M. Keller et al. / Bioorg. Med. Chem. 19 (2011) 2859–2878
2871
(ppm) 24.7, 25.4, 26.7, 28.2, 30.2, 37.3, 40.5, 41.8, 43.8, 44.4, 54.3,
58.7, 128.1, 128.2, 128.4, 128.6, 129.5, 129.9, 138.4, 140.2, 140.8,
141.0, 155.1, 162.1, 173.5, 174.9, 177.0; MS (ES, TFA/acetonitrile):
m/z 322 [M+2H]2+, 643 [M+H]+; HRMS: (LSI-MS): m/z [M+H]+ calcd
for C35H47N8O4þ: 643.3720, found: 643.3715; C35H46N8O4 ꢀ C4H2
F6O4 (870.8).
(LSI-MS): m/z [M+H]+ calcd for C35H46N7O5þ: 644.3560, found:
644.3555; C35H45N7O5 ꢀ C4H2F6O4 (871.7).
x
a
4.2.17.3. (R)-N -(6-Aminohexanoyl)-N -(2,2-diphenylacetyl)-N-
(4-hydroxybenzyl)argininamide bis(hydrotrifluoroacetate)
(33). Prepared from N-Boc-6-aminohexanoic acid 28 (222 mg,
0.96 mmol) and 30 (403 mg, 0.64 mmol); CDI: 166 mg, 1.02 mmol;
NEt3: 19 mg, 0.19 mmol; 94% (490 mg); ½a D20
ꢃ
+8.8 cm3 gꢂ1 dmꢂ1 (c
0.0093 in MeCN/H2O 9:1); IR (neat): 1670, 1630, 1535, 1515, 1495,
4.2.17. General procedure for the synthesis of amines 31–33
CDI (1.6 equiv) was added to a solution of the pertinent carbox-
ylic acid (1.5 equiv) in DCM (2–3 mL) and the mixture was allowed
to stand at rt for 30–40 min. Compound 306 (1 equiv) and NEt3
(0.3 equiv) were added and the mixture was kept under stirring
at rt for 20 h. The mixture was directly subjected to column chro-
matography for purification of the intermediate (31 and 32: DCM/
EtOAc 2:1–EtOAc/MeOH 50:1, 33: DCM/EtOAc 5:1–1:1; for column
packing the starting eluent was supplemented with 1% NEt3). For
deprotection the intermediate was dissolved in DCM/TFA/water
18:6:1 (12.5 mL) and the mixture was stirred for 3 h. DCM
(20 mL) was added three times, each time followed by evaporation
under reduced pressure. The oily residue was dissolved in water
(20 mL) and lyophilized to afford the product as a white fluffy,
hygroscopic solid.
1190, 1130 cmꢂ1 1H NMR (300 MHz, DMSO-d6): d (ppm) 1.32 (m,
;
2H), 1.37–1.6 (m, 7H), 1.67 (m, 1H), 2.42 (t, 2H, 3J = 7.3 Hz), 2.76
(m, 2H), 3.24 (m, 2H), 4.1 (dd, 1H, 2J = 15.2 Hz, 3J = 5.9 Hz), 4.18
(dd, 1H, 2J = 15.1 Hz, 3J = 6.1 Hz), 4.33 (m, 1H), 5.13 (s, 1H), 6.67
(m, 2H), 7.0 (m, 2H), 7.18–7.33 (m, 10H), 7.63 (br s, 3H), 8.38 (t,
1H, 3J = 5.8 Hz), 8.5 (d, 1H, 3J = 8.1 Hz), 8.6 (s, 2H), 8.95 (m, 1H),
9.3 (s, 1H), 11.4 (s, 1H); 13C NMR (150 MHz, MeOH-d4): d (ppm)
24.7, 25.5, 26.7, 28.2, 30.2, 37.3, 40.5, 41.8, 43.7, 54.3, 58.7,
116.3, 117.0 (TFA), 118.9 (TFA), 128.1, 128.2, 129.47, 129.52,
129.8, 129.9, 130.0, 130.3, 140.8, 140.9, 155.1, 157.8, 162.5 (TFA),
162.8 (TFA), 163.0 (TFA), 163.2 (TFA), 173.4, 174.9, 177.0; MS (ES,
DCM/MeOH + 10 mM NH4OAc): m/z 587 [M+H]+, 294 [M+2H]2+
;
HRMS: (LSI-MS): m/z [M+H]+ calcd for C33H43N6O4þ: 587.3346,
found: 587.3357; C33H42N6O4 ꢀ C4H2F6O4 (814.7).
x
4.2.17.1.
(R)-N -[4-(2-Aminoethyl)aminocarbonylbutanoyl]-
x
a
4.2.18. (R)-N -(12-Amino-4,7,10-trioxadodecanoyl)-N -(2,2-
diphenylacetyl)-N-(4-hydroxybenzyl)argininamide
bis(hydrotrifluoroacetate) (34)
a
N -(2,2-diphenylacetyl)-N-(4-hydroxybenzyl)argininamide bis
(hydrotrifluoroacetate) (31). Prepared from 16 (216 mg,
0.79 mmol) and 30 (331 mg, 0.53 mmol); CDI: 136 mg, 0.84 mmol;
NEt3: 16 mg, 0.16 mmol; 71% (320 mg); IR (neat): 1640, 1515,
A
solution of 19 (300 mg, 0.84 mmol) and CDI (156 mg,
0.96 mmol) in DCM (10 mL) was stirred for 30 min. 30 (506 mg,
0.8 mmol) and NEt3 (40.7 mg, 56 L, 0.4 mmol) were added and
1495, 1170, 1130 cmꢂ1 1H NMR (COSY, 600 MHz, DMSO-d6,): d
;
l
(ppm) 1.38–1.50 (m, 2H), 1.55 (m, 1H), 1.68 (m, 1H), 1.79 (p, 2H,
3J = 7.4 Hz), 2.16 (t, 2H, 3J = 7.4 Hz), 2.45 (t, 2H, 3J = 7.4 Hz), 2.85
(m, 2H), 3.23 (m, 2H), 3.28 (m, 2H), 4.1 (dd, 1H, 2J = 14.9 Hz,
3J = 5.7 Hz), 4.17 (dd, 1H, 2J = 14.8 Hz, 3J = 5.9 Hz), 4.33 (m, 1H),
5.13 (s, 1H), 6.68 (m, 2H), 7.00 (m, 2H), 7.22 (m, 2H), 7.28 (m,
8H), 7.85 (br s, 3H), 8.05 (t, 1H, 3J = 5.6 Hz), 8.35 (t, 1H,
3J = 5.8 Hz), 8.48 (d, 1H, 3J = 8.0 Hz), 8.64 (br s, 1H), 8.98 (br s,
1H), 9.35 (t, 1H, 3J = 5.4 Hz), 12.05 (s, 1H); 13C NMR (150 MHz,
DMSO-d6): d (ppm) 19.7, 24.4, 29.4, 34.0, 35.4, 36.4, 38.7, 40.4,
41.6, 52.3, 56.0, 113.5 (TFA), 115.0, 115.4 (TFA), 117.4 (TFA),
119.3 (TFA), 126.6, 128.17, 128.21, 128.4, 128.51, 128.54, 129.1,
140.3, 140.5, 153.0, 156.3, 158.7 (TFA), 158.9 (TFA), 159.1 (TFA),
159.4 (TFA), 171.0, 171.1, 172.4, 175.1; MS (ES, acetonitrile/TFA):
m/z 315.5 [M+2H]2+, 630 [M+H]+; HRMS: (LSI-MS): m/z [M+H]+
calcd for C34H44N7O5þ: 630.3404, found: 630.3408; C34H43N7O5 ꢀ
C4H2F6O4 (857.7).
the mixture was kept under stirring at rt for 20 h. Volatiles were re-
moved under reduced pressure and the intermediate was purified
by column chromatography (DCM/MeOH 50:1–10:1) prior to
hydrogenation at rt and atmospheric pressure in MeOH (20 mL)
using hydrogen and a 10% Pd/C catalyst (120 mg). The catalyst
was removed by filtration; removal of the solvent in vacuo yielded
a highly viscous colourless oil which was dissolved in DCM/TFA
10:1 (v/v). The mixture was allowed to stand at rt overnight and
was subsequently concentrated under reduced pressure. Purifica-
tion by preparative HPLC (gradient: 0–20 min: MeCN/0.1% aq TFA
15:85–38:62, 20–20.1 min: 38:62–67:33, 20.1–25 min: 67:33,
tR = 19.8 min) afforded the product as a white fluffy, hygroscopic
solid (264 mg, 36%). ½a D20
ꢃ
+8.2 cm3 gꢂ1 dmꢂ1 (c 0.0060 in MeCN/
1H NMR
H2O 9:1); IR (neat): 1640, 1515, 1495, 1180, 1130 cmꢂ1
;
(300 MHz, DMSO-d6): d (ppm) 1.32–1.6 (m, 3H), 1.66 (m, 1H),
2.68 (t, 2H, 3J = 5.9 Hz), 2.96 (m, 2H), 3.24 (m, 2H), 3.54 (m, 10H),
3.68 (t, 2H, 3J = 6.0 Hz), 4.1 (dd, 1H, 2J = 15.1 Hz, 3J = 5.9 Hz), 4.19
(dd, 1H, 2J = 15.1 Hz, 3J = 5.8 Hz), 4.34 (m, 1H), 5.12 (s, 1H), 6.67
(m, 2H), 7.0 (m, 2H), 7.18–7.35 (m, 10H), 7.75 (br s, 3H), 8.38 (t,
1H, 3J = 5.7 Hz), 8.50 (d, 1H, 3J = 8.1 Hz), 8.68 (s, 2H), 9.07 (m, 1H),
9.3 (s, 1H), 11.63 (s, 1H); 13C NMR (75 MHz, DMSO-d6): d (ppm)
25.5, 30.2, 38.4, 40.6, 41.8, 43.7, 54.3, 58.7, 66.9, 67.8, 71.16,
71.25, 71.32, 71.44, 116.3, 128.1, 128.2, 129.5, 129.8, 129.9, 130.0,
130.3, 140.8, 140.9, 155.0, 157.8, 173.3, 174.9, 175.4; MS (ES,
x
4.2.17.2. (R)-N -[4-(3-Aminopropyl)aminocarbonylbutanoyl]-
a
N -(2,2-diphenylacetyl)-N-(4-hydroxybenzyl)argininamide bis
(hydrotrifluoroacetate) (32). Prepared from 17 (240 mg,
0.83 mmol) and 30 (350 mg, 0.56 mmol); CDI: 144 mg, 0.89 mmol;
NEt3: 17 mg, 0.17 mmol; 64% (310 mg); ½a D20
ꢃ
+4.8 cm3 gꢂ1 dmꢂ1 (c
0.0108 in MeCN/H2O 9:1); IR (neat): 1635, 1540, 1515, 1495, 1170,
1130 cmꢂ1 1H NMR (300 MHz, DMSO-d6): d (ppm) 1.32–1.6 (m,
;
3H), 1.65 (m, 3H), 1.77 (m, 2H), 2.14 (t, 2H, 3J = 7.4 Hz), 2.43 (t,
2H, 3J = 7.0 Hz), 2.76 (m, 2H), 3.1 (m, 2H), 3.24 (m, 2H), 4.1 (dd,
1H, 2J = 15.2 Hz, 3J = 6.0 Hz), 4.18 (dd, 1H, 2J = 15.1 Hz,
3J = 5.9 Hz), 4.34 (m, 1H), 5.12 (s, 1H), 6.67 (m, 2H), 7.0 (m, 2H),
7.18–7.33 (m, 10H), 7.65 (br s, 3H), 7.98 (t, 1H, 3J = 5.5 Hz), 8.38
(t, 1H, 3J = 5.7 Hz), 8.5 (d, 1H), 8.56 (s, 2H), 8.85 (m, 1H), 9.3 (s,
1H), 11.32 (s, 1H); 13C NMR (150 MHz, MeOH-d4): d (ppm) 21.3,
25.4, 28.8, 30.2, 35.5, 36.8, 36.9, 38.2, 41.8, 43.7, 54.3, 58.7,
116.3, 116.9 (TFA), 118.9 (TFA), 128.1, 128.2, 129.48, 129.53,
129.8, 129.9, 130.0, 130.3, 140.8, 140.9, 155.0, 157.8, 162.4 (TFA),
162.6 (TFA), 162.8 (TFA), 163.1 (TFA), 173.3, 174.9, 176.0, 176.6;
MS (ES, acetonitrile/TFA): m/z 322.5 [M+2H]2+, 644 [M+H]+; HRMS:
DCM/MeOH + 10 mM NH4OAc): m/z 677 [M+H]+, 339 [M+2H]2+
;
HRMS: (LSI-MS): m/z [M+H]+ calcd for C36H49N6O7þ: 677.3663,
found: 677.3655; C36H48N6O7 ꢀ C4H2F6O4 (904.8).
x
a
4.2.19. (R)-N -(8-Amino-3,6-dioxaoctanoyl)-N -(2,2-
diphenylacetyl)-N-(4-hydroxybenzyl)argininamide
bis(hydrotrifluoroacetate) (36)
N-Boc-8-amino-3,6-dioxaoctanoic
(300 mg) was dissolved in dimethoxyethane (10 mL). The amine
acid ꢀ dicyclohexylamine
was precipitated by addition of 37% hydrochloric acid (ꢁ60
and removed by filtration. Removal of the solvent in vacuo yielded
yellow oil (200 mg, 0.76 mmol) which was dissolved in
lL)
a