An efficient approach to?the?asymmetric total synthesis of?(-)-anisodine

Article abstract of DOI:10.1016/j.ejmech.2005.12.001

-Anisodine (l-6,7-epoxy-3-tropyl-α-hydroxytropate), which was isolated from the medicinal plant Scopolia tanguticus Maxim, was the first efficiently prepared using 6-β-acetyltropine as the starting material via a key step of the Sharpless asymmetric dihydroxylation (AD). The intermediate compounds 10 and 11 showed promising cholinergic activity.

Full text of DOI:10.1016/j.ejmech.2005.12.001

European Journal of Medicinal Chemistry 41 (2006) 397–400
http://france.elsevier.com/direct/ejmech
Short communication
An efficient approach to the asymmetric
total synthesis of (–)-anisodine
Junbiao Chang a,b,*, Weilin Xie a, Limin Wang b, Nianchun Ma b, Senxiang Cheng b, Jingxi Xie b
a School of Pharmaceuticals, Xinxiang Medical College, 453003 Xinxiang, China
b The Key Laboratory of Fine Chemical of Henan Province, 450002 Zhengzhou, Henan, China
Received 18 June 2005; received in revised form 6 December 2005; accepted 9 December 2005
Available online 18 January 2006
Abstract
–Anisodine (L-6,7-epoxy-3-tropyl-α-hydroxytropate), which was isolated from the medicinal plant Scopolia tanguticus Maxim, was the first
efficiently prepared using 6-β-acetyltropine as the starting material via a key step of the Sharpless asymmetric dihydroxylation (AD). The inter-
mediate compounds 10 and 11 showed promising cholinergic activity.
© 2006 Elsevier SAS. All rights reserved.
1. Introduction
polamine and its quaternary ammonium salts. In our earlier
work, racemic anisodine was prepared from scopolamine [4].
In order to study the structure-activity relationship of aniso-
dine, it would be desirable to have optical isomers of aniso-
dine. It would also be useful to prepare the related optically
active compounds for the potential studies of chiral drugs,
which are becoming the subject of many research interests [5,
6]. Chemically, transition metal-catalyzed oxidation of carbon–
carbon double bonds has become one of the most commonly
used transformations in organic synthesis [7–11]. Among these
reactions, the osmium-catalyzed dihydroxylation in its asym-
metric version represents a benchmark when it comes to gen-
erality and selectivity [12–20].
The medicinal plant Scopolia tanguticus Maxim is locally
known as “Zhangliushen” in the Qinghai–Xizang Plateau [1].
It has often been used as a folklore medicine for the treatment
of toothache, stomachache and other pains [1]. The close re-
semblance of S. tanguticus Maxim in appearance to Phytolacca
esculenta has caused trouble in the past, since the latter is a
regular article of commerce in traditional medical practice for
the treatment of oedema [1]. When Anisoclus tanguticus was
mistakenly used as P. esculenta, it caused mydriate, hallucina-
tion, and other severe mental disturbances [1]. These led peo-
ple to study their chemical principles of those plants in details.
As a results, (-)anisodine 1 and anisodamine 2, (–)-6(s)-hydro-
xytropane have been isolated (Fig. 1) [2]. The related pharma-
cological studies have showed that (–) anisodine alkaloid pos-
sesses stronger central nervous system action and is a better
antidote against organophosphorous toxicities [3]. Its LD50 is
less than atropine 3, scopolamine 4, and anisodamine 2. It is a
good ganglion-blocking agent, used clinically for the treatment
of motion sickness, migraine and vascular spasm of fundus
oculi [1].
2. Results and discussion
We considered that the stereogenic center of the diol unit in
(–)-anisodine could be installed by the catalytic asymmetric
dihydroxylation of compound 11 (Scheme 1). It is well known
that the chiral ligand [21] plays the most important role in the
Sharpless asymmetric dihydroxylation, since it directs the
stereochemistry of the reaction. Three ligands are commer-
cially available: hydroquinidine 1,4-phthalazinediyl diether
[(DHQD)2PHAL], hydroquinidine 2,5-diphenyl-4,6-pyrimidi-
nediyl diether [(CDHQD)2PYR], and hydroquinidine anthra-
quinone-1,4-diyl diether [(CDHQD)2AQN] [22]. Each of these
has a dihydroquinine analog: (DHQ)2PHAL, (DHQ)2PYR and
(DHQ)2AQN. According to Sharpless [21], the phthalazine
Subsequent research indicates that the quaternary ammo-
nium salts of anisodine had weaker amnestic effect than sco-
* Corresponding author. Fax: +86 371 6751 9822
E-mail address: jbchang@public2.zz.ha.cn (J. Chang).
0223-5234/$ - see front matter © 2006 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2005.12.001

398
J. Chang et al. / European Journal of Medicinal Chemistry 41 (2006) 397–400
ture of potassium osmate, K3[Fe(CN)6], K2CO3 and (DHQ)2-
PHAL, provided the (–)-anisodine in 85% yield and 80% ee.
The enantio selectivity is moderate, but it demonstrates that
low-molecular weight materials can be used as catalyst to reach
the similar enantioselectivities to those obtained in enzymatic
reactions. This is the first example of the total synthesis of the
(–)-enantiomer of anisodine, which is achieved via simple six
steps in overall 21.6% yield.
3. Conclusion
Based on literature results and our own investigations, we
prepared (–)-anisodine using the Sharpless asymmetric dihy-
droxylation (AD) method. Herein, we wish to report our pre-
liminary results on the asymmetric dihydroxylation of dehy-
droxy scopolamine. In particular, the asymmetric
dihydroxylation of 6,7-epoxy-3-(α-methyl-phenylacetoxy)-8-
methyl-bicyclo[3,2,1] azaoctane afforded the diols in high
yield and 80% ee.
Fig. 1. Structures of anisodamine, anisodine, atropine, and scopolamine.
4. Experimental
4.1. General
Melting points were taken on a Reichert microscope and
uncorrected. Infrared spectra were recorded on a PE-580B
1
spectrophotometer. H-NMR spectra data were obtained on a
Bruker-300 spectraspin spectrometer in CDCl3. Mass spectra
were recorded on a Shimadzu ZAB-2B spectrometer. Sillica
gel G and GF254 were used for column chromatography and
TLC.
4.1.1. Synthesis of tropic acid 6
Scheme 1.
Magnesium (25 g) and anhydrous ether (500 ml) were
placed in flask, which was equipped with a stirrer, dropping
funnel and reflux condenser. A mixture of ethyl bromide
(1 ml) and isopropyl chloride (4 ml) was then added. After
the initiation of the reaction by warming, isopropyl chloride
(85 g, 1.41 mol) was then added at such a rate that the mixture
was kept gently refluxed. After all of the chloride had been
added, the mixture was further refluxed for additional one
and half hours.
To above-mentioned solution was added a mixture of phe-
nylacetic acid (60 g, 0.44 mol) and dry benzene (500 ml)
slowly to just maintain the mixture refluxed. After the addition
was completed, the reaction mixture was refluxed until no gas
was evolved. The mixture was then cooled using an ice-bath,
and the dropping funnel was replaced by the side arm of a
distillation flask. Paraformaldehyde (40 g), which had been
dried far two days in a desiccator over P2O5, was placed in a
distillation flask, and heated to 180–200 °C in an oil-bath. The
formaldehyde was carried into the vigorously stirred mixture
by a slow stream of dry nitrogen in the period of 4 hours. After
the reaction mixture was poured into a mixture of concentrated.
H2SO4 (75 ml) and crushed ice (700 g), the mixture was stirred
for 2 hours. The solid material was removed by filtration, the
(PHAL) derivative is most general and leads to high enantios-
electivities for most alkenes; whereas the pyrimidine (PYR)
ligand is best for sterically congested alkenes (especially 1,1′-
disubstituted alkenes) and the anthraquinone (AQN) deriva-
tives is most suitable for almost all alkenes having only alipha-
tic substituents. Armed with this information, we employed the
commercially available AD-mix α with (DHQ)2-PHAL as a
ligand for the Sharpless asymmetric dihydroxylation reaction.
As shown in Scheme 1, the key intermediate 11 can be ea-
sily obtained by straightforward reactions. Phenylacetic acid 5
was converted to chloride 8 through aldol condensation, dehy-
dration and chloride formation. Atropic chloride 8 reacted with
trop-Δ-3α-ol 9 to give 10, which was selectively oxidized to 11
by H2O2/V2O5 oxidation. It is well known that osmium-cata-
lyzed dihydroxylation of olefins is one of most efficient meth-
ods for the preparation of vicinal diols [23]. In 1982, we re-
ported the total synthesis of Anisodine by using N-methyl
morpholine N-oxide (NMO) and osmium tetroxide with low
yield [24]. In this paper, we report efficiently preparing of An-
isodine by using Sharpless asymmetric dihydroxylation(AD)
method in high yield and high ee%. Oxidation of 11 by a stan-
dard procedure with commercially available AD-mix α, a mix-

J. Chang et al. / European Journal of Medicinal Chemistry 41 (2006) 397–400
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

400
J. Chang et al. / European Journal of Medicinal Chemistry 41 (2006) 397–400
Table 1
The percent inhibitory effect on acetylcholine-induced contractions in isolated guinea-pig whole ileal segments
Group
Inhibition (%)
10–5 mol l–1
–2.53 0.95
11.12 3.46**
58.96 13.45**
10–7 mol l–1
2.83 0.86
5.77 1.92**
4.75 1.75
10–6 mol l–1
–1.25 0.32
0.91 .83**
2.63 1.10**
10–4 mol l–1
1.58 0.49
76.38 15.30**
95.13 31.35**
10–3 mol l–1
0.07 0.03
100**
Solvent control group
Compound 10
Compound 11
100**
Note: *P < 0.05, **P < 0.01 vs. that solvent control group. Concentration of acetylcholine = 2.75 × 10–6 mol l–1
.
[9] D.A. Evans, M.R. Wood, B.W. Trotter, T.I. Richardson, J.C. Barrow,
J.L. Katz, Angew. Chem. Int. Ed. Engl. 37 (1998) 2700–2704.
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compounds 10 and 11 had inhibitory function on acetylcholine-
induced contractions in isolated guinea-pig whole ileal seg-
ments.
5.3. Conclusion
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Compound 10 and compound 11 had dose-dependent inhi-
bitory effect on acetylcholine-induced contractions of guinea-
pig whole ileum segments in vitro [25].
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Acknowledgments
[14] (a) R.A. Johnson, K.B. Sharpless, In Catalytic Asymmetric Synthesis,
2nd ed.; I. Ojima, Ed., Wiley-VCH: New York, Weinheim 2000, p.
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The authors acknowledges the Outstanding Scholar Innova-
tion Foundation of Henan Province (0321000900) and the
NSFC (29972009 ; 20342005). J. Chang. thanks for the New
Century Talent Programme of the Ministry of Education,PRC.
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