Synthesis of carbohydrate-conjugated dT analogues using 'click chemistry'

Article abstract of DOI:10.1055/s-2007-983881

A new type furo[2,3-d]pyrimidine nucleoside conjugated with various carbohydrates was synthesized using Sonogashira coupling and 'click chemistry'. In the subsequent deprotection of the 4-toluoyl and acetyl groups with catalytic sodium methoxide in methan

Full text of DOI:10.1055/s-2007-983881

PAPER
2967
Synthesis of Carbohydrate-Conjugated dT Analogues Using
‘Click Chemistry’
S
ynthesis of Carbo
u
hydrate-Con
a
jugated dT
n
A
nalogues ye Jin,a Ruchun Yang,b Peiyuan Jin,a Qiang Xiao,*b Yong Ju*a
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 15 May 2007; revised 18 June 2007
able chemical transformations. It can rapidly build a large
pool of compounds and has found application in all as-
pects of drug discovery, ranging from lead-finding
through combinatorial chemistry and target-templated in
Abstract: A new type furo[2,3-d]pyrimidine nucleoside conjugat-
ed with various carbohydrates was synthesized using Sonogashira
coupling and ‘click chemistry’. In the subsequent deprotection of
the 4-toluoyl and acetyl groups with catalytic sodium methoxide in
methanol, the furo[2,3-d]pyrimidine rearranged to an opened ke- situ chemistry, to proteomics and DNA research utilizing
bioconjugation reactions.10
tone-type structure. Their structures were confirmed on the basis of
spectroscopy.
With this in mind, we have attempted to synthesize a new
Key words: dT analogues, carbohydrate conjugation, Sonogashira
series of furo[2,3-d]pyrimidine nucleosides conjugated
reaction, click chemistry
with carbohydrate by the Sonogashira reaction and ‘click
chemistry’ to improve their aqueous solubility and the
possible molecular recognition. In the last deprotection
Nucleoside analogues have a long history for treatment of
step, the furo[2,3-d]pyrimidine moiety rearranged to a
various viral and tumor diseases.1 A large number of nu-
new type of carbohydrate-conjugated dT analogue. It rep-
cleoside and nucleoside mimics have been synthesized in
resents a new ring-opening reaction that potentially may
the development of drugs for the treatment of influenza
find application in nucleoside chemistry.
virus, hepatitis B and C virus, herpes virus infections, etc.2
The bicyclic furo[2,3-d]pyrimidine nucleoside analogues
represent an entirely new class of fused furo-pyrimidine
derivative with highly selectivity for varicella-zoster virus
Initially, 2¢-deoxy-3¢,5¢-di-O-4-toluoyluridine (2) was
synthesized from 2¢-deoxyuridine (1) in 89% yield.11,12
Treatment of 2 with iodine monochloride (1.2 equiv) in
dichloromethane at 40 °C gave 2¢-deoxy-5-iodo-3¢,5¢-di-
O-4-toluoyluridine (3) in 91% yield.12 The reaction of 3
with propargyl alcohol under Sonogashira conditions [5%
Pd(PPh3)4, 10% CuI, DMF] at 80 °C directly afforded the
bicyclic furo[2,3-d]pyrimidine nucleoside analogue 4 in
one pot in 54% yield.13–15 In the subsequent reaction, the
6-hydroxymethyl group was transformed to the azide
group. An examination of the literature provided many
methods for alcohol to azide conversions.16 In our hands,
the 6-hydroxymethyl is an electron-rich allylic alcohol
which may be converted into the azide using diphe-
nylphosphoryl azide (DPPA) and 1,8-diazabicy-
clo[5.4.0]undec-7-ene in high yield.17 The reaction of 4
with diphenylphosphoryl azide (1.2 equiv) and 1,8-di-
azabicyclo[5.4.0]undec-7-ene (1 equiv) in anhydrous tet-
rahydrofuran under a nitrogen atmosphere gave 5 as a
light yellow solid in 69% yield (Scheme 1).
As a prototype of ‘click chemistry’18 the recent advance of
copper(I)-catalyzed conditions affords superior regio-
selectivity, high tolerance of other functionalities, and al-
most quantitative transformation under mild conditions.
The 1,3-dipolar cycloaddition reactions have been used in
the synthesis of neoglycoconjugates19 and the bioconjuga-
tion study of glycosides.20 The furo[2,3-d]pyrimidine 5
reacted with various propargyl carbohydrate derivatives
6a–e under ‘click chemistry’ conditions to afford the cor-
responding 1,4-disubstituted 1,2,3-triazoles 7a–e by 1,3-
(VZV).3 Although the precise mechanism of action of
these analogues remains to be elucidated; it is clear that
their antiviral activity depends on VZV-encoded thymi-
dine kinase phosphorylation.3a In our project to develop
new anti-VZV drugs, we required the synthesis of a series
of 6-substituted furo[2,3-d]pyrimidine nucleoside ana-
logues.
Carbohydrates are a major class of macromolecules in bi-
ology that exert important effects on many complex bio-
logical events.4 In addition, carbohydrates are highly
branched molecules and their monomeric units may be
connected to one another by many different types of link-
age. For example, oligosaccharides and glycoconjugates
exert important effects on many complex biological
events,5 including cellular recognition in the processes of
inflammation,6 immune response,7 tumor metastasis,8 and
bacterial and viral infections.5a In addition, the glycosyla-
tion of proteins and lipids are key factors in modulating
their structures and functions.9
In recent years, ‘click chemistry’ has emerged as a modu-
lar approach that utilizes only the most practical and reli-
SYNTHESIS 2007, No. 19, pp 2967–2972
x
x.
x
x
.
2
0
0
7
Advanced online publication: 11.09.2007
DOI: 10.1055/s-2007-983881; Art ID: F08707SS
© Georg Thieme Verlag Stuttgart · New York

2968
X. Jin et al.
PAPER
O
N
O
N
OAc
O
OAc
AcO
AcO
O
I
O
HN
HN
HN
O
AcO
AcO
O
OAc
OAc
O
O
O
N
a
6a
6b
b
TolO
TolO
HO
O
O
O
OAc
OAc
AcO
AcO
O
O
O
O
TolO
TolO
OH
1
AcO
OAc
2
3
OAc
6c
OH
O
OMe
AcO
O
O
N
O
O
O
OH
O
N
AcO
AcO
HN
OAc
d
AcO
OAc
c
O
O
N
6d
6e
TolO
O
TolO
O
Figure 1 Propargyl carbohydrates 6a–e
TolO
TolO
4
N
N
N3
N
b
N3
O
O
O
N
R1
N
O
N
O
N
a
O
Tol = 4-MeC6H4CO
O
N
N
TolO
e
O
6a–e
+
TolO
TolO
O
TolO
TolO
7a–e (R2 = Ac )
TolO
5
OMe
N
5
N
N
O
N
Tol = 4-MeC6H4CO
N
Scheme 1 Reagents and conditions: (a) 4-toluoyl chloride (2.2
equiv), pyridine, 50 °C, 2 h (89%); (b) ICl (1.2 equiv), CH2Cl2, 40 °C,
reflux, 2 h (91%); (c) propargyl alcohol (2 equiv), Pd(PPh3)4 (5%),
CuI (10%), Et3N (3 equiv), DMF, 13 h; (d) CuI (30%), Et3N (20
equiv), 80 °C, 3 h (54%); (e) DPPA (1.2 equiv), DBU (1 equiv), THF,
12 h, 0 °C (69%).
O
O
HO
R1
OH
8a–e (R2 = H )
R1
=
OR2
OR2
R2O
R2O
dipolar cycloaddition. The propargyl carbohydrates were
synthesized from the reaction of per-O-acetyl carbohy-
drates with propargyl alcohol in the presence of excess
boron trifluoride–diethyl ether as a catalyst (Figure 1).21
All reactions were highly regioselective and only 1,4-di-
substituted 1,2,3-triazoles were produced; the isolated
yields were from 82–93%.
O
OR2
O
R2O
R2O
O
O
OR2
a
OR2
b
OR2
R2O
R2O
O
O
O
O
R2O
OR2
OR2
OMe
c
In the deprotection of the 4-toluoyl and acetyl groups in
7a–e with sodium methoxide in methanol, we did not
obtain the corresponding furo[2,3-d]pyrimidines
(Scheme 2). In the NMR spectra, there is one more carbo-
nyl signal (C=O), methylene (CH2), and methoxy group
(OMe); the HRMS gave the formula C23H31N5O12 for 8a.
On this basis, we concluded that the newly formed struc-
tures were 8a–e; the isolated yields were from 53–58%.
Mechanistically, the reaction takes place in two discrete
steps, the first of which is methoxide anion attacking C7a
of the furo[2,3-d]pyrimidine followed by enol to ketone
conversion (Scheme 3). The structures were shown to be
consistent with 8a–e by various types of spectroscopy.
R2O
O
O
O
O
R2O
O
R2O
OR2
R2O OR2
d
e
Scheme 2 Reagents and conditions: (a) CuSO4·5 H2O (10%), sodi-
um ascorbate (20%), THF–H2O (1:1), 4 h (7a: 87%; 7b: 82%; 7c:
86%; 7d: 83%; 7e: 93%); (b) NaOMe, MeOH 30 min (8a: 54%; 8b:
53%; 8c: 58%; 8d: 57%; 8e: 56%).
obtain the target furo[2,3-d]pyrimidine, we turned to the
In subsequent experiments, several different deprotection use of 5¢-DMT protected 5-iodo-2¢-deoxyuridine as the
approaches also failed, such as potassium carbonate in starting material; this approach will be reported else-
methanol, saturated ammonia in methanol, etc. In order to where.
Synthesis 2007, No. 19, 2967–2972 © Thieme Stuttgart · New York

PAPER
Synthesis of Carbohydrate-Conjugated dT Analogues
2969
2¢-Deoxy-5-iodo-3¢,5¢-di-O-4-toluoyluridine (3)
MeOH
O
N
N
A stirred soln of 2 (4.5 g, 0.01 mol) in CH2Cl2 (100 mL) was heated
at reflux at 40 °C and ICl (1.95 g, 0.012 mol) was added slowly.
TLC indicated complete consumption of 2 (Rf = 0.34, CHCl3–
MeOH, 30:1). The soln was cooled, diluted with CH2Cl2 (200 mL),
and decolorized (ICl) by careful washing with the minimum re-
quired volume of 2% aq NaHSO3. The organic phase was washed
with H2O, dried (Na2SO4), filtered, and evaporated. The residue was
dissolved in a minimum volume of hot CHCl3, MeOH (5 volumes)
was added, and the mixture was chilled at –18 °C to give the product
3 (5.35 g, 91%).
N
Me
N
N
O
MeO
O
N
N
7a
N
4a
O
N
O
N
O
Me
N
N
O
N
N
N
MeO
1H NMR (400 MHz, DMSO-d6): d = 2.38 (s, 3 H, CH3), 2.40 (s, 3
H, CH3), 2.60 (m, 2 H, H2¢), 4.53 (m, 1 H, H4¢), 4.61 (m, 2 H, H5¢),
5.58 (m, 1 H, H3¢), 6.22 (t, J = 7.04 Hz, 1 H, H1¢), 7.35, 7.90 (arom),
8.07 (s, 1 H, H6).
13C NMR (100 MHz, DMSO-d6): d = 21.12 (2 CH3), 36.52 (C2¢),
64.04 C5¢), 69.72 (C5), 74.76 (C3¢), 81.61 (C4¢), 85.46 (C1¢),
126.361, 129.28, 129.39, 143.99, 144.12 (arom), 144.54 (C6),
149.88 (C2), 160.29 (C4), 165.31, 165.59 (2 C=O).
O
Scheme 3 The mechanism of rearrangement
In conclusion, a series of furo[2,3-d]pyrimidine nucleo-
sides conjugated with carbohydrates were synthesized by
the Sonogashira reaction and ‘click chemistry’. In the sub-
sequent deprotection of the 4-toluoyl and acetyl groups,
the furo[2,3-d]pyrimidine motif was rearranged to an
opened ketone structure. The thus-formed carbohydrate-
conjugated dT analogues represented a new structure
skeleton that may have potential biological activity. The
evaluations of their anti-VZV and antitumor activities are
underway.
MS (ESI+): m/z = 613 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C25H23IN2NaO7: 613.0442;
found: 613.0438.
3-(2-Deoxy-3,5-di-O-4-toluoyl-b-D-ribofuranosyl)-6-(hydroxy-
methyl)furo[2,3-d]pyrimidin-2(3H)-one (4)
To a stirred soln of 3 (2.95 g, 5 mmol) in anhyd DMF (25 mL), at
r.t. under a N2 atmosphere, were added anhyd Et3N (2.1 mL, 15
mmol), CuI (95 mg, 0.5 mmol), Pd(PPh3)4 (288.75 mg, 0.25 mmol),
and propargyl alcohol (0.6 mL, 10 mmol). The mixture was stirred
at r.t. for 13 h, after which time TLC of the mixture showed com-
plete conversion of the starting material. CuI (285 mg, 1.5 mmol)
and Et3N (14 mL, 100 mmol) were then added to the mixture, which
was subsequently heated at 80 °C for 3 h. Complete consumption of
the starting materials was indicated by TLC analysis (Rf = 0.13,
CHCl3–MeOH, 30:1). The mixture was then concentrated in high
vacuo. CH2Cl2–MeOH (1:1, 10 mL) were added to the above resi-
due, and this soln was added an excess of Amberlite IRA-400
DBU and DPPA were purchased from Aldrich. Pyridine, THF and
CH2Cl2 were dried and distilled prior to use. NMR spectra were re-
corded on a Bruker AV400 (400 MHz) spectrometer with TMS as
internal standard. ESI-HRMS were measured on a Bruker APEX II
spectrometer in positive and negative ion mode.
2¢-Deoxy-3¢,5¢-di-O-4-toluoyluridine (2)
A magnetically stirred soln of 2¢-deoxyuridine (1, 11.4 g, 50 mmol)
in anhyd pyridine (250 mL) was cooled to 0 °C and freshly distilled
4-toluoyl chloride (17 g, 110 mmol) was added slowly. The soln
was allowed to warm to r.t., heated at 50 °C for 2 h and evaporated
in vacuo to give a white solid mass. Complete consumption of the
starting materials was indicated by TLC analysis (Rf = 0.27,
CHCl3–MeOH, 30:1). CHCl3 (400 mL) was added and the organic
phase was washed with 1 M H2SO4 (2 × 300 mL) and H2O (2 × 300
mL), dried (Na2SO4), filtered, and evaporated to 150 mL. MeOH
(750 mL) was added and the resulting colorless crystalline mass
was filtered. The filtrate was reduced to a small volume and chilled
at –18 °C to give further crystalline product. The combined crystals
were dried to give the product 2 (20.64 g, 89%).
–
(HCO3 form), and the resulting mixture was stirred at r.t. for 30
min. The resin was filtered and washed with MeOH. The combined
filtrate was evaporated to dryness. The crude product was purified
by column chromatography (silica gel, CH2Cl2 then CH2Cl2–
MeOH, 100:1, 80:1, 60:1, and 30:1). The appropriate fractions were
combined, and the solvent was removed in vacuo to yield 4 as a fine
white solid (1.4 g, 54%).
1H NMR (400 MHz, CDCl3): d = 2.34, 3.15 (m, 2 H, H2¢), 2.37 (s,
3 H, CH3), 2.42 (s, 3 H, CH3), 4.46 (m, 1 H, OH), 4.62 (d, J = 5.26
Hz, 2 H, CH2OH), 4.69 (m, 2 H, H5¢, H4¢), 4.82 (m, 1 H, H5¢), 5.61
(d, J = 6.30 Hz, 1 H, H3¢), 6.21 (s, 1 H, H5), 6.42 (t, J = 6.58 Hz, 1
H, H1¢), 7.17, 7.26, 7.80, 7.94 (arom), 8.34 (s, 1 H, H4).
13C NMR (100 MHz, CDCl3): d = 21.61 (CH3), 21.69 (CH3), 39.51
(C2¢), 57.09 (CH2OH), 63.94 (C5¢), 74.75 (C3¢), 83.90 (C4¢), 88.68
(C1¢), 100.58 (C5), 107.53 (C4a), 126.16, 126.23, 129.23, 129.36,
129.77, 144.52 (arom), 135.59 (C4), 154.64 (C2), 157.96 (C7a),
166.06, 166.10 (2 C=O), 171.74 (C6).
1H NMR (400 MHz, DMSO-d6): d = 2.38 (s, 3 H, CH3), 2.40 (s, 3
H, CH3), 2.59 (m, 2 H, H2¢), 4.50 (m, 1 H, H4¢), 4.58 (m, 2 H, H5¢),
5.59 (m, 1 H, H3¢), 5.61 (d, J = 8.15 Hz, 1 H, H5), 6.27 (t, J = 6.95
Hz, 1 H, H1¢), 7.33–7.37, 7.87–7.93 (arom), 7.71 (d, J = 8.11 Hz, 1
H, H6).
MS (ESI+): m/z = 541 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C28H26N2NaO8: 541.1581;
13C NMR (100 MHz, DMSO-d6): d = 21.94, 21.96 (2 CH3), 36.85
(C2¢), 64.89 (C5¢), 75.21 (C3¢), 82.08 (C4¢), 85.77 (C1¢), 102.86
(C5), 127.13, 127.22, 130.07, 130.13, 130.16, 130.23, 144.82,
144.97 (arom), 141.43 (C6), 151.04 (C2), 163.85 (C4), 166.11,
166.37 (2 C=O).
found: 541.1587.
6-(Azidomethyl)-3-(2-deoxy-3,5-di-O-4-toluoyl-b-D-ribofurano-
syl)furo[2,3-d]pyrimidin-2(3H)-one (5)
MS (ESI+): m/z = 487 [M + Na]+.
A flask was charged with 4 (5 g, 9.65 mmol), freshly distilled THF
(450 mL), and DPPA (2.48 mL, 11.6 mmol) under an N2 atmo-
sphere. The mixture was cooled to 0 °C in an ice-water bath. To the
mixture was added DBU (1.44 mL, 9.65 mmol) dropwise via sy-
HRMS (ESI): m/z [M + Na]+ calcd for C25H24N2NaO7: 487.1476;
found: 487.1470.
Synthesis 2007, No. 19, 2967–2972 © Thieme Stuttgart · New York

2970
X. Jin et al.
PAPER
ringe. The reaction was stirred at 0 °C for 1 h and then it was
warmed to r.t. and stirred for 12 h. Complete consumption of the
starting materials was indicated by TLC analysis (Rf = 0.55,
CHCl3–MeOH, 30:1). The THF was removed to dryness. The resi-
due was purified by column chromatography (silica gel, CH2Cl2
then CH2Cl2–MeOH, 200:1). The appropriate fractions were com-
bined, and the solvent was removed in vacuo to yield the product 5
as a yellow solid (3.6 g, 69%).
1H NMR (400 MHz, CDCl3): d = 2.22, 3.17 (m, 2 H, H2¢), 2.33 (s,
3 H, CH3), 2.37 (s, 3 H, CH3), 4.23 (s, 2 H, CH2OH), 4.61 (m, 2 H,
H5¢, H4¢), 4.83 (m, 1 H, H5¢), 5.56 (d, J = 5.56 Hz, 1 H, H3¢), 6.12
(s, 1 H, H5), 6.36 (t, J = 6.58 Hz, 1 H, H1¢), 7.13–7.22, 7.74–7.90
(arom), 8.32 (s, 1 H, H4).
13C NMR (100 MHz, CDCl3): d = 21.59 (CH3), 21.67 (CH3), 39.75
(C2¢), 47.00 (CH2OH), 63.88 C5¢), 74.74 (C3¢), 84.17 (C4¢), 88.95
(C1¢), 102.61 (C5), 106.39 (C4a), 126.17, 126.26, 129.25–129.80,
144.56, 144.64 (arom), 136.21 (C4), 151.89 (C2), 154.24 (C7a),
166.02, 166.08 (2 C=O), 171.76 (C6).
MS (ESI+): m/z = 566 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C28H25N5O7: 566.1646;
(d, J = 6.39 Hz, 1 H, H3¢), 6.30 (s, 1 H, H5), 6.40 (t, J = 6.58 Hz, 1
H, H1¢), 7.20, 7.28, 7.82, 7.95 (arom), 7.72 (s, 1 H, NCH=C), 8.44
(s, 1 H, H4).
13C NMR (100 MHz, CDCl3): d = 20.57, 20.66, 20.69, 20.83, 21.70,
21.75 (6 CH3), 39.75 (C2¢), 46.68 (CCH2N), 61.27 C5¢), 62.90
(CCH2O), 63.88 (C6¢¢), 67.07 (C4¢¢), 68.74 (C2¢¢), 70.84 (C3¢¢),
70.93 (C5¢¢), 74.65 (C3¢), 84.22 (C4¢), 89.01 (C1¢), 100.62 (C1¢¢),
104.13 (C5), 106.14 (C4a), 123.25 (NCH=C), 126.24, 126.36,
129.34, 129.48, 129.88, 144.75, 145.07 (arom), 137.20 (C4), 149.76
(CH=C), 154.16 (C2), 166.12, 169.12, 169.56, 170.08, 170.22,
170.41, 171.70 (6 C=O, C7a, C6).
MS (ESI+): m/z = 952 [M + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C45H48N5O17: 930.3040;
found: 930.3034.
Tetra-O-acetyl-b-D-galactopyranosyl-(1→4)-tetra-O-acetyl-b-
D-glucopyranosyloxy Derivative 7c
Rf = 0.24 (CHCl3–MeOH, 15:1).
1H NMR (400 MHz, CDCl3): d = 1.90, 1.95, 1.97, 1.98, 2.06, 2.09,
2.11, 2.33, 2.37 (9 CH3), 2.18, 3.14 (m, 2 H, H2¢), 3.56 (m, 1 H,
H5¢¢¢), 3.74 (t, J = 9.39 Hz, 1 H, H4¢¢), 3.82 (t, J = 6.30 Hz, 1 H,
H5¢¢), 4.04 (m, 3 H, H5¢, CCH2O), 4.45 (m, 2 H, CCH2O, H1¢¢¢),
4.56 (d, J = 7.82 Hz, 1 H, H1¢¢), 4.61 (d, 2 H, H4¢, H2¢¢¢), 4.78–4.91
(m, 5 H, H6¢¢, H6¢¢¢, H4¢¢¢), 5.04 (t, J = 9.06 Hz, 1 H, H3¢¢¢), 5.11 (t,
J = 9.23 Hz, 1 H, H3¢¢), 5.28 (s, 1 H, H2¢¢), 5.44 (s, 2 H, CCH2N),
5.54 (d, J = 4.36 Hz, 1 H, H3¢), 6.22 (s, 1 H, H5), 6.33 (t, J = 6.58
Hz, 1 H, H1¢), 7.12, 7.21, 7.74, 7.88 (arom), 7.65 (s, 1 H, NCH=C),
8.36 (s, 1 H, H4).
13C NMR (100 MHz, CDCl3): d = 19.48, 19.61, 19.74, 19.90, 20.67
(9 CH3), 38.75 (C2¢), 45.63 (CCH2N), 59.82 (C5¢), 60.70 (CCH2O),
62.13 (C4¢¢¢), 62.87 (C2¢¢¢), 65.68 (C2¢¢), 68.16 (C3¢¢¢), 69.73 (C6¢¢),
69.98 (C6¢¢¢), 70.56 (C5¢¢), 71.71 (C5¢¢¢), 71.88 (C3¢¢), 73.65 (C3¢),
75.09 (C4¢¢), 83.21 (C4¢), 87.99 (C1¢), 99.06 (C1¢¢), 100.03 (C1¢¢¢),
103.05 (C5), 105.17 (C4a), 122.47 (NCH=C), 125.24, 125.34,
128.31, 128.45, 128.86, 143.73, 144.05 (arom), 136.15 (C4), 148.86
(CH=C), 153.14 (C2), 165.09, 168.01, 168.65, 169.01, 169.12,
169.32 (9 C=O, C7a, C6).
found: 566.1645.
3-(2-Deoxy-3,5-di-O-4-toluoyl-b-D-ribofuranosyl)-6-{[4-(glyco-
syloxymethyl)-1H-1,2,3-triazol-1-yl]methyl}furo[2,3-d]pyrimi-
din-2(3H)-ones 7a–e; General Procedure
To a soln of 5 (0.368 mmol) and 6a–e (0.368 mmol) in THF (5 mL)
and H2O (5 mL) were added CuSO4·5 H2O (0.0368 mmol) and so-
dium ascorbate (0.0737 mmol) at r.t., and the mixture was stirred for
4 h. At the end of the reaction as judged by TLC analysis, the soln
was diluted with CH2Cl2 (100 mL) and the aqueous layer was ex-
tracted with CH2Cl2 (3 × 50 mL). The organic phase was dried
(Na2SO4), filtered, and evaporated. The crude product was purified
by column chromatography (silica gel) to give 7a–e.
2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyloxy Derivative 7a
Rf = 0.33 (CHCl3–MeOH, 15:1).
1H NMR (400 MHz, CDCl3): d = 2.02, 2.03, 2.05, 2.11, 2.42, 2.46
(6 CH3), 2.29, 3.24 (m, 2 H, H2¢), 3.75 (m, 1 H, H5¢¢), 4.23 (m, 2 H,
H6¢¢), 4.68 (m, 3 H, H4¢, H5¢, H1¢¢), 4.86 (m, 2 H, H5¢, CCH2O),
4.97 (d, J = 12.58 Hz, 1 H, CCH2O), 5.03 (t,J = 8.75 Hz, 1 H, H2¢¢),
5.12 (t, J = 9.61 Hz, 1 H, H4¢¢), 5.22 (t, J = 9.44 Hz, 1 H, H3¢¢), 5.54
(s, 2 H, CCH2N), 5.63 (m, 1 H, H3¢), 6.32 (s, 1 H, H5), 6.42 (t,
J = 6.58 Hz, 1 H, H1¢), 7.21–7.31, 7.83–7.98 (arom), 7.75 (s, 1 H,
NCH=C), 8.46 (s, 1 H, H4).
MS (ESI+): m/z = 1240 [M + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C57H64N5O25: 1218.3885;
found: 1218.3898.
2,3,5-Tri-O-acetyl-b-D-ribofuranosyloxy Derivative 7d
Rf = 0.10 (CHCl3–MeOH, 15:1).
1H NMR (400 MHz, CDCl3): d = 2.06, 2.08, 2.11, 2.40, 2.44
(5 CH3), 2.26, 3.21 (m, 2 H, H2¢), 4.16 (m, 1 H, H5¢¢), 4.34 (m, 2 H,
H2¢¢, H5), 4.68 (m, 3 H, H4¢, H5¢, CCH2O), 4.87 (d, J = 12.36 Hz,
2 H, H5¢, CCH2O), 5.14 (d, J = 5.59 Hz, 1 H, H1¢¢), 5.25 (d, J = 4.81
Hz, 1 H, H3¢¢), 5.33 (m, 1 H, H4¢¢), 5.52 (s, 2 H, CCH2N), 5.61 (d,
J = 6.32 Hz, 1 H, H3¢), 6.30 (s, 1 H, H5), 6.41 (t, J = 6.58 Hz, 1 H,
H1¢), 7.19, 7.28, 7.81, 7.95 (arom), 7.76 (s, 1 H, NCH=C), 8.43 (s,
1 H, H4).
13C NMR (100 MHz, CDCl3): d = 20.54, 20.62, 20.86, 21.72, 21.77
(5 CH3), 39.72 (C2¢), 46.65 (CCH2N), 60.96 C5¢), 63.88 (CCH2O),
64.33 (C5¢¢), 71.37 (C4¢¢), 74.71 (C3¢, C2¢¢), 78.80 (C3¢¢), 84.18
(C4¢), 88.97 (C1¢), 104.09 (C4), 104.51 (C1¢¢), 106.21 (C4a), 123.36
(NCH=C), 126.21, 129.32, 129.42, 129.85, 144.77 (arom), 137.14
(C4), 149.80 (CH=C), 154.17 (C2), 166.08, 169.63, 169.73, 170.75,
171.64 (5 C=O, C7a, C6).
13C NMR (100 MHz, CDCl3): d = 20.61–21.76 (6 CH3), 39.72
(C2¢), 46.68 (CCH2N), 61.78 (C6¢¢), 62.91 (CCH2O), 63.90 (C5¢),
68.32 (C4¢¢), 71.16 (C2¢¢), 71.95 (C3¢¢), 72.74 (C5¢¢), 74.67 (C3¢),
84.19 (C4¢), 88.99 (C1¢), 100.05 (C1¢¢), 104.14 (C5), 106.17 (C4a),
123.43 (NCH=C), 126.22, 126.33, 129.33–129.87, 144.65, 144.74
(arom), 137.23 (C4), 149.81 (CH=C), 154.17 (C2), 166.11, 169.43,
170.22 (6 C=O), 170.68 (C7a), 171.68 (C6).
MS (ESI+): m/z = 952 [M + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C45H48N5O17: 930.3040;
found: 930.3042.
2,3,4,6-Tetra-O-acetyl-b-D-galactopyranosyloxy Derivative 7b
Rf = 0.30 (CHCl3–MeOH, 15:1).
1H NMR (400 MHz, CDCl3): d = 1.99, 2.03, 2.06, 2.15, 2.41, 2.44
(6 CH3), 2.25, 3.21 (m, 2 H, H2¢), 3.95 (t, J = 6.59 Hz, 1 H, H5¢¢),
4.15 (m, 2 H, H5¢), 4.64–4.70 (m, 3 H, H1¢¢, H4¢, H6¢¢), 4.82 (m, 2
H, CCH2O, H6¢¢), 4.97–5.04 (m, 2 H, H3¢¢ CCH2O), 5.23 (m, 1 H,
H2¢¢), 5.40 (d, J = 3.06 Hz, 1 H, H4¢¢), 5.51 (s, 2 H, CCH2N), 5.61
MS (ESI+): m/z = 880 [M + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C42H44N5O15: 858.2828;
found: 858.2818.
Synthesis 2007, No. 19, 2967–2972 © Thieme Stuttgart · New York

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Synthesis of Carbohydrate-Conjugated dT Analogues
2971
Methyl (2,3,4-Tri-O-acetyl-b-D-glucopyranosid)uronate Deriv-
ative 7e
J = 6.40 Hz, 1 H, H1¢), 7.98 (s, 1 H, NCH=C), 8.05 (s, 1 H, H6),
4.35, 4.57, 4.66, 4.90, 5.00, 5.23 (6 OH).
Rf = 0.09 (CHCl3–MeOH, 15:1).
13C NMR (100 MHz, DMSO-d6): d = 37.74 (CCH2CO), 41.08
(C2¢), 54.66 (CH3O), 57.81 (COCH2N), 61.03 (C6¢¢), 61.60, 61.84
(C5¢, CCH2O), 68.70 (C5¢¢), 70.52, 71.00 (C3¢, C4¢¢), 73.96 (C3¢¢),
75.85 (C2¢¢), 86.27 (C1¢), 88.23 (C4¢), 100.83 (C5), 103.24 (C1¢¢),
125.97 (NCH=C), 143.52 (C6), 144.39 (CH=C), 154.93 (C2),
169.86 (C4), 200.22 (C=O).
MS (ESI+): m/z = 558 [M + H]+, 580 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C22H31N5NaO12: 580.1861;
1H NMR (400 MHz, CDCl3): d = 1.93, 1.94, 1.96, 2.33, 2.37
(5 CH3), 2.19, 3.12 (m, 2 H, H2¢), 3.68 (s, 3 H, CH3O), 4.01 (d,
J = 9.32 Hz, 1 H, H5¢¢), 4.57–4.67 (m, 3 H, H4¢, H5¢, H1¢¢), 4.78 (m,
2 H, H5¢, CCH2O), 4.86 (d, J = 12.64 Hz, 1 H, CCH2O), 4.95 (t,
J = 8.26 Hz, 1 H, H3¢¢), 5.11–5.21 (m, 2 H, H2¢¢, H4¢¢), 5.44 (s, 2 H,
CCH2N), 5.54 (d, J = 6.32 Hz, 1 H, H3¢), 6.22 (s, 1 H, H5), 6.33 (t,
J = 6.58 Hz, 1 H, H1¢), 7.12, 7.20, 7.74, 7.87 (arom), 7.72 (s, 1 H,
NCH=C), 8.38 (s, 1 H, H4).
13C NMR (100 MHz, CDCl3): d = 19.47, 19.56, 19.65, 20.67, 20.72
(5 CH3), 38.72 (C2¢), 45.69 (CCH2N), 51.92 (CH3O), 62.07
(CCH2O), 62.88 (C5¢), 68.31 (C2¢¢), 70.17 (C3¢¢), 70.93 (C4¢¢),
71.49 (C5¢¢), 73.66 (C3¢), 83.16 (C4¢), 87.97 (C1¢), 99.03 (C1¢¢),
103.16 (C5), 105.23 (C4a), 122.63 (NCH=C), 125.26, 125.35,
128.30, 128.46, 128.85, 143.61, 143.72 (arom), 136.16 (C4), 148.81
(CH=C), 153.18 (C2), 165.07, 166.22, 168.31, 168.39, 168.99,
170.71 (6 C=O, C7a, C6).
found: 580.1856.
1-(2-Deoxy-b-D-ribofuranosyl)-5-(3-{4-[(b-d-galactopyranosyl-
(1→4)-b-D-glucopyranosyloxy)methyl]-1H-1,2,3-triazol-1-yl}-
2-oxopropyl)-4-methoxypyrimidin-2(1H)-one (8c)
Rf = 0.21 (BuOH–AcOH–H2O, 5:1:4).
1H NMR (400 MHz, DMSO-d6): d = 1.97, 2.24 (m, 2 H, H2¢), 3.04–
3.64 (m, 14 H, CCH2CO, H2¢¢, H3¢¢ H4¢¢, H5¢¢, H6¢¢, H2¢¢¢, H3¢¢¢,
H4¢¢¢, H5¢¢¢, H6¢¢¢), 3.77–3.82 (m, 6 H, H4¢, H5¢, CH3O), 4.19 (m, 2
H, H3¢, H1¢¢), 4.33 (d, 1 H, H1¢¢¢), 4.66, 4.87 (m, 2 H, CCH2O), 5.56
(s, 2 H, COCH2N), 6.12 (t, J = 6.35 Hz, 1 H, H1¢), 7.99 (s, 1 H,
NCH=C), 8.05 (s, 1 H, H6), 4.49, 4.63, 4.77, 5.00, 5.08, 5.20, 5.22
(9 OH).
MS (ESI+): m/z = 938 [M + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C44H46N5O17: 916.2883;
found: 916.2877.
1-(2-Deoxy-b-D-ribofuranosyl)-4-methoxy-5-{3-[4-(glycosyl-
oxymethyl)-1H-1,2,3-triazol-1-yl]-2-oxopropyl}pyrimidin-
2(1H)-ones 8a–e; General Procedure
13C NMR (100 MHz, DMSO-d6): d = 37.25 (CCH2CO), 41.11
(C2¢), 54.68 (CH3O), 57.84 (COCH2N), 60.93–70.55 (C3¢, C5¢,
CCH2O, C6¢¢, C2¢¢¢, C3¢¢¢, C6¢¢¢), 71.10–81.24 (C2¢¢, C3¢¢, C4¢¢, C5¢¢,
C4¢¢¢, C5¢¢¢, 86.30 (C1¢), 88.25 (C4¢), 100.85 (C5), 102.34 (C1¢¢¢),
104.33 (C1¢¢), 126.03 (NCH=C), 143.55 (C6), 144.21 (CH=C),
154.96 (C2), 169.89 (C4), 200.22 (C=O).
MS (ESI–): m/z = 754 [M – Cl]–.
HRMS (ESI): m/z [M + Na]+ calcd for C28H41N5NaO17: 742.2390;
To a soln of 7a–e in MeOH was added freshly NaOMe (catalytic
amount) at r.t., and the mixture was stirred for 30 min. TLC of the
mixture showed complete conversion of the starting material. This
soln was added an excess of Amberlite IRA-400 (HCO3– form), and
the resulting mixture was stirred at r.t. for 30 min. The resin was fil-
tered and washed with MeOH. The combined filtrate was evaporat-
ed to dryness. The crude product was purified by column
chromatography (reversed phase silica gel, H2O) to yield 8a–e.
found: 742.2380.
1-(2-Deoxy-b-D-ribofuranosyl)-4-methoxy-5-(2-oxo-3-{4-[(b-D-
ribofuranosyloxy)methyl]-1H-1,2,3-triazol-1-yl}propyl)pyrimi-
din-2(1H)-one (8d)
1-(2-Deoxy-b-D-ribofuranosyl)-5-(3-{4-[(b-D-glucopyranosyl-
oxy)methyl]-1H-1,2,3-triazol-1-yl}-2-oxopropyl)-4-methoxy-
pyrimidin-2(1H)-one (8a)
Rf = 0.23 (BuOH–AcOH–H2O, 5:1:4).
Rf = 0.24 (BuOH–AcOH–H2O, 5:1:4).
1H NMR (400 MHz, DMSO-d6): d = 1.99, 2.24 (m, 2 H, H2¢), 3.38
(m, 2 H, H5¢¢), 3.57 (m, 2 H, H5¢), 3.65 (s, 2 H, CCH2CO), 3.72 (s,
1 H, H2¢¢), 3.78–3.88 (m, 6 H, H4¢, CH3O, H3¢¢ H4¢¢), 4.21 (s, 1 H,
H3¢), 4.51, 4.70 (m, 2 H, CCH2O), 4.79 (d, J = 6.78 Hz, 1 H, H1¢¢),
5.56 (s, 2 H, COCH2N), 6.13 (t, J = 6.36 Hz, 1 H, H1¢), 7.96 (s, 1 H,
NCH=C), 8.06 (s, 1 H, H6), 4.66, 4.84, 5.01, 5.25 (5 OH).
13C NMR (100 MHz, DMSO-d6): d = 37.25 (CCH2CO), 40.61
(C2¢), 54.13 (CH3O), 57.29 (COCH2N), 59.52 (CCH2O), 61.14
C5¢), 63.05 (C5¢¢), 70.05 (C3¢), 70.91 (C3¢¢), 74.42 (C2¢¢), 83.92
(C4¢¢), 85.81 (C1¢), 87.75 (C4¢), 100.31 (C5), 106.13 (C1¢¢), 125.33
(NCH=C), 143.03 (C6), 143.64 (CH=C), 154.43 (C2), 169.37 (C4),
199.66 (C=O).
1H NMR (400 MHz, DMSO-d6): d = 1.99, 2.22 (m, 2 H, H2¢), 2.96
(m, 1 H, H2¢¢), 3.06 (m, 1 H, H4¢¢), 3.14 (m, 2 H, H3¢¢ H5¢¢), 3.46,
3.58 (m, 2 H, H6¢¢), 3.66 (s, 2 H, CCH2CO), 3.71 (m, 2 H, H5¢), 3.82
(m, 4 H, H4¢, CH3O), 4.21 (m, 1 H, H3¢), 4.26 (d, J = 7.70 Hz, 1 H,
H1¢¢), 4.65, 4.87 (m, 2 H, CCH2O), 5.58 (s, 2 H, COCH2N), 6.13 (t,
J = 6.38 Hz, 1 H, H1¢), 8.01 (s, 1 H, NCH=C), 8.07 (s, 1 H, H6),
4.59, 4.95, 4.98, 5.05, 5.10, 5.27 (6 OH).
13C NMR (100 MHz, DMSO-d6): d = 42.48 (CCH2CO), 45.81
(C2¢), 59.45 (CH3O), 62.57 (COCH2N), 66.32, 66.41, 66.61 (C5¢,
C6¢¢, CCH2O), 75.25 (C4¢¢), 75.38 (C3¢), 78.63 (C2¢¢), 81.97 (C3¢¢),
82.19 (C5¢¢), 90.99 (C1¢), 92.95 (C4¢), 105.60 (C5), 107.29 (C1¢¢),
130.84 (NCH=C), 148.27 (C6), 148.97 (CH=C), 159.70 (C2),
174.62 (C4), 205.03 (C=O).
MS (ESI+): m/z = 528 [M + H]+, 550 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C21H29N5NaO11: 550.1756;
MS (ESI–): m/z = 592 [M – Cl]–.
HRMS (ESI): m/z [M + Na]+ calcd for C22H31N5NaO12: 580.1861;
found: 550.1760.
found: 580.1853.
Methyl [(1-{3-[1-(2-Deoxy-b-D-ribofuranosyl)-4-methoxy-2-
oxo-1,2-dihydropyrimidin-5-yl]-2-oxopropyl}-1H-1,2,3-triazol-
4-yl)methyl b-D-glucopyranosid]uronate (8e)
1-(2-Deoxy-b-d-ribofuranosyl)-5-(3-{4-[(b-D-galactopyranosyl-
oxy)methyl]-1H-1,2,3-triazol-1-yl}-2-oxopropyl)-4-methoxy-
pyrimidin-2(1H)-one (8b)
Rf = 0.21 (BuOH–AcOH–H2O, 5:1:4).
1H NMR (400 MHz, DMSO-d6): d = 1.99, 2.22 (m, 2 H, H2¢), 3.01
(m, 1 H, H2¢¢), 3.18 (m, 1 H, H3¢¢), 3.32 (m, 1 H, H4¢¢), 3.58 (m, 2
H, H5¢), 3.66 (m, 2 H, CCH2CO), 3.68 (s, 3 H, CH3O), 3.78 (m, 1
H, H5¢¢), 3.81 (s, 4 H, CH3OCO, H4¢), 4.20 (m, 1 H, H3¢), 4.42 (d,
J = 7.78 Hz, 1 H, H1¢¢), 4.60, 4.79 (m, 2 H, CCH2O), 5.58 (s, 2 H,
Rf = 0.23 (BuOH–AcOH–H2O, 5:1:4).
1H NMR (400 MHz, DMSO-d6): d = 1.99, 2.23 (m, 2 H, H2¢), 3.28–
3.37 (m, 3 H, H2¢¢, H3¢¢ H4¢¢), 3.50–3.60 (m, 4 H, H5¢, H6¢¢), 3.64
(s, 3 H, CCH2CO, H5¢¢), 3.81 (s, 4 H, CH3O, H4¢), 4.21 (d, 2 H, H3¢,
H1¢¢), 4.60, 4.85 (m, 2 H, CCH2O), 5.56 (s, 2 H, COCH2N), 6.12 (t,
Synthesis 2007, No. 19, 2967–2972 © Thieme Stuttgart · New York

2972
X. Jin et al.
PAPER
COCH2N), 6.13 (t, J = 6.39 Hz, 1 H, H1¢), 8.00 (s, 1 H, NCH=C),
8.07 (s, 1 H, H6), 5.05, 5.17, 5.27, 5.35 (5 OH).
(7) Rudd, P. M.; Elliott, T.; Cresswell, P.; Wilson, I. A.; Dwek,
R. A. Science 2001, 291, 2370.
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2003, 8, 1128. (b) Wang, Q.; Chan, T. R.; Hilgraf, R.;
Fokin, V. V.; Sharpless, K. B.; Finn, M. G. J. Am. Chem.
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60, 554.
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2485.
13C NMR (100 MHz, DMSO-d6): d = 37.16 (CCH2CO), 40.49
(C2¢), 51.77 (CH3O), 54.13 (CH3OCO), 57.24 (COCH2N), 60.99
(C5¢), 61.73 (CCH2O), 69.93 (C3¢), 71.45 (C4¢¢), 72.96 (C2¢¢), 75.39
(C3¢¢), 75.71 (C5¢¢), 85.66 (C1¢), 87.63 (C4¢), 100.24 (C5), 102.36
(C1¢¢), 125.51 (NCH=C), 142.94 (C6), 143.31 (CH=C), 154.36
(C2), 169.32 (C4, C6¢¢), 199.64 (C=O).
MS (ESI–): m/z = 620 [M – Cl]–.
HRMS (ESI): m/z [M + Na]+ calcd for C23H31N5NaO13: 608.1811;
found: 608.1806.
Acknowledgment
This work was supported by the Chinese Education Ministry, the
NSF of China (No. 20502009, 20542004), SRFDP (No.
20050003104) and PCSIRT (IRT0404).
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1972, 94, 679. (b) Yu, C. Z.; Liu, B.; Hu, L. Q. Org. Lett.
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Synthesis 2007, No. 19, 2967–2972 © Thieme Stuttgart · New York