Concise syntheses of substituted indolizidine alkaloids via cyclization based on α-sulfinyl carbanions: preparation of (±)-indolizidines 167B and 209D, their epimers, and (±)-tashiromine

Article abstract of DOI:10.1016/j.tet.2008.01.008

(±)-Indolizidines 167B and 209D, their epimers and (±)-tashiromine have been successfully synthesized, starting from simple γ- or α-lactams. The strategy involves the cyclization of α-sulfinyl carbanion onto the carbonyl group of the lactam ring as the ke

Full text of DOI:10.1016/j.tet.2008.01.008

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2339e2347
www.elsevier.com/locate/tet
Concise syntheses of substituted indolizidine alkaloids via cyclization
based on a-sulfinyl carbanions: preparation of (ꢀ)-indolizidines
167B and 209D, their epimers, and (ꢀ)-tashiromine
*
Manat Pohmakotr , Saisuree Prateeptongkum, Soontorn Chooprayoon, Patoomratana Tuchinda,
*
Vichai Reutrakul
Department of Chemistry, Faculty of Science, Mahidol University, Rama VI Road, Bangkok 10400, Thailand
Received 5 October 2007; received in revised form 7 December 2007; accepted 3 January 2008
Available online 5 January 2008
Dedicated to Professor Dieter Seebach on the occasion of his 70th birthday
Abstract
(ꢀ)-Indolizidines 167B and 209D, their epimers and (ꢀ)-tashiromine have been successfully synthesized, starting from simple g- or a-lac-
tams. The strategy involves the cyclization of a-sulfinyl carbanion onto the carbonyl group of the lactam ring as the key step, leading to the
indolizidines containing the phenylsulfinyl group, which are used as precursors for the preparation of the title compounds.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Cyclization; a-Sulfinyl carbanion; (ꢀ)-Tashiromine; (ꢀ)-Indolizidine 167B; (ꢀ)-Indolizidine 209D
1. Introduction
and often minute natural abundance, a number of synthetic
methodologies of indolizidines have been developed.3,6,7
As part of our ongoing research on the cyclization based on
the a-sulfinyl carbanions, we have recently reported a general
synthetic method for the preparation of 1-azabicyclo[m.n.0]
alkanes, starting from lactams.8 In continuation of our success-
ful results, we herein report a concise synthesis of (ꢀ)-tashiro-
mine (1), (ꢀ)-indolizidines 167B (2a) and 209D (2b), and
their epimers. Our retrosynthetic analysis is outlined in
Scheme 1. It is anticipated that the syntheses of (ꢀ)-tashiro-
mine (1) and (ꢀ)-indolizidines 167B (2a) and 209D (2b)
would be accomplished by cyclization of a-sulfinyl carbanions
onto the carbonyl group of the lactam moiety providing the
key intermediates 5 and 6. The presence of the phenylsulfinyl
group in indolizidines 5 and 6 would permit further synthetic
transformation at the a-carbon. The intermediate of type 5
(R¼H) would be used as the precursor for the preparation of
(ꢀ)-tashiromine (1) by a-hydroxymethylation followed by re-
ductive cleavage of the phenylsulfinyl group. Reductive desul-
furization of the resulting indolizidine 6 would provide the
Indolizidine alkaloids1 constitute a class of natural prod-
ucts, which include a large number of pharmaceutically impor-
tant substances. Tashiromine (1) and indolizidines 167B (2a)
and 209D (2b) (Fig. 1) are simple representatives of the series
of this class of alkaloids. Tashiromine (1) was isolated from
the stems of a leguminous plant Maackia tashiroi, a deciduous
shrub of subtropical Asia.2,3 Indolizidines 167B (2a) and 209D
(2b) have been isolated from the skin secretions of neotropical
frogs of the family Dendrobatidae,4,5 from Central and South
America. These compounds have been shown to function as
noncompetitive blockers for muscle type and ganglionic nico-
tinic receptor channels.6 Because of the interesting structural
features and potent biological activities of these alkaloids
* Corresponding authors. Tel.: þ66 (0)2 2015158; fax: þ66 (0)2 6445126.
E-mail address: scmpk@mahidol.ac.th (M. Pohmakotr).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.008

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M. Pohmakotr et al. / Tetrahedron 64 (2008) 2339e2347
H
N
H
N
derived from 4a onto the carbonyl group of the lactam moiety
followed by elimination of the hydroxy group during work-
up.8
OH
H
N
Having the key intermediate indolizidine 5 in hand, the
next step was to carry out the a-hydroxymethylation at the
a-carbon of the phenylsulfinyl group, following by reductive
cleavage. Thus, the a-sulfinyl carbanion of indolizidine 5 gen-
erated using lithium diisopropylamide (1.4 equiv) in THF at
ꢂ78 ꢁC for 1 h was treated with paraformaldehyde (1.2 equiv)
to furnish the corresponding diastereomeric mixture of hy-
droxymethylated indolizidine 7 in 55% yield after chromato-
graphy. Pyrolysis of 7 by refluxing in dry toluene in the
presence of CaCO3 provided unsaturated indolizidine 8 in
47% yield, which underwent highly stereoselective hydroge-
nation in ethyl acetate using Pd/C as catalyst to give (ꢀ)-
tashiromine (1) in 86% yield (Scheme 2).
1
2a
2b
Tashiromine
Indolizidine 167B
Indolizidine 209D
Figure 1.
required indolizidines 2a and 2b. We anticipated that the key
starting sulfinyl lactam 4 could be easily prepared from lactam
3 by N-alkylation, using 3-bromo-1-phenylsulfanylpropane or
4-bromo-1-phenylsulfanylbutane, followed by oxidation.
2. Results and discussion
2.1. Synthesis of (ꢀ)-tashiromine (1)
2.2. Synthesis of indolizidines 167B (2a) and 209D (2b)
Our investigation began with the preparation of (ꢀ)-tashiro-
mine (1), starting from commercially available g-lactam 3a
(R¼H; n¼1). N-Alkylation of g-lactam 3a with 4-bromo-1-
phenylsulfanylbutane, employing NaH as a base in DMF at
0 ꢁC to room temperature overnight, afforded the correspond-
ing sulfide in 75% yield after column chromatography on sili-
ca gel, which was oxidized with NaIO4 in aqueous methanol at
0 ꢁC to give the required starting sulfoxide 4a (m¼1; n¼2) in
70% yield. Cyclization of the sulfoxide 4a to indolizidine 5
was achieved by treatment with 2.2 equiv of lithium hexame-
thyldisilazide (LiHDMS) in THF at ꢂ78 ꢁC to room tempera-
ture overnight, followed by reduction of the resulting crude
cyclized product 4aA with NaBH4 in methanol at 0 ꢁC for
4 h to provide indolizidine 5 in 69% yield as a mixture of in-
separable diastereomers. It was found that the cyclized product
4aA was slowly decomposed during attempted isolation by
chromatography on silica gel. It was therefore converted to
the corresponding indolizidine 5 by reduction with NaBH4.
Compound 4aA was formed by the intramolecular nucleo-
philic addition of the initially formed a-sulfinyl carbanion
Synthesis of the requisite d-lactams 3b and 3c was achieved
by Beckmann rearrangement of oxime derivatives of 2-propyl-
cyclopentanone and 2-hexylcyclopentanone employing NaOH/
p-TsCl in acetone at room temperature overnight. It was found
that inseparable mixtures (4:1) of required d-lactams 3b/9b
and 3c/9c were obtained in 67% and 60% yields, respectively.
The mixture of 3 and 9 was used directly in the next step
(Scheme 3).
Treatment of the mixture of 3b and 9b with 1-bromo-3-phe-
nylsulfanylpropane using NaH in DMF at 0 ꢁC overnight af-
forded 10a and 11a in 46% and 14% yields, respectively.
Under the same conditions, the mixture of 3c and 9c gave
10b and 11b in 41% and 12% yields, respectively. Subsequent
oxidation of sulfides 10a and 10b with NaIO4 in aqueous
methanol at 0 ꢁC afforded the corresponding sulfoxides 4b
and 4c in good yields as diastereomeric mixtures (Scheme 4).
Cyclization of the sulfoxides 4b and 4c to the correspond-
ing 1-azabicyclic compounds 12a and 12b was accomplished
by employing LiHMDS in THF at ꢂ78 ꢁC to room tempera-
ture overnight. Due to the rapid decomposition of 12a and
O
H
OH
Ph
S
H
N
1
N
5
O
O
O
S
Ph
m
m
NH
N
n
R
R
O
H
Ph
S
4a, m = 1; n =2
4b, m = 2; n =1
4c, m = 2; n =1
3a, R = H
3b, R = n-Pr
3c, R = n-Hex
H
N
N
R
R
6
2a, R = n-Pr
2b, R = n-Hex
Scheme 1. Retrosynthetic analysis.

M. Pohmakotr et al. / Tetrahedron 64 (2008) 2339e2347
2341
O
O
O
Ph
SPh
S
SPh
(ii)
O
O
10a, R = n-Pr
(i)
O
(i)
or
NH
N
N
N
10b, R= n-Hex
R
3a
4aA
4a
4b (93%, R = n-Pr)
4c (87%, R = n-Hex)
(iii)
OH
O
H
Ph
O
H
Ph
S
S
(ii)
H
OH
(v)
(iv)
N
N
N
SOPh
SOPh
SOPh
H
N
H
N
8
7
5
(iii)
(vi)
+
N
R
OH
R
R
H
12a, R = n-Pr
12b, R = n-Hex
6aA (41%)
6bA (47%)
6aB (34%)
6bB (45%)
N
Scheme 4. Reaction conditions: (i) NaIO4, MeOH, H2O, 0 ꢁC to rt overnight;
(ii) LiHMDS, THF, ꢂ78 ꢁC to rt overnight; (iii) NaBH4, MeOH, 0 ꢁC to rt
overnight.
( )-Tashiromine (1)
Scheme 2. Reaction conditions: (i) NaH, DMF, PhS(CH2)4Br, 0 ꢁC to rt (75%);
then NaIO4, MeOH, H2O, 0 ꢁC to rt overnight (70%); (ii) LiHMDS, THF,
ꢂ78 ꢁC to rt overnight; (iii) NaBH4, MeOH, 0 ꢁC to rt (69% yield from
4a); (iv) LDA, THF, (CH2O)n, ꢂ78 ꢁC to rt overnight (55%); (v) toluene,
reflux for 8 h (47%); (vi) H2, Pd/C (86%).
to strong deshielding effect caused by the proximate nitrogen
lone pair electrons.9 Moreover, compounds 6aA and 6bA ex-
hibit strong infrared Bohlmann bands at 2778 and 2783 cmꢂ1
,
respectively, indicating that the hydrogen on carbon atoms ad-
jacent to the nitrogen oriented trans to lone pair electrons.10
These characteristic absorption bands in the infrared spectra
were not found in compounds 6aB and 6bB.
12b during chromatography on silica gel, they were used with-
out purification for the reduction with NaBH4 in MeOH to pro-
vide a mixture of two diastereomers of 6aA/6aB and 6bA/
6bB, respectively, in good overall yields (Scheme 4).
The complete assignment of H NMR chemical shifts of
1
6aA, 6aB and 6bA, 6bB was made by comparing their H
NMR spectral data with those of 13 (Fig. 2) (for preparation
and complete characterization of 13, see Supplementary data).
The relative stereochemistry of 6aA/6bA and 6aB/6bB was
also made by comparison of the chemical shifts of C-5 protons
with those of 13. The chemical shifts of C5-Ha of 6aA and
6bA appear at higher field than C5-He of 6aB and 6bB.
C5-He of the latter diastereomers resonate at lower field due
1
To complete the synthesis of 2a and 2b from 6aA and 6bA
by reductive desulfurization, we began our study with 6%
Na(Hg)/MeOH/NaH2PO4 or Raney-nickel. All attempts led
to unsatisfactory results, providing mainly the recovered start-
ing materials. Fortunately, reductive desulfurization of 6aA
and 6bA was successfully made by employing nickel boride
(Ni2B).11 Thus, treatment of 6aA and 6bA with Ni2B, gener-
ated in situ from NiCl2$6H2O and NaBH4 in a mixture of
MeOH and THF (3:1), at 0 ꢁC to room temperature gave the
required (ꢀ)-indolizidines 167B (2a) and 209 D (2b) in 82%
and 80% yields, respectively. Their spectroscopic data were
O
R
O
R
O
(i)
+
SOPh
1
8
H
NH
(4:1)
(ii)
NH
7
9
N
R
2
3
6
5
3b
3c
9b (67%), R = n-Pr
9c (60%), R = n-Hex
Ha
1.88 (dt)
He
3.17 (br d)
13
(iii)
SOPh
SOPh
H
N
H
R
O
SPh
O
SPh
+
N
N
N
Ha
R
R
He
R
6aA, Ha 1.58-1.85 (m)
6bA, Ha 1.79-2.04 (m)
6aB, He 2.89-3.02 (m)
6bB, He 3.02 (m)
10a (46%, R = n-Pr)
10b (41%, R = n-Hex)
11a (14%, R = n-Pr)
11b (12%, R = n-Hex)
Figure 2. Comparing of 1H NMR data of C-5 protons of compounds 6aA/6aB
and 6bA/6bB with compound 13.
Scheme 3. Reaction conditions: (i) NH2OH$HCl, ethanol; (ii) TsCl, NaOH,
acetone, rt, overnight; (iii) NaH, DMF, PhS(CH2)3Br, 0 ꢁC to rt, overnight.

2342
M. Pohmakotr et al. / Tetrahedron 64 (2008) 2339e2347
consistent with those of the reported values in the literature.7e
Similarly, under the same reduction conditions, the diastereo-
mers 6aB and 6bB furnished the corresponding (ꢀ)-epi-indo-
lizidine 167B (2a) and (ꢀ)-epi-indolizidine 209D (2b)7e in
74% and 86% yields (Scheme 5).
methanol, and acetone) were distilled before use. All glass-
wares and syringes were oven-dried and kept in a dessicator
before use. Preparative thin layer chromatography and column
chromatography were performed using Merck silica gel 60F254
(Merck, Art. 7749) and silica gel 60H (Merck, Art. 7736),
respectively.
4.2. Preparation of (ꢀ)-tashiromine (1)
SOPh
H
N
H
N
(i)
4.2.1. 1-(4-Phenylsulfinylbutyl)pyrrolidin-2-one (4a)
a, R = n-Pr
b, R = n-Hex
General procedure. To a suspension of NaH (1.55 g,
38.7 mmol, 80% suspension in mineral oil) in DMF
(58 mL), a DMF (12 mL) solution of g-lactam (3.0 g,
35 mmol) was slowly added at 0 ꢁC under an argon atmo-
sphere. The reaction mixture was stirred for 1 h until the
generation of hydrogen ceased and 1-bromo-4-phenylsulfanyl-
butane (9.5 g, 38.7 mmol) was then added. After the reaction
mixture was stirred at 0 ꢁC to room temperature overnight, it
was poured into ice-water and extracted with EtOAc
(4ꢃ100 mL). The combined organic layers were washed
with H2O and brine, and dried over anhyd Na2SO4. Filtration
followed by concentration in vacuo gave a residue, which was
purified by column chromatography on silica gel (20% EtOAc
in hexanes) to give a pale yellow liquid of 1-(4-phenylsulfa-
nylbutyl)pyrrolidin-2-one (6.6 g, 75% yield). 1H NMR
(300 MHz, CDCl3): d 7.36e7.22 (m, 4H), 7.19e7.13 (m,
1H), 3.38e3.19 (m, 4H), 2.94 (t, J¼6.5 Hz, 2H), 2.36
(t, J¼8.0 Hz, 2H), 1.95 (quint, J¼7.5 Hz, 2H), 1.74e1.56
(m, 4H). 13C NMR (75 MHz, CDCl3): d 174.9, 136.3, 129.1
(2C), 128.8 (2C), 125.8, 46.9, 41.7, 33.1, 30.9, 26.0 (2C),
17.8. IR (neat): nmax 1681 (s), 1583 (m), 1480 (s), 1463 (s),
1290 (s), 1267 (s) cmꢂ1. MS: m/z (%) relative intensity 250
(Mþþ1, 9), 140 (71), 123 (11), 98 (100), 70 (32), 68 (9).
HRMS (ESI): calcd for C14H20NOS, 250.1267; found,
250.1232.
R
R
2a, 82%; ( )-Indolizidine 167B
2b, 80%; ( )-Indolizidine 209D
6aA
6bA
H
SOPh
H
(i)
N
R
N
R
6aB
epi-2a, 74%; ( )-epi-Indolizidine 167B
epi-2b, 86%; ( )-epi-Indolizidine 209D
6bB
Scheme 5. Reaction conditions: (i) NiCl2$6H2O/NaBH4, MeOH/THF (3:1),
0 ꢁC to rt, 2 h.
3. Conclusion
In conclusion, we have developed a concise method for the
synthesis of (ꢀ)-tashiromine (1), (ꢀ)-indolizidine 167B (2a)
and 209D (2b), and their epimers, starting from 2-propyl or
2-hexyl substituted d-lactams, respectively. The synthesis
demonstrates the utilities of the cyclization of a-sulfinyl carb-
anions onto the carbonyl group of the lactam rings as a conve-
nient entry to the indolizidines containing the sulfoxide
functional group that can be employed as the key indolizidines
for the preparation of the title compounds.
A solution of 1-(4-phenylsulfanylbutyl)pyrrolidin-2-one
(5.0 g, 20 mmol) in MeOH (11 mL) was slowly added to a sus-
pension of NaIO4 (4.7 g, 22 mmol) in MeOH (48 mL) and
H2O (12 mL) at 0 ꢁC. The mixture was stirred vigorously
and slowly warmed up to room temperature overnight
(12 h). The precipitates of NaIO3 were filtered and washed
several times with EtOAc (3ꢃ60 mL). The combined extracts
were washed with H2O and brine, and dried over anhyd
Na2SO4. Filtration followed by concentration in vacuo gave
a pale yellow liquid of a crude product, which was purified
by column chromatography (100% EtOAc) to afford a color-
less viscous liquid of 4a (3.75 g, 70% yield). 1H NMR
(300 MHz, CDCl3): d 7.41e7.31 (m, 2H), 7.31e7.19 (m,
3H), 3.34e3.10 (m, 4H), 2.71e2.52 (m, 2H), 2.08
(t, J¼7.8 Hz, 2H), 1.78e1.66 (m, 2H), 1.23e1.59 (m, 4H).
13C NMR (75 MHz, CDCl3): d 147.2, 142.8, 130.2, 128.5
(2C), 123.2 (2C), 55.3, 46.2, 40.7, 30.2, 25.0, 18.4, 17.1. IR
(neat): nmax 1679 (s), 1494 (m), 1464 (s), 1443 (s), 1290 (s),
1087 (s) cmꢂ1. MS: m/z (%) relative intensity 266 (Mþþ1,
51), 248 (39), 165 (23), 163 (22), 140 (87), 138 (30), 98
(100), 70 (47). HRMS (ESI): calcd for C14H20NO2S,
266.1216; found, 266.1182.
4. Experimental
4.1. General methods
The 1H NMR spectra were recorded on either Bruker DPX-
300 (300 MHz) or Bruker Avance-500 (500 MHz) spectrome-
ter in CDCl3 using tetramethylsilane as an internal standard.
The 13C NMR spectra were recorded on a Bruker Avance-
500 (500 MHz) spectrometer using tetramethylsilane as an in-
ternal standard. The IR spectra were recorded on either a Jasco
A-302 or a PerkineElmer 683 infrared spectrometer. The mass
spectra were recorded using Thermo Finnigan Polaris Q mass
spectrometer. The high resolution mass spectra were recorded
on MS Micromass model VQ-TOF2. Elemental analyses were
performed by a PerkineElmer Elemental Analyzer 2400
CHN. Melting points were recorded on a Buchi 501 Melting
¨
Point Apparatus and uncorrected. Tetrahydrofuran (THF)
was distilled from sodium-benzophenone ketyl. Dry N,N-di-
methylformamide (DMF) was obtained by distilling over cal-
cium hydride. Other common solvents (hexanes, ethyl acetate,

M. Pohmakotr et al. / Tetrahedron 64 (2008) 2339e2347
2343
4.2.2. 8-Phenylsulfinyl-1,2,3,5,6,7,8,9-octahydroindolizine
(5)
(0.86 mL, 6 mmol) under an argon atmosphere. After stirring
at ꢂ78 ꢁC for 30 min, a THF (12 mL) solution of 5 (1.0 g,
4 mmol) was added dropwise and allowed to stir for 30 min.
Paraformaldehyde (145 mg, 4.8 mmol) was added as a solid
to the resulting solution at ꢂ78 ꢁC and the resulting mixture
was allowed to stir and slowly warmed up to room temperature
overnight (15 h). The resulting yellow solution was quenched
with H2O and extracted with EtOAc (3ꢃ70 mL). The com-
bined organic extracts were washed with H2O and brine, and
dried over anhyd Na2SO4. Filtration followed by evaporation
gave a crude product, which was purified by column chroma-
tography (SiO2, 10% MeOH in EtOAc) to afford a pale yellow
viscous liquid of 7 (0.62 g, 55% yield) as a mixture of three
diastereomers. 1H NMR (300 MHz, CDCl3): d 7.79e7.70
(m, 3H), 7.56e7.39 (m, 12H), 4.42 (d, J¼11.7 Hz, 1H),
4.17e4.06 (m, 2H), 3.81 (d, J¼11.4 Hz), 3.51 (d,
J¼12.7 Hz, 1H), 3.31 (d, J¼10.6 Hz, 1H), 3.23e3.13 (m,
3H), 3.13e2.94 (m, 3H), 2.76e2.59 (m, 1H), 2.49e1.52 (m,
31H), 1.43e1.39 (m, 1H), 1.21e1.03 (m, 2H), 0.82 (dt,
J¼4.79, 13.9 Hz, 1H). 13C NMR (75 MHz, CDCl3): d 139.5,
138.6, 137.8, 131.8 (2C), 131.6 (2C), 128.9 (2C), 128.7
(2C), 126.7 (2C), 126.2 (3C), 125.9 (2C), 69.9, 67.7, 67.6,
66.2, 64.6, 62.5, 62.4, 61.2, 60.4, 54.1, 53.9, 53.6, 52.8,
52.3, 52.2, 29.7, 28.1, 27.2, 25.3, 24.4, 23.9, 22.7, 22.6,
21.8, 20.9, 20.9, 20.6. IR (neat): nmax 3367 (br), 2709 (s),
1582 (w), 1475 (w), 1443 (s), 1032 (s), 749 (s), 699
(s) cmꢂ1. MS: m/z (%) relative intensity 280 (Mþþ1, 1),
153 (32), 136 (100), 122 (15). HRMS (ESI): calcd for
C15H22NO2S, 280.1366; found, 280.1353.
General procedure. A THF (18 mL) solution of 4a (2.29 g,
8.64 mmol) was added dropwise to a cooled (ꢂ78 ꢁC) THF
(100 mL) solution of LiHMDS [prepared by reacting n-BuLi
(1.36 M in hexane; 14 mL, 19 mmol) with THF (93 mL) solu-
tion of hexamethyldisilazane (HMDS) (4.3 mL, 20.7 mmol) at
ꢂ78 ꢁC for 30 min] under an argon atmosphere. The resulting
mixture was stirred and slowly warmed up from ꢂ78 ꢁC to
room temperature overnight (15 h). The resulting yellow solu-
tion was quenched with H2O and extracted with EtOAc
(3ꢃ100 mL). The combined organic extracts were washed
with H2O and brine, and dried over anhyd Na2SO4. Filtration
followed by concentration in vacuo afforded a viscous liquid
of a crude product 4aA, which was directly subjected to reduc-
tion using NaBH4 as described below.
To a solution of the crude product 4aA in MeOH (21 mL) at
0 ꢁC under argon atmosphere, NaBH4 (3.9 g, 103.6 mmol) was
gradually added over 15 min. The mixture was stirred at room
temperature overnight, diluted with 1 N NaOH (63 mL) and
H2O (38 mL), and extracted with EtOAc (3ꢃ100 mL). The
combined organic extracts were washed with brine, dried
over anhyd Na2SO4, and concentrated. The crude product
was purified by column chromatography (SiO2, 10% MeOH
in EtOAc containing 0.15% NH4OH solution) to afford a mix-
ture of three diastereomers of 5 (1.49 g, 69% yield).
F1 (less polar) was obtained as a yellow viscous liquid of
a mixture of two diastereomers. 1H NMR (300 MHz,
CDCl3): d 7.64e7.58 (m, 2H, ArH), 7.57e7.42 (m, 8H,
ArH), 3.13 (dt, J¼8.6, 1.9 Hz, 1H), 3.09e3.01 (m, 3H),
2.81e2.79 (m, 1H), 2.52e2.35 (m, 4H), 2.32e2.18 (m, 2H),
2.18e1.98 (m, 2H), 1.98e1.43 (m, 13H), 1.26e1.22 (m,
1H), 1.07 (dq, J¼12.6, 4.4 Hz, 1H). 13C NMR (75 MHz,
CDCl3): d 141.3, 141.2, 131.2, 130.5, 128.9 (2C), 128.9
(2C), 125.4 (2C), 124.2 (2C), 66.1, 65.7, 63.8, 63.4, 53.9,
53.2, 51.7, 29.4, 29.2, 24.8, 24.2, 23.4, 20.9, 20.6, 18.1. IR
(neat): nmax 2939 (s), 2788 (s), 1582 (w), 1478 (m), 1461
4.2.4. (1,2,3,5,6,8a-Hexahydroindolizin-8-yl)methanol (8)
A toluene (15 mL) solution of 7 (0.32 g, 1.17 mmol) in the
presence of CaCO3 was stirred at reflux under an argon atmo-
sphere for 8 h. CaCO3 was filtered off and the filtrate was
evaporated to dryness to give a crude product, which was pu-
rified by preparative thin layer chromatography (SiO2, 30%
MeOH in EtOAc) to give a pale brown liquid of 8 (89 mg,
(m), 1443 (s), 1362 (s), 1086 (s), 1045 (s), 749 (s) cmꢂ1
.
47% yield). H NMR (300 Hz, CDCl3): d 5.61 (br s, 1H),
1
MS: m/z (%) relative intensity 250 (Mþþ1, 13), 124 (53),
123 (85), 122 (100), 96 (47). HRMS (EI): calcd for
C14H20NOS, 250.1260; found, 250.1259.
4.25 (br s, 1H), 3.98 (br s, 2H), 3.20 (t, 1H, J¼7.8 Hz),
2.88e2.79 (m, 1H), 2.65e2.79 (m, 2H), 2.59e2.46 (m, 1H),
2.15 (br s, 2H), 2.19e2.06 (m, 1H), 1.91e1.63 (m, 2H),
1.56e1.42 (m, 1H). 13C NMR (75 MHz, CDCl3): d 139.4,
120.1, 64.5, 60.1, 52.9, 46.3, 27.9, 24.7, 22.1. IR (neat):
nmax 3351 (br), 2876 (s), 2729 (s), 1663 (m), 1576 (w), 1457
(s), 1434 (s), 1062 (s), 1018 (s) cmꢂ1. MS: m/z (%) relative in-
tensity 154 (Mþþ1, 36), 152 (36), 136 (16), 122 (100), 120
(23), 94 (14), 79 (12). HRMS (ESI): calcd for C9H16NO,
154.1226; found, 154.1230.
F2 (more polar) was obtained as a colorless viscous liquid
of a single diastereomer. 1H NMR (300 MHz, CDCl3):
d 7.64e7.52 (m, 2H, ArH), 7.49e7.36 (m, 3H, ArH), 3.16e
2.92 (m, 3H), 2.57e2.39 (m, 1H), 2.41e1.59 (m, 8H),
1.58e1.34 (m, 2H). 13C NMR (75 MHz, CDCl3): d 145.4,
130.7, 129.2 (2C), 124.6 (2C), 63.9, 63.3, 54.4, 51.9, 25.8,
22.8, 21.3, 20.9. IR (neat): nmax 2938 (s), 2786 (s), 1582
(w), 1442 (s), 1041 (s), 753 (s) cmꢂ1. MS: m/z (%) relative in-
tensity 250 (Mþþ1, 1), 232 (100), 122 (63), 96 (35), 94 (14).
HRMS (ESI): calcd for C14H20NOS, 250.1260; found,
250.1262.
4.2.5. (ꢀ)-Tashiromine (1)
To a suspension of 10% Pd/C (40 mg, 0.038 mmol) in
EtOAc (2 mL), an EtOAc (3 mL) solution of 8 (58 mg,
0.38 mmol) was slowly added at room temperature under hy-
drogen atmosphere. The reaction mixture was allowed to stir
overnight (15 h) followed by filtration over Celite. The filtrate
was evaporated in vacuo to give a crude product, which was
purified by preparative thin layer chromatography (Al2O3,
4.2.3. [1,2,3,5,6,7,8,9-Octahydro-8-(phenylsulfinyl)indolizin-
8-yl]methanol (7)
n-BuLi (1.36 M in hexane; 4.0 mL, 5.4 mmol) was added to
a cooled (ꢂ78 ꢁC) THF (5 mL) solution of diisopropylamine

2344
M. Pohmakotr et al. / Tetrahedron 64 (2008) 2339e2347
100% EtOAc) to give a pale yellow viscous liquid of (ꢀ)-
tashiromine (1) (51 mg, 86% yield). 1H NMR (300 MHz,
CDCl3): d 3.64e3.52 (m, 1H), 3.49e3.38 (m, 1H), 3.14e
3.01 (m, 2H), 2.17e1.36 (m, 11H), 1.11e0.99 (m, 1H). 13C
NMR (75 MHz, CDCl3): d 66.5, 65.6, 54.0, 52.6, 44.2, 28.9,
27.4, 24.9, 20.6. IR (neat): nmax 3392 (br), 2799 (s), 1648
(m), 1445 (m) cmꢂ1. MS: m/z (%) relative intensity 156
(Mþþ1, 100), 154 (74), 136 (39), 110 (26), 84 (64). HRMS
(ESI): calcd for C9H18NO, 156.1383; found, 156.1393. The
spectroscopic data are consistent with the literature.2,3f,3g
2.13 (m, 3H), 1.96e1.12 (m, 28H), 0.91e0.79 (m, 6H). 13C
NMR (75 MHz, CDCl3): d 175.2, 172.4, 53.0, 42.2, 40.8,
36.8, 31.6, 31.5, 31.4, 31.2, 29.2, 29.0, 28.2, 26.8, 25.9,
25.1, 22.5, 22.4, 21.2, 19.6, 13.9, 13.9. IR (Nujol): nmax
1668 (s), 1485 (s), 1469 (s), 1403 (s), 1377 (m), 1346
(m) cmꢂ1. MS: m/z (%) relative intensity 184 (Mþþ1, 8),
183 (Mþ, 9), 112 (22), 99 (21), 98 (100), 70 (58), 55 (70).
HRMS (ESI): calcd for C11H21NONa, 206.1521; found,
206.1522.
4.3.3. Preparation of a mixture of 6-alkyl-1-(3-phenyl-
sulfanylpropyl)piperidin-2-one 10 and 3-alkyl-1-(3-phenyl-
sulfanylpropyl)piperidin-2-one 11
4.3. Preparation of (ꢀ)-indolizidine 167B (2a) and 209D (2b)
4.3.1. 6-Propyl-2-piperidone (3b)12
General procedure. To a solution of hydroxylamine hydro-
chloride (0.28 g, 4.0 mmol) and NaOH (0.22 g) in EtOH
(5 mL) was added a solution of 2-propylcyclopentanone
(0.39 g, 3.1 mmol) in EtOH (1 mL). The mixture was stirred
at reflux for 2 h, poured into ice-water after cooling to room
temperature, and extracted with EtOAc (3ꢃ15 mL). The com-
bined organic layers were washed with H2O and brine, and
dried over anhyd Na2SO4. Filtration followed by evaporation
gave a crude product of a syn- and anti-mixture of 2-propylcy-
clopentanone oxime. A solution of the crude product of 2-pro-
pylcyclopentanone oxime (0.41 g, 2.9 mmol) in acetone
(3.8 mL) was treated with 1 N NaOH (5 mL) at 0 ꢁC and
p-TsCl (0.72 g, 3.8 mmol) in acetone (2.2 mL) was added
dropwise. Aftre stirring the resulting mixture for 18 h at 25 ꢁC,
it was diluted with H2O (8 mL) and extracted with EtOAc
(3ꢃ15 mL). The combined organic extracts were washed
with H2O and brine, and dried over anhyd Na2SO4. The crude
product was purified by column chromatography (SiO2, 30%
EtOAc in hexanes) to afford a white solid of a 4:1 mixture
of 6-propylvalerolactam (3b) and 3-propylvalerolactam (9b)
4.3.3.1. A mixture of 6-propyl-1-(3-phenylsulfanylpropyl)piper-
idin-2-one (10a) and 3-propyl-1-(3-phenylsulfanylpropyl)pi-
peridin-2-one (11a). General procedure. To a suspension of
NaH (1.01 g, 33.75 mmol, 80% suspension in mineral oil)
in DMF (80 mL), a DMF (7 mL) solution of a 4:1 mixture
of 3b and 9b (3.16 g, 22.41 mmol) was slowly added at
0 ꢁC under an argon atmosphere. The reaction mixture was
stirred for 1 h until the generation of hydrogen ceased and
1-bromo-3-phenylsulfanylpropane (6.20 g, 26.84 mmol) was
then added. After the reaction mixture was stirred at 0 ꢁC
to room temperature overnight (15 h), it was quenched with
water and extracted with EtOAc (4ꢃ80 mL). The combined
organic layers were washed with H2O and brine, and dried
over anhyd Na2SO4. Filtration followed by concentration in
vacuo gave a residue, which was purified by column chroma-
tography (SiO2, 50% EtOAc in hexanes) to give a pale yellow
liquid of 10a (2.99 g, 46% yield) and 11a (0.94 g, 14%
yield).
Compound 10a: 1H NMR (400 MHz, CDCl3): d 7.35e7.21
and 7.19e7.11 (each m, 5H), 3.86 (ddd, J¼14.1, 8.0, 5.6 Hz,
1H), 3.31e3.21 (m, 1H), 2.99 (ddd, J¼13.7, 8.3, 5.6 Hz, 1H),
2.91 (t, J¼7.2 Hz, 2H), 2.38e2.26 (m, 2H), 1.99e1.09 (m,
10H), 0.91 (t, J¼7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d 170.7, 136.9, 129.8 (2C), 129.5 (2C), 126.5, 57.2, 45.1,
35.4, 32.5, 31.9, 27.7, 26.7, 19.9, 17.7, 14.6. IR (neat): nmax
1
(0.293 g, 67% yield). H NMR (300 MHz, CDCl3): d 6.61
(br s, 1H), 6.42 (br s, 1H), 3.39e3.31 (m, 1H), 3.31e3.19
(m, 2H), 2.44e2.16 (m, 3H), 1.99e1.20 (m, 16H), 0.92 and
0.91 (each t, J¼7.1 Hz, 2ꢃ3H). 13C NMR (75 MHz,
CDCl3): d 175.3, 172.4, 52.7, 42.2, 40.6, 38.9, 33.5, 31.2,
28.2, 25.9, 21.1, 20.0, 19.6, 18.4, 13.9, 13.8. IR (Nujol):
1637 (s), 1585 (m), 1473 (s), 1418 (m), 1360 (m) cmꢂ1
.
nmax 1667 (s), 1462 (s), 1403 (m), 1377 (s), 1333 (m) cmꢂ1
.
MS: m/z (%) relative intensity 292 (Mþþ1, 8), 183 (12),
182 (100), 113 (22). HRMS (ESI): calcd for C17H25NONaS,
314.1555; found, 314.1553.
MS: m/z (%) relative intensity 143 (Mþþ2, 9), 142 (Mþþ1,
100), 98 (50), 70 (29).
Compound 11a: 1H NMR (300 MHz, CDCl3): d 7.29e7.09
(m, 5H), 3.47e3.28 (m, 2H), 3.23e3.08 (m, 2H), 2.83 (t,
J¼7.4 Hz, 2H), 2.25e2.13 (m, 1H), 1.92e1.13 (m, 10H),
0.85 (t, J¼7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3):
d 172.8, 136.2, 129.1 (2C), 128.8 (2C), 125.9, 48.1, 46.3,
41.2, 34.0, 31.1, 26.8, 26.2, 21.6, 20.1, 14.0. IR (neat): nmax
1636 (s), 1584 (m), 1490 (s), 1464 (s), 1439 (s), 740
(s) cmꢂ1. MS: m/z (%) relative intensity 292 (Mþþ1, 1),
291 (Mþ, 2), 183 (13), 182 (100), 154 (15).
4.3.2. 6-Hexyl-2-piperidone (3c)
According to the general procedure described for 3b, hy-
droxylamine hydrochloride (2.02 g, 29.01 mmol) in an ethanol
(50 mL) solution of NaOH (30 mmol) was reacted with a solu-
tion of 2-hexylcyclopentanone (3.88 g, 23.10 mmol). The
crude product obtained from the above reaction was treated
with 1 N NaOH (30 mL) and a solution of p-TsCl (5.68 g,
29.82 mmol) in acetone (17 mL). After the usual work-up,
the crude product was purified by column chromatography
(SiO2, 30% EtOAc in hexanes) to afford a yellow liquid of
a 4:1 mixture of 6-hexylvalerolactam (3c) and 3-hexylvalero-
lactam (9c) (2.54 g, 60% yield). 1H NMR (300 MHz, CDCl3):
d 6.55 (br s, 1H), 6.34 (br s, 1H), 3.37e3.17 (m, 3H), 2.43e
4.3.3.2. A mixture of 6-hexyl-1-(3-phenylsulfanylpropyl)piperi-
din-2-one (10b) and 3-hexyl-1-(3-phenylsulfanylpropyl)piperi-
din-2-one (11b). According to the general procedure
described for 10a, a 4:1 mixture of 3c and 9c (4:1) (1.40 g,

M. Pohmakotr et al. / Tetrahedron 64 (2008) 2339e2347
2345
7.65 mmol) in DMF (3 mL) was treated with NaH (0.29 g,
9.58 mmol, 80% suspension in mineral oil) and 1-bromo-3-
phenylsulfanylpropane (2.11 g, 9.13 mmol) in DMF (16 mL)
to afford a crude product, which was purified by column chro-
matography (SiO2, 50% EtOAc in hexanes) to give a pale yel-
low liquid of 10b (1.0412 g, 41% yield) and 11b (0.3094 g,
12% yield).
Compound 10b: 1H NMR (300 MHz, CDCl3): d 7.36e7.13
(m, 5H), 3.88 (ddd, J¼13.8, 8.2, 6.0 Hz, 1H), 3.32e3.21 (m,
1H), 3.00 (ddd, J¼13.7, 8.2, 5.7 Hz, 1H), 2.93 (t, J¼7.2 Hz,
2H), 2.39e2.28 (m, 2H), 2.02e1.09 (m, 16H), 0.90 (t,
J¼6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): d 170.1, 136.2,
129.1 (2C), 128.8 (2C), 125.9, 56.8, 44.4, 32.5, 31.8, 31.6,
31.2, 29.1, 27.0, 26.0, 26.0, 22.5, 17.0, 14.0. IR (neat): nmax
1640 (s), 1585 (w), 1470 (s), 1439 (s), 1275 (m), 738
(s) cmꢂ1. MS: m/z (%) relative intensity 334 (Mþþ1, 4),
225 (15), 224 (100). HRMS (ESI): calcd for C20H31NONaS,
356.2024; found, 356.2024.
Compound 11b: 1H NMR (300 MHz, CDCl3): d 7.36e7.10
(m, 5H), 3.54e3.34 (m, 2H), 3.29e3.13 (m, 2H), 2.90 (t,
J¼7.3 Hz, 2H), 2.30e2.17 (m, 1H), 1.98e1.17 (m, 16H),
0.96e0.79 (m, 3H). 13C NMR (75 MHz, CDCl3): d 172.5,
136.1, 128.9 (2C), 128.6 (2C), 125.7, 47.9, 46.1, 41.2, 31.7,
31.5, 30.9, 29.1, 26.8, 26.6, 26.1, 22.4, 21.5, 13.8. IR (neat):
nmax 1637 (s), 1584 (m), 1490 (m), 1465 (m), 1439 (m),
1352 (m) cmꢂ1. MS: m/z (%) relative intensity 334 (Mþþ1,
3), 225 (15), 224 (100), 196 (14), 168 (15).
CDCl3): d 7.66e7.57 and 7.57e7.44 (each m, 2ꢃ5H),
4.03e3.88 (m, 2H), 3.40e3.19 (m, 2H), 3.05e2.67 (m, 6H),
2.42e2.20 (m, 4H), 2.19e1.08 (m, 32H), 0.89 (t, J¼6.6 Hz,
6H). 13C NMR (75 MHz, CDCl3): d 170.4, 170.2, 143.6,
143.5, 130.8 (4C), 129.1 (4C), 123.9, 123.8, 56.5, 56.4,
54.7, 54.5, 43.8, 43.6, 32.5, 32.4, 31.8, 31.7, 31.6 (2C), 29.1
(2C), 25.9 (4C), 22.4 (2C), 20.5, 20.5, 16.9 (2C), 13.9 (2C).
IR (neat): nmax 1634 (s), 1471 (s), 1444 (m), 1087 (m),
1046 (s), 749 (m) cmꢂ1. MS: m/z (%) relative intensity
350 (Mþþ1, 3), 224 (100), 222 (29), 138 (20), 112 (69).
HRMS (ESI): calcd for C20H31NO2NaS, 372.1973; found,
372.1974.
4.3.3.5. 1-Phenylsulfinyl-5-propyl-1,2,3,5,6,7,8,9-octahydro-
indolizine (6a). According to the general procedure for the
preparation of 5, a THF (12 mL) solution of 4b (1.86 g,
6.06 mmol) was treated with LiHMDS (14.4 mmol) to afford
a crude product (1.73 g, 5.99 mmol), which was dissolved in
methanol (30 mL) followed by treatment with NaBH4
(1.49 g, 39.4 mmol) in a small portion over 15 min. The crude
product obtained was purified by column chromatography
(SiO2, 2% MeOH in EtOAc containing 0.15% NH4OH
solution) to afford two separated diastereomers of 6aA and
6aB.
F1 (less polar) was obtained as a yellow solid of 6aA
[0.72 g, 41% yield; mp 66e68 ꢁC (EtOAc)]. 1H NMR
(300 MHz, CDCl3): d 7.38e7.21 (m, 5H), 3.09 (dt, J¼8.4,
1.1 Hz, 1H), 2.91e2.78 (m, 1H), 2.23e2.04 (m, 2H), 1.85e
1.58 (m, 5H), 1.50e1.30 (m, 2H), 1.28e0.90 (m, 6H), 0.68
(t, J¼7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3): d 143.8,
130.2, 128.9 (2C), 124.2 (2C), 66.8, 66.4, 63.9, 50.5, 36.3,
29.7, 27.6, 24.9, 18.6, 17.6, 14.4. IR (Nujol): nmax 2778 (s),
1441 (s), 1047 (s), 751 (s) cmꢂ1. MS: m/z (%) relative
intensity 292 (Mþþ1, 5), 274 (83), 164 (34), 124 (60), 122
(100).
F2 (more polar) was obtained as a yellow solid of 6aB
[0.60 g, 34% yield; mp 81e83 ꢁC (EtOAc)]. 1H NMR
(300 MHz, CDCl3): d 7.52e7.33 (m, 5H), 3.02e2.89 (m,
3H), 2.85 (dt, J¼8.6, 2.5 Hz, 1H), 2.55 (q, J¼8.0 Hz, 1H),
2.38e2.23 (m, 1H), 1.96e1.55 (m, 4H), 1.53e1.00 (m, 7H),
0.83 (t, J¼7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3):
d 143.5, 130.3, 128.8 (2C), 124.1 (2C), 65.9, 56.9, 55.1,
48.1, 26.9, 26.2, 25.7, 20.6, 19.1, 17.5, 14.2. IR (Nujol):
nmax 2780 (m), 1582 (w), 1457 (m), 1441 (m), 1041 (s), 748
(m) cmꢂ1. MS: m/z (%) relative intensity 292 (Mþþ1, 21),
274 (75), 122 (100), 96 (21). HRMS (ESI): calcd for
C17H25NONaS, 314.1555; found, 314.1549.
4.3.3.3. 6-Propyl-1-(3-phenylsulfinylpropyl)piperidin-2-one (4b).
According to the general procedure as described for 4a, a
solution of 10a (0.21 g, 0.72 mmol) in MeOH (0.5 mL) was
reacted with NaIO4 (0.16 g, 0.75 mmol) in MeOH (1.6 mL)
and H2O (0.4 mL). The crude product obtained was purified
by column chromatography (SiO2, 100% EtOAc) to afford a
colorless viscous liquid of 4b (0.204 g, 93% yield) as a 1:1
1
mixture of two diastereomers. H NMR (300 MHz, CDCl3):
d 7.65e7.58 and 7.57e7.45 (each m, 2ꢃ5H), 4.02e3.87 (m,
2H), 3.40e3.22 (m, 2H), 3.05e2.68 (m, 6H), 2.42e2.22
(m, 4H), 2.21e1.11 (m, 20H), 0.94 (t, J¼7.2 Hz, 3H), 0.93
(t, J¼7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): d 170.4,
170.2, 143.6, 143.5, 130.8 (4C), 129.1 (4C), 123.9, 123.8,
56.2, 56.2, 54.7, 54.5, 43.8, 43.6, 34.6, 34.6, 31.8, 31.7,
26.0, 25.9, 20.5, 20.5, 19.2 (2C), 16.9 (2C), 13.9 (2C); IR
(neat): nmax 3055 (w), 2955 (m), 2872 (m), 1634 (s), 1473
(m), 1446 (m), 1086 (m), 1045 (m), 751 (m) cmꢂ1. MS: m/z
(%) relative intensity 308 (Mþþ1, 7), 290 (29), 182 (100),
180 (27), 112 (67). HRMS (ESI): calcd for C17H25NO2NaS,
330.1504; found, 330.1511.
4.3.3.6.
1-Phenylsulfinyl-5-hexyl-1,2,3,5,6,7,8,9-octahydro-
4.3.3.4. 6-Hexyl-1-(3-phenylsulfinylpropyl)piperidin-2-one (4c).
According to the general procedure described for 4a, a
solution of 10b (2.38 g, 7.15 mmol) in MeOH (5 mL) was
treated with a suspension of NaIO4 (1.68 g, 7.85 mmol) in
MeOH (16 mL) and H2O (4 mL). The crude product was
purified by column chromatography (SiO2, 100% EtOAc) to
afford a colorless viscous liquid of 4c (2.18 g, 87% yield)
as a mixture of two diastereomers. 1H NMR (300 MHz,
indolizine (6b). According to the general procedure described
for 5, the reaction of LiHMDS (15.4 mmol) in THF (77 mL)
with a THF (14 mL) solution of 4c (2.42 g, 6.93 mmol) gave
a viscous liquid of a crude product (2.20 g, 6.65 mmol). The
crude product obtained was dissolved in MeOH (34 mL) and
treated with NaBH4 (1.62 g, 42.63 mmol). After the usual
work-up, the crude product was purified by column chroma-
tography (SiO2, 2% MeOH in EtOAc containing 0.15%

2346
M. Pohmakotr et al. / Tetrahedron 64 (2008) 2339e2347
NH4OH solution) to afford two separated diastereomers 6bA
and 6bB.
d 3.01e2.93 (m, 1H), 2.88 (dt, J¼8.9, 3.4 Hz, 1H, C3-He),
2.71 (q, J¼8.2 Hz, 1H, C3-Ha), 2.63e2.52 (m, 1H), 1.91e
1.31 (m, 14H), 0.94 (t, J¼7.2 Hz, 3H). 13C NMR (100 MHz,
CDCl3): d 55.8, 55.8, 49.3, 31.5, 31.0, 28.0, 26.5, 21.4, 21.3,
19.8, 14.9; IR (neat): nmax 2930 (s), 2872 (s), 2804 (m),
1457 (m) cmꢂ1. MS: m/z (%) relative intensity 168 (Mþþ1,
9), 167 (Mþ, 67), 150 (26), 149 (100), 124 (40), 122 (38),
96 (31), 55 (25). The spectroscopic data were consistent
with the literature.7e
F1 (less polar) was obtained as a yellow solid of 6bA
[1.08 g, 47% yield; mp 54e56 ꢁC (EtOAc)]. 1H NMR
(300 MHz, CDCl3): d 7.59e7.37 (m, 5H), 3.09 (t, J¼8.2 Hz,
1H), 3.05 (ddd, J¼9.3, 7.7, 6.0 Hz, 1H), 2.42e2.26 (m, 2H),
2.04e1.79 (m, 5H), 1.72e1.52 (m, 2H), 1.47e1.10 (m,
12H), 0.88 (t, J¼6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3):
d 143.7, 130.3, 128.9 (2C), 124.2 (2C), 66.8, 66.4, 64.2,
50.6, 34.0, 31.7, 29.8, 29.6, 27.7, 25.5, 24.9, 22.5, 17.6,
14.0. IR (Nujol): nmax 2783 (s), 1441 (s), 1376 (s), 1084 (s),
1045 (s), 751 (s), 704 (s) cmꢂ1. MS: m/z (%) relative intensity
334 (Mþþ1, 1), 316 (30), 122 (100), 94 (16).
4.3.3.9. (ꢀ)-Indolizidine 209D (2b). According to the general
procedure described for (ꢀ)-indolizidine 167B (2a), the reac-
tion of 6bA (0.23 g, 0.69 mmol), NiCl2$6H2O (1.63 g,
6.86 mmol), and NaBH4 (0.79 g, 20.79 mmol) in a mixture
of THF (2 mL) and MeOH (6 mL) gave a pale yellow liquid
of a crude product, which was purified by column chromato-
graphy (Al2O3, hexanes) to afford a colorless liquid of (ꢀ)-in-
dolizidine 209D (2b) (0.116 g, 80% yield). 1H NMR
(400 MHz, CDCl3): d 3.26 (dt, J¼8.7, 2.0 Hz, 1H, C3-He),
1.97 (q, J¼8.8 Hz, 1H, C3-Ha), 1.92e1.07 (m, 22H), 0.89
(app t, J¼6.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 65.6,
64.5, 52.1, 35.2, 32.4, 31.5, 31.4, 31.1, 30.3, 26.4, 25.3,
23.2, 21.0, 14.6; IR (neat): nmax 2781 (s), 1457 (m), 1381
(m), 1129 (m) cmꢂ1. MS: m/z (%) relative intensity 210
(Mþþ1, 6), 149 (35), 124 (100), 96 (43). The spectroscopic
data were consistent with the literature.7e
F2 (more polar) was obtained as a yellow solid of 6bB
[1.04 g, 45% yield; mp 58e60 ꢁC (EtOAc)]. 1H NMR
(300 MHz, CDCl3): d 7.88e7.59 (m, 5H), 3.10e2.91 (m,
3H), 2.91 (dt, J¼8.6, 2.3 Hz, 1H), 2.62 (q, J¼8.0 Hz, 1H),
2.47e2.24 (m, 1H), 2.03e1.63 (m, 4H), 1.60e1.06 (m,
13H), 0.88 (t, J¼6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3):
d 143.4, 130.3, 128.8 (2C), 124.1 (2C), 65.9, 56.9, 55.4,
48.1, 31.8, 29.5, 27.4, 27.1, 25.8, 23.5, 22.5, 19.2, 17.5,
14.0; IR (Nujol): nmax 2783 (m), 1461 (m), 1039 (s), 750
(m) cmꢂ1. MS: m/z (%) relative intensity 334 (Mþþ1, 1),
316 (29), 248 (10), 123 (25), 122 (100). HRMS (ESI): calcd
for C20H32NOS, 334.2205; found, 334.2209.
4.3.3.7. (ꢀ)-Indolizidine 167B (2a). General procedure. A
stirred solution of 6aA (0.21 g, 0.72 mmol) and NiCl2$6H2O
(1.56 g, 6.56 mmol) in a 1:3 mixture of THF and MeOH
(6 mL) was cooled to 0 ꢁC. NaBH4 (0.79 g, 20.79 mmol)
was added in small portions within 20 min at such a rate
that the temperature was kept below 10 ꢁC. The mixture was
stirred at room temperature for 2 h. The black precipitate
was filtered off over Celite and washed with hexanes
(3ꢃ20 mL). The combined extracts were washed with H2O
and brine, and dried over anhyd Na2SO4. Filtration followed
by concentration in vacuo gave a colorless liquid of a crude
product, which was purified by column chromatography
(Al2O3, hexanes) to afford a colorless liquid of (ꢀ)-indolizi-
4.3.3.10. (ꢀ)-epi-Indolizidine 209D (epi-2b). According to the
general procedure described for (ꢀ)-indolizidine 167B (2a),
a
reaction of 6bB (0.236 g, 0.71 mmol), NiCl2$6H2O
(1.64 g, 6.90 mmol), and NaBH4 (0.79 g, 20.79 mmol) in
a mixture of THF (2 mL) and MeOH (6 mL) gave a pale yel-
low liquid of a crude product, which was purified by column
chromatography (Al2O3, 100% hexanes) to afford a colorless
1
liquid of epi-2b (0.127 g, 86% yield). H NMR (300 MHz,
CDCl3): d 2.97e2.87 (m, 1H, C5-H), 2.82 (dt, J¼8.8,
3.2 Hz, 1H, C3-He), 2.64 (q, J¼8.4 Hz, 1H, C3-Ha), 2.53e
2.40 (m, 1H), 1.94e1.01 (m, 20H), 0.92e0.79 (m, 3H). 13C
NMR (75 MHz, CDCl3): d 55.5, 55.1, 48.7, 31.9, 31.2, 30.6,
29.6, 27.6, 27.5, 23.4, 22.6, 20.8, 19.3, 14.0. IR (neat): nmax
2929 (s), 2859 (s), 2804 (m), 1459 (m) cmꢂ1. MS: m/z (%) rela-
tive intensity 209 (Mþ, 2), 149 (28), 124 (100), 96 (53). The
spectroscopic data were consistent with the literature.7e
1
dine 167B (2a) (0.098 g, 82% yield). H NMR (400 MHz,
CDCl3): d 3.29 (dt, J¼8.7, 2.2 Hz, 1H, C3-He), 1.97 (q,
J¼9.0 Hz, 1H, C3-Ha), 1.93e1.09 (m, 16H), 0.91 (t,
J¼7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 65.6, 64.3,
52.0, 37.4, 31.5, 31.3, 31.1, 25.2, 20.9, 19.6, 15.0. IR (neat):
nmax 2781 (s), 1458 (m), 1129 (m), 1056 (w) cmꢂ1. MS: m/z
(%) relative intensity 168 (Mþþ1, 6), 124 (100), 96 (73), 81
(21). The spectroscopic data were consistent with the
literature.7e
Acknowledgements
We thank Center for Innovation in Chemistry: the Postgrad-
uate Education and Research Program in Chemistry (PERCH-
CIC), the Thailand Research Fund (BRG49800005 to M.P.)
and the Commission on Higher Education (CHE-RES-RG)
for financial support.
4.3.3.8. (ꢀ)-epi-Indolizidine 167B (epi-2a). According to the
general procedure described for (ꢀ)-indolizidine 167B (2a),
a reaction of 6aB (0.28 g, 0.96 mmol), NiCl2$6H2O (2.08 g,
8.75 mmol), and NaBH4 (1.14 g, 30 mmol) in a mixture of
THF (2.5 mL) and MeOH (7.5 mL) gave a pale yellow liquid
of a crude product, which was purified by column chromato-
graphy (Al2O3, 100% hexanes) to afford a colorless liquid of
epi-2a (0.118 g, 74% yield). 1H NMR (400 MHz, CDCl3):
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2008.01.008.

M. Pohmakotr et al. / Tetrahedron 64 (2008) 2339e2347
2347
6. For some recent syntheses of indolizidine 167B, see: (a) Peroche, S.;
Remuson, R.; Gelas-Mialhe, Y.; Gramain, J.-C. Tetrahedron Lett. 2001,
42, 4617e4619; (b) Michael, J. P.; Gravestock, D. Pure Appl. Chem.
1997, 69, 583e588; (c) Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.;
Bosch, J. J. Org. Chem. 2003, 68, 1919e1928; (d) Zaminer, J.; Stapper,
C.; Blechert, S. Tetrahedron Lett. 2002, 43, 6739e6741; (e) Back, T. G.;
Nakajima, K. Org. Lett. 1999, 1, 261e263; (f) Chalard, P.; Remuson, R.;
Gelas-Mialhe, Y.; Gramain, J.-C.; Canet, I. Tetrahedron Lett. 1999, 40,
1661e1664.
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