Effect of extended conjugation with a phenylethynyl group on the fluorescence properties of water-soluble arylboronic acids

Article abstract of DOI:10.1016/j.tet.2007.04.035

Boronic acids that change fluorescence properties upon sugar binding are very important reporter units for the development of small molecule lectin mimics (boronolectins). Aimed at developing long wavelength fluorescent boronic acid reporter compounds, we

Full text of DOI:10.1016/j.tet.2007.04.035

Tetrahedron 63 (2007) 5427–5436
Effect of extended conjugation with a phenylethynyl group on
the fluorescence properties of water-soluble arylboronic acids
*
Shi-Long Zheng, Na Lin, Suazette Reid and Binghe Wang
Department of Chemistry and Center for Biotechnology and Drug Design, Georgia State University, Atlanta, GA 30302-4098, USA
Received 12 November 2006; revised 29 March 2007; accepted 16 April 2007
Available online 19 April 2007
Abstract—Boronic acids that change fluorescence properties upon sugar binding are very important reporter units for the development of
small molecule lectin mimics (boronolectins). Aimed at developing long wavelength fluorescent boronic acid reporter compounds, we
have designed and synthesized a series of boronic acid analogs 2a–d with an extended p conjugation. Such designs are based on earlier fluo-
rescent boronic acids that change fluorescence properties upon sugar binding. Compared with the corresponding parent chromophores, these
new compounds with extended conjugations show longer excitation and emission wavelengths as designed. The patterns of fluorescence
changes for the new compounds are also different from that of the corresponding parent compounds.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
developed several such boronic acid fluorescent reporters. In
our continuing effort to develop boronolectins and fluores-
cent boronolectins, we are interested in examining whether
adding conjugation to such known boronic acid fluorescent
reporters would result in more favorable spectroscopic prop-
erties in terms of wavelength and magnitude of fluorescence
property changes. For this, we have selected four representa-
tive compounds (1a–d, Fig. 1). Three of them are naphthyl-
boronic acids (1a–c) that are positional isomers of each other
and one is a quinolinylboronic acid (1d). Out of these four,
1a shows fluorescence intensity increases upon sugar bind-
ing;41 1b shows ratiometric fluorescence intensity changes
at two wavelengths;47 1c shows fluorescence intensity de-
creases upon sugar binding;47 1d did not show significant
fluorescence property changes upon sugar binding. These
compounds were chosen for their (1) water-soluble nature,
(2) known fluorescence property changes upon binding (ex-
cept for 1d), (3) chemical stability, and (4) anticipated ease
of synthetic manipulation. With these reporters having di-
verse patterns of spectroscopic changes upon sugar binding,
we reasoned that the results should allow us to do some rep-
resentative sampling of what could be expected by extending
the conjugation of similar boronic acid fluorescent reporters.
Specifically, we are interested in learning the effect of such
extended conjugations on (1) the excitation and emission
wavelengths, (2) quantum yields of both the free boronic
acids and their corresponding esters, (3) the pattern of fluo-
rescence property changes, and (4) mechanism of fluores-
cence property changes upon sugar binding.
Lectin–carbohydrate binding plays very important roles in
biological and pathological processes such as cell–cell adhe-
sion,1–4 inflammation reactions,5–7 cancer metastasis,1,8–13
etc. Therefore, small molecule mimics of lectins that can rec-
ognize certain carbohydrate biomarkers have the potential to
be developed as therapeutic and diagnostic agents. Along
this line, we have reported the first lectin mimic, termed as
boronolectin,14 which can recognize cell-surface carbo-
hydrate biomarkers for cell labeling and recognition applica-
tions.15,16 In preparing small molecule lectin mimics, the
boronic acid functional group is especially useful because
of its intrinsic affinity for the diol functional group,17–20
which is commonly found in carbohydrates. The intrinsic
affinity of boronic acids for the hydroxyl and diol groups
has been used in the preparation of boronic acid-based sugar
sensors,21–33 carbohydrate transporters,34–36 drug delivery
materials,37,38 and other pharmaceutical agents.39,40,14
In the preparation of boronolectins, water-soluble boronic
acids that change fluorescence properties upon diol binding
are very useful for two reasons.14 First, the fluorescence
property changes upon binding are of tremendous help in
screening combinatorial libraries. Second, they allow for
the development of new boronic acid-based sensors and di-
agnostics without the need of incorporating a separate sig-
naling moiety. Along this line, we14,40–46 and others24 have
Keywords: Boronic acids; p Conjugated system; Fluorescence; Sensing;
Sensor.
* Corresponding author. Tel.: +1 404 651 0289; fax: +1 404 654 5827;
e-mail: wang@gsu.edu
Phenylethynyl and ethynyl groups have received a great
deal of attention as a linker for new materials with potential
applications ranging from chemical sensing to molecular
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.035

5428
S.-L. Zheng et al. / Tetrahedron 63 (2007) 5427–5436
B(OH)2
B(OH)2
B(OH)2
B(OH)2
N
(H3C)2N
N(CH3)2
N(CH3)2
1d
1c
1a
1b
extended conjugation
B(OH)2
B(OH)2
B(OH)2
B(OH)2
N
N(CH3)2
N(CH3)2
2b
(H3C)2N
2d
2c
2a
Figure 1. Design of compounds 2a–d from 1a–d.
B(OH)2
O
B
O
O
O
B
O
O
B
O
O
(ii)
(i)
(i)
TMS
(iii)
B
Br
X
N
X
N
Br
TMS
X
N
2a-d
3
4
5a-d
Scheme 1. Synthesis of 4-arylethynylphenyl boronic acids 2a–d: (i) PdCl2(Ph3P)2, CuI, Ph3P, 120 ꢀC, microwave irradiation, 98% for 3 and 47%–67% for 5a–d;
(ii) K2CO3, MeOH, rt, 80%; (iii) TFA, H2O, 36%–47%.
electronics.48–54 Such elongation affords the needed conju-
gation and only introduces one more rotational degree of
freedom. Therefore, such compounds are expected to have
good fluorescence properties. After considering the ease of
synthesis, potential effect on water solubility, chemical sta-
bility of the extended product, and the desire to minimize the
degree of freedom in the new extended conjugation system,
we decided to use an alkyne group as a way to extend the
conjugation. Therefore, four new compounds (2a–d) with
their conjugation extended by an alkyne group were de-
signed (Fig. 1). The results show that extended conjugation
not only resulted in increased emission and excitation
wavelengths as expected, but also improved fluorescence
property changes upon binding with interesting mechanistic
implications.
group with TFA in water (Scheme 1). Specifically, Sonoga-
shira coupling reaction of 2,2-dimethylpropane-1,3-diyl-4-
bromophenyl boronate with trimethylsilyl acetylene under
microwave irradiation gave 2,2-dimethylpropane-1,3-diyl
[4-trimethylsilylethynylphenyl] boronate (3) in 98% isolated
yield. This yield was much higher than that without using
microwave.55 Deprotection of the trimethylsilyl group
(TMS) of 3 with potassium carbonate afforded 4.55 It should
be noted that the two key reactions for the synthesis of 3 and
5a–d were both microwave-facilitated Sonogashira coupling
reactions and no Suzuki coupling side reactions were
observed. In addition, the use of microwave was found to
significantly shorten the reaction time.
2.2. Fluorescence studies
2. Results and discussions
2.1. Synthesis
The fluorescence properties of compounds 2a–d in the pres-
ence and absence of sugars were examined in phosphate
buffer (0.1 M, pH 7.4). Compound 2a showed an 8-fold
fluorescence intensity increase upon addition of 50 mM
D-fructose (Fig. 2). It also showed significant fluorescence
intensity increases upon addition of other sugars. Compared
with compound 1a (lex¼300 nm and lem¼445 nm),41 the
lex of 2a increased by about 40 nm to 340 nm and the lem
increased by only about 10 nm to 454 nm (Table 1).
The designed 4-arylethynylphenyl boronic acids 2a–d
were synthesized using the Sonogashira coupling reaction
of arylbromides with 2,2-dimethylpropane-1,3-diyl-4-ethy-
nylphenyl boronate (4) as the building block under micro-
wave irradiation followed by the deprotection of neopentyl

S.-L. Zheng et al. / Tetrahedron 63 (2007) 5427–5436
5429
400
350
300
250
200
150
100
50
1/Concentration (1/M)
500.0 1000.0 1500.0
0.0
2000.0
0.1000
0.0800
0.0600
0.0400
0.0200
0.0000
-0.0200
-0.0400
50 mM
0 mM
2a
2b
2c
2d
0
390
440
490
Wavelength (nm)
540
Figure 2. Fluorescence spectral changes of 2a (1.0ꢂ10ꢁ5 M) with different
concentrations of D-fructose (0–50 mM) in 0.1 M aqueous phosphate buffer
at pH 7.4, lex¼340 nm.
Binding constants for 2a as well as the other sensors (2b–d)
with fructose and three other sugars were determined at pH
7.4 by fitting 1/DIf versus 1/concn into a 1:1 binding model.
In all cases, R2 values were >0.99, indicating an excellent fit
into a 1:1 binding model (Fig. 3).
Figure 3. Determination of the Ka for 2a–d with fructose in 0.1 M phosphate
buffer at pH 7.4; R2>0.99 in all cases.
was observed at 454 nm in the pH range 1.57–5.0, while
a new peak increased very significantly at 454 nm as pH
increased from 5.0 to 11.5 (Figs. 4 and 5).
The affinity trend with 2a followed that of 1a17,18 in the
order of sorbitol>fructose>galactose>glucose with Ka
(Mꢁ1) of 619, 293, 8.1, and 2.5, respectively (Table 1). As
has been addressed before in the literature, sorbitol can
engage in trivalent binding, which is the reason for its high
affinity relative to other sugars.57,58,14
The pH-induced spectral changes at 370 nm in the absence
of a sugar were similar to that in the presence of 50 mM fruc-
tose. A decrease in intensity (more than 99%) at 370 nm was
observed when pH increased from 1.57 to 5.0. Plotting the
intensity changes at 370 nm against pH revealed the first ap-
parent pKa of 3.6 for 2a in the absence of sugar and 3.5 in the
presence of fructose. The pH profiles of the fluorescence in-
tensity of 2a at 454 nm revealed the second apparent pKa of
9.4 in the absence of a sugar and 6.8 in the presence of fruc-
tose (50 mM). It is reasonable to assign the first pKa to the
aniline group and the second pKa to the boronic acid. There-
fore, one can use Scheme 2 to show the various ionization
states of 2a, which helps to understand the assignment of
each fluorescence peak to a particular species.
The fluorescence quantum yields (FF) of 2a were determined
in 0.1 M phosphate buffer (pH 7.4) in the absence and pres-
ence of 50 mM fructose, with 8-quinolinic boronic acid
(FF¼0.58 in 12 M H2SO4) as a reference compound.59 The
results (Table 1) show that the FF (0.013) of 2a in the absence
of a sugar is similar to that of 1a (0.01). However, after ad-
dition of 50 mM fructose, the FF of 2a increases to 0.096,
which is lower than the FF (0.42) of 1a under the same
conditions. Therefore, it seems that the increased wave-
length came at the expense of a decreased quantum yield
possibly due to the increased degree of freedom of rotation,
which allows for the irradiative decay of the excited state.
The pH-induced fluorescence changes of 2a and 1a have
a similar trend. The free forms of 2a and 1a are weakly fluo-
rescent and only the protonated form (370 nm) and the boron
ionized form (454 nm) are fluorescent.
The pH-induced fluorescence spectral changes of 2a in the
absence and presence of fructose at a fixed concentration
(50 mM) were studied to examine the relationship between
the fluorescence intensity changes and the different ioniza-
tion states. The fluorescence intensity of 2a at 370 nm de-
creased when pH increased from 1.57 to w5.0, and did not
show further changes beyond 5.0. Almost no fluorescence
With compound 2b, its affinity trend also followed that of
its parent compound, 1b, in the order of sorbitol>fructose>
galactose>glucose with Ka (Mꢁ1) of 311, 178, 7.5, and
7.0, respectively (Table 1). However, compared with the
Table 1. Association constantsa and fluorescence properties of 1a–c and 2a–d with and without added sugar (50 mM fructose)
Compd
lex [nm]
Without sugar
With fructose
Ka (Mꢁ1
)
lem [nm]
FF
lem [nm]
FF
Sorbitol
Fructose
Galactose
Glucose
1a41
2a
300
340
300
340
310
330
310
310
445
454
513, 433
531
432
0.01
0.013
0.07
445
454
433
531
—
448
0.42
0.096
0.23
0.12
226ꢃ12
619ꢃ16
337ꢃ11
311ꢃ9
207ꢃ8
12.0ꢃ3.6
8.1ꢃ1.4
23.0ꢃ5.2
7.5ꢃ0.8
8.0ꢃ1.5
1.8ꢃ0.6
4.0ꢃ2.1
2.5ꢃ1.6
3.6ꢃ1.8
7.0ꢃ2.0
2.4ꢃ1.1
0.1ꢃ0.05
293ꢃ19
311ꢃ13
178ꢃ2.1
120ꢃ6
1b56
2b
0.027
0.89
0.025
1c47
2c
1d
2d
—
227ꢃ10
11.1ꢃ0.3
b
b
448
—
0.058
0.034
0.08
132ꢃ5
b
b
b
b
b
b
—
0.1
412 (Weak)
371, 430
—
822ꢃ17
—
427ꢃ18
—
—
371
49ꢃ6.0
18ꢃ3.0
Constants determined by fitting into a 1:1 binding model. Errors reported are two standard deviations; R2>0.99 in all cases.
Not applicable.
a
b

5430
400
S.-L. Zheng et al. / Tetrahedron 63 (2007) 5427–5436
A
1b. Addition of fructose (50 mM) to a solution of 1b induced
a 61% fluorescence intensity decrease at the longest
wavelength, 513 nm, and a 36-fold increase at 433 nm.47,56
In contrast, 2b showed a 2.5-fold fluorescence intensity
increase upon addition of 50 mM D-fructose (Fig. 6) at
531 nm. With the added conjugation, the excitation wave-
length of 2b increased by 40 nm to 340 nm and the highest
emission wavelength changed from 513 nm to 531 nm. It
should be noted that numerous literature precedents have
shown that substitution patterns make a great difference in
dictating the fluorescence properties of a boronic acid com-
pound.41,56,47,46 Therefore, it is not surprising that positional
isomers behave somewhat differently in their fluorescence
responses upon elongated conjugation.
350
300
250
200
150
100
50
pH 11.5
pH 5.0
0
370
420
470
Wavelength (nm)
520
570
350
300
250
200
150
100
50
B
pH 1.57
pH 5.0
The fluorescence quantum yields (FF) of 2b were deter-
mined in the presence and absence of a sugar using the same
method as with 2a. The results (Table 1) show that FF of
compound 2b in the absence of a sugar was 0.027, which
increased to 0.12 after addition of 50 mM fructose.
0
345
365
385
405
Wavelength (nm)
425
445
465
Figures 7 and 8 show the fluorescence intensity changes of
2b at different pH in the absence and presence of fructose
(50 mM). It can be seen that the fluorescence intensity of
2b at 375 nm decreased when pH increased from 1.39 to
w6.0, and did not show further changes beyond 6.0, while
a new peak increased very significantly at 531 nm as pH
increased from 4.0 to 11.0.
Figure 4. Fluorescence spectral changes of 2a (1.0ꢂ10ꢁ5 M) in 0.1 M
aqueous phosphate buffer at different pH, lex¼340 nm. (A) Fluorescence
intensity changes at 454 nm; (B) fluorescence intensity changes at 370 nm.
situation for 2a, the extension of the conjugation of 5-N,N-
dimethylaminonaphthylboronic acid (1b) gave some very
noticeably different outcomes. Compound 2b exhibited very
different fluorescence properties compared with its parent,
The pH-induced spectral changes at 375 nm in the absence
of a sugar are similar to those in the presence of 50 mM fruc-
tose. A decrease in intensity (more than 99%) at 375 nm was
observed when pH increased from 1.57 to 5.0. Plotting the
intensity changes at 375 nm against pH revealed the first ap-
parent pKa for 2b as 4.0 both in the absence and in the pres-
ence of fructose. The pH profiles of the fluorescence
intensity of 2b at 531 nm revealed the second apparent
pKa of 2b as 9.8 in the absence of a sugar and 6.3 in the pres-
ence of fructose. It is reasonable to assign the first pKa to the
aniline group and the second pKa to the boronic acid.
Scheme 2 shows the various ionization states of 2b and their
relationship to various fluorescence peaks.
pH titration of 2a at 454 nm
450
400
350
300
250
200
150
100
50
2a
2a + fructose
Compound 2c is similar to 2b, where elongation of the con-
jugation resulted in more than just an increase in excitation
and emission wavelengths. It displayed different patterns of
fluorescence intensity changes compared with its parent
compound, 1c. With the addition of fructose to the solution
of 1c, a significant 80% decrease in fluorescence intensity
was observed at 432 nm.47 In contrast, 2c showed a 6-fold
fluorescence intensity increase upon addition of 50 mM
D-fructose (Fig. 9) at 448 nm. The affinities of 2c for various
sugars are in the order of fructose>sorbitol>galactose>
glucose with Ka (Mꢁ1) of 132, 11.1, 0.2, and 0.1, respec-
tively (Table 1). This order of affinity strength is different
from that of its parent compound, 1c. It is very interesting
to note the relatively low affinity of 2c for sorbitol, galactose,
and glucose. It is not readily clear why this is the case. It
should be noted that we have conducted an extensive evalu-
ation of various factors that affect boronic acid–diol binding
constants. Though pKa and pH values are two major factors,
there are other factors that are not well understood at the
present time.17,18
0
0
5
10
15
pH
pH titration of 2a at 370 nm
350
300
250
200
150
100
50
2a
2a + fructose
0
0
5
10
15
pH
Figure 5. pH titration of 2a (1.0ꢂ10ꢁ5 M) with or without sugar (50 mM
fructose) in 0.1 M aqueous phosphate buffer at pH 7.4, lex¼340 nm.

S.-L. Zheng et al. / Tetrahedron 63 (2007) 5427–5436
5431
HO
HO
OH
OH
HO
B
B
B
OH
H2O
OH
H3O
OH-
pKa = 3.6 for 2a
pKa = 4.0 for 2b
pKa = 3.8 for 2c
pKa = 9.4 for 2a
pKa = 9.8 for 2b
pKa = 8.7 for 2c
N
N
N
H
Fluorescent at 370 nm for 2a
Fluorescent at 375 nm for 2b
Fluorescent at 363 nm for 2c
Fluorescent at 454 nm for 2a
Fluorescent at 531 nm for 2b
Fluorescent at 448 nm for 2c
Weekly fluorescent
sugar
R
sugar
sugar
R
R
O
B
O
O
R
R
R
B
O
B
O
O
OH
H2O
H3O
OH-
pKa = 3.5 for 2a
pKa = 4.0 for 2b
pKa = 3.8 for 2c
sugar = fructose
pKa = 6.8 for 2a
pKa = 6.3 for 2b
pKa = 7.1 for 2c
sugar = fructose
N
N
N
H
Fluorescent at 370 nm for 2a
Fluorescent at 375 nm for 2b
Fluorescent at 363 nm for 2c
Fluorescent at 454 nm for 2a
Fluorescent at 531 nm for 2b
Fluorescent at 448 nm for 2c
Weekly fluorescent
Scheme 2. Fluorescence properties of 2a, 2b, and 2c in different ionization states in the absence and presence of a sugar in 0.1 M aqueous phosphate buffer.
The fluorescence quantum yields (FF) of 2c were
determined in a similar fashion as for 2a and 2b. After
addition of 50 mM fructose, the fluorescence quantum
yield (FF) of 2c increased from 0.025 to 0.058 at
448 nm. As a comparison, the fluorescence quantum yield
(FF) of 1c in the absence of a sugar was 0.89, and the quan-
tum yield (FF) decreased after the addition of 50 mM
fructose.
was observed when pH increased from 1.52 to 6.0. Plotting
the intensity changes at 363 nm against pH revealed the first
apparent pKa as 3.8 for 2c both in the absence and presence
of fructose. The pH profiles of the fluorescence intensity of
2c at 448 nm revealed the second apparent pKa of 2c as
300
A
Figures 10 and 11 show the fluorescence intensity changes of
2c at different pH in the absence and presence of fructose
(50 mM). It can be seen that the fluorescence intensity of
2c at 363 nm decreased when pH increased from 1.52 to
w6.0, while a new peak increased in intensity at 448 nm
as pH increased from 4.0 to 11.0.
250
pH 11.0
pH 4.0
200
150
100
50
The pH-induced spectral changes of 2c at 363 nm in the ab-
sence of a sugar are similar to that in the presence of 50 mM
fructose. A more than 200-fold intensity decrease at 363 nm
0
400
450
500
Wavelength (nm)
550
600
650
300
250
450
400
350
300
250
200
150
100
50
B
pH 1.39
50 mM
0 mM
620
200
150
100
50
pH 6.0
0
420
0
470
520
Wavelength (nm)
570
345
365
385
405
Wavelength (nm)
425
445
465
Figure 6. Fluorescence spectral changes of 2b (1.0ꢂ10ꢁ5 M) with different
concentrations of D-fructose (0–50 mM) in 0.1 M aqueous phosphate buffer
at pH 7.4, lex¼340 nm.
Figure 7. Fluorescence spectral changes of 2b in 0.1 M aqueous phosphate
buffer (1.0ꢂ10ꢁ5 M) in the absence of sugar at different pH, lex¼340 nm.
(A) Changes at 531 nm; (B) changes at 375 nm.

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S.-L. Zheng et al. / Tetrahedron 63 (2007) 5427–5436
pH titration of 2b at 531 nm
300
250
200
150
100
50
300
2b
pH 1.52
pH 6.0
250
200
150
100
50
2b + fructose
pH 11.0
pH 4.0
0
0
0
5
10
15
335
385
435
Wavelength (nm)
485
pH
Figure 10. Fluorescence spectral changes of 2c (1.0ꢂ10ꢁ6 M) in 0.1 M
aqueous phosphate buffer at different pH, lex¼330 nm.
pH titration of 2b at 375 nm
450
400
350
300
250
200
150
100
50
2b
2b + fructose
(Scheme 2). In contrast, the free form of 1c is the fluorescent
species, and neither the protonated form nor the boron ion-
ized form of 1c is fluorescent.
pH titration of 2c at 448 nm
35
2c
30
2c + fructose
25
20
15
10
5
0
0
2
4
6
8
10
12
-50
pH
Figure 8. pH titration of 2b (1.0ꢂ10ꢁ5 M) with or without fructose sugar
(50 mM) in 0.1 M aqueous phosphate buffer, lex¼340 nm.
8.7 in the absence of a sugar and 7.1 in the presence of fruc-
tose. It is reasonable to assign the first pKa to the aniline
group and the second pKa to the boronic acid. Scheme 2
shows the various ionization states of 2c and their relation-
ship to various fluorescent emissions.
0
0
5
10
15
pH
pH titration of 2c at 363 nm
300
250
200
150
100
50
It is also interesting to note that the pH-induced fluorescence
changes of 2c are very different from that of 1c. The free
form of 2c is only weakly fluorescent and only the proton-
ated form and the boron ionized form are fluorescent
2c
2c + fructose
140
120
100
80
60
40
20
0
50 mM
0 mM
380
4
30
48
0
Wavelength (nm)
530
0
0
5
10
15
pH
Figure 9. Fluorescence spectral changes of 2c (1.0ꢂ10ꢁ6 M) with different
concentrations of D-fructose (0–50 mM) in 0.1 M aqueous phosphate buffer
at pH 7.4, lex¼330 nm.
Figure 11. pH titration of 2c (1.0ꢂ10ꢁ6 M) with and without fructose
(50 mM) in 0.1 M aqueous phosphate buffer at pH 7.4, lex¼330 nm.

S.-L. Zheng et al. / Tetrahedron 63 (2007) 5427–5436
5433
350
300
250
200
150
100
50
pH titration of 2d at 378 nm
350
0 mM
300
250
200
150
100
50
50 mM
0
330
380
430
Wavelength (nm)
480
5d
5d + fructose
Figure 12. Fluorescence spectral changes of 2d (1.0ꢂ10ꢁ5 M) with differ-
ent concentrations of D-fructose (0–50 mM) in 0.1 M aqueous phosphate
buffer at pH 7.4, lex¼310 nm.
0
0
2
4
6
8
10
12
14
-50
pH
Figure 14. pH titration of 2d (1.0ꢂ10ꢁ5 M) with or without a sugar
(50 mM) in 0.1 M aqueous phosphate buffer at pH 7.4, lex¼310 nm.
The effect of conjugation elongation was most prominent
with compound 2d, which showed a significant fluorescence
intensity decrease upon addition of D-fructose (Fig. 12) at
371 nm, while its parent compound, 1d, showed no signifi-
cant fluorescence intensity changes upon addition of D-fruc-
tose and sorbitol.60 The affinity trend of 2d followed that
of 1a–c, 2a, and 2b in the order of sorbitol>fructose>
galactose>glucose with Ka (Mꢁ1) of 822, 427, 49, and 18,
respectively (Table 1). Compound 2d also showed the high-
est binding affinity with different sugars compared with all
other water-soluble boronic acid sensors described in this
study. This situation is very similar to 3-pyridine boronic
acid, which also showed a high affinity for various sugars.
The key reason seems to be due to the formation of zwitter-
ionic complex, which favors binding.61
3. Conclusion
A series of boronic acid analogs 2a–d with increased
conjugation have been synthesized in four steps from the
corresponding arylbromides and 2,2-dimethylpropane-1,3-
diyl-4-ethynylphenyl boronate. The key reaction was a
microwave-facilitated selective Sonogashira reaction, which
gave 47%–67% yields. Detailed fluorescence studies show
that extending the conjugation with an alkynyl group (1) de-
creased the quantum yield, (2) increased the excitation and
emission wavelengths by 20–40 nm and 9–16 nm, respec-
tively, (3) resulted in alterations in the patterns of the fluores-
cence property changes upon sugar binding, and (4) altered
the pH profiles and thus the mechanism through which fluo-
rescence properties change upon sugar addition. The results
suggested that extending the conjugation of a known fluores-
cent boronic acid with an alkynyl moiety results in more than
a simple increase in excitation and emission wavelengths.
The fluorescence quantum yields (FF) of 2d were also deter-
mined in 0.1 M phosphate buffer (pH 7.4) in the absence of
a sugar and in the presence of 50 mM fructose in a similar
fashion as with 2a–c. The quantum yield of 2d slightly de-
creased from 10% to 8% after addition of 50 mM fructose.
4. Experimental
4.1. General
The pH-induced fluorescence spectral changes of 2d in the
absence of any sugar (Figs. 13 and 14) showed only one ap-
parent pKa at 3.3, while in the presence of 50 mM fructose,
two apparent pKa values were found for 2d at 3.3 and 10. If
the situation is similar to 3-pyridine boronic acid, the first
pKa of the complex could be due to the boron and the second
one could be due to the deprotonation of the quinoline
nitrogen.
All reagents were purchased from Acros and Aldrich. Micro-
wave heating was performed in the single-mode microwave
cavity of a Discover Synthesis System (CEM Co.), and
all microwave-irradiated reactions were conducted in
1
heavy-walled glass vials sealed with Teflon septa. H- and
13C NMR spectra were recorded at 400 and 100 MHz,
respectively, on a Bruker Avance 400 NMR spectrometer.
Mass spectra were performed by the Mass Spectrometry
Facilities at Georgia State University. Fluorescence spectra
were recorded on a Shimadzu RF-5301 PC spectrofluorom-
eter. Absorption spectra were recorded on a Shimadzu
UV-1700 UV–visible spectrophotometer. All pH values
were determined by a UB-10 Ultra Basic Benchtop pH meter
(Denver Instrument).
350
300
pH 1.6
250
200
150
pH 11.7
100
50
0
4.2. Synthesis
330
380
430
480
Wavelength (nm)
530
580
(6-Bromo-naphthalen-2-yl)-methylamine,62 (6-bromo-naph-
thalen-2-yl)-dimethylamine,47 (4-bromo-naphthalen-1-yl)-
dimethylamine,63 and (5-bromo-naphthalen-1-yl)-dimethyl-
amine56 were synthesized following literature procedures.
Figure 13. Fluorescence spectral changes of 2d (1.0ꢂ10ꢁ5 M) in the
absence of sugar at different pH, in 0.1 M aqueous phosphate buffer,
lex¼310 nm.

5434
S.-L. Zheng et al. / Tetrahedron 63 (2007) 5427–5436
4.2.1. 2,2-Dimethylpropane-1,3-diyl [4-trimethylsilyl-
ethynylphenyl] boronate (3).55 A mixture of 2,2-di-
methylpropane-1,3-diyl-4-bromophenyl boronate (0.24 g,
0.9 mmol), Pd(PPh3)2Cl2 (32 mg, 0.05 mmol), CuI (9 mg,
0.05 mmol), triphenylphosphine (48 mg, 0.18 mmol), tri-
methylacetylene (0.14 mL, 1 mmol), and dimethylamine
(1.5 mL, 13.6 mmol) in dimethylformamide (DMF, 0.5 mL)
was irradiated with microwave at 120 ꢀC for 20 min in
a heavy-walled glass vial sealed with a Teflon septum. After
irradiation, the solvent was concentrated under reduced
pressure and the residue was purified by flash column chro-
matography to give 0.25 g (98%) of 2,2-dimethylpropane-
1,3-diyl [4-trimethylsilylethynylphenyl] boronate (3). 1H
NMR (CDCl3): 7.65 (d, J¼8.0 Hz, 2H), 7.37 (d, J¼8.0 Hz,
2H), 3.67 (s, 4H), 0.93 (s, 6H), 0.17 (s, 9H). 13C NMR
(CDCl3): 133.5 (d), 131.0 (d), 125.1 (s), 105.4 (s), 95.0
(s), 72.3 (t), 31.8 (s), 21.9 (q), ꢁ0.05 (q). GC–MS (EI):
286 [M]+.
4.3.2. {5-[4-(5,5-Dimethyl[1,3,2]dioxaborinan-2-yl)-phe-
nylethynyl]naphthalen-1-yl}dimethylamine (5b). Yield:
1
49%. H NMR (CDCl3): 8.27 (d, J¼8.0 Hz, 1H), 8.16 (d,
J¼8.0 Hz, 1H), 7.84 (d, J¼8.0 Hz, 2H), 7.75 (dd, J¼0.8
and 7.2 Hz, 1H), 7.63 (d, J¼8.0 Hz, 2H), 7.51 (m, 1H),
7.46 (m, 1H), 7.13 (d, J¼7.2 Hz, 1H), 3.80 (s, 4H), 2.91
(s, 6H), 1.05 (s, 6H). 13C NMR (CDCl3): 151.3 (s), 134.7
(s), 133.8 (d), 130.7 (d), 130.4 (d), 128.7 (s), 126.7 (d),
125.6 (s), 125.1 (d), 124.4 (d), 121.1 (s), 121.0 (d), 114.6
(d), 94.4 (s), 89.0 (s), 72.3 (t), 45.3 (q), 31.9 (s), 21.9 (q).
GC–MS (EI): 383 [M]+.
4.3.3. {6-[4-(5,5-Dimethyl[1,3,2]dioxaborinan-2-yl)-phe-
nylethynyl]naphthalen-2-yl}dimethylamine (5c). Yield:
1
47%. H NMR (CDCl3): 7.90 (s, 1H), 7.78 (d, J¼8.4 Hz,
2H), 7.67 (d, J¼9.2 Hz, 1H), 7.59 (d, J¼8.4 Hz, 1H), 7.53
(d, J¼8.4 Hz, 2H), 7.46 (dd, J¼1.2 and 8.4 Hz, 1H), 7.16
(dd, J¼2.4 and 9.2 Hz, 1H), 6.87 (d, J¼2.4 Hz, 1H), 3.78
(s, 4H), 3.06 (s, 6H), 1.03 (s, 6H). 13C NMR (CDCl3):
149.1 (s), 134.6 (s), 133.7 (d), 131.3 (d), 130.6 (d), 128.9
(d), 128.7 (d), 126.12 (d), 126.09 (s), 125.8 (s), 116.5 (d),
116.1 (s), 106.0 (d), 91.6 (s), 88.9 (s), 72.3 (t), 40.6 (q),
31.9 (s), 21.9 (q). GC–MS (EI): 383 [M]+.
4.2.2. 2,2-Dimethylpropane-1,3-diyl-4-ethynylphenyl
boronate (4).55 To a solution of 2,2-dimethylpropane-1,3-
diyl [4-trimethylsilylethynylphenyl] boronate (3) (0.14 g,
0.5 mmol) in methanol (10 mL), was added potassium car-
bonate (0.14 g, 1 mmol). The resulting mixture was stirred
at room temperature for 0.5 h and then filtered. The filtrate
was concentrated under reduced pressure. The crude residue
was purified by flash column chromatography to afford
0.22 g (80%) of 2,2-dimethylpropane-1,3-diyl-4-ethynyl-
phenyl boronate (4). 1H NMR (CDCl3): 7.82 (d, J¼8.0 Hz,
2H), 7.54 (d, J¼8.0 Hz, 2H), 3.81 (s, 4H), 3.18 (s, 1H), 1.06
(s, 6H). 13C NMR (CDCl3): 133.6 (d), 131.1 (d), 124.1
(s), 83.9 (s), 78.0 (d), 72.3 (t), 31.8 (s), 21.8 (q). GC–MS
(EI): 214 (M+). HRMS (ESIꢁ) calcd for C18H26BO4
[M+C5H12O2 (neopental glycol)–H]ꢁ: 317.1924. Found:
317.1929.
4.3.4. 3-[4-(5,5-Dimethyl[1,3,2]dioxaborinan-2-yl)phenyl-
ethynyl]quinoline (5d). Yield: 67%. H NMR (CDCl3):
1
9.00 (d, J¼2.0 Hz, 1H), 8.30 (d, J¼1.6 Hz, 1H), 8.10 (d,
J¼8.4 Hz, 1H), 7.83–7.78 (m, 3H), 7.72 (m, 1H), 7.59–
7.54 (m, 3H), 3.78 (s, 4H), 1.03 (s, 6H). 13C NMR
(CDCl3): 152.1 (d), 146.8 (s), 138.3 (d), 133.8 (d), 130.8
(d), 130.0 (d), 129.4 (d), 127.6 (d), 127.3 (d), 124.5 (s),
117.5 (s), 93.0 (s), 87.5 (s), 72.3 (t), 31.9 (s), 21.9 (q).
GC–MS (EI): 341 [M]+. HRMS (ESI+) calcd for
C22H21BNO2 [M+H]+: 342.1665. Found: 342.1670.
4.4. General procedure for the preparation of com-
pounds 2a–d by deprotection of the neopentyl group
4.3. General procedure64,55 for the synthesis of
compounds 5a–d by microwave-assisted Sonogashira
coupling
A mixture of 5 (0.5 mmol) in 70% TFA was stirred at 60–
70 ꢀC overnight. The reaction mixture was neutralized
with saturated Na2CO3 and extracted with dichloromethane.
The combined organic solution was dried over Na2SO4. Af-
ter evaporation of solvent, the crude was purified on silica
gel by flash column chromatography to afford 2.
A mixture of aryl bromide (0.9 mmol), Pd(PPh3)2Cl2 (0.05
mmol), CuI (0.05 mmol), triphenylphosphine (0.18 mmol),
diethylamine (13.6 mmol), and 2,2-dimethylpropane-1,3-
diyl-4-ethynylphenyl boronate (1 mmol) was irradiated
under microwave at 120 ꢀC for 25 min in a heavy-walled
glass vial sealed with a Teflon septum. Then the reaction
mixture was filtered and washed with dichloromethane.
The filtrate was concentrated under reduced pressure and
the residue was purified by flash column chromatography
(silica gel 60) to give compound 5.
1
4.4.1. Compound 2a. Yield: 43%. H NMR (CDCl3): 8.48
(dd, J¼0.8 and 8.4 Hz, 1H), 8.25–8.23 (m, 3H), 7.76–7.72
(m, 3H), 7.60 (m, 1H), 7.54 (m, 1H), 7.03 (d, J¼7.6 Hz,
1H), 2.95 (s, 6H). 13C NMR (CDCl3): 152.0 (s), 135.5 (d),
134.6 (s), 131.1 (d), 130.9 (d), 128.3 (s, two carbon overlap),
126.73 (d), 126.68 (d), 125.5 (d), 124.7 (d), 114.6 (s), 113.3
(d), 93.4 (s), 90.5 (s), 45.0 (q). MS (ESIꢁ): 314.05 [MꢁH]ꢁ.
HRMS (ESIꢁ) calcd for C20H17BNO2 [MꢁH]ꢁ: 314.1352.
Found: 314.1360.
4.3.1. {4-[4-(5,5-Dimethyl[1,3,2]dioxaborinan-2-yl)-
phenylethynyl]naphthalen-1-yl}dimethylamine (5a).
Yield: 51%. 1H NMR (CDCl3): 8.44 (dd, J¼0.8 and
8.0 Hz, 1H), 8.22 (dd, J¼1.2 and 8.0 Hz, 1H), 7.81
(d, J¼8.0 Hz, 2H), 7.67 (d, J¼7.6 Hz, 1H), 7.61
(d, J¼8.4 Hz, 2H), 7.57 (m, 1H), 7.52 (m, 1H), 7.00 (d,
J¼7.6 Hz, 1H), 3.78 (s, 4H), 2.92 (s, 6H), 1.03 (s, 6H).
13C NMR (CDCl3): 151.7 (s), 134.5 (s), 133.7 (d), 130.8
(d), 130.5 (d), 128.3 (s), 126.8 (d), 126.5 (d), 125.9 (s),
125.5 (d), 124.6 (d), 114.9 (s), 113.3 (d), 93.6 (s), 89.1
(s), 72.3 (t), 45.0 (q), 31.9 (s), 21.9 (q). GC–MS (EI):
383 [M]+.
4.4.2. Compound 2b. Yield: 36%. 1H NMR (CDCl3): 8.30–
8.27(m, 2H), 8.18(d, J¼8.4 Hz, 1H), 7.81–7.75(m, 3H), 7.66
(m, 1H), 7.56–7.46 (m, 2H), 7.16 (d, J¼7.2 Hz, 1H), 2.90 (s,
6H). MS (ESIꢁ): 314.10 [MꢁH]ꢁ. HRMS (ESIꢁ) calcd for
C20H17BNO2 [MꢁH]ꢁ: 314.1352. Found: 314.1342.
4.4.3. Compound 2c. Yield: 41%. 1H NMR (CDCl3): 8.22–
8.19 (m, 2H), 7.95 (s, 1H), 7.70–7.67 (m, 3H), 7.62 (d,

S.-L. Zheng et al. / Tetrahedron 63 (2007) 5427–5436
5435
14. Yan, J.; Fang, H.; Wang, B. Med. Res. Rev. 2005, 25, 490–520.
15. Yang, W.; Gao, S.; Gao, X.; Karnati, V. R.; Ni, W.; Wang, B.;
Hooks, W. B.; Carson, J.; Weston, B. Bioorg. Med. Chem.
Lett. 2002, 12, 2175–2177.
16. Yang, W.; Fan, H.; Gao, S.; Gao, X.; Ni, W.; Karnati, V.; Hooks,
W. B.; Carson, J.; Weston, B.; Wang, B. Chem. Biol. 2004,
11, 439–448.
J¼8.8 Hz, 1H), 7.51 (dd, J¼1.6 and 8.4 Hz, 1H), 7.16 (dd,
J¼1.6 and 8.8 Hz, 1H), 6.88 (s, 1H), 3.08 (s, 6H). 13C
NMR (CDCl3): 149.2 (s), 135.5 (d), 134.7 (s), 131.6 (d),
130.9 (d), 128.9 (d), 128.1 (s), 126.2 (d), 126.1 (s), 116.6
(d), 115.8 (s), 106.0 (d), 93.0 (s), 88.7 (s), 40.7 (q). HRMS
(ESIꢁ) calcd for C20H17BNO2 [MꢁH]ꢁ: 314.1352. Found:
314.1351.
17. Springsteen, G.; Wang, B. Tetrahedron 2002, 58, 5291–5300.
18. Yan, J.; Springsteen, G.; Deeter, S.; Wang, B. Tetrahedron
2004, 60, 11205–11209.
19. Lorand, J. P.; Edwards, J. O. J. Org. Chem. 1959, 24, 769–774.
20. Sugihara, J. M.; Bowman, C. M. J. Am. Chem. Soc. 1958,
80, 2443–2446.
4.4.4. Compound 2d. Yield: 47%. 1H NMR (MeOD): 8.96
(s, 1H), 8.54 (s, 1H), 8.07 (d, J¼8.4 Hz, 1H), 7.99 (d,
J¼8.0 Hz, 1H), 7.85–7.82 (m, 3H), 7.69 (m, 1H), 7.59 (d,
J¼7.6 Hz, 2H). 13C NMR (CDCl3): 151.8, 146.3, 138.9,
138.8, 134.5, 133.5, 131.0, 130.4, 129.0, 127.7, 127.5,
92.9, 87.6. HRMS (ESI+) calcd for C17H13BNO2 [M+H]+:
274.1039. Found: 274.1028.
21. Shinkai, S.; Takeuchi, M. Trends Anal. Chem. 1996, 15,
188–193.
22. Yoon, J.; Czarnik, A. W. J. Am. Chem. Soc. 1992, 114, 5874–
5875.
4.5. Procedure for sugar-binding studies
23. Wang, W.; Gao, X.; Wang, B. Curr. Org. Chem. 2002, 6, 1285–
1317.
24. Cao, H. S.; Heagy, M. D. J. Fluoresc. 2004, 14, 569–584.
25. James, T. D.; Linnane, P.; Shinkai, S. Chem. Commun. 1996,
281–288.
26. Wiskur, S. L.; Lavigne, J. J.; Metzger, A.; Tobey, S. L.; Lynch,
V.; Anslyn, E. V. Chem.—Eur. J. 2004, 10, 3792–3804.
27. Jiang, S.; Rusin, O.; Escobedo, J. O.; Kim, K. K.; Yang, Y.;
Fakode, S.; Warner, I. M.; Strongin, R. M. J. Am. Chem. Soc.
2006, 128, 12221–12228.
The solutions of the sensors (1.0ꢂ10ꢁ5 or 1.0ꢂ10ꢁ6 M)
were prepared in 0.1 M phosphate buffer at pH 7.4 and the
solutions of sugars (1.0ꢂ10ꢁ1 M) were prepared in the
above solutions of the sensors at pH 7.4. Then, the final
test solutions were prepared by mixing the sensor solution
with different ratios of the sugar solution to give the desired
sugar concentrations. After stirring for 20 min, the mixture
was transferred into a 1 cm quartz cell and the fluorescence
intensity was recorded immediately.
28. Alpt€urk, O.; Rusin, O.; Fakayode, S. O.; Wang, W.; Escobedo,
ꢀ
J. O.; Warner, I. M.; Kral, V.; Strongin, R. M. Proc. Natl. Acad.
Sci. U.S.A. 2006, 103, 9756–9760.
Acknowledgements
29. Asher, S. A.; Alexeev, V. L.; Goponenko, A. V.; Sharma, A. C.;
Lednev, I. K.; Wilcox, C. S.; Finegold. J. Am. Chem. Soc. 2003,
125, 3322–3329.
30. Jeff, T.; Suri, J. T.; Cordes, D. B.; Cappuccio, F. E.; Wessling,
R. A.; Singaram, B. Angew. Chem., Int. Ed. 2003, 42, 5857–
5859.
Financial support from the National Institutes of Health
(CA123329, CA113917, CA88343, and NO1-CO-27184),
the Georgia Cancer Coalition through a Distinguished
Cancer Scientist Award, and the Georgia Research Alliance
through an Eminent Scholar Endowment and an Eminent
Scholar Challenge Grant is gratefully acknowledged.
31. Badugu, R.; Lakowicz, J. R.; Geddes, C. D. Bioorg. Med.
Chem. 2005, 13, 113–119.
References and notes
32. Stones, D.; Manku, S.; Lu, X.; Hall, D. G. Chem.—Eur. J. 2004,
10, 92–100.
33. Arimori, S.; Phillips, M. D.; James, T. D. Tetrahedron Lett.
2004, 45, 1539–1542.
1. Yamada, N.; Chung, Y. S.; Sawada, T.; Okuno, M.; Sowa, M.
Dig. Dis. Sci. 1995, 40, 1005–1012.
34. Riggs, J. A.; Hossler, K. A.; Smith, B. D.; Karpa, M. J.; Griffin,
G.; Duggan, P. J. Tetrahedron Lett. 1996, 37, 6303–6306.
35. Draffin, S. P.; Duggan, P. J.; Duggan, S. A. M. Org. Lett. 2001,
3, 917–920.
36. Gardiner, S. J.; Smith, B. D.; Duggan, P. J.; Karpa, M. J.;
Griffin, G. J. Tetrahedron 1999, 55, 2857–2864.
37. Shino, D.; Kataoka, K.; Koyama, Y.; Yokoyama, M.;
Okano, T.; Sakutai, Y. J. Intell. Mater. Syst. Struct. 1994,
5, 311–314.
38. Shiino, D.; Murata, Y.; Kubo, A.; Kim, Y. J.; Kataoka, K.;
Koyama, Y.; Kikuchi, A.; Yokoyama, M.; Sakurai, Y.;
Okano, T. J. Controlled Release 1995, 37, 269–276.
39. Yang, W.; Gao, X.; Wang, B. Med. Res. Rev. 2003, 23,
346–368.
40. Yang, W.; Gao, S.; Wang, B. Organoboronic Acids; Hall, D.,
Ed.; John Wiley and Sons: New York, NY, 2005; pp 481–512.
41. Gao, X.; Zhang, Y.; Wang, B. Org. Lett. 2003, 5, 4615–4618.
42. Yang, W.; Lin, L.; Wang, B. Heterocycl. Commun. 2004, 10,
383–388.
2. O’Driscoll, L.; Linehan, R.; Liang, Y. H.; Joyce, H.; Oglesby,
I.; Clynes, M. Anticancer Res. 2002, 22, 3117–3125.
3. Yehiel, Z.; Eisenstein, M.; Goren, R. A.; Hadari, Y. R.; Levy,
Y.; Ronen, D. Glycoconjugate J. 2004, 19, 517–526.
4. Tei, K.; Kawakami-Kimura, N.; Taguchi, O.; Kumamoto, K.;
Higashiyama, S.; Taniguchi, N.; Toda, K.; Kawata, R.; Hisa,
Y.; Kannagi, R. Cancer Res. 2002, 62, 6289–6296.
5. McEver, R. P. Glycoconjugate J. 1997, 14, 585–591.
6. Ley, K. Trends Mol. Med. 2003, 9, 263–268.
7. Young, A. R.; Meeusen, E. N. Glycoconjugate J. 2004, 19,
601–606.
8. Kannagi, R. Glycoconjugate J. 1997, 14, 577–584.
9. Kannagi, R. Glycoconjugate J. 2004, 20, 353–364.
10. Lectins and Cancer; Gabius, H.-J., Gabius, S., Eds.; Springer:
New York, NY, 1991.
11. Danguy, A.; Camby, I.; Kiss, R. Biochim. Biophys. Acta-Gen.
Subj. 2002, 1572, 285–293.
12. Takenaka, Y.; Fukumori, Y.; Raz, A. Glycoconjugate J. 2004,
19, 543–549.
43. Wang, J.; Jin, S.; Wang, B. Tetrahedron Lett. 2005, 46, 7003–
7006.
13. van den Brule, F. E.; Califice, S.; Vastronovo, S.
Glycoconjugate J. 2004, 19, 537–542.

5436
S.-L. Zheng et al. / Tetrahedron 63 (2007) 5427–5436
44. Yang, W.; Lin, L.; Wang, B. Tetrahedron Lett. 2005, 46, 7981–
7984.
54. Yamaguchi, S.; Shirasaka, T.; Tamao, K. Org. Lett. 2000, 2,
4129–4132.
45. Wang, J.; Lin, N.; Jin, S.; Wang, B. Chem. Biol. Drug Des.
2006, 67, 137–144.
55. Zheng, S.-L.; Reid, S.; Lin, N.; Wang, B. Tetrahedron Lett.
2006, 47, 2331–2335.
46. Zhang, Y.; Gao, X.; Hardcastle, K.; Wang, B. Chem.—Eur. J.
2006, 12, 1377–1384.
47. Gao, X.; Zhang, Y.; Wang, B. Tetrahedron 2005, 61, 9111–
9117.
56. Gao, X.; Zhang, Y.; Wang, B. New J. Chem. 2005, 29, 579–586.
57. Norrild, J. C. J. Chem. Soc., Perkin Trans. 2 2001, 719–726.
58. Ori, A.; Shinkai, S. J. Chem. Soc., Chem. Commun. 1995,
1771–1772.
48. Biswas, M.; Nguyen, P.; Marder, T. B.; Khundkar, L. R. J. Phys.
Chem. A 1997, 101, 1689–1695.
59. Goldman, M.; Wehry, E. L. Anal. Chem. 1970, 42, 1186–1188.
60. Yang, W.; Springsteen, G.; Yan, J.; Deeter, S.; Wang, B. Bioorg.
Med. Chem. Lett. 2003, 13, 1019–1022.
61. Boduroglu, S.; El Khoury, J. M.; Reddy, V. D.; Rinaldi, P. L.;
Hu, J. Bioorg. Med. Chem. Lett. 2005, 15, 3974–3977.
62. Canete, A.; Melendrez, M. X.; Saitz, C.; Zanocco, A. L. Synth.
Commun. 2001, 31, 2143–2148.
49. Elangovan, A.; Yang, S.-W.; Lin, J.-H.; Kao, K.-M.; Ho, T.-I.
Org. Biomol. Chem. 2004, 2, 1597–1602.
50. Leroy-Lhez, S.; Fages, F. Eur. J. Org. Chem. 2005, 2684–2688.
51. Metivier, R.; Amengual, R.; Leray, I.; Michelet, V.; Genet, J.-P.
Org. Lett. 2004, 6, 739–742.
52. Odom, S. A.; Parkin, S. R.; Anthony, J. E. Org. Lett. 2003, 5,
4245–4248.
53. Schiedel, M.-S.; Briehn, C. A.; Bauerle, P. Angew. Chem., Int.
Ed. 2001, 40, 4677–4680.
63. de Silva, A. P.; Gunaratne, H. Q. N.; Jayasekera, K. R.;
O’Callaghan, S.; Samankumara, K. R. A.; Sandanayake, S.
Chem. Lett. 1995, 123–124.
64. Erdelyi, M.; Gogoll, A. J. Org. Chem. 2001, 66, 4165–4169.