Influence of the oxime and anomeric configurations on the stability of 2-deoxy-2-hydroxyimino-D-hexopyranosides

Article abstract of DOI:10.1016/j.molstruc.2016.07.019

The Z/E isomerisations of the synthesized benzyl 3,4,6-tri-O-acetyl-2-deoxy-2-hydroxyimino-D-hexopyranosides during the NMR measurement and during the Zemplén O-deacetylation were observed. In order to study stabilities and tendency of the obtained compounds to isomerise, B3LYP/6-311++G^?? level geometry optimisations for four stereoisomers of methyl 2-deoxy-2-hydroxyimino-D-arabino-hexopyranosides in both the O-acetylated and O-deacetylated forms were performed. The results of our theoretical studies are fully in agreement with the experimental data and NMR analysis. Additionally, a single-crystal X-ray diffraction data for benzyl 2-deoxy-2-hydroxyimino-α-D-lyxo-hexopyranoside are reported to supplement our theoretical studies.

Full text of DOI:10.1016/j.molstruc.2016.07.019

Journal of Molecular Structure 1125 (2016) 558e569
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Influence of the oxime and anomeric configurations on the stability of
2-deoxy-2-hydroxyimino-D-hexopyranosides
a
a
a
b
ꢀ
ꢀ
Magdalena Cyman , Justyna Wielinska , Henryk Myszka , Damian Trzybinski ,
Artur Sikorski a, Andrzej Nowacki a, Beata Liberek a
Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland
,
*
a
ꢀ
ꢀ
b
_
Biological and Chemical Research Centre, University of Warsaw, Zwirki i Wigury 101, 02-089 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The Z/E isomerisations of the synthesized benzyl 3,4,6-tri-O-acetyl-2-deoxy-2-hydroxyimino-D-hex-
Received 27 April 2016
Received in revised form
5 July 2016
Accepted 8 July 2016
Available online 9 July 2016
ꢀ
opyranosides during the NMR measurement and during the Zemplen O-deacetylation were observed. In
order to study stabilities and tendency of the obtained compounds to isomerise, B3LYP/6-311þþG** level
geometry optimisations for four stereoisomers of methyl 2-deoxy-2-hydroxyimino-D-arabino-hexopyr-
anosides in both the O-acetylated and O-deacetylated forms were performed. The results of our theo-
retical studies are fully in agreement with the experimental data and NMR analysis. Additionally, a
single-crystal X-ray diffraction data for benzyl 2-deoxy-2-hydroxyimino-
reported to supplement our theoretical studies.
a-D-lyxo-hexopyranoside are
Keywords:
Oximes of hex-2-ulopyranosides
Oxime isomerization
Conformation
© 2016 Elsevier B.V. All rights reserved.
Exo-anomeric effect
DFT calculations
Single-crystal
1. Introduction
oxo group is easily reduced to the 2-hydroxyl group (pathway D)
with a high preference for the respective
hex-2-ulopyranosides with -arabino configuration are reduced by
borohydride reagents [3]. In turn, the 3,4-elimination of acetic or
benzoic acid from 2-uloses, such as O-protected 1,5-anhydro-
fructoses, provides the pyranoid enolone esters (pathway E). A
variety of synthetically useful additions are carried out with these
esters with high selectivity [19].
Different methodologies have been applied to synthesise 2-
deoxy-2-hydroxyimino glycosides. Lemieux introduced a very
useful reaction of acetyl-protected 2-deoxy-2-nitroso-a-D-glyco-
b-D-mannosides when b-
2-Deoxy-2-hydroxyiminohexopyranosides, also called oximes
of hex-2-ulopyranosides, are useful intermediates in sugar syn-
thesis, which have been applied for a long time [1e3]. Their use-
fulness stems from the fact that these compounds are easily
transformed into different sugar derivatives. Thus, nucleophilic
substitution of the allylic 3-OAc group in acetylated 2-deoxy-2-
hydroxyimino glycosides with azide or hydride ions affords 3-
azido-3-deoxy or 3-deoxy derivatives, respectively (pathway A,
Scheme 1) [4,5]. In turn, reduction of the 2-hydroxyimino group is
the straightforward way for the preparation of 2-amino-2-deoxy
sugars (pathway B) [6]. The latter transformation was successfully
applied to the synthesis of 2-NAc oligosaccharides [7,8] as well as
aminoglycoside antibiotics [9e11]. Most importantly, reduction of
the oxime is strongly stereospecific and provides mainly 1,2-cis 2-
amino-2-deoxy glycosides [12e16].
D
D
-
pyranosyl chlorides with the respective glycosyl acceptor to obtain
2-deoxy-2-hydroxyimino glycosides [1]. In turn, Lichtenthaler
proposed the reaction of benzoil-protected 2-deoxy-2-
hydroxyimino-a-glycopyranosyl bromides with the respective
glycosyl acceptor [2]. The same goal was achieved in the reaction of
respective ulosyl bromide with a glycosyl acceptor followed by
oximation of the ketone group [20]. Hex-2-ulopyranoside oximes
were also obtained from the previously prepared ulosides [21] and
Hydroxyimino function is also used to obtain 2-uloses by
deoximination with acetaldehyde/HCl (pathway C) [5,17,18]. The 2-
in the reaction of methyl 3,4,6-tri-O-acetyl-2-bromo-2-deoxy-b-D-
glucopyranoside with sodium cobaloxime followed by photolysis in
the presence of nitrous oxide [12].
* Corresponding author.
E-mail address: beata.liberek@ug.edu.pl (B. Liberek).
2-Deoxy-2-hydroxyimino glycosides are found in four
http://dx.doi.org/10.1016/j.molstruc.2016.07.019
0022-2860/© 2016 Elsevier B.V. All rights reserved.

M. Cyman et al. / Journal of Molecular Structure 1125 (2016) 558e569
559
Scheme 1. Possible transformations of 3,4,6,tri-O-acetyl-2-deoxy-2-hydroxyimino sugars.
stereoisomeric forms. These are
a
or
b
glycosides with Z or E con-
anomeric carbon and oxime configurations can be crucial for
pharmacological properties and reactivity of the synthesized
compounds [24]. Therefore, it seems to be reasoned to well un-
derstand tendency of 2-uloside oximes to isomerise. Importantly,
our theoretical studies are verified with the presented experi-
mental data. It is worthy to notice that the E/Z oxime isomerization
in 2-(hydroxyimino)-2-phenylacetonitrile have been recently
investigated by spectroscopic and theoretical methods [25].
Calculations were performed using DFT methods at the B3LYP/
figurations of the oxime (Fig.1). The ratio of stereoisomers obtained
depends on the method used as well as on the stability of a
particular stereoisomer.
In a search of new effective inhibitors of GlcN-6P synthase, the
enzyme proposed as a target for antifungal chemotherapy [22], we
paid attention to 2-deoxy-2-hydoxyimino sugars. The 2-
hydroxyimino group mimics the 2-imino group present in the
putative reaction intermediate proposed for the reaction catalysed
by GlcN-6P synthase [23]. This prompts the assumption that the 2-
deoxy-2-hydroxyimino alditols may act as GlcN-6P synthase in-
hibitors and consequently as antifungal agents. In order to obtain
such the compounds we first synthesized benzyl 3,4,6-tri-O-acetyl-
6-311þþG** level for methyl 2-deoxy-2-hydroxyimino-
D-arabino-
hexopyranosides in both the O-acetylated and O-deacetylated
forms. To simplify calculations, the methyl glycoside was used
instead of the benzyl glycoside. We assume that this does not
change a general tendency concerning the stability of 2-deoxy-2-
2-deoxy-2-hydroxyimino-D-hexopyranosides with D-arabino and D-
lyxo configurations, which were next O-deacetylated. Undesirable
changes of the 2-hydroxyimino group configuration during the
experiments prompted us to study the influence of the anomeric
carbon and oxime configurations on the stability of 2-deoxy-2-
hydroxyimino glycosides. Oximes are known to undergo revers-
ible E/Z isomerization due to the relatively low transition states
connecting both isomers. However, some of the oxime isomers are
isolable species with good stability. On the other hand, both the
hydroxyimino-
D-hexopyranosides. Additionally, a single-crystal X-
ray diffraction analysis for benzyl 2-deoxy-2-hydroxyimino-
lyxo-hexopyranoside is reported. This improves the geometry
studies presented on 2-deoxy-2-hydroxyimino glycosides.
a-D-
2. Results and discussion
2.1. Synthesis and NMR investigations
Starting from 3,4,6-tri-O-acetyl-2-deoxy-2-nitrosohexopyranosyl
chlorides with
synthesized benzyl 3,4,6-tri-O-acetyl-2-deoxy-2-hydroxyimino-
hexopyranosides with -arabino (3e5) and -lyxo (6e8) configura-
a-D-gluco (1) and a-D-galacto (2) configurations, we
D-
D
D
tions (Scheme 2). Both of the glycosylations provide a mixture of
products, which were separated. Thus, the reaction of 1 with benzyl
alcohol yields glycosides with b-E (3, 9%), a-Z (4, 46%), and b-Z (5, 8%)
configurations of the anomeric carbon and oxime. Compound 5
isomerises to 3 during the NMR measurement in CDCl3 to generate a
mixture of 5 and 3 in a ratio of 1:2, estimated from the NMR spec-
trum. In turn, the reaction of 2 with benzyl alcohol yields a mixture of
glycosides with b-E (6) and b-Z (7) configurations (11%) in a ratio of
1:2 estimated from the NMR spectrum, and glycoside with the a-Z
configuration (8, 43%).
Geometries of the synthesized glycosides were established on
the basis of NMR spectra. Thus, the H1 signals of 4 and 8 ( 6.09 and
Fig. 1. Stereoisomeric forms of 2-deoxy-2-hydroxyimino glycosides.
d

560
M. Cyman et al. / Journal of Molecular Structure 1125 (2016) 558e569
Scheme 2. Synthesis of benzyl 3,4,6-tri-O-acetyl-2-deoxy-2-hydroxyimino-D-hexopyranosides and their O-deacetylation.
6.17, respectively) appear at higher
analogous protons of 3, 5, 6 and 7 (
d
d
values than those of the
5.23, 5.89, 5.19 and 5.79,
glycoside (11) with J3,4 9.25 Hz and J4,5 9.6 Hz, as well the a-Z-D-lyxo
glycoside (12) with J3,4 3.2 Hz adopts the 4C1 conformation. Again, a
lack of coupling between the H4 and H5 protons is additional proof
of the 4C1 conformation of 12 [26]. Examination of the J3,4 8.4 Hz
respectively). This is the result of equatorial orientations of the H1
proton corresponding to the configuration in 4 and 8. Addition-
ally, the hydroxyl pointed toward the H1 proton (the Z configura-
tion) causes its deshielding [5]. In turn, the H3 signals of 3 ( 6.12),
and 6 ( 6.32) indicate the E geometry of the oxime, since the hy-
droxyl pointed toward the H3 proton causes its distinct deshield-
ing. The H3 proton signals of 4 ( 5.82), 5 ( 5.54), 7 ( 5.73) and 8 (
5.90) are due to the Z orientation of the 2-hydroxyimino group.
Analysis of the coupling constants reveals that the -Z- -arabino
-Z- -lyxo
a
and J4,5 9.4 Hz coupling constants of the b-E-D-arabino glycoside 9 is
discussed below with the presented calculations (point 2.3).
d
d
2.2. DFT studies on methyl 3,4,6-tri-O-acetyl-2-deoxy-2-
hydroxyimino-D-arabino-hexopyranosides
d
d
d
d
a
D
To reduce a number of generated structures, we anticipated that
the methyl group of an aglycone would be oriented antiperiplanarly
to the C2 carbon atom of the pyranose ring, in both the axial and the
equatorial orientations of the methoxy group, as a result of the exo-
anomeric and steric effects. This is in agreement with our previ-
ously reported findings [29]. In the starting geometries, hydrogen
from the ¼NeOH group was oriented anti (a) or syn (s) with
reference to the C2 carbon atom.
glycoside (4) with J3,4 9.65 Hz and J4,5 9.8 Hz as well the
a
D
glycoside (8) with J3,4 3.4 Hz adopt the 4C1 conformation. A lack of
coupling between the H4 and H5 protons is additional proof of the
4C1 conformation of 8 [26]. Examination of the analogous coupling
constants of
arabino glycoside 5 (J3,4 5.5 Hz, J4,5 5.5 Hz),
(J3,4 3.9 Hz, J4.5 4.65 Hz) and -Z- -lyxo glycoside 7 (J3,4 3.35 Hz, J4.5
5.8 Hz) calls for the conformations other than 4C1. The chair form is
probably strongly destabilised in the case of glycosides owing to
b
-E-D
-arabino glycoside 3 (J3,4 7.4 Hz, J4,5 8.8 Hz),
b-Z-D-
b
-E- -lyxo glycoside 6
D
b
D
The two conformations were taken into account, i.e. anti-
periplanar (a) and synclinal (s), with reference to the AcO3-C3 and
AcO4-C4 bond rotations. Of the two possible synclinal conforma-
tions, the one with the carbonyl carbon gauche oriented to both
sugar ring carbon atoms (þsc, Fig. 2a and -sc, Fig. 2b) was excluded.
As previously reported, the OAc group avoids such orientation [30].
With reference to the C6eC5 bond rotations, three staggered con-
formations were considered, assigned in a common way as gg, gt
and tg (Fig. 2c). Three staggered conformations were also consid-
ered regarding the AcO6-C6 bond rotations. These were assigned
“a” for the ap orientation, “s” for the þsc orientation and “s’” for the
-sc orientation (Fig. 2d). In turn, one orientation was considered
with reference to the COeO bond rotation in acetyl groups, because,
due to the mesomeric effect, the acetoxy group is planar, starting
from the respective pyranose carbon atom. Being planar, the ace-
toxy group strongly prefers the orientation in which the carbonyl
oxygen is eclipsed by the respective sugar carbon atom [30].
Thus, by taking into account two orientations of the NeOH
group ( ꢀ 2) as well as a rotational freedom of the 3-OAc, 4-OAc, 6-
OAc, and 5-CH2OAc groups (2 ꢀ 2 ꢀ 3 ꢀ 3), 72 starting geometries
b
the steric and electronic interactions between the nearly coplanar
aglycone, oxime and 3-OAc group, both in the Z and E geometry.
Such unfavourable interactions usually cause adoption of
a
conformation other than 4C1 [20,27].
ꢀ
Conventional Zemplen O-deacetylation of benzyl 3,4,6-tri-O-
acetyl-2-deoxy-2-hydroxyimino-
bino (3) and -Z-lyxo (8) configurations provided the respective 2-
deoxy-2-hydroxyimino- -hexopyranosides (9 and 12) with an un-
changed oxime configuration. Unexpectedly, analogous O-deace-
tylation of 4 ( -Z-arabino configuration) led to two products. The
first was 2-hydroxyimino glycoside with the -E-arabino configu-
ration (10) and the second was 2-hydroxyimino glycoside with the
D-hexopyranosides with b-E-ara-
a
D
a
a
a
a
-Z-arabino configuration (11). Surprisingly, this is relatively stable
-Z-arabino stereoisomer (4) which affords the E/Z mixture of O-
deacetylated products. Moreover, isolated 10 isomerises to 11
during NMR measurements in CD3OD, again generating a mixture
of 10 and 11 in a ratio of 1:1.14, estimated from the NMR spectrum.
It has to be mentioned that changes of the 2-hydroxyimino group
ꢀ
configuration were also observed during a Zemplen O-deacylation
for
a
-Z,
a
-E,
b
-Z, and
b
-E stereoisomers of methyl 3,4,6-tri-O-acetyl-
-arabino-hexopyranosides, respectively,
of the derivatives of 1,5-anhydrofructoses [28].
2-deoxy-2-hydroxyimino-
D
Analysis of the coupling constants of 2-deoxy-2-hydroxyimino-
were prepared for the calculations. All geometries were prepared in
the 4C1 conformation. To describe the initial and final geometries of
the pyranose ring substituents, the following assignments and
D
-hexopyranosides with the unprotected hydroxyls reveals that the
a
-E- -arabino glycoside (10) with J3,4 9.45 Hz, the -Z- -arabino
D
a
D

M. Cyman et al. / Journal of Molecular Structure 1125 (2016) 558e569
561
shows steric hindrance for the
a
-E stereoisomer in the 4C1 confor-
mation. Additionally, planar orientation of the O3eC3eC2eNeO
sequence of atoms in a case of the -E stereoisomer should cause
a
electronic repulsions between the oxygen atoms. The calculated
distance between the oxime and O3 oxygen atoms is 2.7 Å (on
average). Such unfavourable interactions in the 4C1 conformation of
the a-E stereoisomer cause an increase of energy (about 2.5 kcal/
mol, as calculated). These also causes a certain deformation of the
4C1 conformation. Although the majority of the relatively stable
rotamers of the
of them prefer the 0H5 conformation. In the case of
3,4,6-tri-O-acetyl-2-deoxy-2-hydroxyimino- -hexopyranosides,
a
-E stereoisomer adopt the 4C1 conformation, some
b
anomers of
D
both the Z and E configurations are unfavourable. The Z-configured
oxime constitutes steric and electronic hindrance for an aglycone in
the 4C1 conformation of
b anomers. In turn, the E-configured oxime
constitutes steric and electronic hindrance for the 3-OAc group in
the 4C1 conformation. Our calculations indicate that these unfav-
ourable interactions are stronger in the case of the
mer. In both cases, these strains cause a change in the chair
conformation. None of the E nor Z isomers of anomers adopt the
4C1 conformation. As illustrated in Table 1, the
-E stereoisomer
prefers the 1,4B conformation, whereas the
-Z stereoisomer exists
in 1S3 1,4B # 4S0 conformational equilibrium. Importantly, the
b-Z stereoiso-
b
b
b
#
calculations confirm the experimental findings of our group and
others [20].
The presented results indicate that all of the stable rotamers of
methyl
3,4,6-tri-O-acetyl-2-deoxy-2-hydroxyimino-D-arabino-
hexopyranosides, regardless of their anomeric and oxime configu-
rations, have the hydrogen from the ]NeOH group oriented anti
(a) with reference to the C2 carbon atom. Such an orientation seems
to be sterically less strained. Additionally, such an orientation al-
lows the oxime oxygen to interact with the anomeric proton in a
Fig. 2. Newman projections along the (a) O3eC3, (b) O4eC4, (c) C5eC6 and (d) O6eC6
bonds corresponding to the respective geometries of the studied compounds.
case of the
O3eC3 bond rotation, the
(s) orientation, whereas the
(a) orientation. In the case of
a
-Z and the
b
-Z stereoisomers. With reference to the
-Z stereoisomer solely prefers the þsc
-E stereoisomer solely prefers the ap
-Z and -E stereoisomers, both
orders of rotations were used: NeOH (a or s), O3eC3, O4eC4 (a or
s), C6eC5 (gg, gt or tg), and O6eC6 (a, s, or s’). The optimisation
procedure reduced the number of geometries since many of them
were converted to the same optimised structure. Table 1 lists the
geometry and energy parameters of the most stable optimised
structures as well as the population of each rotamer in a group of
rotamers with the same anomeric and oxime configurations.
a
b
b
a
the þsc (s) and ap (a) orientations are present among the stable
rotamers. It seems that the O4eC4 bond rotation depends on the
O3eC3 bond rotation, and vice versa. This means that if the O3eC3
bond rotation prefers the þsc (s) orientation, the O4eC4 bond
rotation prefers the ap (a) orientation. In turn, if the O3eC3 bond
rotation prefers the ap (a) orientation, the O4eC4 bond rotation
prefers the þsc (s) orientation. The C5eC6 and O6eC6 bond rota-
tions have a relatively small influence on the stability of the
explored stereoisomers. All of the orientations taken into account
with reference to these rotations are present among the stable
rotamers.
The findings presented in Table 1 show that
stable of the four stereoisomers of methyl 3,4,6-tri-O-acetyl-2-
deoxy-2-hydroxyimino- -arabino-hexopyranosides. Its average
a-Z is the most
D
energy, calculated between the relatively stable rotamers 1e4, is
about 2.5 kcal/mol lower than an analogous energy of the relatively
stable rotamers 1e9 of the
energy difference, the -E stereoisomer is not formed in the gly-
cosidation carried out here. The results also indicate that the -Z
and -E stereoisomers are definitely less stable than the -Z ste-
reoisomer (on average 3.7 kcal/mol and 3 kcal/mol, respectively).
Both of these are also less stable than the -E stereoisomer (on
average 1.2 kcal/mol and 0.5 kcal/mol, respectively). The relatively
small energy difference between the -E and the -Z stereoisomers
justifies the observed 5 ( -Z) / 3 ( -E) isomerization, which occurs
a-E stereoisomer. Probably, due to this
a
b
b
a
2.3. DFT studies on methyl 2-deoxy-2-hydroxyimino-
hexopyranosides
D-arabino-
a
To generate starting structures of 2-deoxy-2-hydroxyimino-D-
b
b
arabino-hexopyranosides, we anticipated, analogously to the pre-
vious point, that the methyl group would be oriented in accordance
with the exo-anomeric effect, i.e. antiperiplanarly to the C2 carbon
atom of the pyranose ring, in both the axial and the equatorial
orientations of the methoxy group. In accordance with the rota-
tional freedom of the 3-OH and 4-OH groups, we considered two
orientations, cw and ccw, with the cooperative arrangement of
b
b
during the NMR measurement in CDCl3.
As demonstrated, all of the most stable
a
-Z rotamers (1e4,
population of 99.98%) adopt the 4C1 conformation (Table 1, Fig. 3).
The
the
a
a
-Z stereoisomer is stable enough in the 4C1 conformation since
-configured aglycone does not show steric hindrance for the Z-
-Z ste-
configured oxime. Moreover, the 4C1 conformation of the
a
intramolecular hydrogen bonding-like interactions that is
a
reoisomer allows the oxime oxygen to interact with the equato-
rially oriented anomeric hydrogen. Such advantageous interaction
is possible since the calculated distance between the oxime oxygen
reasonable approximation [31]. Three low-energy positions of the
hydroxymethyl group, in relation to the sugar ring, designated gg, gt
and tg, were taken into account (Fig. 2c). Rotation about the C6eO6
bond was not considered. The spatial disposition of the 6-OH
hydrogen atom is closely connected to the orientation of the
and the equatorially oriented anomeric hydrogen in the
a-Z ste-
reoisomer (1e4) is 2.31 Å. The equatorially oriented 3-OAc group

562
M. Cyman et al. / Journal of Molecular Structure 1125 (2016) 558e569
Table 1
Geometry parameters, energy parameters, and populations of the most stable rotamers of methyl 3,4,6-tri-O-acetyl-2-deoxy-2-hydroxyimino-
D
-arabino-hexopyranosides.
Structure
Final geometrya
Final conformation
D
Eb
G [a.u.]
D
Gc [kcal/mol]
Populationd [%]
[kcal/mol]
a
1
2
3
4
-Z
-E
a/s/a-s/gt/a
a/s/a-s/gg/s’-a
a/s/a/gt/s
4C1
4C1
4C1
4C1
0.51
0.00
0.48
1.22
ꢁ1238.65463
ꢁ1238.65448
ꢁ1238.65434
ꢁ1238.65280
0.00
0.09
0.18
1.15
36.63
31.21
26.88
5.26
a/s/a/tg/s’
SPi 99.98
a
1
2
3
4
5
6
7
8
9
a/s/a-s/gt/a
a/s/a-s/gg/a-s’
a/s/a/gt/s
a/a/s/gt/s
a/a/s/gg/a
a/a/s/gt/a
a/s/a/gt/s
a/s/a/tg/a
a/s/a/tg/s’
4C1
4C1
4C1
0H5
0H5
0H5
4C1
4C1
4C1
2.75
2.29
2.73
3.82
3.15
3.35
2.74
3.74
3.42
ꢁ1238.65056
ꢁ1238.65040
ꢁ1238.65035
ꢁ1238.64986
ꢁ1238.64945
ꢁ1238.64895
ꢁ1238.64878
ꢁ1238.64836
ꢁ1238.64802
0.00
0.10
0.14
0.44
0.70
1.01
1.12
1.38
1.60
25.42
21.34
20.20
12.03
7.82
4.60
3.84
2.45
1.72
SPi 99.42
b
1
2
3
4
5
6
-Z
a/s/a-s/gt/s-a
a/a-s/a-s/gg/a-s’
a/s/a/gt/s
a/s/a-s/tg/a
a/a/s/gg/a
1S3
4.07
4.18
4.06
4.67
4.30
5.78
ꢁ1238.64805
ꢁ1238.64785
ꢁ1238.64783
ꢁ1238.64764
ꢁ1238.64717
ꢁ1238.64516
0.00
0.13
0.14
0.26
0.55
1.82
26.87
21.74
21.10
17.27
10.58
1.25
1,4B
def
4S0
4S0
1,4B
def
a/s/a-s/tg/s’
4S0
SPi 98.81
b
1
2
3
4
5
6
7
8
9
-E
a/a/s/gg/a
a/a/s/gg/a-s’
a/a/a-s/tg/s’
a/a/a/tg/a
a/a-s/a/gt/s
a/a/s/gt/s’
a/a/s/gt/s
1,4B
2.82
2.63
3.42
4.59
4.13
3.41
4.41
4.58
4.83
ꢁ1238.65013
ꢁ1238.6494
ꢁ1238.64825
ꢁ1238.64813
ꢁ1238.64793
ꢁ1238.6478
ꢁ1238.64764
ꢁ1238.64748
ꢁ1238.64693
0.00
0.46
1.18
1.26
1.38
1.46
1.56
1.66
2.01
48.13
22.30
6.59
5.76
4.68
4.07
3.44
2.90
1.63
def
1,4B
def
1,4B
1,4B
1,4B
1,4B
1,4B
def
a/a/a/tg/a
a/a/a/tg/s’
1,4B
1,4B
def
SPi 99.50
a
b
c
The sign “-” indicates that conformation is in-between the left one and the right one.
With reference to the rotamer 2 (
With reference to the most stable rotamer with the same anomeric and oxime configurations.
In rotamers with the same anomeric and oxime configurations.
a
-Z) with energy of ꢁ1238.923254 a.u.
d
hydroxymethyl group and the ccw/cw arrangement of the 3-OH and
4-OH groups. In the gg and gt orientations, the 6-OH hydrogen atom
is directed towards the O5 oxygen atom, regardless of the ccw/cw
arrangement. In the tg orientation, the 6-OH hydrogen atom is
oriented towards the O4 oxygen atom in the ccw arrangement of
the 3-OH and 4-OH groups, forming an intramolecular hydrogen
bond. In the cw arrangement, the 4-OH hydrogen atom forms an
intramolecular hydrogen bond with the O6 oxygen. In the starting
geometries, hydrogen atom from the ]NeOH group was oriented
anti (a) or syn (s) with reference to the C2 carbon atom.
rotamers of the
less stable than the most stable rotamers of the
(1e3). The analogous difference in the case of acetylated com-
pounds is 2.5 kcal/mol. Taking into account the acidic properties of
oximes (pKa 11) [32] one may expect that these exist in their
anionic form in the strong basic conditions of Zemplen O-deace-
tylation. On the other hand, the anionic form of oximes is charac-
teristic by the lower E/Z transition state [25]. This fact as well as the
decreased energy difference between the
a
-E stereoisomer (1e3) are on average 1.7 kcal/mol
-Z stereoisomer
a
ꢀ
a
-Z and
a
a
-E stereoiso-
-Z) / 10 (a-
mers of deacetylatyd oximes justify the observed 4 (
ꢀ
By taking into account two orientations of the NeOH group
( ꢀ 2), ccw and cw orientations of the 3-OH and 4-OH groups ( ꢀ 2),
and rotational freedom of the CH2OH group ( ꢀ 3), 12 starting ge-
E) þ 11 (
a
-Z) isomerization during the Zemplen O-deacetylation. In
turn, it is not surprising that the less stable 10 (
the more stable 11 ( -Z) during NMR measurements.
The DFT results also indicate that after the acetyl groups
removing, the -Z and -E stereoisomers are still definitely less
stable than their equivalents. The -E stereoisomer is 2.2 kcal/mol
less stable than the -E stereoisomer on average; however, this is
about 1.1 kcal/mol more stable than the -Z stereoisomer. Probably,
this better stability of the -E stereoisomer over the -Z stereo-
during NMR
a-E) isomerises to
a
ometries for
a-Z, a-E, b-Z, and b-E stereoisomers of methyl 2-deoxy-
2-hydroxyimino-
D
-arabino-hexopyranosides were prepared. All of
b
b
the starting geometries were prepared in both the chair (4C1) and
the skew (4S0) conformations. To describe initial and final geome-
tries of the pyranose ring substituents the following assignments
and orders of rotations were used: NOeH (a or s), O3eC3, O4eC4
(cw or ccw), C6eC5 (gg, gt or tg).
a
b
a
b
b
b
isomer inhibits the E/Z isomerization of
9
The findings presented in Table 2 demonstrate that among the
measurements.
four stereoisomers of methyl 2-deoxy-2-hydroxyimino-
hexopyranosides, the -Z is again the most stable. However, the
acetyl group deprotection causes the energy difference between
the -Z and -E stereoisomers to decrease. The most stable
D
-arabino-
The stabilities of the studied methyl hex-2-ulopyranoside ox-
imes are again closely connected with their conformations. The
unstrained
confirmed by the calculated 99.94% population of the rotamers 1e3
a
a
-Z stereoisomer adopts the 4C1 conformation, which is
a
a

M. Cyman et al. / Journal of Molecular Structure 1125 (2016) 558e569
563
Fig. 3. Structures of the most stable methyl 3,4,6-tri-O-acetyl-2-deoxy-2-hydroxyimino-D-arabino-hexopyranosides from each group of the configurational isomers.
(Table 2). The
a
-E stereoisomer also adopts the 4C1 conformation,
stereoisomer adopt the deformed B3,0 conformation (6, population
which is confirmed by the calculated 99.55% population of the
39%) or the 4S0 conformations (7 and 8, populations 29.86% and
12.71%, respectively). There are also relatively stable 4C1 confor-
rotamers 1e3. It seems that the 4C1 conformation facilitates the 3-
OH group hydrogen of the
a-E stereoisomer to interact with the
mations found among the
b-Z stable rotamers with populations of
oxime oxygen. The distance between these two atoms in the
optimised structures 1e3 is 1.86 Å, 1.86 Å, and 1.87 Å, respectively.
The strains resulting from the coplanar orientation of the aglycone,
7.54% (1), 6.22% (2) and 3.65% (3). These results indicate the
conformational equilibrium for the b-Z stereoisomer. In turn, the b-
E stereoisomer adopts the deformed 1,4B conformation, which is
proved by the calculated 99.27% population of the rotamers 4e7.
oxime and 3-OH groups in the 4C1 conformation lead the
b
anomers
to adopt other conformations. The most stable rotamers of the -Z
b
The 1,4B conformation allows the
b-E stereoisomer to avoid the

564
M. Cyman et al. / Journal of Molecular Structure 1125 (2016) 558e569
Table 2
Geometry parameters, energy parameters, and populations of the most stable rotamers of methyl 2-deoxy-2-hydroxyimino-D-arabino-hexopyranosides.
Structure
Final geometry
Final conformation
D
Ea
G [a.u.]
D
Gb
Populationc [%]
D
Gd
Populatione [%]
[kcal/mol]
[kcal/mol]
[kcal/mol]
a
-Z
starting chair
1
2
3
a/ccw/gg
a/ccw/gt
a/ccw/tg
4C1
4C1
4C1
0,02
0.00
0.08
ꢁ780.640737
ꢁ780.640731
ꢁ780.640041
0.00
0.004
0.44
40.43
40.17
19.34
SPi 99.94
0.00
0.004
0.44
40.43
40.17
19.34
SPi 99.94
starting skew
4
5
6
7
a/ccw/gt
a/ccw/tg
s/ccw/gt
s/ccw/gg
B3.0
B3.0
B3.0 def
B3.0 def
7.99
9.73
9.86
10.35
ꢁ780.628876
ꢁ780.626420
ꢁ780.625203
ꢁ780.624877
0.00
1.54
2.30
2.51
89.80
6.65
1.83
1.30
SPi 99.58
7.44
8.98
9.75
9.95
1.41E-04
1.04E-05
2.87E-06
2.03E-06
SPi 1.56E-04
a
-E
starting chair
1
2
3
a/ccw/tg
a/ccw/gt
a/ccw/gg
4C1
4C1
4C1
1.75
1.68
1.64
ꢁ780.638632
ꢁ780.638486
ꢁ780.637786
0.00
0.09
0.53
43.96
37.66
17.93
SPi 99.55
0.00
0.09
0.53
43.96
37.66
17.93
SPi 99.55
starting skew
4
a/ccw/gt
1.4B
8.65
ꢁ780.627165
0.00
99.98
7.20
2.32E-04
def
b-Z
starting chair
1
2
3
4
5
s/ccw/gt
s/ccw/gg
s/ccw/tg
a/ccw/gt
a/ccw/gg
4C1
4C1
4C1
4C1
4C1
5.11
5.25
4.90
7.77
7.73
ꢁ780.631957
ꢁ780.631775
ꢁ780.631273
ꢁ780.628615
ꢁ780.628604
0.00
0.11
0.43
2.10
2.10
42.08
34.70
20.38
1.22
1.20
SPi 99.58
0.97
1.09
1.40
3.07
3.08
7.54
6.22
3.65
0.22
0.22
SPi 17.85
starting skew
6
7
8
a/ccw/gg
a/ccw/gt
a/ccw/tg
B3.0 def
4.18
5.08
5.39
ꢁ780.633508
ꢁ780.633256
ꢁ780.632450
0.00
0.16
0.66
47.51
36.37
15.48
SPi 99.36
0.00
0.16
0.66
39.00
29.86
12.71
SPi 81.57
4S0
4S0
b-E
starting chair
1
2
3
a/ccw/tg
a/ccw/gg
a/ccw/gt
4C1 def
6.80
7.03
7.13
ꢁ780.629693
ꢁ780.629666
ꢁ780.628407
0.00
0.02
0.81
44.84
43.58
11.48
SPi 99.90
2.96
2.98
3.77
0.23
0.22
5.80E-2
SPi 0.51
4C1
4C1
starting skew
4
5
6
7
a/ccw/gt
a/ccw/gg
a/ccw/tg
a/ccw/gg
1.4B
3.85
3.40
3.67
4.70
ꢁ780.634410
ꢁ780.634255
ꢁ780.634185
ꢁ780.633336
0.00
0.10
0.14
0.67
33.74
28.63
26.58
10.81
0.00
0.10
0.14
0.67
33.57
28.49
26.45
10.76
def
1.4B
def
1.4B
1.4B
def
SPi 99.76
SPi 99.27
a
With reference to the rotamer 2 (
a
-Z) with energy of ꢁ780,8167023 a.u.
b
c
With reference to the most stable rotamer with the same anomeric and hydroxyimino configurations and the same starting conformation.
In rotamers with the same anomeric and oxime configurations and the same starting conformation.
With reference to the most stable rotamer with the same anomeric and hydroxyimino configurations, irrespective of its conformation.
In rotamers with the same anomeric and oxime configurations, irrespective of their conformation.
d
e
unfavourable coplanar orientation of the aglycone, oxime and 3-OH
group.
The calculations presented are fully in agreement with our
experimental findings, based on the NMR data. Both, presented
coupling constants and results of the optimisation call for the 4C1
orientation of the 3-OH and 4-OH groups. Such an orientation di-
rects the hydrogen from the 4-OH group towards the oxygen from
the 3-OH group and the hydrogen from the 3-OH group towards the
nitrogen from the 2¼NOH group (in the Z configuration) or towards
the oxygen from the 2¼NOH group (in the E configuration). In the
case of Z configuration, the oxygen from the 2¼NOH group is
subsequently directed towards the anomeric hydrogen, in both the
conformation of the
2-deoxy-2-hydroxyimino-
coupling constants established for the
a
-E (10) and
-arabino-hexopyranosides. In turn, the
-E diastereisomer (9) is
a-Z (11) stereoisomers of methyl
D
b
a
and
anomer in the 4C1 conformation. In the case of
ygen from the 2¼NOH group may interact with the anomeric
b
anomers. Such an orientation is unavoidable for the
a
indicative of the deformed 1,4B conformation, found during the
optimisation process. The 1,4B conformation, analogously to the 4C1
conformation, requires the H3 and H4 as well as the H4 and H5
protons to be oriented antiperiplanarly. Thus, the recorded J3,4
b
anomer, the ox-
hydrogen since the most stable rotamers of the b-Z stereoisomer
(6e7) adopt a conformation other than the 4C1 one (Fig. 4).
Thus, the continuous network of the attractive electronic in-
teractions is created in all of the stable rotamers of methyl 2-deoxy-
8.4 Hz and J4,5 9.6 Hz coupling constants confirm the deformed 1,4
conformation calculated for 9.
B
With reference to the geometry of pyranose ring substituents,
one may see that all of the most stable rotamers of methyl 2-deoxy-
2-hydroxyimino-
D
-arabino-hexopyranosides.
To
make
this
possible, the hydrogen from the 2¼NOH group adopts the anti (a)
2-hydroxyimino-
D
-arabino-hexopyranosides adopt the ccw
orientation with reference to the C2 carbon atom.

M. Cyman et al. / Journal of Molecular Structure 1125 (2016) 558e569
565
Fig. 4. Structures of the most stable methyl 2-deoxy-2-hydroxyimino-D-arabino-hexopyranosides from each group of the configurational isomers.
The only structural differentiation in the stable rotamers of the
respective stereoisomer of methyl 2-deoxy-2-hydroxyimino-
anti-periplanarly to the endocyclic oxygen atom. Such an unfav-
ourable aglycone orientation is probably compensated by
D-
a
arabino-hexopyranosides results from the C6eC5 bond rotation. All
three permitted staggered orientations (gg, gt, tg, Fig. 2c) are rep-
resented among these stable rotamers without any specific
preference.
hydrogen bond created between the gg oriented 6-OH group and
the aglycone oxygen. The 6-OH/OMe distance 2.07 Å and the
OeH/O valence angle 145.96ꢂ give evidence for such the hydrogen
bond. Another relatively stable structure of the b-E stereoisomer
It is worth noticing that in all of the optimised structures, both
acetylated and deacetylated, the methyl group of aglycone is always
oriented in accordance with an exo-anomeric effect, e.g. anti-
periplanarly to the C2 carbon atom. The only exception is structure
with the gg oriented 6-OH group (7, Table 2) has the methyl group
of aglycone oriented in accordance with the exo-anomeric effect.
2.4. X-ray analysis of benzyl 2-deoxy-2-hydroxyimino-a-D-lyxo-
5 of the b-E stereoisomer of methyl 2-deoxy-2-hydroxyimino-D-
hexopyranoside (12)
arabino-hexopyranosides (Fig. 4). In this structure, the methyl
group of aglycone is oriented against an exo-anomeric effect, e.g.
In
the
crystal,
2-deoxy-2-hydroxyimino-a-D-lyxo-

566
M. Cyman et al. / Journal of Molecular Structure 1125 (2016) 558e569
hexopyranoseide (12) adopts the 4C1 conformation [33,34] (Fig. 5)
with the ring-puckering parameters [35,36] Q ¼ 0.5528(15) Å,
q
¼ 14.47(15) Å and
f
¼ 260.1(6)ꢂ. As it was established above, the
4C1 conformation is stable enough for all of the analysed 2-deoxy-2-
hydroxyimino glycosides with the
a-Z configuration and was also
identified for 12 in a CDCl3 solution.
In a crystal structure of 12 the C7 carbon atom of aglycone is
oriented antiperiplanarly to the C2 sugar carbon atom with the
C7eO1eC1eC2 torsional angle of 169.2(1)o. Such an orientation is
due to an exo-anomeric effect and is in accordance with our results
of the DFT calculations. In turn, the oxime hydrogen is oriented anti
with reference to the C2 sugar carbon atom, which is also in
accordance with our geometry optimisation results. In a crystal
structure of 12 the 3-OH hydrogen is oriented towards the C4
carbon atom with the H3BeO3eC3eC4 torsion angle of 85.2(1)o. In
turn, the 4-OH hydrogen is almost eclipsed with the H4 hydrogen,
which is indicated by the H4BeO4eC4eH4A torsion angle of
ꢁ8.8(1)o. The hydroxymethyl group adopts the tg conformation
with the 6-OH hydrogen pointed to the 4-OH oxygen.
The crystal structure of 12 is stabilised by a dense network of
OeH/O hydrogen bonds and CeH/O short contacts between the
molecules (Fig. 6). There is also an intramolecular short contact
between the Z oriented oxime oxygen and the H1 anomeric proton
in the crystal structure of 12. The distance between these two
atoms is 2.22 Å (Table 3). This confirms our assumptions based on
Fig. 6. The arrangement of the molecules of 12 in the crystal structure, viewed along a-
direction. The OeH/O and CeH/O hydrogen bonds are represented by dashed lines.
The H atoms not involved in interactions have been omitted for clarity.
Table 3
Hydrogen bonds and short contacts for 12 with distances (d): d(D/A) < R(D)þR(A)þ
0.50 Å; d(H$$$A) < R(H)þR(A)-0.12 Å and angle (<) <D─H/A > 100.0ꢂ.
the DFT calculations that the
a-Z orientation of 2-deoxy-2-
hydroxyimino glycosides is also advantageous because of the
electronic interactions between the oxime oxygen and the H1
anomeric proton.
D─H
A
d(D─H)
d(H/A)
d(D/A)
< D─H/A
C-1─H-1
O-2
0.98
0.82
0.82
0.82
0.82
0.82
0.98
2.22
1.90
2.09
2.12
1.96
2.57
2.20
2.636 (2)
2.719(2)
2.902(2)
2.912(2)
2.737(2)
3.079(2)
3.144(2)
104
175
172
163
159
121
160
O-2─H-2
O-3─H-3B
O-4─H-4B
O-6─H-6C
O-6─H-6C
C-3─H-3A
O-6i
O-4ii
N-1iii
O-3iii
O-4iii
O-5ii
3. Conclusions
The results of our experimental and theoretical studies indicate
that the
a
-Z stereoisomer is definitely the most stable among all of
-hex-
Symmetry codes: (i) x, y e 1, z; (ii) x þ 1, y, z; (iii) ex, y þ 1/2, ez.
the possible stereoisomers of 2-deoxy-2-hydroxyimino-
D
opyranosides, both in the O-acetylated and O-deacetylated forms.
The stability of the remaining stereoisomers decreases in the
following order a-E > b-E > b-Z. The a-E stereoisomer relatively
gains in stability after O-deacetylation, probably due to the
favourable interactions of the 3-OH group with the E-configured
oxime oxygen. The 2-hydroxyimino compounds easily isomerises
avoidance of basic conditions is important to minimize oxime
isomerization. The
b anomers lack of stability is closely connected
with the fact that these adopt other than 4C1 conformation. The
presented X-ray analysis confirms our experimental and theoretical
studies.
in the direction of the more stable stereoisomer:
or -E to -Z (10 to 11). Even the most stable
provides the mixture of
b
a
-Z to
-Z substrate (4)
-E (10) and a-Z (11) products in the strong
b-E (5 to 3)
a
a
a
ꢀ
basic conditions of Zamplen deacetylation. This indicates that an
4. Experimental
4.1. General methods
Melting points were uncorrected. The IR spectra were recorded
as Nujol mulls with a Bruker IFS 66 spectrophotometer. The 1H and
13C NMR spectra (CDCl3, DMSO or CD3OD, internal Me4Si) were
measured with a Bruker Avance III 500 (500.13/125.75 MHz) in-
strument. Positive-ion mode MALDITOF mass spectra were ob-
tained using a Bruker Biflex III spectrometer with 4-cyano-4-
hydroxycinnamic matrix. The optical rotations were determined
at rt on a Perkin-Elmer polarimeter in a 1-dm tube at the D line of
sodium using CHCl3 or CH3OH as the solvents. Thin-layer chro-
matography (TLC) was performed on the E. Merc Kieselgel 60 F-254
plates using the following eluent systems (v/v): A, 2:1 toluene-
AcOEt; B, 4:1 toluene-AcOEt; C, 3:1 CHCl3eMeOH; D, 6:1
CHCl3eMeOH. Column chromatography was performed on MN
Kieselgel 60 (<0.08 mm) with one of the above listed eluent
systems.
Fig. 5. The molecular structure of 12 showing the atom labelling scheme. Displace-
ment ellipsoids are drawn at the 15% probability level and H atoms are shown as small
spheres of arbitrary radius.

M. Cyman et al. / Journal of Molecular Structure 1125 (2016) 558e569
567
0
0
4.2. Benzyl 3,4,6-tri-O-acetyl-2-deoxy-(2E)-hydroxyimino-
arabino- (3) -(2Z)-hydroxyimino- -arabino- (4) and -(2Z)-
hydroxyimino- -arabino-hexopyranosides (5)
b
-
D
-
6), 4.57 (d, 1 H, JA,B 11.5 Hz, CHBPh), 4.47 (dd, 1 H, J5,6 3.8 Hz, J6.6
a-D
11.95 Hz, H-60), 4.21 (m, 1 H, H-5), 2.02, 2.01, 1.96 (3 s, 9 H, 3 ꢀ OAc);
b
-D
13C NMR (CDCl3, 125 MHz):
d
170.8, 169.8, 169.7 (3 ꢀ C]O), 148.4
(C2), 136.1, 128.5, 127.9 (Carom), 96.1 (C1), 71.4 (C5), 69.1 (CH2), 67.0
8.06
3,4,6-Tri-O-acetyl-2-deoxy-2-nitroso-
ride (1) (0.34 g, 1 mmol) [37], benzyl alcohol (208
dry pyridine (161 L, 2 mmol) were dissolved in anhydrous THF
a-
D-glucopyranosyl chlo-
(C4), 63.9 (C6), 60.6 (C3), 20.9, 20.8, 20.6 (3 ꢀ COCH3); for 7:
d
mL, 2 mmol), and
(bs, 1 H, NOH), 7.27 (m, 5 H, Ph), 5.79 (s, 1 H, H-1), 5.73 (d, 1 H, J3.4
3.35 Hz, H-3), 5.39 (dd, 1 H, J3.4 3.4 Hz, J4.5 5.8 Hz, H-4), 4.87 (d, 1 H,
JA,B 11.5 Hz, CHAPh), 4.63 (d, 1 H, JA,B 11.5 Hz, CHBPh), 4.56 (dd, 1 H,
m
(7.5 mL). The reaction mixture was stirred and refluxed for 0.5 h.
The end of reaction was verified by TLC (solvent A). Then, the
mixture was evaporated, dissolved in CHCl3 (100 mL), washed
several times with H2O (20 mL), dried over Na2SO4, filtered off and
0
0
0
J5,6 8.7 Hz, J6.6 11.6 Hz, H-6), 4.41 (dd, 1 H, J5,6 4.75 Hz, J6.6 11.6 Hz,
H-60), 4.31 (m, 1 H, H-5), 2.02, 2.01, 2.00 (3 s, 9 H, 3 ꢀ OAc); 13C NMR
(CDCl3, 125 MHz):
d
170.7, 169.7, 169.8 (3 ꢀ C]O), 149.1 (C2), 136.8,
concentrated. The residue was chromatographed on silica gel
128.4, 127.8 (Carom), 91.1 (C1), 71.8 (C5), 70.6 (CH2), 67.3 (C3), 67.2
20
(solvent B) to afford first 3 (34.9 mg, 9%, syrup): [
a
]
ꢁ 8ꢂ (c 1.0,
(C4), 63.6 (C6), 20.9, 20.7 (3 ꢀ COCH3); MALDITOF-MS: m/z 432.2
D
CHCl3); Rf 0.48 (solvent A); IR:
n
3375 (OeH), 3032 (Bn CeH), 2932
(MþNa)þ, 448.1 (MþK)þ.
20
(CeH), 1749 (ester C]O), 1238 cmꢁ1 (ester CeO); 1H NMR (CDCl3,
500 MHz): 7.83 (s, 1 H, NOH), 7.37 (m, 5 H, Ph), 6.11 (d, 1 H, J3.4
Eluted second was 8 (519 mg, 42%, syrup): [
a
]
þ66.0ꢂ (c 1.0,
D
d
CHCl3); Rf 0.35 (solvent A); IR: n 3354 (OeH), 3031 (Bn CeH), 2932
7.4 Hz, H-3), 5.68 (dd,1 H, J3.4 7.55 Hz, J4.5 8.8 Hz H-4), 5.22 (s,1 H, H-
1), 4.91 (d, 1 H, JA,B 12.2 Hz, CHAPh), 4.67 (d, 1 H, JA,B 12.05 Hz
(CeH), 1750 (ester C]O), 1230 cmꢁ1 (ester CeO); 1H NMR (CDCl3,
500 MHz): 8.76 (bs, 1 H, NOH), 7.35 (m, 5 H, Ph), 6.13 (s, 1 H, H-1),
d
0
0
CHBPh), 4.35 (dd, 1 H, J5.6 4.7 Hz, J6.6 12.1 Hz, H-6), 4.24 (dd, 1 H, J5,6
5.89 (d,1 H, J3.4 3.4 Hz, H-3), 5.50 (d,1 H, J3.4 3.2 Hz H-4), 4.76 (d,1 H,
JA,B 11.75 Hz, CHAPh), 4.65 (d, 1 H, JA,B 11.75 Hz, CHBPh), 4.43 (t, 1 H,
3.45 Hz, J6.6 12.05 Hz, H-60), 3.97 (m, 1 H, H-5), 2.04 (s, 6 H, 2 ꢀ
0
OAc), 2.01 (s, 3 H, OAc); 13C NMR (CDCl3, 125 MHz):
d
170.7, 169.7,
J5.6 6.6 Hz, J5.6 6.55 Hz H-5), 4.09 (d, 1 H, J5.6 6.6 Hz, H-6), 4.08 (d,
0
1 H, J5.6 6.55 Hz, H-60), 2.13 (s, 3 H, OAc), 2.08 (s, 3 H, OAc), 2.07 (s,
0
169.6 (3 ꢀ C]O), 149.4 (C2), 136.8, 128.5, 127.9, 127.7 (Carom), 95.7
(C1), 71.8 (C5) 69.1 (CH2), 68.1 (C4), 63.7 (C3), 63.1 (C6), 20.72, 20.7,
20.5 (3 ꢀ COCH3); MALDI-TOF-MS: m/z 432.2 (MþNa)þ 448.1
3 H, OAc); 13C NMR (CDCl3, 125 MHz):
d
170.4, 170.3, 169.4 (3 ꢀ C]
O), 147.7 (C2), 136.4, 128.5, 128.2, 128.1 (Carom), 89.7 (C1), 70.1 (CH2),
69.1 (C4), 67.1 (C5), 66.9 (C3), 61.7 (C6), 20.7, 20.6, 20.4 (3 ꢀ
COCH3); MALDITOF-MS: m/z 432.2 (MþNa)þ, 448.1 (MþK)þ.
(MþK)þ.
20
Eluted second was 4 (188.9 mg, 46%, syrup): [
a]
þ81ꢂ (c 1.0,
D
CHCl3); Rf 0.42 (solvent A); IR: n 3375 (OeH), 3032 (Bn CeH), 2930
(CeH), 1754 (ester C]O), 1230 cmꢁ1 (ester CeO); 1H NMR (CDCl3,
500 MHz): 8.11 (s, 1 H, NOH), 7.35 (m, 5 H, Ph), 6.08 (s, 1 H, H-1),
4.4. General procedure for O-deacetylation
d
5.81 (d, 1 H, J3.4 9.65 Hz, H-3), 5.20 (t, 1 H, J3,4 9.65 Hz, J4.5 9.8 Hz, H-
4), 4.74 (d, 1 H, JA,B 11.85 Hz, CHAPh), 4.67 (d, 1 H, JA,B 11.85 Hz,
The mixture of 3, 4, or 7 (40.9 mg, 0.1 mmol) and 0.1 M solution
of MeONa in MeOH (0.6 mL, 0.06 mmol) was stirred at rt for 0.5 h.
The end of reaction was verified with TLC (solvent C). Then, it was
treated with Dowex Hþ 50WX4-400, filtered and concentrated.
0
CHBPh), 4.28 (dd, 1 H, J5,6 4.4 Hz, J6.6 12.35 Hz, H-6), 4.19 (ddd, 1 H,
0
0
0
J4,5 10.1 Hz, J5.6 4.4 Hz, J5.6 2.2 Hz H-5), 4.02 (dd, 1 H, J5.6 2.4 Hz, J6.6
12.3 Hz H-60), 2.08 (s, 3 H, OAc), 2.06 (s, 3 H, OAc), 2.04 (s, 3 H, OAc);
13C NMR (CDCl3, 125 MHz):
d
170.7, 169.7, 169.3 (3 ꢀ C]O), 148.9
4.4.1. Benzyl 2-deoxy-(2E)-hydroxyimino-b-D-arabino-
hexopyranoside (9)
(C2), 136.4, 128.5, 128.2, 128.1 (Carom), 89.8 (C1), 70.2 (CH2), 69.5
(C3), 69.3 (C4), 68.0 (C5), 61.8 (C6), 20.7, 20.6, 20.5 (3 ꢀ COCH3);
MALDI-TOF-MS: m/z 432.2 (MþNa)þ, 448.1 (MþK)þ.
Deacetylation of 3 (51.1 mg, 0.12 mmol) gave 9 (35.3 mg, 99%,
mp 150e151 ꢂC): [
a]
20 ꢁ 23.0 (c 0.8, CH3OH); Rf 0.8 (solvent C); IR:
n
D
Eluted third was 5 (32.9 mg, 8%, syrup): Rf 0.39 (solvent A); IR:
n
3462, 3359 (OeH), 3074 (Bn CeH), 2919 (CeH), 1628 (C]N); 1H
3344 (OeH), 2958, 2928 (CeH), 1747 (ester C]O), 1658 (C]N),
NMR (CD3OD, 500 MHz): d 7.35 (m, 5 H, Ph), 5.14 (s, 1 H, H-1), 4.86
(d, 1 H, JA,B 11.75 Hz, CHAPh), 4.63 (d, 1 H, JA,B 11.75 Hz, CHBPh), 4.57
1230 cmꢁ1 (ester CeO); 1H NMR (CDCl3, 500 MHz):
d
8.12 (s, 1 H,
NOH), 7.34 (m, 5 H, Ph), 5.88 (s, 1 H, H-1), 5.52 (d, 1 H, J3.4 5.5 Hz, H-
3), 5.31 (t, 1 H, J3,4 5.5 Hz J4.5 5.5 Hz, H-4), 4.91 (d, 1 H, JA,B 12.2 Hz,
CHAPh), 4.69 (d, 1 H, JA,B 12.2 Hz, CHBPh), 4.43 (d, 2 H, J5,6 6.1 Hz, 2 ꢀ
H-6), 4.03 (q, 1 H, J4,5 5.85 Hz, J5.6 6.4 Hz, H-5), 2.08 (s, 3 H, OAc),
2.08 (s, 3 H, OAc), 2.07 (s, 3 H, OAc); 13C NMR (CDCl3, 125 MHz):
(d, 1 H, J3.4 8.2 Hz, H-3), 4.21 (dd, 1 H, J3.4 8.6 Hz, J4.5 9.4 Hz, H-4),
3.87 (dd, 1 H, J6.6 11.7 Hz, J5.6 2.8 Hz H-60), 3.75 (dd, 1 H, J5.6 5.6 Hz,
0
0
0
0
J6.6 11.7 Hz, H-6), 3.49 (ddd, 1 H, J4.5 9.4 Hz, J5.6 5.6 Hz, J5.6 2.8 Hz, H-
5); 13C NMR (CD3OD,125 MHz):
d
153.1 (C2),137.7,127.9,127.7,127.2
(Carom), 96.7 (C1), 76.8 (C5), 68.5 (CH2), 68.4 (C4), 67.3 (C3), 62.6
(C6); MALDITOF-MS: m/z 284.3 (MþH)þ, 306.1 (MþNa)þ, 322.1
(MþK)þ.
d
170.6, 169.5, 169.4 (3 ꢀ C]O), 149.1 (C2), 136.7, 128.4, 128.0, 127.0
(Carom), 90.2 (C1), 72.6 (C5), 70.6 (CH2), 68.3 (C4), 68.1 (C3), 64.0
(C6), 20.84, 20.79 (3
ꢀ
COCH3); MALDITOF-MS: m/z 432.2
(MþNa)þ, 448.2 (MþK)þ.
4.4.2. Benzyl 2-deoxy-(2E)-hydroxyimino-
a-D-arabino- (10) and
-(2Z)-hydroxyimino- -arabino-hexopyranosides (11)
a-D
4.3. Benzyl 3,4,6-tri-O-acetyl-2-deoxy-(2E)-hydroxyimino-
lyxo- (6), -(2Z)-hydroxyimino- -lyxo- (7) and -(2Z)-
hydroxyimino- -lyxo-hexopyranosides (8)
b
-D-
Deacetylation of 4 (211.3 mg, 0.5 mmol) gave a mixture of two
products, which was chromatographed (solvent D) yielded first 10
b-D
a-D
(33.3 mg, 23%, syrup): Rf 0.8 (solvent C); IR:
n
3388, 3252 (OeH),
7.35
2927, 2878 (CeH), 1640 (C]N); 1H NMR (CD3OD, 500 MHz):
d
These were synthesized analogously to 3e5 using 3,4,6-tri-O-
acetyl-2-deoxy-2-nitroso- -galactopyranosyl chloride (2) (1 g,
3 mmol) [37], benzyl alcohol (615 L, 6 mmol), pyridine (0.5 mL,
(m, 5 H, Ph), 6.16 (s, 1 H, H-1), 5.04 (d, 1 H, J3.4 9.45 Hz, H-3), 4.81 (d,
1 H, JA,B 11.5 Hz, CHAPh), 4.65 (d, 1 H, JA,B 11.8 Hz, CHBPh), 3.88 (m,
a-D
m
1 H, H-5), 3.74 (m, 1 H, H-4); 13C NMR (CD3OD, 125 MHz):
d; 137.3,
6 mmol) and THF (22.5 mL). Column chromatography (solvent B)
gave first a mixture of 6 and 7 (131.3 mg 11%, syrup): Rf 0.40 (sol-
127.9, 127.7, 127.5 (Carom), 90.3 (C1), 82.2 (C3), 72.9 (C5), 69.7 (C4),
68.9 (CH2), 60.9 (C6); MALDITOF-MS: m/z 306.1 (MþNa)þ, 322.1
(MþK)þ.
vent A); IR:
C]O), 1230 cmꢁ1 (ester CeO); 1H NMR (CDCl3, 500 MHz) for 6:
8.06 (bs, 1 H, NOH), 7.27 (m, 5 H, Ph), 6.32 (d, 1 H, J3.4 3.9 Hz, H-3),
n 3398 (OeH), 3030 (Bn CeH), 2937 (CeH), 1749 (ester
Eluted second was 11 (69 mg, 47%, mp 108 ꢂC): [
a
]
D
20 þ131.8ꢂ (c 1,
d
CH3OH); Rf 0.64 (solvent C); IR:
1641 (C]N); 1H NMR (CD3OD, 500 MHz):
1 H, H-1), 4.80 (d,1H, JA,B 11.75 Hz, CHAPh), 4.63 (d,1 H, JA,B 11.75 Hz,
n 3388, 3244 (OeH), 2928 (CeH),
5.19 (s, 1 H, H-1), 5.17 (t, 1 H, J3.4 4.3 Hz, J4.5 4.65 Hz, H-4), 4.85 (d,
d 7.35 (m, 5 H, Ph), 6.10 (s,
0
1 H, JA,B 11.5 Hz, CHAPh), 4.69 (dd, 1 H, J5,6 8.75 Hz, J6.6 11.95 Hz, H-

568
M. Cyman et al. / Journal of Molecular Structure 1125 (2016) 558e569
0
0
CHBPh), 4.36 (d, 1 H, J3.4 9.25 Hz, H-3), 3.87 (dd, 1 H, J5.6 2.0 Hz, J6.6
The populations of the respective rotamers were calculated
using Equation (1):
11.7 Hz, H-60), 3.81 (ddd, 1 H, J4.5 9.6 Hz, J5.6 5.7 Hz, J5.6 2.0 Hz, H-5),
0
0
3.73 (dd, 1 H, J5.6 5.7 Hz, J6.6 11.7 Hz, H-6), 3.41 (t, 1 H, J3.4 9.25, Hz
D
Gi=RT
eꢁ
J4.5 9.6 Hz, H-4); 13C NMR (CD3OD, 125 MHz):
d 152.5 (C2), 137.4,
P ¼
(1)
P
i
N
i¼1 eꢁ
D
Gi=RT
128.0, 127.8, 127.4 (Carom), 89.6 (C1), 73.0 (C4), 72.7 (C5), 71.3 (C3),
68.9 (CH2), 61.1 (C6); MALDITOF-MS: m/z 306.1 (MþNa)þ, 322.1
(MþK)þ.
Acknowledgements
4.4.3. Benzyl 2-deoxy-(2Z)-hydroxyimino-a-D-lyxo-hexopyranoside
(12)
This research was financed by the Ministry of Science and
Higher Education e Grant DS/530-8457-D603-16. All DFT calcula-
tions were carried out using the resources of the Informatics Center
Deacetylation of 8 (776.8 mg, 1.9 mmol) gave 12 (362.7 mg, 68%,
20
mp 155 ꢂC): [
a]
þ188.7ꢂ (c 1, CH3OH); Rf 0.65 (solvent C); IR:
n
D
3379 (OeH), 2950, 2922, 2900 (CeH), 1641 (C]N); 1H NMR
ꢀ
of the Metropolitan Academic Network in Gdansk (CI TASK).
(CD3OD, 500 MHz): d 7.34 (m, 5 H, Ph), 6.10 (s, 1 H, H-1), 4.81 (d, 1H,
JA,B 11.75 Hz, CHAPh), 4.63 (d, 1 H, JA,B 11.75 Hz, CHBPh), 4.54 (d, 1 H,
Supplementary data
0
J3.4 3.2 Hz, H-3), 4.07 (t, 1 H, J5.6 6.4 Hz, J5.6 5.6 Hz, H-5), 4.03 (d, 1 H,
0
J3.4 3.2 Hz, H-4), 3.76 (dd, 1 H, J5.6 6.4 Hz, J6.6 11.4 Hz, H-6), 3.72 (dd,
1 H, J5.6 5.6 Hz, J6.6 11.4 Hz, H-60); 13C NMR (CD3OD, 125 MHz):
Full crystallographic details, excluding structures features, have
been deposited (deposition No. CCDC 1443825) with the Cam-
bridge Crystallographic Data Center. These data may be obtained,
on request, from The Director, CCDC, 12 Union Road, Cambridge,
CB2 1EZ, UK (tel.: þ44-1223-336408; fax: þ44-1223-336033; e-
mail: deposit@ccdc.cam.ac.uk or www: http://www.ccdc.cam.ac.
uk).
0
0
d
151.5 (C2), 137.4, 127.9, 127.8, 127.4 (Carom), 89.7 (C1), 71.4 (C5),
70.9 (C4), 68.9 (CH2), 68.3 (C3), 61.3 (C6); MALDITOF-MS: m/z 284.1
(MþH)þ, 306.1 (MþNa)þ.
4.5. Description of the crystal structure of 12
Good-quality single-crystal specimen was selected for the X-ray
diffraction experiments at T ¼ 295(2) K and affixed to the tip of
glass capillary with epoxy glue. Diffraction data were obtained on
the Oxford Diffraction Gemini R Ultra Ruby CCD diffractometer, using
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€
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