Synthesis of l-[4-11C]Asparagine by Ring-Opening Nucleophilic 11C-Cyanation Reaction of a Chiral Cyclic Sulfamidate Precursor

Article abstract of DOI:10.1002/chem.201801029

The development of a convenient and rapid method to synthesize radiolabeled, enantiomerically pure amino acids (AAs) as potential positron emission tomography (PET) imaging agents for mapping various biochemical transformations in living organisms remains

Full text of DOI:10.1002/chem.201801029

A Journal of
Accepted Article
Title: Synthesis of L-[4-11C]Asparagine via Ring-Opening Nucleophilic
11C-Cyanation Reaction of a Chiral Cyclic Sulfamidate Precursor
Authors: Youwen Xu, Aylin Sibel Cankaya, Ruma Hoque, So Jeong
Lee, Colleen Shea, Lena Kersting, Michael Schueller, Joanna
S. Fowler, David Szalda, David Alexoff, Barbara Riehl, Tassilo
Gleede, Richard A. Ferrieri, and Wenchao Qu
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Synthesis of L-[4-11C]Asparagine via Ring-Opening Nucleophilic 11C-Cyanation
Reaction of a Chiral Cyclic Sulfamidate Precursor
Youwen Xu†, Aylin Sibel Cankaya†, ‡, Ruma Hoque†, ¶, So Jeong Lee†, §, Colleen Shea†, Lena Kersting†,
‡, Michael Schueller†, Joanna S. Fowler†, §, David Szalda£, David Alexoff†, Barbara Riehl†, ‡, Tassilo
Gleede†, ‡, Richard A. Ferrieri†, Wenchao Qu*, †
†Biological, Environmental and Climate Sciences Department, Brookhaven National Laboratory, Upton,
NY 11973, USA
‡
Institut für Kernchemie, Johannes Gutenberg-Universität, D-55128, Mainz, Germany
¶Biochemistry Department, Medgar Evers College, Brooklyn, NY11225, USA
§Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, USA
£ Department of Natural Sciences, Baruch College, CUNY, New York, NY 10010, USA
*Email: weq2002@med.cornell.edu
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ABSTRACT
The development of a convenient and rapid method to synthesize radiolabeled enantiomerically pure
amino acids (AAs) as potential positron emission tomography (PET) imaging agents for mapping various
biochemical transformations in living organisms remains as a challenge. This is especially true for the
synthesis of carbon-11 labeled AAs given the short half-life of carbon-11 (11C, t1/2 = 20.4 min). A facile
synthetic pathway to prepare enantiomerically pure 11C-labeled L-asparagine was developed using a
partially protected serine as a starting material with a four-step transformation providing a chiral five-
membered cyclic sulfamidate as the radiolabeling precursor. Its structure and absolute configuration were
confirmed by X-Ray crystallography. Utilizing a [11C]cyanide nucleophilic ring opening reaction
followed by selective acidic hydrolysis and deprotection, enantiomerically pure L-[4-11C]asparagine was
synthesized. Further optimization of reaction parameters, including base, metal ion source, solvent, acid
component, reaction temperature and reaction time, a reliable two-step method for synthesizing L-[4-
11C]asparagine was presented; within a 45 ± 3 min (n = 5, from end-of-bombardment), the desired
enantiomerically pure product was synthesized with the initial nucleophilic cyanation yield of 69 ± 4% (n
= 5) and overall two-step radiochemical yield of 53 ± 2% (n = 5) based on starting [11C]HCN, and with
radiochemical purity of 96 ± 2% (n = 5).
2
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INTRODUCTION
Positron emission tomography (PET) is a powerful molecular imaging modality for the in vivo
study of various biochemical processes in living humans, animals and plants. It has been broadly utilized
clinically for diagnostic purposes and for tracking the movement and biochemical transformation of
biological substrates, drugs and xenobiotics. Advances in PET rely heavily on the development of rapid
synthetic methods for labelling organic compounds with short-lived positron emitting nuclides[1]. Amino
acids (AAs) are essential for the synthesis of peptides, proteins, as well as other important bioactive
molecules, such as neurotransmitters, hormones and drugs. They are also utilized in metabolic processes
for energy supply. Due to the biological significance of many AAs and their derivatives, the development
of new methodologies for the synthesis of AAs labeled with short-lived positron-emitters carbon-11 (11C,
t1/2 = 20.4 min) and fluorine-18 (18F, t1/2 = 109.7 min) is particularly interesting and continues to attract
the attention of synthetic radiochemists[1a, 2]
.
Carbon-11 has a number of specific advantages over other radionuclides since its substitution for
replacement of natural abundance carbon in a molecule results in a labeled compound with virtually the
same chemical and biological properties as the unlabeled counterparts. In addition, its short half-life,
provides the opportunity for multiple scans in the same day[1a, 3]. The radiosynthesis of natural AAs labeled
with 11C has drawn attention from researchers for many years. Many different 11C labeled AAs have been
reported and some of them have been extensively evaluated as potential PET imaging agents[1a, 2] [4]. One
11
such example is the development of C-labelled methionine and its investigation for the detection and
delineation of malignant brain tumors[5]. Other 11C-labelled AAs such as [11C]DOPA[6], [11C]tyrosine[7],
[11C]5-hydroxytryptophan[8] as well as L-[5-11C]glutamine[9] have been utilized in PET oncology studies
in recent years. Methods for synthesizing 11C- and 18F-labelled AAs are described in a recent review[2].
Recently, there has been a renaissance in using short-lived radioisotope labeled radiotracers for
investigating plant biology[10]. By implementing positron-emitter labeled bioactive molecules, (such as
3
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[11C]CO2, [13N]NH3, [13N]nitrate, [11C]auxin, 11C-labeled sugars and AAs, etc.), into live plants and using
PET imaging, we may be able to map the transport, utilization, storage, and re-distribution of nitrogen
and carbon sources in plants. Information collected may guide the development of plants with certain
characteristics, such as high-yield, pest resistance, drought-resistance, etc. We have synthesized a series
of 11C labeled bioactive molecules (Figure 1) and utilized them for various plant studies[9b, 11]. The
majority of these tracers were synthesized using [11C]HCN as a radiosynthon. Following our mission of
plant imaging research, we desired the development of another biological important AA, 11C-labeled L-
asparagine (L-[11C]Asn). Herein, we report our recent progress in the synthesis of this biologically
attractive radiotracer, from a five-member ring sulfamidate precursor and nucleophilic ring opening with
[11C]cyanide to introduce the radiolabel.
Figure 1. Carbon-11 labelled radiotracers synthesized recently for plant imaging.
RESULTS AND DISCUSSION
Although an enzymatic method had been reported over two decades ago for the synthesis of L-[4-
11C]asparagine (L-[11C]Asn) with O-acetyl-L-serine and [11C]HCN as starting materials, no experimental
4
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details were reported[12]. Later, another synthesis of [11C]Asn was reported based upon ring-opening of
aziridine-2-carboxylates[13]. However, only racemic [11C]Asn was obtained in spite of the exploration of
different reaction conditions. We set out to develop a method which could be easily adapted to large scale
production L-[11C]Asn and also be adapted to a commercial automatic radiotracer production module.
Exploration of synthesis of L-[11C]Asn with protected L-iodoalanine 6 as radiolabeling precursor
In 2012 we reported a synthesis of L-[5-11C]-glutamine (L-[11C]Gln) using a [11C]cyanide end-
capping radiolabeling method and later presented a refined process for synthesizing this potentially very
useful radiotracer (Scheme 1)[9]. We first attempted the synthesis of L-[11C]Asn using a similar
[11C]cyanide end-capping radiolabeling method (Scheme 2). Starting from a partially protected L-serine
3, the carboxyl group was first protected by esterification with tert-butyl-2,2,2-tricholoroacetimidate (t-
BTCA) in dichloromethane (DCM) and cyclohexane using a catalytic amount of boron trifluoride in ether
to give a fully protected serine derivative 4[14]. Next, the benzyl-group was removed by hydrogenation in
ethanol using 10% palladium on carbon as catalyst to provide the partially protected serine 5 [15]. The
hydroxyl group in compound 5 was then converted to an iodo group to give protected L-iodoalanine 6 by
using a triphenylphosphine, iodine and imidazole combined iodination reaction (see supporting
information for synthesis details)[16]. Radiolabeling via the 11C-cyanation reaction using L-iodoalanine 6
as precursor provided us with 34% yield of [11C]cyanoalanine intermediate 7 (radiochemical yield was
decay-corrected in all research unless specifically mentioned). Deprotection under acidic conditions and
selective hydrolysis yielded the desired product [11C]Asn 1. The Chirex3126 column based analytical
HPLC method, however, could not fully separate the L- and D- isomer of [11C]Asn despite extensive
exploration of various conditions[9a]. Therefore, in order to determine the ratio of the L- and D- isomers
of [11C]Asn, a sample of the [11C]Asn product was hydrolyzed to [11C]aspartic acid ([11C]Asp, 2) by
heating with 4 M HCl at 130 oC for 10 min. The ratio of L- and D- isomer of [11C]Asp, obtained from
5
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chiral HPLC analysis, was used to determine the selectivity of each of the 11C-cyanation conditions[9a, 13]
.
Unfortunately, HPLC analysis results showed that the final product contained nearly equal amount of L-
and D- isomer of [11C]Asn despite the use of several different reaction conditions.
Scheme 1. Updated method for synthesis of L-[11C]Gln.
Scheme 2. Preliminary exploration for the synthesis of [11C]Asn.
A plausible mechanism for the loss of chirality at α-carbon is given in Figure 2 where, the
protected L-iodoalanine 6 quickly went through a β-elimination to give a α, β-unsaturated ester 8 under
6
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the basic 11C-cyanation conditions which we used successfully in the synthesis L-[11C]Gln. Next, this α,
β-unsaturated ester 8 served as a Michael acceptor and reacted with [11C]HCN to give a mixture of L-
and D-[11C]Asn 1 (Figure 2). A similar β-elimination had been reported previously in an attempt to
synthesize sulfur linked glycosyl amino acids using iodoalanine derivatives as starting materials[17]
.
Figure 2. Plausible mechanism for racemization in initial 11C-cyanation experiments.
Cyclic sulfamidate as a precursor for synthesis of L-[11C]Asn
To avoid the racemization and attain stereo-enriched [11C]Asn using [11C]cyanide as radio-
synthon, three nucleophilic ring-opening reactions could be the proposed for adding the [11C]cyano group
at the β-carbon position with minimal perturbation of the α-carbon stereo center: 1). Baldwin et al.
reported a quick synthesis of protected three-member ring (S)-aziridine-2-carboxylate as well as the use
of it as precursor for synthesis of various β-substituted L-alanine by reacting it with Grignard reagents
under the copper bromide catalyzed conditions (Figure 3, eq. a)[18]. The aziridine derivative was later
tested for synthesis [11C]Asn and [11C]Asp using [11C]cyanide as nucleophilic reagent (Figure 3, eq. b).
Both [11C]Asn and [11C]Asp were synthesized in 30 – 40% yield; unfortunately racemization occurred[13]
.
.
2). Second method for the synthesis of chiral cyanoalanine compounds was reported by Vederas et al [19]
7
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This involved conversion of a four-membered N-Boc-L-serine β-lactone to an α-amino-β-propiolactone
o
o
salt, followed by a ring opening reaction with n-Bu4N+CN- in DMF (from -10 C to 25 C) to give β-
cyano-L-alanine in 84% yield (Figure 3, eq. c). Although this method was later successfully adapted by
Unkefer’s group in the synthesis of L-[4-13C]- and L-[3,4-13C2]- aspartic acid with slight modification
(addition of dimethyl azodicarboxylate, DMAD, for stabilizing precursor L-(N-t-Boc)serine-β-lactone)
(Figure 3, eq. d)[20], it was less attractive for synthesis of L-[11C]Asn since the nucleophilic 11C-cyanation
reaction has to be rapid due to the 20.4 minute half-life of carbon-11 isotope. 3). In 1990, Baldwin’s group
reported the synthesis of a five-member ring sulfamidate from a partially protected serine and elegantly
demonstrated ring-opening reactions with various nucleophiles under mild conditions (Figure 3, eq. e)[21]
.
Additionally, such cyclic sulfamidates were demonstrated as efficient precursors for radiosynthesis of 18F-
labeled 2-methyl-3-fluoroalanines (Figure 3, eq. f)[22] as well as 18F-labeled fluoroalkyl analogs of MK801
(Figure 3, eq. g)[23]. We envisioned that sulfamidate precursor 20 could be used for synthesis of L-
[11C]Asn via a [11C]cyanide ring opening nucleophilic reaction followed by a controlled acidic hydrolysis
and deprotection reaction (Figure 3, eq. h).
8
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Figure 3. Reported three ring opening nucleophilic reactions for synthesis of alanine derivatives with
various functional groups at β carbon and our plan for the synthesis of L-[11C]Asn.
9
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At this stage, we used a literature method to obtain the desired cyclic sulfamidate precursor 20[21-22]
:
Partially protected serine 5 was treated with thionyl chloride in acetonitrile at -40 °C with pyridine as an
acid scavenger. After reaction workup, crude product of five-member ring intermediate sulfamidite 21
was immediately treated with sodium periodate in acetonitrile at 0 °C catalyzed with ruthenium chloride
to afford a fully protected cyclic sulfamidate 20. Slow evaporative recrystallization provided high quality
crystals for X-ray crystallographic analysis further confirming the structure and the stereospecificity of
cyclic sulfamidate compound 20 (Scheme 3, crystallographic data: CCDC1415388).
Scheme 3. Synthesis of radiolabeling precursor tert-butyl and Boc- protected sulfamidate 20.
With the desired five-member ring sulfamidate 20 in hand, we immediately tested it as radiolabeling
precursor for the [11C]Asn synthesis using the optimized reaction conditions for the synthesis of L-
[11C]Gln (Vide Supra, Scheme 4). Although overall radiochemical yield was only 2%, we were delighted
to find that the ratio of L- and D- isomers of [11C]Asn changed from 1 : 1 to 2 : 1. Modifications of both
reaction conditions, such as reaction temperature, solvent, bases, acids for hydrolysis, as well as the
purification methods for [11C]cyanoalanine intermediate and final product [11C]Asn etc., dramatically
10
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improved the overall radiochemical yield to 49%. However, the ratio of L- and D- [11C]Asn, only
increased to 3.4 : 1 which was still unsatisfactory (L/D ratio at ≥ 9 was the desired amount in this research
for radiosynthesis of radiotracer L-[11C]Asn). It is reasonable to postulate that the formation of [11C]Asn
not only came from nucleophilic 11C-cyanation but partially from the competitive β-elimination/Michael
addition pathway (Figure 2). This β-elimination was likely being triggered by the NH3 left and the trace
amount of H2O generated in production of the radiosynthon [11C]HCN. To remove NH3 and H2O, the
stream of [11C]HCN was passed through a mildly heated 50% H2SO4 bath and P2O5 drying tube which
had been first reported by Antoni and Långström [24] before it was used for the displacement reaction. The
following experimental results were surprisingly attractive: two-step reactions yielded 43% desired
[11C]Asn product with 97% radiochemical purity and L/D ratio of [11C]Asn at 33/1 (Figure 4).
Scheme 4. Preliminary exploration with cyclic sulfamidate 20 as radiolabeling precursor.
11
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Figure 4. Chiral HPLC analysis results of the amount of L- and D- isomers of [11C]Asp, L-Asp and D-
Asp standards were co-injected with radioactive product for the purpose of verification.
Detailed investigation of nucleophilic 11C-cyanation reaction parameters
This dramatic improvement of the enantiomeric purity of the product encouraged us to further
optimize the entire radiosynthesis protocol. First of all, the nucleophilic 11C-cyanation reaction (Table 1)
was investigated and the results showed that DMF is the best solvent compared with other polar solvents
(DMA and DMSO) and less basic KHCO3 was favored compared with CsHCO3, K2CO3 as well as the
KHCO3/K2CO3 combination. In addition, longer reaction times did not improve the reaction yield when
cyclic sulfamidate 20 was used as the precursor (Table 1, Entry 7 and 8). This observation differed from
[9b]
synthesis of L-[11C]Gln, in which the extension of reaction time improved the radiochemical yield
.
Subsequent investigation on the effect of the reaction time on the conversion of [11C]cyanide to
[11C]cyanoalanine intermediate showed that the conversion was rapid, peaking at three minutes with the
reaction temperature ranging from 60 – 140 oC (Figure 5). These findings implied that the newly formed
[11C]cyanoalanine 22 is less stable under the reaction conditions. Meanwhile, the reaction temperature
o
needs to be more than 90 C to produce a greater than 75% conversion of [11C]cyanide to
[11C]cyanoalanine 22.
Table 1. Exploration of radiosynthesis of L-[11C]Asn: ring-opening nucleophilic 11C-cyanation
Base for [11C]cyanationa
Entry
Reaction solvent and time
12
[11C]Cyanoalanine yield (%)b
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1
2
3
4
5
6
7
8
CsHCO3 (pH = 9)
DMF, 8 min
DMSO, 8 min
DMA, 8 min
DMF, 8 min
DMF, 8 min
DMF, 3 min
DMF, 5 min
DMF, 12 min
57
38
66
68
61
50
69
60
KHCO3 (pH = 8.4)
KHCO3 (pH = 8.4)
KHCO3/K2CO3 (pH = 9)
KHCO3/K2CO3 (pH = 10)
K2CO3 (pH = 11.5)
KHCO3 (pH = 8.4)
KHCO3 (pH = 8.4)
a All pH values listed in this table were obtained by checking the aqueous solutions of various salts.
b Isolated yields from solid phase extraction (SPE) purification using C18 plus cartridge.
Figure 5. Nucleophilic 11C-cyanation profiles at five different reaction temperatures.
11
After the above investigation, several experiments were conducted to further examine the C-
cyanation reaction conditions. Based upon the isolated yield of [11C]cyanoalanine 22 (purified with solid
o
phase extraction (SPE) method), we found that heating at 120 C for 3 minutes provided the desired
[11C]cyanoalanine 22 with over 70% isolated yield (Table 2).
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Table 2. Optimization of nucleophilic [11C]cyanation reaction conditions
[11C]cyanationReaction temperature and time
Entry
1
[11C]Cyanoalanine yield (%)*
100 oC, 1 min
59
2
120 oC, 2 min
61
3
120 oC, 3 min
73
*Isolated yields from solid phase extraction (SPE) purification using C18 plus cartridge.
Investigation of acidic deprotection and hydrolysis conditions
During preliminary exploration of the synthesis of [11C]Asn using protected iodoalanine 6 as
radiolabeling precursor, it was already found that the acidic hydrolysis conditions used for synthesis of
L-[11C]Gln (Scheme 1) were not strong enough to convert [11C]cyanoalanine intermediate 7 to [11C]Asn
[9]. After switching to cyclic sulfamidate 8 as the precursor for [11C]cyanation reaction, stronger acidic
o
hydrolysis conditions were tested (120 vs 90 C, 10 min vs 5 min, Table 3, Entry 1) [25]. We found that
only 36% of the total carbon-11 radioactivity was converted to desired [11C]Asn. Changing the ratio of
TFA/H2SO4 from 4/1 to 2/1 clearly improved the conversion of the radioactive intermediate to product
[11C]Asn (Table 3, Entry 2). Increasing the amount of TFA/H2SO4 from 0.2 mL to 0.25 mL further
facilitated the deprotection and hydrolysis and 90% desired product [11C]Asn formed even in 5 min (Table
3, Entry 3). Eventually, the conditions tested in Table 3, Entry 4 were selected as the standard conditions
for the second step of synthesis of L-[11C]Asn.
Table 3. Acidic deprotection and hydrolysis reaction conditions investigation results
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Entry
Radiochemical purity (%)*
36
Acidic deprotection and hydrolysis conditions
1
2
3
4
5
TFA/H2SO4 (4/1, v/v) 0.2 mL, 10 min
TFA/H2SO4 (2/1, v/v) 0.2 mL, 10 min
TFA/H2SO4 (2/1, v/v) 0.25 mL, 5 min
TFA/H2SO4 (2/1, v/v) 0.25 mL, 7 min
TFA/H2SO4 (2/1, v/v) 0.25 mL, 10 min
73
90
98
96
*Product was isolated from AG11®A8 resin ion exchange column.
Finalization of the complete radiosynthesis process
Once optimized conditions for both reactions were in hand, five repeated radiosyntheses of L-
[11C]Asn were conducted to further confirm the robustness of this new radiosynthesis method (Scheme
5). The results confirmed that L-[11C]Asn was synthesized using a protected cyclic sulfamidate 20 as
radiolabeling precursor: with a 2-minutes cyclotron beam, which generates ~7.29 GBq (197 mCi)
[11C]CO2 radioactivity, 163 – 303 MBq (4.4 – 8.2 mCi), L-[11C]Asn product was obtained at the end of
synthesis (EOS) with a total synthesis time ranging from 43 – 50 min. The overall yield (DCY) of the
whole synthesis was 53 ± 2% and the radiochemical purity of the final product was 96 ± 2%. There was
no detectable D-[11C]Asn in any of the final products. The molar activity (Am) of the [11C]Asn product
based upon a Fmoc-derivatization method[9b] was 88.8 ± 29.6 GBq/µmol (end of cyclotron bombardment,
EOB; or 18.6 ± 6.2 GBq/µmol at the end of synthesis, EOS).
15
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Scheme 5. Optimized process for the radiosynthesis of L-[11C]Asn
CONCLUSION
In summary, we developed a novel method for synthesis of the biologically interesting PET
radiotracer L-[11C]Asn, which highlights with the design and synthesis of a five-member ring cyclic
sulfamidate compound as the radiolabeling precursor, as well as the development of mild radiosynthetic
process which syntehsized desired L-[11C]Asn with over 50% overall radiochemical yields. This semi-
automated radiolabeling process should be adaptable to a commercially available radio-synthesizer and
adjusted to a full-scale automation process, which is beneficial for synthesizing L-[11C]Asn in large scale.
In addition, the development of reaction conditions which retained the stereochemistry during the base
11
sensitive nucleophilic C-cyanation using the chiral cyclic sulfamidate precursor will be beneficial to
future design and synthesis of radioactive L-alanine moiety containing amino acids and analogs for
evaluation as potential molecular imaging agents.
16
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ACKNOWLEDGMENTS This research was supported by the Office of Biological and Environmental
Research, U. S. Department of Energy under contract DE-AC02-98CH10886. Additional support was
provided by the German Academic Exchange Service (Deutscher Akademischer Austauschdienst,
DAAD) Bonn, which supported Lena Kersting, Aylin Sibel Cankaya, Tassilo Gleede and Barbara Riehl.
Ruma Hoque was supported by Science Undergraduate Laboratory Internships (SULI) program, U. S.
Department of Energy. The United States Government retains and the publisher, by accepting the article
for publication, acknowledges that the United States retains a non-exclusive, paid-up irrevocable, world-
wide license to publish or reproduce the published form of this manuscript, or allow others to do so, for
United States Government purpose.
CONFLICT OF INTEREST The authors declare that they have no conflict of interest.
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This article is protected by copyright. All rights reserved.

10.1002/chem.201801029
Chemistry - A European Journal
Table of Contents
One more done! Described herein is a facile method for total radiosynthesis of L-[4-11C]asparagine,
which featured with the design and convenient synthesis of a chiral cyclic sulfamidate as precursor, and
the moisture and basicity strictly controlled ring-opening nucleophilic 11C-cyanation for radiolabeling.
Following strong acid controlled hydrolyzation and deprotection afforded desired product.
Key words: amino acids • L-[4-11C]asparagine • radiochemistry • ring-opening nucleophilic 11C-
cyanation • sulfamidate
19
This article is protected by copyright. All rights reserved.