Poly-γ-S-perillyl-l-glutamate and Poly-γ-S-perillyl-d-glutamate: Diastereomeric Alignment Media Used for the Investigation of the Alignment Process

Article abstract of DOI:10.1002/chem.201905447

Residual dipolar couplings (RDCs) offer additional information for structure elucidation by NMR spectroscopy. They are measured in anisotropic media, such as lyotropic liquid crystalline phases of polypeptides. Today, some suitable polypeptides are known.

Full text of DOI:10.1002/chem.201905447

A Journal of
Accepted Article
Title: Poly-γ-S-perillyl-L-glutamate and Poly-γ-S-perillyl-D-glutamate:
diastereomeric alignment media used for the investigation of the
alignment process
Authors: Marcel Alcaraz Janßen and Christina Thiele
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To be cited as: Chem. Eur. J. 10.1002/chem.201905447
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Poly-γ-S-perillyl-
L
-glutamate and Poly-γ-S-perillyl-
D
-glutamate:
diastereomeric alignment media used for the investigation of the
alignment process
Marcel Alcaraz Janßen and Christina M. Thiele*[a]
Abstract: Residual dipolar couplings offer additional information for
structure elucidation by NMR spectroscopy. They are measured in
anisotropic media such as lyotropic liquid crystalline phases of
polypeptides. Today, some suitable polypeptides are known.
Nevertheless, structural influences of these polypeptides on the
alignment properties are not really understood. Thus the question,
which influence a chiral side chain has on enantiodiscrimination and
whether we can improve the enantiodifferentiation significantly by
adding an additional chiral center in the sidechain, is of interest.
Therefore, we synthesized new diastereomeric polypeptide-based
alignment media with an additional chiral center in the sidechain
derived from perillyl alcohol and investigated their properties
(secondary structure, liquid crystallinity, etc.). The enantiomers of
isopinocampheol and β-pinene were used as model analytes for the
study of enantiodiscrimination. Additionally, the usage of 1H-1H-
RDCs to improve the alignment tensor quality is demonstrated.
most prominent lyotropic liquid crystalline alignment media (poly-
γ-benzyl- -glutamate (PBLG) and poly-γ-ethyl- -glutamate
(PELG))[15,21–25]
the screw sense is determined by the
L
L
,
configuration of the amino acid building up the backbone. For
other examples, like polyacetlylenes[25,26], polyguanidines[27] and
polyisocyanides[17,28] the chiral information for the helical sense
is derived from the sidechain. But no matter what determines the
helical sense, if the helices are homochiral or rather if they have
a preferred handedness they allow for enantiodifferentiation[22–33]
This is one of the most interesting characteristics of the
investigation of alignment properties.
.
The question, which properties of alignment media are mainly
responsible for the extent of the enantiodifferentiation between
enantiomers is so far not really understood. Nevertheless, this
question is of interest as some predictions about the alignment
process are needed. This is especially important concerning the
theoretical aspect of the determination of the absolute
configuration in the future[34]
.
Some alignment media based on polypeptides are known and
have been investigated with respect to enantiodiscrimination and
solute-polymer interaction [15,20,29–31,35–40]. In these investigations
it became clear that the enantiodifferentiation induced by these
polypeptides depends, among other things, on their sidechain.
Hence, the question came up, whether the chirality of the
sidechain in polypeptide-based media would have an influence
on the alignment process.
Introduction
NMR spectroscopy is one of the most popular methods in
structure elucidation of organic molecules. Apart from various
routinely used methods, residual dipolar couplings (RDCs) as
anisotropic NMR parameters provide helpful and complementary
structural information. Over the last decades they have been
receiving a lot of attention[1,2]. This is due to their utility for the
determination of the spatial structure as they yield
complementary information to those of established approaches,
like NOE[3–5] or J-couplings[6,7]
.
RDCs are anisotropic NMR parameters. To get access to
anisotropic NMR parameters, an anisotropic environment which
induces weak alignment is necessary[8]. Two major concepts for
measurements of non-water soluble analytes found their way
into application: There are alignment media based on either
anisotropically swollen gels or lyotropic liquid crystals (LLCs)[9–11]
Apart from a few exceptions[12–14] most of the gels are not chiral.
In contrast to that, the LLCs are mainly based on helical
mesogens[15–17] or other helical constructs[18,19] with a defined
screw sense. In the case of polypeptides[20], which include the
.
[a]
M. Alcaraz Janßen, Prof. Dr. C. M. Thiele
Clemens-Schöpf-Institut für Organische Chemie und Biochemie
Technical University of Darmstadt, Alarich-Weiss-Str. 16
64287 Darmstadt (Germany)
E-mail: cthiele@thielelab.de
Homepage: www.thielelab.de
Supporting information for this article is given via a link at the end of
the document.
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Diastereomorphoussystems
should thus allow for the determination of the influence of the
sidechain’s chirality by permuting the stereogenic elements.
OH
OH
Poly-γ-S-2-methylbutyl-L-glutamate and Poly-γ-S-2-methylbutyl-
D-glutamate have previously been used to determine the
enantiodifferentiation between (+)-isopinocampheol ((+)-IPC)
and (-)-isopinocampheol ((-)-IPC), respectively[36]. The results
indicated, that there is a “matched” and a “mismatched” situation.
This means that the chiral information from the sidechain works
in one case hand in hand with the chiral backbone (matched),
resulting in a higher enantiodifferentiation relative to the other
case, in which the enantiodifferentiation is lower (mismatched).
Nevertheless, the difference between the enantiodifferentiation
of the two situations is rather small. The influence of the chiral
backbone seemed to be higher than the influence of the chiral
sidechain. Thus the idea, to introduce a bulkier chiral sidechain,
which should have a bigger influence, came up. This should not
only contribute to increase the amount of available highly
enantiodifferentiating alignment media but also allow for further
investigations concerning influences on enantiodifferentiation
and the alignment process.
(-)-IPC (1-)
(+)-IPC (1+)
DI
DI
DI
DI
O
O
O
O
P-helix
(right
handed)
M-helix
(left
handed)
N
N
H
H
O
O
n
n
PSPLG (2L)
PSPDG (2D)
DI
DI
DI
DI
OH
OH
DI: diastereomorphous
interactions
(+)-IPC (1+)
(-)-IPC (1-)
In the present study we synthesized the novel polymers poly-γ-
S-perillyl-L-glutamate 2L and poly-γ-S-perillyl-D-glutamate 2D
Diastereomorphoussystems
which are diastereomers to each other. After the synthesis we
were able to prepare liquid crystalline phases of these polymers
and we investigated their alignment properties concerning
enantiodifferentiation and sidechain influence. Furthermore, the
usage of HH RDCs to improve the quality of alignment tensors is
demonstrated.
Figure 1. Possible diastereomorphous interactions (DI) between analytes (1-,
1+) and polypeptide based alignment media (2L, 2D) with chiral sidechains.
The relation of the combinations in the two red boxes is diastereomorphous
with respect to each other (the same is true for the blue combinationones).
This is in contrast to polypeptides with achiral sidechains in which these
combinations would be enantiomorphous.
In the case of a polypeptide with an achiral sidechain the
enantiodifferentiation is caused by diastereomorphous
interactions between the analyte and the homochiral helix of the
polypeptide’s backbone. Hence, different orientations are
Results and Discussion
Synthesis of poly-γ-S-perillyl-L-glutamate 2L and poly-γ-S-
perillyl- -glutamate 2D
D
obtained for two enantiomers measured in
polypeptide. In contrast to that, the same orientation results if
one enantiomer is measured in the polypeptide with the -amino
acid and the other enantiomer is measured in the polypeptide
with the -amino acid. This is due to the enantiomorphous
a homochiral
In order to provide excellent spectral quality polypeptides of high
molecular weight are necessary. It has already been shown for
PBLG that the resulting analyte orientation does not depend on
L
the molecular weight of the polypeptide[41]
. The same is
D
assumed to be valid here. Nevertheless, the macromolecular
properties of the two diastereomeric polymers should be
comparable to avoid any disturbing influences thus asking for a
controlled (ring-opening) polymerization of N-carboxyanhydrides
(NCAs), which are directly obtained from the corresponding
amino acid esters.
Our first step in that direction consists of synthesizing the amino
acid ester 3L (Scheme 1). In the case of glutamic acid (4L),
there are two carboxyl groups. The regioselectivity of the
esterification must thus be controlled to take place exclusively at
the γ-carboxyl group. Different methods for regioselective γ-
esterification of the carboxyl group are known[42–47]. We tried
relation between these systems. As a result, only two different
orientations are obtained by comparing the four possible
combinations (analyte (+ or -) and polypeptide (L or D). The
situation becomes more complex if an additional stereogenic
element is added in the polypeptide’s sidechain, as the polymers
then become diastereomorphous. If one could treat the helix and
the chiral sidechain as separate entities an additional site for
diastereomorphous interactions (DI) is provided (Figure 1). It is
assumed that this additional interaction has
a significant
influence on the induced analyte orientation. The resulting
enantiodifferentiation should thus depend on the helical sense
and on the chiral information from the sidechain. If the
different procedures (using N-phthalyl protection[42]
tetrafluoroboric acid[45] and using alkylboranes[46,47]
access to 3L. None of them were successful, thus we ended up
using the improved copper(II) strategy developed by Van
Heeswijk[44]. Glutamic acid 4L is converted into complex 5L by
reaction with copper(II) acetate in excellent yields. The isolated
complex 5L is then used in the esterification step, which starts
,
using
polypeptide is available with the amino acid in the
configuration (as glutamic acid is available both in
L
and
D
)
to get
L
- and
D
-
configuration), four systems (analyte (+ or -) and polypeptide (S
or S
L
D
) can be prepared (as the side chain is available only in S-
configuration, see Figure 1). Systematic considerations of the
orientations induced by different combinations of analyte
configuration, sidechain configuration and backbone sense
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with
a
change
of
the
counterion
by
N,N,N’,N’-
NCAs before and is highly recommendable to obtain pure
tetramethylguanidine (TMG) to improve the solubility of the
reactants. The following esterification proceeds regioselectively
due to the complexation of the α-carboxyl group by copper(II).
The alkenyl bromide 6 used is derived from the corresponding
alcohol 7 by an Appel reaction. The copper is successfully
removed from the complex with
ethylenediaminetetraacetic acid solution (EDTA) in a following
step.
NCAs[41,49]
.
Last but not least we use the combination of N,N-dimethyl
ethanolamine (DMEA) and N,N’-bis[3,5-
bis(trifluoromethyl)phenyl]thiourea[50] (TUS) as initiation system
to prepare the polypeptides[51]. A monomer to initiator ratio of
500:1 is used to ensure that the desired polypeptides 2L and 2D
are long enough for their use as alignment media. The
synthesized polypeptides 2L and 2D have narrow molecular
weight distributions (Table 1) and decent polydispersity indices
(PDI). Furthermore, the two batches synthesized are
comparable in terms of MW and PDI demonstrating the
reproducibility of the polymerization.
a
freshly prepared
HO
O
O
H2N
An important fact, which should be mentioned, is that the
polymers were found not to be bench stable for prolonged
periods of time. They become insoluble if they are stored at
room temperature. We believe that this is due to the reactivity of
the double bonds. This problem can be easily solved by storage
4L OH
4D
OH
Cu(AcO)2
H2O, 70°C
7
in
a freezer (-30 °C) in the dark. This is thus highly
O
O
PPh
CBr4
3
CH2Cl2, RT
recommended. The polymers stored under these conditions are
stable over months.
O
H2N
Cu
O
Br
1. TMG, 1L, DMF, H2O, 40 °C
2. Acetone, RT
+
O
Cu2+ 4 H2
O
NH2
Table 1. GPC results for the synthesized polymer batches.
O
O
3. EDTA, RT
6: 77 %
5L
: 91 %
5D: 91 %
Polymer[a]
M/I
Mn[c] in
Mw[c] in
PDI
g/mol[b]
g/mol[b]
O
S
S
S
S
L
1
1
2
2
500
500
500
500
2.97·105
2.87·105
2.35·105
2.06·105
3.76·105
3.69·105
2.87·105
2.81·105
1.27
1.29
1.22
1.36
D
L
O
O
O
O
O
DMEA, TUS
CH2Cl2, RT
Phosgene
O
O
pinene,
THF, 40 °C
OH
HN
O
H2N
N
D
H
O
O
O
n
3L: 58 %
3D: 50 %
2L
: 94 %
2D: 91 %
8L: 60 %
8D: 69 %
Scheme 1. Synthesis of PSPLG 2L via regioselective γ-esterification of 4L to
3L, following conversion to 8L using phosgene and polymerisation to yield 2L.
Yields for the synthesis of PSPDG 2D, which follows the same route, are given
in grey.
[a] configuration of sidechain and amino acid followed by batch number [b]
determined relative to polystyrene standards [c] Mn is the number average
molar mass and Mw is the mass average molar mass.
The glutamic acid ester 3L is then converted to the
corresponding NCA 8L by reacting the ester 3L under an argon
atmosphere with a solution of phosgene in toluene in the
Secondary structures, liquid crystalline behavior and
alignment properties
To determine the secondary structure of the polypeptides 2L
and 2D synthesized, their chiroptical properties were
investigated by the measurement of CD-spectra (Fig. 2) in
1,1,2,2-tetrachloroethane (TCE) and THF (see supporting info).
THF does not show a solvent cut off in the region of interest for
α-helical structures in polypeptides (about 220 nm). Thus CD
measurements in THF are straight-forward. TCE is chosen as
solvent as it is halogenated like chloroform (used for NMR). The
issue with the solvent cutoff is circumvented by using a 0.01 mm
cuvette. As expected, a negative Cotton effect was observed for
presence of α-pinene. α-pinene is added to avoid side-reactions
[48]
due to HCl, which stems from the conversion of phosgene
.
This is not only important to avoid side reactions that might lead
to ring opening of the NCA[48] but also to avoid
hydrohalogenation of the double bonds in product 8L. After the
reaction the solution becomes clear (indicating completed
reaction), the product 8L is isolated by transferring the solution
into n-hexane. The white crystals obtained are recrystallized
twice from tetrahydrofuran/n-hexane by adding a n-hexane layer
slowly on top of a tetrahydrofuran layer containing the NCA by
the use of a syringe pump. This strategy, which allows very slow
crystallization, was used by our group for the purification of other
the
the
L
-polymer 2L and a positive Cotton effect was observed for
-polymer 2D. Additionally, the typical two (negative and
D
positive) maxima for α-helices in the region of 220 nm are
observed. This indicates α-helical secondary structures, being
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right and left handed, respectively, for the two polypeptides (2L
and 2D). All these findings are in agreement with literature data
for other polypeptides based on glutamic acid[36,37]. Despite the
fact that the polymers are diastereoisomers the curves are
approximately mirror images with respect to each other. This
behavior indicates the enantiomeric character of the backbone
of the polypeptides. The chiral sidechain has no significant
influence on the CD-spectra. This finding is also in agreement
with literature[36]. Additionally CD-spectra of a 1:1 mixture of both
polypeptides were measured. The resulting curve shows only a
very minor amplitude confirming the “racemic” mixture of right
and left handed backbones. The “racemic” mixtures are
prepared by weighing, which is never perfectly exact. This might
explain, why
nevertheless.
a signal of minor amplitude is observed
Figure 3. Samples of the polypeptides 2L (left) and 2D (right) in CDCl3
between crossed polarization filters. Birefringence is observed for the
polypeptide samples in contrast to the isotropic water reference (middle).
Whether these phases are suitable as alignment media
becomes clear only if quadrupolar splittings of the solvent signal
are observed in the 2H-spectra of the polypeptides in bulk
samples of CDCl3 (see Figure 4). It is highly remarkable that
different sizes of quadrupolar splitting are observed for the
L-
polymer 2L and -polymer 2D with respect to each other despite
D
identical concentrations and similar molecular weights. An
analogous behavior is observed for all samples independent of
analyte (see supporting information). It would thus be interesting
to investigate whether the signs of the quadrupolar splittings of
the solvent are different or identical in these diastereomeric
media. The signs of the quadrupolar splittings of the solvent
have been evaluated based on the known fact that positive one-
bond dipolar couplings (1DCD
)
are related to negative
quadrupolar splittings for the same bond (see corresponding
equation in literature[52]). 1TCD (was measured to be ca. 37 Hz in
all samples), as determined from the 13C-satellites in the 2H-
Figure 2. CD-spectra of poly-γ-S-perillyl-
perillyl- -glutamate 2D (blue) and a 1:1 mixture (red) of them in TCE. [θ]MRW is
the mean residue molar ellipticity.
L-glutamate 2L (black), poly-γ-S-
D
1
1
spectra and JCD (32 Hz) of CDCl3 were used to calculate DCD
(1TCD = 1JCD + 21DCD) which is thus positive in all samples. Hence,
a negative sign results for the quadrupolar splitting of CDCl3 for
all samples. Nevertheless, the different sizes of quadrupolar
splitting suggest that this is caused by the diastereomeric
relationship between the two polymers and was considered very
promising in terms of enantiodiscrimination and the investigation
of the influence of the side chain on the orientational process.
The investigation of the enantiodifferentiation caused by each of
the polypeptides, which might potentially be influenced as well,
was therefore of interest as a next step.
Additionally to the question of helicity, the desired ability to form
lyotropic liquid crystalline phases was of interest and indicates
whether the polypeptides are useful as alignment media.
Therefore, samples of the polypeptides were prepared and
viewed under crossed polarization filters. The birefringent
behavior of these samples provide evidence for their liquid
crystalline behavior.
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Figure 5. CLIP-HSQC[53] spectrum (700M Hz, 300 K) of (-)-IPC in an
anisotropic phase of PSPLG/CDCl3 (green, 10.6 % w/w) and (-)-IPC in CDCl3
(black). The descriptors a (antiperiplanar) and s (synperiplanar) describe the
orientation of the diastereotopic protons relative to the dimethyl bridge.
Chemical shift referencing was done with respect to the isotropic
measurement. The spectrum from the anisotropic measurement is shifted in
order to obtain the stacked plot.
Narrow line shapes demonstrate the high quality of the spectra.
Total and scalar coupling constants are extracted by reading out
specific traces, following phase correction and fitting them to a
copy of themselves using an established approach[54]. The errors
are determined using the same fitting approach, also reported in
the literature[54]. Residual dipolar couplings are calculated using
the expression 1TCH = 1JCH + 21DCH
.
Order tensors are
determined for all data sets using the software
RDC@hotFCHT[55–57]. The eigenvectors of the Saupe tensors
are shown in Figure 6.
Figure 4. 2H-spectra (107 MHz, 300 K) of CDCl3 within LLC phases of 2L
(black, 10.5 % w/w) and 2D (green, 10.6 % w/w) with (+)-IPC, respectively.
The 2H signal of acetone-d6 in the added capillary was used for chemical shift
referencing. Note, that the shift of CDCl3 is affected by the presence of the
polypeptides.
Enantiodifferentiation and influence of the sidechain
For the investigation of the influence of the sidechain’s chirality
the enantiodifferentiation of a pair of enantiomers in both of the
diastereomeric polypeptides has to be considered. It would be
expected that a different extent of enantiodifferentiation, with
respect to the two polymers, is observed. We decided to use the
enantiomers of IPC as well as the enantiomers of β-pinene as
analytes due to the fact that both enantiomers of each of them
are commercially available and rigid. Additionally their structure
is well known and they were already used within RDC
analysis[23,37,41]. According to that, samples for all combinations
((+)- and (-)-IPC in
pinene in - 2L and
L
- 2L and
D-polymer 2D and (+)- and (-)-β-
L
D-polymer 2D) in CDCl3 were prepared. The
resulting CLean In Phase (CLIP)-HSQC[53] spectrum of one
anisotropic sample is shown and compared to the isotropic one
in Figure 5.
Figure 6. Eigenvectors of IPC (upper row) and β-pinene (lower row) in both of
the polymers (SL 2L and SD 2D) and in their 1:1 mixture. The corresponding β
angles are given below. The arrows represent the eigenvectors of the best-
fitting SVD-solution, while the scattered points show the distribution of the
eigenvectors determined by Monte-Carlo-boot-strapping within the range of
experimental RDC uncertainties.
For IPC and β-pinene, respectively, enantiodifferentiation is
observed in both polypeptides. Enantiodifferentiation, in the case
of RDC analysis, is usually quantified and discussed in terms of
the generalized angle β[58,59] which represents the “5D”-angle
between two alignment tensors. The cosine of this angle yields
the normalized scalar product between them. Thus a β-angle of
90° means that the alignment tensors are perpendicular to each
other, whereas a β-angle of 0° means that they are collinear.
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Using the angle
β
to quantify enantiodifferentiation is
obtained for these are even closer to zero than before. Thereby,
it is not only shown that the alignment tensor quality of β-pinene
can be improved using HH RDC, but also that we have not
drawn any wrong conclusions because of the lower quality of the
CH-only-alignment tensors determined for β-pinene.
straightforward as it does not only include considerations of the
orientations but also considerations of the shapes of the
compared tensors[16,58,59]
.
The β-angles determined for IPC in the
L-polymer 2L and in the
D-polymer 2D, respectively, are both above 30°, indicating
comparatively high enantiodiscrimination. One would have
expected different β-angles for the two diastereomeric polymers,
though. Surprisingly, these are very similar. This observation
indicates that no significant influence of the sidechain’s chirality
on the orientation of IPC can be observed. This is the result
expected for enantiomorphous systems, but not for
diastereomeric polymers. For the β-angles obtained from the
measurements of β-pinene analogous findings are made
although tensor orientations are much less well defined. This is
indicated by the rather large spread of points in Figure 6.
The vanishing difference in β between diastereomeric polymers
was not expected and is not in accordance with the literature[36]
.
Therefore further samples, containing both polymers in a 1:1
mixture, were prepared. These samples can be considered as
containing a “racemic” backbone and shall thus demonstrate the
influence of the sidechain’s chirality. In the case of β-pinene as
well as for IPC, β-angles of about 1.3° were obtained. These
results are thus in accordance with the findings discussed above
and seem to indicate that no influence of the bulky chiral
sidechain on enantiodifferentiation can be detected. In order to
consolidate our findings we tried to improve the quality of the β-
pinene tensors as a next step.
The use of HH RDCs to improve tensor quality
Figure 7. Eigenvectors of β-pinene in both of the polymers (SL 2L and SD 2D)
The alignment tensors obtained for the β-pinene samples are
not well defined, as shown by the point distribution obtained
from the Monte-Carlo output of our calculations. In order to
improve the mathematical treatment of data and thus get more
reliable tensor orientations we used HH RDCs. Their absolute
values (in contrast to CH RDCs, the signs are not known a
and in their 1:1 mixture. Calculated with HH RDCs only (upper row) and with
CH + HH RDCs (lower row). The corresponding β angles are given below. The
arrows represent the eigenvectors of the best-fitting SVD-solution, while the
scattered points show the distribution of the eigenvectors determined by
Monte-Carlo-boot-strapping within the range of experimental RDC
uncertainties.
priori)
are
extracted
from
TSE-PSYCHEDELIC[60,61]
measurements. In order to use the HH RDCs additionally in
combination with the CH RDCs and even on their own to
calculate tensors, their signs have to be determined. For this
purpose P.E.HSQMBC[62] experiments and the results from
COSY based experiments, a method, which is going to be
described separately[61], are used in combination. The absolute
signs obtained from the P.E.HSQMBC experiments are used as
starting point to handle the relative information obtained by the
COSY type experiments. All of the signs needed can be
determined successfully using this approach. The resulting
alignment tensors using the HH RDCs alone or in combination
with the CH RDCs are much better defined than before. Their
quality is improved enormously, as indicated by the much
narrower point distribution in the Monte Carlo boot-strapping
Discussion of the influence of the side chain chirality
All of our observations indicate that the influence of the
sidechain’s chirality is rather negligible for the samples
investigated here. Nevertheless, the extent of the
enantiodifferentiation obtained is high. In comparison to other
alignment media based on glutamic acid it is the highest
enantiodifferentiation, obtained under comparable experimental
conditions, for IPC up to now[23,36,37]
.
Over the years of research on the field of alignment media
based on polypeptides a few speculations were made. It
seemed as if sidechains like the benzyl group in PBLG lower the
enantiodifferentiation relative to smaller ones like the ethyl group
in PELG. These findings were explained by more or less steric
demand of the sidechain, influencing the accessibility to the
chiral backbone[23,36]. The results from this work clearly show
that high enantiodifferentiation is possible even if there are bulky
sidechains and this contradicts previous findings. These results
are in accordance with the data of another new alignment
(see Fig. 7). The β-angles from the L-polymer 2L and from the D-
polymer 2D, respectively, are more or less the same, as
compared to the CH-only-tensors. This is true for both
calculations (HH RDCs only and HH + CH RDCs). Furthermore,
the data obtained with the HH RDC measurements of the 1:1
polymer mixture show the same results as before. The β-angles
medium with biphenyl sidechains[37]
.
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reduced pressure. The remaining oil was distilled under vacuum. Finally,
the product 6 (54.601 g, 77.3 %) was obtained as a colourless to light
yellow oil.
We were able to synthesize a novel alignment medium with a
chiral bulky sidechain which shows high enantiodifferentiation.
This seems, however not to be due to the chirality of the
sidechain alone but rather by the performance of the whole
polymer. This result is very interesting and it shows that the
factors controlling or rather guiding the interactions during the
alignment process are very complex and far from being
understood. The speculation, that the chirality of the sidechain
always induces significant enantiodifferentiation and must lead
to a matched/mismatched situation is disproven. The question
which factors contribute to the enantiodifferentiation remains
open. The data available up to now do not show a clear trend
between induced enantiodifferentiation and chemical or steric
properties of the sidechain. To get some more hints and to be
able to predict some of the interactions, which are highly
important for the resulting orientation, further investigations have
to be carried out.
7
1
2
6
Br
5
9
3
4
8
10
[α]D20 = -63.30° (c = 1, CHCl3); 1H-NMR (700 MHz, 300 K, CDCl3): δ =
1.48-1.55 (m, 1H, 6-Ha), 1.74 (s, 3H, 10-H), 1.85-1.90 (m, 1H, 6-Hb),
1.93-2.00 (m, 1H, 4-Ha), 2.12-2.21 (m, 2H, 4-Hb, 5-H), 2.21-2.25 (m, 2H,
7-H), 3.93-3.98 (m, 2H, 1-H), 4.70-4.72 (m, 1H, 9-Ha) 4.73-4.75 (m, 1H,
9-Hb), 5.88-5.91 (m, 1H, 3-H) ppm; 13C-NMR (175 MHz, 300 K, CDCl3): δ
= 20.9 (10-C), 27.0 (7-C), 27.4 (6-C), 31.0 (4-C), 39.3 (1-C), 40.7 (5-C),
109.1 (9-C), 127.8 (3-C), 134.5 (2-C), 149.5 (8-C) ppm. The NMR data
are in accordance with the literature[64,65]
.
Synthesis of γ-S-perillyl- -glutamate
L
The synthesis of γ-S-perillyl-
procedure[44]. Glutamic acid (4L) (29.366 g, 166.6 mmol, 1.0 eq.) was
suspended in 750 ml of water. solution of copper(II) acetate
L-glutamate was done following a literature
A
monohydrate (41.286 g, 206.8 mmol, 1.2 eq.) in water (750 ml) was
added dropwise to this suspension at 70 °C. After addition, the solution
was allowed to cool down. To ensure complete crystallization, the
solution was kept at room temperature for 2 d. Filtration, washing steps
with water, ethanol and diethyl ether and drying in high vacuum yielded
Conclusions
Two polypeptides based on glutamic acid with chiral sidechains,
which are diastereomeric with respect to each other were
successfully synthesized. They have α-helical secondary
structures as indicated by CD spectra. Furthermore they are
able to form lyotropic liquid crystalline phases which can be
used as alignment media within the RDC approach. The
enantiomers of IPC and β-pinene were used for investigations
concerning the alignment properties. The quality of the
alignment tensors determined for β-pinene was significantly
improved by the use of HH-RDCs. For both analytes (IPC and β-
pinene) high enantiodifferentiation was observed. Furthermore,
the enantiodifferentiation for each analyte pair was compared
between the diastereomeric LLC phases. Additionally, 1:1-
mixtures of the diastereomeric polypeptides were used to
determine the resulting enantiodifferentiation in order to get
information about the influence of the sidechain’s chirality. This
influence was determined to be negligible. Nevertheless, the
extent of enantiodifferentiation is really high in comparison with
other media. These results are interesting and demonstrate that
the factors leading to high enantiodifferentiation are still not
understood. The purposive design and the synthesis of highly
promising alignment media is thus still very challenging.
the complex 5L (44.556 g, 91.2 %) as a blue fine powder. This L-glutamic
acid copper(II) complex (5L) (29.486 g, 60.3 mmol, 1.0 eq.) and glutamic
acid (4L) (17.759 g, 120.7 mmol, 2.0 eq.) were suspended in a mixture of
N,N-dimethylformamide (DMF, 107 ml) and water (17.3 ml). N,N,N’,N’-
tetramethylguanidine (30 ml, 283.7 mmol, 4.7 eq.) was added
subsequently. The mixture was stirred for 2 h, so that a homogenous
solution was obtained. Additional DMF (86 ml) and the alkenyl bromide 6
(54.602 g, 253.8 mmol, 4.2 eq.) were added. The resulting mixture was
stirred at 40 °C for 56 h. After this time, 1.45 l of acetone were added. A
fine precipitate resulted after 3 h of stirring and was isolated via filtration.
The resulting powder was suspended in a freshly prepared solution of
ethylenediaminetetraacetic acid (34.455 g, 117.9 mmol 2.0 eq.) and
sodium hydrogen carbonate (19.430 g, 231.3 mmol, 3.8 eq.) in water
(280 ml). The suspension was stirred for 16 h. A following filtration and
several wash cycles using water, yielded a white to light blue solid. The
product 3L (39.883 g, 58.8 %) was obtained as
a white solid by
recrystallization, using a water/ethanol (2/1) mixture.
14
11
10
13
15
12
7
6
9
8
O5
O
4
3
1 OH
H2N
2
O
[α]D20 = -38.40° (c = 0.25, MeOH); 1H-NMR (700 MHz, 300 K,
D2O+DCl): δ = 1.32-1.40 (m, 1H, 11-Ha), 1.63 (s, 3H, 15-H), 1.70-1.75 (m,
1H, 11-Hb), 1.81-1.88 (m, 1H, 9-Ha), 1.95-2.00 (m, 2H, 12-H), 2.01-2.08
(m, 2H, 9-Hb, 10-H), 2.13-2.23 (m, 2H, 3-H), 2.53-2.63 (m, 2H, 4-H), 4.06
Experimental Section
Synthesis of S-perillyl-bromide
3
The synthesis of S-perillyl-bromide was done following a published
procedure[63]. S-perillyl alcohol (7) (50.057 g, 328.8 mmol, 1.0 eq.) and
tetrabromomethane (121.138 g, 365.3 mmol 1.1 eq.) were dissolved in
dichloromethane (150 ml). Triphenylphosphine (94.924 g, 361.9 mmol
1.1 eq.) was added under cooling, using an ice bath. The reaction
solution was stirred for 18h at room temperature. The solvent was
removed under reduced pressure. The obtained residue was poured into
300 ml of n-hexane. The resulting suspension was filtered using silica gel.
Additional n-hexane was used to wash. The solvent was removed under
(t, 1H, 2-H, J2,3 = 6.7Hz), 4.42 (s, 2H, 6-H), 4.63 (s, 2H, 14-H), 5.69 (s,
1H, 8-H) ppm; 13C-NMR (100 MHz, 300 K, D2O+DCl): δ 20.3 (15-C), 25.0
(3-C), 25.9 (12-C), 27.0 (11-C), 29.7 (4-C), 30.2 (9-C), 40.5 (10-C), 52.0
(2-C), 69.0 (6-C), 108.4 (14-C), 125.9 (8-C), 132.4 (7-C), 150.2 (13-C),
171.3 (1-C), 173.8 (5-C) ppm; MS (ESI): m/z = calcd: 282.16998
[C15H24NO4]+ found: 282.17012 [M+H]+.
Synthesis of γ-S-perillyl-D-glutamate
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10.1002/chem.201905447
Chemistry - A European Journal
FULL PAPER
14
13
15
The
D-ester 3D and the corresponding complex 5D (91.7 %) were
11
10
synthesized according to the procedure described for the L-ester 3L. The
product 3D was obtained as a white solid (50.3 %).
12
7
9
6
14
8
O
O
11
10
13
15
5
12
7
4
3
2
6
1
9
O
HN16
8
O5
O
O
O
4
3
1H-NMR (700 MHz, 300 K, THF-d8): δ = 1.44-1.51 (m, 1H, 11-Ha), 1.73
(s, 3H, 15-H), 1.81-1.86 (m, 1H, 11-Hb), 1.93-1.99 (m, 1H, 9-Ha), 1.97-
2.03 (m, 1H, 3-H), 2.06-2.11 (m, 2H, 12-H), 2.11-2.17 (m, 3H, 3-H, 9-Hb,
1 OH
H2N
2
O
[α]D20 = -49.20° (c = 0.25, MeOH); 1H-NMR (600 MHz, 300 K,
D2O+DCl): δ = 1.31-1.40 (m, 1H, 11-Ha), 1.62 (s, 3H, 15-H), 1.70-1.75 (m,
1H, 11-Ha), 1.80-1.88 (m, 1H, 9-Ha), 1.94-2.00 (m, 2H, 12-H), 2.00-2.08
(m, 2H, 9-Hb, 10-H), 2.13-2.24 (m, 2H, 3-H), 2.53-2.64 (m, 2H, 4-H), 4.06
3
10-H), 2.48 (t, 2H, 4-H, J3,4 = 7.5Hz), 4.37-4.40 (m, 1H, 2-H), 4.42-4.49
(m, 2H, 6-H), 4.69-4.71 (m, 2H, 14-H), 5.73-5.75 (m, 1H, 8-H) 7.92 (s, 1H,
N-H) ppm; 13C-NMR (175 MHz, 300 K, THF-d8): δ = 20.7 (15-C), 26.9
(12-C), 27.8 (3-C), 28.1 (11-C), 29.7 (4-C), 31.1 (9-C), 41.7 (10-C), 57.1
(2-C), 68.7 (6-C), 109.0 (14-C), 125.9 (8-C), 133.7 (7-C), 150.1 (13-C),
152.4 (16-C), 171.2 (1-C), 172.0 (5-C) ppm.
3
(t, 1H, 2-H, J2,3 = 6.7Hz), 4.38-4.45 (m, 2H, 6-H), 4.62 (s, 2H, 14-H),
5.69 (s, 1H, 8-H) ppm; 13C-NMR (100 MHz, 300 K, D2O+DCl): δ = 20.3
(15-C), 24.9 (3-C), 25.9 (12-C), 27.0 (11-C), 29.7 (4-C), 30.2 (9-C), 40.4
(10-C), 51.9 (2-C), 69.2 (6-C), 108.4 (14-C), 126.0 (8-C), 132.4 (7-C),
150.4 (13-C), 171.1 (1-C), 173.8 (5-C) ppm; MS (ESI): m/z = calcd:
282.16998 [C15H24NO4]+ found: 282.16993 [M+H]+.
Synthesis of poly-γ-S-perillyl-L-glutamate
The synthesis of the polypeptide 2L was done following a literature
procedure for PBLG.[51]. The corresponding NCA 8L (2.000 g, 6.5 mmol)
was dissolved in degassed absolute dichloromethane (40 ml) inside of a
glovebox. 670 µl of a stock solution, containing 50.3 mg TUS per 5.2 ml
(9.67 mg/ml) degassed absolute dichloromethane, were added.
Subsequently, 160 µl of a stock solution, containing 40 µl DMEA per 5ml
(7.12 mg/ml) degassed absolute dichloromethane, were added. The
resulting reaction mixture was stirred for 116 h. The reaction progress
was controlled using ATR-IR spectroscopy. Isolation of the polypeptide
was achieved by precipitation in n-hexane. Drying in high vacuum was
followed by a second precipitation from dichloromethane/n-hexane. The
finally high vacuum dried product 2L (1.627 g, 94.9 %) was obtained as a
white rubberlike solid. The NMR spectra of the polypeptide 2L showed
broad signals as common for polymers. Multiplicity was beyond
recognition and signals of the backbone or near to it could not be
observed in 13C spectra.
Synthesis of γ-S-perillyl-L-glutamic acid N-carboxyanhydride
The synthesis of the NCA 8L was done following literature
procedures[48,66]. The amino acid ester 3L (10.004 g, 35.6 mmol, 1.0 eq.)
and α-pinene (12.071 g, 88.6 mmol, 2.5 eq.) were added, under argon, to
absolute tetrahydrofuran (THF, 90 ml). A solution of 20 % phosgene in
toluene (22.4 ml, 48.4 mmol, 1.4 eq.) was added to this suspension. The
resulting mixture was stirred at 40 °C for 2 h. The clear reaction solution
was then added to absolute n-hexane (360 ml) using a syringe filter
(0.45 µm, PTFE). The precipitate obtained was isolated by filtration under
inert conditions, washed with 50 ml absolute n-hexane and dried under
high vacuum. The crystals were redissolved in absolute THF (3.5 ml/g)
and recrystallized, by layering with n-hexane (10.5 ml/g) using a syringe
pump. Filtration, washing and drying were repeated and followed by a
second recrystallization using the diffusion controlled crystallisation again.
The product 8L (6.640 g, 60.8 %) was finally obtained as white crystals
by filtration, washing and drying.
14
11
13
15
12
7
10
9
14
6
8
11
13
O
O
12
5
15
10
7
4
3
9
6
8
1
O
O
N
2
H
5
O
n
4
3
2
[α]D20 = -47.50° (c = 0.1, THF); 1H-NMR (700 MHz, 300 K, CDCl3): δ =
1.46 (br, 1H, 11-Ha), 1.71 (br, 3H, 15-H), 1.82 (br, 1H, 11-Hb), 1.93 (br,
1H, 9-Ha), 2.05 (br, 2H, 12-H), 2.12 (br, 2H, 9-Hb, 10-H), 2.37 (br, 2H, 3-
H), 2.72 (br, 2H, 4-H), 3.99 (br, 1H, 2-H), 4.37 (br, 1H, 6-Ha), 4.54 (br, 1H,
6-Hb), 4.69 (br, 1H, 14-Ha), 4.70 (br, 1H, 14-Hb), 5.71 (br, 1H, 8-H) ppm;
13C-NMR (175 MHz, 300 K, CDCl3): δ = 20.9 (15-C), 26.5 (12-C), 27.5
(11-C), 30.6 (9-C), 41.0 (10-C), 68.3 (6-C), 108.9 (14-C), 125.3 (8-C),
132.8 (7-C), 149.7 (13-C), 172.3 (5-C) ppm.
1
O
HN16
O
O
1H-NMR (600 MHz, 300 K, THF-d8): δ = 1.44-1.52 (m, 1H, 11-Ha), 1.73
(s, 3H, 15-H), 1.81-1.86 (m, 1H, 11-Hb), 1.92-2.00 (m, 1H, 9-Ha), 1.97-
2.03 (m, 1H, 3-H), 2.06-2.11 (m, 2H, 12-H), 2.11-2.17 (m, 3H, 3-H, 9-Hb,
10-H), 2.46-2.50 (m, 2H, 4-H), 4.37-4.40 (m, 1H, 2-H), 4.42-4.49 (m, 2H,
6-H), 4.69-4.71 (m, 2H, 14-H), 5.72-5.75 (m, 1H, 8-H) 7.91 (s, 1H, N-H)
ppm; 13C-NMR (150 MHz, 300 K, THF-d8): δ = 20.7 (15-C), 26.9 (12-C),
27.8 (3-C), 28.1 (11-C), 29.7 (4-C), 31.1 (9-C), 41.7 (10-C), 57.1 (2-C),
68.7 (6-C), 109.0 (14-C), 125.9 (8-C), 133.7 (7-C), 150.1 (13-C), 152.4
(16-C), 171.2 (1-C), 172.0 (5-C) ppm.
Synthesis of poly-γ-S-perillyl-D-glutamate
The synthesis of the
D-polypeptide 2D was done according to the
procedure used for the
L-polypeptide 2L. The resulting product 2D
(91.4 %) was obtained as a white rubberlike solid. The NMR spectra of
the polypeptide 2D showed broad signals as common for polymers.
Multiplicity was beyond recognition and signals of the backbone or near
to it could not be observed in 13C spectra.
Synthesis of γ-S-perillyl-
D-glutamic acid N-carboxyanhydride
The synthesis of the -derivative 8D was achieved using the same
D
procedure as described for the
obtained as white crystals.
L-NCA 8L. The product 8D (69.1 %) was
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10.1002/chem.201905447
Chemistry - A European Journal
FULL PAPER
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14
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7
10
15
9
6
8
O
O
5
4
3
1
N
2
H
O
n
[α]D20 = -60.50° (c = 0.1, THF); 1H-NMR (700 MHz, 300 K, CDCl3): δ =
1.46 (br, 1H, 11-Ha), 1.71 (br, 3H, 15-H), 1.82 (br, 1H, 11-Hb), 1.93 (br,
1H, 9-Ha), 2.05 (br, 2H, 12-H), 2.13 (br, 2H, 9-Hb, 10-H), 2.37 (br, 2H, 3-
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NMR samples and data
Detailed information on sample preparation as well as the collection of
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The authors thank the Fonds der chemischen Industrie (FCI) for
a Ph.D. scholarship and financial support. We would like to
thank Davy Sinnaeve for being able to use the pulse sequences
for HH-RDC measurements prior to publication and Julian Ilgen
for the help with setup and evaluation of the resulting data.
Furthermore we acknowledge Volker Schmidts for the support
concerning the software RDC@hotfcht and Max Hirschmann for
advice concerning the 0.01mm cuvettes for CD measurements.
Keywords: polymers • NMR spectroscopy • alignment medium •
chirality • peptides
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Entry for the Table of Contents
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Influences on
M. Alcaraz Janßen, Prof. Dr. C. M.
enantiodifferentiation: The influence
of an additional chiral center in the
sidechain of a polypeptide-based
alignment medium is investigated.
Therefore, new diastereomeric
alignment media are synthesized and
the enantiomers of IPC and β-pinene
are used as analytes. The results are
unexpected. Furthermore HH-RDCs
are used to improve the quality of
alignment tensors.
Thiele *
Page No. – Page No.
Poly-γ-S-perillyl-
Poly-γ-S-perillyl-
diastereomeric alignment media used
for the investigation of the alignment
process
L
-glutamate and
-glutamate:
D
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