Catechol pendant polystyrene for solid-phase synthesis

Article abstract of DOI:10.1016/S0040-4039(02)01370-9

A catechol pendant polystyrene polymer was prepared from the Merrifield resin via a convenient procedure with high-density loading. Due to the high affinity binding between catechol and boronic acid, the polymer resin readily captures boronic acid compounds. The feasibility of using immobilized catechol to capture boronic acid products for purification and solid-phase transformation was demonstrated. Moreover, the immobilized catechol was also used for the preparation of resin-bound catecholborane, which can be used as a solid-phase amidation reagent.

Full text of DOI:10.1016/S0040-4039(02)01370-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6339–6342
Catechol pendant polystyrene for solid-phase synthesis
Wenqian Yang, Xingming Gao, Greg Springsteen and Binghe Wang*
Department of Chemistry, North Carolina State University, Raleigh, NC 27695-8204, USA
Received 19 June 2002; revised 3 July 2002; accepted 8 July 2002
Abstract—A catechol pendant polystyrene polymer was prepared from the Merrifield resin via a convenient procedure with
high-density loading. Due to the high affinity binding between catechol and boronic acid, the polymer resin readily captures
boronic acid compounds. The feasibility of using immobilized catechol to capture boronic acid products for purification and
solid-phase transformation was demonstrated. Moreover, the immobilized catechol was also used for the preparation of
resin-bound catecholborane, which can be used as a solid-phase amidation reagent. © 2002 Published by Elsevier Science Ltd.
Combinatorial chemistry and related parallel synthesis
techniques have emerged as important tools for the
discovery and development of new drugs, catalysts and
Four groups have reported the preparation of three
kinds of diol resins that just be used as a liker system to
21–24
immobilize boronic acids recently.
The macropo-
1
–3
materials.
In particular, synthetic techniques based
rous polymer-supported 1,3-diol resin can sequester
2
3
on solid-phase chemistry have attracted much attention
because of the ease of purification and automated
manipulation. Along this line, polymer resins that selec-
tively capture a functional group commonly seen in
organic synthesis and drug development are very useful
for the development of solid-phase synthesis. Boronic
acids are important intermediates in organic synthesis
and are useful for the development of biologically
active agents. For example, boronic acids have been
boronic acids in modest to good yield, but the use of
excess boronic acids and the requirement of high tem-
perature limit their use. The N,N-diethanolamino-
21
methyl polystyrene resin is more efficient than the
1
,3-diol one that can immobilize boronic acids in high
yield under mild conditions. More recently, a fluorous
version of the boronates was achieved by a 1,2-diol
pendant fluorous tag. In our recent systematic exami-
nation of the binding between boronic acid and various
diol-containing compounds, it was found that catechol
type of compounds have the highest affinity with
boronic acid. Therefore, we reasoned that immobi-
lized catechol should allow for the high efficiency cap-
ture of boronic acids for purification and transforma-
tion applications under mild conditions. Moreover, cat-
echolborane is a well-known reagent that has been used
25
4
widely used in Suzuki cross-coupling reactions, protec-
5
6
tion of diols, Diels–Alder reactions, selective reduc-
7
tion of aldehydes, asymmetric synthesis of amino
acids, and as amidation catalysts.
26
8
9,10
In addition, this
class of compounds has been used for the development
1
1,12
of sensors for carbohydrates and amino acids;
body mimics that target on cell surface carbohydrates,
selective transporters of nucleosides, saccharides and
anti-
13
1
4
27
28
29
nucleotides;
inhibitors of proteases and other
and therapeutic agents in boron neutron
capture therapy (BNCT) of certain brain tumors. Our
group has been engaged in the development of fluores-
cent sensors for saccharides using various boronic acid
in reduction, amidation, hydroboration and even
borylation of aryl halides reactions. Immobilization of
1
5,16
30
enzymes;
17
catechol on a solid-phase material also allows us to
prepare immobilized catecholborane for the aforemen-
tioned applications in solid-phase. Such unique applica-
tions cannot be achieved with either the other diol
resins or the fluorous tag, which are developed solely
for boronic acid immobilization.
1
8–20
compounds.
In our experiments, we found that the
boronic acid product was difficult to isolate and purify
by conventional methods. We believe that solid-phase
synthesis may provide a solution to the isolation and
purification problem.
The preparation of the catechol pendant polystyrene (1)
started with commercially available 3,4-dihydroxybenz-
aldehyde 2 (Scheme 1). Treatment of compound 2 with
methoxymethyl chloride and diisopropylethylamine
gave the dihydroxy-protected aldehyde 3, which was
*
0
Corresponding author. Tel.: 01-919-515-2948; fax: 01-919-515-3757;
e-mail: binghe wang@ncsu.edu
–
040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01370-9

6
340
W. Yang et al. / Tetrahedron Letters 43 (2002) 6339–6342
Scheme 1. Reagents and conditions: (a) i-Pr NEt, MOMCl; (b) (i) 40% MeNH , THF, MeOH, (ii) NaBH , 95% (three steps); (c)
2
2
4
Merrifield resin (1.26 mmol/g), K CO , CH CN, 50°C; (d) TMSBr, DCM, −78°C to rt.
2
3
3
directly subjected to reductive amination to afford
amine 4 in 95% overall yield. Attachment of the sec-
ondary amine to the Merrifield resin was achieved by
heating the resin and amine 4 in the presence of potas-
sium carbonate in acetonitrile. The resulting resin 5
gave a positive outcome with the bromophenol blue
Resin 1 was found to be very efficient in immobilizing
boronic acids in THF at room temperature (Table 1,
entries 2, 6–8). A solvent profile study using phenyl-
boronic acid as the model boronic acid and a slight
excess of resin 1 (1.25 equiv.) showed that methylene
chloride and toluene are also suitable for capture appli-
cations (Table 1, entries 1–3). Higher temperature and a
large excess of boronic acid drove the attachment to
completion (Table 1, entry 4). Cleavage of the boronic
acids from the resin was achieved with a THF/water/
acetic acid (90/5/5) mixture at room temperature to give
3
1
assay due to the presence of tertiary amines, which
indicated the success of the attachment of amine 4 to
the resin. Deprotection of the MOM group in resin 5
using trimethylsilyl bromide gave the desired catechol
pendant polystyrene 1. The solid-phase reactions were
also followed with IR. Upon deprotection of the MOM
1
the pure products as judged by their H NMR. The
3
2
−1
group in resin 5, the peaks at 1153 and 993 cm
resin (1) can be recycled with no apparent loss of
efficiency after neutralization with base washings (for
example, 5% sodium bicarbonate) and drying under
vacuum at 60°C.
disappeared, indicating the completion of the reaction.
The generation of the free hydroxyl group in resin 1
was also reflected in the IR with the appearance of a
−
1
broad intense peak at around 3450 cm . The loading
degree was determined to be about 0.97 mmol/g by
nitrogen combustion analysis of the resin. Further
determination of the loading level was pursued by
immobilizing phenylboronic acid with 1/3 equiv. of
resin 1 in toluene at 80°C, the calculated loading degree
according to the recovered phenylboronic acid was in
agreement with the elemental analysis result (Table 1,
entry 4).
The applications of the resin (1) in solid-phase synthesis
were further investigated. First we examined the feasi-
bility of using immobilized boronic acid for further
solid-phase transformations (Scheme 2). As an example,
benzylamine was coupled to resin-bound p-car-
boxyphenylboronic acid 6, under standard carbodi-
imide conditions, to afford the corresponding amide 7
in 53% yield after cleavage (Scheme 2a). The additional
a
Table 1. The immobilization and release of boronic acids
Entry
R (equiv.)
C H (0.8)
Solvent
Temperature
Yield (%)
Purity (%)b
1
2
3
DCM
THF
Toluene
Toluene
Toluene
THF
rt
rt
rt
80°C
rt
rt
rt
rt
86
67
90
100
80
65
\95
\95
\95
\95
\95
\95
\90
\90
6
4
C H (0.8)
6
4
C H (0.8)
6
4
c
4
C H (3.0)
6
4
5
6
7
8
2-Me-C H (0.8)
6 4
4-CO H-C H (0.8)
2
6
4
4-CHO-C H (0.8)
THF
THF
75
61
6
4
2-CO H-C H (0.8)
2
6
4
a
Loading was conducted by shaking a slight excess of resin 1 (300 mg, 0.97 mmol/g substitution) with the boronic acid (0.8 equiv.) in the indicated
solvent (4.0 mL) at room temperature for 12 h in a solid-phase synthesis vessel. The release was carried out by shaking the resin-bound boronic
acid for 2 h in a THF/H O/AcOH mixture (90/5/5).
2
b
c
Estimated through comparison of the 1H NMR spectra of the recovered boronic acids and the starting material.
This loading was conducted in a round-bottom flask fitted with a stir bar and a reflux condenser.

W. Yang et al. / Tetrahedron Letters 43 (2002) 6339–6342
6341
Scheme 2. NMR purities are given in brackets. Reagents and conditions: (a) BnNH (2.5 equiv.), DIC (2.5 equiv.), HOBt (2.5
2
equiv.), DMF; (b) resin 1 (1.5 equiv.); (c) THF/H O/AcOH 90/5/5; (d) p-carboxyphenylboronic acid (1.0 equiv.), EDC (2.0
2
equiv.), HOBt (1.2 equiv.), DCM.
9,10
use of resin 1 was borne out of the recently developed
tion reactions.
In performing the amidation reaction,
33
resin capture strategy. In this regard, resin 1 could be
used for capturing the organoboron products from
complex reaction mixtures either for purification or to
perform solid-phase transformations. As a significant
demonstration of such an application, resin 1 was
employed in the purification of crude fluorescent
boronic acid compound 10. Treatment of 9-(methyl-
resin-bound catecholborane 11 was shaken with a car-
boxylic acid to give the activated anhydride. An amine
was then added in. After shaking at room temperature
overnight, the amide product was obtained in modest
yield. However, these yields were comparable to what
was obtained in solution-phase synthesis, in which the
amide product was obtained with a yield in the range of
60–90%. Such results indicate that resin-bound cate-
cholborane 11 behaves much the same way as free
catecholborane in mediating amidation reactions.
aminomethyl)anthracene
8
with p-carboxyphenyl-
boronic acid under standard carbodiimide conditions
furnished compound 10 in a reaction mixture. To the
resulting solution was added resin 1 directly, and the
resulting mixture was shaken overnight at room tem-
perature in a solid-phase synthesis vessel to afford resin
In conclusion, we have developed a new versatile diol
resin by immobilizing catechol to a polystyrene solid
support, although other solid support materials can
also be used. The immobilized catechol not only can be
used as a linker system to capture boronic acids for
purification and solid-phase transformations, but also
for the preparation of a solid-supported reagent, immo-
bilized catecholborane. Further work on expanding the
use of the resin is under way.
9
. After cleavage, the fluorescent boronic acid com-
pound 10 was obtained in 84% yield (Scheme 2b).
As mentioned earlier, catecholborane is a well-known
reagent in synthetic chemistry and has many known
applications. Resin 1 also allows for the preparation of
solid-phase catecholborane (11). Therefore, resin 1 was
treated with BH ·THF to afford the immobilized cate-
3
cholborane 11 (Table 2). To examine the feasibility of
using this solid-phase reagent for chemical transforma-
tions, we chose to study catecholborane-mediated ami-
Acknowledgements
2
8
dation
reactions.
Again,
in
solution-phase
catecholborane is known to mediate amidation by acti-
vating a carboxylic acid through anhydride forma-
tion. The formation of the same type of intermediates
is also the reason that boronic acid can catalyze amida-
Financial support from the National Institutes of
Health (DK55062, NO1-CO-27184, and CA88343) is
gratefully acknowledged.
3
4

6
342
W. Yang et al. / Tetrahedron Letters 43 (2002) 6339–6342
a
Table 2. Amidation reaction mediated by polymer-supported catecholborane 11
Entry
1
Acid
Amine
Productb
Yield (%)
Purity (%)c
Octanoic acid
Octanoic acid
Octanoic acid
Octanoic acid
Isovaleric acid
Isovaleric acid
Phenethylamine
Phenethylamine
Phenethylamine
Benzylamine
Phenethylamine
Benzylamine
N-Phenethyloctanoic amide
N-Phenethyloctanoic amide
N-Phenethyloctanoic amide
N-Benzyloctanoic amide
3-Methyl-N-phenethylbutyramide
3-Methyl-N-benzylbutyramide
51
52
35
54
47
42
\90
\90
\90
\95
\90
\95
d
2
3
e
4
5
6
a
The reaction was conducted by shaking resin 1 (1.25 equiv.) with BH ·THF (2.5 equiv.) in a solid-phase synthesis vessel. After washing with dry
3
THF several times, the resulting resin 10 was treated with acid (0.8 equiv.) and amine (1.6 equiv.) in turn to afford amide after standard aqueous
work-up.
b
c
Product identity was established by comparison the 1H NMR spectra with those of authentic samples.
Estimated from 1H NMR data.
d
e
2
.5 equiv. of resin 1 was used.
Mixed solvent (THF:DCM=1:1) was used.
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