Electrostatic Effects Accelerate Decatungstate-Catalyzed C-H Fluorination Using [18F]- And [19F]NFSI in Small Molecules and Peptide Mimics

Article abstract of DOI:10.1021/acscatal.9b02220

The site-selective fluorination of unactivated C(sp³)-H bonds provides unique opportunities to rapidly alter drug properties or generate radiotracers for positron emission tomography (PET) imaging. Toward this goal, photoactivated decatungstate

Full text of DOI:10.1021/acscatal.9b02220

Research Article
Cite This: ACS Catal. 2019, 9, 8276−8284
pubs.acs.org/acscatalysis
Electrostatic Effects Accelerate Decatungstate-Catalyzed C−H
18
19
Fluorination Using [ F]- and [ F]NFSI in Small Molecules and
Peptide Mimics
Zheliang Yuan,†,‡ Hua Yang,‡ Noeen Malik, Milena Colovic,
David S. Weber, Darryl Wilson,
‡
⊥
†
†
,†
̌
́
⊥
§
†
‡
Franc o̧ is Benard, Rainer E. Martin, Jeffrey J. Warren, Paul Schaffer, and Robert Britton*
́
†
‡
§
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S2, Canada
Life Sciences Division, TRIUMF, Vancouver, British Columbia V6T 2A3, Canada
Medicinal Chemistry, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La
Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland
⊥
Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada
S Supporting Information
*
ABSTRACT: The site-selective fluorination of unactivated
3
C(sp )-H bonds provides unique opportunities to rapidly alter
drug properties or generate radiotracers for positron emission
tomography (PET) imaging. Toward this goal, photoactivated
decatungstate (DT) is capable of generating carbon radicals
through hydrogen atom transfer that subsequently undergo
fluorination by reaction with N-fluorobenzenesulfonimide
1
8
3
(
NFSI) or [ F]NFSI. This process enables C(sp )-H
fluorination of a wide range of aliphatic compounds, though
reaction rates can be highly variable and limit applications in
radiotracer synthesis. Here, we demonstrate that cationic
ammonium functions in aliphatic molecules promote formation
of a precursor complex with DT that significantly increases the rate of C−H abstraction. The general utility of this rate-
accelerating electrostatic effect is demonstrated on more than 30 ammonium-containing molecules, including amino acids,
1
8
18
heterocycles, and pseudopeptides. Moreover, this effect is highlighted in the rapid production of [ F]Glu-U-FHLeu, a F-
labeled prostate specific membrane antigen (PSMA)-binding ligand.
KEYWORDS: fluorination, decatungstate, photocatalysis, electrostatic effect, PSMA
INTRODUCTION
useful C−C, C−Si, and C−N bond-forming reactions. In
10a 10b,c
■
3
addition, Noel
̈
and Orfanopolous
have studied alkane
Site-selective functionalization of unactivated C(sp )−H bonds
and alcohol oxidation by photoactivated DT. Recently, a report
from Merck highlighted the utility of this catalyst for oxidation
has become an increasingly common tactic in organic
1
synthesis and provides unique opportunities in medicinal
11
of C−H bonds in aliphatic amines, MacMillan reported the
chemistry to rapidly carry out structure−function relationship
studies without complicated resynthesis efforts. Among the
many C−H functionalization strategies, hydrogen atom
transfer (HAT) processes involving photoactivated catalysts
can provide excellent selectivity based on a combination of
substrate and catalyst bias. In this regard, the inexpensive
polyoxometalate decatungstate (W O
has proven to be particularly useful. Near-UV irradiation of DT
gives rise to a singlet excited state that quickly decays to a more
long-lived reactive intermediate (wO) capable of single
2
coupling of DT catalysis with nickel-mediated cross-coupling
1
2a
reactions to form C−C bonds,
and Melchiorre demon-
3
3,4
strated asymmetric conjugate addition of DT-generated carbon
12b
13
radicals.
In work from our laboratories, we paired DT-
catalyzed HAT with fluorine atom transfer from N-
fluorobenzenesulfonimide (NFSI) to affect the direct fluori-
5
4−
(DT), Figure 1)
10
32
1
3a,b
13d
nation of aliphatic
and benzylic C−H bonds. Further,
18
we recently disclosed the direct F-fluorination of amino
13e,g
13f
acids
and peptides in aqueous media using DT as a
5
,6
means to generate positron emission tomography (PET)
imaging agents for oncology.
electron transfer or HAT from aliphatic compounds.
5
a,7
Pioneering studies by Hill
demonstrated that alkane
7
c
7a
7b
dehydrogenation, epimerization, and carbonylation can
5
b,8
9
be readily affected using DT catalysis. Fagnoni,
Albini,
have demonstrated that DT-
promoted C(sp )−H abstraction can be coupled with several
Received: May 28, 2019
Revised: July 9, 2019
8
d,9
8e,f,j,k
Ravelli,
and Ryu
3
©
XXXX American Chemical Society
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Research Article
Figure 1. Direct functionalization of unactivated C(sp )−H bonds using DT catalysis. Photoactivation of the polyoxometalate DT (DT: W O324−)
3
1
0
produces a reactive intermediate (wO) capable of C−H abstraction from various hydrocarbons. Both steric and polar effects can be exploited for
selective HAT to photoexcited DT in lactones and cyclic ketones. Here, we demonstrate that HAT to DT can be greatly accelerated by electrostatic
effects in a wide range of substrates.
Despite the many practical applications of DT catalysis in
C(sp )−H functionalization, subtle substrate structural fea-
tures often have a significant impact on the rate and
that example, the weaker tertiary C−H bond most remote
from the sterically hindered and electron-deficient peptide
backbone is selected for HAT. However, we have also
encountered several reactivity and selectivity trends that
require further explanation. For example, the yield and rate
3
productivity of the crucial HAT step, thus complicating
14
widespread application. In an effort to rationalize trends in
reactivity and selectivity, Ryu and Fagnoni studied the
alkylation of several lactones and cyclic ketones using
of leucine fluorination in native peptides varies significantly
14c
tetrabutylammonium decatungstate (TBADT). As summar-
ized in Figure 1, those researchers found that, in addition to
13f
depending on neighboring amino acids.
Likewise, γ-
3
fluorination of leucine is much faster than benzylic
C(sp )−H bond strength, polar and steric effects govern
13d
6
,14c
fluorination despite a stronger C−H bond. In the present
article, we systematically explore an electrostatic rate-
accelerating effect on DT-catalyzed HAT (Figure 1, bottom)
selectivity in DT-catalyzed HAT.
Specifically, they
demonstrated that in simple molecules hydrogen atoms remote
to quaternary carbons and electron-withdrawing groups were
most readily abstracted. During our own studies of DT-
1
8
1
3a−f
and exploit this effect in the radiosynthesis of [ F]Glu-U-
catalyzed C−H fluorination,
we observed similar trends
1
8
FHLeu, a potential F-labeled tracer for PET imaging of
manifested in the selectivity for fluorination of the γ- or
branched position in leucine residues in native peptides. In
13f
prostate cancer (PCa; FHLeu: 5-fluorohomoleucine).
8
277
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a
Table 1. DT-Catalyzed C−H Fluorination of Leucine Derivatives
entry
R1
R2
X
conv.
b
,
c
conv.
b
,d
c log P
e
kHAT × 10 (M s−1
)
8
−1
f
g
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
TFA
HCl
80
77
37
14
34
20
20
14
6
100
30
74
74
91
93
34
9
30
18
18
9
−1.59 (−1.56)
−1.59
5.2 ± 0.4
nd
1.0 ± 0.1
nd
nd
nd
CH CO
CF CO
0.80
1.85 (1.89)
3
g
3
C H CO
1.29
2.28
2.08
2
5
C H CO
6
5
tBuCO
Boc
Ts
nd
H
H
CH3
CH3
2.39
2.46
0.72
1.16
0.30 ± 0.1
0.35 ± 0.04
6.3 ± 1.0
2.2 ± 0.2
5.5 ± 1.5
5.2 ± 0.4
7
10
11
12
13
H
HCl
100
37
98
nd
CH CO
CH CO
H
3
(CH ) NH
2
TFA
TFA
0.18
3
2
2
h
g
H
−1.59 (−1.56)
a
b
nd = not determined. Conversion as a percentage relative to the conversion of leucine methyl ester·HCl (entry 10) after 60 min using the
specified reactor configuration (30% conversion in borosilicate NMR tube, 56% conversion in PTFE tube reactor, see the Supporting Information
for details). Reaction carried out in a borosilicate NMR tube (see the Supporting Information for details). Reaction carried out in a PTFE tube
reactor (see the Supporting Information for details). c log P predictions using KOWWIN v1.57 (Syracuse Research Corporation, New York,
USA). Rate constant for C−H abstraction by wO (see the Supporting Information for details). Measured log P values. N-fluoro-N-(4-
c
d
e
f
g
h
(
trifluoromethyl)phenyl)benzenesulfonamide used in place of NFSI.
RESULTS AND DISCUSSION
ethanolamine ester of N-acetyl leucine was prepared and
fluorinated under standard conditions (entry 12). This
addition of a cationic ammounium function improved the
reactivity of N-acyl leucine. Here, rapid fluorination with a rate
similar to that of leucine·TFA (entry 1) was observed. While c
log P values are clearly linked to cationic functions (i.e.,
charged complexes will have innately higher water solubility),
it should be emphasized that compounds with similar c log P
values, but with or without charge, have very different
fluorination rates (e.g., entries 3 and 10).
■
DT-Catalyzed Fluorination of Leucine Derivatives
Reveals Electrostatic Effects. As a first step toward gaining
additional insight into the effects of substitution and the local
environment on the rate and productivity of DT-catalyzed C−
H functionalization, we studied the fluorination of several
derivatives of leucine, which itself is an excellent substrate. The
productivity of fluorination of these derivatives is summarized
in Table 1 as a percentage conversion relative to leucine
methyl ester·HCl. There was little effect of the counterion on
the reaction rate (e.g., entries 1 and 2), and the productivity
of DT-catalyzed fluorination was found to decrease signifi-
cantly when the amine function was acylated (entries 3−7).
For example, the fluorination of trifluoroacetamide or
benzamide derivatives of leucine was ∼4−5 times slower
than that of the leucine methyl ester·HCl salt (entries 4 and 6).
This diminution in rate was also observed for N-Boc (entry 8)
and the p-toluenesulfonamide (entry 9) derivatives. Con-
versely, the methyl and t-butyl (not shown) esters of leucine
were excellent substrates for C−H fluorination (e.g., entry 10)
except when N-acylated (entry 11). This series of experiments
suggested that the ammonium function is crucial for rapid
fluorination and that substrate hydrophobicity is also linked to
fluorination productivity.
We also evaluated the influence of the N−F bond
dissociation energy (BDE) of the fluorination reagent on the
reaction rate using N-fluoro-N-(4-(trifluoromethyl)phenyl)-
13b
−1 16
benzenesulfonamide (BDE(N−F) = 222.3 kJ mol ), an N-
fluoro-N-arylsulfonamide (NFAS) recently reported by
16
Renaud. Although N-fluoro-N-(4-(trifluoromethyl)phenyl)-
−1
benzenesulfonamide has BDE(N−F) ≈ 40 kJ mol lower than
−1
that in NFSI (BDE(N−F) = 259.3 kJ mol ), the rate of
fluorine atom transfer to carbon radicals is predicted to be
16
faster for NFSI. Here, we observed similar kinetics for both
reactions (cf. entries 1 and 13), indicating that C−H
abstraction is likely to be rate-limiting in DT-catalyzed
fluorination of leucine.
Transient Absorption Spectroscopy. DT is known to
17
activate C−H bonds in aliphatic compounds through a
1
8
To explore the impact of hydrophobicity, the measured
partition coefficient (log P) for leucine·TFA (log P = −1.56)
and N-(trifluoroacetyl)leucine (log P = 1.89) was compared
photochemically generated intermediate wO. wO is a
powerful oxidant, and many different C−H, N−H, and O−H
bonds also can be activated via H-abstraction or outer-sphere
15
19
with predicted log P values (c log P = −1.59 and 1.85,
respectively). As experimental and calculated log P values
matched closely, we opted to calculate log P for the remaining
leucine derivatives (Table 1) and found that the most
hydrophilic compounds (c log P < 1) were the best substrates
for fluorination (e.g., entries 1, 2, 10, and 12). Conversely,
lipophilic (c log P > 2) amides, carbamates, and sulfonamides
were poor substrates. To probe the importance of a cationic
function to DT-catalyzed fluorination, the TFA salt of the
electron transfer. The transient spectroscopy of wO is
established, and bond activation reactions are readily
monitored using the blue absorbance band (λmax= 780 nm)
1
8−20
of wO.
In MeCN solvent, wO decays with a time constant
20
(τ) of about 60 ns in the absence of substrate. For C−H
abstraction reactions in MeCN, H can be removed from
aliphatic compounds with rate constants of 10 −10 M s .
In order to compare those data in MeCN with the partially
aqueous experiments described here, the reactivity of NaDT in
•
7
8
−1 −1
8
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Figure 2. (Left) Example kinetics trace (780 nm) and single-exponential fit for reaction of wO with the TFA salt of leucine. Blue × symbols denote
excluded data that are part of the instrument response function. The laser power was 9 mJ/pulse at 355 nm. (Right) Pseudo-first-order plots for
reactions of wO and Leu·TFA (blue circles) and N-Boc-Leu (red squares). The slopes of the linear fits give the second-order rate constants 5.2 ×
8
7
−1 −1
1
0 (Leu·TFA) and 3.0 × 10 M s (N-Boc-Leu).
2
1
MeCN−H O (80:20) was investigated. Reactions were
Leu·TFA as an example substrate). Irradiation of the
precursor complex produces the active oxidant wO, followed
by hydrogen abstraction (kHAT) and subsequent fluorination
2
pumped with 355 nm light from a Nd:YAG laser (7 ns/
pulse, 7−9 mJ/pulse), and transient absorbance traces were
monitored at 780 nm. In the absence of substrate, wO decays
with τ = 53 ± 3 ns. Under pseudo-first-order conditions using
cyclohexane as a substrate, the rate constant for C−H
21
reactions. The remote substitution on the leucine amine
function (4 bonds removed from the reactive C−H) is
expected to have a small effect on C−H bond strength (∼0.5
8
−1 −1
−1 22
abstraction by wO is 1.0 (±0.1) × 10 M s , about a
kcal mol ).
The observation that different groups
20
factor of 3 faster than that in MeCN alone.
substituted at the leucine amine or carboxylate give rise to
similar wO quenching rate constants supports this contention.
Polar and steric effects have been identified as contributors to
selectivity in DT-catalyzed C−H functionalization reactions
see above), but the electrostatic accelerating effect here is
distinct. This concept is demonstrated most clearly by the
order of magnitude increase in the C−H activation rate
constant in N-acetyl Leu (a neutral substrate, k
Next, the reactions of different leucine derivatives with wO
were investigated (Table 1). Typical kinetic traces and pseudo-
first-order plots for two leucine derivatives are shown in Figure
6
2
. In general, cationic leucine (e.g., Leu·TFA) had second-
(
8
−1 −1
order rate constants of ≥5 × 10 M s (entry 1). In contrast,
those compounds with protected amines but free carboxylates
(
entries 3 and 8−9; e.g., N-Boc-Leu) have second-order rate
= (1.0 ±
2 2 3
HAT
constants that are 5−10 times smaller. Leucine in its
zwitterionic form (see the Supporting Information) and
neutral leucine, where both N and O are protected, have
intermediate wO quenching rate constants (e.g., entry 11). All
rate constants are summarized in Table 1. Notably, observed
rate constants for reactions of different leucine derivatives do
not depend strongly on the nature of the N or O substituent.
For example, reactions of Leu·HCl salts with wO have about
the same yield whether the carboxylic acid is protected or not
8
−1 −1
0
.1) × 10 M s ) and N-acetyl Leu-O(CH ) NH ·TFA (a
cationic substrate, kHAT = (5.5 ± 1.5) × 10 M s ) (Table 1,
8
−1 −1
entries 3 and 12).
Exploiting Electrostatic Effects for DT-Catalyzed
Fluorination. Considering the impressive rate-accelerating
electrostatic effect in DT-catalyzed C−H fluorination, the
fluorination of several N-acyl leucine derivatives that also
incorporate an ammonium salt was examined. Remarkably,
while fluorination of N-acetyl leucine (1) proceeded in only
(
entry 10). Introduction of cationic groups also affects the
1
0% yield, after 1 h, the corresponding N-glycyl·TFA salt 2 was
reactivity with wO. For example, incorporation of a cationic
converted into the fluoroleucine analogue 7 in 61% yield after
the same amount of time (Figure 3). Increasing the distance
between the ammonium function and site of C−H abstraction
had little effect on the reaction yield (e.g., 2−5), although DT-
catalyzed fluorination of the TFA salt of the 6-aminohexanoyl
ester 5 was complicated by additional fluorination on the side
chain itself. Likewise, the fluorination of homoleucine (HLeu)·
TFA and 2-amino-6-methylheptanoic acid·TFA provided the
corresponding fluorinated adducts 12 and 13 in similar yield
(
−OCH CH NH ·TFA) group at the carboxylic function of
2
2
2
N-acetyl Leu results in an increase in the second-order rate
constant for reactions with wO by a factor of ∼5 (cf. entries 3
and 12).
These observed kinetics are consistent with a model where
electrostatic interactions between cationic leucine derivatives
promote formation of a precursor complex (e.g., eq 1, with
13e,g
(
∼50%) after 1 h.
Both of these substrates fluorinate faster
than leucine·TFA (25% after 1 h) owing to additional
separation between the site of C−H abstraction and
6
,13g,14c
electron-withdrawing acyl and ammonium functions.
To assess whether the rate-accelerating electrostatic effect
extends to other aliphatic C−H fluorination reactions, the DT-
catalyzed fluorination of N-acetyl and N-glycyl·TFA derivatives
of 2-aminobutane was examined. Again, a distinct increase in
product yield was observed for the N-glycyl·TFA derivative (cf.
1
4 and 15). Likewise, fluorination of O-acetyl-2-hydroxycu-
mene is a nonproductive reaction (∼5% yield), while the O-
glycyl·TFA analogue fluorinated with about a 50% yield to
8
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generally correlate with the additional charge and relative
13g,23
hydrophobicity of the C-terminal amino acid,
with C−H
fluorination of Leu-Lys being ∼4 times faster than that of Leu-
Phe. Interestingly, fluorination of the Leu-Leu dipeptide was
complicated by additional fluorination at the C-terminus,
which occurred ∼2.5 times faster than that at the N-terminal
leucine residue. This latter selectivity is likely derived from the
more optimal spacing between the C-terminal branched
position and the ammonium function (cf. leucine vs HLeu
above).
Finally, the fluorination of other branched alkanes with
appended cationic groups was explored. Over the course of 2 h,
the triphenylphosphonium salt derived from 3-methyl-1-
bromobutane fluorinated with a yield similar to that of the
parent bromide (∼10−15%; cf. 28 and 30), while the
fluorinated dimethyl sulfonium salt 31 was produced in
∼
30% yield (cf. 28 and 31). For comparison, the TFA
ammonium salt fluorinated cleanly in ∼70% yield after the
same reaction time (cf. 28 and 29). These results are
consistent with a model where electrostatic interaction
between DT and cationic substrates is the primary determinant
of fluorination kinetics. Here, the difference in cation structure
(
e.g., triphenylphosphonium vs dimethylsulfonium vs ammo-
nium) plays a key role in reaction kinetics as the electrostatic
effect associated with precursor complex formation (eq 1) is
dependent on 1/r, where r is the internuclear separation
21
between the cation (substrate) and anion (DT).
Fluorination of ZJ-43: A Potent PSMA Ligand. The
prostate specific membrane antigen (PSMA) is a trans-
membrane protein also known as glutamate carboxypeptidase
II (GPCII) that is significantly overexpressed in PCa and
24
linked to both tumor progression and tumorigenesis. The cell
surface location and the upregulation in PCa make PSMA an
25
excellent target for molecular imaging by PET. Toward this
24b
goal, several classes of PSMA ligands have been identified,
prominent among which are the glutamate/urea-based
2
5
26
inhibitors pioneered by Pomper and Kozikowski (e.g.,
27
28
3
2
and 33, Figure 4). A notable requirement for imaging
with this family of ligands is a nucleophilic functionality on the
nonglutamate residue (e.g., thiol or primary amine) that can be
24b
labeled by a radionuclide-containing prosthetic group. Thus,
despite the potent GPCII-inhibitory activity of PSMA-binding
29
ligands such as ZJ-43 (34: K = 0.8 nM), the lack of a
i
Figure 3. Ammonium-promoted DT-catalyzed C−H fluorination. All
nucleophilic functional group on the leucine residue precludes
their investigation as radiotracers for PCa imaging.
reactions were carried out in a custom photobox reactor (see the
a
Supporting Information for details). Accompanied by fluorination on
b
the aliphatic chain; an additional 28% of starting material was
We previously reported the direct fluorination of ZJ-43
c
13f
fluorinated on the C-terminal leucine residue; side-chain hydro-
(34) and found that fluorination occurred cleanly at the
phobicity values from ref 23.
branched position of the leucine residue; however, only 7% of
the fluorinated derivative (Glu-U-FLeu (35); FLeu: 4-
fluoroleucine) was produced after 1 h (a relevant time point
afford 17. This trend extends to saturated heterocycles, where
reaction of N-phenylsulfonyl piperidine provided none of the
expected 4-fluoro derivative 18 but piperidine·TFA fluorinated
cleanly to provide 19 in 51% yield. Although somewhat slower,
homopiperidine·TFA could also be fluorinated to provide 4-
fluorohomopiperidine (21). Introducing a branched position
on piperidine (i.e., 4-methylpiperidine) led to further increases
in fluorination yield, and 4-methyl-4-fluoropiperidine (20) was
produced in 70% yield after only 3 h. The reaction of N-
isopentyl piperidine was examined, and here, the product of
tertiary C−H fluorination 23 predominated.
1
8
for radiosyntheses, F t1/2= 109.8 min). Adjusting the reaction
time, equivalents of NFSI, solvent composition, and catalyst
loading failed to significantly improve on this result (e.g., 12%
after 2 h). Nevertheless, PSMA binding of Glu-U-FLeu (35)
was evaluated, and this fluorinated derivative was found to
retain potent receptor binding (K = 1.9 nM). Considering the
i
profound electrostatic effect on the kinetics of DT-catalyzed
fluorination described here, the relatively slow fluorination (cf.
11, Figure 3) of ZJ-43 could now be attributed to the absence
of a cationic ammonium function.
This insight prompted a re-examination of the fluorination
of several cationic derivatives and analogues of ZJ-43 in an
effort to identify a compound that displayed improved
We additionally examined the fluorination of four N-
terminal leucine-containing dipeptides: Leu-Phe, Leu-Leu,
Leu-Arg, and Leu-Lys. Their fluorination yields after 1 h
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1
8
18
Figure 4. PSMA-binding PET imaging agents [ F]DCFBC and [ F]DCFPyl along with the PSMA ligand ZJ-43. Fluorination of ZJ-43 provides a
novel and potent PSMA binding ligand Glu-U-FLeu (35) in low yield.
1
8
18
Figure 5. Accelerated fluorination of choline and ethanolamine esters of ZJ-43 and Glu-U-HLeu and synthesis of [ F]Glu-U-FHLeu ([ F]40).
1
8
PSMA binding of each ligand (K ) was measured by competition assays (n ≥ 3) using [ F]DCFPyL and determined by applying a one-site Fit K
i
i
1
9
18
model using GraphPad Prism (7.04). F-fluorination carried out in a custom photobox reactor and F-fluorination carried out in the microreactor
depicted placed on top of a transilluminator (see the Supporting Information for full details).
fluorination kinetics and potent PSMA binding (Figure 5).
Gratifyingly, the electrostatic effect extended to DT-catalyzed
fluorination of both TFA·ethanolamine and choline esters of
ZJ-43, both of which fluorinated in ∼4-fold improved yield to
afford the derivatives 36 and 37, respectively. Considering that
the fluorination of HLeu is more rapid than that of leucine
ester 39 was accomplished by gently warming a solution of this
material in MeCN−H O with NaHCO to provide Glu-U-
2
3
FHLeu (40).
18
PSMA Binding and Synthesis of [ F]Glu-U-FHLeu.
The binding to LNCap PCa cell membranes by each of the
fluorinated derivatives 35−40 was also evaluated, and the
HLeu analogue Glu-U-FHLeu (40) proved to be of similar
potency to Glu-U-FLeu (35). Considering the potential utility
of this compound for PET imaging in PCa, we capitalized on
the rapid fluorination of the choline ester 41 for the
13e,g
itself (Figure 3),
we also explored the DT-catalyzed
fluorination of both the TFA·ethanolamine and choline esters
of the HLeu analogue of ZJ-43 (Figure 5). Again, both cationic
substrates fluorinated cleanly, and adducts 38 and 39 were
produced in excellent yield (∼80%). Hydrolysis of the choline
1
8
radiosynthesis of [ F]40 (Figure 5, inset). Using a micro-
8
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reactor placed on a transilluminator and [ F]NFSI,
Research Article
13f
18
13e,f,30
Notes
1
8
the F-fluorination of the choline ester proceeded smoothly.
The authors declare no competing financial interest.
18
Purification of [ F]39 (along with the remaining starting
material) was accomplished by filtration through a strong
ACKNOWLEDGMENTS
18
■
cation exchange resin, which retained [ F]39 but not the
We would like to thank Mr. Bjo
̈
rn Wagner for measurement of
1
8
catalyst, reagents, or byproducts. The purified [ F]39 was
then eluted using aqueous base with >95% radiochemical
purity (RCP) and good radiochemical yield (RCY; decay
log P values. R.B. and J.J.W. acknowledge support from
NSERC Discovery Grants, and R.B. acknowledges support
from a Michael Smith Foundation for Health Research Career
Investigator Award. P.S. acknowledges a Canadian Cancer
Society Research Institute Innovation and Innovation to
Impact Grant. TRIUMF receives federal funding via a
contribution agreement with the National Research Council
of Canada.
18
corrected, 25 ± 9%). Hydrolysis of [ F]39 with heating (75
18
18
°
C) afforded the triacid [ F]40. This synthesis of [ F]Glu-U-
FHLeu well demonstrates the practical utility of this
electrostatic rate acceleration for DT-catalyzed C−H fluorina-
tion.
CONCLUSIONS
The studies described here identify an important electrostatic
■
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
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Corresponding Author
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