Iridium-Catalyzed Radiosynthesis of Branched Allylic [18F]Fluorides

Article abstract of DOI:10.1021/acs.orglett.8b03496

The rapid and operationally simple radiosynthesis of branched allylic [¹⁸F]fluorides bearing a variety of functional groups, via iridium-catalyzed nucleophilic substitution reaction utilizing allylic trichloroacetimidates and [¹⁸F]KF

Full text of DOI:10.1021/acs.orglett.8b03496

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Iridium-Catalyzed Radiosynthesis of Branched Allylic [18F]Fluorides
Jason C. Mixdorf,∥,‡ Alexandre M. Sorlin,∥,‡ David W. Dick,*,§ and Hien M. Nguyen*,†
†Department of Chemistry, Wayne State University, Detroit, Michigan 48202, United States
‡Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, United States
§University of Iowa Hospitals and Clinics, University of Iowa, Iowa City, Iowa 52242, United States
S
* Supporting Information
ABSTRACT: The rapid and operationally simple radiosynthesis
of branched allylic [18F]fluorides bearing a variety of functional
groups, via iridium-catalyzed nucleophilic substitution reaction
utilizing allylic trichloroacetimidates and [18F]KF·Kryptofix[2.2.2]
complex in 5−15 min at room temperature, is reported. The
versatility of the allyl functional group of the resulting radio-
fluorinated products offers the benefit of being subsequently
available for further functionalization.
ethods that enable the rapid and efficient introduction
of fluorine-18 into molecules are powerful applications
M
in positron emission tomography (PET). Radiotracer-based
imaging for qualitative and quantitative assessment of disease
state is one of the most rapidly growing areas of noninvasive
medical imaging.1−5 Presently, PET has been used in diagnosis
of various cancers, cardiovascular diseases, and early stage
neurological disorders.2−5 Measuring physiochemical and
biochemical processes with PET requires radiotracers labeled
with a positron-emitting radionuclide. Commonly used
radioisotopes are carbon-11 and fluorine-18.6 Although the
ubiquitous presence of carbon in many molecules makes
carbon-11 an attractive isotope, its 20 min half-life and
complicated radiometabolite analysis limits its clinical utility.6
Alternatively, fluorine-18 is an equally ideal isotope due to its
low positron emission energy, 110 min half-life, and its ability
to serve as an isostere for hydrogen or hydroxyl group.
Furthermore, a considerable portion of drugs in clinical and
preclinical trials contain a carbon−fluorine (C−F) bond,
making fluorine-18 an ideal choice for imaging applications.7
The use of transition metals and new [18F] reagents has
proven to be a powerful technique to expand the substrate
scope, including [18F]aryl,8−21 [18F]benzylic,22,23 and [18F]-
aliphatic fluorides.18−21,24,25 Despite these advances, allylic C-
[18F] bond formation via transition metal catalysis remains
challenging.26 This is likely because metals are known to insert
onto the allylic fluorides,27 a major concern in radio-
fluorination when metal content is in 100−1000-fold excess
over the allylic [18F]fluoride product. Not surprisingly, there
are only two reports on the synthesis of allylic [18F]fluorides
utilizing allylic carbonates as electrophilic partners under
palladium- and iridium-mediated fluorination (Figure 1a−
b).28,29 The scope of these two methods has only been
investigated with four allylic carbonates, demonstrating the
difficulty forming allylic [18F]fluorides.
Figure 1. Transition-metal-mediated allylic radiofluorination
identify suitable electrophilic partners to enable radiofluorina-
tion in high efficiency. An attractive option is to use a
trichloroacetimidate leaving group whose nitrogen function-
ality can be exploited as a directing group in transition-metal-
catalyzed allylic substitution.30 We discovered that combining
allylic trichloroacetimidates as electrophiles, Et3N·3HF as a
fluoride source, and iridium complexes led to the production of
the branched allylic fluorides in good yields and excellent
selectivity.31−33 We hypothesize that this method can be
adapted with the radioisotope fluorine-18. Herein, we report
an operationally simple, rapid, and stable procedure for the
synthesis of allylic [18F]fluorides (Figure 1c) in 5−15 min at
25 °C utilizing [IrMeO(COD)]2 as a catalyst. The significance
of this catalytic protocol allows rapid access to numerous allylic
[18F]fluorides bearing a variety of functional groups and
overcomes the limitations previously associated with the
radiosynthesis of this [18F]fluoride motif.
The broad success of the transition-metal-catalyzed for-
Received: November 1, 2018
mation of allylic [18F]fluorides has hinged on the ability to
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03496
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimized Reaction Conditions
b
entry
catalyst
catalyst loading (mol %)
solvent
temp (°C)
time (min)
RCC %
c
1
2
3
4
5
6
7
8
[IrCl(COD)]2
15
15
15
15
15
15
15
15
15
7.5
22.5
30
15
15
15
THF
THF
THF
THF
THF
CPME
MTBE
CH3CN
THF
THF
THF
THF
THF
THF
THF
25
25
25
25
25
25
25
25
25
25
25
25
25
25
40
10
5
5
5
5
5
5
5
5
5
5
5
15
25
5
5−12
0
c
[RhCl(COD)]2
[RhCl(NBD)]2
[IrMeO(COD)]2
None
d
2.5 0.5
d
33
1
c
0
d
d
[IrMeO(COD)]2
[IrMeO(COD)]2
[IrMeO(COD)]2
[IrMeO(COD)]2
[IrMeO(COD)]2
[IrMeO(COD)]2
[IrMeO(COD)]2
[IrMeO(COD)]2
[IrMeO(COD)]2
[IrMeO(COD)]2
26
29
<5
33
25
45
11
49
47
13
6
5
d
d
d
d
d
d
d
d
9
1
5
1
2
5
3
1
10
11
12
13
14
15
a
b
c
d
The catalyst was weighed in glovebox and handled thereafter open to air. Determined using radio-TLC. Average RCC (n = 3). Average RCC
(n = 5).
In our reaction development, [18F]KF·Kryptofix (1, Table 1)
Next, the optimized radiofluorination conditions were
applied to a series of allylic substrates (Scheme 1). This
protocol is compatible with a number of functional groups
affording allylic [18F]fluorides in moderate to high RCC. For
β-oxygen substituents, allylic [18F]4 was obtained in moderate
RCC and its azide functionality can undergo “Cu-free”
cycloaddition with cyclooctynes.34,35 The aryl ether motifs (5
and 6) were formed efficiently. Notably, 6 is of significant
interest as it is embedded in long-lived prostaglandin
analogs.36,37 Interestingly, as the α-linear carbon chain is
extended, the product is formed in lower RCC (7 vs 9). In
contrast to the [19F]fluorination,32 both α-branching [18F]-
fluorides 10 and 11 are obtained in higher RCC than β-oxygen
and α-linear containing [18F]fluorides.
The radiofluorination system is also compatible with allylic
β-[18F]fluoroamines 12−19 (Scheme 1), which are valuable
building blocks for the construction of biologically active
targets.38,39 Currently, no practical and operationally simple
fluorination methods are available to prepare them.38,39 This
protocol allows for access to these [18F]fluoroamine motifs in
moderate to high RCC in 5 min, although higher RCC can be
observed at longer reaction time (15 min). For instance, a
variety of amine protecting groups, including phthalimide (12)
and tosyl protecting groups (13 and 14), are amenable under
radiofluorination conditions. Importantly, this catalytic radio-
fluorination system is also applicable to nitrogen-containing
heterocycles (15−19, Scheme 1) as their architectures are of
significant interest in medicinal and PET imaging chem-
istry.40,41 To our excitement, the current method is compatible
with pyrrole (15), indole (16), and carbazoles (17 and 18). In
particular, [18F]-dibromocarbazole 18 is of significant
importance as it is the key intermediate of a neuroprotective
agent, P7C3-A20, which is a potentially useful [18F]-labeled
probe for PET imaging.42,43
was chosen as the source of 18F− ion as it is the most
commonly used source of [18F]fluoride for clinical labeling.6,7
Accordingly, an excess of allylic trichloroacetimidate 2 was
added to the solution of 1 and [IrCl(COD)]2 in THF (entry
1). After 10 min at 25 °C, the radiochemical conversion
(RCC) of [18F]3 was 5−12% (n = 3).31 Although use of
camphorsulfonic acid (CSA) as an additive improved the RCC
of 3, this effect was highly variable (0−38%, n = 5). We
hypothesize that the lack of stirring of the reaction mixture and
choice of catalyst could be the causes of irreproducible RCC.
While the preliminary results validated the feasibility of the
approach, the modest conversion and variable results required
further investigation. A number of rhodium and iridium
catalysts that proved efficacious in the [19F] fluorination
reaction31 were screened in the absence of CSA. Importantly,
all reactions were agitated upon addition of fluoride-18 and
stirred constantly as the fluorination reaction was taking place.
While [RhCl(COD)]2 provided no trace of the desired allylic
[18F]3 (entry 2), utilization of [RhCl(NBD)]2 (entry 3)
afforded 3 in 2.5% RCC. In contrast, [IrMeO(COD)]2 (entry
4) afforded [18F]3 in 33% 1% (n = 5) RCC. In all cases, the
elimination byproduct was not observed in the reaction. A
control experiment without [IrMeO(COD)]2 provided no
detectable [18F]3 (entry 5). An evaluation of solvents
commonly used in radiochemistry and pharmaceuticals was
undertaken (entries 6−8). A number of reaction parameters
were further investigated to optimize the [IrMeO(COD)]2-
catalyzed radiofluorination, including: catalyst loading, temper-
ature, and reaction time (Table 1). Overall, optimal radio-
fluorination conditions were as follows: 15 mol % of
[IrMeO(COD)]2 to allylic trichloroacetimidate 2, 25 °C, and
15 min. Under these conditions, allylic [18F]3 was obtained in
49% 5% radiochemical conversion.
B
DOI: 10.1021/acs.orglett.8b03496
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Organic Letters
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a
Three allylic [18F] products 3, 16, and 20 (Figure 2) were
manually isolated to determine their radiochemical yield
Scheme 1. Substrate Scope
Figure 2. Isolation of allylic [18F]fluorides
(RCY) and molar activity (MA).46−48 In each case, low levels
of activity (3−8 mCi of fluoride-18) were employed for the
determination of molar activity and radiochemical yield. Allylic
fluoride [18F]3 was isolated in 31% RCY. We postulate that a
low molar activity (21 5 Ci/mmol) observed for 3 is a result
of incomplete hydrolysis of the starting material 2 to the
corresponding allylic alcohol upon purification, leading to
coelution as the retention time of the allylic alcohol is less than
1 min from that of the radiolabeled fluoride 3 (see SI). Further,
determining molar activity has been noted to be difficult with
this structural fluoride motif.29 On the other hand, allylic β-
[18F]fluoroamine 16 was isolated in good RCY (37 3%, n =
3) and moderate MA (368 101 Ci/mmol, n = 3). To our
excitement, the challenging estrone-derived [18F]fluoride 20
was isolated with synthetically useful RCY (28%) and molar
activity (82 13 Ci/mmol). Overall, these results suggest the
potential clinical application of this radiofluorination protocol.
We anticipate that the molar activity could be increased
through use of larger quantities of activity of fluorine-18.
Direct labeling of peptides with [18F]fluoride is often
difficult. As a result, labeling of thiol-containing peptides is
often conducted by conjugation to the reactive aryl[18F]-
fluorine-containing maleimide reagents.49,50 These thiol-
reactive reagents have been prepared with difficulty (relatively
low to moderate 15−37% RCY and long synthesis time of
100−150 min).51−53 Therefore, the current limitation for the
use of radiolabeled thiol-reactive reagents is in their
preparation, not in peptide conjugation. The development of
new methods for a practical and efficient synthesis of [18F]-
containing prosthetic groups is therefore desired. The allylic
[18F]fluorides obtained by the iridium-catalyzed substitution of
allylic trichloroacetimidates, developed in this study, provides
an opportunity for expanding the radiochemical space of [18F]
labeled compounds.
To demonstrate this point, we investigated the site-specific
modification by addition of N-Boc-L-cysteine methyl ester 21
to our model allylic [18F]fluoride substrate 3 via radical thiol−
ene “click” chemistry under iridium photocatalysis conditions
(Scheme 2).54−57 The desired product 22 was obtained in
good RCC. Illustrating the utility of this site-specific
modification for clinical application, the resulting [18F]22
was next isolated. Its synthesis lasted approximately 70 min
from the end of bombardment (generating fluoride-18) to
isolation from the semiprep radio-HPLC. Although the
nondecay corrected RCY of 22 over two steps is modest (4
1%, n = 3), to our knowledge this transformation has never
been carried out on any allylic [18F]fluorides due to the paucity
of current methods for their radiosynthesis. This preliminary
result is of significance given the interest in the development of
rapid and efficient protocols for [18F]-labeling of biologically
relevant peptides. Importantly, a broad range of allylic
[18F]fluorides, generated from this study, could be potentially
a
[IrMeO(COD)]2 was weighed in glovebox and handled open to air.
b
c
d
Determined using radio-TLC. Reaction time: 15 min. Reaction
time: 5 min.
Another objective is to increase the synthetic utility of this
transformation in complex molecule settings. As such, we
explored the utility of our radiofluorination method with a
proline-containing substrate bearing an α-stereocenter
(Scheme 1), and allylic [18F]19 was obtained in 45
4%
RCC (n = 5). Encouraged by this result, we extended the
radiofluorination conditions to estrone-derived substrate
bearing multiple stereocenters to produce allylic [18F]20 in
good RCC (51
2%, n = 5). Compound 20 could be of
significant interest, given the importance of estrone analogues
for use as estrogen receptor PET radiotracers.44,45 The
diastereoselectivity of the desired [18F]fluorides 19 and 20
was not analyzed due to difficulty of separating the two
diastereomers by radio-HPLC in a time frame that would allow
for radio-characterization.
Having established a diverse range of substrates suitable for
radiofluorination, we next sought to the determine nondecay
corrected radiochemical yield of several radiolabeled allylic
compounds to illustrate the potential clinical application.
C
DOI: 10.1021/acs.orglett.8b03496
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Organic Letters
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Scheme 2. Thiol−Ene Click Chemistry
Hien M. Nguyen: 0000-0002-7626-8439
Author Contributions
∥J.C.M. and A.M.S contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from Wayne State University is gratefully
acknowledged. J.C.M. thanks the Nuclear Regulatory Com-
mission Program (NRC-HQ-84-14-G-0037) from the Uni-
versity of Iowa for the graduate fellowship.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03496.
Experimental procedures, radio-HPLC, radio-TLC, and
complete characterization for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
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*E-mail: hien.nguyen@chem.wayne.edu.
*E-mail: david-dick@uiowa.edu.
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Alexandre M. Sorlin: 0000-0002-9589-6131
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