Synthesis of C11
N
5
Marine Sponge Alkaloids
J . Org. Chem., Vol. 62, No. 3, 1997 463
tetr a h yd r o-1H-p yr r olo[2,3-c]a zep in -8-on e (18). A solution
of 16 (1.0 g, 2.4 mmol) and AI sulfate (0.38 g, 2.9 mmol) in 5
mL of trifluoroacetic acid was stirred at room temperature for
left standing overnight. The precipitate was filtered and
washed with methanol (2 × 2 mL) to afford the methane-
sulfonic acid salt of 2 (62 mg, 61%) as a colorless solid. The
free base of 2 was generated by passing the salt of 2 through
3
5
d. The reaction mixture was diluted with ether (50 mL ×
) and decanted, and the resulting residue was purified by
a short plug of silica (CH
2 2 3
Cl /MeOH saturated NH 8:2).
flash chromatography (CH
afforded 18 (0.55 g, 50%) as a colorless solid: H NMR (CD
OD) δ 3.40 (dd, 1H, J ) 15.4, 6.6), 3.94 (d, 1H, J ) 15.4), 4.70
dd, 1H, J ) 6.6, 3.4), 5.07 (d, 1H, J ) 3.4), 6.64 (s, 2H); 13
NMR (CD OD) δ 41.6 (t), 50.3 (d), 57.9 (d), 103.3 (s), 108.3 (s),
2
Cl
2
/MeOH saturated with NH
3
9:1)
Method B: A solution of 16 (1.0 g, 2.4 mmol) and AI sulfate
(0.38 g, 2.9 mmol) in 5 mL of methanesulfonic acid was heated
at 90 °C for 20 h. Upon cooling, the reaction mixture was
diluted with ether (50 mL × 5) and decanted, and the resulting
1
3
-
(
C
3
2 2
residue was purified by flash chromatography (CH Cl /MeOH
1
3
18.3 (d × 2), 124.0 (s), 125.2 (s), 149.6 (s), 163.8 (s); IR (Nujol)
saturated with NH
3
9:1) to afford 2 (0.28 g, 30%) as a colorless
-
1
1
240, 2921, 1671, 1566, 1406 cm ; UV (CH
3
OH) λmax 277, 209
solid. H NMR (CD OD) δ 3.50 (d, 2H, J ) 7.0), 6.06 (t, 1H, J
3
+
13
(
(
sh) nm; MS m/ z (relative intensity) 471 (M + 6, 33), 469
) 7.0), 6.42 (s, 1H); C NMR (CD
3
OD) δ 39.1, 100.0, 109.3,
+
+
+
M
+ 4, 100), 467 (M + 2, 100), 465 (M , 33); HRMS, calcd
116.6, 122.9, 125.3, 129.0, 130.4, 131.5, 150.9, 164.7; IR (Nujol)
+
-1
for C11
for C11
H
H
10
N
5
OBr
OBr
3
(M ) 464.8436, found 464.8436. Anal. Calcd
: C, 28.23; H, 2.15; N, 14.97. Found: C,
3158, 1625, 1415, 1190 cm ; UV (CH
3
OH) λmax 274, 225 nm;
(MH ) 385.9253, found 385.9247.
OD) δ 2.70 (s, 3H), 3.58 (d, 2H, J )
+
10
N
5
3
HRMS, calcd for C11
H
10
N
5
OBr
H: H NMR (CD
7.0), 6.26 (t, 1H, J ) 7.0), 6.82 (s, 1H); C NMR (CD
38.9, 39.5, 99.4, 109.6, 112.9, 123.4, 126.8, 127.1, 127.8, 129.3,
148.9, 164.2; UV (CH OH) λmax 284 (sh), 243 nm. Anal. Calcd
for C11 OBr SO H: C, 29.83; H, 2.71; N, 14.50.
2
1
2
2
8.54; H, 1.95; N, 15.21.
tr a n s-(()-5-Br om oh ym en in (19). A solution of 16 (1.0 g,
.4 mmol) and AI sulfate (0.38 g, 2.9 mmol) in 5 mL of
2‚CH
3
SO
3
3
1
3
3
OD) δ
methanesulfonic acid was stirred at room temperature for 5
d. The reaction mixture was diluted with ether (50 mL × 5)
and decanted, and the resulting residue was purified by flash
3
H
9
N
5
2
‚CH
3
3
Found: C, 30.02; H, 2.79; N, 14.37.
chromatography (CH
2
Cl
2
/MeOH saturated with NH
3
9:1) af-
(()-4′-Br om oh ym en in (22). To a stirred solution of (()-
forded 19 (0.51 g, 46%) as a colorless solid. Olefin 17 (0.2 g,
3
hymenin (1) (1.0 g, 2.6 mmol) in 20 mL of CF COOH was
2
0%) was obtained from the ether extracts. 1H NMR (DMSO-
2
added Br (0.16 mL, 3.1 mmol) at room temperature. After
d
6
) δ 3.18 (m, 1H), 3.69 (d, 1H, J ) 14.6), 4.24 (bs, 1H), 4.86
20 min, the reaction mixture was concentrated under reduced
pressure, and the resulting residue was purified by flash
(
(
6
bs, 1H), 5.28 (bs, 2H), 5.95 (s, 1H), 7.91 (d, 1H, J ) 6.8), 10.12
br, 1H), 12.28 (br, 1H); (CD OD) δ 3.25 (dd, 1H, J ) 15.3,
.1), 3.70 (d, 1H, J ) 15.3), 4.40 (d, 1H, J ) 3.2), 4.84 (dd, 1H,
3
chromatography (CH
afford 22 (1.1 g, 95%) as a colorless solid. H NMR (DMSO-
) δ 1.99 (m, 2H), 3.12 (m, 2H), 4.03 (t, 1H, J ) 5.2), 5.05 (bs,
2H), 7.95 (brt, 1H), 10.23 (bs, 1H), 12.50 (br, 1H); IR (Nujol)
2 2 3
Cl /MeOH saturated with NH 9:1) to
1
1
3
J ) 6.1, 3.2), 5.88 (s, 1H); C NMR (DMSO-d
o), 52.2 (o), 101.1 (e), 106.1 (e), 110.2 (o), 122.3 (e), 124.3 (e),
36.0 (e), 149.8 (e), 161.2 (e); UV (CH OH) λmax 277, 214 nm;
(M ) 464.8436, found 464.8438.
H: H NMR (DMSO-d ) δ 2.39 (s, 3H), 3.25 (m, 1H),
6
) δ 41.1 (e), 46.4
d
6
(
1
-
1
3
3240, 2921, 1617, 1555 cm ; UV (CH
3
OH) λmax 277, 213 nm;
(M ) 464.8436, found 464.8427.
OD) δ 2.21-2.13 (m, 2H), 2.33-2.24
+
+
HRMS, calcd for C11
H
10
N
5
OBr
3
10 5 3
HRMS, calcd for C11H N OBr
1
1
1
3
1
1
9‚CH
3
SO
3
6
22‚HCl: H NMR (CD
(m, 2H), 3.35-3.25 (m 2H), 4.25 (dd, 1H, J ) 6.8, 5.5);
NMR (CD OD) δ 34.3 (t), 36.5 (d), 39.6 (t), 96.2 (s), 102.4 (s),
108.6 (s), 124.7 (s), 126.1 (s), 127.4 (s), 148.9 (s), 164.0 (s). Anal.
Calcd for C11 OBr
3
1
3
.49 (d, 1H, J ) 15.5), 4.38 (bs, 1H), 4.80 (bs, 1H), 6.40 (s,
C
H), 7.53 (s, 2H), 8.04 (d, 1H, J ) 6.1), 11.89 (s, 1H), 12.25 (s,
H), 12.81 (s, 1H). Anal. Calcd for C11
3
H
10
N
5
OBr
3
3 3
‚CH SO H:
C, 25.55; H, 2.50; N, 12.42. Found: C, 25.70; H, 2.58; N, 12.31.
H
10
N
5
3
‚HCl: C, 26.19; H, 2.20; N, 13.88.
3
-Deb r om ost even sin e (20) a n d 5-Br om o-3-d eb r om o-
Found: C, 26.11; H, 2.30; N, 13.87.
steven sin e (21). A solution of 19 (100 mg, 0.21 mmol) in 2
mL of methanesulfonic acid was heated at 90 °C in a sealed
tube for 12 h. After cooling, the reaction mixture was diluted
with ether (10 mL × 5) and decanted, and the resulting residue
5-Br om osteven sin e (23). To a stirred solution of 1 (100
mg, 0.26 mmol) in 2 mL of methanesulfonic acid was added
Br (0.16 mL, 0.31 mmol) at room temperature. After 20 min,
2
the reaction mixture was diluted with ether (10 mL × 5) and
was purified by flash chromatography (CH
2
Cl
2
/MeOH satu-
decanted, and the residue was purified by flash chromatog-
rated with NH
mg, 14%) both as colorless solids. 20: H NMR (CD
3
8:2) to afford 21 (38 mg, 47%) and then 20 (11
raphy (CH
mg, 38%) as a colorless solid along with 22 (26 mg, 21%).
NMR (CD
OD) δ 4.12 (s, 2H), 6.92 (s, 1H); 13C NMR (CD
2 2 3
Cl /MeOH saturated with NH 9:1) to afford 23 (46
1
1
3
OD) δ
H
3
1
.55 (d, 2H, J ) 7.1), 6.06 (t, 1H, J ) 7.1), 6.42 (s, 1H), 6.56 (s,
3
3
OD)
1
3
H); C NMR (CD
3
OD) δ 39.4 (e), 105.9 (e), 112.2 (o), 116.5
δ 50.4, 99.9, 110.0, 116.0, 121.1, 124.3, 124.5, 125.8, 128.8,
-
1
(o), 118.1 (o), 127.9 (e), 128.1 (e), 132.8 (e), 133.0 (e), 151.6 (e),
148.6, 163.6; IR (Nujol) 3146, 1684, 1548, 1406, 1185 cm
UV (CH OH) λmax 286 (sh), 242; HRMS, calcd for C11 OBr
(M ) 462.8280, found 462.8284.
;
-
1
1
65.5 (e); IR (Nujol) 3178, 1615, 1480, 1423, 1268 cm ; UV
3
H
8
N
5
3
+
(
CH
3
OH) λmax 260 (sh), 229 nm; HRMS, calcd for C11
H
13
N
5
-
-
+
1
OBr (MH ) 310.0301, found 310.0300. 20‚HCl: H NMR (CD
OD) δ 3.61 (d, 2H, J ) 7.0), 6.14 (t, 1H, J ) 7.0), 6.40 (s, 1H),
3
Deb r om oh ym en ia ld isin e (4) a n d 2,3-Deb r om ost e-
ven sin e (24). A solution of 22 (100 mg, 0.21 mmol) in 10 mL
of 48% HBr was heated at 90 °C in a sealed tube for 4 h. The
solvent was evaporated under reduced pressure, and the
resulting residue was purified by flash chromatography (CH2-
Cl /MeOH saturated with NH 8:2) to afford 24 (10 mg, 21%)
1
3
6
1
λ
.86 (s, 1H); C NMR (CD
22.5, 126.1, 127.7, 128.1, 128.7, 149.1, 164.9, UV (CH
12 5
max 348, 280 (sh) 236 nm. Anal. Calcd for C11H N
3
OD) δ 39.3, 107.1, 111.7, 112.8,
OH)
OBr‚
3
HCl: C, 38.12; H, 3.78; N, 20.20. Found: C, 38.00; H, 3.69;
2
3
1
N, 19.87. 21: H NMR (CD
3
OD) δ 4.10 (s, 2H), 6.10 (s, 1H),
) δ 3.94 (d, 2H, J ) 5.6), 5.44 (bs, 2H),
.06 (s, 1H), 6.71 (s, 1H), 8.22 (t, 1H, J ) 5.6), 10.69 (br, 1H),
as a colorless solid and 4 (20 mg, 40%) as a yellow solid. 24‚
HCl: 1H NMR (CD OD) δ 3.61 (d, 2H, J ) 7.0), 6.13 (t, 1H, J
6
6
1
.78 (s, 1H); (DMSO-d
6
3
) 7.0), 6.40 (d 1H, J ) 2.8), 6.84 (s, 1H), 7.09 (d, 1H, J ) 2.8);
1
3
13
2.67 (bs, 1H); C NMR (CD
3
OD) δ 51.1 (e), 106.3 (e), 113.1
C NMR (CD OD) δ 39.3, 109.6, 112.7, 121.5, 123.7, 124.3,
3
(
(
1
1
o), 113.5 (e), 120.4 (o), 127.4 (e), 129.2 (e) × 2, 130.8 (e), 150.8
e), 164.7 (e); (DMSO-d ) δ 49.5, 103.9, 111.5, 112.2, 118.0,
26.2, 126.9, 127.3, 129.1, 148.8, 161.8; IR (Nujol) 3158, 2356,
685, 1625, 1190 cm-1; UV (CH
OH) λmax 270 (sh), 233, 209
OBr
85.9250. 21‚HCl: H NMR (CD OD) δ 4.14 (s, 2H), 6.13 (s,
H), 6.97 (s, 1H); 13C NMR (CD
OD) δ 50.7 (e), 107.2 (e), 112.2
127.0, 128.4, 129.6, 149.1, 166.1; UV (CH OH) λ
(sh) nm; HRMS, calcd for C H N O (MH ) 230.1040, found
max
265, 225
3
+
6
1
1
12
5
230.1035. Anal. Calcd for C H N O‚HCl: C, 49.73; H, 4.55;
1
1
11
5
1
3
N, 26.36. Found: C, 49.80; H, 4.50; N, 26.50. 4: H NMR
+
nm; HRMS, calcd for C11
3
1
H
10
N
5
2
(MH ) 385.9253, found
(DMSO-d ) δ 3.18 (m, 2H), 3.34 (m, 2H), 6.95 (br, 1H), 6.97
6
1
3
(bs, 1H), 7.89 (bs, 1H), 7.91 (bs, 1H), 10.25 (br, 1H), 11.63 (bs,
3
1H); (CD OD) δ 3.39 (m, 2H), 3.47 (m, 2H), 6.60 (br, 1H), 7.08
3
-1
(
o), 115.3 (o), 118.4 (e), 125.6 (e), 127.3 (e), 127.6 (e), 127.7 (e),
(d, 1H, J ) 2.8); IR (Nujol) 3288, 2473, 1614, 1415, 1123 cm ;
1
3
48.6 (e), 164.3 (e). Anal. Calcd for C11
1.20; H, 2.38; N, 16.54. Found: C, 31.39; H, 2.43; N, 16.40.
H
9
N
5
OBr
2
‚HCl: C,
UV (CH OH) λ
max
344, 268, 230 nm; HRMS, calcd for
3
+
1
C H N O (MH ) 246.0991, found 246.0986. 4‚HCl: H NMR
1
1
12
5
2
Steven sin e (2). Method A: A solution of 19 (100 mg, 0.21
(DMSO-d
6
) δ 3.30 (m, 4H), 6.60 (t, 1H, J ) 2.6), 7.10 (t, 1H, J
mmol) in 2 mL of methanesulfonic acid was heated in an
unsealed flask at 90 °C for 12 h. After cooling, the reaction
mixture was diluted with ether (10 mL × 5) and decanted,
and the resulting residue was dissolved in MeOH (1 mL) and
) 2.6), 8.08 (t, 1H, J ) 4.4), 8.80 (br, 1H), 9.20 (br, 1H), 11.30
(br, 1H), 12.14 (bs, 1H); (D
6.58 (br, 1H, J ) 2.8), 7.15 (d, 1H, J ) 2.8); C NMR (DMSO-
) δ 31.4, 39.2, 109.6, 119.6, 120.0, 122.8, 126.8, 130.2, 154.2,
2
O) δ 3.34 (m, 2H), 3.40 (m, 2H),
13
d
6