ACCEPTED MANUSCRIPT
1
4
Tetrahedron
2
3
eq
eq
1
0b), 81.5 (d, J 169.0 Hz, C-8), 66.2 (t, J 144.5 Hz, C-2), 50.2 (d,
J2,2 11.7, J2e,3a 4.1 Hz, H-2 ), 3.90–3.86 (2 H, m, H-4 and H-
ax 2 3 3 ax
J 138.5 Hz, C-6a), 44.4 (d, J 138.5 Hz, C-7), 37.4 (t, J 139.0 Hz,
2 ), 3.09 (1 H, dt, J4,4 ~ J4a,3a 12.4, J4a,3e 3.4 Hz, H-4 ), 2.98
+
3
C-4), 23.4 (t, J 130.0 Hz, C-3); MS (EI, 70 eV) m/z 251 (2, M ),
and 2.96 (1 H and 1 H, two d, J6a,7 8.9 Hz, H-7 and H-6a), 1.62–
ax
eq
2
(
(
07 (22), 206 (20), 178 (13), 153 (10), 152 (100), 150 (11), 138
18), 124 (26), 122 (18), 121 (27), 110 (11), 99 (20), 96 (19), 95
57), 94 (18), 86 (69), 85 (13), 65 (15), 56 (18), 41 (12), 39 (19),
1.55 (1 H, m, H-3 ), 1.46–1.48 (1 H, m, H-3 ); (3Bc) 12.60 (1
3
H, br.s, CO
2
H), 6.76 and 6.48 (1 H and 1 H, two d, J9,10 5.5 Hz,
2
H-9 and H-10), 5.37 (1 H, s, H-10b), 4.07 (1 H, br.dd, J2,2 11.7,
3
eq
eq
ax
28 (12), 27 (11%).
J2e,3a 4.1 Hz, H-2 ), 3.85–3.82 (2 H, m, H-4 and H-2 ), 3.66 (1
2 3 3 ax
Similar procedure carried out in CH Cl2 (150 mL) leads to a
H, dt, J ~ J
11.7, J
2.0 Hz, H-4 ), 2.98 and 2.96 (1 H
4a,3e
2
4,4
4a,3a
3
diastereomeric mixture 3Aa/3Ba in ratio of ~ 95/5 (44 % yield).
When PhMe was used (150 mL, 10 min reflux), only the major
isomer 3Aa (m.p. 182 °C from an i-PrOH/DMF mixture) was
obtained in 27 % yield.
and 1 H, two d, J6a,7 8.9 Hz, H-7 and H-6a), 1.62–1.55 (1 H, m,
a
x
e
q
H-3 ), 1.55−1.51 (1 H, m, H-3 ); δ
С 6
(100.6 MHz, DMSO-d )
(3Ac) 170.2 and 170.1 (CO H and C-6), 140.7 (C-9), 136.1 (C-
10), 91.3 and 88.6 (C-10a and C-8), 84.8 (C-10b), 67.4 (C-2),
2
(
6aRS,7SR,8RS,10aSR,10bRS)-8-Methyl-6-oxo-3,4,6,6a,7,8-
52.3 (br.s, C-7), 51.3 (C-6a), 38.8 (C-4), 25.5 (C-3); (3Bc)
hexahydro-2H-8,10a-epoxy[1,3]oxazino[2,3-a]isoindole-7-
carboxylic acid (3Ab) and (6aRS,7SR,8RS,10aSR,10bSR)-8-
methyl-6-oxo-3,4,6,6a,7,8-hexahydro-2H-8,10a-
2
170.13 and 170.07 (CO H and C-6), 140.8 (C-9), 137.5 (C-10),
91.4 and 88.1 (C-10a and C-8), 83.2 (C-10b), 67.0 (C-2), 53.4
(C-6a), 51.4 (br.s, C-7), 38.2 (C-4), 23.9 (C-3); δ (100.6 MHz,
С
epoxy[1,3]oxazino[2,3-a]isoindole-7-carboxylic acid (3Bb).
Ratio of isomers 3Ab/3Bb ~ 95/5, pale-yellow powder (15.3 g,
2 2
D O/NaOD (5 mol %)) (3Ac) 173.1 and 171.6 (CO H and C-6),
138.6 (C-10), 132.4 (C-9), 86.2 and 81.2 (C-10a and C-8), 83.7
(C-10b), 66.0 (C-2), 51.4 (br.s, C-7), 51.1 (C-6a), 37.0 (C-4),
5
8 %), m.p. 148−155 °C (decomp.); [Found: C, 58.94; H, 5.77;
N, 5.17. C H NO requires C, 58.86; H, 5.70; N, 5.28%]; R
f
+
81
22.7 (C-3); MS (EI, 70 eV) m/z 331 (1, M , for Br ), 329 (1),
303 (3), 301 (5), 286 (7), 285 (7), 284 (7), 250 (10), 232 (25),
230 (25), 201 (11), 199 (11), 175 (13), 173 (11), 137 (18), 99
(12), 86 (100), 85 (18), 65 (15), 56 (24), 41 (18), 39 (19%).
(6aRS,7RS,8SR,10aSR,10bRS)-8-Iodo-6-oxo-3,4,6,6a,7,8-
hexahydro-2H-8,10a-epoxy[1,3]oxazino[2,3-a]isoindole-7-
carboxylic acid (3Ad) and (6aRS,7RS,8SR,10aSR,10bSR)-8-
iodo-6-oxo-3,4,6,6a,7,8-hexahydro-2H-8,10a-
1
3
15
5
(
1
1
50% EtOH/DMF) 0.90; ν -m ax (KBr) 3083, 2985, 1741, 1661,
1
450, 1170, 1075, 872 cm ; δ
H 6
(400 MHz, DMSO-d ) (3Ab)
3
2.22 (1 H, br.s, CO H), 6.62 (1 H, br.d, J9,10 5.7 Hz, H-10), 6.30
2
3
(
1 H, d, J 5.7 Hz, H-9), 5.11 (1 H, s, H-10b), 4.11 (1 H, br.dd,
2,2 12.1, J2e,3e 4.0 Hz, H-2 ), 3.92 (1 H, br.dd, J4,4 13.0, J4e,3e
1
3
0,9
2
eq
2
3
J
eq
2
3
3
5
2
(
1
.0 Hz, H-4 ), 3.88 (1 H, dt, J2,2 ~ J2a,3a 12.1, J2a,3e 2.0 Hz, H-
ax 2 3 3 ax
), 3.08 (1 H, br.dt, J4,4 ~ J4a,3a 13.0, J4a,3e 4.1 Hz, H-4 ), 2.76
3
3
1 H, d, J 8.9 Hz, H-7), 2.55 (1 H, d, J 8.9 Hz, H-6a),
.68−1.55 (1 H, m, H-3 ), 1.51 (3 H, s, Me-8), 1.50−1.45 (1 H,
epoxy[1,3]oxazino[2,3-a]isoindole-7-carboxylic acid (3Bd).
Ratio of isomers 3Ad/3Bd ∼ 80/20, pale brown powder (20.75 g,
55 %), m.p. 178−182 °C (decomp.); [Found: C, 38.39; H, 3.29;
7
,6a
6a,7
ax
eq
3
m, H-3 ); (3Bb) 12.22 (1 H, br.s, CO
5
1
(
2
(
1
m, H-3 ); δ
(
(
2
H), 6.62 (1 H, br.d, J9,10
3
.7 Hz, H-10), 6.25 (1 H, d, J10,9 5.7 Hz, H-9), 5.32 (1 H, s, H-
0b), 4.07 (1 H, br.dd, J 12.1, J
1 H, m, H-4 ), 3.66 (1 H, dt, J2,2 ~ J2a,3a 12.1, J2a,3e 2.5 Hz, H-
N, 3.60. C12
H
12INO
5
requires C, 38.22; H, 3.21; N, 3.71%]; R
f
2
3
eq
-1
3.8 Hz, H-2 ), 3.94−3.88
(50% EtOH/DMF) 0.72; νmax (KBr) 3153, 1747, 1678 cm ; δ
2
,2
2e,3e
3
H
eq
2
3
(400 MHz, DMSO-d
6.57 (1 H and 1 H, two br.d, J9,10 5.7 Hz, H-9 and H-10), 5.18 (1
6 2
) (3Ad) 12.54 (1 H, br.s, CO H), 6.62 and
3
ax
2
3
3
ax
), 2.95 (1 H, br.dt, J4,4 ~ J4a,3a 12.5, J4a,3e 4.5 Hz, H-4 ), 2.74
3 3
2
3
eq
1 H, d, J7,6a 8.9 Hz, H-7), 2.47 (1 H, d, J6a,7 8.9 Hz, H-6a),
H, s, H-10b), 4.12 (1 H, br.dd, J2,2 11.4, J3a,2e 4.4 Hz, H-2 ),
ax eq 2 3
ax
.68−1.55 (1 H, m, H-3 ), 1.52 (3 H, s, Me-8), 1.50−1.45 (1 H,
3.94–3.88 (2 H, m, H-2 and H-4 ), 3.11 (1 H, br.dt, J ~ J
4,4 4a,3a
3 ax
eq
С
(100.6 MHz, D
H), 173.0 (C-6), 138.3 (C-9), 131.4 (C-10), 88.7 and 86.9
C-10a and C-8), 84.4 (C-10b), 65.7 (C-2), 50.9 (C-7), 48.0 (C-
2
O/NaOD (5 mol %)) (3Ab) 175.2
12.7, J4a,3e 3.8 Hz, H-4 ), 2.91 (2 H, s, H-7 and H-6a), 1.68−1.58
ax eq
CO
2
(1 H, m, H-3 ), 1.53−1.47 (1 H, m, H-3 ); (3Bd) 12.54 (1 H,
3
br.s, CO
2
H), 6.77 and 6.58 (1 H and 1 H, two br.d, J9,10 5.7 Hz,
2
6
d
8
4
a), 36.9 (C-4), 22.7 (C-3), 13.4 (Me-8); δ (100.6 MHz, DMSO-
H-9 and H-10), 5.21 (1 H, s, H-10b), 4.12 (1 H, br.dd, J 11.4,
С
2,2
3
eq
ax
eq
6
) (3Ab) 171.4 (CO
2
H), 170.8 (C-6), 139.6 (C-9), 134.5 (C-10),
J3a,2e 4.4 Hz, H-2 ), 3.94–3.88 (2 H, m, H-2 and H-4 ), 3.11 (1
2 3 3 ax
9.6 (C-8), 89.0 (C-10a), 85.2 (C-10b), 66.7 (C-2), 52.4 (C-7),
7.4 (C-6a), 38.1 (C-4), 25.0 (C-3), 15.6 (Me-8); (3Bb) 171.5
H, br.dt, J4,4 ~ J4a,3a 12.7, J4a,3e 3.8 Hz, H-4 ), 3.02 and 3.00 (1
ax
H and 1 H, two d, H-7 and H-6a), 1.68−1.58 (1 H, m, H-3 ),
1.53−1.47 (1 H, m, H-3 ); δ (100.6 MHz, DMSO-d ) (3Ad)
eq
(
CO H), 170.8 (C-6), 139.9 (C-9), 135.7 (C-10), 88.79 (C-8),
2
С
6
8
8.76 (C-10a), 83.1 (C-10b), 66.2 (C-2), 53.5 (C-7), 47.6 (C-6a),
170.3 and 169.7 (CO
(C-10a), 84.0 (C-10b), 66.8 (C-2), 65.5 (C-8), 52.5 (C-6a), 50.9
(C-7), 38.2 (C-4), 24.9 (C-3); (3Bd) 169.7 and 169.4 (CO H and
2
H and C-6), 143.3 (C-10), 134.7 (C-9), 88.9
37.5 (C-4), 23.3 (C-3), 15.6 (Me-8); MS (EI, 70 eV) m/z 265 (3,
+
M ), 221 (18), 220 (10), 219 (11), 204 (10), 167 (11), 166 (94),
2
1
52 (31), 138 (14), 137 (13), 136 (15), 135 (33), 123 (23), 122
C-6), 140.1 (C-10), 135.5 (C-9), 90.7 (C-10a), 84.2 (C-10b), 66.8
(C-2), 65.5 (C-8), 51.7 (C-6a), 50.7 (C-7), 38.2 (C-4), 24.9 (C-3);
(
(
18), 111 (15), 110 (38), 109 (100), 108 (17), 99 (15), 95 (21), 86
91), 79 (11), 58 (10), 56 (16), 55 (13), 54 (15), 53 (17), 43 (24),
δ
С
2
(100.6 MHz, D O/NaOD (5 mol %)) (3Ad) 173.9 and 171.7
41 (11), 28 (19), 27 (17), 26 (16%).
(CO H and C-6), 141.9 (C-10), 131.6 (C-9), 87.0 and 80.8 (C-10a
2
(
6aRS,7RS,8SR,10aSR,10bRS)-8-Bromo-6-oxo-3,4,6,6a,7,8-
and C-8), 83.4 (C-10b), 66.0 (C-2), 53.5 (br.s, C-7), 53.3 (C-6a),
37.0 (C-4), 22.7 (C-3); MS (EI, 70 eV) m/z 377 (1, M ), 332 (12),
+
hexahydro-2H-8,10a-epoxy[1,3]oxazino[2,3-a]isoindole-7-
carboxylic acid (3Ac) and (6aRS,7RS,8SR,10aSR,10bSR)-8-
bromo-6-oxo-3,4,6,6a,7,8-hexahydro-2H-8,10a-
epoxy[1,3]oxazino[2,3-a]isoindole-7-carboxylic acid (3Bc).
Ratio of isomers 3Ac/3Bc ~ 83/17, (13.86 g, 42 %), yellow
powder, m.p. 205−208 °C; [Found: C, 43.59; H, 3.55; N, 4.16;
278 (100), 253 (11), 250 (34), 249 (47), 235 (65), 222 (50), 221
(68), 207 (21), 206 (31), 194 (17), 180 (28), 179 (42), 178 (62),
151 (29), 149 (36), 138 (24), 137 (47), 128 (46), 123 (49), 107
(59), 99 (50), 86 (77), 79 (38), 68 (32), 66 (35), 59 (54), 56 (79),
45 (19), 44 (28), 43 (35), 42 (37%).
Hal, 23.94. C12
H
12BrNO
5
requires C, 43.66; H, 3.66; N, 4.24; Br,
(6aRS,7SR,8RS,10aSR,10bRS)-8-Nitro-6-oxo-3,4,6,6a,7,8-
hexahydro-2H-8,10a-epoxy[1,3]oxazino[2,3-a]isoindole-7-
carboxylic acid (3Ae) and
(6aRS,7SR,8RS,10aSR,10bSR)-8-nitro-6-oxo-3,4,6,6a,7,8-
hexahydro-2H-8,10a-epoxy[1,3]oxazino[2,3-a]isoindole-7-
2
1
1
5
4.20%]; R (50% EtOH/DMF) 0.73; ν (KBr) 3136, 1751,
f
max
-
1
670, 1449, 1162, 1056 cm ; δ
2.60 (1 H, br.s, CO H), 6.73 and 6.55 (1 H and 1 H, two d, J9,10
.5 Hz, H-9 and H-10), 5.18 (1 H, s, H-10b), 4.07 (1 H, br.dd,
H
(600 MHz, DMSO-d ) (3Ac)
6
3
2