Stabilization of chiral helices for saccharide-linked ethynylpyridine oligomers possessing a conformationally well-defined linkage

Article abstract of DOI:10.1002/ejoc.201201376

Tetrameric and octameric 2,6-pyridylene ethynylene oligomers linked to a β-D-glucopyranoside template through an o-phenylene linker were prepared and studied for their higher-order structure. These oligomers formed chiral helical structures through intramolecular hydrogen bonding between the ethynylpyridine moiety and the glucoside template. The rigidity of the o-phenylene linker stabilizes the helical structure to improve its CD activity and resistance against protic surroundings. Furthermore, the helical stabilization was enhanced by the addition of Cu(OTf)₂ and Zn(NO ₃)₂ salts. Tetrameric and octameric 2,6-pyridylene ethynylene oligomers joined to a β-D-glucopyranoside by a o-phenylene linker were prepared and their higher-order structure studied. The chiral helical structures formed by intramolecular H-bonding and linker stabilization improve CD activity and resistance to protic surroundings. Stabilization was enhanced with the addition of Cu(OTf)₂ and Zn(NO₃) ₂ salts. Copyright

Full text of DOI:10.1002/ejoc.201201376

FULL PAPER
DOI: 10.1002/ejoc.201201376
Stabilization of Chiral Helices for Saccharide-Linked Ethynylpyridine
Oligomers Possessing a Conformationally Well-Defined Linkage
Fumihiro Kayamori,[a] Hajime Abe,*[a] and Masahiko Inouye*[a]
Keywords: Helical structures / Nitrogen heterocycles / Salt effect / Hydrogen bonds / Circular dichroism
Tetrameric and octameric 2,6-pyridylene ethynylene oligo-
mers linked to a β- -glucopyranoside template through an o-
phenylene linker were prepared and studied for their higher-
order structure. These oligomers formed chiral helical struc-
tures through intramolecular hydrogen bonding between the
ethynylpyridine moiety and the glucoside template. The
rigidity of the o-phenylene linker stabilizes the helical struc-
ture to improve its CD activity and resistance against protic
surroundings. Furthermore, the helical stabilization was en-
hanced by the addition of Cu(OTf)2 and Zn(NO3)2 salts.
D
enable the distance between the saccharide template and the
helix inside to be adjustable. This adjustability brings
enthalpic advantages but also entropic disadvantages for
the intramolecular association, and we have examined some
other systems.
Introduction
It is one of the important issues to construct chiral
higher-order structures with synthetic materials.[1] Synthetic
polymers and oligomers that spontaneously form helical
structures are interesting from the viewpoint of supramolec-
ular and also biomimetic chemistry. Helical higher-order
structures are also seen in biopolymers and are essential for
the function of nucleic acids and peptides.[2] Well-designed
synthetic oligomer systems have been used to construct na-
ture-mimicking and artificial achiral and chiral helical
structures.[3,4] Introducing a chiral template at the end of
synthetic oligomers has been one strategy for building chi-
ral helical structures.[5,6]
Our group has developed synthetic host molecules oligo-
and poly(2,6-pyridylene ethynylene)s 1, and ethynylpyridine
oligomer/polymers, in which a number of pyridine rings are
tethered with acetylene bonds at their 2,6-positions (Fig-
ure 1).[6,7] These oligomers and polymers associate with a
saccharide guest[8] to form helical complexes by multipoint
hydrogen bonding. During our research, we have investi-
gated saccharide-linked ethynylpyridine oligomers 2 in
which the ethynylpyridine moiety is linked to a saccharide
template at one end by an alkylene group. At the side
chains, 3-butenyl groups were introduced for further chemi-
cal modification. Oligomers 2 showed strong CDs owing to
the helix formation by intramolecular association between
the ethynylpyridine oligomer moiety and the saccharide
template.[6a] Consequently, an alkylene linker was chosen to
Figure 1. General structures of ethynylpyridine oligomers/polymers
1 and saccharide-linked oligomers 2.
Herein we report the development of new rigid analogues
of saccharide-linked oligomers 3a, 3b, and 4 (Figure 2). The
ethynylpyridine moiety consists of four or eight pyridine
rings. One end of these oligomers is linked with a β-d-
glucopyranoside template with an o-phenylene linker. This
linker has two alkyl groups, tert-butyl and ethyl groups, and
the former stabilizes kinetically the glycosidic bond at the
ortho position through steric hindrance. Without this tert-
butyl group, degradation of the glycosidic bond occasion-
ally occurs during the course of preparation. The other end
of 3a and 4 is substituted with a tert-butyldimethylsilyl
(TBS) group, and is removed in 3b. The o-phenylene linker
is rather more rigid than the alkylene linker in 2, therefore
the intramolecular association and helix formation were ex-
pected to be tighter and improved by the fixing of the rela-
tive positions of the hydrogen bonding components. In ad-
dition, 3a,b and 4 were expected to maintain their chiral
[a] Graduate School of Pharmaceutical Sciences, University of
Toyama,
2630 Sugitani, Toyama 930-0194, Japan
Fax: +81-76-434-5049
E-mail: abeh@pha.u-toyama.ac.jp
inouye@pha.u-toyama.ac.jp
Homepage: www.pha.u-toyama.ac.jp/yakka/index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201376.
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F. Kayamori, H. Abe, M. Inouye
FULL PAPER
helical structures even in polar solvents such as methanol, tert-butyl-4-ethylphenol (5) as described in the literature.[9]
which disturbs hydrogen bonding. In the case of 2, the CD Iodophenol 6 was glycosylated by using α-d-glucopyranosyl
activity was suppressed in a mixed solvent CH2Cl2/MeOH bromide tetrabenzoate (7) as a glucosyl donor in alkaline
(3:1) because hydrogen bonding was inhibited.[6a]
biphasic conditions to give aryl glucoside 8, which was sub-
sequently deprotected to give 9. The iodine atom of 9 was
substituted with trimethylsilylacetylene by a Sonogashira
reaction, and the trimethylsilyl (TMS) group of product 10
was deprotected with tetra-n-butylammonium fluoride
(TBAF) to afford building block 11. A Sonogashira reac-
tion between the acetylene group of 11 and the iodine atom
of 12 afforded β-d-glucoside-linked tetramer 3a, one of the
target compounds. The TBS group of 3a was removed by
TBAF to give 3b, and the free acetylene group of 3b was
coupled with 12 to yield octamer 4.
Figure 2. Ethynylpyridine oligomers 3 and 4 having a glucoside
template linked with an o-phenylene linker.
CD and UV/Vis Analyses
Results and Discussion
The helix-forming ability of glucoside-linked tetramers
3a, 3b and octamer 4 was evaluated on the basis of CD
and UV/Vis analyses in CH2Cl2 solutions (Figure 3). The
pyridine unit concentration of the solutions was set at
5.0ϫ10–4 m. In the CD measurements, a positive CD was
observed around 331 nm in all cases (Figure 3, A). Because
the glucoside moiety does not show absorption around that
region, this indicates the formation of a chiral helical
higher-order structure for the ethynylpyridine moiety. So far
during our study of ethynylpyridine compounds, various
Synthesis
The target glucoside-linked ethynylpyridine oligomers
were prepared as shown in Scheme 1, in which (o-β-d-
glucosyloxyphenyl)acetylene 11 and ethynylpyridine tetra-
mer 12[6a] were used as building blocks. For the synthesis
of 11, first 6-tert-butyl-4-ethyl-2-iodophenol (6) was pre-
pared by oxidative iodination of commercially available 2-
Figure 3. (A) CD and (B) UV/Vis spectra of glucoside-linked eth-
ynylpyridine oligomers 3a (green), 3b (black), and 4 (red). Condi-
tions: 3a, 3b (1.25ϫ10–4 m, pyridine unit: 5.0ϫ10–4 m),
4
Scheme 1. Preparation of glucoside-linked ethynylpyridine oligo-
(6.25ϫ10–5 m, pyridine unit = 5.0ϫ10–4 m), CH2Cl2, 25 °C, path
mers 3a, 3b and 4. TMSA = trimethylsilylacetylene.
length: 1 mm.
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Saccharide-Linked Ethynylpyridine Oligomers
kinds of chiral helical ethynylpyridine oligomers have exhib- Therefore, the intermolecular association of both 3a and 4
ited CD bands of similar shapes around 330 nm.[6,7] The is negligible within those concentration ranges.
advantage of the o-phenylene linker was that even shorter
Previously we reported that the CD activity of sacchar-
oligomers could form a helix. Tetramers 3a and 3b exhib- ide-linked ethynylpyridine oligomer 2 in CH2Cl2 solution
ited CD activity as shown in Figure 3 (A), but β-glucoside- was quenched by the addition of MeOH.[6a] To examine the
linked hexamer 2 with an alkylene linker (see Figure 1, benefit of the o-phenylene linker to stabilize helix forma-
sugar: β-d-glucopyranoside, n = 3, m = 5) showed no mean- tion, we studied the CD activity of octamer 4 and tetramers
ingful CD activity.[6a] It appears that the TBS group at the 3a and 3b and their resistance to the addition of MeOH.
end of 3a had little effect on the helix formation, because CD spectra were measured for solutions of 4, 3a and 3b in
unprotected 3b gave a similar CD and UV spectra. As mixed solvents CH2Cl2/MeOH of various ratio (1:0, 5:1,
shown in Figure 3 (B) the molar absorptivity (ε) of octamer 3:1, and 1:2). The first CD band of 4 around 332 nm de-
4 was approximately twice as strong as that of 3a and 3b, creased by about half upon the first addition of MeOH
because the number of pyridine rings of 4 is double that of (CH2Cl2/MeOH = 5:1), however, the CD was essentially
3a and 3b. However, the molar ellipticity ([θ]) spectrum of preserved in more polar conditions (CH2Cl2/MeOH = 1:2;
4 was very similar to that of 3a and 3b (Figure 3, A). Be- Figure 4, A), showing a higher resistance to the protic sur-
cause the o-phenylene linker is so short and rigid, the four roundings than 2. In the case of 3a and 3b, similar results
extra pyridine rings of 4 were not affected by the template were also observed as shown in Figure 4, B and Figure S3
effect from the β-glucoside moiety.
(see Supporting Information). When the MeOH content in-
Concentration effects of 3a and 4 on the CD and UV/ creased (CH2Cl2/MeOH = 1:2), the observed CD decreased.
Vis spectra were studied in CH2Cl2 solutions, to determine These findings demonstrate that changing the linker moiety
if the CD activity observed in Figure 3 (A) was caused by from alkylene to phenylene reinforced the helical struc-
intramolecular complexation as for 2. The CD ellipticity ture.[10] Unfortunately, 4, 3a and 3b were practically insolu-
and UV absorbance were plotted against the concentrations ble to MeOH, and further increases in the ratio of MeOH
of 3a and 4 (Figures S1 and S2, Supporting Information, caused turbidity. For UV/Vis measurements, the addition of
respectively), and both the CD and absorbance were in pro- MeOH caused small red shifts probably owing to the hydro-
portion to the concentrations 3a or 4 in the range 8.3ϫ10–7 gen bonding of pyridine rings with solvent molecules (Fig-
to 3.0ϫ10–3 m for 3a and 2.3ϫ10–6 to 1.0ϫ10–3 m for 4. ure S4, Supporting Information).
Additive Effect of Metal Salts
Recently, our group has found that the addition of cop-
per salt enhanced the CD activity of ethynylpyridine oligo-
mers.[6d,7b,7c] A similar type of additive effect was also ob-
served with 4. When Cu(OTf)2 (5.0ϫ10–4 m) was added to
a solution of 4 (6.25ϫ10–5 m, unit concentration =
5.0ϫ10–4 m) with a small amount of dimethyl sulfoxide
(DMSO), the CD band around 332 nm was enhanced ap-
proximately four times (Figure 5, A). Even in polar solu-
tions, CD enhancement was observed. As shown in Figure
S7 (Supporting Information), the CD activity of 4 was al-
most suppressed in THF, whereas in the presence of Cu-
(OTf)2, the CD activity was restored around 340 nm. The
intensity of the CD band in THF was comparable to that
in CH2Cl2. These CD enhancements are a result of fixing
the chiral helical structure by coordination as seen in our
previous cases with other types of ethynylpyridine com-
pounds.[6d,7b] Copper cations serve as a bridge between the
nitrogen atoms of the pyridine rings and the hydroxy groups
of the glycoside moiety. However, when Cu(OTf)2 was
added to CH2Cl2 solutions of tetramers 3a and 3b
(1.25ϫ10–4 m, unit concentration: 5.0ϫ10–4 m), no signifi-
cant CD-enhancement effects were observed, but a decrease
in the CD was observed over time (Figure 5, B and Figure
S7 in Supporting Information). Therefore, the copper-medi-
Figure 4. Additive effect of MeOH on CD spectra of (A) 4 and
ated helix fixation for longer oligomer 4 is a result of coor-
(B) 3a in CH2Cl2. Conditions: 4 (6.25ϫ10–5 m, pyridine unit:
dination based on the extra pyridine rings of 4, which is
opposite to the result shown in Figure 3 (A) in the absence
of metal cations.
5.0ϫ10–4 m) or 3a (1.25ϫ10–4 m, pyridine unit: 5.0ϫ10–4 m),
CH2Cl2 (broken) or CH2Cl2/MeOH = 5:1, 3:1, and 1:2 (solid),
25 °C, path length: 1 mm.
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F. Kayamori, H. Abe, M. Inouye
FULL PAPER
Conclusions
New rigid glucoside-linked ethynylpyridine tetramers 3a,
3b and octamer 4 were designed and prepared by using Son-
ogashira reactions. In these oligomers a β-d-glucopyrano-
side template is linked with an ethynylpyridine moiety with
an o-phenylene linker. This rigid linker fixed the relative
positions between the template and the ethynylpyridine
moiety to stabilize the chiral helical structure formed
through intramolecular hydrogen bonding. Oligomers 3a,
3b and 4 showed strong CDs to indicate helix formation in
CH2Cl2, and these CDs showed resistance to the addition
of MeOH, a hydrogen-bonding inhibitor. The addition of
CuII and ZnII salts were found to enhance the CD of 4,
probably because of coordination. This coordination is
based on the remote pyridine rings from the glucoside tem-
plate and shorter oligomers 3a and 3b did not show similar
effects. Oligomers 4, 3a and 3b have 3-butenyl groups on
their pyridine units, for further chemical modification such
as functional group introduction and bridging between heli-
cal pitches. These projects are underway in our group.
Experimental Section
General: NMR spectra were recorded by using tetramethylsilane
as an internal reference. THF was freshly distilled from sodium
benzophenone ketyl before use. High-resolution mass spectra were
recorded with an ESI-TOF-MS mass spectrometer. Tetrameric
building block 12 was prepared according to the method we re-
ported previously.[6a]
Figure 5. Additive effect of copper(II) triflate on CD spectra of
(A) 4 and (B) 3a in CH2Cl2. Conditions: 4 (6.25ϫ10–5 m) or 3a
(1.25ϫ10–4 m), Cu(OTf)2 [5.0ϫ10–4 m; added as a DMSO solution
(0.125 m, 0.40 v/v% to CH2Cl2)], CH2Cl2, 25 °C, path length: 1 mm.
For the corresponding changes of UV/Vis spectrum, see Figures
S8A and S9 (Supporting Information).
2-tert-Butyl-4-ethyl-6-iodophenol (6): This compound was prepared
from 2-tert-butyl-4-ethylphenol by iodination with NaI/NaClO.[9]
To a solution of 2-tert-butyl-4-ethylphenol (7.6 g, 42 mmol) in
MeOH (120 mL) were added NaI (6.5 g, 44 mmol) and NaOH
(2.0 g, 50 mmol) under a nitrogen atmosphere, and the resulting
suspension was cooled to 0 °C with an ice bath. NaOCl (5.0 w/w-
% in an alkaline solution, 28 mL) was added dropwise to the sus-
pension, maintaining the reaction temperature at 0–3 °C. After
complete addition, the reaction mixture was stirred for 1 h at 0–
3 °C, and then 10% aqueous Na2S2O3 solution (100 mL) was added
to the mixture and the pH was adjusted to 3–4 with 5% HCl. The
reaction mixture was extracted with diethyl ether (3ϫ 50 mL) and
the combined organic layers were washed with brine, dried with
anhydrous Na2SO4, and concentrated. The resulting residue was
purified by silica-gel column chromatography (eluent: AcOEt/hex-
ane = 1:100) to afford 6 (12 g, 96%) as a yellow oil. 1H NMR
(CDCl3, 300 MHz): δ = 1.19 (t, J = 7.8 Hz, 3 H), 1.38 (s, 9 H),
2.53 (q, J = 7.6 Hz, 2 H), 5.33 (s, 1 H), 7.05 (d, J = 2.1 Hz, 1 H),
7.36 (d, J = 2.4 Hz, 1 H) ppm. This NMR spectrum agrees with
that reported in the literature.[12]
The additive effect of other metal salts was examined by
applying zinc(II) 4-tert-butylbenzoate and Zn(NO3)2·6H2O.
As shown in Figure S10 (Supporting Information), zinc(II)
4-tert-butylbenzoate resulted in little additive effect even af-
ter two days in a tetrahydrofuran (THF) solution of 4.
However, the addition of excess Zn(NO3)2·6H2O improved
the CD activity of 4 to be as strong as for Cu(OTf)2 in
CH2Cl2 probably owing to chelation between zinc cations
and 4. The bulkiness of the 4-tert-butylbenzoate anion in-
hibits stabilization through coordination of the helix,
whereas the addition of Zn(NO3)2·6H2O did not affect the
CD spectra of 3a and 3b in CH2Cl2 (Figures S11 and S12
in Supporting Information).
Finally, the P- and M-helical conformations of the glucos-
ide-linked oligomers were studied by using DFT calcula-
tions and compound 3c as a model (Figure S13, Supporting
Information). In the optimized conformations, the ethynyl-
pyridine and glucoside moieties associate tightly with mul-
tiple hydrogen bonds. Indeed, these hydrogen bonds were
2-tert-Butyl-4-ethyl-6-iodophenyl
2,3,4,6-Tetra-O-benzoyl-β-D-
glucopyranoside (8): To a stirred solution of 2-tert-butyl-4-ethyl-6-
iodophenol (6, 0.69 g, 2.3 mmol), 2,3,4,6-tetra-O-benzoyl-α-d-
glucopyranosyl bromide (7, 0.76 g, 1.1 mmol), and nBu4NBr
(0.37 g, 1.1 mmol) in CHCl3 (12 mL) was added 1 n NaOH aq.
(12 mL) at room temperature. The resulting mixture was stirred
vigorously at room temperature for 2.5 h, and diluted with AcOEt
(50 mL). The organic layer was subsequently washed with 1 n
NaOH aq., water, brine, and then dried with anhydrous Na2SO4,
and concentrated. The residue was purified by silica-gel column
1
supported by H NMR measurements of 3a, 3b and 4. The
proton signals of 2,3,4-hydroxy groups were observed at δ
= 5.8–6.6 ppm, shifted noticeably downfield (Figure S14,
Supporting Information), relative to those of simple alkyl
β-d-glucosides, in which NMR signals of the OH protons
appear in the range δ = 2–3 ppm.[11]
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Saccharide-Linked Ethynylpyridine Oligomers
chromatography (eluent: AcOEt/hexane = 1:1) to afford 8 (0.78 g,
31.3, 35.5, 61.9, 70.0, 74.6, 75.3, 76.4, 81.8, 83.1, 100.4, 113.2,
128.8, 132.1, 138.7, 142.2, 153.1 ppm. HRMS (ESI-TOF): calcd.
for C20H28NaO6 [M + Na+] 387.1784; found 387.1786.
77%) as a colorless solid, m.p. 103–108 °C. IR (KBr): ν = 3063,
˜
2963, 2872, 1736, 1265, 1092, 1067, 1025 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 1.16 (t, J = 7.8 Hz, 3 H), 1.39 (s, 9 H),
2.50 (q, J = 7.6 Hz, 2 H), 4.03–4.09 (m, 1 H), 4.38 (dd, J = 4.2,
12.0 Hz, 1 H), 4.47 (dd, J = 3.3, 12.0 Hz, 1 H), 5.75 (t, J = 9.9 Hz,
1 H), 5.94–6.08 (m, 3 H), 7.12 (d, J = 2.1 Hz, 1 H), 7.25–7.57 (m,
13 H), 7.84–7.90 (m, 6 H), 7.92–8.08 ppm (m, 2 H). 13C NMR
(75 MHz, CDCl3): δ = 15.4, 27.9, 32.2, 36.6, 62.3, 69.4, 71.8, 72.3,
72.9, 88.7, 99.4, 128.1, 128.3, 128.58, 128.63, 129.0, 129.2, 129.3,
129.57, 129.65, 130.0, 132.9, 133.0, 133.1, 133.3, 137.5, 141.7,
145.2, 149.5, 164.8, 164.9, 165.6, 165.7 ppm. HRMS (ESI-TOF):
calcd. for C46H43INaO10 [M + Na+] 905.1799; found 905.1835.
β-D-Glucoside-Linked Tetramer with a TBS Group (3a): To a sus-
pension of Pd[P(tBu)3]2 (0.014 mg, 0.024 mmol), CuI (2.1 mg,
0.011 mmol), and K2CO3 (0.38 g, 2.7 mmol) in iPr2NH (18 mL)
and THF (18 mL) were added 11 (0.10 g, 0.27 mmol) and 12
(0.31 g, 0.33 mmol) subsequently. The reaction mixture was stirred
for 22 h at room temperature, and then 3-aminopropyl-function-
alizedsilica gel (0.30 g) was added. After 1 h, the resulting mixture
was diluted with THF (20 mL), and insoluble materials were fil-
tered off. The filtrate was concentrated under reduced pressure, and
the resulting residue was subjected to silica-gel column chromatog-
raphy (eluent: CH2Cl2/MeOH = 100:1) to afford 3a (0.24 g, 75%)
2-tert-Butyl-4-ethyl-6-iodophenyl β-D-Glucopyranoside (9): A mixed
solution of 8 (0.65 g, 7.4 mmol) in MeOH (70 mL), Et3N (14 mL), as a pale yellow solid, m.p. 141–144 °C. IR (KBr): ν = 3374, 3076,
˜
and water (14 mL) was prepared at room temperature. The mixture
was heated to reflux for 41 h and the resulting mixture was concen-
trated under reduced pressure. The resulting residue was purified
by silica-gel column chromatography (eluent: CH2Cl2/MeOH =
2953, 2928, 2856, 2214, 2166, 1584, 1548 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 0.20 (s, 6 H), 1.00 (s, 9 H), 1.24 (t, J =
7.2 Hz, 3 H), 1.42 (s, 9 H), 2.20–2.24 (m, 1 H), 2.51–2.63 (m, 10
H), 3.41–3.47 (m, 1 H), 3.59–3.71 (m, 3 H), 3.86–3.90 (m, 1 H),
10:1) to afford 9 (0.20 g, 59%) as a colorless solid, m.p. 94–96 °C. 4.05–4.14 (m, 9 H), 4.68 (br. s, 1 H), 5.09–5.22 (m, 8 H), 5.78–5.95
IR (KBr): ν = 3388, 2963, 2929, 2873, 1070 cm–1. 1H NMR
(m, 5 H), 6.19 (d, J = 7.8 Hz, 1 H), 6.53 (d, J = 4.5 Hz, 1 H), 6.93
(300 MHz, CDCl3): δ = 1.20 (t, J = 7.5 Hz, 3 H), 1.36 (s, 9 H), (d, J = 2.4 Hz, 1 H), 6.98 (d, J = 2.4 Hz, 1 H), 7.01 (d, J = 2.1 Hz,
2.34 (br. s, 1 H), 2.54 (q, J = 7.5 Hz, 2 H), 3.31–3.27 (m, 1 H), 1 H), 7.06 (d, J = 1.8 Hz, 1 H), 7.08 (d, J = 2.1 Hz, 1 H), 7.17–
3.67–3.88 (m, 5 H), 4.03 (br. s, 1 H), 4.69 (br. s, 1 H), 5.08 (br. s, 7.22 ppm (m, 5 H). 13C NMR (75 MHz, CDCl3): δ = –4.7, 15.4,
1 H), 5.44 (d, J = 6.9 Hz, 1 H), 7.15 (d, J = 2.4 Hz, 1 H), 7.48 ppm 16.8, 26.2, 28.2, 31.5, 33.11, 33.14, 35.6, 63.4, 67.6, 67.8, 72.6, 75.1,
(d, J = 1.8 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ = 15.4, 27.9, 75.6, 77.2, 77.3, 86.7, 86.9, 87.3, 87.6, 88.1, 89.5, 92.7, 93.5, 102.8,
˜
32.3, 36.6, 61.9, 70.0, 74.5, 75.6, 76.2, 90.5, 101.2, 128.8, 137.7,
141.6, 144.6, 150.0 ppm. HRMS (ESI-TOF): calcd. for C18H27-
INaO6 [M + Na+] 489.0750; found 489.0770.
103.7, 111.8, 113.0, 113.5, 113.6, 113.7, 113.9, 114.7, 114.8, 115.0,
117.6, 117.7, 129.7, 130.2, 133.1, 133.16, 133.22, 133.4, 138.6,
142.8, 143.2, 143.3, 143.4, 143.5, 143.9, 144.3, 144.6, 155.6, 164.9,
165.0, 165.4, 165.6 ppm. HRMS (ESI-TOF): calcd. for
C70H78N4NaO10Si [M + Na+] 1185.5385; found 1185.5429.
2-tert-Butyl-4-ethyl-6-(trimethylsilylethynyl)phenyl β-D-Glucopyr-
anoside (10): To a suspension of Pd[P(tBu)3]2 (9.7 mg, 0.019 mmol)
and CuI (2.8 mg, 0.019 mmol) in Et2NH (30 mL) and THF
(30 mL) were added 9 (0.22 g, 0.47 mmol) and trimethylsilylacetyl-
ene (0.20 mL, 1.4 mmol) at room temperature. The reaction mix-
β-D-Glucoside-linked Tetramer (3b): To a solution of 3a (0.16 g,
0.14 mmol) in THF (10 mL) were added nBu4NF (1.0 m THF solu-
tion, 0.20 mL, 0.20 mmol), Cs2CO3 (0.044 g, 0.14 mmol), and a few
ture was heated to reflux for 41 h, and then 3-aminopropyl-func- drops of water at room temperature. The reaction mixture was
tionalized-silica gel (0.30 g) was added to remove the metal salts.
After 1 h, the mixture was diluted with THF (20 mL), and the in-
soluble materials were filtered off. The filtrate was concentrated
under reduced pressure and subjected to silica-gel column
chromatography (eluent: CH2Cl2/MeOH = 40:1) to afford 10
stirred for 1 h, filtered, and evaporated under reduced pressure. The
resulting residue was purified by silica-gel column chromatography
(eluent: CH2Cl2/MeOH = 60:1) to afford 3b (0.12 g, 87%) as a
yellow solid, m.p. 134–139 °C. IR (KBr): ν = 3295, 3076, 2960,
˜
2929, 2875, 2214, 2111, 1584, 1548 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 1.24 (t, J = 7.2 Hz, 3 H), 1.42 (s, 9 H), 2.34 (t, J =
6.2 Hz, 1 H), 2.53–2.63 (m, 10 H), 3.12 (s, 1 H), 3.42–3.48 (m, 1
H), 3.59–3.73 (m, 3 H), 3.87–3.94 (m, 1 H), 4.05–4.13 (m, 8 H),
4.79 (d, J = 4.2 Hz, 1 H), 5.09–5.22 (m, 8 H), 5.77–5.94 (m, 5 H),
(0.18 g, 85%) as a brown solid, m.p. 88–92 °C. IR (KBr): ν = 3406,
˜
1
2962, 2871, 2149, 1250, 1074, 949, 844 cm–1. H NMR (300 MHz,
CDCl3): δ = 0.26 (s, 6 H), 1.21 (t, J = 7.5 Hz, 3 H), 1.38 (s, 9 H),
2.00 (br. s, 1 H), 2.55 (q, J = 7.5 Hz, 2 H), 3.09 (br. s, 1 H), 3.30–
3.38 (m, 1 H), 3.61–3.79 (m, 5 H), 6.04 (d, J = 7.2 Hz, 1 H), 6.18 (d, J = 8.1 Hz, 1 H), 6.57 (d, J = 4.8 Hz, 1 H), 6.92 (d, J =
7.14 ppm (s, 2 H). 13C NMR (75 MHz, CDCl3): δ = 0.1, 15.5, 28.2,
31.3, 35.5, 62.0, 70.0, 74.7, 75.3, 76.8, 100.2, 100.3, 100.6, 102.8,
114.5, 128.6, 131.9, 138.9, 142.3, 152.7 ppm. HRMS (ESI-TOF):
calcd. for C23H36NaO6Si [M + Na+] 459.2179; found 459.2169.
2.4 Hz, 1 H), 6.99–7.01 (m, 2 H), 7.05 (d, J = 2.1 Hz, 1 H), 7.08
(d, J = 2.1 Hz, 1 H), 7.16–7.22 ppm (m, 5 H). 13C NMR (75 MHz,
CDCl3): δ = 15.4, 28.2, 31.5, 33.1, 35.7, 63.5, 67.7, 67.8, 72.6, 75.1,
75.6, 77.3, 82.1, 86.8, 87.0, 87.4, 87.6, 88.0, 88.1, 89.5, 92.6, 100.5,
102.8, 111.7, 113.0, 113.6, 113.8, 114.7, 115.1, 117.6, 117.7, 117.8,
129.7, 130.2, 133.1, 133.16, 133.22, 138.6, 142.8, 143.2, 143.37,
143.45, 143.6, 143.8, 144.6, 155.6, 165.0, 165.39, 165.42, 165.6 ppm.
2-tert-Butyl-4-ethyl-6-ethynylphenyl β-D-Glucopyranoside (11): To a
solution of 10 (0.11 g, 1.1 mmol) in THF (15 mL) were added
nBu4NF (1.0 m THF solution, 0.50 mL, 0.50 mmol) and a few
drops of water at room temperature. The reaction mixture was
stirred for 4 h and concentrated under pressure. The resulting resi-
due was purified by silica-gel column chromatography (eluent:
HRMS (ESI-TOF): calcd. for C64H64N4NaO10 [M
1071.4709; found 1071.4756.
+
Na+]
β-D-Glucoside-Linked Octamer with a TBS Group (4): To a suspen-
CH2Cl2/MeOH = 20:1) to afford 11 (0.21 g, 91%) as a colorless sion of Pd[P(tBu)3]2 (3.7 mg, 7.2 μmol), CuI (0.7 mg, 3.6 μmol),
solid, m.p. 62–65 °C. IR (KBr): ν = 3376, 3283, 2963, 2933, 2874,
and K2CO3 (0.25 g, 1.8 mmol) in iPr2NH (20 mL) and THF
(15 mL) were added 3b (0.095 g, 0.091 mmol) and 12 (0.10 g,
0.11 mmol) stepwise. The reaction mixture was stirred for 7 h at
room temperature, and then 3-aminopropyl-functionalized silica
˜
1
2150, 2102, 1073 cm–1. H NMR (300 MHz, CDCl3): δ = 1.20 (t,
J = 7.8 Hz, 3 H), 1.37 (s, 9 H), 2.32 (br. s, 1 H), 2.55 (q, J = 7.5 Hz,
2 H), 3.33–3.36 (m, 1 H), 3.46 (s, 1 H), 3.65–3.72 (m, 5 H), 4.57
(br. s, 1 H), 4.84 (br. s, 1 H), 5.94 (d, J = 6.6 Hz, 1 H), 7.14 ppm gel (0.30 g) was added. After 1 h, the mixture was diluted with THF
(d, J = 3.6 Hz, 2 H). 13C NMR (75 MHz, CDCl3): δ = 15.4, 28.1, (20 mL), and insoluble materials were filtered off. The filtrate was
Eur. J. Org. Chem. 2013, 1677–1682
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1681

F. Kayamori, H. Abe, M. Inouye
FULL PAPER
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concentrated and subjected to silica-gel column chromatography
(eluent: CH2Cl2/MeOH = 100:1) to afford 4 (0.14 g, 81%) as a
yellow solid, m.p. 127–130 °C. IR (KBr): ν = 3373, 3076, 2953,
˜
2927, 2878, 2856, 2216, 2159, 1584, 1547 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 0.20 (s, 6 H), 1.00 (s, 9 H), 1.23 (t, J =
7.5 Hz, 3 H), 1.41 (s, 9 H), 2.27 (br. s, 1 H), 2.55–2.59 (m, 18 H),
3.44–3.49 (m, 1 H), 3.61–3.72 (m, 3 H), 3.88–3.94 (m, 1 H), 4.05–
4.14 (m, 17 H), 4.71 (br. s, 1 H), 5.11–5.22 (m, 16 H), 5.80–5.93
(m, 9 H), 6.19 (d, J = 7.8 Hz, 1 H), 6.54 (br. s, 1 H), 6.94 (d, J =
2.1 Hz, 1 H), 6.98 (d, J = 2.1 Hz, 1 H), 7.01 (d, J = 2.1 Hz, 1 H),
7.09–7.23 ppm (m, 15 H). 13C NMR (75 MHz, CDCl3): δ = –4.7,
11.0, 14.1, 15.3, 16.7, 23.0, 23.8, 26.2, 28.1, 28.9, 30.4, 31.4, 33.0,
33.1, 35.6, 38.7, 63.4, 67.6, 67.7, 67.8, 68.1, 72.6, 75.2, 75.6, 86.9,
87.1, 87.3, 87.5, 87.6, 87.9, 88.1, 89.5, 92.6, 93.5, 102.7, 103.7,
111.7, 113.0, 113.5, 113.6, 114.5, 115.1, 117.6, 117.7, 128.6, 129.6,
130.2, 130.7, 132.2, 133.1, 133.18, 133.22, 138.5, 142.8, 143.1,
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165.5,
C
167.5 ppm.
HRMS
(ESI-TOF):
calcd.
for
114H114N8NaO14Si [M + Na+] 1869.8121; found 1869.8126.
Supporting Information (see footnote on the first page of this arti-
cle): Figures S1–S14; 1H and 13C NMR spectra for compounds
3a,b, 4, 6, 8, 9, 10, and 11; ESI-MS spectra for compounds 3a,b,
and 4; and coordinates and total energies of DFT-optimized struc-
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Acknowledgments
This work was supported by the Japan Society for the Promotion
of Science (JSPS) KAKENHI (grant numbers 17750154 and
19750137).
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Received: October 16, 2012
Published Online: February 6, 2013
1682
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1677–1682