One-step synthesis of novel tricyclic isomeric azidonucleosides

Article abstract of DOI:10.1016/j.tetasy.2006.03.034

Several tricyclic azido-isonucleosides were formed in high yields by the treatment of pyrimidine isonucleosides with triphenylphosphine, tetrabromomethane, and sodium azide. The regioselective ring opening of these tricyclic azido-isonucleosides was also

Full text of DOI:10.1016/j.tetasy.2006.03.034

Tetrahedron: Asymmetry 17 (2006) 1056–1061
One-step synthesis of novel tricyclic isomeric azidonucleosides
Zong-Sheng Li, Ren-Ping Qiao, Zhen-Jun Yang, Liang-Ren Zhang and Li-He Zhang*
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100083, PR China
Received 13 January 2006; revised 30 March 2006; accepted 30 March 2006
Abstract—Several tricyclic azido-isonucleosides were formed in high yields by the treatment of pyrimidine isonucleosides with triphenyl-
phosphine, tetrabromomethane, and sodium azide. The regioselective ring opening of these tricyclic azido-isonucleosides was also
investigated.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
and tricyclic structures and investigate their biological
activities. Herein, we report the synthesis of tricyclic azido-
isonucleosides.
The finding that 30-azido-30-deoxythymidine (AZT) is a
therapeutic agent for the treatment of acquired immuno-
deficiency syndrome (AIDS) has triggered an explosive
new development in the synthetic chemistry of nucleo-
sides.1 Many nucleoside analogues with anti-virus or anti-
cancer activities have been developed, many of which are
used in the current clinical condition including some tricy-
clic nucleosides, for example, 2,20-anhydro-1-b-D-arabino-
syl cytosine.2 However, there still remain some problems
with these drugs such as the development of drug resis-
tance, cytotoxicity, and enzymatic instability in vivo, which
led to the search for new nucleoside analogues with more
potent activity and lower side-effects. Isonucleosides repre-
sent a novel class of carbohydrate modified nucleosides, in
which the nucleobase is linked to various positions of
ribose other than C-10; some of these nucleosides showed
interesting biological activities.3–7 We have also reported
a series of isonucleoside syntheses and their incorporation
into oligonucleotides.8–10 Therefore, it would be interesting
to synthesize some isonucleosides with both azido groups
2. Results and discussion
In order to regioselectively introduce an azido group to the
60 or 10 position of isonucleoside 1a or 3, we preferred to
use the reagent triphenylphosphine/tetrabromomethane/
sodium azide.11 Isonucleoside 1a9 was protected with a
benzoyl group to give compound 2. After hydrolysis and
reduction of the acetal group, compound 2 was then
converted to compound 3 in 84% yield.
When compound 3 was treated with Ph3P, CBr4, and NaN3
(compound 3/Ph3P:CBr4:NaN3 = 1.0/1.1:1.1:5.0) at room
temperature in DMF for 12 h, compound 4 was obtained
in 82% yield (Scheme 1). To study the influence of the ratio
of isonucleoside substrate 3 and azido reagent on this one-
step regioselective azidation, the ratio was increased from
1.0/1.1:1.1:5.0 to 1.0/1.5:1.5:5.0. In addition to compound
O
N
O
N
O
N
O
N
O
N
NH
O OCH3
O OCH3
NH
N
O
NH
NH
a) 1%HCl
b) NaBH4
OCH3
OCH3
BzCl/Py
+
O
Ph3P/CBr4/NaN3/DMF
BzO
O
O
O
OH
N3
N3
O
O
O
HO
BzO
BzO
BzO
OH
OH
OH
OH
3
1a
5
2
4
Scheme 1. Synthesis of azido-isonucleoside 4 and tricyclic azido-isonucleoside 5.
*
Corresponding author. Tel.: +86 10 82801700; fax: +86 10 82802724; e-mail addresses: zdszlh@bjmu.edu.cn; zdszlh@mail.bjmu.edu.cn
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.03.034

Z.-S. Li et al. / Tetrahedron: Asymmetry 17 (2006) 1056–1061
1057
4, which was obtained in 65% yield, a novel tricyclic azido-
isonucleoside 5 was also obtained in 22% yield. When the
ratio of reagent was further changed into 1/2.5:2.5:5, com-
pounds 4 and 5 were afforded in 5% and 83% yields, respec-
tively (Table 1).
Compound 5 was treated with methylamine in methanol at
room temperature for 15 min; O-deprotected compound 8
was provided in 98% yield. Compound 8 could be further
reacted with methylamine to give product 9 and the reac-
tion was complete in several hours in 97% yield. Com-
pound 5 was refluxed in 1 M sodium hydroxide or
treated with aqueous ammonia at 100 ꢁC in a sealed steel
vessel to give compound 10 in 95% yield. 1H NMR of com-
pounds 9 and 10 showed a cis coupling constant between
H-30 and H-40. The structures of compounds 9 and 10 were
also identified by 13C NMR and HRMS. In the case of 2,20-
anhydro-b-D-arabino-furanosylthymine, it was reported
that ‘hard’ nucleophiles such as hydroxide ion or ammonia
attack at C-2 on the pyrimidine, resulting in substitution at
C-2 and leaving the hydroxyl on the 20 position in the ara-
bino configuration; while the ‘soft’ nucleophiles, such as
thiophenolate and azide ions, attack at C-20 of the ribose.14
In this work, the ‘hard’ nucleophiles such as methyl-
amine and hydroxide ion attack at C-2 on the pyrimidine
of the 2,30-anhydro-40-pyrimidine-40-azido-isonucleo-
side 5, affording the corresponding regio- and stereo-
specific ring-opening products 9 and 10 in good yields
(Scheme 4).
Table 1. The yields (%) of 4, 5, 6, and 7 with different reactant ratios
Isonucleoside/Ph3P:CBr4:NaN3
4
5
6a
7a
6b
7b
1/1.1:1.1:5
1/1.5:1.5:5
1/2.5:2.5:5
82
65
5
—
22
83
75
58
8
—
19
74
92
—
24
62
‘—’ Not observed.
1
The structure of compound 5 was identified by H, 13C
NMR, and HRMS spectra. A comparison of the molecular
weight of compound 5 with the molecular weight of com-
pound 4 indicated that compound 5 was formed from com-
1
pound 4 by the loss of a hydroxyl group. The H NMR of
compound 5 showed cis coupling constant between H-20
and H-30. HMBC gave a strong coupling effect of H-30 with
C-2 on thymine, which indicated the formation of the bond
between the O-2 and C-30. The azidation of compound 1a
or 1b with this reagent is similar to that of compound 3
(Table 1). Compounds 6a,b and 7a,b were obtained, conve-
niently, by adjusting the ratio of the reactants and reaction
time (Scheme 2).
When compound 8 was treated with toluene-4-thiol in
methanol in the presence of triethylamine, a new tricyclic
isonucleoside 12 was formed, in which the C2–N10 bond
was formed instead of the C2–O30 bond (Scheme 5). Com-
pound 8 was refluxed with toluene-4-thiol in methanol or
reduced by catalytic hydrogenation (H2/Pd); the azido
group was reduced to give amino derivative 11. When 11
was refluxed further with triethylamine in methanol, the
final tricyclic isonucleoside 12 was formed. The structure
of tricyclic isonucleoside 12 was identified by 1H, 13C
NMR, and HMBC.
The triphenylphosphine-tetrahalomethane system has been
used for the replacement of various hydroxyl groups in the
sugar moiety of nucleosides by chlorine or bromine. An
ionic mechanism wasꢀsuggested for this nucleophilic substi-
tution; Ar3PþX CX3 was involved as an activator.12,13
According to this mechanism, the formation of compounds
6a and 7a is proposed in Scheme 3.
O
O
N
O
N
R
R
R
NH
N
O
NH
OCH3
OCH3
Ph3P/CBr4/NaN3/DMF
N
O
OCH3
OCH3
OCH3
OCH3
O
O
+
O
O
HO
N3
N3
OH
OH
1
7
6
1a R=CH3
1b R=H
6a R=CH3
6b R=H
7a R=CH3
7b R=H
Scheme 2. Synthesis of azido-isonucleoside 6a,b and tricyclic azido-isonucleoside 7a,b.
O
O
O
O
NH
NH
NH
O
N
NH
N
O
OCH3
OCH3
N
O
OCH3
OCH3
N
N
O
O
OCH3
OCH3
O
N
Ph
P
O
OCH3
OCH3
O
+
O
O
OCH3
OCH3
Ph
O
O
HO
OH
OH
N3
OH
N3
Ph
-
O
P
N3
N3
+
Ph
Ph
1a
6a
7a
Ph
Scheme 3. Proposed mechanism for the formation of azido-isonucleoside 6a and tricyclic azido-isonucleoside 7a.

1058
Z.-S. Li et al. / Tetrahedron: Asymmetry 17 (2006) 1056–1061
O
N
O
N
O
N
O
N
NH
N
N
O
N
O
CH3NH2/CH3OH
N3
CH3NH2/CH3OH
N3
1M NaOH, reflux
N3
O
HO
O
NHCH3
O
O
HO
N3
O
HO
HO
BzO
HO
8
10
9
5
Scheme 4. Regio- and stereospecific ring-opening reaction of compound 5.
O
N
O
N
O
N
N
N
N
O
Toluene-4-thiol
CH3OH, reflux
Triethylamine
CH3OH, reflux
O
O
NH
N3
NH2
OH
O
O
HO
HO
HO
8
12
11
Scheme 5. Formation of 10-deoxy-10-amino-40-deoxy-40-(thymin-1-yl)-2,10:20,50-dianhydro-L-altritol 12.
O
N
O
N
O
N
O
N
NH
NH
N
O
N
Toluene-4-thiol
CH3OH, reflux
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
O
OCH3
OCH3
Toluene-4-thiol
CH3OH, reflux
O
O
O
O
O
O
N3
H2N
H2N
N3
OH
14
OH
6a
13
7a
Scheme 6. The reduction of the azido group by toluene-4-thiol.
1
The azido group in compounds 6a and 7a can be easily
reduced to an amino group by a similar reaction to give
compounds 13 and 14. Since the amino group in compound
14 is far from the C2 position of thymine ring, the further
amino substitution did not take place (Scheme 6).
Perkin–Elmer 243B polarimeter. H NMR (500 Hz) and
13C NMR (125.7 Hz) spectra were recorded on Varian
Inova VXR-500 or Avance 500 Bruker spectrometer. When
necessary, 2D experiments were performed to assist in
structure elucidation. Infrared spectra were recorded on a
NEXUS-470 FTIR (Nicolet) spectrometer and only the
more representative frequencies are 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 representative peaks
are reported (m/z).
3. Conclusion
In conclusion, a convenient route has been achieved to the
synthesis of tricyclic isomeric azidonucleosides in one-step;
this kind of isonucleosides can easily be substituted by a
regio-selective nucleophilic opening ring reaction.
4.1. 60-O-Benzoyl-10-deoxy-10-azido-40-deoxy-40-(thymin-1-
yl)-20,50-anhydro-L-mannitol 4
4. Experimental
To a mixture of compound 3 (280 mg, 0.74 mmol), triphen-
ylphosphine (215 mg, 0.82 mmol), and sodium azide
(240 mg, 3.7 mmol) in dry DMF (5 ml) was added carbon
tetrabromide (271 mg, 0.82 mmol) at room temperature.
The mixture was stirred at room temperature for 12 h
and then methanol was added until the mixture turned into
a clear solution. Stirring was continued for another h. After
the usual work-up, the residue was purified by short-col-
umn chromatography using a gradient of MeOH in
CH2Cl2 (2–2.5%) to yield 4 (245 mg, 82%). Compound
Unless specified otherwise, all starting materials and re-
agents were obtained from commercial suppliers and used
without further purification. All anhydrous reactions were
conducted in oven-dried glassware, under a dry argon
atmosphere with anhydrous DMF, which was dried by
P2O5 and distilled before use. Thin layer chromatography
was performed using silica gel GF-254 (Qing-Dao Chemi-
cal Company, China) plates with detection by UV, or
charting with 5% phosphomolybdic acid hydrate in etha-
nol. Column chromatography was performed on silica gel
(200–300 mesh, purchased from Qing-Dao Chemical
Company, China). Optical rotations were recorded on a
24
1
4: ½aꢁD ¼ ꢀ39:2 (c 0.120, MeOH). H NMR (DMSO-d6,
500 MHz) d 1.78 (s, 3H, 5-CH3), 3.46–3.59 (m, 2H, H-10),
3.98 (m, 1H, H-20), 4.35–4.41 (m, 4H, H-50, H-30, and H-
60), 4.84 (t, J4 ,3 = J4 ,5 = 8.5 Hz, 1H, H-40), 5.80 (d,
0
0
0
0

Z.-S. Li et al. / Tetrahedron: Asymmetry 17 (2006) 1056–1061
1059
J = 5.5 Hz, 1H, 30-OH), 7.52 (t · d, J = 2.0 Hz, J = 7.0 Hz,
2H, Bz-3,5), 7.67 (m, 1H, Bz-4), 7.69 (s, 1H, H-6), 7.94 (dd,
J = 2.0 Hz, J = 7.0 Hz, 2H, Bz-2,6), 11.32 (s, 1H, N-3). 13C
NMR (DMSO-d6, 125.7 MHz) d 11.9 (5-CH3), 51.5 (C-10),
63.4 (C-60), 64.6 (C-40), 72.5 (C-30), 75.0 (C-50), 80.8 (C-20),
109.6 (C-5), 128.7 (Bz-3,5), 129.1 (Bz-4), 129.3 (Bz-2,6),
133.4 (Bz-1), 138.4 (C-6), 151.2 (C-2), 163.6 (PhCO),
165.3 (C-4). IR 3212 (br), 2103, 1690. Anal. Calcd for
C18H19N5O6 (401.1): C, 53.86; H, 4.77; N, 17.45. Found:
C, 53.67; H, 4.61; N, 17.26.
10), 109.5 (C-5), 138.1 (C-6), 151.1 (C-4), 163.6 (C-2). IR:
2105, 1691. HRMS (ESI-TOF+) calcd for C13H20N5O6
(M++H): 342.1408; found: 342.1424.
4.4. 60-Deoxy-60-azido-40-deoxy-40-(uracil-1-yl)-20,50-
anhydro-L-mannofuranose dimethyl acetal 6b
To a mixture of compound 1b (100 mg, 0.33 mmol), triphe-
nylphosphine (95 mg, 0.36 mmol), and sodium azide
(120 mg, 1.84 mmol) in dry DMF (5 ml) was added carbon
tetrabromide (120 mg, 0.36 mmol) at room temperature.
The mixture was stirred at room temperature for 16 h
and then methanol was added until the mixture turned into
a clear solution. Stirring was continued for a further hour.
After the usual work-up, the residue was purified by a
short-column chromatography using a gradient of MeOH
4.2. 60-O-Benzoyl-10-deoxy-10-azido-40-deoxy-40-(thymin-1-
yl)-2,30:20,50-dianhydro-L-altritol 5
To a mixture of compound 3 (376 mg, 1.0 mmol), triphen-
ylphosphine (655 mg, 2.5 mmol), and sodium azide
(325 mg, 5.0 mmol) in dry DMF (10 ml) was added carbon
tetrabromide (827 mg, 2.5 mmol) at room temperature.
The mixture was stirred at room temperature for 36 h
and then methanol was added until the mixture turned into
a clear solution. Stirring was continued for a further hour.
After the usual work-up, the residue was purified by a
short-column chromatography using a gradient of MeOH
in CH2Cl2 (2–2.5%) to yield 6b (100 mg, 92%). Com-
24
pound 6b: ½aꢁD ¼ ꢀ23:8 (c 0.080, MeOH). 1H NMR
(DMSO-d6, 500 MHz) d 3.17–3.56 (m, 2H, H-60), 3.33 (s,
10-OCH3), 3.34 (s, 10-OCH3), 3.82 (t, J2 ,1 = J2 ,3 = 5.5 Hz,
0
0
0
0
1H, H-20), 4.16 (m, 1H, H-50), 4.41 (m, 1H, H-30), 4.49 (d,
J1 ,2 = 5.5 Hz, 1H, H-10), 4.65 (t, J4 ,3 = J4 ,5 = 8 Hz, 1H,
H-40), 5.66 (d, J = 5.5 Hz, 1H, 30-OH), 5.67 (d, H-5), 7.66
(d, 1H, H-6), 11.33 (s, 1H, N-3). 13C NMR (DMSO-d6,
125.7 MHz): d 51.7 (C-60), 54.4 (10-OCH3), 55.1 (10-
OCH3), 65.0 (C-40), 74.1 (C-30), 77.6 (C-50), 82.3 (C-20),
102.5 (C-10), 104.5 (C-5), 143.0 (C-6), 151.6 (C-4), 163.5
(C-2). IR: 2107, 1722. HRMS (ESI-TOF+) calcd for
C12H18N5O6 (M++H): 328.1251; found: 328.1265.
0
0
0
0
0
0
in CH2Cl2 (2–3.3%) to yield 4 (20 mg, 5%) and 5
24
(320 mg, 83%). Compound 5: ½aꢁD ¼ þ28:9 (c 0.127,
MeOH). 1H NMR (CDCl3, 500 MHz)
d 1.91 (d,
J = 1.0 Hz, 3H, 5-CH3), 3.60 (m, 2H, H-10), 4.49 (m, 2H,
H-60), 4.65–4.69 (m, 2H, H-20 and H-50), 5.30 (d,
J4 ,3 = 7.5 Hz, 1H, H-40), 5.62 (dd, J3 ,2 = 4.5 Hz,
0
0
0
0
J3 ,4 = 7.5 Hz, 1H, H-30), 7.34 (d, J = 1.5 Hz, 1H, H-6),
7.48 (t, J = 8.0 Hz, 2H, Bz-3,5), 7.61 (t, J = 7.5 Hz, 1H,
Bz-4), 8.00 (m, 2H, Bz-2,6). 13C NMR (CDCl3,
125.7 MHz): d 13.9 (5-CH3), 49.2 (C-30), 64.0 (C-60), 65.3
(C-40), 80.5 (C-10), 81.6 (C-20), 83.2 (C-50), 119.3 (C-5),
128.6 (Bz-3,5), 128.9 (Bz-4), 129.5 (Bz-2,6), 130.9 (Bz-1),
133.7 (C-6), 159.7 (C-2), 165.9 (PhCO), 172.1 (C-4). IR:
2103, 1724. HRMS (ESI-TOF+) calcd for C18H18N5O5
(M++H): 384.1302; found: 384.1292.
0
0
4.5. 60-Deoxy-60-azido-40-deoxy-40-(thymin-1-yl)-2,30:20,50-
dianhydro-L-altrofuranose dimethyl acetal 7a
To a mixture of compound 1a (202 mg, 0.64 mmol), triphen-
ylphosphine (335 mg, 1.28 mmol), and sodium azide
(250 mg, 3.85 mmol) in dry DMF (5 ml) was added carbon
tetrabromide (423 mg, 1.28 mmol) at room temperature.
The mixture was stirred at room temperature for 36 h
and then methanol was added until the mixture turned into
a clear solution. Stirring was continued for another h. After
the usual work-up, the residue was purified by short-col-
umn chromatography using a gradient of MeOH in
CH2Cl2 (2–3.3%) to yield 6a (18 mg, 8%) and 7a (152 mg,
4.3. 60-Deoxy-60-azido-40-deoxy-40-(thymin-1-yl)-20,50-
anhydro-L-mannofuranose dimethyl acetal 6a
To a mixture of compound 1a (4.41 g, 13.95 mmol), triphen-
ylphosphine (4.02 g, 15.35 mmol), and sodium azide
(5.00 g, 76.92 mmol) in dry DMF (100 ml) was added car-
bon tetrabromide (4.90 g, 14.80 mmol) at room tempera-
ture. The mixture was stirred at room temperature for
48 h and then methanol was added until the mixture turned
into a clear solution. Stirring was continued for another
hour. After the usual work-up, the residue was purified
by a short-column chromatography using a gradient of
24
1
74%). Compound 7a: ½aꢁD ¼ þ79:4 (c 0.152, MeOH). H
NMR (DMSO-d6, 500 MHz) d 1.78 (s, 3H, 5-CH3), 3.30
(s, 3H, 10-OCH3), 3.38 (s, 3H, 10-OCH3), 3.31–3.76 (m,
2H, H-60), 4.29 (dd, J2 ,3 = 4.0 Hz, J2 ,1 = 7.5 Hz, 1H, H-
0
0
0
0
20), 4.42–4.54 (m, 2H, H-50 and H-10), 4.87 (d, J4 ,3
=
0
0
7.0 Hz, 1H, H-40), 5.44 (dd, J3 ,2 = 4.0 Hz, J3 ,4 = 7.0 Hz,
1H, H-30), 7.75 (s, 1H, H-6). 13C NMR (DMSO-d6,
125.7 MHz) d 13.6 (5-CH3), 49.2 (C-30), 52.7 (10-OCH3),
54.9 (10-OCH3), 64.7 (C-40), 78.6 (C-60), 82.4 (C-20), 83.5
(C-50), 101.4 (C-10), 116.5 (C-5), 132.8 (C-6), 159.5 (C-2),
171.2 (C-4). HRMS (ESI-TOF+) calcd for C13H18N5O5
(M++H): 324.1302; found: 324.1289.
0
0
0
0
MeOH in CH2Cl2 (2–2.5%) to yield 6a (3.57 g, 75%). Com-
24
pound 6a: ½aꢁD ¼ ꢀ19:6 (c 0.160, MeOH). 1H NMR
(DMSO-d6, 500 MHz) d 1.79 (s, 3H, 5-CH3), 3.29–3.54
(m, 2H, H-60), 3.34 (s, 3H, 10-OCH3), 3.35 (s, 3H, 10-
OCH3), 3.81 (t, J2 ,1 = J2 ,3 = 5.5 Hz, 1H, H-20), 4.16 (m,
0
0
0
0
1H, H-50), 4.40 (m, 1H, H-30), 4.49 (d, J1 ,2 = 5.5 Hz,
1H, H-10), 4.65 (dd, J = 8 Hz, J = 9 Hz, 1H, H-40), 5.58
(d, J = 5.5 Hz, 1H, 30-OH), 7.54 (d, J = 1 Hz, 1H, H-6),
11.30 (s, 1H, N-3). 13C NMR (DMSO-d6, 125.7 MHz): d
(5-CH3), 51.2 (C-60), 53.8 (10-OCH3), 54.3 (10-OCH3),
64.0 (C-40), 73.5 (C-30), 77.0 (C-50), 81.6 (C-20), 103.9 (C-
4.6. 60-Deoxy-60-azido-40-deoxy-40-(uracil-1-yl)-2,30:20,50-
dianhydro-L-altrofuranose dimethyl acetal 7b
0
0
To a mixture of compound 1b (125 mg, 0.41 mmol), triphen-
ylphosphine (265 mg, 1.01 mmol), and sodium azide
(150 mg, 2.31 mmol) in dry DMF (5 ml) was added carbon

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Z.-S. Li et al. / Tetrahedron: Asymmetry 17 (2006) 1056–1061
tetrabromide (340 mg, 1.02 mmol) at room temperature.
The mixture was stirred at room temperature for 58 h
and then methanol was added until the mixture turned into
a clear solution. Stirring was continued for another hour.
After the usual work-up, the residue was purified by
short-column chromatography using a gradient of MeOH
169.7 (C-4). HRMS (ESI-TOF+) calcd for C12H19N6O4
(M++H): 311.1462; found: 311.1462.
4.9. 10-Deoxy-10-azido-40-deoxy-40-(thymin-1-yl)-20,50-
anhydro-L-altritol 10
in CH2Cl2 (2–4%) to yield 6b (32 mg, 24%) and 7b
A solution of 5 (23 mg, 0.06 mmol) in 5 ml aqueous ammo-
nia was heated to 100 ꢁC in a sealed steel vessel for 10 h.
After this time, the solution was evaporated under reduced
pressure until dryness and the residue was purified by
short-column chromatography using MeOH in CH2Cl2
24
(79 mg, 62%). Compound 7b: ½aꢁD ¼ þ92:7 (c 0.070,
1
MeOH). H NMR (DMSO-d6, 500 MHz) d 3.32 (s, 3H,
10-OCH3), 3.39 (s, 3H, 10-OCH3), 3.35–3.78 (m, 2H, H-
60), 4.30 (dd, J2 ,3 = 4.0 Hz, J2 ,1 = 7.5 Hz, 1H, H-20),
0
0
0
0
4.44–4.47 (m, 2H, H-50 and H-10), 4.90 (dd, J4 ,5 = 1.0 Hz,
(2.5–4%) to yield 10 (17 mg, 95%). Compound 10:
0
0
24
J4 ,3 = 7.0 Hz, 1H, H-40), 5.47 (dd, J3 ,2 = 4.0 Hz,
½aꢁD ¼ ꢀ38:5 (c 0.040, MeOH). 1H NMR (DMSO-d6,
0
0
0
0
J3 ,4 = 7.5 Hz, 1H, H-30), 5.88 (d, J = 7.0 Hz, 1H, H-5),
7.84 (d, J = 7.0 Hz, 1H, H-6). 13C NMR (DMSO-d6,
125.7 MHz) d 49.2 (C-30), 52.7 (10-OCH3), 54.9 (10-
OCH3), 64.6 (C-40), 78.5 (C-60), 82.6 (C-20), 83.7 (C-50),
101.4 (C-10), 108.4 (C-5), 137.2 (C-6), 159.9 (C-2), 170.8
(C-4). IR: 2109, 1664, 1632. HRMS (ESI-TOF+) calcd
for C12H16N5O5 (M++H): 310.1145; found: 310.1140.
500 MHz) d 3.31–3.52 (m, 4H, 10 and 60), 4.15–4.20
0
0
(m, 2H, 20 and 30), 4.28–4.32 (m, 1H, H-50), 4.85
(t, J = 5.5 Hz, 1H, 60-OH), 4.91 (dd, J4 ,3 = 4.5 Hz,
0
0
J4 ,5 = 9.5 Hz, 1H, H-40), 5.57 (d, J = 5.5 Hz, 1H,
30-OH), 7.51 (s, 1H, H-6), 11.25 (s, 1H, N-3). 13C NMR
(DMSO-d6, 125.7 MHz) d 12.6 (5-CH3), 50.8 (C-10), 61.5
(C-60), 70.4 (C-40), 77.8 (C-50), 80.3 (C-20), 107.7 (C-
5), 140.2 (C-6), 151.9 (C-2), 164.2 (C-4). HRMS (ESI-
TOF+) calcd for C11H16N5O5 (M++H): 298.1145; found:
298.1152.
0
0
4.7. 10-Deoxy-10-azido-40-deoxy-40-(thymin-1-yl)-2,30:20,50-
dianhydro-L-altritol 8
A solution of 5 (73 mg, 0.19 mmol) in 2 ml 25–30% methyl-
amine alcohol solution was stirred at room temperature for
15 min. After this time, the solution was evaporated
under reduced pressure until dryness and the residue puri-
fied by short-column chromatography using a gradient of
MeOH in CH2Cl2 (2–5%) to yield 8 (52 mg, 98%).
4.10. 10-Deoxy-10-amino-40-deoxy-40-(thymin-1-yl)-
2,10:20,50-dianhydro-L-altritol 12
To a solution of 8 (30 mg, 0.11 mmol) in 3 ml MeOH, tolu-
ene-4-thiol (68 mg, 0.55 mmol), and triethylamine (0.1 ml,
0.71 mmol) were added and the mixture refluxed for 8 h.
After this time, the solution was evaporated under reduced
pressure until dryness and the residue was purified by
short-column chromatography using MeOH in CH2Cl2
24
1
Compound 8: ½aꢁD ¼ þ45:0 (c 0.030, MeOH). H NMR
(DMSO-d6, 500 MHz) d 1.80 (d, J = 1 Hz, 3H, 5-CH3),
3.43–3.68 (m, 4H, H-10 and H-60), 4.30 (t, J = 4.0 Hz,
1H, H-50), 4.48 (d · t, J2 ,1 = 8.0 Hz, J2 ,3 = 4.5 Hz, 1H,
(3.3–20%) to yield 12 (18 mg, 66%). Compound 12:
0
0
0
0
24
H-20), 5.03 (d, J4 ,3 = 7.5 Hz, 1H, H-4 ), 5.17 (t, J =
½aꢁD ¼ þ40:8 (c 0.105, MeOH). 1H NMR (DMSO-d6,
0
0
0
5 Hz, 1H, 60-OH), 5.52 (dd, J3 ,4 = 7.5 Hz, J3 ,2 = 4.5 Hz,
1H, H-30), 7.74 (d, J = 1.0 Hz, H-6). 13C NMR (DMSO-
d6, 125.7 MHz) d 13.6 (5-CH3), 49.3 (C-30), 61.9 (C-60),
64.9 (C-40), 80.2 (C-40), 83.5 and 83.6 (C-20 and C-50),
116.5 (C-5), 132.7 (C-6), 159.5 (C-2), 171.3 (C-4). HRMS
(ESI-TOF+) calcd for C11H14N5O4 (M++H): 280.1040;
found: 280.1044.
500 MHz) d 1.72 (s, 3H, 5-CH3), 3.13–3.21 (m, 2H, H-10),
3.37–3.47 (m, 2H, H-60), 4.22–4.23 (m, 1H, H-40), 4.28–
4.30 (m, 1H, H-30), 4.94–4.96 (t, J = 5.0 Hz, 1H, 60-OH),
5.75 (s, 1H, 30-OH), 6.85 (s, 1H, –NH–), 7.28 (s, 1H, H-
6). 13C NMR (DMSO-d6, 125.7 MHz) d 13.1 (5-CH3), 4.9
(C-10), 62.6 (C-60), 67.4 and 67.5 (C-30 and C-40), 75.1
(C-20), 82.0 (C-50), 114.7 (C-5), 141.4 (C-6), 156.6 (C-2),
170.1 (C-4). IR: 3299 (br), 1662, 1571. MS (ESI-TOF+)
254 (M+1,100), 276 (M+23).
0
0
0
0
4.8. 10-Deoxy-10-azido-40-deoxy-40-(5-methyl-N2-methyl-iso-
cytosin-1-yl)-20,50-anhydro-L-altritol 9
A solution of 5 (68 mg, 0.18 mmol) in 2 ml 25–30% methyl-
amine alcohol solution was stirred at room temperature
overnight. After this time, the solution was evaporated
under reduced pressure until dryness and the residue puri-
fied by short-column chromatography using MeOH
in CH2Cl2 (50%) to yield 9 (55 mg, 97%). Compound
9: ½aꢁD ¼ ꢀ82:3 (c 0.038, MeOH). H NMR (DMSO-d6,
500 MHz) d 1.71 (s, 3H, 5-CH3), 2.73 (d, J = 4.5 Hz, 3H,
–N–CH3), 3.32–3.59 (m, 4H, H-60 and H-10), 4.15–4.18
(m, 1H, H-20), 4.31 (m, 1H, H-30), 4.44–4.46 (m, 1H,
Acknowledgments
This work was supported by the National Natural
Science Foundation of China (20132030, SFCBIC
20320130046), and a Foundation for the Author of
National Excellent Doctoral Dissertation of PR China
(FANEDD200265).
24
1
References
H-50), 4.49 (dd, J4 ,5 = 9.0 Hz, J4 ,3 = 4.0 Hz, 1H, H-40),
5.02 (t, J = 5.5 Hz, 1H, 60-OH), 5.67 (d, J = 5.5 Hz, 1H,
30-OH), 6.97 (q, J = 4.0 Hz, 1H, –NH–), 7.31 (s, 1H,
H-6). 13C NMR (DMSO-d6, 125.7 MHz) d 13.5 (5-CH3),
50.3 (C-50), 58.4 (C-40), 59.7 (C-60), 69.1 (C-20), 77.0
(C-10), 79.5 (C-30), 111.6 (C-5), 136.6 (C-6), 153.9 (C-2),
0
0
0
0
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