Regioselective ruthenium catalysed H-D exchange using D2O as the deuterium source

Article abstract of DOI:10.1039/c4ob01798f

An efficient and convenient ruthenium catalysed method for a regiospecific H/D exchange using D₂O is described. Organic moieties such as pyridine, oxazole, imidazole, pyrazole, ester, ketone and carboxylic acid have been found effective directing groups in this transformation. In addition, the deuteration of the enantiopure (S)-Ketoprofen leads to the incorporation of three deuterium atoms with retention of molecular chirality.

Full text of DOI:10.1039/c4ob01798f

Organic &
Biomolecular Chemistry
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Regioselective ruthenium catalysed H–D exchange
using D O as the deuterium source†
2
Cite this: DOI: 10.1039/c4ob01798f
a
a
a
a,b
Lorenzo Piola, José A. Fernández-Salas, Simone Manzini and Steven P. Nolan*
2
An efficient and convenient ruthenium catalysed method for a regiospecific H/D exchange using D O is
Received 22nd August 2014,
Accepted 18th September 2014
described. Organic moieties such as pyridine, oxazole, imidazole, pyrazole, ester, ketone and carboxylic
acid have been found effective directing groups in this transformation. In addition, the deuteration of
the enantiopure (S)-Ketoprofen leads to the incorporation of three deuterium atoms with retention of
molecular chirality.
DOI: 10.1039/c4ob01798f
www.rsc.org/obc
Introduction
Isotopically labelled molecules are extremely valuable com-
pounds used in a wide range of applications. These facilitate
the study of drug metabolism and biological macromolecules
1
–3
through monitoring of biochemical processes,
and are
Scheme 1 Synthesis of 2.
useful probes enabling mechanistic and kinetic studies. To
these ends, deuterium has been targeted as the alternative, to
the more expensive and less abundant known isotopes
activation, in the presence of various deuterating agents. Peris
has described an arene ortho deuteration procedure using a
NHC-ruthenium complex, which was only active in the pres-
4 2
ence of MeOD-d . Deuterium oxide (D O) is the most attractive
isotopic source for the preparation of deuterated substrates
due to its combined low cost and low toxicity. However,
general procedures for the incorporation of deuterium into the
29
3
13
14
18
19
(
H, C, C, O and F). Hydrogen isotope exchange pro-
vides the most straightforward and direct procedure toward
4
the synthesis of labelled molecules. The versatility of deuter-
ium-labelling molecules has attracted the attention in various
5
6–8
9
fields, from protein crystallography, NMR,
MS, medical
1
0
11
imaging
to the elucidation of either organic
reaction mechanisms. Moreover, very recently,
or bio-
C–H bonds of organic compounds that utilise D
and remain undeveloped. A few examples of ruthenium-cata-
lysed deuteration systems have been reported using D O as the
2
O are limited
1
2,13
14
organic
deuterated molecules are being studied as possible new
drug candidates, incorporating deuterium atoms in the
2
isotope source with substrates such as alcohols and hetero-
cycles, but these reports are marked by non-selective deuter-
1
5
active ingredient. Owing to the usual requirement of multi-
step synthesis with consequent low yields, as well as the use
of costly procedures and isolation problems of deuterating
10,13,30–32
ium incorporation.
With this in mind, we envisioned that the development of a
regioselective ruthenium-catalysed deuteration system using
D O would permit access to practical, easy to handle, and
2
5
,16–18
methodologies,
metal-catalysed H/D exchange systems
have been developed that operate by activation of a C–H bond
using metal-based catalysts (Rh, Ir, Pd and Pt). The main limit-
highly cost effective labelling processes. We initially evaluated
3
,19–23
ations in these practices are low selectivity,
the use of
deuteration reactions using [RuH (SiEt )(PPh )(3-phenylinde-
2
3
3
2
4,25
relatively high catalyst loadings,
the presence of addi-
as well as the use of deuterium gas
nyl)] (2) that has shown important reactivity in arene boryla-
25,26
2,27,28
tives,
or more
33
tion through a C–H activation process. Catalyst 2 is easily
2
2–25
expensive deuterating agents.
Ruthenium has also been
synthesized in good yield by adding triethylsilane to a com-
mercially available ruthenium complex (Scheme 1). Arylpyri-
dines were selected as model substrates as they are commonly
found to be active in deuteration processes through C–H bond
3
4
encountered motif in the pharmaceutical industry.
a
EaStCHEM School of Chemistry, University of St Andrews, St Andrews, KY16 9ST,
UK. E-mail: snolan@st-andrews.ac.uk
b
Chemistry Department, College of Science, King Saud University, Riyadh 11451,
Results and discussion
Saudi Arabia
†
Electronic supplementary information (ESI) available: Experimental details and
Complex 2 was found to be highly efficient and selective in the
dideuteration of phenylpyridine (3a) in the ortho positions of
characterization data for all new compounds and all products. See DOI: 10.1039/
c4ob01798f
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a
Table 1 Scope of the deuteration using N-containing directing groups
the ortho positions of the pyridine moiety was observed
(
Table 1, entry 2). A pyridyl group proved to effectively
direct the deuteration of an olefinic C–H bond, yielding the
deuterated vinyl product (3e) (93%) in the presence of a
higher catalyst loading (5 mol%) (Table 1, entry 5). The
deuteration of benzo[h]quinoline (3f) proceeded with full con-
version (Table 1, entry 6). In order to test this reaction on a
broader range of nitrogen-based directing groups, various het-
erocycles were tested. 4,4-Dimethyl-2-phenyl-2-oxazoline (3h)
and N-phenyl pyrazole (3i) achieved selective deuteration in
the ortho positions with full conversions (Table 1, entries 8
and 9). Deuteration of methylimidazole (3g) proved more chal-
lenging and only 50% of the labelled product was obtained
b
Conversion
(%)
Entry
1
Substrate
Product
c
>95
(
Table 1, entry 7). Encouraged by the generality found for the
ortho selective deuteration protocol using N-based directing
groups, we further increased the level of versatility of the
method by studying oxygen-containing directing groups
2
90
(
Table 2). Surprisingly, and to our delight, complex 2 can
c
successfully catalyse deuteration reactions using several
O-containing functional groups such as esters, ketones, and
carboxylic acids (Table 2). These moieties are often present in
biological environments and drug molecules, thus expanding
the potential use of this system.
3
4
>95
92
Good conversions to the desired deuterated compounds
were obtained with methylbenzoate (3j) and methyl 4-chloro-
benzoate (3k) (Table 2, entries 1 and 2). para, meta or ortho
Substituted methyl bromobenzoate did not react, and in all
cases the starting material was recovered (see ESI†). This is
probably due to steric hindrance, which can interfere with the
formation of the ruthenacycle during the catalytic reaction.
Benzophenone (3l) was also tested, resulting in moderate
deuteration in the ortho positions of both arenes, probably
due again to steric hindrance (Table 2, entry 3). Due to the
expected tautomerization to the corresponding enolates, aceto-
phenone (3m), propiophenone (3n) and 1-indanone (3p) led to
complete deuteration in the α positions of the carbonyl groups
d
5
6
7
94
c
>95
d,e
50
d
8
9
>95
(
Table 2, entries 4–7). In the case of 2-phenylacetophenone
>95
(3o), arene ortho deuteration was also observed with full con-
version (Table 2, entry 7). However, 1-indanone (3p), which
was tested in order to understand how the strain of the metal-
lacycle could affect the reaction, led to moderate deuteration at
all phenyl ring positions (Table 2, entry 6). Unfortunately benz-
aldehyde did not react and the starting material was recovered
unchanged (see ESI†). A S-containing molecule was also tried:
surprisingly, dibenzyl disulfide was partially deuterated (25%)
a
2
Reaction conditions: 2 (2 mol%), 3 (0.25 mmol) and D O (0.5 mL).
e
b
1
c
d
Conversion determined by H-NMR. 8 h. 2 (5 mol%). Solvent is
toluene–D O mixture (1 : 1).
2
the phenyl moiety after 8 h at 110 °C, under the optimised at the CH2 positions instead of the expected aromatic posi-
conditions (see ESI†) in D O without use of any additives. In tions, without the cleavage of the weak S–S bond, showing an
2
3
order to evaluate the steric and electronic effects on this trans- unpredicted sp C–H activation (see ESI†). Next, more challen-
formation, various substituted pyridyl and congeners were ging carboxylic acid containing substrates were investigated.
tested (Table 1). The system was found to be quite tolerant To our delight, both ortho positions of benzoic acid (3q) and β
toward the presence of either electron-donating (Me) or elec- positions of 2-thiophenecarboxylic (3r) were fully labelled
tron-withdrawing groups (F and CO
of the 2-phenylpyridine, giving excellent conversions to the catalyst. This system is the first ruthenium-catalysed procedure
desired dideuterated products (Table 1, entries 2–4).
for ortho deuteration with D O of arene using carboxylic
2
Me) in the para position (Table 2, entries 8 and 9), highlighting the robustness of the
2
Interestingly, the presence of an ester group does not affect acids as directing groups. The protocol also avoids additional
the selectivity of the transformation, and only deuteration in protection–deprotection steps in the labelling process. Only a
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a
Table 2 Scope of the deuteration using O-containing directing groups
Scheme 2 Labelling of (S)-Ketoprofen.
b
Conversion
(%)
conditions. Satisfyingly, we observed complete and selective
deuteration of the positions showed in Scheme 2 at 2 mol%
catalyst loading (see ESI† for further information). This is a
more highly deuterated product compared with the commer-
cially available analytical standard tri-deuterated molecule pre-
Entry
1
Substrate
Product
70
D : 22
1
c
3
7
viously reported. Pleasingly, when the enantiomerically pure
S)-Ketoprofen was used, only a slight erosion of the enantio-
meric excess was observed (from 99% to 95%), when 2 mol%
of is used, leading to the desired enantioenriched
2
3
80
60
(
2
labelled Ketoprofen (Scheme 2). This compound, to the best
of our knowledge, cannot be prepared using conventional
methodologies.
4
5
6
7
0
Conclusions
15
In conclusion, a new application of the recently reported dihy-
dridosilyl ruthenium catalyst 2 has been developed in the field
of hydrogen isotope exchange. This ruthenium catalysed
deuteration procedure functions without the use of any addi-
>95
25
D
D
D
tive, and uses D O as the co-solvent and deuterium source, A
2
very wide range of substrates featuring N- and O-containing
directing groups, including carboxylic acids, are well tolerated
in the deuteration reaction. The complete and regioselective
labelling of a drug, Ketoprofen, was achieved without any pro-
tection/deprotection steps and providing the first example of
metal catalysed deuteration with retention of chirality. The
broad generality of the method examined with deuterated
water should also, in principal, be applicable to tritium and 2
may become a very useful catalyst in the area of molecule
radiolabelling.
1
2
3
: 10
: 15
: 20
8
9
>95
>95
1
D : 60
Experimental section
Material and instrumentation
a
Reaction conditions: 2 (5 mol%), 3 (0.25 mmol) and D
2
O (0.5 mL).
Arene deuteration determined by H-NMR. Solvent is a mixture of
toluene and D O (1 : 1).
b
1
c
2
Complex 2 was synthesized according to the reported pro-
3
3
cedure. 2-Phenyl-pyridine, 2-(4-methylphenyl)pyridine, 4,4-
dimethyl-2-phenyl-2-oxazoline, 2-(1-methylimidazole)-pyridine,
handful of catalytic systems have been found active in C–H/ 1-phenylpyrazole, methylbenzoate, methyl 4-chloro-benzoate,
C–D exchanges using carboxylic acids as directing groups, 1,2-bis(2-pyridyl)ethylene, 7,8-benzoquinoline, ketoprofen,
although high loadings of expensive metal catalysts (Pd, Rh acetophenone, propiophenone, 2-phenylacetophenone, di-
and Ir) are required in order to efficiently obtain the desired phenylketone, benzoic acid, 2-thiophenecarboxylic acid, 1-
2
5,35,36
labelled products.
indanone, dibenzyl disulfide, 4-bromomethylbenzoate, 3-
Finally, in order to exemplify the use of this catalytic bromomethylbenzoate, 2-bromomethylbenzoate, 3,5-dihydroxy-
system, the pharmaceutical blockbuster molecule Ketoprofen methylbenzoate, 2-vinylpyridine, 8-methylquinoline, ketopro-
(an anti-inflammatory drug) was subjected to the deuteration fen and (S)-ketoprofen were purchased from Sigma Aldrich
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and used as received. D
2
O and toluene were purchased from (500 MHz, CDCl
3
): δ 7.61–7.59 (m, 1H), 7.44–7.36 (m, 3H), 7.06
Sigma and were degased prior to use. 2-(4-Fluorophenyl)pyri- (s, 1H), 6.93 (s, 1H), 3.70 (s, 3H). HRMS (EI+): m/z calcd for
dine and 2-(4-carboxyphenyl)pyridine were synthetized as : 161.1042; found 161.1037.
4,4-Dimethyl-4,5-dihydro-2-(2,6-dideuterophenyl) oxazole (4h).
H, H and C Nuclear Magnetic Reso- Compound 4h was obtained using 5% of 2. Conversion: >95%.
10 9 2 2
C H D N
3
8
reported. 2-[4,5-Dihydro-1,3-oxazol-2-yl]pyridine was synthe-
3
9 1
2
13
tized as reported.
nance (NMR) spectra were recorded on a Bruker Avance 400 or
1
3
H NMR (500 MHz, CDCl ): δ 7.50–7.40 (m, 3H), 4.12 (s, 2H),
Bruker Avance III 500 Ultrashield NMR spectrometers. Chemi- 1.40 (s, 6H). HRMS (EI+): m/z calcd for C11
cal shifts are reported in δ ppm. Mass spectrometry was 178.1195; found 178.1192.
12 2 1 1
H D N O :
performed by the EPSRC National Mass Spectrometry Service
Centre at Swansea University, Grove building, Singleton Park,
Swansea, SA2 8PP, Wales, UK.
1-(2,6-Dideuterophenyl)-1H-pyrazole (4i). Conversion: >95%.
1
H NMR (500 MHz, CDCl3): δ 7.92 (d, J = 2.4 Hz, 1H), 7.73 (d,
J = 1.9 Hz, 1H), 7.45 (d, J = 7.4 Hz, 2H), 7.28 (d, J = 14.9 Hz,
H), 6.46 (t, J = 2.1 Hz, 1H). NMR data are consistent with
1
General procedure and characterisation
29
previously reported data.
Inside the glovebox, 2 (0.005 or 0.0125 mmol) and the sub-
Methyl 2,6-dideuterobenzoate (4j). Compound 4j was
strate (3) (0.25 mmol) were placed in a vial fitted with a screw obtained using 5% of 2 in a mixture of D
cap. Outside the glovebox, degassed D O (0.5 mL) or a mixture Conversion: 70%. Partial deuterium incorporation in OCH
of degassed D O and toluene (1 : 1; 0.5 mL) was added. Then, 22%. H NMR (500 MHz, CDCl ): δ 8.07–8.05 (m, 2H),
2
O–toluene (1 : 1).
2
3
:
1
2
3
the mixture was stirred at 110 °C for 16 h. The reaction was 7.59–7.56 (m, 1H) 7.47–7.45 (m, 2H). NMR data are consistent
3
5
allowed to cool to room temperature; when CH
and a liquid–liquid extraction was performed and the organic
phase was passed dried over MgSO . The solvent was removed was obtained using 5% of 2 in a mixture of D
and the crude was analysed by NMR spectroscopy.
-(2,6-Dideuterophenyl)pyridine (4a). Conversion: >95%. 3.93 (s, 3H). HRMS (EI+): m/z calcd for C H D C O : 175.0303;
2
Cl
2
was added with previously reported data.
Methyl 4-chloro-2,6-dideuterobenzoate (4k). Compound 4k
O–toluene (1 : 1).
): δ 7.42 (s, 2H),
4
2
1
Conversion: 85%. H NMR (500 MHz, CDCl
3
2
8
6 2 l1 2
1
H NMR (500 MHz, CDCl
3
): 8.70 (d, J = 7.4 Hz, 1H), 7.74 (d, J = found 175.0302.
4.4 Hz, 2H), 7.48 (d, J = 7.4 Hz, 2H), 7.42 (d, J = 14.6 Hz, 1H), 2,2′,6,6′-Tetradeuteriobenzophenone (4l). Compound 4l was
.22 (d, J = 13.3 Hz, 1H). NMR data are consistent with pre- obtained using 5% of 2. Conversion: 60%. H NMR (400 MHz,
2
7
1
2
9
viously reported data.
3
CDCl ): δ 7.82–7.80 (d, J = 7.83, 2H), 7.61–7.59 (m, 2H)
2
-(4-Carboxy-2,6-dideuterophenyl)pyridine (4b). Conversion: 7.50–7.48 (m, 4H). NMR data are consistent with previously
1
36
9
0%. H NMR (500 MHz, CDCl ): δ 8.73 (d, J = 5.7 Hz, 1H), reported data.
3
8
.15 (s, 2H), 7.79 (s, 2H), 7.32–7.26 (m, 1H), 3.95 (s, 3H).
α,α,α-Trideuteromethyl phenyl ketone (4m). Compound 4m
1
HRMS (EI+): m/z calcd for C13
H
10
D
2
N
1
O
2
: 216.0988, found was obtained using 5% of 2. Conversion: 0%. H NMR (400 MHz,
2
16.0985.
CDCl ): δ 7.97–7.95 (m, 2H), 7.58–7.54 (m, 1H), 7.48-7.44 (m,
3
4
1
2
-(2,6-Dideutero-4-fluoro-phenyl)pyridine (4c). Conversion: 2H). NMR data are consistent with previously reported data.
1
>
7
95%. H NMR (500 MHz, CDCl
.72 (td, J = 7.7, 1.7 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.21 (dd, obtained using 5% of 2. Conversion: 15%. 1H NMR (400 MHz,
): δ 7.97–7.95 (m, 2H), 7.57–7.53 (m, 1H), 7.47–7.44
(m, 2H), 1.23–1.21 (m, 3H). 15% deuterium incorporation
-(4-Methyl-2,6-dideuterophenyl)pyridine (4d). Conversion: at δ 7.87–7.95. NMR data are consistent with previously
3
): δ 8.66 (d, J = 4.7 Hz, 1H),
α,α-Dideuteroethyl phenyl ketone (4n). Compound 4n was
J = 7.2, 4.9 Hz, 1H), 7.14 (d, J = 8.6 Hz, 2H). HRMS (EI+): m/z CDCl
calcd for C11 : 176.0839, found 176.0834.
3
7 2 1 1
H D F N
2
1
42
9
7
1
2.5%. H NMR (500 MHz, CDCl
.73–7.69 (m, 2H), 7.29 (s, 2H), 7.20–7.18 (ddd, J = 6.6, 4.8,
.7 Hz 1H), 2.41 (s, 3H). HRMS (EI+): m/z calcd for was obtained using 5% of 2. Conversion: >95%. H NMR
: 172.1090; found 172.1085. (400 MHz, CDCl ): δ 7.61–7.58 (m, 1H), 7.50–7.48 (m, 2H),
,2-Dideutero-1,2-bis(2-pyridyl)ethylene (4e). Compound 4e 7.38–7.35 (m, 2H), 7.32–7.28 (m, 3H). NMR data are consistent
3
): δ 8.68–8.67 (m, 1H), reported data.
2,2-Dideuterio-1,2-diphenyl-ethanone (4o). Compound 4o
1
C
12
H
10
D
2
N
1
3
1
4
1
was obtained using 5% of 2 in a mixture of D O–toluene (1 : 1). with previously reported data.
Conversion: 93.5%. H NMR (500 MHz, CDCl
5
2
1
3
): δ 8.62 (d, J =
2,2-Dideuterio-1-indanone
(4p). Compound
4p
H
was
NMR
1
.4 Hz, 2H), 7.68–7.64 (m, 2H), 7.41 (d, J = 7.8 Hz, 2H), 7.17 obtained using 5% of 2. Conversion: >95%.
(
ddd, J = 7.5, 4.8, 0.9 Hz, 2H). NMR data are consistent with (400 MHz, CDCl ): δ 7.77 (d, J = 7.6 Hz, 1H) partial deuteration
3
4
0
previously reported data.
25%, 7.60 (t, J = 7.4 Hz, 1H) partial deuteration 20%, 7.49 (d,
7
,8-(4-Deutero)-benzoquinoline (4f). Conversion: >95%. J = 7.7 Hz, 1H) partial deuteration 15%, 7.38 (t, J = 5.7 Hz, 1H)
1
H NMR (500 MHz, CDCl3): δ 9.01 (dd, J = 4.4, 1.7 Hz, 1H), partial deuteration 10%, 3.14 (s, 2H). NMR data are consistent
4
3
8
(
7
.15 (dt, J = 8.1, 1.4 Hz, 1H), 7.91 (dd, J = 7.9, 1.4 Hz, 1H), 7.80 with previously reported data.
2,6-Dideuteriobenzoic acid (4q). Compound 4q was
d, J = 8.8 Hz, 1H), 7.76 (d, J = 6.8 Hz, 1H), 7.72–7.64 (m, 2H),
1
.52–7.49 (m, 1H). NMR data are consistent with previously obtained using 5% of 2. Conversion: >95%.
reported data.
H NMR
2
9
(400 MHz, CDCl
3
): δ 7.61–7.59 (m, 1H), 7.48–7.47 (d, J =
(
5)-Methyl-2-(2,6-dideuterophenyl)-imidazole (4g). Compound 7.5 Hz, 2H). NMR data are consistent with previously reported
1
25
4
g was obtained using 5% of 2. Conversion: 50%. H NMR data.
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3
-Deuteriothiophene-2-carboxylic acid (4r). Compound 4r 11 S. E. Scheppele, Chem. Rev., 1972, 72, 511–532.
1
was obtained using 5% of 2. Conversion: >95%. H NMR 12 J. Basran, M. J. Sutcliffe and N. S. Scrutton, J. Biol. Chem.,
(400 MHz, CDCl
3
): δ 7.62 (d, J = 5.0 Hz, 1H) partial deuteration
2001, 276, 24581–24587.
6
0%, 7.13 (d, J = 3.3 Hz, 1H). NMR data are consistent with 13 W. W. Cleland, Arch. Biochem. Biophys., 2005, 433, 2–12.
4
4
previously reported data.
14 V. L. Schramm, Curr. Opin. Chem. Biol., 2007, 11, 529–536.
Bis(1-deuteriobenzyl) disulphide (4z). Compound 4z was 15 T. G. Gant, J. Med. Chem., 2014, 57, 3595–3611.
1
obtained using 5% of 2. Conversion: 25%. H NMR (400 MHz, 16 R. Sharma, T. J. Strelevitz, H. Gao, A. J. Clark,
CDCl ): δ 7.38–7.27 (m, 10H) 3.64–3.62 (m, 3H). NMR data are
K. Schildknegt, R. S. Obach, S. L. Ripp, D. K. Spracklin,
L. M. Tremaine and A. D. N. Vaz, Drug Metab. Dispos., 2012,
40, 625–634.
3
4
5
consistent with previously reported data.
-(4-Deutero-3-benzoyl-2,6-dideuterophenyl)propionic acid
2
(
d3-Ketoprofen)) (4aa). Compound 4aa was obtained using 2% 17 M. J. Barratt, E. D. Frail, J. A. Morgan, B. A. Pandya,
1
of 2. Conversion: >95%. H NMR (400 MHz, CDCl
J = 1.7 Hz, 1H), 7.63–7.57 (m, 2H), 7.47 (dd, J = 14.0, 7.6 Hz,
H), 3.80 (q, J = 7.2 Hz, 1H), 1.47 (d, J = 7.2 Hz, 3H). HRMS
EI+): m/z calcd for C16 : 258.1204, found 258.1189.
S)-2-(4-Deutero-3-benzoyl-2,6-dideuterophenyl)propionic acid
3
): δ 7.74 (d,
C. E. Masse and S. L. Harbeson, in Drug Repositioning, ed.
M. J. Barratt and D. E. Frail, John Wiley & Sons, 2012, pp.
291–343.
3
(
H
12
D
3
O
3
18 G. S. Coumbarides, J. Eames and N. Weerasooriya,
J. Labelled Compd. Radiopharm., 2003, 46, 515–530.
(
(
2
(S)-d3-Ketoprofen)) (4ab). Compound 4ab was obtained using 19 S. H. Lee, S. I. Gorelsky and G. I. Nikonov, Organometallics,
1
% of 2. Conversion: >95%. H NMR (500 MHz, CDCl
3
): δ 7.78
2013, 32, 6599–6604.
(d, J = 1.9 Hz, 1H), 7.62–7.55 (m, 2H), 7.46 (dd, J = 13.3, 7.6 Hz, 20 M. H. G. Prechtl, M. Hölscher, Y. Ben-David, N. Theyssen,
3
H), 3.83 (q, J = 7.2 Hz, 1H), 1.57 (d, J = 7.2 Hz, 3H). HRMS
R. Loschen, D. Milstein and W. Leitner, Angew. Chem., Int.
Ed., 2007, 119, 2319–2322.
(EI+): m/z calcd for C16 : 258.1204, found 258.1199.
12 3 3
H D O
2
2
1 S. R. Klei, J. T. Golden, T. D. Tilley and R. G. Bergman,
J. Am. Chem. Soc., 2002, 124, 2092–2093.
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Acknowledgements
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We thank the ERC (Advanced Investigator Award ‘FUNCAT’ 23 W. J. S. Lockley and D. Hesk, J. Labelled Compd. Radio-
to SPN), KSU and the EPSRC for funding. We are grateful to pharm., 2010, 53, 704–715.
Dr M. Clarke for use of his group HPLC, Dr T. Lebl for NMR 24 A. R. Cochrane, C. Idziak, W. J. Kerr, B. Mondal,
studies, Dr Catherine Botting and BRSC Mass Spectrometry
and Proteomics facility and the EPSRC NMSSC in Swansea for
L. C. Paterson, T. Tuttle, S. Andersson and G. N. Nilsson,
Org. Biomol. Chem., 2014, 12, 3598–3603.
mass spectrometric analyses. SPN is a Royal Society Wolfson 25 S. Ma, G. Villa, P. S. Thuy-Boun, A. Homs and J. Q. Yu,
Merit Award holder.
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