1960 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 11
Thurston et al.
2H), 4.52 (s, 2H), 6.84 (s, 1H), 7.42-7.49 (m, 5H), 7.53 (s, 1H),
7.66 (d, 1H, J ) 4.4 Hz); 13C NMR (CDCl3) δ 24.2, 29.4, 29.6,
46.6, 53.7, 56.1, 66.1, 66.7, 73.0, 110.6, 111.5, 120.2, 127.5,
127.6, 127.7, 127.8, 128.4, 138.3, 140.6, 147.8, 150.8, 162.4,
164.5; MS (EI) m/z (relative intensity) 394 ([M].+, 68%), 393
(100), 303 (25), 287 (15), 259 (44), 258 (92), 257 (60), 254 (19),
245 (35), 231 (16), 229 (19), 217 (18), 149 (13), 99 (65), 91 (96);
× 50 mL) and washed with saturated aqueous NaHCO3 (2 ×
30 mL) and brine (2 × 20 mL), and the combined aqueous layer
was back-extracted with EtOAc (25 mL). The combined organic
phase was concentrated in vacuo to afford a residue, which
was purified by flash chromatography (MeOH-CHCl3,1:4 v/v)
to give 20 (55 mg, 55%) as a yellow oil: IR (KBr) ν 3600-
3050, 3000-2720, 1610, 1515, 1450, 1275, 1215, 760 cm-1; 1H
NMR (CDCl3) δ 2.02-2.07 (m, 2H, H-1), 2.28-2.36 (m, 2H,
H-2), 3.52-3.88 (m, 3H, H-3, H-11a), 3.92 (s, 3H, OCH3), 6.82
(s, 1H, H-6), 7.28 (br s, 1H, 8-OH), 7.66 (d, 1H, J ) 4.6 Hz,
H-11) and 7.73 (s, 1H, H-9); 13C NMR (CDCl3) δ 24.2, 29.6,
46.7, 53.7, 56.1, 109.3, 115.6, 120.7, 139.9, 144.8, 149.8, 162.2,
164.7; MS (EI) m/z (relative intensity) 246 ([M].+, 100), 217
(22), 177 (8), 150 (13), 122 (15), 107 (5), 89 (9), 70 (30), 45 (9);
HRMS calcd 394.1892 (C23H26O4N2), found 394.1886; [R]D
23
+295.5° (c ) 0.56, CHCl3).
(2S)-N-[4,5-(Met h ylen ed ioxy)-2-n it r oben zoyl]p yr r oli-
d in e-2-ca r boxa ld eh yd e Dieth yl Th ioa ceta l (18). DMF (2
drops) was added to a stirred suspension of 2-nitropiperonylic
acid (17a ) (0.5 g, 2.56 mmol) and oxalyl chloride (0.45 g, 4.46
mmol) in dry THF (15 mL), and stirring continued for 4 h.
Evaporation of the solvent in vacuo gave a yellow residue
which was dissolved in dry THF (10 mL) and added dropwise
over 20 min to a vigorously stirred suspension of (2S)-
pyrrolidine-2-carboxaldehyde diethyl thioacetal (13; 0.58 g,
2.84 mmol), Et3N (0.5 g, 5.0 mmol), and ice-water (0.6 mL)
cooled in an ice bath. The mixture was warmed to room
temperature and stirred for 1.5 h, and the THF was evaporated
in vacuo. The residue was diluted with water (2 × 20 mL),
and this solution was extracted with EtOAc (3 × 20 mL). The
aqueous phase was then adjusted to pH 3 (12 M HCl) and
extracted with EtOAc (2 × 25 mL). The combined organic
phase was washed with water (2 × 25 mL) and brine (2 × 20
mL), dried (Na2SO4), and then concentrated in vacuo to afford
a dark-red oil which was purified by flash chromatography
(EtOAc-hexane, 1:1 v/v; TLC: EtOAc-hexane, 3:2 v/v) to
afford the amide 18 (0.67 g, 66%) as a pale-yellow oil: 1H NMR
(CDCl3) δ 1.22-1.37 (m, 6H), 1.75-2.33 (m, 4H), 2.64-2.86
(m, 4H), 3.23-3.36 (m, 2H), 4.64-4.71 (m, 1H), 4.84 (d, 1H, J
) 4.1 Hz), 6.17 (s, 2H), 6.81 (s, 1H), 7.61 (s, 1H); 13C NMR
(CDCl3) δ 14.9, 15.0, 24.7, 26.2, 26.6, 27.3, 50.3, 52.7, 61.1,
103.5, 105.2, 106.9, 130.6, 139.2, 148.3, 152.7, 166.1; IR (KBr)
ν 3000-2820, 2300, 1640, 1530, 1490, 1440, 1390, 1330, 1250,
1150, 1130, 1040, 940, 870, 810, 750 cm-1; MS (EI) m/z
(relative intensity) 398 ([M].+, 17), 369 (4), 263 (60), 230 (4),
194 (100), 178 (7), 135 (61), 120 (24), 107 (5), 70 (6), 55 (14),
45 (4); HRMS calcd 398.0965 (C17H22O5N2S2), found 398.0970.
(2S)-N-(2-Am in o-5-h yd r oxy-4-m eth oxyben zoyl)p yr r oli-
d in e-2-ca r boxa ld eh yd e Dieth yl Th ioa ceta l (19a ). A solu-
tion of the nitro thioacetal 18 (440 mg, 1.1 mmol) and
SnCl2•2H2O (1.12 g, 5 mmol) in MeOH (30 mL) was refluxed
for 45 min, after which time TLC (EtOAc-hexane, 3:1 v/v)
indicated complete loss of starting material. The solvent was
evaporated in vacuo and the residue cooled to 0 °C and then
quenched with water (2 × 30 mL). The resulting viscous yellow
liquid was triturated with EtOAc (2 × 50 mL) and the mixture
allowed to stir at room temperature for 1 h. The resultant
suspension was filtered through a short bed of Celite which
was rinsed with EtOAc (2 × 25 mL). The combined organic
phase was washed with water (2 × 30 mL) and brine (2 × 25
mL), then dried (Na2SO4), and concentrated in vacuo. The
resulting yellow foam was purified by flash chromatography
(EtOAc-hexane, 4:1 v/v) to give 19a (200 mg, 49%) as a yellow
oil: 1H NMR (CDCl3) δ 1.21-1.32 (m, 6H), 1.66-2.24 (m, 4H),
2.60-2.73 (m, 4H), 3.57-3.63 (m, 2H), 3.81 (s, 3H), 4.67-4.71
(m, 4H), 6.22 (s, 1H), 6.85 (s, 1H), 6.91 (br s, 1H); 13C NMR
(CDCl3) δ 14.9, 15.1, 25.2, 26.4, 27.2, 29.7, 51.7, 53.1, 55.7,
60.9, 99.9, 111.9, 114.4, 137.1, 140.8, 149.3, 169.8; IR (KBr) ν
3600-2800, 1615, 1520, 1440, 1400, 1340, 1270, 1210, 1100,
1030, 970, 875, 840, 760 cm-1; MS (EI) m/z (relative intensity)
370 ([M].+, 13), 246 (4), 235 (17), 167 (11), 166 (100), 149 (5),
138 (13), 75 (6), 55 (4), 43 (5); HRMS calcd 370.1385
(C17H26O3N2S2), found 370.1424.
HRMS calcd 246.1004 (C13H14N2O3), found 246.1041; [R]D
23
+64° (c ) 1.28, CHCl3).
(2S)-N-(2-Am in o-4,5-m et h ylen ed ioxyb en zoyl)p yr r oli-
d in e-2-ca r boxa ld eh yd e Dieth yl Th ioa ceta l (22). The nitro
thioacetal 18 (0.5 g, 1.25 mmol) was dissolved in MeOH (20
mL), and Pd-C (10% w/w, 0.15 g) was added. The mixture
was hydrogenated at room temperature and atmospheric
pressure until no further uptake of H2 was observed (ca. 2 h).
The mixture was filtered through Celite and the filtrate
concentrated in vacuo to afford 22 as a pale-yellow oil (0.39 g,
85%), which was used directly in the next step: IR (neat) ν
3540-3370, 3360-3240, 3080-2770, 1630, 1585, 1540, 1485,
1445, 1400, 1380, 1340, 1260, 1235, 1215, 1150, 1035, 930, 855,
1
830, 700 cm-1; H NMR (CDCl3) δ 1.21-1.40 (m, 6H), 1.62-
2.29 (m, 4H), 2.61-2.79 (m, 4H), 3.55-3.63 (m, 2H), 4.49-
4.60 (br s, 2H), 4.62-4.74 (m, 2H), 5.87 (s, 2H), 6.24 (s, 1H),
6.73 (s, 1H); 13C NMR (CDCl3) δ 14.9, 15.1, 25.2, 26.4, 26.5,
27.2, 51.7, 53.2, 60.9, 98.0, 101.0, 107.8, 111.3, 139.1, 143.1,
150.0, 170.0.
(11a S)-7,8-(Meth ylen ed ioxy)-1,2,3,11a -tetr a h yd r o-5H-
p yr r olo[2,1-c][1,4]ben zod ia zep in -5-on e (23). The method
used to synthesize iso-DC-81 (20) from the amino thioacetal
19a was used (see above). In a typical reaction, 0.38 g (1.03
mmol) of 22 gave 23 (0.18 g, 72%) as a thick yellow syrup: 1H
NMR (CDCl3) δ 1.97-2.18 (m, 2H), 2.07-2.39 (m, 2H), 3.42-
3.85 (m, 3H), 6.04 (s, 2H), 6.75 (s, 1H), 7.43 (s, 1H), 7.65 (d,
1H, J ) 4.6 Hz); 13C NMR (CDCl3) δ 24.1, 29.4, 46.6, 53.5,
102.0, 106.6, 108.5, 121.8, 142.2, 146.3, 150.2, 162.6, 164.2;
MS (EI) m/z (relative intensity) 244 ([M].+, 100%), 243 (83),
215 (14), 175 (20), 148 (22), 120 (18); HRMS calcd 244.0847
(C13H12O3N2), found 244.0911; [R]D +795° (c ) 0.54, CHCl3).
23
3,4-(Eth ylen ed ioxy)ben zoic Acid (25). An aqueous solu-
tion of KMnO4 (13.84 g, 0.084 mol in 300 mL) was added over
40 min to a stirred solution of 3,4-(ethylenedioxy)benzaldehyde
(24; 10 g, 61 mmol) in water (250 mL) at 70-80 °C. After 40
min the reaction mixture was basified (10% aqueous KOH)
and the resulting precipitate collected by filtration and rinsed
with water (3 × 50 mL). The combined filtrate was acidified
(12 M HCl) and the resulting solid separated and dried to
afford 25 as a colorless powder (8.4 g, 76%): mp 136 °C; IR
(KBr) ν 3300-2300, 1680, 1610, 1590, 1500, 1430, 1290, 1260,
1
1240, 1190, 1120, 1070 cm-1; H NMR (Me2SO-d6) δ 4.30 (s,
4H), 6.95 (d, 1H, J ) 8.8 Hz), 7.44 (m, 2H), 12.80 (s, 1H).
4,5-(Eth ylen ed ioxy)-2-n itr oben zoic Acid (26). The nitro
acid 26 was prepared from 25 in 68% yield using the method
of Rault and co-workers:24 mp 210 °C; IR (KBr) ν 3300-2600,
1685, 1520, 1580, 1455, 1420, 1345, 1305, 1275, 1130, 1060,
990, 890 cm-1; 1H NMR (Me2SO-d6) δ 7.55 (s, 1H), 7.25 (s, 1H),
4.35 (s, 4H).
N-[2-Am in o-4,5-(eth ylen ed ioxy)ben zoyl]p yr r olid in e-2-
ca r boxa ld eh yd e Dieth yl Th ioa ceta l (28). The nitro thio-
acetal 27 (0.62 g, 1.5 mmol) was converted into the amino
thioacetal (0.38 g, 66%) using the same SnCl2‚H2O method as
described above for 14a ,b. This material was used directly in
the next step: IR (neat) ν 3660-3100, 3000-2780, 1625, 1580,
(11a S)-7-Hyd r oxy-8-m eth oxy-1,2,3,11a -tetr a h yd r o-5H-
p yr r olo[2,1-c][1,4]ben zod ia zep in -5-on e (20, iso-DC-81). A
suspension of the amino thioacetal 19a (150 mg, 0.4 mmol),
HgCl2 (275 mg, 1.0 mmol), and CaCO3 (0.1 g, 1.0 mmol) in
MeCN-H2O (4:1 v/v, 15 mL) was stirred slowly at room
temperature for 2 h until TLC (EtOAc-hexane, 4:1 v/v)
indicated complete loss of starting material. After evaporation
of the solvent in vacuo, the residue was dissolved in EtOAc (2
1550, 1495, 1390, 1300, 1240, 1160, 1050, 885 cm-1
.
Dioxa n o[2,3-h ]p yr r olo[2,1-c][1,4]b e n zod ia ze p in -5-
on e (29). A suspension of 28 (0.15 g, 0.46 mmol), HgCl2 (0.3
g, 2.2 equiv), and CaCO3 (0.12 g, 2.5 equiv) in MeCN-H2O
(4:1 v/v, 5 mL) was stirred at room temperature for 24 h. The