9538
C.J. Chapman et al. / Tetrahedron 64 (2008) 9528–9539
0.8 mmol, 4 equiv) in the presence of sodium fluoride (25 mg,
(petroleum ether/ethyl acetate 1:1) gave the title compound as
20
0.6 mmol, 3 equiv). The title compound was obtained in 54% yield
a colourless foam in 89% yield (1.88 g). [
(film, cmꢂ1
3435, 3019, 2083, 1696, 1653, 1512, 1455, 1368, 1223,
1167, 1054, 772, 733, 668; 1H NMR (CDCl3, 300 MHz)
8.61 (1H, s),
a
]
D
ꢂ5.5 (c 1.3, CHCl3); IR
20
(70 mg) as an off white solid. Mp 92–94 ꢀC; [
a
]
D
þ6.8 (c 0.15,
) n
CH2Cl2); IR (film, cmꢂ1
)
n
4214, 3390 (br), 3020, 2982, 2932, 2854,
d
2401, 1893, 1737, 1664, 1615, 1512, 1439, 1369, 1216, 1172, 1114, 1054,
1015, 929, 844, 757, 669, 621, 575, 538; 1H NMR (CDCl3, 300 MHz)
8.28 (1H, s), 7.62 (1H, d, J¼7.8), 7.35 (1H, d, J¼7.8), 7.22–7.06 (2H, m),
6.85 (1H, d, J¼2.1), 6.9–6.66 (8H, m), 6.29 (1H, d, J¼8.1), 6.20 (1H, d,
J¼8.1), 5.06 (1H, d, J¼7.8), 4.66 (1H, dt, J¼6.9, 6.0), 4.53–4.34 (2H, m),
3.70 (3H, s), 3.14–2.96 (3H, m), 2.83–2.73 (3H, m), 1.40 (9H. s); 13C
NMR (CDCl3, 75.5 MHz) 172.1, 172.0, 170.3, 155.7, 152.0, 136.6, 132.2
and 132.1, 131.2 (d, J¼8.0), 130.7, 127.7 and 127.6, 124.1, 123.7 and
123.6, 122.9, 120.3, 119.2, 116.2, 115.7 (d, J¼21.9), 111.7, 110.6, 81.1,
54.1, 53.8, 52.9, 52.8, 37.3, 37.2, 30.1, 28.7; 19F NMR (CDCl3,
7.33–7.30 (5H, m), 7.02 (1H, d, J¼6.0), 6.43 (1H, s), 5.36 (1H, s), 5.32
(1H, d, J¼7.5), 5.07 (2H, s), 5.02 (1H, m), 4.59 (1H, app pentet, J¼7.2),
4.21–4.18 (1H, m), 3.75 (3H, s), 3.16 (2H, q, J¼6.0), 1.84–1.76 (1H, m),
1.69–1.38 (5H, m), 1.44 (3H, s), 1.41 (9H, s); 13C NMR (CDCl3,
75.5 MHz)
d 173.9, 172.0, 163.9, 157.0, 156.3, 137.0, 134.1, 128.8,
128.4, 103.91, 80.5, 66.9, 55.6, 53.0, 49.0, 40.8, 32.2, 29.7, 28.7, 23.0,
18.0; HRMS (ESIþ) calcd for C26H38N4NaO8: 557.2587 [MþNa]þ,
found: 557.2553 [MþNa]þ.
4.6.2. Boc-Lys(Cbz)-
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Lys(Cbz)- Ala-Ala-OMe (107 mg,
L-Phe-Ala-OMe
376.5 MHz)
d
ꢂ115.80; HRMS (ESIþ) calcd for C35H39FN4NaO7:
669.2700 [MþNa]þ, found: 669.2699 [MþNa]þ.
D
0.2 mmol) was reacted with benzene boronic acid (98 mg,
4.5.9. Boc-Trp-Phe(4-CN)-Tyr-OMe
0.8 mmol) and (R)-BINAP. The title compound was isolated as
In accordance with the representative procedure for 1,4-addi-
a single diastereomer in 50% yield (61 mg) as a colourless glass.
20
tions with boronic acids, Boc-Trp-DAla-Tyr-OMe (110 mg,
[a
]
ꢂ21.2 (c 0.33, CHCl3); mp 126–129 ꢀC; IR (film, cmꢂ1
)
n
3434,
D
0.2 mmol) was reacted with 4-cyanobenzene boronic acid
(122 mg, 0.8 mmol, 4 equiv) in the presence of sodium fluoride
2094, 1652, 1511, 1162, 806; 1H NMR (CDCl3, 300 MHz)
d 7.37–7.18
(10H, m), 6.67 (2H, d, J¼7.8), 5.22 (1H, br s), 5.10 (2H, s), 5.08–5.03
(1H, m), 4.70 (1H, dt, J¼7.8, 6.6), 4.48 (1H, app pent, J¼7.2), 4.05–
3.98 (1H, m), 3.69 (3H, s), 3.19–3.02 (4H, m), 1.80–1.70 (1H, m),
1.64–1.40 (3H, m), 1.40 (9H, s), 1.32 (3H, d, J¼7.2), 1.33–1.25 (2H, m);
(25 mg, 0.6 mmol, 3 equiv). The title compound was obtained in
20
14% yield (14 mg) as an off white foam. [
IR (film, cmꢂ1
733, 650; 1H NMR (CDCl3, 300 MHz)
a
]
þ6.8 (c 0.15, CH2Cl2);
D
)
n
3413 (br), 2254, 1655, 1516, 1368, 1249, 1175, 908,
8.32 (1H, s), 7.58 (1H, d,
d
13C NMR (CDCl3, 75.5 MHz)
d 173.1, 172.4, 170.7, 157.1, 156.2, 137.0,
J¼7.8), 7.40–7.13 (5H, m), 6.98–6.67 (8H, m), 6.65–6.28 (1H, br s),
6.14 (1H, d, J¼7.2), 5.13 (1H, d, J¼4.5), 4.69–4.60 (2H, m), 4.27 (1H, q,
J¼6.9), 3.69 (3H, s), 3.19–3.12 (2H, m), 3.00–2.82 (3H, m), 2.55 (1H,
136.7, 129.7, 128.9, 128.8, 128.5, 128.4, 127.3, 80.5, 67.0, 55.1, 54.3,
52.7, 48.5, 40.5, 38.3, 31.9, 29.8, 28.6, 22.6, 18.3; HRMS (ESIþ) calcd
for C32H44N4NaO8: 635.3057 [MþNa]þ, found: 635.3035 [MþNa]þ.
dd, J¼13.8, 6.9), 1.39 (9H, s); 13C NMR (CDCl3, 75.5 MHz)
d 172.6,
172.2, 170.1, 155.7, 155.6, 141.9, 136.6, 132.6, 130.7, 130.6, 127.8, 127.7,
123.7, 122.9, 120.4, 119.2, 119.0, 116.1, 111.9, 111.1, 110.3, 80.2, 56.4,
54.1, 53.5, 52.8, 37.4, 37.2, 30.1, 28.7; HRMS (ESIþ) calcd for
4.6.3. Boc-Lys(Cbz)-
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Lys(Cbz)- Ala-Ala-OMe (107 mg,
D-Phe-Ala-OMe
D
C
36H39N5NaO7: 676.2747 [MþNa]þ, found 676.2740 [MþNa]þ.
0.2 mmol) was reacted with benzene boronic acid (98 mg,
0.8 mmol) and (S)-BINAP. The title compound was isolated as
4.5.10. Boc-Trp-Phe(3,5-di-CF3)-OMe
a single diastereomer in 45% yield (55 mg) as a colourless glass.
20
In accordance with the representative procedure for 1,4-addi-
[a
]
þ11.8 (c 0.085, CHCl3); IR (film, cmꢂ1
) n 3423, 3018, 2088,1700,
D
tions with boronic acids, Boc-Trp-DAla-Tyr-OMe (110 mg, 0.2 mmol)
1669, 1517, 1455, 1368, 1225, 1208, 1165, 1057, 1028, 925, 853, 778,
was reacted with 3,5-bis-trifluoromethylbenzene boronic acid
(206 mg, 0.8 mmol, 4 equiv) in the presence of sodium fluoride
(25 mg, 0.6 mmol, 3 equiv). The title compound was obtained in 38%
741, 699, 668; 1H NMR (CDCl3, 300 MHz)
d 7.36–7.19 (10H, m), 6.86
(1H, d, J¼8.1), 6.80 (1H, d, J¼8.1), 5.18 (1H, d, J¼6.9), 5.09 (2H, s),
4.96–4.93 (1H, m), 4.74 (1H, app q, J¼7.5), 4.50 (1H, app pent,
J¼7.2), 3.94 (1H, dt, J¼6.3, 7.2), 3.69 (3H, s), 3.19–3.01 (4H, m), 1.70–
1.10 (6H, m), 1.40 (9H, s), 1.28 (3H, d, J¼7.2); 13C NMR (CDCl3,
yield (59 mg) as an off white foam. IR (film, cmꢂ1
)
n
4214, 3411 (br),
3020, 1651, 1516, 1440, 1379, 1280, 1216, 1177, 1138, 1013, 902, 757,
707, 682, 668; 1H NMR (CDCl3, 300 MHz)
8.31 (1H, d, J¼0.9), 7.68
d
75.5 MHz) d 173.5,172.6,170.7,156.9,156.1, 137.0,136.9,129.7, 129.0,
(1H, s), 7.61 (1H, d, J¼7.8), 7.41 (2H, s), 7.33 (1H, d, J¼8.1), 7.20–7.06
(2H, m), 6.94 (1H, d, J¼2.1), 6.77 (2H, d, J¼8.4), 6.8–6.5 (1H, br s), 6.68
(1H, d, J¼8.4), 6.46–6.30 (2H, m), 5.02 (1H, d, 7.5), 4.68–4.57 (2H, m),
4.36 (1H, dd, J¼14.4, 6.6), 3.69 (3H, s), 3.25 (1H, dd, J¼5.4, 14.4), 3.11
(1H, dd, J¼6.9,14.4), 3.01–2.77 (4H, m),1.37 (9H, s); 13C NMR (CDCl3,
75.5 MHz) 172.4, 171.9, 169.4, 156.1, 155.7, 139.1, 136.7, 132.1, 131.7,
131.2, 130.7, 130.1, 127.6, 127.4, 125.4,123.5, 122.9, 121.8, 121.3, 120.2,
119.3, 116.2, 111.8, 110.4, 81.3, 55.7, 53.8, 53.7, 52.8, 37.6, 37.2, 30.1,
128.9, 128.6, 128.5, 127.3, 80.5, 67.0, 55.1, 54.4, 52.8, 48.4, 40.7, 38.2,
31.9, 29.7, 28.6, 22.6, 18.1; HRMS (ESIþ) calcd for C32H44N4NaO8:
635.3057 [MþNa]þ, found: 635.3035 [MþNa]þ.
4.6.4. Boc-Lys(Cbz)-Phe(3,5-di-F)-Ala-OMe
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Lys(Cbz)-DAla-Ala-OMe (107 mg,
0.2 mmol) was reacted with 3,5-difluorobenzene boronic acid
(126 mg, 0.8 mmol) and (R)-BINAP. The title compound was iso-
28.5; 19F NMR (CDCl3, 376.5 MHz)
d
ꢂ62.92; HRMS (ESIþ) calcd for
[MþH]þ C37H39F6N4O7: 765.2723, found: 765.2716[MþH]þ.
lated as a single diastereomer in 32% yield (42 mg) as a colourless
20
glass. [
a
]
ꢂ17.8 (c 0.51, CHCl3); IR (film, cmꢂ1
) n 4213, 3419, 3019,
D
4.6. Synthesis of urotensin receptor agonist fragments
2100, 1660, 1518, 1222, 1208, 1164, 1119, 786, 732, 668; 1H NMR
(CDCl3, 300 MHz)
d 7.37–7.31 (5H, m), 6.81–6.63 (5H, m), 5.31 (1H,
4.6.1. Boc-Lys(Cbz)-
D
Ala-Ala-OMe (18)
d, J¼6.6), 5.10 (2H, s), 5.08–5.01 (1H, m), 4.72 (1H, dt, J¼6.9, 7.8),
4.50 (1H, pent, J¼7.2), 4.05–3.98 (1H, m), 3.72 (3H, s), 3.22–3.13 (2H,
m), 3.09–3.06 (2H, m), 1.81–1.72 (1H, m), 1.65–1.58 (1H, m), 1.50–
1.31 (4H, m), 1.41 (9H, s), 1.35 (3H, d, J¼7.2); 13C NMR (CDCl3,
An oven dried flask was charged with Boc-Lys(Cbz)-Ser-Ala-
OMe (3.31 g, 10.4 mmol) dissolved in degassed dichloromethane
(40 mL) under an atmosphere of nitrogen. Copper(I) chloride
(117 mg, 1.18 mmol) and EDCI (831 mg, 4.33 mmol) were sub-
sequently added and the resultant suspension stirred for 18 h at
ambient temperature. The solution was washed with two portions
of water (15 mL), dried over MgSO4, filtered and concentrated un-
der reduced pressure. Purification by flash column chromatography
75.5 MHz)
d
173.1, 172.5, 170.0, 164.9 (d, J¼12.8), 161.7 (d, J¼12.8),
157.2, 140.8 (d, J¼9.1), 136.9, 128.9, 128.5, 112.8, 112.5, 102.9 (t,
J¼25.1), 80.8, 67.0, 55.2, 53.8, 52.8, 48.6, 40.3, 37.9, 31.4, 29.8, 28.6,
22.5, 18.3; HRMS (ESIþ) calcd for C32H43F2N4O8: 649.3049 [MþH]þ,
found: 649.3042 [MþH]þ.