Synthesis and application of monodisperse oligo(oxyethylene)-grafted polystyrene resins for solid-phase organic synthesis

Article abstract of DOI:10.1021/co500028h

In a preliminary investigation by our group, we found that poly(styrene-oxyethylene) graft copolymers (PS-PEG), for example, TentaGel resins, are advantageous for gel-phase ¹³C NMR spectroscopy. Because of the solution-like environment provided

Full text of DOI:10.1021/co500028h

Research Article
pubs.acs.org/acscombsci
Synthesis and Application of Monodisperse Oligo(Oxyethylene)-
Grafted Polystyrene Resins for Solid-Phase Organic Synthesis
Daniel Lumpi, Christian Braunshier,* Ernst Horkel, Christian Hametner, and Johannes Frohlich
̈
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163, 1060 Vienna, Austria
S Supporting Information
*
ABSTRACT: In a preliminary investigation by our group, we found that
poly(styrene-oxyethylene) graft copolymers (PS-PEG), for example, TentaGel
resins, are advantageous for gel-phase 1 C NMR spectroscopy. Because of the
solution-like environment provided by the PS-PEG resins, good spectral
quality of the attached moiety can be achieved, which is useful for
nondestructive on-resin analysis. The general drawbacks of such resins are
low loading capacities and the intense signal in the spectra resulting from the
PEG linker (>50 units). Here, we describe the characterization of solvent-
dependent swelling and reaction kinetics on a new type of resin for solid-phase
organic synthesis (SPOS) that allows an accurate monitoring by gel-phase
NMR without the above disadvantages. A series of polystyrene-oligo-
3
(
2
oxyethylene) graft copolymers containing monodisperse PEG units (n =
−12) was synthesized. A strong correlation between the linker (PEG) length
1
3
and the line widths in the C gel-phase spectra was observed, with a grafted PEG chain of 8 units giving similar results in terms
of reactivity and gel-phase NMR monitoring to TentaGel resin. Multistep on-resin reaction sequences were performed to prove
the applicability of the resins in solid-phase organic synthesis.
KEYWORDS: PS-PEG resin, SPOS, gel-phase NMR spectroscopy, nondestructive on-resin analysis, on-resin reaction monitoring
INTRODUCTION
low degree of loading capacity (about 0.2−0.3 mmol/g),
compared to classical PS resin (e.g., Merrifield, 1−1.5 mmol/g),
and an intense signal in the gel-phase spectra resulting from the
■
For the synthesis of substance libraries, the use of combinatorial
chemistry techniques is nowadays state of the art. As a result of
the advantage of simplifying synthesis and product isolation,
polymer-supported approaches are widely applied, and there-
fore suitable for potential automation. Recent developments in
organic synthesis have established the applicability as a catalyst
carrier (e.g., cross-coupling chemistry) enabling practicable
13
long oxyethylene units. Moreover, the effect of variable linker
chain length on the efficiency of immobilized catalyst systems
17
has previously been demonstrated.
Our strategy relies on substituting the long PEG chains for
shorter monodisperse oligo(oxyethylene) tethers (n = 2−12
units) with the goal of increasing the loading and minimizing
the PEG signal in the gel-phase spectra. In our previous
publication, the design and synthetic access of these PS−PEG
1
−4
recycling of expensive compounds.
As a matter of fact, solid-phase organic synthesis (SPOS)
5
,6
plays a major role in combinatorial chemistry. The success of
any SPOS strategy strongly depends on the properties of the
applied resin. Cross-linked polystyrene resins (PS) were
initially used, with the disadvantage of limited swelling
properties in polar solvents, like methanol or water. To obtain
beads with a more universal swelling behavior, PS-based resins
have been modified with poly(ethylene glycol) (PEG) chains as
spacer (PS−PEG) or cross-linking units.
1
8
resins has been presented,
conducting a systematic
investigation focusing on the effects of the PEG group length
on the quality of gel-phase 13C NMR spectra. As a result, an
optimum PEG chain length in terms of NMR properties and
loading capacity has been determined. The objective of this
manuscript is to demonstrate the applicability of the PS−PEG
resins in SPOS compared to commercially available resins.
The contribution is divided into two subunits. First, an
extension of the investigation toward an efficient synthetic
route toward PS−PEG resins is described, including an
advanced analytical characterization (IR, gel-phase NMR,
combustion analysis, microscopy) of the obtained solid
supports. Second, examples of successful application in diverse
The PS−PEG supports (TentaGel), first reported by Bayer
7
and Rapp, show good swelling properties in a variety of
solvents from medium to high polarity. Furthermore, the resins
1
3
provide high quality C gel-phase NMR spectra, a convenient
8
−16
technique for nondestructive on-resin analysis.
The
copolymers are produced by grafting ethylene oxide to the
PS backbone, creating long flexible polydisperse chains (the
commercial resins TentaGel and ArgoGel bear about 60−70
PEG units) to provide a “solution-like” environment for
attached moieties. The main drawback of such resins is the
Received: February 20, 2014
Revised: June 5, 2014
Published: June 8, 2014
©
2014 American Chemical Society
367
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ACS Combinatorial Science
Research Article
multistep reaction sequences are outlined (Wang-linker syn-
thesis, palladium-catalyzed cross coupling, hydantoin syn-
thesis). The performance of the developed resins is compared
to commercially available supports (Wang resin, Reactagel,
TentaGel). Hence, this study reveals the advantageous
properties in terms of efficiency and reaction monitoring, as
well as the broad synthetic applicability of the designed resins
in the field of SPOS.
of a modular synthetic route based on monodisperse
oligo(ethylene glycols) and polymer-bound phenol, leading to
tailor-made resins for SPOS. Finally, we present a convenient
three-step synthesis: monoprotection of glycols, attachment to
solid-phase and deprotection. This synthetic approach as well
1
3
as the implications of the linker length for the C gel-phase
NMR spectroscopy have previously been reported by our
1
8
group. However, the full experimental details and a
characterization of the resins are given in this manuscript.
Glycols 1a−c (n = 2, 4, 6) are commercially available. Higher
homologues have been synthesized according to a recently
RESULTS AND DISCUSSION
■
Scheme 1 shows an overview of the synthesis of the resins 4a−
f. Application examples are presented in Scheme 2 and
subsequently discussed in detail.
19
published procedure. As shown in Scheme 1, the initial step
in the resin synthesis was the monoprotection of glycols 1a−f
(
n = 2, 4, 6, 8, 10, 12) by conversion with tert-butyldimethylsilyl
20
chloride (TBDMS-Cl). This protective group has been
proved to show the best performance in terms of stability
and cleavage behavior. By comparison, in the next reaction step
Scheme 1. Synthesis of the PS−PEG Resins 4a−f and
a
Attachment of Sensor Molecule
(
Mitsunobu reaction), trimethylsilyl was not suitable for
reasons of stability. Furthermore, the synthetic approach
toward mono-TMS-protected oligo(oxyethylene glycols) is
2
1
inconvenient (formation of azeotropic mixtures ). The
triphenylmethyl group was appropriate for Mitsunobu con-
ditions, but deprotection on solid-phase could not be
accomplished.
a
As a second step, protected glycols 2a−f were attached to
Reaction conditions: (i) pyridine/imidazole, TBDMS-Cl, DCM, 0 °C
22
polymer-bound phenol by applying Mitsunobu reactions. As a
result of this strategy, an aryl-alkyl linkage was formed, instead
of a benzylic ether PS-graft linkage (e.g., TentaGel), which is
known to be unstable in strongly acidic conditions.
→
rt, 24 h; (ii) DEAD, PS-phenol resin, P(C H ) , DCM/THF = 1/1,
6 5 3
rt, overnight; (iii) TBAF, THF, rt, overnight; (iv) 4-(dimethylamino)-
butanoic acid, hydrochloride, 1-hydroxybenzotriazole, DMAP, DIC,
DCM/DMF = 9/1, rt, 2 d.
Finally, for the deprotection, resins 3a−f were swollen in
THF and treated with a solution of TBAF in THF to give
monodisperse PEG-grafted resins 4a−f in quantitative yield as
Synthesis of the PS−PEG Resin (4a−f). Starting from
accessible reagents, the intention of our strategy was the design
a
Scheme 2. Application Examples 1−3
a
Reaction conditions: (i) 4-nitrophenyl-chloroformate, Et N, rt, 60 h; (ii) L-phenylalanine, BSA, DMAP, DMF, rt, 48 h; (iii) 1-hydroxybenzotriazole,
3
DIC, benzylamine, DMF, rt, overnight; (iv) 1,1,3,3-tetramethylguanidine, MeOH, reflux, 24 h; (v) 4-iodobenzoic acid, 1-hydroxybenzotriazole,
DMAP, DIC, DCM/DMF = 9/1, rt, overnight; (vi) methylmethacrylate, P(C H ) , tetra-n-butylammoniumchloride, Pd(OAc) , DMF/H O/NEt ,
6
5
3
2
2
3
4
0 °C, overnight; (vii) SOCl , toluene, 75 °C, overnight; (viii) 4-hydroxybenzyl alcohol, NaH, DMF, 75 °C, overnight, (ix) 4-
2
(
dimethylamino)butanoic acid, hydrochloride, 1-hydroxybenzotriazole, DMAP, DIC, DCM/DMF = 9/1, r.t., 2 d.
3
68
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Figure 1. Reaction monitoring on solid-phase of resins 3d−5d via 13C gel-phase NMR and FT-IR spectroscopy. For a detailed view of the NMR
spectra see associated content.
determined by 13C gel-phase NMR spectroscopy (Figure 1).
been demonstrated to be excellent. As a result, resin 4d with
eight ethylene glycol units has shown the best performance in
terms of loading capacity combined with spectral quality. The
surface morphology and spherical behavior of the developed
resins was investigated by polarized optical microscopy and
scanning electron microscopy (SEM). The images demonstrate
homogeneous and spherical properties of the beads; in
addition, the good swelling properties in chloroform are clearly
visible (Figure 2).
18
For a systematic investigation of the effect of the PEG group
1
3
length on the quality of gel-phase C NMR spectra, a sensor
molecule (4-(dimethylamino)-butanoic acid, hydrochloride)
18
was attached and resulted in resins 5a−f. The sensor
molecule was attached to the resins’ hydroxyl groups using a
23
carbodiimide-based coupling method.
Figure 1 shows the reaction monitoring of each synthetic
step on solid-phase (3d−5d), applying two different analytical
1
3
techniques (FT-IR and C gel-phase NMR spectroscopy).
Allowing a precise determination of the reaction progress,
NMR spectroscopy has proved to be superior. For instance, the
deprotection of 3d can be clearly monitored via the signals
from the TBDMS-group (3 signals in the region <30 ppm).
The formation of NMR signals, particularly in the region of
Application Examples of Monodisperse PS−PEG
Resin. In the next step, we intended to demonstrate the
applicability of the presented resins to SPOS. Complex
multistep syntheses require a solid support that performs in
both polar and nonpolar solvents. This was the major selection
criterion of our on-resin sequence examples. To evaluate the
resin performance, we induced the identical reaction sequences
on commercially available resins (Wang, TentaGel).
In application example 1, the developed resin 4d (PEG 8
spacer) was compared to a commercially available resin
TentaGel) in a multistep synthesis involving various reactants,
solvents and conditions. For this purpose, a published synthetic
1
5−35 ppm, allows to examine the attachment of the sensor
molecule toward 5d. By comparison, a significant difference in
the FT-IR spectra is the CO peak in the range of 1700 cm
corresponding to the ester in substance 5d.
−1
As shown in preliminary research, swelling properties,
loading (Table 1) and gel-phase NMR characteristics have
(
24
route toward hydantoin 14 was chosen.
Table 1. Swelling Volume [mL/g] of Selected Resins at 25
Figure 3 shows the corresponding 13C gel-phase NMR
°
C in Different Solvents (Data Extracted from Preliminary
Research)
spectra. Because polar solvents are involved in the sequence,
TentaGel, which shows a chemically comparable spacer
structure, was used as a reference resin. The synthesis was
performed by starting from identical amounts of the respective
resin leading to 14 mg (TentaGel) and 44 mg (resin 4d)
substance 14. This result, a more than 3-fold amount of isolated
hydantoin 14, impressively reveals the effect of higher loading
of the resin due to a shorter spacer unit. Thus, a substantially
lower amount of resin 4d is needed to obtain an intended
quantity of a target substance. After the reaction, the recovered
18
entry
resin
loading [mmol/g] MeOH DMF THF DCM
1
2
3
4
5
Merrifield
4b (n = 4)
4d (n = 8)
4f (n = 12)
TentaGel
1.5
1.1
0.9
0.7
0.3
0.7
1.5
2.1
2.1
2.7
4.3
6.8
6.7
6.0
4.1
7.5
8.5
7.1
7.3
4.2
7.3
7.8
8.0
8.6
5.7
Figure 2. Microscopy images of resin 4d. SEM image (left); polarized optical microscopy image of 4d, dry (middle) and swollen in chloroform
right).
(
3
69
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Figure 3. On-resin reaction monitoring of the hydantoin route (application example 1).
beads feature 13C gel-phase NMR spectra comparable to the
starting material, which is an important factor for resin
recycling. Both higher loading and the possibility of recycling
are essential for efficient industrial scale syntheses.
resins 13a and 13b were determined as 24.4 and 19.2 Hz,
respectively, which is a clear improvement relative to Wang.
The above-mentioned sensor was chosen for the present
work due to its high polarity, which makes it a very demanding
sensor for attachment and gel-phase NMR. The polarity of the
sensor is a key criterion for the achievable quality of the gel-
phase spectrum on a given resin. Highly polar sensor molecules
(like the (4-(dimethylamino)butanoic acid, hydrochloride) can
only be measured in good quality if bound to a solid-phase via a
suitable PEG linker: no signals were obtained for these
molecules on Merrifield resin. The acid was bound to the
hydroxyl groups of the resins as described before (carbodiimide
method); quantitative conversions for each step could be
observed.
Application example 2 points out the applicability in
2
5
heterogenic catalytic systems (Heck coupling ). After
conversion of resin 4b,d,f with 4-iodobenzoic acid, the
palladium catalyzed cross-coupling step (methacrylate as
coupling reagent) was performed. The evaluation of the 13
C
gel-phase NMR spectra showed an increased conversion by
applying extended length of the PEG tether, which is supported
by the swelling behavior (low conversion for 9b (n = 4), good
result for 9d (n = 8), quantitative conversion for 9f (n = 12)).
In comparison with the result obtained from TentaGel, cross
coupling of resin 9f yielded the same performance (similar
reaction progress as determined by gel-phase NMR spectros-
copy), with the advantage of higher loading and improved on-
resin analysis.
13
CONCLUSION
■
In conclusion, we have shown that polystyrene resins grafted
with short, monodisperse PEG units (n = 2−12) can easily be
synthesized in a modular synthetic route from polymer-bound
phenol by Mitsunobu coupling. The resulting solid supports
offer advantageous properties for gel-phase NMR spectroscopy
and are excellent resins for SPOS. In order to prove the
applicability, three reaction sequences on solid-phase have been
performed (Wang-linker synthesis, palladium catalyzed cross
coupling, hydantoin synthesis). Compared to commercially
available PS−PEG resins, our support offers equal swelling
properties in polar and apolar solvents, better on-resin analytic
properties and significantly higher loading, thus being a suitable
choice for industrial application. This approach to tailor-made
resins enables the adjustment of the resin properties by a
proper linker selection depending on the respective field of
application.
In application example 3 (Scheme 2), an end-group
26
modification to a Wang-Linker system (conversion using
thionyl chloride and 4-hydroxybenzyl alcohol) was performed
to achieve resin 12a−b. The goal was to investigate the stability
of our PEG linker in harsh reaction conditions (thionyl
chloride) and to allow a comparison with commercially
available Wang and TentaGel resins. The attachment of the
Wang linker enables the application of the developed PS−PEG
resins in the field of peptide synthesis as a result of mild
cleavage conditions for the target peptides. Subsequently, the
attachment of a sensor molecule (4-(dimethylamino)butanoic
acid, hydrochloride) to obtain resin 13a−b enabled the
comparison of the characteristics of gel-phase NMR spectros-
copy of 13a−b with commercially available beads (the
functionalization of the reference beads with the sensor has
13
EXPERIMENTAL PROCEDURES
been previously described ). To characterize each spectrum by
a single value, an average half-height line width of all
nonquaternary carbon peaks of the immobilized sensor
molecule was determined. Small values correspond to high-
quality spectra, resulting in a better line shape. The values for
the commercially available resins are 28.4 Hz for Wang and 7.3
■
All reactions were conducted under an atmosphere of argon in
oven-dried glassware with magnetic stirring. Unless otherwise
stated, reagents were purchased from commercial sources and
purified in the usual manner. DEAD (diethyl azodicarboxylate),
4-(dimethylamino)butanoic acid, hydrochloride, hexa(ethylene
glycol) and TBDMS-Cl (tert-butylchlorodimethylsilane) were
1
3
Hz for TentaGel. By comparison, the half-hight line widths of
3
70
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purchased from Aldrich and used without prior purification.
Di(ethylene glycol) 1a and tetra(ethylene glycol) 1b were
obtained from Merck and used as purchased. Oligo(ethylene
(s), −5.3 (q) ppm. Anal. Calcd for C H O Si: C, 54.52; H,
2
2
48
9
9.98. Found: C, 54.48; H, 9.72; N, <0.05.
2,2,3,3-Tetramethyl-4,7,10,13,16,19,22,25,28,31-decaoxa-
3-silatritriacontane-33-ol 2e. According to the general
procedure, deca(ethylene glycol) (5.60 g, 12.2 mmol, 1.0
equiv), imidazole (0.82 g, 12.0 mmol, 1.0 equiv), TBDMS-Cl
(1.81 g, 12.0 mmol, 1.0 equiv), and ∼100 mL of anhydrous
DCM were used. Column chromatography: 200 g of silica gel,
1
9
glycols) 1c−f (n = 6, 8, 10, 12) and mono-TBDMS protected
2
0
glycols 2a−c were prepared in analogy to literature.
The resins used were as follows: polymer-bound phenol (1.7
mmol/g, 1% divinylbenzene, 100−200 mesh) was purchased
from Aldrich; TentaGel resin (0.3 mmol/g, 1% divinylbenzene,
80−100 μm), and Reactagel-OH resin (0.7 mmol/g, 1%
gradient elution using CHCl /MeOH = 25/1 → CHCl /
3
3
MeOH = 5/1 → CHCl /MeOH = 4/1. Compound 2e was
divinylbenzene, 100−200 mesh) were purchased from
Advanced ChemTech. All resins were dried prior to usage.
Anhydrous DMF was purchased from Acros. Tetrahydrofur-
an was dried over and distilled from sodium/benzophenone
ketyl. Dichloromethane was dried over and distilled from CaH2.
Technical grade solvents were distilled prior to usage. Analytical
TLC was performed on Merck silica gel 60 F254 plates.
Chromatographic separations at preparative scale were carried
out on silica gel (Merck silica gel 60, 40−63 um).
3
1
obtained as colorless oil (2.19 g, 32%). H NMR (200 MHz,
CDCl ): δ = 3.75−3.43 (m, 40H), 1.91 (bs, 1H), 0.83 (s, 9H),
3
13
0
7
.00 (s, 6H) ppm. C NMR (50 MHz, CDCl ): δ = 72.6 (t),
3
0.7 (t), 70.5 (t), 70.2 (t), 62.6 (t), 61.6 (t), 25.9 (q), 18.3 (s),
−
5.3 (q) ppm. Anal. Calcd for C H O Si: C, 54.52; H, 9.85.
26 56 11
Found: C, 54.59; H, 9.70; N, <0.05.
,2,3,3-Tetramethyl-4,7,10,13,16,19,22,25,28,31,34,37-do-
2
decaoxa-3-silanonatriacontane-39-ol 2f. According to the
general procedure, dodeca(ethylene glycol) (9.83 g, 18.0 mmol,
Nuclear magnetic resonance (NMR) spectra were obtained
using a Bruker DPX-200 or Avance DRX-400 Fourier transform
spectrometer operating at the following frequencies: DPX-
1
.2 equiv), anhydrous pyridine (1.50 g, 19.0 mmol, 1.3 equiv),
TBDMS-Cl (2.26 g, 15.0 mmol, 1.0 equiv), and ∼50 mL of
anhydrous DCM were used. Column chromatography: 400 g of
1
13
2
00:200.1 MHz ( H) and 50.3 MHz ( C); DRX-400:400.1
1
13
13
silica gel, gradient elution using CHCl /MeOH = 30/1 →
3
MHz ( H) and 100.6 MHz ( C). All C gel-phase spectra
were performed at the Avance DRX-400 spectrometer.
Chemical shifts are reported in delta (δ) units, parts per
million (ppm) downfield from tetramethylsilane using solvent
residual signals for calibration. Coupling constants are reported
in Hertz (Hz); multiplicity of signals is indicated by using
following abbreviations: s = singlet, d = doublet, t = triplet, q =
CHCl /MeOH = 20/1. Pure compound 2f was obtained as a
3
1
colorless oil (4.36 g, 44%). H NMR (200 MHz, CDCl ): δ =
3
3
.74−3.44 (m, 48H), 2.13 (bs, 1H), 0.83 (s, 9H), 0.00 (s, 6H)
13
ppm. C NMR (50 MHz, CDCl ): δ = 72.6 (t), 72.5 (t), 70.7
3
(
(
t), 70.5 (t), 70.3 (t), 62.7 (t), 61.7 (t), 25.9 (q), 18.3 (s), −5.3
q) ppm. Anal. Calcd for C H O Si: C, 54.52; H, 9.76;
30
64 13
1
3
Found: C, 54.10; H, 9.47; N, <0.05.
General Procedure for Mitsunobu Reaction on Solid-
Phase. DEAD (5.0 equiv) was added dropwise to a mixture of
quartet, b = broad. Multiplicities of C signals were obtained
by measuring JMOD spectra. Significant peaks corresponding
to compounds attached to solid-phase are indicated in the
NMR code. IR spectra were recorded on a BioRad FTS 135
FT-IR spectrometer from KBr pellets or using the ATR
technique. Elemental analyses were carried out at the
Microanalytical Laboratory, University of Vienna.
1
.0 equiv of polymer-bound phenol (100−200 mesh, 1%
divinylbenzene, Aldrich, 1.7 mmol/g) in dry DCM/THF = 1/1
50 mL/g resin) under argon. In the next step, the
(
corresponding monoprotected glycols 2a−f (5.0 equiv),
dissolved in dry THF, and finally triphenylphosphine were
added slowly. The reaction mixture was stirred overnight and
filtered, and the solid residue was washed 3 times with DCM/
THF = 1/1, DCM, isopropanol, DCM, and finally with
methanol. The resulting resin 3a−f was dried to constant
weight in vacuo. To complete the conversion, the whole
procedure was repeated.
PS-PEG(2)-O-TBDMS 3a. Starting from 999.8 mg (1.70
mmol) of polymer-bound phenol, we isolated 1.2069 g of
yellow resin.
PS-PEG(4)-O-TBDMS 3b. Starting from 1.1413 g (1.94
mmol) of polymer-bound phenol, we isolated 1.5156 g of
yellow resin.
PS-PEG(6)-O-TBDMS 3c. Starting from 513 mg (0.87 mmol)
of polymer-bound phenol, we isolated 733 mg of pink resin.
PS-PEG(8)-O-TBDMS 3d. Starting from 1.5750 g (2.68
mmol) of polymer-bound phenol, we isolated 2.3409 g of pink
resin.
PS-PEG(10)-O-TBDMS 3e. Starting from 354.5 mg (0.60
mmol) of polymer-bound phenol, we isolated 517.0 mg of pink
resin.
Synthesis of TBDMS-Protected Glycols. General
Procedure. A solution of glycol 1a−f in anhydrous DCM was
cooled to 0 °C and the base (imidazole or anhydrous pyridine)
was added slowly. The solution was stirred for 5 min before a
solution of TBDMS-Cl in anhydrous DCM was added
dropwise. The reaction mixture was stirred at 0 °C for 1 h,
and after it was warmed to room temperature, it was stirred for
an additional 24 h. Water was added to the formed suspension,
and after phase separation, the organic layer was consecutively
washed with 10% aqueous HCl, saturated NaHCO solution
3
and brine. After it was dried over MgSO , the solvent was
4
distilled off under reduced pressure to give the crude product,
which was subjected to column chromatography for further
purification leading to monoprotected glycols 2a−f.
2
,2,3,3-Tetramethyl-4,7,10,13,16,19,22,25-octaoxa-3-sila-
heptacosane-27-ol 2d. According to the general procedure,
octa(ethylene glycol) (19.20 g, 51.8 mmol, 1.7 eqiv.), imidazole
(
2.13 g, 31.3 mmol, 1.0 eqiv.), TBDMS-Cl (4.69 g, 31.1 mmol,
1
.0 eqiv.), and ∼70 mL of anhydrous DCM were used. Column
chromatography: 400 g of silica gel, gradient elution using
hexanes/ethyl acetate = 1/5 → ethyl acetate → ethyl acetate/
PS-PEG(12)-O-TBDMS 3f. Starting from 584.1 mg (0.99
mmol) of polymer-bound phenol, we isolated 857.6 mg of
yellow resin.
MeOH = 4/1. The title compound 2d was obtained as slightly
1
yellow oil (6.92 g, 46%). H NMR (200 MHz, CDCl ): δ =
3
3
.80−3.45 (m, 32H), 2.80 (bs, 1H), 0.87 (s, 9H), 0.04 (s, 6H)
General Procedure for the Deprotection of TBDMS
Group on Solid-Phase. Resins 3a−f were suspended in 30
mL/g dry THF under argon. Then 5.0 equiv of 1.0 M
13
ppm. C NMR (50 MHz, CDCl ): δ = 72.6 (t), 72.5 (t), 70.7
3
(
t), 70.6 (t), 70.5 (t), 70.3 (t), 62.7 (t), 61.7 (t), 25.9 (q), 18.3
3
71
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tetrabutylammonium fluoride (TBAF) solution in dry THF
were added dropwise. The reaction suspension, forming a
brown mixture within 1 h, was stirred overnight at room
temperature. Subsequently, the reaction mixture was filtered,
and the solid residue was washed 3 times with THF, THF/
water, THF, methanol/water, DCM, and finally with methanol.
Proper washing is important to get rid of liberated substances.
The resulting resin 4a−f was dried to constant weight in vacuo
PS-PEG(6)-4-(dimethylamino)butanoic Acid, Hydrochlor-
ide 5c. 4c (140.7 mg, 0.27 mmol) resulted in yellow resin 5c
13
(159.8 mg). C gel-phase NMR (100 MHz, CDCl ): δ = 172.2
3
(s), 63.9 (t), 57.1 (t), 43.1 (q), 30.9 (t), 20.0 (t) ppm.
PS-PEG(8)-4-(dimethylamino)butanoic Acid, Hydrochlor-
ide 5d. 4d (193.0 mg, 0.18 mmol) resulted in yellow resin 5d
13
(222.3 mg). C gel-phase NMR (100 MHz, CDCl ): δ = 172.0
3
(s), 63.9 (t), 56.9 (t), 42.9 (q), 30.8 (t), 19.7 (t) ppm.
PS-PEG(10)-4-(dimethylamino)butanoic Acid, Hydrochlor-
ide 5e. 4e (198.0 mg, 0.12 mmol) resulted in yellow resin 5e
(
50 °C).
PS-PEG(2)-OH 4a. Resin 3a (245.6 mg, 0.26 mmol) resulted
in yellow resin 4a (217.1 mg, 1.1 mmol/g). Anal. Found: C,
13
(
(
219.2 mg). C gel-phase NMR (100 MHz, CDCl ): δ = 172.2
3
s), 63.9 (t), 57.2 (t), 43.1 (q), 30.9 (t), 20.0 (t) ppm.
PS-PEG(12)-4-(dimethylamino)butanoic Acid, Hydrochlor-
8
1
1
4.10; H, 7.58; N, <0.05. FT-IR (KBr): 3449, 3024, 2913, 2850,
944, 1872, 1803, 1748, 1601, 1509, 1450, 1354, 1238, 1127,
054, 1027, 906, 827, 754, 696 cm .
−1
ide 5f. 4f (228.8 mg, 0.16 mmol) resulted in yellow resin 5f
13
(
(
261.8 mg). C gel-phase NMR (100 MHz, CDCl ): δ = 172.2
PS-PEG(4)-OH 4b. Resin 3b (924.5 mg, 0.89 mmol) resulted
in yellow resin 4b (820.4 mg, 1.1 mmol/g). Anal. Found: C,
3
s), 63.9 (t), 57.0 (t), 43.1 (q), 30.9 (t), 19.9 (t) ppm.
Application Example 1 (Hydantoin Synthesis). The
8
1
1
2.41; H, 7.88; N, <0.05. FT-IR (KBr): 3460, 3025, 2916, 1945,
876, 1805, 1747, 1602, 1510, 1493, 1452, 1349, 1244, 1108,
064, 1028, 907, 828, 757, 697 cm .
synthetic steps toward hydantoin 14 were accomplished
24
−1
following published procedures. All synthetic steps are in
accordance with the literature, modifications concerning
reaction time and reactant amounts are noted.
PS-PEG(6)-OH 4c. Resin 3c (318.2 mg, 0.27 mmol) resulted
in yellow resin 4c (283.9 mg, 1.0 mmol/g). Anal. Found: C,
Activation of the Solid Support. Resin 4d or TentaGel S
PHB (0.2 mmol/g), respectively, were activated in the presence
8
1
9
0.20; H, 7.90; N, <0.05. FT-IR (KBr): 3449, 3026, 2917, 1945,
877, 1805, 1744, 1720, 1602, 1509, 1452, 1350, 1244, 1100,
43, 828, 757, 697 cm .
−1
of a 10-fold excess of 4-nitrophenyl chloroformate and Et N
3
(
5.0 equiv) at a reaction time of 60 h.
PS-PEG(8)-OH 4d. Resin 3d (361.5 mg, 0.25 mmol) resulted
in yellow resin 4d (327.0 mg, 0.9 mmol/g). Anal. Found: C,
Polymer-Bound 4-Nitrophenylcarbonates. Resin 4d (1.340
g) led to a white resin 6d (1.450 g). 13C gel-phase NMR (100
7
1
7
8.41; H, 7.95; N, <0.05. FT-IR (KBr): 3480, 3026, 2921, 1947,
878, 1808, 1747, 1602, 1511, 1452, 1349, 1098, 943, 908, 827,
57, 695 cm .
MHz, CDCl ): δ = 155.4 (s, ArC−O), 152.4 (s, CO), 145.3
3
−1
(ArC−NO ), 125.2 (d, ArC−H), 121.7 (d, ArC−H) ppm.
2
TentaGel S PHB resin (1.127 g) resulted in slightly yellow
PS-PEG(10)-OH 4e. Resin 3e (347.0 mg, 0.19 mmol)
resulted in slightly brown resin 4e (343.6 mg, 0.8 mmol/g).
Anal. Found: C, 80.32; H, 7.96; N, <0.05. FT-IR (KBr): 3480,
resin 6g (1.180 g). 13C gel-phase NMR (100 MHz, CDCl ): δ
3
=
155.2, 152.1, 145.0, 124.9, 121.5 ppm.
Attachment of the Amino Acid. The respective resins 6d
and 6g were treated with a solution of L-phenylalanine (4.0
equiv) in BSA (4.0 equiv) and DMF, followed by the addition
of DMAP (2.0 equiv) and stirred for a reaction time of 48 h.
3
1
025, 2915, 1946, 1877, 1805, 1747, 1602, 1509, 1493, 1349,
243, 1099, 944, 828, 757, 697 cm .
−1
PS-PEG(12)-OH 4f. Resin 3f (728.8 mg, 0.44 mmol) resulted
in yellow resin 4f (327.0 mg, 0.7 mmol/g). Anal. Found: C,
Polymer-Bound N-Carboxy-L-phenylalanin. PS-PEG Resin
7
1
8
6.30; H, 8.06; N, <0.05. FT-IR (KBr): 3505, 3026, 2919, 1945,
874, 1804, 1734, 1602, 1453, 1350, 1289, 1251, 1104, 948,
41, 758, 698 cm .
13
6
d (1.141 g, 0.52 mmol) led to a white resin 7d (1.155 g). C
gel-phase NMR (100 MHz, CDCl ): δ = 173.4 (s, OC−
−1
3
OH), 155.3 (s, CO), 136.1 (ArC-CH ), 129.3 (d, ArC−H),
2
General Procedure for Attachment of Sensor Mole-
cule to Solid Support. Resins 4a−f were suspended in dry
DCM/DMF = 9/1 (15 mL/g resin), and then 4-
1
(
28.4 (d, ArC−H), 126.9 (d, ArC−H) ppm. TentaGel resin 6g
13
350 mg, 0.07 mmol) resulted in yellow resin 7g (341 mg). C
gel-phase NMR (100 MHz, CDCl ): δ = 172.9, 155.8, 136.2,
3
(
1
dimethylamino)butanoic acid, hydrochloride (5.0 equiv), and
-hydroxybenzotriazole (5.0 equiv) were added in a minimum
1
29.4, 129.2, 126.4 ppm.
Addition of the Amine. Resins 7d and 7g were suspended in
amount of dry DMF. 4-(N,N-Dimethylamino)pyridine (1.0
equiv) in dry DMF and N,N′-diisopropylcarbodiimide (5.0
equiv) were added to the mixture and stirred under argon at
room temperature for 2 days. The resulting suspension was
filtered and the solid residue was washed 3 times with DMF,
then with DCM, and finally with methanol. The resin was dried
to constant weight in vacuo.
DMF; dissolved 1-hydroxybenzotriazole (4.0 equiv) was added,
and subsequently, DIC (4.0 equiv) was transferred to the vessel
dropwise. Then, the mixture was stirred for 1 h. Finally,
benzylamine (4.0 equiv) was added, and the reaction was
allowed to proceed overnight. After the filtration of the resin,
the procedure was repeated to ensure full conversion.
Polymer-Bound N-Carboxy-L-phenylalanin-benzylamide.
PS-PEG(2)-4-(dimethylamino)butanoic Acid, Hydrochlor-
Bead 7d (930 mg, 0.43 mmol) resulted in beige resin 8d
(
935 mg). 13C gel-phase NMR (100 MHz, CDCl ): δ = 170.7
3
ide 5a. 4a (165.7 mg, 1.01 mmol) resulted in yellow resin 5a
1
3
(
(
4
194.0 mg). C gel-phase NMR (100 MHz, CDCl ): δ = 172.1
(s, OC−NR), 155.9 (s, CO), 137.6 (ArC−CH ), 136.4 (s,
3
2
s, O−CO), 63.9 (t, CH −O−CO), 57.0 (t, CH −N),
ArC−CH ) ppm. Starting from resin 7g (984 mg, 0.17 mmol)
2
2
2
13
3.0 (q, N−CH ), 30.8 (t, CH −CO), 19.8 (t, CH −CH −
yellow resin 8g (854 mg) was achieved. C gel-phase NMR
3
2
2
2
CH ) ppm; assignment of the signals was supported by 2D-
(100 MHz, CDCl ): δ = 170.4, 155.6, 137.5, 136.2 ppm.
2
3
NMR experiments.
PS-PEG(4)-4-(dimethylamino)butanoic Acid, Hydrochlor-
Release of the Hydantoin. The cleavage of hydantion 14
was realized by reaction of 1,1,3,3-tetramethylguanidine (2.0
equiv) in MeOH with bead 8d (507 mg) and resin 8g (503
mg), respectively. The reaction was allowed to proceed at reflux
(65 °C) for 24 h (to complete the cleavage for 8d the reaction
ide 5b. 4b (302.2 mg, 0.89 mmol) resulted in yellow resin 5b
1
3
(
(
358.9 mg). C gel-phase NMR (100 MHz, CDCl ): δ = 172.1
3
s), 63.9 (t), 57.0 (t), 43.1 (q), 30.9 (t), 19.9 (t) ppm.
3
72
dx.doi.org/10.1021/co500028h | ACS Comb. Sci. 2014, 16, 367−374

ACS Combinatorial Science
Research Article
was repeated at reflux overnight). After work-up, 4d and
120.1, 51.8 ppm. Beads 9f (187 mg) resulted in 191 mg of gray
1
3
13
TentaGel resin could be recovered showing C gel-phase
spectra comparable to the starting resin. The filtrates were
concentrated in vacuo and purified by column chromatography
resin 10f. C gel-phase NMR (100 MHz, CDCl ): δ = 166.9,
3
165.8, 143.4, 138.6, 120.1, 51.8 ppm. Starting from Reactagel-
based 9g (291 mg), we could isolate 272 mg of 10g as back
beads. 13C gel-phase NMR (100 MHz, CDCl ): δ = 166.7,
(
4.5 g silica gel, diethyl ether) leading to 44 mg of 14 starting
3
from resin 8d and 14 mg of hydantoin 14 applying TentaGel-
165.6, 143.2, 138.4, 120.0, 51.7 ppm.
based resin 8g.
Application Example 3 (Wang Linker Attachment).
General Procedure for the Chlorination of PS−PEG Resins.
Beads 4a−b were suspended in anhydrous toluene. Thionyl
chloride (7.0 equiv) was added, and the reaction mixture was
stirred overnight at 75 °C. After it was cooled to 55 °C, the
resin was filtered and washed with warm toluene (5×) and
methanol (3×). The polymer-bound poly(ethylene glycol)
derivatives 11a−b were dried to constant weight in vacuo.
Chlorinated PS-PEG-Bound Linker. Resin 4a (1.648 g) in 20
3,5-Bis(phenylmethyl)-2,4-imidazolidinedione 14. 14 was
1
obtained as white solid. H NMR (400 MHz, CDCl ): δ =
3
7
.35−6.95 (m, 10H), 5.44 (bs, 1H), 4.62−4.43 (m, 2H), 4.18
(
ddd, J = 8.5 Hz, 3.8 Hz, 1.2 Hz, 1H), 3.19 (dd, J = 14.0 Hz, 3.8
13
Hz, 1H), 2.78 (dd, J = 14.0 Hz, 8.5 Hz, 1H) ppm. C NMR
(
(
100 MHz, CDCl ): δ = 172.8 (s), 157.0 (s), 135.7 (s), 134.9
s), 129.3 (d, 2C), 128.8 (d, 2C), 128.6 (d, 2C), 128.2 (d, 2C),
3
127.7 (d), 127.3 (d), 58.3 (d), 42.0 (t), 37.6 (t) ppm. Anal.
1
3
Calcd for C H N O : C, 72.84; H, 5.75; N, 9.99. Found: C,
mL anhydrous toluene yielded in 0.787 g white resin 11a.
C
17
16
2
2
7
2.62; H, 5.48; N, 9.71.
Application Example 2 (Heck-Coupling Route). Load-
gel-phase NMR (100 MHz, CDCl ): δ = 71.5 (t), 69.9 (t), 67.4
3
(t), 42.7 (t, C-Cl) ppm. PS-PEG beads 4b (0.904 g, 1.36 mmol)
ing of the Resins with 4-Iodobenzoic Acid. Resin 4b,d,f and
Reactagel (0.7 mmol/g) were stirred in a mixture DCM/DMF
in 20 mL of anhydrous toluene resulted in 0.873 g of white
resin 11b. 13C gel-phase NMR (100 MHz, CDCl ): δ = 71.3
3
(
9/1) for 15 min to ensure sufficient swelling. 4-Iodobenzoic
(t), 70.8 (t), 69.8 (t), 67.2 (t), 42.7 (t) ppm.
acid (5.0 equiv) and 1-hydroxybenzotriazole (5.0 equiv)
dissolved in DMF, as well as DIC (5.0 equiv), were added to
the resin. Finally DMAP (1.0 equiv) was transferred to the
reaction vessel and the mixture was stirred overnight at room
temperature under argon. The work-up of the beads was in
accordance with the procedure reported in the literature;
because of incomplete loading of resins 9d and 9f (determined
by 13C gel-phase NMR spectra), the reaction sequence was
repeated applying a 0.2-fold amount of all reactants compared
to the first loading step.
Addition of the Wang Linker. General Procedure. Sodium
hydride (5.0 equiv) was added to a solution of 4-hydroxybenzyl
alcohol (5.0 equiv) in anhydrous DMF. After it was stirred for
30 min at room temperature, resins 11a−b were added to the
reaction mixture. The suspension was heated to 75 °C and
stirred overnight at this temperature. The resin was filtered off
and washed twice with each of the following solvents: DMF,
DMF/H O, THF/H O, MeOH/H O, MeOH, alternating
2
2
2
DCM, and MeOH. The isolated resin was dried to constant
weight in vacuo overnight.
Polymer-Bound 4-Iodobenzoic Acid. Starting from resin 4b
610 mg), we could isolate 691 mg of 9b as a yellowish resin.
PS-PEG-Bound Wang Linker. Resin 11a (0.516 g, 0.538
mmol) in 25 mL of anhydrous DMF resulted in 0.549 g of
(
1
3
13
C gel-phase NMR (100 MHz, CDCl ): δ 166.0 (s, OC−
3
brown resin 12a. C gel-phase NMR (100 MHz, CDCl ): δ =
3
OR), 137.6 (d, ArC−H), 131.1 (d, ArC−H), 129.5 (s, ArC−
CO), 100.8 (s, ArC−I). Resin 4d (292 mg) led to 330 mg of
slightly yellow beads 9d after a second loading step. 13C gel-
128.5 (d, ArC−H), 114.6 (d, ArC−H), 69.9 (t), 67.4 (t, CH −
2
O−Ar), 64.8 (t, CH −OH) ppm. Starting from 11b (0.574 g,
2
0.599 mmol) in 25 mL of anhydrous DMF, we could isolated
0.621 g of brown resin 12b. 13C gel-phase NMR (100 MHz,
phase NMR (100 MHz, CDCl ): δ 165.9, 137.6, 131.1, 129.5,
3
1
00.8. 4f (210 mg) overall resulted in 244 mg of white resin 9f.
CDCl ): δ = 128.5 (d), 114.6 (d), 70.6 (t), 69.6 (t), 67.3 (t),
3
1
3
C gel-phase NMR (100 MHz, CDCl ): δ = 165.9, 137.6,
64.7 (t) ppm.
3
1
31.1, 129.5, 100.7 ppm. Starting from Reactagel (1.138 g), we
Attachment of Sensor Molecule to the Wang Linker. The
reaction was carried out analogous to the general procedure of
the sensor attachment, except for stirring the reaction mixture
overnight.
1
3
could obtain 1.175 mg of white resin 9g. C gel-phase NMR
(
100 MHz, CDCl ): δ = 165.8, 137.5, 131.0, 129.4, 100.7 ppm.
3
Heck-Coupling Reactions. The different resins (9b,d,f and
loaded Reactagel 9g) were swollen in a mixture of DMF/H O/
PS-PEG-Bound Sensor 4-(Dimethylamino)butanoic Acid,
Hydrochloride. Beads 12a (0.196 g, 0.193 mmol) in 7 mL of
solvent yielded 0.217 g of brown polymer 13a. C gel-phase
2
NEt3 over a period of 15 min. Subsequently, methyl
methacrylate (2.0 equiv), triphenylphosphine (0.4 equiv),
tetra-n-butylammonium chloride (0.4 equiv) and finally
palladium(II)acetate (0.2 equiv) were added. The reaction
was carried out overnight at 40 °C under argon atmosphere;
the isolation of the beads was carried out according to
1
3
NMR (100 MHz, CDCl ): δ = 172.1 (s, O−CO), 57.2 (t,
3
CH −N), 43.3 (q, N−CH ), 31.1 (t, CH2−CO), 20.2 (t,
2
3
CH −CH −CH ) ppm. Starting from 12b (0.209 g, 0.191
2
2
2
mmol) in 7 mL of solvent, we isolated 0.240 g of brown resin
2
5
13
literature. The black/gray color of the resin is attributed to
residual palladium remaining adsorbed on the beads.
13b. C gel-phase NMR (100 MHz, CDCl ): δ = 172.0 (s),
3
57.0 (t), 43.1 (q), 30.9 (t), 20.0 (t) ppm.
Polymer-Bound Phenylmethylmethcrylate. Resin 9b (291
1
3
mg) leads to black resin 10b (264 mg). C gel-phase NMR
100 MHz, CDCl ): δ = 166.8 (s, OC−OCHH ), 165.9 (s,
ASSOCIATED CONTENT
■
(
3
3
*
S
Supporting Information
OC−OR), 143.4 (d, H−CC), 138.5 (s, ArC−CC),
1
3
13
1
20.1 (d, H−CC), 51.8 (q, CH ) ppm. C gel-phase NMR
Gel-phase C NMR characterization of target PS−PEG resins
3
13
spectra indicated incomplete conversion, which is attributed to
the low swelling ability in polar-solvent mixtures of the resin
bearing a short PEG spacer unit. Starting from 9d (196 mg), we
(3a−f, 4a−f), gel-phase C NMR spectra of compounds 4a−f,
5a−f and the application example 2 (Heck coupling,
compounds 9b,d,f and 10b,d,f, Reactagel), and IR spectra of
compounds 4a−f. This material is available free of charge via
the Internet at http://pubs.acs.org.
1
3
could obtain 198 mg of 10d as a black solid. C gel-phase
NMR (100 MHz, CDCl ): δ = 166.8, 165.9, 143.3, 138.5,
3
3
73
dx.doi.org/10.1021/co500028h | ACS Comb. Sci. 2014, 16, 367−374

ACS Combinatorial Science
Research Article
(
18) Braunshier, C.; Hametner, C.; Froehlich, J.; Schnoeller, J.;
AUTHOR INFORMATION
■
*
Hutter, H. Novel monodisperse PEG-grafted polystyrene resins:
Synthesis and application in gel-phase C NMR spectroscopy.
Tetrahedron Lett. 2008, 49 (50), 7103−7105.
(19) Lumpi, D.; Braunshier, C.; Hametner, C.; Horkel, E.;
Zachhuber, B.; Lendl, B.; Froehlich, J. Convenient multigram synthesis
of monodisperse oligo(ethylene glycols): Effective reaction monitoring
by infrared spectroscopy using an attenuated total reflection fibre optic
probe. Tetrahedron Lett. 2009, 50 (47), 6469−6471.
Corresponding Author
E-mail: christian@braunshier.at. Phone: 0043 650 4531979.
Fax: 0043 1 58801 15499.
13
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(20) Ishizone, T.; Han, S.; Okuyama, S.; Nakahama, S. Synthesis of
water-soluble polymethacrylates by living anionic polymerization of
trialkylsilyl-protected oligo(ethylene glycol) methacrylates. Macro-
molecules 2003, 36 (1), 42−49.
■
The authors are grateful to G. Ebner, C. Gorsche, H. Gschiel,
C. Trimmel, and B. Waldner for supporting the synthetic
experiments. Prof. H. Hutter and M. Holzweber are acknowl-
edged for assistance in performing the microscopy.
(
21) Sprung, M. M.; Nelson, L. S. Trimethylsilyl derivatives of
polyols. J. Org. Chem. 1955, 20, 1750−1756.
22) Rano, T. A.; Chapman, K. T. Solid phase synthesis of aryl ethers
via the Mitsunobu reaction. Tetrahedron Lett. 1995, 36 (22), 3789−
792.
23) Bennett, W. D.; Christensen, J., Eds. Advanced ChemTech
(
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dx.doi.org/10.1021/co500028h | ACS Comb. Sci. 2014, 16, 367−374