Synthesis of ether-linked sugar by nucleophilic opening of carbohydrate oxiranes

Article abstract of DOI:10.1055/s-0028-1083221

A new synthesis of ether-linked sugar utilizing the nucleophilic ring-opening reaction of carbohydrate α- or β-oxirane was developed. The reaction of 2,3-anhydro-α-D-mannopyranosides resulted in the expected high regioselectivity. In contrast, 2,3-anhydro-α-D-allopyranosides showed an unusual regioselectivity shift. The differentiating properties of carbohydrate α- or β-oxirane were investigated by comparing various conditions of the reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083221

PAPER
3761
Synthesis of Ether-Linked Sugar by Nucleophilic Opening of Carbohydrate
Oxiranes
E
ther-Linked Suga
a
r
by
N
ucleo
z
philic Ope
u
ning of
C
arb
s
ohydrate
O
a
xiranes Nishiyama, Takahiro Nakayama, Hideaki Natsugari, Hideyo Takahashi*
School of Pharmaceutical Sciences, Teikyo University, Sagamiko, Sagamihara, Kanagawa 229-0195, Japan
Fax +81(426)853728; E-mail: hide-tak@pharm.teikyo-u.ac.jp
Received 9 July 2008; revised 25 August 2008
opening of 2,3-anhydropyranosides and examined the re-
Abstract: A new synthesis of ether-linked sugar utilizing the nu-
cleophilic ring-opening reaction of carbohydrate a- or b-oxirane
was developed. The reaction of 2,3-anhydro-a-D-mannopyrano-
sides resulted in the expected high regioselectivity. In contrast, 2,3-
anhydro-a-D-allopyranosides showed an unusual regioselectivity
shift. The differentiating properties of carbohydrate a- or b-oxirane
were investigated by comparing various conditions of the reaction.
gioselective nucleophilic attack by the hydroxy group of
another pyranoside, by which ether-linked pyranosides
could be provided efficiently.
The ring-opening reaction of carbohydrate oxirane with
–
strong anionic nucleophiles (e.g., N3 ) has been investi-
gated with great interest.8 However, the use of weakly nu-
cleophilic reagents has not been fully established. We
therefore studied the nucleophilic opening of carbohy-
drate a- and b-oxiranes with alcohols or alkoxides under
various conditions (Scheme 1).
Key words: carbohydrates, epoxides, ethers, ring opening, regio-
selectivity
It was a promising discovery when coyolosa (Figure 1)
was isolated from Acrocomia mexicana as a unique 6,6¢-
ether-linked sugar.1 Since coyolosa has significant effects
on fasting blood glucose levels, new light has been shed
on the ether linkage of sugars2 with the expectation of a
new candidate in the search for drugs to combat diabetes.
R1O
R2O
R1O
R2O
R1O
R2O
OH
O
O
O
O
HO
3
3
2
2 Nu
OMe
Nu
OMe
BnO
OMe
Nu
OH
β-oxirane
O
1: R1–R2 = CHPh
2: R1 = R2 = Bn
5a NuH =
OH
HO
BnO
BnO
OMe
HO
OH
O
O
R1O
R2O
R1O
R2O
Nu
O
R1O
R2O
Nu
O
O
HO
OH
O
Nu
2
3
3
OH
OH
OH
2
OMe
OH
OMe
OMe
O
coyolosa
α-oxirane
3: R1–R2 = CHPh
Figure 1
4: R1 = R2 = Bn
Scheme 1 Regioselective nucleophilic opening of the oxirane on a
six-membered ring
We have therefore investigated a novel synthesis of 6,6¢-
ether-linked pyranoses through an acetalization–reduc-
tion procedure.3 While this approach was successfully ap-
plied to the synthesis of various new ether-linked sugars,4
we continued to examine an alternative method by which
an ether linkage could be introduced at other positions of
pyranoses. Herein, we describe a new synthesis of ether-
linked sugar by regiospecific nucleophilic opening of car-
bohydrate oxiranes.
Carbohydrate oxiranes are useful in synthetic studies.5
Numerous studies have been carried out on 1,2-anhydro
sugars as glycosyl donors in glycosylation.6 1,6/2,3-An-
hydro sugars were demonstrated to be appropriate inter-
mediates in the preparation of various carbohydrate
derivatives.7 We became interested in the oxirane ring
In general, the nucleophilic opening of an oxirane on a
six-membered ring results in high regioselectivity; only
an axial attack occurs (Fürst–Plattner rule9). Thus, nucleo-
philes are presumed to attack the C-3 carbon of 2,3-b-ox-
irane, and the transition state requires the linearity of the
entering nucleophile with a C–O bond to be broken to pro-
vide the 2,3-trans-diaxial conformation.10 Similarly, nu-
cleophiles should attack the C-2 carbon of 2,3-a-oxirane
to provide the 2,3-trans-diaxial conformation (Scheme 1).
We therefore examined the regioselectivity of the reaction
under various conditions. Particularly informative are
comparisons of basic conditions using metal alkoxide as a
nucleophile and acidic conditions using alcohol as a nu-
cleophile in the presence of a Lewis acid as promoter.
First, we investigated the regioselectivity of the ring open-
ing of the b-oxirane derivatives methyl 2,3-anhydro-4,6-
O-benzylidene-a-D-mannopyranoside (1),11 and methyl
SYNTHESIS 2008, No. 23, pp 3761–3768
Advanced online publication: 14.11.2008
DOI: 10.1055/s-0028-1083221; Art ID: F15808SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
8

3762
K. Nishiyama et al.
PAPER
Table 1 Nucleophilic Ring Opening of b-Oxiranes 1 and 2 with Alcohols 5a
β-oxirane
R1O
R2O
R1O
R2O
HO
HO
O
R1O
R2O
O
O
O
R3OH
2
+
+
3
3
R3O
5
OR3
2
OMe
OMe
OMe
A
1, 2
B
Entry b-Oxirane
5
R1
R2
R3
Base
(equiv)
Solvent
Time
(h)
Product Yieldb Ratioc
(%)
(A/B)
H2C
O
1
2
3
1
1
2
5a
5a
5a
CHPh
CHPh
NaH (4)
DMF–THF (1:1)
DMF–THF (1:1)
2
6
6
6
7
84
1:0
BnO
BnO
BnO
OMe
MeLi (10)
NaH (4)
45
1:0
H2C
O
Bn
Bn
DMF–THF (1:1) 12
34
1:0
BnO
BnO
BnO
OMe
4
5
6
7
2
2
2
2
5a
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
MeLi (10)
MeLi (10)
NaH (8)
DMF–THF (1:1) 12
7
7
8
9
68
53
76
55
1:0
5a
toluene
6
16
2
10:1
1:0
5bd
5cd
Me
Bn
–
–
NaH (8)
4.5:1
a Reagents and conditions: 1 or 2 (1 equiv), 5 (10 equiv), base, solvent, reflux.
b The combined yield of the products.
c The ratio of the isolated products.
d Used as solvent.
2,3-anhydro-4,6-di-O-benzyl-a-D-mannopyranoside (2)12 also examined as nucleophiles (Table 1, entries 6 and 7).
by the nucleophilic reaction of the alkoxides derived from While sodium methoxide attacked C-3 regioselectively to
the corresponding hydroxy derivatives methyl 2,3,4-tri- give a-D-altropyranoside 8A15 in 76% yield (entry 6), the
O-benzyl-a-D-glucopyranoside (5a),13 methanol (5b), and bulkier sodium benzyloxide, less potent as a nucleophile,
benzyl alcohol (5c) (Table 1).
gave mixture of products 9A and 9B (9A16/9B17 = 4.5:1)
in 55% yield (entry 7). As a whole, the stereochemical
outcome in the reaction of b-oxiranes 1 and 2 is the result
of the expected stereoelectronic preference for axial at-
tack by the metal alkoxide. It is difficult to achieve the un-
usual C-2 attack in this oxirane.
As shown in Table 1, the ring-opening reaction of b-ox-
iranes 1 and 2 required an excess amount of metal alkox-
ide (10 equiv)14 and harsh conditions (refluxing DMF–
THF, 1:1). The conformationally locked substrate 1 react-
ed with the sodium alkoxide of 5a to give the 3,6¢-ether-
linked sugar 6A15 in 84% yield, with no formation of 6B We next investigated the regioselectivity of the ring-open-
observed (Table 1, entry 1); as expected, the reaction was ing reaction of a-oxiranes 318 and 4 using the metal alkox-
highly regioselective. This is the first example of the syn- ides of 5a (Table 2). Even the conformationally locked
thesis of the 3,6¢-ether-linked sugar (the 3-position of D- substrate 3 gave mixtures of the 2,3-trans-diaxial 10A15
altroside and the 6-position of D-glucoside are linked by and the 2,3-trans-diequatorial 10B15 in 64% yield (10A/
ether bonding). Using lithium alkoxide lowered the yield 10B = 8.1:1) (Table 2, entry 1). A marked selectivity shift
of 6A, but complete regiospecificity was also observed was observed in the case of the more flexible oxirane 4
(Table 1, entry 2). We then examined 2, which does not (11A15/11B15 = 1.5:1) (Table 2, entry 3). A large solvent
have a rigidly locked conformation. The reaction with the effect, which is a common feature of the reaction with
sodium alkoxide of 5a gave only the 2,3-trans-diaxial lithium alkoxide, was also observed. While the best result
compound 7A15in 34% yield (Table 1, entry 3). In this with regard to the selectivity for C-2 attack was obtained
case, the lithium alkoxide of 5a proved to be a better nu- with tetrahydrofuran (11A/11B = 4.3:1) (Table 2, entry
cleophile, affording 7A in 68% yield (Table 1, entry 4). 4), less polar solvents (benzene and toluene) increased the
Interestingly, a slight amount of 7B was obtained (7A/ ratio of C-3 attack (entries 9 and 10). It is likely that the
7B = 10:1) when toluene was used instead of N,N-dimeth- lithium ion, which has a strong ability to form a chelate
ylformamide–tetrahydrofuran as the solvent (Table 1, en- structure with the oxygen atoms of the pyranoside sub-
try 5). Sodium methoxide and sodium benzyloxide were strate, and the solvent cooperatively functioned to provide
Synthesis 2008, No. 23, 3761–3768 © Thieme Stuttgart · New York

PAPER
Ether-Linked Sugar by Nucleophilic Opening of Carbohydrate Oxiranes
3763
Table 2 Nucleophilic Ring Opening of a-Oxiranes 3 and 4 with Alkoxidesa
O-R1
O
R1O
R2O
OH
R1O
R2O
R1O
R2O
R3 =
BnO
BnO
H2C
O
O
O
+
O
3
BnO
BnO
2
+
R3O
2
3
HO
BnO
OMe
HO
OMe
BnO
OMe
OMe
O
OMe
5a
10A,11A
10B,11B
α-oxirane 3, 4
Entry a-Oxirane R1
R2
Equiv of 5a Base (equiv) Solvent
Time (h) Product Yieldb (%) Ratioc (A/B)
1
2
3
3
4
4
4
4
4
4
4
4
4
4
CHPh
CHPh
4
20
10
10
10
10
10
10
10
10
10
10
NaH (4)
DMF–THF (1:1)
DMF–THF (1:1)
DMF–THF (1:1)
THF
1.5
2.5
2
10
10
11
11
11
11
11
11
11
11
11
11
64
88
84
71
77
95
84
89
59
83
61
85
8.1:1d
7.8:1d
1.5:1
4.3:1
4:1
NaH (4)
3
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
NaH (4)
4
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
MeLi (10)
MeLi (10)
MeLi (10)
MeLi (10)
MeLi (10)
MeLi (10)
MeLi (10)
t-BuOK (4)
t-BuOK (4)
13.5
5.5
4
5
DMF–THF (1:1)
DMSOe
6
2.9:1
2.8:1
2.5:1
1.1:1
1.1:1
1.1:1
1:1
7
MeCN
13
11
33
12
18
2
8
dioxane
9
benzene
10
11
12
toluene
DMF–THF (1:1)
toluene
a Reagents and conditions: 3 or 4 (1 equiv), 5a, base, solvent, reflux.
b The combined yield of the products.
c The ratio was determined by NMR.
d The ratio of the isolated products.
e At 125 °C.
the various conformations to 4, leading to such a change though the addition of a small amount of tetramethylurea
in the regioselectivity. In sharp contrast to lithium alkox- (TMU)19 to this system increased the yields, further im-
ide, potassium alkoxide gave very low regioselectivity provement was not likely.20
(Table 2, entries 11 and 12). We have so far not succeeded
in obtaining excellent C-2 selectivity with metal alkox-
ides. However, it should be noted that C-3 attack, which
is generally recognized as stereoelectronically unfavor-
We therefore turned to oxirane 2, of which the conforma-
tion is not rigidly locked. The reaction proceeded highly
regioselectively to provide the 2,3-trans-diaxial 7A
(Table 3, entry 1). When a large excess of nucleophile 5a
able, was frequently observed in this case. a-Oxiranes 3
(10 equiv) was used in the presence of trimethylsilyl tri-
and 4 are probably more flexible than b-oxiranes 1 and 2,
flate (1 equiv), 7A was obtained as the sole product in
and this would lead to the difference in the degree of re-
82% yield (Table 3, entry 1). It is interesting that invari-
gioselectivity.
able regioselectivity was again observed in this case. Un-
Next, we investigated acidic conditions. For this, a strong
Lewis acid is needed to activate the oxirane. A survey of
O
Ph
O
O
OH
O
a number of Lewis acids was carried out, and trimethylsi-
lyl triflate was found to be the most promising promotor.
First, the conformationally locked substrate 1 was treated
with 5a in the presence of trimethylsilyl triflate (1 equiv)
(Scheme 2). It was found, however, that 4,6-benzylidene
protection was unstable under such strongly acidic condi-
tions, and a major byproduct was detected, which was de-
termined to be the partially deprotected ether-linked
version of product 12. To avoid a cumbersome separation
process, we adopted the ring-opening reaction followed
by acidic deprotection of the benzylidene group (AcOH,
THF) to obtain triol 12 as the product (Scheme 2). Al-
HO
HO
O
3
2
3
OMe
a
O
β-oxirane 1
OMe
O
42%
BnO
BnO
BnO
OMe
OH
O
12
BnO
BnO
BnO
OMe
5a
Scheme 2 Nucleophilic ring opening of 1 with 5a promoted by tri-
methylsilyl triflate. Reagents and conditions: (a) 1. TMSOTf, TMU,
CH2Cl2; 2. AcOH, THF.
Synthesis 2008, No. 23, 3761–3768 © Thieme Stuttgart · New York

3764
K. Nishiyama et al.
PAPER
Table 3 Nucleophilic Ring Opening of b-Oxirane 2 with Alcohol Promoted by Trimethylsilyl Triflatea
BnO
BnO
HO
HO
BnO
BnO
O
O
O
BnO
BnO
O
R1H
TMSOTf
+
3
2
+
R1
CH2Cl2 at –10 °C
5a,d,e
3
OMe
OMe
7A,13A
2
R1
OMe
7B,13B
β-oxirane 2
Entry
1
5
R1
Equiv of 5
Time (h)
24
Product
Yieldb (%)
82
Ratioc (A/B)
O
5a
5d
5e
10
7
1:0
O
BnO
BnO
BnO
OMe
OBn
O
O
2
3
4
27
5
–
0
BnO
BnO
OMe
S
10
13
66
1:0
O
BnO
BnO
BnO
OMe
a Reagents and conditions: 2 (1 equiv), 5, TMSOTf (1 equiv), CH2Cl2, –10 °C.
b The combined yield of the products.
c The ratio of the isolated products.
fortunately, no reaction occurred with the secondary Our results showed that the orientation of the oxirane on
hydroxyl group of carbohydrate 5d21 (Table 3, entry 2). It the pyranose ring affects the reactivity and regioselectivi-
is likely that the poor nucleophilicity and the bulkiness of ty toward nucleophilic ring-opening reactions. 2,3-Anhy-
the secondary alcohol prevent the reaction from occur- dro-a-D-mannopyranosides (b-oxiranes) afforded the
ring. Yet the strongly nucleophilic thiol 5e22 reacted with 3,6¢-ether-linked sugar selectively in good yields. In con-
b-oxirane 2 to give the corresponding 13A stereoselec- trast, the reaction of 2,3-anhydro-a-D-allopyranosides (a-
tively in 66% yield (Table 3, entry 3). It should be stressed oxiranes) resulted in an unusual selectivity shift. Although
that the ring-opening reaction of b-oxirane 2 occurred ste- we have only limited information on the properties of a-
reospecifically at the C-3 position in all cases.
and b-oxiranes, a closer examination of these compounds
might contribute to further progress in the ring-opening
reactions of carbohydrate oxiranes in the future.
Finally, ring opening of a-oxiranes 3 and 4 was examined
under acidic conditions. This gave messy reactions, al-
though the addition of the boron trifluoride–diethyl ether In conclusion, a new synthesis of ether-linked sugar utiliz-
complex23 to the system partially improved the results. It ing nucleophilic ring opening was developed. We also
is strange that the 4,6-benzylidene-protected 3 provided found that the differentiating property of 2,3-a-D-oxirane
stereoelectronically unfavored 10A (structure shown in affects the results of the nucleophilic ring-opening reac-
Table 2) solely, but in very low yield (7%). The reaction tion.
of the more flexible 4 gave mixtures of 2,3-trans-diaxial
11A and 2,3-trans-diequatorial 11B (11A/11B = 1:2.4)
All reactions sensitive to air or moisture were conducted under an
(Scheme 3). Although limited, the data suggest a tendency
of a-oxirane to give the 2,3-trans-diequatorial product un-
der acidic conditions.
argon atmosphere. Materials were obtained from commercial sup-
pliers. All anhydrous solvents were purified according to standard
methods. NMR spectra were recorded on a JEOL AL-400 spec-
1
trometer at 400 MHz for H NMR and 100 MHz for 13C NMR.
Chemical shifts are given relative to TMS as an internal standard.
BnO
OR1
BnO
BnO
O
OH
O
BnO
BnO
BnO
R1O
a
+
O
O
+
3
BnO
BnO
2
HO
27%
3
HO
OMe
OMe
2
BnO
OMe
OMe
11B
11A
O
α-oxirane 4
R1 =
BnO
H2C
BnO
5a
11A/11B = 1:2.4
O
BnO
OMe
Scheme 3 Nucleophilic ring opening of 4 with 5a promoted by trimethylsilyl triflate. Reagents and conditions: (a) TMSOTf, BF3·OEt2,
CH2Cl2.
Synthesis 2008, No. 23, 3761–3768 © Thieme Stuttgart · New York

PAPER
Ether-Linked Sugar by Nucleophilic Opening of Carbohydrate Oxiranes
3765
EI and ESI mass spectra were measured on JEOL JMS-SX102A
and JEOL LCMS-ITTOF spectrometers, respectively. FAB mass
spectra were obtained with m-nitrobenzyl alcohol (NBA) as a ma-
trix. Melting points were determined on a Yanaco micro melting
point apparatus. Analytical TLC was carried out on Merck silica gel
60 F254. Column chromatography was performed on silica gel (Wa-
kogel C-300, 45–60 mm).
(dd, J = 9.9, 5.2 Hz, 1 H), 3.98 (m, 1 H), 3.94 (t, J = 9.4 Hz, 1 H),
3.93 (m, 1 H), 3.90 (dd, J = 11.8, 1.9 Hz, 1 H), 3.90 (m, 1 H), 3.84
(dd, J = 11.8, 5.2 Hz, 1 H), 3.74 (m, 2 H), 3.63 (t, J = 9.4 Hz, 1 H),
3.42 (dd, J = 9.4, 3.6 Hz, 1 H), 3.33 (s, 3 H), 3.32 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 138.8, 138.5, 138.2, 137.6, 128.9,
128.3, 128.2, 127.9, 127.8, 127.7, 127.5, 127.4, 126.3, 102.5, 101.9,
97.8, 82.1, 80.2, 77.9, 76.5, 75.7, 74.8, 74.8, 73.4, 70.9, 69.9, 69.5,
69.3, 58.5, 55.5, 54.9.
Oxiranes 2 and 4
MS (FAB) (MeCN–NBA + NaI): m/z = 752 [M + Na].
Pd(OH)2/C (30 mg) was added to 1 or 3 (290.5 mg, 1.10 mmol) in
EtOH (110 mL). The reaction mixture was stirred at r.t. for 12 h un-
der an atmosphere of H2. After filtration, the filtrate was evaporated
to give the crude diol, which was directly dissolved in DMF–THF
(5:1, 12 mL). The mixture was treated with 60% NaH in oil (114
mg), and BnCl (0.4 mL, 3.4 mmol) at 0 °C and gradually warmed to
r.t. After the mixture had stirred for 6.5 h, ice water (100 mL) was
added and the mixture was extracted with EtOAc (3 × 100 mL). The
crude product was purified by chromatography (silica gel, EtOAc–
hexane, 1:4); this gave 2 (from 1) or 4 (from 3).
HRMS (FAB) (MeCN–NBA + NaI): m/z calcd for C42H50O11Na:
751.3095; found: 751.3096.
Compounds 7A and 7B
A 1.6 M soln of MeLi in Et2O (0.95 mL, 1.52 mmol) was added to
a soln of 2 (54.2 mg, 0.152 mmol) and 5a (707 mg, 1.52 mmol) in
toluene (1.5 mL) at 0 °C, and the mixture was refluxed for 6 h. H2O
(100 mL) was added and the mixture was extracted with CH2Cl2 (3
× 100 mL). The crude product was purified by chromatography (sil-
ica gel, EtOAc–hexane, 3:2); this gave 7A (46%) and 7B (5%).
Methyl 2,3-Anhydro-4,6-di-O-benzyl-a-D-mannopyranoside (2)
Yield: 337 mg (86%); Rf = 0.50 (EtOAc–hexane, 1:2); [a]D23 +169.4
(c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.32–7.25 (m, 10 H), 4.91 (s, 1 H,
H1), 4.71 (d, J = 11.6 Hz, 1 H), 4.59 (d, J = 12.0 Hz, 1 H), 4.48 (d,
J = 12.0 Hz, 1 H), 4.47 (d, J = 11.6 Hz, 1 H), 3.72 (ddd, J = 9.2, 4.8,
1.6 Hz, 1 H, H5), 3.64 (d, J = 9.2 Hz, 1 H, H4), 3.62 (dd, J = 9.2,
1.6 Hz, 1 H, H6), 3.56 (dd, J = 9.2, 4.8 Hz, 1 H, H6), 3.45 (s, 3 H),
3.35 (d, J = 3.6 Hz, 1 H, H3), 3.08 (d, J = 3.6 Hz, 1 H, H2).
Compound 7A
Yield: 60 mg (46%); Rf = 0.32 (EtOAc–hexane, 1:1); [a]D23 +47.3
(c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.28–7.15 (m, 25 H), 4.90 (d,
J = 10.8 Hz, 1 H), 4.79 (d, J = 11.2 Hz, 1 H), 4.75 (d, J = 10.8 Hz,
1 H), 4.67 (d, J = 12.4 Hz, 1 H), 4.62 (d, J = 12.0 Hz, 1 H), 4.59 (d,
J = 11.2 Hz, 1 H), 4.53 (d, J = 11.6 Hz, 1 H), 4.52 (d, J = 3.6 Hz, 1
H), 4.50 (d, J = 11.6 Hz, 1 H), 4.49 (d, J = 3.6 Hz, 1 H), 4.44 (d,
J = 12.4 Hz, 1 H), 4.43 (d, J = 12.0 Hz, 1 H), 4.07 (dd, J = 3.8, 2.0
Hz, 1 H), 3.91 (t, J = 9.6 Hz, 1 H), 3.91 (dd, J = 7.2, 4.0 Hz, 1 H),
3.80 (dd, J = 3.8, 3.6 Hz, 1 H), 3.77 (d, J = 9.6 Hz, 1 H), 3.73–3.68
(m, 1 H), 3.68 (d, J = 9.6 Hz, 1 H), 3.61 (dd, J = 7.2, 3.6 Hz, 1 H),
3.55 (dd, J = 4.8, 2.0 Hz, 1 H), 3.55 (dd, J = 4.8, 2.0 Hz, 1 H), 3.48
(t, J = 9.6 Hz, 1 H), 3.39 (dd, J = 9.6, 3.6 Hz, 1 H), 3.29 (s, 3 H),
3.29 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 138.0, 137.3, 128.3, 128.3, 128.2,
128.2, 128.0, 127.9, 127.9, 127.8, 127.6, 127.4, 95.9, 73.1, 72.0,
68.9, 68.9, 67.1, 55.4, 53.3, 49.6.
MS (EI, 70 eV): m/z = 356 [M+].
HRMS (EI): m/z calcd for C21H24O5: 356.1623; found: 356.1622.
Methyl 2,3-Anhydro-4,6-di-O-benzyl-a-D-allopyranoside (4)
Yield: 330 mg (83%); Rf = 0.50 (EtOAc–hexane, 1:1); [a]D20 +129.8
(c 1.00, CHCl3).
1H NMR (600 MHz, CDCl3): d = 7.08–7.43 (m, 10 H), 4.76 (s, 1 H),
4.67 (d, J = 11.8 Hz, 1 H), 4.63 (d, J = 12.4 Hz, 1 H), 4.60 (d,
J = 11.8 Hz, 1 H), 4.50 (d, J = 12.4 Hz, 1 H), 3.99 (dd, J = 9.6, 1.7
Hz, 1 H, H4), 3.93 (ddd, J = 9.6, 3.9, 2.2 Hz, 1 H), 3.72 (dd,
J = 10.7, 3.9 Hz, 1 H), 3.65 (dd, J = 10.7, 2.2 Hz, 1 H), 3.48 (dd,
J = 4.2, 3.0 Hz, 1 H), 3.46 (s, 3 H), 3.42 (dd, J = 4.2, 1.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 138.6, 138.3, 138.3, 138.0, 137.9,
128.3, 128.3, 128.3, 128.3, 128.3, 128.1, 127.9, 127.9, 127.8, 127.8,
127.6, 127.6, 127.6, 127.5, 127.4, 102.6, 98.0, 81.9, 79.9, 79.1,
77.8, 75.7, 74.9, 73.3, 73.3, 71.6, 70.0, 69.6, 72.4, 70.7, 70.6, 69.9,
55.6, 55.2.
MS (FAB) (MeCN–NBA + NaI): m/z = 843 [M + Na].
HRMS (FAB) (MeCN–NBA + NaI): m/z calcd for C49H56O11Na:
843.3720; found: 843.3726.
13C NMR (150 MHz, CDCl3): d = 138.0, 138.0, 128.3, 128.3, 128.3,
Compound 7B
127.8, 127.6, 94.8, 73.4, 71.8, 71.6, 68.5, 66.7, 55.7, 54.6, 51.6.
Yield: 5.8 mg (5%); mp 158 °C; Rf = 0.57 (EtOAc–hexane, 1:1);
MS (EI, 70 eV): m/z = 356 [M+].
[a]D22 +47.9 (c 0.30, CHCl3).
HRMS (EI): m/z calcd for C21H24O5: 356.1623; found: 356.1619.
1H NMR (600 MHz, CDCl3): d = 7.30–7.15 (m, 25 H), 4.89 (d,
J = 10.7 Hz, 1 H), 4.81 (d, J = 11.1 Hz, 1 H), 4.80 (d, J = 11.0 Hz,
1 H), 4.74 (d, J = 10.7 Hz, 1 H), 4.73 (d, J = 3.6 Hz, 1 H), 4.72 (d,
J = 12.2 Hz, 1 H), 4.60 (d, J = 11.0 Hz, 1 H), 4.60 (d, J = 12.2 Hz,
1 H), 4.56 (d, J = 3.6 Hz, 1 H), 4.55 (d, J = 12.1 Hz, 1 H), 4.46 (d,
J = 11.1 Hz, 1 H), 4.42 (d, J = 12.1 Hz, 1 H), 3.97 (t, J = 9.1 Hz, 1
H), 3.93 (dd, J = 11.0, 3.6 Hz, 1 H), 3.90 (t, J = 9.6 Hz, 1 H), 3.66–
3.62 (m, 4 H), 3.60–3.56 (m, 2 H), 3.49 (t, J = 9.1 Hz, 1 H), 3.46
(dd, J = 9.6, 3.6 Hz, 1 H), 3.31 (dd, J = 9.1, 3.6 Hz, 1 H), 3.31 (s, 3
H), 3.22 (s, 3 H).
3,6¢-Ether-Linked Sugar 6A
A 60% suspension of NaH in oil (30.2 mg, 0.76 mmol) was added
to a soln of 5a (878 mg, 1.89 mmol) in DMF–THF (1:1, 1.9 mL) at
0 °C, and the mixture was stirred at r.t. After 30 min, 1 (50 mg, 0.19
mmol) was added to the mixture, which was subsequently stirred at
reflux for 2 h. H2O (100 mL) was added, and the mixture was ex-
tracted with CH2Cl2 (300 mL). The crude product was purified by
chromatography (silica gel, EtOAc–hexane, 3:7); this gave 6A.
Yield: 122 mg (84%); mp 158 °C; Rf = 0.29 (EtOAc–hexane, 1:1);
[a]D20 +56.9 (c 1.00, CHCl3).
1H NMR (600 MHz, CDCl3): d = 7.50–7.21 (m, 20 H), 5.55 (s, 1 H),
4.94 (d, J = 10.7 Hz, 1 H), 4.85 (d, J = 11.0 Hz, 1 H), 4.85 (d,
J = 10.7 Hz, 1 H), 4.71 (d, J = 12.1 Hz, 1 H), 4.69 (d, J = 11.0 Hz,
1 H), 4.58 (m, 2 H), 4.57 (d, J = 12.1 Hz, 1 H), 4.32 (m, 1 H), 4.28
13C NMR (150 MHz, CDCl3): d = 138.8, 138.5, 138.5, 138.1, 138.0,
128.5, 128.4, 128.3, 128.3, 128.0, 127.9, 127.9, 127.8, 127.7, 127.7,
127.6, 127.5, 98.2, 97.7, 81.9, 81.2, 80.0, 77.5, 77.4, 75.7, 74.9,
74.4, 73.8, 73.5, 72.4, 70.4, 69.7, 69.6, 68.6, 55.4, 55.0.
MS (FAB) (MeCN–NBA + NaI): m/z = 843 [M + Na].
Synthesis 2008, No. 23, 3761–3768 © Thieme Stuttgart · New York

3766
K. Nishiyama et al.
PAPER
HRMS (FAB) (MeCN–NBA + NaI): m/z calcd for C49H56O11Na:
843.3721; found: 843.3732.
Compound 10B
Yield: 13.5 mg (10%); Rf = 0.47 (EtOAc–hexane, 1:1); [a]D18 +41.0
(c 0.50, CHCl3).
Methyl 4,6-Di-O-benzyl-3-O-methyl-a-D-altropyranoside (8A)
A 60% suspension of NaH in oil (84.0 mg, 2.10 mmol) was added
to a soln of 2 (93.6 mg, 0.263 mmol) in MeOH (1.05 mL) at 0 °C
and the mixture was refluxed for 16 h. H2O (100 mL) was added and
the mixture was extracted with CH2Cl2 (3 × 100 mL). The crude
product was purified by chromatography (silica gel, EtOAc–hex-
ane, 1:1); this gave 8A.
1H NMR (600 MHz, CDCl3): d = 7.35–7.07 (m, 20 H), 5.43 (s, 1 H),
4.87 (d, J = 11.0 Hz, 1 H), 4.74 (d, J = 11.0 Hz, 1 H), 4.73 (d,
J = 2.5 Hz, 1 H), 4.70 (d, J = 12.0 Hz, 1 H), 4.66 (d, J = 10.7 Hz, 1
H), 4.58 (d, J = 12.0 Hz, 1 H), 4.58 (d, J = 3.9 Hz, 1 H), 4.54 (d,
J = 10.7 Hz, 1 H), 4.21 (dd, J = 10.2, 4.7 Hz, 1 H), 4.15 (dd,
J = 11.7, 2.2 Hz, 1 H), 3.87 (t, J = 9.6 Hz, 1 H), 3.84 (dd, J = 11.7,
2.2 Hz, 1 H), 3.74 (ddd, J = 10.2, 10.2, 5.0 Hz, 1 H), 3.67–3.64 (m,
4 H), 3.59 (ddd, J = 9.9, 2.2, 2.2 Hz, 1 H), 3.46 (m, 1 H), 3.45 (dd,
J = 9.6, 3.9 Hz, 1 H), 3.38 (s, 3 H), 3.27 (s, 3 H).
Yield: 77.2 mg (76%); Rf = 0.18 (EtOAc–hexane, 1:1); [a]D18 +77.3
(c 0.27, CHCl3).
1H NMR (600 MHz, CDCl3): d = 7.34–7.25 (m, 10 H), 4.63 (d,
J = 11.8 Hz, 1 H), 4.61(d, J = 3.0 Hz, 1 H), 4.59 (d, J = 11.0 Hz, 1
H), 4.54 (d, J = 12.1 Hz, 1 H), 4.52 (d, J = 12.1 Hz, 1 H), 4.17 (ddd,
J = 7.4, 4.4, 3.3 Hz, 1 H), 3.95 (dd, J = 5.6, 3.0 Hz, 1 H), 3.90 (dd,
J = 7.4, 3.6 Hz, 1 H), 3.70 (dd, J = 10.7, 4.4 Hz, 1 H), 3.66 (dd,
J = 10.7, 3.3 Hz, 1 H), 3.56 (dd, J = 5.6, 3.6 Hz, 1 H), 3.45 (s, 3 H),
3.42 (s, 3 H).
13C NMR (150 MHz, CDCl3): d = 138.1, 138.0, 128.4, 128.3, 127.9,
127.7, 127.6, 102.2, 78.7, 73.5, 71.8, 71.7, 69.5, 69.3, 58.8, 55.8.
MS (EI, 70 eV): m/z = 388 [M+].
13C NMR (150 MHz, CDCl3): d = 128.9, 128.4, 128.3, 128.3, 128.2,
128.0, 127.9, 127.9, 127.9, 127.5, 127.5, 126.0, 101.4, 99.8, 98.2,
81.9, 81.2, 80.9, 80.0, 77.2, 75.7, 75.1, 73.4, 73.2, 71.3, 70.6, 69.0,
62.7, 55.4, 55.3.
MS (FAB) (MeCN–NBA + NaI): m/z = 752 [M + Na].
HRMS (FAB) (MeCN–NBA + NaI): m/z calcd for C42H48O11Na:
751.3095; found: 751.3070.
Compounds 11A and 11B
A 1.6 M soln of MeLi in Et2O (0.88 mL, 1.4 mmol) was added to a
soln of 5a (650 mg, 1.4 mmol) in DMSO (1.40 mL) at 0 °C and the
mixture was stirred at r.t. After 0.5 h, 4 (50 mg, 0.14 mmol) was
added and the mixture was refluxed for 4 h. H2O (100 mL) was add-
ed and the mixture was extracted with CH2Cl2 (3 × 100 mL). The
crude product was purified by chromatography (silica gel, EtOAc–
hexane, 1:3); this gave the mixture of 11A and 11B.
HRMS (EI): m/z calcd for C22H28O6: 388.1886; found: 388.1886.
Methyl 3,4,6-Tri-O-benzyl-a-D-altropyranoside (9A) and Meth-
yl 2,4,6-Tri-O-benzyl-a-D-glucopyranoside (9B)
A 60% suspension of NaH in oil (82.2 mg, 2.05 mmol) was added
to a soln of 2 (91.5 mg, 0.257 mmol) in BnOH (1.28 mL) at 0 °C
and the mixture was refluxed for 2 h. H2O (100 mL) was added and
the mixture was extracted with CH2Cl2 (3 × 100 mL). The crude
product was purified by chromatography (silica gel, EtOAc–hex-
ane, 3:7); this gave 9A [yield: 53.3 mg (45%)] and 9B [yield: 12.4
mg (10%)].
Yield: 108.8 mg (95%); 11A/11B = 2.9:1.
Compound 11A
Rf = 0.45 (EtOAc–hexane, 1:1); [a]D20 +71.9 (c 1.00, CHCl3).
1H NMR (600 MHz, CDCl3): d = 7.35–7.18 (m, 25 H), 4.97 (d,
J = 11.0 Hz, 1 H), 4.87 (d, J = 11.3 Hz, 1 H), 4.80 (d, J = 11.0 Hz,
1 H), 4.78 (d, J = 12.0 Hz, 1 H), 4.73 (d, J = 1.4 Hz, 1 H), 4.65 (d,
J = 12.0 Hz, 1 H), 4.63 (d, J = 12.0 Hz, 1 H), 4.57 (d, J = 11.3 Hz,
1 H), 4.54 (d, J = 3.6 Hz, 1 H), 4.53 (d, J = 12.0 Hz, 1 H), 4.52 (d,
J = 11.4 Hz, 1 H), 4.37 (d, J = 11.4 Hz, 1 H), 4.10 (m, 1 H), 4.00
(ddd, J = 9.9, 3.6, 3.6 Hz, 1 H), 3.97 (t, J = 9.9 Hz, 1 H), 3.76 (dd,
J = 9.6, 3.6 Hz, 1 H), 3.73 (m, 5 H), 3.61 (dd, J = 3.9, 1.4 Hz, 1 H),
3.49 (dd, J = 9.9, 3.6 Hz, 1 H), 3.47 (t, J = 9.9 Hz, 1 H), 3.38 (s, 3
H), 3.31 (s, 3 H).
13C NMR (150 MHz, CDCl3): d = 128.5, 128.4, 128.4, 128.3, 128.3,
128.1, 127.9, 127.9, 127.8, 127.7, 127.6, 127.5, 99.7, 97.7, 82.0,
79.9, 78.1, 77.7, 75.7, 74.9, 73.4, 73.3, 71.3, 72.2, 70.3, 69.6, 69.5,
66.5, 66.0, 55.3, 55.1.
Compounds 10A and 10B
A 60% suspension of NaH in oil (30.2 mg, 0.76 mmol) was added
to a soln of 5a (1.76 g, 3.78 mmol) in DMF–THF (1:1, 3.8 mL) at
0 °C and the mixture was stirred at r.t. After 30 min, 3 (50 mg, 0.19
mmol) was added to the mixture, which was then stirred at reflux for
2.5 h. H2O (100 mL) was added and the mixture was extracted with
CH2Cl2 (3 × 100 mL). The crude product was purified by chroma-
tography (silica gel, EtOAc–hexane, 3:7); this gave 10A (78%) and
10B (10%).
Compound 10A
Yield: 106.8 mg (78%); Rf = 0.4 (EtOAc–hexane, 1:1); [a]D18 +47.2
(c 1.00, CHCl3).
1H NMR (600 MHz, CDCl3): d = 7.39–7.19 (m, 20 H), 5.43 (s, 1 H),
4.92 (d, J = 10.7 Hz, 1 H), 4.88 (d, J = 11.0 Hz, 1 H), 4.74 (d,
J = 10.7 Hz, 1 H), 4.73 (d, J = 12.1 Hz, 1 H), 4.63 (d, J = 1.1 Hz, 1
H), 4.61 (d, J = 12.1 Hz, 1 H), 4.54 (d, J = 11.0 Hz, 1 H), 4.53 (dd,
J = 3.6 Hz, 1 H), 4.23 (dd, J = 10.0, 5.2 Hz, 1 H), 4.07 (ddd,
J = 10.0, 10.0, 5.2 Hz, 1 H), 4.07 (m, 1 H), 3.94 (t, J = 9.3), 3.78 (dd,
J = 10.0, 3.0 Hz, 1 H), 3.73 (dd, J = 11.0, 4.5 Hz, 1 H), 3.69 (t,
J = 10.0 Hz, 1 H), 3.67 (ddd, J = 9.3, 4.5, 1.7 Hz, 1 H), 3.63 (dd,
J = 11.0, 1.7 Hz, 1 H), 3.60 (dd, J = 3.3, 1.1 Hz, 1 H), 3.45 (t, J = 9.3
Hz, 1 H), 3.45 (dd, J = 9.3, 3.6 Hz, 1 H), 3.33 (s, 3 H), 3.31 (s, 3 H).
MS (FAB) (MeCN–NBA + NaI): m/z = 844 [M + Na].
HRMS (FAB) (MeCN–NBA + NaI): m/z calcd for C49H56O11Na:
843.3720; found: 843.3719.
Compound 11B
Rf = 0.45 (EtOAc–hexane, 1:1); [a]D20 +81.3 (c 1.00, CHCl3).
1H NMR (600 MHz, CDCl3): d = 7.35–7.06 (m, 25 H), 4.89 (d,
J = 10.7 Hz, 1 H), 4.80 (d, J = 10.7 Hz, 1 H), 4.74 (d, J = 2.0 Hz, 1
H), 4.73 (d, J = 10.7 Hz, 1 H), 4.70 (d, J = 11.8 Hz, 1 H), 4.65 (d,
J = 10.7 Hz, 1 H), 4.61 (d, J = 3.3 Hz, 1 H), 4.58 (d, J = 11.8 Hz, 1
H), 4.57 (d, J = 10.7 Hz, 1 H), 4.56 (d, J = 12.1 Hz, 1 H), 4.43 (d,
J = 12.1 Hz, 1 H), 4.36 (d, J = 10.7 Hz, 1 H), 4.25 (dd, J = 12.1, 1.9
Hz, 1 H), 3.90 (dd, J = 9.4, 8.5 Hz, 1 H), 3.81 (dd, J = 12.1, 2.2 Hz,
1 H), 3.68 (t, J = 8.5 Hz, 1 H), 3.66 (m, 3 H), 3.59 (m, 3 H), 3.48
(dd, J = 9.4, 3.3 Hz, 1 H), 3.48 (m, 1 H), 3.34 (s, 3 H), 3.27(s, 3 H).
13C NMR (150 MHz, CDCl3): d = 129.3, 128.7, 128.4, 128.3, 128.2,
128.0, 127.9, 127.8, 126.4, 102.4, 100.3, 98.2, 82.3, 80.1, 78.7,
77.8, 76.8, 76.1, 75.2, 73.6, 70.5, 70.0, 69.4, 67.2, 58.4, 55.8, 55.5.
MS (FAB) (MeCN–NBA + NaI): m/z = 752 [M + Na].
HRMS (FAB) (MeCN–NBA + NaI): m/z calcd for C42H48O11Na:
751.3095; found: 751.3038.
13C NMR (150 MHz, CDCl3): d = 138.7, 138.1, 138.0, 138.0, 137.9,
128.4, 128.4, 128.3, 128.3, 127.9, 127.9, 127.7, 127.6, 127.5, 99.2,
Synthesis 2008, No. 23, 3761–3768 © Thieme Stuttgart · New York

PAPER
Ether-Linked Sugar by Nucleophilic Opening of Carbohydrate Oxiranes
3767
98.2, 86.0, 81.8, 80.2, 77.3, 77.2, 75.7, 75.1, 74.7, 73.5, 73.5, 72.8,
71.5, 71.0, 70.3, 68.5, 55.5, 55.1.
Acknowledgment
We wish to thank Ms. J. Shimode, Ms. A. Tonoki, and Ms. A.
Kawaji for spectroscopic measurements. This work was partially
supported by a Grant-in-Aid for Scientific Research from the Mini-
stry of Education, Science, Sports, Culture and Technology, Japan.
Support from the Takeda Science Foundation, Uehara Memorial
Foundation, and Research Foundation for Pharmaceutical Sciences
to H.T. are gratefully acknowledged.
MS (FAB) (MeCN–NBA + NaI): m/z = 844 [M + Na].
HRMS (FAB) (MeCN–NBA + NaI): m/z calcd for C49H56O11Na:
843.3720; found: 843.3716.
Triol 12
TMSOTf (34 mL, 0.19 mmol) and TMU (11 mL, 0.10 mmol) were
added to a soln of 5a (350 mg, 0.76 mmol) and 1 (50 mg, 0.19
mmol) in CH2Cl2 (2.72 mL) at –78 °C. The reaction mixture was
gradually warmed to –10 °C and stirred for 4.5 h. Sat. aq NaHCO3
(100 mL) was added and the mixture was extracted with CH2Cl2 (3
× 100 mL). The crude product was dissolved in AcOH–THF (1:1, 5
mL) and stirred for 12 h. The reaction mixture was poured into sat.
aq NaHCO3 (100 mL) and extracted with CH2Cl2 (3 × 100 mL). Pu-
rification by chromatography (silica gel, MeOH–CH2Cl2, 4:96)
gave triol 12.
References
(1) Pérez, S.; Pérez, R. M.; Pérez, C.; Zavala, M. A.; Vargas, R.
Pharm. Acta Helv. 1997, 72, 105.
(2) (a) Haines, A. H. Tetrahedron Lett. 2004, 45, 835.
(b) Haines, A. H. Org. Biomol. Chem. 2004, 2, 2352.
(c) Cumpstey, I. Synlett 2006, 1711. (d) Ogawa, S.;
Matsunaga, N.; Li, H.; Palcic, M. M. Eur. J. Org. Chem.
1999, 631. (e) Hodosi, G.; Kovac, P. Carbohydr. Res. 1998,
308, 63. (f) Whistler, R. L.; Frowein, A. J. Org. Chem. 1961,
26, 3946.
(3) Takahashi, H.; Fukuda, T.; Mitsuzuka, H.; Namme, R.;
Miyamoto, H.; Ohkura, Y.; Ikegami, S. Angew. Chem. Int.
Ed. 2003, 42, 5069.
(4) Takahashi, H.; Mitsuzuka, H.; Nishiyama, K.; Ikegami, S.
Synthesis 2006, 1415.
(5) (a) Williams, N. R. Adv. Carbohydr. Chem. 1970, 25, 109.
(b) Rehnberg, N.; Magnusson, G. J. Org. Chem. 1990, 55,
5467. (c) Boullanger, P.; Descotes, G. Glycoscience 2001, 1,
253.
Yield: 51 mg (42%); Rf = 0.23 (CH2Cl2–MeOH, 15:1); [a]D29 +66.0
(c 0.50, CHCl3).
1H NMR (600 MHz, CDCl3): d = 7.32–7.21 (m, 15 H), 4.96 (d,
J = 10.8 Hz, 1 H), 4.87 (d, J = 10.8 Hz, 1 H), 4.83 (d, J = 10.8 Hz,
1 H), 4.79 (d, J = 12.6 Hz, 1 H), 4.73 (d, J = 10.8 Hz, 1 H), 4.67 (d,
J = 12.6 Hz, 1 H), 4.62 (d, J = 3.6 Hz, 1 H), 4.60 (d, J = 1.8 Hz, 1
H), 4.15 (dd, J = 10.2, 2.4 Hz, 1 H), 3.97 (t, J = 3.6 Hz, 1 H), 3.92
(dd, J = 1.8, 3.6 Hz, 1 H), 3.88 (dd, J = 3.6, 14.4 Hz, 1 H), 3.87–
3.83 (m, 2 H), 3.79 (dd, J = 4.8, 11.4 Hz, 1 H), 3.72 (ddd, J = 9.6,
4.2, 2.4 Hz, 1 H), 3.64 (t, J = 9.6 Hz, 1 H), 3.61 (t, J = 3.6 Hz, 1 H),
3.58 (dd, J = 10.2, 2.4 Hz, 1 H), 3.51 (dd, J = 9.6, 3.6 Hz, 1 H), 3.36
(s, 3 H), 3.32 (s, 3 H).
(6) (a) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc.
1989, 111, 6661. (b) Danishefsky, S. J.; Bilodeau, M. T.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1380.
13C NMR (150 MHz, CDCl3): d = 138.6, 138.0, 128.5 128.4, 128.1,
128.0, 127.9, 127.8, 127.7, 101.7, 98.2, 81.8, 80.2, 79.7, 77.4, 75.9,
74.9, 73.5, 70.1, 69.8, 69.7, 68.7, 64.2, 62.7, 55.4, 55.3.
(7) For 1,6-anhydro sugars, see: (a) Hung, S.-C.; Wang, C.-C.;
Chang, S.-W.; Chen, C.-S. Tetrahedron Lett. 2001, 42,
1321. (b) Hung, S.-C.; Thopate, S. R.; Chi, F.-C.; Cheng, S.-
W.; Lee, J.-C.; Wang, C.-C.; Wen, Y.-S. J. Am. Chem. Soc.
2001, 123, 3153. For 2,3-anhydro sugars, see: (c) Nogami,
Y.; Nasu, K.; Koga, T.; Ohta, K.; Fujita, K.; Immel, S.;
Lindner, H. J.; Schmitt, G. E.; Lichtenthaler, F. W. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1899. (d) Chiu, S.-H.;
Myles, D. C.; Garrell, R. L.; Stoddart, J. F. J. Org. Chem.
2000, 65, 2792. (e) Callam, C. S.; Gadikota, R. R.; Lowary,
T. L. Synlett 2003, 1271. (f) Callam, C. S.; Gadikota, R. R.;
Krein, D. M.; Lowary, T. L. J. Am. Chem. Soc. 2003, 125,
13112.
MS (FAB) (MeCN–NBA + NaI): m/z = 664 [M + Na].
HRMS (FAB) (MeCN–NBA + NaI): m/z calcd for C35H44O11Na:
663.2781; found: 663.2773.
Compound 13A
TMSOTf (27.9 mL, 0.155 mmol) was added to a soln of 5e (743 mg,
1.55 mmol) and 2 (55.1 mg, 0.16 mmol) in CH2Cl2(1.55 mL) at
–10 °C, and the mixture was stirred for 5 h. Ice water (100 mL) was
added and the mixture was extracted with CH2Cl2 (3 × 100 mL). The
crude product was purified by chromatography (silica gel, EtOAc–
hexane, 1:3); this gave 13A.
Yield: 85.6 mg (66%); Rf = 0.10 (EtOAc–hexane, 1:1); [a]D23 +31.0
(c 0.60, CHCl3).
(8) (a) Hirota, K.; Takasu, H.; Sajiki, H. Heterocycles 2000, 52,
1329. (b) Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92,
1745. (c) Roussev, C. D.; Simeonov, M. F.; Petkov, D. D.
J. Org. Chem. 1997, 62, 5238.
1H NMR (600 MHz, CDCl3): d = 7.34–7.24 (m, 25 H), 4.96 (d,
J = 10.9 Hz, 1 H), 4.86 (d, J = 10.7 Hz, 1 H), 4.79 (d, J = 10.9 Hz,
1 H), 4.75 (d, J = 12.1 Hz, 1 H), 4.63 (d, J = 12.1 Hz, 1 H), 4.61 (d,
J = 3.6 Hz, 1 H), 4.59 (d, J = 11.5 Hz, 1 H), 4.54 (d, J = 11.5 Hz, 1
H), 4.54 (d, J = 10.7 Hz, 1 H), 4.54 (d, J = 4.7 Hz, 1 H), 4.48 (d,
J = 11.5 Hz, 1 H), 4.48 (d, J = 11.5 Hz, 1 H), 4.05 (m, 1 H), 3.94 (d,
J = 9.6 Hz, 1 H), 3.93 (dd, J = 6.1, 4.4 Hz, 1 H), 3.88 (m, 1 H), 3.77
(ddd, J = 9.6, 8.0, 2.5 Hz, 1 H), 3.55 (m, 2 H), 3.48 (dd, J = 9.6, 3.6
Hz, 1 H), 3.40 (s, 3 H), 3.40 (s, 3 H), 3.33 (t, J = 9.6 Hz, 1 H), 3.13
(dd, J = 14.0, 2.5 Hz, 1 H), 3.11 (dd, J = 8.0, 4.4 Hz, 1 H), 2.69 (dd,
J = 14.0, 8.0 Hz, 1 H).
(9) (a) Fürst, A.; Plattner, P. A. Abstracts of Papers of the 12th
International Congress of Pure and Applied Chemistry;
New York, 1951, 409. (b) Angyal, S. J. Chem. Ind. 1954,
222, 1230. (c) Cookson, R. C. Chem. Ind. 1953, 223, 1512.
(d) Eliel, E. L.; Allinger, N. L.; Angyal, S. J.; Morrison, G.
A. Conformational Analysis; Wiley: New York, 1965.
(10) A detailed analysis of the regiospecificity of the nucleophilic
ring opening of oxiranes was reported: (a) Crotti, P.;
Bussolo, V. D.; Favero, L.; Macchia, F.; Pineschi, M.
Tetrahedron 2002, 58, 6069. (b) Crotti, P.; Renzi, G.;
Favero, L.; Roselli, G.; Bussolo, V. D.; Caselli, M.
Tetrahedron 2003, 59, 1453.
(11) (a) Abdel-Malik, M. M.; Perlin, A. S. Carbohydr. Res. 1989,
190, 39. (b) Knapp, S.; Naughton, A. B. J.; Jaramillo, C.;
Pipik, B. J. Org. Chem. 1992, 57, 7328.
(12) Wu, X.; Kong, F.; Lu, D.; Li, G. Carbohydr. Res. 1992, 235,
163.
13C NMR (100 MHz, CDCl3): d = 138.5, 138.0, 137.9, 137.8, 137.7,
128.4, 128.3, 128.3, 128.2, 127.9, 127.9, 127.9, 127.8, 127.7, 127.7,
127.6, 127.6, 102.7, 97.8, 81.9, 80.4, 79.8, 76.1, 75.7, 75.2, 73.4,
73.3, 73.0, 71.7, 71.3, 71.0, 70.0, 55.7, 55.3, 51.5, 34.6.
MS (FAB) (MeCN–NBA + NaI): m/z = 860 [M + Na].
HRMS (FAB) (MeCN–NBA + NaI): m/z calcd for C49H56O10SNa:
859.3492; found: 859.3485.
Synthesis 2008, No. 23, 3761–3768 © Thieme Stuttgart · New York

3768
K. Nishiyama et al.
PAPER
(13) Lipták, A.; Jodal, I.; Nanasi, P. Carbohydr. Res. 1975, 44, 1.
(14) In every reaction, the theoretical amount of alcohol was
recovered almost completely.
(15) The product was derivatized as its acetate to confirm the
structure.
(16) Du, Y.; Mao, W.; Kong, F. Carbohydr. Res. 1996, 282, 315.
(17) Koto, S.; Takebe, Y.; Zen, S. Bull. Chem. Soc. Jpn. 1972, 45,
291.
(19) For the effect of TMU, see: (a) Imagawa, H.; Fujikawa, Y.;
Tsuchihiro, A.; Kinoshita, A.; Yoshinaga, T.; Takao, H.;
Nishizawa, M. Synlett 2006, 639. (b) Imagawa, H.;Iyenaga,
T.; Nishizawa, M. Org. Lett. 2005, 7, 451. (c) Nishizawa,
M.; Takao, H.; Yadav, V. K.; Imagawa, H.; Sugihara, T.
Org. Lett. 2003, 5, 4563.
(20) TMSOTf might be deactivated by partially deprotected
oxirane and product, which would lower the yield of 12.
(21) Shie, C.-R.; Tzeng, Z.-H.; Kulkarni, S.-S.; Uang, B.-J.; Hsu,
C.-Y.; Hung, S.-C. Angew. Chem. Int. Ed. 2005, 44, 1665.
(22) Weng, S.-S.; Lin, Y.-D.; Chen, C.-T. Org. Lett. 2006, 8,
5633.
(18) Inch, T. D.; Lewis, G. J. Carbohydr. Res. 1972, 22, 91.
(23) Yamanoi, T.; Iwai, Y.; Inazu, T. Heterocycles 2000, 53,
1263.
Synthesis 2008, No. 23, 3761–3768 © Thieme Stuttgart · New York