Catalytic Decarboxylation/Carboxylation Platform for Accessing Isotopically Labeled Carboxylic Acids

Article abstract of DOI:10.1021/acscatal.9b01921

An integrated catalytic decarboxylation/carboxylation for accessing isotopically labeled carboxylic acids with¹³CO₂ or¹⁴CO₂ is described. The method shows a wide scope under mild conditions, even in the context of late-stage functionalization, and does not require stoichiometric organometallics, thus complementing existing carbon-labeling techniques en route to carboxylic acids.

Full text of DOI:10.1021/acscatal.9b01921

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Letter
A Catalytic Decarboxylation/Carboxylation Platform
for Accessing Isotopically-Labeled Carboxylic Acids
Andreu Tortajada Navarro, Yaya Duan, Basudev Sahoo, Fei Cong, Georgios
Toupalas, antoine sallustrau, Olivier Loreau, Davide Audisio, and Ruben Martin
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b01921 • Publication Date (Web): 29 May 2019
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A Catalytic Decarboxylation/Carboxylation Platform for Accessing
Isotopically-Labeled Carboxylic Acids
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Andreu Tortajada,1,3 Yaya Duan,1,‡ Basudev Sahoo,1,‡ Fei Cong,1,3,‡ Georgios Toupalas,1,‡ Antoine
Sallustrau,4 Olivier Loreau,4 Davide Audisio4 and Ruben Martin1,2,*
1 Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology. Av. Països
Catalans 16, 43007 Tarragona, Spain
2 ICREA, Passeig Lluís Companys, 23, 08010 Barcelona, Spain
3 Departament de Química Analítica i Química Orgànica, Universitat Rovira i Virgili, C/ Marcel·lí Domingo, 1, 43007
Tarragona, Spain
4 Service de Chimie Bio-organique et Marquage (SCBM), CEA-DRF-JOLIOT-SCBM, Université Paris-Saclay 91191 Gif sur
Yvette, France
ABSTRACT: An integrated catalytic decarboxylation/carboxylation for accessing isotopically-labeled carboxylic acids with 13CO2
or 14CO2 is described. The method shows a wide scope under mild conditions, even in the context of late-stage functionalization, and
does not require stoichiometric organometallics, thus complementing existing carbon-labeling techniques en route to carboxylic acids.
KEYWORDS: Carboxylation, nickel, isotopic labeling, carbon dioxide, carboxylic acid
The evaluation of the metabolic profile of lead compounds
through preclinical testing is of utmost importance in drug
discovery.1 Although these studies require isotopically-labeled
active pharmaceutical ingredients (APIs), their synthesis is
oftentimes more problematic than that of the parent compound,
reinforcing the need for strategies that rapidly and reliably
incorporate isotopes into molecules.2 Among different
scenarios, carbon labeling is often preferred due to its high
sensitivity and lower risk of label metabolic cleavage, rendering
the interpretation of preclinical data easy.3 While 11C is utilized
Prompted by the prevalence of carboxylic acids in
for positron emitting tomography (PET) imaging,4 its short half-
biologically active molecules (Scheme 1, bottom),8
carboxylation reactions with isotopically-labeled CO2 has
attracted considerable attention.9,10 At present, high levels of 13C
and 14C–incorporation can be achieved with stoichiometric and
polarized organometallics;11 however, their high reactivity and
low chemoselectivity severely limits the synthetic application
of these processes (Scheme 2, top left). Although
decarboxylation allows carbon isotopes of carboxylic acids in
drug molecules to be rapidly interchanged without modifying
the established route to the drug molecule (Scheme 2, top
middle/right),12 such techniques require stoichiometric nickel
species13a or harsh conditions.13b In addition, modest C-labeling
exchange is observed due to competitive hydrolysis of the
starting precursor or in situ carboxylation with initially extruded
12CO2.13 Taken together, these features contribute to the
perception that designing a mild, robust and modular catalytic
decarboxylation/carboxylation that enables the access to C–
labeled aliphatic and aromatic carboxylic acids in high specific
activities is deemed necessary. As part of our interest in
life precludes long-term studies. However, 13C and 14C-labeling
are appropriate for evaluating drug profiles, including
absorption, distribution, metabolism and excretion (ADME),
and pharmacokinetic studies (Scheme 1).5,6 Although
radioactive 14C has oftentimes displaced 13C as metabolic
tracers, recent advances in mass spectrometry and nuclear
magnetic resonance has allowed the latter to be used for similar
purposes,7 thus improving the practicality of these studies by
employing stable 13C probes.
Scheme 1. Carbon Isotope Labeling.
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catalytic carboxylation reactions,14 we report the successful
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containing heterocycles (2d) could all be well-accommodated.
Interestingly, not even traces of competitive Ni-catalyzed
carboxylation at the C–Cl terminus was observed in 2b and
2k,17 thus leaving ample room for further functionalization via
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realization of a catalytic carbon isotope exchange by merging
decarboxylative events with carboxylation protocols with 13CO2
or 14CO2 via the intermediacy of halogenated species or
activated esters (Scheme 2, bottom). Our protocols are
distinguished by their mild conditions, versatility, excellent
chemoselectivity profile and high isotopic incorporations (up to
>99% C-labeling), thus expediting the design of radiolabeling
techniques – even in the context of late-stage functionalization
– en route to labeled carboxylic acids while obviating the need
for stoichiometric organometallic species.
conventional
cross-coupling
reactions.18
Particularly
noteworthy was the ability to enable the targeted 12C/13C-
exchange at late-stages with advanced carboxylic acid
intermediates such as citronellic acid (2j), MCPB (2k),
lithocholic acid (2l) or pregabalin (2m), thus showing the
potential that our catalytic protocol might have in preclinical
studies for drug discovery.19 Putting these results into
perspective, the examples shown in Table 1 represent a
powerful alternative to existing methodologies based on the
utilization of stoichiometric amounts of organometallics11 or Ni
complexes.13a
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Our investigations began by evaluating the feasibility of the
approach highlighted in Scheme 2 (bottom) with easy-to-handle
13CO2 in lieu of radioactive 14CO2 and the N-
hydroxyphthalimido ester 1a, readily available in a single step
from octanoic acid.15 A judicious optimization of all reaction
parameters revealed that a combination of NiCl2·dme (10
mol%), 6,6’-dimethyl-4,4’-diphenyl-2,2’-bipyridine L1 (25
mol %) in DMF:MeOH (3:1) at 0 ºC with Mn as reducing agent
under an atmospheric pressure of 13CO2 provided the best
results, affording [13C]2a in 55% yield and 56% 12C/13C
exchange.15 In line with our expectations, bipyridine and
phenanthroline ligands possessing substituents adjacent to the
nitrogen atom were critical for success.16 Indeed, the absence of
the latter resulted in negligible conversions, if any, to [13C]2a,
thus showing the structural intricacies on the ligand backbone.
Likewise, solvents and reducing agents other than DMF:MeOH
or Mn had a deleterious effect on reactivity and specificity,
whereas control experiments revealed that all reaction
parameters were essential for the catalytic carboxylation to
occur.15
Table 1. 12C/13C-Isotopic Exchange of Carboxylic Acids.a
Scheme 2. 13C & 14C-Labeling Carboxylations with CO2.
a NHP-ester (0.1 mmol), NiCl2·dme (10 mol %), L1 (25 mol %),
Mn (2 equiv), 13CO2 (1 atm) in DMF:MeOH (3:1, 0.06 M) at 0 ºC.
The data shown in Scheme 3 (top) illustrates the prospective
impact of our 12C/13C-exchange by converting 3a and 3b into
their [13C]5a and [13C]5b congeners without chromatographic
purification.15 However, a number of daunting challenges
remain. Among these, a seemingly trivial extension to 13C-
labeled phenyl acetic acids or benzoic acids events still
constitutes terra incognita; substantial homodimerization is
observed in the former whereas a difficult decarboxylation of
aryl NHP-esters prevents a 12C/13C-exchange in the latter. More
importantly, modest isotope exchange was observed for all
substrates shown in Table 1 due to unavoidable hydrolysis of
the parent NHP-ester and competitive carboxylation with
12CO2. These observations are particularly problematic due to
With a set of conditions in hand, we turned our attention to
study
the
generality
of
of
our
Ni-catalyzed
decarboxylative/carboxylation
N-hydroxyphthalimido
esters. As shown in Table 1, an array of linear (2a-2f, 2i-2m) or
-branched (2g, 2h) labeled carboxylic acids could easily be
within reach from their parent analogues. The chemoselectivity
of our 12C/13C-carbon labeling exchange posed no problems, as
nitriles (2i), alkenes (2j), carbamates (2m) or nitrogen-
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the prevalence of carboxylic acids in APIs as well as the need
for maximizing the 12C/13C-exhange for preclinical testing. To
such end, we anticipated that the merger of decarboxylative
halogenation with the robustness of catalytic carboxylation of
organic halides might offer a powerful platform for obtaining
otherwise inaccessible carboxylic acids with >99% 13C-content.
As shown in Scheme 3 (bottom), this turned out to be the case.
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Indeed,
a
Ag-catalyzed decarboxylative halogenation20
followed by Ni/L2 or Ni/L3-catalyzed carboxylation afforded
[13C]5a and [13C]5b in slightly lower overall yields to those
shown for NHP-esters, but with >99% 13C-labeling.
Encouraged by these results, we examined the 13C–
carboxylation of a host of benzyl, aryl or unactivated alkyl
chlorides obtained via decarboxylative halogenation of the
parent carboxylic acids (Table 2). Notably, nitriles (5c), esters
(5d-5f) or nitrogen-containing heterocycles (5e) do not
interfere, obtaining in all cases >99% 13C-labeling. Albeit in
lower yields, secondary and tertiary alkyl carboxylic acids such
as 5b, 5g or 5h were within reach, with 5g being obtained as a
single diastereoisomer. Importantly, 13C-labeled aryl acetic
acids (5i-j) and (hetero)aryl carboxylic acids (5k-m) –
compounds that were beyond reach from NHP-esters – could
also be coupled under Ni/neocuproine or Ni/PPh3 regimes, thus
representing an opportunity to improve upon existing C-
labeling techniques.
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Scheme 3. Direct 12C/13C Exchange of Carboxylic Acids.a
a As scheme 4, Ni/L2. b Ni/L3. c Using 4g with a 1:1 diastereomeric
ratio. d As scheme 4, Ni/L3, TBAB (2 equiv), DMA (0.4 M) at 80
e
ºC. NiCl2·dme (10 mol %), PCp3·HBF4 (20 mol %), MgCl2 (2
equiv), Zn (5 equiv), DMF (0.5 M) at rt. f NiBr2·dme (10 mol %),
g
neocuproine (20 mol %), Mn (2 equiv), DMA (0.2 M) at 50 ºC.
NiCl2(PPh3)2 (5 mol %), PPh3 (10 mol %), TEAI (10 mol %), Mn
(3 equiv), DMA (0.25 M) at rt.
Aimed at extending the applicability of our carbon isotope
exchange, we next focused our attention on converting -
branched carboxylic acids into their labeled linear analogues via
chain-walking scenarios,14a,21 a transformation that has proven
elusive in related labeling approaches.13a Although in low
yields, the preparation of [13C]2a,5a,6 with >99% 13C–labeling
does not only demonstrate the successful realization of this goal
(Scheme 4), but also set the basis for designing site-selective
radiolabeling techniques at remote sp3 C–H sites.22 Given the
key role of 14C-radiolabeling in pharmacokinetic and ADME
studies,5 the ability to access 14C-labeled molecules was then
explored. Preliminary results successfully highlighted the
applicability of this method under otherwise similar
conditions.15 It is particularly noteworthy that [14C]5i and
a Ni/L1: Table 1; Ni/L2: NiBr2·dme (10 mol %), L2 (24 mol %),
Mn (2 equiv), TBAB (1 equiv), 13CO2 (1 atm) in DMF (0.17M), at
60 ºC; Ni/L3: NiBr2·diglyme (10 mol %), L3 (24 mol %), Mn (3
equiv), LiCl (1 equiv), 13CO2 (1 atm) in DMF (0.40M), at 90 ºC.
[14C]5k are obtained in high molar activities (≥ 2.04 GBq mmol-
1
)
23 with negligible isotope dilution, thus opening a gateway to
Table 2. Decarboxylative Halogenation/Carboxylation.
study the metabolic activity of drugs containing carboxylic acid
motifs.
Scheme 4. Chain-Walking 13C Exchange and 14C-Labeling.
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a NiI2 (2.5 mol %), L4 (4.4 mol %), Mn (2 equiv), DMF (1.0 M),
25 ºC, 20 h. b Reactions performed with 4i and 4k as substrates.
In conclusion, we have developed a simple, efficient and
highly versatile catalytic decarboxylation/carboxylation for
carbon isotope exchange of carboxylic acids with 13CO2 or
14CO2. This route enables the access to labeled aliphatic or
aromatic carboxylic acids, even at late-stages, without changing
the already established sequence en route to the parent
compound, thus offering a robust and economical gateway for
rapidly and reliably obtaining preclinical data for lead
generation in drug discovery. Further work on radiolabeling
techniques is ongoing.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Experimental procedures and characterization data (1H,13C and 19
NMR, HRMS, IR) for all new compounds.
F
AUTHOR INFORMATION
Corresponding Author
(3‐dimethyl
Aminopropyl)
* Email: rmartinromo@iciq.es
‐N‐(Ethylaminocarbonyl)‐6‐(2‐propenyl)Ergoline‐8β‐carboxamide
(Cabergoline), a Potent Long Lasting Prolactin Lowering Agent. J.
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Georgin, D.; Taran, F.; Audisio, D. Palladium-Catalyzed
Decarboxylative Cyanation of Aromatic Carboxylic Acids Using [13C]
and [14C]-KCN. J. Label. Compd. Radiopharm. 2015, 58, 425–428. (d)
Neumann, K. T.; Lindhardt, A. T.; Bang-Andersen, B.; Skrydstrup, T.
Synthesis and Selective 2H-, 13C-, and 15N-Labeling of the Tau Protein
Binder THK-523. J. Label. Compd. Radiopharm. 2017, 60, 30–35. (e)
Song, F.; Salter, R.; Chen, L. Development of Decarboxylative
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Author Contributions
All authors have given approval to the final version of the
manuscript, ‡These authors contributed equally.
ACKNOWLEDGMENT
We thank ICIQ, European Research Council (ERC-PoC-2016-
755251) and MINECO (CTQ2015-65496-R) for financial support.
A. Tortajada and F. Cong thank MECD (FPU program) and China
Scholarship Council (CSC) for predoctoral fellowships, and B.
Sahoo thanks European Union’s Horizon 2020 under the Marie
Sklodowska-Curie grant agreement (795961). We thank Dr. Noemí
Cabello (ICIQ-HRMS department) for mass analysis and Dr.
Yasuhiro Okuda for conducting initial experiments.
REFERENCES
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(23) In the international system of units (SI) the radioactivity is
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