New synthetic approaches to sugar ureas. Access to ureido-β- cyclodextrins

Article abstract of DOI:10.1016/j.tet.2005.07.041

An efficient method for the preparation of urea-bridged cyclodextrins using triphosgene in the isocyanation step in an aqueous two-phase system is reported. Per-O-acetylated glycopyranosylamines and 2-amino-2-deoxy-α and β-d-glucose were also transformed

Full text of DOI:10.1016/j.tet.2005.07.041

Tetrahedron 61 (2005) 9058–9069
New synthetic approaches to sugar ureas.
Access to ureido-b-cyclodextrins
´
Oscar Lopez, Susana Maza, Ines Maya, Jose Fuentes and Jose G. Fernandez-Bolanos
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Departamento Quımica Organica, Facultad Quımica, Universidad Sevilla, Apartado 553, E-41071 Seville, Spain
Received 14 May 2005; revised 6 July 2005; accepted 14 July 2005
Available online 3 August 2005
Abstract—An efficient method for the preparation of urea-bridged cyclodextrins using triphosgene in the isocyanation step in an aqueous
two-phase system is reported. Per-O-acetylated glycopyranosylamines and 2-amino-2-deoxy-a and b-D-glucose were also transformed into
the corresponding isocyanates using either an aqueous two-phase or an anhydrous dichloromethane medium, and converted in situ into ureas.
An alternative method for the preparation of sugar-derived ureas consisting of desulfurization of sugar thioureas with mercury oxide is also
presented.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
artificial enzymes28,29 and for separation of enantiomers.30
Much effort has been devoted to the preparation of
cyclodextrin dimers31 in order to improve the binding
properties of the parent structure.28 For this purpose, many
different linkages have been introduced32 in the preparation
of dimers, among which we can find the urea tether.33
Urea functionality is a structural feature present in many
biologically active compounds, such as anti-mycobacterial1
and anti-trypanosomal2 agents, plant and insect growth
regulators,3,4 and as antagonists of natural receptors.5,6
Several ureido derivatives have also proved to be anti-tumor
agents,7–9 and to inhibit HIV protease10–15 and glycine
transporter GlyT-2.16
Sugar ureas have often been obtained by reaction of
glycosylamines or amino sugars with alkyl or aryl
isocyanates34,35 in anhydrous solvents. The synthesis of
fully O-protected sugar isocyanates has also been reported
by Jochims36 by reaction of O-protected amino sugars and
toxic phosgene in anhydrous toluene.
In the carbohydrate field, pseudooligosaccharides incorpor-
ating a urea bridge have been found in glycocinnamoyl
spermidine antibiotics.17 Synthetic N-nitrosoureas derived
from aminosugars have shown to be useful as antitumorals18
and naturally-occuring streptozotocin,19 a N-nitrosourea
derived from 2-amino-2-deoxy-D-glucose, is widely used to
induce diabetes mellitus in experimental animals.20 Further-
more, some ureido glycuronate derivatives have shown to
be a-glucosidase inhibitors21 and N-acyl-N0-b-D-gluco-
pyranosyl ureas exhibit strong inhibition against glycogen
phosphorylase,22 and so they could act as antidiabetic
agents.23
To avoid handling hazardous phosgene, other methods to
afford sugar ureas have been developed. These methods
involve the use of aryl carbamates derived from amino
sugars,37 the use of phosphinimines38 or carbodiimides39 as
intermediates, or the oxidation of glycosyl isocyanides with
pyridine N-oxide proposed by Ichikawa et al.40 By the last
procedure, Prosperi et al. have described the synthesis of
nonsymmetrical urea-linked disaccharides in which two
glycopyranoside units are bound at the 1/2, 1/4, and
1/6 positions.41
Cyclodextrins are cyclic oligosaccharides that possess
practical applications in medicinal24 and supramolecular
chemistry.25 For instance, they are able to form complexes,
improving solubilization and bioavailability of lipophilic
drugs,26,27 and they have also been used in the design of
Recently, we have communicated42 our preliminary results
on the one-pot two-phase preparation of sugar-derived
ureas, including cyclodextrin derivatives. Ureas were
obtained starting from sugar amines and glycopyranosyl-
amines by using triphosgene43 in the isocyanation step.
Herein we report the full details of this procedure and our
results of a different approach to access sugar ureas, based
Keywords: Cyclodextrin; Triphosgene; Sugar isocyanates; Ureas; Mercury
oxide; Two-phase system.
Corresponding author. Tel.: C34 95 4557151; fax: C34 95 4624960;
e-mail: bolanos@us.es
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.041

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O. Lopez et al. / Tetrahedron 61 (2005) 9058–9069
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Scheme 1.
on desulfurization of sugar thioureas through non-isolated
carbodiimides. Fischer’s per-O-acetylated b-D-gluco-
pyranosyl isocyanate 20,44 which we use without isolation
in the synthesis of b-D-glucopyranosyl ureas, has been
recently prepared as a crystalline form from the O-protected
b-D-glucopyranosylamine with triphosgene under Schotten-
Baumann conditions.45
coupling with the same amine). The overall yield for the
preparation of 4 is comparable to a recently described
procedure48 involving
phosphine, carbon dioxide and azide 1.
a polymer-bound triphenyl-
The same method was applied to the preparation of per-O-
acetylated 6-monodeoxy-6-mono[3-(b-D-glucopyranos-2-
yl)ureido]-b-cyclodextrin 15 starting from readily available
hydrochloride 649 (Scheme 2). Treatment of compound 6
with triphosgene under the conditions described above led
to isocyanate 8 which was used in situ for coupling with
amine 2 to give b-cyclodextrin-derived urea 15 in a 46%
yield, calculated from azide 1.
2. Results and discussion
We have carried out the synthesis of b-cyclodextrin dimer 4
starting from per-O-acetylated 6A-azido-6A-deoxy-b-cyclo-
dextrin 1,46 which was prepared in three steps from
b-cyclodextrin: monotosylation with 1-(p-toluenesulfonyl)-
imidazole,47 acetylation and displacement of the tosyloxy
group with sodium azide (Scheme 1).
Similarly, 2-ureido-a and b-D-glucopyranoses 9, 10, 12 and
13 and urea-linked symmetrical pseudo-disaccharides 11
and 14 were obtained (Scheme 2) in good yields (63–86%)
starting from 2-amino-2-deoxy-D-glucopyranose hydro-
halides of a- and b-configurations 550 and 6, and using
alkyl and arylamines or the same hydrohalide for the
coupling reaction with the non-isolated isocyanates 7 and 8
(Table 1, Method A).
Compound 1 was hydrogenated in the presence of palladium
over charcoal to afford monoamino derivative 2, which was
used without further purification for the isocyanation step;
thus, crude 2 was dissolved in a vigorously stirred 1:1
CH2Cl2–saturated aqueous NaHCO3 mixture at 0 8C, to
which solid triphosgene was added. After 15 min of stirring
at 0 8C, another equivalent of monoamino 2 was added to
afford b-cyclodextrin dimer 4 in a 49% yield for the three
steps (hydrogenation, isocyanation of the amine and
Isocyanates 7 and 8 were obtained as syrups in quantitative
yields by extraction with dichloromethane after the
isocyanation step. NMR spectra of crude 7 and 8 showed
no impurities; however, column chromatography of these
Scheme 2.

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9060
Table 1. Synthesis of ureas 9–15 and 22–27
Entry
1
Amines
Products
Ureas
Method
Aa
Bb
9
12
73c
86
58c
—
CH3(CH2)3NH2
2
10
13
63
86
66
—
3
4
11
14
82
78
62
—
5
6
7
15
46
—
CH3(CH2)3NH2
22
25
63
71
65
—
23
26
66
58
64
—
8
9
24
27
99
69
54
—
a Biphasic CH2Cl2/water reaction conditions.
b Monophasic anhydrous CH2Cl2 reaction conditions.
c Isolated yields.
isocyanates led to extensive decomposition. Resonances at
125.9 and 126.7 ppm, for compounds 7 and 8 in 13C NMR
(Table 2), together with strong IR absortions at 2261 and
2253 cmK1, respectively, confirm the presence of a –NCO
moiety. These data are in agreement to those found for
Fischer’s isocyanate 20,44 studied spectroscopically by
Ichikawa.45
22–24, via the non-isolated isocyanate 20, in a 63–99%
yield calculated from 18 (Table 1, Method A).
As hydrohalide 1952,53 could not be obtained as a crystalline
product, the enamino group of compound 17 was removed
by adding aliquots of a saturated solution of Cl2 in moist
CH2Cl2 at 0 8C over a 2 h period, until disappearance of the
starting material by TLC. After solvent removal, crude
hydrohalide 19 was directly used for the next two steps
(isocyanation and coupling of isocyanate 21 with amines) to
afford mannopyranosyl ureas 25–27 (Scheme 3) in a 58–
71% overall yield for the three steps (Table 1, Method A).
By-products formed in chlorolysis of enamine-derived
17 did not interfere with the following two steps. 1H
and 13C NMR spectra of crude isocyanates 2045 and the
hitherto unknown 21 (Table 2), obtained after the
Following the same one-pot biphasic procedure we have
also carried out the preparation of per-O-acetylated
glycopyranosyl ureas of D-gluco and D-manno configuration
(Scheme 3). Crystalline hydrobromide 1851 was prepared
from compound 16 after removal of the enamino group by
oxidation with bromine in moist dichloromethane. Com-
pound 18 was treated subsequently with triphosgene and
with several amines in the biphasic medium to afford ureas

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Table 2. Selected data for isocyanates 7, 8 and 21
1H and 13C NMR dataa (d, ppm; J, Hz)
Compound
H-1
H-2
H-3
H-4
H-5
H-6a
H-6b
7
8
21
6.25
5.59
4.77
3.80
3.78
5.39
5.39
5.14
5.05
5.07
5.01
5.22
4.08
3.83
3.71
4.29
4.29
4.23
4.04
4.07
4.17
J1,2
J2,3
J3,4
J4,5
J5,6a
J5,6b
J6a,6b
7
8
21
3.6
8.6
1.2
10.4
10.2
3.2
9.7
9.4
10.0
9.9
9.7
10.0
3.9
4.6
5.0
2.3
2.1
2.5
12.3
12.6
12.5
C-1
C-2
C-3
C-4
C-5
C-6
NCO
7
8
21
89.9
92.4
81.7
55.6
56.8
69.4
71.9
73.3
70.8
67.3
67.5
65.2
69.8
72.9
74.5
61.3
61.3
62.3
125.9
126.7
129.6
a In CDCl3.
isocyanation step, showed these isocyanates to be the
main products.
obtaining sugar ureas from the corresponding thioureas.
They have been more extensively studied than the ureas
counterparts due to easier preparation of sugar iso-
thiocyanates56 as compared to sugar isocyanates. This
third procedure is based on the desulfurization of sugar
thioureas by treatment with yellow mercury (II) oxide; these
results contrast with the desulfurization of O-unprotected
glucopyanosyl thioureas to afford trans-fused bicyclic
isoureas.57
For the preparation of ureas 9–11, and 22–24, we also
carried out the two steps (isocyanation and coupling with
amines) in an anhydrous monophasic system. Thus,
hydrohalides 5 and 18 were dissolved in dry dichloro-
˚
methane containing 4 A molecular sieves and diisopropyl-
ethylamine, and to the corresponding solutions at rt was
dropwise added a solution of triphosgene in dry dichloro-
methane to give isocyanates 7 and 20, respectively. These
isocyanates were converted in situ into ureas 9–11 and 22–
24 by addition of the corresponding amines in a 54–66%
yield (Table 1, Method B). However, this procedure proved
to be sensitive to moisture, and the use of molecular sieves
proved to be essential for the yield of the reaction.
Furthermore, the yields obtained by using anhydrous
dichloromethane were in some examples lower than those
obtained by the biphasic procedure (Table 1, Method A),
despite moisture sensitivity associated to triphosgene and
isocyanates.54,55
Treatment of thioureas 28–30 in aqueous acetonitrile with
mercury oxide at rt for 1 h led to the corresponding
carbodiimides, detected by TLC as a faster-moving
compound; carbodiimides reacted slowly (24 h) at rt with
water to give ureas 10, 23 and 24 in a 67–74% yield
(Table 3). For N,N-diethyl thiourea 31, no carbodiimide was
detected by TLC and a slower transformation (40 h) of
thiourea into urea 32 took place in a 72% yield.
Per-O-acetylated thiourea 29 was prepared starting from
thiourea 33, easily available in a one-pot fashion from b-D-
glucopyranosylamine.57 Conventional acetylation of 33 at rt
led regiospecifically to the new penta acetyl derivative 34 in
Finally, we have considered a third procedure for
Scheme 3.

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O. Lopez et al. / Tetrahedron 61 (2005) 9058–9069
9062
Table 3. Synthesis of ureas by desulfurization of thioureas 28–31
Entry
1
Thiourea
R1
R2
H
R3
Urea
Yield (%)
67
28
10
2
3
4
29
30
31
H
H
23
24
32
74
68
72
CH3CH2–
CH3CH2–
a 73% yield (Scheme 4); probably due to steric hindrance no
acetylation took place on the nitrogen attached to the sugar
moiety. The strong deshielding exhibited by the NH proton
in 1H NMR of 34 (12.01 ppm) indicated the presence of an
intramolecular hydrogen bonding with the carbonyl group
of the vicinal N-acetyl moiety. Li et al. have recently
reported58 the use of imidazole as a mild base for the
selective anomeric O-deacetylation of carbohydrates; using
the same procedure we have carried out the selective
N-deacetylation of 34 to give tetra-O-acetylated 29 in a 86%
yield (Scheme 4).
tetra-O-acetyl-b-D-glucopyranosylisothiocyanate51 with
the corresponding amines in EtOAc at rt.
In conclusion, we report a practical one-pot two-step
synthesis in an aqueous two-phase system of urea-tethered
cyclodextrin dimer 4 and of 6-monodeoxy-6-mono(N0-
glucopyranos-2-ylureido)-b-cyclodextrin 15 through non-
isolated sugar isocyanates. This procedure was also
successfully applied to the preparation of other symmetrical
and unsymmetrical N,N0-disubstituted sugar ureas including
pseudodisaccharides with a (1/1) or (2/2) urea linkage.
An anhydrous monophasic system was also used for the
two-step synthesis, although the yields were generally
lower. We also report the desulfurization of O-protected
sugar thioureas with yellow mercury (II) oxide in aqueous
Tetra-O-acetyl thioureas 28, 31 and known 3051 were
prepared by coupling reaction of 1,3,4,6-tetra-O-acetyl-2-
deoxy-2-isothiocianato-a-D-glucopyranose59 and 2,3,4,6-
Scheme 4.

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acetonitrile as an alternative pathway for the preparation of
sugar ureas.
3.3. General methods for the synthesis of ureas 9–15,
22–27 and 32.
Method A. To a vigorously stirred solution of the
hydrohalides 5, 6 or 18 (0.6 mmol) in an 1:1 mixture of
CH2Cl2 and saturated aqueous NaHCO3 (12 mL) at 0 8C in
an ice bath was added triphosgene (0.22 mmol); after
10 min of stirring, butylamine, p-toluidine, or the hydro-
halides 5, 6 or 18 (0.66 mmol) were added. For the
preparation of D-glucosamine derived ureas 9–14 the
coupling with the amines was performed at rt for 10 min;
for the preparation of glycopyranosyl ureas 22–24 the
coupling of the isocyanate with the amines was carried out
at 0 8C for 20 min. Conventional work-up and column
chromatography afforded ureas 9–14 and 22–24. For the
preparation of 15, this procedure was carried out starting
from hydrochloride 6 (0.13 mmol). Azide 1 (260 mg,
0.13 mmol) was hydrogenated as described in Section 3.2
to give amino cyclodextrin derivative 2, which was added to
the crude isocyanate 8 and the coupling reaction took place
at rt for 15 min.
3. Experimental
3.1. General procedures
Melting points were recorded on an Gallenkamp apparatus
and are uncorrected. Optical rotations were measured with a
Perkin-Elmer 241 MC polarimeter, and IR spectra (KBr
disks) were obtained with an FT-IR Bomem MB-120
spectrophotometer. H (300 and 500 MHz) and 13C (75.5
1
and 125.7 MHz) NMR spectra were recorded on Bruker
AMX-300 and AMX-500 spectrometers. The assignments
of 1H and 13C signals were confirmed by homonuclear
COSY and heteronuclear 2D correlated spectra, respect-
ively. Mass spectra (EI, CI and FAB) were recorded on
Kratos MS80-RFA and Micromass AutoSpec-Q mass
spectrometers with a resolution of 1000 or 60,000 (10%
valley definition). For the FAB spectra, ions were produced
by a beam of xenon atoms (6–7 keV), using thioglycerol as
matrix and NaI as salt. MALDI spectra were recorded with a
TOFSPEC spectrometer. TLC was performed on aluminium
pre-coated sheets (E. Merck Silica Gel 60 F254); spots were
visualized by UV light, by charring with 10% H2SO4 in
EtOH. Column chromatography was performed using
E. Merck Silica Gel 60 (40–63 mm).
In the case of ureas 25–27, to a solution of enamine 17
(0.6 mmol) in wet CH2Cl2 (10 mL) at 0 8C were added small
portions of a saturated solution of Cl2 in CH2Cl2 until
disappearance of the starting material by TLC. Then the
mixture was concentrated to dryness and the residue
containing hydrochloride 19 was treated as described
above to give ureas 25–27.
Method B. To a stirred mixture of hydrohalides 5 or 18
(0.6 mmol) and N,N-diisopropylethylamine (DIEA,
˚
1.8 mmol) in CH2Cl2 (6 mL) containing 4 A molecular
3.2. N,N0-Bis[icosa-O-acetyl-6A-deoxy-b-cyclodextrin-
6A-yl]urea (4)
sieves under Ar at rt was dropwise added a solution of
triphosgene (0.2 mmol) in dry CH2Cl2 (3 mL) over 30 min.
After a further 10 min of stirring a solution of butylamine or
p-toluidine (0.6 mmol) in dry CH2Cl2 (3 mL) was added in
one portion. In the case of adding the hydrohalides 5 or 18
(0.6 mmol), their solutions in CH2Cl2 (3 mL) had an extra
portion of DIEA (1.2 mmol). The reaction mixture was
stirred at rt for 10 min. Conventional work-up and column
chromatography afforded ureas 9–11 and 22–24.
A solution of 6A-azido-6A-deoxy-b-cyclodextrin 1 (260 mg,
0.13 mmol) in methanol (10 mL) was hydrogenated at
atmospheric pressure by stirring with 10% Pd(C) catalyst
for 2.5 h at rt. After filtration of the mixture through a Celite
pad, the filtrate was concentrated to dryness to afford the
crude amine 2 and divided into two equal portions. One
portion was dissolved in an 1:1 CH2Cl2–saturated aqueous
NaHCO3 mixture (12 mL), cooled to 0 8C in an ice bath and
treated with triphosgene (6.5 mg, 0.022 mmol). After
15 min of vigorous stirring the other portion of amine 2
was added and the stirring was maintained at rt for 15 min.
Conventional work-up and column chromatography
(CH2Cl2/40:1 CH2Cl2–MeOH) afforded cyclodextrin
dimer 4 (127 mg, 49%) as a white amorphous powder, mp
172–178 8C; [a]D26 C117 (c 1.1, CH2Cl2); lit.33 [a]2D5 C121
(c 1.0, CHCl3); IR nmax 3300, 1748, 1541, 1433, 1371, 1233,
Method C. To a solution of thioureas 28–31 (0.44 mmol) in
1:1 water–acetonitrile (20 mL) was added yellow mercury
(II) oxide (572 mg, 2.64 mmol). The mixture was stirred at
rt in the darkness for 24–40 h and then it was filtered
through a Celite pad. The filtrate was concentrated to
dryness and purified by column chromatography.
1
1042 cmK1; H NMR (500 MHz, CDCl3) d 5.32–5.25 (m,
3.3.1. N-Butyl-N0-(1,3,4,6-tetra-O-acetyl-2-deoxy-a-D-
glucopyranos-2-yl)urea (9). Method A. Column chroma-
tography (CH2Cl2/40:1 CH2Cl2–MeOH) gave 9: 196 mg,
73% as a syrup.
7H, H-3A–G), 5.17 (d, 1H, J1,2Z3.5 Hz, H-1A), 5.14–5.11
(m, 1H, NH), 5.10–5.05 (m, 6H, H-1B–G), 4.87–4.71 (m, 7H,
H-2A–G), 4.58–4.49 (m, 6H, H-6aB–G), 4.31–4.23 (m, 6H, H-
6bB–G), 4.18–4.11 (m, 6H, H-5B–G), 3.98–3.94 (m, 1H, H-
5A), 3.88–3.82 (m, 1H, H-6aA), 3.76–3.64 (m, 7H, H-4A–G),
3.46–3.41 (m, 1H, H-6bA), 2.14–2.03 (20 s, 60H, 20Ac);
13C NMR (125.7 MHz, CDCl3) d 170.6–170.3, 169.6–169.3
(CH3CO), 158.2 (CO urea), 96.9–96.7 (C-1), 77.8–76.5 (C-
Method B. Column chromatography gave 9: 150 mg, 58%.
RfZ0.33 (40:1 CH2Cl2–MeOH); [a]2D5 C62 (c 0.5,
CH2Cl2); IR nmax 3322, 2920, 1750, 1642, 1561, 1370,
1
1221, 1125, 1007 cmK1; H NMR (500 MHz, CDCl3) d
4
6
A–G), 71.2–69.4 (C-2A–G, C-3A–G, C-5A–G), 62.9–62.4 (C-
6.47 (d, 1H, J2,NHZ9.2 Hz, NH0), 6.16 (d, 1H, J1,2Z3.5 Hz,
B–G), 40.4 (C-6A), 20.8–20.6 (CH3CO); MALDITOF-MS
H-1), 5.19–5.17 (m, 2H, H-3, H-4), 4.43 (t, 1H, JNH,CH Z
2
m/z 3980 [MCH]C. Anal. Calcd for C165H220N2O109 4H2O:
5.5 Hz, NH), 4.31 (m, 1H, H-2), 4.22 (dd, 1H, J5,6aZ4.2 Hz,
J6a,6bZ12.5 Hz, H-6a), 4.03 (dd, 1H, J5,6bZ2.2 Hz, H-6b),
C, 48.96; H, 5.68; N, 0.96, found: C, 48.72; H, 5.35; N, 0.89.

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1
3.95 (m, 1H, H-5), 3.08 (m, 2H, CH2a), 2.14, 2.06, 2.02,
2.01 (4s, 12H, 4Ac), 1.40 (m, 2H, CH2b), 1.29 (m, 2H,
CH2g), 0.88 (t, 3H, JZ7.4 Hz, CH3); 13C NMR
(125.7 MHz, CDCl3) d 171.8, 170.7, 169.1, 168.6 (4 CO),
156.7 (CO urea), 91.5 (C-1), 71.2 (C-3), 69.7 (C-5), 67.6
(C-4), 61.7 (C-6), 52.0 (C-2), 40.3 (CH2a), 32.1 (CH2b),
20.9, 20.8, 20.7, 20.5 (4 CH3CO), 19.9 (CH2g), 13.7 (CH3);
FAB-MS m/z 469 ([MCNa]C, 100%), 915 ([2MCNa]C,
10%); EI-MS m/z 446 ([M]C, 1%); HREI-MS m/z calcd for
[M]CC19H30N2O10: 446.1900, found: 446.1897.
1665, 1582, 1370, 1044, 910 cmK1; H NMR (500 MHz,
CDCl3) d 5.68 (d, 1H, J1,2Z8.5 Hz, H-1), 5.14–5.10 (m, 2H,
H-3, H-4), 4.57 (d, 1H, J2,NHZ9.5 Hz, NH0), 4.55 (t, 1H,
JNH,CH Z5.5 Hz, NH), 4.27 (dd, 1H, J5,6aZ5.0 Hz, J6a,6b
Z
2
12.5 Hz, H-6a), 4.12 (dd, 1H, J5,6bZ2.0 Hz, H-6b), 4.08 (m,
1H, H-2), 3.81 (m, 1H, H-5), 3.12 (m, 2H, CH2a), 2.12,
2.09, 2.05, 2.03 (4s, 12H, 4Ac), 1.43 (m, 2H, CH2b), 1.31
(m, 2H, CH2g), 0.90 (t, 3H, JZ7.1 Hz, CH3); 13C NMR
(125.7 MHz, CDCl3) d 171.3, 170.7, 169.6, 169.3 (4CO),
157.0 (CO urea), 93.3 (C-1), 73.1, 72.9 (C-3, C-5), 67.9
(C-4), 61.8 (C-6), 54.2 (C-2), 40.2 (CH2a), 32.2 (CH2b),
20.9, 20.7, 20.6, (4 CH3CO), 19.9 (CH2g), 13.7 (CH3);
FAB-MS m/z 469 ([MCNa]C, 92%), 915 ([2MCNa]C,
10%); HRCI-MS m/z calcd for [MCH]CC19H31N2O10:
447.1978, found: 447.1981.
3.3.2. N-(p-Methylphenyl)-N0-(1,3,4,6-tetra-O-acetyl-2-
deoxy-a-D-glucopyranos-2-yl)urea (10). Method A.
Column chromatography (CH2Cl2/40:1 CH2Cl2–MeOH)
gave 10 as a white solid: 182 mg, 63%.
Method B. Column chromatography gave 10: 191 mg, 66%.
3.3.5. N-(p-Methylphenyl)-N0-(1,3,4,6-tetra-O-acetyl-2-
deoxy-b-D-glucopyranos-2-yl)urea (13). Method A.
Column chromatography (CH2Cl2/40:1 CH2Cl2–MeOH)
gave 13: 248 mg, 86% as a white solid; mp 184–186 8C;
[a]1D8 C32 (c 1.0, CH2Cl2); IR nmax 3304, 2918, 1748, 1636,
Method C. The mixture was stirred for 24 h and purified by
column chromatography to give 10: 128 mg, 67%; mp 184–
188 8C; Rf 0.30 (40:1 CH2Cl2–MeOH); [a]2D3 C103 (c 1.2,
CH2Cl2); IR nmax 3345, 1753, 1659, 1603, 1533, 1514,
1370, 1223, 1132, 926 cmK1; 1H NMR (500 MHz, CDCl3)
1570, 1454, 1377, 1084, 1040, 820 cmK1 1H NMR
;
(300 MHz, CDCl3) d 7.14–7.00 (m, 5H, Ar–H, NH), 5.78
(d, 1H, J1,2Z8.7 Hz, H-1), 5.27 (t, 1H, J2,3Z9.0 Hz, J3,4Z
d 7.09 (m, 4H, Ar–H), 6.97 (s, 1H, NH), 6.23 (d, 1H, J1,2
3.4 Hz, H-1), 5.19 (m, 2H, H-3, H-4), 4.41 (t, 1H, J2,NH
8.1 Hz, NH0), 4.24 (m, 1H, H-2), 4.24 (dd, 1H, J5,6a
Z
Z
Z
9.5 Hz, H-3), 5.25 (d, 1H, NH0), 5.10 (t, 1H, J4,5Z9.6 Hz,
H-4), 4.25 (dd, 1H, J5,6aZ4.6 Hz, J6a,6bZ12.3 Hz, H-6a),
4.10 (dd, 1H, J5,6bZ1.5 Hz, H-6b), 4.05 (m, 1H, H-2), 3.82
(m, 1H, H-5), 2.27 (s, 3H, Me), 2.08, 2.06, 2.02 (4s, 12H,
4Ac); 13C NMR (75.5 MHz, CDCl3) d 171.2, 170.7, 169.5,
169.4 (4CO), 155.4 (CO urea), 135.4, 133.9, 129.8, 121.4
(Ar), 92.8 (C-1), 72.7 (C-3), 72.6 (C-5), 68.1 (C-4), 61.8 (C-
6), 54.0 (C-2), 20.9, 20.8, 20.6 (CH3Ar, 4Ac); FAB-MS m/z
480 ([M]C, 22%), 503 ([MCNa]C, 60%), 983 ([2MC
Na]C, 11%); HRFAB-MS m/z calcd for [M]CC22H28N2O10:
480.1744, found: 480.1739. Anal. Calcd for C22H28N2O10:
C, 55.00; H, 5.87; N, 5.83, found: C, 55.09; H, 5.90; N, 5.93.
4.0 Hz, J6a,6bZ12.4 Hz, H-6a), 4.05 (dd, 1H, J5,6bZ2.2 Hz,
H-6b), 3.97 (m, 1H, H-5), 2.29 (s, 3H, CH3), 2.08, 2.07,
2.03, 2.01 (4s, 12H, 4Ac); 13C NMR (125.7 MHz, CDCl3) d
171.5, 170.8, 169.1, 168.7 (4CO), 155.2 (CO urea), 135.1,
134.3, 129.8, 121.7 (Ar), 91.2 (C-1), 70.9 (C-3), 69.7 (C-5),
67.6 (C-4), 61.6 (C-6), 51.7 (C-2), 20.7, 20.7, 20.7, 20.5
(CH3Ar, 4Ac); FAB-MS m/z 503 ([MCNa]C, 100%);
HREI-MS m/z calcd for [M]CC22H28N2O10: 480.1744,
found: 480.1740.
3.3.3. N,N0-Bis(1,3,4,6-tetra-O-acetyl-2-deoxy-a-D-gluco-
pyranos-2-yl)urea (11). Method A. Column chromato-
graphy (CH2Cl2/40:1 CH2Cl2–MeOH) gave 11 as a white
solid: 177 mg, 82%.
3.3.6. N,N0-Bis(1,3,4,6-tetra-O-acetyl-2-deoxy-b-D-gluco-
pyranos-2-yl)urea (14). Method A. Column chromato-
graphy (CH2Cl2/40:1 CH2Cl2–MeOH) gave 14 as a white
solid: 169 mg, 78%. Rf 0.18 (40:1 CH2Cl2–MeOH); mp
218–220 8C; [a]2D2 C25 (c 1.0, CH2Cl2); IR nmax 3331,
Method B. Column chromatography gave 11: 134 mg, 62%;
mp 193–194 8C; Rf 0.12 (40:1 CH2Cl2–MeOH); [a]D18
C1158 (c 1.0, CH2Cl2); IR nmax 3366, 2963, 1753, 1562,
1373, 1227, 1040, 926 cmK1; 1H NMR (300 MHz, CDCl3)
d 6.09 (d, 1H, J1,2Z3.6 Hz, H-1), 5.16 (t, 1H, J3,4Z10.0 Hz,
J4,5Z9.8 Hz, H-4), 5.09 (t, 1H, J2,3Z10.5 Hz, H-3), 4.66 (d,
1H, J2,NHZ9.4 Hz, NH), 4.28 (ddd, 1H, H-2), 4.20 (dd, 1H,
2940, 1750, 1659, 1599, 1433, 1371, 1227, 1040, 907 cmK1
;
1H NMR (300 MHz, CDCl3) d 5.73 (d, 1H, J1,2Z8.7 Hz,
H-1), 5.22 (d, 1H, J2,NHZ8.9 Hz, NH), 5.18 (t, 1H, J2,3
Z
8.7 Hz, J3,4Z9.5 Hz, H-3), 5.10 (t, 1H, J4,5Z9.5 Hz, H-4),
4.26 (dd, 1H, J5,6aZ5.0 Hz, J6a,6bZ12.4 Hz, H-6a), 4.10 (q,
1H, H-2), 4.10 (dd, 1H, J5,6bZ1.5 Hz, H-6b), 3.83 (ddd, 1H,
H-5), 2.08, 2.06. 2.03 (4s, 12H, 4Ac); 13C NMR (75.5 MHz,
CDCl3) d 171.3, 170.6, 169.7, 169.4 (4CO), 156.2 (CO
urea), 93.3 (C-1), 72.7 (C-3), 72.6 (C-5), 68.1 (C-4), 61.9
(C-6), 54.2 (C-2), 20.8, 20.7, 20.6 (4Ac); FAB-MS m/z 743
([MCNa]C, 100%); HRFAB-MS m/z calcd for [MC
H]CC29H41N2O19: 721.2303, found: 721.2286. Anal.
Calcd for C29H40N2O19: C, 48.33; H, 5.59; N, 3.89,
found: C, 48.37; H, 5.58; N, 3.93.
J5,6aZ4.1 Hz, J6a,6bZ12.5 Hz, H-6a), 4.02 (dd, 1H, J5,6b
Z
2.1 Hz, H-6b), 3.94 (ddd, 1H, H-5), 2.14, 2.06, 2.00 (4s,
12H, 4Ac); 13C NMR (75.5 MHz, CDCl3) d 172.0, 170.7,
169.0, 168.6 (4CO), 155.5 (CO urea), 91.2 (C-1), 70.9
(C-3), 69.7 (C-5), 67.5 (C-4), 61.6 (C-6), 51.9 (C-2), 20.8,
20.7, 20.6, 20.5 (4Ac); FAB-MS m/z 743 ([MCNa]C,
100%); HRFAB-MS m/z calcd for [MCH]CC29H41N2O19:
721.2303, found: 721.2296. Anal. Calcd for C29H40N2O: C,
48.33; H, 5.59; N, 3.89, found: C, 48.13; H, 5.54; N, 3.96.
3.3.7. Icosa-O-acetyl-6A-deoxy-6A-[3-(10,30,40,60-tetra-O-
acetyl-b-D-glucopyranos-20-yl)ureido)]-b-cyclodextrin
(15). Method A. Column chromatography (CH2Cl2/40:1
CH2Cl2–MeOH) gave 15: 140 mg, 46%, as a white solid;
mp 146–152 8C; Rf 0.31 (40:1 CH2Cl2–MeOH, 2 elutions);
[a]2D6 C101 (c 1.0, CH2Cl2); IR nmax 3295, 1746, 1520,
3.3.4. N-Butyl-N0-(1,3,4,6-tetra-O-acetyl-2-deoxy-b-D-
glucopyranos-2-yl)urea (12). Method A. Column chroma-
tography (CH2Cl2/40:1 CH2Cl2–MeOH) gave 12 as a
syrup: 230 mg, 86%. Rf 0.33 (40:1 CH2Cl2–MeOH); [a]D23
C33 (c 0.8, CH2Cl2); IR nmax 3356, 2926, 2870, 1769,

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O. Lopez et al. / Tetrahedron 61 (2005) 9058–9069
´
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1
1456, 1366, 1221 cmK1; H NMR (500 MHz, CDCl3) d
(300 MHz, CDCl3) d 7.14–7.06 (m, 4H, Ar–H), 6.87 (s,
0
5.80 (d, 1H, J1,2Z8.9 Hz, H-10), 5.35–5.21 (m, 8H, H-3A–G
,
1H, NH), 5.74 (d, 1H, J1,NH Z9.3 Hz, NH ), 5.29 (t, 1H,
0
H-30), 5.14 (d, 1H, J1,2Z3.5 Hz, H-1), 5.15–5.12 (m, 1H,
J2,3Z9.6 Hz, J3,4Z9.5 Hz, H-3), 5.21 (t, 1H, J1,2Z9.4 Hz,
H-1), 5.03 (t, 1H, J4,5Z10.0 Hz, H-4), 4.89 (t, 1H, H-2),
4.29 (dd, 1H, J5,6aZ4.5 Hz, J6a,6bZ12.5 Hz, H-6a), 4.05
(dd, 1H, J5,6bZ1.9 Hz, H-6b), 3.79 (ddd, 1H, H-5), 2.28 (s,
3H, Me), 2.05, 2.02, 2.01, 1.99 (4s, 12H, 4Ac); 13C NMR
(75.5 MHz, CDCl3) d 171.0, 170.7, 169.9, 169.6 (4CO),
154.4 (CO urea), 134.8, 129.8, 121.5 (Ar), 80.0 (C-1), 73.3
(C-5), 72.9 (C-3), 70.4 (C-2), 68.3 (C-4), 61.8 (C-6), 20.8,
20.7, 20.6 (CH3Ar, 4CH3CO); FAB-MS m/z 481 ([MC
H]C, 80%), 503 ([MCNa]C, 45%); HRFAB-MS m/z calcd
for [MCH]CC22H29N2O10: 481.1822, found: 481.1813.
Anal. Calcd for C22H28N2O10 H2O: C, 53.01; H, 6.07; N,
5.62, found: C, 53.33; H, 5.78; N, 5.37.
0
0
0
NH), 5.10 (t, 1H, J3 ,4 Z10.0 Hz, H-4 ), 5.09–5.06 (m, 5H,
H-1B–F), 4.98 (d, 1H, J1,2Z3.0 Hz, H-1), 4.94–4.91 (m, 1H,
NH–CH2), 4.89 (dd, 1H, J1,2Z4.5 Hz, J2,3Z8.5 Hz, H-2),
4.84 (dd, 1H, J1,2Z4.0 Hz, J2,3Z9.7 Hz, H-2), 4.81 (dd, 1H,
J1,2Z3.5 Hz, J2,3Z10.0 Hz, H-2), 4.80 (dd, 1H, J1,2
3.5 Hz, J2,3Z9.5 Hz, H-2), 4.77 (dd, 1H, J1,2Z4.1 Hz,
J2,3Z9.5 Hz, H-2), 4.75 (dd, 1H, J1,2Z3.6 Hz, J2,3
9.5 Hz, H-2), 4.67 (dd, 1H, J1,2Z3.5 Hz, J2,3Z10.0 Hz,
H-2), 4.65–4.47 (m, 6H, H-6aB–G), 4.33–4.22 (m, 7H,
H-6bB–G, H-6a0), 4.18–4.07 (m, 8H, H-5B–G, H-20, H-6b0),
4.01–3.97 (m, 1H, H-5A), 3.94–3.89 (m, 1H, H-50), 3.76–
3.59 (m, 8H, H-4A–G, H-6aA), 3.47–3.42 (m, 1H, H-6bA),
2.16–1.99 (24s, 72H, 24Ac); 13C NMR (125.7 MHz,
CDCl3) d 171.5, 170.9–170.3, 169.6–169.3 (24CO), 157.7
(CO urea), 97.4, 97.0, 96.9, 96.9, 96.8, 96.5, 96.5 (C-1A–G0),
92.8 (C-10), 78.4 (C-4A), 77.2–76.1 (C-4B–G), 72.8 (C-5 ),
72.40 (C-30), 71.5–69.0 (C-2A–G, C-3A–G, C-5A–G), 68.1
(C-4 ), 63.0, 62.8, 62.8, 62.5, 62.4, 62.2 (C-6B–G), 61.8
(C-60), 54.0 (C-20), 40.9 (C-6A), 20.9–20.6 (24Ac); FAB-
MS m/z 2370 ([MCNa]C, 29%). Anal. Calcd for
C97H130N2O64 2H2O: C, 48.87; H, 5.67; N, 1.18, found:
C, 48.50; H, 5.24; N, 1.31.
Z
Z
3.3.10. N,N0-Bis(2,3,4,6-tetra-O-acetyl-b-D-glucopyrano-
syl)urea (24). Method A. Column chromatography
(CH2Cl2/40:1 CH2Cl2–MeOH) yielded 24 as a white
solid: 214 mg, 99%.
Method B. Column chromatography yielded 24: 117 mg,
54%.
Method C. The mixture was stirred for 24 h and purified by
column chromatography to give 24: 197 mg, 68%. Rf 0.19
(40:1 CH2Cl2–MeOH); mp: 152–155 8C. [a]1D8 K5 (c 1.0,
CH2Cl2); IR nmax 3362, 1750, 1543, 1435, 1370, 1229,
3.3.8. N-Butyl-N0-(2,3,4,6-tetra-O-acetyl-b-D-glucopyra-
nosyl)urea (22). Method A. Column chromatography
(hexane/1:1 hexane–EtOAc) yielded 22 as a syrup:
169 mg, 63%.
1
1036, 909 cmK1; H NMR (300 MHz, CDCl3) d 5.77 (d,
1H, J1,NHZ9.1 Hz, NH), 5.28 (t, 1H, J1,2Z9.4 Hz, J2,3
9.5 Hz, H-2), 5.02 (m, 2H, J3,4Z9.5 Hz, J4,5Z10.0 Hz, H-1,
H-4), 4.85 (t, 1H, H-3), 4.29 (dd, 1H, J5,6aZ4.5 Hz, J6a,6b
Z
Method B. Column chromatography yielded 22: 174 mg,
65%. Rf 0.24 (40:1 CH2Cl2–MeOH); [a]2D2 0 (c 0.7,
CH2Cl2); IR nmax 3329, 2957, 1753, 1657, 1562, 1433,
Z
12.5 Hz, H-6a), 4.07 (dd, 1H, J5,6bZ2.0 Hz, H-6b), 3.81
(ddd, 1H, H-5), 2.05, 2.04, 2.01, 1.99 (4s, 12H, 4Ac); 13C
NMR (75.5 MHz, CDCl3) d 171.1, 170.6, 169.9, 169.6
(4CO), 155.3 (CO urea), 80.0 (C-1), 73.2 (C-5), 72.8 (C-2),
70.5 (C-3), 68.2 (C-4), 61.7 (C-6), 20.7, 20.6 (4CH3CO);
CI-MS m/z 721 ([MCH]C, 9%); HRCI-MS m/z calcd for
[MCH]CC29H41N2O19: 721.2303, found: 721.2290. Anal.
Calcd for C29H40N2O19 H2O: C, 47.16; H, 5.73; N, 3.79,
found: C, 47.10; H, 5.74; N, 3.55.
1368, 1227, 1101, 1036, 907 cmK1; H NMR (300 MHz,
1
0
CDCl3) d 5.28 (m, 2H, J1,NH Z9.3 Hz, J2,3Z9.5 Hz, J3,4
Z
9.5 Hz, NH0, H-3), 5.14 (t, 1H, J1,2Z9.4 Hz, H-1), 5.04 (t,
1H, J4,5Z9.7 Hz, H-4), 4.87 (t, 1H, H-2), 4.62 (t, 1H,
JNH,CH Z6.5 Hz, NH), 4.30 (dd, 1H, J5,6aZ4.3 Hz, J6a,6b
Z
2
12.5 Hz, H-6a), 4.06 (dd, 1H, J5,6bZ1.8 Hz, H-6b), 3.79
(ddd, 1H, H-5), 2.05, 2.03, 2.00, 1.99 (4s, 12H, 4Ac), 3.12
(q, 2H, CH2a), 1.43 (m, 2H, CH2b), 1.29 (m, 2H, CH2g),
0.89 (t, 3H, JZ7.2 Hz, CH3); 13C NMR (75.5 MHz,
CDCl3) d 171.2, 170.7, 169.9, 169.6 (4 CO), 156.2 (CO
urea), 80.2 (C-1), 73.1 (C-5), 72.9 (C-3), 70.6 (C-2),
68.3 (C-4), 61.8 (C-6), 40.2 (CH2a), 32.0 (CH2b), 20.7,
20.6 (4 CH3CO), 19.9 (CH2g), 13.7 (CH3); FAB-MS
m/z 447 ([MCH]C, 40%), 469 ([MCNa]C, 100%);
HRFAB-MS m/z calcd for [MCH]CC19H31N2O10:
447.1979, found: 447.1971.
3.3.11. N-Butyl-N0-(2,3,4,6-tetra-O-acetyl-b-D-manno-
pyranosyl)urea (25). Method A. Column chromatography
(CH2Cl2/40:1 CH2Cl2–MeOH) yielded 25 as a syrup:
190 mg, 71%. Rf 0.22 (1:1 hexane–EtOAc); [a]2D1 K19 (c
0.8, CH2Cl2); IR nmax 3314, 2932, 1748, 1663, 1370, 1225,
1
1053, 964 cmK1; H NMR (300 MHz, CDCl3) d 5.41 (dd,
0
1H, J1,2Z1.2 Hz, J1,NH Z9.6 Hz, H-1), 5.35 (dd, 1H, J2,3
Z
3.3 Hz, H-2), 5.26 (d, 1H, NH0), 5.20 (t, 1H, J3,4Z10.0 Hz,
J4,5Z9.8 Hz, H-4), 5.08 (dd, 1H, H-3), 4.60 (t, 1H, JNH,CH
3.3.9. N-(p-Methylphenyl)-N0-(2,3,4,6-tetra-O-acetyl-b-
D-glucopyranosyl)urea (23). Method A. Column chroma-
tography (hexane/1:1 hexane–EtOAc) yielded 23 as a
white solid, 190 mg, 66%.
Z
2
6.6 Hz, NH), 4.30 (dd, 1H, J5,6aZ5.0 Hz, J6a,6bZ12.4 Hz,
H-6a), 4.06 (dd, 1H, J5,6bZ2.3 Hz, H-6b), 3.75 (ddd, 1H,
H-5), 3.15 (q, 2H, JZ6.6 Hz, CH2a), 2.18, 2.06, 2.02, 1.95
(4s, 12H, 4Ac), 1.44 (m, 2H, CH2b), 1.30 (m, 2H, CH2g),
0.89 (t, 3H, JZ7.2 Hz, CH3); 13C NMR (75.5 MHz, CDCl3)
d 170.7, 170.4, 169.8, 169.7 (4CO), 155.9 (CO urea), 77.9
(C-1), 73.7 (C-5), 71.8 (C-3), 70.5 (C-2), 65.3 (C-4), 62.3
(C-6), 40.2 (CH2a), 30.0 (CH2b), 20.9, 20.8, 20.7, 20.5
(4CH3CO), 19.9 (CH2g), 13.7 (CH3); CI-MS m/z 447 ([MC
H]C, 100%); HRCI-MS m/z calcd for [MC
H]CC19H31N2O10: 447.1979, found: 447.1980.
Method B. Column yielded 23, 184 mg, 64%.
Method C. The mixture was stirred for 24 h and purified by
column chromatography (hexane/1:1 hexane–EtOAc) to
give 23: 143 mg, 74%. Rf 0.22 (40:1 CH2Cl2–MeOH); mp
93–96 8C; [a]D18 K17 (c 1.0, CH2Cl2); IR nmax 3189, 1746,
1645, 1575, 1393, 1092, 1034, 874 cmK1 1H NMR
;

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O. Lopez et al. / Tetrahedron 61 (2005) 9058–9069
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3.3.12. N-(p-Methylphenyl)-N0-(2,3,4,6-tetra-O-acetyl-b-
D-mannopyranosyl)urea (26). Method A. Column chroma-
tography (CH2Cl2/40:1 CH2Cl2–MeOH) gave 26 as a
white solid: 167 mg, 58%. Rf 0.25 (1:1 hexane–EtOAc); mp
80–88 8C; [a]D18 K21 (c 1.0, CH2Cl2); IR nmax 3291, 2922,
1767, 1555, 1096, 909 cmK1; 1H NMR (300 MHz, CDCl3)
3.4. Method for the preparation of isocyanates 7 and 8
To a vigorously stirred solution of the hydrohalides 5 or 6
(0.6 mmol) in a 1:1 mixture of CH2Cl2 and saturated
aqueous NaHCO3 (12 mL) at 0 8C was added triphosgene
(0.22 mmol) in a single portion. After 10 min of stirring, the
organic layer was separated, dried (MgSO4), filtered and
concentrated to dryness to give pure 7 or 8.
d 7.07 (m, 4H, Ar–H), 6.89 (s, 1H, NH), 5.92 (d, 1H,
0
0
J1,NH Z9.5 Hz, NH ), 5.45 (dd, 1H, J1,2Z0.9 Hz, H-1), 5.39
(d, 1H, J2,3Z3.1 Hz, H-2), 5.17 (t, 1H, J3,4Z10.0 Hz, J4,5
9.9 Hz, H-4), 5.08 (dd, 1H, H-3), 4.25 (dd, 1H, J5,6a
Z
Z
3.4.1. 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-isocyanato-a-D-
glucopyranose (7). Yield: 224 mg, quantitative, as a
syrup. Rf 0.32 (40:1 CH2Cl2–MeOH); [a]2D0 C126 (c 1.3,
CH2Cl2); IR nmax 2963, 2261, 1765, 1371, 1217, 1026,
936 cmK1; 1H NMR (500 MHz, CDCl3) Table 2 and d 2.22,
2.11, 2.07, 2.04 (4s, 12H, 4Ac); 13C NMR (125.7 MHz,
CDCl3) Table 2 and d 170.5, 170.2, 169.4, 168.6 (4CO),
20.8, 20.6, 20.5 (4CH3CO). Anal. Calcd for
C15H19NO10$1/3H2O: C, 47.50; H, 5.23; N, 3.69, found:
C, 47.55; H, 5.30; N, 3.69.
5.0 Hz, J6a,6bZ12.5 Hz, H-6a), 4.01 (dd, 1H, J5,6bZ2.0 Hz,
H6b), 3.75 (ddd, 1H, H-5), 2.27 (s, 3H, Me), 2.08, 2.01, 1.95
(4s, 12H, 4Ac); 13C NMR (75.5 MHz, CDCl3) d 170.7,
170.2, 169.8, 169.7 (4CO), 154.3 (CO urea), 134.7, 129.8,
122.0 (Ar), 77.6 (C-1), 73.8 (C-5), 71.6 (C-3), 70.3 (C-2),
64.3 (C-4), 62.3 (C-6), 20.8, 20.7, 20.6, 20.4 (CH3Ar,
4CH3CO); FAB-MS m/z 481 ([MCH]C, 28%), 503 ([MC
Na]C, 100%); HRFAB-MS m/z calcd for [MC
H]CC22H29N2O10: 481.1822, found: 481.1814.
3.3.13. N,N0-Bis(2,3,4,6-tetra-O-acetyl-b-D-manopyrano-
syl)urea (27). Method A. Column chromatography
(CH2Cl2/40:1 CH2Cl2–MeOH) gave 27 as a white solid:
149 mg, 69%. Rf 0.12 (1:1 hexane–EtOAc); mp 154–156 8C
(from EtOH); [a]D25 K24 (c 0.3, CH2Cl2); IR nmax 3352,
3.4.2. 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-isocyanato-b-D-
glucopyranose (8). Yield: 224 mg, quantitative, as a
syrup. Rf 0.21 (40:1 CH2Cl2–MeOH); [a]2D5 C32 (c 1.0,
CH2Cl2); IR nmax 2959, 2253, 1765, 1371, 1215, 1090,
872 cmK1; 1H NMR (500 MHz, CDCl3) Table 2 and d 2.18,
2.09, 2.07, 2.02 (4s, 12H, 4Ac); 13C NMR (125.7 MHz,
CDCl3) Table 2 and d 170.5, 169.8, 169.5, 168.6 (4CO),
20.7, 20.6, 20.5 (4CH3CO). Anal. Calcd for C15H19NO10: C,
48.26; H, 5.13; N, 3.75, found: C, 48.17; H, 5.20; N, 3.79.
2917, 1746, 1647, 1537, 1370, 1227, 1092, 1051, 874 cmK1
;
1H NMR (500 MHz, CDCl3) d 5.45 (dd, 1H, J1,2Z0.9 Hz,
H-1), 5.45 (d, 1H, J1,NHZ9.6 Hz, NH), 5.37 (dd, 1H, J2,3
Z
3.3 Hz, H-2), 5.20 (t, 1H, J3,4Z10.0 Hz, J4,5Z10.0 Hz,
H-4), 5.11 (dd, 1H, H-3), 4.29 (dd, 1H, J5,6aZ5.2 Hz,
J6a,6bZ12.4 Hz, H-6a), 4.05 (dd, 1H, J5,6bZ2.0 Hz, H-6b),
3.77 (ddd, 1H, H-5), 2.21, 2.09, 2.04, 1.97 (4s, 12H, 4Ac);
13C NMR (125.7 MHz, CDCl3) d 170.8, 170.2, 169.8, 169.7
(4CO), 153.8 (CO urea), 77.4 (C-1), 73.8 (C-5), 71.6 (C-3),
70.3 (C-2), 65.1 (C-4), 62.2 (C-6), 20.9, 20.8, 20.7, 20.5
(4CH3CO); FAB-MS m/z 721 ([MCH]C, 36%), 743 ([MC
Na]C, 100%); HRFAB-MS m/z calcd for [MC
H]CC29H41N2O19: 721.2304, found: 721.2294. Anal.
Calcd for C29H40N2O19 H2O: C, 47.16; H, 5.73; N, 3.79,
found: C, 47.26; H, 5.61; N, 3.83.
3.5. N-(p-Methylphenyl)-N0-(1,3,4,6-tetra-O-acetyl-2-
deoxy-a-D-glucopyranos-2-yl)thiourea (28)
A mixture of hydrobromide 18 (250 mg, 0.58 mmol),
thiophosgene (0.07 mL, 0.88 mmol) and calcium carbonate
(176 mg, 1.76 mmol) in 1:1 water–CH2Cl2 (20 mL) was
vigorously stirred at rt for 2 h. Then the mixture was filtered
off and the organic layer containing known 1,3,4,6-tetra-O-
acetyl-2-deoxy-2-isothiocyanato-a-D-glucopyranose59 was
separated and concentrated to dryness. To a solution of
crude isothiocyanate in EtOAc (10 mL) was added p-
toluidine (62 mg, 0.58 mmol). The solution was kept at rt
for 5 h and then it was concentrated to dryness and the
residue was purified by column chromatography
(CH2Cl2/ 80:1 CH2Cl2–MeOH) to give 28 as a white
solid: 295 mg (93%). Rf 0.5 (40:1 CH2Cl2–MeOH); mp
140–142 8C; [a]2D5 C96 (c 1.0, CH2Cl2); IR nmax 3332,
3.3.14. N,N-Diethyl-N0-(2,3,4,6-tetra-O-acetyl-b-D-gluco-
pyranosyl)urea (32). Method C. The mixture was stirred
for 40 h and purified by column chromatography
(CH2Cl2/40:1 CH2Cl2–MeOH) to give 32, as an
amorphous solid: 94 mg, 72%; mp 39–42 8C; [a]2D0 C19
(c 0.9, CH2Cl2); IR nmax 3320, 2936, 1753, 1379, 1225,
1
1036 cmK1; H NMR (300 MHz, CDCl3) d 5.32 (d, 1H,
1
1750, 1532, 1370, 1223, 930 cmK1; H NMR (300 MHz,
J1,NHZ9.3 Hz, NH0), 5.31 (t, 1H, J2,3Z9.5 Hz, J3,4
Z
CDCl3) d 7.82 (s, 1H, NH), 7.24–6.99 (m, 4H, Ar–H), 6.31
(d, 1H, J1,2Z6.3 Hz, H-1), 5.80 (d, 1H, J2,NHZ8.3 Hz,
NH0), 5.21 (m, 1H, H-4), 5.16 (m, 1H, H-3), 5.13 (m, 1H, H-
2), 4.23 (dd, 1H, J5,6aZ4.1 Hz, J6a,6bZ12.5 Hz, H-6a), 4.03
(dd, 1H, J5,6bZ2.3 Hz, H-6b), 3.91 (ddd, 1H, J4,5Z9.5 Hz,
H-5), 2.37 (s, 3H, CH3), 2.08, 2.07, 2.00 1.94 (4s, 12H,
4Ac); 13C NMR (75.5 MHz, CDCl3) d 181.6 (CS), 171.5,
170.8, 169.1, 168.3 (4CO), 138.6, 132.7, 130.9, 126.2 (Ar),
90.5 (C-1), 70.9 (C-3), 69.9 (C-5), 67.5 (C-4), 61.6 (C-6),
56.3 (C-2), 21.2 (CH3Ar), 20.9, 20.8, 20.7, 20.6 (4CH3CO);
CI-MS m/z 497 ([MCH]C, 35%); HRCI-MS m/z calcd for
[MCH]CC22H29N2O9S: 497.1594, found: 497.1570.
9.4 Hz, H-3), 5.20 (t, 1H, J1,2Z9.3 Hz, H-1), 5.06 (t, 1H,
J4,5Z9.6 Hz, H-4), 4.93 (t, 1H, H-2), 4.33 (dd, 1H, J5,6a
Z
4.0 Hz, J6a,6bZ12.4 Hz, H-6a), 4.07 (dd, 1H, J5,6bZ2.2 Hz,
H-6b), 3.80 (ddd, 1H, H-5), 3.18 (m, 4H, 2CH2), 2.07, 2.03,
2.01, 2.0 (4s, 12H, 4Ac), 1.11 (t, 6H, JH,HZ7.2 Hz, 2CH3);
13C NMR (125.7 MHz, CDCl3) d 171.4, 170.7, 169.98,
169.7 (4CO), 155.4 (CO urea), 80.8 (C-1), 73.2 (C-5),
73.0 (C-3), 70.8 (C-2), 68.5 (C-4), 61.8 (C-6), 41.3
(2CH2), 20.8, 20.8, 20.7, 20.6 (4CH3CO); 13.7
(2CH3); CI-MS m/z 447 ([MCH]C, 100%); HRCI-MS
m/z calcd for [MCH]CC19H31N2O10: 447.1979, found:
447.1955.

´
O. Lopez et al. / Tetrahedron 61 (2005) 9058–9069
´
9067
3.6. N-(p-Methylphenyl)-N0-(2,3,4,6-tetra-O-acetyl-b-D-
glucopyranosyl)thiourea (29)
thiourea 3342 (2.22 g, 6.76 mmol) in pyridine (15 mL) at
0 8C was added acetic anhydride (15 mL). The solution was
kept at rt for 24 h and then it was co-concentrated with
toluene and ethanol to dryness and the residue was
crystallized from ethanol to give 34: 2.66 g, 73%. Mp
140–144 8C; [a]2D5 C15 (c 1.0, CH2Cl2); IR nmax 3318,
To a solution of N-acetyl-N-(p-methylphenyl)-N0-(2,3,4,6-
tetra-O-acetyl-b-D-glucopyranosyl)thiourea 34 (22 mg,
0.04 mmol) in MeOH (10 mL) was added imidazole
(2.8 mg, 0.04 mmol). The solution was heated at 40 8C for
24 h and then it was concentrated to dryness and the residue
was purified by column chromatography (CH2Cl2/80:1
CH2Cl2–MeOH) to give 29 as a syrup: 18 mg (86%). [a]D23
K11 (c 1.0, CH2Cl2); IR nmax 3329, 1751, 1535, 1370,
1229, 1040, 733 cmK1; 1H NMR (300 MHz, CDCl3) d 8.02
1
2922, 1753, 1682, 1370, 1225, 1044, 708 cmK1; H NMR
0
0
(300 MHz, CDCl3) d 12.01 (d, 1H, J1,NH Z8.8 Hz, NH ),
7.26–7.05 (m, 4H, Ar–H), 5.79 (dd, 1H, J1,2Z9.3 Hz, H-1),
5.34 (t, 1H, J2,3Z9.3 Hz, J3,4Z9.3 Hz, H-3), 5.21 (t, 1H, H-
2), 5.11 (t, 1H, J4,5Z10.0 Hz, H-4), 4.28 (dd, 1H, J5,6a
Z
4.6 Hz, J6a,6bZ12.4 Hz, H-6a), 4.12 (dd, 1H, J5,6bZ2.1 Hz,
H-6b), 3.82 (ddd, 1H, H-5), 2.39 (s, 3H, Me), 2.08, 2.07,
2.02, 1.92 (4s, 15H, 5Ac); 13C NMR (75.5 MHz, CDCl3) d
186.8 (CS), 175.1, 170.8, 170.1, 169.6 (5CO), 139.6, 139.3,
130.3, 129.2 (Ar), 83.4 (C-1), 73.8 (C-5), 73.2 (C-3), 70.5
(C-2), 68.4 (C-4), 61.7 (C-6), 28.0 (NAc), 21.4 (CH3Ar),
20.9, 20.7, 20.7, 20.7 (4CH3CO); FAB-MS m/z 561 ([MC
Na]C, 28%); HRFAB-MS m/z calcd for [MCH]CC24H31-
N2O10S: 539.1699, found: 539.1676. Anal. Calcd for
C24H30N2O10S: C, 53.52; H, 5.61; N, 5.20; S, 5.95, found:
C, 53.76; H, 5.77; N, 4.95; S, 5.43.
(s, 1H, NH), 7.25–7.03 (m, 4H, Ar–H), 6.52 (d, 1H, J1,NH
8.7 Hz, NH0), 5.82 (t, 1H, J1,2Z9.0 Hz, H-1), 5.33 (t, 1H,
J2,3Z9.3 Hz, J3,4Z9.6 Hz, H-3), 5.01 (t, 1H, J4,5Z9.9 Hz,
Z
H-4), 4.88 (t, 1H, H-2), 4.30 (dd, 1H, J5,6aZ4.5 Hz, J6a,6b
Z
12.3 Hz, H-6a), 4.08 (dd, 1H, J5,6bZ2.0 Hz, H-6b), 3.84
(ddd, 1H, H-5), 2.37 (s, 3H, Me), 2.06, 2.05, 2.01, 1.98 (4s,
12H, 4Ac); 13C NMR (75.5 MHz, CDCl3) d 182.3 (CS),
170.7, 170.6, 169.8, 169.5 (4CO), 138.3, 132.3, 130.7, 125.6
(Ar), 83.2 (C-1), 73.6 (C-5), 72.7 (C-3), 70.5 (C-2), 68.2
(C-4), 61.6 (C-6), 21.1 (CH3Ar), 20.7, 20.6, 20.5, 20.5
(4CH3CO); FAB-MS m/z 497 ([MCH]C, 100%); HRFAB-
MS m/z calcd for [MCH]CC22H29N2O9S: 497.1594, found:
497.1625. Anal. Calcd for C22H28N2O9S: C, 53.22; H, 5.68;
N, 5.64; S, 6.46, found: C, 53.35; H, 5.73; N, 5.55; S, 6.07.
Acknowledgements
´
We thank the Direccion General de Ensen˜anza Superior e
Investigacion Cientıfica (Grant BQU 2001-3740) and the
´
Junta de Andalucıa (FQM134) for financial support.
3.7. N,N-Diethyl-N0-(2,3,4,6-tetra-O-acetyl-b-D-gluco-
pyranosyl)thiourea (31)
´
´
A mixture of 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl
hydrobromide 18 (400 mg, 0.94 mmol), thiophosgene
(0.104 mL, 1.36 mmol) and calcium carbonate (280 mg,
2.8 mmol) in 1:1 water–CH2Cl2 (20 mL) was vigorously
stirred at rt for 2 h. Then the mixture was filtered off and the
organic layer, containing known 2,3,4,6-tetra-O-acetyl-b-D-
glucopyranosylisothiocyanate51 was separated and concen-
trated to dryness. Crude isothiocyanate was dissolved in
EtOAc (5 mL) and to the solution was added N,N-
diethylamine (0.100 mL, 0.94 mmol). The solution was
kept at rt for 1 h and then it was concentrated to dryness and
the residue was purified by column chromatography
(CH2Cl2/80:1 CH2Cl2–MeOH) to give 31 as a white
solid: 299 mg (69%); mp. 140–142 8C; Rf 0.54 (40:1
CH2Cl2–MeOH); [a]2D0 C14 (c 1.0, CH2Cl2); IR nmax
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