Expeditious synthesis of cyclic isourea derivatives of β-D-glucopyranosylamine

Article abstract of DOI:10.1016/S0040-4039(02)00798-0

2-(Alkylamino, dialkylamino, arylamino)tetrahydropyrano[2,3-d]oxazoles are prepared in good yield by a one-pot three-step synthesis from O-unprotected β-D-glucopyranosylamine, by its transformation into glucopyranosyl isothiocyanate in dioxane-water, coupling with amines, and reaction of the corresponding thioureas with yellow mercury(II) oxide in the same reaction medium. In the case of diethylamine prolonged reaction time during the last step, with an extra portion of yellow HgO, led to N,N-diethyl-N′-(β-D-glucopyranosyl)urea in a one-pot four-step synthesis. 2-(β-D-Glucopyranosylamino)tetrahydropyrano[2,3-d]oxazole, an analogue of trehazolin, is obtained in good yield by cyclocondensation of 1,3-bis(β-D-glucopyranosyl)thiourea.

Full text of DOI:10.1016/S0040-4039(02)00798-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4313–4316
Expeditious synthesis of cyclic isourea derivatives of
b- -glucopyranosylamine
D
´
Oscar Lo´pez, Ine´s Maya, V´ıctor Ulgar, Inmaculada Robina, Jose´ Fuentes and
Jose´ G. Ferna´ndez-Bolan˜os*
Departamento Qu´ımica Orga´nica, Facultad Qu´ımica, Universidad Sevilla, Apartado 553, E-41071 Seville, Spain
Received 19 April 2002; accepted 23 April 2002
Abstract—2-(Alkylamino, dialkylamino, arylamino)tetrahydropyrano[2,3-d]oxazoles are prepared in good yield by a one-pot
-glucopyranosylamine, by its transformation into glucopyranosyl isothiocyanate in
three-step synthesis from O-unprotected b-
D
dioxane–water, coupling with amines, and reaction of the corresponding thioureas with yellow mercury(II) oxide in the same
reaction medium. In the case of diethylamine prolonged reaction time during the last step, with an extra portion of yellow HgO,
led to N,N-diethyl-N%-(b-
D
-glucopyranosyl)urea in a one-pot four-step synthesis. 2-(b-D-Glucopyranosylamino)tetrahydro-
pyrano[2,3-d]oxazole, an analogue of trehazolin, is obtained in good yield by cyclocondensation of 1,3-bis(b-D-glucopyranosyl)-
thiourea. © 2002 Elsevier Science Ltd. All rights reserved.
2-Amino-2-oxazolines have received considerable atten-
tion due to their interest as biological active molecules,
which show adrenergic,1 octapamine,2 imidazoline3
receptor agonist activity as well as histamine receptor
antagonist,4 and may be useful for the treatment of
hypertension and glaucoma, and as specific inhibitors
of pheromone biosynthesis. Among the methods to
prepare 2-amino-2-oxazolines, cyclodesulfurization of
conveniently hydroxylated thiourea derivatives with
lead(II) oxide,5 yellow mercury(II) oxide,2b,6 2-chloro-3-
ethylbenzoxazolium tetrafluoroborate,7 superoxide rad-
ical anion,8 p-toluenesulfonyl chloride/NaOH,9 or
MeI/lutidine10 have been used.
carbocycle16–18 or by a tetrahydropyran unit19 have
been reported. Syntheses of tetrahydrofurano[2,3-
d]oxazoles from cis-fused cyclic sugar thiocarbamates
by sequential S-p-chlorobenzylation and nucleophilic
displacement of the p-chlorobenzylthio group with
amines have been undertaken by Pinter’s group.20
In the carbohydrate field, natural N-substituted cyclic
isourea derivatives of aminocyclitols have been found
to display potent and selective inhibitory effects on a
variety of glycosidases. Examples include trehazolin 111
and allosamidin 2,12 potent inhibitors of trehalase and
chitinase, respectively. This led to intensive research on
the total synthesis of 1, 2, and structural analogues
which contain the chemically modified cyclitol or sugar
portion.13–15 The syntheses of trehazolin analogues
wherein the aminocyclopentitol ring has been replaced
either
by
a
six-membered
polyhydroxylated
We now report the in situ preparation of 2-aminotetra-
hydropyrano[2,3-d]oxazoles 7a–g from b-D-glucopyran-
osylamine 321 in a one-pot three-step procedure.
Treatment of 3 with thiophosgene in 1:1 water/dioxane
buffered with NaHCO3/CO2, followed by addition of
several amines, as described recently,22 and finally,
treatment in the same flask with yellow mercury(II)
Keywords: thiourea desulfurization; cyclizations; mercury(II) oxide;
isoureas; ureas; trehazolin.
* Corresponding author. Tel.: +34 95 4557151; fax: 34 95 4624960;
e-mail: bolanos@us.es
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00798-0

´
O. Lo´pez et al. / Tetrahedron Letters 43 (2002) 4313–4316
4314
We also report the synthesis of trehazolin analogue 7h36
in 89% yield by treatment of symmetrical O-unpro-
oxide (3 equiv.) for 1–3 h at room temperature, led to
7a–g (Scheme 1). These compounds were isolated in
50–70% yield after silica gel column chromatography
(Table 1).23 Bola-amphiphile24 7f was purified by crys-
tallization from ethanol. This method when applied to
tected N,N%-bis(b-
-glucopyranosyl)thiourea 6h22 with
D
yellow mercury(II) oxide (3 equiv.) in 1:1 water/dioxane
for 3 h. No formation of urea was detected. Similarly,
2-octyl and p-tolylaminooxazolines 7b and 7c were
prepared from thioureas 6b and 6c in 75 and 94% yield,
respectively, using methanol as solvent. Synthesis of 7h
has previously been reported by Shiozaki19 by
hydrogenolysis of the derivative of 7h tetra-O-benzyl-
ated in the glucopyranose unit, which was prepared
from per-O-acetylated and per-O%-benzylated N,N%-
polar amines, such as taurine or b-D-glucopyran-
osylamine, also gave the expected cyclic isoureas as the
1
main compounds as deduced by the H NMR of the
crude reaction mixture; however, purification by silica
gel or gel filtration chromatography led to extensive
decomposition. Use of commercial yellow HgO for the
cyclodesulfurization of thioureas in aqueous dioxane,
buffered with NaHCO3/CO2 containing minor amounts
of amines, contrasts with the use of isolated sugar
thioureas and freshly prepared and dried mercury(II)
oxide25,26 in solvents such as dried THF,25 Et2O,27
MeCN,28 Et2O/Me2CO17,29 or EtOH/Me2CO.26 Simi-
larly, Mukaiyama’s method of thiourea cyclization7a is
carried out with 2-chloro-3-ethylbenzoxazolium tetra-
fluoroborate in dried MeCN under N2.19,30 Our results
indicate that the proposed transient carbodiimides
should react faster with the adjacent trans-hydroxy
group to construct cyclic isoureas, than with water
molecules to form ureas.
bis(b-D-glucopyranosyl)thiourea, following a sequence
of Zemple´n deacetylation and cyclodesulfurization
using Mukaiyama’s method. The reported hydrogenol-
ysis with Pd(OH)2-on-charcoal gave19 an inseparable
mixture of 7h (17%) and N,N%-bis(b-D-glucopyran-
osyl)urea (32%).
In conclusion, we have developed a versatile and expe-
ditious three-step one-pot synthetic route to transform
primary or secondary amines into tetrahydropyrano-
[2,3-d]oxazoles starting from the easily available b-D-
glucopyranosylamine 3. The protection–deprotection
steps are avoided, simplifying the synthetic route with
good overall yields. We have proved that cyclodesulfur-
ization of glycosyl thioureas with yellow HgO can be
carried out in aqueous dioxane or in methanol, and in
the case of diethylamine conversion of cyclic isourea
into urea was achieved.
In the case of diethylamine, in situ treatment of 6e with
3 equiv. of yellow HgO for 2 h gave isourea 7e together
with urea 9 in 70 and 18% yield, respectively, after
column chromatography. When 6e was in situ treated
with two portions of yellow HgO (3 equiv. each) for 4
h, complete conversion of 7e into urea 9 was observed
(85% isolated yield).31 When this procedure was applied
to the transformation of N-butyl and tolyl isoureas 7a
and 7c to the corresponding ureas, no significant con-
version of the starting materials was observed on pro-
longed reaction times (48 h) at room temperature. The
formation of 9 might be explained through the transient
carbodiimide derivative 8 (Scheme 1). Other methods to
convert cyclic isoureas into ureas have previously been
reported,32,33 and conversion of thioureas directly into
ureas have also been described.14d,34,35
Acknowledgements
We thank the Direccio´n General de Ensen˜anza Supe-
rior e Investigacio´n Cient´ıfica (Grant BQU 2001-3740)
and the Junta de Andalucia (FQM134) for financial
support. O. Lo´pez thanks the Ministerio de Educacio´n
y Cultura for the award of a fellowship. This work is
part of the European Programme COSTD13, action
number D13/0001/98.
H
N
NR1R2
NH2
NCS
O
O
O
HO
HO
HO
HO
HO
HO
ii
i
S
OH
OH
OH
OH
OH
OH
4
6a-h
3
iii
H
N
NEt2
N
C NEt2
O
O
O
N
O
HO
HO
HO
HO
HO
HO
NR1R2
iv
O
OH
OH
OH
OH
OH
7a-h
9
8
Scheme 1. Reagents and conditions: (i) CSCl2 (1.2 equiv.), pH 8 (NaHCO3/CO2), 1:1 water/dioxane, −10°C, 30 min; (ii) R1R2NH
5a–h (1.2 equiv.) [0.6 equiv. of 5f], pH 9 (NaHCO3/CO2), rt, 2–5 h; (iii) yellow HgO (3 equiv.), rt, 1–3 h; (iv) yellow HgO (3
equiv.), rt, 2 h.

´
O. Lo´pez et al. / Tetrahedron Letters 43 (2002) 4313–4316
4315
Table 1. Synthesis of tetrahydropyrano[2,3-d]oxazoles 7a–h from b-D-glucopyranosylamine 3
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