Synthesis of an ether-linked alkyl 5a-carba-β-D-glucoside, a 5a-carba-β-D-galactoside, a 2-acetamido-2-deoxy-5a-carba-β-D-glucoside, and an alkyl 5a′-carba-β-lactoside

Article abstract of DOI:10.1016/S0008-6215(02)00294-X

For the purpose of providing biologically stable building blocks for the biocombinatorial synthesis using a living cell, some ether-linked alkyl 5a-carba-β-D-glycoside primers were prepared. The key step of the synthesis was coupling of 1-bromo-n-alkanes with the 1-OH unprotected derivatives of 5a-carba-sugar analogues of D-glucose, D-galactose, and 2-acetamido-2-deoxy-D-glucose (N-acetyl-D-glucosamine), in DMF in the presence of sodium hydride. Alternatively, alkyl carba-lactoside was synthesized by incorporation of a 5a-carba-β-D-galactose residue into the 4-position of dodecyl β-D-glucopyranoside. A strong and specific inhibition of β-galactosidase (K_i 0.67 μM, bovine liver) was found for dodecyl 5a-carba-β-D-galactopyranoside.

Full text of DOI:10.1016/S0008-6215(02)00294-X

Carbohydrate Research 337 (2002) 1979–1992
www.elsevier.com/locate/carres
Synthesis of an ether-linked alkyl 5a-carba-b-
D
-glucoside, a
5a-carba-b-
D
-galactoside, a
2-acetamido-2-deoxy-5a-carba-b-
D-glucoside, and an alkyl
5a%-carba-b-lactoside
Seiichiro Ogawa,* Hiroshi Aoyama, Toshinori Sato
Department of Applied Chemistry, Faculty of Science and Technology, Keio Uni6ersity, Hiyoshi, Kohoku-ku, Yokohama, 223-8522 Japan
Received 1 April 2002; accepted 24 June 2002
Dedicated to Professor Derek Horton on the occasion of his 70th birthday
Abstract
For the purpose of providing biologically stable building blocks for the biocombinatorial synthesis using a living cell, some
ether-linked alkyl 5a-carba-b- -glycoside primers were prepared. The key step of the synthesis was coupling of 1-bromo-n-alkanes
with the 1-OH unprotected derivatives of 5a-carba-sugar analogues of -glucose, -galactose, and 2-acetamido-2-deoxy- -glucose
(N-acetyl- -glucosamine), in DMF in the presence of sodium hydride. Alternatively, alkyl carba-lactoside was synthesized by
incorporation of a 5a-carba-b- -glucopyranoside. A strong and specific
-galactopyranoside. © 2002 Elsevier
D
D
D
D
D
D
-galactose residue into the 4-position of dodecyl b-
D
inhibition of b-galactosidase (Ki 0.67 mM, bovine liver) was found for dodecyl 5a-carba-b-
Science Ltd. All rights reserved.
D
Keywords: Sugar mimics; Carba-sugars; Alkyl 5a-carba-glycosides, ether-linked; Biocombinatorial synthesis using a living cell; b-Galactosidase
inhibitor
1. Introduction
effectively from the cell medium. Therefore, tagged
hydrophobic-aglycon moieties of the primers would be
desirable to remain unchanged throughout successive
biochemical processes, allowing easy recovery of
oligosaccharides formed. Since certain carba-sugars2
and oligosaccharides3 have been well demonstrated to
act as substrate analogues of some glycosyltransferases,
unhydrolyzable glycoside-mimics 5a-carba-glycosides
are now expected to be efficient substrates that can be
taken up in a variety of cells. Four structures targeted
for synthesis and evaluation are 1–4.
Biocombinatorial synthesis using a living cell has
become an important tool for generating libraries of
oligosaccharides and glycopolymers with desirable bio-
logical activities.1 The standard procedure successfully
carried out so far is to incorporate the building blocks,
glycoside-based primers, into cells in which the primers
act as substrates with cellular biosynthetic processes,
leading to construction of a large number of oligosac-
charides. The building blocks used are amphipathic
glycosides, which are hydrophilic hexose moieties with
hydrophobic aglycons of various alkyl chain lengths.
After incubation of these primers, there should be
important processes to isolate oligosaccharides formed
Simple ether-linked methyl, ethyl, and isopropyl
carba-hexopyranoside derivatives were previously pre-
pared when some reactivity of the unsaturated carba-
hexopyranosyl bromides4 needed to be elucidated. No
alkyl 5a-carba-glycosides have so far been synthesized
systematically, except for the preparation of an octyl
N-acetyl-5a-carba-glucosaminide derivative that was
used as a building block of octyl N-acetyl-5a-carba-b-
* Corresponding author. Present address. Department of
Biosciences and Bioinformatics. Fax: +81-45-566-1559
E-mail address: ogawa@bio.keio.ac.jp (S. Ogawa).
D
-isolactosaminide.5
0008-6215/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(02)00294-X

1980
S. Ogawa et al. / Carbohydrate Research 337 (2002) 1979–1992
protected carba sugar derivatives used in this study
were provided starting from intermediates previously
reported by us.
According to the preceding results1 that dodecyl b-
D-
glucoside6 showed high reaction efficiency involving cell
uptake, glycosylation, and secretion process, dodecyl
ether groups have been chosen for the appropriate
aglycons of 5a-carba-b-
deoxy-5a-carba-b- -glucoside, and 5a%-carba-b-lac-
toside. However, since the efficiency of octyl
b- -glucoside as a primer had recently been demon-
strated, the octyl ether group was employed for the
-glucoside. Certain toxic effects
D-galactoside, 2-acetamido-2-
D
D
aglycon of 5a-carba-b-
D
of dodecyl b-glucoside toward cells suggested avoiding
the dodecyl group.
Octyl 5a-carba-i- -glucopyranoside (1).—Acetolysis
D
of (1S)-2-exo,3-endo-diacetoxy-5-endo-acetoxymethyl-
7-oxabicyclo[2.2.1]heptane7 (5) produced, after chro-
matography, penta-O-acetyl-5a-carba-b-
D-glucopyran-
ose (6, 42%) and a- -galactopyranose (7, 43%) (Scheme
D
1). Zemple´n O-deacetylation of 6, followed by treat-
ment with a,a-dimethoxytoluene–TsOH in DMF, gave
the 4,6-O-benzylidene derivative 8 (59%). Isopropylide-
nation of 8 with 2,2-methoxypropane8 in DMF gave,
after chromatography, the 1,2- (9, 48%) and 2,3-O-iso-
propylidene derivatives (11, 52%), which were further
characterized as the corresponding acetates 10 and 12.
Treatment of 9 with TsOH in DMF led to a ca. 1:1
equilibrium mixture of positional isomers, from which
11 was obtained in 45% yield, along with 9 (45%).
Therefore the desired 11 was practically furnished in
ꢀ70% yield through the above process. Treatment of
2. Results and discussion
Construction of ether-linked 5a-carba-hexoside
derivatives has been conducted by coupling between the
1-OH unprotected derivatives of 5a-carba-D-hexoses
and 1-bromo-n-alkanes in the presence of sodium hy-
dride in DMF, in order to establish a generally applica-
ble procedure to obtain various 5a-carba-glycosides. All
Scheme 1. Reagents and conditions: (a) 15:9:1 HOAc–Ac2O–concd H2SO4, 20 h, 80 °C; (b) 1 M NaOMe, MeOH, rt;
a,a-dimethoxytoluene, p-TsOH, DMF, 3 h, 50 °C; (c) 2,2-dimethoxypropane, p-TsOH, DMF, 1 h, 70 °C; (d) Ac2O, pyridine, rt;
(e) NaH, 1-bromooctane (2 molar equiv), DMF, 5 h, rt; (f) 80% aq HOAc, 50 °C; Ac2O, pyridine; (g) 1 M NaOMe, MeOH.

S. Ogawa et al. / Carbohydrate Research 337 (2002) 1979–1992
1981
Scheme 2. Reagents and conditions: (a) 1 M NaOMe, MeOH, rt; a,a-dimethoxytoluene, p-TsOH, DMF, 3 h, 50 °C; (b)
2-methoxypropene, p-TsOH, DMF, 0 °C; Ac2O, pyridine, rt; (c) 1 M NaOMe, rt; MsCl (3 molar equiv), pyridine, rt; 80% aq
HOAc, 50 °C; MeOCH2Cl (8 molar equiv), DMAP, CH2Cl2, 40 °C; (d) KOAc (20 molar equiv), DMF, 100 °C; (e) 1 M NaOMe,
MeOH; (f) NaH, 1-bromododecane (3 molar equiv), DMF, rt; (g) 4 M HCl, 60 °C; Ac2O, pyridine, rt; (h) 1 M NaOMe, 1:2
MeOH–CH2Cl2.
11 with sodium hydride and 1-bromooctane (2 molar
equiv) in DMF at room temperature gave octyl 5a-
derivatives 23 (56%) and 24 (18%) (Scheme 3), having
the b-gluco and b-gulo configuration, respectively, fol-
lowing the procedure9 previously reported for the
racemic analogue. Compound 23 was hydrogenated
with Raney nickel and acetylated to give the tri-N,O-
acetyl derivative 25 (67%), O-deacetylation of which
gave the diol 26 (ꢀ100%). Selective benzylation of 26
was carried out by treatment with a molar equiv of
benzyl bromide and sodium hydride in DMF at 0 °C,
and the resulting two monobenzyl ethers 27 (3%) and
29 (41%), and dibenzyl ether 31 (32%) were isolated by
chromatography. The structures of 27 and 29 were
carba-b- -glucopyranoside derivative 13 (80%), which
D
was deprotected by treatment with aqueous acetic acid
followed by acetylation, giving the tetraacetyl derivative
14 (98%). O-Deacetylation gave the free glucoside 1
(88%).
Dodecyl 5a-carba-i-D-galactopyranoside (2).—The
4,6-O-benzylidene derivative 15 of 5a-carba-a-
D-galac-
tose was similarly prepared from 7 in 57% yield
(Scheme 2). Acetalation of 15 was effected by using
2-methoxypropene8 to produce, after acetylation, the
1,2- (16, 38%) and 2,3-O-isopropylidene derivatives (17,
59%). Compound 17 was O-deacetylated, and the re-
sulting alcohol was mesylated conventionally to the
mesyl ester, the protecting groups of which were subse-
quently replaced by methoxymethyl groups (“18,
67%). Nucleophilic substitution of 18 with potassium
acetate in DMF at 100 °C procceded slowly to give a
sole acetate 19 (77%), which was O-deacetylated (“20,
88%) and subsequently treated with sodium hydride
and 1-bromododecane in DMF to give protected dode-
1
readily established on the basis of the H NMR spectra
by converting them into the acetyl derivatives 28 and
30. The 3-O-benzyl ether 29 was treated with 1-bro-
mododecane–NaH in DMF as in the preparation of
21, giving a 68% yield of 32. The resulting ether was
hydrogenolyzed with 10% Pd/C in ethanol containing
small amount of 1 M hydrochloric acid, followed by
acetylation, yielding the per-O-acetyl derivative 33
(95%), which was O-deacetylated to give the free gly-
coside 3 (99%).
cyl 5a-carba-b-
D
-galactopyranoside 21 (79%). Hydroly-
Dodecyl 5a%-carba-i-lactoside (4).—According to the
standard procedure10 to prepare ether-linked 5a%-car-
balactose, coupling of 1,2-anhydro-3-O-benzyl-4,6-ben-
sis of 21 with 4 M hydrochloric acid, followed by
acetylation, gave the pentaacetyl derivative 22 (72%),
which was O-deacetylated to afford the free galactoside
2 (92%).
zylidene-5a-carba-b-
-mannopyranose11,12 (38) and the
D
4-unprotected derivative of dodecyl b-D-glucopyran-
oside was conducted to synthesize the target com-
Dodecyl 2-acetamido-2-deoxy-5a-carba-i-
D-glucopy-
ranoside (3).—Base-catalyzed nitroaldol condensation
of the dialdehyde generated by periodate oxidation of 8
pound. Thus, dodecyl 2,3-di-O-benzyl-4,6-O-benzyl-
idene-
D
-glucopyranoside (35) was prepared convention-
produced
two
2-deoxy-2-nitro-5a-carba-
D-hexose
ally from dodecyl b-
D
-glucopyranoside6 (Scheme 4).

1982
S. Ogawa et al. / Carbohydrate Research 337 (2002) 1979–1992
Scheme 3. Reagents and conditions: (a) NaIO4, NaHCO3, H2O; MeNO2, NaOMe, MeOH, rt; (b) H2, Raney Ni, MeOH, Ac2O;
Ac2O, pyridine; (c) 1 M NaOMe, MeOH, rt; (d) NaH, BzlBr (molar equiv), DMF, 0 °C; (e) Ac2O, pyridine, rt; (f) NaH,
1-bromododecane (3 molar equiv), DMF, rt; (g) H2, 10% Pd/C, 1:1 EtOH–EtOAc, HCl; Ac2O, pyridine, rt; (h) 1 M NaOMe, 1:2
MeOH–CH2Cl2.
Scheme 4. Reagents and conditions: (a) 1 M NaOMe, MeOH; a,a-dimethoxytoluene, p-TsOH, DMF, 50 °C; NaH, BzlBr, DMF,
rt; (b) BH3·Et3N, AlCl3, THF, 0 °C“rt; (c) Ac2O, pyridine, rt.
Treatment of 35 with borane·triethylamine and alu-
minum chloride in THF afforded the 2,3,6-tribenzyl
ether 36. Condensation of 36, after treatment with 3
molar equiv of sodium hydride, with 38 (2 molar equiv)
in DMF was carried out for 5 days at 70 °C, giving the
coupled compound 39 (84%), together with 36 (12%)
recovered (Scheme 5). The structure was confirmed by
converting it into the acetate 40. Oxidation of 39 with
dimethyl sulfoxide in acetic anhydride yielded the ke-
tone (41, 98%), which underwent epimerization
smoothly by treatment with DBU in toluene at 70 °C,
giving a ca. 1:3 mixture of C-1 epimers. Chromatogra-
phy afforded the major ketone 42 in 67% isolated yield.
Selective reduction of 42 was effected by treatment with
borane·THF at 0 °C to give, after acetylation, a 52%
yield of the desired 5a-carba-b-glucosyl-b-glucoside 43,
together with the b-mannosyl 44 (9%). The structures of
43 and 44 were easily differentiated by the downfield
shift (ꢀ0.5 ppm) of the signal for the axial H-5a%,
attributable to deshielding effect due to the axial 2%-ace-
toxyl group of the latter. Removal of the benzylidene
group of 43 with aqueous acetic acid, followed by
mesylation, led to the dimesylate 45 (59%). Nucle-
ophilic substitution of 45 with excess of sodium acetate
in DMF proceeded very slowly at 120 °C to afford the
protected 5a%-carbalactoside derivative 46 (91%), which
was similarly hydrogenolyzed, followed by acetylation,
to give the heptaacetyl derivative 47 of dodecyl 5a%-
carba-b-lactoside. Zemple´n O-deacetylation afforded
the carba-disaccharide 4 (96%).
Biological assay.—Before examining a feasibility† of
ether-linked carba-hexosides as candidates for the
† Very recently, alkyl carba-glycosides 1–4 have been
shown to be useful as good primers for biocombinatorial
glycosylation, involving efficient uptake in mouse melanoma
C-13 cells.13 Interestingly, compounds 1 and 3 produced 2–4
times more glycosphingolipids, containing carba-sugar
residues, than the corresponding glycoside primers did.

S. Ogawa et al. / Carbohydrate Research 337 (2002) 1979–1992
1983
Scheme 5. Reagents and conditions: (a) 38 (2 molar equiv), NaH, 15-crown-5 ether, DMF, 5 days, 70 °C; (b) Ac2O, pyridine, rt;
(c) Ac2O, Me2SO, rt; (d) DBU, toluene, 1 h, 70 °C; (e) 1 M BH3·THF, 0 °C“rt; Ac2O, pyridine, rt; (f) 80% aq HOAc; MsCl (4
molar equiv), pyridine, rt; (g) NaOAc (40 molar equiv), 80% aq DMF, 3 days, 120 °C; Ac2O, pyridine, rt; (h) H2, 10% Pd/C,
EtOH, 1 M HCl; Ac2O, pyridine; (i) 1 M NaOMe, 1:2 MeOH–CH2Cl2.
building blocks in biocombinatorial synthesis using a
living cell, it was necessary to establish the biological
activity of such compounds. In order to test their
inhibitory activity, if any, toward several glycosidases,
the four compounds were assayed against seven glycosi-
dases: a-glucosidase (baker’s yeast and rat intestine),
3. Experimental
General methods.—Melting points were determined
with micro melting point apparatus (Yanagimoto,
Tokyo), and uncorrected. Optical rotations were mea-
sured with a Jasco DIP-370 polarimeter. IR spectra
were recorded with Jasco FTIR-200 and IR-810 spec-
b-glucosidase
(almonds),
a-galactosidase
(green
1
coffee beans and rat liver), b-galactosidase (bovine
liver), a-mannosidase (Jack beans), a-fucosidase
(bovine kidney), and b-N-acetyl-glucosaminidase
(bovine liver). Unexpectedly, compound 2 has been
demonstrated to be a strong and specific inhibitor of
b-galactosidase (IC50 6.4 mM, Ki 0.67 mM, bovine liver),
and 3 to be a moderate inhibitor (IC50 52 mM). Com-
pounds 1 and 4 did not show any inhibitory activity at
all, while 2 and 3 were only active against b-galactosi-
dase.
Contrary to well-accepted mechanistic rationale con-
cerning hydrolytic transition-state analogue in-
hibitors,14 it may be rather surprising that such simple
carbohydrate mimics, having neither a basic het-
eroatom that may be protonated nor biologically active
functional groups, seem to play an important role as
competitive inhibitors, possibly in binding in the active
site of the enzyme as mimics of either the substrate or
product in the ground state. In addition to the main
subject in hand, the present findings concerning a new-
type glycosidase inhibitors are likely to stimulate fur-
ther interests in carba sugars.
trometers. H NMR (300 MHz) spectra were recorded
on a Jeol Lambda 300 (300 MHz) spectrometer: sol-
vents: CDCl3 and CD3OD; internal standard: Me4Si.
Chemical shifts are expressed in ppm. High-resolution
(HR) mass spectra were recorded with Jeol GC-Mass
GC-Mare, EI (70 eV) or FAB (positive-ion mode)
spectrometers. TLC was conducted with Silica Gel 60
GF (E. Merck, Darmstadt), detecting by charring with
concd H2SO4. Column chromatography was carried out
on Silica Gel 60 K070 (Katayama Chemicals, Osaka),
Wakogel C-33 (Silica Gel, 300 mesh, Wako Chemical,
Osaka), Disogel sp-60 (Silica Gel, 60 mesh, Daiso,
Osaka). Organic solutions, after drying with anhydrous
Na2SO4, were concentrated at B50 °C at diminished
pressure.
Preparation of pentaacetyl 5a-carba-i-
ose (6) and pentaacetyl 5a-carba-h- -galactopyranose
(7).—A 3.0-g portion of (1S)-2-exo,3-endo-diacetoxy-5-
endo-acetoxymethyl-7-oxabicyclo[2.2.1]heptane7 (10.7
mmol) was treated with a mixture of HOAc (9 mL),
Ac2O (5.5 mL) and concd H2SO4 (0.6 mL) in a sealed
tube for 20 h at 80 °C. A reaction mixture obtained
D-glucopyran-
D

1984
S. Ogawa et al. / Carbohydrate Research 337 (2002) 1979–1992
from the 14 sealed tubes (totally 42.0 g of the triacetate)
was combined and poured into ice-water (300 mL).
After neutralization with sodium hydrogen carbonate,
the mixture was extracted with EtOAc (1.2 L), and the
organic layer was thoroughly washed with brine, dried,
and evaporated. Chromatography on silica gel (500 g,
1:8 acetone–hexane) gave 7 (24.5 g, 42.5%) as crystals:
Rf 0.21 (1:3 acetone–hexane); [h]2D7 +43° (c 1.1,
CHCl3), and 6 (24 g, 42%) as a syrup: Rf 0.17 (1:3
acetone–hexane); [h]2D7 +17° (c 1.8, CHCl3). Both
compounds were identical with authentic samples7 in all
dimethoxypropane (0.22 mL) and p-TsOH·H2O (9 mg)
for 1 h at 70 °C giving, after chromatography, 11 (24.5
mg, 45%) and 9 (24.5 mg, 45% recovery). Data for 9:
[h]2D1 −21° (c 1.7, CHCl3); Rf 0.47 (1:2 acetone–tolu-
1
ene); H NMR (CD3OD): l 7.53–7.35 (m, 5 H, Ph),
5.52 (s, 1 H, PhCH), 4.25 (dd, 1 H, J5,6a 3.7, J6gem 11.0
Hz, H-6a), 3.91 (dd, 1 H, J2,3=J3,4=8.8 Hz, H-3),
3.82–3.36 (m, 5 H, H-1, H-2, H-4, H-6b, OH), 2.04–
1.85 [m, 2 H, H-5, H-5a(eq)], 1.47 and 1.45 (2 s, each 3
H, CMe2), 1.29 [ddd, 1 H, J1,5a(ax)=J5,5a(ax)=J5agem
=
12.5 Hz, H-5a(ax)]. HREIMS: Calcd for C17H22O5
[M+]: 306.1467; Found: 306.1466. Data for 11: mp
150–151 °C; [h]2D0 −20° (c 1.2, CHCl3); Rf 0.37 (1:2
1
respects. Data for 6: H NMR (CDCl3) (partial): l 4.93
[ddd, 1 H, J1,2 10.0, J1,5a(ax) 11.0, J1,5a(eq) 5.7 Hz, H-1],
4.09 (dd, 1 H, J5,6a 5.7, J6gem 11.3 Hz, H-6a), 3.95 (dd,
1 H, J5,6b 5.0 Hz, H-6b), 2.06, 2.05, 2.03, 2.02, and 2.01
1
acetone–toluene); H NMR (CD3OD): l 7.54–7.30 (m,
5 H, Ph), 5.58 (s, 1 H, PhCH), 4.18 (dd, 1 H, J5,6a 3.9,
J6gem 11.7 Hz, H-6a), 3.99 [dd, 1 H, J1,2 9.3, J1,5a(ax) 9.8,
J1,5a(eq) 4.9 Hz, H-1], 3.81 (dd, 1 H, J3,4=J4,5=9.3 Hz,
H-4), 3.77 (m, 1 H, H-6b), 3.65 (dd, 1 H, J2,3 9.3 Hz,
H-3), 3.44 (dd, 1 H, H-2), 3.38 (br s, 1 H, OH),
2.02–1.81 [m, 2 H, H-5, H-5a(eq)], 1.49 and 1.46 (2 s,
each 3 H, CMe2), 1.18 [ddd, 1 H, J1,5a(ax) 9.3, J5,5a(ax)
10.3, J5agem 13.2 Hz, H-5a(ax)]. HREIMS: Calcd for
C17H22O5 [M+]: 306.1467; Found: 306.1463.
(5 s, each 3 H, 5×Ac), 1.58 [ddd, 1 H, J5,5a(ax)
J
=
5agem=12.7 Hz, H-5a(ax)]. Data for 7: 1H NMR
(CDCl3) (partial): l 5.51 [ddd, 1 H J1,2=J1,5a(eq)=2.7,
J1,5a(ax) 5.6 Hz, H-1], 5.20 (dd, 1 H, J2,3 7.1 Hz, H-2),
5.15 (dd, 1 H, H-3), 3.96 (dd, 1 H, J5,6a 9.4, J6gem 11.0
Hz, H-6a), 3.88 (dd, 1 H, J5,6b 6.1 Hz, H-6b), 2.12, 2.11,
2.04, 2.01, and 1.99 (5 s, each 3 H, 5×Ac).
4,6-O-Benzylidene-5a-carba-i- -glucopyranose (8).—
D
A solution of 6 (9.68 g, 28 mmol) in MeOH (70 mL)
was treated with 1 M methanolic NaOMe (15 mL) for
1 h at room temperature. After neutralization with
Amberlite IR-120B (H+) resin, the mixture was evapo-
rated to dryness. The residue was dissolved in DMF (50
mL), and the solution was treated with a,a-dimethoxy-
toluene (5.5 mL, 37 mmol) and p-TsOH·H2O (0.85 g,
5.0 mmol) for 3 h at 50 °C. After neutralization with
Et3N, the mixture was concentrated, and the residue
was chromatographed on silica gel (300 g, 1:15
MeOH–CHCl3) to give 8 (4.5 g, 59%) as crystals (from
EtOH): mp 167–168 °C; [h]2D0 −43° (c 1.2, MeOH); Rf
3-O-Acetyl-4,6-O-benzylidene-1,2-O-isopropylidene-
5a-carba-i- -glucopyranose (10).—Compound 9 (18
D
mg, 0.057 mmol) was treated with Ac2O (0.5 mL) in
pyridine (1 mL) for 15 h at room temperature. After
addition of a small amount of MeOH, the mixture was
evaporated, and the residue was chromatographed on
silica gel (1:8 acetone–hexane) to give 10 (20 mg, 96%)
as a syrup: [h]2D0 −26° (c 2.0, CHCl3); Rf 0.22 (1:4
1
acetone–hexane); H NMR (CD3OD): l 7.50–7.30 (m,
5 H, Ph), 5.48 (s, 1 H, PhCH), 5.34 (dd, 1 H, J2,3
=
J
3,4=9.4 Hz, H-3), 4.23 (dd, 1 H, J5,6a 3.9, J6gem 11.0
Hz, H-6a), 3.72 (dd, 1 H, J5,6b 11.0 Hz, H-6b), 3.72–
3.46 (m, 3 H, H-1, H-2, H-4), 2.12 (s, 3 H, Ac),
2.15–1.94 [m, 2 H, H-5, H-5a(eq)], 1.48 and 1.40 (m, 6
H, CMe2), 1.28 [ddd, 1 H, J1,5a(ax)=J5,5a(ax)=11.7,
J5agem 12.0 Hz, H-5a(ax)]. HREIMS: Calcd for
C19H24O6 [M+]: 348.1573; Found: 348.1575.
1
0.48 (1:15 MeOH–CHCl3); H NMR (CDCl3): l 7.52–
7.30 (m, 5 H, Ph), 5.55 (s, 1 H, PhCH), 4.12 (dd, 1 H,
J5,6a 4.4, J6gem 11.0 Hz, H-6a), 3.65 (dd, 1 H, J5,6b 11.0
Hz, H-6b), 3.51 [ddd, 1 H, J1,2 8.8, J1,5a(ax) 11.1, J1,5a(eq)
4.9 Hz, H-1], 3.50–3.36 (m, 2 H, H-3, H-4), 3.23 (dd, 2
H, J2,3 11.0 Hz, H-2), 1.86–1.78 (m, 2 H, H-5, H-5a),
1.10 [ddd, 1 H, J5,5a(ax)=J5agem=12.9 Hz, H-5a(ax)].
HREIMS: Calcd for C11H18O5 [M+]: 266.1154; Found:
266.1157.
1-O-Acetyl-4-6-O-benzylidene-2,3-O-isopropylidene-
5a-carba-i- -glucopyranose (12).—Compound 11 (9.5
D
mg, 0.03 mmol) was acetylated as described in the
preparation of 10 to give, after chromatography, 12 (11
mg, 98%) as crystals: mp 167–168 °C; [h]2D0 −49° (c
4,6-O-Benzylidene-1,2-O-isopropylidene-5a-carba-i-
D-glucopyranose (9) and 4,6-O-benzylidene-2,3-O-iso-
1
1.1, CHCl3); Rf 0.60 (1:4 acetone–hexane); H NMR
propylidene-5a-carba-i- -glucopyranose (11).—To
D
a
(CD3OD): l 7.55–7.20 (m, 5 H, Ph), 5.58 (s, 1 H,
PhCH), 5.04 [dd, 1 H, J1,2=J1,5a(ax)=10.1, J1,5a(eq) 4.6
Hz, H-1], 4.18 (dd, 1 H, J5,6a 4.2, J6gem 10.9 Hz, H-6a),
3.82 (dd, 1 H, J3,4=J4,5=9.3 Hz, H-4), 3.63 (dd, 1 H,
J2,3 9.3 Hz, H-2), 2.11 (s, 3 H, Ac), 2.20–1.94 [m, 2 H,
H-5, H-5a(eq)], 1.50 and 1.46 (2 s, each 3 H, CMe2),
1.11 [ddd, 1 H, J5,5a(ax) 12.9, J5agem 13.2 Hz, H-5a(ax)].
HREIMS: Calcd for C19H24O6 [M+]: 348.1573; Found:
348.1567.
solution of 8 (63 mg, 0.24 mmol) in DMF (1.9 mL)
were added 2,2-dimethoxypropane (0.29 mL, 2.2 mmol)
and p-TsOH·H2O (9 mg, 0.05 mmol), and the mixture
was stirred for 1 h at 70 °C. After neutralization with
Et3N, the mixture was concentrated, and the residue
was chromatographed on silica gel (5 g, 1:5 acetone–
hexane) to give 9 (38 mg, 52%) and 11 (48 mg, 48%) as
a syrup. Compound 9 (54 mg, 0.18 mmol) was isomer-
ized by treatment with DMF (1.6 mL) containing 2,2-

S. Ogawa et al. / Carbohydrate Research 337 (2002) 1979–1992
1985
Octyl
carba-i-
4,6-O-benzylidene-1,2-O-isopropylidene-5a-
-glucopyranoside (13).—To dry DMF (7 mL)
OCH2CH2), 1.40–1.20 [m, 10 H, (CH2)5CH3], 1.04
[ddd, J1,5a(ax) 11.7 Hz, H-5a(ax)], 0.81 (t, 3 H, J 7.1 Hz,
CH2CH3). HREIMS: Calcd for C15H30O5 [M+]:
290.2093; Found: 290.2116.
D
were added, in turn, hexane-washed NaH (106 mg, 2.63
mmol) and a solution of 11 (404 mg, 1.32 mmol) in
DMF (12 mL) under argon, and the resulting mixture
was stirred for 30 min at 0 °C. 1-Bromooctane (0.457
mL, 2.63 mmol) was then added to the mixture, which
was stirred for 5 h at room temperature. After addition
of a small amount of MeOH, the mixture was diluted
with EtOAc (100 mL), and the solution was washed
thoroughly with brine, dried, and evaporated. The
residue was chromatographed on silica gel (25 g, 1:15
acetone–hexane) to give 13 (439 mg, 79.5%) as crystals:
mp 57–58 °C; [h]2D0 −27° (c 1.5, CHCl3); Rf 0.43 (1:4
4,6 - O - Benzylidene - 5a - carba - h -
D - galactopyranose
(15).—A solution of 7 (12.7 g, 32.8 mmol) in MeOH
(50 mL) was treated with methanolic NaOMe (10 mL)
for 2 h at room temperature. After neutralization with
Amberlite IR-120B (H+) resin, the mixture as evapo-
rated to dryness. The residue was dissolved in DMF (50
mL), and a,a-dimethoxytoluene (6.8 mL, 46 mmol) and
p-TsOH·H2O (1.1 g, 6.4 mmol) were added to it, and
the mixture was stirred for 3 h at 50 °C under dimin-
ished pressure (water aspirator). After neutralization
with Et3N, the mixture was evaporated, and the residue
was chromatographed (silica gel 400 g, 1:20 MeOH–
CHCl3) to give 15 (4.95 g, 56.7%) as crystals: mp
155.5–157 °C; [h]D20 +46.5° (c 1.0, MeOH); Rf 0.54
(1:10 MeOH–CHCl3); 1H NMR (CD3OD): l 7.55–7.25
(m, 5 H, Ph), 5.52 (s, 1 H, CHPh), 4.25 (br s, 1 H,
H-4), 4.19–4.06 (m, 2 H, H-1, H-6a), 3.91 (m, 1 H,
H-6b), 3.82 (dd, 1 H, J2,3 10.1, J3,4 2.7 Hz, H-3), 3.71
(dd, 1 H, J1,2 2.4 Hz, H-2), 2.34 [ddd, 1 H, J1,5a(eq) 2.0,
J5,5a(eq) 12.0, J5agem 13.9 Hz, H-5a(eq)], 1.99–1.88 (m, 1
H, H-5), 1.65 [m, 1 H, H-5a(ax)]. HREIMS: Calcd for
C14H18O5 [M+]: 266.1154; Found: 266.1184.
1
acetone–hexane); H NMR (CD3OD): l 7.60–7.25 (m,
5 H, Ph), 5.58 (s, 1 H, PhCH), 4.18 (dd, 1 H, J5,6a 3.7,
J6gem 10.7 Hz, H-6a), 3.83–3.40 (m, 7 H, H-1, H-2,
H-3, H-4, H-6b, OCH2), 2.03–1.82 [m, 2 H, H-5,
H-5a(eq)], 1.62–1.53 [m, 2 H, OCH2CH2], 1.47 and
1.45 (2 s, each 3 H, CMe2), 1.40–1.15 [m, 10 H,
(CH2)5Me], 1.08 [ddd, 1 H, J1,5a(ax) 10.1, J5,5a(ax) 12.9,
J5agem 13.2 Hz, H-5a(ax)], 0.88 (t, 3 H, J 6.6 Hz,
CH2CH3). HREIMS: Calcd for C25H38O5 [M+]:
418.2719; Found: 418.2746.
Octyl 2,3,4,6-tetra-O-acetyl-5a-carba-i-D-glucopy-
ranoside (14).—Compound 13 (387 mg, 0.93 mmol)
was treated with 80% aq HOAc (10 mL) for 1 h at
50 °C. A mixture was evaporated to dryness, and the
residue was acetylated conventionally to give, after
chromatography on silica gel (20 g, 1:4 EtOAc–hex-
ane), 14 (424 mg, 98%) as a syrup: [h]2D0 +0.2° (c 2.5,
CHCl3); Rf 0.38 (1:2 EtOAc–hexane); 1H NMR
(CD3OD): l 5.04–4.88 (m, 3 H, H-2, H-3, H-4), 4.00
(dd, 1 H, J5,6a 5.6, J6gem 11.6 Hz, H-6a), 3.89 (dd, 1 H,
J5,6b 5.6 Hz, H-6b), 3.60–3.58 (m, 2 H, OCH2), 3.39–
3-O-Acetyl-4,6-O-benzylidene-1,2-O-isopropylidene-
5a-carba-h-D-galactopyranose (16) and 1-O-acetyl-4,6-
O-benzylidene-2,3-O-isopropylidene-5a-carba-h-
D-galac-
topyranose acetate (17).—To a solution of 15 (242 mg,
0.91 mmol) in DMF (4.8 mL) were added 2-
methoxypropene (0.45 mL, 4.7 mmol) and p-
TsOH·H2O (31 mg, 0.18 mmol), and the mixture was
stirred for 30 min at 0 °C. After neutralization with
Et3N, the mixture was evaporated, and the residue was
chromatographed (silica gel 5 g, 1:2 acetone–hexane) to
give an inseparable mixture of the expected alcohols.
The mixture was acetylated conventionally, and the
products were chromatographed on silica gel (1:10“
1:5 EtOAc–hexane) to give 16 (111 mg, 38%), as a
syrup, and 17 (173 mg, 59%), as crystals. Data for 16:
[h]2D2 +131° (c 1.1, CHCl3); Rf 0.48 (1:2 EtOAc–hex-
3.22 (m, 2 H, OCH2), 2.08 [ddd, 1 H, J1,5a(eq)
5,5a(eq)=4.2, J5agem 13.2 Hz, H-5a(eq)], 1.99, 1.97, 1.95,
=
J
and 1.92 (4 s, each 3 H, 4×Ac), 1.95–1.80 (m, 1 H,
H-5), 1.50–1.30 [m, 3 H, H-5a(ax), OCH2] 1.30–1.10
[m, 10 H, (CH2)5CH3], 0.81 (t, 3 H, J 6.1 Hz, CH2CH3).
HREIMS: Calcd for C23H38O9 [M+]: 458.2515; Found:
458.2530.
1
Octyl 5a-carba-i-
D-glucopyranoside (1).—A solution
ane); H NMR (CD3OD): l 7.48–7.35 (m, 5 H, Ph),
of 14 (387 mg, 0.84 mmol) in MeOH (2 mL) was
treated with 1 M methanolic NaOMe (0.8 mL) at room
temperature for 2 h. After neutralization with Amber-
lite IR-120B (H+) resin, the mixture was evaporated,
and the residue was chromatographed on silica gel (15
g, 1:20 MeOH–CHCl3) to give 1 (215 mg, 88%) as
crystals: mp 83–84 °C; [h]1D9 −14° (c 0.9, 1:1 MeOH–
CHCl3); Rf 0.16 (1:10 MeOH–CHCl3), 1H NMR
(CD3OD): l 3.77–3.70 (m, 2 H, H-6a, OH), 3.54–3.26
(m, 5 H, H-2, H-3, H-4, H-6b, OCH2), 3.20 (m, 1 H,
H-1), 3.06, 2.92, and 2.76 (3 br s, each 1 H, 3×OH),
1.99 [ddd, 1 H, J1,5a(eq)=J5,5a(eq)=4.2, J5agem 13.4 Hz,
H-5a(eq)], 1.80–1.65 (m, 1 H, H-5), 1.65–1.50 (m, 2 H,
5.44 (s, 1 H, CHPh), 4.72 (dd, 1 H, J2,3 8.6, J3,4 2.9 Hz,
H-3), 4.47 (m, 1 H, H-1), 4.31–4.27 (m, 2 H, H-2, H-4),
4.10 (dd, 1 H, J5,6a 2.4, J6gem 11.5 Hz, H-6a), 3.97 (dd,
1 H, J5,6b 1.2 Hz, H-6b), 2.63 [dd, 1 H, J1,5a(ax) 4.4,
J5,5a(ax) 12.5, J5agem 15.4 Hz, H-5a(ax)], 2.20–2.04 [m, 1
H, H-5a(eq)], 2.14 (s, 3 H, Ac), 2.03–1.94 (m, 1 H,
H-5), 1.52 and 1.38 (2 br s, each 3 H, CMe2).
HREIMS: Calcd for C19H24O6 [M+]: 348.1573; Found:
348.1579. Data for 17: mp 106–107 °C; [h]2D2 +44° (c
1
1.1, CHCl3); Rf 0.38 (1:2 EtOAc–hexane); H NMR
(CD3OD): l 7.49–7.26 (m, 5 H, Ph), 5.55 (s, 1 H,
CHPh), 5.60–5.45 (m, 1 H, H-1), 4.58 (m, 1 H, H-4),
4.19 (dd, 1 H, J1,2 2.6, J2,3 9.9 Hz, H-2), 4.17 (dd, 1 H,

1986
S. Ogawa et al. / Carbohydrate Research 337 (2002) 1979–1992
H, H-5a(ax)]. HREIMS: Calcd for C17H32O10S [M+]:
396.1996; Found: 396.1985.
2,3,4,6-Tetra-O-methoxymethyl-5a-carba-i-D-galac-
J5,6a 2.9, J6gem 11.7 Hz, H-6a), 4.01 (dd, 1 H, J3,4 2.5
Hz, H-3), 4.04–3.95 (m, 1 H, H-6b), 2.37 [ddd, 1 H,
J1,5a(ax) 2.9, J5,5a(ax) 12.7, J5agem 17.6 Hz, H-5a(ax)], 2.10
(s, 3 H, Ac), 1.95–1.85 [m, 1 H, H-5a(eq)], 1.85–1.75
(m, 1 H, H-5), 1.45 and 1.44 (2 s, each 3 H, CMe2).
HREIMS: Calcd for C19H24O6 [M+]: 348.1573; Found:
348.1562.
topyranose (20).—Compound 19 (533 mg, 1.34 mmol)
was treated with 1 M NaOMe (0.53 mL) in MeOH (2.7
mL) for 2 h at room temperature. The product was
chromatographed (silica gel 20 g, 1:4 acetone–hexane)
to give 20 (420 mg, 88%) as a syrup: Rf 0.30 (1:2
1-O-Methanesulfonyl-2,3,4,6-tetra-O-methoxymethyl-
1
acetone–hexane); [h]2D2 −51° (c 1.1, CHCl3); H NMR
5a-carba-h- -galactopyranose (18).—Compound 17
D
(CD3OD): l 4.80–4.52 (m, 8 H, 4×OCH2), 4.10–3.90
(m, 2 H, H-2, H-4), 3.60–3.20 (m, 16 H, H-1, H-3,
H-6,6, 4×OCH3), 3.12 (s, 3 H, Ms), 1.82–1.65 [m, 2
H, H-5, H-5a(eq)], 1.45 [ddd, 1 H, J1,5a(ax)=J5,5a(ax)
11.2, J5agem 13.4 Hz, H-5a(ax)]. HREIMS: Calcd for
C13H25O8 [M−CH2OCH3]: 309.1549; Found: 309.1543.
Dodecyl 2,3,4,6-tetra-O-methoxymethyl-5a-carba-i-
(12 mg, 33 mmol) was treated with 1 M methanolic
NaOMe (0.2 mL) in MeOH (1.0 mL) for 1 h at room
temperature. After careful neutralization with Amber-
lite IR-120B (H+) resin, the mixture was evaporated.
The residue was dissolved in pyridine (1.0 mL) and
treated with methanesulfonyl chloride (7.7 mL, 0.10
mmol) for 22 h at room temperature. The mixture was
evaporated after addition of a small amount of MeOH,
and the residue was dissolved in EtOAc (15 mL). The
solution was washed with brine, dried, and evaporated.
The residue was treated with 80% aq HOAc (1 mL) for
1 h at 60 °C, and the mixture was evaporated. The
residual product was dissolved in CH2Cl2 (1.0 mL) and
treated with chloromethylmethyl ether (28 mL, 0.27
mmol) and N,N-diisopropylethylamine (32 mL, 0.27
mmol) for 12 h at 40 °C. The mixture was extracted with
CHCl3 (15 mL), and the solution was thoroughly
washed with water. The product was chromatographed
(0.5 g, 1:3 acetone–hexane) to give 18 (9.7 mg, 67%) as
a syrup: [h]2D2 +11° (c 2.7, CHCl3); Rf 0.35 (1:2 ace-
tone–hexane); 1H NMR (CD3OD): l 5.17–5.10 (s, 1 H,
H-1), 4.85–4.60 (m, 8 H, 4×OCH2), 4.13 (m, 1 H,
H-4), 4.05 (dd, 1 H, J5,6a 2.9, J6gem 10.3 Hz, H-6a), 3.86
(dd, 1 H, J5,6b 2.4 Hz, H-6b), 3.55–3.46 (m, 14 H, H-2,
H-3, 4×OCH3), 3.12 (s, 3 H, Ms), 2.28–2.15 (m, 1 H,
H-5), 1.91 [ddd, 1 H, J1,5a(eq)=J5,5a(eq) 3.7, J5agem 14.4
Hz, H-5a(eq)], 1.11 [m, 1 H, H-5a(ax)]. HREIMS:
Calcd for C16H32O11 [M+]: 432.1666; Found: 432.1636.
On a preparative scale, starting from 17 (1.39 g, 3.99
mmol), a syrupy sample of compound 18 (0.894 g, 52%)
was obtained.
D-galactopyranoside (21).—A solution of 20 (171 mg,
0.48 mmol) in DMF (5.0 mL) was treated with NaH
(58 mg, 1.45 mmol) for 30 min at 0 °C as in the
preparation of 13. Then 1-bromododecane (0.35 mL,
1.45 mmol) was added to it, and the resulting mixture
was stirred for 27 h at room temperature. After addi-
tion of a small amount of MeOH, the mixture was
diluted with EtOAc (60 mL), and the solution was
washed with brine, dried, and evaporated. The residue
was chromatographed (silica gel 15 g, 1:8 EtOAc–tolu-
ene) to give 21 (198 mg, 79%) as a syrup: Rf 0.52 (1:2
1
acetone–hexane); [h]2D2 −20° (c 1.1, CHCl3); H NMR
(CD3OD): l 4.88–4.56 (m, 8 H, 4×OCH2), 4.03 (m, 1
H, H-4), 3.83 (ddd, 1 H, J1,2=J2,3 9.5 Hz, H-2),
3.63–3.48 (m, 4 H, H-6,6, OCH2CH2), 3.48–3.15 (m,
14 H, H-1, H-3, 4×OCH3), 1.83 [m, 1 H, H-5a(eq)],
1.75–1.48 [m, 4 H, H-5, H-5a(ax), OCH2CH2], 1.34–
1.18 [m, 18 H, OCH2CH2(CH2)9], 0.88 (t, 3 H, J 6.8 Hz,
CH2CH3). HREIMS: Calcd for C25H49O8 [M−
CH2OCH3]: 477.3427; Found: 477.3428.
Dodecyl 2,3,4,6-tetra-O-acetyl-5a-carba-i-D-galacto-
pyranoside (22).—A solution of 21 (186 mg, 0.35 mmol)
in 4 M HCl (5.5 mL) was stirred for 3 h at 60 °C, and
then evaporated. The residue was acetylated conven-
tionally, and the product was chromatographed on
silica gel (12 g, 1:10 acetone–hexane) to give 22 (132
mg, 72%) as a syrup: [h]2D2 −8° (c 0.9, CHCl3); Rf 0.46
1-O-Acetyl-2,3,4,6-tetra-O-methoxymethyl-5a-carba-
i- -galactopyranose (19).—A mixture of 18 (795 mg,
D
1
1.83 mmol), KOAc (3.6 g, 37 mmol), and DMF (16
mL) was stirred for 2 days at 100 °C. The cooled
mixture was diluted with EtOAc (150 mL), and the
resulting solution washed with brine, dried, and evapo-
rated. The residue was chromatographed on silica gel
(40 g, 1:10 acetone–hexane) to give 19 (562 mg, 77%)
as a syrup: [h]2D2 +52° (c 1.0, CHCl3); Rf 0.59 (1:2
acetone–hexane); 1H NMR (CD3OD): l 5.17–5.10 (s, 1
H, H-1), 4.88–4.58 (m, 8 H, 4×OCH2), 4.08 (m, 1 H,
H-4), 3.96 (dd, 1 H, J1,2 9.6, J2,3 8.8 Hz, H-2), 3.53 (dd,
1 H, J5,6a 2.2, J6gem 9.8 Hz, H-6a), 3.49 (dd, J3,4 8.8 Hz,
H-3), 3.47–3.30 (m, 13 H, H-6b, 4×OCH3), 2.08 (s, 3
H, Ac), 1.90–1.76 [m, 2 H, H-5, H-5a(eq)], 1.52 [m, 1
(1:2 EtOAc–hexane); H NMR (CD3OD): l 5.45 (m, 1
H, H-4), 5.29 (dd, 1 H, J1,2=J2,3 10.5 Hz, H-2), 4.84
(dd, 1 H, J3,4 2.8 Hz, H-3), 4.10–3.87 (m, 2 H, H-6,6),
4.88–4.56 (m, 8 H, 4×OCH2), 4.03 (m, 1 H, H-4),
3.68–3.29 (m, 3 H, H-1, OCH2CH2), 2.10, 2.05, 2.04,
and 1.98 (4 s, each 3 H, 4×Ac), 2.10–1.90 [m, 2 H,
H-5, H-5a(eq)], 1.65–1.45 [m,
3
H, H-5a(ax),
OCH2CH2], 1.32–1.24 [m, 18 H, OCH2CH2(CH2)9],
0.88 (t, 3 H, J 6.8 Hz, CH2CH3). HREIMS: Calcd for
C27H46O9 [M+]: 514.3142; Found: 514.3143.
Dodecyl 5a-carba-i- -galactopyranoside (2).—Com-
D
pound 22 (94 mg, 0.18 mmol) was treated with 1 M
methanolic NaOMe (0.4 mL) in 1:2 MeOH–CHCl3 (2

S. Ogawa et al. / Carbohydrate Research 337 (2002) 1979–1992
1987
mL) for 2 h at room temperature. The product was
chromatographed on silica gel (5 g, 1:20 MeOH–
CHCl3) to give 2 (58 mg, 92%) as crystals: mp 78–
79 °C; [h]2D2 −22° (c 0.6, 1:1 MeOH–CHCl3); Rf 0.46
Benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-5a-
carba-i- -glucopyranoside (26).—Compound 25 (1.16
D
g, 2.96 mmol) was O-deacetylated with 1 M NaOMe
(2.3 mL) in MeOH (23 mL) as in the preparation of 8
to give 26 (0.91 g, ꢀ100%) as crystals: mp 215–226 °C;
[h]2D0 +65° (c 1.2, MeOH); Rf 0.13 (1:10 MeOH–
1
(1:2 MeOH–CHCl3); H NMR (CD3OD): l 3.95 (m, 1
H, H-4), 3.88–3.65 (m, 5 H, H-2, H-6,6, OCH2CH2),
3.26 (m, 1 H, H-3), 3.10 [ddd, 1 H, J1,2 9.4, J1,5a(ax) 10.3,
J1,5a(eq) 4.9 Hz, H-1], 1.73 [m, 1 H, H-5a(eq)], 1.60–1.45
(m, 3 H, H-5, OCH2CH2), 1.37 [m, 1 H, H-5a(ax)],
1.28–1.17 [m, 18 H, OCH2CH2(CH2)9], 0.80 (t, 3 H, J
6.1 Hz, CH2CH3). HREIMS: Calcd for C19H38O5 [M+]:
346.2719; Found: 346.2726.
1
CHCl3); IR (KBr): w 3445, 3275, 1650, 1575 cm−1; H
NMR (CD3OD): l 7.55–7.30 (m, 5 H, Ph), 5.80 (s, 1
H, CHPh), 4.14 (dd, 1 H, J5,6a 3.9, J6gem 10.7 Hz,
H-6a), 3.75–3.62 (m, 2 H, H-2, H-3), 3.62–3.45 (m, 3
H, H-1, H-4, H-6b), 2.01 (s, 3 H, Ac), 1.86–1.70 [m, 1
H, H-5, H-5a(eq)], 1.21 [ddd, 1 H, J1,5a(ax)=J5,5a(ax)
=
4,6-O-Benzylidene-2-deoxy-2-nitro-5a-carba-i-
glucopyranose (23) and 4,6-O-benzylidene-2-deoxy-2-ni-
tro-5a-carba-i- -gulopyranose (24).—To a solution of
D
-
9.8, J5agem 13.3 Hz, H-5a(ax)]. HREIMS: Calcd for
C16H21NO5 [M+]: 307.1420; Found 307.1430.
D
Benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-5a-
8 (2.49 g, 9.3 mmol) in water (100 mL) were added, in
turn, NaHCO3 (1.49 g, 17 mmol) and NaIO4 (6.97 g,
32.5 mmol), and the resulting mixture was stirred for 5
h at room temperature. Precipitates were removed by
filtration, and the filtrate was evaporated. The residue
was dissolved in MeOH (75 mL), and the solution was
treated with nitromethane (1.66 mL, 31 mmol) and 1 M
methanolic NaOMe (6.6 mL) for 12 h at room temper-
ature. After neutralization with Amberlite IR-120B
(H+) resin, the mixture was evaporated. The residual
products were chromatographed on a silica gel column
(180 g, 1:40 MeOH–CHCl3) to give 23 (1.55 g, 56%) as
an amorphous solid and 24 (0.49 g, 18%) as a syrup.
Data for 23: Rf 0.48 (1:15 MeOH–CHCl3); IR (KBr):
w 3400, 1560, 1370 cm−1. HREIMS: Calcd for
C14H17NO6 [M+]: 295.1056; Found 295.1055. 24: Rf
0.55 (1:15 MeOH–CHCl3); IR (neat): w 3400, 1550,
1380 cm−1. HREIMS: Calcd for C14H17NO6 [M+]:
295.1056; Found 295.1061.
carba-i-
zyl-4,6-O-benzylidene-2-deoxy-5a-carba-i-
ranose (29), and benzyl 2-acetamido-3-O-benzyl-4,6-O-
benzylidene - 2 - deoxy - 5a - carba - i - - glucopyranoside
D
-glucopyranoside (27), 2-acetamido-3-O-ben-
D
-glucopy-
D
(31).—To a solution of 26 (32 mg, 0.14 mmol) in DMF
(1.0 mL) was added NaH (11 mg, 0.27 mmol), and the
mixture was stirred for 30 min at 0 °C. After addition
of benzyl bromide (18.2 mL, 0.15 mmol), the mixture
was stirred for 1 h at 0 °C, and then the reaction was
quenched by addition of small amount of MeOH. The
mixture was evaporated and the residue was chro-
matographed on silica gel (5 g, 1:2 acetone–toluene) to
give 31 (21 mg, 32%), 27 (2 mg, 3%), 29 (22 mg, 41%),
and recovered 26 (10 mg) remained unchanged. Data
for 27: mp 200–201 °C; [h]2D5 −50° (c 0.8, CHCl3); Rf
0.38 (1:10 MeOH–CHCl3); IR (neat): w 3450, 3305,
1
1650, 1555 cm−1; H NMR (CDCl3): l 7.50–7.20 (m,
10 H, 2×Ph), 5.49 (s, 1 H, CHPh), 5.42 (d, 1 H, J2,NH
6.6 Hz, NH), 4.64 and 4.34 (ABq, Jgem 12.0 Hz,
CH2Ph), 4.12 (dd, 1 H, J5,6a 4.4, J6gem 11.2 Hz, H-6a),
4.04 (br s, 1 H, OH), 3.70 (ddd, 1 H, J1,2=J2,3=9.4
Hz, H-2), 3.67–3.38 (m, 4 H, H-1, H-3, H-4, H-6b),
1.90 (s, 3 H, Ac), 1.93 [m, 1 H, H-5a(eq)], 1.70 (m, 1 H,
H-5), 1.17 [m, 1 H, H-5a(ax)]. HREIMS: Calcd for
C23H27NO5 [M+]: 397.1889; Found: 397.1889. Data for
29: mp 217–218 °C; Rf 0.31 (1:10 MeOH–CHCl3); [h]D22
+30° (c 0.8, CHCl3); IR (neat): w 3450, 3305, 1650,
2-Acetamido-3-O-acetyl-4,6-O-benzylidene-2-deoxy-
5a-carba-i- -glucopyranose acetate (25).—A solution
D
of 23 (1.47 g, 4.98 mmol) in MeOH (50 mL) containing
Ac2O (2.1 mL, 22.0 mmol) was hydrogenated for 40 h
at room temperature in the presence of Raney nickel
T-4 (three-microspoonfuls) in a Parr shaker-type ap-
paratus and using an initial hydrogen pressure of ꢀ250
kPa. The catalyst was removed by filtration and the
filtrate was evaporated. The residue was acetylated
conventionally, and the product was chromatographed
on silica gel (130 g, 1:2 acetone–hexane) to give 25 (1.3
g, 67%) as crystals: mp 232–233 °C; [h]2D7 −33° (c 1.0,
CHCl3); Rf 0.34 (1:3 acetone–toluene); IR (KBr): 3305,
1740, 1665, 1540 cm−1; 1H NMR (CDCl3): l 7.50–7.27
(m, 5 H, Ph), 5.77 (d, 1 H, J2,NH 9.8 Hz, NH), 5.52 (s,
1 H, CHPh), 5.08 (dd, 1 H, J2,3=J3,4=10.0 Hz, H-3),
4.86 (ddd, 1 H, J1,2 10.3, J1,5a(ax) 11.0, J1,5a(eq) 4.9 Hz,
H-1), 4.28 (ddd, 1 H, H-2), 4.14 (dd, 1 H, J5,6a 4.4, J6gem
11.0 Hz, H-6a), 3.71–3.58 (m, 2 H, H-4, H-6b), 2.08,
2.04, and 2.02 (3 s, each 3 H, 3×Ac), 1.71 (m, 1 H,
H-5), 1.36–1.20 (m, 2 H, H-5a,5a). HREIMS: Calcd
for C20H25NO7 [M+]: 391.1631; Found 391.1620.
1
1555 cm−1; H NMR (CDCl3): l 7.55–7.34 (m, 10 H,
2×Ph), 5.61 (s, 1 H, CHPh), 5.35 (d, 1 H, J2,NH 3.4
Hz, NH), 5.00 (br s, 1 H, OH), 4.94 and 4.69 (ABq,
Jgem 12.2 Hz, CH2Ph), 4.18 (dd, 1 H, J5,6a 4.2, J6gem 11.0
Hz, H-6a), 3.75–3.50 (m, 4 H, H-1, H-2, H-4, H-6b),
3.44 (dd, 1 H, J2,3=J3,4=9.6 Hz, H-3), 1.84 (s, 3 H,
Ac), 1.90–1.72 [m, 2 H, H-5, H-5a(eq)], 1.17 [m, 1 H,
H-5a(ax)]. HREIMS: Calcd for C23H27NO5 [M+]:
397.1889; Found: 397.1887. Data for 31: mp 210.5–
212 °C; [h]2D2 −15° (c 2.4, CHCl3); Rf 0.48 (1:10 ace-
1
tone–toluene); IR (neat): w 3290, 1650, 1555 cm−1; H
NMR (CDCl3): l 7.55–7.20 (m, 10 H, 2×Ph), 5.57 (s,
1 H, CHPh), 5.27 (d, 1 H, J2,NH 7.8 Hz, NH), 4.91 and
4.43 (ABq, Jgem 11.7 Hz, CH2Ph), 4.17 (dd, 1 H, J5,6a

1988
S. Ogawa et al. / Carbohydrate Research 337 (2002) 1979–1992
4.4, J6gem 11.0 Hz, H-6a), 3.88 (dd, 1 H, J2,3=J3,4=9.5
Hz, H-3), 3.70–3.50 (m, 3 H, H-2, H-4, H-6b), 1.87 (s,
3 H, Ac), 1.98–1.76 [m, 2 H, H-5, H-5a(eq)], 1.08 [ddd,
1 H, J5agem 12.5 Hz, H-5a(ax)]. HREIMS: Calcd for
C30H33NO5 [M+]: 487.2359; Found: 487.2362.
(s, 3 H, Ac), 1.85–1.60 [m, 2 H, H-5, H-5a(eq)], 1.48–
1.30 (m, 2 H, OCH2CH2), 1.28–1.00 [m, 18 H,
(CH2)9CH3], 0.92 [m, 1 H, J5,5a(ax) 11.0, J5agem 13.2 Hz,
H-5a(ax)]. 0.81 (t, 3 H, J 6.8 Hz, CH2CH3). HREIMS:
Calcd for C28H44NO5 [M−Bzl]: 474.3279; Found:
474.3217.
Benzyl 2-acetamido-3-O-acetyl-4,6-O-benzylidene-2-
deoxy-5a-carba-i-
D-glucopyranoside
(28).—Com-
Dodecyl 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-5a-
pound 27 (1.8 mg, 4.5 mmol) was acetylated
conventionally, and the product was chromatographed
on silica gel (1.5 g, 1:2 acetone–hexane) to give 28 (2.0
mg, ꢀ100%) as crystals: mp 214–215 °C; [h]2D5 −61° (c
1.1, CHCl3); Rf 0.53 (1:2 acetone–toluene); IR (neat): w
3295, 1635, 1560 cm−1; 1H NMR (CDCl3): l 7.50–7.20
(m, 10 H, 2×Ph), 5.51 (s, 1 H, CHPh), 5.35 (d, 1 H,
J2,NH 9.5 Hz, NH), 4.97 (dd, 1 H, J2,3=J3,4=10.1 Hz,
H-3), 4.66 and 4.38 (ABq, Jgem 12.1 Hz, CH2Ph), 4.23
(m, 1 H, H-2), 4.19 (dd, 1 H, J5,6a 4.4, J6gem 11.0 Hz,
H-6a), 3.66 (ddd, 1 H, J5,6b 10.9 Hz, H-6b), 3.64 (dd, 1
carba-i-D-glucopyranoside (33).—A solution of 32 (217
mg, 0.38 mmol) in a mixture (22 mL) in 1:1 EtOH–
EtOAc containing 1 M aq HCl (0.2 mL) was hy-
drogenolyzed in the presence of 10% Pd/C
(two-microspoonfuls) in an atmospheric pressure of
hydrogen. After removal of the catalyst, the solution
was evaporated, and the residue was acetylated conven-
tionally. The product was chromatographed on silica
gel (15 g, 1:3 acetone–hexane) to give 33 (187 mg, 95%)
as a colorless syrup: [h]2D5 −5° (c 1.3, CHCl3); Rf 0.60
(1:2 acetone–toluene); IR (neat): w 3275, 2925, 2855,
1
H, J4,5 10.1 Hz, H-4), 3.32 [ddd, 1 H, J1,2=J1,5a(ax)
=
1745, 1655, 1560 cm−1; H NMR (CDCl3): l 5.43 (d, 1
10.5, J1,5a(eq) 4.4 Hz, H-1], 2.05 and 1.92 (2 s, each 3 H,
2×Ac), 1.92–1.80 [m, 2 H, H-5, H-5a(eq)], 0.87 [m, 1
H, H-5a(ax)]. HREIMS: Calcd for C25H23NO6 [M+]:
439.1995; Found: 439.1997.
H, J2,NH 9.3 Hz, NH), 5.00 (dd, 1 H, J2,3 9.8, J3,4 10.3
Hz, H-3), 4.90 (dd, 1 H, J4,5 10.5 Hz, H-4), 4.03 (dd, 1
H, J5,6a 5.1, J6gem 11.2 Hz, H-6a), 3.93 (dd, 1 H, J5,6b
3.9, H-6b), 4.30–3.93 (m, 1 H, H-2), 3.60–3.25 (m, 3 H,
H-1, OCH2), 2.03, 1.98, and 1.91 (3 s, 3, 6, 3 H,
4×Ac), 2.00–1.80 (m, 1 H, H-5), 1.55–1.45 [m, 3 H,
H-5a(ax), OCH2CH2], 1.30–1.19 [m, 18 H, (CH2)9CH3],
0.84 (t, 3 H, J 6.6 Hz, CH2CH3). HREIMS: Calcd for
C27H47NO8 [M+]: 513.3301; Found: 513.3305.
2-Acetamido-1-O-acetyl-3-O-benzyl-4,6-O-benzyli-
dene-2-deoxy-5a-carba-i-D-glucopyranose
(30).—
Compound 29 (17 mg, 0.043 mmol) was acetylated
conventionally, and the product was chromatographed
on silica gel (1.5 g, 1:2 acetone–hexane) to give 30 (19
mg, ꢀ100%) as crystals: mp 208–209 °C; [h]2D0 +15° (c
Dodecyl 2-acetamido-2-deoxy-5a-carba-i-D-glucopy-
1
0.8, CHCl3); Rf 0.47 (1:2 acetone–toluene); H NMR
ranoside (3).—Compound 35 (162 mg, 0.32 mmol) was
O-deacetylated in a mixture (2 mL) of 1:2 MeOH–
CH2Cl2 with 1 M methanolic NaOMe (0.4 mL). The
product was chromatographed on silica gel (6 g, gradi-
ent 1:20“1:10 MeOH–CHCl3) to give 3 (120 mg, 99%)
as crystals: mp 72–73 °C; [h]2D5 −9° (c 1.2, 1:1 MeOH–
CHCl3); Rf 0.60 (1:2 acetone–toluene); IR (neat): w
3380, 3280, 2915, 2850, 1650, 1560 cm−1; 1H NMR (1:1
CD3OD–CDCl3): l 3.78–3.15 (m, 8 H, H-1, H-2, H-3,
H-4, H-6,6, OCH2), 4.90 (dd, 1 H, J3,4 9.8, J4,5 10.5 Hz,
H-4), 2.40–2.00 [m, 1 H, H-5a(eq)], 1.55–1.45 [m, 3 H,
H-5a(ax), OCH2CH2], 1.40–1.16 [m, 18 H, (CH2)9CH3],
0.84 (t, 3 H, J 6.1 Hz, CH2CH3). HREIMS: Calcd for
C21H41NO5 [M+]: 387.2985; Found: 387.2989.
(CDCl3): l 7.55–7.25 (m, 10 H, 2×Ph), 5.59 (s, 1 H,
CHPh), 5.14 (d, 1 H, J2,NH 9.5 Hz, NH), 4.91 and 4.67
(ABq, Jgem 12.0 Hz, CH2Ph), 4.81 [ddd, 1 H, J1,2 9.3,
J1,5a(ax) 11.0, J1,5a(eq) 4.6 Hz, H-1], 4.18 (dd, 1 H, J5,6a
4.4, J6gem 11.2 Hz, H-6a), 4.08 (ddd, 1 H, J1,2=J2,3
=
9.3 Hz, H-2), 3.72 (dd, 1 H, J3,4 9.6, J4,5 11.0 Hz, H-4),
3.64 (ddd, 1 H, J5,6b 11.0 Hz, H-6b), 3.47 (dd, 1 H,
H-3), 2.02 and 1.84 (2 s, each 3 H, 2×Ac), 1.98–1.70
[m, 2 H, H-5, H-5a(eq)], 1.27 [ddd, 1 H, J5,5a(ax) 11.2,
J5agem 12.5 Hz, H-5a(ax)]. HREIMS: Calcd for
C25H23NO6 [M+]: 439.1995; Found: 439.1990.
Dodecyl 2-acetamido-3-O-benzyl-4,6-O-benzylidene-
2-deoxy-5a-carba-i-D-glucopyranoside
(32).—Com-
pound 29 (36.0 mg, 0.091 mmol) was treated with
1-bromododecane (43.4 mL, 0.18 mmol) in the presence
of NaH (7.2 mg, 0.18 mmol) in DMF (1.0 mL) as in the
preparation of 13. The product was chromatographed
on silica gel (4 g, 1:3 EtOAc–hexane) to give 32 (35.0
mg, 68%) as crystals: mp 97–98 °C; [h]2D5 −5° (c 1.0,
CHCl3); Rf 0.47 (1:2 acetone–toluene); IR (neat): w
Preparation of dodecyl 2,3,4,6-tetra-O-acetyl-i-D-
glucopyranoside (34).—This compound was prepared
conventionally by coupling of 2,3,4,6-tetra-O-acetyl-a-
-glucopyranosyl bromide with dodecanol in CH2Cl2 in
D
the presence of silver perchlorate, silver carbonate, and
,
4 A molecular sieves. The product was purified by
chromatography on silica gel (1:4 EtOAc–hexane) to
1
3280, 2915, 2855, 1650, 1555 cm−1; H NMR (CDCl3):
give colorless crystals: mp 53–54.5 °C; [h]2D0 −14° (c
1
l 7.50–7.10 (m, 10 H, 2×Ph), 5.50 (s, 1 H, CHPh),
5.40 (d, 1 H, J2,NH 7.8 Hz, NH), 4.84 and 4.56 (ABq,
Jgem 12.0 Hz, CH2Ph), 4.10 (dd, 1 H, J5,6a 3.9, J6gem 11.2
Hz, H-6a), 3.87 (dd, 1 H, J2,3=J3,4=9.3 Hz, H-3),
3.64–3.18 (m, 6 H, H-1, H-2, H-4, H-6b, OCH2), 1.83
1.1, CHCl3); Rf 0.63 (1:3 acetone–toluene); H NMR
(CD3OD) (inter alia): l 5.21 (dd, 1 H, J2,3 8.8, J3,4 9.5
Hz, H-3), 5.09 (dd, 1 H, J4,5 9.8 Hz, H-4), 4.99 (1 H,
J1,2 8.8 Hz, H-2), 4.49 (d, 1 H, H-1), 4.27 (dd, 1 H, J5,6a
4.6, J6gem 12.5 Hz, H-6a), 4.13 (d, 1 H, J5,6b ꢀ0 Hz,

S. Ogawa et al. / Carbohydrate Research 337 (2002) 1979–1992
1989
H-6b), 2.09, 2.04, 2.03, and 2.01 (4 s, each 3 H, 4×Ac),
0.88 (t, 3 H, J 6.8 CH2CH3). HREIMS: Calcd for
C24H40O8 [M−HOAc]: 456.2723; Found: 456.2726.
Rf 0.54 (1:3 EtOAc–hexane); 1H NMR (CD3OD): l
7.35–7.20 (m, 15 H, 3×Ph), 4.94 and 4.70 (ABq, J
11.0 Hz), and 4.82 and 4.70 (ABq, J 11.4 Hz), 4.53 (m,
2 H) (3×CH2Ph), 4.42 (d, 1 H, J1,2 7.4 Hz, H-1),
4.01–3.91 (m, 1 H, OCH2), 3.75–3.40 (m, 7 H, H-2,
H-3, H-4, H-5, H-6,6, OCH2), 1.82 (s, 3 H, Ac), 1.75–
1.55 (m, 2 H, OCH2CH2), 1.45–1.20 [m, 18 H,
(CH2)9CH3], 0.88 (t, 3 H, J 6.6 Hz, CH2CH3).
HREIMS: Calcd for C34H49O7 [M −Bzl]: 569.3478;
Found: 569.3473.
Dodecyl
2,3-di-O-benzyl-4,6-O-benzylidene-i-D-
glucopyranoside (35).—Compound 34 (11.0 g, 21.3
mmol) was O-deacetylated as in the preparation of 8.
The product was dissolved in DMF (100 mL) and
treated with a,a-dimethoxytoluene (4.7 mL, 32 mmol)
and p-TsOH·H2O (0.73 g, 4.3 mmol) for 4.5 h at 50 °C
under diminished pressure (water aspirator). The mix-
ture was evaporated after treatment with Et3N, and the
residue was chromatographed on silica gel (300 g, 1:2
EtOAc–hexane) to give the 4,6-O-benzylidene deriva-
tive as a syrup. This compound was directly benzylated
with benzyl bromide and NaH in DMF as in the
preparation of 13, and the product was chro-
matographed on silica gel (500 g, 1:30 EtOAc–hexane)
to give 35 (10.1 g, 77%) as crystals: mp 78–79 °C; [h]D21
Preparation of 1,2-O-anhydro-3-O-benzyl-4,6-O-ben-
zylidene-5a-carba-i- -mannopyranose (38).—Epoxida-
D
tion of (1R,3R,6R,10S)-10-hydroxy-3-phenyl-2,4-di-
oxabicylo[4.4.0]dec-8-ene,11 prepared in four steps
through
3,4-di-O-acetyl-2-bromo-5a-carba-b-D-glu-
curopyranuronic acid bromide,12 with MCPBA in
CH2Cl2 in the presence of phosphate buffer solution
and subsequent benzylation with BzlBr–NaH in DMF
gave, after chromatography (silica gel, 1:6“1:5
EtOAc–hexane gradient), 38 [ꢀ20% overall yield
based on the (−)-endo-adduct7 of furan and acrylic
acid], identical with an authentic sample in all re-
spects.11
1
−23° (c 1.4, CHCl3); Rf 0.74 (1:3 EtOAc–hexane); H
NMR (CD3OD): l 7.51–7.20 (m, 15 H, 3×Ph), 5.57
(s, 1 H, CHPh), 4.91 (ABq, 2 H, Jgem 11.0 Hz, CH2Ph),
4.80 (ABq, Jgem 11.5 Hz, CH2Ph), 4.50 (d, 1 H, J1,2 7.6
Hz, H-1), 4.35 (dd, 1 H, J5,6a 4.9, J6gem 10.5 Hz, H-6a),
3.88 and 3.56 (2 m, each 1 H, OCH2), 3.79 (dd, 1 H,
J5,6b 10.3 Hz, H-6b), 3.80–3.60 (m, 2 H, H-3, H-4), 3.46
(dd, 1 H, J2,3 7.6 Hz, H-2), 3.40 (m, 1 H, H-5),
1.71–1.58 (m, 2 H, OCH2CH2), 1.36–1.20 [m, 18 H,
(CH2)9CH3], 0.88 (t, 3 H, J 7.1 Hz, CH2CH3).
HREIMS: Calcd for C24H40O8 [M −Bzl]: 456.2723;
Found: 456.2726.
Dodecyl 3-O-benzyl-4,6-O-benzylidene-5a-carba-h-
D-
mannopyranosyl-(1“4)-2,3,6-tri-O-benzyl-i- -gluco-
D
pyranoside (39).—To a solution of 36 (6.55 g, 10.6
mmol) in DMF (50 mL) were added NaH (1.27 g, 31.8
mmol, washed thoroughly with hexane) and 15-crown-5
ether (6.31 mL, 31.8 mmol) under argon, and the
mixture was stirred for 1.5 h at room temperature. A
solution of 38 (7.16 g, 21.2 mmol) in DMF (50 mL) was
added to it, and the mixture was stirred for 5 days at
70 °C. After addition of MeOH (1 mL), the mixture
was diluted with EtOAc (1.2 L), and the solution was
thoroughly washed with water, dried, and evaporated.
The product was chromatographed on silica gel (500 g,
1:40 acetone–toluene) to give 39 (8.53 g, 96% based on
36 consumed) as a syrup, together with 36 (0.77 g, 12%)
recovered: [h]2D3 −10° (c 1.8, CHCl3); Rf 0.38 (1:10
Dodecyl
2,3,6-tri-O-benzyl-i-D-glucopyranoside
(36).—To a stirred suspension of 35 (3.99 g, 6.47
,
mmol) and 4 A molecular sieves (16 g) in THF (240
mL) were added borane·Et3N (2.92 g, 38.8 mmol) and
AlCl3 (5.18 g, 38.8 mmol) at 0 °C, and the mixture was
stirred for 21 h at room temperature. An insoluble
material was removed by filtration, and the filtrate was
evaporated. The product was chromatographed on sil-
ica gel (300 g, 1:8 EtOAc–hexane) to give 36 (3.81 g,
95%) as crystals: mp 42–43 °C; [h]2D2 −12° (c 1.3,
CHCl3); Rf 0.38 (1:3 EtOAc–hexane); 1H NMR
(CD3OD): l 7.35–7.20 (m, 15 H, 3×Ph), 4.95 and 4.71
(ABq, J 11.0 Hz), 4.93 and 4.73 (ABq, J 11.4 Hz), and
4.58 (m, 2 H) (3×CH2Ph), 4.40 (d, 1 H, J1,2 6.1 Hz,
H-1), 3.98–3.88 (m, 1 H, OCH2), 3.77 (dd, 1 H, J5,6a
2.4, J6gem 10.4 Hz, H-6a), 3.69 (dd, 1 H, J5,6b 5.4 Hz,
H-6b), 3.62–3.49 (m, 2 H, H-4, OCH2), 3.49–3.36 (m,
3 H, H-2, H-3, H-5), 2.55 (m, 1 H, OH), 1.70–1.55 (m,
2 H, OCH2CH2), 1.42–1.20 [m, 18 H, (CH2)9CH3], 0.86
(t, 3 H, J 5.6 Hz, CH2CH3). HREIMS: Calcd for
C32H47O6 [M−Bzl]: 527.3373; Found: 527.3373.
1
EtOAc–toluene); H NMR (CD3OD): l 7.55–7.20 (m,
25 H, 5×Ph), 5.59 (s, 1 H, CHPh), 5.09 (ABq, 1 H,
Jgem 11.2 Hz) and 4.96 (ABq, Jgem 10.7 Hz), 4.39 (ABq,
Jgem 11.7 Hz) (3×CH2Ph), 4.38 (d, 1 H, J1,2 7.6 Hz,
H-1), 4.20–3.87 (m, 3 H, H-4%, H-6%, OCH2), 4.16–4.09
(m, 2 H, H-1%, H-2%), 3.75–3.67 (m, 3 H, H-3, H-6a,
H-3%), 3.62–3.41 (m, 5 H, H-2, H-4, H-6b, H-6%b,
OCH2), 3.37–3.29 (m, 1 H, H-5), 2.39 (m, 1 H, OH),
2.18–2.02 (m,
1 H, H-5%), 1.70–1.55 (m, 2 H,
OCH2CH2), 1.50–1.20 [m, 20 H, H-5a,5a, (CH2)9CH3],
0.88 (t, 3 H, J 7.1 Hz, CH2CH3). HRFABMS: Calcd
for C60H76O10Na [M+Na]: 979.5337; Found: 979.5339.
Dodecyl 4-O-acetyl-2,3,6-tri-O-benzyl-i-
D
-glucopy-
Dodecyl
5a-carba-h-D
2-O-acetyl-3-O-benzyl-4,6-O-benzylidene-
-mannopyranosyl-(1“4)-2,3,6-tri-O-benz-
ranoside (37).—Compound 36 (50 mg, 8.3 mmol) was
acetylated conventionally, and the product was chro-
matographed on silica gel (5 g, EtOAc–hexane) to give
37 (47 mg, 88%) as a syrup: [h]2D2 −11° (c 1.3, CHCl3);
yl-i- -glucopyranoside (40).—Compound 39 (20.4 mg,
D
21 mmol) was acetylated conventionally, and the
product was chromatographed on silica gel (1 g, 1:10

1990
S. Ogawa et al. / Carbohydrate Research 337 (2002) 1979–1992
H-6b), 2.09, 2.04, 2.03, and 2.01 (4 s, each 3 H, 4×Ac),
0.88 (t, 3 H, J 6.8 CH2CH3). HREIMS: Calcd for
C24H40O8 [M−HOAc]: 456.2723; Found: 456.2726.
toluene) to give 42 (4.66 g, 67%), together with 41 (1.63
g, 23%) unchanged: [h]2D2 −8° (c 0.5, CHCl3); Rf 0.40
(1:10 EtOAc–toluene); H NMR (CD3OD) (inter alia):
1
Dodecyl
2,3-di-O-benzyl-4,6-O-benzylidene-i-
D
-
l 7.50–7.20 (m, 25 H, 5×Ph), 5.46 (s, 1 H, CHPh),
4.40 (d, 1 H, J1,2 7.6 Hz, H-1), 4.28 [dd, 1 H, J1%,5a%(ax)
12.5, J1%,5a%(eq) 6.8 Hz, H-1%], 1.03 [m, 1 H, H-5a%(ax)],
0.88 (t, 3 H, J 6.8 Hz, CH2CH3). HRFABMS: Calcd
for C60H74NaO10 [M+Na]: 977.5180; Found: 977.5178.
glucopyranoside (35).—Compound 34 (11.0 g, 21.3
mmol) was O-deacetylated as in the preparation of 8.
The product was dissolved in DMF (100 mL) and
treated with a,a-dimethoxytoluene (4.7 mL, 32 mmol)
and p-TsOH·H2O (0.73 g, 4.3 mmol) for 4.5 h at 50 °C
under diminished pressure (water aspirator). The mix-
ture was evaporated after treatment with Et3N, and the
residue was chromatographed on silica gel (300 g, 1:2
EtOAc–hexane) to give the 4,6-O-benzylidene deriva-
tive as a syrup. This compound was directly benzylated
EtOAc–hexane) to give 40 (21.6 mg, ꢀ100%) as a
syrup: [h]2D2 +0.4° (c 1.1, CHCl3); Rf 0.35 (1:5 EtOAc–
Dodecyl
5a-carba-i-
2-O-acetyl-3-O-benzyl-4,6-O-benzylidene-
-glucopyranosyl-(1“4)-2,3,6-tri-O-benz-
D
yl-i-
O-benzyl-4,6-O-benzylidene-5a-carba-i-
osyl-(1“4)-2,3,6-tri-O-benzyl-i- -glucopyranoside
D-glucopyranoside (43) and dodecyl 2-O-acetyl-3-
D-mannopyran-
D
(44).—To a solution of 42 (304 mg, 0.32 mmol) in
THF (6.0 mL) was added 1 M BH3·THF complex (1.27
mL, 1.27 mmol) under argon, and the mixture was
stirred for 16 h at 0 °C to room temperature. The
mixture was diluted with EtOAc (60 mL), and a solu-
tion was washed with water, dried, and evaporated. A
mixture of the products was chromatographed on silica
gel (30 g, 1:10 acetone–hexane) to give a crude mixture
1
toluene); H NMR (CD3OD) (inter alia): l 7.55–7.20
(m, 25 H, 5×Ph), 5.60 (s, 1 H, CHPh), 5.57 (m, 1 H,
H-2%), 4.38 (d, 1 H, J1,2 7.6 Hz, H-1), 4.20–3.87 (m, 3
H, H-4%, H-6%, OCH2), 4.20–4.10 (m, 2 H, H-1%, H-2%),
3.98 (dd, 1 H, J5%,6%a 4.4, J6%gem 11.0 Hz, H-6%a), 4.00–
3.78 (m, 4 H, H-1%, H-3%, H-6%b, OCH2), 3.76–3.43 (m,
6 H, H-2, H-3, H-4, H-6,6, OCH2), 3.37–3.28 (m, 1 H,
H-5), 2.20–2.00 (m, 1 H, H-5%), 1.75–1.55 [m, 3 H,
H-5a%(eq), OCH2CH2], 1.50–1.12 [m, 19 H, H-5a%(ax),
(CH2)9CH3], 0.88 (t, 3 H, J 7.1 Hz, CH2CH3). Anal.
Calcd for C62H78O11 (999.3): C, 74.52; H, 7.87. Found:
C, 74.40; H, 7.57.
of the 5a-carba-b-
D
-glucosyl (ꢀ220 mg) and a-D-man-
nosyl compounds (ꢀ27 mg), the structures of which
1
were roughly assigned on the basis of their H NMR
spectral data. The former was acetylated convention-
ally, and the product was chromatographed on silica
gel (18 g, 1:10 EtOAc–hexane) to give 43 (136 mg, 52%
based on 42) as a syrup. The latter was acetylated, and
the product was chromatographed on silica gel (18 g,
1:7 EtOAc–hexane) to give 44 (16 mg, 9% based on 42)
as a syrup. Data for 43: [h]2D2 +9° (c 0.9, CHCl3); Rf
0.52 (1:3 EtOAc–hexane); 1H NMR (CD3OD) (inter
alia): l 7.50–7.20 (m, 25 H, 5×Ph), 5.44 (s, 1 H,
CHPh), 4.34 (d, 1 H, J1,2 7.1 Hz, H-1), 3.94 (m, 1 H,
OCH2), 3.82 (dd, 1 H, J5%,6%a 4.6, J6%gem 11.0 Hz, H-6%a),
3.72 (m, 2 H, H-6,6), 3.18 (dd, 1 H, J5%,6%b 10.7 Hz,
H-6%b), 1.91 (s, 3 H, Ac), 1.85 [m, 1 H, H-5a%(eq)],
1.72–1.53 (m, 2 H, OCH2CH2), 1.50–1.20 [m, 19 H,
H-5%, (CH2)9CH3], 0.88 (t, 3 H, CH2CH3), 0.67 [ddd, 1
H, J1,5a%(ax)=J5%,5a%(ax)=12.0, J5a%gem 13.7 Hz, H-5a%(ax)].
HRFABMS: Calcd for C62H79O11 [M+H]: 999.5623;
Found: 999.5632. Data for 44: [h]2D3 −1.4° (c 0.7,
CHCl3); Rf 0.45 (1:3 EtOAc–hexane); 1H NMR
(CD3OD) (inter alia): l 7.55–7.15 (m, 25 H, 5×Ph),
5.64 (m, 1 H, H-2%), 5.50 (s, 1 H, CHPh), 4.36 (d, 1 H,
J1,2 7.3 Hz, H-1), 3.95 (m, 1 H, OCH2), 3.24 (dd, 1 H,
J2,3 2.7, J3,4 9.8 Hz, H-3), 2.11 (s, 3 H, Ac), 1.80–1.50
(m, 3 H, H-5%, OCH2CH2), 1.50–1.20 [m, 20 H, H-
5a%,5a%, (CH2)9CH3], 0.88 (t, 3 H, J 6.8 Hz, CH2CH3).
Dodecyl 2-O-acetyl-3-O-benzyl-4,6-di-O-methanesul-
Dodecyl 3-O-benzyl-4,6-O-benzylidene-5a-carba-h-
arabino-hex-2-ulopyranosyl-(1“4)-2,3,6-tri-O-benzyl-
i- -glucopyranoside (41).—A solution of 40 (7.39 g,
D-
D
77.2 mmol) in DMSO (120 mL) was treated with Ac2O
(22 mL, 0.23 mol) for 11 h at room temperature. After
careful addition of MeOH (10 mL), the mixture was
diluted with EtOAc (1.2 L), and the solution was
thoroughly washed with water, dried, and evaporated.
The residue was chromatographed on silica gel (500 g,
1:8 EtOAc–hexane) to give 41 (7.2 g, 98%) as a syrup:
[h]2D2 −8° (c 1.1, CHCl3); Rf 0.41 (1:5 EtOAc–toluene);
1H NMR (CD3OD) (inter alia): l 8.10–7.20 (m, 25 H,
5×Ph), 5.53 (s, 1 H, CHPh), 4.37 (d, 1 H, J3%,4% 7.6 Hz,
H-3%), 4.31 (m, 1 H, H-1%), 3.32 (ddd, 1 H, J4,5 9.0,
J
5,6a=J5,6b=2.7 Hz, H-5), 2.52 (m, 1 H, H-5%), 1.81
[ddd, 1 H, J1%,5a%(eq)=J5%,5a%(eq)=2.9, J5a%gem 14.7 Hz,
H-5a%(eq)], 1.03 [ddd, 1 H, J1%,5a%(ax) 6.3, J5%,5a%(ax) 6.8 Hz,
H-5a%(ax)], 0.88 (t, 3 H, J 6.4 Hz, CH2CH3). HR-
FABMS: Calcd for C60H74NaO10 [M+Na]: 977.5180;
Found: 977.5171.
Dodecyl 3-O-benzyl-4,6-O-benzylidene-5a-carba-i-
arabino-hex-2-ulopyranosyl-(1“4)-2,3,6-tri-O-benzyl-
i- -glucopyranoside (42).—A solution of 41 (6.98 g,
D-
D
fonyl-5a-carba-i-
D
-glucopyranosyl-(1“4)-2,3,6-tri-O-
7.31 mmol) in toluene (140 mL) was treated with DBU
(2.2 mL, 14.6 mmol) for 1 h at 70 °C. The mixture was
diluted with EtOAc (1.2 L), and the solution was
washed with water, dried, and evaporated. The product
was chromatographed on silica gel (500 g, 1:40 EtOAc–
benzyl-i- -glucopyranoside (45).—A solution of 43
D
(1.42 g, 1.42 mmol) in 80% aq HOAc (60 mL) was
heated for 10 h at 70 °C and then evaporated. The
residue was chromatographed on silica gel (100 g, 1:2
EtOAc–hexane) to give crude diol (805 mg). This com-

S. Ogawa et al. / Carbohydrate Research 337 (2002) 1979–1992
1991
pound was treated with MsCl (0.41 mL, 5.3 mmol) in
pyridine (16 mL) for 14 h at 0 °C to room temperature.
After addition of MeOH (0.1 mL), the mixture was
evaporated. The residue was diluted with EtOAc (180
mL), and the solution was washed successively with 1
M HCl, satd aq NaHCO3, and water, dried, and evapo-
rated. The product was chromatographed on a silica gel
(60 g, 1:5 EtOAc–hexane) to give 45 (888 mg, 59%) as
a syrup: Rf 0.25 (1:2 EtOAc–hexane); [h]2D3 +10° (c
H, J2,3=J3,4=8.8 Hz, H-3), 4.76 (dd, 1 H, J1,2 7.8 Hz,
H-2), 4.68 (dd, 1 H, J3%,4% 2.7 Hz, H-3%), 4.45 (m, 1 H,
H-6a), 4.38 (d, 1 H, H-1), 4.10 (dd, 1 H, J5,6b 4.8, J6gem
12.0 Hz, H-6b), 3.95–3.70 (m, 3 H, H-6%,6%, OCH2),
3.52–3.33 (m, 4 H, H-4, H-5, H-1%, OCH2), 2.07, 2.04,
1.98, 1.96, and 1.89 (5 s, 3, 3, 9, 3, 3 H, 7×Ac),
2.00–1.90 [m, 2 H, H-5%, H-5a%(eq)], 1.55–1.40 (m, 2 H,
OCH2CH2), 1.50–1.00 [m, 19 H, H-5a%(ax),
(CH2)9CH3], 0.80 (t, 3 H, J 7.3 Hz, CH2CH3). HR-
FABMS: Calcd for C39H63O17 [M+H]: 803.4065;
Found: 803.4056. Anal. Calcd for C39H62O17 (802.90):
C, 58.34; H, 7.78. Found: C, 58.18; H, 7.32.
1
1.2, CHCl3); H NMR (CD3OD): l 7.30–7.20 (m, 20
H, 4×Ph), 4.95–4.82 (m, 3 H, H-2%, CH2Ph), 4.62–
4.41 (m, 6 H, 3×CH2Ph), 4.31–4.20 (m, 2 H, H-1,
H-4%), 3.95–3.80 (m, 4 H, H-6%,6%, OCH2), 3.71–3.57
(m, 2 H, H-6,6), 3.27–3.10 (m, 2 H, H-5, H-3%), 3.08
(dd, 1 H, J2,3 10.0, J3,4 2.7 Hz, H-3), 2.85 and 2.70 (2 s,
each 3 H, 2×Ms), 2.06 [m, 1 H, H-5a%(eq)], 1.82 (s, 3
H, Ac), 1.65–1.40 (m, 3 H, H-5%, OCH2CH2), 1.50–1.20
[m, 19 H, H-5a%(ax), (CH2)9CH3], 0.81 (t, 3 H, J 6.8 Hz,
CH2CH3). Anal. Calcd for C57H78O15S (1067.4): C,
64.14; H, 7.37. Found: C, 64.14; H, 6.99.
Dodecyl 5a%-carba-i-lactoside (4).—Compound 47
(336 mg, 0.42 mmol) was O-deacetylated as in the
preparation of 1, and the product was chro-
matographed on silica gel (20 g, 1:5 MeOH–CHCl3) to
give 4 (204 mg, 96%) as crystals: mp 76–78 °C; [h]D19
−21° (c 1.0, 1:1 MeOH–CHCl3); Rf 0.13 (1:5 MeOH–
1
CHCl3); H NMR (CD3OD) (inter alia): l 4.24 (d, 1 H,
J1,2 7.6 Hz, H-1), 2.00–1.90 [m, 1 H, H-5a%(eq)], 1.40–
1.20 [m, 18 H, (CH2)9CH3], 0.89 (t, 3 H, J 6.8 Hz,
CH2CH3). HRFABMS: Calcd for C25H48NaO10 [M+
Na]: 531.3146; Found: 531.3144. Anal. Calcd for
C25H48O10·H2O (508.3): C, 58.01; H, 9.54. Found: C,
57.92; H, 9.30.
Biological Assay.—Evaluation of inhibitory activity
of compounds 1–4 for seven glycosidases were carried
out in the standard manner15 by Dr Akihiro Tomoda
(Hokko Chemical Industry Co. Ltd.). a-Glucosidases
(baker’s yeast) was purchased from Wako Chemical
Co., b-glucosidase (almonds), b-galactosidase (bovine
liver), a-mannosidase (Jack beans), a-fucosidase
(bovine kidney) and N-acetyl-b-glucosaminidase
(bovine liver) from Sigma Chemical Co., and a-galac-
tosidase (green coffee beans) from Boellinger–
Mannheim. a-Glucosidase (rat intestine) and
a-galactosidase (rat liver) were provided with by Hokko
Chemical Industry.
Dodecyl 2,4,6-tri-O-acetyl-3-O-benzyl-5a-carba-i-
D-
galactopyranosyl-(1“4)-2,3,6-tri-O-benzyl-i- -gluco-
D
pyranoside (46).—A mixture of 45 (723 mg, 0.72 mmol)
and NaOAc (2.38 g, 29 mmol) in aqueous 80% DMF
(15 mL) was stirred for 3 days at 120 °C. The mixture
was diluted with EtOAc (150 mL), and the solution was
washed with water, dried, and evaporated. The residue
was acetylated conventionally, and the product was
chromatographed on silica gel (60 g, 1:10 acetone–hex-
ane) to give 46 (653 mg, 91%) as a syrup: [h]2D3 +17° (c
1
1.2, CHCl3); Rf 0.39 (1:2 acetone–hexane); H NMR
(CD3OD): l 7.45–7.20 (m, 20 H, 4×Ph), 5.44 (m, 1 H,
H-4%), 5.05–4.90 (m, 2 H, CH2Ph), 4.70–4.60 (m, 6 H,
H-6%,6%, 2×CH2Ph), 4.46 and 4.30 (ABq, Jgem 12.2 Hz,
CH2Ph), 4.35 (d, 1 H, J1,2 7.1 Hz, H-1), 3.98–3.89 (m,
1 H, OCH2), 3.79–3.34 (m, 7 H, H-2, H-3, H-4, H-6,6,
H-1%, OCH2), 3.35–3.25 (m, 1 H, H-5), 3.08 (dd, 1 H,
J2,3 10.0, J3,4 2.7 Hz, H-3), 2.06, 2.01, and 1.94 (3 s,
each 3 H, 3×Ac), 2.05–1.95 [m, 2 H, H-5%, H-5a%(eq)],
1.70–1.50 (m, 2 H, H-2, OCH2CH2), 1.45–1.20 [m, 19
H, H-5a%(eq), (CH2)9CH3], 0.88 (t, 3 H, J 6.8 Hz,
CH2CH3). Anal. Calcd for C59H78O13 (995.2): C, 71.20;
H, 7.90. Found: C, 71.02; H, 7.48.
Acknowledgements
The authors sincerely thank Drs A. Takahashi and
A. Tomoda (Hokko Chemical Industry Co. Ltd., At-
sugi, Tokyo) for biological assays, Miss L. Zhao for
elemental analyses, and Yamakawa Chemical Industry
Co. Ltd. (Tokyo) for providing optical resolution
reagents.
Dodecyl 2,3,4,6-tetra-O-acetyl-5a-carba-i-
D-galacto-
pyranosyl-(1“4)-2,3,6-tri-O-acetyl-i- -glucopyran-
D
oside (dodecyl 5a%-carba-i-lactoside heptaacetate)
(47).—A solution of 46 (551 mg, 0.553 mmol) in EtOH
(16 mL) containing 1 M HCl (0.5 mL) was hy-
drogenolyzed in the presence of 10% Pd/C (five-mi-
crospoonfuls) in an atmospheric pressure of hydrogen
for 7 h at room temperature. The product was acety-
lated conventionally, and chromatographed (silica gel
30 g, 1:5 acetone–hexane) to give 47 (407 mg, 92%) as
a syrup: [h]2D2 −7° (c 0.9, CHCl3); Rf 0.37 (1:2 acetone–
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