A rapid and highly enantioselective C-11C bond formation of l-[11C]phenylalanine via chiral phase-transfer catalysis

Article abstract of DOI:10.1039/c6ob02633h

A rapid method for the synthesis of carbon-11 radiolabeled phenylalanine was developed using a chiral phase-transfer catalyst and a sub-nanomolar quantity of [¹¹C]benzyl iodide as a radio-precursor. Based on a reported synthesis of [¹¹

Full text of DOI:10.1039/c6ob02633h

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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A Rapid and Highly Enantioselective C-11C Bond Formation of
L-[11C]Phenylalanine via Chiral Phase-Transfer Catalysis
Aleksandra Pekošaka, Ulrike Filpa, Janja Škrinjara,b, Alex J. Poota and Albert D. Windhorsta
tge Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A rapid method for the synthesis of carbon-11 radiolabeled
phenyalanine was developed using a chiral phase-transfer catalyst
and sub-nanomolar quantity of [11C]benzyl iodide as radio-
precursor. Based upon a reported synthesis of [11C]benzyl iodide, a
Schiff base precursor was evaluated for stereoselective
[11C]benzylation. Extensive and interactive screening of precursor,
catalyst, base, stirring and temperature was required to achieve
high stereoinduction. The result is an efficient 5-step radiolabeling
method to reliably synthesize L- or D-[11C]phenylalanine with an
excellent enantiomeric excess of >90% and almost quantitative
radiochemical conversion of >95% (n>5).
Additionally, a phase-transfer catalyzed alkylation was utilized
on the preparative scale using automated platform. The
application resulted in high specific activity ranging from 85-135
GBq·μmol−1 of the enantiomericaly pure [11C]phenylalanine,
showing the process is robust and amenable to broad use in PET.
8,9
Figure 1: General synthetic routes to obtain [11C]phenylalanine
.
Positron emission tomography (PET) is a non-invasive
imaging technique used for clinical diagnostic applications in
oncology, neurology and cardiology, as well as drug
development. The radionuclide carbon-11 (t1/2=20.4 min, 99%
β+, 0.96 MeV) is commonly used in PET, since the ubiquity of
carbon atoms in all naturally occurring organic compounds
makes it an attractive isotope for radiolabeling.1–4 The notable
information PET can provide strongly depends on the
development and availability of PET-tracers. Current tracer
development remains challenging and still relies on the
application of a very small number of radiochemistry methods,
where carbon-12 is substituted with radioactive carbon-11.
The formidable challenge in the synthesis of 11C-labeled AAs
still lies in the stereoselective reaction on the α-carbon
avoiding time consuming chiral separation via HPLC to ontain
enantimoerically pure form9, next to convenience and
reliability of the radiolabeling process, limited by synthesis
time and specific activity (SA) (GBq·μmol-1), all important
parameters that apply to radiopharmaceuticals.1,5,8,10,11
Our approach to synthesize chiral α-AAs utilizes the
alkylation of an activated methylene group, the glycine Schiff
base, in the presence of quaternary ammonium salts as chiral
phase-transfer catalysts (PTCs).12–15 To the extent of our
knowledge, the use of chiral alkylation reactions in the
presence of PTCs have not been described for the
enantioselective radiolabeling of phenyalanine with carbon-11,
as depicted in Figure 1.8,16–20 Accordingly, asymmetric
alkylation would be a powerful approach to overcome the
mentioned limitations in 11C-chemistry preserving the known
properties, like target affinity, selectivity and specificity.
consequently
limiting
facile
synthesis
of
novel
radiopharmaceuticals.3,5
An important class of chiral PET radiopharmaceuticals are
radiolabeled amino acids (AAs) used to image e.g. up-
regulated AA metabolism that is described for cancer cells.6,7
With variable successes, and often in an asymmetric manner,
many carbon-11 AAs isotopologues have been accomplished,
The importance of enantiopurity of radiopharmaceuticals is
paramount for radiolabeled AAs where stereochemistry
influences the rate and selectivity of AA transport, preferential
a.Department of Radiology and Nuclear Medicine, VU University Medical Center,
Amsterdam, the Netherlands. E-mail: a.pekosak@vumc.nl
b.Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
† Electronic Supplementary Information (ESI) available: See
DOI: 10.1039/x0xx00000x
for
application of
enzymatic separation, where the
L
-enantiomers in mammalian cells.21 Demonstrated by the
L
- and
D
-[11C]phenylalanine, synthesized using
-enantiomer of
L
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[11C]phenylalanine showed better pancreas-to-liver ratios.22
This was even further proven by the better imaging properties
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DOI: 10.1039/C6OB02633H
of
demonstrating high uptake in tumor compared to surrounding
tissues. These studies, not mentioning the gold standards
[11C]methionine and -[18F]-fluoroethyl tyrosine, thus
L
-18F-labeled fluoroalkyl phenylalanine analogues, all
L
-
L
emphasize the need for methods to synthesize
enantiomerically pure AAs as PET tracers.23–25
In this communication we describe a new and generally
applicable radiosynthetic method for the enantioselective
synthesis of carbon-11 labeled
L
- and
D
-AAs by employing
- and D-
chiral PTC. This method is applied to synthesize
L
Scheme 1: Radiosynthesis of
[11C]phenylalanine amide 11.
L 8 and DL-
-[11C]phenylalanine
[11C]phenylalanine, an essential aromatic AA used for tumor
imaging, and its unnatural analogue phenylalanine amide.26
The methodology described was translated from manual
proof-of-concept radiosynthesis to a preparative scale on an
range form 55-60 mM. The radio-HPLC analysis was very
encouraging and proved 85±6% RCC (of to racemic ) after
10 min at 45 ⁰C in presence of DCM and DMSO as a solvent§§
5
7
automated platform in
a GMP compliant laboratory.
.
Furthermore, the here described rapid and robust
radiolabeling might enable unprecedented native 11C-labeling
of peptides by alkylating a prochiral Schiff base-activated
glycine residue.
Encouraged by the rapid and near quantitative [11C]benzylation,
we turned our attention to five commercially available chiral PTCs
and their influence on stereoinduction (Figure 2). Adapting the
conditions from sucessful organic chemistry, we envisioned that
high excess of hydroxide base CsOH·H2O, namely 150 eq compared
to precursor 6, toluene as solvent at 0 ⁰C provided us almost
quantitative RCC with moderate stereoselectivity (enantiomeric
excess (ee) of 46±2%) for L-[11C]phenylalanine 8 in presence of 10
mol%‡‡ Corey’s28 Cat 1 (Table 1, Entry 9). Large excess of base
provided suficcient interfacial area between the two phases for this
solid-liquid PTC. The ee was further increased to 75% by cooling the
[11C]benzyl iodide solution 5 to 0 ⁰C prior to the addition of 6 (Table
1, Entry 11). These series of experiments also revealed new
optimized reaction conditions, 170 eq‡‡ of CsOH·H2O for 7 min
at 0 ⁰C, where precursor concentration could even ranged
between 20-90 mM.
The enantioselective synthesis of L- and D
-[11C]phenylalanine
was achieved in 5 steps starting from cyclotron produced
[11C]CO2, as depicted in Scheme 1. The first 3 steps involved a
one-pot Grignard reaction to obtain [11C]benzyl iodide 5,26 as
alkylating reagent followed by subsequent asymmetric
[11C]benzylation on the commercially available Schiff base
precursor 615 with the aid of a commercially available chiral
PTC. Acidic deprotection of the alkylated intermediate yielded
enantiopure [11C]phenylalanine, the desired product.
A major challenge in translating the mild phase-transfer
conditions from successful organic to carbon-11
radiochemistry is the reaction time and the distorted
stoichiometric condition in radiochemistry. Where in organic
chemistry, reactions are allowed for several hours, in carbon-
11 radiochemistry only a few minutes are acceptable. In
addition, one is limited in radiochemistry by the low amount of
carbon-11 labelled reagent, typically between 50-100 nmoles,
resulting in large excess of non-radiolabelled reagents which
are typically in the mmol range, influencing the reaction
kinetics dramatically. Furthermore, small contaminants
present in the reaction mixture might destroy the low amounts
of carbon-11 labeled reagent easily.
Table 1: Screening the [11C]alkylation conditions for Cat 1.
RCC
Eq of
basea
T
ee 8
[%]c
c of 6
[mM]
Entry
Base
Solvent
7
[%]b
5
[⁰C]
1
2
55-60
55
KOH
KOH
10
20
PhMe+DCM
PhMe+DCM
PhMe+DCM
PhMe+DCM
PhMe+DCM
PhMe+DCM
PhMe+DCM
PhMe
-5
-5
-5
-5
RT
-5
RT
RT
-5
0
/
<1
/
3
55
KOH
30
4±2
4±0
10
/
4
55-60
55
KOH
35
/
We first engaged in the SN2 alkylation to obtain high
5
radiochemical conversion (RCC) into the intermediate
controlling the following parameters: order of addition, mixing
of the reaction, amount of precursor and precursor
concentration, reaction time, base, amount of base, solvent
and temperature (T) (Table 2, ESI ). As a proof-of-principle, we
initially investigated reaction conditions in presence of a
strong base, tetra-n-butylammonium fluoride (TBAF).27 At this
stage, we speculated that it was necessary to carefully
examine the precursor concentration in order out-compete an
undesired side effect during the radiolabeling, namely
cleavage of the diphenylmethylene group on N-terminus27 to
benzophenone and glycine tert-butylester, crucial for
7 by
KOH
40
/
6
60
CsOH·H2O
CsOH·H2O
CsOH·HO
CsOH·H2O
CsOH·H2O
CsOH·H2O
10
4
/
6
7
60
10
2
/
/
8
60
10
6
†
9
40
150
150
170
PhMe
92±1
83±8
91±1
46±2
/
10
14
20
PhMe
90
PhMe
0*
75±2
All reactions were conducted with 17 µmol
6 and 0.1 eq of Cat 1 in 10 min.
PhMe stands for toluene and DCM for dichloromethane. aCompared to
6.
bRadiochemical conversions were determined by HPLC. cEnantiomeric excess
was determined by chiral HPLC. *Reaction was performed for 7 min.
activation of
6
, and provide a sufficinet amount of
6 for the
[11C]benzylation. An increased amount of
6
(17 µmol per
An enhanced enantioselective formation of
L-
[11C]phenylalanine was observed by employing Maruoka’s
catalyst (R)-Cat 3 to ee of 91%, without having an effect on the
RCC (Table 2). Unfortunately, the combination of toluene and
dichloromethane as solvent mixture resulted in a decrease of
alkylation reaction), gave indeed high RCC and further
experiments confirmed that precursor concentration can
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enantioselectivity (ee of 78%). Employing a lower mol% of
Despite the success of N-spiro C2-symmetric chiral Cat 414
catalyst‡‡ was fruitless as well (ee of 78%), contrary to in organic chemistry and also in tDhOeI: 1r0a.d10io3V9si/yeCwn6tAOhrtBeic0lse2isO6n3l3ionHef
Kitamura.29 However, a high ee could also be obtained at [18F]FDOPA30, this catalyst did not demonstrate desired
lower T of -20 ⁰C (ee of 88%).
enantioselectivity in the [11C]benzylation reaction. Standard
conditions, resulted in an excellent RCC of 90%, but undesired
ee of only 66% for L
-[11C]phenylalanine (Table 2, Entry 12).
Lastly, the use of dimeric Cinchona-derived alkaloid Cat 5
was investigated. The use of Cat 5 resulted in a high RCC of the
reaction, but unfortunately, a lower ee of the product of 79%
towards
L
-[11C]phenylalanine was obtained (Table 2).
Experiments with lower mol%‡‡ of catalyst or lower T (-20 ⁰C)
were meaningless, contrary to remarkable catalytic and chiral
efficiency in organic chemistry.31 Introduction of
a
naphthalene ligand in Cat 5, compared to 9-anthracenylmethyl
in Cat 1, resulted in enhancement in enantioselectivity.
Unexpectedly, as can be concluded from the results
obtained, slight reaction rate retardation in the enantiofacial
differentiation compared to benzylation in organic chemistry
seems inevitable. The excellent RCCs obtained can be
explained by the effective surface area of solid base and
nanomolar and sub-stoichiometric amounts of
5 that react
instantly. On the other hand, latest advantage might serve as a
drawback for enantioselectivity, since the alkylating agent
should be longer exposed to the PTC conditions employing
lower Ts (-78 to -40 ⁰C), which are regularly used in organic
chemistry, to result in extremely high enantioselectivities.13–15
Extrapolations of these conditions to radiochemistry,
especially with short-lived isotopes like carbon-11, is not
feasible as the synthesis time must be kept as short as possible
in radiochemistry.
Figure 2: Chiral PTC explored for the radiosynthesis of L- and D-
[11C]phenylalanine and L- and D-[11C]phenylalanine amide. Blue:
catalysts yielding L-product; Red: catalyst yielding D-product.
Catalyst-controlled asymmetric induction of the [11C]benzyl
group was investigated when (S)-Cat 2 was used to yield
specifically
D
-[11C]phenylalanine (Table 2). As depicted in
Figure 2, Cat 2 and Cat 3 are enantiomers, therefore both
chiral PTCs should yield comparable RCC and ee under the
same reaction conditions, however with opposite enantiomers
as product. Surprisingly, slightly lower enantioselectivity of ee
up to 86%, relative to Cat 3 was observed (ESI‡‡). In contrast,
lower T of -20 ⁰C this time gave rather disappointing results,
decrease of enantioselectivity to 57%, next to a lower RCC. The
lower RCC is explained by the lower T and consequently slower
RCC (%)
ee (%)
100
90
80
70
60
50
reaction kinetics, as
6 was still observed on HPLC.
Table 2: Screening the [11C]alkylation conditions for Cat 1.
Eq of
base a
150
150
170
170
170
170
150
150
170
170
40
Time
[min]
10
10
7
RCC 7
[±SD; %]b
91
ee 8
[±SD; %]c
85
PTC
Entry
[mol%]a
T [⁰C]
Cat 1
Cat 2
Cat 3
Cat 4
Cat 5
Phase-Transfer Catalysts
1
2
Cat 3 (10)
Cat 3 (10)
Cat 3 (10)
Cat 3 (2.5)
Cat 3 (10)
Cat 3 (10)
Cat 2 (10)
Cat 2 (10)
Cat 2 (10)
Cat 2 (10)
Cat 2 (10)
Cat 4 (10)
Cat 5 (10)
Cat 5 (5)
0
0*
Graph 1: An overview of the screened PTC for the
radiosynthesis of - or
-[11C]phenylalanine. All reactions were
80±11
84±5
84
91±10
74±1
78
L
D
3
0*
conducted with 17 µmol of
6, 10% of catalyst, 170 eq of
4
5d
0*
7
CsOH·H2O(s) and 400 µL of toluene for 7 min at 0 ⁰C. ‡‡
0*
7
84
78
6
-20*
0
7
89
88±1
72±4
83±5
85.5
After screening all selected chiral PTCs, Cat 3 has been
7
10
10
7
53±2
74±12
92±1
56±7
54±13
90±1
91±3
91±1
87±2
identified as a catalyst of choice for the preparation of
L-
8
[11C]phenylalanine
8
(Graph 1). Further investigations
0*
9
0*
therefore focused on decreasing the excess of base used,
monitoring the effect on RCC and ee. With 40 eq‡‡ of
CsOH·H2O(s) high conversion and enantioselectivity (RCC:
90±6%; ee: 83±5%) were still observed (Graph 2), and are
consistent with results of other reports.30–33 Recently Kano
reported asymmetric solid-liquid phase-transfer benzylation
10
11
12
13
14
15
-20*
0*
7
57±1
76±6
66±10
77±0
68±1
79±2
7
150
170
170
170
0*
10
7
0*
0*
7
on the
6 in organic chemistry using the homogenizer in 5
Cat 5 (10)
-20*
7
min.34 Aiming to adapt these conditions we achieved RCC of
93±0% and ee of 90±3% in only 40 s using vortex mixing.
Though the superfast 11C-benzylation (from 7 min to 40s)
provided slighly better results (Graph 2), the manual use of
All reactions were conducted with 17 µmol
a% of catalyst and eq of base are compared to
were determined by HPLC. cEnantiomeric excess was determined by chiral HPLC.
*Precooled
to desired T. dCombination of toluene and DCM (400 µL; v/v=1/1).
6
and 400 µL of toluene in 10 min.
6.
bRadiochemical conversions
5
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Vortex mixer is not justified due to the radioation dose
radiochemist is exposed during the experiment. Base upon, it efficient multi-step synthesis to obtain DeOnIa: n10t.i1o0m39e/Cri6cOalBly02p63u3rHe
was clear that vigorous stirring enlarges the interfacial contact
-[11C]phenylalanine by applying a chiral PTC, so far unexplored
between the two phases and results in considerable rate in carbon-11 radiochemistry. Moreover, this methodology
enhacement. At this stage, we could speculate that even lower enables enantiomerically pure
-[11C]phenylalanine, which
amounts of base would attain a sufficient raction rate on cannot be obtained using well established enzyme-catalyzed
In summary, we successfully developed a novel, rapid and
View Article Online
L
D
Vortex mixer.
synthesis. The overall process illustrates the challenges in
determining optimal conditions for controling this
[11C]benzylation that yielded an enantiopure [11C]phenylalanine
.
RCC (%)
ee (%)
More specifically, an interactive systematic automation of all
5steps revealed the procedure is reliable and reproducible,
100
90
and employs commercially available precursor
6 and Cat 3.
80
Further research that is under investigation focuses on translating
this powerful methodology towards carbon-11 labeling of peptides
in an enantioselective manner.
70
%
60
50
40
30
UV:
1,00
L-Phenylalanine
mV *1000
0,80
D-Phenylalanine
0,60
10
20 40 ** 40
60
80
100
150
170
0,40
0,20
0,00
Eq of CsOH*H2O
Graph 2: Effect of CsOH·H2O on RCC [±SD;%] and ee [±SD;%] of
Cat 3
.
00"00
02'00
04'00
06'00
08'00
10'00
12'00
14'00
16'00
18'00
min
Radioactivity:
CPS *1000
Having established an efficient enantioselective synthesis
-[11C]phenylalanine, we extended the PTC use and
application to the asymmetric synthesis of unnatural α-AAs as
well, since nonproteinogenic AAs play a special role in
peptidomimetics. In order to explore the applicability of the
5,00
4,00
3,00
2,00
1,00
0,00
L-[11C]Phenylalanine
for
L
D-[11C]Phenylalanine
7
developed method, achiral glycinamide precursor
9 has been
studied (Scheme 1), since amides tend to be more stable under
PTC conditions and in vivo.35–37 As anticipated from initial
experiments with TBAF for LD-[11C]phenylalanine§, this strong
00"00
02'00
04'00
06'00
08'00
10'00
12'00
14'00
16'00
18'00
min
Figure 3: HPLC UV and radioactivity profile of the crude reaction
base appeared sufficient for [11C]benzylation towards 10 (RCC mixture after automation procedure with co-injection of the cold
standard L- and D-Phenylalanine: Separation of D- and L-
up to 70%), while Cs2CO3(s) or PTCs, like TBAB(s) and TBAHS(s)‡,
were ineffective (RCC of <5%). Aiming to achieve the [11C]phenylalanine on chiral column to determine ee %.
enantioselective synthesis of unnatural
amide 11 chiral PTC from Figure
L
-[11C]phenylalanine
2 demonstrated no
,
The research leading to these results has been financially
supported by the European Marie Curie Actions RADIOMI ITN
(FP7-PEOPLE-2012-ITN; no. 316882). BV Cyclotron VU
(Amsterdam) is acknowledged for providing [11C]CO2.
stereocontrol, despite the superb incorporation (RCC up to
99%) of and variations in the solvent and temperature (Table
3, ESI‡). Evidently, deprotonation of α-hydrogen of does not
5
9
generate the enolate to interact with the ammonium cation
from chiral catalysts resulting in formation of lipophilic onium
enolate, like 6
(Figure 15, ESI‡).13,38,39
Notes and references
Final step, removal of protecting groups has been achieved
at elevated temperatures (120 ⁰C for 2 min) and under acidic
conditions by addition of 12M HCl(aq) (200 µL) resulting in a
‡ Footnotes are explained in the ESI.
‡‡ mol% and equivalents (eq) compared to precursor
7 or 9.
§
Reaction conditions: 1 eq of precursor 6, 2 eq of TBAF, 100
quantitative >96% conversion to product
8 or 11 (Table 4,
µL of DCM, 300 µL of DMSO and in situ produced [11C]benzyl
iodide vigorously stirred for 10 min at 45 ⁰C.
ESI†). Afterwards, the exact stereochemical outcome was
determined using chiral radioHPLC (ESI† and Figure 3).
§§ Reaction conditions: 1 eq of precursor 6, 0.1 eq of Cat 3, 40
In order to demonstrate the utility of the developed
method in producing a novel PET-tracer, the total synthesis of
eq of CsOH·H2O, 400 µL of toluene and in situ produced
[11C]benzyl iodide vigorously stirred for 7 min at 0 ⁰C, followed
by addition of 200 µL of 12M HCl for 2 min at 120 ⁰C.
L
-[11C]phenylalanine was scaled-up and fully automated with
starting amounts of approximately 50 GBq of [11C]CO2
according to GMP standards (ESI ).
-[11C]Phenylalanine was
synthesized within 24 minutes and yields were 5-7 GBq§§ at the
end of synthesis, corresponding to decay-corrected
†
† L
1
2
3
W. Wadsak and M. Mitterhauser, Eur. J. Radiol., 2010, 73,
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a
radiochemical yield of 27±7%, calculated from the end of the
production of [11C]CO2. Analysis showed an ee of >90% (Figure
2) and a SA of 85-135 GBq/µmol at the end of synthesis (EOS).
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