5728 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 18
Hernández et al.
dried, and concentrated. The final product was purified by prepara-
tive HPLC using H2O (0.04% TFA) and MeCN (0.04% TFA) as
eluents (gradient 20-38% in 70 min; flow rate 15 mL/min) to afford
3b (13 mg, 13%) as a yellow solid. Mp (CHCl3) 145-147 °C. [R]D
-30.2 (c 0.61, CHCl3). 1H NMR (CDCl3, 400 MHz) δ 0.84-1.07
(m, 12H); 1.26-1.35 (m, 2H); 1.52-1.75 (m, 1H); 1.81-1.96 (m,
1H); 3.34 (s, 3H); 3.53-3.71 (m, 6H); 4.09-4.22 (m, 2H);
4.46-4.56 (m, 1H); 4.59-4.81 (m, 1H); 5.55 (bs, 1H); 5.73-5.80
(m, 1H); 7.41-7.51 (m, 4H); 7.94 (s, 1H); 8.20 (s, 1H); 8.24 (s,
1H); 8.27 (s, 1H); 8.34 (d, J ) 8.0 Hz, 2H); 8.57 (bs, 1H). 13C
NMR (CDCl3, 100 MHz) δ 11.8 (q); 14.2 (q); 18.7 (q); 18.8 (q);
25.8 (d); 29.6 (t); 39.6 (d); 46.7 (d); 56.3 (d); 58.8 (q); 59.7 (d);
67.9 (t); 69.9 (t); 70.5 (t); 71.6 (t); 119.6 (d); 126.5 (s); 127.9 (s);
128.4 (d); 128.5 (2d); 129.9 (s); 130.3 (s); 130.3 (s); 130.4 (2d);
135.7 (s); 137.5 (d); 137.7 (d); 139.7 (d); 139.9 (s); 141.8 (s); 151.3
(s); 152.9 (s); 158.0 (s); 158.3 (s); 160.4 (s); 170.3 (s); 171.8 (s);
172.0 (s). MS (ES) m/z 860 (M + NH4, 100), 744 (55), 726 (45),
316 (45), 288 (98), 242 (22). HRMS m/z calcd for C40H43N8O11S
843.2750 (M + H), found 843.6727.
Peptide-Heterocycle 3c. The alcohol 3 (111 mg, 0.15 mmol)
was dissolved in dry CH2Cl2 (10 mL). 2-[2-(2-Methoxyethoxy)-
ethoxy]acetic acid (0.25 mL, 1.65 mmol), EDC ·HCl (316 mg, 1.65
mmol), and DMAP (30 mg, 0.25 mmol) were then added dropwise.
The resulting solution was stirred for 8 h at room temperature,
washed with NaHCO3, dried, and concentrated. The final product
was purified by preparative HPLC using H2O (0.04% TFA) and
MeCN (0.04% TFA) as eluents (gradient 20-38% in 70 min; flow
rate 15 mL/min) to afford 3c (16 mg, 12%) as a yellow solid. Mp
(CHCl3) 139-141 °C. [R]D -63.4 (c 0.56, CHCl3). 1H NMR (DMF,
400 MHz) δ 0.93-0.98 (m, 6H); 1.01 (d, J ) 6.8 Hz, 3H); 1.07
(d, J ) 6.8 Hz, 3H); 1.24-1.30 (m, 2H); 1.38 (d, J ) 6.4 Hz, 1H);
1.54-1.74 (m, 1H); 2.11-2.28 (m, 1H); 3.28 (s, 3H); 3.55-3.70
(m, 10H); 4.08-4.20 (m, 2H); 4.70-4.79 (m, 2H); 5.82 (s, 1H);
6.17 (s, 1H); 7.49-7.61 (m, 3H); 8.44 (d, J ) 8.0 Hz, 2H); 8.59
(s, 1H); 8.98 (s, 1H); 9.14 (s, 1H); 9.17 (s, 1H); 10.03 (bs, 1H).
13C NMR (DMF, 100 MHz) δ 11.8 (q); 14.5 (q); 18.9 (q); 19.2
(q); 26.8 (d); 29.4 (t); 32.4 (d); 39.4 (d); 58.1 (d); 58.2 (q); 60.1
(d); 68.1 (t); 68.3 (t); 70.3 (t); 70.4 (t); 70.5 (t); 71.9 (t); 121.6 (d);
127.3 (s); 127.9 (2d); 128.4 (s); 128.7 (s); 128.8 (2d); 129.4 (s);
130.3 (s); 130.4 (d); 136.5 (s); 139.8 (d); 140.7 (d); 140.8 (d); 142.2
(s); 152.8 (s); 155.8 (s); 158.1 (s); 158.5 (s); 159.6 (s); 160.7 (s);
171.0 (s); 171.6 (s); 171.9 (s). MS (ES) m/z 904 (M + NH4, 40),
726 (100), 316 (8), 288 (38). HRMS m/z calcd for C42H47N8O12S
887.3029 (M + H), found 887.3037.
Peptide-Heterocycle 3d. The alcohol 3 (50 mg, 0.068 mmol)
was dissolved in dry CH2Cl2 (7 mL). Boc-L-Arg-(Alloc)2-OH (120
mg, 0.27 mmol), EDC ·HCl (52 mg, 0.27 mmol), and DMAP (7
mg, 0.57 mmol) were added dropwise. The resulting solution was
stirred for 31 h at room temperature, washed with NaHCO3 and
NH4Cl, dried, and concentrated. The final product was purified by
flash chromatography on silica Bondesil C8 using H2O (0.04%
TFA) and MeCN (0.04% TFA) as eluents (gradient 0-50%) to
afford 3d (15.9 mg, 16%) as a yellow solid. [R]D -11.6 (c 0.82,
DMSO). 1H NMR (DMSO, 400 MHz) δ 0.82-0.94 (m, 9H); 0.99
(d, J ) 6.8 Hz, 3H); 1.07-1.17 (m, 2H); 1.25 (s, 9H); 1.35-1.37
(m, 2H); 1.57-1.64 (m, 2H); 1.73-1.78 (m, 1H); 2.01-2.11 (m,
1H); 3.09-3.16 (m, 2H); 3.57-3.65 (m, 1H); 3.79-3.91 (m, 3H);
4.47-4.51 (m, 2H); 4.62-4.70 (m, 3H); 4.75-4.79 (m, 1H);
5.12-5.40 (m, 4H); 5.87-5.99 (m, 2H); 7.08 (bs, 1H); 7.17 (bs,
1H); 7.30 (bs, 1H); 7.48-7.59 (m, 3H); 8.30-8.33 (m, 2H); 8.51
(s, 1H); 8.53 (s, 1H); 8.79 (bs, 1H); 8.98 (s, 1H); 9.11 (s, 1H);
9.12 (s, 1H); 9.98 (bs, 1H). 13C NMR (DMSO, 100 MHz) δ 12.3
(q); 14.2 (q); 17.9 (q); 18.5 (q); 19.0 (q); 22.4 (d); 26.9 (t); 28.1
(t); 28.9 (t); 31.9 (d); 41.7 (t); 53.4 (2d); 56.9 (d); 58.1 (d); 65.1
(t); 67.0 (t); 69.7 (t); 78.1 (s); 117.1 (s); 117.2 (t); 118.3 (t); 121.2
(d); 126.4 (s); 127.2 (s); 127.5 (s); 127.8 (s); 128.6 (2d); 129.1 (s);
129.6 (2d); 129.7 (s); 130.7 (d); 131.8 (d); 133.5 (s); 133.6 (d);
135.6 (s); 139.5 (d); 140.4 (d); 141.4 (d); 150.4 (s); 152.1 (s); 154.7
(s); 157.4 (s); 157.5 (s); 158.9 (s); 160.0 (s); 170.2 (s); 170.7 (s);
170.9 (s); 173.8 (s). MS (MALDI-TOF) m/z 1189 (M + K), 1173
(M + Na, 15), 1151 (M, 10). HRMS m/z calcd for C54H63N12O15S
1151.4295 (M + H), found 1151.4251.
Peptide-Heterocycle 3e. The O-deprotected product (74 mg,
0.101 mmol) was dissolved in dry CH2Cl2 (10 mL). Boc-L-Arg-
(Boc)2-OH (193 mg, 0.41 mmol), EDC ·HCl (78 mg, 0.41 mmol),
and DMAP (12.4 mg, 0.102 mmol) were then added dropwise. The
resulting solution was stirred for 15 h at room temperature, washed
with NaHCO3 and NH4Cl, dried, and concentrated. The final product
was purified by flash chromatography on silica Bondesil C8 using
H2O (0.04% TFA) and MeCN (0.04% TFA) as eluents (gradient
0-50%) to give 3e (19 mg, 17%) as a white solid. [R]D -19.4 (c
0.12, DMSO). 1H NMR (DMSO, 400 MHz) δ 0.83-0.95 (m, 12H);
1.09-1.18 (m, 2H); 1.23 (s, 9H); 1.36 (s, 9H); 1.43 (s, 9H);
1.45-1.52 (m, 4H); 1.60-1.68 (m, 1H); 1.96-2.03 (m, 1H);
3.95-4.04 (m, 1H); 4.11-4.18 (m, 2H); 4.39-4.48 (m, 2H);
4.63-4.69 (m, 1H); 5.63-5.70 (m, 1H); 7.14-7.28 (m, 2H);
7.50-7.75 (m, 3H); 8.17 (bs, 1H); 8.24 (bs, 1H); 8.39-8.41 (m,
2H); 8.55 (s, 1H); 8.72 (bs, 1H); 8.96 (s, 1H); 9.09 (s, 1H); 9.14
(s, 1H); 10.7 (bs, 1H). 13C NMR (DMSO, 100 MHz) δ 12.4 (q);
14.5 (q); 19.5 (q); 18.4 (q); 24.6 (d); 28.0 (q); 28.1 (t); 28.3 (t);
28.4 (q); 28.7 (q); 29.4 (t); 31.2 (d); 46.8 (d); 53.7 (d); 56.0 (d);
60.2 (t); 64.6 (t); 122.4 (d); 128.4 (2d); 129.3 (2d); 131.0 (d); 140.2
(d); 141.1 (d); 141.4 (d). MS (ES) m/z 1185 (M + 2H, 60), 1184
(M + H, 100). HRMS m/z calcd for C51H63N12O13S (M - Boc)
1083.4352, found 1083.4351.
Peptide-Heterocycle 3f. A solution of 3e (5 mg, 4.2 µmol) in
TFA-CH2Cl2 (25:75, 1 mL) was stirred at room temperature for
2 h. The TFA was removed, and the product was used without
1
purification. [R]D -40.1 (c 0.23, DMSO). H NMR (DMSO, 500
MHz) δ 0.83-0.98 (m, 12H); 1.07-1.18 (m, 2H); 1.41-1.76 (m,
5H); 2.03-2.08 (m, 1H); 3.57-3.64 (m, 1H); 4.0-4.04 (m, 1H);
4.08-4.18 (m, 3H); 4.49-4.56 (m, 2H); 4.65-4.68 (m, 1H);
5.69-5.73 (m, 1H); 7.51-7.62 (m, 7H); 8.20 (d, J ) 5.0 Hz, 1H);
8.39-8.41 (m, 2H); 8.56 (s, 1H); 8.71 (d, J ) 8.0 Hz, 1H); 8.80
(d, J ) 9.0 Hz, 1H); 8.99 (s, 1H); 9.10 (s, 1H); 9.14 (s, 1H). 13C
NMR (DMSO, 125 MHz) δ 12.5 (q); 14.4 (q); 19.5 (q); 19.7 (q);
25.0 (t); 25.1 (t); 26.0 (t); 26.8 (d); 30.4 (d); 46.9 (d); 56.2 (d);
58.4 (d); 60.3 (t); 65.2 (t); 70.4 (d); 122.3 (d); 128.4 (2d); 129.3
(2d); 131.0 (d); 139.6 (d); 140.9 (d); 141.0 (d). MS (ES) m/z 883
(M, 100). HRMS m/z calcd for C41H47N12O9S 883.3304, found
883.3317.
Peptide-Heterocycle 9b. Reaction (20 h) of the free acid 7a
(816 mg, 1.28 mmol) and 8b (500 mg, 1.54 mmol) using the general
procedure for amide formation gave 9b (1.14 g, 94%) as a solid.
An analytical sample was purified by column chromatography (4:1
to 2:3 hexane-EtOAc) to afford 9b as a yellow solid. Mp (CHCl3)
1
143-145 °C. [R]D +1.4 (c 0.42, CHCl3). H NMR (CDCl3, 400
MHz) δ 0.91-1.02 (m, 12H); 1.07 (s, 9H); 1.19-1.29 (m, 1H);
1.48-1.58 (m, 1H); 2.07-2.15 (m, 1H); 2.20-2.27 (m, 1H); 2.58
(s, 3H); 3.37 (s, 6H); 3.67-3.73 (m, 1H); 3.76-3.80 (m, 1H); 3.89
(s, 2H); 4.46-4.50 (m, 1H); 4.58-4.63 (m, 1H); 5.24-5.37 (m,
1H); 6.70 (d, J ) 8.4 Hz, 1H); 7.17 (bs, 1H); 7.38-7.46 (m, 4H);
7.80 (d, J ) 8.4 Hz, 1H); 8.24-8.30 (m, 2H); 8.36 (s, 1H); 8.37
(s, 1H); 8.47 (bs, 1H). 13C NMR (CDCl3, 100 MHz) δ 11.6 (q);
11.7 (q); 14.8 (q); 17.7 (q); 19.3 (q); 26.3 (t); 27.2 (q); 30.9 (d);
31.7 (t); 37.2 (d); 48.4 (d); 50.2 (2q); 57.4 (d); 58.3 (d); 62.2 (t);
73.9 (s); 99.3 (s); 124.3 (s); 126.5 (s); 128.3 (2d); 128.5 (2d); 129.6
(s); 130.2 (d); 140.0 (d); 141.2 (s); 142.6 (s); 143.0 (d); 151.3 (s);
151.7 (s); 153.0 (s); 155.8 (s); 161.3 (s); 161.4 (s); 161.6 (s); 170.9
(s); 171.2 (s); 188.3 (s). MS (MALDI-TOF) 965 (M81Br + Na,
100), 963 (M79Br
+ Na, 85). HRMS m/z calcd for
C42H5479BrN8O10S 941.2861 and to C42H5681BrN8O10S 943.2850,
found 941.2867 and 943.2853.
Peptide-Heterocycle 9c. Reaction (20 h) of the free acid 7b (1
g, 1.54 mmol) and the N-deprotected 8a (573 mg, 1.84 mmol) using
the general procedure for amide formation gave 9c (1.38 g, 95%)
as a yellow solid. An analytical sample was purified by column
chromatography (1:1 to 2:3 hexane-EtOAc) to give 9c as a yellow
1
solid. Mp (CHCl3) 116-118 °C. [R]D +2.3 (c 0.61, CHCl3). H
NMR (CDCl3, 400 MHz) δ 0.88-0.98 (m, 9H); 1.01 (d, J ) 6.8
Hz, 3H); 1.06 (s, 9H); 1.18-1.31 (m, 1H); 1.46-1.61 (m, 1H);