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K. Ishida et al. / Tetrahedron 58 (2002) 7645–7652
4.3.3. Aeruginoguanidine 98-C (3). [a]2D8¼21.48 (c 0.5,
DMF); UV (50% MeOH) lmax 265 nm (1 1030);
HRFABMS m/z 996.3851 [M2H]2 (C39H66N9O15S3, D
þ1.1 mmu), HMBC correlations: H-1/C-2, C-3, C-4 and
C-5, H-2/C-1, C-3 and C-4, H-3/C-1 and C-2, H-5/C-1, C-7,
C-9 and C-10, H-8/C-4, C-6 and C-7, H-9/C-1, C-5 and C-7,
H-10a/C-5, C-6 and C-7, H-10b/C-5, C-6 and C-7, 2-NH/
C-11, H-12/C-11, C-14 and C-22, H-15a/C-14, C-16 and
C-17, H-17/C-15, C-16, C-18 and C-19, H-18/C-20 and
C-21, H-20/C-18, C-19 and C-21, H-21/C-18, C-19 and
C-20, H-22/C-12 and C-23, H-29/C-27, C-30 and C-31,
H-30/C-32 and C-38, H-32/C-31, H-34/C-32, C-33, C-35,
C-36 and C-37, H-36a/C-34 and C-37, H-36b/C-34 and
C-37, H-37/C-34, C-35 and C-36, H-38/C-30, C-31 and
C-32, H-39/C-24.
room temperature for 1.5 h. After the solvent was removed
by lyophilization, the reaction mixture was subjected to
reversed-phase HPLC (Cosmosil 5C18-MS, 10£250 mm;
10–70% MeCN containing 0.05% TFA; UV-detection
210 nm; flow rate 2.0 mL/min) to yield N a-methyl-N v-
isoamylarginine (S)-PGME amide (2.3 mg): HRFABMS
1
m/z 406.2780 [MþH]þ (C21H36N5O3, D 23.8 mmu); H
NMR specrum (CD3OD; 300 K), N a-methyl-N v-isoamyl-
arginine d 0.980 (d, J¼6.8 Hz, 6H, H-10 and 100), 1.552 (m,
2H, H-8), 1.670 (m, 1H, H-9), 1.788 (m, 1H, H-4), 1.920 (m,
2H, H-3 and H-4), 1.970 (m, 1H, H-3), 2.630 (s, 3H, N-Me),
3.381 (m, 2H, H-5), 3.420 (m, 2H, H-7), 3.862 (dd, J¼7.3,
4.3 Hz, 1H, H-2), (S)-PGME d 3.710 (s, 3H, CO2Me), 5.520
(s, 1H, H-2), 7.370–7.426 (m, 5H, phenyl). N a-methyl-N v-
isoamylarginine (R)-PGME amide was also derivatized as
described above. N a-methyl-N v-isoamylarginine (R )-
PGME amide (0.9 mg): HRFABMS m/z 406.2818
4.3.4. MiArg (N a-methyl-N v-isoamylarginine) and
MdoArg (N a-methyl-N v-2,6-dimethyloctylarginine). 1
(100 mg) was dissolved in DMF (3.0 mL) and EtOH
(5.0 mL) and then 30 mg of palladium black was added to
a solution, and the mixture was stirred at room temperature
for 4 days under hydrogen. The reaction mixture was filtered
and concentrated. This crude residue was dissolved in DMF
(3.0 mL) and 6 M HCl (5.0 mL), and heated at 1108C for 2.5
days. After the solvent was removed by evaporation, the
reaction mixture was subjected to reversed-phase HPLC
(Cosmosil 5C18-MS, 10£250 mm; 0–80% MeCN contain-
ing 0.05% TFA; UV detection at 210 nm; flow rate
2.0 mL/min) to yield MdoArg (33.4 mg) and a fraction
containing MiArg (32.8 mg). The fraction containing
MiArg was further subjected to reversed-phase HPLC
(Cosmosil 5C18-MS, 10£250 mm; 13% MeCN containing
0.05% TFA; UV detection at 210 nm; flow rate 2.0 mL/min)
to yield MiArg (16.9 mg). N a-methyl-N v-isoamylarginine:
[a ]2D3¼þ18.68 (c 0.1, MeOH); HRFABMS m/z 259.2159
1
[MþH]þ (C21H36N5O3, D 0.0 mmu); H NMR spectrum
(CD3OD; 300 K), N a-methyl-N v-isoamylarginine d 0.915
(d, J¼6.8 Hz, 3H, H-10), 0.920 (d, J¼6.4 Hz, 3H, H-100),
1.420 (m, 2H, H-7), 1.445 (m, 1H, H-4), 1.556 (m, 1H, H-9),
1.576 (m, 1H, H-4), 1.839 (m, 2H, H-3), 2.720 (s, 3H,
N-Me), 3.190 (m, 2H, H-7), 3.220 (ddd, J¼9.8, 6.0, 3.8 Hz,
2H, H-5), 3.890 (t J¼6.8 Hz, 1H, H-2), (R )-PGME d 3.720
(s, 3h, CO2Me), 5.560 (s, 1H, H-2), 7.360–7.420 (m, 5H,
phenyl).
4.3.6. N a-Methyl-N v-2,6-dimethyloctylarginine (S,R )-
PGME amides. A solution of N a-methyl-N v-dimethyl-
octylarginine (3.0 mg) in DMF (0.5 mL) was added with
(S )-PGME (2.2 mg), PyBOP (7.0 mg), HOBt (1.8 mg) and
N-methylmorphorine (3.0 mL) at 08C, and the mixture was
stirred at room temperature for 1.5 h. After the solvent was
removed by lyophilization, the reaction mixture was
subjected to reversed-phase HPLC (Cosmosil 5C18-MS,
10£250 mm; 20–100% MeCN containing 0.05% TFA;
UV-detection 210 nm; flow rate 2.0 mL/min) to yield
N a-methyl-N v-dimethyloctylarginine (S)-PGME amide
1
[MþH]þ C12H27N4O2, D þ2.5 mmu); H NMR spectrum
(DMSO-d6; 300 K), d 0.87 (m, 6H, H-10 and 100), 1.37 (m,
2H, H-8), 1.55 (m, 2H, H-4 and H-9), 1.58 (m, 1H, H-3),
1.70 (m, 1H, H-4), 1.77 (m, 1H, H-3), 2.45 (s, 3H, N-Me),
3.12 (m, 1H, H-5), 3.23 (m, 2H, H-7), 3.35 (m, 1H, H-2),
3.40 (m, 1H, H-5), 13C NMR spectrum (DMSO-d6; 300 K),
22.2 (C-10 and C-100), 23.0 (C-4), 25.4 (C-9), 25.6 (C-3),
32.0 (N-Me), 35.5 (C-8), 46.8 (C-7), 47.6 (C-5), 59.5 (C-2),
N a-methyl-N v-2,6-dimethyloctylarginine: [a]2D3¼þ18.68
(c 0.1, MeOH); HRFABMS m/z 329.2874 [MþH]þ
(2.0 mg):
(C26H46N5O3,
HRFABMS
m/z
476.3591
[MþH]þ
D
21.0 mmu); 1H NMR spectrum
(CD3OD; 300 K), N a-methyl-N v-dimethyloctylarginine d
0.877 (m, 6H, H-14 and 140), 0.965 (d, J¼6.4 Hz, 3H, H-90),
1.174 (m, 1H, H-10), 1.175 (m, 1H, H-12), 1.280 (m, 1H,
H-11), 1.380 (m, 1H, H-10), 1.480 (m, 1H, H-8), 1.520 (m,
1H, H-9), 1.540 (m, 1H, H-13), 1.680 (m, 1H, H-8), 1.800
(m, 1H, H-4), 1.924 (m, 1H, H-4), 1.948 (m, 2H, H-3), 2.630
(s, 3H, N-Me), 3.398 (m, 2H, H-5), 3.428 (m, 2H, H-7),
3.870 (dd, J¼7.7 Hz, 4.3, 1H, H-2), (S)-PGME d 3.720 (s,
3H, CO2Me), 5.515 (s, 1H, H-2), 7.380–7.440 (m, 5H,
phenyl). N a-methyl-N v-dimethyloctylarginine (R )-PGME
amide was also derivatized as described above. N a-methyl-
N v-dimethyloctylarginine (R )-PGME amide (4.7 mg):
HRFABMS m/z 476.3591 [MþH]þ (C26H46N5O3, D
21.0 mmu); 1H NMR spectrum (CD3OD; 300 K), N a-
methyl-N v-dimethyloctylarginine d 0.879 (d, J¼6.4 Hz,
3H, H-14), 0.881 (d, J¼6.8 Hz, 3H, H-140), 0.901 (d,
J¼6.4 Hz, 3H, H-90), 1.120 (m, 1H, H-10), 1.172 (m, 2H,
H-12), 1.272 (m, 1H, H-11), 1.310 (m, 1H, H-10), 1.340 (m,
1H, H-8), 1.368 (m, 1H, H-11), 1.425 (m, 1H, H-9), 1.450
(m, 1H, H-4), 1.530 (m, 1H, H-13), 1.545 (m, 1H, H-8),
1.590 (m, 1H, H-4), 1.850 (m, 2H, H-3), 2.720 (s, 3H,
N-Me), 3.205 (m, 2H, H-7), 3.220 (m, 2H, H-5), 3.900 (dd,
1
(C17H37N4O2, D 24.3 mmu); H NMR spectrum (DMSO-
d6; 300 K), d 0.84 (m, 6H, H-14 and 140), 0.87 (m, 3H, H-90),
1.07 (m, 1H, H-10), 1.12 (m, 2H, H-12), 1.20 (m, 1H, H-11),
1.26 (m, 1H, H-10), 1.28 (m, 1H, H-11), 1.30 (m, 1H, H-7),
1.41 (m, 1H, H-9), 1.51 (m, 2H, H-8 and H-13), 1.56 (m, 1H,
H-4), 1.65 (m, 1H, H-3), 1.69 (m, 1H, H-4), 1.79 (m, 1H,
H-3), 2.52 (s, 3H, N-Me), 3.20 (m, 1H, H-5), 3.25 (m, 2H,
H-7), 3.36 (m, 1H, H-5), 3.60 (m, 1H, H-2), 13C NMR
spectrum (DMSO-d6; 300 K), 19.1 (C-90), 22.5 (C-4), 22.6
(C-14 and C-140), 24.0 (C-11), 25.5 (C-3), 27.5 (C-13), 30.0
(C-9), 31.2 (N-Me), 34.0 (C-8), 36.5 (C-10), 38.8 (C-12),
46.5 (C-7), 47.5 (C-5), 61.0 (C-2).
4.3.5. N a-Methyl-N v-isoamylarginine (S,R )-PGME
amides. A solution of N a-methyl-N v-isoamylarginine
(3.0 mg) in DMF (0.5 mL) was added with (S )-PGME
(2.2 mg), PyBOP (7.0 mg), HOBt (1.8 mg) and N-methyl-
morphorine (3.0 mL) at 08C, and the mixture was stirred at