Influence of protecting groups on the anomeric equilibrium; Case of the 4,6-O-benzylidene acetal in the mannopyranose series

Article abstract of DOI:10.1016/j.carres.2012.05.025

It is reported that the replacement of the 4- and 6-O-benzyl ethers in 2,3,4,6-tetra-O-benzyl-α,β-mannopyranose by a 4,6-O-benzylidene acetal results in an increased population of the β-anomer at equilibrium in CDCl₃ solution. The phenomenon is considered to arise from the lower steric bulk of the benzylidene acetal that, through diminished buttressing interactions, reduces steric interactions normally present in the β-anomer.

Full text of DOI:10.1016/j.carres.2012.05.025

Carbohydrate Research 357 (2012) 126–131
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Influence of protecting groups on the anomeric equilibrium; case of the
4,6-O-benzylidene acetal in the mannopyranose series
Indrajeet Sharma a, Luis Bohé b, David Crich a,b,
⇑
a Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202, USA
b Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 1 Avenue de la Terrasse, 91190 Gif-sur-Yvette, France
a r t i c l e i n f o
a b s t r a c t
Article history:
It is reported that the replacement of the 4- and 6-O-benzyl ethers in 2,3,4,6-tetra-O-benzyl-a,b-manno-
Received 23 April 2012
Received in revised form 25 May 2012
Accepted 28 May 2012
pyranose by a 4,6-O-benzylidene acetal results in an increased population of the b-anomer at equilibrium
in CDCl3 solution. The phenomenon is considered to arise from the lower steric bulk of the benzylidene
acetal that, through diminished buttressing interactions, reduces steric interactions normally present in
the b-anomer.
Available online 7 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Mannopyranosides
4,6-O-Benzylidene acetal
Anomeric equilibrium
Anomeric effect
Conformational analysis
1. Introduction
effects on the stereoselectivity of various glycosyl donors.24–36
With the possible exception of the 2N,3O-oxazolidinone protected
Cyclic protecting groups have come to be recognized as having a
major influence on the reactivity and stereoselectivity of numerous
glycosylation reactions.1–6 Fraser-Reid and co-workers were the
first to note the retarding influence of 4,6-O-benzylidene acetals
on the hydrolysis of a pentenyl glucopyranoside; a phenomenon
they attributed to a torsional disarming effect.7,8 Bols and co-work-
ers subsequently attributed the disarming nature of the benzyli-
dene acetal to the locking of the C5–C6 bond in the trans–gauche
(tg)9 conformation that maximizes the electron-withdrawing
capacity of the C6–O6 bond toward incipient positive charge at
the anomeric position.10 Ley and co-workers noted the effects of
cyclic bisacetal groups on the reactivity of various thio and seleno-
glycosides and exploited them in one pot oligosaccharide synthesis
protocols.11 The influences of many different acetals on the reactiv-
ity of thioglycosides on activation with the NIS/TfOH pair under a
standard set of conditions are quantified in Wong’s extensive series
of relative reactivity values (RRV’s).12 The influence of a 4,6-O-ben-
zylidene acetal on glycosylation stereoselectivity was noted in our
laboratory13,14 and has been extensively studied.15,16 A 3,5-O-silyl-
ene acetal and a related disiloxane acetal has been found to have a
stereodirecting influence in arabinofuranosylation.17–19 Cyclic car-
bonates and oxazolidinones have been found to enhance the reac-
tivity of certain glycosyl acceptors20–23 and to have beneficial
2-amino-2-deoxy-a-D
-glucopyranosyl donors,24–28,30 these effects
are best rationalized as kinetic phenomena, that is, phenomena
in which the cyclic protecting group exerts its influence by either
accelerating or decelerating a particular reaction pathway.
Protecting groups are also known to influence reactions under
equilibrium control, that is, by influencing thermodynamic factors,
of which the anomeric effect is a case in point. Thus, it has long
been known that protecting groups influence the position of the
anomeric equilibrium.37 For example, in the series of mannopyra-
nose, 2-O-methylmannopyranose, 2,3-di-O-methylmannopyranose
and 2,3,4,6-tetra-O-methylmannopyranose the percentage of the
axial isomer at equilibrium increases regularly from 68 through
75 and 80% to 85% (Fig. 1a).38 Likewise, in a series of 1,2,3,4-tet-
ra-O-acetyl-6-deoxy-D-glucopyranose derivatives the anomeric ef-
fect increases along the series as the substituent at the 6-position is
changed from hydrogen to iodide to chloride, to acetoxy and to
tosyloxy (Fig. 1b).39 It also has been reported that the installation
of a 4,6-O-ethylidene group onto mannopyranose causes a modest
decrease in the proportion of the b-anomer at equilibrium in both
water and DMSO, but essentially no change in the glucopyranose
series (Fig. 1c).38 Concerning the influence of cyclic protecting
groups on the anomeric equilibrium, we noted that a 2N,3O-oxazo-
lidinone in the glucosamine series both facilitates the interconver-
sion of b- to
a-anomers and strongly favors the a
-anomer.23
Similar observations were made by the Oscarson, Ye, and Ito
groups,25,26,28,29,40–43 all of which concluded that the equilibration
occurs via an endocyclic cleavage mechanism.
⇑
Corresponding author. Tel.: +1 313 577 6203; fax: +1 313 577 8822.
E-mail address: dcrich@chem.wayne.edu (D. Crich).
0008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2012.05.025

I. Sharma et al. / Carbohydrate Research 357 (2012) 126–131
127
were prepared as outlined in Scheme 1 from the thioglycosides
6, obtained from the alcohol 5,46 and 747 by hydrolysis of the thio-
glycoside function with N-bromosuccinimide and aqueous ace-
tone, and acetylation.
The various
a- and b-acetates were cleaved selectively with
potassium tert-butoxide in methanolic solution and after work-
up the resulting hemiacetals were examined by 1H NMR spectros-
copy in CDCl3 solution until no further change was observed. The
so-obtained anomeric ratios are presented in Table 1, from which
it is apparent that essentially the same ratios of a given hemiacetal
were observed irrespective of the configuration of the starting ace-
tate, thereby ensuring that the values recorded present true equi-
librium positions.
Comparison of the equilibrated anomeric ratio for the perben-
zylated system 8
responding 4,6-O-benzylidene acetal 9
a
b (Table 1, entries 1 and 2) with that of the cor-
b (Table 1, entries 3 and 4)
a
reveals the effect of the benzylidene group on the anomeric effect.
This effect is maintained in systems containing a carboxylate ester
at the 3-position, as is clear from comparison of the equilibrated
ratios for 10ab (Table 1, entries 5 and 6) with those for 11ab (Table
1, entries 7 and 8). In both instances the introduction of a 4,6-O-
benzylidene acetal in the place of two benzyl ethers at the
4- and 6-positions results in an increased proportion of the b-
hemiacetal at equilibrium. The benzylidene acetal therefore either
stabilizes the b-anomer of the hemiacetal and/or destabilizes the
a-anomer with respect to the corresponding 4,6-di-O-benzyl ether.
It is known that the population of the different conformers of the
C5–C6 bond in glycopyranosides is affected by the aglycone and
by the anomeric configuration both in general,9,48–50 and in the
mannopyranosides,51,52 and that this effect is transmitted through
multiple glycosidic linkages in oligosaccharides.53 Such effects are
usually interpreted (i) in terms of changes in the hydrogen bonding
pattern around the pyranoside ring and (ii) as changes in the rela-
tive populations of the gauche–gauche (gg) and gauche–trans (gt)
conformers (Fig. 3). The trans–gauche (tg) conformer is usually ex-
cluded from such considerations owing to its low incidence in all
but the galactopyranose series. However, it is apparent that such
effects, albeit small, persist in fully protected mannopyranosides
in aprotic organic solvents, and moreover that the tg conformer
is not an insignificant bystander.51,52
Figure 1. (a) Influence of methylation on the mannopyranose anomeric equilib-
rium.38 (b) Effect of the 6-substituent on the anomeric effect in glucopyranosyl
acetates.39 (c) Influence of a 4,6-O-ethylidene group on the anomeric equilibrium in
manno and glucopyranose.38
For example, in the tetra-O-acetylmannopyranosides (Fig. 4) the
tg conformer was more highly populated in the b-anomer in deu-
teriochloroform solution for three out of the four systems available
for comparison.51,52 More data exist in the glucopyranoside series,
where the same trend is seen in the same solvent (Fig. 5).48 Similar
comparisons made in perdeuterioacetonitrile, however, do not
show the same differences in rotomer populations and hence high-
light the effect of solvent on such distributions.
In the course of our ongoing studies we isolated benzylidene-
protected mannopyranose hemicacetals and have found them to
contain an unexpectedly high proportion of the b-anomer. We re-
port here on this observation and on the influence of 3-O-esters on
the anomeric effect both alone and in combination with a 4,6-O-
benzylidene group.
Bols has suggested and has provided evidence in favor of the
rate retarding effect of a 4,6-O-acetal on glycoside hydrolysis being
2. Results and discussion
Our study began with the preparation of various mannopyran-
osyl esters carrying different protecting groups suitable for the re-
lease of hemiacetals. Anomeric mixtures of tetra-O-benzyl-
mannopyranosyl acetate 1 ,b and 2,3-di-O-benzyl-4,6-O-benzyli-
dene- -mannopyranosyl acetate 2 ,b (Fig. 2) were prepared and
separated into the constituent anomers as described in the litera-
ture.44,45 The corresponding 3-O-benzoyl analogs 3
,b and 4 ,b
D-
a
D
a
a
a
Figure 2. Anomeric
D
-mannopyranosyl acetates 1 and 2.
Scheme 1. Preparation of the anomeric acetates 3 and 4.

128
I. Sharma et al. / Carbohydrate Research 357 (2012) 126–131
Table 1
The effect of protecting groups on the mannopyranoside anomeric equilibrium in CDCl3 solution
Entry
Substrate
Product
a
:b Ratioa
D,D )
Ga (kcal molꢀ1
1
80:20
80:20
54:46
54:46
73:27
73:27
55:45
55:45
ꢀ0.82
ꢀ0.82
ꢀ0.10
ꢀ0.10
ꢀ0.59
ꢀ0.59
ꢀ0.12
ꢀ0.13
2
3
4
5
6
7
8
a
At 298 K.
Figure 3. Staggered conformations of the C5–C6 bond in the hexopyranosides.
Figure 5. Rotomeric populations (%) of the C5–C6 bond in tetra-O-acetyl gluco-
3
pyranosides in CDCl3 as determined by measurement of JH5,H6 coupling
constants.51,52
anomeric center.10 By extrapolation it can be argued that the pres-
ence of a 4,6-O-acetal reduces the anomeric effect by lowering the
availability of the electron density in the lone pairs of the ring oxy-
gen and, thus, its availability to participate in the endo-anomeric
effect. By the same token the imposition of the electron withdraw-
ing tg conformation through the installation of a 4,6-O-benzylidene
acetal should be expected to augment the exo-anomeric effect by
lowering the energy of the O5–C1 r⁄-orbital. As the endo-anomeric
effect only operates for the axial glycoside whereas the exo-ano-
meric effect exists for both anomers the benzylidene acetal might
reasonably be expected to increase the population of the equatorial
glycoside in line with the observations reported in Table 1, and
consistent with the greater population of the tg conformer in
Figure 4. Rotomeric populations (%) of the C5–C6 bond in tetra-O-acetyl manno-
3
pyranosides in CDCl3 as determined by measurement of JH5,H6 coupling
constants.51,52
in part a consequence of the locking of C5–C6 bond in the tg con-
formation in which the C5–O5 and C6–O6 bonds are antiperipla-
nar. Such a conformation maximizes the electron-withdrawing
effect of O6 and destabilizes any incipient positive charge at the

I. Sharma et al. / Carbohydrate Research 357 (2012) 126–131
129
b-manno and glucopyranosides with respect to the corresponding
-anomers (Figs. 3 and 4). In apparent conflict with this line of rea-
a
soning is the observation (Fig. 1a)38 that increasing the degree of
methylation of mannopyranose increases the anomeric effect as
methyl ethers are considered54 to be more electron-withdrawing
than alcohols. Similarly, Lemieux’s observation (Fig. 1b) that in a
conformationally mobile system increasing the electron withdraw-
ing capability of the O6 protecting group leads to an increase in the
anomeric effect,39 conflicts with the suggestion that the benzyli-
dene acetal exerts its influence on the anomeric effect by maximiz-
ing the electron-withdrawing effect of the C6–O6 bond.
Steric effects transmitted through buttressing interactions
provide an alternative explanation for the observed phenomena.
A 4,6-O-benzylidene acetal has five degrees of freedom less than
the corresponding 4,6-di-O-benzyl ether (Fig. 6) and is therefore
considerably less bulky.
The greater steric bulk of a 4,6-di-O-benzyl ether with respect
to a benzylidene acetal will affect the anomeric equilibrium in
two ways. First, there will be a direct steric interaction between
the benzyloxy group at the 6-position and the aglycone, owing to
the population of the gg and especially the gt conformers (Fig. 7).
This direct interaction will be greater for the b-anomer than for
Figure 7. Direct steric interactions of a 6-O-benzyl ether with the aglycone in the
preferred exo-anomeric effect conformation.
that steric interactions between the 2- and 3-O-substituents are
negligible in this series.
We conclude that the reduction of steric interactions between
the aglcyone on the one hand and O2 and O6 substituents are ade-
quate to rationalize the change in the anomeric ratio on replace-
ment of a 4,6-di-O-benzyl ether by a 4,6-O-benzylidene acetal. By
the same token the greater steric interactions between the C6-sub-
stituent and the aglycone in the b- as opposed to the a-glycosides
the a-one and so will favor the a-anomer.
are sufficient to explain the increased population of the tg-con-
former in the b-glycosides. Steric arguments also appear sufficient
to rationalize the same change in the anomeric ratio observed on
the replacement of a 3-O-benzyl ether by a 3-O-benzoate ester in
the presence of benzyl ethers at the 2-, 4-, and 6-O-positions of
mannopyranose.
Second, the bulk of the benzyloxy group at the 4-position will
restrict the conformational space available to the 3-O-benzyl ether,
which in turn will impinge on the conformation of the 2-O-benzyl
ether, ultimately destabilizing the b-anomer with respect to the a-
one in the mannose series. Indeed, we have remarked previously55
on the importance of such steric buttressing interactions in
mannopyranosylation and have demonstrated how they may be af-
fected by manipulating the steric bulk of the protecting groups at
O2 and O3.56,57 Taking all things into consideration, we believe that
steric arguments of this kind appear best suited to rationalize the
effect of the 4,6-O-benzylidene acetal on the anomeric effect re-
ported in Table 1 as well as the literature observations on the in-
creased population of the tg-conformer in b-manno- and
3. Experimental
3.1. Phenyl 3-O-benzoyl-2,4,6-tri-O-benzyl-1-deoxy-a-D-
thiomannopyranoside (6)
To a stirred solution of phenyl 2,4,6-tri-O-benzyl-1-deoxy-1-
thio-
-mannopyranoside 546 (300 mg, 0.55 mmol) at room tem-
glucopyranosides with respect to the corresponding a-anomers.
a-D
Comparison of Table 1 (entries 1 and 2) with Table 1 (entries 5
and 6) reveals that in 2,3,4,6-tetra-O-benzylmannopyranose the
exchange of the 3-O-benzyl ether for a benzoate ester results in a
small reduction in the anomeric effect. On the other hand no such
effect is observed in the 4,6-O-benzylidene acetal protected series
as is clear from the comparison of Table 1 (entries 3 and 4) with
Table 1 (entries 7 and 8). With their well-defined conformations
and planar topologies58,59 carboxylate esters are typically consid-
ered to be less bulky than the corresponding ethers, which ac-
counts for the well-known ability of peresterified b-
pentopyranosyl glycosides, esters, and halides to adopt inverted
chair and twist conformations when compared to their peretheri-
fied analogs.37,60,61 Thus, the 3-O-benzoate ester in the hemiacetal
10 has less of a buttressing interaction with the flanking benzyl
ethers than the 3-O-benzyl ether in 8 and thereby opens up more
conformational space for the 2- and 6-O-benzyl ethers and relieves
steric interactions of these later with the b-hemiacetal, thereby
reducing the anomeric effect. In the benzylidene acetal series
changing a 3-O-benzyl ether 9 for a 3-O-benzoate ester 11 has no
measurable influence on the anomeric effect, which simply implies
perature in dry pyridine (5 mL) was added benzoyl chloride
(315 mg, 2.25 mmol) followed by DMAP (67 mg, 0.55 mmol). After
3 h, pyridine was removed under reduced pressure and the residue
was diluted with ethyl acetate. The organic layer was washed with
5% aqueous sodium carbonate, water and brine, dried over sodium
sulfate and concentrated under reduced pressure. Chromato-
graphic purification on silica gel (eluent 10–20% ethyl acetate/hex-
ane) afforded the title product (325 mg, 91%); ½a D23
ꢁ
+33 (c 1, CHCl3);
1H NMR (CDCl3, 500 MHz) d 8.09 (d, J = 7.5 Hz, 2H), 7.63–7.13 (m,
23H), 5.70 (d, J = 1.5 Hz, 1H), 5.53 (dd, J = 3.5, 9.5 Hz, 1H), 4.78–
4.72 (m, 3H), 4.61–4.53 (m, 3H), 4.47–4.44 (m, 1H), 4.35 (t,
J = 9.5 Hz, 1H), 4.31–4.29 (m, 1H), 3.94 (dd, J = 4.5, 11.0 Hz, 1H),
3.80 (dd, J = 1.5, 11.0 Hz, 1H), 13C NMR (CDCl3, 125.6 MHz) d
166.0, 138.5, 138.1, 134.6, 133.5, 132.0, 130.2, 130.1, 129.3,
128.7, 128.6, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 85.9, 75.2,
74.8, 73.9, 73.7, 72.8, 72.6, 69.2; ESI-HRMS Calcd for C40H38O6SNa
[M+Na]+, 669.2287; Found, 669.2292.
3.2. 1-O-Acetyl-3-O-benzoyl-2,4,6-tri-O-benzyl-
mannopyranose (3 ) and 1-O-acetyl-3-O-benzoyl-2,4,6-tri-O-
benzyl-b- -mannopyranose (3b)
a-D-
a
D
To a stirred solution of 6 (370 mg, 0.57 mmol) in 9:1 acetone/
water (10 mL) was added at room temperature N-bromosuccini-
mide (306 mg, 1.72 mmol). After 45 min, the acetone was removed
under reduced pressure and the residue was diluted with ethyl
acetate, washed with saturated aqueous sodium bicarbonate,
water and brine, dried over sodium sulfate, and concentrated un-
Figure 6. Degrees of freedom of a dibenzyl ether not available to a benzylidene
acetal.

130
I. Sharma et al. / Carbohydrate Research 357 (2012) 126–131
der reduced pressure. The residue was taken up in pyridine (2 mL),
treated with acetic anhydride (0.7 mL) and stirred at room temper-
ature for 3 h. The solvents were removed under reduced pressure
and the crude product was subjected to chromatographic purifica-
tion on silica gel (eluent 20–30% ethyl acetate/hexane) to provide
with water and brine, dried over sodium sulfate, and concentrated
under reduced pressure to give the crude hemiacetals which were
employed as such in the equilibration experiments.
3.5. Equilibration of hemiacetals in CDCl3
the title products (300 mg, 88%, 4:1
a
/b). 3
a
: ½a 2D3
ꢀ37 (c 1, CHCl3);
ꢁ
1H NMR (CDCl3, 500 MHz) d 8.06 (dd, J = 1.0, 7.5 Hz, 2H), 7.50–7.08
(m, 18H), 6.30 (d, J = 2.0 Hz, 1H), 5.51 (dd, J = 3.0, 10.0 Hz, 1H),
4.76–4.71 (m, 3H), 4.62–4.56 (m, 3H), 4.35 (t, J = 10.0 Hz, 1H),
4.02–4.00 (m, 2H), 3.87 (dd, J = 4.0, 11.5 Hz, 1H), 3.76 (dd, J = 1.5,
11.5 Hz, 1H), 2.14 (s, 3H); 13C NMR (125.6 MHz, CDCl3) d 169.4,
166.0, 138.4, 137.9, 137.6, 133.5, 130.0, 128.6, 128.5, 128.2,
128.1, 127.9, 91.8, 75.3, 74.8, 74.4, 74.1, 73.9, 73.1, 73.0, 68.8,
21.4; ESI-HRMS Calcd for C36H36O8Na [M+Na]+, 619.2308; Found,
The
the general procedure and the resulting crude hemiacetals were
dissolved in CDCl3 (700
L) and examined by 1H NMR spectroscopy
a- and b-acetates were cleaved selectively as described in
l
at 500 MHz. The spectra were monitored at intervals of 1 h for the
first 6 h and then every 4 h. After 24 h in CDCl3, the both anomers
of a given starting material (a- and b-acetates) gave essentially the
same result as reported in Table 1. Subsequent chromatographic
purification on silica gel (eluent 30–40% ethyl acetate/hexane)
afforded the pure products, which were again analyzed by
619.2314. Compound 3b: ½a D23
ꢁ
ꢀ44 (c 1, CHCl3); 1H NMR (CDCl3,
500 MHz) d 8.03 (d, J = 7.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.41–
7.04 (m, 17H), 5.82 (s, 1H), 5.24 (dd, J = 3.0, 9.5 Hz, 1H), 4.82 (d,
J = 12.5 Hz, 1H), 4.73–4.67 (m, 3H), 4.54 (d, J = 11.5 Hz, 2H), 4.27
(t, J = 10.0 Hz, 1H), 4.16 (d, J = 2.5 Hz, 1H), 3.84–3.81 (m, 2H),
3.70 (d, J = 12.5 Hz, 1H), 2.13 (s, 3H); 13C NMR (CDCl3,
125.6 MHz) d 169.1, 165.9, 138.2, 138.1, 133.6, 130.1, 128.7,
128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 92.9,
76.5, 76.2, 75.2, 75.0, 73.8, 73.0, 68.8, 21.3; ESI-HRMS Calcd for
500 MHz 1H NMR spectroscopy in CDCl3 (700
l
L).
3.6. 2,3,4,6-Tetra-O-benzyl-
a
,b-D
-mannopyranose (8a,b)
Isolated following the general hydrolysis procedure and equili-
bration (1.0/0.24
/b). 1H NMR (CDCl3, 500 MHz) d 7.39–7.29 (m,
a
22.40H), 7.21–7.19 (m, 2.50H), 5.28 (s, 1H), 5.10 (d, J = 12.0 Hz,
0.24H), 4.93–4.88 (m, 1.25H), 4.79–4.73 (m, 2.79H), 4.67 (d,
J = 12.5 Hz, 0.50H), 4.64 (s, 2H) 4.62 (s, 0.24H), 4.59–4.54 (m,
2.24H), 4.52 (s, 0.51H), 4.08 (t, J = 7.5 Hz, 1H), 3.99 (dd, J = 3.0,
10.0 Hz, 1H), 3.96 (t, J = 10.0 Hz, 0.24H), 3.92 (d, J = 10.0 Hz,
0.24H), 3.90 (s, 3H), 3.86 (s, 1H), 3.85–3.84 (m, 0.49H), 3.82 (t,
J = 2.5 Hz, 1H), 3.76 (d, J = 4.5 Hz, 1H), 3.74 (s, 1H), 3.70 (d,
J = 7.0 Hz, 1H), 3.68 (d, J = 7.0 Hz, 0.24H), 3.65 (d, J = 3.5 Hz, 1H),
3.62 (d, J = 3.0 Hz, 0.24H), 3.60 (d, J = 3.0 Hz, 0.24H), 3.50–3.47
(m, 0.24H); 13C NMR (CDCl3, 125.6 MHz) d 138.7, 138.6, 138.4,
138.3, 138.2, 128.8, 128.8, 128.6, 128.3, 128.2, 128.1, 128.0,
127.9, 94.0, 93.0, 83.3, 80.0, 77.5, 76.2, 75.5, 75.4, 75.3, 75.0, 74.9,
73.8, 73.5, 73.0, 72.9, 72.4, 71.7, 69.9, 69.3; ESI-HRMS Calcd for
C
36H36O8Na [M+Na]+, 619.2308; Found, 619.2305.
3.3. 1-O-Acetyl-3-O-benzoyl-2-O-benzyl-4,6-O-benzylidene-
mannopyranose (4 ) and 1-O-acetyl-3-O-benzoyl-2-O-benzyl-
4,6-O-benzylidene-b- -mannopyranose (4b)
a-D-
a
D
To a stirred solution of 7 (400 mg, 0.72 mmol) in 9:1 acetone/
water (10 mL) was added at room temperature pyridine (1 mL) fol-
lowed by N-bromosuccinimide (386 mg, 2.16 mmol). After 45 min,
the solvents were removed under reduced pressure and the residue
was diluted with ethyl acetate, washed with saturated aqueous so-
dium bicarbonate, water and brine, dried over sodium sulfate, and
concentrated under reduced pressure. The residue was taken up in
pyridine (4 mL) and treated with acetic anhydride (1 mL) and stir-
red at room temperature for 3 h. The solvents were removed under
reduced pressure and the residue was subjected to chromato-
graphic purification on silica gel (eluent 20–30% ethyl acetate/hex-
C
34H36O6Na [M+Na]+, 563.2410; Found, 563.2414.
3.7. 2,3-Di-O-benzyl-4,6-O-benzylidene-
(9 ,b)
a,b-D-mannopyranose
a
Isolated following the general hydrolysis procedure and equili-
bration (1.0/0.85
/b). 1H NMR (CDCl3, 500 MHz) d 7.55–7.52 (m,
ane) to give the title products (298 mg, 82%, 3:1
a
/b). 4
a
: ½a 2D3
ꢁ
ꢀ30
a
(c 1, CHCl3); 1H NMR (CDCl3, 500 MHz) d 8.08 (d, J = 7.5 Hz, 2H),
7.49–7.20 (m, 13H), 6.24 (d, J = 1.5 Hz, 1H), 5.66 (s, 1H), 5.58 (d,
J = 7.0 Hz, 1H), 4.74 (d, J = 12.0 Hz, 1H), 4.63 (d, J = 12.0 Hz, 1H),
4.44 (d, J = 10.0 Hz, 1H), 4.35 (dd, J = 5.0, 10.0, 1H), 4.10–4.05 (m,
2H), 3.91 (t, J = 10.0 Hz, 1H), 2.20 (s, 3H); 13C NMR (CDCl3,
125.6 MHz) d 169.2, 166.1, 137.4, 137.2, 133.6, 130.2, 129.3,
128.7, 128.6, 128.5, 128.3, 128.2, 126.4, 102.0, 92.1, 76.0, 73.8,
70.8, 68.8, 66.6, 21.3; ESI-HRMS Calcd for C29H28O8Na [M+Na]+,
3.70H), 7.44–7.29 (m, 24H), 5.67 (s, 1H), 5.65 (s, 0.85H), 5.20–
5.18 (m, 1.85H), 4.98 (d, J = 12.5 Hz, 0.82H), 4.85 (dd, J = 7.0,
12.5 Hz, 2H), 4.80–4.68 (m, 4.85H), 4.36–4.33 (m, 0.85H), 4.30–
4.24 (m, 2H), 4.18 (t, J = 10.0 Hz, 0.86H), 4.07–4.02 (m, 2H), 3.92–
3.91 (m, 1H), 3.88–3.86 (m, 3H), 3.83 (s, 0.84H), 3.78 (dd, J = 3.0,
10.0 Hz, 1H); 13C NMR (CDCl3, 125.6 MHz) d 138.9, 138.5, 138.3,
137.9, 137.7, 129.2, 129.1, 129.0, 128.8, 128.7, 128.6, 128.5,
128.4, 128.0, 127.9, 127.8, 126.3, 101.7, 101.6, 94.5, 94.3, 79.5,
79.2, 79.0, 78.1, 76.6, 76.2, 75.9, 73.9, 73.8, 73.4, 69.1, 68.8, 67.1,
64.5; ESI-HRMS Calcd for C27H28O6Na [M+Na]+, 471.1784; Found,
471.1781.
527.1682; Found, 527.1686. Compound 4b: ½a D23
ꢀ51 (c 1, CHCl3);
ꢁ
1H NMR (CDCl3, 500 MHz,) d 8.07 (dd, J = 1.5, 8.0 Hz, 2H), 7.48–
7.19 (m, 13H), 5.90 (s, 1H), 5.63 (s, 1H), 5.32 (d, J = 10.5 Hz, 1H),
4.81 (d, J = 12.0 Hz, 1H), 4.72 (d, J = 12.0 Hz, 1H), 4.39–4.36 (m,
2H), 4.28 (d, J = 3.0 Hz, 1H), 3.95 (t, J = 10.0 Hz, 1H), 3.71–3.67
(m, 1H), 2.13 (s, 3H); 13C NMR (CDCl3, 125.6 MHz) d 169.0, 166.1,
137.6, 137.2, 133.6, 130.2, 129.3, 128.7, 128.6, 128.5, 128.2,
126.4, 102.0, 93.1, 75.8, 75.7, 75.6, 73.0, 68.6, 68.4, 21.1; ESI-HRMS
Calcd for C29H28O8Na [M+Na]+, 527.1682; Found, 527.1677.
3.8. 3-O-Benzoyl-2,4,6-tri-O-benzyl-a,b-D-mannopyranose
(10 ,b)
a
Isolated following the general hydrolysis procedure and equili-
bration (1.0/0.35
/b). 1H NMR (CDCl3, 500 MHz) d 8.09–8.05 (m,
a
2.74H), 7.62–7.59 (m, 1.35H), 7.49–7.46 (m, 2.89H), 7.40–7.27
(m, 11.5H), 7.20–7.18 (m, 7.2H), 7.09–7.07 (m, 2H), 7.09–7.07 (m,
2H), 7.06–7.04 (m, 0.7H), 5.63 (dd, J = 3.0, 7.0 Hz, 1H), 5.34 (s,
1H), 5.30 (dd, J = 3.0, 10.0 Hz, 0.35H), 4.89–4.85 (m, 0.66H), 4.74–
4.51 (m, 8.16H), 4.23–4.18 (m, 1.35H), 4.14 (t, J = 9.5 Hz, 1H),
4.07 (t, J = 3.0 Hz, 0.35H), 4.02 (dd, J = 2.5, 3.0 Hz, 1H), 3.84–3.72
(m, 3.20H), 3.60–3.57 (m, 0.24H), 3.55 (d, J = 8.5 Hz, 1H); 13C
NMR (CDCl3, 125.6 MHz) d 166.0, 165.9, 138.3, 138.2, 138.1,
3.4. General procedure for the hydrolysis of anomeric acetates
To a stirred solution of anomeric acetate (0.1 mmol) in metha-
nol (1 mL) was added KOtBu (11 mg, 0.1 mmol) at ꢀ30 °C. The
reaction mixture was warmed up to 0 °C over 1 h and then
quenched with saturated aqueous ammonium chloride (3 mL)
and extracted with ethyl acetate. The organic layer was washed

I. Sharma et al. / Carbohydrate Research 357 (2012) 126–131
131
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1553–1565.
138.0, 137.8, 133.7, 133.4, 130.3, 130.0, 129.7, 128.9, 128.8, 128.7,
128.6, 128.5, 128.4, 128.3, 128.2, 128.0, 127.9, 93.9, 92.9, 77.5,
77.3, 76.5, 75.7, 75.4, 75.2, 74.4, 74.0, 73.8, 73.3, 73.1, 71.5, 69.5,
69.0; ESI-HRMS Calcd for C34H34O7Na [M+Na]+, 577.2202; Found,
577.2208.
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3.9. 3-O-Benzoyl-2-O-benzyl-4,6-O-benzylidene-
a,b-D-
mannopyranose (11 ,b)
a
Isolated following the general hydrolysis procedure and equili-
bration (1.0/0.81
/b). 1H NMR (CDCl3, 500 MHz) d 8.13–8.08 (m,
a
3.61H), 7.61–7.58 (m, 1.84H), 7.49–7.22 (m, 22H), 5.67–5.63 (m,
2.83H), 5.43 (dd, J = 3.0, 10.0 Hz, 0.81H), 5.30–5.29 (m, 1H), 4.97–
4.93 (m, 1.61H), 4.69–4.63 (m, 2.05H), 4.57 (d, J = 12.0 Hz,
0.79H), 4.38–4.36 (m, 1.85H), 4.31–4.21 (m, 3.72H), 4.16–4.15
(m, 1H), 3.94–3.88 (m, 1.86H), 3.71 (dd, J = 4.5, 12.5 Hz, 0.82H),
3.59–3.55 (m, 0.76H), 2.90–2.84 (m, 1H); 13C NMR (CDCl3,
125.6 MHz) d 166.2, 166.1, 137.7, 137.5, 137.3, 133.8, 130.2,
130.1, 129.6, 129.3, 129.2, 129.0, 128.8, 128.7, 128.6, 128.5,
128.2, 126.4, 126.3, 102.0, 101.9, 94.2, 94.1, 77.8, 77.5, 76.7, 76.4,
75.9, 74.1, 73.8, 71.1, 69.1, 68.8, 67.3, 64.4; ESI-HRMS Calcd for
C
27H26O7Na [M+Na]+, 485.1576; Found, 485.1573.
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Acknowledgment
We thank the NIH (GM 62160) for partial support of this work.
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Supplementary data
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Supplementary data (1H and 13C NMR spectra for compounds
3a,b; 4a,b; 6; 8a,b; 9a,b; 10a,b; 11a,b) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.carres.2012.05.025.
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