Synthesis of building blocks for carba-oligosaccharides: 5a′-Carbamaltose and 5a′-carbacellobiose, and 5a-carba-β-D-mannopyranosyl-(1→4)-D-glucopyranose

Article abstract of DOI:10.1055/s-2001-10800

Practical synthesis of ether-linked 5a′-carbamaltose and -cellobiose, and the related carbadisaccharide starting from a sole condensate of the 1,2-anhydro-3-O-benzyl-4,6-O-benzylidene-5a-carba-β-D-mannopyranose and methyl 2,3,6-tri-O-benzyl-α-D-glucopyranoside is described.

Full text of DOI:10.1055/s-2001-10800

312
SPECIAL TOPIC
Synthesis of Building Blocks for Carba-oligosaccharides: 5a¢-Carbamaltose
and 5a¢-Carbacellobiose, and 5a-Carba-b-D-mannopyranosyl-(1Æ4)-D-
glucopyranose†
Seiichiro Ogawa,* Masahiro Ohmura, Seiichi Hisamatsu
Department of Applied Chemistry, Faculty of Science and Engineering, Keio University, Hiyoshi, Kohoku-ku, Yokohama, 223-8522 Japan
Fax +81(45)5661551; E-mail: ogawa@applc.keio.ac.jp
Received 30 October 2000
1,2-anhydro-3,4,6-tri-O-benzyl-5a-carba-b-D-manno-py-
Abstract: Practical synthesis of ether-linked 5a¢-carbamaltose and
ranose9 (4) and methyl 2,3,6-tri-O-benzyl-a-D-
-cellobiose, and the related carbadisaccharide starting from a sole
condensate of the 1,2-anhydro-3-O-benzyl-4,6-O-benzylidene-5a-
glucopyranoside10 (10), with successful oxidation of the
2¢-OH group followed by reduction with NaBH4. Howev-
er, under the basic conditions required to induce epimer-
ization at the C-1 anomeric position (aÆb), the benzyl-
protected 5a-carba-hexulopyranose portion was found to
be rather unstable, featuring b-elimination to give a,b-un-
saturated ketones. Thus there has been a focus on incorpo-
ration of the 4¢,6¢-O-benzylidene function (Æ5) into the
carba-sugar moiety to hinder this undesired elimination
reaction and facilitate smooth configurational inversion at
C-1 under basic conditions.
carba-b-D-mannopyranose and methyl 2,3,6-tri-O-benzyl-a-D-glu-
copyranoside is described.
Key words: cyclitols, carbohydrate mimics, pseudo-oligosaccha-
rides, carba-oligosaccharides, ether-linked 5a-carbadisaccharides
In recent years, much attentions have been focused on the
chemistry and biochemistry of 5a-carbaoligosaccharides,1
with extensive synthetic studies carried out.2 In fact, the
imino-linked 5a-carbaoligosaccharide validamycins,3 and
acarbose4 and modified carba-amino sugar voglibose5
have been widely used as agricultural antibiotics to con-
trol sheath blight of rice plant, and as an effective clinical
remedy for treatment of diabetes, respectively. Ether-
linked oligosaccharides6,7 have been shown to act as sub-
strate analogs7 for some glycosyltransferases involved in
oligosaccharide-chain biosynthesis. Because of their sta-
bility with regard to various glycosidases in vivo and an
expected non-toxic nature for mammals, ether-linked car-
ba-oligosaccharides might be expected to become one of
the major subject for development of biologically active
carbohydrate mimics as well as useful research tools for
glycobiology.
BzlO
BzlO
OBzl
5
OBzl
6
Ph
O
5a O
1
4
O
O
O
BzlO
BzlO
3
2
BzlO
5
4
6
O
OBzl
O
OBzl
O
Ph
O
O
BzlO
BzlO
O
BzlO
O
8
9
7
OBzl
O
HO
HO
HO
HO
HO
HO
HO
BzlO
OR
BzlO
HO
HO
OR
OMe
1
2
10
5a-carba-β-D-Glcp-(1-4)-α-D-Glcp
5a-carba-α-D-Glcp-(1-4)-α-D-Glcp
Figure 2
OH
HO
HO
HO
HO
HO
O
OR
We would like to describe here the established procedure
to access carbamaltose, carbacellobiose, and related car-
badisaccharides of biological interest, by use of the con-
densate 11 of 1,2-anhydro-3-O-benzyl-4,6-O-benzyl-
idene-5a-carba-b-D-mannopyranose (5) and the 4-OH un-
protected acceptor 10. Acetolysis of methyl 5a-carba-hex-
R =
HO
3
OH
5a-carba-β-D-Manp-(1-4)-α-D-Glcp
Figure 1
opyranosyl-(1Æ4)-a-D-glucopyranoside
derivatives
readily afforded the corresponding 5a¢-carbadisaccharide
peracetates in high yields. The b-allo-type epoxide 6 of
this kind has been found to react similarly with methyl
Methyl 5a¢-carba-a-maltose has previously been
synthesized8 starting from the coupling product (45%) of
Synthesis 2001, No. 2, 312–316 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis of Building Blocks for Carba-oligosaccharides
313
DMF, NaH
15-crown-5 ether
50 °C
6'
5O' R
OBzl
O
Ph
O
4'
5a'
Ph
O
O
O
3'
O
HO
BzlO
OBzl
6
+
1'
BzlO
2'
BzlO
4
60%
5
2O
O
BzlO
3
OMe
1
1) FeCl3, Ac2O, –20 °C
2) H2, Pd/C, EtOH
3) Ac2O, Pyridine
BzlO
5
10
BzlO
11, 11a
OMe
DMSO, Ac2O, r.t.
72%
11, 14–16: R = H
11a, 14a–16a: R = Ac
Ph
O
OMe
O
DBU, PhCH3
70 °C
BzlO
BzlO
OBzl
O
Ph
O
BzlO
O
O
O
O
O
OBzl
BzlO
56%
NaBH4
CH2Cl2/MeOH, 0 °C
BzlO
O
(12: 26%)
BzlO
OMe
12
13
NaBH4
CH2Cl2/MeOH, 0 °C
66%
43%
BzlO
44%
Ph
O
OMe
OMe
BzlO
O
BzlO
OR
Ph
O
Ph
O
OBzl
BzlO
BzlO
O
O
O
RO
O
O
O
BzlO
BzlO
O
OBzl
O
BzlO
OR
OR
BzlO
OMe
16, 16a
14, 14a
15, 15a
1) FeCl3, Ac2O, –20 °C
2) H2, Pd/C, EtOH
3) Ac2O, Pyridine
1) FeCl3, Ac2O, –20 °C
2) H2, Pd/C, EtOH
3) Ac2O, Pyridine
1) FeCl3, Ac2O, –20 °C
2) H2, Pd/C, EtOH
3) Ac2O, Pyridine
OAc
AcO
OAc
AcO
AcO
AcO
OAc
OAc
O
OAc
AcO
AcO
OAc
AcO
AcO
AcO
AcO
AcO
AcO
O
O
O
O
AcO
O
OAc
OAc
AcO
OAc
OAc
1a
2a
72%
79%
3a
60%
Scheme
2-acetamido-3,6-di-O-benzyl-2-deoxy-a-D-glucopyrano-
in toluene for 1.5 h at 70 °C to afford about a 1:2 equilib-
side to furnish the coupling product (40%).11 Compound 6 rium mixture, which was readily separable by silica gel
should be a versatile donor for incorporation of 5a-carba- chromatography to give the 1¢-epimer 13 (56%), along
a-galactopyranose residues into oligosaccharide-chains.
with 12 (26%). These ketones are also thought to be po-
tential intermediates for 2-amino-2-deoxy-5a-carbahex-
opyranosyl-oligosaccharides.
Alternatively, attempted direct incorporation of 5a-carba-
b-glucose or -b-galactose residue into oligosaccharide-
chains has been attempted to generate the donors12 such as Reduction of 12 with sodium borohydride in CH2Cl2/
the a-1,2-anhydro-5a-carba-hexopyranose derivatives 7- MeOH at 0 °C gave a mixture of new disaccharide deriv-
9, but, under the influence of an oxide anion, all a-ep- ative 14 (66%), along with 11 (22%). These proved readi-
oxides tested underwent elimination reaction at 5a-meth- ly separable on a silica gel column and the structure of 14
ylene,13 giving a,b-unsaturated ketones mainly, and no was established by the 1H NMR spectrum of its 2¢-acetate
substitution products are formed.
14a, with a doublet of doublets (d = 4.93 ppm, J1¢,2¢ = 3.7
Hz, J2¢,3¢ = 10.0 Hz) attributable to the 2¢-proton.
Coupling of 5 (2 molar equivalents) and an oxide anion
generated from 10 by treatment with sodium hydride in Acetolysis15 of 14a with acetic anhydride with ferric chlo-
DMF was carried out in the presence of 15-crown-5 ether ride for 3 h at <-20 °C, followed by hydrogenolysis in the
overnight at 50 °C to give the condensate 11, which, with- presence of 10% Pd/C under atmospheric pressure of hy-
out further purification, was acetylated with acetic anhy- drogen and subsequent conventional acetylation, afforded
dride in pyridine to afford the 2¢-acetate 11a (60%). 5a¢-carbamaltose octaacetate 1a in a 72% overall yield.
Formation of other condensates was not detected. The 5a- The 1H NMR spectrum supported the proposed structure,
1
carba-a-manno configuration was supported by the H demonstrating it to be a 3:1 mixture of the a- and b-ano-
NMR spectrum, which revealed a broad doublet (d = 4.10 mers.
ppm, J1¢,2¢ = J1¢,5a¢(eq) = ~0 Hz, J1¢,5a¢(ax) = 2.6 Hz) due to 1¢-
Similar reduction of 13 with NaBH4 produced, after chro-
matography, two new disaccharides 15 (43%) and 16
proton.
Compound 11 regenerated from 11a by Zemplén de-O- (44%) without selectivity.16 These were converted into the
acetylation14 was treated with acetic anhydride in DMSO 2¢-acetates 15a and 16a, respectively, the assigned struc-
at room temperature to give the ketone 12 (72%). Epimer- tures of which were fully supported by the 1H NMR spec-
ization at C-1¢ was effected by treatment of 12 with DBU tra. Similar acetolysis of 15a and 16a, followed by
Synthesis 2001, No. 2, 312–316 ISSN 0039-7881 © Thieme Stuttgart · New York

314
S. Ogawa et al.
SPECIAL TOPIC
1H NMR (300 MHz, CDCl3): d = 0.91 [ddd, 1H, J1¢,5a¢(ax) = 2.4,
J5¢,5a¢(ax) = 9.5, J5a¢’gem = 14.4 Hz, 5a¢(ax)-H], 1.64 [ddd, 1H,
J1¢,5a¢(eq) = J5¢,5a¢(eq) = 2.9 Hz, 5a¢(eq)-H], 2.44 (m, 1H, 5¢-H), 3.28 (s,
3H, OMe), 3.41-3.65 (m, 7H, 2-H, 3-H, 4-H, 6,6-CH2, 4¢-H, 6¢a-H),
3.76 (m, 1H, 5-H), 3.99 (dd, 1H, J5¢,6¢a = 4.4, J6¢gem = 11.0 Hz, 6¢b-H),
4.16 (d, 1H, J3,4 = 9.5 Hz, 3¢-H), 4.18 [dd, 1H, J1¢,5a¢(eq) = 2.9 Hz, 1¢-
H], 4.47 (d, 1H, J1,2 = 3.7 Hz, 1-H), 4.40-4.50 (m, 3H) and 4.58-
4.65 (m, 5H) (4 ¥ CH2Ph), 5.45 (s, 1H, CHPh), 7.09-7.47 (m, 25H,
5 ¥ Ph).
hydrogenolysis and subsequent acetylation, afforded the
respective peracetyl 5a¢-carbacellobiose 2a (a-:b-
anomer = 6:1)17 and 5a-carba-b-D-Manp-(1Æ4)-D-Glcp
3a (a-:b-anomer = 6:1) in 79% and 60% yields, respec-
tively.
The 5a¢-carbamaltose and -cellobiose thus obtained have
now been assayed for enzyme-inhibitory activity and, in-
terestingly, for possible substrate analogs for amylases
and cellulases18 to furnish unique oligo- and polysaccha-
rides incorporating 5a-carba-D-glucopyranose residues.19
Anal. Calcd for C49H52O10 (801.0): C, 73.48; H, 6.54. Found: C,
73.26; H, 6.46.
Methyl (3-O-Benzyl-4,6-O-benzylidene-5a-carba-a-D-manno-
(11) and -glucopyranosyl)-(1Æ4)-2,3,6-tri-O-benzyl-a-D-glu-
copyranoside (14)
Specific rotations: Jasco DIP-370 polarimeter, 1-dm cells. IR spec-
tra: Jasco A-202 or FT-IR-200. H NMR spectra: Jeol JNM GSX-
1
To a solution of 12 (1.27 g, 1.59 mmol) in CH2Cl2/MeOH (10:1,
25 mL) was added NaBH4 (0.40 g, 9.5 mmol), and the mixture was
stirred for 1 h at 0 °C. TLC (EtOAc/toluene, 1:4) showed the ap-
pearance of two components (RF = 0.38 and 0.51) and the disappear-
ance of 12 (RF = 0.58). The mixture was diluted with EtOAc
(250 mL), washed with H2O, dried, and evaporated. The residue
was chromatographed on a silica gel column (120 g; EtOAc/hexane,
1:6) to give 11 (0.28 g, 22%) and 14 (0.84 g, 66%) as syrups.
270 f.t. (270 MHz) and Jeol Lambda-300 (300 MHz); solvent:
CDCl3; internal standard: TMS. TLC: Silica Gel 60 GF (E. Merck,
Darmstadt); detection by charring with concd H2SO4. Column chro-
matography: Silica gel 60 K070 (Katayama Chemicals, Osaka) and
Wakogel C-300 (silica gel, 300 Mesh, Wako Chemical, Osaka). Or-
ganic solutions, after drying (Na2SO4), were concentrated <50 °C at
diminished pressure.
Methyl (2-O-Acetyl-3-O-benzyl-4,6-O-benzylidene-5a-carba-a-
D-mannopyranosyl)-(1Æ4)-2,3,6-tri-O-benzyl-a-D-glucopyra-
noside (11a)
11:
1H NMR (300 MHz, CDCl3): d = 1.25 [m, 1H, 5a¢(eq)-H], 1.39 [m,
1H, 5a¢(ax)-H], 2.29 (m, 1H, 5¢-H), 3.38 (s, 3H, OMe), 3.51-3.99
(m, 10H, 2-H, 3-H, 4-H, 5-H 6,6-CH2, 3¢-H,. 4¢-H, 6¢,6¢-H2), 4.15
(m, 2H, 1¢-H, 2¢-H), 4.61 (m, 1H, 1-H), 4.39-4.73 (m, 4H), 4.70 and
4.87 (ABq, Jgem = 10.7 Hz), and 4.70-5.05 (ABq, Jgem = 10.7 Hz) (4
¥ CH2Ph), 5.63 (s, 1H, CHPh), 7.53 (m, 25H, 5 ¥ Ph).
To a suspension of 60% NaH (258 mg, 6.45 mmol) in DMF
(2.5 mL) was added a solution of methyl 2,3,6-tri-O-benzyl-a-D-
glucopyranoside10 (10, 1.00 g, 2.15 mmol) in DMF (7.5 mL) and
15-crown-5 ether (1.3 mL, 6.5 mmol) at 0 °C, followed by stirring
for 1.5 h at r.t. A solution of 1,2-anhydro-3-O-benzyl-4,6-O-ben-
zylidene-5a-carba-b-D-mannopyranose9 (5, 1.46 g, 4.31 mmol) was
added and the mixture was stirred for 15 h at 50 °C. After cooling
to 0 °C, the mixture was treated with a small amount of MeOH and
then diluted with EtOAc (250 mL). The solution was washed with
H2O (3 ¥ 50 mL), dried, and evaporated to dryness. The residue was
treated with acetic anhydride (9 mL) in pyridine (17 mL) for 17 h at
25 °C. After treatment with MeOH, the mixture was evaporated and
the residue was chromatographed on a silica gel column (150 g;
EtOAc/toluene, 1:20) to give 11a (1.05 g, 60%) as a white syrup,
[a]D28 = +22° (c 1.5, CHCl3).
14:
[a]D18 = -9.4° (c 0.68, CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.71 [ddd, 1H, J1¢,5a¢(ax) = 1.8,
J5¢,5a¢(ax) = J5a¢gem = 14.0 Hz, 5a¢(ax)-H], 1.37 [ddd, 1H,
J1¢,5a¢(eq) = J5¢,5a¢(ax) = 2.9 Hz, 5a¢(eq)-H], 2.11 (m, 1H, 5¢-H), 3.38 (s,
3H, OMe), 3.40-3.47 (m, 3H, 2¢-H, 4¢-H, 6¢b-H), 3.52 (dd, 1H,
J2¢,3¢ = J3¢,4¢ = 9.4 Hz, 3¢-H), 3.66-3.71 (m, 4H, 2-H, 3-H, 4-H, 6a-H),
3.90-4.03 (m, 4H, 5-H, 6b-H, 1¢-H, 6¢a-H), 4.20 and 4.26 (ABq,
Jgem = 11.0 Hz), 4.55 and 4.66 (ABq, Jgem = 11.0 Hz) and 4.48 and
4.68 (ABq, Jgem = 12.2 Hz) (3 ¥ CH2Ph), 4.60 (d, 1H, J1,2 = 3.4 Hz,
1-H), 5.52 (s, 1H, CHPh), 7.19-7.50 (m, 25H, 5 ¥ Ph).
1H NMR (270 MHz, CDCl3): d = 1.16 [ddd, 1H, J1¢,5a¢(ax) = 2.6,
J5¢,5a¢(ax) = J5a¢gem = 14.1 Hz, 5a¢(ax)-H], 1.55 [br d, 1H, 5a¢ (eq)-H],
1.98 (s, 3H, Ac), 2.14 (m, 1H, 5¢-H), 3.36 (s, 3H, OMe), 3.52-3.98
(m, 8H, 2-H, 3-H, 4-H, 5-H, 6,6-CH2, 4¢-H, 6¢a-H), 3.87 (br dd, 1H,
Anal. Calcd for C49H54O10 (803.0): C, 73.30; H, 6.78. Found: C,
73.22; H, 6.81.
J2¢,3¢ = ~0, J3¢,4¢ = 8.9 Hz, 3¢-H), 3.95 (dd,1H, J5¢,6¢a = 4.3, J6¢gem = 10.9
Methyl (2-O-Acetyl-3-O-benzyl-4,6-O-benzylidene-5a-carba-a-
D-glucopyranosyl)-(1Æ4)-2,3,6-tri-O-benzyl-a-D-glucopyrano-
side (14a)
Compound 14 (31 mg, 0.039 mmol) was treated with acetic anhy-
dride (0.5 mL) and pyridine (1 mL) for 17 h at 25 °C. The reaction
mixture was processed in the usual manner and the product was
chromatographed on a silica gel column (3 g; EtOAc/toluene, 1:20)
to give 14a (29 mg, 92%) as a syrup, [a]D28 = +23° (c 1.5, CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.90 [ddd, 1H, J1¢,5a¢(ax) = 1.6,
J5¢,5a¢(ax) = J5a¢gem = 14.8 Hz, 5a¢ (ax)-H], 1.84 [ddd, 1H,
J1¢,5a¢(eq) = J5¢,5a¢(eq) = 3.5 Hz, 5a¢(eq)-H], 2.00 (s, 3H, Ac), 2.15 (m,
1H, 5¢-H), 3.38 (s, 3H, OMe), 3.48 (dd, 1H, J3¢,4¢ = J4¢,5¢ = 11.1 Hz, 4-
H), 3.70-3.78 (m, 3H, 2-H, 6-H, 6¢b-H), 3.82 (dd, 1H, J5,6a = 2.9,
J6gem = 10.3 Hz, 6a-H), 3.89-3.98 (m, 3H, 3-H, 3¢-H, 6¢a-H), 4.59-
4.73 (m, 6H, 1-H, 1¢-H, 2 ¥ CH2Ph), 4.93 (dd, 1H, J1¢,2¢ = 3.7,
Hz, 6¢b-H), 4.10 [br d, 1H J1¢,5a¢(ax) = 2.6 Hz, 1¢-H], 4.60 (m, 1H, 1-
H), 4.55 and 4.68 (ABq, Jgem = 12.0 Hz), 4.61 (m, 4H), 4.82 and
5.05 (ABq, Jgem = 11.4 Hz) (4 ¥ CH2Ph), 5.59 (s, 1H, CHPh), 5.64
(br s, 1H, 2¢-H), 7.20-7.53 (m, 25H, 5 ¥ Ph).
Anal. Calcd for C56H57O11 (845.0): C, 72.49; H, 6.68. Found: C,
72.36; H, 6.68.
Methyl (3-O-Benzyl-4,6-O-benzylidene-5a-carba-a-D-arabino-
hex-2-ulopyranosyl)-(1Æ4)-2,3,6-tri-O-benzyl-a-D-glucopyra-
noside (12)
To a solution of 11a (1.07 g, 1.27 mmol) in MeOH (11 mL) was
added 1 M sodium methoxide/MeOH (2 mL) for 17 h at 25 °C. Af-
ter neutralization with Amberlite IR-120B (H+), the mixture was
evaporated to dryness. The residue was treated with acetic anhy-
dride (3.2 mL) in DMSO (18.6 mL) for 17 h at 25 °C. After treat-
ment with MeOH at 0 °C to destroy excess acetic anhydride, the
mixture was diluted with EtOAc (240 mL), washed thoroughly with
H2O, dried, and concentrated. The residue was chromatographed on
a silica gel column (90 g; EtOAc/toluene, 1:30) to give 12 (0.72 g,
72%) as a colorless syrup, [a]D28 = -6.3° (c 1.1, CHCl3).
J
2¢,3¢ = 10.0 Hz, 2¢-H), 4.54 and 4.85 (ABq, Jgem = 11.6 Hz) and 4.65
and 5.01 (ABq, Jgem = 10.7 Hz) (2 ¥ CH2Ph), 5.59 (s, 1H, CHPh),
7.22-7.72 (m, 25H, 5 ¥ Ph).
Anal. Calcd for C51H56O11 (845.0): C, 72.49; H, 6.68. Found: C,
72.24; H, 6.59.
Synthesis 2001, No. 2, 312–316 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis of Building Blocks for Carba-oligosaccharides
315
(2,3,4,6-Tetra-O-acetyl-5a-carba-a-D-glucopyranosyl)-(1Æ4)-
1,2,3,6-tetra-O-acetyl-D-glucopyranose (1a)
15:
[a]D18 = +11° (c 0.95, CHCl3).
To a stirred solution of 14a (566 mg, 0.70 mmol) in acetic anhydride
(17 mL) was added ferric (III) chloride (17 mg, 0.11 mmol) at
-20 °C, and the mixture was stirred for a further 3 h at the same
temperature. TLC (EtOAc/toluene, 1:2) showed a disappearance of
14a (RF = 0.54) and formation of two components (RF = 0.21 and
0.37). The mixture was diluted with EtOAc (300 mL) and the solu-
tion was washed with sat. NaHCO3 and H2O, dried, and evaporated.
The residue was dissolved in EtOH (17 mL), and the solution was
hydrogenated in the presence of 10% Pd/C in the presence of two
drops of 1 M hydrochloric acid for 17 h at 25 °C. The catalyst was
removed by filtration and the filtrate was evaporated. The residue
was acetylated in the usual manner and the product was chromato-
graphed on a silica gel column (30 g, acetone/toluene, 1:6) to give
an anomeric mixture (343 mg, 72%) of 1a as a white solid,
[a]D19 = +77° (c 0.55, CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.71 [ddd, 1H,
J1¢,5a¢(ax) = J5¢,5a¢(ax) = 12.0, J5a¢gem = 12.9 Hz, 5a¢(ax)-H], 1.40 (m, 1H,
5¢-H), 1.69 [ddd, 1H, J1¢,5a¢(eq) = J5¢,5a¢(eq) = 3.9 Hz, 5a¢(eq)-H], 3.09 (s,
1H, OH), 3.27 (dd, 1H, J2¢,3¢ = J3¢,4¢ = 10.9 Hz, 3¢-H), 3.30 (dd, 1H,
J5¢,6¢a = 2.9, J6¢gem = 11.2 Hz, 6¢a-H), 3.37 (s, 3H, OMe), 3.38-3.46
(m, 3H, 1¢-H, 2¢-H, 4¢-H), 3.51 (dd, 1H, J1,2 = 3.8, J2,3 = 9.5 Hz, 2-
H), 3.66-3.70 (m, 3H, 4-H, 5-H, 6a-H), 3.81 (m, 2H, 3-H, 6¢b-H),
4.02 (dd, 1H, J5,6b = 2.4, J6gem = 10.4 Hz, 6b-H), 4.48 and 4.59
(ABq, Jgem= 11.5 Hz, CH2Ph), 4.60 (d, 1H, J1,2 = 3.8 Hz, 1-H), 4.60
and 5.07 (ABq, Jgem = 11.0 Hz), 4.70 and 4.76 (ABq, Jgem = 11.4
Hz), and 4.70 and 4.94 (ABq, Jgem = 11.4 Hz) (3 ¥ CH2Ph), 5.46 (m,
25H, 5 x Ph).
Anal. Calcd for C49H54O10 (803.0): C, 73.30; H, 6.78. Found: C,
73.19; H, 6.70.
1H NMR (300 MHz, CDCl3): d = 1.50 [m, 1H, 5a¢(ax)-H], 1.90-
2.16 (s, each 3H, 8 ¥ Ac), 3.71 (dd, 1H, J3,4 = J4,5 = 9.7 Hz, 4-H),
3.80 (dd, 1H, J5¢,6¢a = 2.8, J6¢gem = 11.3 Hz, 6¢a-H), 4.01 (m, 1H, 4-H),
4.04 (dd, 1H, J5¢,6¢b = 3.8 Hz, 6¢b-H), 4.13 (dd, 1H, J5,6a = 3.4,
J6gem = 12.4 Hz, 6a-H), 4.20 (m, 1H, 1¢-H), 4.34 (dd, 1H, J5,6b = 2.2
Hz, 6b-H), 4.72 (dd, 1H, J1¢,2¢ = 3.2, J2¢,3¢ = 10.3 Hz, 2¢-H), 4.90 (dd,
1H, J1a,2 = 3.7, J2,3 = 9.7 Hz, 2-H), 4.91 (m, 1H, 4¢-H), 5.24 (dd, 1H,
16:
[a]D18 = +18° (c 1.7, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.34-1.39 (m, 3H, 5¢-H, 5a¢,
5a¢-CH2), 2.49 (s, 1H, OH), 3.26 (dd, 1H, J2¢,3¢ = 2.4, J3¢,4¢ = 9.0 Hz,
3¢-H), 3.37 (s, 3H, OMe), 3.64-3.72 (m, 6H, 2-H, 4-H, 5-H, 6a-H,
1¢-H, 6¢a-H), 3.84-3.95 (m, 4H, 3-H, 6b-H, 4¢-H, 6¢b-H), 4.21 (br s,
1H, 2¢-H), 4.47 and 4.64 (ABq, Jgem = 11.5 Hz), and 4.56 and 4.65
(ABq, Jgem = 11.9 Hz) (2 ¥ CH2Ph), 4.61 (d, 1H, J1,2 = 3.4 Hz, 1-H),
4.63 and 5.05 (ABq, Jgem = 11.0 Hz), and 4.68 and 4.78 (ABq,
Jgem = 12.5 Hz) (2 ¥ CH2Ph), 5.53 (s, 1H, CHPh), 7.24-7.50 (m,
25H, 5 ¥ Ph).
J
3¢,4¢ = 9.8 Hz, 3¢-H), 5.43 (dd, 1H, J3,4 = 9.7 Hz, 3-H), 5.66 (d, 1H,
J1b,2 = 8.3 Hz, 1b-H), 6.16 (d, 1H, J1a,2= 3.7 Hz1a-H) (a:b ~ 3:1).
Anal. Calcd for C29H40O18 (676.6): C, 51.48; H, 5.96. Found: C,
51.63; H, 6.03.
Anal. Calcd for C49H54O10 (803.0): C, 73.48; H, 6.54. Found: C,
73.37; H, 6.74.
Methyl (3-O-Benzyl-4,6-O-benzylidene-5a-carba-b-D-arabino-
hex-2-ulopyranosyl)-(1Æ4)-2,3,6-tri-O-benzyl-a-D-glucopyra-
noside (13)
Methyl (2-O-Acetyl-3-O-benzyl-4,6-O-benzylidene-5a-carba-b-
D-glucopyranosyl)-(1Æ4)-2,3,6-tri-O-benzyl-a-D-glucopyrano-
side (15a)
Compound 15 (110 mg, 0.14 mmol) was acetylated as for the prep-
aration of 14a, and the product was chromatographed on a silica gel
column (10 g; EtOAc/toluene, 1:15) to give 15a (102 mg, 88%) as
a syrup, [a]D19 = +1.3° (c 1.2, CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.60 [m, 1H, 5a¢(ax)-H], 1.36 (m,
1H, 5¢-H), 1.80 [m, 1H, 5a¢(eq)-H], 1.82 (s, 3H, Ac), 3.11 (dd, 1H,
J5¢,6¢a = J6¢gem = 11.3 Hz, 6¢a-H), 3.22 [dd, 1H, J1¢,2¢ = J1¢,5a¢(ax) = 9.5
Hz, 1¢-H], 3.22 (dd, 1H, J2¢,3¢ = J3¢,4¢ = 9.5 Hz, 3¢-H), 3.29 (s, 3H,
OMe), 3.35-3.51 (m, 5H, 2-H, 4-H, 5-H, 6a-H, 4¢-H), 3.66 (dd, 1H,
J2,3 = J3,4 = 9.3 Hz, 3-H), 3.71 (dd, 1H, J5,6b = 2.9, J6gem = 10.7 Hz,
6b-H), 3.78 (dd, 1H, J5¢,6¢b = 4.2 Hz, 6¢b-H), 4.51 (d, 1H, J1,2 = 2.9
Hz, 1-H), 4.32, 4.51, 4.53, 4.56, 4.61, 4.70, 4.79, 4.92 (ABq, 2
CH2Ph), 4.84 (dd, 1H, J1¢,2¢ = J2¢,3¢ = 9.5 Hz, 2¢-H), 5.38 (s, 1H,
CHPh), 7.17-7.42 (m, 25H, 5 Ph).
To a solution of 12 (675 mg, 0.84 mmol) in toluene (13 mL) was
added DBU (250 mg, 1.68 mmol), and the mixture was stirred for
1.5 h at 70 °C. TLC (EtOAc/toluene, 1:4) revealed the formation of
a new component (RF = 0.33). The reaction mixture was diluted
with EtOAc (100 mL), washed with H2O, dried, and evaporated.
The residue was chromatographed on a silica gel column (70 g;
EtOAc/toluene, 1:30) to give 12 (178 mg, 26%) and 13 (340 mg,
56%) as syrups.
13:
[a]D21 = -1.8° (c 1.1, CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.97 [ddd, 1H, J1¢,5a¢(ax) = 12.5,
J5¢,5a¢(ax) = J5a¢gem = 12.7 Hz, 5a¢(ax)-H], 1.66 (m, 1H, 5¢-H), 1.79
[ddd, 1H, J1¢,5a¢(eq) = 6.6, J5¢,5a¢(eq) = 3.2 Hz, 5a¢(eq)-H], 3.39 (s, 3H,
OMe), 3.40 (dd, 1H, J5¢,6¢a = 2.9, J6¢gem = 11.7 Hz, 6¢a-H), 3.48-3.54
(m, 3H, 2-H, 5-H, 4¢-H), 3.81-3.97 (m, 6H, 3-H, 4-H, 6,6-H2, 3¢-H,
6¢b-H), 4.21 (dd, 1H, 1¢-H), 4.56-4.80 (m, 6H), and 4.60 and 5.09
(ABq, Jgem = 11.7 Hz) (4 ¥ CH2Ph), 5.46 (s, 1H, CHPh), 7.22-7.41
(m, 25H, 5 ¥ Ph).
Anal. Calcd for C51H56O11 (845.0): C, 72.49; H, 6.68. Found: C,
72.28; H, 6.75.
Anal. Calcd for C49H52O10 (801.0): C, 73.48; H, 6.54. Found: C,
73.46; H, 6.47.
Methyl (2-O-Acetyl-3-O-benzyl-4,6-O-benzylidene-5a-carba-b-
D-mannopyranosyl)-(1Æ4)-2,3,6-tri-O-benzyl-a-D-glucopyra-
noside (16a)
Compound 16 (112 mg, 0.14 mmol) was acetylated as for the prep-
aration of 14a, and the product was chromatographed on a silica gel
column (10 g; EtOAc/toluene, 1:15) to give 16a (115 mg, 97%) as
a white syrup, [a]D28 = -7.2° (c 1.3, CHCl3).
Methyl (3-O-Benzyl-4,6-O-benzylidene-5a-carba-b-D-gluco-
(15) and b-D-mannopyranosyl)-(1Æ4)-2,3,6-tri-O-benzyl-a-D-
glucopyranoside (16)
A solution of 13 (1.13 g, 1.4 mmol) in CH2Cl2/MeOH (10:1)
(23 mL) was treated with NaBH4 (0.36 g, 9.4 mmol) for 2 h at 0 °C.
TLC (EtOAc/toluene, 1:4) showed formation of new components
(RF = 0.18 and 0.38) and disappearance of 13 (RF = 0.50). The reac-
tion mixture was processed as for the preparation of 14, and the
products were chromatographed on a silica gel column (100 g,
EtOAc/toluene, 1:10) to give 15 (0.48 g, 43%) and 16 (0.49 g, 44%)
as syrups.
1H NMR (300 MHz, CDCl3): d = 1.32 [m, 2H, 5¢-H, 5a¢(ax)-H],
1.62 [m, 2H, 5a¢ (eq)-H], 2.12 (s, 3H, Ac), 3.21 (dd, 1H, J2¢,3¢ = 2.8,
J3¢,4¢ = 9.6 Hz, 3¢-H), 3.37 (s, 3H, OMe), 3.41-3.81 (m, 10H), 4.60
(m, 1H, 1-H), 4.55-4.66 (m, 4H, 2 ¥ CH2Ph), 4.42, 4.51, 4.76, and
5.07 (ABq, 4H, 2 ¥ CH2Ph), 5.51 (s, 1H, CHPh), 5.59 (br s, 1H, 2¢-
H), 7.23-7.50 (m, 25H, 5 ¥ Ph).
Synthesis 2001, No. 2, 312–316 ISSN 0039-7881 © Thieme Stuttgart · New York

316
S. Ogawa et al.
SPECIAL TOPIC
(1) For reviews see: Suami, T.; Ogawa, S. Adv. Carbohydr.
Anal. Calcd for C51H56O11 (845.0): C, 72.49; H, 6.68. Found: C,
72.15; H, 6.68.
Chem. Biochem. 1990, 48, 21.
Suami, T. Curr. Chem. 1990, 154, 257.
Heightman, T. D.; Vassela, A. T. Angew. Chem., Int. Ed.
1999, 38, 750.
(2,3,4,6-Tetra-O-acetyl-5a-carba-b-D-glucopyranosyl)-(1Æ4)-
1,2,3,6-tetra-O-acetyl-D-glucopyranose (2a)
(2) For reviews see: Ogawa, S. In Carbohydrate Mimics;
Chapleur, Y., Ed.; Wiley-VCH: Weinheim, 1997; p 87.
Ogawa, S. In Carbohydrates in Drug Design; Witczak, Z. J.,
Nieforth, K. A., Eds.; Marcel Dekker: New York, 1998; p 433.
(3) Iwasa, T.; Yamamoto, H.; Shibata, M. J. Antibiot. 1970, 32,
595.
(4) Schmidt, D. D.; Frommer, W.; Junge, B.; Müller, L.;
Wingender, W.; Truscheit, E.; Schafer, H.
Naturwissenschaften 1977, 64, 535.
(5) Horii, S.; Fukase, H.; Matsuo, T.; Kameda, Y.; Asano, N.;
Matsui, K. J. Med. Chem. 1986, 29, 1038.
Compound 15a (462 mg, 0.58 mmol) was treated with ferric chlo-
ride (14 mg, 0.09 mmol) in acetic anhydride (14 mL) for 1 h at
-20 °C. The reaction mixture was processed as for the preparation
of 1a. The product was then hydrogenolyzed in the presence of 10%
Pd/C, and acetylated in the usual manner. The product was chro-
matographed on a silica gel column (3 g, acetone/toluene, 1:8) to
give 2a (309 mg, 79%) as a white syrup, [a]D19 = +47° (c 0.65,
CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.33 [m, 1H, 5a¢(ax)-H], 1.80 (m,
1H, 5¢-H), 1.98, 2.00, 2.02, 2.05, 2.06, 2.08, 2.12, and 2.19 (8s, each
3H, 8 ¥ Ac), 2.25 [m, 1H, 5a¢(eq)-H], 3.51 (m, 1H, 1¢-H), 3.57 (dd,
1H, J3,4 = J4,5 = 9.6 Hz, 4-H), 3.84 (ddd, 1H, J4,5 = 9.6, J5,6a = 2.2,
J5,6b = 4.8 Hz, 5-H), 3.88 (dd, 1H, J5¢,6¢a = 2.9, J6¢gem = 11.5 Hz, 6¢a-
H), 4.04 (dd, 1H, J5¢,6¢b = 5.1 Hz, 6¢b-H), 4.11 (dd, 1H, J5,6a = 4.8,
J6gem = 12.0 Hz, 6a-H), 4.44 (dd, 1H, J5,6b = 2.2 Hz, 6b-H), 4.94-
5.04 (m, 4H, 2-H, 2¢-H, 3¢-H, 4¢-H), 5.37 (dd, 1H, J2,3 = J3,4 = 9.6
Hz, 3-H), 6.16 (d, 1H, J1a,2 = 3.7 Hz, 1a -H), 5.59 (d, 1H, J1b,2 = 8.3
Hz, 1b-H) (a:b ~ 6:1).
(6) a) Tsunoda, H.; Sasaki, S.; Furuya, T.; Ogawa, S. Liebigs Ann.
Chem. 1996, 159.
b) Ogawa, S.; Hirai, K.; Odagiri, T.; Matsunaga, N.;
Yamazaki, T.; Nakajima, A. Eur. J. Org. Chem. 1998, 1099.
(7) a) Ogawa, S.; Furuya, T.; Tsunoda, H.; Hindsgaul, O.;
Stangier, K.; Palcic, M. M.; Carbohydr. Res. 1995, 271, 197.
b) Ogawa, S.; Matsunaga, N.; Li, H.; Palcic, M. M. Eur. J.
Org. Chem. 1999, 631.
Anal. Calcd for C29H40O18 (676.6): C, 51.48; H, 5.96. Found: C,
51.37; H, 5.91.
(8) Tsunoda, H.; Ogawa, S. Liebigs Ann. Chem. 1994, 103.
(9) Ogawa, S.; Tonegawa, T.; Nishi, K.; Yokoyama, J.
Carbohydr. Res. 1992, 229, 173.
(10) Kuster, J. M.; Dyong, I. Liebigs Ann. Chem. 1975, 2179.
(11) Ogawa, S.; Natori, R. Unpublished results.
(12) However, these epoxides are potential donors for construction
of imino-linked carba-oligosaccharides; see Ref. 7b.
(13) Under the influence of an oxide anion, pseudo-axially 5a-H
adjacent to the reactive sites is likely to be eliminated.
(14) Zemplén, G.; Pacus, E. Ber. Dtsch. Chem. Ges. 1929, 62,
1613.
(2,3,4,6-Tetra-O-acetyl-5a-carba-b-D-mannopyranosyl)-(1Æ4)-
1,2,3,6-tetra-O-acetyl-D-glucopyranose (3a)
Compound 16 (40 mg, 0.050 mmol) was similarly subjected to ac-
etolysis, hydrogenolysis, and acetylation. The peracetate was ob-
tained by chromatography on a silica gel column (3 g, acetone/
toluene, 1:9) to give 3a (20 mg, 60%) as a white syrup,
[a]D21 = +46° (c 0.60, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.76 [ddd, 1H,
J1¢,5a¢(eq) = J5¢,5a¢(eq) = J5a¢gem = 12.6 Hz, 5a¢(ax)-H], 1.82-1.87 [m, 2H,
5¢-H, 5a¢(eq)-H], 1.97, 2.01, 2.04, 2.09, 2.12, 2.13, 2.14, and 2.17
(8s, each 3H, 8 ¥ Ac), 3.73 (m, 1H, 1¢-H), 3.74 (dd, 1H,
J3,4 = J4,5 = 9.3 Hz, 4-H), 3.94 (dd, 1H, J5,6a = 3.7, J6gem = 12.0 Hz,
6a-H), 3.89-4.07 (m, 3H, 5-H, 6¢,6¢-CH2). 4.44 (dd, 1H, J5,6b = 2.0
Hz, 6b-H), 4.77 (dd, 1H, J2¢,3¢ = 2.8, J3¢,4¢ = 10.3 Hz, 3¢-H), 4.99 (dd,
1H, J1a,2 = 3.7, J2,3 = 10.4 Hz, 2-H), 5.14 (dd, 1H, J4¢,5¢ = 10.3 Hz, 4¢-
H), 5.44 (dd, 1H, J3,4 = 9.3 Hz, 3-H), 5.58 (br s, 1H, 2¢-H), 5.68 (d,
1H, J1b,2 = 8.5 Hz, 1b-H), 6.24 (d, 1H, J1a,2 = 3.7 Hz, 1a-H) (a:b ~
6:1).
(15) Dasgupta, F.; Singh, P. P.; Srivastava, H. C. Indian J. Chem.
1988, 27B, 527.
Under these conditions, acetolysis of the corresponding
b-anomers hardly occurred: MaPhail, D. R.; Lee, J. R.; Fraser-
Reid, B. J. Am. Chem. Soc. 1992, 114, 1905.
(16) The corresponding b-anomer of 13 was reduced with borane-
dimethylsulfide-THF to afford a 5:1 mixture of 5a¢-carba-
gluco (78%) and -mannopyranosyl derivatives (15%); see
Ref. 6b. On the other hand, reduction of the carba-hex-2-ulose
residue of related 5a-carbadisaccharide with L-Selectride in
THF gave almost selectively the carba-mannose one: Ogawa,
S.; Gamou, K.; Kugimiya, Y.; Senba, Y.; Lu, A.; Palcic, M.
M. Carbohydr. Lett. 2000, 3, 451.
Anal. Calcd for C29H40O18 (676.6): C, 51.48; H, 5.96. Found: C,
51.16; H, 5.97.
(17) The ratio of the anomers was estimated on the basis of 1H
NMR signals due to each anomeric protons.
(18) Fujita, M.; Shoda, S. J. Am. Chem. Soc. 1998, 120, 6411; and
references therein.
(19) 5a-Carba-b-D-glucopyranose has been demonstrated to act as
a substrate analog for cellulase (from Trichoderma reesei),
giving a carbatrisaccharide: Shoda, S.; Hisamatsu, S.; Ogawa,
S. Unpublished results.
Acknowledgement
The authors thank Miss L. Zhao for elementary analyses, Yamaka-
wa Chemical Industry Co. Ltd. (Tokyo) for the gift of optically re-
solving reagents, and Prof. Dr. S. Shoda (Tohoku University,
Sendai) for helpful discussions.
References
Article Identifier:
1437-210X,E;2001,0,02,0312,0316,ftx,en;C13200SS.pdf
† This paper constitutes Pseudosugars, 43. Part 42: Ogawa, S.;
Maruyama, A.; Odagiri, T.; Yuasa, H.; Hashimoto, H. Eur. J.
Org. Chem. in press.
Synthesis 2001, No. 2, 312–316 ISSN 0039-7881 © Thieme Stuttgart · New York