Schiff bases from d-glucosamine and aliphatic ketones

Article abstract of DOI:10.1016/j.carres.2009.08.032

Despite the comprehensive literature and enormous versatility of chiral imines derived from aminosugars and aldehydes, the corresponding counterparts generated from ketones remain an underestimated research subject. Filling in the gap, this manuscript she

Full text of DOI:10.1016/j.carres.2009.08.032

Carbohydrate Research 345 (2010) 23–32
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Schiff bases from D-glucosamine and aliphatic ketones
Esther M. S. Pérez a, , Martín Ávalos a,b, Reyes Babiano a, Pedro Cintas a, Mark E. Light b, José L. Jiménez a,
*
Juan C. Palacios a, Ana Sancho a
a Departamento de Química Orgánica e Inorgánica, QUOREX Research Group, Universidad de Extremadura, E-06071 Badajoz, Spain
b University of Southampton, Southampton SO17 1BJ, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 June 2009
Received in revised form 31 July 2009
Accepted 13 August 2009
Available online 28 August 2009
Despite the comprehensive literature and enormous versatility of chiral imines derived from aminosug-
ars and aldehydes, the corresponding counterparts generated from ketones remain an underestimated
research subject. Filling in the gap, this manuscript sheds light on the synthetic and structural aspects
of such substances and updates the few antecedents reported so far.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Carbohydrates
Schiff bases
Ketones
1. Introduction
method for isolating D-glucosamine from a reaction mixture of syn-
thetic or natural origin.16a Moreover, sugar imines have proven to
be a convenient strategy for protecting free amino groups,17–31 and
in this context O-protected imines have been prepared by reacting
aldehydes with O-protected aminosugars32–38,10 or the corre-
sponding phosphinimine.39
Imines or Schiff bases, compounds dating back to the early days
of synthetic organic chemistry, are easily generated by condensa-
tion of carbonyl groups and primary amines. The process takes
place with the intermediacy of a carbinolamine that undergoes fur-
ther dehydration to give a double carbon–nitrogen bond.1 In carbo-
hydrate chemistry, a large number of imines has been reported,
both by reaction of sugar aldehydes with amines and by reaction
of aminosugars with aldehydes. Such inherently chiral imines have
been employed in asymmetric syntheses serving the carbohydrate
fragment as a chiral inductor. Thus, Kunz et al.2 have applied Schiff
bases from O-protected glycosylamines to asymmetric versions of
Strecker,3 Ugi,4 Mannich,5 tandem Mannich-Michael,6 hetero-
Diels–Alder,7 and organometallics addition reactions.8 Likewise,
Georg et al. have employed such sugar imines in the Staudinger
reaction.9 As mentioned above, these Schiff bases can easily be pre-
pared by condensation of protected glycosylamines with the corre-
sponding aldehyde.4,10,11 Ugi and associates have also used a
thiosugar-derived glycosylimine in the stereoselective synthesis
In stark contrast with the relatively abundant information on
sugar imines derived from aldehydes, there are, to the best of our
knowledge, only two examples of carbohydrate imines from ke-
tones, without clear-cut structural evidences. In the mid-1950s,
Micheel and Wulff report one of these ketone derivatives (2) by
treating an unprotected glycosylazide (1) with acetone in acid
medium.36 Notably, these authors also reported the failure to
obtain the per-O-acetylated imine 3 by conventional acetylation;
instead 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-D-glucopyranosyl
azide (4), a product lacking the isopropylidene moiety, was de-
scribed (Scheme 1).
The second imine (7), equally derived from acetone, was pre-
pared by Fodor and coworkers,40 who described it as an oxazoli-
dine derivative (6) resulting from the migration of a vicinal
acetyl to the free amino group at C-2 of compound 5. However, a
further re-assessment by Capon and associates evidenced the
structure of imine 7 (Scheme 2).41
of
a
-amino acids and peptides.12 Finally, sugar imines have been
postulated as intermediates in the formation of glycosylamines13,14
and in their mutarotation reactions.15
The first imines derived from 2-amino-2-deoxyaldoses were de-
scribed by Irvine and Hynd as early as 1913.16 Since such transfor-
mations take place in high yield, produce insoluble products, and
give the starting aminosugar back by reaction with dilute acids,
these authors suggest the salicylidene derivative to be a suitable
2. Results and discussion
In order to explore the chemistry of sugar imines derived from
aliphatic ketones still further, disclosing new structural data and
potential applications, a series of such compounds has been pre-
pared and fully characterized.
* Corresponding author. Tel.: +34 924289383; fax: +34 924271149.
E-mail address: espero@unex.es (E.M.S. Pérez).
0008-6215/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2009.08.032

24
E. M. S. Pérez et al. / Carbohydrate Research 345 (2010) 23–32
CH2OAc
O
AcO
N3
AcO
ii
CH2OH
CH2OH
Me
Me
N
O
O
HO
HO
HO
HO
i
N3
N3
ii
3
Me
Me
N
NH2
CH2OAc
O
1
AcO
AcO
N3
2
NHAc
4
Scheme 1. Reagents: (i) CH3COCH3, HCl; (ii) Ac2O, C5H5N.
CH2OAc
O
CH2OAc
O
CH2OAc
O
AcO
AcO
AcO
i
AcO
AcO
OEt
OEt
O
OEt
NH2
N
NH
Me
Me
OH
5
Me
7
6
Scheme 2. Reagents: (i) CH3COCH3.
Our starting point was the previous synthesis of Micheel and
small or negligible variations, one should reasonably conclude that
the C@N bond has only appreciable effects on the vicinal atoms.
The imine function can also be detected as a new carbon resonance
at 172.48 ppm in the 13C NMR spectrum (Table 1).
Wulff, who reported the facile synthesis of imine 2 by reaction of
the unprotected azide 1 in acetone.36 Extension of this protocol
to D-glucosamine hydrochloride (8), deprotected as free base, was
however unsuccessful. This fact points to a protection of the ano-
meric position, thus avoiding the formation of side products and
diastereomeric mixtures. To this end, the synthesis of per-O-acet-
The non-deuterated imine 3 could also be prepared by dissolv-
ing the starting azide (10) in acetone, evaporating the solvent after
three days and crystallizing the residue from diethyl ether.
Remarkably, this transformation can advantageously be monitored
by polarimetry, on measuring the temporal variation of the optical
rotation of compound 10 in acetone solution (Table 1, Fig. 2).
For comparative effects, we have also synthesized imines 12
and 13 (Scheme 4),35 derived from anisaldehyde and salicylalde-
hyde, respectively, and evaluated their spectroscopic data.
The structures proposed for 3, 12, and 13 are supported by their
elemental analysis and spectroscopic data. IR spectra of these com-
pounds show the strong absorption for the azido group at
ꢀ2115 cmꢁ1 along with a weaker band at ꢀ1668 cmꢁ1, which is
a characteristic of the imine functionality.
yl-D-glucopyranosyl azide (10) could easily be accomplished in a
two-step protocol from 835,42 (Scheme 3).
That imine formation occurs in the presence of aliphatic ke-
tones could be sequentially determined by 1H NMR monitoring
of a solution of 10 in hexadeuterated acetone (Fig. 1). After three
days at room temperature, the diagnostic proton signals of the
starting material have almost disappeared, while a new signal set
of equal multiplicity and coupling pattern, but markedly different
chemical shifts, emerged, which should be attributed to the forma-
tion of compound 11. The largest difference is observed for the H-2
proton, close to the nitrogen atom, which undergoes a strong desh-
ielding (
case, are observed for the anomeric proton (
H-3 ( dH-3 = 0.2 ppm). Since the remaining signals undergo very
D
dH-2 = 0.9 ppm). Similar effects, to a lesser extent in any
Both proton and carbon NMR spectra of 3 in CDCl3 were almost
coincidental with those recorded in acetone-d6. The methyl groups
of acetone show distinctive chemical shifts at 29.44 ppm and
19.44 ppm. Such a difference, similar to that observed for simple
imines (e.g., Me2C@NMe: 29.1 and 18.0 ppm),43 also evidences
the iminic structure attributed to 3. The chemical shift for C-2 in
D
dH-1 = 0.3 ppm) and
D
CH2OH
CH2OAc
O
O
HO
HO
AcO
AcO
i
3 and 11 shows an appreciable deshielding (
D
d ꢀ8 ppm) relative
HCl.H2N
to the corresponding carbon atom in 10, a fact supporting forma-
tion of the imino group. In addition, the high-resolution mass spec-
trum displays peaks corresponding to [M+Na+] and [M+H+]
fragments (the latter with 100% intensity). Salient fragmentations
also correspond to the loss of ketene and acetic acid, which are typ-
ical of monosaccharide acetyl derivatives.
OH
HBr.H2N Br
8
9
ii
CH2OAc
In addition, the structure of 1244 was elucidated by single crys-
tal X-ray diffraction analysis. The solid-state structure reveals an E
configuration around the imine bond (Fig. 3).
O
AcO
AcO
CH2OAc
O
iii
N3
AcO
AcO
N3
R
N
As expected, the signal for the H-2 proton of 12 and 13 also
NH2
R
undergoes a significant deshielding (DdH-2 = 0.43 ppm), although
10
3 R=CH3
to a lesser extent than that of compounds 3 and 11. In contrast,
11 R=CD3
the deshielding for the C-2 atom of 12 and 13 is much larger (
Dd
Scheme 3. Reagents: (i) CH3COBr; (ii) AgN3; (iii) CH3COCH3 or CD3COCD3.
ꢀ18 ppm) than that observed for 3 and 11.

E. M. S. Pérez et al. / Carbohydrate Research 345 (2010) 23–32
25
Figure 1. 1H NMR spectra of compound 10 in acetone-d6: (a) just dissolved, (b) after three days.
Table 1
t (h)
[a]
D
5a
2
ꢁ14.8
ꢁ22.2
ꢁ34.8
ꢁ38.6
ꢁ40.4
ꢁ45.2
ꢁ46.0
ꢁ46.0
ꢁ51.2
4.5
6.5
8.5
23
25
26
98
a
In min.
Figure 3. ORTEP diagram for 12.
0
The hydroxy group of the phenolic moiety in 13 appears at
12.09 ppm, a deshielding pointing to a strong intramolecular
hydrogen bond.
-10
-20
-30
-40
-50
-60
A similar study has been conducted for b and
a 1,3,4,6-tetra-O-
acetyl-2-amino-2-deoxy-
D
-glucopyranoses (1817 and 19,32,45
respectively), generated as free bases from their halohydrates
1617 and 17,32 which have also been obtained according to the
well-established literature protocols (Scheme 5).
Similar results to those described for 10 can likewise be ob-
tained in the case of imines 20 and 21, whose formation has been
gradually recorded by 1H NMR in acetone-d6. The non-deuterated
imines 22 and 23 could also be isolated (Scheme 6).
0
20
40
60
80
100
Within three to five days, the proton signals of the starting ami-
nosugars have almost completely disappeared and replaced by
those of the corresponding imines 20 and 21. Likewise, the forma-
tion of imines 22 and 23 could also be monitored by polarimetry on
measuring the temporal variation of the optical rotation of amino-
sugars 18 and 19 when dissolved in dry acetone.
time (h)
Figure 2. Plot of optical rotation (Table 1) versus time for the conversion of 10 to 3
in acetone.
Data collected in Table 2 reveal a series of significant variations
in both proton and carbon resonances during imine formation.
CH2OAc
O
CH2OAc
O
AcO
AcO
AcO
AcO
Thus, the H-2 proton undergoes
a substantial change from
N3
N3
ꢀ3.0 ppm to ꢀ3.9 ppm and C-2 from ꢀ55 ppm to ꢀ62 ppm. Again,
the imino functionality (C@N bond) manifests itself as a typical
carbon resonance at ꢀ172 ppm in the 13C NMR spectrum, as well
as by its IR absorption at ꢀ1650 cmꢁ1 (stretching band). Consistent
with the previous data, the methyl groups linked to the iminic car-
bon resonate at markedly different frequencies (corresponding to
ꢀ30 ppm and ꢀ20 ppm).
N
N
H
O
OMe
13
12
For comparativepurposes we were interested in assessing imines
having b configuration (i.e., 14) and
a anomers (such as 24). How-
Scheme 4.

26
E. M. S. Pérez et al. / Carbohydrate Research 345 (2010) 23–32
CH2OAc
O
CH2OAc
O
AcO
AcO
iii
AcO
AcO
OAc
OAc
i,ii
N
HCl.H2N
CH2OH
16
4-MeOC6H4
O
HO
HO
14
iv,ii
HCl.H2N
OH
CH2OAc
O
CH2OAc
O
8
AcO
AcO
v
AcO
AcO
N
OAc
OAc
HBr.H2N
H
17
O
MeOOC
OMe
15
Scheme 5. Reagents: (i) 4-MeOC6H4CHO, NaOH; (ii) Ac2O, C5H5N; (iii) HCl 5 M, CH3COCH3; (iv) EtOCH@C(COOEt)2, Et3N, MeOH; (v) Br2, H2O, CHCl3.
CH2OAc
O
CH2OAc
O
CH2OAc
O
AcO
AcO
ii
AcO
AcO
i
AcO
AcO
R
R
R
R1
1
H2N
R1
N
CD3
N
Me
Me
R
CD3
20 R=OAc, R1=H
18 R=OAc, R1=H
19 R=H, R1=OAc
22 R=OAc, R1=H
21 R=H, R1=OAc
23 R=H, R1=OAc
Scheme 6. Reagents: (i) CD3COCD3, (ii) CH3COCH3.
Table 2
CH2OAc
O
CH2OAc
NMR data (d, ppm; J, Hz) of representative compounds
O
AcO
AcO
AcO
AcO
i
Compd H-1 H-2 H-3 J1,2 C@N
C-1
C-2
C-3
N
10a
10b
11a
3b
4.77 d 2.71 t
4.54 d 2.82 t
5.06 d 3.59 t
4.93 d 3.57 t
5.04 d 3.25 t
5.00 d 3.26 t
5.59 d 2.90 t
5.47 d 3.04 t
5.81 d 3.77 t
5.79 d 3.77 t
5.02 t 8.8
5.03 t 8.8
5.21 t 8.6 172.48 90.80 65.05 74.54
5.26 t 8.4 172.87 90.22 64.12 73.91
5.38 t 8.3 164.80 89.56 73.94 73.12
5.42 t 8.4 169.41 89.12 74.00 72.48
5.10 t 8.4
5.04 t 8.4
5.30 t 8.4 171.28 93.76 63.55 73.77
5.31 t 8.4 172.22 93.91 63.42 74.17
—
—
92.44 56.95 74.82
91.89 55.82 75.17
OAc
H2N
OAc
17
4-MeOC6H4
24
12b
13b
18a
18b
20a
22b
19a
19b
21a
23a
14b
24b
28b
29b
30b
Scheme 7. Reagents: (i) 4-MeOC6H4CHO.
—
—
95.23 55.50 72.28
95.20 55.06 72.71
avoid unwanted side products. This aminosugar underwent O?N
acetyl migration leading to 2-acetamido-2-deoxy-3,4,6-tri-O-acet-
yl-D-glucopyranose (25), which often contaminates the reaction
6.07 d 3.04 dd 4.99 t 3.6
6.20 d 3.13 dd 5.01 t 3.6
6.01 d 3.98 dd 5.47 t 3.6 171.72 91.07 61.49 71.83
6.07 d 3.89 dd 5.54 t 3.6 172.11 91.32 61.03 71.25
—
—
92.88 53.73 69.68
92.90 53.44 69.69
mixture, thereby impeding to obtain the imine 23 as an analyti-
cally pure sample. In contrast, the opposite b anomer (18) does
not experience this isomerization. Presumably, the trans relation-
ship between the acetate at C-1 and the amino group at C-2 avoids
the rearrangement as the intermediate adduct 27, generated by
intramolecular migration of the anomeric acetate, is considerably
5.95 d 3.45 t
5.43 t 8.3 164.29 93.14 73.23 72.73
6.22 d 3.66 dd 5.60 t 3.6 164.28 91.80 71.14 70.05
5.03 d 3.40 t
4.93 d 3.60 t
5.23 d 3.61 t
5.32 t 8.8 187.44 89.99 68.84 73.94
5.27 t 8.4 176.91 90.27 64.23 73.97
4.96 t 8.4 179.13 89.57 64.25 73.49
a
strained46 and therefore less stable than 26 arising from the
a ano-
In acetone-d6 at 400 MHz.
In CDCl3 at 400 MHz.
b
mer (Scheme 8).
These problems can be overcome by using compound 10 as the
starting aminosugar for the preparation of other imines derived
from aliphatic ketones. Thus, compound 28 (Scheme 9) could be
isolated by reaction with clean cyclopentanone for three days at
room temperature. Evaporation gave rise to an oily residue that
crystallized on standing. Its IR spectrum showed the imine signal
at ꢀ1685 cmꢁ1 and both proton and carbon shifts were similar to
those encountered for compound 3, although the proton H-2
undergoes a smaller variation (ꢀ0.6 ppm) when the imine 28 is
generated than that observed for 11 (ꢀ0.9 ppm). The coupling pat-
tern reveals no conformational change of the pyranose ring (4C1)
with respect to the starting azide (10).
ever, compound 24 cannot be obtained by the procedure employed
for the preparation of 14. Alternatively, compound 24 can easily be
generated by reaction of 17 with anisaldehyde (Scheme 7).
Elemental analyses of 22 and 24 as well as the high-resolution
mass spectrum of 22 ([M+Na+] and [M+H+] peaks) fully agree with
their structures. Again, the most relevant fragmentations corre-
spond to sequential losses of acetic acid. An inspection of the cou-
pling pattern in compounds 3, 10, 12, and 13 evidences the same
conformation (4C1) of the glucopyranose ring, as it occurs for 18,
22, and 24 as well as for 14, 19, and 23.
It is worthy to point out that both preparation and reactions of
19 (including work-up protocols) should be performed at 0 °C to
When the synthetic transformation was applied to 2-butanone
and 3-methyl-2-butanone for six days at room temperature, the

E. M. S. Pérez et al. / Carbohydrate Research 345 (2010) 23–32
27
The E stereochemistry certainly creates a allylic 1,3-strain be-
tween the H-2 proton and the methyl group of the imine (R =
Me); however, the opposite Z geometry would give rise to a stron-
ger 1,3-diaxial interaction between that proton and the ethyl, iso-
propyl or tert-butyl group (R = Et, Pr, and Bu). This interaction
make them less stable and more susceptible to hydrolytic cleavage
than their counterparts derived from aldehydes such as 12–14 and
24 (R = H, R1 = Ar).
It is remarkable that in the geometries calculated above as well as
in the solid-state structure elucidated for 12 ( Fig. 3), the plane
containing the imine functionality is roughly perpendicular to the
mean plane of the pyranose ring. In other words, the imino group
therefore adopts a preferential disposition relative to the pyranose
ring in which the lone pair on the nitrogen atom is parallel to the
axial substituents of the sugar skeleton (Fig. 6A). Moreover, the eval-
uation of NOE experiments likewise shows that imines derived from
CH2OAc
O
AcO
AcO
19
H2N
O
i
t
CH2OAc
O
-O
26
CH3
AcO
AcO
OH
CH2OAc
O
NHAc
25
AcO
AcO
18
O
CH3
H2+N
-O
27
Scheme 8.
CH2OAc
O
CH2OAc
O
CH2OAc
O
D
-glucosamine adopt the same conformation in solution (Fig. 5), in
both polar (DMSO-d6, = 48.9, for 35) and less polar solvents (CDCl3,
= 4.8, for 14).
AcO
AcO
AcO
AcO
AcO
e
N3
N3
N3
AcO
e
N
N
N
R
Me
The conformational arrangement encountered in solution for
imines derived from glycosylamines4b and aldehydes through NOE
R
Me
measurements3,4b (Fig. 6B) appears to be identical to that for imines
29E R=Et
29Z R=Et
30E R= iPr
30Z R= iPr
28
derived from D-glucosamine. This particular conformation has been
invoked to account for the stereoselectivity found in asymmetric
reactions.2–8 It has been argued that such a conformation arises from
Scheme 9.
delocalization of the
of the pyranose C–O-bond.3,6 However, this delocalization cannot be
attained in imines derived from -glucosamine. In addition, syn
p electrons of the C@N bond into the r
* orbital
corresponding imines (29 and 30) were obtained as mixtures of E
and Z stereoisomers, in which the former is largely prevalent. In-
stead, 3,3-dimethyl-2-butanone led to a complex mixture, proba-
bly due to strong steric effects caused by the tert-butyl group.
The high-resolution mass spectrum of 30 shows the molecular
peak [M+H+] and fragmentations similar to those previously de-
scribed. The imine function can equally be detected by the typical
IR band of moderate intensity at ꢀ1663 cmꢁ1. It is interesting to
note that 1H NMR monitoring of 29 reveals the facile decomposi-
tion of the imine derivative. Diagnostic signals of the imine can
be inferred from its 1H NMR spectrum such as the H-2 proton at
3.57 ppm, that is, a deshielding of ꢀ0.8 ppm relative to that proton
in azide 10.
D
arrangements of the CamineH and CimineH bonds are preferred for
the lowest energy conformers of cyclohexane ring-substituted imi-
nes, according to both calculations (PM3 and DFT) and X-ray diffrac-
tion data.49 Accordingly, the origin of these conformational features
should largely be steric rather than stereoelectronic. In these confor-
mations the C@N bond eclipses H-2 and, it is well established that
eclipsed conformers of propene are more stable than gauche
arrangements.50,51 Furthermore, the eclipsed disposition is respon-
sible to a significant extent of the strong deshielding that undergoes
the H-2 proton in
vided by the carbonyl group in acyl derivatives (amides, ureas, and
thioureas) of -glucosamine in the Z-anti conformation, in which
D-glucosamine imines. An analogous effect is pro-
D
Although coupling constants are consistent with a 4C1 confor-
mation for the glucopyranose ring, the actual stereochemistry
around the C@N bond for 29 and 30 cannot be unambiguously
established. This should most likely correspond to an E geometry
that minimizes the steric interactions among the different substit-
uents. On the other hand, NOEs measured between the H-2 and
imine protons in imines derived from aldehydes (14 and 35) are
only compatible with an E configuration for the C@N bond (Fig. 4).
Additional information on the relative stability of both stereo-
isomers could be obtained from DFT calculations at the B3LYP/6-
31G* level of theory47,48 on 32–34, the deacetylated analogs of
29–31. Figure 6 shows the more stable conformations found for
the E and Z isomers, the former being more stable (Table 3).
the plane containing the acyl moiety is approximately orthogonal
to the mean plane of the pyranose ring.52
3. Conclusion
The present work constitutes the first detailed study on the
Schiff bases formed by reaction of D-glucosamine with aliphatic ke-
tones, a fact that contrasts with chiral imines derived from amino-
sugars and aldehydes which have been successfully employed in
asymmetric transformations.
Previous syntheses of the title compounds, reported several
decades ago, have been thoroughly reinvestigated, often with the
help of the related model compounds. Formation of imines can
be monitored by analytical and spectroscopic techniques. With
non-symmetrical ketones, the formation of E and Z diastereomers
is possible, although the former stereochemistry is prevalent. This
observation is consistent with NOE experiments and DFT calcula-
tions of conformational stability.
Moreover, all data support a preferential disposition for the imi-
no group in which the lone pair on the nitrogen atom is parallel to
the axial substituents of the glucopyranose unit. Contrary to the
previous arguments, the origin of this conformational feature lies
in steric rather than stereoelectronic effects. Our rationale also
supports the strong deshielding found experimentally for the H-2
4.3
9.1
3.9
6.7
H2
H4
H2
HOCH2
HO
HO
2.7
CH2OAc
4.6
O
H
3.9
O
H
AcO
AcO
OH
H
OAc
H
N
N
OMe
OMe
14
35
resonance in D-glucosamine imines.
Figure 4. NOEs measured in compounds 14 and 35.

28
E. M. S. Pérez et al. / Carbohydrate Research 345 (2010) 23–32
32E
32Z
33E
34E
33Z
34Z
Figure 5. Stable conformations (at the B3LYP/6-31G* level) calculated for the E and Z isomers of 32–34.
spectra were recorded on a Bruker Avance 400 instrument at 400
Table 3
Relative stabilitya,b for the E and Z isomers of 32–34
and 100 MHz, respectively, in different solvent systems. Assign-
ments were confirmed by homo- and hetero-nuclear double-reso-
nance and DEPT (distortionless enhancement by polarization
transfer). TMS was used as the internal standard (d = 0.00 ppm)
and all J values are given in hertz. Microanalyses were determined
with a Leco 932 analyser at the University of Extremadura (Spain).
High-resolution mass spectra (chemical ionization) were recorded
with a Micromass Autospec spectrometer by the ‘Servicio de Espe-
ctrometría de Masas’ of the University of Sevilla (Spain).
Compound
EE
EZ
D
Ec
32
33
34
ꢁ516640.292
ꢁ541309.267
ꢁ565970.720
ꢁ516638.006
ꢁ541308.174
ꢁ565977.493
2.29
1.09
6.77
At B3LYP/6-31G*.
a
b
In kcal molꢁ1
.
c DE = Ez ꢁ EE.
4.2. 3,4,6-Tri-O-acetyl-2-amino-2-deoxy-b-D-glucopyrano-
sylazide (10)
4. Experimental
4.1. General methods
To a suspension of AgN3 in chloroform was added a solution of 9
(4.51 g, 10.90 mmol) in ethanol-free chloroform (40.0 mL). The
mixture was refluxed under stirring at 60–70 °C. Then, it was fil-
tered to eliminate the salts. Finally, it was evaporated to dryness
All solvents were purchased from commercial sources and were
used as received unless otherwise stated. Melting points were
determined with Gallenkamp and Electrothermal apparatus and
are uncorrected. Optical rotations were measured at 20 2 °C with
a Perkin–Elmer 241 polarimeter. IR spectra were recorded in the
range 4000–600 cmꢁ1 with FT-IR THERMO spectrophotometer. So-
lid samples were recorded on KBr (Merck) pellets. 1H and 13C NMR
and the obtained solid was recrystallized from EtOH (1.97 g,
25
578
55%); mp 124–126 °C (lit.35 mp 123 °C); ½a D25
ꢂ
ꢁ14.8; ½
aꢂ
ꢁ16.0
25
546
25
436
25
578
25
546
½aꢂ
ꢁ17.8; ½
aꢂ
ꢁ30.0 (c 0.5, dry acetone); ½
a
ꢂ
ꢁ18.8 ½ ꢂ
a
ꢁ19.0 (c 0.5, CHCl3); IR (KBr) mmax 3375, 3326 (NH2), 2964, 2855
H
R
AcOCH2
R2
O
O
N
R1
AcO
AcOCH2
AcO
N
R1
OAc
AcO
AcO
H
R
A
B
Figure 6. Preferential conformation of sugar imines derived from aldehydes (R = H) and ketones (R = R1 = alkyl).

E. M. S. Pérez et al. / Carbohydrate Research 345 (2010) 23–32
29
(CH3), 2112 (N3), 1758 (C@O), 1238 (C–O–C), 1104, 1058, 1041 (C–
O) cmꢁ1 1H NMR (400 MHz, Me2CO-d6) d 5.02 (t, 1H, J3,4 = J2,3
2H, H-arom), 6.92 (d, 2H, J 8.8 Hz, H-arom), 5.38 (t, 1H, J3,4 = J2,3
9.6 Hz, H-3), 5.12 (t, 1H, J3,4 = J4,5 9.8 Hz, H-4), 5.04 (d, 1H, J1,2
;
0
9.8 Hz, H-3), 4.93 (t, 1H, J4,5 = J3,4 9.6 Hz, H-4), 4.77 (d, 1H, J1,2
8.3 Hz, H-1), 4.37 (dd, 1H, J5,6 5.0 Hz, J6,6 12.4 Hz, H-6), 4.19 (dd,
1H, J5,6 2.4 Hz, J6,6 12.4 Hz, H-60), 3.92 (ddd, 1H, J4,5 10.1 Hz, J5,6
0
0
0
8.8 Hz, H-1), 4.25 (dd, 1H, J5,6 5.2 Hz, J6,6 12.4 Hz, H-6), 4.10 (dd,
1H, J5,6 2.2 Hz, J6,6 12.2 Hz, H-60), 3.96 (ddd, 1H, J4,5 10.0 Hz, J5,6
4.8 Hz, J5,6 2.4 Hz, H-5), 3.85 (s, 3H, OCH3), 3.25 (t, 1H, J1,2 ꢃ J2,3
0
0
0
0
4.7 Hz, J5,6 2.2 Hz, H-5), 2.71 (t, 1H, J1,2 ꢃ J2,3 9.4 Hz, H-2), 2.01,
9.2 Hz, H-2), 2.13, 2.04, 1.88 (s, 3 ꢄ 3H, CH3). 13C NMR (100 MHz,
CDCl3): 170.65, 169.75, 169.53 (C@O), 164.80 (N@C), 162.29,
130.32, 128.07, 114.03 (C-arom), 89.56 (C-1), 73.94 (C-2), 73.69
(C-5), 73.12 (C-3), 67.96 (C-4), 61.96 (C-6), 55.38 (OCH3), 20.74,
20.62, 20.47 (CH3).
2.00, 1.98 (s, 3 ꢄ 3H, CH3); 13C NMR (100 MHz, Me2CO-d6) d
170.87, 170.26, 169.83 (4C@O), 92.44 (C-1), 56.95 (C-2), 75.82
(C-5), 74.54 (C-3), 65.05 (C-4), 62.87 (C-6), 20.80, 20.66, 20.55
(CH3); 1H NMR (400 MHz, CDCl3) d 5.03 (t, 1H, J3,4 = J2,3 9.4 Hz, H-
3), 4.96 (t, 1H, J4,5 = J3,4 9.6 Hz, H-4), 4.54 (d, 1H, J1,2 8.8 Hz, H-1),
0
4.30 (dd, 1H, J5,6 4.8 Hz, J6,6 12.4 Hz, H-6), 4.14 (dd, 1H, J5,6
4.6. 3,4,6-Tri-O-acetyl-2-deoxy-2-(2-hydroxybenzylidenami-
no)-b-D-glucopyranosylazide (13)
´
2.4 Hz, J6,6 12.4 Hz, H-60), 3.78 (ddd, 1H, J4,5 9.6 Hz, J5,6 4.8 Hz,
0
0
J5,6 2.4 Hz, H-5), 2.82 (t, 1H, J1,2 ꢃ J2,3 9.4 Hz, H-2), 2.10, 2.08,
2.03 (s, 3 ꢄ 3H, CH3). 13C NMR (100 MHz, CDCl3): 170.64, 169.62
(3C@O), 91.89 (C-1), 75.17 (C-5), 73.94 (C-3), 68.30 (C-4), 61.98
(C-6), 55.82 (C-2), 20.75, 20.73, 20.62 (CH3).
This compound was synthesized following the recipe for com-
pound 12 (0.024 g, 56%); Mp 88–90 °C; [Lit.35 mp 95 °C]; ½a D24
ꢂ
24
578
24
546
24
436
ꢁ6.0; ½
aꢂ
ꢁ6.4; ½
aꢂ
ꢁ7.4; ½
a
ꢂ
ꢁ15.6 (c 0.5, CHCl3); IR (KBr)
mmax 2118 (N3), 1753, 1742 (C@O), 1629 (C@N), 1578 (arom),
1279, 1239 (C–O–C, ester), 1040 cmꢁ1 (C–O); 1H NMR (400 MHz,
CDCl3) d 12.09 (s, 1H, OH-arom), 8.33 (s, 1H, N@CH), 7.37 (t, 1H,
H-arom), 7.31 (d, 1H, H-arom), 6.97 (t, 1H, H-arom), 6.92 (t, 1H,
H-arom), 5.42 (t, 1H, J3,4 = J2,3 9.8 Hz, H-3), 5.13 (t, 1H, J3,4 = J4,5
9.8 Hz, H-4), 5.00 (d, 1H, J1,2 8.4 Hz, H-1), 4.37 (dd, 1H, J5,6 4.8 Hz,
4.3. 3,4,6-Tri-O-acetyl-2-deoxy-2-isopropylidenamino-b-d-
glucopyranosylazide (3)
A solution of 10 (0.50 g, 1.51 mmol) in dry acetone (25.0 mL) was
kept for 40 h at room temperature. Then, the solvent was evaporated
and the process was repeated, another solution in dry acetone
(25.0 mL) was prepared and was kept for 40 h. After this, the solvent
was evaporated and the residue was dried in vacuum (0.54 g, 97%);
J6,6 12.4 Hz, H-6), 4.19 (dd, 1H, J5,6 2.4 Hz, J6,6 12.4 Hz, H-60),
0
0
0
0
3.95 (ddd, 1H, J4,5 10.0 Hz, J5,6 4.8 Hz, J5,6 1.6 Hz, H-5), 3.26 (t,
1H, J1,2 ꢃ J2,3 9.0 Hz, H-2), 2.12, 2.05, 1.92 (s, 3 ꢄ 3H, CH3). 13C
NMR (100 MHz, CDCl3): 170.72, 170.59, 169.68, 169.50 (C@O),
169.41 (N@C), 160.86, 133.50, 132.17, 119.04, 118.07, 117.28 (C-
arom), 89.13 (C-1), 74.00 (C-2), 73.06 (C-5), 72.48 (C-3), 67.78 (C-
4), 61.81 (C-6), 20.83, 20.71, 20.59, 20.44 (CH3).
25
578
25
546
25
436
Mp 137–139 °C; ½a D25
ꢂ
ꢁ51.2; ½
aꢂ
ꢁ66.6; ½
aꢂ
ꢁ63.2; ½
a
ꢂ
ꢁ47.8 (c
0.5, CHCl3); IR (KBr) mmax 2114 (N3, azide), 1747 (C@O, ester), 1668
(C@N), 1240 (C–O–C, ester), 1106, 1065, 1032 cmꢁ1 (C–O); 1H
NMR (400 MHz, CDCl3) d 5.26 (t, 1H, J3,4 = J2,3 9.6 Hz, H-3), 5.11 (t,
1H, J3,4 = J4,5 9.8 Hz, H-4), 4.93 (d, 1H, J1,2 8.4 Hz, H-1), 4.37 (dd, 1H,
0
0
0
J5,6 4.8 Hz, J6,6 12.4 Hz, H-6), 4.18 (dd, 1H, J5,6 2.0 Hz, J6,6 12.4 Hz,
4.7. 1,3,4,6-Tetra-O-acetyl-2-amino-2-deoxy-b-D-glucopyranose
(18)
H-60), 3.88 (ddd, 1H, J4,5 10.0 Hz, J5,6 4.8 Hz, J5,6 2.0 Hz, H-5), 3.57
0
(t, 1H, J1,2 8.8 Hz, J2,3 9.6 Hz, H-2), 2.12, 2.05, 1.97, 1.94 (s, 5 ꢄ 3H,
CH3). 13C NMR (100 MHz, CDCl3): 172.87 (C@N), 170.87, 170.26,
169.83 (4C@O), 90.22 (C-1), 73.91 (C-3), 73.79 (C-5), 68.05 (C-4),
64.14 (C-2), 61.87 (C-6), 20.65, 20.53 (CH3). Anal Calcd for
C15H22N4O7: C, 48.64; H, 5.99; N, 15.13. Found: C, 48.33; H, 6.05;
N, 15.01. HRMS-FAB calcd for C15H22N4O7[M+Na]+: 393.1386;
found: 393.1397.
To compound 16 (1.0 g, 2.61 mmol) were added water (10 mL)
and CH2Cl2 and the mixture was treated with NaHCO3 (0.2 g). Then,
the aqueous phase was extracted three times more with 10, 5, and
3 mL of CH2Cl2. Finally, it was dried (MgSO4) and evaporated to
dryness (0.6 g, 66%); mp 141 °C [Lit.17 mp 143 °C, [
a]D +25.9° (chlo-
25
25
25
roform)]; ½a 2D5
ꢂ
+20.0; ½
a
m
ꢂ
+20.8; ½
aꢂ
+24.0; ½
aꢂ
+42.2 (c 0.5,
436
578
546
dry acetone); IR (KBr)
3000–2597 NH3þ, 2920 (OCH3), 1755,
max
4.4. Spectroscopic data of 3,4,6-tri-O-acetyl-2-deoxy-2-hexadeu-
1738 (C@O), 1242, 1212 (C–O–C, ester), 1072, 1031, 1016 (C–O)
terio-isopropyliden-amino-b-D-glucopyranosylazide (11)
cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 5.47 (d, 1H, J1,2 8,4 Hz, H-1),
0
5.04 (m, 2H, H-3 and H-4), 4.34 (dd, 1H, J6,6 12.4 Hz, J5,6 4.4 Hz,
1H NMR (400 MHz, Me2CO-d6) d 5.21 (t, 1H, J3,4 = J2,3 9.8 Hz, H-3),
5.03 (t, 1H, J3,4 = J4,5 8.6 Hz, H-4), 5.06 (d, 1H, J1,2 7.2 Hz, H-1), 4.29
H-6), 4.09 (dd, 1H, J6,6 12.4 Hz, J5,6 2.0 Hz, H-60), 3.82 (ddd, 1H,
0
0
0
J4,5 9.6 Hz, J5,6 4.4 Hz, J5,6 2.5 Hz, H-5), 3.04 (t, 1H, J1,2 8,4 Hz, H-
2), 2.19, 2.11, 2.09, 2.04 (4 ꢄ 3H, s, CH3), 1.22 (2H, br s, NH2); 13C
NMR (100 MHz, CDCl3) d 170.66, 169.63, 169.69, 169.20 (4C@O),
95.26 (C-1), 75.11 (C-5), 72.71 (C-3), 68.22 (C-4), 61.77 (C-6),
55.06 (C-2), 20.97, 20.78, 20.65 (CH3); 1H NMR (400 MHz,
Me2CO-d6) d 5.59 (d, 1H, J1,2 8.4 Hz, H-1), 5.10 (t, 1H, J2,3 = J3,4
9.8 Hz, H-3), 4.96 (t, 1H, J3,4 = J4,5 9.6 Hz, H-4), 4.24 (dd, 1H, J5,6
0
0
0
(dd, 1H, J5,6 5.2 Hz, J6,6 12.4 Hz, H-6), 4.14 (dd, 1H, J5,6 2.4 Hz, J6,6
12.4 Hz, H-60), 4.08 (ddd, 1H, J4,5 10.0 Hz, J5,6 5.4 Hz, J5,6 2.2 Hz, H-
5), 3.59 (t, 1H, J1,2 8.6 Hz, J2,3 9.8 Hz, H-2), 2.02, 1.97, 1.91 (s,
5 ꢄ 3H, CH3). 13C NMR (100 MHz, Me2CO-d6): 172.48 (C@N),
170.80. 170.29, 169.83 (4C@O), 90.80 (C-1), 74.54 (C-3), 74.54 (C-
5), 69.24 (C-4), 65.05 (C-2), 62.87 (C-6), 20.65, 20.53 (CH3).
0
0
0
4.8 Hz, J6,6 12.4 Hz, H-6), 4.06 (dd, 1H, J5,6 2.4 Hz, J6,6 12.4 Hz, H-
0
4.5. 3,4,6-Tri-O-acetyl-2-deoxy-2-(4-methoxybenzylidenami-
60), 3.97 (ddd, 1H, J4,5 10.0 Hz, J5,6 2.4 Hz, J5,6 4.8 Hz, H-5), 2.90
no)-b-
D
-glucopyranosyl-azide (12)
(dd, 1H, J1,2 8.6 Hz, J2,3 10.4 Hz, H-2), 2.12, 2.02, 2.01, 1.99 (s,
4 ꢄ 3H, CH3), 1.57 (br s, 1H, NH2) ppm; 13C NMR (100 MHz,
Me2CO-d6): 169.87, 169.81, 169.27, 168.86 (4C@O), 95.23 (C-1),
74.86 (C-5), 72.28 (C-3), 68.59 (C-4), 61.88 (C-6), 55.50 (C-2),
19.95, 19.92, 19.80, 19.76 (CH3).
To a solution of 10 (0.033 g, 0.1 mmol) in MeOH (1 mL) was
added a solution of 4-methoxybenzaldehyde (0.012 mL, 0.1 mmol)
in MeOH (1 mL). The solution was stirred until a solid appeared,
then was maintained in the refrigerator for a few hours. The solid
was filtered, washed with a cold methanol and the product was
recrystallized from MeOH (0.04 g, 90%). Mp 134–136 °C; [Lit.35
4.8. 1,3,4,6-Tetra-O-acetyl-2-amino-2-deoxy-a-D-glucopyranose
(19)
mp 134 °C]; ½a 2D3
ꢂ
+34.0; ½
aꢂ
+36.8; ½
a
ꢂ
+44.0; ½
aꢂ
+109.4 (c
23
23
546
23
436
578
0.5, CHCl3); IR (KBr) mmax 2361 (N3), 1749 (C@O), 1639 (C@N),
1604, 1513 (arom), 1240 (C–O–C, ester), 1037 cmꢁ1 (C–O); 1H
NMR (400 MHz, CDCl3) d 8.16 (s, 1H, N@CH), 7.67 (d, J 8.8 Hz,
To compound 17 (1.0 g, 2.34 mmol) was added water (10 mL)
and CH2Cl2 (10 mL), the mixture was treated with NaHCO3
(0.2 g). Then, the organic phase was separated and the aqueous

30
E. M. S. Pérez et al. / Carbohydrate Research 345 (2010) 23–32
phase was extracted three times more with 10, 5, and 3 mL of
CH2Cl2. Finally, it was dried and evaporated to dryness (0.7 g,
the solvent was evaporated and another 25.0 mL of dry Me2CO
was added. After three days, the solvent was evaporated and the
24
24
24
26
26
66%); Mp 119–121 °C; ½
aꢂ
+133.2; ½
a
D
ꢂ
+126.4; ½
a
ꢂ
+95.2 (c
residue was dried in vacuum. ½a D26
ꢂ
+80.2; ½
a
ꢂ
+84.4; ½ ꢂ
a
578
546
436
578
546
26
436
0.5, CHCl3); [Lit.32 mp 118–9 °C; [
a
]
+145.5° (c 1, CHCl3)]; IR
+95.1; ½
a
ꢂ
+157.3 (c 0.5, dry Me2CO). IR (KBr) mmax 2980, 2904
(KBr)
(C@O), 1600 (NH2), 1256, 1234 (C–O–C), 1110, 1074, 1040, 1020
(C–O) cmꢁ1 1H NMR (400 MHz, CDCl3) d 6.20 (d, 1H, J1,2 3.6 Hz,
m
max) 3380, 3293 (NH2), 2992, 2910 (CH3), 1753, 1736
(CH3), 1753 (C@O), 1663 (C@N), 1224 (C–O–C, ester), 1069, 1040
(C–O) cmꢁ1 1H NMR (400 MHz, CDCl3) d 6.07 (d, 1H, J1,2 3.6 Hz,
.
;
H-1), 5.54 (t, 1H, J3,4 = J2,3 9.8 Hz, H-3), 5.15 (t, 1H, J3,4 = J4,5
0
H-1), 5.16 (d, 1H, J3,4 = J4,5 10.0 Hz, H-4), 5.01 (dd, 1H, J2,3 = J3,4
10.2 Hz, H-4), 4.35 (dd, 1H, J5,6 3.8 Hz, J6,6 12.2 Hz, H-6), 4.22 (m,
0
9.7 Hz, H-3), 4.29 (dd, 1H, J6,5 3.8 Hz, J6,6 12.2 Hz, H-6), 4.06 (m,
1H, H-5), 4.08 (m, 1H, H-60), 3.89 (dd, 1H, J1,2 3.6 Hz, J2,3 10.0 Hz,
H-2), 2.18, 2.09, 2.03, 2.00, 1.97, 1.95 (s, 6 ꢄ 3H, CH3) ppm.
2H, H-5, H-60), 3.13 (dd, 1H, J1,2 3.6 Hz, J2,3 10.4 Hz, H-2), 2.19 (s,
3H, OCH3), 2.10, 2.08, 2.04 (m, 3 ꢄ 3H, OCH3) ppm; 13C NMR
(100 MHz, CDCl3) d 170.91, 170.58, 169.52, 169.02 (C@O, acetates),
92.90 (C-1), 73.99 (C-5), 69.69 (C-3), 68.17 (C-4), 61.72 (C-6), 53.44
(C-2), 20.86, 20.79, 20.65, 20.58 (OAc) ppm; 1H NMR (400 MHz,
acetone-d6) d 6.08 (d, 1H, J1,2 3.6 Hz, H-1), 5.13 (d, 1H, J3,4 = J4,5
10.0 Hz, H-4), 5.00 (t, 1H, J2,3 = J3,4 9.8 Hz, H-3), 4.21 (dd, 1H, J6,5
4.12. Spectroscopic data of 3,4,6-tri-O-acetyl-2-deoxy-2-
hexadeuterio-isopropyliden-amino-a-D-glucopyranose (21)
1
H NMR (400 MHz, Me2CO-d6) d 6.01 (d, 1H, J1,2 3.6 Hz, H-1),
5.47 (t, 1H, J2,3 = J3,4 = 9.6 Hz, H-3), 5.12 (t, 1H, J3,4 = J4,5 = 9.6 Hz,
0
0
0
4.4 Hz, J6,6 12.0 Hz, H-6), 4.11 (ddd, 1H, J4,5 10.0 Hz, J5,6 4.4 Hz,
H-4), 4.24 (m, 1H, H-6, H-5), 4.05 (dd, 1H, J6,6 12.0 Hz, J5,6
J5,6 2.4 Hz, H-5), 4.01 (dd, 1H, J5,6 2.4 Hz, J6,6 12.4 Hz, H-60), 3.06
(dd, 1H, J1,2 3.6 Hz, J2,3 10.4 Hz, H-2), 2.19, 2.07, 2.03, 2.00 (s,
4 ꢄ 3H, OCH3) ppm; 13C NMR (100 MHz, Me2CO-d6) d 170.13,
169.80, 169.14, 169.00 (C@O, acetates), 92.88 (C-1), 73.71 (C-5),
69.68 (C-3), 68.47 (C-4), 61.82 (C-6), 53.73 (C-2), 19.95, 19.78,
19.74 (OAc) ppm.
1.2 Hz, H-60), 3.98 (dd, 1H, J1,2 3.6 Hz, J2,3 10.0 Hz, H-2), 2.14,
2.07, 2.06, 2.05, 2.03, 1.92 (s, 6 ꢄ 3H, CH3) ppm. 13C NMR
(100 MHz, Me2CO-d6): 171.72 (N@C), 169.78, 169.27, 169.06,
168.64 (C@O), 91.05 (C-1), 71.83 (C-3), 70.03 (C-5), 68.58 (C-4),
61.94 (C-6), 61.49 (C-2), 19.97, 19.79, 19.76 (4C, CH3) ppm.
0
0
0
4.13. 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-(4-methoxybenzyl-
4.9. 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-isopropylidenamino-b-
D
-
idene)amino–D-glucopyranose (24)
glucopyranose (22)
To a suspension of 17 (1.4 g, 3.0 mmol) in EtOH 96% (14 mL)
was added sodium acetate trihydrate (0.41 g, 3.0 mmol) dissolved
in a mixture of water (2 mL) and pyridine (0.8 mL). Then, the 4-
methoxybenzaldehyde was added (3.0 mmol) the mixture was
heated for 2 min in a bath of boiling water. The solution was fil-
tered to eliminate the impurities and kept to room temperature.
When the solution was cooled the product crystallized. The solu-
tion was kept at room temperature for an hour and then main-
tained in the refrigerator. Finally, it was filtered, washed with a
cooled mixture of EtOH–H2O 50% and was dried in vacuum
Compound 18 (0.54 g, 1.55 mmol) was dissolved in dry Me2CO
(25.0 mL), and was kept at room temperature for 40 h. Then, it
was evaporated to dryness and another 25.0 mL of dry Me2CO
was added. After 40 h the solvent was evaporated and the residue
was dried in vacuum (0.42 g, 70%); mp 129–130 °C; ½a D28
ꢂ
+7.2;
+11.6;
28
28
28
436
½
½
a
a
ꢂ
ꢂ
+7.4; ½
a
ꢂ
+8.8; ½
a
ꢂ
+17.6 (c 0.5, dry Me2CO); ½a D28
ꢂ
578
546
28
28
546
28
436
+13.0; ½
aꢂ
+14.2; ½
a
ꢂ
+28.0 (c 0.5, CHCl3); IR (KBr) mmax
578
2952, 2907 (CH3), 1756, 1732 (C@O), 1663 (C@N), 1242 (C–O–C,
ester), 1100, 1077, 1046 (C–O) cmꢁ1 1H NMR (400 MHz, CDCl3) d
;
5.78 (d, 1H, J1,2 8.4 Hz, H-1), 5.31 (t, 1H, J3,4 = J2,3 9.4 Hz, H-3),
(0.44 g, 32%); Recrystallized from EtOH had mp 181–183 °C; ½a D24
ꢂ
24
578
24
546
24
436
24
365
0
5.12 (t, 1H, J3,4 = J4,5 9.8 Hz, H-4), 4.37 (dd, 1H, J5,6 4.4 Hz, J6,6
+104.2; ½
a
ꢂ
+108.8; ½
aꢂ
+126.0, ½
a
ꢂ
+240.6; ½
a
ꢂ
+474.2 (c
12.4 Hz, H-6), 4.10 (dd, 1H, J5,6 2.2 Hz, J6,6 12.4 Hz, H-60), 3.92
0.5, CHCl3); IR (KBr) mmax 2857 (C–O, OCH3), 1746 (C@O), 1643
(C@N), 1617, 1514 (arom), 1250 (C–O–C, ester), 1154, 1030 (C–O)
and 841 cmꢁ1 (arom); 1H NMR (400 MHz, CDCl3) d 8.21 (s, 1H,
CH@), 7.62 (d, 2H, arom), 6.90 (d, 2H, arom), 6.22 (d, 1H, J1,2
3.6 Hz, H-1), 5.60 (t, 1H, J3,4 = J4,5 9.8 Hz, H-4), 5.18 (t, 1H,
J2,3 = J3,4 9.8 Hz, H-3), 4.35 (dd, 1H, J5,6 4.2 Hz, J6,6´ 12.3 Hz, H-6),
0
0
0
(ddd, 1H, J4,5 10.2 Hz, J5,6 4.4 Hz, J5,6 2.4 Hz, H-5), 3.78 (dd, 1H,
J1,2 8.4 Hz, J2,3 9.8 Hz, H-2), 2.09, 2.06, 2.02, 1.99, 1.94, 1.92 (s,
6 ꢄ 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3): 172.22 (N@C),
170.68, 169.97, 169.44, 168.61 (C@O), 93.91 (C-1), 74.17 (C-3),
72.64 (C-5), 68.16 (C-4), 63.42 (C-2), 61.78 (C-6), 29.51 (2C, CH3,
isopropyl), 20.88, 20.78, 20.70, 20.61, 19.36 (5C, CH3). Anal. Calcd
for C17H25NO9: C, 52.71; H, 6.50; N, 3.62. Found: C, 52.41; H,
6.30; N, 3.71. HRMS-FAB calcd for C17H25N4O9[M+Na]+:
410.1419; found: 410.1427.
0
4.25 (ddd, 1H, J4,5 10.2 Hz, J5,6 4.0 Hz, J5,6 2.1 Hz, H-5), 4.12 (dd,
1H, J5,6 2.1 Hz, J6,6 12.3 Hz, H-60), 3.84 (s, 3H, OCH3), 3.66 (dd,
1H,J1,2 3.6 Hz, J2,3 10.1 Hz, H-2), 2.21, 2.10, 2.05, 1.88 (s, 4 ꢄ 3H,
CH3); 13C NMR (100 MHz, CDCl3): 170.64 (C@O), 169.81 (2C@ O),
168.96 (C@O), 164.28 (CH@N), 162.23 (C-arom), 130.20 (2C-arom),
128.38 (C-arom), 113.97 (2C-arom), 91.80 (C-1), 71.14 (C-2), 70.87
(C-5), 70.05 (C-3), 68.30 (C-4), 61.90 (C-6), 55.34 (OCH3), 21.00,
20.70, 20.65, 20.55 (CH3). Anal. Calcd for C22H27O10N: C, 56.77; H,
5.85; N, 3.01. Found: C, 56.42; H, 5.76; N, 3.13.
0
0
4.10. Spectroscopic data of 3,4,6-tri-O-acetyl-2-deoxy-2-
hexadeuterio-isopropyliden-amino-b-D-glucopyranose (20)
1H NMR (400 MHz, Me2CO-d6) d 5.81 (d, 1H, J1,2 8.4 Hz, H-1), 5.30
(t, 1H, J3,4 = J2,3 9.6 Hz, H-3), 5.03 (t, 1H, J3,4 = J4,5 9.6 Hz, H-4), 4.31
0
0
(dd, 1H, J5,6 5.0 Hz, J6,6 13.0 Hz, H-6), 4.09 (d, 1H, J6,6 10.8 Hz, H-
60), 4.08 (m, 1H, H-5), 3.77 (dd, 1H, J1,2 8.0 Hz, J1,2 9.6 Hz, H-2),
2.03, 2.02, 1.99, 1.96, 1.93, 1.92 (s, 6 ꢄ 3H, CH3) ppm; 13C NMR
(100 MHz, Me2CO-d6): 171.28 (N@C), 169.80, 169.34, 168.84,
168.34 (C@O), 93.76 (C-1), 73.77 (C-3), 72.41 (C-5), 68.40 (C-4),
63.55 (C-2), 61.86 (C-6), 19.81, 19.71, 19.69, 18.28 (4C, CH3).
4.14. 3,4,6-Tri-O-acetyl-2-deoxy-2-cyclopentylidenamino-b-D-
glucopyranosylazide (28)
A
solution of 10 (0.15 g, 0.45 mmol) in cyclopentanone
(10.0 mL) was kept for 3 days at room temperature. Then, the sol-
vent was evaporated and a syrup was obtained (0.16 g, 27%); IR
(KBr) mmax 2964, 2920 (CH3), 2117 (N3), 1747 (C@O), 1685 (C@N),
4.11. 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-isopropylidenamino-
a
-
1241 (C–O–C), 1065, 1038 (C–O) cmꢁ1 1H NMR (400 MHz, CDCl3)
;
D-glucopyranose (23)
d 5.32 (t, 1H, J2,3 = J3,4 9.6 Hz, H-3), 5.09 (t, 1H, J3,4 = J4,5 9.6 Hz, H-4),
0
5.03 (d, 1H, J1,2 8.8 Hz, H-1), 4.35 (dd, 1H, J5,6 4.4 Hz, J6,6 12.4 Hz, H-
0
0
Compound 19 (0.50 g, 1.44 mmol) was dissolved in dry Me2CO
(25.0 mL), and was kept for 40 h at room temperature. After this,
6), 4.16 (dd, 1H, J5,6 2.0 Hz, J6,6 12.4 Hz, H-60), 3.90 (ddd, 1H, J4,5
0
10.0 Hz, J5,6 4.8 Hz, J5,6 2.0 Hz, H-5), 3.40 (t, 1H, J1,2 = J2,3 9.6 Hz,

E. M. S. Pérez et al. / Carbohydrate Research 345 (2010) 23–32
31
H-2), 2.45 (m, 2H, CH2), 2.33 (m, 2H, CH2), 1.95 (m, 2H, CH2), 1.77
References
(m, 2H, CH2), 2.11, 2.03, 1.96 (s, 3 ꢄ 3H, CH3) ppm; 13C NMR
(100 MHz, CDCl3): 187.44 (C@N), 170.69, 169.87, 169.38 (3C,
C@O), 89.99 (C-1), 73.94 (C-3), 73.87 (C-5), 69.18 (C-4), 68.84 (C-
2), 62.00 (C-6), 36.58 (CH2), 30.40 (CH2), 24.94 (CH2), 24.17
(CH2), 20.77, 20.68, 20.57 (3C, CH3). HRMS-FAB calcd for
C17H25N4O9[M+H]+: 397.1723; found: 397.1728.
1. Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic Chemistry, 3rd
ed.; Harper&Row: NY, 1987; pp 702–709.
2. Kunz, H. In Selectivities in Lewis Acid Promoted Reactions; Schinzer, D., Ed.;
Kluwer Academic: Dordrecht, 1989; pp 189–202.
3. (a) Kunz, H.; Sager, W. Angew. Chem., Int. Ed. Engl. 1987, 26, 557–559; (b) Kunz,
H.; Pfrengle, W.; Rück, K.; Sager, W. Synthesis 1991, 1039–1042.
4. (a) Kunz, H.; Pfrengle, W. J. Am. Chem. Soc. 1988, 110, 651–652; (b) Kunz, H.;
Pfrengle, W. Tetrahedron 1988, 44, 5487–5494.
5. (a) Kunz, H.; Schanzenbach, D. Angew. Chem., Int. Ed. Engl. 1989, 28, 1068–1969;
(b) Kunz, H.; Burgard, A.; Schanzenbach, D. Angew. Chem., Int. Ed. 1997, 36, 386–
387; (c) Allef, P.; Kunz, H. Tetrahedron: Asymmetry 2000, 11, 375–378.
6. Kunz, H.; Pfrengle, W. Angew. Chem., Int. Ed. Engl. 1989, 28, 1067–1068.
7. Pfrengle, W.; Kunz, H. J. Org. Chem. 1989, 54, 4261–4263.
8. Laschat, S.; Kunz, H. J. Org. Chem. 1991, 56, 5883–5889.
9. Georg, G. I.; Akgün, E.; Mashava, P. M.; Milstead, M.; Ping, H.; Wu, Z.; Velde, D.
V. Tetrahedron Lett. 1992, 33, 2111–2114.
10. Helferich, B.; Mitrowsky, A. Chem. Ber. 1952, 85, 1–8.
11. Kunz, H.; Sager, W.; Schanzenbach, D.; Decker, M. Liebigs Ann. Chem. 1991,
649–654.
12. Ross, G. F.; Herdwetck, E. H.; Ugi, I. Tetrahedron 2002, 58, 6127–6133.
13. Isbell, H. S.; Pigman, W. Adv. Carbohydr. Chem. Biochem. 1969, 24, 13–65.
14. Goodwin, J. F. Anal. Biochem. 1972, 48, 120–128.
15. Smiataczowa, H.; Maj, K.; Skurski, P. Eur. J. Org. Chem. 2001, 4269–4274.
16. (a) Irvine, J. C.; Hynd, A. J. Chem. Soc. 1913, 103, 41–56; (b) Irvine, J. C.; Earl, J. C.
J. Chem. Soc. 1922, 121, 2370–2376; (c) Irvine, J. C.; Earl, J. C. J. Chem. Soc. 1922,
121, 2376–2381.
4.15. (E)- 3,4,6-Tri-O-acetyl-2-deoxy-2-(1-methyl-1-
propyliden)amino-b-D-glucopyranosylazide (29)
A solution of 10 (0.15 g, 0.45 mmol) in 2-butanone (10.0 mL)
was kept for 4 days at room temperature. Then, the solvent was
evaporated and a white solid was obtained (0.18 g, 98%); Mp 97–
25
578
25
546
98 °C; ½a 2D5
ꢂ
ꢁ20.2; ½
aꢂ
ꢁ22.8; ½
aꢂ
ꢁ38.0 (c 0.5, chloroform);
IR (KBr) mmax 2947 (CH3), 2116 (N3), 1747 (C@O), 1662 (C@N),
1241 (C–O–C), 1070, 1035 (C–O) cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d 5.28 (t, 1H, J2,3 = J3,4 9.6 Hz, H-3), 5.11 (t, 1H, J3,4 = J4,5 9.8 Hz, H-4),
0
4.94 (d, 1H, J1,2 8.4 Hz, H-1), 4.35 (dd, 1H, J5,6 4.8 Hz, J6,6 12.4 Hz, H-
6), 4.17 (dd, 1H, J5,6 2.0 Hz, J6,6 12.4 Hz, H-60), 3.88 (ddd, 1H, J4,5
0
0
0
10.2 Hz, J5,6 4.8 Hz, J5,6 2.0 H z, H-5), 3.58 (dd, 1H, J1,2 8.8 Hz, J2,3
9.2 Hz, H-2), 2.27 (q, 2H, JCH2,CH3 7.4 Hz, CH2), 2.11, 2.04, 1.95,
1.92 (s, 4 ꢄ 3H, CH3), 1.06 (t, JCH2,CH3 7.8 Hz, 3H, CH3) ppm; 13C
NMR (100 MHz, CDCl3): 176.91 (C@N), 170.69, 168.88, 169.42
(3C, C@O), 90.46 (C-1), 73.97 (C-3), 73.93 (C-5), 68.11 (C-4),
64.23 (C-2), 62.02 (C-6), 35.92 (CH2), 20.80, 20.71, 20.54 (3C,
CH3), 10.92 (CH3).
17. Bergmann, M.; Zervas, L. Chem. Ber. 1931, 64, 975–980.
18. (a) Bertho, A.; Maier, J. Liebigs Ann. Chem. 1932, 495, 113–121; (b) Bertho, A.;
Maier, J. Liebigs Ann. Chem. 1932, 498, 50–61; (c) Bertho, A.; Maier, J. Z. Physiol.
Chem. 1933, 222, 139–147.
19. Morel, C. J. Helv. Chim. Acta 1961, 44, 403–412.
20. (a) Ávalos, M.; Babiano, R.; Cintas, P.; Jiménez, J. L.; Palacios, J. C.; Fuentes, J. J.
Chem. Soc., Perkin Trans. 1 1990, 495–501; (b) Ávalos, M.; Babiano, R.; Cintas, P.;
Jiménez, J. L.; Palacios, J. C.; Valencia, C. Tetrahedron 1993, 49, 2676–2690; (c)
Ávalos, M.; Babiano, R.; Cintas, P.; Higes, F. J.; Jiménez, J. L.; Palacios, J. C.;
Silvero, G. Tetrahedron: Asymmetry 1999, 10, 4071–4074.
21. Simanek, E. E.; Huang, D. H.; Pasternack, L.; Machajewski, T. D.; Seitz, O.; Millar,
D. S.; Dyson, H. J.; Wong, C. H. J. Am. Chem. Soc. 1998, 120, 11567–11575.
22. Medgyes, A.; Farkas, E.; Lipták, A.; Pozgay, V. Tetrahedron 1997, 53, 4159–4178.
23. Maley, F.; Lardy, H. A. J. Am. Chem. Soc. 1956, 78, 1393–1397.
24. Morel, C. J. Helv. Chim. Acta 1958, 41, 1501–1504.
4.16. (E)-3,4,6-Tri-O-acetyl-2-deoxy-2-(1,2-dimethyl-1-
propyliden)amino-b-D-glucopyranosylazide (30)
A solution of 10 (0.15 g, 0.30 mmol) in 3-methyl-2-butanone
(10.0 mL) was kept for 4 days at room temperature. Then, the sol-
vent was evaporated and a white solid was obtained (0.28 g, 47%);
25. Zervas, L.; Konstas, S. Chem. Ber. 1960, 93, 435–436.
24
578
24
546
24
436
Mp 65–68 °C; ½a 2D4
ꢂ
ꢁ22.4; ½
aꢂ
ꢁ22.6; ½
aꢂ
ꢁ25.6; ½
a
ꢂ
ꢁ43.2 (c
26. (a) Meyer zu Reckendorf, W.; Bonner, W. A. J. Org. Chem. 1961, 26, 4596–4599;
(b) Meyer zu Reckendorf, W.; Bonner, W. A. Chem. Ber. 1961, 94, 2431–2436.
27. Kiso, M.; Nishihori, K.; Hasegawa, A.; Okumura, H.; Azuma, I. Carbohydr. Res.
1981, 95, C5–C8.
28. Marra, A.; Sinaÿ, P. Carbohydr. Res. 1990, 200, 319–337.
29. For a revision on the use of imines as protecting groups during the total
syntheses of aminoglycosidic antibiotics, see: Umezawa, S. Adv. Carbohydr.
Chem. Biochem. 1974, 30, 111–225.
0.5, CHCl3); IR (KBr) mmax 2963, 2932 (CH3), 2118 (N3), 1747 (C@O),
1660 (C@N), 1242 (C–O–C, ester), 1111, 1071, 1033 (C–O) cmꢁ1; 1H
NMR (400 MHz, CDCl3) d 5.23 (d, 1H, J1,2 8.4 Hz, H-1), 5.21 (t, 1H,
J2,3 = J3,4 10.0 Hz, H-4), 4.96 (t, 1H, J3,4 = J4,5 9.8 Hz, H-3), 4.20 (dd,
0
0
1H,, J5,6 4.8 Hz, J6,6 12.0 Hz, H-6), 4.13 (m, 1H, J4,5 9.6 Hz, J5,6
2.0 Hz, H-5), 4.06 (dd, 1H, J5,6 2.0 Hz, J6,6 12.0 Hz, H-60), 3.61 (t,
1H, J1,2 = J2,3 9.0 Hz, H-2), 2.41 (m, 1H, JCH,CH3 6.8 Hz, CH), 2.04,
1.97, 1.90, 1.85 (s, 4 ꢄ 3H, CH3), 0.96 (d, 3H, JCH,CH3 6.8 Hz, CH3),
0.95 (d, 3H, JCH,CH3 6.8 Hz, CH3) ppm; 13C NMR (100 MHz, CDCl3):
179.13 (C@N), 170.53, 169.89, 169.41 (3C, C@O), 89.57 (C-1),
73.49 (C-3), 73.34 (C-5), 68.32 (C-4), 64.25 (C-2), 62.37 (C-6),
39.69 (CH), 21.04, 20.91, 20.69, 20.09, 19.91 (5C, CH3), 16.57
(CH3). HRMS-FAB calcd for C17H27N4O7 [M+H]+: 399.1873; found:
399.1880.
30. Wan, L.; Wang, Y.; Qian, S. J. Appl. Polym. Sci. 2002, 84, 29–34.
31. Wacker, O.; Fritz, H. Helv. Chim. Acta 1967, 50, 2481–2490.
32. Micheel, F.; van de Kamp, F. P.; Wulff, H. Chem. Ber. 1955, 88, 2011–2019.
33. Inouye, Y.; Onodera, K.; Kitaoka, S.; Ochiai, H. J. Am. Chem. Soc. 1957, 79, 4218–
4222.
34. Fodor, G.; Otvös, L. Chem. Ber. 1956, 89, 701–708.
35. Bertho, A.; Révész, A. Liebigs Ann. Chem. 1953, 581, 161–167.
36. Micheel, F.; Wulff, H. Chem. Ber. 1956, 89, 1521–1530.
37. (a) Kuzuhara, H.; Iwata, M.; Emoto, S. J. Am. Chem. Soc. 1977, 99, 4173–4175;
(b) Miyashita, K.; Miyabe, H.; Tai, K.; Iwaki, H.; Imanishi, T. Tetrahedron 2000,
56, 4691–4700.
38. de Almeida, M. V.; Le Hyaric, M.; Siqueira, L. J. A.; Pinto, L. D.; Valle, M. S.; Alves,
W. A. Molecules 2001, 6, 728–735.
0
0
39. Pintér, I.; Kovács, J.; Messmer, A. Carbohydr. Res. 1977, 53. 117–112.
40. Fodor, G.; Letourneau, F.; Mandava, N. Can. J. Chem. 1970, 48, 1465–1471.
41. Capon, B.; Labbé, C.; Rycroft, D. S. Can. J. Chem. 1979, 57, 2978–2980.
42. Wolfrom, M. L.; Shen Han, T. M. J. Org. Chem. 1961, 26, 2145–2146.
43. Naulet, M.; Filleux, M. L.; Martin, G. J.; Pornet, J. Org. Magn. Reson. 1975, 7, 326–
330.
44. Crystal data for compound 12 have been deposited with the Cambridge
Crystallographic Data Centre (CCDC-728626) and can be obtained, upon
request, from the Director, Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CBL 1EZ, UK.
5. Supplementary data
Complete crystallographic data for compound 12 have been
deposited with the Cambrigde Crystallographic Data Centre (CCDC
728626). Copies of this information may be obtained free of charge
from the Director, Cambrigde Crystallographic Data Centre, 12 Un-
ion Road, Cambridge CBL 1EZ, UK. (fax: +44 1223 336033, e-mail:
deposit@ccdc.cam.ac.uk or via: www.ccdc.cam.ac.uk).
45. Moggridge, R. C. G.; Neuberger, A. J. Chem. Soc. 1936, 745–750.
46. Ávalos, M.; Babiano, R.; Cintas, P.; Hursthouse, M. B.; Jiménez, J. L.; Light, M. E.;
Palacios, J. C.; Silvero, G. Tetrahedron 2005, 61, 7931–7944.
47. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, J. T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.
Acknowledgments
Financial support from the Junta de Extremadura (PRI08A032)
and the Ministry of Education and Science (CTQ2007-66641) is
gratefully acknowledged.

32
E. M. S. Pérez et al. / Carbohydrate Research 345 (2010) 23–32
J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. 50. Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry; Plenum Press: NY,
A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe,
M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
GAUSSIAN 03, Revision C.02, Gaussian, Inc.: Wallingford CT, 2004.
1977. pp 80–82.
51. Shimanouchi, T.; Abe, Y.; Kuchitsu, K. J. Mol. Struct. 1968, 2, 82–85.
52. (a) Ávalos, M.; Babiano, R.; Cintas, P.; Gómez-Carretero, A.; Jiménez, J. L.;
Lozano, M.; Ortiz, A. L.; Palacios, J. C.; Pinazo, A. Chem. Eur. J. 2008, 14, 5656–
5669; (b) Ávalos, M.; Babiano, R.; Cintas, P.; Hursthouse, M. B.; Jiménez, J. L.;
Light, M. E.; Palacios, J. C.; Pérez, E. M. S. Eur. J. Org. Chem. 2006, 657–671; (c)
Ávalos, M.; Babiano, R.; Barneto, J. L.; Bravo, J. L.; Cintas, P.; Jiménez, J. L.;
Palacios, J. C. J. Org. Chem. 2001, 66, 7275–7282; (d) Ávalos, M.; Babiano, R.;
Carretero, M. J.; Cintas, P.; Higes, F. J.; Jiménez, J. L.; Palacios, J. C. Tetrahedron
1998, 54, 615–618; (e) Ávalos, M.; Babiano, R.; Durán, C. J.; Jiménez, J. L.;
Palacios, J. C. J. Chem. Soc., Perkin 2 1992, 2205–2215.
48. (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652; (b) Lee, C.; Yang, W.; Parr, R.
G. Phys. Rev. B 1988, 37, 785–789.
49. Kwit, M.; Plutecka, A.; Rychlewska, U.; Gawzon´ ski, J.; Khlebnikov, A. F.;
Kozhushkov, S. I.; Rauch, K.; de Meijere, A. Chem. Eur. J. 2007, 13, 8688–8695.