Designing Silylated l-Amino Acids using a Wittig Strategy: Synthesis of Peptide Derivatives and 18F-Labelling

Article abstract of DOI:10.1002/ejoc.201701170

An efficient semisynthesis of silylated l-amino acids by reaction of silylated benzaldehydes with a phosphonium l-amino acid used as a Wittig reagent is described. The efficiency of the silylated l-amino acids in peptide synthesis was investigated by coup

Full text of DOI:10.1002/ejoc.201701170

DOI: 10.1002/ejoc.201701170
Full Paper
Si-Amino Acids
Designing Silylated -Amino Acids using a Wittig Strategy:
L
18
Synthesis of Peptide Derivatives and F-Labelling
Baptiste Rugeri, Hassib Audi, Pawel Jewula, Radouane Koudih,
Raluca Malacea-Kabbara,* Delphine Vimont, Jürgen Schulz, Philippe Fernandez, and
[a]
[a]
[a]
[a]
[a]
[b]
[b]
[a]
[
a]
Sylvain Jugé*
Abstract: An efficient semisynthesis of silylated
by reaction of silylated benzaldehydes with a phosphonium
amino acid used as a Wittig reagent is described. The efficiency ture of K[ F]/cryptand (K2.2.2) and acetic acid. The F-labelled
of the silylated -amino acids in peptide synthesis was investi- dipeptides were obtained with radiochemical yields and molar
gated by coupling both the carboxylic acid and the amino moi- activities of up to 31 % and 410 GBq/μmol, respectively. Conse-
ety with -alanine and phenylalanine derivatives, respectively. quently, this semisynthesis involving a Wittig reaction offers a
L
-amino acids Finally, the 18F-labelling of di-tert-butylsilylated saturated and
unsaturated dipeptides was achieved in hot DMSO with a mix-
L-
1
8
18
L
L
1
8
The silylated derivatives were treated with KF or tetrabutyl- new and efficient route for the design and F-labelling of
ammonium fluoride to give the corresponding fluorosilyl deriv- Si-based amino acids and peptide derivatives, which may find
atives without racemization. The hydrolysis of the fluorosilyl- applications in PET imaging.
ated derivatives in phosphate buffer at pH 7.2 was checked.
1
8
+
Introduction
Fluorine-18 ( F) is a ꢀ radionuclide with a half-life of
1
10 min. Its size is comparable to that of a proton, which gives
it a good hydrophilic–lipophilic balance, and results in
only modest alterations of the amino acid or peptide frame-
The use of radioisotopic, optical, fluorescent, electrochemical,
or nanomaterials tags to label biologically active molecules is
an approach that is now used extensively to explore metabolic
pathways, to establish diagnosis and monitor the progression
[
4–6]
18
works.
effective methods to label amino acids and peptides with the
The formation of Si– F bonds is one of the most
[
1,2]
of diseases, to treat pathologies, or to guide surgery.
The
1
8
[7]
F radionuclide, and is one of the few strategies not to use
development of new methods to track biomolecules like pept-
ides, proteins, or antibodies is a constant challenge. These mol-
ecules occupy prominent positions in all living processes, so
visualizing and characterizing them in their native environment
is essential to understanding these biological processes and
1
8
carbon– F bond formation. This method is based on the use
of prosthetic groups bearing hydrosilane, fluorosilane (through
isotopic exchange), silanol, or siloxane groups with peptides, as
[
8–11]
illustrated by compounds 1–4 (Figure 1).
[
3]
finding new diagnostic methods.
Usually the labelling of peptides and proteins is achieved
using either fluorescent probes or metal radioisotopes, such as
6
4
68
177
99m
186
Cu, Ga,
Lu,
Tc, or
Re complexed to polydentate
[
4]
18
chelators. Due to the increasing use of 2-[ F]fluoro-2-deoxy-
D
-glucose (FDG) for cancer diagnosis by positron-emission
tomography (PET) during recent decades, the 18F radionuclide
has become more accessible for the labelling of amino acids
and peptides.
[
2,4,5]
[
a] Institut de Chimie Moléculaire de l'Université de
Bourgogne-Franche-Comté, ICMUB-OCS (UMR CNRS 6302),
1
9 avenue A. Savary BP 47870, 21078 Dijon CEDEX, France
Figure 1. Representative Si-based prosthetic groups for the 18F-labelling of
peptides.
E-mail: raluca.malacea@u-bourgogne.fr
sylvain.juge@u-bourgogne.fr
http://www.icmub.fr/185-membres
[
b] Department Institut des Neurosciences Cognitives et Intégratives
d'Aquitaine (INCIA-UMR CNRS 5287),
Prosthetic groups are widely used in labelling,[2,4,5] but link-
ing them to biomolecules such as peptides, which is usually
done as the last step of the synthesis, may alter the biological
properties of the biomolecules and limit the possibilities of cus-
1
46 rue Léo Saignat, 33076 Bordeaux CEDEX, France
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201701170.
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Scheme 1. Synthesis of silylated amino acids, applied to the 18F-labelling of peptides. Cbz = benzyloxycarbonyl.
tomizing them. This is the reason why it is very interesting to dure,[13] or by direct fluorination of the hydrosilyl moiety,[14,15]
develop methods for the modular synthesis of amino acid pre- respectively (Scheme 1).
markers that can be used in peptide coupling reactions, and
then radiolabelled in a final step. In addition, such premarkers phorus and boron derivatives that may be used in F-label-
In connection with our ongoing investigations into phos-
[
6]
18
[
16,17]
offer the possibility of changing the position of the modified ling,
amino acid in the sequence in order to mimic the native pept- of silylated Si-amino acids, and studied their efficiency in
we have investigated a new stereoselective synthesis
[
4,6]
ide or to permit a possible tracking of metabolites.
radiofluorination. We developed a semisynthetic approach to
The synthesis of silicon-containing amino acids has been in- Si-amino acids 15 bearing a free carboxylic acid group, using a
tensively developed with the aim of maintaining or reinforcing Wittig reaction as a key step to form a C=C bond on the side-
the biological activity of peptides, while enhancing their resist- chain (Scheme 2). We investigated the use of the Si-amino acids
[
12]
ance towards enzymatic degradation. However, very few ex- in peptide synthesis by coupling both the acid and amino
amples concerning their use in 18F-labelling have been re- groups; we also investigated their fluorination and their stabil-
18
18
ported. This is explained by the fact that the [ F]fluorosilane ity, and finally the F-labelling of the Si-peptides (Scheme 3,
moiety is prone to in vivo hydrolysis, unless bulky groups such Tables 1 and 2).
as isopropyl or tert-butyl substitute the silicon centre (Fig-
[
9a,10c]
ure 1).
In this context, Wängler, Jurkschat et al. have de-
Results and Discussion
scribed the synthesis of (S)-4-[(di-tert-butyl)fluorosilyl]phenyl-
alanine derivative 7 by asymmetric Rh-catalysed hydrogenation
of dehydro amino acid substrate 6. The Si-amino acid was then
Stereoselective Synthesis of Silylated Amino Acid
Derivatives Using a Wittig Reaction
3
incorporated into a Tyr -octreotate derivative for a radiolabel-
[
13]
ling study (Scheme 1a).
In addition, (±)-(di-tert-butyl)- Silylated amino acids 15a–15c were synthesized by Wittig reac-
hydrosilylated amino acid 10, obtained by Huisgen cycloaddi- tion of the corresponding aldehydes 13a–13c with phosphon-
tion of azidoethylsilane 8 with racemic propargyl glycine 9, was ium salt 14 in hot chlorobenzene (or dioxane) with K PO as
3
17]
4
[
reported by Ametamey et al. for the labelling of peptides base, according to a published procedure (Scheme 2).
Silyl-
[
14]
18
(
Scheme 1b).
The F-labelling of silicon-based amino acids ated aldehydes 13a–13c were prepared in yields up to 91 % by
7
and 10 was then achieved either by isotopic exchange ac- halogen/metal exchange on commercially available 4-bromo-
cording to the SiFA (silicon-based fluoride acceptor) proce- benzaldehyde diethyl acetal 12, and trapping with the appro-
Scheme 2. Synthesis of silylated amino acid derivatives 15a–15c by Wittig reaction. Boc = tert-butoxycarbonyl.
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priate chloro- or dichlorosilane, followed by hydrolysis as coupling agent. The corresponding dipeptide 18a (or 18b)
(
Scheme 2). Wittig reagent 14 was prepared in 30 % overall was formed in up to 93 % yield. Under similar conditions, silanol
yield starting from -aspartic acid, according to a previously es- amino acid (Z/E)-15c led to peptide 18c as a (Z)/(E) mixture in
L
[
17]
tablished procedure.
38 % yield (Scheme 3). The coupling reaction proceeded with-
Silylated amino acids 15a–15c were initially obtained with a out racemization, as shown by comparing the NMR spectrum
free carboxylic acid group and as a (Z)/(E) mixture in 3:7 ratio, of dipeptide 18a with that of an epimeric sample previously
as shown by the signals due to the silane moiety in the NMR prepared starting from racemic Wittig reagent (±)-14 (see Sup-
spectrum of compound 15a (Figure 2a). Further heating in THF porting Information). The Boc (tert-butoxycarbonyl) group was
with diphenyl disulfide triggered isomerization to give pure (E)- removed by treatment with HCl (1
1
1
M
in EtOAc), and then silyl
5a in 88 % yield (Figure 2b). Treatment of silylated amino acid dipeptide 18a was coupled with phenylalanine derivative 17
5b under the same conditions also led to the pure (E) isomer, using the same HATU-mediated procedure, to give the corre-
but in the case of silanol derivative (Z/E)-15c, no isomerization sponding tripeptide 19 in 72 % yield (Scheme 3). Finally, di-
was observed under these conditions (Scheme 2).
peptide 18a was quantitatively hydrogenated in MeOH in the
presence of Pd/C as catalyst to give the corresponding satu-
[
18]
rated methoxysilane 20a;
pound 18c led to a mixture of silanol 20b and methoxysilane
0c in a 2:3 ratio (Scheme 3). It is interesting to note that silanol
amino acids and peptides have only rarely been described in
under the same conditions, com-
Application of Silylated Amino Acids 15a–15c in Peptide
Synthesis
2
The efficiency of silylated amino acids 15a–15c in peptide syn-
thesis through reaction at both the carboxylic acid group and
[
12,19]
the literature to date.
the amino group was investigated by coupling with
L-alanine
1
6 and -phenylalanine derivative 17, respectively (Scheme 3).
L
Fluorination of Hydrosilylated Amino Acids 15a and 15b
and Dipeptides 18a and 18b
Silylated compound (E)-15a [or (E)-15b] bearing a free carb-
oxylic acid group was treated with methyl alaninate 16 at room
temperature, using 1-[bis(dimethylamino)methylene]-1H-1,2,3- Bearing in mind the half-life of 18F (110 min),[10d] both fluorin-
triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) ation kinetics and stability are crucial for the development of
Figure 2. 1H and 29Si NMR spectra of compound 15a. [a] (Z/E) mixture. [b] (E) isomer after isomerization.
Scheme 3. Synthesis of silylated peptides 18–20. DIPEA = diisopropylethylamine.
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radiolabelled agents for use in PET medical imaging.[20] In a first yield (Table 1, Entry 2). Finally, under conditions similar to those
attempt, the fluorination of silylated amino acid derivative 15a used for 15a, fluorination of dipeptides 18a and 18b led to the
[
10c]
was investigated under literature conditions,
by treatment corresponding fluorosilylated dipeptides 21c and 21d in 96 and
with KF in refluxing THF in the presence of the cryptand 1,10- 92 % yields, respectively (Table 2, Entries 3 and 4). These results
diaza-4,7,13,16,21,24-hexaoxabicyclo[8.8.8]hexacosane (Krypto- demonstrate that hydrosilylated amino acids and peptides can
fix® K2.2.2) and a small amount of acetic acid. Kryptofix® K2.2.2 be quickly fluorinated under mild conditions, and thus this of-
1
8
is a sequestering agent for the potassium counterion, used to fers an efficient alternative method for direct F-labelling.
–
enhance the nucleophilicity of F . Under these conditions, the
fluorosilylated product 21a was obtained in 97 % yield as a
stable compound after chromatography on silica gel (Table 1,
Stability of Fluorosilylated Dipeptides 21c and 21d in
Phosphate Buffer
29
19
Entry 1). It showed signals in the Si and F NMR spectra at
1
δ = +13.9 (d, J = 298 Hz) and –188 ppm, respectively.
Si,F
The stability of fluorosilylated dipeptides 21c and 21d (chosen
as examples) was investigated in a mixture of aqueous phos-
Table 1. Preparation of fluorosilylated amino acid and dipeptide derivatives
phate buffer (pH 7.2) and [D ]acetonitrile (8:2) at room tempera-
21.
3
ture. The reaction was monitored by observing the Si–F signal
1
9
in the F NMR spectra (Figures 3 and 4). Under these condi-
tions, in the hydrolysis of 21c only traces of free fluoride ion
were observed after 10 d (Figure 3).
Entry
1
R
2
Si substrate
R1
Conditions
R
2
SiF product
Yield [%]
[a]
R
15a
tBu
H
KF/K2.2.2
AcOH/THF
reflux, 48 h
TBAF/THF
r.t./20 min
KF/K2.2.2
21a
97
2
3
15b
18a
iPr
H
21b
21c
79
96
tBu
L-Ala-OMe
AcOH/THF
reflux, 24 h
KF/K2.2.2
4
18b
iPr
L-Ala-OMe
21d
92
AcOH/THF
reflux, 24 h
Figure 3. Hydrolysis of fluorosilylated dipeptide 21c at pH 7.2, monitored by
F NMR spectroscopy.
1
9
[
a] Isolated yields.
On the other hand, fluorination of diisopropylsilyl amino acid
analogue 15b was achieved by treatment with tetrabutyl- released 40 % of the F within 5 min, while at the same time a
ammonium fluoride (TBAF) in THF at room temperature for slightly high-field-shifted signal appeared at δ = –191.8 ppm
In contrast, diisopropylfluorosilane dipeptide analogue 21d
–
20 min; this gave fluorosilylated derivative 21b in 79 % isolated (vs. δ = –191.4 ppm); after this initial rapid drop, the intensity
Figure 4. Hydrolysis of fluorosilylated dipeptide 21d at pH 7.2, monitored by 19F NMR spectroscopy.
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of the signal due to 21d decreased steadily with time (Figure 4).
The results show that carrying out the radiolabelling at 80 °C
This transient signal can be explained by the formation of a gave the best compromise between molar activity and RCY
solvated hypervalent intermediate such as 22, in equilibrium (Table 2, Entries 1, 2, and 4). We also found that the radiolabel-
with the fluorosilylated precursor 21d, which leads to silanol ling was not facilitated by more acidic conditions, possibly be-
–
[9b]
product 18c and free fluoride F (Figure 4).
It should also be cause the dipeptide was partially degraded, either through re-
noted that the formation of a solvated hypervalent intermedi- action of the alkene or through deprotection of the Boc group
ate analogous to 22 has previously been predicted by DFT cal- (Table 2, Entry 3).
culations as an intermediate in the hydrolysis of a fluorosil-
18
Unlike 21c, [ F]-21c evolved to give a new radiolabelled
ane.[
10c]
species with a slightly different retention time in HPLC analysis.
Assuming that its decomposition follows first-order kinetics, the
rate constant k and the half-life were found to be 3.0 × 10–5
s
–1
18F-Labelling of Dipeptide Derivatives 18a and 20a
and 385 min, respectively (see Supporting Information). This
18
unexpected reaction was slowed down by diluting the [ F]-21c
in saline solution (NaCl; 0.9 %), and it was nearly stopped by
using aqueous ascorbic acid (0.1 %). We established that this
process was the result of an addition reaction onto the C=C
double bond with radical intermediates due to the ionizing
The 18F-labelling of organosilylated compounds is currently
1
8
[21]
achieved using K[ F] in the presence of Kryptofix® K2.2.2.
The fluorination of hydrosilylated “prosthetic compounds” such
as 3 (X = H) and 4 has been carried out by heating between
3
0 and 100 °C in the presence of a small quantity of acid such
[23]
conditions (see Supporting Information).
[
10,11]
18
as AcOH.
Under these conditions, F incorporation (73 %)
Since stability over time is mandatory for potential PET-imag-
ing applications, the radiolabelling was considered in a second
instance with saturated methoxysilylated dipeptide 20a, ob-
tained by hydrogenation of 18a (Scheme 3). When the radiola-
belling of saturated dipeptide 20a was carried out by heating
was achieved, and molar activities of up to 62 GBq/μmol were
[
10d]
observed.
In this study, direct radiofluorination was investi-
gated with di-tert-butylsilylated dipeptides 18a and 20a bear-
ing hydrosilane and methoxysilane moieties, respectively
[
22]
(
Table 2).
The labelling was carried out by heating the di-
1
8
18
at 100 °C for 15 min with K[ F] with a starting activity of
peptide for 15 min with a mixture of K[ F], Kryptofix® K2.2.2,
1
8
and AcOH in DMSO. The initial activity of the 18F solution at
111 GBq, labelled product [ F]-21e was obtained in 15 % RCY
with a molar activity of 82 GBq/μmol (Table 2, Entry 5). By heat-
cyclotron output was in the range 103–127 Gbq, and the num-
ber of trials for each of the sets of radiolabelling conditions
was in the range 1–5. The total reaction time for the labelling,
including HPLC purification, was about 60 min. The results are
1
8
ing at 80 °C, radiolabelled dipeptide [ F]-21e was obtained in
2 % RCY with a molar activity of 88 ± 11 GBq/μmol (Table 2,
1
1
8
18
Entry 6; n = 5). Dipeptides [ F]-21c and [ F]-21e were analysed
by HPLC, and the chromatograms were compared to those of
the corresponding nonradioactive reference compounds 21c
and 21e, the latter prepared by hydrogenation of 21c. This
proved that no degradation was seen for saturated dipeptide
18
reported in Table 2. Compound [ F]-21c was obtained in 26 %
radiochemical yield (RCY; radiochemical purity >97 %) with a
molar activity (MA) of 410 GBq/μmol when the radiolabelling
of the unsaturated dipeptide 18a was carried out by heating at
1
8
00 °C with a starting 1 F activity of 120 GBq (Table 2, Entry 1).
Different RCYs and molar activities of [ F]-21c were obtained
by changing the quantities of acetic acid and the heating condi-
tions (Table 2, Entries 2 and 3).
8
[ F]-21e for at least 5 h 40 min (see Supporting Information).
Although the RCYs are moderate, it should be pointed out that
high molar activities could be a critical parameter to avoid satu-
1
18
[
24]
ration in receptor binding studies.
Table 2. 18F-Labelling of dipeptide derivatives 18a and 20a.
Entry
Dipeptide
Conditions
T [°C] (no. trials)
18F-Labelled dipeptide
RCY[a,b,c]
[%]
MA[c]
[GBq/μmol]
Y
1
1
8
8
1
2
3
4
5
6
18a
18a
18a
18a
20a
20a
H
H
H
H
MeO
MeO
100 (n = 1)
80 (n = 3)
80 (n = 1)
60 (n = 1)
100 (n = 1)
80 (n = 5)
[
[
[
[
[
[
F]-21c
F]-21c
F]-21c
F]-21c
26
31 ± 8
19
28
15
410
169 ± 86
117
158
82
[
d]
18
1
8
1
8
F]-21e
F]-21e
1
8
12 ± 1
88 ± 11
[
a] Initial activity 103–127 GBq. [b] Radiochemical purity >97 %. [c] Total reaction time: 60 min. [d] 50 μL of AcOH instead of 3 μL.
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Conclusions
was used under the conditions indicated. IR spectra were recorded
with Bruker FTIR Vector 22 or Vertex 70v instruments, and the data
This article describes an efficient and versatile stereoselective
–1
are reported in cm . The buffer solution pH 7.2 (0.2
M) was pre-
synthesis of silylated enantiopure -amino acids and peptides pared by mixing Na HPO ·7H O (5.3 g) and NaH PO ·H O (40 mg)
L
2 4 2 2 4 2
that are useful for fluorination and labelling with the 1 F radio- in H O (100 mL). Melting points were measured with a Kofler melt-
8
2
nuclide. The synthesis is based on the Wittig reaction between ing point apparatus. Optical rotation values were measured with a
Perkin–Elmer 241 polarimeter at 589 nm (sodium lamp). All radio-
fluorination experiments were run with a commercial TRACERLab
FxF-N® (GE Healthcare) instrument.
easily accessible silylated benzaldehydes and a phosphonium
salt reagent derived from -aspartic acid, and leads to the corre-
sponding amino acids as (Z)/(E) mixtures (yields up to 88 %).
L
The products were isomerized to give (E)-silylated amino acid 4-[Hydro(di-tert-butyl)silyl]benzaldehyde (13a): tBuLi (1.84
M in
derivatives bearing a free carboxylic acid group, ready for pept- hexane; 11 mL, 20.2 mmol) was added dropwise to a solution of 4-
ide coupling. The silyl group tolerates the conditions of peptide bromobenzaldehyde diethyl acetal (12; 2 mL, 10 mmol) in dry THF
(
20 mL) in a Schlenk tube at –78 °C under argon. After 30 min, di-
coupling, allowing the synthesis of several di- and tripeptides.
The fluorination of diisopropylsilylated and di-tert-butylsilylated
amino acids and dipeptides did not give any racemization, and
the more hindered compounds are stable to hydrolysis. Finally,
di-tert-butylsilylated unsaturated and saturated dipeptides were
fluorinated with the 18F nuclide in a short total preparation time
under mild conditions, to give the labelled products with excel-
tert-butylchlorosilane (1.8 mL, 11.4 mmol) was added. The mixture
was stirred at –78 °C for 2 h, and then it was allowed to warm to
room temperature overnight. After this time, HCl (1
until pH 3, and the mixture was stirred at room temperature for 1 h.
The mixture was then extracted with CH Cl (3 × 50 mL). The or-
M) was added
2
2
ganic phases were combined, dried with MgSO , filtered, and con-
centrated under reduced pressure. The residue was purified by col-
4
lent radiochemical purities, radiochemical yields up to 31 %, umn chromatography on silica gel (petroleum ether/EtOAc, 19:1).
and molar activities up to 410 GBq/μmol. The radiolabelled un- The solvent was removed under vacuum to give 13a (2.2 g,
saturated dipeptide turned out to be radiosensitive, but this 8.83 mmol, 88 %) as a colourless oil with an intense almond-like
odor, which crystallized as a white solid. M.p. 60–61 °C. R = 0.58
was not the case of the corresponding saturated analogue.
Given the potential impact of silylated amino acids as premark-
ers, this efficient synthesis should enable further development
in the field of radiolabelling of peptides.
f
(
2
petroleum ether/Et O, 9:1). FTIR (neat): ν˜ = 2959–2856 (CH, CHO),
2
–1 1
105 (SiH), 1701 (C=O), 1592 (C=C), 1466, 1207, 793, 686 cm . H
NMR (500 MHz, CDCl ): δ = 1.05 [s, 18 H, C(CH ) ], 3.92 (s, 1 H, SiH),
.76 (d, J = 8.0 Hz, 2 H, ArH), 7.83 (d, J = 8.0 Hz, 2 H, ArH),
0.03 (s, 1 H, CHO) ppm. C NMR (75 MHz, CDCl ): δ = 19.2
3
3 3
3
3
7
1
H,H H,H
13
3
[
1
C(CH ) ], 29.0 [C(CH ) ], 128.5 (C
44.6 (Carom), 192.7 (CHO) ppm. Si NMR (99 MHz, CDCl ): δ =
), 136.4 (Carom), 136.7 (Carom),
3
3
3 3
arom
Experimental Section
29
3
+
General Remarks: All reactions were carried out using standard
Schlenk techniques under an inert gas. Solvents were dried and
purified by conventional methods before use. Chlorobenzene, tolu-
ene, diethyl ether, n-hexane, ethyl acetate, petroleum ether (PE),
methanol, dimethyl sulfoxide (DMSO), and acetic acid were pur-
chased in anhydrous form. The reagents tert-butyllithium, 4-bromo-
benzaldehyde diethyl acetal, di-tert-butylchlorosilane, chlorodiiso-
propylsilane, dichlorodi-tert-butylsilane, cryptand K2.2.2 (Krypto-
fix®), diphenyl disulfide, ethyldiisopropylamine (DIPEA), O-(7-aza-1H-
benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium
phate (HATU), N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)-
uronium hexafluorophosphate (HBTU), -Boc-Phe-OH, -alanine
methyl ester hydrochloride, hydrogen chloride (1 in EtOAc), and
tetrabutylammonium fluoride (TBAF; 1 in THF) were purchased
+12.9 ppm. HRMS (ESI-Q-TOF): calcd. for C15
271.14833; found 271.14940.
H24OSiNa [M + Na]
4
-[Hydro(diisopropyl)silyl]benzaldehyde (13b): This compound
was prepared according to a new procedure based on a literature
[
25]
method.
dropwise to a solution of 4-bromobenzaldehyde diethyl acetal (12;
.5 mL, 2 mmol) in dry THF (5 mL) in a Schlenk tube at –78 °C under
nBuLi (2.23 M in hexane; 1.8 mL, 4 mmol) was added
0
argon. After 30 min, chloro(diisopropyl)silane (2 mL, 2.2 mmol) was
added. The mixture was stirred at –78 °C for 2 h, and then it was
allowed to warm to room temperature overnight. The mixture was
acidified to pH 3 with HCl (1
temperature for 1 h. The mixture was extracted with CH Cl (3 ×
hexafluorophos-
M aq.), and then it was stirred at room
L
L
2
2
M
3
0 mL). The organic phases were combined, dried with MgSO , fil-
4
M
tered, and concentrated under reduced pressure. The residue was
purified by chromatography on silica gel (petroleum ether/EtOAc,
9
with an intense almond-like odor. R = 0.40 (petroleum ether/Et O,
1
7
from commercial suppliers. The phosphonium salt 14 was prepared
according to a published procedure.[ Flash chromatography was
carried out with the indicated solvents using silica gel 60 (60AAC,
17]
:1) to give 13b (365 mg, 1.37 mmol, 69 %) as a colourless liquid
1
13
19
29
f
2
3
5–70 μm; SDS). H, C, F, and Si NMR spectra were recorded
9:1). FTIR (neat): ν = 2944–2864 (CH, CHO), 2107 (SiH), 1702 (C=O),
˜
with Bruker Avance 600, 500, or 300 MHz spectrometers at ambient
–
1
1
3
83 cm . H NMR (500 MHz, CDCl ): δ = 1.00 [d, J = 7.4 Hz, 6
1
3
H,H
temperature, using trimethylsilane as an internal reference for H,
3
H, CH(CH ) ], 1.08 [d, JH,H = 7.4 Hz, 6 H, CH(CH ) ], 1.24 [septd,
13
29
19
3 2
3
3 2
3
C, and Si NMR spectra, and CCl F for F NMR spectra. Data are
3
3
JH,H = 7.4, J = 3.3 Hz, 2 H, 2 CH(CH ) ], 4.00 (t, J = 3.3 Hz, 1
H,H
3
3 2
H,H
reported in ppm as follows: multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet, br. s = broad signal), coupling
constants in Hertz [Hz], integration. Mass spectrometry and accu-
rate mass measurements (HRMS) were carried out under ESI condi-
tions with a Bruker micro Q-TOF detector or a Thermo Orbitrap
detector. HPLC analysis was carried out either with a Shimadzu
chromatograph equipped with a UV detector at λ = 210 and
3
H, SiH), 7.70 (d, J = 8.0 Hz, 2 H, ArH), 7.84 (d, J = 8.0 Hz, 2 H,
ArH), 10.03 (s, 1 H, CHO) ppm. C NMR (125 MHz, CDCl ): δ =
1
H,H
H,H
1
3
3
0.8 [CH(CH ) ], 18.6 [CH(CH ) ], 18.7 [CH(CH ) ], 128.6 (Carom), 136.1
3 2 3 2 3 2
(Carom), 136.9 (Carom), 143.4 (Carom), 192.7 (CHO) ppm. HRMS (ESI-Q-
+
TOF): calcd. for C H OSi [M + H] 221.13562; found 221.13478.
13 21
4-[Hydroxy(diisopropyl)silyl]benzaldehyde (13c): tBuLi (1.71
M in
2
54 nm, or with a JASCO system equipped with an MD-2010 Plus
hexane; 5.9 mL, 10 mmol) was added dropwise to a solution of 4-
bromobenzaldehyde diethyl acetal (12; 1.0 mL, 5 mmol) in dry THF
(5 mL) in a Schlenk tube at –78 °C under argon. After 30 min, the
mixture was transferred by cannula to a solution of dichloro(diiso-
photodiode-array detector, or with a Dionex P680 system equipped
with UV multiwavelength and Raytest Gabi Star detectors. A Phe-
nomenex Luna C18 column (250 × 4.6 mm, 5 μm, flow 1 mL/min)
Eur. J. Org. Chem. 2017, 5399–5409
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5404
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
3
propyl)silane (1.2 mL, 6.6 mmol) in dry THF (5 mL). The mixture was
ArCH=CH), 6.49 (d, 3JH,H = 16.0 Hz, 1 H, ArCH=CH), 7.32 (d, J
=
H,H
3
stirred at –78 °C for 2 h, then it was allowed to warm to room 8.0 Hz, 2 H, ArH), 7.52 (d, J = 8.0 Hz, 2 H, ArH), 10.76 (br. s, 1 H,
H,H
13
temperature overnight. The reaction was quenched with water
10 mL), and the mixture was extracted with CH Cl (3 × 30 mL).
CO H) ppm. C NMR (125 MHz, CDCl ): δ = 19.0 [C(CH ) ], 28.3
2 3 3 3
(
[C(CH ) ], 28.9 [C(CH ) ], 35.9 (CH ), 53.1 (CHN), 80.4 [OC(CH ) ],
3 3 3 3 2 3 3
2
2
The organic phases were then combined, dried with MgSO , fil-
tered, and concentrated under reduced pressure. The residue was
purified by column chromatography (petroleum ether/EtOAc, 6:4)
123.9 (CH=), 125.5 (Carom), 134.3 (CH=), 134.9 (C
), 136.0 (Carom),
4
arom
29
137.3 (Carom), 155.5 (CO tBu), 176.8 (CO H) ppm. Si NMR (99 MHz,
2
2
CDCl ): δ = +12.7 (s) ppm.
3
to give 13c (1.07 g, 4.52 mmol, 91 %) as a pale yellow liquid. R =
f
(
±)-(4E) Isomer of 15a: The racemic silylated amino acid trans-15a
0
2
.60 (petroleum ether/EtOAc, 6:4). FTIR (neat): ν = 3442 (OH), 2946–
˜
was synthesized from (±)-amino acid Wittig reagent 14, previously
prepared from (±)-aspartic acid, according to the procedure de-
scribed above.
–
1 1
864 (CH, CHO), 1683 (C=O), 810 cm . H NMR (300 MHz, CDCl ):
3
3
3
δ = 0.90 [d, J = 7.2 Hz, 6 H, CH(CH ) ], 0.99 [d, J = 7.2 Hz, 6
H, CH(CH ) ], 1.17 [sept, J = 7.4 Hz, 2 H, CH(CH ) ], 2.16 (br. s, 1
H, SiOH), 7.67 (d, J = 7.8 Hz, 2 H, ArH), 7.88 (d, J = 7.8 Hz, 2
H,H
3 2
H,H
3
3
2
H,H
3 2
3
3
H,H
H,H
(2S)-2-(tert-Butoxycarbonyl)amino-5-[4-hydro(diisopropyl)silyl-
1
3
H, ArH), 9.95 (s, 1 H, CHO) ppm. C NMR (125 MHz, CDCl ): δ = phenyl]pent-4-enoic Acid (15b)
3
1
2.4 [CH(CH ) ], 16.8 [CH(CH ) ], 17.1 [CH(CH ) ], 128.6 (Carom), 134.6
3 2 3 2 3 2
(
Z)/(E) Mixture: Aldehyde 13b (240 mg, 1.09 mmol) and K PO
3 4
(Carom), 136.8 (Carom), 144.2 (Carom), 192.8 (CHO) ppm. HRMS (ESI-Q-
(600 mg, 2.83 mmol; previously dried by heating under vacuum)
–
TOF): calcd. for C H O Si [M – H] 235.11598; found 235.11528.
13 21 2
were added to a solution of phosphonium salt 14 (260 mg,
0.44 mmol) in dry dioxane (5 mL). The reaction mixture was stirred
at 80 °C for 12 h. The mixture was then cooled and filtered through
a Celite pad, and the filter residue was washed with CH Cl (10 mL).
The filtrate was concentrated under reduced pressure. The crude
product was purified by chromatography on silica gel (petroleum
ether/EtOAc, 9:1 + 1 % AcOH) to give amino acid 15b (158 mg,
(2S)-2-(tert-Butoxycarbonyl)amino-5-[4-(di-tert-butylhydro-
silyl)phenyl]pent-4-enoic Acid (15a)
2
2
(
Z)/(E) Mixture: Aldehyde 13a (500 mg, 2.0 mmol) and K PO4
3
(1.08 g, 5.1 mmol; previously dried by heating under vacuum) were
added to a solution of phosphonium salt 14 (500 mg, 0.85 mmol)
in chlorobenzene (6.5 mL). The reaction mixture was stirred at 90 °C
for 16 h, then the reaction was quenched by the addition of distilled
water (5 mL). The mixture was extracted with diethyl ether (3 ×
0
.39 mmol, 89 %) as a colourless uncrystallized solid, as a 3:7 (Z)/(E)
1
mixture. R = 0.23 (petroleum ether/EtOAc, 9:1 + 1 % AcOH). H NMR
f
3
(500 MHz, CDCl ): δ = 0.98 [d, J = 7.2 Hz, 4.2 H, CH(CH ) trans],
3
H,H
3 2
5
mL). The resulting aqueous phase was acidified with KHSO (1 M)
4
3
3
1
4
1
.00 [d, J
= 7.1 Hz, 1.8 H, CH(CH ) cis], 1.06 [d, J
= 7.2 Hz,
H,H
3 2
H,H
to pH 3, and then extracted with EtOAc (3 × 5 mL). The organic
phase was then dried with MgSO , and the solvent was evaporated
under reduced pressure. The crude product was purified by chroma-
tography on silica gel (petroleum ether/EtOAc, 8:2 + 1 % AcOH) to
give silylated amino acid 15a (330 mg, 0.76 mmol, 90 %) as a col-
3
.2 H, CH(CH ) trans], 1.07 [d, J
= 7.1 Hz, 1.8 H, CH(CH ) cis],
3
2
H,H
3 2
4
.21 [m, 2 H, CH(CH ) Z,E overlapping], 1.42 [s, 9 H, OC(CH ) ], 2.50–
3
2
3 3
3
3
.03 (m, 2 H, CH ), 3.92 (t, J = 3.1 Hz, 0.7 H, SiH trans), 3.93 (t,
2 H,H
3
JH,H = 3.1 Hz, 0.3 H, SiH cis), 4.17–4.57 (br. s, 1 H, CHN), 4.92–5.09
(br. s, 1 H, NH), 5.64 (m, 0.3 H, ArCH=CH), 6.17 (m, 0.7 H, ArCH=CH),
ourless solid, as a 3:7 (Z)/(E) mixture. R = 0.39 (petroleum ether/
EtOAc, 8:2 + 1 % AcOH). [α]D = +17.1 (c = 0.2 in CHCl ). FTIR (neat):
f
.49 (d, 3JH,H = 15.8 Hz, 0.7 H, ArCH=CH trans), 6.58 (d, JH,H
3
6
1
7
=
2
0
3
3
1.7 Hz, 0.3 H, ArCH=CH cis), 7.23 (d, J = 8.1 Hz, 0.7 H, ArH cis),
H,H
ν = 3346 (OH), 2981–2881 (CH), 2105 (SiH), 1714 (C=O), 1400, 1356,
˜
3
3
.32 (d, J = 8.1 Hz, 1.3 H, ArH trans), 7.45 (d, J = 8 Hz, 1.3 H,
–1
1
H,H
H,H
1
1
3
5
160 cm . H NMR (500 MHz, CDCl ): δ = 1.05 [s, 18 H, C(CH ) ],
3 3 3
3
ArH trans), 7.58 (d, J
CO H) ppm.
= 8.1 Hz, 0.7 H, ArH cis), 9.50 (br. s, 1 H,
H,H
.43 [s, 9 H, OC(CH ) ], 2.61–2.99 (m, 2 H, CH ), 3.86 (s, 0.6 H, SiH),
3
3
2
2
.87 (s, 0.4 H, SiH), 4.26 (br. s, 0.4 H, CHN), 4.49 (br. s, 0.6 H, CHN),
.09–5.13 (m, 1 H, NH), 5.65 (m, 0.3 H, ArCH=CH), 6.15–6.19 (m, 0.7
(2S,4E) Isomer of 15b: The isomerization of the (Z)/(E) mixture 15b
(172 mg, 0.42 mmol) was achieved by heating with diphenyl disulf-
3
3
H, ArCH=CH), 6.49 (d, J = 16 Hz, 0.7 H, ArCH=CH), 6.58 (d, J
=
H,H
H,H
1
1.5 Hz, 0.3 H, ArCH=CH), 7.22–7.55 (m, 4 H, ArH), 11.03 (s, 1 H, ide in THF under argon for 15 h, according to the procedure de-
13
CO H) ppm. C NMR (125 MHz, CDCl ): δ = 19.1 [C(CH ) , trans], scribed above, to give the (E) isomer of 15b (147 mg, 0.36 mmol,
2
3
3 3
1
9.2 [C(CH ) , cis], 28.4 [C(CH ) ], 29.0 [C(CH ) , trans], 29.1 [C(CH ) , 86 %) as a colourless solid. R = 0.23 (petroleum ether/EtOAc, 9:1 +
3 3 3 3 3 3 3 3
f
2
0
1
cis], 36.0 (CH , trans), 36.2 (CH , cis), 53.2 (CHN, trans), 53.4 (CHN,
cis), 80.5 [OC(CH ) ], 124.0 (CH=), 125.6 (Carom, trans), 125.9 (CH=),
1 % AcOH). [α] = +9.6 (c = 4.1 in CH Cl ). H NMR (500 MHz,
D
2 2
2
2
3
3
3
3
CDCl ): δ = 0.99 [d, J
3
H,H
= 7.4 Hz, 6 H, CH(CH ) ], 1.06 [d, J
3 2
H,H
=
7.4 Hz, 6 H, CH(CH ) ], 1.24 [d, JH,H = 7.3, 3JH,H = 3.2 Hz, 2 H,
3
1
28.0 (Carom, cis), 134.4 (CH=), 135.1 (Carom), 135.9 (Carom, cis), 136.2
3 2
(
Carom, trans), 137.4 (C
), 155.7 (NCO ), 176.7 (CO H, cis), 176.9 CH(CH ) ], 1.43 [s, 9 H, OC(CH ) ], 2.70–2.78 (m, 2 H, CH ), 3.93 (t,
arom
2 2
3 2 3 3 2
29
3
3
(CO H, trans) ppm. Si NMR (99 MHz, CDCl ): δ = +12.7 (s, trans),
JH,H = 3.2 Hz, 1 H, SiH), 4.49 (br. s, 1 H, CHN), 5.07 (d, J = 6.0 Hz,
2
3
H,H
3
+
12.8 (s, cis) ppm. HRMS (ESI-Q-TOF): calcd. for C H NO Si [M –
1 H, NH), 6.17 (m, 1 H, ArCH=CH), 6.51 (d, J = 16 Hz, 1 H, ArCH=
2
4
38
4
H,H
–
3
3
H] 432.25646; found 432.25790.
CH), 7.33 (d, J
= 8.0 Hz, 2 H, ArH), 7.47 (d, J
ArH), 9.26 (br. s, 1 H, CO H) ppm. C NMR (125 MHz, CDCl ): δ =
= 8.1 Hz, 2 H,
H,H
H,H
13
2
3
(
1
2S,4E) Isomer of 15a: The isomerization of the (Z)/(E) mixture of
5a (275 mg, 0.63 mmol) was carried out by heating with diphenyl
1
0.7 [CH(CH ) ], 18.5 [CH(CH ) ], 18.6 [CH(CH ) ], 28.3 [C(CH ) ], 35.8
3 2 3 2 3 2 3 3
(
CH ), 53.1 (CHN), 80.4 [OC(CH ) ], 123.9 (CH=), 125.6 (Carom), 133.7
2 3 3
disulfide (27.7 mg, 0.127 mmol) in THF (10 mL) under argon for
1
cooled, and the solvent was removed. The crude product was puri-
fied by chromatography on silica gel (petroleum ether/EtOAc, 7:3 +
(
CH=), 134.3 (Carom), 135.7 (Carom), 137.5 (Carom), 155.6 (NCO ), 176.5
5 h according to a published procedure.[ The mixture was then
17]
2
+
(CO H) ppm. HRMS (ESI-Q-TOF): calcd. for C H NO SiNa [M + Na]
2
22 35
4
428.22276; found 428.22214.
1
% AcOH) to give trans-15a (270 mg, 0.62 mmol, 98 %) as a colour-
(2S)-2-(tert-Butoxycarbonyl)amino-5-[4-(hydroxydiisopropylsil-
yl)phenyl]pent-4-enoic Acid (15c): This amino acid was prepared
less solid. M.p. 60–61 °C. R = 0.46 (petroleum ether/EtOAc, 7:3 +
f
2
0
1
2
1
% AcOH). [α]D = +19 (c = 0.2 in CHCl ). FTIR (neat): ν˜ = 3368 (OH), according to the same procedure described above for 15a. The re-
3
929–2855 (CH), 2096 (SiH), 1715 (C=O), 1501 (CC), 1248 (C–O), action of aldehyde 13c (850 mg, 3.6 mmol) with phosphonium salt
–1 1
104, 796, 669 cm . H NMR (500 MHz, CDCl ): δ = 1.04 [s, 18 H,
14 (1.55 g, 2.6 mmol) and K PO (3.4 g, 15.8 mmol) in chloro-
3
3 4
C(CH ) ], 1.43 [s, 9 H, OC(CH ) ], 2.67–2.77 (m, 2 H, CH ), 3.86 (s, 1
H, SiH), 4.50 (m, 1 H, CHN), 5.15 (br. s, 1 H, NH), 6.15–6.18 (m, 1 H,
benzene (24 mL) led, after purification by column chromatography,
to amino acid 15c (750 mg, 80 % purity by H NMR spectroscopy,
3
3
3 3
2
1
Eur. J. Org. Chem. 2017, 5399–5409
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5405
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
1
.42 mmol, 55 % yield) as a 3:7 (Z)/(E) mixture. For analytical pur- for 18a, starting from
L-amino acid 15b. DIPEA (90 μL, 0.55 mmol),
poses, a sample (100 mg) was purified by preparative HPLC to give HATU (46 mg, 0.12 mmol), and methyl
L-alaninate·HCl 16 (22 mg,
the product as a colourless uncrystallized material, as a 1:9 (Z)/(E)
0.15 mmol) were added to a solution of 15b (40 mg, 0.100 mmol)
in DMF (1.5 mL). Dipeptide 18b (46 mg, 0.093 mmol, 93 %) was
obtained as a colourless solid. R = 0.31 (petroleum ether/Et O, 1:1).
1
mixture. R = 0.4 (petroleum ether/EtOAc, 1:1 + 1 % AcOH). H NMR
f
3
(
[
300 MHz, CD CN): δ = 0.92 [d, J = 7.1 Hz, 6 H, CH(CH ) ], 1.00
d, J = 7.1 Hz, 6 H, CH(CH ) ], 1.15 [m, 2 H, CH(CH ) ], 1.38 [s, 9
3
H,H
3 2
f
1
2
3
20
[α] = +7.9 (c = 0.9 in CHCl ). H NMR (500 MHz, CDCl ): δ = 0.98
H,H
3 2
3 2
D
3
3
[d, 3J
= 7.3 Hz, 6 H, CH(CH ) ], 1.05 [d, JH,H = 7.3 Hz, 6 H,
CH(CH ) ], 1.20 [septd, JH,H = 7.3, JH,H = 3.2 Hz, 2 H, CH(CH3)2],
1.40 (d, J = 7.5 Hz, 3 H, CHCH ), 1.41 [s, 9 H, OC(CH ) ], 2.67 (m,
3
H, C(CH ) ], 2.77 (m, 2 H, CH ), 4.19 (m, 1 H, CHN), 5.63 (m, 2 H,
3
3
2
H,H
3 2
3
3
3
ArCH=CH, NH), 6.56 (d, JH,H = 11.8 Hz, 1 H, ArCH=CH), 7.29 (d,
JH,H = 7.9 Hz, 2 H, ArH), 7.52 (d, J = 7.9 Hz, 2 H, ArH) ppm.
3 2
3
3
3
13
C
H,H
H,H
3
3 3
3
NMR (75 MHz, CD CN): δ = 12.9 [CH(CH ) ], 16.9 [CH(CH ) ], 17.2 2 H, CH ), 3.70 (s, 3 H, OCH ), 3.92 (t, J = 3.2 Hz, 1 H, SiH), 4.24
3
3 2
3 2
2
3
H,H
[
1
CH(CH ) ], 28.1 [C(CH ) ], 127.8 (CH=), 128.3 (Carom), 132.0 (CH=), (br. s, 1 H, CHN), 4.57 [m, 1 H, NCH(CH )], 5.13 (br. s, 1 H, NH), 6.15–
3
2
3
3
3
34.8 (Carom), 135.6 (Carom), 138.2 (Carom) ppm; signals of 5 C not 6.19 (m, 1 H, ArCH=CH), 6.48 (d, 3JH,H = 15.6 Hz, 1 H, ArCH=CH),
+
3
observed. HRMS (ESI-Q-TOF): calcd. for C H NO SiNa [M + Na]
4
6.70 (br. s, 1 H, NHCHCH ), 7.32 (d, J = 7.6 Hz, 2 H, ArH), 7.44 (d,
2
2
35
5
3 H,H
3
13
44.21767; found 444.21698.
JH,H = 7.6 Hz, 2 H, ArH) ppm. C NMR (125 MHz, CDCl ): δ = 10.9
3
[
4
(
(
CH(CH ) ], 18.4 (CHCH ), 18.8 [CH(CH ) ], 28.4 [OC(CH ) ], 36.3 (CH ),
8.2 (CHN), 52.5 (OCH ), 53.5 (NCHCH ), 80.4 [OC(CH ) ], 124.9
3 3 3 3
(
5
4
S,S)-Di-tert-butylhydrosilylated Dipeptide 18a: DIPEA (0.95 mL,
3 2 3 3 2 3 3 2
.5 mmol) was added to a solution of methyl
L-alaninate·HCl (16;
ArCH=CH), 125.6 (Carom), 133.6 (ArCH=CH), 134.1 (Carom), 135.8
Carom), 137.7 (Carom), 155.6 (NCO ), 171.1 (CON), 173.1 (CO CH )
60 mg, 3.3 mmol) in dry DMF (14 mL). The reaction mixture was
stirred at room temperature for 30 min. Meanwhile in another flask,
HATU (1 g, 2.63 mmol) and DIPEA (0.95 mL, 5.5 mmol) were succes-
sively added to a solution of trans-15a (950 mg, 2.2 mmol) in dry
2
2
3
+
ppm. HRMS (ESI-Q-TOF): calcd. for C H N O Si [M + H] 491.29358;
found 491.29469.
26 43
2 5
DMF (22 mL) at 0 °C under argon. This reaction mixture was stirred (E,Z)-(S,S)-Hydroxy(diisopropyl)silylated Dipeptide 18c: This di-
for 10 min, and then the methyl -alaninate 16 (prepared in the
peptide was prepared according to the same procedure as de-
scribed above for 18a, starting from (E,Z)- -amino acid 15c (270 mg,
0.64 mmol). The reaction of 15c with DIPEA (0.56 mL, 3.2 mmol),
-alaninate·HCl 16 (135 mg,
L
first flask) was added. The resulting mixture was stirred at room
temperature for 4 h; then the solvent was removed under vacuum.
L
The residue was purified by chromatography on silica gel (petro- HBTU (291 mg, 0.77 mmol), and methyl
L
leum ether/Et O, 1:1) to give silylated dipeptide 18a (850 mg,
0.96 mmol) in DMF (10 mL) led to dipeptide 18c (122 mg,
0.24 mmol, 38 %) as a colourless solid and as a 55:45 isomeric mix-
2
1
.64 mmol, 74.5 %) as a colourless foam. R = 0.30 (petroleum ether/
f
2
0
20
Et O, 1:1). [α] = +13.3 (c = 0.6 in CHCl ); FTIR (neat): ν = 3302 ture. R = 0.31 (petroleum ether/EtOAc, 1:1). [α] 20 °CD = +4.8 (c =
2
D
3
˜
f
D
1
3
(
NH), 2929–2855 (CH), 2095 (SiH), 1747 (C=O), 1658 (C=O), 1596 (C= 0.8 in CHCl ). H NMR (300 MHz, CDCl ): δ = 0.80 [d, J = 4.2 Hz,
3 3 H,H
–
1
3
C), 1525 (C=C), 1364 (CC), 1248 (C–O), 1160 (C–O), 797, 668 cm . 2.6 H, CH(CH ) ], 0.82 [d, J
= 4.2 Hz, 3.2 H, CH(CH ) ], 0.88 [d,
3
2
H,H
3 2
1
3
3
3
H NMR (500 MHz, CDCl ): δ = 1.03 [s, 18 H, C(CH ) ], 1.41 (d, J
=
JH,H = 3.6 Hz, 2.7 H, CH(CH ) ], 0.90 [d, JH,H = 3.6 Hz, 3.2 H,
3
3 3
H,H
3 2
8
.5 Hz, 3 H, CH ), 1.42 [s, 9 H, C(CH ) ], 2.67 (m, 2 H, CH ), 3.70 (s, 3
CH(CH ) ], 1.05 [m, 2 H, CH(CH ) ], 1.27 [m, 12 H, OC(CH ) , CHCH ],
3
3 3
2
3 2 3 2 3 3 3
H, OCH ), 3.84 (s, 1 H, SiH), 4.24 (m, 1 H, CHN), 4.56–4.61 (m, 1 H,
CHN), 5.08 (m, 1 H, NH), 6.16–6.23 (m, 1 H, ArCH=CH), 6.48 (d, J
2.65 (m, 2 H, CH ), 3.56 (m, 3 H, OCH ), 4.08 (br. s, 1 H, CHN), 4.41
2 3
3
3
=
(m, 1 H, NCHCH ), 4.88 (br. s, 1 H, SiOH), 5.49 (m, 0.5 H, ArCH=CH),
H,H
3
3
1
6.0 Hz, 1 H, ArCH=CH), 6.68 [d, J = 7.0 Hz, 1 H, NCH(CH )], 7.31 6.04 (m, 0.5 H, ArCH=CH), 6.30–6.54 (m, 1 H, ArCH=CH), 7.10 (m, 1
H,H 3
3
3
13
(
d, J = 8.0 Hz, 2 H, ArH), 7.50 (d, J = 8.0 Hz, 2 H, ArH) ppm.
H, ArH), 7.18 (m, 1 H, ArH), 7.35 (m, 2 H, ArH) ppm. C NMR (75 MHz,
H,H
H,H
1
3
C NMR (125 MHz, CDCl ): δ = 18.4 (CHCH ), 19.0 [C(CH ) ], 28.3 CDCl ): δ = 12.4 [CH(CH ) ], 14.2 [CH(CH ) ], 16.9 [CH(CH ) ], 17.2
3
3
3 3
3
3 2
3 2
3 2
[
[
(
1
+
C(CH ) ], 28.9 [C(CH ) ], 36.1 (CH ), 48.0 (CHN), 52.4 (OCH ), 54.1 [CH(CH ) ], 18.4 (CHCH ), 21.3 (CHCH ), 28.2 [OC(CH ) ], 31.4 (CH ),
3 3 3 3 2 3
3 2 3 3 3 3 2
NCH(CH )], 80.3 [OC(CH ) ], 124.6 (ArCH=CH), 125.4 (Carom), 134.0 48.1 (CHN), 52.5 (OCH ), 60.4 (NCHCH ), 125.5 (ArCH=CH), 127.9
3
3 3
3
3
ArCH=CH), 134.9 (Carom), 136.0 (C
70.9 (CON), 173.0 (CO CH ) ppm. Si NMR (99 MHz, CDCl ): δ =
12.7 (s) ppm. HRMS (ESI-Q-TOF): calcd. for C H N O Si [M + Na]
41.30682; found 541.30724.
R,S)- and (S,S)-Di-tert-butylhydrosilylated Dipeptide 18a: An
epimeric mixture of silylated dipeptide 18a was prepared from (±)-
trans-15a and methyl -alaninate 16 according to the same proce-
dure as described above. An epimeric mixture of 18a (81 %) was
obtained as a colourless oil. R = 0.4 (petroleum ether/EtOAc, 7:3).
H NMR (500 MHz, CDCl ): δ = 1.03 [s, 18 H, C(CH ) ], 1.39 (d, J =
.5 Hz, 3 H, CH ), 1.42 [s, 9 H, OC(CH ) ], 2.65–2.69 (m, 2 H, CH ),
3 3 3 2
.70 (s, 1.33 H, OCH ), 3.74 (s, 1.57 H, OCH ), 3.84 (s, 1 H, SiH), 4.26
br. s, 1 H, CHN), 4.56–4.61 [m, 1 H, NCH(CH )], 5.03–5.06 (br. s, 1 H,
NH), 6.16–6.22 (m, 1 H, ArCH=CH), 6.47 (d, JH,H = 16.0 Hz, 1 H,
ArCH=CH), 6.66–6.69 [m, 1 H, NHCH(CH )], 7.31 (d, J = 7.5 Hz, 2
H, ArH), 7.52 (d, J = 7.5 Hz, 2 H, ArH) ppm. C NMR (125 MHz,
), 137.3 (Carom), 155.5 (NCO2),
(Carom), 134.1 (ArCH=CH), 134.4 (Carom), 171.0 (CON), 173.1 (CO CH )
arom
2 3
2
9
2
3
3
ppm, 4 C not observed. HRMS (ESI-Q-TOF): calcd. for C H N O Si
26 43 2 6
+
+
2
8 46 2 5
[M + H] 507.28849; found 507.28969.
S,S,S)-(Di-tert-butyl)hydrosilylated Tripeptide 19: A solution of
S,S)-di-tert-butylhydrosilylated dipeptide 18a (70 mg, 0.135 mmol)
in HCl (1 in EtOAc; 3 mL) was stirred at room temperature under
5
(
(
(
M
L
argon for 12 h. After this time, the solvent was removed under
vacuum. The residue was dissolved in dry DMF (1 mL) under argon,
and DIPEA (60 μL, 0.340 mmol) was added. The mixture was stirred
for 1 h. Meanwhile, a solution of (S)-Boc-Phe-OH 17 (36.1 mg,
0.136 mmol) in dry DMF (2 mL) was treated with HATU (62.1 mg,
0.163 mmol) and DIPEA (60 μL, 0.340 mmol). This mixture was
stirred at 0 °C for 10 min and was then added to the activated
dipeptide solution. The resulting mixture was stirred for 2 h. After
f
1
3
3
3 3
H,H
8
3
(
3
3
3
3
3
3
H,H
this time, KHSO (1
M
aq.) was added, and the mixture was extracted
4
3
13
H,H
with CH Cl . The organic phases were combined, dried with MgSO ,
2
2
4
CDCl ): δ = 18.2 (CH ), 18.4 (CH ), 19.0 [C(CH ) ], 28.2 [OC(CH ) ],
3
3
3
3 3
3 3
and then filtered, and the solvent was removed under vacuum. The
residue was purified by chromatography on silica gel (EtOAc/petro-
leum ether, 1:1) to give silylated tripeptide 19 (65 mg, 97.6 μmol,
2
[
(
1
8.9 [C(CH ) ], 36.1 (CH ), 48.0 (CHN), 48.1 (CHN), 52.4 (OCH ), 54.2
3 3 2 3
NCH(CH )], 80.5 [OC(CH ) ], 124.7 (ArCH=CH), 125.3 (Carom), 134.1
3 3 3
ArCH=CH), 134.9 (Carom), 136.0 (Carom), 137.3 (Carom), 155.5 (NCO ),
70.9 (CON), 173.0 (CO CH ), 173.1 (CO CH ) ppm. Si NMR
99 MHz, CDCl ): δ = +12.7 (s) ppm.
2
72 %) as an uncrystallized compound. R = 0.30 (EtOAc/petroleum
f
1
2
9
20
2
3
2
3
ether, 1:1). [α]D = –3.4 (c = 1 in CHCl ). H NMR (300 MHz, CDCl ):
3
3
(
3
3
δ = 1.02 [s, 18 H, C(CH ) ], 1.30 [s, 9 H, OC(CH ) ], 1.38 (d, J
=
3
3
3 3
H,H
(
S,S)-Hydro(diisopropyl)silylated Dipeptide 18b: This dipeptide
7.2 Hz, 3 H, CHCH ), 2.53–2.72 (m, 2 H, CH ), 3.06 (m, 2 H, PhCH ),
3 2 2
was prepared according to the same procedure described above
3.69 (s, 3 H, OCH ), 3.83 (s, 1 H, SiH), 4.30–4.42 (m, 1 H, CHN), 4.44–
3
Eur. J. Org. Chem. 2017, 5399–5409
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5406
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
4
6
6
7
1
3
.63 (m, 2 H, CHN, overlapping signals), 4.95 (br. s, 1 H, NH), 5.99–
.20 (m, 1 H, ArCH=CH), 6.32 (d, JH,H = 15.9 Hz, 1 H, ArCH=CH),
successively added to a solution of 15a (26 mg, 0.058 mmol) in dry
THF (3 mL). The reaction mixture was stirred at the reflux tempera-
ture of THF for 48 h. After this time, the mixture was cooled, and
3
.58 (br. s, 1 H, NH), 6.84 (br. s, 1 H, NH), 7.13–7.31 (m, 7 H, ArH),
3
13
.49 (d, J = 8.0 Hz, 2 H, ArH) ppm. C NMR (75 MHz, CDCl ): δ = the solvent was removed under vacuum. The crude residue was
H,H
3
8.1 (CHCH ), 19.1 [C(CH ) ], 28.3 [C(CH ) ], 29.0 [C(CH ) ], 35.7 (CH ),
purified by chromatography on silica gel (CH Cl /MeOH, 2 % to
3
3 3
3 3
3 3
2
2 2
8.1 (PhCH ), 48.4 (CHN), 52.5 (CHN), 52.6 (OCH ), 55.9 (CHN), 80.6
10 %) to give compound 21a (25 mg, 97 %) as a colourless solid.
2
3
2
0
[
(
1
1
OC(CH ) ], 124.3 (ArCH=CH), 125.5 (Carom), 127.3 (Carom), 128.9 Rf = 0.30 (petroleum ether/EtOAc, 8:2 + 1 % AcOH). [α] = +7.6 (c =
3 3
D
Carom), 129.4 (Carom), 134.3 (ArCH=CH), 135.1 (Carom), 136.2 (Carom), 1 in MeOH). FTIR (neat): ν˜ = 3322 (NH, OH), 2970–2850 (CH), 1727
36.4 (Carom), 137.3 (Carom), 155.8 (NCO ), 170.2 (CON), 171.3 (CON), (C=O), 1659 (C=O), 1599 (C=C), 1397–1367 (CC), 1162 (CO), 1110,
2
2
9
–1 1
73.0 (CO CH ) ppm, 2 C not observed. Si NMR (59 MHz, CDCl3):
1048 (CO), 835, 823, 811, 686, 646, 585, 492, 442 cm . H NMR
2
3
+
δ = +12.7 ppm. HRMS (ESI-Q-TOF): calcd. for C H N O Si [M + H]
(500 MHz, CDCl ): δ = 1.05 [s, 18 H, C(CH ) ], 1.42 [s, 9 H, OC(CH ) ],
3
7
56
3
6
3
3 3
3 3
3
6
66.39329; found 666.39188.
2.68–2.80 (2 br. s, 2 H, CH ), 4.48 (m, 1 H, NCHCH ), 5.07 (d, J
.0 Hz, 1 H, NH), 6.16–6.22 (m, 1 H, ArCH=CH), 6.50 (d, JH,H =
5.5 Hz, 1 H, ArCH=CH), 7.35 (d, J
JH,H = 8.0 Hz, 2 H, ArH) ppm, signal of acid H not observed.
=
2
3
H,H
3
7
(
S,S)-Di-tert-butylmethoxysilylated Saturated Dipeptide 20a:
3
1
= 8.0 Hz, 2 H, ArH), 7.54 (d,
H,H
Pd/C (10 %; 29 mg, 27 μmol) was added to a solution of silylated
dipeptide 18a (250 mg, 0.48 mmol) in dry MeOH (2 mL) under
argon in an autoclave. The reaction mixture was stirred under H2
3
13
C
NMR (125 MHz, CDCl , 300 K): δ = 20.4 [C(CH ) ], 27.5 [C(CH ) ], 28.3
3
3 3
3 3
[
C(CH ) ], 36.0 (CH ), 53.1 (CHN), 80.6 [OC(CH ) ], 124.4 (ArCH=CH),
3 3 2 3 3
(10 bar) overnight, then the mixture was filtered through Celite, and
1
25.5 (Carom), 133.3 (ArCH=CH), 134.2 (Carom), 137.9 (C
), 155.4
arom
the solvent was removed under vacuum. The residue was purified
by chromatography on silica gel (petroleum ether/acetone, 8:2) to
give saturated methoxysilylated dipeptide 20a (265 mg, 0.48 mmol,
quantitative) as a colourless uncrystallized compound. R = 0.32 (pe-
troleum ether/acetone, 8:2). [α]D = –4.8 (c = 0.5 in CH Cl ). H NMR
1
9
(
(
NCO ), 180.5 (CO H) ppm; signal of 1 C not observed. F NMR
2 2
28/30
1
470 MHz, CDCl ): δ = –188.9 (s, 0.95 F,
Si–F), –188.9 (d, J
=
3
9
Si,F
29
2
98 Hz, 0.05 F, 2 Si–F) ppm. Si NMR (99 MHz, CDCl ): δ = +13.9 (d,
3
f
1
JSi,F = 298 Hz) ppm. HRMS (ESI-Q-TOF): calcd. for C H FNO SiNa
2
0
1
24 38
4
2
3
2
+
[
M + Na] 474.24463; found 474.24364.
(500 MHz, CDCl ): δ = 0.97 [s, 18 H, C(CH ) ], 1.32 (d, J = 7.5 Hz,
3 3 3 H,H
(
2S,4E)-2-(tert-Butoxycarbonylamino)-5-[4-(fluorodiisopropyl-
in THF; 0.2 mL,
3
2
4
H, CHCH ), 1.37 [s, 9 H, OC(CH ) ], 1.62–1.83 [m, 4 H, (CH ) ], 2.55–
3 3 3 2 2
silyl)phenyl]-4-pentenoic Acid (21b): TBAF (1
M
.58 (m, 2 H, ArCH ), 3.65–3.66 (m, 6 H, OCH , overlapping signals),
.03 (br. s, 1 H, CHN), 4.51 (quint, J = 7.5 Hz, 1 H, CHCH ), 4.88
2
3
3
200 μmol) was added to a solution of 15b (35 mg, 86 μmol) in dry
THF (2 mL) under argon. The mixture was stirred for 20 min; then
the solvent was removed under vacuum. The residue was purified
by chromatography on silica gel (petroleum ether/EtOAc, 9:1 + 1 %
AcOH) to give compound 21b (28.7 mg, 68 μmol, 79 %) as a colour-
H,H
3
3
3
(br. s, 1 H, NH), 6.41 (d,
J
H,H
= 7.5 Hz, 1 H, NH), 7.09 (d, JH,H
=
.0 Hz, 2 H, ArH), 7.44 (d, 3JH,H = 8 Hz, 2 H, ArH) ppm. C NMR
13
8
(125 MHz, CDCl ): δ = 18.5 (CHCH ), 21.0 [C(CH ) ], 27.2 (CH CHN),
3 3 3 3 2
2
8.5 [C(CH ) ], 28.6 [C(CH ) ], 32.3 (PhCH CH ), 35.7 (PhCH ), 48.2
3 3 3 3 2 2 2
2
0
less solid. R = 0.20 (petroleum ether/EtOAc, 9:1 + 1 % AcOH). [α]
=
(
(
(
CHN), 52.6 (OCH ), 53.2 (CHN), 54.5 (SiOCH ), 80.3 [OC(CH ) ], 127.6
Carom), 135.3 (Carom), 142.7 (Carom), 159.5 (NCO ), 171.7 (NCO), 173.2
CO CH ) ppm, 1 C not observed. HRMS (ESI-Q-TOF): calcd. for
f
D
3
3
3 3
1
+
11.4 (c = 0.5 in CH Cl ). H NMR (300 MHz, CDCl ): δ = 0.93 [dd,
2
2
3
2
3
3
3
3
JH,H = 7.4, J = 1.5 Hz, 6 H, CH(CH ) ], 1.00 [dd, J = 7.4, J
=
H,H
3 2
H,H
H,H
2
3
+
1.5 Hz, 6 H, CH(CH ) ], 1.15–1.21 [m, 2 H, CH(CH ) ], 1.42 [s, 9 H,
C H N O Si [M + H] 551.35109; found 551.35067.
3 2 3 2
2
9 51 2 6
OC(CH ) ], 2.63–2.68 (m, 2 H, CH ), 4.41 (br. s, 1 H, CHN), 5.20 (br. s,
3
3
2
(
S,S)-Hydroxy- and Methoxy(diisopropyl)silylated Saturated Di-
3
1
H, NH), 6.09–6.14 (m, 1 H, ArCH=CH), 6.43 (d, J = 15.9 Hz, 1 H,
ArCH=CH), 7.29 (d, J = 7.8 Hz, 2 H, ArH), 7.41 (d, J = 7.8 Hz,
H, ArH) ppm, acid H not observed. C NMR (75 MHz, CDCl ): δ =
2.4 [d, J = 12.8 Hz, CH(CH ) ], 16.8 [d, J = 10.0 Hz, CH(CH3)2],
H,H
peptides 20b and 20c: These dipeptides were obtained according
to the same procedure described above for 20a. Pd/C (10 %; 15 mg,
1
peptide 18c (92 mg, 0.18 mmol) in dry MeOH (1.8 mL), and the
mixture was stirred under H (10 bar) overnight. The mixture was
then filtered through Celite, and the solvent was removed under
vacuum to give a mixture of saturated dipeptides 20b and 20c in
a 2:3 ratio (79 mg, 0.15 mmol, 85 %) as a colourless foam. R = 0.50
3
3
H,H
H,H
13
2
1
2
3
3 μmol) was added to an enantiopure (E)/(Z) isomeric mixture of
2
3
C,F
3 2
C,F
8.4 [C(CH ) ], 36.0 (CH ), 80.6 [OC(CH ) ], 124.7 (ArCH=CH), 125.9
3
3
2
3 3
2
(Carom), 132.3 (Carom), 134.2 (ArCH=CH), 134.3 (Carom), 138.4 (Carom),
19
1
55.7 (NCO ), 176.3 (CO H) ppm; signal of 1 C not observed.
F
2
2
NMR (282 MHz, CDCl ): δ = –187.2 ppm. HRMS (ESI-Q-TOF): calcd.
3
+
f
for C H FNO SiNa [M + Na] 446.21333; found 446.214333.
22 34 4
1
(
[
petroleum ether/EtOAc, 1:1). H NMR (300 MHz, CDCl ): δ = 1.04
m, 12 H, CH(CH ) ], 1.26 (m, 2 H, CHCH ), 1.39 (d, J = 7.3 Hz, 3
3
Di-tert-butylfluorosilylated Dipeptide 21c: KF (36.8 mg,
3
3
2
3
H,H
0.63 mmol), K2.2.2 (94 mg, 0.251 mmol), and acetic acid (80 μL,
H, CHCH ), 1.44 [s, 9 H, OC(CH ) ], 1.70–1.90 [m, 4 H, (CH ) ], 2.64
3
3 3
2 2
1.4 mmol) were added successively to a solution of (S,S)-di-tert-
(
m, 2 H, PhCH ), 3.6 (s, 2 H, OCH ), 3.72 (s, 3 H, OCH ), 4.15 (br. s, 1
2 3 3
butylhydrosilylated dipeptide 18a (130 mg, 0.251 mmol) in dry THF
6.5 mL) under argon. The reaction mixture was heated at the reflux
H, CHN), 4.57 (m, 1 H, NCHCH ), 5.13 (br. s, 1 H, NH), 6.77 (br. s, 1
H, NH), 7.17 (m, 2 H, ArH), 7.46 (m, 2 H, ArH) ppm. C NMR (75 MHz,
CDCl ): δ = 12.0 [CH(CH ) ], 12.5 [CH(CH ) ], 17.0 [CH(CH ) ], 17.2
3
(
1
3
temperature of THF for 24 h. The mixture was then cooled, and the
solvent was evaporated under vacuum. The residue was purified by
3
3 2
3 2
3 2
[
CH(CH ) ], 17.3 [CH(CH ) ], 17.5 [CH(CH ) ], 18.2 (CHCH ), 27.1
3 2 3 2 3 2 3
chromatography on silica gel (petroleum ether/Et O, 1:1) to give
2
(
CH CHN), 32.1 (PhCH CH ), 32.3 (PhCH CH ), 35.5 (PhCH ), 35.6
2 2 2 2 2 2
fluorinated dipeptide 21c (130 mg, 0.242 mmol, 96 %) as a colour-
(PhCH ), 48.0 (CHN), 52.0 (OCH ), 52.4 (SiOCH ), 52.5 (CHN), 54.3
2 3 3
20
less foam. R = 0.25 (petroleum ether/Et O, 1:1). [α] = +8.5 (c = 1.9
f
2
D
(
CHN), 80.1 [OC(CH ) ], 127.8 (Carom), 131.1 (Carom), 134.3 (Carom),
3 3
1
in CHCl ). H NMR (500 MHz, CDCl ): δ = 1.04 [s, 18 H, SiC(CH ) ],
3
3
3 3
1
34.8 (Carom), 142.9 (Carom), 155.7 (NCO ), 171.7 (NCO), 173.1
2
3
1
.39 (d, J
= 7.0 Hz, 3 H, CHCH ), 1.41 [s, 9 H, OC(CH ) ], 2.62–
H,H 3 3 3
(
CO CH ), 173.2 (CO CH ) ppm. HRMS (ESI-Q-TOF): calcd. for
2 3 2 3
2
.71 (m, 2 H, CH ), 3.70 (s, 3 H, OCH ), 4.26 (m, 1 H, CHN), 4.55–4.61
+
2
3
C26H44N O SiNa (silanol 20b) [M + Na] 531.28608; found
5
2
6
3
(
m, 1 H, NCHCH ), 5.11 (d, J = 7.0 Hz, 1 H, NH), 6.18–6.24 (m, 1
+
3 H,H
31.28686; calcd. for C27H46N O SiNa (siloxane 20c) [M + Na]
2 6
3
H, ArCH=CH), 6.48 (d, J
= 15.5 Hz, 1 H, ArCH=CH), 6.71 (br. d,
H,H
5
45.30229; found 545.302680.
3
3
JH,H = 7.0 Hz, 1 H, NH), 7.34 (d, J
= 8.0 Hz, 2 H, ArH), 7.53 (d,
H,H
3J
= 8.0 Hz, 2 H, ArH) ppm. C NMR (125 MHz, CDCl ): δ =
13
(
2S,4E)-2-(tert-Butoxycarbonylamino)-5-[4-(di-tert-butylfluoro-
H,H
3
2
silyl)phenyl]-4-pentenoic Acid (21a): KF (11 mg, 0.18 mmol),
18.3 (CHCH ), 20.2 [d, J = 12.5 Hz, C(CH ) ], 27.3 [C(CH ) ], 28.2
3
C,F
3 3
3 3
K2.2.2 (16 mg, 0.04 mmol), and acetic acid (20 μL, 0.35 mmol) were
[OC(CH ) ], 36.2 (CH ), 48.1 (CHN), 52.4 (OCH ), 53.7 (CHN), 80.3
3 3 2 3
Eur. J. Org. Chem. 2017, 5399–5409
www.eurjoc.org
5407
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[
(
1
OC(CH ) ], 125.2 (ArCH=CH), 125.5 (Carom), 132.9 (Carom), 133.8 the spectra were integrated. The ratio of the 19F signal due to the
3
3
ArCH=CH), 134.2 (C
), 138.0 (Carom), 155.6 (NCO ), 170.9 (CON), fluorosilylated compound to the total 19F signals was plotted
arom
2
1
9
73.0 (CO CH ) ppm. F NMR (470 MHz, CDCl ): δ = –188.9 (s, 0.95 against time to determine the kinetics of the hydrolysis.
2
3
3
28/30
1
29
29
F,
Si–F), –188.9 (d, J = 298 Hz, 0.05 F, Si–F) ppm. Si NMR
[18
F]-Fluorination of Compounds 18a and 20a To Give [18F]-21c
Si,F
1
(99 MHz, CDCl ): δ = +13.9 (d, J = 297 Hz) ppm. HRMS (ESI-Q-
18
18
3
Si,F
and [ F]-21e: No-carrier-added [ F]fluoride was produced by the
+
TOF): calcd. for C28H45FN O SiNa [M + Na] 559.29740; found
5
18
O(p,n)18F nuclear reaction by irradiation of enriched [ O]H O.
F]Fluoride production: Bombarded 30–60 min; 60 μA; target vol-
18
2
5
2
59.29540.
[18
1
8
ume 1.8–2.5 mL; 100–130 GBq were obtained. [ F]Fluoride was
trapped on an anion-exchange resin cartridge (Sep-Pak QMA light,
Waters). The cartridge was eluted with a solution of Kryptofix®
Fluorodiisopropylsilylated Dipeptide 21d: KF (16.6 mg,
0
.285 mmol), K2.2.2 (53.7 mg, 0.143 mmol), and acetic acid (70 μL)
were successively added to a solution of (S,S)-18b (70 mg,
.143 mmol) in dry THF (2.4 mL) under argon. The reaction mixture
(
K2.2.2; 22 mg) and potassium carbonate (7 mg) in H O (0.3 mL)
0
2
and CH CN (0.3 mL). The solvents were removed by heating at
was heated at the reflux temperature of THF for 24 h. After this
time, the mixture was cooled, and the solvent was removed under
vacuum. The residue was purified by chromatography on silica gel
3
1
00 °C under a gentle stream of nitrogen for 8 min. During this
18
time, a dry K[ F]F/K2.2.2 complex was prepared by azeotropic dry-
ing using CH CN (4 × 0.25 mL). Silylated compound 18a (or 20a)
(
(
petroleum ether/Et O, 1:1) to give fluorosilylated dipeptide 21d
3
2
(
4.8–5.4 mg) dissolved in a mixture of DMSO (500 μL) and acetic
67 mg, 0.132 mmol, 92 %) as a colourless foam. R = 0.25 (petro-
f
18
1
3
acid (3 μL) was added to the dry K[ F]F/K2.2.2 complex, and the
resulting mixture was allowed to react at 60–100 °C under constant
stirring for 15 min. After this time, the mixture was diluted with
leum ether/Et O, 1:1). H NMR (500 MHz, CDCl ): δ = 0.93 [d, J =
7
2
3
H,H
3
.5 Hz, 6 H, CH(CH ) ], 1.00 [d, J
= 7.5 Hz, 6 H, CH(CH ) ], 1.18
H,H 3 2
3
2
3
[m, 2 H, CH(CH ) ], 1.33 [d, J = 7.25 Hz, 3 H, CH(CH )], 1.34 [s, 9
3 2 H,H 3
CH CN (3 mL) and H O (2 mL). The resulting solution was injected
H, OC(CH ) ], 2.60 (m, 2 H, CH ), 3.63 (s, 3 H, OCH ), 4.20 (br. s, 1 H,
CHN), 4.51 [m, 1 H, NCH(CH )], 5.08 (br. s, 1 H, NH), 6.17 (m, 1 H,
ArCH=CH), 6.42 (d, J = 16.0 Hz, 1 H, ArCH=CH), 6.70 (br. s, 1 H,
3
2
3
3
2
3
into a semipreparative HPLC instrument [CH CN/(H O/TFA, 0.1 %,
v/v), 85/15; 2.5 mL/min]. Then, [ F]-21c (or [ F]-21e) was formu-
lated in an aqueous physiological solution (0.9 % NaCl solution),
3
18
2
3
18
3
H,H
3
3
NH), 7.29 (d, J
= 8.0 Hz, 2 H, ArH), 7.41 (d, J
= 8.0 Hz, 2 H,
H,H
H,H
2
ArH) ppm. 13C NMR (125 MHz, CDCl ): δ = 11.2 [d, J = 13.7 Hz,
and the purity was checked by analytical HPLC [CH CN/(H O/TFA,
3 2
3
C,F
3
0.1 %, v/v), 85/15; 1 mL/min flow], using the corresponding nonra-
CH(CH ) ], 15.6 [d, JC,F = 19 Hz, CH(CH ) ], 17.3 (CHCH ), 27.3
3
2
3 2
3
dioactive molecule 21c (or 21e) as a reference. The results showed
[
[
(
OC(CH ) ], 35.2 (CH ), 47.1 (CHN), 51.4 (OCH ), 53.1 (CHN), 79.3
3 3 2 3
18
18
that [ F]-21c and [ F]-21e were obtained after a total preparation
time of 60 min, with radiochemical purity >97 %, with an RCY in
the range 12–31 %, and with molar activities from 82 to 410 GBq/
μmol (Table 2).
OC(CH ) ], 124.4 (ArCH=CH), 124.7 (Carom), 130.9 (Carom), 132.7
3
3
ArCH=CH), 133.1 (C
), 137.4 (Carom), 155.6 (NCO ), 170.0 (CON),
arom
2
1
9
1
F,
72.0 (CO CH ) ppm. F NMR (470 MHz, CDCl ): δ = –187.2 (s, 0.95
2
3
3
28/30
1
29
Si–F), –187.2 (d, JSi,F = 294 Hz, 0.05 F, Si–F) ppm. HRMS
+
(ESI-Q-TOF): calcd. for C H FN O SiNa [M + Na] 531.26610; found
26 41 2 5
5
31.26647.
Acknowledgments
Hydrogenation of Di-tert-butylfluorosilyl Dipeptide 21c To Give
Saturated Derivative 21e: See Supporting Information. In an auto-
clave, Pd/C (10 %; 15 mg, 13 μmol) was added to a solution of
fluorosilylated dipeptide 21c (82 mg, 0.15 mmol) in dry MeOH
The authors are grateful for fellowships and post-doctoral
grants to H. A., B. R., and R. K. provided by the Conseil Régional
de Bourgogne (research programs 3MIM and PARI-santé), and
for financial support from the Ministère de l'éducation nationale
de l'enseignement supérieur et de la recherche and the CNRS
(
1.5 mL). The mixture was stirred under H (10 bar) overnight. After
2
this time, the mixture was filtered through Celite. The solvent was
removed under vacuum to give fluorosilylated dipeptide 21e
(Centre National de la Recherche Scientifique). The authors
(
82 mg, 0.15 mmol, quantitative) as a colourless oil. R = 0.30 (petro- would like also to thank M. J.-B. Deloye and the Sté Cyclo-
f
2
0
1
leum ether/acetone, 8:2). [α]D = –5.8 (c = 1 in CH Cl ). H NMR pharma for their support through a fellowship to B. R. Ms. M. J.
2
3
2
(
300 MHz, CDCl ): δ = 1.05 [s, 18 H, C(CH ) ], 1.40 (d, J = 7.5 Hz, Penouilh and F. Chaux at the Welience/Pôle Chimie Moléculaire,
3
3 3
H,H
3
H, CHCH ), 1.44 [s, 9 H, OC(CH ) ], 1.69–1.71 [m, 4 H, (CH ) , over-
3 3 3 2 2
Ms. C. Moulatsa, M.-J. Eymin, and M. J.-C. Chambron at the IC-
MUB-StéréochIM, and Ms L. Jugé-Qin at the Neurosciences Re-
search and School of Medical Sciences, University of New South
Wales, Australia, are warmly thanked for their technical assist-
ance and their help with the preparation of this manuscript.
lapping signals], 2.63–2.65 (m, 2 H, ArCH ), 3.73 (s, 3 H, OCH ), 4.10
2
3
3
(
br. s, 1 H, CHN), 4.57 (quint, J = 7.5 Hz, 1 H, NCHCH ), 4.95 (br.
H,H 3
3
3
s, 1 H, NH), 6.48 (d, J = 7.5 Hz, 1 H, NHCHCH ), 7.17 (d, J =
.8 Hz, 2 H, ArH), 7.50 (d, JH,H = 8.1 Hz, 2 H, ArH) ppm. C NMR
H,H
3
H,H
3
13
7
(
2
75 MHz, CDCl ): δ = 18.4 (CHCH ), 20.3 [d, J = 12.8 Hz, C(CH3)3],
3 3 C,F
2
3
1
1
7.0 (ArCH CH CH ), 27.4 [C(CH ) ], 28.3 [C(CH ) ], 32.1 (ArCH CH ),
2 2 2 3 3 3 3 2 2
5.5 (ArCH ), 48.0 (CHN), 52.4 (OCH ), 57.1 (CHN), 80.3 [OC(CH ) ], Keywords: Fluorinated compounds · Radiochemistry ·
2
3
3 3
27.7 (ArCH=CH), 130.6 (Carom), 134.2 (ArCH=CH), 143.5 (Carom), Isotopic labeling · Wittig reactions · Amino acids · Peptides
1
9
59.5 (NCO ), 171.5 (CON), 173.2 (CO CH ) ppm. F NMR (282 MHz,
2
2
3
2
8/30
1
CDCl ): δ = –189.0 (s, 0.95 F,
Si–F), –189.0 (d, JSi,F = 296 Hz,
3
[
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Received: August 21, 2017
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© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim