Preparation of reusable dihydropyran-functionalized resins cross-linked with tetrahydrofuran

Article abstract of DOI:10.2174/157017812802850302

The novel dihydropyranyl-functionalized resins, referred to as JJ-DHP , prepared from JandaJel-Cl resin, have been developed. We have also clarified that JJ-DHP has shown a good swelling property in common organic solvents and reusable ability in solid-phase organic synthesis.

Full text of DOI:10.2174/157017812802850302

556
Letters in Organic Chemistry, 2012, 9, 556-558
Preparation of Reusable Dihydropyran-Functionalized Resins Cross-
Linked with Tetrahydrofuran
Tomikazu Kawano*, a, Seri Kurosawab, Kousuke Ikeuchib and Satoshi Ogawac
aSchool of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba, Iwate 028-3694, Japan
bGraduate School of Engineering, Iwate University, 4-3-5 Ueda, Morioka, Iwate 020-8551, Japan
cIwate University, 3-18-8 Ueda, Morioka, Iwate 020-8550, Japan
Received February 24, 2012: Revised June 12, 2012: Accepted July 12, 2012
Abstract: The novel dihydropyranyl-functionalized resins, referred to as “JJ-DHP”, prepared from JandaJel-Cl resin,
have been developed. We have also clarified that JJ-DHP has shown a good swelling property in common organic sol-
vents and reusable ability in solid-phase organic synthesis.
Keywords: Dihydropyran, resin, reusable solid-phase organic synthesis, swelling property.
INTRODUCTION
libraries, we needed novel resins with good swelling proper-
ties, reactivity to an alcohol functional group, and reusabil-
ity. The resins with a dihydropyranyl group (DHP) are at-
tractive because they can satisfy these requirements. How-
ever, only a few reports regarding the preparation and swel-
ling properties of DHP-functionalized resins have published,
though most such resins were prepared from Merrifield res-
ins, SynPhase [5] Lanterns, or linear polystyrene-supported
polymers [6]. Therefore, we speculated that JJ resins with a
DHP group (JJ-DHP) should become a valuable asset for
solid-phase organic synthesis.
In recent years, solid-phase organic synthesis (SPOS) has
evolved into a widely used synthetic tool for the construction
of biopolymers, catalysts, and more complicated organic
compound libraries [1]. The main advantages of SPOS are
that its reactions can be driven to completion by the use of a
large molar excess of reagents, and that desired products can
be isolated easily by simple filtration and removed from
chemically inert insoluble polymers (resins). Moreover,
SPOS enables the automation of all steps in a synthesis pro-
tocol: the addition of reagents, agitation, filtration, and wash-
ing. Despite these advantages, this technique presents some
drawbacks: the physicochemical parameters of the resin,
such as loading capacity, bead size, and swelling properties,
can influence the reaction kinetics. Side reactions with the
polymer support itself may occur. We focused on JandaJel
(JJ) polystyrene resins [2], which are cross-linked with a
polytetrahydrofuranic structure because they exhibit excel-
lent swelling characteristics when evaluated against com-
mercially available Merrifield resins, which are cross-linked
with divinylbenzene [3]. JJ resins can swell well in common
organic solvents (even in lower polar solvents such as ben-
zene and toluene). Among commercially available JJ resins,
those with a chloromethyl group (JJ-Cl), an aminomethyl
group (JJ-NH2), a hydroxymethyl group (JJ-OH), or a (4-
hydroxymethyl)phenoxymethyl group (JJ-Wang-OH) are
known as versatile JJ resins. In recent years, JJ resins with a
triphenylphosphine group (JJ-TPP) have also been devel-
oped as a reusable organocatalyst [4].
In this paper, we report the preparation and properties of
JJ-DHP. Its application to solid-phase organic synthesis and
its reusability are also discussed.
RESULTS AND DISCUSSION
The preparation of JJ-DHP is shown in Scheme 1. The
commercially available JJ-Cl, with a loading level of 0.96
mmol/g, was shaken with sodium salt of 3,4-dihydro-2H-
pyran-2-methanol, which was prepared by treatment with
sodium hydride, in dry N,N-dimethylformamide (DMF) at
room temperature for 18 h. The resulting reddish-brown res-
ins were then washed with DMF, dichloromethane, and
methanol, and then dried in vacuo for 48 h to give JJ-DHP
[7]. The loading level of JJ-DHP was determined to be 0.469
mmol/g by FMOC release assay [8]. The resulting JJ-DHP
was thermally stable and was also mechanically stable
against magnetic stirring during a 48 h period.
In the course of our research toward the development of
novel chemical tools for the construction of our chemical
Next, the swelling property of JJ-DHP was estimated in
several common solvents [9]. The Merrifield resins with a
DHP group (MR-DHP) were also prepared to compare the
relative importance of cross-linkers in resins: a cross-linker
with a polytetrahydrofuranic structure for JJ resins and a
cross-linker with divinylbenzene for MR resins (Scheme 1).
The results are summarized in Table 1.
* Address correspondence to these authors at the School of Pharmacy, Iwate
Medical University, 2-1-1 Nishitokuta, Yahaba, Iwate 028-3694, Japan;
Tel: +81 19 651 5111 (ext. 5272), Fax: +81 19 698 1932;
E-mail: tkawano@iwate-med.ac.jp
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

Preparation of Reusable Dihydropyran-functionalized Resins
Letters in Organic Chemistry, 2012, Vol. 9, No. 8 557
1. NaH / DMF, 0 °C
2. JJ-Cl, DMF, rt
JJ
O
OH
O
O
JJ
JJ-Cl:
Cl
Scheme 1. Preparation of JJ-DHP and MR-DHP.
Table 1. Swollen Volume (mL/g) of Various Resins. a
Entry
Resins
DMF
CH2Cl2
1,2-DCE b
MeOH
THF
CH3CN
1
2
3
4
JJ-DHP
MR- DHP
JJ-Cl c
7.0
5.2
5.4
4.0
10.0
8.3
8.6
7.5
7.4
4.7
1.2
1.1
10.8
8.6
2.0
1.5
1.3
1.1
7.8
0.89
0.80
8.3
MR-Cl c
5.9
5.5
aVolumes were measured in syringes equipped with a sintered frit after equilibrating for 24h. b1,2-dichloroethane. cThese resins were purchased from Aldrich Chemical Co. Inc., and
used as received.
JJ-DHP was found to have superior swollen volumes
compared to the corresponding MR-DHP in all solvents
tested (Entries 1 and 2). The distinctive advantage of the
swelling property of JJ-Cl over that of MR-Cl is consistent
with the theoretical explanation (Entries 3 and 4). It is also
noteworthy that the chemical transformation to the DHP
group from the chloro group leads to higher swollen volumes
of the resins prepared in this study (Entries 1 and 2 (for en-
tries 3 and 4, respectively)). These findings indicate that the
increased hydrophilic character of a resin significantly af-
fects its swelling properties. Ether group, which was con-
nected with a resin backbone and a DHP group, may also
play an important role in increased swollen volumes. Prepa-
ration of JJ resins with greater hydrophilicity should lead to
the development of novel JJ resins with better swelling abil-
ity.
panied by the recovery of JJ-DHP [10]. Compounds 5a-d
were identified by comparison with spectral data of com-
pounds 5a-d obtained by conventional solution-phase or-
ganic synthesis. The overall isolated yields of 5a-d were
determined to be 17% (for 5a), 20% (for 5b), 19% (for 5c),
and 21% (for 5d) yields, based on the initial loading level of
JJ-DHP, respectively. The lower yield may be attributed to a
lower loading rate in the steps of synthesis of 2 and the
cleavage of 4a-d, because Kaiser Test allowed us to thor-
oughly monitor the synthetic steps from 2 to 4.
Finally, we investigated the reusability of “recovered JJ-
DHP” as a by-product in this study. The loading level of
“recovered JJ-DHP” was determined to be 0.330 mmol/g by
the FMOC release assay mentioned above. Therefore, it was
clarified that the “recovered JJ-DHP” had a loading level of
about 70% that of the original JJ-DHP. Moreover, the load-
ing level of “recovered JJ-DHP (2nd generation)”, obtained
from SPOS in scheme 2 by using “recovered JJ-DHP” as a
starting resin, was determined to be 0.234 mmol/g. This in-
dicates that even the “recovered JJ-DHP (2nd generation)”
has a loading level of about 50% that of the original JJ-DHP.
Therefore, JJ-DHP should become a versatile resin for solid-
phase organic synthesis.
To investigate the application of JJ-DHP in organic syn-
thesis, we used it for the synthesis of amino acid-
functionalized alcohol derivatives (5a-d), which we needed
for another project regarding chemical library of pepti-
domimetics. The reaction scheme is outlined in Scheme 2.
Alcohol derivative 1 was attached to JJ-DHP employing
pyridinium p-toluenesulfonate (PPTS) in 1,2-dichloroethane
(DCE) at 80 °C, and then tetrahydrofuranyl-functionalized JJ
resins 2 was obtained. The coupling reaction of four (L)-
amino acid derivatives (alanine, valine, phenylalanine, and
tryptophane) with amine-functionalized resins 3, obtained by
treatment of 2 with hydrazine, in the presence of 1-ethyl-3-
CONCLUSIONS
We have succeeded in synthesizing the novel dihydro-
pyranyl-functionalized JJ resin (JJ-DHP) with good swelling
property in common organic solvents. We have also demon-
strated JJ-DHP’s usefulness for reacting with an alcohol de-
rivative in solid-phase organic synthesis, and as well as its
great ability as a reusable resin. Further studies on the scope
and limitation of JJ-DHP in organic synthesis are in pro-
(3-dimethylaminopropyl)
carbodiimide
hydrochloride
(WSC-HCl) and 1-hydroxybenzotriazole (HOBt) proceeded
at room temperature smoothly to give resins 4a-d, respec-
tively. These coupling reactions were monitored by Kaiser
Test. Cleavage of 4a-d with PPTS in DCE at 60 °C gave
amino acid-functionalized alcohol derivatives 5a-d, accom-

558 Letters in Organic Chemistry, 2012, Vol. 9, No. 8
Kawano et al.
JJ
O
O
O
pyridinium p-toluenesulfonate
OH
O
O
(PPTS)
+
JJ
N
N
O
DCE, 80 °C
O
O
O
SPh
SPh
JJ-DHP
1
2
JJ
O
O
O
R
O
(Z)-(
L
)-Amino acids
H
JJ
N
O
WSC•HCl
N
O
O
O
H
HOBt, Et3N
NH2NH2
DMF
SPh
O
NH2
DMF
4a (R = Me)
SPh
OH
4b (R = CH(CH3)2)
4c (R = CH2Ph)
4d (R = 2-indolyl)
3
R
O
H
PPTS
DCE, 60 °C
N
JJ
N
O
O
H
O
SPh
O
5a (R = Me)
5b (R = CH(CH3)2)
5c (R = CH2Ph)
"Recovered" JJ-DHP
5d (R = 2-indolyl)
Scheme 2. SPOS of amino acid-functionalized alcohol derivatives (5) by using JJ-DHP.
carbon nucleophiles to ꢀ,ꢁ-unsaturated compounds, Tetrahedron,
2008, 64, 2120-2125.
gress, and the construction of a chemical library by using JJ-
DHP will be described elsewhere.
[5]
[6]
SynPhase is a registered trademark of Mimotopes Pty Ltd.
(a) for attachment to Merrifield resins, see: Ramaseshan, M.; Dory,
Y.L.; Deslongchamps, P. Solid Phase Combinatorial Synthesis of a
Library of Macro-Heterocycles and Related Acyclic Compounds,
J. Comb. Chem., 2000, 2, 615-623. (b) For attachment to SynPhase
Lanterns, see: Basso, A.; Ernst, B. Solid-phase synthesis of hy-
droxyproline-based cyclic hexapeptides, Tetrahedron Lett., 2001,
42, 6687-6690. (c) For attachment to linear polystyrene-supported
polymers, see: Toy, P.H.; Janda, K.D. Soluble Polymer-supported
Organic Synthesis, Acc. Chem. Res., 2000, 33, 546-554.
General procedure for the preparation of JJ-DHP: To a solution of
3,4-dihydro-2H-2-methanol (0.256 ml, 2.40 mmol) was added so-
dium hydride (0.098 g, 2.45 mmol) at room temperature. After be-
ing stirred at the same temperature for 0.5 h, JJ-Cl (0.96 mmol/g;
0.500 g, 0.48 mmol) was added, and then the resulting reaction
mixture was shaken at room temperature for 18 h. The suspension
was quenched with water, and the solvent was filtered off. The
resin was washed with DMF (10 ml), dichloromethane (10ml x 2),
methanol (10 ml x2) and dried in vacuo to give JJ-DHP (0.525 g).
(a) Rodriquez, M.; Terracciano, S.; Cini, E.; Settembrini, G.;
Bruno, I.; Bifulco, G.; Taddei, M.; Gomez-Paloma, L. Total syn-
thesis, NMR solution structure, and binding model of the potent
histone deacetylase inhibitor FR235222. Angew. Chem., Int. Ed.,
2006, 45, 423-427. Also see its supporting information. (b) Hori,
M.; Gravert, D.J.; Wentworth, P., Jr.; Janda, K.D. Investigating
highly crosslinked macroporous resins for solid-phase synthesis,
Bioorg. Med. Chem. Lett., 1998, 8, 2363-2368.
CONFLICT OF INTEREST
The author(s) confirm that this article content has no con-
flicts of interest.
ACKNOWLEDGEMENTS
[7]
We thank Dr. Kazuaki Shimada and Dr. Hiroki Muraoka
for stimulating discussions.
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[1]
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[8]
[2]
[3]
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[9]
Measurement of swollen volumes: JJ-DHP (0.250 g) were placed
in syringes equipped with a sintered frit, the desired solvent (4.0
mL) was added at room temperature. The suspension was left to
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[10]
[4]
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