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399
organic layer separated. The aqueous layer and the filtered so-
lid, which were placed in the original reaction flask, were
warmed on a steam bath for 2 hours until most of the solid
disappeared. After thoroughly cooled, solid materials were fil-
tered and aqueous layer was extracted with ether (2 × 100 ml).
The ether extracts and the organic layer were combined, and
the solvents were removed under reduced pressure until the
volume was reduced to about 100 ml. The mixture was then
cooled for overnight to precipitated tropic acid, which was col-
lected by filtration. The filtrate was concentrated and cooled to
give the second crop of tropic acid after filtration. The crude
tropic acid was heated with benzene (120 ml), cooled, filtered,
and washed with a small amount of cold benzene. The col-
lected materials were air-dried to give tropic acid 6 (51 g,
8 h. After removal of the solvent, aqueous K2CO3 was added
slowly to pH ~ 8.0 and the solution was extracted with chloro-
form (4 × 15 ml). The organic layer was dried over anhydrous
Na2SO4 and evaporated. The resulting crude product was pur-
ified by flash column chromatography on Al2O3 using 3:1:0.01
CHCl3/EtOAc/25% NH3·H2O as an eluent to give 11 (450 mg,
78.9%), which was converted to its hydrochloride salt; m.p.
1
128–130 °C. H-NMR (CDCl3) δ ppm: 1.90–1.95 (m, 2H),
2.87 (s, 3H, –NCH3), 3.23–3.56 (m, 2H), 3.55 (s, 2H), 3.82
(br, s, 2H, 2 × NCH), 5.43 (t, J = 5.12 Hz, 1H, CH–O–), 5.60
(d, J = 1.10 Hz, 1H, =CH), 6.45 (d, J = 1.10 Hz, 1H, =CH),
7.38 (m, 5H, Ar–H). IR (KBr, cm–1): 3080 (=C–H), 1700 (–
O–C=O), 1600 (C=C). m/z (%): 285 (M+, 65), 154 (45), 138
(80), 103 (55), 94 (100).
1
69.6%), m.p. 116–117 °C ([25]; m.p. 116–117 °C). H-NMR
(CDCl3) δ ppm: 3.70–4.30 (m, 4H, CHCH2OH), 7.30 (m, 5H,
Ph). IR (KBr, cm–1): 3399(–OH), 3087(=C–H), 1710(–O–
C=O). MS: m/z(%), M-30(100), 118(55), 104(39), 91(58), 77
(19).
4.1.5. Synthesis of (–)-anisodine 1
To a mixture of 25 ml of t-butyl alcohol and 25 ml of water,
8 g of AD-mix α was added. The solution was stirred at room
temperature to produce two clear phases. The mixture was
cooled to 0 °C, compound 11 (2.85 g, 10 mmol) was then
added at once to give a heterogeneous slurry, which was stirred
at 0 °C for 24 h. After the completion of the reaction (progress
was monitored by TLC), solid sodium sulfite (8 g) was added
to the stirred mixture, which was allowed to warm to room
temperature and to be further stirred for 30 min. Methylene
chloride was added to the reaction mixture and, after separation
of the organic layer, the aqueous phase was further extracted
with methylene chloride. The combined organic layers were
dried over anhydrous Na2SO4 and concentrated. The crude pro-
duct was purified by column chromatography using 90:8:2
CH3OH/CH2Cl2/25% NH3·H2O as an eluent to give (–)-aniso-
dine 1 (2.71 g, 85.1%). Anisodine HBr: [α]D [25] = 22.64
(c = 0.27 CH3OH), ([2] [α]D [15] = 29.46 (c1.0 H2O); [α]D
4.1.2. Synthesis of atropic acid 7
To a solution of KOH (19.0 g) in H2O (40 ml) was added
tropic acid 6 (15.2 g, 91.6 mmol). The reaction mixture was
refluxed for 1 hour, and then cooled to 0 °C. The 35% HCl
(60 ml) was added to give white solid, which was filtered
and washed with a small amount of cold water. Removal of
residue solvents in vacuo afforded 12.2 g of the compound 7
1
(90.0%), m.p. 101–103 °C. H-NMR (CDCl3) δ ppm: 5.2 (d,
J = 1.10 Hz, 1H, =CH), 5.55 (d, J = 1.10 Hz, 1H, =CH), 7.40
(m, 5H, Ph), 11.0 (br, s, 1H, COOH). IR (KBr, cm–1): 3423
(OH), 3063(=C–H), 1699(C=O), 1600(C=C).
4.1.3. Synthesis of 3α-atropoyltropene-6 10
[15] = 12.26 (c0.93 CH3CH2OH)). m.p.
>
192 °C
To a solution of compound 7 (3.7 g, 25 mmol) in dry ben-
zene (20 ml) was added SOCl2 (40 ml). The reaction mixture
was heated at 60 °C for 4 h. After removal of the solvent, the
TsOH salt of trop-Δ6-3α-ol (6 g, 20 mmol) in dry chloroform
(200 ml) was added, and kept at 60 °C for 8 h under N2. After
the completion of the reaction by TLC, solvent was removed
and the resulting crude product was purified by flash column
chromatography on neutral Al2O3 using 3:1:0.01
CHCl3/EtOAc/25% NH3·H2O as an eluent to give 3.5 g
(51.4%) of 10. This compound was acidified with 16% aqu-
eous hydrochloric acid; m.p. 190–191 °C (3α-atropoyltropene
1
(decompose). H-NMR (CDCl3) δ ppm: 1.53 (1H, d, 2-eq-H),
1.66 (1H, d, 4-eq-H), 2.16 (2H, m, 2,4-ax-H), 2.50 (3H, s,
–NCH3), 3.18–3.25 (4H, m, 2 × NCH, 2-OH), 3.30, 3.57
(2H, d, J = 3 Hz, 6,7-H), 3.75 (1H, d, J = 10 Hz, CH2–OH),
4.30 (1H, d, J = 10 Hz, –CH2OH), 4.98 (1H, t, J = 5.4 Hz, 3-
H), 7.31–7.57 (5H, m, Ar–H). IR (KBr, cm–1): 3450 (–OH),
3051 (=C–H), 1730 (–O–CO–), 1600 (C=C). m/z (%): 319
(M+, 25), 154 (20), 138 (100), 108 (40), 94 (60).
5. Cholinergic activity
1
hydrochloride). H-NMR (CDCl3) δ ppm: 2.20 (m, 2H), 2.92
5.1. Method
(s, 3H, NCH3), 2.90–3.41 (m, 2H), 4.28 (br, s, 2H, 2 × NCH),
5.25 (d, J = 5.12 Hz, 1H, CH–O–), 5.85 (d, J = 1.10 Hz, 1H,
=CH), 6.10 (brs, 2H, CH=CH), 6.35 (d, J = 1.10 Hz, 1H,
=CH), 7.35(m, 5H, Ar–H). IR (KBr, cm–1): 3078(=C–H),
1700(O–C=O), 1600(C=C). MS: m/z(%), 269(M+, 60), 138
(50), 103(30), 122(80), 94(100).
Anticholinergic activity was characterized in isolated gui-
nea-pig whole ideal segments. The experiment was divided
into three groups: compound 10 group, compound 11 group,
solvent comparison group (Table 1).
5.2. Results
4.1.4. 3α-acetoxytrop-6β,7β-epoxy-tropane 11
To a solution of compound 10 (538 mg, 2 mmol) in anhy-
drous CH3CN (30 ml) was added V2O5 (100 mg) and 30%
H2O2 (3.5 ml). The reaction mixture was heated at 45 °C for
The frequency and height of contractions were used to cal-
culate the percent inhibitory actions. The results showed that