Organomediated Enantioselective 18F Fluorination for PET Applications

Article abstract of DOI:10.1002/anie.201506035

The first organomediated asymmetric ¹⁸F fluorination has been accomplished using a chiral imidazolidinone and [¹⁸F]N-fluorobenzenesulfonimide. The method provides access to enantioenriched ¹⁸F-labeled α-fluoroaldehydes (>90 % ee), which are versatile chiral ¹⁸F synthons for the synthesis of radiotracers. The utility of this process is demonstrated with the synthesis of the PET (positron emission tomography) tracer (2S,4S)-4-[¹⁸F]fluoroglutamic acid.

Full text of DOI:10.1002/anie.201506035

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Angewandte
Communications
International Edition: DOI: 10.1002/anie.201506035
German Edition: DOI: 10.1002/ange.201506035
18F Fluorination
Organomediated Enantioselective 18F Fluorination for PET
Applications
Faye Buckingham, Anna K. Kirjavainen, Sarita Forsback, Anna Krzyczmonik, Thomas Keller,
Ian M. Newington, Matthias Glaser, Sajinder K. Luthra, Olof Solin, and VØronique Gouverneur*
Abstract:
The
first
organomediated
asymmetric
associated with 18F incorporation,[8] especially when control
over stereoselectivity is required. Herein, we report that
organocatalysis, one of the current major branches of
enantioselective synthesis, is applicable in the context of
18F radiochemistry, an advance opening new opportunities for
PET radiotracer development and drug discovery.
18F fluorination has been accomplished using a chiral imida-
zolidinone and [18F]N-fluorobenzenesulfonimide. The method
provides access to enantioenriched 18F-labeled a-fluoro-
aldehydes (> 90% ee), which are versatile chiral 18F synthons
for the synthesis of radiotracers. The utility of this process is
demonstrated with the synthesis of the PET (positron emission
tomography) tracer (2S,4S)-4-[18F]fluoroglutamic acid.
Currently, 18F fluorination at a stereogenic carbon is
achieved using an enantiomerically pure precursor armed
with a leaving group amenable to SN2 displacement with
[18F]fluoride.[9] This method is limited to substrates which
tolerate high temperatures, are not prone to elimination, and
can resist racemization or epimerization under the harsh
reaction conditions required for 18F fluorination. This last
criterion also stands true for the newly formed 18F-substituted
stereogenic carbon of the product. Incomplete inversion is an
additional complication narrowing the scope of conventional
SN2 strategies. In response to these drawbacks, transition
metals have been exploited to induce regio- and stereocon-
trolled 18F fluorination of prefunctionalized precursors;[10]
isolated examples of metal-mediated enantioselective
18F fluorination of either meso[11] or prochiral precursors[12]
have recently appeared but have met with limited success
because of a lack of generality in terms of substrate scope and/
or low enantiomeric excesses. The benefits of organocatalytic
research,[13] offering a range of generic modes of catalyst
activation, induction, and reactivity, encouraged us to merge
P
hysiological processes typically show a high degree of
chiral discrimination towards exogenous racemic compounds
administered in vivo. The effects of enantiomers can be
dissimilar as a consequence of their differential interaction
with chiral targets, such as receptors, enzymes, and ion
channels.[1] In medicinal chemistry, the use of single-enantio-
mer drugs is therefore advantageous and would be expected
to decrease the total dose given to patients, simplify the dose
regimen relationship, and minimize side effects (or in some
cases toxicity) induced by the inactive enantiomer.[2] Chirality
is equally important in the context of positron emission
tomography (PET).[3] PET is a widely employed medical
imaging technology, which uses radiotracers labeled with
positron emitting isotopes, more often 18F (t1/2 = 109.8 min), to
interrogate biochemical pathways, track changes brought
about by disease, or streamline drug research. Several radio-
tracers used in the clinic are nonracemic chiral entities.
Amongst those tracers, 2-[18F]fluoro-2-deoxy-d-glucose
(18F]FDG),[4] 3’-deoxy-3’-[18F]fluorothymidine ([18F]FLT),[5]
16-a-[18F]fluoroestradiol ([18F]FES),[6] and 16-b-[18F]fluoro-
5a-dihydrotestosterone ([18F]FDHT)[7] stand out as they
contain the 18F substituent itself on a stereogenic carbon.
With the drive in industry to develop optically pure pharma-
ceutical drugs, PET is becoming an important tool to study the
behavior of enantiomers in living systems. To date, however,
the input of nuclear medicine into clinical pharmacology has
progressed slowly, a trend underscoring the challenges
the
disconnected
fields
of
organocatalysis
and
18F radiochemistry. As a proof of concept, we opted to
develop a method converting readily available achiral alde-
hyde precursors into enantioenriched a-[18F]fluoroaldehydes.
These versatile synthons are valuable but notoriously suscep-
tible to epimerization, thus a study to develop an asymmetric
18F-labeling procedure for their preparation and subsequent
derivatization provides an ideal platform to establish the field
of organomediated 18F radiofluorination (Scheme 1).
The enantioselective fluorination of aldehydes employing
a chiral secondary amine catalyst and an achiral electrophilic
fluorine source was first reported in 2005.[14] Enamine-
catalyzed fluorination afforded enantioenriched a-fluoro-
aldehydes, which can be subjected to a variety of trans-
formations. Preliminary studies indicate that the development
of a radiochemical variant presents numerous challenges. The
inherently low concentration of the [18F]F+ reagent with
respect to the precursor and the chiral organomediator, which
are both employed in equimolar quantities, could induce
product racemization. The half-life of the 18F isotope imposes
the restriction that reaction times must be kept to a minimum
with the radiofluorination proceeding ideally at room temper-
ature, and not at the lower temperatures typically required in
[*] F. Buckingham, Prof. V. Gouverneur
University of Oxford, Chemistry Research Laboratory
12 Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: veronique.gouverneur@chem.ox.ac.uk
Dr. A. K. Kirjavainen, Dr. S. Forsback, A. Krzyczmonik, T. Keller,
Prof. O. Solin
Turku PET Centre, Radiopharmaceutical Chemistry Laboratory
Kiinamyllynkatu 4–8, 20520 Turku (Finland)
Dr. I. M. Newington, Dr. M. Glaser, Dr. S. K. Luthra
GE Healthcare, The Grove Centre
White Lion Road, Amersham, HP7 9LL (UK)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201506035.
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of methyl tert-butyl ether (MTBE) as a solvent led to a similar
RCC (62%) but pleasingly increased the ee value to 92%
(Table 1, entry 2). Amine (S)-B also gave 92% ee but a lower
RCC of 45% (Table 1, entry 3). The use of [18F]Selectfluor
bis-triflate[21] instead of [18F]NFSI was unsuccessful, likely
because of the poor solubility of this reagent in the solvent
system employed (Table 1, entry 4). This study highlights the
dramatic influence of the [18F]F+ source on the reaction
outcome and underscores the importance of [18F]F+ reagent
diversity for radiofluorination. Significant differences were
observed between experiments conducted with [19F]F+ or
[18F]F+ reagents.[18,22] Three representative aldehydic sub-
strates responded well to 18F fluorination under our optimized
conditions, as shown in Figure 1. The enantiomeric excesses
measured for all 18F-labeled a-fluoroaldehydes (S)-[18F]3b,
(S)-[18F]3c, and (S)-[18F]3d were found to be greater than
90%.
The success of the first asymmetric organomediated
18F fluorination encouraged further derivatization of the
chiral a-[18F]fluoroaldehyde (S)-[18F]2a into a range of addi-
tional high value 18F-labeled molecules (Scheme 2).
Oxidation leading to the formation of 2-fluoro-3-phenyl-
propanoic acid ((S)-[18F]4) was investigated first. With this in
mind, (S)-[18F]2a was prepared in MTBE applying the
optimum procedure (Table 1, entry 2) and was directly
treated with a range of oxidants. No product of oxidation
was observed upon addition of either oxone in DMF or
potassium permanganate in methanol/water. Pleasingly, the
Pinnick–Lindgren oxidation[23] performed with sodium hypo-
chlorite in acetonitrile afforded (S)-[18F]4 with 75% RCC[19]
Scheme 1. a) Conventional and unconventional approaches for
18F incorporation at a stereogenic carbon. b) Organomediated enantio-
selective 18F fluorination affords enantioenriched 18F-labeled a-fluoro-
aldehydes. OTs =tosylate; OTf =trifluoromethylsulfonate.
enantioselective organocatalysis. Finally, the production and
derivatization of a-[18F]fluoroaldehydes should be amenable
to a one-pot process, and occur under mild reactions
conditions to avoid racemization of the newly formed
stereocenter after 18F fluorination. Preliminary studies
employed hydrocinnamaldehyde (1a) as the model substrate,
the chiral imidazolidinone (S)-A or pyrrolidine (S)-B, and the
[18F]F+ reagent N-[18F]fluorobenzenesulfonimide ([18F]NFSI)
(Table 1).
[18F]NFSI was synthesized according to a previously
reported procedure.[15] This method involved the reaction of
sodium bis(phenylsulfonyl)amide in acetonitrile/water with
[16]
[18F]F2 to afford [18F]NFSI with the theoretical maximum
radiochemical yield of 50%, along with 50% of [18F]NaF.
Following azeotropic drying, [18F]NFSI was dissolved in the
reaction solvent and aliquots were taken for reactions (circa
200 MBq). A 5 min cyclotron irradiation provided [18F]NFSI
with a specific activity of 1.9 GBqmmolÀ1, in line with the
short irradiation time applied to the 18O target.[17] Hydro-
cinnamaldehyde (1a) was treated with an aliquot of [18F]NFSI
in a THF/isopropanol solvent mixture at room temperature in
the presence of amine (S)-A (1 equiv with respect to 1a). The
resulting a-fluoroaldehyde (S)-[18F]2a was not isolated but
was derivatized in situ with benzhydrazide in MeOH. Anal-
ysis of the crude reaction mixture by HPLC[18] indicated that
this one-pot process afforded the desired hydrazone (S)-
[18F]3a in 71% radiochemical conversion (RCC)[19] with an
enantiomeric excess (ee) of 64% (Table 1, entry 1).[20] The use
Figure 1. Enantioselective a-18F fluorination: substrate scope. [a] RCC
determined by radio-HPLC relative to [18F]NFSI.
Table 1: Optimization of the reaction conditions with aldehyde 1.
Scheme 2. One-pot radiosynthesis of carboxylic acid (S)-[18F]4, amides
(S)-[18F]5 and (S)-[18F]6, and amine (S)-[18F]7 from hydrocinnamalde-
hyde. Conditions: i) [18F]NFSI, MTBE, amine (S)-A (1 equiv), RT,
20 min; ii) NaClO2 (2.5 equiv), NaH2PO4 (4 equiv), 2-methyl-2-butene
(5 equiv), MeCN, H2O, RT, 30 min; iii) NH2CH(p-OMePh)2 (1.5 equiv),
2-methyl-2-butene (5 equiv), toluene, RT, 5 min then NaClO2
(2.5 equiv), NaH2PO4 (4 equiv), H2O, RT, 30 min then TFA, anisole,
608C, 10 min; iv) benzylamine (1.5 equiv), 2-methyl-2-butene (5 equiv),
toluene, RT, 5 min then NaClO2 (2.5 equiv), NaH2PO4 (4 equiv), H2O,
RT, 30 min; v) benzylamine (2 equiv), DCE, RT, 5 min then NaBH-
(OAc)3 (4 equiv), RT, 30 min. [a] RCC determined by radio-HPLC
relative to [18F]NFSI.[19] Bn=benzyl.
Entry
F+ Source
Amine
Solvent
RCC [%][a]
ee [%][b]
1
2
3
4
[18F]NFSI
(S)-A
(S)-A
(S)-B
(S)-A
THF/IPA[c]
MTBE
71 (n=1)
62 (n=5)
45 (n=1)
0 (n=2)
64 (S)
92 (S)
92 (S)
–
[18F]NFSI
[18F]NFSI
MTBE
[18F]Selectfluor
MTBE[d]
[a] RCC of (S)-[18F]-3a determined by radio-HPLC relative to [18F]F+
source. [b] Determined by radio-HPLC of isolated (S)-[18F]-3a on a chiral
stationary phase. [c] Ratio 9:1. [d] 5% H2O. DCA=dichloroacetic acid;
TMS=trimethylsilyl.
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and 93% ee. This reaction required sodium dihydrogen
phosphate and 2-methyl-2-butene acting as a scavenger of
hypochlorous acid generated in situ. Next, we successfully
developed the oxidative amidation[24] of (S)-[18F]2a as a route
to the secondary amide (S)-[18F]6 directly from hydrocinna-
maldehyde. The aldehyde (S)-[18F]2a was generated first and
stirred with benzylamine in toluene for 5 min. Subsequent
Pinnick–Lindgren oxidation of the resultant imine afforded
amide (S)-[18F]6 in 46% RCC over three steps, all carried out
in one pot, with a slightly decreased ee value of 83%.
Alternatively, the treatment of (S)-[18F]2a with NH2CH(p-
[25]
OMePh)2
followed by Pinnick oxidation (30 min) then
addition of trifluoroacetic acid (TFA; 10 min) afforded the
primary a-fluoroamide (S)-[18F]5 in 49% RCC[19] and 88% ee.
Finally, the formation of the chiral b-fluoroamine (S)-[18F]7
was also possible from (S)-[18F]2a by imine formation in
dichloroethane (DCE) followed by reduction with sodium
triacetoxyborohydride.[26] This reductive amination was ach-
ieved affording (S)-[18F]7 in 85% RCC[19] and 90% ee.
Scheme 3. One-pot radiosynthesis of 4-[18F]fluoroglutamic acid
(2S,4S)-[18F]9. [a] RCC determined by radio-HPLC relative to
[18F]NFSI.[19] BOC=tert-butoxycarbonyl.
aldehydic substrate (S)-8. When the 18F fluorination was
performed with amine (R)-A applying the reaction sequence
shown in Scheme 3, 4-[18F]fluoroglutamic acid was formed in
47% Æ 5% RCC and a d.r. of 7:3 favoring the formation of
diastereomer (2S,4R)-[18F]9; this result indicates that a mis-
match effect operates between (S)-8 and the chiral amine
(R)-A.
In conclusion, we report that enamine catalysis, one of the
main activation modes of organocatalysis, allows for the
enantioselective 18F fluorination of aldehydes in high radio-
chemical conversion and with ee values reaching 93%. These
versatile synthons can be transformed into 18F-labeled
carboxylic acids, amides, and amines in a one-pot process
directly from the achiral aldehydic precursor. We have further
demonstrated the utility of this method with the synthesis of
(2S,4S)-4-[18F]fluoroglutamic acid. This radiochemistry is
significant as it merges for the first time the fields of
organocatalysis and 18F fluorination, opening the door to
a myriad of opportunities for labeling with the 18F isotope or
with alternative imaging-appropriate isotopes.
After establishing these conditions for the synthesis and
transformation of aldehyde (S)-[18F]2a, we focused on the
labeling of (2S,4S)-4-fluoroglutamic acid, a radiotracer diffi-
cult to access as a single stereoisomer applying known
methods. Glutamine and glutamate play key roles in the
metabolism of tumors and may act as a useful alternative
radiotracer for [18F]FDG negative tumors.[27] After deamida-
tion of glutamine, glutamate is transaminated to 2-oxogluta-
rate, which is channeled into the tricarboxylic acid cycle. We
opted to focus on 4-[18F]fluoroglutamic acid ([18F]9) since
preclinical trials indicate that this tracer has potential in
breast and lung tumor imaging as a result of high uptake in
these cell lines.[28] Previous syntheses of 4-[18F]fluoroglutamic
acid involve SN2 18F fluorination of stereochemically pure
starting materials. This method has provided access to
(2S,4R)-4-[18F]fluoroglutamic acid but access to the alterna-
tive diastereomer (2S,4S) proved difficult because of epime-
rization at one of the stereocenters under the 18F fluorination
conditions; time-consuming purification by HPLC on a chiral
stationary phase was therefore required prior to imaging Experimental Section
studies.[29] We envisaged a radiosynthesis of (2S,4S)-[18F]9
starting from the enantiopure aldehyde precursor (S)-8
applying our optimized electrophilic 18F fluorination, a pro-
cess that would be stereocontrolled by the chiral amine
activator. Aldehyde (S)-8 was synthesized from l-glutamic
acid in five facile steps.[18] In a one-pot process, (S)-8 was
reacted with [18F]NFSI followed by Pinnick oxidation under
the optimum reaction conditions (Scheme 3). The resulting
protected 18F-labeled glutamic acid (2S,4S)-[18F]10 was
formed in 65% RCC. Following removal of the solvent,
deprotection was effected by heating in a TFA/anisole
General procedure for asymmetric fluorination of aldehyde: To an
Eppendorf vial containing a stirrer bar and (S)-2,2,3-trimethyl-5-
benzyl-4-imidazolidinone dichloroacetic acid (1.7 mg, 5.0 mmol) was
added a solution of aldehyde (5.0 mmol) in MTBE (50 mL). The
reaction was stirred for 10 min prior to the addition of an aliquot of
[18F]NFSI in MTBE (250 mL, circa 200 MBq). The reaction was
stirred at room temperature for 20 min. Reagents for derivatization
were added and stirred for reaction times as described, followed by
analysis by analytical HPLC. The peak corresponding to 18F-labeled
product was collected and analyzed by reverse-phase HPLC on
a chiral stationary phase.
solution for
10 min; this process provided 4-
Acknowledgements
[18F]fluoroglutamic acid (2S,4S)-[18F]9 (more than 95% con-
version) with a d.r. value of 19:1, the stereochemical outcome
of the 18F fluorination being controlled by the chiral amine.
Careful analysis of this product confirmed that no racemiza-
tion occurred at the C2 position during 18F fluorination and
deprotection (ee > 99%).
Financial support was provided by the BBSRC (F.B.), GE
Healthcare (F.B.), the Academy of Finland Grant Agreement
266891 (A.K.K., S.F.), the EC (FP7-PEOPLE-2012-ITN-
RADIOMI-316882 to A.K. and T.K.) and Advion. V.G.
holds a Royal Society Wolfson Research Merit Award (2013–
2018).
Further experiments studied the possible match/mismatch
effect between the chiral imidazolidinone and the chiral
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[12] X. Huang, W. Liu, H. Ren, R. Neelamegam, J. M. Hooker, J. T.
Keywords: asymmetric synthesis · enamines · fluorine-18 ·
Groves, J. Am. Chem. Soc. 2014, 136, 6842 – 6845 (one example,
25% ee).
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Received: July 1, 2015
Revised: July 30, 2015
Published online: September 11, 2015
Angew. Chem. Int. Ed. 2015, 54, 13366 –13369
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 13369