-aza-D-5-methyluracil 27
respectively. Removal of the silyl groups of 25 and 27
were accomplished with Et3N.3HF at room temperature to
give 4'-deoxy-4'-(acetamido)-D-thymidine 26 and 4',5'-
dideoxy-4'-(acetamido)-D-5-methyl-uracil 28 in high
yields.
Finally, in view of the potent properties of 2',3'-dideoxy
nucleosides, the synthesis of 1-(2,3,4-trideoxy-4-aceta-
mido-ꢀ-D-ribofuranosyl)thymine 32 was pursued. Thus,
selective protection of the 5'-hydroxyl group of 17 with
TBDMSCl gave the corresponding silyl ether which upon
treatment with methanesulfonyl chloride gave fully
protected intermediate dimesylate 29. The dimesylate upon

328
C. V. N. S. Varaprasad, K. S. Ramasamy, Z. Hong
Vol 43
reaction with freshly prepared telluride dianion [30] in
tetrahydrofuran at room temperature for 16 h afforded the
silyl-protected 2',3'-didehydro-3'-deoxy-4'-aza-thymidine
30. The silyl group in 30 was then removed using
Et3N.3HF to afford 2',3'-didehydro-3',4'-dideoxy-4'-
(acetamido)-D-thymidine 31 in 65% yield. Hydrogenation
of 31 using Pd/C in methanol furnished the final target
compound 3',4'-dideoxy-4'-aza-D-thymidine 32 in high
yield.
negative values of bond lengths, -0.6615 and –0.8899 Å
respectively. Further , as can be seen from the Figure 1,
the azaribose ring adopts a typical C3' endo confor-
mation. It's interesting to note the C=O group of N-
acetyl is anchored away from the base thus minimizing
the interactions between them. The N-acetyl group may
also be responsible for the base to adopt an exo
conformation. The above data clearly suggests that the
triazole base of 6 has ꢀ orientation.
The anomeric configurations of the monocyclic 4'-aza-
1
D-nucleosides were assigned on the basis of H NMR.
1
For example the H NMR spectrum of 6 indicated a
doublet at ꢀ 6.28 with a J value of 6.04 Hz supporting
the assignment of ꢀ configuration [25] for H1'. Further
the J values for H1ꢁ of 12 were also in agreement with
1
that of its L-isomer [21]. Additionally H NMR spectra
of 7, 12, 13, 14, 15, 21, 23 and 27 indicated the presence
of a mixture of rotational isomers in varying ratios.
However, the ratio of peaks for all the protons in a single
compound was maintained constant. For example, the
1H NMR spectrum of 7 showed singlets at ꢁ 8.69
(0.75H, major rotamer) and 8.95 (0.25H, minor rotamer)
for H5 and doublets at ꢁ 6.03 (J = 6.04, 0.75H, major)
and 6.81 (J = 4.13 Hz, 0.25H, minor) for H1' proton. On
the other hand, H2', H3', H4' and H5' protons appeared as
multiplets accounting for the rotamers. Also, the methyl
protons of 4'-aminoacetyl appeared as singlets at ꢁ 1.87
(0.75H, COCH3, minor), 2.14 (2.25H, COCH3, major).
Interestingly, the silyl protected derivative of deoxy
didehydro thymidine 30 showed very high ratio (99:1) of
Figure 1. ORTEP diagram for 6.
rotamers.
The stereochemical assignments of the
The compounds prepared in this report are yet to be
evaluated for the Type 1 cytokine enhancing activity in
activated human T cells in comparison to ribavirin, the
positive control and the results will be reported elsewhere.
In summary, we have accomplished the synthesis of a
fully protected 4-deoxy-4-(acetamido)-ꢀ-D-ribofuranose
nucleosides were further confirmed by X-ray
crystallographic studies of 6 (Figure 1). The N2 atom of
the base is located 1.3218 Å above the C1-N1-C4 plane
while C9 atom lies 0.8627 Å above the defined plane.
The H1' and H4' are below the plane as indicated by their

Mar-Apr 2006
Synthesis of Some Monocyclic-N-acetyl 4'-Aza-D-nucleosides
329
and the organic layer was separated. The aqueous phase was
extracted with CH2Cl2 (2x100 mL). The combined organic layer
was washed with water (2x150 mL) and brine (400 mL), dried
(Na2SO4) and evaporated to give 8 g intermediate triflate product
as pale yellow gummy solid.
as well as certain selected novel monocyclic D-nucleo-
sides containing the 4-azasugar moiety.
EXPERIMENTAL
The above crude intermediate methyl 4-O-trifluoromethane-
sulfonyl-2,3-O-isopropylidene-ꢂ-L-lyxopyranoside was dis-
solved in 150 mL DMF and then cooled (0 °C). 6.2 g (126.77
mmol) lithium azide was slowly added and stirred at room
temperature for 3 h. The reaction mixture was diluted with 200
mL toluene and evaporated to dryness. The residue was
dissolved in a mixture of 300 mL CH2Cl2 and 200 mL water.
The organic layer was separated and washed with water (2x250
mL) and brine (300 mL), dried (Na2SO4) and evaporated to
obtain an oily residue which on purification by silica gel flash
chromatography (hexane/ethyl acetate) afforded 4.44 g, (78%
Melting points were measured on a Haake Büchler capillary
melting point apparatus and are uncorrected. Nuclear magnetic
resonance (1H NMR & 13C) spectra were recorded on Varian
mercury 300 MHz and Bruker DRX 500 MHz spectrometer. The
chemical shifts are expressed in ꢀ values (ppm) relative to
tetramethylsilane as internal standard. IR spectra were recorded
using a MIDAC Grams/380 Prospect FT-IR spectrometer.
Elemental analyses were performed by Quantitative
technologies Inc., Whitehouse, NJ. Thin layer chromatography
(tlc) was performed on plates of silica gel 60F254 coated on
aluminum sheets (5x10 cm; EM Science) using different
solvents prepared freshly. ICN silica gel 18-32 (60 Å) was used
for flash column chromatography. All solvents used were
reagent grade. Most of the dry solvents were purchased from
Fluka and used as such without further purification. Most of the
reactions were conducted under argon atmosphere. Evaporations
were carried out under reduced pressure with the bath
temperature below 35 °C.
1
overall yield for both the steps) pure azido product 3. H NMR
(300 MHz, CDCl3): ꢀ 1.35 (s, 3H, CH3), 1.53 (s, 3H, CH3), 3.42
(s, 3H, OCH3), 3.6-3.8 (m, 3H), 4.01 (dd, 1H, J = 6.30 & 3.90
Hz), 4.45 – 4.52 (m, 2H).
Anal. Calcd. for C9H15N3O4: C, 47.15; H, 6.59; N, 18.33.
Found: C, 47.19; H, 6.50; N, 18.29.
Methyl 4-Deoxy-4-acetamido-2,3-O-isopropylidene-ꢂ-D-ribo-
pyranoside (4).
Methyl 2, 3-O-Isopropylidene-ꢁ-L-lyxopyranoside (2).
To 6.5 g (28.38 mmol) of methyl 4-deoxy-4-azido-2,3-O-
isopropylidene-ꢂ-D-ribopyranoside (3) in 40.0 mL MeOH was
added 0.65 g Pd/C (5% w/w) and the reaction mixture was
hydrogenated under H2 atmosphere (50 psi) for 1 h. The reaction
mixture was filtered over celite bed and evaporated to dryness.
The residue was co-evaporated with toluene (2x50 mL) and
followed by pyridine (2x25 mL). The residue was then carried
forward to the next reaction without further purification.
To a methanolic HCl solution (0.5% w/v), prepared in situ by
the reaction of 6 mL of acetyl chloride (84.44 mmol) with 600
mL MeOH (Fisher HPLC grade), was added 118 g (786.66
mmol) of L-lyxose (1) and the mixture was refluxed for 5 h
under N2 atmosphere. The reaction mixture was neutralized with
100 g amberlite basic resin IRA-410 under stirring. The resin
was filtered and washed with methanol (3x125 mL). The filtrate
and the washings were combined and evaporated to give
colorless syrup which was recrystallized from 500 mL ethyl
acetate to obtain white crystalline methyl glycoside 87 g (67%
total from both 1st and 2nd crops).
Methyl ꢂ-L-lyxopyranoside (69 g, 420 mmol) suspended in
200 mL anhydrous acetone was treated with 200 mL 2,2-
dimethoxy propane followed by the addition of 4 mL of 4 M
solution of HCl in dioxane and the stirring was continued at 25
°C for 16 h. The reaction was quenched with 500 mg solid
sodium bicarbonate and filtered. The filtrate was evaporated and
the oily residue (pinkish) was purified by silica gel flash
chromatography (CH2Cl2/ethyl acetate) to obtain 80 g (93.2%)
product 2.
To the above crude product in 150 mL CH2Cl2, 50 mg (0.36
mmol) DMAP and 13.70 mL (170.28 mmol) pyridine were
added and cooled (0 °C). To the cold solution was added 13.4
mL (142.04 mmol) acetic anhydride at 0-5 °C and the reaction
mixture was stirred for 16 h at room temperature. The reaction
mixture quenched with the addition of 10 mL MeOH and the
volatiles were evaporated. The residue was dissolved in 250 mL
CH2Cl2 and washed with water (2x100 mL) and brine (200 mL),
dried (Na2SO4) and evaporated. The residue was purified by
flash silica gel chromatography (hexane/ethyl acetate) to obtain
1
6.2 g (89.39% overall yield for both the steps) product 4. H
NMR (300 MHz, CDCl3): ꢀ 1.31 (s, 3H, CH3), 1.48 (s, 3H,
CH3), 1.97 (s, 3H, COCH3), 3.35 (t, J = 10.65, 1H), 3.42 (s, 3H,
OCH3), 3.80 (dd, 1H, J = 10.44 & 5.77 Hz), 3.98 (dd, 1H, J =
6.04 & 4.67 Hz), 4.35 (dd, 1H, J = 6.04 & 4.12 Hz), 4.39 (d, 1H,
J = 4.4 Hz), 4.49 (m, 1H), 5.79 (bd, 1H, J = 8.52 Hz).
Anal. Calcd. for C11H19NO5: C, 53.86; H, 7.81; N, 5.71.
Found: C, 53.78; H, 7.80; N, 5.67.
Anal. Calcd. for C9H16O5: C, 52.93; H, 7.89. Found: C, 52.70;
H, 7.82.
Methyl 4-Deoxy-4-azido-2,3-O-isopropylidene-ꢂ-D-riboparano-
side (3).
Pyridine (3.2 mL, 39.85 mmol) and 50 mg (0.35 mmol) 4-
(dimethylamino)pyridine in 300 mL anhydrous CH2Cl2 was
treated slowly with 5.36 mL (32.5 mmol) trifluoromethane-
sulfonic anhydride at –20 °C under argon atmosphere. The
reaction mixture was allowed to stir at –20 °C for 5 min. 5.1 g
(25 mmol) of methyl 2,3-O-isopropylidene-ꢁ-L-lyxopyranoside
in 100 mL CH2Cl2 was then added and the stirring was
continued at –20 °C for additional 15 min. The tlc (15% ethyl
acetate/hexane) indicated completion of the reaction. The
reaction mixture was poured into 250 mL mixture of ice-water
1,2,3,5-Tetra-O-acetyl-4-deoxy-4-(acetamido)-ꢂ-D-ribofuranose
(5).
Methyl 4-deoxy-4-acetamido-2,3-O-isopropylidene-ꢂ-D-ribo-
pyranoside (4) (5.0 g, 20.40 mmol) was dissolved in 50 mL
mixture (1:1) of distilled water and AcOH and was heated at 70-
75 °C for 1.5 h. Absolute EtOH (2x50 mL) was added and co-
evaporated to give dry solid residue. The solid was treated with
50 mL mixture (1:1) of glacial acetic acid and acetic anhydride
and cooled (0 °C) and treated with 1 mL conc. H2SO4. The

330
C. V. N. S. Varaprasad, K. S. Ramasamy, Z. Hong
Vol 43
reaction mixture was stirred at 0 °C for 30 min and then kept at
4 °C for 2 days. 10 g anhydrous NaOAc was added and stirred
at room temperature for 30 min. The reaction mixture was then
poured into 400 mL ice-water mixture and extracted with
CH2Cl2 (2x150 mL). The combined organic layer was washed
with water (2x200 mL) and brine (200 mL), dried (Na2SO4)
and evaporated. The crude product was purified by flash silica
gel chromatography (hexane/ethyl acetate) to obtain 3.71 g
(50.82%) 5. 1H NMR (300 MHz, CDCl3): ꢀ 2.0-2.16 (m, 15H,
5xCOCH3), 4.18-4.51 (m, 3H), 5.33-5.36 (m, 1H), 5.45-5.55 (m,
1H), 6.36 (s, 0.75H, H1'), 6.55 (d, 0.25H, J = 5.22 Hz, H1ꢀ);
Anal. Calcd. for C15H21NO9: C, 50.13; H, 5.89; N, 3.89.
Found: C, 50.06; H, 5.61; N, 3.67.
(maj.)}, 8.95 {s, 0.25H, H5, minor rotamer (min.)}. ES-MS: m/z
286 (M+1)+.
1-{(3,5-O- (1,1,3,3-Tetraisopropyl-1,3-disiloxanediyl)-4-deoxy-
4-acetamido-ꢁ-D-ribofuranosyl}-1,2,4-triazole-3-carboxamide
(8).
1-(4-Deoxy-4-acetamido-ꢁ-D-ribofuranosyl)-1,2,4-triazole-3-
carboxamide (7) (0.7 g, 2.45 mmol) was suspended in 15 mL
pyridine and treated with 1.06 mL (3.31 mmol, 1.35 eq) 1,3-
dichloro-1,1,3,3-tetraisopropyl-disiloxane and stirred at room
temperature for 16 h. The reaction mixture was carefully
quenched with 5 mL aq. saturated NaHCO3 solution and then it
was diluted with 100 mL CH2Cl2. The organic layer was
separated and the aqueous layer was extracted with CH2Cl2
(2x25 mL). The combined organic layer was washed with water
(2x100 mL) and brine (100 mL), dried (Na2SO4) and evaporated.
The crude residue obtained so was purified by flash silica gel
chromatography (CHCl3/MeOH) to afford 0.7 g (54%) product
7. 1H NMR (300 MHz, CDCl3): ꢁ 0.94-1.18 (m, 24H, 4 x
(CH3)2CHSi), 1.38 (m, 4H, 4 x (CH3)2CHSi), 2.02 {s, 0.9H,
COCH3, minor rotamer (min)}, 2.15 {s, 2.1H, COCH3, major
rotamer (maj)}, 3.33 (br s, 1H, OH, D2O exchangeable), 3.82
{m, 0.7H, H4ꢀ, (maj)}, 3.98-4.13 (m, 2.3 H, 2 x H5ꢀ & 0.3H, H4',
min), 4.32 (d, J = 3.85 Hz, 0.3H, H2ꢀ, min), 4.42 (d, J = 4.67 Hz,
0.7H, H2ꢀ, maj), 4.52 (m), 4.65 (dd, J = 8.25 & 4.12 Hz, min),
5.29 (t, J = 4.95 Hz, 0.7H, H3ꢀ, maj), 5.80 (br s, 0.7H, NH, maj.,
D2O exchangeable), 5.94 (br s, 0.3 H, NH, min., D2O
exchangeable), 5.99 (s, 0.3H, H1ꢀ, min), 6.40 (s, 0.7H, H1ꢀ, maj),
6.91 (br s, 0.7H, NH, maj., D2O exchangeable), 7.01 (br s, 0.3 H,
NH, min., D2O exchangeable), 8.38 (s, 0.7H, H5, maj), 8.53 (s,
0.3H, H5, min). ES-MS: m/z 528 (M+1)+.
Methyl-1-(2,3,5-triacetyl-4-deoxy-4-acetamido-ꢁ-D-ribofurano-
syl)-1,2,4-triazole-3-carboxylate (6).
Methyl-1, 2, 4-triazole-3-carboxylate (1.77 g, 13.97 mmol,
1.14 eq) and 177 mg ammonium sulphate were suspended in 40
mL hexamethyldisilazane and the mixture was refluxed for 2.5 h
under N2 atmosphere. The volatiles evaporated and the residue
was resuspended in 50 mL 1,2-dichloroethane. It was then
treated with 4.4 g (12.25 mmol) 1,2,3,5-tetra-O-acetyl-4-deoxy-
4-(acetamido)-ꢁ-D-ribofuranose (5) in 50 mL of 1,2-dichloro-
ethane. The reaction mixture was then treated with 1.63 mL
(13.97 mmol, 1.14 eq) fuming SnCl4 at 0-5 °C. The reaction
mixture was stirred at room temperature for 1 h. The reaction
mixture was carefully quenched with aq. saturated solution of
NaHCO3 (50 mL) and then it was diluted with CH2Cl2 (200 mL).
The mixture was filtered over 5 g celite bed. The organic layer
of the filtrate was separated and the aqueous layer was extracted
with CH2Cl2 (2x 100 mL). The combined organic layer was
washed with water (2x300 mL) and brine (500 mL), dried
(Na2SO4) and evaporated. The crude residue obtained so was
recrystallized from 40 mL ethyl acetate to obtain 2.7 g, (51.71%)
1-{2-O-(p-Tolylthionoformyl)-3,5-O-(1,1,3,3-tetraisopropyl-1,3-
disiloxanediyl)-4-deoxy-4-acetamido-ꢁ-D-ribofuranosyl}-1,2,4-
triazole-3-carboxamide (9).
1
pure title product 6. H NMR (300 MHz, CDCl3): ꢀ 2.03-2.16
(m, 12H, 4xCOCH3), 3.95 (s, 3H, OCH3), 4.21 (m, 1H, H4'), 4.43
(m, 2H, H5'), 5.65 (dd, J = 4.67 & 1.1 Hz, 1H, H3'), 6.17 (t, 1H, J
= 6.04 & 4.67 Hz, H2'), 6.28 (d, 1H, J = 6.04 Hz, H1'), 8.47 (s,
1H, H5).
Anal. Calcd. for (C17H22N4O9): C, 47.89; H, 5.20; N, 13.14.
Found: C, 47.81; H, 5.19; N, 13.10.
1-{(3,5-O-(1,1,3,3-Tetraisopropyl-1,3-disiloxanediyl)-4-deoxy-4-
acetamido-ꢁ-D-ribofuranosyl}-1,2,4-triazole-3-carboxamide (8)
(0.6 g, 1.138 mmol) was dissolved in 10 mL mixture (9:1) of
CH2Cl2 and pyridine. 0.219 mL (1.42 m mol, 1.25 eq) O-(p-
tolyl)thionochloroformate was added and the reaction mixture
was stirred at room temperature for 16 h. The reaction mixture
was quenched with 5 mL aq. saturated NaHCO3 solution and
then it was diluted with 100 mL CH2Cl2. The organic layer was
separated and the aqueous layer was extracted with CH2Cl2
(2x25 mL). The combined organic layer was washed with water
(2x100 mL) and brine (100 mL), dried (Na2SO4) and evaporated.
The crude residue obtained so was purified over flash silica gel
chromatography (CHCl3/ethyl acetate) to afford 0.35 g (45%)
1-(4-Deoxy-4-acetamido-ꢁ-D-ribofuranosyl)-1,2,4-triazole-3-
carboxamide (7).
Methyl-1-(2,3,5-triacetyl-4-deoxy-4-acetamido-ꢁ-D-ribofurano-
syl)-1,2,4-triazole-3-carboxylate (6) (2.7 g, 6.33 mmol) in 100
mL saturated methanolic ammonia was stirred at room
temperature for 16 h. The volatiles were evaporated and the
residue obtained was purified by flash alumina chromatography
(eluant: decantant of the solvent mixture ethyl acetate/n-propyl
alcohol/water: 64/4/32 to 57/14/29 %) to afford 1.7 g title
product 7. The product was wet with some (~5%) ethyl alcohol
and also contaminated with acetamide. All our attempts to purify
1
product 9. H NMR (300 MHz, CDCl3): ꢁ 0.92-1.15 (m, 24H, 4
x (CH3)2CHSi), 1.30 (m, 4H, 4 x (CH3)2CHSi), 2.01 {s, 0.9H,
COCH3, minor rotamer (min)}, 2.19 {s, 2.1H, COCH3, major
rotamer (maj)}, 2.35 (s, 3H, ArCH3), 3.92 {m, 0.7H, H4ꢀ, (maj)},
4.05 (m, 2 H, 1.7 x H5ꢀ & 0.3H, H4ꢀ, min), 4.70 (m), 4.81 (m),
5.50 (t, J = 5.22 & 6.05 Hz, 1H, H3ꢀ), 5.75 (br s, 0.7H, NH, maj.,
D2O exchangeable), 5.89 (br s, 0.3 H, NH, min., D2O
exchangeable), 6.10 (d, J = 4.67 Hz, 1H, H2ꢀ ), 6.12 (s, 0.3H, H1ꢀ,
min), 6.54 (s, 0.7H, H1ꢀ, maj), 6.87 (br s, 0.7H, NH, maj., D2O
exchangeable), 6.96 (br d, J = 8.24 Hz, 2.3H, 2H of aromatic
ring & 0.3H NH, min., D2O exchangeable), 7.21 (d, J = 8.24 Hz,
2H of aromatic ring), 8.41 (s, 0.7H, H5, maj), 8.69 (s, 0.3H, H5,
min). ES-MS: m/z 678 (M+1)+.
1
the product free of acetamide have summarily been failed. H
NMR (300 MHz, CD3OD): ꢁ 1.87 {s, 0.86, CH3 (Ac), min.},
2.14 {s, 2.14 H, CH3 (Ac), maj.}, 3.87 (d, J = 6.59 Hz, 2H x
H5'), 4.01-4.10 (m, 1H, H4'), 4.26 (d, J = 4.12 Hz, 0.75 H, H3',
maj.), 4.31 (t, J = 3.8 Hz, 0.25 H, H3', min.), 4.54 (t, J = 4.1 Hz,
0.25 H, H2' min.), 4.85 (dd, J = 4.4 & 6.05 Hz, 0.75 H, H2'',
maj.), 6.03 (d, J = 6.04 Hz, 0.75 H, H1', maj.), 6.81 (d, J = 4.13
Hz, 0.25 H, H1' min.), 8.69 {s, 0.75 H, H5, major rotamer

Mar-Apr 2006
Synthesis of Some Monocyclic-N-acetyl 4'-Aza-D-nucleosides
331
1-{(3,5-O-(1,1,3,3-Tetraisopropyl-1,3-disiloxanediyl)-2,4-dideoxy-
4-acetamido-ꢀ-D-ribofuranosyl}-1,2,4-triazole-3-carboxamide
(10).
of the filtrate was separated and the aqueous layer was extracted
with CH2Cl2 (2x100 mL). The combined organic extract was
washed with water (2x300 mL) and brine (500 mL), dried
(Na2SO4) and evaporated. The residue was purified by flash
silica gel chromatography (CHCl3/acetone) to give 5.35 g
(90.0%) pure titled product ꢀ-isomer 12a and 0.38 g (6.47%) ꢂ-
1-{2-O-(p-Tolylthionoformyl)- 3,5-O- (1,1,3,3-tetraisopropyl-
1,3-disiloxanediyl)-4-deoxy-4-acetamido-ꢀ-D-ribofuranosyl}-1,2,4-
triazole-3-carboxamide (0.35 g, 0.516 mmol) (9) was dissolved
in 20 mL toluene and was purged with argon for 20 min. and
1
isomer 12b. H NMR (300 MHz, CDCl3) of ꢀ-isomer: ꢃ 1.88-
2.19 (m, 15H, 4xCOCH3 & CH3), 4.07 (m, 0.5H, H4'), 4.36-4.55
then treated with 0.084
g (0.516 mmol) 2,2'-azobisiso-
(m, 2.5H, H4' & H5'), 5.30 (m, 0.5H, H3'), 5.47 (m, 1.5H, H2'
&
butyronitrile (AIBN) and 0.274 ml (1.03 mmol, 2 eq) tributyltin
hydride. The reaction mixture was refluxed for 3 h under a
stream of argon. The volatiles evaporated and the crude residue
obtained so was purified by flash silica gel chromatography
H3'), 6.15 (br t, J = 6.05 & 5.77 Hz, 0.5H, H1'), 6.37 (d, 0.5H, J =
6.59 Hz, H1'), 7.16 (s, 0.5H, C6H), 7.42 (s, 0.5H, C6H), 9.13 (s,
0.5H, NH, D2O exchangeable ), 9.32 (s, 0.5H, NH, D2O
exchangeable). IR (KBr) ꢂmax 3350, 2970, 1700, 1412, 1236
1
(CHCl3/ethyl acetate) to afford 0.23 g (87 %) product 10. H
1
cm-1. ES-MS: m/z 426 (M+1)+. H NMR (300 MHz, CDCl3) of
NMR (300 MHz, CDCl3): ꢀ 0.94-1.18 (m, 24H, 4 x (CH3)2-
CHSi), 1.26 (m, 4H, 4 x (CH3)2CHSi), 2.00 {s, 0.75H, COCH3,
minor rotamer (min)}, 2.13 {s, 2.25H, COCH3, major rotamer
(maj)}, 2.42 (m, 1H, H2ꢁ), 2.54 (m, 0.25H, H2ꢁ, min.), 2.85 (dd, J
= 13.5 & 7.5 Hz, 0.75H, H2ꢁ, maj ), 3.78 {m, 1H, H4ꢁ), 3.88 (m,
2H, 2 x H5ꢁ), 4.50 (m), 4.67 (m), 5.30 (m, 1H, H3ꢁ), 5.88 (br s,
0.75H, NH, maj., D2O exchangeable), 6.01 (br s, 0.25 H, NH,
min., D2O exchangeable), 6.14 (d, J = 6.0 Hz, 0.25H, H1ꢁ, min),
6.40 (d, J = 7.8 Hz, 0.75H, H1ꢁ, maj), 6.89 (br s, 0.75H, NH,
maj., D2O exchangeable), 7.03 (br s, 0.25 H, NH, min., D2O
exchangeable), 8.35 (s, 0.75H, H5, maj), 8.55 (s, 0.25H, H5,
min). ES-MS: m/z 511 (M+1)+.
ꢂ-isomer: ꢃ 1.87-2.17 (m, 15H, 4xCOCH3 & C5CH3), 4.25 (m,
1H, H4'), 4.49-4.58 (m, 2H, H5'), 5.15 (d, J = 9.9 Hz, 0.55H, H3'),
5.17 (d, J = 10.5 Hz, 0.45H, H3'), 5.40 (d, J = 5.1 Hz, 0.45H,
H2'), 5.79 (dd, J = 5.1 & 7.2 Hz, 0.55H, H2'), 6.22 (s, 0.45H,
H1'), 6.47 (d, J = 7.2 Hz, 0.55H, H1') 7.07 (d, J = 1.2 Hz, 0.55H,
C6H), 7.15 (d, J = 1.2 Hz, 0.45H, C6H), 9.04 (s, 0.55H, NH),
9.21 (s, 0.45H, NH). IR (KBr) ꢂmax 3354, 2968, 1702, 1410,
1240 cm-1. ES-MS: m/z 426 (M+1)+.
1-(2,3,5-Tri-O-acetyl-4-deoxy-4-acetamido-ꢀ-D-ribofuranosyl)-
6-azauracil (13).
A suspension of 1.13 g (10.0 mmol) 6-azauracil and 113 mg
ammonium sulphate in 25 mL hexamethyldisilazane was
refluxed for 1 h under N2 atmosphere. The reaction mixture was
evaporated to dryness and the residue was resuspended in 25 mL
1,2-dichloroethane. To this stirred solution was added a solution
of 2.51 g (7 mmol) 1,2,3,5-tetra-O-acetyl-4-deoxy-4-(aceta-
mido)-ꢀ-D-ribofuranose (5) in 25 mL 1,2-dichloroethane
followed by the addition of 1.17 mL (10.0 mmol) fuming SnCl4
at 0°C. After the addition of 1,2,3,5-tetra-O-acetyl-4-deoxy-4-
(acetamido)-ꢀ-D-ribofuranose (5) the reaction mixture was
stirred at room temperature for 1 h. The reaction was carefully
quenched with 50 mL aq. saturated NaHCO3 solution and
diluted with CH2Cl2 (200 mL). The mixture was filtered through
5 g celite and washed with CH2Cl2 (100 mL). The organic layer
of the filtrate was separated and the aqueous layer was extracted
with CH2Cl2 (2x 100 mL). The combined organic extract was
washed with water (2x300 mL) and brine (500 mL), dried
(Na2SO4) and evaporated. The crude residue was purified by
flash silica gel chromatography (hexane/ethyl acetate) to obtain
1.43 g (49.58%) title product 13 (ꢀ-isomer) and 0.8 g (27.74%)
ꢂ-isomer. 1H NMR (300 MHz, CDCl3) of ꢀ-isomer: ꢃ 2.01-2.14
(m, 15H), 4.11-4.48 (m, 3H, H4' & 2 x H5'), 5.45 (d, J = 4.5 Hz,
0.55H, H3'), 5.49 (d, J = 5.1 Hz, 0.45H, H3'), 5.57 (t, J = 5.1 Hz,
0.35H, H2'), 5.63 (dd, J = 6.9 & 4.5 Hz, 0.65H, H2'), 6.41 (d, J =
4.8 Hz, 0.35H, H1'), 6.52 (d, J = 7.2 Hz, 0.65H, H1'), 7.23 (s,
0.35H, C5H), 7.38 (s, 0.65H, C5H), 9.59 (bs, 1H, NH, D2O
exchangeable). IR (KBr) ꢂmax 3210, 2983, 1678, 1336, 1017
1-(2,4-Dideoxy-4-acetamido-ꢀ-D-ribofuranosyl)-1,2,4-triazole-
3-carboxamide (11).
1-{(3,5-O-(1,1,3,3-Tetraisopropyl-1,3-disiloxanediyl)-2, 4-dideoxy-
4-acetamido-ꢀ-D-ribofuranosyl}-1,2,4-triazole-3-carboxamide (10)
(0.23 g, 0.45 mmol) was dissolved in 5 mL CH2Cl2 and treated
with 0.29 mL (1.79 mmol, 4 eq) triethylamine trishydrofluoride
at room temperature. The reaction mixture was stirred for 48 h at
room temperature. The volatiles were removed and the residue
was purified by flash silica gel chromatography (CHCl3/MeOH
eluents) to afford 0.08 g (66%) product 11. 1H NMR (300 MHz,
CD3OD): ꢀ 1.95 {s, 0.36, CH3 (Ac), min.}, 2.16{s, 2.64 H, CH3
(Ac), maj.}, 2.51(m, 1H, H2ꢁ), 2.87 (m, 1H, Hꢁ'), 3.82 (m, 2H, 1x
H5ꢁ & H4ꢁ), 3.99 (t, J = 6.87 Hz, 1H, H5ꢁ ), 4.44 (d, J = 4.12 Hz,
H3ꢁ), 6.54 (t, J = 7.69 Hz, H1ꢁ), 8.63 {s, 0.88H, H5, major rotamer
(maj.)}, 8.88 {s, 0.12H, H5, minor rotamer (min.)}.
Anal. Calcd. for C11H16N4O5: C, 46.48; H, 5.67; N, 19.71.
Found: C, 46.55; H, 5.72; N, 19.52.
1-(2, 3, 5-Tri-O-acetyl-4-deoxy-4-acetamido-ꢀ-D-ribofuranosyl)-
thymine (12a) and 1-(2, 3, 5-Tri-O-acetyl-4-deoxy-4-acetamido-
ꢂ-D-ribofuranosyl)thymine (12b).
Thymine (2.52 g, 20.0 mmol) and 250 mg ammonium
sulphate were suspended in 50 mL hexamethyldisilazane and
then heated at reflux for 3 h under N2 atmosphere. The reaction
mixture was evaporated to dryness and the residue was
resuspended in 50 mL of 1,2-dichloroethane and cooled to 0 °C
in an ice bath. 5.026 g (14.0 mmol) 1,2,3,5-tetra-O-acetyl-4-
deoxy-4-(acetamido)-ꢀ-D-ribofuranose (5) in 50 mL 1,2-
dichloroethane was added followed by the addition of 2.34 mL
(20.0 mmol) fuming SnCl4 at 0°C. The reaction mixture was
stirred at room temperature for 1 h. The reaction was carefully
quenched with 50 mL aq. saturated NaHCO3 solution and
diluted with CH2Cl2 (200 mL). The mixture was filtered over 5 g
celite bed and washed with CH2Cl2 (100 mL). The organic layer
1
cm-1. ES-MS: m/z 413 (M+1)+. H NMR (300 MHz, CDCl3) of
ꢂ-isomer: ꢃ 1.96-2.18 (m, 15H), 4.15 (m, 2H, 2 x H5'), 4.49 (m,
0.5H, H4'), 4.59 (dd, J = 3.6 & 3.0 Hz, 0.5H, H4'), 5.25 (d, J = 5.7
Hz, 0.75H, H3'), 5.32 (d, J = 5.4 Hz, 0.25H, H3'), 5.65 (t, J = 6.9
& 5.7 Hz, 0.25H, H2'), 5.72 (t, J = 6.3 & 6.0 Hz, 0.75H, H2'),
6.49 (d, J = 6.3 Hz, 0.75H, H1'), 6.60 (d, J = 6.9 Hz, 0.25H, H1'),
7.24 (s, 0.65H, C5H), 7.32 (s, 0.35H, C5H), 9.85 (bs, 1H, NH,
D2O exchangeable). ES-MS: m/z 413 (M+1)+.

332
C. V. N. S. Varaprasad, K. S. Ramasamy, Z. Hong
Vol 43
Methyl 1-(2,3,5-Tri-O-acetyl-4-deoxy-4-acetamido-ꢀ -D-ribo-
furanosyl)uracil-6-carboxylate (14).
H3'), 5.74 (dd, 0.20H, J = 7.69 & 5.22 Hz, H2'), 5.82 (dd, 0.80H,
J = 7.15 & 5.22 Hz, H2'), 6.47 (dd, 0.80H, J = 7.15 & 1.38 Hz,
H1'), 6.52 (dd, 0.20H, J = 8.24 & 1.2 Hz, H1'), 7.40 (dd, 0.20H, J
= 9.62 & 6.32 Hz, C6H), 7.51 (d, 0.80H, J = 6.33 Hz, C6H), 9.28
(d, 0.80H, J = 4.8 Hz, NH), 9.34 (d, 0.20H, J = 4.8 Hz, NH). IR
(KBr) ꢀmax 3408, 3060, 1710, 1394, 1240, 1082 cm-1. ES-MS:
m/z 430 (M+1)+.
6-Carbomethoxyuracil (1.7 g, 10.00 mmol) and 170 mg
ammonium sulphate were suspended in 30 mL hexamethyl-
disilazane and was refluxed for 1 h under N2 atmosphere. The
volatiles were evaporated and the residue was resuspended in
1,2-dichloroethane (25 mL). To this was added 2.51 g (7.00
mmol) 1,2,3,5-tetra-O-acetyl-4-deoxy-4-(acetamido)-ꢀ-D-ribo-
furanose (5) in 50 mL 1,2-dichloroethane and was followed by
the addition of 1.17 mL, (10.00 mmol) fuming SnCl4 at 0 °C.
The reaction mixture was stirred at room temperature for 16 h,
carefully quenched with 50 mL aq. saturated NaHCO3 solution
and diluted with CH2Cl2 (200 mL). The mixture was filtered
over 5 g celite bed. The organic layer of the filtrate was
separated and the aqueous layer was extracted with CH2Cl2
(2x100 mL). The combined organic extract was washed with
water (2x300 mL) and brine (500 mL), dried (Na2SO4) and
evaporated. The crude residue was purified by flash
chromatography over silica gel (hexane/ethyl acetate) to obtain
2.2 g (67%) pure titled product 14; IR (KBr) ꢀmax 3204, 2983,
1764, 1372, 1217 cm-1; 1H NMR (300 MHz, CDCl3): ꢁ 1.99-2.13
(m, 12H), 3.90 (s, 0.75H, OCH3), 3.92 (s, 2.25H, OCH3), 3.96-
4.06 (m, 1H, H5'), 4.46-4.58 (m, 2H, H4' & H5'), 5.43 (d, 0.2H, J
= 5.7 Hz, H3'), 5.48 (d, 0.8H, J = 4.50 Hz, H3'), 6.13 (m, 0.2H,
H2'), 6.21 (dd, 0.8H, J = 5.10 & 8.40 Hz, H2'), 6.31 (s, 0.8H,
C5H), 6.37 (s, 0.2H, C5H), 6.57 (d, 0.2H, J = 6.30 Hz, H1', min),
6.67 (d, 0.8H, J = 8.40 Hz, H1', maj), 8.33 (bs, 0.80H, NH, maj),
8.50 (bs, 0.20H, NH, min). ES-MS: m/z 470 (M+1)+.
1-(2,3,5-Tri-O-acetyl-4-deoxy-4-acetamido-ꢀ-D-ribofuranosyl)-
5-fluorocytosine (16).
A suspension of 1.0 g (7.75 mmol) 5-fluorocytosine and 100
mg ammonium sulphate in 25 mL hexamethyldisilazane was
refluxed for 2 h under N2 atmosphere. The volatiles were
evaporated and the residue was resuspended in 25 mL 1,2-
dichloroethane. To this stirred solution was added a solution of
2.51 g (7 mmol) 1,2,3,5-tetra-O-acetyl-4-deoxy-4-(acetamido)-
ꢀ-D-ribofuranose (5) in 1,2-dichloroethane (25 mL) followed by
the addition of 1.17 mL (10 mmol) fuming SnCl4 at 0 °C. The
reaction mixture was stirred at room temperature for 4 h. The
reaction mixture was carefully quenched with aq. saturated
NaHCO3 solution (50 mL) and diluted with CH2Cl2 (200 mL).
The mixture was filtered over a celite bed (5 g). The organic
layer of the filtrate was separated and the aqueous layer was
extracted with CH2Cl2 (2x100 mL). The combined organic
extract was washed with water (2x300 mL) and brine (500 mL),
dried (Na2SO4) and evaporated. The crude residue was purified
by flash chromatography over silica gel (CHCl3/acetone: 80/20)
to obtain pure product isomers (ꢀ-isomer, 2.38 g, 79.44%; ꢂ-
1
isomer 0.29 g 9.68%); ꢀ-isomer: H NMR (300 MHz, CDCl3) ꢁ
1.97-2.18 (m, 12H), 4.05 (m, 0.25H, H4'), 4.35-4.59 (m, 2.75H,
H4' & H5'), 5.28 (t, J = 4.4Hz, 0.75H, H3'), 5.33 (d, J = 6.32 Hz,
0.25H, H3'), 5.44 (t,, J = 4.67 Hz, 0.75H, H2'), 5.54 (d, J = 3.85
Hz, 0.25H, H2'), 5.72 (bs, 0.25H, NH2), 5.95 (bs, 0.75H, NH2),
6.25 (bt, 0.25H, H1'), 6.34 (d, 0.75H, J = 3.57 Hz, H1'), 7.47 (d,
0.25H, J = 5.49 Hz, C6H), 7.93 (d, 0.75H, J = 6.05 Hz, C6H),
8.36 (bs, 1H, NH2): IR (KBr) ꢀmax 3346, 3098, 1766, 1511, 1209
1-(2,3,5-Tri-O-acetyl-4-deoxy-4-acetamido-ꢀ-D-ribofuranosyl)-
5-fluorouracil (15).
A suspension of 1.3 g (10 mmol) 5-fluorouracil and 130 mg
ammonium sulphate in 25 mL hexamethyldisilazane was
refluxed for 2 h under N2 atmosphere. The reaction mixture was
evaporated to dryness and the residue was resuspended in 50 mL
1,2-dichloroethane. The solution was then treated with a solution
of 2.51 g (7 mmol) 1,2,3,5-tetra-O-acetyl-4-deoxy-4-(aceta-
mido)-ꢀ-D-ribofuranose (5) in 50 mL 1,2-dichloroethane
followed by the addition of 1.17 mL (10 mmol) fuming SnCl4 at
0 °C. The reaction mixture was stirred at room temperature for 3
h and carefully quenched with 50 mL aq. saturated NaHCO3
solution and diluted with CH2Cl2 (200 mL). The mixture was
filtered over 5 g celite bed and washed with CH2Cl2 (100 mL).
The organic layer of the filtrate was separated and the aqueous
layer was extracted with CH2Cl2 (2x100 mL). The combined
organic extract was washed with water (2x300 mL) and brine
(500 mL), dried (Na2SO4) and evaporated. The crude residue
was purified by flash chromatography over silica gel
(CHCl3/acetone: 80/20) to provide pure anomeric isomers of title
product 15 (ꢀ-isomer, 2.35 g, 78.25%; ꢂ-isomer 0.4 g 13.32%).
1H NMR (300 MHz, CDCl3) of ꢀ-isomer: ꢁ 2.03-2.22 (m, 12H),
4.10 (m, 0.45H, H4', min), 4.48 (m, 2.55H, H4' & H5'), 5.31 (m,
0.45H, H3'), 5.47-5.55 (m, 1.55H, H2' & H3'), 6.10 (t, 0.45H, J =
5.4 & 5.7 Hz, H1'), 6.29 (d, 0.55H, J = 6.0 Hz, H1'), 7.49 (d,
0.45H, J = 6.05 Hz, C6H), 7.95 (d, 0.55H, J = 5.77 Hz, C6H),
9.37 (bs, 0.45H, NH), 9.54 (bs, 0.55H, NH). IR (KBr) ꢀmax 3400,
3063, 1708, 1394, 1245, 1085 cm-1. ES-MS: m/z 430 (M+1)+. 1H
NMR (300 MHz, CDCl3) of ꢂ-isomer: ꢁ 1.98-2.29 (m, 12H),
4.21-4.33 (m, 1.45H, H4' & H5'), 4.50-4.62 (m, 1.55H, H4' & H5'),
5.40 (d, 0.80H, J = 5.21 Hz, H3'), 5.49 (d, 0.20H, J = 4.94 Hz,
1
cm-1. ES-MS: m/z 429 (M+1)+. H NMR (300 MHz, CDCl3) of
ꢂ-isomer: ꢁ 1.82-2.31 (m, 12H), 4.15 (m, 0.25H, H4'), 4.38 (m,
2H, 2 x H5'), 5.15 (d, J = 17.04 Hz, 0.75H, H3'), 5.40 (d, J = 5.21
Hz, 0.25H, H3'), 5.54 (d, J = 3.85 Hz, 0.25H, H2', min), 5.75 (bs,
0.75H, NH2), 5.82 (dd, J = 7.42 & 5.49 Hz, 1H, H2'), 6.18 (bs,
0.25H, NH2), 6.26 (s, 0.45H, H1'), 6.58 (dd, J = 7.41 & 1.92 Hz,
0.55H, H1'), 7.30 (d, J = 6.32 Hz, 0.45H, C6H), 7.46 (d, J = 6.59
Hz, 0.55H, C6H), 8.04 (bs, 0.45H, NH2, exchangeable), 8.35 (bs,
0.55H, NH2, exchangeable); IR (KBr) ꢀmax 3346, 3098, 1766,
1511, 1209 cm-1. ES-MS: m/z 429 (M+1)+.
1-(4-Deoxy-4-acetamido-ꢀ-D-ribofuranosyl)thymine (17).
A solution of 3.7 g (8.7 mmol) 1-(2, 3, 5-tri-O-acetyl-4-
deoxy-4-acetamido-ꢀ-D-ribofuranosyl)thymine (12a) in 100 mL
saturated methanolic ammonia was stirred at room temperature
in a steel bomb for 16 h. The steel bomb was cooled to 0 °C,
opened and the contents were evaporated to dryness. The residue
was purified by flash silica gel chromatography over silica gel
(CHCl3/MeOH) to afford the titled product 2.28 g (87.78%) 17;
mp 201-203 °C (dec); IR (KBr) ꢀmax 3355, 2962, 2840, 1610,
1415, 1236 cm-1; 1H NMR (300 MHz, CD3OD): ꢁ 1.84 (s,
1.35H, C5CH3), 1.85 (s, 1.65H, C5CH3), 1.94 (s, 1.65H, COCH3),
2.13 (s, 1.35H, COCH3), 3.75-4.18 (m, 4H, H3', H4' & 2 x H5'),
4.36 (t, 0.55H, J = 4.8 Hz, H2', maj), 4.56 (dd, 0.45H, J = 4.2 &
6.6 Hz, H2', min), 5.87 (d, 0.45H, J = 6.9 Hz, H1', min), 6.11 (d,

Mar-Apr 2006
Synthesis of Some Monocyclic-N-acetyl 4'-Aza-D-nucleosides
333
0.55H, J = 5.1 Hz, H1', maj), 7.87 (s, 0.45H, C6H, min), 8.24 (s,
0.55H, C6H, maj).
Anal. Calcd. for C12H17N3O6: C, 48.16; H, 5.73; N, 14.04.
Found: C, 48.23; H, 5.81; N, 14.29.
A solution of 2.25 g (5.25 mmol) 1-(2,3,5-tri-O-acetyl-4-
deoxy-4-acetamido-ꢀ-D-ribofuranosyl)-5-fluorocytosine (16) in
35 mL saturated methanolic ammonia was stirred in a steel
bomb at room temperature for 16 h. The steel bomb was cooled
to 0 °C, opened and evaporated to dryness. The residue was
purified by flash chromatography over silica gel (CHCl3/MeOH)
to afford 1.45 g (91.33%) titled product 21; mp 106-108 °C
1-(4-Deoxy-4-acetamido-ꢀ-D-ribofuranosyl)-6-azauracil (18).
A solution of 1.25 g (3.03 mmol) 1-(2,3,5-tri-O-acetyl-4-
deoxy-4-acetamido-ꢀ-D-ribofuranosyl)-6-azauracil (13) in 30
mL saturated methanolic ammonia was stirred in a steel bomb at
room temperature for 16 h. The steel bomb was cooled to 0 °C,
opened and evaporated to dryness. The residue was purified by
flash chromatography over silica gel (CHCl3/MeOH) to afford
0.65 g (74.90%) titled product 18; mp 225-228 °C (dec); IR
1
(dec); IR (KBr) ꢀmax 3536, 2926, 1684, 1490, 1177 cm-1; H
NMR (300 MHz, CD3OD) ꢁ 1.92 (s, 1.95H, COCH3), 2.17(s,
1.05H, COCH3), 3.75-3.93 (m, 2H, 2xH5'), 4.02-4.07 (m, 0.35H,
H4' ), 4.15-4.20 (m, 1.65H, H4' & H3'), 4.26 (dd, J = 8.76 & 4.2
Hz, 0.8H, H2'), 4.49 (t, J = 4.5 Hz, 0.2H, H2'), 5.76 (d, J = 5.1
Hz, 0.34H, H1', min), 6.12 (dd, 0.66H, J = 1.2 & 3.9 Hz, H1',
maj), 8.19 (d, 0.33H, J = 6.9 Hz, C6H, min), 8.66 (d, J = 6.9 Hz,
0.66H, C6H, maj).
1
(KBr) ꢀmax 3292, 2990, 1725, 1620, 1272 cm-1; H NMR (300
MHz, Me2SO-d6 + D2O): ꢁ 1.82 (s, 1.02H, COCH3), 1.95 (s,
1.98H, COCH3), 3.33-3.55 (m, 2H, H4' & H5'), 3.72 (dd, J = 8.4
& 6.0 Hz, 0.6H, H5'), 3.86 (dd, J = 8.1 & 5.1 Hz, 0.4H, H5'), 4.01
(m, 1H, H3'), 4.25 (m, 1H, H2'), 5.97 (d, J = 7.20 Hz, 0.60H,
H1'), 6.04 (d, J = 6.0 Hz, 0.40H, H1'), 7.43 (s, 0.60H, C5H), 7.51
(s, 0.40H, C5H).
Anal. Calcd. for C11H15FN4O5: C, 43.71; H, 5.00; N, 18.54.
Found: C, 43.77; H, 5.17; N, 18.79.
1-[3,5-O-(1,1,3,3-Tetraisopropyldisiloxane-1,3-diyl)-4-deoxy-4-
acetamido-ꢀ-D-ribofuranosyl]thymine (22a) & 1-[2,3-O-(1,1,3,
3-Tetraisopropyldisiloxane-1,3-diyl)-4-deoxy-4-acetamido-ꢀ-D-
ribofuranosyl]thymine (22b).
Anal. Calcd. for C10H14N4O6: C, 41.96; H, 4.93; N, 19.57.
Found: C, 42.03; H, 5.11; N, 19.64.
A suspension of 1.794 g (6.0 mmol) 1-(4-deoxy-4-acetamido-
ꢀ-D-ribofuranosyl)thymine (17) in 60 mL pyridine was treated
with 2.48 mL (7.5 mmol) 1,3-dichloro-1,1,3,3-tetraisopropyl-
disiloxane and stirred at room temperature for 16 h. The reaction
mixture was carefully quenched with aq. saturated NaHCO3
solution (50 mL) and diluted with CH2Cl2 (100 mL). The
organic layer was separated and the aqueous layer was extracted
with CH2Cl2 (2x25 mL). The combined organic extract was
washed with water (2x100 mL) and brine (100 mL), dried
(Na2SO4) and evaporated. The crude residue was purified by
flash chromatography over silica gel using (hexane/ethyl
acetate) to afford a mixture of inseparable products 22a & 22b
(2.17 g, 66.79%). The mixture was not characterized further and
carried forward for the next reaction without purification.
1-(4-Deoxy-4-acetamido-ꢀ-D-ribofuranosyl)uracil-6-carbox-
amide (19).
A solution of 1.6 g (3.41 mmol) methyl 1-(2,3,5-tri-O-acetyl-
4-deoxy-4-acetamido-ꢀ-D-ribofuranosyl)uracil-6-carboxylate
(14) in 25 mL saturated methanolic ammonia was stirred at
room temperature in a steel bomb for 16 h. The steel bomb was
cooled to 0 °C, opened and evaporated to dryness. The residue
obtained was purified by flash chromatography over silica gel
(CHCl3/MeOH) to afford 0.7 g (62.55%) titled product 19; mp
115-118 °C; IR (KBr) ꢀmax 3310, 2980, 1640, 1412, 1032 cm-1;
1H NMR (300 MHz, CD3OD): ꢁ 1.91 (s, 1.08H, COCH3), 2.07
(s, 1.92H, COCH3), 3.75-3.99 (m, 3H, H4' & 2 x H5'), 4.16 (d, J =
4.5 Hz, 0.72H, H3'), 4.21 (d, J = 4.5 Hz, 0.28H, H3'), 4.96 ( m,
1H, H2'), 6.19 (s, 0.6H, H1'), 6.26 (s, 0.4H, H1', min), 6.48 (d, J =
7.8 Hz, 0.60H, H5), 6.53 (d, J = 6.9 Hz, 0.40H, H5).
1-[2-O-(p-Tolylthionoformyl)-3,5-O-(1,1,3,3-tetraisopropyldi-
siloxane-1,3-diyl)-4-deoxy-4-acetamido-ꢀ-D-ribofuranosyl]-
thymine (23) & 1-[5-O-(p-Tolylthionoformyl)-2, 3-O-(1,1,3,3-
tetraisopropyldisiloxane-1,3-diyl)-4-deoxy-4-acetamido-ꢀ-D-
ribofuranosyl]thymine (24).
Anal. Calcd. for C12H16N4O7: C, 43.90; H, 4.91; N, 17.07.
Found: C, 43.99; H, 5.06; N, 17.21.
1-(4-Deoxy-4-acetamido-ꢀ-D-ribofuranosyl)-5-fluorouracil (20).
To 2.10 g (3.87 mmol) mixture of 1-[3,5-O-(1,1,3,3-tetraiso-
propyldisiloxane-1,3-diyl)-4-deoxy-4-acetamido-ꢀ-D-ribofurano-
syl]thymine (22a) & 1-[2,3-O-(1,1,3,3-tetraisopropyldisiloxane-
1,3-diyl)-4-deoxy-4-acetamido-ꢀ-D-ribofuranosyl]thymine (22b)
in 25 mL pyridine was added 0.83 mL (5.42 mmol) p-tolyl
chlorothionoformate and the reaction mixture was stirred at
room temperature for 16 h under argon atmosphere. The reaction
mixture was quenched with aq. saturated NaHCO3 solution (50
mL) and diluted with CH2Cl2 (100 mL). The organic layer was
separated and the aqueous layer was extracted with CH2Cl2
(2x25 mL). The combined organic extract was washed with
water (2x100 mL) and brine (100 mL), dried (Na2SO4) and
evaporated to dryness. The crude residue was purified by flash
chromatography over silica gel (hexane/ethyl acetate) to afford
0.94 g faster moving product and 0.65 g slower moving product.
The combined yield was 1.59 g (59.32%). The 1H NMR analysis
of the products indicated that the structure of slower product as
A solution of 2.15 g (5.01 mmol) 1-(2,3,5-tri-O-acetyl-4-
deoxy-4-acetamido-ꢀ-D-ribofuranosyl)-5-fluorouracil (15) in 60
mL saturated methanolic ammonia was stirred in a steel bomb at
room temperature for 16 h. The steel bomb was cooled to 0 °C,
opened and evaporated to dryness. The residue was purified by
flash chromatography over silica gel (CHCl3/MeOH) to afford
1.18 g (77.7%) titled product 20; mp 125-127 °C (dec); IR
1
(KBr) ꢀmax 3438, 3080, 2961, 1667, 1392, 1131 cm-1; H NMR
(300 MHz, CD2OD): ꢁ 1.98 {s, 1.65H, COCH3}, 2.14 {s, 1.65H,
COCH3}, 3.75-4.18 (m, 3H, H3', H4' & 2 x H5'), 4.35 (t, J = 4.5 &
5.1 Hz, 0.55H, H2'), 4.5 (dd, J = 4.2 & 6.3 Hz, 0.45H, H2'), 5.94
(d, J = 6.6 Hz, 0.45H, H1'), 6.11 ( dd, J = 1.2 & 4.8 Hz, 0.55H,
H1'), 8.36 (d, J = 6.9 Hz, 0.45H, C6H), 8.69 (d, J = 6.9 Hz,
0.55H, C6H);
Anal. Calcd. for C11H14FN3O6: C, 43.57; H, 4.65; N, 13.86.
Found: C, 43.40; H, 4.71; N, 13.80.
1
23 and the structure of the faster product as 24. H NMR (300
MHz, CDCl3) of 23: ꢁ 0.98-1.06 (m, 24H), 1.92 (s, 3H, CH3),
1-(4-Deoxy-4-acetamido-ꢀ-D-ribofuranosyl)-5-fluorocytosine
(21).

334
C. V. N. S. Varaprasad, K. S. Ramasamy, Z. Hong
Vol 43
2.00 (s, 2H, COCH3), 2.252 (s, 1H, COCH3), 2.35 (s, 3H, CH3),
3.89-4.38 (m, 3H, H5' & H4'), 4.66-4.81 (m, 1.5H, H2' & H3'), 5.3
& 5.67 (bs, 0.5H, H2' & H3'), 6.01 (s, 1H, H1'), 6.95 (d, J = 8.7
Hz, 2H, Ph-H), 7.19 (d, J = 8.4 Hz, 2H, Ph-H), 7.35 (s, 0.24H,
C6H), 7.57 (s, 0.76H, C6H), 8.17 (bs, 0.24H, NH), 8.50 (s,
0.76H, NH). ES-MS: m/z 692 (M+1)+. 1H NMR (300 MHz,
CDCl3) of 24: ꢀ 1.00-1.07 (m, 24H), 1.88 (s, 3H, CH3), 2.02 (s,
2.4H, COCH3), 2.22 (s, 0.6H, COCH3), 2.36 (s, 3H, CH3), 4.17-
4.55 (m, 2H, H4' & H3'), 4.85-5.29 (m, 3H, H2' & 2 x H5'), 6.01
(d, 1H, J = 3.00 Hz, H1'), 6.94 (d, J = 8.4 Hz, 2H, Ph-H), 7.21 (d,
2H, J = 8.4 Hz, Ph-H), 7.78 (s, 1H, C6H), 8.48 (bs, 0.16H, NH,
min), 8.55 (s, 0.84H, NH, maj). ES-MS: m/z 692 (M+1)+.
was evaporated to dryness. The crude residue was purified by
flash chromatography over silica gel (hexane/ethyl acetate) to
give 0.69 g 27 in quantitative yield. 1H NMR (300 MHz,
CDCl3): ꢀ 0.98-1.04 (m, 24H), 1.06-1.16 (m, 2H), 1.22-1.36 (m,
2H). 1.45 (d, 0.99H, J = 6.9 Hz, H5'), 1.51 (d, 2.01H, J = 7.2 Hz,
H5'), 1.89 (s, 1.98H, CH3), 1.92 (s, 1.02H, CH3), 1.93 (s, 1.98H,
COCH3), 2.09 (s, 1.02H, COCH3), 3.86 (m, 0.6H, H4'), 3.98 (m,
0.4H, H4'), 4.09-4.19 (m, 1H, H3'), 4.35 (m, 0.5H, H2'), 5.18 (dd,
J = 6.0 & 3.9 Hz, 0.5H, H2'), 5.30 (d, J = 6.0 Hz, 0.6H, H1'), 5.98
(t, 0.4H, J = 4.2 Hz, H1'), 6.99 (s, 0.44H, C6H), 7.09 (d, J = 0.6
Hz, 0.56H, C6H), 8.56 (bs, 0.66H, NH), 8.69 (bs, 0.34H, NH).
ES-MS: m/z 526 (M+1)+.
1-[3,5-O-(1,1,3,3-Tetraisopropyldisiloxane-1,3-diyl)-2,4-dideoxy-
4-acetamido-ꢁ-D-ribofuranosyl]thymine (25).
1-(4,5-Dideoxy-4-acetamido-ꢁ-D-ribofuranosyl)thymine (28).
A solution of 1-[2,3-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-
diyl)-4,5-dideoxy-4-acetamido-ꢁ-D-ribofuranosyl]thymine (27)
(0.75 g, 1.43 mmol) in 30 mL CH2Cl2 was treated with 0.7 mL
(4.29 mmol) triethylamine trishydrofluoride at room temp-
erature. The reaction mixture was stirred at room temperature
for 20 h and the volatiles were evaporated to dryness. The
residue was purified by flash chromatography over silica gel
(CHCl3/MeOH) to afford 0.385 g (95.23 %) 28. IR (KBr) ꢀmax
3484, 2978, 1728, 1478, 1252 cm-1; 1H NMR (300 MHz,
CD3OD): ꢀ 1.40 (d, 1.36H, J = 6.87 Hz, H5'), 1.48 (d, 1.64H, J
= 6.87 Hz, H5'), 1.87 (s, 1.08H, CH3), 1.91 (s, 1.92H, CH3), 1.91
(s, 1.08H, COCH3), 2.09 (s, 1.92H, COCH3), 3.84-4.00 (m, 1H,
H4'), 4.06 (m, 0.60H, H3'), 4.33 (m, 0.40H, H3'), 4.66 (m, 1H,
H2'), 5.72 (d, J = 6.87 Hz, 0.64H, H1'), 6.08 (d, J = 5.77 Hz,
0.36H, H1'), 7.21 (s, 0.36H, C6H), 7.27 (s, 0.64H, C6H).
A solution of 0.62 g (0.89 mmol) 1-[2-O-(p-tolylthiono-
formyl)-3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-4-
deoxy-4-acetamido-ꢁ-D-ribofuranosyl]thymine (23) in dry
toluene (20 mL) was purged with argon for 20 min. To this
stirred solution was added 0.14 g (0.92 mmol) AIBN followed
by the addition of 0.47 mL (1.78 mmol) tributyltin hydride. The
reaction mixture was refluxed for 5 h under a stream of argon.
The volatiles were evaporated and the crude residue was purified
by flash chromatography over silica gel (hexane/ethyl acetate) to
1
afford 0.35 g (74.3%) the desired product 25. H NMR (300
MHz, CDCl3): ꢀ 0.98-1.08 (m, 24H), 1.92 (s, 3H, CH3), 1.99 (s,
2.25H, COCH3), 2.18 (s, 0.75H, COCH3), 2.2-2.42 (m, 1.5H,
H2'), 2.68 (m, 0.5H, H2'), 3.70 (m, 1H, H5'), 4.04 (m, 0.75H, H5'),
4.35 (m, 0.25H, H5'), 4.64 (m, 1.55H, H3' & H4'), 5.12 (m, 0.45H,
H3'), 5.73 (m, 0.15H, H1'), 6.08 (m, 0.85H, J = 6.3 Hz, H1'), 7.34
(s, 0.15H, C6H), 7.55 (s, 0.85H, C6H,), 8.45 (bs, 0.15H, NH,),
9.07 (s, 0.85H, NH). ES-MS: m/z 526 (M+1)+.
Anal. Calcd. for C12H17N3O5: C, 50.88; H, 6.05; N, 14.83.
Found: C, 50.91; H, 6.23; N, 14.91.
1-(5-O-t-Butyldimethylsilyl-4-deoxy-4-acetamido-ꢁ-D-ribo-
furanosyl)-thymine (29).
1-(2, 4-Dideoxy-4-acetamido-ꢁ-D-ribofuranosyl)thymine (26).
A solution of 0.34 g (0.65 mmol) 1-[3,5-O-(1,1,3,3-tetraiso-
propyldisiloxane-1,3-diyl)-2,4-dideoxy-4-acetamido-ꢁ-D-ribo-
furanosyl]thymine (25) in 15 mL CH2Cl2 was treated with 0.53
mL (3.23 mmol) triethylamine trishydrofluoride at room
temperature. The reaction mixture was stirred for 48 h and
evaporated to dryness. The residue was purified by flash
chromatography over silica gel (CHCl3/MeOH) to give the titled
compound 0.16 g (87.29%) 26; mp 119-121 °C; IR (KBr) ꢀmax
3420, 2828, 1632, 1418, 1127 cm-1; 1H NMR (300 MHz,
CD3OD): ꢀ 1.83 (s, 1.71H, CH3), 1.86 (d, J = 0.6 Hz, 1.29H,
CH3), 1.95 (s, 1.29H, COCH3), 2.19 (s, 1.71H, COCH3), 2.26-
2.44 (m, 2H, 2 x H2'), 3.74-4.06 (m, 3H, H4' & H 5'), 4.31 (d, J =
3.6 Hz, 0.57H, H3'), 4.37 (bs, 0.43H, H3'), 6.27 (t, J = 8.1 Hz,
0.57H, H1'), 6.49 (t, J = 7.5 Hz, 0.43H, H1'), 7.70 (d, J = 1.2 Hz,
0.57H, C6H), 8.18 (d, J = 0.9 Hz, 0.43H, C6H).
A suspension of 2.3 g (1.92 mmol) 1-(4-deoxy-4-acetamido-
ꢁ-D-ribofuranosyl)thymine (17) in 50 mL pyridine was treated
with 1.45 g (9.61 mmol) t-butyldimethylsilyl chloride and stirred
at room temperature for 16 h. The reaction mixture was carefully
quenched with aq. saturated NaHCO3 solution (5 mL) and
diluted with CH2Cl2 (100 mL). The organic layer was separated
and the aqueous layer was extracted with CH2Cl2 (2x25 mL).
The combined organic extract was washed with water (2x100
mL) and brine (100 mL), dried (Na2SO4) and evaporated. The
crude residue was purified by flash silica gel chromatography
1
(CHCl3/MeOH) to obtain 2.22 g (69.87%) title product 29. H
NMR (300 MHz, CDO3D): ꢁ 0.15 (m, 6H, Si(CH3)2), 0.95 (m,
9H, SiC(CH3)3), 1.86 (s, 0.45H, CH3), 1.90 (s, 0.55H, CH3), 1.92
(s, 0.55H, COCH3), 2.13 (s, 0.45H, COCH3), 3.90-4.11 (m, 3H,
H4' 2x H5'), 4.38 (m, 0.5H, H3'), 4.61 (m, 0.5H, H3'), 5.81 (d, J =
7.2 Hz, 0.35H, H1'), 6.15 (d, J = 6.60 Hz, 0.65H, H1'), 7.48 (s,
0.35H, C6H), 7.68 (s, 0.65H, C6H). ES-MS: m/z 414 (M+1)+.
Anal. Calcd. for C12H17N3O5.1/2H2O: C, 49.31; H, 6.21; N,
14.38. Found: C, 49.49; H, 6.43; N, 14.51.
1-[2,3-O-(1,1,3,3-Tetraisopropyldisiloxane-1,3-diyl)-4,5-dideoxy-
4-acetamido-ꢁ-D-ribofuranosyl]thymine (27).
1–(5-O-t-Butyldimethylsilyl-2,3,4-trideoxy-2,3-didehydro–4–
acetamido-ꢁ-D–ribofuranosyl)-thymine (30).
A solution of 0.91 g (1.32 mmol) 1-[5-O-(p-tolylthiono-
formyl)-2,3-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-4-
deoxy-4-acetamido-ꢁ-D-ribofuranosyl]thymine (24) in 25 mL
dry toluene was purged with argon for 20 min. To this stirred
solution was added 0.215 g (1.32 mmol) AIBN and 0.69 mL
(2.63 mmol) tri-n-butyltin hydride. The reaction mixture was
refluxed for 1.5 h under a stream of argon. The reaction mixture
A solution of 2.22 g (5.37 mmol) diol, 1-(5-O-t-butyl-
dimethylsilyl-4-deoxy-4-acetamido-ꢁ-D-ribofuranosyl)-thymine
(29), in 125 ml CH2Cl2 was treated with 0.93 mL (12.09 mmol)
methanesulfonyl chloride in presence of 1.8 ml (13.44 mmol)
triethylamine and stirred at room temperature for 4 h. The
reaction mixture was quenched with aq. saturated NaHCO3
solution (5 mL) and the volatiles were evaporated to dryness.

Mar-Apr 2006
Synthesis of Some Monocyclic-N-acetyl 4'-Aza-D-nucleosides
335
The residue that obtained was suspended in water (50 mL) and
filtered. The solid was washed with water (200 mL) to afford
almost pure intermediate dimesylate product (2.82 g, 92.20%).
The product was dried over P2O5 for 48 h at room temperature
under vacuum before carrying forward to the next reaction.
Lithium triethylborohydride solution (13.0 mL, 13 mmol) in
tetrahydrofuran (1 M) was added to 0.758 g (5.94 mmol)
tellurium powder (200 mesh). The mixture was stirred at room
maj), 2.00-2.16 (m, 3H, H2' & H3'), 2.19 (s, 1.35H, COCH3), 2.34
(m, 0.55H, H2'), 2.40 (m, 0.45H, H2'), 3.68–3.74 (m, 1H, H5'),
3.92 (dd, 0.45H, H4'), 4.08-4.16 (m, 1H, H5'), 4.28 (dd, 0.55H,
H4'), 6.11 (t, 0.45H, H1'), 6.31 (m, 0.55H, H1'), 7.74 (s, 0.45H,
C5H), 8.33 (s, 0.55H, C5H, maj), 11.08 (bs, NH), 11.21 (bs, NH).
Anal. Calcd. for C12H17N3O4: C, 53.92; H, 6.41; N, 15.72.
Found: C, 53.99; H, 6.13; N, 15.49.
temperature until
a pinkish-milky white suspension was
REFERENCES
obtained. To this stirred mixture was added 6 mL solution of the
above mesylate (1.4 g, 2.7 mmol) in anhydrous tetrahydrofuran.
After the addition of mesylate, the stirring was continued at
room temperature for 48 h and filtered over a celite bed. The
filtrate was evaporated and the residue was purified by flash
chromatography over silica gel (CHCl3/ethyl acetate) to afford
[1a] W. E. Aulitzky, C. Huber, C. Peschel, Int. Arch. Allergy
Immunol., 101, 221, (1993); [b] G. Kroemer, F. Hirsch, A. Gonzalez-
Garcia, C. Martinez, Autoimmunity., 24, 25, (1996).
[2] A. K. Simon, E. Seipelt, J. Sieper, Proc. Natl. Acad. Sci.,
USA., 30, 8562, (1994).
[3] T. R. Mosmann, R. L. Coffman, Annu. Rev. Immunol., 7,
145, (1989).
[4] C. Dubey, B. Bellon, P. Druet, Eur. Cytokine, Network, 2,
147, (1991).
1
0.61 g 960%) pure titled product 30. Major rotamer: H NMR
(300 MHz, CDCl3): ꢀ 0.10 (s, 3H, CH3), 0.12 (s, 3H, CH3), 0.92
(s, 9H, tert-butyl), 1.92 (d, 3H, J=1.2 Hz, C5CH3), 2.06 (s, 3H,
COCH3), 4.02-4.07 (dd, 1H, J = 11.10 & 3.15 Hz, H5'), 4.14-
4.19 (dd, 1H, J = 11.1 & 3.6 Hz, H5'), 4.83 (bd, J = 1.8 Hz, 1H,
H4'), 5.75 (dt, J = 6.3 & 2.1 Hz, 1H, H3'), 6.18 (dt, J = 6.3 & 1.8
Hz, 1H, H2'), 7.03 (d, 1H, J = 1.5 Hz, H1'), 7.62 (d, 1H, J = 1.2
Hz, C6H), 8.94 (s, 1H, NH). Minor rotamer peaks were appeared
in the ratio of 1-2% of major rotamer peaks and found difficult
to designate. ES-MS: m/z 380 (M+1)+.
[5] E. Beraud, Lorberboun-Galski, C. C. Chan, P. I. Fitzerald, R.
B. Nussenblatt, Cell
Immunol., 133, 379, (1991).
[6] H. J. Hahn, J. Gerdes, S. Lucke, L. Liepe, C. Kauret, H. D.
Volk, H. H. Wacker, S. Brocke, H. Stein, T. Diamantein, Eur. J.
Immunol. Today, 12, 392, (1991).
[7] M. L. Kapsenberg, E. A. Wierenga, J. D. Bos, H. M.Jansen,
Immunol. Today, 12, 392, (1991).
1–(2,3,4-Trideoxy-2,3-didehydro–4–acetamido-ꢁ-D–ribofurano-
syl)thymine (31).
[8a] C. Walker, E. Bode, L. Boer, T. T. Hansel, K. Blaser, J. C. Jr.
Virchow, Am. Rev. Respir. Dis., 146, 109, (1992); [b] F. L. van der
Heijden, E. A. Wierenga, J. D. Bos, M. L. Kapsenberg, J. Invest.
Dermatol., 97, 389, (1991).
[9] F. D. Finkelman, E. J. Pearce, J. F. Jr. Urban, A. Sher,
Immunol. Today, 12, A62, (1991).
[10] G. Caceres-Dittmar, F. J. Tapia, M. A. Sanchez, M.
Yamamura, K. Uyemura, R. L. Modlin, B. R. Bloom, J. Convit, Clin.
Exp. Immunol., 91, 500, (1993).
[11] G. Del Prete, A. Tiri, E. Maggi, M. De Carli, D. Macchia, P.
Parronchi, M. E. Rossi, M. C. Pietrogrande, M. Ricci, S. Romagnani, J.
Clin. Invest., 84, 1830, (1989).
[12] L. Schandene, A. Ferster, F. Mascart-Lemone, A. Crusiaux,
C. Gerard, A. Marchant, M. Lybin, T. Velu, E. Sariban, M. Goldman,
Eur. J. Immunol., 23, 56, (1993).
[13] E. Barker, C. E. Mackewicz, J. A. Levy, Proc. Natl. Acad.
Sci. USA., 92, 11135, (1995).
[14] C. B. Hall, J. T. McBride, E. E. Walsh, D. M. Bell, C. L.
Gala, S. Hildreth, L. G. Ten Eyck, W. J. Hall, N. Engl. J. Med., 308,
1443, (1983).
[15] O. Reichard, G. Norkrans, A. Fryden, J-H. Braconier, A.
Sonnerberg, O. Weiland, Lancet, 351, 83, (1998).
[16] C. Hultgren, D. R. Milich, O. Weiland, M. Sällberg, J. Gen.
Virol., 79, 238, (1998).
A solution of 0.61 g (1.60 mmol) 1–(5-O-t-butyldimethyl-
silyl-2,3,4-trideoxy-2,3-didehydro–4–acetamido-ꢁ-D–ribo-
furanosyl)thymine (30) in 30 mL CH2Cl2 was treated with 1 mL
(6.4 mmol) triethylamine trishydrofluoride at room temperature.
The reaction mixture was stirred for 20 h and the volatiles were
removed under reduced pressure. The residue was purified by
flash chromatography over silica gel (CHCl3/MeOH) to afford
0.425 g (99.64%) 31. IR (KBr) ꢀmax 3349, 2835, 1710, 1402,
1125 cm-1; 1H NMR (300 MHz, CD3OD) ꢀ 1.79 (s, 0.9H,
C5CH3), 1.82 (d, 2.1H, J = 1.2 Hz, C5CH3), 2.04 (s, 2.1H,
COCH3), 2.2 (s, 0.9H, COCH3), 3.84 (dd, J = 12 & 2.1 Hz,
0.7H, H5'), 3.93 (dd, J = 12.3 & 2.1 Hz, 0.3H, H5'), 4.05 (dd, J =
12.6 & 3.15 Hz, 0.3H, H5'), 4.20 (dd, J = 12.0 & 2.7 Hz, 0.7H,
H5'), 4.73 (bd, 1H, H4', min), 5.79 (dt, J = 6.3 & 1.8, 0.7H, H3'),
5.85 (dt, J = 6.3 & 1.8, 0.3H, H3', min), 6.19 (dt, J = 6.3 & 1.3,
0.3H, H2'), 6.24 (dt, J = 6.3 & 1.5, 0.7H, H2'), 6.97 (bs, 0.3H,
H1'), 7.11 (d, 0.7H, J = 1.8 Hz, H1'), 8.12 (s, 0.3H, C6H), 8.33 (d,
0.7H, J = 1.8 Hz, C6H,).
Anal. Calcd. for C12H15N3O4: C, 54.33; H, 5.70; N, 15.84.
Found: C, 54.11; H, 5.84; N, 15.68.
[17] Q. Ning, D. Brown, J. Parodo, M. Cattral, L. Fung, R.
Gorezynski, E. Cole, L. Fung, J. W. Ding, M. F. Liu, O. Rotstein, M. J.
Phillips, G. Levy, J. Immunol., 160, 3487, (1998).
[18] M. J. Martin, S. Navas, J. A. Quiroga, M. Pardo, V. Carreno,
Cytokine, 79, 2381, (1998).
1-(2,3,4-Trideoxy-4-acetamido-ꢁ-D-ribofuranosyl)thymine (32).
To 200 mg (0.75 mmol) of 1-(2,3,4-trideoxy-2,3-didehydro-4-
acetamido-ꢁ-D-ribofuranosyl)thymine (31) in 20 mL methanol
was added 20 mg Pd/C (10% w/w) under argon atmosphere. The
reaction mixture was shaken well under H2 atmosphere (40 psi)
at room temperature for 2 h. The catalyst was filtered over celite
bed and the filtrate was evaporated to afford 200 mg titled
product 32 as colorless solid in quantitative yield. IR (KBr) ꢀmax
3345, 2840, 1718, 1408, 1125 cm-1; 1H NMR (500 MHz,
CD3OD) ꢀ 1.84 (s, 1.65H, C5CH3, major rotamer (maj)), 1.86 (s,
1.35H, C5CH3, minor rotamer (min)), 1.97 (s, 1.65H, COCH3,
[19] R. C. Tam, B. Pai, J. Bard, C. Lim, D. R. Averett, U. T. Phan,
T. Milovanovic, J. Hepatol., 30, 376, (1999).
[20a] R. C. Tam, C. Lim, J. Bard, B. Pai, J. Immunol., 163, 3709,
(1999); [b] K. S Ramasamy, R. C. Tam, J. Bard, D. R. Averett, J. Med.
Chem., 43, 1019, (2000); [c] R. C. Tam, K. S. Ramasamy, J. Bard, B.
Pai, C. Lim, D. R. Averett, Antimicrob. Agents Chemother., 44, 1276,
(2000).
[21] C. V. Varaprasad, D. Averett, K. S. Ramasamy, Tetrahedron,
55, 13345, (1999).

336
C. V. N. S. Varaprasad, K. S. Ramasamy, Z. Hong
Vol 43
[22a] K. H. Altmann, Tetrahedron Lett., 34, 7721, (1993); [b] G.
Schramm, Tetrahedron, 53, 2915, (1997); [c] A. Momotake, J.
Mito, K. Yamaguchi, H. Togo, M. Yokoyama, J. Org. Chem., 63,
7207, (1998).
[27] H. Vorbrüggen, Acc. Chem. Res., 28, 509, (1995).
[28a] W. T. Markiewicz, J. Chem. Res. (S), 24, (1979); (b). W. T.
Markiewicz, J. Chem. Res. (M), 181, (1979).
[29a] D. H. R. Barton, S. W. McCombie, J. Chem. Soc., Perkin
Trans. 1, 1574, (1975); [b] D. H. R. Barton, R. Subramanian, J. Chem.
Soc., Perkin Trans. 1, 1718, (1977).
[30] D. L. J. Clive, P. L. Wickens, P. W. M. Sgarbi, J. Org.
Chem., 61, 7426, (1996).
Rassu, L. Pinna, P. Spanu, F. Ulgheri, G. Casiraghi, Tetrahedron Lett.,
35, 4019, (1994); [c] L. Pickering, B. S. Malhi P. L. Coe , R. T. Walker,
Nucleosides & Nucleotides, 31, 1496, (1994).
[23a] F. M. Kaspersen, U. K. Pandit, J. Chem. Soc., Perkin Trans.
1, 1617, (1975); [b] F. M. Kaspersen, U. K. Pandit, J. Chem. Soc.,
Perkin Trans. 1, 1798, (1975); [c] K. E. Ng, L. E. Orgel, J. Med. Chem.,
32, 1754, (1989); [d] M. L. Peterson, R. Vince, J. Med. Chem., 34, 2787,
(1991); [e] L. Pickering, B. S. Malhi, P. L. Coe, R. T. Walker,
Tetrahedron, 51, 2719, (1995).
[24] B. Huang, B. Chen, Y. Hui, Synthesis, 769, (1993).
[25] E. J. Reist, D. E. Gueffroy, R. W. Blackford, L. Goodman, J.
Org. Chem., 31, 4025, (1966).
[31] K. Stott, J. Keeler, Q. N. Van, A. J. Shaka, J. Mag.
Resonance, 125, 302, (1997).
[26a] G. D. Kini, W. J. Hennen, R. K. Robins, J. Org. Chem., 51,
4436, (1986); [b] R. H. Furneaux, G. Limberg, P. C. Tyler, V. L.
[32] M. Yokoyama, T. Ikeue, O. Ochiai, A. Momotake, K.
Yamaguchi, H. Togo, J. Chem. Soc., Perkin Trans. 1, 2185, (1998).