Homogeneous deuteriodeiodination of iodinated tyrosine in angiotensin-I using synthesized triethyl[2H]silane and Pd(0)

Article abstract of DOI:10.1002/jlcr.1843

In our efforts to develop new reactions for the efficient labelling of peptides and proteins with tritium, we now report the use of silane hydrides together with homogenous Pd(0) catalysis for the protio- and deuteriodeiodination of an o-iodo-tyrosine con

Full text of DOI:10.1002/jlcr.1843

Research Article
Received 15 April 2010,
Revised 11 August 2010,
Accepted 19 September 2010
Published online 29 December 2010 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.1843
Homogeneous deuteriodeiodination of
iodinated tyrosine in angiotensin-I using
synthesized triethyl[2H]silane and Pd(0)z
Ã
Martin Holst Friborg Pedersen, and Lars Martiny
In our efforts to develop new reactions for the efficient labelling of peptides and proteins with tritium, we now report
the use of silane hydrides together with homogenous Pd(0) catalysis for the protio- and deuteriodeiodination of an
o-iodo-tyrosine containing peptide (angiotensin-I) performed at room temperature.
Keywords: deuterium; peptide; hydrodehalogenation; homogenious catalysis; palladium
iodinated precursor peptide using palladium catalysis and
tritiated silanes.
Introduction
Tritium-labelled compounds are an essential tool for ADME
studies of new drug candidates and of new chemical entities in
particular. Current methodologies for the efficient tritium
labelling of peptides include tritioacylation,1 spillover isotope
exchange,2,3 olefin reduction4–7 and hydrodehalogenations, e.g.
using Pd/C and gaseous tritium.8–13 The latter has been one of
the preferred labelling methods for peptides while tritioacyla-
tion with N-succinimidyl-[2,3-3H]propionate presently is the
reagent of choice for conjugation and labelling of free amino-
groups in proteins.1,14–16 In contrast, the labelling reaction may
fail or give low yield when larger peptides or proteins are
subjected to tritium gas using heterogeneous supported
palladium as the catalyst.17 Plausible theories are either that
the substrate undergoes unproductive adsorption to the metal
or support or that the halogenated amino acid is not available at
the surface of the metal-hydride and thus not accessible for the
reaction with tritium at the metal surface. We therefore set out
to investigate the potential of using homogeneous palladium as
a labelling technique for hydrogen–halogen exchange of
iodinated peptides. A homogeneous transition-state metal-
mediated reaction could possibly reduce both adsorption and
steric hindrance at the halogenated reaction site and would
potentially lead to increased reaction rates and/or yields.
Only a few groups have applied cross-coupling techniques for
the functionalization of peptides and proteins with homogeneous
palladium.18,19 Cross-coupling reactions are frequently performed
with boron and stannane derivatives, but also silanes has been
employed for the silylation of aromatic halides.20,21 Although the
objective of the latter work was functionalization of the aryl
halide to give the organosilane, they described how the use of
the bulky tri-tert-butylphosphine as ligand in the palladium cross-
coupling reaction almost exclusively resulted in the reductive
replacement of the aromatic iodide with hydrogen.22
To optimize the reductive hydrodehalogenation reaction, the
development work was performed using deuterium gas (D2),
resulting in deuterated silanes and subsequently deuterated
peptide. The use of deuterium allows for optimization without
the use of large amounts of tritium gas and the deuterium
incorporation may be established by mass spectrometry. In
order to ensure that the developed chemistry will transfer
smoothly to the intended tritium labelling methodology,
deuterium-labelling reactions were performed under typical
tritium radiolabelling conditions.
Experimental section
General
All reactions were performed on a custom build deuterium/
tritium manifold system manufactured by RC Tritec AG,
Switzerland. Deuterium gas was used in the manifold and all
chemical manipulations were performed in glassware and in
amounts analogous to working with tritium. Reagents and
solvents were used as received from Sigma-Aldrich without
further purification. Catalysts, phosphines and compounds
unstable to oxygen were handled under an argon atmosphere
in a custom-made glovebox. Solvents were deoxygenated by
ultrasonic irradiation followed by bubbling with argon gas.
nBuLi was titrated with diphenylacetic acid prior to use and
silane reagents checked by GC-FID.
zSupporting information may be requested from the authors.
Hevesy Laboratory, Radiation Research Division, Risø-DTU, Technical University
of Denmark, Frederiksborgvej 399, Dk-4000 Roskilde, Denmark
*Correspondence to: Lars Martiny, Hevesy Laboratory, Radiation Research
Division, Risø-DTU, Technical University of Denmark, Frederiksborgvej 399,
Dk-4000 Roskilde, Denmark.
The objective of this work was the development of new
homogeneous tritiation methods for the dehalogenation of an
E-mail: lmar@risoe.dtu.dk
J. Label Compd. Radiopharm 2011, 54 191–195
Copyright r 2010 John Wiley & Sons, Ltd.

M. H. F. Pedersen and L. Martiny
[Iodo-Tyr4]angiotensin-I and [H-Tyr4]angiotensin-I
solution (300 mL, 150 mmol of TESCl) was added to the prepared
lithium deuteride. The suspension was allowed to react for 1 h at
room temperature under stirring. Near completion of the reaction
was confirmed after 30min by GC-FID (GC: RtSi-(D/H) = 4.50min;
RtSi-Cl = 10.99 min). 1H NMR (500MHz, CDCl3), d ppm 0.59 (q, 8 Hz),
0.98 (t, 8 Hz).
The peptide substrate and reference compound were synthe-
sized on solid support with standard Fmoc chemistry using
HATU/DiPEA as the activation protocol. The synthesis of the two
peptides was performed by splitting the resin (20:1) after the
isoleucine coupling.
CG-FID specifications
Purification of [Iodo-Tyr4]angiotensin-I
Column; FactorFourTM (Fused Silica) capillary column (VF-
200 ms, 30 m ꢀ 0.32 mm ID, DF = 1.0, Varian). Oven temperature
program; (0–3 min, 401C); (41C/min until 1001C); (401C/min until
2601C); (3 min at 2601C). Injector temperature: 2201C.
In the labelling reaction, the suspension of triethyl[2H]silane
and LiCl in THF was used directly in the subsequent labelling
reaction without further analysis.
The crude product was dissolved in water (5 mL) and gently washed
with ethyl acetate (2 ꢀ 5 mL). The organic phase was discarded and
the aqueous solution containing the peptide was purified on a
preparative HPLC system with UV detection set at 280 nm. Column:
C18-Knauer. (250 mm ꢀ 20 mm, 5 mm Eurosphere-100) Flow: 10 mL/
min. Eluents: (A) 5% acetonitrile, 0.1% trifluoroacetic acid (TFA) and
purified H2O. (B) 99.9% acetonitrile and 0.1% TFA. Gradient:
(0 min–4 min, 0% B); (ꢁ17 min, 35% B); (17–25 min, 100% B);
(25–28 min, 100% B);(ꢁ29 min, 0% B); (29–33 min, 0% B). The
product ([Iodo-Tyr4]Angiotensin-I) was collected after 17.4 min and
lyophilized to yield a white flocculent powder: 319 mg.
The purified peptide was analysed on an analytical rp-HPLC
system equipped with UV detection at 280 nm. Column: Phenom-
enexs Luna PFP(2) (250 mm ꢀ 4.6 mm, 5 mm). Flow: 1 mL/min.
Eluents: (A) 5% acetonitrile, 0.1% TFA and purified water. (B) 99.9%
acetonitrile, 0.1% TFA. Gradient: (0–2 min, 0% B); (ꢁ40 min, 100%
B); (40–42 min, 100% B); (ꢁ44 min, 0% B);(44–50 min, 0% B). The
product ([iodo-Tyr4]angiotensin-I) was eluted at 17.4 min. Purity
was determined by HPLC-UV to be: 97%. (C62H88IN17O14,
Mw = 1421.6) m/z = 1422.7 (M1H1), 1444.5 (M1Na1).
Deuteriodeiodination of [iodo-Tyr4]angiotensin-I
A solution of the palladium catalyst was prepared prior to use
under argon; Palladium acetate was added tri-tert-butylpho-
sphine (5 eq., 1 M in toluene) and allowed to react at room
temperature for 30 min (a change from deep orange to bright
yellow-coloured solution was observed).
In a vial, [iodo-Tyr4]angiotensin-I (2.9 mg, 1.56 mmoles) was
dissolved in thoroughly deoxygenated DMF (600 mL). To this
substrate vial, the palladium catalyst (20 mmole, 100 mL) was
added. It was allowed to react for 10 min before all was
transferred to the reaction vessel containing the synthesized
triethyl[2H]silane, leaving a pale yellow homogenous reaction
mixture. After 3 h of reaction time. 1 eq. of tetrabutylammonium
fluoride (TBAF; 160 mmole, fluoride) was added to the reaction
and after 30 min the workup of product was performed.
A Sep-Paks Plus C18 Cartridge (360 mg) equipped with a
0.45-mm Whatman CF-C filter was preconditionized with ethanol
(5 mL) for 1 min then washed with distilled water (5 mL). Semi-
purification of product was performed by mixing the reaction
with five times the volume of purified water (5 mL) and filtering
this mixture through the filter and Sep-Pak. The filter and
Sep-Pak was washed with ultra-purified water (5 mL) for the
removal of salts and other polar compounds. The filter was
disposed and the peptide eluted from the Sep-Pak using a
mixture of 80% MeCN, 20% Water and 0.1% TFA (5 mL). Products
and conversion of substrate was analysed using mass spectro-
metry (MS) (ESI-IT) and HPLC. The final purification was
performed by preparative HPLC and the product was subse-
quently lyophilized to give an isolated yield: 1.19 mg, app.
0.68 mmoles, 44%. The product was identified by comparison
with retention time of the reference peptide on RP-HPLC and
the purity was determined to be 97%. MS of [D-Tyr4]angioten-
sin-I (C62H88DN17O14, Mw = 1296.7) m/z = 1297.7 (M1H1), 1319.6
(M1Na1), 1341.6 (M12 ꢀ Na1), 1362.6 (M13 ꢀ Na1).
Purification of [H-Tyr4]angiotensin-I
This peptide was prepared by the same procedure as described
above. The desired product (Angiotensin-I) was collected on
prep-HPLC after 17.4 min and lyophilized to yield a white
flocculent power: 16 mg. Purity determined by UV detection:
97%. (C62H89N17O14, Mw = 1295.7) m/z = 1296.8 (M1H1),
m/z = 1318.6 (M1Na1), 1340.6 (M12ꢀ Na1), 1362.6 (M13ꢀ Na1).
Lithium deuteride
A 3-mL round-bottomed flask with a side arm stir-bar was
mounted onto the manifold system, evacuated to below
5 ꢀ 10ꢁ3 mbar and flame dried. The flask was flushed with
deuterium gas and evacuated repeatedly to ensure an
anhydrous and oxygen-free reaction vessel. Finally, the flask
was loaded with deuterium gas to a pressure of 800 mbar.
TMEDA (50 mL) and nBuLi (100 mL, 1.6 M in hexane) were added
with a syringe through the septum and within 5–10 min a white
precipitate of LiD was formed. The reaction was stirred and
allowed to react for 2 h. Subsequently the flask was cooled with
liquid nitrogen and the deuterated butane (byproduct), solvent
(hexane) and TMEDA was removed under reduced pressure. The
LiD formed was thoroughly dried under vacuum (to yield a
white and flaky LiD, theoretical amount of 160 mmole, 1.44 mg).
Finally the reaction vessel was flushed with argon at 800 mbar to
ensure an inert atmosphere before the following reaction.
Results
The new labelling method was optimized using the iodinated
version of the natural peptide angiotension-I as a model
substrate, as shown in Figure 1. Both the iodinated [iodo-
Tyr4]angiotensin-I and the reference [H-Tyr4]angiotensin-I pep-
tides were synthesized on solid phase using standard Fmoc,
HATU/DiPEA chemistry (solid-phase peptide synthesis) in a
Triethyl[2H]silane (Et3SiD)
Under an atmosphere of argon, a solution of chlorotriethylsilane manual synthesizer.23 This ten-mer peptide contains a tyrosine
(0.5 M, 2 mL) in dry THF was prepared just prior to use. This residue at the fourth amino acid position and furthermore
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Copyright r 2010 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2011, 54 191–195

M. H. F. Pedersen and L. Martiny
Figure 1. The labelling substrate [iodo-Tyr4]angiotensin-I and the reference compound [H-Tyr4]angiotensin-I, both synthesized by solid-phase peptide synthesis.
Scheme 1. Sequential synthesis of triethyl[2H]silane by the treatment of deuterium with nBuLi and TMEDA followed by the addition of chlorotriethylsilane.
Figure 2. Stacked GC-FID chromatograms from the silane synthesis.
carries a variety of functional groups which could be imagined working with tritium). The GC-FID chromatograms from the
to interfere with the use of homogenous transition metal synthesis of triethyl[2H]silane, starting material and commercial
complexes and was thus considered a suitable model substrate. available triethylsilane are stacked and illustrated on Figure 2.
We have investigated the preparation of deuteriated triethyl- The solvent used in the GC analysis was diisopropyl ether (iPr2O)
silane (Et3SiD) and triethoxysilane ((EtO)3SiD) from lithium containing an unidentified residual solvent peak used as the
deuteride. However, the ethoxysilane proved insufficiently internal standard.
stable in our hands, and deuteriated triethylsilane was selected
as the reagent for further investigations.
The 1H-NMR analysis of the Et3SiD product furthermore
demonstrated the expected loss of a J2 coupling between the
The lithium hydrides of hydrogen isotopes are ready available a-methylene and Si-H bond.
via synthesis on the micromolar scale using n-butyllithium
After having optimized the reaction conditions for the
(160 mmoles) and TMEDA (N,N,N0,N0-tetramethylethylene- efficient formation of the silane reagent, attention was focused
on the palladium-mediated hydrodehalogenation reaction.
A selection of chemically different phosphine ligands were
diamine) following literature procedures.24
After the formation of the hydride, the volatiles (butane,
solvents and TMEDA) were removed under vacuum and the dry investigated with Pd(OAc)2 for the formation of a reactive Pd(0)
lithium deuteride was used directly in the subsequent reactions. catalyst. The labelling reactions were performed at room
The reaction conditions for formation of triethyl[2H]silane temperature and the conversion of starting material (2–4 mg,
from LiD and chlorotriethylsilane (Scheme 1) were investigated 1–3 mmol) and the formation of deuterated peptide was measured
using GC with FID detection, and we found almost complete using Mass Spectroscopy (MS). By tuning the steric properties and
conversion within 30 min. The reactions were performed at the Lewis base character of the phosphine ligand, the conversion
room temperature in anhydrous THF and the deuteriosilane and yield was optimized. In Table 1, a summary of the results from
formed was used without further purification in the subsequent the initial labelling reactions is listed for comparison.
labelling reactions. Isolation and purification of the triethyl[2H]-
It was found that the bulky and electron-donating tri-tert-
silane was attempted but with no success, as the silane is highly butyl phosphine ligand yielded the best conversion of the
volatile, and was synthesized in such small amounts (160 mmol is iodinated peptide to deuterated product. It should be
suitable compromise between yield and radiation safety when emphasized that this ligand is very sensitive to oxidation, and
J. Label Compd. Radiopharm 2011, 54 191–195
Copyright r 2010 John Wiley & Sons, Ltd.
www.jlcr.org

M. H. F. Pedersen and L. Martiny
that the reactions were performed carefully under inert atmo-
The addition of TBAF to the reaction mixture seemed both to
sphere (argon). The amount of silane used and palladium eliminate the formed TES-conjugate and to accelerate the
catalyst were varied in a series of reactions and eventually the deuteration reaction, but the mechanism for this acceleration
conclusion was that use of not less than 135 mmol of silane and was not investigated further. With these optimizations, we were
20 mmol of catalyst resulted in optimal conversion. able to perform the efficient deuteration of iodinated angioten-
The undesired byproduct from triethylsilyl (TES) conjugation sion starting from deuterium gas in just one day.
with the labelled peptide was formed in some of the most
efficient reactions. Further experiments demonstrated its Discussion
effective cleavage with treatment of TFA or one equivalent of
This study concerns the use of silanes in the selective
TBAF. The formation of TES-conjugated angiotensin can be
dehalogenation of an iodinated model peptide using homo-
explained by a reaction between the hydroxyl group on the
genous palladium catalysis. The reaction uses mild reducing
deuterated or iodinated peptide and unreacted halosilane
conditions and has been shown to tolerate several peptide
(chlorosilane or iodosilane formed in the reductive elimination
functional groups, such as, for example, amides, carboxylic acids,
step).
imidazoles and amidines. We have demonstrated that it was
possible to label an iodinated model peptide (angiotensin-I)
with deuterium using this chemistry. Although the exact
Table 1. Optimization of the phosphine ligand
mechanism for this deuteriodeiodination reaction is not clear,
we propose the reaction to go through the generally accepted
palladacycle illustrated in Scheme 2. The tri-tert-butylphosphine
ligand is well known to generate low-ligated and very reactive
palladium species,25–28 which after oxidative addition across
the aryl-iodine bond could undergo transmetallation with the
synthesized deuteriosilane. The mechanism below is in line with
a recent publication showing that the addition of base to the
system results in formation of C–Si silylated products.29
Finally, it should also be noted that the labelling reaction
using triethyl[2H]silane in combination with palladium acetate
and without phosphine ligand gave a complete conversion of
the iodinated substrate to the labelled peptide. However, this
reaction turned heterogeneous instantly and was not pursued
further in our development of a homogeneous labelling
method.
Et3SiD
(mmol)
Phosphine
Conv.(%)a
Productsa
No phosphine
DPPP
PCy3
DPPF
PPh3
PPh3
P(o-furyl)3
P(tBu)3
135
256
135
160
1100
320
270
160
100
N/A
0
10
15
14
69
100
100% Db
Tracesc
0% D
30% H/ 70% Dd
100% D
100% D
28% D138% D/TES
36% D164% D/TES
aConversion of [iodo-Tyr4]angiotensin-I and analysis of
products formed in these screening reactions were deter-
mined by using MS. D represents [D-Tyr4]angiotensin-I and
D/TES corresponds to [D-Tyr4]angiotensin-I with a conju-
gated triethylsilyl group.
bReaction with Pd(OAc)2 gave instant formation of palladium
black and an inhomogenous reaction. Full conversion was
observed by using MS with Pd adducts.
cSeveral unidentified products was observed in MS.
dEstimated ratio of H and D from MS.
Conclusions
With these studies, we have been able to utilize a homogeneous
palladium catalyst and one-pot synthesized triethyl[2H]silane for
the specific labelling of a small model peptide. The idea of using
homogeneous labelling under these reductive conditions could
Scheme 2. Proposed mechanism for the palladium-mediated deuteriodeiodination of an iodinated aromatic compound.
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J. Label Compd. Radiopharm 2011, 54 191–195

M. H. F. Pedersen and L. Martiny
potentially result in new tritium-labelling techniques for
peptides or substrates with sensitive functional groups. We
have illustrated the synthesis of triethyl[2H]silane from gaseous
deuterium and subsequently their use in a following labelling
reaction. With the use of the bulky tri-tert-butylphoshine ligand,
total conversion of the model peptide was observed after 3 h of
reaction at room temperature with an isolated yield of 44% of
the deuterated product after HPLC purification.
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Acknowledgements
We wish to thank the Isotope Department at Novo Nordisk A/S,
for their collaboration and interest in developing peptide and
protein labelling methods. Also, great thanks to the staff at the
Hevesy Laboratory, especially Dr Palle Rasmussen for support
with peptide synthesis and technicians Henrik Prip and Lasse
Hauerberg for their great expertise for setting up the necessary
laboratory instruments. Great acknowledgement also goes to
the Risø National Laboratory a part of the Technical University of
Denmark and the Hevesy Laboratory who supported this project
financially. Finally, we want to thank the JLCR reviewers for their
detailed comments and corrections.
Supporting Information Available: More detailed experimental
procedures, material and methods, mass-spectra, HPLC chromato-
grams, NMR data and GC-FID can be requested from the author.
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