Selective saccharide recognition using modular diboronic acid fluorescent sensors

Article abstract of DOI:10.1002/ejoc.201101633

Modular diboronic acid receptors R-1 and S-1 were synthesized and found to be selective fluorescent chemosensors for saccharides. The fluorescence intensity of R-1 and S-1 increased on addition of saccharides due to the formation of intramolecular 1:1 cyc

Full text of DOI:10.1002/ejoc.201101633

FULL PAPER
DOI: 10.1002/ejoc.201101633
Selective Saccharide Recognition Using Modular Diboronic Acid Fluorescent
Sensors
Zhitao Xing,[a,b] Hui-Chen Wang,[b] Yixiang Cheng,[a] Chengjian Zhu,*[a] Tony D. James,*[b]
and Jianzhang Zhao[c]
Keywords: Sensors / Chirality / Receptors / Boronic acid / Saccharides / Fluorescence
Modular diboronic acid receptors R-1 and S-1 were synthe-
sized and found to be selective fluorescent chemosensors for
saccharides. The fluorescence intensity of R-1 and S-1 in-
creased on addition of saccharides due to the formation of
intramolecular 1:1 cyclic complexes. In general, R-1 has
higher binding constants and produces a higher fluorescent
response with saccharides than S-1.
hydroxy carboxylic acids,[7] d-glucuronic acid,[8] d-glucaric
acid,[9] mandelic acid[10] and ginsenosides[11] have been re-
ported.
Introduction
Saccharides are of great importance to a wealth of bio-
logical functions within nature. By providing the building
blocks for processes that range from the production of
metabolic energy through to tissue recognition, saccharides
are the focus of a vast body of research aimed at under-
standing and mimicking their specific role and function at
a cellular level.[1]
Much recent attention has been directed to the develop-
ment of synthetic molecular receptors with the ability to
selectively recognize small molecules involved in biological
pathways. Fluorescent sensors are preferred, because they
are well suited for in vivo probes, which are required to
map the spatial and temporal distribution of the biological
analytes.[2] Many synthetic receptors developed for neutral
guests rely on noncovalent interactions for recognition,
such as hydrogen bonding.[3] However, in aqueous systems,
neutral guests may become heavily solvated, which makes
We have previously developed modular photoinduced
electron transfer (PET) sensors that contain two phenylbo-
ronic acid groups with a hexamethylene linker, which were
selective towards d-glucose.[12] In this work, we decided to
explore the possibility of using chiral units to enhance the
fluorescent response towards saccharides. Therefore, we
synthesized PET sensors that contain chiral units R-1, S-1,
R-2 and S-2 and nonchiral units 3a,b and 4 as model sys-
tems (Schemes 1, 2 and 3). The binding of these receptors
towards representative saccharides was then evaluated
(Scheme 4).
Results and Discussion
The synthesis of chiral sensors R-1, S-1, R-2 and S-2 was
recognition by hydrogen-bonding receptors significantly achieved according to Scheme 2 with (1R)- or (1S)-1-(1-
more challenging.[4]
naphthyl)ethanamine and (1R)- or (1S)-1-(4-meth-
Boronic acid receptors have attracted considerable inter- oxyphenyl)ethanamine, respectively, as chiral building
est due to their ability to bind guests in aqueous media.[5] blocks. The nonchiral sensors 3a,b and 4 were also prepared
Fluorescent boronic acid based sensors for saccharides,[6] α- (Scheme 3). The pH titration curves of R-1 (pKa
=
6.04Ϯ0.07) and S-1 (pKa = 6.08Ϯ0.09), R-1 with d-glucose
(pKa = 8.80Ϯ0.02) and S-1 with d-glucose (pKa
=
[a] State Key Laboratory of Coordination Chemistry, School of
Chemistry and Chemical Engineering, Nanjing University,
Nanjing 210093, P. R. China
8.07Ϯ0.03) are shown in Figure 1. Similar shifts, but to a
lesser degree, are also observed for R-2 and S-2 (Figure S1).
From these curves it is clear that the interaction of R-1 (and
R-2) with d-glucose is stronger than the interaction of S-1
(and S-2) with d-glucose as the saccharide–receptor com-
plex is stable at higher pH values (Figures 1 and S1).
Titrations of 1 and 2 with d-glucose were performed in
52.1% methanol/47.9% H2O buffer (50 mm, pH = 8.21)[13]
as shown in Figure 2. Selective fluorescent enhancement
was observed for R-1 and S-1, and binding constants (K)
with d-glucose of 1177Ϯ162 and 314Ϯ60 dm3 mol–1,
Fax: +86-25-83594886
E-mail: cjzhu@nju.edu.cn
[b] Department of Chemistry, University of Bath,
Bath BA2 7AY, UK
E-mail: t.d.james@bath.ac.uk
[c] State Key Laboratory of Fine Chemicals, School of Chemical
Engineering, School of Chemical Engineering, Dalian
University of Technology,
2 Ling-Gong Road, Dalian 116024, P. R. China
E-mail: zhaojzh@dlut.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101633.
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Scheme 1. Fluorescent sensors for saccharides.
Scheme 2. Synthesis of R-1, S-1, R-2 and S-2. Reagents and conditions: (i) pyridinium chlorochromate (PCC), CH2Cl2; (ii) chiral amine,
MeOH, NaBH4; (iii) trifluoroacetic acid (TFA), CH2Cl2; (iv) pyrene-1-carbaldehyde, MeOH, NaBH4; (v) [2-(bromomethyl)phenyl]boronic
acid pinacol ester, K2CO3, CH3CN, reflux.
respectively, were obtained (KR/KS = 3.7:1.0). In contrast, also show differential selectivity towards d-galactose. The
for R-2 and S-2 with d-glucose, we obtained K = 828Ϯ105 titration of R-1 and S-1 with d-galactose produced binding
and 586Ϯ74 dm3 mol–1, respectively (KR/KS = 1.4:1.0). The constants K = 1229Ϯ98 and 370Ϯ40 dm3 mol–1, respec-
pH and d-glucose titrations indicate that the two chiral tively (KR/KS = 3.3:1.0). Whereas, for R-2 and S-2 with d-
forms [(R) or (S)] of 1 have different binding strengths with galactose, binding constants
d-glucose. The naphthyl group of 1 is bulkier than the 1195Ϯ86 dm3 mol–1 were obtained (KR/KS = 2.2:1.0).
phenyl group of 2, and we believe that these differences in The fluorescence titrations for 1, 2, 3a,b and 4 towards
K = 2670 Ϯ272 and
binding are simply due to the increased steric demand of saccharides in pH = 8.21 aqueous methanolic buffer are
the larger naphthyl group of 1 over the smaller phenyl summarized in Table 1. In all cases, the fluorescence inten-
group of 2. As well as the difference in binding constants sity of 1, 2, 3a,b and 4 increased with increasing saccharide
for R-1 and S-1 with d-glucose, a lower background and concentration (Supporting Information). From Table 1, the
higher fluorescent enhancement was observed with R-1 highest stability constant for R-1 is 1229Ϯ98 dm3 mol–1
than S-1 (Figure 3). R-1 shows 2.85-fold fluorescent en- with d-galactose, whereas the highest stability constant for
hancement vs. 2.20-fold observed for S-1 at a d-glucose S-1 is 799Ϯ61 dm3 mol–1 with d-fructose. The chemoselec-
concentration of 2.2ϫ10–2 moldm–3.
tivities of R-1 and S-1, KR/KS = 3.7:1.0 and 3.3:1.0 for d-
Evaluation of the binding with d-galactose was more glucose and d-galactose, respectively, are consistent with
challenging due to the lower solubility of d-galactose in the the fluorescent enhancement selectivities FR/FS = 4.1:1.0
buffer. However, our titrations indicate that R-1 and S-1 and 3.5:1.0. The highest stability constant for R-2 is
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Saccharide Recognition with Fluorescent Sensors
Scheme 3. Synthesis of 3a,b and 4. Reagents and conditions: (i) pyrene-1-carbaldehyde, MeOH, NaBH4; (ii) TFA, CH2Cl2; (iii) benzalde-
hyde or p-methoxybenzaldehyde, MeOH, NaBH4; (iv) [2-(bromomethyl)phenyl]boronic acid pinacol ester, K2CO3, CH3CN, reflux; (v)
KHF2, H2O/MeOH, LiOH/H2O.
Scheme 4. Analytes used in this study.
Figure 1. Fluorescence intensity/pH profile of R-1 and S-1 with
d-glucose; 1.1ϫ10–7 moldm–3 of sensor in 0.05 moldm–3 sodium
Figure 2. Relative fluorescence intensity of 1 (a) and 2 (b) vs. con-
centration of d-glucose; 1.1ϫ10–7 moldm–3 sensor in 52.1% meth-
chloride ionic buffer (52.1% methanol); [d-glucose]
=
2.2ϫ10–2 moldm–3; λex = 342 nm, λem = 397 nm; 22 °C.
anol/47.9% H2O buffer (50 mm, pH = 8.21); λex = 342 nm, λem
=
397 nm.
2670Ϯ272 dm3 mol–1 with d-galactose, whereas the highest
stability constant for S-2 is 1195Ϯ86 dm3 mol–1 with d-ga- FR/FS = 1.4:1.0 and 2.1:1.0. There is nearly no chemoselec-
lactose. The chemoselectivities of 2 are KR/KS = 1.4:1.0 and tivity for 1 or 2 with d-fructose or d-mannose.
2.2:1.0 for d-glucose and d-galactose, respectively, which
As expected for nonchiral 3a,b and 4, the stability con-
are consistent with the fluorescent enhancement selectivities stants and fluorescent enhancements are similar. Moreover,
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FULL PAPER
In order to confirm that the complex formed between R-
1 and d-glucose was of 1:1 stoichiometry, we performed a
continuous-variation Job plot at pH = 8.21 (Figure 4).
From the Job plot, a maximum is observed at 50%, which
indicates that R-1 forms a 1:1 complex with d-glucose.
Figure 4. Job plot of R-1 with d-glucose at a constant total concen-
tration c (d-glucose) + c (R-1) of 1.0ϫ10–7 moldm–3 in 52.1%
methanol/47.9% H2O buffer (50 mm, pH = 8.21); λex = 342 nm,
λem = 397 nm.
Conclusions
Figure 3. Normalized emission spectra of R-1 (a) and S-1 (b) in
the presence of d-glucose; 1.1ϫ10–7 moldm–3 sensor in 52.1%
methanol/47.9% H2O buffer (50 mm, pH = 8.21); λex = 342 nm.
Diboronic acid sensors R-1, S-1, R-2, S-2, 3a,b and 4
were prepared, and their binding behaviour with saccha-
rides was investigated. Chiral sensors 1 and 2 were found
to be chemoselective fluorescent chemosensors for saccha-
the stability constants and fluorescent enhancements ob- rides, such as d-glucose and d-galactose. R-1 increased its
tained for 3a are comparable to those obtained with fluorescence intensity upon the formation of intramolecular
4[12c,12d] (4 was synthesized as a reference compound), 1:1 complexes with d-glucose. The addition of d-glucose to
which indicates that the pinacol group does not signifi- R-1 caused an increase in fluorescence, whereas the ad-
cantly influence the binding.
dition of d-glucose to S-1 produced smaller changes in fluo-
Table 1. Stability constant K (determination of coefficient, r2), fluorescent enhancement (F) and enantioselectivity (KR/KS) of 1, 2, 3a,b
and 4.
Analyte
K
R-1
F[a]
R-1
KR/KS
Response selectivity[b]
S-1
S-1
d-Glucose
1177Ϯ162(0.99)
314Ϯ60(0.96)
370Ϯ40(0.99)
799Ϯ61(0.99)
72Ϯ3(1.00)
3.0
2.4
3.2
2.8
2.7
2.3
3.0
2.8
3.7:1.0
3.3:1.0
1.1:1.0
1.1:1.0
4.1:1.0
3.5:1.0
1.1:1.0
1.1:1.0
d-Galactose 1229Ϯ98(0.99)
d-Fructose 860Ϯ80(0.99)
d-Mannose 76Ϯ3(1.00)
Analyte
K
R-2
F[a]
R-2
KR/KS
Response selectivity[b]
S-2
S-2
d-Glucose
828Ϯ105(0.98)
586Ϯ74(0.98)
1195Ϯ86(0.99)
1164Ϯ96(0.99)
68Ϯ3(1.00)
2.7
2.3
2.9
2.8
2.7
2.4
2.9
2.8
1.4:1.0
2.2:1.0
1.0:1.0
1.0:1.0
1.4:1.0
2.1:1.0
1.0:1.0
1.0:1.0
d-Galactose 2670Ϯ272(0.99)
d-Fructose 1107Ϯ109(0.99)
d-Mannose 72Ϯ5(1.00)
Sensor
d-Glucose
d-Galactose
d-Fructose
d-Mannose
K [dm3 mol–1]
F[a]
K [dm3 mol–1]
F[a]
K [dm3 mol–1]
F[a]
K [dm3 mol–1] F[a]
3a
3b
4
1465Ϯ183(0.98)
1489Ϯ127(0.99)
1369Ϯ141(0.99)
2.7
2.9
2.6
1156Ϯ56(1.00)
1278Ϯ78(1.00)
1010Ϯ39(0.99)
2.6
2.6
2.6
980Ϯ116(0.98)
1084Ϯ84(0.99)
839Ϯ87(0.99)
3.2
3.2
3.0
72Ϯ3(1.00)
76Ϯ3(1.00)
70Ϯ3(1.00)
3.1
3.0
2.9
[a] Maximum observed fluorescent enhancement. [b] Response selectivity = [K(R)F(R)]/[K(S)F(S)].
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Saccharide Recognition with Fluorescent Sensors
= 21.7, 26.3, 28.4, 29.9, 40.3, 43.8, 79.4, 156.0, 202.5 ppm. HRMS
(ESI): calcd. for C11H21NO3 [M + H]+ 216.1599; found 216.1607.
rescence. Although saccharides are available in nature as a
single chiral form, we have shown that it is possible to use
the chirality of a synthetic receptor to either enhance or
reduce the binding with a particular saccharide. Therefore,
we have demonstrated the importance of chiral units in the
tert-Butyl N-(6-{1-[(Naphthalen-1-yl)ethyl]amino}hexyl)carbamate
(5a). R-5a: To
a solution of N-Boc-6-aminohexanal (0.5 g,
2.32 mmol) in MeOH/CH2Cl2 (1:3, v/v) was added a solution of
design of selective saccharide receptors and believe our re- (1R)-1-(1-naphthyl)ethylamine (0.397 g, 2.32 mmol) in MeOH/
CH2Cl2 (10 mL), and the mixture was heated to reflux for 6 h.
NaBH4 (0.2 g, 5.26 mmol) was added in small portions, and the
mixture was stirred at room temp. for 4 h. The solvent was removed
under reduced pressure, the residue was taken up with CH2Cl2, and
the organic phase washed with saturated NaCl solution
(3ϫ50 mL). The organic phase was dried with anhydrous Na2SO4,
concentrated to dryness, and the residue was chromatographed (sil-
sults will encourage others to use chiral units in the design
of other saccharide-selective sensors with practical utility.
Experimental Section
General: NMR spectra were run in either [D]chloroform or [D6]-
ica gel; CH2Cl2/MeOH, 50:1, v/v). R-5a (0.4 g, 46.0%) was ob-
1
dimethyl sulfoxide (DMSO). 1H NMR spectra were recorded at tained as a white solid. H NMR (300 MHz, CDCl3): δ = 1.32 (d,
300 MHz, 13C NMR spectra at 96 MHz and 13C{1H} NMR spec-
tra at 75 MHz. Chemical shifts (δ) are expressed in parts per million
and are reported relative to the residual solvent peak or to tet-
ramethylsilane as an internal standard in 1H and 13C{1H} NMR
spectra and boron trifluoride–diethyl ether as an external standard
in 11B {1H} NMR spectra. The multiplicities and general assign-
ments of the spectroscopic data are denoted as: singlet (s), doublet
(d), triplet (t), quartet (q), quintet (quint), doublet of doublets (dd),
doublet of triplets (dt), triplet of triplets (tt), unresolved multiplet
(m), broad (br.) and aryl (Ar). Coupling constants (J) are expressed
in Hertz. Data acquisition and automated processing were con-
trolled by Compass OpenAccess 1.3 software. The observed mass
and isotope patterns perfectly matched the corresponding theoreti-
cal values as calculated from the expected elemental formula.
Quartz cuvets with 10 mm path lengths, four faces polished. All
pH measurements taken during fluorescence experiments were car-
ried out with a pH meter that was calibrated by using standard
buffer solutions. All solvents used in fluorescence measurements
were of HPLC or fluorescent grade, and the water was deionized.
All saccharides used in fluorescence measurements were certified
as Ն 99% pure. The fluorescence studies were carried out in an
aqueous methanolic pH = 8.21 buffer. The buffer was prepared in
a 1 L volumetric flask according to a procedure laid out by Perrin
and Dempsey and consisted of 52.1 wt.-% HPLC grade methanol
in deionized water with KCl (0.7456 g, 0.01000 moldm–3), KH2PO4
3 H), 1.47–1.57 (m, 17 H), 2.58 (m, 2 H), 3.11 (t, J = 7.2 Hz, 2 H),
4.65 (q, J = 6.6 Hz, 1 H), 7.48–8.23 (m, 7 H) ppm. HRMS (ESI):
calcd. for C23H35N2O2 [M + H]+ 371.2620; found 371.2751. S-5a:
1
A similar procedure was applied. H NMR (300 MHz, CDCl3): δ
= 1.28 (d, 3 H), 1.44–1.54 (m, 17 H), 2.55 (m, 2 H), 3.08 (t, J =
7.2 Hz, 2 H), 4.62 (q, J = 6.6 Hz, 1 H), 7.45–8.19 (m, 7 H) ppm.
HRMS (ESI): calcd. for C23H35N2O2 [M + H]+ 371.2620; found
371.2749.
N-[1-(Naphthalen-1-yl)ethyl]-NЈ-(pyren-1-ylmethyl)hexane-1,6-di-
amine (6a). R-6a: R-5a (0.4 g, 1.0 mmol) was dissolved in CH2Cl2
(2 mL), and TFA (2 mL) was added to the solution. The mixture
was stirred for 4 h. The solvent was removed under reduced pres-
sure, the residue was dissolved in MeOH (10 mL), and triethyl-
amine (TEA, 0.2 mL) and pyrene-1-carbaldehyde (0.25 g,
1.0 mmol) were added, and the mixture was stirred at room temp.
overnight. NaBH4 (0.1 g, 2.63 mmol) was added in small portions,
and the mixture was stirred at room temp. for 4 h. The solvent was
removed under reduced pressure, the residue was taken up with
CH2Cl2, and the organic phase was washed with saturated NaCl
solution (3ϫ50 mL). The organic phase was dried with anhydrous
Na2SO4, concentrated to dryness, and the residue chromato-
graphed (silica gel; CH2Cl2/MeOH, 10:1, v/v). R-6a (0.39 g, 80.0%)
was obtained as a white solid. 1H NMR (300 MHz, CDCl3): δ =
1.32–1.57 (m, 11 H), 2.55 (m, 2 H), 2.76 (t, J = 7.2 Hz, 2 H), 4.48
(s, 2 H), 4.62 (q, J = 6.6 Hz, 1 H), 7.44–8.38 (m, 16 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 141.1, 133.9, 131.3, 130.8, 130.6,
129.0, 129.0, 127.6, 127.1, 125.9, 125.8, 125.7, 125.3, 125.1, 125.0,
(0.3745 g,
0.002752 moldm–3)
and
Na2HPO4
(0.3914 g,
0.002757 moldm–3).
N-Boc-6-aminohexanol:[14] 6-Aminohexanol (1.00 g, 8.50 mmol) 124.9, 124.7, 123.1, 122.8, 122.6, 77.4, 77.2, 77.0, 76.6, 70.5, 53.6,
was dissolved in tetrahydrofuran (5.00 mL), and di-tert-butyl dicar-
bonate (1.86 g, 8.50 mmol) was added. The solution was stirred at
room temperature for 3 h, and the solvent was removed with a ro-
tary evaporator to give the desired product (99%) as a colourless
oil. The compound was used without further purification. 1H
NMR (300 MHz, CDCl3): δ = 1.28–1.62 (m, 18 H), 3.09 (q, J =
6.1 Hz, 2 H), 3.61 (t, J = 6.3 Hz, 2 H), 4.56 (br. s, 1 H) ppm. 13C
51.8, 49.9, 47.9, 30.2, 30.0, 27.3, 23.6 ppm. HRMS (ESI): calcd.
for C35H36N2 [M + H]+ 485.2956; found 485.2989. S-6a: A similar
procedure was applied. 1H NMR (300 MHz, CDCl3): δ = 1.31–
1.55 (m, 11 H), 2.54 (m, 2 H), 2.75 (t, J = 7.2 Hz, 2 H), 4.47 (s, 2
H), 4.61 (q, J = 6.6 Hz, 1 H), 7.42–8.37 (m, 16 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 141.1, 133.9, 131.3, 130.8, 130.6, 129.2,
129.0, 127.6, 127.1, 125.9, 125.8, 125.7, 125.3, 125.1, 125.0, 124.9,
NMR (75 MHz, CDCl3): δ = 25.3, 26.4, 27.4, 28.4, 30.1, 32.6, 40.4, 124.7, 123.1, 122.8, 122.6, 77.4, 77.3, 77.0, 76.6, 70.5, 53.6, 51.8,
62.6, 79.1, 156.1 ppm. HRMS (ESI): calcd. for C11H24NO3 [M +
49.9, 47.9, 30.2, 30.0, 27.3, 23.6 ppm. HRMS (ESI): calcd. for
H]+ 218.1756; found 218.1766.
C35H36N2 [M + H]+ 485.2956; found 485.2931.
N-Boc-6-aminohexanal:[15] N-Boc-6-aminohexanol (7.2 g, 33 mmol) tert-Butyl N-6-{[1-(4-Methoxyphenyl)ethyl]amino}hexylcarbamate
was added to a CH2Cl2 solution (500 mL) that contained neutral (5b). R-5b: A similar procedure was applied as described for R-5a.
alumina (51 g) and PCC (11 g, 50 mmol). The reaction mixture was 1H NMR (300 MHz, CDCl3): δ = 1.19–1.30 (m, 11 H), 1.37 (s, 9
stirred at room temperature for 3 h and was loaded directly onto a
flash chromatography column. The product was eluted with
EtOAc/hexanes (1:1) to afford the product (6.5 g, 30 mmol, 91%).
1H NMR (300 MHz, CDCl3): δ = 1.25–1.47 (m, 13 H), 1.61 (quint,
J = 7.2 Hz, 2 H), 2.43 (t, J = 7.2 Hz, 2 H), 3.10 (q, J = 6.6 Hz, 2 H),
4.54 (br. s, 1 H), 9.75 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ
H), 2.32 (m, 2 H), 3.01 (q, J = 7.2 Hz, 2 H), 3.63 (q, J = 6.6 Hz, 1
H), 3.73 (s, 3 H), 6.78–6.81 (d, J = 8.3 Hz, 2 H), 7.13–7.21 (d, J =
8.3 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 158.4, 140.0,
137.9, 127.5, 126.7, 113.8, 113.7, 79.0, 77.4, 77.0, 76.6, 57.7, 55.3,
55.2, 50.7, 47.7, 30.2, 28.4, 27.0, 26.7, 25.8, 24.4 ppm. HRMS
(ESI): calcd. for C20H35N2O3 [M + H]+ 351.2647; found 351.2712.
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S-5b: A similar procedure was applied. 1H NMR (300 MHz,
CDCl3): δ = 1.11–1.26 (m, 11 H), 1.37 (s, 9 H), 2.32 (m, 2 H), 3.01
(q, J = 7.2 Hz, 2 H), 3.63 (q, J = 6.6 Hz, 1 H), 3.72 (s, 3 H), 6.78–
CDCl3): δ = 1.22–1.47 (m, 8 H), 2.50 (t, J = 7.2 Hz, 2 H), 2.68 (t,
J = 7.2 Hz, 2 H), 3.66 (s, 2 H), 4.37 (s, 2 H), 7.22 (s, 5 H), 7.87–
8.27 (m, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 140.5, 134.1,
6.80 (d, J = 8.3 Hz, 2 H), 7.13–7.16 (d, J = 8.3 Hz, 2 H) ppm. 13C 131.3, 130.8, 130.6, 129.0, 128.4, 128.1, 127.6, 127.5, 127.0, 127.0,
NMR (75 MHz, CDCl3): δ = 158.4, 140.0, 138.0, 127.6, 126.7,
126.9, 125.9, 125.0, 125.0, 124.9, 124.7, 123.1, 77.5, 77.1, 76.6, 54.1,
113.8, 113.7, 79.1, 77.5, 77.1, 76.6, 57.7, 55.3, 55.3, 50.7, 47.8, 30.2, 51.9, 50.0, 49.4, 30.1, 30.1, 27.3, 27.3 ppm. HRMS (ESI): calcd. for
28.5, 27.1, 26.7, 25.8, 24.4 ppm. HRMS (ESI): calcd. for
C30H32N2Na [M + H]+ 443.2463; found 443.2472.
C20H35N2O3 [M + H]+ 351.2647; found 351.2738.
Compound 8b: Synthesized according to the same method as 8a.
1H NMR (300 MHz, CDCl3): δ = 1.22–1.55 (m, 8 H), 2.40 (t, J =
7.2 Hz, 2 H), 2.52 (t, J = 7.2 Hz, 2 H), 3.48 (s, 2 H), 3.67 (s, 3 H),
4.25 (s, 2 H), 7.22 (s, 5 H), 6.74–6.77 (d, J = 7.2 Hz, 2 H) 7.82–
8.37 (m, 11 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.1, 145.9,
134.2, 131.3, 130.8, 130.6, 129.7, 129.0, 128.7, 127.9, 127.6, 127.5,
127.0, 127.0, 125.9, 125.1, 124.9, 124.7, 123.2, 77.5, 77.0, 76.6, 53.7,
52.0, 51.9, 49.9, 49.4, 30.1, 30.0, 27.3, 27.2 ppm. HRMS (ESI):
calcd. for C31H35N2O [M + H]+ 451.2749; found 451.2766.
N-{1-(4-Methoxyphenyl)ethyl}-NЈ-(pyren-1-ylmethyl)hexane-1,6-di-
amine (6b). R-6b: A similar procedure was applied as described for
R-6a. H NMR (300 MHz, CDCl3): δ = 1.30–1.60 (m, 11 H), 2.40
1
(m, 2 H), 2.76 (t, J = 7.2 Hz, 2 H), 3.68 (q, J = 6.6 Hz, 1 H), 3.78
(s, 3 H), 4.47 (s, 2 H), 6.84–6.87 (d, J = 8.3 Hz, 2 H), 7.20–7.23 (d,
J = 8.3 Hz, 2 H), 7.97–8.37 (m, 9 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 158.5, 137.9, 134.1, 131.3, 130.87, 130.6, 129.1, 127.6,
127.6, 127.5, 127.0, 127.0, 125.9, 125.1, 125.0, 124.9, 124.7, 123.2,
113.7, 77.5, 77.1, 76.6, 57.7, 55.2, 51.9, 50.0, 47.8, 30.2, 30.1, 27.3,
24.4 ppm. HRMS (ESI): calcd. for C32H37N2O [M + H]+ 465.2905;
R-1: A mixture of N-[(1R)-1-(naphthalen-1-yl)ethyl]-NЈ-(pyren-1-
ylmethyl)hexane-1,6-diamine (100 mg, 0.21 mmol), K2CO3 (85 mg,
0.62 mmol) and [2-(bromomethyl)phenyl]boronic acid pinacol ester
(135 mg, 0.46 mmol) in dry MeCN was heated to reflux for 8 h.
The reaction mixture was cooled to room temperature, and the
solvent was removed under vacuum. The residue was taken up with
H2O (10 mL), the aqueous phase was extracted with CH2Cl2
(3ϫ30 mL), and the organic phase was washed with brine
(2ϫ20 mL) and dried with anhydrous MgSO4. The solvent was
removed under vacuum, and the residue was chromatographed (sil-
ica gel; CH2Cl2/MeOH, 10:1, v/v). R-1 was obtained as a pale yel-
low powder. Yield: 38.0%. 1H NMR (300 MHz, CDCl3): δ = 0.89–
1.46 (m, 8 H), 1.29 (s, 3 H), 1.36 (s, 24 H), 2.37–2.39 (m, 2 H),
2.42–2.44 (m, 2 H), 3.93–3.99 (m, 2 H), 4.15 (s, 2 H), 4.19 (m, 2
H), 4.60–4.64 (m, 1 H), 7.24–7.62 (m, 10 H), 7.70–7.79 (m, 2 H),
8.00–8.16 (m, 11 H), 8.30–8.34 (m, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 146.4, 145.6 140.5, 135.3, 133.9, 132.2, 131.3, 130.9,
129.9, 128.7, 128.3, 127.5, 127.0, 126.8, 126.7, 125.7, 125.3, 125.1,
125.0, 124.9, 124.7, 124.5, 124.3, 122.9, 122.5, 83.4, 57.8, 56.8, 55.7,
54.3, 53.6, 50.3, 30.1, 27.2, 25.7, 25.0, 24.9 ppm. HRMS (ESI):
calcd. for C61H71B2N2O4 [M + H]+ 917.5599; found 917.5606.
[α]2D2 = –34Ϯ1 (c = 1.0; CH3OH/CH2Cl2, 1:1).
1
found 465.2907. S-6b: A similar procedure was applied. H NMR
(300 MHz, CDCl3): δ = 1.32–1.58 (m, 11 H), 2.43 (m, 2 H), 2.77
(t, J = 7.2 Hz, 2 H), 3.70 (q, J = 6.6 Hz, 1 H), 3.78 (s, 3 H), 4.47
(s, 2 H), 6.85–6.88 (d, J = 8.3 Hz, 2 H), 7.21–7.26 (d, J = 8.3 Hz,
2 H), 7.99–8.38 (m, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
158.5, 137.9, 134.2, 131.3, 130.8, 130.6, 129.0, 127.6, 127.5, 127.5,
127.0, 126.9, 125.8, 125.1, 124.9, 124.9, 124.7, 123.2, 113.7, 77.5,
77.0, 76.6, 57.7, 55.2, 51.9, 50.0, 47.8, 30.2, 30.1, 27.3, 24.3 ppm.
HRMS (ESI): calcd. for C32H36N2NaO [M + H]+ 487.2725; found
487.2723.
tert-Butyl N-(6-{[(Pyren-1-ylmethyl)amino}hexyl)carbamate (7):
tert-Butyl N-(6-aminohexyl)carbamate (2.0 g, 9.25 mmol) was dis-
solved in MeOH/CH2Cl2 (1:3, v/v). To this solution was added a
solution of pyrene-1-carbaldehyde (2.13 g, 9.26 mmol) in MeOH/
CH2Cl2 (10 mL). The mixture was heated to reflux for 6 h. NaBH4
(0.55 g, 14.5 mmol) was added in small portions, and the mixture
was stirred at room temp. for 4 h. The solvent was removed under
reduced pressure, the residue was taken up with CH2Cl2, and the
organic phase was washed with saturated NaCl solution
(3ϫ50 mL). The organic phase was dried with anhydrous Na2SO4,
concentrated to dryness, and the residue was chromatographed (sil-
ica gel; hexane/ethyl acetate, 20:1, v/v). Compound 7 (3.0 g, 74.9%)
S-1: Synthesized according to the same method. 1H NMR
(300 MHz, CDCl3): δ = 0.91–1.46 (m, 8 H), 1.11 (s, 3 H), 1.36 (s,
24 H), 2.37–2.39 (m, 2 H), 2.42–2.52 (m, 2 H), 3.96–4.00 (m, 2 H),
4.01 (s, 2 H), 4.17–4.21 (m, 2 H), 4.52–4.66 (m, 1 H), 7.26–7.57 (m,
10 H), 7.59–7.85 (m, 2 H), 7.97–8.16 (m, 11 H), 8.33–8.36 (m, 1 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 147.9, 146.4, 140.5, 135.3,
133.9, 132.2, 131.3, 130.9, 129.9, 128.7, 128.3, 127.5, 127.0, 126.8,
126.7, 125.7, 125.3, 125.1, 125.0, 124.9, 124.7, 124.5, 124.30, 122.9,
122.5, 83.6, 57.8, 56.0, 55.7, 53.8, 50.3, 47.9, 30.4, 27.3, 25.7, 25.0,
23.6 ppm. HRMS (ESI): calcd. for C61H71B2N2O4 [M + H]+
917.5599; found 917.5631. [α]2D2 = +33Ϯ1 (c = 1.0; CH3OH/
CH2Cl2, 1:1).
1
was obtained as a yellow solid. H NMR (300 MHz, CDCl3): δ =
1.29–1.55 (m, 17 H), 2.76 (t, J = 7.2 Hz, 2 H), 3.07 (q, J = 6.6 Hz,
2 H), 4.46 (s, 2 H), 7.97–8.37 (m, 9 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 156.0, 134.1, 131.3, 130.8, 130.6, 129.0, 127.6, 127.5,
127.0, 127.0, 125.8, 125.0, 125.0, 125.0, 124.9, 124.7, 123.1, 79.0,
77.5, 77.1, 76.6, 51.9, 49.9, 40.5, 30.1, 30.0, 28.4, 27.0, 26.7 ppm.
HRMS (ESI): calcd. for C28H34N2NaO2 [M + H]+ 453.2517; found
453.2537.
Compound 8a: Compound 7 (0.5, 1.16 mmol) was dissolved in
CH2Cl2 (2 mL), and TFA (2 mL) was added to the solution. The
mixture was stirred for 4 h. The solvent was removed under reduced
pressure, the residue was dissolved in MeOH (10 mL), TEA
R-2: Synthesized according to the same method. 1H NMR
(300 MHz, CDCl3): δ = 0.76–1.26 (m, 8 H), 0.90 (s, 3 H), 1.22 (s,
(0.2 mL) and phenylmethanamine (0.12 g, 1.16 mmol) were added 24 H), 2.18–2.22 (m, 2 H), 2.35–2.42 (m, 2 H), 3.41–3.45 (m, 1 H),
to the solution, and the mixture was stirred at room temp. over-
night. NaBH4 (0.1 g, 2.63 mmol) was added in small portions, and
the mixture was stirred at room temp. for 4 h. The solvent was
removed under reduced pressure, the residue was taken up with
CH2Cl2, and the organic phase was washed with saturated NaCl
solution (3ϫ50 mL). The organic phase was dried with anhydrous
Na2SO4, concentrated to dryness, and the residue was chromato-
graphed (silica gel; CH2Cl2/MeOH, 10:1, v/v). Compound 8a
3.58–3.60 (m, 2 H), 3.67 (s, 3 H), 3.82–3.89 (m, 2 H), 4.09–4.15 (m,
2 H), 6.73–6.75 (m, 2 H), 7.15–7.31 (m, 8 H), 7.45–7.72 (m, 2 H),
7.88–8.17 (m, 8 H), 8.22–8.27 (m, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 158.1, 147.9, 146.4, 136.1, 135.5, 133.9, 131.0, 130.6,
129.8, 128.9, 127.5, 126.8, 125.7, 124.7, 124.3, 113.1, 83.6, 57.9,
57.0, 55.9, 55.1, 53.9, 53.1, 49.4, 27.8, 27.5, 25.8, 25.0, 24.9,
19.9 ppm. HRMS (ESI): calcd. for C58H71B2N2O5 [M + H]+
897.5549; found 897.5615. [α]2D2 = –22Ϯ1 (c = 1.0, CH3OH/CH2Cl2
= 1:1).
1
(0.4 g, 82.1%) was obtained as a white solid. H NMR (300 MHz,
1228
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1223–1229

Saccharide Recognition with Fluorescent Sensors
S-2: Synthesized according to the same method. 1H NMR
sis and Sensing for our Environment (CASE) network. T. D. J. and
(300 MHz, CDCl3): δ = 0.84–1.44 (m, 8 H), 1.04 (s, 3 H), 1.32 (s, J. Z. thank the Royal Society (UK) and the National Natural Sci-
24 H), 2.22–2.35 (m, 2 H), 2.42–2.50 (m, 2 H), 3.55–3.65 (m, 1 H), ence Foundation of China (NSFC) (China-UK Cost-Share Science
3.75–3.77 (m, 2 H), 3.77 (s, 3 H), 3.97–3.98 (m, 2 H), 4.17–4.22 (m,
2 H), 6.78–6.85 (m, 2 H), 7.12–7.37 (m, 8 H), 7.53–7.81 (m, 2 H),
7.94–8.16 (m, 8 H), 8.30–8.35 (m, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 158.0, 147.9, 146.4, 136.1, 135.5, 133.9, 131.3, 130.4,
129.8, 128.9, 127.4, 126.8, 125.7, 124.7, 124.3, 113.0, 83.6, 57.8,
57.0, 55.9, 55.1, 53.9, 53.1, 49.4, 27.4, 27.2, 25.8, 24.9, 24.8,
19.9 ppm. HRMS (ESI): calcd. for C58H71B2N2O5 [M + H]+
897.5549; found 897.5608. [α]2D2 = +21Ϯ1 (c = 1.0; CH3OH/
CH2Cl2, 1:1).
Networks, 21011130154). T. D. J. thanks Dalian University of
Technology for a Hai-Tian Scholarship.
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Compound 3a: Synthesized according to the same method as R-1.
1H NMR (300 MHz, CDCl3): δ = 1.08–1.56 (m, 32 H), 2.32 (t, J
= 7.2 Hz, 2 H), 2.50 (t, J = 7.2 Hz, 2 H), 3.49 (s, 2 H), 3.77 (s, 2
H), 4.00 (s, 2 H), 4.21 (s, 2 H), 7.19–8.34 (m, 22 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 146.4, 139.8, 135.3, 134.9, 133.9, 131.3,
130.9, 130.4, 130.2, 129.8, 129.7, 129.0, 128.8, 128.2, 127.9, 127.5,
126.8, 126.7, 126.5, 126.0, 125.8, 125.7, 124.9, 124.7, 124.7, 124.5,
124.3, 83.5, 83.4, 77.4, 77.0, 76.6, 57.9, 57.6, 57.3, 55.9, 53.9, 53.0,
27.4, 27.3, 26.0, 25.9, 25.0, 24.9 ppm. HRMS (ESI): calcd. for
C56H67B2N2O4 [M + H]+ 853.5287; found 853.5342.
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Han, L. N. Chi, X. F. Liang, S. M. Ji, S. S. Liu, F. K. Zhou,
Y. B. Wu, K. L. Han, T. D. James, J. Z. Zhao, J. Org. Chem.
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2588.
Compound 3b: Synthesized according to the same method as R-1.
1H NMR (300 MHz, CDCl3): δ = 0.75–1.42 (m, 32 H), 2.12 (m, 2
H), 2.40 (m, 2 H), 3.33 (s, 1 H), 3.65 (s, 3 H), 3.89 (s, 2 H), 4.08
(s, 2 H), 6.70–8.23 (m, 21 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 158.9, 147.9, 146.4, 136.4, 135.5, 133.9, 131.1, 130.8, 129.8, 128.6,
127.4, 127.2, 126.6, 125.6, 124.7, 124.5, 124.2, 113.6, 113.1, 83.5,
57.8, 57.4, 56.4, 55.1, 53.1, 52.6, 51.3, 26.9, 26.8, 25.7, 24.9,
24.8 ppm. HRMS (ESI): calcd. for C57H69B2N2O5 [M + H]+
883.5393; found 883.5600.
Compound 4: Compound 3a (85 mg, 0.1 mmol) in methanol (7 mL)
was added to aqueous potassium hydrogen difluoride (1 mL, 4.5 m,
4.5 mmol) in a plastic beaker. The resulting white slurry was stirred
at room temperature for 15 min, concentrated in vacuo, the residue
was taken up with CH2Cl2, and the organic phase was washed with
saturated NaCl solution (3ϫ50 mL). The organic phase was dried
with anhydrous Na2SO4, concentrated to dryness, and the residue
was chromatographed (silica gel; CH2Cl2/MeOH, 5:1, v/v). Com-
1
pound 4 (40 mg, 58.1%) was obtained as a white solid. H NMR
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(300 MHz, CDCl3): δ = 1.04 (s, 4 H), 1.38 (s, 2 H), 1.57 (s, 2 H),
2.28 (m, 2 H), 2.49 (dd, J = 8.8, 6.5 Hz, 2 H), 3.46 (s, 2 H), 3.60
(s, 2 H), 3.74 (s, 2 H), 4.25 (s, 2 H), 6.41–8.43 (m, 22 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 136.8, 131.1, 130.6, 129.5, 128.6,
128.5, 128.1, 127.5, 127.3, 126.0, 125.3, 124.6, 122.8, 122.2, 122.0,
119.1, 116.0, 115.9, 77.4, 77.0, 76.6, 57.9, 57.6, 57.5, 56.4, 53.6,
52.7, 26.9, 26.8, 25.9, 25.8 ppm. HRMS (ESI): calcd. for
C44H44B2N2O3 [M + H]+ 670.3538; found 670.3793.
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Supporting Information (see footnote on the first page of this arti-
cle): General remarks; 1H NMR, 13C NMR, mass spectra; fluores-
cence data.
Acknowledgments
We gratefully acknowledge the National Natural Science Founda-
tion of China (20832001, 20972065, 21074054) and the National
Basic Research Program of China (2007CB925103, 2010CB923303)
for financial support. T. D. J. and Z. X. wish to acknowledge the
University of Bath for support. T. D. J. and J. Z. thank the Cataly-
Received: November 11, 2011
Published Online: January 5, 2012
Eur. J. Org. Chem. 2012, 1223–1229
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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