Alkyl galactopyranosides: Rotational population dependence of the hydroxymethyl group on the aglycon and its absolute configuration and on the anomeric configuration

Article abstract of DOI:10.1021/jo981002t

The rotational populations of the hydroxymethyl group in chiral and nonchiral alkyl α- and β-galactopyranosides proved, on the basis of circular dichroism (CD) and ¹H NMR data, to be dependent on the structure of the aglycon: the population of the gt and tg rotamers increased and decreased, respectively, as the pK(a) of the bonded alcohol (aglycon) increased, while the population of the gg rotamer remained practically constant. Furthermore, low-temperature CD measurements proved that the most stable rotamer is the gt, and not the tg. In addition, a clear correlation between the rotational populations and the absolute configuration of the chiral aglycon was observed; namely, higher and smaller gt and tg populations were observed for the (S)-alkyl β-D-galactopyranosides than for their (R)- alkyl β-D-galactopyranoside counterparts, the opposite behavior being observed for the α-anomers. The results point to the exo anomeric effect as being responsible for these rotational dependencies, as well as to nonbonding interactions between the aglycon and the chromophore at C6 for those stereoisomers having in their aglycon a bulky substituent syn to the endocyclic oxygen (O5). In addition, the chemical shift differences (Δδ) of the aglyconic protons of galactosylated chiral alcohols proved to be characteristic of the absolute configuration of the bonded chiral alcohol.

Full text of DOI:10.1021/jo981002t

J . Org. Chem. 1998, 63, 8247-8258
8247
Alk yl Ga la ctop yr a n osid es: Rota tion a l P op u la tion Dep en d en ce of
th e Hyd r oxym eth yl Gr ou p on th e Aglycon a n d Its Absolu te
Con figu r a tion a n d on th e An om er ic Con figu r a tion
J uan I. Padro´n, Ezequiel Q. Morales,† and J esu´s T. Va´zquez*
Instituto Universitario de Bio-Orga´nica “Antonio Gonza´lez”, Universidad de La Laguna,
Carretera de La Esperanza 2, 38206 La Laguna, Tenerife, Spain
Received May 26, 1998
The rotational populations of the hydroxymethyl group in chiral and nonchiral alkyl R- and
â-galactopyranosides proved, on the basis of circular dichroism (CD) and 1H NMR data, to be
dependent on the structure of the aglycon: the population of the gt and tg rotamers increased and
decreased, respectively, as the pKa of the bonded alcohol (aglycon) increased, while the population
of the gg rotamer remained practically constant. Furthermore, low-temperature CD measurements
proved that the most stable rotamer is the gt, and not the tg. In addition, a clear correlation between
the rotational populations and the absolute configuration of the chiral aglycon was observed; namely,
higher and smaller gt and tg populations were observed for the (S)-alkyl â-D-galactopyranosides
than for their (R)-alkyl â-D-galactopyranoside counterparts, the opposite behavior being observed
for the R-anomers. The results point to the exo anomeric effect as being responsible for these
rotational dependencies, as well as to nonbonding interactions between the aglycon and the
chromophore at C6 for those stereoisomers having in their aglycon a bulky substituent syn to the
endocyclic oxygen (O5). In addition, the chemical shift differences (∆δ) of the aglyconic protons of
galactosylated chiral alcohols proved to be characteristic of the absolute configuration of the bonded
chiral alcohol.
In tr od u ction
A better knowledge of the conformational properties
of carbohydrates would allow a more precise and faster
determination of the overall conformation of oligosaccha-
rides and, therefore, of the interactions responsible for
their biological properties. The overall conformation of
oligosaccharides is determined by the torsion angles (φ
and Ψ) about the glycosidic linkages. In addition, when
1-6 linkages are present in the structure the torsion
angle about the C5-C6 bond (ω) has to be considered
(Figure 1).
We have recently reported, on the basis of the CD and
1H NMR spectroscopic study performed with esterified
alkyl glucopyranosides, that the rotational population of
F igu r e 1. Torsion angles φ and ψ, about the glycosidic
linkage, and torsion angle ω, around the C5-C6 bond (top).
Newman projections of the rotamers around the C5-C6 bond
(bottom).
the hydroxymethyl group depends on the aglycon and its
absolute configuration.1,2 Thus, it was observed that
independent of the anomeric configuration the population
of the gt rotamer increased as the pKa of the bonded
alcohol (aglycon) increased, while, depending on the
anomeric configuration, either the population of the gg
rotamer (â-anomers)1 or that of the tg rotamer (R-
anomers)2 decreased. Moreover, the results showed the
existence of a clear correlation between the stereoelec-
tronic exo anomeric effect and the rotamer distribution,
the endo anomeric effect not being directly involved. In
addition, a stereochemical study was performed to prove
the origin of the CD spectral differences between anomers
of alkyl glucopyranosides.3
The rotational population of the hydroxymethyl group
in galactopyranosides is without any doubt the most
controversial, thus depending on the scientists, the
population of the gt or tg rotamer is assigned as the
majority.4 As a consequence of the excellent results
1
obtained by using CD and H NMR as a tandem in the
rotational population study of alkyl glucopyranosides and
of the above-mentioned controversy, a complete spectro-
scopic study of the rotational population of the hy-
† Present address: Instituto de Investigaciones Qu´ımicas, Centro
de Investigaciones Cient´ıficas Isla de la Cartuja, c/ Americo Vespucio
s/n, 41092 Seville, Spain. E-mail: ezequiel@cica.es.
(1) Morales, E. Q.; Padro´n, J . I.; Trujillo, M.; Va´zquez, J . T. J . Org.
Chem. 1995, 60, 2537.
(3) Padro´n, J . I.; Va´zquez, J . T. Tetrahedron: Asymmetry 1998, 9,
613.
(2) Padro´n, J . I.; Va´zquez, J . T. Chirality 1997, 9, 626.
(4) Review: Bock, K.; Duus, J . J . Carbohydr. Chem 1994, 13, 513.
10.1021/jo981002t CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/29/1998

8248 J . Org. Chem., Vol. 63, No. 23, 1998
Padro´n et al.
Sch em e 1a
Sch em e 2a
a
Key: (a) AgOTf, TMU, CH2Cl2, -40 °C; (b) anhydrous FeCl3,
dry CH2Cl2.
zoyl)-R-D-galactopyranosyl bromide (5). The 2,3,4,6-
tetrakis-O-(p-bromobenzoyl)-R-D-galactopyranosyl bro-
mide 17 was prepared by per-p-bromobenzoylation of the
D-galactose and subsequent treatment of the resulting
pentakis-(p-bromobenzoyl) derivative 16, with HBr/
AcOH.
Ch a r a cter iza tion . All these compounds were char-
acterized on the basis of their spectral NMR data, one-
(1H and 13C) and two-dimensional (COSY and HMQC),
as well as UV and CD spectroscopy. The anomeric
configuration was confirmed in each case by measuring
the coupling constant between H1 and H2 (doublet) (â
a
Key: (a) PhCH(OCH3)2, p-TsOH, DMF, 50 °C-vacuum; (b)
Ac2O/Py (c) AcOH/H2O (8:2), 60 °C; (d) p-BrBzCl, Py, DMAP, 60
°C; (e) HBr/AcOH (3:7), dry CH2Cl2; (f) ROH, AgOTf, TMU, dry
CH2Cl2, -40 °C; (g) anhydrous FeCl3, dry CH2Cl2.
droxymethyl group in esterified chiral and nonchiral
alkyl R-D- and â-D-galactopyranosides was performed.
1
anomers: 7.7-7.9 Hz; R anomers: 3.5-3.8 Hz). The H
NMR signals of the prochiral protons at C6, H6R, and
H6S were differentiated on the basis of their chemical
shifts,7,8 namely, H6R signals appear at a lower field than
H6S signals.
Resu lts a n d Discu ssion
Syn th esis. All alkyl R-D-galactopyranosides, model
compounds 11-15 and 23-27, were obtained in high
yields by epimerization of the corresponding alkyl â-D-
galactopyranosides, 6-10 and 18-22, with anhydrous
ferric chloride in dry dichloromethane.5 These â-anomers
were prepared in good yields by a modified Koenigs-
Knorr method:6 by treatment of the R-D-galactopyranosyl
bromide 5 or 17 with the corresponding alcohol in the
presence of 1,1,3,3-tetramethylurea (TMU), as the proton
acceptor, and silver trifluoromethanesulfonate, as the
catalyst. All these model compounds contain two (Scheme
1) or four (Scheme 2) exciton-coupled chromophores,
namely, p-bromobenzoate esters.
The 2,3-bis-O-acetyl-4,6-bis-O-(p-bromobenzoyl)-R-D-
galactopyranosyl bromide 5 was synthesized in good yield
from D-galactose in five steps (Scheme 1). Protection of
D-galactose with benzaldehyde dimethyl acetal and p-
toluenesulfonic acid led to the 4,6-benzylidene-D-galac-
topyranoses (1, mixture of â- and R-anomers), which by
peracetylation afforded the 1,2,3-tris-O-acetyl-4,6-O-ben-
zylidene-D-galactopyranoses (2). Treatment of the ano-
mers 2 with AcOH/H2O, to remove the benzylidene
residue, and subsequent per-p-bromobenzoylation gave
1,2,3-tris-O-acetyl-4,6-bis-O-(p-bromobenzoyl)-D-galacto-
pyranoses (4). Finally, treatment of 4 with HBr/AcOH
led to the desired 2,3-bis-O-acetyl-4,6-bis-O-(p-bromoben-
13C NMR data comparison of the galactosylated non-
chiral alcohols showed from the methyl to the isopropyl
and to the tert-butyl galactopyranoside 6-8 (â-anomers)
and 11-13 (R-anomers) the following features confirming
the structure of these compounds: (i) the R-effect on the
aglyconic C1′ carbons; (ii) the γ-effect on the anomeric
carbons; and (iii) a very small shift to lower field of the
C6 carbon. On the other hand, the 13C NMR features
observed with the galactosylated chiral alcohols proved
to be dependent on the anomeric configuration. Thus,
the (R)-alkyl â-D-galactopyranosides showed chemical
shifts at a higher field for the anomeric (2-3 ppm) and
for the aglyconic carbons (2-4 ppm) than their S-alkyl
counterparts, while the opposite behavior was observed
with the R-anomers (2-5 ppm).
The model compounds exhibited the intramolecular
charge-transfer band around 245 nm in the UV spectra.
The wavelengths of the Cotton effects of the exciton CD
spectra of bis- and tetrakis-p-bromobenzoates 6-15 and
18-27, respectively, were at the correct positions, namely
around 250 and 232 nm.
Ca lcu la ted Rota m er ic P op u la tion s. Four different
sets of equations were used to calculate from the J H5,H6
coupling constants the rotamer distributions of the model
compounds 6-15 and 18-27,9 and the results were
(5) (a) Park, M. H.; Takeda, R.; Nakanishi, K. Tetrahedron Lett.
1987, 28, 3823. (b) Ikemoto, N.; Kim, O. K.; Lo, L. C.; Satyanarayana,
V.; Chang, M.; Nakanishi, K. Tetrahedron Lett. 1992, 33, 4295. (c)
Padro´n, J . I.; Va´zquez, J . T. Tetrahedron: Asymmetry 1995, 6, 857.
(6) (a) Hanessian, S.; Banoub, J . Carbohydr. Res. 1977, 53, C13.
(b) Banoub, J .; Bundle, D. R. Can. J . Chem. 1979, 57, 2091. (c) Garegg,
P. J .; Norberg, T. Acta Chem. Scand. 1979, B33, 116.
(7) Nishida, Y.; Ohrui, H.; Meguro, H. Tetrahedron Lett. 1984, 25,
1575.
(8) Ohrui, H.; Nishida, Y.; Higuchi, H.; Hori, H.; Meguro, H. Can.
J . Chem. 1987, 65, 1145.
(9) Software for the calculation of rotameric populations, by using
any of the four sets of equations mentioned in the text, is available
upon request from E.Q.M.

Alkyl Galactopyranosides
J . Org. Chem., Vol. 63, No. 23, 1998 8249
F igu r e 2. 2/6, 3/6, and 4/6 pairwise interactions involving the
chromophore at the 6 position in each of the three stable
rotamers (gg, gt, and tg) for the galactopyranosyl system.
compared with those from CD. The calculated rotameric
populations shown in Tables 1, 2, 4, and 5 are those
obtained by using the set of equations reported by
Nishida et al.,10 which showed the maximal agreement
with CD data. These rotameric populations were very
similar to those obtained from the set of equations
reported by Haasnoot et al.11 and from those reported by
De Vries et al.,12 although somewhat different from those
obtained by using the set of equations reported by Manor
et al.13
Rotation al P opu lation An alysis. Dich r om oph or ic
System . To study the rotational dependence of the
hydroxymethyl on the structure of the aglycon by means
of the CD exciton chirality method,14 the chromophoric
system 4,6-bis-O-(p-bromobenzoyl) was chosen. This
system allows a straightforward interpretation of the CD
data, since it contains only the 4/6 pairwise interaction
(top of Figure 2), which depends on the population of the
gg, gt, and tg rotamers of the hydroxymethyl group.
â-An om er s. To have information about how the
population of the hydroxymethyl group changes as the
pKa of the aglycon increases, the methyl, the isopropyl,
and the tert-butyl â-D-galactopyranoside derivatives 6-8
were analyzed, as well as the menthyl galactopyranosides
9 and 10 (Scheme 1). As can be observed in Figure 3,
negative split CD curves were obtained for the â-anomers
6-10. Furthermore, the amplitude (A value)15,16 de-
F igu r e 3. Comparison of the CD spectra (in CH3CN) of
methyl, isopropyl, and tert-butyl â-D-galactopyranosides 6-8
(top). Comparison of the CD spectra (in CH3CN) of methyl and
(-)- and (+)-menthyl â-D-galactopyranosides 6, 9, and 10,
respectively (bottom).
creased as the pKa of the nonchiral alcohol bonded
(aglycon) increased, namely, from -21.0 (methyl) to
-19.5 (isopropyl) and to -13.6 (tert-butyl) (CH3CN)
(Table 1). The galactosylated secondary chiral alcohols
9 and 10 also exhibited lower amplitudes than the methyl
derivative 6, the stereoisomer having the R absolute
configuration at the aglyconic carbon, compound 9,
showing a higher amplitude than the stereoisomer with
the S configuration.
The same behavior was observed when the CD mea-
surements were performed in EtOH at 25 °C (Table 1).
In addition, the amplitude of the methyl and the isopro-
pyl derivatives 6 and 7 proved to be almost independent
of the temperature. However, the bulkier model com-
pounds 8-10 exhibited a deep dependence on the tem-
perature, their amplitudes decreasing significantly by
lowering the temperature.
The decrease in the amplitude of the CD curves
obtained either by increasing the pKa of the nonchiral
alcohol bonded to the sugar residue or by lowering the
temperature can be explained by an increase in the
population of the gt rotamer, which has a 4/6 positive
contribution, and/or by a decreases in the population of
the tg rotamer, which contributes negatively to the 4/6
pairwise interaction (top of Figure 2).17,18 This result
showed that the most stable rotamer for compounds
8-10, and probably also for compounds 6 and 7, is the
gt, the only one having a positive contribution. To
(10) Nishida, Y.; Hori, H.; Ohrui, H.; Meguro, H. J . Carbohydr.
Chem. 1988, 7, 239.
(11) Haasnoot, C. A. G.; de Leeuw, F. A. A. M.; Altona, C.
Tetrahedron 1980, 36, 2783.
(12) DeVries, N.; Buck, H. M. Carbohydr. Res. 1987, 165, 1.
(13) Manor, P. C.; Saenger, W.; Davies, D. B.; J ankowski, K.;
Rabczenko, A. Biochim. Biophys. Acta 1974, 340, 472.
(14) For a monograph on exciton CD spectroscopy see: (a) Harada,
N.; Nakanishi, K. Circular Dichroic Spectroscopy Exciton Coupling in
Organic Stereochemistry; University Science Books: California, 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.
(15) The amplitude (A value) of split CD Cotton effects is defined
as A ) ∆ꢀ1 - ∆ꢀ2 where ∆ꢀ1 and ∆ꢀ2 are the intensities of the first and
the second Cotton effect, respectively.
(16) Occasionally, the presence of a background ellipticity alters the
intensity of the Cotton effects at short wavelengths. Thus, the
intensities of the second Cotton effect and, therefore, the amplitudes
(A value) of the CD spectra of our model compounds may not be precise,
the intensities of the first Cotton effect therefore being more accurate
for comparative analysis.

8250 J . Org. Chem., Vol. 63, No. 23, 1998
Padro´n et al.
Ta ble 1. CD Da ta , J H5,H6 Cou p lin g Con sta n ts, a n d Ca lcu la ted Rota m er ic P op u la tion s (%) a r ou n d th e C5-C6 Bon d for
th e â-An om er s 6-10 (Aceton itr ile)
compd
aglycon (R)
∆ꢀ at 252/236
A
Aa (25 °C)
Aa (-110 °C)
J H5,H6S
J H5,H6R
Pgg
Pgt
Ptg
6
7
8
9
10
methyl
isopropyl
tert-butyl
(1R)-(-)-menthyl
(1S)-(+)-menthyl
-13.3/7.7
-12.4/7.1
-7.7/5.9
-9.3/5.2
-5.9/6.0
-21.0
-19.5
-13.6
-14.5
-11.9
-27.2
-25.9
-18.1
-20.6
-16.4
-23.8
-22.7
-8.8
-13.6
-7.4
6.1
5.9
5.2
5.4
4.9
6.3
6.5
6.6
6.4
9.0
18
17
22
23
0
39
42
45
42
72
43
41
33
35
28
a
EtOH.
isopropyl and to the tert-butyl galactopyranoside deriva-
tives,21 producing a gradual shortening and a lengthening
of the O1-C1 and O5-C1 bonds, respectively, and
leading to different rotamer populations. Thus, an
increase in the exo anomeric effect produces increases
and decreases in the gt and tg populations, respectively.
The results described above for the alkyl galactopyra-
noside derivatives are opposite to those reported by Vries
and Buck12 in that by increasing the pKa of the anomeric
substituent, the tg population increased. These differ-
ences may be due to the fact that these authors used
aromatic alcohols at the anomeric carbon and phosphate
groups at the 6 position.
r-An om er s. The CD spectra of compounds 11-15 can
be observed in Figure 5. The amplitude of the galacto-
sylated nonchiral alcohols decreased slightly as the pKa
of the bonded alcohol increased, pointing to an increase
in the gt population (Table 2). For the galactosylated
chiral alcohols, the (1S)-(+)-menthyl galactopyranoside
15 exhibited higher amplitude (negative sign) than its
stereoisomer 14. However, this compound showed a
higher amplitude than the methyl derivative 11, and in
addition, its amplitude increased as the temperature
decreased (Table 2 and Figure 6). For this particular
compound (15), the most stable rotamer is the tg instead
of the gt.
Analysis of the J H5,H6 coupling constants (CD3CN and
CDCl3) of these compounds showed an excellent concor-
dance with CD data. For the galactosylated nonchiral
alcohols the J H5,H6R increased as the pKa of the alcohol
increased, while the J H5,H6S remained constant. For the
galactosylated chiral alcohols, a higher J H5,H6R and a
smaller J H5,H6S coupling constant were observed for the
(1R)-(-)-menthyl galactopyranoside 14 than for its cor-
responding stereoisomer 15, in agreement with the
amplitudes observed by CD. The calculated rotameric
populations are also in excellent agreement with the
observed CD amplitudes at room and at low temperature.
F igu r e 4. CD spectra of (+)-menthyl â-D-galactopyranoside
10 at room and low temperatures (25, -30, -80, and -110
°C) in EtOH and in EtOH/MeOH (4:1) (-140 °C).
confirm that this rotamer is the most stable, the (+)-
menthyl galactopyranoside 10 was measured at a lower
temperature (-140 °C) by using the EtOH/MeOH (4:1)
solvent system. The observed negative amplitudes (Fig-
ure 4) changed to positive at -140 °C (A ) +5.7),
confirming that the most stable rotamer is the gt (the
one with a positive contribution).
The rotameric populations of galactopyranosides have
been shown to be dependent on the solvent.12 Therefore,
1
the CD and H NMR data comparison performed in the
present study was done by analyzing data in the same
solvent, acetonitrile. Analysis of the J H5,H6 coupling
constants (Table 1) showed for the galactosylated non-
chiral alcohols 6-8 an increase and a decrease in the
J H5,H6R and J H5,H6S, respectively, as the pKa of the alcohol
increased, in agreement with the decreases in the CD
amplitudes. This result led to an increase and decrease
of the gt and tg populations, respectively, from the methyl
to the isopropyl and to the tert-butyl derivatives. For the
menthyl derivatives, a higher J H5,H6R and a smaller
J H5,H6S value were observed for the (1S)-(+)-menthyl
galactopyranoside 10 than for its corresponding stereo-
isomer 9, in agreement with its smaller CD amplitude
and its high gt population.
The R-anomers also showed a correlation between the
pKa of the bonded alcohol and the rotamer distribution.
However, the degree of dependence was smaller than that
observed with the â-anomers, this fact being easily
observed by CD spectra comparison of compounds 6-8
and 11-13 (tops of Figures 3 and 5). This dependence
can also be explained by the exo anomeric effect, which
has a smaller significance in the rotamer population than
the â-anomers. The simultaneous presence of the exo
The observed correlation between the rotamer distri-
bution and the pKa of the nonchiral alcohol bonded to
the galactopyranosyl system can be explained by means
of the stereoelectronic exo anomeric effect.19,20 The value
of this effect must increase from the methyl to the
(20) (a) Kirby, A. J . In The Anomeric Effect and Related Stereoelec-
tronic Effects at Oxygen in Reactivity and Structure Concepts in Organic
Chemistry; Hafner, K., Rees, C. W., Trost, B. M., Lehn, J . M., Schleyer,
P. v. R., Zahradnik, R., Eds.; Springer-Verlag: Berlin, 1983; Vol. 15.
(b) 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; American Chemical Society: Washington, DC, 1993.
(17) Liu, H. L.; Nakanishi, K. J . Am. Chem. Soc. 1981, 103, 5591.
(18) Va´zquez, J . T.; Wiesler, W. T.; Nakanishi, K. Carbohydr. Res.
1988, 176, 175.
(19) The stereoelectronic exo anomeric effect is the preference for
the gauche (sc) conformation about the glycosidic C-OR bond of sugar
derivatives. Lemieux, R. U.; Pavia, A. A.; Martin, J . C.; Watanabe, K.
A. Can. J . Chem. 1969, 47, 4427.
(21) Briggs, A. J .; Glenn, R.; J ones, P. G.; Kirby, A. J .; Ramaswamy,
P. J . Am. Chem. Soc. 1984, 106, 6200.

Alkyl Galactopyranosides
J . Org. Chem., Vol. 63, No. 23, 1998 8251
hydroxymethyl group wrongly in the tg disposition in
their publications.17,18,22
The observed negative signs for the 3/6 and 4/6
pairwise interactions, the most stable rotamer being the
gt, with a nil and a positive CD contribution, respectively
(Figure 2), can be explained as follows: (i) The negative
sign for the 3/6 interaction comes from the second more
populated rotamer, the tg rotamer (with negative con-
tribution), since the gt rotamer has a nil contribution for
this interaction. (ii) The contribution of the tg rotamer
to the 4/6 pairwise interaction must be much stronger
than that of the gt rotamer, as a consequence of the
shorter distance and more favorable dihedral angle. To
prove this assessment, the contributions to the 4/6
pairwise interaction were estimated by correlating the
calculated rotamer distributions with the observed CD
amplitudes and assuming a nil contribution for the gg
rotamer, as a consequence of its dihedral angle, which is
near 0°. Thus, it was found that the contribution of the
tg rotamer to the amplitude (A value) of the 4/6 pairwise
interaction was 10 times higher (A ≈ - 50) than the gt
contribution (A ≈ +5), the amplitude following the
equation: A ) 5gt - 50tg. Therefore, this result explains
satisfactorily the observed negative sign for the 4/6
pairwise interaction, although the most stable rotamer
is the gt (positive contribution). Table 3 shows observed
and calculated amplitudes for compounds 6-15, as well
as their differences ∆A (obsd - calcd). The very small
differences obtained in general confirm the correct esti-
mation performed of the rotameric contributions to the
4/6 pairwise interaction.
R ot a t ion a l P op u la t ion An a lysis. Tet r a ch r om o-
p h or ic System . To complete the above rotational study
of the galactosylated chiral alcohols and confirm that the
galactopyranosyl system can also be used to determine
the absolute configuration of chiral alcohols, the alkyl
2,3,4,6-tetrakis-O-(p-bromobenzoyl)-â- and R-D-galacto-
pyranosides 18-27 were prepared (Scheme 2). These
compounds contain the necessary chromophore at C2 to
give rise to anisotropic shifts in the aglycon 1H NMR
peaks and, thus, be able to determine the absolute
configuration of the bonded chiral alcohol (aglycon) (see
below).23
â-An om er s. CD analysis of the galactosylated chiral
alcohols 19-22 showed similar amplitudes, but with
slightly higher values than that of the methyl galacto-
pyranoside derivative 18 (Table 4). Furthermore, those
derivatives having an S absolute configuration at the
aglyconic carbon exhibited higher values in the intensity
of their first Cotton effects than their stereoisomer with
the R absolute configuration.16 Low-temperature CD
measurement of compounds 18-22 (EtOH) revealed for
each of these compounds a gradual increase in the
amplitude as the temperature decreased from 25 to -110
°C.
F igu r e 5. Comparison of the CD spectra (in CH3CN) of
methyl, isopropyl, and tert-butyl R-D-galactopyranosides 11-
13 (top). Comparison of the CD spectra (in CH3CN) of methyl
and (-)- and (+)-menthyl R-D-galactopyranosides 11, 14 and
15, respectively (bottom).
and endo anomeric effects in the R-anomers could be the
reason for the smaller effect of the exo anomeric effect.20
This explanation is contrary to that reported by us in a
previous study with alkyl R-glucopyranosides,2 where the
results pointed to the nonparticipation of the endo
anomeric effect, since the same degree of correlation was
observed for both anomers.
Ca lcu la tion of th e Rota m er ic Con tr ibu tion s to
t h e 4/6 P a ir w ise In t er a ct ion . The exciton coupling
between two chromophores depends on the interchro-
mophoric distance and on the dihedral angle.14 There-
fore, the observed 4/6 pairwise interaction is the percent-
age sum of the interaction between the chromophore at
C4 and the chromophore at C6 in the gg, gt, and tg
rotamers.
Previous interpretation of the observed negative signs
of the split CD curves of methyl 4,6-bis-O-(p-bromoben-
zoyl) and methyl 3,6-bis-O-(p-bromobenzoyl) galactopy-
ranosides17,18 led to establishing incorrectly the tg rota-
mer as the most stable one, since the contributions of
this rotamer to the 3/6 and 4/6 interactions are negative
(Figure 2). However, this result could not explain the
negative split CD exhibited by methyl 2,6-bis-O-(p-
bromobenzoyl)galactopyranoside,17,18 which possesses a
positive sign for the tg rotamer (Figure 2). Their confi-
dence in this CD result also led the authors to draw the
To analyze these CD data, it is necessary to take into
account all the pairwise interactions involved in the
galactopyranosyl system. The CD spectrum of a chro-
mophorically 2,3,4,6-tetra-substituted galactopyranosyl
system is composed of six pairwise interactions.17,18
These interactions can be divided into two groups: those
(22) Wiesler, W. T.; Berova, N.; Ojika, M.; Meyers, H. V.; Chang,
M.; Zhou, P.; Lo, L.-C., Niwa, M.; Takeda, R.; Nakanishi, K. Helv. Chim.
Acta 1990, 73, 509.
(23) Trujillo, M.; Morales, E. Q.; Va´zquez, J . T. J . Org. Chem. 1994,
59, 6637.

8252 J . Org. Chem., Vol. 63, No. 23, 1998
Padro´n et al.
Ta ble 2. CD Da ta , J H5,H6 Cou p lin g Con sta n ts, a n d Ca lcu la ted Rota m er ic P op u la tion s (%) a r ou n d th e C5-C6 Bon d for
th e r-An om er s 11-15 (Aceton itr ile)
compd
aglycon (R)
∆ꢀ at 253/237
A
Aa (25 °C)
Aa (-110 °C)
J H5,H6S
J H5,H6R
Pgg
Pgt
Ptg
11
12
13
14
15
methyl
isopropyl
tert-butyl
(1R)-(-)-menthyl
(1S)-(+)-menthyl
-11.5/5.5
-11.2/5.5
-10.4/6.2
-10.4/5.3
-15.7/7.9
-17.0
-16.7
-16.6
-15.7
-23.6
-21.5
-20.5
-20.2
-19.2
-29.2
-10.5
-16.1
-13.7
-8.7
5.7
5.7
5.7
5.3
6.0
6.4
6.6
6.8
6.9
6.4
20
18
16
18
18
42
44
46
48
40
38
38
38
34
42
-38.3
a
EtOH.
ondary alcohols showed higher gt and smaller tg popu-
lations than the methyl derivative 18.
Due to the superposition of 1H NMR signals observed
for the â-anomers 18-22 in acetonitrile and, therefore,
the impossibility of measuring accurately their J H5,H6
coupling constants, these compounds were analyzed in
methanol. Analysis of the J H5,H6 coupling constants
showed higher J H5,H6R and smaller J H5,H6S values for the
secondary alkyl galactopyranosides 19-22 than for the
methyl derivative 18 (Table 4), confirming higher gt and
smaller tg populations for the galactosylated secondary
alcohols 19-22 than for the reference galactosylated
primary alcohol 18. In addition, the calculated rotameric
populations for these compounds showed that Pgt > Ptg
> Pgg, with the exception of the methyl derivative 18,
which showed Ptg > Pgt > Pgg. CD and calculated
rotameric populations data comparison revealed an
excellent agreement in all cases except for the methyl
galactopyranoside 18. This single discrepancy may be
due to an overestimation in the calculation of the popula-
tions of the tg rotamer.
F igu r e 6. CD spectra of (+)-menthyl R-D-galactopyranoside
15 at room and low temperatures in EtOH.
Ta ble 3. Obser ved vs Ca lcu la ted Am p litu d es for
Com p ou n d s 6-15 (CH3CN)
compd
A (obsd)
A (calcd)
∆A (obsd - calcd)
Similarly to the alkyl â-D-glucopyranosides, there are
two possible ways to explain that in general stereoiso-
mers with the R absolute configuration at the aglyconic
carbon show smaller and higher gt and tg populations
than their stereoisomers having the S configuration: (i)
Since the stereoisomer with the R absolute configuration
at the aglyconic carbon possesses greater bulkiness in a
syn location to the endocyclic oxygen (O5) than its
stereoisomer having the enantiomeric aglycon, weak
nonbonded interactions between the aglycon and the
chromophore at C6 in its gt rotamer can account for the
smaller gt population of the (R)-alkyl â-D-galactopyra-
noside (Figure 8). (ii) The torsional angle ψ depends on
the structure of the aglycon:24 a small clockwise or
counterclockwise rotation along the O1-C1′ bond occurs
depending on whether the main nonbonded interactions
between the aglycon and the galactopyranosyl residue
are located syn or anti, respectively, to the endocyclic
oxygen (O5). Thus, the nonbonding electron pair of the
exocyclic oxygen involved in the exo anomeric effect could
adopt a different disposition depending on the absolute
configuration of the aglycon, and therefore, the stereo-
isomer having the S absolute configuration at the agly-
conic carbon could adopt a better antiperiplanar disposi-
tion with respect to the C1-O5 bond than its stereoiso-
mer with the R configuration (Figure 8).
6
7
8
-21.0
-19.5
-13.6
-14.5
-11.9
-17.0
-16.7
-16.6
-15.7
-23.6
-19.5
-18.4
-14.2
-15.4
-10.4
-16.9
-16.8
-16.7
-14.6
-19.0
-1.5
-1.1
0.6
9
0.9
10
11
12
13
14
15
-1.5
-0.1
0.1
0.1
-1.1
-4.6
having a practically constant intensity and a positive
sign, the 2/3, the 3/4, and the 2/4 pairwise interactions
(Figure 7), and those interactions involving the chro-
mophore at the six position with variable intensity and
sign, the 2/6, the 3/6, and the 4/6 pairwise interactions,
which depend on the rotamer population of the hy-
droxymethyl group (Figure 2).
In accordance with the exciton chirality method,14 the
amplitude of split Cotton effects is inversely proportional
to the square of interchromophoric distance; therefore,
the 4/6 pairwise interaction contributes more signifi-
cantly to the observed spectrum than the 3/6 or 2/6
pairwise interactions, as observed.17,18 Therefore, the
increase in the amplitude of the CD curves obtained by
lowering the temperature is in agreement with an
increase in the population of the gt rotamer, which has
a 4/6 positive contribution, and with a decrease in the
population of the tg rotamer, which contributes nega-
tively to this 4/6 pairwise interaction (Figure 2). This
result also points to the gt rotamer as the most stable.
In addition, stereoisomers with an S absolute configu-
ration should have higher and smaller gt and tg popula-
tions than their stereoisomers with the R configuration,
as occurred in the dichromophoric system with com-
pounds 9 and 10. Furthermore, all galactosylated sec-
r-An om er s. CD data of the alkyl R-D-galactopyrano-
side derivatives 23-27 are shown in Table 5. As oc-
curred with the â-anomers, all galactosylated secondary
alcohols 24-27 exhibited higher amplitudes than the
methyl galactopyranoside 23, and contrary to the â-ano-
mers, the galactosylated chiral alcohols having an S
absolute configuration at the aglyconic carbon exhibited
(24) Lemieux, R. U.; Koto, S. Tetrahedron 1974, 30, 1933.

Alkyl Galactopyranosides
J . Org. Chem., Vol. 63, No. 23, 1998 8253
Ta ble 4. CD Da ta , J H5,H6 Cou p lin g Con sta n ts, a n d Ca lcu la ted Rota m er ic P op u la tion s (%) a r ou n d th e C5-C6 Bon d for
th e â-An om er s 18-22
c
c
compd
aglycon (R)
∆ꢀ at 252/234a
Aa
Ab (25 °C)
Ab (-110 °C)
J H5,H6S
J H5,H6R
Pgg
Pgt
Ptg
18
19
20
21
22
methyl
(2R)-(-)-octyl
(2S)-(+)-octyl
(1R)-(-)-menthyl
(1S)-(+)-menthyl
65.0/-22.6
65.5/-24.3
66.6/-23.2
65.7/-24.3
67.0/-22.0
87.6
89.8
89.8
90.0
89.0
81.4
86.7
79.5
85.2
87.4
98.7
101.9
102.1
111.0
111.2
6.1
5.5
5.7
5.5
4.8
5.9
6.5
6.5
6.3
7.4
22
21
19
23
17
35
43
43
41
55
43
36
38
36
28
a
b
CH3CN. EtOH. c CD3OD.
having an R absolute configuration at the aglyconic
carbon than for those with the opposite absolute config-
uration. This conduct can be explained by means of the
two same arguments used for the â-anomers, but taking
into account that for the R-anomers (i) the stereoisomer
with the S absolute configuration at the aglyconic carbon
possesses bulkiness in a syn location to the endocyclic
oxygen (O5) greater than its stereoisomer having the
enantiomeric aglycon (Figure 9) and (ii) the stereoisomer
having the R absolute configuration at the aglyconic
carbon could adopt a better antiperiplanar disposition
with respect to the C1-O5 bond than its stereoisomer
with the S configuration (Figure 9). In addition, the
unusual behavior of the (1S)-(+)-menthyl galactopyra-
noside 15 points clearly to the presence of an appreciable
nonbonding interaction between the chromophore at C6,
in its gt rotamer, and the aglycon, closer to the sugar
residue due to its R anomeric configuration.
F igu r e 7. 2/3, 3/4, and 2/4 pairwise interactions having
constant intensity and positive sign for the galactopyranosyl
system.
F igu r e 8. Top: (-)-menthyl â-D-galactopyranosides 9 (R )
p-bromobenzoyl, R1 ) acetyl) and 21 (R ) R1 ) p-bromoben-
zoyl)). Bottom: (+)-menthyl â-D-galactopyranosides 10 (R )
p-bromobenzoyl, R1) acetyl) and 22 (R ) R1 ) p-bromoben-
zoyl).
Absolu te Con figu r a tion of Secon d a r y Alcoh ols
(Aglycon s) a n d Ga la ctop yr a n osid ic Con for m a tion .
The galactosylated chiral alcohols 19-22 (â-anomers) and
24-27 (R-anomers) showed important chemical shift
differences (either as δD - δROH or as δD - δL) in the
1
smaller amplitudes than their stereoisomers with the R
configuration, in agreement with the higher negative
amplitude observed for compound 15 compared with 14,
analogues in the dichromophoric system.
aglycon H NMR peaks, as a consequence of the dramatic
chemical shifts produced by the anisotropic effect and by
1
the galactosylation-induced H NMR shifts. As can be
observed in Figure 10 and as occurred in the alkyl tetra-
O-benzoylglucopyranosides,1,2,23 these differences are char-
acteristic of the absolute configuration of the secondary
chiral alcohol and confirm that the galactopyranosyl
system can also be used to determine the absolute
configuration of chiral alcohols or the aglyconic moiety
of natural glycosides. Furthermore, the chemical shift
of the carbinyl protons of the â-glucosylated R-alcohols
appears at a lower field than that of the â-glucosylated
S-alcohol counterparts, the former giving rise to a positive
sign and the latter to a negative sign of ∆δ. The opposite
behavior was observed for the R-anomers.
Low-temperature CD measurements (EtOH) showed
an important and gradual increase in amplitude by
lowering the temperature, indicating that the most stable
rotamer is the gt, as occurred with the â-anomers.
Furthermore, while the dependence of the amplitude on
the temperature was very similar for the octyl derivatives
24 and 25, it was very different for the menthyl deriva-
tives 26 and 27, showing a much higher and a much
lower amplitude, respectively, than the methyl galacto-
pyranoside 23.
1
Analysis of the H NMR coupling constants between
H5 and H6R and H6S showed higher J H5,H6R and smaller
J H5,H6S values for the secondary alkyl galactopyranosides
24-27 than for the methyl derivative 23 (Table 5), with
the exception of the J H5,H6S of the menthyl derivative 27,
which has a higher value. This general behavior means
higher gt and smaller tg populations for these galacto-
pyranosides than for the methyl galactopyranoside 23.
The calculated rotamer distributions showed the same
order as for the â-anomers (Pgt > Ptg > Pgg), in total
agreement with CD results. In addition, a correlation
between the amplitude of the CD spectra (CH3CN) and
the percentage of the rotameric populations was ob-
served, namely, the higher the amplitude the higher the
population of the gt rotamer.
The chemical shift differences (∆δ) obtained by tetra-
O-benzoylglycosylation of chiral alcohols of known abso-
lute configuration, as occurs in the present study, allow
the most stable conformation around the interglycosidic
linkage to be determined. Thus, the negative and the
positive signs obtained for those aglyconic protons located
anti or syn, respectively, to the endocyclic galactopyra-
noside oxygen (O5) confirm that the most stable confor-
mation for the R- and â-anomers is similar to that shown
for each anomer in Figure 10. Note that the same
absolute values of ∆δ but with opposite signs correspond
to the enantiomeric aglycons.
Con clu sion s
1
CD and H NMR data of the chiral alkyl R-D-galacto-
pyranosides, either in the di- or in the tetrachromophoric
system, agree in higher and smaller populations of the
gt and tg rotamers, respectively, for those stereoisomers
It can be concluded, on the basis of the CD and 1H
NMR data, that the rotational population of the hy-
droxymethyl group in esterified alkyl R- and â-galacto-

8254 J . Org. Chem., Vol. 63, No. 23, 1998
Padro´n et al.
Ta ble 5. CD Da ta , J H5,H6 Cou p lin g Con sta n ts, a n d Ca lcu la ted Rota m er ic P op u la tion s (%) a r ou n d th e C5-C6 Bon d for
th e r-An om er s 23-27 (Aceton itr ile)
compd
aglycon (R)
∆ꢀ at 252/235
A
Aa (25 °C)
Αa (-110 °C)
J H5,H6S
J H5,H6R
Pgg
Pgt
Ptg
23
24
25
26
27
methyl
(2R)-(-)-octyl
(2S)-(+)-octyl
(1R)-(-)-menthyl
(1S)-(+)-menthyl
69.2/-28.5
73.3/-31.2
71.9/-27.4
74.7/-30.2
70.3/-28.2
97.7
104.5
99.3
104.9
98.5
105.4
107.5
107.0
137.9
98.8
133.4
137.5
137.1
180.4
113.8
5.8
5.6
5.6
5.4
5.9
6.4
6.7
6.7
6.8
6.5
19
18
18
18
17
41
45
45
47
42
40
37
37
35
41
a
EtOH.
Ta ble 6. Su m m a r ized Resu lts of th e Rota tion a l
P op u la tion Stu d y of th e Hyd r oxym eth yl Gr ou p in Alk yl
Ga la ctop yr a n osid es
nonchiral aglycons
chiral aglycons
pKa v, Pgg ≈ constant, Pgt v, Ptg
â-anomers R-anomers
V
Pgt (R) < Pgt (S)
Ptg (R) > Ptg (S)
Pgt (R) > Pgt (S)
Ptg (R) < Ptg (S)
tron pair of the exocyclic oxygen to the O5-C1 bond and
to a higher significance of this stereoelectronic effect in
the â-anomers.
The rotational populations of the hydroxymethyl group
in galactosylated chiral alcohols revealed a clear correla-
tion with the anomeric configuration as well as with the
absolute configuration of the aglycon. Thus, â-anomers
having an S absolute configuration at the aglyconic
carbon showed higher and smaller gt and tg populations,
respectively, than their stereoisomers of opposite absolute
configuration, while for the R-anomers, the one having
higher and smaller gt and tg populations, respectively,
was the stereoisomer with the R absolute configuration
at the aglyconic carbon. Similar to the chiral alkyl
glucopyranosides, a more stabilizing stereoelectronic exo
anomeric effect for diastereoisomers with an S absolute
configuration (â-anomers) or an R configuration (R-
anomers) may account for these rotational dependencies.
In addition, nonbonding interactions between the aglycon
and the chromophore at C6 may be involved in those
stereoisomers having in their aglycon a bulky substituent
syn to the endocyclic oxygen (O5), as occurred in the (+)-
menthyl R-D-galactopyranoside derivative 15. Table 6
summarizes these results.
F igu r e 9. Top: (-)-menthyl R-D-galactopyranosides 14 (R )
p-bromobenzoyl, R1 ) acetyl) and 26 (R ) R1 ) p-bromoben-
zoyl). Bottom: (+)-menthyl R-D-galactopyranosides 15 (R )
p-bromobenzoyl, R1) acetyl) and 27 (R ) R1 ) p-bromoben-
zoyl).
In addition, it was confirmed that the chemical shift
differences (δD - δROH or δD - δL) of the aglyconic protons
of the galactosylated chiral alcohols, as either the R- or
â-anomer, are characteristic of the absolute configuration
of the bonded chiral alcohol. Therefore, the recently
1
proposed H NMR method for the determination of the
absolute configuration of secondary alcohols or the ag-
lyconic moiety of natural glycosides, based on tetra-O-
benzoyl glucosylation, can be extended to the use of the
tetra-O-benzoyl galactopyranosyl as a chiral auxiliary.
F igu r e 10. Chemical shift differences (∆δ ) δD - δL) (in hertz;
400 MHz; room temperature; solvent CDCl3) of the tetra-O-
(p-bromobenzoyl)galactopyranoside derivatives of (+)-2-octanol
and of (+)-menthol; anomeric configuration: â (top), and R
(bottom).
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR spectra were recorded at 400
MHz, and 13C NMR were recorded at 100 MHz, VTU 300.0 K.
Chemical shifts are reported in parts per million. The residual
solvent peak was used as an internal reference. Optical
rotations were measured on a digital polarimeter in a 1 dm
cell. UV and CD spectra were recorded in the range 400-200
nm and using 10 mm cells. Prior to measurement of CD
spectra, all compounds were purified by HPLC using a
µ-Porasil column, 300 × 7.8 mm i.d., 254 nm, and HPLC grade
n-hexane/EtOAc solvent systems. The concentrations of the
CD samples were ascertained from the UV spectra, using the
standard ꢀ values at 245 nm: bis-(p-bromobenzoate) ꢀ 38 200;
pyranosides depends on the structure of the aglycon and
that its most stable rotamer is the gt, and not the tg.
Moreover, it was observed that the population of the gt
and tg rotamers increases and decreases, respectively,
as the pKa of the bonded alcohol increases, while the
population of the gg rotamer remains practically con-
stant. Furthermore, the results pointed to the stereo-
electronic exo anomeric effect as being responsible for this
rotational dependence, probably as a consequence of a
better antiperiplanar disposition of the nonbonding elec-

Alkyl Galactopyranosides
J . Org. Chem., Vol. 63, No. 23, 1998 8255
tetrakis-(p-bromobenzoate) 76 400.17 Density correction was
realized in all CD low-temperature measurements.
) 6.5 Hz, H-5R), 4.51 (dd, J ) 6.1, 11.0 Hz, H-6R), 4.28 (dd, J
) 6.7, 11.2 Hz, H-6R), 2.18 (s), 2.16 (s), 2.05 (s), 2.04 (s), 1.96
(s), 1.95 (s).
For analytical and preparative thin-layer chromatography
silica gel ready-foils and glass-backed plates (1 mm) were used,
respectively, being developed with 254 nm UV light and/or
spraying with AcOH/H2O/H2SO4 (80:16:4) and heating at 150
°C. Flash column chromatography was performed using silica
gel (0.015-0.04 mm). All reagents as well as the chiral
alcohols were obtained from commercial sources and used
without further purification. Solvents were dried and distilled
before use. All reactions were performed under a dry argon
atmosphere.
Gen er a l P r oced u r es. The general procedure for p-bro-
mobenzoylation is well described in ref 1, as well as the
preparation of glucopyranosyl bromides and the procedure for
â-glucosylation, which were used in the same way as for the
preparation of galactopyranosyl bromides and for â-galacto-
sylation.
Gen er a l P r oced u r e for An om er iza tion . To a stirred
solution of the substrate (20-70 µmol) in dry CH2Cl2 (20 mL/
mmol) at room temperature under dry argon was added 3
equiv of anhydrous FeCl3 and the reaction left until the color
of the reaction mixture changed to brown. The reaction was
quenched by addition of water (1 mL). This mixture was
stirred for 1 min and then extracted with CH2Cl2 (25 mL). The
combined organic layers were dried over magnesium sulfate,
and the solvent was removed under reduced pressure. This
crude reaction mixture was purified by flash silica gel column
chromatography (n-hexane/EtOAc solvent systems).
2,3-Bis-O-a cetyl-4,6-bis-O-(p-br om oben zoyl)-r-D-ga la c-
top yr a n osyl Br om id e (5). Following the general procedure
for the preparation of galactopyranosyl bromides, 2.07 g (3.08
mmol) of 4 led to compound 5 (2.19 mmol, 71% yield): TLC Rf
) 0.61 (n-hexane/EtOAc 7:3); [R]25 ) +86.67 (c 0.15, CHCl3);
D
1H NMR (CDCl3) δ 7.90-7.55 (aromatic H’s), 6.81 (d, J ) 4.0
Hz, 1H), 5.86 (brd, J ) 2.5 Hz, 1H), 5.54 (dd, J ) 3.3, 10.6 Hz,
1H), 5.13 (dd, J ) 4.0, 10.6 Hz, 1H), 4.73 (t, J ) 6.4 Hz, 1H),
4.53 (dd, J ) 6.7, 11.6 Hz, 1H), 4.35 (dd, J ) 6.1, 11.6 Hz,
1H), 2.12 (s, 3H), 1.97 (s, 3H); 13C NMR (CDCl3) δ 170.05,
169.77, 165.10, 164.78, 132.12-127.52 (aromatic C’s), 87.91,
71.23, 68.04, 67.98, 67.94, 61.94, 20.71, 20.55. Anal. Calcd
for C24H21O9Br3: C, 41.75; H, 3.07. Found: C, 41.78; H, 3.44.
Meth yl 2,3-Bis-O-a cetyl-4,6-bis-O-(p-br om oben zoyl)-â-
D-ga la ctop yr a n osid e (6). According to the general procedure
for â-galactosylation, 120 mg (0.173 mmol) of 5 and 1 mL of
dry MeOH led to the desired galactopyranoside 6 (0.155 mmol,
90% yield): TLC Rf ) 0.5 (n-hexane/EtOAc 7:3); [R]25D ) -27.6
(c 2.33, CHCl3); CI-MS (CH4) m/z 724 (1.8, [M + Br]-), 643 (2,
1
[M]-), 484 (2, [M - 2Br]-), 80 (100, Br); H NMR (CDCl3) δ
7.94-7.55 (aromatic H’s), 5.73 (brd, J ) 3.3 Hz, 1H), 5.28 (dd,
J ) 7.9, 10.4 Hz, 1H), 5.15 (dd, J ) 3.3, 10.4 Hz, 1H), 4.59
(dd, J ) 6.5, 11.3 Hz, 1H), 4.49 (d, J ) 7.9 Hz, 1H), 4.31 (dd,
J ) 6.9, 11.3 Hz, 1H), 4.14 (t, J ) 6.7 Hz, 1H), 3.55 (s, 3H),
2.06 (s, 3H), 1.93 (s, 3H); 13C NMR (CDCl3) δ 170.11, 169.40,
165.18, 165.00, 131.98-127.75 (aromatic C’s), 102.21, 70.91,
68.89, 68.06, 61.91, 57.10, 20.74, 20.51. Anal. Calcd for
4,6-O-Ben zylid en e-D-ga la ctop yr a n ose (1). To a solution
of D-(+)-galactose (4.0 g, 22.20 mmol) in DMF (20 mL) were
added benzaldehyde dimethyl acetal (3.3 mL, 22.20 mmol) and
p-toluenesulfonic acid (42 mg, 0.222 mmol). The reaction
mixture was heated to 50 °C, under vacuum, and left over-
night. Then, the solvent was removed by distillation and the
resulting oil chromatographed on silica gel (CHCl3/MeOH 9:1).
Compound 1 (8.6 mmol) was obtained in 39% yield: TLC Rf )
0.34 (CHCl3/MeOH 9:1).
C
25H24O10Br2: C, 46.73; H, 3.77. Found: C, 46.66; H, 3.89.
Isop r op yl 2,3-Bis-O-a cetyl-4,6-bis-O-(p-br om oben zoyl)-
â-D-ga la ctop yr a n osid e (7). Following the general procedure
for â-galactosylation, from 120 mg (0.173 mmol) of 5 and 1
mL of dry 2-propanol was obtained compound 7 (0.132 mmol,
76% yield): TLC Rf ) 0.56 (n-hexane/EtOAc 7.5:2.5); [R]25
)
D
-21.4 (c 2.78, CHCl3); CI-MS (CH4) m/z 753 (4, [M+Br]-), 672
(2.8, [M]-), 200 (100, BrBzO); H NMR (CDCl3) δ 7.95-7.55
1
(aromatic H’s), 5.71 (brd, J ) 3.4 Hz, 1H), 5.25 (dd, J ) 7.8 ,
10.4 Hz, 1H), 5.15 (dd, J ) 3.4, 10.4 Hz, 1H), 4.59 (d, J ) 7.8
Hz, 1H), 4.55 (dd, J ) 6.7, 11.3 Hz, 1H), 4.30 (dd, J ) 6.7,
11.3 Hz, 1H), 4.12 (t, J ) 6.6 Hz, 1H), 3.94 (sep, J ) 6.2 Hz,
1H), 2.04 (s, 3H), 1.93 (s, 3H), 1.26 (d, J ) 6.2 Hz, 3H), 1.16
(d, J ) 6.1 Hz, 3H); 13C NMR (CDCl3) δ 170.14, 169.25, 165.17,
165.09, 131.97-127.77 (aromatic C’s), 100.47, 73.46, 70.96,
70.74, 69.17, 68.09, 62.05, 23.26, 22.04, 20.67, 20.52. Anal.
Calcd for C27H28O10Br2: C, 48.36; H, 4.21. Found: C, 48.38;
H, 4.14.
4,6-O-Ben zylid en e-1,2,3-tr is-O-a cetyl-D-ga la ctop yr a n o-
sid e (2). To a solution of compound 1 (2.26 g, 8.43 mmol) in
dry pyridine (8 mL) at room temperature was added acetic
anhydride (8 mL), the reaction being monitored by TLC. Then,
excess solvent was removed under reduced pressure in the
presence of n-heptane, and the residue was chromatographed
to afford compound 2 (2.99 g, 7.6 mmol, 90% yield) as a 4:6
mixture of R- and â-anomers: TLC Rf ) 0.38 (n-hexane/EtOAc
1
7:3); H NMR (mixture of anomers) (CDCl3) δ 7.50 (m), 7.37
(m), 6.48 (d, J ) 3.5 Hz, H-1R), 5.70 (d, J ) 8.3 Hz, H-1â),
5.52 (m, H-2R and H-2â), 5.31 (dd, J ) 3.2, 10.9 Hz, H-3R),
5.00 (dd, J ) 3.6, 10.3 Hz, H-3â), 4.50 (d, J ) 2.6 Hz, H-4R),
4.40 (d, J ) 1.5 Hz, H-4â), 4.32 (brd, J ) 1.5 Hz), 4.29 (brt, J
) 2.6 Hz), 4.25 (d, J ) 1.5 Hz), 4.05 (brt, J ) 1.4 Hz), 4.02
(brt, J ) 1.4 Hz), 3.91 (brs), 3.65 (brd, J ) 1.0 Hz), 2.14 (s),
2.10 (s), 2.09 (s), 2.07 (s), 2.03 (s), 2.01 (s).
ter t-Bu tyl 2,3-Bis-O-a cetyl-4,6-bis-O-(p-br om oben zoyl)-
â-D-ga la ctop yr a n osid e (8). This compound was prepared in
38% yield from 1 mL of dry 2-methyl-2-propanol and 120 mg
(0.173 mmol) of the galactopyranosyl bromide 5, following the
general procedure for â-galactosylation: TLC Rf ) 0.61 (n-
hexane/EtOAc 7.5:2.5); [R]25 ) +5.5 (c 1.27, CHCl3); CI-MS
D
1
(CH4) m/z 685 (0.5, [M]-), 116 (100, BzO); H NMR (CDCl3) δ
1,2,3-Tr is-O-a cetyl-r-D-ga la ctop yr a n osid e (3). A solu-
tion of compound 2 (2.11 g, 5.32 mmol) in AcOH/H2O (20 mL,
8:2, v/v) was heated at 60 °C and monitored by TLC. Then,
the excess solvent was removed under reduced pressure and
the residue chromatographed on silica gel (MeOH/CHCl3 5:95)
to afford compound 3 (4.77 mmol, 89% yield): TLC Rf ) 0.38
(CHCl3/MeOH 9.5:0.5); 1H NMR (CDCl3) δ 6.24 (d, J ) 3.7 Hz,
1H), 3.35 (dd, J ) 3.7, 10.8 Hz, 1H), 5.09 (dd, J ) 3.0, 10.8
Hz, 1H), 4.15 (d, J ) 2.6 Hz, 1H), 3.89 (brt, J ) 5.2 Hz, 1H),
3.71 (dd, J ) 5.4, 11.7 Hz, 1H), 3.65 (dd, J ) 5.2, 11.7 Hz,
1H), 2.05 (s, 3H), 2.03 (s, 3H), 1.92 (s, 3H).
1,2,3-Tr is-O-a cetyl-4,6-bis-O-(p-br om oben zoyl)-D-ga la c-
top yr a n osid e (4). Following the general procedure for p-
bromobenzoylation, 1.45 g (4.74 mmol) of 3 led to compound 4
(3.79 mmol, 80% yield) as a 9:1 mixture of R- and â-anomers:
TLC Rf ) 0.42 (n-hexane/EtOAc 7:3); 1H NMR (mixture of
anomers) (CDCl3) δ 7.93-7.55 (aromatic H’s), 6.50 (d, J ) 3.4
Hz, H-1R), 5.85 (d, J ) 2.4 Hz, H-4R), 5.79 (d, J ) 8.3 Hz,
H-1â), 5.48 (dd, J ) 3.1, 11.0 Hz, H-3R), 5.43 (dd, J ) 3.4,
10.9 Hz, H-2R), 5.23 (dd, J ) 3.4, 11.0 Hz, H-3â), 4.57 (brt, J
7.97-7.55 (aromatic H’s), 5.70 (brd, J ) 3.4 Hz, 1H), 5.25 (dd,
J ) 7.7, 10.4 Hz, 1H), 5.17 (dd, J ) 3.4, 10.4 Hz, 1H), 4.69 (d,
J ) 7.7 Hz, 1H), 4.50 (dd, J ) 7.4, 11.4 Hz, 1H), 4.33 (dd, J )
5.8, 11.4 Hz, 1H), 4.13 (t, J ) 6.9 Hz, 1H), 2.04 (s, 3H), 1.93
(s, 3H), 1.25 (s, 9H); 13C NMR (CDCl3) δ 170.19, 169.18, 165.20,
131.96-127.77 (aromatic C’s), 96.12, 76.56, 71.16, 70.82, 69.23,
68.26, 62.45, 28.45, 20.77, 20.56. Anal. Calcd for C28H30O10
Br2: C, 49.12; H, 4.42. Found: C, 49.15; H, 4.25.
-
(1R,2S,5R)-(-)-1-Men th yl 2,3-Bis-O-a cetyl-4,6-bis-O-(p-
br om oben zoyl)-â-D-ga la ctop yr a n osid e (9). Galactosyla-
tion of (-)-menthol (120 mg, 0.769 mmol, 5 equiv) led to
compound 9 (40% yield): TLC Rf ) 0.47 (n-hexane/EtOAc 8:2);
1
[R]25 ) -21.3 (c 1.48, CHCl3); H NMR (CDCl3) δ 7.94-7.55
D
(aromatic H’s), 5.71 (brd, J ) 2.6 Hz, 1H), 5.22 (dd, J ) 7.7,
10.4 Hz, 1H), 5.15 (dd, J ) 3.4, 10.4 Hz, 1H), 4.60 (d, J ) 7.7
Hz, 1H), 4.51 (dd, J ) 6.6, 11.3 Hz, 1H), 4.30 (dd, J ) 6.5,
11.3 Hz, 1H), 4.09 (t, J ) 6.6 Hz, 1H), 3.42 (ddd, J ) 4.2, 10.6,
14.9 Hz, 1H), 2.30 (ddd, J ) 2.4, 6.9, 9.4 Hz, 1H), 2.07 (s, 3H),
1.97 (m, 1H), 1.94 (s, 3H), 1.64 (brdd, J ) 2.5, 10.7 Hz, 3H),
1.33 (m, 1H), 1.25 (brt, J ) 7.1 Hz, 2H), 0.88 (t, J ) 7.2 Hz,

8256 J . Org. Chem., Vol. 63, No. 23, 1998
Padro´n et al.
6H), 0.83 (m, 1H), 0.73 (d, J ) 6.7 Hz, 3H); 13C NMR (CDCl3)
δ 170.21, 169.30, 165.26, 165.13, 132.02-127.90 (aromatic C’s),
99.65, 79.54, 71.19, 70.68, 69.29, 68.33, 62.29, 47.42, 41.00,
34.17, 31.46, 25.11, 23.05, 22.23, 20.86, 20.81, 20.58, 15.69.
Anal. Calcd for C34H40O10Br2: C, 53.26; H, 5.26. Found: C,
53.42; H, 5.09.
(CDCl3) δ 7.92-7.54 (aromatic H’s), 5.80 (brd, J ) 2.4 Hz, 1H),
5.49 (dd, J ) 3.4, 11.0 Hz, 1H), 5.29 (brd, J ) 3.6 Hz, 1H),
5.20 (dd, J ) 3.6, 11.0 Hz, 1H), 4.61 (t, J ) 6.2 Hz, 1H), 4.44
(dd, J ) 7.1, 11.4 Hz, 1H), 4.29 (dd, J ) 5.6, 11.4 Hz, 1H),
3.33 (m, 1H), 2.20 (m, 1H), 2.13 (brd, J ) 11.8 Hz, 1H), 2.04
(s, 3H), 1.97 (s, 3H), 1.62 (brd, J ) 9.8 Hz, 2H), 1.59 (m, 2H),
1.28 (q, J ) 11.0 Hz, 1H), 0.89 (d, J ) 7.3 Hz, 3H), 0.84 (m,
2H), 0.74 (d, J ) 6.6 Hz, 3H), 0.71 (d, J ) 7.0 Hz, 3H); 13C
NMR (CDCl3) δ 170.38, 170.15, 165.30, 165.09, 132.02-128.00
(aromatic C’s), 98.01, 82.27, 69.48, 68.77, 67.69, 66.64, 62.97,
48.55, 42.72, 34.11, 31.58, 24.87, 23.17, 22.05, 21.05, 20.99,
20.67, 15.78. Anal. Calcd for C34H40O10Br2: C, 53.26; H, 5.26.
Found: C, 53.28; H, 5.49.
(1S,2R,5S)-(+)-1-Men th yl 2,3-Bis-O-a cetyl-4,6-bis-O-(p-
br om oben zoyl)-r-D-ga la ctop yr a n osid e (15). According to
the general procedure for anomerization, compound 10 (10.7
mg, 0.014 mmol) was treated with anhydrous FeCl3 (7 mg,
0.041 mmol) and led to the desired compound 15 (4.7 mg, 6.1
µmol, 70% conversion, 60% yield): TLC Rf ) 0.51 (n-hexane/
EtOAc 8:2); [R]25D ) +71.0 (c 0.43, CHCl3); 1H NMR (CDCl3) δ
7.92-7.53 (aromatic H’s), 5.83 (brd, J ) 2.8 Hz, 1H), 5.47 (dd,
J ) 3.3, 11.0 Hz, 1H), 5.41 (d, J ) 3.8 Hz, 1H), 5.19 (dd, J )
3.8, 11.0 Hz, 1H), 4.52 (t, J ) 6.5 Hz, 1H), 4.48 (dd, J ) 6.2,
10.7 Hz, 1H), 4.25 (dd, J ) 6.2, 10.7 Hz, 1H), 3.46 (ddd, J )
4.0, 10.6, 14.5 Hz, 1H), 2.22 (ddd, J ) 2.4, 6.7, 9.5 Hz, 1H),
2.07 (s, 3H), 1.95 (s, 3H), 1.93 (m, 1H), 1.66 (brd, J ) 9.6 Hz,
2H), 1.36 (m, 2H), 1.31 (brs, 1H), 0.92 (d, J ) 7.0 Hz, 3H),
0.90 (d, J ) 6.6 Hz, 3H), 0.84 (m, 2H), 0.76 (d, J ) 6.9 Hz,
3H); 13C NMR (CDCl3) δ 170.46, 170.09, 165.18, 165.08,
132.01-128.03 (aromatic C’s), 93.12, 77.25, 69.20, 68.39, 67.59,
66.74, 62.40, 47.69, 40.07, 34.24, 31.31, 25.62, 22.66, 22. 24,
21.10, 20.79, 20.68, 15.24. Anal. Calcd for C34H40O10Br2: C,
53.26; H, 5.26. Found: C, 53.15; H, 5.46.
(1S,2R,5S)-(+)-1-Men th yl 2,3-Bis-O-a cetyl-4,6-bis-O-(p-
br om oben zoyl)-â-D-ga la ctop yr a n osid e (10). This com-
pound was obtained in 31% yield from 5 equiv of (+)-menthol
(120 mg, 0.769 mmol) following the general procedure for
â-galactosylation: TLC Rf ) 0.57 (n-hexane/EtOAc 8:2); [R]25
D
) +17.6 (c 1.58, CHCl3); 1H NMR (CDCl3) δ 7.96-7.56
(aromatic H’s), 5.70 (brd, J ) 2.8 Hz, 1H), 5.31 (dd, J ) 7.9,
10.4 Hz, 1H), 5.14 (dd, J ) 3.4, 10.4 Hz, 1H), 4.62 (d, J ) 7.9
Hz, 1H), 4.52 (dd, J ) 7.3, 11.4 Hz, 1H), 4.34 (dd, J ) 5.9,
11.4 Hz, 1H), 4.15 (t, J ) 6.5 Hz, 1H), 3.34 (ddd, J ) 4.3, 10.6,
14.9 Hz, 1H), 2.11 (m, 2H), 2.02 (s, 3H), 1.93 (s, 3H), 1.62 (brd,
J ) 9.6 Hz, 3H), 1.31 (m, 2H), 1.13 (q, J ) 12.2 Hz, 1H), 0.94
(m, 1H), 0.88 (d, J ) 7.1 Hz, 3H), 0.80 (d, J ) 6.5 Hz, 3H),
0.75 (d, J ) 6.9 Hz, 3H); 13C NMR (CDCl3) δ 170.18, 169.26,
165.24, 165.15, 131.97-127.76 (aromatic C’s), 102.62, 83.37,
71.17, 70.76, 69.26, 68.24, 62.43, 48.01, 42.95, 34.09, 31.61,
24.94, 22.74, 22.12, 21.00, 20.59, 20.54, 15.84. Anal. Calcd
for C34H40O10Br2: C, 53.26; H, 5.26. Found: C, 53.30; H, 5.61.
Meth yl 2,3-Bis-O-a cetyl-4,6-bis-O-(p-br om oben zoyl)-r-
D-ga la ctop yr a n osid e (11). According to the general proce-
dure for anomerization, compound 6 (23 mg, 0.037 mmol) was
treated with anhydrous FeCl3 (0.111 mmol) and led to the
desired compound 11 (0.022 mmol, 60% yield): TLC Rf ) 0.37
(n-hexane/EtOAc 6:4); [R]25D ) +54.1 (c 0.48, CHCl3); 1H NMR
(CDCl3) δ 7.93-7.56 (aromatic H’s), 5.79 (brd, J ) 2.7 Hz, 1H),
5.48 (dd, J ) 3.4, 10.8 Hz, 1H), 5.24 (dd, J ) 3.5, 10.8 Hz,
1H), 5.11 (d, J ) 3.5 Hz, 1H), 4.51 (dd, J ) 6.8, 11.0 Hz, 1H),
4.43 (t, J ) 6.2 Hz, 1H), 4.29 (dd, J ) 5.8, 11.0 Hz, 1H), 3.44
(s, 3H), 2.09 (s, 3H), 1.94 (s, 3H); 13C NMR (CDCl3) δ 170.39,
169.97, 165.23, 165.05, 132.04-127.95 (aromatic C’s), 97.29,
69.16, 68.29, 67.59, 66.33, 62.55, 55.62, 20.80, 20.62. Anal.
Calcd for C25H24O10Br2: C, 46.73; H, 3.77. Found: C, 46.66;
H, 3.89.
1,2,3,4,6-P en ta k is-O-(p-br om oben zoyl)-D-ga la ctop yr a -
n osid e (16). Following the general procedure for p-bromoben-
zoylation, D-(+)-galactose (1.0 g, 5.55 mmol) led to the mixture
of anomers of 16 (5.55 g, 5.05 mmol, 91%): TLC Rf ) 0.5 (n-
1
hexane/EtOAc 7:3); H NMR (mixture of anomers) (CDCl3) δ
7.95-7.42 (aromatic H’s), 6.22 (brd, J ) 8.3 Hz, 1H), 5.98 (m,
2H), 5.71 (brdd, J ) 3.4, 10.4 Hz, 1H), 4.63 (brdd, J ) 6.4,
11.0 Hz, 1H), 4.54 (brt, J ) 6.4 Hz, 1H), 4.43 (brdd, J ) 6.4,
11.0 Hz, 1H).
Isop r op yl 2,3-Bis-O-a cetyl-4,6-bis-O-(p-br om oben zoyl)-
r-D-ga la ctop yr a n osid e (12). Compound 12 (75% yield) was
obtained from its â-anomer 7 (22 mg, 0.033 mmol) following
the general procedure for anomerization (82% conversion):
2,3,4,6-Tetr a k is-O-(p-br om oben zoyl)-r-D-ga la ctop yr a -
n osyl Br om id e (17). This reaction was performed from the
mixture of anomers of 16 (4.98 g, 4.55 mmol) and following
the corresponding general procedure. Purification by flash
column chromatography (n-hexane/EtOAc 9:1) afforded com-
pound 17 (4.01 g, 4.11 mmol, 90%): TLC Rf ) 0.53 (n-hexane/
TLC Rf ) 0.31 (n-hexane/EtOAc 7:3); [R]25 ) +67.3 (c 1.11,
D
CHCl3); 1H NMR (CDCl3) δ 7.93-7.55 (aromatic H’s), 5.79 (brd,
J ) 2.5 Hz, 1H), 5.47 (dd, J ) 3.4, 10.9 Hz, 1H), 5.33 (d, J )
3.7 Hz, 1H), 5.15 (dd, J ) 3.7, 10.9 Hz, 1H), 4.55 (t, J ) 6.4
Hz, 1H), 4.48 (dd, J ) 6.9, 11.1 Hz, 1H), 4.27 (dd, J ) 5.9,
11.1 Hz, 1H), 3.89 (sep, J ) 6.2 Hz, 1H), 2.07 (s, 3H), 1.94 (s,
3H), 1.24 (d, J ) 6.2 Hz, 3H), 1.13 (d, J ) 6.1 Hz, 3H); 13C
NMR (CDCl3) δ 170.43, 170.07, 165.25, 165.08, 132.01-128.01
(aromatic C’s), 94.84, 71.49, 69.26, 68.54, 67.74, 66.35, 62.69,
23.15, 21.66, 20.72, 20.65. Anal. Calcd for C27H28O10Br2: C,
48.36; H, 4.21. Found: C, 48.38; H, 4.14.
EtOAc 7:3); [R]25 ) +193.6 (c 1.90, CHCl3); FAB-MS m/z 998
D
(7, [M + Na]+), 895 (3, [M - Br]+), 711 (3, [M - Br-BrBz]+),
183 (100, BrBz); 1H NMR (CDCl3) δ 7.89-7.42 (aromatic H’s),
6.92 (d, J ) 4.0 Hz, 1H), 6.05 (brd, J ) 2.6 Hz, 1H), 5.98 (dd,
J ) 3.3, 10.4 Hz, 1H), 5.60 (dd, J ) 4.0, 10.4 Hz, 1H), 4.89 (t,
J ) 6.3 Hz, 1H), 4.61 (dd, J ) 6.7, 11.6 Hz, 1H), 4.44 (dd, J )
6.1, 11.6 Hz, 1H); 13C NMR (CDCl3) δ 165.10, 164.75, 164.62,
164.55, 132.21-127.22 (aromatic C’s), 87.71, 71.55, 69.08,
68.48, 68.19, 61.61. Anal. Calcd for C34H23O9Br5: C, 41.88;
H, 2.38. Found: C, 42.26; H, 2.25.
ter t-Bu tyl 2,3-Bis-O-a cetyl-4,6-bis-O-(p-br om oben zoyl)-
r-D-ga la ctop yr a n osid e (13). According to the general pro-
cedure for anomerization, compound 8 (22 mg, 0.032 mmol)
was treated with anhydrous FeCl3 (15 mg, 0.096 mmol) and
led to the desired compound 13 (2.3 mg, 3.3 µmol, 10% yield):
Meth yl 2,3,4,6-Tetr a k is-O-(p-br om oben zoyl)-â-D-ga la c-
top yr a n osid e (18). Following the general procedure for
â-galactosylation, from 300 mg (0.31 mmol) of 17 and 1 mL of
dry MeOH was obtained the desired galactopyranoside 18 (282
mg, 0.30 mmol, 98%): TLC Rf ) 0.35 (n-hexane/EtOAc 7:3);
TLC Rf ) 0.35 (n-hexane/EtOAc 8:2); [R]25 ) +70.0 (c 0.21,
D
CHCl3); 1H NMR (CDCl3) δ 7.93-7.55 (aromatic H’s), 5.78 (brd,
J ) 3.0 Hz, 1H), 5.51 (d, J ) 3.6 Hz, 1H), 5.48 (dd, J ) 3.2,
10.9 Hz, 1H), 5.14 (dd, J ) 3.6, 10.9 Hz, 1H), 4.63 (t, J ) 6.3
Hz, 1H), 4.45 (dd, J ) 7.2, 11.3 Hz, 1H), 4.26 (dd, J ) 6.0,
11.3 Hz, 1H), 2.06 (s, 3H), 1.94 (s, 3H), 1.22 (s, 9H); 13C NMR
(CDCl3) δ 170.47, 170.18, 165.29, 165.11, 132.01-128.06
(aromatic C’s), 90.78, 75.97, 69.38, 68.65, 67.78, 66.05, 62.77,
28.37, 20.82, 20.69. Anal. Calcd for C28H30O10Br2: C, 49.12;
H, 4.42. Found: C, 49.15; H, 4.15.
[R]25 ) +132.63 (c 3.8, CHCl3); FAB-MS m/z 948 (13, [M +
D
Na]+), 895 (3, [M - OMe]+), 183 (100, BrBz). 1H NMR (CDCl3)
δ: 7.92-7.40 (aromatic H’s), 5.92 (d, J ) 3.3 Hz, 1H), 5.70
(dd, J ) 7.7, 10.4 Hz, 1H), 5.54 (dd, J ) 3.3, 10.4 Hz, 1H),
4.73 (d, J ) 7.7 Hz, 1H), 4.67 (dd, J ) 6.6, 11.2, 1H), 4.39 (dd,
J ) 6.6, 11.2 Hz, 1H), 4.30 (brt, J ) 6.6 Hz, 1H), 3.59 (s, 3H);
13C NMR (CDCl3) δ 165.28, 164.87, 164.79, 164.62, 132.13-
127.45 (aromatic C’s), 102.26, 71.81, 71.02, 69.86, 68.23, 61.95,
57.33. Anal. Calcd for C35H26O10Br4: C, 45.39; H, 2.83.
Found: C, 45.39; H, 2.79.
(1R,2S,5R)-(-)-1-Men th yl 2,3-Bis-O-a cetyl-4,6-bis-O-(p-
br om oben zoyl)-r-D-ga la ctop yr a n osid e (14). Following the
general procedure, anomerization of 9 (36 mg, 0.047 mmol)
with anhydrous FeCl3 (23 mg, 0.141 mmol) led to compound
14 (0.019 mmol, 89% conversion, 47% yield): TLC Rf ) 0.47
(n-hexane/EtOAc 8:2); [R]25D ) +41.5 (c 0.84, CHCl3); 1H NMR
(2R)-(-)-2-Octyl 2,3,4,6-Tetr a k is-O-(p-br om oben zoyl)-
â-D-ga la ctop yr a n osid e (19). Using the general procedure

Alkyl Galactopyranosides
J . Org. Chem., Vol. 63, No. 23, 1998 8257
for â-galactosylation, from 300 mg (0.31 mmol) of 17 and 417
µL (2.69 mmol) of (-)-octanol was obtained compound 19 (114.2
mg, 0.111 mmol, 36%): TLC Rf ) 0.51 (n-hexane/EtOAc 7:3);
(26 mg, 0.162 mmol) led to compound 23 (32 mg, 0.034 mmol,
64% yield): TLC Rf ) 0.39 (n-hexane/EtOAc 7:3); [R]25
)
D
+178.1 (c 1.16, CHCl3); FAB-MS m/z 949 (6, [M + Na]+), 895
(5, [M - OMe]+), 183 (100, BrBz); 1H NMR(CDCl3) δ 7.91-
7.40 (aromatic H’s), 5.97 (d, J ) 3.3 Hz, 1H), 5.92 (dd, J )
3.3, 10.5 Hz, 1H), 5.62 (dd, J ) 3.5, 10.5 Hz, 1H), 5.28 (d, J )
3.5 Hz, 1H), 4.58 (m, 2H), 4.39 (dd, J ) 9.0, 11.9 Hz, 1H), 3.48
(s, 3H); 13C NMR (CDCl3) δ 165.28, 165.25, 164.89, 164.71,
132.12-127.82 (aromatic C’s), 97.52, 69.35, 69.26, 68.50, 66.55,
62.50, 55.79. Anal. Calcd for C35H26O10Br4: C, 45.39; H, 2.83.
Found: C, 45.38; H, 2.96.
[R]25 ) +115.9 (c 2.85, CHCl3); FAB-MS m/z 1047 (9, [M +
D
Na]+), 183 (100, BrBz); 1H NMR (CDCl3) δ 7.93-7.40 (aromatic
H’s), 5.91 (d, J ) 3.3 Hz, 1H), 5.66 (dd, J ) 7.9, 10.4 Hz, 1H),
5.53 (dd, J ) 3.3, 10.4 Hz, 1H), 4.83 (d, J ) 7.9, 1H), 4.63 (dd,
J ) 6.6, 11.3 Hz, 1H), 4.39 (dd, J ) 6.6, 11.3 Hz, 1H), 4.28
(brt, J ) 6.6 Hz, 1H), 3.81 (sep, J ) 6.2 Hz, 1H), 1.62 (m, 1H),
1.42 (m, 1H), 1.23 (m, 8H), 1.05 (d, J ) 6.2 Hz, 3H), 0.86 (brt,
J ) 6.9 Hz, 3H); 13C NMR (CDCl3) δ 165.22, 164.93, 164.77,
164.42, 132.05-127.54 (aromatic C’s), 99.92, 76.87, 72.00,
70.90, 70.11, 68.36, 62.14, 36.83, 31.76, 29.12, 25.26, 22.55,
19.78, 14.06. Anal. Calcd for C42H40O10Br4: C, 49.25; H, 3.94.
Found: C, 49.26; H, 3.97.
(2R)-(-)-2-Octyl 2,3,4,6-Tetr a k is-O-(p-br om oben zoyl)-
r-D-ga la ctop yr a n osid e (24). According to the general pro-
cedure for anomerization, compound 19 (48 mg, 0.046 mmol)
was treated with anhydrous FeCl3 (23 mg, 0.14 mmol) and led
to the desired compound 24 (0.039 mmol, 95% conversion and
(2S)-(+)-2-Octyl 2,3,4,6-Tetr a k is-O-(p-br om oben zoyl)-
â-D-ga la ctop yr a n osid e (20). This compound was obtained
by using (+)-2-octanol (425 µL, 2.69 mmol) and according to
the general procedure for â-galactosylation (60% yield): TLC
Rf ) 0.5 (n-hexane/EtOAc 7:3); [R]25D ) +127.7 (c 2.84, CHCl3);
88% yield): TLC Rf ) 0.53 (n-hexane/EtOAc 8:2); [R]25
)
D
+165.8 (c 1.65, CHCl3); FAB-MS m/z 1047 (4, [M + Na]+), 894
(4, [M - C8H17O]+), 183 (100, BrBz); 1H NMR (CDCl3) δ 7.91-
7.40 (aromatic H’s), 5.96 (brs, 1H), 5.93 (dd, J ) 3.4, 10.3 Hz,
1H), 5.55 (dd, J ) 3.7, 10.3 Hz, 1H), 5.48 (d, J ) 3.7 Hz, 1H),
4.71 (t, J ) 6.4 Hz, 1H), 4.55 (dd, J ) 7.0, 11.4 Hz, 1H), 4.36
(dd, J ) 5.9, 11.4 Hz, 1H), 3.70 (sep, J ) 6.5 Hz, 1H), 1.47 (m,
1H), 1.32 (m, 1H), 1.26 (d, J ) 6.2 Hz, 4H), 1.07 (m, 5H), 0.90
(m, 2H), 0.77 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3) δ 165.29,
165.26, 164.92, 164.81, 132.11-127.87 (aromatic C’s), 96.90,
77.62, 69.64, 69.52, 68.64, 66.67, 62.71, 36.83, 31.66, 29.32,
25.20, 22.57, 21.58, 14.02. Anal. Calcd for C42H40O10Br4: C,
49.25; H, 3.94. Found: C, 49.13; H, 4.04.
1
FAB-MS m/z 1047 (4, [M + Na]+), 183 (100, BrBz); H NMR
(CDCl3) δ 7.93-7.39 (aromatic H’s), 5.91 (brd, J ) 3.0 Hz, 1H),
5.70 (dd, J ) 7.9, 10.4 Hz, 1H), 5.54 (dd, J ) 3.3, 10.4 Hz,
1H), 4.82 (d, J ) 7.9 Hz, 1H), 4.62 (dd, J ) 6.8, 11.3 Hz, 1H),
4.40 (dd, J ) 6.5, 11.3 Hz, 1H), 4.29 (brt, J ) 6.6 Hz, 1H),
3.72 (sep, J ) 6.2 Hz, 1H), 1.46 (m, 1H), 1.26 (brd, J ) 6.2 Hz,
5H), 1.18 (brd, J ) 6.2 Hz, 1H), 1.09 (brt, J ) 7.3 Hz, 1H),
1.04 (m, 3H), 0.87 (m, 2H), 0.77 (t, J ) 7.3 Hz, 3H); 13C NMR
(CDCl3) δ 165.23, 164.95, 164.78, 164.40, 132.05-127.50
(aromatic C’s), 101.89, 79.32, 71.90, 70.92, 70.08, 68.31, 62.15,
36.89, 31.59, 29.25, 25.38, 22.50, 21.80, 14.02. Anal. Calcd
for C42H40O10Br4: C, 49.25; H, 3.94. Found: C, 49.34; H, 3.94.
(1R,2S,5R)-(-)-1-Men th yl 2,3,4,6-Tetr a k is-O-(p-br om o-
ben zoyl)-â-D-ga la ctop yr a n osid e (21). This compound was
prepared in 38% yield from (-)-menthol (242 mg, 1.55 mmol),
following the general procedure for â-galactosylation. Chro-
matography was performed on Sephadex LH-20 (CHCl3/
MeOH/n-hexane 1:1:2): TLC Rf ) 0.53 (n-hexane/EtOAc 7:3);
(2S)-(+)-2-Octyl 2,3,4,6-Tetr a k is-O-(p-br om oben zoyl)-
r-D-ga la ctop yr a n osid e (25). Compound 25 (0.028 mmol, 77
yield, 95% conversion) was obtained from its â-anomer 20 (39
mg, 0.038 mmol) following the general procedure for anomer-
ization: TLC Rf ) 0.67 (n-hexane/EtOAc 8:2); [R]25D ) +190.2
(c 1.22, CHCl3); FAB-MS m/z 1047 (3, [M + Na]+), 894 (4, [M
1
- C8H17O]+), 183 (100, BrBz); H NMR (CDCl3) δ 7.91-7.41
(aromatic H’s), 5.97 (brd, J ) 3.0 Hz, 1H), 5.91 (dd, J ) 3.4,
10.4 Hz, 1H), 5.58 (dd, J ) 3.7, 10.4 Hz, 1H), 5.48 (d, J ) 3.7
Hz, 1H), 4.69 (t, J ) 6.4 Hz, 1H), 4.52 (dd, J ) 6.9, 11.4 Hz,
1H), 4.38 (dd, J ) 5.8, 11.4 Hz, 1H), 3.77 (sep, J ) 6.2 Hz,
1H), 1.60 (m, 1H), 1.45 (m, 1H), 1.28 (m, 8H), 1.02 (d, J ) 6.1
Hz, 3H), 0.86 (t, J ) 6.8 Hz, 3H); 13C NMR (CDCl3) δ 165.30,
165.22, 164.94, 164.81, 132.11-127.88 (aromatic C’s), 94.52,
75.13, 69.51, 69.34, 68.72, 66.94, 62.77, 37.07, 31.79, 29.29,
25.90, 22.63, 19.36, 14.08. Anal. Calcd for C42H40O10Br4: C,
49.25; H, 3.94. Found: C, 49.32; H, 3.93.
[R]25 ) +97.6 (c 2.77, CHCl3); FAB-MS m/z 1073 (13,
D
[M+Na]+), 895 (3, [M-C10H20O]+), 183 (100, BrBz); H NMR
1
(CDCl3) δ 7.91-7.41 (aromatic H’s), 5.90 (brd, J ) 3.1 Hz, 1H),
5.64 (dd, J ) 7.9, 10.4 Hz, 1H), 5.50 (dd, J ) 3.3, 10.4 Hz,
1H), 4.85 (d, J ) 7.9 Hz, 1H), 4.58 (dd, J ) 6.6, 11.3 Hz, 1H),
4.38 (dd, J ) 6.4, 11.3 Hz, 1H), 4.25 (t, J ) 6.5 Hz, 1H), 3.47
(ddd, J ) 4.2, 10.7, 14.8 Hz, 1H), 2.31 (ddd, J ) 2.4, 6.9, 9.2
Hz, 1H), 1.92 (brd, J ) 12.0 Hz, 1H), 1.59 (brs, 3H), 1.24 (m,
3H), 0.92 (m, 1H), 0.88 (d, J ) 7.0 Hz, 3H), 0.77 (d, J ) 6.6
Hz, 3H), 0.75 (d, J ) 6.9 Hz, 3H); 13C NMR (CDCl3) δ 165.30,
164.97, 164.82, 164.49, 132.11-127.58 (aromatic C’s), 99.49,
79.74, 72.18, 70.90, 70.16, 68.50, 62.30, 47.30, 41.13, 34.02,
31.40, 25.19, 23.04, 22.03, 20.81, 15.71. Anal. Calcd for
(1R,2S,5R)-(-)-1-Men th yl 2,3,4,6-Tetr a k is-O-(p-br om o-
ben zoyl)-r-D-ga la ctop yr a n osid e (26). Following the gen-
eral procedure, anomerization of 21 (30 mg, 0.028 mmol) with
anhydrous FeCl3 (14 mg, 0.086 mmol) led to compound 26
(0.015 mmol, 83% conversion, 64% yield): TLC Rf ) 0.52 (n-
C
44H42O10Br4: C, 50.31; H, 4.03. Found: C, 50.37; H, 4.01.
hexane/EtOAc 7.5:2.5); [R]25 ) +154.6 (c 1.79, CHCl3); FAB-
D
(1S,2R,5S)-(+)-1-Men th yl 2,3,4,6-Tetr a k is-O-(p-br om o-
MS m/z 1073 (8, [M + Na]+), 895 (3, [M - C10H20O]+), 183
(100, BrBz); 1H NMR (CDCl3) δ 7.90-7.40 (aromatic H’s), 5.95
(m, 2H), 5.59 (dd, J ) 3.6, 10.4 Hz, 1H), 5.48 (d, J ) 3.6 Hz,
1H), 4.74 (t, J ) 6.3 Hz, 1H), 4.52 (dd, J ) 7.1, 11.5 Hz, 1H),
4.37 (dd, J ) 5.6, 11.5 Hz, 1H), 3.34 (ddd, J ) 6.3, 10.5, 16.8
Hz, 1H), 2.18 (brd, J ) 12.2 Hz, 1H), 2.10 (ddd, J ) 2.2, 4.8,
7.0 Hz, 1H), 1.56 (m, 2H), 1.29 (brt, J ) 11.7 Hz, 2H), 1.11 (q,
J ) 12.2 Hz, 1H), 0.87 (m, 2H), 0.74 (d, J ) 6.5 Hz, 3H), 0.62
(d, J ) 7.0 Hz, 3H), 0.37 (d, J ) 6.9 Hz, 3H); 13C NMR (CDCl3)
δ 165.33, 165.26, 164.93, 164.84, 132.12-127.87 (aromatic C’s),
98.33, 82.71, 69.82, 69.68, 68.48, 66.84, 62.92, 48.56, 42.81,
34.08, 31.60, 24.72, 22.67, 22.05, 20.84, 13.41. Anal. Calcd
for C44H42O10Br4: C, 50.31; H, 4.03. Found: C, 50.31; H, 4.26.
ben zoyl)-â-D-ga la ctop yr a n osid e (22). Following the gen-
eral procedure for â-galactosylation, 2 equiv of (+)-menthol
(242 mg, 1.55 mmol) led to the desired galactopyranoside 22
in 34% yield: TLC Rf ) 0.49 (n-hexane/EtOAc 7:3); [R]25
)
D
+144.3 (c 2.8, CHCl3); FAB-MS m/z 1072 (4, [M + Na]+), 894
(3, [M-C10H20O]+), 183 (100, BrBz); 1H NMR (CDCl3) δ 7.94-
7.39 (aromatic H’s), 5.90 (brd, J ) 3.0 Hz, 1H), 5.74 (dd, J )
7.9, 10.4 Hz, 1H), 5.54 (dd, J ) 3.3, 10.4 Hz, 1H), 4.84 (d, J )
7.9, 1H), 4.61 (dd, J ) 7.3, 11.3 Hz, 1H), 4.42 (dd, J ) 5.9,
11.3 Hz, 1H), 4.31 (brt, J ) 6.4 Hz, 1H), 3.35 (ddd, J ) 4.2,
10.5, 14.7 Hz, 1H), 2.20 (brd, J ) 12.4 Hz, 1H), 1.89 (ddd, J )
1.9, 6.8, 11.8 Hz, 1H), 1.58 (m, 2H), 1.26 (brs, 2H), 1.19 (q, J
) 11.4 Hz, 1H), 0.95 (brt, J ) 6.8 Hz, 1H), 0.87 (m, 1H), 0.81
(d, J ) 6.3 Hz, 3H), 0.53 (d, J ) 7.0 Hz, 3H), 0.40 (d, J ) 6.9
Hz, 3H); 13C NMR (CDCl3) δ 165.26, 164.96, 164.79, 164.45,
132.06-127.46 (aromatic C’s), 102.76, 83.61, 71.91, 70.93,
70.01, 68.39, 62.40, 47.95, 43.03, 34.04, 31.62, 24.75, 22.70,
22.12, 20.66, 15.56. Anal. Calcd for C44H42O10Br4: C, 50.31;
H, 4.03. Found: C, 50.32; H, 4.05.
(1S,2R,5S)-(+)-1-Men th yl 2,3,4,6-Tetr a k is-O-(p-br om o-
ben zoyl)-r-D-ga la ctop yr a n osid e (27). This compound (18.3
mg, 0.015 mmol) was obtained from its â-anomer 22 (30 mg,
0.028 mmol) following the general procedure for anomerization
(90% conversion and 68% yield): TLC Rf ) 0.6 (n-hexane/
EtOAc 8:2); [R]25D ) +166.5 (c 0.52, CHCl3); FAB-MS m/z 1073
1
Meth yl 2,3,4,6-Tetr a k is-O-(p-br om oben zoyl)-r-D-ga la c-
top yr a n osid e (23). Following the general procedure, ano-
merization of 18 (50 mg, 0.054 mmol) with anhydrous FeCl3
(5, [M + Na]+), 895 (5, [M - C10H20O]+), 183 (100, BrBz); H
NMR (CDCl3) δ 7.90-7.41 (aromatic H’s), 6.00 (brd, J ) 2.6
Hz, 1H), 5.92 (dd, J ) 3.3, 10.6 Hz, 1H), 5.60 (dd, J ) 3.8,

8258 J . Org. Chem., Vol. 63, No. 23, 1998
Padro´n et al.
10.6 Hz, 1H), 5.56 (d, J ) 3.8 Hz, 1H), 4.66 (t, J ) 6.5 Hz,
1H), 4.55 (dd, J ) 6.3, 11.3 Hz, 1H), 4.34 (dd, J ) 6.8, 11.3
Hz, 1H), 3.50 (ddd, J ) 4.0, 10.6, 14.5 Hz, 1H), 2.26 (ddd, J )
2.4, 6.9, 9.4 Hz, 1H), 1.85 (brd, J ) 12.0 Hz, 1H), 1.63 (brt, J
) 12.3 Hz, 2H), 1.30 (m, 2H), 0.94 (d, J ) 7.0 Hz, 3H), 0.87
(m, 1H), 0.78 (d, J ) 7.0 Hz, 3H), 0.71 (d, J ) 6.5 Hz, 3H),
0.66 (m, 1H); 13C NMR (CDCl3) δ 165.40, 165.21, 164.93,
164.84, 132.11-127.91 (aromatic C’s), 93.56, 77.91, 69.42,
69.30, 68.59, 67.02, 62.41, 47.42, 40.34, 34.09, 31.25, 25.73,
22.67, 21.99, 21.09, 15.32. Anal. Calcd for C44H42O10Br4: C,
50.31; H, 4.03. Found: C, 50.29; H, 4.34.
de Educacio´n y Cultura (Spain), through Grant No.
PB96-1040, is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Eleven tables con-
taining low-temperature CD data (EtOH), calculated rotameric
populations by using the four mentioned sets of equations in
CD3CN and CDCl3, and 1H and 13C NMR data (CDCl3) of
compounds 6-15 and 18-27 (9 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
Ack n ow led gm en t. Support of this work by the
Direccio´n General de Ensen˜anza Superior, Ministerio
J O981002T