Conformational domino effect in saccharides: A prediction from alkyl β-(1→6)-diglucopyranosides

Article abstract of DOI:10.1021/jo800191z

(Chemical Equation Presented) A series of alkyl β-D-glucopyranosyl- (1→6)-β-D-glucopyranosides, containing nonchiral and chiral aglycons, were synthesized and analyzed by NMR and CD. The results, collected from four sets of disaccharides, demonstrated that the rotational properties of the interglycosidic linkage depend on the structural natures of both the aglycon and the solvent. Stereoelectronic and steric factors explain this rotational dependence, the gauche-trans (gt) rotamer being the most stable. Furthermore, correlations between Taft's steric parameters or between the pK_a values of the alkyl substituent (aglycon) versus corresponding rotamer populations were observed. These results point to a natural conformational domino effect in oligosaccharides, where the conformational properties of each (1→6) interglycosidic linkage will depend on the structure of the previous residue or its aglycon. In addition, a very weak rotational population dependence of the hydroxymethyl group at residue II on the aglycon at residue I was observed. The population of the gauche-gauche (gg) rotamer decreased, and that of gt increased as the Taft's steric parameters of the remote aglycon increased, independently of the disaccharide series and of the solvent.

Full text of DOI:10.1021/jo800191z

Conformational Domino Effect in Saccharides: A Prediction from
Alkyl ꢀ-(1f6)-Diglucopyranosides
Alfredo Roën, Juan I. Padrón, Carlos Mayato, and Jesús T. Vázquez*
Instituto UniVersitario de Bio-Orgánica “Antonio González”, Departamento de Química Orgánica,
UniVersidad de La Laguna, 38206 La Laguna, Tenerife, Spain
jtruVaz@ull.es
ReceiVed July 3, 2007
A series of alkyl ꢀ-D-glucopyranosyl-(1f6)-ꢀ-D-glucopyranosides, containing nonchiral and chiral
aglycons, were synthesized and analyzed by NMR and CD. The results, collected from four sets of
disaccharides, demonstrated that the rotational properties of the interglycosidic linkage depend on the
structural natures of both the aglycon and the solvent. Stereoelectronic and steric factors explain this
rotational dependence, the gauche-trans (gt) rotamer being the most stable. Furthermore, correlations
between Taft’s steric parameters or between the pKa values of the alkyl substituent (aglycon) versus
corresponding rotamer populations were observed. These results point to a natural conformational domino
effect in oligosaccharides, where the conformational properties of each (1f6) interglycosidic linkage
will depend on the structure of the previous residue or its aglycon. In addition, a very weak rotational
population dependence of the hydroxymethyl group at residue II on the aglycon at residue I was observed.
The population of the gauche-gauche (gg) rotamer decreased, and that of gt increased as the Taft’s
steric parameters of the remote aglycon increased, independently of the disaccharide series and of the
solvent.
Introduction
(O5-C5-C6-O6) needs to be considered when the hydroxy-
methyl group is involved in the linkage. This angle is also used
to describe the conformation of unsubstituted hydroxymethyl
groups. The conformation of the hydroxymethyl group around
the C5-C6 bond is generally described by means of the
populations of the gauche-gauche (gg), gauche-trans (gt), and
trans-gauche (tg) rotamers (Figure 2).4
Many theoretical and experimental studies on the rotational
preferences of the hydroxymethyl group have also been carried
out,5– 27 mainly with monosaccharides, but the factors governing
their conformational preferences in solution are still not fully
understood. Our studies in this field, on the basis of NMR and
CD data, have shown that the populations of the hydroxymethyl
group in alkyl gluco,24 galacto,25 and mannopyranosides26
depend on the structure of the aglycon and its absolute
configuration, as well as on the anomeric configuration.
Many studies on the conformational properties of carbohydrates
have been performed, mainly by NMR,1 X-ray diffraction,2,3 and
molecular modeling.2 In spite of this, the conformation of an
oligosaccharide is very difficult to determine due to the
flexibility of the glycosidic linkages and the rotation of
hydroxymethyl and other pendant groups. The conformation of
a disaccharide in solution depends fundamentally on the
rotations around its glycosidic linkage, so the relative orienta-
tions of the saccharide units are expressed in terms of the
glycosidic linkage torsion angles Φ (O5′-C1′-O-Cx) and Ψ
(C1′-O-Cx-C(x-1)), for a 1fx linkage (Figure 1). In
addition to these torsion angles, a third torsion angle ω
(1) Duus, J. Ø.; Gotfredsen, C. H.; Bock, K. Chem. ReV. 2000, 100, 4589.
(2) (a) Imberty, A.; Pérez, S. Chem. ReV. 2000, 100, 4567. (b) Wormald,
M. R.; Petruscu, A. J.; Pao, Y.-L.; Glithero, A.; Elliott, T.; Dwek, R. A. Chem.
ReV. 2002, 102, 371.
(4) The first descriptor indicates the torsional relationship between O6 and
O5, and the second that between O6 and C4.
(3) Jeffrey, G. A. Acta Cryst. 1990, B46, 89.
10.1021/jo800191z CCC: $40.75
Published on Web 04/03/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 3351–3363 3351

Roën et al.
become convenient.29 Therefore, our model disaccharides were
synthesized in this way by coupling different alcohols to the
disaccharide 9, which was similarly obtained from the monosac-
charides 4 and 7 (Schemes 1 and 2).The glucosyl donor 4 and
the glucosyl acceptor 7 were obtained in three steps from
D-glucal (1) as shown in Scheme 1.
The disaccharide 8 was obtained in a 62% yield by coupling
glucosyl donor 4 with glucosyl acceptor 7, as shown in Scheme
2. Donor 4 was treated with dimethyldioxirane (DMDO) at 0
°C in CH2Cl2 to lead to the 1,2-anhydro sugar and then with
the glucosyl acceptor 7 and ZnCl2 at -78 °C in THF. The
disaccharide 8 was obtained as an R/ꢀ mixture, which was
acetylated and separated to give the ꢀ-disaccharide 9.
FIGURE 1. Torsion angles Φ and ψ around the glycosidic linkages
and ω around the C5-C6 bonds.
The different alkyl ꢀ-D-glucopyranosyl-(1f6)-ꢀ-D-glucopy-
ranosides 10-16 (Scheme 3) were obtained by coupling
different primary, secondary, and tertiary alcohols to disaccha-
ride 9, protecting the resulting hydroxyl group at C2 as an
acetate, and isolating the ꢀ-derivatives. Disaccharides 17-21
were obtained by deprotection of the p-methoxybenzyl group
with DDQ.30 Then, the silyl and acetyl groups were removed
in just one step by acetyl chloride/MeOH in diethyl ether, to
give disaccharides 22-25. Under these conditions, undesired
methanolysis occurs with the tert-butyl derivative 21, so the
tert-butyl disaccharide 27 was obtained in two steps: deprotec-
tion of the silyl groups with HF ·Py in CH3CN, then the acetyl
groups with p-TsOH (Scheme 4).31,32 Finally, the penta-O-acetyl
derivatives 28-32 were obtained by treating compounds 22-26
with acetic anhydride and pyridine.
Characterization and Spectroscopic Analysis. All these
compounds were characterized on the basis of their one- (1H
and 13C) and two-dimensional (COSY, HMQC, and T-ROESY)
NMR spectra. The anomeric configurations were assigned in
each case by analyzing the coupling constant between H1 and
H2 for each glucopyranosidic ring (CDCl3, doublet, ꢀ-config-
uration: 7.8-8.0 Hz) (Figure 3). The chemical shifts of C1 and
FIGURE 2. Newman projections of the gg (ω ) -60°), gt (ω ) 60°),
and tg (ω ) 180°) rotamers around the C5-C6 bond.
Furthermore, studies on disaccharides with different glycosidic
linkages but the same aglycon (methyl group) revealed that these
populations also depend on the glycosidic linkage type.27
The present study performed in solution on ꢀ-(1f6)-linked
diglucopyranosides with nonchiral and chiral aglycons revealed
that the rotational populations of the hydroxymethyl group
involved in the glycosidic linkage (residue I) depend clearly
on the structural nature of the aglycon, their gt and gg
populations increased and decreased, respectively, as the bulki-
ness of the aglycon increased. These conclusions predict the
existence of a natural conformational domino effect in oligosac-
charides.
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D. G. J. Comput. Chem. 1998, 19, 1111.
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Chem. 1995, 60, 2537. (b) Padrón, J. I.; Vázquez, J. T. Chirality 1997, 9, 626.
(c) Padrón, J. I.; Vázquez, J. T. Tetrahedron: Asymmetry 1998, 9, 613.
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Results and Discussion
Synthesis. Among the synthetic methods proposed for
glycosylation reactions,28 the direct epoxidation of glycals has
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(b) Mayato, C.; Dorta, R.; Vázquez, J. Tetrahedron: Asymmetry 2004, 15, 2385.
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K.; Seitz, S.; Papahatjis, D. J. Am. Chem. Soc. 1983, 105, 2430. (d) Kahne, D.;
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Boom, J. Van Tetrahedron Lett. 1990, 31, 1331. (f) Sinaÿ, P.; Marra, A.; Esnault,
J.; Veyrieres, A. J. Am. Chem. Soc. 1992, 114, 6354. (g) Schmidt, R.; Kinzy,
W. AdV. Carbohydr. Chem. Biochem. 1994, 50, 21. (h) Danishefsky, S.; Bilodeau,
M. Angew. Chem., Int. Ed. Engl. 1996, 35, 1381. (i) Mukaiyama, T. Angew.
Chem., Int. Ed. 2004, 43, 5590. (j) Crich, D.; Lim, L. B. L. Org. Reactions
2004, 64, 115.
(5) Review: Bock, K.; Duus, J. J. Carbohydr. Chem. 1994, 184, 513.
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2002, 337, 353.
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10541.
(8) Molteni, C.; Parrinello, M. J. Am. Chem. Soc. 1998, 120, 2168.
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(10) Tvaroška, I.; Carver, J. P. J. Phys. Chem. B 1997, 101, 2992.
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Carbohydr. Res. 1999, 322, 264.
(13) Senderowitz, H.; Parish, C.; Still, W. C. J. Am. Chem. Soc. 1996, 118,
2078.
(29) (a) Gervay, J.; Danishefsky, S. J. J. Org. Chem. 1991, 56, 5448. (b)
Bilodeau, M. T.; Danishefsky, S. J. Coupling of glycals: a new strategy for the
rapid assembly of oligosaccharides Frontiers in Natural Product Research; 1996;
Vol. 1, (Modern Methods in Carbohydrate Synthesis), p 171. (c) Danishefsky,
S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1380. (d) Seeberger,
P. H.; Danishefsky, S. J. Acc. Chem. Res. 1998, 31, 685. and cited references.
(30) Oikawa, Y.; Tanaka, T.; Yonemitsu, O. Tetrahedron Lett. 1992, 23,
885.
(14) (a) Liu, H.-W.; Nakanishi, K. J. Am. Chem. Soc. 1981, 103, 5591. (b)
Liu, H. W.; Nakanishi, K. J. Am. Chem. Soc. 1982, 104, 1178.
(15) (a) Nishida, Y.; Ohrui, H.; Meguro, H. Tetrahedron Lett. 1984, 25, 1575.
(b) Ohrui, H.; Nishida, Y.; Watanabe, M.; Hori, H.; Meguro, H. Tetrahedron
Lett. 1985, 26, 3251. (c) Nishida, Y.; Hori, H.; Ohrui, H.; Meguro, H.
J. Carbohydr. Chem. 1988, 7, 239.
(16) DeVries, N.; Buck, H. M. Carbohydr. Res. 1987, 165, 1.
(17) Nishida, Y.; Hori, H.; Ohrui, H.; Meguro, H.; Uzawa, J.; Reimer, D.;
Sinnwell, V.; Paulsen, H. Tetrahedron Lett. 1988, 29, 4461.
(18) Poppe, L. J. Am. Chem. Soc. 1993, 115, 8421.
(31) Nicolau, K. C.; Webber, S. E. Synthesis 1986, 453.
(32) Gonzalez, A. G.; Brouard, I.; Leon, F.; Padron, J. I.; Bermejo, J.
Tetrahedron Lett. 2001, 42, 3187.
3352 J. Org. Chem. Vol. 73, No. 9, 2008

Conformational Domino Effect in Saccharides
SCHEME 1. Synthesis of Monosaccharide Precursors
SCHEME 2. Synthesis of the Disaccharide Precursor 9
accurately under a first-order NMR analysis, the hydroxyl groups
at C4′ and C6′ were derivatized with chromophores, namely
p-bromobenzoates. Therefore, since all model disaccharides
contain CD exciton-coupled chromophores,35 UV and CD
spectroscopy was also used to characterize these compounds.
The intramolecular charge-transfer band was around 245 nm
in the UV, and the exciton Cotton effects were around 251 and
234 nm in the CD spectra.
Conformational Analysis. General. Although there is ap-
parently wide conformational freedom in disaccharides, steric
and stereoelectronic effects in these biomolecules lead to a
reduced number of conformations. Thus, in gluco-24 and
mannosides,26 while the gauche effect between oxygens O5 and
O6 stabilizes the gg and gt rotamers, the 1,3-diaxial type
interaction between the O4 and O6 in the tg conformation
destabilizes this rotamer, being nil or negligible in all analyzed
cases.5,36 Similarly, in galactosides the gt and tg rotamers are
favored, while the gg rotamer is disfavored as a consequence
of the axial configuration at C4.25 In addition, the exo-anomeric
effect37,38 restricts the rotation around the glycosidic linkage,
the exo-syn conformation being widely accepted as the most
stable and predominant (Figure 4). Based on these consider-
ations, we can limit the conformational study to the main
staggered rotamers around both C5-C6 and C5′-C6′ bonds.
Conformational Analysis of the Hydroxymethyl Group
around the C5-C6 Bond (Residue I). The model disaccharides
10-32 are divided into four sets of compounds on the basis of
their substituents. T-ROESY experiments performed with the
model disaccharides showed the main cross-peaks indicated in
Figure 5, clearly confirming the anomeric configuration of both
sugar residues. Moreover, in many cases, the cross-peaks are
H1 for compounds in the four sets of disaccharides were
shielded (95-104 ppm) or deshielded (4.10-4.62 ppm),
respectively, from the methyl to tert-butyl derivative. Further-
more, as observed for alkyl glucosides,24–26 comparison of the
NMR data of (-)- and (+)-menthyl disaccharides shows
chemical shifts for the former compounds at higher fields for
C1 (3-4 ppm) and for H1 (0.03-0.11 ppm).
The 1H NMR signals of the prochiral protons at C6 and C6′
were differentiated according to the data in the literature5,15 on
their chemical shifts and coupling constants; i.e., in general,
for the D-gluco-series saccharides, the signals of the H6R proton
are more shielded than those of H6S (δH6S > δH6R), and JH5,H6R
coupling constants have higher values than JH5,H6S. This NMR
behavior is also observed in (1f6) glc-glc, gal-gal, or man-
man disaccharides. Occasionally, homonuclear spin decoupling
was performed for spectral simplification. The rotamer popula-
tions of the hydroxymethyl groups were calculated from the
3JH5,H6 coupling constants by means of Serianni’s equations.33
Among the different types of Karplus equations,34 those of
Serianni yield the most accurate representation of the rotameric
populations in solution and, generally, positive values for the
tg population.
(35) For a monograph on exciton CD spectroscopy see: (a) Harada, N.;
Nakanishi, K. Circular Dichroic Spectroscopy. Exciton Coupling in Organic
Stereochemistry; University Science Books: CA, 1983. (b) Nakanishi, K.; Berova,
N. The Exciton Chirality Method in Circular Dichroism, Principles and
Applications; Nakanishi, K., Berova, N., Woody, R. W., Eds.; VCH Publishers:
New York, 1994.
(36) Juaristi, E.; Antúñez, S. Tetrahedron 1992, 48, 5941.
(37) The stereoelectronic exo-anomeric effect consists of the conformational
preference of glycosides for the gauche orientation (Lemieux, R. U.; Pavia, A. A.;
Martin, J. C.; Watanabe, K. A. Can. J. Chem. 1969, 47, 4427), as a consequence
of the stereoelectronic interaction between the p orbital of the interannular oxygen
and the σ* orbital of the pyranose C1-O5 bond. Furthermore, this effect is
responsible for the reduction and extension of C1-O1 and C1-O5 bonds,
respectively, as observed in X-ray diffraction studies (Briggs, A. J.; Glenn, R.;
Jones, P. G.; Kirby, A. J.; Ramaswamy, P. J. Am. Chem. Soc. 1984, 106, 6200).
(38) (a) Thatcher, G. R. J. Anomeric and Associated Stereoelectronic Effects.
Scope and ControVersy in the Anomeric Effect and Associated Stereoelectronic
Effects; Thatcher, G. R. J., Ed.; ACS Symposium Series 539: Washington, DC,
1993. (b) Juaristi, E.; Cuevas, G. The Anomeric Effect in New Directions in
Organic and Biological Chemistry; Rees, C. W., Ed.; CRC Press, Inc.: Boca
Ratón, FL, 1995.
To analyze by CD the rotational populations of the hy-
droxymethyl group in C6′ and to obtain less crowded NMR
spectra that allow the coupling constants to be determined more
(33) Thibaudeau, C.; Stenutz, R.; Hertz, B.; Klepach, T.; Zhao, S.; Wu, Q.;
Carmichael, I.; Serianni, A. J. Am. Chem. Soc. 2004, 121, 15668. Equations: (i)
2.8Pgg + 2.2Pgt + 11.1Ptg ) JH5,H6proS; (ii) 0.9Pgg + 10.8Pgt + 4.7Ptg ) JH5,H6proR
;
(iii) Pgg + Pgt + Ptg ) 1.
(34) (a) Haasnoot, C. A. G.; De Leeuw, F. A. A. M.; Altona, C. Tetrahedron
1980, 36, 2783. (b) Manor, P. C.; Saenger, W.; Davies, D. B.; Jankowski, K.;
Rabczenko, A. Biochim. Biophys. Acta 1974, 340, 472. (c) Stenutz, R.;
Carmichael, I.; Widmalm, G.; Serianni, A. S. J. Org. Chem. 2002, 67, 949.
J. Org. Chem. Vol. 73, No. 9, 2008 3353

Roën et al.
SCHEME 3. Synthesis of the Model Disaccharides
SCHEME 4. Synthesis of the tert-Butyl Disaccharides 27 and 32
totally in agreement with exo-syn and gt conformations for the
glycosidic linkage. Thus, strong cross-peaks were observed
between H1′ and H6R, and between H6S and H5, as well as
weak cross-peaks between H6R and H4.
appeared as doublets (J ≈ 11 Hz), meaning a very low value
of the JH5,H6S coupling constants and therefore of the tg
population. NMR measurements of these compounds in polar
solvents such as C5D5N or CDCl3/CD3OD led to superimposed
or complex signals, while in solvents (CD3)2CO, CD3OD, C6D6,
or CDCl3, they were not soluble. To calculate the rotational
populations of these disaccharides, the JH5,H6S coupling constant
values are introduced into the equations. So, as an approxima-
tion, a low value of 0.9 Hz was assigned to this constant for
the purpose.34c The resulting calculated populations (Table 1)
reflect a higher gt than gg population in all cases and confirm
the rotational population around C5-C6 to be dependent on
the structure of the aglycon.
1H NMR analysis of the alkyl ꢀ-D-glucopyranosyl-(1f6)-ꢀ-
D-glucopyranosides 22-25 and 27 were measured in DMSO-
d6, showing high values of the JH5,H6R in this solvent (Table 1).
Furthermore, the signals corresponding to the H6S protons
FIGURE 3. General NMR characteristics of model disaccharides.
FIGURE 5. Main cross-peaks observed for the model disaccharides
in the T-ROESY experiments (CDCl3).
FIGURE 4. Exo-syn rotamer around the O1-C1 bond.
3354 J. Org. Chem. Vol. 73, No. 9, 2008

Conformational Domino Effect in Saccharides
TABLE 1. Coupling Constants and Calculated Rotameric
Populations (%) around the C5-C6 Bond (Residue I) for the Model
Disaccharides 22-25 and 27 (DMSO-d6)
(+)- and (-)-menthyl derivatives 30 and 31, the JH5,H6R coupling
constant showed a higher dependence on the nature of the
solvent, the (-)-methyl derivative showing an equal or smaller
value than the (+)-derivative (Figure 6). On the other hand,
the JH5,H6S coupling constant remained almost constant for each
solvent. Horizontal analysis of the data contained in Table 3
reveals, independently of the aglycon, similar JH5,H6R values for
nonpolar solvents and smaller values for the polar ones,
especially for acetonitrile. This result means that the gt rotamer
is less favored in polar solvents.
a
compd
R
JH5,H6R
JH5,H6S
Pgg
Pgt
Ptg
22
23
24
25
27
Me
iso-Pr
(+)-Mn
(-)-Mn
tert-Bu
6.8
7.0
7.4
6.6
7.2
-
-
-
-
-
44
42
38
46
40
56
58
62
54
60
0
0
0
0
0
a Not detected. An estimated value of 0.9 Hz was used for
calculations.
As seen from Figure 7, there is a linear correlation40 between
the gg and gt rotational populations around the C5-C6 bond
for compounds 22-25 and 27 with the corresponding Taft’s
steric parameters.41 The ES values are composite terms, derived
from both potential energy steric effects (steric strains) and
entropy effects (steric hindrances to motions). According to
Taft,41 introduction of a straight-chain alkyl group in place of
the standard hydrogen substituent raises the activation energy
due to steric hindrance. Therefore, the bulkier alkyl groups
freeze out the rotation around the O1-C1 bond, and therefore
the more stable exo-syn rotamer increases its population (Figure
8). Simultaneously to steric hindrances to motions, steric factors
between the aglycon and the substituent at position 2 are also
probably involved in the conformational behavior around the
glucosidic bond,42 reducing the population of the non-exo
rotamer as the aglycon increases in size.
The plot of the rotamer populations of the totally protected
disaccharides 10-16, also containing the acetyl and cyclohexyl
disaccharides, was carried out against the pKa of bonded alcohols
instead of the ES values, to be able to include the acetyl group
(Figure 9). Since pKa values of bonded alcohols are related to
steric bulk, this plot is a good approximation for studying these
compounds. The gt rotamer increased from the acetyl derivative
(39%) to the methyl derivative (60%), and to the isopropyl and
cyclohexyl disaccharides (65 and 64%, respectively). The bulkier
(+)- and (-)-menthyl and the tert-butyl disaccharides showed
smaller gt (56, 57, and 63%, respectively) and higher gg
populations (43, 44, and 37%, respectively) than expected from
the experimental regression line (see below).24
TABLE 2. Coupling Constants and Calculated Rotameric
Populations (%) around the C5-C6 Bond (Residue I) for the Model
Disaccharides 28-32 (CDCl3)
compd
R
JH5,H6R
JH5,H6S
Pgg
Pgt
Ptg
28
29
30
31
32
Me
iso-Pr
(+)-Mn
(-)-Mn
tert-Bu
7.4
7.7
–
6.5
7.8
1.8
1.7
–
1.9
1.7
36
33
–
44
32
64
67
–
56
68
0
0
–
0
0
a
a
a H6R and H6S signals are isochronous.
The JH5,H6 coupling constants for the model penta-O-acetyl
disaccharides 28-32 in CDCl3 are shown in Table 2, together
with the calculated rotameric populations around the C5-C6
bond. An increase in the JH5,H6R coupling constant around the
C5-C6 bond (ω) was observed as the bulkiness of the aglycon
increased. Thus, this coupling constant gradually increased from
the methyl derivative 28 (7.4 Hz), to the isopropyl 29 (7.7 Hz),
and to the tert-butyl derivative 32 (7.8 Hz). On the other hand,
the JH5,H6S value remained more or less constant (around 1.8
Hz). The (-)-menthyl derivative 31 showed the smallest value
of the JH5,H6R coupling constant, pointing to the existence of
nonbonded interactions between the isopropyl group in the
menthyl aglycon and the hydroxymethyl group at C6 or the
residue II, as will be discussed below.
The rotamer populations around C5-C6 of the alkyl ꢀ-D-
glucopyranosyl-(1f6)-ꢀ-D-glucopyranosides 28-32 were cal-
culated by applying the Serianni equations system,33 using the
experimental JH5 H6R and JH5 H6S coupling constants (Table 2).
It was observed that the gt rotamer was the most populated in
all cases and that its population slightly increases from 56%
((-)-menthyl) to 68% (tert-butyl) at the expense of the gg, from
44% ((-)-menthyl) to 32% (tert-butyl). Since it is accepted that
the ω population depends to some extent on solvation effects,39
1H NMR analyses of these disaccharides were run in nonpolar
as well as polar solvents with different dielectric constants and
dynamic viscosity coefficients. Analyzing vertically the data in
Table 3, the JH5,H6R coupling constants depend on the structural
nature of the aglycon. For compounds possessing a nonchiral
aglycon, the JH5,H6R increased from the methyl, to isopropyl,
and tert-butyl derivative, these differences being less effective
and even disappearing as the dielectric constant of the solvent
increased (Figure 6). For compounds with a chiral aglycon, the
These correlations are explained by the exo-anomeric effect,37,38
which rises as the charge delocalization from the aglycon to
the anomeric carbon becomes easier.43,44 Thus, as the aglycon
becomes branched, the exo-syn population increases at the
expense of the non-exo conformation, due to steric hindrances
to motions and/or steric factors, as explained above. So, the
stereoelectronic nSfσ*CO interaction (the exo-anomeric effect)
increases. Very recently, studies performed with C-glycosides,45,46
which enabled the exo-syn, exo-anti, and non-exo populations
to be calculated, have demonstrated that the population exo-
syn rotamer increased and that of the non-exo decreased as the
substitution of the C-aglycon increased, supporting our
explanation.
(41) (a) Taft, R. W., Jr. J. Am. Chem. Soc. 1952, 74, 2729. (b) Taft, R. W.,
Jr. J. Am. Chem. Soc. 1952, 74, 3120. (c) Taft, R. W., Jr. J. Am. Chem. Soc.
1953, 75, 4532. (d) Taft, R. W., Jr. J. Am. Chem. Soc. 1953, 75, 4538.
(42) Asensio, J. L.; Cañada, F. J.; García-Herrero, A.; Murillo, M. T.;
Fernández-Mayoralas, A.; Johns, B. A.; Kozak, J.; Zhu, Z.; Johnson, C. R.;
Jiménez-Barbero, J. J. Am. Chem. Soc. 1999, 121, 11318.
(39) (a) Rockwell, G. D.; Grindley, T. B. J. Am. Chem. Soc. 1998, 120, 10953.
(b) Kirschner, K. N.; Woods, R. J. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 10541.
(c) Gonzalez-Outeriño, J.; Kirschner, K. N.; Thobhani, S.; Woods, R. J. Can.
J. Chem. 2006, 84, 569.
(43) Tvaroška, I.; Kozár, T. J. Am. Chem. Soc. 1980, 102, 6929.
(44) Praly, J. P.; Lemieux, R. U. Can. J. Chem. 1987, 65, 213.
(45) Jiménez-Barbero, J.; Espinosa, J. F.; Asensio, J. L.; Cañada, F. J.;
Poveda, A. AdV. Carbohydr. Chem. Biochem. 2001, 56, 235.
(40) Regression line equations: (a) Figure 7: Pgg ) 3.2057ES + 3.725; R2 )
0.8399; Pgt ) -3.2057ES + 56.275; R2 ) 0.8399. (b) Figure 11: Pgg ) 2.2014ES
+ 58.909; R2 ) 0.6116; Pgt ) -2.1415ES + 35.948; R2 ) 0.8566. (c) Figure 12:
Pgt ) -2.1415ES + 35.948; R2 ) 0.8566 (blue line); Pgt ) -1.317ES + 35.738;
R2 ) 0.8100 (green line); and Pgt ) -1.8599ES + 31.618; R2 ) 0.7023 (red
line).
(46) (a) Mayato, C.; Dorta, R. L.; Vázquez, J. T. Tetrahedron: Asymmetry
2007, 18, 931. (b) Mayato, C.; Dorta, R. L.; Vázquez, J. T. Tetrahedron:
Asymmetry 2007, 18, 2803.
J. Org. Chem. Vol. 73, No. 9, 2008 3355

Roën et al.
DMSO
TABLE 3. JH5,H6 Coupling Constants (Residue I) for the Model Disaccharides 28-32 in Different Solventsa
JH5,H6R
JH5,H6S
R
C6D6
CDCl3
(CD3)2CO
CD3CN
DMSO
C6D6
CDCl3
(CD3)2CO
CD3CN
ꢀ
µ
28
29
30
31
32
2.3
0.65
7.3
7.4
6.6
6.6
7.7
4.8
0.57
7.4
7.7
-
20.7
0.32
6.6
7.1
6.6
37.5
0.37
5.8
5.8
6.1
46.7
2.00
6.5
6.6
6.3
Me
iso-Pr
(+)-Mn
(-)-Mn
tert-Bu
2.2
2.2
2.3
2.5
2.0
1.8
1.7
-
1.9
1.7
2.0
1.9
2.1
2.1
2.0
2.0
2.0
2.0
2.0
2.0
-
-
-
2.1
1.6
6.5
7.8
5.9
6.8
5.4
5.8
5.8
6.6
a ꢀ ) dielectric constant; µ (Poise) ) dynamic viscosity coefficient.
FIGURE 6. Plot of JH5,H6R coupling constants versus dielectric constants
for disaccharides 28-32: tert-butyl 32 (green line), isopropyl 29 (red
line), methyl 28 (dark blue line), (+)-menthyl 30 (yellow line), and
(-)-menthyl 31 (blue line).
FIGURE 9. Plot of gt populations around the C5-C6 bond versus
pKa of bonded alcohols for compounds 10-16 (totally protected
disaccharides).40
FIGURE 10. Molecular orbitals involved in the gauche effect for the
two idealized staggered gg and gt rotamers around the C5-C6 bond.
and modify the conformational preferences around the C5-C6
bond (O5-C5-C6-O6), by varying the effectiveness of the
stereoelectronic σCH-σ*CO interactions. Figure 10 shows the
hyperconjugative mechanism proposed for the gauche effect,
two σCH-σ*CO interactions for the gg, one for the gt, and none
for the tg rotamer,5,47 this mechanism having been used to
explain the higher stability of the gg rotamer in monosaccha-
rides.5
FIGURE 7. Rotational populations of gg/gt rotamers around the
C5-C6 bond versus corresponding ES values for aliphatic substituents
for compounds 22-25 and 27 (pentahydroxy disaccharides). Pgg (red
line) and Pgt (blue line).40a
In addition to stereoelectronic interactions, nonbonded inter-
actions between the aglycon and the hydroxymethyl group could
be important in compounds with bulky aglycons or aglycons
with bulky substituents syn to the endocyclic oxygen O5. As
seen in Tables 1-3, the (-)-menthyl derivative possesses the
smallest JH5,H6R values and therefore the smallest gt populations.
A reasonable explanation of this could be the existence of
nonbonded interactions between the isopropyl group located syn
to O5 and the hydroxymethyl group at C6 (residue II in the gt
conformation). On the other hand, the anti disposition of the
FIGURE 8. Molecular orbitals involved in the exo-anomeric effect
for the three idealized staggered rotamers around the C1-O bond.
The progressive shortness of the O1-C1 bond and lengthen-
ing of the C1-O5 bond, as the exo-anomeric effect increases,
should affect the gauche effect between oxygens O5 and O6
(47) Dionne, P.; St.-Jacques, M. J. Am. Chem. Soc. 1987, 109, 2616.
3356 J. Org. Chem. Vol. 73, No. 9, 2008

Conformational Domino Effect in Saccharides
TABLE 4. Coupling Constants, Calculated Rotameric Populations
(%) around the C5′-C6′ Bond (Residue ΙΙ) (in DMSO), and CD
Data (in EtOH) for Model Disaccharides 22-25 and 27
compd
R
JH5′,H6′R JH5′,H6′S Pgg Pgt Ptg 1EC 2EC A value
22
23
24
25
27
Me
iso-Pr
(+)-Mn
(-)-Mn
tert-Bu
4.7
4.7
4.9
4.9
5.1
3.1
2.9
3.1
2.9
3.0
58 36
59 37
56 38
57 39
54 40
6
4
6
4
6
13.3 -4.2
13.1 -4.0
12.9 -3.9
13.0 -3.9
12.8 -3.9
17.5
17.1
16.8
16.9
16.7
isopropyl group in the (+)-menthyl derivative prevents the
mentioned nonbonded interactions. Of course, these steric factors
depend on the solvent (Table 3) and on the substitution type.
For the totally protected disaccharide set, compounds 10-16
(Figure 9), both menthyl and the tert-butyl derivatives, showed
smaller gt populations, due probably to severe nonbonded
interactions. This does not rule out the participation of the exo-
anomeric effect for them since the populations of the menthyl
and methyl derivatives are more similar than they are to those
of the acetyl derivative 10. For this compound, the exo-anomeric
effect is nil, due to the nonshared electron pair of the exocyclic
oxygen being involved by resonance with the carbonyl group.
This explains the low value of its gt population (gg:gt:tg ) 38:
39:23%). Therefore, the rotational populations around C5-C6
(residue I) can be explained on the basis of both nonbonded
and stereoelectronic effects.
FIGURE 11. Plot of rotamer populations around the C5′-C6′ (in
DMSO) versus corresponding ES values for aliphatic substituents for
compounds 22-25 and 27 (pentahydroxy disaccharides). Pgg (red line)
and Pgt (blue line).40b
FIGURE 12. Plot of gt rotamer populations around the C5′-C6′ versus
corresponding ES values for compounds 22-25 and 27 (in DMSO,
blue line) and for compounds 28-32 (in C6D6, green line; in CD3CN,
red line).40c
Conformational Analysis of the Hydroxymethyl Group
around the C5′-C6′ Bond (Residue II). The rotameric popula-
tions around C5′-C6′, calculated from JH5′,H6′R and JH5′,H6′S
coupling constants, for compounds 10-32 showed that the gg
rotamer is the most populated, then the gt rotamer, and finally
the tg, the general relation Pgg:Pgt:Ptg being 60:35:5. T-ROESY
experiments also support this conclusion since the cross-peaks
between the prochiral H6′ protons and H5′ were of different
size (Figure 5), the one between H6′S and H5′ being double
the magnitude of that between H6′R and H5′, indicating a greater
gt population than tg. Besides this, in general, the JH5′,H6′R
coupling constant was found to increase very slightly as the
aglycone changed from methyl to secondary alkyl to tertiary
alkyl. Table 4 shows this behavior for the case of the
pentahydroxy disaccharides 22-25 and 27 in DMSO. The gt
population slightly increased from the methyl (36%), isopropyl
(37%), (+)-menthyl (38%), (-)-menthyl (39%), and tert-butyl
disaccharides (40%), while the gg population decreased from
the methyl (58%) to the tert-butyl disaccharide (54%). Figure
11 shows the linear correlation between the gg and gt popula-
tions at residue II versus ES values for aliphatic substituents
(aglycon, residue I) for these compounds.40b Figure 12 shows
how the gt population increased linearly as Taft’s steric
parameters increased, independently of the disaccharide series
and the solvent.40c
FIGURE 13. Sign and relative intensities for the pairwise interaction
between the chromophores at C4 and C6 in the three rotamers.
13, the 4/6 pairwise interaction between the chromophores has
a positive exciton coupling for the gg rotamer, negative for the
gt, and nil for the tg rotamer. Furthermore, the A value slightly
decreased from the methyl (17.5), to the isopropyl (17.1), and
to the tert-butyl disaccharides (16.7) in complete agreement with
an increase in the gt population from primary, to secondary, to
tertiary alkyl disaccharides. Therefore, CD and NMR data are
in complete agreement about this remote rotational dependence.
The relationship between the gg and gt populations at residue
II and the Taft’s steric parameters of the aglycons at residue I
shows a remote conformational relay from the aglycon to the
(48) The amplitude (A value) of split CD Cotton effects is defined as A )
∆ꢀ1 - ∆ꢀ2 where ∆ꢀ1 and ∆ꢀ2 are intensities of the first and second Cotton
effects, respectively. Occasionally, the presence of a background ellipticity alters
the intensity of the Cotton effects at short wavelengths. For this reason, the
intensities of the second Cotton effects and the amplitudes (A values) of the CD
spectra of our model compounds may not be precise. The intensities of the first
Cotton effects are thus more accurate for comparative analysis.
The rotational populations around the C5′-C6′ bond were
also analyzed by the CD exciton chirality method.35 The positive
A values48 (Table 4) obtained for all these compounds confirm
that the gg rotamer is the most populated. As seen in Figure
J. Org. Chem. Vol. 73, No. 9, 2008 3357

Roën et al.
a stirred solution of disaccharide 9 in dry CH2Cl2 (5 mL/mmol) at
0 °C under argon atmosphere, and the reaction was stirred for 30
min. The 1,2-anhydrosugar thus obtained was concentrated under
reduced pressure and left under a vacuum for 2 h. Then it was
dissolved in dry THF (10 mL/mmol) under argon, and molecular
sieves and the corresponding alcohol were added. The reaction
mixture was cooled to -78 °C, and then 0.5 equiv of a 1.0 M
solution of ZnCl2 in diethyl ether was added. The reaction was
allowed to warm to room temperature and stirred overnight. The
mixture was diluted with EtOAc, filtered, and washed with water;
then the combined organic layers were dried over MgSO4, filtered,
and the solvent removed under reduced pressure. After this, 2 mL
of a 1:1 solution of dry pyridine/acetic anhydride was added at
room temperature and stirred overnight. Excess solvent was
removed under reduced pressure, and the residue was purified with
column chromatography.
General Procedure for Debenzylation. An amount of 2.5 equiv
of DDQ at room temperature was added to a stirred solution of the
starting material in CH2Cl2/H2O (9:1, 50 mL/mmol). Then, this was
diluted with CH2Cl2 and washed with saturated NaHCO3 solution.
The aqueous layer was extracted with CH2Cl2 twice, and the
combined organic layers were dried over MgSO4, filtered, and the
solvent removed under reduced pressure. The residue was purified
with column chromatography.
General Procedure for Deprotection of Silyl and Acetyl
Groups. A solution of starting material in dry diethylether (40 mL/
mmol) was added to a stirred solution of acetyl chloride (40 equiv)
in dry methanol (40 mL/mmol). When the reaction was completed,
it was concentrated under vacuum, and the residue was purified
by Sephadex column chromatography (n-hexane/CHCl3/MeOH,
2:1:1).
FIGURE 14. Schematic representation of a conformational cascade
in linear (top) or branched (bottom) oligosaccharides. (1f2)-, (1f3)-,
and (1f4)-bonded saccharides start a new domino effect; however,
(1f6)-interglycosidic linkages continue the domino effect.
hydroxymethyl group at residue II, although to a much lesser
degree, as a consequence of the greater distance between them.
This correlation could be due to minute differences in the values
of the exo-anomeric effect on residue II, as a result of the
different rotameric populations around C5-C6, since for these
disaccharides nonbonded interactions between the aglycon and
this distantly located hydroxymethyl group cannot be expected.
Conclusions
The rotational populations of the hydroxymethyl groups of a
series of alkyl ꢀ-D-glucopyranosyl-(1f6)-ꢀ-D-glucopyranosides
were analyzed by means of NMR and CD. The experimental
data, collected from four sets of disaccharides, proved a
rotational dependence of the hydroxymethyl group involved in
the glycosidic linkage (torsion angle ω, O5-C5-C6-O6) on
the structure of the aglycon and on the solvent nature, gt usually
being the most stable rotamer. Furthermore, the gt and gg
populations of this hydroxymethyl group increased and de-
creased, respectively, as Taft’s steric parameter for the aglycon
increased. This rotational behavior can be explained by the
stereoelectronic exo-anomeric effect, steric hindrances to mo-
tions, and nonbonded interactions between the aglycon and the
substituent at position 2 and/or the hydroxymethyl group at C6
(residue II in the gt conformation) altering this stereoelectronic
effect. Extending these results, and those previously described
on the dependence on the glycosidic linkage type,27 to oligosac-
charides, the existence of a conformational cascade can be
predicted, where the conformational preferences around the
torsion angle ω in an interglycosidic linkage depend on the
stereostructure of the preceding residue and so on repeatedly
(Figure 14). This knowledge can be of great help when studying
oligosaccharides three-dimensionally.
2,6-Anhydro-1-O-(4-bromobenzoyl)-5-deoxy-D-arabino-hex-
5-enitol (2). To a solution of D-glucal (658 mg, 4.5 mmol) in dry
methanol (20 mL) was added 1.35 g of dibutyltin oxide (5.4 mmol,
1.2 equiv) under an argon atmosphere and heated under reflux for
4 h. When the reaction was completed, it was evaporated to dryness.
Then the crude reaction mixture was dissolved in 20 mL of CH2Cl2,
cooled at -10 °C, and treated with 1.74 g (5.4 mmol, 1.2 equiv)
of n-Bu4NBr and 1.28 g (5.8 mmol, 1.3 equiv) of p-bromobenzoyl
chloride. The reaction was quenched with a few drops of water.
The solvent was removed under reduced pressure, and the residue
was cromatographed. Flash column chromatography (n-hexane/
EtOAc, 1:1) of the residue afforded 2 (895 mg, 2.7 mmol) in 61%
yield: TLC Rf ) 0.4 (n-hexane/EtOAc, 3:7); colorless syrup; [R]D
) +44.5 (c 2.0, CHCl3); MS (FAB) Calcd for C13H14BrO5 (M +
1
1)+ 327, Found 327; H NMR (CDCl3) δ 7.93 (dd, J ) 8.6 Hz,
2H), 7.61 (dd, J ) 8.6 Hz, 2H), 6.34 (dd, J ) 1.6 and 6.0 Hz, 1H),
4.90 (dd, J ) 3.4 and 12.5 Hz, 1H), 4.76 (dd, J ) 2.1 and 6.0 Hz,
1H), 4.52 (dd, J ) 2.3 and 12.5 Hz, 1H), 4.34 (dd, J ) 2.1 and 7.3
Hz, 1H), 4.02 (m, 1H), 3.60 (dd, J ) 7.3 and 10.1 Hz, 1H), 3.36
(br s, 1H), 2.15 (br s, 1H); 13C NMR (CDCl3) δ 166.8, 144.2,
131.9–128.2, 102.9, 76.4, 69.7, 69.5, 63.3. Anal. Calcd for
C13H13BrO5: C, 47.44; H, 3.98. Found: C, 47.70; H, 4.00.
2,6-Anhydro-1-O-(4-bromobenzoyl)-4-O-[tert-butyl(dimethyl)
silyl]-5-deoxy-D-arabino-hex-5-enitol (3). Compound 2 (435 mg,
1.32 mmol) was dissolved in dry DMF (6.5 mL) under an argon
atmosphere and treated with imidazole (198 mg, 2.91 mmol, 2.2
equiv) and tert-butyldimethylsilyl chloride (210 mg, 1.39 mmol,
1.05 equiv). When the reaction was completed, it was quenched
with a few drops of water, concentrated under vacuum, and the
residue purified by column chromatography (n-hexane/EtOAc, 8.5:
1.5) to lead to compound 3 (416 mg, 0.95 mmol, 71%): TLC Rf )
0.2 (n-hexane/EtOAc, 9:1); colorless syrup; [R]D ) +29.6 (c 0.7,
CHCl3); MS (FAB) Calcd for C19H28BrO5Si (M + 1)+ 441, Found
The results also seem to demonstrate another rotational
dependence, namely, a very weak rotational population depen-
dence of the hydroxymethyl group at residue II (torsion angle
ω′, O5′-C5′-C6′-O6′) on the aglycon at residue I. Further-
more, the populations of gg, the most stable rotamer around
the C5′-C6′ bond, decreased, and those of gt increased as the
Taft steric parameters of the remote aglycon increased, inde-
pendently of the disaccharide series and of the solvent.
1
441; H NMR (CDCl3) δ 7.93 (d, J ) 8.6 Hz, 2H), 7.59 (d, J )
8.6 Hz, 2H), 6.31 (dd, J ) 1.2 and 6.1 Hz, 1H), 4.77 (dd, J ) 4.9
and 12.3 Hz, 1H), 4.69 (dd, J ) 2.5 and 6.1 Hz, 1H), 4.55 (dd, J
) 2.4 and 12.3 Hz, 1H), 4.27 (m, 1H), 4.12 (m, 1H), 3.72 (dd, J
) 6.5 and 8.8 Hz, 1H), 2.60 (br s, 1H), 0.91 (s, 9H), 0.12 (s, 6H);
Experimental Section
General Procedure for Preparation of Disaccharides 10-16.
A solution of dimethyldioxirane in acetone (2 equiv) was added to
3358 J. Org. Chem. Vol. 73, No. 9, 2008

Conformational Domino Effect in Saccharides
13C NMR (CDCl3) δ 166.2, 143.3, 131.8–128.4, 103.7, 76.3, 69.6,
69.5, 63.4, 25.8 (x3), 18.1, -4.5, -4.6. Anal. Calcd for
C19H27BrO5Si: C, 51.47; H, 6.14. Found: C, 51.47; H, 5.83.
2,6-Anhydro-1,3-bis-O-(4-bromobenzoyl)-4-O-[tert-butyl(di-
methyl)silyl]-5-deoxy-D-arabino-hex-5-enitol (4). A solution of
3 (2.36 g, 5.32 mmol) in dry CH2Cl2 (30 mL) was treated with
Et3N (2.2 mL, 16.0 mmol, 3 equiv), 2 equiv of p-bromobenzoyl
chloride (2.33 g, 10.63 mmol), and DMAP as catalyst. The reaction
was quenched with the addition of a few drops of water and the
solvent removed under reduced pressure. The product was purified
by silica gel column chromatography (n-hexane/EtOAc, 9:1),
obtaining 3.22 g of compound 4 (5.14 mmol, 97%): TLC Rf ) 0.5
(n-hexane/EtOAc, 9:1); colorless syrup; [R]D ) +39.8 (c 1.2,
CHCl3); MS (FAB) Calcd for C26H31Br2O6Si (M + 1)+ 625, Found
in an 87% yield, isolated after column chromatography (n-hexane/
EtOAc, 8:2). Thus, 85.6 mg of R- and 41.7 mg of ꢀ-anomer were
obtained. Compound 10 (ꢀ anomer): colorless syrup; 1H NMR
(CDCl3) δ 7.82 (d, J ) 8.5 Hz, 2H), 7.76 (d, J ) 8.4 Hz, 2H),
7.54 (d, J ) 8.5 Hz, 2H), 7.49 (d, J ) 8.6 Hz, 2H), 7.21 (d, J )
8.6 Hz, 2H), 6.86 (d, J ) 8.6 Hz, 2H), 5.55 (d, J ) 8.0 Hz, 1H),
5.32 (t, J ) 9.2 Hz, 1H), 5.02 (t, J ) 8.4 Hz, 1H), 4.93 (t, J ) 8.6
Hz, 1H), 4.71 (d, J ) 10.9 Hz, 1H), 4.52 (d, J ) 7.8 Hz, 1H), 4.47
(d, J ) 10.9 Hz, 1H), 4.46 (dd, J ) 3.7 and 12.1 Hz, 1H), 4.35
(dd, J ) 5.1 and 12.1 Hz, 1H), 4.03 (dd, J ) 4.5 and 13.4 Hz,
1H), 3.99 (t, J ) 8.9 Hz, 1H), 3.80 (m, 2H), 3.79 (s, 3H), 3.60 (m,
1H), 3.59 (dd, J ) 5.6 and 13.4 Hz, 1H), 3.37 (t, J ) 8.9 Hz, 1H),
2.06 (s, 3H), 2.05 (s, 3H), 2.04 (s, 3H), 0.88 (s, 9H), 0.71 (s, 9H),
0.04 (s, 6H), -0.01 (s, 3H), -0.20 (s, 3H); 13C NMR (CDCl3) δ
169.0, 168.9, 165.2, 164.1, 159.1, 131.6–128.0, 113.6 (x2), 100.5,
91.9, 77.8, 75.4, 74.5, 74.3, 73.0, 72.7, 72.6, 72.1, 71.5, 67.1, 63.4,
55.0, 29.4, 25.5 (x3), 25.1 (x3), 20.9, 20.6, 18.0, 17.6, 17.5, -4.3,
-4.7 (x 3). Anal. Calcd for C52H70Br2O17Si2: C, 52.79; H, 5.96.
Found: C, 52.92; H, 6.09.
1
625; H NMR (CDCl3) δ 7.90 (d, J ) 8.5 Hz, 2H), 7.88 (d, J )
8.5 Hz, 2H), 7.59–7.55 (m, 4H), 6.42 (dd, J ) 0.8 and 6.1 Hz,
1H), 5.38 (t, J ) 5.2 Hz, 1H), 4.85 (dd, J ) 3.5 and 6.1 Hz, 1H),
4.64 (dd, J ) 6.6 and 11.9 Hz, 1H), 4.54 (dd, J ) 3.3 and 11.9 Hz,
1H), 4.51 (m, 1H), 4.33 (br t, J ) 4.1 Hz, 1H), 0.86 (s, 9H), 0.09
(s, 3H), 0.04 (s, 3H); 13C NMR (CDCl3) δ 165.5, 164.5, 143.2,
131.8–128.3, 102.8, 73.8, 71.2, 64.6, 62.8, 25.6 (x3), 17.9, -4.6,
-4.9. Anal. Calcd for C26H30Br2O6Si: C, 49.85; H, 4.83. Found:
C, 49.81; H, 4.86.
Methyl 2-O-Acetyl-6-O-{2-O-acetyl-4,6-bis-O-(4-bromoben-
zoyl)-3-O-[tert-butyl(dimethyl)silyl]-ꢀ-D-glucopyranosyl}-3-O-
[tert-butyl(dimethyl)silyl]-4-O-(4-methoxybenzyl)-ꢀ-D-glucopy-
ranoside (11). Following the general procedure for preparation of
disaccharides, 78.0 mg (0.07 mmol) of compound 9 was treated with
500 µL of methanol to provide 82.2 mg of compound 11 (0.07 mmol,
97% yield) after column chromatography (n-hexane/EtOAc, 8:2): TLC
Rf ) 0.5 (n-hexane/EtOAc, 7:3); mp ) 171.0-171.9 °C; [R]D ) +8.9
(c 1.1, CHCl3); MS (FAB) Calcd for C51H70Br2O16Si2Na (M + Na)+
6-O-{2-O-Acetyl-4,6-bis-O-(4-bromobenzoyl)-3-O-[tert-bu-
tyl(dimethyl)silyl]-ꢀ-D-glucopyranosyl}-1,5-anhydro-3-O-[tert-
butyl(dimethyl)silyl]-2-deoxy-4-O-(4-methoxybenzyl)-D-arabino-
hex-1-enitol (9). A solution of dimethyldioxirane in acetone (2
equiv) was added to a stirred solution of compound 4 (520 mg,
0.83 mmol) in dry CH2Cl2 (5 mL/mmol) at 0 °C under argon, and
the reaction was stirred for 30 min. The 1,2-anhydrosugar thus
obtained was concentrated under reduced pressure and left under
vacuum for 2 h. Then it was dissolved in dry THF (10 mL/mmol)
under argon, and molecular sieves and compound 7 (474 mg, 1.25
mmol, 1.5 equiv) were added. The reaction mixture was cooled to
-78 °C, and then 0.5 equiv of a 1.0 M solution of ZnCl2 in diethyl
ether was added. The reaction was allowed to warm to room
temperature and stirred overnight. The mixture was diluted with
EtOAc, filtered, and washed with water. The combined organic
layers were then dried over MgSO4, filtered, and the solvent
removed under reduced pressure, giving 527 mg of compound 8
as a mixture (ꢀ:R ) 6:1) (62% yield). Then, 2 mL of a 1:1 solution
of dry pyridine/acetic anhydride was added at room temperature
and stirred overnight. Excess solvent was removed under reduced
pressure, and the residue was purified with column chromatography
(n-hexane/EtOAc, 19:1) to lead to 9 (92% yield), its ꢀ anomer (505
mg, 0.47 mmol) being isolated in a 57% overall yield: TLC Rf )
0.5 (n-hexane/EtOAc, 7:3); colorless syrup; [R]D ) +5.7 (c 0.8,
CHCl3); MS (FAB) Calcd for C48H64Br2O13Si2 (M)+ 1062, Found
1
1177, Found 1177; H NMR (CDCl3) δ 7.83 (d, J ) 8.6 Hz, 2H),
7.76 (d, J ) 8.6 Hz, 2H), 7.55 (d, J ) 8.6 Hz, 2H), 7.47 (d, J ) 8.5
Hz, 2H), 7.17 (d, J ) 8.6 Hz, 2H), 6.83 (d, J ) 8.6 Hz, 2H), 5.34 (t,
J ) 9.3 Hz, 1H), 5.03 (t, J ) 8.5 Hz, 1H), 4.82 (t, J ) 8.6 Hz, 1H),
4.69 (d, J ) 10.9 Hz, 1H), 4.56 (d, J ) 8.0 Hz, 1H), 4.45 (dd, J ) 3.6
and 12.1 Hz, 1H), 4.42 (d, J ) 10.9 Hz, 1H), 4.33 (dd, J ) 4.7 and
12.1 Hz, 1H), 4.18 (d, J ) 8.0 Hz, 1H), 4.03 (dd, J ) 1.3 and 10.6
Hz, 1H), 3.96 (t, J ) 8.9 Hz, 1H), 3.83 (m, 1H), 3.77 (s, 3H), 3.74 (t,
J ) 9.0, 1H), 3.54 (dd, J ) 7.1 and 10.6 Hz, 1H), 3.50 (m, 1H), 3.47
(s, 3H), 3.26 (t, J ) 9.0 Hz, 1H), 2.09 (s, 3H), 2.07 (s, 3H), 0.88 (s,
9H), 0.71 (s, 9H), 0.05 (s, 3H), 0.05 (s, 3H), -0.02 (s, 3H), -0.20 (s,
3H); 13C NMR (CDCl3) δ 169.6 (s), 169.1 (s), 165.4, 164.3, 159.3,
131.8–128.3, 113.8 (x2), 101.8, 100.9, 78.9, 75.0, 74.9, 74.7, 73.7,
73.2, 73.0, 72.2, 71.8, 67.6, 63.6, 56.7, 55.3, 25.7 (x3), 25.4 (x3), 21.3,
21.2, 17.9, 17.7, -4.0, -4.4 (x2), -4.5. Anal. Calcd for
C51H70Br2O16Si2: C, 53.00; H, 6.10. Found: C, 53.16; H, 5.80.
iso-Propyl 2-O-Acetyl-6-O-{2-O-acetyl-4,6-bis-O-(4-bromoben-
zoyl)-3-O-[tert-butyl(dimethyl)silyl]-ꢀ-D-glucopyranosyl}-3-O-[tert-
butyl(dimethyl)silyl]-4-O-(4-methoxybenzyl)-ꢀ-D-glucopyrano-
side (12). Following the general procedure, 123 mg (0.12 mmol)
of compound 9 was treated with 1 mL of iso-propanol to lead, after
column chromatography (n-hexane/EtOAc, 9:1), to 109 mg of
compound 12 (0.09 mmol) in 77% yield: TLC Rf ) 0.6 (n-hexane/
EtOAc, 7:3); mp ) 176.8-178.1 °C; [R]D ) +6.3 (c 0.8, CHCl3);
MS (FAB) Calcd for C53H74Br2O16Si2Na (M + Na)+ 1205, Found
1
1062; H NMR (CDCl3) δ 7.82 (d, J ) 8.4 Hz, 2H), 7.78 (d, J )
8.4 Hz, 2H), 7.54 (d, J ) 8.4 Hz, 2H), 7.49 (d, J ) 8.4 Hz, 2H),
7.25 (d, J ) 8.4 Hz, 2H), 6.88 (d, J ) 8.4 Hz, 2H), 6.30 (d, J )
6.2 Hz, 1H), 5.34 (t, J ) 9.3 Hz, 1H), 5.03 (t, J ) 8.5 Hz, 1H),
4.71 (d, J ) 11.3 Hz, 1H), 4.67 (dd, J ) 3.3 and 6.2 Hz, 1H), 4.57
(d, J ) 11.3 Hz, 1H), 4.49 (d, J ) 7.9 Hz, 1H), 4.44 (dd, J ) 3.5
and 12.1 Hz, 1H), 4.34 (dd, J ) 4.7 and 12.1 Hz, 1H), 4.21 (t, J
) 3.3 Hz, 1H), 4.10 (m, 1H), 4.03–3.96 (m, 2H), 3.85–3.80 (m,
2H), 3.80 (s, 3H), 3.49 (br t, J ) 9.0 Hz, 1H), 2.09 (s, 3H), 0.87
(s, 9H), 0.72 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H), 0.00 (s, 3H), -0.18
(s, 3H); 13C NMR (CDCl3) δ 169.3, 165.5, 164.3, 159.4, 143.0,
131.8–128.4, 113.9 (x2), 103.0, 101.7, 76.1, 76.0, 73.6, 72.9, 72.8,
72.4, 71.7, 68.3, 67.3, 63.7, 55.3, 25.8 (x3), 25.5 (x3), 21.2, 17.9,
17.8, -4.3 (x2), -4.5, -4.6. Anal. Calcd for C48H64Br2O13Si2: C,
54.13; H, 6.06. Found: C, 54.11; H, 6.20.
1
1205; H NMR (CDCl3) δ 7.82 (d, J ) 8.5 Hz, 2H), 7.76 (d, J )
8.5 Hz, 2H), 7.54 (d, J ) 8.5 Hz, 2H), 7.47 (d, J ) 8.5 Hz, 2H),
7.20 (d, J ) 8.6 Hz, 2H), 6.83 (d, J ) 8.6 Hz, 2H), 5.34 (t, J ) 9.3
Hz, 1H), 5.02 (t, J ) 8.5 Hz, 1H), 4.79 (t, J ) 9.0 Hz, 1H), 4.69
(d, J ) 10.9 Hz, 1H), 4.58 (d, J ) 8.0 Hz, 1H), 4.43 (dd, J ) 3.6
and 12.1 Hz, 1H), 4.40 (d, J ) 11.0 Hz, 1H), 4.32 (dd, J ) 4.8
and 12.1 Hz, 1H), 4.30 (d, J ) 7.9 Hz, 1H), 4.01 (dd, J ) 1.3 and
10.5 Hz, 1H), 3.94 (t, J ) 9.0 Hz, 1H), 3.91 (m, 1H), 3.81 (m,
1H), 3.77 (s, 3H), 3.73 (t, J ) 9.0 Hz, 1H), 3.53 (dd, J ) 7.6 and
10.5 Hz, 1H), 3.47 (m, 1H), 3.20 (t, J ) 9.1 Hz, 1H), 2.06 (s, 3H),
2.05 (s, 3H), 1.22 (d, J ) 6.2 Hz, 3H), 1.11 (d, J ) 6.2 Hz, 3H),
0.88 (s, 9H), 0.71 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H), -0.02 (s,
3H), -0.21 (s, 3H); 13C NMR (CDCl3) δ 169.3, 169.0, 165.4, 164.3,
159.3, 131.8–128.4, 113.8 (x2), 100.8, 99.8, 78.9, 75.2 (x2), 74.7,
74.0, 73.4, 73.0, 72.3, 72.2, 71.7, 67.7, 63.6, 55.3, 25.8 (x3), 25.4
1,2-Di-O-acetyl-6-O-{2-O-acetyl-4,6-bis-O-(4-bromobenzoyl)-3-
O-[tert-butyl(dimethyl)silyl]-ꢀ-D-glucopyranosyl}-3-O-[tert-butyl(di-
methyl)silyl]-4-O-(4-methoxybenzyl)-ꢀ-D-glucopyranose (10). Fol-
lowing the general procedure for preparation of disaccharides, 130
mg (0.12 mmol) of compound 9 was treated with 500 µL of water,
giving compound 10 (127 mg, 0.11 mmol) as a mixture R:ꢀ ) 2:1
J. Org. Chem. Vol. 73, No. 9, 2008 3359

Roën et al.
(x3), 23.5, 22.0, 21.2 (x2), 17.9, 17.7, -4.1, -4.4, -4.5 (x2). Anal.
Calcd for C53H74Br2O16Si2: C, 53.81; H, 6.30. Found: C, 53.82; H,
6.41.
°C; [R]D ) -12.3 (c 0.3, CHCl3); MS (FAB) Calcd for
C60H86Br2O16Si2Na (M + Na)+ 1278, Found 1278; 1H NMR
(CDCl3) δ 7.81 (d, J ) 8.8 Hz, 2H), 7.79 (d, J ) 8.8 Hz, 2H),
7.54 (d, J ) 8.5 Hz, 2H), 7.50 (d, J ) 8.5 Hz, 2H), 7.20 (d, J )
8.6 Hz, 2H), 6.84 (d, J ) 8.5 Hz, 2H), 5.33 (t, J ) 9.3 Hz, 1H),
5.00 (d, J ) 8.5 Hz, 1H), 4.78 (d, J ) 8.7 Hz, 1H), 4.70 (d, J )
10.9 Hz, 1H), 4.61 (d, J ) 7.9 Hz, 1H), 4.43 (dd, J ) 3.6 and 12.1
Hz, 1H), 4.40 (d, J ) 10.9 Hz, 1H), 4.34 (d, J ) 8.0 Hz, 1H), 4.29
(dd, J ) 4.9 and 12.1 Hz, 1H), 3.96 (dd, J ) 1.3 and 11.8 Hz,
1H), 3.93 (t, J ) 8.9 Hz, 1H), 3.76 (s, 3H), 3.75 (m, 1H), 3.71 (t,
J ) 8.9 Hz, 1H), 3.62 (dd, J ) 6.7 and 11.8 Hz, 1H), 3.40 (m,
2H), 3.26 (t, J ) 9.2 Hz, 1H), 2.25 (m, 1H), 2.06 (s, 3H), 2.05 (s,
3H), 1.97 (m, 1H), 1.63 (m, 3H), 1.26 (m, 2H), 0.92 (m, 6H), 0.87
(s, 9H), 0.81 (d, J ) 6.8 Hz, 3H), 0.72 (s, 9H), 0.04 (s, 6H), -0.02
(s, 3H), -0.20 (s, 3H); 13C NMR (CDCl3) δ 169.2, 168.9, 165.3,
164.3, 159.2, 131.8–128.2, 113.8 (x2), 101.1, 97.9, 78.9, 77.0, 75.6,
75.2, 74.7, 74.1, 73.8, 73.0, 72.3, 71.6, 68.4, 63.5, 55.2, 47.7, 40.5,
34.3, 31.4, 25.7 (x3), 25.4 (x3), 25.2, 23.3, 22.3, 21.3 (x2), 21.0
(x2), 17.8, 17.7, 16.4, -4.1, -4.3, -4.5 (x2). Anal. Calcd for
C60H86Br2O16Si2: C, 56.30; H, 6.80. Found: C, 56.38; H, 6.81.
tert-Butyl 2-O-Acetyl-6-O-{2-O-acetyl-4,6-bis-O-(4-bromoben-
zoyl)-3-O-[tert-butyl(dimethyl)silyl]-ꢀ-D-glucopyranosyl}-3-O-
[tert-butyl(dimethyl)silyl]-4-O-(4-methoxybenzyl)-ꢀ-D-glucopy-
ranoside (16). Following the general procedure, 151 mg (0.14
mmol) of compound 9 was treated with 1 mL of tert-butanol to
give, after column chromatography (n-hexane/EtOAc, 9:1), 84 mg
(0.07 mmol) of compound 16 in a 56% yield as an anomer mixture
(ꢀ/R ) 1.4:1): TLC Rf ) 0.5 (n-hexane/EtOAc, 7.5:2.5); colorless
syrup; [R]D ) +7.2 (c 0.4, CHCl3); MS (FAB) Calcd for
C54H76Br2O16Si2Na (M + Na)+ 1219, Found 1219; 1H NMR
(CDCl3) δ 7.82 (d, J ) 8.6 Hz, 2H), 7.75 (d, J ) 8.5 Hz, 2H),
7.54 (d, J ) 8.6 Hz, 2H), 7.48 (d, J ) 8.5 Hz, 2H), 7.18 (d, J )
8.6 Hz, 2H), 6.82 (d, J ) 8.6 Hz, 2H), 5.33 (t, J ) 9.3 Hz, 1H),
5.01 (t, J ) 8.5 Hz, 1H), 4.78 (dd, J ) 8.2 and 9.1 Hz, 1H), 4.68
(d, J ) 10.9 Hz, 1H), 4.55 (d, J ) 8.0 Hz, 1H), 4.43 (d, J ) 7.9
Hz, 1H), 4.40 (d, J ) 10.9 Hz, 1H), 4.41 (dd, J ) 3.2 and 12.1 Hz,
1H), 4.32 (dd, J ) 4.8 and 12.1 Hz, 1H), 3.98 (dd, J ) 1.0 and 9.6
Hz, 1H), 3.93 (t, J ) 8.9 Hz, 1H), 3.81 (m, 1H), 3.76 (s, 3H), 3.74
(t, J ) 9.0 Hz, 1H), 3.52 (dd, J ) 7.5 and 10.7 Hz, 1H), 3.47 (m,
1H), 3.18 (t, J ) 9.1 Hz, 1H), 2.06 (s, 6H), 1.21 (s, 9H), 0.90 (s,
9H), 0.71 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H), -0.02 (s, 3H), -0.21
(s, 3H); 13C NMR (CDCl3) δ 168.9 (x2), 165.4, 164.4, 159.3,
131.8–128.4, 113.8 (x2), 100.8, 95.5, 78.7, 75.7, 75.3, 75.0, 74.7,
74.1, 73.3, 73.1, 71.7, 67.6, 63.6, 55.3, 28.7 (x3), 25.8 (x3), 25.4
(x3), 21.4 (x2), 17.7 (x2), -4.0, -4.2, -4.4 (x2). Anal. Calcd for
C54H76Br2O16Si2: C, 54.20; H, 6.40. Found: C, 54.34; H, 6.17.
Methyl 2-O-Acetyl-6-O-{2-O-acetyl-4,6-bis-O-(4-bromoben-
zoyl)-3-O-[tert-butyl(dimethyl)silyl]-ꢀ-D-glucopyranosyl}-3-O-
[tert-butyl(dimethyl)silyl]-ꢀ-D-glucopyranoside (17). Following
the general procedure for debenzylation, 82.3 mg (0.07 mmol) of
compound 11 yielded 67.8 mg (0.06 mmol) of compound 17 (91%):
TLC Rf ) 0.3 (n-hexane/EtOAc, 7:3); mp ) 82.0-82.7 °C; [R]D
) +1.0 (c 1.0, CHCl3); MS (FAB) Calcd for C43H63Br2O15Si2 (M
+ 1)+ 1057, Found 1057; 1H NMR (CDCl3) δ 7.83 (d, J ) 8.5 Hz,
4H), 7.55 (d, J ) 8.3 Hz, 2H), 7.53 (d, J ) 8.3 Hz, 2H), 5.36 (t,
J ) 9.4 Hz, 1H), 5.03 (dd, J ) 8.2 and 8.8 Hz, 1H), 4.80 (dd, J )
8.3 and 9.1 Hz, 1H), 4.61 (d, J ) 8.0 Hz, 1H), 4.50 (dd, J ) 3.4
and 12.2 Hz, 1H), 4.35 (dd, J ) 4.6 and 12.2 Hz, 1H), 4.21 (d, J
) 8.0 Hz, 1H), 4.09 (dd, J ) 2.2 and 10.8 Hz, 1H), 4.00 (t, J )
9.0 Hz, 1H), 3.88 (m, 1H), 3.77 (m, 1H), 3.61 (t, J ) 9.1 Hz, 1H),
3.46 (s, 3H), 3.46–3.42 (m, 2H), 2.43 (s, 1H), 2.10 (s, 3H), 2.09
(s, 3H), 0.85 (s, 9H), 0.71 (s, 9H), 0.09 (s, 3H), 0.05 (s, 3H), -0.01
(s, 3H), -0.20 (s, 3H); 13C NMR (CDCl3) δ 169.5, 169.3, 165.5,
164.3, 131.9–128.4, 101.9, 101.1, 75.8, 74.4, 73.5, 73.4, 73.0, 72.4,
72.0, 71.9, 68.8, 63.2, 56.7, 25.7 (x3), 25.4 (x3), 21.3 (x2), 18.0,
17.7, -4.2, -4.5 (x2), -4.7. Anal. Calcd for C43H62Br2O15Si2: C,
49.90; H, 6.04. Found: C, 49.99; H, 6.00.
Cyclohexyl 2-O-Acetyl-6-O-{2-O-acetyl-4,6-bis-O-(4-bromoben-
zoyl)-3-O-[tert-butyl(dimethyl)silyl]-ꢀ-D-glucopyranosyl}-3-O-
[tert-butyl(dimethyl)silyl]-4-O-(4-methoxybenzyl)-ꢀ-D-glucopy-
ranoside (13). Following the general procedure for disaccharides,
140 mg (0.13 mmol) of compound 9 was treated with 1 mL of
cyclohexanol to lead, after column chromatography (n-hexane/
EtOAc, 9:1), to 96 mg of compound 13 (0.08 mmol) in a 60%
yield: TLC Rf ) 0.6 (n-hexane/EtOAc, 7:3); mp ) 172.4-174.3
°C; [R]D ) +3.5 (c 1.1, CHCl3); MS (FAB) Calcd for
C56H78Br2O16Si2Na (M + Na)+: 1245. Found 1245; 1H NMR
(CDCl3) δ 7.82 (d, J ) 8.6 Hz, 2H), 7.76 (d, J ) 8.5 Hz, 2H),
7.54 (d, J ) 8.6 Hz, 2H), 7.48 (d, J ) 8.5 Hz, 2H), 7.19 (d, J )
8.6 Hz, 2H), 6.82 (d, J ) 8.6 Hz, 2H), 5.33 (t, J ) 9.3 Hz, 1H),
5.01 (t, J ) 8.6 Hz, 1H), 4.81 (dd, J ) 8.1 and 9.3 Hz, 1H), 4.69
(d, J ) 10.9 Hz, 1H), 4.58 (d, J ) 8.0 Hz, 1H), 4.43 (dd, J ) 3.6
and 12.1 Hz, 1H), 4.40 (d, J ) 11.1 Hz, 1H), 4.35 (d, J ) 8.1 Hz,
1H), 4.33 (dd, J ) 4.7 and 12.1 Hz, 1H), 3.99 (dd, J ) 1.6 and
11.0 Hz, 1H), 3.94 (t, J ) 8.9 Hz, 1H), 3.80 (m, 1H), 3.77 (s, 3H),
3.73 (t, J ) 9.0 Hz, 1H), 3.62 (m, 1H), 3.55 (dd, J ) 7.5 and 11.0
Hz, 1H), 3.46 (m, 1H), 3.21 (t, J ) 9.2 Hz, 1H), 2.07 (s, 3H), 2.06
(s, 3H), 1.90–1.20 (m, 10H), 0.88 (s, 9H), 0.71 (s, 9H), 0.05 (s,
3H), 0.04 (s, 3H), -0.02 (s, 3H), -0.20 (s, 3H); 13C NMR (CDCl3)
δ 169.2 (s), 169.0 (s), 165.4, 164.3, 159.3, 131.8–128.4, 113.8 (x2),
100.8, 99.4, 78.9, 77.0, 75.3, 75.1, 74.7, 74.0, 73.4, 73.0, 72.3, 71.7,
67.5, 63.6, 55.2, 33.4, 31.5, 29.7, 25.8 (x3), 25.5, 25.4 (x3), 23.7,
23.4, 21.3, 21.2, 17.9, 17.7, -4.0, -4.4 (x2), -4.5. Anal. Calcd
for C56H78Br2O16Si2: C, 53.99; H, 6.43. Found: C, 53.83; H, 6.58.
(+)-Menthyl 2-O-Acetyl-6-O-{2-O-acetyl-4,6-bis-O-(4-bro-
mobenzoyl)-3-O-[tert-butyl(dimethyl)silyl]-ꢀ-D-glucopyranosyl}-
3-O-[tert-butyl(dimethyl)silyl]-4-O-(4-methoxybenzyl)-ꢀ-D-glu-
copyranoside (14). Following the general procedure, 136 mg (0.13
mmol) of compound 9 was treated with 100 mg of (+)-menthol
(0.64 mmol, 5 equiv) to provide, after column chromatography (n-
hexane/EtOAc, 9.5:0.5), 65 mg of compound 14 (0.05 mmol) in
40% yield as an anomer mixture (ꢀ/R ) 1.2:1): TLC Rf ) 0.6 (n-
hexane/EtOAc, 7:3); mp ) 173.1-174.9 °C; [R]D ) +11.0 (c 0.5,
CHCl3); MS (FAB) Calcd for C60H86Br2O16Si2Na (M + Na)+ 1278,
1
Found 1278; H NMR (CDCl3) δ 7.80 (d, J ) 8.7 Hz, 2H), 7.78
(d, J ) 8.5 Hz, 2H), 7.54 (d, J ) 8.5 Hz, 2H), 7.50 (d, J ) 8.5 Hz,
2H), 7.19 (d, J ) 8.5 Hz, 2H), 6.83 (d, J ) 8.6 Hz, 2H), 5.34 (t,
J ) 9.3 Hz, 1H), 5.02 (d, J ) 8.5 Hz, 1H), 4.84 (d, J ) 8.6 Hz,
1H), 4.67 (d, J ) 10.9 Hz, 1H), 4.66 (d, J ) 7.8 Hz, 1H), 4.44 (d,
J ) 10.9 Hz, 1H), 4.43 (dd, J ) 3.6 and 12.2 Hz, 1H), 4.31 (d, J
) 7.8 Hz, 1H), 4.29 (dd, J ) 4.9 and 12.2 Hz, 1H), 3.94 (t, J )
8.9 Hz, 1H), 3.91 (dd, J ) 1.0 and 11.6 Hz, 1H), 3.79 (m, 1H),
3.77 (s, 3H), 3.69 (t, J ) 9.0 Hz, 1H), 3.67 (dd, J ) 6.8 and 11.6
Hz, 1H), 3.45 (m, 1H), 3.25 (m, 1H), 3.22 (t, J ) 9.2 Hz, 1H),
2.11 (m, 1H), 2.09 (s, 3H), 2.07 (m, 1H), 2.05 (s, 3H), 1.61 (m,
2H), 1.25 (m, 1H), 1.11 (m, 1H), 0.97 (d, J ) 6.5 Hz, 3H), 0.90
(d, J ) 6.5 Hz, 3H), 0.88 (s, 9H), 0.75 (d, J ) 6.9 Hz, 3H), 0.71
(s, 9H), 0.04 (s, 3H), 0.04 (s, 3H), -0.02 (s, 3H), -0.22 (s, 3H);
13C NMR (CDCl3) δ 169.2, 168.9, 165.3, 164.3, 159.2, 131.8–128.3,
113.8 (x2), 102.0, 100.8, 80.8, 78.8, 75.7, 75.1, 74.7, 74.3, 73.6,
73.1, 72.3, 71.7, 67.2, 63.5, 55.2, 48.5, 43.3, 34.1, 31.9, 25.7 (x3),
25.3 (x3), 24.6, 22.7, 22.5, 21.4, 21.3 (x2), 17.8, 17.7, 14.0, -4.1,
-4.4, -4.5, -4.6. Anal. Calcd for C60H86Br2O16Si2: C, 56.30; H,
6.80. Found: C, 56.27; H, 7.01.
(-)-Menthyl 2-O-Acetyl-6-O-{2-O-acetyl-4,6-bis-O-(4-bro-
mobenzoyl)-3-O-[tert-butyl(dimethyl)silyl]-ꢀ-D-glucopyranosyl}-
3-O-[tert-butyl(dimethyl)silyl]-4-O-(4-methoxybenzyl)-ꢀ-D-glu-
copyranoside (15). Following the general procedure for preparation
of disaccharides, 140 mg (0.13 mmol) of compound 9 was treated
with 100 mg of (-)-menthol (0.64 mmol, 5 equiv) to give, after
column chromatography (n-hexane/EtOAc, 9.5:0.5), 87 mg (0.07
mmol) of compound 15 in 52% yield as an anomer mixture (ꢀ/R
) 1.5:1): TLC Rf ) 0.5 (n-hexane/EtOAc, 8:2); mp ) 171.3-173.6
iso-Propyl 2-O-Acetyl-6-O-{2-O-acetyl-4,6-bis-O-(4-bromoben-
zoyl)-3-O-[tert-butyl(dimethyl)silyl]-ꢀ-D-glucopyranosyl}-3-O-
3360 J. Org. Chem. Vol. 73, No. 9, 2008

Conformational Domino Effect in Saccharides
[tert-butyl(dimethyl)silyl]-ꢀ-D-glucopyranoside (18). Following
the general procedure for debenzylation, 70.0 mg (0.06 mmol) of
compound 12 yielded 54.0 mg (0.05 mmol) of compound 18 (86%):
TLC Rf ) 0.4 (n-hexane/EtOAc, 7:3); mp ) 82.1-83.8 °C; [R]D
) -2.4 (c 1.1, CHCl3); MS (FAB) Calcd for C45H66Br2O15Si2Na
tert-Butyl 2-O-Acetyl-6-O-{2-O-acetyl-4,6-bis-O-(4-bromoben-
zoyl)-3-O-[tert-butyl(dimethyl)silyl]-ꢀ-D-glucopyranosyl}-3-O-
[tert-butyl(dimethyl)silyl]-ꢀ-D-glucopyranoside (21). Following
the general procedure for debenzylation, 143 mg (0.12 mmol) of
compound 16 yielded 113 mg (0.11 mmol) of compound 21 (88%):
TLC Rf ) 0.4 (n-hexane/EtOAc, 7:3); colorless syrup; [R]D ) +7.7
(c 0.7, CHCl3); MS (FAB) Calcd for C46H68Br2O15Si2Na (M + Na)+
1099, Found 1099; 1H NMR (CDCl3) δ 7.84 (d, J ) 8.5 Hz, 4H),
7.56 (d, J ) 8.5 Hz, 2H), 7.54 (d, J ) 8.5 Hz, 2H), 5.34 (t, J ) 9.4
Hz, 1H), 5.01 (dd, J ) 8.0 and 9.0 Hz, 1H), 4.75 (dd, J ) 8.0 and
9.3 Hz, 1H), 4.59 (d, J ) 8.0 Hz, 1H), 4.50 (dd, J ) 3.3 and 12.1
Hz, 1H), 4.44 (d, J ) 8.0 Hz, 1H), 4.32 (dd, J ) 5.0 and 12.1 Hz,
1H), 4.05 (dd, J ) 3.1 and 11.0 Hz, 1H), 3.98 (t, J ) 9.0 Hz, 1H),
3.86 (m, 1H), 3.76 (dd, J ) 6.1 and 11.0 Hz, 1H), 3.61 (dd, J )
8.2 and 9.3 Hz, 1H), 3.42 (m, 2H), 2.40 (d, J ) 3.4 Hz, 1H), 2.09
(s, 3H), 2.05 (s, 3H), 1.20 (s, 9H), 0.85 (s, 9H), 0.71 (s, 9H), 0.09
(s, 3H), 0.05 (s, 3H), -0.01 (s, 3H), -0.20 (s, 3H); 13C NMR
(CDCl3) δ 169.2, 169.1, 165.5, 164.4, 131.9–128.3, 100.9, 95.6,
77.2, 76.0, 75.8, 74.3, 73.7, 73.5, 73.0, 72.6, 72.1, 71.9, 69.1, 63.3,
28.6 (x3), 25.7 (x3), 25.4 (x3), 21.3 (x2), 18.1, 17.7, -4.3, -4.5
(x2), -4.7. Anal. Calcd for C46H68Br2O15Si2: C, 51.30; H, 6.36.
Found: C, 51.51; H, 6.00.
Methyl 6-O-[4,6-Bis-O-(4-bromobenzoyl)-ꢀ-D-glucopyrano-
syl]-ꢀ-D-glucopyranoside (22). Following the general procedure
for desilylation and deacetylation, 50.0 mg (0.05 mmol) of
compound 17 yielded 27.1 mg (0.04 mmol) of compound 22 (77%):
TLC Rf ) 0.2 (CH2Cl2/MeOH, 9:1); mp ) 151.3-153.6 °C; [R]D
) +7.0 (c 0.5, CHCl3); MS (FAB) Calcd for C27H30Br2O13Na (M
+ Na)+ 745, Found 745; 1H NMR (DMSO) δ 7.89 (d, J ) 8.5 Hz,
2H), 7.85 (d, J ) 8.6 Hz, 2H), 7.75 (d, J ) 8.5 Hz, 2H), 7.73 (d,
J ) 8.6 Hz, 2H), 5.50 (d, J ) 5.7 Hz, 1H), 5.37 (d, J ) 5.0 Hz,
1H), 5.11 (d, J ) 4.9 Hz, 1H), 5.08 (d, J ) 5.4 Hz, 1H), 5.06 (d,
J ) 5.6 Hz, 1H), 5.03 (t, J ) 9.6 Hz, H-4′), 4.53 (d, J ) 7.8 Hz,
1H), 4.40 (dd, J ) 3.1 and 12.1 Hz, H-6′proS), 4.33 (dd, J ) 4.7
and 12.1 Hz, H-6′proR), 4.07 (d, J ) 7.8 Hz, H-1), 4.05 (br d, J )
10.5 Hz, H-6proS), 3.96 (m, H-5′), 3.65 (dd, J ) 6.8 and 11.5 Hz,
H-6proR), 3.63 (dd, J ) 5.8 and 9.2 Hz, H-3′), 3.42 (s, 3H), 3.35
(m, H-5), 3.22 (m, H-2′), 3.18 (m, H-3), 3.10 (m, H-4), 3.00 (m,
H-2); 13C NMR (DMSO) δ 165.1, 164.8, 132.2–127.8, 104.2, 103.9,
76.9, 75.9, 74.1, 73.9, 73.7, 72.6, 71.0, 70.4, 69.4, 63.9, 56.4; UV
(EtOH)λmax 245 nm; CD (EtOH) λ(∆ε) 251 (13.3), 234 nm (-4.2).
Anal. Calcd for C27H30Br2O13: C, 44.90; H, 4.19. Found: C, 44.90;
H, 4.62.
iso-Propyl 6-O-[4,6-Bis-O-(4-bromobenzoyl)-ꢀ-D-glucopyra-
nosyl]-ꢀ-D-glucopyranoside (23). Following the general procedure
for desilylation and deacetylation, 63.7 mg (0.06 mmol) of
compound 18 yielded 24.6 mg (0.03 mmol) of compound 23 (54%):
TLC Rf ) 0.2 (CH2Cl2/MeOH, 9:1); mp ) 153.1-154.9 °C; [R]D
) +15.6 (c 0.7, CHCl3); MS (FAB) Calcd for C29H34Br2O13Na
(M + Na)+ 773, Found 773; 1H NMR (DMSO) δ 7.89 (d, J ) 8.4
Hz, 2H), 7.85 (d, J ) 8.5 Hz, 2H), 7.76 (d, J ) 8.6 Hz, 2H), 7.73
(d, J ) 8.4 Hz, 2H), 5.52 (d, J ) 5.6 Hz, 1H), 5.36 (d, J ) 5.0 Hz,
1H), 5.04 (m, 2H), 5.02 (t, J ) 9.5 Hz, H-4′), 4.95 (d, J ) 5.0 Hz,
1H), 4.53 (d, J ) 7.9 Hz, H-1′), 4.40 (dd, J ) 2.9 and 12.0 Hz,
H-6′proS), 4.32 (dd, J ) 4.7 and 12.0 Hz, H-6′proR), 4.20 (d, J ) 7.8
Hz, H-1), 4.02 (br d, J ) 11.1 Hz, H-6proS), 3.96–3.91 (m, 2H),
3.66 (dd, J ) 7.0 and 11.6 Hz, H-6proR), 3.61 (m, H-3′), 3.38 (m,
H-5), 3.24–3.15 (m, H-2′, H-3), 3.08 (m, H-4), 2.95 (m, H-2), 1.16
(d, J ) 6.2 Hz, 3H), 1.11 (d, J ) 6.2 Hz, 3H); 13C NMR (DMSO)
δ 165.7, 165.4, 132.8–128.4, 104.5, 102.1, 77.7, 76.4, 74.6, 74.3
(x2), 73.2, 71.6, 71.0 (x2), 70.1, 64.5, 24.5, 22.8; UV (EtOH)λmax
245 nm; CD (EtOH) λ(∆ε) 251 (13.1), 234 nm (-4.0). Anal. Calcd
for C29H34Br2O13: C, 46.42; H, 4.57. Found: C, 46.44; H, 4.65.
(+)-Menthyl 6-O-[4,6-Bis-O-(4-bromobenzoyl)-ꢀ-D-glucopy-
ranosyl]-ꢀ-D-glucopyranoside (24). Following the general proce-
dure for desilylation and deacetylation, 111 mg (0.10 mmol) of
compound 19 yielded 38 mg (0.05 mmol) of compound 24 (47%):
TLC Rf ) 0.4 (CH2Cl2/MeOH, 9:1); mp ) 154.2-155.6 °C; [R]D
) +33.0 (c 0.3, CHCl3); MS (FAB) Calcd for C36H46Br2O13Na
1
(M + Na)+ 1085, Found 1085; H NMR (CDCl3) δ 7.83 (d, J )
8.5 Hz, 4H), 7.55 (d, J ) 8.5 Hz, 2H), 7.53 (d, J ) 8.5 Hz, 2H),
5.34 (t, J ) 9.3 Hz, 1H), 5.02 (dd, J ) 8.2 and 8.8 Hz, 1H), 4.76
(dd, J ) 8.2 and 9.1 Hz, 1H), 4.62 (d, J ) 8.0 Hz, 1H), 4.50 (dd,
J ) 3.1 and 12.2 Hz, 1H), 4.34 (m, 2H), 4.08 (dd, J ) 2.9 and
11.1 Hz, 1H), 3.99 (t, J ) 9.0 Hz, 1H), 3.89 (m, 1H), 3.88 (m,
1H), 3.76 (dd, J ) 6.0 and 11.1 Hz, 1H), 3.60 (t, J ) 9.1 Hz, 1H),
3.46–3.36 (m, 2H), 2.40 (d, J ) 3.2 Hz, 1H), 2.09 (s, 3H), 2.06 (s,
3H), 1.21 (d, J ) 6.2 Hz, 3H), 1.11 (d, J ) 6.1 Hz, 3H), 0.85 (s,
9H), 0.71 (s, 9H), 0.09 (s, 3H), 0.05 (s, 3H), -0.01 (s, 3H), -0.20
(s, 3H); 13C NMR (CDCl3) δ 169.2 (x2), 165.5, 164.3, 131.9–128.3,
101.0, 99.9, 75.9, 74.5, 73.7, 73.5, 73.0, 72.5, 72.3, 72.1, 71.9, 69.0,
63.3, 25.7 (x2), 25.4 (x2), 23.4, 22.0, 21.3, 21.1, 18.0, 17.7, -4.3,
-4.5 (x2), -4.7. Anal. Calcd for C45H66Br2O15Si2: C, 50.85; H,
6.26. Found: C, 50.99; H, 6.36.
(+)-Menthyl 2-O-Acetyl-6-O-{2-O-acetyl-4,6-bis-O-(4-bro-
mobenzoyl)-3-O-[tert-butyl(dimethyl)silyl]-ꢀ-D-glucopyranosyl}-
3-O-[tert-butyl(dimethyl)silyl]-ꢀ-D-glucopyranoside (19). Fol-
lowing the general procedure for debenzylation, 162 mg (0.13
mmol) of compound 14 yielded 133 mg (0.11 mmol) of compound
19 (90%): TLC Rf ) 0.4 (n-hexane/EtOAc, 8:2); mp ) 75.8-77.4
°C; [R]D ) +10.6 (c 1.1, CHCl3); MS (FAB) Calcd for
C52H78Br2O15Si2Na (M + Na)+ 1181, Found 1181; 1H NMR
(CDCl3) δ 7.84 (d, J ) 8.6 Hz, 2H), 7.82 (d, J ) 8.6 Hz, 2H),
7.56 (d, J ) 8.5 Hz, 2H), 7.55 (d, J ) 8.5 Hz, 2H), 5.35 (t, J ) 9.4
Hz, 1H), 5.02 (t, J ) 8.5 Hz, 1H), 4.81 (t, J ) 9.2 Hz, 1H), 4.66
(d, J ) 8.0 Hz, 1H), 4.54 (dd, J ) 3.3 and 12.1 Hz, 1H), 4.34 (d,
J ) 7.9 Hz, 1H), 4.33 (dd, J ) 4.8 and 12.1 Hz, 1H), 4.02–3.97
(m, 2H), 3.88-3.84 (m, 2H), 3.60 (t, J ) 9.0 Hz, 1H), 3.45–3.37
(m, 2H), 3.24 (dt, J ) 4.3 and 10.5 Hz, 1H), 2.55 (s, 1H), 2.11 (s,
3H), 2.08 (m, 2H), 2.04 (s, 3H), 1.56 (m, 2H), 1.25 (m, 3H), 0.92
(d, J ) 6.5 Hz, 3H), 0.90 (d, J ) 6.5 Hz, 3H), 0.85 (s, 9H), 0.74
(d, J ) 6.9 Hz, 3H), 0.72 (s, 9H), 0.09 (s, 3H), 0.05 (s, 3H), -0.01
(s, 3H), -0.19 (s, 3H); 13C NMR (CDCl3) δ 169.2 (x2), 165.5,
164.3, 131.9–128.4, 102.2, 101.1, 81.5, 75.9, 74.4, 73.9, 73.7, 73.0,
72.7, 72.1, 72.0, 69.1, 63.2, 48.3, 43.2, 34.1, 31.8, 25.7 (x3), 25.4
(x3), 24.7, 22.7, 22.4, 21.3, 21.2, 21.1, 18.1, 17.7, 15.9, -4.1, -4.4,
-4.5, -4.7. Anal. Calcd for C52H78Br2O15Si2: C, 53.88; H, 6.78.
Found: C, 53.88; H, 6.92.
(-)-Menthyl 2-O-Acetyl-6-O-{2-O-acetyl-4,6-bis-O-(4-bro-
mobenzoyl)-3-O-[tert-butyl(dimethyl)silyl]-ꢀ-D-glucopyranosyl}-
3-O-[tert-butyl(dimethyl)silyl]-ꢀ-D-glucopyranoside (20). Fol-
lowing the general procedure for debenzylation, 150 mg (0.12
mmol) of compound 15 yielded 107 mg (0.09 mmol) of compound
20 (79%): TLC Rf ) 0.4 (n-hexane/EtOAc, 8:2); mp ) 76.0-77.6
°C; [R]D ) -11.7 (c 0.8, CHCl3); MS (FAB) Calcd for
C52H78Br2O15Si2Na (M + Na)+ 1181, Found 1181; 1H NMR
(CDCl3) δ 7.83 (d, J ) 8.4 Hz, 4H), 7.56 (d, J ) 8.5 Hz, 2H),
7.55 (d, J ) 8.5 Hz, 2H), 5.35 (t, J ) 9.3 Hz, 1H), 5.02 (t, J ) 8.4
Hz, 1H), 4.76 (t, J ) 9.1 Hz, 1H), 4.62 (d, J ) 7.9 Hz, 1H), 4.53
(dd, J ) 3.3 and 12.1 Hz, 1H), 4.35 (d, J ) 8.9 Hz, 1H), 4.33 (dd,
J ) 4.8 and 12.1 Hz, 1H), 3.99 (m, 2H), 3.84 (m, 1H), 3.80 (dd,
J ) 5.3 and 11.2 Hz, 1H), 3.61 (t, J ) 9.3 Hz, 1H), 3.46 (m, 1H),
3.34 (m, 2H), 2.52 (br s, 1H), 2.24 (m, 1H), 2.10 (s, 3H), 2.06 (s,
3H), 1.94 (br d, J ) 10.6 Hz, 1H), 1.59 (m, 2H), 1.26 (m, 2H),
0.91 (d, J ) 6.2 Hz, 3H), 0.86 (d, J ) 6.2 Hz, 3H), 0.85 (s, 9H),
0.74 (d, J ) 7.0 Hz, 3H), 0.72 (s, 9H), 0.09 (s, 3H), 0.05 (s, 3H),
-0.01 (s, 3H), -0.19 (s, 3H); 13C NMR (CDCl3) δ 169.2 (x2),
165.5, 164.3, 131.9–128.4, 101.1, 98.6, 77.9, 75.9, 74.4, 73.8, 73.6,
72.9, 72.7, 72.1, 72.0, 69.4, 63.3, 47.6, 40.7, 34.3, 31.5, 25.7 (x3),
25.4 (x3), 25.0, 23.2, 22.3, 21.2 (x2), 20.9, 17.8, 17.7, 16.4, -4.1,
-4.3, -4.5 (x2). Anal. Calcd for C52H78Br2O15Si2: C, 53.88; H,
6.78. Found: C, 53.88; H, 6.70.
J. Org. Chem. Vol. 73, No. 9, 2008 3361

Roën et al.
(M + Na)+ 869, Found 869; 1H NMR (DMSO) δ 7.86 (d, J ) 8.5
Hz, 2H), 7.84 (d, J ) 8.5 Hz, 2H), 7.75 (d, J ) 8.6 Hz, 2H), 7.72
(d, J ) 8.6 Hz, 2H), 7.66 (d, J ) 8.5 Hz, 2H), 5.52 (d, J ) 5.3 Hz,
1H), 5.38 (d, J ) 4.3 Hz, 1H), 5.08 (d, J ) 4.8 Hz, 1H), 5.02 (t,
J ) 9.8 Hz, H-4′), 4.98 (m, 2H), 4.59 (d, J ) 7.8 Hz, H-1′), 4.41
(dd, J ) 3.1 and 12.1 Hz, H-6′proS), 4.31 (d, J ) 4.9 and 12.1 Hz,
H-6′proR), 4.18 (d, J ) 7.7 Hz, H-1), 4.00 (br d, J ) 11.4 Hz,
H-6proS), 3.90 (m, H-5′), 3.69 (dd, J ) 7.4 and 12.1 Hz, H-6proR),
3.60 (m, H-3′), 3.42 (m, H-5), 3.36 (m, 1H), 3.21 (m, H-2′), 3.15
(br t, J ) 8.8 Hz, H-3), 3.03–2.97 (m, H-2, H-4), 2.44 (m, 1H),
2.22 (m, 1H), 1.59 (m, 2H), 1.39 (m, 1H), 1.17 (m, 2H), 0.90 (d,
J ) 6.4 Hz, 3H), 0.87 (d, J ) 7.1 Hz, 3H), 0.74 (d, J ) 6.9 Hz,
3H); 13C NMR (DMSO) δ 165.6, 165.4, 132.7–128.5, 105.1, 104.5,
80.4, 76.9, 74.7 (x2), 74.5, 73.2, 71.6, 71.2, 70.0, 64.6, 49.4, 44.4,
34.9, 32.0, 24.8, 23.4, 23.2, 22.1, 16.9; UV (EtOH)λmax 245 nm;
CD (EtOH) λ(∆ε) 251 (12.9), 234 nm (-3.9). Anal. Calcd for
C36H46Br2O13: C, 51.08; H, 5.48. Found: C, 51.06; H, 5.58.
(-)-Menthyl 6-O-[4,6-Bis-O-(4-bromobenzoyl)-ꢀ-D-glucopy-
ranosyl]-ꢀ-D-glucopyranoside (25). Following the general proce-
dure for desilylation and deacetylation, 50.0 mg (0.04 mmol) of
compound 20 yielded 19.3 mg (0.02 mmol) of compound 25 (53%):
TLC Rf ) 0.3 (CH2Cl2/MeOH, 9:1); mp ) 151.3-153.6 °C; [R]D
) -9.4 (c 0.7, CHCl3); MS (FAB) Calcd for C36H46Br2O13Na (M
+ Na)+ 869, Found 869; 1H NMR (DMSO) δ 7.88 (d, J ) 8.4 Hz,
2H), 7.84 (d, J ) 8.4 Hz, 2H), 7.76 (d, J ) 8.6 Hz, 2H), 7.73 (d,
J ) 8.4 Hz, 2H), 5.51 (d, J ) 5.4 Hz, 1H), 5.31 (d, J ) 4.3 Hz,
1H), 5.02 (m, 2H), 5.01 (t, J ) 9.5 Hz, H-4′), 4.91 (d, J ) 4.7 Hz,
1H), 4.48 (d, J ) 7.8 Hz, H-1′), 4.38 (dd, J ) 2.9 and 12.0 Hz,
H-6′proS), 4.27 (dd, J ) 4.9 and 12.0 Hz, H-6′proR), 4.23 (d, J ) 7.9
Hz, H-1), 4.01 (br d, J ) 10.9 Hz, H-6proS), 3.91 (m, H-5′), 3.68
(dd, J ) 6.6 and 11.6 Hz, H-6proR), 3.60 (m, H-3′), 3.46 (dt, J )
3.9 and 10.5 Hz, 1H), 3.35 (m, H-5), 3.22 (m, H-2′), 3.14 (m, H-3,
H-4), 2.95 (m, H-2), 2.23 (m, 1H), 2.05 (m, 1H), 1.59 (m, 2H),
1.30 (m, 2H), 1.14 (m, 1H), 0.91 (d, J ) 6.5 Hz, 3H), 0.83 (d, J )
7.2 Hz, 3H), 0.76 (d, J ) 6.8 Hz, 3H); 13C NMR (DMSO) δ 165.6,
165.3, 132.7–128.4, 104.5, 100.6, 77.8, 76.6, 76.2, 74.6, 74.4, 74.2,
73.2, 71.6, 71.1, 70.4, 64.6, 48.4, 44.4, 35.0, 31.7, 25.5, 23.6, 23.2,
21.8, 16.7; UV (EtOH)λmax 245 nm; CD (EtOH) λ(∆ε) 251 (13.0),
234 nm (-3.9). Anal. Calcd for C36H46Br2O13: C, 51.08; H, 5.48.
Found: C, 51.08; H, 5.49.
was completed, it was diluted with CH2Cl2 and washed with a
saturated NaHCO3 solution. The aqueous layer was extracted with
CH2Cl2 (2 times). The combined extracts were dried over MgSO4,
filtered, and concentrated. Flash chromatography of the residue (n-
hexane/CHCl3/MeOH, 2:1:1), led to 27 (10.8 mg, 0.02 mmol) in
78% yield: TLC Rf ) 0.2 (CH2Cl2/MeOH, 9:1); colorless syrup;
[R]D ) +15.8 (c 0.8, CHCl3); MS (FAB) Calcd for C30H36Br2O13Na
(M + Na)+ 787, Found 787; 1H NMR (DMSO) δ 7.89 (d, J ) 8.6
Hz, 2H), 7.85 (d, J ) 8.6 Hz, 2H), 7.75 (d, J ) 8.7 Hz, 2H), 7.73
(d, J ) 8.7 Hz, 2H), 5.50 (br d, J ) 5.6 Hz, 1H), 5.29 (br d, J )
5.0 Hz, 1H), 5.03 (br d, J ) 4.6 Hz, H-4′), 4.97 (br d, J ) 4.5 Hz,
1H), 4.79 (br d, J ) 4.6 Hz, 1H), 4.51 (d, J ) 7.8 Hz, H-1′), 4.41
(dd, J ) 3.0 and 12.0 Hz, H-6′proS), 4.31 (dd, J ) 5.1 and 12.0 Hz,
H-6′proR), 4.29 (d, J ) 7.8 Hz, H-1), 3.97 (br d, J ) 10.5 Hz,
H-6proS), 3.94 (m, H-5′), 3.65 (dd, J ) 7.2 and 11.6 Hz, H-6proR),
3.64 (m, H-3′), 3.38 (m, H-5), 3.22–3.15 (m, H-3, H-2′), 3.07 (m,
H-4), 2.92 (m, H-2), 1.20 (s, 9H); 13C NMR (DMSO) δ 165.2,
164.9, 132.3–127.9, 105.9, 97.7, 77.3, 75.6, 74.9, 74.1, 74.0, 73.9,
72.7, 71.1, 70.6, 69.8, 64.0, 29.0 (x3); UV (EtOH)λmax 245 nm;
CD (EtOH) λ(∆ε) 251 (12.8), 234 nm (-3.9). Anal. Calcd for
C30H36Br2O13: C, 47.14; H, 4.75. Found: C, 47.17; H, 4.53.
Methyl 2,3,4-Tri-O-acetyl-6-O-[2,3-di-O-acetyl-4,6-bis-O-(4-
bromobenzoyl)-ꢀ-D-glucopyranosyl]-ꢀ-D-glucopyranoside (28).
Compound 22 (45.0 mg, 0.06 mmol) was dissolved in 1 mL of a
1:1 dry pyridine/acetic anhydride solution. Excess solvent was
removed under reduced pressure to give, after column chromatog-
raphy (n-hexane/EtOAc, 8:2), compound 28 (50.1 mg, 0.05 mmol)
in 90% yield: TLC Rf ) 0.3 (n-hexane/EtOAc, 1:1); mp )
199.2-204.6 °C (decomp.); [R]D ) +8.2 (c 1.7, CHCl3); MS (FAB)
1
Calcd for C37H40Br2O18Na (M + Na)+ 955, Found 955; H NMR
(CDCl3) δ 7.83 (d, J ) 8.5 Hz, 2H), 7.78 (d, J ) 8.5 Hz, 2H),
7.55 (d, J ) 8.5 Hz, 4H), 5.43–5.38 (m, H-3′, H-4′), 5.19 (t, J )
9.5 Hz, H-3), 5.08 (t, J ) 7.9 Hz, H-2′), 4.93 (dd, J ) 8.0 and 9.5
Hz, H-2), 4.88 (t, J ) 9.5 Hz, H-4), 4.70 (d, J ) 7.9 Hz, H-1′),
4.53 (dd, J ) 3.2 and 12.2 Hz, H-6′proS), 4.39 (d, J ) 8.0 Hz, H-1),
4.38 (dd, J ) 4.9 and 12.2 Hz, H-6′proR), 3.96 (m, H-5′), 3.89 (dd,
J ) 1.8 and 10.8 Hz, H-6proS), 3.69 (m, H-5), 3.63 (dd, J ) 7.4
and 10.8 Hz, H-6proR), 3.51 (s, 3H), 2.06 (s, 3H), 2.04 (s, 3H), 1.99
(s, 3H), 1.98 (s, 3H), 1.90 (s, 3H); 13C NMR (CDCl3) δ 170.2,
170.1, 169.6, 169.4, 169.3, 165.3, 164.4, 132.0–127.5, 101.5, 101.0,
73.3, 72.8, 72.4, 71.8, 71.3, 71.2, 69.7, 69.2, 68.3, 63.0, 57.0, 20.7,
20.6 (x3), 20.5. Anal. Calcd for C37H40Br2O18: C, 47.66; H, 4.32.
Found: C, 47.65; H, 4.33.
tert-Butyl 2-O-Acetyl-6-O-[2-O-acetyl-4,6-bis-O-(4-bromoben-
zoyl)-ꢀ-D-glucopyranosyl]-ꢀ-D-glucopyranoside (26). Compound
21 (40.0 mg, 0.04 mmol) was dissolved in dry acetonitrile under
an argon atmosphere at 0 °C, treated with 2.5 equiv of HF-Py, and
left at room temperature. When the reaction was completed, it was
diluted with CH2Cl2 and washed with a saturated solution of
NaHCO3. The aqueous layer was extracted with CH2Cl2 (2 times).
The combined extracts were dried over MgSO4, filtered, and
concentrated. Flash chromatography of the residue (n-hexane/
CHCl3/MeOH, 2:1:1) furnished 26 (17.1 mg, 0.02 mmol) in 54%
yield: TLC Rf ) 0.5 (CH2Cl2/MeOH, 9:1); colorless syrup; [R]D )
+3.0 (c 1.1, CHCl3); MS (FAB) Calcd for C34H40Br2O15Na (M +
iso-Propyl 2,3,4-Tri-O-acetyl-6-O-[2,3-di-O-acetyl-4,6-bis-O-(4-
bromobenzoyl)-ꢀ-D-glucopyranosyl]-ꢀ-D-glucopyranoside (29). Com-
pound 23 (20.0 mg, 0.03 mmol) was dissolved in 1 mL of a 1:1
solution of dry pyridine/acetic anhydride. Excess solvent was
removed under reduced pressure to give, after column chromatog-
raphy (n-hexane/EtOAc, 8:2), compound 29 (21.0 mg, 0.05 mmol)
in 82% yield: TLC Rf ) 0.4 (n-hexane/EtOAc, 1:1); mp )
198.9-204.0 °C (decomp.); [R]D ) -3.6 (c 1.2, CHCl3); MS (FAB)
1
Calcd for C39H44Br2O18Na (M+Na)+ 983, Found 983; H NMR
1
Na)+ 871, Found 871; H NMR (DMSO) δ 7.89 (d, J ) 8.6 Hz,
(CDCl3) δ 7.83 (d, J ) 8.4 Hz, 2H), 7.78 (d, J ) 8.4 Hz, 2H),
7.55 (d, J ) 7.8 Hz, 4H), 5.40–5.35 (m, H-3′, H-4′), 5.19 (t, J )
9.5 Hz, H-3), 5.08 (dd, J ) 7.9 and 9.5 Hz, H-2′), 4.89 (dd, J )
7.9 and 9.7 Hz, H-2), 4.85 (t, J ) 9.5 Hz, H-4), 4.71 (d, J ) 7.9
Hz, H-1′), 4.54 (dd, J ) 3.2 and 12.2 Hz, H-6′proS), 4.52 (d, J )
7.9 Hz, H-1), 4.37 (dd, J ) 5.0 and 12.2 Hz, H-6′proR), 3.94–3.89
(m, 2H), 3.85 (d, J ) 9.2 Hz, H-6proS), 3.69 (m, H-5), 3.65 (dd, J
) 7.7 and 10.6 Hz, H-6proR), 2.05 (s, 3H), 2.03 (s, 3H), 1.99 (s,
3H), 1.97 (s, 3H), 1.90 (s, 3H), 1.24 (d, J ) 6 Hz, 3H), 1.14 (d, J
) 6.0 Hz, 3H); 13C NMR (CDCl3) δ 170.2, 170.1, 169.6, 169.3,
169.2, 165.3, 164.4, 132.0–127.5, 100.8, 99.4, 73.4, 72.8, 72.7, 72.4,
71.9, 71.6, 71.2, 69.7, 69.2, 68.3, 63.0, 23.4, 21.9, 20.6 (x3), 20.5,
20.4. Anal. Calcd for C39H44Br2O18: C, 48.76; H, 4.62. Found: C,
48.74; H, 4.34.
2H), 7.85 (d, J ) 8.6 Hz, 2H), 7.75 (d, J ) 8.7 Hz, 2H), 7.73 (d,
J ) 8.7 Hz, 2H), 5.29 (t, J ) 9.5 Hz, H-4′), 4.94 (dd, J ) 7.9 and
9.3 Hz, H-2′), 4.69 (dd, J ) 7.9 and 9.3 Hz, H-2), 4.66 (d, J ) 7.6
H-1′), 4.61 (dd, J ) 3.0 and 12.1 Hz, H-6′proS), 4.53 (d, J ) 7.9
Hz, H-1), 4.39 (dd, J ) 5.1 and 12.1 Hz, H-6′proR), 4.08 (dd, J )
2.3 and 11.2 Hz, H-6proS), 3.93 (m, H-5′), 3.88 (t, J ) 9.3 Hz, H-3′),
3.78 (dd, J ) 5.8 and 10.9 Hz, H-6proR), 3.56 (t, J ) 9.2 Hz, H-3),
3.46 (m, H-5, H-4′), 2.12 (s, 3H), 2.10 (s, 3H), 1.21 (s, 9H); 13C
NMR (DMSO) δ 170.9, 170.8, 165.5, 165.3, 131.9–127.9, 100.7,
95.2, 76.1, 75.8, 74.4, 74.2, 74.1, 73.8, 72.2, 72.0, 71.8, 69.3, 63.2,
28.6 (x3), 20.9 (x2). Anal. Calcd for C34H40Br2O15: C, 48.13; H,
4.75. Found: C, 48.21; H, 5.01.
tert-Butyl 6-O-[4,6-Bis-O-(4-bromobenzoyl)-ꢀ-D-glucopyra-
nosyl]-ꢀ-D-glucopyranoside (27). Compound 26 (13.0 mg, 0.02
mmol) was dissolved in 2 mL of CH2Cl2/MeOH (9:1), and 1.5 equiv
of p-TsOH-H2O (6.0 mg, 0.03 mmol) was added. When the reaction
(+)-Menthyl 2,3,4-Tri-O-acetyl-6-O-[2,3-di-O-acetyl-4,6-bis-
O-(4-bromobenzoyl)-ꢀ-D-glucopyranosyl]-ꢀ-D-glucopyrano-
side (30). Compound 24 (10.0 mg, 0.01 mmol) was dissolved in 1
3362 J. Org. Chem. Vol. 73, No. 9, 2008

Conformational Domino Effect in Saccharides
mL of a 1:1 solution of dry pyridine/acetic anhydride. Excess
solvent was removed under reduced pressure to give, after column
chromatography (n-hexane/EtOAc, 8:2), compound 30 (12.2 mg,
0.01 mmol, 96% yield): TLC Rf ) 0.3 (n-hexane/EtOAc, 6:4); mp
) 198.2-201.9 °C (decomp.); [R]D ) +9.3 (c 0.4, CHCl3); MS
(FAB) Calcd for C46H56Br2O18Na (M + Na)+ 1077, Found 1077;
1H NMR (CDCl3) δ 7.84 (d, J ) 8.6 Hz, 2H), 7.76 (d, J ) 8.6 Hz,
2H), 7.55 (d, J ) 8.5 Hz, 2H), 7.54 (d, J ) 8.5 Hz, 2H), 5.42–5.35
(m, H-3′, H-4′), 5.17 (t, J ) 9.5 Hz, H-3), 5.05 (dd, J ) 7.9 and
9.6 Hz, H-2′), 4.94 (dd, J ) 8.0 and 9.7 Hz, H-2), 4.87 (t, J ) 9.7
Hz, H-4), 4.79 (d, J ) 7.9 Hz, H-1′), 4.55 (dd, J ) 3.3 and 12.2
Hz, H-6′proS), 4.53 (d, J ) 8.1 Hz, H-1), 4.38 (dd, J ) 4.9 and 12.2
Hz, H-6′proR), 3.94 (m, H-5′), 3.82–3.77 (m, 2H-6), 3.70 (m, H-5),
3.32 (dt, J ) 4.4 and 10.4 Hz, 1H), 2.12 (m, 1H), 2.08 (s, 3H),
2.00 (s, 3H), 1.98 (s, 3H), 1.97 (s, 3H), 1.89 (s, 3H), 1.67 (m, 1H),
1.56 (m, 2H), 1.21 (m, 2H), 1.13 (m, 1H), 0.96 (d, J ) 6.5 Hz,
3H), 0.87 (d, J ) 7.0 Hz, 3H), 0.74 (d, J ) 6.9 Hz, 3H); 13C NMR
(CDCl3) δ 170.3, 170.0, 169.5, 169.2 (x2), 165.3, 164.4, 132.0–127.5,
101.7, 100.8, 82.2, 73.7, 73.0, 72.5, 71.9 (x2), 71.4, 69.8, 69.1,
68.0, 63.1, 48.4, 43.2, 34.1, 31.6, 24.8, 22.8, 22.3, 21.1, 20.7, 20.6
(x3), 20.5, 16.0. Anal. Calcd for C46H56Br2O18: C, 52.28; H, 5.34.
Found: C, 52.26; H, 5.26.
(-)-Menthyl 2,3,4-Tri-O-acetyl-6-O-[2,3-di-O-acetyl-4,6-bis-
O-(4-bromobenzoyl)-ꢀ-D-glucopyranosyl]-ꢀ-D-glucopyrano-
side (31). Compound 25 (13.0 mg, 0.02 mmol) was dissolved in 1
mL of a 1:1 solution of dry pyridine/acetic anhydride. Excess
solvent was removed under reduced pressure to give, after column
chromatography (n-hexane/EtOAc, 8:2), compound 31 (15.1 mg,
0.02 mmol, 95% yield): TLC Rf ) 0.4 (n-hexane/EtOAc, 6:4); mp
) 192.1-195.4 °C (decomp.); [R]D ) -22.0 (c 1.4, CHCl3); MS
(FAB) Calcd for C46H56Br2O18Na (M + Na)+ 1077, Found 1077;
1H NMR (CDCl3) δ 7.83 (d, J ) 8.6 Hz, 2H), 7.77 (d, J ) 8.6 Hz,
2H), 7.55 (d, J ) 8.6 Hz, 2H), 7.54 (d, J ) 8.6 Hz, 2H), 5.38 (m,
H-3′, H-4′), 5.17 (t, J ) 9.5 Hz, H-3), 5.05 (dd, J ) 7.9 and 9.7
Hz, H-2′), 4.92 (t, J ) 9.6 Hz, H-4), 4.88 (dd, J ) 8.0 and 9.6 Hz,
H-2), 4.71 (d, J ) 7.9 Hz, H-1′), 4.56 (d, J ) 8.0 Hz, H-1), 4.52
(dd, J ) 3.3 and 12.2 Hz, H-6′proS), 4.36 (dd, J ) 4.9 and 12.2 Hz,
H-6′proR), 3.92 (m, H-5′), 3.84 (dd, J ) 1.9 and 11.0 Hz, H-6proS),
3.67 (dd, J ) 6.5 and 11.0 Hz, H-6proR), 3.64 (m, H-5), 3.40 (dt, J
) 4.1 and 10.5 Hz, 1H), 2.21 (m, 1H), 2.06 (s, 3H), 2.01 (s, 3H),
1.99 (s, 3H), 1.98 (s, 3H), 1.95 (m, 1H), 1.90 (s, 3H), 1.63 (m,
2H), 1.31 (m, 1H), 1.19 (m, 1H), 0.93 (m, 1H), 0.91 (d, J ) 6.5
Hz, 3H), 0.86 (d, J ) 7.1 Hz, 3H), 0.77 (d, J ) 6.9 Hz, 3H); 13C
NMR (CDCl3) δ 170.3, 170.0, 169.5, 169.3, 169.2, 165.3, 164.4,
132.0–127.5, 100.7, 98.0, 78.1, 73.3, 73.0, 72.5, 71.8, 71.6, 71.2,
69.7, 69.2, 68.3, 63.1, 47.6, 40.5, 34.2, 31.4, 25.1, 23.1, 22.2, 20.9,
20.7 (x2), 20.6 (x2), 20.5, 16.0. Anal. Calcd for C46H56Br2O18: C,
52.28; H, 5.34. Found: C, 52.26; H, 5.35.
tert-Butyl 2,3,4-Tri-O-acetyl-6-O-[2,3-di-O-acetyl-4,6-bis-O-(4-
bromobenzoyl)-ꢀ-D-glucopyranosyl]-ꢀ-D-glucopyranoside (32). Com-
pound 26 (16.2 mg, 0.02 mmol) was dissolved in 1 mL of a 1:1
solution of dry pyridine/acetic anhydride. Excess solvent was
removed under reduced pressure to give, after column chromatog-
raphy (n-hexane/EtOAc, 8:2), compound 32 (17.4 mg, 0.02 mmol,
89% yield): TLC Rf ) 0.4 (n-hexane/EtOAc, 1:1); mp )
195.3-200.2 °C (decomp.); [R]D ) +3.0 (c 0.6, CHCl3); MS (FAB)
1
Calcd for C40H46Br2O18 (M)+ 901, Found 901; H NMR (CDCl3)
δ 7.83 (d, J ) 8.6 Hz, 2H), 7.78 (d, J ) 8.6 Hz, 2H), 7.57 (d, J )
8.6 Hz, 2H), 7.55 (d, J ) 8.6 Hz, 2H), 5.38 (m, H-3′, H-4′), 5.19
(t, J ) 9.5 Hz, H-3), 5.05 (dd, J ) 7.9 and 9.6 Hz, H-2′), 4.88 (dd,
J ) 8.0 and 9.7 Hz, H-2), 4.83 (t, J ) 9.6 Hz, H-4), 4.69 (d, J )
7.9 Hz, H-1′), 4.62 (d, J ) 8.0 Hz, H-1), 4.54 (dd, J ) 3.2 and
12.2 Hz, H-6′proS), 4.35 (dd, J ) 5.1 and 12.2 Hz, H-6′proR), 3.93
(m, H-5′), 3.81 (dd, J ) 1.7 and 10.3 Hz, H-6proS), 3.68 (m, H-5),
3.65 (dd, J ) 7.8 and 10.3 Hz, H-6proR), 2.04 (s, 3H), 2.02 (s, 3H),
1.99 (s, 3H), 1.96 (s, 3H), 1.89 (s, 3H), 1.22 (s, 9H); 13C NMR
(CDCl3) δ 170.3, 170.1, 169.7, 169.2 (x2), 165.3, 164.4, 132.0–127.5,
100.5, 95.3, 76.5, 73.2, 73.0, 72.5, 71.8, 71.6, 71.2, 69.7, 69.2, 68.2,
63.0, 28.5 (x3), 20.7 (x2), 20.6 (x2), 20.5. Anal. Calcd for
C40H46Br2O18: C, 49.30; H, 4.76. Found: C, 49.32; H, 4.82.
Acknowledgment. This research was supported by the
Ministerio de Educación y Ciencia (Spain), through grant
CTQ2007-67532-C02-02/BQU. A.R.M. and C.M. thank Banco
Santander and the Consejería de Educación y Deportes (Gobi-
erno de Canarias), respectively, for fellowships. J.I.P. thanks
the Spanish MCYT-FSE for a Ramón y Cajal contract.
Supporting Information Available: Synthesis and charac-
terization of known compounds 5–7, Tables containing JH5,H6
and JH5′,H6′ coupling constants and calculated rotameric popula-
1
tions (%) for disaccharides 10–21 and 28–32, as well as H
and 13C NMR spectra of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO800191Z
J. Org. Chem. Vol. 73, No. 9, 2008 3363