Chiral synthesis of indolizidines 209D and 167B via asymmetric oxidation of sulfides and sulfoxides

Article abstract of DOI:10.1016/j.tet.2012.04.054

Chiral synthesis of indolizidine natural products (-)-209D and (-)-167B, as well as their antipodes, has been achieved through asymmetric oxidation of racemic thio-substituted indolizidines to the chiral sulfoxides and sulfones followed by Raney nickel re

Full text of DOI:10.1016/j.tet.2012.04.054

Tetrahedron 68 (2012) 5025e5030
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Tetrahedron
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Chiral synthesis of indolizidines 209D and 167B via asymmetric oxidation
of sulfides and sulfoxides
*
Shang-Shing P. Chou , Chien-Jung J. Wu
Department of Chemistry, Fu Jen Catholic University, New Taipei City 24205, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral synthesis of indolizidine natural products (ꢀ)-209D and (ꢀ)-167B, as well as their antipodes, has
been achieved through asymmetric oxidation of racemic thio-substituted indolizidines to the chiral
sulfoxides and sulfones followed by Raney nickel reduction.
Received 29 February 2012
Received in revised form 4 April 2012
Accepted 12 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 21 April 2012
Keywords:
Indolizidines
Asymmetric oxidation
Kinetic resolution
Sulfides
Sulfoxides
1. Introduction
Many indolizidine alkaloids have been isolated from amphibian
skin,1 some of which show interesting biological activities.2 Many
methods have been developed for the synthesis of these novel
compounds.3 We have previously developed a new aza-Diel-
seAlder reaction of thio-substituted 3-sulfolenes with p-toluene-
sulfonyl isocyanate (PTSI) to synthesize piperidine derivatives,4 and
have used this method to prepare some indolizidines and quinoli-
zidines.5 We recently reported that the reaction of thio-substituted
indolizidine 1 with hexylmagnesium bromide at room tempera-
ture, followed by treatment sequentially with acetic acid and
NaBH4/MeOH, gave the vinyl sulfide 2, which was subsequently
converted to (ꢁ)-indolizidine 209D by reacting with RaeNi in
refluxing EtOH (Scheme 1).6 We have now completed the chiral
synthesis of natural products indolizidines (ꢀ)-209D and
(ꢀ)-167B,7 as well as their antipodes via asymmetric oxidation of
racemic sulfides through kinetic resolution.8
Scheme 1.
further subjected to hexylmagnesium bromide at room tempera-
ture, followed by sequential addition of acetic acid and NaBH4/
MeOH, however, did not undergo the expected reaction at the C]O
double bond, but gave a mixture of hexyl phenyl sulfoxide (4),9 the
CeS cleavage product 5,10 and the hexyl-substituted product 611
(Scheme 2). Apparently, the nucleophile attacked the sulfoxide
group of compound 3 to afford the cleavage products 4 and 5, or
reacted with the activated C]C double bond to provide the sub-
stitution product 6. We also tried to activate the C]O group of
compound 3 with BF.3OEt2, but a mixture of products 4e6 was still
obtained.13
Having failed to add the carbon nucleophile to the C]O group of
compound 3, we intended to carry out the chiral oxidation of the
thio group of compound 2. We have previously reported asym-
metric oxidation of 3-(phenylthio)-3-sulfolene to its sulfoxide us-
ing Sharpless oxidation procedures.12 However, the basic nitrogen
atom in compound 2 could be problematic under oxidation con-
ditions. Indeed, attempted oxidation of compound 2 with mCPBA in
CH2Cl2 gave a very low yield of the sulfoxide 7. We then first treated
compound 2 with 1 M sulfuric acid in 95% EtOH, and then with
2. Results and discussion
Before using chiral sulfoxides for our studies, we first oxidized
compound 1 with mCPBA in CH2Cl2 at room temperature to give
a 1:1.4 diastereomeric mixture of sulfoxides 3. Compound 3, when
* Corresponding author. Fax: þ886 2 29023209; e-mail address: chem1004@
mails.fju.edu.tw (S.-S.P. Chou).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.054

5026
S.-S.P. Chou, C.-J.J. Wu / Tetrahedron 68 (2012) 5025e5030
recovered starting material 2. We then gradually increased the
amount of t-BuOOH (entries 5e8) while keeping the reaction at
0 ꢂC for 18 h. It was noted that the amount of sulfoxide (ꢀ)-7a was
greater that of sulfoxide (þ)-7b in all cases. Under the optimum
reaction condition (entry 8), we were able to isolate chiral sulfoxide
(ꢀ)-7a (40%) and chiral sulfone (þ)-8 (41%) by column chroma-
tography. The optical purity of compounds (ꢀ)-7a and (þ)-8 was
determined by chiral HPLC as 99% and 81%, respectively. A pure
compound (þ)-8 was obtained by recrystallization from CH2Cl2/
hexane and its X-ray crystal structure (Fig. 1) indicates the (5S,8aR)
absolute configuration.14 Consequently, compound (ꢀ)-7a must
have the (5R,8aS) configuration.
Scheme 2.
An explanation for the chiral oxidation of compound 2 is shown
in Fig. 2. It was reported that with (þ)-DET as the chiral ligand, the
oxidation of aryl alkyl sulfides proceeds mainly from the Re face to
give the chiral sulfoxides probably due to steric effect.13b In the case
of vinyl sulfide 2, the bicyclic portion would be larger than the
phenyl group. So with (ꢀ)-DET as the chiral ligand, it is proposed
that oxidation of compound 2 occurs faster from the Si face to give
sulfoxide A as the major intermediate. This would explain why
sulfoxide (ꢀ)-7a was formed faster than sulfoxide (þ)-7b due to
steric hindrance of the hexyl group in the latter. Since the amount
of sulfoxide (ꢀ)-7a remained quite steady while the amount of
sulfoxide (þ)-7b diminished with increasing amounts of oxidant
t-BuOOH, we propose that sulfoxide (þ)-7b was oxidized faster
than sulfoxide (ꢀ)-7a to the corresponding sulfones 8. This as-
sumption was proven by subjecting (ꢀ)-7a and (þ)-7b separately to
6 equiv of t-BuOOH at 0 ꢂC for 6 h. Compound (ꢀ)-7a remained
virtually intact while (þ)-7b was almost completely converted to
sulfone (þ)-8. Theoretical calculations in the literature proposed
that the most favorable conformation of vinyl sulfoxides has the
SeO bond syn to the C]C double bond (structures A0 and B0 in
Fig. 2).15 With this preferred conformation, sulfoxide (ꢀ)-7a would
be more difficult to be further oxidized to the corresponding sul-
fone (ꢀ)-8 not only due to steric hindrance of the hexyl group, but
also because the sulfur lone pair electrons of intermediate A0 reside
in the concave face of the bicyclic system.
mCPBA (Scheme 3) to give a 1:1 diastereomeric mixture of sulf-
oxides 7a and 7b (four diastereomers), which could be separated by
column chromatography.
O
O
Ph
Ph
Ph
S
N
S
N
S
N
(a) H2SO4 (1 M, 10 equiv)
95% EtOH
H
+
H
H
(
H
(b) mCPBA (1.1 equiv)
C6H13
C6H13
C6H13
CH2Cl2
2
)-7a (29%)
(
)-7b (29%)
Scheme 3.
Having established that oxidation of compound 2 could be
carried out in the presence of sulfuric acid, we then studied the
Sharpless asymmetric oxidation13 of compound 2. However, the
reaction under 1 M H2SO4 gave only recovered starting material.
We thought that the oxidation might not be compatible with the
aqueous system, so we first treated compound 2 with p-toluene-
sulfonic acid and 4 A molecular sieves in toluene before adding the
chiral oxidizing agents. The ratio of Ti(O-i-Pr)4 to (ꢀ)-DET was kept
at 1:4 while the amount of t-BuOOH (Table 1) was varied. Reaction
of compound 2 with 2 equiv of t-BuOOH for 12 h at ꢀ20 ꢂC (entry 1)
gave only recovered starting material 2; at 0 ꢂC (entry 2) gave
a small amount of products (ꢀ)-7a. The reaction at 25 ꢂC for 12 h
(entry 3) yielded only the racemic sulfone 8, but the reaction at 0 ꢂC
for 18 h (entry 4) produced no sulfone (þ)-8, instead gave an in-
creased amount of (ꢀ)-7a and (þ)-7b together with mostly the
We have also carried out chiral oxidation of (ꢁ)-2 using (þ)-DET
as the catalyst (Scheme 4). The reaction of (ꢁ)-2 with (þ)-DET was
much slower than with (ꢀ)-DET. The TLC showed that a significant
amount of (ꢁ)-2 was unreacted after 18 h. Thus we monitored the
reaction with TLC every 2 h, and found that a reaction time of 36 h
Table 1
Chiral oxidation of compound (ꢁ)-2a
Entry
Ti(O-i-Pr)4 (eq)
(ꢀ)-DET (eq)
t-BuOOH (eq)
Temp (ꢂC)
Time (h)
Ratio ofb
2
7a
7b
8
1
2
3
4
5
6
7
8
3
3
3
3
4
5
6
7
12
12
12
12
16
20
24
28
2
2
2
2
3
4
5
6
ꢀ20
0
25
0
0
0
12
12
12
18
18
18
18
18
100
90
0
60
18
17
6
0
7
0
24
36
49
49
50
0
3
0
17
22
17
16
0
0
0
100c
0
24
17
29
50
0
0
0
a
The reaction conditions were as follows: 2 (1 equiv) in toluene was added to a mixture of TsOH (1.6 equiv) and 4 A molecular sieves. The reaction mixture was stirred at
room temperature for 10 min, and then a solution of Ti(O-i-Pr)4 and (ꢀ)-DET in toluene was added and stirred at rt for 10 min before t-BuOOH was added (different reaction
conditions).
b
The ratio of 2:7a:7b:8 was determined from the 1H NMR of the crude product. The optical purities were not determined. Their absolute configuration was established by X-
ray crystallography and chemical transformations (vide infra).
c
A racemic mixture of 8 was obtained.

S.-S.P. Chou, C.-J.J. Wu / Tetrahedron 68 (2012) 5025e5030
5027
Scheme 5.
Fig. 1. X-ray crystal structure of chiral sulfone (þ)-8.
Fig. 2. Chiral oxidation of (ꢁ)-2 to (ꢀ)-7a and (ꢀ)-8.
Scheme 6.
3. Conclusions
In summary, starting from racemic thio-substituted indolizidine
1, we have achieved a chemoselective addition of Grignard reagents
to the C]O group followed by stereospecific reduction to give cis-
indolizidines 2 and 9, which were then asymmetrically oxidized by
the Sharpless oxidation to afford chiral sulfoxides (ꢀ)-7a and
(ꢀ)-10, and their antipodal chiral sulfones (þ)-8 and (þ)-11, re-
spectively. Treatment of sulfoxides (ꢀ)-7a and (ꢀ)-10 with Raney
nickel provided indolizidines (ꢀ)-209D and (ꢀ)-167B, whereas the
reactions of sulfones (þ)-8 and (þ)-11 with Raney nickel afforded
indolizidines (þ)-209D and (þ)-167B, respectively. We believe this
methodology can be applied to the chiral synthesis of other indo-
lizidines and quinolizidines.
Scheme 4.
was needed for completion. After purification by column chroma-
tography, we were able to isolate chiral sulfoxide (þ)-7a (27%, 97%
ee), [
(c¼4.0, CH2Cl2).
a
]Dþ26.4 (c¼0.33, CH2Cl2) and (ꢀ)-8 (31%, 91% ee), [ ]Dꢀ7.2
a
Compounds (ꢀ)-7a and (þ)-8 were then converted to indolizi-
dines (ꢀ)-209D and (þ)-209D, respectively by treatment with Raney
nickel in refluxing 95% EtOH (Scheme 5). The specific rotation of
indolizidine (ꢀ)-209D obtained from (ꢀ)-7a, [ ]Dꢀ87.5 (c¼0.03,
a
CH2Cl2), was almost identical with that reported for the natural
product, [
a
]Dꢀ87.6 (c¼1, CH2Cl2).16 The specific rotation of indoli-
4. Experimental section
zidine (þ)-209D obtained from (þ)-8, [ ]Dþ77.0 (c¼1.15, CH2Cl2),
a
indicated that compound (þ)-8 has an ee of about 87.9%, which is
probably caused by partial formation of (ꢀ)-8 from (ꢀ)-7a (Fig. 2).
Using a similar method the synthesis of indolizidines (ꢀ)-167B
and (þ)-167B was also achieved (Scheme 6). Sulfoxide (ꢀ)-10 and
sulfone (þ)-11 were obtained in 40% and 41%, respectively. Treat-
ment of sulfoxide (ꢀ)-10 with Raney nickel in refluxing 95% EtOH
4.1. General
Melting points were uncorrected. Infrared spectra were recor-
ded on a FTIR spectrophotometer, nmax in cmꢀ1 1H NMR spectra
.
were recorded on 300 or 600 MHz spectrometers and are reported
in parts per million from tetramethylsilane as the internal standard.
13C NMR spectra were recorded on 75 or 150 MHz spectrometers
with complete proton decoupling. Chemical shifts are reported
for 2 h provided indolizidine (ꢀ)-167B with [ ]Dꢀ106.8 (c¼0.01,
a
CH2Cl2), which was almost identical with that reported for the
natural product, [
a
]Dꢀ106.9 (c¼1.1, CH2Cl2).17 On the other hand,
relative to deuterated solvent signals (CDCl3: d 77.1 ppm). High-
the specific rotation of indolizidine (þ)-167B obtained from (þ)-11,
resolution mass spectra were obtained using the electron ioniza-
tion (EI), fast atom bombardment (FAB) or eletrospray ionozation
(ESI) method in positive ion mode. Chiral HPLC was carried out with
[a
]Dþ93.8 (c¼0.16, CH2Cl2), indicated that compound (þ)-11 has an
ee of about 87.7%.

5028
S.-S.P. Chou, C.-J.J. Wu / Tetrahedron 68 (2012) 5025e5030
a DAICEL CHIRALAAK IA column (0.46 cmꢃ25 cm I.D.) using Hex-
ane/IPA¼19/1 as eluent (flow rate 0.3 mL/mim) with UV detection
at 254 nm.
d 142.7, 142.3, 136.7, 130.5, 129.0, 124.6, 63.3, 60.4, 51.9, 33.3, 31.8,
30.3, 29.5, 25.6, 25.1, 22.6, 21.2, 14.1; IR (ATR, film) v: 3049, 2951,
2928, 2857, 2786, 1044 cmꢀ1; EIMS (rel intensity) m/z 314 (15), 247
(18), 246 (100), 204 (37), 137 (47), 136 (19), 120 (22); HRMS m/z
calcd for C20H29NOS 331.1970, found 331.1971. Compound 7b: 1H
4.2. ( )-7-(Phenylsulfinyl)-2,3,8,8a-tetrahydroindolizin-
5(1H)-one (3)
NMR (CDCl3)
d 7.62e7.57 (2H, m), 7.48e7.43 (3H, m), 6.52 (1H, t,
J¼1.8 Hz), 3.28 (1H, dt, J¼3.0, 8.4 Hz), 2.93e2.86 (1H, m), 2.22 (1H,
ddt, J¼3.6, 6.0, 9.9 Hz), 2.15e2.00 (2H, m), 1.93e1.64 (5H, m),
1.60e1.40 (2H, m), 1.37e1.23 (8H, m), 0.88 (3H, t, J¼6.6 Hz); 13C
To a solution of compound 1 (122 mg, 0.5 mmol) in CH2Cl2
(20 mL) at 0 ꢂC was added mCPBA (145 mg, 70%, 0.55 mmol) in
small portions. The reaction mixture was stirred at room temper-
ature for 17 h, and Na2S2O3 (0.5 g), and H2O (10 mL) were added
sequentially. After stirring for 10 min, the solvent was removed
under vacuum, and saturated sodium bicarbonate was added. The
mixture was extracted with ethyl acetate, dried (MgSO4), and
evaporated. The crude product was purified by flash chromatog-
raphy on basic alumina using ethyl acetate/hexane (4: 1) as eluent
to give an approximately 1:1.4 diastereomeric mixture of sulfoxides
NMR (CDCl3) d 142.7, 141.3, 132.5, 131.1, 129.2, 125.4, 63.3, 60.5, 51.8,
33.3, 31.7, 30.4, 29.5, 29.1, 24.9, 22.5, 21.2, 14.0; IR (ATR, film) v:
3060, 2956, 2928, 2862, 2797, 1723, 1689, 1087 cmꢀ1; FABMS (rel
intensity) m/z 332 (MþH,100), 331 (13), 330 (46), 314 (74), 206 (47),
70 (88); FAB-HRMS m/z calcd for C20H29NOS 331.1970, found
331.1972.
4.5. (L)-(5R,8aS)-5-Hexyl-7-(phenylsulfinyl)-1,2,3,5,8,8a-
hexahydroindolizine ((L)-7a) and (D)-(5S,8aR)-5-hexyl-7-
(phenylsulfonyl)-1,2,3,5,8,8a-hexahydroindolizine ((D)-8)
3 (113 mg, 87%) as a colorless oil: 1H NMR (CDCl3)
d 7.62e7.56 (4H,
m), 7.52e7.47 (6H, m), 6.65 (1H, d, J¼2.7 Hz), 6.61 (1H, d, J¼2.7 Hz),
3.71e3.56 (4H, m), 3.45e3.33 (2H, m), 2.81 (1H, dd, J¼4.6, 16.6 Hz),
2.37 (1H, dd, J¼4.6, 16.6 Hz), 2.20e2.12 (2H, m), 2.03e1.93 (2H, m),
A mixture of compound 2 (50 mg, 0.158 mmol), TsOH (43 mg,
0.253 mmol) and powdered 4 A molecular sieves (0.5 g) in toluene
(2 mL) was stirred at room temperature for 10 min. A solution of
Ti(O-i-Pr)4 (0.33 mL, 1.106 mmol) and (ꢀ)-DET (0.759 mL,
4.424 mmol) in tolune (2 mL) was added, stirred for 10 min, and
then cooled in an ice bath before t-BuOOH (0.119 mL, 80%,
0.948 mmol) was added. The mixture was stirred at 0 ꢂC for 18 h,
and then Na2S2O3 (0.5 g) and H2O (2 mL) were added sequentially.
After stirring for 20 min, the solvent was removed under vacuum,
and saturated sodium bicarbonate solution (20 mL) was added. The
mixture was extracted with ethyl acetate (3ꢃ20 mL). Since severe
emulsion resulted, we used centrifugation to separate the aqueous
and organic layers. The combined organic layers were then dried
(MgSO4) and evaporated. The crude product was purified by flash
chromatography on basic alumina (deactivated with 10% water)
using ethyl acetate/hexane (1:6) as eluent to give compound (ꢀ)-7a
(21 mg, 40%) and compound (þ)-8 (23 mg, 41%). (ꢀ)-7a: a colorless
1.87e1.64 (4H, m), 1.59e1.45 (2H, m); 13C NMR (CDCl3)
d 161.4,
161.0, 155.7 (ꢃ2), 141.4, 141.1, 132.2, 131.6, 129.8, 129.6, 126.4, 125.5,
124.6, 124.3, 57.1, 57.0, 44.3, 44.2, 33.2 (ꢃ2), 28.4, 24.6, 23.1, 23.0; IR
(ATR, film) v: 3060, 2973, 2951, 2881, 1656, 1603, 1444, 1050 cmꢀ1
;
EIMS (rel intensity) m/z 261 (5), 244 (15),136 (12), 91 (7), 77 (21), 70
(100), 67 (18); HRMS m/z calcd for C14H15NO2S 261.0823, found
261.0822.
4.3. Reaction of compound 3 to give products 4, 5 and 6
To a solution of compound 3 (52 mg, 0.20 mmol) in THF (3 mL) at
room temperature was added slowly another solution of
C6H13MgBr (0.80 mmol) in THF (5 mL). The reaction mixture was
stirred at room temperature for 6 h, and then cooled in an ice bath.
Acetic acid (0.025 mL) was then added dropwise. The mixture was
stirred for 10 min, and NaBH4 (80 mg, 2 mmol), and methanol
(2 mL) were added sequentially. After stirring for 30 min, the sol-
vent was removed under vacuum, and saturated sodium bi-
carbonate solution was added. The mixture was extracted with
ethyl acetate, dried (MgSO4) and evaporated. The crude product
was purified by flash chromatography on silica gel using Et3N/ethyl
acetate/hexane (1:2:20) as eluent to give compound 4 (23 mg,
56%),9 compound 5 (6.5 mg, 24%),10 and compound 6 (14.7 mg,
33%).11
liquid, chiral HPLC Rt¼34.96 min, [
spectral data, of which are the same as the (ꢁ)-7a. (þ)-8: a white
solid, chiral HPLC Rt¼24.56 min, [ ]Dþ6.4 (c¼1.00, CH2Cl2); mp
42.4e44.1 ꢂC (recryst. CH2Cl2/hexanes); 1H NMR (CDCl3)
a
]Dꢀ26.9 (c¼1.15, CH2Cl2), the
a
d
7.85e7.82 (2H, m), 7.61e7.46 (3H, m), 6.92 (1H, t, J¼2.0 Hz), 3.26
(1H, dt, J¼2.8, 8.4 Hz), 2.92e2.85 (1H, m), 2.50 (1H, dt, J¼16.2,
3.0 Hz), 2.25 (1H, ddt, J¼3.8, 6.6, 10.2 Hz), 2.04 (1H, q, J¼9.0 Hz),
1.98e1.64 (5H, m), 1.58e1.35 (3H, m), 1.32e1.20 (7H, m), 0.87 (3H, t,
J¼6.3 Hz); 13C NMR (CDCl3)
d 140.0, 139.3, 138.5, 133.1, 129.1, 127.9,
4.4. ( )-cis-5-Hexyl-7-(phenylsulfinyl)-1,2,3,5,8,8a-
hexahydroidoindolizine (7a) and (7b)
62.7, 60.2, 51.6, 32.9, 31.6, 30.2, 30.1, 29.4, 24.9, 22.5, 21.2, 14.0; IR
(ATR, film) v: 3060, 2951, 2928, 2857, 2791, 1306, 1153 cmꢀ1; EIMS
(rel intensity) m/z 347 (Mþ, 1), 263 (22), 262 (100), 206 (16), 120
(23); HRMS m/z calcd for C20H29NO2S 347.1919, found 347.1915.
A mixture of compound 2 (50 mg, 0.158 mmol) and H2SO4 (1 M,
0.15 mL) in 95% EtOH (2 mL) was stirred at room temperature for
30 min, and then mCPBA (42 mg, 70%, 0.174 mmol) was added in
small portions. The reaction mixture was stirred at room temper-
ature for 17 h, and Na2S2O3 (0.2 g) and H2O (2 mL) were added
sequentially. After stirring for 10 min, the solvent was removed
under vacuum, and saturated sodium bicarbonate was added. The
mixture was extracted with ethyl acetate, dried (MgSO4) and
evaporated. The crude product was purified by flash chromatog-
raphy on basic alumina (deactivated with 10% water) using ethyl
acetate/hexane (4:1) as eluent to give compound 7a (15.2 mg, 29%)
and compound 7b (15.3 mg, 29%), both as a colorless oil. Compound
4.6. (D)-(5S,8aR)-5-Hexyl-7-(phenylsulfinyl)-1,2,3,5,8,8a-
hexahydroidoindolizine ((D)-7a) and (L)-(5R,8aS)-5-hexyl-7-
(phenylsulfonyl)-1,2,3,5,8,8a-hexahydroidoindolizine ((L)-8)
A mixture of compound 2 (100 mg, 0.317 mmol), TsOH (86 mg,
0.506 mmol) and powdered 4 A molecular sieves (0.5 g) in toluene
(2 mL) was stirred at room temperature for 10 min. A solution of
Ti(O-i-Pr)4 (0.66 mL, 1.212 mmol) and (þ)-DET (1518 mL,
8.848 mmol) in toluene (2 mL) was added, stirred for 10 min, and
then cooled in an ice bath before t-BuOOH (0.238 mL, 80%,
1.902 mmol) was added. The mixture was stirred at 0 ꢂC for 36 h,
and then Na2S2O3 (0.5 g) and H2O (2 mL) were added sequentially.
After stirring for 20 min, the solvent was removed under vacuum,
and saturated sodium bicarbonate solution was added. The mixture
was extracted with ethyl acetate, dried (MgSO4) and evaporated.
7a: 1H NMR (CDCl3)
d 7.56e7.53 (2H, m), 7.48e7.41 (3H, m), 6.56
(1H, t, J¼1.8 Hz), 3.26 (1H, dt, J¼3.0, 8.7 Hz), 2.94e2.86 (1H, m), 2.49
(1H, dt, J¼16.5, 3.3 Hz), 2.23 (1H, ddt, J¼3.6, 6.9, 10.0 Hz), 2.03 (1H,
q, J¼8.7 Hz), 1.94e1.84 (1H, m), 1.82e1.64 (4H, m), 1.56e1.40 (3H,
m), 1.37e1.23 (7H, m), 0.88 (3H, t, J¼6.9 Hz); 13C NMR (CDCl3)

S.-S.P. Chou, C.-J.J. Wu / Tetrahedron 68 (2012) 5025e5030
5029
The crude product was purified by flash chromatography on basic
alumina using ethyl acetate/hexane (1:6) as eluent to give com-
pound (þ)-7a (28 mg, 27%) and compound (ꢀ)-8 (34 mg, 31%).
129.2, 124.7, 63.2, 60.6, 52.1, 35.6, 30.4, 25.7, 21.3, 18.6, 14.5; IR (ATR,
film) v: 3053, 2951, 2927, 2868, 2786, 1045 cmꢀ1; EIMS (rel in-
tensity) m/z 247 (18), 246 (100), 204 (46), 198 (18), 164 (24), 137
(70), 136 (28), 120 (32), 70 (60); HRMS m/z calcd for C17H23NOS
(þ)-7a: a colorless liquid, [ ]Dþ26.4 (c¼0.33, CH2Cl2), (ꢀ)-8:
a
a white solid, chiral HPLC Rt¼8.5 min (94.8%), 9.6 min (5.2%),
]Dꢀ7.2 (c¼4.0, CH2Cl2).
289.1500, found 289.1485. (þ)-11: 1H NMR (CDCl3)
d 7.85e7.81 (2H,
[
a
m), 7.61e7.46 (3H, m), 6.92 (1H, t, J¼2.0 Hz), 3.26 (1H, dt, J¼2.4,
8.7 Hz), 2.89 (1H, br s), 2.55 (1H, dt, J¼15.9, 3.0 Hz), 2.34e2.22 (1H,
m), 2.04 (1H, q, J¼9.0 Hz), 1.99e1.81 (2H, m), 1.80e1.62 (3H, m),
1.59e1.32 (3H, m), 1.31e1.19 (1H, m), 0.92 (3H, t, J¼7.2 Hz); 13C NMR
4.7. Indolizidine (L)-209D
A mixture of compound (ꢀ)-7a (30 mg, 0.090 mmol) and a W-2
RaeNi (100 mg) in 95% EtOH (5 mL) was heated at reflux under
nitrogen for 2 h. The solid was filtered off, and the residue was
evaporated under vacuum in an ice bath. The crude product was
purified by flash chromatography using Et3N/ethyl acetate/hexane
(1:1:20) as eluent to give indolizidine (ꢀ)-209D (13.5 mg, 71%) as
(CDCl3) d 140.0, 139.3, 138.5, 133.2, 129.1, 128.0, 62.6, 60.2, 51.7, 35.1,
30.3, 30.2, 21.3, 18.2, 14.3; IR (ATR, film) v: 3055, 2958, 2929, 2868,
2786, 1305, 1152 cmꢀ1; FABMS (rel intensity) m/z 306 (MþþH, 48),
250 (21), 208 (18), 180 (20); HRMS m/z calcd for C17H24NO2S
306.1528, found 306.1524.
a colorless liquid, [
CH2Cl2).16
a
]Dꢀ87.5 (c¼0.03, CH2Cl2); Lit. [ ]Dꢀ87.6 (c¼1,
a
4.11. Indolizidine (L)-167B
Using a procedure similar to that for the preparation of indoli-
4.8. Indolizidine (D)-209D
zidine (ꢀ)-209D, compound 10 (30 mg, 0.103 mmol) gave (ꢀ)-167B
(11.3 mg, 65%), [
CH2Cl2).17
a
]Dꢀ106.8 (c¼0.01, CH2Cl2); lit. [ ]Dꢀ106.9 (c¼1.1,
a
A mixture of compound (þ)-8 (36 mg, 0.104 mmol) and a W-2
RaeNi (90 mg) in 95% EtOH (5 mL) was heated at reflux under
nitrogen for 6 h. The solid was filtered off, and the residue was
evaporated under vacuum in an ice bath. The crude product was
purified by flash chromatography using Et3N/ethyl acetate/hexane
(1:1:20) as eluent to give indolizidine (þ)-209D (14.5 mg, 67%) as
4.12. Indolizidine (D)-167B
Using a procedure similar to that for the preparation of indoli-
zidine (þ)-209D, compound (þ)-11 (35 mg, 0.103 mmol) gave
a colorless liquid, [
a
]Dþ77.0 (c¼1.15, CH2Cl2).
(þ)-167B (11.9 mg, 62%), [ ]Dþ93.8 (c¼0.16, CH2Cl2).
a
4.9. ( )-cis-7-(Phenylthio)-5-propyl-1,2,3,5,8,8a-
hexahydroindolizine (9)
Acknowledgements
Financial support of this work by the National Science Council of
the Republic of China (NSC 97-2113-M-030-001-MY3) is gratefully
acknowledged. We also thank Prof. Kwunmin Chen of National
Taiwan Normal University for the assistance in chiral HPLC
analyses.
To a solution of compound 1 (50 mg, 0.20 mmol) in THF (3 mL) at
room temperature was added slowly another solution of C3H7MgBr
(0.80 mmol) in THF (5 mL). The reaction mixture was stirred at room
temperature for 6 h, and then cooled in an ice bath. Acetic acid
(0.025 mL) was then added dropwise. The mixture was stirred for
10 min, and NaBH4 (80 mg, 2 mmol), and methanol (2 mL) were
added sequentially. After stirring for 30min, the solvent was removed
under vacuum, and saturated sodium bicarbonate solution was
added. The mixture was extracted with ethyl acetate, dried (MgSO4)
and evaporated. The crude product was purified by flash chroma-
tography on silica gel using Et3N/ethyl acetate/hexane (1:2:20) as
eluent to give compound 9 (40.1 mg, 73%) as a colorless oil: 1H NMR
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2012.04.054.
References and notes
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(CDCl3)
d
7.36e7.18 (5H, m), 5.99 (1H, t, J¼1.5 Hz), 3.34 (1H, dt, J¼2.4,
8.5 Hz), 2.81 (1H, br s), 2.39e2.11 (3H, m), 2.06 (1H, q, J¼9.0 Hz),
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Using a procedure similar to that for the preparation of (ꢀ)-7a
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(ꢀ)-10 (41.6 mg, 40%), [
a
a
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]Dþ3.8 (c¼1.00, CH2Cl2). (ꢀ)-10: 1H NMR
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5030
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