Syntheses and doxorubicin-inclusion abilities of β-cyclodextrin derivatives with a hydroquinone α-glycoside residue attached at the primary side

Article abstract of DOI:10.1248/cpb.57.74

This paper describes syntheses and doxorubicin-inclusion abilities of β-cyclodextrin (CyD) derivatives with a hydroquinone α-glycoside residue attached at the primary side. The hydroquinone glycoside having an α-D-glucosidic or 2-acetamido-2-deoxy-α-D-glu

Full text of DOI:10.1248/cpb.57.74

74
Notes
Chem. Pharm. Bull. 57(1) 74—78 (2009)
Vol. 57, No. 1
b
Syntheses and Doxorubicin-Inclusion Abilities of -Cyclodextrin
a
Derivatives with a Hydroquinone -Glycoside Residue Attached at the
Primary Side
b
,a
Yoshiki ODA,a Masumi MIURA,a,b Kenjiro HATTORI, and Takashi YAMANOI
*
a The Noguchi Institute; 1–8–1 Kaga, Itabashi-ku, Tokyo 173–0003, Japan: and b Department of Nanochemistry, Faculty of
Engineering, Tokyo Polytechnic University; 1583 Iiyama, Atsugi, Kanagawa 243–0297, Japan.
Received June 25, 2008; accepted October 13, 2008; published online October 15, 2008
This paper describes syntheses and doxorubicin-inclusion abilities of b-cyclodextrin (CyD) derivatives with
a hydroquinone a-glycoside residue attached at the primary side. The hydroquinone glycoside having an a-D-
glucosidic or 2-acetamido-2-deoxy-a-D-glucosidic linkage became a useful component for providing an a-D-glu-
cose- or 2-acetamido-2-deoxy-a-D-glucose–b-CyD conjugate. The surface plasmon resonance analyses of these b-
CyD derivatives for the anticancer agent, doxorubicin, indicated that they had excellent inclusion associations on
the order of 105 ꢀ1 for the immobilized doxorubicin.
M
Key words synthesis; b-cyclodextrin; hydroquinone; surface plasmon resonance; saccharide-attached cyclodextrin; doxorubicin
Our recent study showed that the b-glucose–b-cyclodex- N,N-dimethylformamide (DMF) for 70 h gave the allylated
trin (CyD) conjugates 1 and 2 as shown in Fig. 1 were suc- compound 8 in 84% yield. The benzylation of 8 using benzyl
cessfully prepared from b-CyD and arbutin (4-hydrox- bromide (4.8 eq) and NaH (16 eq) in DMF for 21 h afforded
yphenyl b-glucopyranoside, 3).1—3) Arbutin 3 is a naturally compound 9 in 99% yield. The hydroboration of 9 with 9-
occurring hydroquinone glycoside containing a b-D-gluco- borabicyclo[3.3.1]nonane (9-BBN) (2 eq) in tetrahydrofuran
sidic linkage. An appropriate linker necessary to connect 3 (THF) at 0 °C for 5 h, followed by oxidation using aq. H2O2
with a b-CyD derivative was conveniently introduced into (10 eq) and by hydrolysis with aq. NaOH (3 eq) for 48 h gave
the phenolic alcohol of 3. The inclusion association constants compound 10 in 94% yield. The iodination of 10 with iodine
(Ka) of 1 and 2 for the immobilized doxorubicin (DXR, anti- (4 eq) in the presence of Ph3P (4 eq) in DMF at 35 °C for 2 h
cancer agent) measured using a surface plasmon resonance quantitatively gave compound 11 in 89% yield. The conden-
(SPR) optical biosensor were 105—106 Mꢀ1. These Ka values sation of 11 (3.8 eq) with the benzylated b-CyD 1223) using
are remarkably high when compared with the inclusion asso- KOH (ca. 120 eq) and tetra-n-butylammonium iodide (n-
ciation of the lactose–b-CyD conjugate 44) or normal b-CyD Bu4NI) (0.5 eq) in DMF for 64 h gave 13 in 69% yield. The
which was on the order of 103 Mꢀ1. The b-CyD derivatives 1 treatment of 13 with H2–Pd(OH)2 in DMF for 6 h provided
and 2 were characterized by the existence of the phenyl the desired compound 5, which was purified by gel-filtration
group in the spacer between the glucose and b-CyD. The using LH 20 (MeOH) in 98% yield.
p–p stacking interaction effect between the phenyl group
and DXR would increase their inclusion associations for
DXR.3) Thus, our former study showed that the hydro-
quinone glycoside could be a synthetically useful component
for providing a saccharide–b-CyD conjugate which is ex-
pected to have an excellent DXR-inclusion ability.5)
The CyD derivatives attached to saccharide moieties are
expected to carry drug molecules to specific cells, because
they have both the drug-inclusion ability of CyDs and the
cell-recognition of saccharides.4,6—22) Then, our next objec-
tive was the synthesis of a novel b-CyD conjugate having an-
other hydroquinone glycoside. This paper describes the syn-
thesis of two novel b-CyD derivatives attached to a hydro-
quinone glycoside containing an a-D-glucopyranosidic or 2-
acetamido-2-deoxy-a-D-glucopyranosidic linkage and the
evaluation of their DXR-inclusion abilities.
Results and Discussion
We designed two novel b-CyD derivatives 5 and 6 attached
to a hydroquinone glycoside containing an a-D-glucosidic or
2-acetamido-2-deoxy-a-D-glucosidic linkage as shown in
Fig. 1.
Chart 1 shows the synthetic procedure of 5 using 4-hy-
droxyphenyl a-glucopyranoside (a-arbutin, 7). The reaction
of allyl bromide (1.2 eq) with the dry sodium salt of 7 in Fig. 1. Saccharide–b-CyD Conjugates (1, 2, 4, 5, 6), Arbutin (3) and DXR
∗ To whom correspondence should be addressed. e-mail: tyama@noguchi.or.jp
© 2009 Pharmaceutical Society of Japan

January 2009
75
a) 1) 0.5 M NaOH aq., H2O, 2) AllBr, DMF, 84%, b) BnBr, NaH, DMF, 99%, c) 1) 9-BBN, THF, 2) H2O2 aq., 0.5 M NaOH aq., 94%, d) Ph3P, I 2, DMF, 35 °C, 89%, e) KOH, n-
Bu4NI, DMF, 69%, f) Pd(OH)2, H2 gas, DMF, 98%.
Chart 1. Synthetic Approach to the D-Glucose–b-CyD Conjugate (5)
a) Yb(OTf)3, BF3·OEt2, 4-allyloxyphenol, CH2Cl2, 61%, b) 1) O3 gas, Ph3P, 2) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH, H2O, 70%, c) Me2P(S)Cl, DIEA, DMF, d)
Pd(OH)2, H2 gas, DMF, 56%.
Chart 2. Synthetic Approach to the 2-Acetamido-2-deoxy-a-D-glucose–b-CyD Conjugate (6)
Chart 2 shows the synthetic procedure of 6. The glycosyla- yield.
tion of 2-acetamido-3,4,6-tri-O-benzyl-2-deoxy-a-D-gluco-
Next, the inclusion associations of 5 and 6 with immobi-
syl acetate (14)24) to 4-allyloxyphenol (0.84 eq) was carried lized DXR were estimated by using an SPR optical biosensor
out using Yb(OTf)3 (0.84 eq) and BF3·OEt2 (0.025 eq) in according to the reported method.22) Figure 2 indicates the
CH2Cl2 at room temperature for 24 h that gave the hydro- kinetic linear plots of 5 and 6. The association rate constant
quinone glycoside derivative 15 in 61% yield.25) The (ka) and dissociation rate constant (kd) of 5 (or 6) were
ozonization of 15 in the presence of Ph3P (10 eq), followed 1.4ꢁ104 Mꢀ1 sꢀ1 (1.3ꢁ103 Mꢀ1 sꢀ1) and 4.1ꢁ10ꢀ2 sꢀ1 (2.7ꢁ
by oxidation using NaClO2 (10 eq)–NaH2PO4 (1.8 eq) in the 10ꢀ3 sꢀ1), and Ka of 5 (or 6), calculated by the relationship of
presence of 2-methyl-2-butene in t-BuOH–H2O afforded Kaꢂka/kd, was 3.5ꢁ105 M (4.6ꢁ105 Mꢀ1). The conjugates 5
ꢀ1
compound 16 in 70% yield. The condensation of 16 with 6- and 6 indicated high inclusion associations for immobilized
monoamino-6-monodeoxy-b-CyD (17) using Me2P(S)Cl (1.6 DXR. The Ka values of 5 and 6 were about 100 times higher
eq) in the presence of N,N-diisopropylethylamine (DIEA) (2 than that of the b-CyD conjugate 4 having no phenyl group
ꢀ1
eq) in DMF for 24 h, followed by the debenzylation using and almost corresponded to those of 1 and 2 of 105—106 M
H2–Pd(OH)2 produced the desired product 6, which was puri- levels. These results suggested the formation of the p–p
fied by gel-filtration using DIAION HP 20 (MeOH) in 56% stacking inclusion complex between the conjugate 5 (or 6)

76
Vol. 57, No. 1
spectrometer. Preparative TLC was performed on Merck silica gel 60GF254.
The column chromatography was conducted using silica gel 60N (40—
50 mm, Kanto Chemical Co., INC.) All anhydrous solvents were purified ac-
cording to the standard methods. The immobilization of DXR on the sensor
cuvette of the SPR optical biosensor was carried out under the same condi-
tions as previously reported.1—3) The amount of immobilized DXR was
1.1 ng/mm2. The interactions of 5 and 6 with the immobilized DXR were
measured at the concentration of 10ꢀ6—10ꢀ5 M in acetate buffer, pH 5.3 at
25 °C.
4-Allyloxyphenyl a-D-Glucopyranoside (8) A 0.5 M NaOH aqueous
solution (8 ml, 4 mmol) was added to 7 (1000 mg, 3.7 mmol). After the reac-
tion mixture was stirred for 3 h at room temperature, the solvent was evapo-
rated under reduced pressure and the reaction residue was crystallized. The
reaction residue was dissolved in DMF (80 ml) and allyl bromide (413 ml,
4.8 mmol) was added. After the reaction mixture was stirred for 70 h, the
solvent was evaporated under reduced pressure. The crude product was puri-
fied by flash column chromatography on silica-gel (chloroform/methanolꢂ
9/1) to afford 8 (963 mg, 84%) as white crystals. mp: 159.0—160.2 °C; [a]D23
Fig. 2. Kinetic Linear Plots for the Immobilized DXR and the Conjugates
5 (ꢀ; rꢂ0.998) and 6 (ꢁ; rꢂ0.988).
1
ꢃ154° (cꢂ1.1, CH3OH); H-NMR (CD3OD) d: 3.40 (1H, t, Jꢂ11.0 Hz, H-
4), 3.53 (1H, m, dd, Jꢂ3.4 Hz, Jꢂ9.7 Hz, H-2), 3.68—3.72 (2H, m, H-5, Ha-
6), 3.76 (1H, dd, Jꢂ4.1 Hz, Jꢂ9.6 Hz, Hb-6), 3.82 (1H, t, Jꢂ8.9 Hz, H-3),
4.48 (2H, dt, Jꢂ1.3 Hz, Jꢂ5.5 Hz, CH2CHꢂCH2), 5.21 (1H, dd, Jꢂ1.4 Hz,
Jꢂ10.3 Hz, CHꢂCHaHb), 5.32 (1H, d, Jꢂ4.1 Hz, H-1), 5.36 (1H, dd,
Jꢂ1.4 Hz, Jꢂ18.5 Hz, CHꢂCHaHb), 6.03 (1H, m, CHꢂCH2), 6.84 (2H, dd,
Jꢂ2.7 Hz, Jꢂ9.6 Hz, Ph), 7.08 (2H, dd, Jꢂ2.1 Hz, Jꢂ13.1 Hz, Ph); 13C-
NMR (CD3OD) d: 62.4 (C-6), 70.3 (CH2CHꢂCH2), 71.6 (C-4), 73.4 (C-2),
74.3 (C-5), 75.0 (C-3), 100.3 (C-1), 116.6 (Ph), 119.6 (Ph), 117.3
(CHꢂCH2), 135.1 (CHꢂCH2), 152.8 (Ph), 155.6 (Ph); HR-MS (ESI) m/z:
335.1124 (Calcd for C15H20O7: MꢃꢃNa, 335.1101).
4-Allyloxyphenyl 2,3,4,6-Tetra-O-benzyl-a-D-glucopyranoside (9) To
a solution of 8 (458 mg, 1.5 mmol) in DMF (30 ml) was added sodium hy-
dride (585 mg, 24.4 mmol) at 0 °C. After the reaction mixture was stirred for
45 min, benzyl bromide (9 ml, 7 mmol) was added. After the reaction mix-
ture was stirred for 21 h at room temperature, the reaction was then
quenched by adding methanol (50 ml) and water (50 ml). The mixture was
extracted with EtOAc (three times) and the combined organic solvent was
dried over anhydrous Na2SO4. The organic solvent was filtered and evapo-
rated under reduced pressure. The crude product was purified by flash col-
umn chromatography on silica-gel (hexane/ethyl acetateꢂ8/1) to afford 9
(973 mg, 99%) as white crystals. mp: 57.6—58.2 °C; [a]D23 ꢃ73° (cꢂ1.3,
CHCl3); 1H-NMR (CDCl3) d: 3.59 (1H, dd, Jꢂ2.0 Hz, Jꢂ10.3 Hz, Ha-6),
3.69—3.73 (2H, m, H-2, Hb-6), 3.75 (1H, t, Jꢂ9.0 Hz, H-4), 3.91—3.93
(1H, m, H-5), 4.18 (1H, t, Jꢂ8.9 Hz, H-3), 4.40 (1H, d, Jꢂ12.4 Hz, CH2Ph),
4.47—4.50 (3H, m, CH2CHꢂCH2, CH2Ph), 4.58 (1H, d, Jꢂ11.7 Hz,
CH2Ph), 4.68 (1H, d, Jꢂ12.3 Hz, CH2Ph), 4.79 (1H, d, Jꢂ11.7 Hz, CH2Ph),
4.85 (1H, d, Jꢂ11.0 Hz, CH2Ph), 4.87 (1H, d, Jꢂ11.7 Hz, CH2Ph), 5.04 (1H,
d, Jꢂ11.0 Hz, CH2Ph), 5.27 (1H, dd, Jꢂ1.3 Hz, Jꢂ10.3 Hz, CHꢂCHaHb),
5.36 (1H, d, Jꢂ3.4 Hz, H-1), 5.40 (1H, dd, Jꢂ1.4 Hz, Jꢂ17.2 Hz, CHꢂ
CHaHb), 6.04 (1H, m, CHꢂCH2), 6.82 (2H, dd, Jꢂ2.8 Hz, Jꢂ6.9 Hz, Ph),
7.00 (2H, dd, Jꢂ2.1 Hz, Jꢂ6.9 Hz, Ph), 7.24—7.39 (20H, m, Ph); 13C-NMR
(CDCl3) d: 68.3 (C-6), 69.3 (CH2CHꢂCH2), 70.7 (C-5), 73.2 (CH2), 73.4
Fig. 3. NOE Interactions Observed in the Inclusion Complex of 5 and
DXR
1
and DXR. In the measurement of the H-NOESY spectra of
the mixed sample of 5 and DXR (1 : 1) in D2O, the NOE in-
teractions between the protons (Hx; d; 6.72 ppm and Hy; d;
7.01 ppm) on the phenyl group and the protons (Ha and Hc;
br; 7.20 ppm and Hb; br; 7.46 ppm) on DXR were observed
as shown in Fig. 3.3) The observation indicated that these
protons were located close to each other and there was a
strong possibility of the formation of the stacking complex
between the phenyl group of 5 and the included DXR, as we
speculated. The phenyl group in the conjugates 5 and 6
would also contribute to the increase in the inclusion associa-
tions for the immobilized DXR.
Conclusions
We demonstrated the synthesis of two novel b-CyD deriv- (CH2), 75.1 (CH2), 75.7 (CH2), 77.4 (C-4), 79.7 (C-2), 81.9 (C-3), 96.3 (C-
atives 5 and 6 attached to a hydroquinone glycoside. The hy-
1), 115.4 (Ph), 117.5 (CHꢂCH2), 118.1 (Ph), 127.6—128.4 (Ph), 133.4
(CHꢂCH2), 137.8 (Ph), 138.0 (Ph), 138.2 (Ph), 138.8 (Ph), 150.8 (Ph),
droquinone glycosides 7 and 15 containing an a-D-glucosidic
or 2-acetamido-2-deoxy-a-D-glucosidic linkage were syn-
thetically useful components for providing these CyDs. The
SPR analyses indicated that the conjugates 5 and 6, which
had the phenyl group derived from a hydroquinone glycoside
in the spacers between the saccharide and b-CyD, indicated
154.0 (Ph); HR-MS (ESI) m/z: 695.2985 (Calcd for C43H44O7: MꢃꢃNa,
695.2979).
4-O-(3-Hydroxypropyl)phenyl 2,3,4,6-Tetra-O-benzyl-a-D-glucopyra-
noside (10) To a solution of 9 (303 mg, 0.45 mmol) in THF (7 ml) was
added in 0.5 M 9-BBN THF solution (2 ml, 1 mmol) at 0 °C. After the reac-
tion mixture was stirred for 5 h at room temperature, a 0.5 M NaOH aqueous
solution (2.7 ml, 1.4 mmol) and a 30% H2O2 aqueous solution (0.46 ml,
4.5 mmol) were added. After the reaction mixture was stirred for 48 h, the
reaction was then quenched by adding water (10 ml). The mixture was ex-
tracted with EtOAc (three times) and the combined organic solvent was
dried over anhydrous Na2SO4. The organic solvent was filtered and evapo-
rated under reduced pressure. The crude product was purified by flash col-
umn chromatography on silica-gel (hexane/ethyl acetateꢂ3/1) to afford 10
(291 mg, 94%) as a colorless oil. [a]D23 ꢃ11° (cꢂ1.1, CHCl3); 1H-NMR
ꢀ1
the excellent inclusion associations of 3.5—4.6ꢁ105 M for
the immobilized DXR. The newly synthesized b-CyD deriva-
tives 5 and 6, which have high DXR-transportabilities, are
promising models of drug-carrying molecules.
Experimental
General The 1H-NMR (600 MHz) and 13C-NMR (150 MHz) spectra
were recorded by a JEOL ECA-600 spectrometer. The NOESY experiment (CDCl3) d: 1.74 (1H, s, OH), 1.99 (2H, m, CH2CH2OH), 3.53 (1H, dd,
was done at 25 °C using a mixing time of 2 ms. Melting points (mp) were
measured by a B-545 (BÜCHI Labortechnik AG) and are uncorrected. Opti-
Jꢂ1.3 Hz, Jꢂ10.3 Hz, Ha-6), 3.64—3.69 (2H, m, H-2, Hb-6), 3.71 (1H, t,
Jꢂ8.9 Hz, H-4), 3.82 (2H, m, CH2CH2CH2OH), 3.85—3.88 (1H, m, H-5),
cal rotations were recorded by a JASCO DIP-360 digital polarimeter. The 4.03 (2H, t, Jꢂ5.5 Hz, CH2OH), 4.13 (1H, t, Jꢂ9.6 Hz, H-3), 4.36 (1H, d,
HR-MS were obtained using a Mariner spectrometer (PerSeptive Biosystems Jꢂ11.7 Hz, CH2Ph), 4.44 (1H, d, Jꢂ10.3 Hz, CH2Ph), 4.53 (1H, d,
Inc.). The MALDI-TOF-MS spectra were recorded by a Voyager DE STR Jꢂ12.3 Hz, CH2Ph), 4.63 (1H, d, Jꢂ11.7 Hz, CH2Ph), 4.75 (1H, d,

January 2009
77
Jꢂ11.7 Hz, CH2Ph), 4.81 (1H, d, Jꢂ11.0 Hz, CH2Ph), 4.83 (1H, d, preparative silica-gel TLC (ethyl acetate/hexaneꢂ2/1) to give 15 (389 mg,
Jꢂ11.0 Hz, CH2Ph), 5.00 (1H, d, Jꢂ11.0 Hz, CH2Ph), 5.31 (1H, d, 61%) as white crystals. mp: 195.0—197.0 °C; [a]D23 ꢃ159° (cꢂ1.0, CHCl3);
Jꢂ3.4 Hz, H-1), 6.76 (2H, d, Jꢂ8.9 Hz, Ph), 6.96 (2H, d, Jꢂ8.9 Hz, Ph),
1H-NMR (CDCl3) d: 1.58 (3H, s, CH3), 3.63 (1H, dd, Jꢂ2.0 Hz, Jꢂ11.0 Hz,
7.20—7.34 (20H, m, Ph); 13C-NMR (CDCl3) d: 32.0 (CH2CH2OH), 60.7 Ha-6), 3.76 (1H, dd, Jꢂ3.4 Hz, Jꢂ11.0 Hz, Hb-6), 3.34—3.90 (2H, m, H-3,
(CH2CH2CH2OH), 66.4 (CH2OH), 68.3 (C-6), 70.7 (C-5), 73.3 (CH2), 73.4 H-4), 3.92—3.94 (1H, m, H-5), 4.38 (1H, dt, Jꢂ2.7 Hz, Jꢂ8.9 Hz, H-2),
(CH2), 75.1 (CH2), 75.8 (CH2), 77.5 (C-2), 79.7 (C-4), 82.0 (C-3), 96.3 (C-
4.45—4.47 (3H, m, CH2CHꢂCH2, CHaHbPh), 4.57 (1H, d, Jꢂ10.3 Hz,
1), 115.2 (Ph), 118.1 (Ph), 127.6—128.45 (Ph), 137.8—138.7 (Ph), 150.9 CH2Ph), 4.61 (1H, d, Jꢂ11.7 Hz, CH2Ph), 4.70 (1H, d, Jꢂ12.3 Hz, CH2Ph),
(Ph), 154.1 (Ph); HR-MS (ESI) m/z: 713.3099 (Calcd for C43H46O8: 4.83 (1H, d, Jꢂ10.4 Hz, CH2Ph), 4.90 (1H, d, Jꢂ11.7 Hz, CH2Ph), 5.27—
MꢃꢃNa, 713.3085).
4-O-(3-Iodoxypropyl)phenyl 2,3,4,6-Tetra-O-benzyl-a-D-glucopyra-
noside (11) To a solution of 10 (100 mg, 0.14 mmol) in DMF (3 ml) were (2H, d, Jꢂ9.0 Hz, Ph), 6.90 (2H, d, Jꢂ8.9 Hz, Ph), 7.20—7.37 (15H, m, Ph);
added triphenylphosphine (156 mg, 0.6 mmol) and iodine (148 mg, 0.58
mmol) at 35 °C under argon. After the reaction mixture was stirred for 2 h,
5.31 (2H, m, CHꢂCHaHb, NH), 5.34 (1H, dd, Jꢂ2.1 Hz, Jꢂ17.9 Hz,
CHꢂCHaHb), 5.41 (1H, d, Jꢂ3.4 Hz, H-1), 6.03 (1H, m, CHꢂCH2), 6.81
13C-NMR (CDCl3) d: 23.4 (CH3), 52.5 (C-2), 68.4 (C-6), 69.3
(CH2CHꢂCH2), 71.6 (C-5), 73.4 (CH2Ph), 74.8 (CH2Ph), 75.1 (CH2Ph),
the reaction was then quenched by adding water (10 ml). The mixture was 78.3 (C-4), 79.9 (C-3), 92.2 (C-1), 115.6 (Ph), 117.6 (CHꢂCH2), 117.9
extracted with EtOAc (three times) and the combined organic solvent was (Ph), 127.6—128.7 (Ph), 133.3 (CHꢂCH2), 134.1—166.8 (Ph), 169.8
dried over anhydrous Na2SO4. The organic solvent was filtered and evapo- (CꢂO); HR-MS (ESI) m/z: 646.2787 (Calcd for C38H41NO7: MꢃꢃNa,
rated under reduced pressure. The crude product was purified by preparative 646.2775).
silica-gel TLC (hexane/ethyl acetateꢂ6/1) to afford 11 (103 mg, 89%) as a
4-O-(Carboxymethyl)phenyl 2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-
a-D-glucopyranoside (16) Ozone was bubbled through a stirred solution
of 15 (389 mg, 0.62 mmol) in CH2Cl2 (15 ml) at ꢀ78 °C for 2 h. After tri-
1
colorless oil. [a]D23 ꢃ102° (cꢂ1.1, CHCl3); H-NMR (CDCl3) d: 2.25 (2H,
m, CH2CH2I), 3.37 (2H, t, Jꢂ6.9 Hz, CH2I), 3.59 (1H, dd, Jꢂ2.0 Hz,
Jꢂ10.3 Hz, Ha-6), 3.69—3.74 (2H, m, H-2, Hb-6), 3.75 (1H, t, Jꢂ10.3 Hz, phenylphosphine (497 mg, 1.9 mmol) was added at ꢀ78 °C and the reaction
H-4), 3.91 (1H, m, H-5), 3.98 (2H, t, Jꢂ5.5 Hz, CH2CH2CH2I), 4.18 (1H, t, temperature was raised to room temperature, the reaction mixture was
Jꢂ8.9 Hz, H-3), 4.41 (1H, d, Jꢂ12.4 Hz, CH2Ph), 4.49 (1H, d, Jꢂ11.0 Hz, stirred for 2 h. The solvent was then evaporated under reduced pressure. To a
CH2Ph), 4.58 (1H, d, Jꢂ11.7 Hz, CH2Ph), 4.68 (1H, d, Jꢂ11.7 Hz, CH2Ph), solution of the crude product in t-butylalcohol (10 ml)–H2O (2 ml) was
4.79 (1H, d, Jꢂ12.4 Hz, CH2Ph), 4.85 (1H, d, Jꢂ10.4 Hz, CH2Ph), 4.87 (1H, added NaClO2 (561 mg, 6.2 mmol), NaH2PO4 (116 mg, 0.74 mmol) and 2-
d, Jꢂ11.0 Hz, CH2Ph), 5.04 (1H, d, Jꢂ10.3 Hz, CH2Ph), 5.36 (1H, d, methyl-2-butene (305 ml, 2.9 mmol). After the reaction mixture was stirred
Jꢂ3.4 Hz, H-1), 6.80 (2H, d, Jꢂ8.9 Hz, Ph), 7.00 (2H, d, Jꢂ8.9 Hz,
for 15 h, the reaction was quenched by adding 2 M HCl (1 ml) and water
(5 ml). After the reaction mixture was extracted with CH2Cl2 (three times),
Ph), 7.13—7.39 (20H, m, Ph); 13C-NMR (CDCl3) d: 2.6 (CH2I), 33.0
(CH2CH2I), 67.7 (CH2CH2CH2I), 68.3 (C-6), 70.7 (C-5), 73.3 (CH2), 73.4 the combined organic solvent was dried over anhydrous Na2SO4. The or-
(CH2), 75.1 (CH2), 75.8 (CH2), 77.4 (C-4), 79.7 (C-2), 82.0 (C-3), 96.3 (C-
ganic solvent was filtered and evaporated under reduced pressure. The crude
1), 115.3 (Ph), 118.1 (Ph), 127.6—128.5 (Ph), 137.8—138.8 (Ph), 150.9 product was purified by preparative silica-gel TLC (chloroform/methanolꢂ
(Ph), 154.0 (Ph); HR-MS (ESI) m/z: 823.2098 (Calcd for C43H45O7I:
MꢃꢃNa, 823.2102).
5/1) to afford 16 (281 mg, 70%) as white crystals. mp: 165.0—165.9 °C;
1
[a]D23 ꢃ79° (cꢂ1.0, CHCl3); H-NMR (CDCl3) d: 1.90 (3H, s, CH3), 3.63
Heptaxis-(2,3-di-O-benzyl)-6B,C,E,F,G-penta-O-benzyl-6A-O-(3-O-[4-O- (1H, d, Jꢂ10.9 Hz, Ha-6), 3.77 (1H, dd, Jꢂ4.2 Hz, Jꢂ11.0 Hz, Hb-6), 3.83
{2,3,4,6-tetra-O-benzyl-a-D-glucopyranoside-1-yl}phenyl]propane-1-
yl)b-cyclodextrin or Heptaxis-(2,3-di-O-benzyl)-6B,C,E,F,G-penta-O-ben-
zyl-6D-O-(3-O-[4-O-{2,3,4,6-tetra-O-benzyl-a-D-glucopyranoside-1-
yl}phenyl]propane-1-yl)b-cyclodextrin (13) To a solution of 11 (84 mg,
(3H, m, H-4, CH2COOH), 3.94—3.98 (2H, m, H-3, H-5), 4.37 (1H, s, NH),
4.38 (1H, dt, Jꢂ3.4 Hz, Jꢂ11.0 Hz, H-2), 4.46 (1H, d, Jꢂ12.4 Hz, CH2Ph),
4.54 (1H, d, Jꢂ10.3 Hz, CH2Ph), 4.61 (1H, d, Jꢂ12.4 Hz, CH2Ph), 4.76 (1H,
d, Jꢂ11.0 Hz, CH2Ph), 4.81 (1H, d, Jꢂ11.0 Hz, CH2Ph), 4.89 (1H, d,
0.1 mmol), 12 (75 mg, 0.026 mmol) in DMF (4 ml) were added KOH Jꢂ11.0 Hz, CH2Ph), 5.36 (1H, d, Jꢂ4.2 Hz, H-1), 6.96 (2H, d, Jꢂ9.0 Hz,
(179 mg, 3.19 mmol) and n-Bu4NI (4.9 mg, 0.013 mmol). After the reaction
Ph), 7.18 (2H, d, Jꢂ7.6 Hz, Ph), 7.29—7.39 (15H, m, Ph); 13C-NMR
mixture was stirred for 64 h, the reaction was then quenched by adding water (CDCl3) d: 22.5 (CH3), 52.6 (C-2), 67.4 (C-6), 71.3 (C-5), 73.2 (CH2Ph),
(10 ml). The mixture was extracted with EtOAc (three times) and the com- 74.8 (CH2Ph), 74.9 (CH2Ph), 78.0 (CH2COOH), 78.1 (C-4), 79.9 (C-3), 97.2
bined organic solvent was dried over anhydrous Na2SO4. The organic sol- (C-1), 115.9 (Ph), 117.9 (Ph), 127.5—128.3 (Ph), 133.0—138.2 (Ph), 150.9
vent was filtered and evaporated under reduced pressure. The crude product (Ph), 180.0 (CꢂO); HR-MS (ESI) m/z: 664.2508 (Calcd for C37H39NO9:
was purified by preparative silica-gel TLC (hexane/ethyl acetateꢂ3/1) to af- MꢃꢃNa, 664.2517).
1
ford 13 (64 mg, 69%) as a colorless oil. H-NMR (CDCl3) d: 1.87 (2H, m,
4-O-(2-Acetamido-2-deoxy-a-D-glucopyranoside-1-yl)phenyl-N-(6A-
CH2CH2OPh), 3.36—5.39 (106H, m, CyD, H-1, H-2, H-3, H-4, H-5, H-6,
deoxy-b-cyclodextrin-6A-yl)acetamide (6) To a solution of 16 (41 mg,
CH2CH2CH2OPh, CH2Ph), 6.73 (2H, dd, Jꢂ3.4 Hz, Jꢂ8.9 Hz, Ph), 6.96 0.062 mmol) in DMF (1.5 ml) were added dimethylphosphinothioyl chloride
(2H, dd, Jꢂ1.4 Hz, Jꢂ8.9 Hz, Ph), 7.05—7.38 (115H, m, Ph); 13C-NMR (13 mg, 0.097 mmol) and DIEA (21 ml, 0.12 mmol). After the reaction mix-
(CDCl3) d: 14.2, 21.0, 29.5, 60.3—82.0, 96.3, 98.3—98.7, 115.1, 118.1, ture was stirred for 40 min, 17 (84 mg, 0.074 mmol) in DMF (1.5 ml) was
126.9—128.4, 137.8—139.3, 150.7, 154.2; MALDI-TOF-MS m/z: 3540.6 added. After the reaction mixture was stirred for 24 h, the solvent was evap-
(Calcd for C218H228O42: MꢃꢃNa, 3540.6).
orated under reduced pressure. The resulting reaction mixture was washed
with diethyl ether (eight times) and dissolved in DMF (3 ml). Palladium hy-
droxide (29 mg, 0.18 mmol) was added to the solution and hydrogen was
6A-O-(3-O-[4-O-{a-D-Glucopyranoside-1-yl}phenyl]propane-1-yl)b-
cyclodextrin (5) To a solution of 13 (56 mg, 0.015 mmol) in DMF (5 ml)
was added palladium hydroxide (76 mg, 0.49 mmol). Hydrogen was bubbled bubbled through it for 24 h. After the solvent was filtered and evaporated
through the solution for 6 h. After the solvent was filtered and evaporated under reduced pressure, the crude product was isolated by adsorption on HP
under reduced pressure, the crude product was isolated by adsorption on LH
20 (DIAION) followed by eluting with methanol to afford 6 (52 mg, 56%) as
1
20 followed by eluting with methanol to afford 5 (22 mg, 98%) as white white crystals. mp: 281.0—283.0 °C; H-NMR (D2O) d: 1.92 (3H, s, CH3),
crystals. mp: 284.1—286.0 °C; [a]D23 ꢃ97° (cꢂ1.0, CH3OH); 1H-NMR 3.21—3.93 (51H, m, CyD, H-2, H-3, H-4, H-5, H-6, CH2C(O)NH), 4.65—
(D2O) d: 1.88 (2H, m, CH2CH2OPh), 3.43—4.08 (52H, m, CyD-2, CyD-3, 4.96 (7H, m, CyD), 5.59 (1H, d,Jꢂ3.4 Hz, H-1), 6.63 (2H, d, Jꢂ8.9 Hz, Ph),
CyD-4, CyD-5, CyD-6, H-2, H-3, H-4, H-5, H-6, CH2CH2CH2OPh), 4.90— 7.01 (2H, d, Jꢂ9.0 Hz, Ph); MALDI-TOF-MS m/z: 1510.1 (Calcd for
5.06 (7H, m, CyD-1), 5.56 (1H, d, Jꢂ2.1 Hz, H-1), 6.82 (2H, d, Jꢂ8.2 Hz,
Ph), 7.12 (2H, d, Jꢂ8.9 Hz, Ph); 13C-NMR (D2O) d: 29.4, 60.2—74.5,
81.2—82.9, 98.2, 101.4—102.7, 115.9—118.3, 151.3, 154.7; MALDI-TOF-
MS m/z: 1469.2 (Calcd for C57H90O42: MꢃꢃNa, 1469.5).
C58H90N2O42: MꢃꢃNa, 1509.5).
Acknowledgment We thank Ezaki Glico Co., Ltd. for the gift of a-ar-
butin.
4-Allyloxyphenyl 2-Acetamido-3,4,6-tri-O-benzyl-2-deoxy-a-D-gluco-
pyranoside (15) Yb(OTf)3 (635 mg, 1 mmol) was added to a solution of
14 (653 mg, 1.2 mmol), 4-allyloxyphenol (153 mg, 1 mmol) and BF3·OEt2
(3.9 ml, 0.03 mmol) in CH2Cl2 (8 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 sat. NaHCO3 solution (5 ml). The reaction mixture was ex-
tracted with CH2Cl2, and the organic layer was washed with water and a sat.
NaCl solution. After the organic layer was dried over Na2SO4, the solvent
was evaporated under reduced pressure. The crude product was purified by
References and Notes
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(1 : 1) also strongly indicated the formation of the stacking complex

78
Vol. 57, No. 1
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ꢀ1
similarly had excellent inclusion associations of approximately 105
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2-deoxy-a-D-glucopyranosidic linkages. The detailed reaction speci-
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