New synthesis of all the four stereoisomers of indolizidine 209D and their affinity for nicotinic acetylcholine receptor

Article abstract of DOI:10.1016/S0957-4166(98)00338-3

Both enantiomers of a 2-(4-pentenyl)pyrrolidine derivative 4 (65-90% ee), prepared via the asymmetric dihydroxylation (AD) of terminal olefin 2, underwent a second AD to provide all of the four stereoisomers of indolizidine 209D 1 with enantiomeric enhanc

Full text of DOI:10.1016/S0957-4166(98)00338-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3289–3301
New synthesis of all the four stereoisomers of indolizidine 209D
and their affinity for nicotinic acetylcholine receptor
Hiroki Takahata,a,∗ Minoru Kubota,a Kozue Ihara,a Naoki Okamoto,a Takefumi Momose,a
Nehad Azer,b Amira T. Eldefrawi b and Mohyee E. Eldefrawi b
aFaculty of Pharmaceutical Sciences, Toyama Medical & Pharmaceutical University, Sugitani 2630, Toyama 930-01, Japan
bDepartment of Pharmacology and Experimental Therapeutics, School of Medicine, University of Maryland at Baltimore,
655 West Baltimore Street, Bressler Building, Room 4-029, Baltimore, Maryland 21201, USA
Received 6 August 1998; revised 21 August 1998
Abstract
Both enantiomers of a 2-(4-pentenyl)pyrrolidine derivative 4 (65–90% ee), prepared via the asymmetric di-
hydroxylation (AD) of terminal olefin 2, underwent a second AD to provide all of the four stereoisomers of
indolizidine 209D 1 with enantiomeric enhancement (92–98% ee). The affinity of 1 for nicotinic acetylcholine
receptor was evaluated. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
The indolizidine ring system is found in many biologically active and structurally interesting
alkaloids.1 Among these alkaloids, the poison-dart frog alkaloids,2 3,5-disubstituted3 and 5,8-
disubstituted indolizidines4 appear to represent an atypical and potent class of noncompetitive blockers
for muscle-type and ganglionic nicotinic receptor-channels. However, the biological activity for simpler
5-substituted indolizidines such as indolizidine 209D 12 isolated from skin extracts of neotropical
members of the Dendrobatidae family of frogs has not been investigated (Fig. 1). So far, among four
stereoisomers of 1, the synthesis of (5R,9R)-(−)-5 and (5S,9R)-indolizidine (+)-209D6 have been
reported. In contrast, the synthesis of the other two isomers have never been reported. Accordingly,
we were stimulated to develop a comprehensive synthetic program for these alkaloids. Our interest in
this field has focused on the potential strategies based on the enantiomeric enhancement7 caused by the
two-fold or more application of the Sharpless asymmetric dihydroxylation (AD) reaction.8 In this report,
we describe a new synthesis of all the four stereoisomers of 1 with high enantiomeric purity via an
iterative AD reaction together with their binding test for the nicotinic acetylcholine receptor (nAChR).
∗
Corresponding author. E-mail: takahata@ms.toyama-mpu.ac.jp
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00338-3

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Fig. 1.
2. Results and discussion
As shown in Scheme 1, we considered that the two stereogenic centers in 1 would be installed with
high enantio-enhancement via a sequence of two-fold AD reactions starting with olefins 2 and 4. Recently
we have reported a general route to 2-substituted pyrrolidines starting from N-pentenylphthalimide 2.9
Scheme 1.
According to this procedure, the olefin 2 was successively subjected to (DHQ)2-PYR10 ligand-induced
AD reaction, epoxidation,11 and regioselective cleavage of the resulting epoxide ring of (R)-6 with
homoallylmagnesium bromide in combination with cuprous iodide to give the alcohol 7 in 34% overall
yield from 2. The phthalimide was transformed by a two-step sequence (1. hydrazine; 2. CbzCl/NaOH)
into the N-benzyloxycarbonyl group (N-Cbz) (R)-8. Mesylation of (R)-8 followed by cyclization with
sodium hydride afforded the pyrrolidine (S)-4 in 69% overall yield. In a similar sequence of reactions,
the (DHQD)2-PYR ligand-derived diol (S)-3 was transformed into (R)-4 in 35% overall yield. The
enantiomeric purities of (S)-4 and (R)-4 were estimated to be 65% and 90%, respectively, on the basis of
the ees of (R)-3 and (S)-3 (Scheme 2).12
Scheme 2. (a) AD-mix-α [(DHQ)2-PYR ligand]. (b) (1) (CH3O)3CCH3/PPTS; (2) CH3COBr; (3) K2CO3/MeOH. (c)
Homoallylmagnesium bromide/CuI. (d) (1) NH2NH2; (2) CbzCl/NaOH. (e) (1) MsCl/pyridine; (2) NaH. (f) AD-mix-β
[(DHQD)2-PYR ligand]
With both enantiomers of N-Cbz-pyrrolidines 4 in hand, we turned our attention to the iterative AD to
effect enantiomeric enhancement. The second AD [(DHQ)2-PYR ligand] reaction at the terminal olefin
in (S)-4 was carried out to afford a diastereomeric mixture of the diols [2S-(4S)]-9 and [2S-(4R)]-9.

H. Takahata et al. / Tetrahedron: Asymmetry 9 (1998) 3289–3301
3291
Unfortunately, at this stage the diastereomers of 9 were inseparable. The diastereomeric mixtures of
four diols 9 prepared from (S)-4 and (R)-4 by the AD reaction using two kinds of chiral ligands were
converted into the four epoxides 10 by Sharpless’s one-pot procedure11 in a three-step sequence in good
yields. Only major diastereomers of 10 are shown in Scheme 3.
Scheme 3. (a) (1) (CH3O)3CCH3; (2) CH3COBr; (3) K2CO3/MeOH. (b) pentylmagnesium bromide/CuI. (c) (1) H2/Pd(OH)2;
(2) TrocCl/K2CO3. (d) (1) MsCl/pyridine/cat. DMAP; (2) 10% Cd–Pb/1N NH4OAc
The regioselective cleavage of the resulting epoxide rings in 10 with n-pentylmagnesium bromide
in the presence of cuprous iodide gave the secondary alcohols 1113 in good yields. The N-protecting
group exchange of Cbz for 2,2,2-trichloroethoxycarbonyl (Troc) in 11 was carried out in a two-step
sequence [1. H2/Pd(OH)2; 2. TrocCl/K2CO3] to afford the Troc carbamates 12.13 After mesylation of
[2S-(4R)]-12, N-deprotection of the resulting mesylate with 10% Cd–Pb14 gave desired (5S,9S)-(+)-1

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Fig. 2.
25
25
{[α]D +81.8 (c 0.54; CH2Cl2)} in 46% yield and (5S,9R)-(+)-1 {[α]D +2.83 (c 0.35; CH2Cl2)} in
20% yield. Having obtained this result, a similar sequence with [2S-(4S)]-12, [2R-(4R)]-12, and [2R-
(4S)]-12 provided (5R,9S)-(−)-1 {[α]D −9.55 (c 1.16; CH2Cl2)}, (5S,9R)-(+)-1 {[α]D25 +9.86 (c 0.84;
25
CH2Cl2)}, lit.5a {[α]D +10.1} and (5R,9R)-(−)-1 {[α]D −89.6 (c 1.88; CH2Cl2)}, lit. 6d {[α]D −87.6}
25
25
as the major products together with (5R,9R)-(−)-1 {[α]D −19.3 (c 0.71; CH2Cl2)}, (5R,9R)-(−)-1
25
25
{[α]D −23.7 (c 0.50; CH2Cl2)}, and (5S,9R)-(+)-1 {[α]D +2.33 (c 0.31; CH2Cl2)}, as the minor
products, respectively.
Although the ees of the four stereoisomers of 1 were not determined directly, they were indirectly
calculated by 1H NMR analysis of the corresponding bis-Mosher ester 14 [obtained by esterification of
the diol 9 with (S)-MTPA-Cl followed by debenzyloxycarbonylation of the resulting bis-MTPA ester 13]
as follows. We made the assumption that the second AD reaction of 4 and its enantiomer contaminant
occur with the same ee for both enantiomers. In addition, we expected that the chemical shifts of
methylene protons at C5 of the side chain are the same values in both 14a and 14b as well as in both
14c and 14d by NMR spectroscopy because of the remoteness between the 2 position of the pyrrolidine
and the 4 position of the side chain. Fortunately, the signals of H1 or H2 of 14a,b and H3 or H4 of 14c,d
were readily distinguishable by 1H NMR (500 MHz) (Fig. 2). On the basis of this assumption, the ratio
of 14a,b to 14c,d would refer to the diastereoselectivity of the second AD reaction. In the case of using
two consecutive reactions with AD-mix-α [first AD (65% ee); second AD (68% de, a+b:c+d=84:16)],
the ratio of the four stereoisomers was calculated to be [2S-(4S)]-9:[2S-(4R)]-9:[2R-(4S)]-9:[2R-(4R)]-
9=(82.5×84=6930):(82.5×16=1320):(17.5×84=1470):(17.5×16=280). Accordingly, the ee of (5S,9S)-
(+)-1 derived from [2S(4S)]-9 was calculated to be 92%. Based on a similar calculation, the ees of the
other three major products (5R,9S)-(−)-, (5S,9R)-(+)-, and (5R,9R)-(−)-1 were evaluated to be 94%,
97%, and 98%, respectively.
With all the four homochiral indolizidine 209D 1 isomers in hand, our attention was directed toward
their biological activity. The interaction of the four stereoisomeric indolizidines 1 with binding sites on
carbamylcholine-activated nicotinic acetylcholine receptor (nAChR) channel complex from Torpedo cal-
ifornica electric organ was investigated using the radiolabeled probe, [3H]-thienyl-cyclohexylpiperidine
([3H]-TCP).15 The Ki values for inhibition of [3H]-TCP by 1, compared to those of 3,5-disubstituted
indolizidines 15 and 16 (Fig. 3),3 are shown in Table 1. As a result, the configuration of 1 had little effect
on the ion channel interactions. Although the affinities for the nAChR channel complex of 1 lacking
a substitution at C3 compared to those of 3,5-disubstituted indolizidines 15 and 16 were somewhat
diminished, it was found that the substituent at C3 was not necessarily required for this affinity.
Table 1
Evaluation of the affinity of 1 for the nAChR of Torpedo californica

H. Takahata et al. / Tetrahedron: Asymmetry 9 (1998) 3289–3301
3293
Fig. 3.
In summary, we have developed general access to 5-substituted indolizidines starting from an achi-
ral N-pentenylphthalimide 2. The two stereogenic centers in 1 were constructed with high enantio-
enhancement via a sequence of two-fold AD reactions. In practice, we demonstrated the asymmetric
synthesis of all four stereoisomers of indolizidine 209D 1, of which the affinity for the nAChR channel of
Torpedo californica was tested. Further application of this methodology (the enantiomeric enhancement
via the two-fold or more AD reactions) to asymmetric synthesis of other biologically active compounds
is under investigation.
3. Experimental
3.1. General
Infrared spectra (IR) were measured with a Perkin–Elmer 1600 series FTIR spectrophotometer. Proton
magnetic resonance (1H NMR) spectra were recorded either at 300 MHz on a Varian Gemini-300, or 500
MHz on a Varian Unity-500 with CHCl3 (7.26 ppm) as an internal standard. Carbon-13 NMR spectra
were recorded at 75 or 125 MHz with CDCl3 (77.2 ppm) as an internal standard unless otherwise
specified. Mass spectra (MS) and high resolution mass spectra (HRMS) were measured on a JEOL
JMS D-200 spectrometer. Optical rotations were measured on a JASCO DIP-140 instrument. Column
chromatography was performed on silica gel (Fuji-Division BW-200 or Merck 60 (No. 9385)) with a
medium pressure apparatus using a mixture of ethyl acetate:hexane as eluant unless otherwise specified.
The extracts were dried over Na2SO4 unless otherwise specified.
3.2. (R)-2-(4-Hydroxy-8-noneyl)-1H-isoindole-1,3(2H)-dione (R)-7
To a slurry of CuI (2.50 g, 13.1 mmol) in THF (22.4 ml) was added a 0.658M 3-butenylmagnesium
bromide–THF solution (34.8 ml, 22.9 mmol) at −78°C with stirring. After stirring for 1 h at −45°C, a
solution of (R)-69 (3.0 g, 13.1 mmol) in THF (19 ml) was slowly added. The mixture was gradually
warmed to −35°C, stirred for 3 h, and quenched with sat. NH4Cl. The mixture was diluted with
ether, washed with brine, dried, and evaporated. The residue was chromatographed using 25% ethyl
25
acetate:hexane as eluant to give (R)-7 (1.75 g, 47%) as an oil; [α]D −0.72 (c 2.230; CHCl3); IR cm−1
1
(neat) 3462, 2934, 1771, 1714, 1437, 1398, 1362, 1050, 720; H NMR (500 MHz, CDCl3) δ 1.38–1.56
(6H, m), 1.71–2.07 (5H, m), 3.62–3.65 (1H, m), 3.71 (2H, t, J=7.3 Hz), 4.92–5.01 (2H, m), 5.74–5.82
(1H, m), 7.69–7.72 (2H, m), 7.81–7.84 (2H, m); 13C NMR (125 MHz, CDCl3) δ 25.0, 25.1, 33.8, 34.5,
37.1, 38.1, 71.4, 114.8, 123.3, 132.2, 134.1, 138.8, 168.7; HRMS calcd for C17H21O3N (M+) 287.1521,
found 287.1512.

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3.3. (S)-2-(4-Hydroxy-8-nonenyl)-1H-isoindole-1,3(2H)-dione (S)-7
By a procedure similar to that for the preparation of (R)-7, the reaction of (S)-6 (3.6 g, 15.6 mmol)
with CuI (3.0 g, 15.6 mmol) and 1M homoallylmagnesium bromide–THF (31 ml, 31 mmol) gave (S)-7
(2.38 g, 53%): [α]D25 +1.08 (c 3.10; CHCl3).
3.4. (R)-1-(Benzyloxycarbonyl)aminonon-8-en-4-ol (R)-8
A solution of (R)-7 (223 mg, 0.81 mmol) and hydrazine hydrate (43 µl, 0.89 mmol) in ethanol (2.5
ml) was heated for 6 h at 90°C. To the mixture was added conc. HCl (0.4 ml) at room temperature.
The mixture was filtered through Celite. The filtrate was evaporated to leave the hydrochloride salt. To a
mixture of the salt and 2N NaOH (0.8 ml) was added benzyloxycarbonyl chloride (166 µl, 0.81 mmol) at
0°C. The mixture was stirred for 2 h at rt and extracted with ether. The extract was successively washed
with 20% KHSO4, satd NaHCO3, brine, dried, and evaporated. The residue was chromatographed using
25
13% ethyl acetate:hexane as eluant to give (R)-8 (195 mg, 83%) as an oil; [α]D −0.76 (c 1.145; CHCl3);
IR cm−1 (neat) 3334, 2932, 1699, 1455, 1137, 911; 1H NMR (500 MHz, CDCl3) δ 1.42–1.75 (9H, m),
2.07 (2H, t, J=6.6 Hz), 3.19–3.26 (2H, m), 3.62 (1H, s), 4.93–5.04 (3H, m), 5.10–5.19 (2H, m), 5.80–5.85
(1H, m), 7.28–7.37 (5H, m); 13C NMR (125 MHz, CDCl3) δ 25.0, 26.2, 33.7, 34.2, 37.0, 41.0, 66.5, 71.0,
114.5, 127.9, 128.3, 136.5, 138.5, 156.5; HRMS calcd for C17H25O3N (M+) 291.1835, found 291.1852.
3.5. (S)-1-(Benzyloxycarbonyl)aminonon-8-en-4-ol (S)-8
By a procedure similar to that for the preparation of (R)-8, the reaction of (S)-7 (597 mg, 15.6
mmol) with hydrazine monohydrate (110 µg, 2.3 mmol) in EtOH (3.2 ml) gave the amine, which was
benzyloxycarbonylated with benzyloxycarbonyl chloride (330 µl, 2.3 mmol) and 2N NaOH (2.2 ml) to
25
yield (S)-8 (447 mg, 73%). [α]D +0.86 (c 1.225; CHCl3).
3.6. (S)-N-Benzyloxycarbonyl-2-(4-pentenyl)pyrrolidine (S)-4
To a mixture of (R)-8 (600 mg, 2.1 mmol) and DMAP (38 mg, 0.31 mmol) in pyridine (4.2 ml)
was added methanesulfonyl chloride (0.24 ml, 3.1 mmol) at 0°C. After being stirred for 2 h at the
same temperature, the mixture was diluted with ether and then acidified with 20% KHSO4. The organic
layer was successively washed with H2O and brine, dried, and evaporated. The residue was purified
by chromatography to yield the mesylate (783 mg) as an oil. To a suspension of NaH (109 mg, 2.7
mmol) in THF (9.3 ml) was added a solution of the mesylate (783 mg) in THF (9.3 ml) at 0°C. The
mixture was stirred for 15 h at 50°C, quenched with sat. NH4Cl, and diluted with ether. The mixture
was successively washed with water and brine, then the mixture was dried, and evaporated. The residue
was chromatographed using 10% ethyl acetate:hexane as eluant to give (S)-4 (476 mg, 83%) as an oil;
25
1
[α]D +27.23 (c 1.145; CHCl3); IR cm−1 (neat) 2929, 1700, 1187, 912; H NMR (500 MHz, CDCl3)
δ 1.21–1.44 (3H, m), 1.67–1.71 (2H, m), 1.80–2.12 (5H, m), 3.38–3.51 (2H, m), 3.86 (1H, t, J=4.3 Hz),
4.92–5.03 (2H, m), 5.10–5.20 (2H, m), 5.73–5.85 (1H, m), 7.25–7.40 (5H, m); 13C NMR (125 MHz,
CDCl3) δ 23.2, 24.0, 25.7, 25.8, 30.0, 30.7, 31.8, 33.6, 33.8, 34.0, 34.2, 46.4, 46.7, 57.4, 58.1, 66.6, 66.8,
114.7, 128.0, 128.6, 128.7, 137.3, 139.0, 155.0; HRMS calcd for C17H23O2N (M+) 273.1729, found
273.1715.

H. Takahata et al. / Tetrahedron: Asymmetry 9 (1998) 3289–3301
3295
3.7. (R)-N-Benzyloxycarbonyl-2-(4-pentenyl)pyrrolidine (R)-4
By a procedure similar to that for the preparation of (S)-4, the reaction of (S)-8 (822 mg, 2.8 mmol)
with methanesulfonyl chloride (0.33 ml, 4.2 mmol) in the presence of pyridine (5.8 ml) and DMAP (51
mg, 0.421 mmol) gave the mesylate, which was cyclized with 60% NaH (144 mg, 3.6 mmol) in THF (12
25
ml) to yield (R)-4 (692 mg, 90%); [α]D −39.94 (c 1.25; CHCl3).
3.8. [2S-(4S)]-N-Benzyloxycarbonyl-2-(4,5-dihydroxypentyl)pyrrolidine [2S-(4S)]-9
The pyrrolidine (S)-4 (583 mg, 2.13 mmol) was added to a mixture of AD-mix-α (2.77 g), prepared
from K2OsO4·2H2O (11 mg), (DHQ)2PYR (0.138 g), K3Fe(CN)6 (15.1 g), and K2CO3 (6.35 g) by a
known procedure,10 in tert-BuOH (10.2 ml), and H2O (10.2 ml) at 0°C. After the reaction mixture was
stirred for 24 h at the same temperature, sodium sulfite (3.2 g) was added to the mixture. After stirring for
30 min, the mixture was filtered through a Celite pad. The organic layer was separated, and the aqueous
layer was extracted with ethyl acetate three times. The combined organic layers were washed with brine,
dried, and evaporated. The residue was chromatographed using 90% ethyl acetate:hexane as eluant to
yield a mixture of [2S-(4S)]-9 and [2S-(4R)]-9 (556 mg, 85%) as an oil; IR cm−1 (neat) 3419, 2940,
1682, 1417, 1359, 1107, 698; 1H NMR (500 MHz, CDCl3) δ 1.23–1.49 (5H, m), 1.66 (1H, d, J=6.0 Hz),
1.81–1.92 (4H, m), 3.36–3.68 (7H, m), 3.84 (1H, d, J=17.1 Hz), 5.06–5.16 (2H, m), 7.27–7.35 (5H, m);
13C NMR (125 MHz, CDCl3) δ 22.1, 22.2, 22.3, 23.1, 23.7, 29.9, 30.5, 32.7, 32.8, 33.0, 33.8, 34.5, 34.6,
46.3, 46.6, 57.2, 57.31, 57.7, 57.9, 66.6, 66.7, 66.8, 66.9, 71.8, 72.1, 127.8, 128.0, 128.5, 136.88, 136.93,
155.2; HRMS calcd for C17H25O4N (M+) 307.1783, found 307.1777.
3.9. [2S-(4R)]-N-Benzyloxycarbonyl-2-(4,5-dihydroxypentyl)pyrrolidine [2S-(4R)]-9
By a procedure similar to that for the preparation of [2S-(4S)]-9, the AD reaction of (S)-4 (432 mg,
1.58 mmol) with AD-mix-β [(DHQD)2PYR ligand] (2.05 g) in a mixture of tert-BuOH (7.5 ml) and H2O
(7.5 ml) gave [2S-(4R)]-9 (413 mg, 85%).
3.10. [2R-(4S)]-N-Benzyloxycarbonyl-2-(4,5-dihydroxypentyl)pyrrolidine [2R-(4S)]-9
By a procedure similar to that for the preparation of [2S-(4S)]-9, the AD reaction of (R)-4 (750 mg,
2.7 mmol) with AD-mix-α [(DHQ)2PYR ligand] (3.6 g) in a mixture of tert-BuOH (13 ml) and H2O (13
ml) gave [2S-(4R)]-9 (790 mg, 95%).
3.11. [2R-(4R)]-N-Benzyloxycarbonyl-2-(4,5-dihydroxypentyl)pyrrolidine [2R-(4R)]-9
By a procedure similar to that for the preparation of [2S-(4S)]-9, the AD reaction of (R)-4 (455 mg,
1.66 mmol)) with AD-mix-β [(DHQD)2PYR ligand] (2.1 g) in a mixture of tert-BuOH (7.9 ml) and H2O
(7.9 ml) gave [2R-(4R)]-9 (413 mg, 90%).
3.12. [2S-(4S)]-N-Benzyloxycarbonyl-2-(4,5-epoxypentyl)pyrrolidine [2S-(4S)]-10
A mixture of [2S-(4S)]-9 (556 mg, 1.81 mmol), pyridinium p-toluenesulfonate (PPTS) (36 mg, 14.5
mmol), and trimethyl orthoacetate (276 µl, 2.17 mmol) in CH2Cl2 (2.8 ml) was stirred for 1.5 h at rt.
After the solvent was removed by rotary evaporation, CH2Cl2 (2.8 ml) and acetyl bromide (161 µl,

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2.17 mmol) were successively added to the resulting residue. After vigorous stirring, the mixture was
evaporated. Methanol (6.1 ml) and K2CO3 (325 mg) were successively added to the resulting residue.
After stirring for 2.5 h, the mixture was quenched with satd NH4Cl, and extracted with CH2Cl2. The
extracts were washed with brine, dried, and evaporated. The residue was chromatographed using 18%
ethyl acetate:hexane as eluant to yield [2S-(4S)]-10 (379 mg, 72%) as an oil; IR cm−1 (neat) 2945, 1698,
1
1411, 1187, 769; H NMR (500 MHz, CDCl3) δ 1.26–1.59 (5H, m), 1.62–1.68 (2H, m), 1.71–1.96
(3H, m), 2.32–2.37 (1H, m), 2.60–2.82 (2H, m), 3.26–3.37 (2H, m), 3.75 (1H, br s), 5.09–5.20 (2H, m),
7.30–7.37 (5H, m); 13C NMR (125 MHz, CDCl3) δ 22.5, 22.7, 22.9, 23.0, 23.8, 29.8, 30.6, 32.2, 32.4,
32.6, 33.8, 34.4, 46.2, 46.5, 46.9, 47.0, 52.0, 52.2, 57.1, 57.8, 66.3, 66.5, 127.55, 127.60, 128.2, 136.9,
154.6; HRMS calcd for C17H23O3N (M+) 289.1678, found 289.1681.
3.13. [2S-(4R)]-N-Benzyloxycarbonyl-2-(4,5-epoxypentyl)pyrrolidine [2S-(4R)]-10
By a procedure similar to that for the preparation of [2S-(4S)]-10, [2S-(4R)]-9 (88 mg, 0.29 mmol) was
treated successively with PPTS (0.6 mg, 2.29 µmol), trimethyl orthoacetate (43 µl, 0.34 mmol), acetyl
bromide (25 µl, 0.34 mmol), and K2CO3 (52 mg, 0.38 mmol) to give [2S-(4R)]-10 (62 mg, 75%).
3.14. [2R-(4S)]-N-Benzyloxycarbonyl-2-(4,5-epoxypentyl)pyrrolidine [2R-(4S)]-10
By a procedure similar to that for the preparation of [2S-(4S)]-10, the reaction of [2R-(4S)]-9 (790 mg,
2.57 mmol) with PPTS (5.0 mg, 20 µmol), trimethyl orthoacetate (390 µl, 3.1 mmol), acetyl bromide
(230 µl, 3.1 mmol), and K2CO3 (456 mg, 3.3 mmol) gave [2R-(4S)]-10 (629 mg, 85%).
3.15. [2R-(4R)]-N-Benzyloxycarbonyl-2-(4,5-epoxypentyl)pyrrolidine [2R-(4R)]-10
By a procedure similar to that for the preparation of [2S-(4S)]-10, the reaction of [2R-(4R)]-9 (456 mg,
1.48 mmol) with PPTS (2.5 mg, 10 µmol), trimethyl orthoacetate (230 µl, 1.78 mmol), acetyl bromide
(130 µl, 1.78 mmol), and K2CO3 (266 mg, 1.92 mmol) gave [2R-(4R)]-10 (359 mg, 84%).
3.16. [2S-(4R)]-N-Benzyloxycarbonyl-2-(4-hydroxydecyl)pyrrolidine [2S-(4R)]-11
To a slurry of CuI (147 mg, 0.77 mmol) in THF (1.5 ml) was added a 0.642M pentylmagnesium
bromide–THF solution (2.4 ml, 1.54 mmol) at −78°C with stirring. After stirring for 1 h at −45°C,
a solution of [2S-(4S)]-10 (224 mg, 0.77 mmol) in THF (1.3 ml) was slowly added. The mixture was
gradually warmed to −35°C, stirred for 3.5 h, and quenched with sat. NH4Cl. The mixture was diluted
with ether, washed with brine, dried, and evaporated. The residue was chromatographed using 20% ethyl
acetate:hexane as eluant to give [2S-(4R)]-11 (254 mg, 91%) as an oil; IR cm−1 (neat) 3446, 2928, 1698,
1
1415, 1358; H NMR (500 MHz, CDCl3) δ 0.88 (3H, t, J=8.3 Hz), 1.25–1.49 (16H, m), 1.68 (1H, s),
1.79–1.93 (4H, m), 3.39–3.61 (3H, m), 3.86 (1H, br s), 5.09–5.20 (2H, m), 7.27–7.39 (5H, m); 13C NMR
(125 MHz, CDCl3) δ 14.4, 22.6, 22.9, 23.3, 24.0, 25.9, 29.6, 30.1, 30.8, 32.1, 34.1, 34.9, 37.3, 37.36,
37.42, 37.7, 37.8, 37.9, 46.4, 46.7, 57.4, 57.9, 66.6, 66.7, 66.8, 71.7, 71.8, 127.9, 128.0, 128.4, 137.9,
155.0; HRMS calcd for C22H35O3N (M+) 361.2617, found 361.2617.

H. Takahata et al. / Tetrahedron: Asymmetry 9 (1998) 3289–3301
3297
3.17. [2S-(4S)]-N-Benzyloxycarbonyl-2-(4-hydroxydecyl)pyrrolidine [2S-(4S)]-11
By a procedure similar to that for the preparation of [2S-(4R)]-11, the reaction of [2S-(4R)]-10 (207
mg, 0.715 mmol) with 0.642M pentylmagnesium bromide–THF solution (2.23 ml, 1.43 mmol) in the
presence of CuI (207 mg, 0.72 mmol) gave [2S-(4S)]-11 (251 mg, 90%).
3.18. [2R-(4R)]-N-Benzyloxycarbonyl-2-(4-hydroxydecyl)pyrrolidine [2R-(4R)]-11
By a procedure similar to that for the preparation of [2S-(4R)]-11, the reaction of [2R-(4S)]-10 (553 mg,
1.9 mmol) with 0.642M pentylmagnesium bromide–THF solution (5.92 ml, 3.8 mmol) in the presence
of CuI (361 mg, 1.9 mmol) gave [2R-(4R)]-11 (534 mg, 78%).
3.19. [2R-(4S)]-N-Benzyloxycarbonyl-2-(4-hydroxydecyl)pyrrolidine [2R-(4S)]-11
By a procedure similar to that for the preparation of [2S-(4R)]-11, the reaction of [2R-(4R)]-10
(338 mg, 1.2 mmol) with 0.642M pentylmagnesium bromide–THF solution (3.74 ml, 2.4 mmol) in the
presence of CuI (229 mg, 1.2 mmol) gave [2R-(4S)]-11 (380 mg, 88%).
3.20. [2S-(4R)]-N-(2,2,2-Trichloroethoxycarbonyl)-2-(4-hydroxydecyl)pyrrolidine [2S-(4R)]-12
A mixture of [2S-(4R)]-11 and its minor diastereomer (96 mg, 0.27 mmol) and Pd(OH)2 (9.6 mg) in
MeOH (1.3 ml) was stirred for 15 h under a hydrogen atmosphere. The mixture was filtered through a
Celite pad, and the filtrate was evaporated. To the residue dissolved in a mixture of CH2Cl2 (2.2 ml) and
H2O (0.7 ml) was successively added K2CO3 (75 mg, 0.54 mmol) and 2,2,2-trichloroethyl chloroformate
(TrocCl) (41 ml, 0.30 mmol) at 0°C. After being stirred at rt for 15 h, the mixture was extracted with
CH2Cl2. The extracts were dried and evaporated. The residue was chromatographed using 15% ethyl
acetate:hexane as eluant to give [2S-(4R)]-12 (85 mg, 79%). IR cm−1 (neat) 3446, 2928, 2857, 1717,
1
1411, 1123; H NMR (300 MHz, CDCl3) δ 0.88 (3H, br t, J=6.3 Hz), 1.28–1.50 (15H, m), 1.65–2.01
(5H, m), 3.38–3.57 (4H, m), 3.87–3.90 (1H, m), 4.60–4.90 (2H, m); 13C NMR (75 MHz, CDCl3) δ 14.4,
22.1, 22.5, 22.70, 22.73, 22.9, 23.3, 24.0, 25.8, 25.88, 25.91, 29.6, 30.1, 30.2, 30.7, 32.1, 33.71, 33.9,
34.6, 34.8, 37.3, 37.36, 37.42, 37.6, 37.7, 37.76, 37.82, 37.9, 46.6, 47.1, 56.7, 57.9, 58.0, 58.1, 58.2, 58.3,
71.8, 71.9, 74.8, 75.08, 77.4, 95.9, 153.02, 153.06; HRMS calcd for C17H29O3NCl3 (M+−H) 400.1213,
found 400.1197.
3.21. [2S-(4S)]-N-(2,2,2-Trichloroethoxycarbonyl)-2-(4-hydroxydecyl)pyrrolidine [2S-(4S)]-12
By a procedure similar to that for the preparation of [2S-(4R)]-12, the hydrogenolysis of [2S-(4S)]-
11 and its diastereomer (228 mg, 0.63 mmol) in the presence of Pd(OH)2 (23 mg) in MeOH (3.0 ml)
under a hydrogen atmosphere gave the corresponding amine, which was trichloroethoxycarbonylated
with TrocCl (196 µl, 0.70 mmol) using K2CO3 (174 mg, 1.25 mmol) to yield [2S-(4S)]-12 (218 mg,
86%).
3.22. [2R-(4R)]-N-(2,2,2-Trichloroethoxycarbonyl)-2-(4-hydroxydecyl)pyrrolidine [2R-(4R)]-12
By a procedure similar to that for the preparation of [2S-(4R)]-12, the hydrogenolysis of [2R-(4R)]-
11 and its diastereomer (534 mg, 1.48 mmol) in the presence of Pd(OH)2 (53 mg) in MeOH (7.0 ml)

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H. Takahata et al. / Tetrahedron: Asymmetry 9 (1998) 3289–3301
under a hydrogen atmosphere gave the corresponding amine, which was trichloroethoxycarbonylated
with TrocCl (220 µl, 1.63 mmol) using K2CO3 (408 mg, 2.96 mmol) to yield [2R-(4R)]-12 (513 mg,
86%).
3.23. [2R-(4S)]-N-(2,2,2-Trichloroethoxycarbonyl)-2-(4-hydroxydecyl)pyrrolidine [2R-(4S)]-12
By a procedure similar to that for the preparation of [2S-(4R)]-12, the hydrogenolysis of [2R-(4S)]-
11 and its diastereomer (249 mg, 0.69 mmol) in the presence of Pd(OH)2 (25 mg) in MeOH (3.3 ml)
under a hydrogen atmosphere gave the corresponding amine, which was trichloroethoxycarbonylated
with TrocCl (100 µl, 1.63 mmol) using K2CO3 (190 mg, 1.38 mmol) to yield [2R-(4S)]-12 (215 mg,
77%).
3.24. (5S,9S)-(+)-Indolizidine 209D (5S,9S)-(+)-1 and (5S,9R)-(+)-indolizidine 209D (5S,9R)-(+)-1
Methanesulfonyl chloride (MsCl) (19 µl, 0.25 mmol) was added to a mixture of [2S-(4R)]-12
containing its diastereomer (67 mg, 0.166 mmol), DMAP (2.9 mg, 0.024 mmol) and pyridine (0.3 ml)
at 0°C. After being stirred for 2 h, the mixture was diluted with ether at 0°C and quenched with 20%
KHSO4. The mixture was successively washed with water and brine and then dried and evaporated.
The residue was chromatographed using 10% ethyl acetate:hexane as eluant to give the corresponding
mesylate, which was dissolved in THF (1.3 ml). To the solution were added 1N NH4OAc (1.3 ml) and
10% Cd–Pb couple (221 mg, 1.66 mmol). After being stirred for 15 h, the mixture was basified with
2N NaOH and filtered through Celite. The filtrate was extracted with CH2Cl2 three times. The extracts
were dried with K2CO3 and evaporated. The residue was chromatographed using 1–3% EtOAc:hexane
as eluant to give (5S,9S)-(+)-1 (16 mg, 46%) as the major diastereomer and (5S,9R)-(+)-1 (7 mg, 20%)
as the minor diastereomer.
(5S,9S)-(+)-1; [α]D +81.8 (c 0.540; CH2Cl2), lit.6d [α]D −87.6 (c 1; CH2Cl2); IR cm−1 (neat)
2929, 2857, 2780; 1H NMR (500 MHz, CDCl3) δ 0.89 (3H, t, J=7.1 Hz), 1.13–1.45 (13H, m), 1.62–1.90
(9H, m), 1.97 (1H, q, J=9.0 Hz), 3.27 (1H, td, J=9.0 Hz, 2.10 Hz); 13C NMR (125 MHz, CDCl3) δ 14.3,
20.6, 22.8, 24.9, 26.0, 29.9, 30.7, 31.0, 31.2, 32.0, 34.8, 51.7, 64.1, 65.2; HRMS calcd for C14H27N (M+)
209.2143, found 209.2178.
25
20
25
5a
24
1
(5S,9R)-(+)-1; [α]D +2.83 (c 0.345; CH2Cl2), lit.
[α]D +10.1 (c 0.42; CH2Cl2); H NMR
(500 MHz, CDCl3) δ 0.90 (3H, t, J=7.1 Hz), 1.13–1.19 (1H, m), 1.21–1.86 (19H, m), 2.53 (1H, br
s), 2.65–2.70 (1H, m), 2.86 (1H, t, J=8.3 Hz), 2.91–2.95 (1H, m).
3.25. (5R,9S)-(−)-Indolizidine 209D (5R,9S)-(−)-1 and (5R,9R)-(−)-indolizidine 209D (5R,9R)-(−)-1
By a procedure similar to that for the preparation of (5S,9S)-(+)-1, the reaction of [2S-(4S)]-12
containing its diastereomer (67 mg, 0.166 mmol) with MsCl (62 µl, 0.80 mmol) using pyridine (1.0
ml) and DMAP (10 mg, 0.08 mmol) as bases gave the corresponding mesylate, which was deprotected
with 10% Cd–Pb couple (706 mg, 5.3 mmol) in a mixture of 1N NH4OAc (4.1 ml) and THF (4.1 ml) to
yield (5R,9S)-(−)-1 (48 mg, 43%) and its diastereomer (5R,9R)-(−)-1 (20 mg, 18%).
25
(5R,9S)-(−)-1; [α]D −9.55 (c 1.165; CH2Cl2), lit.5a [α]D24 +10.1 (c 0.42; CH2Cl2); IR cm−1 (neat)
2927, 2856; 1H NMR (500 MHz, CDCl3) δ 0.90 (3H, t, J=7.5 Hz), 1.13–1.20 (1H, m), 1.21–1.84 (19H,
m), 2.45 (1H, br s), 2.65 (1H, q, J=8.1 Hz), 2.83 (1H, td, J=8.8, 3.20 Hz), 2.91–2.95 (1H, m); 13C NMR
(125 MHz, CDCl3) δ 14.3, 19.4, 21.0, 22.9, 23.6, 27.7, 27.8, 29.9, 29.9, 30.7, 31.3, 32.1, 49.0, 55.4, 55.7;
HRMS calcd for C14H27N (M+) 209.2144, found 209.2155.

H. Takahata et al. / Tetrahedron: Asymmetry 9 (1998) 3289–3301
3299
(5R,9R)-(−)-1; [α]D −19.3 (c 0.710; CH2Cl2), lit.6d [α]D −87.6 (c 1; CH2Cl2); H NMR (500
MHz, CDCl3) δ 0.89 (3H, t, J=6.4 Hz), 1.16–1.89 (22H, m), 1.99 (1H, d, J=8.3 Hz), 3.28 (1H, br s).
25
20
1
3.26. (5S,9R)-(+)-Indolizidine 209D (5S,9R)-(+)-1 and (5R,9R)-(−)-indolizidine 209D (5R,9R)-(−)-1
By a procedure similar to that for the preparation of (5S,9S)-(+)-1, the reaction of [2R-(4R)]-12
containing its diastereomer (171 mg, 0.42 mmol) with MsCl (49 µl, 0.63 mmol) using pyridine (0.79
ml) and DMAP (8 mg, 0.06 mmol) as bases gave the corresponding mesylate, which was deprotected
with 10% Cd–Pb couple (554 mg, 4.2 mmol) in a mixture of 1N NH4OAc (3.3 ml) and THF (3.3 ml) to
yield (5S,9R)-(+)-1 (36 mg, 41%) and its diastereomer (5R,9R)-(−)-1 (17 mg, 19%).
25
24
(5S,9R)-(+)-1; [α]D +9.86 (c 0.840; CH2Cl2), lit.5a [α]D +10.1 (c 0.42; CH2Cl2); IR cm−1 (neat)
2927, 2857; 1H NMR (300 MHz, CDCl3) δ 0.87 (3H, t, J=6.6 Hz), 1.07–1.84 (20H, m), 2.38–2.48 (1H,
m), 2.57–2.66 (1H, m), 2.78–2.83 (1H, m), 2.86–2.92 (1H, m); 13C NMR (75 MHz, CDCl3) δ 14.4,
19.7, 21.2, 23.0, 23.6, 27.9, 28.0, 30.0, 30.9, 31.6, 32.2, 49.0, 55.3, 55.7; HRMS calcd for C14H27N (M+)
209.2144, found 209.2124.
(5R,9R)-(−)-1; [α]D −23.65 (c 0.496; CH2Cl2), lit.6d [α]D −87.6 (c 1; CH2Cl2); H NMR (300
25
20
1
MHz, CDCl3) δ 0.88 (3H, t, J=6.6 Hz), 1.05–2.04 (23H, m), 3.27–3.33 (1H, m).
3.27. (5R,9R)-(−)-Indolizidine 209D (5R,9R)-(−)-1 and (5S,9R)-(+)-indolizidine 209D (5S,9R)-(+)-1
By a procedure similar to that for the preparation of (5S,9S)-(+)-1, the reaction of [2R-(4S)]-12
containing its diastereomer (199 mg, 0.49 mmol) with MsCl (57 µl, 0.74 mmol) using pyridine (0.92
ml) and DMAP (9 mg, 0.07 mmol) as bases gave the mesylate, which was deprotected with 10% Cd–Pb
couple (662 mg, 4.97 mmol) in a mixture of 1N NH4OAc (3.9 ml) and THF (3.9 ml) to yield (5S,9R)-
(−)-1 (52 mg, 50%) and its diastereomer (5S,9R)-(+)-1 (15 mg, 15%).
(5R,9R)-(−)-1; [α]D −89.64 (c 1.880; CH2Cl2), lit.6d [α]D −87.6 (c 1; CH2Cl2); IR cm−1 (neat)
2929, 2857, 2780; 1H NMR (300 MHz, CDCl3) δ 0.87 (3H, t, J=6.6 Hz), 1.06–1.49 (13H, m), 1.58–2.00
(10H, m), 3.25 (1H, td, J=8.8 Hz, 2.2 Hz); 13C NMR (75 MHz, CDCl3) δ 14.4, 20.7, 22.9, 25.0, 26.1,
30.0, 30.8, 31.1, 31.3, 32.1, 34.9, 51.8, 64.1, 65.2; HRMS calcd for C14H27N (M+) 209.2143, found
209.2175.
25
20
25
24
1
(5S,9R)-(+)-1; [α]D +2.33 (c 0.305; CH2Cl2), lit.5a [α]D +10.1 (c 0.42; CH2Cl2); H NMR (300
MHz, CDCl3) δ 0.88 (3H, t, J=6.6 Hz), 1.07–2.04 (20H, m), 2.46–2.54 (1H, m), 2.62–2.71 (1H, m),
2.80–2.94 (2H, m).
3.28. Bis-Mosher ester 14a from [2S-(4S)]-9
A solution of [2S-(4S)]-9 (18 mg, 59 µmol) and DMAP (17 mg, 141 µmol) in THF (0.3 ml) was
treated with (S)-Mosher’s chloride (S)-MTPA-Cl, (22.5 µl, 134 µmol) at 25°C, and the reaction mixture
was stirred for 30 h. After dilution with ether, the mixture was washed with 20% KHSO4, water, and satd
NaHCO3, dried and evaporated to afford the bis-Mosher ester 13a (41 mg) of [2S-(4S)]-9. A suspension
of 13a (41 mg) and Pd(OH)2 (4.1 mg) in MeOH (0.3 ml) was stirred under a hydrogen atmosphere for
1
15 h. After filtration of the mixture through a Celite pad, the filtrate was evaporated to 14a. H NMR
(500 MHz, CDCl3) δ 4.57 (0.84H, dd, J=12.2, 2.8 Hz, CH2OMTPA), 4.64 (0.16H, dd, J=12.2, 2.8 Hz,
CH2OMTPA).

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H. Takahata et al. / Tetrahedron: Asymmetry 9 (1998) 3289–3301
3.29. Bis-Mosher ester 14b from [2R-(4S)]-9
By a procedure similar to that for the preparation of bis-Mosher ester 14a, the reaction of [2R-(4S)]-9
(17 mg, 54 µmol) with (S)-MTPA-Cl (27 µl, 160 µmol) and DMAP (26 mg, 210 µmol) in THF (0.29
ml) afforded the bis-Mosher ester 13b, which was deprotected with hydrogenolysis using Pd(OH)2 (4.3
mg) to yield 14b. 1H NMR (500 MHz, CDCl3) δ 4.58 (0.79H, dd, J=12.2, 2.8 Hz, CH2OMTPA), 4.66
(0.21H, dd, J=12.2, 2.8 Hz, CH2OMTPA).
3.30. Bis-Mosher ester 14c from [2S-(4R)]-9
By a procedure similar to that for the preparation of bis-Mosher ester 14a, the reaction of [2S-(4R)]-9
(17 mg, 54 µmol) with (S)-MTPA-Cl (27 µl, 160 µmol) and DMAP (26 mg, 210 µmol) in THF (0.29
ml) afforded the bis-Mosher ester 13c, which was deprotected with hydrogenolysis using Pd(OH)2 (4.3
mg) to yield 14c. 1H NMR (500 MHz, CDCl3) δ 4.58 (0.12H, dd, J=12.2, 2.8 Hz, CH2OMTPA), 4.65
(0.88H, dd, J=12.2, 2.8 Hz, CH2OMTPA).
3.31. Bis-Mosher ester 14d from [2R-(4R)]-9
By a procedure similar to that for the preparation of bis-Mosher ester 14a, the reaction of [2R-(4R)]-9
(19 mg, 60 µmol) with (S)-MTPA-Cl (30 µl, 180 µmol) and DMAP (29 mg, 240 µmol) in THF (0.32
ml) afforded the bis-Mosher ester 13d, which was deprotected with hydrogenolysis using Pd(OH)2 (4.1
mg) to yield 14d. 1H NMR (500 MHz, CDCl3) δ 4.57 (0.18H, dd, J=12.4, 2.8 Hz, CH2OMTPA), 4.65
(0.82H, dd, J=12.2, 2.8 Hz, CH2OMTPA).
3.32. Evaluation of the affinity of 1 for the nAChR of Torpedo californica
3.32.1. Assay protocol
Membranes enriched in nAChR are harvested from homogenates of Torpedo californica electric organs
by differential centrifugation as described in the literature. Binding of [3H]-TCP (sp. act 57.6 Ci/mmole)
to carbamylcoline-activated nAChR is used as a functional binding assay as described by Kats et al.15.
[3H]-TCP is available from the National Institute of Drug Abuse.
3.32.2. Binding assay
Test compounds 1 were dissolved in DMSO to make 100 mM stocks. A second stock of 1 mM
in buffer (50 mM Tris HCl, pH=7.4) is prepared by diluting 10 µl DMSO stock into 1 ml buffer.
Stocks of 100 times the desired test concentrations were prepared by further dilutions with buffer.
25 µg of Torpedo membranes were added to the final volume of 250 µl of buffer containing [3H]-
TCP, 100 µM carbamylcoline, and the test drug 1 at varied concentrations. Nonspecific binding is
determined in presence of 5 mM amantadiene HCl. Bound [3H]-TCP is separated by vacuum filtration
over GF/B filters presoaked in 0.05% polyethyleneimine. Incubation time was 30 s at 23°C. Radioactivity
retained on the filters, after washing with 5 ml ice cold buffer, was quantitated by liquid scintillation.
All tests were performed in triplicate and data reported as % of control. Six concentrations were
selected for each test compound covering a range 1000 times the lowest effective concentration. The
percent inhibition of carbamylcholine stimulated [3H]-TCP binding was plotted vs concentration. Each
compound was tested twice and means +SEM from 6 values at each concentration were used to
generate the concentration–response function. The IC50 values determined graphically from the log

H. Takahata et al. / Tetrahedron: Asymmetry 9 (1998) 3289–3301
3301
concentration–response curves were then used to obtain the inhibitory equilibrium constant (Ki) using
the Cheng–Prusoff equation (Ki=IC50/1+[D]/KD). The results are shown in Table 1.
Acknowledgements
We are grateful to Professor Kinzo Matsumoto, Toyama Medical and Pharmaceutical University, for
many valuable discussions.
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to be 90% ee and 65% ee, respectively (cf. Ref. 7b).
13. Only the major diastereomers are depicted in Scheme 3.
14. Dong, Q.; Anderson, C. E.; Ciufolini, M. A. Tetrahedron Lett. 1995, 36, 5681–5682.
15. Katz, E. J.; Cortes, V. I.; Eldefrawi, M. E.; Eldefrawi, A. T. Toxicol. Appl. Pharmacol. 1997, 146, 227–236.