Carbon isotope labeling of carbamates by late-stage [11C], [13C] and [14C]carbon dioxide incorporation

Article abstract of DOI:10.1039/d0cc05031h

A general procedure for the late-stage [11C], [13C] and [14C]carbon isotope labeling of cyclic carbamates is reported. This protocol allows the incorporation of carbon dioxide, the primary source of carbon-14 and carbon-11 radioisotopes, in a direct, cost-effective and sustainable manner. A disconnection/reconnection strategy, involving ring opening/isotopic closure, was also implemented.

Full text of DOI:10.1039/d0cc05031h

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Talbot, F. Caillé, A. Chevalier, A. Sallustrau, O. Loreau, G. Destro, F. Taran and D. Audisio, Chem.
Commun., 2020, DOI: 10.1039/D0CC05031H.
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DOI: 10.1039/D0CC05031H
COMMUNICATION
Carbon Isotope Labeling of Carbamates by Late-Stage [11C], [13C]
and [14C] Carbon Dioxide Incorporation
Received 00th January 20xx,
Antonio Del Vecchio,[a]+ Alex Talbot,[a]+ Fabien Caillé,[b] Arnaud Chevalier,[a][c] Antoine Sallustrau,[a]
Olivier Loreau,[a] Gianluca Destro,[a] Frédéric Taran,[a] Davide Audisio*[a]
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A general procedure for the late-stage [11C], [13C] and [14C]carbon isotope labeling of cyclic carbamates is reported. This
protocol allows the incorporation of carbon dioxide, the primary source of carbon-14 and carbon-11 radioisotopes, in a
direct, cost-effective and sustainable manner. This method was applied to
a variety of carbamates, including
pharmaceuticals. A disconnection / reconnection strategy, involving ring opening / isotopic closure, was also implemented.
appealing, but their application was mainly focused on linear
carbamates.13
Introduction
Radiolabeling with carbon isotopes is an attractive strategy in
human/veterinary drug development, as well as in plant protecting
agent research.1 The two relevant radioactive isotopes of carbon
display antipodean physical properties, which usually require ad hoc
strategies for their insertion into organic structures. Carbon-14 (14C)
is a long-lived β- emitter relevant in the determination of (pre)clinical
drug metabolism and biodistribution.2 14C radio-synthesis remains
challenging due to the limited number of available row materials,
prohibitive costs and generation of long lasting waste (t1/2 5730
years).3 On the other hand, carbon-11 (11C) is a short-lived positron
emitter (β+), whose implication in positron emission tomography
(PET) can hardly be overstated. Challenges related to the 20.4
minutes half-life and the limited amounts of isotope generated by a
cyclotron dramatically affect the chemical space tackled in PET
centers.4 In such a dichotomy, the two isotopes share the same
primary chemical source: carbon dioxide ([14C]CO2 and [11C]CO2).
Given the complementarity of their applications, drug discovery
would highly benefit from general procedures easily transmutable to
both 11C and 14C radioisotopes. Unfortunately, recent developments
in late-stage carbon isotope labeling are specific and unsuitable for
application to both radioisotopes, either due to practical and/or
safety related issues.5,6 Carbamates are a fundamental functional
group, largely found in biologically active compounds and marketed
pharmaceuticals (Scheme 1, top).7 In particular, cyclic carbamates
are generally metabolically stable and the carbonyl moiety
represents a suitable position for labeling.8 Due to its high reactivity,
the use of [14C] and [11C]phosgene has been investigated, but
shortcomings related to safety and the requirement for specialized
apparatus have largely limited its utilization (Scheme 1, bottom).9 In
2002, Långström reported a selenium-mediated carbamoylation
reaction in presence of [11C]carbon monoxide.10 The procedure was
applied to simple carbamate derivatives, and later on one drug
(Zolmitriptan).11,12 Methods that utilize [11C]CO2 and [14C]CO2 are
Representative carbamate-containing drugs
Me
O
O
Me
N
NH
H
N
N
H
Cl
N
C
O
O
O
O
N
H
Fenspiride
(respiratory inflammatory
diseases)
Chlorzoxazone
(muscle relaxant)
Zolmitriptan
(acute migraine)
14C &11C Building blocks
OH
R'
H2N
O
O
n
Primary
C
R
precursor
O
dehydrating agent
OH
O
H2N
R'
Hight temperatures
(450 to 850 °C)
or multi-step
n
O
R
C
O
HN
R'
Selenium
n
R
OH
limited
scope
H2N
R'
Hazardous
Specialized
equipment
n
R
Cl
C
Cl
carbon-11
This work
O
O
carbon-14
O
O
OH
R'
HN
broad scope
N3
R
n
PPhMe2
28 examples
easy applicability in
radioisotope centers
R
R
Scheme 1. Top: Relevant examples of cyclic carbamates containing pharmaceuticals;
middle: synthetic strategies for cyclic carbamate radiosyntesis; bottom: Staudinger / aza-
Wittig approach.
Vasdev and co-workers labeled cyclic carbamate [11C]SL25.1188
using BEMP as fixating base in presence of POCl3 as dehydrating
reagent.14 In 2019, Horkka et al. reported a procedure where the
dehydration step was performed under Mitsunobu conditions, and
labeled one cyclic carbamate, benzoxazol-2-one.15 Very recently,
Jakobsson et al. reported the synthesis of [11C]carbonyl difluoride.16
While this reagent has a similar reactivity to phosgene, it is generated
from [11C]CO,17 a secondary precursor obtained from [11C]CO2 with
technically challenging and time-consuming conditions which are
unpractical to implement in most PET centers. The current state of
the art highlights the need for general procedures that would prove
effective on elaborate molecules. Here, we report on a late-stage
[a] Dr. A. Del Vecchio, A. Talbot, Dr. A. Chevalier, Dr. A. Sallustrau, O. Loreau, Dr. F.
Taran, Dr. D. Audisio
Université́ Paris-Saclay, Service de Chimie Bio-organique et Marquage (SCBM),
CEA/DRF/JOLIOT, 91191, Gif sur Yvette, France
E-mail: davide.audisio@cea.fr
[b] Dr. F. Caillé,
UMR 1023 IMIV, Service Hospitalier Frédéric Joliot, CEA, Inserm, Université Paris Sud,
CNRS, Université Paris-Saclay, Orsay, France
[c] Dr. A. Chevalier,
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-
Saclay, 1, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
+ A. D. V. and A. T. contributed equally
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EDGE ARTICLE
O
C
N
O
labeling of cyclic carbamates that utilized CO2 as isotope source. This
procedure is suitable to 13C, 11C and 14C, on a variety of substrates
including pharmaceuticals.
N3
OH
View Article Online
O
C
N
DOI: 1H0.1039/D0CC05031H
PPhMe2
*
OH
R
n
5 min
R
C
O2
n
R
n
n = 0,1
Our recent results on the late-stage labeling of cyclic ureas18
encouraged us to investigate a Staudinger aza-Wittig approach
(SAW) for the 14C- and 11C-labeling of cyclic carbamates, directly from
CO2. Reaction optimization was conducted at room temperature in 5
minutes on model substrate 1, using stoichiometric [13C]CO2, as 14C-
surrogate, and its precise addition was monitored utilizing a RC Tritec
manifold.
5 membered rings
O
C
NH
O
O
O
C
NH
O
C
O
O
O
NH
NH
O2N
Br
13
14
11
[a]
[b]
[c]
13
14
11
[a]
2
3
C] = 81%
[
[
C] = 84%
[
[
13
11
[a]
[c]
13
11
[a]
4
5
C] = 62%
[
[
C] = 67%
[
[
[b]
[c]
2
3
C] = 73%
C] = 71%
[c]
4
5
C] = 74%
C] = 77%
2
3
[
C] = 76%
[
C] = 80%
O
C
NH
O
C
NH
O
C
NH
O
C
NH
O
O
O
R
R
O
Me Me
P
R
N
N
O
Me
P
N
Me
OH
labeled-C
O2
O
Cl
Cl
MeO
a
, R = Ph
e
N3
F3C
NH
Me
Me
CF3
b
, R = Cy
13
[a]
[b]
[c]
8
C] = 80%
[
[
Conditions
13
[a]
13
[a]
13
[a]
c
6
7
9
C] = 87%
, R = nBu
[
[
[
C] = 89%
14C]6 = 75%[b]
[
C] = 50%
[
[
14
8
C] = 55%
1
[
11C]7 = 68%[c]
11C]9 = 82%[c]
2
Cy
11
8
[
C] = 83%
11
[c]
6
C] = 79%
Me
Me
Cy
P
P
P
Cy
6 membered rings
Ph
Cy
f
d
O
C
O
C
O
O
C
Entry
*CO2
Phosphine
Temperature
25 °C
Time
Yield (%)
HN
O
C
O
HN
HN
O
HN
O
Me
1
2
3
4
5
6
7
8
[
[
[
[
[
[
[
[
13C]CO2
13C]CO2
13C]CO2
13C]CO2
13C]CO2
13C]CO2
14C]CO2
11C]CO2
a
b
c
d
e
f
5 min
5 min
5 min
5 min
5 min
5 min
5 min
5 min
63
46
62
84
0
NO2
13
11
[a]
[c]
25 °C
13
[a]
[c]
13
[a]
[c]
10
C] = 67%
[
[
11
C] = 87%
12
C] = 88%
[
[
[
[
13
13
= traces
[
C]
11
11
10
C] = 57%
11
12
C] = 62%
C] = 50%
25 °C
O
C
O
O
HN
Cl
O
O
O
HN
HN
O
O
25 °C
C
NH
O2N
Me
Ph
25 °C
Cl
13
[a]
[c]
13
11
[a,d]
[c]
13
[a,d]
[c]
13
[a]
14
C] = 80%
15
C] = 35%
16
C] = 28%
17
C] = 74%
[
[
[
[
[
[
[
[
11
11
11
[c]
14
C] = 24%
15
16
17
C] = 18%
C] = 12%
C] = 72%
25 °C
0
5 membered phenols
d
d
25 °C
71[a]
76[b]
H
N
H
N
H
N
C
O
H
N
70 °C
C
O
C
O
O
C
O
O
O
Me
O
Table 1. Optimization of the Staudinger aza-Wittig procedure [a] radiochemical
yield; [b] decay-corrected radiochemical conversion. Carbon-13 and -14
experiments were performed in 0.7 mL DMF on a 0.1 mmol scale, in presence of
stoichiometric amounts of [13C and 14C]CO2; for carbon-11 labeling, precursor 1 and
the phosphine were typically in a 100-fold excess compared to [11C]CO2.20
13
11
[a]
[c]
13
[a]
[c]
13
11
[a]
[c]
13
[a]
[c]
18
C] = 85%
19
C] = 78%
20
C] = 37%
21
C] = 45%
[
[
[
[
[
[
[
[
11
11
18
C] = 59%
19
C] = 48%
20
C] = 53%
21
C] = 19%
Scheme 2. Late-stage labeling of cyclic carbamates with carbon isotopes. [a] Yield of the
isolated product; [b] radiochemical yield; [c] d.c. radiochemical conversion; [d] reaction
temperature, 150 °C.20
As expected, the nature of the phosphine had a major impact on
the transformation. While the use of triphenylphosphine (a) allowed
the formation of [13C]2 in 63% isolated yield, with electron-rich
tricyclohexylphosphine (b) the yield dropped to 46%. When tri-n-
butylphosphine (c) was utilized, carbamate [13C]2 was isolated in 62%
yield. The best result was obtained with dimethylphenylphosphine
(d) which provided the corresponding [13C]carbamate with 84%
isolated yield. The use of (e), reminder of the core structure of
commonly used iminophosphoranes trapping agents such as BEMP,
was unproductive. While the phosphazide is formed rapidly from (e),
the subsequent nitrogen release required harsh conditions, as
reported by Lyapkalo and co-workers.19 Finally, the use of bidentate
phosphine (f) did not provide the desired product.20 Without further
optimization, the procedure was applied to 14C. Pleasingly, [14C]2 was
isolated in 71% RCY directly from [14C]CO2. Compared to previous
methods, this procedure is cost-effective and drastically minimizes
the generation of radioactive waste. Based on the short reaction
time required, application to 11C-labeling seemed feasible. Despite
the diametrically different environment and the CO2 stoichiometry,
[11C]2 was labeled in 76% decay-corrected (d.c.) RCC, under slightly
different conditions (70 °C). Importantly, the radiosynthesis was
carried out in automated modules, according to nuclear safety
requirements for PET tracers production.
Next, we explored the scope on a series of substituted azido
alcohols (Scheme 2).21 Aliphatic 5-membered carbamates were
labeled with 13C to provide [13C]3 to [13C]9 in 50 to 89% yield. The
electronic nature of substituents on the aromatic ring did not affect
the reaction outcome and also a sterically hindered quaternary
alcohol precursor delivered 9 in 87% yield. Selected substrates were
labeled with radiocarbon, to provide [14C]2, 3, 6 and 8 in 55 to 75%
RCY, under otherwise identical reaction conditions. Pleasingly, 11C
labeling proceeded smoothly in all tested substrates in 68 to 83% d.c.
RCC. Next, we looked at the labeling of six membered ring
carbamates. The presence of a methyl or phenyl substituent in alpha
position to the hydroxyl did not affect its reactivity and 2-
benzoxazinones 10-12 could be efficiently labeled with 13C and 11C
isotopes. These derivatives would be quite challenging to label with
current methods using CO2, because of the poor nucleophilicity of
anilines.13 On the other hand, from tertiary alcohol precursors,
derivatives 15 and 16 were delivered with a significant drop in the
yields and required higher reaction temperature (Scheme 2). In
addition, when a strong electron-withdrawing p-NO2 substituent was
present on the aromatic azide, only traces amounts of [13C]13 were
recovered. The increased electrophilicity of the isocyanate
2 | J. Name., 2012, 00, 1-3
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EDGE ARTICLE
Carbon-14
Labeling of drug derivatives
Carbon-11
intermediate, which presumably undergoes fast hydrolysis under the
View Article Online
DOI: 10.1039/D0CC05031H
reaction conditions, was detrimental to the process. Interestingly,
also regioisomeric carbamate 17 could be labeled both with 11C and
13C from the corresponding benzylic azide precursor. In this case, the
presence of a nitro group in para position to the alcohol was well
tolerated: [13C]17 and [11C]17 were obtained in 74% and 72% d.c.
RCC, respectively. Benzoxazol-2-ones are widely present in
pharmaceuticals and their late-stage labeling is a worthwhile
endeavour.22 After some optimization, benzoxazol-2-ones 18-21
could be labeled with 13C, in presence of 2 equiv. of DIPEA.
Interestingly, the use of CO2 fixating agents such as DBU, DABCO,
DBN and TBD was detrimental to the reaction outcome and did not
provide formation of the desired product.20 On the other hand, when
the reaction on model substrate 18 was performed in the absence of
DIPEA, the isolated yield dropped to 64%.20 For short-lived 11C, the
optimal conditions were in absence of additive; gentle heating at 70
°C was required and [11C]18-21 were obtained in 19 to 59% RCC. With
these results in hand, we next turned our attention to the labeling of
pharmaceutically relevant derivatives (Scheme 3). Chlorzoxazone, a
FDA approved drug displaying muscle relaxant properties,23 was
labeled from the corresponding azidoalcohol precursor under
standard conditions to isolate [14C]22 in 39% RCY and high molar
activity (Am) 2.0 GBq mmol-1. The short-lived isotopomer, ready-to-
inject [11C]22 was isolated after HPLC purification and formulation in
37 ± 2% d.c. RCY and d.c. Am of 85 ± 4 GBq/µmol. Caroxazone
precursor 23 was labeled in 30% RCY from [14C]CO2 and 25 ± 5% RCY
from [11C]CO2. Metaxalone, an aliphatic five-membered carbamate
with muscle relaxant properties, was obtained in 59% RCY and 44 ±
3% d.c. RCY with carbon-14 and carbon-11, respectively. Next, we
focused on Fenspiride, an anti-inflammatory drug, which was
recently labeled with tritium.24 The required beta-azido alcohol
precursor was obtained in a three-step sequence, including an
alkylation, a Corey-Chaykovsky epoxidation and a regioselective ring
opening azidation from commercially available materials.20 This
substrate underwent 14C-labeling in 45% RCY and 11C-labeling in 23 ±
3% d.c. RCY. The procedure was also applied for the 14C and 11C
labeling of N-Boc protected Tobramycine derivative 26,25 on a non-
pharmacophoric position, according to previous SAR studies.26 The
SAW approach allowed to isolate the carbamates [14C]26 and [11C]26
in 35% and 68 ± 2% d.c. RCY, respectively. In all cases, consistent high
Am and radiochemical purities for both radioisotopes were obtained.
The concept of isotope exchange has been largely exploited for
hydrogen,27 but only recently introduced for carbon and, to our
knowledge, strictly limited to carboxylic acids.5 In order to accelerate
the access to labeled carbamates and limit the synthesis of
precursors, we envisioned a disconnection/reconnection strategy
(DRS).9a The DRS was first validated on model compound 28. After
carbamate cleavage under strong basic conditions, the
corresponding beta-amino alcohol underwent a diazo-transfer
reaction to obtain the azido alcohol 29 and further converted into
[13C]28 in 65% yield. With this procedure in hand, we next looked to
Zolmitriptan, a compound in use for the treatment of acute migraine,
commercialized by AstraZeneca. From commercially available
unlabeled Zolmitriptan, the azido alcohol 31 was obtained in 46%
yield, over two steps. Subsequent SAW reaction allowed to obtain
[14C]30 in moderated 8% RCY, nonetheless with a high Am of 2 GBq
mmol-1. Carbon-11 labeled Zolmitriptan was also synthesized in 25 ±
2% RCY and Am 74 ± 6 GBq/µmol. Compared to the previous 11C-
labeling performed using [11C]CO and selenium,10,28 this procedure
has the advantage to use a more readily accessible carbon-11 source
(i.e. [11C]CO2) and avoid the manipulation of selenium derivatives.
14
11
22
C] = 39% RCY
22
[ C] = 37 ± 2% RCY (n=2)
[
H
Cl
N
Isolated activity: 70.8 MBq
Am: 2.0 GBq mmol-1
Isolated activity: 2.8 ± 0.3 GBq
Am: 85 ± 4 GBq/µmol
C
O
O
Radiochemical purity: 99%
Radiochemical purity: 99%
22
, Chlorzoxazone
14
11
23
C] = 30% RCY
23
[ C] = 25 ± 5% RCY (n=2)
[
NH
Isolated activity: 55.4 MBq
Am: 2.0 GBq mmol-1
Isolated activity: 0.9 ± 0.1 GBq
Am: 75 ± 10 GBq µmol-1
C
O
O
Radiochemical purity: 99%
Radiochemical purity: 99%
23
, Caroxazone precursor
O
C
O
14
11
24
C] = 59% RCY
24
[ C] = 44 ± 3% RCY (n=2)
[
HN
O
Me
Isolated activity: 111.0 MBq
Am: 2.0 GBq mmol-1
Isolated activity: 2.1 ± 0.4 GBq
Am: 78 ± 3 GBq µmol-1
Radiochemical purity: 99%
Radiochemical purity: 99%
24
, Metaxalone
Me
H
N
O
14
O
25
C] = 45% RCY
[
11C]25 = 23 ± 3% RCY (n=3)
[
Isolated activity: 90.3 MBq
Am: 1.7 GBq mmol-1
Isolated activity: 0.8 ± 0.2 GBq
Am: 81 ± 8 GBq µmol-1
N
Radiochemical purity: 99%
Radiochemical purity: 99%
25
, Fenspiride
O
BocHN
HO
O
NH
O
14
O
26
C] = 35% RCY
[
11
NHBoc
26
C] = 68 ± 2% RCY (n=2)
[
Isolated activity: 48.5 MBq
Am: 1.9 GBq mmol-1
Isolated activity: 1.1 ± 0.2 GBq
Radiochemical purity: 99%
HO
NHBoc
Radiochemical purity: 99%
NHBoc
NHBoc
, Tobramycine derivative
O
O
HO
26
Scheme 3. Late-stage radiolabeling of pharmaceutically relevant carbamates. RCY:
radiochemical yield; Am : molar activity. For carbon-11, RCY and Am are decay-corrected.
Disconnection/reconnection strategy
i, 80%
ii, 64%
H
H
*CO2
N3
N
N
O
O
PPhMe2
DMF, r.t.
OH
O
O
29
13
28
[
C]
28= 65%
Me
Me
N
14C]30 = 8% RCY
Me
[
Me
N
Isolated activity: 14.4 MBq
Am: 2.0 GBq mmol-1
H
N
*CO2
O
N3
Radiochemical purity: 99%
O
N
H
PPhMe2
N
H
HO
DMF, 70 °C
30, Zolmitriptan
[
11C]30 = 25 ± 2% RCY (n=2)
31
Isolated activity: 1.0 ± 0.2 GBq
-1
Am: 74 ± 6 GBq µmol
i, 95%; ii, 46%
[
12C]30, Zolmitriptan
Linear carbamate labeling
H
*CO2
PPhMe2
Ph
N
O
HO
Ph
N3
+
O
DMF,
r.t. to 150 °C
13
C]
32 = 64%
[
11
[
C]
32 = 4% RCC
Scheme 4. Top: disconnection/reconnection strategy labeling of carbamates with carbon
dioxide. Conditions: i) KOH, EtOH/H2O (4:1), 100 °C, ii) TfN3, DCM, CuSO4,5H2O, K2CO3,
MeOH, overnight, r.t. (see SI for details). Bottom: labeling of linear carbamates.
Additionally, the DRS was also successfully performed on
Fenspiride.20 Finally, we looked to extend the methodology to linear
carbamates. Although metabolically more labile and generally used
as prodrugs, linear carbamates have been labeled with 11C with more
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Page 4 of 5
EDGE ARTICLE
[11] O. Lindhe, P. Almqvist, M. Kagedal, S. A. GVuieswtaAfrstsicolenO,nlMine.
or less success and usually under harsh conditions. For a first proof
of concept, we selected substrate 32 that proved highly challenging
with previous methods.13c,29 After some optimization of the
intermolecular reaction, [13C]32 was labeled in 64% yield, after
heating the mixture for 15 min at 150 °C. For the application to 11C,
the product was observed only in 4% d.c. RCC. This result clearly
highlights the challenges related to the inherent physical and
technical differences between carbon isotopes. Thought preliminary,
this work shows the possibility to reach challenging linear carbamate
systems. To conclude, a general methodology for the radiolabeling of
cyclic aliphatic and aromatic carbamates has been developed. The
reaction takes place with controlled amounts of CO2, the first
available building block for 14C and 11C radioisotopes, resulting in a
late-stage carbon isotope labeling of carbamate-containing drugs
Bergström, D. Nilsson, G. Antoni, Int. J.DMOoI:l1.0Im.10a3g9./2D001C1C,0A5r0t3ic1lHe
ID 694179, doi.org/10.1155/2011/694179.
[12] For another procedure using [11C]CO, see: H. Doi, J. Barletta, M.
Suzuki, R. Noyori, Y. Watanabe, B. Långström, Org. Biomol.
Chem. 2004, 2, 3063-3066.
[13] a) A. A. Wilson, A. Garcia, S. Houle, O. Sadovski, N. Vasdev,
Chem. Eur. J. 2011, 17, 259-264. b) A. Pekošak, J. Ž. Bulc, Š.
Korat, R. C. Schuit, E. Kooijman, R. Vos, M. Rongen, M. Verlaan,
K. Takkenkamp, W. Beaino, A. J. Poot, A. D. Windhorst, Mol.
Pharmaceutics 2018, 15, 4872-4883. c) J. M. Hooker, A. T.
Reibel, S. M. Hill, M. J. Schueller, J. S. Fowler, Angew. Chem. Int.
Ed. 2009, 48, 3482-3485; Angew. Chem. 2009, 121, 3534-3537.
d) J. M. Hooker, S. W. Kim, D. Alexoff, Y. Xu, C. Shea, A. Reid, N.
Volkow, J. S. Fowler, ACS Chem. Neurosci. 2010, 1, 65-73.
[14] a) N. Vasdev, O. Sadovski, A. Garcia, F. Dollé, J. H. Meyer, S.
Houle, A. A. Wilson, J. Label.Compd. Radiopharm. 2011, 54,
678-680. b) K. Dahl, T. L. Collier, R. Cheng, X. Zhang, O. Sadovski,
S. H. Liang, N. Vasdev, J. Label. Compd. Radiopharm. 2018, 61,
252-262.
and analogues.
A disconnection/reconnection strategy was
successfully implemented thus simplifying the synthesis of precursor
and accelerating the whole labeling process. Finally, a proof of
concept was obtained with a more challenging linear carbamate.
[15] K. Horkka, K. Dahl, J. Bergare, C. S. Elmore, C. Halldin, M. Schou,
ChemistrySelect 2019, 4, 1846-1849.
[16] E. J. Jakobsson, S. Lu, S. Telu, V. W. Pike, Angew. Chem. Int. Ed.,
2020, 59, 7256-7260.
Acknowledgments
[17] K. Dahl, C. Halldin, M. Schou, Clin. Transl. Imaging 2017, 5, 275-
289.
This project received funding from the European Union’s Horizon
2020 research and innovation program under the Marie Sklodowska-
Curie (g. a. N°675071) and CEA. The authors thank D.-A. Buisson, A.
Goudet, S. Lebrequier and E. Marcon for the excellent analytical
support and Dr. B. Kuhnast for helpful discussion.
[18] A. Del Vecchio, F. Caillé, A. Chevalier, O. Loreau, K. Horkka, C.
Halldin, M. Schou, N. Camus, P. Kessler, B. Kuhnast, F. Taran, D.
Audisio, Angew. Chem. Int. Ed., 2018, 57, 9744-9748.
[19] A. V. Alexandrova, T. Mašek, S. M. Polyakova, I. Císařová, J.
Saame, I. Leito, I. M. Lyapkalo, Eur. J. Org. Chem. 2013, 1811-
1823.
[20] For additional information, see the Supporting Information.
[21] For an example of aza-Wittig reaction with non-labeled CO2,
see: a) P. Molina, M. Alajarin, A. Arques, Synthesis 1982, 596-
597. For reviews on aza-Wittig reactions, see : b) S. Eguchi,Y.
Matsushita, K. Yamashita, Org. Prep. Proced. Int. 1992, 24, 209-
243. c) Palacios, F.; Alonso, C.; Aparicio, D.; Rubiales, G.; de los
Santos, J. M. Tetrahedron 2007, 63, 523-575.
[22] See previous examples of labeled benzoxazol-2-ones, see: a) A.
Zerilli, D. Lucas, F. Berthou, L. G. Bardou, J. F. Ménez, J.
Chromatogr. B 1996, 677, 156-160. b) G. Roger, F. Dollé, B. de
Bruin, X. Liu, L. Besret, Y. Bramoullé, C. Coulon, M. Ottaviani,
M. Bottlaender, H. Valette, M. Kassiou, Bioorg. Med. Chem.
2004, 12, 3229-3237.
[23] D.-L. Dong, Y. Luan, T.-M. Feng, C.-L. Fan, P. Yue, Z.-J. Sun, R.-
M. Gu, B.-F. Yang, Eur. J. Pharmacol. 2006, 545, 161-166.
[24] Y. Y. Loh, K. Nagao, A. J. Hoover, D. Hesk, N. R. Rivera, S. L.
Colletti, I. W. Davies, D. W. C. MacMillan, Science, 2017, 358,
1182-1187.
[25] K. Michael, H. Wang, Y. Tor, Bioorg. Med. Chem. 1999, 7, 1361-
1371.
[26] R. J. Fair, L. S. McCoy, M. E. Hensler, B. Aguilar, V. Nizet, Y. Tor,
ChemMedChem 2014, 9, 2164-2171.
[27] J. Atzrodt, V. Derdau, W. J. Kerr, M. Reid, Angew. Chem. Int. Ed.
2018, 57, 3022-3047; Angew. Chem. 2018, 130, 3074-3101.
[28] a) M. Bergström, R. Yates, A. Wall, M. Kågedal, S. Syvänen, B.
Långström, J. Pharmacokinet. Pharmacodyn. 2006, 33, 75-91.
[29] In ref. 13c, [11C]32 was labeled using [11C]CO2 in < 1 % yield,
from benzylamine and chlorocyclohexane in presence of DBU.
Notes and reference
[1] C. S. Elmore, R. A. Bragg, Bioorg. Med. Chem. Lett. 2015, 25,
167–171.
[2] E. M. Isin, C. S. Elmore, G. N. Nilsson, R. A. Thompson, L.
Weidolf, Chem. Res. Toxicol. 2009, 25, 532–542.
[3] D. Hesk, P. McNamara, J. Label. Compd. Radiopharm. 2007, 50,
875-887.
[4] a) B. H. Rotstein, S. H. Liang, M. S. Placzek, J. M. Hooker, A. D.
Gee, F. Dollé, A. A. Wilson, N. Vasdev, Chem. Soc. Rev. 2016, 45,
4708-4726. b) X. Deng, J. Rong, L. Wang, N. Vasdev, L. Zhang, L.
Josephson, S. H. Liang, Angew. Chem. Int. Ed. 2019, 58, 2580-
2605.
[5] Carbon isotope exchange is not suitable for 11C, due to isotopic
dilution, see: a) G. Destro, O. Loreau, E. Marcon, F. Taran, T.
Cantat, D. Audisio. J. Am. Chem. Soc. 2019, 141, 780-784. b) A.
Tortajada, Y. Duan, B. Sahoo, F. Cong, G. Toupalas, A. Sallustrau,
O. Loreau, D. Audisio, R. Martin, ACS Catal. 2019, 9, 5897−5901.
[6] [11C]fluoroform is
a
high value building block. Its
implementation to 14C would represent a technical challenge.
M. B. Haskali, V. W. Pike, Chem. Eur. J. 2017, 23, 8156-8160.
[7] a) P. K., Singh, O. Silakari ChemMedChem, 2018, 13, 1071-1087.
b) M. D. Delost, D. T. Smith, B. J. Anderson, J. T. Njardarson, J.
Med. Chem. 2018, 61, 10996-11020.
[8] For example, see: Efavirenz a) N. N. Bumpus, U. M. Kent, P. F.
Hollenberg, J. Pharmacol. Exp. Ther. 2006, 318, 345-351. For
Metaxalone see: b) R. B. Bruce, L. Turnbull, J. Newman, J. Pitts,
J. Med. Chem. 1966, 9, 286-288. For Fenspiride, see: c) M. C.
Dumasia, E. Houghton, W. Hyde, D. Greulich, T. Nelson, J.
Peterson, J. Chromatogr. B 2002, 767, 131-144.
[9] a) R. Voges, J. R. Heys, T. Moenius, Preparation of Compounds
Labeled with Tritium and Carbon-14 (John Wiley & Sons, 2009).
b) Z. Chen, W. Mori, X. Deng, R. Cheng, D. Ogasawara, G. Zhang,
M. A. Schafroth, K. Dahl, H. Fu, et al. J. Med. Chem. 2019, 62,
3336-3353.
[10] T. Kihlberg, F. Karimi, B. Långström, J. Org. Chem. 2002, 67,
3687-3692.
4 | J. Name., 2012, 00, 1-3
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Late-Stage Carbon Isotope Labeling
DOI: 10.1039/D0CC05031H
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28 examples
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easy applicability in radioisotope centers
A general procedure which allows to label cyclic carbamates with all carbon isotopes (11C, 13C, 14C)
has been developed. This mild protocol valorizes carbon dioxide, the universal building block for
radiolabeling. A series of pharmaceuticals were obtained in high radiochemical yield and purity and a
disconnection/reconnection strategy was implemented.