Synthesis of carbohydrate-conjugated furo[2,3-d]pyrimidine by 'Click Chemistry'

Article abstract of DOI:10.1055/s-2008-1032191

Compounds belonging to a new type of furo[2,3-d]pyrimidine nucleoside conjugated with carbohydrate were synthesized by Sonogashira coupling and 'click chemistry'. Their structures were confirmed on the basis of various types of spectroscopy. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032191

PAPER
865
Synthesis of Carbohydrate-Conjugated Furo[2,3-d]pyrimidine by ‘Click
Chemistry’
a
b
b
b
a
S
X
ynthesis of Carbo
u
hydrate-Con
a
jugated Fu
n
d
]pyr
i
y
midine e Jin, Haixin Ding, Ruchun Yang, Qiang Xiao,* Yong Ju*
a
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Ministry of Education, Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. of China
Fax +86(10)62781695; E-mail: juyong@tsinghua.edu.cn
Jiangxi Key Laboratory of Organic Chemistry, Jiangxi Science and Technology Normal University, Nanchang 330013, P. R. of China
Fax +86(791)3826894; E-mail: qxiao75@yahoo.com.cn
b
Received 5 November 2007; revised 3 December 2007
conjugates exert important effects on many complex bio-
Abstract: Compounds belonging to a new type of furo[2,3-d]pyri-
midine nucleoside conjugated with carbohydrate were synthesized
by Sonogashira coupling and ‘click chemistry’. Their structures
were confirmed on the basis of various types of spectroscopy.
6
logical events, including the cellular recognition in the
7
8
processes of inflammation, immune response, tumor
9
6a
metastasis, and bacterial and viral infections. In addi-
tion, the glycosylation of proteins and lipids is a key factor
in modulating their structures and functions.10 Carbohy-
drates appended to pharmaceutical compounds are known
to possibly influence drug solubility, pharmacology, tar-
get recognition, toxicity, and mechanism of action.1
These are important factors for improving the bioactivi-
ties of potential drug candidates. With this stimulating bi-
ological background and our extended program for
synthesizing new derivatives of furo[2,3-d]pyrimidine
nucleosides, various monosaccharides and oligosaccha-
rides may be conjugated to improve their antiviral activi-
ty.
Key words: Sonogashira coupling, click chemistry, nucleosides,
heterocycles, carbohydrates
1–14
Bicyclic furo[2,3-d]pyrimidine nucleosides represent an
entirely new class of fused furopyrimidine derivatives
with unprecedented selectivity for varicella-zoster virus
1
(
VZV). The bicyclic furo[2,3-d]pyrimidine nucleoside
analogues can be viewed as somewhat related to Brivu-
dine [(E)-5-(2-bromovinyl)-2¢-deoxyuridine, BVDU]2,
which is approved for the treatment of herpes zoster.
However, these analogues differ from BVDU in several
biological and biochemical aspects that make these fu- The O-glycosylation approach is a crucial synthetic meth-
ro[2,3-d]pyrimidine derivatives ideally suited as selective odology to attach sugars to other molecules (aglycon). It
3
anti-VZV drugs. Although the precise mechanism of ac- is becoming more and more important and attracting
tion of these analogues remains to be elucidated, it is clear many chemists to focus on methods with high chemical
that their antiviral activity depends on phosphorylation by yields and stereoselectivities. But, at the moment, glyco-
3
the VZV-encoded thymidine kinase. Recently, many 6- sylation chemistry does not offer a general solution, and is
substituted furo[2,3-d]pyrimidine nucleosides with differ- still not a routine, predictable, or generally accessible
ent side chains have been synthesized and their biological technique. Therefore, a new glycoconjugation strategy is
4
activity has been studied. In terms of activity, both labo- highly desirable. The azide–alkyne dipolar cycloaddition
ratory and clinical VZV strains, prototype furo[2,3-d]py- catalyzed by copper(I) has the merits of high efficiency
rimidine nucleosides, which have side chains of optimal and simplicity, and has become known as ‘click chemis-
length and the appropriate lipophilicity and hydrophilici- try’. Because of benign reaction conditions and simple
ty, are much more potent and selective in their anti-VZV workup, it can be used in the construction of large molec-
3
,4a,c
activity.
Related research is necessary to expand the ular diversity through the use of corresponding reactive
structural diversity, as it is possible that bicyclic furo[2,3- modular building blocks. It has found many impressive
d]pyrimidine nucleosides are promising anti-VZV drug applications in many fields in recent years, such as the
candidates.
construction of fluorescent oligonucleotides for DNA se-
quencing, labeling of enzymes in vitro and in vivo, syn-
15
Carbohydrates make up the most abundant group of natu-
ral products, and the role of sugars as energy and biosyn-
thetic resources (glycolysis, pentose phosphate cycle,
etc.), ‘energy storage devices’ (photosynthesis), and key
thesis of a GDP-triazole library as inhibitor of fucosyl
16
transferases, and the functionalization of surfaces coated
with self-assembled monolayers.1
7,18
structural elements in the formation of biological back- With this in mind, we synthesized a series of bicyclic fu-
bones (2-deoxyribose for DNA or N-acetylglucosamine ro[2,3-d]pyrimidine nucleosides conjugated with carbo-
5
for murein) is well known. Oligosaccharides and glyco- hydrate by the Sonogashira reaction and click chemistry
to improve their aqueous solubility and the possible target
recognition to improve their biological activities.19
SYNTHESIS 2008, No. 6, pp 0865–0870
x
x
.
x
x
.2
0
0
8
The designed bicyclic furo[2,3-d]pyrimidine nucleosides
a–e were prepared from the commercially available
starting material 5-iodo-2¢-deoxyuridine 1 (Schemes 1
Advanced online publication: 28.02.2008
DOI: 10.1055/s-2008-1032191; Art ID: F20207SS
Georg Thieme Verlag Stuttgart · New York
7
©

8
66
X. Jin et al.
PAPER
and 2). First, the 3¢- and 5¢-hydroxyl groups of compound
were protected to avoid possible side reactions and to fa-
N
N
N3
N
1
O
O
cilitate purification in subsequent reactions. In our previ-
ous work, p-toluoyl was used as the protecting group,
which makes the subsequent intermediates easy to crystal-
lize and to be detected. However, furo[2,3-d]pyrimidine
will undergo a rearrangement reaction to produce 5-sub-
stituted uridine during the classic deprotection with cata-
lytic sodium methoxide in methanol. After several
experiments, it was found that C-7a of furo[2,3-d]pyrimi-
dine was easily attacked by nucleophiles. Therefore, a
group much easier to deprotect should be used. Our model
reaction showed acetyl to be suited for this purpose, as it
can be removed with freshly prepared saturated ammonia
in methanol at room temperature without the furo[2,3-
d]pyrimidine skeleton being destroyed. Thus, acetyl was
chosen during this work as the protecting group for the 3¢-
and 5¢-hydroxyl of compound 1.
R1
N
O
N
O
O
N
a
O
N
AcO
+
5a–e
AcO
N
N
OAc
4
OAc
6a–e (R = Ac)
N
6
7
O
7a
5
1
R2
N
4a
4
2
b
O
N 3
HO
O
OH
a–e (R = H)
7
OR
OR
O
OR
O
RO
RO
O
O
N
O
OR
I
O
I
OH
O
HN
RO
RO
HN
O
O
O
OR
HN
RO
O
N
OR
O
a
a
c
N
b
AcO
O
OR
HO
O
RO
RO
RO
O
O
O
AcO
O
O
RO
RO
O
O
OR
OAc
OR
OH
1
OR OR
e
OAc
2
b
d
N3
Scheme 2 Reagents and conditions: (a) CuSO ·5H O (10%), sodi-
4 2
OH
7
6
O
um ascorbate (20%), THF–H O (1:1), 10 h (6a: 91%, 6b: 73%, 6c:
2
O
N
7
a
5
87%, 6d: 98%, 6e: 79%); (b) sat. NH –MeOH, 0 °C, 3 h (7a: 63%, 7b:
3
1
N
4a
1
N
O
51%, 7c: 52%, 7d: 57%, 7e: 57%). Fragments a–e represent R and
2
2
4
R in 6a–e and 7a–e.
c
d
O
O
N 3
AcO
AcO
O
pale amorphous yellow solid 4 was obtained in 75% yield
after the reaction of 3 with 1.2 equivalents DPPA and one
equivalent DBU in anhydrous tetrahydrofuran under an
argon atmosphere (Scheme 1).
OAc
OAc
3
4
Next, various glycosides with terminal alkyne groups
Scheme 1 Reagents and conditions: (a) NaOAc (0.72 equiv), Ac O,
2
1
40 °C, 2 h (72%); (b) propargyl alcohol (2 equiv), Pd(PPh ) (5%), needed to be prepared. The syntheses of some related gly-
3
4
CuI (10%), Et N (3 equiv), DMF, 13 h; (c) CuI (30%), Et N (20 cosides in several steps from glucose, galactose, lactose,
3
3
equiv), 80 °C, 3 h (55%, two steps); (d) DPPA (1.2 equiv), DBU
1 equiv), THF, 0 °C, 1 h, then 40 °C, 10 h (75%).
and so forth have been reported in the literature. During
our continuous related work, a simple and large-scale syn-
thetic approach was needed to afford adequate alkyne-
(
First, treatment of 1 with 0.72 equivalents sodium acetate terminal glycosides. Mereyala et al. reported that the reac-
in acetic anhydride at 140 °C gave 5-iodo-3¢,5¢-di-O- tions of b-D-glucopyranose pentaacetate, b-D-galactopyr-
acetyl-2¢-deoxyuridine (2) in 72% yield (Scheme 1). anose pentaacetate, and b-D-lactose heptaacetate with
Then, reaction of 2 with propargyl alcohol under Sono- propargyl alcohol in the presence of the boron trifluoride–
gashira conditions [5% Pd(PPh ) , 10% CuI, DMF] at diethyl ether complex as catalyst give the corresponding
3
4
3,24
8
0 °C directly afforded the bicyclic furo[2,3-d]pyrimidine propargyl derivatives in high yields and selectivity.2 In
nucleoside 3 in one pot in 55% overall yield (Scheme 1).
20
this reaction, all starting materials are commercially avail-
In the subsequent reaction, the 6-hydroxymethyl group able. The reaction is reproducible and easy to scale up. Af-
needed to be transformed into an azide group. An exami- ter workup, the product can be crystallized from ethanol
nation of the literature provided many approaches for al- without column chromatographic purification. Accord-
2
1
cohol-to-azide transformations. We found that the 6- ingly, propargyl glycosides 5a–e were synthesized in
hydroxymethyl group, part of an electron-rich allylic alco- good yields and excellent b-selectivity (Figure 1). In addi-
hol, could be converted in high yield into azide when tion, the first propargyl glycoside crystal structure, of 5a,
diphenylphosphoryl azide (DPPA) and 1,8-diazabicyc- was also obtained (Figure 2).
2
2
lo[5,4,0]undec-7-ene (DBU) were used. At the end, the
Synthesis 2008, No. 6, 865–870 © Thieme Stuttgart · New York

PAPER
Synthesis of Carbohydrate-Conjugated Furo[2,3-d]pyrimidine
867
AcO
OAc
OAc
AcO
AcO
O
O
O
AcO
AcO
O
O
O
AcO
OAc
OAc
OAc
a
b
c
OAc
O
AcO
AcO
O
O
O
AcO
AcO
O
O
AcO
OAc
OAc
AcO OAc
d
e
Figure 1 Propargyl carbohydrates 5a–e
DBU, propargyl alcohol, and DPPA were purchased from Aldrich
Company. THF and CH Cl were dried over CaH and distilled
2
2
2
prior to use. NMR spectra were recorded on a Bruker AV400 (400
MHz) spectrometer. Chemical shifts are reported as d values rela-
tive to TMS as internal standard. The ESI-HRMS spectra were mea-
sured on a Bruker APEX II spectrometer in positive and negative
ion mode.
5
-Iodo-3¢,5¢-di-O-acetyl-2¢-deoxyuridine (2)
A stirred soln of NaOAc (0.81 g, 10 mmol) in Ac O (18 mL) was
2
heated to reflux (140 °C). Then 1 (5 g, 14 mmol) was added slowly
to this soln. The reaction mixture was refluxed for a further 2 h,
when TLC showed the reaction to be complete. The mixture was
poured into ice water, and left in a refrigerator overnight. The pre-
cipitate was collected by filtration, washed with cooled EtOH, and
dried in vacuo. The crude product was recrystallized (EtOH); this
provided 2.
Yield: 4.47 g (72%); white amorphous solid; R = 0.38 (CH Cl –
f
2
2
MeOH, 30:1).
1
Figure 2 ORTEP drawing of 5a with 35% probability ellipsoids,
showing the atomic numbering
H NMR (400 MHz, CDCl ): d = 2.06 (s, CH ), 2.12, 2.49 (m, 2 H,
3 3
H-2¢), 2.16 (s, CH ), 4.23–4.36 (m, 3 H, H-4¢, H-5¢), 5.17 (m, 1 H,
H-3¢), 6.23 (t, J = 6.4 Hz, 1 H, H-1¢), 7.90 (s, 1 H, H-6).
3
1
3
Finally, propargyl glycosides 5a–e needed to be conju-
C NMR (100 MHz, CDCl ): d = 19.9, 20.1 (2 × CH ), 37.3 (C-2¢),
3
3
gated to azide-group-bearing bicyclic furo[2,3-d]pyrimi- 62.9 (C-5¢), 68.0 (C-5), 73.1 (C-3¢), 81.8 (C-4¢), 84.5 (C-1¢), 142.8
C-6), 149.0 (C-2), 158.9 (C-4), 169.2, 169.4 (2 × C=O).
copper(I)-catalyzed click chemistry in an N,N-dimethyl- ESI-MS (+): m/z = 460.6 [M + Na]+.
(
dine nucleoside 4 (Scheme 2). We first used the reported
formamide–water (1:1) system. The copper(I) species was
generated in situ from a sodium ascorbate and copper(II)
sulfate solution. But the reaction was quite slow and the
+
HRMS (ESI): m/z [M + Na] calcd for C H IN O : 460.9816;
found: 460.9810.
1
3
15
2
7
starting material was not consumed completely after 24 3-(2¢-Deoxy-b-D-ribofuranosyl)-6-(hydroxymethyl)-2,3-di-
hydrofuro[2,3-d]pyrimidin-2-one (3)
hours. Further experiments showed that the tetrahydrofu-
Et N (4.76 mL, 34 mmol), CuI (217 mg, 1.14 mmol), Pd(PPh )
659 mg, 0.57 mmol), and propargyl alcohol (1.28 g, 22.8 mmol)
were added successively to a stirred soln of 2 (5 g, 11.4 mmol) in
anhyd DMF (80 mL) under an argon atmosphere. The reaction mix-
ture was stirred at r.t. until TLC showed the reaction to be complete.
3
3 4
ran–water (1:1) solvent system was suitable for this trans-
formation, and the reaction gave 1,4-disubstituted 1,2,3-
triazoles 6a–e in 73–98% isolated yields and completely
selectively (Scheme 2). The characteristic proton of 1,2,3-
(
triazoles has a single peak at about d = 7.67, and also cor- Additional CuI (646 mg, 3.4 mmol) and Et N (31 mL, 228 mmol)
3
relates with C-6 by HMBC NMR spectroscopy. At the were added. The reaction mixture was heated to 80 °C for 6 h and
concentrated in vacuo. The crude product was purified by column
end, all acetyl protecting groups were removed by freshly
chromatography (silica gel, CH Cl –MeOH, 1:0, then 50:1, then
2
2
prepared saturated ammonia in methanol at 0 °C to give
a–e in moderate yields (Scheme 2). All the structures
3
0:1, then 20:1). The appropriate fractions were combined and the
7
solvent was evaporated.
were confirmed by various spectroscopic investigations.
Yield: 2.3 g (55%); white amorphous solid; R = 0.19 (CH Cl –
f
2
2
A new type of furo[2,3-d]pyrimidine nucleoside conjugat- MeOH, 30:1).
ed with carbohydrate has been synthesized by Sonogash-
ira coupling and click chemistry. The evaluation of their
anti-VZV and antitumor activities is underway. The ap- 5.18 (m, 1 H, H-3¢), 6.22 (t, J = 6.4 Hz, 1 H, H-1¢), 6.49 (s, 1 H, H-
proach is straightforward and can be used to expand the 5), 8.33 (s, 1 H, H-4).
structure diversity efficiently for structure–activity rela-
tionship studies.
1
H NMR (400 MHz, CDCl ): d = 2.02 (s, CH ), 2.06 (s, CH ), 2.14,
3
3
3
2
.81 (m, 2 H, H-2¢), 4.36 (m, 3 H, H-5¢, H-4¢), 4.60 (s, 2 H, CH OH),
2
13
C NMR (100 MHz, CDCl ): d = 20.4 (2 × CH ), 38.6 (C-2¢), 56.4
3
3
(CH OH), 63.1 (C-5¢), 73.4 (C-3¢), 82.7 (C-4¢), 88.0 (C-1¢), 100.6
2
Synthesis 2008, No. 6, 865–870 © Thieme Stuttgart · New York

8
68
X. Jin et al.
PAPER
(
C-5), 107.1 (C-4a), 135.4 (C-4), 154.2 (C-2), 157.6 (C-7a), 169.8,
Compound 6b
1
69.9 (2 × C=O), 171.3 (C-6).
R = 0.26 (CH Cl –MeOH, 30:1).
f
2
2
ESI-MS (+): m/z = 388.8 [M + Na]+.
1
H NMR (400 MHz, CDCl ): d = 1.91, 1.95, 1.98, 1.99, 2.08, 2.10
3
+
(6 × CH
1
1
3
), 2.04, 2.89 (m, 2 H, H-2¢), 3.79 (m, 1 H, H-5¢¢), 4.09 (m,
H, H-6¢¢), 4.35 (m, 3 H, H-4¢, H-5¢), 4.58 (d, J = 7.9 Hz, 1 H, H-
¢¢), 4.75 (d, J = 12.6 Hz, 1 H, CCH O), 4.91 (d, J = 12.6 Hz, 1 H,
HRMS (ESI): m/z [M + H] calcd for C H N O : 367.1136; found:
3
1
6
18
2
8
67.1142.
2
CCH O), 4.95 (m, 1 H, H-3¢¢), 5.14 (m, J = 9.7 Hz, 2 H, H-3¢, H-
2
3
-(2¢-Deoxy-b-D-ribofuranosyl)-6-(azidomethyl)-2,3-dihydro-
2
1
4
¢¢), 5.31 (m, 1 H, H-4¢¢), 5.51 (s, 2 H, CCH N), 6.21 (t, J = 6.5 Hz,
2
furo[2,3-d]pyrimidin-2-one (4)
H, H-1¢), 6.53 (s, 1 H, H-5), 7.74 (s, 1 H, CH=C), 8.36 (s, 1 H, H-
A flask was charged with 3 (2.8 g, 7.65 mmol), freshly distilled THF
).
(
250 mL), and DPPA (1.97 mL, 9.18 mmol) under a N atmosphere.
2
1
3
DBU (1.14 mL, 7.65 mmol) was added dropwise by syringe and the
mixture was stirred for 1 h, while cooled by an ice–water bath. The
reaction was warmed to 40 °C and stirred for 10 h. The reaction was
shown to be completed by TLC. The reaction mixture was concen-
trated to dryness. The obtained residue was purified by column
chromatography (silica gel, CH Cl –MeOH, 1:0, then 200:1, then
C NMR (100 MHz, CDCl ): d = 19.6, 19.7, 19.7, 19.8, 19.9
3
(6 × CH ), 38.3 (C-2¢), 45.7 (CCH N), 60.2 (C-6¢¢), 61.9 (CCH O),
3
2
2
62.6 (C-5¢), 66.0 (C-4¢¢), 67.7 (C-2¢¢), 69.8, 69.9 (C-3¢¢, C-5¢¢), 72.9
(C-3¢), 82.4 (C-4¢), 87.7 (C-1¢), 99.6 (C-1¢¢), 103.2 (C-5), 105.2 (C-
4a), 122.4 (NCH=C), 136.2 (C-4), 144.0 (CH=C), 149.2 (C-2),
153.1 (C-7a), 168.6, 169.1, 169.2, 169.3, 169.4, 169.4 (6 × C=O),
170.7 (C-6).
2
2
1
00:1, then 80:1). The appropriate fractions were combined and
evaporated in vacuo.
+
+
ESI-MS (+): m/z = 778.1 [M + H] , 800.2 [M + Na] .
Yield: 2.24 g (75%); pale yellow solid; R = 0.41 (CH Cl –MeOH,
HRMS (ESI): m/z [M + H]+ calcd for C H N O : 778.2414;
found: 778.2409.
f
2
2
3
3
39
5
17
3
0:1).
1
H NMR (400 MHz, CDCl ): d = 2.08, 2.88 (m, 2 H, H-2¢), 2.00,
3
2
5
5
.05 (2 × CH ), 4.30 (s, 2 H, CH OH), 4.35 (m, 3 H, H-4¢, H-5¢),
Compound 6c
3
2
.16 (m, 1 H, H-3¢), 6.23 (t, J = 6.4 Hz, 1 H, H-1¢), 6.47 (s, 1 H, H-
), 8.33 (s, 1 H, H-4).
R = 0.23 (CH Cl –MeOH, 30:1).
f
2
2
1
H NMR (400 MHz, CDCl ): d = 1.85, 1.90, 1.94, 1.97, 1.98, 1.99,
3
1
3
C NMR (100 MHz, CDCl ): d = 19.8, 19.9 (2 × CH ), 38.3 (C-2¢),
2.00, 2.05, 2.08 (9 × CH ), 2.03, 2.88 (m, 2 H, H-2¢), 3.56 (m, 1 H,
3
3
3
4
1
1
6.1 (CH OH), 62.7 (C-5¢), 73.0 (C-3¢), 82.4 (C-4¢), 87.7 (C-1¢),
01.9 (C-5), 105.5 (C-4a), 135.4 (C-4), 151.2 (C-2), 153.3 (C-7a),
69.3, 169.4 (2 × C=O), 170.9 (C-6).
H-4¢¢), 3.75 (t, J = 9.5 Hz, 1 H, H-3¢¢¢), 3.84 (t, J = 6.7 Hz, 1 H, H-
2
3¢¢), 4.03 (m, 2 H, H-6¢¢, CCH O), 4.34 (m, 3 H, H-4¢, H-5¢), 4.44
2
(m, 2 H, H-1¢¢, CCH O), 4.56 (d, J = 7.9 Hz, 1 H, H-1¢¢¢), 4.76–4.92
2
ESI-MS (+): m/z = 413.8 [M + Na]+.
(m, 4 H, H-5¢¢, H-5¢¢¢, H-6¢¢¢), 5.03 (m, 1 H, H-2¢¢¢), 5.16 (t, J = 9.3
Hz, 1 H, H-2¢¢), 5.15 (m, 1 H, H-3¢), 5.28 (m, 1 H, H-4¢¢¢), 5.51 (s, 2
+
HRMS (ESI): m/z [M + H] calcd for C H N O : 392.1201; found:
1
6
17
5
7
H, CCH N), 6.20 (t, J = 5.9 Hz, 1 H, H-1¢), 6.52 (s, 1 H, H-5), 7.70
(
2
3
92.1205.
s, 1 H, CH=C), 8.36 (s, 1 H, H-4).
1
3
C NMR (100 MHz, CDCl ): d = 19.5, 19.6, 19.8, 19.8, 19.9
3
Compounds 6a–e; General Procedure
CuSO ·5H O (6.4 mg, 0.0256 mmol) and sodium ascorbate (10.1
(
(
7
(
(
9 × CH ), 38.3 (C-2¢), 45.7 (CCH N), 59.8, 60.7, 62.1, 62.6
3
2
4
2
CCH O, C-5¢, C-6¢¢, C-6¢¢¢), 65.7 (C-4¢¢¢), 68.1, 69.7, 70.0, 70.5,
2
mg, 0.0512 mmol) were added to a soln of 4 (100 mg, 0.256 mmol)
1.7, 71.8, 72.9 (C-3¢, C-2¢¢, C-3¢¢, C-4¢¢, C-2¢¢¢, C-3¢¢¢, C-5¢¢¢), 75.1
and one of 5a–e (0.256 mmol) in THF–H O (1:1, 10 mL) at r.t., and
2
C-3¢¢¢), 82.4 (C-4¢), 87.7 (C-1¢), 99.0 (C-1¢¢¢), 100.0 (C-1¢¢), 103.2
the mixture was stirred for 10 h. At the end of the reaction (by TLC
analysis), the soln was diluted with CH Cl (100 mL), and the aque-
C-5), 105.3 (C-4a), 122.7 (NCH=C), 136.2 (C-4), 144.0 (CH=C),
2
2
1
1
49.2 (C-2), 153.1 (C-7a), 168.1, 168.7, 168.8, 169.1, 169.2, 169.3,
69.4, 169.4 (9 × C=O), 170.7 (C-6).
ous layer was extracted with CH Cl (3 × 50 mL). The combined or-
2
2
ganic phase was dried (Na SO ), filtered, and evaporated. The crude
2
4
product was purified by column chromatography (silica gel); this
ESI-MS (+): m/z = 1088.4 [M + Na]+.
gave the corresponding compound 6.
+
HRMS (ESI): m/z [M + H] calcd for C H N O : 1066.3259;
4
5
55
5
25
found: 1066.3248.
Compound 6a
R = 0.19 (CH Cl –MeOH, 30:1).
f
2
2
Compound 6d
1
H NMR (400 MHz, CDCl ): d = 1.93, 1.94, 1.96, 2.00, 2.02, 2.05
R = 0.24 (CH Cl –MeOH, 30:1).
3
f
2
2
(
1
1
6 × CH ), 1.98, 2.89 (m, 2 H, H-2¢), 3.66 (m, 1 H, H-5¢¢), 4.13 (m,
1
3
H NMR (400 MHz, CDCl ): d = 1.96, 1.98, 2.00, 2.02, 2.05
3
H, H-6¢¢), 4.34 (m, 3 H, H-4¢, H-5¢), 4.60 (d, J = 7.9 Hz, 1 H, H-
¢¢), 4.60 (d, J = 12.6 Hz, 1 H, CCH O), 4.76 (d, J = 12.6 Hz, 1 H,
(
5 × CH ), 2.04, 2.89 (m, 2 H, H-2¢), 3.33 (m, 1 H, H-5¢¢), 4.07 (m,
3
2
1
1
2
(
7
H, H-5¢¢), 4.34 (m, 3 H, H-5¢, H-4¢), 4.56 (d, J = 6.8 Hz, 1 H, H-
¢), 4.70 (d, J = 12.6 Hz, 1 H, CCH O), 4.86 (m, 3 H, CCH O, H-
CCH O), 4.93 (t, J = 7.9 Hz, 1 H, H-2¢¢), 5.02 (t, J = 9.7 Hz, 1 H, H-
4
Hz, 1 H, H-1¢), 6.51 (s, 1 H, H-5), 7.68 (s, 1 H, CH=C), 8.35 (s, 1
H, H-4).
2
2
2
¢¢), 5.12 (m, 2 H, H-3¢, H-3¢¢), 5.50 (s, 2 H, CCH N), 6.21 (t, J = 6.4
2
¢¢, H-4¢¢), 5.09 (t, J = 8.6 Hz, 1 H, H-3¢¢), 5.15 (m, 1 H, H-3¢), 5.50
s, 2 H, CCH N), 6.21 (t, J = 5.9 Hz, 1 H, H-1¢), 6.51 (s, 1 H, H-5),
2
.73 (s, 1 H, CH=C), 8.35 (s, 1 H, H-4).
1
3
C NMR (100 MHz, CDCl ): d = 19.6, 19.6, 19.7, 19.7, 19.8, 19.8
13
3
C NMR (100 MHz, CDCl ): d = 19.7, 19.7, 19.7, 19.8, 19.8
3
(
5
7
(
6 × CH ), 38.3 (C-2¢), 45.8 (CCH N), 60.9 (C-6¢¢), 62.0, 62.6 (C-
3
2
(
6
(
(
5 × CH ), 38.3 (C-2¢), 45.7 (CCH N), 61.2, 61.4 (CCH O, C-5¢¢),
3
2
2
¢, CCH O), 67.5 (C-4¢¢), 70.3 (C-2¢¢), 71.0 (C-3¢¢), 71.8 (C-5¢¢),
2
2.6 (C-5¢), 67.9 (C-2¢¢), 69.8 (C-4¢¢), 70.3 (C-3¢¢), 72.9 (C-3¢), 82.5
2.9 (C-3¢), 82.5 (C-4¢), 87.8 (C-1¢), 99.1 (C-1¢¢), 103.1 (C-5), 105.2
C-4¢), 87.8 (C-1¢), 99.0 (C-1¢¢), 103.1 (C-5), 105.3 (C-4a), 122.3
C-4a), 122.5 (NCH=C), 136.1 (C-4), 144.0 (CH=C), 149.2 (C-2),
NCH=C), 136.1 (C-4), 144.1 (CH=C), 149.2 (C-2), 153.2 (C-7a),
1
1
53.1 (C-7a), 168.4, 169.2, 169.2, 169.3, 169.4, 169.6 (6 × C=O),
70.8 (C-6).
1
68.5, 168.9, 169.0, 169.3, 169.3 (5 × C=O), 170.8 (C-6).
ESI-MS (+): m/z = 728.0 [M + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C H N O : 706.2202;
+
+
ESI-MS (+): m/z = 778.3 [M + H] , 800.3 [M + Na] .
HRMS (ESI): m/z [M + H]+ calcd for C H N O : 778.2414;
found: 778.2426.
30
35
5
15
3
3
39
5
17
found: 706.2202.
Synthesis 2008, No. 6, 865–870 © Thieme Stuttgart · New York

PAPER
Synthesis of Carbohydrate-Conjugated Furo[2,3-d]pyrimidine
869
Compound 6e
Compound 7c
R = 0.21 (CH Cl –MeOH, 30:1).
R = 0.07 (n-BuOH–AcOH–H O, 5:1:4).
f
2
2
f
2
1
1
H NMR (400 MHz, CDCl ): d = 1.98, 1.99, 2.00, 2.05, 2.07
H NMR (400 MHz, DMSO-d ): d = 2.05, 2.42 (m, 2 H, H-2¢), 3.04
3
6
(
1
5 × CH ), 2.03, 2.87 (m, 2 H, H-2¢), 4.08 (m, 1 H, H-5¢¢), 4.24 (m,
(m, 1 H, H-2¢¢¢), 3.34–3.82 (m, 13 H, H-5¢, H-2¢¢, H-3¢¢, H-4¢¢, H-5¢¢,
H-6¢¢, H-3¢¢¢, H-4¢¢¢, H-5¢¢¢, H-6¢¢¢), 3.92 (m, 1 H, H-4¢), 4.21 (m, 2
H, H-3¢, H-1¢¢), 4.34 (d, J = 7.8 Hz, 1 H, H-1¢¢¢), 4.64 (m, 1 H,
CCH O), 4.87 (m, 1 H, CCH O), 5.74 (s, 2 H, CCH N), 6.13 (m, 1
H, H-1¢), 6.88 (s, 1 H, H-5), 8.20 (s, 1 H, NCH=C), 8.86 (s, 1 H, H-
4).
3
H, H-5¢¢), 4.27 (m, 1 H, H-2¢¢), 4.34 (m, 3 H, H-4¢, H-5¢), 4.58 (d,
J = 12.3 Hz, 1 H, CCH O), 4.79 (m, J = 12.3 Hz, 1 H, CCH O), 5.06
(
H-3¢¢), 5.52 (s, 2 H, CCH N), 6.20 (t, J = 6.6 Hz, 1 H, H-1¢), 6.53 (s,
1
2
2
m, 1 H, H-1¢¢), 5.16 (m, 2 H, H-3¢, H-4¢¢), 5.24 (t, J = 5.9 Hz, 1 H,
2
2
2
2
H, H-5), 7.75 (s, 1 H, CH=C), 8.35 (s, 1 H, H-4).
1
3
13
C NMR (100 MHz, CDCl ): d = 20.4, 20.5, 20.6, 20.8, 20.9
C NMR (100 MHz, CDCl ): d = 41.7 (C-2¢), 46.4 (CCH N), 60.9,
3
3
2
(
6
(
(
1
5 × CH ), 39.2 (C-2¢), 46.7 (CCH N), 61.0 (CCH O), 63.6 (C-5¢),
61.1, 61.3, 62.1 (CCH O, C-5¢, C-6¢¢, C-6¢¢¢), 68.7, 70.1, 71.1, 73.6,
3
2
2
2
4.3 (C-5¢¢), 71.4 (C-3¢¢), 74.0 (C-4¢¢), 74.7 (C-3¢), 78.8 (C-2¢¢), 83.4
73.8, 75.4, 76.0, 81.2 (C-3¢, H-2¢¢, H-3¢¢, H-4¢¢, H-5¢¢, H-3¢¢¢, H-4¢¢¢,
H-5¢¢¢, H-6¢¢¢), 88.3 (C-1¢), 88.8 (C-4¢), 102.4, (C-1¢¢¢), 104.3 (C-1¢¢),
105.3 (C-5), 105.7 (C-4a), 125.0 (NCH=C), 140.0 (C-4), 144.7
(CH=C), 150.5 (C-2), 154.1 (C-7a), 171.6 (C-6).
C-4¢), 88.7 (C-1¢), 104.2 (C-1¢¢), 104.5 (C-5), 106.3 (C-4a), 123.5
NCH=C), 137.1 (C-4), 144.7 (CH=C), 150.2 (C-2), 154.2 (C-7a),
68.6, 168.7, 169.3, 169.4, 169.7 (5 × C=O), 170.8 (C-6).
+
+
ESI-MS (+): m/z = 709.9 [M + Na]+.
ESI-MS (+): m/z = 706.1 [M + H] , 728.0 [M + Na] .
HRMS (ESI): m/z [M + H]+ calcd for C H N O : 706.2202;
HRMS (ESI): m/z [M + Na] calcd for C H N O : 710.2128;
+
3
0
35
5
15
27 37
5
16
found: 706.2203.
found: 710.2135.
Compounds 7a–e; General Procedure
A soln of one of 6a–e (0.15 mmol) in a sat. soln of NH in MeOH
Compound 7d
R = 0.24 (n-BuOH–AcOH–H O, 5:1:4).
3
f
2
(
15 mL) was stirred at 0 °C until the starting material was complete-
1
H NMR (400 MHz, DMSO-d ): d = 2.04, 2.39 (m, 2 H, H-2¢), 2.97
6
ly deprotected (ca. 3 h). The reaction mixture was then concentrated
to dryness, and the residue was purified by reversed-phase column
chromatography (silica gel, H O); this gave the corresponding com-
(
(
m, 1 H, H-2¢¢), 3.07 (m, 2 H, H-4¢¢, H-5¢¢), 3.28 (m, 1 H, H-3¢¢), 3.61
m, 2 H, H-5¢), 3.73 (m, 1 H, H-5¢¢), 3.92 (m, 1 H, H-4¢), 4.23 (m, 2
2
H, H-3¢, H-1¢¢), 4.60 (d, J = 12.1 Hz, 1 H, CCH O), 4.79 (d, J = 12.1
2
pound 7.
Hz, 1 H, CCH O), 5.74 (s, 2 H, CCH N), 6.12 (m, 1 H, H-1¢), 6.88
2
2
(
1
s, 1 H, H-5), 8.19 (s, 1 H, NCH=C), 8.86 (s, 1 H, H-4).
Compound 7a
R = 0.17 (n-BuOH–AcOH–H O, 5:1:4).
3
C NMR (100 MHz, CDCl ): d = 41.2 (C-2¢), 45.8 (CCH N), 60.7
3
2
f
2
(
7
1
C-5¢), 61.4 (CCH O), 65.7 (C-5¢¢), 69.5 (C-3¢, C-3¢¢), 73.2 (C-2¢¢),
1
2
H NMR (400 MHz, DMSO-d ): d = 2.05, 2.39 (m, 2 H, H-2¢), 2.97
6
6.5 (C-4¢¢), 87.7 (C-1¢), 88.2 (C-4¢), 102.9 (C-1¢¢), 104.8 (C-5),
05.2 (C-4a), 124.4 (NCH=C), 139.5 (C-4), 144.1 (CH=C), 150.0
C-2), 153.6 (C-7a), 171.1 (C-6).
(
3
4
m, 1 H, H-2¢¢), 3.05 (m, 1 H, H-4¢¢), 3.12 (m, 2 H, H-3¢¢, H-5¢¢),
.45, 3.62 (m, 2 H, H-6¢¢), 3.67 (m, 2 H, H-5¢), 3.92 (m, 1 H, H-4¢),
.21 (m, 1 H, H-3¢), 4.26 (d, J = 7.8 Hz, 1 H, H-1¢¢), 4.63 (d, J = 12.2
(
ESI-MS (+): m/z = 517.8 [M + Na]+.
Hz, 1 H, CCH O), 4.86 (d, J = 12.2 Hz, 1 H, CCH O), 5.74 (s, 2 H,
CCH N), 6.12 (m, J = 6.0 Hz, 1 H, H-1¢), 6.88 (s, 1 H, H-5), 8.20 (s,
1
2
2
+
2
HRMS (ESI): m/z [M + Na] calcd for C H N O : 518.1494;
20 25 5 10
found: 518.1498.
H, NCH=C), 8.86 (s, 1 H, H-4).
1
3
C NMR (100 MHz, DMSO-d ): d = 41.1 (C-2¢), 45.8 (CCH N),
6
2
Compound 7e
R = 0.29 (n-BuOH–AcOH–H O, 5:1:4).
6
7
(
0.7 (C-5¢), 61.1 (CCH O), 61.4 (C-6¢¢), 69.5 (C-3¢), 70.1 (C-4¢¢),
2
3.3 (C-2¢¢), 76.6, 76.9 (C-3¢¢, C-5¢¢), 87.7 (C-1¢), 88.2 (C-4¢), 102.2
f
2
C-1¢¢), 104.7 (C-5), 105.1 (C-4a), 124.4 (NCH=C), 139.4 (C-4),
1
H NMR (400 MHz, DMSO-d ): d = 2.10, 2.39 (m, 2 H, H-2¢),
6
1
44.2 (CH=C), 149.9 (C-2), 153.5 (C-7a), 171.0 (C-6).
3
.44–3.79 (m, 6 H, H-5¢, H-2¢¢, H-4¢¢, H-5¢¢), 3.94 (m, 1 H, H-3¢¢),
ESI-MS (+): m/z = 560.5 [M + Na]+.
4.01 (m, 1 H, H-4¢), 4.28 (m, 1 H, H-3¢), 4.58 (d, J = 12.2 Hz, 1 H,
CCH O), 4.76 (d, J = 12.1 Hz, 1 H, CCH O), 4.92 (s, 1 H, H-1¢¢),
+
2
2
HRMS (ESI): m/z [M + Na] calcd for C H N O : 560.1599;
found: 560.1604.
2
1
27
5
11
5
.79 (s, 2 H, CCH N), 6.19 (t, J = 6.1 Hz, 1 H, H-1¢), 6.96 (s, 1 H,
2
H-5), 8.22 (s, 1 H, NCH=C), 8.94 (s, 1 H, H-4).
1
3
C NMR (100 MHz, CDCl ): d = 41.1 (C-2¢), 45.9 (CCH N), 59.4
Compound 7b
3
2
(
(
(
CCH O), 60.6 (C-5¢), 62.8 (C-5¢¢), 69.5 (C-3¢), 70.7 (C-3¢¢), 74.2
C-2¢¢), 83.6 (C-4¢¢), 87.8 (C-1¢), 88.1 (C-4¢), 104.8 (C-1¢¢), 105.4
C-5), 106.1 (C-4a), 124.3 (NCH=C), 139.5 (C-4), 144.1 (CH=C),
R = 0.14 (n-BuOH–AcOH–H O, 5:1:4).
2
f
2
1
H NMR (400 MHz, DMSO-d ): d = 2.05, 2.38 (m, 2 H, H-2¢), 3.30
6
(
3
m, 3 H, H-2¢¢, H-4¢¢, H-5¢¢), 3.53–3.63 (m, 5 H, H-5¢, H-3¢¢, H-6¢¢),
1
50.0 (C-2), 153.8 (C-7a), 171.1 (C-6).
.91 (m, 1 H, H-4¢), 4.22 (m, 2 H, H-3¢, H-1¢¢), 4.62 (m, 1 H,
ESI-MS (+): m/z = 517.9 [M + Na]+.
CCH O), 4.85 (m, 1 H, CCH O), 5.74 (s, 2 H, CCH N), 6.12 (m, 1
2
2
2
H, H-1¢), 6.88 (s, 1 H, H-5), 8.19 (s, 1 H, NCH=C), 8.86 (s, 1 H, H-
+
HRMS (ESI): m/z [M + NH ] calcd for C H N O : 513.1940;
found: 513.1940.
4
20 25
5
10
4
).
1
3
C NMR (100 MHz, DMSO-d ): d = 41.2 (C-2¢), 45.9 (CCH N),
6
2
6
7
(
0.5 (C-6¢¢), 60.7 (C-5¢), 61.4 (CCH O), 68.2 (C-3¢¢), 69.6 (C-3¢),
2
Acknowledgment
0.5 (C-2¢¢), 73.4, 75.3 (C-4¢¢, C-5¢¢), 87.8 (C-1¢), 88.3 (C-4¢), 102.7
C-1¢¢), 104.8 (C-5), 105.2 (C-4a), 124.4 (NCH=C), 139.5 (C-4),
Financial support from the Chinese Education Ministry, the NSF of
China (No. 20502009, 20772071), and Jiangxi Science & Techno-
logy Normal University is greatly appreciated.
1
44.4 (CH=C), 150.0 (C-2), 153.6 (C-7a), 171.4 (C-6).
ESI-MS (–): m/z = 560.5 [M + Cl]–.
+
HRMS (ESI): m/z [M + NH ] calcd for C H N O : 543.2045;
4
21 27
5
11
found: 543.2046.
Synthesis 2008, No. 6, 865–870 © Thieme Stuttgart · New York

8
70
X. Jin et al.
PAPER
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Synthesis 2008, No. 6, 865–870 © Thieme Stuttgart · New York