Experimental evidence on the hydroxymethyl group conformation in alkyl β-D-mannopyranosides

Article abstract of DOI:10.1016/j.tetasy.2004.06.019

A rotational population study of the hydroxymethyl group of alkyl β-D-mannopyranosides was performed by means of CD and NMR spectroscopy. Three different benzyl, acetyl, and p-bromobenzoyl series of alkyl β-D-mannopyranosides with different chiral and non

Full text of DOI:10.1016/j.tetasy.2004.06.019

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2385–2397
Experimental evidence on the hydroxymethyl group conformation
in alkyl b-D-mannopyranosides
*
´
Carlos Mayato, Rosa L. Dorta and Jesu´s T. Vazquez
´ ´ ´
Instituto Universitario de Bio-Organica ‘Antonio Gonzalez’, Universidad de La Laguna, Avda, Astrofısico Fco,
´
Sanchez 2, 38206 La Laguna, Tenerife, Spain
Received 11 May 2004; accepted 16 June 2004
Abstract—A rotational population study of the hydroxymethyl group of alkyl b-D-mannopyranosides was performed by means of
CD and NMR spectroscopy. Three different benzyl, acetyl, and p-bromobenzoyl series of alkyl b-D-mannopyranosides with different
chiral and nonchiral aglycons were synthesized and analyzed. Different rotational populations were observed for each series by
changing the structure of the aglycon. The results showed a clear correlation between the rotational population of the hydroxymeth-
yl group around the C5–C6 bond and the pKa of the bonded alcohol (aglycon). The population of the gt rotamer gradually increased
as the pKa increased while that of the gg rotamer decreased and the population of the tg rotamer remained almost constant. This is
explained by the exo-anomeric effect. For chiral alkyl derivatives, the results also showed a close dependence on the absolute con-
figuration of the aglycon. Comparison of rotational population anomers revealed the dependence of the hydroxymethyl group on
the anomeric configuration and a greater dependence on the aglycon structure in the b anomers.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
The conformation of the hydroxymethyl group around
the C5–C6 bond can be expressed by the torsional angle
x (O5–C5–C6–O6), although it is generally defined by
means of the populations of its three main rotamers,
the gauche gauche (gg), the gauche trans (gt), and the
trans gauche (tg) (Fig. 1).
Apart from their well-appreciated roles as supporting
matrices, energy storage, and biosynthetic starting mate-
rials, carbohydrates are cast in a variety of interesting
settings such as glycoconjugate antibiotics,1 antitumor
agents2 and cardiotonic glycosides.3 The importance of
carbohydrate domains (in the context of glycoproteins
and glycolipids) as elements in cell surface recognition
is clear from their role in cellular adhesion4,5 and as
blood group determinants.6
gg
OH
H
H
S
R
gt
tg
OH
O
OH
O
OH
H
R
HO
HO
H
H
H
6
OH
R
S
S
O
HO
HO
5
OR
OR
OR
HO
HO
HO
H
H
H
To understand the biological functions of saccharides
from a molecular point of view, it is of primary impor-
tance7 to know the conformational preferences of these
species in solution, in addition to their three-dimen-
sional structures. Due to the flexibility of the glycosidic
linkages and the rotation of the hydroxymethyl and
other pendant groups, the conformational analysis of
an oligosaccharide is difficult. In fact, the factors gov-
erning the rotamer populations of the hydroxymethyl
group are still not fully understood.
Figure 1. Molecular structure of an alkyl b-D-mannopyranoside in its
three main rotamers, the gg (x=ꢀ60ꢁ), gt (x=60ꢁ), and tg (x=180ꢁ)
rotamers around the C5–C6 bond.
Our previous studies on the rotational population
dependence of the hydroxymethyl group in gluco-,8
galacto-,9 and a-D-mannopyranosides,10 as well as in
disaccharides,11 on the aglycon and its absolute configu-
ration, have revealed remarkable conformational prop-
erties. To complete our hydroxymethyl rotamer
population studies for the three most important mono-
saccharides in nature, we have synthesized three differ-
ent alkyl b-D-mannopyranosides series and analyzed
them by means of CD and NMR spectroscopy. The
*
Corresponding author. Tel.: +34-922-318581; fax: +34-922-
318571; e-mail: jtruvaz@ull.es
0957-4166/$ - see front matter ꢀ 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.06.019

2386
C. Mayato et al. / Tetrahedron: Asymmetry 15 (2004) 2385–2397
results show a clear correlation between the hydroxy-
methyl rotational populations around the C5–C6
bond and the pKa of the bonded alcohol (aglycon).
The rotational populations are explained on the basis
of different values of the exo-anomeric effect and by
occasionally also taking into account nonbonded inter-
actions. The results also establish the highest population
as the gg or gt rotamer depending on the aglycon.
the Karplus equations recently proposed by Serianni
co-workers.14 The 1H NMR signals of the prochiral pro-
tons at C6, H6R and H6S were differentiated according
to the data in the literature,15 on the basis of their chem-
ical shifts and coupling constants. In general, for the D-
manno-series saccharides, H6R proton signals appear at
a higher field than H6S signals (dH6S>dH6R). The re-
verse behavior was observed for acetyl-D-manno-series
saccharides (dH6R>dH6S), and JH5,H6R coupling con-
stants have higher values than JH5,H6S. Thus, com-
pounds 7–12 showed chemical shifts for H6S between
d 3.82 and 3.74and for H6 R between 3.73 and 3.68,
compounds 19–24 for H6S between d 4.78 and 4.68
and for H6R between 4.51 and 4.43. As expected, the
acetyl derivatives 13–18 showed the reverse behavior,
chemical shifts for H6S were located at a higher field
(d 4.17–4.12) than those for H6R (d 4.31–4.23). Inde-
pendent of the substitution, all model compounds 7–24
2. Results and discussion
The model alkyl b-D-mannopyranosides were synthe-
sized in good yields as shown in Scheme 1. The commer-
cially available tri-O-benzyl-glucal was treated with
dimethyldioxirane (DMDO) to obtain the correspond-
ing 1,2-anhydro sugar, which by adding ZnCl2 and the
appropriate alcohol led to the alkyl b-D-glucopyrano-
sides 1–6 in good yields.12 Oxidation with DMSO–
Ac2O and subsequent reduction with NaBH4 in
CH2Cl2/MeOH (1:1) led to the alkyl b-D-mannopyrano-
sides 7–12.13 Deprotection of the benzyl groups and sub-
sequent acetylation or p-bromobenzoylation led to the
tetra-O-acetyl derivatives 13–18 or to the tetra-O-(p-
bromobenzoyl) derivatives 19–24, respectively. The
1-acyl derivatives 25 and 26 were obtained by per-acetyl-
ation and per-p-bromobenzoylation of D-mannose,
respectively.
showed higher JH5,H6R coupling constants than JH5,H6S
.
Tables 1–3 show the JH5,H6 coupling constants and cal-
culated rotameric populations (%) around the C5–C6
bond for the b-D-mannose derivatives 7–26.16
Analysis of the data for the three sets of model com-
pounds (Tables 1–3) revealed a general increase in the
JH5,H6R coupling constant values from 1-acyl, to pri-
mary, to secondary, and to tertiary alkyl b-D-mannopyr-
anosides; the chiral (ꢀ)-menthyl mannopyranosides 10
and 22 being an exception in this behavior. On the other
hand, the JH5,H6S coupling constant values obtained for
the alkyl mannopyranosides remained almost constant
in each series. To calculate rotamer populations of the
hydroxymethyl group, each pair of JH5,H6 coupling con-
stant values were used in the Karplus equations pro-
All these compounds were mainly characterized on the
basis of their one- (1H and 13C) and two-dimensional
NMR spectra. The anomeric configuration was assigned
in each case on the basis of the T-ROESY NMR experi-
ment. Furthermore, the lower chemical shift values ob-
tained for H3 and H5 in the acetyl derivatives than in
the corresponding a-anomers10 confirmed the assign-
ment. In addition, the T-ROESY NMR spectra also
showed a strong cross-peak between the anomeric pro-
ton H1 and the aglyconic proton Hx, confirming that
for the more stable conformation, these two protons
are located on the same side.
Table 1. JH5,H6 Coupling constants (CDCl3) and calculated rotameric
populations (%) for the alkyl tri-benzyl b-D-mannopyranosides 7–12
Compd. Aglycon
JH5,H6S JH5,H6R Pgg Pgt Ptg
7
Methyl
Isopropyl
Cyclohexyl
2.0
1.9
1.9
5.2
5.6
5.7
5.1
5.8
5.7
48
44
43
50
43
44
46
51
52
46
54
53
6
5
5
4
3
3
8
9
10
11
12
(ꢀ)-Menthyl 1.8
The rotamer populations of the hydroxymethyl group
were calculated from the observed JH5,H6R and JH5,H6S
coupling constants (accuracy 0.1Hz) and by using
(+)-Menthyl
tert-Butyl
1.7
1.7
OBn
OBn
OBn
OBn
OH
O
1. DMDO-Acetone
CH2Cl2, 0 oC
O
NaBH4
O
O
DMSO-Ac2O
BnO
BnO
BnO
BnO
BnO
BnO
OR
OR
OR
2. ROH, ZnCl2
THF, -78oC—r.t.
CH2Cl2/MeOH
0oC—r.t.
BnO
OH
O
7—12
1—6
OBn
OAc
OAc
O
Ac2O/Py
AcO
AcO
1, 7, 13, 19: R = methyl
2, 8, 14, 20: R = isopropyl
3, 9, 15, 21: R = cyclohexyl
4, 10, 16, 22: R = (−)-menthyl
5, 11, 17, 23: R = (+)-menthyl
6, 12, 18, 24: R = t-butyl
OR
OR
13 —18
OR
H2/Pd-C
EtOH
O
25, R = Ac
26, R = p-BrBz
RO
RO
OBzBr
OBzBr
OR
p-BrBzCl
O
H
BrBzO
BrBzO
Py, DMAP,60 ºC
OR
19—24
Scheme 1. Synthesis of the alkyl b-D-mannopyranosides 7–24.

C. Mayato et al. / Tetrahedron: Asymmetry 15 (2004) 2385–2397
Table 2. JH5,H6 Coupling constants (CDCl3) and calculated rotameric
2387
Pgg Pgt Ptg
populations (%) for the alkyl tetra-acetyl b-D-mannopyranosides 13–
18 and for the penta-acetyl b-D-mannopyranoside 25
60
40
20
0
Compd. Aglycon
JH5,H6S JH5,H6R Pgg Pgt Ptg
25
13
14
15
16
17
18
(Acetyl)
Methyl
1.5
2.6
2.3
2.7
4.9
5.3
54
43
39
37
31
45
44
51
49
53
1
13
10
14
16
Isopropyl
Cyclohexyl
5.8
5.8
25 13 14 15 16 17 18
(ꢀ)-Menthyl 2.9
6.2
6.429
6.5
(+)-Menthyl
tert-Butyl
2.5
2.7
55
29
16
57
Figure 3. Calculated rotameric populations for compounds 13–18 and
25 (acetyl series).
14
Pgg Pgt Ptg
60
Table 3. JH5,H6 Coupling constants (CDCl3) and calculated rotameric
populations (%) for the alkyl tetra-(p-bromobenzoyl)-b-D-mannopyr-
anosides 19–24 and for the penta-(p-bromobenzoyl)-b-D-mannopyr-
anoside 26
40
20
Compd. Aglycon
JH5,H6S JH5,H6R Pgg Pgt Ptg
26
19
20
21
22
23
24
(p-Br-benzoyl) 2.8
4.5
4.6
5.0
5.3
4.5
5.8
6.1
50
47
42
38
50
35
34
38
41
34
15
18
19
21
16
0
Methyl
3.1
3.2
3.3
2.9
3.1
3.2
26 19 20 21 22 23 24
Isopropyl
Cyclohexyl
(ꢀ)-Menthyl
(+)-Menthyl
tert-Butyl
Figure 4. Calculated rotameric populations for compounds 19–24 and
26 (benzoyl series).
8344 18
31 51
19
60
40
20
posed by Serianni et al.14 This set of equations was cho-
sen since it provides a more accurate representation of
the rotameric populations in solution and, in contrast
to other Karplus equations, positive values for the tg ro-
tamer population.16
As expected, the mentioned coupling constants behavior
was reflected in the calculated rotamer populations of
the hydroxymethyl group (Tables 1–3). Thus, as shown
in Figures 2–4 from the 1-acyl (25, 26), to the primary
(7, 13, 19), to secondaries (8–11, 14–17, 20–23), and to
the tertiary (12, 18, 24) alkyl b-D-mannopyranosides
the gt rotamer population increased, the gg population
decreased, and that for the least populated tg rotamer
remained almost constant, with the (ꢀ)-menthyl deriva-
tives 10 and 22 being an exception.
0
60
40
20
0
60
Pgg
Pgt
Ptg
60
40
20
0
40
20
iPrOH
tBuOH
0
MeOH
Menthols
7
8
9
10
11
12
Figure 2. Calculated rotameric populations for compounds 7–12
(benzyl series).
15
18
20
17
19
16
pKa of ROH
Figure 5. Plots of rotamer populations versus pKa of bonded alcohols
for the three different series. Pgg (blue lines), Pgt (red lines) and Ptg
(yellow lines).
As can be observed in Figure 5 there is a clear correla-
tion between the rotamer population (Tables 1–3) and
the pKa of the alcohol17 bonded to the mannopyranosyl
system for all model compounds, except the (ꢀ)-menthyl
derivatives 10 (benzyl series) and 22 (benzoyl series) (see
below).18 This correlation can be explained by the stereo-
electronic exo-anomeric effect (Fig. 6)19 but not by steric
effects, since the bulkier secondary and tertiary alkyl

2388
C. Mayato et al. / Tetrahedron: Asymmetry 15 (2004) 2385–2397
endocyclic oxygen O5 and therefore without nonbonded
O
1
H
interactions. In addition, these secondary alkyl man-
nopyranosides possess higher gt and lower gg rotamer
populations than the other secondary alkyl mannopyr-
anosides (Tables 1–3). This result can be explained in
terms of a stronger exo-anomeric effect, as a conse-
quence of its high pKa value.
R
1
O
R
2
exo
H
Figure 6. Illustration of the molecular orbitals involved in the exo-
anomeric effect.
group (compared to the methyl) would lead to decreased
gt populations through nonbonded interactions with the
hydroxymethyl group. The value of the exo-anomeric
effect must increase from primary, to secondary, and
to tertiary alkyl mannopyranoside derivatives,20 produc-
ing a gradual shortening and lengthening of the O1–C1
and O5–C1 bonds, respectively, and leading to different
rotamer populations. Thus, an increase in the exo-ano-
meric effect produces increases and decreases in the gt
and gg populations, respectively. The smaller JH5,H6
coupling constant values obtained for the 1-acyl deriva-
tives 25 and 26 compared to the alkyl mannopyrano-
sides 13–18 and 19–24, respectively, support this
explanation. The delocalization of the nonbonding elec-
tron pair of the exocyclic oxygen with the C@O bond in
the 1-acyl derivatives lead to a low or nil participation of
the stereoelectronic exo-anomeric effect and therefore
high gg and low gt rotamer populations were obtained.
This relationship between the exo-anomeric effect and
the rotamer population of the hydroxymethyl group
seems to be general, since in alkyl gluco-8 and galacto-
pyranosides,9 an increase in the stereoelectronic exo-
anomeric effect also led to an increase in the population
of the gt rotamer. Additionally, according to the pyr-
anoside substitution (benzyl, acetyl, or benzoyl) and
the aglycon, the gg or gt rotamer has the highest
population.
The alkyl b-D-mannopyranosides have been substituted
with p-bromobenzoyl groups in order to accurately ana-
lyze the JH5,H6 coupling constant of the prochiral H6
proton signals, since these groups affect the proton
and carbon resonances where they are located, leading
therefore to less crowded NMR spectra. In addition,
these exciton-coupled chromophores permit their circu-
lar dichroism (CD) spectra to be measured. The high
sensitivity and straightforward spectral interpretation
of the circular dichroic exciton chirality method21 pro-
vides additional conformational information. On the
basis of the additivity of the amplitude (A value)22,23
or the principle of pairwise additivity,24 and taking into
account the interchromophoric distance and the dihe-
dral angle of the chromophores involved in a pairwise
interaction, the CD spectra of our model alkyl manno-
pyranosides must show deep negative split CD curves,
mainly as a consequence of the intense negative sign of
the 2/3, 3/4, and 2/4 pairwise interactions (Fig. 8). How-
ever, the amplitudes of the CD curves cannot be identi-
cal, because the alkyl mannopyranosides with different
rotamer populations will exhibit different contributions
of the pairwise interactions involving the chromophore
at the 6 position (Fig. 9).
O
O
O
The (ꢀ)-menthyl mannopyranosides 10, 16, and 22 de-
serve special consideration. Depending on the series, this
aglycon led to the gg (benzyl and benzoyl series) or gt
(acetyl series) rotamer as the most populated. For these
stereoisomers, the isopropyl group, located syn to the
endocyclic oxygen O5 in its most stable conformation,
is close to the hydroxymethyl group at C6 and therefore
nonbonded interactions between these two groups are
possible (Fig. 7). This explains why for these benzyl
and benzoyl derivatives the gg rotamer is the most pop-
ulated and in the acetyl series it is gt. The larger size of
the benzyl and benzoyl groups than the acetyl group led
the former derivatives to higher nonbonded interactions
with the isopropyl group. For this reason, the rotamer
populations of the (ꢀ)-menthyl derivatives 10 and 22
do not show the above mentioned correlation with its
pKa (Fig. 5).
3/4
2/4
2/3
Figure 8. Pairwise interactions with constant intensity and negative
sign for mannopyranosides.
nil
O
O
O
O
O
O
4/6
3/6
2/6
nil
nil
O
O
O
gg
gt
tg
ω
O
Figure 9. Pairwise interactions involving the chromophore at the 6
position in each of the three stable rotamers.
O
R
ψ
Figure 7. (ꢀ)-Menthyl b-D-mannopyranosides 10, 16, and 22.
The alkyl tetra-O-(p-bromobenzoyl)-b-D-mannopyrano-
sides exhibited negative split CD curves, more specifi-
cally, negative first Cotton effects at 250nm and
On the other hand, the (+)-menthyl derivatives have the
isopropyl group in an anti disposition with respect to the

C. Mayato et al. / Tetrahedron: Asymmetry 15 (2004) 2385–2397
2389
positive second Cotton affects at 232nm, centered on the
p-bromobenzoate kmax 245nm (Figs. 10 and 11).
effect was observed for the (ꢀ)-menthyl derivative 22
(ꢀ63.2) than for its stereoisomer (+)-menthyl 23
(ꢀ67.9), as expected. These intensities are consistent
only with a gradual decrease in the contribution of the
positively coupled 4/6 pairwise interaction (gg rotamer)
(Fig. 9).
30
∆ε
0
1
For CD and NMR data comparison, H NMR spectra
of compounds 19–24 were also recorded in CD3CN
(Table 4), since rotamer populations might be solvent
dependent. As listed in Table 4, the intensities of the
CD first Cotton effects (De1) and the rotamer popula-
tions calculated from the JH5,H6 coupling constants of
the NMR spectra are in good agreement.
19
21
20
20
24
250
300
−70
200
350 nm
250
Figure 10. CD spectra comparison of the model methyl, isopropyl,
cyclohexyl, and tert-butyl b-D-mannopyranosides 19–21 and 24,
respectively (in CH3CN).
In addition, comparison of the NMR data in CDCl3
(Table 3) with those in CD3CN (Table 4) reveals a slight
solvent dependence of the rotamer populations, the pop-
ulation of the gg rotamer increasing at the expense of the
gt for the polar solvent.
30
Comparative analysis, b versus a: The calculated rota-
tional populations of the a-10 and b-anomers of alkyl
mannopyranosides, obtained by applying the same set
of equations, were compared (Scheme 2). The analysis
shows a higher dependence on the structure of the agly-
con and a clearer behavior for the b than for the a ano-
mers (Fig. 12 for the acetyl series, Fig. 13 for benzoyl).
∆ε
0
19
22
23
250
−70
α-anomer β-anomer
200
350 nm
250
300
OAc
OAc
O
R = Methyl
13α
13
14
16
17
R = Isopropyl
14α
AcO
AcO
Figure 11. CD spectra comparison of the model methyl, (ꢀ)-menthyl,
and (+)-menthyl b-D-mannopyranosides 19, 22 and 23, respectively (in
CH3CN).
R = (—)-Menthyl 16α
R = (+)-Menthyl 17α
OR
α-anomer β-anomer
OAc
O
R = Methyl
27
28
29
30
31
19
20
24
22
23
R = Isopropyl
R = tert-Butyl
R = (—)-Menthyl
R = (+)-Menthyl
O
AcO
OR
For comparative analysis, the intensities of the first Cot-
ton effects are more accurate, because occasionally the
presence of a background ellipticity alters the intensity
of the Cotton effects at short wavelengths and therefore,
the intensities of the second Cotton effects and the
amplitudes (A values) of the CD spectra of our model
compounds may not be precise. For this reason, Figures
10 and 11 contain an amplified view of these first Cotton
effects at 250nm and Table 4, their intensities (De1).
OR
β
α
Scheme 2.
Pgg Pgt Ptg
60
40
20
0
The intensity of the first Cotton effect of the CD spectra
for nonchiral alkyl b-D-mannopyranosides 19–21 and 24
gradually increased from the methyl (ꢀ62.8), isopropyl
(ꢀ63.7), cyclohexyl (ꢀ63.9), and tert-butyl (ꢀ67.9) b-
D-mannopyranosides, while for the chiral alkyl b-D-
mannopyranosides, a higher intensity of the first Cotton
13α 14α 16α 17α 13 14 16 17
Figure 12. Comparison between rotational population of anomers for
the acetyl series.
Table 4. JH5,H6 Coupling constants (CD3CN), calculated rotameric populations (%), and CD data (CH3CN) for the alkyl tetra-(p-bromobenzoyl)-b-
D-mannopyranosides 19–24
Compd.
Aglycon
JH5,H6S
JH5,H6R
Pgg
Pgt
Ptg
De1
19
20
21
22
23
24
Methyl
3.0
3.0
3.1
2.9
3.0
3.0
3.9
4.2
4.6
4.0
5.1
4.9
56
52
47
55
43
44
27
30
34
29
40
38
17
17
18
16
17
17
ꢀ62.8
ꢀ63.7
ꢀ63.9
ꢀ63.2
ꢀ67.9
ꢀ67.9
Isopropyl
Cyclohexyl
(ꢀ)-Menthyl
(+)-Menthyl
tert-Butyl

2390
C. Mayato et al. / Tetrahedron: Asymmetry 15 (2004) 2385–2397
4. Experimental
Pgg Pgt Ptg
60
50
40
30
20
10
0
4.1. General
1H NMR spectra were recorded at 400MHz, and 13C
NMR at 100MHz, VTU 300.0K. Chemical shifts are re-
ported in parts per million. The residual solvent peak
(CDCl3) was used as an internal reference, 7.26 for pro-
ton and 77.0ppm for the central peak for carbon NMR.
Optical rotations were measured on a digital polarimeter
in a 1dm cell. UV and CD spectra were recorded in the
range 400–200nm using 10mm cells. The concentrations
of the CD samples were ascertained from the UV spec-
tra, using the experimentally determined e values at
245nm: tetra-(p-bromobenzoate) e 76,400.
27 28 29
19 20 24
Pgg
Pgt
Ptg
60
40
20
0
30
31
22
23
For analytical and preparative thin-layer chromatogra-
phy, silica gel ready-foils and glass-backed plates
(1mm) were used, being respectively, developed with
254nm UV light and/or spraying with AcOH/H2O/
H2SO4 (80:16:4) and heating at 150ꢁC. Flash column
Figure 13. Comparison between rotational population of anomers for
the benzoyl series: nonchiral alkyl (top) and chiral alkyl (bottom)
mannopyranosides.
˚
chromatography was performed using silica gel (60A).
In addition, as the pKa of the aglycon increases, the pop-
ulation of the gt rotamer does also, independently of the
anomeric configuration, and the population of the gg or
tg rotamer decreases, depending respectively on the b or
a anomeric configuration.
All reagents were obtained from commercial
sources and used without further purification. Solvents
were dried and distilled before use. All reactions were
performed under a dry nitrogen atmosphere. The
compounds prepared were characterized on the basis
of their one- (1H and 13C) and two-dimensional
(COSY, HMQC, and TROESY) NMR spectra, as well
as by elemental analysis, MS, UV, and CD
spectroscopy.
As can be observed at the bottom of Figure 13, the rota-
tional population of the hydroxymethyl group in the
menthyl mannopyranosides depends on the nonbonded
interactions between this group and the isopropyl
group. Thus the syn location to the endocyclic oxygen
O5 of the isopropyl group for the (ꢀ)-menthyl b-D-
and (+)-menthyl a-D-mannopyranosides leads to higher
gg and smaller gt population than the (+)-menthyl b-D-
and (ꢀ)-menthyl a-D-mannopyranosides, which have
the isopropyl group in the anti location.
4.2. General procedure for the preparation of b-
glucopyranosides
A solution of dimethyldioxirane in acetone (2equiv, ca.
0.075M) was added to a stirred solution of the tri-O-
benzyl-D-glucal in dry CH2Cl2 (5mL/mmol) at 0ꢁC
under nitrogen atmosphere, and the reaction stirred at
0ꢁC for 30min. The 1,2-anhydro sugar thus obtained
was concentrated under reduced pressure and left under
vacuum for 2h. Then it was dissolved in dry THF
(10mL/mmol) under dry nitrogen, and molecular sieves
and the corresponding alcohol (10equiv) added. The
reaction mixture was cooled to ꢀ78ꢁC and 0.5equiv of
a 1.0M solution of ZnCl2 in diethyl ether then added.
The reaction was allowed to warm to room temperature
and stirred overnight. The mixture was diluted with Et-
OAc, filtered, and washed with water; then the com-
bined organic layers were dried over sodium sulfate,
filtered, and the solvent removed under reduced pres-
sure. The product was purified by flash column
chromatography.
This analysis reveals that the hydroxymethyl group rota-
tional population depends on the anomeric configura-
tion. The b-anomers show a higher dependence and
unambiguous rotational behavior.
3. Conclusions
The rotational population of the hydroxymethyl group
of alkyl b-D-mannopyranosides is dependent on the
structure of the aglycon and its absolute configuration,
as well as on the anomeric configuration. This was deter-
mined by analyzing the 3JH5,H6R and 3JH5,H6S values and
CD spectral data. Furthermore, a clear relationship be-
tween this population around the C5–C6 bond and the
pKa of the bonded alcohol (aglycon) was observed.
Thus, as the pKa increased, the population of the gt/gg
rotamers gradually increased/decreased respectively,
while the population of the tg rotamer remained almost
constant. These results point to a stereoelectronic exo-
anomeric effect as responsible for this, along with steric
effects. In addition, a different, higher dependence on the
structure of the aglycon was observed for the b-anomers
than for the a-anomers.
4.3. General procedure for the preparation of b-
mannopyranosides
The sugar was treated with a 1:2 acetic anhydride/
dimethyl sulfoxide (8mL/mmol) mixture, that was
previously stirred for 15min. The reaction was left 1–
2days at room temperature under a nitrogen atmo-
sphere. Then it was concentrated to dryness, dissolved
in CH2Cl2, and washed with water. The combined

C. Mayato et al. / Tetrahedron: Asymmetry 15 (2004) 2385–2397
2391
organic extracts were dried over anhydrous sodium sul-
fate, filtered, and evaporated in vacuum. Then, 2equiv
of sodium borohydride was added to a solution of the
crude reaction mixture in dry 1:1 CH2Cl2/MeOH
(10mL/mmol) at 0ꢁC in a nitrogen atmosphere and then
the ice bath removed. When the reaction was complete
(approx. 2h), it was diluted with CH2Cl2 and washed
with water, 1% citric acid solution, NaHCO3, and brine.
The combined organic layers were dried over anhydrous
sodium sulfate, filtered and evaporated in a vacuum.
The product was purified by silica gel column
chromatography.
4.6. iso-Propyl 3,4,6-tri-O-benzyl-b-D-glucopyranoside 2
Following the general procedure for the preparation of
b-glucosides, 35.0mL (2.63mmol) of a solution of
DMDO in acetone was added to a solution of the glucal
(512mg, 1.23mmol) in 6.0mL of dry CH2Cl2 at 0ꢁC.
Later, the product was directly dissolved in THF
(12.0mL), and isopropanol (1mL, 13.0mmol) and zinc
chloride (600lL, 0.60mmol) were added. Flash column
chromatography with n-hexane/EtOAc (7.5:2.5) as elu-
ent yielded 2 (451mg, 0.92mmol, 75% yield): TLC
Rf =0.37 (n-hexane/EtOAc, 7:3); [a]D =ꢀ7.7 (c 1.4,
CHCl3); MS (EI) m/z (relative intensity) 401
([M+ꢀC7H7], 3.2), 341 (3.9), 91 (100); 1H NMR (CDCl3)
d 7.37–7.19 (15H), 4.95 (d, J=11.3Hz, 1H), 4.85 (d,
J=10.8Hz, 1H), 4.83 (d, J=11.3Hz, 1H), 4.61 (d,
J=12.2Hz, 1H), 4.58 (d, J=12.2Hz, 1H), 4.55 (d,
J=10.8Hz, 1H), 4.31 (d, J=7.6Hz, H-1), 4.02 (sep,
J=6.1Hz, H20), 3.74 (dd, J=1.7 and 10.8Hz, H-6proS),
3.68 (dd, J=4.9 and 10.8Hz, H-6proR), 3.60–3.48 (m,
4H), 1.29 (d, J=6.1Hz, 3H), 1.21 (d, J=6.1Hz, 3H);
13C NMR (CDCl3) d 138.7 (s), 138.2 (s), 138.1(s),
128.3–127.5 (aromatic Cs), 101.1 (d, C-1), 84.6 (d, C-
3), 77.6 (d, C-4), 75.1 (t), 75.0 (d, C-5), 74.9 (t), 74.7
(d, C-2), 73.3 (t), 71.8 (d, C20), 69.0 (t, C-6), 23.4 (q),
21.9 (q); Anal. Calcd for C30H36O6: C, 73.15; H, 7.37.
Found: C, 73.18; H, 7.49.
4.4. General procedure for the debenzylation and
acetylation or benzoylation
To a solution of the substrate in dry ethanol (10mL/
mmol) was added 50mg/mmol of palladium at 5% on
activated carbon with sufficient hydrogen. After the
reaction was complete, the mixture was diluted in
ethanol, filtered through a bed of Celite and evapo-
rated under reduced pressure. Then the crude reaction
mixture was divided between two round-bottom flasks.
To the first flask, 20mL/mmol of a 1:1 solution of dry
pyridine/acetic anhydride was added at room tempera-
ture and stirred overnight. Excess solvent was removed
under reduced pressure in the presence of toluene,
and the residue purified with column chromatography.
Dry pyridine (10mL/mmol) was added to the sec-
ond flask, and then treated with 6equiv of p-bro-
mobenzoyl chloride and DMAP as catalyst. The
solution was heated at 60ꢁC and stirred overnight.
The solvent was removed under reduced pressure in
4.7. Cyclohexyl 3,4,6-tri-O-benzyl-b-D-glucopyranoside 3
Following the general procedure for the preparation of
b-glucosides, a solution of dimethyldioxirane (34.0mL,
2.55mmol) and the glucal (442mg, 1.06mmol) in
5.0mL of CH2Cl2 were utilized. Then, a solution of
the resulting substrate in 10.0mL of THF was treated
with ZnCl2 (500lL, 0.50mmol) and cyclohexanol
(1.0mL, 9.5mmol), to yield compound 3 (313mg,
0.59mmol, 55% yield) after chromatography on silica
gel (n-hexane/EtOAc, 9:1): TLC Rf =0.44 (n-hexane/Et-
OAc, 7.5:2.5); [a]D =ꢀ9.9 (c 3.3, CHCl3); MS (EI) m/z
(relative intensity) 441 ([M+ꢀC7H7], 0.8), 341 (1.9), 91
(100); 1H NMR (CDCl3) d 7.39–7.22 (m, 15H), 4.98
(d, J=11.3Hz, 1H), 4.87 (d, J=10.8Hz, 1H), 4.85 (d,
J=11.3Hz, 1H), 4.63 (d, J=12.2Hz, 1H), 4.57 (d,
J=12.2Hz, 1H), 4.56 (d, J=10.8Hz, 1H), 4.37 (d,
J=7.5Hz, H-1), 3.77 (dd, J=1.8 and 10.8Hz, H-6proS),
3.70 (dd, J=4.9 and 10.8Hz, H-6proR), 3.69 (m, H10),
3.63–3.55 (m, 3H), 3.52 (m, H-5), 2.07 (m, 1H), 2.00
(m, 1H), 1.81 (m, 2H), 1.60 (m, 1H), 1.50 (m, 1H),
1.45–1.21 (m, 4H); 13C NMR (CDCl3) d 138.6 (s),
138.1 (s), 138.0 (s), 128.2–127.4(aromatic Cs), 101.0
(d, C-1), 84.5 (d, C-3), 77.5 (d, C-4), 77.5 (d, C10), 74.9
(d, C-5), 74.9 (t), 74.8 (t), 74.6 (d, C-2), 73.2 (t), 68.9
(t, C-6), 33.5 (t), 31.8 (t), 25.4(t), 24.0 (t ·2); Anal. Cal-
cd for C33H40O6: C, 74.41; H, 7.57. Found: C, 74.43; H,
7.81.
the presence
chromatographed.
of
toluene
and
the
residue
4.5. Methyl 3,4,6-tri-O-benzyl-b-D-glucopyranoside 1
Following the general procedure for the preparation of
a
b-glucosides,
solution of DMDO in acetone
(10.0mL, 0.75mmol) was added to a solution of
222mg (0.53mmol) of the tri-O-benzyl-D-glucal in
CH2Cl2 (2.5mL) at 0ꢁC. The anhydro sugar was
dissolved in 5.0mL of dry THF and MeOH
(1.0mL, 24.7mmol) and a 1.0M solution of ZnCl2 in
Et2O (250lL, 0.25mmol) were added. The crude reac-
tion mixture was purified by chromatography on silica
gel (n-hexane/EtOAc, 7.5:2.5) to give
1 (189mg,
0.41mmol, 77% yield): TLC Rf =0.29 (n-hexane/EtOAc,
6:4); [a]D =+1.9 (c 1.4, CHCl3); MS (EI) m/z (rela-
tive intensity) 373 ([M+ꢀC7H7], 8.9), 341 (5.2), 91
(100); 1H NMR (CDCl3) d 7.36–7.18 (m, 15H), 4.91
(d, J=11.2Hz, 1H), 4.85 (d, J=11.2Hz, 1H), 4.83 (d,
J=10.7Hz, 1H), 4.63 (d, J=12.2Hz, 1H), 4.55 (d,
J=12.2Hz, 1H), 4.54 (d, J=10.7Hz, 1H), 4.18 (d,
J=7.4Hz, H-1), 3.75 (dd, J=1.9 and 10.8Hz, H-6proS),
3.71 (dd, J=4.5 and 10.8Hz, H-6proR), 3.63–3.52 (m,
3H), 3.55 (s, 3H), 3.49 (m, H-5); 13C NMR (CDCl3) d
138.5 (s), 137.9 (s·2), 128.2–127.4(aromatic Cs),
103.6 (d, C-1), 84.4 (d, C-3), 77.4 (d, C-4), 74.9 (t·2),
74.8 (d, C-5), 74.4 (d, C-2), 73.3 (t), 68.7 (t, C-6), 56.9
(q, C-10). Anal. Calcd for C28H32O6: C, 72.39; H, 6.94.
Found: C, 72.33; H, 7.12.
4.8. (1R,2S,5R)-Menthyl 3,4,6-tri-O-benzyl-b-D-gluco-
pyranoside 4
Following the general procedure for the preparation of
b-glucosides, D-glucal (924mg, 2.22mmol), and DMDO
(82.0mL, 6.02mmol) in dry CH2Cl2 (11.0mL) were

2392
C. Mayato et al. / Tetrahedron: Asymmetry 15 (2004) 2385–2397
used. Then, the residue was dissolved in 25.0mL of THF
and treated with a solution of ZnCl2 in diethyl ether
(1.0mL, 1.00mmol) and L-(ꢀ)-menthol (3.5g,
22.2mmol). After flash chromatography (n-hexane/
EtOAc, 9:1), compound 4 (655mg, 1.11mmol, 50%)
was obtained: TLC Rf =0.50 (n-hexane/EtOAc, 8:2);
[a]D =ꢀ37.8 (c 1.3, CHCl3); MS (EI) m/z (relative
intensity) 497 ([M+ꢀC7H7], 0.8), 341 (3.0), 91 (100);
1H NMR (CDCl3) d 7.39–7.22 (m, 15H), 4.95 (d,
J=11.4Hz, 1H), 4.85 (d, J=10.8Hz, 1H), 4.84 (d,
J=11.4Hz, 1H), 4.60 (d, J=12.2Hz, 1H), 4.59 (d,
J=10.8Hz, 1H), 4.54 (d, J=12.2Hz, 1H), 4.32 (d,
J=7.7Hz, H-1), 3.70 (m, 2H), 3.62–3.59 (m, 2H),
3.53–3.46 (m, 3H), 2.30 (m, 1H), 2.06 (br d,
J=12.5Hz, 1H), 1.66 (d, J=12.7Hz, 2H), 1.37 (m,
TLC Rf =0.44 (n-hexane/EtOAc, 7.5:2.5); [a]D =ꢀ12.9
(c 1.0, CHCl3); MS (EI) m/z (relative intensity) 415
([M+ꢀC7H7], 0.8), 341 (2.2), 91 (100); 1H NMR (CDCl3)
d 7.38–7.21 (m, 15H), 4.98 (d, J=11.2Hz, 1H), 4.86 (d,
J=11.2Hz, 1H), 4.83 (d, J=11.7Hz, 1H), 4.60 (d,
J=12.2Hz, 1H), 4.56 (d, J=11.7Hz, 1H), 4.54 (d,
J=12.2Hz, 1H), 4.43 (d, J=7.7Hz, H-1), 3.73 (dd,
J=1.8 and 10.7Hz, H-6proS), 3.66 (dd, J=5.2 and
10.7Hz, H-6proR), 3.63–3.48 (m, 4H), 1.32 (s, 9H); 13C
NMR (CDCl3) d 138.7 (s), 138.2 (s), 138.1 (s), 128.2–
127.4 (aromatic Cs), 97.2 (d, C-1), 84.7 (d, C-3), 77.6
(d, C-4), 76.0 (d, C-20), 74.9 (t), 74.8 (d, C-5), 74.8 (t),
74.7 (d, C-2), 73.2 (t), 69.1 (t, C-6), 28.7 (q·3); Anal.
Calcd for C31H38O6: C, 73.49; H, 7.56. Found: C,
73.49; H, 7.78.
1H), 1.24(m, 1H), 1.0–40.80 (m, 12H);
13C NMR
(CDCl3) d 138.7 (s), 138.2 (s), 138.1 (s), 128.4–127.5
(aromatic Cs), 99.9 (d, C-1), 84.7 (d, C-3), 77.5 (d, C-
4), 77.0 (d, C-10), 75.1 (t), 75.0 (d, C-5), 75.0 (t), 74.5
(d, C-2), 73.6 (t), 69.2 (t, C-6), 47.7 (d), 40.8 (t), 34.3
(t), 31.4(d), 25.1 (d), 23.0 (t), 22.2 (q), 21.0 (q), 15.7
(q); Anal. Calcd for C37H48O6: C, 75.48; H, 8.22.
Found: C, 75.44; H, 8.66.
4.11. Methyl 3,4,6-tri-O-benzyl-b-D-mannopyranoside 7
Following the general procedure for b-mannosides,
compound 7 was obtained with a 65% yield (96mg,
0.21mmol) after column chromatography (n-hexane/
EtOAc, 6:4): TLC Rf =0.15 (n-hexane/EtOAc, 6:4);
[a]D =ꢀ18.6 (c 1.6, CHCl3); MS (EI) m/z (relative inten-
sity) 373 ([M+ꢀC7H7], 0.2), 341 (2.8), 91 (100); 1H
4.9. (1S,2R,5S)-Menthyl 3,4,6-tri-O-benzyl-b-D-
glucopyranoside 5
NMR (CDCl3) d 7.21–7.37 (m, 15H), 4.89 (d,
J=10.8Hz, 1H), 4.77 (d, J=11.9Hz, 1H), 4.68 (d,
J=11.9Hz, 1H), 4.64 (d, J=12.2Hz, 1H), 4.57 (d,
J=12.2Hz, 1H), 4.54 (d, J=10.8Hz, 1H), 4.33 (s, H-
1), 4.10 (br s, H-2), 3.86 (t, J=9.3Hz, H-4), 3.79 (dd,
J=2.0 and 10.8Hz, H-6proS), 3.73 (dd, J=5.2 and
10.8Hz, H-6proR), 3.57 (dd, J=3.1 and 9.3Hz, H-3),
3.56 (s, 3H), 3.44 (m, H-5); 13C NMR (CDCl3) d 138.2
(s), 138.1 (s), 137.7 (s), 128.4–127.5 (aromatic Cs),
100.6 (d, C-1), 81.4(d, C-3), 75.2 (d, C-5), 75.0 (t),
74.2 (d, C-4), 73.4 (t), 71.3 (t), 69.1 (t, C-6), 68.1 (d,
C-2), 56.8 (q, C-10); Anal. Calcd for C28H32O6: C,
72.39; H, 6.94. Found: C, 72.38; H, 7.24.
Following the general procedure for the preparation of
b-glucosides, 483mg (1.16mmol) of D-glucal in 5.8mL
of dry CH2Cl2 was treated with 44mL (3.30mmol) of
a DMDO solution in acetone. Later, the residue was dis-
solved in THF (16.4mL) and 1.3g (8.24mmol) of D-(+)-
menthol and 0.58mmol of ZnCl2 (580lL of a solution
1.0M) were added. Column chromatography (n-hex-
ane/EtOAc, 9:1) of the residue gave
5 (376mg,
0.64mmol, 55%): TLC Rf =0.48 (n-hexane/EtOAc,
8:2); [a]D =+17.0 (c 1.5, CHCl3); MS (EI) m/z (relative
intensity) 497 ([M+ꢀC7H7], 1.4), 432 (0.4), 341 (3.4),
91 (100); 1H NMR (CDCl3) d 7.42–7.25 (m, 15 H),
5.01 (d, J=11.2Hz, 1H), 4.89 (d, J=10.7Hz, 1H), 4.87
(d, J=10.7Hz, 1H), 4.64–4.59 (m, 3H), 4.36 (d,
J=7.0Hz, H-1), 3.79 (br d, J=10.7Hz, H-6proS), 3.72–
3.57 (m, 5H), 3.45 (dd, J=3.9 and 10.6Hz, H-10),
2.34–2.28 (m, 2H), 1.70–1.65 (m, 2H), 1.43–1.35 (m,
2H), 1.16 (m, 1H), 1.07–0.83 (m, 11H); 13C NMR
(CDCl3) d 138.5 (s), 138.1 (s), 138.0 (s), 128.1–127.2
(aromatic Cs), 103.7 (d, C-1), 84.5 (d, C-3), 81.3 (d, C-
10), 77.4 (d, C-4), 75.1 (d, C-5), 74.9 (t), 74.8 (t), 74.6
(d, C-2), 73.0 (t), 68.9 (t, C-6), 48.2 (d), 43.1 (t), 34.0
(t), 31.4(d), 25.1 (d), 22.7 (t), 22.1 (q), 20.9 (q), 15.7
(q); Anal. Calcd for C37H48O6: C, 75.48; H, 8.22.
Found: C, 75.47; H, 8.43.
4.12. iso-Propyl 3,4,6-tri-O-benzyl-b-D-mannopyranoside
8
According to the general procedure for the prepara-
tion of b-mannosides, 430mg (0.87mmol) of glucopyr-
anoside 2 provided, after column chromatography
(n-hexane/EtOAc, 7.5:2.5), compound
8
(277mg,
0.56mmol, 64%): TLC Rf =0.19 (n-hexane/EtOAc,
7:3); [a]D =ꢀ27.4( c 2.2, CHCl3); MS (EI) m/z (relative
intensity) 401 ([M+ꢀC7H7], 0.7), 341 (4.4), 91 (100);
1H NMR (CDCl3) d 7.38–7.22 (m, 15H), 4.90 (d,
J=10.8Hz, 1H), 4.78 (d, J=11.9Hz, 1H), 4.67 (d,
J=11.9Hz, 1H), 4.62 (d, J=12.1Hz, 1H), 4.58 (d,
J=12.1Hz, 1H), 4.55 (d, J=10.8Hz, 1H), 4.50 (s, H-
1), 4.09 (sept, J=6.1Hz, H-20), 4.06 (br s, H-2), 3.84
(t, J=9.4Hz, H-4), 3.77 (dd, J=1.9 and 10.8Hz, H-
6proS), 3.69 (dd, J=5.6 and 10.8Hz, H-6proR), 3.58 (dd,
J=3.1 and 9.4Hz, H-3), 3.43 (m, H-5), 1.29 (d,
J=6.1Hz, 3H), 1.17 (d, J=6.1Hz, 3H); 13C NMR
(CDCl3) d 138.1 (s), 138.0 (s), 137.7 (s), 128.1–127.2
(aromatic Cs), 97.4(d, C-1), 81.4(d, C-3), 75.0 (t),
74.8 (d, C-5), 74.0 (d, C-4), 73.1 (t), 70.9 (t), 70.7 (d,
C-20), 69.1 (t, C-6), 68.5 (d, C-2), 23.2 (q), 21.4(q); Anal.
Calcd for C30H36O6: C, 73.15; H, 7.37. Found: C, 73.15;
H, 7.72.
4.10. tert-Butyl 3,4,6-tri-O-benzyl-b-D-glucopyranoside 6
Following the general procedure for the preparation of
b-glucosides, a solution of 526mg (1.26mmol) of D-glu-
cal in CH2Cl2 (6.0mL) and 33.5mL (2.51mmol) of
DMDO were used. Treatment of the anhydro sugar with
1.0mL of tert-butanol (10.5mmol) and 650lL
(0.65mmol) of ZnCl2 in dry THF (13.0mL), after
column chromatography (n-hexane/EtOAc, 9:1),
gave compound 6 (285mg, 0.56mmol, 45%, yield):

C. Mayato et al. / Tetrahedron: Asymmetry 15 (2004) 2385–2397
2393
4.13. Cyclohexyl 3,4,6-tri-O-benzyl-b-D-mannopyrano-
side 9
1H), 4.69 (d, J=11.8Hz, 1H), 4.63 (d, J=12.2Hz, 1H),
4.59 (d, J=12.2Hz, 1H), 4.58 (d, J=10.9Hz, 1H),
4.46 (s, H-1), 4.10 (d, J=2.3Hz, H-2), 3.86–3.78 (m,
2H), 3.70 (dd, J=5.8 and 10.7Hz, H-6proR), 3.57 (dd,
J=2.4 and 9.0Hz, H-3), 3.48–3.40 (m, 2H), 2.28 (m,
1H), 2.10 (m, 1H), 1.64(m, 2H), 1.40–1.28 (m, 2H),
1.40 (q, J=11.7Hz, 1H), 1.00–0.83 (m, 8H), 0.76 (d,
J=6.9Hz, 3H); 13C NMR (CDCl3) d 138.2 (s), 138.1
(s), 137.7 (s), 128.1–127.2 (aromatic Cs), 100.9 (d,
C-1), 81.7 (d, C-3), 81.3 (d, C-10), 75.0 (d, C-5), 74.8
(t), 74.1 (d, C-4), 73.2 (t), 71.0 (t), 69.3 (t, C-6), 68.3
(d, C-2), 48.0 (d), 43.0 (t), 34.0 (t), 31.4 (d), 25.4 (d),
22.9 (t), 22.0 (q), 20.9 (q), 16.0 (q); Anal. Calcd
for C37H48O6: C, 75.48; H, 8.22. Found: C, 75.45; H,
8.34.
Synthesis of compound 9 was carried out from 3
(437mg, 0.82mmol) as described in the general proce-
dure for b-mannosides. Column chromatography (n-
hexane/EtOAc, 7.5:2.5) of the residue gave 9 (267mg,
0.50mmol, 61%): TLC Rf =0.21 (n-hexane/EtOAc,
7.5:2.5); [a]D =ꢀ27.7 (c 2.6, CHCl3); MS (EI) m/z (rela-
tive intensity) 441 ([M+ꢀC7H7], 0.6), 341 (4.7), 91 (100);
1H NMR (CDCl3) d 7.38–7.24(m, 15H), .490 (d,
J=10.9Hz, 1H), 4.79 (d, J=11.9Hz, 1H), 4.67 (d,
J=11.9Hz, 1H), 4.62 (d, J=12.1Hz, 1H), 4.58–4.53
(m, 2H), 4.54 (s, H-1), 4.07 (d, J=2.6Hz, H-2), 3.84(t,
J=9.4Hz, H-04), 3.79 (dd, J=1.9 and 10.8Hz, H-6proS),
3.74(m, H-1 ), 3.69 (dd, J=5.7 and 10.8Hz, H-6proR),
3.57 (dd, J=3.1 and 9.1Hz, H-3), 3.43 (m, H-5), 2.00
(m, 1H), 1.88 (m, 1H), 1.74(m, 2H), 1.54(m, 1H),
1.45 (m, 1H), 1.33–1.18 (m, 4H); 13C NMR (CDCl3) d
138.2 (s), 138.1 (s), 137.7 (s), 128.2–127.3 0 (aromatic
Cs), 97.2 (d, C-1), 81.5 (d, C-3), 76.4(d, C-1 ), 75.0 (d,
C-5), 74.9 (t), 74.1 (d, C-4), 73.2 (t), 71.0 (t), 69.2 (t,
C-6), 68.6 (d, C-2), 33.3 (t), 31.5 (t), 25.4(t), 23.9 (t),
23.8 (t); Anal. Calcd for C33H40O6: C, 74.41; H, 7.57.
Found: C, 74.42; H, 7.56.
4.16. tert-Butyl 3,4,6-tri-O-benzyl-b-D-mannopyranoside
12
Compound 12 was synthesized from
6 (376mg,
0.74mmol) as described in the general procedure for
preparation of b-mannosides. Column chromatography
(n-hexane/EtOAc, 8.5:1.5) of the residue gave com-
pound 12 (218mg, 0.43mmol, 58%): TLC Rf =0.19 (n-
hexane/EtOAc, 7.5:2.5); [a]D =ꢀ28.5 (c 1.9, CHCl3);
MS (EI) m/z (relative intensity) 415 ([M+ꢀC7H7], 0.2),
1
4.14. (1R,2S,5R)-Menthyl 3,4,6-tri-O-benzyl-b-D-
mannopyranoside 10
341 (3.1), 91 (100); H NMR (CDCl3) d 7.40–7.22 (m,
15H), 4.91 (d, J=10.9Hz, 1H), 4.79 (d, J=11.9Hz,
1H), 4.69 (d, J=11.9Hz, 1H), 4.61 (d, J=12.1Hz, 1H),
4.60 (s, H-1), 4.56 (d, J=10.9Hz, 1H), 4.55 (d,
J=12.1Hz, 1H), 3.99 (d, J=3.1Hz, H-2), 3.83 (t,
J=9.4Hz, H-4), 3.76 (dd, J=1.7 and 10.7Hz, H-6proS),
3.68 (dd, J=5.7 and 10.7Hz, H-6proR), 3.59 (dd, J=3.1
and 9.1Hz, H-3), 3.42 (m, H-5), 1.30 (s, 9H); 13C
NMR (CDCl3) d 138.2 (s), 138.1 (s), 137.7 (s), 128.1–
127.1 (aromatic Cs), 94.1 (d, C-1), 81.7 (d, C-3), 75.9
(s, C-20), 74.7 (t), 74.6 (d, C-5), 74.0 (d, C-4), 73.0 (t),
70.9 (t), 69.3 (d, C-2), 69.2 (t, C-6), 28.4(q ·3); Anal.
Calcd for C31H38O6: C, 73.49; H, 7.56. Found: C,
73.46; H, 7.82.
Following the procedure for b-mannosides, compound
10 was obtained from glucopyranoside 4 (611mg,
1.04mmol) with a 65% yield (395mg, 0.67mmol), after
column chromatography (n-hexane/EtOAc, 9:1): TLC
Rf =0.44 (n-hexane/EtOAc, 7.5:2.5); [a]D =ꢀ49.6 (c 1.6,
CHCl3); MS (EI) m/z (relative intensity) 497
([M+ꢀC7H7], 0.3), 341 (2.5), 91 (100); 1H NMR (CDCl3)
d 7.39–7.24 (m, 15H), 4.90 (d, J=10.9Hz, 1H), 4.79 (d,
J=12.0Hz, 1H), 4.67 (d, J=12.0Hz, 1H), 4.63–4.56
(m, 3H), 4.53 (s, H-1), 4.02 (d, J=2.9Hz, H-2), 3.86
(t, J=9.5Hz, H-4), 3.74 (dd, J=1.8 and 10.7Hz, H-
6proS), 3.70 (dd, J=5.1 and 10.7Hz, H-6proR), 3.60–
3.54 (m, 2H), 3.40 (m, H-5), 2.28 (m, 1H), 1.98 (d,
J=12.1Hz, 1H), 1.65 (d, J=12.2Hz, 2H), 1.35 (m,
1H), 1.28 (m, 1H), 1.00–0.81 (m, 12H); 13C NMR
(CDCl3) d 138.4 (s), 138.3 (s), 138.0 (s), 128.4–127.5
(aromatic Cs), 96.1 (d, C-1), 81.9 (d, C-3), 76.5 (d, C-
10), 75.3 (d, C-5), 75.2 (t), 74.4 (d, C-4), 73.6 (t), 71.2
(t), 69.7 (t, C-6), 69.2 (d, C-2), 47.7 (d), 40.4 (t), 34.3
(t), 31.3 (d), 25.3 (d), 23.1 (t), 22.3 (q), 21.0 (q), 15.9
(q); Anal. Calcd for C37H48O6: C, 75.48; H, 8.22.
Found: C, 75.43; H, 8.60.
4.17. Methyl 2,3,4,6-tetra-O-acetyl-b-D-mannopyranoside
13
Following the procedure for debenzylation and acetyl-
ation, using 72mg (0.16mmol) of compound 7, com-
pound 13 (36mg, 0.10mmol) was obtained with a
64% yield after chromatography on silica gel (n-hexane/
EtOAc, 5:5): TLC Rf =0.27 (n-hexane/EtOAc, 1:1);
[a]D =ꢀ43.4 (c 1.1, CHCl3); MS (EI) m/z (relative
intensity) 331 ([M+ꢀCH3O], 2.7), 289 (12.8), 243
1
(32.2), 200 (46.5), 157 (100); H NMR (CDCl3) d 5.48
4.15. (1S,2R,5S)-Menthyl 3,4,6-tri-O-benzyl-b-D-
mannopyranoside 11
(dd, J=0.9 and 3.3Hz, H-2), 5.27 (t, J=10.0Hz, H-4),
5.06 (dd, J=3.3 and 10.0Hz, H-3), 4.56 (d, J=0.9Hz,
H-1), 4.31 (dd, J=5.3 and 12.2Hz, H-6proR), 4.17 (dd,
J=2.6 and 12.2Hz, H-6proS), 3.67 (m, H-5), 3.53 (s, 3
H), 2.19 (s, 3H), 2.10 (s, 3H), 2.05 (s, 3H), 1.99 (s,
3H); 13C NMR (CDCl3) d 170.7 (s), 170.4(s), 170.0
(s), 169.6 (s), 99.7 (d, C-1), 72.4(d, C-5), 71.1 (d, C-3),
68.6 (d, C-2), 66.0 (d, C-4), 62.5 (t, C-6), 57.5 (q,
C-10), 20.8 (q), 20.7 (q), 20.6 (q), 20.5 (q); Anal. Calcd
for C15H22O10: C, 49.72; H, 6.12. Found: C, 49.72; H,
6.41.
Following the procedure for b-mannosides, 324mg
(0.55mmol) of glucopyranoside 5 led to compound 11
(239mg, 0.41mmol, 74%), after column chromatogra-
phy (n-hexane/EtOAc, 9:1): TLC Rf =0.42 (n-hexane/Et-
OAc, 7.5:2.5); [a]D =+8.9 (c 1.1, CHCl3); MS (EI) m/z
(relative intensity) 497 ([M+ꢀC7H7], 0.1), 432 (0.3),
1
341 (3.8), 91 (100); H NMR (CDCl3) d 7.41–7.24 (m,
15H), 4.91 (d, J=10.9Hz, 1H), 4.80 (d, J=11.8Hz,

2394
C. Mayato et al. / Tetrahedron: Asymmetry 15 (2004) 2385–2397
4.18. iso-Propyl 2,3,4,6-tetra-O-acetyl-b-D-mannopyr-
anoside 14
2H), 1.64–1.59 (m, 2H), 1.32 (m, 1H), 1.22 (m, 1H),
1.00–0.75 (m, 12H); 13C NMR (CDCl3) d 170.6 (s),
170.4(s), 170.1 (s), 169.7 (s), 95.2 (d, C-1), 77.3 (d, C-
10), 72.0 (d, C-5), 71.3 (d, C-3), 69.7 (d, C-2), 66.7 (d,
C-4), 63.0 (t, C-6), 47.5 (d), 40.1 (t), 34.2 (t), 31.4 (d),
25.6 (d), 23.5 (t), 22.2 (q), 20.8 (q), 20.7 (q·2), 20.6
(q), 20.5 (q), 16.0 (q); Anal. Calcd for C24H38O10: C,
59.24; H, 7.87. Found: C, 59.26; H, 7.98.
Debenzylation and acetylation of compound 8 (120mg,
0.25mmol) was performed as described in the general
procedure, leading to compound 14 (66mg, 0.17mmol,
61%) after column chromatography (n-hexane/EtOAc,
7.5:2.5): TLC Rf =0.26 (n-hexane/EtOAc, 6:4);
[a]D =ꢀ42.9 (c 1.8, CHCl3); MS (EI) m/z (relative inten-
sity) 347 ([M+ꢀC3H7], 0.6), 331 ([M+ꢀC3H7O], 6.5),
4.21. (1S,2R,5S)-Menthyl 2,3,4,6-tetra-O-acetyl-b-D-
mannopyranoside 17
1
289 (1.9), 243 (26.3), 200 (41.4), 157 (100); H NMR
(CDCl3) d 5.40 (d, J=3.3Hz, H-2), 5.21 (t, J=10.0Hz,
H-4), 5.03 (dd, J=3.3 and 10.0Hz, H-3), 4.69 (s, H-1),
4.27 (dd, J=5.8 and 12.1Hz, H-6proR), 4.12 (dd, J=2.3
and 12.1Hz, H-6proS), 3.96 (sep, J=6.2Hz, H-20), 3.65
(m, H-5), 2.17 (s, 3 H), 2.06 (s, 3H), 2.02 (s, 3H), 1.97
(s, 3H), 1.21 (d, J=6.2Hz, 3H), 1.14(d, J=6.2Hz,
3H); 13C NMR (CDCl3) d 170.6 (s), 170.4(s), 170.0
(s), 169.5 (s), 96.7 (d, C-1), 72.2 (d, C-5), 72.1 (d, C-
20), 71.2 (d, C-3), 69.4(d, C-2), 66.2 (d, C-4), 62.7 (t,
C-6), 22.9 (q), 21.6 (q); Anal. Calcd for C17H26O10: C,
52.30; H, 6.71. Found: C, 52.31; H, 6.71.
Debenzylation and acetylation of compound 11 (52mg,
0.09mmol) was performed as in the general procedure,
leading to compound 17 (40mg, 0.08mmol, 93%) after
column chromatography (n-hexane/EtOAc, 7.5:2.5):
TLC Rf =0.42 (n-hexane/EtOAc, 6:4); [a]D =+9.0 (c
0.4, CHCl3); MS (FAB) m/z (relative intensity) 509
([M+Na]+, 4.9), 487 ([M+H]+, 1.4), 331 (100), 289
(6.9); 1H NMR (CDCl3) d 5.43 (d, J=3.3Hz, H-2),
5.20 (t, J=9.9Hz, H-4), 5.05 (dd, J=3.3 and 9.9Hz,
H-3), 4.66 (s, H-1), 4.28 (dd, J=6.4and 12.0Hz, H-
6proR), 4.13 (dd, J=2.5 and 12.0Hz, H-6proS), 3.68 (m,
H-5), 3.35 (dt, J=4.2 and 10.6Hz, H-10), 2.18 (s, 3H),
2.12–1.98 (m, 2H), 2.08 (s, 3H), 2.04(s, 3H), 1.99 (s,
3H), 1.64–1.56 (m, 2H), 1.39–1.24 (m, 2H), 1.11 (qu,
J=11.7Hz, 1H), 0.97–0.80 (m, 8H), 0.73 (d, J=6.9Hz,
3H); 13C NMR (CDCl3) d 170.6 (s), 170.3 (s), 170.0
(s), 169.5 (s), 99.3 (d, C-1), 82.6 (d, C-10), 72.0 (d, C-
5), 71.1 (d, C-3), 69.1 (d, C-2), 66.3 (d, C-4), 62.8 (t,
C-6), 47.7 (d), 42.3 (t), 34.1 (t), 31.5 (d), 25.6 (d), 23.3
(t), 22.2 (q), 20.8 (q), 20.7 (q), 20.6 (q·2), 20.5 (q),
16.2 (q); Anal. Calcd for C24H38O10: C, 59.24; H, 7.87.
Found: C, 59.29; H, 7.79.
4.19. Cyclohexyl 2,3,4,6-tetra-O-acetyl-b-D-mannopyr-
anoside 15
Debenzylation of 9 (115mg, 0.22mmol) and acetylation
yielded compound 15 (70mg, 0.16mmol, 75%), after
column chromatography (n-hexane/EtOAc, 7.5:2.5):
TLC Rf =0.36 (n-hexane/EtOAc, 6:4); [a]D =ꢀ42.3 (c
1.3, CHCl3); MS (EI) m/z (relative intensity) 357
([M+ꢀC3H5O2], 2.1), 331 (5.0), 289 (2.6), 243 (15.9),
200 (56.0), 157 (100); 1H NMR (CDCl3) d 5.42 (dd,
J=1.0 and 3.4Hz, H-2), 5.23 (t, J=10.0Hz, H-4), 5.04
(dd, J=3.4and 10.0Hz, H-3), 4.74(d, J=1.0Hz, H-1),
4.30 (dd, J=5.8 and 12.1Hz, H-6proR), 4.13 (dd, J=2.7
and 12.1Hz, H-6proS), 3.67–3.63 (m, 2H), 2.18 (s, 3H),
2.07 (s, 3H), 2.03 (s, 3H), 1.98 (s, 3H), 1.87 (m, 1H),
1.80 (m, 1H), 1.70 (m, 2H), 1.49 (m, 1H), 1.41 (m,
1H), 1.35–1.17 (m, 4H); 13C NMR (CDCl3) d 170.5
(s), 170.3 (s), 169.9 (s), 169.4(s), 96.4(d, C-1), 77.5 (d,
C-10), 72.1 (d, C-5), 71.1 (d, C-3), 69.4(d, C-2), 66.2
(d, C-4), 62.6 (t, C-6), 32.8 (t), 31.3 (t), 25.3 (t), 23.6
(t), 23.5 (t), 20.7 (q), 20.6 (q), 20.5 (q), 20.4(q); Anal.
Calcd for C20H30O10: C, 55.81; H, 7.02. Found: C,
55.80; H, 7.21.
4.22. tert-Butyl 2,3,4,6-tetra-O-acetyl-b-D-mannopyrano-
side 18
Debenzylation of compound 12 (91mg, 0.18mmol) and
acetylation gave compound 18 (71mg, 0.18mmol, 97%),
after column chromatography (n-hexane/EtOAc,
7.5:2.5): TLC Rf =0.35 (n-hexane/EtOAc, 7.5:2.5);
[a]D =ꢀ30.4( c 2.0, CHCl3); MS (EI) m/z (relative inten-
sity) 347 (0.6), 331 ([M+ꢀC4H9O], 18.9), 289 (12.3), 242
1
(67.4), 200 (48.4), 157 (100); H NMR (CDCl3) d 5.33
(dd, J=1.0 and 3.4Hz, H-2), 5.20 (t, J=9.9Hz, H-4),
5.08 (dd, J=3.4and 10.0Hz, H-3), 4.78 (d, J=1.0Hz,
H-1), 4.26 (dd, J=6.5 and 12.0Hz, H-6proR), 4.12 (dd,
J=2.7 and 12.0Hz, H-6proS), 3.67 (m, H-5), 2.19 (s, 3
H), 2.05 (s, 3 H), 2.04(s, 3 H), 1.99 (s, 3 H), 1.24(s, 9
H); 13C NMR (CDCl3) d 170.5 (s), 170.4(s), 169.9 (s),
169.5 (s), 93.1 (d, C-1), 76.5 (d, C-20), 71.9 (d, C-5),
71.2 (d, C-3), 70.3 (d, C-2), 66.2 (d, C-4), 62.8 (t, C-6),
28.1 (q·3), 20.7 (q), 20.5 (q·2), 20.4(q); Anal. Calcd
for C18H28O10: C, 53.46; H, 6.98. Found: C, 53.47; H,
7.10.
4.20. (1R,2S,5R)-Menthyl 2,3,4,6-tetra-O-acetyl-b-D-
mannopyranoside 16
After debenzylation and acetylation of 186mg
(0.31mmol) of compound 10, compound 16 was ob-
tained (145mg, 0.30mmol, 95% yield) after chromato-
graphy on silica gel (n-hexane/EtOAc, 7.5:2.5): TLC
Rf =0.46 (n-hexane/EtOAc, 6:4); [a]D =ꢀ81.2 (c 1.5,
CHCl3); MS (FAB) m/z (relative intensity) 509
([M+Na]+, 7.0), 487 ([M+H]+, 2.2), 331 (100), 289
(6.1); 1H NMR (CDCl3) d 5.37 (d, J=3.3Hz, H-2),
5.21 (t, J=10.0Hz, H-4), 5.06 (dd, J=3.3 and 10.0Hz,
H-3), 4.73 (s, H-1), 4.23 (dd, J=6.2 and 12.0Hz, H-
6proR), 4.16 (dd, J=3.0 and 12.0Hz, H-6proS), 3.63 (m,
H-5), 3.50 (dt, J=4.1 and 10.6Hz, H-10), 2.15 (s, 3H),
2.06 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H), 2.15–1.94(m,
4.23. Methyl 2,3,4,6-tetra-O-(p-bromobenzoyl)-b-D-
mannopyranoside 19
Debenzylation of compound 7 (45mg, 0.10mmol) and
then p-bromobenzoylation, led to compound 19
(75mg, 0.081mmol) in an 83% yield, after chromatogra-

C. Mayato et al. / Tetrahedron: Asymmetry 15 (2004) 2385–2397
2395
phy on silica gel (n-hexane/EtOAc, 7.5:2.5): TLC
4.26. (1R,2S,5R)-Menthyl 2,3,4,6-tetra-O-(p-bromo-
benzoyl)-b-D-mannopyranoside 22
Rf =0.40 (n-hexane/EtOAc, 6:4); [a]D =ꢀ177.8 (c 0.2,
CHCl3); MS (FAB) m/z (relative intensity) 926 (M+,
52.0), 895 (100); 1H NMR (CDCl3) d 7.92–7.41 (m,
16H), 5.90 (t, J=10.0Hz, H-4), 5.88 (d, J=3.1Hz, H-
2), 5.57 (dd, J=3.1 and 10.0Hz, H-3), 4.84 (s, H-1),
4.75 (dd, J=3.1 and 12.1Hz, H-6proS), 4.51 (dd, J=4.6
and 12.1Hz, H-6proR), 4.11 (m, H-5), 3.56 (s, 3 H); 13C
NMR (CDCl3) d 165.3 (s), 164.9 (s), 164.8 (s), 164.7
(s), 132.0–127.5 (aromatic Cs), 100.0 (d, C-1), 72.2 (d,
C-5), 71.9 (d, C-3), 69.7 (d, C-2), 67.3 (d, C-4), 63.1 (t,
C-6), 57.6 (q, C-10); UV (CH3CN) kmax 245nm; CD
(CH3CN) kext (De) 252nm (ꢀ62.8), 234nm (20.0); Anal.
Calcd for C35H26Br4O10: C, 45.39; H, 2.83. Found: C,
45.35; H, 3.23.
Debenzylation of compound 10 (186mg, 0.31mmol) and
then p-bromobenzoylation, gave compound 22 in an
83% yield (275mg, 0.26mmol) after chromatography
on silica gel (n-hexane/EtOAc, 9:1): TLC Rf =0.59 (n-
hexane/EtOAc, 7.5:2.5); [a]D =ꢀ155.3 (c 1.4, CHCl3);
MS (FAB) m/z (relative intensity) 1050 (M+, 10.1), 895
1
(100); H NMR (CDCl3) d 7.92–7.43 (m, 16H), 5.86 (t,
J=10.0Hz, H-4), 5.77 (d, J=3.0Hz, H-2), 5.58 (dd,
J=3.0 and 10.0Hz, H-3), 5.07 (s, H-1), 4.78 (dd,
J=2.9 and 11.9Hz, H-6proS), 4.43 (dd, J=4.5 and
11.9Hz, H-6proR), 4.06 (m, H-5), 3.60 (m, H-10), 2.02
(m, 1H), 1.94(m, 1H), 1.62 (m, 2H), 1.27 (m, 1H),
1.12 (m, 1H), 0.93–0.70 (m, 6H), 0.63 (d, J=8.1Hz,
3H), 0.61 (d, J=7.3Hz, 3H); 13C NMR (CDCl3) d
165.1 (s), 164.9 (s), 164.8 (s), 164.6 (s), 131.8–127.5 (aro-
matic Cs), 94.6 (d, C-1), 76.0 (d, C-10), 72.1 (d, C-3), 71.9
(d, C-5), 70.7 (d, C-2), 67.4 (d, C-4), 62.8 (t, C-6), 47.4
(d), 39.5 (t), 34.2 (t), 31.3 (d), 25.5 (d), 23.4 (t), 22.2
4.24. iso-Propyl 2,3,4,6-tetra-O-(p-bromobenzoyl)-b-D-
mannopyranoside 20
Debenzylation of compound 8 (120mg, 0.25mmol)
and then p-bromobenzoylation was performed as in
the general procedure, to give compound 20 (167mg,
0.18mmol, 72%) after column chromatography (n-hex-
ane/EtOAc, 8.5:1.5): TLC Rf =0.50 (n-hexane/EtOAc,
7:3); [a]D =ꢀ163.4( c 1.6, CHCl3); MS (FAB) m/z (rela-
tive intensity) 977 ([M+Na]+, 10.5), 955 ([M+H]+,
41.1), 895 (100); 1H NMR (CDCl3) d 7.90–7.42 (m,
16H), 5.85 (t, J=9.9Hz, H-4), 5.80 (d, J=3.1Hz, H-2),
5.57 (dd, J=3.1 and 9.9Hz, H-3), 5.00 (br s, H-1),
4.73 (dd, J=3.2 and 12.0Hz, H-6proS), 4.49 (dd, J=5.0
and 12.0Hz, H-6proR), 4.10 (m, H-5), 4.03 (sep,
J=6.2Hz, H-20), 1.19–1.16 (m, 6H); 13C NMR (CDCl3)
d 165.3 (s), 165.0 (s), 164.8 (s), 164.7 (s), 132.3–127.5
(aromatic Cs), 96.9 (d, C-1), 72.0 (d, C-3), 72.0 (d, C-
5), 72.0 (d, C-20), 70.5 (d, C-2), 67.5 (d, C-4), 63.4 (t,
C-6), 23.0 (q), 21.6 (q); UV (CH3CN) kmax 245nm;
CD (CH3CN) kext (De) 252nm (ꢀ63.7), 234nm (20.7);
Anal. Calcd for C37H30Br4O10: C, 46.57; H, 3.17.
Found: C, 46.56; H, 3.20.
(q), 20.4(q), 16.0 (q); UV (CH CN) kmax 245nm; CD
3
(CH3CN) kext (D e) 252nm (ꢀ63.2), 234nm (23.5); Anal.
Calcd for C44H42Br4O10: C, 50.31; H, 4.03. Found: C,
50.30; H, 4.22.
4.27. (1S,2R,5S)-Menthyl 2,3,4,6-tetra-O-(p-bromo-
benzoyl)-b-D-mannopyranoside 23
Debenzylation of compound 11 (52mg, 0.09mmol) and
then p-bromobenzoylation led to compound 23 (81mg,
0.08mmol, 88%) after column chromatography (n-hex-
ane/EtOAc, 9:1): TLC Rf =0.62 (n-hexane/EtOAc,
7.5:2.5); [a]D =ꢀ104.7 (c 0.8, CHCl3); MS (FAB) m/z
(relative intensity) 1049 (M+, 45.9), 895 (100); 1H
NMR (CDCl3)
d 7.90–7.42 (m, 16H), 5.83 (d,
J=3.2Hz, H-2), 5.79 (t, J=9.9Hz, H-4), 5.57 (dd,
J=3.2 and 9.9Hz, H-3), 4.96 (s, H-1), 4.72 (dd, J=3.0
and 11.9Hz, H-6proS), 4.48 (dd, J=5.8 and 11.9Hz, H-
6proR), 4.11 (m, H-5), 3.41 (dt, J=4.2 and 10.6Hz, H-
10), 2.12 (d, J=12.8Hz, 1H), 2.01 (dt, J=2.4and
6.9Hz, 1H), 1.60-1.56 (m, 2H), 1.33-1.18 (m, 2H), 1.03
(q, J=12.0Hz, 1H), 0.98–0.79 (m, 8H), 0.72 (d,
J=6.9Hz, 3 H); 13C NMR (CDCl3) d 165.2 (s), 164.9
(s), 164.8 (s), 164.7 (s), 132.3–127.5 (aromatic Cs), 99.3
(d, C-1), 82.1 (d, C-10), 72.0 (d, C-3), 72.0 (d, C-5),
70.1 (d, C-2), 67.6 (d, C-4), 63.5 (t, C-6), 47.9 (d), 42.4
(t), 34.1 (t), 31.6 (d), 25.5 (d), 23.2 (t), 22.1 (q), 20.8
(q), 16.2 (q); UV (CH3CN) kmax 245nm; CD (CH3CN)
kext (De) 252nm (ꢀ67.9), 234nm (23.2); Anal. Calcd
for C44H42Br4O10: C, 50.31; H, 4.03. Found: C, 50.34;
H, 4.50.
4.25. Cyclohexyl 2,3,4,6-tetra-O-(p-bromobenzoyl)-
b-D-mannopyranoside 21
Following the procedure, debenzylation of compound 9
(115mg, 0.22mmol) and then p-bromobenzoylation led
to compound 21 (196mg, 0.20mmol, 91%) after column
chromatography (n-hexane/EtOAc, 8.5:1.5): TLC
Rf =0.58 (n-hexane/EtOAc, 7:3); [a]D =ꢀ159.9 (c 1.2,
CHCl3); MS (FAB) m/z (relative intensity) 1019
1
([M+Na]+, 10.5), 995 (M+, 39.6), 895 (100); H NMR
(CDCl3) d 7.89–7.42 (m, 16H), 5.84 (t, J=9.9Hz, H-4),
5.81 (d, J=3.2Hz, H-2), 5.57 (dd, J=3.2 and 9.9Hz,
H-3), 5.04(s, H-1), 4.71 (dd, J=3.3 and 11.9Hz, H-
6proS), 4.50 (dd, J=5.3 and 11.9Hz, H-6proR), 4.09 (m,
H-5), 3.72 (m, H-10), 1.82 (m, 2H), 1.64(m, 2H), 1.47
(m, 1H), 1.41–1.14 (m, 5H); 13C NMR (CDCl3) d
165.2 (s), 165.0 (s), 164.8 (s), 164.6 (s), 132.3–127.5 (aro-
4.28. tert-Butyl 2,3,4,6-tetra-O-(p-bromobenzoyl)-b-D-
mannopyranoside 24
Compound 24 (131mg, 0.14mmol, 75%) was obtained
from compound 12 (91mg, 0.18mmol), following the
procedure for debenzylation and p-bromobenzoylation,
after column chromatography (n-hexane/EtOAc, 9:1):
TLC Rf =0.59 (n-hexane/EtOAc, 7:3); [a]D =ꢀ127.9 (c
0.4, CHCl3); MS (FAB) m/z (relative intensity) 992
([M+Na]+, 38.9), 895 (100); 1H NMR (CDCl3) d
0
matic Cs), 96.7 (d, C-1), 77.4(d, C-1 ), 72.0 (d, C-3), 71.9
(d, C-5), 70.5 (d, C-2), 67.6 (d, C-4), 63.4 (t, C-6), 33.0
(t), 31.4(t), 25.4(t), 23.7 (t ·2); UV (CH3CN) kmax
245nm; CD (CH3CN) kext (De) 252nm (ꢀ63.9), 234nm
(20.7); Anal. Calcd for C40H34Br4O10: C, 48.32; H,
3.45. Found: C, 48.54; H, 3.53.

2396
C. Mayato et al. / Tetrahedron: Asymmetry 15 (2004) 2385–2397
7.91–7.42 (m, 16H), 5.78 (t, J=9.8Hz, H-4), 5.72 (d,
J=3.2Hz, H-2), 5.61 (dd, J=3.2 and 9.8Hz, H-3),
5.08 (s, H-1), 4.68 (dd, J=3.2 and 11.9Hz, H-6proS),
4.49 (dd, J=6.1 and 11.9Hz, H-6proR), 4.12 (m, H-5),
1.25 (s, 9 H); 13C NMR (CDCl3) d 165.1 (s), 165.0 (s),
164.7 (s), 164.6 (s), 132.2–127.5 (aromatic Cs), 93.4 (d,
C-1), 76.7 (s, C-20), 72.0 (d, C-3), 71.8 (d, C-5), 71.3
(d, C-2), 67.6 (d, C-4), 63.6 (t, C-6), 28.2 (q·3); UV
(CH3CN) kmax 245nm; CD (CH3CN) kext (D e) 252nm
(ꢀ67.9), 234nm (20.7); Anal. Calcd for C38H32Br4O10:
C, 47.14; H, 3.33. Found: C, 47.17; H, 3.33.
2.63. Compound 25 b: TLC Rf =0.43 (n-hexane/EtOAc,
7.5:2.5); [a]D =ꢀ85.5 (c 1.5, CHCl3); MS (FAB) m/z (rel-
ative intensity) 895 ([M+ꢀC7H4BrO2]+, 3.3), 307 (100);
1H NMR (CDCl3) d 7.94–7.43 (m, 20H), 6.36 (s, H-1),
6.03 (d, J=3.2Hz, H-2), 6.02 (t, J=10.0Hz, H-4), 5.73
(dd, J=3.1 and 10.0Hz, H-3), 4.74 (dd, J=2.8 and
12.3Hz, H-6proS), 4.51 (dd, J=4.5 and 12.3Hz, H-
6proR), 4.34 (m, H-5); 13C NMR (CDCl3) d 165.2 (s),
164.8 (s), 164.6 (s·2), 163.3 (s), 132.2–127.2 (aromatic
Cs), 91.2 (d, C-1), 73.1 (d, C-5), 71.5 (d, C-3), 69.5 (d,
C-2), 66.6 (d, C-4), 62.7 (t, C-6); Anal. Calcd for
C41H24Br5O11: C, 44.96; H, 2.48. Found: C, 44.89; H,
2.70.
4.29. 1,2,3,4,6-Penta-O-acetyl-b-D-mannopyranoside 25
Commercial D-(+)-mannose (2g, 11.0mmol) was dis-
solved in 20mL/mmol of a 1:1 solution of dry pyr-
idine–acetic anhydride and the reaction stirred over-
night. The solvent was removed under reduced pressure
in the presence of toluene, and the residue purified by
column chromatography (n-hexane/EtOAc, 6:4) to yield
compound 25 in a quantitative amount, as a 2:1 mixture
of a- and b-anomers. The pure b-anomer was obtained
by recrystallization in n-hexane/EtOAc. Spectroscopic
data of compound 25 a were identical to those de-
scribed.10 Compound 25 b: TLC Rf =0.35 (n-hexane/Et-
OAc, 1:1); [a]D =ꢀ22.8 (c 1.6, CHCl3); MS (EI) m/z
(relative intensity) 347 ([MꢀCH3CO]+, 0.6), 331 (6.2),
Acknowledgements
This research was supported by the Ministerio de Cien-
´
cia y Tecnologıa (Spain), through grant BQU2000-0250.
C.M. thanks Caja Canarias-Universidad de La Laguna
´
as well as the Direccion General de Universidades e
Investigacion (Gobierno de Canarias) for a fellowship.
´
References and notes
1
242 (72.7), 200 (52.1), 157 (100); H NMR (CDCl3) d
1. Mallams, A. K. The Carbohydrate-Containing Antibiot-
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5.86 (s, H-1), 5.48 (d, J=3.2Hz, H-2), 5.29 (t,
J=9.9Hz, H-4), 5.13 (dd, J=3.2 and 9.9Hz, H-3),
4.30 (dd, J=4.9 and 12.4Hz, H-6proR), 4.14 (dd, J=1.5
and 12.4Hz, H-6proS), 3.80 (m, H-5), 2.21 (s, 3 H),
2.10 (s, 3 H), 2.09 (s, 3 H), 2.05 (s, 3 H), 2.00 (s, 3 H);
13C NMR (CDCl3) d 170.2 (s), 169.7 (s), 169.4(s),
169.2 (s), 168.0 (s), 90.1 (d, C-1), 72.7 (d, C-5), 70.3 (d,
C-4), 67.9 (d, C-2), 65.1 (d, C-3), 61.7 (t, C-6), 20.3
(q·2), 20.2 (q·2), 20.1 (q); Anal. Calcd for
C16H22O11: C, 49.23; H, 5.68. Found: C, 49.24; H, 5.74.
4.30. 1,2,3,4,6-Penta-O-(p-bromobenzoyl)-D-mannopyr-
anoside 26
DMAP as catalyst and p-bromobenzoyl chloride
(900mg, 4.10mmol) were added to a solution of D-(+)-
mannose (100mg, 0.55mmol) in dry pyridine (10mL/
mmol). The solution was heated at 60ꢁC and stirred
overnight. The excess solvent was then removed under
reduced pressure in the presence of toluene, and the res-
idue chromatographed with CH2Cl2 as eluent, yielding
26 as a 3:1 mixture of a- and b-anomers in a quantitative
amount. Compound 26 a: TLC Rf =0.58 (n-hexane/EtO-
Ac, 7.5:2.5); [a]D =ꢀ64.7 (c 1.2, CHCl3); MS (FAB) m/z
(relative intensity) 895 ([M+ꢀC7H4BrO2]+, 27.3), 307
1
´
8. (a) Morales, E. Q.; Padron, J. I.; Trujillo, M.; Vazquez, J.
T. J. Org. Chem. 1995, 60, 2537–2548; (b) Padron, J. I.;
´
(100); H NMR (CDCl3) d 8.03–7.44 (m, 20H), 6.56 (s,
´
H-1), 6.12 (t, J=10.1Hz, H-4), 5.95 (dd, J=3.1 and
10.1Hz, H-3), 5.84(br s, H-2), 4.71 (br d, J=12.1Hz,
H-6proS), 4.51 (m, H-5), 4.51 (dd, J=3.7 and 12.1Hz,
H-6proR); 13C NMR (CDCl3) d 165.1 (s), 164.9 (s),
164.6 (s), 164.3 (s), 163.1 (s), 132.3–127.3 (aromatic
Cs), 91.4(d, C-1), 71.0 (d, C-5), 70.0 (d, C-3), 69.4(d,
C-2), 66.2 (d, C-4), 62.3 (t, C-6); Anal. Calcd for
C41H24Br5O11: C, 44.96; H, 2.48. Found: C, 44.80; H,
´
´
´
Vazquez, J. T. Chirality 1997, 9, 626–637; (c) Padron, J. I.;
Vazquez, J. T. Tetrahedron: Asymmetry 1998, 9, 613–627.
´
´
9. Padron, J. I.; Morales, E. Q.; Vazquez, J. T. J. Org. Chem.
1998, 63, 8247–8258.
´
´
10. Nobrega, C.; Vazquez, J. T. Tetrahedron: Asymmetry
2003, 14, 2793–2801.
´ ´
11. Roe¨n, A.; Padron, J. I.; Vazquez, J. T. J. Org. Chem. 2003,
68, 4615–4630.

C. Mayato et al. / Tetrahedron: Asymmetry 15 (2004) 2385–2397
2397
12. Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc.
1989, 111, 6661–6666.
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14. Stenutz, R.; Carmichael, I.; Widmalm, G.; Serianni, A. S.
J. Org. Chem. 2002, 67, 949–958. Set of equations: (i)
1.3gg+1.5gt+10.8tg=JS; (ii) 0.8gg+9.9gt+4.5tg=JR;
(iii) gg+gt+tg=1.
19. (a) Thatcher, G. R. J. Anomeric and Associated Stereo-
electronic Effects. Scope and Controversy. In The Ano-
meric Effect and Associated Stereoelectronic Effects;
Thatcher, G. R. J., Ed.; ACS Symposium Series 539;
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The Anomeric Effect in New Directions in Organic and
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Boca Raton, FL, 1995.
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16. Different rotamer populations are obtained depending
on the set of equations used in their calculations,
therefore this must be taken into account when compar-
ing rotamer population data obtained from different
equations.
21. 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.;
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22. The amplitude (A value) of split CD Cotton effects is
defined as A=De1ꢀDe2 where De1 and De2 are intensities of
the first and second Cotton effects, respectively.
23. (a) Liu, H.-W.; Nakanishi, K. J. Am. Chem. Soc. 1981,
103, 5591–5593; (b) Liu, H.-W.; Nakanishi, K. J. Am.
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1971, 36, 1205–1209, and references cited therein; (b) pKa
Value for Menthol McEwen, W. K. J. Am. Chem. Soc.
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18. The equations of the lines drawn in Figure 5 for the three
series are: (a) Benzyl series: Pgg =ꢀ1.1033 pKa +64.275
(r=0.8706);
Pgt =1.9545
pKa +16.411
(r=0.9608);
Ptg =ꢀ0.8512 pKa +19.314( r=0.9929). (b) Acetyl series:
Pgg =ꢀ3.8940 pKa +104.13 (r=0.9848); Pgt =2.9389
pKa ꢀ0.7772 (r=0.9542); Ptg =0.9551 pKa ꢀ3.3517
(r=0.6227). (c) Benzoyl series: Pgg =ꢀ4.1960 pKa +
111.70 (r=0.9878); Pgt =4.5064 pKa ꢀ37.003 (r=0.9786);
Ptg =0.0985 pKa +16.756 (r=0.2987).
´
24. (a) Wiesler, W. T.; Vazquez, J. T.; Nakanishi, K. J. Am.
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