The design and synthesis of highly branched and spherically symmetric fluorinated macrocyclic chelators

Article abstract of DOI:10.1055/s-2007-1000857

Two novel, highly fluorinated macrocyclic chelators with highly branched and spherically symmetric fluorocarbon moieties have been designed and efficiently synthesized. This is achieved by conjugating a spherically symmetric fluorocarbon moiety to the mac

Full text of DOI:10.1055/s-2007-1000857

PAPER
215
The Design and Synthesis of Highly Branched and Spherically Symmetric
Fluorinated Macrocyclic Chelators
S
ynthesis of Flu
h
orinate
d
Ma
o
crocyclic Ch
n
elators g-Xing Jiang,b Y. Bruce Yu*a,b
a
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, USA
Fax +1(410)7065017; E-mail: byu@rx.umaryland.edu
b
Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, Salt Lake City, UT 84112, USA
Received 10 July 2007; revised 24 September 2007
conjugated to a fluorocarbon moiety so that it can be in-
corporated into the outer shell of a fluorocarbon nanopar-
ticle. Note that a fluorinated chelator is an F-amphile as
the fluorocarbon moiety is hydrophobic while the chelator
Abstract: Two novel, highly fluorinated macrocyclic chelators
with highly branched and spherically symmetric fluorocarbon moi-
eties have been designed and efficiently synthesized. This is
achieved by conjugating a spherically symmetric fluorocarbon moi-
ety to the macrocyclic chelator DOTA, with or without a flexible is hydrophilic.
oligo-oxyethylene linker between these two parts. As a result of the
We chose the macrocyclic chelator DOTA (1,4,7,10-tet-
spherical symmetry, all 27 fluorine atoms in each fluorinated chela-
tor give a sharp singlet 19F NMR signal. The hydrophilicity and the
19F relaxation behavior of fluorinated chelators can be modulated by
the insertion of a flexible linker between the fluorocarbon moiety
and the macrocyclic linker. These chelators serve as prototypes for
1H-19F dual nuclei magnetic resonance imaging agents.
raazacyclododecane-1,4,7,10-tetraacetate) and its deriva-
tive for our application because DOTA forms very stable
complexes with metallic ions,3 which is essential for
radionuclide therapy. DOTA and its derivative are already
in clinical use as MR imaging contrast agents (Dotarem®
and ProHance®). DOTA is also the chelator used in the
radiotherapeutic drug candidate (OctreoTher®), which is
under clinical trial.4 Hence, DOTA has a proven record in
radionuclide therapy and MR imaging.
Key words: fluorinated macrocyclic chelator, fluorinated amphile,
19F NMR, spherical symmetry, DOTA
We are interested in using fluorocarbon liquid nanoparti-
cles, formulated as microemulsions, as multifunctional
drug delivery vehicles for 19F MR image-guided targeted
drug therapy, particularly for radionuclide therapy.1 In our
first paper of this series, the synthesis of prototypical fluo-
rinated oils (F-oils) and fluorinated amphiles (F-am-
philes) was described.2 F-oils and F-amphiles (serving as
emulsifiers) will constitute the inner core and the outer
shell of the fluorocarbon nanoparticles, respectively. To
facilitate 19F MR imaging, the fluorocarbon moiety, con-
taining three perfluoro-tert-butyl groups centered around
a pentaerythritol hub, is designed to be highly branched
and spherically symmetric so that all fluorine atoms will
give a sharp singlet 19F signal. To enable the nanoparticles
with 1H-19F dual nuclei MR imaging capacity, some high-
ly fluorinated chelators are needed. Detailed discussions
of the design principles of the nanoparticle (e.g., rationale
for 1H-19F dual nuclei MR imaging) and that of F-oils and
F-amphiles (e.g., the rationale for size and shape match-
ing and branching) can be found in references 1 and 2, re-
spectively.
In its simplest form, DOTA is conjugated directly to the
fluorocarbon moiety, forming the chelator F-DOTA 1, as
shown in Figure 1. However, it might be necessary to in-
sert a flexible hydrophilic linker between the macrocyclic
chelator and the fluorocarbon moiety to increase amphi-
pathicity and to alleviate potential steric hindrance to che-
lation caused by the bulky fluorocarbon moiety. An
obvious choice for the flexible linker is oligo-oxyethyl-
ene, as oxyethylene is hydrophilic and biocompatible.
One such chelator with a tetra-oxyethylene linker (F-
DOTA 2) is presented in Figure 1. The fluorocarbon moi-
eties of both molecules have spherical symmetry.
OC(CF3)3
HO2C
OC(CF3)3
N
N
N
N
OC(CF3)3
HO2C
CO2H
F-DOTA 1
OC(CF3)3
OC(CF3)3
HO2C
HO2C
In this paper, the syntheses of two highly fluorinated mac-
rocyclic chelators are described. For targeted radionuclide
therapy, a macrocylic chelator serves two functions: car-
rying metallic radionuclides (e.g., 90Y3+) for radiotherapy
and carrying Gd3+ for contrast-enhanced 1H MR imaging
(See Figure 1 of reference 1). The macrocyclic chelator is
O
N
N
N
N
4
OC(CF3)3
CO2H
F-DOTA 2
Figure 1 Structures of target molecules F-DOTA 1 and F-DOTA 2.
The fluorocarbon moiety of both 1 and 2 has spherical symmetry.
SYNTHESIS 2008, No. 2, pp 0215–0220
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x
.
x
x
.2
0
0
7
Advanced online publication: 18.12.2007
DOI: 10.1055/s-2007-1000857; Art ID: M05207SS
© Georg Thieme Verlag Stuttgart · New York

216
Z.-X. Jiang, Y. B. Yu
PAPER
The purpose of this synthesis paper is to establish the fea-
sibility of conjugating a bulky fluorocarbon moiety to the
macrocyclic DOTA and the feasibility of inserting an oli-
go-oxyethylene linker between the fluorocarbon moiety
and DOTA. Detailed investigation of metal ion chelation
and MR imaging capacity will be conducted in the future.
Tf2O, py,
THF, r.t.
(F3C)3CO
(F3C)3CO
OC(CF3)3
OH
(F3C)3CO
(F3C)3CO
OC(CF3)3
OTf
96%
3
4
OC(CF3)3
OC(CF3)3
cyclen,
THF–CH2Cl2,
45 °C
BrCH2CO2Et, K2CO3,
THF–DMF, 60 °C
The synthesis of F-DOTA 1 is depicted in Scheme 1. By
employing the method described in our previous paper,2
the highly fluorinated alcohol 3 was prepared on a 50-
gram scale that will be used as the common starting mate-
rial for both F-DOTA 1 and F-DOTA 2 synthesis. Treat-
NH
N
OC(CF3)3
92%
88%
5
NH HN
ment of alcohol
3
with trifluoromethanesulfonic
OC(CF3)3
OC(CF3)3
LiOH,
H2O–MeOH, r.t.
EtO2C
N
anhydride in the presence of pyridine gave triflate 4 in ex-
cellent yield, which was isolated through phase separation
after the addition of 10% water to the reaction mixture. It
is noteworthy that tetrahydrofuran, instead of the com-
monly used dichloromethane for such esterification,
turned out to be the ideal solvent for this reaction because
alcohol 3 has very limited solubility in dichloromethane.
It is necessary to use an excess of trifluoromethanesulfon-
ic anhydride and pyridine to achieve high conversion of
the well-buried highly fluorinated alcohol 3 to triflate 4.
Triflate 4 was then conjugated to the cyclen ring after re-
acting with 2 equivalents of cyclen in a mixture of tetrahy-
drofuran and dichloromethane (1:1) at 45 °C overnight.
The product 5 was extracted with FC-72 (perfluorohex-
anes) from the dried reaction residue (dissolved in dichlo-
romethane) in 88% yield. Again, the choice of solvent is
crucial for the conjugation. Instead of reacting with dis-
solved cyclen, triflate 4 decomposed slowly, when dichlo-
romethane or chloroform alone was used as the solvent,
because it is not stable at ambient temperature and has low
solubility in dichloromethane or chloroform. The reaction
of compound 5 with ethyl bromoacetate in the presence of
potassium carbonate in a mixture of tetrahydrofuran–di-
methylformamide (1:1) at 60 °C provided ester 6 in an ex-
cellent yield after flash chromatography purification on
neutral aluminum oxide. Finally, hydrolysis of the three
ethyl esters in 6 with lithium hydroxide in water and meth-
anol afforded the target molecular F-DOTA 1 in 97%
yield.
N
F-DOTA 1
OC(CF3)3
97%
6
N
N
EtO2C
CO2Et
Scheme 1 Synthesis of F-DOTA 1
NaH, BnBr
THF, r.t.
BnO(CH2CH2O)4H
HO(CH2CH2O)4H
90%
7
8
MsCl, Et3N,
CH2Cl2, 0 °C
BnO(CH2CH2O)4Ms
98%
9
Scheme 2 Preparation of mesylate 9
With 9 in hand, the synthesis of F-DOTA 2 proceeded as
follows (Scheme 3). The highly fluorinated alcohol 3 was
first attached to the hydrophilic tetra-oxyethylene linker 9
to afford compound 10 in good yield. Then, removal of
the benzyl group in compound 10 by palladium hydroxide
catalyzed hydrogenolysis gave alcohol 11 in an excellent
yield, which was then treated with methanesulfonyl chlo-
ride and triethylamine to give the mesylate 12 in quantita-
tive yield. Attaching cyclen to the fluorocarbon moiety
was achieved by treating compound 12 with 2 equivalents
of cyclen. However, the resulting cyclen derivative 13 can
hardly be isolated from the reaction mixture by flash chro-
matography. Fortunately, solid-phase extraction of the re-
action mixture on fluorinated silica gel6 provided amine
13 in 93% yield. Compound 13 was then reacted with eth-
yl bromoacetate to afford ester 14 in good yield. Finally,
treatment of compound 14 with lithium hydroxide gave
the target molecule F-DOTA 2 in 99% yield.
With F-DOTA 1 and F-DOTA 2 in hand, the 19F NMR
spectrum of each chelator was then acquired. As designed,
both F-DOTA 1 and F-DOTA 2 gave only one sharp sin-
glet 19F NMR signal with a peak width of around 0.02
ppm (Figure 2). These highly fluorinated chelators are
ideal for19F MR imaging applications because a sharp sin-
glet 19F NMR signal can not only eliminate chemical shift
artifacts but also get rid of the signal intensity modulation
caused by J-coupling from adjacent 19F or 1H atoms.7
Before starting the synthesis of the target molecule F-
DOTA 2, the tetra-oxyethylene linker 9 between the fluo-
rocarbon moiety and the DOTA moiety was synthesized
in good yield on a 50-gram scale from the commercially
available tetraethylene glycol 7 by selectively protecting
one of the hydroxyl groups with benzyl bromide5 and
transforming the other hydroxyl group into mesylate
(Scheme 2). It is an improvement over our former
synthesis2a by changing the protective group for the hy-
droxyl group in tetraethylene glycol 7 from the tert-bu-
tyldimethylsilyl (TBDMS) group to the benzyl (Bn)
group, because the mesylate 9 can be prepared on a larger
scale and in a much simpler and cheaper way. This also re-
duces side reaction (when coupling 9 with alcohol 3 in
Scheme 3) and simplifies the purification process (when
deprotecting 10 in Scheme 3) for subsequent steps.
The flexible oligo-oxyethylene linker is the variable por-
tion of our chelator design. Hence, its impact on the phys-
Synthesis 2008, No. 2, 215–220 © Thieme Stuttgart · New York

PAPER
Synthesis of Fluorinated Macrocyclic Chelators
217
KH, THF,
(F3C)3CO
(F3C)3CO
OC(CF3)3
OH
(F3C)3CO
(F3C)3CO
OC(CF3)3
r.t., then 9
80%
(OCH2CH2)4OBn
3
10
H2, Pd(OH)2,
MeOH, r.t.
(F3C)3CO
(F3C)3CO
OC(CF3)3
MsCl, Et3N, CH2Cl2, r.t.
99%
97%
(OCH2CH2)4OH
11
(F3C)3CO
(F3C)3CO
OC(CF3)3
(OCH2CH2)4OMs
cyclen, DMF, 60 °C
93%
12
OC(CF3)3
OC(CF3)3
K2CO3, BrCH2CO2Et,
DMF–THF (1:1), 60 °C
O
NH
N
4
OC(CF3)3
82%
13
NH HN
OC(CF3)3
LiOH,
EtO2C
OC(CF3)3 H2O–MeOH,
r.t.
O
N
N
N
4
F-DOTA 2
OC(CF3)3
99%
N
EtO2C
CO2Et
14
Scheme 3 Synthesis of F-DOTA 2
T1- or T2- weighted. The impact of the tetra-oxyethylene
linker on 19F relaxation behavior was evaluated by NMR
spectroscopy (376 MHz). F-DOTA 1 and F-DOTA 2 in
methanol-d4 at a concentration of 0.025 M gave the fol-
lowing T1 and T2 values: F-DOTA 1, T1 = 708 ms,
T2 = 424 ms; F-DOTA 2, T1 = 1067 ms, T2 = 824 ms (As
a reference point, the trifluoromethyl group of perfluo-
rooctyl bromide, a fluorocarbon compound previously
used in 19F MRI, has a T1 of 2881 ms and a T2 of 2184 ms
in methanol-d4 under the same condition.10). This demon-
strates clearly that, in addition to modulating hydrophilic-
ity, the oligo-oxyethylene linker can also modulate T1 and
T2 of fluorinated chelators.
Figure 2 19F NMR spectra of F-DOTA 1 and F-DOTA 2 (0.025 M
in CD3OD, 376 MHz)
In short, both the hydrophilicity and the 19F relaxation be-
havior of fluorinated chelators can be modulated by the
addition of the flexible linker. Hence, one way to improve
the physicochemical properties of future generation of
fluorinated chelators for MR imaging applications is to
engineer the flexible linker to achieve desired aqueous
solubility and 19F relaxation profile.
icochemical properties of fluorinated chelators is
assessed. The impact of the tetra-oxyethylene linker on
the hydrophilicity of the chelator was evaluated by com-
paring the 1-octanol/water partition coefficients (Poct) of
F-DOTA 1 and F-DOTA 2. Poct is a standard physico-
chemical parameter in assessing the hydrophilicity of
pharmaceuticals.8 Poct of F-DOTA 1 and F-DOTA 2 was
determined by 19F NMR spectroscopy.9 Poct of F-DOTA 1
and F-DOTA 2 are 7.63 and 1.40 × 10–2, respectively.
Hence, the tetra-oxyethylene linker significantly in-
creased the hydrophilicity of the fluorinated chelator.
1H NMR spectra were recorded with trimethylsilane as internal ref-
erence and 19F NMR spectra were recorded with hexafluorobenzene
as internal reference on a Varian 400 spectrometer. Measurements
of pH in mobile phases for high performance liquid chromatogra-
phy (HPLC) were taken after pH calibration with aqueous standard
solutions. Molecular mass was obtained using a Voyager-DE MAL-
DI-TOF mass spectrometer.
The NMR signal relaxation times, T1 and T2 are important
parameters for MR imaging, because MRI contrasts are
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218
Z.-X. Jiang, Y. B. Yu
PAPER
Triflate 4
1H NMR (400 MHz, CD3OD): d = 4.20 (s, 6 H), 3.59 (s, 2 H), 3.41
To a stirred solution of alcohol 3 (7.9 g, 10.0 mmol) and pyridine
(8.2 mL, 7.9 g, 100.0 mmol) in THF (250 mL) was added dropwise
a solution of trifluoromethanesulfonic anhydride (8.2 mL, 14.1 g,
50.0 mmol) in THF (20 mL) at 0 °C. After stirring at this tempera-
ture for 1 h, the reaction was quenched by the slow addition of H2O
(27 mL). The mixture was then transferred to a separatory funnel
and the lower phase was collected. Washing the oil with CH2Cl2 (10
mL) gave the pure triflate 4 as a clear oil; yield: 8.8 g (96%). This
compound is unstable at r.t. and needs to be used immediately after
preparation.
(s, 3 H), 3.22 (br, 4 H), 3.06 (br, 4 H), 2.98 (s, 8 H), 2.80 (br, 3 H).
13C NMR (100.7 MHz, CD3OD): d = 180.1, 177.4, 121.6 (q,
J = 292.5 Hz), 81.0 (m), 69.9, 58.5, 56.8, 52.2, 51.9, 48.9, 45.9,
45.7, 22.2.
19F NMR (376 MHz, CD3OD): d = –70.93 (s).
MS (MALDI-TOF): m/z = 1119 ([M + H]+, 100).
HRMS (CI): m/z calcd for C31H36F27N4O9: 1121.2051; found:
1121.2792.
1H NMR (400 MHz, acetone-d6): d = 4.82 (s, 2 H), 4.39 (s, 6 H).
19F NMR (376 MHz, acetone-d6): d = 71.21 (s, 27 F), 75.93 (s, 3 F).
Alcohol 8
To a stirred solution of tetraethylene glycol 7 (97.0 g, 500.0 mmol)
in THF (450 mL) at 0 °C was added NaH (60% in paraffin, 20.8 g,
520.0 mmol) slowly and the resulting mixture was stirred for 30 min
at r.t. Then benzyl bromide (51.2 g, 300.0 mmol) was added and the
resulting mixture was stirred overnight at r.t. After quenching the
reaction with H2O (200 mL), the mixture was extracted with EtOAc
(4 × 100 mL), and the combined organic phases were dried
(MgSO4). After concentration under vacuum, the residue was puri-
fied by flash chromatography on silica gel (n-hexane–EtOAc, 1:1)
to give the alcohol 8 as a clear oil; yield: 76.5 g (90%).
Amine 5
A suspension of triflate 4 (8.5 g, 9.3 mmol) and cyclen (3.3 g, 18.9
mmol) in a mixture of THF and CH2Cl2 (50 mL/50 mL) was stirred
at r.t. for 2 h. Then the temperature was slowly raised to 45 °C and
the mixture was then stirred overnight at this temperature. After
concentrating the reaction mixture to dryness under vacuum, the
residue was dissolved in CH2Cl2 (50 mL) and extracted with FC-72
(3 × 50 mL). Evaporation of the combined FC-72 phases gave the
product 5 as a clear oil; yield: 7.7 g (88%).
1H NMR (400 MHz, CDCl3): d = 4.19 (s, 6 H), 2.72–2.75 (m, 6 H),
2.58–2.60 (m, 4 H), 2.51–2.54 (m, 8 H).
13C NMR (100.7 MHz, CDCl3): d = 120.1 (q, J = 293.3 Hz), 79.1–
80.0 (m), 68.4, 54.4, 53.4, 46.9, 46.0, 45.7, 45.5.
1H NMR (400 MHz, CDCl3): d = 7.28–7.29 (m, 5 H), 4.51 (s, 2 H),
3.52–3.66 (m, 16 H).
Mesylate 9
To a stirred solution of alcohol 8 (69.3 g, 243.7 mmol) and Et3N
(49.2 g, 68.4 mL, 487.0 mmol) in CH2Cl2 (700 mL) at 0 °C was add-
ed MsCl (41.9 g, 28.3 mL, 365.6 mmol). The resulting mixture was
stirred overnight at r.t. and quenched with H2O (400 mL). The or-
ganic phase was collected and the aqueous phase was extracted with
EtOAc (3 × 200 mL). The combined organic phases were washed
with aq 2 N HCl (100 mL), brine (100 mL), and dried (MgSO4).
Concentration of the solution under vacuum gave the mesylate 9 as
a clear oil; yield: 86.6 g (98%).
19F NMR (376 MHz, CDCl3): d = –73.31 (s).
MS (CI): m/z = 945 ([M + H]+, 100).
HRMS (CI): m/z calcd for C25H28F27N4O3: 945.1730; found:
945.1717.
Triethyl Ester 6
Powdered K2CO3 (8.3 g, 60.2 mmol) and ethyl bromoacetate (4.2
mL, 6.3 g, 37.5 mmol) were added to a stirred solution of amine 5
(7.1 g, 7.5 mmol) in a mixture of THF and DMF (35 mL/35 mL) at
r.t. and the resulting suspension was stirred overnight at 60 °C. Af-
ter filtration, the solvent was removed under vacuum and the resi-
due was purified by flash chromatography on neutral aluminum
oxide (CH2Cl2–MeOH, 10:1) to give the product 6 as a clear oil;
yield: 6.3 g (92%).
1H NMR (400 MHz, CDCl3): d = 7.25–7.32 (m, 5 H), 4.54 (s, 2 H),
4.32–4.34 (m, 2 H), 3.71–3.73 (m, 2 H), 3.59–3.66 (m, 12 H), 3.03
(s, 3 H).
Compound 10
A solution of alcohol 3 (5.9 g, 7.5 mmol) in THF (50 mL) was
stirred at 0 °C and KH (25% in paraffin, 1.4 g, 8.5 mmol) was added
slowly to the solution. After the addition, the mixture was stirred for
an additional 10 min at 0 °C and mesylate 9 (4.2 g, 7.5 mmol) was
then added in one portion. The resulting mixture was stirred over-
night at r.t. and quenched with H2O (100 mL). The organic phase
was collected and the aqueous phase was extracted with EtOAc (3 ×
50 mL). The combined organic phases were washed with aq 2 N
HCl (100 mL) and brine (100 mL), and dried (MgSO4). Concentra-
tion under vacuum and flash chromatography on silica gel (n-hex-
ane–EtOAc, 10:1) gave the compound 10 as a clear oil; yield: 6.4 g
(80%).
1H NMR (400 MHz, CDCl3): d = 4.03–4.10 (m, 12 H), 3.34 (s, 2 H),
3.25 (s, 4 H), 2.62–2.76 (m, 18 H), 1.16–1.21 (m, 9 H).
13C NMR (100.7 MHz, CDCl3): d = 171.7, 171.4, 120.3 (q,
J = 293.3 Hz), 79.1–80.0 (m), 68.3, 60.2, 56.0, 54.9, 54.8, 54.0,
52.6, 52.2, 51.9, 46.7, 29.8, 14.3, 14.1.
19F NMR (376 MHz, CDCl3): d = –73.42 (s).
MS (MALDI-TOF): m/z = 1203 ([M + H]+, 100).
HRMS (MALDI-TOF): m/z calcd for C37H46F27N4O9: 1203.2834;
found: 1203.2883.
1H NMR (400 MHz, CDCl3): d = 7.26–7.33 (m, 5 H), 4.56 (s, 2 H),
4.07 (s, 6 H), 3.54–3.69 (m, 16 H), 3.45 (s, 2 H).
F-DOTA 1 = 2,2¢,2¢¢-[10-(3-[2,2,2-trifluoro-1,1-bis(trifluoro-
methyl)ethoxy]-2,2-bis{[2,2,2 trifluoro-1,1-bis(trifluorometh-
yl)ethoxy]methyl}propyl)-1,4,7,10-tetraazacyclododecane-
1,4,7-triyl]triacetic Acid
To a solution of LiOH (1.4 g, 60.0 mmol) in H2O (10 mL) was add-
ed a solution of ester 6 (6.0 g, 5.0 mmol) in MeOH (200 mL) at r.t.
The resulting mixture was stirred overnight at r.t. Then aq 2 N HCl
was added to the cloudy suspension to adjust the reaction mixture to
pH 1. The solid was collected through centrifugation and then
washed with H2O (5 mL) and Et2O (10 mL). Removal of solvent un-
der vacuum gave the product 1 as a white solid; yield: 5.4 g (97%).
13C NMR (100.7 MHz, CDCl3): d = 138.3, 128.3, 127.7, 127.5,
120.1 (q, J = 292.6 Hz), 78.9–79.8 (m), 73.2, 70.7, 70.65, 70.6,
70.56, 70.3, 69.4, 66.3, 65.5, 46.2.
19F NMR (376 MHz, CDCl3): d = –73.28 (s).
MS (MALDI-TOF): m/z = 1079 ([M + Na]+, 100).
HRMS (MALDI-TOF): m/z calcd for C32H31F27O8
+ Na:
1079.1458; found: 1079.1517.
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Synthesis of Fluorinated Macrocyclic Chelators
219
Alcohol 11
HRMS (MALDI-TOF): m/z calcd for C45H62F27N4O13: 1379.3882;
found: 1379.3902.
A suspension of compound 10 (6.0 g, 5.7 mmol) and Pd(OH)2
(10%, 1.2 g) in MeOH (80 mL) was stirred under H2 for 2 h. After
filtration, the mixture was concentrated under vacuum and purified
by flash chromatography on silica gel (n-hexane–EtOAc, 8:1) to
give the alcohol 11 as a clear oil; yield: 5.3 g (97%).
1H NMR (400 MHz, CDCl3): d = 3.99 (s, 6 H), 3.53–3.60 (m, 16
H), 3.39 (s, 2 H).
F-DOTA 2 = 2,2¢,2¢¢-{10-[18,18,18-trifluoro-14,14-bis{[(2,2,2-
trifluoro-1,1-bis(trifluoromethyl)ethoxy]methyl}-17,17-bis(tri-
fluoromethyl)-3,6,9,12,16-pentaoxaoctadec-1-yl]-1,4,7,10-tetra-
azacyclododecane-1,4,7-triyl}triacetic Acid
LiOH (0.9 g, 37.0 mmol) was added to a solution of compound 14
(5.1 g, 3.7 mmol) in MeOH (100 mL) and H2O (10 mL). The result-
ing mixture was stirred for 8 h at r.t. Then aq 1 N HCl was added to
adjust the solution to pH 1. After removing the solvent under vacu-
um, the residue was purified by flash column chromatography on
neutral aluminum oxide (CH2Cl2–MeOH, 10:1) to give the com-
pound 2 as a white solid; yield: 4.7 g (99%).
Mesylate 12
To a stirred solution of alcohol 11 (5.1 g, 5.3 mmol) and Et3N (3.2
g, 31.8 mmol) in CH2Cl2 (80 mL) at 0 °C was added MsCl (1.9 g,
15.9 mmol). The resulting mixture was stirred for 1 h at r.t. and
quenched with H2O (50 mL). The organic phase was collected and
the aqueous phase was extracted with EtOAc (3 × 30 mL). The com-
bined organic phases were dried (MgSO4). After concentration un-
der vacuum, the residue was purified by flash chromatography on
silica gel (n-hexane–EtOAc, 10:1) to give the mesylate 12 as a clear
oil; yield: 5.5 g (99%).
1H NMR (400 MHz, acetone-d6): d = 4.20 (s, 6 H), 3.53–3.59 (m,
16 H), 2.2–3.2 (m, 24 H).
13C NMR (100.7 MHz, CD3OD): d = 180.9, 179.6, 175.3, 175.1,
121.5 (q, J = 292.6 Hz), 80.5–81.4 (m), 71.9, 71.6, 71.5, 71.4, 71.3,
69.9, 68.8, 67.5, 67.1, 60.6, 59.2, 53.9, 52.4, 51.9, 47.4.
19F NMR (376 MHz, CD3OD): d = –71.15 (s).
MS (MALDI-TOF): m/z = 1295 ([M + H]+, 100).
1H NMR (400 MHz, CDCl3): d = 4.34–437 (m, 2 H), 4.04 (s, 6 H),
3.73–3.76 (m, 2 H), 3.53–3.67 (m, 12 H), 3.43 (s, 2 H), 3.04 (s, 3 H).
Amine 13
HRMS (MALDI-TOF): m/z calcd for C39H50F27N4O13: 1295.2943;
A suspension of mesylate 12 (5.3 g, 5.1 mmol) and cyclen (1.8 g,
10.2 mmol) in DMF (50 mL) was stirred overnight at 60 °C. After
concentrating the mixture to dryness under vacuum, the residue was
found: 1295.2953.
purified by solid-phase extraction on FluoroFlash® silica gel. After Acknowledgment
loading the sample to fluorous silica gel, it was washed first with
This research was supported by the National Institutes of Health un-
der grants EB002880 and EB004416. We wish to thank G. Mahika
Weerasekare for her kind help with NMR experiments.
MeOH–H2O (4:1, 200 mL) and then with MeOH (400 mL). The
product was obtained as a clear oil by concentrating the MeOH elu-
ent; yield: 5.2 g (93%).
1H NMR (400 MHz, CD3OD): d = 4.14 (s, 6 H), 3.57–3.69 (m, 14
H), 3.49 (s, 2 H), 2.95–3.04 (m, 7 H), 2.85–2.89 (m, 5 H), 2.76–2.82
(m, 2 H), 2.69 (s, 4 H).
13C NMR (100.7 MHz, CD3OD): d = 121.6 (q, J = 292.5 Hz), 80.5–
81.4 (m), 78.3, 72.0, 71.9, 71.73, 71.7, 71.67, 71.6, 71.56, 71.5,
71.4, 71.41, 71.4, 71.2, 69.6, 67.5, 67.2, 50.9, 46.4, 44.4.
19F NMR (376 MHz, CD3OD): d = –71.14 (s).
MS (MALDI-TOF): m/z = 1121 ([M + H]+, 100).
References
(1) Yu, Y. B. J. Drug Targeting 2006, 14, 663.
(2) (a) Jiang, Z.-X.; Yu, Y. B. Tetrahedron 2007, 63, 3982.
(b) Jiang, Z.-X.; Yu, Y. B. J. Org. Chem. 2007, 72, 1464.
(3) Bianchi, A.; Calabi, L.; Corana, F.; Fontana, S.; Losi, P.;
Maiocchi, A.; Paleari, L.; Valtancoli, B. Coord. Chem. Rev.
2000, 204, 309.
(4) (a) Otte, A.; Jermann, E.; Behe, M.; Goetze, M.; Buche, H.
C.; Roser, H. C.; Heppeler, A.; Mueller-Brand, J.; Maecke,
H. R. Eur. J. Nucl. Med. 1997, 24, 792. (b) Smith, M. C.;
Liu, J.; Chen, T.; Schran, H.; Yeh, C.-M.; Jamar, F.;
Valkema, R.; Bakker, W.; Kvols, L.; Krenning, E.; Pauwels,
S. Digestion 2000, 62 (Suppl 1), 69.
HRMS (MALDI-TOF): m/z calcd for C33H44F27N7O4: 1021.2779;
found: 1021.2790.
Triethyl Ester 14
To a stirred solution of amine 13 (5.1 g, 4.6 mmol) in THF (25 mL)
and DMF (25 mL) was added powdered anhyd K2CO3 (6.3 g, 46.0
mmol) and ethyl bromoacetate (2.6 mL, 3.8 g, 23.0 mmol). The re-
sulting mixture was stirred overnight at 60 °C. After filtration, the
solvent was removed under vacuum and the residue was purified by
flash chromatography on neutral aluminum oxide (CH2Cl2–
MeOH, 10:1) to give the product 14 as a clear oil; yield: 5.2 g
(82%).
1H NMR (400 MHz, CD3OD): d = 4.16–4.29 (m, 8 H), 4.14 (s, 6 H),
3.56–3.67 (m, 16 H), 3.48 (s, 4 H), 2.70–3.45 (m, 4 H), 2.41–2.76
(m, 14 H), 1.27–1.30 (m, 9 H).
(5) Grobelny, Z.; Stolarzewicz, A.; Czaja, M.; Demuth, W.;
Maercker, A. J. Org. Chem. 1999, 64, 8990.
(6) Gladysz, J. A.; Curran, D. P. Handbook of Fluorous
Chemistry; Wiley-VCH: Weinheim, 2003, ; and references
cited therein.
(7) (a) Kimura, A.; Narazaki, M.; Kanazawa, Y.; Fujiwara, H.
Magn. Reson. Imag. 2004, 22, 855. (b) Singh, M.; Waluch,
V. Adv. Drug Del. Rev. 2000, 41, 7.
(8) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J.
Adv. Drug Del. Rev. 1997, 23, 3.
(9) Since F-DOTA 1 and F-DOTA 2 each contains three
carboxylic groups, the protonation status of which is pH-
dependent, the 1-octanol/H2O partition measurements were
conducted with physiological saline buffer (PBS, 50 mM
phosphate, 100 mM NaCl, 1 mM EDTA, pH 7.0) as the
aqueous phase. Specifically, F-DOTA 1 or F-DOTA 2 (5
mg) was dissolved in mixture of PBS buffer (0.5 mL) and
1-octanol (0.5 mL). The sample was put into an Eppendorf®
13C NMR (100.7 MHz, CD3OD): d = 175.3, 175.1, 121.6 (q,
J = 292.6 Hz), 80.7–81.5 (m), 71.9, 71.5, 71.4, 71.3, 71.2, 70.8,
68.5, 67.4, 67.1, 62.3, 62.26, 56.4, 56.1, 53.6, 51.9, 51.1, 48.4, 47.4,
14.5, 14.3.
19F NMR (376 MHz, CD3OD): d = –71.12 (s).
MS (MALDI-TOF): m/z = 1379 ([M + H]+, 100).
Synthesis 2008, No. 2, 215–220 © Thieme Stuttgart · New York

220
Z.-X. Jiang, Y. B. Yu
PAPER
microcentrifuge tube (1.5 mL), which was then taped to a
type 16700 mixer from Thermolyne to be shaken vigorously
for 20 min. After phase separation, the aqueous phase and
1-octanol phases were taken out for 19F NMR, respectively,
with a sealed capillary of 1% hexafluorobenzene in MeOH-
d4 as the internal standard. Poct was calculated based on the
ratio of 19F NMR signal areas in the 1-octanol and H2O.
(10) T1 and T2 of of the trifluoromethyl group of perfluorooctyl
bromide were measured under the same condition as for F-
DOTA 1 and F-DOTA 2 by 19F NMR spectroscopy (376
MHz) in MeOH-d4 at a concentration of 0.025 M.
Synthesis 2008, No. 2, 215–220 © Thieme Stuttgart · New York