A new synthesis of the oligosaccharide domain of acarbose

Article abstract of DOI:10.1016/j.carres.2003.09.004

Synthesis of the oligosaccharide domain of acarbose was reinvestigated and was optimally performed using a maltosidic acceptor, already bearing a α-D-Glc-(1→4)-D-Glc bond, and a new D-fucopyranosyl donor. The crucial glycosylation step was improved by varying three different parameters and notably by focusing on the C-4 protecting group of the fucosyl residue, solvent and promoter. The resulting trisaccharide was further transformed into an electrophilic species in order to open further derivatization perspectives for designing new acarbose analogues. Substitution reactions were efficiently carried out with azide and thiocyanate anions. Two other potentially interesting trisaccharidic compounds were also synthesized, i.e. the C-4 ^III amine and the corresponding isothiocyanate.

Full text of DOI:10.1016/j.carres.2003.09.004

Carbohydrate Research 338 (2003) 2779Á2792
/
www.elsevier.com/locate/carres
A new synthesis of the oligosaccharide domain of acarbose
Re´gis Pe´rion,a,b Le´naıck Leme´e,a Vincent Ferrie`res,a,* Raphael Duval,b
¨
¨
Daniel Plusquelleca
a Synthe`ses et Activations de Biomole´cules, UMR CNRS 6052, Ecole Nationale Supe´rieure de Chimie de Rennes, Avenue du Ge´ne´ral Leclerc, F-35700
Rennes, France
b Chiralsep, Parc d’activite´s de la Boissie`re, 11 Rue de la Boissie`re, F-76170 La Frenaye, France
Received 25 July 2003; accepted 9 September 2003
Abstract
Synthesis of the oligosaccharide domain of acarbose was reinvestigated and was optimally performed using a maltosidic acceptor,
D
already bearing a a-
-Glc-(10/4)-D-Glc bond, and a new D-fucopyranosyl donor. The crucial glycosylation step was improved by
varying three different parameters and notably by focusing on the C-4 protecting group of the fucosyl residue, solvent and promoter.
The resulting trisaccharide was further transformed into an electrophilic species in order to open further derivatization perspectives
for designing new acarbose analogues. Substitution reactions were efficiently carried out with azide and thiocyanate anions. Two
other potentially interesting trisaccharidic compounds were also synthesized, i.e. the C-4III amine and the corresponding
isothiocyanate.
# 2003 Elsevier Ltd. All rights reserved.
Keywords: Acarbose; Maltose; D-Fucose; Thioglycosides; Glycosylation reactions
1. Introduction
glucosidases, structural modifications are able to alter
the initial biological property. These observations were
interestingly reviewed by Nishimura in the 1990s.3 More
Acarbose is one of the most famous hypoglycemic
agents. Owing to its inhibiting effects on a-glucosidases,
it is frequently used for the treatment of type II insulin-
independent diabetes.1 Acarbose history began in 1975
with its isolation from Actynomycetals species.2 Since
that time, numerous projects have been instigated on the
basis of both its biological properties and its particular
chemical structure so that more than 100 related studies
have been published in the last 5 years. Moreover,
concomitant increasing number of patients suffering
recently, transfer of acarviosineÁglucose residue from
/
acarbose to various mono- and disaccharidic acceptors
under the action of Bacillus stearothermophilus malto-
genic amylase allowed Robyt and coworkers to prepare
acarbose analogues containing isomaltose, cellobiose
and lactose structures.4 The latter derivative was indeed
a potent competitive inhibitor for b-glucosidase but no
more for a-glucosidase. This result demonstrates that
modification of the reducing part, two or three glycosyl
units far away from the cyclitol moiety, involves serious
biological changes. Actually, structural variations were
generally introduced directly on acarbose either on the
terminal valienamine or on the reducing residue. On this
basis, acarbose 1 can be viewed as a pseudotetrasac-
charide built with an aminocyclitol and a trisaccharide
domain which is characterized by a linear connection
between one rare quinovosyl residue and two glucosyl
entities (Fig. 1). Moreover, previous total synthesis of
acarbose suggested that the final key-step consists in
binding a valienamine derivative to a trisaccharidic
building block.5Á7 In this context, we have initiated a
from diabetes*
/
150 million people in 2000, but twice
that in 2025 estimates the World Health Organization*
/
continuously supports further research works for find-
ing new drugs for the treatment of this incurable disease
and also more efficient preparation procedures. While
acarbose shows high selectivity and activity toward a-
* Corresponding author. Tel.: ꢀ
/
33-223-238-058; fax: ꢀ
/
33-
223-238-046.
E-mail address:
Ferrie`res).
vincent.ferrieres@ensc-rennes.fr (V.
0008-6215/03/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2003.09.004

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/
Scheme 1. Proposed retrosynthetic scheme for 2 and 3.
already possessing an appropriate a-
D
-Glc-(10/4)-D-
Fig. 1. Structure of acarbose 1.
Glc linkage.
program devoted to a novel route for synthesizing
acarbose along with new derivatives. Since valienamine
can be produced according to different methods,8 we
first focused on the preparation of the carbohydrate
domain. Ogawa’s approach relies on a pre-formed
maltotriosyl compound5 further transformed into an
epoxide. However, introduction of the valienamine part
on the trisaccharidic epoxide was not regiospecific. In a
second possibility, Danishefsky and coworkers used a-
glycal epoxides and glycosyl fluorides as donors for the
construction of two new glycosidic linkages.6 The third
known synthesis was proposed by Schmidt and Lae-
secke who performed a coupling reaction between a
maltosidic acceptor and an extremely rare quinovosyl
trichloroacetimidate.7 Unfortunately, the two latter
methodologies were achieved without total diastereo-
control of the glycosylation reactions. In consideration
of these precedents, the choice of glycosyl donor(s)
proves to be crucial to success in this project.
2. Results and discussion
Acceptor 3 has been prepared as a mixture of a,b-
anomers from maltose in only three steps.11 However,
we anticipated that the resulting a,b-mixture would
significantly complicate NMR assignments after fuco-
sylation reaction since two or four different diastereoi-
somers could theoretically be obtained. Therefore, the
structurally well defined compound 3, presenting a
reducing unit with an anomeric b configuration, was
prepared according to a multi-step approach by first
acetalizing maltose in dimethylsulfateÁdimethylforma-
/
mide mixture at 70 8C.12 This procedure cleanly af-
forded the 4II,6II-benzylidene maltose in 67% yield.
Acetylation under standard conditions followed by
selective anomeric deacylation under the action of
morpholine afforded the hemiacetal 4 (Scheme 2). The
key 1-O-benzylation was further achieved in a similar
fashion as that already described for the preparation of
methyl maltoside.13 Using silver(I) oxide as a base in
dichloromethane, the kinetically favored b-anomer 5
was isolated in 83% yield and exclusively obtained as
revealed the NMR spectrum and more particularly the
coupling constant value of 7.6 Hz between H-1a and H-
2a. Subsequent Zemple´n transesterification followed by
standard benzylation furnished 6 which was submitted
to reductive opening of the benzylidene ring. The latter
reaction proved to be tightly dependent on both the
reductive agent and the proton source. First attempted
Numerous studies have shown that the reactivity of
both donor and acceptor is closely connected with the
nature and the position of protecting groups present on
these substrates. Amongst the most popular donors, we
turned to thioglycosides owing to their easy availability
and their compatibility with various protecting group
manipulations. Conversely, Wong and coworkers were
able to establish a reactivity database of thioglycosides
in which the more reactive donor is a perbenzylated 1-
thio-
ported that 1,2-cis-
L
-fucopyranoside.9 Moreover, other authors re-
-fucosides are often obtained with
L
excellent stereoselectivities using non-participating ben-
zyl ether groups.10 Therefore, we assumed that a similar
behavior occurs starting from the enantiomeric 1-thio-
opening by the boraneÁtetrahydrofuran complex in the
/
presence of methanesulfonic acid gave the undesired 4-
OBn, 6-OH maltoside in 65% yield along with 16% of
diol 7. Although this by-product could not be totally
avoided, the required compound 3 was synthesized using
D-fucopyranosyl donor. For our purpose, further car-
bohydrate domain elongation requires an orthogonal
protecting group at the axial hydroxyl on the donor, and
the effect of four groups was examined (Scheme 1).
the boraneÁtrimethylamine complex and aluminum
/
trichloride, or better still, methanesulfonic acid. The
maltosidic acceptor 3 was thus chromatographically
isolated in 56% and 68% yield, respectively.
Our attention was further turned to the synthesis of
the D-fucopyranosyl donor. Its preparation started from
known thiogalactopyranoside 814 (Scheme 3). This latter
substrate was obtained in our laboratory in five steps
Since
of the required donor 2 was best achieved starting from
-galactose. Finally, in order to limit glycosylation
D-fucose is an expensive raw material, preparation
D
reactions, we selected the 4II-OH free maltoside 3 as
an acceptor since it can be obtained in a few steps from
maltose, a common and easily available disaccharide

R. Pe´rion et al. / Carbohydrate Research 338 (2003) 2779Á
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2781
Scheme 2. Preparation of maltosidic acceptor 3. Conditions: (a) i. PhCHO, Me2SO4, DMF (67%); ii. Ac2O, Pyr (94%); iii.
morpholine, CH2Cl2 (88%); (b) BnBr, Ag2O, CH2Cl2 (83%); (c) i. NaOMe, MeOH; ii. BnBr, NaH, DMF (88%); (d) BH3:NMe3,
MeSO3H, THF (3: 68%; 7: 17%).
or in toluene. Conversely, it was shown that electron-
donating solvent such as ethers are able to stabilize an
intermediate oxycarbenium and so strengthen the a-
directed introduction of the nucleophile.17 First cou-
pling was achieved from 4-O-acetylated fucosyl donor
2a and acceptor 3 in a 1:2.4 toluene-1,4-dioxane mixture
and was promoted by NIS/Sn(OTf)2. After stirring for
45 min at room temperature, standard work-up and
chromatography, the desired trisaccharide 10a and its
stereoisomer 11a presenting a b-D-fucopyranosyl entity
were isolated in 63% global yield (Table 1, entry 1).
Considering 2D NMR data, the non-reducing fucosides
in 10a and 11a clearly differed from one another in
coupling constant values, J1c,2c 3.8 Hz for the major 10a
while J1c,2c 7.8 Hz for 11a. These results were corrobo-
rated by JC-1,H-1 values obtained according to a HMQC
technique.18 Indeed, a characteristic difference of 11 Hz
between one-bond coupling constants was observed for
Scheme 3. Synthesis of
D
-fucopyranosyl donors 2aÁd. Condi-
/
tions: (a) i. MsCl, Et3N, CH2Cl2; ii. LiAlH4, THF (80%); (b)
Ac2O, Pyr, DMAP (97%); (c) PMBCl, NaH, DMF (69%); (d)
TBDMSCl, imidazole, DMF (84%); (e) TESCl, imidazole,
DMF (99%).
from peracetyl
D-galactose (thioglycosidation under
Ferrier conditions, Zemple´n deacetylation, acido-cata-
lyzed transbenzylidenation, benzylation and acidic hy-
drolysis) in 64% overall yield. Regiospecific activation of
the primary position yielded a mesylate which was
reduced by lithium aluminum hydride. The resulting
monohydroxylated thiofucopyranoside 9 was subse-
quently protected either with electron-withdrawing
the C-1ꢀ/H-1 bond of the fucopyranosyl residues in 10a
and 11a with a greater value for the a-anomer (JC-1c,H-1c
172.9 Hz in 10a and JC-1c,H-1c 161.3 Hz in 11a).
Improved yields and, more interestingly, better selec-
tivities were observed with donors 2bÁ
PMB or 4-O-silyl ether groups (entries 2Á
trisaccharides 10bÁd were thus exclusively obtained in
/d bearing 4-O-
/7). Target
group, i.e., acetyl (0
ybenzyl (PMB, 02b), t-butyldimethysilyl (TBDMS, 0
2c) and triethylsilyl (TES, 02d). During this work, a
/
2a), or as ethers, i.e., p-methox-
/
/
/
good to excellent yield. It is noteworthy that: (i) reaction
times significantly decreased by performing the coupling
/
similar procedure was proposed by Floss et al. starting
from a 2-(trimethylsilyl)ethyl galactopyranoside.15
With acceptor 3 and donors 2aÁd in hand, optimiza-
in dry toluene without molecular sieves (entries 5Á7); (ii)
/
using the sterically less demanding TES group and; (iii)
substituting the stannous salt by the corresponding
copper(II) ditriflate lead to optimum conditions (entry
7). These results highlighted the impact of C-4 protect-
ing group on the stereochemistry of the glycosylation
reaction starting from fucopyranosyl donor and the
need for a C-4-electron-donating group to ensure the
target a-stereodirection.19 Moreover, this procedure
proved to be highly reproducible so that the required
trisaccharide 10d was stereospecifically prepared on a
multi-gram scale and isolated in 95% yield.
/
tion of both stereoselectivity and yield of the glycosyla-
tion step was carried out considering three parameters:
(i) the solvent; (ii) the nature of C-4 protecting group on
the donor and; (iii) the promoter. On the basis of our
experiment relative to the preparation of 1,2-cis-hexo-
furanosides from perbenzylated thiofuranosyl donors,16
the coupling reactions were promoted by a small excess
of N-iodosuccinimide (NIS) in the presence of a
catalytic amount of an added Lewis acid, tin(II)
trifluoromethanesulfonate [Sn(OTf)2]. Since SN2 type
reactions are favored in solvents with low polarity,
glycosylations were also performed in dichloromethane
Carrying out this project involved further inversion of
the C-4c configuration on the trisaccharide. Conse-
quently, selective removal of silyl group by fluoride

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R. Pe´rion et al. / Carbohydrate Research 338 (2003) 2779Á2792
/
Table 1
Optimization of glycosidic coupling starting from 12aÁd as donors and 3 as acceptor
/
Entry Donor Promoter (equiv.)
Time (min) Solvent (v/v)
Products (selectivity) a
R
Yield (%)
1
2
3
4
5
6
7
2a
2b
2b
2c
2c
2d
2d
NIS (1.2), Sn(OTf)2 (0.2) 45
NIS (1.2), Sn(OTf)2 (0.2) 45
NIS (1.2), Sn(OTf)2 (0.2) 45
NIS (1.2), Sn(OTf)2 (0.2) 45
NIS (1.2), Sn(OTf)2 (0.2) 10
Toluene-1,4-dioxane (1:2.4) b 10a/11a (5.2:1)
Ac
PMB
PMB
63
73
75
b
CH2Cl2
10b/11b (19.4:1)
Toluene-1,4-dioxane (1:2.4) b 10b/11b (1:0)
Toluene-1,4-dioxane (1:2.4) b 10c/11c (1:0)
TBDMS 81
TBDMS 70
Toluene
Toluene
Toluene
10c/11c (1:0)
10d/11d (1:0)
10d/11d (1:0)
NIS (1.2), Sn(OTf)2 (0.2)
NIS (1.2), Cu(OTf)2 (0.2) 15
5
TES
TES
60
95
a
Selectivities were established on the integrating values corresponding to H-1c.
˚
Reactions were carried out in the presence of 4 A molecular sieves.
b
anions led to derivative 12 (Scheme 4). According to
previous results on the synthesis of b-acarbose,20
displacement of an axial triflate group by a nucleophilic
aminocyclitol resulted in b-elimination. On this con-
sideration, a mesyl group was preferred to a triflate one.
However, owing to the low reactivity of the axial
hydroxyl, mesylation required addition of a nucleophilic
catalyst. Thus, in the presence of N,N-dimethylamino-
pyridine (DMAP), target compound 13 was isolated in
90% yield. Subsequently, and in order to mimic mesylate
substitution by a free amino-valienamine, the primary
cyclohexylamine (CyNH2) was chosen as a nucleophile.
After refluxing 13 in pure CyNH2 for 3 days, no reaction
occurred. In a second attempt, displacement was per-
formed with the corresponding lithium amide (CyNHLi)
in dry THF. Unfortunately, even at ꢁ60 8C, substitu-
/
tion was performed on the sulfur atom so that trisac-
charide 12 was finally isolated in 70% yield. These
results may be ascribed to some hindrance of the
Scheme 4. Synthesis of scaffolds 12Á17. Conditions: (a)
/
TBAF, THF (95%); (b) MsCl, DMAP, CH2Cl2 (90%); (c)
NaN3, TBABr, DMF (95%); (d) KSCN, TBABr, DMF (65%);
(e) i. PPh3, toluene; ii. H2O, NaOH (90%); (f) CSCl2, DMAP,
CH2Cl2 (90%).
Fig. 2. Conformation constrain during the nucleophilic sub-
stitution.

R. Pe´rion et al. / Carbohydrate Research 338 (2003) 2779Á
/2792
2783
incoming nucleophile and to some increased energy in
3. Experimental
the transition state following on required ring distortion
and consequently eclipsing between mesylate group and
3-O-benzyl and 6-methyl ones (Fig. 2). Therefore, we
assumed that less sterically demanding but good nu-
cleophile species could be more suitable. Thus, the azide
and ambivalent thiocyanate anions21 were reacted with
13 to give the desired trisaccharidic azide 14 and
thiocyanate 15 exclusively. The structure of the resulting
thiocyanato derivative was unambiguously established
on the basis of a band at 2152 cmꢁ1 obtained by IR
spectroscopy. Although the yields in 14 and 15 were
significant, 95% and 65%, respectively, the reactions
required heating and a phase transfer catalyst such as
tetrabutylammonium bromide (TBABr), strengthening
the idea that a nucleophilic substitution at the axial C-4c
position was energetically demanding. Two other syn-
thons, potentially interesting for the preparation of
acarbose and analogues, were also obtained from azide
14. The amine 16 was synthesized by chemoselective
reduction under Staudinger procedure. Since this trisac-
charidic amine could act as a nucleophile for further
linking to an electrophilic cyclitol derivative, our
approach complements well that proposed by Da-
nishefsky6 in which the carbohydrate domain was used
as an electrophile. Moreover, this amine 16 was further
transformed into the new thiocyanato derivative 17
under the action of thiophosgene and DMAP. The IR
spectra of the product differ from those of 15 and results
in a typical absorption band at 2050 cmꢁ1. Both amine
16 and thiocyanate 17 were isolated in excellent 90%
yield.
3.1. General methods
Melting points were determined on a Reichert micro-
scope and are uncorrected. TLC analyses were con-
ducted on E. Merck 60 F254 silica gel non-activated
plates and compounds were revealed using a 5% soln of
H2SO4 in EtOH followed by heating. For column
chromatography, E. Merck 60H (5Á
/
40 mm) silica gel
was used. Optical rotations were measured on a PerkinÁ
/
Elmer 341 polarimeter. H, 13C, HETCOR and COSY
1
NMR spectra were recorded in CDCl3 on a Bruker
¨
ARX 400 spectrometer at 400 MHz for 1H and 100
MHz for 13C analyses. Chemical shifts are given in d-
units measured downfield from Me4Si. Assignments of
1H and 13C for carbohydrate residues of compounds 2Á
/
17 are given in Tables 2Á7. Microanalyses were per-
/
formed by the Service de Microanalyse de l’ICSN (Gif
sur Yvette, France) and by the Service de Microanalyse
de l’Institut de Chimie de Rennes (CRMPO, Rennes,
France).
3.2. 2,3-Di-O-acetyl-4,6-O-benzylidene-a-
glucopyranosyl-(104)-2,3,6-tri-O-acetyl-(a,b)-
glucopyranose (4)
D-
/
D-
Maltose (5 g, 13.14 mmol) and benzaldehyde (3.07 mL,
30 mmol) were successively added at rt to a soln of
dimethylsulfate (2.5 mL, 26.28 mmol) in DMF (10 mL).
The mixture was then heated to 70 8C for 12 h and
cooled to rt before quenching with Et3N (3.66 mL, 52.56
mmol). Excess of the base was evaporated under
diminished pressure and the residue was diluted with
water (200 mL), extracted with CH2Cl2 (3150 mL) and
In conclusion, we have designed a new strategy for the
synthesis of the carbohydrate domain of acarbose. We
therefore prepared attractive and new trisaccharidic
synthons which could be used as precursors for the
total synthesis of the therapeutic pseudotetrasaccharide.
The crucial glycosylation reaction in this approach
involved a maltosidic acceptor, easily available from
with 1:1 EtOAcÁ
were concentrated and purification by flash chromato-
graphy (22:3 CH2Cl2ÁMeOH) gave a white solid (4 g,
67%).
/n-BuOH (5200 mL). The organic layers
/
A soln of the latter compound (47.8 g, 111 mmol) and
Ac2O (75.4 mL, 800 mmol) in pyridine (250 mL, 3.5
mol) was stirred at rt for 24 h. The reaction media was
further concentrated under diminished pressure and
then poured into water (1.5 L). After 10 h, the white
precipitate was filtered and then dissolved with CH2Cl2
(1 L), washed with water (2500 mL), dried (MgSO4) and
concentrated under diminished pressure to give a color-
less solid (71 g, 94%).
To a soln of this solid (8.6 g, 12.6 mmol) in dry
CH2Cl2 (40 mL) was added morpholine (4.4 ml, 50
mmol). The reaction media was heated to 40 8C for 20 h
and then diluted with CH2Cl2 (200 mL). The mixture
was successively washed with 5% aq HCl (100 mL), 5%
aq NaHCO3 (50 mL) and water (100 mL), dried
(MgSO4) and concentrated. The residue was triturated
in cyclohexane (200 mL) and finally filtered to give 4
maltose in a few steps, and a D-fucopyranosyl donor
specifically prepared from -galactose. Various para-
D
meters were improved and this allowed us to select
toluene as solvent, NIS/Cu(OTf)2 as a promoter and
more importantly a silyl protecting group at the axial
hydroxyl on the fucosyl donor. Because of its low steric
bulk, the TES group was straightforwardly introduced
on the less reactive 4-OH and was also efficiently
removed after glycosylation. Moreover, we have pre-
pared an amino trisaccharide, for further reacting with a
precursor of the valienamine part, and three trisacchari-
dic building blocks, an azide, a thiocyanate and an
isothiocyanate, which are likely to be elongated for the
preparation of novel families of acarbose analogues.
Such a project is currently developed in our laboratory
and results will be published in due time.

2784
R. Pe´rion et al. / Carbohydrate Research 338 (2003) 2779Á2792
/
(7.07 g, 88%) as a white solid: mp 218 8C; [a]D20
1.0, CHCl3); TLC (1:1 petroleum etherÁEtOAc): Rf ꢂ
0.3; 4a: 1H NMR (CDCl3): d carbohydrate ring protons
(see Table 2), 7.37Á7.25 (m, 5 H, C6H5), 5.42 (s, 1 H,
ꢀ
/
738 (c
allowed to stir at rt for 10 h, quenched with MeOH (5
mL) and concentrated under diminished pressure.
Purification by flash chromatography (7:3 light pet-
/
/
/
roleumÁ
solid: mp 92 8C; [a]D20
petroleum etherÁEtOAc): Rf ꢂ
d carbohydrate ring protons (see Table 2), 7.55Á
/EtOAc) lead to 6 (3.74 g, 88%) as a colorless
OCHPh), 2.13 (s, 3 H, OAc), 2.07 (s, 3 H, OAc), 2.05 (s,
3 H, OAc), 2.04 (s, 3 H, OAc), 2.02 (s, 3 H, OAc); 13C
NMR (CDCl3): d carbohydrate ring carbon atoms (see
Table 3), 171.0, 170.9, 170.6, 170.4, 170.1 (CO), 136.4
(Cipso), 129.0, 128.0, 126.0 (C6H5), 101.5 (OCHPh),
ꢁ
/
38 (c 1.0, CHCl3); TLC: (4:1
1
/
/
0.6; H NMR (CDCl3):
7.15
4.55 (m,
/
(m, 35 H, C6H5), 5.58 (s, 1 H, OCHPh), 5.03Á
/
14 H, OCH2Ph); 13C NMR (CDCl3): d carbohydrate
20.8Á
/
20.3 (COCH3); 4b: 1H NMR (CDCl3): d carbohy-
7.25 (m, 5 H,
ring carbon atoms (see Table 3), 138.7, 138.6, 138.2,
drate ring protons (see Table 2), 7.37Á
/
138.1, 137.8, 137.5, 137.4 (Cipso), 128.8Á126.0 (C6H5),
/
C6H5), 5.42 (s, 1 H, OCHPh), 2.13 (s, 3 H, OAc), 2.07 (s,
3 H, OAc), 2.05 (s, 3 H, OAc), 2.04 (s, 3 H, OAc), 2.02
(s, 3 H, OAc); 13C NMR (CDCl3): d carbohydrate ring
carbon atoms (see Table 3), 171.0, 170.9, 170.6, 170.4,
170.1 (CO), 136.4 (Cipso), 129.0, 128.0, 126.0 (C6H5),
101.1 (OCHPh), 75.3, 74.7, 73.8, 73.7, 73.4, 71.0
(OCH2Ph). Anal. Calcd for C61H62O11: C, 75.44; H,
6.44. Found: C, 75.64; H, 6.51.
3.5. Benzyl 2,3,6-tri-O-benzyl-a-
4)-2,3,6-tri-O-benzyl-b-D-glucopyranoside (3)
D-glucopyranosyl-(10
/
101.5 (OCHPh), 20.8Á
/
20.3 (COCH3). Anal. Calcd for
C29H36O16: C, 54.37; H, 5.66. Found: C, 54.00; H, 5.75.
To a soln of 6 (37.74 g, 38.9 mmol) in dry THF (350 mL)
were successively added BH3:NMe3 (16.8 g, 220.8 mmol)
and fractions of MeSO3H (14.28 mL, 220.8 mmol) in
THF (50 mL). The mixture was stirred for 12 h,
neutralized with Et3N (28 mL, 220.8 mmol) and then
concentrated under diminished pressure. The residue
was diluted with CH2Cl2 (500 mL) and successively
washed with 1N aq H2SO4 (150 mL), 5% aq NaHCO3
(150 mL) and water (200 mL). The organic layer was
dried (MgSO4), concentrated and flash chromato-
3.3. Benzyl 2,3-di-O-acetyl-4,6-O-benzylidene-a-
glucopyranosyl-(104)-2,3,6-tri-O-acetyl-b-
glucopyranoside (5)
D-
/
D-
To a soln of 4 (1.21 g, 1.9 mmol) in CH2Cl2 (25 mL) was
added freshly prepared Ag2O (800 mg, 3.8 mmol). The
mixture was stirred in the dark for 30 min before adding
BnBr (452 mL, 3.8 mmol). The media was stirred for a
further 10 h, filtered through a bed of celite and
concentrated under diminished pressure. Flash column
graphed (4:1 light petroleumÁ
g, 68%) as a colorless oil and diol 7 (5.85 g, 17%). 3: [a]D20
138 (c 1.0, CHCl3); TLC: (7:3 petroleum etherÁ
/
EtOAc) to yield 3 (25.7
chromatography with 3:2 light petroleumÁ
forded 5 (1.15 g, 83%) as a white solid: mp 218 8C; [a]D20
28 (c 1.0, CHCl3); TLC (3:2 petroleum etherÁEtOAc):
Rf ꢂ
0.4; 1H NMR (CDCl3): d carbohydrate ring
protons (see Table 2), 7.30Á7.15 (m, 10 H, C6H5), 4.78
/EtOAc af-
ꢀ
/
/
1
ꢀ
/
/
EtOAc): Rf ꢂ
ring protons (see Table 2), 7.42Á
4.97Á
4.39 (m, 14 H, OCH2Ph); 13C NMR (CDCl3): d
carbohydrate ring carbon atoms (see Table 3), 138.7,
138.4, 138.2, 137.9, 137.8, 137.4 (Cipso), 128.5Á126.6
/
0.4; H NMR (CDCl3): d carbohydrate
/
/
7.14 (m, 35 H, C6H5),
/
/
(d, 1 H, J 12.2 Hz, OCH2Ph), 5.39 (s, 1 H, OCHPh),
4.51 (d, 1 H, OCH2Ph), 2.04 (s, 3 H, OAc), 1.95 (s, 6 H,
OAc), 1.91 (s, 3 H, OAc), 1.90 (s, 3 H, OAc); 13C NMR
(CDCl3): d carbohydrate ring carbon atoms (see Table
3), 170.9, 170.4, 170.3, 170.8 (CO), 136.7, 136.7 (Cipso),
129.2, 128.5, 128.3, 128.1, 127.9, 126.2 (C6H5), 101.6
(OCHPh), 70.7 (OCH2Ph), 21.0, 20.9, 20.8, 20.7
(COCH3). Anal. Calcd for C36H42O16: C, 59.17; H,
5.79. Found: C, 59.62; H, 5.79.
/
(C6H5), 75.3, 74.6, 73.8, 73.5, 73.2, 73.0, 70.9
(OCH2Ph). Anal. Calcd for C61H64O11: C, 75.29; H,
6.63. Found: C, 75.14; H, 6.69; 7: mp: 107 8C; [a]D20
ꢀ
/
138 (c 1.0, CHCl3); TLC: (3:2 petroleum etherÁ
Rf ꢂ
0.2; 1H NMR (CDCl3): d carbohydrate ring
protons (see Table 2), 7.42Á7.14 (m, 30 H, C6H5),
4.98Á
4.50 (m, 12 H, OCH2Ph); 13C NMR (CDCl3): d
carbohydrate ring carbon atoms (see Table 3), 137.6,
137.5, 137.0, 136.7, 136.3 (Cipso), 127.5Á125.5 (C6H5),
/EtOAc):
/
/
/
3.4. Benzyl 2,3-di-O-benzyl-4,6-O-benzylidene-a-
glucopyranosyl-(104)-2,3,6-tri-O-benzyl-b-
glucopyranoside (6)
D-
/
/
D-
74.2, 73.6, 72.8, 72.4, 72.0, 69.9 (OCH2Ph). Anal. Calcd
for C54H58O11: C, 73.45; H, 6.62. Found: C, 73.51; H,
6.61.
To a soln of 5 (3.7 g, 5.06 mmol) in dry MeOH (37 mL)
was added sodium (20 mg, 0.9 mmol). After stirring at rt
for 3 h, the reaction was neutralized with IR-120 (Hꢀ-
form), filtered and concentrated under diminished
pressure. To the resulting residue diluted with DMF
(56 mL) and cooled to 0 8C were successively added a
60% dispersion of NaH in mineral oil (2.3 g, 57.5 mmol)
and BnBr (3.1 mL, 26.2 mmol). The mixture was
3.6. Ethyl 2,3-di-O-benzyl-1-thio-b-D-fucopyranoside (9)
To a soln of 8 (1.7 g, 4.2 mmol) in CH2Cl2 (7.5 mL) were
successively added Et3N (1.17 mL, 8.4 mmol) and MsCl
(365 ml, 5.04 mmol) at 0 8C. After 1 h at rt, the reaction
media was diluted with CH2Cl2 (80 mL), washed with aq
satd NH4Cl (230 mL) and water (40 mL), dried

Table 2
1H NMR (400 MHz) chemical shifts and coupling constants (1HÁ1
/
H) for maltosidic derivatives 3Á7
/
Compound d (ppm), J (Hz)
H-1a (J1a,2a
)
H-2a (J2a,3a
)
H-3a (J3a,4a
)
H-4a (J4a,5a
)
H-5a (J5a,6a
)
H-6a (J6a,6?a
)
H-6?a (J5a,6?a
)
H-1b (J1b,2b
)
H-2b (J2b,3b
)
H-3b (J3b,4b
)
H-4b (J4b,5b) H-5b (J5b,6b) H-6b (J6b,6?b) H-6?b (J5b,6?b)
4a
4b
5
5.18
(nd)
4.72Á
/
4.66
4.66
3.75
3.45
3.56
3.50
5.53
(9.4)
3.96 Á
/
3.91
3.95
4.22Á
/
4.15
3.66
3.55
3.45
3.56
3.50
4.50Á
/
4.43
4.43
4.46
4.22Á
/
4.15
4.15
4.14
3.64
5.33Á
/
5.30
4.81
5.41Á
/
5.36
5.36
3.49
(9.7)
3.49
(9.7)
3.58
(9.7)
3.80Á
/
3.76
3.76
3.74
4.22Á
/
4.15
4.15
4.14
3.72Á
/
3.66
3.66
(nd)
(9.4)
(nd)
(nd)
(nd)
(4.3)
(10.2)
4.81
(9.7)
(nd)
(nd)
(nd)
4.72Á
/4.66
4.72Á
/
5.22Á
/
5.18
4.00Á
(nd)
3.95
(9.1)
4.02
(9.1)
4.09
(9.1)
4.02
(nd)
/
3.72Á
/
4.50Á
/
4.22Á
/
5.33Á
/
5.30
5.24
5.41Á
(9.7)
5.36
(9.9)
3.87
(9.4)
3.74
(9.1)
3.63
(9.1)
/
3.80Á
/
4.22Á
/
3.72Á
/
(3.8)
4.47
(7.6)
4.42
(7.6)
4.55
(7.6)
4.46
(7.6)
(9.5)
(9.5)
5.13
(9.1)
(nd)
(nd)
(nd)
(4.1)
(10.2)
(nd)
(nd)
(nd)
3.83Á
/
3.60 Á
/
4.50Á
(nd)
3.74
(nd)
/
4.20Á
/
5.30Á
(3.1)
5.60
(3.8)
5.67
(3.6)
5.59
(3.8)
/
3.83Á
/
3.75
3.78Á
(4.3)
3.76
/
4.20Á
(4.3)
4.06
(nd)
3.85
(4.8)
/
3.64
(9.1)
(nd)
(nd)
(12.5)
3.38
(9.4)
3.45
(9.4)
3.31
(9.7)
(10.4)
6
3.55Á
/
3.71Á
/
3.64
3.75
3.68
3.55 Á
/
3.71Á
(10.9)
3.50
/
3.55Á
/3.45
3.55Á
/
3.45
3.75
3.50
(nd)
(8.9)
(3.8)
(nd)
3.65
(2.3
(4.8)
(10.2)
3
3.62Á
/
3.82Á
/
3.62 Á
/
3.62Á
(3.8)
3.75
/
3.56
3.82Á
/
3.75
3.82Á
/
(nd)
(9.1)
(nd)
(10.2)
(nd)
(11.2)
7
3.60Á
/
3.75Á
/
3.60 Á
/
3.75Á
/
3.68
3.41
(8.6)
3.60Á
/
3.50
3.60Á
/
3.50
3.60Á
/
(nd)
(nd)
(3.8)
(nd)
(11.4)
(nd)
(nd)
(nd)
nd: not determined.

2786
R. Pe´rion et al. / Carbohydrate Research 338 (2003) 2779Á2792
/
Table 3
13C NMR (400 MHz) chemical shifts for maltosidic derivatives 3Á
7
/
Compound
d (ppm)
C-1a
C-2a
C-3a
C-4a
C-5a
C-6a
C-1b
C-2b
C-3b
C-4b
C-5b
C-6b
4a
4b
5
94.2
94.2
73.5
73.5
72.2
82.4
82.3
82.2
75.5
75.5
75.6
85.0
84.9
84.9
72.5
72.5
72.7
72.0
72.5
72.2
71.9
71.9
72.2
74.3
74.6
74.6
62.7
62.7
62.6
68.8
69.7
68.6
96.1
96.1
96.4
97.3
96.6
96.4
70.7
70.7
70.8
78.7
79.0
79.1
68.4
68.4
68.5
78.9
81.3
81.2
78.5
78.5
78.8
82.3
71.4
70.4
63.5
63.5
63.7
63.3
70.7
71.9
68.2
68.2
68.5
69.0
69.2
62.3
98.7
6
102.4
102.4
102.3
3
7
(MgSO4) and finally concentrated under diminished
pressure. The resulting crude oil was diluted with THF
(25 mL) and added dropwise to a cooled (0 8C)
suspension of LAH (478 mg, 12.6 mmol) in THF (15
mL). After 30 min at 0 8C and diluting with THF (50
mL), acetone (5 mL) and 10% NaOH (1.2 mL) were
successively and carefully added to give a white pre-
cipitate that could be filtered and washed with EtOAc
(100 mL). The organic layer was washed with aq satd
NH4Cl (250 mL) and water (250 mL), dried (MgSO4)
and concentrated under diminished pressure. Flash
Table 5
13C NMR (400 MHz) chemical shifts for derivatives 2aÁ
and 9
/d, 8
Compound
d (ppm)
C-1 C-2
C-3
C-4
C-5
C-6
8
9
85.6 78.2 82.6 67.8 78.2 62.9
84.7 77.8 82.7 69.5 74.1 16.7
84.9 77.7 81.0 69.4 72.9 15.0
84.9 78.4 84.5 75.8 74.5 17.2
83.5 76.1 82.6 70.9 73.9 16.7
84.8 77.6 83.6 72.1 75.0 17.4
2a
2b
2c
2d
chromatography (73:27 light petroleumÁ
9 (1.22 g, 75%) as a white solid: mp: 67Á
70 8C; [a]2D0
38 (c 1, CHCl3); TLC (7:3 tolueneÁEt2O): Rf ꢂ
NMR (CDCl3): d carbohydrate ring protons (see Table
4), 7.42Á7.39 (m, 2 H, C6H5), 7.36Á7.29 (m, 8 H, C6H5),
/EtOAc) gave
/
ꢁ
0.4; H
/
1
/
/
24.7 (CH2CH3), 15.0 (CH2CH3). Anal. Calcd for
C22H28O4S: C, 68.01; H, 7.26. Found: C, 68.29; H, 7.27.
/
/
4.88 (d, 1 H, J 10.3 Hz, OCH2Ph), 4.77 (d, 1 H, J 10.3
Hz, OCH2Ph), 4.73 (d, 1 H, J 12.4 Hz, OCH2Ph), 4.70
(d, 1 H, J 12.4 Hz, OCH2Ph), 3.81 (ddd, 1 H, J4,OH 2.2
3.7. Ethyl 2,3-di-O-benzyl-4-O-acetyl-1-thio-b-D-
fucopyranoside (2a)
Hz, H-4), 2.83Á2.67 (m, 2 H, CH2CH3), 1.31 (t, 3 H, J
/
7.4 Hz, CH2CH3); 13C NMR (CDCl3): d carbohydrate
ring carbon atoms (see Table 5), 138.2, 137.8 (Cipso),
A soln of monohydroxylated fucoside 9 (2.5 g, 6.4
mmol), Ac2O (3 mL, 32.2 mmol) and DMAP (16 mg,
0,13 mmol) in dry pyridine (25 mL) was stirred over-
128.5Á127.8 (C6H5), 75.8 (OCH2Ph), 72.1 (OCH2Ph),
/
Table 4
1H NMR (400 MHz) chemical shifts and coupling constants (1HÁ1
/
H) for derivatives 2aÁd, 8 and 9
/
Compound
d (ppm), J (Hz)
H-1 (J1,2
)
H-2 (J2,3
)
H-3 (J3,4
)
H-4 (J4,5
)
H-5 (J5,6
)
H-6 (J6,6?
)
H-6? (J5,6?)
8
4.43
(9.7)
4.39
(9.6)
4.45
(9.1)
4.38
(9.7)
4.34
(9.5)
4.29
(9.7)
3.67
(9.0)
3.62
(9.1)
3.58
(9.0)
3.81
(9.4)
3.75
(9.3)
3.67
(9.4)
3.55
(3.3)
4.05
(0.9)
3.81
(0.9)
5.38
(1.0)
3.53
(0.9)
3.81
3.46
(6.5)
3.92
(4.6)
1.34
3.78
(11.8)
9
3.56Á
/
3.53
3.56Á
(6.5)
3.65
(6.4)
3.45
(6.3)
3.49
(6.2)
3.4
/3.53
(3.2)
3.62
(3.0)
3.55
(2.9)
3.41
(2.4)
3.33
(2.3)
2a
2b
2c
2d
1.22
1.16
1.23
1.23
(B
/
1.0)
3.76
1.0)
(B
/
(6.4)

R. Pe´rion et al. / Carbohydrate Research 338 (2003) 2779Á
/2792
2787
night at rt. After removal of the solvent, the crude oil
was diluted in CH2Cl2 and purified by chromatography
mixture was heated at 90 8C for 24 h. After cooling and
diluting with CH2Cl2, the molecular sieves were re-
moved by filtration over a bed of Celite. The filtrate was
finally washed with aq satd NaCl (10 mL) and water (20
mL), dried (MgSO4) and chromatographed (7:3 petro-
eluting with 9:1 petroleum etherÁ
(2.69 g) was obtained in 97% yield: mp: 61 8C; [a]D20
218 (c 1, CHCl3); TLC (9:1 petroleum etherÁEtOAc):
Rf ꢂ
0.2; 1H NMR (CDCl3): d carbohydrate ring
protons (see Table 4), 7.41Á7.37 (m, 2 H, C6H5),
7.36Á7.24 (m, 8 H, C6H5), 4.83 (d, 1 H, J 10.2 Hz,
/
EtOAc. Compound 2a
ꢀ
/
/
/
leum etherÁ
a white amorphous solid: mp: 49 8C; [a]D20
CHCl3); TLC (7:3 petroleum etherÁEtOAc): Rf ꢂ
1H NMR (CDCl3): d carbohydrate ring protons (see
Table 4), 7.41Á7.24 (m, 10 H, C6H5), 4.89 (d, 1 H, J 10.2
Hz, OCH2Ph), 4.78 (d, 1 H, J 10.2 Hz, OCH2Ph), 4.75Á
/
EtOAc) to afford target 2c (325 mg, 84%) as
38 (c 1,
0.3;
/
ꢀ
/
/
/
/
OCHPh), 4.77 (d, 1 H, J 10.3 Hz, OCHPh), 4.74 (d, 1 H,
J 11.3 Hz, OCHPh), 4.52 (d, 1 H, J 11.3 Hz, OCHPh),
2.76 (qd, 2 H, 2J 12.5 Hz, J 7.4 Hz, CH2CH3), 2.18 (s, 3
H, CH3CO), 1.32 (t, 3 H, CH2CH3); 13C NMR (CDCl3):
d carbohydrate ring carbon atoms (see Table 5), 171.0
/
/
4.68 (m, 2 H, OCH2Ph), 2.72 (qd, 2 H, J 12.5, J 7.4 Hz,
CH2CH3), 1.30 (t, 3 H, CH2CH3), 0.92 [s, 9 H,
C(CH3)3], 0.09 (s, 3 H, CH3Si), 0.04 (s, 3 H, CH3Si);
13C NMR (CDCl3): d carbohydrate ring carbon atoms
(see Table 5), 137.3 (Cipso), 127.4, 127.2, 126.7, 126.6,
126.4 (C6H5), 74.4 (OCH2Ph), 72.0 (OCH2Ph), 25.1
[C(CH3)3], 22.6 (CH2CH3), 17.5 [C(CH3)3], 14.1
(CO), 137.7, 138.2 (Cipso), 128.4Á127.8 (C6H5), 75.8
/
(OCH2Ph), 71.8 (OCH2Ph), 24.9 (CH2CH3),
21.0 (CH3CO), 16.7 (CH2CH3). Anal. Calcd
for C22H28O4S: C, 65.95; H, 7.00. Found: C, 66.68; H,
6.96.
(CH2CH3), ꢁ
/
4.9 (CH3Si), ꢁ5.6 (CH3Si). Anal. Calcd
/
3.8. Ethyl 2,3-di-O-benzyl-4-O-p-methoxybenzyl-1-thio-
b-D-fucopyranoside (2b)
for C28H42O4SSi: C, 66.89; H, 8.42. Found: C, 67.02; H,
8.45.
To a soln of 9 (300 mg, 0.77 mmol) in freshly distilled
DMF (5 mL) cooled at 0 8C were successively added p-
methoxybenzyl chloride (209 mL, 1.54 mmol) and a 60%
suspension of sodium hydride in oil (62 mg, 1.54 mmol).
The media was slowly warmed to rt and stirred for 3 h.
After diluting with CH2Cl2 (20 mL), the soln was
washed with aq satd NH4Cl (10 mL) and water (20
mL), the organic layer dried (MgSO4) and concentrated.
3.10. Ethyl 2,3-di-O-benzyl-4-O-triethylsilyl-1-thio-b-D-
fucopyranoside (2d)
To a soln of 9 (6.9 g, 17.86 mmol) in DMF (35 mL)
cooled to 0 8C were successively added imidazole (2.4 g,
35.72 mmol) and then Et3SiCl (4.5 mL, 26.79 mmol).
After stirring at rt for 12 h, the reaction media was
diluted with Et2O (200 mL), washed with aq satd NH4Cl
(100 mL) and water (100 mL), dried (MgSO4) and
finally concentrated under diminished pressure. Flash
Purification by chromatography (9:1 light petroleumÁ
EtOAc) yielded the desired donor 2b (271 mg, 69%): mp:
61 8C; [a]2D0
118 (c 1, CHCl3); TLC (7:3 petroleum
etherÁEtOAc): Rf ꢂ
0.5; 1H NMR (CDCl3): d carbohy-
drate ring protons (see Table 4), 7.42Á7.24 (m, 12 H,
C6H5), 6.87Á6.82 (m, 2 H, C6H5), 4.91 (d, 1 H, J 11.5
/
ꢁ
/
chromatography eluting with 9:1 light petroleumÁ
EtOAc gave 2d (8.10 g, 90%) as a colorless oil: [a]D20
88 (c 1, CHCl3); TLC (9:1 petroleum etherÁEtOAc):
Rf ꢂ
0.5; 1H NMR (CDCl3): d carbohydrate ring
protons (see Table 4), 7.42Á7.25 (m, 10 H, C6H5), 4.88
(d, 1 H, J 10.2 Hz, OCH2Ph), 4.77 (d, 1 H, J 10.2 Hz,
OCH2Ph), 4.74Á4.70 (m, 2 H, OCH2Ph), 2.84Á2.68 (qd,
/
/
/
ꢀ
/
/
/
/
/
Hz, OCH2Ph), 4.90 (d, 1 H, J 10.2 Hz, OCH2Ph), 4.80
(d, 1 H, J 10.2 Hz, OCH2Ph), 4.76 (d, 1 H, J 11.8 Hz,
OCH2Ph), 4.72 (d, 1 H, J 11.8 Hz, OCH2Ph), 4.64 (d, 1
H, J 11.5 Hz, OCH2Ph), 3.79 (s, 3 H, OCH3), 2.73 (qd,
2 H, J 12.5, J 7.4 Hz, CH2CH3), 1.29 (t, 3 H, CH2CH3);
13C NMR (CDCl3): d carbohydrate ring carbon atoms
/
/
/
2 H, J 12.6, J 7.4 Hz, CH2CH3), 1.31 (t, 3 H, CH2CH3);
13C NMR (CDCl3): d carbohydrate ring carbon atoms
(see Table 5), 138.5, 138.0 (Cipso), 128.6Á127.6 (C6H5),
/
(see Table 5), 159.1, 138.5, 138.4 (Cipso), 130.8Á
/
113.5
75.5 (OCH2Ph), 75.0 (OCH2Ph), 24.3 (CH2CH3), 15.1
(CH2CH3). Anal. Calcd for C28H42O4SSi: C, 66.89; H,
8.42. Found: C, 66.75; H, 8.35.
(C6H5), 75.7 (OCH2Ph), 74.0 (OCH2Ph), 72.8
(OCH2Ph), 55.2 (OCH3), 24.7 (CH2CH3), 15.0
(CH2CH3). Anal. Calcd for C30H36O5S: C, 70.83; H,
7.13. Found: C, 70.83; H, 7.17.
3.11. Benzyl 2,3-di-O-benzyl-4-O-acetyl-a-
fucopyranosyl-(104)-2,3,6-tri-O-benzyl-a-
glucopyranosyl-(104)-2,3,6-tri-O-benzyl-b-
glucopyranoside (10a) and benzyl 2,3-di-O-benzyl-4-O-
acetyl-b- 4)-2,3,6-tri-O-benzyl-a-
-fucopyranosyl-(10
glucopyranosyl-(104)-2,3,6-tri-O-benzyl-b-
glucopyranoside (11a)
D-
/
D-
3.9. Ethyl 2,3-di-O-benzyl-4-O-t-butyldimethysilyl-1-
thio-b-D-fucopyranoside (2c)
/
D-
D
/
D-
A suspension of fucopyranoside 9 (300 mg, 0,77 mmol)
and imidazole (209 mg, 3,08 mmol) in dry DMF (6 mL)
/
D-
˚
containing 3 A molecular sieves (300 mg) was stirred at
rt and under N2 for 30 min. t-Butyldimethysilyl chloride
(700 mg, 4,64 mmol) was then added and the resulting
Donor 2a (80 mg, 0.18 mmol) and acceptor 3 (180 mg,
0.18 mmol) diluted in toluene (5 mL) were rotoevapo-

2788
R. Pe´rion et al. / Carbohydrate Research 338 (2003) 2779Á2792
/
rated into dryness. To the mixture was further added
˚
1:2.4 toluene-1,4-dioxane (3.4 mL), activated 4 A
3.12. Benzyl 2,3-di-O-benzyl-4-O-p-methoxybenzyl-a-
fucopyranosyl-(104)-2,3,6-tri-O-benzyl-a-
glucopyranosyl-(104)-2,3,6-tri-O-benzyl-b-
glucopyranoside (10b)
D-
/
D-
/
D-
molecular sieves (380 mg), NIS (48 mg, 0.22 mmol)
and tin(II) ditrifluoromethanesulfonate (13 mg, 0.03
mmol). After completion of the reaction (45 min at rt),
acids were neutralized by NaHCO3 (150 mg). Finally,
the reaction media was filtered, diluted with toluene (14
mL), washed with 20% aq Na2S2O3, water (10 mL),
dried (MgSO4), concentrated and chromatographed
This glycosylation reaction was performed as described
for 10a starting from donor 2b (46 mg, 0.09 mmol),
acceptor 3 (88 mg, 0.09 mmol), NIS (24 mg, 0.11 mmol)
and tin(II) ditrifluoromethanesulfonate (8 mg, 0.02
mmol) in 1:2.4 toluene-1,4-dioxane (1.4 mL). After
work-up and chromatographic purification (24:1
(19:1 tolueneÁ
(21 mg) in 63% overall yield; 10a: TLC Rf (9:1 tolueneÁ
Et2O): 0.5; [a]2D0 49.18 (c 1, CHCl3); 1H NMR
(CDCl3): d carbohydrate ring carbon atoms (see Table
6), 7.40Á
7.03 (m, 45 H, C6H5), 4.97 (d, 1 H, 2J 11.8 Hz,
OCH2Ph), 4.94 (d, 1H, 2J 11.3 Hz, OCH2Ph), 4.93 (d, 1
/Et2O) to afford 10a (109 mg) and 11a
/
tolueneÁ
/
Et2O), the target trisaccharide 11b (93 mg)
Et2O): Rf
39.68 (c 1, CHCl3); H NMR (CDCl3): d
carbohydrate ring carbon atoms (see Table 6), 7.46Á7.06
(m, 47 H, C6H5), 6.88Á6.86 (m, 2 H, C6H5), 5.00 (d, 1 H,
ꢀ
/
was isolated in 73% yield; TLC (9:1 tolueneÁ
/
0.6; [a]2D0
ꢀ
/
1
/
/
/
2
2
H, J 10.9 Hz, OCH2Ph), 4.85 (d, 1 H, J 11.6 Hz,
OCH2Ph), 4.76 (d, 1 H, 2J 11.6 Hz, OCH2Ph), 4.75 (d, 1
2J 11.9 Hz, OCH2Ph), 4.98Á
4.96 (m, 2 H, OCH2Ph),
/
4.89 (d, 1 H, 2J 11.7 Hz, OCH2Ph), 4.87 (d, 1 H, 2J 11.2
2
2
H, J 11.6 Hz, OCH2Ph), 4.68 (d, 1 H, J 12.0 Hz,
OCH2Ph), 4.66 (d, 1 H, 2J 11.4 Hz, OCH2Ph), 4.64 (d, 1
2
Hz, OCH2Ph), 4.82 (d, 1 H, J 12.5 Hz, OCH2Ph), 4.79
(d, 1 H, 2J 12.3 Hz, OCH2Ph), 4.72 (d, 1 H, 2J 12.0 Hz,
2
2
H, J 10.9 Hz, OCH2Ph), 4.63 (d, 1 H, J 10.8 Hz,
OCH2Ph), 4.58 (d, 1 H, 2J 12.2 Hz, OCH2Ph), 4.54 (d, 1
OCH2Ph), 4.69Á
/
4.65 (m, 5 H, OCH2Ph), 4.64Á4.58 (m,
/
4 H, OCH2Ph), 4.54Á4.43 (m, 3 H, OCH2Ph), 3.83 (s, 3
/
2
2
H, OCH3); 13C NMR (CDCl3): d carbohydrate ring
carbon atoms (see Table 7), 159.2, 138.8, 138.7, 138.5,
H, J 12.3 Hz, OCH2Ph), 4.50 (d, 1 H, J 13.0 Hz,
OCH2Ph), 4.47 (d, 1 H, 2J 11.9 Hz, OCH2Ph), 4.45 (d, 1
2
2
H, J 12.3 Hz, OCH2Ph), 4.42 (d, 1 H, J 12.0 Hz,
OCH2Ph), 4.39 (d, 1 H, 2J 12.0 Hz, OCH2Ph), 4.37 (d, 1
138.4, 138.2, 137.7, 137.4 (Cipso), 130.7Á126.5 (C6H5),
/
113.5 (C6H5), 74.6, 74.1, 74.0, 73.8, 73.4, 73.3, 73.2, 72.9,
72.8, 70.9 (OCH2Ph), 55.2 (OCH3); HMQC (CDCl3):
JC-1a,H-1a 159.5 Hz, JC-1b,H-1b 171.5 Hz, JC-1c,H-1c 172.7
Hz. Anal. Calcd for C89H94O16: C, 75.30; H, 6.67.
Found: C, 75.56; H, 6.81.
2
H, J 11.0 Hz, OCH2Ph), 2.10 (s, 3 H, CH3CO); 13C
NMR (CDCl3): d carbohydrate ring carbon atoms (see
Table 7), 170.0 (CO), 137.8, 137.4, 137.2, 137.0, 136.7,
136.4, (Cipso), 127.4Á125.6 (C6H5), 73.7, 72.9, 72.8, 72.5,
/
72.2, 72.0, 70.8, 70.0 (OCH2Ph); HMQC (CDCl3): JC-
1a,H-1a 159.7 Hz, JC-1b,H-1b 174.5 Hz, JC-1c,H-1c 172.9 Hz.
Anal. Calcd for C83H88O16: C, 74.31; H, 6.61. Found: C,
3.13. Benzyl 2,3-di-O-benzyl-4-O-t-butyldimethylsilyl-a-
D
-fucopyranosyl-(10
glucopyranosyl-(104)-2,3,6-tri-O-benzyl-b-
glucopyranoside (10c)
/
4)-2,3,6-tri-O-benzyl-a-D-
/
D-
74.33; H, 6.68; 11a: TLC (9:1 tolueneÁ
[a]2D0 28.48 (c 1, CHCl3); 1H NMR (CDCl3): d
carbohydrate ring carbon atoms (see Table 6),
/Et2O): Rf 0.4;
ꢀ
/
2
This glycosylation reaction was performed as previously
described for 11a starting from donor 2c (80 mg, 0.16
mmol), acceptor 3 (155 mg, 0.16 mmol), NIS (43 mg,
0.19 mmol) and tin(II) ditrifluoromethanesulfonate (13
mg, 0.03 mmol) in 1:2.4 toluene-1,4-dioxane (3.4 mL).
After work-up and chromatographic purification (24:1
7.34Á
/
7.05 (m, 45 H, C6H5), 5.00 (d, 1 H, J 10.5 Hz,
OCH2Ph), 4.87 (d, 1 H, 2J 10.8 Hz, OCH2Ph), 4.84 (d, 1
2
2
H, J 10.8 Hz, OCH2Ph), 4.83 (d, 1 H, J 11.6 Hz,
OCH2Ph), 4.72 (d, 1 H, 2J 11.5 Hz, OCH2Ph),
2
4.69 (d, 1 H, J 11.5 Hz, OCH2Ph), 4.67 (d, 1 H, J
2
11.5 Hz, OCH2Ph), 4.62Á4.57 (m, 4 H, OCH2Ph), 4.53
/
tolueneÁ
/
Et2O), the target trisaccharide 10c (183 mg)
Et2O): Rf
46.78 (c 1, CHCl3); H NMR (CDCl3): d
carbohydrate ring carbon atoms (see Table 6), 7.41Á7.10
2
2
(d,1 H, J 11.8 Hz, OCH2Ph), 4.43 (d, 1 H, J 12.2 Hz,
OCH2Ph), 4.39 (d,1 H, 2J 12.9 Hz, OCH2Ph), 4.39 (d, 1
was obtained in 81% yield; TLC (19:1 tolueneÁ
/
0.4; [a]2D0
ꢀ
/
1
2
2
H, J 11.6 Hz, OCH2Ph), 4.38 (d, 1 H, J 11.4 Hz,
OCH2Ph), 4.31 (d, 1 H, 2J 12.0 Hz, OCH2Ph), 4.10 (d, 1
H, J 12.1 Hz, OCH2Ph), 2.10 (s, 3 H, CH3CO); 13C
NMR (CDCl3): d carbohydrate ring carbon atoms (see
Table 7), 170.0 (CO), 138.3, 137.8, 137.4, 137.2, 136.7,
/
2
(m, 45 H, C6H5), 4.97 (d, 1 H, J 12.1 Hz, OCH2Ph),
4.94 (d, 1 H, 2J 13.0 Hz, OCH2Ph), 4.84 (d, 1 H, 2J 11.9
2
2
Hz, OCH2Ph), 4.79 (d, 1 H, J 11.5 Hz, OCH2Ph), 4.68
(d, 1 H, 2J 11.9 Hz, OCH2Ph), 4.66 (d, 1 H, 2J 10.9 Hz,
2
136.9, 136.4 (Cipso), 127.4Á125.7 (C6H5), 74.0, 73.9,
/
OCH2Ph), 4.64 (d, 1 H, J 10.8 Hz, OCH2Ph), 4.62Á
/
4.54 (m, 8 H, OCH2Ph), 4.54 (d, 1 H, 2J 12.5 Hz,
OCH2Ph), 4.52 (d, 1 H, 2J 12.7 Hz, OCH2Ph), 4.48 (d, 1
H, J 11.9 Hz, OCH2Ph), 4.46 (d, 1 H, J 12.1 Hz,
OCH2Ph), 0.84 [s, 9 H, C(CH3)3], ꢁ0.01 (s, 3 H,
CH3Si); 13C NMR (CDCl3): d carbohydrate ring carbon
73.7, 73.1, 72.6, 72.4, 72.1, 70.7, 69.9 (OCH2Ph), 19.8
(CH3CO); HMQC (CDCl3): JC-1a,H-1a 159.7 Hz, JC-1b,H-
2
2
174.2 Hz, JC-1c,H-1c 161.3 Hz. Anal. Calcd
for C83H88O16: C, 74.31; H, 6.61. Found: C, 74.04; H,
6.67.
1b
/

Table 6
1H NMR (400 MHz) chemical shifts and coupling constants (1HÁ1
/
H) for trisaccharides 10Á
/17
Compound d (ppm), J
(Hz)
10a
11a
10b
10c
10d
12
13
14
15
16
17
H-1a (J1a,2a
H-2a (J2a,3a
H-3a (J3a,4a
H-4a (J4a,5a
H-5a (J5a,6a
)
)
)
)
)
4.55 (7.7)
4.45 (7.8)
(9.5)
4.57 (7.4)
4.62Á
(nd)
/
4.54
4.70 (7.6)
3.58 (8.6)
3.76 (8.9)
4.05 (9.1)
4.53 (7.6)
4.55 (9.1)
4.55 (7.6)
4.55 (7.9)
4.55 (8.0)
4.56 (7.6)
3.62 (8.9)
5.01Á
(nd)
/
3.74
3.74
3.74
3.46
3.46
3.46
3.82Á
(8.8)
4.09 (8.8)
/3.49
3.95Á
/
3.81
3.63Á/3.55
3.63Á/3.56
3.63Á
/
3.5 (nd) 3.63Á
/
3.51
3.74
3.93
3.51
3.63Á
/
3.51
(9.1)
(nd)
(8.9)
(nd)
(8.8)
5.01Á
/
4.00 (8.8)
3.78 (8.9)
4.07 (8.9)
3.80Á/3.72
3.78 (8.9)
4.09 (9.1)
3.82Á
(8.9)
4.07 (9.1)
/
3.73
3.80Á
(nd)
/
3.78 (8.9)
4.09 (9.1)
3.83Á
(9.4)
4.12 (9.4)
/3.75
(nd)
(8.9)
5.01Á
/
3.82Á
(nd)
/
3.67
3.34
3.34
3.34
4.06Á
(nd)
/
3.86
3.49
3.49
3.49
4.07 (9.1)
4.15Á
(nd)
/
(nd)
3.63Á
/
3.54Á
/
3.82Á
/
3.73Á
/
3.55
3.55
3.55
3.81
3.66Á
(nd)
/
3.55
3.55
3.55
3.63Á
(nd)
/
3.55
3.55
3.55
3.63Á
(nd)
/
3.56
3.56
3.48
3.63Á
(3.8)
3.65 (nd)
/
3.51
3.63Á
(4.1)
/
3.63Á
(3.2)
3.76 (nd)
/
3.51
3.65Á
(nd)
/
3.56
3.86
3.56
(nd)
(nd)
(nd)
(nd)
H-6a (J6a,6?a
)
3.63Á
/
3.54Á
/
3.82Á
/
3.73Á
/
3.66Á
/
3.63Á
/
3.63Á
/
3.86 (nd)
3.93Á
/
(nd)
(nd)
(nd)
(nd)
(nd)
(nd)
(nd)
(nd)
H-6?a (J5a,6?a
)
3.63Á
/
3.54Á
/
3.82Á
/
3.73Á
/
3.66Á
/
3.63Á
/
3.53Á
/
3.63Á
(11.9)
5.60 (3.6)
/
3.51
3.80Á
(10.9)
5.60 (3.6)
/3.74
3.63Á
(10.5)
5.59 (3.6)
/
3.51
3.65Á
/
(nd)
(nd)
(nd)
(nd)
(nd)
(nd)
(nd)
(nd)
H-1b (J1b,2b
H-2b (J2b,3b
H-3b (J3b,4b
H-4b (J4b,5b
H-5b (J5b,6b
)
)
)
)
)
6.55 (3.7)
5.60 (3.9)
3.22 (9.6)
5.56 (3.6)
3.95Á
/
5.65 (3.6)
3.48 (9.4)
3.97 (8.1)
5.55 (3.6)
3.51 (nd)
5.57 (3.6)
5.62 (3.6)
(3.5)
5.01Á
(nd)
/
3.74
3.74
3.74
3.74
3.46
3.46
3.82Á
(nd)
/
3.49
3.86
3.49
3.49
3.49
3.49
3.49 (9.3)
3.53Á
(nd)
/
3.48
3.87
3.87
3.87
3.87
3.80
3.63Á
(nd)
/
3.55
3.90
3.90
3.76
3.76
3.67
3.63Á
(9.6)
4.05 (8.6)
/3.51
3.63Á
(nd)
/
3.51
3.97
3.97
3.90
3.86
3.56Á
(nd)
/
3.50
3.97
3.97
3.86
3.75
3.50
5.01Á
/
3.82Á
(nd)
/
3.67
3.67
3.67
3.34
3.34
4.06Á
/
3.95Á
/
3.81
3.81
3.81
3.55
3.55
3.81
3.55
4.00Á
(nd)
/
3.92
3.92
3.92
4.02Á
/
3.98Á
/
4.03Á
/
4.08Á
/
(nd)
(nd)
(nd)
(nd)
(nd)
(nd)
(nd)
5.01Á
/
3.82Á
/
3.82Á
/
3.95Á
/
3.95Á
(nd)
/
3.82
3.82
3.82
3.82
4.00Á
/
4.02Á
/
3.98Á
/
4.15Á
(nd)
/
3.93
3.93
3.93
3.51
4.03Á
/
4.08Á
/
(nd)
(nd)
(nd)
(nd)
(nd)
(nd)
(nd)
(nd)
(nd)
5.01Á
/
3.82Á
/
3.82Á
/
3.95Á
/
3.95Á
/
4.00Á
/
4.02Á
/
3.84Á
/
4.15Á
/
3.96Á
/
3.93Á
/
(nd)
(nd)
(nd)
(nd)
(nd)
(3.8)
(nd)
(4.2)
(nd)
(nd)
(nd)
H-6b (J6b,6?b
)
3.63Á
/
3.54Á
/
3.82Á
/
3.73Á
/
3.95Á
/
3.90 (nd)
4.02Á
/
3.84Á
/
4.15Á
/
3.90Á
/
3.83Á
/
(nd)
(nd)
(nd)
(nd)
(nd)
(nd)
(1.5)
(nd)
(nd)
(nd)
H-6?b (J5b,6?b
)
3.63Á
/
3.54Á
/
3.82Á
/
3.73Á
/
3.95Á
/
3.90Á
(10.9)
5.64 (nd)
/3.80
3.87Á
/
3.75Á
/
3.63Á
/
3.88 (nd)
5.55 (3.6)
3.43 (9.7)
3.52 (9.4)
2.44 (9.4)
3.56Á
/
(nd)
(nd)
(nd)
(nd)
(nd)
(nd)
(11.1)
(nd)
(nd)
H-1c (J1c,2c
H-2c (J2c,3c
H-3c (J3c,4c
H-4c (J4c,5c
H-5c (J5c,6c
H-6c
)
)
)
)
)
5.67 (3.8)
4.22 (7.8)
(10.0)
5.70 (3.9)
3.95Á
/
5.85 (3.6)
5.65 (3.6)
3.64 (10.9)
3.75 (2.8)
5.55 (3.6)
3.40 (9.7)
5.74 (3.6)
3.43 (9.4)
5.57 (3.6)
3.33 (9.7)
(nd)
5.01Á/3.74
4.06Á
(nd)
/
3.86
3.86
3.86
3.49
3.73Á
/
3.66Á
(nd)
/
3.55
3.55
3.69
3.55
3.80Á
(nd)
/
3.72
3.72
3.69
3.72
(nd)
(9.0)
5.01Á/3.74
3.93 (2.9)
4.06Á
/
3.99 (9.0)
3.66Á
/
3.80Á
/
3.82Á
(9.8)
3.04 (9.8)
/
3.73
4.15Á
(10.4)
2.50 (10.4)
/3.93
3.83Á
(nd)
/
3.75
3.28
3.75
(nd)
(nd)
(nd)
(nd)
5.23 (1.1)
5.12 (B/1)
4.06Á
/
3.95Á
/
3.81
3.72Á
/
3.73Á
/
4.77Á/3.74
3.35Á
/
(nd)
(nd)
(nd)
(nd)
(nd)
(nd)
3.63Á3.46
/
3.17 (6.4)
0.97
3.82Á
(6.4)
0.99
/
3.73Á
(6.0)
1.02
/
3.55
3.66Á
(6.4)
1.15
/
3.80Á
(6.4)
1.12
/
3.87Á
(7.4)
1.00
/3.80
3.63Á
/
3.51
4.15Á/3.93
3.63Á
/
3.51
3.83Á
(6.1)
1.12
/
(6.5)
0.96
(6.4)
1.13
(6.1)
1.22
(6.2)
1.10
(nd): not determined.

2790
R. Pe´rion et al. / Carbohydrate Research 338 (2003) 2779Á2792
/
atoms (see Table 7), 139.0, 138.9, 138.6, 138.5, 138.3,
137.8, 137.5 (Cipso), 128.5Á126.6 (C6H5), 74.7, 74.1,
73.9, 73.5, 73.3, 73.2, 73.0, 71.0 (OCH2Ph), 26.1
[C(CH3)3], 18.6 [C(CH3)3], 3.9, 4.5 (CH3Si);
/
ꢁ
/
ꢁ
/
HMQC (CDCl3): JC-1a,H-1a 159.7 Hz; JC-1b,H-1b 175.0
Hz; JC-1c,H-1c 175.0 Hz. Anal. Calcd for C87H100O15Si:
C, 73.91; H, 7.13. Found: C, 74.21; H, 7.14.
3.14. Benzyl 2,3-di-O-benzyl-4-O-triethylsilyl-a-
fucopyranosyl-(104)-2,3,6-tri-O-benzyl-a-
glucopyranosyl-(104)-2,3,6-tri-O-benzyl-b-
glucopyranoside (10d)
D-
/
D-
/
D-
To a soln of donor 2d (6 g, 11.93 mmol) and maltosidic
acceptor 3 (9.6 g, 9.94 mmol) in dry toluene (200 mL)
were successively added at 0 8C and under vigorous
stirring NIS (2.68 g, 11.93 mmol) followed by copper(II)
ditrifluoromethanesulfonate (719 mg, 2 mmol). Com-
plete consumption of both substrates was attained after
10 min so that acidic media could be neutralized by
adding NEt3 and further partitioned between Et2O (200
mL) and aq Na2S2O3. The resulting organic layer was
washed with water (2200 mL) and dried (MgSO4). After
removal of the solvent, the product was chromato-
graphed (6.7:1 light petroleumÁ
95% yield (13.3 g); TLC (9:1 light petroleumÁ
Rf 0.2; [a]2D0 ꢀ42.18 (c 1, CHCl3); 1H NMR (CDCl3): d
carbohydrate ring carbon atoms (see Table 6), 7.40Á7.00
(m, 45 H, C6H5), 4.90Á4.41 (m, 18 H, OCH2Ph), 0.87 (t,
/
EtOAc) and isolated in
/
EtOAc):
/
/
/
9 H, J 7.9 Hz, CH2CH3), 0.55 (qd, 8 H, J 1.8 Hz,
CH2CH3); 13C NMR (CDCl3): d carbohydrate ring
carbon atoms (see Table 7), 139.0, 138.9, 139.6, 138.6,
138.5, 138.4, 138.3, 137.8, 137.5 (Cipso), 128.5Á126.5
/
(C6H5), 74.7, 74.1, 74.0, 73.5, 73.4, 73.3, 73.2, 73.0, 71.1
(OCH2Ph), 7.1 (CH2CH3), 5.2 (CH2CH3). Anal. Calcd
for C87H100O15Si: C, 73.91; H, 7.13. Found: C, 73.62; H,
7.12.
3.15. Benzyl 2,3-di-O-benzyl-a-
2,3,6-tri-O-benzyl-a- -glucopyranosyl-(10
O-benzyl-b- -glucopyranoside (12)
D
-fucopyranosyl-(10
/
4)-
D
/
4)-2,3,6-tri-
D
To a soln of silylated trisaccharide 10d (6.7 g, 4.67
mmol) was added a molar soln of tetrabutylammonium
fluoride in THF (7 mL, 7 mmol). After 1 h at rt, the
reaction media was partitioned between Et2O (300 mL)
and aq satd NH4Cl (150 mL). The organic layer was
then washed with water (150 mL), dried (MgSO4),
concentrated under diminished pressure and purified
by flash chromatography (3:1 light petroleumÁ
Compound 12 was thus isolated in 95% yield as a
colorless oil (5.76 g); TLC (4:1 light petroleumÁEtOAc):
Rf 0.2; [a]2D0 ꢀ46.88 (c 1, CHCl3); 1H NMR (CDCl3): d
carbohydrate ring carbon atoms (see Table 6), 7.40Á7.04
(m, 45 H, C6H5), 4.97Á4.41 (m, 18 H, OCH2Ph); 2.33 (s,
1 H, J4c-OH
1 Hz, OH-4c); 13C NMR (CDCl3): d
/
EtOAc).
/
/
/
/
B
/

R. Pe´rion et al. / Carbohydrate Research 338 (2003) 2779Á
/2792
2791
carbohydrate ring carbon atoms (see Table 7), 138.8,
138.4, 138.3, 138.2, 138.0, 137.7, 137.4, (Cipso), 128.5Á
for C81H85N3O14: C, 73.45; H, 6.47; N, 3.17. Found: C,
73.59; H, 6.54; N, 2.92.
/
126.6 (C6H5), 74.7, 74.0, 73.9, 73.7, 73.5, 73.2, 73.0, 72.3,
71.1 (OCH2Ph). Anal. Calcd for C81H86O15: C, 74.86;
H, 6.67. Found: C, 75.14; H, 6.71.
3.18. Benzyl 2,3-di-O-benzyl-4,6-dideoxy-4-thiocyanato-
a-
glucopyranosyl-(10
glucopyranoside (15)
D
-glucopyranosyl-(10
/
4)-2,3,6-tri-O-benzyl-a-D-
3.16. Benzyl 2,3-di-O-benzyl-4-O-methanesulfonyl-a-
fucopyranosyl-(104)-2,3,6-tri-O-benzyl-a-
glucopyranosyl-(104)-2,3,6-tri-O-benzyl-b-
glucopyranoside (13)
D
-
/
4)-2,3,6-tri-O-benzyl-b-D-
/
D-
/
D-
Mesylate 13 (100 mg, 0.07 mmol), potassium thiocya-
nate (40 mg, 0.4 mmol) and TBABr (3 mg, 0.007 mmol)
were combined into DMF (1 mL) and warmed at 140 8C
for 5 h. After cooling at rt and diluting with Et2O (20
mL), the mixture was washed with water (28 mL). The
resulting organic layer was finally dried (MgSO4),
concentrated and submitted to chromatographic purifi-
cation (4.3:1 light petroleumÁ
was thus obtained as a colorless oil (60 mg) in 65% yield;
EtOAc): Rf 0.4; [a]D20
TLC (4:1 light petroleumÁ 2.28
(c 1, CHCl3); IR: n 2152 (SCN) cmꢁ1 1H NMR
(CDCl3): d carbohydrate ring carbon atoms (see Table
Mesylation was performed by mixing a soln of 12 (6.07
g, 4.67 mmol) in dry CH2Cl2 (60 mL) containing 4-N,N-
dimethylaminopyridine (776 mg, 6.35 mmol) to a soln of
methanesulfonyl chloride (435 mL, 6 mmol) in dry
CH2Cl2 (5 mL). The reaction was completed after 10
min stirring at rt. The media was diluted with additional
CH2Cl2 (200 mL) and successively washed with aq satd
NH4Cl (270 mL) and water (100 mL), dried (MgSO4),
concentrated and finally chromatographed (4:1 light
/EtOAc). The product 15
/
ꢀ
/
;
petroleumÁ
isolated in 90% yield as a colorless oil (5.47 g); Rf 0.6
(3:1 light petroleumÁ 48.58 (c 1, CHCl3);
EtOAc); [a]2D0 ꢀ
1H NMR (CDCl3): d carbohydrate ring carbon atoms
/EtOAc). The desired product 13 was thus
6), 7.40Á
/
7.04 (m, 45 H, C6H5), 4.98Á4.40 (m, 18 H,
/
/
/
OCH2Ph); 13C NMR (CDCl3): d carbohydrate ring
carbon atoms (see Table 7), 138.9, 138.4, 138.3, 138.8,
(see Table 6), 7.40Á
/
7.04 (m, 45 H, C6H5), 5.00Á
/
4.41 (m,
138.7, 137.6, 137.5 (Cipso), 128.5Á126.4 (C6H5). 110.1
/
18 H, OCH2Ph), 2.85 (s, 3 H, SO2CH3); 13C NMR
(CDCl3): d carbohydrate ring carbon atoms (see Table
7), 138.1, 138.8, 138.4, 138.3, 138.0, 137.9, 137.7, 137.5,
(SCN), 76.3, 74.7, 73.9, 73.4, 73.2, 73.0, 72.9, 71.0
(OCH2Ph). Anal. Calcd for C82H85NO14S: C, 73.46; H,
6.39. Found: C, 73.30; H, 6.54.
137.4 (Cipso), 128.5Á126.5 (C6H5), 74.8, 74.0, 73.9, 73.7,
/
73.4, 73.0, 71.1 (OCH2Ph), 39.0 (SO2CH3). Anal. Calcd
for C82H88O17S, 1H2O: C, 70.56; H, 6.50. Found: C,
70.84; H, 6.52.
3.19. Benzyl 4-amino-2,3-di-O-benzyl-4,6-dideoxy-a-D-
glucopyranosyl-(10
glucopyranosyl-(10
glucopyranoside (16)
/
4)-2,3,6-tri-O-benzyl-a-
D
-
/
4)-2,3,6-tri-O-benzyl-b-
D
-
3.17. Benzyl 4-azido-2,3-di-O-benzyl-4,6-dideoxy-a-D-
glucopyranosyl-(10
glucopyranosyl-(10
glucopyranoside (14)
/
4)-2,3,6-tri-O-benzyl-a-
D
-
/
4)-2,3,6-tri-O-benzyl-b-
D
-
A soln of azide 14 (1.7 mg, 1.28 mmol) and triphenyl-
phosphine (673 mg, 2.56 mmol) in dry toluene (10 mL)
was stirred at rt for 12 h. The resulting iminopho-
sphorane was hydrolyzed in situ by adding 10% aq
NaOH (10 mL) and by heating at 90 8C for 12 h. After
cooling at rt, the media was diluted with Et2O (20 mL)
and washed with water until neutral pH. The organic
layer was then dried over MgSO4 and the solvent
removed under diminished pressure. Chromatography
To a soln of mesylate 13 (2.4 g, 1.74 mmol) in DMF (20
mL) were added TBABr (112 mg, 0.35 mmol) and
sodium azide (340 mg, 5.22 mmol). The reaction was
allowed to warm at 85 8C and stirred for 3 days. The
mixture was further partitioned between Et2O (150 mL)
and aq satd tetrabutylammonium chloride (100 mL).
The resulting organic layer was then washed with water
(100 mL), dried (MgSO4) and the solvent removed
under diminished pressure. A flash chromatography
(3:2 light petroleumÁ
the desired trisaccharidic amine 16 (1.5 g, 90%); TLC
(3:2 light petroleumÁ 33.08 (c 1,
EtOAc): Rf 0.2; [a]D20
CHCl3); 1H NMR (CDCl3): d carbohydrate ring carbon
/EtOAc) of the crude oil afforded
/
ꢀ
/
(87:13 light petroleumÁ
/EtOAc) finally yielded 14 (2.21
g, 95%) as a colorless oil; TLC (9:1 light petroleumÁ
/
atoms (see Table 6), 7.40Á
/
6.91 (m, 45 H, C6H5), 4.90Á
/
1
EtOAc): Rf 0.3; [a]D20
(CDCl3): d carbohydrate ring carbon atoms (see Table
ꢀ
/
55.28 (c 1, CHCl3); H NMR
4.35 (m, 18 H, OCH2Ph); 13C NMR (CDCl3): d
carbohydrate ring carbon atoms (see Table 7), 139.0,
138.9, 138.7, 138.4, 138.3, 138.1, 137.8, 137.5 (Cipso),
6), 7.40Á
/
7.04 (m, 45 H, C6H5), 5.00Á4.41 (m, 18 H,
/
OCH2Ph); 13C NMR (CDCl3): d carbohydrate ring
carbon atoms (see Table 7), 138.8, 138.3, 138.0, 137.9,
128.5Á126.6 (C6H5), 75.4, 74.7, 74.1, 74.0, 73.4, 73.3,
/
73.0, 72.4, 71.0 (OCH2Ph). Anal. Calcd for
C81H87NO14: C, 74.92; H, 6.75. Found: C, 75.23; H,
6.82.
137.7, 137.5, 137.4 (Cipso), 128.5Á/126.6 (C6H5), 75.5,
74.7, 74.0, 73.4, 73.0, 72.8, 71.1 (OCH2Ph). Anal. Calcd

2792
R. Pe´rion et al. / Carbohydrate Research 338 (2003) 2779Á2792
/
(b) Ogawa, S.; Shibata, Y. Carbohydr. Res. 1989, 189,
309Á322.
6. Park, T. K.; Peterson, J. M.; Danishefski, S. J. Tetrahe-
dron Lett. 1994, 35, 2671Á2674.
3.20. Benzyl 2,3-di-O-benzyl-4,6-dideoxy-4-
/
isothiocyanato-a-
benzyl-a-
-glucopyranosyl-(10
-glucopyranoside (17)
D
-glucopyranosyl-(10
/
4)-2,3,6-tri-O-
D
/
4)-2,3,6-tri-O-benzyl-b-
/
D
7. Schmidt, R. R.; Laesecke, K. Pat. Appl. CH 648 326 A5,
1985.
8. Chen, X.; Fan, Y.; Zhen, Y.; Shen, Y. Chem. Rev. 2003,
To a soln of 16 (100 mg, 0.07 mmol) in dry CH2Cl2 (1.5
mL) cooled at ꢁ20 8C were successively added 4-N,N-
dimethylaminopyridine (39 mg, 0.31 mmol) and thio-
phosgene (8.4 mL, 0.11 mmol). After complete disap-
pearance of the substrates and heating to rt, the solvent
was removed and the crude oil purified on silica gel (4:1
/
103, 1955Á
9. Zhang, Z.; Ollmann, I. R.; Ye, X. S.; Wishnat, R.; Baasov,
T.; Wong, C. H. J. Am. Chem. Soc. 1999, 121, 734Á753.
10. (a) Lay, L.; Windmuller, R.; Reinhardt, S.; Schmidt, R. R.
/1977.
/
¨
Carbohydr. Res. 1997, 303, 39Á
(b) Cao, S.; Gan, Z.; Roy, R. Carbohydr. Res. 1999, 318,
75Á81;
(c) Amer, H.; Hofinger, A.; Kosma, P. Carbohydr. Res.
2003, 338, 35Á45.
11. Motawia, M. H.; Olsen, C. E.; Denyer, K.; Smith, A. M.;
/49;
light petroleumÁ
tained in 90% yield (91 mg) as a colorless oil; Rf 0.3 (4:1
light petroleumÁ 30.08 (c 1, CHCl3); IR:
EtOAc); [a]2D0 ꢀ
n 2050 (NCS) cmꢁ1; 1H NMR (CDCl3): d carbohydrate
ring carbon atoms (see Table 6), 7.40Á7.04 (m, 45 H,
C6H5), 5.00Á
4.43 (m, 18 H, OCH2Ph); 13C NMR
(CDCl3): d carbohydrate ring carbon atoms (see Table
7), 138.8Á137.4 (Cipso), 135.4 (NCS), 128.5Á126.5
/EtOAc). Compound 17 was thus ob-
/
/
/
/
/
Møller, B. L. Carbohydr. Res. 2001, 330, 309Á
/318.
/
12. (a) Mani, N. S. Ind. J. Chem. 1989, 28B, 602Á
/603;
(b) Kantlehner, W.; Gutbrod, H. D. Liebigs Ann. Chem.
1979, 1362Á1369.
13. Gebbie, S. J.; Gosney, I.; Harrison, P. R.; Lacan, I. M. F.;
/
/
/
(C6H5), 75.8, 74.7, 74.0, 73.9, 73.4, 73.0, 72.9, 71.1
(OCH2Ph). Anal. Calcd for C82H85NO14S: C, 73.46; H,
6.39. Found: C, 73.37; H, 6.27.
Sanderson, W. R.; Sankey, J. P. Carbohydr. Res. 1998,
308, 345Á/348.
14. Garegg, P. J.; Kvarnstom, I.; Niklasson, A.; Niklasson,
¨
G.; Svensson, S. C. T. J. Carbohydr. Chem. 1993, 12, 933Á
953.
15. Bowers, S. G.; Mahmud, T.; Floss, H. G. Carbohydr. Res.
/
References
1. (a) Tattersall, R. Diabetic Med. 1993, 10, 688Á
(b) Balfour, J. A.; McTavish, D. Drugs 1993, 46, 688Á
(c) Campbell, L. K.; White, J. R.; Campbell, R. K. Ann.
Pharmacother. 1996, 30, 1255Á1262.
2. (a) Frommer, W.; Junge, B.; Keup, Muller, L.; Puls,
¨
Schmidt, D. D. 1975, Ger. Offen. 2 347 782, Pat. Appl. 23
/693;
2002, 337, 297Á
16. Gelin, M.; Ferrie`res, V.; Plusquellec, D. Eur. J. Org.
Chem. 2000, 1423Á1431.
17. (a) Schmidt, R. R. Comprehensive Organic Synthesis; Vol.
6; Pergamon Press, 1991; pp 33Á64;
(b) Demchenko, A. V.; Rousson, E.; Boons, G. J.
Tetrahedron Lett. 1999, 40, 6523Á6526.
18. Hansen, P. E. Prog. NMR Spectrosc. 1981, 14, 175Á
/
304.
/
693;
/
/
/
467 782 9;
/
(b) Truscheit, E.; Frommer, W.; Junge, B.; Muller, L.;
¨
Schmidt, D. D.; Wingender, W. Angew. Chem., Int. Ed.
/
296.
19. Zhang, Z.; Ollmann, I. R.; Ye, X. S.; Wischnat, R.;
1981, 20, 744Á761.
3. Nishimura, Y. In Studies in Natural Products Chemistry;
Atta-ur-Rahman, Ed.; Vol. 10; Elsevier Science, 1992; pp
/
Baasov, T.; Wong, C. H. J. Am. Chem. Soc. 1999, 121,
734Á
20. McAuliffe, J. C.; Stick, R. V. Aust. J. Chem. 1997, 50,
203Á207.
/
753.
495Á
4. Park, K. H.; Kim, M. J.; Lee, H. S.; Han, N. S.; Kim, D.;
Robyt, J. F. Carbohydr. Res. 1998, 313, 235Á246.
5. (a) Ogawa, S.; Shibata, Y. J. Chem. Soc., Chem. Commun.
1988, 605Á606;
/583.
/
21. Collins, P.; Ferrier, R. Monosaccharides: Their Chemistry
/
and their Roles in Natural Products; 2nd ed; John Wiley &
Sons, 1995; pp 189Á198.
/
/