Journal of Medicinal Chemistry
Article
product. The residue was further purified by a flash chromatography
2H), 1.51−1.44 (m, 2H), 1.32−1.18 (m, 24H), 0.85 (t, J = 6.9 Hz,
3H). 13C NMR (126 MHz, DMSO) δ 172.57, 170.35, 167.92, 61.06,
54.76, 52.13, 51.68, 38.12, 35.41, 32.82, 31.36, 31.32, 29.08, 29.04,
(
5% MeOH/CH Cl ) to yield product 29 (110 mg, 67%) as a white
2 2
+
solid. MS (ESI-TOF) for C H N O S [M + H] found 690.4659,
calculated 690.4722; [M + Na] found 712.4478, calculated 712.4541.
35
67
3
8
+
28.98, 28.84, 28.73, 28.70, 25.28, 22.12, 13.99. MS (ESI-TOF) for
+
The global deprotection of compound 29 using TFA resulted in
C
26
H
51
N
3
O
6
S [M + H] found 534.3530, calculated 534.3571; [M +
1
+
compound 30 as a TFA salt in quantitative yield. H NMR (500 MHz,
Na] found 556.3351, calculated 556.3391.
CDCl ) δ 8.53 (d, J = 7.6 Hz, 1H), 5.41 (t, J = 5.7 Hz, 1H), 4.72−4.63
Synthesis of Compound 34, (2S,5R)-Methyl 5-Acetamido-2-
hydroxymethyl)-4,11-dioxo-12-oxa-7-thia-3,10-diazaoctaco-
3
(
(
m, 1H), 4.36 (t, J = 6.5 Hz, 1H), 4.22 (ddd, J = 23.1, 11.5, 5.7 Hz,
san-1-oate. To a solution of compound 33 (60 mg, 0.093 mmol) in
dichloromethane (2 mL) were added pyridine (8 μL, 0.102 mmol) and
acetic anhydride (10 μL, 0.102 mmol). The reaction mixture was
stirred at room temperature for 30 min and then concentrated. The
residue was purified by flash chromatography (5% MeOH/CH Cl ) to
2
H), 3.89 (dt, J = 11.7, 7.2 Hz, 2H), 3.75 (s, 3H), 3.24−2.96 (m, 4H),
2.80 (t, J = 5.5 Hz, 2H), 1.46 (m, 2H), 1.25 (s, 26H), 0.88 (t, J = 7.0
13
Hz, 3H). C NMR (126 MHz, CDCl ) δ 170.45, 168.42, 156.76,
3
6
2
3.91, 61.89, 55.41, 52.94, 52.89, 41.32, 33.41, 32.08, 31.40, 29.94,
2
2
9.87, 29.86, 29.82, 29.77, 29.52, 26.97, 22.84, 14.28. MS (ESI-TOF)
1
+
yield product 34. H NMR (500 MHz, CDCl ) δ 7.56 (d, J = 7.4 Hz,
3
for C H N O S [M + H] found 534.3524, calculated 534.3571.
26
51
3
6
1
2
2
H), 6.75 (d, J = 6.7 Hz, 1H), 5.20 (d, J = 5.2 Hz, 1H), 4.74−4.58 (m,
H), 4.10−3.89 (m, 4H), 3.79 (s, 3H), 3.42 (dd, J = 12.5, 6.2 Hz, 3H),
.94 (d, J = 6.1 Hz, 2H), 2.83−2.67 (m, 2H), 2.05 (s, 3H), 1.66−1.53
Synthesis of Compound 31, (2S,5R)-Methyl 5-Acetamido-2-
(
hydroxymethyl)-4,11-dioxo-10-oxa-7-thia-3,12-diazaoctaco-
san-1-oate. To a solution of compound 30 (56 mg, 0.087 mmol) in
CH Cl (1 mL) were added pyridine (8 μL, 0.1 mmol) and acetic
1
3
(
(
m, 2H), 1.36−1.20 (m, 26H), 0.88 (t, J = 7.0 Hz, 3H). C NMR
2
2
126 MHz, CDCl ) δ 170.87, 170.66, 157.61, 65.69, 62.77, 55.23,
anhydride (9 μL, 0.1 mmol). The reaction mixture was stirred at room
temperature for 30 min and then concentrated. The residue was
purified by a flash chromatography (5% MeOH/CH Cl ) to yield
3
5
2
2.90, 52.58, 40.34, 34.48, 32.92, 32.07, 29.85, 29.84, 29.81, 29.75,
9.71, 29.51, 29.45, 29.09, 26.00, 23.27, 22.84, 14.28. MS (ESI-TOF)
2
2
+
1
for C H N O S [M + H] found 576.3602, calculated 576.3677; [M
+
product 31 (32 mg, 64%) as a white solid. H NMR (500 MHz,
28 53
3
7
+
Na] found 598.3416, calculated 598.3496.
CDCl ) δ 7.48 (d, J = 7.6 Hz, 1H), 6.66 (d, J = 7.1 Hz, 1H), 5.25 (t, J
3
Synthesis of Compound 35, (2S,5R)-5-((tert-
=
5.5 Hz, 1H), 4.67 (dd, J = 14.1, 7.1 Hz, 1H), 4.63 (dd, J = 7.5, 3.6
Hz, 1H), 4.32 (dt, J = 12.2, 6.2 Hz, 1H), 4.25 (dt, J = 11.7, 6.0 Hz,
H), 3.97 (q, J = 11.4 Hz, 2H), 3.79 (s, 3H), 3.31 (bs, 1H), 3.15 (dd, J
13.4, 6.8 Hz, 2H), 2.96 (qd, J = 14.1, 6.6 Hz, 2H), 2.89−2.78 (m,
H), 2.05 (s, 3H), 1.52−1.44 (m, 2H), 1.34−1.20 (m, 26H), 0.88 (t, J
7.0 Hz, 3H). 13C NMR (126 MHz, CDCl ) δ 170.83, 170.68,
Butoxycarbonyl)amino)-2-(tert-butoxymethyl)-4,11-dioxo-12-
oxa-7-thia-3,10-diazaoctacosan-1-oic Acid. To a solution of
compound 32 (100 mg, 0.145 mmol) in dichloroethane (2.5 mL)
was added trimethyltin hydroxide (79 mg, 0.435 mmol), and the
reaction mixture was heated to reflux for 6 h. After the completion of
reaction, the solvent was removed under reduced pressure to obtain
1
=
2
=
3
1
3
2
5
5
70.63, 156.79, 64.06, 62.80, 55.23, 52.91, 52.78, 41.31, 34.86, 32.07,
1.87, 29.98, 29.85, 29.81, 29.76, 29.72, 29.51, 29.46, 26.94, 23.29,
the crude product which was purified using column chromatography
1
(
50% CH Cl /EtOAc) to obtain compound 35 (72 mg, 73%). H
+
2
2
2.84, 14.28. MS (ESI-TOF) for C H N O S [M + H] found
28
53
3
7
NMR (500 MHz, CDCl ) δ 7.23 (d, J = 6.8 Hz, 1H), 5.55 (d, J = 7.3
+
3
76.3594, calculated 576.3677; [M + Na] found 598.3414, calculated
Hz, 1H), 5.28 (s, 1H), 4.70−4.60 (m, 1H), 4.34 (s, 1H), 4.04 (t, J =
98.3496.
6
1
2
2
.4 Hz, 2H), 3.90 (dd, J = 9.0, 3.5 Hz, 1H), 3.57 (dd, J = 8.5, 4.9 Hz,
H), 3.36 (dd, J = 16.2, 10.1 Hz, 2H), 2.93 (qd, J = 13.9, 6.2 Hz, 2H),
.78−2.61 (m, 2H), 1.64−1.54 (m, 2H), 1.45 (s, 9H), 1.35−1.22 (m,
6H), 1.19 (s, 3H), 0.88 (t, J = 7.0 Hz, 3H). 13C NMR (126 MHz,
Synthesis of Compound 32, (2S,5R)-Methyl 5-((tert-
Butoxycarbonyl)amino)-2-(tert-butoxymethyl)-4,11-dioxo-12-
oxa-7-thia-3,10-diazaoctacosan-1-oate. To a solution of com-
pound 20 (100 mg, 0.238 mmol) in dry CH Cl (5 mL) were added
2
2
CDCl ) δ 172.38, 171.01, 157.13, 155.65, 80.69, 74.63, 65.46, 61.26,
3
triethylamine (50 μL, 0.356 mmol) and cetyl chloroformate (117 μL,
5
2
3.86, 52.90, 40.17, 34.31, 32.65, 32.07, 29.85, 29.81, 29.76, 29.72,
0
.356 mmol), and the reaction mixture was stirred at room
9.51, 29.48, 29.15, 28.44, 27.45, 26.01, 22.84, 14.28. MS (ESI-TOF)
temperature for 30 min. After the completion of reaction, water (10
mL) was added to the mixture and the product obtained was extracted
in CH Cl . The organic layer was washed with water (10 mL × 2) and
+
for C H N O S [M + Na] found 698.4272, calculated 698.4385.
34
65
3
8
Synthesis of Compound 36, tert-Butyl Hexadecyl-((8S,11R)-
2
2
8
-(tert-butoxymethyl)-2-methyl-7,10-dioxo-13-thia-2,6,9-tria-
brine (10 mL), dried over anhydrous sodium sulfate and the solvent
was removed under reduced pressure to obtain the crude product
which was purified using column chromatography (50% EtOAc/
zapentadecane-11,15-diyl)dicarbamate. To a solution of acid 35
1
1
(
563 mg, 0.833 mmol) and N ,N -dimethylpropane-1,3-diamine (115
μL, 0.916 mmol) in DMF (5 mL) were added triethylamine (232 μL,
.67 mmol) and N-hydroxybenzotriazole (HOBt, 56 mg, 0.417
1
hexanes) to obtain compound 32 (120 mg, 74%). H NMR (500
1
MHz, CDCl ) δ 7.15 (d, J = 8.0 Hz, 1H), 5.47 (s, 1H), 5.26 (s, 1H),
3
mmol). The reaction mixture was cooled to 0 °C, and EDCI (258
mg, 1.67 mmol) was added after 30 min. The resulting mixture was
stirred at room temperature overnight. After the completion of
reaction, water (20 mL) was added to the mixture and the product
obtained was extracted in EtOAc. The organic layer was washed with
water (10 mL × 3) and brine (10 mL), dried over anhydrous sodium
sulfate and the solvent was removed under reduced pressure to obtain
the crude product which was purified using column chromatography
4.66 (dt, J = 8.2, 3.1 Hz, 1H), 4.32 (s, 1H), 4.03 (t, J = 6.6 Hz, 2H),
3.82 (dd, J = 9.1, 3.0 Hz, 1H), 3.74 (s, 3H), 3.57 (dd, J = 9.1, 3.2 Hz,
1H), 3.39 (d, J = 5.4 Hz, 2H), 2.97 (dd, J = 13.9, 5.4 Hz, 1H), 2.87
(
dd, J = 13.8, 6.8 Hz, 1H), 2.80−2.65 (m, 2H), 1.63−1.54 (m, 2H),
1
3
8
3
2
.45 (s, 9H), 1.33−1.23 (m, 26H), 1.14 (s, 9H), 0.87 (t, J = 7.0 Hz,
H). 13C NMR (126 MHz, CDCl ) δ 170.68, 170.52, 156.92, 155.44,
3
0.44, 73.73, 65.28, 61.78, 53.79, 53.30, 52.60, 40.15, 34.50, 32.73,
2.06, 29.84, 29.82, 29.80, 29.75, 29.71, 29.50, 29.47, 29.16, 28.44,
7.42, 26.01, 22.83, 14.27. MS (ESI-TOF) for C H N O S [M +
(
10% MeOH/CH Cl ) to obtain compound 36 (530 mg, 84%). MS
2 2
+
35
67
3
8
(ESI-TOF) for C H N O S [M + H] found 760.5486, calculated
39 77
5
7
+
Na] found 712.4461, calculated 712.4547.
760.5616.
Synthesis of Compound 33, (2S,5R)-Methyl 5-Amino-2-
Synthesis of Compound 38, Hexadecyl ((8S,11R)-11-Acet-
amido-8-(hydroxymethyl)-2-methyl-7,10-dioxo-13-thia-2,6,9-
triazapentadecan-15-yl)carbamate. To compound 36 (521 mg,
0.685 mmol) was added TFA (5 mL). The reaction mixture was
stirred at room temperature for 30 min and then dried by blowing
nitrogen through the solution. The crude product was used directly for
the next step. To a solution of the crude intermediate 37 in CH Cl (5
(
hydroxymethyl)-4,11-dioxo-12-oxa-7-thia-3,10-diazaoctaco-
san-1-oate. To compound 32 (110 mg, 0.159 mmol) was added TFA
(
2 mL). The reaction mixture was stirred at room temperature for 30
min and then dried by blowing nitrogen through the solution. The
residue was purified by flash chromatography (10% MeOH/CH Cl )
2
2
1
to yield product 33 in quantitative yield. H NMR (500 MHz, DMSO)
δ 8.96 (d, J = 7.8 Hz, 1H), 8.09 (s, 2H), 7.98 (t, J = 5.7 Hz, 1H), 5.26
2
2
mL) were added pyridine (61 μL, 0.754 mmol) and acetic anhydride
(71 μL, 0.754 mmol). The reaction mixture was stirred at room
temperature for 30 min and then concentrated. The residue was
purified by a flash chromatography (20% MeOH/CH Cl ) to give
(
3
(
1
t, J = 5.4 Hz, 1H), 4.47−4.41 (m, 1H), 4.02 (dd, J = 8.9, 4.6 Hz, 1H),
.79 (dt, J = 10.4, 5.1 Hz, 1H), 3.65 (s, 3H), 3.64−3.60 (m, 1H), 3.24
tt, J = 13.7, 7.0 Hz, 2H), 3.03 (dd, J = 14.4, 4.5 Hz, 1H), 2.74 (dd, J =
4.4, 8.9 Hz, 1H), 2.65 (td, J = 6.6, 2.6 Hz, 2H), 2.06 (t, J = 7.4 Hz,
2
2
1
product 38 as a white solid. H NMR (500 MHz, MeOD) δ 4.49 (dd, J
M
dx.doi.org/10.1021/jm400620g | J. Med. Chem. XXXX, XXX, XXX−XXX