A concise synthesis of 4,6-dideoxy-4-base-6-amino-2,5-anhydro-l-mannitols

Article abstract of DOI:10.1016/j.tetasy.2007.08.032

3,6-Di-O-methanesulfonyl-2,5-anhydro-l-idofuranose dimethyl acetal 9 was reacted with NaN₃ in DMF to give 6-azido substituted carbohydrate 10 selectively. A series of 6-amino-isonucleosides 4a-d were synthesized by the reaction of nucleobases with epoxide 13, followed by hydrolysis, reduction, and deprotection, in good yield.

Full text of DOI:10.1016/j.tetasy.2007.08.032

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2139–2146
A concise synthesis of 4,6-dideoxy-4-base-6-amino-
2,5-anhydro-L-mannitols
Fang Wang, Zhen-Jun Yang,* Hong-Wei Jin, Liang-Ren Zhang
and Li-He Zhang
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences,
Peking University, Beijing 100083, China
Received 28 June 2007; accepted 23 August 2007
Abstract—3,6-Di-O-methanesulfonyl-2,5-anhydro-L-idofuranose dimethyl acetal 9 was reacted with NaN3 in DMF to give 6-azido
substituted carbohydrate 10 selectively. A series of 6-amino-isonucleosides 4a–d were synthesized by the reaction of nucleobases with
epoxide 13, followed by hydrolysis, reduction, and deprotection, in good yield.
Ó 2007 Elsevier Ltd. All rights reserved.
O
N
1. Introduction
OCH3
OCH3
OCH3
OCH3
N
B
B
OCH3
OCH3
Nucleoside and nucleotide analogues play an important
role in antiviral and anticancer chemotherapy.1 Isonucleo-
sides, which are a kind of nucleoside analogues where the
nucleobase is linked at C-20 or C-30 of ribose, have
attracted much attention owing not only to their chemical
and enzymatic stability but also to their biological activi-
ties.2 Among these isonucleosides, D- and L-isonucleosides
have exhibited some activity against a broad spectrum of
viruses and tumor cell lines3 and some isonucleoside mono-
phosphates showed very good activities against HIV-1.4
O
O
O
O
N3
HO
OH
2. B = A,T
OH
OH
N3
1
3
OCH3
OCH3
OCH3
OCH3
B
MsO
O
OH
O
O
H2N
R
AcHN
O
13
OAc
9. R = MsO;
4
10. R = N3
Figure 1.
Antisense oligonucleotides (ASODNs) and small interfer-
ing RNAs (siRNAs) are both widely anticipated to become
the next generation of mRNA-targeting drugs.5 However,
ASODN and siRNA-based therapy are obstructed by their
intrinsic qualities, such as poor intracellular uptake, limited
blood stability, and non-specific immune stimulation.
Many efforts have been made to solve such problems.6
We have reported a series of isonucleoside incorporated
oligonucleotides, which showed better stability against
degradation by nucleases.7 The isonucleoside modification
is also superior to other chemical modifications, since such
modified oligonucleotides are good substrates for RNase
H,8 and isonucleoside triphosphates can be recognized by
many different DNA polymerases.9 We have reported the
synthesis of amino-isonucleosides 4 (B = adenine, thymine;
Fig. 1), and incorporated them into different positions of
siRNA duplexes in the sense or antisense strands. Struc-
tural and functional analyses of such kinds of siRNAs
indicated that sense strand modifications with amino-
isonucleoside had less effect on the RNA duplex thermal
and serum stabilities, and their functional activities were
also comparable to their native siRNAs. In contrast,
antisense strand modifications at the corresponding posi-
tions brought a striking negative effect on RNA duplex
stability.10
In the previous reports, amino-isonucleosides 4 (B = ade-
nine, thymine) were synthesized from azide-isonucleosides
2, which could be obtained by a Misunobu reaction from
*
Corresponding author. Tel./fax: +86 10 82802503; e-mail: yangzj@
bjmu.edu.cn
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.08.032

2140
F. Wang et al. / Tetrahedron: Asymmetry 18 (2007) 2139–2146
isonucleoside 1 with NaN3. However, tricyclic isonucleo-
sides, for example 3, were unavoidable byproducts during
the Misunobu reaction (Fig. 1) and isonucleoside 1 was
obtained by the reaction of a nucleobase with an epoxide
intermediate.10,11 In this paper, we report a new method,
in which the amino group was induced into the molecule
first by selective 6-azido substitution of 3,6-di-O-methane-
sulfonyl-4-O-acetyl-2,5-anhydro-L-idofuranose dimethyl
acetal 9, and then the key intermediate compound 13 was
reacted with nucleobases to afford the desired compounds
4 (Fig. 1).
OCH3
OCH3
OCH3
OCH3
ii
O
O
i
6b
MsO
N3
88.3%
O
7
O
8
Scheme 2. Reagents and conditions: (i) K2CO3/MeOH, rt; (ii) NaN3/
DMF.
lithium azide in HMPT at 140 °C for 1 h afforded the
3,5-di-azido sugar derivative.14 Compound 6b was acetyl-
ated to give compound 9. Compound 9 was treated with
sodium azide in anhydrous DMF at 70 °C to yield 3-O-
methanesulfonyl-4-O-acetyl-6-deoxy-6-azido-2,5-anhydro-
L-idofuranose dimethyl-acetal 10 selectively in 93.8% yield
(Scheme 3). The diazido substituted derivative, 3,6-di-
deoxy-3,6-di-azido-4-O-acetyl-2,5-anhydro-L-idofuranose
dimethylacetal 11, was not found in this reaction, even at
100 °C or by increasing the ratio of sodium azide. Com-
puter simulation of the structures of 9, 10, and 11 was
investigated with the semi-empirical quantum chemical
method; it seemed that the reaction was endothermic
and the 4-O-acetyl group might hinder the attack of N3
to C-3 and could not result in the leaving of 3-methane-
sulfonyloxy group. Therefore, compound 10 was reduced
by catalytic hydrogenation (H2/Pd/C) in anhydrous
ethanol followed by acetylation (Ac2O/pridine) to give
compound 12. Compound 13 was obtained by treating 12
with K2CO3/MeOH (Scheme 3).
2. Results and discussion
It is known that toluenesulfonyl protected D-glucose 5a
was treated with 1% HCl in methanol for 7 days to give
2,5-anhydro-L-idofuranose 6a in 87.2% yield.12 After
optimization of the reaction condition, it was found that
the reaction could be accelerated by using methanesulfonyl
D-glucose 5b instead of 5a.13 We found that compound 5b
was refluxed in 1% HCl/MeOH for 40 h to afford 6b in
91.4% yield (Scheme 1). This indicated clearly that the
smaller methanesulfonyl protected D-glucose is a better
substance for this structural transformation.
RO
RO
OCH3
OR
RO
1% HCl
CH3OH
OCH3
O
O
RO
O
O
OH
Epoxide 8 can be obtained from 10 by the general proce-
dure, but the azido group at the 6-position made the epox-
ide ring opening reaction more difficult. Compound 14
cannot be obtained by the reaction of 8 with a nucleobase
in the presence of K2CO3 and 18-crown-6 in DMF at
100 °C (Scheme 4).
6
5
a. R = Ts, 87.2%; b. R = Ms, 91.4%
Scheme 1.
Starting from compound 6b, several approaches were
investigated for the synthesis of the key intermediate 13.
Compound 6b could be converted into 7 by treatment with
K2CO3 in methanol, but the substitution of the 6-methane-
sulfonyloxy group in 7 by NaN3 in DMF to form 8 failed
(Scheme 2).
The isonucleoside formation by the epoxide ring opening
reaction by the nucleobase itself could be carried out with
a different epoxide compound, that is, compound 13
reacted with adenine in anhydrous DMF in the presence
of potassium carbonate and 18-crown-6 at 100 °C to give
15a in 61.7% yield. HMBC NMR of 15a gave a strong
coupling effect of H-4 of the sugar ring with H-8 on the
adenine, which indicated the formation of the linkage
between N-9 of adenine and C-4 of the sugar ring. NOESY
It was reported that 1,2-O-isopropylidene-a-D-xylofura-
nose-3,5-di-O-tosylate reacted with 1.5 equiv of sodium
azide in DMF at 120 °C for 2 h to give 5-azido sugar deriv-
atives selectively in good yield (98%), while reaction with
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
MsO
O
MsO
O
ii
i
O
6b
93.8%
97.7%
MsO
N3
N3
OAc
9
OAc
10
OAc N3
11
73.7% iii
OCH3
OCH3
OCH3
OCH3
MsO
O
iv
89.7%
O
AcHN
AcHN
O
OAc
13
12
Scheme 3. Synthesis of key intermediate 13. Reagents and conditions: (i) Ac2O, Py; (ii) NaN3, DMF, 70 °C; (iii) (a) H2, Pd/C, EtOH; (b) Ac2O, Py;
(iv) K2CO3, CH3OH.

F. Wang et al. / Tetrahedron: Asymmetry 18 (2007) 2139–2146
2141
further purification. All anhydrous reactions were con-
ducted in oven-dried glassware, under an argon atmos-
phere with anhydrous DMF, which was dried by CaH2
and distilled before use. Thin layer chromatography was
performed using silica gel GF-254 (Qing-Dao Chemical
Company, China) plates with detection by UV, or charting
with 5% phosphomolybdic acid hydrate in ethanol.
Column chromatography was performed on silica gel
(200–300 mesh, purchased from Qing-Dao Chemical
Company, China). Optical rotations were recorded on a
Perkin–Elmer 243B polarimeter. 1H NMR (300 or
500 MHz) and 13C NMR (75 or 125.7 MHz) spectra were
recorded on Varian VXR-300, Varian Inova VXR-500,
or Avance 500 Bruker spectrometer. When necessary, 2D
NMR experiments were performed to assist in structure
OCH3
OCH3
B
ii
i
O
10
8
87.5%
N3
OH
14
Scheme 4. Reagents and conditions: (i) K2CO3, CH3OH; (ii) Nucleobase,
K2CO3, 18-crown-6, DMF, 100 °C.
NMR of 15a gave a strong coupling effect of H-8 on
adenine with H-3 and H-5 of the sugar ring to confirm
the structure of 15a. Compound 13 reacted with a pyrimi-
dine base under the same conditions but affording the
products in lower yields. In the case of cytosine, a mixture
of 15b-N (43.3%) and 15b-O (37.7%) was obtained. After
separation, isomers 15b-N and 15b-O were characterized
by HMBC NMR and 15b-N also showed different
elucidation. Infrared spectra were recorded on
a
NEXUS-470 FTIR (Nicolet) spectrometer and only the
more representative frequencies were reported (cmꢀ1).
Mass spectra (ESI-TOF+ MS) and high-resolution mass
spectra (ESI-TOF+ HRMS) were obtained on a MDS
SCLEX QSTAR instrument and only the most representa-
tive peaks were reported (m/z).
UV absorptions (kmax = 272 nm) from 15b-O (kmax
=
275 nm). However, 5-fluorocytosine made the epoxide ring
opening reaction more regioselective, 15c was obtained in
59.1% yield. Thymine opened the epoxide ring of com-
pound 13 under the conditions as described for 15a and
15b, but in very low yields. Isonucleoside 15d (B =
thymine) was obtained by the reaction of thymine and
compound 13 by heating in a microwave reactor (180 °C)
for 30 min. Compounds 15a–d were reacted with 1%
HCl, followed by reduction with sodium borohydride to
give 16a–d. After deacetylation, the desired compounds
4a–d were provided in good yields (Scheme 5).
4.1. 1,2-O-Isopropylidene-3,5,6-tri-O-methanesulfonyl-a-D-
glucofuranose 5b
Compound 5b (white powder) was obtained from 1,2-O-
isopropylidene-a-D-glucofuranose in 97.4% yield. 1H
NMR (500 MHz, CDCl3): d 1.33 (s, 3H, –CH3), 1.51 (s,
3H, –CH3), 3.09 (s, 3H, –SO2CH3), 3.20 (s, 6H, –SO2CH3),
4.45 (dd, J = 4.5, 12.0 Hz, 1H, H-6a), 4.50 (dd, J = 2.5,
9.0 Hz, 1H, H-4), 4.70 (dd, J = 2.5, 12.0 Hz, 1H, H-6b),
4.99 (d, J = 3.5 Hz, 1H, H-2), 5.08 (m, 1H, H-5), 5.12 (d,
J = 3 Hz, 1H, H-3), 5.97 (d, J = 3.5 Hz, 1H, H-1).
3. Conclusion
Compared to toluenesulfonyl protected D-glucose 5a,
methanesulfonyl D-glucofuranose 5b was much easier to
convert into 2,5-anhydro-L-idofuranose 6b, and 3,6-di-
methanesulfonyl compound 9 can be substituted selectively
by NaN3 to obtain the 6-azido compound 10 in high yield.
The key intermediate epoxide 13 was reacted with a series
of nucleobases (A, C, 5-FC, and T) at different conditions
to give isonucleosides 15a–d. In the cases of 15a, 15c, and
15d, the epoxide ring opening reaction is regioselective.
After reduction and deprotection, 6-amino-isonucleosides
4(a–d) were afforded in good yields.
4.2. 3,6-Di-O-methanesulfonyl-2,5-anhydro-L-idofuranose
dimethylacetal 6b
Compound 5b (1.0 g, 2.20 mmol) was dissolved in metha-
nol (100 ml). After hydrochloric acid (37%) (1.2 ml) was
added, the solution was refluxed for 48 h. After cooling,
neutralization with NaHCO3 and evaporation, the residue
was extracted with CH2Cl2. The extract was purified by
silica gel chromatography; 6b (0.76 g, colorless syrup)
25
was obtained in 91.4% yield. ½aꢁD ¼ þ10:1 (c 0.156,
4. Experimental
MeOH). 1H NMR (500 MHz, CDCl3): d 3.08 (s, 6H,
–SO2CH3), 3.40 (s, 3H, –OCH3), 3.45 (s, 3H, –OCH3),
4.38 (m, 2H, H-2, H-5), 4.50 (m, 3H, H-4, H-6), 4.64 (m,
1H, H-3), 4.95 (dd, J = 1.5, 3.5 Hz, 1H, H-1). 13C NMR
Unless specified otherwise, all starting materials and
reagents were obtained from commercial suppliers without
OCH3
OCH3
NH2
N
B
B
B
OH
OH
i
ii
iii
O
O
O
N
13 + B
OCH3
OCH3
H2N
AcHN
AcHN
O
OH
OH
OH
O
16a 85.5%
16b 82.8%
16c 81.3%
4a 79.2%
4b 74.1%
4c 70.2%
4d 80.8%
15a 61.7%
15b-N 43.3%
15c. 59.1%
15d
AcHN
OH
15b-O 37.7%
16d 46.7% (two steps)
a. B = Adenine; b. B = Cytosine; c. B = 5-Fluorocytosine; d. B = Thymine
Scheme 5. Synthesis of amino-isonucleosides 4a–d. Reagents and conditions: (i) B (A, C, 5-FC)/K2CO3/18-crown-6/DMF/100 °C or 180 °C in microwave
reactor for B = T; (ii) (a) H+/H2O; (b) NaBH4; (iii) 1.2 N HCl, reflux.

2142
F. Wang et al. / Tetrahedron: Asymmetry 18 (2007) 2139–2146
(125 MHz, CDCl3): d 37.6 (–SO2CH3), 38.1 (–SO2CH3),
53.6 (–OCH3), 54.1 (–OCH3), 66.2 (C-6), 74.9 (C-4), 77.9
(C-5), 78.2 (C-2), 84.5 (C-3), 101.2 (C-1). MS (ESI-
TOF+): calcd for C10H20O10S2 373, found m/z = 382
(M++NH4), 387 (M++Na). Elemental Anal. Calcd for
C10H20O10S2Æ0.5H2O: C, 32.07; H, 5.6. Found: C, 31.54;
H, 5.16.
–OCH3), 4.26 (dd, J = 3.5, 7.5 Hz, 1H, H-2), 4.35 (s, 1H,
H-6a), 4.37 (s, 1H, H-6b), 4.54 (d, J = 7.5 Hz, 1H, H-1),
4.61–4.64 (m, 1H, H-5), 5.04 (dd, J = 1.5, 3.5 Hz, 1H,
H-3), 5.47 (dd, J = 1.5, 4.5 Hz, 1H, H-4). 13C NMR
(125 MHz, CDCl3): d 20.6 (–COCH3), 37.8 (–SO2CH3),
38.5 (–SO2CH3), 53.8 (–OCH3), 55.2 (–OCH3), 65.7
(C-6), 75.6 (C-4), 77.3 (C-5), 78.8 (C-2), 82.2 (C-3),
101.5 (C-1), 169.4 (–COCH3). MS (ESI-TOF+): calcd
for C12H22O11S2 406, found m/z = 424 (M++NH4), 429
(M++Na). Elemental Anal. Calcd for C12H22O11S2
(406.1): C, 35.46; H, 5.46. Found: C, 35.50; H, 5.56.
4.3. 6-O-Methylsulfonyl-2,5:3,4-dianhydro-L-talose dimethyl
acetal 7
Compound 6b (6.65 g, 18.92 mmol) was dissolved in meth-
anol (90 ml), and potassium carbonate (7.5 g) was added.
The mixture was stirred at room temperature for 2.5 h.
After filtration, neutralization, and evaporation, the
residue was extracted with chloroform. The extract was
purified by silica gel chromatography eluting with cyclo-
4.6. 3-O-Methanesulfonyl-4-O-acetyl-6-deoxy-6-azido-2,5-
anhydro-L-idofuranose dimethylacetal 10
A mixture of 9 (2.7 g, 6.42 mmol) and sodium azide (3.3 g,
51.4 mmol) was suspended in anhydrous DMF (80 ml).
The reaction was heated at 70 °C for 64 h. The mixture
was filtered, and evaporated under reduced pressure. The
residue was purified by silica gel chromatography, 10
hexane and ethyl acetate to give 7 (light yellow syrup in
25
88.3% yield). ½aꢁD ¼ þ14:4 (c 0.190, MeOH); 1H NMR
(500 MHz, CDCl3): d 3.06 (s, 3H, –SO2CH3), 3.46 (s, 3H,
–OCH3), 3.48 (s, 3H, –OCH3), 3.81 (d, J = 3.0 Hz, 1H,
H-4), 3.87 (d, J = 3.0 Hz, 1H, H-3), 4.14 (d, J = 4.0 Hz,
1H, H-2), 4.32 (m, 4H, H-1, H-5, H-6a, H-6b). 13C NMR
(125 MHz, CDCl3): d = 37.4 (–SO2CH3), 55.9 (–OCH3),
56.2 (C-4), 56.8 (–OCH3), 57.0 (C-3), 67.8 (C-6), 75.5
(C-5), 78.6 (C-2), 105.0 (C-1). MS (ESI-TOF+): calcd
for C9H16O7S 268, found m/z = 286 (M++NH4), 291
(M++Na). Elemental Anal. Calcd for C9H16O7S (268.3):
C, 40.29; H, 6.02. Found: C, 40.29; H, 5.74.
1
(2.12 g, colorless syrup) was obtained in 93.8% yield. H
NMR (500 MHz, CDCl3): d 2.14 (s, 3H, –COCH3), 3.16
(s, 3H, –SO2CH3), 3.44 (m, 4H, –OCH3, H-6a), 3.48 (m,
4H, –OCH3, H-6b), 4.26 (dd, J = 4.0, 7.5 Hz, 1H, H-2),
4.46–4.48 (m, 1H, H-5), 4.53 (d, J = 7.5 Hz, 1H, H-1),
5.05 (dd, J = 1.5, 4.0 Hz, 1H, H-3), 5.40 (dd, J = 1.5,
4.0 Hz, 1H, H-4). 13C NMR (125 MHz, CDCl3): d 20.6
(–COCH3), 38.4 (–SO2CH3), 49.4 (C-6), 53.8 (–OCH3),
55.1 (–OCH3), 76.1 (C-4), 78.1 (C-5), 78.7 (C-2), 82.4
(C-3), 101.5 (C-1), 169.4 (–COCH3). MS (ESI-TOF+):
calcd for C11H19N3O8S 353, found m/z = 371
(M++NH4), 376 (M++Na). Elemental Anal. Calcd for
C11H19N3O8S(353.1): C, 37.39; H, 5.42; N, 11.89. Found:
C, 37.74; H, 5.47; N, 12.01. IR: 2104 (–N3).
4.4. 6-Deoxy-6-azido-2,5:3,4-dianhydro-L-talose dimethyl-
acetal 8
3-O-Methanesulfonyl-4-O-acetyl-6-deoxy-6-azido-2,5-an-
hydro-L-idofuranose dimethylacetal 10 (0.30 g, 0.85 mmol)
was dissolved in methanol (8 ml), and potassium carbonate
(0.31 g, 2.2 mmol) was added. The mixture was stirred at
room temperature for 2.5 h. After filtration, neutralization,
and evaporation, the residue was extracted with CH2Cl2.
The extract was purified on silica gel chromatography.
Compound 8 (colorless syrup) was obtained (0.16 g,
4.7. 3-O-Methanesulfonyl-4-O-acetyl-6-deoxy-6-acetyl-
amino-2,5-anhydro-L-idofuranose dimethylacetal 12
Azide 10 (0.73 g, 2.06 mmol) was dissolved in anhydrous
ethanol (30 ml), Pd/C (73 mg, 10% w/w) was added and
the mixture was evacuated with H2 (4 kg/cm2) several
times. The suspension was stirred under an atmosphere
of hydrogen for 7 h. After filtration, the volatile materials
were evaporated. The residue was dissolved in anhydrous
pyridine (20 ml), and Ac2O (0.3 ml, 3.1 mmol) was added
dropwise under an ice bath. The mixture was stirred for
18 h at room temperature. After evaporation, the residue
1
87.5%). H NMR (500 MHz, CDCl3): d 3.41–3.50 (m, 8
H, –OCH3, H-6), 3.76 (dd, J = 1.0, 3.0 Hz, 1H, H-2),
3.85 (d, J = 3.0 Hz, 1H, H-5), 4.15–4.18 (m, 2H, H-1,
H-3), 4.33 (d, J = 4.0 Hz, 1H, H-4). MS (ESI-TOF+) calcd
for C8H13N3O4, 215, found: m/z = 233 (M++NH4), 238
(M++Na). IR: 2103 (–N3).
was purified on silica gel chromatography, 12 (0.56 g, col-
25
4.5. 3,6-Di-O-methanesulfonyl-4-O-acetyl-2,5-anhydro-L-
idofuranose dimethylacetal 9
orless syrup) was obtained in 73.7% yield. ½aꢁD ¼ ꢀ5:5 (c
0.004, MeOH). 1H NMR (500 MHz, CDCl3): d 1.99 (s, 3H,
–NHAc), 2.14 (s, 3H, 4-COCH3), 3.15 (s, 3H, –SO2CH3),
3.35–3.41 (m, 1H, H-6a), 3.44 (s, 3H, –OCH3), 3.48 (s,
3H, –OCH3), 3.50–3.55 (m, 1H, H-6b), 4.24 (dd, J = 4.0,
7.5 Hz, 1H, H-2), 4.39 (m, 1H, H-5), 4.52 (d, J = 7.5 Hz,
1H, H-1), 5.02 (dd, J = 1.0, 4.0 Hz, 1H, H-3), 5.37 (dd,
J = 1.0, 3.5 Hz, 1H, H-4), 5.94 (t, J = 5.0 Hz, 1H, 6-NH).
13C NMR (125 MHz, CDCl3): d 20.6 (–NHAc), 23.2
(4-COCH3), 38.1 (C-6), 38.5 (–SO2CH3), 53.7 (–OCH3),
55.1 (–OCH3), 76.2 (C-4), 78.3 (C-5), 78.5 (C-2), 82.5
(C-3), 101.5 (C-1), 169.7 (6-NHAc), 170.1 (4-COCH3).
MS (ESI-TOF+): calcd for C13H23NO9S 369, found
m/z = 370 (M++H), 392 (M++Na). Elemental Anal. Calcd
Compound 6b (4.0 g, 10.6 mmol) was dissolved in anhy-
drous pyridine (120 ml), under an ice bath and Ac2O
(3.0 ml, 31.7 mmol) was added dropwise. The solution
was stirred for 17 h at room temperature. Volatile materials
were evaporated, EtOAc/H2O was added, the layers were
separated, and the organic phase was washed (saturated
NaHCO3 and brine) and dried (Na2SO4). After evapora-
tion, the residue was chromatographed to give 9 in 97.7%
25
1
yield. ½aꢁD ¼ þ0:7 (c 0.003, MeOH). H NMR (500 MHz,
CDCl3): d 2.14 (s, 3H, –COCH3), 3.06 (s, 3H, –SO2CH3),
3.16 (s, 3H, –SO2CH3), 3.44 (s, 3H, –OCH3), 3.46 (s, 3H,

F. Wang et al. / Tetrahedron: Asymmetry 18 (2007) 2139–2146
2143
for C13H23NO9S (369.1): C, 42.27; H, 6.28; N, 3.79. Found:
C, 42.20; H, 6.16; N, 3.71.
The solution of 13 (2.06 g, 8.91 mmol) in anhydrous
DMF (15 ml) was added under argon at room temperature.
After stirring for 0.5 h, the mixture was heated at 100 °C
for 64 h. After filtration and evaporation, the residue was
purified by silica gel chromatography eluting with CH2Cl2
and methanol. Compound 15b-N (1.32 g, white foam) was
obtained in 43.3% yield and 15b-O (1.15 g, white foam) was
obtained in 37.7% yield.
4.8. 6-Deoxy-6-acetylamino-2,5:3,4-dianhydro-L-talose
dimethylacetal 13
Compound 12 (0.56 g, 1.71 mmol) was dissolved in metha-
nol (30 ml), and potassium carbonate (0.24 g, 1.71 mmol)
was added. The mixture was stirred at room temperature
for 2.5 h. After filtration, neutralization, and evaporation,
the residue was extracted with CH2Cl2. The extract was
purified by silica gel chromatography eluting with CH2Cl2
Compound 15b-N, UV (MeOH): kmax = 272 (e = 7300).
25
½aꢁD ¼ ꢀ11:0 (c 0.002, MeOH). 1H NMR (500 MHz,
DMSO-d6): d 1.78 (s, 3H, 6-CH3CO), 3.07–3.12 (m, 1H,
H-6a), 3.17–3.24 (m, 1H, H-6b), 3.33 (s, 6H, 1-OCH3),
3.75 (t, J = 5.5 Hz, 1H, H-2), 4.10–4.14 (m, 1H, H-5),
4.24 (t, J = 6.5 Hz, 1H, H-4), 4.47 (d, J = 6.5 Hz, 1H,
H-1), 4.50 (d, J = 5.5 Hz, 1H, H-3), 5.49 (s, 1H, 3-OH),
7.97 (t, J = 6.0 Hz, 1H, 6-NHAc). For cytosin-1-yl: 5.71
(d, J = 7.5 Hz, 1H, H-5), 7.12 (br s, 2H, 4-NH2), 7.48
(d, J = 7.5 Hz, 1H, H-6). 13C NMR (125 MHz, DMSO-
d6): d 22.5 (6-CH3CO), 40.7 (C-6), 53.8 (1-OCH3), 54.6
(1-OCH3), 69.0 (C-4), 73.9 (C-3), 77.3 (C-5), 82.7 (C-2),
103.9 (C-1), 169.4 (6-COCH3). For cytosin-1-yl: 93.9
(C-5), 144.6 (C-6), 155.6 (C-2), 165.4 (C-4). HRMS (ESI-
TOF+): calcd for C14H22N4O6 (M++Na) 365.14316;
found: 365.14357.
and methanol. Compound 13 (0.35 g, white crystal) was
25
obtained in 89.7% yield. ½aꢁD ¼ þ34:6 (c 0.005, MeOH).
1H NMR (500 MHz, CDCl3): d 1.99 (s, 3H, –COCH3),
3.46 (m, 8H, 2-OCH3, H-6a, H-6b), 3.70 (m, 1H, H-2),
3.73 (m, 1H, H-5), 4.13 (d, J = 4.0 Hz, 1H, H-1), 4.18
(dd, J = 4.0, 6.0 Hz, 1H, H-3), 4.30 (d, J = 4.5 Hz, 1H,
H-4). 13C NMR (125 MHz, CDCl3): d 18.1 (–COCH3),
35.2 (C-6), 50.5 (–OCH3), 50.9 (–OCH3), 51.3 (C-4), 51.8
(C-3), 70.6 (C-5), 73.1 (C-2), 99.6 (C-1). MS (ESI-TOF+)
calcd for C10H17NO5 231, found m/z = 232 (M++H), 254
(M++Na), 270 (M++K). Elemental Anal. Calcd for
C10H17NO5 (231.1): C, 51.94; H, 7.41; N, 6.06. Found: C,
52.02; H, 7.40; N, 5.98.
4.9. 4,6-Dideoxy-4-(adenin-9-yl)-6-acetylamino-2,5-anhy-
dro-L-mannofuranose dimethyl acetal 15a
Compound 15b-O, UV (MeOH): kmax = 275 (e = 7349).
25
½aꢁD ¼ ꢀ13:5 (c 0.002, MeOH). 1H NMR (500 MHz,
DMSO-d6): d 1.78 (s, 3H, N6-CH3CO), 3.30 (m, 8H,
1-OCH3, H-6), 3.85 (dd, J = 3.0, 7.0 Hz, 1H, H-2), 3.95–
3.98 (m, 1H, H-3), 4.12 (br s, 1H, H-4), 4.30 (d,
J = 7.5 Hz, 1H, H-1), 4.87 (t, J = 2.0 Hz, 1H, H-5), 5.50
(d, J = 3.5 Hz, 1H, 3-OH), 7.94 (t, J = 6.0 Hz, 1H,
6-NHAc). For cytosin-2-O-yl: 6.10 (d, J = 6.0 Hz, 1H,
H-5), 6.92 (s, 2H, 4-NH2), 7.85 (d, J = 6. Hz, 1H, H-6).
13C NMR (125 MHz, DMSO-d6): d 22.6 (N6-CH3CO),
40.8 (C-6), 53.2 (1-OCH3), 54.2 (1-OCH3), 76.5 (C-4),
82.0 (C-3), 83.7 (C-5), 84.5 (C-2), 103.2 (C-1), 169.3
(6-COCH3). For cytosin-2-O-yl: 99.8 (C-5), 156.2 (C-6),
164.0 (C-2), 165.4 (C-4). HRMS (ESI-TOF+): calcd for
C14H22N4O6 (M++Na) 365.14316; found: 365.14350.
A mixture of adenine (1.91 g, 14.2 mmol), potassium
carbonate (2.60 g, 18.9 mmol), and 18-crown-6 (1.50 g,
5.53 mmol) was suspended in anhydrous DMF (50 ml).
The solution of 13 (2.18 g, 9.43 mmol) in anhydrous
DMF (20 ml) was added under argon at room temperature.
After stirring for 0.5 h, the mixture was heated at 100 °C
for 72 h. After filtration and evaporation, the residue was
purified by silica gel chromatography eluting with CH2Cl2
and methanol. Compound 15a (2.13 g, white foam) was
obtained in 61.7% yield. UV (MeOH):
kmax = 260
25
(e = 11,345). ½aꢁD ¼ þ4:0 (c 0.001, MeOH). 1H NMR
(500 MHz, DMSO-d6): d 1.75 (s, 3H, 6-CH3CO), 3.20–
3.40 (m, 8H, 1-OCH3, H-6), 3.86 (t, J = 6.0 Hz, 1H,
H-2), 4.43–4.50 (m, 2H, H-5, H-4), 4.60 (d, J = 6.0 Hz,
1H, H-1), 4.84 (dd, J = 6.0, 12.0 Hz, 1H, H-3), 5.67 (d,
J = 5.5 Hz, 1H, 3-OH), 8.02 (t, J = 5.5 Hz, 1H, 6-NHAc).
For adenin-9-yl: 7.26 (s, 2H, 6-NH2), 8.08 (s, 1H, H-8),
8.15 (s, 1H, H-2). 13C NMR (125 MHz, DMSO-d6): d
22.4 (6-CH3CO), 40.2 (C-6), 53.8 (1-CH3O), 54.5
(1-CH3O), 65.0 (C-4), 74.4 (C-3), 77.2 (C-5), 82.2 (C-2),
103.7 (C-1), 169.6 (6-COCH3). For adenin-9-yl: 119.3
(C-5), 140.6 (C-8), 149.3 (C-4), 152.3 (C-2), 156.1 (C-6).
HRMS (ESI-TOF+): calcd for C15H22N6O5 (M++Na)
389.15439; found: 389.15462.
4.11. 4,6-Dideoxy-4-(5-fluorocytosin-1-yl)-6-acetylamino-
2,5-anhydro-L-mannofuranose dimethyl acetal 15c
A mixture of 5-fluorocytosine (1.24 g, 9.60 mmol), potas-
sium carbonate (1.77 g, 12.8 mmol), and 18-crown-6
(0.87 g, 3.20 mmol) was suspended in anhydrous DMF
(40 ml). The solution of 13 (1.48 g, 6.40 mmol) in anhy-
drous DMF (10 ml) was added under argon at room
temperature. After stirring for 0.5 h, the mixture was
heated at 100 °C for 72 h. After filtration and evaporation,
the residue was purified on silica gel chromatography
eluting with CH2Cl2 and methanol. Compound 15c
4.10. 4,6-Dideoxy-4-(cytosin-1-yl)-6-acetylamino-2,5-
anhydro-L-mannofuranose dimethyl acetal 15b-N and 4,6-
Dideoxy-4-(cytosin-2-O-yl)-6-acetylamino-2,5-anhydro-L-
mannofuranose dimethyl acetal 15b-O
(1.36 g, white foam) was obtained in 59.1% yield. UV
25
(MeOH): kmax = 278 (e = 7524). ½aꢁD ¼ ꢀ6:0 (c 0.002,
1
MeOH). H NMR (500 MHz, DMSO-d6): d 1.80 (s, 3H,
6-CH3CO), 3.26–3.32 (m, 8H, H-6, 1-OCH3), 3.87 (dd,
J = 3.0, 7.5 Hz, 1H, H-2), 3.96–3.99 (m, 1H, H-5), 4.12
(t, J = 3.5 Hz, 1H, H-4), 4.30 (d, J = 7.0 Hz, 1H, H-1),
4.84 (t, J = 2.0 Hz, 1H, H-3), 5.49 (d, J = 4.0 Hz, 1H, 3-
OH), 7.95 (s, 1H, 6-NHAc). For 5-fluorocytosin-1-yl:
A mixture of cytosine (1.49 g, 13.37 mmol), potassium
carbonate (2.46 g, 17.8 mmol), and 18-crown-6 (1.21 g,
4.46 mmol) was suspended in anhydrous DMF (45 ml).

2144
F. Wang et al. / Tetrahedron: Asymmetry 18 (2007) 2139–2146
7.35 (s, 2H, 4-NH2), 7.95 (s, 1H, H-6). 13C NMR
(125 MHz, DMSO-d6): d 22.5 (6-CH3CO), 40.7 (C-6),
53.1 (1-OCH3), 54.2 (1-OCH3), 76.4 (C-4), 82.0 (C-3),
84.3 (C-5), 84.5 (C-2), 103.1 (C-1), 169.3 (6-COCH3). For
5-fluorocytosin-1-yl: 139.7, 139.9 (C-6), 141.2, 143.2
(C-5), 155.0, 155.1 (C-2), 159.3 (C-4). HRMS (ESI-
TOF+): calcd for C14H21FN4O6 (M++K, Na) 399.10767,
383.13374; found: 399.10669, 383.13347.
5), 4.52 (d, J = 7.5 Hz, 1H, H-3), 4.70 (dd, J = 7.5,
13.5 Hz, 1H, H-4), 4.84 (t, J = 5.0 Hz, 1H, 1-OH), 5.61
(d, J = 5.5 Hz, 1H, 3-OH), 8.00 (t, J = 5.5 Hz, 1H, 6-
NHAc). For adenin-9-yl: 7.24 (s, 2H, 6-NH2), 8.09 (s,
1H, H-8), 8.13 (s, 1H, H-2). 13C NMR (125 MHz,
DMSO-d6): d 22.4 (6-CH3CO), 40.0 (C-6), 61.5 (C-1),
64.5 (C-4), 73.3 (C-3), 76.9 (C-5), 83.3 (C-2), 169.6 (6-
COCH3). For adenin-9-yl: 119.3 (C-5), 140.5 (C-8), 149.4
(C-4), 152.3 (C-2), 156.1 (C-6). HRMS (ESI-TOF+): calcd
for C13H18N6O4 (M++K) 361.10211; found: 361.10311.
4.12. 4,6-Dideoxy-4-(thymin-1-yl)-6-acetylamino-2,5-anhy-
dro-L-mannofuranose dimethyl acetal 15d and 4,6-dideoxy-4-
(thymin-1-yl)-6-acetylamino-2,5-anhydro-L-mannitol 16d
4.14. 4,6-Dideoxy-4-(cytosin-1-yl)-6-acetylamino-2,5-anhy-
dro-L-mannitol 16b
A mixture of compound 13 (2.50 g, 10.8 mmol), thymine
(2.20 g, 16.2 mmol), potassium carbonate (3.00 g,
21.6 mmol), and 18-crown-6 (1.50 g, 5.40 mmol) was
suspended in anhydrous DMF (40 ml). The solution was
stirred at 180 °C under microwave heating conditions for
30 min employing a focused microwave oven. After filtra-
tion and evaporation, the residue was purified by silica
gel chromatography eluting with CH2Cl2 and methanol.
The mixture of thymine and 15d (yellow solid) was
obtained. The mixture (3.86 g) was dissolved in 1% hydro-
chloric acid (200 ml) and heated at 70 °C for 9 h. After
cooling and neutralization, sodium borohydride (900 mg)
was added. The solution was stirred at room temperature
for 2 h then neutralized with 2 N HCl. The mixture was
purified by silica gel chromatography. Compound 16d
(1.58 g, white foam) was obtained in 46.7% yield (two
steps).
Compound 15b-N (1.00 g, 2.92 mmol) was dissolved in 1%
hydrochloric acid (25 ml) and heated at 60 °C for 5 h. After
cooling and neutralization, sodium borohydride (250 mg)
was added. The solution was stirred at room temperature
for 1.5 h then neutralized with 2 N HCl. The mixture was
purified by silica gel chromatography. Compound 16b
(0.72 g, white foam) was obtained in 82.8% yield. UV
25
(MeOH): kmax = 276 (e = 7186). ½aꢁD ¼ þ7:0 (c 0.001,
1
MeOH). H NMR (500 MHz, DMSO-d6): d 1.77 (s, 3H,
6-CH3CO), 3.10 (m, 1H, H-6a), 3.24 (m, 1H, H-6b), 3.52
(m, 1H, H-1a), 3.60 (m, 1H, H-1b), 3.72 (m, 1H, H-2),
4.05 (m, 1H, H-5), 4.34 (dd, J = 7.0, 13.0 Hz, 1H, H-3),
4.42 (t, J = 7.5 Hz, 1H, H-4), 4.77 (t, J = 5.5 Hz,1H,
1-OH), 5.46 (d, J = 6.0 Hz, 1H, 3-OH), 7.95 (t,
J = 6.0 Hz, 1H, 6-NHAc). For cytosin-1-yl: 5.72 (d,
J = 7.5 Hz, 1H, H-5), 7.10 (br s, 2H, 4-NH2), 7.53 (d,
1H, J = 7.5 Hz, H-6). 13C NMR (125 MHz, DMSO-d6): d
22.5 (6-CH3CO), 41.3 (C-6), 61.5 (C-1), 67.5 (C-4), 73.2
(C-3), 77.5 (C-5), 83.5 (C-2), 169.4 (6-COCH3). For
cytosin-1-yl: 94.1 (C-5), 144.0 (C-6), 155.8 (C-2), 165.4
(C-4). MS (ESI-TOF+): calcd for C12H18N4O5 298, found
m/z = 299 (M++H), 321 (M++Na). Elemental Anal. Calcd
for C12H18N4O5 (298.1): C, 48.32; H, 6.08; N, 18.78.
Found: C, 48.28; H, 6.27; N, 18.74.
Compound 16d, UV (MeOH): kmax = 271.5 (e = 7986).
25
½aꢁD ¼ ꢀ16:0 (c 0.001, MeOH). 1H NMR (500 MHz,
DMSO-d6): d 1.78 (s, 3H, 6-CH3CO), 3.08–3.12 (m, 1H,
H-6a), 3.23–3.33 (m, 1H, H-6b), 3.50–3.54 (m, 1H, H-1a),
3.60–3.66 (m, 1H, H-1b), 3.72–3.75 (m, 1H, H-2), 4.01–
4.10 (m, 1H, H-5), 4.25–4.29 (m, 1H, H-3), 4.46 (t,
J = 7.5 Hz, 1H, H-4), 4.80 (t, J = 6.5 Hz, 1H, 1-OH),
5.53 (d, J = 5.5 Hz, 1H, 3-OH), 7.97 (t, J = 5.5 Hz, 1H,
6-NHAc). For thymin-1-yl: 1.78 (s, 3H, 5-CH3), 7.51 (d,
J = 1.0 Hz, 1H, H-6), 11.30 (s, 1H, N3-H). 13C NMR
(125 MHz, DMSO-d6): d 22.5 (6-CH3CO), 41.3 (C-6),
61.3 (C-1), 65.4 (C-4), 72.9 (C-3), 76.9 (C-5), 82.9 (C-2),
169.4 (6-COCH3). For thymin-1-yl: 12.1 (5-CH3), 109.3
(C-5), 138.6 (C-6), 151.0 (C-2), 163.7 (C-4). HRMS (ESI-
TOF+): calcd for C13H19N3O6 (M++H) 314.13466; found:
314.13510.
4.15. 4,6-Dideoxy-4-(5-fluorocytosin-1-yl)-6-acetylamino-
2,5-anhydro-L-mannitol 16c
Compound 15c (37 mg, 0.10 mmol) was dissolved in 1%
hydrochloric acid (3.5 ml) and heated at 60 °C for 6 h.
After cooling and neutralization, sodium borohydride
(8 mg) was added. The solution was stirred at room
temperature for 1.5 h then neutralized with 2 N HCl. The
mixture was purified by silica gel chromatography.
Compound 16c (26 mg, white foam) was obtained in
4.13. 4,6-Dideoxy-4-(adenin-9-yl)-6-acetylamino-2,5-anhy-
dro-L-mannitol 16a
81.3% yield. UV (MeOH):
kmax = 279 (e = 6086).
25
½aꢁD ¼ ꢀ6:5 (c 0.002, MeOH). 1H NMR (500 MHz,
DMSO-d6): d 1.78 (s, 3H, 6-CH3CO), 3.27 (m, 1H, H-
6a), 3.45 (m, 3H, H-6b, H-1a, H-1b), 3.80 (dd, J = 5.5,
10.0 Hz, 1H, H-2), 3.91 (m, 1H, H-5), 4.05 (dd, J = 5.5,
8.5 Hz, 1H, H-3), 4.73 (t, J = 5.5 Hz, 1H, H-4), 4.84 (t,
J = 3.0 Hz, 1H, 1-OH), 5.39 (d, J = 4.0 Hz, 1H, 3-OH),
7.90 (t, J = 5.5 Hz,1H, 6-NHAc). For 5-fluorocytosin-1-yl:
7.31 (s, 2H, 4-NH2), 7.93 (d, J = 3.0 Hz, 1H, H-6).
13C NMR (125 MHz, DMSO-d6): d 22.6 (6-CH3CO), 40.9
(C-6), 61.2 (C-1), 75.9 (C-4), 81.2 (C-3), 84.7 (C-5), 84.9
(C-2), 169.2 (6-COCH3); For 5-fluorocytosin-1-yl: 139.8,
139.9 (C-6), 141.2, 143.2 (C-5), 154.9, 155.0 (C-2), 159.6
Compound 15a (1.49 g, 4.07 mmol) was dissolved in 1%
hydrochloric acid (50 ml) and heated at 60 °C for 3 h. After
cooling and neutralization, sodium borohydride (450 mg)
was added. The solution was stirred at room temperature
for 2 h then neutralized with 2 N HCl. The mixture was
purified by silica gel chromatography. Compound 16a
(1.12 g, white foam) was obtained in 85.5% yield. UV
25
(MeOH): kmax = 259.5 (e = 11746). ½aꢁD ¼ þ12:0 (c 0.002,
1
MeOH). H NMR (500 MHz, DMSO-d6): d 1.73 (s, 3H,
6-CH3CO), 3.18 (m, 2H, H-6), 3.56 (m, 1H, H-1a), 3.66
(m, 1H, H-1b), 3.81 (m, 1H, H-2), 4.40–4.43 (m, 1H, H-

F. Wang et al. / Tetrahedron: Asymmetry 18 (2007) 2139–2146
2145
(C-4). MS (ESI-TOF+): calcd for C12H17FN4O5 316, found
m/z = 317 (M++H), 339 (M++Na). Anal. Calcd for
C12H17FN4O5 (316.1): C, 45.57; H, 5.42; N, 17.71. Found:
C, 45.39; H, 5.57; N, 17.49.
and dissolved in anhydrous ethanol. After filtration and
evaporation, the residue was purified by silica gel chroma-
tography. Compound 4c (73 mg, white foam) was obtained
in 70.2% yield. UV (MeOH): kmax = 278 (e = 6990).
25
½aꢁD ¼ ꢀ15:0 (c 0.001, MeOH). 1H NMR (500 MHz,
4.16. 4,6-Dideoxy-4-(adenin-9-yl)-6-amino-2,5-anhydro-L-
mannitol 4a
DMSO-d6): d 2.71–2.75 (m, 1H, H-6a), 2.79–2.83 (m, 1H,
H-6b), 3.37 (br s, 1H, 1-OH), 3.41–3.44 (m, 1H, H-1a),
3.46–3.50 (m, 1H, H-1b), 3.79–3.82 (m, 1H, H-2), 3.82–
3.85 (m, 1H, H-5), 4.02 (t, J = 2.5 Hz, 1H, H-3), 4.71 (br
s, 2H, 6-NH2), 4.93 (t, J = 2.5 Hz, 1H, H-4), 5.42 (br s,
<1H, 3-OH). For 5-fluorocytosin-1-yl: 7.32 (s, 2H, 4-
NH2), 7.93 (d, J = 3.5 Hz, 1H, H-6). 13C NMR (125
MHz, DMSO-d6): d 43.1 (C-6), 61.4 (C-1), 75.6 (C-4),
84.2 (C-3), 84.5 (C-5), 85.8 (C-2). For 5-fluorocytosin-1-
yl: 139.7, 139.8 (C-6), 141.2, 143.2 (C-5), 154.9, 155.0
(C-2), 159.6 (C-4). HRMS (ESI-TOF+): calcd for
C10H15FN4O4 (M++H), 275.11501; found: 275.11552.
Compound 16a (28 mg, 0.087 mmol) was dissolved in
1.2 N hydrochloric acid (350 ml of H2O and 40 ml of con-
centrated HCl, 7 ml) and heated at reflux for 10 h. After
cooling and neutralization, the mixture was evaporated
and dissolved in anhydrous ethanol. After filtration and
evaporation, the residue was purified by silica gel chroma-
tography. Compound 4a (19 mg, white foam) was obtained
in 79.2% yield.
25
UV (MeOH): kmax = 260 (e = 13,125). ½aꢁD ¼ ꢀ11:0 (c
1
0.001, MeOH). H NMR (500 MHz, DMSO-d6): d 2.53–
4.19. 4,6-Dideoxy-4-(thymin-1-yl)-6-amino-2,5-anhydro-L-
mannitol 4d
2.57 (m, 1H, H-6a), 2.66–2.70 (m, 1H, H-6b), 3.42 (br s,
1H, 1-OH), 3.54–3.58 (m, 1H, H-1a), 3.64–3.67 (m, 1H,
H-1b), 3.78–3.81 (m, 1H, H-2), 4.21–4.25 (m, 1H, H-5),
4.67 (t, J = 8.0 Hz, 1H, H-3), 4.73 (t, J = 8.0 Hz, 1H,
H-4), 4.72 (br s, 2H, 6-NH2), 5.46 (br s, 1H, 3-OH). For
adenin-9-yl: 7.23 (s, 2H, 6-NH2), 8.13 (s, 1H, H-8), 8.24
(s, 1H, H-2). 13C NMR (125 MHz, DMSO-d6): d 43.5
(C-6), 61.7 (C-1), 63.1 (C-4), 73.7 (C-3), 80.0 (C-5), 83.4
(C-2); For adenin-9-yl: 119.2 (C-5), 140.1 (C-8), 149.6
(C-4), 152.4 (C-2), 156.1 (C-6). HRMS (ESI-TOF+): calcd
for C11H16N6O3 (M++H) 281.13567; found: 281.13555.
Compound 16d (31 mg, 0.099 mmol) was dissolved in
1.2 N hydrochloric acid (350 ml of H2O and 40 ml of con-
centrated HCl, 6 ml) and heated under reflux for 12 h.
After cooling and neutralization, the mixture was evapo-
rated and dissolved in anhydrous ethanol. After filtration
and evaporation, the residue was purified by silica gel chro-
matography. Compound 4d (21 mg, white foam) was
obtained in 80.8% yield. UV (MeOH): kmax = 270.5
25
(e = 7950). ½aꢁD ¼ ꢀ10:0 (c 0.001, MeOH). 1H NMR
(500 MHz, DMSO-d6): d 2.58–2.61 (m, 1H, H-6a), 2.64–
2.68 (m, 1H, H-6b), 3.36 (br s, 1H, 1-OH), 3.50–3.53
(m, 1H, H-1a), 3.60–3.63 (m, 1H, H-1b), 3.70–3.73 (m,
1H, H-2), 3.83–3.86 (m, 1H, H-5), 4.25 (t, J = 8.0 Hz,
1H, H-3), 4.65 (t, J = 8.0 Hz, 1H, H-4), 4.78 (br s, 2H,
6-NH2), 5.42 (br s, <1H, 3-OH). For thymin-1-yl: 1.79 (s,
3H, 5-CH3), 7.59 (s, 1H, H-6). 13C NMR (125 MHz,
DMSO-d6): d 43.8 (C-6), 61.6 (C-1), 63.7 (C-4), 72.9
(C-3), 79.7 (C-5), 82.9 (C-2). For thymin-1-yl: 12.0
(5-CH3), 109.5 (C-5), 138.1 (C-6), 151.3 (C-2), 163.7
(C-4). HRMS (ESI-TOF+): calcd for C11H17N3O5
(M++H) 272.12410; found: 272.12408.
4.17. 4,6-Dideoxy-4-(cytosin-1-yl)-6-amino-2,5-anhydro-L-
mannitol 4b
Compound 16b (32 mg, 0.107 mmol) was dissolved in
1.2 N hydrochloric acid (350 ml of H2O and 40 ml of con-
centrated HCl, 8 ml) and heated at reflux overnight. After
cooling and neutralization, the mixture was evaporated
and dissolved in anhydrous ethanol. After filtration and
evaporation, the residue was purified by silica gel chroma-
tography. Compound 4b (20 mg, white foam) was obtained
1
in 74.1% yield. H NMR (500 MHz, DMSO-d6): d 2.50–
2.55 (m, 1H, H-6a), 2.56–2.65 (m, 1H, H-6b), 3.43 (br s,
1H, 1-OH), 3.48–3.52 (m, 1H, H-1a), 3.58–3.61 (m, 1H,
H-1b), 3.69–3.72 (m, 1H, H-2), 3.77–3.81 (m, 1H, H-5),
4.27 (t, J = 7.5 Hz, 1H, H-3), 4.71 (t, J = 7.5 Hz, 1H,
H-4), 4.76 (br s, 2H, 6-NH2), 5.45 (br s, 1H, 3-OH). For
cytosin-1-yl: 5.72 (d, J = 7.5 Hz, 1H, H-5), 7.04 and 7.10
(s, 2H, 4-NH2), 7.63 (d, J = 7.5 Hz, 1H, H-6). 13C NMR
(125 MHz, DMSO-d6): d 43.8 (C-6), 61.6 (C-1), 64.7 (C-
4), 73.4 (C-3), 80.9 (C-5), 83.4 (C-2); For cytosin-1-yl:
94.2 (C-5), 143.1 (C-6), 156.1 (C-2), 165.2 (C-4). HRMS
(ESI-TOF+): calcd for C10H16N4O4 (M++H) 257.12443;
found: 257.12455.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (20332010), and a foundation for the
Author of National Excellent Doctoral Dissertation of PR
China (FANEDD200265).
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