The natural alkaloid isoanabasine: Synthesis from 2,3′-bipyridine, efficient resolution with BINOL, and assignment of absolute configuration by Mosher's method

Article abstract of DOI:10.1016/j.tetasy.2005.05.012

A highly efficient and practical resolution of racemic 1- benzylisoanabasine, which was synthesized by reduction of the benzyl salt of 2,3′-bipyridine, has been achieved through molecular complexation with (R)-BINOL or (S)-BINOL to afford pure enantiomers (100% ee). The two enantiomers of the natural alkaloid isoanabasine have been obtained by debenzylation of the corresponding enantiomeric 1-benzylisoanabasine. Using Mosher's method by NMR techniques, the absolute configuration of (-)-isoanabasine has been assigned as the (R)-configuration for the first time. Moreover, an unexpected rotamer ratio of Mosher's amide was observed. The syn-form of two rotamers of (R)-MTPA-(R)-isoanabasine was predominant over the anti-form.

Full text of DOI:10.1016/j.tetasy.2005.05.012

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2141–2147
The natural alkaloid isoanabasine: synthesis from
2,30-bipyridine, efficient resolution with BINOL, and assignment
of absolute configuration by Mosherꢀs method
Chuan-Qing Kang, Yan-Qin Cheng, Hai-Quan Guo, Xue-Peng Qiu and Lian-Xun Gao*
The State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry,
Chinese Academy of Sciences, Graduate School of Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, PR China
Received 18 April 2005; accepted 10 May 2005
Abstract—A highly efficient and practical resolution of racemic 1-benzylisoanabasine, which was synthesized by reduction of the
benzyl salt of 2,30-bipyridine, has been achieved through molecular complexation with (R)-BINOL or (S)-BINOL to afford pure
enantiomers (100% ee). The two enantiomers of the natural alkaloid isoanabasine have been obtained by debenzylation of the cor-
responding enantiomeric 1-benzylisoanabasine. Using Mosherꢀs method by NMR techniques, the absolute configuration of (ꢀ)-iso-
anabasine has been assigned as the (R)-configuration for the first time. Moreover, an unexpected rotamer ratio of Mosherꢀs amide
was observed. The syn-form of two rotamers of (R)-MTPA-(R)-isoanabasine was predominant over the anti-form.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
RO
RO
CO2H
CO2H
OH
OH
OH
OH
The rarely investigated minor natural alkaloid isoanaba-
sine 1 (Fig. 1) has been discovered only in low quantities
in the desert plant Anabasis aphylla L., which can be
found in the northwest of China and Central Asia.1 Re-
cently, much attention has been paid to the synthesis
and biological activities of its skeleton analogues includ-
ing natural and synthetic alkaloids, such as anabasine,
anatabine, cytisine, and some other pyridyl piperi-
dines.2,3 These analogues displayed potential as thera-
peutic agents for peripheral and central nervous
system diseases and other disorders because of their
affinity activities to neuronal nicotinic acetylcholine
receptors (nAChRs) but with lower toxicities than the
well-known alkaloid nicotine.3 Experience has shown
that important biological activities of chiral natural
products are related with their absolute configuration,
so that methods providing single enantiomers were
of utmost importance. However, to the best of our
knowledge, the enantiomers of 1 had never gained as
much attention, no report has ever clarified the absolute
configuration or focused on the preparation of its enan-
tiomer. Limited preliminary studies related to 1 were
5 R = H
(R)-7
(S)-7
6 R = p-Toluoyl
Figure 1. Chiral reagents bearing double acidic groups for resolution.
conducted only on reactions of the pyridine or the piper-
idine ring during the 1970s in the former Soviet Union.4
Herein, we report our approach to the two enantiomers
of 1 via synthesis and resolution, plus assignment of
absolute configuration of 1 by Mosherꢀs method.
N
N
R
1 R = H
2 R = Bn
2. Results and discussion
2.1. Synthesis of racemic alkaloids
*
Syntheses of substituted piperidines have been reported
using a variety of methods including stereoselective
Corresponding author. Tel.: +86 431 526 2259; fax: +86 431 568
5653; e-mail: lxgao@ciac.jl.cn
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.05.012

2142
C.-Q. Kang et al. / Tetrahedron: Asymmetry 16 (2005) 2141–2147
approaches in the development of new drugs.5 However,
those methods involving enantioselective reaction usu-
ally lead to a complex mixture of products, low yield,
or quantitative consumption of the chiral auxiliary
meaning that they are not practical. All reported prepa-
rations of 1 were based on the reduction of 2,30-bipyri-
dine 3 in two approaches. One involved the direct use
of a large amount of reductive metals in low to moderate
yields.6a,b The other method was the oxidation of
2,30-bipyridine prior to catalytic hydrogenation with
Pd/C.6c,d In view of the advantages of a pre-constructed
heterocyclic skeleton upon reduction of bipyridines to
pyridyl piperidines, we have utilized an improved reduc-
tive approach to 1 from 3.
acid 6 and (R)-7 (Fig. 1), were selected as candidates to
screen out better resolving process. As shown in Table 1,
fortunately, (R)-7 could form crystals with one enantio-
mer of 2 in ethanol in a molar ratio of 1:2 [(R)-7:rac-2].
The solvent was then changed with methanol to give a
similar result. Acetonitrile and toluene were not suitable
for the resolution. Varying the ratio of the resolving re-
agent and racemic alkaloid to 1:1 did not afford better
results. Hence, we selected (R)-7 and (S)-7 as resolving
reagents to optimize the resolution process.
Table 1. Screening of resolving reagents by formation of precipitatesa
Alkaloids
Resolving reagents
L-5
L-6
(R)-7
Formation of the piperidine ring of 1 was accomplished
on a large scale by selective reduction of 30-pyridyl
through benzylation on less hindered nitrogen atom of
3 (Scheme 1). Benzyl salt 4, obtained by heating a solu-
tion of 3 and benzyl chloride in acetonitrile, was elabo-
rated to 2 via hydrogenation in the presence of
triethylamine catalyzed with PtO2 or Pd/C. Debenzyl-
ation of 2 was performed by substituent exchange reac-
tion on nitrogen with benzyl chloroformate and then
hydrolysis with 37% HCl to afford racemic 1 in total
67% yield.
1
2
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
+
a Those formed precipitates after mixing were marked with ꢁ+ꢀ,
otherwise with ꢁꢀꢀ.
The typical resolution process employed is as follows.
A solution of (R)-7 (0.5 equiv) and rac-2 (1.0 equiv) in
ethanol was stirred under reflux for 0.5 h. The crystals
formed during cooling to room temperature were col-
lected by filtration and purified by recrystallization.
The resulting crystals were characterized as a 1:1 mole-
cular complex of 2 and (R)-7 by 1H NMR and elemental
analysis.9 Decomposition of the resolving complex with
15% NaOH afforded the (ꢀ)-enantiomer of 2 (100%
BnCl, MeCN
reflux, 4 hr
94%
Cl
N
N
N
N
N
Bn
3
4
2
ee,10 79% yield based on half of the starting rac-2),
20
H2, Et3N, EtOH
which displayed ½aꢁ ¼ ꢀ65.4 (c 2.0, ethanol). All mother
D
PtO2 at 1 atm
or Pd/C at 10 atm
95%
liquids from resolution and recrystallization, enriched
in the (+)-enantiomer of 2, were combined and washed
with 15% NaOH to remove (R)-7. The resulting residues
were applied to form molecular complex with (S)-7
N
Bn
1) CbzCl, toluene
reflux, 15 hr
(0.5 equiv) to afford (+)-2 (100% ee,10 83% yield based
2) 37% HCl
reflux, 6 hr
76%
20
D
N
NH
on half of the starting rac-2), which displayed ½aꢁ
¼
1
þ65.2 (c 2.0, ethanol). Both (R)- and (S)-7 were recovered
in >80% yield by acidification of the corresponding
alkali aqueous solution, respectively (Scheme 2).
Scheme 1.
2.2. Enantiomerically pure alkaloids from resolution
rac-2 + (R)-7
(1.0 equiv : 0.5 equiv)
Molecular complexation, based on molecular recogni-
tion between host and guest molecules directed by ste-
ric complementary action and specific intermolecular
forces (such as hydrogen bonding and second-order
interaction), has proven to be an effective method for
the resolution of organic molecules.7 Optically active
1,10-bi-2-naphthol 7 (BINOL) has shown excellent per-
formances in this field. A few successful examples on
resolution of alkaloids by forming host–guest complex
with resolving reagent bearing double carboxylic or
phenolic groups have been published.8 The selectively
formed diastereomeric salt in well-matched chirality, if
possible, would display marked differences in physical
or chemical properties such as solubility and stability
compared with the alkali guest and acidic host them-
selves or the chirality-mismatched diastereomeric salt.
recycled
(R)-7 (-)-2
(+)-2
(R)-7 (-)-2
(R)-7
(-)-2
(S)-7
100% ee
(+)-2, (-)-2
(S)-7 (+)-2
(0.5 equiv)
recycled
(+)-2
(S)-7
100%ee
(mother liquor)
Scheme 2. Schematic procedure of the resolution.
Unfortunately, no crystals of the molecular complex of
(R)-7 and (ꢀ)-2 suitable for X-ray crystallography struc-
ture analysis have been obtained until now. However, by
1H NMR (Fig. 2), we have observed that the hydroxy
Three readily available chiral reagents bearing double
acidic groups, l-tartaric acid 5, l-O,O0-ditoluoyl tartaric

C.-Q. Kang et al. / Tetrahedron: Asymmetry 16 (2005) 2141–2147
2143
the phenyl group on MTPA moiety of the amides
shielded one of four possible quadrants of the molecule
depending on the specific rotamer and absolute stereo-
chemistry. Furthermore, it was reasonable to assume
that the larger pyridyl group at the 3-position in the
equatorial position was favorable over that at the axial
position. For Mosherꢀs amide isomers 8 and 9 (Scheme
3), one rotamer of 8 in which the axial protons shielded
most at the 2- and 6-positions, should take the same
rotation conformation around the amide bond to that
of 9 in which most-shielded axial protons at 3- and 5-
positions and vice versa.16
Figure 2. Partial 1H NMR spectra of diastereomeric 1:1 mixtures of
(ꢀ)-2 with (R)-7 and (S)-7.
Ph
5
OMe
3
Cl
4
6
Ph
protons in the molecular complex (R)-7Æ(ꢀ)-2 have
shown a downfield shift from d 5.02 [in (R)-7] to d
6.80 ppm, while the protons on benzyl methylene
showed a double doublet peak with a large coupling con-
stant (J = 60.0 and 13.2 Hz). The 1:1 mixture of (S)-7
and (ꢀ)-2 in the same concentration11 to the molecular
complex (R)-7Æ(ꢀ)-2 exhibited great differences and that
the hydroxy protons also showed a downfield shift from
d 5.02 to d 6.50 ppm and the protons on benzyl methy-
lene showed double doublet with small split (J = 18.0
CF
OMe
N
O
N
O
1
CF
3
3
2
(R)-MTPACl
N
+
+
N
O
MeO
CF
3
Ph
anti-8
syn-8
(-)-1
OMe
Ph
CF
N
O
OMe
Ph
N
3
Cl
N
CF
N
O
3
CF
Ph
OMe 3
O
anti-9
syn-9
(S)-MTPACl
1
and 13.2 Hz).12 The larger split in H NMR spectra of
Scheme 3. Conversion of (ꢀ)-1 to corresponding Mosher amides.16
the molecular complex (R)-7Æ(ꢀ)-2 demonstrated the
stronger hindered rotation of benzyl around its C–N
bond, which should come from the stronger binding be-
tween (R)-7 and (ꢀ)-2. These phenomena suggested that
the hydrogen bonding present in both diastereomeric
mixtures, and the stronger interactions in (R)-7Æ(ꢀ)-2
originated from the matching of chirality of the host
and guest in terms of chiral recognition, which was a
fundamental driver to the stereoselectivity of (R)-7 to
(ꢀ)-2 or (S)-7 to (+)-2 during resolution.
1
Based on the above principles and in light of the H
NMR, 13C NMR, H–1H COSY, and H–13C HMQC,
the chemical shifts of the rotamers were assigned and
we easily knew that the minor of 8 and the major of 9
were a pair of rotamers, which had taken the syn-form
while another pair were anti-rotamers (Table 2). Hence,
the molar ratio17 of syn-8 to anti-8 was 1:3.1 similar to
what has generally been reported14,15a–e and that of
syn-9 to anti-9 was unexpectedly 2.8:1, which had been
presented only once in the literature.15f From the differ-
ences of chemical shifts (DdS–R), the axial 20-proton in
the syn-8 and the axial 30-proton in syn-9 should take
syn-form with phenyl on corresponding MTPA moiety
based on the carbonyl plane. Thus, the absolute stereo-
chemistry on stereogenic center of (ꢀ)-1 was deduced to
be an (R)-configuration. The rendered 3D representa-
tions have clearly exhibited the absolute configuration
1
1
Based on the debenzylation procedure described in the
last section, both enantiomers of 2 were converted to
corresponding pure enantiomers of 1, which displayed
a specific rotation of 15.2 (c 1.0, ethanol) with the same
sign to their benzyl precursors.
2.3. Assignment of absolute configuration of (ꢀ)-1
After pioneering work in the 1970s, Mosherꢀs method
has been one of the most useful techniques amongst
those employed to determine the absolute configuration
of organic compounds.13 Hoye and Renner extended
and modified Mosherꢀs method to cyclic secondary
amines, which have a stereogenic center on the ring.14
It has been proven that Hoyeꢀs method was the most effi-
cient technique for the assignment of the absolute
configuration of substituted cycloamines15a–f even
though the inconveniences presented in MTPA amide
synthesis and NMR spectra analysis might limit its
application.15g,h
Table 2. Assignment of chemical shifts (ppm) of protons on piperid-
inyl ring of Mosher amides
Ha syn-8
(minor) (major) (major) (minor)
anti-8
syn-9
anti-9
DdS–R
anti
ꢀ0.76 ꢀ0.03
0.02 0.05
syn
2a
2e
3
2.41
4.10
2.86
1.70
2.05
1.63
1.92
2.57
4.85
2.96
4.83
2.78
1.75
1.84
0.48
1.18
2.91
4.01
3.17
4.08
1.67
1.87
1.76
1.50
1.79
2.62
4.78
2.99
4.80
3.05
1.76
2.02
1.55
1.55
2.30
3.84
1.19 ꢀ0.24
ꢀ0.18 ꢀ0.01
0.29 ꢀ0.18
0.13 ꢀ1.07
0.13 ꢀ0.37
4a
4e
5a
5e
6a
6e
In principle, the most stable conformation of the
Mosher amides derived from the secondary amines
(such as those derived from piperidine) has the trifluo-
romethyl group coplanar with the carbonyl group
syn-periplanar and with the nitrogen anti-periplanar,
ꢀ0.05
0.61
0.07
0.17
a Protons at axial position were marked with ꢁaꢀ and those at equatorial
position marked with ꢁeꢀ.

2144
C.-Q. Kang et al. / Tetrahedron: Asymmetry 16 (2005) 2141–2147
and the shielding circumstance in Mosher amides (Fig.
3).
were measured with a hot-stage microscope XT-4. Ele-
mental analysis was carried out with a VarioEL instru-
ment. TLC was performed on aluminum TLC-layers
Silica gel GF-254. Detection was done by UV light
(254 and 365 nm). All materials were available commer-
cially without further purification. All products were
dried in vacuum prior to further reaction and analysis.
4.1. Preparation of 10-benzyl-2,30-bipyridinium chloride 4
A
stirring solution of 2,30-bipyridine
3 (15.60 g,
0.10 mol) and benzyl chloride (13.8 mL, 0.12 mol) in
acetonitrile (100 mL) was heated to reflux for 4 h. After
being cooled to room temperature, the precipitates were
collected by filtration, washed with acetonitrile (30 mL),
and dried in vacuum to give 26.56 g of 10-benzyl-2,30-
bipyridinium chloride 4 as buff granule (94% yield).
Mp 78–80 ꢂC. 1H NMR (600 MHz, DMSO-d6): d
10.15 (s, 1H), 9.38 (d, 1H, J = 6.0 Hz), 9.27 (d, 1H,
J = 8.4 Hz), 9.79 (d, 1H, J = 4.2 Hz), 8.39 (d, 1H,
J = 7.8 Hz), 8.30 (dd, 1H, J = 7.8, 6.0 Hz), 8.08 (dt,
1H, J = 7.8, 1.8 Hz), 7.68 (d, 2H, J = 6.6 Hz), 7.59 (dd,
1H, J = 7.2, 4.8 Hz), 7.44 (m, 3H), 6.10 (s, 2H). 13C
NMR (150 MHz): d 150.1, 149.6, 144.4, 143.0, 142.5,
138.4, 138.0, 134.3, 129.2, 129.1, 128.9, 128.5, 125.1,
122.0, 63.2. ESI-MS (m/z): [MꢀI]+ 247.0.
Figure 3. 3D representations of rotamers of Mosher amides 8 and 9
from minimizing energy.
3. Conclusions
4.2. Preparation of racemic 1-benzylisoanabasine [i.e., 1-
benzyl-3-(pyridin-2-yl)piperidine] rac-2
In conclusion, we have synthesized the natural alkaloid
isoanabasine 1 via a facile and practical route in which
the intermediate 1-benzylisoanabasine 2 was resolved
to both enantiomers in 100% ee efficiently by forming
a molecular complex with (R)- and (S)-1,10-bi-2-naph-
thol 7. The preliminary investigation to the chiral recog-
nition involving in resolution, studied by 1H NMR,
revealed that the matching of chirality between (R)-7
and (R)-(ꢀ)-2 [or (S)-7 and (S)-(+)-2] strengthened the
hydrogen bonding of the host–guest complex. Enantio-
merically pure 1 was obtained by debenzylation of cor-
responding enantiomeric 2. The absolute configuration
of (ꢀ)-1 was assigned as an (R)-configuration using
Mosherꢀs method by NMR techniques. During the
deduction, it was observed from unexpected rotamer
ratio of Mosher amide derived from (R)-(ꢀ)-1 and (S)-
MTPACl that the syn-rotamer predominated over the
anti-one.
A suspension of 4 (11.28 g, 0.040 mol), triethylamine
(6.2 mL, 0.044 mol), and 10% Pd/C (0.6 g) in ethanol
(100 mL) was stirred in an autoclave under hydrogen
atmosphere at 10 atm for 6–8 h at room temperature.
Upon deflation of the hydrogen, the insoluble species
were removed by filtration through Celite. After
evaporation of the ethanol, the residues were dissolved
in dichloromethane (100 mL) and washed with 10%
NaOH (30 mL · 2) and water. The organic layer was
dried over magnesium sulfate. The solvent was removed
by evaporation to give 9.57 g of 1-benzylisoanabasine 2
as colorless oil (95% yield). 1H NMR (600 MHz,
CDCl3): 8.52 (d, 1H, J = 4.2 Hz), 7.57 (dt, 1H, J = 7.8,
1.8 Hz), 7.35 (d, 2H, J = 7.2 Hz), 7.30 (t, 2H, J = 7.2
Hz), 7.24 (t, 1H, J = 7.2 Hz), 7.16 (d, 1H, J = 7.8 Hz),
7.09 (dd, 1H, J = 7.8, 4.8 Hz), 3.59 (s, 2H), 3.07
(m, 2H), 2.94 (d, 1H, J = 11.4 Hz), 2.28 (t, 1H, J = 10.8
Hz), 2.07 (m, 1H), 1.97 (dt, 1H, J = 12.6, 1.8 Hz),
1.78 (m, 2H), 1.61 (m, 1H). 13C NMR (150 MHz):
d 163.6, 149.1, 138.1, 136.3, 129.2, 128.2, 127.0, 122.0,
121.3, 63.4, 59.0, 53.6, 44.6, 30.5, 25.3. ESI-MS (m/z):
[M+H]+ 253.1.
4. Experiments
Generally, chiral HPLC measurements were carried out
on a Shimadzu Class-VP workstation through CHI-
RALCELꢁ OD-H column (Daicel Chemical Industries,
Ltd) with a UV detector at 254 nm. Optical rotations
were measured on a Perkin Elmer 341LC polarimeter.
ESI-MS measurements were conducted with a LCQ
An alternative hydrogenation using PtO2 as catalyst was
carried out at ambient pressure in a similar procedure.
4.3. Preparation of racemic isoanabasine [i.e., 3-(pyridin-
2-yl)piperidine] rac-1
1
instrument. Unless otherwise noted, H spectra were re-
corded on a Bruker 600 MHz spectrometer and the pro-
ton chemical shifts referenced to TMS as internal
standard at 0.00 ppm. 13C NMR chemical shifts were re-
ported in parts per million relative to the solvent CDCl3
at 77.0 ppm or DMSO-d6 at 39.5 ppm. Melting points
A stirred solution of 2 (2.52 g, 0.010 mol) and benzyl
chloroformate (1.7 mL, 0.012 mol) in toluene (30 mL)
was heated to reflux for 10 h under a nitrogen atmo-
sphere. After being cooled to room temperature, the

C.-Q. Kang et al. / Tetrahedron: Asymmetry 16 (2005) 2141–2147
2145
reaction mixture was filtered through silica gel (200
mesh) and eluted with ethyl acetate (100 mL) to remove
tar and decolorizing. The filtrate was then washed with
saturated NaHCO3 (40 mL · 2) and water. The solvent
was removed by evaporation and the residues dissolved
in a mixture of acetic acid (20 mL) and 37% HCl
(10 mL). The acidic solution was stirred and heated to
reflux for 6 h and the acids then distilled off. The
residues were suspended in 10% NaOH (30 mL) and
extracted with dichloromethane (50 mL · 2). The organic
layer was dried over magnesium sulfate and evaporated
to give 1.23 g of rac-1 as viscous oil (76% yield).
1H NMR (600 MHz, CDCl3): d 8.49 (d, 1H, J = 4.8
Hz), 7.56 (dt, 1H, J = 7.8, 1.8 Hz), 7.12 (d, 1H, J =
7.8 Hz), 7.07 (dd, 1H, J = 7.2, 4.8 Hz), 3.23 (m, 1H), 3.15
(s, 1H), 3.08 (d, 1H, J = 12.8 Hz), 2.86 (m, 2H), 2.66
(dt, 1H, J = 12.2, 2.4 Hz), 2.00 (dd, 1H, J = 12.6,
3.0 Hz), 1.76 (m, 2H), 1.60 (m, 1H). 13C NMR (150
MHz): d 163.4, 149.0, 136.3, 121.6, 121.3, 51.7, 46.1,
45.2, 30.6, 26.1. ESI-MS (m/z): [M+H]+ 163.1.
4.7. Preparation of Mosherꢀs amide (3R,20S)-1-(2-meth-
oxy-2-trifluoromethyl-phenylaceto)-3-(pyridin-2-yl)piperi-
dine anti- and syn-8
To a solution of (R)-(ꢀ)-1 (21.0 mg, 0.12 mmol) and tri-
ethylamine (18.4 lL, 0.13 mmol) in dichloromethane
(2.0 mL) was added dropwise a solution of (R)-(ꢀ)-2-
methoxy-2-trifluoromethyl-phenylacetyl chloride [(R)-
MTPACl, 24.5 lL, 0.13 mmol] in dichloromethane
(1 mL) at 0 ꢂC. The reaction mixture was stirred for
another 4 h at room temperature and diluted with
dichloromethane (5 mL) followed by quenching with
water (3 mL). The organic layer was separated and
washed with water (3 mL) again, dried over magnesium
sulfate, and evaporated to dryness. The residues were
purified with silica-gel chromatography column to give
40.0 mg of rotameric mixture of 8 as oil (86% yield),
which showed a single Rf value on TLC. The molar ratio
1
of syn-8 to anti-8 was 1:3.1 characterized by H NMR.
anti-8: 1H NMR (600 MHz, CDCl3): d 8.53 (d, 1H,
J = 4.5 Hz), 7.62 (d, 2H, J = 7.4 Hz), 7.61 (m, 1H),
7.41 (m, 2H), 7.39 (d, 1H, J = 7.3 Hz), 7.18 (d, 1H,
J = 7.8 Hz), 7.13 (dd, 1H, J = 7.3, 5.0 Hz), 4.83 (d, 1H,
J = 12.9 Hz), 4.01 (d, 1H, J = 13.5 Hz), 3.68 (s, 3H),
2.96 (t, 1H, J = 12.4 Hz), 2.91 (dt, 1H, J = 13.6,
2.8 Hz), 2.78 (tt, 1H, J = 11.4, 3.7 Hz), 1.84 (d, 1H,
J = 12.3 Hz), 1.75 (dt, 1H, J = 12.5, 4.0 Hz), 1.18 (dt,
1H, J = 13.6, 3.1 Hz), 0.48 (m, 1H). 13C NMR
(150 MHz): d 163.7, 161.6, 149.1, 136.5, 134.1, 129.1,
128.1, 126.5, 123.6 (q, J = 288 Hz), 122.0, 121.7, 84.7
(q, J = 24.9 Hz), 55.3, 47.2, 45.1, 43.6, 30.3, 23.5. syn-
8: 1H NMR (600 MHz, CDCl3): d 8.43 (d, 1H,
J = 4.1 Hz), 7.55 (dt, 1H, J = 7.7, 1.5 Hz), 7.44 (dd,
2H, J = 8.0, 3.2 Hz), 7.30 (m, 3H), 7.08 (dd, 1H,
J = 7.3, 5.0 Hz), 6.97 (d, 1H, J = 7.8 Hz), 4.85 (overlap
with a peak of anti-8, 1H), 4.10 (dd, 1H, J = 13.5,
1.7 Hz), 3.85 (s, 3H), 2.86 (tt, 1H, J = 11.8, 3.7 Hz),
2.57 (dt, 1H, J = 13.0, 2.7 Hz), 2.41 (t, 1H,
J = 12.5 Hz), 2.05 (d, 1H, J = 13.4 Hz), 1.92 (dt, 1H,
J = 13.3, 2.5 Hz), 1.70 (m, 1H), 1.63 (m, 1H). 13C
NMR (150 MHz): d 164.0, 161.3, 149.2, 136.5, 133.8,
129.0, 128.2, 126.3, 123.5 (q, J = 288 Hz), 121.8, 121.4,
84.9 (q, J = 24.9 Hz), 56.2, 50.5, 44.8, 42.9, 30.6, 25.2.
ESI-MS (m/z): [M+H]+ 378.3.
4.4. Resolution of racemic 1-benzylisoanabasine to enan-
tiomers (R)-(ꢀ)-2 and (S)-(+)-2
A solution of rac-2 (5.56 g, 0.022 mol) and (R)-1,10-bi-2-
naphthol (R)-7 (3.15 g, 0.011 mol) in ethanol (25 mL)
was stirred at 70 ꢂC for 0.5 h and cooled naturally to
room temperature. After 1 h, the precipitates were
collected by filtration and purified by recrystallization
in ethanol (15 mL). The resultant molecular complex
was suspended in 15% NaOH (12 mL) and extracted
with dichloromethane (30 mL · 3). The extract was
washed with saturated NaHCO3, dried over magnesium
sulfate, and evaporated to dryness to give 2.20 g of
(R)-(ꢀ)-2 (79% yield). All filtrates from the separation
of the crystals and recrystallization were combined and
evaporated to remove ethanol. The residues were
dissolved in dichloromethane (60 mL) and washed with
15% NaOH (15 mL · 2) to remove (R)-7. All aqueous
solutions containing sodium salt of (R)-7 were combined
and acidified with 10% HCl to form precipitates, which
were collected by filtration, washed with water, and
recrystallized in toluene to give 2.57 g of (R)-7 (82%
yield). The organic phase enriched with (S)-(+)-2 was
then dried with magnesium sulfate and evaporated to
give an oil, which was complexed with (S)-7 (3.15 g,
0.011 mol) in ethanol to give 2.31 g of (S)-(+)-2
(83% yield) in similar procedure as described above.
(S)-7 was recovered in 80% yield and the terminal
4.8. Preparation of Mosherꢀs amide (3R,20R)-1-(2-meth-
oxy-2-trifluoromethyl-phenylaceto)-3-(pyridin-2-yl)piperi-
dine anti- and syn-9
residual oil, usually >0% ee, could be used for resolution
The synthesis of 9 was performed by amidation of (R)-
(ꢀ)-1 with (S)-MTPACl to give 41.8 mg of rotameric
mixture (90% yield) in similar procedure to that of 8.
20
D
again. (R)-(+)-2: ½aꢁ ¼ ꢀ65.4 (c 2.0, ethanol), 100% ee
20
[tR(R) = 5.5 min]. (S)-(ꢀ)-2: ½aꢁ ¼ þ65.2 (c 2.0,
D
1
ethanol), 100% ee [tR(S) = 6.6 min].9,10
The molar ratio of syn-9 to anti-9 was 2.8:1. syn-9: H
NMR (600 MHz, CDCl3): d 8.54 (d, 1H, J = 4.5 Hz),
7.58 (d, 2H, J = 7.6 Hz), 7.53 (dt, 1H, J = 7.7, 1.6 Hz),
7.43 (m, 3H), 7.16 (m, 1H), 6.21 (d, 1H, J = 7.8 Hz),
4.78 (dt, 1H, J = 13.0, 1.9 Hz), 4.08 (dt, 1H, J = 13.0,
1.9 Hz), 3.62 (s, 3H), 3.17 (dd, 1H, J = 11.7, 13.5 Hz),
2.62 (dt, 1H, J = 13.0, 2.4 Hz), 1.87 (m, 1H), 1.78 (m,
2H), 1.67 (tt, 1H, J = 11.9, 3.7 Hz), 1.50 (m, 1H). 13C
NMR (150 MHz): d 163.5, 160.3, 147.8, 137.8, 134.5,
129.1, 128.3, 126.8, 123.6 (q, J = 288 Hz), 123.3, 122.3,
84.5 (q, J = 24.9 Hz), 55.4, 49.3, 43.0, 42.8, 29.7, 24.7.
4.5. (R)-(ꢀ)-Isoanabasine (R)-(ꢀ)-1
Prepared from (R)-(ꢀ)-2 in a similar procedure to rac-1
20
from rac-2. ½aꢁ ¼ ꢀ15.2 (c 1.0, ethanol).
D
4.6. (S)-(+)-Isoanabasine (S)-(+)-1
Prepared from (S)-(+)-2 in a similar procedure to rac-1
20
D
from rac-2. ½aꢁ ¼ þ15.2 (c 1.0, ethanol).

2146
C.-Q. Kang et al. / Tetrahedron: Asymmetry 16 (2005) 2141–2147
anti-9: 1H NMR (600 MHz, CDCl3): d 8.64 (d, 1H,
J = 4.5 Hz), 7.76 (dt, 1H, J = 7.7, 1.6 Hz), 7.47 (m,
2H), 7.36 (m, 3H), 7.29 (m, 2H), 4.80 (overlap with a
peak of syn-9, 1H), 3.84 (d, 1H, J = 13.4 Hz), 3.78 (s,
3H), 3.05 (m, 1H), 2.99 (m, 1H), 2.30 (dt, 1H,
J = 12.0, 4.5 Hz), 2.02 (d, 1H, J = 13.4 Hz), 1.76 (over-
lap with a peak of syn-9, 1H), 1.55 (m, 2H). 13C NMR
(150 MHz): d 164.2, 160.8, 147.9, 138.3, 133.9, 129.1,
128.2, 126.4, 123.7 (q, J = 288 Hz), 122.6, 122.5, 84.9
(q, J = 24.9 Hz), 56.1, 46.7, 45.9, 43.5, 30.2, 25.0. ESI-
MS (m/z): [M+H]+ 378.3.
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Acknowledgments
We appreciate greatly Dr. Zheng Bian and Dr. Xiaoli
Baiꢀs valuable suggestions and corrections to this paper.
We also express our thanks to Mr. Yijie Wu and Ms.
Fengying Jing for their help on NMR data acquirement.
1
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9. The integrals of all proton peaks in H NMR spectra and
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rotamers showed two different groups of peaks and one
predominated over another.
17. The rotamer ratios of Mosher amides measured by NMR
after purification were consistent with those before
purification.
16. Both amides were composed of two inseparable rotamers
from hindered rotation around amido C–N bond. The