8348
K.-i. Nihei et al. / Tetrahedron 62 (2006) 8335–8350
compound 32 (730 mg, 90%) as a colorless oil. IR (film)
J¼6.3, 15.0 Hz), 2.39 (dd, 1H, J¼6.0, 15.0 Hz), 2.69 (m,
4H), 3.17 (m, 8H), 3.84 (m, 3H), 4.16 (dd, 1H, J¼6.0,
6.3 Hz), 4.97 (s, 2H), 5.02 (s, 2H), 5.20 (s, 2H), 6.81 (d,
1H, J¼7.5 Hz), 6.86 (br s, 1H), 7.32 (m, 17H), 7.67 (br s,
1H), 7.87 (m, 9H), 9.14 (br s, 2H). 13C NMR (75 MHz,
DMSO-d6): d 23.3, 25.3, 26.9, 27.5, 28.3, 28.4, 28.7, 29.3,
36.2, 37.6, 38.6, 44.6, 44.8, 45.0, 45.6, 47.3, 51.7, 54.8,
65.6, 66.3, 68.4, 78.3, 124.5, 124.6, 127.8, 127.9, 128.1,
128.4, 128.5, 128.7, 129.9, 131.8, 131.9, 132.7, 134.7,
134.8, 135.5, 137.2, 137.3, 147.7, 155.2, 155.3, 156.2,
159.9, 163.1, 171.4, 171.8. FABHRMS calcd for
C62H78N12O19S2Na (M+Na)+ 1381.4845, found 1381.4835.
1
1715, 1546, 1440, 1373, 1247, 1162, 931, 852 cmꢂ1. H
NMR (300 MHz, CDCl3): d 1.80 (quin, 2H, J¼6.3 Hz),
2.10 (quin, 2H, J¼6.3 Hz), 3.25 (q, 2H, J¼6.3 Hz), 3.40
(m, 6H), 4.56 (d, 2H, J¼5.4 Hz), 5.08 (br s, 1H), 5.22 (dd,
1H, J¼1.8, 10.8 Hz), 5.31 (dd, 1H, J¼1.8, 15.9 Hz), 5.92
(ddd, 1H, J¼5.4, 10.8, 15.9 Hz), 7.66 (m, 1H), 7.72 (m,
2H), 8.04 (m, 1H). 13C NMR (75 MHz, CDCl3): d 28.1,
29.7, 31.1, 37.5, 45.3, 45.6, 65.4, 117.5, 124.2, 130.9,
131.6, 132.7, 133.6, 147.9, 156.2. HRMS calcd for
C10H18N2O2Br (M+ꢂNs) 277.0551, found 277.0564.
4.1.33. N-(Na-tert-Butoxycarbonyl-L-asparaginyl)-12-
(Na,Nd,Nu-tribenzyloxycarbonylarginyl)-amino-6,10-
[di-(2-nitrobenzenesulfonyl)]-6,10-diaza-1-aminounde-
cane (34). To a solution of sulfonamide 10 (200 mg,
399 mmol) and bromide 32 (278 mg, 599 mmol) in DMF
(2 mL) were added Cs2CO3 (391 mg, 1.20 mmol) and
TBAI (15.0 mg, 40.6 mmol). After being stirred for 1 h at
70 ꢀC, the reaction mixture was diluted with EtOAc
(150 mL) and washed with H2O (3ꢁ30 mL) and brine
(3ꢁ30 mL). Aqueous layers were extracted with EtOAc
(3ꢁ30 mL) and combined organic layers were dried over
Na2SO4. Filtration and concentration followed by chromato-
graphy on silica gel (2–4% MeOH/CH2Cl2) gave the title
compound 33 (332 mg), which was used in the next step
without further purification. 1H NMR (300 MHz,
CD3COCD3): d 1.27 (m, 2H), 1.40 (s, 9H), 1.48 (m, 4H),
1.78 (quin, 2H, J¼6.9 Hz), 1.86 (quin, 2H, J¼7.2 Hz),
2.59 (dd, 1H, J¼6.6, 15.9 Hz), 2.73 (dd, 1H, J¼4.8,
15.9 Hz), 3.16 (m, 4H), 3.36 (m, 8H), 4.35 (dd, 1H, J¼4.8,
6.6 Hz), 4.50 (d, 2H, J¼5.4 Hz), 5.14 (dd, 1H, J¼1.2,
10.8 Hz), 5.27 (dd, 1H, J¼1.2, 16.2 Hz), 5.92 (ddd, 1H,
J¼5.4, 10.8, 16.2 Hz), 6.36 (m, 3H), 6.98 (br s, 1H), 7.33
(br s, 1H), 7.87 (m, 6H), 8.06 (m, 2H). 13C NMR
(75 MHz, CD3COCD3): d 24.6, 28.3, 28.8, 28.9, 30.1,
38.4, 39.3, 39.8, 46.1, 46.3, 46.7, 48.8, 52.7, 65.8, 79.9,
117.5, 125.5, 125.6, 131.5, 133.3, 133.4, 135.1, 135.4,
135.5, 149.5, 156.6, 157.4, 172.3, 173.9.
4.1.34. N-(Na-2,4-Dibenzyloxyphenylacetyl-L-aspara-
ginyl)-12-(Na,Nd,Nu-tribenzyloxycarbonylarginyl)-amino-
6,10-[di-(2-nitrobenzenesulfonyl)]-6,10-diaza-1-amino-
undecane (35). To a cold (0 ꢀC) and stirred suspension of
polyamine 34 (90 mg, 66.2 mmol) in CHCl3 (1 mL) was added
TFA (1 mL) slowly. After being stirred for 1 h at room tem-
perature, the reaction mixture was concentrated in vacuo to
give the crude amine TFA salt as a colorless solid.
To a stirred solution of obtained amine TFA salt in DMF
(1 mL) were added Et3N (7 mg, 69.2 mmol) and 2,4-di-
benzyloxyphenylacetic acid succinimide ester28 (45 mg,
101 mmol) slowly. After being stirred for 2 h at room temper-
ature, the reaction mixture was directly subjected to silica
gel chromatography (2–10% MeOH/CH2Cl2) to afford the
title compound 35 (84 mg, 80%, two steps) as a white
powder. [a]2D4 ꢂ0.43 (c 0.70, DMSO). IR (Nujol) 1721,
1
1658, 1545, 1457, 1377, 1262, 1162, 852 cmꢂ1. H NMR
(300 MHz, DMSO-d6): d 1.06 (m, 2H), 1.23 (m, 2H), 1.33
(m, 2H), 1.54 (m, 8H), 2.35 (dd, 1H, J¼7.2, 15.0 Hz), 2.42
(dd, 1H, J¼6.3, 15.0 Hz), 2.89 (m, 2H), 2.97 (m, 2H), 3.16
(m, 8H), 3.37 (m, 2H), 3.83 (m, 3H), 4.51 (m, 1H), 4.96 (s,
2H), 5.01 (s, 2H), 5.02 (s, 2H), 5.07 (s, 2H), 5.18 (s, 2H),
6.51 (s, 2H), 6.67 (br s, 1H), 6.85 (br s, 1H), 7.07 (m, 2H),
7.33 (m, 26H), 7.61 (m, 1H), 7.85 (m, 10H), 9.14 (br
s, 2H). 13C NMR (75 MHz, DMSO-d6): d 23.4, 25.3, 26.8,
27.5, 28.2, 28.7, 29.3, 36.2, 36.4, 37.5, 38.7, 44.6, 44.7,
45.0, 45.6, 47.3, 50.0, 54.8, 65.6, 66.3, 68.4, 69.4, 69.5,
127.3, 127.8, 127.9, 128.0, 128.1, 128.5, 128.6, 128.7, 129.9,
131.2, 131.8, 131.9, 132.7, 134.7, 134.8, 135.5, 137.2, 137.3,
137.4, 147.7, 155.2, 156.2, 157.1, 158.5, 160.0, 163.1, 170.5,
170.9, 171.7, 171.8. FABHRMS calcd for C79H88N12O20S2Na
(M+Na)+ 1611.5577, found 1611.5571.
To a cold (0 ꢀC) and stirred solution of polyamine 33
(135 mg, 153 mmol) in CH2Cl2 (4 mL) were added PPh3
(8 mg, 30.5 mmol), Pd(PPh3)4 (9 mg, 7.8 mmol), and pyrroli-
dine (54 mg, 759 mmol). After being stirred for 0.5 h at room
temperature, the reaction mixture was concentrated in vacuo.
The residue was subjected to silica gel chromatography (2–
10% EtOH/CH2Cl2, then 7.5% MeOH/CHCl3 containing
2.5% i-PrNH2) to afford the primary amine as a colorless oil.
4.1.35. Argiotoxin-636 (8). To a stirred solution of poly-
amine 35 (40 mg, 25.2 mmol) in DMF (1 mL) were added
2-mercaptoethanol (39 mg, 499 mmol) and DBU (77 mg,
506 mmol). After being stirred for 0.5 h at room temperature,
the reaction mixture was directly purified on silica gel
column (2–12% EtOH/CH2Cl2, then, 7.5% MeOH/CHCl3
containing 2.5% i-PrNH2) and then, further purification
by preparative TLC (7.5% MeOH/CHCl3 containing 2.5%
i-PrNH2) gave the secondary amine as a white powder.
To a stirred solution of amine obtained in DMF (1 mL) was
added tri-Cbz-arginine succinimide ester48 (154 mg,
229 mmol) slowly. After being stirred for 1 h at room temper-
ature, the reaction mixture was diluted with EtOAc
(100 mL) and washed with saturated NaHCO3 solution
(3ꢁ20 mL) and brine (3ꢁ20 mL). Aqueous layers were ex-
tracted with EtOAc (3ꢁ20 mL) and combined organic layers
were dried over Na2SO4. Filtration and concentration
followed by chromatography on silica gel (2–6% MeOH/
CH2Cl2) gave the title compound 34 (146 mg, 66%, three
steps from 10) as a white powder. [a]2D2 +3.06 (c 1.11,
DMSO). IR (Nujol) 1727, 1681, 1646, 1544, 1456, 1376,
A solution of the secondary amine in AcOH (1 mL) was hy-
drogenated over 20% Pd(OH)2 on carbon (20 mg) for 2 h.
The mixture was filtrated through Celite and the filtrate
was evaporated to dryness. The resultant residue was dis-
solved in water and was purified by preparative RP-HPLC
with a linear gradient from 5% H2O/MeCN containing
1
1255, 1162, 852 cmꢂ1. H NMR (300 MHz, DMSO-d6):
d 1.09 (m, 2H), 1.34 (m, 13H), 1.55 (m, 8H), 2.32 (dd, 1H,