F. Tramutola, et al.
Bioorganic & Medicinal Chemistry 27 (2019) 1863–1870
quenched with H
2
SO
4
5% solution. Organic phase was washed adding
solution and brine. The organic phases were
5.9; S, 6.6.
saturated aqueous NaHCO
3
collected, dried over Na
2
SO4, filtered and concentrated in vacuo. The
4.1.7. (2S)-{2-Hydroxy-3-[isobutyl-(4-methoxy-benzenesulfonyl)-amino]-
propyl}-carbamic acid benzo[b]thiophen-5-yl ester (10b)
crude containing compound 6 was used in the subsequent reaction
without any purification.
The product 10b was obtained as white solid (72% yield).
2
0
1
[
α]
D
= 4.5 (c 0.5, CH
2
Cl
2
). H NMR (500 MHz, CDCl
3
) δ (ppm): 7.84
4
.1.3. (2S)-N-(3-Azido-2-hydroxy-propyl)-N-isobutyl-4-methoxy-
(d, J = 8.6 Hz, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 2.1 Hz, 1H),
7.49 (d, J = 5.4 Hz, 1H), 7.29 (d, J = 5.4 Hz, 1H), 7.13 (dd,
benzenesulfonamide (7)
The product 6 (0.78 mmol) was dissolved in anhydrous DMF
J
1
= 8.8 Hz, J = 2.1 Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H), 5.81 (bs, 1H),
2
(
10 mL) and NaN
3
(0.104 g, 1.60 mmol) was added at room temper-
4.01 (bs, 1H), 3.87 (s, 3H), 3.61 (m, 2H), 3.36 (m, 1H), 3.14 (A of ABX
arure and under Ar atmosphere. The reaction mixture was warmed at
reflux and kept stirring for 4 h. The reaction was then quenched by
system, JAB = 15.1 Hz, JAX = 4.9 Hz, 1H), 3.05 (B of ABX system,
J
AB = 15.1 Hz, JBX = 7.2 Hz, 1H), 2.90 (d, J = 7.9 Hz, 2H), 1.89 (m,
adding H
2
O (20 mL). The mixture was then extracted with CH
2
SO
Cl
2
1H), 1.63 (bs, 1H), 0.93 (A of AB system, JAB = 6.8 Hz, 3H), 0.92 (B of
13
(
3 × 30 mL) and the organic layer was dried with anhydrous Na
2
4
,
AB system, JAB = 6.8 Hz, 3H). C NMR (125 MHz, CDCl ) δ (ppm):
3
filtered and concentrated in vacuo. The crude was purified on silica gel
163.1, 156.3, 148.3, 140.3, 136.7, 129.7, 129.5, 128.1, 123.7, 122.9,
(
(
CH
2
Cl
2
/EtOAc 98:2) and compound 7 was isolated as brown oil
118.7, 115.9, 114.4, 69.9, 59.1, 55.6, 53.2, 44.2, 27.4, 20.1. MS (m/z):
+
0.219 g, 82% from 5).
493 (MH ). Anal. Calcd for C23
H
28
2
N O
6
S : C, 56.08; H, 5.73; N, 5.69;
2
2
0
[
α]
D
= −8.0 (c 0.5, CH
2
3
Cl
2
)
O, 19.49; S, 13.02. Found C, 56.2; H, 5.5; N, 5.7; S, 13.2.
1
H NMR (400 MHz, CDCl
) δ (ppm): 7.73 (d, J = 6.8 Hz, 2H), 6.90
(
d, J = 6.8 Hz, 2H), 4.03–3.92 (m, 1H), 3.86 (s, 3H), 3.41–3.23 (m, 3H),
.18–2.88 (m, 4H), 1.95–1.88 (m, 1H), 0.92 (d, J = 5.6 Hz, 3H), 0.85
d, J = 5.6 Hz, 3H).
4.1.8. (2S)-{2-Hydroxy-3-[isobutyl-(4-methoxy-benzenesulfonyl)-amino]-
propyl}-carbamic acid 1H-indol-5-yl ester (10c).
3
(
The product 10c was obtained as white solid (72% yield).
+
20
1
MS (m/z): 343 (MH ). Anal. Calcd. for C14
H
22
N
4
O
4
S: C, 49.11; H,
[α]
D
= 32.4 (c 0.5, CH
2
Cl
2
). H NMR (500 MHz, CDCl
3
) δ (ppm): 8.32
6
4
.48; N, 16.36; O, 18.69; S, 9.36. Found C, 49.0; H, 6.5; N, 16.4; S, 9.4.
(bs, 1H), 7.76 (d, J = 8.6 Hz, 2H), 7.37 (bs, 1H), 7.32 (d, J = 8.5 Hz,
1
H), 7.22 (bs, 1H), 7.00 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.5 Hz, 1H),
.1.4. (2S)-N-(3-Amino-2-hydroxy-propyl)-N-isobutyl-4-methoxy-
6.52 (bs, 1H), 5.76 (bs, 1H), 3.98 (bs, 1H), 3.86 (s, 3H), 3.60 (m, 1H),
3.35 (m, 1H), 3.16 (A of ABX system, JAB = 15.1 Hz, JAX = 4.9 Hz, 1H),
3.04 (B of ABX system, JAB = 15.1 Hz, JAX = 7.4 Hz, 1H), 2.91 (d,
J = 7.4 Hz, 2H), 2.18 (s, 3H), 1.89 (m, 1H), 0.94 (A of AB system,
benzenesulfonamide (8)
Pd/C 10% (0.026 g) was added to a solution of compound 7
(
0.171 g, 0.50 mmol) in EtOH (10 mL). The reaction mixture was stirred
1
3
under H
2
atmosphere at room temperature. After 4 h the reaction
JAB = 5.9 Hz, 3H), 0.92 (B of AB system, JAB = 5.9 Hz, 3H). C NMR
mixture was fluxed with Ar, filtered on a Celite path, washed with EtOH
and concentrated in vacuo. The crude containing compound 8 was used
in the subsequent reaction without any purification.
(100 MHz, CDCl ) δ (ppm): 163.1, 157.1, 144.6, 133.6, 129.7, 129.5,
3
128.1, 125.5, 116.3, 114.4, 112.7, 111.3, 102.9, 70.0, 59.1, 55.6, 53.2,
44.2, 27.4, 20.0.
2
0
+
[
α]
D
= −6.0 (c 0.5, CH
2
3
Cl
2
)
MS (m/z): 476 (MH ). Anal. Calcd for C23
H
29
N
3
O S: C, 58.09; H,
6
1
H NMR (400 MHz, CDCl
) δ (ppm): 7.76 (d, J = 8.4 Hz, 2H), 6.99
6.15; N, 8.84; O, 20.19; S, 6.74. Found C, 58.2; H, 6.2; N, 8.9; S, 6.7.
(
d, J = 8.4 Hz, 2H), 4.70 (s, 2H), 4.10 (s, 1H), 3.88 (s, 3H), 3.79 (m,
1
0
H), 3.38–3.36 (m, 2H), 3.10–2.80 (m, 2H), 2.74 (m, 2H), 1.64 (m, 1H),
4.1.9. (1R,2S)- (1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic
.91 (d, J = 6.8 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H).
acid tert-butyl ester (16)
i-BuNH (8.0 mL, 80 mmol) was added to a stirred solution of
15 (1.053 g,
+
MS (m/z): 317 (MH ). Anal. Calcd. for C14
H
24
N
2
O
4
S: C, 53.14; H,
2
7
.65; N, 8.85; O, 20.23; S, 10.13. Found C, 53.0; H, 7.4; N, 8.7; S, 9.8.
(2S,3S)-1,2-epoxy-3-(Boc-amino)-4-phenylbutane
4
.0 mmol) in i-PrOH (20 mL). The mixture was warmed at 60 °C. After
4
.1.5. Preparation of carbamates: general procedure
6 h the solvent and the excess of i-BuNH
2
were removed under reduced
Et
3
N
(0.033 mL, 0.24 mmol) and p-nitrophenylchloroformiate
pressure. The product 16 was obtained as white solid in quantitative
yield. 1H and C NMR spectra were consistent to literature data.
13
8
(
0.048 g, 0.24 mmol) were added to
a
solution of 5-hydro-
Cl (1 mL), under Ar
xyheteroarenes 9a-c (0.24 mmol) in anhydrous CH
2
2
atmosphere. The mixture was kept stirring at room temperature for 1 h
to afford intermediates 11a-c; then amine 8 (or 18) (0.20 mmol) was
added and the mixture was kept stirring for 24 h. The solvent was
evaporated and the crude compounds were purified on silica gel (EP/
EtOAc 97:3), affording to compounds 10a-c (or 19a-c).
4.1.10. (1S,2R)-{1-Benzyl-2-hydroxy-3-[isobutyl-(4-methoxy-
benzenesulfonyl)-amino]-propyl}-carbamic acid tert-butyl ester (17)
To a stirred solution of aminoalcohol 16 (0.262 g, 0.78 mmol) in
anhydrous CH
2
Cl
2
(40 mL), Et N (0.28 mL, 2.02 mmol) and 4-methox-
3
ybenzenesulfonyl chloride (0.192 g, 0.93 mmol) were added at room
temperature and under Ar atmosphere. After 24 h the reaction was
4
.1.6. (2S)-{2-Hydroxy-3-[isobutyl-(4-methoxy-benzenesulfonyl)-amino]-
quenched with 5% aqueous H
2
SO solution. The organic layer was
4
propyl}-carbamic acid benzofuran-5-yl ester (10a)
washed adding saturated aqueous NaHCO
3
solution and brine. The
SO4, filtered and con-
2
0
The product 10a was obtained as white solid (74% yield). [α]
D
=
organic phases collected were dried over Na
2
1
+
10.7 (c 0.5, CH
2
Cl
2
). H NMR (500 MHz, CDCl
3
) δ (ppm): 7.75 (d,
centrated in vacuo. The crude was purified on silica gel (CH
2
2
Cl /EtOAc
J = 8.8 Hz, 2H), 7.64 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.35
d, J = 2.0 Hz, 1H), 7.04 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H), 6.99 (d,
98:2) and compound 17 was isolated as white solid.
1
13
8
(
1
2
H and C NMR spectra were consistent to literature data.
J = 8.8 Hz, 2H), 6.74 (brs, 1H), 3.99 (bs, 1H), 3.86 (s, 3H), 3.60 (m,
2
H), 3.35 (m, 1H), 3.14 (A of ABX system, JAB = 15.1 Hz, JAX = 4.8 Hz,
H), 3.04 (B of ABX system, JAB = 15.1 Hz, JBX = 7.3 Hz, 1H), 2.90 (d,
4.1.11. (2R,3S)
N-(3-Amino-2-hydroxy-4-phenyl-butyl)-N-isobutyl-4-
1
methoxy-benzenesulfonamide (18)
J = 7.8 Hz, 2H), 1.88 (m, 1H), 0.93 (A of AB system, JAB = 6.8 Hz, 3H),
To a stirred solution of 17 (0.395 g, 0.78 mmol) in anhydrous
1
3
0
.92 (B of AB system, JAB = 6.8 Hz, 3H). C NMR (125 MHz, CDCl
3
) δ
CH
2
Cl (29 mL), trifluoroacetic acid (13 mL) was added at room tem-
2
(
ppm): 163.1, 156.5, 152.4, 146.5, 146.3, 146.1, 129.6, 129.6, 129.4,
perature. After 1 h the reaction mixture was concentrated, treated with
toluene (3x20 mL) and evaporated under vacuum. The crude was
1
2
27.9, 118.2, 114.4, 113.7, 111.6, 106.8, 69.9, 59.1, 55.5, 53.1, 44.1,
+
7.19, 20.1, 19.8. MS (m/z): 477 (MH ). Anal. Calcd for C23
H
28
N
2
O
7
S:
purified on silica gel (CHCl
3
/CH OH = 9:1) and the product 18 was
3
C, 57.97; H, 5.92; N, 5.88; O, 23.50; S, 6.73. Found C, 57.8; H, 5.7; N,
obtained as white solid in 84% yield.
1868