Efficient synthesis of 2,3-unsaturated sulfonamidoglycosides by Amberlyst 15

Article abstract of DOI:10.1016/j.tetlet.2010.07.076

Sulfonamidoglycosylation of D-glycals in the presence of Amberlyst 15 proceeded effectively to afford the sulfonamidoglycosides in good to high yields with minimal workup and short reaction times. Two N-glycosyl sulfonamides were tested as inhibitors of t

Full text of DOI:10.1016/j.tetlet.2010.07.076

Tetrahedron Letters 51 (2010) 5372–5374
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Tetrahedron Letters
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Efficient synthesis of 2,3-unsaturated sulfonamidoglycosides by Amberlyst 15
*
Carlos A. Témpera, Pedro A. Colinas , Rodolfo D. Bravo
LADECOR, Departamento de Química, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 47 y 115, 1900 La Plata, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
Sulfonamidoglycosylation of D-glycals in the presence of Amberlyst 15 proceeded effectively to afford the
Received 15 June 2010
Revised 12 July 2010
Accepted 13 July 2010
Available online 18 July 2010
sulfonamidoglycosides in good to high yields with minimal workup and short reaction times. Two N-glyco-
syl sulfonamides were tested as inhibitors of tumor cell growth in vitro and showed antiproliferative
properties in the micromolar range.
Ó 2010 Elsevier Ltd. All rights reserved.
Several sulfonamides had emerged as chemotherapeutic agents
for the treatment of cancer. Among them, E7010,1 E7070,1
ABT751,2 and T1380673 are under clinical evaluation and will soon
be launched as antitumor drugs (Fig. 1). For several years we have
been interested in the synthesis of glycosylsulfonamides.4 Some of
the sulfonamidoglycosides prepared by us showed antiproliferative
activity against human hepatocellular carcinoma in the micromolar
range.4a Recently, we have reported that N-glycosyl sulfonamides
effect of the catalyst, the reactions were carried out in the presence
of variable amounts of Amberlyst 15 (Table 1).
As can be seen in Table 1, the use of 30 wt % of Amberlyst 15
(entry 3) was enough for a fairly high yield. To our surprise, sulfo-
namidoglycosylations required a much lower amount of catalyst
than the reported O- and S-glycosylations.7 Reducing the quantity
of catalyst resulted in lower yields (entries 1 and 2). Higher quan-
tities of the catalyst only led to lower yields. In all cases the
a-iso-
can be prepared by the sulfonamidoglycosylation of
D
-glycals on
mer was produced predominantly, and /b ratios are not affected
a
treatment with boron trifluoride etherate.4c One of these novel com-
pounds, showed selectivity for inhibiting the tumor-associated iso-
forms carbonic anhydrase IX and XII over the ubiquitous isozyme
hCA II.5 Unfortunately, our methodology has an important draw-
back: boron trifluoride etherate is a highly toxic reagent. This
prompted us to initiate studies designed to provide an environmen-
tally friendlier route for the synthesis of sulfonamidoglycosides. We
have shown that HClO4ÁSiO2 and HBF4ÁSiO2 are efficient catalysts for
the sulfonamidoglycosylation of carbohydrate derivatives.4c–e
Although fluoroboronic acid adsorbed in silica gel catalyzes the sul-
O
O
O
O
S
S
N
N
H
Cl
N
H
H2N
HN
HN
S
MeO
O
O
OH
E7070
E7010
OMe
F
F
F
O
O
fonamidoglycosylation of D
-glycals,4e the method entails the prob-
O
O
S
N
F
F
S
F
lem of a tedious workup procedure due to the presence of a large
excess of nucleophile. It seems very interesting to study the use of
ion exchange resins to promote the addition of sulfonamides to D-
N
N
H
H
HN
MeO
glycals. Ion exchange resins are the most widely used heterogeneous
catalysts due to their advantages such as high activity and selectiv-
ity, reusability, ease of separation, no corrosion, or disposal of efflu-
ent problems.6 Recent reports on the use of Amberlyst 15 in the
preparation of 2,3-unsaturated O- and S-glycosides from 3,4,6-tri-
OH
ABT-751
T138067
Figure 1. Antimitotic sulfonamides.
O-acetyl-D
-glucal via Ferrier rearrangement,7 prompted us to inves-
OAc
OAc
R1
tigate its use as an alternative catalyst to prepare 2,3-unsaturated
sulfonamidoglycosides (Scheme 1).
O
O
O
N
O
O
S
R
i
O
+
The reaction of 3,4,6-tri-O-acetyl-
D
-glucal 1 and ethanesulfona-
S
NHR1
R
mide in acetonitrile was chosen as a model reaction .8 To study the
AcO
AcO
OAc
1-2
3-4
R = alkyl, aryl
R1 = H, CH3
* Corresponding author. Tel.: +54 221 42423104; fax: +54 221 4226947.
E-mail address: pcolinas@quimica.unlp.edu.ar (P.A. Colinas).
Scheme 1. Reagents and condition: (i) Amberlyst 15, rt, CH3CN.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.076

C. A. Témpera et al. / Tetrahedron Letters 51 (2010) 5372–5374
5373
Table 1
place under kinetic control and no anomerization occurred under
our conditions.
Reaction of 3,4,6-tri-O-acetyl-D-glucal and ethanesulfonamidea
In view of green chemistry, recyclable catalysts are highly pre-
ferred. In our process, Amberlyst 15, was easily recovered from the
reaction mixture by filtration and subsequently used for the next
reaction cycle (Table 3). Using our conditions for the glucosylation
of ethanesulfonamide with the recycled catalyst, this protocol was
repeated two times, the yields were always more than 85% and no
change of the anomeric selectivity was found.
Entry Wt % of Amberlyst 15 Time (min) Temperature (°C)
a
:bb Yield (%)
1
2
3
4
5
10
20
30
30
40
60
60
50
30
40
25
25
25
40
25
87:13 78
85:15 80
87:13 90
86:14 86
87:13 76
a
Reactions were performed using 1 mmol of the glucal, 1.1 equiv of sulfonamide
in acetonitrile.
The antitumor activity of sulfonamides 3b and 4b against hu-
Anomeric ratios were determined by 1H NMR spectroscopy.
b
man hepatocellular carcinoma cell lines Hep-G2 was assessed.12
They act as inhibitors of growth in the 190–230 lM range, which
makes them as interesting leads for the development of novel anti-
cancer agents.
Table 2
Although yields are comparable to those obtained in the sulfon-
amidoglycosylation of D-glycals using boron trifluoride etherate as
Reaction of 3,4,6-tri-O-acetyl-D-glucal
1 and 3,4,6-tri-O-acetyl-D-galactal 2 with
different sulfonamidesa
catalyst, Amberlyst 15 is highly preferred. The present methodol-
ogy has the following advantages: (a) the catalyst is inexpensive
and could be reused, (b) the workup required only filtration of
the catalyst followed by flash chromatography, and (c) only a slight
excess of sulfonamide is used.
In conclusion, we have developed a mild and eco-friendly ap-
proach for the synthesis of N-glycosyl sulfonamides in the presence
of Amberlyst 15. Low-cost reagents and no aqueous workup are re-
quired, and the catalyst could be recycled.
Entry Glycal
1
Sulfonamide
Product Time
(min)
a
:bb,c
Yieldc
(%)
Methyl
Ethyl
3a9
3b
40
60
95:5
94
D-Glucal
2
87:13
(85:15)
88:12
78:22
(87:13)
90:10
(95:5)
90 (95)
3
4
Benzyl
p-Toluene
3c
3d
40
60
94
92 (95)
5
N-Methyl-p-
toluene
4e
60
78 (80)
6
7
Methyl
Ethyl
4a10
4b
40
50
95:5
75
D-Galactal
Acknowledgments
84:16
(83:17)
95:5
90:10
(80:20)
87:13
(95:5)
88 (97)
8
9
Benzyl
p-Toluene
4c11
4d
60
60
72
90 (96)
The authors are grateful to UNLP and CICPBA, for the financial
help and to Dr. Rubén S. Rimada for the NMR measurements.
C.A.T. is a holder of a CONICET fellowship. P.A.C. is a member of
CIC of CONICET.
10
N-methyl-p-
toluene
4e
40
80 (86)
a
Reactions were performed using 1 mmol of the glucal, 1.1 equiv of sulfonamide
References and notes
and 30 wt % of Amberlyst 15 in acetonitrile.
b
Anomeric ratios were determined by 1H NMR spectroscopy.
c
Ratios and yields previously reported are shown between parentheses (Ref. 4c).
1. Supuran, C. T. Exp. Opin. Invest. Drugs 2003, 12, 283–287.
2. Jordan, M. A.; Wilson, L. Nat. Rev. Cancer 2004, 4, 253–265.
3. Medina, J. C.; Roche, D.; Shan, B.; Learned, M.; Frankmoelle, W. P.; Clark, D. L.;
Rosen, T.; Jaen, J. C. Bioorg. Med. Chem. Lett. 1999, 9, 1843–1846.
4. (a) Colinas, P. A.; Bravo, R. D. Org. Lett. 2003, 5, 4509–4511; (b) Colinas, P. A.;
Bravo, R. D. Tetrahedron Lett. 2005, 46, 1687–1689; (c) Colinas, P. A.; Bravo, R. D.
Carbohydr. Res. 2007, 342, 2297–2302; (d) Colinas, P. A.; Núñez, N. A.; Bravo, R.
D. J. Carbohydr. Chem. 2008, 27, 141–147; (e) Rodríguez, O. M.; Colinas, P. A.;
Bravo, R. D. Synlett 2009, 1154–1156.
by the amount of catalyst or by the temperature. To enhance the
synthetic utility of our conditions, we next tested the reaction of
per-O-acetylated D-glucal 1 and D-galactal 2 with a selected group
5. Colinas, P. A.; Bravo, R. D.; Vullo, D.; Scozzafava, A.; Supuran, C. T. Bioorg. Med.
Chem. Lett. 2007, 17, 5086–5090.
of sulfonamides using Amberlyst 15 as a catalyst (Table 2).8
6. De Angelis, A.; Ingallina, P.; Perego, C. Ind. Eng. Chem. Res. 2004, 43, 1169–1178.
7. Tian, Q.; Zhu, X.-M.; Yang, J.-S. Synth. Commun. 2007, 37, 691–701.
In all the cases we examined, 4,6-di-O-acetyl-2,3-dideoxy-D-
hex-2-enopyranosyl sulfonamides 3 and 4 were obtained in good
to excellent yields and with very good selectivity. The anomeric
mixtures could be easily purified by flash chromatography or crys-
tallization to afford the pure
anomer. 1H and 13C NMR data of the
8. Typical experimental procedure: To
a solution of glycal (1 mmol) and
a
sulfonamide (1.1 mmol) in 5 ml of dry CH3CN was added, 30 wt % of resin
Amberlyst 15 at room temperature. The mixture was stirred for the desired
time (Table 2), until the complete disappearance of the starting materials as
judged by TLC. The reaction mixture was filtered, and the resin was washed
with acetone. The combined filtrate and washings were concentrated under
reduced pressure. The residue was chromatographed on silica gel (eluent
hexane–EtOAc) and/or crystallized (hexane–EtOAc) to afford the products.
a
products confirmed the anomeric configuration of sulfonamidogly-
cosides. The stereochemical outcome was in accordance with the
results previously described by us and could be explained in terms
of a kinetically-controlled reaction.
9. 4,6-Di-O-acetyl-2,3-dideoxy-a-D-erithro-hex-2-enopiranosyl
methanesulfonamide (3a). White needles. Mp: 92–93 °C; 1H RMN (200 MHz)
CDCl3 d 5.86 (br d, 1H, J = 9.2 Hz, H-3), 5.84 (m, 2H, H-2, NH), 5.54 (br d, 1H,
J = 9.2 Hz, H-1), 5.22 (dd, 1H, J = 9.1, 1.6 Hz, H-4), 3.96 (ddd, 1H, J = 9.1, 6.3,
2.4 Hz, H-5), 4.25 (dd, 1H, J = 12.0, 4.3, 2.4 Hz, H-6a), 4.11 (dd, 1H, J = 12.0, 6.3,
We have studied the reaction of per-O-acetylated
with methanesulfonamide over shorter times (10, 20, or 30 min)
to analyze the /b ratio. No change in the stereochemical outcome
D-glucal 1
a
2.4 Hz, H-6b), 3.12 (s, 1H, CH3), 2.07 (s, 3H, CH3COO), 2.04 (s, 3H, CH3COO); 13
C
was found which suggests that sulfonamidoglycosylations take
RMN (50 MHz) CDCl3 d 170.76 (CH3COO), 170.34 (CH3COO), 130.60 (C-3),
126.88 (C-2), 76.63 (C-1), 67.68 (C-5), 64.65 (C-4), 63.45 (C-6), 43.23 (CH3),
21,15 (CH3COO), 20.94 (CH3COO).
Table 3
Reusability of Amberlyst 15 as Catalyst for sulfonamidoglycosylationa
10. 4,6-Di-O-acetyl-2,3-dideoxy-
methanesulfonamide (4a). White needles. Mp: 159–160 °C; 1H RMN
(200 MHz) CDCl3 6.27 (ddd, 1H, J = 10, 5.4, 1.6 Hz, H-3), 6.02 (dd, 1H,
a-D-threo-hex-2-enopiranosyl
d
Round
Sulfonamide
Reaction time (min)
Yield (%)
J = 10.0, 3.1 Hz, H-2), 6.01 (m, 1H, NH), 5.58 (ddd, 1H, J = 9.1, 3.1, 1.6 Hz, H-1),
5.03 (dd, 1H, J = 5.3, 1.7 Hz, H-4), 4.20 (m, 3H, H-5, 2xH-6), 3.12 (s, 3H, CH3),
2.07 (s, 3H, CH3COO), 2.02 (s, 3H, CH3COO); 13C RMN (50 MHz) CDCl3 d 170.79
(CH3COO), 170.58 (CH3COO), 126.71 (C-3), 129.76 (C-2), 76.65 (C-1), 67.41 (C-
5), 63.36 (C-4), 62.49 (C-6), 43.38 (CH3), 20,94 (CH3COO), 21.16 (CH3COO).
1
2
3
Ethyl
Ethyl
Ethyl
60
60
60
90
90
85
a
Reactions were performed using 1 mmol of
onamide and 30 wt % of Amberlyst 15 in acetonitrile.
D
-glucal, 1.1 equiv of ethanesulf-
11. 4,6-Di-O-acetyl-2,3-dideoxi-
a-D-threo-hex-2-enopiranosyl benzylsulfonamide
(4c). White needles. Mp: 132–134 °C; 1H RMN (200 MHz) CDCl3 d 7.41–7.35

5374
C. A. Témpera et al. / Tetrahedron Letters 51 (2010) 5372–5374
(m, 5H, Ph), 6.17 (ddd, 1H, J = 9.9, 5.1, 1.91, H-3), 5.96 (dd, 1H, J = 9.9, 2.9 Hz, H-
(Ph), 129.76 (C-2), 126.65 (C-3), 76.91 (C-1), 67.42 (C-5), 63.27 (C-4), 62.42 (C-
6), 61,75 (CH2), 21,15 (CH3COO), 20.94 (CH3COO).
12. García, M. G. INIBIOLP (UNLP-CONICET), Fac. Cs. Médicas (personal
communication).
2), 5.75 (d, 1H, J = 8.7 Hz, NH), 5.60 (ddd, 1H, J = 8.7, 2.9, 1.7 Hz, H-1), 5.03
(appd, 1H, J = 5.1 Hz, H-4), 4.54 (d, 1H, J = 13.7 Hz, H-6a), 4.28 (m, 3H, CH2, H-5,
H-6), 2.08 (s, 3H, CH3COO), 1.95 (s, 3H, CH3COO); 13C RMN (50 MHz) CDCl3
d
170.81 (CH3COO), 170.57 (CH3COO), 131.02, 129.11, 129.66, 128.87, 126.65