Facile synthesis of per-O-tort-butyldimethylsilyl-β-D-galactofuranose and efficient glyeosylation via the galactofuranosyl iodide

Article abstract of DOI:10.1021/jo8025274

The synthesis of crystalline per-0-TBS-β-D-galactofuranose (Aβ) as a new precursor of D-Galf units is described. Anomeric iodination by reaction with TMSI followed by in situ coupling with simple alcohols and a wide variety of glycosyl acceptors, in the absence of a promoter, was employed as a new efficient glycosylation method for the assembly of D-galactofuranosyl moieties with high β-stereoselectivity. Under the mild conditions of this reaction labile protective groups, like acetals, and furanosyl linkages are preserved.

Full text of DOI:10.1021/jo8025274

Facile Synthesis of per-O-tert-Butyldimethylsilyl-ꢀ-D-galactofuranose
and Efficient Glycosylation via the Galactofuranosyl Iodide
Luciana Baldoni and Carla Marino*
CIHIDECAR-CONICET, Departamento de Qu´ımica Orga´nica, Facultad de Ciencias Exactas y Naturales,
UniVersidad de Buenos Aires, Pabello´n II, Ciudad UniVersitaria, 1428 Buenos Aires, Argentina
cmarino@qo.fcen.uba.ar
ReceiVed NoVember 12, 2008
The synthesis of crystalline per-O-TBS-ꢀ-D-galactofuranose (4ꢀ) as a new precursor of D-Galf units is
described. Anomeric iodination by reaction with TMSI followed by in situ coupling with simple alcohols
and a wide variety of glycosyl acceptors, in the absence of a promoter, was employed as a new efficient
glycosylation method for the assembly of D-galactofuranosyl moieties with high ꢀ-stereoselectivity. Under
the mild conditions of this reaction labile protective groups, like acetals, and furanosyl linkages are
preserved.
Introduction
investigation on its biosynthetic pathways.9,10 Therefore, the
synthesis of oligosaccharides and conjugates containing D-Galf
units11 as tools in glycobiology is an area of active research.
Our laboratory has also been largely interested in the glycobi-
ology of galactofuranose.12 Thus, we have reported the synthesis
of derivatives of galactofuranose, which act as substrates13 or
inhibitors14 of related enzymes, and the preparation of deoxy-
genated analogues of the natural substrates for the characteriza-
tion of the carbohydrate-protein interactions.15 Nevertheless,
devising new galactofuranosyl donors and developing new
glycosylation methodologies for both the synthesis of galacto-
furanosyl precursors and glycosylation methods are still required.
Highly immunogenic galactofuranosyl residues are present
in glycoconjugates of many pathogenic bacteria, such as
Mycobacterium tuberculosis and M. leprae,1,2 protozoan para-
sites, such as Trypanosoma cruzi and Leishmania,3-6 and fungi,
such as Paracoccidioides brasilensis.7 The fact that D-Galf is
essential for the survival or virulence of various pathogenic
bacteria,8,9 but is absent in higher eukaryotes, prompted
(1) Crick, D. C.; Mahaprata, S.; Brennan, P. J. Glycobiology 2001, 11, 107–
118.
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2007, 46, 6723–6732. (d) Kleczka, R.; Lamers, A.-C.; van Zandbergen, G.;
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1994 J. Org. Chem. 2009, 74, 1994–2003
10.1021/jo8025274 CCC: $40.75 2009 American Chemical Society
Published on Web 02/12/2009

Synthesis of per-O-tert-Butyldimethylsilyl-ꢀ-D-galactofuranose
Many efforts have been directed to the development of
galactofuranosyl precursors by us14,15a and by other
teams.11a,16-19 The peracylated derivatives 1-3 (Figure 1) are
frequently used as precursors of D-Galf units in oligosaccharides
and glycoconjugates.16,17 They offer the advantage that they may
be glycosylated in one pot, without previous activation, affording
ꢀ-D-galactofuranosides as result of the anchimeric assistance.
With the exception of 1, which was obtained in one step by
benzoylation of D-galactose at high temperature and purified
from the pyranosic forms by crystallization, the other precursors
needed at least three reaction steps and corresponding purifica-
tions. On the other hand, successful glycosylation reactions have
been optimized for the assembly of D-Galf units for the synthesis
of oligosaccharides and glycoconjugates. Glycosyl bromides and
chlorides,20 thioglycosides,21 trichloacetimidates,22 pentenyl-
glycosides,23 and thioimidoyl-type donors11f have been used
successfully. The synthesis of these donors generally involves
more than one step.
FIGURE 1. Galactofuranosyl precursors.
oligosaccharides has been well demonstrated.25,26 The most
convenient procedure for the synthesis of glycopyranosyl iodides
is the treatment of per-O-acetyl derivatives with TMSI intro-
duced by Thiem and Meyer.27 Hindsgaul and Uchiyama showed
that anomeric TMS derivatives could serve as precursors of in
situ formed glycopyranosyl iodides, which react with different
acceptors to give the corresponding glycosides.28 Persilylated
derivatives of glycopyranoses have shown to be useful to afford
glycoconjugates.25f,29 By iodonium replacement of the free
anomeric hydroxyl groups with a polymer-bound triaryl
phosphane-iodine complex and imidazole, several glycopyra-
nosyl and D-mannofuranosyl iodides were prepared.30 Neverthe-
less, to the best of our knowledge, the use of galactofuranosyl
iodides has not been previously reported.
As continuation of our studies on the development of new
methodologies for the synthesis of galactofuranose derivatives,
we decided to explore the synthesis of per-O-silylated derivatives
of D-Galf. In the previous procedure described for the preparation
of the anomeric mixture of the TMS derivative of D-Galf, the
isolation was performed by GC, and it was useful only for
analytical purposes.31 In contrast, we described here the easy
preparation of a new donor of D-galactofuranosyl moieties, per-
O-silyl derivative 4ꢀ (Figure 1), the scope, and the limitations
as a glycosyl donor in glycosylations via the galactofuranosyl
iodide generated in situ.
Two decades ago, the glycopyranosyl iodides had been
considered too reactive, often difficult to handle and isolate,
and not suitable as glycosyl donors.24 However, their efficiency
for the synthesis of O-, S-, and C-glycopyranosides and
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J. Org. Chem. Vol. 74, No. 5, 2009 1995

Baldoni and Marino
TABLE 1. Reaction Conditions Employed for the Synthesis of
isolated by crystallization from MeOH (35% yield) and identi-
fied as 4ꢀ (Scheme 1). Column chromatography of the mother
liquors increased the overall yield to 45%. The lower migrating
component was identified as 5ꢀ and isolated in 42% yield after
column chromatography (entry 4).
per-O-Silylated Derivatives of D-Galf
product distribution (%)
entry silylating agent solvent temp time (h) 4ꢀ 5ꢀ 4r 5r
1
2
TMSCl
TBSCl
DMF
DMF
rt
3
3
-
-
-
100a
rtb
14a 32a
4a,c
With the aim of establishing a procedure for easily obtaining
a galactofuranose derivative, we studied different conditions.
Fortunately, we found that under standard conditions (DMF as
solvent, 30 °C) and a longer reaction time (48 h), the 4ꢀ isomer
was practically the only product, which was isolated in 79%
yield (Table 1, entry 5). Sterically demanding TBS groups
require more time than TMS in order to complete the full
protection. Long reaction time favors the formation of the
ꢀ-furanose form, as also observed for the Fisher’s
glycosylation.13b
3
4
TMSCl
TBSCl
1:1 Py-DMF 80 °C
1:1 Py-DMF 80 °C
3
3
55a,d 25a,d 10a,d 10a,d
48a 43a 5a
4a
45e 42e
100a
-
-
5
TBSCl
DMF
30 °C
48
79e
a
Determined by H NMR spectroscopy. b 50% of unreacted galactose.
1
c Corresponds to the integration of the signals of the 4r and 5r
glycosides, which were not resolved. d Unresolved by preparative
chromatography. e Isolated pure products after column chromatography.
1
The H NMR spectrum of 4ꢀ showed the H-1 signal as a
SCHEME 1. Synthesis of per-O-TBS-ꢀ-D-galactofuranoside
(4ꢀ)
doublet at δ 5.15 with a small J1,2 (2.6 Hz), indicating a trans
relationship for H-1 and H-2 and hence a ꢀ configuration.33
The 13C NMR spectrum showed the resonances at 102.8 ppm
for C-1, and signals at 85.5 and 84.9 ppm for C-4 and C-2,
respectively, also characteristic of ꢀ anomers of galactofuranosyl
derivatives.34 The chemical shifts for the protons were in good
agreement with those reported for the trimethylsilyl analogue,
TMS-ꢀ-D-Galf,31 although the 3JH,H values for the ring protons
were 0.3-1.9 Hz smaller than in compound 4ꢀ. The presence
of adjacent TBS protective groups induces important confor-
mational distortions in pyranose derivatives, which result in the
enhancement of their reactivity as glycosyl donors. This is
the basis of the “super-armed glycosyl donor concept”.35 In the
3
case of 4ꢀ, the JH,H values were similar to those observed for
the acylated14,17 and for other derivatives,11a suggesting that
no important distortion occurs by the effect of bulky TBS groups
in the galactofuranosyl ring.
The arabinose analogue of 4ꢀ, per-O-TBS-R,ꢀ-D-arabino-
furanose, was extensively used for the synthesis of ꢀ-D-
arabinofuranosyl-1-monophosphorylpolyprenols using different
approaches, which involved selective 1-O-desilylation using
TFA.36 With the aim of developing a similar chemistry for
galactofuranose, the anomeric O-desilylation of 4ꢀ was per-
formed, but acid treatment under the controlled conditions
described for the arabinose analogue led to a complex mixture
of products, as a result of the O-desilylation of other positions.
Compound 6 was isolated by column chromatography as an
anomeric mixture in low yield (10%, Scheme 1).
Results and Discussion
Silylation of hydroxyl groups is usually conducted in DMF
and in the presence of imidazole.32 Thus, silylation of D-
galactose with trimethylsilyl chloride (TMSCl) led to the per-
O-TMS-R-pyranose derivative (Table 1, entry 1). Under the
same conditions, silylation with tert-butyldimethylsilyl chloride
(TBSCl) afforded a complex mixture of furanosyl and pyranosyl
silylated derivatives together with an important proportion of
free galactose, as determined by 13C NMR spectroscopy (entry
2).
With compound 4ꢀ in hand, we decided to investigate the
glycosylation reaction promoted by TMSI.28 Thus, compound
4ꢀ was treated with 1.2 equiv of TMSI in anhydrous CH2Cl2 at
0 °C for 30 min, when TLC examination showed total
consumption of the starting material. Also, the presence of two
products was detected, one of Rf ) 0.70 attributed to the 1-iodo
intermediate 7, and the other one with the same mobility as
compound 6 (Rf ) 0.54). Probably, hydrolysis of the galacto-
furanosyl iodide 7 occurs on the silica gel plate, leading to 6.
Subsequent addition of common alcohols (nBuOH, benzyl
alcohol, 4-nitrophenol) and EtN(iPr)2 as an acid scavenger
afforded glycosides 8-10 (Scheme 2, Table 2, entries 1-3).
In order to mimic the conditions employed for the preparation
of per-O-benzoylated derivative 1,17 D-galactose in different
proportions of pyridine was refluxed to favor the furanosic
configuration, and then the silylating agent and the imidazole
were added (Scheme 1). The best results were obtained when
1:1 pyridine/DMF solvent was used. With TMSCl, a chromato-
graphically homogeneous mixture was obtained, which showed
1
by H NMR spectroscopy the presence of the ꢀ-pyranosic and
the ꢀ-furanosic forms as main products (Table 1, entry 3). The
mixture could not be separated by column chromatography or
by fractioned crystallization. Analogous silylation of galactose
1
with TBSCl afforded, according to the H NMR spectrum of
the crude product, the ꢀ-pyranose (δ 4.42, J1,2 ) 7.9 Hz) and
the ꢀ-furanose (δ 5.15, J1,2 ) 2.6 Hz) as main products (table
1, entry 4), and accordingly two spots were detected by TLC
(Rf ) 0.87 and Rf ) 0.75). The faster migrating compound was
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1996 J. Org. Chem. Vol. 74, No. 5, 2009

Synthesis of per-O-tert-Butyldimethylsilyl-ꢀ-D-galactofuranose
SCHEME 2. Synthesis of Galactofuranosyl Glycosides via in
Situ Formed Galactofuranosyl Iodide
Based on our experience with the glycosyl-aldonolactone
approach for the assembly of galactofuranose moieties,15d,e we
selected as acceptors selectively substituted aldonolactones 15,
17, 19, 21, and 23 (Table 2, entries 4-8). Also compounds 26,
28, and 30 (entries 9-11) were tested as acceptors. D-Galf units
have been shown to be present O-glycosidically linked to other
D-Galf units by (1f2), (1f3), (1f5), and (1f6) linkages in
many natural structures and also attached to D-Manp, D-Glcp,
D-Galp units,6 so the acceptors chosen would give access to
disaccharide precursors of such structures. The condensation
of 4ꢀ with acceptors having one hydroxyl group free (15, 17,
26, 28, and 30) led to the expected products 16, 18, 27, 29, and
31 in good isolated yield (Table 2, entries 4, 5, 9-11). The
low yield on coupling 4ꢀ with 19 to afford 20 (entry 6) could
be due to the steric hindrance. In this case, most of 4ꢀ was
recovered as a result of recombination with the living group
TBS. It is noteworthy that labile acceptors like 26, with a
galactofuranose linkage and an isopropylidene protective group,
could not be glycosylated using SnCl4 as a promoter; a milder
strategy like the trichloroacetimidate method22 would require
several steps to prepare the glycosyl donor. Although EtN(iPr)2
was not essential for the glycosylation, it was necessary in the
case of such labile acceptors in order to prevent their decom-
position by the iodhydric acid released during the glycosylation.
Attempts to isolate the intermediate iodide 7, as described
for pyranosyl analogues,25b,30 were unsuccessful. However, 1H
NMR spectrum of the reaction mixture showed at 6.52 ppm
the anomeric signal of 7 as a broad singlet (J1,2 < 0.5 Hz)
indicating the formation of the ꢀ-iodide. In the 13C NMR
spectrum, the anomeric signal was observed at 89.3 ppm. Both
values were in accordance with those observed for the 2,3,4,6-
tetra-O-benzoyl-ꢀ-D-galactofuranosyl bromide described by
Varela et al.20a Depending on the conditions, a third product
was detected by TLC analysis (Rf ) 0.62) during the iodide
formation. This product remained in the product mixture after
the workup, and it was identified as the 1,6-anhydro-R-D-
galactofuranose derivative 11 (10-15%, Scheme 2) formed as
result of the nucleophilic attack of desilylated HO-6. Its
formation was suppressed by strict control of the TMSI amount
employed. Several conditions were tested for conducting the
reaction. The presence of tetrabutyl ammonium iodide did not
change the course of the reaction, in contrast with pyranosyl
derivatives, in which halide-ion catalysis was observed.25a When
diethyl ether was used as a solvent the reaction proceeded
slowly, and the insolubility of 4ꢀ in DMF or acetonitrile
precluded the use of these solvents. The advantage of 4ꢀ as
galactofuranosyl precursor and this glycosylation method is that
the formation of the glycosyl iodide occurs under milder
conditions and faster than the formation of the analogous
chloride or bromide, which require several hours.20
The NMR spectra of 8-10 showed that the glycosylation
proceeded with moderate diastereoselectivity and with predomi-
nance of the ꢀ-anomer (Table 2, entries 1-3). This fact suggests
a SN1 mechanism with formation of the anomeric oxonium ion.
The attack of the nucleophile to C-1 from the ꢀ face could be
determined because of the steric effect of the bulky subtituent
at C-2 and the lateral chain at C-4.
Removal of the TBS groups from 8-10 was accomplished
with nBu4NF (TBAF) in THF32 and afforded glycosides 12-14,
having physical and spectral properties identical to those
previously reported.13c,f
Condensation with acceptors with more than one hydroxyl
free was also investigated. Excellent regioselectivity was
observed on coupling 4ꢀ with 5,6-di-O-isopropylidene derivative
21 (Table 2, entry 7) which led to 22, the glycosylation occurring
only at the C-2 hydroxyl group activated by the vicinal lactone
function. In the 13C NMR spectrum of 22, the signal corre-
sponding to C-1 appeared at δ 170, shielded 4 ppm in
comparison with the corresponding signal of 21, as a result of
the glycosylation at the vicinal position. For the synthesis of
R-D-Galf-(1f2)-D-galactitol, the aldonolactone approach was
also used. Although glycosylation of 2,3-diol 21 with 2,3,5,6-
tetra-O-benzyl-D-galactofuranosyl trichloroacetimidate under
conditions favoring 1,2-cis-glycosylation occurred mainly at
HO-2, the reaction was not completely regioselective, and
byproducts resulting from 3-O-glycosylation of the lactone were
also obtained.37
Condensation of 4ꢀ with the dibenzoylated lactone 23 was
expected to occur at the less hindered exocyclic C-5 hydroxyl
group, as previously observed for the SnCl4-promoted glyco-
sylation of 1 with 2311n or in the condensation of the 2,6-di-
O-pivaloyl-D-galactono-1,4-lactone with 1, either promoted by
SnCl4 or via the trichloroacetimidate.11b,j In contrast, two
products in this case were formed as deduced by NMR analysis,
leading to glycosylation of the aldonolactone at HO-5 (24) and
HO-3 (25) in similar amounts (Table 2, entry 8).
The NMR spectra of the products obtained by reaction of 4ꢀ
with sugar acceptors (Table 2, entries 4-11) showed in all cases
small J1,2 values and low-field resonances for the anomeric
carbons (>105 ppm) and C-2 and C-4 (>80 ppm), consistent
with the ꢀ-D-galactofuranoside stereochemistry.33,34 Thus, the
TMSI-promoted glycosylation of 4ꢀ with sugar acceptors
proceeded in all the cases with complete stereoselectivity,
affording the corresponding ꢀ-products. The fact that lower
stereoselectivity was observed in glycosylations with common
alcohols would indicate that steric factors may be responsible
for the 1,2-trans diastereocontrol.
Once the conditions for TMSI-promoted glycosylation of 4ꢀ
with simple alcohols were optimized, attention was focused on
the condensation with different carbohydrate acceptors.
In order to demonstrate the utility of 4ꢀ, the TMSI-promoted
glycosylation, and the stability of the glycosylated products as
J. Org. Chem. Vol. 74, No. 5, 2009 1997

Baldoni and Marino
TABLE 2. Glycosylation of 4ꢀ via the Galactofuranosyl Iodide Generated in Situ
a
Determined from the H NMR spectrum of the crude reaction mixture. b Yields refer to isolated pure products after column chromatography.
1
1998 J. Org. Chem. Vol. 74, No. 5, 2009

Synthesis of per-O-tert-Butyldimethylsilyl-ꢀ-D-galactofuranose
SCHEME 3. Synthesis of ꢀ-D-Galf(1f3)-D-Galp (33) and de-9-enyl ꢀ-D-Galf(1f3)-ꢀ-D-Galf (35)
intermediates for further reactions, we synthesized ꢀ-D-Galf(1f3)-
D-Galp (33) and 9-decenyl ꢀ-D-Galf(1f3)-ꢀ-D-Galf (35). Dis-
accharide 33 is the repeating unit of the backbone structure of
the O-antigenic polysaccharide present in the lipopolysaccharide
(LPS) of the genus Klebsiella.38 The motif ꢀ-D-Galf(1f3)-D-
Galp was recently found in a neutral exopolysaccharide
produced by Lactobacillus delbrueckii ssp. bulgaricus
LBB.B26.39 Compound 33 has been previously synthesized by
condensation of 2,3,5,6-tetra-O-benzoyl-ꢀ-D-galactofuranosyl
trichloroacetimidate and 1,2:5,6-di-O-isopropylidene-R-D-ga-
lactofuranose.40 Although this strategy seems to be very
straightforward, the isopropylidene acceptor was obtained only
in 50% yield after an improved procedure and the preparation
of the trichloroacetimidate donor involved five steps. Methyl
ꢀ-D-Galf(1f3)-ꢀ-D-Galf has been synthesized using as a key
step the non-regioselective coupling of 2,3,5,6-tetra-O-acetyl-
ꢀ-D-galactofuranosyl chloride with methyl 5,6-di-O-isopropy-
lidene-ꢀ-D-galactofuranoside.41 The synthesis of 33 described
here involves the glycosyl-aldonolactone 16 as intermediate,
which is obtained by condensation of 4ꢀ and 15 in 75% yield
(Table 2, entry 4). Reduction of 16 with diisoamylborane42 led
to lactol 32, as a 0.85:1 R/ꢀ anomeric mixture, as indicated by
the 1H NMR spectrum. The free disaccharide 33 was obtained
in 82% yield by treatment of 32 with HOAc/THF/H2O for the
cleavage of the acetal-protecting group, by removal of the TBS
groups with TBAF,32 and by conventional debenzoylation. The
13C NMR spectrum showed resonances at 109.7 ppm corre-
sponding to C-1′ of both anomers, and signals at 96.9 ppm and
92.8 ppm due to C-1 ꢀ- and R-pyranose (1:1 ratio), respectively.
The 1H NMR spectrum showed signals characteristic of galac-
topyranose for the reducing end. The spectroscopical data were
in disagreement with those previously reported.40 The signals
observed at 109.0, 105.9, and 96.0 ppm, which were assigned
to C-1′, C-1R, and C-1ꢀ-furanose, respectively, suggested that
upon deprotection the expansion to the galactopyranosyl form
did not occur.
On the other hand, 32 was converted into the corresponding
trichloroacetimidate by treatment with trichloroacetonitrile and
DBU22 and after purification by column chromatography was
coupled with 9-decenol, affording glycoside 34 in good yield.
Deprotection of 34 was conducted, as described for 32, to afford
the target 35 in very good yield (Scheme 3). The NMR spectra
of 35 showed broad singlets at 5.14 and 4.96 ppm for H-1′ and
H-1 and signals at δ 107.5 and 107.2, confirming the ꢀ-furanose
configuration for both D-Gal units.
In conclusion, we have described the easy preparation of a
new precursor of D-galactofuranosyl moieties, the per-O-silyl-
ꢀ-D-Galf derivative 4ꢀ obtained as a crystalline product in just
one high-yielding step from D-galactose. We also investigated
the glycosylation of this donor by in situ activation as galacto-
furanosyl iodide. This is the first time that this rather unstable
intermediate has been employed in glycosylation reactions. We
tested the efficiency of the glycosylating method for the
introduction of ꢀ-D-Galf units at different positions of partially
protected sugar acceptors, affording precursors of relevant
galactofuranose-containing disaccharides. The advantage of
derivative 4ꢀ relies on the possibility of introducing a ꢀ-D-Galf
unit without previous activation under mild conditions that are
compatible with labile acceptors. TBS as protective group
combines stability under a wide range of conditions, with
susceptibility to facile removal by highly specific reagents.
Experimental Section
(37) Gandolfi-Donadio, L.; Gola, G.; Lederkremer, R. M.; Gallo-Rodriguez,
C. Carbohydr. Res. 2006, 341, 2487–2497.
1,2,3,5,6-Penta-O-tert-butyldimethylsilyl-ꢀ-D-galactofura-
nose (4ꢀ) and 1,2,3,5,6-Penta-O-tert-butyldimethylsilyl-ꢀ-D-ga-
lactopyranose (5ꢀ). Method A. A solution of D-galactose (0.5 g,
2.77 mmol) in dry pyridine (7 mL) and DMF (7 mL) was heated
at 100 °C for 2 h. Then, imidazole (2.74 g, 18.25 mmol) and TBSCl
(3.0 g, 20.08 mmol) were added, and the reaction mixture was
stirred at 80 °C for 3 h. The solution was poured into ice/water
(38) Whitfield, C.; Richards, J. C.; Perry, M. B.; Clarke, B. R.; MacLean,
L. L. J. Bacteriol. 1991, 173, 1420–1431.
(39) Sa´nchez-Medina, I.; Gerwig, G. J.; Urshev, Z. L.; Kamerling, J. P.
Carbohydr. Res. 2007, 342, 2430–2439.
(40) Wang, H.; Zhang, G.; Ning, J. Carbohydr. Res. 2003, 338, 1033–1037.
(41) Veeneman, G.; Notermans, S.; Liskamp, R. M. J.; van der Marel, G. M.;
van Boom, J. H. Recl. TraV. Chim. Pays-Bas 1989, 108, 344–350.
(42) Lerner, L. M. Methods Carbohydr. Chem. 1972, 6, 131–134.
J. Org. Chem. Vol. 74, No. 5, 2009 1999

Baldoni and Marino
and was diluted with CH2Cl2. The organic layer was washed with
HCl (5%), water, NaHCO3 (ss), and water, dried (Na2SO4), and
concentrated. TLC analysis of the syrup showed two products of
Rf ) 0.87 and Rf ) 0.75 (10:1 hexane/EtOAc). Addition of MeOH
(5 mL) to the syrup afforded crystalline compound 4ꢀ (0.72 g,
35%). Purification by column chromatography (100:1 hexane/
EtOAc) of the mother liquors afforded a second crop of crystals of
4ꢀ (0.21 g, 10%, Rf ) 0.87). Recrystallized from MeOH, compound
4ꢀ gave mp 109-111 °C, [R]D -24 (c 1, CHCl3). 1H NMR (CDCl3,
500 MHz) δ 5.15 (d, J ) 2.6 Hz, 1H, H-1), 4.09 (dd, J ) 2.9, 4.7
Hz, 1H, H-3), 4.00 (dd, J ) 3.5, 4.7 Hz, 1H, H-4), 3.92 (apparent
t, J ) 2.9 Hz, 1H, H-2), 3.74 (m, 1H, H-5), 3.67 (dd, J ) 5.1, 10.1
Hz, 1H, H-6a), 3.55 (dd, J ) 5.8, 10.1 Hz, 1H, H-6b), 0.90, 0.89,
0.883, 0.881, 0.86 (5 s, SiC(CH3)3, 45 H), 0.10, 0.09, 0.086, 0.082,
0.07 × 2, 0.069, 0.060, 0.043, 0.041 (9 s, Si(CH3)2, 30H). 13C NMR
(CDCl3, 50.3 MHz) δ 102.8, 85.8, 84.4, 79.5, 74.0, 64.7, 25.9-24.7
(SiC(CH3)3), 17.9-17.8 (SiC(CH3)3), -4.3-(-5.5) (Si(CH3)2).
Anal. calcd for C36H82O6Si5 C 57.54, H 11.00. Found C 57.70, H
11.20.
The second fraction from the column Rf ) 0.75 was identified
as 5ꢀ (0.87 g, 42%), [R]D -2 (c 1, CHCl3). 1H NMR (CDCl3, 500
MHz) δ 4.41 (d, J ) 7.1 Hz, 1H, H-1), 3.57 (m, 2H, H-2, 3), 4.00
(d, J ) 2.3 Hz, 1H, H-4), 3.38 (ddd, J ) 9.3, 5.4, 2.9 Hz, 1H,
H-5), 3.85 (dd, J ) 10.0, 5.8, 2.9 Hz, 1H, H-6), 3.71 (dd, J )
10.0, 5.8 Hz, 1H, H-6′), 0.93, 0.91, 0.905, 0.90, 0.89, 0.88, 0.87
(SiC(CH3)3, 45H), 0.14, 0.12, 0.116, 0.110, 0.099, 0.095, 0.088,
0.080, 0.068, 0.060, 0.05, 0.04 (30H, Si(CH3)2). 13C NMR (CDCl3,
125.8 MHz) δ 98.7, 76.2, 75.2, 74.1, 69.2, 61.6, 26.29, 26.25, 26.22,
26.1, 26.0, 25.9, 25.88, 25.84, 25.79, 25.74, 18.49, 18.40, 18.25,
18.23, 18.1, 18.0, -3.2, -3.54, -3.56, -3.58, -3.75, -3.77, -4.1,
-4.42, -4.45.
11.4 Hz, 1H, H-1 ꢀ-anomer), 5.05 (d, J ) 4.7, 11.6 Hz, 0.6H, H-1
R-anomer), 4.20-4.18 (m, 1.6H, H-3 R,ꢀ-anomers), 4.09 (dd, J )
1.1, 8.1 Hz, 1H, H-4 ꢀ-anomer), 4.03-4.00 (m, 1.2H, H-2,4
R-anomer), 3.96 (d, J ) 1.2 Hz, 1H, H-2 ꢀ-anomer), 3.86 (d, J )
11.6 Hz, 0.6H, OH R-anomer), 3.77 (ddd, J ) 5.3, 5.3, 8.1 Hz,
1H, H-5 ꢀ-anomer), 3.73-3.64 (m, 2.2H, H-5, 6 R-anomer, H-6
ꢀ-anomer), 3.59 (dd, J ) 4.5, 10.75 Hz, 1H, H-6′ ꢀ-anomer),
3.57-3.55 (m, 0.6H, H-6′ R-anomer), 3.53 (d, J ) 11.4 Hz, 1H,
HO ꢀ-anomer), 0.96-0.83 (SiC(CH3)3), 0.20-0.01 (Si(CH3)2). 13
C
NMR (CDCl3, 50.3 MHz) δ 103.4, 97.2, 90.0, 84.0, 81.9, 81.6,
78.2, 77.6, 73.8, 73.5, 66.2, 63.8, 25.9-25.1 (SiC(CH3)3), 17.8-17.7
(SiC(CH3)3), -4.3-(-5.5) (Si(CH3)2). HRMS (ESI/APCI) calcd
for C30H68O6Si4 [M + NH4]+ 654.4437, found 654.4459.
General Procedure for the Glycosylation of 4ꢀ Promoted
by Iodotrimethylsilane. A solution of 4ꢀ (0.20 g, 0.26 mmol) in
anhydrous CH2Cl2 (10.0 mL) containing dry 4 Å powdered
molecular sieves was cooled to 0 °C and stirred for 10 min under
Ar. Then, iodotrimethylsilane (1.2 equiv, 0.042 mL, 0.32 mmol)
was added, and the solution was stirred at 0 °C until TLC
monitoring showed complete transformation of 4ꢀ in two products
Rf ) 0.70 and Rf ) 0.54 (10:1 hexane/EtOAc). Then, EtN(iPr)2
(0.054 mL, 0.32 mmol) and a solution of the acceptor (1.3 equiv,
0.34 mmol) in CH2Cl2 (5.0 mL) were added by syringe, and the
stirring was continued until consumption of the components of Rf
) 0.70 and Rf ) 0.54. The solution was diluted with CH2Cl2,
washed with NaHCO3 (ss) and water, dried (Na2SO4), and
concentrated. The syrup obtained was purified by column chroma-
tography, as indicated in each individual case.
n-Butyl 2,3,5,6-Tetra-O-tert-butyldimethylsilyl-r,ꢀ-D-galacto-
furanoside (8). Compound 8 was obtained according to the general
procedure, using n-butanol (0.023 g, 27 µL, 0.31 mmol) as acceptor.
After purification by column chromatography (99:1 hexane/EtOAc)
syrupy compound 10 (0.16 g, 90%) was obtained as an inseparable
ꢀ/R mixture in a 2:1 ratio, which gave Rf ) 0.80 (10:1 hexane/
EtOAc). For the major product (ꢀ-anomer): 1H NMR (CDCl3, 500
MHz) δ 4.79 (d, J ) 2.6 Hz, 1H, H-1), 4.12 (dd, J ) 3.5, 6.2 Hz,
1H, H-3), 3.98 (dd, J ) 2.5, 3.5 Hz, 1H, H-2), 3.94 (dd, J ) 2.5,
6.2 Hz, 1H, H-4), 3.76 (m, 1H, H-5), 3.67(m, 2H, H-6, OCH2 butyl),
3.57 (dd, J ) 5.8, 9.9 Hz, 1H, H-6′), 1.54 (m, 2H, CH2 butyl),
1.37 (m, 2H, CH2 butyl), 0.91-0.80 (m, 38H, CH2 butyl and
SiC(CH3)3), 0.10-0.04 (m, 27H, CH3 butyl and Si(CH3)2). 13C
NMR (CDCl3, 125.8 MHz) δ 107.9, 84.6, 83.1, 79.7, 73.2, 67.6,
64.5, 31.8, 26.0, 25.9, 25.8, 25.76, 25.72, 19.3, 17.9-17.8
(SiC(CH3)3), 13.9, 13.8, -3.5, -3.8, -4.0, -4.1, -4.3, -4.5, -4.6,
-4.8, -5.2, -5.3, -5.4. For R-anomer, anomeric region: 1H NMR
(CDCl3, 500 MHz) δ 4.84 (d, J ) 3.85 Hz). 13C NMR (CDCl3,
125.8 MHz) δ 102.10. Anal. calcd for C34H76O5Si4, C 60.29, H
11.31. Found C 60.10, H 11.14.
Benzyl 2,3,5,6-Tetra-O-tert-butyldimethylsilyl-r,ꢀ-D-galacto-
furanoside (9). Compound 9 was obtained according to the general
procedure using benzyl alcohol (0.033 g, 32 µL, 0.31 mmol) as
acceptor. After purification by column chromatography (99:1
hexane/EtOAc) syrupy compound 9 (0.134 g, 69%) was obtained
as an inseparable anomeric mixture (ꢀ/R 6:1), Rf ) 0.73 (10:1
hexane/EtOAc). For the major product (ꢀ-anomer): 1H NMR
(CDCl3, 500 MHz) δ 7.36-7.27 (m, aromatic), 4.91 (d, J ) 2.2
Hz, 1H, H-1), 4.76, 4.46 (2 d, J ) 11.9 Hz, 2H, CH2Ph), 4.16 (dd,
J ) 3.2, 6.1 Hz, 1H, H-3), 4.09 (dd, J ) 2.2, 3.2 Hz, 1H, H-2),
4.02 (dd, J ) 2.9, 6.1 Hz, 1H, H-4), 3.80 (m, 1H, H-5), 3.72 (dd,
J ) 7.6, 9.8 Hz, 1H, H-6), 3.60 (dd, J ) 5.9, 9.9 Hz, 1H, H-6′),
0.889, 0.882, 0.87, 0.86 (SiC(CH3)3), 0.12, 0.10, 0.09, 0.08
(Si(CH3)2). 13C NMR (CDCl3, 125.8 MHz) δ 138.1, 128.2, 127.92,
127.89, 127.4, 127.1, 107.3, 84.8, 83.8, 79.7, 73.2, 69.1, 64.6, 26.05,
26.03, 26.00, 25.9, 25.8, 25.77, 25.73, 18.35, 18.32, 18.08, 17.88,
17.85, -3.5, -3.7, -3.95, -3.99, -4.1, -4.4. For the minor
product (R-anomer), selected signals: 1H NMR (CDCl3, 500 MHz)
δ 4.90 (partially overlapped with H-1ꢀ, 1H, H-1), 4.33 (apparent
t, J ) 5.5 Hz, 1H, H-3), 3.98 (dd, J ) 4.0, 6.1 Hz, 1H, H-2), 3.85
(dd, J ) 3.9, 5.6 Hz, 1H, H-4). 13C NMR (CDCl3, 125.8 MHz) δ
Method B. To a solution of D-galactose (0.5 g, 2.77 mmol) in
dry DMF (14 mL), imidazole (2.74 g, 18.25 mmol) and TBSCl
(3.0 g, 20.08 mmol) were added, and the reaction mixture was
stirred at room temperature. After 48 h TLC monitoring showed
total consumption of the starting material. The reaction solution
1
was treated as described in method A, and the H NMR spectrum
of the crude showed that 4ꢀ was the only product. Addition of
MeOH (5 mL) to the syrup gave crystalline 4ꢀ (1.29 g, 62%).
Column chromatography (100:1 hexane/EtOAc) of the mother
liquors afforded a second fraction of 4ꢀ (0.36 g, overall yield 79%).
1,2,3,5,6-Penta-O-trimethylsilyl-r-D-galactopyranose. Treat-
ment of D-galactose (0.5 g, 2.77 mmol) with TMSCl (3.0 mL, 23.56
mmol), according to method A, afforded a crude product chro-
matographically homogeneous Rf ) 0.79 (10:1 hexane/EtOAc),
which showed in the 1H NMR (CDCl3, 200 MHz) spectrum
anomeric signals with the following integration: δ 5.13 (d, J ) 2.5
Hz, 0.10H, H-1 R-pyranosic), 5.10 (d, J ) 4.2 Hz, 0.10H, H-1
R-furanosic), 5.06 (br s, 0.55H, H-1 ꢀ-furanosic), 4.40 (d, J ) 7.9
Hz, 0.25H, H-1 ꢀ-pyranosic). 13C NMR (CDCl3, 50.3 MHz)
anomeric region δ 102.4, 98.3, 95.5, 94.5.
Silylation of D-Gal under the conditions of method B (3 h of
reaction) gave 1,2,3,5,6-penta-O-trimethylsilyl-R-D-galactopyranose
1
(1.38 g, 92%). H NMR (CDCl3, 200 MHz) anomeric region δ
5.06 (bs, 1H, H-1). 13C NMR (CDCl3, 50.3 MHz) δ 94.5, 72.3,
71.1, 70.5, 69.9, 61.2, in agreement with reported data.43
2,3,5,6-Tetra-O-tert-butyldimethylsilyl-r,ꢀ-D-galactofura-
nose (6). To a solution of 4ꢀ (0.40 g, 0.53 mmol) in CH2Cl2 (15
mL) TFA (2.0 mL) was added, and the mixture was stirred 1 min
and immediately poured into a stirred solution of NH4OH (5.0 mL)
in MeOH (40 mL) at -20 °C.36 The mixture was allowed to reach
room temperature and then was partitionated with CH2Cl2/H2O. The
organic phase was washed with NaCl (ss), dried (Na2SO4),
concentrated, and purified by column chromatography (99:1f98:2
hexane/EtOAc). Fractions of Rf ) 0.35 (10:1 hexane/EtOAc)
afforded compound 6 (0.027 g, 8%), as a 0.6:1 R/ꢀ mixture [R]D
1
-4.6 (c 1.5, CHCl3). H NMR (CDCl3, 500 MHz) δ 5.07 (d, J )
(43) Bhat, A. S.; Gervay-Hague, J. Org. Lett. 2002, 3, 2081–2084.
2000 J. Org. Chem. Vol. 74, No. 5, 2009

Synthesis of per-O-tert-Butyldimethylsilyl-ꢀ-D-galactofuranose
100.5, 83.2, 78.9, 76.1, 73.0, 69.1, 64.9. Anal. calcd for C37H74O6Si4
C 61.10, H 10.26. Found C 61.18, H 10.16.
4.11 (dd, J ) 2.6, 5.3 Hz, 1H, H-3′), 4.05 (t, J ) 8.8 Hz, 1H,
H-6a), 3.97 (br s, 1H, H-2′), 3.94 (apparent t, J ) 3.8 Hz, 1H,
H-4′), 3.76 (m, 2H, H-5′, 6b), 3.69 (dd, J ) 5.7, 10.1 Hz, 1H,
H-6′a), 3.57 (dd, J ) 6.0, 10.1 Hz, 1H, H-6′b), 1.57 (s, 1H), 0.89,
0.88, 0.86, 0.85, 0.84, 0.83 (SiC(CH3)3), 0.10, 0.09, 0.06, 0.05,
-0.001, -0.016 (SiC(CH3)2). 13C NMR (CDCl3, 125.8 MHz) δ
168.9, 165.3, 165.2, 164.9, 133.8-128.0 (C-aromatic), 108.0, 105.0,
85.2, 84.1, 79.2, 79.0, 74.0, 73.6, 72.4, 70.6, 64.9, 63.8, 26.04,
26.00, 25.7, 25.6, 18.36, 18.35, 17.8, 17.7, -3.74, -4.1, -4.40,
-4.47, -4.5, -4.9. HRMS (ESI/APCI) calcd for C57H88O14Si4 [M
+ NH4]+ 1126.5595, found 1126.5560.
2,3,5,6-Tetra-O-tert-butyldimethylsilyl-ꢀ-D-galactofuranosyl-
(1f3)-2,5,6-tri-O-benzoyl-D-mannono-1,4-lactone (20). Com-
pound 20 was obtained according to the general procedure, using
2,5,6-tri-O-benzoyl-D-mannono-1,4-lactone15e (19, 0.156 g, 0.32
mmol) as acceptor. After purification by column chromatography
(95:5 toluene/EtOAc) fractions of Rf ) 0.22 (10:1 hexane/EtOAc)
afforded syrupy compound 20 (0.11 g, 37%), [R]D -59 (c 1,
CHCl3). 1H NMR (CDCl3, 500 MHz) δ 8.08-7.32 (15H, aromatic),
6.09 (dd, J ) 3.3, 4.5 Hz, 1H, H-3), 5.71 (m, 1H, H-5), 5.36 (s, J
< 0.5 Hz, 1H, H-1′), 4.99 (dd, J ) 2.9, 9.3 Hz, 1H, H-4), 4.93
(dd, J ) 2.3, 12.6 Hz, 1H, H-6a), 4.61 (dd, J ) 4.3, 12.6 Hz, 1H,
H-6b), 4.10 (dd, J ) 2.6, 6.4 Hz, 1H, H-3′), 3.92 (d, J ) 1.5 Hz,
1H, H-2′), 3.84 (dd, J ) 2.4, 6.4 Hz, 1H, H-4′), 3.73 (m, 1H, H-5′),
3.66 (dd, J ) 5.6, 10.2 Hz, 1H, H-6′a), 3.59 (dd, J ) 6.6, 10.2 Hz,
1H, H-6′b), 0.95-0.81 (SiC(CH3)3), 0.10-(-0.1) (Si(CH3)2). 13C
NMR (CDCl3, 125.8 MHz) δ 171.6, 165.9, 164.8, 164.4, 133.3-128.3
(C-aromatic), 107.3, 84.9, 84.8, 79.9, 75.2, 72.8, 71.9, 70.4, 65.2,
62.8, 26.01, 26.00, 25.9, 25.8, 25.71, 25.69, 25.60, 25.5, 18.4, 18.3,
18.2, 17.8, 17.7, 17.6, -3.5, -4.2, -4.4, -4.5, -4.7, -5.1, -5.2,
-5.3. Anal. calcd for C57H88O14Si4 C 61.70, H 7.99. Found C 61.47,
H 7.92.
4-Nitrophenyl 2,3,5,6-Tetra-O-tert-butyldimethylsilyl-ꢀ-D-ga-
lactofuranoside (10ꢀ). It was prepared according to the general
procedure, using 4-nitrophenol (0.05 g, 0.35 mmol) as acceptor.
Crude compound 10 was obtained as an anomeric mixture in a 4:1
ꢀ/R ratio, as observed by 1H NMR spectroscopy. A fraction enriched
in the major ꢀ-isomer (10ꢀ) was isolated by column chromatog-
raphy (2:1 hexane/chloroform) as a syrup (0.15 g, 75%), Rf ) 0.72
(10:1 hexane/EtOAc). For the major product (ꢀ-anomer): 1H NMR
(CDCl3, 500 MHz) δ 8.18 (d, J ) 7.0 Hz, 2H, aromatic), 7.08 (d,
J ) 7.0 Hz, 2H, aromatic), 5.52 (d, J ) 3.1 Hz, 1H, H-1), 4.32 (t,
J ) 3.2 Hz, 1H, H-2), 4.27 (dd, J ) 3.2, 4.8 Hz, 1H, H-3), 4.12
(dd, J ) 3.4, 4.8 Hz, 1H, H-4), 3.79 (ddd, J ) 3.3, 5.5, 7.1 Hz,
1H, H-5), 3.63 (dd, J ) 7.1, 9.9 Hz, 1H, H-6), 3.58 (dd, J ) 5.5,
9.9 Hz, 1H, H-6′), 0.95-0.82 (SiC(CH3)3), 0.10-0.02 (Si(CH3)2).
13C NMR (CDCl3, 125 MHz) δ 162.2, 142.2, 125.7 × 2, 116.2 ×
2 (6C, aromatic), 105.89 (C-1), 85.6 (C-4), 84.00 (C-2), 78.57 (C-
3), 73.37 (C-5), 64.23 (C-6), 25.88, 25.81, 25.68, 25.62, 18.2, 18.1,
17.8, 17.7, -3.7, -4.2, -4.3, -4.4, -4.5, -4.7, -5.4, -5.5.
Selected signals for the R-anomer: 1H NMR (CDCl3, 500 MHz,) δ
5.43 (d, J ) 4.5 Hz, 1H, H-1), 4.45 (t, J ) 6.7, 1H, H-3), 4.22 (dd,
J ) 4.5, 6.7 Hz, 1H, H-2), 4.04 (dd, J ) 2.7, 6.7 Hz, 1H, H-4),
3.72 (m, 1H, H-5), 3.53 (m, 2H, H-6,6′). 13C NMR (CDCl3, 125.8
MHz) δ 99.7, 83.2, 78.7, 75.7, 71.4, 63.7. Anal. calcd for
C36H71NO8Si4 C 57.02, H 9.44. Found C 57.34, H 9.46.
2,3,5-Tri-O-tert-butyldimethylsilyl-1,6-anhydro-r-D-galacto-
furanose (11). It was isolated by column chromatography (98.6:
1.4 hexane/EtOAc) from the crude mixture of glycosides 8-10,
yield 8-15%, syrupy compound 11 gave Rf ) 0.52 (10:1 hexane/
1
EtOAc), [R]D +42 (c 1, CHCl3). H NMR (CDCl3, 500 MHz) δ
5.05 (d, J ) 4.5 Hz, 1H, H-1), 4.20 (d, J ) 1.8 Hz, 1H, H-3), 4.15
(dd, J ) 1.8, 4.5 Hz, 1H, H-2), 3.97 (ddd, J ) 4.3, 6.3, 10.5 Hz,
1H, H-5), 3.91 (br d, J ) 4.0 Hz, 1H, H-4), 3.72 (ddd, J ) 1.5,
6.2, 10.5 Hz, 1H, H-6), 3.60 (apparent t, J ) 10.7 Hz, 1H, H-6′),
0.94-0.86 (SiC(CH3)3), 0.12-0.04 (Si(CH3)2). 13C NMR (CDCl3,
125.8 MHz) δ 98.4, 85.3, 83.2, 77.6, 65.9, 64.2, 25.84, 25.89, 25.6,
17.9, -4.49, -4.57, -4.64, -4.68, -4.93, -5.02. Anal. calcd for
C24H52O5Si3 C 57.09, H 10.38. Found C 56.90, H 10.52.
2,3,5,6-Tetra-O-tert-butyldimethylsilyl-ꢀ-D-galactofuranosyl-
(1f2)-5,6-diisopropylidene-D-galactono-1,4-lactone (22). Com-
pound 22 was obtained according to the general procedure, using
5,6-O-isopropylidene-D-galactono-1,4-lactone44 (21, 0.07 g, 0.32
mmol) as acceptor. After purification by column chromatography
(4:1 hexane/EtOAc) fractions of Rf ) 0.29 (3:1 hexane/EtOAc)
afforded syrupy compound 22 (0.18 g, 83%) which gave [R]D -46
1
(c 0.6, CHCl3). H NMR (CDCl3, 500 MHz) δ 5.17 (d, J ) 1.3
2,3,5,6-Tetra-O-tert-butyldimethylsilyl-ꢀ-D-galactofuranosyl-
(1f3)-2-O-benzoyl-5,6-diisopropylidene-D-galactono-1,4-lac-
tone (16). Compound 16 was obtained according to the general
procedure, using 2-O-benzoyl-5,6-diisopropylidene-D-galactono-1,4-
lactone11j (15, 0.10 g, 0.31 mmol) as acceptor. After purification
by column chromatography (49:1f49:3 hexane/EtOAc), fractions
of Rf ) 0.31 (10:1 hexane/EtOAc) afforded compound 16 as a foam
(0.18 g, 75%), [R]D -59 (c 1, CHCl3). 1H NMR (CDCl3, 500 MHz)
δ 8.07-7.58 (5H, aromatic), 5.86 (d, J ) 7.3 Hz, 1H, H-2), 4.98
(d, J ) 1.6 Hz, 1H, H-1′), 4.73 (apparent t, J ) 7.0 Hz, 1H, H-3),
4.50 (m, 1H, H-5), 4.34 (dd, J ) 2.9, 6.6 Hz, 1H, H-4), 4.11-4.07
(m, 2H, H-3′,6a), 4.02-4.00 (m, 2H, H-2′,6b), 3.96 (apparent t, J
) 4.6 Hz, 1H, H-4′), 3.70 (m, 1H, H-5′), 3.58 (m, 2H, H-6′a,b),
0.93-0.86 (SiC(CH3)3), 0.09-0.04 (Si(CH3)2). 13C NMR
(CDCl3,125.8 MHz) δ 169.2, 164.9, 133.7, 130.1 × 2, 128.6, 128.4
× 2, 110.2, 108.1, 86.6, 83.8, 80.0, 78.8, 76.6, 74.2, 74.0, 73.4,
65.2, 64.7, 26.0, 25.9, 25.7, 25.6, 25.5, 18.3, 18.2, 17.8, 17.3, -3.9,
-4.2, -4.4, -4.5, -4.6, -4.9, -5.23, -5.25. Anal. calcd for
C46H84O12Si4 C 58.68, H 8.99. Found C 59.11, H 9.04.
Hz, 1H, H-1′), 4.63 (d, J ) 9.2 Hz, 1H, H-2), 4.56 (apparent t, J
) 8.8 Hz, 1H, H-3), 4.30 (m, 1H, H-5), 4.17 (m, 2H, H-4′,3′),
4.14 (bs, 1H, H-2′), 4.08 (dd, J ) 6.7, 8.6 Hz, 1H, H-6a), 4.03
(dd, J ) 4.5, 8.3 Hz, 1H, H-4), 3.98 (dd, J ) 6.9, 8.6 Hz, 1H,
H-6b), 3.80 (m, 1H, H-5′), 3.65 (m, 2H, H-6′a,b), 1.39 (2s, 6H,
C(CH3)2), 0.91-0.86 (SiC(CH3)3), 0.10-0.04 (Si(CH3)2). 13C NMR
(CDCl3, 125.8 MHz), δ 170.2, 110.1, 107.2, 85.1, 84.1, 79.1, 78.7,
77.9, 74.6, 72.9, 71.7, 65.0, 64.8, 26.1, 25.96, 25.90, 25.7, 25.6,
25.5, 18.4, 18.2, 17.83, 17.81, -3.7, -4.1, -4.4, -4.5, -4.6, -4.9,
-5.2, -5.3. Anal. calcd for C39H80O11Si4 C 55.94, H 9.63. Found
C 56.09, H 9.50.
2,3,5,6-Tetra-O-tert-butyldimethylsilyl-ꢀ-D-galactofuranosyl-
(1f5)-2,6-di-O-benzoyl-D-galactono-1,4-lactone (24) and 2,3,5,6-
Tetra-O-tert-butyldimethylsilyl-ꢀ-D-galactofuranosyl-(1f3)-2,6-
di-O-benzoyl-D-galactono-1,4-lactone (25). 2,6-Di-O-benzoyl-D-
galactono-1,4-lactone11n (23, 0.10 g, 0.54 mmol) previously
dissolved in anhydrous acetonitrile (6.0 mL) was coupled with 4ꢀ
according to the general procedure. After the usual workup, the
excess of 23 was removed by treatment of the syrup with ether.
Compound 23 was suspended and filtered off, and the soluble
material was purified by column chromatography (19:1 toluene/
EtOAc). Fractions of Rf ) 0.42 (19:1 toluene/EtOAc) were
evaporated (0.23 g, 87%), and NMR analysis showed the presence
of two regioisomers (1:1 ratio). 1H NMR (CDCl3, 500 MHz)
selected signals δ 5.92 (d, J ) 2.8 Hz, 1H, H-2 25), 5.91 (d, J )
3.6 Hz, 1H, H-2 24), 5.11 (d, J ) 1.4 Hz, 1H, H-1′ 24 or 25), 5.01
(t, J ) 8.0 Hz, 1H, H-3 25), 4.99 (d, J ) 1.9 Hz, 1H, H-1′ 24 or
2,3,5,6-Tetra-O-tert-butyldimethylsilyl-ꢀ-D-galactofuranosyl-
(1f6)-2,3,5-tri-O-benzoyl-D-galactono-1,4-lactone (18). Com-
pound 18 was obtained according to the general procedure, using
2,3,5-tri-O-benzoyl-D-galactono-1,4-lactone11o (17, 0.156 g, 0.32
mmol) as acceptor. After purification by column chromatography
(98:2f95:5 hexane/EtOAc) fractions of Rf ) 0.26 (10:1 hexane/
EtOAc) afforded compound 18 as a foam (0.25 g, 87%), [R]D -28
1
(c 1.9, CHCl3). H NMR (CDCl3, 500 MHz) δ 8.15-7.27 (15H,
aromatic), 6.07 (d, J ) 5.9 Hz, 1H, H-2), 5.79 (apparent t, J ) 5.6
Hz, 1H, H-3), 5.73, (apparent t, J ) 7.1 Hz, 1H, H-5), 5.04
(apparent d, J ) 5.6 Hz, 1H, H-4), 4.86 (d, J ) 1.4 Hz, 1H, H-1′),
(44) Fleet, G. W. J.; Son, J. C. Tetrahedron 1988, 44, 2637–2647.
J. Org. Chem. Vol. 74, No. 5, 2009 2001

Baldoni and Marino
25), 4.88 (dt, J ) 5.3, 9.0 Hz, 1H, H-3 24). 13C NMR (CDCl3,
125.8 MHz) δ 168.9, 168.8 (C-1 24 and 25), 166.0, 165.0, 165.4,
133.7, 133.6, 133.27, 133.24, 130.2, 130.1, 129.9, 129.79, 129.72,
129.61, 128.47, 128.45, 128.41, 128.3, 108.2, 108.0, 85.7, 84.4,
84.1, 83.9, 79.9, 79.5, 79.1, 78.8, 75.2, 74.7, 73.9, 72.9, 71.5, 70.7,
69.2, 66.5, 65.2, 64.4, 64.1, 62.9, 25.9, 25.87, 25.85, 25.83, 25.,
25.64, 25.63, 25.5, 18.3, 18.2, 18.1, 17.8, 17.75, 17.73, 17.71, -3.4,
-3.8, -4.1, -4.25, -4.26, -4.27, -4.44, -4.47, -4.6, -4.8, -5.0,
-5.2, -5.3, -5.4. Anal. calcd for C50H84O13Si4 C 59.72, H 8.42.
Found C 59.87, H 8.53.
3.2, 5.5 Hz, 1H, H-3′), 4.01 (dd, J ) 2.5, 3.2 Hz, 1H, H-2′),
3.96-3.93 (m, 2H, H-5, 4′), 3.89 (dd, J ) 6.2, 10.0 Hz, 1H, H-6a),
3.75 (dt, J ) 3.1, 6.1 Hz, 1H, H-5′), 3.67 (dd, J ) 6.1, 10.0 Hz,
1H, H-6′a), 3.59-3.52 (m, 2H, H-6b,6′b), 1.61, 1.52, 1.43, 1.33
(4s, 12H, C(CH3)2), 0.90-0.86 (SiC(CH3)3), 0.10-0.04 (Si(CH3)2).
13C NMR (CDCl3, 125.8 MHz) δ 109.1, 108.4, 108.2, 96.3, 84.2,
84.0, 79.5, 73.6, 71.0, 70.7, 70.6, 67.0, 66.1, 64.7, 26.1, 26.0, 25.9,
25.8, 25.7, 24.9, 24.4, 18.35, 18.31, 17.9, 17.8, -3.7, -4.0, -4.3,
-4.4, -4.6, -4.8, -5.2, -5.3. Anal. calcd for C42H86O11Si4 C
57.36, H 9.86. Found C 57.20, H 10.16.
Methyl 2,3,5,6-Tetra-O-tert-butyldimethylsilyl-ꢀ-D-galacto-
furanosyl-(1f3)-2-O-benzoyl-5,6-O-isopropylidene-ꢀ-D-galacto-
furanoside (27). Methyl 2-O-benzoyl-5,6-O-isopropylidene-ꢀ-D-
galactofuranoside (26) was obtained by 5,6-O-isopropylidenation
of methyl ꢀ-D-Galf13b and further benzoylation with 1.0 equiv of
BzCl. Compound 27 was obtained according to the general
procedure using 26 (0.11 g, 0.32 mmol) as acceptor. After
purification by column chromatography (98:2 toluene/EtOAc)
fractions of Rf ) 0.21 (10:1 hexane/EtOAc) afforded syrupy
2,3,5,6-Tetra-O-tert-butyldimethylsilyl-ꢀ-D-galactofuranosyl-
(1f3)-2-O-benzoyl-5,6-diisopropylidene-D-galactofuranose (32).
To a solution of bis(2-butyl-3-methyl)borane (4.38 mmol) in anhyd
THF (3.0 mL) cooled to 0 °C under argon atmosphere was added
a solution of compound 16 (0.41 g, 0.43 mmol) in THF (2.0 mL).
The resulting solution was stirred at room temperature for 16 h
and then processed as previously described.42 The organic layer
was washed with water, dried (Na2SO4), and concentrated. Boric
acid was eliminated by coevaporations with MeOH. The syrup
obtained was purified by column chromatography (9:1:0.05f6:4:
0.05 hexane/EtOAc/Et3N) to give syrupy compound 32 (0.37 g,
93%), as a 0.85:1 R/ꢀ anomeric mixture, Rf ) 0.50 (3:1 hexane/
1
compound 27 (0.2 g, 79%), [R]D -42.2 (c 1, CHCl3). H NMR
(CDCl3, 500 MHz) δ 8.04-7.42 (aromatic), 5.20 (dd, J ) 0.9, 4.6
Hz, 1H, H-2), 5.07 (d, J ) 1.2 Hz, 1H, H-1′), 5.05 (d, J ) 0.9 Hz,
1H, H-1), 4.37 (dd, J ) 6.5, 13.2 Hz, 1H, H-5), 4.20 (m, 2H, H-4,
3), 4.11 (dd, J ) 2.5, 5.3 Hz, 1H, H-3′), 4.06 (dd, J ) 6.8, 8.6 Hz,
1H, H-6a), 4.03 (dd, J ) 1.2, 2.5 Hz, 1H, H-2′), 3.93 (dd, J ) 3.9,
5.3 Hz, 1H, H-4′), 3.89 (dd, J ) 6.3, 8.6 Hz, 1H, H-6b), 3.74 (m,
1H, H-5′), 3.64 (dd, J ) 6.1, 10.1 Hz, 1H, H-6′a), 3.56 (dd, J )
5.9, 10.1 Hz, 1H, H-6′b), 3.40 (s, 3H, OCH3), 1.43, 1.37 (2s, 6H,
C(CH3)2), 0.88, 0.87, 0.86 (SiC(CH3)3), 0.11, 0.10, 0.08, 0.07, 0.05,
0.045, 0.041 (Si(CH3)2). 13C NMR (CDCl3, 125.8 MHz) δ 165.7,
133.3, 129.8, 129.5, 128.3, 108.3, 107.7, 85.2, 84.7, 84.4, 83.0,
79.4, 77.9, 75.9, 73.3, 65.6, 64.8, 54.9, 26.5, 25.98, 25.97, 25.7,
25.6, 25.2, 18.31, 18.30, 17.8, -3.7, -4.1, -4.3, -4.4, -4.5, -4.8,
-5.1, -5.2, -5.3. Anal. calcd for C47H88O12Si4 C 58.95, H 9.26.
Found C 58.71, H 9.40.
2,3,5,6-Tetra-O-tert-butyldimethylsilyl-ꢀ-D-galactofuranosyl-
(1f3)-1,2:5,6-di-O-isopropylidene-D-glucofuranose (29). Com-
pound 29 was obtained according to the general procedure using
1,2:5,6-di-O-isopropylidene-R-D-glucofuranose45 (28, 0.083 g, 0.32
mmol) as acceptor. After purification by column chromatography
(49:1f4:1 hexane/EtOAc containing a trace of Et3N) compound
29 was obtained as a syrup (0.16 g, 69%), which gave Rf ) 0.30
(10:1 hexane/EtOAc), [R]D -39 (c 1.1, CHCl3). 1H NMR (CDCl3,
500 MHz) δ 5.86 (d, J ) 3.7 Hz, 1H, H-1), 4.93 (br s, 1H, H-1′),
4.43 (d, J ) 3.7 Hz, 1H, H-2), 4.35-4.28 (m, 3H, H-3, 4, 5), 4.14
(dd, J ) 2.0, 6.3 Hz, 1H, H-3′), 4.06 (dd, J ) 6.4, 8.5 Hz, 1H,
H-6a), 4.01 (dd, J ) 5.8, 8.5 Hz, 1H, H-6b), 3.95 (m, 1H, H-4′),
3.94 (m, 1H, H-2′), 3.78 (m, 1H, H-5′), 3.65 (dd, J ) 5.3, 10.3 Hz,
1H, H-6′a), 3.61(dd, J ) 6.5, 10.3 Hz, 1H, H-6′b), 1.60, 1.49, 1.31,
1.39 (4s, 12H, C(CH3)2), 0.90-0.87 (SiC(CH3)3), 0.11-0.05
(Si(CH3)2). 13C NMR (CDCl3, 125.8 MHz) δ 111.9, 108.5, 105.4,
105.2, 85.5, 84.9, 81.8, 80.7, 79.9, 76.4, 73.4, 73.0, 66.2, 65.3, 26.8,
26.6, 26.2, 26.1, 26.0, 25.7, 25.6, 25.4, 18.4, 18.3, 17.86, 17.81,
-3.6, -4.1, -4.2, -4.4, -4.6, -4.7, -5.23, -5.28. Anal. calcd
for C42H86O11Si4 C 57.36, H 9.86. Found C 57.03, H 10.06.
2,3,5,6-Tetra-O-tert-butyldimethylsilyl-ꢀ-D-galactofuranosyl-
(1f6)-1,2:3,4-di-O-isopropylidene-r-D-galactopyranose (31). Com-
pound 31 was obtained according to the general procedure using
1,2:3,4-di-O-isopropylidene-R-D-galactopyranose46 (30, 0.083 g,
0.32 mmol) as acceptor. After purification by column chromatog-
raphy (49:1f31:1 hexane/EtOAc) compound 31 was obtained as
a syrup (0.18 g, 80%), which gave Rf ) 0.36 (10:1 hexane/EtOAc),
[R]D -62 (c 1.3, CHCl3). 1H NMR (CDCl3, 500 MHz), δ 5.51 (d,
J ) 5.0 Hz, 1H, H-1), 4.86 (d, J ) 2.5 Hz, 1H, H-1′), 4.57 (dd, J
) 2.3, 7.9 Hz, 1H, H-3), 4.29-4.26 (m, 2H, H-2,4), 4.12 (dd, J )
1
EtOAc), [R]D -14 (c 1.7, CHCl3). H NMR (CDCl3, 500 MHz),
only the assigned δ are listed: 5.55 (dd, J ) 10.0, 4.5 Hz, 0.46H,
H-1R), 5.50 (d, J ) 5.3 Hz, 0.54H, H-1ꢀ), 5.27 (d, J ) 2.0 Hz,
0.54H, H-2ꢀ), 5.16 (ddd, J ) 0.6, 4.3, 7.2 Hz, 0.46H, H-2R), 5.08
(d, J ) 1.5 Hz, 0.54H, H-1′ꢀ), 5.02 (d, J ) 2.3 Hz, 0.46H, H-1′R),
4.55 (dd, J ) 5.6, 7.1 Hz, 0.46H, H-3R), 3.76 (d, J ) 10.0 Hz,
0.46H, HO), 3.02 (d, J ) 5.3 Hz, 0.54H, HO). 13C NMR (CDCl3,
125.8 MHz) δ 165.8, 133.4, 133.2, 129.9, 129.8, 129.3, 129.2,
128.3, 128.2, 109.8, 108.9, 107.6, 101.1, 94.4, 87.0, 84.5, 84.2,
83.82, 83.80, 82.2, 80.5, 80.0, 79.8, 79.5, 79.0, 78.9, 76.3, 75.1,
73.9, 72.9, 65.74, 65.71, 65.0, 64.4, 26.4, 26.0, 25.96, 25.92, 25.76,
25.71, 25.66, 25.62, 25.61, 25.5, 18.27, 18.25, 17.8, 17.7, -3.6,
-4.1, -4.2, -4.3, -4.4, -4.46, -4.49, -4.8, -4.9, -5.21, -5.23,
-5.24, -5.29. Anal. calcd. for C46H86O12Si4 C 58.56, H 9.19. Found
C 58.10, H 9.21.
ꢀ-D-Galactofuranosyl-3-O-r,ꢀ-D-galactopyranose (33). A solu-
tion of compound 32 (0.10 g, 0.10 mmol) in 3:1:1 HOAc/THF/
H2O (6 mL) was heated at 65 °C for 3 h. After evaporation of the
solvent and several co-evaporations with water and toluene, the
product was desilylated by treatment with (nBu)4NF (0.34 g, 1.3
mmol)32 and without purification was debenzoylated with 3 mL of
0.1 M NaOMe at 0 °C. The solution was deionized by elution with
MeOH through a column of ion exchange mixed resin. The eluate
was evaporated, and the residue was dissolved in water and purified
through a RP18 cartridge. Lyophilization of the solution gave
compound 33 (0.03 g, 82%) as a 1:1 anomeric mixture, Rf ) 0.25
(7:1:2 nPrOH/NH3/H2O), [R]D -32 (c 1.3, MeOH). 1H NMR (D2O,
500 MHz) anomeric region δ 5.25 (d, J ) 3.2 Hz, 1H, H-1R),
5.19 (d, J ) 1.6 Hz, 1H, H-1′R), 5.18 (d, J ) 1.7 Hz, 1H, H-1′ꢀ),
4.61 (d, J ) 3.2 Hz, 1H, H-1ꢀ). 13C NMR (D2O,125.8 MHz) δ
109.7 (C-1′ R and ꢀ anomers), 96.9 (C-1 ꢀ anomer), 92.8 (C-1 R
anomer), 83.3, 82.0, 81.1, 77.8, 77.4, 77.3, 75.6, 71.6, 71.3, 71.2,
70.9, 69.9, 69.3, 68.0, 63.3, 61.7, 61.5. HRMS (ESI/APCI) calcd
for C12H22O11 [M + NH4]+ 360.1506, found 360.1482.
9-Decenyl 2,3,5,6-Tetra-O-tert-butyldimethylsilyl-ꢀ-D-galacto-
furanosyl-(1f3)-2-O-benzoyl-5,6-diisopropylidene-ꢀ-D-galacto-
furanoside (34). To a stirred solution of 32 (0.37 g, 0.39 mmol)
and trichloroacetonitrile (0.65 mL, 6.54 mmol) in CH2Cl2 (8 mL)
cooled to 0 °C was slowly added DBU (63 µL, 0.43 mmol). After
1 h, the solution was carefully concentrated under reduced pressure
at room temperature, and the residue was purified by column
chromatography (5:2 hexane/EtOAc) to give 356 mg (84%) of the
trichloroacetimidate of 32 as a syrup, Rf ) 0.75 (5:2 hexane/EtOAc).
A stirred suspension of the trichloroacetimidate of 32 (356 mg,
0.33 mmol), 9-decen-1-ol (0.086 mL, 0.49 mmol), and 4 Å
powdered molecular sieves (0.5 g) in anhyd CH2Cl2 (8 mL) was
cooled to -78 °C, and TMSOTf (18 µL, 0.099 mmol) was slowly
(45) Schmidt, O. T. Methods Carbohydr. Chem. 1963, 2, 319–321.
(46) Martins Alho, M. A.; D’Accorso, N. B.; Thiel, I. M. E. J. Heterocycl.
Chem. 1996, 33, 1339–1343.
2002 J. Org. Chem. Vol. 74, No. 5, 2009

Synthesis of per-O-tert-Butyldimethylsilyl-ꢀ-D-galactofuranose
added. After 48 h of stirring at 5 °C, the mixture was quenched by
addition of saturated aq NaHCO3 (10 mL) and then extracted with
CH2Cl2. After purification by column chromatography (5:1 hexane/
EtOAc) compound 34 was obtained as a syrup (0.25 g, 71%), Rf )
exchange resin (H+). The syrup obtained was purified by silica gel
column chromatography (95:5:0.3 EtOAc/MeOH/TEA) to afford
34 mg (76%) of compound 35, Rf ) 0.62 (7:1:2 nPrOH/NH3/H2O);
[R]D -134 (c 0.7, MeOH). 1H NMR (D2O, 500 MHz) δ 5.80 (ddt,
1 H, J ) 17.2, 10.8, 6.8 Hz, 1H, CH)CH2), 5.14 (d, J ) 1.3 Hz,
1H, H-1′), 4.98 (dd, 1H, J ) 17.2, 1.4 Hz, CH)CHaH), 4.96 (br s,
1H, H-1), 4.92 (m, 1H, CH)CHHb), 4.17-4.15 (m, 2H, H-2, 3),
4.10-4.06 (m, 2H, H-2′, 3′), 4.00-3.99 (m, 1H, H-4), 3.93-3.90
(m, 2H, H-4′, 5), 3.83 (m, 1H, H-5), 3.71-3.64 (m, 5H, H-6a, 6b,
6′a, 6′b, CHaHO), 3.47 (m, 1H, CHbHO), 2.04 (dd, J ) 13.7, 7.2
Hz, 2H, CH2), 1.6 (m, 2H, CH2), 1.41-1.32 (m, 10H, CH2). 13C
NMR (D2O, 125.8 MHz) δ 139.1, 114.2, 107.5, 107.2, 82.8, 82.7,
81.7, 81.5, 79.9, 76.7, 70.6, 70.5, 68.0, 63.3, 62.9. HRMS (ESI/
APCI) calcd for C22H40O11 [M + NH4]+ 498.2914, found 498.2905.
1
0.83 (5:2 hexane/EtOAc); [R]D -49.7 (c 0.7, CHCl3). H NMR
(CDCl3, 500 MHz) δ 8.02, 7.56, 7.43 (3H, aromatic), 5.80 (m, 1H,
CH)CH2), 5.27 (d, J ) 1.3 Hz, 1H, H-2), 5.12 (br s, 1H, H-1),
5.08 (d, J ) 1.5 Hz, 1H, H-1′), 4.98 (m, 1H, CH)CHaH), 4.92 (m,
1H, CH)CHHb), 4.27 (dd, J ) 6.85, 13.7 Hz, 1H, H-5), 4.10 (m,
2H, H-3, 3′), 4.03 (m, 3H, H-6a, 4, 2′), 3.90 (m, 2H, H-6b, 4′),
3.73 (m, 2H, H-5′, CHaHO), 3.59 (m, 2H, H-6′a, 6′b), 3.45 (m,
1H, CHHbO). 13C NMR (CDCl3, 125.8 MHz) δ 165.1, 139.2, 133.2,
129.8, 129.5, 128.3, 114.0, 109.6, 106.8, 105.9, 86.4, 83.9, 83.1,
82.0, 80.6, 79.1, 76.5, 73.9, 67.4, 65.7, 65.0, 63.3, 62.7, 33.7, 32.8,
32.7, 29.6, 29.48, 29.43, 29.3, 29.1, 29.0, 28.93, 28.90, 26.5, 26.03,
26.00, 25.97, 25.91, 25.77, 25.72, 25.6, 18.3, 18.2, 17.8, -3.9, -4.3,
-4.47, -4.49, -4.8, -5.25, -5.27, -5.3. Anal. calcd for
C56H104O12Si4 C 62.18, H 9.69. Found C 62.54, H 9.79.
9-Decenyl ꢀ-D-Galactofuranosyl-3-O-ꢀ-D-galactofuranoside
(35). A solution of compound 34 (0.10 g, 0.093 mmol) in 3:1:1
HOAc/THF/H2O (6 mL) was heated at 50 °C for 13 h. After
evaporation of the solvent and several co-evaporations with water
and toluene, the product was desilylated with TBAF in THF32 and
purified by column chromatography (99:1 EtOAc/MeOH). Fractions
of Rf ) 0.49 (9:1 EtOAc/MeOH) were treated with 3 mL of 0.1 M
NaOMe/MeOH at 0 °C, and after 1 h the solution was deionized
by elution with MeOH through a column of strongly acidic cation
Acknowledgment. We acknowledge financial support from
the University of Buenos Aires and the National Research
Council of Argentina (CONICET). C.M. is a Research Member
of CONICET, and L.B. was supported by a fellowship from
CONICET.
Supporting Information Available: Details on the desily-
1
lation, data for the products not included above, H NMR and
13C NMR spectra for new compounds are included. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO8025274
J. Org. Chem. Vol. 74, No. 5, 2009 2003