B. Kçnig and T. Suhs
refluxed for 15 h. The solvent was evaporated and the crude product was
purified by CC (EtOAc/hexane 1:1; Rf =0.4) to obtain 37-Boc (621 mg,
(121 mg, 0.166 mL, 1.20 mmol) was added and the reaction mixture was
refluxed for 18 h. After filtration the solvent was evaporated and the
crude product was purified by CC (EtOAc/hexane 1:1; Rf =0.3) giving
40-Boc (412 mg, 54%) as a yellow solid. M.p. 1038C; [a]2D0 =+31.0 (c=
0.6 in MeOH); 1H NMR (CDCl3): d=1.31–1.65 (m, 20H), 1.71–1.83 (m,
2H), 2.83–2.93 (m, 8H), 3.21–3.37 (m, 2H), 3.70 (s, 3H), 4.10–4.21 (m,
1H), 4.53 (d, J=5.2 Hz, 2H), 5.17 (dd, J=1.7, 9.3 Hz, 1H), 5.28 (dd, J=
1.7 Hz, 16.2 Hz, 1H), 5.52 (brs, 1H), 5.83–5.97 (m, 1H), 6.87 (brs, 1H),
7.13 (d, J=7.7 Hz, 1H), 7.41–7.53 (m, 2H), 8.11–8.22 (m, 2H), 8.34 (d,
J=8.0 Hz, 1H), 9.82 ppm (brs, 1H); 13C NMR (CDCl3): d=22.2 (+),
27.8 (À), 28.1 (+), 28.2 (+), 28.4 (+), 40.4 (Cquat), 42.7 (À), 45.5 (+), 52.5
(+), 65.5 (À), 68.6 (À), 115.3 (+), 117.4 (Cquat), 123.3 (+), 128.3 (+),
129.4 (+), 129.8 (Cquat), 130.2 (+), 152.3 (Cquat), 157.5 (Cquat), 171.4 ppm
(Cquat); IR (KBr): n˜ = 3256, 3112, 2978, 2934, 1722, 1645, 1523, 1411,
56%) as
a
pale yellow solid. M.p. 1128C; [a]2D0 =À13.5 (c=0.6 in
MeOH); 1H NMR (CDCl3): d=1.40 (s, 9H), 1.45 (s, 9H), 2.81–3.50 (m,
6H), 3.78 (s, 3H), 4.05–4.22 (m, 1H), 4.53 (d, J=5.2 Hz, 2H), 5.17 (dd,
J=1.7, 9.3 Hz, 1H), 5.28 (dd, J=1.7 Hz, 16.2 Hz, 1H), 5.83–5.97 (m,
1H), 6.78 (d, J=8.0 Hz, 2H), 6.87 (t, J=5.3 Hz, 1H), 6.99 (d, J=8.0 Hz,
2H), 10.12 ppm (brs, 1H); 13C NMR (CDCl3): d=28.0 (+), 28.1 (+), 40.2
(À), 52.6 (+), 65.5 (À), 80.2 (Cquat), 116.0 (Cquat), 117.5 (À), 127.1 (Cquat),
130.4 (+), 133.0 ppm (Cquat); IR (KBr): n˜ =3374, 3076, 2979, 1720, 1615,
1517, 1448, 1368, 1251, 1147, 1069, 994, 929, 840, 773 cmÀ1; MS (ESI, di-
chloromethane/MeOH+10 mmolLÀ1 NH4OAc): m/z (%): 565.4 (100)
[M ++H], 509.3 (20) [M ++HÀC4H8], 465.4 (25) [M ++HÀBoc]; HRMS:
m/z: calcd for C27H41N4O9: 565.2874, found 565.2879Æ0.02 ppm.
1367, 1287, 1188, 1002, 956, 845 cmÀ1
; MS (ESI, dichloromethane/
(S)-2-[N’-(2-Allyloxycarbonylaminoethyl)guanidino]-3(4-hydroxyphenyl)-
propionic acid methyl ester hydrochloride (37-H): Compound 37-Boc
(621 mg, 1.10 mmol) was dissolved in dichloromethane/TFA 4:1 (15 mL)
and the reaction mixture was stirred at room temperature for 1 h. The
solvent was evaporated and the product was dissolved in 1n HCl
(10 mL). After lyophylization compound 37-H (440 mg, 100%) was ob-
MeOH+10 mmolLÀ1 NH4OAc): m/z (%): calcd for C36H54N6O10S;
762.36; found: 763.5 (100) [M ++H], 663.4 (15) [M ++HÀBoc].
(S)-2-[N’-(2-Allyloxycarbonylaminoethyl)guanidino]-6-(5-dimethylamino-
naphthalene-1-sulfonylamino) hexanoic acid methyl ester hydrochloride
(40-H): Compound 40-Boc (412 mg, 0.54 mmol) was dissolved in di-
chloromethane/TFA 4:1 (15 mL) and the reaction mixture was stirred at
room temperature for 1 h. The solvent was evaporated and the product
was dissolved in 1n HCl (10 mL). After lyophilization compound 40-H
(306 mg, 0.54 mmol, 100%) was obtained as a pale yellow solid. M.p.
1
tained as a yellow solid. M.p. 898C; H NMR: d=2.76–3.21 (m, 6H), 3.78
(s, 3H), 4.05–4.22 (m, 1H), 4.53 (d, J=5.2 Hz, 2H), 5.17 (dd, J=1.7,
9.3 Hz, 1H), 5.28 (dd, J=1.7 Hz, 16.2 Hz, 1H), 5.83–5.97 (m, 1H), 6.75
(d, J=8.0 Hz, 2H), 6.99 (d, J=8.0 Hz, 2H), 7.23 (t, J=5.3 Hz, 1H), 7.61–
7.98 (m, 3H), 9.39 ppm (brs, 1H); 13C NMR: d=31.2 (Cquat), 36.4 (À),
39.2 (À), 39.6 (+), 40.7 (À), 48.5 (+), 52.3 (+), 55.1 (Cquat), 64.4 (À),
115.1 (+), 117.0 (À), 125.7 (Cquat), 130.1 (+), 133.5 (+), 155.5 (Cquat),
170.6 ppm (Cquat); MS (ESI, dichloromethane/MeOH+10 mmolLÀ1
NH4OAc): m/z (%): calcd for C17H25N4O5Cl: 400.15; found: 365.1 (100)
[M ++H].
1
1048C; H NMR: d=1.34–1.75 (m, 4H), 2.83–2.93 (m, 8H), 3.21–3.37 (m,
2H), 3.72 (s, 3H), 4.10–4.20 (m, 1H), 4.53 (d, J=5.2 Hz, 2H), 5.17 (dd,
J=1.7, 9.3 Hz, 1H), 5.28 (dd, J=1.7, 16.2 Hz, 1H), 5.52 (brs, 1H), 5.83–
5.97 (m, 1H), 6.89 (brs, 1H), 7.13 (d, J=7.7 Hz, 1H), 7.41–7.53 (m, 4H),
8.11–8.22 (m, 3H), 8.34 (d, J=8.0 Hz, 1H), 8.56 ppm (brs, 1H); IR
(KBr): n˜ =3385, 2945, 2868, 2787, 1710, 1575, 1508, 1456, 1363, 1319,
1161, 1085, 791, 625, 571 cmÀ1
; MS (ESI, dichloromethane/MeOH+
(S)-2[N’-(2-Allyloxycarbonylaminoethyl)-N’,N’’-di(tert-butoxycarbonyl)-
E
10 mmolLÀ1 NH4OAc): m/z (%): calcd for C26H39N6O6SCl: 566.26;
found: 563.4 (100) [M ++H].
guanidino]-3-(1H-indol-3-yl)propionic acid methyl ester (38-Boc): Com-
pound 34 (1.44 g, 3.45 mmol) and MeO-Trp-NH2 (1.32 g, 5.18 mmol)
were dissolved in THF (20 mL) and the reaction mixture was heated
under reflux for 15 h. The solvent was evaporated and the crude product
was purified by column chromatography on silica gel (EtOAc/hexane 1:1;
Rf =0.45) to yield 38-Boc (1.26 g, 62%) as a orange oil. [a]2D0 = À24.7
(c=0.6 in MeOH); 1H NMR (CDCl3): d=1.40 (s, 9H), 1.46 (s, 9H),
2.81–3.50 (m, 6H), 3.78 (s, 3H), 4.30–4.48 (m, 1H), 4.53 (d, J=5.2 Hz,
2H), 5.18 (dd, J=1.7, 9.3 Hz, 1H), 5.27 (dd, J=1.7 Hz, 16.2 Hz, 1H),
5.81–5.94 (m, 1H), 6.97–7.21 (m, 4H), 7.33 (d, J=8.0 Hz, 1H), 7.55 (d,
J=8.0 Hz, 1H), 8.36 (brs, 1H), 10.17 ppm (brs, 1H); 13C NMR (CDCl3):
d=28.0 (+), 28.1 (+), 28.2 (+), 28.4 (+), 40.1 (À), 52.4 (Cquat), 52.6 (À),
65.3 (À), 82.9 (Cquat), 109.6 (Cquat), 111.5 (+), 117.3 (À), 119.5 (+), 122.4
(+), 122.9 (+), 123.4 (+), 133.3 (Cquat), 136.2 (Cquat), 152.7 ppm (Cquat); IR
(KBr):
(S)-2-(N’,N’’-Di(tert-butoxycarbonyl)-N’-{2-[2-(9H-fluoren-9-ylmethoxy-
carbonylamino)acetylamino]ethyl}guanidino)-3-(4-hydroxyphenyl)-pro-
pionic acid methyl ester (45-Boc): Fmoc-glycine (110 mg, 0.37 mmol),
DIC (47 mg, 0.057 mL, 0.37 mmol) and HOBt (50 mg, 0.37 mmol) were
dissolved in dichloromethane (15 mL) and the reaction mixture was stir-
red at room temperature for 30 min. Compound 37-H (207 mg,
0.37 mmol), [Pd(PPh3)4](29 mg, 7 mol%) and Bu 3SnH (119 mg,
E
0.108 mL, 0.41 mmol) were added and the solution was stirred at room
temperature for 12 h. The solvent was evaporated and the crude product
was purified by CC (EtOAc; Rf =0.45) to obtain 31 (182 mg, 0.25 mmol,
1
67%) as a colourless oil. H NMR (CDCl3): d=1.40 (s, 9H), 1.47 (s, 9H),
2.81–3.17 (m, 6H), 3.81 (s, 3H), 4.08–4.21 (m, 2H), 4.31–4.43 (m, 4H),
6.02 (brs, 1H), 6.77 (d, J=8.2 Hz, 2H), 7.01 (d, J=8.2 Hz, 2H), 7.11–
7.20 (m, 4H), 7.43–7.50 (m, 2H), 7.56–7.63 (m, 2H), 9.01 (brs, 1H),
10.12 ppm (brs, 1H); MS (ESI, dichloromethane/MeOH+10 mmolLÀ1
NH4OAc): m/z (%): calcd for C40H49N5O10: 759.35, found: 760.4 (100)
[M ++H].
n˜ =3388, 3059, 2978, 1716, 1618, 1533, 1437, 1368, 1249, 1147, 1064, 1011,
928, 743 cmÀ1
;
MS (ESI, dichloromethane/MeOH+10 mmolLÀ1
NH4OAc): m/z (%): calcd for C29H41N5O8: 587.29; found: 588.4 (100)
[M ++H], 532.3 (10) [M ++HÀC4H8], 488.3 (15) [M ++HÀBoc].
(S)-2-[N’-(2-Allyloxycarbonylaminoethyl)guanidino]-3-(1H-indol-3-yl)-
propionic acid methyl ester hydrochloride (38-H): Compound 38-Boc
(1.26 g, 2.14 mmol) was dissolved in dichloromethane/TFA 4:1 (15 mL)
and the reaction mixture was stirred at room temperature for 1 h. The
solvent was evaporated and the product was dissolved in 1n HCl
(10 mL). After lyophilization compound 38-H (906 mg, 2.14 mmol,
100%) was obtained as an orange solid. M.p. 1038C; 1H NMR: d=2.91–
3.34 (m, 6H), 3.78 (s, 3H), 4.30–4.48 (m, 1H), 4.53 (d, J=5.2 Hz, 2H),
5.18 (dd, J=1.7, 9.3 Hz, 1H), 5.27 (dd, J=1.7 Hz, 16.2 Hz, 1H), 5.81–5.94
(m, 1H), 6.97–7.21 (m, 4H), 7.33 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.0 Hz,
1H), 7.59–7.79 (m, 3H), 7.93 (brs, 1H), 9.19 ppm (brs, 1H); IR (KBr):
n˜ =3327, 1697, 1635, 1527, 1341, 1261, 1151, 932, 745 cmÀ1; MS (ESI, di-
chloromethane/MeOH+10 mmolLÀ1 NH4OAc): m/z (%): calcd for
C19H26N5O4Cl: 423.17; found 388.2 (100) [M ++H].
Glycine-bridged bis-guanidine 47-Boc: Compound 45-Boc (164 mg,
0.21 mmol) was dissolved in 20% piperidine/DMF (10 mL) and the reac-
tion mixture was stirred at room temperature for 1 h. The reaction proc-
ess was monitored by TLC. The solvent was evaporated and dried under
high vacuum. The amine was used without further purification and dis-
solved in dichloromethane (10 mL), compound 32 (117 mg, 0.21 mmol),
DIC (27 mg, 0.033 mL, 0.21 mmol) and HOBt (28 mg, 0.21 mmol) were
added and the reaction was stirred at room temperature for 18 h. The sol-
vent was evaporated and the crude product was purified by CC (EtOAc;
Rf =0.1) to obtain 33 (38 mg, 17%) as
a yellow solid. M.p. 938C;
1H NMR: d=1.35 (s, 9H), 1.39 (s, 9H), 1.43 (s, 18H), 2.79–3.43 (m,
12H), 3.78 (s, 3H), 3.85–3.97 (m, 1H), 4.11–4.19 (m, 1H), 4.53 (d, 5.2 Hz,
2H), 4.79–4.88 (m, 2H), 5.17 (dd, J=1.7, 9.3 Hz, 1H), 5.28 (dd, J=
1.7 Hz, 16.2 Hz, 1H), 5.83–5.97 (m, 1H), 6.73–7.08 (m, 7H), 7.13–7.19
(m, 2H), 8.23 (brs, 1H), 8.49 (brs, 1H), 9.12 ppm (brs, 1H); 13C NMR:
d=14.0 (+), 21.8 (+), 23.2 (+), 24.4 (À), 25.2 (À), 25.7 (Cquat), 26.2 (À),
27.4 (+), 27.6 (+), 27.7 (+), 27.8 (+), 28.1 (+), 33.2 (+), 40.2 (Cquat), 40.6
(À), 47.4 (+), 51.8 (+), 54.2 (+), 59.6 (Cquat), 64.1 (À), 67.7 (À), 109.6
(S)-2-[N’-(2-Allyloxycarbonylaminoethyl)-N’,N’’-di(tert-butoxycarbonyl)-
guanidino]-6-(5-dimethylaminonaphthalene-1-sulfonylamino)hexanoic
acid methyl ester (40-Boc): Compound 39-H (397 mg, 1.00 mmol) and
compound 34 (626 mg, 1.5 mmol) were dissolved in THF (20 mL). NEt3
8156
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8150 – 8157