Influence of the solvent in low temperature glycosylations with O-(2,3,5,6-tetra-O-benzyl-β-d-galactofuranosyl) trichloroacetimidate for 1,2-cis α-d-galactofuranosylation

Article abstract of DOI:10.1016/j.carres.2011.04.005

Glycosylation studies for the construction of 1,2-cis α-linkages with O-(2,3,5,6-tetra-O-benzyl-β-d-galactofuranosyl) trichloroacetimidate (1) and several acceptors, including d-mannosyl and l-rhamnosyl derivatives were performed. The reactions were condu

Full text of DOI:10.1016/j.carres.2011.04.005

Carbohydrate Research 346 (2011) 1495–1502
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Carbohydrate Research
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Influence of the solvent in low temperature glycosylations with O-(2,3,5,6-tetra-
O-benzyl-b-D-galactofuranosyl) trichloroacetimidate for 1,2-cis
a-D-galactofuranosylation
⇑
Gabriel Gola, Mariano J. Tilve, Carola Gallo-Rodriguez
CIHIDECAR, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón II, 1428 Buenos Aires, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
Glycosylation studies for the construction of 1,2-cis
tofuranosyl) trichloroacetimidate (1) and several acceptors, including
a
-linkages with O-(2,3,5,6-tetra-O-benzyl-b-
-mannosyl and -rhamnosyl deriv-
atives were performed. The reactions were conducted at low temperatures using CH2Cl2, Et2O, and
acetonitrile as solvents. A non-participating solvent such as CH2Cl2 at ꢀ78 °C, favored the -configura-
tion. In contrast, acetonitrile strongly favored the b- -configuration, whereas no selectivities were
observed with Et2O. The use of thiophene as an additive did not enhance the -selectivity as in the
pyranose counterpart. Although selectivities strongly depended on the acceptor, trichloroacetimidate 1
constitutes a valuable donor for the synthesis of -Galf-(1?2)- -Rha and -Galf-(1?6)- -Man. As
D-galac-
Received 25 February 2011
Received in revised form 31 March 2011
Accepted 4 April 2011
D
L
a
-D
Available online 8 April 2011
D
a
-D
Dedicated to Professor Dr. András Lipták on
the occasion of his 75th birthday
a
-
D
L
a
-D
D
these motifs are present in pathogenic microorganisms, these procedures described here are useful for
the straightforward synthesis of natural oligosaccharides.
Keywords:
Glycosylation
Trichloroacetimidate
1,2-Cis
Ó 2011 Elsevier Ltd. All rights reserved.
Galactofuranose
Solvents effects
Diastereoselectivity
1. Introduction
common in nature than those containing
a-D-Galf. The synthesis
of the 1,2-trans b- -galactofuranosyl linkage has been accom-
D
The synthesis of oligosaccharides is a topic of increasing interest
because these molecules are involved in many biological processes
and, in consequence, pure samples are required for biological stud-
ies.1 Particularly, galactofuranose-containing oligosaccharides
have deserved much attention, since they are present in many
pathogenic microorganisms such as Mycobacterium tuberculosis,
Leishmania, Trypanosoma cruzi, and Klebsiella pneumoniae.2–5 As
Galf is absent in mammals, the metabolism of this sugar has been
proposed as a potential target for antimicrobial chemotherapy6
and studies on the biosynthesis are currently being pursued.7,8
plished diastereoselectively by neighboring group participation by
an acyl group attached to O-2, and many methods of glycosylation
have been reported.3–5 The 1,2-cis configuration is more difficult to
be achieved as a single diastereomer and so far, no general method
is available for this purpose.12,13 The first requirement for the
construction of a 1,2-cis a-D-Galf linkage is the presence of a non-
participating group in the O-2 of the galactofuranosyl donor. How-
ever, the use of the pentenyl method of glycosylation applied to the
2,3,5,6-tetra-O-benzyl-b-
b- -products. Moreover, different kinds of solvents did not affect
the stereochemical course of the reaction.14 The trichloroacetimi-
date method for -galactofuranosylation was first described by
Plusquellec et al. using O-(2,3,5,6-tetra-O-benzyl-b- -galactofur-
D-galactofuranosyl derivative gave mainly
D
Although less common in nature,
a-D-Galf with 1,2-cis configura-
tion, has been found in several bacteria and fungi,3–5 some of them
pathogenic like Streptococcus pneumoniae 22F,9 Escherichia coli
O167,10 and Paracoccidioides brasiliensis.11 The latter is the etiolog-
ical agent of paracoccidioidomycosis, the most common systemic
mycosis in Latin America. The biosynthesis of this rather unusual
unit has not been studied and the synthesis of oligosaccharides
a-D
D
anosyl) trichloroacetimidate (1) with galacto- and glucopyranosyl
acceptors having primary 6-OH free, to afford moderate yields
and selectivities.15 By taking advantage of this method, we have
synthesized
a-D-Galf-(1?2)-D-galactitol, which has been isolated
containing
a
-
D
-Galf units would provide tools for these studies.
by reductive b-elimination from glycoproteins of Clostridium ther-
mocellum and Bacteroides cellulosolvens.16 The thioglycoside meth-
od, evaluated on galacto and gluco acceptors, gave better yields
but moderate selectivities which depended on the acceptor used.17
Most of the synthetic efforts have been focused on the construc-
tion of b-D-Galf containing oligosaccharides, which are more
The difficulty to construct
a-D-Galf linkages has been overcome
⇑
Corresponding author. Tel./fax: +54 11 4576 3352.
E-mail address: cgallo@qo.fcen.uba.ar (C. Gallo-Rodriguez).
by means of few approaches. Thus, the 20-carboxybenzyl (CB)
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.04.005

1496
G. Gola et al. / Carbohydrate Research 346 (2011) 1495–1502
glycoside method, developed for 1,2-cis b-
D
-mannosides, has been
O
O
O
CCl3
NH
R OH
O R
OBn
successfully applied to the diastereoselective synthesis of the anti-
neoplastic glycosphingolipid agelagalastatin, which presents a ter-
OBn
TMSOTf
Solvent
MS4Å
a-D-Galf-(1?2)-D a-D-isomer
-Galf unit.18 Exclusively the
OBn
OBn
minal
was formed at ꢀ78 °C with high yield and constituted the first
example of a single diasteromer in an -galactofuranosylation.
OBn
OBn
7-12
OBn
OBn
1
-78 ºC
a
More recently, di- and tetrasaccharide subunits of the cell wall
Scheme 1. Glycosylation of acceptors 2–6 with trichloroacetimidate 1.
polysaccharide of Talaromyces flavus were obtained employing
the same method.19 In this case, the
a-D-Galf-(1?2)-Man linkage
was obtained as a single diastereomer at ꢀ78 °C, after evaluation
of several glycosylation methods such as sulfoxide, thioglycosides,
and fluoride, as well as protecting groups pattern in the acceptor
and the donor.
Several acceptors were selected as precursors of disaccharide
constituents of glycoconjugates in microorganisms. Methyl 2,3,4-
tri-O-benzyl-
a-D
-mannopyranoside30,31 (2) and its benzoyl analog
332 (Table 1) were chosen as precursors of disaccharide constitu-
Lowary et al. have applied the 2,3-anhydrosugar methodology,
ents of Paracoccidiodes brasiliensis and allyl 3,4-di-O-benzyl-a-L-
formerly developed for the construction of 1,2-cis b-
ages, to the synthesis of
-galactofuranosides.20 In this case,
the galactofuranosyl precursor is a 2,3-anhydro- -gulofuranosyl
D
-Araf link-
rhamnopyranoside33 (4) for the construction of the disaccharide
present in Streptococcus pneumoniae 22F. Methyl 3-O-benzoyl-
a-D
D
4,6-O-benzylidene-
precursor of disaccharides present in Talaromyces flavus. As glyco-
sylation of 2-O-benzoyl-5,6-O-isopropylidene- -galactono-1,4-lac-
tone24 (6) with O-(2,3,4,6-tetra-O-benzyl-
-galactopyranosyl)
trichloroacetimidate led stereoselectively to the -Galp-(1?3)
linkage,24 we have also selected acceptor 6 for comparison pur-
poses with its -Galf counterpart.
The diastereomeric
a-D
-mannopyranoside34 (5) was employed as
thioglycoside or sulfoxide, which reacts with the acceptor by
SN2-like displacement, to form a disaccharide epoxide derivative
with a new 1,2-cis glycosidic linkage. After the stereoselective
opening of the epoxide, the desired disaccharide was obtained.
The use of 2,3-anhydro-5,6-di-O-benzoyl-b-D-gulofuranosyl-p-to-
lyl-(R/S)-sulfoxide as donor allowed the synthesis of the pentasac-
D
a
-D
a-D
D
charide repeating unit of varianose, a polysaccharide produced by
a/b ratio of the products of glycosylation
the fungus Penicillium varians which possesses an internal
a
-
D
-
was determined from the 1H NMR spectrum of the crude reaction
mixture by integration of the signals of each diastereomer and
Galf.21 Glycosylation reaction afforded one single diastereomer,
however, further epoxide opening was not completely
regioselective.
comparison with pure isolated disaccharides. The
a
/b ratio was
confirmed by weighting the isolated
cation by column chromatography.
a and b products after purifi-
These two elegant strategies described above have succeeded in
complete stereoselective glycosylation, however, the synthesis of
the described donors requires many steps, as well as previous eval-
uation of its reactivity with the desired glycosyl acceptor. Carb-
oxybenzyl galactofuranoside donor is synthesized in four reaction
steps, involving the use of mercuric salts from pentaacetylgalactof-
uranose, which also requires three additional reaction steps from
The configuration of the new galactofuranosyl linkages of the
new products were readily established by 1H and 13C NMR spec-
troscopy. In the 1H NMR spectra, the b-
D
-Galf anomeric hydrogen
resonated as a broad singlet or as a doublet with a small coupling
constant (1–1.5 Hz), whereas -Galf H-1 appeared as a doublet
with J1,2 4.2–4.5 Hz. In the 13C NMR spectra, b-
-Galf anomeric car-
bon resonated deshielded (d 104.0–107.9) compared to the same
signal in the
-Galf product (d 97.9–101.0).16,23–28
Preliminary results on our synthesis of -Galf disaccharides of
Clostridium thermocellum, using the imidate method in CH2Cl2,
indicated that low temperature reaction favored the -stereose-
lectivity. On the other hand, excellent stereoselectivities were ob-
tained on -galactopyranoside acceptors having the OH-6 free
employing the carboxybenzyl method from ꢀ78 °C to 0 °C. Same
reaction conditions allowed the formation of the single -isomer
when reacted with a -mannopyranosyl derivative with free OH-2,
whereas the thioglycoside and the sulfoxide method gave 3:1 and
8:1
/b ratios, respectively.19 These facts, together with the high
a
-D
D
galactose.18 The 2,3-anhydro-5,6-di-O-benzoyl-b-
p-tolyl-(R/S)-sulfoxide is synthesized in four steps from p-tolyl 1-
D-gulofuranosyl-
a
-D
thio-
a
/b-
D
-galactofuranoside, which requires additional five steps
a-D
from galactose.20
The trichloroacetimidate method proved to be a very valuable
and reliable method of glycosylation, as it was employed for the
synthesis of many oligosaccharides.12 In this sense, we and other
groups have synthesized Galf-containing oligosaccharides from
Mycobacterium, Leishmania and T. cruzi, as well as the already men-
a-D
D
a-D
tioned
cellulosolvens.3–5,22–28 Particularly, among the donors employed
for -galactofuranosylation, O-(2,3,5,6-tetra-O-benzyl-b- -galac-
tofuranosyl) trichloroacetimidate (1) has been readily synthesized
a-
D-Galf-containing di- and trisaccharides alditol from B.
D
a-
D
D
a
reactivity previously shown by imidate 1, prompted us to set the
from
D-galactose, in four reaction steps via its allyl a-D-glyco-
reaction temperature at ꢀ78 °C.
side.16,29 Taking into account the easy access to imidate donor 1
We first evaluated CH2Cl2 as a non-participating solvent at
ꢀ78 °C. The simple cyclic alcohol cyclohexanol gave moderate
and as a continuation of previous work,15,16 we now describe a gly-
cosylation study on different acceptors including
-mannosyl derivatives for the construction of
L
-rhamnosyl and
-Galf 1,2-cis
selectivity toward the a-D
-isomer (entry 1).15 We next evaluated
the glycosylation reaction on primary OH-6 of D-mannosyl accep-
D
a-
D
linkage present in natural oligosaccharides. Low temperature reac-
tions, the influence of the solvent employed, as well as the use of
additives like thiophene, have been evaluated.
tors 2 and 3. A marked effect was observed depending on the substi-
tution pattern. Interestingly, while the benzyl substituted mannosyl
2 gave separable disaccharides 8
the selectivity was significantly increased to 12.6:1
a
and 8b in 3.3:1
a
/b ratio (entry 2),
/b ratio with
a
2. Results and discussion
the less nucleophlilic benzoyl counterpart 3 (entry 3) as shown by
the 1H NMR spectrum of the crude reaction mixture. In this case,
To explore the diastereoselectivity in glycosylation reactions of
Galf we employed trichloroacetimidate 1 (1 equiv) as donor and
TMSOTf as catalyst (0.3 equiv) in the presence of molecular sieves
(Scheme 1). Four general procedures (methods A–D) were followed
involving solvents such as CH2Cl2 (method A), Et2O (method B),
CH3CN (method C), and CH2Cl2 with thiophene as additive
(method D).
only the a-D-product 9a was recovered in 63% yield after column
chromatography. In this sense, donor 1 and benzoyl substituted
acceptor 3 constitute a matched pair and a reliable method is now
available for the construction
the pathogen fungus Paracoccidiodes brasiliensis. Compound 9
was previously obtained by the carbobenzoxy method of
glycosylation in 8:1 /b ratio, however, no characterization data
a-D-Galf-(1?6)-D-Man, present in
a
a

G. Gola et al. / Carbohydrate Research 346 (2011) 1495–1502
1497
Table 1
Glycosylation of cyclohexanol and acceptors 2–6 with donor 1 (methods A–D)
Entry
Acceptor
Product
Method A
CH2Cl2
Method B
Ether
Method C
CH3CN
Method D
CH2Cl2
ꢀ78 °C
ꢀ78 °C
ꢀ40 °C
thiophene
ꢀ78 °C
a
/ba
a
/ba
a
/ba
(yield)b
(yield)b
(yield)b
a
/ba
(yield)b
O
OBn
2.0:1.0
(93%)
2.4:1.0
(94%)
1.0:3.9
(69%)
2.5:1.0
(44%)
O
1
2
Cyclohexanol
OBn
OBn
7
OBn
O
OH
OBn
O
O
BnO
BnO
OBn
OBn
OBn
3.3:1.0
(75%)
2.4:1.0
(89%)
1.0:6.7
(86%)
2.4:1.0
(64%)
O
OMe
OBn
O
2
BnO
BnO
8
OMe
OH
O
OBn
OBz
O
BzO
BzO
OBn
12.6:1.0
(63%)
1.5:1.0
(68%)c
1.0:12.5
(90%)c
4.5:1.0
(66%)c
OBn
OBn
O
3
OMe
OBz
O
3
BzO
BzO
9
OMe
O
O
OBn
H3C
BnO
O
OBn
BnO
OBn
10.0:1.0
(48%)
3.0:1.0
(56%)
0:1.0
(92%)
10.0:1.0
(63%)
OH
OBn
BnO
4
O
4
(13 24%)d
(13 31%)d
(13 34%)d
BnO
H3C
O
O
10
OH
O
O
O
O
BzO
Ph
OBn
OBn
OMe
OBn
3.3:1.0
(36%)
0:0
1.0:1.4
(39%)
1.7:1.0
(7%)
OBn
O
5
5
(0%)
O
(13 36%)d
(13 45%)d
(13 12%)d
Ph
O
O
BzO
OMe
11
O
OH
O
OBn
O
O
OBz
OBn
OBn
OBn
O
O
O6
2.8:1.0
(27%)
1.0:0.0
(8%)
1.4:1.0
(60%)
3.7:1.0
(22%)
O
6
(13 30%)d
(13 73%)d
(13 33%)d
OBz
O
12O
/b ratio established from 1H NMR (500 MHz) spectrum of the crude and confirmed by weights of isolated
Yield of isolated products (combined yield of the - and b- -isomers).
/b unseparable mixture.
% of 2,3,5,6-tetra-O-benzyl-1-N-trichloroacetyl-
a
and b products.
a
b
c
a
a
D
a
d
a-D-galactofuranosylamine (13) also recovered.
were reported.19 Glycosylation reaction occurred with inversion of
C-1 configuration as expected in CH2Cl2, a non-participating
solvent. b-D-Imidate 1 afforded 1,2-cis glycoside, a SN2-type
reaction, with the nucleophile acceptor attacking from the face of
the ring opposite to the leaving group could be proposed. However,
as the activator is TMSOTf, a covalent triflate intermediate could be
involved.35–38 In this sense, low-temperature NMR studies of thio-
arabinofuranosyl constrained donors activation allowed the identi-
fication of a triflate arabinofuranosyl intermediate in 1,2-trans
relationship.38 Questions also arise on the selectivity obtained be-
cause benzyl protected acceptor 2 should be more nucleophilic than
the benzoyl counterpart 3. Thus, higher selectivities should be ex-
pected in the SN2-type reaction, and the opposite situation was
experimentally found, indicating that other factors are involved.
Many aspects of the mechanism of glycosylation of furanoses
remain unclear.

1498
G. Gola et al. / Carbohydrate Research 346 (2011) 1495–1502
Preliminary results showed that reaction of imidate 1 with 2-OH
-rhamnosyl acceptor 4 at ꢀ15 °C led only to the b- -isomer. Inter-
estingly, the same reaction conducted at ꢀ78 °C gave 10 with higher
diastereoselectivity in favor of the -isomer (10.0:1 /b ratio),
however, with moderate yield (48%). The transposition by-product
thiophene as additive (method D), gave no improvement of the
-selectivities compared to the reactions without additive.
The nature of the solvent strongly determined the stereochem-
ical course of glycosylation reaction as demonstrated above.
Recently, -Galf thrichloroacetimidate donors that lack anchimeric
L
D
a-D
a-
D
a
D
2,3,5,6-tetra-O-benzyl-1-N-trichloroacetyl-
a
-
D
-galactofuranosyl-
assistance by substitution either by 2-O-Galp or 2-O-Galf have
been evaluated with derivatives of 4-OH GlcNAc acceptors. In this
amine (13)16 was also obtained (24%). N-Glycosyl trichloroaceta-
mides have been observed as by-products in glycosylation
reactions when low nucleophilic or sterically hindered acceptors
case, acetonitrile favored the b-linkage when b-
Galf was the donor,27 whereas in contrast with these results
dichloromethane favored the b- -configuration employing the
b- -Galf-(1?2)- -Galf donor.
D-Galp-(1?2)-D-
were employed.12,16,27,39–42 As compounds 10
isolated by column chromatography, a straightforward method is
a
and 10b could be
D
D
D
now available for the synthesis of disaccharides constituents of
Streptococcus pneumoniae 22F. The disaccharide methyl
a-D-Galf-
3. Conclusions
(1?2)-L-Rhap has been previously synthesized by the 2,3-anhydro-
sugar methodology with high stereoselectivity.20 The 2-OH manno-
The glycosylation studies with readily available O-(2,3,5,
6-tetra-O-benzyl-b- -galactofuranosyl) trichloroacetimidate (1) of
several selectively protected sugar acceptors show that non-partic-
ipating solvents as Cl2CH2 at ꢀ78 °C, favored the -configuration.
The inclusion of thiophene as additive did not enhance the
-selectivity, as reported in the pyranose counterpart. Glycosyl-
ation in acetonitrile strongly favored the formation of glycosidic
linkages with b- -configuration, whereas no substantial differ-
sylacceptor5 affordedthedisaccharide11withmoderateselectivity
D
toward the
a product, and in low yield. In this case, 13 was obtained
as the main product (36%), and this result is in agreement with the
lesser nucleophilicity of mannosyl acceptor 5 compared to deoxy-
sugar acceptor 4. Similar results in terms of selectivities, yields,
and by-product 13 were achieved with lactone 6.
a
-D
a-D
As next step we evaluated the glycosylation reaction in partici-
D
pating solvents. As it is known, diethylether enhances the a-selec-
ences on selectivities were observed with Et2O.
tivities on the pyranose counterpart.12,13,43 In this case, this solvent
(method B) had almost no effect for cyclohexanol, or lowered the
Protecting group pattern on the acceptor was decisive for the
increment on selectivity. For instance, the
a-D-Galf-(1?6)-D-Man
a-D-selectivities compared to CH2Cl2 (entry 2–4). No glycosylation
linkage was obtained in 12.6:1 /b ratio when the benzoylated
a
product was obtained with mannosyl acceptor 5 and transposition
by-product 13 was mainly formed, suggesting that this solvent
lowered the reactivity of the acceptor. Similar results were ob-
tained with the lactone acceptor 6. As a conclusion, ethyl ether is
not suitable for this method of glycosylation. In agreement with
this result, no selectivity had been observed by the thioglycoside
method using this solvent.17
Acetonitrile is a participating solvent which is frequently used
for 1,2-trans b-linkage construction in galacto- and glucopyrano-
syl donors lacking a participating group at the vicinal 2-posi-
tion.35–38,43 It is accepted that nitrile effect is due to the
mannosyl acceptor 3 was employed instead of the benzyl counter-
part. Moreover, by changing the solvent from CH2Cl2 to CH3CN, the
b-disaccharide was obtained in high selectivity. A similar behavior
was found with rhamnosyl acceptor 3.
In conclusion, trichloroacetimidate 1 constitutes a valuable do-
nor for the synthesis of a-D-Galf containing glycoconjugates pres-
ent in pathogenic microorganisms. Straightforward procedures
for the synthesis of linkages found in natural oligosaccharides are
reported.
4. Experimental
formation of a
displaced by the acceptor. Reactions in this solvent at ꢀ40 °C
(method C) favored the b- -isomer in almost all cases, with the
exception of lactone acceptor 6. Glycosylation of the benzylated
mannopyranoside acceptor 2 gave separable 8 and 8b in 1:6.7
/b ratio in high yield (entry 2). Higher diastereomeric ratio favor-
a-D-glycopyranosyl nitrilium ion, which is further
4.1. General Methods
D
TLC was performed on 0.2 mm Silica Gel 60 F254 aluminum
supported plates. Detection was effected by exposure to UV light,
then by spraying with 5% (v/v) sulfuric acid in EtOH and charring.
Column chromatography was performed on Silica Gel 60 (230–400
mesh). NMR spectra were recorded with a Bruker AVANCE II 500
spectrometer at 500 MHz (1H) and 125.8 MHz (13C). Chemical
shifts are given relative to the signal of internal TMS standard at
0.00 ppm for 1H NMR and the signal for CDCl3 at 77.0 ppm for
13C NMR. 1H and 13C assignments were supported by COSY and
HSQC experiments. High resolution mass spectra (HRMS) were re-
corded on a BRUKER micrOTOF-Q II electrospray ionization mass
spectrometer. Optical rotations were measured with a path length
of 1 dm at 25 °C.
a
a
ing the 1,2-trans b-D-isomer 9b was obtained with the benzoylat-
ed analogue 3 (entry 3) also with high yields. It is interesting to
note that the use of benzoyl protecting group in 3 instead of
benzyl, increased the selectivity toward the b- -product. Similar
D
result was obtained using CH2Cl2 toward the -D-product.
a
Interestingly, on glycosylation of rhamnosyl acceptor 4, disac-
charide 10b was obtained as a single diastereomer in very good
yield (entry 4). Thus, donor 1 can be used to construct
a- or b-D-
Galf with high diastereoselection by varying the solvent reaction
(and temperature). Almost no selectivities were observed with
mannosyl acceptor 5 (entry 5) and lactone 6 (entry 6). Enhance-
ment of the b-
coside method with 2,3,4-tri-O-acetyl-
D
-selectivity had been also observed by the thiogly-
-glucopyranoside as
4.2. General procedures for glycosylation reactions
a
-D
acceptor in this solvent.17 Thus, reactive acceptors such as primary
6-OH derivatives or deoxysugar derivative 4 favored the b-selectiv-
ity, suggesting that a common nitrilium intermediate is involved.
Recently, thiophene additive in Cl2CH2 has been shown to favor
4.2.1. Method A
To a solution of O-(2,3,5,6-tetra-O-benzyl-b-D-galactofuranosyl)
trichloroacetimidate16 (1, 1 equiv) and the acceptor (1.3 equiv) in
anhyd CH2Cl2 (3.0 mL/50 mg of 1) was added activated powdered
4 Å molecular sieves (150 mg), and the mixture was vigorously
stirred at room temperature under argon. After 10 min, the mix-
ture was cooled to ꢀ78 °C, TMSOTf (0.3 equiv) was added and
the stirring continued for 40 min. The reaction was monitored by
TLC, and quenched by the addition of triethylamine (0.3 equiv)
1,2-cis
a-D-glycopyranosylation of donors lacking a participating
group at the 2-position by formation of b-equatorial covalent sul-
fonium ion-type adducts with the glycopyranosyl cation. Through
this procedure, 2-azido-a-D-glucosyl derivatives have been suc-
cessfully synthesized with high diastereoselectivities.44 However,
in our hands this glycosylation series in Cl2CH2 as solvent and

G. Gola et al. / Carbohydrate Research 346 (2011) 1495–1502
1499
after total disappearance of 1 or 2,3,5,6-tetra-O-benzyl-
D
-galacto-
9.9 Hz, H-6a), 3.66 (dd, 1H, J = 5.2, 9.9 Hz, H-6b), 3.59–3.53 (m,
1H, (CH2)5CHO), 1.91–1.82 (m, 2H), 1.75–1.65 (m, 2H), 1.54–1.47
(m, 1H), 1.41–1.14 (m, 5H), (H-1 signal is in agreement with lit.
and was the only physical data described for this compound45);
13C NMR (125 MHz,CDCl3): d 138.3–127.5 (aromatic), 104.2 (C-1),
89.0 (C-2), 82.7 (C-3), 80.2 (C-4), 76.4 (C-5), 75.3 ((CH2)5CHO);
73.4, 73.3, 72.0, 71.8 (PhCH2); 71.0 (C-6), 33.7, 31.8, 25.7, 24.2,
24.1 ((CH2)5CHO); HRMS (ESI) calcd for (M+Na) C40H46O6Na:
645.3187. Found: 645.3186.
furanose. The mixture was diluted with CH2Cl2 (5 mL) and filtered.
The filtrate was concentrated and the residue was purified by silica
gel column chromatography, as indicated in each case.
a
/b ratio was established from the 1H NMR spectrum of the
crude reaction and then corroborated by weights of isolated
and b products (Table 1).
a
4.2.2. Method B
Same procedure described for method A was followed, using
anhyd diethylether as solvent.
Method A: Compound 1 (64 mg, 0.093 mmol) and cyclohexanol
(12.8
(31%).
Method B: Compound 1 (63 mg, 0.092 mmol) and cyclohexanol
(12.6 L, 0.120 mmol) gave 38 mg of 7 (66%) and 16 mg of 7b
(28%).
Method C: Compound
(10.8 L, 0.102 mmol) gave 7 mg of 7
(55%).
Method D: Compound 1 (39 mg, 0.057 mmol) and cyclohexanol
lL, 0.121 mmol) gave 36 mg of 7a (62%) and 18 mg of 7b
4.2.3. Method C
Same procedure described for method A was followed, using
CH3CN as solvent at ꢀ40 °C.
l
a
1
(54 mg, 0.079) and cyclohexanol
(14%) and 27 mg of 7b
4.2.4. Method D44
l
a
To a solution of donor 1 (1 equiv), the acceptor (1.5 equiv) and
thiophene (1 equiv) in anhydr CH2Cl2 (3.0 mL/50 mg of 1) was
added activated 4 Å molecular sieves (150 mg) at room tempera-
ture under argon. After vigorously stirring for 10 min, the mixture
was cooled to ꢀ78 °C and TMSOTf (0.1 equiv) was added and the
stirring continued for 40 min. The reaction was monitored by
TLC, and quenched by the addition of triethylamine (0.1 equiv)
(9.0
l
L, 0.086 mmol) gave 11 mg of 7
a
(31%) and 4.5 mg of 7b
(13%).
4.2.7. Methyl 2,3,5,6-tetra-O-benzyl-
(1?6)-2,3,4-tri-O-benzyl-
Compound 8 was obtained according to general procedures,
using methyl 2,3,4-tri-O-benzyl- -mannopyranoside (2) as
a-
D-galactofuranosyl-
a-D-mannopyranoside (8a)
after total disappearance of 1 or 2,3,5,6-tetra-O-benzyl-
D
-galacto-
a
furanose. The solution was diluted with CH2Cl2 (5 mL) and filtered.
The filtrate was concentrated and the residue was purified by silica
gel column chromatography, as indicated in each case.
a-D
acceptor. The crude was purified by column chromatography
(40:1 toluene–EtOAc) to give a syrup; Rf 0.50 (10:1 toluene–
a
/b ratio was established from the 1H NMR spectrum of the
EtOAc); [
a]
+23.8 (c 1.3, CHCl3). 1H NMR (500 MHz, CDCl3): d
D
crude reaction, and then corroborated by weighting the isolated
7.36–7.16 (m, 35H, ArH), 5.32 (d, 1H, J = 4.2 Hz, H-10), 4.80 (d,
1H, J = 11.0 Hz, PhCH2), 4.74 (d, 1H, J = 1.8 Hz, H-1), 4.71, 4.65
(2d, 2H, J = 11.8 Hz, PhCH2), 4.70, 4.47 (2d, 2H, J = 11.7 Hz,
PhCH2), 4.66, 4.37 (2d, 2H, J = 11.6 Hz, PhCH2), 4.64–4.58 (m,
5H, PhCH2), 4.44, 4.42 (2d, 2H, J = 12.0 Hz, PhCH2), 4.25 (t, 1H,
J = 7.0 Hz, H-30), 4.04 (t, 1H, J = 9.7 Hz, H-4), 3.99 (dd, 1H,
J = 4.2, 7.2 Hz, H-20), 3.97 (t, 1H, J = 6.7 Hz, H-40), 3.88 (dd, 1H,
J = 3.2, 9.5 Hz, H-3), 3.84–3.81 (m, 2H, H-6a, H-6b), 3.79 (dd,
1H, J = 1.8, 3.1 Hz, H-2), 3.74 (dt, 1H, J = 3.8, 6.5 Hz, H-50), 3.65
(m, 1H, H-5), 3.63 (dd, 1H, J = 3.8, 10.4 Hz, H-6a0), 3.55 (dd, 1H,
J = 6.3, 10.4 Hz, H-6b0), 3.27 (s, 3H, OCH3). 13C NMR
(125 MHz,CDCl3): d 138.9–127.3 (aromatic), 100.1 (C-10), 98.9
(C-1), 84.0 (C-20), 81.3 (C-30), 80.7 (C-40), 80.0 (C-3, C-50), 75.03
(PhCH2), 75.0 (C-2), 74.9 (C-4); 73.3, 73.0, 72.9 (PhCH2); 72.3
(C-5); 72.0 (x2), 71.9 (PhCH2); 70.5 (C-60), 65.1 (C-6), 54.7
(OCH3); HRMS (ESI) calcd for (M+Na) C62H66O11Na: 1009.4497.
Found: 1009.4471.
a
and b products (Table 1).
4.2.5. Cyclohexyl 2,3,5,6-tetra-O-benzyl-a-D-galactofuranoside
(7a
)
Compound 7a was obtained according to general procedures,
using cyclohexanol as acceptor. The crude was purified by column
chromatography (80:1 toluene–EtOAc) to give a syrup; Rf 0.59
(10:1 toluene–EtOAc);
[a]
+35.0 (c 0.9, CHCl3). 1H NMR
D
(500 MHz, CDCl3): d 7.39–7.20 (m, 20H, ArH), 5.12 (d, 1H,
J = 4.4 Hz, H-1), 4.74, 4.48 (2d, 2H, J = 11.6 Hz, PhCH2), 4.74, 4.63
(2d, 2H, J = 11.7 Hz, PhCH2), 4.65, 4.51 (2d, 2H, J = 11.6 Hz, PhCH2),
4.50, 4.44 (2d, 2H, J = 12.1 Hz, PhCH2), 4.27 (t, 1H, J = 7.3 Hz, H-3),
4.03 (dd, 1H, J = 4.4, 7.5 Hz, H-2), 3.94 (t, 1H, J = 6.9 Hz, H-4), 3.74
(dt, 1H, J = 3.8, 6.5 Hz, H-5), 3.66 (dd, 1H, J = 3.8, 10.4 Hz, H-6a),
3.62–3.58 (m, 1H, (CH2)5CHO), 3.56 (dd, 1H, J = 6.4, 10.4 Hz, H-
6b), 1.93–1.85 (m, 2H), 1.77–1.66 (m, 2H), 1.55–1.48 (m, 1H),
1.43–1.11 (m, 5H), (H-1 signal is in agreement with lit. and was
the only physical data described for this compound45); 13C NMR
(125 MHz, CDCl3): d 138.9–127.3 (aromatic), 97.9 (C-1), 83.9 (C-
2), 81.3 (C-3), 80.4 (C-5), 80.2 (C-4), 75.6 ((CH2)5CHO); 73.3, 73.0,
72.2, 72.1 (PhCH2); 70.4 (C-6), 33.6, 31.6, 25.6, 24.4, 24.2
((CH2)5CHO); HRMS (ESI) calcd for (M+Na) C40H46O6Na:
645.3187. Found: 645.3195.
4.2.8. Methyl 2,3,5,6-tetra-O-benzyl-b-
(1?6)-2,3,4-tri-O-benzyl- -mannopyranoside (8b)
Compound 8b was obtained according to general procedures,
using methyl 2,3,4-tri-O-benzyl- -mannopyranoside (2) as
D-galactofuranosyl-
a
-D
a-D
acceptor. The crude was purified by column chromatography
(40:1 toluene–EtOAc) to give a syrup; Rf 0.44 (10:1 toluene–
EtOAc); [
a
]
ꢀ19.5 (c 0.3, CHCl3). 1H NMR (500 MHz, CDCl3): d
D
4.2.6. Cyclohexyl 2,3,5,6-tetra-O-benzyl-b-
D
-galactofuranoside
7.37–7.16 (m, 35H, ArH), 5.18 (d, 1H, J = 1.3 Hz, H-10), 4.90 (d,
1H, J = 11.1 Hz, PhCH2), 4.74–4.69 (m, 3H, PhCH2), 4.70 (br s, 1H,
H-1), 4.58–4.41 (m, 9H, PhCH2), 4.28 (d, 1H, J = 11.8 Hz, PhCH2),
4.18 (dd, 1H, J = 3.2, 7.2 Hz, H-30), 4.06 (dd, 1H, J = 1.3, 3.6 Hz,
H-20), 4.04–4.01 (m, 2H, H-6a, H-40), 3.86 (dd, 1H, J = 3.1,
8.8 Hz, H-3), 3.81–3.70 (m, 5H, H-4, H-5, H-50,H-6a0), 3.70–3.64
(m, 2H, H-6b, H-6b0), 3.25 (s, 3H, OCH3). 13C NMR (125 MHz,CDCl3):
d 138.5–127.4 (aromatic), 106.6 (C-10), 98.8 (C-1), 88.3 (C-20), 82.7
(C-40), 80.9 (C-30), 80.2 (C-3); 76.4, 75.3 (C-50, C-4); 75.0 (PhCH2),
74.6 (C-2); 73.4, 73.3, 72.7, 72.1, 72.0, 71.8 (PhCH2); 71.6 (C-5),
71.3 (C-60), 67.1 (C-6), 54.6 (OCH3); HRMS (ESI) calcd for (M+Na)
(7b)
Compound 7b was obtained according to general procedures,
using cyclohexanol as acceptor. The crude was purified by column
chromatography (80:1 toluene–EtOAc) to give a syrup; Rf 0.67
(10:1 toluene–EtOAc);
[
a
]
ꢀ49.0 (c 0.5, CHCl3). 1H NMR
D
(500 MHz, CDCl3): d 7.37–7.15 (m, 20H, ArH), 5.21 (d, 1H,
J = 1.4 Hz, H-1), 4.71, 4.52 (2d, 2H, J = 11.8 Hz, PhCH2), 4.58, 4.48
(2d, 2H, J = 11.9 Hz, PhCH2), 4.50(s, 2H, PhCH2), 4.47, 4.29 (2d,
2H, J = 11.7 Hz, PhCH2), 4.15 (dd, 1H, J = 3.1, 7.3 Hz, H-4), 4.01
(dd, 1H, J = 3.7, 7.1 Hz, H-3), 3.99 (dd, 1H, J = 1.6, 3.7 Hz, H-2),
3.77 (ddd, 1H, J = 3.1, 5.2, 6.5 Hz, H-5), 3.71 (dd, 1H, J = 6.5,
C62H66O11Na: 1009.4497. Found: 1009.4535.

1500
G. Gola et al. / Carbohydrate Research 346 (2011) 1495–1502
Method A: Compound 1 (48 mg, 0.070 mmol) and 2 (42 mg,
0.090 mmol) gave 40 mg of 8 (58%) and 12 mg of 8b (17%).
Method B: Compound 1 (57 mg, 0.083 mmol) and 2 (50 mg,
0.108 mmol) gave 51.5 mg of 8 (63%) and 21.5 mg of 8b (26%).
Method C: Compound 1 (58 mg, 0.085 mmol) and 2 (51 mg,
0.110 mmol) gave 9.5 mg of 8 (11%) and 62.5 mg of 8b (75%).
Method D: Compound 1 (46 mg, 0.067 mmol) and 2 (47 mg,
0.101 mmol) gave 30 mg of 8 (45%) and 12.5 mg of 8b (19%).
4.2.11. Allyl 2,3,5,6-tetra-O-benzyl-
3,4-di-O-benzyl- -L-rhamnopyranoside (10
Compound 10 was obtained according to general procedures,
using allyl 3,4-di-O-benzyl- -L-rhamnopyranoside (4) as acceptor.
a-D-galactofuranosyl-(1?2)-
a
a
a
a)
a
a
The crude was purified by column chromatography (100:0.75 and
a
80:1 toluene–EtOAc) to give a syrup; Rf 0.45 (10:1 toluene–EtOAc);
[a]
+14.0 (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): d 7.38–
D
a
7.17 (m, 30H, ArH), 5.78 (dddd, 1H, J = 5.2, 6.0, 10.4, 17.1 Hz,
OCH2CH=CH2), 5.30 (d, 1H, J = 4.2 Hz, H-10), 5.19 (dq, 1H, J = 1.6,
17.2 Hz, OCH2CH=CHaH), 5.09 (dq, 1H, J = 1.4, 10.4 Hz,
OCH2CH=CHHb), 4.96, 4.54 (2d, 2H, J = 11.2 Hz, PhCH2), 4.84 (d,
1H, J = 2.2 Hz, H-1), 4.73–4.60 (m, 6H, PhCH2), 4.49 (d, 1H,
J = 11.7 Hz, PhCHH), 4.42 (d, 1H, J = 11.4 Hz, PhCHH), 4.36–4.29
(m, 2H, PhCH2), 4.27 (dd, 1H, J = 3.2, 8.7 Hz, H-3), 4.23 (t, 1H,
J = 7.0 Hz, H-30), 4.11–4.06 (m, 2H, H-20, OCHH-CH=CH2), 4.02 (t,
1H, J = 6.9 Hz, H-40), 3.98 (t, 1H, J = 2.7 Hz, H-2), 3.91 (ddt, 1H,
J = 1.3, 6.1, 13.0 Hz, OCHH-CH=CH2), 3.78 (ddd, 1H, J = 4.0, 5.8,
6.8 Hz, H-50), 3.71 (dq, 1H, J = 6.3, 9.2 Hz, H-5), 3.58 (t, 1H,
J = 8.9 Hz, H-4), 3.48 (dd, 1H, J = 4.0, 10.5 Hz, H-6a0), 3.38 (dd, 1H,
J = 5.8, 10.5 Hz, H-6b0), 1.26 (d, 3H, J = 6.3 Hz, H-6). 13C NMR
(125 MHz,CDCl3): d 138.9–127.3 (aromatic), 134.0 (OCH2CH=CH2),
117.1 (OCH2CH=CH2), 98.2 (C-10), 96.7 (C-1), 84.5 (C-20), 81.0 (C-30,
C-40), 80.1 (C-4), 79.9 (C-50), 75.5 (C-3), 75.3 (C-2), 73.2, 73.1, 72.6,
72.0, 71.9 (PhCH2), 70.0 (C-60), 68.0 (C-5), 67.9 (OCH2CH=CH2), 18.0
4.2.9. Methyl 2,3,5,6-tetra-O-benzyl-
(1?6)-2,3,4-tri-O-benzoyl- -mannopyranoside (9
Compound 9 was obtained according to general procedure
(method A), using methyl 2,3,4-tri-O-benzoyl- -mannopyrano-
a-D-galactofuranosyl-
a-
D
a)
a
a
-D
side (3) as acceptor. The crude was purified by column chromatog-
raphy (30:1 toluene–EtOAc) to give a syrup; Rf 0.44 (10:1 toluene–
EtOAc); [
a]
ꢀ33.7 (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): d
D
8.03–7.14 (m, 35H, ArH), 5.89 (t, 1H, J = 9.4 Hz, H-4), 5.85 (dd,
1H, J = 3.3, 9.5 Hz, H-3), 5.67 (dd, 1H, J = 1.7, 3.0 Hz, H-2), 4.94 (d,
1H, J = 1.7 Hz, H-1), 4.89 (d, 1H, J = 4.1 Hz, H-10), 4.72, 4.47 (2d,
2H, J = 11.6 Hz, PhCH2), 4.58, 4.51 (2d, 2H, J = 12.0 Hz, PhCH2),
4.56–450 (m, 2H, PhCH2), 4.45, 4.40 (2d, 2H, J = 12.3 Hz, PhCH2),
4.27 (m, 1H, H-5), 4.26 (t, 1H, J = 7.3 Hz, H-30), 4.01 (dd, 1H,
J = 4.1, 7.3 Hz, H-20), 3.98 (dd, 1H, J = 6.0, 10.9 Hz, H-6a), 3.93 (t,
1H, J = 7.1 Hz, H-40), 3.75 (m, 1H, H-50), 3.61–3.57 (m, 2H, H-6a0,
H-6b), 3.49 (dd, 1H, J = 6.2, 10.5 Hz, H-6b0), 3.46 (s, 3H, OCH3).
13C NMR (125 MHz,CDCl3): d 165.6, 165.5 (COPh), 138.8–127.3
(aromatic), 100.2 (C-10), 98.5 (C-1), 84.1 (C-20), 81.1 (C-30), 80.8
(C-40), 80.6 (C-50); 73.3, 73.1, 72.3, 72.1 (PhCH2), 70.5 (C-2), 70.3
(C-3, C-60), 69.7 (C-5), 67.4 (C-4), 66.5 (C-6), 55.4 (OCH3);
HRMS (ESI) calcd for (M+Na) C62H60O14Na: 1051.3875. Found:
1051.3869.
(C-6); HRMS (ESI) calcd for (M+Na)
Found: 929.4207.
C57H62O10Na: 929.4235.
4.2.12. Allyl 2,3,5,6-tetra-O-benzyl-b-
3,4-di-O-benzyl- -L-rhamnopyranoside (10b)
Compound 10b was obtained according to general procedures,
using allyl 3,4-di-O-benzyl- -L-rhamnopyranoside (4) as acceptor.
D-galactofuranosyl-(1?2)-
a
a
The crude was purified by column chromatography (100:0.75 and
4.2.10. Methyl 2,3,5,6-tetra-O-benzyl-b-
(1?6)-2,3,4-tri-O-benzoyl- -mannopyranoside (9b)
Compound 9b was obtained according to general procedure
(method C), using methyl 2,3,4-tri-O-benzoyl- -mannopyrano-
D
-galactofuranosyl-
80:1 toluene–EtOAc) to give a syrup; Rf 0.63 (10:1 toluene–EtOAc);
a-
D
[a]
ꢀ31.1 (c 0.9, CHCl3). 1H NMR (500 MHz, CDCl3): d 7.34–7.07
D
(m, 30H, ArH), 5.82 (dddd, 1H, J = 5.1, 6.0, 10.8, 17.3 Hz,
OCH2CH=CH2), 5.43 (s, 1H, H-10), 5.23 (dq, 1H, J = 1.7, 17.3 Hz,
OCH2CH=CHH), 5.13 (dq, 1H, J = 1.5, 10.5 Hz, OCH2CH=CHH), 4.90,
4.66 (2d, 2H, J = 11.5 Hz, PhCH2), 4.77, 4.56 (2d, 2H, J = 12.3 Hz,
PhCH2), 4.69, 4.52 (2d, 2H, J = 11.9 Hz, PhCH2), 4.68 (d, 1H,
J = 1.8 Hz, H-1), 4.45, 4.30 (2d, 2H, J = 11.7 Hz, PhCH2), 4.43 (s,
2H, PhCH2), 4.37, 4.28 (2d, 2H, J = 11.7 Hz, PhCH2), 4.27 (dd, 1H,
J = 3.8, 6.8 Hz, H-40), 4.14 (dd, 1H, J = 3.1, 9.6 Hz, H-3), 4.13–4.08
(m, 2H, OCHH-CH=CH2, H-20), 4.02 (dd, 1H, J = 2.5, 6.8 Hz, H-30),
3.88 (ddt, 1H, J = 1.4, 5.9, 13.1 Hz, OCHH-CH=CH2), 3.80 (dd, 1H,
J = 1.8, 3.1 Hz, H-2), 3.77 (m, 1H, H-50), 3.73 (dq, 1H, J = 6.2,
9.5 Hz, H-5), 3.66 (dd, 1H, J = 6.3, 9.9 Hz, H-6a0), 3.62 (dd, 1H,
J = 3.2, 9.8 Hz, H-6b0), 3.61 (dd, 1H, J = 7.1, 9.5 Hz, H-4), 1.30 (d,
3H, J = 6.2 Hz, H-6). 13C NMR (125 MHz, CDCl3): d138.8–127.1 (aro-
matic), 133.9 (OCH2CH=CH2), 116.9 (OCH2CH=CH2), 107.9 (C-10),
97.4 (C-1), 88.6 (C-20), 83.3 (C-30), 81.6 (C-40), 80.5 (C-4), 78.7 (C-
2), 78.4 (C-3), 76.6 (C-50); 74.9, 73.4, 73.2, 72.1, 71.5 (PhCH2);
70.5 (C-60), 68.2 (C-5), 67.7 (OCH2CH=CH2), 17.9 (C-6); HRMS
(ESI) calcd for (M+Na) C57H62O10Na: 929.4235. Found: 929.4207.
Method A: Compound 1 (62 mg, 0.091 mmol) and 4 (45 mg,
a
-D
side (3) as acceptor. The crude was purified by column chromatog-
raphy (30:1 toluene–EtOAc) to give a syrup. A second column
chromatography purification allowed the isolation of 9b (as a
35:1 b/
purposes. Rf 0.44 (10:1 toluene–EtOAc); [
a
mixture according to 1H NMR spectrum) for identification
a]
ꢀ78.2 (c 1.0, CHCl3).
D
1H NMR (500 MHz, CDCl3): d 8.08–7.16 (m, 35H, ArH), 5.90 (t,
1H, J = 9.9 Hz, H-4), 5.86 (dd, 1H, J = 3.2, 9.9 Hz, H-3), 5.66 (dd,
1H, J = 1.9, 3.2 Hz, H-2), 5.13 (d, 1H, J = 1.2 Hz, H-10), 4.95 (d, 1H,
J = 1.7 Hz, H-1), 4.68, 4.47 (2d, 2H, J = 11.8 Hz, PhCH2), 4.63, 4.49
(2d, 2H, J = 11.8 Hz, PhCH2), 4.45, 4.28 (2d, 2H, J = 11.8 Hz, PhCH2),
4.43 (br s, 2H, PhCH2), 4.23 (m, 1H, H-5), 4.16 (dd, 1H, J = 3.2,
7.3 Hz, H-40), 4.06 (dd, 1H, J = 1.2, 3.5 Hz, H-20), 4.01 (dd, 1H,
J = 3.5, 7.3 Hz, H-30), 3.93 (dd, 1H, J = 2.4, 11.5 Hz, H-6a), 3.74 (m,
1H, H-50), 3.71 (dd, 1H, J = 6.1, 11.5 Hz, H-6b), 3.66 (dd, 1H,
J = 6.6, 10.1 Hz, H-6a0), 3.60 (dd, 1H, J = 4.9, 10.1 Hz, H-6b0), 3.46
(s, 3H, OCH3). 13C NMR (125 MHz,CDCl3): d 165.5, 165.4, 163.4
(COPh); 138.3–127.5 (aromatic), 106.8 (C-10), 98.4 (C-1), 88.4 (C-
20), 82.6 (C-30), 80.9 (C-40), 76.2 (C-50), 73.4, 73.2, 72.0, 71.8
(PhCH2), 70.9 (C-60), 70.4 (C-2), 70.1 (C-5), 70.0 (C-4), 67.2 (C-3),
66.5 (C-6), 55.4 (OCH3); HRMS (ESI) calcd for (M+Na) C62H60O14Na:
1051.3875. Found: 1051.3868
0.117 mmol) gave 36 mg (43.6%) of 10a, 3.6 mg of 10b (4%), and
15 mg of 2,3,5,6-tetra-O-benzyl-1-N-trichloroacetyl-
a-D-galacto-
furanosylamine (13) (24%).
Method A: Compound 1 (56 mg, 0.082 mmol) and 3 (54 mg,
Method B: Compound 1 (58 mg, 0.085 mmol) and 4 (41 mg,
0.106 mmol) gave 53 mg (63%) of 9
Method B: Compound 1 (61 mg, 0.089 mmol) and 3 (59 mg,
0.116 mmol) gave 62 mg of 9 and 9b (68%).
Method C: Compound 1 (50 mg, 0.073 mmol) and 3 (48 mg,
0.095 mmol) gave 68 mg of 9 and 9b (90%).
Method D: Compound 1 (42 mg, 0.061 mmol) and 3 (47 mg,
0.093) gave 41.5 mg of 9 and 9b (66%).
a
0.107 mmol) gave 32 mg of 10
18 mg of 13 (31%).
Method C: Compound 1 (42 mg, 0.061 mmol) and 4 (31 mg,
0.080 mmol) gave 51 mg of 10b (92%).
Method D: Compound 1 (32 mg, 0.047 mmol) and 4 (27 mg,
0.070 mmol) gave 24.5 mg of 10
11 mg of 13 (34%).
a (42%), 11 mg of 10b (14%) and
a
a
a (57%), 2.5 mg of 10b (6%) and
a

G. Gola et al. / Carbohydrate Research 346 (2011) 1495–1502
1501
4.2.13. Methyl 2,3,5,6-tetra-O-benzyl-
(1?2)-3-O-benzoyl-4,6-O-benzylidene-
(11
Compound 11
using methyl 3-O-benzoyl-4,6-O-benzylidene-
side (5) as acceptor. The crude was purified by column chromatog-
a
-
a
D
-galactofuranosyl-
lactone (6) as acceptor. The crude was purified by column chro-
matography (50:1 toluene–EtOAc) to give a syrup; Rf 0.34 (10:1
-D-mannopyranoside
a)
toluene–EtOAc); [
a]
+24.8 (c 0.9, CHCl3). 1H NMR (500 MHz,
D
a
was obtained according to general procedures,
-mannopyrano-
CDCl3): d 8.03–7.22 (m, 25H, ArH), 6.00 (d, 1H, J = 8.0 Hz, H-2),
4.77, 4.60 (2d, 2H, J = 11.9 Hz, PhCH2), 4.73 (d, 1H, J = 4.3 Hz,
H-10), 4.70, 4.03 (2d, 2H, J = 10.1 Hz, PhCH2), 4.61, 4.51 (2d, 2H,
J = 11.7 Hz, PhCH2), 4.49, 4.41 (2d, 2H, J = 11.8 Hz, PhCH2), 4.36
(t, 1H, J = 8.0 Hz, H-30), 4.35 (t, 1H, J = 8.2 Hz, H-3), 4.17 (dt,
1H, J = 2.6, 6.9 Hz, H-5), 3.97 (dd, 1H, J = 4.2, 8.4 Hz, H-20), 3.94
(dd, 1H, J = 6.8, 8.2 Hz, H-6a), 3.86 (dd, 1H, J = 1.1, 8.0 Hz, H-40),
3.81 (dd, 1H, J = 7.0, 8.4 Hz, H-6b), 3.77 (dd, 1H, J = 8.8,
12.2 Hz, H-6a0), 3.56–3.50 (m, 2H, H-50,H-6b0), 3.31 (dd, 1H,
J = 2.6, 7.9 Hz, H-4), 1.40, 1.37 (2 s, 6H, (CH3)2C). 13C NMR
(125 MHz, CDCl3): d 169.5 (C-1), 164.8 (COPh), 138.3–127.6 (aro-
matic), 110.2 (CH3)2C), 99.8 (C-10), 83.7 (C-20), 79.5 (C-40), 78.3
(C-30), 77.9 (C-3), 77.3 (C-4), 75.8 (C-50), 74.2 (C-2), 73.4 (PhCH2),
73.1 (C-5), 72.7, 72.5 (PhCH2), 70.2 (C-60), 65.0 (C-6), 26.0, 25.7
(CH3)2C); HRMS (ESI) calcd for (M+Na) C50H52O12Na: 867.3351.
Found: 867.3324.
a
-D
raphy (40:1 toluene–EtOAc) to give
a syrup; Rf 0.52 (10:1
toluene–EtOAc); [
a]
ꢀ2.7 (c 0.8, CHCl3). 1H NMR (500 MHz,
D
CDCl3): d 8.03–7.10 (m, 30H, ArH), 5.53 (dd, 1H, J = 3.2, 10.5 Hz,
H-3), 5.38 (s, 1H, CHPh), 5.14 (d, 1H, J = 4.5 Hz , H-10), 5.04 (d,
1H, J = 1.7 Hz, H-1), 4.82, 4.44 (2d, 2H, J = 11.7 Hz, PhCH2), 4.71,
4.41 (2d, 2H, J = 11.6 Hz, PhCH2), 4.68, 4.52 (2d, 2H, J = 11.7 Hz,
PhCH2), 4.50 (s, 2H, PhCH2), 4.40 (t, 1H, J = 7.7 Hz, H-30), 4.38 (dd,
1H, J = 1.7, 3.2 Hz, H-2), 4.25 (dd, 1H, J = 9.0, 10.2 Hz, H-4), 4.23
(dd, 1H, J = 4.3, 9.5 Hz, H-6a), 4.02 (dd, 1H, J = 4.5, 7.7 Hz, H-20),
3.93 (dd, 1H, J = 4.3, 7.7 Hz, H-40), 3.89 (m, 1H, H-5), 3.83 (t, 1H,
J = 10.1 Hz, H-6b), 3.71 (m, 1H, H-50), 3.65 (dd, 1H, J = 4.8,
10.0 Hz, H-6a0), 3.62 (dd, 1H, J = 6.3, 10.0 Hz, H-6b0), 3.17 (s, 3H,
OCH3). 13C NMR (125 MHz, CDCl3): d 165.9 (COPh), 138.5–126.1
(aromatic), 101.5 (CHPh), 101.0 (C-10), 100.8 (C-1), 83.5 (C-20),
80.1 (C-40), 79.9 (C-30), 77.7 (C-50), 76.3 (C-4), 74.5 (C-2), 73.4,
73.0, 72.4 (PhCH2), 71.8 (C-3), 71.5 (PhCH2), 70.5 (C-60), 68.9
(C-6), 63.9 (C-5), 54.8 (OCH3); HRMS (ESI) calcd for (M+Na)
4.2.16. 2,3,5,6-Tetra-O-benzyl-b-
benzoyl-5,6-O-isopropylidene- -galactono-1,4-lactone (12b)
Compound 12b was obtained according to general procedures,
using 2-O-benzoyl-5,6-O-isopropylidene- -galactono-1,4-lactone
D-galactofuranosyl-(1?3)-2-O-
D
C55H56O12Na: 931.3664. Found: 931.3636.
D
(6) as acceptor. The crude was purified by column chromatography
(50:1 toluene–EtOAc) to give a syrup; Rf 0.27 (10:1 toluene–
4.2.14. Methyl 2,3,5,6-tetra-O-benzyl-b-
D
-galactofuranosyl-
(1?2)-3-O-benzoyl-4,6-O-benzylidene-
(11b)
a
-
D-mannopyranoside
EtOAc); [
a]
D
ꢀ31.2 (c 0.6, CHCl3). 1H NMR (500 MHz, CDCl3): d
8.10–7.18 (m, 35H, ArH), 5.84 (d, 1H, J = 7.0 Hz, H-2), 5.23 (br s,
1H, H-10), 4.73 (t, 1H, J = 6.7 Hz, H-3), 4.63 (d, 1H, J = 11.8 Hz,
PhCH2), 4.56 (d, 1H, J = 11.8 Hz, PhCH2), 4.47–4.40 (m, 5H, PhCH2),
4.36 (m, 1H, H-5), 4.28 (dd, 1H, J = 2.6, 6.4 Hz, H-4), 4.26 (d, 1H,
J = 11.7 Hz, PhCH2), 4.11 (dd, 1H, J = 3.5, 7.1 Hz, H-40), 4.02 (dd,
1H, J = 1.2, 3.4 Hz, H-20), 4.00 (dd, 1H, J = 3.4, 7.1 Hz, H-30), 3.92–
3.88 (m, 2H, H-6a, H-6b), 3.70 (m, 1H, H-50), 3.63–3.59 (m, 2H,
H-6a0, H-6b0), 1.41, 1.32 (2 s, 6H, (CH3)2C). 13C NMR (125 MHz,
CDCl3): d 169.2 (C-1), 133.9–127.5 (aromatic), 106.1 (C-10), 87.9
(C-20), 82.6 (C-30), 81.2 (C-40), 79.8 (C-4), 76.9 (C-3), 75.9 (C-50),
74.1 (C-2), 73.9 (C-5), 73.3, 72.1, 72.0 (PhCH2), 70.1 (C-60), 65.0
(C-6), 25.9, 25.7 (CH3)2C); HRMS (ESI) calcd for (M+Na)
Compound 11b was obtained according to generals procedures,
using methyl 3-O-benzoyl-4,6-O-benzylidene- -mannopyrano-
a
-D
side (5) as acceptor. The crude was purified by column chromatog-
raphy (40:1 toluene–EtOAc) to give a syrup; Rf 0.36 (10:1 toluene–
EtOAc); [
a]
ꢀ43.9 (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): d
D
8.09–7.15 (m, 30H, ArH), 5.61 (s, 1H, CHPh), 5.54 (dd, 1H, J = 3.6,
10.4 Hz, H-3), 5.14 (d, 1H, J = 1.2 Hz, H-10), 4.74 (d, 1H, J = 1.5 Hz,
H-1), 4.59, 4.49 (2d, 2H, J = 12.0 Hz, PhCH2), 4.55, 4.27 (2d, 2H,
J = 11.7 Hz, PhCH2), 4.44, 4.29 (2d, 2H, J = 11.7 Hz, PhCH2), 4.38
(dd, 1H, J = 1.6, 3.6 Hz, H-2), 4.33 (dd, 1H, J = 4.5, 9.9 Hz, H-6a),
4.27 (dd, 1H, J = 8.7, 9.9 Hz, H-4), 4.23, 4.20 (2d, 2H, J = 12.0 Hz,
PhCH2), 4.10 (dd, 1H, J = 1.2, 3.2 Hz, H-20), 4.01 (dd, 1H, J = 3.2,
6.7 Hz, H-30), 3.98 (m, 1H, H-5), 3.95 (dd, 1H, J = 2.9, 6.7 Hz, H-40),
3.90 (t, 1H, J = 10.2 Hz, H-6b), 3.45 (m, 1H, H-50), 3.43 (s, 3H,
OCH3), 3.42 (dd, 1H, J = 7.7, 9.5 Hz, H-6a0), 3.10 (dd, 1H, J = 2.1,
9.5 Hz, H-6b0). 13C NMR (125 MHz,CDCl3): d 165.7 (COPh), 138.4–
126.1 (aromatic), 104.0 (C-10), 101.7 (CHPh), 98.7 (C-1), 87.8 (C-
20), 82.5 (C30), 81.9 (C-40), 76.2 (C-50, C-4), 73.05, 73.14 (PhCH2),
72.3 (C-2), 71.9, 71.8 (PhCH2), 71.7 (C-60), 69.8 (C-3), 68.9 (C-6),
64.1 (C-5), 55.2 (OCH3); HRMS (ESI) calcd for (M+Na) C55H56O12Na:
931.3664. Found: 931.3627.
C50H52O12Na: 867.3351. Found: 867.3325
Method A: Compound 1 (51 mg, 0.074 mmol) and 6 (31 mg,
0.096 mmol) gave 12.5 mg of 12a (20%), 4.5 mg of 12b (7%), and
15.5 mg of 13 (30%)
Method B: Compound 1 (48 mg, 0.070 mmol) and 6 (29 mg,
0.090 mmol) gave 5 mg of 12 (8%) and 35 mg of 13 (73%).
Method C: Compound 1 (46 mg, 0.067 mmol) and 6 (28 mg,
0.087 mmol) gave 20 mg of 12 (35%) and 14 mg of 12b (25%).
Method D: Compound 1 (53 mg, 0.077 mmol) and 6 (37 mg,
a
a
0.115 mmol) gave 11 mg of 12a (17%), 3 mg of 12b (5%) and
Method A: Compound 1 (58 mg, 0.085 mmol) and 5 (51 mg,
17.5 mg of 13 (33%).
0.110 mmol) gave 21 mg of 11a (28%), 6 mg of 11b (8%), and 21
mg of 13 (36%)
Acknowledgments
Method B: Compound 1 (56 mg, 0.082 mmol) and 5 (48 mg,
0.104 mmol) gave 25 mg of 13 (45%).
This work was supported by grants from Agencia Nacional de
Promoción Científica y Tecnológica, Universidad de Buenos Aires
and CONICET. C. Gallo-Rodriguez is a research member of CONICET.
M. J. Tilve is a fellow from CONICET.
Method C: Compound 1 (52 mg, 0.076 mmol) and 5 (46 mg,
0.099 mmol) gave 11 mg of 11a (16%) and 15.5 mg of 11b
(23%).
Method D: Compound 1 (29 mg, 0.042 mmol) and 5 (29 mg,
0.063 mmol) gave 2.6 mg of 11
a and 11b (7%), and 3.5 mg of 13
Supplementary data
(12%).
Supplementary data (1H and 13C NMR spectra for compounds
4.2.15. 2,3,5,6-Tetra-O-benzyl-
a
-D
-galactofuranosyl-(1?3)-2-O-
7
a
and 7b, and new compounds 8
11b, 12 , and 12b) associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2011.04.005.
a, 8b, 9a, 9b, 10a, 10b, 11a,
benzoyl-5,6-O-isopropylidene-
D
-galactono-1,4-lactone (12
a)
a
Compound 12
a
was obtained according to general proce-
dures, using 2-O-benzoyl-5,6-O-isopropylidene-
D
-galactono-1,4-

1502
G. Gola et al. / Carbohydrate Research 346 (2011) 1495–1502
25. Gandolfi-Donadío, L.; Gallo-Rodriguez, C.; de Lederkremer, R. M. J. Org. Chem.
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