Proline-Based Boronic Acid Receptors for Chiral Recognition of Glucose

Article abstract of DOI:10.1021/acs.joc.8b02425

Chiral recognition remains a major challenge in the area of molecular receptor design. With this research, we set out to explore the use of proline-based receptors for chiral recognition. Importantly, the proline structure allows for the introduction of a

Full text of DOI:10.1021/acs.joc.8b02425

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Article
Proline-Based Boronic Acid Receptors for Chiral Recognition of Glucose
Lin-E Guo, Yuan Hong, Shu-Ying Zhang, Miao Zhang, Xiao-Sheng
Yan, Jin-Lian Cao, Zhao Li, Tony D. James, and Yun-Bao Jiang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02425 • Publication Date (Web): 22 Nov 2018
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Proline-Based Boronic Acid Receptors for Chiral Recognition of
Glucose
Lin-E Guo,a Yuan Hong,a Shu-Ying Zhang,a Miao Zhang,a Xiao-Sheng Yan,a Jin-Lian Cao,a Zhao
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Li,a Tony D. James,* b and Yun-Bao Jiang*a
a Department of Chemistry, College of Chemistry and Chemical Engineering, The MOE Key Laboratory of
Spectrochemical Analysis and Instrumentation, and iChEM, Xiamen University, Xiamen 361005, China.
b Department of Chemistry, University of Bath, Bath BA2 7AY, UK.
KEYWORDS: proline, chiral recognition, monosaccharide, boronic acid
ABSTRACT: Chiral recognition remains a major challenge in the area of molecular receptor design. With this research we
set out to explore the use of proline based receptors for chiral recognition. Importantly, the proline structure allows for
the introduction of at least two different binding groups due to the availability of both an amine and carboxylic acid
group. Here we report a proof-of-concept exploration into the chiral recognition of D-/L-glucose, as model chiral species
which prefers to bind to at least two boronic acid groups. We evaluated several proline-based receptors incorporating two
phenylboronic acid groups, respectively at the N- and C-termini of the amino acid residue, via amide bonds. We
1
confirmed that the receptors exhibited chiral recognition using CD, H NMR and 19F NMR spectroscopy. Given the
derivation diversity available, our strategy to use proline-based receptors for chiral recognition holds significant promise
for extension to other chiral systems.
recognition, which in general requires multiple
INTRODUCTION
interactions of the receptor with the chiral species, so that
While molecular recognition and chiral sensing have
the receptor contains at least two binding groups to allow
seen tremendous developments,1,2 chiral recognition
the chiral center(s) of the chiral species to be included
remains a significant challenge. In many of the reported
within the interaction network. Our first model system
examples, 1,1’-binaphthol was the major structural
framework that was derived into receptors bearing two
identical binding groups and in the majority of the cases
macrocyclic receptors are produced.3-6 1,1’-Binaphthol and
proline are two of the major frameworks used for
constructing asymmetric organocatalysts,7-13 yet we noted
that surprisingly much less attention has been paid to
proline-based receptors for chiral recognition.2,14-16 We
therefore proposed that by using proline as a structural
framework to construct receptors for chiral recognition
could have several advantages, since it can contain at
least two different binding groups at the N- and C-termini
of the amino acid residue, the approach is simpler when
compared to the 1,1’-binaphthol framework since its two
reactive sites at 2,2’-positions, the -OHs, are the same in
terms of reactivity and, subsequently, allows us to create
receptors with larger structural diversity for a broader
spectrum of chiral species. While the cis-/trans-
conformation equilibrium of the proline residue,17-19 in
addition to its favorable cleft-shaped structure, can be
employed to enhance chiral recognition.
was aimed at developing receptors for the chiral
recognition of L-/D-glucose, which has been shown to
prefer binding with diboronic acid derivatives.20,21
Therefore, we designed diboronic acid derivatives of L-/D-
proline, L-/D-1 to 4 (Scheme 1a), which differ in the
positions of the boronic acid groups on the phenyl rings
at the N- and C-termini of proline residue. Their binding
with L-/D-glucose was first investigated by circular
dichroism (CD) spectroscopy, a powerful tool for chiral
research.22-26 Next fluorine atoms were introduced into the
phenyl rings to facilitate the use of spectrally simpler 19F
NMR for receptor evaluation. Our results confirm that the
proline-based receptors are indeed well suited towards
chiral recognition.
RESULTS AND DISCUSSION
Absorption spectra of the four receptors of L-
configuration, L-1 to L-4, were studied in optimized media
consisting of 1:1 (v/v) MeOH/0.05 M pH 10.0 NH4Cl-
NH3·H2O buffer (Fig. S1). Despite the difference in the
substitution positions of the two boronic acid groups, L-1
to L-4 all exhibit a major absorption around 245 nm with
molar extinction coefficients of magnitude 104 M-1 cm-1,
Here we report our proof-of-concept exploration into
the development of proline-based receptors for chiral
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indicative of the π-π* nature of the transition of the our delight, L-1 to L-4 all exhibited CD signals at the
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phenylboronic acid chromophores (Fig. S2). Similar
absorption wavelength (Fig. S2), suggesting that the
chirality of
observations were made with D-1 to D-4 (Fig. S3). Much to
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Scheme1. (a) Chemical structures of stereoisomers of 1 to 10 and D-1Br investigated, and crystal structure of the
intermediate D-1Br. L-5 and L-6, are monophenylboronic acid control compounds of L-1; L-/D-7 are alanine
counterparts of L-/D-1. compounds L-8 to L-10 are fluorine-substituted L-1; The two boronic acid groups in 1-4 are
substituted at the phenyl rings respectively at (L-/D-1) m,m’-, (L-/D-2) m,p’-, (L-/D-3) p,m’-, and (L-/D-4) p,p’-
positions; fluorine atoms are introduced into the phenyl rings at different positions in L-8 to L-10 and are
labelled as Fa and Fb, respectively; “*” on the structures highlights the chiral carbon. (b) Structures of the tested
monosaccharide.
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(a)
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O
B
O
B
O
O


O
O
O
O
O
O
O
O


N
HN
B
N
HN
B
N
HN
N
HN
O
O
O
O
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8
9
O
3
B
L-/D-
O
1
L-/D-
2
4
L-/D-
L-/D-
B
O
B
O
O
B
O
O
O
O
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O
B
O
B
O
B
O
O
O
O
O
O

N
N
HN
HN
N
H
N
HN
O
O
O
NH
Fb
O
Fa
8
L-
6
7
L-
L-/D-
O
5
L-
B
B
O
O
B
O
O
O
O
B
O
B
O
O
O
O
O
Br
N
HN
N
HN
N
HN
O
O
Fa
O
Fb
10
1Br
D-
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L-
L-
B
B
1Br
Crystal structure of D-
O
O
Br
O
O
(b)
HO
O
HO
HO
O
O
HO
HO
O
HO
HO
HO
HO
OH
OH
-D-mannofuranose
HO
HO
OH
OH
OH
OH
-D-glucofuranose
OH
OH
-D-xylofuranose
-D-galactofuranose
OH
HO
OH
OH
O
OH
OH
O
O
O
OH
OH
OH
OH
HO
HO
-L-mannofuranose
OH
HO
HO
HO
HO
OH
-D-fructofuranose
HO
-L-glucofuranose
-L-xylofuranose
the proline residue is transferred to the achiral
phenylboronic acid chromophores. This was supported by
the mirror-imaged CD spectra of the corresponding D-
enantiomers D-1 to D-4 (Fig. S4). Therefore, the structural
advantage of the cleft-shaped proline residue in rendering
the binding sites chiral was fully demonstrated.
in the latter cases the spectral variations are minor (Fig.
1b, d). Likewise, D-1 exhibits chiral recognition toward D-
glucose (Fig. 1e-h), while the CD spectral traces show
mirror-image profiles for L-1/L-glucose and D-1/D-glucose
(Fig. S5). The chiral recognition is therefore driven by the
intrinsic chirality of the proline residue. The observation
of an isosbestic point at 258 nm in the absorption
titration profiles of L-1 with L-glucose (Fig. 1a) suggests
the
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We next evaluated the interactions of receptors L-/D-1
to 4 with L-/D-glucose via absorption and CD titrations.
Fig. 1a-d shows the absorption and CD spectral traces of L-
1 upon addition of L- and D-glucose, respectively. Both the
absorption and CD spectral responses of L-1 toward L-
glucose are much more dramatic than those to D-glucose,
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The elegant work of Drueckhammer et al.21 determined
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that in order to achieve strong binding with glucose the
two boronic acid groups should be appropriately
positioned. Therefore, we expected that the four receptors
with different boronic acid positioning would display
differential binding towards glucose. Comparative assays
using CD signaling (Fig. S10) confirms that L-/D-1 exhibit
the highest chiral recognition between the L-/D-
enantiomers of glucose amongst receptors 1-4. L-4, despite
being less capable, showed chiral recognition towards L-
glucose. Unlike the other receptors, L-2 exhibited a
significant response in its CD at 244 nm toward L-glucose
(Fig. S10c), while a distinct band at 255 nm was discovered
in the presence of D-glucose (Fig. S10d). No significant
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Table 1. Binding constants of receptors 1-4 with L-/D-
glucose.a
Ka ± sd, 103 M-1
Receptor
L-glucose
D-glucose
L-1 (m,m’-)
6.72 ± 0.66
0.85 ± 0.09
D-1 (m,m’-)
L-2 (m,p’-)
D-2 (m,p’-)
L-3 (p,m’-)
D-3 (p,m’-)
L-4 (p,p’-)
D-4 (p,p’-)
0.62 ± 0.08
4.01 ± 0.23
5.42 ± 0.55
3.36 ± 0.27
3.52 ± 0.93
3.56 ± 0.32
[b]
0.48 ± 0.07
[b]
0.68 ± 0.22
0.51 ± 0.08
0.64 ± 0.11
[b]
1.0 ± 0.11
Figure 1. Absorption (a, b, e, f) and CD (c, d, g, h) spectra of
L-1 (a-d) and D-1 (e-h) in the presence of L- or D-glucose in 1:1
(v/v) MeOH/0.05 M pH 10.0 NH4Cl-NH3·H2O buffer. [L-1] =
[D-1] = 30 μM, [glucose] = 0 - 6 mM.
[a]
Binding constants (Ka) were obtained by nonlinear fitting
of the CD signal as a function of glucose concentration
assuming a 1:1 stoichiometry. [Receptor] = 30 μM, T = 298 K.
Due to minor changes in CD spectra accurate Ka values
could not be fitted.
[b]
formation of a boronate of defined composition. This is
significant since there are two boronic acid groups in L-1
and there are two cis-diol moieties in α-L-furanoglucose
(Scheme 1b) which can interact. Job plot experiments
under total concentrations of o.5 mM and 1.0 mM both
indicated a 1:1 stoichiometry between L-1 and L-glucose
(Fig. S6).27,28 Mass spectrometry provided direct evidence
for the 1:1 interaction. A mixture of L-1 (3 mg) and 200
equivalents of L-glucose incubated in 1:1 (v/v) MeOH/0.05
M pH 10.0 NH3-NH4Cl buffer for 3 hr afforded a distinct
peak at m/z 491.1795 (Fig. S7), which corresponds to the
1:1 cyclic diboronate of calculated m/z 491.1719 for
C24H24B2N2O8 ([M+H]+). Control compounds of L-1, L-5
and L-6 (Scheme 1a) that bear only one phenylboronic
acid group were found to show very small spectral
responses toward L-/D-glucose (Fig. S8 and S9). We
therefore propose that a two-point interaction occurs
between L-1 and L-glucose and that each phenylboronic
acid group in L-1 interacts with a cis-diol moiety in L-
glucose, leading to a cyclic boronate, likely in a
cooperative manner. A substantial increase in the CD
signal of L-1 upon interaction with L-glucose supports this
conclusion since it suggests a rigid conformation of the
formed boronate.
change in the CD spectrum of L-3 was observed upon the
addition of L-glucose (Fig. S10e), while a weak CD signal
was observed in the presence of D-glucose (Fig. S10f). The
binding constants (Ka) obtained using nonlinear fitting
for a 1:1 binding27 of the CD data are listed in Table 1,
which indicates that the L-1/L-glucose and D-1/D-glucose
binding of Ka (5 - 7) × 103 M-1 (Table 1) is stronger than
that of the L-1/D-glucose and D-1/L-glucose of Ka (0.6 –
0.9) × 103 M-1 (For titration curves see Fig. S11 and S12),
indicating the chiral recognition of L-1 towards L-glucose
and D-1 towards D-glucose.
Chiral recognition of receptor L-1 was also examined for
other monosaccharides, such as D-/L-mannose, D-/L-
xylose and D-galactose that bear two sets of cis-diols yet
of different distance or relative orientation, or D-fructose
that bears only one set of cis-diol (Scheme 1b). No
significant changes in the CD spectra were observed (Fig.
S19 and S20), suggesting weak interaction occurred and
the chiral recognition was not significant. This means that
the ability of the proline-based receptor L-1 for chiral
recognition of L- over D-glucose is highly selective.
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resonances at around 2.10 ppm is accompanied by the
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disappearance of resonances at 1.95 ppm. Upon addition
of D-glucose, however, resonances of the aromatic
protons of L-1 became irregular and broad (Fig. 2b and
S22). This is indicative of a weaker and loose interaction
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for L-1 with D-glucose. The H NMR titrations therefore
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confirmed that the chiral recognition of L-1 towards L-
glucose results from the formation of the 1:1 cyclic
diboronate complex via a two-point interaction (Fig. 3).
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This was further supported by the fact that the H NMR
profiles remain unchanged when the titrations were
performed at dilutting concentrations of L-1 of 4, 3, 2, 1,
0.5, 0.1 and 0.05 mM with 6 eq of L-glucose (Fig. S23).
Likewise the chiral recognition of D-1 for D-glucose over L-
glucose was demonstrated in Fig. 2c, contrasting the well-
resolved 1H NMR of D-1/D-glucose boronate complex with
the irregular and blurred 1H NMR of D-1/L-glucose
boronate complex. According to H NMR data, the trans-
to cis-conformation ratio is ca. 1.3 in L-1, which dropped
slightly to 1.0 in the L-1/L-glucose boronate (Fig. S24).
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DFT optimized structure of the trans-L-1 is slightly (3.61
kJ mol-1) more stable than the cis-conformer (Fig. S25a),
which agrees with the observed trans-/cis-ratio of 1.3 in
solution (Fig. 3). This was also supported by the crystal
structure of the bromide precursor of D-1, D-1Br of the
trans-conformation (Scheme 1a and Fig. S26) and the
similar CD profiles of D-1Br and D-1 (Fig. S27). Moreover,
the optimized structures indicate that the boronates of
both trans- and cis-forms of L-1 are more stable than the
corresponding L-1/D-glucose boronates, again showing
the favored interactions of L-1 with L-glucose against D-
glucose (Fig. S28 and S29). It should be pointed out that
the two-point binding of L-1 with D-glucose was only
assumed for the purpose of calculations, it actually did
not exist as revealed by their huge energy difference and
Figure 2. Chiral recognition for glucose by 1H NMR
signalling. Partial H NMR spectra of L-1 upon addition of L-
glucose (a), and L-1 (b) and D-1 (c) in the presence of 6 eq L-
glucose and D-glucose, respectively, in pH 9 NH3-NH4Cl
buffer in D2O. [1] = 5 mM; [NH4Cl] + [NH3] = 50 mM.
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the irregular H NMR spectrum (Fig. 2b). Calculations
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showed that the optimized boronate of L-glucose of cis-
form L-1 is more stable than that of the trans-form L-1
(Fig. S25b), which explained the lowered ratio of the L-
glucose boronates of trans- to cis-L-1, being 1.0, compared
to that (1.3) of the trans- to cis- L-1 (Fig. 2 and 3).
For understanding the binding of 1 with glucose, we
1
performed H NMR titrations. The resonances of protons
on the aromatic ring (Fig. 2a) and the proline methylene
region (δ 2.0-2.5 ppm, Fig. S21) of L-1 in D2O buffer
changed significantly upon addition of L-glucose. In
particular, the resonances of the aromatic protons
become well-resolved in the presence of 1 eq or more of L-
glucose, indicating thatL-1 binds tightly with L-glucose to
generate a rigid structure,29 in agreement with the
appearance of an isosbestic point in the absorption
spectral evolution and adramatic change in CD signal
(Fig. 1a, c). These observations support the two-point
interaction mode for L-1 with L-glucose. Meanwhile, the
signals of the methylene protons at 2.50 ppm disappear
and new signals at 2.45 ppm appear (Fig. S21), indicating a
shift of the conformation equilibrium of L-1 towards the
cis-conformer upon the formation of the L-1/L-glucose
boronates. A similar observation was made for the
resonance around 2 ppm in that an enhancement of the
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the 19F NMR spectra of L-8, L-9, and L-10 are much simpler
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than the H NMR spectrum of L-1 (Fig. 2a). 19F NMR
spectra of L-8 and the complex formed on the addition of
6 equivalents of D-/L- monosaccharides are shown in
Figure 4. Only with L-glucose, the 19F NMR of L-8
appeared as a well-resolved pattern, suggesting that L-8
and L-glucose forms a stable boronate of defined
stoichiometry. This demonstrates the chiral recognition
of L-8 for L-glucose, a conclusion that was also made for
its analogue L-1 with L-glucose shown by the 1H NMR and
CD analyses. Again, the chiral recognition was observed
for L-glucose, but not the other monosaccharides despite
subtle differences in terms of the distance and relative
orientation of the two sets of cis-diols (Fig. 1b). The ratios
of the trans- to cis-conformation of free L-8 and L-8/L-
glucose boronate are 1.3 and 1.0, respectively, calculated
from the 19F NMR data (Fig. S34), close to those of L-1 and
its L-glucose boronate obtained from 1H NMR data.
Similar observations were found for L-9 and L-10 in their
19F NMR response toward L-glucose, producing well-
resolved spectra (Fig. S35-S39). 19F NMR titrations also
allowed the L-/D-glucose binding constants of L-8 and L-
10 to be evaluated as (2.5 ± 0.3) × 103 M-1/(0.4 ± 0.09) × 103
M-1 and (1.9 ± 0.4) × 103 M-1/(0.3 ± 0.04) × 103 M-1 (Table
S2), respectively. Meanwhile, substantial changes in the
absorption and CD spectra of L-8, L-9, and L-10 (Fig. S40-
S42) allowed the binding constants with L-glucose to be
evaluated as (3.62 ± 0.17) × 103 M-1, (5.67 ± 0.28) × 103 M-1,
and (3.48 ± 0.15) × 103 M-1(see Fig. S43-S45, Table S3),
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Figure 3. DFT-optimized structures of trans- and cis-L-1 (a)
and the corresponding boronates with L-glucose (b) in H2O
at B3LYP/6-31G* level. The ratio of trans- to cis-conformation
were calculated from 1H NMR data given in Figure S24.
By using the more flexible alanine counterparts of L-/D-
1, L-/D-7 (Scheme 1a), we found that their absorption, CD,
and 1H NMR did not change much in the presence of L- or
D-glucose (Fig. S30-S32). These observations pointed to
the important contribution of the rigidity of the proline
19
respectively, comparable to those obtained from F NMR
titrations.
residue in
1 for the chiral recognition of L-/D-
glucose.17,19,30,31
CONCLUSIONS
In conclusion, we have successfully developed proline
based receptors for chiral recognition. Highly efficient
and selective chiral recognition was demonstrated for L-
/D-glucose using the designed diboronic acid meta-
substituted derivatives of rigid L-/D-proline constructed
using amide bonds at both the N- and C-termini of the
proline residue. The limited conformational flexibility of
the receptor molecule, thanks to the conformational
character of the proline residue, was shown to be locked
within the formed of 1:1 cyclic diboronates with glucose
1
using two-points of interaction. H NMR clearly displays
the conformational change in the receptor molecule upon
interaction with glucose since the formed boronate
produces well-resolved NMR spectra. The strategy has
been successfully extended by the introduction of fluorine
atoms onto the phenyl rings of receptor L-1 thus enabling
the use of spectrally simpler 19F NMR to determine the
chiral recognition of L-8, L-9, or L-10 with L-glucose. The
strategy of using the proline residue to build receptors for
chiral recognition is expected to be of general utility,
since suitable combinations of binding sites can be
introduced stepwise to the N- and C-termini of the
proline residue. We are currently exploring the use of
different receptors in order to develop a number of chiral
receptors using this modular approach, preliminary work
Figure 4. 19F NMR spectra of L-8 in the presence of given
monosaccharide in pH 9.0 buffer in D2O. [L-8] = 5 mM,
[saccharide] = 30 mM.
In order to establish the potential utility of the proline-
based structural framework, we introduced fluorine
atoms into the phenylboronic acid moieties so that the
spectrally simpler 19F NMR32-36 might be employed to
evaluate the chiral recognition. Fluorine-containing
receptors L-8 to L-10 (Scheme 1a) that correspond to L-1
were synthesized. Three sets of 19F NMR signals were
observed for L-8 and were assigned to Fa and Fb on the
two aromatic rings respectively (Scheme 1a), by referring
19
to the F NMR spectra of L-9 and L-10 (Fig. S33). Indeed,
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on chiral recognition of L-/D-Dopa appears to be
promising.
1H), 2.06 - 1.84 (m, 3H), 1.51 (s, 9H). 13C{1H} NMR (214
1
2
3
4
5
6
7
8
MHz, CDCl3) δ (ppm) 170.1, 156.7, 139.7, 130.1, 126.7, 122.5,
118.0, 81.1, 60.5, 47.3, 28.4, 27.2, 24.6. HRMS (FTICR MS
ESI+) [M+Na]+ calcd for C16H21NaBrN2O3: 391.0628, found
391.0628.
EXPERIMENTAL SECTION
General Experimental Information. All reagents
were purchased from commercial sources and were used
without further purification. Solvents for spectral
titrations were deionized water and redistilled MeOH.
Boc Deprotection (b). a (2 g, 5.4 mmol) was dissolved
in 20 mL methylene dichloride. Then TFA (8 mL) was
added to the mixed solution dropwise followed by stirring
at room temperature for 2 h. Solvent was removed under
reduced pressure to yield a white solid.
Details of the synthesis of 1 to 10 are given in the
9
Supporting Information (SI) together with full
1
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characterization by H NMR, C NMR, and HRMS. Flash
General Procedure for the (c). m-Bromobenzoic acid
chromatography was carried out on silica gel (230 − 400
(1.21 g, 6 mmol) in dichloromethane (10 mL) was stirred at
1
13
o
mesh). H NMR and C NMR spectra (CDCl3 or CD3CN)
were recorded on Bruker AV500MHz, AV600MHz or
AV850MHz spectrometer; highre solution mass spectra
(HRMS) were acquired on Bruker En Apex ultra 7.0 TFT-
MS spectrometer. The melting point range was recorded
by Melting Point M-560. Circular dichroism (CD) spectra
were obtained on Jasco J-810 or Biologic spectrometer.
Absorption spectra were obtained on Thermo Evolution
300 spectrometer with a 1 cm standard quartz cell. Job
plot was obtained from absorption measurements of 11
solutions with fixed total concentration of L-1 and L-
glucose at 0.5 mM and 1 mM respectively.
0 C, to which HOBt (1.05 g, 7.8 mmol), EDCI (1.72 g, 9
mmol), trimethylamine (5 mL, 36 mmol) were added and
the resultant mixture was stirred at this temperature for
30 min. To this mixture was added dropwise the above
white solid product dissolved in dichloromethane, which
was allowed to react at room temperature overnight. The
mixture was washed with 0.1 M HCl (3 × 10 mL), saturated
sodium bicarbonate solution (3 × 10 mL), saturated
sodium chloride solution (3 × 10 mL) respectively, and the
organic layer was dried with anhydrous Na2SO4. The
solution was evaporated to afford a crude oil. After
washing with the mixed solvent of petroleum
ether/EtOAc (5/1, v/v) (4 × 10 mL) to afforded a white
Absorption and CD spectral measurements were carried
out using a stock solution of 1 of 2 mM in MeOH, which
was diluted with 1:1 (v/v) MeOH/0.05 M pH 10.0 NH4Cl
buffer to afford the desired concentration of 1 at 30 μM, to
which 0 - 6 mM of L-glucose and D-glucose or other guest
species were added and recorded CD and UV spectra after
30 min.
1
solid c (1.970 g, 80.7 %), mp 220-221 °C. H NMR (500
MHz, CDCl3) δ (ppm) δ 9.61 (s, 1H), 7.82 (s, 1H), 7.71 (s,
1H), 7.61 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 7.0 Hz, 1H), 7.32
(dd, J = 16.2, 7.8 Hz, 2H), 7.14 (d, J = 7.4 Hz, 1H), 7.06 (t, J
= 7.6 Hz, 1H), 4.93 (s, 1H), 3.58 (d, J = 42.9 Hz, 2H), 2.50 (s,
1H), 2.14 (s, 2H), 1.91 (s, 1H). 13C{1H} NMR (125 MHz, CDCl3)
δ (ppm) 169.9, 169.1, 139.4, 137.7, 133.6, 130.2 130.16 , 130.0,
126.9, 125.7, 122.6, 122.5, 122.5, 118.1, 61.1, 50.7, 27.5, 25.4.
HRMS (FTICR MS ESI+) [M+Na]+ calcd for
C18H16NaBr2N2O2: 472.9471, found 472.9475.
1H NMR and 19F NMR spectral measurements were
recorded using a stock solution of 1 of 5 mM in D2O and
adjusted the pH reach to 9 by NH4Cl and NaOD. L-/D-
glucose and other monosaccharides were dissolved in
D2O to obtained 0.1 M concentrated solutions. Then 0 - 30
mM (0 - 6 equivalent) of L- or D-glucose was added to
solution 1 respectively, the mixture was incubated at 27 °C,
General Procedure for L-1. c (1.97 g, 4.4 mmol), boric
acid pinacol ester (3.35 g, 13.2 mmol) and KOAc (2.68 g,
26.4 mmol) in DMF was stirred under nitrogen at room
temperature for 30 min. Then Pd(dppf)Cl2 (0.2 g) was
added. In nitrogen atmosphere, the mixture was stirred at
1
after 30 min, the H NMR and 19F NMR spectra were
recorded using Bruker AV500MHz or AV600MHz
spectrometer.
o
80 C in oil bath for 24 h. After which the mixture was
allowed to cool down and filtered. The filtrate was
evaporated in vacuo to obtain a crude mixture solid. The
target compound L-1 was isolated by silica
chromatography eluted by petroleum ether/ EtOAc (20/1
General Procedure for Preparation of Proline
based Receptors.
General Procedure for the (a). Boc-L-proline (2.15 g,
10 mmol) was dissolved in dichloromethane under
stirring in ice bath, to which trimethylamine (2.5 mL) and
isobutyl chloroformate (1.7 mL, 13 mmol) were added. The
mixture was kept in ice-bath for 30 min. 3-
Bromobenzenamine (1.09 mL, 10 mmol) was next added
dropwise and the solution was stirred at room
temperature overnight. Solvent was removed in vacuo to
lead to a crude mixture solid. This solid was washed with
water, and the residue was washed with petroleum
ether/EtOAc (8/1, v/v) (4 × 10 mL) to afford a white solid
a (2.740 g, 74%), mp 211-212 °C. 1H NMR (850 MHz, CDCl3)
δ (ppm) 9.65 (s, 1H), 7.82 (s, 1H), 7.34 (s, 1H), 7.14 (d, J =
41.8 Hz, 2H), 4.47 (s, 1H), 3.39 (d, J = 74.6 Hz, 2H), 2.50 (s,
1
- 8/1, v/v) (0.800 g, 33 %), mp 210-221 °C. H NMR (500
MHz, CDCl3) δ (ppm) 9.48 (s, 1H), 7.94 (s, 1H), 7.87 (t, J =
6.9 Hz, 2H), 7.82 (s, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.51 (d, J
= 7.2 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H),
4.98 (dd, J = 7.8, 4.3 Hz, 1H), 3.53 (dtd, J = 17.4, 10.6, 7.0 Hz,
2H), 2.69 (dt, J = 11.3, 5.9 Hz, 1H), 2.11 (tt, J = 13.6, 6.9 Hz,
1H), 2.04 - 1.96 (m, 1H), 1.93 - 1.83 (m, 1H), 1.33 (d, J = 10.3
Hz, 24H). 13C{1H} NMR (125 MHz, CDCl3) δ (ppm) 172.1,
168.6, 137.8, 136.6, 135.4, 133.2, 130.4, 129.8, 128.4, 127.9,
125.9, 122.8, 84.1, 83.8, 60.7, 50.6, 26.3, 25.4, 24.9. HRMS
(FTICR MS ESI+) [M+Na]+ calcd for C30H40NaB2N2O6:
569.2965, found 569.2976.
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Compounds 1-10 were synthesized by the same
Page 8 of 11
60.9, 50.8, 26.5, 25.5, 25.0. HRMS (FTICR MS ESI+)
[M+H]+ calcd for C30H41B2N2O6: 547.3145, found 547.3158.
1
2
3
4
5
6
7
8
procedures.
Compound D-1: White solid; 0.820 g, 34 % yield; mp
223-224 °C. H NMR (500 MHz, CDCl3) δ (ppm) 9.50 (s,
Compound L-4. White solid; 0.823 g, 34 % yield; mp
296-297 °C. H NMR (500 MHz, CDCl3) δ (ppm) 9.65 (s,
1
1
1H), 7.94 (s, 1H), 7.88 (d, J = 7.6 Hz, 2H), 7.82 (s, 1H), 7.60
(d, J = 7.6 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.43 (t, J = 7.5 Hz,
1H), 7.32 (t, J = 7.7 Hz, 1H), 4.99 (dd, J = 7.8, 4.3 Hz, 1H),
3.52 (dtd, J = 17.4, 10.6, 6.9 Hz, 2H), 2.70 (td, J = 11.8, 6.3
Hz, 1H), 2.17 - 2.06 (m, 1H), 2.04 - 1.96 (m, 1H), 1.93 - 1.82
1H), 7.86 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.58
(d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 4.98 (dd, J =
8.0, 4.3 Hz, 1H), 3.49 (ddt, J = 39.4, 10.7, 6.8 Hz, 2H), 2.69
(dt, J = 17.2, 6.1 Hz, 1H), 2.16 - 1.95 (m, 2H), 1.87 (tt, J = 12.5,
6.3 Hz, 1H), 1.34 (d, J = 10.1 Hz, 24H). C{1H} NMR (125
13
9
13
(m, 1H), 1.33 (d, J = 10.9 Hz, 24H). C{1H} NMR (125 MHz,
MHz, CDCl3) δ (ppm) 172.0, 168.9, 141.0, 138.3, 135.8, 134.9,
131.7, 126.3, 121.3, 118.8, 84.2, 83.8, 60.9, 50.6, 26.6, 25.5,
25.0. HRMS (FTICR MS ESI+) [M+H]+ calcd for
C30H41B2N2O6: 547.3145, found 547.3159.
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CD3CN) δ (ppm) 171.3, 170.9, 139.3, 137.4, 136.7, 133.9, 130.7,
129.4, 128.8, 126.4, 123.6, 85.1, 84.9, 62.3, 51.2, 29.9, 26.1,
25.2. HRMS (FTICR MS ESI+) [M+H]+ calcd for
C30H41B2N2O6: 547.3145, found 547.3155.
Compound D-4. White solid; 0.770 g, 32 % yield; mp
1
Compound L-2: White solid; 0.780 g, 32 % yield; mp
147-148 °C. 1H NMR (500 MHz, CDCl3) δ (ppm) 9.43 (s, 1H),
7.97 - 7.72 (m, 4H), 7.51 (t, J = 7.5 Hz, 3H), 7.32 (t, J = 7.7
Hz, 1H), 4.98 (d, J = 2.9 Hz, 1H), 3.49 (dtd, J = 17.2, 10.6,
6.8 Hz, 2H), 2.68 (dd, J = 10.3, 5.0 Hz, 1H), 2.18 - 1.95 (m,
300-301 °C. H NMR (500 MHz, CDCl3) δ (ppm) 9.67 (s,
1H), 7.86 (d, J = 7.3 Hz, 2H), 7.75 (d, J = 7.8 Hz, 2H), 7.58
(d, J = 7.8 Hz, 2H), 7.49 (d, J = 7.4 Hz, 2H), 4.99 (dd, J =
5.4, 2.5 Hz, 1H), 3.49 (dq, J = 23.1, 8.4 Hz, 2H), 2.69 (dd, J =
10.0, 5.1 Hz, 1H), 2.17 - 1.94 (m, 2H), 1.93 - 1.80 (m, 1H), 1.34
13
2H), 1.94 - 1.81 (m, 1H), 1.33 (d, J = 17.0 Hz, 24H). C{1H}
(d, J = 10.0 Hz, 24H). C{1H} NMR (125 MHz, CDCl3) δ
13
NMR (125 MHz, CDCl3) δ (ppm) 170.7, 167.7, 137.3, 136.7,
133.8, 129.4, 127.4, 125.2, 124.8, 121.8, 83.1, 82.8, 59.7, 49.4,
25.5, 24.4, 23.8. HRMS (FTICR MS ESI+) [M+Na]+ calcd for
C30H40NaB2N2O6: 569.2965, found 569.2977.
(ppm) 172.2, 168.7, 141.1, 138.4, 135.9, 135.0, 131.9, 126.3, 121.5,
118.9, 84.3, 83.8, 60.9, 50.6, 26.3, 25.5, 25.0. HRMS (FTICR
MS ESI+) [M+Na]+ calcd for C30H40NaB2N2O6: 569.2965,
found 569.2982.
Compound D-2. White solid; 0.805 g, 33 % yield; mp 151-
152 °C. H NMR (500 MHz, CDCl3) δ (ppm) 9.42 (s, 1H),
Compound L-5. White solid; 0.910 g, 43 % yield; mp 214-
215 °C. H NMR (850 MHz, CDCl3) δ (ppm) 9.62 (s, 1H),
1
1
7.85 (dd, J = 13.5, 7.3 Hz, 4H), 7.51 (t, J = 7.2 Hz, 3H), 7.32 (t,
J = 7.7 Hz, 1H), 4.97 (dd, J = 7.9, 4.3 Hz, 1H), 3.49 (ddt, J =
45.7, 10.6, 6.9 Hz, 2H), 2.67 (td, J = 11.8, 6.2 Hz, 1H), 2.16 -
1.96 (m, 2H), 1.92 - 1.80 (m, 1H), 1.33 (d, J = 16.8 Hz, 24H).
13C{1H} NMR (125 MHz, CDCl3) δ (ppm) 172.0, 168.7, 138.5,
137.9, 134.9, 130.5, 128.5, 126.3, 126.0, 122.9, 84.3, 84.0, 60.8,
50.6, 26.5, 25.5, 25.0. HRMS (FTICR MS ESI+) [M+Na]+
calcd for C30H40NaB2N2O6: 569.2965, found 569.2974.
7.96 (s, 1H), 7.91 (d, J = 7.3 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H),
7.59 (d, J = 7.9 Hz, 2H), 7.46 (t, J = 7.5 Hz, 1H), 7.32 (t, J =
7.8 Hz, 2H), 7.10 (t, J = 7.2 Hz, 1H), 5.01 (dd, J = 7.8, 4.4 Hz,
1H), 3.56 (ddt, J = 84.3, 10.6, 6.9 Hz, 2H), 2.71 (td, J = 11.9,
13
6.3 Hz, 1H), 2.19 - 1.86 (m, 3H), 1.36 (s, 12H). C{1H} NMR
(214 MHz, CDCl3) δ (ppm) 171.9, 168.9, 138.3, 136.7, 135.4,
133.1, 129.8, 128.8, 127.9, 123.9, 119.8, 84.1, 60.8, 50.6, 26.8,
25.4, 24.6. HRMS (FTICR MS ESI+) [M+Na]+ calcd for
C24H29NaBN2O4: 443.2113, found 443.2114.
Compound L-3. White solid; 0.793 g, 33 % yield; mp
1
232-233 °C. H NMR (500 MHz, CDCl3) δ (ppm) 9.72 (s,
Compound L-6. White solid; 0.830 g, 39 % yield; mp
212-213 °C. 1H NMR (850 MHz, CDCl3) δ (ppm) 9.44 (s, 1H),
7.89 (d, J = 6.9 Hz, 1H), 7.85 (s, 1H), 7.55 (t, J = 7.4 Hz, 3H),
7.51 - 7.47 (m, 1H), 7.46 (t, J = 6.7 Hz, 2H), 7.35 (t, J = 7.4
Hz, 1H), 5.02 (s, 1H), 3.57 (d, J = 54.8 Hz, 2H), 2.72 (s, 1H),
1H), 7.93 (s, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.75 (d, J = 8.5 Hz,
2H), 7.59 (t, J = 7.0 Hz, 3H), 7.43 (t, J = 7.6 Hz, 1H), 4.99
(dd, J = 7.8, 4.1 Hz, 1H), 3.62 - 3.43 (m, 2H), 2.70 (dt, J =
11.6, 6.1 Hz, 1H), 2.15 - 1.95 (m, 2H), 1.87 (tt, J = 13.1, 6.7 Hz,
1H), 1.33 (d, J = 2.2 Hz, 24H). 13C{1H} NMR (125 MHz,
CDCl3) δ (ppm) 172.2, 168.9, 141.0, 136.8, 135.8, 135.4, 133.2,
129.9, 128.0, 118.9, 84.2, 83.8, 60.9, 50.8, 26.5, 25.5, 25.0.
HRMS (FTICR MS ESI+) [M+H]+ calcd for C30H41B2N2O6:
547.3145, found 547.3158.
13
2.22 - 2.01 (m, 2H), 1.91 (s, 1H), 1.34 (s, 12H). C{1H} NMR
(214 MHz, CDCl3) δ (ppm) 171.9, 168.8, 137.8, 135.9, 130.5,
130.4, 128.5, 128.4, 127.2, 125.9, 122.8, 83.9, 60.7, 50.6, 26.5,
25.5, 24.9, 24.9. HRMS (FTICR MS ESI+) [M+Na]+ calcd for
C24H29NaBN2O4: 443.2113, found 443.2115.
Compound D-3. White solid; 0.840 g, 35 % yield; mp
233-234 °C. H NMR (500 MHz, CDCl3) δ (ppm) 9.73 (s,
Compound L-7: White solid; 0.520 g, 53 % yield; mp 134-
135 °C. H NMR (600 MHz, CDCl3) δ (ppm) 9.12 (s, 1H),
1
1
1H), 7.93 (s, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.75 (d, J = 8.4 Hz,
2H), 7.59 (t, J = 6.9 Hz, 3H), 7.43 (t, J = 7.5 Hz, 1H), 4.99
(dd, J = 7.9, 4.3 Hz, 1H), 3.53 (ddt, J = 49.9, 10.5, 6.8 Hz,
2H), 2.70 (dt, J = 11.6, 6.1 Hz, 1H), 2.05 (ddt, J = 47.4, 20.3,
7.3 Hz, 2H), 1.87 (tt, J = 12.7, 6.4 Hz, 1H), 1.33 (d, J = 2.1 Hz,
24H). 13C{1H} NMR (125 MHz, CDCl3) δ (ppm) 172.3, 168.9,
141.0, 136.8, 135.8, 135.4, 133.2, 129.9, 128.0, 118.9, 84.3, 83.8,
8.21 (s, 1H), 8.03 (d, J = 7.7 Hz, 1H), 7.98 (d, J = 7.3 Hz, 1H),
7.95 (s, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 7.2 Hz, 1H),
7.49 (t, J = 7.6 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H), 7.18 (d, J =
7.1 Hz, 1H), 5.10 (dd, J = 13.9, 6.8 Hz, 1H), 1.66 (d, J = 6.9
Hz, 3H), 1.36 (d, J = 22.5 Hz, 24H). 13C{1H} NMR (151 MHz,
CDCl3) δ (ppm) 170.7, 167.8, 138.4, 137.5, 133.0, 132.8, 130.84,
130.7, 128.5, 128.4, 126.2, 123.3, 84.3, 84.0, 50.3, 25.0, 24.99,
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The Journal of Organic Chemistry
24.98, 24.96, 18.7. HRMS (FTICR MS ESI+) [M+Na]+ calcd
for C28H38NaB2N2O6: 543.2808, found 543.2803.
Hz, 1H), 7.06 (t, J = 8.0 Hz, 1H), 5.00-4.87 (m, 1H), 3.62 (dd,
1
2
3
4
5
6
7
8
J = 11.4, 5.7 Hz, 1H), 3.57-3.47 (m, 1H), 2.57-2.42 (m, 1H),
2.26-2.07 (m, 2H), 1.93 (ddd, J = 18.3, 14.6, 5.9 Hz, 1H). 13C
NMR (125 MHz, CDCl3) δ (ppm) 169.8, 169.0, 139.4, 137.7,
133.6, 130.2, 130.2, 130.0, 126.9, 125.7, 122.7, 122.5, 122.5, 118.0,
61.1, 50.7, 27.4, 25.4. HRMS (FTICR MS ESI+) [M+Na]+
calcd for C18H16NaBr2N2O2: 472.9471, found 472.9477.
Compound D-7. White solid; 0.600 g, 56 % yield; mp
132-133 °C. 1H NMR (600 MHz, CDCl3) δ (ppm) 9.10 (s, 1H),
8.21 (s, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 7.3 Hz, 1H),
7.94 (s, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 7.3 Hz, 1H),
7.53 - 7.44 (m, 1H), 7.34 (t, J = 7.7 Hz, 1H), 7.15 (dd, J = 22.6,
7.4 Hz, 1H), 5.43 - 4.84 (m, 1H), 1.66 (d, J = 6.9 Hz, 3H),
1.36 (d, J = 22.5 Hz, 24H). 13C{1H} NMR (151 MHz, CDCl3) δ
(ppm) 170.7, 167.8, 138.4, 137.5, 133.0, 132.7, 130.8, 130.7,
128.6, 128.4, 126.2, 123.3, 84.3, 84.0, 50.3, 25.0, 24.99, 24.98,
24.96, 18.7. HRMS (FTICR MS ESI+) [M+Na]+ calcd for
C28H38NaB2N2O6: 543.2808, found 543.2816.
ASSOCIATED CONTENT
Supporting Information
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The Supporting Information is available free of charge on the
ACS publications website.
Synthesis; absorption and CD titration curves; 19F NMR
1
spectral titration profiles; H, 13C NMR and HRMS spectra of
Compound L-8. White solid; 0.430 g, 49 % yield; mp
182-183 °C. 1H NMR (500 MHz, CDCl3) δ (ppm) 9.55 (s, 1H),
7.84 (d, J = 11.0 Hz, 1H), 7.70 (s, 1H), 7.56 (dd, J = 8.6, 2.3
Hz, 1H), 7.43 (s, 1H), 7.31 (d, J = 8.7 Hz, 1H), 7.19 (dd, J =
8.4, 2.2 Hz, 1H), 4.94 (dd, J = 7.9, 4.4 Hz, 1H), 3.59 (dt, J =
10.6, 6.8 Hz, 1H), 3.47 (dt, J = 10.7, 7.0 Hz, 1H), 2.68 (td, J =
12.0, 6.3 Hz, 1H), 2.12 (dq, J = 14.1, 7.1 Hz, 1H), 2.01 (dt, J =
15.1, 7.5 Hz, 1H), 1.95 - 1.85 (m, 1H), 1.32 (d, J = 11.6 Hz,
24H). 13C{1H} NMR (125 MHz, CDCl3) δ (ppm) 170.7, 168.5,
163.5, 163.0, 161.8, 161.4, 139.3, 139.2, 137.31, 137.27, 128.8,
123.2, 123.1, 121.2, 117.1, 117.0, 116.4, 116.2, 110.2, 110.0, 84.5,
84.2, 60.9, 50.6, 26.3, 25.4, 24.9, 24.8. HRMS (FTICR MS
ESI+) [M+Na]+ calcd for C30H38NaB2F2N2O6: 605.2776,
found 605.2787.
1-10, computational data and others (PDF). Crystallographic
information for D-1Br (CCDC 1574044) (CIF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: ybjiang@xmu.edu.cn
*E-mail: t.d.james@bath.ac.uk
ORCID
Yun-Bao Jiang, 0000-0001-6912-8721
Notes
Compound L-9. White solid; 0.420 g, 52 % yield; mp
216-217 °C. 1H NMR (500 MHz, CDCl3) δ (ppm) 9.72 (s, 1H),
7.94 (s, 1H), 7.88 (d, J = 7.3 Hz, 1H), 7.84 (d, J = 11.0 Hz, 1H),
7.60 (d, J = 7.6 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 7.21 - 7.15
(m, 1H), 4.97 (dd, J = 7.9, 4.4 Hz, 1H), 3.65 - 3.53 (m, 1H),
3.52 - 3.41 (m, 1H), 2.68 (td, J = 11.5, 6.0 Hz, 1H), 2.10 (dq, J
= 20.1, 6.7 Hz, 1H), 2.00 (dt, J = 20.4, 7.5 Hz, 1H), 1.95 - 1.82
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank Professor Eric V. Anslyn of the University of Texas
at Austin for useful discussion. We are grateful for the
financial support from the NSF of China (grants 21435003,
91427304, 21521004, and J1310024), the Ministry of Education
of China (grant IRT13036) and the NSFC RS Joint Project
(grant 21311130122).
13
(m, 1H), 1.32 (d, J = 15.3 Hz, 24H). C{1H} NMR (125 MHz,
CDCl3) δ (ppm) 172.3, 168.7, 163.5, 161.8, 139.4, 139.3, 136.7,
135.2, 133.1, 129.8, 127.9, 121.2, 116.3, 116.1, 110.2, 110.0 (d, J =
20.5 Hz), 84.2, 84.1, 60.7, 50.7, 26.1, 25.4, 25.0, 24.9, 24.8.
HRMS (FTICR MS ESI+) [M+Na]+ calcd for
C30H39NaB2FN2O6: 587.2870, found 587.2876.
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10.3 Hz, 1H), 7.31 (dd, J = 16.4, 8.2 Hz, 2H), 7.14 (d, J = 7.9
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