Enantioselective synthesis of homo-N-nucleosides containing a 1,4-dioxane sugar analog

Article abstract of DOI:10.3390/molecules13122962

A dioxane homo-sugar analog, (2S,5S)-and (2R,5S)-5-[(4S)-2,2-dimethyl-1,3- dioxolan-4-yl]-2-iodomethyl-1,4-dioxane was prepared from (2R,3R)-dimethyl tartrate, and further elaborated into the corresponding homo-N-nucleoside analogs by its reactions with uracil and adenine, respectively.

Full text of DOI:10.3390/molecules13122962

Molecules 2008, 13, 2962-2974; DOI: 10.3390/molecules13122962
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Enantioselective Synthesis of Homo-N-Nucleosides Containing a
1,4-Dioxane Sugar Analog
Qiang Yu and Per Carlsen *
Department of Chemistry, Norwegian University of Science and Technology (NTNU), N-7491
Trondheim, Norway; E-mail: qiang@nt.ntnu.no
* Author to whom correspondence should be addressed; E-mail: per.carlsen@chem.ntnu.no; Fax: +47
73594256.
Received: 3 September 2008; in revised form: 30 October 2088 / Accepted: 7 November 2008 /
Published: 3 December 2008
Abstract: A dioxane homo-sugar analog, (2S,5S)-and (2R,5S)-5-[(4S)-2,2-dimethyl-1,3-
dioxolan-4-yl]-2-iodomethyl-1,4-dioxane was prepared from (2R,3R)-dimethyl tartrate,
and further elaborated into the corresponding homo-N-nucleoside analogs by its reactions
with uracil and adenine, respectively.
Keywords: Sugar analog; Nucleoside analogs; Homo-N-Nucleoside; 1,4-Dioxane, Hetero-
cycles.
Introduction
There has been an increasing interest in the synthesis of nucleoside analogs with modifications of
the sugar moiety for the purpose of obtaining new antiviral and antitumor agents [1-3]. A well known
class of modified nucleosides are the homo-N- and C-glycosidic nucleosides [4-8] The insertion of a
methylene group between the heterocyclic base and the sugar moiety results in a more flexible
structure, and due to the lack of an anomeric acetal position, these nucleosides are in general resistant
to enzymatic degradation [8]. For these reasons, we decided to pursue the synthesis of nucleoside
analogs, however, based on the conformationally more flexible, optically active homo-1,4-dioxane
sugar analogs. The objective was thus to construct novel homo-N-nucleoside analogs containing a 1,4-

Molecules 2008, 13
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dioxane sugar moiety. A representative structure is shown in Figure 1, where the 1,4-dioxane homo-
sugar analog is substituted with uracil or adenine, respectively.
Figure 1. A representative structure of the 1,4-dioxane homo-N-nucleoside analogs.
HO
O
CH2
B
HO
O
B = uracil, adenine
Results and Discussion
The formation of the 1,4-dioxane homo-sugar analog 4 was readily achieved starting from (2R,3R)-
dimethyl tartrate, an inexpensive and commercial available chiral starting material. Thus, (2R,3R)-
dimethyl tartrate was converted into the corresponding enantiomerically pure allyl ether 1 [9] either by
the reaction with allyl bromide in the presence of silver oxide [10] or in a tin assisted reaction with
dibutyltin oxide [11-12]. The dimethyl (2R,3R)-2-O-allyltartrate 1 was then reduced by LiAlH4 [13-15]
or NaBH4 [16-17] to give triol 2. The two vicinal hydroxyl groups in 2 were next protected through
formation of acetal 3 by the reaction with 2,2-dimethoxypropane in the presence of p-toluenesulfonic
acid (Scheme 1). The use of the tartrates as chiral starting materials conveniently allows for the
synthesis of all the possible, optically active stereoisomers of 3 and subsequently the corresponding
homo-sugar analogs.
Scheme 1. Synthesis of the partially protected (2S,3S)-2(allyloxy)butane-1,3,4-triol, 3.
HO
OH
HO
OCH2CH=CH2
COOCH3
Ref. 9-12
LAH or
NaBH4
H3COOC
COOCH3
H3COOC
1
HO
OCH2CH=CH2
CH2OH
OCH3
H3CO
O
OCH2CH=CH2
CH2OH
HOH2C
p-TsOH
O
2
3
Iodocyclization of intermediate 3 in the presence of anhydrous NaHCO3 in dry acetonitrile [18-21]
gave the 1,4-dioxane pseudo-sugar as a diastereomeric mixture of trans- and cis- iodides 4a and 4b in
26.4 % and 25.4 % isolated yields, respectively. The trans-compound 4a and cis-compound 4b were
separated by flash chromatography using a solvent mixture of diethyl ether and n-hexane (gradient
1/4-1/1), Scheme 2.
Scheme 2. Formation of homo-sugar iodides 4a and 4b.
I
HA
HB
O
HB
O
I
O
OCH2CH=CH2
CH2OH
O
I2, NaHCO3
CH3CN
O
O
HA
+
O
O
O
O
HC
HC
3
4b, cis-
4a, trans-

Molecules 2008, 13
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1
13
Structures 4a and 4b were elucidated and verified by H-, C-, and DEPT-NMR experiments in
combination with 2D NMR spectroscopy techniques (COSY, HSQC, HMBC, NOESY). The assigned
structures were in full agreement with the NMR data. Product 4a was assigned the trans-configuration
as the coupling constants JAC and JAB were measured to 10.2Hz and 2.4Hz, respectively. This was in
agreement with the –CH2I group being in an equatorial position. The corresponding coupling values
for the other isomer were 3.6Hz and 3.3Hz, respectively, being in agreement with the structure of the
cis-isomer 4b.
The uracil homo-N-nucleoside analog 5a was obtained by reacting uracil with sodium hydride in
DMF [22], followed by the reaction with trans-iodide 4a. A byproduct containing two 1,4-dioxane
rings was also obtained and assigned the structure 6a. This byproduct was not easily separated from
product 5a. The acetal functions in compounds 5a and 6a were then removed using Amberlyst 15 in
methanol providing a mixture of homo-N-nucleoside analog 7a and dimer 8a, Scheme 3. Compounds
7a and 8a were now readily separated by flash chromatography. The cis-nucleoside analogs 7b and 8b
were obtained from 4b by the same sequence of reactions.
Scheme 3. Synthesis of uracil N-nucleoside analogs 7a and 7b.
NMR spectra of the crude reaction mixtures gave indication of an additional byproduct, which as a
working hypothesis was assumed to be the corresponding 3-regioisomer 10. To confirm the identity of
the two regioisomers 5 and 10, uracil was first selectively protected as the 3-N position by
benzoylation with benzoyl chloride in pyridine to provide pure N-3-benzoyluracil 9, [23]. Compound 9
was next reacted with iodide 4b in DMF to give product 5b (Scheme 4). The NMR spectral data of 5b
prepared by the two different routes were in good agreement. Interestingly, the N-3 alkylation
compound 10 was also observed in the product from the protected uracil 9. A 6:5 ratio of products 5b
and 10 was observed. The results imply that a benzoyl-walk reaction probably took place under the
reaction conditions. The pure 10 was isolated from the mixture of 5b and 10 by preparative TLC and

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its structure was confirmed by NMR spectroscopy. The detailed nature of these transformations was
not further investigated.
Scheme 4. Reaction of iodide 4b with 3-benzoyluracil, 9.
BzCl
O
O
HN
O
HN
O
1) NaH/DMF
+
CH2I
Pyridine
NH
N
2) MeOH
O
O
O
O
Bz
4b cis
9
O
O
NH
NH
O
O
O
O
O
N
+
N
O
O
O
O
O
5b cis
10 cis
Using anhydrous potassium carbonate [24-25] as the base, the trans- iodide 4a and cis- iodide 4b
respectively were reacted with adenine to give compound 11a and 11b in 42% and 30% isolated
yields, respectively, after flash chromatography. Deprotection of acetals 11a and 11b in the presence
of Amberlyst-15 in methanol gave compound 12a and 12b in 85% and 70% yields (Scheme 5).
Different from natural occurring purine nucleosides, 12a and 12b were stable under acidic conditions.
The depurination reaction was avoided due to the presence of the methylene group between adenine
and 1,4-dioxane homo-sugar analog moiety.
Scheme 5. Synthesis of adenine N-nucleoside analogs 12a and 12b.
The structures of the four adenine nucleoside analogs 11a, 11b, 12a, 12b were verified to be the N-
9 adenine regioisomers by HMBC-NMR spectroscopy technique. In the case of 11a, three bond
correlations, between C4 and HA and between C8 and HA, were observed, while three bond correlation
between C5 and HA was not found (Figure 2). These findings were in agreement with e.g. product 11a
be the N-9 adenine regioisomer.

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Figure 2. Structure of adenine homo-N-nucleoside analog 11a.
NH2
N
C5
C8
N
N
O
O
C4
N
HA
O
O
11a trans
Conclusions
In conclusion, optically active homo-N-sugar nucleoside analogs containing a 1,4-dioxane moiety
as the sugar analog and substituted with uracil or adenine as the base were synthesized from dimethyl
tartrate. These nucleoside analogs were stable under acidic conditions. Plans for the biological
screening of the produced nucleoside analogs are currently in progress.
Experimental
General
NMR spectra were recorded on Bruker Avance DPX 300 or DPX 400 instruments. Chemical shifts
1
are reported in ppm using TMS as the internal standard in CDCl3 or relative to 2.50 ppm for H and
1
39.99 ppm for 13C in DMSO-d6 or 3.31 ppm for H and 49.15 ppm for 13C in CD3OD. Structural
1
13
assignments were based on H, C, DEPT135 and 2D spetra, COSY, HSQC, HMBC, NOESY. EI-
Mass and ESI spectra were recorded on a Finnigan MAT 95XL spectrometer. IR spectra were obtained
on a Thermo Nicolet FT-IR Nexus spectrometer using a Smart Endurance reflection cell. Silica gel
Kieselgel 60G (Merck) was used for Flash Chromatography. The solvents were purified by standard
methods. The preparations of compounds 1 were described elsewhere [9-12].
(2S,3S)-3-(allyloxy)butane-1,2,4-triol, (2)
This product was obtained by reduction of 1 with either LiAlH4 or NaBH4. LiAlH4 reduction: To a
suspension of LiAlH4 (3.72 g, 95 %, 93 mmol) in dry diethyl ether (50 mL) was drop wise added a
solution of 1 (4.36 g, 20 mmol) in 4 mL of diethyl ether at 0-5 °C. The reaction mixture was refluxed
for 18 hours and then cooled in an ice bath. Then 5 mL of water was added and the mixture stirred for
20 minutes, followed by addition of a 15 % NaOH solution (12 mL) and then 10 mL of water. The
resulting mixture was stirred and the granular salt formed, was separated by filtration, washed with hot
THF (200 mL), and the filtrate concentrated under reduced pressure. The residue was purified by flash
chromatography (CHCl3/CH3OH, 9:1 mixture) to give 0.83 g, 26 % of the pure product 2. NaBH4
reduction. Sodium borohydride (3.45 g, 93 mmol) in ethanol (50mL) was stirred for half an hour and
then dropwise added a solution of 1 (4.35 g, 20 mmol) in ethanol (15 mL). The resulting solution was
refluxed gently for 5 hours. The solution was cooled in an ice bath and added 10 mL of acetic acid.
The mixture was stirred for 20 minutes and filtered. The solid was washed with 2x50 ml ethanol. The

Molecules 2008, 13
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combined organic phase was concentrated under reduced pressure. The crude product was purified by
flash chromatography using a 19:1 mixture of CH2Cl2 / MeOH as the eluent yielding 2.88 g, 88 % of
1
the pure product, which exhibited the following spectroscopic properties: H-NMR (CDCl3, 400
MHz): δ = 3.45 (q, 1H, CH-OAllyl), 3.66-3.74 (m, 3H, 1H from CH2-CHOH, 2H from CH2-CH-OAll),
3.80 (dd, 1H from CH2-CHOH), 3.86 (q, 1H, CHOH), 4.03-4.20 (m, 2H, OCH2-CH=CH2), 4.32 (s,
broad, 3H, OH), 5.18-5.38 (m, 2H, CH2=CH), 5.86-5.96 (m, 1H, CH=CH2) ppm.13C-NMR (CDCl3,
100MHz): δ = 60.6, 63.3, 71.6, 71.8, 79.1, 117.8, 134.5 ppm. MS (EI) m/z: 145 (M+-OH), 131 (M+-
CH2OH), 101 (OH-CH2=O+CH2-CH=CH2), 61 (HOCH2CH=O+H). IR (neat): 3365, 2881, 1736, 1448
cm-1.
(S)-2-(allyloxy)-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethanol (3)
A solution of 2 (6.20 g, 38 mmol), 2,2-dimethoxylpropane (4.00 g, 38.5 mmol) and p-TsOH (223
mg, 1.2 mmol) in 100 mL acetone was stirred overnight at room temperature. The solvent was then
removed and the residue was purified by flash chromatography using a 3:2 mixture of Et2O / n-hexane
as the eluent to provide product 3 as acolorless oil (5.11 g, 85 %). Unreacted starting material 2 (1.05 g
crude product) was recovered by continued elusion with a 19:1 mixture of CH2Cl2 / MeOH. Product 3
1
exhibited the following spectroscopic properties: H-NMR (CDCl3, 400MHz): δ = 1.37 (s, 3H, CH3),
1.44 (s, 1H, CH3), 2.48 (s, broad, 1H, OH), 3.49-3.53 (m, 1H, CH-OAll), 3.59 (dd, J= 10.8Hz, 12Hz,
1H, HOCH2-CHOAll), 3.73 (dd, J= 4.2Hz, 12Hz, 1H, HOCH2-CHOAll), 3.81 (dd, J= 7.2Hz, 8.4Hz,
1H, C-OCH2CHO-C), 4.03 (dd, J= 6.4Hz, 8.4Hz, 1H, C-OCH2CHO-C), 4.18-4.22 (m, 2H, OCH2-
CH=CH2), 4.26-4.31 (m, 1H, C-OCH2CHO-C), 5.24-5.33 (m, 2H, CH2=CH), 5.88-5.95 (m, 1H,
CH=CH2) ppm.13C-NMR (CDCl3, 100MHz): δ 25.3, 26.4, 61.6, 65.4, 71.8, 76.4, 79.1, 109.4, 117.4,
+
134.7 ppm. MS: (EI) m/z: 202(M+), 187 (M+-CH3), 171(M+-CH2OH), 101(C5H9O2 ).
(2S,5S)-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-iodomethyl-1,4-dioxane (4a) and (2R,5S)-5-[(4S)-
2,2-dimethyl-1,3-dioxolan-4-yl]-2-iodomethyl-1,4-dioxane (4b)
To a solution of 3 (3.20 g, 15.8 mmol) in dry acetonitrile (50 mL) was added NaHCO3 (4.19 g, 49.9
mmol) at -15°C. The mixture was stirred for 10 minutes and iodine (12.10 g, 47.7 mmol) was added.
The reaction mixture was stirred for 68 hours with exclusion of light at -15 to -0°C. Ethyl acetate (80
mL) was added to the mixture and the solution was neutralized by saturated sodium thiosulfate
solution until a colorless solution was obtained. The aqueous phase was extracted with ethyl acetate
and the combined organic phase was dried over anhydrous sodium sulfate. The solution was filtered
and evaporated. The residue was purified by gradient column chromatography using Et2O/n-hexane
(1:4, 1:1) as eluent. The two diastereomers were separated in yields of 26.4% (4a) and 25.4% (4b).
The pure compounds were white solid. Rf was 0.43 and 0.36 respectively (n-hexane/Et2O 1:1). The
1
product 4a exhibited the following spectroscopic properties: H-NMR (CDCl3, 400 MHz) δ = 4.10-
4.02 (m, 1H, H-4”), 4.04 (dd, 1H, J = 11.6 Hz, 2.4 Hz, H-3eq), 3.97 (dd, 1H, J= 8.0 Hz, 6.6 Hz, H-5”),
3.79 (dd, 1H, J= 8.0 Hz, 6.8 Hz, H-5”), 3.79-3.53 (m, 4H, H-2, H-5’, H-6), 3.39 (dd, 1H, J= 11.6 Hz,
10.2 Hz, H-3ax), 3.07 (d, 2H, J = 6.0 Hz, H-7), 1.42 (d, 3 H, 5JH-4” – H-8 = 0.4 Hz, H-8), 1.35 (d, 3 H, 5JH-

Molecules 2008, 13
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4” – H-8 = 0.4 Hz, H-8) ppm; 13C-NMR (CDCl3, 100 MHz) δ = 109.9, 75.4, 75.0, 74.2, 70.9, 67.9, 65.3,
26.4, 25.5, 25.4 ppm; HRMS (ESI) m/z: for C10H17IO4 [M+Na]+, Calcd. 351.0069, Found 351.0063.
1
4b: H-NMR (CDCl3, 400 MHz): δ = 4.29 (dd, 1H, J = 6.8 Hz, 13.2 Hz, H-4”), 4.02 (dd, 1H, J= 8.0
Hz, 6.4 Hz, H-5”), 3.97 (dd, 1H, J = 12.0 Hz, 3.6 Hz, H-3eq), 3.84 (dd, 1H, J= 12.0 Hz, 3.0 Hz, H-
3ax), 3.80-3.75 (m, 1 H, H-2), 3.75 (dd, 1H, J = 8.0 Hz, J = 6.8 Hz, H-5”), 3.67 (dd, 1H, J = 12.4 Hz,
8.0 Hz, H-6ax), 3.61-3.57 (m, 1H, H-5), 3.60 (dd, 1H, J = 12.4 Hz, 2.8 Hz, H-6eq), 3.42 (dd, 1H, J = 7.0
Hz, 12.6 Hz, H-7a), 3.40 (dd, 1H, J = 7.0 Hz, 13.0 Hz, H-7b), 1.44 (d, 3H, 5JH-4” – H-8 = 0.4 Hz, H-8),
13
1.38 (d, 3 H, 5JH-4” – H-8 = 0.4 Hz, H-8) ppm; C-NMR (CDCl3, 100MHz) δ = 109.8, 74.8, 73.4, 72.5,
66.3, 65.5, 62.3, 26.4, 25.3, 3.2 ppm; HRMS (ESI) m/z: for C10H17IO4 [M+Na]+, Calcd. 351.0069,
Found 351.0079; IR (neat): 2980, 2867, 1461, 1413, 1380, 1370 cm-1.
Figure 3. Structures 4a and 4b.
8
8
I
7
8
8
2
O
O
3
3
I
O
O
2
O
O
O
O
7
6
6
4"
4"
5
5
5"
5"
4a
4b
(2S,5S)-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(uracil-1-yl-methyl)-1,4-dioxane (5a)
To a stirred suspension of uracil (0.253 g, 2.3 mmol) in dry DMF (19 mL), sodium hydride (0.065
g, 2.7 mmol) was added at room temperature. After stirring for one hour, compound 4a (0.35 g, 1.1
mmol) was added. The mixture was heated to 80°C and stirred overnight. The resulting mixture was
evaporated under high vacuum. The residue was extracted with ethyl acetate. The solution was
concentrated and purified by flash chromatography using ethyl acetate as the eluent. The product (201
mg) containing the inseparable byproduct 6a was obtained in 60% crude yield. The product 5a
exhibited the following spectroscopic properties: 13C-NMR (CDCl3, 100 MHz): δ= 163.3, 150.9,
145.6, 109.8, 101.8, 75.2, 74.9, 73.3, 68.3, 67.4, 65.0, 48.8, 26.3, 25.2 ppm. The product contains
inseparable byproduct 6a which makes the assignments of protons difficult; IR (neat) of the mixture of
5a and 6a: 3214, 3093, 2983, 2869, 1659, 1453, 1054 cm-1; HRMS (ESI) m/z: for C14H20N2O6
[M+Na]+, Calcd. 335.1219, Found 335.1222.
Figure 4. Structure 5a.
6
5
8
3"
O
8
2'
O
3'
N
O
O
NH
O
7'
O
6'
1"
4"
5'
5"
5a

Molecules 2008, 13
2969
(2R,5S)-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(uracil-1-yl-methyl)-1,4-dioxane (5b)
Method 1: The preparation of 5b was the same as used for the synthesis of 5a. Method 2: Sodium
hydride (18 mg, 0.75 mmol) in 10 mL of dry DMF was stirred for half an hour at room temperature. N-
3-benzoyluracil 9 (130 mg, 0.60 mmol) was added and stirred for an hour. To this suspension, iodide
4b (98 mg, 0.30 mmol) was added. The resulting stirred mixture was heated at 90°C overnight. The
mixture was concentrated under reduced pressure to remove DMF. To the residue was added 20 mL
methanol and the resulting mixture was stirred for 5 minutes. The solution was concentrated and
purified by flash chromatography using CH2Cl2/CH3OH as the eluent. The obtained product (30 mg,
32 %) containing products 5b and 10 in a 5:6 ratio and was further purified by preparative TLC. The
isolated product 5b exhibited the following spectroscopic properties: 1H-NMR (CDCl3, 400 MHz): δ =
1.39, 1.45 (s, 2x3H, H8), 3.60 (m, 1H, H-5’), 3.67-3.74 (m, 2H, H-6’), 3.74-3.80 (m, 2H, H-5” and H-
3’), 3.82-3.86 (m, 1H, H-3’), 3.91-3.96 (m, 3H, H-7’ and H-2’), 4.05 (dd, 1H, J= 8.2 Hz, 6.6 Hz, H-
5”), 4.32-4.37 (m, 1H, H-4”), 5.70 (d, 1H, J= 7.8 Hz, H-5), 7.20 (d, 1H, J= 7.8 Hz, H-6), 8.73 (brs, 1H,
13
NH) ppm; C-NMR (CDCl3, 100 MHz): δ= 163.3, 150.8, 145.1, 109.9, 102.1, 74.4, 73.8, 71.0, 65.7,
64.9, 63.3, 47.6, 26.5, 25.4 ppm; IR (neat): 3097, 2985, 2874, 1682, 1652, 1455, 1124, 1060; HRMS
(ESI) m/z: for C14H20N2O6 [M+Na]+, Calcd. 335.1219, Found 335.1222. The product 10 exhibited the
1
following spectroscopic properties: H-NMR (CDCl3, 400 MHz): δ = 1.38, 1.45 (2×3H, CH3), 3.41
(dd, 1H, J = 4 Hz, 12 Hz), 3.62-3.67 (m, 1H), 3.70-3.75 (m, 2H), 3.87 (d, 2H), 3.97-4.08 (m, 3H),
4.23-4.28 (m, 1H), 4.81 (dd, J= 10 Hz, 14 Hz, 1H), 5.77 (dd, J= 7.6 Hz, 1.6 Hz, 1H, NCH=CH), 7.16
(dd, J= 7.6 Hz, 5.6 Hz, 1H, NCH=CH), 8.66 (d, 1H) ppm; 13C-NMR (CDCl3, 100MHz): δ= 25.3, 26.4,
39.8, 61.7, 65.4, 66.9, 69.1, 74.8, 76.0, 102.2, 109.6, 137.8, 151.8, 163.0 ppm; MS (m/z): (M+Na)+,
335.16.
Figure 5. Structures 5b and 10.
O
3
5
6
5
NH
O
6
3
N
O
8
N
8
NH
7'
7'
8
8
O
O
3'
3'
O
4"
O
4"
5'
O
2'
2'
O
O
O
O
6'
5b
6'
5'
5"
5"
10
(2S,5S)-5-[(1S)-1, 2-dihydroxyethyl]-2-(uracil-1-yl-methyl)-1,4-dioxane (7a)
The mixture of 5a and 6a (60mg, 5/6 ratio) was dissolved in methanol (10 mL), Amberlyst 15 (50
mg) was added and the mixture refluxed. The reaction was monitored by TLC until no more 7a was
observed. The solution was filtered and the solvent was evaporated. The obtained product was further
purified by flash chromatography to give pure 5a (12 mg, 34 %) and 8a (25 mg, 38 %) using
1
CH2Cl2/MeOH (13:1) as eluent. The product 7a exhibited the following spectroscopic properties: H-
NMR (CD3OD, 400 MHz): δ = 3.32-3.38 (m, 1H, H-3’), 3.47-3.55 (m, 2H, H-1” and H-2”), 3.55-3.67
(m, 4H, H-5’, H-2”, H-6’ and H-7’), 3.74-3.80 (m, 1H, H-2’), 3.82 (dd, 1H, J= 1.2 Hz, 10.4 Hz, H-6’),

Molecules 2008, 13
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3.88 (dd, 1H, J= 2.8 Hz, 8.4 Hz, H-3’), 3.91 (dd, 1H, J= 3 Hz, 11 Hz, H-7’), 5.61 (d, 1H, J= 8 Hz, H-
13
5), 7.52 (d, 1H, J= 8 Hz, H-6) ppm; C-NMR (CD3OD, 100MHz): δ = 50.0, 63.7, 69.3, 69.7, 72.6,
74.4, 76.6, 101.8, 148.5, 153.0, 166.9 ppm; IR (neat): 3396, 2871, 1651, 1455, 1101, 1043 cm-1;
HRMS (ESI) m/z: for C11H16N2O6 [M+Na]+, Calcd. 295.0906, Found 295.0911.
Figure 6. Structure 7a.
6
5
2'
HO
3'
O
N
O
O
NH
HO
O
7'
6'
1"
3
5'
2"
7a
1
The product 8a exhibited the following spectroscopic properties: H-NMR (CD3OD, 400 MHz): δ =
3.34-3.43 (m, 2H), 3.46-3.54 (m, 4H), 3.57-3.74 (m, 8H), 3.75-3.86 (m, 6H), 3.87-3.90 (m, 1H), 3.92-
3.96 (m, 1H), 4.05-4.10 (m, 1H), 5.70 (d, 1H, J= 7.8 Hz, NCH=CH), 7.52 (d, 1H, J= 7.8 Hz,
13
NCH=CH) ppm; C-NMR (CD3OD, 100 MHz): δ = 42.8, 51.1, 63.7, 63.8, 69.3, 69.4, 69.7, 72.57,
72.61, 74.0, 74.4, 76.56, 76.57, 101.2, 146.8, 153.3, 165.6 ppm; MS (m/z): HRMS (ESI) m/z: for
C18H28N2O10 [M+Na]+, Calcd. 455.1641, Found 455.1645.
(2R,5S)-5-[(1S)-1,2-dihydroxyethyl]-2-(-uracil-1-yl-methyl)-1,4-dioxane (7b)
The method for preparation of 7b was as same as applied for the synthesis of 7a. The product 7b
exhibited the following spectroscopic properties: 1H-NMR (CD3OD, 400 MHz): δ= 3.53-3.66 (m, 3H,
H-2” and H-6’), 3.60-3.70 (m, 2H, H-1” and H-5’), 3.78-3.80 (m, 2H, H-3’), 3.80-3.92 (2H, H-2’ and
H-7’), 4.00 (dd, 1H, J= 11.6 Hz, 8 Hz, H-2” or H-6’), 4.23-4.31 (m, 1H, H-7’), 5.65 (d, J= 8 Hz, H-5),
7.58 (d, J= 8 Hz, H-8) ppm; 13C-NMR (CD3OD, 100 MHz): δ= 166.8, 153.0, 147.9, 102.2, 76.4, 71.8,
71.5, 66.9, 63.9, 63.8, 48.2 ppm; IR (neat): 3352, 3056, 2931, 2875, 1667, 1456, 1129, 1101 cm-1;
HRMS (ESI) m/z: for C11H16N2O6 [M+Na]+, Calcd. 295.0906, Found 295.0915.
Figure 7. Structure 7b.
O
5
NH
6
N
2'
O
7'
3'
HO
O
HO
O
6'
1"
5'
2"
7b

Molecules 2008, 13
2971
(2S,5S)-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(adenin-9-yl-methyl)-1,4-dioxane (11a)
A mixture of adenine (0.279 g, 2 mmol) and anhydrous potassium carbonate (0.300 g, 2.2 mmol) in
dry DMF (10 mL) was heated at 120°C. After two hours, compound 4a (0.304 g, 0.9 mmol) was added
to the solution. The mixture was stirred overnight at 120°C. The mixture was concentrated under
reduced pressure and the residue purified by flash chromatography using a mixture of dichloromethane
and methanol (14:1) as the eluent. The product (130 mg) was obtained in 42 % yield. The product 11a
1
exhibited the following spectroscopic properties: H-NMR (CDCl3, 400 MHz): δ= 8.35 (s, 1H, H-2),
7.88 (s, 1H, H-8), 5.75 (s, 2H, NH2), 4.29 (dd, 1H, J= 14.6 Hz, 3.4 Hz, H-7’), 4.12 (dd, 1H, J= 14.6
Hz, 6.8 Hz, H-7’), 4.01- 4.07 (m, 1H, H-4”), 3.97 (dd, J= 11.4 Hz, 2.6 Hz, H-3’eq), 3.87-3.95 (m, 2H,
H-2’, H-5”), 3.75-3.82 (m, 2H, H-5”, H-6’), 3.46-3.57 (m, 2H, H-5’, H-6’), 3.32 (dd, J= 11.4 Hz, 10.6
Hz, H-3’ax), 1.39 (s, 1H, H-10), 1.33 (s, 1H, H-10) ppm. 13C-NMR (CDCl3, 100 MHz): δ= 155.6,
153.2, 150.4, 141.6, 141.1, 119.4, 109.7, 75.1, 74.9, 73.2, 68.5, 67.5, 65.0, 44.2, 26.2, 25.3 ppm; IR
(neat): 3322, 3161, 2983, 2938, 2864, 1673, 1606, 1064, 1048 cm-1; HRMS (ESI) m/z: for C15H22N5O4
M+, Calcd. 336.1671, Found 336.1676.
Figure 8. Structure 11a.
NH2
7
5
10
N
1
2
N
8
3"
O
2'
3'
N
9
N
3
10
O
4
4"
O
O
7'
6'
1"
5'
5"
11a
(2R,5S)-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(adenin-9-yl-methyl)-1,4-dioxane (11b)
Synthesis of 11b was carried out as described for 11a. The product exhibited the following
spectroscopic properties: 1H-NMR (CDCl3, 400 MHz): δ= 8.35 (s, 1H, H-2), 7.87 (s, 1H, H-8), 6.14 (s,
2H, NH2), 4.54 (dd, 1H, J= 14.8 Hz, 8.8 Hz, H-7’), 4.32-4.38 (m, 2H, H-4”, H-7’), 4.06- 4.11 (m, 1H,
H-2’), 4.05 (dd, J= 8.4 Hz, 6.6 Hz, H-5”), 3.80-3.90 (m, 3H, H-3’, H-6’), 3.77 (dd, J= 8.4 Hz, 6.8 Hz,
13
H-5”), 3.61-3.67 (m, 2H, H-5’, H-6’), 1.46 (s, 1H, H-10), 1.39 (s, 1H, H-10) ppm; C-NMR (CDCl3,
100 MHz): δ= 155.7, 153.1, 150.1, 140.9, 119.4, 109.9, 74.6, 73.8, 71.1, 65.6, 65.1, 63.0, 42.8, 26.5,
25.4 ppm; IR (neat): 3276, 3134, 2984, 2935, 2870, 1676, 1600, 1575, 1126, 1066 cm-1; HRMS (ESI)
m/z: for C15H22N5O4 M+, Calcd. 336.1671, Found 336.1675.
Figure 9. Structure 11b.
NH2
N
7
1
N
8
2
N
9
N
8
7'
O
3'
O
8
4"
2'
O
O
6'
11b
5'
5"

Molecules 2008, 13
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(2S,5S)-5-[(1S)-1,2-dihydroxyethyl]-2-(adenin-9-yl-methyl)-1,4-dioxane (12a)
Compound 11a (108 mg, 0.32 mmol) was dissolved in methanol (10 mL), Amberlyst 15 (45 mg)
was added and the mixture was refluxed until TLC showed that all 11a was consumed. The solution
was filtered and the solvent was evaporated. The product 12a (81 mg, 85 %) exhibited the following
1
spectroscopic properties: H-NMR (DMSO-d6, 400 MHz): δ= 8.17 (s, 1H, H-2), 8.08 (s, 1H, H-8),
7.35 (brs, 2H, NH2), 4.3-4.8 (brs, 2H, OH), 4.21 (dd, 1H, J= 14.4 Hz, 4.2 Hz, H-7’), 4.13 (dd, 1H, J=
14.4 Hz, 6.8 Hz, H-7’), 3.83-3.88 (m, 2H, H-2’, H-3’), 3.67-3.73 (m, 1H, H-6’), 3.17-3.48 (m, 6H, H-
6’, H-5’, H-3’, H-1”, H-2”) ppm; 13C-NMR (DMSO-d6, 100 MHz): δ= 155.5, 151.9, 149.6, 141.6,
118.4, 75.2, 72.6, 70.8, 68.1, 67.5, 61.9, 43.7 ppm; IR (neat): 3271, 3117, 2918, 2881, 1668, 1604,
1120, 1106, 1066 cm-1; HRMS (ESI) m/z: for C12H17N5O4 [M+1]+, Calcd. 296.1358, Found 296.1356.
Figure 11. Structure 12a.
NH2
N
7
N
1
8
2'
HO
2"
2
3'
N
9
N
O
HO
O
7'
6'
1"
5'
12a
(2R,5S)-5-[(1S)-1,2-dihydroxyethyl]-2-(adenin-9-yl-methyl)-1,4-dioxane (12b)
Compound 12b was prepared using the same method as described for the synthesis of 12a. Thus,
11b (79 mg, 0.24 mmol) in methanol (10 mL) containing added Amberlyst-15 (36 mg) was refluxed
until TLC showed that all 11b was consumed. The solution was filtered and the solvent was
evaporated. The product 12b (49 mg, 70%) exhibited the following spectroscopic properties: 1H-NMR
(DMSO-d6, 400 MHz): δ= 8.16 (s, 1H, H-2 or H-8), 8.15 (s, 1H, H-8 or H-2), 7.30 (brs, 2H, NH2),
4.69 (dd, 1H, J= 14.4 Hz, 9.6 Hz, H-7’), 4.22 (dd, 1H, J= 14.4 Hz, 4.2 Hz, H-7’), 4.00-4.05 (m, 1H, H-
2’), 3.92-3.98 (m, 1H, H-2” or H-6’), 3.78 (dd, 1H, J = 12.2 Hz, 2.2 Hz, H-3’), 3.69 (dd, 1H, J= 12.2
Hz, 3.2 Hz, H-3’), 3.34-3.56 (m, 5H, remining protons) ppm; 13C-NMR (DMSO-d6, 100MHz): δ=
155.7, 152.0, 149.6, 141.3, 118.5, 75.5, 70.4, 69.6, 65.6, 62.2, 61.4, 40.6 ppm; IR (neat): 3271, 3125,
2883, 1674, 1604, 1119, 1065 cm-1; HRMS (ESI) m/z: for C12H17N5O4 [M+1]+, Calcd. 296.1358,
Found 296.1355.
Figure 10. Structure 12b.
NH2
N
7
N
8
2
N
9
N
7'
HO
2"
3'
O
1"
5'
2'
HO
O
6'
12b

Molecules 2008, 13
2973
Acknowledgements
The authors wish to thank the Norwegian Research Council, NFR, for financial support. We will
also thank Professor E. Uggerud, University of Oslo, for performing the mass spectrometric
measurements.
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Sample Availability: Selected samples are available from the authors.
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