Design, synthesis and evaluation of d-galactose-β-cyclodextrin conjugates as drug-carrying molecules

Article abstract of DOI:10.1016/j.bmc.2008.08.076

Several kinds of d-galactose-β-cyclodextrin conjugates having a phenyl group in the spacers between the d-galactose and β-cyclodextrin were designed and synthesized as drug-carrying molecules. Their evaluation as drug-carrying molecules was done by measur

Full text of DOI:10.1016/j.bmc.2008.08.076

Bioorganic & Medicinal Chemistry 16 (2008) 8830–8840
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Design, synthesis and evaluation of D-galactose-b-cyclodextrin
conjugates as drug-carrying molecules
Yoshiki Oda a, Hironari Yanagisawa a,b, Machiko Maruyama a,b, Kenjiro Hattori b, Takashi Yamanoi a,
*
a The Noguchi Institute, 1-8-1 Kaga, Itabashi-ku, Tokyo 173-0003, Japan
b Department of Nanochemistry, Faculty of Engineering, Tokyo Polytechnic University, Atsugi 243-0297, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Several kinds of
the
evaluation as drug-carrying molecules was done by measuring the molecular interactions with the
anticancer agent, doxorubicin, and with the -galactose-binding peanut lectin using an SPR optical
D
-galactose-b-cyclodextrin conjugates having a phenyl group in the spacers between
Received 21 April 2008
Revised 27 August 2008
Accepted 29 August 2008
Available online 3 September 2008
D
-galactose and b-cyclodextrin were designed and synthesized as drug-carrying molecules. Their
D
biosensor. The SPR analyses showed that these conjugates had remarkably high inclusion associations
of 105 ꢀ 107 Mꢁ1 levels for the immobilized doxorubicin. Their association constants for immobilized
peanut lectin were at the level of 104 ꢀ 105 Mꢁ1, as we expected. These conjugates will be useful
Keywords:
Cyclodextrin
Galactose
Doxorubicin
Peanut lectin
drug-carrying models which can site-specifically carry doxorubicin to the cells containing
ose-binding lectin.
D-galact-
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
These findings urged us to develop more practicable saccharide-b-
CyD conjugate models having spacer structures which are similar to
those of 1–3 and necessary for the high DXR-inclusion abilities. We
Cyclodextrins (CyDs) have the ability to include drug molecules
within their cavities. Saccharides are known to be involved in a
number of significant biological recognition phenomena on the
surfaces of cell membranes. Therefore, the CyD derivatives conju-
gated with saccharide moieties, which have both the drug-inclu-
sion ability of CyDs and the cell-recognition of saccharides, are
expected to carry drug molecules to specific cells. They will be use-
ful for the targeting drug delivery systems (TDDS).1
Our recent paper describes the synthesis of glucose-b-CyD con-
jugates (1–3) using arbutin. Arbutin is a naturally occurring 4-
hydroxyphenyl b-
The conjugates 1–3 are characterized by the existence of a phenyl
group in the spacers between the
Figure 1.2
designed several
spacer lengths as shown in Figure 3. Due to
with lectin present on liver cells, these conjugates were expected to
selectively carry DXR to hepatic cancer cells. As there were no
D-galactose-b-CyD conjugates (4–7) with various
D-galactose’s high affinity
D-
galactoside derivatives having hydroquinone as seen in arbutin, we
designed novel spacers (–O(CH2CH2O)n–CH2CH2PhOCH2CH2CH2–)
(n = 0, 1, 2). The common part (–PhOCH2CH2CH2–), which was also
found in the spacers of 1 and 3, was necessary for the appearance
of the high inclusion associations for DXR. The variable part (–(CH2
CH2O)n) (n = 0, 1, 2) made it possible to examine the effect due to
the difference in the spacer length.
D-glucopyranoside (hydroquinone glucoside).
D
-glucose and b-CyD as shown in
The synthesized 6A-mono-
D-galactose-b-CyD conjugates (4–6)
and 6A,6D-bis-
D
-galactose-b-CyD conjugate (7) were evaluated as
They indicated excellent inclusion associations of 105–108 M–1
for the immobilized doxorubicin (DXR, anthracycline-related anti-
cancer agent) by measurement using an SPR optical biosensor. The
NMR analyses of the DXR-inclusion complex from 1 suggested that
its phenyl group significantly contributed to the increase in the
inclusion associations for DXR. The suggested complexes between
the conjugates and DXR are shown in Figure 2. The formation of the
drug-carrying molecules. Both the DXR-inclusion abilities and
cell-recognition abilities were determined by measuring the
molecular interactions with immobilized DXR and with peanut
lectin (PNA,
sensor. This paper describes the synthesis and evaluation of the
-galactose-b-CyD conjugates (4–7).
D-galactose-binding lectin) using an SPR optical bio-
D
stacking complexes by the
p–p interactions between the phenyl
2. Results and discussion
group and the included DXR seems to enhance the inclusion abili-
ties of 1–3 for DXR.3 These conjugates are promising DXR-related
drug-carrying models for the TDDS.
2.1. Syntheses of novel
D
-galactose-b-CyD conjugates (4–7)
The syntheses of the
D-galactose-b-CyD conjugates 4–7 were
* Corresponding author. Tel./fax: +81 3 5944 3213.
investigated as shown in Scheme 1. The spacer precursors 9, 11,
E-mail address: tyama@noguchi.or.jp (T. Yamanoi).
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.08.076

Y. Oda et al. / Bioorg. Med. Chem. 16 (2008) 8830–8840
8831
X
Y
X
Y
A
D
A
D
OH
O
OH
O
HO
HO
:Y= OH
1: X=
O
O
O
HO
HO
O
4: X=
O
O
O
OH
:Y= OH
OH
OH
O
O
OH
O
HO
HO
2: X=
O
O
HO
HO
O
O
5: X=
N
O
H
OH
OH
:Y= OH
:Y= OH
OH
O
OH
O
HO
O
O
3: X= Y= HO
HO
O
6: X=
O
O
O
O
HO
O
OH
OH
:Y= OH
OMe
OH
O
HO
O
O
O
7: X= Y=
O
HO
O
O
OH
Me
HO
OH
O
Figure 3. Galactose-b-CyD conjugates (4–7).
O
OH
HO
HO
NH2
O
anol and the following benzylation using sodium hydride and ben-
zyl bromide in DMF gave 17–19. The hydroboration of 17–19 with
9-BBN, followed by hydrolysis using aqueous NaOH and oxidation
using aqueous H2O2 gave 20–22. The iodonation of 20–22 using
PPh3-I2 afforded 23–25. The reactions of 23–25 with the partially
benzylated b-CyD 264 using KOH and n-Bu4NI in DMF produced
27–30. The treatment of 27–30 with H2/Pd(OH)2 in DMF gave the
Doxorubicin (DXR)
Figure 1. Our reported arbutin-b-CyD conjugates (1–3) and DXR.
desired 4–7. The b-CyD derivative 35 having no D-galactose moiety
Proposed π-π stacking
HO
OH
O
HO
was prepared by the synthetic procedure as shown in Scheme 2 in
order to clarify whether the PNA lectin indicates the non-specific
bindings for the conjugates 4–7.
OH
O
O
OMe
(D-Glucose)
2.2. Molecular interactions
O
O
The synthesized conjugates 4–7 were evaluated as the drug-
carrying molecules. The molecular interactions both with DXR
and with the PNA lectin were investigated in order to determine
their DXR-inclusion abilities and lectin-association abilities. The
association constants of 4–7 for the immobilized DXR and for the
immobilized PNA lectin were measured using an SPR optical bio-
sensor according to our previously reported methods.1r In situ dual
molecular interactions of 4 for DXR and the PNA lectin were inves-
tigated using an SPR assay for a more practical evaluation of the
drug-carrying molecule as shown in Figure 4.
Me
HO
OH
O
OH
NH
O
HO
HO
O
Immobilized DXR
Figure 2. Speculated stacking complexes between arbutin-b-CyD conjugates and
DXR.
2.2.1. Inclusion associations of 4–7 with immobilized DXR
DXR was immobilized on the sensor cuvette of the optical bio-
sensor and the measurements were carried out under the same
conditions as previously reported.1r The amount of the immobi-
lized DXR was 0.313 ng/mm2. The immobilization of DXR was
35% of the aminosilane based on the assumption that the density
of the aminosilane was one per 1 nm2 area. The interactions of
4–7 with the immobilized DXR were measured at the concentra-
tion of 10ꢁ5–10ꢁ7 M in acetate buffer, pH 5.3, at 25 °C. Figures 5
and 6 indicate the kinetic linear plots of 4–7. Table 1 shows the
association rate constants (ka), dissociation rate constants (kd),
and 13 were prepared from 4-hydroxyphenyl ethanol 8. 2-(4-Allyl-
oxyphenyl)ethanol 9 was prepared by the reaction of allyl bromide
and the dry sodium salt of 8 in DMF. The reaction of 9 with 2-(1-
chloro-3-oxapropane-3-yl)tetrahydro-2H-pyran or 2-(1-chloro-
3,6-dioxahexane-6-yl)tetrahydro-2H-pyran using sodium hydride
in DMF gave 10 and 12. The following acidic hydrolysis using
1 M HCl–THF solution afforded 11 and 13. The galactosylation from
9, 11, and 13 to 14–16 was done using penta-O-acetyl-b-D-galacto-
pyranose in propionitrile at 0 °C in the presence of boron trifluoride
diethyletherate. The deacetylation of 14–16 using NaOMe in meth-

8832
Y. Oda et al. / Bioorg. Med. Chem. 16 (2008) 8830–8840
OH
HO
8
a
b
R1O
O
O
O
O
c
O
HO
R1O
O
R1= THP; 10
R1= H; 11
9
R1= THP; 12
d
d
R1= H; 13
e
OR2
O
R2O
R2O
OBn
O
O
BnO
BnO
R3
O
O
g
O
O
O
n
n
OR2
OBn
R3= OH; 20 (n=0): 21 (n= 1): 22 (n= 2)
R3= I; 23 (n=0): 24 (n= 1): 25 (n= 2)
R2= Ac; 14 (n=0): 15 (n= 1): 16 (n= 2)
R2= Bn; 17 (n=0): 18 (n= 1): 19 (n= 2)
f
h
HO
OH
A
D
i
(OBn)19
26
OR4
O
R4O
R4O
O
O
O
(OH)2-p
O
n
OR4
p
(OR4)19
R4= Bn; p= 1; 27 (n=0): 28 (n= 1): 29 (n= 2), R4= Bn; p= 2; 30 (n= 1)
R4= H; p= 1; 4 (n=0): 5 (n= 1): 6 (n= 2), R4= H; p= 2; 7 (n= 1)
j
Scheme 1. Synthetic approaches to the galactose-b-CyD conjugates (4–7). Reagents and conditions: (a) 1—0.5 M NaOH aq, MeOH; 2—AllBr, DMF, 98%; (b) THPOCH2CH2Cl,
NaH, DMF, 62%; (c) THPOCH2CH2OCH2CH2Cl, NaH, DMF, 41%; (d) 1 M HCl aq, THF, 94%; (e) penta-O-acetyl-b-
D
-galactopyranose, BF3ꢃOEt2, CH3CH2CN, 0 °C, 14: 61%, 15: 65%,
16: 65%; (f) 1—NaOMe, MeOH; 2—NaH, BnBr, DMF, 17: 93%, 18: 84%, 19: 82%; (g) 1—9-BBN, THF, 2—30% H2O2 aq, 0.5 M NaOH aq, 20: 98%, 21: 96%, 22: 82%; (h) Ph3P, I2, DMF,
70 °C, 23: 75%, 24: 75%, 25: 82%; (i) 26, KOH, DMF, n-Bu4NI, 27: 49%, 28: 52%, 29: 72%, 30: 9%; (j) Pd(OH)2, H2 gas, DMF, 4: 92%, 5: 90%, 6: 81%, 7: 83%.
and association constants (Ka) calculated by the relationship,
Ka = ka/kd of 4–7.
of 4–6. The presence of the two phenyl groups in 7 would strength-
en the stacking effect based on interactions by the formation
p–p
The ka values of 4–6 were 4.0–4.6 ꢂ 102 Mꢁ1 sꢁ1, the kd values
were 3.0–3.8 ꢂ 10ꢁ3 s–1, and their Ka values were calculated to be
1.1–1.5 ꢂ 105 M–1. The conjugates 4–6 indicated high inclusion
associations for the immobilized DXR as we anticipated. The differ-
ence in the spacer lengths of 4–6 had almost no influence over
their DXR-inclusion abilities. The ka value of 7 was 1.8 ꢂ 105
Mꢁ1 sꢁ1, the kd value was 12 ꢂ 10ꢁ3 sꢁ1, and its Ka value was calcu-
lated to be 1.5 ꢂ 107 Mꢁ1. The conjugate 7 was found to have an
excellent inclusion association of 107 Mꢁ1 level for the immobi-
lized DXR. The Ka value of 7 was about 102 times higher than those
of the inclusion complex whose DXR was interposed into the space
between the two phenyl groups. The Ka values of 4–7 approxi-
mately corresponded to those of 1–3.2b
2.2.2. Association constants of 4–7 and 35 with immobilized
PNA lectin
The immobilization of the PNA lectin on the sensor cuvette of
the optical biosensor was carried out under the same conditions
as previously reported.1r The amount of the immobilized PNA lec-
tin was 0.523 ng/mm2. The immobilization of PNA was 30% of the

Y. Oda et al. / Bioorg. Med. Chem. 16 (2008) 8830–8840
8833
a
R5
O
PMBO
9
Immobilized PNA lectin
or
R5= CH=CH2; 31
PNA lectin
b
R5= CH2CH2OH; 32
c
R5= CH2CH2I; 33
d
R6O
O
O
OH
0~2
(OR7)19
R6= PMB; R7= Bn; 34
R6=R7= H; 35
O
e
O
Scheme 2. Synthetic approaches to the b-CyD conjugate (35). Reagents and
conditions: (a) NaH, PMBCl, DMF, 31: 97%; (b) 1—9-BBN, THF; 2—30% H2O2 aq,
0.5 M NaOH aq, 32: 88%; (c) Ph3P, I2, DMF, 40 °C, 33: 87%; (d) 26, KOH, DMF, n-
Bu4NI, 34: 58%; (e) Pd(OH)2, H2 gas, DMF, 35: 64%.
A or A,D
aminosilane based on the assumption that the density of the ami-
nosilane was one per 1 nm2 area. The molecular interactions of 4–7
and 35 were measured at the concentration of 10ꢁ4–10ꢁ6 M in
10 mM acetate buffer, pH 5.3, containing 1 mM CaCl2, 1 mM MgCl2
and 100 mM NaCl at 25 °C. Figure 7 shows the kinetic linear plots
of 4–7, and Table 2 summarizes the ka, kd, and Ka of 4–7.
The ka values of 4–6 were 1.8–3.4 ꢂ 102 Mꢁ1 sꢁ1, and the kd val-
ues of those were 3.3–6.1 ꢂ 10ꢁ3 s–1. Their Ka values were then cal-
culated to be 5.4–9.2 ꢂ 104 Mꢁ1. These Ka values were close to the
values predicted from the result of our former research using a lac-
tose conjugated b-CyD,1k which indicated the association constant
of 8.1 ꢂ 103 Mꢁ1 for the immobilized PNA lectin. The Ka values of
4–6 suggested that these conjugates maintained the galactose’s
binding affinity with the PNA lectin. The difference in the spacer
lengths of 4–6 had almost no influence over the recognition of
the PNA lectin. The ka value of 7 was 11 ꢂ 102 Mꢁ1 sꢁ1, the kd value
Immobilized DXR
Figure 4. Molecular interactions of 4 for the immobilized DXR and the PNA lectin.
was 8.0 ꢂ 10ꢁ3 sꢁ1
, and its Ka value was calculated to be
1.3 ꢂ 105 Mꢁ1. The Ka value of 7 was about two times higher than
that of 5.
In contrast, the binding of 35 with the immobilized PNA lectin
was not observed at the level of an SPR assay. This result indicated
that there was no non-specific molecular interaction by the immo-
bilized PNA lectin, that is, the immobilized PNA lectin specifically
bound with the D-galactose moieties of 4–7.
2.2.3. In situ dual molecular interactions of 4 for DXR and PNA
lectin
The SPR experimental procedure for in situ dual molecular
interactions of 4 for DXR and the PNA lectin was as follows. After
the formation of the inclusion complex between 4 and the immo-
bilized DXR on the cuvette surface, the association of the complex
with the PNA lectin was measured. Figure 8 shows the SPR sensor-
gram for this experiment. After an increase of 4500 in the SPR signal
was observed in the formation process of the inclusion complex
between 4 and the immobilized DXR, an increase of 8400 in SPR sig-
nal was observed in the association process of the complex with
the PNA lectin. The SPR experiment successfully indicated in situ
Figure 5. Kinetic linear plots for the immobilized DXR and 4 (s; r = 0.988), 5 (h;
r = 0.991), and 6 (4; r = 0.998).
dual molecular interactions of 4 for DXR and the PNA lectin on
the cuvette surface.

8834
Y. Oda et al. / Bioorg. Med. Chem. 16 (2008) 8830–8840
Figure 8. SPR sensorgram for the experimental of in situ dual molecular interac-
tions of 4 for the immobilized DXR and the PNA lectin. (A) Addition of 100 L of
10ꢁ4 M 4 in 10 mM acetate buffer to the sensor cuvette surface immobilized with
l
DXR. (B) Washing the sensor cuvette with acetate buffer. (C) Addition of 100 lL of
10ꢁ6 M PNA lectin in acetate buffer to the sensor cuvette presented the inclusion
complex between 4 and immobilized DXR. (D) Washing the sensor cuvette with
acetate buffer.
Figure 6. Kinetic linear plots for the immobilized DXR and 7 (e; r = 0.995).
104–105 levels for the immobilized peanut lectin. In situ dual
Table 1
molecular interactions of 4 for DXR and the PNA lectin were ob-
Kinetic parameters of conjugates for association with the immobilized DXR
served using an SPR technique. These
D-galactose-b-CyD conju-
ka (ꢂ102 Mꢁ1 sꢁ1
4.0 0.3
4.1 0.3
4.6 0.1
1800 100
)
kd (ꢂ10ꢁ3 sꢁ1
3.8 0.1
3.5 0.2
3.0 0.1
12.0 5.0
)
Ka (ꢂ105 Mꢁ1
1.1 0.1
1.2 0.2
1.5 0.1
150 70
)
gates are expected to be useful drug-carrying molecules which
Entry
Conjugate
can selectively carry DXR to the cells having the
ing lectin.
D-galactose-bind-
1
2
3
4
4
5
6
7
4. Experimental
4.1. General
The 1H NMR and 13C NMR spectra were recorded on a JEOL ECA-
600 spectrometer in CDCl3 using TMS as the internal standard. The
optical rotations were recorded on a JASCO DIP-360 digital polar-
imeter. The HRMS were obtained using a Mariner spectrometer
(PerSeptive Biosystems, Inc.). The MALDI-TOF-MS spectra were re-
corded by a Voyager DE STR spectrometer. The preparative TLC was
performed using Merck 60GF254 silica gel. Column chromatogra-
phy was conducted using 60 N silica gel (40–50 lm, Kanto Chem-
ical Co., Inc.) All anhydrous solvents were purified according to the
standard methods. The balance was used on a METTLER TOLEDO
AT261.
4.1.1. 2-(4-Allyloxyphenyl)ethanol (9)
A 0.5 M NaOH aqueous solution (72 mL, 36 mmol) was added to
a solution of 8 (5.0 g, 36.2 mmol) in MeOH (30 mL). The resulting
mixture was stirred for 1 h, the solvent was evaporated under re-
duced pressure and the reaction residue was crystallized. The reac-
tion residue was dissolved in DMF (50 mL) and allyl bromide
(3.7 mL, 43.7 mmol) was added. The resulting mixture was stirred
for 3.5 h. The solvent was evaporated under reduced pressure. The
crude product was purified by flash column chromatography (silica
gel, EtOAc/hexane, 1:3) to give 9 (5.5 g, 98%) as a colorless oil. 1H
NMR (CDCl3): d 1.45 (s, 1H, OH), 2.80 (t, J = 6.6 Hz, 2H, CH2Ph),
3.81 (m, 2H, CH2CH@CH2), 4.51 (d, J = 5.1 Hz, 2H, HOCH2), 5.27
(d, J = 10.5 Hz, 1H, CH@CHaHb), 5.40 (d, J = 17.1 Hz, 1H, CH@CHaHb),
6.00–6.10 (m, 1H, CH@CH2), 6.86 (d, J = 8.5 Hz, 2H, Ph), 7.13 (d,
Figure 7. Kinetic linear plots for the immobilized PNA and 4 (s; r = 0.995), 5 (h;
r = 0.990), 6 (4; r = 0.995), and 7 (e; r = 0.985).
Table 2
Kinetic parameters of conjugates for association with the immobilized PNA
Entry
Conjugate
ka (ꢂ102 Mꢁ1 sꢁ1
)
kd (ꢂ10ꢁ3 sꢁ1
)
Ka (ꢂ104 Mꢁ1
)
1
2
3
4
4
5
6
7
3.4 0.2
1.8 0.1
3.3 0.2
11.0 1.0
3.7 0.1
3.3 0.1
6.1 0.1
8.0 0.6
9.2 0.8
5.5 0.5
5.4 0.4
13.0 2.0
J = 8.3 Hz, 2H, Ph); 13C NMR (CDCl3):
d 38.3 (CH2Ph), 63.8
(CH2CH@CH2), 68.8 (HOCH2), 114.8 (Ph), 117.6 (CH@CH2), 129.9
(Ph), 130.5 (Ph), 133.3 (CH@CH2), 157.2 (Ph). HRMS (ESI): m/z calcd
for C11H14O2Na: 201.0886; found 201.0895.
3. Conclusions
Several kinds of
D-galactose-b-CyD conjugates (4–7) having a
phenyl group in the spacers between the
D-galactose and b-CyD
4.1.2. 2-[6-(4-Allyloxyphenyl)-1,4-dioxahexane-1-
were successfully synthesized. Their capabilities as drug-carrying
molecules were evaluated by measuring the molecular interactions
with the immobilized DXR and peanut lectin using an SPR optical
biosensor. They had high inclusion associations of 105–107 levels
for the immobilized DXR and expected association constants of
yl]tetrahydro-2H-pyran (10)
NaH (600 mg, 25 mmol) was added to a solution of 9 (513.6 mg,
2.88 mmol) and 2-(1-chloro-3-oxapropane-3-yl)tetrahydro-2H-
pyran (1153.7 mg, 7 mmol) in DMF (15 mL) at 0 °C. The resulting
mixture was stirred for 164 h at room temperature. The reaction

Y. Oda et al. / Bioorg. Med. Chem. 16 (2008) 8830–8840
8835
was then quenched by the addition of a satd NaCl solution (20 mL).
The reaction mixture was extracted with CH2Cl2. After the organic
layer was dried over Na2SO4, the solvent was evaporated under re-
duced pressure. The crude product was purified by flash column
chromatography (silica gel, EtOAc/hexane, 1:4) to give 10
(546.2 mg, 62%) as a colorless oil. 1H NMR (CDCl3): d 1.48–1.62
(m, 4H, Ha-3, Ha-4, H-5), 1.67–1.73 (m, 1H, Hb-3), 1.78–1.86 (m,
1H, Hb-4), 2.83 (t, J = 7.2 Hz, 2H, CH2Ph), 3.45–3.49 (m, 1H, Ha-6),
3.55–3.67 (m, 5H, CH2CH2 or CH2CH2Ph), 3.82–3.86 (m, 2H, Hb-6,
CH2CH2 or CH2CH2Ph), 4.48 (d, J = 4.8 Hz, 2H, CH2CH@CH2), 4.61
(t, J = 3.6 Hz, 1H, H-2), 5.25 (dd, J = 1.2 Hz, J = 10.4 Hz, 1H,
CH@CHaHb), 5.38 (dd, J = 1.6 Hz, J = 17.2 Hz, 1H, CH@CHaHb),
5.98–6.08 (m, 1H, CH@CH2), 6.82 (d, J = 8.8 Hz, 2H, Ph), 7.12 (d,
J = 8.8 Hz, 2H, Ph); 13C NMR (CDCl3): d 19.4 (C-4), 25.4 (C-5), 30.5
(C-3), 35.3 (CH2Ph), 61.9 (C-6), 66.4 (CH2CH2 or CH2CH2Ph), 68.6
(CH2C@CH2), 70.0 (CH2CH2 or CH2CH2Ph), 72.2 (CH2CH2 or
CH2CH2Ph), 98.6 (C-2), 114.3 (Ph), 117.1 (CH@CH2), 129.5 (Ph),
130.9 (Ph), 133.1 (CH@CH2), 156.6 (Ph). HRMS (ESI): m/z calcd
for C18H26O4Na: 329.1723; found: 329.1756.
4.1.5. 9-(4-Allyloxyphenyl)-4,7-dioxanonanol (13)
A 1 M HCl solution (2.5 mL, 2.5 mmol) was added to a solution
of 12 (59 mg, 0.17 mmol) in THF (4 mL). The resulting mixture was
stirred for 1 h. The reaction was then quenched by the addition of a
satd NaHCO3 solution (10 mL). The reaction mixture was extracted
with CH2Cl2, and the organic layer was washed with water and a
satd NaCl solution. After the organic layer was dried over Na2SO4,
the solvent was evaporated under reduced pressure. The crude
product was purified by preparative TLC (silica gel, CHCl3/MeOH,
20:1) to give 13 (41.3 mg, 93%) as a colorless oil. 1H NMR (CDCl3):
d 2.85 (t, J = 7.6 Hz, 2H, CH2Ph), 2.85–3.72 (m, 10H, CH2CH2OCH2-
CH2OCH2CH2Ph), 4.51 (d, J = 4.8 Hz, 2H, CH2CH@CH2), 5.27 (d,
J = 9.0 Hz, 1H, CH@CHaHb), 5.40 (d, J = 17.2 Hz, 1H, CH@CHaHb),
6.02–6.08 (m, 1H, CH@CH2), 6.84 (d, J = 8.9 Hz, 2H, Ph), 7.13 (d,
J = 8.2 Hz, 2H, Ph); 13C NMR (CDCl3): d 35.3 (CH2Ph), 61.8 (CH2CH2),
68.9 (CH2CH@CH2), 70.3 (CH2CH2), 70.4 (CH2CH2), 72.5 (CH2CH2),
72.6 (CH2CH2), 114.7 (Ph), 117.5 (CH@CH2), 129.8 (Ph), 131.0
(Ph), 133.4 (CH@CH2), 157.1 (Ph). HRMS (ESI): m/z calcd for
C15H22O4Na: 289.1410; found: 289.1364.
4.1.3. 6-(4-Allyloxyphenyl)-4-oxahexanol (11)
4.1.6. 2-(4-Allyloxyphenyl)ethyl 2,3,4,6-tetra-O-acetyl-b-D-
A 1 M HCl (6 mL, 6 mmol) solution was added to a solution of 10
(501.2 mg, 1.64 mmol) in THF (11 mL). The resulting mixture was
stirred for 2 h. The reaction was then quenched by the addition
of a satd NaHCO3 solution (15 mL). The reaction mixture was ex-
tracted with CH2Cl2, and the organic layer was washed with water
and a satd NaCl solution. After the organic layer was dried over
Na2SO4, the solvent was evaporated under reduced pressure. The
crude product was purified by preparative TLC (silica gel, CHCl3/
MeOH, 20:1) to give 11 (342 mg, 94%) as a colorless oil. 1H NMR
(CDCl3): d 2.84 (t, J = 7.6 Hz, 2H, CH2Ph), 3.53–3.69 (m, 6H,
CH2CH2OCH2CH2Ph), 4.50 (d, J = 5.5 Hz, 2H, CH2CH@CH2), 5.27
(dd, J = 1.4 Hz, J = 12.4 Hz, 1H, CH@CHaHb), 5.40 (dd, J = 2.1 Hz,
J = 17.2 Hz, 1H, CH@CHaHb), 6.00–6.07 (m, 1H, CH@CH2), 6.84 (d,
J = 8.9 Hz, 2H, Ph), 7.12 (d, J = 8.9 Hz, 2H, Ph); 13C NMR (CDCl3): d
35.2 (CH2Ph), 61.6 (HOCH2 or CH2CH2 or CH2CH2Ph), 68.7
(CH2CH@CH2), 71.8 (HOCH2 or CH2CH2 or CH2CH2Ph), 72.2 (HOCH2
or CH2CH2 or CH2CH2Ph), 114.6 (Ph), 117.5 (CH@CH2), 129.7 (Ph),
130.9 (Ph), 133.3 (CH@CH2), 157.1 (Ph). HRMS (ESI): m/z calcd
for C13H18O3Na: 245.1148; found: 245.1116.
galactopyranoside (14)
BF3ꢃOEt2 (99.0
lL, 0.79 mmol) was added to a solution of penta-
O-acetyl-b- -galactopyranose (153.8 mg, 0.39 mmol) and
D
9
(87.1 mg, 0.49 mmol) in CH3CH2CN (2 mL) at 0 °C. The resulting
mixture was stirred for 24 h at room temperature. The reaction
was then quenched by the addition of a satd NaHCO3 solution
(5 mL). The reaction mixture was extracted with EtOAc, and the or-
ganic layer was washed with water and a satd NaCl solution. After
the organic layer was dried over Na2SO4, the solvent was evapo-
rated under reduced pressure. The crude product was purified by
preparative TLC (silica gel, EtOAc/hexane, 1:3) to give 14
(122.7 mg, 61%) as a colorless oil. ½a D23
ꢄ
+3.83 (c 4.18, CHCl3). 1H
NMR (CDCl3): d 1.92 (s, 3H, CH3), 1.98 (s, 3H, CH3), 2.05 (s, 3H,
CH3), 2.15 (s, 3H, CH3), 2.83–2.85 (m, 2H, CH2Ph), 3.63 (dd,
J = 7.5 Hz, J = 15.8 Hz, 1H, CHaHbCH2Ph), 3.39 (t, J = 6.9 Hz, 1H, H-
5), 4.09–4.14 (m, 2H, Ha-6, CHaHbCH2Ph), 4.18 (dd, J = 6.2 Hz,
J = 11.0 Hz, 1H, Hb-6), 4.44 (d, J = 7.5 Hz, 1H, H-1), 4.50 (dd,
J = 1.4 Hz, J = 5.5 Hz, 2H, CH2CH@CH2), 4.98 (dd, J = 2.5 Hz,
J = 9.6 Hz, 1H, H-3), 5.21 (dd, J = 8.2 Hz, J = 10.3 Hz, 1H, H-2), 5.27
(dt, J = 1.4 Hz, J = 10.3 Hz, 1H, CH@CHaHb), 5.36–5.41 (m, 1H, H-
4), 5.40 (dt, J = 8.2 Hz, J = 10.3 Hz, 1H, CH@CHaHb), 6.01–6.07 (m,
1H, CH@CH2), 6.83 (d, J = 8.3 Hz, 2H, Ph), 7.10 (d, J = 8.2 Hz, 2H,
Ph); 13C NMR (CDCl3): d 20.6 (CH3), 20.7 (CH3 ꢂ 3), 35.1 (CH2Ph),
61.3 (C-6), 67.1 (C-4), 68.7 (C-2), 68.8 (CH2CH@CH2), 70.7 (C-5),
70.9 (CH2CH2Ph, C-3), 101.3 (C-1), 114.7 (Ph), 117.6 (CH@CH2),
129.9 (Ph), 130.7 (Ph), 133.4 (CH@CH2), 157.2 (Ph), 169.4–170.4
(C@O). HRMS (ESI): m/z calcd for C25H32O11Na: 531.1837; found:
531.1860.
4.1.4. 2-[9-(4-Allyloxyphenyl)-1,4,7-trioxanonane-1-
yl]tetrahydro-2H-pyran (12)
NaH (564.0 mg, 23.5 mmol) was added to a solution of 9
(1008.8 mg, 5.66 mmol) and 2-(1-chloro-3,6-dioxahexane-6-
yl)tetrahydro-2H-pyran (1426.7 mg, 6.84 mmol) in DMF (20 mL)
at 0 °C. The resulting mixture was stirred for 19 h at room temper-
ature. The reaction was then quenched by the addition of a satd
NaCl solution (25 mL). The reaction mixture was extracted with
EtOAc. After the organic layer was dried over Na2SO4, the solvent
was evaporated under reduced pressure. The crude product was
purified by flash column chromatography (silica gel, EtOAc/hexane,
1:3) to give 12 (808.8 mg, 41%) as a colorless oil. 1H NMR (CDCl3): d
1.50–1.54 (m, 2H, Ha-5, Ha-4), 1.56–1.62 (m, 2H, Ha-3, Hb-5), 1.69–
1.74 (m, 1H, Hb-3), 1.81–1.84 (m, 1H, Hb-4), 2.84 (t, J = 7.6 Hz, 2H,
CH2Ph), 3.48–3.52 (m, 1H, Ha-6), 3.59–3.68 (m, 9H, CH2CH2OCH2-
CH2OCHaHbCH2Ph), 3.85–3.89 (m, 2H, Hb-6, CHaHbCH2Ph), 4.51
(d, 2H, J = 4.9 Hz, CH2CH@CH2), 4.63 (t, J = 3.6 Hz, 1H, H-2), 5.27
(d, 1H, J = 1.4 Hz, CH@CHaHb), 5.40 (d, J = 1.4 Hz, 1H, CH@CHaHb),
6.02–6.08 (m, 1H, CH@CH2), 6.84 (d, J = 8.9 Hz, 2H, Ph), 7.12 (d,
J = 8.3 Hz, 2H, Ph); 13C NMR (CDCl3): d 19.4 (C-4), 25.4 (C-5), 30.5
(C-3), 35.3 (CH2Ph), 62.2 (C-6), 66.6 (CH2CH2), 68.8 (CH2CH@CH2),
70.3 (CH2CH2), 70.5 (CH2CH2), 70.6 (CH2CH2), 72.5 (CH2CH2), 98.9
(C-2), 114.6 (Ph), 117.5 (CH@CH2), 129.5 (Ph), 131.1 (Ph), 133.4
(CH@CH2), 157.0 (Ph). HRMS (ESI): m/z calcd for C20H30O5Na:
373.1985; found: 373.1942.
4.1.7. 2-(4-Allyloxyphenyl)ethyl 2,3,4,6-tetra-O-benzyl-b-D-
galactopyranoside (17)
A
28% sodium methylate methanol solution (0.3 mL,
0.0016 mmol) was added to a solution of 14 (110.3 mg, 0.22 mmol)
in MeOH (20 mL). The resulting mixture was stirred for 16 h. The
solvent was evaporated under reduced pressure. The crude product
was added to a solution of NaH (146.0 mg, 6.08 mmol) in DMF
(15 mL) at 0 °C. After the reaction mixture was stirred for 30 min,
benzyl bromide (531.8 lL, 4.48 mmol) was added. The resulting
mixture was stirred for 24 h at room temperature. The reaction
was then quenched by the addition of a MeOH solution (15 mL).
The reaction mixture was extracted with EtOAc, and the organic
layer was washed with water and a satd NaCl solution. After the or-
ganic layer was dried over Na2SO4, the solvent was evaporated un-
der reduced pressure. The crude product was purified by
preparative TLC (silica gel, EtOAc/hexane, 1:4) to give 17

8836
Y. Oda et al. / Bioorg. Med. Chem. 16 (2008) 8830–8840
(141.6 mg, 93%) as a colorless oil. ½a D23
ꢄ
ꢁ2.65 (c 3.58, CHCl3). 1H
8H, CH2Ph), 6.75–7.34 (m, 24H, Ph); 13C NMR (CDCl3): d 2.6
(CH2I), 33.1 (CH2CH2I), 35.4 (CH2CH2Ph), 67.2 (CH2CH2CH2I), 68.9
(C-6), 70.8 (CH2CH2Ph), 73.1 (CH2Ph), 73.4 (C-4), 73.5 (C-5), 73.6
(CH2Ph), 74.5 (CH2Ph), 75.1 (CH2Ph), 79.6 (C-2), 82.1 (C-3), 103.9
(C-1), 114.4–151.2 (Ph). HRMS (ESI): m/z calcd for C45H49O7INa:
851.2415; found: 851.2410.
NMR (CDCl3): d 2.89 (d, J = 6.6 Hz, 2H, CH2CH2Ph), 3.48 (dd,
J = 2.7 Hz, J = 9.5 Hz, 1H, H-5), 3.51 (t, J = 8.0 Hz, 1H, H-3), 3.56 (d,
J = 6.1 Hz, 2H, H-6), 3.67 (q, J = 7.8 Hz, 1H, CHaHbCH2Ph), 3.79 (t,
J = 7.2 Hz, 1H, H-2), 3.87 (d, J = 1.5 Hz, 1H, H-4), 4.10–4.15 (m,
1H, CHaHbCH2Ph), 4.35 (d, J = 7.6 Hz, 1H, H-1), 4.39–4.49 (m, 4H,
CH2Ph), 4.61–4.74 (m, 4 H, CH2Ph), 4.63 (d, J = 10.7 Hz, 1H,
CHaHbCH@CH2), 4.93 (d, J = 11.7 Hz, 1H, CHaHbCH@CH2), 5.25 (d,
J = 10.5 Hz, 1H, CH@CHaHb), 5.38 (d, J = 17.2 Hz, 1H, CH@CHaHb),
6.00–6.06 (m, 1H, CH@CH2), 6.78 (d, J = 8.6 Hz, 2H, Ph), 7.11 (d,
J = 8.6 Hz, 2H, Ph), 7.22–7.34 (m, 20H, Ph); 13C NMR (CDCl3): d
35.3 (CH2CH2Ph), 68.8 (C-6), 68.9 (CH2CH2Ph), 70.8 (CH2Ph), 73.0
(CH2Ph), 73.4 (C-4), 73.47 (C-2), 73.52 (CH2Ph), 74.5 (CH2CH@CH2),
70.8 (CH2Ph), 79.6 (C-5), 82.1 (C-3), 103.8 (C-1), 114.6 (Ph), 117.5
(CH@CH2), 127.4–131.1 (Ph), 133.5 (CH@CH2), 137.9–138.8 (Ph).
HRMS (ESI): m/z calcd for C45H48O7Na: 723.3292; found: 723.3255.
4.1.10. 5-(4-Allyloxyphenyl)-3-oxapentyl 2,3,4,6-tetra-O-acetyl-
b-D
-galactopyranoside (15)
BF3ꢃOEt2 (97.0 L, 0.77 mmol) was added to a solution of penta-
O-acetyl-b- -galactopyranose (150.2 mg, 0.38 mmol) and 11
l
D
(114.8 mg, 0.52 mmol) in CH3CH2CN (3 mL) at 0 °C. The resulting
mixture was stirred for 24 h at room temperature. The reaction
was then quenched by the addition of a satd NaHCO3 solution
(5 mL). The reaction mixture was extracted with EtOAc, and the or-
ganic layer was washed with water and a satd NaCl solution. After
the organic layer was dried over Na2SO4, the solvent was evapo-
rated under reduced pressure. The crude product was purified by
preparative TLC (silica gel, CH2Cl2/MeOH, 20:1) to give 15
4.1.8. 2-[4-O-(3-Hydroxypropyl)phenyl]ethyl 2,3,4,6-tetra-O-
benzyl-b-D-galactopyranoside (20)
To a solution of 17 (341 mg, 0.49 mmol) in THF (3 mL) was
added a 0.5 M 9-borabicyclo[3.3.1]nonane-THF solution (5.8 mL,
2.9 mmol) at 0 °C. After the reaction mixture was stirred for 24 h
at room temperature, a 0.5 M NaOH aqueous solution (2.9 mL,
(139.1 mg, 65%) as a colorless oil. ½a D23
ꢄ
ꢁ10.3 (c 0.73, CHCl3). 1H
NMR (CDCl3): d 1.99 (s, 3H, CH3), 2.02 (s, 3H, CH3), 2.05 (s, 3H,
CH3), 2.15 (s, 3H, CH3), 2.81 (t, J = 6.9 Hz, 2H, CH2Ph), 3.60–3.64
(m, 4H, CH2CH2OCH2CH2Ph), 3.72–3.76 (m, 1H, Ha-6), 3.84 (t,
J = 6.9 Hz, 1H, H-5), 3.91–3.94 (m, 1H, Hb-6), 4.11–4.18 (m, 1H,
CH2OCH2CH2Ph), 4.52 (d, J = 5.5 Hz, 2H, CH2CH@CH2), 4.55 (d,
J = 8.3 Hz, 1H, H-1), 5.00 (dd, J = 3.4 Hz, J = 10.3 Hz, 1H, H-3), 5.21
(dd, J = 2.1 Hz, J = 10.3 Hz, 1H, H-2), 5.28 (dd, J = 1.4 Hz,
J = 11.0 Hz, 1H, CH@CHaHb), 5.38 (d, J = 3.4 Hz, 1H, H-4), 5.41 (dd,
J = 1.4 Hz, J = 17.2 Hz, 1H, CH@CHaHb), 6.02–6.09 (m, 1H, CH@CH2),
6.86 (d, J = 8.2 Hz, 2H, Ph), 7.12 (d, J = 8.3 Hz, 2H, Ph); 13C NMR
(CDCl3): d 20.61 (CH3), 20.67 (CH3), 20.69 (CH3), 20.74 (CH3), 35.4
(CH2Ph), 61.3 (CH2OCH2CH2Ph), 67.1 (C-4), 68.8 (C-2, C-6), 68.9
(CH2CH@CH2), 70.1 (CH2CH2Ph), 70.6 (C-5), 70.9 (C-3), 72.5
(CH2CH2OCH2CH2Ph), 101.3 (C-1), 114.7 (Ph), 117.6 (CH@CH2),
129.8 (Ph), 131.1 (Ph), 133.5 CH@CH2), 157.2 (Ph), 169.5 (C=O),
170.2 (C=O), 170.3 (C=O), 170.4 (C=O). HRMS (ESI): m/z calcd for
1.5 mmol) and 30% H2O2 aqueous solution (515.6 lL, 4.5 mmol)
were added. After the reaction mixture was stirred for 16 h, the
reaction was then quenched by adding water (15 mL). The reaction
mixture was extracted with EtOAc, and the organic layer was
washed with water and a satd NaCl solution. After the organic layer
was dried over Na2SO4, the solvent was evaporated under reduced
pressure. The crude product was purified by preparative TLC (silica
gel, EtOAc/hexane, 1:1) to give 20 (335.8 mg, 98%) as a colorless oil.
½
a 2D3
ꢄ
ꢁ4.42 (c 5.39, CHCl3). 1H NMR (CDCl3): d 1.90–1.93 (m, 2H,
CH2CH2OH), 2.86–2.91 (m, 2H, CH2CH2Ph), 3.49 (dd, J = 2.7 Hz,
J = 9.6 Hz, 1H, H-3), 3.51 (t, J = 6.2 Hz, 1H, H-5), 3.57 (dd,
J = 2.0 Hz, J = 6.2 Hz, 2H, H-6), 3.66 (q, J = 7.5 Hz, 1H, CHaHbCH2Ph),
3.78–3.83 (m, 3H, H-4, CH2OH), 3.87 (d, J = 2.8 Hz, 1H, H-2), 4.01–
4.07 (m, 2H, CH2CH2CH2OH), 4.08–4.17 (m, 1H, CHaHbCH2Ph), 4.35
(d, J = 7.5 Hz, 1H, H-1), 4.39 (d, J = 11.7 Hz, 1H, CH2Ph), 4.43 (d,
J = 11.7 Hz, 1H, CH2Ph), 4.61 (d, J = 11.7 Hz, 1H, CH2Ph), 4.63 (d,
J = 11.7 Hz, 1H, CH2Ph), 4.68–4.74 (m, 3H, CH2Ph), 4.93 (d,
J = 11.7 Hz, 1H, CH2Ph), 6.77 (d, J = 5.2 Hz, 2H, Ph), 7.11 (d,
J = 8.9 Hz, 2H, Ph), 7.20–7.34 (m, 20H, Ph); 13C NMR (CDCl3): d
32.0 (CH2CH2OH), 35.3 (CH2CH2Ph), 60.7 (CH2OH), 65.8
(CH2CH2CH2OH), 68.9 (C-6), 70.8 (CH2CH2Ph), 73.0 (CH2Ph), 73.41
(C-4), 73.44 (C-5), 73.5 (CH2Ph), 74.5 (CH2Ph), 75.1 (CH2Ph), 79.6
(C-2), 82.1 (C-3), 103.9 (C-1), 114.4–157.1 (Ph). HRMS (ESI): m/z
calcd for C45H50O8Na: 741.3398; found: 741.3447.
C27H36O12Na: 575.2099; found: 575.2089.
4.1.11. 5-(4-Allyloxyphenyl)-3-oxapentyl 2,3,4,6-tetra-O-
benzyl-b- -galactopyranoside (18)
28% sodium methylate methanol solution (0.3 mL,
D
A
0.0016 mmol) was added to a solution of 15 (132.6 mg, 0.24 mmol)
in MeOH (20 mL). The resulting mixture was stirred for 2 h. The
solvent was evaporated under reduced pressure. The crude product
was added to a solution of NaH (183.0 mg, 7.63 mmol) in DMF
(10 mL) at 0 °C. After the reaction mixture was stirred for 30 min,
benzyl bromide (239.0 lL, 2.01 mmol) was added. The resulting
mixture was stirred for 24 h at room temperature. The reaction
was then quenched by the addition of a MeOH solution (15 mL).
The reaction mixture was extracted with EtOAc, and the organic
layer was washed with water and a satd NaCl solution. After the or-
ganic layer was dried over Na2SO4, the solvent was evaporated un-
der reduced pressure. The crude product was purified by
preparative TLC (silica gel, EtOAc/hexane, 1:3) to give 18
4.1.9. 2-[4-O-(3-Iodopropyl)phenyl]ethyl 2,3,4,6-tetra-O-
benzyl-b-D-galactopyranoside (23)
To a solution of 20 (108.9 mg, 0.15 mmol) in DMF (5 mL) was
added triphenylphosphine (189.0 mg, 0.72 mmol) and iodine
(189.3 mg, 0.75 mmol) at 70 °C under an argon atmosphere. After
the reaction mixture was stirred for 24 h, the reaction was then
quenched by adding water (10 mL). The reaction mixture was ex-
tracted with EtOAc, and the organic layer was washed with water
and a satd NaCl solution. After the organic layer was dried over
Na2SO4, the solvent was evaporated under reduced pressure. The
crude product was purified by preparative TLC (silica gel, EtOAc/
(260.6 mg, 84%) as a colorless oil. ½a D23
ꢄ
ꢁ9.9 (c 0.97, CHCl3). 1H
NMR (CDCl3):
d 2.79 (t, J = 7.6 Hz, 2H, CH2CH2Ph), 3.50 (d,
J = 2.8 Hz, 1H, H-3), 3.52 (d, J = 6.9 Hz, 1H, H-5), 3.58 (t, J = 6.2 Hz,
1H, Ha-6), 3.61–3.69 (m, 5H, Hb-6, CH2CH2Ph), 3.71–3.75 (m, 1H,
CHaHbCH2OCH2CH2Ph), 3.82 (dd, J = 2.1 Hz, J = 7.5 Hz, 1H, H-2),
3.88 (d, J = 2.7 Hz, 1H, H-4), 3.98–4.02 (m, 1H, CHaHb-
CH2OCH2CH2Ph), 4.39 (d, J = 8.2 Hz, 1H, H-1), 4.41–4.45 (m, 4H,
CH2OCH2CH2Ph, CH2Ph), 4.47 (d, J = 5.5 Hz, 1H, CHaHbCH@CH2),
4.61 (d, J = 11.7 Hz, 1H, CHaHbCH@CH2), 4.69–4.77 (m, 4H, CH2Ph),
4.92–4.96 (m, 2H, CH2Ph), 5.26 (d, J = 9.6 Hz, 1H, CH@CHaHb), 5.38
(dd, J = 1.4 Hz, J = 17.2 Hz, 1H, CH@CHaHb), 6.00–6.06 (m, 1H,
CH@CH2), 6.80 (d, J = 8.2 Hz, 2H, Ph), 7.07 (d, J = 8.2 Hz, 2H, Ph),
hexane, 1:4) to give 23 (96.2 mg, 75%) as a colorless oil. ½a D23
ꢄ
ꢁ3.3 (c 1.81, CHCl3). 1H NMR (CDCl3): d 2.21–2.25 (m, 2H, CH2CH2I),
2.87–2.90 (m, 2H, CH2CH2Ph), 3.33 (t, J = 6.8 Hz, 2H, CH2I), 3.48–
3.52 (m, 2H, H-3, H-5), 3.57 (d, J = 6.1 Hz, 2H, Ha-6), 3.57 (t,
J = 9.6 Hz, 1H, CHaHbCH2Ph), 3.79 (t, J = 6.8 Hz, 1H, H-2), 3.87 (d,
J = 2.7 Hz, 1H, H-4), 3.90–3.96 (m, 2H, CH2CH2CH2I), 4.12–4.15
(m, 1H, CHaHbCH2Ph), 4.35 (d, J = 7.6 Hz, 1H, H-1), 4.41–4.94 (m,

Y. Oda et al. / Bioorg. Med. Chem. 16 (2008) 8830–8840
8837
7.25–7.38 (m, 20H, Ph); 13C NMR (CDCl3): d 35.4 (CH2CH2Ph),
4.1.14. 8-(4-Allyloxyphenyl)-3,6-dioxaoctyl 2,3,4,6-tetra-O-
acetyl-b- -galactopyranoside (16)
BF3ꢃOEt2 (298.0 L, 2.37 mmol) was added to a solution of pen-
ta-O-acetyl-b- -galactopyranose (463.5 mg, 1.19 mmol) and 13
(379.4 mg, 1.42 mmol) in CH3CH2CN (6 mL) at 0 °C. The resulting
mixture was stirred for 12 h at room temperature. The reaction
was then quenched by the addition of a satd NaHCO3 solution
(10 mL). The reaction mixture was extracted with EtOAc, and the
organic layer was washed with water and a satd NaCl solution.
After the organic layer was dried over Na2SO4, the solvent was
evaporated under reduced pressure. The crude product was puri-
fied by flash column chromatography on a silica-gel (EtOAc/hex-
68.79, 68.80 (CH2CH2OCH2CH2Ph), 68.9 (CH2CH2Ph), 70.0 (CH2Ph),
72.4 (C-6), 73.1 (CH2Ph), 73.4 (C-5), 73.5 (C-4, CH2Ph), 74.5
(CH2CH@CH2), 75.0 (CH2Ph), 79.4 (C-2), 82.1 (C-3), 104.1 (C-1),
114.6 (Ph), 117.5 (CH@CH2), 127.4–131.1 (Ph), 133.4 (CH@CH2),
137.9–138.9 (Ph), 157.0 (Ph). HRMS (ESI): m/z calcd for
D
l
D
C47H52O8Na: 767.3554; found: 767.3538.
4.1.12. 5-[4-O-(3-Hydroxypropyl)phenyl]-3-oxapentyl 2,3,4,6-
tetra-O-benzyl-b- -galactopyranoside (21)
D
To a solution of 18 (293.8 mg, 0.39 mmol) in THF (2 mL) was
added a 0.5 M 9-borabicyclo[3.3.1]nonane-THF solution (4.7 mL,
2.35 mmol) at 0 °C. After the reaction mixture was stirred for
ane/allyl alcohol, 1:12:1) to give 16 (458.4 mg, 65%) as
a
6 h at room temperature,
a
0.5 M NaOH aqueous solution
colorless oil. ½a D23
ꢄ
ꢁ4.3 (c 9.5, CHCl3). 1H NMR (CDCl3): d 1.99 (s,
(2.4 mL, 1.2 mmol) and 30% H2O2 aqueous solution (447.0
lL,
3H, CH3), 2.05 (s, 6H, CH3), 2.14 (s, 3H, CH3), 2.84 (t, J = 6.9 Hz,
2H, CH2Ph), 3.58–3.67 (m, 8H, CH2CH2), 3.73–3.77 (m, 1H, Ha-6),
3.90 (t, J = 6.9 Hz, 1H, H-5), 3.94–3.97 (m, 1H, Hb-6), 4.14–4.18
(m, 2H, CH2CH2), 4.51 (d, J = 4.8 Hz, 2H, CH2CH@CH2), 4.57 (d,
J = 8.2 Hz, 1H, H-1), 5.02 (dd, J = 2.7 Hz, J = 10.3 Hz, 1H, H-3), 5.21
(dd, J = 8.2 Hz, J = 10.3 Hz, 1H, H-2), 5.27 (dd, J = 2.0 Hz,
J = 10.3 Hz, 2H, CH@CHaHb), 5.38 (d, J = 3.4 Hz, 1H, H-4), 5.42 (d,
J = 18.5 Hz, 2H, CH@CHaHb), 6.02–6.08 (m, 1H, CH@CH2), 6.84 (d,
J = 8.2 Hz, 2H, Ph), 7.12 (d, J = 8.2 Hz, 2H, Ph); 13C NMR (CDCl3): d
20.5 (CH3), 20.63 (CH3 ꢂ 2), 20.64 (CH3), 35.2 (CH2CH2), 61.2
(CH2CH2), 67.0 (C-4), 68.7 (C-2, C-6), 69.0 (CH2CH@CH2), 70.1
(CH2CH2), 70.2 (CH2CH2), 70.5 (C-5), 70.6 (CH2CH2), 70.8 (C-3),
72.4 (CH2CH2), 101.2 (C-1), 114.5 (Ph), 117.4 (CH@CH2), 129.6
(Ph), 131.1 (Ph), 133.3 (CH@CH2), 157.0 (Ph), 169.3 (C@O), 170.0
(C@O), 170.1 (C@O), 170.2 (C@O). HRMS (ESI): m/z calcd for
3.94 mmol) were added. After the reaction mixture was stirred
for 12 h, the reaction was then quenched by adding water
(15 mL). The reaction mixture was extracted with EtOAc, and
the organic layer was washed with water and a satd NaCl solu-
tion. After the organic layer was dried over Na2SO4, the solvent
was evaporated under reduced pressure. The crude product
was purified by preparative TLC (silica gel, EtOAc/hexane, 1:1)
to give 21 (290.2 mg, 96%) as a colorless oil. ½a D23
ꢁ14.9 (c
ꢄ
1.01, CHCl3). 1H NMR (CDCl3): d 1.58 (s, 1H, OH), 2.01–2.02
(m, 2H, CH2CH2OH), 2.78 (t, J = 7.5 Hz, 2H, CH2CH2Ph), 3.49–
3.51 (m, 2H, H-3, H-5), 3.56 (d, J = 6.2 Hz, 2 H, CH2), 3.61–3.74
(m, 5H, H-6, CH2CH2, CH2CHaHb), 3.80–3.85 (m, 3H, H-2, CH2OH),
3.88 (d, J = 2.7 Hz, 1H, H-4), 3.98–4.01 (m, 1H, CH2CHaHb), 4.05
(t, J = 5.5 Hz, 2H, CH2CH2CH2OH), 4.38 (d, J = 7.6 Hz, 1H, H-1),
4.39–4.45 (m, 2H, CH2Ph), 4.61 (d, J = 11.7 Hz, 1H, CH2Ph),
4.70–4.77 (m, 3H, CH2Ph), 4.92–4.96 (m, 2H, CH2Ph), 6.78 (d,
J = 8.3 Hz, 2H, Ph), 7.08 (d, J = 8.3 Hz, 2H, Ph), 7.26–7.37 (m,
20H, Ph); 13C NMR (CDCl3): d 32.0 (CH2CH2OH), 35.4 (CH2CH2Ph),
60.7 (CH2OH), 65.9 (CH2CH2CH2OH), 68.85 (CH2CH2), 68.89
(CH2CH2), 70.0 (CH2CH2), 72.4 (C-6), 73.1 (CH2Ph), 73.4 (C-5),
73.5 (C-4, CH2Ph), 74.5 (CH2Ph), 75.0 (CH2Ph), 79.4 (C-2), 82.1
(C-3), 104.1 (C-1), 114.4 (Ph), 127.5–131.3 (Ph), 137.9–138.9
C29H49O13Na: 619.2361; found: 619.2354.
4.1.15. 8-(4-Allyloxyphenyl)-3,6-dioxaoctyl 2,3,4,6-tetra-O-
benzyl-b- -galactopyranoside (19)
28% sodium methylate methanol solution (0.3 mL,
D
A
0.0016 mmol) was added to a solution of 16 (106.8 mg, 0.18 mmol)
in MeOH (20 mL). The resulting mixture was stirred for 2 h. The
solvent was then evaporated under reduced pressure. The crude
product was added to a solution of NaH (73.1 mg, 3.05 mmol) in
DMF (8 mL) at 0 °C. After the reaction mixture was stirred for
(Ph), 157.2 (Ph). HRMS (ESI): m/z calcd for
C47H54O9Na:
785.3660; found: 785.3612.
30 min, benzyl bromide (102.2 lL, 0.86 mmol) was added. The
4.1.13. 5-[4-O-(3-Iodopropyl)phenyl]-3-oxapentyl 2,3,4,6-tetra-
O-benzyl-b- -galactopyranoside (24)
resulting mixture was stirred for 24 h at room temperature. The
reaction was then quenched by the addition of a MeOH solution
(15 mL). The reaction mixture was extracted with EtOAc, and the
organic layer was washed with water and a satd NaCl solution.
After the organic layer was dried over Na2SO4, the solvent was
evaporated under reduced pressure. The crude product was puri-
fied by preparative TLC (silica gel, EtOAc/hexane, 1:2) to give 19
D
To a solution of 21 (207.7 mg, 0.27 mmol) in DMF (6 mL) was
added triphenylphosphine (298.0 mg, 1.14 mmol) and iodine
(290.3 mg, 1.14 mmol) at 70 °C under an argon atmosphere. After
the reaction mixture was stirred for 24 h, the reaction was then
quenched by adding water (10 mL). The reaction mixture was ex-
tracted with EtOAc, and the organic layer was washed with water
and a satd NaCl solution. After the organic layer was dried over
Na2SO4, the solvent was evaporated under reduced pressure. The
crude product was purified by preparative TLC (silica gel, EtOAc/
(115.8 mg, 82%) as a colorless oil. ½a D23
ꢄ
ꢁ21.7 (c 0.84, CHCl3). 1H
NMR (CDCl3):
d 2.79 (t, J = 7.6 Hz, 2H, CH2CH2Ph), 3.50 (d,
J = 2.7 Hz, 1H, H-3), 3.52–3.54 (m, H-5, 3H, CH2CH2), 3.57–3.62
(m, 8H, H-6, CH2CH2Ph, CH2CH2), 3.67–3.69 (m, 2H, CH2CH2),
3.72–3.76 (m, 1H, CH2CH2), 3.80–3.83 (dd, J = 8.2 Hz, J = 9.6 Hz,
1H, H-2), 3.88 (t, J = 8.2 Hz, 1H, H-4), 4.00–4.03 (m, 1H, CH2Ph),
4.40 (d, J = 9.6 Hz, 1H, H-1), 4.43–4.49 (m, 3H, CH2Ph,
CHaHbCH@CH2), 4.61 (d, J = 11.7 Hz, 1H, CHaHbCH@CH2), 4.69–
4.78 (m, 2H, CH2Ph), 4.92–4.96 (m, 2H, CH2Ph), 5.26 (dd,
J = 0.69 Hz, J = 10.3 Hz, 1H, CH@CHaHb), 5.40 (dd, J = 1.4 Hz,
J = 17.2 Hz, 1H, CH@CHaHb), 6.00–6.06 (m, 1H, CH@CH2), 6.80 (d,
J = 8.2 Hz, 2H, Ph), 7.08 (d, J = 8.2 Hz, 2H, Ph), 7.23–7.38 (m, 20H,
Ph); 13C NMR (CDCl3): d 35.4 (CH2CH2Ph), 68.78 (CH2CH2 ꢂ 2),
68.79 (CH2CH2), 68.9 (CH2CH2), 70.2 (CH2CH2 or CH2Ph), 70.3
(CH2CH2 or CH2Ph), 70.5 (CH2CH2 or CH2Ph), 72.5 (C-6), 73.0
(CH2Ph), 73.4 (C-5), 73.5 (C-4), 74.4 (CH2Ph), 75.0 (CH2Ph), 79.4
(C-2), 82.1 (C-3), 104.1 (C-1), 114.6 (Ph), 117.5 (CH@CH2), 127.4–
131.1 (Ph), 133.4 (CH@CH2), 137.9–138.9 (Ph), 157.0 (Ph). HRMS
(ESI): m/z calcd for C49H56O9Na: 811.3817; found: 811.3781.
hexane, 1:2) to give 24 (177.3 mg, 75%) as a colorless oil. ½a D23
ꢄ
ꢁ9.5 (c 1.38, CHCl3). 1H NMR (CDCl3): d 2.21–2.25 (m, 2H, CH2CH2I),
2.79 (t, J = 7.6 Hz, 2H, CH2CH2Ph), 3.34 (t, J = 6.2 Hz, 2H, CH2I),
3.50–3.52 (m, 2H, H-3, H-5), 3.57–3.74 (m, 8H, H-6, CH2CH2),
3.82 (t, J = 8.2 Hz, 1H, H-2), 3.88 (d, J = 2.0 Hz, 1H, H-4), 3.95–4.02
(m, 4H, CH2CH2), 4.39 (t, J = 6.9 Hz, 1H, H-1), 4.40–4.45 (m, 2H,
CH2Ph), 4.61 (d, J = 11.7 Hz, 1H, CH2Ph), 4.70–4.77 (m, 3H, CH2Ph),
4.93–4.96 (m, 2H, CH2Ph), 6.77 (d, J = 8.2 Hz, 2H, Ph), 7.08 (d,
J = 8.2 Hz, 2H, Ph), 7.25–7.38 (m, 20H, Ph); 13C NMR (CDCl3): d
2.6 (CH2I), 33.0 (CH2CH2I), 35.4 (CH2CH2Ph), 67.2 (CH2CH2CH2I),
68.85 (CH2CH2), 68.88 (CH2CH2), 70.0 (CH2CH2), 72.4 (C-6), 73.0
(CH2Ph), 73.4 (C-5), 73.52 (C-4), 73.53 (CH2Ph), 74.5 (CH2Ph),
75.0 (CH2Ph), 79.4 (C-2), 82.1 (C-3), 104.1 (C-1), 114.4 (Ph),
127.5–131.3 (Ph), 137.9–138.9 (Ph), 157.1 (Ph). HRMS (ESI): m/z
calcd for C47H53O8INa: 895.2677; found: 895.2664.

8838
Y. Oda et al. / Bioorg. Med. Chem. 16 (2008) 8830–8840
4.1.16. 8-[4-O-(3-Hydroxypropyl)phenyl]-3,6-dioxaoctyl 2,3,4,6-
tetra-O-benzyl-b- -galactopyranoside (22)
To a solution of 19 (89.4 mg, 0.11 mmol) in THF (2 mL) was
added a 0.5 M 9-borabicyclo[3.3.1]nonane–THF solution (1.6 mL,
0.8 mmol) at 0 °C. After the reaction mixture was stirred for 6 h
reaction mixture was stirred for 30 min, the mixed sample was
added to a solution of 23 (90.9 mg, 0.11 mmol) and tetra-n-butyl-
ammonium iodide (3.6 mg, 0.0097 mol) in DMF (2 mL). After the
reaction mixture was stirred for 48 h, the reaction was then
quenched by the addition of water (10 mL). The reaction mixture
was extracted with EtOAc, and the organic layer was washed with
water and a satd NaCl solution. After the organic layer was dried
over Na2SO4, the solvent was evaporated under reduced pressure.
The crude product was purified by preparative TLC (silica gel,
EtOAc/hexane, 2:3) to give 27 (72.0 mg, 73%) as a colorless oil. 1H
NMR (CDCl3): d 1.85–1.87 (m, 2H, CH2CH2CH2), 2.82–2.83 (m, 2H,
CH2CH2Ph), 3.44–3.58 (m, 18H), 3.88–4.31 (m, 30H), 4.33–4.75
(m, 50H), 4.83-5.36 (m, 12H), 6.69–6.70 (d, J = 8.2 Hz, 2H, Ph),
7.00–7.38 (m, 122H, Ph); 13C NMR (CDCl3): d 20.3, 29.5, 35.3,
61.5–82.1, 97.9-98.8, 103.9, 114.3, 126.9–129.8, 130.6, 137.8–
D
at room temperature, a 0.5 M NaOH aqueous solution (680.0
lL,
0.34 mmol) and 30% H2O2 aqueous solution (128.5 L, 1.13 mmol)
l
were added. After the reaction mixture was stirred for 18 h, the
reaction was then quenched by adding water (5 mL). The reaction
mixture was extracted with EtOAc, and the organic layer was
washed with water and a satd NaCl solution. After the organic layer
was dried over Na2SO4, the solvent was evaporated under reduced
pressure. The crude product was purified by preparative TLC (silica
gel, EtOAc/hexane, 1:1) to give 22 (75.3 mg, 82%) as a colorless oil.
½
a 2D3
ꢄ
ꢁ4.7 (c 2.42, CHCl3). 1H NMR (CDCl3): d 1.60 (s, 1H, OH), 1.62–
1.65 (m, 2H, CH2CH2), 1.87–1.91 (m, 3H, CH2CH2), 2.79 (t, J = 6.9 Hz,
2H, CH2CH2), 3.50–3.74 (m, 10H, H-3, H-5, H-6, CH2CH2), 3.82 (dd,
J = 2.0 Hz, J = 7.6 Hz, 1H, H-2), 3.88 (d, J = 1.3 Hz, 1H, H-4), 3.90–
4.02 (m, 3H, CH2CH2), 4.10–4.14 (m, 2H, CH2CH2), 4.39 (d,
J = 7.6 Hz, 1H, H-1), 4.41–4.45 (m, 2H, CH2Ph), 4.60 (d, J = 11.7 Hz,
1H, CH2Ph), 4.69–4.76 (m, 3H, CH2Ph), 4.94 (t, J = 12.3 Hz, 2H,
CH2Ph), 6.81 (d, J = 8.3 Hz, 2H, Ph), 7.10 (d, J = 8.9 Hz, 2H, Ph),
7.25–7.38 (m, 20H, Ph); 13C NMR (CDCl3): d 14.1 (CH2CH2OH),
21.0 (CH2CH2), 35.2 (CH2CH2Ph), 60.3 (CH2OH), 68.7 (CH2CH2),
68.9 (CH2CH2), 70.1 (CH2CH2), 70.3 (CH2CH2), 70.5 (CH2CH2), 73.0
(C-6), 73.3 (C-5), 73.40 (C-4), 73.43 (CH2Ph ꢂ 2), 74.4 (CH2Ph),
74.9 (CH2Ph), 79.4 (C-2), 82.0 (C-3), 104.0 (C-1), 114.3 (Ph),
127.4–129.7 (Ph), 137.8–138.8 (Ph), 171.1 (Ph). HRMS (ESI): m/z
calcd for C49H58O10Na: 829.3922; found: 829.3877.
139.3, 157.3. MALDI-TOF-MS: m/z calcd for C227H238O42Na:
3658.6; found 3658.2.
4.1.19. 6A-O-(1-O-{4-[1-O-(b-
D-Galactopyranside-1-yl)ethyl-2-
yl]phenyl}propane-3-yl)-b-cyclodextrin (4)
Compound 27 (92.3 mg, 0.025 mmol) was added to a solution of
Pd(OH)2 (117.4 mg, 0.75 mmol) in DMF (15 mL). Hydrogen was
bubbled through the solution for 12 h. After the solvent was fil-
tered and evaporated under reduced pressure, the crude product
was isolated by adsorbing on LH-20 followed by eluting with
methanol to afford 4 (34.5 mg, 92%) as white crystals. 1H NMR
(D2O): d 1.19–1.20 (m, 2H), 1.77–1.85 (m, 2H, CH2CH2CH2), 2.88–
2.91 (m, 2H, CH2Ph), 3.12–4.05 (m, 52H), 4.36 (d, J = 7.6 Hz, 1H,
H-1), 4.83–4.98 (m, 7H, CyD-1), 6.75 (d, J = 8.3 Hz, 2H, Ph), 7.10
(d, J = 8.2 Hz, 2H, Ph); 13C NMR (CDCl3): d 20.6, 29.5, 35.8, 60.4–
81.8, 83.0–83.4, 101.5–104.3, 115.7, 130.3, 131.5. MALDI-TOF-
MS: m/z calcd for C59H94O42Na: 1497.5; found 1497.9.
4.1.17. 8-[4-O-(3-Iodopropyl)phenyl]-3,6-dioxaoctyl 2,3,4,6-
tetra-O-benzyl-b-D-galactopyranoside (25)
To a solution of 22 (47.0 mg, 0.058 mmol) in DMF (3 mL) was
added triphenylphosphine (93.0 mg, 0.35 mmol) and iodine
(90.0 mg, 0.35 mmol) at 70 °C under an argon atmosphere. After
the reaction mixture was stirred for 24 h, the reaction was then
quenched by adding water (10 mL). The reaction mixture was ex-
tracted with EtOAc, and the organic layer was washed with water
and a satd NaCl solution. After the organic layer was dried over
Na2SO4, the solvent was evaporated under reduced pressure. The
crude product was purified by preparative TLC (silica gel, EtOAc/
4.1.20. Heptaxis-(2,3-di-O-benzyl)-6B,C,E,F,G-penta-O-benzyl-6A-
O-(1-O-{4-[1-(2,3,4,6-tetra-O-benzyl-b-D-galactopyranside-1-yl)-
1,4-dioxahexane-6-yl]phenyl}propane-3-yl)-b-cyclodextrin or
heptaxis-(2,3-di-O-benzyl)-6B,C,E,F,G-penta-O-benzyl-6D-O-(1-O-
{4-[1-(2,3,4,6-tetra-O-benzyl-b-D-galactopyranside-1-yl)-1,4-
dioxahexane-6-yl]phenyl}propane-3-yl)-b-cyclodextrin (28)
Compound 26 (131.8 mg, 0.046 mmol) was added to a solution
of potassium hydrate (316.5 mg, 5.64 mmol) in DMF (3 mL). After
the reaction mixture was stirred for 30 min, the mixed sample
was added to a solution of 24 (152.2 mg, 0.17 mmol) and tetra-n-
butylammonium iodide (1.8 mg, 0.0049 mmol) in DMF (4 mL).
After the reaction mixture was stirred for 48 h, the reaction was
then quenched by the addition of water (10 mL). The reaction mix-
ture was extracted with EtOAc, and the organic layer was washed
with water and a satd NaCl solution. After the organic layer was
dried over Na2SO4, the solvent was evaporated under reduced pres-
sure. The crude product was purified by preparative TLC (silica gel,
EtOAc/hexane/MeOH, 2:12:1) to give 28 (86.4 mg, 52%) as a color-
less oil. 1H NMR (CDCl3): d 1.86–1.87 (m, 2H, CH2CH2CH2), 2.73–
2.80 (m, 2H, CH2CH2Ph), 3.38–3.69 (m, 25H), 3.80–4.05 (m, 30H),
4.30–4.49 (m, 30H), 4.59–4.77 (m, 14H), 4.90–5.01 (m, 7H), 5.05–
5.20 (m, 4H), 5.25–5.40 (m, 2H), 6.70–6.72 (m, 2H, Ph), 7.00–7.36
(m, 117H, Ph); 13C NMR (CDCl3): d 14.2, 21.0, 29.1–29.7, 31.9,
35.32, 35.34, 60.3, 60.6, 61.4, 64.56, 64.61, 65.8, 68.0, 68.1–69.9,
71.2–71.7, 72.3–73.4, 74.4–75.8, 78.3–79.7, 80.6–82.0, 98.1–98.6,
104.0, 114.2, 126.7–130.6, 137.7–139.1, 157.1. MALDI-TOF-MS:
m/z calcd for C229H242O43 Na: 3612.6; found 3612.3.
hexane, 1:1) to give 25 (43.8 mg, 82%) as a colorless oil. ½a D23
ꢄ
ꢁ4.0 (c 2.1, CHCl3). 1H NMR (CDCl3): d 2.23–2.25 (m, 2H, CH2CH2I),
2.80 (t, J = 7.6 Hz, 2H, CH2CH2), 3.35 (t, J = 6.9 Hz, 2H, CH2CH2),
3.49–3.74 (m, 13H, H-3, H-5, H-6, CH2CH2), 3.81 (dd, J = 2.1 Hz,
J = 7.5 Hz, 1H, H-2), 3.88 (d, J = 2.8 Hz, 1H, H-4), 3.98–4.03 (m,
3H, CH2CH2), 4.39 (d, J = 8.2 Hz, 1H, H-1), 4.41–4.45 (m, 2H, CH2Ph),
4.61 (d, J = 11.7 Hz, 1H, CH2Ph), 4.69–4.76 (m, 3H, CH2Ph), 4.92–
4.96 (m, 2H, CH2Ph), 6.80 (d, J = 9.0 Hz, 2H, Ph), 7.09 (d,
J = 8.3 Hz, 2H, Ph), 7.24–7.38 (m, 20H, Ph); 13C NMR (CDCl3): d
2.6 (CH2I), 33.0 (CH2CH2I), 35.3 (CH2CH2Ph), 67.2 (CH2CH2), 68.8
(CH2CH2), 69.0 (CH2CH2), 70.2 (CH2CH2), 70.4 (CH2CH2), 70.6
(CH2CH2), 72.5 (C-6), 73.1 (CH2Ph), 73.49 (C-5), 73.52 (C-4), 73.52
(CH2Ph), 74.5 (CH2Ph), 75.0 (CH2Ph), 79.4 (C-2), 82.1 (C-3), 104.1
(C-1), 114.4 (Ph), 114.4 (Ph), 127.5–131.2 (Ph), 137.9–138.9 (Ph).
HRMS (ESI): m/z calcd for
C49H57O9INa: 939.2939; found:
939.2955.
4.1.18. Heptaxis-(2,3-di-O-benzyl)-6B,C,E,F,G-penta-O-benzyl-6A-
O-(1-O-{4-[1-O-(2,3,4,6-tetra-O-benzyl-b- -galactopyranside-1-
D
yl)ethyl-2-yl]phenyl}propane-3-yl)-b-cyclodextrin or heptaxis-
(2,3-di-O-benzyl)-6B,C,E,F,G-penta-O-benzyl-6D-O-(1-O-{4-[1-O-
4.1.21. 6A-O-(1-O-{4-[1-(b-
D-Galactopyranside-1-yl)-1,4-
(2,3,4,6-tetra-O-benzyl-b-
yl]phenyl}propane-3-yl)-b-cyclodextrin (27)
Compound 26 (79.1 mg, 0.028 mmol) was added to a solution of
potassium hydrate (193.5 mg, 3.45 mmol) in DMF (2 mL). After the
D
-galactopyranside-1-yl)ethyl-2-
dioxahexane-6-yl]phenyl}propane-3-yl)-b-cyclodextrin (5)
Compound 28 (72.5 mg, 0.020 mmol) was added to a solution of
Pd(OH)2 (104.9 mg, 0.67 mmol) in DMF (15 mL). Hydrogen was
bubbled through the solution for 24 h. After the solvent was fil-

Y. Oda et al. / Bioorg. Med. Chem. 16 (2008) 8830–8840
8839
tered and evaporated under reduced pressure, the crude product
4.1.25. 6A-O-(1-O-{4-[1-(b-
trioxanonane-9-yl]phenyl}propane-3-yl)-b-cyclodextrin (6)
D-Galactopyranside-1-yl)-1,4,7-
was isolated by adsorbing on LH-20 followed by eluting with
methanol to afford 5 (27.7 mg, 90%) as white crystals. 1H NMR
(D2O): d 1.77–1.95 (m, 2H, CH2CH2CH2), 2.81–2.83 (m, 2H, CH2Ph),
3.21–4.07 (m, 58H), 4.33 (d, J = 7.6 Hz, 1H, H-1), 4.84–4.98 (m, 7H,
CyD-1), 6.74 (d, J = 7.8 Hz, 2H, Ph), 7.09 (d, J = 7.8 Hz, 2H, Ph). MAL-
DI-TOF-MS: m/z calcd for C61H98O43Na: 1541.8; found 1541.5.
Compound 29 (8.4 mg, 0.0023 mmol) was added to a solution of
Pd(OH)2 (16.2 mg, 0.10 mmol) in DMF (6 mL). Hydrogen was bub-
bled through the solution for 24 h. After the solvent was filtered
and evaporated under reduced pressure, the crude product was
isolated by adsorbing on LH-20 followed by eluting with methanol
to afford 6 (2.9 mg, 81%) as white crystals. 1H NMR (D2O): d 1.08–
1.18 (m, 2H), 1.76–1.93 (m, 2H, CH2CH2CH2), 2.81 (m, 2H, CH2Ph),
3.35–3.98 (m, 61H), 4.65–5.25 (m, 7H, CyD-1), 6.72 (d, J = 7.1 Hz,
2H, Ph), 7.07 (d, J = 7.8 Hz, 2H, Ph). MALDI-TOF-MS: m/z calcd for
4.1.22. Heptaxis-(2,3-di-O-benzyl)-6B,C,E,F,G-penta-O-benzyl-
6A,6D-bis-O-(1-O-{4-[1-(2,3,4,6-tetra-O-benzyl-b-
D-galactopy-
ranside-1-yl)-1,4-dioxahexane-6-yl]phenyl}propane-3-yl)-b-
cyclodextrin (30)
C63H102O44Na: 1585.6; found 1585.9.
Compound 26 (131.8 mg, 0.046 mmol) was added to a solution
of potassium hydrate (316.5 mg, 5.64 mmol) in DMF (3 mL). After
the reaction mixture was stirred for 30 min, the mixed sample
was added to a solution of 24 (152.2 mg, 0.17 mmol) and tetra-n-
butylammonium iodide (1.8 mg, 0.0049 mmol) in DMF (4 mL).
After the reaction mixture was stirred for 48 h, the reaction was
then quenched by the addition of water (10 mL). The reaction mix-
ture was extracted with EtOAc, and the organic layer was washed
with water and a satd NaCl solution. After the organic layer was
dried over Na2SO4, the solvent was evaporated under reduced pres-
sure. The crude product was purified by preparative TLC (silica gel,
EtOAc/hexane/MeOH, 2:12:1) to give 30 (18.1 mg, 9%) as a color-
less oil. 1H NMR (CDCl3): d 1.85–1.88 (m, 4H, CH2CH2CH2), 2.70–
2.80 (m, 4H, CH2CH2Ph), 3.38–5.40 (m, 137H), 6.69–7.38 (m,
143H, Ph). MALDI-TOF-MS: m/z calcd for C269H288O51Na: 4357.0;
found 4356.1.
4.1.26. 4-Allyloxyphenylethyl 4-methoxybenzyl ether (31)
NaH (206.7 mg, 8.6 mmol) was added to a solution of 9
(337.5 mg, 1.89 mmol) in DMF (20 mL) at 0 °C. After the reaction
mixture was stirred for 30 min, 4-methoxybenzyl chloride
(310 lL, 2.28 mmol) was added. The resulting mixture was stirred
for 2 h at room temperature. The reaction was then quenched by
the addition of a MeOH solution (30 mL). The reaction mixture
was extracted with EtOAc, and the organic layer was washed with
water and a satd NaCl solution. After the organic layer was dried
over Na2SO4, the solvent was evaporated under reduced pressure.
The crude product was purified by flash column chromatography
(silica gel, EtOAc/hexane, 1:10) to give 31 (548.6 mg, 97%) as a col-
orless oil. 1H NMR (CDCl3): d 2.85 (t, J = 7.6 Hz, 2H, CH2CH2Ph), 3.62
(t, J = 7.6 Hz, 2H, CH2CH2Ph), 3.80 (s, 3H, CH3), 4.45 (s, 2H,
CH3OPhCH2), 4.51 (d, J = 5.5 Hz, 2H, CH2CH@CH2), 5.27 (dd,
J = 1.4 Hz, J = 10.3 Hz, 1H, CH@CHaHb), 5.40 (dd, J = 1.4 Hz,
J = 17.2 Hz, 1H, CH@CHaHb), 6.02–6.08 (m, 1H, CH@CH2), 6.81–
6.87 (m, 4H, Ph), 7.12 (d, J = 8.9 Hz, 2H, Ph), 7.23 (d, J = 8.2 Hz,
2H, Ph); 13C NMR (CDCl3): d 35.5 (CH2CH2Ph), 55.3 (CH3), 68.8
(CH2CH2Ph), 71.2 (CH2CH@CH2), 72.6 (CH3OPhCH2), 113.8 (Ph),
114.6 (Ph), 117.5 (CH@CH2), 129.2-131.2 (Ph), 133.5 (CH@CH2),
157.1 (Ph), 159.1 (Ph). HRMS (ESI): m/z calcd for C19H22O3Na:
321.1461; found: 321.1413.
4.1.23. 6A,6D-Bis-O-(1-O-{4-[1-(b-
D-galactopyranside-1-yl)-1,4-
dioxahexane-6-yl]phenyl}propane-3-yl)-b-cyclodextrin (7)
Compound 30 (16.1 mg, 0.0037 mmol) was added to a solution
of Pd(OH)2 (26.3 mg, 0.17 mmol) in DMF (8 mL). Hydrogen was
bubbled through the solution for 24 h. After the solvent was fil-
tered and evaporated under reduced pressure, the crude product
was isolated by adsorbing on LH-20 followed by eluting with
methanol to afford 7 (5.9 mg, 83%) as white crystals. 1H NMR
(D2O): d 1.76–1.85 (m, 4H, CH2CH2CH2), 2.76 (m, 4H, CH2Ph),
3.12–3.95 (m, 74H), 4.20 (m, 1H, H-1), 4.30 (m, 1H, H-1’), 4.59–
4.96 (m, 7H, CyD-1), 6.63 (m, 2H, Ph), 6.84 (m, 2H, Ph), 7.04–7.14
(m, 4H, Ph). MALDI-TOF-MS: m/z calcd for C80H126O51Na: 1925.7;
found 1926.3.
4.1.27. [4-(4-Methoxybenzyloxyethyl)phenyl]-1-oxabutane-4-
ol (32)
To a solution of 31 (935.9 mg, 3.14 mmol) in THF (10 mL) was
added a 0.5 M 9-borabicyclo[3.3.1]nonane-THF solution (12 mL,
6 mmol) at 0 °C. After the reaction mixture was stirred for 21 h
at room temperature, a 0.5 M NaOH aqueous solution (18.8 mL,
9.4 mmol) and 30% H2O2 aqueous solution (3.5 mL, 30.5 mmol)
were added. After the reaction mixture was stirred for 4.5 h, the
reaction was then quenched by adding water (50 mL). The reaction
mixture was extracted with EtOAc, and the organic layer was
washed with water and a satd NaCl solution. After the organic layer
was dried over Na2SO4, the solvent was evaporated under reduced
pressure. The crude product was purified by flash column chroma-
tography (silica gel, EtOAc/hexane, 1:1) to give 32 (877.6 mg, 88%)
as a colorless oil. 1H NMR (CDCl3): d 2.03 (m, 2H, CH2CH2OH), 2.85
(t, J = 6.9 Hz, 2H, CH2CH2Ph), 3.62 (t, J = 6.9 Hz, CH2CH2Ph), 3.80 (s,
3H, CH3), 3.85 (t, J = 5.5 Hz, 2H, CH2OH), 4.10 (t, J = 6.2 Hz, 2H,
CH2CH2CH2OH), 4.44 (s, 2H, CH3OPhCH2), 6.83 (dd, J = 2.1 Hz,
J = 6.2 Hz, 2H, Ph), 6.86 (dd, J = 2.1 Hz, J = 6.2 Hz, 2H, Ph), 7.12 (d,
J = 8.9 Hz, 2H, Ph), 7.23 (d, J = 8.2 Hz, 2H, Ph); 13C NMR (CDCl3): d
32.0 (CH2CH2OH), 35.4 (CH2CH2Ph), 55.2 (CH3), 60.6 (CH2OH),
65.9 (CH2CH2CH2OH), 71.1 (CH2CH2Ph), 72.6 (CH3OPhCH2), 113.7
(Ph), 114.3 (Ph), 129.2–131.3 (Ph), 157.2 (Ph), 159.1 (Ph). HRMS
(ESI): m/z calcd for C19H24O4Na: 339.1567; found: 339.1539.
4.1.24. Heptaxis-(2,3-di-O-benzyl)-6B,C,E,F,G-penta-O-benzyl-6A-
O-(1-O-{4-[1-(2,3,4,6-tetra-O-benzyl-b-D-galactopyranside-1-yl)-
1,4,7-trioxanonane-9-yl]phenyl}propane-3-yl)-b-cyclodextrin
or heptaxis-(2,3-di-O-benzyl)-6B,C,E,F,G-penta-O-benzyl-6D-O-(1-
O-{4-[1-(2,3,4,6-tetra-O-benzyl-b-D-galactopyranside-1-yl)-
1,4,7-trioxanonane-9-yl]phenyl}propane-3-yl)-b-
cyclodextrin (29)
Compound 26 (9.1 mg, 0.0032 mmol) was added to a solution of
potassium hydrate (22.1 mg, 0.39 mmol) in DMF (1 mL). After the
reaction mixture was stirred for 30 min, the mixed sample was
added to a solution of 25 (11.2 mg, 0.012 mmol) and tetra-n-butyl-
ammonium iodide (0.3 mg, 0.00081 mmol) in DMF (1.5 mL). After
the reaction mixture was stirred for 48 h, the reaction was then
quenched by the addition of water (10 mL). The reaction mixture
was extracted with EtOAc, and the organic layer was washed with
water and a satd NaCl solution. After the organic layer was dried
over Na2SO4, the solvent was evaporated under reduced pressure.
The crude product was purified by preparative TLC (silica gel,
EtOAc/hexane, 2:3) to give 29 (8.4 mg, 72%) as a colorless oil. 1H
NMR (CDCl3): d 1.57 (m, 2H, CH2CH2CH2), 2.72–2.81 (m, 2H,
CH2CH2Ph), 3.48–5.45 (m, 116H), 6.70–7.38 (m, 96H, Ph). MALDI-
TOF-MS: m/z calcd for C231H246O44Na: 3656.6; found 3656.9.
4.1.28. 4-Iodo-[4-(4-methoxybenzyloxyethyl)phenyl]-1-
oxabutane (33)
To a solution of 32 (112.7 mg, 0.36 mmol) in DMF (3 mL) was
added triphenylphosphine (377.1 mg, 1.44 mmol) and iodine

8840
Y. Oda et al. / Bioorg. Med. Chem. 16 (2008) 8830–8840
(399.5 mg, 1.57 mmol) at 40 °C under an argon atmosphere. After
the reaction mixture was stirred for 2 h, the reaction was then
quenched by adding water (10 mL). The reaction mixture was ex-
tracted with EtOAc, and the organic layer was washed with water
and a satd NaCl solution. After the organic layer was dried over
Na2SO4, the solvent was evaporated under reduced pressure. The
crude product was purified by preparative TLC (silica gel, EtOAc/
hexane, 1:10) to give 33 (132.6 mg, 87%) as a colorless oil. 1H
NMR (CDCl3): d 2.26 (m, 2H, CH2CH2I), 2.85 (t, J = 7.6 Hz, 2H,
CH2CH2Ph), 3.37 (t, J = 6.9 Hz, 2H, CH2I), 3.62 (t, J = 6.9 Hz, 2H,
CH2CH2Ph), 3.80 (s, 3H, CH3), 4.01 (t, J = 5.5 Hz, 2H, CH2CH2CH2I),
4.45 (s, 2H, CH3OPhCH2), 6.82 (dd, J = 2.1 Hz, J = 6.9 Hz, 2H, Ph),
6.87 (dd, J = 2.1 Hz, J = 6.9 Hz, 2H, Ph), 7.13 (d, J = 8.2 Hz, 2H, Ph),
7.23 (d, J = 8.9 Hz, 2H, Ph); 13C NMR (CDCl3): d 2.6 (CH2I), 33.0
(CH2CH2I), 35.4 (CH2CH2Ph), 55.3 (CH3), 67.3 (CH2CH2CH2I), 71.1
(CH2CH2Ph), 72.6 (CH3OPhCH2), 113.7 (Ph), 114.4 (Ph), 129.2–
131.4 (Ph), 157.1 (Ph), 159.1 (Ph). HRMS (ESI): m/z calcd for
4.1.30. 6A-O-[1-O-(4-Hydroxyethylphenyl)-propane-3-yl]-b-
cyclodextrin (35)
Compound 29 (76.6 mg, 0.024 mmol) was added to a solution of
Pd(OH)2 (93.7 mg, 0.60 mmol) in DMF (20 mL). Hydrogen was bub-
bled through the solution for 24 h. After the solvent was filtered
and evaporated under reduced pressure, the crude product was
isolated by adsorbing on HP-20 followed by eluting with methanol
to afford 6 (20.5 mg, 64%) as white crystals. 1H NMR (D2O): d 1.91–
1.99 (m, 2H, CH2CH2CH2), 2.89 (t, J = 7.7 Hz, 2H, CH2Ph), 3.33–4.16
(m, 48H), 4.98–4.99 (m, 3H, CyD-1), 5.05 (d, J = 3.6 Hz, 1H, CyD-1),
5.06 (d, J = 3.6 Hz, 1H, CyD-1), 5.08 (d, J = 3.6 Hz, 1H, CyD-1), 5.09
(d, J = 3.6 Hz, 1H, CyD-1), 6.87 (d, J = 8.4 Hz, 2H, Ph), 7.22 (d,
J = 8.6 Hz, 2H, Ph). MALDI-TOF-MS: m/z calcd for C53H84O37Na:
1335.5; found 1335.6.
References and notes
C
19H23O3INa: 449.0584; found: 449.0593.
1. (a) Abe, H.; Kenmoku, A.; Yamaguchi, N.; Hattori, K. J. Incl. Phenom.
Macrocyclic Chem. 2002, 44, 39; (b) Ikuta, A.; Koizumi, K.; Tanimoto, T. J.
Carbohydr. Chem. 2000, 19, 13; (c) Furuike, T.; Aiba, S.; Nishimura, S.-I.
Tetrahedron 2000, 56, 9909; (d) Kassab, R.; Felix, C.; Parrot-Lopez, H.; Bonaly,
R. Tetrahedron Lett. 1997, 38, 7555; (e) Baussanne, I.; Benito, J. M.; Mellet, C.
O.; Fernandez, J. M. G.; Law, H.; Defaye, J. Chem. Commun. 2000, 1489; (f)
Garcia-Lopez, J. J.; Hernandez-Mateo, F.; Isac-Garcia, J.; Kim, J. M.; Roy, R.;
Santoyo-Gonzalez, F.; Vargas-Berenguel, A. J. Org. Chem. 1999, 64, 522; (g)
Roy, R.; Hernandez-Mateo, F.; Santoyo-Gonzalez, F. J. Org. Chem. 2000, 65,
8743; (h) Shinoda, T.; Maeda, A.; Kagatani, S.; Konno, Y.; Sonobe, T.; Fukui,
M.; Hashimoto, H.; Hara, K.; Fujuta, K. Int. J. Pharm. 1998, 167, 147; (i)
Shinoda, T.; Kagatani, S.; Maeda, A.; Konno, Y.; Hashimoto, H.; Hara, K.;
Fujuta, K.; Sonobe, T. Drug Dev. Ind. Pharm. 1999, 25, 1185; (j) Andre, S.;
Kaltner, H.; Furuike, T.; Nishimura, S.-I.; Gabius, H.-J. Bioconjug. Chem. 2004,
15, 87; (k) Yasuda, N.; Aoki, N.; Abe, H.; Hattori, K. Chem. Lett. 2000, 706; (l)
Ortega-Caballero, F.; Gimenez-Martinez, J. J.; Garcia-Fuentes, L.; Ortiz-
Salmeron, E.; Santoyo-Gonzalez, F.; Vargas-Berenguel, A. J. Org. Chem. 2001,
66, 7786; (m) Ichikawa, M.; Woods, A. S.; Mo, H.; Goldstein, I. J.; Ichikawa, Y.
Tetrahedron: Asymm. 2000, 11, 289; (n) Mallet, C. O.; Defaye, J.; Fernandez, J.
M. G. Chem. Eur. J. 2002, 8, 1982; (o) Baussanne, I.; Benito, J. M.; Mallet, C. O.;
Fernandez, J. M. G. ChemBioChem 2002, 2, 777; (p) Furuike, T.; Sukegawa, T.;
Nishimura, S.-I. Macromolecules 2000, 49, E933; (q) Tanimoto, T.; Omatsu, M.;
Ikuta, A.; Nishi, Y.; Murakami, H.; Nakano, H.; Kitahata, S. Biosci. Biotechnol.
Biochem. 2005, 69, 732; (r) Imata, H.; Kubota, K.; Hattori, K.; Aoyagi, M.;
Jindoh, C. Polymer J. 1997, 29, 563; (s) Wada, K.; Arima, H.; Tsutsumi, T.;
Hirayama, F.; Uekama, K. Biol. Pharm. Bull. 2005, 283, 500; (t) Smiljanic, N.;
Moreau, V.; Yockot, D.; Benito, J. M.; Fernandez, J. M. G.; Djedaini-Pilard, F.
Angew. Chem. Int. Ed. 2006, 45, 5465.
4.1.29. Heptaxis-(2,3-di-O-benzyl)-6B,C,E,F,G-penta-O-benzyl-6A-
O-{1-O-[4-(4-methoxybenzyloxyethyl)phenyl]-propane-3-yl}-b-
cyclodextrin or heptaxis-(2,3-di-O-benzyl)-6B,C,E,F,G-penta-O-
benzyl-6D-O-{1-O-[4-(4-methoxybenzyloxyethyl)phenyl]-
propane-3-yl}-b-cyclodextrin (34)
Compound 26 (129.5 mg, 0.045 mmol) was added to a solution
of potassium hydrate (399.2 mg, 7.1 mmol) in DMF (3 mL). After
the reaction mixture was stirred for 2 h, the mixed sample was
added to a solution of 33 (78.4 mg, 0.18 mmol) and tetra-n-butyl-
ammonium iodide (8.4 mg, 0.022 mmol) in DMF (3 mL). After the
reaction mixture was stirred for 19.5 h, the reaction was then
quenched by the addition of water (10 mL). The reaction mixture
was extracted with EtOAc, and the organic layer was washed with
water and a satd NaCl solution. After the organic layer was dried
over Na2SO4, the solvent was evaporated under reduced pressure.
The crude product was purified by preparative TLC (silica gel,
EtOAc/benzene, 1:15) to give 34 (82.4 mg, 58%) as a colorless oil.
1H NMR (CDCl3): d 1.84–1.89 (m, 2H, CH2CH2CH2), 2.47 (s, 1H,
OH), 2.76–2.81 (m, 2H, CH2CH2Ph), 3.35–3.70 (m, 21H), 3.77 (s,
3H, CH3), 3.79–4.04 (m, 28H), 4.28–5.39 (m, 46H), 6.75 (dd,
J = 3.2 Hz, J = 8.0 Hz, 2H, Ph), 6.75 (d, J = 8.8 Hz, 2H, Ph), 7.01–7.25
(m, 99H, Ph); 13C NMR (CDCl3): d 29.7, 35.5, 55.3, 61.5, 64.7,
68.1, 69.2, 69.3, 71.2–71.8, 72.4–73.3, 74.8–75.9, 77.2, 77.8, 78.6–
79.0, 79.5–80.0, 80.7–81.0, 98.1, 98.2, 98.3, 98.4, 98.5, 98.6, 98.7,
113.6, 114.2, 126.8-130.7, 137.8-139.1, 157.0, 158.9. MALDI-TOF-
MS: m/z calcd for C194H206O38Na: 3166.4; found 3166.5.
2. (a) Yamanoi, T.; Yoshida, N.; Oda, Y.; Akaike, E.; Tsutsumida, M.; Kobayashi, N.;
Osumi, K.; Yamamoto, K.; Fujita, K.; Takahashi, K.; Hattori, K. Bioorg. Med. Chem.
Lett. 2005, 15, 1009; (b) Yamanoi, T.; Kobayashi, N.; Takahashi, K.; Hattori, K.
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3. Oda, Y.; Kobayashi, N.; Yamanoi, T.; Katsuraya, K.; Takahashi, K.; Hattori, K. Med.
Chem. 2008, 4, 244.
4. Wang, W.; Pearce, A. J.; Zhang, Y.; Sinay, P. Tetrahedron: Asymm. 2001, 12,
517.