Silole Amino Acids with Aggregation-Induced Emission Features Synthesized by Hydrosilylation

Article abstract of DOI:10.1002/ejoc.201801869

The synthesis of silole amino acids was achieved through hydrosilylation of alkene or alkyne-containing amino acids with 1-methyl-2,3,4,5-tetraphenyl-1H-silole, using Karstedt's catalyst with yield up to 95 % and without epimerization. After selective deprotection of carboxylic acid or amine functions respectively, C- or N-peptide coupling with an alanine moiety proved their possible incorporation into peptides. A model tripeptide was synthesized by solid phase synthesis with the N-Fmoc protected silole amino acid version. The silole moiety can be also grafted on a precursor peptide directly on the solid support. These amino acids and peptides exhibit AIE properties with λ_em ca. 500 nm and Δλ ca. 100 nm. This approach constitutes an alternative and promising strategy for incorporation of such AIE fluorogens to peptides.

Full text of DOI:10.1002/ejoc.201801869

A Journal of
Accepted Article
Title: Silole amino acids with Aggregation-Induced Emission features
synthezised by hydrosilylation reaction
Authors: Mathieu Arribat, Emmanuelle Rémond, Sébastien Richeter,
Philippe Gerbier, Sébastien Clément, and Florine Cavelier
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801869
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801869
Supported by

10.1002/ejoc.201801869
European Journal of Organic Chemistry
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Silole amino acids with Aggregation-Induced Emission features
synthesized by hydrosilylation reaction
Mathieu Arribat,[a] Emmanuelle Rémond,[a] Sébastien Richeter,[b] Philippe Gerbier,[b] Sébastien
Clément,*[b] and Florine Cavelier*[a]
Abstract: The synthesis of silole amino acids was achieved through
hydrosilylation of alkene or alkyne-containing amino acids with 1-
methyl-2,3,4,5-tetraphenyl-1H-silole, using Karstedt’s catalyst with
yield up to 95% and without epimerization. After selective
deprotection of carboxylic acid or amine functions respectively, C- or
N-peptide coupling with an alanine moiety proved their possible
incorporation into peptides. A model tripeptide was synthesized by
solid phase synthesis with the N-Fmoc protected silole amino acid
version. The silole moiety can be also grafted on a precursor peptide
directly on the solid support. These amino acids and peptides exhibit
AIE properties with λem ~500 nm and Δλ ~100 nm. This approach
constitutes an alternative and promising strategy for incorporation of
such AIE fluorogens to peptides.
also exhibit in general higher sensitivity and better photo-
bleaching resistance than conventional organic fluorophores.[8]
By exploiting such strategy, highly specific AIE-fluorogens
probes have been notably prepared through the incorporation of
specific peptide-based recognition elements for integrin and
caspase activity studies,[9] and targeting transferrin receptor.[10]
Click-chemistry strategy was commonly used, allowing efficient
linkage in aqueous media and without by-products, starting from
azide-functionalized AIE-fluorogen and alkyne-peptide both in
solution and on solid-phase,[9a, 11] as well as thiourea or amide
linkages.[12] An alternative to prosthetic groups anchoring is
direct incorporation of fluorescent amino acids[13] and many
efforts have converged to the development of various
fluorescent structures that may potentially be carried by the
amino acid side chain, including phospholyl(borane) that we
recently described.[14] Herein, we exploit the structural feature of
silole to design new highly luminescent amino acids. Silole
Introduction
derivatives are
a class of archetypal AIE-fluorogens with
Fluorescence technique has become an essential tool for
biosensing, bioimaging and diagnosis by virtue of its high
sensitivity, easy operation and non-invasiveness.[1] The
continuous development of sophisticated optics and electronics
associated to fluorescence requires the design of fluorophores
with suitable features.[2] To date, several design strategies led to
successful practical applications in living systems exploiting
photo-induced electron transfer (PET),[3] internal charge transfer
(ICT)[4] and fluorescence resonance energy transfer (FRET).[5]
Peptides labelled with fluorescent dyes have been widely used
for such purpose. However, they often involve conventional
organic fluorophores such as fluorescein or rhodamine, which
have a strong natural tendency to aggregate when dispersed in
aqueous media due to π−π stacking interactions.[6] This
aggregation generally implies a self-quenching and thus, leads
to a drastic decrease of fluorescence (“turn off”), which is a
thorny problem for developing efficient bioprobes. To address
these issues, organic luminogens with aggregation-induced
emission properties (AIE-fluorogens) have been developed.[7]
These luminogens are found to be weakly or not fluorescent
when molecularly dissolved but highly fluorescent when
aggregated, due to the well-known restriction of the
intramolecular motion (RIM) mechanism. As such, these AIE-
fluorogens can be used in highly concentrated solution. They
fascinating properties such as high thermal stability, high photo-
stability and easy synthetic tunability.[15] Based on the previous
work of our laboratory on silylated amino acids,[16] and especially,
the study of the hydrosilylation reaction,[17] we incorporated 1-
methyl-2,3,4,5-tetraphenyl-1H-silole into amino acids through
hydrosilylation reactions with alkene- or alkyne- functionalized
amino acids.[18] After selective deprotection of carboxylic function
or amine, the C- or N-peptide coupling in solution and on solid
phase peptide synthesis (SPPS) of the silole amino acids proved
their possible incorporation into peptides. The resulting silole
amino acids and peptides exhibit fluorescent properties with AIE
effect.
Results and Discussion
The commercially available Boc-allylglycine
transformed into the corresponding methyl ester
trimethylsilyldiazomethane in 90% yield (Scheme 1).
1
was first
with
2
[a]
M. Arribat, Dr. E. Rémond and Dr. F. Cavelier
Institut des Biomolécules Max Mousseron, IBMM, UMR 5247,
CNRS, Université de Montpellier, ENSCM, Place Eugène Bataillon,
34095 Montpellier cedex 5, France
Scheme 1. Hydrosilylation of protected allylglycine 2.
E-mail: florine.cavelier@umontpellier.fr
This fully protected allylglycine
2 was then submitted to
[b]
Dr. S. Richeter, Pr. P. Gerbier, Pr. S. Clément
Institut Charles Gerhardt Montpellier, ICGM, UMR 5253, CNRS,
Université de Montpellier, ENSCM, Place Eugène Bataillon, 34095
Montpellier cedex 5, France
hydrosilylation reaction with 1-methyl-2,3,4,5-tetraphenyl-1H-
silole 3 in the presence of different platinum catalysts to select
the most effective one (Table 1). When tetrabutylammonium
hexachloroplatinate (IV) was used in refluxing dichloromethane,
no reaction occurred even when doubling the quantity of silole
E-mail: sebastien.clement1@umontpellier.fr
Supporting information for this article is given via a link at the end of
the document
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10.1002/ejoc.201801869
European Journal of Organic Chemistry
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(entries 1 and 2, Table 1). Compound 4 was obtained in 72%
yield with Speier’s catalyst, H2PtCl6.6H2O (entry 3, Table 1).
Interestingly, switching to Karstedt’s catalyst led to further
improved yield (95%) as well as shorter reaction time (only 2 h
are sufficient to convert 2 into 4 instead of 8 h). The success of
the hydrosilylation reaction was confirmed by IR spectroscopy
since the Si-H band of the silole reagent precursor 3 at ν = 2118
cm-1 disappeared in the IR spectrum of 4 (Figure S1, Supporting
Information). The optical purity of 4 was verified on HPLC using
a chiral column by comparison with a racemic sample (See
Supporting Information). Formation of silole amino acid 4 was
also confirmed by 1H, 13C{1H}, 29Si{1H} NMR spectroscopies in
CDCl3 (See supporting information). Indeed, significant 29Si{1H]
NMR chemical shift differences were observed between the
silole 3 (δ = -11 ppm) and the hydrosilylation product 4 (δ = -17.7
ppm).
Scheme 3. Synthesis of silole dipeptide derivatives.
Solid phase peptide synthesis (SPPS) was demonstrated by
synthesizing the tripeptide 17 with the N-Fmoc protected
derivative 14 (Scheme 4, pathway A). The coupling step
between Ala-Wang 13 and silole 14 was first carried out using
HATU and Et3N in DMF. Then, dipeptide 15 was deprotected
with 20 % piperidine solution in DMF and coupled with Fmoc-(L)-
Ala-OH 16. Final cleavage with TFA/TIS/H2O afforded the
corresponding tripeptide 17 with a silole group in 60 % overall
yield. On the other hand, tripeptide 19 obtained by SPPS from
Table 1. Optimization of the reaction conditions of the hydrosilylation of
protected allylglycine 2 with silole 3.
Entry
Catalyst[a]
Eq. of 3
Reaction time (h)
Yield (%)[b]
n.d.
1
2
3
4
(Bu4N)2PtCl6
(Bu4N)2PtCl6
H2PtCl6.6H2O
Karstedt
2
4
2
2
12
12
8
n.d.
72
Ala-Wang 13 in 88
% overall yield was subjected to
hydrosilylation with silole 3, directly on support under
microwaves irradiations in CH2Cl2 at 40°C for 2 hours. Silole-
containing tripeptide 17 was finally obtained in higher yield of
80 % after final cleavage by this strategy.
2
95
[a]
5 mol% per mol of 2. [b] Isolated yield after purification by flash
chromatography on silica gel with EtOAc/petroleum ether (1/9) as eluent.
Using these optimized conditions (Table 1, entry 4), the N-
protected alkyne amino ester 5 was transformed into the
corresponding silole 6 (Scheme 2). Only one signal was
observed by 29Si{1H} NMR spectroscopy at δ = -2.1 ppm. 1H
NMR spectrum of 6 revealed a trans-product probably due to the
steric hindrance of the silole moiety. Doublets assigned to the
vinylic protons appear at 6.23 and 5.83 ppm with a coupling
constant of ~19 Hz, a value generally observed for silane
substituted trans-vinylene products.[19]
Scheme 4. Solid Phase Peptide Synthesis (SPPS).
Scheme 2. Hydrosilylation of alkyne amino acid 5.
The optical properties of the new silole amino acids and
peptides were then studied. The UV-visible absorption and
photoluminescence (PL) spectra of these silole derivatives were
recorded in THF at a concentration of 5.10-4 M (Figure 1 and
S11-S22, Supporting Information). All the silole amino acids and
peptides exhibit an absorption band (λabs) between 350 and 365
nm ascribed to the π−π* transition of the silacyclopentadiene ring
(Table 2).[20]
The fully protected silole amino acid 4 was selectively N- or C-
deprotected in order to prove the coupling feasibility (Scheme 3).
The amine function was deprotected under acidic conditions
(TFA) to afford the corresponding ammonium salt 7 in 80 % yield.
The methyl ester was saponified with lithium hydroxide to afford
the free carboxylic acid 8 in 85% yield. The peptide coupling of 7
and 8 was achieved under classical conditions (HATU, DIPEA,
DMF) with alanine moiety as model (9 and 10).
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10.1002/ejoc.201801869
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Table 2. Absorption and emission characteristics of silole amino acids
and peptides at room temperature.
Entry
Compound
λabs (nm)[a]
λex (nm) [a]
λem (nm) [a]
491
Δλ
φTHF (%) [a]
φagg (%) [a]
Ιagg/ITHF
5.6
1
2
3
4
5
4
287 (sh)[b], 358
290 (sh), 365
290, 354
360
380
380
380
400
131
120
115
112
102
1
2
1
1
1
5
6
500
12
10
8
44
11
12
17
495
5.8
286, 350
492
7.3
289 (sh), 365
502
8
6.4
[a] measured in THF or THF/H2O at 25°C. [b] sh = shoulder.
Silole amino acids and peptides 4, 6, 11, 12 and 17 are weakly
emissive in THF, usually a good solvent, with emission maxima
absorption and emission maxima cannot be related to the
difference in the inductive effects between the substituents due
between 485 and 500 nm and large Stokes shifts (~100-130 nm). to their similarity but rather on value of the torsion angles
between the central silole ring and the adjacent phenyl rings
(see below).
Figure 1. UV-Vis absorption and emission spectra of 4 in THF (C: 5.10-4 M,
λexc = 360 nm).
1.0
THF/water
20/80
THF
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
The AIE properties of silole amino acids and peptides were then
studied in THF/water mixtures with different water fractions (fw)
in view of fine-tuning the water content as well as the
aggregation extent (Figure 2). Each PL intensity was divided by
its maximum PL intensity (i.e. the PL intensity for the highest fw)
to get I/I0 ranging from 0 to 1. As expected, the greater the water
fraction, the more the fluorescence increases; molecular
aggregation inducing a slight red shift (~5-10 nm) in the
emission spectrum. As shown in Figure 2 and Figure S15-S18 in
the Supporting Information, when fw varies from 0 to 60 % vol,
the fluorescence remains very low. A remarkable increase in the
fluorescence was noted after the water fraction reached 70 and
80 % vol, typical from AIE-fluorogens leading to Iagg/ITHF ~ 6
(except for 6, Iagg/ITHF ~ 44).
0
10
20
30
40
50
60
70
80
90
fw (vol% water)
Figure 2. Emission spectra of 4 in THF/water mixtures with different water
fractions (fw) (Concentration: 5.10-4 M, λexc = 360 nm) (top). Plot of I/I0 values
vs. water fractions. I0 is the PL intensity for the highest fw (bottom). Inset:
photos of silole amino acid 4 under the illumination of a UV lamp at 405 nm in
THF\water mixture (fw = 0 and 80%).
These silole amino acids and peptides differ by the nature of the
substituents introduced on the silicon atom. However, the effect
on absorption and emission maxima of the substituents on the
1,1 position is known to be rather small and mostly due to
inductive effects.[21] As such, the trend observed in the
To gain insight into the relationship between the optical
properties and the conjugation pattern in silole amino acids 4
and 6, density functional theory calculations were performed.
B3LYP method with 6-31G* basis set was used for the
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10.1002/ejoc.201801869
European Journal of Organic Chemistry
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calculation.[22] The optimized structures and the orbital
distributions of the HOMO and LUMO energy levels of silole
amino acids 4 and 6 are depicted in Figure 3. As previously
observed, the four phenyl rings decorating the central
silacyclopentadiene ring adopt a propeller-like arrangement
(Figure S23, Supporting Information).[23]
500 nm and Δλ ~ 100 nm. As such, this approach constitutes an
alternative and promising strategy for incorporation of AIE
fluorogens in peptides.
Experimental Section
The selected parameters for these compounds are summarized
in Table S1 (Supporting Information). Interestingly, the average
value of the torsion angles between the central silole ring and
the adjacent phenyl rings at the 2,5-positions decreases going
from 51.2° for 4 to 46.8° for 6, suggesting a more efficient π-
conjugation over the three benzene-silole-benzene rings. This
difference originates from the disposition of the substituents at
the 1,1-position. Indeed, the double bond in 6 allows the CH3-
SiC2-CH=CH- fragment adopting an eclipsed conformation
whereas a gauche conformation of the CH3-SiC2-CH2-CH2-
fragment is found in 4, leading to an increase of the torsion
angle of the adjacent phenyl ring. The DFT calculations at the
B3LYP/6-31G* level on amino acids 4 and 6 were carried out to
gain more insight into their electronic structures (Figure 3). The
orbital plots 4 and 6 are typical for the HOMO and LUMO
orbitals of siloles, i.e. the LUMO of the silole ring displays a
General remarks: All reactions involving air-sensitive reagents were
performed under argon. Solvents and reagents were purchased from
commercial sources and used without purification. THF was freshly
distilled from benzophenone/sodium prior to use. All reagents were
purchased from commercial sources and used without purification. 1-
methyl-2,3,4,5-tetraphenyl-1H-silole (3) was prepared according to the
literature method.[24] Thin layer chromatography was carried out using
silicagel 60 F254 sheets. Spots were visualized by treatment with an
ethanolic solution of ninhydrin 10%, followed by heating. Purifications
were performed with column chromatography using silica gel 60 (230-
400 mesh). Melting points were determined on a Buchi 510 melting point
apparatus and are uncorrected. Nuclear magnetic resonance 1H, 13C{1H}
and 29Si{1H} NMR spectra were recorded on 300, 400 or 500
spectrometer at room temperature. Data are reported as s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, br. s = broad signal,
coupling constant(s) in Hertz, integration. Low resolution electrospray
ionization (ESI) mass spectra were recorded on a Micromass Platform
Electrospray mass spectrometer. Spectra were recorded in the positive
mode (ESI+). UV chromatogram was performed using an Agilent 1220
HPLC equipped with a Chromolith® high resolution C-18 column (50 µm
x 4.6 mm). High resolution mass spectra (HRMS) were recorded using a
Synapt G2-S mass detector operating at capillary tension of 1 kV and
cone tension of 20 V. Optical rotations values were measured on a
Perkin-Elmer 341 polarimeter (20°C, 589 nm). Chiral HPLC analyses
were performed on a Beckman chromatograph with a variable detector at
λ = 210 nm and λ = 254 nm using a chiral column OD-H, AS-H or AD-H
(0.46 x 25 cm). Ultra-violet absorption spectra were recorded at 25°C on
a JASCO V-750 spectrophotometer in 10 mm quartz cells (Hellma);
abbreviation used sh, shoulder. All the extinction coefficients were
determined by preparing solutions of silole amino-acids at different
concentrations (at least five different concentrations) through the Beer-
Lambert relationship. The concentration solution range was judiciously
chosen to stay in the linear range of the Beer-Lambert relationship (A ~
0.2-0.8). Emission spectra were recorded at 25°C on a fluorescence
spectrometer (FS920, Edinburgh Instruments) equipped with a calibrated
photomultiplier in a Peltier (air cooled) housing (R928P, Hamamatsu),
with a 450 W continuous xenon arc lamp as the excitation source for
steady-state photoluminescence measurements using a quartz cuvette
with 1.0 cm excitation path length. Emission and excitation spectra were
corrected for the wavelength response of the system using correction
factors supplied by the manufacturer. The quantum yields of the samples
were determined using an integrating sphere (120 mm diameter) of
Edinburgh Instruments under air.
typical
σ(Si–Cexocyclic)*–π(butadiene)*
hyperconjugation
responsible for its remarkable electronic properties.[15a, 21] With
the exception of carbon atoms directly connected to the silicon
atom, a negligible electronic density was noted on the chains
bearing the amino acid moiety. The decrease of 70 meV in the
energy band gap from 4 to 6 is in good agreement with the red-
shifted absorption and emission spectra of 6 compared to 4.
Figure 3. DFT-B3LYP/6-31G* calculated molecular orbital amplitude plots of
the HOMO and LUMO energy levels of silole amino acids 4 (top) and 6
(bottom).
Methyl (S)-2-((tert-butoxycarbonyl)amino)pent-4-enoate 2: To
a
solution of Boc-allylglycine 1 (500 mg, 2.32 mmol) in toluene/MeOH (2/3,
20 mL) under argon at 0°C was added dropwise TMSCHN2 (1.74 mL,
3.48 mmol, 2M in hexane). The mixture was stirred at r.t. during 1 hour
then quenched with 1 mL of acetic acid and evaporated to dryness. The
crude product was purified by flash column chromatography on silica gel
with petroleum ether/ethyl acetate (80:20) to afford desired compound 2
with 90 % yield. The spectroscopic data are in accordance with the
literature.[25]
Conclusions
In conclusion, new silole amino acids were synthesized by
hydrosilylation of alkyne or alkene amino acids. After selective
deprotection of carboxylic function or amine, C- or N-peptide
coupling in solution and on solid phase proved their possible
incorporation into peptides. The silole moiety can be also grafted
on a precursor peptide directly on the solid support. Such silole
amino acids and peptides exhibit AIE properties with λem around
General procedure for hydrosilylation reaction: To a solution of
alkene or alkyne (1 eq.) in anhydrous CH2Cl2 (7.7 mL / mmol of amino
acid) under argon were added 1-methyl-2,3,4,5-tetraphenyl-1H-silole 3 (2
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10.1002/ejoc.201801869
European Journal of Organic Chemistry
FULL PAPER
eq.) and catalyst (5 mol %). The mixture was stirred at reflux and
monitored by TLC (petroleum ether/ethyl acetate 90:10) until reaction
was completed. The solvent was removed and the crude product was
purified by flash column chromatography on silica gel with petroleum
ether/ethyl acetate (90:10) to afford the corresponding 1-methyl-2,3,4,5-
tetraphenylsilole amino esters 4 and 6.
to dryness to afford the amino acid 8 as a yellow sticky solid with 80 %
yield. The amino acid 8 was used without further purification for peptide
coupling. LCMS: tR = 2.57 min. ESI-MS: 613.3 [M+H]+, 638.2 [M+Na]+ (λ
= 214 nm).
Dipeptide 11: To a solution of Boc-Ala-OH (14 mg, 0.076 mmol) in DMF
(800 µL) were added HATU (31 mg, 0.083 mmol) and DIPEA (47 µL,
0.29 mmol). After 10 minutes, silole amino ester 7 (43 mg, 0.076 mmol)
was added and the mixture was stirred overnight at room temperature.
DMF was evaporated and the residue was taken up in EtOAc and
washed with aqueous saturated NaHCO3, KHSO4 (1M) and brine. The
organic layer was dried on magnesium sulfate, filtered and evaporated to
afford the dipeptide 11 with 65 % yield as yellow sticky solid. Rf = 0.22
(petroleum ether/ethyl acetate 7:3). Enantiomeric excess > 99 % was
determined using chiralcel AD-H, n-hexane/iPrOH (95:5), 0.8 mL.min-1, λ
= 214 nm, 30°C, tR (S,R) = 28.7 min, tR (S,S) = 32.3 min. 1H NMR (400
Methyl
(S)-2-((tert-butoxycarbonyl)amino)-5-(1-methyl-2,3,4,5-
tetraphenyl-1H-silol-1-yl)pentanoate 4: Following the general
procedure, Boc-AllylGly-OMe 1 (100 mg, 0.43 mmol), 3 (344 mg, 0.86
mmol) and Karstedt catalyst (10 µL, 0.02 mmol) were used to afford the
silole amino ester 4 in 95 % yield as a yellow sticky solid. Rf = 0.48
(petroleum ether/ethyl acetate 8:2). [α]D
= -31 (c = 1, CHCl3).
Enantiomeric excess > 99 % was determined using chiralcel AD-H, n-
hexane/iPrOH (98:2), 0.8 mL.min-1, λ = 214 nm, 30°C, tR (S) = 9.7 min, tR
(R) = 11.4 min. 1H NMR (400 MHz, CDCl3) δ 7.12 (ddd, JH,H = 6.1, 5.4,
2.4 Hz, 5H, Harom), 7.02 – 6.99 (m, 5H, Harom), 6.92 – 6.88 (m, 5H,
3
MHz, CDCl3) δ 7.13-6.78 (m, 20H, Harom), 6.45 (d, JH,H = 8.0 Hz, 1H,
3
Harom), 6.82 – 6.78 (m, 5H, Harom), 4.82 (d, JH,H = 8.2 Hz, 1H, NH),
NH amide), 4.88 (d, 3JH,H = 10.3 Hz, 1H, NHBoc), 4.42 (td, JH,H = 7.9, 5.3
Hz, 1H, CHN), 4.04 (dt, JH,H = 11.7, 5.9 Hz, 1H, CHN), 3.59 (s, 3H, O-
4.23 (q, JH,H = 13.4, 7.7 Hz, 1H, CHN), 3.64 (s, 3H, O-CH3), 1.84 – 1.73
(m, 1H, CH-Cα), 1.65 – 1.55 (m, 2H, CH2), 1.47 – 1.43 (m, 1H, CH-Cα),
1.42 (s, 9H, (CH3)3), 1.09 – 0.98 (m, 1H, CH-Si), 0.94 – 0.85 (m, 1H, CH-
Si), 0.47 (s, 3H, CH3-Si). 13C{1H} NMR (101 MHz, CDCl3) δ 173.5, 155.5,
155.1, 155, 140.9, 140.8, 140, 139.9, 138.8, 130.1, 128.9, 128.1, 127.56,
126.4, 125.7, 79.9, 53.3, 52.2, 35.9, 28.5, 19.9, 13.1, -5.3. 29Si{1H} NMR
(99 MHz, CDCl3) δ -17.7 (s). HRMS calculated for C40H44NO4Si+ [M+H]+
630.3034 found 630.3031. UV-Vis (THF): λ (ε L.mol-1.cm-1) = 287 (1860),
358 (1080) nm.
3
CH3), 3.45-3.17 (m, 1H, CH2), 1.36 (d, JH,H = 5.1 Hz, 9H, (CH3)3), 1.22
(dd, JH,H = 6.8, 2.0 Hz, 3H, CH3), 1.04 (t, JH,H = 7.1 Hz, 2H, CH2), 0.88-
0.73 (m, 2H, CH2-Si), 0.27 (d, JH,H = 6.6 Hz, 3H, CH3-Si). 13C{1H} NMR
(101 MHz, CDCl3) δ 172.4, 156.9, 156.8, 144.9, 143.2, 142.5, 140, 137.7,
136.2, 136.2, 130, 129.7, 129.6, 129.6, 129.6, 129.3, 128.3, 128.3,
128.2, 127.7, 127.5, 127.4, 127.4, 127, 126.2, 125.5, 52.3, 51.8, 46.2,
41.8, 40.3, 35.6, 29.7, 28.4, 28.3, 19.7, 19.3, 17.4, 17.2, 14.6, 12.9.
29Si{1H} NMR (99 MHz, CDCl3) δ -15.8 (s). FTIR (neat): ꢀ = 3042, 1582,
1505, 1437, 1326, 1211, 1028, 810, 747, 643 cm-1. HRMS calculated for
C43H48N2O5Si [M+H]+ 701.3405 found 701.3404. UV-Vis (THF): λ (ε
L.mol-1.cm-1) = 290 (23970), 354 (18780) nm.
Benzyl
(S),(E)-2-((tert-butoxycarbonyl)amino)-6-(1-methyl-2,3,4,5-
tetraphenyl-1H-silol-1-yl)hex-5-enoate 6: Following the general
procedure, alkyne 5 (100 mg, 0.31 mmol), 3 (252 mg, 0.62 mmol) and
Karstedt catalyst (8 µL, 0.02 mmol) were used to afford the silole amino
ester 6 in 88 % yield as a yellow sticky solid. Rf = 0.52 (petroleum
ether/ethyl acetate 8:2). [α]D = -28 (c = 1, CHCl3). Enantiomeric excess >
99 % was determined using chiralcel AD-H, n-hexane/iPrOH (99:1), 0.8
mL.min-1, λ = 214 nm, 30°C, tR (S) = 17.5 min, tR (R) = 24.5 min. 1H NMR
(400 MHz, CDCl3) δ 7.34 (s, 5H, Harom), 7.04-7.01 (m, 10H, Harom),
Dipeptide 12. To a solution of silole amino acid 8 (23 mg, 0.037 mmol) in
DMF (400 µL) were added HATU (0.041 mmol, 16 mg) and DIPEA (0.13
mmol, 21 µL). After 10 minutes, HCl.H-Ala-OMe (0.041 mmol, 5.7 mg)
was added and the mixture was stirred overnight at room temperature.
The DMF was evaporated and the residue taken up in EtOAc and
washed with aqueous saturated NaHCO3, KHSO4 (1M) and brine. The
organic layer was dried on magnesium sulfate, filtered and evaporated to
afford the dipeptide 12 with 60 % yield as a yellow sticky solid. Rf = 0.24
(petroleum ether/ethyl acetate 4:1). Enantiomeric excess > 99 % was
determined using chiralcel AD-H, hexane/iPrOH (95:5), 0.8 mL.min-1, λ =
214 nm, 30°C, tR (S,R) = 28.1 min, tR (S,S) = 31.5 min. 1H NMR (400
6.94-6.88 (m, 5H, Harom), 6.83-6.77 (m, 5H, Harom), 6.23 (dt, JH,H
=
18.6, 6.1 Hz, 1H, -CH=), 5.83 (d, JH,H = 18.6 Hz, 1H, =CH-Si), 5.23-5.12
(m, 2H, O-CH2), 5.00 (d, JH,H = 7.7 Hz, 1H, NH), 4.37-4.28 (m, 1H, CHN),
2.21-2.15 (m, 1H, CH-Cα), 1.74-1.67 (m, 1H, CH-Cα), 1.44 (s, 9H,
(CH3)3), 0.94-0.88 (m, 2H, CH2-C=), 0.54 (s, 3H, CH3-Si). 13C{1H} NMR
(101 MHz, CDCl3) δ 172.5, 154.8, 140.3, 139.6, 138.9, 138.6, 135.4,
129.9, 129.8, 129, 128.9, 128.6, 128, 127.9, 127.5, 79.8, 67, 53.2, 31.5,
28.3, -6.0. 29Si{1H} NMR (99 MHz, CDCl3) δ -2.1 (s). HRMS calculated for
C47H48NO4Si+ [M+H]+ 718.3347 found 718.3346. UV-Vis (THF): λ (ε
L.mol-1.cm-1) = 290 (157100), 365 (14130) nm.
3
MHz, CDCl3) δ 7.15-6.77 (m, 20H, Harom), 6.52 (d, JH,H = 7.2 Hz, 1H,
NHamide), 4.74 (br. s, 1H, NHBoc), 4.61-4.48 (m, 2H, 2 x CHN), 3.72 (s,
3
3H, OCH3), 3.43-3.33 (m, 2H, CH2), 1.43 (d, JH,H = 5.2 Hz, 9H, (CH3)3),
1.26 (d, 3JH,H = 7.1 Hz, 3H, CH3), 0.97-0.83 (m, 2H, CH2-CH2-Si), 0.48 (s,
3H, CH3-Si). 13C{1H} NMR (101 MHz, CDCl3) δ 172.5, 155.2, 142.3,
142.1, 140.4, 139.9, 137.8, 137.7, 135.7, 135.6, 134.4, 128.4, 128.2,
128.1, 128.0, 127.9, 127.7, 126.3, 126.2, 125.9, 125.8, 125.4, 125.1,
124.4,124.3, 123.7, 38.90, 27.7, 21.9, 12.5. 29Si{1H} NMR (99 MHz,
CDCl3) δ -15.8 (s). FTIR (neat): ꢀ = 3000, 1582, 1506, 1436, 1334, 1211,
1025, 812, 748, 644 cm-1. HRMS calculated for C43H48N2O5Si [M+H]+
Methyl-(S)-2-amino-5-(1-methyl-2,3,4,5-tetraphenyl-1H-silol-1-
l)pentanoate 7: Silole amino ester 4 (50 mg, 0.08 mmol) was dissolved
in 0.6 mL of HCl (4M in dioxane). The mixture was stirred at room
temperature for 2 hours and the solvent evaporated under vacuum. The
residue was triturated in Et2O to afford the desired compound 7 in 95 %
yield. The crude product was used without further purification for peptide
coupling. LC-MS: tR = 2.36 min. ESI-MS: 530.3 [M+H]+, 548.2 [M+H3O]+
(λ = 214 nm).
701.3405 found 701.3403. UV-Vis (THF):
(23440) 354 (19900) nm.
λ = 286
(ε L.mol-1.cm-1)
(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(1-methyl-
2,3,4,5-tetraphenyl-1H-silol-1-yl)pentanoic acid 14: To a solution of
silole amino acid hydrochloride (100 mg, 0.19 mmol) in 1.5 mL of
aqueous sodium carbonate (10 %), was added Fmoc-Cl (88 mg, 0.38
mmol) in dioxane (1.5 mL) at 0°C. After 2 hours stirring, the reaction
mixture was diluted with H2O (3 mL) and extracted with Et2O (2 x 3 mL).
The aqueous layer was acidified with HCl (1N) to pH 2 and extracted with
AcOEt (3 x 3 mL). The combined organic layers were dried over MgSO4,
and evaporated under vacuo to afford the corresponding N-Fmoc silole
amino acid 14 as a yellow sticky solid in 60 % yield. 1H NMR (400 MHz,
(S)-2-((tert-butoxycarbonyl)amino)-5-(1-methyl-2,3,4,5-tetraphenyl-
1H-silol-1-yl)pentanoic acid 8: To a solution of silole amino ester 4 (30
mg, 0.05 mmol) in THF/MeOH (1:1, 500 µL) was added LiOH (4 mg, 0.1
mmol). The reaction mixture was stirred at room temperature for 2 hours
and the solvent was removed under vacuum. The residue was taken up
in water and extracted with Et2O. The aqueous layer was then acidified to
pH 3 to 4 with KHSO4 (1M) and extracted with EtOAc (3 x 5 mL). The
organic layer was dried over magnesium sulfate, filtered and evaporated
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10.1002/ejoc.201801869
European Journal of Organic Chemistry
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CDCl3) δ 7.49-7.44 (m, 4H, HFmoc), 7.30-7.25 (m, 4H, HFmoc), 7.16-7.01
(m, 15H, Harom), 6.78 (dd, JH,H = 8.2, 1.3 Hz, 5H, Harom).4.55-4.42 (m,
2H, O-CH2), 4.30 (dd, JH,H = 48.4, 7.8 Hz, 1H, CHFmoc), 3.73-3.57 (m, 1H,
Biol. 2017, 39, 32-38; d) T. Ueno, T. Nagano, Nature Methods 2011, 8,
642.
[2]
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a) M. Ptaszek, in Progress in Molecular Biology and Translational
Science, Vol. 113, Elsevier ed. (Ed.: M. C. Morris), Academic Press,
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Y. Urano, Chem. Rev. 2010, 110, 2620-2640.
CHN), 1.64-1.44 (m, 2H, CH2), 1.16-0.98 (m, 2H, CH2), 0.26 (dd, JH,H
=
15.0, 7.9 Hz, 2H, CH2), -0.12 (s, 3H, CH3, Si).13C{1H} NMR (101 MHz,
CDCl3) δ 174.5, 156.1, 154.9, 140.1, 139.4, 138.7, 138.5, 136.1, 135.8,
133.6, 130.0, 129.7, 129.4, 128.7, 128.5, 128.1, 127.9, 127.7, 127.4,
79.7, 67.1, 53.7, 31.4, 28.1, -5.4. 29Si{1H} NMR (99 MHz, CDCl3) δ -16.5
(s). FTIR (neat): ꢀ = 2988, 2912, 1656, 1593, 1484, 1442, 1248, 1018,
765, 700 cm-1. HRMS calculated for C49H44NO4Si [M+H]+ 738.3034 found
738.3031.
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Procedure for preparation of tripeptide 17
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Pathway A: A solution of N-Fmoc-protected silole amino acid 14 (30 mg,
40 µmol), HATU (16 mg, 44 µmol) and NEt3 (16 µL, 120 µmol) in DMF
(0.6 mL) was added to H-Ala-Wang resin 13 (40 mg, 1 mmol/g). The
mixture was stirred in a 5 mL syringe for 10 min, then washed with (2 x 3
mL) of DMF. Then the dipeptide 15 was deprotected with piperidine 20%
in DMF (3 x 1 mL) and washed with 3 mL of DMF. A solution of (L)-
Fmoc-Ala-OH (56 mg, 160 µmol), HATU (66 mg, 176 µmol) and NEt3 (67
µL, 480 µmol) in 0.6 mL of DMF was added to the previous deprotected
dipeptide. After 10 min stirring, the resin was washed with DMF (3 mL),
CH2Cl2 (3 mL) and the final cleavage from the resin was performed with 1
mL of TFA/TIS/H2O (95/2.5/2.5) for 30 min. The solution was
concentrated under vacuo and the residue was washed with Et2O (2 x 3
mL) to afford the tripeptide 17 in 60% overall yield.
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was added to H-Ala-Wang resin 13 (100 mg, 1 mmol/g). The mixture was
stirred in a 5mL syringe for 30 min, then washed with (2 x 3 mL) of DMF.
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mL) and washed with 3 mL of DMF. A solution of (L)-Fmoc-Ala-OH (124
mg, 0.4 mmol), HATU (152 mg, 0.44 mmol) and NEt3 (70 µL, 0.6 mmol)
in 2 mL of DMF was added to the previous deprotected dipeptide. After
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vial with tetraphenylsilole 3 (80 mg, 0.2 mmol), Karstedt’s catalyst (10 µL,
0.02 mmol) and dichloromethane (1.5 mL). The mixture was heated
under microwaves at 40°C for two hours. The final cleavage from the
resin was performed with 1 mL of TFA/TIS/H2O (95/2.5/2.5) for 30 min.
The solution was concentrated under vacuo and the residue was washed
with Et2O (2 x 3 mL) to afford the tripeptide 17 in 80 % overall yield.
29Si{1H} NMR (99 MHz, CDCl3) δ –12.3 (s). LCMS: tR = 1.52 min, [M+H]+
880.1, [M+H3O+] 898.4. HRMS for C55H53N3O6Si [M+H]+ calculated
880.3776 found 880.3774. UV-Vis (THF): λ (ε L mol-1 cm-1) = 289
(17100), 365 (15860) nm.
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Acknowledgments
The authors are grateful to the University of Montpellier, the
CNRS and the French Ministry of Research for financial support.
Authors thanks IKA for providing the amino acid alkyne 5. M.A.
thanks University of Montpellier for his PhD grant.
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Keywords: Silole • Amino acids • Hydrosilylation • Fluorescent
probe • Aggregation-Induced Emission
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AIEgens Silole amino acids *
M. Arribat, E. Rémond, S. Richeter, P.
Gerbier; S. Clément,* F. Cavelier*
Page No. – Page No.
Silole amino acids with Aggregation-
Induced Emission features
synthezised by hydrosilylation
reaction
Silole amino acids were obtained by hydrosilylation of unsaturated amino acids with
yield up to 95%. After selective deprotection, C- or N-peptide coupling was
performed in solution or on solid support. They exhibit AIE properties (λem ~500
nm; Δλ ~100 nm) and constitute a promising strategy for incorporation of AIE
fluorogens in peptides.
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