Fluorination of an arylboronic ester using [18F]selectfluor bis(triflate): Application to 6-[18F]fluoro-l-DOPA

Article abstract of DOI:10.1039/c2cc38646a

The Ag-mediated electrophilic [¹⁸F]fluorination of an arylboronic ester is reported. This new radiochemical transformation uses [ ¹⁸F]selectfluor bis(triflate) in acetone. The process gave 6-[ ¹⁸F]fluoro-l-DOPA with a RCY of 19 ± 12% and a specific activity of 2.6 ± 0.3 GBq μmol^-1.

Full text of DOI:10.1039/c2cc38646a

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[18F]Fluorination of an arylboronic ester using
[18F]selectfluor bis(triflate): application to
Cite this: Chem. Commun., 2013,
49, 1386
6-[18F]fluoro-L-DOPA†
Received 2nd December 2012,
Accepted 2nd January 2013
a
b
Ida S. R. Stenhagen,z Anna K. Kirjavainen,z Sarita J. Forsback,b
Charlotte G. Jørgensen,a Edward G. Robins,c Sajinder K. Luthra,c Olof Solinb and
DOI: 10.1039/c2cc38646a
a
´
Veronique Gouverneur*
www.rsc.org/chemcomm
The Ag-mediated electrophilic [18F]fluorination of an arylboronic a reagent for which appropriate taming may be necessary
ester is reported. This new radiochemical transformation uses for late stage fluorination. The well-documented value of N–F
[
18F]selectfluor bis(triflate) in acetone. The process gave 6-[18F]- reagents in fluorine chemistry encouraged us to use [18F]F2 to
fluoro-L-DOPA with a RCY of 19 ꢀ 12% and a specific activity of access [18F]N-fluorobenzenesulfonimide8 and [18F]selectfluor
2.6 ꢀ 0.3 GBq lmolꢁ1
.
bis(triflate),9 two reagents offering unique opportunities in
[18F]radiochemistry for the synthesis of [18F]arenes and more
Positron Emission Tomography (PET) is a diagnostic imaging generally electron rich substrates. In our initial report,9
modality used regularly to acquire essential clinical information.1 [18F]selectfluor bis(triflate) was successfully used for the silver(I)-
At the present time, the field relies on innovative radiochemistry mediated fluorination of model electron-rich arylstannanes.
to access high performance PET radiotracers that can advance Following these precedents, our next objective was to illustrate
medicine.2 The use of [18F]fluorodeoxyglucose (FDG) and other the value of [18F]selectfluor bis(triflate) with the preparation of
[18F]labeled radiotracers in oncology, brain diseases and cardio- 6-[18F]fluoro-L-DOPA.10 This important PET radiotracer tradi-
logy has established the value of 18F as a positron emitter tionally employed in studies of the dopaminergic system has
for PET and encouraged new developments for late stage found use in the diagnosis and post-treatment monitoring of
fluorination.3 PET radiotracers difficult to access directly with Parkinson’s disease.11 Its utility has expanded to oncology,
[18F]fluoride serve as a platform for reaction discovery with particularly in the study of neuroendocrine tumors12 and con-
much effort currently focused on the [18F]labeling of arenes not genital hyperinsulinism.13 To access 6-[18F]fluoro-L-DOPA, we
amenable to SNAr. More recently, transition metals have been opted to explore the [18F]fluorination of a novel arylboronic
exploited for the [18F]fluorination of allyl4 and aryl5 motifs ester with [18F]selectfluor bis(triflate), along with a comparative
using various [18F]fluoride sources; for arenes, this radio- study investigating the reactivity of commonly used arylstannane
chemistry requires the preparation of discrete organometallic precursors. To the best of our knowledge, there is no literature
Pd(II)–aryl5a or Ni(II)–aryl5b complexes prepared from aryl- precedent on the direct [18F]fluorination of arylboronic acid
boronic acids or aryl bromides respectively. A metal free derivatives using either [18F]F2 or any other electrophilic
approach was also developed featuring a reactivity switch of [18F]labeled reagents (Fig. 1).14
electron rich aromatics from nucleophilic to electrophilic enti-
ties in the presence of an external oxidant.6
Prior to undertaking the labeling work, we interrogated the
reactivity of three 6-fluoro-L-DOPA precursors towards 1-chloro-
The most logical approach for the labeling of electron rich methyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]-octanebis(tetra-fluoro-
substrates remains the direct electrophilic fluorination of pre- borate) (selectfluor). We selected the arylstannanes (S)-1a and
cursors that are ideally either commercially available or easily (S)-1b as well as the novel arylboronic ester (S)-2a (Table 1). As
accessible. This approach requires the production of [18F]F2,7 anticipated, the protected N-Boc arylstannane precursor (S)-1a
underwent fluorination using 1.2 equivalents (equiv.) of select-
a Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford,
OX1 3TA, UK. E-mail: veronique.gouverneur@chem.ox.ac.uk;
Fax: +44 (0)1865 285002; Tel: +44 (0)1865 276544
fluor and 2 equiv. of AgOTf in acetonitrile at room temperature
(entry 1). The reaction, which can also be performed success-
fully in acetone (entry 2), produced the desired fluorinated
product (S)-3a and the side-product (S)-4a resulting from com-
petitive protodestannylation with an overall yield of B65%. The
addition of NaHCO3 or the addition of molecular sieves (3 Å)
did not encourage fluorination over protonation (entries 3 and 4).
b Turku PET Centre, Radiopharmaceutical Chemistry Laboratory,
Kiinamyllynkatu 4-8, FIN-20520 Turku, Finland
c The Grove Centre, White Lion Road, Amersham, HP7 9LL, UK
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c2cc38646a
‡ The authors contributed equally to this work.
c
1386 Chem. Commun., 2013, 49, 1386--1388
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was less pronounced for the arylboronic ester (S)-2a than for
the arylstannanes (S)-1a and (S)-1b. Using selectfluor, (S)-2a
delivered the protected 6-fluoro-L-DOPA derivative (S)-6a and
the side-product (S)-7a (ratio 5 : 1) in 35% overall yield (entry 7).
The counter-ion of selectfluor influenced the efficiency of this
process. The yield of the reaction was improved to 50% and the
formation of (S)-7a (ratio (S)-6a : (S)-7a = B10 : 1) minimized
using triflate instead of tetra-fluoroborate (entry 8). Based on
these observations, selectfluor bis(triflate) was chosen as most
suitable for [18F]radiolabeling.
A solution of [18F]selectfluor bis(triflate) [18F]9 in acetone-d6
was therefore preferentially required for the radiosynthesis of
[18F]6-fluoro-L-DOPA. The protocol applied for the preparation
of [18F]9 was similar to that reported in the literature except for
the solvent since the original protocol used acetonitrile. [18F]9
was prepared from high specific [18F]F2 generated following the
post-target synthesis described by Bergman and Solin.7b The
[18F]F2 gas was bubbled into a vial containing a mixture
of 1-chloromethyl-4-aza-1-azoniabicyclo[2.2.2]octane triflate 8
(2.0 or 7.5 mmol) and lithium triflate (1 equiv.) in dry acetone-d6
(0.75 mL) at ꢁ10 1C for approximately 30 seconds. [18F]selectfluor
bis(triflate) [18F]9 formed instantaneously. The activity of the
crude stock solution in acetone-d6 ranged from 5 to 10 GBq,
depending on the cyclotron irradiation time. Aliquots (0.2 mL)
of this crude stock solution were used directly in subsequent
reactions. [18F]selectfluor bis(triflate) was therefore prepared in
acetone as efficiently as in acetonitrile. This could be advanta-
geous for some applications as acetone is more volatile and has
a different solubilisation profile (Scheme 1).
Fig. 1 Reactivity of arylboronic esters with [18F]selectfluor.
Table 1 Fluorination of (S)-1 and (S)-2 with selectfluor
Entry
Precursor
Cond.a
Solvent
Ratiof
Yieldj (%)
1
2
3
4
5
6
7
8
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1b
(S)-1b
(S)-2a
(S)-2a
I
Acetonitrile
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
1 : 0.57g
1 : 0.23g
1 : 0.37g
1 : 0.40g
1 : 0.54h
1 : 0.41h
1 : 0.23i
1 : 0.09i
69
67
66
56
65
59
35
50
I
Ib
Ic
I
The [18F]radiolabeling of the arylstannane precursor (S)-1b
was considered first (Scheme 2). A solution of [18F]9 in acetone-d6
(0.2 mL) was added to a reaction vial containing (S)-1b (10 mmol).
Silver(I) triflate (20 mmol) was added and the solution stirred at
room temperature for 20 minutes. The solvent was evaporated
under a stream of helium. The deprotection of (S)-3b was
carried out with 48% aqueous HBr (0.3 mL) at 130 1C for
5 minutes to release [18F]-6-fluoro-L-DOPA [18F](S)-10. The
identity of both [18F](S)-3b and [18F](S)-10 was confirmed by
HPLC analysis. Optimization studies revealed that there was
significant difference in the RCYs of the protected intermediate
[18F](S)-3b when using different amounts of precursor 8 in the
Id
II
IIe
a
I: selectfluor (1.2 equiv.), AgOTf (2.0 equiv.), RT, 30 min; II: (i) NaOH
(1.2 equiv.), MeOH (0.2 M), RT, 3 h, (ii) AgOTf (3.0 equiv.), 0 1C, 30 min,
(iii) selectfluor (1.05 equiv.), acetone, 3 Å molecular sieves, RT, 30 min.
b
c
d
3 Å molecular sieves. NaHCO3 (1.2 equiv.). Selectfluor bis(triflate)
e
(1.2 equiv.), NaHCO3 (1.2 equiv.), 60 1C. Selectfluor bis(triflate)
(1.2 equiv.). Ratio determined by 1H NMR. Ratio (S)-3a : (S)-4a.
f
g
h
i
j
Ratio (S)-3b : (S)-4b. Ratio (S)-6a : (S)-7a. Isolated yield of the mixture
of products.
Similar results were obtained using the N-formyl protected preparation of selectfluor bis(triflate) [18F]9. The average decay
precursors (S)-1b (entries 5 and 6). The fluorination of aryl- corrected radiochemical yield (RCY) of [18F](S)-10 was 12.1 ꢀ
boronic acids mediated by silver(I)triflate with selectfluor was 3.7% when using 2 mmol of 1-chloromethyl-4-aza-1-azonia-
reported by Ritter and co-workers in 2009.15 Based on this bicyclo[2.2.2]-octane triflate 8 in 0.75 mL acetone-d6 for the
precedent, the new N-Boc protected arylboronate esters (S)-2a
and (S)-2b were prepared by coupling the corresponding iodi-
nated aryl precursor with bis(neopentylglycolato)diboron under
Pd catalysis.16 Optimization studies in cold mode were carried
out on (S)-2a. The fluorination of (S)-2a proceeded in three
stages: (i) treatment with 1.2 equiv. of NaOH in MeOH (0.2 M),
(ii) transmetalation of the resulting boronic acid with 3.0 equiv.
of AgOTf, a process leading to the aryl Ag(I) complex (S)-5a, and
(iii) fluorination of (S)-5a with 1.05 equiv. of selectfluor after
solvent exchange from methanol to acetone. In addition to the
fluorinated product (S)-6a, undesired C–H bond formation
leading to (S)-7a was observed but this competing pathway Scheme 1 Synthesis of [18F]selectfluor bis(triflate) in acetone-d6.
c
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the arylstannane (S)-1b or the protected arylboronic ester
(S)-2b. These new developments suggest that fluorination using
unlabeled selectfluor could be favorably considered, after ade-
quate optimization, for the production of [18F]material.
We gratefully acknowledge the BBSRC and GE Healthcare
(ISRS), the Academy of Finland and the Finnish Centre of
Excellence in Molecular Imaging in Cardiovascular and Meta-
bolic Research (AK, SF), and the Lundbeck and Carlsberg
Foundations (CGJ) for generous funding.
Scheme 2 Synthesis of [18F]-6-fluoro-L-DOPA from (S)-1b.
Notes and references
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Scheme 3 Synthesis of [18F]-6-fluoro-L-DOPA from (S)-2b.
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Fig. 2 Statistical analysis of the RCYs of [18F]10 from (S)-1b or (S)-2b.
preparation of selectfluor bis(triflate) [18F]9. When 7.5 mmol of
precursor 8 was used to access [18F]9, the RCY was significantly
lower (6.8 ꢀ 1.8%). The specific activity (SA) of the final product
was consistently in the range of 3.4 ꢀ 0.1 GBq mmolꢁ1
.
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the arylboronic ester (S)-2b was performed prior to [18F]labeling.
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the corresponding aryl Ag(I) complex (S)-5b prior to [18F]fluorina-
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¨
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from (S)-1b did not differ significantly from the yield obtained
when using (S)-2b (Fig. 2).
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In conclusion, we have extended the scope of [18F]selectfluor
bis(triflate) for [18F]radiochemistry. The demonstration that
the arylboronic ester (S)-2b is a competent substrate for
[18F]fluorination suggests that a plethora of arylboronic acid
derivatives can be radiolabeled using this new protocol. This
study demonstrates that [18F]selectfluor bis(triflate) is a suitable
15 T. Furuya and T. Ritter, Org. Lett., 2009, 11, 2860–2863.
alternative to [18F]F2 to access [18F]6-fluoro-L-DOPA from either 16 For details, see the ESI†.
c
This journal is The Royal Society of Chemistry 2013
1388 Chem. Commun., 2013, 49, 1386--1388