Non-biaryl atropisomers derived from carbohydrates. Part 4: Absolute stereochemistry of carbohydrate-based imidazolidine-2-ones and 2-thiones with axial and central chirality

Article abstract of DOI:10.1016/j.tet.2005.06.018

NMR spectroscopy has proven to be an enabling methodology in elucidating the axial chirality of a series of non-biaryl atropisomers attached to a carbohydrate moiety, based on deshielding effects caused by the aromatic ring.

Full text of DOI:10.1016/j.tet.2005.06.018

Tetrahedron 61 (2005) 7945–7959
Non-biaryl atropisomers derived from carbohydrates.
Part 4: Absolute stereochemistry of carbohydrate-based
imidazolidine-2-ones and 2-thiones with axial and
central chirality*
a
Martın Avalos, Reyes Babiano, Pedro Cintas, Michael B. Hursthouse, Jose L. Jimenez,
a,
a
b
a
´
*
´
´
´
Mark E. Light,b Juan C. Palaciosa and Guadalupe Silveroa
a
´
´
Departamento de Quımica Organica, Universidad de Extremadura, E-06071 Badajoz, Spain
bDepartment of Chemistry, University of Southampton, Southampton SO17 1BJ, UK
Received 23 December 2004; revised 3 June 2005; accepted 7 June 2005
Available online 5 July 2005
Abstract—NMR spectroscopy has proven to be an enabling methodology in elucidating the axial chirality of a series of non-biaryl
atropisomers attached to a carbohydrate moiety, based on deshielding effects caused by the aromatic ring.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
correspond to the peaks of highest potential energy through
a 3608 rotation. There are two possible and unequally
populated isomeric transition states, in which one of the
substituents at the ortho position on the aromatic ring
interacts with the C]X function and this steric crowding is
largely responsible for the high barrier to rotation.
Molecular mechanics calculations predict that o,o0-
disubstitution will cause high enough barriers to rotation
(O23 kcal molK1) for isolation of atropisomers to occur.3
The peaks of higher potential energy were found at qZ30
and 2108, approximately1 (Fig. 1).
In the preceding paper,1 we reported the synthesis and
isolation of some carbohydrate-appended imidazolidine-2-
ones and -2-thiones (1–6) as well as imidazoline-2-thiones
(7 and 8) as room temperature stable atropisomers. Free
rotation around a single bond converts the M (aR) isomer
into its P (aS) counterpart and vice versa.2
Figure 1. Transition states for interconversion of P and M rotamers.
Such an interconversion takes place by rotation around the
N–C (aryl) single bond and the transition structures
In order to verify our theoretical predictions, we have
synthesized a series of derivatives featuring the above-
mentioned structural requirements, and establishing the
absolute stereochemistry of the isolated atropisomers by
means of NMR chemical shift correlations, some further
confirmed by single-crystal X-ray diffractometry.
* See Ref. 1.
Keywords: Atropisomerism; Carbohydrates; Imidazolidines; Molecular
mechanics; NMR spectroscopy.
*
Corresponding author. Tel.: C34 924 289 382; fax: C34 924 271 149;
e-mail: reyes@unex.es
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.018

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7946
2. Results and discussion
(22–24), although in the case of compounds 13 and 15,
pure a-anomers 19 and 21 were isolated, the latter being a
mixture of two atropisomers. Formation of 19 and 21 not
only involves O-deprotection of 13 and 15 to afford 16 and
18, respectively, but also an anomeric change. Their
glucopyranoid structures are supported by 13C NMR data,
in agreement with those of other ureidosugars.7 The
a-anomeric configuration is consistent with the small
value of J1,2 (3.6 Hz) (Scheme 2).
The protocol utilized in these syntheses has been previously
described.1 Thus, condensation of 1,3,4,6-tetra-O-acetyl-2-
amino-2-deoxy-b-D-glucopyranose4 (9) with 2-ethyl-6-
methylphenyl isocyanate (10), 2-isopropyl-6-methylphenyl
isocyanate (11) and 2-tert-butyl-6-methylphenyl isocyanate
(12), afforded the corresponding ureido derivatives 13–15
with good yields5 (Scheme 1).
The 5-hydroxyimidazolidine-2-one 22, arising from cycli-
zation of ureas 16 and 19, was also isolated as mixture of
rotamers, as evidenced by the two signal sets observed in its
1H and 13C NMR spectra. The chemical shift for C-5
(w84 ppm) rules out both an ureido derivative and a
bicyclic structure such as 1, (dC-1w90–92 ppm).7,8 The R
configuration at C-5, that is, the heterocyclic carbon bearing
the hydroxyl group, could be assigned on the basis of
the coupling constant J4,5w0–3 Hz.7,9 The two atropi-
somers were formed in a w1:1 ratio and crystallized with a
molecule of ethanol, as evidenced by their spectral data and
elemental analyses. The structure of compound 22 was
confirmed by preparing its per-O-acetyl derivative 25, as
mixture of rotamers, although leaving intact the initial
stereochemistry. The methylenic hydrogens on the ethyl
groups are diastereotopic and show complex 1H NMR
patterns.
Scheme 1.
1
The H NMR spectra for the ureido derivatives 14 and 15,
when registered at K30 8C, show four signal sets
corresponding to four atropisomers (Table 1). This fact
was also found in similar thioureido derivatives.1 These
experiments at variable temperature allowed us to calculate
the experimental barriers to rotation. Thus, the barrier for
compound 14 resulted to be 15.0 kcal molK1 (TcZ298 K,
DnZ28.96 Hz) while a value of 16.2 kcal molK1 (TcZ
328 K, DnZ50.77 Hz) was found for the ureido derivative
15.6
Treatment of the crude mixtures, generated by deacetylation
of 13–15, with hot aqueous acetic acid led to the
corresponding 1-aryl-(1,2-dideoxy-a-D-glucofurano)[2,1-
d]imidazolidine-2-ones (26–28). While 26 and 27 appeared
as mixtures of two rotational isomers, only the (M)-
atropisomer of 28 could be isolated. The structures of
these compounds are consistent with their elemental
analysis, as well as polarimetric and spectroscopic data
analogous to similar bicycles.1,7 The magnitudes of J1,2
Deacetylation at room temperature of compounds 13–15
gave anomeric mixtures of a and b ureido derivatives
(16–21) together with 5-hydroxyimidazolidine-2-ones
Table 1. Selected spectroscopic data and population for rotamers of 14 and 15a
14, Rotamers
15, Rotamers
a
b
c
d
a
b
c
d
NH
H-1
6.97
5.88
6.90
5.88
6.38
5.73
36.9
6.37
5.66
37.1
6.79
5.89
16.1
6.73
5.77
17.0
6.33
5.69
28.5
6.29
5.56
38.4
Populationsb
26.0c
a In CDCl3 at 258 K.
b In %.
c Combined population of rotamers a and b.
Scheme 2. (i) NH3–MeOH.

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7947
(O6.2 Hz) and J2,3 (w0 Hz) reveal the furanosic character
of the sugar with a cis fusion of both rings. As expected, 1H
and 13C NMR spectra for 26 and 27 showed duplicated
signals corresponding in each case to a mixture of two
atropisomers in w1:1 (P:M) ratio,2 which could not be
resolved.
with methanol, its rotamer 29P (RfZ0.5) underwent
deacetylation giving rise to pure 26P, while the other
rotamer (29M, RfZ0.6) remained unaffected. This curious
and unexpected result is not so surprising as the
deacetylating properties of silica gel in methanol have
been documented.11 The structures attributed to the
individual rotamers of 29 and 30 and 31M are equally
1
supported by their spectroscopic data. H and 13C NMR
spectra reveal that the heterocyclic nitrogen remains
unprotected. IR spectra for M and P rotamers of 29 show
absorptions at 3500–3000 cmK1 due to the presence of
water in the crystal lattice.12
The absolute configuration of 28M could be unambiguously
determined by single-crystal diffractrometry as depicted in
the ORTEP diagram with the crystallographic numbering10
(Fig. 2).
We next attempted isolation of the remaining rotamers via
their per-O-acetyl derivatives. Thus, treatment of atropiso-
meric mixtures of 26 or 27 with acetic anhydride and
pyridine at K20 8C provided high yields of 29 or 30,
respectively. In a similar way, acetylation of 28M led to
31M in pure form as this O-protection does not affect the
axial stereochemistry.
On the other hand, condensation of the O-protected
aminosugar 9 with 2-ethyl-6-methylphenyl isothiocyanate
(32) at room temperature afforded the thioureido derivative
33 (Scheme 3), although yields were invariably low. In an
attempt to improve this yield, the reaction was also carried
out under reflux but large amounts of 2-acetamido-2-deoxy-
1,3,4,6-tetra-O-acetyl-b-D-glucopyranose (34) were formed.
This substance was identified by comparison of its physical
and spectroscopic properties with an authentic sample.13
M and P atropisomers of 29 and 30 could be separated by
preparative thin-layer chromatography (using ethyl ether as
eluent). When silica gel was extracted with ethyl acetate
pure M and P rotamers of 29 and 30 were obtained.
However, when extraction of compound 29, was carried out
The structure assigned to 33 is supported by its elemental
analysis, spectral and polarimetric data. The room
Figure 2. X-ray diffraction structure for 28M.

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7948
Scheme 3. (i) CH2Cl2, 6 (ii) NH3–MeOH.
temperature 1H NMR spectrum showed two well-separated
signal sets of the corresponding atropisomers in w1:1 ratio.
Further treatment of 33 with ammonia in methanol at
room temperature provided the deacetylated derivative
5-hydroxyimidazolidine-2-thione (35) in high yield. Its
R-configuration at C-5 is consistent with a zero value for
9
J4,5
.
Compound 37P could be separated by crystallization from
aqueous ethanol. Again, its structure is supported by
elemental analysis and spectral data found in similar
bicycles.1,9 Likewise, the atropisomers of 36 and 37 showed
complex signals for the diastereotopic methylene protons on
the ethyl groups.
The subsequent treatment of 35 with hot aqueous acetic acid
led to the corresponding bicyclic imidazolidine-2-thione 36
with yields no higher than 25%.
The structure of 36 is consistent with its elemental analysis
and spectroscopic data. NMR spectra showed a mixture of
two rotamers in w1:1 ratio. Rotamer 36P was isolated by
crystallization from aqueous ethanol.
The absolute stereochemistry of 37P could also be
unambiguously determined by single-crystal X-ray diffrac-
tometry as depicted in its ORTEP diagram with the
crystallographic numbering (Fig. 3).14
Acetylation of the M and P mixture of 36 with acetic
anhydride and pyridine at K20 8C provided the correspond-
ing per-O-acetyl derivative 37, also as mixture of
atropisomers.
All the new synthesized rotamers were stable at room
temperature and no coalescence could be observed for either
Figure 3. X-ray diffraction analysis of compound 37P.

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7949
atropisomeric mixture on heating up to 150 8C. This finding
clearly suggest that coalescence should occur at a higher
temperature (TcO423 K) and, even at that threshold value,
into the corresponding deacetylated derivatives (3M and
3P), as this reaction has no effect on the axial chirality.
the resulting rotational barriers (20–22 kcal molK1 6,15
are
)
Obviously, the major atropisomer of 3 has the same axial
stereochemistry as the major atropisomer of 4, both P (the
presence of acetyl groups does not affect to the priority rules
of the Cahn–Ingold–Prelog system).
in full agreement with our theoretical data.1
2.1. Assignment of the absolute stereochemistry of
atropisomers derived from imidazolidine-2-one,
imidazoline-2-one and their thioanalogues
On the other hand, X-ray diffractrometry showed that the
major atropisomer of compound 2 had P configuration.16
This fact immediately attributes the opposite M-configur-
ation to the minor counterpart. Again, as the axial
stereochemistry is not influenced by acetylation, one can
reasonably conclude that major and minor atropisomers of
compound 1 exhibit P and M axial conformations,
respectively.
The main aspect on elucidating the structure of the
described atropisomers is to establish their axial absolute
stereochemistry. Obviously, the most important technique is
X-ray diffractometry, although it has sometimes a restricted
use, hampered by availability of suitable crystals. This
limitation could be overcome by stereochemical corre-
lations with other products with well-known structures.
Having established the absolute stereochemistry for
rotamers of compounds 1–4, we accomplished a study of
their NMR spectroscopic data (Table 2) and finding some
regularities that can be used in a predictive way. Thus, all
major rotamers show P configurations and their methyl
groups on the aromatic ring resonate at higher field than the
corresponding (M)-rotamers both in 1H and 13C NMR
spectra.
Since the structures of some characteristic rotamers could be
unequivocally established,1,16 we were able to assign the
axial stereochemistry for all the synthesized atropisomers.
2.2. Axial stereochemistry of 1-arylimidazolidine-2-one
and 2-thiones derived from 2-chloro-6-methylphenyl
isocyanate and isothiocyanate
Although DdCH are not too large, the order of such chemical
shifts remains constant. Unfortunately, this trend could not
be observed for H-1.
3
The synthesis of 1-(2-chloro-6-methylphenyl)imidazoli-
dine-2-one (1 and 2) and imidazolidine-2-thione (3 and 4)
has been already described.1 Atropisomers of 2, 3 and 4
could be isolated and the absolute stereochemistry for the
two rotamers of 3 and the P rotamer of 2 were determined
by means of X-ray diffractrometry.1,16 The unambiguous
knowledge of these structures has been harnessed to
establish a useful stereochemical correlation with the rest
of atropisomers.
It is interesting to point out how coherent these data are. A
couple of atropisomers can only be distinguished from a
stereochemical point of view, and therefore the different
chemical shift of the methyl groups should reflect two
distinctive chemical environments. The methyl group
appears deshielded when placed in the concavity formed
by the two heterocyclic rings (M atropisomers), whereas the
same group located in the opposite spatial orientation
(P atropisomers) shows more shielded resonances (Fig. 4).
This variation can be observed for all compounds listed in
Table 2 when going from M to P atropisomers.
These two spatial dispositions are present at the same time
on compounds 38 and 39,1 where methyl groups bear both
ortho positions of the aromatic ring. Accordingly, such
methyl groups exhibit the chemical shift differences
described in Figure 4.
The axial stereochemistry for M and P atropisomers of 4
was unequivocally determined when each was transformed
Table 2. Selected NMR data for compounds 1–4
Comp.
1H NMR
13C NMR
Abund.
Axial stereo-
chemistry
a
d
Dd
dH-1
d
CH3
Dd
CH3
CH3
CH3
1b
2c
3b
4c
2.24
2.20
2.36
2.27
2.29
2.17
2.39
2.25
0.04
0.09
0.12
0.14
5.73
5.71
5.99
5.85
5.85
5.88
6.12
5.97
18.5
18.0
18.6
18.2
18.8
17.9
18.6
18.1
0.5
0.4
0.9
0.5
K
C
K
C
K
C
K
C
M
P
M
P
M
P
M
P
a Symbols C/K indicate major/minor atropisomers.
b In DMSO-d6.
c In CDCl3.

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M. Avalos et al. / Tetrahedron 61 (2005) 7945–7959
7950
in a similar ratio, their relative abundance cannot be used to
make any correlation with the M and P rotamers of their
acetyl derivatives 29, 30 and 37.
However, chemical shifts for the methyl groups on the
aromatic ring should behave as those of compounds 1–4.
The presence of an ethyl group instead of a chlorine atom
has no effect on the sequence rules established by the Cahn–
Ingold–Prelog system. This does mean that the NMR signals
at higher field for this methyl group should reasonably be
attributed to P atropisomers (Fig. 5).
Figure 4. Average values of dCH (1H and 13C NMR).
3
Spectroscopic data for methylene and methine hydrogens in
ethyl and isopropyl groups also reflect the soundness of the
assigned stereochemical configurations. Thus, as expected,
the chemical shifts for such methylene and methine groups
follow the opposite order than that observed for the methyl
group.
2.3. Axial stereochemistry of 1-arylimidazolidine-2-ones
and 2-thiones derived from 2-alkyl-6-methylphenyl
isocyanates and isothiocyanates
The coupling pattern observed for the methylene protons in
ethyl groups also reinforces our stereochemical assignment.
These protons are diastereotopics resonating at different
chemical shifts, and we have observed that such a methylene
group in P atropisomers always undergoes a larger
diamagnetic anisotropy. Probably, the ethyl groups in
P atropisomers have less conformational freedom than
their M counterparts, as depicted in Figure 5. The ethyl
group in P atropisomers is located in the concavity formed
Selected NMR data for compounds 26–28 and 29–31,
derived from 2-ethyl-6-methylphenyl, 2-isopropyl-6-
methyl, and 2-tert-butyl-6-methylphenyl isocyanates, and
their thioanalogues 36 and 37 are collected in Table 3.
Because of M and P rotamers for 26, 27 and 36 are obtained
Table 3. Selected NMR data for compounds 26–31, 36 and 37
Comp.
1H NMR
13C NMR
Axial
stereochem
ArCHRR0
DdCHR
ArCH3
Dd
ArCH3
Dd
ArCCH3
a
CH3
a
b
CH3
d
dCHR
d
CH3
d
Dd
CH3
CH3
CH3
26c
27c
2.17
2.10
2.17
2.10
2.17
2.32
2.19
2.32
2.18
2.31
2.23
2.09
2.34
2.18
2.45
2.57
2.83
3.14
1.30
2.49
2.69
2.77
3.22
1.40
2.41
2.59
2.46
2.68
18.6
17.9
18.7
18.0
19.2
18.4
18.0
18.6
18.2
19.1
18.8
17.8
18.6
17.9
15.0
14.7
24.9/23.5
24.7/23.7
32.4
14.6
14.7
24.9/23.6
24.7/23.6
32.6
M
P
M
P
M
M
P
M
P
M
M
P
M
P
0.07
K0.12
K0.31
0.7
0.3
0.07
—
0.7
—
0.2
—
28c
29c
0.13
K0.20
0.4
0.4
K0.1
30d
0.14
—
K0.45
0.2
—
31d
36d
—
14.7
14.1
14.4
14.2
0.14
0.16
K0.18
K0.22
1.0
0.7
0.6
0.2
37d
a dArCH
.
3
b dCH for Et, iPr or tBu groups.
3
c In DMSO-d6.
d In CDCl3.
Figure 5. dCH and dCH average values (1H and 13C NMR).
3

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M. Avalos et al. / Tetrahedron 61 (2005) 7945–7959
7951
by the glucofuranose and imidazolidine rings, while that
ethyl in M atropisomers is situated on the convex area and
has more mobility.
It is worth pointing out that compound 5 is a precursor of 3
as outlined in Scheme 4. On considering the mechanism for
this cyclisation reaction, there are two possibilities. It has
been previously suggested7,9 a SNi mechanism assisted by
acid catalysis (40). Were this hypothesis correct, the
cyclisation would have no effect on the axial stereo-
chemistry of 5, that is, the configuration would be the same
as in compound 3. In other words, the M atropisomers of 5
would be stereospecifically transformed into the M
atropisomers of 3. Similarly, 3P would stem from 5P.
For compound 28, only one rotamer could be isolated.
Chemical shifts for the methyl group bound to the aromatic
ring are consistent with M configurations, a fact also
supported by the X-ray diffraction analysis of rotamer 28M.
Probably, the P atropisomer is not formed at all or formed in
tiny amounts due to the large steric effect caused by the tert-
butyl group in the cavity formed by the two fused
heterocyclic rings.
Therefore, like 3, the major atropisomer of 5 would be (P)-
configured and, the acetylation reaction will equally
produce the major atropisomer of 6, also with P chirality.
In this way, the axial stereochemistry for 5 and 6 can easily
be established.
2.4. Axial stereochemistry in monocyclic o,o0-disubsti-
tuted 1-arylimidazolidine-2-thiones and imidazoline-2-
thiones
Some selected NMR data for compounds 5–8,1 22, 25, and
35 are collected in Tables 4 and 5.
By considering a SN1 mechanism, one can arrive at the same
conclusions (Scheme 4). In this case, the formation of the
Table 4. Selected NMR data for compounds 5–8
Comp.
1H NMR
13C NMR
Abund.b
Axial stereo-
chem.
a
d
Dd
dH-5
d
CH3
Dd
CH3
CH3
CH3
5c
6d
7c
2.36
2.18
2.37
2.33
2.08
6.79
6.61
6.58
6.41
6.82
6.62
6.64
19.3
18.1
18.7
C
K
C
K
C
K
C
P
M
P
M
P
M
P
0.08
0.04
1.2
18.3
18.3
8d
2.18
a dArCH
.
3
b Symbols C/K indicate major/minor atropisomers.
c In DMSO-d6.
d In CDCl3..
Table 5. Selected NMR data for compounds 22, 25, and 35
Comp.
1H NMR
13C NMR
Axial
stereo-
chem.
a
CH3
a
b
dEt
d
Dd
CH3
dH-5
d
CH2
Dd
CH2
d
Dd
CH3
DdEt
CH3
22c
25d
35c
2.25
2.13
2.31
2.27
2.30
2.12
6.29
6.28
6.31
6.27
5.21
5.17
2.48
2.69
2.59
2.68
2.50
2.68
18.8
18.2
18.4
18.1
21.2
19.3
15.3
14.9
14.6
14.4
15.0
14.6
P
M
P
M
P
M
0.12
0.04
0.18
K0.19
K0.09
K0.18
0.6
0.3
1.9
0.4
0.2
0.4
a dArCH
.
3
b dCH
.
3
c In DMSO-d6.
d In CDCl3.

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7952
Scheme 4. (i) AcOH 30%, 6.
intermediate carbocation 41 does not imply the loss of axial
stereochemistry as the planar geometry of that carbocation
must be analogous to that of C-5 in compound 7, for which
room temperature stable M and P atropisomers were found.
Accordingly, were a carbocationic intermediate involved,
the process would also be stereospecific, from the viewpoint
of the axial chirality.
process corresponds to a pericyclic mechanism (42), the
axial stereochemistry of the atropisomers will not be
affected. In contrast, if elimination proceeds via an E1
mechanism (43), the above discussion about the inter-
mediate carbocation will be valid (Scheme 5).
Remarkably, comparisons of data from Table 4 with those
of Table 2 evidence that the sequence of chemical shifts for
the methyl group is reversed. Thus, the P atropisomers of 5
and 6 now exhibit more deshielded signals (Fig. 6).
In a further extension, the stereochemistry for atropisomers
of 7 and 8 can be assigned, because like 5 and 6, the major
atropisomer will have P chirality. It is interesting to point
out that the latter conclusion can be reached regardless of
the elimination mechanism converting 6 into 8. If the
Nevertheless, this change is totally justified considering that
configuration at C-5 is inverted when going from 5 (5R) to 3
Scheme 5. (i) KHCO3, C6H6, 6.

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7953
(150 mL) was added under stirring 1,3,4,6-tetra-O-acetyl-
2-amino-2-deoxy-b-D-glucopyranose hydrochloride4 9,
(11.9 g, 31.0 mmol) and dichloromethane (150 mL), keep-
ing the stirring for 30 min. The organic layer was separated
and the aqueous phase was extracted with dichloromethane
(50 mL). The combined organic fractions were washed with
water and dried over anhydrous magnesium sulfate and
concentrated to approx. 50 mL. 2-Ethyl-6-methylphenyl
isocyanate (5.0 g, 31.0 mmol) was then added and the
reaction mixture was left at room temperature for 24 h.
Compound 13 crystallized as a white solid, which was
filtered and washed with cold diethyl ether, (84%), mp 230–
232 8C (dec), [a]D C13.58 (c 1.0, CHCl3); nmax 3350 (NH),
1730 (C]O), 1660 (C]O), 1520 (NH), 1210 (C–O–C),
1060, 1025 (C–O), 780 cmK1 (aromatic); 1H NMR
(200 MHz, CDCl3) d 7.09 (br s, 3H, Ar), 6.92 (br s, 1H,
Figure 6. Average values of dCH (1H and 13C NMR).
3
(5S) and, consequently, the spatial interaction between the
methyl group on the aromatic ring and the oxygenated
substituent at C-5 is also exchanged.
ArNH), 5.77 (d, J1,2Z8.7 Hz, 1H, H-1), 5.26 (t, J2,3ZJ3,4
Z
The axial stereochemistry for atropisomers of 22, 25 and 35
can equally be assigned by comparison of their spectro-
scopic data with those of 5 and 6 (Tables 4 and 5, Fig. 7).
9.5 Hz, 1H, H-3), 5.04 (t, J3,4ZJ4,5Z9.5 Hz, 1H, H-4), 4.23
0
0
(dd, J5,6Z4.5 Hz, J6,6 Z12.4 Hz, 1H, H-6), 4.07 (d, J6,6
Z
12.2 Hz, 1H, H-60), 4.00 (m, 1H, H-2), 3.84 (m, 1H, H-5),
2.51 (m, 2H, CH2CH3), 2.18 (s, 3H, CH3), 2.09 (s, 3H,
OAc), 2.07 (s, 3H, OAc), 2.02 (s, 3H, OAc), 1.99 (s, 3H,
OAc), 1.15 (t, JZ7.5 Hz, 3H, CH2CH3); 13C NMR
(50.33 MHz, CDCl3) d 170.6 (CH3–CO), 170.5 (CH3–
CO), 169.3 (CH3–CO), 169.2 (CH3–CO), 156.0 (NH–CO–
NH), 142.4, 136.9, 132.2, 128.4 (2C), 126.6 (aromatics),
92.4 (C-1), 72.3 (2C, C-3, C-5), 68.3 (C-4), 61.7 (C-6), 53.6
(C-2), 24.5 (CH2CH3), 20.7 (CH3–CO), 20.6 (CH3–CO),
20.5 (CH3–CO), 20.4 (CH3–CO), 17.8 (CH3), 14.4
(CH2CH3). Anal. Calcd for C24H32N2O10: C, 56.67; H,
6.34; N, 5.51. Found: C, 56.80; H, 6.30; N, 5.55.
3. Conclusions
A new family of nonbiaryl atropisomers, generated by
reaction of protected aminosugars with o,o0-disubstituted
aryl isocyanates and isothiocyanates, have been prepared
and fully characterized, including X-ray diffraction analyses
of some individual rotamers. The axial stereochemistry of
these substances can be established by means of their 1H and
13C NMR data in solution. Furthermore, we have suggested
a series of mechanistic insights that are consistent with the
observed stereochemical outcome.
4.1.2. 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-[3-(2-isopropyl-
6-methylphenyl)ureido]-b-D-glucopyranose (14). Follow-
ing the procedure described for 13 and using 2-isopropyl-6-
methylphenylisocyanate, compound 14 crystallized as a
white solid, which was filtered and washed with cold diethyl
ether, (73%), mp 229–231 8C, [a]D C7.38 (c 0.5, CHCl3);
nmax 3381 (NH), 1749 (C]O), 1668 (C]O), 1543 (NH),
1219 (C–O–C), 1045 (C–O), 601 cmK1 (aromatic); 1H
NMR (400 MHz, CDCl3, 318 K) d 7.26–7.08 (m, 3H, Ar),
6.03 (br s, 1H, ArNH), 5.72 (d, J1,2Z8.6 Hz, 1H, H-1), 5.20
(t, J2,3ZJ3,4Z9.4 Hz, 1H, H-3), 5.04 (t, J3,4ZJ4,5Z9.4 Hz,
4. Experimental
4.1. General methods
General methods have been described in a previous paper.1
High resolution mass spectra (chemical ionisation) were
recorded on a Micromass Autospec spectrometer by
Unidade de Masas da Universidade de Santiago de
Compostela (Spain). Compounds 10–12 and 32 were
purchased from Lancaster and used as received.
0
1H, H-4), 4.24 (dd, J5,6Z4.7 Hz, J6,6 Z12.4 Hz, 1H, H-6),
0
0
0
4.10 (dd, J5,6 Z2.3 Hz, J6,6 Z12.3 Hz, 1H, H-6 ), 4.07 (m,
1H, H-2), 3.80 (m, 1H, H-5), 3.12 (m, JZ6.9 Hz,1H, CH),
2.20 (s, 3H, CH3), 2.10 (s, 3H, OAc), 2.05 (s, 3H, OAc),
2.02 (s, 3H, OAc), 1.97 (s, 3H, OAc), 1.18 (d, JZ7.5 Hz,
3H, CH3CH), 1.17 (d, JZ6.9 Hz, 3H, CH3CH); 13C NMR
4.1.1. 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-[3-(2-ethyl-6-
methylphenyl)ureido]-b-D-glucopyranose (13). To a
solution of NaHCO3 (3.13 g, 37.3 mmol) in water
Figure 7. Average values of dCH and dCH (1H and 13C NMR).
3
2

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M. Avalos et al. / Tetrahedron 61 (2005) 7945–7959
7954
(100 MHz, CDCl3, 298 K) d 170.7 (2C, CH3–CO), 169.4
(CH3–CO), 169.2 (CH3–CO), 155.9 (NH–CO–NH), 147.2,
137.1, 131.7, 128.5 (2C), 124.2 (aromatics), 92.4 (C-1), 72.3
(2C, C-3, C-5), 68.3 (C-4), 61.6 (C-6), 53.4 (C-2), 28.3
(CH3CH), 24.2 (CH3CH), 22.7 (CH3CH), 20.9 (CH3–CO),
20.7 (2C, CH3–CO), 20.5 (CH3–CO), 17.9 (CH3). Anal.
Calcd for C25H34N2O10: C, 57.46; H, 6.56; N, 5.36. Found:
C, 57.26; H, 6.33; N, 5.27.
NMR (100 MHz, DMSO-d6) d 156.8 (C]O), 141.6, 136.4,
135.6, 127.8, 126.1 (2C), (aromatics), 91.5 (C-1), 72.4
(C-5), 71.9 (C-4), 71.4 (C-3), 61.4 (C-6), 54.9 (C-2), 24.6
(CH2CH3), 18.6 (CH3), 15.0 (CH2CH3). Anal. Calcd for
C16H24N2O6$3/2H2O: C, 52.31; H, 7.41; N, 7.62. Found: C,
52.28; H, 7.13; N, 7.71.
Recrystallization of the second fraction (0.7 g) from ethanol
gave compound 22 as mixture of rotamers (w1:1), (0.23 g,
6.5%): mp 115–117 8C, [a]D C26.08 (c 0.5, N,N-
dimethylformamide), nmax 3600–3000 (OH, NH), 1680
(C]O), 1050, 1020 (C–O); 1H NMR (400 MHz, DMSO-d6)
d 7.19–7.07 (m, 6H, Ar, M and P), 6.29 (d, J5,OHZ5.7 Hz,
1H, C5–OH, P), 6.28 (d, J5,OHZ6.5 Hz, 1H, C5–OH, M),
6.21 (d, JZ6.9 Hz, 1H, ethanol), 5.06 (d, J5,OHZ6.4 Hz,
1H, H-5, P), 5.01 (dd, J4,5Z3.0 Hz, J5,OHZ6.8 Hz, 1H,
H-5, M), 4.65–4.36 (m, 8H, C10–OH, C20–OH, C030–OH,
C40–OH, 0M and P), 3.70–3.37 (m, 12H, H-4, H1 , H-20,
H-30, H-4 and H-400, M and P), 2.75 (m, JgemZ22.3 Hz, JZ
7.6 Hz, 1H, CH2CH3, M), 2.60 (m, JgemZ22.2 Hz, JZ
7.8 Hz, 1H, CH2CH3, M), 2.48 (m, 2H, CH2CH3, P), 2.25 (s,
3H, CH3, P), 2.13 (s, 3H, CH3, M), 1.11 (t, JZ7.5 Hz, 3H,
CH2CH3, P), 1.07 (t, JZ6.5 Hz, 3H, CH2CH3, M), 1.05 (t,
JZ7.0 Hz, 3H, ethanol); 13C NMR (100 MHz, DMSO-d6) d
158.6 (C]O, P), 158.4 (C]O, M), 145.6, 143.3, 139.9,
137.3 (2C), 134.8, 134.6, 128.1, 127.9, 127.8, 126.4, 126.2
(aromatics, M and P), 84.6 (C-5, P), 84.1 (C-5, M), 71.5
(C-10, M), 71.4 (C-10, P), 71.3 (C-20, M and P), 69.9 (C-30,
P), 69.8 (C-30, M), 63.6 (C-40, M and P), 62.3 (C-4, M and
P), 56.3 (CH2 ethanol), 24.2 (CH2CH3, M), 23.9 (CH2CH3,
P), 19.1 (ethanol), 18.8 (C0H3, P), 18.2 (CH3, M), 15.3
(CH2CH3, P), 14.9 (CH2 CH3, M). Anal. Calcd for
C16H24N2O6$C2H5OH$H2O: C, 53.46; H, 7.97; N, 6.93.
Found: C, 53.24; H, 8.20; N, 7.43.
4.1.3. 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-[3-(2-tert-butyl-
6-methylphenyl)ureido]-b-D-glucopyranose (15). Follow-
ing the procedure described for 13 and using 2-tert-butyl-6-
methylphenylisocyanate, a mixture of rotamers of 15
crystallized as a white solid, which was filtered and washed
with cold diethyl ether, (67%), mp 203–205 8C, [a]D
C11.28 (c 0.5, CHCl3); nmax 3331 (NH), 1757 (C]O),
1641 (C]O), 1562 (NH), 1229 (C–O–C), 1041 (C–O),
781 cmK1 (aromatic); 1H NMR (400 MHz, CDCl3) d 7.33–
7.09 (m, 7H, Ar and NH), 6.35 (s, 1H, NH), 6.09 (s, 1H,
NH), 6.05 (s, 1H, NH), 5.71 (d, J1,2Z8.5 Hz, 1H, H-1), 5.59
(d, J1,2Z8.5 Hz, 1H, H-1), 5.26 (t, J2,3ZJ3,4Z9.1 Hz, 1H,
H-3), 5.17 (t, J2,3ZJ3,4Z9.1 Hz, 1H, H-3), 5.08 (m, 2H, H-
4), 4.29 (m, 2H, H-6), 4.08 (m, 4H, H-60, H-2), 3.82 (m, 2H,
H-5), 2.19 (s, 3H, CH3), 2.18 (s, 3H, CH3), 2.14 (s, 3H,
OAc), 2.10 (s, 3H, OAc) 2.07 (s, 6H, OAc), 2.04 (s, 3H,
OAc), 1.98 (s, 6H, OAc), 1.97 (s, 3H, OAc) 1.34 (s, 18H, 2
(CH3)3C); 13C NMR (100 MHz, CDCl3) d 170.7 (2C, CH3–
CO), 170.5 (2C, CH3–CO), 169.6 (2C, CH3–CO), 169.3
(2C, CH3–CO), 156.1 (NH–CO–NH), 156.0 (NH–CO–NH),
149.0 (2C), 139.2, 138.8 (2C), 132.7, 129.6 (2C), 128.7
(2C), 125.6 (2C) (aromatics), 92.4 (C-1), 92.2 (C-1), 72.6
(C-3), 72.1 (3C, C-3, C-5), 68.8 (2C, C-4), 61.6 (2C, C-6),
53.0 (C-2), 52.9 (C-2), 35.4 (C), 35.0 (C), 30.9 (3C,
(CH3)3C), 30.7 (3C, (CH3)3C), 21.0 (CH3–CO), 20.9 (CH3–
CO), 20.8 (2C, CH3–CO), 20.7 (2C, CH3–CO), 20.6 (2C,
CH3–CO), 18.3 (CH3), 17.9 (CH3). Anal. Calcd for
C26H36N2O10: C, 58.20; H, 6.76; N, 5.22. Found: C,
57.60; H, 6.28; N, 5.01.
4.1.5. (4R,5R)-4-(1,2,3,4-Tetra-O-acetyl-D-arabino-tetri-
tol-1-yl)-5-acetoxy-1-(2-ethyl-6-methylphenyl)imidazoli-
dine-2-one (25). To a solution of (4R,5R)-1-(2-ethyl-6-
methylphenyl)-5-hydroxy-4-(D-arabino-tetritol-1-yl)imi-
dazolidine-2-thione (22), (0.080 g, 0.24 mmol), in pyridine
(1 mL) cooled at K20 8C for 15 min, was added acetic
anhydride (1.2 mL) and the reaction mixture was kept at that
temperature for 24 h. Then it was poured into ice-water and
the resulting solid was filtered and washed with cold water,
affording 25 (0.08 g, 59%) as mixture of rotamers in w2:3
ratio, mp: 123–125 8C, [a]D C58.58 (c 0.5, CHCl3), nmax
3360 (NH), 1740 (C]O, ester), 1540 (NH), 1260, 1220
(C–O–C, ester), 1480, 780 cmK1 (aromatics); 1H NMR
(400 MHz, CDCl3) d 7.26–7.08 (m, 6H, Ar, M and P), 6.31
4.1.4. 2-[3-(2-Ethyl-6-methylphenyl)ureido]-2-deoxy-a-
D-glucopyranose (19) and (4R,5R)-1-(2-ethyl-6-methyl-
phenyl)-5-hydroxy-4-(D-arabino-tetritol-1-yl)-imidazoli-
dine-2-one (22). To a solution of 1,3,4,6-tetra-O-acetyl-2-
deoxy-2-[3-(2-ethyl-6-methylphenyl)ureido]-b-D-gluco-
pyranose, 13, (10.0 g, 19.7 mmol) in methanol (310 mL),
was added a saturated solution of ammonia in methanol
(315 mL). The reaction was controlled by TLC (chloro-
form–methanol, 3:1) and left for 24 h at room temperature.
The mixture was then evaporated to dryness and the crude
crystallized from 96% ethanol. Several fractions were
collected as mixtures of 19 and 22 in different proportions.
The third fraction resulted to be compound 19 (0.25 g, 7%),
mp 188–190 8C (dec), [a]D C40.08 (c 0.5, N,N-dimethyl-
formamide); nmax 3500–3100 (OH, NH), 1600 (C]O,
urea), 1560 (NH), 1065, 1015 (C–O), 760 cmK1
(aromatics); 1H NMR (400 MHz, DMSO-d6) d 7.63 (s,
1H, ArNH), 7.04 (m, 3H, Ar), 6.54 (d, J1,OHZ4.0 Hz, 1H,
C1–OH), 4.98 (t, J1,2ZJ1,OHZ3.6 Hz, 1H, H-1), 4.89 (d,
J3,OHZ5.4 Hz, 1H, C3–OH), 4.74 (d, J4,OHZ5.3 Hz, 1H,
(s, 1H, H-5, P), 6.27 (s, 2H, H-5, M and NH, P), 6.20 (s, 1H,
0
0
0
0
NH, M), 5.53 (dd, J1 ,2 Z2.5 Hz, J4,1 Z7.4 Hz, 1H, H-1 ,
0
0
0
0
M), 5.51 (dd, J1 ,2 Z2.4 Hz, J4,1 Z8.6 Hz, 1H,0 H-1 , P),
0
0
0
0
5.36 (dd, J1 ,2 Z2.4 Hz, J2 ,3 Z8.2 Hz, 1H,0 H-2 , P), 5.34
0
0
0
0
(dd, J1 ,2 Z2.5 Hz, J2 ,3 Z8.5 Hz, 1H, H-2 , M), 5.03 (m,
2H, H-30, P and M), 4.23 (dd, J3 ,4 Z2.4 Hz, J4 ,4
Z
0
0
0
00
12.6 Hz, 2H, H-40, P and M), 4.17 (dd, J3 ,4 Z4.2 Hz,
0
00
00
0
00
0
J4 ,4 Z12.6 Hz, 2H, H-4 , P and M), 3.80 (bd, J4,1
Z
0
7.5 Hz, 1H, H-4, M), 3.78 (bd, J4,1 Z9.5 Hz, 1H, H-4, P),
2.76 (m, JgemZ22.5 Hz, JZ7.5 Hz, 1H, CH2CH3, M), 2.62
(m, JgemZ22.5 Hz, JZ7.5 Hz, 1H, CH2CH3, M), 2.59 (m,
2H, CH2CH3, P), 2.31 (s, 3H, CH3, P), 2.27 (s, 3H CH3, M),
2.11 (s, 6H, OAc, M), 2.10 (s, 3H, OAc, P), 2.09 (s, 3H,
OAc, M), 2.08 (s, 3H, OAc, P), 2.06 (s, 3H, OAc, M), 2.04
0
C4–OH), 4.42 (t, J6,OHZJ6 ,OHZ5.8 Hz, 1H, C6–OH), 3.60
(m, 2H, H-5, H-6), 3.48 (m, 2H, H-2, H-60), 3.35 (m, 1H,
H-4), 3.14 (m, 1H, H-3), 2.53 (c, JZ7.4 Hz, 2H, CH2CH3),
2.15 (s, 3H, CH3), 1.09 (t, JZ7.5 Hz, 3H, CH2CH3); 13C

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M. Avalos et al. / Tetrahedron 61 (2005) 7945–7959
7955
(s, 6H, OAc, P and M), 1.99 (s, 3H, OAc, M), 1.98 (s, 3H,
OAc, P), 1.25 (t, JZ7.2 Hz, 3H, CH2CH3, P), 1.23 (t, JZ
7.5 Hz, 3H, CH2CH3, M); 13C NMR (100 MHz, CDCl3) d
170.6 (CH3–CO), 170.0 (CH3–CO), 169.9 (CH3–CO), 169.7
(CH3–CO, P and M), 158.6 (C]O, P and M), 144.4, 142.5,
138.7, 136.5, 131.7, 131.6, 128.9, 128.8 (2C), 128.5, 126.6
(2C) (aromatics, P and M), 84.4 (C-5, M), 83.8 (C-5, P),
69.30(C-20, P), 69.2 (C-20, 0M), 68.5 (C-10, P and M), 68.4
(C-3 , P and M), 61.2 (C-4 , P and M), 57.5 (C-4, P), 57.4
(C-4, M), 24.3 (CH2CH3, P), 23.6 (CH2CH3, M), 20.8 (CH3–
CO), 20.7 (CH3–CO), 20.6 (CH3–CO), 20.4 (CH3–CO), P and
M, 18.4 (CH3, M), 18.1 (CH3, P), 14.6 (CH2CH3, M), 14.4
(CH2CH3, P). Anal. Calcd for C26H34N2O11: C, 56.72; H,
6.23; N, 5.09. Found: C, 57.00; H, 6.20; N, 5.34.
rotamers of 29, due to deacetylation of 29P in methanol/
silica gel (see procedure for 29), mp 198–200 8C (dec), [a]D
C838 (c 0.5, N,N-dimethylformamide); nmax 3600–3200
(OH, NH), 1650 (C]O), 1475 (NH), 1080, 1030 (C–O),
1590, 790, and 730 cmK1 (aromatics); 1H NMR (400 MHz,
DMSO-d6) d 7.23–7.09 (m, 4H, Ar and NH), 5.60 (d, J1,2
Z
6.4 Hz, 1H, H-1), 5.27 (d, J3,OHZ3.9 Hz, 1H, C3–OH), 4.80
0
(d, J5,OHZ4.2 Hz, 1H, C5–OH), 4.46 (t, J6,OHZJ6 ,OH
Z
5.5 Hz, 1H, C6–OH), 4.09 (m, 2H, H-2, H-3), 3.81 (dd,
J3,4Z2.2 Hz, J4,5Z8.7 Hz, 1H, H-4), 3.72 (m, 1H, H-5),
3.54 (m, 1H, H-6), 3.32 (m, 1H, H-60), 2.61 (m, Jgem
Z
26.1 Hz, JZ7.5 Hz, 1H, CH2CH3), 2.51 (m, 1H, CH2CH3),
2.10 (s, 3H, CH3), 1.11 (t, JZ7.5 Hz, 3H, CH2CH3); 13C
NMR (100 MHz, DMSO-d6) d 158.9 (C]O), 144.6, 136.8,
135.3, 128.2, 128.0, 126.1, (aromatics), 91.4 (C-1), 79.7
(C-4), 74.5 (C-3), 68.7 (C-5), 64.3 (C-6), 61.9 (C-2), 23.7
(CH2CH3), 17.8 (CH3), 14.7 (CH2CH3). Anal. Calcd for
C16H22N2O5$3/2H2O: C, 55.00; H, 7.21; N, 8.02. Found: C,
55.14; H, 7.19; N, 8.04.
4.1.6. 1-(2-Ethyl-6-methylphenyl)-(1,2-dideoxy-a-D-
glucofurano)[2,1-d]imidazolidine-2-one (26). Procedure
A. To a solution of 1,3,4,6-tetra-O-acetyl-2-deoxy-2-[3-(2-
ethyl-6-methylphenyl)ureido]-b-D-glucopyranose, 13,
(2.0 g, 3.9 mmol) in methanol (70 mL), was added a
saturated solution of ammonia in methanol (80 mL). The
reaction was controlled by TLC (chloroform–methanol 3:1)
and after 48 h it was evaporated to dryness. The resulting
residue was treated with acetic acid (72 mL) and heated at
w100 8C (external bath), for 30 min. After evaporating to
dryness, the solid was crystallized from 96% ethanol,
affording 26 (0.11 g, 13%), as mixture of rotamers in w1:1
ratio.
4.1.7. 1-(2-Isopropyl-6-methylphenyl)-(1,2-dideoxy-a-D-
glucofurano)[2,1-d]imidazolidine-2-one (27). To a
solution of 1,3,4,6-tetra-O-acetyl-2-deoxy-2-[3-(2-iso-
propyl-6-methylphenyl)ureido]-b-D-glucopyranose, 14,
(4.0 g, 7.7 mmol) in methanol (120 mL) was added a
saturated solution of ammonia in methanol (120 mL). The
reaction was controlled by TLC (chloroform–methanol 3:1)
and after 48 h it was evaporated to dryness. The resulting
residue was treated with aqueous acetic acid (137 mL) and
heated at w100 8C (external bath) for 30 min. After
evaporating to dryness, the solid was purified by column
chromatography affording 27 (1.27 g, 50%) as mixture of
rotamers (w1:1), mp 108–110 8C, [a]D C59.68 (c 0.5, N,N-
dimethylformamide); nmax 3500–3000 (OH, NH), 1695
(C]O), 1472 (NH), 1080, 1022 (C–O), 789 cmK1
Procedure B. A mixture of 19 and 22 (1.2 g, 3.5 mmol)
dissolved in acetic acid (44 mL) was heated at w100 8C
(external bath), for 30 minutes. After evaporating to
dryness, the solid was crystallized from 96% ethanol,
affording a mixture of rotamers of 26 (0.6 g, 66%) in w1:1
ratio, mp 207–209 8C (dec), [a]D C91.48 (c 0.5, N,N-
dimethylformamide); nmax 3500–3000 (OH, NH), 1690
(C]O), 1470 (NH), 1080, 1020 (C–O), 1590, and 780 cmK1
(aromatics); 1H NMR (400 MHz, DMSO-d6) d 7.23–7.08 (m,
8H, ArandNHM andP), 5.60(d, J1,2Z6.3 Hz, 2H, H-1M and
P), 5.21 (d, J3,OHZ4.8 Hz, 2H, C3–OH M and P), 4.74 (d,
J5,OHZ6.9 Hz, 1H, C5–OH M), 4.72 (d, J5,OHZ6.7 Hz, 1H,
1
(aromatics); H NMR (400 MHz, DMSO-d6) d 7.24–7.07
(m, 8H, Ar and NH P and M), 5.59 (d, J1,2Z6.4 Hz, 1H, H-1
P), 5.52 (d, J1,2Z6.2 Hz, 1H, H-1 M), 5.24 (d, J3,OH
3.1 Hz, 2H, C3–OH P and M), 4.75 (br s, 2H, C5–OH P and
Z
0
M), 4.47 (t, J6,OHZJ6 ,OHZ5.3 Hz, 2H, C6–OH P and M),
4.13 (m, 2H, H-2 P and M), 4.09 (m, 2H, H-3 P and M), 3.86
0
(dd, J3,4Z2.3 Hz, J4,5Z8.6 Hz, 1H, H-4 M), 3.78 (dd, J3,4
Z
C5–OH P), 4.46 (t, J6,OHZJ6 ,OHZ5.6 Hz, 1H, C6–OH P),
0
2.1 Hz, J4,5Z8.6 Hz, 1H, H-4 P), 3.71 (m, 2H, H-5 P and
M), 3.55 (m, 2H, H-6 P and M), 3.33 (m, 2H, H-60 P and M),
3.14 (sept, JZ6.9 Hz, 1H, CH(CH3)2 P), 2.83 (sept, JZ
6.8 Hz, 1H, CH(CH3)2 M), 2.17 (s, 3H, CH3 M), 2.10 (s, 3H,
CH3 P), 1.21 (d, JZ6.9 Hz, 3H, CH(CH3)2 M), 1.15 (d, JZ
6.8 Hz, 3H, CH(CH3)2 M), 1.07 (d, JZ6.9 Hz, 3H,
CH(CH3)2 P), 1.04 (d, JZ6.7 Hz, 3H, CH(CH3)2 P); 13C
NMR (100 MHz, DMSO-d6) d 159.2 (C]O M), 158.7
(C]O P), 149.5, 139.1, 133.9, 128.4, 128.0, 123.9
(aromatics, M), 147.5, 136.7, 134.4, 128.3, 127.9, 124.0,
(aromatics P), 92.6 (C-1 M), 91.5 (C-1 P), 80.0 (C-4 P), 79.9
(C-4 M), 74.6 (C-3 P), 74.5 (C-3 M), 68.9 (C-5 M), 68.8
(C-5 P), 64.5 (C-6 P), 64.2 (C-6 M), 61.9 (C-2 P), 61.8 (C-2
M), 27.9 (CH(CH3)2 M), 27.8 (CH(CH3)2 P), 24.9
(CH(CH3)2 M), 24.7 (CH(CH3)2 P), 23.7 (CH(CH3)2 P),
23.5 (CH(CH3)2 M), 18.7 (CH3 M), 18.0 (CH3 P). Anal.
Calcd for C17H24N2O5$3/2H2O: C, 56.14; H, 7.43; N, 7.71.
Found: C, 56.04; H, 7.10; N, 7.70.
4.45 (t, J6,OHZJ6 ,OHZ5.4 Hz, 1H, C6–OH M), 4.10 (m, 4H,
H-2, H-3 M and P), 3.86 (dd, J3,4Z2.0 Hz, J4,5Z8.6 Hz, 1H,
H-4 M), 3.81 (dd, J3,4Z2.1 Hz, J4,5Z8.7 Hz, 1H, H-4 P), 3.71
(m, 2H, H-5MandP),3.55(m, 2H, H-6MandP),3.33(m, 2H,
H-60 M and P), 2.61 (m, JgemZ22.1 Hz, JZ7.5 Hz, 1H,
CH2CH3 P), 2.51 (m, JgemZ22.1 Hz, JZ7.5 Hz, 1H,
CH2CH3 P), 2.45 (c, JZ7.5 Hz, 2H, CH2CH3 M), 2.17 (s,
3H, CH3 M), 2.10 (s, 3H, CH3 P), 1.11 (t, JZ7.5 Hz, 3H,
CH2CH3 M), 1.10 (t, JZ7.5 Hz, 3H, CH2CH3 P); 13C NMR
(100 MHz, DMSO-d6) d 158.9 (C]O M), 158.6 (C]O P),
144.7, 142.6, 139.2, 136.9, 135.3, 134.8, 128.2 (2C), 128.1
(2C), 126.5, 126.2 (aromatics M and P), 91.8 (C-1 P), 91.4
(C-1 M), 79.9 (C-4 M), 79.7 (C-4 P), 74.5 (C-3 M), 74.4 (C-3
P), 68.7 (C-5 M and P), 64.3 (C-6 M), 64.2 (C-6 P), 61.9 (C-2
P), 61.8 (C-2 M), 23.8 (CH2CH3 M and P), 18.6 (CH3 M), 17.9
(CH3 P), 15.0(CH2CH3 M), 14.7(CH2CH3 P). Anal. Calcdfor
C16H22N2O5: C, 59.62; H, 6.88; N, 8.69. Found: C, 59.52; H,
6.93; N, 8.55.
Procedure C. The rotamer of low Rf, 26P, was obtained pure
by preparative TLC separation of the mixture of acetylated
4.1.8. 2-[3-(2-tert-Butyl-6-methylphenyl)ureido]-2-
deoxy-a-D-glucopyranose (21) and (M)-1-(2-tert-butyl-6-

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M. Avalos et al. / Tetrahedron 61 (2005) 7945–7959
7956
methylphenyl)-(1,2-dideoxy-a-D-glucofurano)[2,1-d]imi-
dazolidine-2-one (28M). To a solution of 1,3,4,6-tetra-O-
acetyl-2-deoxy-2-[3-(2-tert-butyl-6-methylphenyl)ureido]-
b-D-glucopyranose, 15, (4.0 g, 7.5 mmol) in methanol
(118 mL) was added a saturated solution of ammonia in
methanol (118 mL). The reaction was controlled by TLC
(chloroform–methanol, 3:1) and left for 24 h at room
temperature. The mixture was then evaporated to dryness
and the resulting residue was treated with aqueous acetic
acid (120 mL) and heated at w100 8C (external bath), for
30 min. After evaporating to dryness, the solid was
crystallized from 96% ethanol and water, affording 21
(0.43 g, 16%) as mixture of rotamers (w1:1), mp 195–
197 8C (dec), [a]D C34.68 (c 0.5, N,N-dimethylformamide);
nmax 3500–3100 (OH, NH), 1618 (C]O, urea), 1570 (NH),
1072, 1026 (C–O), 775 cmK1 (aromatics); 1H NMR
(400 MHz, DMSO-d6) d 7.48 and 7.46 (s, 1H, NH M and
P), 7.17–7.05 (m, 6H, Ar M and P), 6.56 (br s, 2H, C1–OH),
6.12 (br s, 2H, NH M and P), 5.01 and 4.93 (br s, 1H, H-1 M
and P), 4.88 (d, J3,OHZ3.6 Hz, 1H, C3–OH M and P), 4.72
(d, J4,OHZ4.5 Hz, 1H, C4–OH), 4.67 (d, J4,OHZ4.1 Hz, 1H,
was extracted with ethyl acetate and the residue was
crystallized from 96% ethanol.
Compound 29P. RfZ0.5, mp 174–176 8C, [a]D C106.08 (c
0.1, CHCl3), nmax 3500–3100 (H2O, NH)12, 1750, 1720
(C]O), 1690 (NC]O) 1240 (C–O–C), 1040 (C–O), 1590,
1570, 790 cmK1 (aromatics); 1H NMR (400 MHz, CDCl3) d
7.26–7.11 (m, 3H, Ar), 5.77 (d, J1,2Z6.3 Hz, 1H, H-1), 5.49
(s, 1H, NH), 5.33 (d, J3,4Z2.8 Hz, 1H, H-3), 5.23 (m, 1H,
0
H-5), 4.64 (dd, J5,6Z2.5 Hz, J6,6 Z12.3 Hz, 1H, H-6), 4.55
(dd, J3,4Z2.8 Hz, J4,5Z9.2 Hz, 1H, H-4), 4.26 (dd, J2,NH
Z
0
2.3 Hz, J1,2Z6.4 Hz, 1H, H-2), 3.99 (dd, J5,6 Z4.8 Hz,
0
0
J6,6 Z12.3 Hz, 1H, H-6 ), 2.74 (m, JgemZ22.3 Hz, JZ
7.5 Hz, 1H, CH2CH3), 2.61 (m, JgemZ22.3 Hz, JZ7.5 Hz,
1H, CH2CH3), 2.18 (s, 3H, CH3), 2.10 (s, 3H, OAc), 2.08 (s,
3H, OAc), 2.04 (s, 3H, OAc), 1.25 (t, JZ7.5 Hz, 3H,
CH2CH3); 13C NMR (100 MHz, CDCl3) d 170.5 (CH3–CO),
169.9 (CH3–CO), 169.7 (CH3–CO), 159.0 (C]O), 144.5,
136.1, 133.4, 128.9, 128.6, 126.7 (aromatics), 92.4 (C-1),
75.9 (C-3), 75.7 (C-4), 67.7 (C-5), 62.8 (C-6), 60.4 (C-2),
24.1 (CH2CH3), 20.7 (3C, CH3–CO), 18.0 (CH3), 14.7
(CH2CH3). Anal. Calcd for C22H28N2O8]H2O: C, 56.64;
H, 6.48; N, 6.01. Found: C, 56.45; H, 5.86; N, 6.28.
0
C4–OH), 4.42 (t, J6,OHZJ6 ,OHZ5.8 Hz, 2H, C6–OH M and
P), 3.64 (m, 2H, H-5, H-6), 3.48 (m, 3H, H-2, H-4, H-60),
3.12 (m, 1H, H-3), 2.13 (s, 3H, CH3), 2.11 (s, 3H, CH3), 1.31
(s, 18H, (CH3)3C); 13C NMR (100 MHz, DMSO-d6) d 158.9
(C]O), 157.1 (C]O) 147.8 (2C), 139.4, 139.2, 136.2,
136.1, 128.3, (2C), 126.6 (2C), 124.01 (2C), (aromatics),
91.8 (C-1), 91.7 (C-1), 72.4 (2C, C-5), 71.9 (2C, C-4), 71.2
(2C, C-3), 61.4 (2C, C-6), 55.0 (C-2), 54.9 (C-2), 35.1 (2C,
C), 31.1 (6C, (CH3)3C), 18.7 (2C, CH3). Anal. Calcd for
C18H28N2O6: C, 58.68; H, 7.66; N, 7.60. Found: C, 58.31;
H, 7.64; N, 7.49.
Compound 29M. RfZ0.6, mp 163–165 8C, [a]DC101.58 (c
0.4, CHCl3); nmax 3500–3000 (H2O, NH)12, 1750, 1740
(C]O), 1680 (NC]O), 1230 (C–O–C), 1040 (C–O), 1590,
790 cmK1 (aromatics); 1H NMR (400 MHz, CDCl3) d 7.26–
7.13 (m, 3H, Ar), 5.81 (d, J1,2Z6.3 Hz, 1H, H-1), 5.49 (d,
J2,NHZ1.8 Hz, 1H, NH), 5.35 (d, J3,4Z2.8 Hz, 1H, H-3),
5.22 (m, 1H, H-5), 4.61 (dd, J3,4Z2.8 Hz, J4,5Z9.6 Hz, 1H,
0
H-4), 4.58 (dd, J5,6Z2.2 Hz, J6,6 Z12.1 Hz, 1H, H-6), 4.32
0
(dd, J2,NHZ2.3 Hz, J1,2Z6.3 Hz0, 1H, H-2), 4.04 (dd, J5,6
Z
0
When the mother liquors were treated with water, a small
amount of compound 28M spontaneously crystallized
(0.105 g, 4%), mp 240–242 8C, [a]D C70.68 (c 0.5, N,N-
dimethylformamide); nmax 3388, 2965 (OH, NH), 1467
(NH), 1670 (C]O), 1043 (C–O), 887, 785 cmK1
4.4 Hz, J6,6 Z12.4 Hz, 1H, H-6 ), 2.49 (m, 2H, CH2CH3),
2.32 (s, 3H, CH3), 2.08 (s, 3H, OAc), 2.07 (s, 3H, OAc),
2.03 (s, 3H, OAc), 1.22 (t, JZ7.6 Hz, 3H, CH2CH3); 13C
NMR (100 MHz, CDCl3) d 170.5 (CH3–CO), 169.9 (CH3–
CO), 169.7 (CH3–CO), 158.7 (C]O), 142.0, 138.7, 133.0,
128.9, 128.7, 126.7 (aromatics), 92.8 (C-1), 75.8 (C-3), 75.6
(C-4), 67.6 (C-5), 62.8 (C-6), 60.3 (C-2), 24.1 (CH2CH3),
20.8 (2C, CH3–CO), 20.7 (CH3–CO), 18.4 (CH3), 14.6
(CH2CH3). Anal. Calcd for C22H28N2O8$1/2H2O: C, 57.76;
H, 6.39; N, 6.12. Found: C, 57.87; H, 6.65; N, 6.56.
1
(aromatics); H NMR (400 MHz, DMSO-d6) d 7.38–7.10
(m, 3H, Ar), 7.26 (s, 1H, NH), 5.60 (d, J1,2Z5.8 Hz, 1H,
H-1), 5.22 (d, J3,OHZ5.0 Hz, 1H, C3–OH), 4.72 (d, J5,OH
5.8 Hz, 1H, C5–OH), 4.44 (t, J6,OHZJ6 ,OHZ5.4 Hz, 1H,
Z
0
C6–OH), 4.10 (d, J3,4Z2.7 Hz, 1H, H-3), 4.04 (d, J1,2
Z
5.8 Hz, 1H, H-2), 3.89 (d, J4,5Z8.6 Hz, 1H, H-4), 3.68 (m,
1H, H-5), 3.54 (m, 1H, H-6), 3.32 (m, 1H, H-60), 2.17 (s, 3H,
CH3), 1.30 (s, 9H, (CH3)3C); 13C NMR (100 MHz, DMSO-
d6) d 158.8 (C]O), 148.7, 140.8, 134.0, 128.6, 127.9,
126.7, (aromatics), 93.6 (C-1), 80.5 (C-3), 74.0 (C-4), 68.8
(C-5), 64.1 (C-6), 61.6 (C-2), 36.0 (C), 32.4 (3C, (CH3)3C),
19.2 (CH3). Anal. Calcd for C18H26N2O5: C, 61.70; H, 7.48;
N, 7.99. Found: C, 61.47; H, 7.45; N, 7.99.
The rotamer 26P, was obtained pure by preparative TLC
separation of the mixture of acetylated rotamers of 29, due
to deacetylation of 29P in methanol silica gel (see above
procedure for 26).
4.1.10. 1-(2-Isopropyl-6-methylphenyl)-(3,5,6-tri-O-
acetyl-1,2-dideoxy-a-D-glucofurano)[2,1-d]imidazoli-
dine-2-one (30). To a solution of 1-(2-isopropyl-6-
methylphenyl)-(1,2-dideoxy-a-D-glucofurano)[2,1-d]imi-
dazolidine-2-one, 27, (0.3 g, 0.89 mmol) in pyridine
(2.3 mL), cooled at K20 8C, was added acetic anhydride
(2.3 mL) and the reaction mixture was kept at that
temperature overnight. Then it was poured into ice-water
and the resulting solid was filtered and washed with cold
water and identified as mixture of rotamers (0.33 g, 79%), in
a 60:40 ratio (P:M). Both rotamers were isolated by
preparative TLC (diethyl ether). Silica-gel was extracted
with ethyl acetate and the residue was crystallized from 96%
ethanol.
4.1.9. 1-(2-Ethyl-6-methylphenyl)-(3,5,6-tri-O-acetyl-
1,2-dideoxy-a-D-glucofurano)[2,1-d]imidazolidine-2-one
(29). To a solution of 1-(2-ethyl-6-methylphenyl)-(1,2-
dideoxy-a-D-glucofurano)[2,1-d]imidazolidine-2-one, 26,
(0.4 g, 1.2 mmol) in pyridine (3.0 mL), cooled at K20 8C,
was added acetic anhydride (3.1 mL) and the reaction
mixture was kept at that temperature overnight. Then it was
poured into ice-water and the resulting solid was filtered and
washed with cold water and identified as mixture of
rotamers of 29 (0.4 g, 73%), in w1:1 ratio. Both rotamers
were isolated by preparative TLC (diethyl ether). Silica-gel

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M. Avalos et al. / Tetrahedron 61 (2005) 7945–7959
7957
Major rotamer, 30P. RfZ0.2 (diethyl ether), mp 221–223 8C
(dec), [a]D C85.08 (c 0.3, CHCl3), nmax 3242, 2973 (NH),
1753 (C]O), 1242 (C–O–C), 1040 (C–O), 1445, 796 cmK1
169.8 (CH3–CO), 169.7 (CH3–CO), 159.0 (C]O), 148.4,
140.1, 132.1, 129.3, 128.7, 127.2 (aromatics), 94.5 (C-1),
76.4 (C-3), 75.2 (C-4), 67.7 (C-5), 62.8 (C-6), 60.0 (C-2),
36.3 (C), 32.6 (3C, (CH3)3C), 20.7 (3C, CH3–CO), 19.1
(CH3). Anal. Calcd for C24H32N2O8: C, 60.49; H, 6.77; N,
5.88. Found: C, 60.00; H, 6.60; N, 5.60.
1
(aromatics); H NMR (400 MHz, CDCl3) d 7.30–7.10 (m,
3H, Ar), 5.75 (d, J1,2Z6.4 Hz, 1H, H-1), 5.34 (d, J3,4
Z
2.8 Hz, 1H, H-3), 5.26 (m, 1H, H-5), 5.18 (d, J2,NHZ1.8 Hz,
0
1H, NH), 4.71 (dd, J5,6Z2.4 Hz, J6,6 Z12.3 Hz, 1H, H-6),
4.55 (dd, J3,4Z2.9 Hz, J4,5Z9.0 Hz, 1H, H-4), 4.32 (dd,
4.1.12. 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-[3-(2-ethyl-6-
methylphenyl)thioureido]-b-D-glucopyranose (33).
Following the procedure described for 13 and using
2-ethyl-6-methylphenyl isothiocyanate, compound 33
(13%) was obtained as a mixture of atropisomers (w1:1),
mp 173–1758 C, [a]D K10.88 (c 0.5, CHCl3); nmax 3300,
3190, 1530 (NH), 1740 (C]O), 1210 (C–O–C), 1060, 1030
0
J2,NHZ2.3 Hz, J1,2Z6.4 Hz, 1H, H-2), 3.97 (dd, J5,6
Z
0
0
5.6 Hz, J6,6 Z12.3 Hz, 1H, H-6 ), 3.22 (sept, JZ6.9 Hz,
1H, CH(CH3)2), 2.18 (s, 3H, CH3), 2.09 (s, 6H, OAc), 2.03
(s, 3H, OAc), 1.23 (d, JZ6.9 Hz, 3H, CH(CH3)2), 1.22 (d,
JZ6.9 Hz, 3H, CH(CH3)2); 13C NMR (100 MHz, CDCl3) d
170.5 (CH3–CO), 170.0 (CH3–CO), 169.7 (CH3–CO), 159.1
(C]O), 149.3, 135.9, 132.6, 129.2, 128.5, 124.4
(aromatics), 92.5 (C-1), 76.2 (C-3), 75.7 (C-4), 67.8 (C-5),
63.0 (C-6), 60.3 (C-2), 28.4 (CH(CH3)2), 24.7 (CH(CH3)2),
23.6 CH(CH3)2), 20.7 (3C, CH3–CO), 18.2 (CH3). Anal.
Calcd for C23H30N2O8: C, 59.73; H, 6.54; N, 6.06. Found:
C, 59.69; H, 6.41; N, 5.97.
1
(C–O), 780 cmK1 (aromatic); H NMR (400 MHz, CDCl3)
d 7.52 (s, 2H, NH–Ar), 7.32–7.14 (m, 6H, Ar), 5.55 (d,
J1,2Z8.6 Hz, 1H, H-1), 5.52 (d, J1,2Z8.9 Hz, 1H, H-1),
5.28 (d, J2,NHZ9.5 Hz, 2H, NH), 5.18 (c, J1,2ZJ2,NH
Z
J2,3Z9.3 Hz, 2H, H-2), 5.13 (t, J4,5ZJ3,4Z9.3 Hz, 2H,
H-4), 4.99 (t, J2,3ZJ3,4Z9.0 Hz, 1H, H-3), 4.97 (t, J2,3
Z
0
J3,4Z9.0 Hz, 1H, H-3), 4.23 (dd, J5,6Z4.3 Hz, J6,6
Z
0
0
Minor rotamer, 30M. RfZ0.3 (diethyl ether), mp 168–
170 8C, [a]D C68.88 (c 0.3, CHCl3); nmax 2953 (NH), 1745
(C]O), 1232 (C–O–C), 1030 (C–O), 1458, 793 cmK1
12.5 Hz, 2H, H-6), 4.08 (bd, J6,6 Z12.2 Hz, 2H, H-6 ),
0
3.70 (ddd, J5,6 Z2.2 Hz, J4,5Z9.6 Hz, J5,6Z4.1 Hz, 2H,
H-5), 2.52 (m, JgemZ22.0 Hz, JZ7.2 Hz, 2H, CH2CH3),
2.41 (m, JgemZ23.0 Hz, JZ7.3 Hz, 2H, CH2CH3), 2.17 (s,
3H, CH3), 2.15 (s, 6H, OAc), 2.14 (s, 3H, CH3), 2.08 (s, 3H,
OAc), 2.07 (s, 3H, OAc), 2.06 (s, 3H, OAc), 1.97 (s, 3H,
OAc), 1.96 (s, 3H, OAc), 1.18 (t, JZ7.7 Hz, 3H, CH2CH3),
1.16 (t, JZ7.7 Hz, 3H, CH2CH3); 13C NMR (50.33 MHz,
CDCl3) d 182.3 (C]S), 170.7 (2C, CH3–CO), 169.2 (2C,
CH3–CO), 136.9, 131.3 (2C), 129.7, 129.1, 127.2
(aromatics), 92.3 (C-1), 72.4 (C-3), 72.2 C-5), 67.9 (C-4),
61.5 (C-6), 57.2 (C-2), 24.2 (CH2CH3), 20.9 (CH3–CO),
20.7 (2C, CH3–CO), 20.5 (CH3–CO), 17.7 (CH3), 14.4
(CH2CH3). Anal. Calcd for C24H32N2O9S: C, 54.95; H,
6.15; N, 5.34; S, 6.11. Found: C, 54.50; H, 6.08; N, 5.37; S,
6.00.
1
(aromatics); H NMR (400 MHz, CDCl3) d 7.30–7.11 (m,
3H, Ar), 5.75 (d, J1,2Z6.3 Hz, 1H, H-1), 5.34 (d, J3,4
Z
2.8 Hz, 1H, H-3), 5.23 (m, 1H, H-5), 5.17 (d, J2,NHZ1.8 Hz,
1H, NH), 4.61 (dd, J3,4Z2.9 Hz, J4,5Z9.2 Hz, 1H, H-4),
0
4.60 (dd, J5,6Z2.4 Hz, J6,6 Z12.4 Hz, 1H, H-6), 4.34 (dd,
0
J2,NHZ2.3 Hz, J1,2Z6.3 Hz, 1H, H-2), 4.04 (dd, J5,6
Z
0
0
4.3 Hz, J6,6 Z12.4 Hz, 1H, H-6 ), 2.77 (sept, JZ6.9 Hz,
1H, CH(CH3)2), 2.32 (s, 3H, CH3), 2.10 (s, 3H, OAc), 2.08
(s, 3H, OAc), 2.04 (s, 3H, OAc), 1.28 (d, JZ6.9 Hz, 3H,
CH(CH3)2), 1.16 (d, JZ6.8 Hz, 3H, CH(CH3)2); 13C NMR
(100 MHz, CDCl3) d 170.5 (CH3–CO), 169.9 (CH3–CO),
169.6 (CH3–CO), 158.6 (C]O), 146.9, 138.5, 132.1, 129.2,
128.5, 124.3 (aromatics), 93.5 (C-1), 75.8 (C-3), 75.7 (C-4),
67.6 (C-5), 62.8 (C-6), 60.2 (C-2), 28.6 (CH(CH3)2), 24.9
(CH(CH3)2), 23.6 CH(CH3)2), 20.7 (3C, CH3–CO), 18.6
(CH3). Anal. Calcd for C23H30N2O8: C, 59.73; H, 6.54; N,
6.06. Found: C, 59.33; H, 6.22; N, 5.95.
4.1.13. (4R,5R)-1-(2-Ethyl-6-methylphenyl)-5-hydroxy-
4-(D-arabino-tetritol-1-yl)imidazolidine-2-thione (35).
To a solution of 1,3,4,6-tetra-O-acetyl-2-deoxy-2-[3-(2-
ethyl-6-methylphenyl)thioureido]-b-D-glucopyranose, 33,
(0.12 g, 0.25 mmol) in methanol (4.0 mL), under vigorous
stirring, was added a saturated solution of ammonia in
methanol (4.0 mL). The process was followed by TLC
(chloroform–methanol, 3:1) and after 12 h at room
temperature, the reaction crude was evaporated to dryness
yielding an oily compound (0.089 g, 99%), as mixture of
atropisomers (w1:1); nmax 3500–3000 (OH, NH), 1650
(C]O), 1450 (NH), 1100, 1050, 1020 (C–O) and 780 cmK1
4.1.11. (M)-1-(2-tert-Butyl-6-methylphenyl)-(3,5,6-tri-O-
acetyl-1,2-dideoxy-a-D-glucofurano)[2,1-d]imidazoli-
dine-2-one (31M). To a solution of (M)-1-(2-tert-butyl-6-
methylphenyl)-(1,2-dideoxy-a-D-glucofurano)[2,1-d]imi-
dazolidine-2-one, 28M, (0.05 g, 0.14 mmol) in pyridine
(0.36 mL), cooled at K20 8C, was added acetic anhydride
(0.36 mL) and the reaction mixture was kept at that
temperature overnight. Then it was poured into ice-water
and the resulting solid was filtered and washed with cold
water and identified as rotamer 31M (0.03 g, 45%), mp 196–
199 8C (dec), [a]D C76.08 (c 0.25, CHCl3), nmax 3366 (NH),
1750, (C]O), 1442, 1373, 1229 (C–O–C), 1035 (C–O),
790, 718 cmK1 (aromatics); 1H NMR (400 MHz, CDCl3) d
7.41–7.13 (m, 3H, Ar), 5.86 (d, J1,2Z5.9 Hz, 1H, H-1), 5.49
(d, J2,NHZ1.5 Hz, 1H, NH), 5.37 (d, J3,4Z2.7 Hz, 1H, H-3),
5.18 (m, 1H, H-5), 4.63 (dd, J3,4Z2.8 Hz, J4,5Z9.3 Hz, 1H,
1
(aromatic); H NMR (400 MHz, DMSO-d6) d 8.05 (s, 1H,
NH, P), 8.03 (s, 1H, NH, M), 7.22–7.07 (m, 6H, Ar, P and
M), 6.72 (d, J5,OHZ6.9 Hz, 1H, C5–OH, P), 6.69 (d,
J5,OHZ7.4 Hz, 1H, C5–OH, M), 5.21 (d, J5,OHZ6.5 Hz, 1H,
H-5, P), 5.17 (d, J5,OHZ6.8 Hz, 1H, H-5, M) 4.81 (br s, 2H,
C10–OH, M and P), 4.060 (m, 4H, C20–OH, C30–OH, M and
P), 4.43 (br s, 02H, C4 –OH, M 0a0 nd P), 3.78–3.35 (m, 12H,
H-4, H-10, H-2 , H-30, H-40, H-4 , P and M), 2.68 (m, Jgem
Z
0
H-4), 4.58 (dd, J5,6Z2.2 Hz, J6,6 Z12.4 Hz, 1H, H-6), 4.28
21.8 Hz, JZ6.9 Hz, 1H, CH2CH3, M), 2.50 (m, 2H,
CH2CH3, P), 2.45 (m, JgemZ22.8 Hz, JZ7.5 Hz, 1H,
CH2CH3, M), 2.30 (s, 3H, CH3, P), 2.12 (s, 3H, CH3, M),
1.17 (t, JZ7.6 Hz, 3H, CH2CH3, P), 1.14 (t, JZ7.6 Hz, 3H,
CH2CH3, M); 13C NMR (100 MHz, DMSO-d6) d 181.1
0
(dd, J2,NHZ2.1 Hz, J1,2Z5.9 Hz, 1H, H-2), 4.03 (dd, J5,6
Z
0
0
4.5 Hz, J6,6 Z12.4 Hz, 1H, H-6 ), 2.31 (s, 3H, CH3), 2.09 (s,
3H, OAc), 2.08 (s, 3H, OAc), 2.03 (s, 3H, OAc), 1.40 (s, 9H,
(CH3)3C); 13C NMR (100 MHz, CDCl3) d 170.5 (CH3–CO),

´
M. Avalos et al. / Tetrahedron 61 (2005) 7945–7959
7958
(C]S, P), 180.9 (C]S, M), 145.0, 142.5, 140.0, 136.7,
135.7, 135.5, 128.1 (2C), 128.0 (2C), 126.3, 125.9
(aromatics M and P), 88.5 (C-5, P), 87.7 (C-5, M), 71.4
(C-100, 2C, M and P), 71.2 (C-20, M), 71.1 (C-20, P), 69.9
(C-30, P), 69.8 (C-30, M), 66.0 (C-4, M), 65.9 (C-4, P), 63.5
(C-4 , M and P), 23.9 (CH2CH3, M), 23.5 (CH2CH3, P), 21.2
(CH3, P), 19.3 (CH3, M), 15.0 (CH2CH3, P), 14.6 (CH2CH3,
M). HRMS: Calcd for MCC1 (C16H25N2O5S): 357.1484.
Found: 357.1483.
(100 MHz, DMSO-d6) d 182.4 (C]S), 144.0, 136.3,
135.9, 128.3, 128.1, 125.7 (aromatics), 94.9 (C-1), 80.3
(C-4), 73.9 (C-3), 68.6 (C-5), 66.0 (C-2), 64.1 (C-6), 23.4
(CH2CH3), 17.8 (CH3), 14.1 (CH2CH3). Anal. Calcd for
C16H22N2O4S: C, 56.79; H, 6.55; N, 8.28; S, 9.47. Found: C,
56.71; H, 6.45; N, 8.23; S, 9.41.
Procedure B. A solution of 35 (0.040 g, 0.112 mmol) in
30% aqueous acetic acid (1.4 mL) was heated at 100 8C for
30 min. After that time the mixture was evaporated to
dryness and the crude obtained characterized as compound
36 (0.037 g, 98%).
4.1.14. 1-(2-Ethyl-6-methylphenyl)-(1,2-dideoxy-a-D-
glucofurano)[2,1-d]imidazolidine-2-thione
(36).
Procedure A. To a solution of 2-amino-2-deoxy-D-gluco-
pyranose hydrochloride (2.44 g, 11.3 mmol) in water
(14 mL) was added NaHCO3 (1.04 g, 12.4 mmol), 2-ethyl-
6-methylphenyl isothiocyanate (2.0 g, 11.3 mmol) and
ethanol (72 mL). The mixture was stirred vigorously and
heated to 80 8C for 2.5 h. The reaction was followed by TLC
(chloroform–methanol 3:1). The solution was evaporated to
dryness and the dark residue obtained was dissolved in 30%
aqueous acetic acid (100 mL) and heated to 100 8C (external
bath) for 30 min. Then the reaction mixture was evaporated
to dryness and treated with 96% ethanol, affording a solid
(0.64 g, 25%), identified as a mixture of rotamers of 36 in a
ratio w1:1, which was purified by flash chromatography,
(chloroform–methanol, 4:1), mp 243–245 8C (dec), [a]D
C1208 (c 0.5, N,N-dimethylformamide), nmax 3460, 3420,
3320 (OH, NH), 1480 (NH), 1030 (C–O), 770 cmK1
4.1.15. 3,5,6-Tri-O-acetyl-1-(2-ethyl-6-methylphenyl)-
(1,2-dideoxy-a-D-glucofurano)[2,1-d]imidazolidine-2-
thione (37). To a solution of 36 (3.0 mmol) in pyridine
(10.0 mL), cooled at K20 8C for 15 min, was added acetic
anhydride (6.0 mL) and the reaction mixture was kept at that
temperature for 24 h. Then it was poured into ice-water and
the resulting solid was filtered and washed with cold water
affording the title compound in 75% yield, as mixture of
rotamers (w1:1). 1H NMR (400 MHz, CDCl3) d 7.32–7.13
(m, 8H, Ar and NH, P and M), 5.93 (d, J1,2Z6.5 Hz, 1H,
H-1, M), 5.90 (d, J1,2Z6.6 Hz, 1H, H-1, P), 5.39 (d, J3,4
2.8 Hz, 2H, H-3, P and M), 5.23 (m, 2H, H-5, P and M), 4.68
Z
0
(dd, J5,6Z2.3, J6,6 Z12.3 Hz, 1H, H-6, P), 4.61 (dd, J5,6
Z
0
2.3 Hz, J6,6 Z10.8 Hz, 1H, H-6, M), 4.56 (dd, J3,4Z2.8 Hz,
J4,5Z9.3 Hz, 2H, H-4, P and M), 4.47 (d, J1,2Z4.7 Hz, 1H,
1
(aromatic); H NMR (400 MHz, DMSO-d6) d 9.07 (s, 1H,
H-2, M), 4.45 (dd, J2,NHZ0.9 Hz, J1,2Z5.9 Hz, 1H, H-2, P),
0
0
0
NH, P), 9.05 (s, 1H, NH, M), 7.24–7.11 (m, 6H, Ar, P and
M), 5.78 (d, J1,2Z6.9 Hz, 1H, H-1, P), 5.76 (d, J1,2Z8.1 Hz,
1H, H-1, M), 5.38 (d, J3,OHZ4.7 Hz, 2H, C3–OH, P and M),
4.02 (dd, J5,6 Z4.3, J6,6 Z12.4 Hz, 1H, H-6 , M), 3.97 (dd,
0
0
0
J5,6 Z5.0, J6,6 Z12.4 Hz, 1H, H-6 , P), 2.74 (m, Jgem
22.6 Hz, JZ7.5 Hz, 1H, CH2CH3, P), 2.62 (m, Jgem
Z
Z
4.77 (d, J5,OHZ5.2 Hz, 1H, C5–OH, P), 4.76 (d, J5,OH
Z
22.6 Hz, JZ7.5 Hz, 1H, CH2CH3, P), 2.49 (m, JZ7.5 Hz,
1H, CH2CH3, M), 2.43 (m, JgemZ22.5 Hz, JZ7.5 Hz, 1H,
CH2CH3, M), 2.34 (s, 3H, CH3, M), 2.18 (s, 3H, CH3, P),
2.13 (s, 3H, OAc), 2.10 (s, 3H, OAc), 2.08 (s, 3H, OAc),
2.06 (s, 3H, OAc), 2.03 (s, 6H, OAc), 1.29 (t, JZ7.6 Hz,
0
5.9 Hz, 1H, C5–OH, M), 4.48 (t, J6,OHZJ6 ,OHZ5.5 Hz, 2H,
C6–OH, P and M), 4.30 (d, J1,2Z7.2 Hz, 1H, H-2, M), 4.28
(d, J1,2Z7.2 Hz, 1H, H-2, P), 4.17 (m, 2H, H-3, P and M),
3.77 (m, 4H, H-4, H-5, P and M), 3.55 (m, 2H, H-6, P and
M), 3.34 (m, 2H, H-60, P and M), 2.59 (m, 2H, CH2CH3, P),
2.41 (m, 2H, CH2CH3, M), 2.23 (s, 3H, CH3, M), 2.09 (s,
3H, CH3, P), 1.17 (t, JZ7.2 Hz, 3H, CH2CH3, P), 1.16 (t,
JZ7.1 Hz, 3H, CH2CH3,M); 13C NMR (100 MHz, DMSO-
d6) d 185.2 (C]S, M), 182.4 (C]S, P), 144.0, 141.9, 136.3,
136.2, 135.9, 128.3 (2C), 128.1 (2C), 126.3, 125.7 (2C)
(aromatics), 95.5 (C-1, M), 94.9 (C-1, P), 80.3 (C-4, P and
M), 73.9 (C-3, P and M), 68.6 (C-5, P and M), 66.0 (C-2, P),
65.9 (C-2, M), 64.1 (C-6, P), 64.0 (C-6, M), 23.4 (CH2CH3,
P and M), 18.8 (CH3, M), 17.8 (CH3, P), 14.7 (CH2CH3, M),
14.1 (CH2CH3, P). Anal. Calcd for C16H22N2O4S: C, 56.79;
H, 6.55; N, 8.28; S, 9.47. Found: C, 56.69; H, 6.53; N, 8.27;
S, 9.45.
3H, CH2CH3, P), 1.27 (t, JZ7.6 Hz, 3H, CH2CH3, M); 13
C
NMR (100 MHz, CDCl3) d 184.2 (C]S, P), 183.5 (C]S,
M), 170.5 (CH3–CO), 169.7 (CH3–CO), 169.6 (CH3–CO),
149.2, 143.9, 141.2, 135.5, 134.8, 134.5, 129.2 (2C), 128.7,
128.6, 126.5, 126.4 (aromatics), 96.3 (C-1, M), 95.7 (C-1,
P), 76.3 (C-3, P and M), 75.2 (C-4, P), 75.1 (C-4, M), 67.5
(C-5, P), 67.4 (C-5, M), 64.1 (C-2, P), 64.0 (C-2, M), 62.6
(C-6, P and M), 23.7 (CH2CH3, P and M), 20.7 (6C,CH3–
CO), 18.6 (CH3, M), 17.9 (CH3, P), 14.4 (CH2CH3, M), 14.2
(CH2CH3, P).
The rotamer 37P was isolated by recrystallization from 96%
ethanol (50%), RfZ0.5, mp 180–182 8C, [a]D C1478 (c 0.5,
CHCl3), nmax 3440 (NH), 1740 (C]O), 1450, 1350, 1240
(C–O–C), 1040 (C–O), 780 cmK1 (aromatic); 1H NMR
(400 MHz, CDCl3) d 7.32–7.13 (m, 3H, Ar), 6.81 (s, 1H,
NH), 5.90 (d, J1,2Z6.6 Hz, 1H, H-1), 5.38 (d, J3,4Z2.9 Hz,
0
Recrystallization from 96% ethanol gave pure material 36P,
with mp 245–247 8C (dec), [a]D C1228 (c 0.5, N,N-
dimethylformamide), nmax 3460, 3320 (OH, NH), 1480
(NH), 1030 (C–O), 790 cmK1 (aromatic); 1H NMR
(400 MHz, DMSO-d6) d 9.07 (s, 1H, NH), 7.22–7.10 (m,
1H, H-3), 5.24 (m, 1H, H-5), 4.68 (dd, J5,6Z2.5 Hz, J6,6
Z
12.3 Hz, 1H, H-6), 4.56 (dd, J3,4Z3.0 Hz, J4,5Z9.1 Hz, 1H,
3H, Ar), 5.78 (d, J1,2Z6.9 Hz, 1H, H-1), 5.38 (d, J3,OH
Z
H-4), 4.45 (dd, J2,NHZ1.5 Hz, J1,2Z6.8 Hz, 1H, H-2), 3.97
(dd, J5,6 Z4.9 Hz, J6,6 Z12.3 Hz, 1H, H-6 ), 2.74 (m,
JgemZ22.6, JZ7.6 Hz, 1H, CH2CH3), 2.62 (m, JgemZ
0
0
0
4.8 Hz, 2H, C3–OH), 4.78 (d, J5,OHZ5.4 Hz, 1H, C5–OH),
0
4.49 (t, J6,OHZJ6 ,OHZ5.6 Hz, 1H, C6–OH), 4.28 (d, J1,2
Z
6.7 Hz, 1H, H-2), 4.17 (d, J3,4Z3.3 Hz, 1H, H-3), 3.74 (m,
2H, H-4, H-5), 3.54 (m, 1H, H-6), 3.33 (m, 1H, H-60), 2.58
(m, JgemZ21.6 Hz, JZ7.5 Hz, 2H, CH2CH3), 2.09 (s, 3H,
CH3), 1.17 (t, JZ7.5 Hz, 3H, CH2CH3); 13C NMR
22.6, JZ7.6 Hz, 1H, CH2CH3), 2.18 (s, 3H, CH3), 2.15 (s,
3H, OAc), 2.14 (s, 3H, OAc), 2.03 (s, 3H, OAc), 1.29 (t, JZ
7.6 Hz, 3H, CH2CH3); 13C NMR (100 MHz, CDCl3) d
184.2 (C]S), 170.5 (CH3–CO), 169.8 (CH3–CO), 169.6

´
M. Avalos et al. / Tetrahedron 61 (2005) 7945–7959
7959
´
8. Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.; Palacios,
´
(CH3–CO), 143.9, 135.5, 134.8, 129.2, 128.6, 126.4
(aromatics), 95.8 (C-1), 75.2 (C-3, C-4), 67.6 (C-5), 64.1
(C-2), 62.6 (C-6), 23.7 (CH2CH3), 20.7 (CH3–CO), 20.6
(2C, CH3–CO), 17.9 (CH3), 14.2 (CH2CH3). Anal. Calcd for
C22H28N2O7S: C, 56.88; H, 6.08; N, 6.03; S, 6.90. Found: C,
56.64; H, 6.14; N, 6.18; S, 7.26.
J. C.; Silvero, G. Tetrahedron 1999, 55, 4401.
´
´
9. Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.; Palacios,
J. C.; Valencia, C. Tetrahedron 1994, 50, 3273.
10. The authors have deposited the atomic coordinates for this
structure with the Cambridge Crystallographic Data Centre.
The coordinates can be obtained, upon request, from the
Director, Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge, CB2 1EZ, UK. Crystal data for 29M,
(CCDC-245086), C18H26N2O5, MrZ350.41, orthorhombic,
Acknowledgements
This work was made possible by the financial support from
´
˚
P212121 aZ8.013(5), bZ16.480(5), cZ26.449(5) A, VZ
3
3493(3) A , ZZ8 (2 molecules), DcalcdZ1.333 g cmK3
,
Ministerio de Ciencia y Tecnologıa (BQU2002-00015 and
˚
l(Mo Ka)Z0.71073 A, mZ0.097 mmK1
,
F(000)Z1504,
BQU2003-05946) and Junta de Extremadura-Fondo Social
Europeo (2PR02-A016). Special thanks to Dr. J. L. Bravo
for his valuable help in NMR studies.
˚
TZ150(2) K, GooF2Z1.026, independent reflectionsZ
61,758 [RintZ0.0580] of a total of 21035 collected reflections,
R(F) obeying F2O2s(F2)Z0.0514, wR(F2)Z0.1087, R(all
data)Z0.0842, wR(F2)Z0.1223.
´
´
11. Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.; Palacios,
J. C.; Valencia, C. Tetrahedron Lett. 1993, 34, 1359.
12. (a) Nakanishi, K.; Solomon, P. H. Infrared Absorption
Spectroscopy 2nd ed.; Holden-Day: San Francisco, 1977; p
25. (b) Nakamoto, K. Infrared and Raman Spectra of
Inorganic and Coordination Compounds 3rd ed.; Wiley:
New York, 1978; p 227.
References and notes
´
1. For Part 3: Avalos, M.; Babiano, R.; Cintas, P.; Hursthouse, M.
´
B.; Jimenez, J. L.; Light, M. E.; Palacios, J. C.; Silvero, G.
Tetrahedron, 2005, 61, see doi:10.1016/j.tet.2005.06.017,
preceding paper.
2. For further information about M and P descriptors, see: Eliel,
E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley: New York, 1994; pp 1119–1122.
13. Tejima, S.; Ness, R. K.; Kaufman, R. L.; Fletcher, H. G., Jr.
Carbohydr. Res. 1968, 7, 485.
14. The authors have deposited the atomic coordinates for this
structure with the Cambridge Crystallographic Data Centre.
The coordinates can be obtained, upon request, from the
Director, Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge, CB2 1EZ, UK. Crystal data for 38P,
(CCDC-241005), C22H28N2O7S, MrZ464.52, orthorhombic,
3. (a) Kalinowski, H.; Kessler, H. Top. Stereochem. 1972, 7, 295.
(b) Oki, M. In The Chemistry of Rotational Isomers; Hafner,
´
K., Lehn, J.-M., Rees, C. W., Rague Schleyer, P. V., Trost,
´
B. M., Zahradnık, R., Eds.; Reactivity and Structure Concepts
in Organic Chemistry; Springer: Berlin, 1993; Vol. 30, p 7.
4. Bergmann, M.; Zervas, L. Ber. 1931, 64, 975.
5. When a-anomer of 9 is utilized as starting material, variable
amounts of 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-D-gluco-
pyranose (38) are formed.1
˚
P212121 aZ11.8399(3), bZ11.9763(3), cZ16.5247(4) A,
˚
VZ2343.17(10) 3A,
ZZ4,
DcalcdZ1.317 g cmK3
,
l(Mo Ka)Z0.71073 A, mZ0.183 mmK1, F(000)Z984, TZ
150(2) K, GooF2Z1.074, independent reflectionsZ4139
[RintZ0.0643] of a total of 24,350 collected reflections, R(F)
obeying F2O2s(F2)Z0.0383, wR(F2)Z0.0920, R(all data)Z
0.0495, wR(F2)Z0.0979.
˚
15. Compounds: 23 (DGsO20.84 kcal molK1), 26 (DGsO
21.76 kcal molK1), 27 (DGsO21.62 kcal molK1), 30
(DGsO21.18 kcal molK1), 36 (DGsO20.50 kcal molK1),
37 (DGsO20.71 kcal molK1), 38 (DGsO20.60 kcal molK1),
and 31 (DGsO20.71 kcal molK1).
6. Equation DG‡(cal molK1)Z1.987Tc[22.961Cln(Tc/Dn)] was
¨
used for this calculation: Sandstrom, J. Dynamic NMR
Spectroscopy; Academic: London, 1982.
´
7. (a) Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.;
´
´
´
16. Avalos, M.; Babiano, R.; Cintas, P.; Higes, F. J.; Jimenez,
J. L.; Palacios, J. C.; Silvero, G. Tetrahedron: Asymmetry
1999, 10, 4071.
Palacios, J. C.; Valencia, C. Tetrahedron 1993, 49, 2655. (b)
´
Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.; Palacios,
´
J. C.; Valencia, C. Tetrahedron 1993, 49, 2676.