Synthesis of N-aryl spiro-sulfamides as potential glycogen phosphorylase inhibitors

Article abstract of DOI:10.1016/j.tetlet.2011.12.049

A new C-glucosylated spiro-sulfamide has been prepared and evaluated toward glycogen phosphorylase inhibition. The synthesis was carried out successfully by nucleophilic displacement of 1-O-tosyl or 1-deoxy-1-iodo-α-d-gluco- hept-2-ulopyranose tetra-O-benzylated derivative using aryl amines, followed by the formation of the corresponding cyclic sulfamide.

Full text of DOI:10.1016/j.tetlet.2011.12.049

Tetrahedron Letters 53 (2012) 959–961
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of N-aryl spiro-sulfamides as potential glycogen
phosphorylase inhibitors
Tony Tite a, Loic Tomas b, Tibor Docsa c, Pal Gergely c, José Kovensky a, David Gueyrard b,
,
⇑
Anne Wadouachi a,
⇑
a Laboratoire des Glucides-UMR CNRS 6219, Université de Picardie Jules Verne, 33 rue Saint Leu, 80039 Amiens, France
b Université de Lyon, ICBMS, Laboratoire de Chimie Organique 2-Glycochimie, UMR CNRS 5246, Université Claude Bernard Lyon 1-CNRS, Bâtiment 308(CPE),
43 Boulevard du 11 novembre 1918, F-69622 Villeurbanne, France
c Department of Medical Chemistry, Medical and Health Science Centre, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
A new C-glucosylated spiro-sulfamide has been prepared and evaluated toward glycogen phosphorylase
inhibition. The synthesis was carried out successfully by nucleophilic displacement of 1-O-tosyl or
Received 2 November 2011
Revised 7 December 2011
Accepted 12 December 2011
Available online 17 December 2011
1-deoxy-1-iodo-
a-D-gluco-hept-2-ulopyranose tetra-O-benzylated derivative using aryl amines, followed
by the formation of the corresponding cyclic sulfamide.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
exo-glucal
Gluconolactone
Spiro-sulfamide
Burgess reagent
Glycogen phosphorylase (GP) is the enzyme in charge of the
transformation of glycogen to glucose (glycogenolysis) in the liver.
Because of its crucial role in the degradation of glycogen, the inhi-
bition of GP has been considered a valuable and promising thera-
peutic approach1 for the treatment of hyperglycemia.2,3 Different
classes of compounds have been designed for GP inhibition, com-
Two synthetic approaches were considered, starting from meth-
ylene exo-glucal 1 and from gluconolactone 8.
D-Gluco-hept-2-
ulopyranose derivatives with an activated primary carbon were
first synthesized to obtain amino-alcohols precursors of the
spiro-sulfamides. Osmylation11,12 of the methylene exo-glucal 18
into diol 2 and subsequent tosylation of the primary alcohol
furnished the O-tosylate compound 3. The tosylation reaction pro-
ceeded in a 90% yield, with the formation of a minor chlorinated
side-product 4, which could be easily separated from 3 (Scheme 1).
Microwave-assisted nucleophilic substitution of tosylate deriv-
ative 3 was conducted under pressure in a sealed vessel,13 with
petitive inhibitors of the catalytic site being generally D-glucose
derivatives. Among them, spiro-isoxazolines4,5 and spiro-oxathiaz-
oles derivatives,6,7 two families of spiro compounds bearing a het-
erocyclic ring, are the most active against GP (Fig. 1).
In our ongoing project devoted to the synthesis of original
glycomimetics starting from exoglycals8,9 using the Burgess re-
agent,10,11 we were interested in the preparation of spiro-sulfamides
bearing an aromatic substituent. The key structural characteristics
of the glucose-based GP inhibitors are thus conserved: the presence
of heteroatoms (sulfur, oxygen, and nitrogen atoms) in the heterocy-
clic ring that contributes to hydrogen bonding with amino-acids, the
occurrence of an aromatic substituent that can be placed in the
b-pocket of the enzyme, and the 4C1 conformation of the sugar ring.5
In this Letter, the synthesis of new C-glucosylated spiro-sulfamides
is reported together with the inhibition results on GP.
HO
HO
HO
HO
O
O
HO
S
Ar
Ar
HO
OH
OH
O N
O N
Spiro-isoxazoline
Spiro-oxathiazole
HO
HO
HO
O
Ar
O
N
S
OH
H
N
O
⇑
Corresponding authors. Tel.: +33 3 22 82 75 63; fax: +33 3 22 82 75 60 (A.W.),
tel.: +33 4 72 44 83 49; fax: +33 4 72 44 81 09 (D.G.).
Spiro-sulfamide
E-mail addresses: david.gueyrard@univ-lyon1.fr (D. Gueyrard), anne.wadoua-
chi@sc.u-picardie.fr, anne.wadouachi@u-picardie.fr (A. Wadouachi).
Figure 1. Structure of two representative families of GP inhibitors and similarity
with the spiro-sulfamide.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.049

960
T. Tite et al. / Tetrahedron Letters 53 (2012) 959–961
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
CH2I2
O
O
O
O
O
OsO4/NMO
OH
I
+
O
DCM
CH3Li
BnO
BnO
BnO
BnO
acetone/H2O
(5/1 v/v)
BnO
OH
94%
OH
OH
8
10 10%
9 46%
1
2
Scheme 3. Iodomethylenation reaction.
TsCl, DMAP
DCM
Table 2
Synthesis of amino-alcohols from iodo compound 9
BnO
BnO
BnO
BnO
BnO
O
O
Amine
Base
Time
Compound
Yield (%)
+
OTs
BnO
Cl
NH4OH
b-Naphthylamine
Tryptamine
—
4 h 30 min
35 min
45 min
2 h
5
7
11
12
73
70
75
69
BnO
BnO
OH
90%
OH
NaH
NaH
NaH
5%
4
3
2-Aminopyridine
Scheme 1. Preparation of the tosylated compound 3.
7
BnO
BnO
BnO
BnO
BnO
BnO
5
6
3
1
O
O
O
O
BnO
THF
MW
BnO
BnO
THF
RT
OTs
+ amine
BnO
NHR
BnO
NHR
BnO
I
+ amine
2
BnO
BnO
4
BnO
BnO
OH
OH
OH
OH
3
5-7
5, 7, 11
9
β
R= H, p-anisyl, -naphthyl
β
R= H, p-anisyl, -naphthyl
Scheme 2. Substitution reaction on the tosylated compound 3.
BnO
O
H
N
BnO
BnO
N
several amines (aqueous ammonia, p-anisidine, and b-naphthyl-
amine) to afford the corresponding amino compounds 5, 6, and
7, respectively (Scheme 2). Microwave-assisted reactions gave
shortened reaction times comparatively to the aminolysis of pri-
mary tosylates reported in the literature (100 °C for 24 h).13 The
addition of a non nucleophilic base as K2CO3 was essential to ob-
tain these two aryl amines (Table 1).
BnO
12
Scheme 4. Substitution reaction of the iodo derivative 9.
trum of 12, no adjacent methylene proton appears in the
2.5–3.5 ppm range as seen for the amino-alcohols derivatives
5–7 and 11. In the 13C NMR spectrum, a signal corresponding to
an enamine carbon appeared at 111 ppm. The structure of 12 in
accordance with these data is depicted in Scheme 4.
The synthetic route, to obtain the aminoalcohols, from iodo
compound 9 gave better yields. Moreover, for the aminoalcohols,
5–7 and 11 the clear NOE cross-peaks between H-3/H1a,b; H-3/
H-5 and H-3/H-7a,b support the syn relationship of these protons
and also confirm the structures of these derivatives.
In the second synthetic approach, 1-deoxy-1-iodo compound
9
14 was synthesized via iodomethylenation15 of an easily available
tetrabenzylated gluconolactone 8. In these conditions, 1-deoxy-1-
iodo compound 9 was provided as a single anomer (b) but together
with the b-1-deoxy-1-methyl derivative 1016 (Scheme 3).
Under the above mentioned microwave conditions, the b-1-
deoxy-1-iodo derivative 9 was proved to be unstable, and much
degradation was observed. So, the aminolysis of 9 was realized
using conventional conditions. The nucleophilic substitution of 9
furnished
the
corresponding
1-deoxy-1-amino-hept-2-
To synthesize cyclic sulfamide derivatives, the Burgess-type re-
agent tert-butyl N-(triethylammoniumsulfonyl)-carbamate17,18
was used. We have previously described a synthesis of sulfam-
ulopyranose derivatives with higher yields (Table 2).
At room temperature, ammonium hydroxide provided without
the addition of base, the desired amino alcohol 5 in a good yield
(73%). In the case of aromatic amines, sodium hydride was neces-
sary to generate the corresponding anion and to carry out the reac-
tion (Scheme 4, Table 2). In such conditions, the b-naphthylamino
and tryptamino alcohols were provided, respectively, in 70% and
75% yields. Surprisingly, for the 2-aminopyridine reagent, the cor-
responding amino alcohol was not obtained. By HRMS, compound
12 shows a [M+H]+ ion at m/z 629.2992. The full assignment of the
protons has been performed using the combination of standard 2D
experiments such as COSY, HSQC, and HMBC. In the 1H NMR spec-
ide-type indolizidines from 5-amino-5-deoxy D-gluco and D-man-
nofuranose compounds used as precursors.10 In an analogous
strategy we managed to synthesize the N-(Boc)-sulfamide deriva-
tives from the compounds 5, 6, and 7, the spiro-sulfamides
13–15 were obtained in satisfactory yields (Table 3, Scheme 5).
The spiro formation of compounds 13–16 and 17, 18, and 20
was confirmed by the NMR chemical shift of the C-5 (Table 4),
and as example a NOESY experiment for compound 18 showed
the correlation between the H-4 and H-10 which is presented in
Figure 2.
Table 1
Optimization of the synthesis of aminoalcohols 5–7 from tosyl 3
Amine
Compound
R
100 °C
60 psi
20 W
1 h
100 °C
20 psi
60 W
K2CO31 h (%)
Table 3
Synthesis of spiro-sulfamides compounds from aminoalcohols 5–7
Amino-alcohols
R
Compounds
Yield (%)
NH4OH
Anisidine
b-Naphthylamine
5
6
7
H
60%
Inert
Inert
—
52
52
5
6
7
H
13
14
15
68
73
85
p-Anisyl
bÀNaphthyl
p-Anisyl
b-Naphthyl

T. Tite et al. / Tetrahedron Letters 53 (2012) 959–961
961
product (75%) when spiro-sulfamide 17 was hydrogenated in the
presence of Pd/C 10% at 50 °C under pressure (11 bar) on a H-Cube.
Preliminary biological evaluation on glycogen phosphorylase
was performed on spiro-sulfamide with the p-anisyl derivative
Et3N
NBoc
BnO
BnO
BnO
BnO
S
O
O
BnO
O
O
NR
BnO
NHR
BnO
BnO
THF
S
O
N
OH
O
18 which inhibited the GP with a 15 lM Ki value. This result
O
showed that this novel family inhibits the rabbit muscle glycogen
phosphorylase (RMGP)b and strongly suggests that the rigid spiro-
bicyclic structure oriented properly the large apolar aromatic
group in the b-pocket to bind strongly the catalytic site of GP.
In conclusion, we designed and synthesized a novel family of
N-arylated spirosulfamides. Preliminary biological test on GP
shows that the p-anisyl derivative is an active inhibitor of GP. Fur-
ther works are in progress to synthesize several members of this
family and to prepare more potent inhibitors of glycogen
phosphorylase.
O
5-7
13
14
R=H
R=p-anisyl
β
15 R= -naphthyl
TFA/CH2Cl2
HO
8
6
O
BnO
BnO
BnO
7
3
NR
O
H2/ cat
MeOH
5
HO
NR
HO
4
10
9
BnO
HN
HO
S
O
S O
O
HN
2
1
O
Acknowledgements
18 R=p-anisyl
16 R=p-anisyl
β
19 R= -naphthyl
β
17 R= -naphthyl
The authors thank the MESR for a grant (L.T.) and David Lesur
for HRMS experiments.
20 R=
Scheme 5. Preparation of the spiro-sulfamides.
Supplementary data
Table 4
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.049.
NMR chemical shifts of spiro-carbon of compounds 13–16 and 17,
18, and 20
Compounds
d C-5 (ppm)
References and notes
13
14
16
17
18
20
93.7a
90.3a
88.8a
88.5a
90.2b
89.9c
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