5230 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25
Strømgaard et al.
pale yellow oil (1.102 g). The oil was further purified by
preparative HPLC with TIC detection to give 0.723 g (25%) of
the trifluoroacetate of 7 as a clear gum. The material was
98.7% pure according to HPLC with MS (total ion current)
detection. 1H NMR (400 MHz, CD3OD): δ 0.84 (t), 1.54 (s),
and 2.15 (t) (respectively 4-CH3, 3-CH2, and 2-CH2 of the
HRMS (FAB): C24H42N4O3 requires M + 1 at m/z 435.333,
found 435.333.
(R,S)-N-[8-[(3-Am in op r op yl)a m in o]oct yl]-4-h yd r oxy-
R-[(1-oxobu tyl)a m in o]ben zen ep r op a n a m id e (10). (R,S)-
N-(1-Oxobutyl)tyrosine (13) (0.173 g, 0.69 mmol) and DCC
(0.157 g, 0.76 mmol) were dissolved in DMF (10 mL) and
stirred at room temperature for 30 min. The solution was
added dropwise to a solution of 18 (0.400 g, 1.04 mmol) in DMF
(10 mL), and the reaction mixture was stirred at room
temperature for 16 h. The solvent was evaporated in vacuo
and the crude product purified by flash chromatography
[EtOAc/heptane/(CH3)2CHNH2 5:5:1 and 3:3:1]. Second puri-
fication by flash chromatography (CH2Cl2/MeOH 1:1) gave 22
as a pale yellow oil (0.196 g, 46%). 1H NMR (500 MHz,
CDCl3): δ 0.92 (t), 1.63 (s), and 2.17 (t) (respectively 4-CH3,
3
1-oxobutyl moiety, both J ) 7.3), 2.77 and 2.95 (each dd, 2J AB
3
3
) 13.7, J AX ) 8.2, J BX ) 7.2, â-CH2), 4.48 (dd, R-CH), 6.68
and 7.03 (each 2 H, aromatic H), 2.87-3.18 (m, 1- and 12-
CH2), 1.18-1.43 (m, 18 H) and 1.64 (m, 2 H) (remaining CH2
of the diamine moiety). 13C NMR (100.6 MHz, CD3OD): δ 14.0,
20.3, 27.5, 27.9, 28.7, 30.2, 30.3, 30.4, 30.5, 30.6 (3 C), 38.5,
38.8, 40.5, 40.8, 56.5, 116.2 (2 C), 129.1, 131.3 (2C), 157.4,
173.8, 175.9. HRMS (FAB): C25H43N3O3 requires M + 1 at m/z
434.338, found 434.340.
3
3-CH2, and 2-CH2 of the 1-oxobutyl moiety, both J ) 7.2), 2.82
(R,S)-N-(4,9-Dioxa -12-a m in od od ecyl)-4-h yd r oxy-r-[(1-
oxobu tyl)am in o]ben zen epr opan am ide (8). (R,S)-N-(1-Oxo-
butyl)tyrosine (13) (0.250 g, 1.00 mmol) and DCC (0.226 g, 1.09
mmol) were dissolved in DME/CH2Cl2 (1:1, 10 mL) and stirred
at room temperature for 30 min. The solution was added
dropwise to a solution of 4,9-dioxa-1,12-dodecanediamine (16)
(0.423 mL, 1.99 mmol) in CH2Cl2 (5 mL), and the reaction
mixture was stirred at room temperature for 20 h. The solvent
was evaporated in vacuo, and the oily residue was purified by
flash chromatography [CH2Cl2/MeOH/(CH3)2CHNH2 100:100:
1] to give a viscous, clear oil (0.260 g). The oil was further
purified by preparative HPLC with TIC detection to give 0.232
g (42%) of the trifluoroacetate of 8 as a clear gum. The material
was 100% pure according to HPLC with MS (total ion current)
detection. 1H NMR (400 MHz, CD3OD): δ 0.85 (t), 1.55 (s),
and 2.15 (t) (respectively 4-CH3, 3-CH2, and 2-CH2 of the
2
3
3
and 3.01 (each dd, J AB ) 13.2, J AX ) 9.4, J BX ) 5.2, â-CH2),
4.54 (m, R-CH), 6.69 and 7.03 (each 2 H, tyrosine H), 1.17-
1.30 (m, 8 H), 1.50 (p, 2 H) and 1.74 (p, 2 H) (2-, 3-, 4-, 5-, 6-,
3
3
7-, and 11-CH2), 2.75 (t, 2 H, J ) 6.6), 2.61 (t, 2 H, J ) 7.1),
2.99 (m, 1 H) and 3.17-3.24 (m, 3 H) (1-, 8-, 10-, and 12-CH2),
7.67-7.71 (m, 2 H), 7.79-7.81 (m, 1 H), and 8.08-8.10 (m, 1
H) (sulfonamide aromatic H), 1.04 (m, 2 H). 13C NMR (125.8
MHz, CDCl3): δ 13.5, 18.9, 26.2, 26.5, 28.3, 28.6, 28.7, 28.8,
29.2, 38.3, 39.2, 42.9, 47.8, 49.4, 50.6, 54.9, 115.6 (2 C), 125.0,
127.4, 130.2 (2 C), 130.9, 132.4, 133.3, 133.6, 148.0, 155.8,
170.7, 172.8. MS (ES): 630 (M + 1).
For deprotection of 22, 0.475 g (0.77 mmol) was dissolved
in DMF (50 mL), DBU (0.46 mL, 3.07 mmol) and 2-mercap-
toethanol (0.11 mL, 1.53 mmol) were added, and the mixture
was stirred at room temperature for 2 h. The solvent was
evaporated in vacuo, and the residue was purified by flash
chromatography [CH2Cl2/MeOH/(CH3)2CHNH2] to give a yel-
low oil (0.159 g), which was further purified by preparative
HPLC with TIC detection to give the bis(trifluoroacetate) of
10 as a clear viscous oil (0.140 g, 28%). The material was 97.8%
pure according to HPLC with MS (total ion current) detection.
1H NMR (400 MHz, CD3OD): δ 0.85 (t), 1.54 (s), and 2.15 (t)
(respectively 4-CH3, 3-CH2, and 2-CH2 of the 1-oxobutyl moiety,
3
1-oxobutyl moiety, both J ) 7.4), 2.78 and 2.95 (each dd, 2J AB
3
3
) 13.9, J AX ) 7.9, J BX ) 7.4, â-CH2), 4.46 (dd, R-CH), 6.69
and 7.03 (each 2 H, aromatic H), 1.59-1.76 (m, 2-, 6-, 7-, and
11-CH2), 3.10-3.51 (m, 1-, 3-, 5-, 8-, 10-, and 12-CH2). 13C NMR
(100.6 MHz, CD3OD): δ 14.0, 20.3, 27.6 (2 C), 30.3, 33.5, 37.8,
38.5, 38.8, 40.2, 56.5, 69.4, 70.1, 71.8 (2 C), 116.3 (2 C), 128.9,
131.3 (2 C), 157.6, 173.7, 175.9. HRMS (FAB): C23H39N3O5
requires M + 1 at m/z 438.297, found 438.299.
3
both J ) 7.4), 2.78 and 2.95 (each dd, 2J AB ) 13.8, 3J AX ) 8.2,
(R,S)-N-[3-[(8-Am in ooctyl)a m in o]p r op yl]-4-h yd r oxy-r-
[(1-oxobu tyl)a m in o]ben zen ep r op a n a m id e (9). (R,S)-N-(1-
Oxobutyl)tyrosine (13) (0.111 g, 0.442 mmol) and 17 (0.177 g,
0.44 mmol) were dissolved in DME/CH2Cl2 (1:5, 30 mL), DCC
(0.100 g, 0.49 mmol) was added, and the reaction mixture was
stirred at room temperature for 20 h. The solution was filtered
through Celite, the filtrate was concentrated in vacuo, and the
residue was purified by flash chromatography (CH2Cl2/MeOH
50:1, 40:1, 30:1, and 20:1) to give 21 as a white, sticky solid
(0.230 g, 82%). 1H NMR (400 MHz, CDCl3): δ 0.91 (t) and 2.19
(m) (respectively 4-CH3 and 2-CH2 of the 1-oxobutyl moiety,
both 3J ) 7.4), 4.62 (br m, R-CH), 6.74 and 7.04 (each 2 H,
aromatic H), 1.19-1.67 [m, 2 × C(CH3)3, 2-, 6-, 7-, 8-, 9-, 10-,
and 11-CH2, 3-CH2 of the 1-oxobutyl moiety], 2.82-3.18 (m,
1-, 3-, 5-, and 12-CH2, â-CH2). 13C NMR (100.6 MHz, CDCl3):
δ 13.7, 19.0, 26.5, 26.6, 27.5, 28.4 (7 C), 28.6, 28.9, 29.1, 30.0,
35.6, 38.1, 38.6, 40.5, 43.0, 47.0, 54.4, 79.4, 79.7, 115.4 (2 C),
128.0, 130.5 (2 C), 155.4, 156.3, 156.5, 170.8, 172.7.
3J BX ) 7.2, â-CH2), 4.46 (dd, R-CH), 6.69 and 7.04 (each 2 H,
aromatic H), 1.18-1.44 (m, 10 H) and 1.69 (p, 2 H) (2-, 3-, 4-,
5-, 6-, and 7-CH2), 2.05 (m, 11-CH2), 2.98-3.18 (m, 1-, 8-, 10-,
and 12-CH2). 13C NMR (100.6 MHz, H2O/D2O 9:1, pH 7.64): δ
15.3, 21.7, 26.6, 28.1, 28.2, 28.3, 30.5, 30.6 (2 C), 39.1, 39.5,
39.9, 41.9, 47.2, 50.6, 58.3, 118.1 (2 C), 130.8, 133.1 (2 C), 157.1,
175.5, 179.5. HRMS (FAB): C24H42N4O3 requires M + 1 at m/z
435.333, found 435.334.
(R,S)-N-[3-[(5-Oxa -8-a m in ooct yl)a m in o]p r op yl]-4-h y-
d r oxy-r-[(1-oxobu tyl)a m in o]ben zen ep r op a n a m id e (11).
(R,S)-N-(1-Oxobutyl)tyrosine (13) (0.087 g, 0.35 mmol) and
DCC in DME/CH2Cl2 (1:1, 10 mL) were stirred at room
temperature for 30 min, and the solution was added to a
solution of 19 (0.140 g, 0.35 mmol) in CH2Cl2 (5 mL). After
being stirred overnight at room temperature the solution was
filtered, and the filtrate was concentrated in vacuo. The
residue was purified by flash chromatography (CH2Cl2/MeOH
40:1 and 20:1) to give 23 as a clear oil (0.106 g, 48%). 1H NMR
[500 MHz, (CD3)2SO]: δ 0.73 (t), 1.36 (s), and 2.00 (t)
For deprotection of 21, 0.209 g (0.33 mmol) was dissolved
in CH2Cl2 (25 mL), TFA (2.5 mL, 32.5 mmol) was added, and
the solution was stirred for 2 h at room temperature, concen-
trated, triturated with diethyl ether, and dried under high
vacuum to give 0.194 g of a yellow, sticky solid. The product
was purified by preparative HPLC with TIC detection to give
the bis(trifluoroacetate) of 9 as a slightly yellow oil (0.143 g,
66%). The material was 99.5% pure according to HPLC with
MS (total ion current) detection. 1H NMR (400 MHz,
CD3OD): δ 0.87 (t), 1.56 (s), and 2.17 (m) (respectively 4-CH3,
(respectively 4-CH3, 3-CH2, and 2-CH2 of the 1-oxobutyl moiety,
2
both 3J ) 7.4), 4.34 (m, R-CH), 2.61 and 2.80 (each dd, J AB
)
3
3
13.7, J AX ) 9.3, J BX ) 4.7, â-CH2), 6.60 and 6.97 (each 2 H,
aromatic H), 1.20-1.60 (m, 6 H) and 1.57 (p, 2 H) (2-, 6-, 7-,
and 11-CH2), 1.35 (s, 9 H) and 1.36 (s, 9 H) [2 × C(CH3)3],
2.92-3.09 (m, 1-, 3-, 5-, and 12-CH2), 3.31 (apparent t, 8- and
10-CH2). 13C NMR [125.8 MHz, (CD3)2SO]: δ 67.7, 69.8, 77.4,
78.3, 114.8 (2 C), 128.7, 130.0 (2 C), 154.7, 155.6, 155.7, 171.3,
171.8, remaining signals at 13.5-40.1. MS (ES): 637 (M +
1), 537 [(M + 1) - (CH3)2CdCH2 - CO2], 437 [(M + 1) -
2(CH3)2CdCH2 - 2CO2].
3
3-CH2, and 2-CH2 of the 1-oxobutyl moiety, both J ) 7.4), 4.37
(t, 3J ) 7.6, R-CH), 6.71 and 7.05 (each 2 H, aromatic H), 1.40
(br s, 7-, 8-, 9-, and 10-CH2), 1.62-1.70 (m, 6- and 12-CH2),
1.78 (p, 2-CH2), 2.81-3.28 (m, 1-, 3-, 5-, 12-, and â-CH2). 13C
NMR (100.6 MHz, H2O/D2O 9:1, pH 7.40): δ 15.3, 21.5, 28.0
(2 C), 28.1 (2 C), 29.4, 30.5 (2 C), 38.7, 38.8, 40.0, 42.4, 42.5,
50.5, 58.3, 118.2 (2 C), 130.8, 133.1 (2 C), 157.1, 176.4, 179.7.
Deprotection of 23 (0.082 g, 0.129 mmol) was carried out
with TFA (1.25 mL, 12.9 mmol) in CH2Cl2 (20 mL) during 2 h
at room temperature. Evaporation of the solvents and flash
chromatography [CH2Cl2/MeOH/(CH3)2CHNH2 50:50:1], fol-