A new and improved synthesis of the precursor of the hypoxia marker [ 18F]-FMISO

Article abstract of DOI:10.1055/s-0030-1258269

A new synthetic approach to the precursor of the hypoxia marker [ ¹⁸F]-FMISO has been developed. Three different tosylation methods were studied for the preparation of the key intermediate. The overall yield is markedly higher than the yields reported for previous syntheses. The precursor was used to prepare [¹⁸F]-FMISO and the results were comparable to those obtained when a commercial precursor was used.

Full text of DOI:10.1055/s-0030-1258269

3700
PAPER
A New and Improved Synthesis of the Precursor of the Hypoxia Marker
[18F]-FMISO
I
mprove
d
Synth
l
esis of
e
the Precurs
n
or of the
H
y
apoxia 18
M
arker
[
F
N
]
-FMISO ieto,a Ramón Alajarín,a Julio Álvarez-Builla,*a Ignacio Larrañaga,b Elena Gorospe,b Miguel A. Pozoc
a
Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Alcalá, Ctra. Madrid-Barcelona km 33.6,
28871 Alcalá de Henares, Madrid, Spain
Fax +34918854686; E-mail: julio.alvarez@uah.es
Instituto Tecnológico PET, Manuel Bartolomé Cossío, 28040 Madrid, Spain
Instituto Pluridisciplinar, Universidad Complutense de Madrid, Paseo Juan XXIII, 28040 Madrid, Spain
b
c
Received 23 June 2010; revised 13 July 2010
Dedicated to Prof. Carmen Nájera on the occasion of her 60th birthday
adays, the procedure has been replaced by another
approach that has proven to be more reliable and effi-
cient.6 Thus, 1 is currently prepared from its precursor 4,
a high added value chemical,7 by SN2 displacement of to-
Abstract: A new synthetic approach to the precursor of the hypoxia
marker [18F]-FMISO has been developed. Three different tosylation
methods were studied for the preparation of the key intermediate.
The overall yield is markedly higher than the yields reported for
previous syntheses. The precursor was used to prepare [18F]-FMISO sylate with [18F]-fluoride and subsequent treatment with
and the results were comparable to those obtained when a commer-
hydrochloric acid to remove the tetrahydropyranyl ketal
(Scheme 1).8 Compound 5 has also been studied as a start-
cial precursor was used.
Key words: [18F]-FMISO, hypoxia, radiopharmaceutical, regiose-
lective tosylation
ing material, but a lower radiochemical yield was ob-
tained compared to 4.9
TsO
H
O
[18F]-FMISO (1, Fluoromisonidazole) is currently the
most widely studied and validated PET (Positron Emis-
sion Tomography) radiotracer for noninvasive mapping
and assessment of regional hypoxia in both animals and
humans.1 Hypoxia is a condition of reduced oxygenation
in tissues when the vascular supply is interrupted, as in
stroke or heart infarct, or when a tumor outgrows its vas-
cular supply.2 The degree of hypoxia is highly relevant in
functional recovery in these ischemic events and, in tu-
mors, it is also an important determinant of treatment re-
sponse, relapse-free survival, and overall prognosis
regardless of the treatment modality used in cancer pa-
tients.3 The ability of 1 to act as a hypoxia marker is due
to the reduction of the nitro group by intracellular nitro-
reductase enzymes such as xanthine oxidase, lipoxy-
genases, and NADPH oxidases. These enzymes produce
metabolites (probably amine and/or hydroxylamine) that
are trapped inside viable hypoxic cells, but not in necrotic
or normoxic conditions, thus allowing the accumulation
of the marker and making it possible to detect hypoxic tis-
sues by PET.4
2
1) [18F]F–
2)
NO2
18F
1) [18F]F–
N
N
N
1) [18F]F–
NO2
N
H
3
NO2
OTs
N
N
2) 1 M HCl
ref. 6, 8
K2CO3
ref. 5, 6
OH
OTHP
1
4
N
2) 1 M HCl
ref. 9
NO2
OTs
N
OAc
5
Scheme 1 Radiochemical methods for the synthesis of [18F]-
FMISO (1)
Three methods have been reported for the synthesis of 4
and all of these involve linking the 2-nitroimidazole (3) in
the last step (Scheme 2). Lim and Berridge’s synthesis
starts from glycerol 6 and requires five steps to give 4 in
18% yield.8a Adamsen et al. later reported a five-step pro-
cedure that gave 4 in 18% yield starting from 1,3-dibro-
mopropan-2-ol (7).8c In the same year, Oh et al. published
the synthesis of 4 (21%) in three steps from 6.8e In all of
these syntheses the limiting step is the nucleophilic dis-
placement of tosylate by 3 on the common ditosylate in-
termediate 8 at the end of the synthesis (31–41%). It is
worth noting at this point that 3 is also an expensive re-
agent.10
Several radiochemical methods have been reported to date
for the synthesis of 1,2c and the approaches that give the
best results are depicted in Scheme 1. Originally, 1 was
prepared by reacting (R)-glycidyl tosylate (2) with [18F]-
fluoride and subsequent epoxide opening by 2-nitroimida-
zole (3).5 The starting material in this radiosynthesis is an
enantiomerically pure compound, but differences be-
tween enantiomers of 1 have not been reported. Now-
We are involved in a research program aimed at the devel-
opment of new and more lipophilic hypoxia markers
based on the FMISO structure, which can be obtained
from 4 as the starting material.11 Due to the importance of
1 as a marker in diagnostic imaging, and hence its poten-
SYNTHESIS 2010, No. 21, pp 3700–3704
Advanced online publication: 28.09.2010
DOI: 10.1055/s-0030-1258269; Art ID: Z16010SS
© Georg Thieme Verlag Stuttgart · New York
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x.
x
x
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PAPER
Improved Synthesis of the Precursor of the Hypoxia Marker [18F]-FMISO
3701
O2N
Br
Br
OH
7
NH
N
O2N
ref. 8c
4 steps
(45%)
O
3
O
NH
NO2
N
TsO
Cs2CO3, DMF
21 h, 110 °C
59% (chromat.)
94% (crude)
N
N
O
O
9
10
N
OTs
3
OTs
TsO
OTHP
NO2
Cs2CO3, DMF
1 h, 110 ºC
(31–41%)
N
OTHP
8
HN
HO
N
4
ref. 8e
2 steps
(68%)
ref. 8a
4 steps
(44%)
overall: 18–21%
O2N
N
NO2
3
+
EtOH
K2CO3
Dowex (H+)
OH
N
reflux
80 min
37%
H2O, 2 h
r.t., 88%
O
OH
HO
OH
11
OH
6
ref. 14
12
Scheme 3 Improved synthesis of the diol 11
Scheme 2 Reported methods for the synthesis of the precursor of
[18F]-FMISO (1)
O2N
N
O2N
N
method
A or C
tial to predict the response to treatment and provide a
prognosis in a wide range of pathological processes, as
well as the high price of its precursor, we became interest-
ed in developing a new synthetic method for 4 that could
improve the overall yield and reduce its high cost. In this
context, we report herein a new and improved synthesis of
4.
OH
OTs
OH
N
N
N
OH
OH
13
+
11
10
O2N
N
O2N
N
O
N
method
B
OTs
O
The medium-low yield reported in previous syntheses of
4 is a consequence of the presence of two reactive sites in
8 and we therefore considered alkylation of 3 with a
monotosylate derivative such as 9, an inexpensive com-
mercially available compound (Scheme 3).12 Initially, the
SN2 displacement of tosylate 9 by 3 was performed to give
10. In order to complete the conversion it was necessary
to heat the reaction mixture at 110 °C for 18 hours. Open-
ing of the acetonide during purification by chromatogra-
phy was observed and 10 was obtained in 59% yield. As a
result, it was decided to continue with crude 10. At the end
of the process, evaporation of DMF and further treatment
of the residue with EtOAc and removal of Cs2CO3 by fil-
tration gave 10 in 94% yield. Hydrolysis of the acetonide
was performed by treating crude 10 at room temperature
in water in the presence of Dowex 50WX4 for two hours,
which gave 11 in 88% yield.13 The synthesis of 11 has
been previously reported by reaction of 3 and glycidol 12
in the presence of K2CO3 in refluxing EtOH, but this only
gave a low yield (37%).14
13a
Scheme 4 Regioselective tosylation methods
material and only 14% yield of 13 (13/13a, 99.5:0.5) was
obtained when PPTS was used as acidic catalyst (entry 3).
The one-pot transformation of 10 into 13 was tested in an
effort to achieve a better yield for this intermediate
(Table 1, method B). Recently, a one-pot procedure for
the transformation of acetonides into diacetates was re-
ported and involved the use of catalytic Bi(OTf)3 and
Ac2O.16 Initial experiments using Bi(OTf)3 (0.2 equiv)
and Ts2O (1 equiv) for 20 hours at room temperature gave
low yields of 13 (25%; 13/13a, 95:5; Table 1, entry 4).
PPTS (0.2 equiv) was also tested as a catalyst and the
yield of 13 improved slightly (45%; 13/13a, 98:2; entry
5). Reactions performed with PPTS in pyridine or DMF
did not lead to conversion of 10. In fact, small amounts of
3 and 14 were isolated as by-products from the mixture,
probably due to displacement of 2-nitroimidazole (3)
from 15 by the tosylate anion (Scheme 5). A possible
mechanistic pathway for the observed acetonide cleavage
is proposed and this is based on a previously reported
mechanistic proposal for the deprotection of N,O-ace-
tonides with TMSOTf.17
The regioselective tosylation of 11 was studied next
(Scheme 4). Initially, 11 was treated under classical con-
ditions for sulfonic acid ester formation (Table 1, method
A).15 Reaction with tosyl chloride/triethylamine in
CH2Cl2 at room temperature gave 13 in only 15% yield as
a mixture of 13/13a in the ratio 85:15 (Table 1, entry 1),
which could not be improved on using longer reaction
times, reflux temperature, or the addition of DMAP.
When pyridine was used as the solvent and base the reac-
tion gave, after 28 hours at room temperature, a low yield
of 13 (34%; 13/13a, 92:8; entry 2). Ts2O was also ex-
plored as a sulfonylating reagent. The reaction using tri-
ethylamine did not give any conversion of starting
Tosylation of 11 was subsequently further explored
(Scheme 4). A highly efficient procedure for the regiose-
lective tosylation of glycols through an intermediate stan-
nylene acetal has been reported and involves the use of
catalytic n-Bu2SnO.18 This approach represents an im-
provement on previous methods that use the isolated inter-
mediate.19 This approach has also been applied to a
perfluoro derivative of the catalyst, which is readily re-
Synthesis 2010, No. 21, 3700–3704 © Thieme Stuttgart · New York

3702
E. Nieto et al.
PAPER
Table 1 Regioselective Tosylation of 10 (Method B) and 11 (Methods A and C)
Entry
1d
Method,areagent
A, TsCl
Additive
Et3N
Solvent
Time (h)
Ratiob 13/13a
85:15
Yield (%)c
CH2Cl2
6
24
23
20
27
6
15
34
14
25
45
39
65
84
53
83
15
2d
A, TsCl
pyridine
PPTSe
Bi(OTf)3
PPTSe
Et3N
pyridine
CH2Cl2
92:8
3d
A, Ts2O
B, Ts2O
B, Ts2O
C, TsCl
99.5:0.5
95:5
e
4
CH2Cl2
5
CH2Cl2
98:2
6d
CH2Cl2
98:2
7d
C,f TsCl
C,f TsCl
C,f TsCl
C, TsCl
Et3N
CH2Cl2
24
18
26
5
99.6:0.4
98.6:1.4
99:1
8d
Et3N
CH2Cl2–1,4-dioxane
MeCN
9
Et3N
10
11d
Et3N
MeCN
99.3:0.7
85:15
A, TsCl
Et3N
CH2Cl2
6
a Methods A to C were performed using stoichiometric amounts of starting materials (10 or 11), reagents (TsCl or Ts2O), and basic additive
(Et3N) at r.t.
b Determined by HPLC-MS.
c Yield of 13 calculated from the regioisomeric mixture isolated by column chromatography.
d Reactions were not complete.
e Amount of catalyst [PPTS or Bi(OTf3)] added: 0.2 equiv.
f Performed at 0 °C.
medium yield (53%, 13/13a, 99:1, entry 9). The same re-
O2N
O2N
N
O
O
action performed at room temperature gave the best com-
bination of yield and regioselectivity (83%, 13/13a,
99.3:0.7, entry 10). Finally, 13 was treated with 3,4-dihy-
dro-2H-pyran (DHP) to give 4 (88%) as a mixture of dia-
stereomers 4a/4b (57:43) (Scheme 6). Thus, the global
yield of 4 (60%) was improved in comparison to the best
procedure reported to date (21%).8e
PPTS
N
N
N
O
O
+
TsO–
10
H
–OTs
OTs
O2N
N
O2N
OH
Ts2O
N
workup
N
N
O
O
+
+
TsO–
TsO–
O2N
N
O2N
N
15
DHP
PPTS
OTs
OTHP
OTs
N
N
O2N
N
O2N
N
CH2Cl2
7 h, r.t.
OH
13
OTs
N
NH
OTs
TsO
4
+
+
(88%)
OH
13
OH
14
overall: 60%
3
Scheme 6 Protection of 13 as THP ether
Scheme 5 One-pot acetonide opening and tosylation of 10
The quality of 4 prepared through method C was validated
by carrying out the synthesis of the hypoxia marker 1. A
TracerLab Mx FDG synthesis module from Coincidence
Technologies was used for the production of [18F]-FMISO
(1). Modifications in standard disposable [18F]-FDG cas-
settes, reagents and the synthesis sequence were per-
formed as reported by Oh et al.8e Synthesis of [18F]-
FMISO was carried out starting from a sample of 4 ob-
tained as reported here and a sample of 4 obtained from a
commercial source (Scheme 7, Table 2). Significant dif-
ferences in the syntheses were not observed on using 4 ob-
tained from either source. The radiochemical yield of the
synthesis performed with the commercial precursor was
higher, as was the amount of 1 in the crude mixture. How-
ever, from our precursor a smaller proportion of radio-
covered and reused, in order to achieve a more environ-
mentally benign methodology.20 This procedure was
applied to diol 11 (Table 1, method C) in CH2Cl2 at room
temperature, giving 13 in 39% yield (13/13a, 98:2,
Table 1, entry 6). When diol 11 was reacted at 0 °C for a
longer time, tosylate 13 was obtained in higher yield
(65%, entry 7) and improved regioselectivity (13/13a,
99.6:0.4) was achieved. Conversion of the starting mate-
rial was incomplete when CH2Cl2 was used as solvent,
probably due to the partial solubility of the diol 11. Addi-
tion of 1,4-dioxane as a co-solvent improved the yield of
13 (84%, 13/13a, 98.6:1.4, entry 8) but some starting ma-
terial still remained. Diol 11 showed high solubility in
MeCN at 0 °C and in this solvent the reaction gave 13 in
Synthesis 2010, No. 21, 3700–3704 © Thieme Stuttgart · New York

PAPER
Improved Synthesis of the Precursor of the Hypoxia Marker [18F]-FMISO
3703
Ltd. Precursor 4 was purchased from ABX Advanced Biochemical
Compounds, Germany.
chemical impurities was found in the crude reaction
mixture (7.4% vs 12.1%; see Figures 1 and 2 in Support-
ing Information). Using 557 mCi of [18F]-fluoride as a
starting activity, we achieved an EOS radiochemical yield
of 35.9% (purity >99%) for 55 min (n = 12). The synthe-
sized [18F]-FMISO maintained its radiochemical purity
for five hours.
1-(2,2-Dimethyl[1,3]dioxolan-4-ylmethyl)-2-nitro-1H-imida-
zole (10)
A mixture of tosylate 9 (12.00 g, 41.80 mmol), 3 (5.19 g, 45.98
mmol), Cs2CO3 (13.58 g, 41.80 mmol), and anhyd DMF (144 mL)
was heated at 110 °C for 21 h under argon atmosphere (argon
should be bubbled through the mixture for 5 min before the process
starts). The solvent was removed under reduced pressure, the resi-
due was taken up in EtOAc (150 mL), and the solid was filtered off.
The filtrate was evaporated under reduced pressure to give 10 as a
brownish oil (8.88 g, 94%; HPLC: 93%). A sample was chromato-
graphed on silica gel using EtOAc–hexane (4:6) as eluent.
N
N
1) [18F]F–/Kryptofix® 222
K2CO3, MeCN, 100 °C
NO2
OTs
NO2
18F
N
N
2) 1 M HCl, 100 °C
OH
OTHP
IR (CHCl3): 1539 (C=N), 1787 (NO2), 1363 (NO2), 1066, 969 cm–1
(C–O).
4
1
Scheme 7 Radiosynthesis of [18F]-FMISO (1)
1H NMR (300 MHz, CDCl3): d = 7.17 (s, 1 H, HIm-H5), 7.10 (s, 1 H,
HIm-H4), 4.69 (dd, J = 13.5 Hz, J = 2.3 Hz, 1 H, CH2–Im), 4.47–4.38
Table 2 Comparative Synthesis of [18F]-FMISO (1) (n = 12)
(m, 1 H, CH), 4.35 (dd, J = 13.5, 7.2 Hz, 1 H, CH2–Im), 4.13 (dd,
J = 8.9, 5.6 Hz, 1 H, CH2O), 3.65 (dd, J = 8.9, 5.6 Hz, 1 H, CH2O),
1.34 (s, 3 H, CH3), 1.28 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 144.74 (C2Im), 128.09 (C5Im),
127.07 (C4Im), 110.24 (C2ketal), 73.87 (CH2–Im), 66.23 (C4ketal),
51.98 (C4ketal), 26.49 (CH3), 25.05 (CH3).
Precursor source
Ref. 7
482
This work
557
Starting 18F– activity (mCi)
Crude mixture activity (mCi)
1 in crude mixture (%)
227
216
MS (ESI+): m/z (%) = 228 (M + H, 7), 250 (M + Na, 13), 266 (M +
K, 42).
HRMS (ESI): m/z calcd for C9H14N3O4 (M + H+): 228.0984; found:
228.1012.
13.1
87.9
199.5
41.4
>99
7.6
1 activity in crude mixture (%)
1 activity in final solution (%)
Radiochemical yield (%)a
Radiochemical purity (%)
Starting 18F– activity (mCi)
a Decay corrected.
92.6
200
3-(2-Nitroimidazol-1-yl)propane-1,2-diol (11)
35.9
>99
A mixture of 10 (8.87 g, 39.0 mmol) and Dowex 50WX4 (26.98 g,
34.3 mmol) in H2O (50 mL) was stirred at 100 °C for 2 h. Then, the
resin was filtered and washed with MeOH (3 × 20 mL). The solvent
was evaporated and the residue was crystallized from EtOH to give
11 (6.38 g, 88%) as a yellowish solid; mp 109.4–112.7 °C (Lit.15 mp
110–112 °C).
482
557
IR (KBr): 3275 (OH), 1537 (C=N), 1491 (NO2), 1366 (NO2), 1053
cm–1.
1H NMR (300 MHz, CD3OD): d = 7.48 (s, 1 H, HIm-H5), 7.16 (s, 1
H, HIm-H4), 4.77 (dd, J = 13.8, 3.3 Hz, 1 H, CH2–Im), 4.39 (dd,
J = 13.8, 8.4 Hz, 1 H, CH2–Im), 4.01–3.93 (m, 1 H, CH), 3.64–3.53
(m, 2 H, CH2OH).
In summary, a new synthesis of 4, the precursor of the hy-
poxia marker [18F]-FMISO 1, has been developed. In this
synthesis the key step is the formation of the intermediate
tosylate 13, which was prepared by three different meth-
ods. The best method consisted of catalytic tosylation in
the presence of n-Bu2SnO. This new synthesis involves
four steps from a commercially available starting materi-
al, uses fewer purification steps and gives the product 4 in
improved yield. The synthesis of 1 starting from 4, either
prepared by our method or obtained from a commercial
source, was performed. Significant differences in the
products were not found on using samples of either origin.
13C NMR (75 MHz, CD3OD): d = 146.41 (C2Im), 129.20 (C5Im),
127.99 (C4Im), 71.64 (CH2–Im), 64.70 (CH), 53.62 (CH2OH).
MS (ESI+): m/z (%) = 188 (M + H, 8).
Anal. Calcd for C6H9N3O4: C, 38.50; H, 4.85; N, 22.45. Found: C,
38.29; H, 4.94; N, 22.19.
Toluene-4-sulfonic Acid 2-Hydroxy-3-(2-nitroimidazol-1-
yl)propyl Ester (13)
Method A: A solution of diol 11 (117 mg, 0.62 mmol) in anhyd py-
ridine (3 mL) under an argon atmosphere was cooled to 0 °C and a
solution of TsCl (119 mg, 0.62 mmol) in anhyd pyridine (3 mL) was
added dropwise during 15 min. The cooling bath was removed and
the mixture was stirred for 24 h at r.t. Ice (3 mL) and aq 2 M HCl (5
mL) were added and the mixture was extracted with Et2O (3 × 3
mL). The combined organic extracts were washed with brine (2 × 3
mL) and dried (Na2SO4). After filtration and evaporation, the resi-
due was chromatographed on silica gel using EtOAc as eluent to
give a yellowish solid 13 (73.2 mg, 34.2%) as a mixture 13/13a
(92:8).
IR spectra were recorded on a PerkinElmer FTIR 1725X spectro-
photometer. 1H and 13C NMR spectra were recorded at r.t. using ei-
ther a Varian UNITY-300, a Varian Mercury-VX300, or a Varian
Gemini 200 spectrometer in CDCl3 or CD3OD. J values are reported
in Hertz and chemical shifts are reported in parts per million with
the solvent signal as internal standard. Mass spectra were recorded
on an Agilent HP1100 spectrometer. HRMS were recorded with an
Agilent 6210 LC/MS TOF spectrometer. Melting points were deter-
mined on a Gallenkamp apparatus. A TracerLab Mx FDG synthesis
module from Coincidence Technologies was used for the synthesis
of 1. Reagents (reagent grade) and solvents were purchased from
Merck and were used without further purification. 18O-enriched wa-
ter and disposable cassettes were purchased from Rotem Industries
Method B: A solution of acetonide 10 (50.0 mg, 0.22 mmol), Ts2O
(71.9 mg, 0.22 mmol), and PPTS (11.1 mg, 0.044 mmol) in CH2Cl2
Synthesis 2010, No. 21, 3700–3704 © Thieme Stuttgart · New York

3704
E. Nieto et al.
PAPER
In Imaging of Hypoxia; Machulla, H.-J., Ed.; Kluwer
Academic Publishers: Dordrecht, 1999, 85–117.
(c) Grierson, J.; Patt, M. In Imaging of Hypoxia; Machulla,
H.-J., Ed.; Kluwer Academic Publishers: Dordrecht, 1999,
75–84.
(1.1 mL) under argon atmosphere was vigorously stirred at r.t. for
27 h. The solvent was removed and the residue was chromato-
graphed on silica gel using EtOAc to give 13 as a yellowish solid
(33.6 mg, 45%) as a mixture 13/13a (98:2).
Method C: TsCl (509 mg, 2.67 mmol) was added to a solution of 11
(0.50 g, 2.67 mmol), Et3N (2.72 g; 2.67 mmol), and Bu2SnO (13
mg; 0.53 mmol) in anhyd MeCN (40 mL) and the reaction mixture
was stirred at r.t. for 5 h and then evaporated. The residue was puri-
fied by column chromatography on silica gel using EtOAc–hexane
(8:2) as eluent to yield 13 (760 mg, 83%) as a yellowish solid mix-
ture of regioisomers 13/13a (99.3:0.7); mp 140.9–143.5 °C.
(3) (a) Tatum, J. L.; Kelloff, G. J.; Gillies, R. J.; Arbeit, J. M.;
Brown, J. M.; Chao, K. S. C.; Chapman, J. D.; Eckelman, W.
C.; Fyles, A. W.; Giaccia, A. J.; Hill, R. P.; Koch, C. J.;
Krishna, M. C.; Krohn, K. A.; Lewis, J. S.; Mason, R. P.;
Melillo, G.; Padhani, A. R.; Powis, G.; Rajendran, J. G.;
Reba, R.; Robinson, S. P.; Semenza, G. L.; Swartz, H. M.;
Vaupel, P.; Yang, D.; Croft, B.; Hoffman, J.; Liu, G.; Stone,
H.; Sullivan, D. Int. J. Radiat. Biol. 2006, 82, 699. (b) Foo,
S. S.; Abbott, D. F.; Lawrentschuk, N.; Scott, A. M. Mol.
Imaging Biol. 2004, 6, 291.
IR (KBr): 3204 (OH), 1539 (C=N), 1492 (NO2), 1365 (NO2), 1365
(SO2), 1171 cm–1 (SO2).
1H NMR (300 MHz, CD3OD): d = 7.85 (d, J = 8.2 Hz, 2 H, H2-Ar),
7.49 (d, J = 8.2 Hz, 2 H, H3-Ar), 7.41 (s, 1 H, H5-Im), 7.13 (2, 1 H,
H4-Im), 4.66 (dd, J = 13.8, 3.3 Hz, 1 H, CH2–Im), 4.36 (dd,
J = 13.8, 8.2 Hz, 1 H, CH2–Im), 4.12–4.05 (m, 3 H, CH and
CH2OTs), 2.50 (s, 3 H, CH3)
(4) (a) Prekeges, J. L.; Rasey, J. S.; Grunbaum, Z.; Krohn, K. H.
Biochem. Pharmacol. 1991, 42, 2387. (b) McClelland, R.
A.; Panicucci, R.; Rauth, A. M. J. Am. Chem. Soc. 1987, 109,
4308.
(5) (a) Grierson, J. R.; Link, J. M.; Mathis, C. A.; Rasey, J. S.;
Krohn, K. A. J. Nucl. Med. 1989, 30, 343. (b) Tada, M.;
Iwata, R.; Sugiyama, H.; Sato, K.; Kubota, K.; Kubota, R.;
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13C NMR (50 MHz, DMSO-d6): d = 144.58 (C4Ts), 144.38 (C2Im),
131.38 (C1Ts), 129.66 (C3Ts), 127.86 (C5Im), 127.16 (C2Ts), 126.85
(C4Im), 70.99 (CH2–Im), 66.20 (CHOH), 50.73 (CH2OTs), 20.62
(CH3)
MS (ES+): m/z (%) = 342 (M + H, 100).
HRMS (ESI): m/z calcd for C13H15N3O6S (M + H+): 342.0760;
found: 342.0624.
Toluene-4-sulfonic Acid 3-(2-Nitroimidazol-1-yl)-2-(tetrahy-
dropyran-2-yloxy)propyl Ester (4)
A solution of 13 (0.270 g, 0.79 mmol), PPTS (0.238 g, 0.948 mmol),
and 3,4-dihydro-2H-pyran (0.600 g, 7.12 mmol) in anhyd CH2Cl2
(20 mL) was stirred at r.t. for 7 h. The reaction mixture was evapo-
rated and the residue was purified by column chromatography on
silica gel using EtOAc–hexane (6:4) as eluent to yield 4 as a yellow-
ish solid (0.294 g, 88%) mixture of diastereomers 4a/4b (57:43);
mp 104.7–106.9 °C (Lit.:8e mp 106–109 °C; mixture of diastereo-
mers 71:29).
1H NMR (300 MHz, CDCl3): d = 7.80 (d, J = 8.2 Hz, 2 H, 2 H2a-
Ar), 7.78 (d, J = 8.2 Hz, 2 H, 2 H2b-Ar), 7.36 (d, J = 8.2 Hz, 4 H, 2
H3a-Ar + 2 H3b-Ar), 7.13 (s, 1 H, H4b-Im), 7.09 (s, 2 H, H4a-Im +
H5b-Im), 7.07 (s, 1 H, H5a-Im), 4.78 (dd, J = 14.0, 2.9 Hz, 1 H,
H2a-THP), 4.67 (dd, J = 13.6 Hz, J = 3.2 Hz, 1 H, H2b-THP),
4.46–3.96 (m, 5 H, 2 H1 + H2 + 2 H3, a + b), 3.68–3.57 (m, 1 H,
H6a-THP), 3.35–3.18 (m, 2 H, H6a + H6b-THP), 3.12–3.06 (m, 1
H, H6b-THP), 2.45 (s, 3 H, CH3, a + b), 1.72–1.30 (m, 6 H, H3 +
H4 + H5-THP, a + b).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
We wish to thank the Comunidad de Madrid (CM S-BIO-0170-
2006) and the Consejería de Economía y Hacienda de la Comunidad
de Madrid (33/09 BIO-2009) for financial support. E.N. also thanks
multiMAG research group for a fellowship.
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J. Org. Chem. 2008, 73, 752.
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N. K.; Dhokte, U. P.; Doecke, C. W.; Zollars, L. M. H.;
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Synthesis 2010, No. 21, 3700–3704 © Thieme Stuttgart · New York