Transition-Metal-Free Carbon Isotope Exchange of Phenyl Acetic Acids

Article abstract of DOI:10.1002/anie.202002341

A transition-metal-free carbon isotope exchange procedure on phenyl acetic acids is described. Utilizing the universal precursor CO₂, this protocol allows the carbon isotope to be inserted into the carboxylic acid position, with no need of precursor synthesis. This procedure enabled the labeling of 15 pharmaceuticals and was compatible with carbon isotopes [¹⁴C] and [¹³C]. A proof of concept with [¹¹C] was also obtained with low molar activity valuable for distribution studies.

Full text of DOI:10.1002/anie.202002341

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Transition-Metal-Free Carbon Isotope Exchange of Phenyl Acetic
Acids
Authors: Gianluca Destro, Kaisa Horkka, Olivier Loreau, David-
Alexandre Buisson, Lee Kingston, Antonio Del Vecchio,
Magnus Schou, Charles Elmore, Frédéric Taran, Thibault
Cantat, and Davide Audisio
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202002341
Link to VoR: https://doi.org/10.1002/anie.202002341

10.1002/anie.202002341
Angewandte Chemie International Edition
COMMUNICATION
Transition-Metal-Free Carbon Isotope Exchange of Phenyl Acetic
Acids
Gianluca Destro,[a],[b] Kaisa Horkka,[c] Olivier Loreau,[a] David-Alexandre Buisson,[a] Lee Kingston,[e]
Antonio Del Vecchio,[a] Magnus Schou,[c],[d] Charles S. Elmore,[e] Frédéric Taran,[a] Thibault Cantat,[b]
Davide Audisio[a]*
Abstract: A transition-metal-free carbon isotope exchange procedure
on phenyl acetic acids is described. Utilizing the universal precursor
CO2, this protocol allows the carbon isotope to be inserted into the
carboxylic acid position, with no need of precursor synthesis. This
procedure enabled the labeling of 15 pharmaceuticals and was
compatible with carbon isotopes [14C] and [13C]. A proof of concept
with [11C] was also obtained with low molar activity valuable for
distribution studies.
Nonetheless, 14C radiosynthesis remains a significative
challenge:14C is generated in nuclear reactors as Ba[14C]CO3 and
converted into [14C]CO26,7 Consequently, ¹⁴C syntheses rely on
[14C]CO2 as sole basic starting material8 and, in the end, all ¹⁴C-
labeled compounds have to be build up from [¹⁴C]CO₂. The whole
labeling procedures are multi-step and time-consuming. In
addition, costs associated to this building block ([14C]CO2: 1600 €
per mmol) and the generation of long-lived radioactive waste
(half-life 5730 years) affect even further the radiosynthesis. More
advanced building blocks are commercially available, but they are
often highly expensive and still a bottleneck when planning an
actual synthesis.9 Recent breakthroughs in late-stage 14C labeling
have challenged this traditional approach and showcased direct
access to complex scaffolds from [14C]CO2.10 In addition, the first
examples of transition-metal-catalyzed carbon isotope exchange
(CIE) have recently emerged.11 Such technology enable selective
replacement of molecular moieties into complex organic
molecules, by reversible molecular deconstruction/reconstruction
thus providing access to 14C labeled compounds in a single
operation, directly from the end-use molecules. We described a
Radiolabeling with long-lived - emitters carbon-14 (14C) and
tritium (3H) plays
a critical role in drug discovery and
development.1 These techniques allow the determination of key
data such as the absorption, distribution, metabolism, and
excretion (ADME), both for human and veterinary drug
development.2,3
In this context, technologies allowing the direct incorporation
of carbon and hydrogen labels onto organic molecules are of
critical importance. Over the last decade, hydrogen isotope
exchange (HIE)4 has emerged as the most effective way to
introduce 3H and 2H into organic molecules. Despite recent
progress on HIE, risks for potential tritium loss due to metabolic
instability in biological media, such as cytochrome P450-mediated
oxidative cleavage of the C-3H bonds, limit the use of tritiated
radiotracers to early drug discovery and preclinical phase.5 On the
other hand, due to the higher metabolic stability of C-C bonds, the
utilization of 14C is strongly recommended by regulatory agencies
for advanced human ADME studies, new drug submission and it
is almost exclusive for human food safety and environmental fate
studies.
copper-catalyzed
decarboxylative-carboxylation
of
(hetero)aromatic carboxylic acid salts with [14C]CO2.12 In 2019,
Baran13 and Martin14 independently reported a nickel-catalyzed
approach utilizing [14C]CO2. Gauthier et al. developed
a
palladium-catalyzed decarbonylative-carbonylative CIE15 of acid
chlorides, using in situ generated [14C]CO.16 While these
complementary approaches are particularly attractive, novel
developments in CIE are highly desirable.
Phenyl acetic acids (PAA) are important scaffolds for carbon
labeling.17 This pharmacophore is quintessential in Non-Steroidal
Anti-Inflammatory Drugs (NSAIDs), and largely found in anti-
muscarinics, anti-narcoleptics, analgesic opioids, agrochemicals,
and plant protection products (Scheme 1A).18
[a]
Dr. G. Destro, O. Loreau, D.-A. Buisson, Dr. Del Vecchio, Dr. F.
Taran, Dr. D. Audisio
While carbon labeling of PAA at the carbonyl position is
metabolically stable and suitable for biological studies, no general
procedures are available.19 The most utilized is the 14C-cyanation
of the benzyl halides (Scheme 1B),20 which requires the prior
synthesis of tailored precursors: a time-consuming and often non-
trivial task, especially for poly-functionalized PAAs. The work by
Gauthier et al. on carbon monoxide CIE has shown promise.
Examples of PAAs were labeled from the parent compound, after
prior carboxylic acid activation (Scheme 1B). Unfortunately,
[14C]CO is a less convenient 14C reagent because of the
requirement that it is freshly generated from 14COgen. The price
of this precursor, which is obtained in two radiochemical steps
from [14C]CO2, and the inherent toxicity of this poisonous
radioactive gas somewhat limits the immediacy for its
implementation. In 1979, Parnes reported an exchange
Université Paris-Saclay, CEA, Service de Chimie Bio-organique et
de Marquage, 91191, Gif-sur-Yvette, France
E-mail: davide.audisio@cea.fr
[b]
Dr. G. Destro, Dr. T. Cantat
Université Paris-Saclay, CEA, CNRS, NIMBE, 91191, Gif-sur-
Yvette, France
[c]
[d]
K. Horkka, Dr. M. Schou
Karolinska Institutet, 17176 Stockholm, Sweden
Dr. M. Schou
PET Science Centre, Precision Medicine, Oncology R&D,
AstraZeneca, Karolinska Institutet, 17176 Stockholm, Sweden
L. Kingston, Dr. C. S. Elmore
[e]
Early Chemical Development, Pharmaceutical Sciences, R&D,
AstraZeneca, Gothenburg, Sweden
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.202002341
Angewandte Chemie International Edition
COMMUNICATION
procedure using strong basic conditions (LDA) in presence of
HMPA and [14C]CO2.19 Since this seminal publication, only one
example of PAA was labeled by this method, probably due to poor
functional group compatibility.
As part of our interest in carbon isotope labeling, we report a
transition-metal-free carbon isotope exchange on PAA (Scheme
1C). Our protocol allowed the labeling of a variety of PAA
derivatives, including pharmaceuticals, with [13C]CO2 and
[14C]CO2 without need for substrate pre-functionalization. The
procedure allowed application of CIE to short-lived positron
emitting 11C radioisotope, for the first time.
Recent years have witnessed the development of catalytic
decarboxylative transformations, which enable the use of
carboxylic acids as versatile handles for a variety of high-value
functionalisations.21 In particular, the use of PAA salts in
decarboxylative cross-coupling transformations has been
reported by Liu,22 Zhu23 and others.24 Recently, the group of
Lundgren have shown that electron deficient aryl acetates
decarboxylate under thermal conditions, in the absence of Pd-
catalysts.25 The authors suggested that aryl acetate
decarboxylation generates a basic benzylic anion species which
can deprotonate another aryl acetate partner.26
Scheme 1: Carbon isotope labeling of PAA. A) Examples of biologically relevant PAA. B) Previous methodologies towards the introduction of 14C. C) Transition-
metal-free CIE for PAA.
After the cross-coupling and C-C bond formation, the carbonyl
group would spontaneously decarboxylate. Inspired by this
hypothesis, it was reasoned that after decarboxylation, anion I
might either react directly with CO2 or, alternatively, generate in
situ a dienolate species II (Scheme 2A). Intermediate II could
undergo nucleophilic attack onto isotopically labeled carbon
dioxide, thus forming a malonate derivative (III). Subsequent
decarboxylation would afford the carbon-enriched material (IV),
which might either act as a base, deprotonating another substrate
or, after protonation, deliver the enriched PAA (labeled-1).
labeled in 39% and 34% IE, respectively. The presence of di- and
tri-methoxy groups is well tolerated, hence compound [13C]5
could be obtained with 29% IE and 98% yield. In addition, [13C]9
bearing a p-naphthamide moiety was labeled with 35% IE (56%
yield), and the presence of a secondary amide did not affect the
transformation.
To test our hypothesis, we selected 4-methoxyphenylacetate
cesium salt 2 as a model substrate (Scheme 2C). Temperature,
time, and solvent screening was initially conducted with [13C]CO2
gas as a convenient and readily handled [14C]CO2 surrogate. All
of the reactions were performed under standard conditions
employing 0.1 mmol of substrate in dry DMF with 3 equiv. of
[13C]CO2.27 The extent of isotopic exchange was determined after
2 hours using mass spectroscopy. For model substrate 2, the best
conditions were found to be 1 hour 150 °C in DMSO; [13C]2 was
isolated in 43% yield and with 48% isotopic enrichment (IE).28,29
Next, we examined the scope of the reaction. A series of electron-
rich derivatives were screened: labeled PAAs [13C]2-[13C]8 were
isolated in 32% to 98% yields and 29% to 55% IE. The presence
of steric hindrance in the ortho position on the ring, slightly
affected the efficiency of the CIE, as [13C]4 and [13C]7 were
Scheme 2: A) Potential mechanisms for transition-metal-free CIE. B) Hurdles
in 14C radio-synthesis. C) Optimized conditions for substrate 2. Colored circles
and numbers denote the positions of the carbon atoms labeled and the percent
incorporation of the carbon isotope. DMSO, dimethyl sulfoxide.
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10.1002/anie.202002341
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Scheme 3: 13C-labeling of PAA. The green colored circles and numbers denote the positions of the atoms labeled and the percent incorporation of the isotope.
Reaction conditions: substrate (0.1 mmol, 1 equiv.), 13CO2 (3 equiv.), DMSO (0.5 mL), temperature 150 °C, time 2 h. DMSO, dimethyl sulfoxide. a Reaction time 5
minutes, temperature 80 °C. b Reaction time 1h, temperature 130 °C. c Reaction time 4h. d Reaction time 6h, temperature 190 °C. e Reaction time 3.5h, temperature
190 °C. f Reaction time 0.5h, temperature 190 °C. g Reaction time: 5 minutes.
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Electron-donating thioether [13C]10 was labeled in 70% IE (40%
yield). Finally, heterocyclic derivatives such as oxazole and
thiophene were obtained: [13C]11 in 57% yield (63% IE) and
[13C]12 in 40% yield (50% IE). When standard conditions were
applied to p-nitro PAA 13, complete decarboxylation was
observed. After optimization, it was found that time and
temperature reduction to 5 minutes and 80 °C, allowed to isolate
[13C]13 in 39% yield and 46% IE. The presence of the methyl
group in alpha to the carboxylic acid was tolerated and [13C]14
was isolated in 42% yield with 45% IE. For other electron poor
derivatives, we found that optimal isotope incorporation was
substrate dependent. For example, 130 °C and 1 hour were
necessary for derivatives p-CF3-15 and o-CF3-16: [13C]15 and
[13C]16 could be obtained in 53% IE and 64% IE, respectively. On
the other hand, for p-Cl-17 2 hours and 150 °C were utilized and
[13C]17 obtained with 43% IE.
1570 MBq mmol-1 Am (68% IE). Similarly, [14C]-Fenclofenac was
prepared for ADME studies with an Am of 36 MBq mmol-1.35 This
procedure allowed the radiolabeling of [14C]18 Fenclofenac in
50% yield and 1510 MBq mmol-1 (65% IE).
Next, we explored the labeling of pharmaceuticals. Pleasingly,
Fenclofenac (18), AZ12742227 (19), Lonazolac (20),
AZ12738777 (21), and Methiazinic acid (22) reacted under
standard conditions in 40% to 83% yields and 56% to 75% IE.
Notably, [13C]18 (70% IE, 40% yield) and [13C]20 (58% IE, 64%
yield) were isolated without any traces of de-halogenation. PAAs
displaying structural complexity such as [13C]19 and [13C]21 were
obtained in high levels of 13C incorporation in 74% IE (48% yield)
and 68% IE (49% yield). Felbinac (23) and Carprofen (24)
required longer reaction time (4h). Nonetheless, [13C]23 was
obtained with 75% IE (63% yield) and [13C]24, bearing an
unprotected carbazole core, with 29% IE (36% yield). The current
protocol was successfully applied to anti-inflammatory drugs such
as Ibuprofen (25), Naproxene (26), and Ketoprofen (27), though
a higher temperature (190 °C) was necessary to achieve
reasonable carbon-13 incorporations (26% to 32% IE).
Flurbiprofen (28) did not perform effectively under standard
conditions; further optimization allowed to label [13C]28 in 51% IE
(33% yield) at 190 °C in only 30 minutes.
Finally, when pyrrole derivatives Tolmetin (29) and Zomepirac
(30) were tested, full decarboxylation was observed. Thus, the
reaction was shortened to 5 minutes and [13C]29 and [13C]30
were obtained in 45% and 40% IE. Next, we explored the
reactivity of allyl carboxylate 31. Gladly, cesium carboxylate 31
smoothly underwent CIE yielding [13C]31 in 49% yield and 66%
IE. Notably, under previously reported hydrogenation conditions,
[13C]31 can be directly converted into phenylbutyric acid (Scheme
3),30 a histone deacetylase inhibitor that displays anticancer
activity.31
An inherent limitation of the method is the loss of chiral
information, Piragliatin precursor [13C]32 was obtained with
isotopic enrichment of 61% (in a 1:1 diastereomer ratio). In this
context, it is worth noting that NSAIDs are known to racemize in
vivo and are generally administered as racemic mixtures.32
Diclofenacl 33 and amino acid 34 were not productive.33 Finally,
alpha disubstituted carboxylate 35 was fully recovered without
any isotope incorporation.
Scheme 4: Transition-metal-free CIE 14C- and 11C-labeling of
pharmaceuticals. A) Methods previously reported. B) CIE with [14C]CO2. Molar
activities for 14C in MBq mmol-1. C) CIE with [11C]CO2. Molar activities for 11C in
GBq mol-1. a Potassium salt prepared in situ and reaction performed out of the
glovebox. b Preparative run, isolated yield.
An advantage of this methodology is its operational simplicity that
is convenient for implementation in radiochemistry. In addition,
compared to concurrent CIE, the absence of transition-metal
catalyst is attractive, as no residual metal traces are released in
the transformation. A relevant point for safety in animal and
human ADME studies. The preparation of the cesium salts and
the use of a glovebox (to reduce moisture) might still be a hurdle
for its proliferation. To avoid it, we tested compound 20 under
modified conditions: out of the glovebox and adding 0.3 equiv. of
Next, a series of pharmaceuticals were labeled using [14C]CO2
under otherwise identical conditions (Scheme 4). [14C]-Felbinac
was previously labeled by Bruce and co-workers on the same
position, for ADME studies,34 from the Grignard precursor,
affording [14C]-Felbinac with a molar activity (Am) of 820 MBq
mmol-1. The current approach provided [14C]23 in 76% yield and
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10.1002/anie.202002341
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anhydrous K3PO4: [14C]20 was obtained in 1540 MBq mmol-1
(67% IE).27 Lonazolac was previously labeled by means of CO
CIE with carbon-13. Comparatively, we obtained the 14C radio-
isotopomer in a higher IE and a more cost-effective manner,
without need for radiolabeled 14C-carbon monoxide. Finally,
[14C]22 Metiazinic acid was obtained in Am of 1490 MBq mmol-1.
While CIE has been so far reported on long-lived 14C, to the best
of our knowledge, there are no examples on carbon-11 (11C).36
[11C]CO2 is a primary source of 11C, but its use has been
hampered by difficulties associated with the high energy +
emission, the minute concentrations of [11C]CO2 produced in the
cyclotron and its short half-life (20.33 min).37 During the
optimization, we observed that some compounds underwent CIE
in short reaction time, compatible with this isotope. Pleasingly, a
proof-of-concept was obtained on substrate [11C]13, which was
labeled with only minimal optimization in a promising 50% RCY.
In a preparative experiment, [11C]13 was isolated in 11% RCY
and a Am of 0.16 GBq mol-1. Although this Am is unsuitable for
receptor binding studies with high affinity radioligands, it is
valuable for studying in vivo organ distribution of druglike
molecules in drug development. [11C]Flurbiprofen (28) was
obtained under modified conditions at 150 °C in 10 minutes with
7% RCY, and [11C]Tolmetin (29) was labeled, under non-
optimized conditions, with 3% RCY. These preliminary results
open new perspectives in 11C isotope labeling.38
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In conclusion, a transition-metal-free procedure enabling carbon
isotope exchange with all carbon isotopes was developed. This
technology utilizes the universal precursor [14C]CO2, [13C]CO2,
and [11C]CO2 allowing the insertion, in one single step, of the
desired carbon tag into phenyl acetic acids, with no need of
structural modifications or precursor synthesis. The practical
utility of the method was showcased on the labeling of a variety
of pharmaceuticals.
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Acknowledgements
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This work was supported by CEA and by the European Union’s
Horizon 2020 research and innovation program under the Marie
Sklodowska-Curie grant agreement N°675071. The authors thank
Amélie Gaudet and Sabrina Lebrequier for the excellent analytical
support. Dr. Fabien Caillé and Dr. Antoine Sallustrau are
acknowledged for helpful discussions.
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Keywords: Isotope labeling • Carbon-14 • Carbon-11 • Isotope
exchange • Carbon dioxide
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This article is protected by copyright. All rights reserved.

10.1002/anie.202002341
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Gianluca Destro,[a],[b] Kaisa Horkka,[c]
Olivier Loreau,[a] David-Alexandre
Buisson,[a] Lee Kingston,[e] Antonio Del
Vecchio,[a] Magnus Schou,[c],[d] Charles
S. Elmore,[e] Frédéric Taran,[a] Thibault
Cantat,[b] Davide Audisio[a]*
Just Labeled: A transition-metal-free carbon isotope exchange procedure on phenyl
acetic acids is described. Utilizing the universal precursor CO2, this protocol allows
the carbon isotope to be inserted into the carboxylic acid position, with no need of
precursor synthesis. This procedure enabled the labeling of 15 pharmaceuticals and
was compatible with carbon isotopes [14C] and [13C]. A proof of concept with [11C]
was also obtained with low molar activity valuable for distribution studies.
Page No. – Page No.
Transition-Metal-Free Carbon Isotope
Exchange of Phenyl Acetic Acids
Institute and/or researcher Twitter usernames:
@TaranLMC
@TCantat
@CEAParisSaclay
This article is protected by copyright. All rights reserved.