The traceless Staudinger ligation for indirect 18F- radiolabelling

Article abstract of DOI:10.1039/c0ob00564a

The Staudinger ligation of phosphine-substituted thioesters with ¹⁸F-fluoroethylazide has been successfully applied to access ¹⁸F-labelled molecules in radiochemical yields superior to 95%; the first fluorous variant of a Staudinger

Full text of DOI:10.1039/c0ob00564a

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PAPER
The traceless Staudinger ligation for indirect 18F-radiolabelling†‡
Laurence Carroll,a Sophie Boldon,a Romain Bejot,a Jane E. Moore,b Je´roˆme Declerckc and
Ve´ronique Gouverneur*a
Received 10th August 2010, Accepted 6th October 2010
DOI: 10.1039/c0ob00564a
The Staudinger ligation of phosphine-substituted thioesters with 18F-fluoroethylazide has been
successfully applied to access 18F-labelled molecules in radiochemical yields superior to 95%; the first
fluorous variant of a Staudinger radio-ligation has been validated.
of the phosphine oxide in the final product.6 The synthetic
Introduction
value of this remarkable transformation has been demonstrated
by Raines and coworkers with the ligation of complex peptide
fragments, possibly best illustrated with the total synthesis of
ribonuclease A.7
Two transformations involving the azide group currently dominate
bioorthogonal chemistry, the azide-alkyne 1,3-dipolar cycloaddi-
tion leading to triazoles, and the Staudinger ligation, a process
forming an amide bond by reacting an azide with a phosphine-
substituted ester.1 Both reactions have appealing features to study
biomolecules in their native settings and have found endless
applications for labelling and beyond.2 The ability to radiolabel
biomarkers with the nuclide 18F is essential to advance positron
emission tomography (PET), an imaging modality used to conduct
diagnostic clinical studies, understand biochemical processes and
support drug development programmes.3 The short half-life of
positron-emitting fluorine-18 (t1 = 109.7 min) demands rapid and
efficient methodology to access2 [18F]-labelled biomarkers in high
radiochemical yield and purity.4 Fluorine-labelling of complex
biomolecules such as peptides, antibodies or oligonucleotides
remains challenging and is not always compatible with existing
direct 18F-labelling strategies. Methods have therefore been devel-
oped that employ non carrier-added 18F-labelled prosthetic groups
for chemoselective coupling under mild reaction conditions.4 For
this multi-step indirect labelling approach, it is of the utmost
importance for the coupling process to be highly efficient and for
the new functionality installed upon labelling, not to perturb the
physicochemical properties or in vivo behavior of the 18F-labelled
biomarker. Copper-catalysed cycloaddition with either the alkyne
or the azide carrying the 18F-tag has been successfully applied for
labelling small molecules and peptides.5 The process generates a
1,2,3-triazole motif, a convenient bioisosteric replacement of the
amide bond but the toxicity of copper(I) is limiting for some in vivo
applications. The so-called traceless Staudinger ligation is a highly
attractive process leading to a native amide bond without inclusion
Herein, we report the first examples of Staudinger ligation with
2-[18F]fluoroethylazide 1 for the 18F-labelling of small molecules
through formation of an amide bond. For this study, we selected
the traceless Staudinger ligation of a phosphinothioester with
an 18F-labelled azide fragment. Mechanistically, the attack of the
phosphine onto the azide leads to an iminophosphorane, which
rearranges to afford an amidophosphonium salt. After hydrolysis,
the labelled amide is formed with concomitant release of the
phosphine oxide (Scheme 1). This transformation benefits from
the absence of metal catalyst but its value in the context of
radiolabelling relies on the validation of a protocol with favorable
reaction kinetics, and which allows for easy separation of the 18F-
labelled amide from the phosphine oxide by-product.
Scheme 1 18F-labelled azide 1 as a prosthetic group for indirect labelling.
aUniversity of Oxford, Chemistry Research Laboratory, Mansfield Road,
Oxford, OX1 3TA, UK. E-mail: veronique.gouverneur@chem.ox.ac.uk
bAstraZeneca UK, Alderley Park, Cheshire, UK, SK10 4TG
Results and discussion
cSiemens Molecular Imaging, 23–38 Hythe Bridge Street, Oxford, OX1 2EP,
UK
† This publication is part of the web themed issue on fluorine chemistry.
‡ Electronic supplementary information (ESI) available: HPLC data of
radiolabelling experiments. See DOI: 10.1039/c0ob00564a
The borane-protected phosphinothiol
2 was chosen as a
common building block to access masked (diphenylphos-
phino)methanethiol thioesters, which after deprotection, could
136 | Org. Biomol. Chem., 2011, 9, 136–140
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undergo traceless Staudinger ligation with the azide 1. De-
protonation of the commercially available (diphenylphospho-
nio)trihydroborate complex with sodium hydride in DMF at 0 ◦C
followed by alkylation with (bromomethyl)ethanethioate 3 (easily
prepared in two steps from thioacetic acid), gave the doubly
protected trihydroborate complex 4 in a moderate yield of 60%.8
Treatment of 4 with sodium methoxide in methanol for ten minutes
at room temperature revealed the borane-protected thiol moiety
2. This thiol was engaged in the next step without purification
(Scheme 2, Stage 1). Coupling of 2 with different carboxylic
acids was undertaken using standard DCC conditions. Subsequent
removal of the borane protecting group by treating the coupled
adduct with 1,4-diazabicyclo [2.2.2]octane (DABCO) in toluene at
60 ◦C for 1 h afforded adducts 5 in moderate yields over two steps
(Scheme 2, Stage 2).9
Starting from 5-phenylpentanoic acid, 5a could be accessed in
40% overall yield. Compound 5b was synthesised in 60% yield
over two steps and starting from N-acetylphenylalanine or N-
acetyltryptophan, 5c and 5d were accessed in 55% and 63% overall
yield respectively. The Staudinger ligation of 5a–d with 1 in THF–
H2O (3 : 1) under standard ligation conditions (RT, 16 h) gave
the desired fluorinated targets 6 in moderate to excellent yields
(Scheme 2, Stage 3, Method A). Reacting 5a and 5b with 1
accessed 6a and 6b in isolated yields of 79% and 82% respectively.
Staudinger ligation of the (L)-phenylalanine-derived precursor 5c
with 1 gave the fluorinated amide 6c in 82% yield. The ligation
of 5d was slightly less efficient as the product was contaminated
with the starting material both as free phosphine and phosphine
oxide. Since the long reaction times employed in these initial
studies are not compatible with fluorine-18 radiolabelling, further
optimisation was undertaken (Scheme 2, Stage 3, Method B).
Heating the ligation mixture at 80 ◦C enabled the reaction time to
be reduced to 30 min with conversion up to 100%.
In addition to thioesters 5a–d, we also prepared the fluorous
derivative 7 (Scheme 3).10 The fluorodetagging of fluorous precur-
sors has recently been validated using direct 18F-fluorination,11–13
however detagging upon displacement with a 18F-labelled pros-
thetic group has not been reported. The Staudinger ligation
is an ideal platform for proof of concept as the fluorous tag
can be attached onto the phosphino fragment of the starting
thioester.14 The fluorous-tagged thioester 7 bearing two C4F9 tags
on the phosphine was therefore synthesised following a reaction
sequence similar to the one applied for the preparation of non
fluorous thioesters. This compound was found to oxidise to the
corresponding phosphine oxide faster than the non fluorous
counterpart. The extent of oxidation was minimised during
purification by performing the silica gel chromatography under
an atmosphere of N2. Staudinger ligation with 1 using standard
conditions led to the formation of 6c in 27% yield with purification
of the reaction mixture using FSPE. The decrease in isolated yield
could be attributed to the propensity of the phosphane precursor
7 towards oxidation.
Scheme 3 Fluorous Staudinger ligation with 1.
With key studies of the Staudinger ligation with the fluorinated
azide 1 in hand, focus turned to the validation of a radiochemical
variant of this approach using 2-[18F]fluoroethylazide 1. This
18F-labelled azide was prepared by nucleophilic fluorination
of the fluorous-tagged precursor 2-azido-ethyl-1H,1H,2H,2H-
perfluorodecane-1-sulfonate. The fluorination was performed in
acetonitrile using [18F]-/K+-Kryptofix 222 and fluorous solid
Scheme 2 Staudinger ligation with fluorinated azide 1.
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Table 1 Staudinger ligation with [18F]1
(entry 5, Table 1). The overall synthesis duration was within 30
min. Pleasingly, all radio-HPLC traces typically showed only the
presence of the ligated product in crude reaction mixture (Fig. 1).
Starting
Reaction
conditions
Entry material
RCY (%)
Product
1
2
5a
5b
C
C
>95 (n = 2)
>95 (n = 3)
Fig. 1 Radio-HPLC trace of crude material [18F]6a.
3
4
5c
7
C
D
>95 (n = 6)
>95 (n = 3)
Conclusions
In conclusion, we have demonstrated that the Staudinger ligation
is a suitable strategy for prosthetic group labelling using [18F]2-
fluoroethylazide. This catalyst-free ligation process benefits from
short reaction times and very high radiochemical yields, a clear ad-
vantage for multi-step indirect 18F-labelling. Fluorous technology
has been implemented for the fast and highly efficient purification
of the prosthetic group [18F]2-fluoroethylazide and for the traceless
Staudinger ligation itself. In the context of 18F-radiochemistry,
this is the first example of fluorous detagging by indirect 18F-
labelling.16 In recognition of the importance of the Staudinger
ligation in the conjugation of biomolecules, we anticipate that
this novel prosthetic group 18F-radiochemistry may find numerous
applications in the context of peptide 18F-labelling as the new
functionality installed upon ligation is the native amide bond.
D
C
>95 (n = 3)
5
5d
>95 (n = 6)
a Method C: THF–H2O (4 : 1), 120 ◦C, 15 min; Method D: DMF–H2O
(6 : 1), 120 ◦C, 15 min.
Experimental
phase extraction (FSPE) implemented to separate the radiola-
belled product [18F]1 from the excess fluorous precursor (specific
activity of ~10 GB q mmol-1).11 This protocol is superior to
previous radiosyntheses that rely on purification by distillation.
The FSPE-purified azide [18F]1 was recovered in a mixture of H2O
and CH3CN. The ligations were performed adding [18F]1 to a
solution of the thioester dissolved in THF–H2O (4 : 1) followed
by heating at 80 ◦C for 30 min. The reaction time could be
reduced to 15 min by increasing the temperature to 120 ◦C
(Method C). Under these conditions, the ligation of 5a–b with
[18F]1 proceeded in excellent radiochemical yields superior to 95%
(entries 1–2, Table 1). The reactions were equally successful when
performed in a mixture of DMF–H2O (6 : 1) (Method D).15 In
contrast to couplings carried out in THF, the efficiency of the
ligation process in DMF was not found to be dependent on
concentration. Pleasingly, the labelling of both the non fluorous
and fluorous alanine derivative 5c and 7 with [18F]1 in DMF–
General methods
1H NMRs were reported on Bruker DPX 200, DPX 400, AV 400
and AV 500 spectrometers, at a frequency of 200, 400 and 500 MHz
respectively. 13C NMRs were recorded on Bruker AV 400 and AV
500 spectrometers at a frequency of 100 or 125 MHz respectively.
Mass spectra (m/z) were obtained on a Bruker MicroTOF in
Electrospray (ESI). Analytical thin layer chromatography (TLC)
was performed on Merck Silica 60 F254 plates. Crude reaction
mixtures were analysed by TLC and HPLC. HPLC analysis was
performed with a Gilson 322 or Dionex Ultimate 3000 system,
equipped with a NaI/PMT radiodetector (Raytest) and a UV-
detector (Gilson). Radio-TLC was performed on Macherey-Nagel
Polygram Silica Plates and eluted with EtOAc or 95% aq. MeCN.
Analysis was performed with a plastic scintillator/PMT detector.
FSPE separation was carried out using pre-assembled Waters Sep-
Pak cartridges (Waters, Milford, MA) and FluoroFlash Silica gel
(Fluorous Technologies Inc., Pittsburgh, PA). Pre-assembled Sep-
Pak C18SPE cartridges (Waters, Milford, MA) were used in the
same way.
◦
H2O (6 : 1) at 120 C for 15 min afforded [18F]6c in an excellent
RCY in excess of 95% (entries 3–4, Table 1). For the ligation of 7,
purification using FSPE led to an improvement in chemical purity
although breakthrough of fluorous material into the fluorophobic
eluted fraction was seen. HPLC was therefore necessary to obtain
analytically pure sample of the 18F-labelled amide. The ligation
of the tryptophan derivative 5d was also very high yielding with
the totality of the azide converted into the 18F-labelled amide
[18F]Fluoride was produced by the cyclotron of PETNET
Solutions at Mont Vernon Hospital (UK) via the 18O(p,n)18F
reaction and delivered as [18F]fluoride in [18O]water (1–2 GBq,
1–3 mL). This target solution was passed through a QMA anion
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exchange resin cartridge (20 mg, Waters). [18F]Fluoride adsorbed
on the charged-resin was eluted into a reaction vial with a solution
of Kryptofix 222 (15 mg) and K2CO3 (3 mg) in 1 mL acetonitrile–
water (8 : 2). Excess water was removed under N2 stream at 100–
110 ◦C, and the resulting complex was dried an additional 3
times by azeotropic distillation with 0.5 mL acetonitrile each
under N2 stream. The resulting dry complex of K18F/Kryptofix
222 was further dissolved by anhydrous acetonitrile (2–4 mL)
and dispensed into reaction vials containing the precursor for
nucleophilic fluorination.
(2H, ddd, J = 28.6, 13.6, 3.8 Hz, SCH2P), 5.05 (1H, dt, J = 8.6,
5.6 Hz, CHCH2), 6.90 (1H, d, J = 2.3 Hz, NH), 7.14 (1H, td, J =
7.1, 1.0 Hz, Ar), 7.22 (1H, td, J = 8.1, 1.0 Hz, Ar), 7.35–7.46 (11H,
m, Ar), 7.54 (1H, d, J = 7.5 Hz, Ar); dC (100 MHz, CDCl3) 23.2,
25.8 (d, J = 23.8 Hz), 28.0, 59.4, 109.4, 111.3, 118.4, 119.9, 122.3,
123.2, 127.8, 128.6 (d, J = 6.7 Hz), 129.2 (d, J = 5.7 Hz), 132.1
(d, J = 19.1), 132.7 (d, J = 19.1), 136.0, 136.7 (d, J = 14.3), 169.8,
199.5; dP (162 MHz, CDCl3) -15.6; m/z (ESI) C26H26N2O2PS
([M + H]+) calc. 461.1447, found 461.1450.
Selected experimental data are given below—full experimental
procedures and spectroscopic data for all compounds in the paper
are given in the supporting information.
General procedure for compounds 6a–d
Phosphinothioate 5 (0.05 mmol) was dissolved in a mixture of
THF and water (3 : 1, 1 mL) and 2-fluoroethylazide (150 mL of
a 0.33 M solution in THF, 0.05 mmol) was added. The reaction
mixture was stirred at room temperature for 16 h then concentrated
in vacuo. The residue was purified by flash chromatography (95 : 5
DCM–MeOH) to afford the desired products 6.
General procedure for compounds 5a–d
(Diphenylphosphino)methanethiol (2) (416 mg, 1.8 mmol) was
dissolved in DCM (20 mL), to which DCC (408 mg, 1.98 mmol),
DMAP(1 crystal) andthencarboxylic acid (1.8mmol)were added.
The reaction was stirred for 16 h at room temperature, during
which time, a white precipitate formed. The reaction mixture was
N-(2-Fluoroethyl)-5-phenylpentanamide (6a). White solid.
Yield: 79%; dH (400 MHz, CDCl3) 1.61–1.75 (4H, m, (CH2)2),
2.23 (2H, t, J = 6.6 Hz, CH2CH2CO), 2.64 (2H, t, J = 7.2 Hz,
PhCH2CH2), 3.57 (2H, dq, J = 28.1, 5.1 Hz, NHCH2CH2), 4.50
(2H, dt, J = 47.3, 4.8 Hz, CH2CH2F), 5.77 (1H, s, NH), 7.15–7.21
(3H, m, Ph), 7.26–7.31 (2H, m, Ph); dC (100 MHz, CDCl3) 25.2,
31.0, 35.5, 36.5, 39.7 (d, J = 22.5 Hz), 54.1, 82.9 (d, J = 166.2 Hz),
125.8, 128.3, 128.4, 173.0; dF (377 MHz, CDCl3) -224.3; m/z (ESI)
C13H19FNO ([M + H]+) calc. 224.1445, found 224.1440.
R
passed through Celiteꢀ and concentrated to dryness. The residue
was purified by flash chromatography (40% EtOAc in hexane)
to afford the desired product which was subsequently dissolved
in toluene (5 mL) and DABCO (92 mg, 0.82 mmol) was added.
The reaction mixture was stirred at 60 ◦C for 1 h, at which point
it was cooled to room temperature and concentrated to dryness.
The residue was purified by flash chromatography (50% EtOAc in
hexane) to afford the desired products 5.
N-(2-Fluoroethyl)-4-formylbenzamide (6b). White solid. Yield:
82%; dH (400 MHz, CDCl3) 3.79 (2H, d, J = 28.0 Hz,
NHCH2CH2), 4.60 (2H, d, J = 47.1 Hz, CH2CH2F), 6.92 (1H, br
s, NH), 7.94 (4H, app. s, Ph), 10.06 (1H, s, CHO); dC (100 MHz,
CDCl3) 40.6 (d, J = 19.0 Hz), 82.5 (d, J = 168.2 Hz), 127.8, 129.8,
138.3, 139.2, 166.7, 191.6; dF (377 MHz, CDCl3) -223.9; m/z (ESI)
C10H11FNO2 ([M + H]+) calc. 196.0768, found 196.0776.
S-((Diphenylphosphino)methyl) 5-phenylpentanethioate (5a).
Yellow oil. Yield: 40%; dH (400 MHz, CDCl3) 1.55–1.79 (4H, m,
(CH2)2), 2.54 (2H, t, J = 6.6 Hz, CH2CH2CO), 2.59 (2H, t, J =
7.6 Hz, PhCH2CH2), 3.53 (2H, dd, J = 3.8, 1.0 Hz, SCH2P), 7.12–
7.22 (3H, m, Ph), 7.25–7.29 (3H, m, Ph), 7.33–7.38 (5H, m, Ph),
7.40–7.48 (4H, m, Ph); dC (100 MHz, CDCl3) 25.2, 25.3, 25.5, 30.6,
35.5, 43.6, 125.8, 128.3, 128.4, 128.5, 128.6, 128.7, 129.1, 131.1 (d,
J = 9.5 Hz), 132.7, 132.8, 136.7 (d, J = 13.4 Hz), 141.9, 198.1; dP
(162 MHz, CDCl3) -14.8; m/z (ESI) C24H26OPS ([M + H]+) calc.
393.1436, found 393.1440.
(R)-2-Acetamido-N-(2-fluoroethyl)-3-phenylpropanamide (6c).
White solid. Yield: 92%; dH (400 MHz, CDCl3) 2.01 (3H, s, OAc),
2.99 (1H, dd, J = 13.4, 8.1 Hz, CHCHH), 3.13 (1H, dd, J = 13.6,
6.1 Hz, CHCHH), 3.40–3.55 (2H, m, NHCH2CH2), 4.21–4.48
(2H, m, CH2CH2F), 4.62 (1H, dt, J = 16.2, 7.8 Hz, CHCH2),
5.90–5.98 (1H, m, NH), 6.15 (1H, d, J = 7.3 Hz, NH), 7.22 (2H,
d, J = 8.1 Hz, Ph), 7.28–7.35 (3H, m, Ph); dC (100 MHz, CDCl3)
23.2, 38.6, 39.8 (d, J = 20.0 Hz), 53.4, 54.7, 81.9 (d, J = 167.9 Hz),
127.2, 128.8, 129.2, 136.4, 170.0, 171.0; dF (377 MHz, CDCl3)
-224.0; m/z (ESI) C13H16FN2O2 ([M + H]+) calc. 251.1197, found
251.1201.
S-((Diphenylphosphino)methyl) 4-formylbenzothioate (5b).
Yellow oil. Yield: 60%; dH (400 MHz, CDCl3) 3.74 (2H, d, J =
3.8 Hz), 7.29–7.55 (10H, m), 7.80–8.10 (4H, m), 10.09 (1H, s,
CHO); dC (100 MHz, CDCl3) 127.9, 128.9, 129.0, 129.8, 130.2,
131.9, 132.4, 132.5, 191.3; dP (162 MHz, CDCl3) -50.0; m/z (ESI)
C22H17O2PS ([M + H]+) calc. 365.0760, found 365.0755.
(R)-S-((Diphenylphosphino)methyl)
2-acetamido-3-phenyl-
propanethioate (5c)6. Yellow oil. Yield: 55%; dH (200 MHz,
CDCl3) 1.94 (3H, s), 2.94 (1H, dd, J = 14.0, 7.5 Hz), 3.09 (1H, dd,
J = 14.0, 5.2 Hz), 3.42–3.61 (2H, m), 4.91–5.03 (1H, m), 5.72 (1H,
d, J = 8.2 Hz), 7.05–7.12 (2H, m), 7.22–7.29 (3H, m), 7.34–7.49
(10H, m); dC (100 MHz, CDCl3) 23.0, 25.6 (d, J = 24.5 Hz), 38.0,
59.6, 127.0, 128.47, 128.49, 128.8 (d, J = 36.0 Hz), 129.1 (d, J =
9.8 Hz), 132.6 (d, J = 19.4 Hz), 135.5, 169.9, 198.9; dP (162 MHz,
CDCl3) -44.7; m/z (ESI) 422 ([M + H]+).
2-Acetamido-N-(2-fluoroethyl)-3-(1H-indol-3-yl)propan-amide
(6d). White solid. Yield: 60%; dH (400 MHz, CDCl3) 2.08 (3H,
s, OAc), 3.07 (1H, dd, J = 12.9, 7.6 Hz, CHCHH), 3.37 (12 H,
t, J = 3.8 Hz, NHCH2CH2F), 3.41 (1H, dt, J = 5.6, 3.7 Hz,
NHCH2CH2F), 3.46 (1 H, t, J = 3.8 Hz, NHCH2CH2F), 3.57 (1H,
2
dd, J = 12.7, 7.9 Hz, CHCHH), 4.35 (2H, dt, J = 46.2, 3.9 Hz,
CH2CH2F), 4.58 (1H, s, NH), 4.93 (1H, t, J = 7.7 Hz, NHCHCO),
5.07 (1H, s, NH), 7.04 (1H, s, Ar), 7.18–7.24 (3H, m, Ar), 7.32–
7.36 (2H, m, Ar); dC (100 MHz, CDCl3) 22.8, 30.5, 40.5 (d, J =
27.0 Hz), 54.7, 82.6 (d, J = 168.4 Hz), 108.5, 111.6, 119.5, 120.1,
121.7, 123.4, 128.0, 137.3, 172.6, 174.0.; dF (377 MHz, CDCl3)
S-((Diphenylphosphino)methyl)
2-acetamido-3-(1H-indol-2-
yl)propanethioate (5d). Yellow oil. Yield: 55%; dH (400 MHz,
CDCl3) 1.91 (3H, s, OAc), 3.26 (2H, t, J = 6.1 Hz, CHCH2), 3.50
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-222.0; m/z (ESI) C15H19FN3O2 ([M + H]+) calc. 292.1456, found
292.1460.
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(R)-2-Acetamido-N-(2-fluoroethyl)-3-phenylpropanamide (6c)
prepared from the reaction of 7 with 1. Phosphinothioate 7
(120 mg, 0.13 mmol) was dissolved in a mixture of THF and water
(4 : 1, 1 mL) and 2-fluoroethylazide (390 mL of a 0.33 M solution
in THF, 0.13 mmol) was added. The reaction mixture was stirred
at room temperature for 16 h then concentrated in vacuo. The
residue was purified by FSPE to afford the desired product 6c in
27% yield.
4 R. Schirrmacher, C. Wa¨ngler and E. Schirrmacher, Mini-Rev. Org.
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Radiochemical procedures
2-[18F]fluoroethylazide [18F]1 was prepared as previously reported
and purified by FSPE.11
6 B. L. Nilsson, L. K. Kiessling and R. T. Raines, Org. Lett., 2000, 2,
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3, 9.
7 B. L. Nilsson, R. J. Hondal, M. B. Soellner and R. T. Raines, J. Am.
Chem. Soc., 2003, 125, 5269.
8 M. B. Soellner, B. L. Nilsson and R. T. Raines, J. Org. Chem., 2002,
67, 4993; Y. He, R. J. Hinklin, J. Chang and L. K. Kiessling, Org. Lett.,
2004, 6, 4479.
9 Deprotection was performed immediately prior to ligation with 1 as
adducts 6 were found to be susceptible to oxidation.
10 For selected reviews on fluorous synthesis see: W. Zhang, Tetrahedron,
2003, 59, 4475; W. Zhang, Chem. Rev., 2004, 104, 2531; W. Zhang,
Chem. Rev., 2009, 109, 749.
General procedure for 18F-labelled Staudinger ligation reactions
In a sealed reaction vial, the FSPE purified solution of 2-
[18F]fluoroethylazide (20–100 MBq) in MeCN–H2O (7 : 3, 0.5 mL)
was mixed with a thiophosphane 5 (1 mg) in either 300 mL
THF–H2O (4 : 1) or 300 mL DMF–H2O (6 : 1) and heated for
15 min at 120 ◦C. Analysis by reverse-phase HPLC gave retention
times that correlated to the cold reference compounds, with >95%
conversion from [18F]2-fluoroethylazide to the product [18F]6 in
each case.
11 R. Bejot, T. Fowler, L. Carroll, S. Boldon, J. E. Moore, J. Declerck and
V. Gouverneur, Angew. Chem., Int. Ed., 2009, 48, 586.
12 E. Blom, F. Karimi and B. La˚ngstro¨m, J. Label. Compd. Radiopharm.,
2010, 53, 24.
13 For an example of fluorous electrophilic fluorodetagging: S.
Boldon, J. E. Moore and V. Gouverneur, Chem. Commun., 2008,
3622.
14 For a fluorous Staudinger reaction: C. W. Lindsley, Z. Zhao, R. C.
Newton, W. H. Leister and K. A. Strauss, Tetrahedron Lett., 2002, 43,
4467; D. P. Curran, X. Wang and Q. Zheng, J. Org. Chem., 2005, 70,
3716.
Acknowledgements
We are grateful for financial support from the DIUS and Siemens
Molecular Imaging (Project No TP/16636) (LC, RB) and from
AstraZeneca (SB).
References
15 C. Mamat, A. Flemming, M. Ko¨ckerling, J. Steinbach and F. R. Wuest,
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16 During the preparation of this manuscript, the Staudinger Ligation has
been reported for the radiosynthesis of [18F]GABAA receptor binding
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Battle, W. Trigg, S. Luthra and M. Glaser, Bioorg. Med. Chem. Lett.,
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