Synthesis of nucleoside conjugates as potential inhibitors of glycogen phosphorylase

Article abstract of DOI:10.1055/s-0029-1218629

Click chemistry has been successfully used for the synthesis of novel nucleoside conjugates between uridine and N-acetylglucosamine or oleanolic acid derivatives. These molecules displayed micromolar inhibition towards glycogen phosphorylase.

Full text of DOI:10.1055/s-0029-1218629

1046
PAPER
Synthesis of Nucleoside Conjugates as Potential Inhibitors of Glycogen
Phosphorylase
Synthesis of
N
ucle
e
oside Conj
g
ugate
s
uang Cheng,a,b Jun Liu,c Hongbin Sun,*b Juan Xie*a
a
b
c
PPSM, ENS Cachan, Institut d’Alembert, CNRS, Universud, 61 av. Président Wilson, 94230 Cachan, France
Fax +33(1)47402454; E-mail: joanne.xie@ens-cachan.fr
Center for Drug Discovery, College of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, P. R. of China
Fax +86(25)83271198; E-mail: hbsun2000@yahoo.com
Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, P. R. of China
Received 9 November 2009; revised 17 November 2009
that compounds 1 and 2 displayed moderate inhibition to-
wards GPa (Figure 1). To the best of our knowledge, uri-
dine derivatives have not been reported as GP inhibitors.
As an ongoing program on the research of novel GP inhib-
itors,12 we decided to synthesize novel uridine conjugates
with N-acetylglucosamine or oleanolic acid derivatives,
by employing the very efficient click chemistry.13
Abstract: Click chemistry has been successfully used for the syn-
thesis of novel nucleoside conjugates between uridine and N-acetyl-
glucosamine or oleanolic acid derivatives. These molecules
displayed micromolar inhibition towards glycogen phosphorylase.
Key words: bioorganic chemistry, carbohydrates, click chemistry,
inhibitors, nucleosides
OBn
O
Nucleosides are components of nucleic acids. They also
exist in other natural compounds like complex nucleoside
antibiotics.1 Synthesis of modified nucleosides as well as
of their conjugates is of interest for medical, biochemical,
and physiological applications. For example, nucleoside
conjugates with sugars,2 sterols,3 lipids,4 amino acids,5
and pleuromutilin6 have been designed and synthesized
for various biological applications.
OBn
O
CONH
BnO
O
NH
NHAc
OBn
O
N
CONH
BnO
O
OBn
BnO OBn
1
IC50 = 101.9 μM (GPa)
Glycogen phosphorylase (GP) is the enzyme responsible
for glycogen breakdown to produce glucose and related
metabolites to supply energy.7 Due to the key role of GP
in the modulation of glycogen metabolism, inhibition of
GP has been regarded as an effective therapeutic approach
for the treatment of diseases caused by abnormalities in
glycogen metabolism, such as type 2 diabetes, myocardial
ischemia, and tumors. Most notably, GP inhibitors lower
glucose in diabetic animal models, both acutely and
chronically, and demonstrate potential for a beneficial ef-
fect on cardiovascular risk factors.8 This information has
bolstered interest and promise in glycogen phosphorylase
inhibitors as potential new hypoglycaemic agents for the
treatment of type 2 diabetes mellitus. Several classes of
GP inhibitor have been reported, including glucose and
derivatives, iminosugars, hydantocidins, caffeine, flavo-
piridol, etc.9 We have recently reported that oleanolic acid
and related pentacyclic triterpenes represented a new class
of inhibitors of glycogen phosphorylases.10 GP is an allos-
teric enzyme that exists in two interconvertible forms,
GPa (the phosphorylated form, high activity, high sub-
strate affinity) and GPb (the nonphosphorylated form, low
activity, low substrate affinity). Screening of our previ-
ously synthesized sugar–nucleoside conjugates11 showed
O
NH
N
O
OBn
O
O
HN
OBn
BnO
O
OBn
BnO
AcHN
O
O
N
OBn
H
BnO
OBn
IC50 = 54.8 μM (GPa)
2
Figure 1 Structure of sugar–nucleoside conjugates
To prepare uridine conjugates with click chemistry, we
chose to introduce either an alkyne or an azide group at the
5¢-position of uridine. Both isopropylidene- or benzyl-
protected uridine derivatives have been used as starting
materials. Compound 3 was prepared according to known
procedures.14 The perbenzylated uridine 715 was convert-
ed into 5¢-O-propargyl derivative 8 by treatment with pro-
pargyl bromide and sodium hydride in 63% yield
(Scheme 1). Click reaction of alkynes 3 or 8 with azido
derivative of N-acetylglucosamine 42b led to the corre-
sponding conjugates 5 and 9 in 75% and 60% yields, re-
spectively. Deprotection of the isopropylidene group in 5
by trifluoroacetic acid in dichloromethane afforded com-
SYNTHESIS 2010, No. 6, pp 1046–1052
x
x
.
x
x
.2
0
1
0
Advanced online publication: 04.01.2010
DOI: 10.1055/s-0029-1218629; Art ID: Z24209SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Nucleoside Conjugates
1047
OBn
O
O
N
O
H
O
N
OBn
O
BnO
BnO
H
N
N
O
a
BnO
BnO
AcHN
N
O
O
O
+
O
N
75%
N
AcHN
N3
5
O
O
O
O
4
85%
b
3
OBn
O
O
N
H
BnO
BnO
N
N
N
AcHN
Bn
O
O
O
O
N
O
N
Bn
O
N
N
HO OH
c
6
N
O
HO
O
O
O
63%
OBn
BnO
OBn
BnO
8
7
OBn
O
O
Bn
N
BnO
BnO
a
4 +
8
N
N
AcHN
O
O
60%
O
N
N
BnO
9
OBn
Scheme 1 Reagents and conditions: (a) sodium ascorbate, CuSO4, CH2Cl2, H2O; (b) TFA, CH2Cl2; (c) propargyl bromide, NaH, THF.
pound 6. However, debenzylation of 5, 6, and 9 under cat- alkyne 8 gave the conjugate 17. We have also prepared
alytic hydrogenation conditions failed.
compound 19 with a shorter linker between uridine and
oleanolic acid, by treating propargyl ester 1812 with azide
12. Reaction of 12 with 3-O-propargyloleanoate 2012 led
to the conjugate 21 linked at the 3-position of oleanolic
acid. The carbonate derivative of oleanolic acid 2212 has
been converted into its azido derivative 23 with sodium
azide. Cycloaddition reaction between 23 and 8 allowed
the synthesis of the conjugate 24.
We have also prepared sugar–nucleoside conjugate 13
with an ester linkage (Scheme 2). For this synthesis, the
known carboxylic acid 1011 was converted into propargyl
ester 11 in 85% yield. Uridine 7 was transformed into its
azido derivative 12 through activation as the mesylate fol-
lowed by nucleophilic substitution with sodium azide.
Copper(I)-catalyzed Huisgen cycloaddition between 11
and 12 led to the desired compound 13 in 42% yield. Once The above synthesized conjugates were evaluated in the
again, we failed to debenzylate the nucleoside conjugate enzyme inhibition assay against rabbit muscle glycogen
13.
phosphorylase a (RMGPa) (Table 1), which shared con-
siderable sequence similarity with human liver GPa. As
described previously,16 the activity of rabbit muscle GPa
was measured through detecting the release of phosphate
from glucose-1-phosphate in the direction of glycogen
synthesis. Among the nucleoside derivatives 3, 7, 8, and
12, the isopropylidene-protected compound 3 exhibited a
For the synthesis of uridine–oleanolic acid conjugates, the
azido derivative of oleanolic acid 1412 was reacted with
alkyne 3 catalyzed by sodium ascorbate/copper sulfate to
afford the conjugate 15 in 82% yield (Scheme 3). Depro-
tection under acidic condition led to the fully deprotected
compound 16. Click reaction of 14 with perbenzylated
OBn
OBn
a
85%
O
O
O
BnO
BnO
BnO
BnO
O
AcHN
11
O
AcHN
10
OH
O
N
O
N
OBn
O
Bn
Bn
N
N
O
BnO
BnO
b,c
11, d
O
7
O
N3
O
71%
42%
AcHN
O
O
N
N
N
BnO
OBn
12
13
OBn
BnO
Scheme 2 Reagents and conditions: (a) propargyl bromide, K2CO3, DMF; (b) MsCl, Et3N, CH2Cl2; (c) NaN3, DMF; (d) sodium ascorbate,
CuSO4, CH2Cl2, H2O.
Synthesis 2010, No. 6, 1046–1052 © Thieme Stuttgart · New York

1048
K. Cheng et al.
PAPER
O
N
H
H
NH
N3
O
O
N
O
6
O
3, a
6
O
N
N
O
O
82%
HO
HO
15
14
O
O
O
H
NH
O
N
N
O
b
O
6
O
N
O
N
58%
HO
16
HO
OH
O
N
NBn
H
8, a
O
O
14
O
N
O
60%
N
O
N
HO
H
BnO
OBn
17
O
N
H
N
N
NBn
12, a
O
O
N
O
80%
O
O
O
HO
HO
BnO
OBn
18
19
H
OBn
O
H
12, a
OBn
O
N
85%
O
N
O
N
O
20
21
NBn
O
N
O
BnO
BnO
H
H
c
OBn
OBn
O
85%
O
O
O
O
O
O
O
O
22
23
N3
Cl
NBn
O
N
O
O
H
8, a
46%
OBn
N
N
BnO
O
OBn
O
N
O
O
24
Scheme 3 Reagents and conditions: (a) sodium ascorbate, CuSO4, CH2Cl2, H2O; (b) TFA, CH2Cl2; (c) NaN3, DMF.
micromolar inhibition of GPa. However, the correspond- similar inhibitory activities. For the nucleoside–oleanolic
ing glycoconjugate 5 was less active. Nevertheless, par- acid conjugates, the fully deprotected compound 16 was
tially deprotected compound 6 was shown to be the most more potent (IC50 = 15.5 mM). No significant difference
potent inhibitor, with an IC50 value of 13.6 mM. The gly- existed between different conjugates. With the exception
coconjugates with ether 9 or ester 13 linkages showed
Synthesis 2010, No. 6, 1046–1052 © Thieme Stuttgart · New York

PAPER
Synthesis of Nucleoside Conjugates
1049
NH), 7.20–7.34 (m, 15 H, Ph), 7.43 (d, J = 8.2 Hz, 1 H, H6), 7.46
(s, 1 H, NCH-triazole), 9.61 (s, 1 H, NH).
Table 1 IC50 Values for RMGPa Inhibition Assay Results
Compd
GPa IC50a (mM) Compd
GPa IC50a (mM)
13C NMR (100 MHz, CDCl3): d = 14.3, 23.3, 25.3, 27.2, 32.2, 47.4,
48.0, 65.0, 66.1, 67.4, 70.5, 72.2, 72.3, 73.1, 73.5, 74.0, 74.8, 81.2,
85.5, 86.3, 94.6, 101.4, 113.8, 122.6, 127.7, 127.8, 128.0, 128.3,
128.5, 128.6, 128.7, 137.1, 137.5, 138.1, 141.4, 144.0, 150.1, 163.6,
170.7.
HRMS (ESI): m/z [M + Na]+ calcd for C46H54N6NaO11: 889.3748;
found: 889.3743.
3
5
55.1
120.3
13.6
nab
13
48.7
35.7
15.5
85.5
65.1
70.2
nab
15
6
16
7
17
8
nab
19
Sugar–Nucleoside Conjugate 6
To a soln of 5 (0.12 g, 0.14 mmol) in CH2Cl2 (5 mL) was added
dropwise TFA (0.1 mL, 1.4 mmol). After stirring at r.t. for 8 h, the
mixture was concentrated. The residue was taken up in EtOAc (20
mL), and washed with H2O and brine, dried (MgSO4), filtered and
concentrated. Purification by flash column chromatography
(CH2Cl2–MeOH, 18:1) afforded 6 (97 mg, 85%) as a white solid;
Rf = 0.48 (CH2Cl2–MeOH, 10:1).
9
55.6
nab
21
11
24
12
nab
caffeine
98.5
a Values are the mean of 3 experiments.
b na = no activity.
[a]D22 –3.1 (c 0.65, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.82 (s, 3 H, CH3), 1.97 (br s, 2 H,
CH2), 3.49 (br s, 1 H, H3¢¢), 3.59–3.64 (m, 3 H, CH2N, H5¢a), 3.75
(d, J = 9.6 Hz, 1 H, H5¢b), 3.85 (dd, J = 7.8, 10.1 Hz, 1 H, H4¢¢),
3.92–3.93 (m, 1 H, H4¢), 4.15–4.19 (m, 5 H, H2¢, H3¢, H2¢¢, H6¢¢),
4.39–4.60 (m, 11 H, 3 PhCH2, CH2O, H1¢¢, H2¢¢, H5¢¢), 5.53 (d,
J = 6.9 Hz, 1 H, H5), 5.83 (s, 1 H, H1¢), 6.90 (d, J = 8.2 Hz, 1 H,
NH), 7.18–7.32 (m, 15 H, Ph), 7.58 (s, 1 H, NCH-triazole), 7.73 (d,
J = 7.8 Hz, 1 H, H6), 10.1 (br s, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 23.2, 29.8, 31.8, 47.2, 48.4, 64.4,
66.0, 67.6, 69.5, 71.0, 72.3, 72.4, 73.2, 73.6, 74.3, 74.7, 75.3, 84.1,
90.2, 102.2, 123.4, 127.8, 127.86, 127.91, 128.0, 128.1, 128.3,
128.5, 128.6, 128.7, 137.2, 137.5, 138.0, 140.9, 143.9, 151.3, 164.1,
171.0.
of 24, all these molecules inhibited GPa in the micromolar
range.
In summary, sugar–nucleoside and oleanolic acid–
nucleoside conjugates have been readily prepared with
click chemistry. These novel molecules have been tested
as potential glycogen phosphorylase inhibitors. Micromo-
lar inhibition was obtained with most synthetic nucleoside
conjugates. These results enlarge the application of
nucleoside conjugates in molecular design.
All air-sensitive reactions were carried out under N2. Column chro-
matography was performed on E. Merck Silica Gel 60 (230–400
mesh); petroleum ether = PE. Analytical TLC was performed on E.
Merck aluminum percolated plates of Silica Gel 60F-254 with de-
tection by UV and by spraying with 3 M H2SO4 and heating at 300
°C for ~2 min. NMR spectra were recorded on a Bruker AV-300 or
Jeol DX 400 spectrometers in CDCl3. IR spectra were recorded on
Shimadzu FTIR-8400S spectrophotometer. Optical rotations were
measured using a Jasco P-2000 polarimeter. HRMS were recorded
on a MA1212 instrument using standard conditions (ESI, 70 eV).
HRMS (ESI): m/z [M + Na]+ calcd for C43H50N6NaO11: 849.3435;
found: 849.3430.
3-Benzyl-2¢,3¢-di-O-benzyl-5¢-O-propargyluridine (8)
A soln of 7 (1.8 g, 3.5 mmol) in anhyd THF (5 mL) was added drop-
wise to a suspension of NaH (60%, 280 mg, 7.0 mmol) in anhyd
THF (10 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min
and then propargyl bromide (0.58 mL, 5.0 mmol) was added and the
mixture was stirred at r.t. for 12 h. MeOH (0.3 mL) was added at 0
°C. The mixture was concentrated and diluted with H2O–EtOAc
(1:2, 30 mL). After separation, the organic layer was washed with
H2O and brine, dried (MgSO4), filtered, and concentrated. Purifica-
tion by flash column chromatography (EtOAc–PE, 1:4) afforded 8
(1.2 g, 63%) as a yellow oil; Rf = 0.74 (EtOAc–PE, 1:1).
Click Reaction; General Procedure
To a soln of alkyne (0.28 mmol) and azide (0.28 mmol) in CH2Cl2
(2 mL) and H2O (2 mL) was added CuSO4·5 H2O (0.2 mmol) and
sodium ascorbate (0.4 mmol). The resulting soln was stirred at r.t.
for 8 h. The mixture was extracted with CH2Cl2 (3 ×). The combined
organic layers were dried (MgSO4), filtered, and concentrated. The
residue was purified by column chromatography.
[a]D22 +122.1 (c 0.86, CHCl3).
1H NMR (400 MHz, CDCl3): d = 2.45 (t, J = 2.3 Hz, 1 H, CH≡C),
3.68 (dd, J = 1.8, 11.0 Hz, 1 H, H5¢a), 3.88–3.91 (m, 2 H, H2¢,
H5¢b), 3.96 (dd, J = 4.6, 7.8 Hz, 1 H, H3¢), 4.12 (d, J = 2.3 Hz, 2 H,
CH2O), 4.30–4.34 (m, 2 H, H4¢, PhCH), 4.45 (d, J = 11.5 Hz, 1 H,
PhCH), 4.80 (d, J = 12.4 Hz, 2 H, PhCH2), 5.12 (s, 2 H, PhCH2),
5.67 (d, J = 8.3 Hz, 1 H, H5), 6.04 (d, J = 1.8 Hz, 1 H, H1¢), 7.22–
7.52 (m, 15 H, Ph), 7.81 (d, J = 8.2 Hz, 1 H, H6).
13C NMR (100 MHz, CDCl3): d = 44.0 (NCH2), 58.6 (OCH2), 67.5
(C5¢), 71.5 (OCH2), 72.3 (OCH2), 74.3 (C3¢), 75.1 (CH≡), 78.6
(C2¢), 78.8 (≡C), 81.0 (C4¢), 89.0 (C1¢), 101.4 (C5), 127.6, 127.7,
127.9, 128.0, 128.4, 128.7, 129.1 (CH-Ph), 136.8, 137.2, 137.3
(Cipso-Ph), 137.8 (C6), 150.8 (C2), 162.7 (C4).
Sugar–Nucleoside Conjugate 5
Prepared from 3 (90 mg, 0.28 mmol) and 4 (150 mg, 0.28 mmol) ac-
cording to the general procedure. The residue was purified by col-
umn chromatography (CH2Cl2–MeOH, 20:1) to afford 5 (180 mg,
75%) as a white solid; Rf = 0.15 (CH2Cl2–MeOH, 30:1).
[a]D22 –14.7 (c 0.29, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.29 (s, 3 H, CH3), 1.53 (s, 3 H,
CH3), 1.88 (s, 3 H, CH3), 1.92–2.01 (m, 2 H, CH2), 3.51 (t, J = 1.6
Hz, 1 H, H3¢¢), 3.61–3.75 (m, 4 H, CH2N, H5¢), 3.90 (dd, J = 7.8,
10.1 Hz, 1 H, H4¢¢), 3.95–3.98 (m, 1 H, H6¢¢a), 4.18 (m, 1 H, H6¢¢b),
4.28 (t, J = 6.9 Hz, 1 H, H4¢), 4.38–4.62 (m, 11 H, H1¢¢, H2¢¢, H5¢¢,
OCH2, 3 PhCH2), 4.78 (m, 2 H, H2¢, H3¢), 5.55 (dd, J = 2.1, 8.0 Hz,
1 H, H5), 5.68 (d, J = 1.4 Hz, 1 H, H1¢), 7.01 (d, J = 9.2 Hz, 1 H,
HRMS (ESI): m/z [M + Na]+ calcd for C33H32N2NaO6: 575.2158;
found: 575.2153.
Synthesis 2010, No. 6, 1046–1052 © Thieme Stuttgart · New York

1050
K. Cheng et al.
PAPER
Sugar–Nucleoside Conjugate 9
[a]D22 +127.9 (c 0.27, CHCl3).
Prepared from 4 (100 mg, 0.18 mmol) and 8 (100 mg, 0.18 mmol)
according to the general procedure. The residue was purified by col-
umn chromatography (CH2Cl2–MeOH, 40:1) to afford 9 (120 mg,
60%) as a light yellow solid; Rf = 0.43 (CH2Cl2–MeOH, 30:1).
1H NMR (400 MHz, CDCl3): d = 3.56 (dd, J = 3.2, 13.7 Hz, 1 H,
H5¢a), 3.79–3.83 (m, 2 H, H3¢, H5¢b), 3.92 (dd, J = 1.6, 5.3 Hz, 1 H,
H2¢), 4.26–4.30 (m, 2 H, H4¢, PhCH), 4.46 (d, J = 11.4 Hz, 1 H,
PhCH), 4.78 (s, 2 H, PhCH2), 5.12 (s, 2 H, PhCH2), 5.74 (d, J = 8.3
Hz, 1 H, H5), 5.95 (d, J = 1.4 Hz, 1 H, H1¢), 7.22–7.52 (m, 16 H,
H6, Ph).
13C NMR (100 MHz, CDCl3): d = 44.2 (NCH2), 50.9 (C5¢), 71.8
(OCH2), 72.5 (OCH2), 75.1 (C3¢), 78.1 (C2¢), 79.7 (C4¢), 90.1 (C1¢),
102.1 (C5), 127.8, 127.9, 128.3, 128.5, 128.6, 128.8, 129.3 (CHPh),
136.7, 137.0, 137.1, 137.4 (Cipso-Ph), 137.4 (C6), 150.7 (C2), 162.5
(C4).
[a]D22 +79.0 (c 0.37, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.83 (s, 3 H, CH3), 2.02–2.03 (m,
2 H, CH2), 3.54 (t, J = 3.7 Hz, 1 H, H3¢¢), 3.63–3.67 (m, 3 H, CH2N,
H5¢a), 3.83–3.93 (m, 3 H, H2¢, H3¢, H5¢b), 4.00 (m, 2 H, H4¢¢,
H6¢¢a), 4.22–4.32 (m, 3 H, H1¢¢, H2¢¢, H6¢¢b), 4.38–4.63 (m, 12 H,
H5¢¢, H4¢, OCH2, 4 PhCH2), 4.78 (d, J = 11.9 Hz, 1 H, PhCH), 4.81
(d, J = 12.4 Hz, 1 H, PhCH), 5.05 (d, J = 14.2 Hz, 1 H, PhCH), 5.08
(d, J = 13.8 Hz, 1 H, PhCH), 5.36 (d, J = 7.3 Hz, 1 H, H5), 6.00 (s,
1 H, H1¢), 6.97 (d, J = 9.2 Hz, 1 H, NH), 7.20–7.47 (m, 31 H, NCH-
triazole, Ph), 7.87 (d, J = 6.9 Hz, 1 H, H6).
HRMS (ESI): m/z [M + Na]+ calcd for C30H29N5NaO5: 562.2066;
found: 562.2061.
13C NMR (100 MHz, CDCl3): d = 14.2, 21.0, 23.2, 31.5, 43.9, 48.6,
60.4, 66.6, 67.7, 67.8, 71.4, 72.1, 72.6, 72.7, 73.2, 74.2, 75.3, 78.5,
81.2, 89.1, 100.8, 127.5, 127.6, 127.65, 127.7, 127.8, 127.9, 127.92,
128.0, 128.1, 128.2, 128.4, 128.45, 128.5, 128.6, 128.7, 128.9,
136.6, 137.16, 137.19, 137.4, 137.5, 137.9, 138.3, 150.6, 162.8,
170.2, 171.1.
Sugar–Nucleoside Conjugate 13
Prepared from 11 (100 mg, 0.17 mmol) and 12 (90 mg, 0.17 mmol)
according to the general procedure. The residue was purified by col-
umn chromatography (CH2Cl2–MeOH, 40:1) to afford 13 (80 mg,
42%) as a white solid; Rf = 0.4 (CH2Cl2–MeOH, 30:1).
[a]D22 +50.4 (c 0.35, CHCl3).
HRMS (ESI): m/z [M + Na]+ calcd for C64H68N6NaO11: 1119.4844;
found: 1119.4838.
1H NMR (400 MHz, CDCl3): d = 1.76 (s, 3 H, CH3), 2.40–2.53 (m,
2 H, CH2CO2), 3.56–3.57 (m, 1 H, H3¢¢), 3.64–3.65 (m, 1 H, H4¢¢),
3.75–3.82 (m, 3 H, H6¢¢, H3¢), 3.91 (dd, J = 2.7, 5.5 Hz, 1 H, H2¢),
4.19–4.24 (m, 2 H, H2¢¢, H5¢¢), 4.36–4.70 (m, 14 H, H1¢¢, H4¢, H5¢,
5 PhCH2), 5.02 (d, J = 13.7 Hz, 1 H, PhCH), 5.06 (d, J = 13.7 Hz, 1
H, PhCH), 5.18 (d, J = 12.8 Hz, 1 H, CO2CH), 5.19 (d, J = 12.8 Hz,
1 H, CO2CH), 5.63 (d, J = 8.3 Hz, 1 H, H5), 5.77 (d, J = 2.8 Hz, 1
H, H1¢), 6.48 (d, J = 8.3 Hz, 1 H, H6), 6.72 (d, J = 9.6 Hz, 1 H, NH),
7.14–7.46 (m, 30 H, Ph), 7.54 (s, 1 H, NCH-triazole).
13C NMR (100 MHz, CDCl3): d = 23.3, 36.9, 44.2, 47.2, 50.4, 57.8,
65.2, 68.0, 71.9, 72.1, 72.2, 72.7, 72.9, 73.5, 74.0, 75.3, 76.1, 79.6,
91.6, 102.3, 125.5, 127.7, 127.8, 127.9, 128.0, 128.2, 128.4, 128.49,
128.54, 128.6, 128.7, 129.1, 129.8, 136.6, 136.9, 137.0, 137.3,
137.5, 137.9, 138.2, 143.2, 150.4, 162.2, 170.1, 170.8.
Propargyl [2-(Acetylamino)-3,4,6-tri-O-benzyl-2-deoxy-a-D-
glucopyranosyl]acetate (11)
To a soln of 10 (49 mg, 0.09 mmol) in DMF (0.5 mL) was added
K2CO3 (27 mg, 0.19 mmol) and propargyl bromide (80% wt% in
toluene, 0.22 mL) successively. The mixture was stirred at r.t. for 8
h, 1 M HCl (0.3 mL) was added, and it was diluted with EtOAc (30
mL) and washed successively with H2O and brine. The organic lay-
er was dried (MgSO4), filtered, and concentrated and then it was pu-
rified by flash column chromatography (EtOAc–PE, 3:7) to give 11
(45 mg, 85%) as a light yellow oil; Rf = 0.22 (EtOAc–PE, 3:7).
[a]D22 +5.4 (c 0.77, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.83 (s, 3 H, CH3), 2.39 (t, J = 2.3
Hz, 1 H, CH≡), 2.50 (s, 1 H, H2a), 2.52 (d, J = 3.2 Hz, 1 H, H2b),
3.63–3.64 (m, 1 H, H3¢), 3.68 (m, 1 H, H4¢), 3.83–3.88 (m, 2 H,
H6¢), 4.23–4.26 (m, 2 H, H2¢, H5¢), 4.60–4.67 (m, 9 H, 3 OCH2,
CO2CH2, H1¢), 6.70 (d, J = 9.6 Hz, 1 H, NH), 7.24–7.36 (m, 15 H,
Ph).
13C NMR (100 MHz, CDCl3): d = 23.4 (CH3), 37.0 (C2), 47.2 (C2¢),
52.2 (OCH2), 65.3 (C1¢), 67.9 (C6¢), 71.8 (OCH2), 72.0 (OCH2),
72.8 (C3¢), 73.5 (OCH2), 74.1 (C4¢), 75.0 (CH≡), 75.2 (C5¢), 77.7
(≡C), 127.66, 127.7, 127.9, 128.0, 128.2, 128.5, 128.6, 128.7 (CH-
Ph), 137.3, 137.5, 138.3 (Cipso-Ph), 170.0 (CO), 170.3 (CO).
HRMS (ESI): m/z [M + Na]+ calcd for C64H66N6NaO12: 1133.4636;
found: 1133.4632.
Oleanolic Acid–Nucleoside Conjugate 15
Prepared from 3 (60 mg, 0.19 mmol) and 14 (110 mg, 0.19 mmol)
according to the general procedure. The residue was purified by col-
umn chromatography (CH2Cl2–MeOH, 30:1) to afford 15 (140 mg,
82%) as a white solid; Rf = 0.2 (CH2Cl2–MeOH, 30:1).
[a]D22 +23.2 (c 0.29, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.69, 0.75, 0.89, 0.96, 1.10, 1.31,
1.55 (7 s, 21 H, 7 CH3), 0.87 (s, 6 H, 2 CH3), 0.69–1.98 (m, 30 H),
2.82–2.84 (m, 1 H, H18¢¢), 3.18–3.21 (m, 1 H, H3¢¢), 3.70–3.81 (m,
2 H, H5¢), 3.98 (t, J = 6.4 Hz, 2 H, NCH2), 4.31–4.36 (m, 3 H, H4¢,
CO2CH2), 4.64 (s, 2 H, OCH2), 4.76 (br s, 2 H, H2¢, H3¢), 5.25 (br
s, 1 H, H12¢¢), 5.64 (d, J = 8.2 Hz, 1 H, H5), 5.85 (s, 1 H, H1¢), 7.47
(s, 1 H, NCH-triazole), 7.53 (d, J = 8.2 Hz, 1 H, H6), 8.78 (br s, 1
H, NH).
13C NMR (100 MHz, CDCl3): d = 14.3, 15.4, 15.7, 17.1, 18.4, 23.1,
23.5, 23.7, 25.4, 25.9, 26.3, 27.2, 27.3, 27.7, 28.2, 28.5, 30.3, 30.8,
32.6, 32.8, 33.2, 33.9, 37.1, 38.5, 38.8, 39.4, 41.4, 41.8, 45.9, 46.8,
47.7, 50.4, 55.3, 60.5, 64.0, 64.7, 70.5, 79.1, 81.0, 85.0, 85.7, 93.1,
102.2, 114.3, 122.4, 141.5, 143.9, 150.1, 163.1, 177.8.
HRMS (ESI): m/z [M + Na]+ calcd for C34H37NNaO7: 594.2468;
found: 594.2468.
5¢-Azido-3-benzyl-2¢,3¢-di-O-benzyl-5¢-deoxyuridine (12)
MsCl (0.38 mL, 4.9 mmol) was added to a soln of 7 (1.8 g, 3.5
mmol) and Et3N (0.88 mL, 6.3 mmol) in CH2Cl2 (30 mL) at 0 °C.
The ice bath was removed and stirring was continued at r.t. for 14
h. After which MeOH (0.3 mL) was added, the soln was concentrat-
ed. The residue was dissolved in EtOAc (50 mL) and washed suc-
cessively with H2O, 5% NaHCO3, and brine. The organic layer was
dried (MgSO4), filtered, and concentrated to give an oil that was
used directly for next step without purification. This mesylate was
dissolved in DMF (25 mL), NaN3 (1.14 g, 18 mmol) was added. The
mixture was stirred at 90 °C for 12 h and then concentrated. The res-
idue was dissolved in EtOAc (50 mL) and washed successively with
H2O and brine, dried (MgSO4), filtered, and concentrated. Purifica-
tion by flash column chromatography (EtOAc–PE, 1:3) gave 12
(1.35 g, 71%) as a colorless oil; Rf = 0.38 (EtOAc–PE, 1:1).
HRMS (ESI): m/z [M + Na]+ calcd for C51H77N5NaO9: 926.5619;
found: 926.5614.
Oleanolic Acid–Nucleoside Conjugate 16
To a soln of 15 (90 mg, 0.10 mmol) in CH2Cl2 (3 mL) was added
TFA (0.07 mL, 0.9 mmol). The mixture was stirred at r.t. for 8 h and
Synthesis 2010, No. 6, 1046–1052 © Thieme Stuttgart · New York

PAPER
Synthesis of Nucleoside Conjugates
1051
then concentrated. The residue was taken up in EtOAc (20 mL), and
washed with H2O and brine, dried (MgSO4), filtered, and concen-
trated. Purification by flash column chromatography (CH2Cl2–
MeOH, 18:1) afforded 16 (50 mg, 58%) as a white solid; Rf = 0.3
(CH2Cl2–MeOH, 10:1).
J = 2.3 Hz, 1 H, H1¢), 6.49 (d, J = 8.2 Hz, 1 H, H6), 7.23–7.46 (m,
15 H, Ph), 7.49 (s, 1 H, NCH-triazole).
13C NMR (100 MHz, CDCl3): d = 15.4, 15.7, 16.8, 18.4, 23.0, 23.4,
23.7, 25.9, 27.2, 27.7, 28.2, 30.7, 32.4, 32.7, 33.1, 33.8, 37.1, 38.5,
38.8, 39.4, 41.4, 41.8, 44.2, 45.9, 46.8, 47.6, 50.4, 55.2, 57.3, 72.2,
72.7, 76.3, 79.0, 79.5, 91.9, 102.4, 122.5, 125.7, 127.9, 128.2,
128.4, 128.6, 128.66, 128.70, 128.71, 129.2, 136.6, 136.8, 136.9,
137.8, 143.5, 143.6, 150.4, 162.2, 177.7.
[a]D22 +28.9 (c 0.28, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.69, 0.75, 0.86, 0.88, 0.90, 0.96,
1.10 (7 s, 21 H, 7 CH3), 0.69–1.98 (m, 30 H), 2.82 (dd, J = 4.1, 13.7
Hz, 1 H, H18¢¢), 3.18 (dd, J = 4.6, 10.5 Hz, 1 H, H3¢¢), 3.72 (d,
J = 9.2 Hz, 1 H, H5¢a), 3.85 (d, J = 9.2 Hz, 1 H, H5¢b), 2.97 (t,
J = 6.4 Hz, 2 H, NCH2), 4.19–4.22 (m, 3 H, H2¢, H3¢, H4¢), 4.35 (t,
J = 7.3 Hz, 2 H, CO2CH2), 4.67 (s, 2 H, OCH2), 5.25 (br s, 1 H,
H12¢¢), 5.60 (d, J = 7.8 Hz, 1 H, H5), 5.87 (s, 1 H, H1¢), 7.55 (s, 1
H, NCH-triazole), 7.83 (d, J = 8.2 Hz, 1 H, H6), 10.03 (br s, 1 H,
NH).
13C NMR (100 MHz, CDCl3): d = 15.4, 15.7, 17.1, 18.4, 23.1, 23.5,
23.7, 25.6, 26.0, 26.3, 27.2, 27.7, 28.2, 28.5, 30.3, 30.8, 32.6, 32.8,
33.2, 33.9, 37.1, 38.5, 38.8, 39.4, 41.4, 41.8, 45.9, 46.8, 47.6, 50.5,
55.3, 64.0, 64.5, 69.4, 70.5, 75.3, 79.1, 83.8, 90.2, 102.3, 122.4,
122.6, 140.8, 143.9, 144.1, 151.3, 163.9, 178.0.
HRMS (ESI): m/z [M + Na]+ calcd for C63H79N5NaO8: 1056.5826;
found: 1056.5824.
Oleanolic Acid–Nucleoside Conjugate 21
Prepared from 12 (130 mg, 0.24 mmol) and 20 (140 mg, 0.24 mmol)
according to the general procedure. The residue was purified by col-
umn chromatography (EtOAc–PE, 1:1) to afford 21 (230 mg, 85%)
as a white solid; Rf = 0.10 (EtOAc–PE, 1:2).
[a]D22 +94.9 (c 0.63, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.59, 0.73, 0.87, 0.88, 0.90, 0.92,
1.11 (7 s, 21 H, 7 CH3), 0.59–1.98 (m, 22 H), 2.88–2.97 (m, 2 H,
H3¢¢, H18¢¢), 3.79 (dd, J = 5.5, 7.3 Hz, 1 H, H3¢), 3.88 (dd, J = 2.7,
5.5 Hz, 1 H, H2¢), 4.40–4.52 (m, 4 H, H4¢, H5¢a, OCH2), 4.58–4.74
(m, 5 H, H5¢b, 2 PhCH2), 5.06 (m, 4 H, 2 PhCH2), 5.29 (t, J = 3.4
Hz, 1 H, H12¢¢), 5.59 (d, J = 8.2 Hz, 1 H, H5), 5.82 (d, J = 2.7 Hz,
1 H, H1¢), 6.38 (d, J = 8.2 Hz, 1 H, H6), 7.24–7.37 (m, 18 H, Ph),
7.43 (s, 1 H, NCH-triazole), 7.46–7.48 (m, 2 H, Ph).
13C NMR (100 MHz, CDCl3): d = 15.3, 16.5, 16.9, 18.2, 22.7, 23.0,
23.4, 23.7, 25.9, 26.9, 27.6, 28.2, 30.7, 32.4, 32.7, 33.1, 33.9, 37.0,
38.3, 38.7, 39.3, 41.4, 41.7, 44.1, 45.9, 46.7, 47.6, 50.1, 55.6, 63.1,
65.9, 72.1, 72.7, 76.1, 79.5, 86.9, 91.3, 102.3, 122.5, 124.0, 127.7,
127.9, 128.0, 128.1, 128.3, 128.40, 128.44, 128.5, 128.6, 129.1,
136.4, 136.5, 136.8, 136.9, 137.5, 143.7, 146.7, 150.4, 162.1, 177.5.
HRMS (ESI): m/z [M + Na]+ calcd for C48H73N5NaO9: 886.5306;
found: 886.5301.
Oleanolic Acid–Nucleoside Conjugate 17
Prepared from 8 (120 mg, 0.21 mmol) and 14 (130 mg, 0.21 mmol)
according to the general procedure. The residue was purified by col-
umn chromatography (EtOAc–PE, 2:1) to afford 17 (150 mg, 60%)
as a white solid; Rf = 0.13 (EtOAc–PE, 1:1).
[a]D22 +89.9 (c 0.69, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.70, 0.76, 0.90, 0.97, 1.11 (5 s,
15 H, 5 CH3), 0.88 (s, 6 H, 2 CH3), 0.70–1.98 (m, 30 H), 2.84 (dd,
J = 3.9, 14.0 Hz, 1 H, H18¢¢), 3.19 (dd, J = 4.6, 11.0 Hz, 1 H, H3¢¢),
3.68 (dd, J = 2.1, 11.2 Hz, 1 H, H5¢a), 3.87 (dd, J = 1.6, 4.8 Hz, 1
H, H2¢), 3.91–3.99 (m, 4 H, H4¢, H5¢b, NCH2), 4.23–4.32 (m, 4 H,
H3¢, CO2CH2, OCH), 4.40 (d, J = 11.5 Hz, 1 H, OCH), 4.59 (d,
J = 12.5 Hz, 1 H, PhCH), 4.61 (d, J = 12.4 Hz, 1 H, PhCH), 4.78 (d,
J = 11.9 Hz, 1 H, PhCH), 4.80 (d, J = 12.4 Hz, 1 H, PhCH), 5.10 (s,
2 H, PhCH2), 5.26 (t, J = 3.4 Hz, 1 H, H12¢¢), 5.48 (d, J = 8.2 Hz, 1
H, H5), 6.01 (d, J = 1.4 Hz, 1 H, H1¢), 7.20–7.33 (m, 13 H, Ph), 7.34
(s, 1 H, NCH-triazole), 7.48–7.50 (m, 2 H, Ph), 7.80 (d, J = 8.2 Hz,
1 H, H6).
13C NMR (100 MHz, CDCl3): d = 15.4, 15.7, 17.1, 18.4, 23.1, 23.5,
23.7, 25.6, 25.9, 26.3, 27.3, 27.7, 28.2, 28.5, 30.3, 30.8, 32.6, 32.8,
33.2, 34.0, 37.1, 38.5, 38.8, 39.4, 41.4, 41.8, 44.1, 45.9, 46.8, 47.7,
50.4, 55.3, 64.0, 64.7, 68.0, 71.5, 72.2, 74.4, 78.6, 79.1, 81.2, 89.2,
101.4, 122.1, 122.4, 127.7, 127.9, 128.1, 128.5, 128.8, 129.3, 136.9,
137.3, 137.5, 138.0, 143.9, 144.2, 150.8, 162.6, 177.8.
HRMS (ESI): m/z [M + Na]+ calcd for C70H85N5NaO8: 1146.6296;
found: 1146.6293.
Benzyl 3b-O-[(2-Azidoethoxy)carbonyl]olean-12-en-28-oate
(23)
To a soln of 22 (260 mg, 0.4 mmol) in DMF (2 mL), was added
NaN3 (250 mg, 4 mmol). The mixture was stirred at 80 °C for 8 h
and then it was diluted with H2O (20 mL) and extracted with EtOAc
(3 × 10 mL). The combined organic layers were washed with H2O
and brine, dried (Na2SO4), filtered, and concentrated. The residue
was purified by flash column chromatography (EtOAc–PE, 1:60) to
give 23 (230 mg, 85%) as a white solid; Rf = 0.36 (EtOAc–PE,
1:20).
IR (KBr): 3439, 2943, 2103, 1738, 1258 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.60, 0.87, 0.92, 0.94, 1.13 (5 s,
15 H, 5 CH3), 0.90 (s, 6 H, 2 CH3), 0.60–1.98 (m, 22 H), 2.91 (dd,
J = 3.7, 13.5 Hz, 1 H, H18), 3.52 (t, J = 5.2 Hz, 2 H, N3CH2), 4.28
(t, J = 5.2 Hz, 2 H, CO2CH2), 4.35 (t, J = 8.1 Hz, 1 H, H3), 5.06 (d,
J = 12.5 Hz, 1 H, PhCH2), 5.08 (d, J = 12.5 Hz, 1 H, PhCH2), 5.29
(t, J = 3.2 Hz, 1 H, H12), 7.30–7.35 (m, 5 H, Ph).
HRMS (ESI): m/z [M + Na]+ calcd for C69H91N5NaO9: 1156.6715;
found: 1156.6709.
Oleanolic Acid–Nucleoside Conjugate 19
Prepared from 12 (130 mg, 0.24 mmol) and 18 (120 mg, 0.24 mmol)
according to the general procedure. The residue was purified by col-
umn chromatography (EtOAc–PE, 1:1) to afford 19 (200 mg, 80%)
as a white solid; Rf = 0.10 (EtOAc–PE, 1:2).
13C NMR (75 MHz, CDCl3): d = 15.3, 16.5, 16.9, 18.1, 23.0, 23.4,
23.5, 23.6, 25.8, 27.6, 27.9, 30.7, 32.3, 32.6, 33.1, 33.8, 36.9, 37.9,
38.1, 39.3, 41.4, 41.7, 45.9, 46.7, 47.5, 49.7, 55.3, 65.7, 65.9, 86.0,
122.3, 127.9, 128.0, 128.4, 136.4, 143.7, 154.9, 177.3.
[a]D22 +85.4 (c 0.46, CHCl3).
HRMS (ESI): m/z [M + Na]+ calcd for C40H57N3NaO5: 682.4196;
1H NMR (400 MHz, CDCl3): d = 0.54, 0.74, 0.83, 0.84, 0.85, 0.96,
1.08 (7s, 21 H, 7 CH3), 0.54–1.92 (m, 22 H), 2.78 (dd, J = 3.6, 13.7
Hz, 1 H, H18¢¢), 3.18 (dd, J = 4.6, 11.0 Hz, 1 H, H3¢¢), 3.74 (dd,
J = 5.3, 7.6 Hz, 1 H, H3¢), 3.93 (dd, J = 2.3, 5.0 Hz, 1 H, H2¢), 4.36–
4.72 (m, 7 H, H4¢, H5¢, 2 PhCH2), 5.05 (d, J = 14.2 Hz, 1 H, PhCH),
5.06 (d, J = 14.2 Hz, 1 H, PhCH), 5.09 (s, 2 H, CO2CH2), 5.24 (t,
J = 3.4 Hz, 1 H, H12¢¢), 5.62 (d, J = 8.2 Hz, 1 H, H5), 5.77 (d,
found: 682.4190.
Oleanolic Acid–Nucleoside Conjugate 24
Prepared from 8 (120 g, 0.21 mmol) and 23 (140 mg, 0.21 mmol)
according to the general procedure. The residue was purified by col-
umn chromatography (EtOAc–PE, 1:1) to afford 24 (120 mg, 46%)
as a white solid; Rf = 0.18 (EtOAc–PE, 1:1).
Synthesis 2010, No. 6, 1046–1052 © Thieme Stuttgart · New York

1052
K. Cheng et al.
PAPER
[a]D22 +89.7 (c 0.64, CHCl3).
(4) Godeau, G.; Staedel, C.; Barthélémy, P. J. Med. Chem. 2008,
51, 4374.
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Juillerat-Jeanneret, L. Synthesis 2008, 3957.
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Nielsen, H.; Steffansen, S. I.; Sparving, L.; Nielsen, A. B.;
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N. J. Med. Chem. 2004, 47, 3537.
(8) (a) Hoover, D.; Lefkowitz-Snow, S.; Burgess-Henry, J.;
Martin, W.; Armento, S.; Stock, I.; McPherson, R.;
Genereux, P.; Gibbs, M.; Treadway, J. J. Med. Chem. 1998,
41, 2934. (b) Baker, D. J.; Timmons, J. A.; Greenhaff, P. L.
Diabetes 2005, 54, 2453.
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561. (b) Somsák, L.; Czifrák, K.; Tóth, M.; Bokor, É.;
Chrysina, E. D.; Alexacou, K.-M.; Hayes, J. M.; Tiraidis, C.;
Lazoura, E.; Leonidas, D. D.; Zographos, S. E.;
Oikonomakos, N. G. Curr. Med. Chem. 2008, 15, 2933.
(c) Oikonomakos, N. G.; Somsák, L. Curr. Opin. Investig.
Drugs 2008, 9, 379.
1H NMR (400 MHz, CDCl3): d = 0.58, 0.80, 0.89, 0.91, 1.10 (5 s,
15 H, 5 CH3), 0.86 (s, 6 H, 2 CH3), 0.58–1.96 (m, 22 H), 2.89 (dd,
J = 3.9, 13.5 Hz, 1 H, H18¢¢), 3.67 (dd, J = 2.1, 11.2 Hz, 1 H, H5¢a),
3.87–3.97 (m, 3 H, H5¢b, H2¢, H3¢¢), 4.23 (d, J = 11.9 Hz, 1 H,
OCH), 4.28–4.32 (m, 2 H, H3¢, H4¢), 4.40 (d, J = 11.4 Hz, 1 H,
OCH), 4.47 (t, J = 5.3 Hz, 2 H, CO2CH2), 4.55–4.64 (m, 4 H,
PhCH2, NCH2), 4.79 (d, J = 12.4 Hz, 1 H, PhCH), 4.80 (d, J = 11.9
Hz, 1 H, PhCH), 5.05 (d, J = 12.4 Hz, 1 H, PhCH), 5.07 (d, J = 12.4
Hz, 1 H, PhCH), 5.10 (s, 2 H, PhCH2), 5.27 (t, J = 3.4 Hz, 1 H,
H12¢¢), 5.53 (d, J = 8.2 Hz, 1 H, H5), 6.02 (d, J = 1.8 Hz, 1 H, H1¢),
7.20–7.35 (m, 18 H, Ph), 7.47 (s, 1 H, NCH-triazole), 7.48–7.50 (m,
2 H, Ph), 7.80 (d, J = 7.8 Hz, 1 H, H6).
13C NMR (100 MHz, CDCl3): d = 15.4, 16.7, 16.9, 18.2, 23.1, 23.5,
23.7, 25.9, 27.7, 28.0, 30.8, 32.4, 32.7, 33.2, 33.9, 36.9, 38.0, 38.1,
39.4, 41.5, 41.8, 44.1, 45.9, 46.8, 47.6, 49.2, 55.3, 64.6, 65.4, 66.0,
68.0, 71.5, 72.2, 74.4, 78.6, 81.2, 86.4, 89.2, 101.4, 122.4, 123.2,
127.7, 127.8, 128.0, 128.1, 128.5, 128.7, 129.2, 136.5, 136.9, 137.3,
137.5, 138.0, 143.8, 144.4, 150.9, 154.6, 162.7, 177.5.
HRMS (ESI): m/z [M + Na]+ calcd for C73H89N5NaO11: 1234.6456;
(10) (a) Chen, J.; Liu, J.; Zhang, L. Y.; Wu, G. Z.; Hua, W. Y.;
Wu, X. M.; Sun, H. B. Bioorg. Med. Chem. Lett. 2006, 16,
2915. (b) Hao, J.; Zhang, P.; Wen, X. A.; Sun, H. B. J. Org.
Chem. 2008, 73, 7405. (c) Cheng, K. G.; Zhang, P.; Liu, J.;
Xie, J.; Sun, H. B. J. Nat. Prod. 2008, 71, 1877. (d) Wen,
X. A.; Sun, H. B.; Liu, J.; Cheng, K. G.; Zhang, P.; Zhang,
L. Y.; Hao, J.; Zhang, L. Y.; Ni, P. Z.; Zographos, S. E.;
Leonidas, D. D.; Alexacou, K. M.; Gimisis, T.; Hayes, J. M.;
Oikonomakos, N. G. J. Med. Chem. 2008, 51, 3540.
(11) Xie, J. Eur. J. Org. Chem. 2002, 3411.
found: 1234.6454.
Acknowledgment
K.C. thanks the French Embassy in China for a co-tutor Doctorate
fellowship. This work is supported by a grant from Region Ile-de-
France.
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