SiFA azide: A new building block for PET imaging using click chemistry

Article abstract of DOI:10.1055/s-0030-1260942

We present a new highly potent building block for PET imaging based on silicon fluoride acceptors (SiFA) which can easily be coupled to bioactive compounds by means of click chemistry. Owing to a remarkable chemoselectivity, short reaction times, and high yields the labeling reactions thoroughly meet the stringent demands for PET investigations. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260942

LETTER
1697
SiFA Azide: A New Building Block for PET Imaging Using Click Chemistry
SiFA
Azide utz F. Tietze,* Kianga Schmuck
Institute of Organic and Biomolecular Chemistry, Georg-August-University Göttingen, Tammannstr. 2, 37077 Göttingen, Germany
Fax +49(551)399476; E-mail: ltietze@gwdg.de
Received 12 May 2011
Cl
Abstract: We present a new highly potent building block for PET
O
imaging based on silicon fluoride acceptors (SiFA) which can easily
be coupled to bioactive compounds by means of click chemistry.
Owing to a remarkable chemoselectivity, short reaction times, and
high yields the labeling reactions thoroughly meet the stringent de-
mands for PET investigations.
NMe2
N
N
H
O
OH
HO
O
O
Key words: azides, cancer, click chemistry, fluorine labeling, PET
HO
OH
1
Imaging technologies, which allow a noninvasive moni-
toring of biological processes in vivo are very important
tools for the understanding of living systems and the de-
velopment of new drugs. Several methods as optical im-
aging employing compounds labeled with fluorescence
dyes,1 magnetic resonance imaging (MRI),2 single-photon
emission tomography (SPECT),3 and positron-emission
tomography (PET)4 are in use. The latter nuclear imaging
technique, which is mainly employed in the field of clini-
cal oncology, neurology, and cardiology has the advan-
tage of high sensitivity and only minor structural changes
of the molecules to be investigated are necessary. Thus,
PET can give valuable information about the in vivo dis-
tribution of diagnostic as well as bioactive compounds
and allows one to map the corresponding molecules. On
the other hand, a major disadvantage of this procedure is
that positron-emitting radioisotopes such as 18F, 11C, and
13N with a short lifetime have to be used. Therefore, as a
prerequisite, the introduction of the radioisotope must be
fast.
Figure 1 Glycosidic duocarmycin analogue prodrug 1 as anticancer
agent for application in ADEPT
preferably 18F as the most stable positron-emitting radio-
isotope with t1/2 = 109.7 min.
Previously, Waengler and Schirrmacher et al. reported on
silicon fluoride acceptors (SiFA) like p-(di-tert-butylfluo-
rosilyl)benzaldehyde (2) as potent labeling reagents for
PET (Scheme 1).8 Using a fast and highly efficient isoto-
pic 19F–18F exchange specific activities of up to 680 GBq/
mmol for [18F]-2 can be obtained and thus only a small
amount of the precursor is needed. Furthermore, [18F]-2
was proven to be stable under physiological conditions,
and the group has shown that [18F]-2 can be efficiently
coupled to aminooxy-derivatized peptides via oxime for-
mation in a fast and high-yielding reaction.
t-Bu
Si 19F
t-Bu
Si 18F
O
H
O
H
t-Bu
t-Bu
In our work on the development of novel highly selective
anticancer agents using the antibody-directed enzyme
prodrug therapy (ADEPT)5 and the prodrug mono therapy
(PMT)6 we have designed glycosidic derivatives of ana-
logues of the natural antibiotic duocarmycin SA (1) with
relatively low cytotoxicity which can be cleaved either by
an antibody–enzyme conjugate or an enzyme overex-
pressed in the tumor tissue (Figure 1).7 The cytotoxicity of
the formed drugs is very high with an IC50 value of as low
as 110 fM. On the other hand, the selectivity which corre-
sponds to the therapeutic window in a treatment and
which was defined by us by the QIC50 value (QIC50 = IC50
of prodrug/IC50 of prodrug in the presence of cleaving en-
zyme)5a can reach the value of almost one million.7b For
the determination of the in vivo distribution of our pro-
drugs and drugs the only suitable procedure is PET using
2
[
18F]-2
Scheme 1 Radiosynthesis of SiFA aldehyde [18F]-2. Reagents and
conditions: 18F–/K222/K+ (1–2.5 GBq), MeCN, r.t., 10 min, 80–95%
radiochemical yield. K222 = Kryptofix® 222.
Unfortunately, we were not able to successfully employ
aldehyde 2 for fluorine labeling of our anticancer agents
containing a primary amino functionality probably due to
the more complex and electronically different structure of
our compounds compared to the given examples. There-
fore we have developed SiFA azide 4, which can be intro-
duced to any compound containing a terminal alkyne
moiety using click chemistry based on the work of
Huisgen, Sharpless, and Meldal.9
For the synthesis of SiFA azide 4, the alcohol 3, being
available from 4-bromobenzylic alcohol in three steps,8a
was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) and diphenylphosphoryl azide (DPPA) in toluene
for 13 hours at 50 °C to give the azide 4 in an excellent
SYNLETT 2011, No. 12, pp 1697–1700
x
x
.x
x
.2
0
1
1
Advanced online publication: 05.07.2011
DOI: 10.1055/s-0030-1260942; Art ID: B08911ST
© Georg Thieme Verlag Stuttgart · New York

1698
L. F. Tietze, K. Schmuck
LETTER
yield of 92% (Scheme 2). SiFA azide 4 was proven to be
stable under labeling-like conditions with KF (1.0 equiv)
and 18-crown-6 (1.3 equiv) in acetonitrile for 10 minutes
at room temperature. The compound was recovered with-
out any changes and especially with no loss of the azide
group.
Table 1 Copper(I)-Catalyzed Coupling of Alkynes 5–8 with SiFA
Azide 4 To Give the 1,4-Substituted Triazoles 9
R
N
N
R
t-Bu
Si
t-Bu
t-Bu
Si
t-Bu
N
N3
5–8
F
F
4
9
t-Bu
Si
t-Bu
t-Bu
Si
t-Bu
HO
N3
F
F
R
Time Product Yield
(min)
(%)
3
4
Me2N
Scheme 2 Synthesis of SiFA azide 4. Reagents and conditions:
20
9a
quant.
DPPA, DBU, toluene, 50 °C, 13 h, 92%.
5
O
O
The Cu(I)-catalyzed cycloaddition of azide 4 with differ-
ent alkynes 5–8 consistently furnished high yields of the
corresponding 1,4-substituted triazoles 9 in a reaction
time of 60 minutes or less as shown in Table 1. All trans-
formations were performed in aqueous tert-butyl alcohol
and under convenient in situ generation of Cu(I) out of
CuSO4 and sodium ascorbate. With regard to our antitu-
mor active duocarmycin analogues for application in
ADEPT and PMT we were also able to rapidly connect
our modified DNA binder 7 to the SiFA azide 4 to give the
triazole 9c in 88% yield within 20 minutes. In addition, we
employed the corresponding acid 8, which again gave
high yields of the desired cycloadduct 9d. However, the
compound could not be separated completely from the
used copper salt presumably due to the chelating proper-
ties of the COOH and NH functionalities in 8 resulting in
broad signals in the NMR spectrum.
30
20
60
rac-9b 88
rac-6
O
N
EtO2C
9c
95
Me
N
H
7
O
N
9d
80b
HO2C
Me
N
OMe
H
8
a Reaction conditions: (a) CuSO4·5H2O, Na ascorbate, t-BuOH–H2O,
r.t.
b Compound contains small amounts of copper ions.
1H NMR (300 MHz, CDCl3): d = 1.06 [d, JH,F = 1.1 Hz, 18 H,
4
2 × C(CH3)3], 4.37 (s, 2 H, CH2), 7.33 (d, 3JH,H = 7.8 Hz, 2 H, 2-H,
In summary, the new SiFA azide 4 comprises a highly ef-
ficient labeling reagent for PET imaging with remarkable
chemoselectivity, short reaction times, and facile perfor-
mance.
6-H), 7.63 (d, 3JH,H = 7.9 Hz, 2 H, 3-H, 5-H) ppm. 13C NMR (125
2
MHz, CDCl3): d = 20.2 [d, JC,F = 12.4 Hz, 2 × C(CH3)3], 27.3 [d,
3JC,F = 1.1 Hz, 2 × C(CH3)3], 54.7 (CH2), 127.2 (C-2, C-6), 133.8 (d,
2JC,F = 13.7 Hz, C-4), 134.4 (d, 3JC,F = 4.5 Hz, C-3,C-5), 136.7 (C-
1) ppm. 19F NMR (282 MHz, CDCl3): d = –188.9 (1JSi,F = 298 Hz)
ppm. IR: n = 2933, 2859, 2095, 1605, 1471, 1273, 1251, 1106, 824,
813 cm–1. UV (MeCN): lmax (lg e) = 225 (4.1394), 267 (2.7330),
358 (2.2454) nm. HRMS (EI): m/z [M]+ calcd for C15H24FN3Si:
293.1724; found: 293.1726.
The reactions were carried out under argon. Solvents were used
from commercial sources in p.a. grade and stored over molecular
sieves. All reagents purchased from commercial sources were used
without further purification. TLC was performed on silica gel 60
F254 plates from Merck and silica gel 60 (0.032–0.063 mm, Merck)
was used for column chromatography. UV spectra were taken with
General Procedure for the Cu(I)-Catalyzed Cycloaddition To
Give the Triazoles 9
1
a V-630 (Jasco), IR spectra with a FT/IR-4100 (Jasco). H NMR,
A mixture of the alkyne 5–8, the azide 4, CuSO4·5H2O, and sodium
L-ascorbate in t-BuOH–H2O (3:1, degassed) was stirred for 20–60
min at r.t. Then, H2O (5 mL) and CH2Cl2 (10 mL) were added and
the phases separated. The aqueous layer was extracted with CH2Cl2
(2 × 10 mL), and the combined organic layers were washed with
brine (10 mL), dried over Na2SO4, and the solvent was removed un-
der reduced pressure. In the case of rac-9b double the amount of
solvents was used in workup.
19F NMR, and 13C NMR spectra were recorded with Mercury-300,
Unity-300, and Inova-500 spectrometers. Spectra were taken at r.t.
in deuterated solvents as indicated using the solvent peak as internal
standard. ESI-HRMS was performed on a micrOTOF (Bruker)
spectrometer and on an AccuTOF (Jeol) spectrometer for EI-
HRMS.
4-(Di-tert-butylfluorosilyl)benzylazide (4)
A solution of alcohol 3 (1.00 g, 3.73 mmol, 1.0 equiv) in toluene (10
mL) was treated with DBU (835 mL, 5.59 mmol, 1.5 equiv) and
DPPA (1.20 mL, 5.59 mmol, 1.5 equiv), and the mixture was stirred
for 13 h at 50 °C. The reaction was quenched by addition of sat.
NH4Cl solution (20 mL) and MTBE (20 mL), and the aqueous layer
was extracted with MTBE (3 × 40 mL). The combined organic lay-
ers were washed with brine (60 mL), dried over Na2SO4, and the
solvent was evaporated. The crude product was purified by column
chromatography on silica gel (PE–EtOAc = 50:1) to give 4 as a col-
orless oil (1.01 g, 3.43 mmol, 92%). Rf = 0.55 (PE–EtOAc = 10:1).
{1-[4-(Di-tert-butylfluorosilanyl)benzyl]-1H-1,2,3-triazole-4-yl-
methyl}dimethylamine (9a)
A suspension of 1-dimethylamino-2-propyne (5, 8.1 mL, 75 mmol,
1.1 equiv), 4 (20 mg, 68 mmol, 1.0 equiv), CuSO4·5H2O (3.4 mg, 14
mmol, 0.2 equiv), and Na ascorbate (8.1 mg, 41 mmol, 0.6 equiv) in
t-BuOH–H2O (3:1, 2.8 mL) was stirred for 20 min at r.t. After work-
up, the triazole 9a was obtained as slightly yellow solid (26 mg, 68
1
mmol, quant.). Rf = 0.52 (CH2Cl2–MeOH = 1:1). H NMR (300
MHz, CDCl3): d = 1.01 [s, 18 H, 2 × C(CH3)3], 2.26 (s, 6 H, NMe2),
Synlett 2011, No. 12, 1697–1700 © Thieme Stuttgart · New York

LETTER
SiFA Azide
1699
3.60 (s, 2 H, Me2N-CH2), 5.51 (s, 2 H, triazole-CH2-Ar), 7.22 (d,
3JH,H = 7.9 Hz, 2 H, 2¢-H, 6¢-H), 7.45 (s, 1 H, 5-H), 7.57 (d,
3JH,H = 7.7 Hz, 2 H, 3¢-H, 5¢-H) ppm. 13C NMR (125 MHz, DMSO-
d6): d = 19.6 [d, 2JC,F = 12.5 Hz, 2 × C(CH3)3], 26.9 [2 × C(CH3)3],
43.1 (NMe2), 52.1 (Me2N-CH2), 52.5 (triazole-CH2-Ar), 125.4 (C-
ppm. 19F NMR (282 MHz, CDCl3): d = –188.8 (1JSi,F = 304 Hz)
ppm. IR: n = 3320, 2931, 2858, 1688, 1526, 1469, 1449, 1399,
1378, 1337, 1207, 1103, 1018, 803 cm–1. UV (MeCN): lmax (lg
e) = 194 (4.7546), 220 (4.5712), 294 (4.2371), 324 (3.626) nm.
ESI-HRMS: m/z [M + H]+ calcd for C32H44FN5O3Si: 594.3270;
found: 594.3268.
2
5), 126.9 (C-2¢, C-6¢), 132.4 (d, JC,F = 13.8 Hz, C-4¢), 133.9 (d,
3JC,F = 4.4 Hz, C-3¢, C-5¢).137.6 (C-1¢), 145.5 (C-4) ppm. 19F NMR
(282 MHz, CDCl3): d = –188.8 (1JSi,F = 304 Hz) ppm. IR: n = 2941,
2857, 1605, 1466, 1433, 1223, 1107, 1057, 1012, 824 cm–1. UV
(MeCN): lmax (lg e) = 223 (4.2115), 261 (2.7447) nm. ESI-HRMS:
m/z [M + H]+ calcd for C20H33FN4Si: 377.2531; found: 377.2526.
5-[2-({1-[4-(Di-tert-butylfluorosilyl)benzyl]-1H-1,2,3-triazole-4-
ylmethyl}methylamino)ethoxy]-1H-indole-2-carboxylic Acid
(9d)
The compound was prepared as described for 9c with a yield of
about 80%, it contains small amounts of copper ions, which could
not be removed, resulting in broad signals in the NMR spectra.
Thus, an unambiguous spectroscopic identification was not possi-
ble. ESI-HRMS: m/z [M + H]+ calcd for C31H42 FN5O4Si: 596.3063;
found: 596.3064.
rac-1-[4-(Di-tert-butylfluorosilyl)benzyl]-4-(tetrahydro-2H-
pyran-2-yl-oxymethyl)-1H-1,2,3-triazole (rac-9b)
A suspension of tetrahydro-2-(2-propynyloxy)-2H-pyran (rac-6,
23.9 mg, 170 mmol, 1.0 equiv), 4 (50.0 mg, 170 mmol, 1.0 equiv),
CuSO4·5H2O (8.50 mg, 34.1 mmol, 0.2 equiv ) and Na ascorbate
(20.2 mg, 102 mmol, 0.6 equiv) in t-BuOH–H2O (3:1, 4 mL) was
stirred for 30 min at r.t. After workup, the crude product was puri-
fied by column chromatography on silica gel (PE–EtOAc = 2:1, 1%
Et3N) to give the triazole rac-9b as white solid (64.7 mg, 149 mmol,
88%). Rf = 0.14 (PE–EtOAc = 2:1, 0.5% Et3N). 1H NMR (300
MHz, CDCl3): d = 1.02, 1.03 [d, 4JH,F = 1.1 Hz, 18 H, 2 × C(CH3)3],
1.41–1.63 (m, 4 H, 3¢-Ha, 4¢-Ha, 5¢-H2), 1.64–1.86 (m, 2 H, 3¢-Hb,
4¢-Hb), 3.45–3.55 (m, 1 H, 6¢-Ha), 3.78–3.92 (m, 1 H, 6¢-Hb), 4.63
Acknowledgment
The work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie. K.S. thanks the Fonds der
Chemischen Industrie for a PhD scholarship. K.S. is also grateful to
Viktoria Meier and to Ljuba Iovkova for advices regarding the syn-
thesis of t-Bu2SiF2.
2
3
(d, JH,H = 12.4 Hz, 1 H, OCHa-triazole), 4.71 (dd, JH,H = 4.2, 2.6
Hz, 1 H, 2¢-H), 4.84 (d, 2JH,H = 12.4 Hz, 1 H, OCHb-triazole), 5.51
(s, 2 H, triazole-CH2-Ar), 7.24 (d, 3JH,H = 8.0 Hz, 2 H, 2¢¢-H, 6¢¢-H),
7.48 (s, 1 H, 5-H), 7.58 (d, 3JH,H = 8.0 Hz, 2 H, 3¢¢-H, 5¢¢-H) ppm.
13C NMR (125 MHz, CDCl3): d = 19.4 (C-4¢), 20.2 [d, 2JC,F = 12.4
Hz, 2 × C(CH3)3], 25.3 (C-5¢), 27.2 [2 × C(CH3)3], 30.4 (C-3¢), 54.0
(triazole-CH2-Ar), 60.7 (OCH2-triazole), 62.4 (C-6¢), 98.4 (C-2¢),
122.5 (C-5), 127.1 (C-2¢¢, C-6¢¢), 134.5 (d, J = 13.6 Hz, C-4¢¢), 134.6
(d, J = 4.5 Hz, C-3¢¢, C-5¢¢), 135.9 (C-1¢¢), 145.6 (C-4) ppm. 19F
NMR (282 MHz, CDCl3): d = –188.8 (1JSi,F = 304 Hz) ppm. IR:
n = 2945, 2931, 2857, 1469, 1367, 1213, 1201, 1103, 1037, 825,
807, 646 cm–1. UV (MeCN): lmax (lg e) = 223 (4.1933), 262
(2.5451), 267 (2.5511), 272 (2.4169) nm. ESI-HRMS: m/z [M +
Na]+ calcd for C23H36FN3O2Si: 456.2453; found: 456.2453.
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azole-4-ylmethyl}methylamino)ethoxy]-1H-indole-2-carboxy-
late (9c)
A suspension of indole 7 (22 mg, 68 mmol, 1.0 equiv), 4 (22 mg, 75
mmol, 1.1 equiv), CuSO4·5H2O (3.4 mg, 14 mmol, 0.2 equiv), and
Na ascorbate (8.1 mg, 41 mmol, 0.6 equiv) in t-BuOH–H2O (3:1, 2.8
mL) was stirred for 20 min at r.t. After workup, the crude product
was purified by column chromatography on silica gel (CH2Cl2–
MeOH = 60:1, 0.5% Et3N) to give the triazole 9c as slightly brown
solid (38 mg, 64 mmol, 95%). Rf = 0.15 (CH2Cl2–MeOH = 20:1,
1
2
0.5% Et3N). H NMR (300 MHz, CDCl3): d = 1.01 [d, JH,F = 1.0
3
Hz, 18 H, 2 × C(CH3)3], 1.38 (t, JH,H = 7.1 Hz, 3 H, OCH2CH3),
2.42 (s, 3 H, NMe), 2.91 (t, 3JH,H = 5.2 Hz, 2 H, OCH2CH2), 3.87 (s,
3
2 H, MeN-CH2-triazole), 4.13 (t, JH,H = 5.5 Hz, 2 H, OCH2CH2),
4.37 (q, 3JH,H = 7.1 Hz, 2 H, OCH2CH3), 5.48 (s, 2 H, triazole-CH2-
3
4
Ar), 6.94 (dd, JH,H = 8.9 Hz, JH,H = 2.4 Hz, 1 H, 6-H), 7.03 (d,
4JH,H = 2.4 Hz, 1 H, 4-H), 7.10 (dd, JH,H = 2.1, 0.9 Hz, 1 H, 3-H),
4
7.20 (d, 3JH,H = 8.0 Hz, 2 H, 2¢¢-H, 6¢¢-H), 7.28 (d, 3JH,H = 8.9 Hz, 1
H, 7-H), 7.54 (s, 1 H, 5¢-H), 7.56 (d, 3JH,H = 8.0 Hz, 2 H, 3¢¢-H, 5¢¢-
H), 8.92 (br s, 1 H, NH) ppm. 13C NMR (125 MHz, CDCl3): d = 14.4
2
(OCH2CH3), 20.2 [d, JC,F = 12.4 Hz, 2 × C(CH3)3], 27.2 [d,
3JC,F = 1.0 Hz, C(CH3)3], 42.7 (NMe), 52.6 (MeN-CH2-triazole),
54.0 (triazole-CH2-Ar), 55.5 (OCH2CH2), 60.9 (OCH2CH3), 66.3
(OCH2CH2), 103.7 (C-4), 108.1 (C-3), 112.7 (C-7), 117.2 (C-6),
123.1 (C-5¢), 126.9 (C-2¢¢, C-6¢¢), 127.8 (C-3a), 128.0 (C-2), 132.2
(C-7a), 134.4 (d, 2JC,F = 13.7 Hz, C-4¢¢), 134.6 (d, 3JC,F = 4.5 Hz, C-
3¢¢, C-5¢¢), 135.9 (C-1¢¢), 144.8 (C-4¢), 153.6 (C-5), 161.8 (C=O)
Synlett 2011, No. 12, 1697–1700 © Thieme Stuttgart · New York

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L. F. Tietze, K. Schmuck
LETTER
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R.; Bradtmöller, G.; Schirrmacher, E.; Thews, O.;
Synlett 2011, No. 12, 1697–1700 © Thieme Stuttgart · New York

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