Fast Carbon Isotope Exchange of Carboxylic Acids Enabled by Organic Photoredox Catalysis

Article abstract of DOI:10.1021/jacs.0c12819

Carbazole/cyanobenzene photocatalysts promote the direct isotopic carboxylate exchange of C(sp3) acids with labeled CO2. Substrates that are not compatible with transition-metal-catalyzed degradation-reconstruction approaches or prone to thermally induced reversible decarboxylation undergo isotopic incorporation at room temperature in short reaction times. The radiolabeling of drug molecules and precursors with [11C]CO2 is demonstrated.

Full text of DOI:10.1021/jacs.0c12819

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Fast Carbon Isotope Exchange of Carboxylic Acids Enabled by
Organic Photoredox Catalysis
Duanyang Kong, Maxime Munch, Qiqige Qiqige, Christopher J. C. Cooze, Benjamin H. Rotstein,*
and Rylan J. Lundgren*
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ABSTRACT: Carbazole/cyanobenzene photocatalysts promote the direct isotopic carboxylate exchange of C(sp3) acids with
labeled CO2. Substrates that are not compatible with transition-metal-catalyzed degradation−reconstruction approaches or prone to
thermally induced reversible decarboxylation undergo isotopic incorporation at room temperature in short reaction times. The
radiolabeling of drug molecules and precursors with [11C]CO2 is demonstrated.
he synthesis of isotopically labeled molecules is essential
to drug development and nuclear medicine. As drug
The use of redox-active hydroxyphthalimide ester substrates
in combination with Ni-based mediators and stoichiometric
metal reductants enables carboxylate groups to undergo net
exchange with CO2 via a series of single electron transfer
processes (Figure 1A).27,28 These reactions are limited to
primary alkyl or cyclic secondary alkyl acids lacking β-
heteroatoms to achieve >10% label incorporation. The
requirements for long reaction times (≥16 h) and use of
large excesses of CO2 (often >20 equiv) make these methods
incompatible with 11C PET applications. C(sp3) acids that
form stabilized carbanions upon ionic decarboxylation can
undergo exchange with CO2 spontaneously at high temper-
atures in the solid state29 or in solution.30−32 (Figure 1A). In
contrast, compounds that lack strong anion stabilizing groups
like nitro- or cyanoarylacetate groups require high reaction
temperatures (≥150 °C) and long reaction times (≥24 h) or
are simply inert toward exchange. Audisio and co-workers
demonstrated the 11C labeling of the arylacetate drugs
flurbiprofen and tolmetin by uncatalyzed exchange with
[11C]CO2, although slow kinetics and harsh conditions
resulted in low radiochemical yields (RCYs) (7% and 3%,
respectively, at 150 °C).30
With the goal of developing a mild method for direct
carboxylate exchange at rates appropriate for 11C labeling, we
considered alternative strategies for C(sp3)−carboxylate bond
cleavage and subsequent CO2 recapture. Here we show that a
family of organic photocatalysts mediate the exchange of CO2
groups without the need for prior stoichiometric carboxylate
activation or high temperatures (Figure 1B). The radical-polar
crossover process combines the advantages of low-barrier C−
CO2 bond cleavage initiated by carboxylate single-electron
T
candidates move toward clinical research and human trials,
absorption, distribution, metabolism, and excretion (ADME)
studies require compounds enriched with long-lived radio-
isotopes like 3H and 14C.1 Positron emission tomography
(PET) techniques that probe the advance of disease states and
can determine the efficacy of drug treatment require molecular
targets radiolabeled with short-lived positron-emitting isotopes
such as 11C and 18F.2 The limited availability and high cost of
isotopically enriched precursors make the preparation of
complex targets challenging. For PET studies, compounds
must be synthesized and purified within a few half-lives of the
radiolabel (t1/2 = 20.3 min for 11C). Approaches that selectively
introduce isotopic labels from feedstock sources with
compatibility toward common structural motifs found in
clinical candidates will have a positive impact on both drug
discovery efforts and medical imaging.
1
Metal-catalyzed H/3H exchange is widely used in drug
development to introduce long-lived radiolabels into target
molecules.3−9 The loss of H labels through (bio)chemical
3
reactions and metabolic shifting due to primary kinetic isotope
10,11
3
effects are liabilities of H-labeling approaches.
ADME
tracer compounds with greater stability can be obtained by
using 14C radiolabels.12 Similarly, 11C isotopologues of native
bioactive molecules enable PET probe generation without
changes to their biological or pharmacological properties.2,13
The incorporation of 14C, 13C, or 11C (*C) units into drug
molecules or precursors by the formation of a *C−C bond is
challenging and often requires revised synthetic pathways to
introduce the label from *CO,14−18 *CH3I,19,20 or other small
molecules derived by reduction of *CO2.21−25 The direct
exchange of carboxylate groups with CO2 offers the potential
for simple and cost-effective syntheses of C-labeled small
molecules, particularly as CO2 (or BaCO3) is the feedstock for
all radiolabeled carbon-based precursors.26 The easy con-
version of carboxylic acids into other common functionalities
(esters, amides, ketones, alcohols) makes this an attractive
tactic for isotope incorporation.
Received: December 9, 2020
Published: January 28, 2021
https://dx.doi.org/10.1021/jacs.0c12819
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Figure 1. (A) Existing approaches for carboxylate/CO2 exchange for
isotopic labeling (NHPI = N-hydroxyphthalimide). (B) Fast, mild
isotopic carboxylate exchange by organic photoredox catalysis (Cz =
carbazole).
oxidation with the efficient uncatalyzed recombination of
carbanion intermediates with CO2.33 Tertiary carboxylic acid
substrates that are not compatible with either Ni catalysis or
thermal reactions can be labeled to useful levels. The kinetics
of CO2 exchange are compatible with 11C labeling of
nonsteroidal anti-inflammatory drugs (NSAIDs) and precur-
sors to other bioactive molecules.
Photoredox catalysis can be used to induce decarboxylation
by substrate single-electron oxidation, but the recapture of
CO2 under these conditions has not been reported.34−39 In
considering new strategies for reversible decarboxylation of
40,41
̈
organic acids, we were inspired by Konig’s studies,
which
demonstrated that carbazole/dicyanobenzene-based photo-
catalysts could mediate decarboxylative electrophile trapping
by radical-polar crossover mechanisms.42 Upon surveying a
wide array of organic and metal-based catalysts, we found that
5 mol % 4CzIPN43,44 enabled the isotopic labeling of
ibuprofen (1) with [13C]CO2 at room temperature upon
irradiation with blue LEDs (52% 13C incorporation, 77%
yield). Other donor−acceptor cyanoarenes or isomers of
4CzIPN performed poorly under similar conditions regardless
of their redox properties (Figure 2A).45 Cs2CO3 was the
optimal base, although other bases could be used (K2CO3,
DBU). DMA could be replaced with DMSO, but the use of
less polar solvents (THF, MeCN) resulted in low 13C
incorporation (Figure 2A; see the Supporting Information
(SI) for optimization details). Radical traps (TEMPO, BHT)
completely inhibit reactivity. The exchange process remains
efficient when only 2 equiv of [13C]CO2 is used (43% 13C
incorporation, 75% yield).
Figure 2. (A) Overview of photocatalyst effects and changes to
reaction parameters. (B) 4CzIPN and 4CzBnBN rate comparison for
[13C]CO2 exchange with ibuprofen. (C) 4CzBnBN enables
carboxylate exchange with tertiary carboxylic acids.
with phenylacetic acid) resulted in a pronounced increase in
13C incorporation rates (Figure 2B). With 3 equiv of
[13C]CO2, >40% labeling of ibuprofen was obtained in 10
min using 4CzBnBN, which is double the incorporation
observed with 4CzIPN. 4CzBnBN enabled isotopic labeling of
more challenging substrate classes. Tertiary acid 2 undergoes
efficient labeling using 4CzBnBN (63% 13C incorporation, 70%
yield), while low levels of exchange were detected using
Under standard reaction conditions, alkylative decyanation
of 4CzIPN occurs,40,41 and this process is important for
generating a more active catalyst. The direct use of the
benzylated catalyst 4CzBnBN (prepared by reacting 4CzIPN
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a
1
b
Figure 3. Scope and limitations. Unless otherwise noted, yields are of isolated material. Calibrated H NMR spectroscopy yield. Percent 13C
incorporation and yield determined after conversion to the benzyl ester. 5 mol % 4CzBnBN. ∼3 equiv of [13C]CO2. 2.5 mol % 4CzIPN.
c
d
e
fObtained by Pd/C hydrogenation of allylic carboxylate. See the SI for details.
4CzIPN (2%). The difference in the catalytic activities of these
two catalysts with tertiary substrates can be rationalized by the
observation that tertiary acid 2 reacts with 4CzIPN to give the
carbazole elimination species 3CzBn−2 (Figure 2C). 3CzBn−
2 is a poor mediator of carboxylate exchange, likely because of
attenuated donor−acceptor properties. Catalyst screening
studies showed little correlation between the activity in
carboxylate exchange and the (pre)catalyst electrochemical
potential (see the SI for details). The selective generation of
monoalkylated benzonitrile species under the reaction
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conditions appears to be the most important factor in dictating
successful carboxylate exchange. For example, 4ClCzIPN
undergoes double benzylation in the presence of phenylacetic
acid to generate an inactive species, while 4MeOCzIPN and
4DPAIPN are resistant to benzylation and perform sluggishly
(Figure 2A; see the SI for details). These findings should have
broader implications for the design and optimization of
photocatalytic decarboxylative coupling reactions with
donor−acceptor cyanoarenes.
With optimized reaction conditions, the scope and
limitations of photoredox-catalyzed carboxylate isotopic
exchange were explored (Figure 3). For less challenging
substrate classes, the commercially available 4CzIPN catalyst
was used. Arylacetates, including those with a halogen (4, 5) or
a moderate electron-withdrawing group, including amide (6),
sulfonyl (7), CF3 (8), or Bpin (9), underwent smooth
carboxylate exchange. Electron-rich arylacetates with methoxy,
thioether, or NHBoc group(s) (10−13, 21) also underwent
13C labeling using the standard conditions. Heterocycles (18,
19) and more complex structures bearing potentially reactive
ketone or phenol groups (20) were tolerated. Arylacetates
substituted with an α-alkyl, α-alkoxy, or α-NH benzoyl group
were productive substrates (23−25), as were molecules
featuring an alkene or terminal alkyne (26, 27). Alkylated or
heteroatom-containing β-carboxy amides, β-carboxy lactams,
malonate half-esters, and β-carboxy nitriles were compatible
substrates (30−33). The labeling of complex molecules
featuring malonate half-esters was possible (34, 35). Labeled
alkyl carboxylic acid 36 could be obtained by carboxylate
exchange of the corresponding allylic substrate followed by
hydrogenation (47% incorporation, 44% yield). A series of
tertiary carboxylic acids were isotopically labeled using
4CzBnBN as the catalyst, including α,α-dialkylated arylacetates
(2, 37−39), a fully substituted malonate half-ester (41), and a
carboxy lactam (42). These tertiary substrates do not undergo
significant carboxylate exchange without catalyst under thermal
conditions (see the SI for details). Scope limitations include 4-
OH- or 4-SH-containing arylacetates (15, 16), simple alkyl
acids like cyclohexylcarboxylic acid, and α-cyclopropyl acid 40.
Photoredox-catalyzed carboxylate exchange enables direct
isotopic labeling of drug molecules and synthetic precursors
under mild conditions. An array of NSAIDs underwent smooth
exchange at room temperature, including those with potentially
reactive functionalities and heterocyclic fragments (Figure 3,
43−50). Precursors to other classes of pharmaceuticals and
clinical candidates that feature arylacetate units, such as the
acid of zolpidem (51) or pentoxyverine (52) and the core of a
VLA-4 antagonist (53),46 could be labeled with good 13C
incorporation and yield. In the above cases, replacement of
[13C]CO2 with [14C]CO2 would allow for the preparation of
compounds with specific activities suitable for most radio-
labeling ADME studies (37−300 μCi/mg).
Figure 4. Photoredox-catalyzed carboxylate exchange with 11CO2.
Data are averages of two runs with 11.6 μmol of precursor and a
starting radioactivity of ∼2 GBq. (TE = trapping efficiency of
radioactivity in solution; RCP = radiochemical purity; RCY = TE ×
RCP. RCYs are decay-corrected). See the SI for experimental details.
propionates carprofen, loxoprofen, and fenoprofen could be
radiolabeled under the standard conditions in 7−37% RCY.
[11C]Fenoprofen could be radiolabeled and isolated in 20 min
starting from [11C]CO2 (∼2 GBq) to give the product in 9.5%
RCY and >99% radiochemical purity with a molar activity of
0.029 GBq/μmol (Figure 4). This level of molar activity is
consistent with isotopic exchange reactions and is useful for
studying biodistribution processes. The 11C radiolabeling
reactions were partially automated using a commercial
synthesis module with an external photochemical reactor
(see the SI). Efforts toward implementation in a Good
Manufacturing Practice (GMP) environment are underway.48
In conclusion, organic photoredox catalysis provides a mild
and rapid pathway for direct carboxylate exchange, including
processes that use [11C]CO2.49 The reaction conditions and
substrate scope complement Ni-catalyzed strategies for
isotopic labeling of alkyl carboxylates using CO2. Compatibility
with potentially reactive functional groups, heterocycles, and
tertiary acids combined with the opportunity to refine the
The rapid labeling of arylacetate drug molecules with
[11C]CO2 is feasible using a photocatalytic approach.47
[11C]Ibuprofen could be generated in 17% RCY following 10
min of LED irradiation (Figure 4). The use of 4CzBnBN as the
catalyst was essential for 11C radiolabeling; no exchange was
observed when 4CzIPN was used. N-Protected α-amino acid
25, fully substituted malonate half-ester 41, and tertiary
arylacetate 52 could be radiolabeled in reasonable yields.
These substrates do not undergo 11C-labeling under thermal
conditions (see the SI for details). The primary arylacetates of
pharmaceutical relevance 53 and felbinac along with the
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c12819.
■
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Experimental procedures and compound characteriza-
tion data (PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
Rylan J. Lundgren − Department of Chemistry, University of
Alberta, Edmonton, Alberta T6G 2G2, Canada;
orcid.org/0000-0002-7760-6946;
Email: rylan.lundgren@ualberta.ca
Benjamin H. Rotstein − Department of Biochemistry,
Microbiology and Immunology and Department of Chemistry
and Biomolecular Sciences, University of Ottawa, Ottawa,
Ontario K1H 8M5, Canada; University of Ottawa Heart
Institute, Ottawa, Ontario K1Y 4W7, Canada; orcid.org/
0000-0001-9707-9357; Email: Benjamin.Rotstein@
uottawa.ca
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Dispos. 2009, 30 (4), 185−203.
Authors
Duanyang Kong − Department of Chemistry, University of
Alberta, Edmonton, Alberta T6G 2G2, Canada
Maxime Munch − Department of Biochemistry, Microbiology
and Immunology and Department of Chemistry and
Biomolecular Sciences, University of Ottawa, Ottawa,
Ontario K1H 8M5, Canada; University of Ottawa Heart
Institute, Ottawa, Ontario K1Y 4W7, Canada
Qiqige Qiqige − Department of Chemistry, University of
Alberta, Edmonton, Alberta T6G 2G2, Canada
Christopher J. C. Cooze − Department of Chemistry,
University of Alberta, Edmonton, Alberta T6G 2G2, Canada
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Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c12819
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support was provided by NSERC Canada (RGPIN-2019-
06050 and RGPAS-2019-00051 to R.J.L, RGPIN-2017-06167
to B.H.R., and a PGS-D Fellowship for C.J.C.C.), the Canadian
Foundation for Innovation (IOF 32691 to R.J.L and JELF
36848 to B.H.R.), the University of Alberta, the Province of
Alberta (AGES Fellowship to C.J.C.C.), and the Province of
Ontario (ER17-13-119).
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2205
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J. Am. Chem. Soc. 2021, 143, 2200−2206

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Isotope Exchange with CO2. ChemRxiv 2020, DOI: 10.26434/
chemrxiv.13173227.v1.
2206
https://dx.doi.org/10.1021/jacs.0c12819
J. Am. Chem. Soc. 2021, 143, 2200−2206