118
N. Alencar et al. / European Journal of Medicinal Chemistry 146 (2018) 108e122
0
0
J’ ¼ 7.2 Hz, 1H, 1 -H
b
), 3.03 (dd, J ¼ 14.4 Hz, J’ ¼ 2.4 Hz, 1H, 6-H
.24 (dd, J ¼ J’ ¼ 9.6 Hz, 1H, 4-H), 3.40 (dd, J ¼ 9.6 Hz, J’ ¼ 3.6 Hz, 1H,
-H), 3.44 (s, 3H, 1-OCH
), 3.58 (dd, J ¼ J’ ¼ 9.6 Hz, 1H, 3-H), 3.66
b
),
3.51 (dd, J ¼ 14.0 Hz, J’ ¼ 9.6 Hz, 1H, 6-H
b
), 3.53 (m, 1 H, 1 -H
a
), 3.58
0
3
2
(dd, J ¼ 14.0 Hz, J’ ¼ 7.2 Hz, 1H, 1 -H
b
), 3.62 (dd, J ¼ 9.6 Hz,
3
J’ ¼ 8.8 Hz, 1H, 3-H), 4.06 (ddd, J ¼ J’ ¼ 9.6 Hz, J” ¼ 2.4 Hz, 1H, 5-H),
13
(
ddd, J ¼ 9.6 Hz, J’ ¼ 8.0 Hz, J” ¼ 2.4 Hz, 1H, 5-H), 4.65 (d, J ¼ 3.6 Hz,
4.71 (d, J ¼ 3.6 Hz, 1H, 1-H), 4.85 (s, OH); C NMR (100.6 MHz,
13
0
0
1
H, 1-H), 4.84 (s, OH); C NMR (100.6 MHz, CD
3
OD)
d
19.3 (CH
2
,
3
CD OD)
d
11.5 (CH
2
, C2 ), 51.3 (CH
2
, C1 ), 56.0 (CH
2
, C6), 56.4 (CH
3
, 1-
0
0
C2 ), 29.9 (CH
2
, C1 ), 34.7 (CH
2
, C6), 55.6 (CH
3
3
, 1-OCH ), 73.6 (CH,
OCH
3
), 68.7 (CH, C5), 73.2 (CH, C2), 74.1 (CH, C4), 74.7 (CH, C3),101.6
þ
C2), 73.8 (CH, C5), 74.4 (CH, C4), 75.0 (CH, C3), 101.2 (CH, C1), 120.2
C, CN); HRMS (ESI), calcd for (C10
(CH, C1), 118.6 (C, CN); HRMS (ESI), calcd for (C15
313.1064, found 313.1062.
H17NO
7
S þ NH
4
)
þ
(
H17NO
5
S þ NH
4
) 281.1166, found
2
81.1166.
4
.4.6. Methyl 6-[(3-aminopropyl)sulfonyl]-6-deoxy-
a-D-
4.4.4. Methyl 6-[(3-aminopropyl)thio]-6-deoxy-a-D-
glucopyranoside (7)
glucopyranoside (5)
A mixture of nitrile 4 (213 mg, 0.81 mmol) and Raney-Ni (50%
water, 300 mg) in MeOH (80 mL) was reacted with hydrogen
A mixture of cyanosulfone 6 (289 mg, 0.98 mmol) and Raney-Ni
(50% water, 300 mg) in MeOH (80 mL) was reacted with hydrogen
(16 atm) at room temperature overnight in a Parr stirred reactor.
The resulting suspension was filtered through Celite and rinsed
with MeOH (25 mL). The solvent was removed in vacuo to afford a
®
(
16 atm) at room temperature overnight in a Parr stirred reactor.
®
The resulting suspension was filtered through Celite and rinsed
with MeOH (25 mL). The solvent was removed in vacuo to afford a
brownish oil (205 mg), which was purified through column chro-
yellow oil (186 mg), which was purified through column chroma-
tography (40e60
elution). On elution with CH
sulfone 7 (82 mg, 28% yield) was isolated; R
50% aq. NH OH 7:3:0.1).
A solution of 7 (29 mg, 0.10 mmol) in MeOH (5 mL) was filtered
through a 0.20 m NYL filter, treated with methanolic HCl (0.5 N,
0.87 mL) and evaporated under reduced pressure. The resulting
m
m silica gel, CH
Cl /MeOH 82:18 to 78:22, amino-
0.09 (CH Cl /MeOH/
2 2
Cl /MeOH mixtures, gradient
matography (40e60
mixtures, gradient elution). On elution with CH
NH OH 75:25:1 to 65:35:1, amine 5 (88 mg, 41% yield) was isolated
as a colourless sticky solid; R 0.11 (CH Cl /MeOH/50% aq. NH OH
:3:0.1).
A solution of 5 (40 mg, 0.15 mmol) in MeOH (5 mL) was filtered
through a 0.20 m NYL filter, treated with methanolic HCl (0.5 N,
.35 mL) and evaporated under reduced pressure. The resulting
m
m silica gel, CH
2
Cl
2
/MeOH/50% aq. NH
4
OH
2
2
2
Cl /MeOH/50% aq.
2
f
2
2
4
4
f
2
2
4
7
m
m
solid was washed successively with CH
(2 ꢂ 3 mL) to give, after drying at 35 C/30 Torr, 7$HCl (19 mg) as a
2
Cl
2
(2 ꢂ 5 mL) and pentane
ꢁ
1
2
0
solid was washed successively with CH
2
Cl
2
(2 ꢂ 5 mL) and pentane
yellowish hygroscopic solid; [
a
]
D
¼ þ 147 (c 1.3, MeOH); IR (ATR)
ꢁ
þ
(
2 ꢂ 3 mL) to give, after drying at 35 C/30 Torr, 5$HCl (44 mg) as a
n
3500e2500 (max at 3241, 2916, 2844, OH, NH, CH st), 1280, 1132,
2
0
ꢀ1
0
1
yellowish hygroscopic solid; [
a
]
D
¼ þ 171 (c 0.46, MeOH); IR
1102 (SO
J ¼ J’ ¼ 7.6 Hz, 2H, 2 -H
2
st) cm
;
H NMR (400 MHz, CD
3
OD)
d
2.19 (tt,
þ
0
(
ATR)
n
3500e2500 (max at 3301, 2912, 2854, 2839, OH, NH, CH st)
2
), 3.13 (t, J ¼ 7.6 Hz, 2H, 3 -H
2
), 3.15 (dd,
ꢀ
1
1
0
cm ; H NMR (400 MHz, CD
3
OD)
d
1.99 (tt, J ¼ J’ ¼ 8.0 Hz, 2H, 2 -
J ¼ 9.6 Hz, J’ ¼ 8.8 Hz, 1H, 4-H), superimposed in part with the sol-
0
H
2
), 2.66 (dd, J ¼ 14.0 Hz, J’ ¼ 8.0 Hz, 1H), 2.68 (dd, J ¼ 14.0 Hz,
vent signal 3.22 (dt, J ¼ 14.0 Hz, J’ ¼ 7.6 Hz,1H,1 -H
a
), superimposed
0
0
0
J’ ¼ 8.0 Hz, 1H), 2.73 (m, 1H) (6-H
a
, 1 -H
a
, 1 -H
b
), 2.98 (dd,
in part with the solvent signal 3.33 (dt, J ¼ 14.0 Hz, J’ ¼ 7.6 Hz,1H,1 -
0
J ¼ 14.0 Hz, J’ ¼ 2.8 Hz, 1H, 6-H
b
), 3.13 (t, J ¼ 8.0 Hz, 2H, 3 -H
2
), 3.22
H
b
), 3.40 (dd, J ¼ 10.0 Hz, J’ ¼ 3.6 Hz, 1H, 2-H), superimposed in part
3.45 (dd, J ¼ 12.0 Hz, J’ ¼ 8.0 Hz, 1H, 6-H ), superimposed in part
), 3.460 (s, 3H, 1-OCH ),
(
1
dd, J ¼ 9.6 Hz, J’ ¼ 8.8 Hz, 1H, 4-H), 3.38 (dd, J ¼ 9.6 Hz, J’ ¼ 3.6 Hz,
a
H, 2-H), 3.42 (s, 3H, 1-OCH
3
), 3.58 (dd, J ¼ 9.6 Hz, J’ ¼ 8.8 Hz, 1H, 3-
3.459 (dd, J ¼ 12.0 Hz, J’ ¼ 4.0 Hz, 1H, 6-H
b
3
H), 3.65 (br dd, J ¼ 9.6 Hz, J’ ¼ 8.0 Hz,1H, 5-H), 4.63 (d, J ¼ 3.6 Hz,1H,
3.62 (dd, J ¼ 10.0 Hz, J’ ¼ 8.8 Hz, 1H, 3-H), 4.06 (ddd, J ¼ 9.6 Hz,
þ
13
1
-H), 4.85 (s, OH, NH
3
); C NMR (100.6 MHz, CD
3
0
OD)
, C3 ), 55.6 (CH
d
27.1 (CH
2
,
J’ ¼ 8.0 Hz, J” ¼ 4.0 Hz, 1H, 5-H), 4.69 (d, J ¼ 3.6 Hz, 1H, 1-H), 4.85 (s,
0
0
þ
13
0
C2 ), 30.6 (CH
2
, C1 ), 34.4 (CH
2
, C6), 47.9 (CH
2
3
, 1-
OH, NH
(CH
3
); C NMR (100.6 MHz, CD
3
OD)
d
21.3 (CH
2
, C2 ), 39.5
), 68.6
0
0
OCH
3
), 73.5 (CH, C2), 73.6 (CH, C5), 74.5 (CH, C4), 75.0 (CH, C3),
2
, C3 ), 53.0 (CH
2
, C1 ), 55.9 (CH
2
, C6), 56.3 (CH
3
, 1-OCH
3
þ
101.1 (CH, C1), HRMS (ESI), calcd for (C10
H
21NO
5
S þ H ) 268.1213,
(CH, C5), 73.3 (CH, C2), 74.2 (CH, C4), 74.7 (CH, C3), 101.5 (CH, C1);
þ
found 268.1214.
HRMS (ESI), calcd for (C10
H21NO
7
S þ H ) 300.1111; found 300.1114.
4.4.5. Methyl 6-[(2-cyanoethyl)sulfonyl]-6-deoxy-
a-D-
4.4.7. Methyl 6-deoxy-6-[(3-guanidinopropyl)sulfonyl]-a-D-
glucopyranoside (6)
glucopyranoside (8)
A suspension of nitrile 4 (210 mg, 0.80 mmol) and NaHCO
3
To a suspension of aminosulfone 7 (27 mg, 0.09 mmol) in
acetonitrile (1 mL), Et N (0.02 mL, 15 mg, 0.14 mmol) and 1H-pyr-
ꢁ
(
181 mg, 2.16 mmol) in CH
2
Cl
2
(3.5 mL) was cooled at 0 C with an
3
ice bath and treated with m-chloroperbenzoic acid (77% purity,
83 mg, 2.16 mmol). The reaction mixture was stirred at room
temperature for 3 h and evaporated under reduced pressure to give
azole-1-carboxamidine hydrochloride (16 mg, 0.11 mmol) were
added. The reaction mixture was stirred under reflux for 6 h and
cooled to room temperature. The solvent was poured off and the
precipitate was dried in vacuo. The resulting yellow sticky solid
(39 mg) was taken in MeOH (2 mL), treated with methanolic HCl
4
a solid residue (726 mg), which was purified through column
chromatography (40e60
gradient elution). On elution with CH
slightly impure cyanosulfone 6 (289 mg, quantitative yield) was
isolated; R 0.57 (CH Cl /MeOH 8:2). A solution of 6 (21 mg,
.07 mmol) in MeOH (5 mL) was filtered through a 0.20 m NYL
2 2
mm silica gel, CH Cl /MeOH mixtures,
2
2
Cl /MeOH 92:8 to 88:12,
(0.5 N, 2 mL), and filtered through a 0.2
mm NYL filter. The filtrate
was evaporated under reduced pressure, washed successively with
f
2
2
CH
3
CN (2 ꢂ 2 mL), CH
2
Cl
2
(2 ꢂ 2 mL), and pentane (2 ꢂ 2 mL), and
ꢁ
0
m
dried at 35 C/30 Torr, to provide guanidine 8$HCl (21 mg,
0.05 mmol, 62% yield) as a yellowish hygroscopic solid; [
155 (c 0.80, MeOH); IR (ATR)
filter and evaporated under reduced pressure. The analytical sam-
ple of 6 (18 mg) was obtained by washing the resulting solid suc-
a
]2
0
D
¼ þ
n 3500e2500 (max at a 3335, 3313,
þ
cessively with CH
2
Cl
2
(2 ꢂ 5 mL) and pentane (2 ꢂ 3 mL), and
3160, 2928, 2912, OH, NH , NH, CH st), 1644, 1630 (C¼N st), 1293,
ꢁ
ꢁ
20
ꢀ1
0
1
drying at 35 C/30 Torr; mp 151e153 C; [
a
]
D
¼ þ 127 (c 0.38,
3378, 3308 (OH st), 2270 (CN st), 1295, 1137, 1115
st) cm ; H NMR (400 MHz, CD OD)
3.00 (t, J ¼ 7.2 Hz, 2H,
), 3.16 (dd, J ¼ 9.6 Hz, J’ ¼ 8.8 Hz, 1H, 4-H), 3.41 (dd, J ¼ 9.6 Hz,
1104 (SO
2
st) cm
;
3
H NMR (400 MHz, CD OD) d 2.10 (tt,
MeOH); IR (ATR)
n
J ¼ J’ ¼ 7.6 Hz, 2H, 2 -H
2
), 3.15 (dd, J ¼ 9.6 Hz, J’ ¼ 9.2 Hz, 1H, 4-H),
ꢀ
1
1
0
0
(
2
SO
-H
2
3
d
3.24e3.35 (complex signal, 2H, 1 -H
a
, 1 -H
b
), 3.35 (t, J ¼ 7.6 Hz, 2H,
0
0
2
3 -H
2
), 3.41 (dd, J ¼ 9.6 Hz, J’ ¼ 4.0 Hz,1H, 2-H), 3.42e3.48 (complex
, 6-H ), 3.46 (s, 3H, 1-OCH
), 3.62 (dd, J ¼ 9.6 Hz,
J’ ¼ 9.2 Hz, 1H, 3-H), 4.06 (ddd, J ¼ J’ ¼ 9.6 Hz, J” ¼ 5.6 Hz, 1H, 5-H),
J’ ¼ 3.6 Hz, 1H, 2-H), superimposed in part 3.46 (dd, J ¼ 14.0 Hz,
signal, 2H, 6-H
a
b
3
J’ ¼ 2.4 Hz, 1H, 6-H ), 3.47 (s, 3H, 1-OCH ), superimposed in part
a
3