Glycosyl iodides are highly efficient donors under neutral conditions

Article abstract of DOI:10.1016/S0008-6215(99)00146-9

Glycosyl iodides have been prepared and subjected to glycosylation under neutral conditions. The reactions are highly efficient, giving α glycosides even with sterically demanding glycosyl acceptors. Glucosyl iodides react with allyl alcohol slowest and require refluxing conditions. Galactosyl iodides are intermediate in reactivity, providing the allyl glycoside in 3 h at room temperature, whereas glycosylation of fucosyl iodides occurs in less than 1 h under similar conditions. The scope and limitations of the reactions were demonstrated with a variety of acceptors, including an anomeric hydroxyl group, to give trehalose analogs. β-Selective glycosylation of glucosyl iodides, in the absence of C-2 participation, could be achieved by simply changing the solvent from benzene to acetonitrile. Copyright (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0008-6215(99)00146-9

www.elsevier.nl/locate/carres
Carbohydrate Research 320 (1999) 61–69
Glycosyl iodides are highly efficient donors under
neutral conditions
Michael J. Hadd, Jacquelyn Gervay *
The Uni6ersity of Arizona, Department of Chemistry, Tucson, Arizona 85721, USA
Received 25 February 1999; accepted 3 June 1999
Abstract
Glycosyl iodides have been prepared and subjected to glycosylation under neutral conditions. The reactions are
highly efficient, giving a glycosides even with sterically demanding glycosyl acceptors. Glucosyl iodides react with
allyl alcohol slowest and require refluxing conditions. Galactosyl iodides are intermediate in reactivity, providing the
allyl glycoside in 3 h at room temperature, whereas glycosylation of fucosyl iodides occurs in less than 1 h under
similar conditions. The scope and limitations of the reactions were demonstrated with a variety of acceptors,
including an anomeric hydroxyl group, to give trehalose analogs. b-Selective glycosylation of glucosyl iodides, in the
absence of C-2 participation, could be achieved by simply changing the solvent from benzene to acetonitrile. © 1999
Elsevier Science Ltd. All rights reserved.
Keywords: Glycosyl iodide; Glycosyl bromide; a-Glycosylation; In situ anomerization; Halide-catalyzed anomerization; Trehalose
analogs
(1) with 10 equivalents of methanol under
1. Introduction
neutral conditions in acetonitrile does not pro-
ceed, and that the corresponding bromide
takes 8 h to react with 5 equivalents of 2-
propanol (Scheme 1). They also demonstrated
that, upon addition of excess sodium iodide,
the glucosyl chloride started to react after 10
min to produce selectively methyl 2,3,4-6-tri-
Activation of glycosyl halides in the pres-
ence of an acceptor alcohol using a Lewis acid
promoter is the most widely utilized method
of O-glycoside formation [1]. However, the
use of glycosyl halides in the absence of a
Lewis acid promoter has received far less at-
tention, largely due to their low reactivity
toward nucleophilic displacement under neu-
tral conditions. For example, Kronzer and
Schuerch [2] reported that reaction of 2,3,4,6-
O-benzyl-a- -glycoside (2).
D
tetra-O-benzyl-a-
D
-glucopyranosyl
chloride
Abbre6iations: 1,2:5,6-di-O-isopropylidene-a-
D
-glucofura-
nose (‘diacetoneglucose’), DAG; Ethyldiisopropylamine (‘di-
isopropylethylamine’), DIEA; tetrabutylammonium iodide,
TBAI.
* Corresponding author. Tel.: +1-520-621-8843; fax: +1-
520-621-8407.
E-mail address: gervay@u.arizona.edu (J. Gervay)
Scheme 1. Sodium iodide catalysis of glucosyl chlorides.
0008-6215/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(99)00146-9

62
M.J. Hadd, J. Ger6ay / Carbohydrate Research 320 (1999) 61–69
responding glycosyl bromide. Our initial
experiments focused on the formation of allyl
glycosides from the corresponding a-glycosyl
iodides, using tetrabutylammonium iodide
(TBAI) as the soluble iodide source and diiso-
propylethyl amine as a hindered base (Scheme
3). The reactions proceeded swiftly to give the
allyl a-glycosides in good yield with high
stereoselectivity. The reactivities of the glyco-
syl iodides varied tremendously, with the glu-
cosyl iodide 5 reacting slowest, followed by
the galactosyl iodide 7, and the fucosyl iodide
9, which was fastest.
Scheme 2. Tetraethylamonium bromide catalysis of glycosyl
bromides.
Lemieux and co-workers have also investi-
gated the reaction of anomeric bromides un-
der neutral conditions [3]. They showed that
the sluggish reaction rate of glycosyl bromides
under neutral conditions could be greatly in-
creased by the addition of tetraethylammon-
ium bromide. The proposed explanation for
this rate increase is the in situ formation of the
b glycosyl bromide (4), which is more reactive
than its a counterpart (3) (Scheme 2). The
highly reactive b glycosyl bromide undergoes
SN2 displacement by the acceptor alcohol to
give selectively the a glycoside. Halide-ion
catalysis has been shown to work using both
simple alcohols and selectively protected car-
bohydrates as acceptors. However, when gly-
cosyl bromides are employed, the typical
procedure calls for a long (4-day) reaction
time, and certain secondary alcohols give low
yields [4,5].
We recently reported that a glycosyl iodides
are easily accessible from the corresponding
anomeric acetate [6], and that they readily
undergo nucleophilic displacement with stabi-
lized anions [7]. As a natural extension of that
work, we decided to investigate the reaction of
glycosyl iodides [8] with alcohols under neu-
tral conditions with the hope that they would
be more efficient glycosyl donors than the
corresponding bromides.
Although allyl alcohol added to the glycosyl
iodides quickly at room temperature, more
pressing conditions were necessary for hin-
dered alcohols. 1,2:5,6-Di-O-isopropylidene-
a- -glucopyranose (DAG) was chosen as
D
a representative secondary alcohol of moder-
ate reactivity, in order to demonstrate the
applicability of this glycosylation method to
common
glycosyl
acceptors.
Initially,
dichloromethane was used as solvent, and
refluxing conditions were employed in order
to facilitate the reaction. After 24 h, reaction
with the galactosyl iodide produced the a
glycoside 11 in low yield (45%) along with
a major by-product. Mass spectral and
1H NMR analysis confirmed that the by-
product formed was the galactosyl chloride 12
(Scheme 4). Other solvents were employed in
an attempt to increase the reaction rate. For
example, after 3 h in refluxing THF, all of the
galactosyl iodide had been consumed, but
2. Results and discussion
The direct addition of methanol to glycosyl
iodides is very slow and does not always lead
to stereospecific product formation [9]. Based
on the work of Lemieux and co-workers [4],
we thought that introduction of a soluble
iodide source might catalyze the reaction by in
situ formation of the more reactive b-glycosyl
iodide, leading to more efficient and stereospe-
cific a glycoside formation than with the cor-
Scheme 3. Reaction of allyl alcohol with glycosyl iodides.

M.J. Hadd, J. Ger6ay / Carbohydrate Research 320 (1999) 61–69
63
Scheme 4. Reaction of the galactosyl iodide with DAG in CH2Cl2.
again a low yield of 11 was obtained and a
reactivity of glycosyl iodides and the glycosyl
bromides used by Lemieux and co-workers [4]
is shown in Table 1.
1
by-product had formed. Mass spectral and H
NMR data were used to assign the byprod-
uct’s structure as the THF adduct1.
We also looked at the possibility of using
glycosyl bromides as donors under TBAI
catalysis. In an analogous reaction to that
used for the preparation of 9, the fucosyl
bromide was generated by the action of
bromotrimethylsilane (2.2 equivalents) on 1-O
- acetyl - 2,3,4 - tri - O - benzyl - l - fucopyranose.
While reaction of the anomeric acetate with
iodotrimethylsilane (1.1 equivalents) was com-
plete within 20 min, generation of the glycosyl
bromide required 2.5 h. However, subsequent
reaction of the bromide under TBAI catalysis
proceeded at a similar rate to that for 9, with
complete consumption of the acceptor within
4 h (Table 1, entries 8 and 9). This result
suggests that the fucosyl bromide and 9 un-
dergo in situ halide exchange with equal facil-
ity. A comparative rate study between
bromides and iodides of less reactive donors is
currently under investigation, in order to de-
termine the generality of this finding.
Nonetheless, the experiments reported herein
clearly illustrate the advantages of using gly-
cosyl iodides: shorter reaction times, as well as
improved yields, are realized.
In order to avoid solvent reaction with the
glycosyl iodides, benzene was employed, even
though TBAI solubility was low at room tem-
perature. Reaction of 7 in refluxing benzene
with DAG and 2 equiv of TBAI proceeded
smoothly in 5.5 h to give a 93% yield of a 9:1
a:b mixture along with a minor amount of the
glycal (Scheme 5). Addition of 10 equivalents
of TBAI increased the rate of glycosyl iodide
disappearance, but the a selectivity did not
change, and the rate of glycal formation in-
creased. A lower temperature (40 °C) was also
tried, but it only slowed the overall reaction,
with little or no gain in selectivity.
Several other glycosyl iodides were reacted
with TBAI and DAG. The fucosyl iodide 9
reacted in refluxing CH2Cl2 to give a 62%
yield of only the a product 14 in 3 h. This
result was in agreement with our earlier obser-
vation that the fucosyl iodide was more reac-
tive than the galactosyl iodide. The mannosyl
iodide differed from the other glycosyl iodides
in that no TBAI was needed in order to give a
selectivity. Reaction of the mannosyl iodide 15
in refluxing benzene gave a 67% yield of the a
glycoside 16, with the glycal 17 as a by-
product. Reaction of 5 gave a 45% yield of the
a glycoside 18, along with a 44% yield of 172.
Attempts to limit elimination by changing to a
milder base failed. A comparison between the
In order to investigate the ability of the
glycosyl iodides to react with other secondary
alcohol acceptors, the C-2 hydroxyl group of
1,6-anhydro-3,4-O-isopropylidene-b- -galac-
D
topyranose was chosen as an example of a
secondary axial alcohol acceptor. Reaction of
9 with the anhydrosugar and TBAI in
dichloromethane at room temperature pro-
vided a 91% yield of only the a glycoside 19 in
5.5 h (Scheme 6).
1 Similar product formation was observed by Iadonisi and
co-workers upon activation of trichloracetimidates with air-
oxidised samarium diiodide in tetrahydrofuran. M. Adinolfi,
G. Barone, A. Iadonisi, R. Lanzetta, Tetrahedron Lett., 39
(1998) 5605–5608.
The facility with which the glycosyl iodides
underwent glycoside formation prompted us
to investigate the possibility of using them as
donors in constructing the 1,1%-linkage found
2 The yield of 18 is based upon the theoretical yield of the
acceptor, which is the limiting reagent. The yield of 17 is
based upon using 1.3 equivalents of the glycosyl iodide.

64
M.J. Hadd, J. Ger6ay / Carbohydrate Research 320 (1999) 61–69
Scheme 5. Reaction of glycosyl iodides in refluxing benzene.
Once it was established that high a selectiv-
ity was attainable in glycosylation reactions
using glycosyl iodide donors, b-selective glyco-
sylation strategies were investigated. Since the
glycosyl donors have a nonparticipating group
at the C-2 position, the only viable mechanism
that would produce a b linkage would be SN2
displacement of an a iodide or other leaving
group. High a selectivity is achieved in TBAI-
catalyzed reactions because the b iodide is a
more reactive glycosyl donor than the a
anomer due to the anomeric effect [10]. There-
fore we considered the possibility of exploiting
the anti-anomeric effect in order achieve b
selectivity [11]. The anti-anomeric effect arises
from the fact that a positively charged
anomeric substituent is more stable in the b
configuration. Therefore, if an equilibrium be-
in trehalose. The fucose derivative of trehalose
has to our knowledge never been synthesized.
For this reason, we chose it as our synthetic
target in probing the formation of the 1,1%-gly-
cosidic linkage. Fucosyl iodide 9 was reacted
with 2,3,4-tri-O-benzyl- -fucopyranose in
L
refluxing benzene in the presence of 10 equiva-
lents of TBAI and 2 equivalents of DIEA.
After 1 h, the reaction gave a 90% yield of a
1.1:1 ratio of the a,a:a,b (20:21) trehalose
derivatives (Scheme 7). Several different mech-
anistic scenarios, which are currently under
investigation in our laboratory, could explain
the product mixture. However, it is notewor-
thy that the a,a:a,b ratio increased to 6.5:1
when only 2 equivalents of TBAI were used
and the reaction was performed at room tem-
perature in CH2Cl2.

M.J. Hadd, J. Ger6ay / Carbohydrate Research 320 (1999) 61–69
65
Table 1
Halide catalysis: comparison of glycosyl bromides [4,5] with glycosyl iodides
Entry
Donor
Catalyst
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
Glc-Br (3)+DAG
N(Et)4Br
N(Bu)4I
N(Et)4Br
N(Bu)4I
N(Et)4Br
N(Bu)4I
none
48
1.5
48
5.5
48
3
5.5
4
4
42
44
62
Glc-I (5)+DAG
Gal-Br+DAG
Gal-I (7)+DAG
Fuc-Br+DAG
Fuc-I (9)+DAG
Man-I (15)+DAG
Fuc-Br+dodecanol (bromide formed in 2.5 h)
Fuc-I (9)+dodecanol (iodide formed in 20 min)
93 (9:1 a:b)
47
62
67
Quant.
Quant.
N(Bu)4I
N(Bu)4I
ate. Support for this theory was recently pub-
lished by Miljkovic´ and co-workers [13],
where they demonstrated that oxonium ion
formation is stabilized by the presence of an
axial substituent at the C-4 position of the
pyranose ring, and that this stabilization is
greatest if the substituent is an ether. Due to
the stabilizing effect of the C-4 axial benzyl
ether, the oxonium ion would be formed at a
faster rate in the galactose case and might
exhibit selectivity for reaction with the alcohol
over solvent participation by acetonitrile. Ex-
tension of these reaction conditions to the
mannosyl iodide gave an approximately 1:1
ratio of a and b anomers both in the presence
and absence of TBAI (Scheme 11). This result
might be explained by an oxonium ion with a
stability that is between that of the glucosyl
and galactosyl oxonium species, thus yielding
a mixture of anomers. At this point, however,
several other mechanistic explanations cannot
be discounted, and further research must be
done to clearly demonstrate the effects of
solvent and carbohydrate structure on the spe-
cificity and rate of reaction for the glycosyl
iodides in polar solvents.
Scheme 6. 1,6-Anhydrogalactose reactions with fucosyl iodide
9.
tween the two anomers could be established,
the a anomer should be more reactive, selec-
tively producing the b glycoside (Scheme 8).
Our plan for setting up such an equilibrium
was to utilize an a nitrilium ion [12] that could
be formed from either the b glycosyl iodide or
the oxonium ion. To test this hypothesis, the
glucosyl iodide 5 was reacted with allyl alco-
hol, DIEA, and TBAI in acetonitrile. After 2
h at room temperature, a 9.8:1 ratio of b:a
glycosides was obtained (Scheme 9).
Two mechanisms for the b selectivity were
probable, either the a nitrilium ion formed
and reacted with the alcohol, or due to the
increased polarity of the solvent the a iodide
reacted by a type I SN2 reaction (Scheme 10).
If 5 reacted by the type I SN2 process, we
would expect the galactosyl iodide 7, which
was shown earlier to be more reactive, to
show better b selectivity and a faster reaction
rate. However, when 7 was reacted under the
same conditions, it yielded only the a gly-
coside after 45 min. One explanation for this
result is that the rate of formation of the
galactosyl oxonium ion is faster than the rate
of formation of the glucosyl oxonium ion, and
that the galactosyl oxonium species is trapped
by the alcohol with no nitrilium ion intermedi-
3. Conclusions
The use of glycosyl iodides as efficient
donors in the selective synthesis of a glyco-
sidic linkages has been demonstrated. The ad-
vantages of using glycosyl iodides over the
corresponding bromides include more rapid
generation of the iodide donor, increased rates
of glycosylation, and more efficient incorpora-
tion of sterically demanding acceptors. Fur-

66
M.J. Hadd, J. Ger6ay / Carbohydrate Research 320 (1999) 61–69
Scheme 7. Preparation of fucosyl trehalose derivatives.
400 mesh ASTM). Mass spectrometry was
performed by the University of Minnesota
Mass Spectrometry Service and the University
of Arizona Mass Spectrometry Facility.
Known compounds showed physicochemical
and spectral data that were consistent with
those reported in the indicated references.
General procedure for allyl h-glycoside for-
mation (6, 8 and 10).—To a solution of the
1-O-acetyl-tetra-O-benzylglycose (0.1 mmol)
in 1 mL of CH2Cl2 cooled to 0 °C is added
iodotrimethylsilane (0.11 mmol for glucose
and fucose, and 0.1 mmol for galactose), and
the mixture was allowed to stand for 30 min.
The solvent was then evaporated in vacuo,
and 1.5 mL of toluene was added and again
evaporated in vacuo3. CH2Cl2 (1 mL) was
added, and the resulting solution was pipeted
into an already stirring solution of CH2Cl2 (1
mL), allyl alcohol (14 mL, 0.2 mmol), DIEA
(35 mL, 0.2 mmol) and TBAI (74 mg, 0.2
Scheme 8. Utilization of the anti-anomeric effect to obtain b
glycosides.
thermore, our initial experiments suggest that
glycosyl iodides may also be suitable donors
for the construction of b glycosides by simply
altering the solvent polarity. The results re-
ported herein raise important mechanistic
questions, which are currently under investiga-
tion in our laboratory.
,
mmol) with 4 A molecular sieves (150 mg).
The solution was then stirred for 40 min (fu-
cose), 3 h (galactose), or 2 h reflux (glucose),
and the solvent was evaporated in vacuo. The
resulting oil was subjected to flash column
chromatography using 9:1 hexanes–ethyl ac-
etate for the fucose reaction or 6:1 hexanes–
ethyl acetate for the galactose and glucose
reactions to yield the allyl a-glycosides: fu-
cose, 62%; galactose [14], 69%; and glucose
4. Experimental
Starting materials and reagents purchased
from suppliers were used without further
purification. Chemicals were obtained from
Fluka Chemical Co.: iodotrimethylsilane, te-
tra-O-benzyl- -glucopyranose. Solvents were
D
dried by distillation prior to use. Dichloro-
methane and toluene were dried over calcium
hydride, and tetrahydrofuran was dried over
sodium–benzophenone ketyl. Chromatogra-
phy was performed using Silica Gel 60 (230–
1
[15], 71%. Data for the allyl a-fucoside 8: H
NMR (250 MHz, C6D6): l 0.9 (d, 3 H, J
6.5Hz), 3.35 (1 H, m), 3.74–3.90 (2 H, m),
4.0–4.12 (2 H, m), 4.25 (1 H, dd, J 8.1, 4.5
Hz) 4.41–4.62 (4 H, m), 4.79 (1 H, d, J 12.0
Hz), 4.93 (1 H, d, J 3.6 Hz, H-1), 5.0–5.07 (2
3 Toluene is added and evaporated in order to remove the
trimethylsilyl acetate by azeotropic distillation. Trimethylsilyl
acetate adds to the iodide to reform the anomeric acetate.
This process competes with glycoside formation.
Scheme 9. Reaction of the glucosyl iodide in acetonitrile.

M.J. Hadd, J. Ger6ay / Carbohydrate Research 320 (1999) 61–69
67
Scheme 11. Reaction of the mannosyl iodide in acetonitrile.
(MH); Found: 781.3605 (MH); [h]D +42.7° (c
0.02, CHCl3).
1,2:5,6-Di-O-isopropylidene-h-
anos-3-yl 2,3,4-tri-O-benzyl-h- -fucopyranose
(14).—To a solution of 1-O-acetyl-2,3,4-tri-O-
benzyl- -fucopyranose (97 mg, 0.20 mmol) in
D
-glucofur-
Scheme 10. Possible mechanistic routes into b glycoside for-
mation.
L
L
H, m), 5.27–5.34 (1 H, m), 5.81 (1 H, m)
7.08–7.42 (15 H, m); 13C NMR (62.5 MHz,
C6D6): l 16.9, 66.8, 68.5, 73.0, 73.4, 75.4, 77.6,
79.1, 79.4, 97.3, 116.5, 127.6, 127.7, 128.0,
128.4, 128.5, 128.6, 139.6, 139.8; HRFABMS:
Anal. Calcd: 473.2328 (MH); Found: 473.2340
(MH); [h]D −67.0° (c 0.04, CHCl3).
1 mL CH2Cl2 cooled to 0 °C was added
iodotrimethylsilane (29 mL, 0.20 mmol), and
the mixture was allowed to stand for 20 min.
The solvent was evaporated in vacuo, and 1.0
mL of toluene was added and again evapo-
rated in vacuo. CH2Cl2 (1 mL) was then
added, and the resulting solution was pipeted
into an already stirring solution of DAG (41
mg, 0.16 mmol), DIEA (55 mL, 0.31 mmol),
and TBAI (116 mg, 0.31 mmol) in 1 mL of
1,2:5,6-Di-O-isopropylidene-h-
anos-3-yl 2,3,4,6-tetra-O-benzyl-h-
topyranose (11).—To a solution of 1-O-acetyl-
2,3,4,6-tetra-O-benzyl- -galactopyranose (140
D
-glucofur-
D
-galac-
D
,
CH2Cl2 with 4 A molecular sieves. After
mg, 0.24 mmol) in CH2Cl2 cooled to 0 °C was
added (34 mL, 0.24 mmol) of iodotrimethylsi-
lane, and the mixture was allowed to stand for
30 min. The solvent was removed in vacuo,
and 1.5 mL of toluene was added and again
removed in vacuo. Then 1 mL of benzene was
added, and the solution was pipeted into an
already stirring solution of DAG (48 mg, 0.18
mmol), (DIEA 65 mL, 0.37 mmol), and TBAI
(137 mg, 0.37 mmol) in 1 mL of benzene with
refluxing for 3 h, the solvent was evaporated in
vacuo, and the resulting oil was subjected to
flash column chromatography using 9:1 hex-
anes–ethyl acetate as eluent to yield 67 mg
(62%) of the a glycoside 14 [17].
1,2:5,6-Di-O-isopropylidene-h-
anos-3-yl 2,3,4,6-tetra-O-benzyl-h-
pyranose (16).—To a solution of 1-O-acetyl-
2,3,4,6-tetra-O-benzyl- -mannopyranose (89
D
-glucofur-
-manno-
D
D
mg, 0.15 mmol) in 1.5 mL of CH2Cl2 cooled to
0 °C was added iodotrimethylsilane (22 mL,
0.15 mmol), and the mixture was allowed to
stand for 30 min. The solvent was evaporated
in vacuo, and 1.5 mL of toluene was added
and again evaporated in vacuo. Then 1 mL of
benzene was added, and the solution was
pipeted into an already stirring solution of
DAG (31 mg, 0.18 mmol), and DIEA (40 mL,
,
4 A molecular sieves. After refluxing for 5.5 h,
the solvent was evaporated in vacuo, and the
resulting oil was subjected to flash column
chromatography using 6:1 hexanes–ethyl ac-
etate as eluent to yield 7 mg of 3,4,6-tri-O-ben-
zyl- -galactal, 122 mg of the a anomer 11a
D
[16], and 14 mg of the b anomer 11b, for a
1
total yield of 93%. Data for 11b: H NMR
(250 MHz, C6D6): l 1.14 (s, 3 H), 1.27 (s, 3 H),
1.34 (s, 3 H), 1.49 (s, 3 H), 3.29 (m, 2 H), 3.55
(dd, 1 H), 3.69 (t, 1 H), 3.81 (d, 1 H), 3.92 (dd,
1 H), 4.18–4.72 (m, 14 H), 4.97 (d, 1 H), 5.81
,
0.24 mmol) in 1 mL of benzene with 4 A
molecular sieves. After refluxing for 5.5 h, the
solvent was evaporated in vacuo, and the re-
sulting oil was subjected to flash column
chromatography using 6:1 hexanes–ethyl
acetate as eluent to yield 62 mg (67%) of the
a glycoside 16 along with 24 mg of the
glycal 17. Data for a glycoside 16: 1H
13
(d, 1 H). C NMR (62.5 MHz, C6D6): l 26.2,
26.9, 66.3, 68.7, 73.6, 73.9, 75.1, 79.8, 81.0,
81.3, 82.4, 83.2, 102.5, 105.6, 127.5, 127.6,
127.8, 128.0, 128.1, 128.3, 128.4, 128.6, 138.6,
139.4; HRFABMS: Anal. Calcd: 781.3588

68
M.J. Hadd, J. Ger6ay / Carbohydrate Research 320 (1999) 61–69
NMR (250 MHz, C6D6): l 1.06 (s, 1 H), 1.21
(s, 3 H), 1.30 (s, 1 H), 1.39 (s, 3 H), 3.76 (d, 2
H, J 3.6 Hz), 3.92 (t, 1 H, J 2.1 Hz), 4.03–
4.14 (4 H), 4.19–4.41 (9 H), 4.62 (s, 2 H), 4.86
(d, 1 H, J 3.6 Hz), 4.97 (d, 1 H, J 11.2 Hz),
5.40 (d, 1 H, J 1.7 Hz, H-1), 5.90 (d, 1 H, J
3.6 Hz), 7.07–7.43 (20 H); 13C NMR (62.5
MHz, C6D6): l 25.6, 26.2, 29.9, 67.9, 70.1,
72.2, 72.8, 73.1, 73.5, 73.7, 75.2, 75.5, 75.6,
80.3, 81.7, 84.2, 99.7, 105.8, 109.4, 127.4,
127.6, 127.7, 127.8, 128.0, 128.3, 128.4, 128.5;
HRFABMS: Anal. Calcd: 781.3588 (MH);
Found: 781.3593 (MH); [h]D +15.9° (c 0.08,
CHCl3).
was stirred for 5.5 h, at the end of which time
the solvent was evaporated in vacuo, and the
resulting oil was subjected to flash column
chromatography using 3:1 hexanes–EtOAc)
as eluent to yield 209 mg (91%) of the a
1
glycoside 19: H NMR (250 MHz, C6D6): l
1.08–1.12 (m, 6 H), 1.37 (s, 3 H), 3.30 (s, 1
H), 3.42 (t, 1 H, J 6.1 Hz), 3.91–4.01 (m, 3
H), 4.09–4.35 (m, 6 H), 4.42–4.59 (m, 5 H),
4.68 (d, 1 H, J 11.9), 4.95 (d, 1 H, J 6.8 Hz,
H-1 fucose), 4.98 (s, 1 H), 5.80 (s, 1 H); 13C
NMR (62.5 MHz, C6D6): l 16.8, 24.1, 25.8,
63.3, 67.4, 69.7, 72.5, 73.2, 75.3, 75.4, 77.2,
78.6, 78.8, 79.5, 99.7, 101.1, 108.4, 127.6,
127.8, 128.0, 128.4, 128.5, 139.4; HRFABMS:
Anal. Calcd: 617.2751 (MH); Found: 617.2750
(MH); [h]D −44.2° (c 0.3, CHCl3).
1,2:5,6-Di-O-isopropylidene-h-
anos-3-yl 2,3,4,6-tetra-O-benzyl-h-
ranose (18).—To a solution of 1-O-acetyl-
2,3,4,6-tetra-O-benzyl- -mannopyranose (219
D
-glucofur-
D-glucopy-
D
2,3,4-Tri-O-benzyl-h-
tri-O-benzyl-h- -fucopyranoside
2,3,4-tri-O-benzyl-i- -fucopyranosyl 2,3,4-tri-
O-benzyl-h- -fucopyranoside (21).—To a so-
lution of 1-O-acetyl-2,3,4-tri-O-benzyl- -fuco-
L
-fucopyranosyl 2,3,4-
mg, 0.38 mmol) in 1.5 mL of CH2Cl2 cooled
to 0 °C was added iodotrimethylsilane (54 mL,
0.38 mmol), and the mixture was allowed to
stand for 30 min. The solvent was then evapo-
rated in vacuo, and 2.0 mL of toluene was
added and again evaporated in vacuo. Then
1.5 mL of benzene was added, and the solu-
tion was pipeted into an already stirring solu-
tion of DAG (75 mg, 0.29 mmol), TBAI (214
mg, 0.58 mmol), and DIEA (100 mL, 0.24
L
(20) and
L
L
L
pyranose (100 mg, 0.21 mmol) in 1.5 mL
CH2Cl2 cooled to 0 °C was added iodotrime-
thylsilane (30 mL, 0.21 mmol), and the mixture
was allowed to stand for 20 min. The solvent
was evaporated in vacuo, and 1.5 mL of
toluene was added and again evaporated in
vacuo. Benzene (1 mL) was added, and the
resulting solution was pipeted into an already
,
mmol) in 1 mL of benzene with 4 A molecular
sieves. After refluxing for 1.5 h, the solvent
was evaporated in vacuo, and the resulting oil
was subjected to flash column chromatogra-
phy using 7:1 hexanes–ethyl acetate as eluent
to yield 102 mg (45%) of the a glycoside 18
[18] along with 86 mg of the glycal 17.
stirring solution of 2,3,4-tri-O-benzyl- -fu-
L
copyranoside (70 mg, 0.16 mmol), TBAI (600
mg, 1.62 mmol), and DIEA (56 mL, 0.32
mmol) preheated to reflux in 1 mL of benzene
,
with 4 A molecular sieves. The reaction was
1,6-Anhydro-3,4-O-isopropylidene-
topyranos-2-yl 2,3,4-tri-O-benzyl-h-
ranoside (19).—To a solution of 1-O-acetyl-
2,3,4-tri-O-benzyl- -fucopyranose (231 mg,
D
-galac-
refluxed for 1 h, at the end of which time the
solvent was evaporated in vacuo, and the re-
sulting oil was subjected to flash column chro-
matography using 7:1 hexanes–EtOAc as
eluent to yield 66 mg of the a,a 20, 58 mg of
L
-fucopy-
L
0.49 mmol) in 2 mL of CH2Cl2 cooled to 0 °C
was added iodotrimethylsilane (74 mL, 0.52
mmol), and the mixture was let stand for 10
min. The solvent was evaporated in vacuo,
and 1.5 mL of toluene was added and again
evaporated in vacuo. CH2Cl2 (1 mL) was then
added, and the resulting solution added to an
already stirring solution of 1,6-anhydro-3,4-
the a,b 21, and 6 mg of 3,4,6-tri-O-benzyl- -
L
fucal. The overall yield is 90% with a 1.14:1,
a,a:a,b ratio of anomers. Data for a,a anomer
1
20: H NMR (250 MHz, C6D6): l 1.25 (d, 6
H, J 6.5 Hz, H-6), 3.40 (d, 2 H, J 1.5 Hz), 4.14
(dd, 2 H, J 10.2, 2.8 Hz), 4.29 (dd, 2 H, J 10.1,
3.5 Hz), 4.35 (q, 2 H, J 6.6 Hz), 4.48 (d, 4 H,
J 11.5 Hz), 4.56 (d, 2 H, J 8.5 Hz), 4.60 (d, 2
H, J 8.5 Hz), 4.71 (d, 2 H, J 11.7 Hz), 4.98 (d,
2 H, J 11.3 Hz), 5.50 (d, 2 H, J 3.5 Hz,
H-1,H-1%), 7.00–7.40 (m, 20 H); 13C NMR
O-isopropylidene- -galactopyranose (75 mg,
D
0.37 mmol), TBAI (344 mg, 0.93 mmol),
,
DIEA (110 mL, 0.63 mmol), and 4 A molecu-
lar sieves in 1 mL of CH2Cl2. The solution

M.J. Hadd, J. Ger6ay / Carbohydrate Research 320 (1999) 61–69
69
21 (1982) 155–224. (c) G. Boons, Tetrahedron, 52 (1996)
1095–1121. (d) D.M. Whitfield, S.P. Douglas, Gylcocon-
jugate J., 13 (1996) 5–17.
(62.5 MHz, C6D6): l 17.1, 67.2, 73.0, 73.4,
75.4, 77.2, 78.7, 79.9, 94.2, 127.6, 127.7, 128.0,
128.3, 128.4, 128.6; HRFABMS: Anal. Calcd:
849.4003; Found: 849.4031 (MH); [h]D
−100.5° (c 0.04, CHCl3). Data for a,b anomer
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4063–4068.
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1
21: H NMR (250 MHz, C6D6): l 1.22 (d, 3
H, J 6.3 Hz, H-6), 1.30 (d, 3 H, J 6.3 Hz,
H-6), 3.10 (q, 1 H, J 7.2 Hz), 3.18 (d, 1 H, J
2.8 Hz), 3.33 (dd, 1 H, J 9.7, 2.6 Hz), 3.37 (s,
1 H), 4.07–4.19 (m, 2 H), 4.26 (dd, 1 H, J
10.3, 3.3 Hz), 4.40–4.72 (m, 10 H), 4.82 (d, 1
H, J 11.6 Hz), 4.99 (d, 2 H, J 11.4 Hz), 5.33
(d, 1 H, J 11.8 Hz), 5.39 (d, 1 H, J 3.5 Hz,
H-1a), 6.95–7.45 (m, 20 H); 13C NMR (62.5
MHz, C6D6): l 16.8, 17.2, 67.7, 70.7, 73.1,
73.3, 74.9, 75.2, 75.3, 77.1, 77.5, 78.8, 79.7,
80.1, 82.9, 100.4, 104.2, 127.2, 127.4, 127.6,
127.9, 128, 128.4, 128.6, 139.6, 139.7; HR-
FABMS: Anal. Calcd: 849.4003; Found:
849.4031 (MH); [h]D −59.1° (c 0.04, CHCl3).
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Acknowledgements
Financial support for this research was
gratefully received from The Arizona Disease
Control Research Commission, Eli Lilly and
Co, and the Alfred P. Sloan Foundation.
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