Stereospecific radiosynthesis of 3-fluoro amino acids: Access to enantiomerically pure radioligands for positron emission tomography

Article abstract of DOI:10.1039/c8ob00184g

A variety of substituted non-racemic aziridine-2-carboxylates equivalent to amino acids were prepared and subjected to ring opening reaction by [¹⁸F/¹⁹F]fluoride. The regio and stereospecific ring opening depends on the substituents on the nitrogen as well as both the carbons of aziridines. The applicability of the methods to afford access to 3-[¹⁸F/¹⁹F]fluoro amino acids are illustrated.

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Stereospecific radiosynthesis of 3-fluoro amino acids: Access to
enantiomerically pure radioligands for positron emission
tomography
Received 00th January 20xx,
Accepted 00th January 20xx
Santosh R Alluri and Patrick J Riss *a,b,c
DOI: 10.1039/x0xx00000x
A variety of substituted non-racemic aziridine-2-carboxylates equivalent to amino acids were prepared and
sbjected to ring opening reaction by [18F/19F]fluoride. The regio and stereospecific ring openig depends on
the substituents on the nitrogen as well as both the carbons of aziridines. The applicability of the methods to
afford access to 3-[18F/19F]fluoro amino acids are illustrated.
www.rsc.org/
generation of HF-amines by combining hexafluoroisopropanol,
benzoyl fluoride, Lewis base and DMPU-HF were also used to
Introduction
ring open activated aziridines12,13
.
Aziridines or 1-aza-cyclopropanes are the smallest N-
containing heterocycles, analogue to oxiranes (1-oxa-
cyclopropanes) and thiiranes (1-thia-cyclopropanes). The
inherent strain of these narrow rings renders these functional
groups vulnerable to opening in presence of nucleophiles.
Hence, the aziridine is useful to make a variety of substituted
amines1,2,3. We are particularly interested in the fluoroethyl
amine motif, an important building block in synthetic
chemistry to synthesize peptidomimetics and amino acids.
Aliphatic amino acids labelled with fluorine-18 (t1/2 = 110 min)
are a promising class of positron emission tomography (PET)
radiotracers for the use in neuroimaging. Besides abnormal
The synthesis of fluorinated, aliphatic amino acids is
complicated by stereochemical implications. Besides the chiral
amino-acid functionality, introduction of an additional
substituent creates
a new stereocenter leading to four
possible diastereomers as products. Due to the short half-life
of fluorine-18, which is most available in the form of no-carrier
added [18F]fluoride ion, we sought a nucleophilic method that
reliably produces one desired 2-amino-3-fluorocarboxylic acid
stereoisomer in one synthetic step using activated complexes
of fluoride ion. These considerations led us to investigate
trans-aziridines as starting materials for producing the desired
products. Due to the necessity for a carboxylic acid function on
tissue proliferation, derivatives of N-methyl-D-aspartate as
the amine-carbon configured to yield the L-amino acid motif,
well as L-Glutamate and its homologues have shown promise
its influence on regioselectivity in the nucleophilic substitution
must be mitigated. Electron attracting properties of carbonyl
groups affect the electrophilicity of the adjacent carbon and
thereby direct the nucleophile to that carbon. Steric bulk is not
effective to direct the attack of small nucleophile such as
fluoride. Therefore, to favour the 3-fluoro product at all, the
rate constants for 3-fluorination must be increased. We
surmised, that introducing allylic or benzylic functionalities at
the C-3 position of aziridine-2-carboxylates leads to favorable
distribution of electrophilicity centered on position-3. E.g. the
relative reaction rate of substitution at allylic carbons is 8.1
times higher compared to that of an aliphatic 2° carbon
in assessing cellular stress in tissues due to reactive oxygen
species, hypoxia and hypoglycaemia. Since 2-[18F]fluoro-2-
deoxy-D-glucose ([18F]FDG-PET) suffers from high retention in
normal brain tissue in neuro-oncology, aminoacid-PET is
becoming a powerful and versatile alternative owed to low
uptake of amino acids in healthy brain tissue4-7
.
Compared to oxiranes and in particular thiiranes, aziridines
lag behind in reactivity. In order to improve reactivity, the
imine-nitrogen is ideally activated as a leaving group by acids
or by conversion into an amide or carbamate. Consequently,
anhydrous HF or Olah’s HF was used to ring open aziridines in
the past with recent reports using other acidic sources of
fluoride (e.g. KHF2 or NEt3-HF complex)8,9,10,11. The in situ
(isopropyl)14,15
.
With respect to stereochemistry, the aziridine allows for
two distinguished ring opening mechanisms based on
nucleophilic substitution - SN1, SN2 – with opposite outcomes.
Aziridines reacted with catalytic amounts of Lewis acid for
amine coordination prior to ring opening (mostly SN1
mechanism). Whereas the aziridines containing an activating
group generally undergo ring opening in presence of
nucleophiles (mostly SN2 mechanism).
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Scheme 3: Synthesis of 3, 4 and
i. R = Boc
5
. Reagents and conditions-
3
, (Boc)2O, DMAP, THF, rt, 2 d, 56%; R = Cbz
4, Cbz-Cl,
DIPEA, THF, 0°C-rt, 24 h, 97%; R = Ts
DCM, rt, 2 days, 42%
5, (Ts)2O, Pyridine, DMAP,
methylating reagent (Table 1). Pleasingly, the base KHMDS for
the respective methylation gave the desired compounds in
good yields (Table 1, entry 15).
Scheme 1 Schematic of SN1, SN2 and regioselectivity of aziridine-2-
carboxylates ring opening by fluoride ion
The substrates
7 to 14 were made via selective reduction
With respect to stereochemistry, the SN1 mechanism tends
to fail retention of the configuration giving the racemic
products. The SN2 mechanism inverts the configuration at the
reaction center and gives the non-racemic product. Scheme 1
shows the possible substitution and the regioselectivity in ring
opening of aziridine-2-carboxyaltes by fluoride.
of one ethyl ester of diacids 3, 4, 5 to their aldehyde
derivatives followed by the subsequent olefination with the
corresponding Wittig reagents (Scheme 4). For the synthesis of
13 and 14, the corresponding Wittig reagent was made using
KHMDS
base
and [3-(Methoxycarbonyl)propyl]triphenyl-
phosphoniumbromide in situ prior to the addition of
corresponding aldehyde. The major products in all the Wittig
reactions are E isomers except with the –tosyl aziridine 12
where approximately equal amounts of E and Z isomers were
obtained. Two sets of enantiomers were made for the aziridine
Based on these criteria, symmetric and non-symmetric
trans aziridine-2-carboxylates with N-protecting groups, and N-
methyl aziridines were synthesized to establish feasibility of
obtaining only one stereoisomer as reaction product from
activated fluoride ion as follows.
precursors in order to obtain
compounds. Aziridines to
is the fluorinated N-methyl aspartic acid
lead to 2-amino-3-fluoro adipic acids, 10 to
D
and
L forms of fluorinated
1
5 to give 3-fluoro aspartic acid
equivalents,
equivalent,
6
7
to
9
Results and Discussion:
12 3-fluoro lysine equivalents and 13, 14 to give 2-amino-3-
fluoro-suberic acid equivalents. It was noticed that the ring
opening mechanism occurred via SN2 pathway as the NMR
analysis shown a single isomer, therefore anti configuration
was assigned to fluorinated products.
Organic chemistry: The non-racemic starting materials
1 and 2
were prepared from the chiral pool using reported methods
starting from (R,R) and (S,S) diethyl tartrate16. All other
molecules were built-up by modifying these starting aziridines.
Scheme 2 shows the one set of enantiomers of different
synthesized aziridines. At first, protecting groups were
Aziridines
open by fluoride ion. Several fluorinating agents were
screened to ring open or or . Table 2 shows the various
1 to 4 were chosen as model substrates to ring
introduced to
1 as shown in scheme 3 to synthesize 3, 4 and 5.
Contrary to formation of sulfonamides and carbamates,
methylation of the nitrogen was not straightforward. As a
result we screened the approaches surveyed in table 1 for
appropriate conditions. Even the most reactive methylating
reagents (MeOTs, MeOMs MeONs) did not give products in
presence of weak to moderate bases. We surmised that the
failed reactions might be due to the weakly basic and non-
nucleophilic nature of the aziridine nitrogen. For this reason,
we investigated strong bases including n-BuLi and KHMDS to
achieve complete deprotonation of amine in presence of a
1
3
4
reaction conditions and fluorinating sources used. None of the
fluorinating agents, except entries 13-14, gave the desired
fluorinated products. Metal fluorides and tetrabutyl
ammonium fluorides (TBAF) gave trace amounts of products
(19F NMR). While rather low yields were obtained we
attributed the limitation to concurrent side reactions.
Observed side products originating from elimination are the
main culprit. The HF reagents such as DMPU-HF (65% HF), and
Olah’s Pyridine-HF (70% HF) gave the fluorinated
intermediates in isolable yield. Another HF reagent Et3N.3HF
did not give any fluorinated product.
Scheme 4: Synthesis of alkenyl aziridines 7 to 14
Scheme 2 Various synthesized aziridine substrates
2 | J. Name., 2012, 00, 1-3
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Table 1 N-methylation reaction optimization of 1a
Entry
Base
Methyl source
Solvent
Temp Time
(°C)
Isolated
Yield (%)
1
2
NaH
K2CO3
CH3I
Methyl nosylate
Methyl nosylate
37% HCHO, Pd/C, H2
Methyl nosylate
Methyl tosylate
Methyl tosylate
Methyl mesylate
Methyl mesylate
Methyl mesylate
37% HCHO, (CH3COO)3BHNa
Methyl tosylate
Methyl tosylate
CH3I
THF or DMF
CH3CN or DMF
THF or DMF
EtOH
0-rt
rt
16 h
24 h
24 h
12 h
50 h
26 h
24 h
30 h
90 h
120 h
25 h
95 h
14 h
4 h
0
0
3
DBU
rt
0
4
-
rt
0
5
DIPEA
K2CO3
THF
rt-50
rt
0
6
DMF
0
7
DIPEA
Proton sponge
NaHCO3
NaHCO3
-
THF
rt
0
8
THF or CH3CN
DMF or CH3CN
EtOH
rt
0
9
rt
0
10
11
12
13
14
15
rt
5
DCE
rt
0
NaHCO3
NaH
EtOH
rt
7
DMF
0-rt
-78-rt
0 – rt
0 – rt
0 – rt
4
n-BuLi
KHMDS
KHMDS
KHMDS
THF
15
40
5
Methyl tosylate
Methyl mesylate
CH3I
THF
7 h
THF
14 h
14 h
THF
11
aReactions were performed with 1 (0.4 mmol), methyl source (0.4 to 0.8 mmol), solvent (2.5 mL) n≥2; DBU 1,8-diazabicyclo[5.4.0]undec-7-
ene, DIPEA N-ethyl-N,N-diisopropylamine, KHMDS potassium bis(trimethylsilyl)amide, THF tetrahydrofuran, DCE 1,2-dichloroethane, DMF
N,N-dimethylformamide
Table 2 Screening of fluoride sources to ring open 1, 3, 4a
Entry Aziridine Fluoride source
Solvent
CH3CN or DCE
DMSO or CH3CN
DCE
Temperature(°C)
rt-50
rt-80
rt
Time
48 h
6 h
Yield (%)
1
2
1
Et3N.3HF
TBAF (tBuOH)4
Olah’s HF
-
b
-
3
24 h
24 h
6 h
-
4
DMPU-HF
DCE
rt
-
5
3
TBAF (tBuOH)4
[KF][K222
CH3CN
rt - 80
rt - 80
rt - 50
rt - 50
rt - 80
rt - 80
rt - 80
rt
-
6
]
CH3CN or DMSO
CH3CN
16 h
84 h
26 h
16 h
24 h
6 h
Trace
7
[KF][18-C-6]
TBAFc
-
8
CH3CN or THF
DMSO
Trace
9
[CsF]
-
-
10
11
12
13d
14d
4
[KF][K222
]
DMSO or CH3CN
CH3CN
TBAF (tBuOH)4
Et3N.3HF
-
DCE
60 h
48 h
48 h
48 h
48 h
48 h
30 min
-
Olah’s HF
DCE
0 - rt
16
24
6
DMPU-HF
DCE
0 - rt
DMPU-HF
TBME
0 – rt
0 – rt
0 – rt
50
DMPU-HF
DCM
13
5
DMPU-HF
THF
15e
5
TBAF (tBuOH)4
CH3CN
31
aAziridine (0.3 mmol), Fluoride (0.3 to 3.0 mmol), solvent (2 mL); HF reactions in 6 mL PE vial; n≥2; bfor preparation see reference17; c1 M in
THF; disolated yield, esee radio chemsitry section; DCM 1,1-dichloromethane, DCE 1,2-dichloroethane, DMPU 1,3-dimethyl-3,4,5,6-
tetrahydro-2(1H)-pyrimidinone, 18-crown-6- 1,4,7,10,13,16-hexacyclopctadecane, K222crypt-222
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Table 3 Ring opening of various aziridines by DMPU-HFa
Journal Name
Entry Substrate
R1
R
Temperature
0°C-rt
Time
48 h
7 d
Product Isolated yield %b
1c
2d
3
4
6
-Cbz
-CH3
-Boc
-Cbz
-Ts
-COOEt
4a
6a
7a
8a
9a
10a
11a
12a
-
24
6
-COOEt
rt-50°C
0°C
7
-CH=CH-COOMe
-CH=CH-COOMe
-CH=CH-COOMe
-CH=CH-CN
-CH=CH-CN
-CH=CH-CN
30 min
1 h
32
43
48
21
45
37
0
4
8
0°C
5
9
0°C - rt
0°C
1 h
6
10
11
12
13 or
14
-Boc
-Cbz
-Ts
30 min
1 h
7
0°C
8
9e
0°C - rt
-78°C (DCM)
0°C-rt
1 h
-Boc or -Cbz -CH=CH-CH2-CH2-COOMe
1 h
2-10 h
-
aReactions were performed with Aziridine (0.3 mmol), DMPU-65%HF (1.2 mmol), DCE (1 mL), in 6 mL PE vial; n≥2; bsimilar yields were
obtained with another set of starting aziridines; c3 mmol 65%HF; d4.5 mmol Olah’s-70%HF; eonly side products also with Olah’s-HF, Et3N-HF
Given the ease of making the reference compounds, HF discussion can be ignored. Non-symmetric aziridines
7 to 12
reagents was used for synthesis of reference materials. are prone to ring open at C3 because the adjacent allylic group
However, with fluorine-18 (t1/2 110 min) this is not an option
because of the problems associated with [18F]HF reagent(s)
preparation and stoichiometry1819. Table 3 shows the ring
opening of the mentioned aziridine substrates with DMPU-
65% HF except the entry 2, in which Olah’s 70% HF was used.
Since the absence of activating group on nitrogen of
6 and the
weak acidic nature of HF complexes to protonate these
amines, the fluorinated products were obtained in very low
yield (Table 3, entry 2). Lewis acids such as yttrium triflate or
copper triflate were used to coordinate the amine prior to ring
opening by fluoride. Most of the starting material was
consumed in presence of catalytic amounts of these acids but
the products obtained are complex fluorinated side products.
The high reactivity towards ring opening of aziridine substrates
Scheme 5: Synthesis of 15 and 16. Reagent and conditions i. a)
Pd/C, H2, EtOH, CHCl3, 40 min, b) 4M HCl (aq), reflux, 20 h, 15
(81%) ii. a) Pt/Al2O3, H2, EtOH, few drops conc.HCl, 1 h, b) 4M
HCl (aq), reflux, 16 h, 16 (36%)
7
to 12 arise from the adjacent allylic group and also the
nitrogen activating groups (Table 3, entries 3-8). Partial
hydrolysis of the protective groups was noticed under the
acidic reaction conditions in all the cases accounting to the
moderate yields.
which we believe stabilizes the SN2 transition state and
increases the rate constant. It was noticed that an electron
withdrawing group conjugated to olefin is necessary to obtain
the desired fluorinated products. Indeed, aziridines 13-14,
The fluorinated intermediates 7a, 8a and 10a, 11a were
further modified to synthesize 2-amino-3-fluoro adipic acid 15
and 3-fluoro lysine 16 respectively. Scheme 5 shows the
which were expected to give 2-amino-3-fluoro suberic acid, did
not lead to fluorination. Instead, -OH group substitution was
noticed giving the diastereomeric products.SI With
confirmation of the stereoselective outcome as a motivation
we began translation of the chemistry into a radiolabeling
protocol.
reaction steps to prepare 15, 16
.
At this point, the remaining challenge was to find a non-
acidic fluoride complex as used in radiochemistry to achieve
the desired fluorination reaction. We suspected that our
fluoride complexes contains too much moisture under
stoichiometric conditions20 and prepared TBAF(tBuOH)4. This
effort was rewarded ring opened products when sulfonamides
were used, though none of the other starting materials
reacted. This allowed for analysis of the stereochemical
product distribution under radiochemical conditions.
Radiochemistry: Very few publications are known for the
chemistry with aziridines and [18F]fluoride ion and have
described the aziridine ring opening by [18F]fluoride to obtain
biologically important motifs18,19,21-23. All synthesized aziridine
precursors in this work were subjected to ring opening by
various [18F]fluoride ion systems. Similar disappointing results,
as with non-radioactive fluoride, were noticed with
With respect to the expected products, aziridines 1 to 6 are
[18F]fluoride. Initially, aziridines
3 and 4 were reacted with
symmetric in nature and therefore the regioselectivity
potassium-crypt-222 cryptate [18F]fluoride ion complex in
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Table 5: aRadiochemical yields of [18F]intermediates and tosyl
[
various solvents and temperatures with conventional heating
(SI, T1). Some 18F incorporation was noticed in most of the
labeling reactions, but the labelled products were not the
desired ones26. The same substrates were then reacted with
18F]fluoride (n≥4)
Entry Aziridine Product Yield (±4%)
[
18F]TsF (±2%)
1
2
3
5
9
[
[
18F]5a
57
9
3
3
5
18F]9a
other
combinations
of
fluorine-
18F]12a
16
18, phase transfer catalyst and bases such as
tetraethyl
12
[
-
ammonium bicarbonate (TEAHCO3 ), tetrabutyl ammonium
hydroxide (TBAOH), cesium carbonate (Cs2CO3), crypt-222-
potassium oxalate (K2C2O4), and 18-C-6/KHCO3. Changing the
[18F]fluoride systems had no impact on the result. Other
aLabelings were performed with [18F] (0.3 to 1 GBq), aziridine (10
µmol), TEAHCO3 (10 µmol), DMSO (0.3 mL); 50°C, 10 minutes;
-
Decay corrected yields based on the starting radioactivity
aziridines 6, 7, 8,
10 and 11 were also reacted with above [18F]
fluoride systems (SI, T2). The failed radioactive experiments
are in line with the non-radioactive experiments (Table 2).
Attempts to ring open with pyridine. [18F]HF24 and
DMAP.[18F]HF25 were unsuccessful as expected.
Table 4 shows several of the attempted conditions and the
[18F]labelled products. With respect to the results, we felt that
harder complex cations performed worse than softer
alternatives such as TEA and TBA. Only the –tosyl activated
aziridines were labelled as expected giving the desired [18F]
intermediate products (Table 4, entries 3, 7, 10). Having
noticed the formation of desired [18F]intermediates with tosyl
aziridines, labeling conditions were further optimized. The
fluoride systems [18F]KF(crypt-222), [18F]TEAF, [18F]TBAF in
different solvents and temperatures were used to ring open
the tosyl aziridines. All of them gave the desired fluorine-18
labelled intermediates and also tosyl [18F]fluoride ([18F]TsF) as
a minor product (SI, T3 for optimization conditions).
Figure 1 RadioꢀHPLC, UV traces of [18F]5a (below), [19F]5a
(top); Supelco supelcosil ABZ plus C18, 5 µm, 250 x 4.6 mm,
CH3CN:H2O (50:50), 1 mL/min
The desired [18F]products and tosyl [18F]fluoride were
separated from free fluorine-18 using C18 and silica cartridges.
Table 5 shows the decay corrected radiochemical yields of
(synthesis time of 35-40 minutes from end of bombardment
(EOB)) [18F]products and tosyl [18F]fluoride. The radiolabelled
products were identified by co-elution with the authentic
samples. HPLC analyses of [18F]9a and [18F]12a have also
shown an additional radioactive signal co-eluting with the
desired radioactive products not visible by TLC. We presumed
this additional radioactive peak belongs to the C2 ring opened
product. As mentioned before, a similar soluble and anhydrous
[19F]TBAF(tBuOH)4 was used to ring open tosyl aziridines. The
[19F]fluoride ring opened products with this source are in line
with the [18F]fluoride ring opened products. Figure 1 shows the
radio-HPLC, UV traces of [18F/19F]5a
Table 4 a 18F]incorporated yields based on radio TLC (n≥10)
[
18F]TEAF
R1
N
[
18F
O
O
R
O
DMSO
R
HN
R1
O
80 °C, 10 minutes
Entry Aziridine
R1
Product Conversion (±5%)b
1
2
3
4
-Boc
-Cbz
-Ts
[
[
[
[
[
[
[
18F]3a
18F]4a
18F]5a
18F]6a
18F]7a
18F]8a
18F]9a
-
-
3
5
70
-
4
6
-CH3
-Boc
-Cbz
-Ts
5
7
-
6
8
-
7
9
19
-
8
10
11
12
-Boc
-Cbz
-Ts
[
[
[
18F]10a
18F]11a
18F]12a
Conclusions
9
-
In conclusion, we have prepared enantiomerically pure acid
and base sensitive aziridines equivalent to various amino acid
precursors and subjected to ring opening with [18F/19F]fluoride
ions. The -tosyl aziridines were found superior compared to –
Boc or –Cbz aziridines towards ring opening by non-acidic
[18F/19F]fluoride sources. Non-activated N-methyl aziridines led
to dissatisfactory results. We are convinced that the presented
results bode well for production of novel amino acid
radiotracers.
10
24
aLabelings were performed with [18F] (0.2 to 1.1 GBq), aziridine (10
-
µmol), TEAHCO3 (10 µmol), DMSO (0.3 mL); b50% Ethyl acetate in
hexanes and the yields were related to the total radioactivity
Conflicts of interest
There are no conflicts to declare.
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C18 cartridges and subjected to acidic hydrolysis or
hydrogenation followed by hydrolysis reactions. These
reactions followed by work-up resulted in complete loss of
activity, whereas the reaction mixture gave mainly the
baseline species in radio-HPLC and radio-TLC (normal phase,
reverse phase TLCs) with the amino-acid standard mobile
phase systems.
Acknowledgements
Financial support from the faculty of Mathematics and Natural
Sciences (realomics SRI), University of Oslo is gratefully
acknowledged.
Notes and references
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2
3
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L. Antolini, M. Bucciarelli, E. Caselli, P. Davoli, A. Forni, I.
Moretti, F. Prati and G. Torre, Reactions, 1997, 3263, 8784–
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5
6
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