Conformational study of the hydroxymethyl group in α-D-mannose derivatives

Article abstract of DOI:10.1016/S0957-4166(03)00623-2

A study of the dependence of the hydroxymethyl group in α-D-mannose derivatives on the aglycon and its absolute configuration was performed by means of circular dichroism (CD) and NMR data. Depending mainly on the aglycon present, the gg or the gt rotamer was the most populated, the tg rotamer having a small population. In addition, the study showed a correlation between the rotational populations and the aglycon, the population of the gt rotamer increasing as the pK_a of the bonded alcohol (aglycon) increased. Furthermore, the results revealed a strong dependence on the absolute configuration of the aglycon and point to the stereoelectronic exo-anomeric effect being responsible for these rotational dependencies besides nonbonding interactions.

Full text of DOI:10.1016/S0957-4166(03)00623-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2793–2801
Conformational study of the hydroxymethyl group in
a- -mannose derivatives
D
Chaxiraxi No´brega and Jesu´s T. Va´zquez*
Instituto Universitario de Bio-Orga´nica ‘Antonio Gonza´lez’, Universidad de La Laguna, Avda. Astrof´ısico Fco. Sa´nchez 2,
38206 La Laguna, Tenerife, Spain
Received 2 July 2003; accepted 25 July 2003
Abstract—A study of the dependence of the hydroxymethyl group in a-D-mannose derivatives on the aglycon and its absolute
configuration was performed by means of circular dichroism (CD) and NMR data. Depending mainly on the aglycon present, the
gg or the gt rotamer was the most populated, the tg rotamer having a small population. In addition, the study showed a
correlation between the rotational populations and the aglycon, the population of the gt rotamer increasing as the pKa of the
bonded alcohol (aglycon) increased. Furthermore, the results revealed a strong dependence on the absolute configuration of the
aglycon and point to the stereoelectronic exo-anomeric effect being responsible for these rotational dependencies besides
nonbonding interactions.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
tion to these, a third torsion angle ꢀ (O5ꢀC5ꢀC6ꢀO6)
needs to be considered when the hydroxymethyl group
is involved in a linkage (see Fig. 1). This torsion angle
is also used to describe the conformation of unsubsti-
tuted hydroxymethyl groups. The conformation of the
hydroxymethyl group around the C5ꢀC6 bond is gener-
ally described by means of the populations of the
gauche–gauche (gg), gauche–trans (gt) and trans–gauche
(tg) rotamers (see Fig. 2). The first descriptor indicates
the torsional relationship between O6 and O5, and the
second that between O6 and C4.
To understand the biological functions of saccharides
and protein-bound saccharides from a molecular point
of view, it is necessary to know their conformational
preferences in solution, in addition to their three-
dimensional structure. The conformational analysis of
an oligosaccharide normally presents great difficulty
due to the flexibility of the glycosidic linkages and to
the rotation of the hydroxymethyl and other pendant
groups, the relative orientations of saccharide units
being expressed in terms of the glycosidic linkage tor-
The rotamer populations of the hydroxymethyl group1
are generally determined from JH5,H6R and JH5,H6S cou-
pling constants by means of a set of Karplus-equa-
tions,1–5 the unequivocal assignments of H6proR and
H6proS are therefore of major importance for this type
sion
angles
ƒ
(O5%ꢀC1%ꢀOꢀCx)
and
c
(C1%ꢀOꢀCxꢀC(xꢀ1)), for a 1–x linkage (Fig. 1). In addi-
1
of study. The H NMR study performed by Hori et al.6
with
D-mannose derivatives stereospecifically deuter-
ated at C6 led to the definite assignment of H6proR and
H6proS, and to the preferred conformation of the
hydroxymethyl group in these compounds. The greatest
rotamer populations around the C5ꢀC6 single bond
were gg and gt, with a ratio gg/gt of 60/40 for the
protected derivatives, the population of the tg rotamer
usually being negligible. These results were explained in
terms of both the gauche effect, which stabilizes the gg
and gt rotamers, and the 1,3-syn interaction between
O4 and O6, which destabilizes the tg rotamer.
Figure 1. Torsion angles ƒ and „ around the glycosidic
linkages, and torsion angles ꢀ around the C5ꢀC6 bonds.
* Corresponding author. Tel.: +34-922-318581; fax: +34-922-318571;
e-mail: jtruvaz@ull.es
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00623-2

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C. No´brega, J. T. Va´zquez / Tetrahedron: Asymmetry 14 (2003) 2793–2801
Figure 2. Molecular structure of an a-D-mannopyranoside in its three main rotamers, the gg (ꢀ=−60°), gt (ꢀ=60°), and tg
(ꢀ=180°) rotamers around the C5ꢀC6 bond.
Although several conformational studies on the
hydroxymethyl group of
D-mannose derivatives have
already been performed,6–9 we present here a systematic
study of the influence of the aglycon and its absolute
configuration on the populations of the hydroxymethyl
group in two series of a-
tetrakis-O-acetyl- and 2,3-bis-O-acetyl-4,6-bis-O-(p-
bromobenzoyl)-a- -mannose, having different
D-mannose derivatives: 2,3,4,6-
D
substituents at the anomeric carbon. On the basis of
CD and NMR data the results show a dependence of
the hydroxymethyl group rotational population on the
aglycon and its absolute configuration, and that the gg
or the gt rotamer has the highest population depending
mainly on the aglycon. Furthermore, the results indi-
cate that the stereoelectronic exo-anomeric effect has
an effect on the rotational population of the hydroxy-
methyl group, in addition to the steric effects, increas-
ing the gt population as the pKa of the aglycon
increases.
Scheme 1. Synthesis of the alkyl 2,3,4,6-tetrakis-O-acetyl-a-
-mannopyranosides.
D
configuration was assigned in each case on the basis of
T-ROESY NMR experiments, and confirmed by the
chemical shift in 13C NMR (92.3–99.2 ppm). Table 1
shows the results obtained for these model compounds.
2. Results
Table 1. JH5,H6 coupling constants and calculated
rotameric populations (%) around the C5ꢀC6 bond for the
1
a-D-mannose derivatives 1–6 (CDCl3)
The H NMR signals of the prochiral protons at C6,
H6R and H6S were differentiated according to the data
in the literature,6 on the basis of their chemical shifts
and coupling constants (accuracy 0.1 Hz). In general,
Compd.
Aglycon
JH5,H6R JH5,H6S Pgg Pgt Ptg
for the
appear at a higher field than H6S signals (lH6S>lH6R),
the reverse behavior being observed for acetyl-
D-manno-series saccharides, H6R proton signals
1a
2
3
4
5
(Acetyl)
(Br)
Methyl
Isopropyl
(+)-Menthyl
(−)-Menthyl
4.8
4.9
5.4
5.3
5.2
5.7
2.4
2.2
2.4
2.4
1.9
2.0
50
50
43
44
48
43
40
41
46
45
46
51
10
9
11
11
6
D
-
manno-series saccharides (lH6R>lH6S), and JH5,H6R cou-
pling constants have higher values than JH5,H6S. The
rotamer populations of the hydroxymethyl group were
calculated from the observed JH5,H6R and JH5,H6S cou-
pling constants and by using the Karplus-equations
recently proposed by Serianni and co-workers.5 This
approach yields a more accurate representation of the
rotamer populations in solution and positive values for
the tg rotamer population in all cases, in contrast to
other Karplus-equations used before.
6
6
(B) Series 2,3-bis-O-acetyl-4,6-bis-O-(p-bromoben-
zoyl)-h-D-mannose derivatives. Similarly to the studies
performed with alkyl gluco-11–13 and galactopyran-
osides,14 this series possesses two chromophores with a
high molar extinction coefficient, namely the p-bromo-
benzoates, to be able to perform the analysis by the
circular dichroic exciton chirality method (CD),15 in
addition to those by 1H NMR. These model com-
pounds were synthesized according to Scheme 2. Ben-
(A)
derivatives. These model compounds were synthesized
as shown in Scheme 1. Peracetylation of -mannose
Series
2,3,4,6-tetrakis-O-acetyl-h-D-mannose
D
followed by treatment with HBr in acetic acid led to the
mannosyl bromide 2 in high yield. This mannosyl
donor was then coupled with the corresponding alcohol
by means of a modified Koenigs–Knorr method to give
zylidenation of D-mannose with benzaldehyde dimethyl
acetal and p-TsOH, acetylation of the resulting 4,6-O-
benzylidene 7, and removal of this protecting group by
treatment with AcOH/H2O (8:2) led to a good yield of
the mixture of anomers 9 (a:b=2:1). Then, p-bromo-
benzoylation of 9 and treatment of 10 with HBr/AcOH
led to 2,3-bis-O-acetyl-4,6-bis-O-(p-bromobenzoyl)-a-
the desired alkyl a-
-mannopyranosides 3ꢀ6.10
D
All these compounds were characterized on the basis of
their one- (1H and 13C) and two-dimensional (COSY-G,
HMQC and T-ROESY) NMR spectra. The anomeric
D
-mannopyranosyl bromide 11 with a 77% yield.

C. No´brega, J. T. Va´zquez / Tetrahedron: Asymmetry 14 (2003) 2793–2801
2795
Scheme 2. Synthesis of the alkyl 2,3-bis-O-acetyl-4,6-bis-O-(p-bromobenzoyl)-a-D-mannopyranosides.
The Koenigs–Knorr coupling reaction between the
mannosyl donor 11 and the corresponding alcohols led
Table 2. JH5,H6 coupling constants and calculated
rotameric populations (%) around the C5ꢀC6 bond for the
a- -mannose derivatives 10–16 (CDCl3)
D
to the desired alkyl a- -mannopyranosides 12–16,
D
which were characterized in the same way as the previ-
ous series, on the basis of their one- and two-dimen-
sional NMR spectra.
Compd.
Aglycon
JH5,H6R JH5,H6S Pgg Pgt Ptg
10a
11
12
13
14
15
16
(Acetyl)
(Br)
Methyl
Isopropyl
tert-Butyl
(+)-Menthyl
(−)-Menthyl
4.2
4.5
5.1
5.3
5.4
4.7
5.7a
2.2
2.3
2.9
2.7
2.4
2.7
2.7a
57
54
43
42
43
49
38
34
37
41
44
46
37
48
9
9
The observed JH5,H6R and JH5,H6S coupling constants
obtained for the model 2,3-bis-O-acetyl-4,6-bis-O-(p-
16
14
11
14
14
bromobenzoyl)-a-
D
-mannopyranosides,
and
the
rotamer populations of the hydroxymethyl group calcu-
lated on the basis of the Karplus equations proposed by
Serianni and co-workers,5 are shown in Table 2.
a Calculated value (second order).
3. Discussion
As occurred with gluco-11–13 and galactopyranosides,14
this result points to a low participation of the
stereoelectronic exo-anomeric effect17,18 (Fig. 3) for the
acetyl and bromide derivatives and can be explained in
terms of the longer CꢀBr bond in the bromides, and the
delocalization of the nonbonding electron pair of the
exocyclic oxygen with the CꢁO bond in the acetyl
derivatives.
As mentioned above, we have used the Karplus equa-
tions proposed by Serianni et al. to calculate rotamer
populations of the hydroxymethyl group since this set
of equations yields a more accurate representation of
the rotameric populations in solution. The set of equa-
tions used in the calculations must be taken into
account when comparing rotamer population data.
Thus, using the values of the coupling constants
JH5,H6R=5.4 Hz and JH5,H6S=2.4 Hz and applying the
equations of Wu et al.16 used by Hori et al.,6 the
already mentioned 60/40 ratio is obtained for the
rotamers gg/gt in protected
D-mannose derivatives,
while using the same coupling constant and the Seri-
anni and co-workers’ equations5 a 43/46/11 ratio is
obtained for gg/gt/tg.
Figure 3. Illustration of the molecular orbitals involved in the
exo- and endo-anomeric effects.
In general, similar rotamer behavior was observed for
the two structural series analyzed, although slightly
higher tg populations were obtained for the series con-
taining benzoates than for the tetra-acetyl series (Tables
1 and 2). The increases in the rotational population of
the tg rotamer in the former series can be explained by
favourable p–p interactions between the two aromatic
rings in this array.
For the alkyl a-D-mannopyranosides, nonbonded inter-
actions and an active participation of the exo-anomeric
effect must be expected, both factors acting simulta-
neously. In addition, there should be a higher value of
the exo-anomeric effect for the tertiary alkyl mannopy-
ranosides than for the secondary ones, and for these
latter compared to the primary alkyl mannopyran-
osides, due to the increasing ease of charge delocaliza-
tion from the aglycon to the anomeric carbon.19,20 In
alkyl gluco- and galactopyranosides, an increase in the
stereoelectronic exo-anomeric effect led to an increase
in the population of the gt rotamer.
Analysis of the data reveals higher gg and smaller gt
populations for the acetyl derivatives 1a and 10a and
for the bromides 2 and 11 than for the alkyl mannopy-
ranosides 3–6 and 12–16, as consequence of the smaller
JH5,H6R coupling constant for the former compounds.

2796
C. No´brega, J. T. Va´zquez / Tetrahedron: Asymmetry 14 (2003) 2793–2801
Analysis of the data of the nonchiral alkyl a-
mannopyranosides revealed no significant rotational
population differences for the tetra-acetyl h- -manno-
D
-
curves of bichromophoric systems22 (two types of chro-
mophores) were studied in methyl glycopyranosides
containing chromophoric esters, thus allowing an easy
interpretation of the CD spectra of these types of
compounds and establishing an oligosaccharide
micromethod by CD spectroscopy.24 Therefore, CD
spectra of the 2,3-bis-O-acetyl-4,6-bis-O-(p-bromoben-
D
series, compounds 3 and 4: Pgg (45%); Pgt (45%); and
Ptg (10%). However, differences in rotational popula-
tions were observed for the 2,3-bis-O-acetyl-4,6-bis-O-
(p-bromobenzoyl)-h- -manno-series, compounds 12–14.
D
zoyl)-a-D-mannose derivatives were recorded and
These compounds show a gradual increase/decrease in
the rotamer population of the gt and tg rotamers
respectively, from the methyl, to the isopropyl, and to
the tert-butyl derivative, the gg population remaining
constant. These conformational differences can only be
explained on the basis of the exo-anomeric effect and
not on steric effects, because the higher bulkiness of the
secondary and tertiary alkyl group compared to the
methyl one would lead to decreased gt populations
through nonbonded interactions with the hydroxy-
methyl group.
shown to be positive CD exciton-coupled spectra, more
specifically, with positive first Cotton effects at 250 nm
and negative second Cotton affects at 232 nm, centered
on the p-bromobenzoate umax 245 nm (CH3CN) (Fig.
5).
The chiral alkyl mannopyranosides showed clear and
similar rotamer population differences in both series.
Thus, higher gg and smaller gt populations were
observed for the (+)-menthyl mannopyranosides 5 and
15 than for the corresponding (−)-menthyl derivatives 6
and 16, respectively. Nonbonded interactions can
explain the higher gg and smaller gt populations
observed for the (+)-menthyl mannopyranosides,
because the isopropyl group of the cyclohexyl ring is
syn (Fig. 4, left) to O5, spatial disposition confirmed by
ROESY experiments, and therefore closer to the
hydroxymethyl group at C6. In sharp contrast with the
(+)-menthyl mannopyranosides, the calculated rotamer
populations obtained for the corresponding (−)-men-
thyl derivatives 6 and 16 are the highest gt and smallest
Figure 5. CD spectra comparison of the 1-acetyl 10a, the
bromide 11, as well as the model alkyl mannopyranosides
12–16 (CH3CN).
gg observed for all the a-D-mannose derivatives ana-
A correct CD spectral interpretation must include con-
siderations on the interchromophoric distance and the
dihedral angle of the chromophores.15 Thus, the greater
proximity and the more favourable dihedral angle for
the 4/6 pairwise interaction in the gg disposition than in
the gt, confers a higher CD contribution on the gg
rotamer and explains why all CD spectra are of positive
sign (Fig. 6). However, the unlike amplitudes observed
for the model derivatives are a consequence of the
different ratios between the populations of the gg (pos-
itive CD contribution), gt (negative CD contribution)
and tg (nil CD contribution) rotamers.
lyzed in each series. This result cannot be explained by
nonbonded interaction between the aglycon and the
hydroxymethyl group because it would lead to a
smaller population of the gt rotamer. Therefore, an
active participation of the stereoelectronic exo-
anomeric effect is proposed to explain the rotamer
populations obtained for these (−)-menthyl derivatives.
Figure 4. Structures of (1S,2R,5S)-(+)- and (1R,2S,5R)-(−)-
menthyl a-D-mannopyranosides, left and right, respectively.
Figure 6. 4/6 Pairwise interaction for the mannopyranosyl
system in each of the three stable rotamers (gg, gt, and tg).
The circular dichroic exciton chirality method15 has
proved to be extremely sensitive to the conformational
changes of chromophorically substituted hydroxy-
methyl groups in hexopyranosides.21,22 Furthermore,
the additivity of the amplitude (A value)23 in the CD
exciton curves of multichromophoric systems21 (one
type of chromophore) and the additivity of the CD
The intensity of the first Cotton effect25 of the CD
spectra for 2,3-bis-O-acetyl-4,6-bis-O-(p-bromoben-
zoyl)-a-
D
-mannose
derivatives
10–16
gradually
decreased from the acetyl (17.8), to bromide (17.7),
methyl (16.2), isopropyl (14.1), (+)-menthyl (13.6), (−)-

C. No´brega, J. T. Va´zquez / Tetrahedron: Asymmetry 14 (2003) 2793–2801
2797
menthyl (10.8) and tert-butyl a-
D
-mannose derivatives
imentally determined m values at 245 nm: bis(p-bro-
mobenzoate) m 38200.21
(6.4). These intensities are consistent with a gradual
decrease in the contribution of the positively coupled
4/6 pairwise interaction (gg rotamer) and with a grad-
ual increase in the contribution of the negatively cou-
pled 4/6 pairwise interaction (gt rotamer).
For analytical and preparative thin-layer chromatogra-
phy, silica gel ready-foils and glass-backed plates (1
mm) were used respectively, developed with 254 nm UV
light and/or spraying with AcOH/H2O/H2SO4 (80:16:4)
and heating to 150°C. Flash column chromatography
The observed CD spectral behavior is in good agree-
ment with the results obtained from the NMR analysis.
Thus, the acetyl 10a and bromide 11 exhibit the highest
CD amplitudes reflecting the highest gg and smallest gt
,
was performed using silica gel (60 A). 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
argon atmosphere. The compounds prepared were
characterized on the basis of their one- (1H and 13C)
and two-dimensional (COSY and HSQC) NMR spec-
tra, as well as by UV and CD spectroscopy.
populations, the nonchiral alkyl a-D-mannopyranosides
show gradual decreases in amplitude from methyl, to
isopropyl and tert-butyl derivatives in agreement with
the gradual increases observed by NMR for the gt
population, and the chiral alkyl a-D-mannopyranosides
exhibit different amplitudes, as a higher amplitude was
expected for the (+)-menthyl derivative 15 than for the
(−)-menthyl mannopyranoside 16.
5.2. General procedure for a-mannosylation
To a stirred solution of mannosyl donor (acylmannosyl
bromide) in dry CH2Cl2 (8 mL/mmol) at room temper-
ature under Ar, a mannosyl acceptor (alcohol) and base
were added. The reaction mixture was cooled at 0°C in
an ice bath, and 1.5 equiv. of AgOTf was then added in
the dark under anhydrous conditions, the reaction
being monitored by TLC. After quenching the reaction
with a few drops of pyridine and filtration through a
bed of Celite with CH2Cl2, the filtrate was evaporated
under reduced pressure, and column chromatography
(n-hexane/EtOAc solvent systems) yielded the purified
product.
4. Conclusions
The rotational population study of the hydroxymethyl
group performed on a-D-mannose derivatives, by
means of CD and NMR spectroscopic techniques,
shows that the two main rotamers are the gg and gt,
and then in a smaller proportion the tg, and confirms
the dependence of the rotational population of the
hydroxymethyl group on the aglycon and its absolute
configuration. According mainly to the aglycon, the gg
or the gt rotamer has the highest population. In gen-
eral, a similar rotamer behavior was observed for the
two structural series analyzed, but a slightly higher tg
populations were obtained for the series containing
benzoates probably by a favourable p–p interaction
between the two aromatic rings.
5.3. 1,2,3,4,6-Pentakis-O-acetyl-D-mannopyranoside 1
To a solution of -mannose (1 g, 5.55 mmol) in dry
D
pyridine (4 mL) at room temperature, acetic anhydride
(4 mL) was added, the reaction being monitored by
TLC. Excess solvent was then removed under reduced
pressure in the presence of toluene, and the residue
(2.16 g, Rf=0.57 (n-hexane/EtOAc, 1:1)) was used
directly in the next step. 1H NMR showed a 3:1 ratio of
the a- and b-anomers, respectively, the data of the
major stereoisomer 1a being in complete agreement
with those from a commercial sample: 1H NMR
(CDCl3) l 6.09 (d, J=1.7 Hz, H-1), 5.35 (m, 2H), 5.26
(m, 1H), 4.28 (dd, J=4.8 and 12.4, H-6proR), 4.10 (dd,
J=2.4 and 12.4 Hz, H-6proS), 4.05 (m, H-5), 2.18 (s,
3H), 2.17 (s, 3H), 2.10 (s, 3H), 2.06 (s, 3H), 2.01 (s,
3H).
In addition, the results indicate that the stereoelectronic
exo-anomeric effect is directly related to the rotational
population of the hydroxymethyl group in a-D-man-
nose derivatives, along with the steric effects, the gt
population increasing as the pKa of the aglycon
increases.
5. Experimental
5.1. General
1H NMR spectra were recorded at 400 MHz, and 13C
NMR at 100 MHz, VTU 300.0 °K. Chemical shifts are
reported in parts per million. The residual solvent peak
(CDCl3) was used as an internal reference, 7.26 for
proton and 7.70 ppm for the central peak for carbon
NMR. 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 using 10 mm cells.
Prior to measurement of CD spectra, all compounds
were purified by HPLC using a m-Porasil column, 150×
19 mm ID, 254 nm, and HPLC grade n-hexane/EtOAc
solvent systems. The concentrations of the CD samples
were ascertained from the UV spectra, using the exper-
5.4. 2,3,4,6-Tetrakis-O-acetyl-a-D-mannopyranosyl bro-
mide 2
HBr/AcOH (30:70) (11.4 mL, 55.5 mmol) was added to
a stirred solution of compound 1 (2.16 g, 5.53 mmol) in
dry CH2Cl2 (16 mL) at room temperature under argon.
Once the reaction was finished, CH2Cl2 was added and
the mixture extracted with saturated solutions of
NaHCO3 and then NaCl. The combined organic layers
were dried over Na2SO4, filtered and concentrated.
Flash column chromatography with n-hexane/EtOAc
(6:4) as the eluent yielded 2 (1.84 g, 81% yield). TLC
1
Rf=0.33 (n-hexane/EtOAc, 6:4); H NMR (CDCl3) l

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C. No´brega, J. T. Va´zquez / Tetrahedron: Asymmetry 14 (2003) 2793–2801
6.29 (brs, H-1), 5.72 (dd, J=3.3 and 10.2 Hz, H-3), 5.45
(brd, J=3.3 Hz, H-2), 5.37 (t, J=10.1 Hz, H-4), 4.33
(dd, J=4.9 and 12.4, H-6proR), 4.23 (m, H-5), 4.14 (dd,
J=2.2 and 12.4 Hz, H-6proS), 2.18 (s, 3H), 2.11 (s, 3H),
2.08 (s, 3H), 2.01 (s, 3H); 13C NMR (CDCl3) l: 170.32
(s), 169.52 (s), 169.39 (2×s), 83.00 (d, C-1), 72.70 (d,
C-5), 71.97 (d, C-2), 67.78 (d, C-3), 65.14 (d, C-4), 61.29
(t, C-6), 20.60 (q), 20.51 (2×q), 20.41 (q).
242 (100), 157 (57); 1H NMR (CDCl3) l 5.32 (dd,
J=3.1 and 10.0 Hz, H-3), 5.27 (t, J=10.0 Hz, H-4),
5.12 (brd, J=3.1 Hz, H-2), 5.00 (brs, H-1), 4.24 (dd,
J=5.2 and 12.2 Hz, H-6proR), 4.08 (dd, J=1.9 and 12.2
Hz, H-6proS), 4.02 (m, H-5), 3.45 (dt, J=4.0 and 10.6
Hz, H-1%), 2.19 (m, H-7%), 2.15 (s, 3H), 2.07 (s, 3H), 2.04
(s, 3H), 2.03 (m, H-6% ), 1.98 (s, 3H), 1.65 (m, 2H), 1.31
ec.
(m, 2H), 0.93 (d, J=7.0 Hz, 3H), 0.90 (d, J=6.5 Hz,
3H), 0.83 (m, 3H), 0.75 (d, J=7.0, 3H); 13C NMR
(CDCl3) l 170.63 (s), 170.18 (s), 169.90 (s), 169.74 (s),
94.27 (d, C-1), 77.31 (d, C-1%), 70.65 (d, C-2), 69.17 (d,
C-3), 69.03 (d, C-5), 66.14 (d, C-4), 62.59 (t, C-6), 47.52
(d), 39.63 (t, C-6%), 34.21 (t), 31.37 (d), 25.40 (d, C-7%),
22.69 (t), 22.15 (q), 21.10 (q), 20.92 (q), 20.68 (3×q),
15.30 (q). Anal. calcd for C24H38O10: C, 59.24; H, 7.87.
Found: C, 59.23; H, 8.26.
5.5. Methyl 2,3,4,6-tetrakis-O-acetyl-a-D-mannopyran-
oside 3
Following the general procedure for a-mannosylation
without base, compound 2 (163.1 mg, 0.397 mmol) was
treated with dry methanol (61.8 equiv.) to produce
compound 3 (35.9 mg, 0.10 mmol, 25% yield): TLC
Rf=0.27 (n-hexane/EtOAc, 6:4); [h]2D5=+53.0 (c 0.2,
CHCl3); MS (EI) m/z (relative intensity) 331 ([M+−
MeO], 7), 243 (27), 200 (47), 157 (100); 1H NMR
(CDCl3) l: 5.33 (dd, J=3.3 and 10.0 Hz, H-3), 5.27 (t,
J=10.0 Hz, H-4), 5.24 (dd, J=1.4 and 3.3 Hz, H-2),
4.71 (d, J=1.4 Hz, H-1), 4.28 (dd, J=5.4 and 12.2 Hz,
H-6proR), 4.12 (dd, J=2.4 and 12.2 Hz, H-6proS), 3.96
(m, H-5), 3.40 (s, 3H), 2.15 (s, 3H), 2.10 (s, 3H), 2.03 (s,
3H), 1.99 (s, 3H); 13C NMR (CDCl3) l: 170.64 (s),
170.03 (s), 169.87 (s), 169.71 (s), 98.55 (d, C-1), 69.47
(d, C-2), 69.0 (d, C-3), 68.34 (d, C-5), 66.11 (d, C-4),
62.47 (t, C-6), 55.27 (q, C-1%), 20.85(q), 20.70 (q), 20.66
(2×q). Anal. calcd for C15H22O10: C, 49.72; H, 6.12.
Found: C 49.71; H, 6.33.
5.8. (1R,2S,5R)-(−)-Menthyl 2,3,4,6-tetrakis-O-acetyl-
a-D-mannopyranoside 6
Following the general procedure without base, a-man-
nosylation of (−)-menthol (100.5 mg, 0.643 mmol) with
compound 2 (396 mg, 0.964 mmol, 1.5 equiv.) led to 6
(79.8 mg, 0.164 mmol, 26% yield): TLC Rf=0.46 (n-
hexane/EtOAc, 6:4); [h]2D5=+12.0 (c 0.1, CHCl3); MS
(EI) m/z (relative intensity) 331 ([M+−C10H19O], 15),
1
242 (69), 83 (100); H NMR (CDCl3) l 5.37 (dd, J=3.3
and 10.0 Hz, H-3), 5.24 (t, J=10.0 Hz, H-4), 5.16 (brd,
J=3.3 Hz, H-2), 4.89 (brs, H-1), 4.23 (dd, J=5.7 and
11.9 Hz, H-6proR), 4.16 (m, H-5), 4.12 (dd, J=2.0 and
11.9 Hz, H-6proS), 3.36 (dt, J=4.3 and 10.7 Hz, H-1%),
2.15 (s, 3H), 2.09 (s, 3H), 2.07 (m, 2H), 2.04 (s, 3H),
1.99 (s, 3H), 1.61 (m, 2H), 1.27 (m, 2H), 1.01 (m, 3H),
0.88 (d, J=9.0 Hz, 3H), 0.83 (d, J=9.0 Hz, 3H), 0.76
(d, J=7.0 Hz, 3H). 13C NMR (CDCl3) l 170.66 (s),
170.19 (s), 169.96 (s), 169.81 (s), 99.19 (d, C-1), 82.69
(d, C-1%), 70.17 (d, C-2), 69.06 (d, C-3), 68.60 (d, C-5),
66.54 (d, C-4), 62.82 (t, C-6), 48.31 (d), 42.65 (t, C-6%),
34.16 (t), 31.62 (d), 25.80 (d, C-7%), 23.24 (t), 22.30 (q),
20.92 (q), 20.71 (4×q), 16.19 (q). Anal. calcd for
C24H38O10: C, 59.24; H, 7.87. Found: C, 59.25; H, 8.29.
5.6. Isopropyl 2,3,4,6-tetrakis-O-acetyl-a-D-mannopy-
ranoside 4
i
Using 61.8 equiv. of PrOH, 0.7 equiv. of 2,4,6-collidine
as base, and 345 mg (0.839 mmol) of compound 2, and
following the general procedure for a-mannosylation,
compound 4 (72.0 mg, 0.185 mmol) was obtained in
22% yield: TLC Rf=0.35 (n-hexane/EtOAc, 6:4);
[h]2D5=+57.5 (c 0.2, CHCl3); MS (EI) m/z (relative
1
intensity) 331 ([M+−C3H7O], 12), 157 (100); H NMR
(CDCl3) l: 5.35 (dd, J=3.4 and 10.0 Hz, H-3), 5.25 (t,
J=10.0 Hz, H-4), 5.16 (dd, J=1.8 and 3.3 Hz, H-2),
4.90 (d, J=1.8 Hz, H-1), 4.25 (dd, J=5.3 and 12.1,
H-6proR), 4.09 (dd, J=2.4 and 12.1 Hz, H-6proS), 4.04
(m, H-5), 3.90 (m, H-1%), 2.14 (s, 3H), 2.08 (s, 3H), 2.03
(s, 3H), 1.23 (d, J=6.2 Hz, 3H), 1.16 (d, J=6.1 Hz,
3H); 13C NMR (CDCl3) l: 170.62 (s), 170.12 (s), 169.88
(s), 169.75 (s), 95.93 (d, C-1), 70.97 (d, C-1%), 70.23 (d,
C-2), 69.12 (d, C-3), 68.37 (d, C-5), 66.43 (d, C-4), 62.57
(t, C-6), 23.01 (q), 21.49 (q), 20.90 (q), 20.67 (3×q).
Anal. calcd for C17H26O10: C, 52.30; H, 6.71. Found: C,
52.32; H, 6.82.
5.9. 4,6-O-Benzylidene-D-mannopyranose 7
Benzaldehyde dimethyl acetal (5.5 mL, 36.63 mmol)
and p-toluenesulfonic acid (62.7 mg, 0.33 mmol) were
added to a solution of
D-mannose (6 g, 33.3 mmol) in
DMF (67 mL). The reaction mixture was heated to
50°C under vacuum, for 3 h. The solvent was then
removed by distillation and the resulting oil chro-
matographed on silica gel (n-hexane/EtOAc, 2:8). Com-
pound 7 (6.97 g, 26.0 mmol) was obtained with a 78%
yield (Rf=0.55, CH2Cl2/MeOH, 9:1) and was then
directly acetylated.
5.7. (1S,2R,5S)-(+)-Menthyl 2,3,4,6-tetrakis-O-acetyl-
a-
D
-mannopyranoside 5
5.10. 4,6-O-Benzylidene-1,2,3-tris-O-acetyl-D-mannopy-
ranoside 8
Following the general procedure without base, a-man-
nosylation of (+)-menthol (97 mg, 0.623 mmol) with
compound 2 (384 mg, 0.934 mmol, 1.5 equiv.) led to 5
(56.4 mg, 0.116 mmol, 19% yield): TLC Rf=0.46 (n-
hexane/EtOAc, 6:4); [h]2D5=+85.0 (c 0.2, CHCl3); MS
(EI) m/z (relative intensity) 331 ([M+−C10H19O], 40),
Acetic anhydride (8 mL) was added to a solution of
compound 7 (5.02 g, 18.7 mmol) in dry pyridine (8 mL)
at room temperature, the reaction being monitored by
TLC. Excess solvent was then removed under reduced
pressure in the presence of toluene, and the residue

C. No´brega, J. T. Va´zquez / Tetrahedron: Asymmetry 14 (2003) 2793–2801
2799
chromatographed (n-hexane/EtOAc, 8:2), to produce
compound 8: a-anomer (4.18 g, 10.6 mmol, 57%) and
b-anomer (2.09 g, 5.3 mmol, 28%). Compound 8a: TLC
2H), 7.55 (d, J=8.2 Hz, 2H), 7.52 (d, J=8.2 Hz, 2H),
6.14 (s, H-1), 5.72 (t, J=10.0 Hz, H-4), 5.58 (dd, J=2.7
and 10.0 Hz, H-3), 5.32 (brs, H-2), 4.53 (dd, J=2.2 and
12.2 Hz, H-6proS), 4.38 (dd, J=4.2 and 12.2 Hz, H-
6proR), 4.30 (m, H-5), 2.20 (s, 3H), 2.18 (s, 3H), 1.92 (s,
3H); 13C NMR (CDCl3) l 169.9 (s), 169.6 (s), 168.0 (s),
165.2 (s), 164.6 (s), 131.9–127.6 (aromatic Cs), 90.6 (d,
C-1), 70.5(d, C-5), 68.5 (d, C-2), 68.4 (d, C-3), 67.0 (d,
C-4), 63.1 (t, C-6), 20.8 (q), 20.7 (q), 20.5 (q); UV
(CH3CN) umax 245 nm; CD (CH3CN) uext (Dm) 250
(17.8), 232 nm (−4.9). Compound 10b: TLC Rf=0.30
1
Rf=0.38 (n-hexane/EtOAc, 6:4); H NMR (CDCl3) l
7.44 (m, 2H), 7.34 (m, 3H), 6.02 (d, J=1.0 Hz, H-1),
5.57 (s, H-1%), 5.41 (dd, J=3.5 and 10.3 Hz, H-3), 5.34
(brd, J=3.5 Hz, H-2), 4.29 (dd, J=4.7 and 10.2 Hz,
H-6proR), 4.09, (t, J=10.3 Hz, H-4), 4.01 (m, H-5), 3.82
(t, J=10.2 Hz, H-6proS), 2.17 (s, 3H), 2.15 (s, 3H), 2.02
(3H); 13C NMR (CDCl3) l 170.6 (s), 169.9 (s), 168.6 (s),
136.9–126.2 (aromatic Cs), 101.9 (d, C-1%), 93.8 (d,
C-1), 75.5 (d, C-4), 68.8 (d, C-2), 68.6 (d, C-6), 68.3 (d,
C-3), 66.4 (d, C-5), 20.7 (3×q). Compound 8b: TLC
1
(n-hexane/EtOAc, 7:3); H NMR (CDCl3) l 7.83 (d,
J=8.5 Hz, 2H), 7.79 (d, J=8.5 Hz, 2H), 7.56 (d, J=8.5
Hz, 2H), 7.52 (d, J=8.5 Hz, 2H), 5.96 (brs, H-1), 5.63
(t, J=10.0 Hz, H-4), 5.55 (brd, J=3.1 Hz, H-2), 5.37
(dd, J=3.1 and 10.0 Hz, H-3), 4.54 (d, J=3.2 and 12.2
Hz, H-6proS), 4.41 (dd, J=6.3 and 12.2 Hz, H-6proR),
4.10 (m, H-5), 2.23 (s, 3H), 2.11 (s, 3H), 1.92 (s, 3H);
13C NMR (CDCl3) l 170.05 (s), 169.76 (s), 168.34 (s),
165.27 (s), 164.64 (s), 131.99–127.46 (aromatic Cs),
90.47 (d, C-1), 73.02 (d, C-5), 70.36 (d, C-3), 68.34 (d,
C-2), 66.94 (d, C-4), 63.22 (t, C-6), 20.73 (2×q), 20.47
(q).
1
Rf=0.34 (n-hexane/EtOAc, 6:4); H NMR (CDCl3) l
7.44 (m, 2H), 7.35 (m, 3H), 5.93 (s, H-1), 5.58 (brd,
J=3.3 Hz, H-2), 5.56 (s, H-1%), 5.21(dd, J=3.3 and 10.3
Hz, H-3), 4.36 (dd, J=4.9 and 10.4 Hz, H-6proR), 4.04
(t, J=10.3 Hz, H-4), 3.86 (t, J=10.4 Hz, H-6proS), 3.66
(m, H-5), 2.22 (s, 3H), 2.09 (s, 3H), 2.02 (s, 3H); 13C
NMR (CDCl3) l 169.8 (s), 169.5 (s), 168.4 (s), 136.9–
126.2 (aromatic Cs), 102.0 (d, C-1%), 90.7 (d, C-1), 75.3
(d, C-4), 69.9 (d, C-3), 68.9 (d, C-2), 68.4 (t, C-6), 68.2
(d, C-5), 2.07 (3×q).
5.11. 1,2,3-Tris-O-acetyl-
D
-mannopyranoside 9
5.13. 2,3-Bis-O-acetyl-4,6-bis-O-(p-bromobenzoyl)-a-D-
mannopyranosyl bromide 11
Compound 8 (3.59 g, 9.10 mmol) in AcOH/H2O (28
mL, 80:20, v/v) was heated at 60°C, monitoring the
reaction by TLC. Excess solvent was then removed
under reduced pressure and the residue chro-
matographed on silica gel (n-hexane/EtOAc, 2:8), to
yield compound 9 (2.09 g, 6.82 mmol, 75% yield) as a
2:1 mixture of a- and b-anomers: TLC Rf=0.53
(CH2Cl2/MeOH, 9:1); 1H NMR (CDCl3) l 6.01 (s,
H-1a), 5.85 (s, H-1b), 5.45 (s, H-2b), 5.22 (s, H-2a),
5.18 (dd, J=3.2 and 9.9 Hz, H-3a), 4.97 (dd, J=2.9
and 9.9 Hz, H-3b), 4.05 (t, J=9.8 Hz, H-4a), 3.97 (t,
J=9.8 Hz, H-4b), 3.89 (m, 4H), 3.76 (m, H-5a), 3.54
(m, H-5b), 2.16 (s, 3H), 2.14 (s, 3H), 2.12 (s, 3H), 2.07
(s, 3H), 2.06 (s, 3H), 2.05 (s, 3H); 13C NMR (CDCl3) l
170.8 (s), 170.6 (s), 170.1 (s), 169.7 (s), 168.6 (s), 168.5
(s), 90.8 (d, C-1a), 90.5 (d, C-1b), 76.6 (d, C-5b), 74.4(d,
C-5a), 73.3 (d, C-3b), 71.4 (d, C-3a), 62.5 (2×d, C-2a y
C-2b), 65.4 (d, C-4b), 65.2 (d, C-4a), 62.0 (t, C-6b), 61.7
(t, C-6a), 20.8 (2×q), 20.7 (2×q), 20.6 (2×q).
HBr/AcOH (30:70) (10.0 mL) were added to a stirred
solution of compound 10 (3.30 g, 4.91 mmol) in dry
CH2Cl2 (15 mL) at room temperature under argon.
Once the reaction was finished, CH2Cl2 was added and
then extracted with NaHCO3 and NaCl saturated solu-
tions. The combined organic layers were dried over
Na2SO4, filtered and concentrated. Flash column chro-
matography with n-hexane/EtOAc (7:3) as the eluent
yielded 11 (2.63 g, 3.80 mmol, 77% yield). TLC Rf=
0.44 (n-hexane/EtOAc, 7:3); [h]2D5=+116.5 (c 0.2,
1
CHCl3); H NMR (CDCl3) l 7.86 (d, J=8.6 Hz, 2H),
7.84 (d, J=8.6 Hz, 2H), 7.57 (d, J=8.6 Hz, 2H), 7.54
(d, J=8.6 Hz, 2H), 6.34 (brs, H-1), 5.96 (dd, J=3.2
and 10.0 Hz, H-3), 5.74 (t, J=10.0 Hz, H-4), 5.49 (brd,
J=3.2 Hz, H-2), 4.57 (dd, J=2.3 and 12.0 Hz, H-6proS),
4.47 (m, H-5), 4.42 (dd, J=4.5 and 12.0 Hz, H-6proR),
2.16 (s, 3H), 1.92 (s, 3H); 13C NMR (CDCl3) l 169.52
(s), 169.24 (s), 164.95 (s), 164.46 (s), 131.83–125.11
(aromatic Cs), 82.88 (d, C-1), 72.56 (d, C-5), 72.12 (d,
C-2), 67.52 (d, C-3), 66.48 (d, C-4), 62.20 (t, C-6), 20.53
(q), 20.35 (q); UV (CH3CN) umax 245 nm; CD (CH3CN)
uext (Dm) 250 (17.7), 232 nm (−5.7).
5.12. 1,2,3-Tris-O-acetyl-4,6-bis-O-(p-bromobenzoyl)-D-
mannopyranoside 10
A solution of compound 9 (1.99 g, 6.50 mmol) in dry
pyridine (18.3 mL) with DMAP as catalyst was treated
with p-bromobenzoyl chloride (4 g, 18.25 mmol). The
resulting pale yellow solution was heated at 60°C and
stirred overnight. The excess solvent was then removed
under reduced pressure in the presence of toluene and
the residue flash chromatographed with CH2Cl2 as the
eluent, yielding 10 (3.38 g, 5.03 mmol, 77% yield) as a
2:1 mixture of a- and b-anomers. This mixture was then
chromatographed with n-hexane/EtOAc (7:3), giving
2.25 g (3.35 mmol, 52%) of the a-anomer and 1.13 g
(1.68 mmol, 26%) of the b-anomer. Compound 10a:
TLC Rf=0.32 (n-hexane/EtOAc, 7:3); 1H NMR
(CDCl3) l 7.83 (d, J=8.2 Hz, 2H), 7.81 (d, J=8.2 Hz,
5.14. Methyl 2,3-bis-O-acetyl-4,6-bis-O-(p-bromoben-
zoyl)-a-D-mannopyranoside 12
Following the general procedure for a-mannosylation
and using 0.7 equiv. of 2,4,6-collidine as base, com-
pound 11 (100 mg, 0.144 mmol) was treated with dry
methanol (61.8 equiv.) to provide 12 (41.9 mg, 0.065
mmol, 45% yield): TLC Rf=0.33 (n-hexane/EtOAc,
7:3); [h]2D5=+37.0 (c 0.2, CHCl3); MS (EI) m/z (relative
intensity) 611, 613, 615 ([M+−OMe], 0.3); 523, 525, 527
([M+−C4H7O4], 8); 183, 181 ([M+−C18H20BrO9], 100);
1H NMR (CDCl3) l 7.85 (d, J=8.4 Hz, 2H), 7.81 (d,
J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4

2800
C. No´brega, J. T. Va´zquez / Tetrahedron: Asymmetry 14 (2003) 2793–2801
Hz, 2H), 5.63 (t, J=10.0 Hz, H-4), 5.57 (dd, J=3.0 and
10.0 Hz, H-3), 5.28 (brd, J=3.0 Hz, H-2), 4.77 (brs,
H-1), 4.54 (dd, J=2.9 and 12.0 Hz, H-6proS), 4.41 (dd,
J=5.1 and 12.0 Hz, H-6proR), 4.22 (m, H-5), 3.44 (s,
3H), 2.15 (s, 3H), 1.90 (s, 3H); 13C NMR (CDCl3) l
169.91 (s), 169.85 (s), 165.33 (s), 164.81 (s), 131.93–
127.76 (aromatic Cs), 98.54 (d, C-1), 69.71 (d, C-2),
68.69 (d, C-3), 68.41 (d, C-5), 67.63 (d, C-4), 63.51 (t,
C-6), 55.43 (q), 20.83 (q), 20.61 (q); UV (CH3CN) umax
245 nm; CD (CH3CN) uext (Dm) 250 (16.2), 232 nm
(−4.8). Anal. calcd for C25H24Br2O10: C, 46.61; H, 3.75.
Found: C, 46.70; H, 4.35.
uext (Dm) 250 (6.4), 232 nm (−3.0). Anal. calcd for
C28H30Br2O10: C, 49.00; H, 4.41. Found: C, 49.03; H,
4.75.
5.17. (1S,2R,5S)-(+)-Menthyl 2,3-bis-O-acetyl-4,6-bis-
O-(p-bromobenzoyl)-a-D-mannopyranoside 15
Following the general procedure without base, a-man-
nosylation of (−)-menthol (34 mg, 0.216 mmol, 1
equiv.) with compound 11 (300 mg, 0.433 mmol) in dry
CH3NO2 led to 15 (53.1 mg, 0.069 mmol, 32% yield):
TLC Rf=0.54 (n-hexane/EtOAc, 7:3); [h]2D5=+72.0 (c
0.2, CHCl3); MS (EI) m/z (relative intensity) 611, 613,
615 ([M+−C10H19O2], 3); 522, 524, 526 ([M+−C14H28O4],
15); 183, 185 ([M+−C28H40BrO9], 100); 1H NMR
(CDCl3) l 7.87 (d, J=8.5 Hz, 2H), 7.82 (d, J=8.5 Hz,
2H), 7.56 (d, J=8.5 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H),
5.66 (t, J=10.0 Hz, H-4), 5.74 (dd, J=3.1 and 10.0 Hz,
H-3), 5.19 (brd, J=3.1 Hz, H-2), 5.06 (brs, H-1), 4.53
(dd, J=2.7 and 12.1 Hz, H-6proS), 4.36 (dd, J=4.7 and
12.1 Hz, H-6proR), 4.26 (m, H-5), 3.49 (dt, J=4.1 and
10.6 Hz, H-1%), 2.24 (m, H-7%), 2.15 (s, 3H), 2.05 (m,
5.15. Isopropyl 2,3-bis-O-acetyl-4,6-bis-O-(p-bromoben-
zoyl)-a-D-mannopyranoside 13
Following the general procedure for mannosylation and
using 100 mg (0.144 mmol) of compound 11, 61.8
equiv. of iPrOH, and 0.7 equiv. of 1,1,3,3-tetra-
methylurea, compound 13 (48.5 mg, 0.072 mmol) was
obtained with a 50% yield: TLC Rf=0.44 (n-hexane/
EtOAc, 7:3); [h]2D5=+41.0 (c 0.2, CHCl3); MS (EI) m/z
(relative intensity) 611, 613, 615 ([M+−OC3H7], 2); 523,
525, 527 ([M+−C6H11O4], 11); 183, 185 ([M+−
H-6% ), 1.90 (s, 3H), 1.66 (m, 2H), 1.35 (m, 2H), 0.95
ec.
(d, J=7.0 Hz, 3H), 0.91 (d, J=6.4 Hz, 3H), 0.84 (m,
3H), 0.76 (d, J=7.0 Hz, 3H); 13C NMR (CDCl3) l
170.06 (s), 169.90 (s), 165.33 (s), 164.85 (s), 131.92–
127.79 (aromatic Cs), 94.26 (d, C-1), 77.32 (d, C-1%),
70.86 (d, C-2), 69.12 (d, C-5), 68.83 (d, C-3), 67.56 (d,
C-4), 63.48 (d, C-6), 47.53 (d), 39.68 (t, C-6%), 34.21 (t),
31.41 (d), 25.57 (d, C-7%), 22.76 (t), 22.15 (q), 21.13 (q),
20.88 (q), 20.64 (q), 15.48 (q); UV (CH3CN) umax 245
nm; CD (CH3CN) uext (Dm) 250 (13.6), 232 nm (−5.1).
Anal. calcd for C34H40Br2O10: C, 53.14; H, 5.25. Found:
C, 53.47; H, 5.74.
1
C20H24BrO9], 100); H NMR (CDCl3) l 7.85 (d, J=8.4
Hz, 2H), 7.83 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz,
2H), 7.52 (d, J=8.4 Hz, 2H), 5.62 (m, H-3 and H-4),
5.22 (brd, J=2.8 Hz, H-2), 4.96 (brs, H-1), 4.50 (dd,
J=2.7 and 12.1 Hz, H-6proS), 4.39 (dd, J=5.3 and 12.1
Hz, H-6proR), 4.31 (m, H-5), 3.95 (m, H-1%), 2.15 (s,
3H), 1.89 (s, 3H), 1.26 (d, J=6.1 Hz, 3H), 1.19 (d,
J=6.1 Hz, 3H); 13C NMR (CDCl3) l 170.03 (s), 169.88
(s), 165.36 (s), 164.88 (s), 131.91–127.80 (aromatic Cs),
96.03 (d, C-1), 71.31 (d, C-1%), 70.48 (d, C-2), 68.81 (d,
C-3), 68.48 (d, C-5), 67.88 (d, C-4), 63.63 (t, C-6), 23.16
(q), 21.61 (q), 20.89 (q), 20.64 (q); UV (CH3CN) umax
245 nm; CD (CH3CN) uext (Dm) 250 (14.1), 232 nm
(−4.6). Anal. calcd for C27H28Br2O10: C, 48.23; H, 4.20.
Found: C, 48.24; H, 4.66.
5.18. (1R,2S,5R)-(−)-Menthyl 2,3-bis-O-acetyl-4,6-bis-
O-(p-bromobenzoyl)-a-D-mannopyranoside 16
The reaction of (−)-menthol (60.63 mg, 0.388 mmol)
with the mannosyl bromide 11 (307 mg, 0.443 mmol)
and 2,4,6-collidine (41 mL, 0.310 mmol, 0.8 equiv.) as
base was performed as described in the general proce-
dure for mannosylation, to give compound 16 (46.2 mg,
0.060 mmol) with a 15% yield: TLC Rf=0.54 (n-hex-
ane/EtOAc, 7:3); [h]D25=+15.0 (c 0.1, CHCl3); MS (EI)
m/z (relative intensity) 611, 613, 615 ([M+−C10H19O2],
4); 522, 524, 526 ([M+−C14H28O4], 20); 183, 185 ([M+−
C28H40BrO9], 100); 1H NMR (CDCl3) l 7.87 (d, 8.6 Hz,
2H), 7.85 (d, J=8.6 Hz, 2H), 7.57 (d, J=8.6 Hz, 2H),
7.52 (d, J=8.6 Hz, 2H), 5.59 (m, H-3 and H-4), 5.21
(dd, J=1.8 and 2.7 Hz, H-2), 4.95 (d, J=1.8 Hz, H-1),
4.50 (dd, J=2.7 and 10.2 Hz, H-6proS), 4.40 (m, H-5),
4.37 (dd, J=5.7 and 10.2 Hz, H-6proR), 3.39 (dt, J=4.4
5.16. tert-Butyl 2,3-bis-O-acetyl-4,6-bis-O-(p-bromo-
benzoyl)-a-
D
-manopyranoside 14
t
Mannosylation of BuOH (1.4 mL, 15.14 mmol, 61.8
equiv.) with compound 11 (170 mg, 0.245 mmol) was
carried out as described in the general procedure using
as base 2,4,6-collidine (26 mL, 0.196 mmol, 0.8 equiv.)
to produce 14 (26.9 mg, 0.039 mmol) with an 16% yield:
TLC Rf=0.49 (n-hexane/EtOAc, 7:3); [h]2D5=+42.0 (c
0.1, CHCl3); MS (EI) m/z (relative intensity) 611, 613,
615 ([M+−OC4H9], 3); 522, 524, 526 ([M+−C7H13O4],
12); 183, 185 ([M+−C21H26BrO9], 100); 1H NMR
(CDCl3) l 7.84 (d, J=8.6 Hz, 4H), 7.56 (d, J=8.6 Hz,
2H), 7.51 (d, J=8.6 Hz, 2H), 5.63 (dd, J=3.1 and 10.0
Hz, H-3), 5.59 (t, J=10.0 Hz, H-4), 5.16 (d, J=1.7 Hz,
H-1), 5.10 (t, J=2.2 Hz, H-2), 4.47 (dd, J=2.4 and 11.1
Hz, H-6proS), 4.41 (m, H-5), 4.37 (dd, J=5.4 and 11.1
and 10.6 Hz, H-1%), 2.16 (s, 3H), 2.10 (m, H-6% and
ec.
H-7%), 1.90 (s, 3H), 1.62 (m, 2H), 1.31 (m, 2H), 0.93 (d,
J=7.0, 3H), 0.85 (m, 3H), 0.78 (d, J=6.0 Hz, 3H), 0.76
(d, J=7.0 Hz, 3H); 13C NMR (CDCl3) l 170.07 (s),
169.92 (s), 165.39 (s), 164.91 (s), 131.93–127.80 (aro-
matic Cs), 99.16 (d, C-1), 82.72 (d, C-1%), 70.37 (d, C-2),
68.78 (d, C-3), 68.70 (d, C-5), 67.85 (d, C-4), 63.79 (t,
C-6), 48.41 (d), 42.74 (t, C-6%), 34.17 (t), 31.64 (d), 25.78
(d, C-7%), 23.17 (t), 22.07 (q), 20.98 (q), 20.91 (q), 20.65
(q), 16.15 (q); UV (CH3CN) umax 245 nm; CD (CH3CN)
Hz, H-6proR), 2.17 (s, 3H), 1.90 (s, 3H), 1.29 (s, 9H); 13
C
NMR (CDCl3) l 170.14 (s), 169.90 (s), 165.31 (s),
164.81 (s), 131.88–127.85 (aromatic Cs), 92.28 (d, C-1),
77.15 (d, C-1%), 71.46 (d, C-2), 68.77 (d, C-3), 68.13 (d,
C-5), 68.06 (d, C-4), 63.79 (t, C-6), 28.36 (3×q), 20.90
(q), 20.62 (q); UV (CH3CN) umax 245 nm; CD (CH3CN)

C. No´brega, J. T. Va´zquez / Tetrahedron: Asymmetry 14 (2003) 2793–2801
2801
uext (Dm) 250 (10.8), 232 nm (−4.4). Anal. calcd for
C34H40Br2O10: C, 53.14; H, 5.25. Found: C, 53.36; H,
5.73.
troscopy Exciton Coupling in Organic Stereochemistry;
University Science Books: California, 1983; (b) Nakan-
ishi, K.; Berova, N. The Exciton Chirality Method in
Circular Dichroism, Principles and Applications; Nakan-
ishi, K.; Berova, N.; Woody, R. W., Eds.; VCH Publish-
ers: New York, 1994.
Acknowledgements
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This research was supported by the Ministerio de Cien-
cia y Tecnolog´ıa (Spain), through grants BQU2000-
0250 and 1FD97-0747-C04-01.
17. Spieser, S. A. H.; Kuik, J. A.v.; Kroon-Batenburg, L. M.
J.; Kroon, J. Carbohydr. Res. 1999, 322, 264–273.
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Stereoelectronic Effects. Scope and Controversy in The
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Thatcher, G. R. J., ed.; ACS Symposium Series 539:
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