Bicyclic nucleoside analogues from D-glucose: Synthesis of chiral as well as racemic 1,4-dioxepane ring-fused derivatives

Article abstract of DOI:10.1016/j.carres.2005.02.007

The dioxepanofuranose derivatives 4 and 12, obtained through the cyclization of the 3-(2-hydroxyethyl) ether of a d-xylo-pentodialdose derivative, were appropriately functionalized and elaborated to the first examples of the new class of 3′-O and 5′-O-bicyclic nucleoside analogues 9, 10, and 14 with a fused seven-membered ring. Reactions carried out through the intermediacy of the d-xylo-pentodialdose derivative 5 yielded racemic products, while prior protection of the 4-formyl group (as in 7) before deprotection of the 1,2-hydroxyl groups led to optically active analogues.

Full text of DOI:10.1016/j.carres.2005.02.007

Carbohydrate
RESEARCH
Carbohydrate Research 340 (2005) 1081–1087
Bicyclic nucleoside analogues from D-glucose: synthesis of chiral
as well as racemic 1,4-dioxepane ring-fused derivatives
Subhankar Tripathi, Joy Krishna Maity, Basudeb Achari and Sukhendu B. Mandal*
Division of Medicinal Chemistry, Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Jadavpur, Kolkata 700 032, India
Received 1 December 2004; accepted 7 February 2005
Abstract—The dioxepanofuranose derivatives 4 and 12, obtained through the cyclization of the 3-(2-hydroxyethyl) ether of a
D-xylo-pentodialdose derivative, were appropriately functionalized and elaborated to the first examples of the new class of 30-O,
and 50-O-bicyclic nucleoside analogues 9, 10, and 14 with a fused seven-membered ring. Reactions carried out through the interme-
diacy of the D-xylo-pentodialdose derivative 5 yielded racemic products, while prior protection of the 4-formyl group (as in 7) before
deprotection of the 1,2-hydroxyl groups led to optically active analogues.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Keywords: Bicyclic nucleosides; Synthesis; Chiral; Racemic; 1,4-Dioxepane
1. Introduction
work appears to have been reported so far. In this com-
munication we wish to report a simple convergent ap-
proach for the synthesis of bicyclic nucleosides with a
fused dioxepane ring.
The recent decades have witnessed an increased quest
for unnatural nucleoside analogues in search of effective
inhibitors of HIV, HSV, and tumor cells. The desire to
achieve structural alterations in the heterocyclic ring,
in the sugar moiety or in both has culminated in feverish
synthetic activity in the generation of C-branched sugar
nucleosides,1 bicyclic sugar nucleosides2 (20,40-linked,3
10,30-linked,4 20,30-linked,5 30,40-linked,6 30,50-linked7),
acyclic sugar nucleosides,8 carbocyclic nucleosides,9
and dideoxy nucleosides.10 Later on, dideoxy nucleoside
prototypes such as dioxolane-T11 and BCH-18912 hav-
ing two heteroatoms within the carbohydrate frame-
work, and dioxepanyl nucleoside analogues13 have also
been added to the list. The fact that the presence of
one more heteroatom in the ribose ring of a nucleo-
side11,12 imparts anti-HIV/anti-neoplastic activities to
it prompted us to take up a programme on the synthesis
of bicyclic nucleosides having dioxygenated heterocycles
of varied ring sizes fused to the ribose ring, on which no
2. Results and discussion
Compound 1, prepared via etherification14 of the 3-OH
group of the commercially available 1,2:5,6-di-O-isoprop-
ylidene-a-D-glucofuranose with methyl bromoacetate,
was conveniently reduced with NaBH4–tert-BuOH–
MeOH15 to furnish 2. Selective removal of the 5,6-O-iso-
propylidene group by dil HOAc treatment provided 3,
the vicinal diol group of which was cleaved by sodium
periodate in aq EtOH to yield 4; the product was found
to exist in the hemi-acetal form as determined by NMR
spectroscopy. Treatment of 4 with dil H2SO4 in 3:1
CH3CN–H2O released the 1,2-O-isopropylidene group,
furnishing an optically inactive triol mixture through
the intermediacy of the open-chain meso dialdose 5
(Scheme 1). The central carbon atom (C-3) of 5 is achi-
rotopic but stereogenic, having a r-plane of symmetry.
The residues around C-3 are structurally identical but
have opposite configurations (S and R), giving rise to
*
Corresponding author. Tel.: +91 33 2473 3491; fax: +91 33 2473
5197; e-mail: sbmandal@iicb.res.in
0008-6215/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2005.02.007

1082
S. Tripathi et al. / Carbohydrate Research 340 (2005) 1081–1087
O
HO
HO
O
4
O
H
5
H
H
H
O
O
3
O
O
O
O
O
O
O
O
O
b
ref. 14
6
a
2
(78%)
O
1
O
O
O
O
(79%)
HO
O
H
H
3
O
H
H
H3CO2C
OH
1
2
(1,2:5,6-di-O-isopropyli-
dene-α-D-glucofuranose)
OH
c
(80%)
AcO
H
CHO
HO
H
O
H
O
HO
H
O
H
S
R
H
HO
H
H
O
OAc
O
O
OH
OH
S
e
(56%)
d
OCH2CH2OH
H
O
S
s
R
S
OAc
HO
O
R
H
R
O
H
O
O
H
CHO
6
5
4
(optically inactive)
AcO
H
O
AcO
H
O
H
H
S
O
O
S
OAc
OAc
O
f, e
(60%)
e
R
O
H
8
O
O
7
(84%)
H
Scheme 1. Construction of D-glucose-based chiral dioxepane 4 and its conversion to furodioxepanes 6, 7 and 8. Reagents and conditions: (a) NaBH4,
tert-BuOH, MeOH, reflux, 1 h; (b) 4:1 HOAc–H2O, rt, 12 h; (c) NaIO4 (1.2 equiv), 1:1 EtOH–H2O, 5–10 ꢁC, 45 min; (d) H2SO4 (4%), 3:1 CH3CN–
H2O, rt, 12 h; (e) Ac2O/Py, rt, 12 h; (f) aq HOAc (75%), reflux, 5 h.
an optically inactive mixture. Acetylation of the triol
mixture using Ac2O–pyridine afforded a mixture of
triacetates 6 lacking optical activity. Chirality of the
product could, however, be secured by initial protection
of the 5-hydroxyl group of 4 through acetylation (Ac2O–
pyridine) to furnish 7, which after removal of the O-iso-
propylidene group, followed by acetylation, afforded a
mixture of optically active anomers 8.
in good yields (Scheme 2). Repeating the sequence of the
reactions with 8 produced the optically active nucleoside
9.
On the other hand, the C-3-epimer of 1 (11,
derived from 1,2:5,6-di-O-isopropylidine-a-D-glucofura-
nose through the oxidation of the 3-OH group, reduc-
tion of the generated carbonyl group with NaBH4, and
alkylation with methyl bromoacetate) on being sub-
jected to reactions as adopted in Scheme 1 afforded 12.
This was elaborated to the optically inactive isomer of
the nucleoside derivative 14 through the triacetoxy inter-
mediate 13 (Scheme 3) using the procedure described in
Treatment of
oxy)pyrimidine in dichloroethane in presence of
6
with 2,4-bis-O-(trimethylsilyl-
TMSOTf under Vorbruggen reaction conditions16 affor-
ded the optically inactive dioxepanonucleosides 9 and 10
¨
O
O
N
HN
HN
AcO
H
O
AcO
H
O
O
N
O
O
H
H
2,4-bis-(trimethylsilyloxy)pyrimidine,
DCE, TMSOTf, rt, 6 h
O
H
+
H
6
(60%)
OAc
OAc
O
O
H
H
H
H
9
10
(optically inactive)
(optically inactive)
(optically active)
9
2,4-bis-(trimethylsilyloxy)pyrimidine,
DCE, TMSOTf, rt, 6 h
8
55%
Scheme 2. Synthesis of bicyclic dioxepanonucleosides 9 and 10.

S. Tripathi et al. / Carbohydrate Research 340 (2005) 1081–1087
1083
O
HN
N
O
O
HO
H
O
AcO
H
O
AcO
H
O
O
H
R
H
H
H
O
O
OAc
O
O
S
f
H
O
d, e
O
a, b, c
(48%)
R
(53%)
(63%)
O
O
O
H
OAc
O
O
OAc
O
H
H
H3CO2C
H
11
12
13
14
(optically inactive)
e
(89%)
AcO
H
O
O
H
O
H
O
O
O
O
g, e, f
(35%)
14 (optically active)
O
O
O
(1,2:5,6-di-O-isopropylidene-α-D-glucofuranose)
H
HO
15
Scheme 3. Synthesis of dioxepane 12 and its conversion to bicyclic nucleoside 14. Reagents and conditions: (a) NaBH4, tert-BuOH, MeOH, reflux,
1 h; (b) aq HOAc (80%), rt, 15 h; (c) NaIO4, aq EtOH (50%), 5–10 ꢁC, 45 min; (d) H2SO4 (4%), aq CH3CN (75%), rt, 12 h; (e) Ac2O/Py, rt, 12 h; (f)
2,4-bis-(trimethylsilyloxy)pyrimidine, DCE, TMSOTf, rt, 6 h; (g) aq HOAc (75%), reflux, 5 h.
Scheme 2. The generation of only one isomer of the sec-
ond hemiacetal center was observed in this case. How-
ever, compound 15 (obtained from 12 by prior
protection of the hemiacetal moiety through acetyl-
ation) furnished the optically active bicyclic nucleoside
14.
nature. The stereochemistries of the precursor molecules
4 and 12 could be similarly settled.
3. Conclusions
Regarding the structures and stereochemistry of the
nucleosides, introduction of the uracil heterocycle was
borne out by the presence of typical signals in the
NMR spectra of the products. In the 1H NMR spectrum
of 9, for example, signals for H-5 and H-6 were observed
at d 5.83 (d) and 7.55 (d), while the 13C NMR spectrum
contained signals for two olefinic methine carbons (d
104.1 and 140.1) and two carbonyl carbons (d 150.4
and 162.9). Mechanistic considerations (participation
of the C-20-OAc group through a dioxolonium interme-
diate) dictated that the heterocycle must be trans to the
20-OAc group in the product formed. In support, the 1H
NMR spectrum of 9 displayed a doublet (d 6.12, J
3.3 Hz) and a doublet of a doublet (d 5.08, J 1.2,
3.3 Hz) for the protons H-10 and H-20 as observed in re-
lated systems.17 Similar spectral data (1H and 13C
NMR) were also obtained for the compounds 10 and
14. The trans disposition of H-40 and H-50 in 9 and 14
and the cis geometry of these protons in 10 were de-
In summary, spontaneous cyclization involving the hy-
droxy group of a C-3 2-hydroxyethyl ether of a C-6 nor-
glucose substrate and the aldehyde function at C-5 is
shown to afford, through suitable manipulations of reac-
tion conditions, a new class of bicyclic dioxepane nucleo-
side analogues in both optically active as well as
inactive forms. The latent aldehyde group may serve as
a scavenger of many biological nucleophiles and as a
handle to yield a variety of derivatives in the laboratory.
The method of precursor preparations is straightforward
and can be applied to other carbohydrate precursors
also, providing a synthetic route to other analogues.
4. Experimental
4.1. General
1H (300 MHz) and 13C (75 MHz) NMR spectra were re-
corded in CDCl3 as a solvent using Me4Si as an internal
standard. Fast-atom bombardment mass spectra (FAB-
MS) were obtained using a spectrometer operating at
an accelerating voltage of 3 kV and a neutral atom
accelerating energy of 6 kV with argon gas and m-
nitrobenzyl alcohol (m-NBA) as the matrix. Specific
rotations were measured at 589 nm. TLC was performed
on the pre-coated plates (0.25 mm, Silica Gel 60F254).
HPLC was performed on a l-BondapakTM C-18 column
(7.8 · 300 mm).
0
0
duced from the observed coupling constants (J4 ;5
7.5 Hz in 9, 9.0 Hz in 14 and 0 Hz in 10). The observed
J-values (in Hz) were best suited for the indicated struc-
tures of the respective nucleosides, based on the calcu-
lated dihedral angles for the H–C-40–C-50–H unit
[ꢀ160ꢁ in both 9 and 14 and ꢀ 80ꢁ in 10 in the en-
ergy-minimized structures obtained using ChemOffice,
version 6.0].18 The FABMS of all the bicyclic nucleo-
sides showed pseudo molecular ion peaks at m/z 371
(M+H+) and 393 (M+Na+) indicating their isomeric

1084
S. Tripathi et al. / Carbohydrate Research 340 (2005) 1081–1087
4.2. (3aR,4R,5R,6S,6aR) [5-(2,2-Dimethyl-[1,3]dioxolan-
4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-
yloxy]acetic acid methyl ester (1)
4.4. (1R,3aR,5R,6S,6aR) 1-[6-(2-Hydroxyethoxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]ethan-1,2-
diol (3)
Oil-free NaH (obtained from 1.0 g, 60% in oil suspension
thoroughly washed with dry petroleum ether) was added
portionwise to a solution of 1,2:5,6-di-O-isopropylidene-
a-D-glucofuranose (5 g, 19.2 mmol) in THF (50 mL),
and the mixture was stirred at rt for 30 min under N2.
Methyl bromoacetate (3 mL) was added dropwise to
the refluxing solution, and heating was continued for
3.5 h. The solvent was evaporated in vacuo after destroy-
ing excess NaH by adding satd aq NH4Cl. The resulting
brown mass was extracted with CHCl3 (3 · 15 mL). The
CHCl3 solution was washed with brine, dried (Na2SO4),
and concentrated to afford a crude residue. The product
from the residue was purified by silica gel (60–120 mesh)
column chromatography, eluting with a 1:10 EtOAc–
petroleum ether mixture to furnish 5.48 g of 1 (84%) as
Compound 2 (1.21 g, 3.98 mmol) was dissolved in a mix-
ture of 4:1 HOAc–H2O (50 mL), and the mixture was
stirred at rt for 12 h at the end of which time TLC
showed complete disappearance of the starting material.
The solvent was evaporated in vacuo to a thick material,
which was purified by a silica gel (60–120 mesh) column
chromatography eluting with 19:1 CHCl3–MeOH mix-
ture to furnish 820 mg of 3 (78%) as a gum: ½aꢁ
26
D
1
ꢂ37.2 (c 1.2, CHCl3); H NMR: d 1.32 (s, 3H), 1.49
(s, 3H), 3.30 (br s, 3H), 3.54–3.61 (m, 1H), 3.69 (dd,
1H, J 5.7, 11.4 Hz), 3.73–3.76 (m, 2H), 3.86–3.90 (m,
2H), 4.00–4.05 (m, 1H), 4.09–4.15 (m, 2H), 4.55 (d,
1H, J 3.6 Hz), 5.92 (d, 1H, J 3.6 Hz); 13C NMR: d
25.9 (CH3), 26.5 (CH3), 60.8 (CH2), 64.1 (CH2), 68.9
(CH), 71.1 (CH2), 79.7 (CH), 81.8 (CH), 82.4 (CH),
105.1 (CH), 111.6 (C); FABMS, m/z: 265 (M+H+) and
287 (M+Na+). Anal. Calcd for C11H20O7: C, 49.99; H,
7.63; found: C, 50.07; H, 7.81.
26
1
a solid: ½aꢁ ꢂ7.7 (c 2.3, CHCl3); H NMR: d 1.31 (s,
D
3H), 1.35 (s, 3H), 1.42 (s, 3H), 1.49 (s, 3H), 3.77 (s,
3H), 3.96 (d, 1H, J 2.6 Hz), 4.00 (dd, 1H, J 5.5,
8.5 Hz), 4.10 (m, 2H), 4.27 (s, 2H), 4.33 (m, 1H), 4.72
(d, 1H, J 3.6 Hz), 5.91 (d, 1H, 3.6 Hz); 13C NMR: d
25.1 (CH3), 26.0 (CH3), 26.6 (2 · CH3), 51.7 (CH3),
67.0 (CH2), 68.0 (CH2), 72.4 (CH), 80.8 (CH), 83.0
(CH), 83.4 (CH), 105.0 (CH), 108.8 (C), 111.6 (C);
170.4 (C); FABMS, m/z: 333 (M+H+). Anal. Calcd for
C15H24O8: C, 54.21; H, 7.28; found: C, 54.07; H, 7.12.
4.5. (3aR,3bS,8S,8aS,9aR) 2,2-Dimethyl-hexahydro-
1,3,4,7,9-pentaoxa-cyclopenta[a]azulen-8-ol (4)
To an ice-cooled stirred solution of
3 (790 mg,
3.0 mmol) in 1:1 EtOH–H2O (20 mL) was added drop-
wise a solution of NaIO4 (770 mg, 3.35 mmol) in water
(2 mL). After 45 min of stirring, the mixture was filtered,
the filtrate was evaporated under reduced pressure, and
the residue thus obtained was extracted with CHCl3
(3 · 20 mL). The CHCl3 solution was washed with
brine, dried (Na2SO4) and concentrated to a crude mate-
rial that was purified by column chromatography using
CHCl3 as the eluting solvent to furnish 556 mg of 4
4.3. (3aR,4R,5R,6S,6aR) 2-[5-(2,2-Dimethyl-[1,3]dioxo-
lan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-
yloxy]ethanol (2)
A solution of 1 (1.0 g, 3.0 mmol) in t-BuOH (10 mL)
containing NaBH4 (340 mg, 10.0 mmol) was heated at
reflux for 1 h on a water bath with addition of 2–3 drops
of MeOH at an interval of 10 min. The reaction mixture
was cooled to rt, water (1 mL) was added to it, and the
solvent was evaporated in vacuo. The residue was ex-
tracted with CHCl3 (3 · 20 mL). The CHCl3 solution
was washed with brine, dried over Na2SO4, and concen-
trated to furnish an oil that was purified by silica gel
(60–120 mesh) column chromatography, eluting with
26
D
1
(80%) as a thick gum: ½aꢁ +13.6 (c 1.2, CHCl3); H
NMR: d 1.32 (s, 3H), 1.49 (s, 3H), 3.62 (t-like, 1H, J
11.0 Hz), 3.81 (t-like, 1H, J 11.0 Hz), 3.96 (d, 2H, J
12.3 Hz), 4.13 (d, 1H, J 3.6 Hz), 4.35 (dd, 1H, J 3.9,
6.0 Hz), 4.51 (d, 1H, J 3.6 Hz), 4.95 (d, 1H, J 6.0 Hz),
5.98 (d, 1H, J 3.6 Hz); 13C NMR: d 26.3 (CH3), 26.9
(CH3), 70.3 (CH2), 74.0 (CH2), 84.9 (CH), 86.2 (CH),
86.4 (CH), 101.3 (CH), 105.3 (CH), 111.8 (C); FABMS,
m/z: 233 (M+H+) and 255 (M+Na+). Anal. Calcd for
C10H16O6: C, 51.72; H, 6.94; found: C, 51.45; H, 6.70.
9:1 CHCl3–petroleum ether mixture to afford 722 mg
26
of 2 (79%) as a thick liquid: ½aꢁ ꢂ43.7 (c 2.3, CHCl3);
D
1H NMR: d 1.32 (s, 3H), 1.37 (s, 3H), 1.44 (s, 3H),
1.50 (s, 3H), 3.42 (t, 1H, J 6.5 Hz), 3.55–3.61 (m, 1H),
3.64–3.79 (m, 2H), 3.83–3.91 (m, 1H), 4.00–4.18 (m,
4H), 4.32–4.39 (m, 1H), 4.55 (d, 1H, J 3.6 Hz), 5.91
(d, 1H, J 3.6 Hz); 13C NMR: d 25.5 (CH3), 26.6
(CH3), 27.2 (CH3), 27.3 (CH3), 61.5 (CH2), 68.3
(CH2), 72.0 (CH2), 73.3 (CH), 81.7 (CH), 82.7 (CH),
83.2 (C), 106.1 (CH), 109.8 (C), 112.3 (C); FABMS,
m/z: 305 (M+H+). Anal. Calcd for C14H24O7: C, 55.25;
H, 7.95; found: C, 55.07; H, 7.80.
4.6. (3aR,3bS,8S,8aS,9aR) Acetic acid 2,2-dimethyl-
hexahydro-1,3,4,7,9-pentaoxacyclopent[a]azulen-8-yl
ester (7)
Compound 4 (300 mg, 1.30 mmol) was dissolved in pyr-
idine (10 mL), Ac2O (1 mL) was added, and the solution
was stirred at rt for 12 h. The solvent was evaporated in
vacuo, and the crude product was purified by silica gel
column chromatography eluting with 3:17 EtOAc–

S. Tripathi et al. / Carbohydrate Research 340 (2005) 1081–1087
1085
petroleum ether mixture to afford 297 mg of 7 (84%):
9.16 (br s, 1H); 13C NMR: d 20.8 (CH3), 21.3 (CH3),
66.8 (CH2), 71.9 (CH), 72.0 (CH2), 80.1 (CH), 81.1
(CH), 83.2 (CH), 93.3 (CH), 102.5 (CH), 142.0 (CH),
150.3 (C), 163.4 (C), 169.5 (C), 170.3 (C); FABMS,
m/z: 371 (M+H+) and 393 (M+Na+). Anal. Calcd for
C15H18N2O9: C, 48.65; H, 4.90; N, 7.56; found: C,
48.55; H, 4.72; N, 7.30.
26
D
½aꢁ +3.6 (c 2.0, CHCl3); 1H NMR: d 1.32 (s, 3H),
1.50 (s, 3H), 2.13 (s, 3H), 3.57–3.68 (m, 1H), 3.93–4.03
(m, 3H), 4.16 (d, 1H, J 3.6 Hz), 4.52–4.55 (m, 2H),
5.68 (d, 1H, J 7.3 Hz), 5.97 (d, 1H, J 3.6 Hz); 13C
NMR: d 21.1 (CH3), 26.5 (CH3), 27.2 (CH3), 61.5
(CH2), 71.5 (CH2), 74.2 (CH2), 83.7 (CH), 84.9 (CH),
86.8 (CH), 99.3 (CH), 105.9 (CH), 112.1 (C), 169.9
(C); FABMS, m/z: 275 (M+H+). Anal. Calcd for
C12H18O7: C, 52.55; H, 6.62; found: C, 52.70; H, 6.48.
1
Compound 10 as a foam: H NMR: d 2.14 (s, 6H),
3.69 (m, 1H), 4.00–4.14 (m, 3H), 4.22 (dd, 1H, J 1.2,
4.5 Hz), 4.43 (dd, 1H, J 4.5, 7.3 Hz), 5.08 (dd, 1H, J
1.2, 3.0 Hz), 5.83 (d, 2H, J 7.5 Hz), 6.12 (d, 1H, J
3.3 Hz), 7.55 (d, 1H, J 8.0 Hz), 8.75 (br s, 1H); 13C
NMR: d 21.0 (CH3), 21.3 (CH3), 72.0 (CH2), 74.8
(CH2), 81.8 (CH), 84.2 (CH), 86.2 (CH), 89.1 (CH),
98.6 (CH), 104.1 (CH), 140.1 (CH), 150.4 (C), 162.9
(C), 169.9 (C), 170.1 (C); FABMS, m/z: 371 (M+H+),
393 (M+Na+). Anal. Calcd for C15H18N2O9: C, 48.65;
H, 4.90; N, 7.56; found: C, 48.62; H, 4.83; N, 7.38.
Optically active form of 9: Compound 7 (200 mg,
0.73 mmol) was dissolved in 75% aqueous HOAc
(20 mL) and heated at reflux for 5 h. The solvent was
evaporated; the last traces of pyridine were removed
by co-evaporation with toluene, and the residue was
acetylated with pyridine (5 mL) and Ac2O (1 mL) at rt.
Usual work-up afforded the mixture of triacetates 8
(232 mg), 75 mg of which was transformed into 48 mg
4.7. (5R,5aS,7R,8R,8aR) Acetic acid 8-acetoxy-7-(2,4-
dioxo-3,4-dihydro-2H-pyrimidin-1-yl)hexahydrofuro[3,2-
e][1,4]dioxepin-5-yl ester (9) and (5S,5aS,7R,8R,8aR)
Acetic acid 8-acetoxy-7-(2,4-dioxo-3,4-dihydro-2H-
pyrimidin-1-yl)hexahydrofuro[3,2-e][1,4]dioxepin-5-yl
ester (10)
A solution of 4 (340 mg, 1.46 mmol) in a mixture of
1:18:6 H2SO4–CH3CN–H2O (20 mL) was stirred at rt
for 12 h. The acidic solution was neutralized by portion-
wise addition of solid CaCO3. The precipitate was fil-
tered off, and the solvent was evaporated in vacuo to a
gummy mass, which was dried over P2O5 under vacuum.
The gummy mass was then treated with pyridine (5 mL)
and Ac2O (1 mL), and the mixture was stirred at rt for
12 h. The solvent was evaporated, and the sticky mate-
rial was dried in vacuo to furnish a triacetate mixture
6 (260 mg, 56%), which was subsequently used without
further purification. Then a mixture of uracil (200 mg,
1.79 mmol) in hexamethyldisilazane (7 mL) and freshly
distilled chlorotrimethylsilane (two drops) was heated
at reflux under N2 for 12 h. The solvent was distilled
off under vacuum, and a solution of the residue in
dichloroethane (5 mL) was added to a stirred solution
of the triacetate mixture 6 (200 mg, 0.63 mmol) in
dichloroethane (5 mL) containing TMSOTf (0.4 mL).
The solution was stirred at rt for 6 h under N2, when
TLC showed complete disappearance of the starting
material. The reaction mixture was neutralized with so-
lid NaHCO3, water (2–3 drops) was added to it, and the
solvent was evaporated in a rotary evaporator. The
residue was extracted with 49:1 CHCl3–MeOH
(20 mL). The solution was washed with brine, dried
(Na2SO4) and concentrated. The crude product was pri-
marily purified by silica gel column chromatography
using methanolic CHCl3 (2%) as eluent to afford an ano-
meric mixture of 9 and 10 (200 mg, 60%), 75 mg of
which was separated by reversed-phase HPLC using
3:17 CH3CN–H2O as eluent to afford 45 mg of 9 and
18 mg of 10.
of 9 (55%) as a foamy solid using a procedure similar
26
D
to that described earlier: ½aꢁ +15.6 (c 1.2, CHCl3).
Anal. Calcd for C15H18N2O9: C, 48.65; H, 4.90; N,
7.56; found: C, 48.46; H, 4.80; N, 7.43.
4.8. (3aR,4R,5R,6R,6aR) [5-(2,2-Dimethyl-[1,3]dioxolan-
4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-
yloxy]acetic acid methyl ester (11)
1,2:5,6-Di-O-isopropylidene-D-allofuranose (2.5 g, 9.6
mmol) was converted to 11 (2.42 g, 76%) through
O-alkylation with methyl bromoacetate according to
the procedure as described in the preparation of 1.
Compound 11 as a thick oil: ½aꢁ26 +71.7 (c 1.6, CHCl3);
D
1H NMR: d 1.37 (s, 6H), 1.47 (s, 3H), 1.59 (s, 3H), 3.76
(s, 3H), 3.92 (dd, 1H, J 4.5, 8.5 Hz), 3.97–4.12 (m, 3H),
4.25 (d, 1H, J 16.8 Hz), 4.31 (dd, 1H, J 6.6, 11.0 Hz),
4.40 (d, 1H, J 16.8 Hz), 4.77 (t, 1H, J 3.9 Hz), 5.75 (d,
1H, J 3.6 Hz). 13C NMR: d 24.9 (CH3), 26.2 (CH3),
26.4 (CH3), 26.7 (CH3), 51.8 (CH3), 65.5 (CH2), 67.6
(CH2), 75.1 (CH), 78.1 (CH), 78.5 (CH), 79.9 (CH),
103.5 (CH), 109.6 (C), 113.0 (C), 170.6 (C); FABMS,
m/z: 333 (M+H+). Anal. Calcd for C15H24O8: C, 54.21;
H, 7.28; found: C, 54.13; H, 7.20.
Compound 9 as a foam: 1H NMR: d 2.08 (s, 3H), 2.11
(s, 3H), 3.80–3.86 (m, 2H), 3.98–4.06 (m, 2H), 4.58 (d,
1H, J 7.3 Hz), 4.76 (t-like, 1H, J 6.2, 6.6 Hz), 5.65 (t-
like, 1H, J 5.1, 5.3 Hz), 5.73 (d, 1H, J 8.2 Hz), 5.99 (s,
1H), 6.49 (d, 1H, J 4.5 Hz), 7.58 (d, 1H, J 8.2 Hz),
4.9. (3aR,3bR,8S,8aS,9aR) 2,2-Dimethylhexahydro-
1,3,4,7,9-pentaoxacyclopenta[a]azulen-8-ol (12)
The conversion of 11 (100 mg, 0.3 mmol) to 12 (33 mg,
48%) was performed through reduction of the ester

1086
S. Tripathi et al. / Carbohydrate Research 340 (2005) 1081–1087
group, selective removal of the 5,6-O-isopropylidene
group, and vicinal diol cleavage following the procedure
1H, J 10.6, 13.5 Hz), 4.46 (dd, 1H, J 6.6, 9.0 Hz), 4.69
(t, 1H, J 3.6 Hz), 5.81 (d, 1H, J 3.0 Hz), 5.92 (d, 1H, J
6.3 Hz); 13C NMR: d 21.6 (CH3), 26.6 (CH3), 27.2
(CH3), 67.4 (CH2), 71.3 (CH2), 79.3 (CH), 79.8 (CH),
82.0 (CH), 96.6 (CH), 104.8 (CH), 114.0 (C), 170.4
(C); FABMS, m/z: 275 (M+H+) and 297 (M+Na+).
Anal. Calcd for C12H18O7: C, 55.55; H, 6.62; found:
C, 55.28; H, 6.60.
Preparation of optically active nucleoside 14: The O-
isopropylidene group of 15 (15 mg, 0.054 mmol) was
cleaved by heating in 75% aq HOAc (5 mL) at reflux
for 5 h. The residue after solvent removal was acetylated
with a pyridine (2 mL) and Ac2O (0.5 mL) mixture to
give a mixture of triacetates, which was used for the
preparation of 14 using the protocol: uracil (20 mg),
hexamethyldisilazane (1 mL), TMSCl (one drop),
as described in the preparation of 4 from 2.
26
D
Compound 12 as a sticky mass: ½aꢁ +26.0 (c 2.0,
1
CHCl3); H NMR: d 1.35 (s, 3H), 1.62 (s, 3H), 2.89
(br s, 1H), 3.66 (t-like, 1H, J 13.5 Hz), 3.76 (d, 1H, J
10.4 Hz), 3.93 (m, 2H), 4.19 (t-like, 1H, J 13.5 Hz),
4.27 (dd, 1H, J 8.0, 13.5 Hz), 4.64 (s, 1H), 5.06 (d, 1H,
J 5.0 Hz), 5.79 (s, 1H); 13C NMR: d 26.2 (CH3), 26.7
(CH3), 64.8 (CH2), 70.9 (CH2), 78.8 (CH), 79.1 (CH),
83.9 (CH), 96.9 (CH), 104.2 (CH), 113.4 (C); FABMS,
m/z: 233 (M+H+) and 255 (M+Na+). Anal. Calcd for
C10H16O6: C, 51.72; H, 6.94; found: C, 51.55; H, 6.74.
4.10. (5R,5aS,7R,8R,8aS) Acetic acid 5-acetoxy-7-(2,4-
dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-hexahydrofuro-
[3,2-e][1,4]dioxepin-8-yl ester (14)
TMSOTf (0.1 mL) and dichloroethane (4 mL). Yield,
26
D
7 mg of 14 (35%) as a foamy solid: ½aꢁ +8.0 (c 1.1,
The 1,2-O-isopropylidene group of 12 (225 mg,
0.97 mmol) was cleaved by treatment with 4% H2SO4
in 1:3 CH3CN–H2O (20 mL), followed by acetylation
of the product with pyridine (3 mL) and Ac2O (1 mL)
according to the method described above afforded a
mixture of crude triacetates 13 (195 mg, 63%). A solu-
tion of 13 (105 mg, 0.33 mmol) in dichloroethane
(5 mL) was added to a solution of 2,4-bis-(trimethylsilyl-
oxy)pyrimidine [prepared by refluxing a mixture of ura-
cil (1.34 mmol), hexamethyldisilazane (7 mL) and
TMSCl (two drops)] in dichloroethane (5 mL) with
stirring at rt for 6 h. Usual work-up, followed by reversed-
phase HPLC (eluting solvent: 3:17 CH3CN–H2O) affor-
ded 65 mg of 14 (53%) as an optically inactive foamy so-
lid: 1H NMR: d 2.11 (s, 3H), 2.18 (s, 3H), 3.84–3.92 (m,
1H), 3.98–4.03 (m, 2H), 4.35–4.47 (m, 2H), 4.78 (t, 1H, J
9.0 Hz), 5.37 (d, 1H, J 4.5 Hz), 5.47 (d, 1H, J 9.0 Hz),
5.75 (dd, 1H, J 2.0, 8.0 Hz), 6.07 (s, 1H), 7.24 (d, 1H,
J 8.0 Hz), 8.71 (br s, 1H); 13C NMR: d 21.1 (CH3),
21.4 (CH3), 69.1 (CH2), 71.5 (CH2), 75.3 (CH), 77.7
(CH), 79.2 (CH), 89.2 (CH), 98.4 (CH), 103.3 (CH),
141.4 (CH), 150.8 (C), 162.9 (C), 168.9 (C), 169.9 (C);
FABMS, m/z: 371 (M+H+) and 393 (M+Na+). Anal.
Calcd for C15H18N2O9: C, 48.65; H, 4.90; N, 7.56;
found: C, 48.47; H, 4.81; N, 7.45.
CHCl3). Anal. Calcd for C15H18N2O9: C, 48.65; H,
4.90; N, 7.56; found: C, 48.38; H, 4.78; N, 7.32.
Acknowledgements
The work has been supported by a grant from the
Department of Science and Technology (Govt. of In-
dia). The authors (S.T. and J.K.M.) gratefully acknowl-
edge the Council of Scientific and Industrial Research
for providing them Junior Research Fellowships.
Supplementary data
1
Copies of H and 13C NMR spectra of the compounds
1–4, 7, 9–12, 14, and 15 can be found in the electronic
version of this paper. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.carres.2005.02.007.
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