Synthesis of N-homobicyclic dideoxynucleoside analogues

Article abstract of DOI:10.1016/j.carres.2012.01.018

Syntheses of six N-homobicyclic dideoxynucleoside analogues are described. The reaction of mannose diacetonide with trimethylsulfoxonium iodide gave a mixture of diastereomeric hydroxymethyl mannose diacetonides in a ratio of 2:5, which was separated by f

Full text of DOI:10.1016/j.carres.2012.01.018

Carbohydrate Research 352 (2012) 191–196
Contents lists available at SciVerse ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Synthesis of N-homobicyclic dideoxynucleoside analogues
⇑
N. Raghavendra Swamy, N. Suryakiran, P. Paradesi Naidu, Y. Venkateswarlu
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Syntheses of six N-homobicyclic dideoxynucleoside analogues are described. The reaction of mannose
diacetonide with trimethylsulfoxonium iodide gave a mixture of diastereomeric hydroxymethyl mannose
diacetonides in a ratio of 2:5, which was separated by fractional crystallization. The two stereoisomers
were converted to bicyclic furanolactols each of which was coupled with three nucleoside bases. Further
debenzylations gave the six target N-homobicyclic dideoxynucleosides.
Received 16 December 2011
Received in revised form 18 January 2012
Accepted 22 January 2012
Available online 28 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Palladium(II) chloride
N-Homobicyclic dideoxy nucleosides
D-Mannose
1. Introduction
cleosides as inhibitors of HIV-RT44 and further studies on bicyclic
nucleosides.45–49 Certain members of the class possess interesting
The synthesis of modified nucleosides has been of interest for
over four decades. The finding that 30-azido-30-deoxy thymidine
(AZT) is a therapeutic agent for the treatment of AIDS1 triggered
explosive new development in this area. Nucleoside modification
has been reviewed extensively2–10 and specialized reviews pub-
lished on the synthesis of sugar-modified nucleosides such as keto-
nucleosides,11 3-branched nucleoside analogues,12 AIDS-driven
nucleosides chemistry,13 bicyclic heterocyclic nucleosides,14 C-
nucleosides10,15–19 C-branched nucleoside analogues,20 carbocyclic
nuleosides,21–24 nucleosides with six-membered carbohydrate
cellular activities, for example, naturally occurring bicyclic nucleo-
sides called griseolic acids, isolated from the cultured broth of
Streptomyces griseoaurantiacus, show significant inhibitory activity
against 30,50-cyclic nucleotide phosphodiesterases.50,51
Synthetic guanosine analogues of griseolic acids are even more
potent against these enzymes51; other derivatives are potent anti-
hypertensive agents.52 Recently, bicyclic nucleosides have also re-
ceived attention in studies of the stabilities of antisense
oligonucleotides.53–57 Bicyclic nucleosides exhibit increased affin-
ity for complementary RNA or DNA and are also important in the
preparation of triple-helix-forming oligonucleotides.53,56
Several authors have used similar nucleosides to prepare oligo-
nucleotides.58–60 As a continuation of our efforts in the discovery of
antiviral agents, we chose the synthesis of the bicyclic nucleosides
1–6 (Fig. 1).
moieties,25–27
nucleoside antibiotics,28,29
azanucleosides,30
L
-nucleosides,31,32 20,30-dideoxynucleosides,33,34 40,50-unsaturated
nucleosides,35 C-alkenylated pyrimidine nucleosides,36 anomeric
spironucleosides,37 and isonucleosides.38 Most of the nucleosides
are reverse transcriptase inhibitors like Zidovudine, Zalcitabine,
and Stavudine; a few non-nucleosides such as Nevirapine, Delavir-
dine, and Efavirenzes also inhibit HIV reverse transcriptase. Many
2,3-dideoxyribonucleosides possess significant antiviral activity
against HIV and other viruses. It has been suggested that proper
puckering of the five-membered monocyclic carbohydrate moiety
is required for antiviral activity.39 However, bicyclic nucleosides
from a conformationally different class, such as fused ring cytidine
analogues40–42 and oxytanylthymidine,43 were recently found to
have moderate to significant activity against HIV through the
inhibition of HIV reverse transcriptase. These findings led to an
investigation of the conformational requirements for dideoxynu-
2. Results and discussion
The synthesis started from mannose diacetonide 7,61 readily
obtainable from D-mannose in 85% yield (Scheme 1). The reaction
of mannose diacetonide 7 with trimethylsulfoxonium iodide and
potassium tert-butoxide at room temperature for 3 h62 gave the
diastereomeric mixture of key intermediates 8 and 9 in the ratio
of 2:5 (by NMR), as a viscous oil in 79% yield.63 Among the bases
(NaH, n-BuLi, LiHMDS, NaHMDS, LDA, t-BuOK) tried, t-BuOK gave
the best result for 8, 9 in terms of yield and separation of the dia-
stereomeric mixture. Here, the lactol moiety reacted with the
in situ generated dimethyloxosulfonium methylide to form an
epoxide to give hydroxymethyl mannose diacetonide. Fractional
crystallization of this mixture (CH2Cl2–hexane 1:4) gave 8, as a
⇑
Corresponding author. Tel.: +91 40 27193167; fax: +91 40 27160512.
E-mail addresses: snavath@email.arizona.edu, luchem@iict.res.in (Y. Venkates-
warlu).
0008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2012.01.018

192
N. Raghavendra Swamy et al. / Carbohydrate Research 352 (2012) 191–196
H2N
OTs
OTs
HO
HO
O
N
O
H
O
H
O
O
N
O
O
N
a
b
N
NH
O
9
NH
N
N
O
O
H
O
H
O
O
O
H
O
19
OTs
20
HO
OTs
HO
OTs
O
O
HO
H
OH
N
H
O
H
H
OH
O
H
O
O
OH
H
O
c
d
1
e
2
3
H2N
O
O
N
HO
O
N
N
OH
O
O
H
HO
OH
NH
NH
22
23
H
21
H
B
OTs
B
N
O
N
O
H
H
H
H
O
O
O
O
O
f
g
h
HO
HO
BnO
HO
HO
BnO
O
O
4
O
O
O
O
OH
OBn
OBn
H
OH
H
OH
H
H
H
OH
H
5
6
4
-6
25-27
24
O
O
NH2
N
NH
Figure 1. N-Homobicyclic dideoxynucleoside analogues.
NH
B =
N
N
O
N
O
N
N
6
crystalline compound (30%), mp 83–85 °C and 9 as viscous oil
(70%). Tosylation of 8 with p-toluenesulfonyl chloride in pyridine
5
4
Scheme 2. Synthesis of N-homobicyclic-dideoxy nucleosides 4–6. Reagents and
conditions: (a) TsCl, pyridine, DMAP, (b) BiCl3, DCM; (c) TPP, imidazole, I2, toluene,
80 °C; (d) 5% aq H2SO4, 1,4-dioxane; (e) PdCl2, CuCl, O2, DMF, H2O; (f) NaH, BnBr,
DMF; (g) NaH, DMF, nucleoside base, 90 °C; (h) Pd(OH)2–H2.
to give tosylate 10 in 92% yield. Regioselective hydrolysis of isopro-
64,65
pylidene of 10 with BiCl3
in DCM gave diol 11 in 85% yield.
Treatment of diol 11 with triphenylphosphine imidazole and io-
dine in toluene at 80 °C by reductive elimination gave vinyl furan
12 in 87% yield as viscous oil. Removal of isopropylidene group
of vinyl furan 12 with 5% aq H2SO4 in 1,4-dioxane gave the desired
hydroxy vinyl furan 13. The crucial step of converting 13 to lactol
14 was achieved in 90% yield using PdCl2, CuCl, DMF, H2O, and O2
at room temperature for 4 h.66,67 Treatment of 14 with NaH, BnBr
in DMF gave benzyl derivative 15 in 95% yield. Intermediate 15
was used for the synthesis of bicyclic dideoxynucleosides.
Thus uracil on treatment with NaH in DMF at 90 °C for 15 min
followed by addition of tosylate 15 gave N-homobicyclic dideoxy-
uridine nucleoside 16. Further deprotection of benzyl groups with
20% Pd(OH)2 in methanol under hydrogen atmosphere gave the
corresponding N-homobicyclic dideoxyuridine nucleoside 1. Using
similar reactions of dibenzyl homobicyclic tosylate 15 with ade-
nine and thymine gave the N-homobicyclic dideoxy nucleosides
2 and 3, respectively. As described in Scheme 2 compound 9 was
subjected to similar reactions to obtain N-homobicyclo dideoxy
nucleosides 4–6.
OH
OH
O
O
H
O
H
O
O
H
O
O
O
O
OH
O
O
a
O
+
3. Experimental section
3.1. General methods
O
O
O
8
9
7
OTs
OTs
O
HO
HO
H
O
H
Melting points were measured on a Buchi-510 instrument and
are uncorrected. Spectra were recorded with the following instru-
ments: IR, Perkin Elmer spectrophotometer; NMR, 200 MHz (Var-
ian) and Unity 300 MHz (Bruker) and mass spectra LC–MS and
Micro mass VG 7070H (70 eV). Column chromatography was per-
formed with silica gel (Achme 60–120 mesh or >300 mesh flash
chromatography) and TLC with silica gel MERCK GF254 (pre-
coated). Visualization of the spots on TLC plates was carried out
either in UV light (short wave 250 nm) or by exposing the plates
to iodine vapors or spraying with 10% sulfuric acid in CH3OH and
subsequently heating on a hot plate.
O
O
b
c
O
8
O
O
O
11
10
OTs
OTs
OTs
H
H
H
O
O
O
d
e
f
HO
O
OH
O
O
O
H
OH
HO
14
H
13
12
B
OTs
B
H
H
O
O
g
h
i
3.2. Experimental procedures and spectral data
HO
BnO
BnO
O
O
O
OH
OBn
OBn
H
H
H
3.2.1. 2,3;5,6-Di-O-isopropylidene–
Anhydrous CuSO4 (30 g, 188.6 mmol) was added in one portion
to a suspension of -mannose (20 g, 111.1 mmol) in dry acetone
D-mannofuranose (7)
1-3
NH2
16-18
15
O
O
N
D
NH
N
NH
N
B =
(200 mL); then sulfuric acid (6 drops) was added. The suspension
was stirred for 8 h. The solution was filtered under vacuum and
then stirred with potassium carbonate (3.4 g) at room temperature
until (pH 8). The mixture was filtered through Celite and evapora-
tion of solvent in vacuum gave a white solid, which was dissolved
in CH2Cl2, and filtered through a bed of silica gel topped with Cel-
ite. Evaporation of solvent under reduced pressure gave a white so-
lid. Recrystallisation from diethyl ether–hexane gave 7 as colorless
N
O
N
O
N
3
1
2
Scheme 1. Synthesis of N-homobicyclic-dideoxy nucleosides 1–3. Reagents and
conditions: (a) TMSOI, KOBut, DMSO (b) TsCl, pyridine, DMAP, (c) BiCl3, DCM, (d)
TPP, imidazole, I2, toluene, 80 °C; (e) 5% aq H2SO4, 1,4-dioxane; (f) PdCl2, CuCl, O2,
DMF, H2O, rt; (g) NaH, BnBr, DMF, rt; (h) NaH, DMF, nucleoside base, 90 °C; (i)
Pd(OH)2–H2.

N. Raghavendra Swamy et al. / Carbohydrate Research 352 (2012) 191–196
193
crystals in (24.6 g 94.4 mmol) 85% yield. Mp 119–121 °C; [
a
]
21.8; FABMS: 429 (M+1)+; HRMS (ESI+): calcd for C20H29O8S
429.2267, observed 429.2260 (M+H)+.
D
+12.1 (c 1.1, CHCl3); IR: mmax (KBr) 3441 cmꢀ1 (OH); 1H NMR
(200 MHz, CDCl3): d 1.3 (s, 3H), 1.32 (s, 3H), 1.35 (s, 3H), 1.4 (s,
3H), 3.0 (br s, 1H, OH), 4.0 (dd, 1H, J = 5.1, 8.6 Hz, H-6), 4.1 (dd,
1H, J = 6.0, 8.6 Hz, H-61), 4.15 (dd, 1H, J = 3.7, 7.2 Hz, H-4), 4.3–
4.4 (m, 1H, H-5), 4.6 (d, 1H, J = 5.9 Hz, H-2), 4.8 (dd, 1H, J = 3.7,
5.9 Hz, H-3), 5.31 (br s, 1H, H-1); FABMS: 261 (M+1)+; Anal. Calcd
for C12H20O6: C, 55.37; H, 7.74. Found: C, 55.33; H, 7.71.
3.2.4. 6-(2,2-Dimethyl-1,3-dioxolan-4yl)-2,2-dimethyl-4
(4-ethylphenylsulfonyloxymethyl)-(3aR,4R,6aS)-perhy-
drofuro[3,4-d][1,3]-dioxole (19)
Same procedure as above. Obtained 19 from 9 in 93% yield
(8.71 g, 20.36 mmol) as viscous oil. [
a]
+2.5 (c 1.0, CHCl3); 1H
D
NMR (300 MHz, CDCl3): d 1.31 (s, 3H), 1.35 (s, 6H), 1.45 (s, 3H),
2.41 (s, 3H), 3.50 (dd, 1H, J7,71 = 10.4 Hz, J6,7 = 5.5 Hz, H-7), 3.8–
4.40 (m, 5H, H-1, H-11, H-2), 4.61–4.72 (m, 2H, H-4, H-5), 7.30
(d, 2H, J = 8.0 Hz), 7.81 (d, 2H, J = 8.0 Hz); 13C NMR (50 MHz,
CDCl3): d 145.5, 132.7, 130.0, 128.0, 113.2, 109.2, 83.0, 81.0, 80.0,
73.5, 69.8, 66.8, 27.0, 26.0, 25.0, 24.5, 21.8; FABMS: 429 (M+1)+;
HRMS (ESI+): calcd for C20H29O8S 429.2267, observed 429.2262
(M+H)+.
3.2.2. 3,6-Anhydro-1,2,4,5-di-O-isopropylidene-
-manno-heptitol (8), and 3,6-anhydro-1,2;4,5-di-O-iso-
propylidene- -glycero-
-galacto-heptitol (9)63
A mixture of trimethylsulfoxonium iodide (25.2 g, 114.5 mmol)
and potassium-tert-butoxide (11.2 g, 100 mmol) in dry dimethyl-
sulfoxide (100 mL) was stirred for 30 min at 10 °C. A solution of
D-glycero-
D
D
D
2,3;5,6-di-O-isopropylidene-
a-
D-mannofuranose
7
(20 g,
76.92 mmol) in dimethylsulfoxide (50 mL) was added to the above
reaction mixture and brought to room temperature and stirred for
1 h. When the reaction was complete, it was quenched by the addi-
tion of saturated aqueous ammonium chloride solution (100 mL)
and was extracted into diethyl ether (3 ꢁ 75 mL). The combined
organic phase was washed with water (2 ꢁ 50 mL), dried over
Na2SO4, and concentrated under reduced pressure to obtain a res-
idue that was filtered on a bed of Silica Gel 60–120 mesh eluted
with hexane–EtOAc (1:1). This gave a diastereomeric mixture of
8 and 9 (16.65 g, 79%) from which the title compound 8 (4.75 g,
17.3 mmol) was separated as white needles by fractional crystalli-
zation using dichloromethane–hexane (1:4) 8 and 9 (2:5 ratio).
This mixture was passed through silica gel column chromatogra-
phy using 30% ethylacetate and hexane to give the pure diastereo-
3.2.5. 6-(1,2-Dihydroxyethyl)-2,2-dimethyl-4-(4-methylphenyl-
sulfonyloxymethyl)-(3aR,4S,6aS)-perhydrofuro[3,4-d][1,3]-
dioxole (11)
To a solution of compound 10 (10 g, 23.41 mmol) in CH2Cl2
(35 mL) was added bismuth trichloride (150 mg) and stirred at
room temperature for 2 h. Reaction was monitored by TLC and
on completion of the reaction, NaHCO3 (3 g) and water (50 mL)
were added and extracted into CH2Cl2 (3 ꢁ 25 mL). The combined
organic layer was dried over Na2SO4 and concentrated under vac-
uum to give a residue, which was chromatographed SiO2, 60–120
mesh; hexane–EtOAc (2:1) to yield 11 in 85% (7.70 g, 19.90 mmol)
yield. [a] ;
+2.7 (c 1.0, CH3OH); IR: mmax (KBr) 3481.5, 3569 cmꢀ1
D
1H NMR (300 MHz, CDCl3): d 1.31 (s, 3H), 1. 51 (s, 3H), 2.0 (br s,
1H, OH), 2.52 (s, 3H), 2.61 (br s, 1H, OH), 3.51–3.71 (m, 2H, H-7,
H-71), 3.72–3.91 (m, 2H, H-1, H-11), 3.95 (d, 1H, J = 5.0 Hz, H-3),
4.05 (d, 1H, J = 5.5 Hz, H-6), 4.25 (d, 1H J = 5.5 Hz, H-6), 4.81 (d,
1H, J = 7.0 Hz), 7.41 (d, 2H, J = 8.0 Hz), 7.82 (d, 2H, J = 8.1 Hz); 13C
NMR (50 MHz, CDCl3): d 145.2, 132.5, 129.9, 127.8, 113.09, 82.2,
81.4, 70.5, 69.5, 64.2, 28.8, 26.1, 24.6, 21.5; FABMS: 389 (M+1)+;
HRMS (ESI+): calcd for C17H25O8S 389.4407, observed 389.4406
(M+H)+.
mers 8 and 9. Data for 8: mp 83–85 °C; [
a
]
D
ꢀ12.6 (c 1.0, CHCl3);
IR: mmax (KBr) 3600 cmꢀ1 (OH); 1H NMR (300 MHz, CDCl3): d 1.31
(s, 3H), 1.32 (s, 3H), 1.42 (s, 3H), 1.51 (s, 3H), 3.6 (m, 2H, H-6,7),
4.0 (m, 1H, H-1), 4.15 (m, 2H, H-11, 6), 4.41 (m, 1H, H-2), 4.62
(m, 1H, H-3), 4.81 (m, 1H, H-4); 13C NMR (50 MHz, CDCl3): d
112.7, 108.9, 84.7, 82.4, 81.3, 80.9, 73.6, 66.4, 62.0, 26.5, 25.8,
24.8, 24.3; FABMS: 276 (M+1)+; Anal. Calcd for C13H22O6: C,
56.92; H, 8.08. Found: C, 56.84; H, 7.95. Data for 9: Obtained 9
(11.9 g, 43 mmol) as viscus liquid. [
a
]
D ꢀ9.0 (c 2.6, CHCl3); IR: mmax
(KBr) 3600 cmꢀ1 (OH); 1H NMR (200 MHz, CDCl3): d 1.31 (s, 3H),
1.35 (s, 3H), 1.45 (s, 3H), 1.49 (s, 3H), 2.21 (br s, 1H, OH), 3.49 (d,
1H, J = 3.0 Hz), 3.6–4.10 (m, 5H, 11, 3, 6, 7, 71), 4.35 (m, 1H, H-2),
4.6–4.7 (m, 2H, H-4, H-5); 13C NMR (50 MHz, CDCl3): d 112.7,
108.9, 84.8, 82.4, 81.3, 80.9, 73.6, 66.4, 62.0, 26.5, 25.8, 24.8,
24.3; FABMS: 275 (M+1)+; Anal. Calcd for C13H22O6: C, 56.84; H,
7.95. Found: C, 56.77, H, 7.89.
3.2.6. 6-(1,2-Dihydroxyethyl)-2,2-dimethyl-4-(4-methylphenyl-
sulfonyloxymethyl)-(3aR,4R,6aS)-perhydrofuro[3,4-d][1,3]-
dioxole (20)
Same procedure as above. Obtained 20 from 19 (5.39 g,
13.90 mmol) in 85% as syrup. [a]
+6.5 (c 1.0, MeOH); 1H NMR
D
(300 MHz, CDCl3): d 1.31 (s, 3H), 1.42 (s, 3H), 2.5 (s, 3H) 3.5 (dd,
1H, J = 5.0, 8.0 Hz), 3.61–3.71 (m, 1H), 3.72–3.8 (m, 1H), 3.81–
3.92 (m, 1H), 4.11–4.21 (m, 2H), 4.22–4.31 (m, 1H), 4.61–4.71
(m, 1H), 4.75–4.81 (m, 1H), 7.31 (d, 2H, J = 8.0 Hz, Ar), 7.81 (d,
2H, J = 8.0 Hz, Ar); 13C NMR (50 MHz, CDCl3): d 145.2, 132.5,
129.9, 127.8, 113.1, 82.2, 81.4, 70.5, 69.5, 64.2, 28.8, 26.1, 24.7,
21.5; FABMS: 389 (M+1)+; HRMS (ESI+): calcd for C17H25O8S
389.4407, observed 389.4404 (M+H)+.
3.2.3. 6-(2,2-Dimethyl-1,3-dioxolan-4yl)-2,2-dimethyl-4
(4-methylphenylsulfonyloxymethyl)-(3aR,4S,6aS)-perhy-
drofuro[3,4-d][1,3]dioxole (10)
To a stirred solution of the alcohol 8 (15 g, 54.7 mmol) in pyri-
dine (100 mL) at 0 °C were added p-toluenesulfonyl chloride
(12.48 g, 65.7 mmol) and catalytic amount of DMAP (100 mg)
and the mixture stirred for 30 min and brought to room tempera-
ture and stirred for 3 h. The reaction mixture was diluted with
chilled water (200 mL) and ether was added and the organic layer
was separated. The aqueous phase was extracted with diethyl
ether (2 ꢁ 75 mL) and the combined organic layer was dried over
Na2SO4, filtered, and concentrated to obtain 10 in 92% yield
3.2.7. 2,2-Dimethyl-4-(4-methylphenylsulfonyloxymethyl)-
6-vinyl-(3aR,4R,6aS)-perhydrofuro[3,4-d][1,3]-dioxole (12)
A mixture of compound 11 (7 g, 22.29 mmol), triphenylphos-
phine (18.95 g, 72.35 mmol) and imidazole (4.91 g, 72.2 mmol)
was heated to 78 °C in toluene (150 mL) with stirring, while adding
iodine (18.37 g, 144.70 mmol) in small portions. The white, finely
dispersed complex that initially formed was transformed into clear
yellow solution that darkened as an iodine tarry complex was
formed from which the product was gradually dissolved. After
15 min, the reaction mixture was cooled and iodine (18.37 g,
144.70 mmol) was added, followed by aqueous 10% sodium
hydroxide (100 mL). The mixture was stirred until virtually all of
the tarry red deposits were dissolved and extracted into EtOAc
(21.50 g, 50.36 mmol); mp 105–107 °C; [a] +2.0 (c 1.0, CHCl3);
D
1H NMR (300 MHz, CDCl3): d 1.31 (s, 3H), 1.35 (s, 3H), 1.40 (s,
3H), 1.45 (s, 3H), 2.42 (s, 3H), 3.80–3.85 (m, 2H, H-7, H-71), 3.92–
4.15 (m, 4H, H-3, H-1. H-11, H-6), 4.21 (m, 1H, H-2), 4.85 (m, 2H,
H-4, H-5), 7.39 (d, 2H, J = 8.0 Hz, Ar), 7.81 (d, 2H, J = 8.0 Hz, Ar);
13C NMR (50 MHz, CDCl3): d 145.5, 132.7, 130.0, 128.0, 113.2,
109.2, 83.0, 81.0, 80.0, 73.5, 69.8, 66.8, 27.0, 26.0, 25.0, 24.5,

194
N. Raghavendra Swamy et al. / Carbohydrate Research 352 (2012) 191–196
(3 ꢁ 50 mL) the combined organic layer was washed successively
with water, saturated aqueous sodium thiosulphate, saturated
aqueous NaHCO3, and brine. The organic layer was dried over
Na2SO4, filtered, and concentrated in vacuum. The residue was
purified by column chromatography 60–120 mesh; 2–5% EtOAc
in hexane as the eluant to gave 12 in 87% yield (5.57 g,
(3 ꢁ 50 mL). The combined ethereal solution was washed with
water, dried over Na2SO4, filtered, and concentrated to obtain 14
in 90% yield (2.83 g, 8.57 mmol) as an oil. [a]D +50.7 (c 1.0, CHCl3);
1H NMR (300 MHz, CDCl3): d 0.91 (br s, 1H, OH), 2.11–2.21 (m, 2H),
2.52 (s, 3H), 3.41 (br s, 1H, OH), 4.0–4.11 (m, 2H), 4.21–4.52 (m,
2H), 4.61 (m, 1H), 4.82 (m, 1H), 5.71 (m, 1H), 7.41 (d, 2H,
J = 8.0 Hz, Ar), 7.81 (d, 2H, J = 8.0 Hz, Ar); 13C NMR (50 MHz, CDCl3):
d 145.4, 133.1, 130.3, 128.3, 100.7, 100.2, 84.0, 82.6, 81.7, 81.1,
80.8, 79.3, 73.1, 73.0, 70.1, 69.7, 42.8, 42.1, 22.0; FABMS: 330
(M+1)+; HRMS (ESI+): calcd for C14H19O7S 331.3841, observed
330.3844 (M+H)+.
15.74 mmol); mp 109–111 °C; [
a
]
D
ꢀ19.3 (c 1.0, CHCl3); IR: mmax
(KBr) 1598.9 cmꢀ1 1H NMR (200 MHz, CDCl3): d 1.31 (s, 3H),
;
1.42 (s, 3H), 2.51 (s, 3H), 4.0–4.11 (m, 1H), 4.12 (m, 1H), 4.29 (d,
1H, J = 4.0 Hz), 4.33 (d, 1H, J = 4.0 Hz), 4.62 (d, 1H, J = 4.0 Hz),
4.71 (d, 1H, J = 4.0 Hz), 5.32 (d, 1H, J = 5.0 Hz), 5.33 (d, 1H,
J = 8.0 Hz), 5.81–5.92 (m, 1H), 7.4 (d, 2H, J = 7.0 Hz, Ar), 7.8 (d,
2H, J = 7.0 Hz, Ar); 13C NMR (50 MHz, CDCl3): d 133.9, 131.3,
129.3, 120.1, 114.1, 84.9, 83.9, 82.7, 71.5, 27.5, 26.1, 22.9; FABMS:
355 (M+1)+; HRMS (ESI+): calcd for C17H23O6S 355.4260, observed
355.4262 (M+H)+.
3.2.12. ((2S,3R,3aR,6aR)-3,5-Dihydroxyhexahydrofuro[3,2-b]-
furan-2-yl)methyl 4-methylbenzenesulfonate (23)
Same procedure as above. Obtained 23 from 22 (2.33 g,
7.08 mmol) in 89% yield as semisolid. [
a
]
ꢀ44.5 (c 1.0, CHCl3);
D
1H NMR (300 MHz, CDCl3): d 0.91 (br s, 1H, OH), 2.21 (m, 2H),
2.51 (m, 3H), 3.41 (br s, 1H, OH), 4.11 (m, 2H), 4.31 (m, 2H), 4.61
(m, 1H), 4.81 (m, 1H), 5.61 (m, 1H), 7.32 (d, 2H, J = 8.0 Hz, Ar),
7.82 (d, 2H, J = 8.0 Hz, Ar). FABMS: 331 (M+1)+; HRMS (ESI+): calcd
for C14H19O7S 331.3841, observed 331.3842 (M+H)+.
3.2.8. 2,2-Dimethyl-4-(4-methylphenylsulfonyloxymethyl)-
6-vinyl-(3aR,4S,6aS)-perhydrofuro[3,4-d][1,3]-dioxole (21)
Same procedure as above. Obtained 21 from 20 (3.93 g,
11.1 mmol) in 86% as viscous oil. [
a]
+12.6 (c 1.0, CHCl3); 1H
D
NMR (300 MHz, CDCl3): d 1.31 (s, 3H), 1.42 (s, 3H), 2.51 (s, 3H),
3.72 (dd, 1H, J = 5.0, 8.0 Hz), 3.92 (dd, 1H, J = 5.0, 8.0 Hz), 4.0–
4.21 (m, 1H), 4.31–4.36 (m, 1H), 4.6–4.7 (m, 1H), 4.75 (m, 1H),
5.32 (d, 1H, J = 9.0 Hz), 5.36 (d, 1H, J = 9.0 Hz), 5.82–5.92 (m, 1H),
7.31 (d, 2H, J = 8.0 Hz, Ar), 7.92 (d, 1H, J = 8.0 Hz, Ar); FABMS:
355 (M++1); HRMS (ESI+): calcd for C17H23O6S 355.4260, observed
355.4266 (M+H)+.
3.2.13. 3,5-Di(benzyloxy)-2-(4-methylphenylsulfonyloxymeth-
yl)-(2R,3R,3aR,6aS)-perhydrofuro[3,2-b]furan (15)
To a cool stirred suspension of NaH (60% 0.545 g, 22.72 mmol)
in dry DMF (15 mL), was added a solution of compound 14 (2.5 g,
7.57 mmol) in dry DMF (10 mL). After 15 min, benzyl bromide
(1 mL 9.09 mmol) was added to the reaction mixture, stirring
was continued for 1 h at 0 °C temperature, the reaction was
quenched by the addition of crushed ice, and diluted with water
(25 mL). The reaction mixture was extracted into ether
(3 ꢁ 100 mL). The combined organic layer was washed with brine
solution, dried over anhydrous Na2SO4, and concentrated under re-
duced pressure to give a crude product, which was purified on a
silica gel column, eluting with 3–5% EtOAc in hexane to give 15
as a pale yellow gum (3.67 g, 7.19 mmol) in 95% yield as syrup.
3.2.9. 3,4-Dihydroxy-2-(4-methylphenylsulfonyloxymethyl)-
5-vinyl-(2R,3S,4S)-tetrahydrofuran (13)
To a solution of 12 (4.5 g, 14.33 mmol) in 1,4-dioxane (20 mL)
was added 5% aq sulfuric acid (5 mL), stirred at 80 °C temperature
for 2 h. After completion of the reaction, solvent was removed in
vacuum to obtain a residue, which was extracted in to EtOAc
(3 ꢁ 50 mL). The combined organic layer was washed with satu-
rated NaHCO3 solution, water, dried anhydrous Na2SO4 (5 g), fil-
tered, and concentrated to obtain the corresponding diol as
viscous oil, which was purified by column chromatography 60–
120 mesh; hexane–EtOAc (1:3) to yield 13 in 85% yield (3.39 g,
[a]
+89.2 (c 1.0, MeOH); 1H NMR (200 MHz, CDCl3): d 2.11 (dd,
D
1H, J = 7.5, 11.5 Hz), 2.31 (dd, 1H, J = 7.5, 11.5 Hz), 2.41 (s, 3H),
3.81 (m, 1H), 3.91 (m, 1H), 4.11 (m, 1H, J = 7.5, 11.5 Hz), 4.32 (dd,
1H, J = 7.5, 11.5 Hz), 4.41 (m, 1H), 4.51 (d, 2H), 4.61 (d, 2H),
4.71–4.81 (m, 1H), 5.41 (d, 1H, J = 7.5 Hz), 7.21–7.42 (m, 12H,
Ar), 7.81 (d, 2H, Ar); 13C NMR (50 MHz, CDCl3): d 144.8, 138.0,
137.4, 129.8, 128.5, 128.4, 128.1, 127.9, 127.8, 127.7, 105.2, 81.8,
78.5, 76.5, 72.5, 69.6, 68.6, 41.8, 21.6; FABMS: 512 (M+1)+; HRMS
(ESI+): calcd for C28H31O7S 512.6066, observed 512.6060 (M+H)+.
10.80 mmol) as a syrup. [
a] +32.5 (c 1.0, CHCl3); IR: mmax (KBr):
D
3414, 1716, 1682, 1599 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d 2.5
(s, 3H), 4.0 (m, 1H), 4.12 (m, 1H), 4.2–4.3 (m, 3H), 4.35–4.4 (m,
1H), 5.31 (d, 1H, J = 6.0 Hz), 5.35 (d, 1H, J = 8.0 Hz), 5.8–6.0 (m,
1H), 7.4 (d, 2H, J = 8.0 Hz, Ar), 7.81 (d, 2H, J = 8.0 Hz, Ar); 13C
NMR (50 MHz, CDCl3): d 145.1, 133.2, 132.8, 130.0, 128.01, 118.9,
82.1, 79.7, 73.2, 73.0, 70.0, 21.7; FABMS: 315 (M+1)+; HRMS
(ESI+): calcd for C14H19O6S 315.3621, observed 315.3622 (M+H)+.
3.2.14. 3,5-Di(benzyloxy)-2-(4-methylphenylsulfonyloxymeth-
yl)-(2S,3R,3aR,6aS)-perhydro furo[3,2-b]furan (24)
Same procedure as above. Obtained 24 from 23 (2.93 g,
3.2.10. 3,4-Dihydroxy-2-(4-methylphenylsulfonyloxymethyl)-
5-vinyl-(2S,3S,4S)-tetrahydro furan (22)
5.75 mmol) in 95% yield as semisolid. [a] +19.5 (c 1.0, MeOH);
D
1H NMR (200 MHz, CDCl3): d 2.0–2.21 (m, 2H), 2.51 (s, 3H), 3.81–
3.91 (m, 1H), 4.11–4.21 (m, 2H), 4.25 (d, 1H, J = 7.0 Hz), 4.41 (d,
1H, J = 7.5 Hz), 4.51 (d, 1H, J = 7.5 Hz), 4.61 (m, 1H), 4.70 (m, 1H),
4.81 (m, 2H); FABMS: 512 (M+1)+; HRMS (ESI+): calcd for
Same procedure as above. Obtained 22 from 21 (2.6 g,
8.3 mmol) in 84% yield as syrup. [
a
]
ꢀ27.6 (c 1.0, CHCl3); 1H
D
NMR (300 MHz, CDCl3): d 2.41 (s, 3H), 3.22 (br s, 2H, OH), 3.9–
4.0 (m, 1H), 4.11 (m, 1H), 4.22 (m, 1H), 4.31 (m, 1H), 4.31–4.41
(m, 2H), 5.22–5.31 (m, 2H), 5.81–5.91 (m, 1H), 7.31 (d, 2H,
J = 8.0 Hz), 7.81 (d, 2H, J = 8.0 Hz); FABMS: 315 (M+1)+; HRMS
(ESI+): calcd for C14H19O6S 315.3621, observed 315.3620 (M+H)+.
C
28H31O7S 512.6066, observed 512.6062 (M+H)+.
3.2.15. 1-[3,5-Di(benzyloxy)-(2R,3R,3aR,6aS)-perhydrofuro[3,2-
b]furan-2-yl-methyl]-1,2,3,4-tetrahydro-2,4-pyrimidinedione
(16)
3.2.11. ((2R,3R,3aR,6aR)-3,5-Dihydroxyhexahydrofuro[3,2-b]-
furan-2-yl)methyl 4-methylbenzenesulfonate (14)
A mixture of uracil (0.043 g, 0.39 mmol) and NaH (60% 0.028 g,
1.16 mmol) in DMF (5 mL) was stirred at 90 °C for 15 min. Then,
compound 15 (0.1 g, 0.19 mmol) in DMF (5 mL) was added to the
reaction mixture and heated at 90 °C for 3 h. The reaction mixture
was cooled to room temperature and the solvent was removed in
vacuo to give the crude product which was filtered on a bed of Sil-
ica Gel 60–120 mesh, eluting with hexane–EtOAc (1:10) to obtain
To a solution of 13 (3 g, 9.55 mmol) in DMF–H2O (4:1, 20 mL)
was added palladium(II) chloride (0.169 g, 0.955 mmol), copper(I)
chloride (1.04 g, 10.50 mmol), and oxygen was bubbled in for 4 h
at room temperature. After completion of the reaction 2% HCl
was added and the mixture was extracted with diethyl ether

N. Raghavendra Swamy et al. / Carbohydrate Research 352 (2012) 191–196
195
16 in 60% yield (0.052 g, 0.11 mmol) as semisolid. [
a
]
+3.0 (c 0.5,
(br s, 1H, NH); FABMS: 465 (M+1)+.; HRMS (ESI+): calcd for
26H29N2O6 465.5183, observed 465.5184 (M+H)+.
D
MeOH); 1H NMR (200 MHz, CDCl3): d 2.0–2.11 (m, 1H), 2.61 (m,
1H), 3.51 (m, 1H), 3.91–4.0 (m, 3H), 4.41 (m, 1H), 4.45–4.6 (m,
4H), 4.71 (d, 1H, J = 6.0 Hz), 4.75–4.82 (m, 1H), 5.42 (d, 1H,
J = 7.5 Hz), 5.51 (d, 1H, J = 8.0 Hz) 7.21–7.41 (m, 10H, Ar), 8.51 (br
s, 1H, NH); 13C NMR (50 MHz, CDCl3): d 145.4, 137.8, 137.3,
128.4, 128.3, 128.9, 127.8, 127.6, 104.9, 101.6, 81.6, 80.1, 78.3,
76.3, 72.6, 69.4, 47.9, 41.8; FABMS: 451 (M+1)+; HRMS (ESI+): calcd
for C25H27N2O6 451.4917, observed 451.4916 (M+H)+.
C
3.2.20. 1-[3,5-Di(benzyloxy)-(2S,3R,3aR,6aS)-perhydrofuro-
[3,2-b]-furan-2-yl-methyl]-5-methyl,1,2,3,4-tetrahydro-2,4-
pyrimidinedione (27)
Same procedure as above. Obtained 27 from 24 in 56% yield
(0.050 g, 0.10 mmol) as a semisolid. [a]
+49.6 (c 1.0, CHCl3); 1H
D
NMR (300 MHz, CDCl3): d 1.81 (s, 3H), 2.12–2.21 (m, 2H), 3.61–
3.71 (m, 1H), 3.81–3.92 (m, 2H), 4.31–4.41 (m, 1H), 4.45 (d, 1H,
J = 9.0 Hz), 4.67 (d, 1H, J = 9.0 Hz), 4.69 (m, 1H), 4.75 (m, 2H),
4.81 (d, 1H, J = 7.0 Hz), 5.31 (d, 1H, J = 6.0 Hz), 6.91 (br s, 1H),
7.21–7.31 (m, 8H, Ar), 7.41 (d, 2H, J = 8.0 Hz), 9.71 (br s, 1H, NH);
FABMS: 465 (M+1)+.; HRMS (ESI+): calcd for C26H29N2O6
465.5183, observed 465.5182 (M+H)+.
3.2.16. 1-[3,5-Di(benzyloxy)-(2S,3R,3aR,6aS)-perhydrofuro[3,2-
b]furan-2-ylmethyl]-1,2,3,4-tetrahydro-2,4-pyrimidinedione
(25)
Same procedure as above. Obtained 25 from 24 in 59% yield
(0.052 g, 0.11 mmol) as a semisolid. [a]
+37.0 (c 0.5, CHCl3); 1H
D
NMR (300 MHz, CDCl3): d 2.11–2.21 (m, 2H), 3.62 (m, 1H), 3.81
(m, 2H), 4.11–4.21 (m, 1H), 4.31–4.41 (m, 1H), 4.45 (d, 1H,
J = 8.0 Hz), 4.61 (d, 1H, J = 8.0 Hz), 4.72 (d, 1H, J = 7.0 Hz), 4.72–
4.82 (m, 3H), 5.31 (d, 1H, J = 6.0 Hz) 5.51 (d, 1H, J = 7.0 Hz); FABMS:
451 (M+1)+; HRMS (ESI+): calcd for C25H27N2O6 451.4917, observed
451.4912 (M+H)+.
3.2.21. 1-[3,5-Dihydroxy-(2R,3R,3aR,6aS)-perhydrofuro[3,2-b]-
furan-2-yl-methyl]-1,2,3,4-tetrahydro-2,4-pyrimidinedione (1)
A solution of 16 (0.04 g, 0.08 mmol) in MeOH (5 mL), palladium
hydroxide (5 mg) was stirred under hydrogen atmosphere (1 atm)
at room temperature. After 3 h, catalyst was filtered washed with
MeOH (2 ꢁ 10 mL). The filtrate was concentrated under reduced
pressure, which was purified on a small bed of silica gel (5–95%
3.2.17. 9-[3,5-Di(benzyloxy)-(2R,3R,3aR,6aS)-perhydrofuro[3,2-
b]furan-2-yl-methyl]-9H-pyrinamine (17)
CHCl3–CH3OH) to afford the title compound
1
(0.022 g,
A mixture of adenine, (0.10 g, 0.39 mmol) and NaH (60% 0.028 g,
1.17 mmol) in dry DMF (5 mL) was stirred at 90 °C for 15 min.
Then, compound 15 (0.1 g, 0.19 mmol) in DMF (5 mL) was added
and the reaction mixture was kept at 90 °C for 3 h. The reaction
mixture was cooled to room temperature and the solvent was re-
moved in vacuo to give the crude product, which was filtered on
a bed of silica gel (SiO2, 60–120 mesh; hexane–EtOAc (1:10) to ob-
0.084 mmol) in 95% yield, as a semisolid. [ D +68.0 (c 2.0, CH3OH);
a]
1H NMR (300 MHz, CD3OD): d 2.0–2.11 (m, 2H), 2.6 (br s, 1H, OH),
3.41–3.62 (m, 1H), 3.71–3.92 (m, 2H), 4.11–4.21 (m, 1H), 4.51 (m,
1H), 4.71 (m, 1H), 5.11 (m, 1H), 5.61 (d, 1H, J = 5.0 Hz), 7.52 (d, 1H,
J = 5.0 Hz); 13C NMR (50 MHz, CDCl3): d 148.1, 107.9, 101.8, 85.5,
82.3,82.1, 79.5, 78.8, 75.8, 75.6, 50.6, 50.4, 44.6, 42.5, 42.2, 31.9;
FABMS: 271 (M+1)+; HRMS (ESI+): calcd for C11H15N2O6
271.2467, observed 271.2464 (M+H)+.
tain 17 in 58% yield (0.053 g, 0.11 mmol) as semisolid. [a]D +60.7 (c
1.0, MeOH); 1H NMR (200 MHz, CDCl3): d 2.11–2.21 (m, 1H), 2.31–
2.35 (m, 1H), 3.30 (m, 1H), 4.11 (m, 1H), 4.31 (m, 1H), 4.41 (dd, 1H,
J = 6.0, 11.0 Hz), 4.51 (dd, 3H, J = 6.0, 11.0 Hz), 4.61 (d, 2H,
J = 9.0 Hz), 4.71 (m, 1H), 5.41 (d, 1H, J = 8.0 Hz), 5.91 (br s, 2H,
NH2), 7.21–7.41 (m, 10H, Ar), 7.81 (s, 1H), 8.41 (s, 1H); FABMS:
474 (M+1)+; HRMS (ESI+): calcd for C26H28N5O4 474.5317, observed
474.5322 (M+H)+.
3.2.22. 1-[3,5-Dihydroxy-(2R,3R,3aR,6aS)-perhydrofuro[3,2-b]-
furan-2-ylmethyl]-1,2,3,4-tetrahydro-2,4-pyrimidinedione (4)
Same procedure as above. Obtained 4 from 25 yield (0.022 g,
0.084 mmol) in 94% yield as semisolid. [a] +73.0 (c 2.0, CH3OH);
D
1H NMR (300 MHz, CD3OD): d 2.0–2.21 (m, 2H), 2.62 (br s, 1H,
OH), 3.41–3.61 (m, 1H), 3.71–3.91 (m, 2H), 4.11–4.21 (m, 1H),
4.51 (m, 1H), 4.81 (m, 1H), 5.21 (m, 1H), 5.61 (d, 1H, J = 5.0 Hz),
7.51 (d, 1H, J = 5.0 Hz); FABMS: 271 (M+1)+; HRMS (ESI+): calcd
for C11H15N2O6 271.2467, observed 271.2468 (M+H)+.
3.2.18. 9-[3,5-Di(benzyloxy)-(2S,3R,3aR,6aS)-perhydrofuro[3,2-
b]furan-2-yl-methyl]-9H-6-pyrinamine (26)
Same procedure as above. Obtained 26 from 24 in 57% yield
(0.052 g, 0.11 mmol) as semisolid. [
a
]
+4.3 (c 1.0, CHCl3); 1H
3.2.23. 5-(6-Amino-9H-9-purinylmethyl)-(3aS,5R,6R,6aR)-per-
hydrofuro[3,2-b]-furan 2,6-diol (2)
D
NMR (300 MHz, CDCl3): d 2.41–2.51 (m, 2H), 3.52 (m, 1H), 4.31–
4.41 (m, 1H), 4.51 (d, 1H, J = 7.5 Hz), 4.51 (d, 1H, J = 7.5 Hz),
4.61–4.71 (m, 1H), 4.77–4.81 (m, 3H), 4.86 (d, 2H, J = 9.0 Hz),
5.31 (d, 1H, J = 7.0 Hz), 6.11 (br s, 2H), 7.21–7.41 (m, 10H, Ar),
7.71 (s, 1H, base), 8.31 (s, 1H); FABMS: 474 (M+1)+; HRMS (ESI+):
calcd for C26H28N5O4 474.5317, observed 474.5320 (M+H)+.
A solution of 17 (0.045 g, 0.095 mmol) in CH3OH (5 mL), palla-
dium hydroxide (5 mg) was stirred under hydrogen atmosphere
(1 atm) at room temperature. After 3.5 h catalyst was filtered
washed with CH3OH (2 ꢁ 10 mL). The filtrate was concentrated un-
der reduced pressure, which was purified on a small bed of silica
gel (20–30% EtOAc hexane) to afford the title compound 2
3.2.19. 1-[3,5-Di(benzyloxy)-(2R,3R,3aR,6aS)-perhydrofuro[3,2-
b]furan-2-yl-methyl]-5-methyl-1,2,3,4-tetrahydro-2,4-pyrimi-
dinedione (18)
To a mixture of thymine, (0.049 g, 0.096 mmol) and NaH (60%,
0.028 g, 1.17 mmol) in DMF (5 mL) was stirred at 90 °C for
15 min. Then compound 15 (0.1 g, 0.19 mmol) in DMF (5 mL)
was added and the reaction mixture was kept at 90 °C for 3 h.
The reaction mixture was cooled to room temperature and the sol-
vent was removed in vacuo to give the crude product, which was
filtered on a bed of Silica Gel 60–120 mesh; hexane–EtOAc (1:10)
(0.027 g, 0.095 mmol) in 94% yield as a semisolid. [a] +60.7 (c
D
1.0, CH3OH); 1H NMR (300 MHz, CDCl3): d 2.11–2.21 (m, 1H),
2.81–2.31 (m, 1H), 3.31–3.41 (m, 1H), 4.1–4.15 (m, 1H), 4.21–
4.31 (m, 1H), 4.41 (m, 1H), 4.51 (m, 3H), 4.61 (d, 2H, J = 9.0 Hz),
4.71–4.81 (m, 1H), 5.41 (d, 1H, J = 8.0 Hz), 5.91 (br s, 2H, NH2),
7.21–7.31 (m, 10H, Ar), 7.81 (s, 1H), 8.42 (s, 1H); FABMS: 294
(M+1)+; HRMS (ESI+): calcd for C12H16N5O4 294.2866, observed
294.2864 (M+H)+.
3.2.24. 5-(6-Amino-9H-9-purinylmethyl)-(3aS,5S,6R,6aR)-per-
hydrofuro[3,2-b]-furan-2,6-diol (5)
to obtain 18 in 57% yield (0.051 g, 0.11 mmol), as semisolid. [a]
D
ꢀ31.6 (c 1.0, MeOH); 1H NMR (200 MHz, CDCl3): d 1.91 (s, 3H),
2.1 (m, 1H), 2.31–2.41 (m, 1H), 3.51–3.61 (m, 1H), 3.91–4.0 (m,
2H), 4.31–4.41 (m, 1H), 4.51–4.71 (m, 4H), 4.61–4.81 (m, 1H),
5.41 (d, 1H, J = 6.0 Hz), 7.0 (s, 1H), 7.22–7.42 (m, 10H, Ar), 8.41
Same procedure as above. Obtained 5 from 26 yield (0.027 g,
0.095 mmol) in 94% yield as a semisolid. [a] +4.4 (c 1.0, CHCl3);
D
1H NMR (200 MHz, CD3OD): d 2.12–2.21 (m, 2H), 3.81 (m, 2H),
4.0–4.11 (m, 2H), 4.12 (m, 2H), 4.41–4.51 (m, 1H), 4.61–4.71 (m,

196
N. Raghavendra Swamy et al. / Carbohydrate Research 352 (2012) 191–196
1H), 5.41 (d, 2H), 8.21 (d, 1H), 7.91 (d, 1H); FABMS: 294 (M+1)+;
HRMS (ESI+): calcd for C12H16N5O4 294.2866, observed 294.2865
(M+H)+.
9. Jung, M. E.; Nichols, C. J.; Kretschik, O.; Xu, Y. Nucleosides Nucleotides 1999, 18,
541–546.
10. Togo, H. W.; Waki, Y.; Yokoyama, M. Synlett 1998, 321–322.
11. Antonakis, K. Adv. Carbohydr. Chem. Biochem. 1984, 42, 227–264.
12. Sterzycki, R. Z.; Martin, J. C.; Wittman, M.; Brankovan, V.; Yang, H.; Hitchcock,
M. J.; Mansuri, M. M. Nucleosides Nucleotides 1991, 10, 291–294.
13. Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745–1768.
14. Pfleiderer, W. In Chemistry of Nucleosides and Nucleotides; Townsend, L. B., Ed.;
Plenum Press: New York, 1994; Vol. 3, p 145.
3.2.25. 1-[3,5-Dihydroxy-(2R,3R,3aR,6aS)-perhydrofuro[3,2-b]-
furan-2-yl-methyl]-5-methyl-1,2,3,4-tetrahydro-2,4-pyrimi-
dinedione (3)
15. Knutsen Lars, J. S. Nucleosides Nucleotides 1992, 11, 961–983.
16. Watanabe, K. A. The Chemistry of C-nucleosides In Chemistry of Nucleosides and
Nucleotides; Townsend, L. B., Ed.; Plenum: New York, 1994; Vol. 3, p 421.
17. Chaudhuri, N. C.; Ren, R. X. F.; Kool, E. T. Synlett 1997, 341–347.
18. Shaban, M. A. E. Adv. Heterocycl. Chem. 1997, 68, 223–432.
19. Shaban, M. A. E. Adv. Heterocycl. Chem. 1997, 70, 163–337.
20. Jorgensen, P. N.; Wengel, J. Stud. Nat. Prod. Chem. 1997, 19, 511 (Structure and
chemistry part E).
To a solution of 18 (0.04 g, 0.086 mmol) in CH3OH (5 mL), palla-
dium hydroxide (5 mg) was stirred under hydrogen atmosphere
(1 atm) at room temperature. After 3 h catalyst was filtered and
washed with CH3OH (2 ꢁ 10 mL). The filtrate was concentrated un-
der reduced pressure, which was purified on a small bed of silica
gel (5–95% CHCl3–CH3OH) to afford the title compound
(0.024 g, 0.086 mmol) in 93% yield as a semisolid. [ ] +32.2 (c
D
3
21. Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571–623.
22. Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S. R.; Earl, R. A.;
Guedj, R. Tetrahedron 1994, 50, 10611–10670.
a
2.0, CH3OH); 1H NMR (300 MHz, CD3OD): d 1.81 (s, 3H), 2.11–
2.22 (m, 2H), 3.71–3.81 (m, 2H), 4.01–4.21 (m, 1H), 4.41–4.05
(m, 1H), 4.51–4.81 (m, 2H, OH), 5.11 (br d, 1H, J = 5.0 Hz), 7.42 (s,
1H); FABMS: 285 (M+1)+; HRMS (ESI+): calcd for C12H17N2O6
285.2732, observed 285.2734 (M+H)+.
23. Crimmins, M. T. Tetrahedron 1998, 54, 9229–9272.
24. Zhu, X.-F. Nucleosides, Nucleotides Nucleic Acids 2000, 19, 651–690.
25. Herdewijn, P.; Van Aerschot, A.; Balzarini, J.; De Clercq, E. Nucleosides
Nucleotides 1991, 10, 119–127.
26. Herdewijn, P. Spec. Publ.-R. Soc. Chem. 1997, 198, 316–320 (Anti-Infectives).
27. Herdewijn, P. Anhydrohexitols as Conformationally Constrained Furanose
Mimics; Design of an RNA-receptor. In Carbohydrate Mimics; Chapleur, Y.,
Ed.; Wiley-VCH: H. Verlag Gmb, Weinheim, Germany, 1998; p 553.
28. Knapp, S. Chem. Rev. 1995, 95, 1859–1876.
29. Zhang, D.; Miller, M. J. Curr. Pharm. Des. 1999, 5, 73–99.
30. Yokoyama, M.; Momotake, A. Synthesis 1999, 1541–1554.
31. Wang, P.; Hong, J. H.; Cooperwood, J. S.; Chu, C. K. Antiviral Res. 1998, 40, 19–44.
32. Graciet, J. C. G.; Schinazi, R. F. Adv. Antiviral Drug Des. 1999, 3, 1–68.
33. Dueholm, K. L.; Pedersen, E. B. Synthesis 1992, 1–22.
34. Converso, A.; Siciliano, C.; Sindona, G. Targets Heterocycl. Syst. 1998, 2, 17–25.
35. Lamberth, C. Org. Prep. Proced. Int. 1999, 31, 379–397.
36. Nasonov, A. F.; Korshunov, G. A. Russ. Chem. Rev. 1999, 68, 483–505.
37. Chatgilialoglu, C. Farmaco 1999, 54, 321–325.
3.2.26. 1-[3,5-Dihydroxy-(2S,3R,3aR,6aS)-perhydrofuro[3,2-b]-
furan-2-ylmethyl]-5-methyl-1,2,3,4-tetrahydro-2,4-pyrimi-
dinedione (6)
Same procedure as above. Obtained 6 from 27 yield (0.024 g,
0.086 mmol) in 93% yield as a semisolid. [a] +2.0 (c 2, CH3OH);
D
1H NMR (300 MHz, CD3OD), d 1.81 (s, 3H), 2.11–2.22 (m, 2H),
3.71–3.81 (m, 2H), 4.11–4.22 (m, 1H), 4.31–4.41 (m, 1H), 4.45–
4.85 (m, 2H, OH), 5.61 (m, 1H), 7.32 (s, 1H); FABMS: 285 (M+1)+;
HRMS (ESI+): calcd for C12H17N2O6 285.2732, observed 285.2736
(M+H)+.
38. Walczak, K. Pol. J. Chem. 1999, 73, 1613–1629.
39. Taylor, E. W.; Van Roey, P.; Schinazi, R. F.; Chu, C. K. Antiviral Chem. Chemother.
1990, 1, 163–173.
40. Okabe, M.; Sun, R. C. Tetrahedron Lett. 1989, 30, 2203–2206.
41. Beard, A. R.; Butler, P. I.; Mann, J.; Partlett, N. K. Carbohydr. Res. 1990, 205, 87–
91.
42. Webb, T. R.; Mitsuya, H.; Broder, S. J. Med. Chem. 1988, 31, 1475–1479.
43. Yang, C.-O.; Kurz, W.; Eugui, E. M.; Mc Roberts, M. J.; Verheyden, J. P. H.; Kurz, L.
J.; Walker, K. A. M. Tetrahedron Lett. 1992, 33, 41–44.
44. Rodriguez, J. B.; Marquez, V. E.; Nilcklaus, M. C.; Mitsuya, H.; Barchi, J., Jr. J. Med.
Chem. 1994, 37, 3389–3399.
45. Chao, Q.; Nair, V. Tetrahedron Lett. 1995, 36, 7375–7378.
46. Chao, Q.; Nair, V. Tetrahedron Lett. 1997, 38, 1957–1960.
47. Bjorsne, M.; Szabo, T.; Samuelsson, B.; Classon, B. Bioorg. Med. Chem. 1995, 3,
397–402.
4. Conclusions
The syntheses of six N-homobicyclic-dideoxy nucleosides have
been achieved. These bicyclic nucleosides containing [3.3.0] fused
bicyclic carbohydrate moieties may be of biological importance,
as other members of this class are known to possess interesting
cellular activities.
Acknowledgements
48. Xiang, Y.; Schinazi, R. F.; Zhao, K. Bioorg. Med. Chem. Lett. 1996, 6, 1475–1478.
49. Pickering, L.; Nair, V. Nucleosides Nucleotides 1998, 15, 1751–1760.
50. Nakagawa, F.; Okazaki, T.; Naito, A.; Iijima, Y.; Yamazki, M. J. Antibiotics 1985,
38, 823–829.
51. Tulshian, D. B.; Doll, R. J.; Stansberry, M. F.; McPhil, A. T. J. Org. Chem. 1991, 56,
6819–6822.
The authors thank Dr. J. S. Yadav, Director, IICT for his constant
encouragement and the CSIR, MoES New Delhi for financial sup-
port. Special thanks to Dr. Robert Bates of the University of Arizona.
52. Tulshian, D. B.; Czarniecki, M. J. Am. Chem. Soc. 1995, 117, 7009–7010.
53. Bolli, M.; Leumann, C. Angew. Chem., Int. Ed. Engl. 1995, 34, 694–696.
54. Takoy, M.; Bolli, M.; Leumann, C. Helv. Chim. Acta 1994, 77, 716–744.
55. Takoy, M.; Bolli, M.; Schweizer, B.; Leumann, C. Helv. Chim. Acta 1993, 74, 481–
510.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2012.01.018.
56. Altmann, K. H.; Kesselring, R.; Francotte, E.; Rihs, G. Tetrahedron Lett. 1994, 35,
2331–2334.
57. Altmann, K. H.; Imwinkelried, R.; Kesselring, R.; Francotte, E.; Rihs, G.
Tetrahedron Lett. 1994, 35, 7625–7628.
References
58. Molas, M. P.; Matheu, M. I.; Castillon, S. Tetrahedron 1999, 55, 14649–14664.
59. Ramos, J. C.; Bracco, P.; Mazzini, M.; Fernández, J. R.; Gamenara, D.; Seoane, G.
A. Tetrahedron: Asymmetry 2010, 21, 969–972.
60. Jogi, A.; Paju, A.; Pehk, T.; Kailas, T.; Muurisepp, A.-M.; Lopp, M. Tetrahedron
2009, 65, 2959–2965.
61. Manta, S.; Tsoukala, E.; Tzioumaki, N.; Kiritsis, C.; Balzarini, J.; Komiotis, D.
Bioorg. Chem. 2010, 38, 48–55.
62. Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353–1364.
63. Frechou, C.; Dheilly, L.; Beaupere, D.; Uzanet, R.; Demailly, D. Tetrahedron Lett.
1992, 33, 5067–5070.
64. Raghvendra, N. S.; Venkateswarlu, Y. Tetrahedron Lett. 2003, 43, 7549–7552.
65. Yadav, J. S.; Raghavendra, S.; Satyanarayana, M.; Balanarsaiah, E. Synlett 2005,
2461–2464.
66. Hari Babu, M.; Geetha, B.; Khaja, S.-D. J. Indian Inst. Sci. 2001, 81, 453–459.
67. Krishnudu, K.; Radha Krishna, P.; Haribabu, M. Tetrahedron Lett. 1996, 37,
6007–6010.
1. Pathak, T. Chem. Rev. 2002, 102, 1623–1668.
2. Fox, J. J. Pure Appl. Chem. 1969, 18, 223–256.
3. Moffatt, J. G. In Advanced Study Institutes Series, Series A; Plenum Press: New
York, 1979; Vol. A26, p 71.
4. Ueda, T. In Chemistry of Nucleosides and Nucleotides; Townsend, L. B., Ed.;
Plenum Press: New York, 1988; Vol. 1, p 195.
5. Srivastava, P. C.; Robins, R. K.; Meyer, R. B., Jr. In Chemistry of Nucleosides and
Nucleotides; Townsend, L. B., Ed.; Plenum Press: New York, 1988; Vol. 1, p 1.
6. De las Heras, F. G.; Camarasa, M. J.; Fiandor, J. In Recent Progress in the Chemistry
and Synthesis of Antibiotics; Lukacs, G., Ohno, M., Eds.; Springer: Berlin,
Germany, 1990; p 321.
7. Minamoto, K.; Mem. Sch. Eng., Nagoya Univ. 1997, 48, 91; Chem. Abstract. 1997,
127, 66000.
8. Czernecki, S.; Valery, J. M. In Sugar-modified Pyrimidine Nucleoside Analogs with
Potential Antiviral Activity in Carbohydrate Drug Design; Witczak, Z. J., Nieforth,
K. A., Eds.; Dekker: New York, 1997; p 495.