Synthesis of alkylated indolizidine alkaloids via Pummerer mediated cyclization: synthesis of (±)-indolizidine 167B, (±)-5-butylindolizidine and (±)-monomorine I

Article abstract of DOI:10.1016/j.tet.2007.12.013

The syntheses of indolizidine alkaloids, i.e., (±)-coniceine, (±)-indolizidine 167B, (±)-5-butylindolizidine and (±)-monomorine I via Pummerer cyclization are described. The key step is the transformation of lactam sulfoxide to bicyclic lactam via the Pum

Full text of DOI:10.1016/j.tet.2007.12.013

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1663e1670
www.elsevier.com/locate/tet
Synthesis of alkylated indolizidine alkaloids via Pummerer mediated
cyclization: synthesis of (ꢀ)-indolizidine 167B, (ꢀ)-5-butylindolizidine
and (ꢀ)-monomorine I
a
b
Chutima Kuhakarn a, , Phachanee Seehasombat , Thaworn Jaipetch ,
*
Manat Pohmakotr a, Vichai Reutrakul a
a Department of Chemistry, Faculty of Science, Mahidol University, Rama VI Road, Bangkok 10400, Thailand
b Mahidol University, Kanchanaburi Campus, Saiyok, Kanchanaburi 71150, Thailand
Received 3 October 2007; received in revised form 16 November 2007; accepted 6 December 2007
Available online 8 December 2007
Abstract
The syntheses of indolizidine alkaloids, i.e., (ꢀ)-coniceine, (ꢀ)-indolizidine 167B, (ꢀ)-5-butylindolizidine and (ꢀ)-monomorine I via Pum-
merer cyclization are described. The key step is the transformation of lactam sulfoxide to bicyclic lactam via the Pummerer cyclization.
Ó 2007 Elsevier Ltd. All rights reserved.
H
N
H
N
1. Introduction
N
Indolizidine alkaloids have become important targets for
the synthesis in the past few decades due to their vast array
of structural diversity and biological activity.1 A consider-
able number of synthetic strategies, both racemic and enan-
tioselective syntheses, have been developed for the
preparation of substituted indolizidines.2,3 As witnessed by
several review papers, Pummerer-based reaction is a power-
ful methodology and has been widely used as a key step for
the synthesis of nitrogen heterocycles.4 Our ongoing re-
search interest in sulfur chemistry led us to investigate the
Pummerer cyclization as an alternative route to indolizidine
alkaloids, i.e., (ꢀ)-coniceine (1), (ꢀ)-indolizidine 167B (2),
Bu
Me
R
Coniceine (1)
Monomorine (4)
R = n-Pr, Indolizidine 167B (2)
R = n-Bu, 5-Butylindolizidine (3)
Scheme 1. Indolizidine alkaloids.
which, in turn, could be synthesized via a five-step sequence
starting from the commercially available methyl 2-oxocyclo-
pentanecarboxylate (Scheme 2).
intramolecular
Pummerer reaction
3
N
5
N
NH
(ꢀ)-5-butylindolizidine (3) and (ꢀ)-monomorine
I (4)
R1
R2
SPh
S Ph
O
O
(Scheme 1).
O
3,5-dialkylated
indolizidines
We envisioned the lactam sulfide 5 as a key intermediate
leading to 3,5-alkylated indolizidine derivatives. The construc-
tion of the bicyclic sulfide 5 should be achieved by the intra-
molecular Pummerer cyclization of the lactam sulfoxide 6
5
5 steps
OMe
O
O
* Corresponding author. Tel.: þ66 2 201 5155; fax: þ66 2 354 7151.
E-mail address: scckk@mahidol.ac.th (C. Kuhakarn).
Scheme 2. Synthetic strategy.
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.12.013

1664
C. Kuhakarn et al. / Tetrahedron 64 (2008) 1663e1670
H
3
H
N
2. Results and discussion
3
N
d 5.66
H
H
d 5.31
The synthesis of the lactam sulfoxide 6 is outlined in
Scheme 3. Alkylation of methyl 2-oxocyclopentanecarboxy-
late using sodium hydride with 1,3-dibromopropane followed
by the reaction with thiophenol in the presence of triethyl-
amine afforded b-ketoester 7.5 Krapcho decarboxylation of
b-ketoester 7 with NaCN in refluxing DMSO afforded ketosul-
fide 8 in high yield.6 The ketosulfide 8 was transformed quan-
titatively to oxime 9 as a single isomer (13C NMR analysis) by
the treatment with hydroxylamine hydrochloride and sodium
acetate in aqueous ethanol. Beckmann rearrangement gave
lactam sulfide 10 which could be converted to lactam sulfox-
ide 6 employing NaIO4 in aqueous MeOH. The lactam sulfox-
ide 6 was obtained as a 1:1 mixture of two diastereomers (13C
NMR analysis).
(dd, J = 7.8, 5.4 Hz)
(d, J = 6.3 Hz)
O
O
SPh
cis-5
SPh
trans-5
NOE Experiments
X
X
H
8a
H
N
O
N
H
PhS
H
O
SPh
trans-5
Figure 1. Relative stereochemistry of lactam sulfide 5.
diastereomers (trans/cis¼5:1) (Fig. 1). The H-3 signal of the
trans-5 appeared as a doublet of doublets at d 5.66 (J¼7.8
and 5.4 Hz) whereas that of the cis-5 exhibited as a doublet
at d 5.31 with J¼6.3 Hz (Fig. 1). The H-3 (equatorial,
d 5.66 ppm) of trans-5 appeared at lower field than H-3 (axial,
d 5.31 ppm) of the cis-5. This can be explained by a strong de-
shielding effect by the lone pair electrons of the proximate ni-
trogen atom.9 The relative stereochemistry of trans-5 could
also be confirmed by NOE experiments as shown in Figure 1.
No enhancement in the signal of H-8a was observed when H-3
was irradiated, and vice versa. Desulfurization by treatment of
lactam sulfide 5 with tri-n-butyltin hydride and AIBN in re-
fluxing toluene furnished bicyclic lactam 12 in good yield
(Scheme 4).10 It is worth mentioning that the known bicyclic
lactam 12 was previously synthesized via different routes.11
Its spectral characteristics are identical to those reported in
the literature.11a,b
SPh
a
b
OMe
SPh
OMe
57%
87%
O
O
O
O
O
8
7
c
quantitative
e
95%
d
SPh
NH
NH
64%
S
Ph
S Ph
N
O
O
O
HO
6
10
9
1:1 mixture of
two diastereomers
OMe
f
OTBDMS
85%
11
a
b
N
N
N
75%
ref. 12
N
SPh
O
O
Coniceine (1)
SPh
5
12
O
5
c or d ref. 13
H
Scheme 3. Reagents and conditions: (a) (i) NaH (1.2 equiv), DMF, 1,3-dibro-
mopropane (3 equiv), rt, 20 h; (ii) PhSH (1.05 equiv), Et3N (1.25 equiv), THF,
0 ꢁC to rt, 24 h; (b) NaCN (1.2 equiv), DMSO, 160 ꢁC, 3 h; (c) NH2OH$HCl
(1.2 equiv), NaOAc (1.73 equiv), aq EtOH; (d) 1 N NaOH (1.1 equiv),
PhSO2Cl (1.1 equiv), acetone, rt, 24 h; (e) NaIO4 (1.15 equiv), aq MeOH,
0 ꢁC to rt, 24 h; (f) ZnI2 (10 mol %), 11 (2 equiv), CH3CN, rt, 24 h.
N
R
R = n-Pr, Indolizidine 167B (2)
R = n-Bu, 5-Butylindolizidine (3)
Having successfully prepared the lactam sulfoxide 6, we
then explored the ring closure to form a fused bicyclic lactam
5 based upon the Pummerer reaction. Pummerer reaction using
trifluoroacetic anhydride in acetonitrile or TMSOTf/Et3N in
CH2Cl2 gave the desired lactam sulfide 5 in low yield. Grati-
fyingly, a satisfactory result was obtained using silicon-in-
duced Pummerer reaction first reported by Kita employing
an O-silylated ketene acetal.7,8 Treatment of lactam sulfoxide
6 with 2.0 equiv of O-silylated ketene acetal 11 in the presence
of a catalytic amount of zinc iodide (10 mol %) in dry CH3CN
at room temperature for 24 h afforded lactam sulfide 5 in high
yield (85%) (Scheme 3).
Scheme 4. Synthesis of indolizidine alkaloids 1e3. Reagents and conditions:
(a) n-Bu3SnH (2.5 equiv), AIBN (0.3 equiv), toluene, reflux 20 h; (b) LiAlH4
(2.54 equiv), THF, reflux 15 h; (c) (i) n-PrMgBr (3 equiv), THF, 0 ꢁC to rt, 4 h;
(ii) AcOH then NaBH4 (2 equiv), 0 ꢁC, 1 h; (d) (i) n-BuMgCl (3 equiv), THF,
0 ꢁC to rt, 4 h; (ii) AcOH then NaBH4 (2 equiv), 0 ꢁC, 1 h.
The bicyclic lactam 12 was readily transformed to (ꢀ)-coni-
ceine (1),12 (ꢀ)-indolizidine 167B (2)13 and (ꢀ)-5-butylindoli-
zidine (3)13 by following the previously reported procedures
(Scheme 4). The spectral data (1H and 13C NMR) of the syn-
thesized 111a,14 and 215 were completely identical to those re-
ported in the literature. The relative stereochemistry of 3 was
assigned by comparison with the spectral data of 2. It is worth
mentioning that the relative stereochemical outcome of 2 and 3
1H (500 MHz) and 13C (125 MHz) NMR analyses showed
that the lactam sulfide 5 was obtained as a mixture of two

C. Kuhakarn et al. / Tetrahedron 64 (2008) 1663e1670
1665
H
N
was predicted based on the stereoelectronic principles of
Stevens.16 In addition, compounds 1, 2 and 3 also exhibited
Bohlmann peaks at 2780, 2782 and 2781 cmꢂ1, respectively,
in their IR spectra.
MeMgBr
then
AcOH
N
Bu
Me
H
Bu
H
H
H
O
cis-14
To further demonstrate the synthetic utility of the key inter-
mediate lactam sulfide 5, the synthesis of (ꢀ)-monomorine I
(4) was undertaken (Scheme 5). It was planned to install the
butyl substituent of monomorine I using Ley’s protocol.17
Therefore, treatment of lactam sulfide 5 using m-CPBA in
CH2Cl2 yielded the corresponding sulfone 13 as a single dia-
stereomer (trans) after column chromatography followed by
crystallization. The sulfone 13 was treated with the butyl or-
ganometallic reagent prepared from n-butylmagnesium chlo-
ride and zinc chloride to yield alkylated lactam 14 which
consists of two inseparable diastereomers (cis/trans¼3:2) as
determined by 1H NMR (500 MHz) analysis. The relative ste-
reochemistry of 14 was assigned by comparison with the 13C
NMR spectrum of the known cis-14, which was reported by
Jones and co-workers.18 The H-3 proton of cis-14 appeared
as a triplet at d 3.96 ppm (J¼7.6 Hz), which corresponded
well with the value reported by Jones and co-workers
(d 3.94 ppm, multiplet).18 The H-3 proton of trans-14 ex-
hibited a multiplet between d 4.12 and 4.04 ppm. According
to the published procedure, treatment of 14 (3:2 mixture of
cis/trans) with methylmagnesium bromide followed by acidifi-
cation and NaBH4 reduction gave the desired (ꢀ)-monomorine
I (4) as a single isomer in 50% yield (based on cis-14) as
shown in Scheme 5.2c It should be emphasized that the other
possible product, (ꢀ)-indolizidine 195B derived from the reac-
NaBH4
Me
N
Bu
H
H
H
Monomorine I (4)
H
N
N
H
MeMgBr
Me
H
H
then
AcOH
Bu
O
Bu
H
trans-14
slow
NaBH4
Me
H
N
H
H
Bu
Indolizidine 195B
Not observed
Scheme 6.
hydrolysis during aqueous work-up, leading to water soluble
salt. The stereochemical outcome of this reaction could be ex-
plained based on the stereoelectronic principles of Stevens.16
Thus, addition of methylmagnesium bromide followed by
acidification afforded an iminium ion intermediate, which
was reduced from the pseudoaxial direction to give the target
(ꢀ)-monomorine I (4) as a single isomer (Scheme 6). The
spectral data (1H and 13C NMR) of (ꢀ)-monomorine I (4)
were identical to those reported in the literature.19
1
tion of trans-14 was not isolated. In addition, H NMR of the
crude material also did not show, to significant degree, the
presence of a multiplet signal at d 3.31e3.26 (1H) belonging
to (ꢀ)-indolizidine 195B.19 This could be attributed to a slower
rate of reduction of the iminium ion intermediate due to steric
hindrance from the n-butyl substituent at the pseudoaxial po-
sition. The unreacted iminium ion was believed to undergo
3. Conclusion
We have described an alternative route for the preparation
of 3-alkyl- and 3,5-dialkylindolizidines. The synthesis was
achieved starting from the commercially available methyl 2-
oxocyclopentanecarboxylate by the exploitation of silicon-
induced Pummerer reaction as the key step to form the key
precursor lactam sulfide 5 (six steps, 26%). Transformation
of the lactam sulfide 5 to (ꢀ)-coniceine (1), (ꢀ)-indolizidine
167B (2), (ꢀ)-5-butylindolizidine (3) and (ꢀ)-monomorine I
(4) was carried out according to the existing procedures.
H
N
H
N
a
30%
b
3
N
H
R2
63%
R1
SO2Ph
O
O
O
SPh
R1 = H, R2 = Bu; cis-14
5
trans
-13
(single isomer)
2
R1 = Bu, R = H; trans-14
trans:cis= 5:1
cis:trans = 3:2
50%
c
based on cis-14
4. Experimental
H
N
4.1. General
Bu
1H and 13C NMR spectra were recorded on a Bruker DPX-
300 (300 MHz) or a Bruker AV-500 (500 MHz) spectrometer
using CDCl3 as a solvent with tetramethylsilane as an internal
standard. Chemical shifts (d) reported are given in parts per
million (ppm) and the coupling constants (J) are in hertz
(Hz). Melting points were determined on electrothermal
Me
Monomorine I (4)
Scheme 5. Synthesis of (ꢀ)-monomorine I (4). Reagents and conditions: (a)
m-CPBA (2.1 equiv), CH2Cl2, 0 ꢁC to rt, 16 h; (b) n-BuMgCl (2 equiv),
ZnCl2 (1.2 equiv), CH2Cl2, 0 ꢁC to rt, 24 h; (c) (i) MeMgBr (3.5 equiv),
THF, reflux, 5 h; (ii) AcOH then NaBH4 (11.6 equiv), 0 ꢁC, 2 h.

1666
C. Kuhakarn et al. / Tetrahedron 64 (2008) 1663e1670
melting point apparatus (Electrothermal 9100) and were un-
corrected. The IR spectra were recorded on a Jasco A-302
spectrometer or a Perkin Elmer 683 Infrared spectrometer.
The EI mass spectra were recorded by using a Thermo Finni-
gan Polaris Q mass spectrometer. The high-resolution mass
spectra (HRMS) were recorded on a Bruker Esquire apparatus.
Elemental analyses were performed by a Perkin Elmer Ele-
mental Analyzer 2400 CHN. Column chromatography was
performed using silica gel 60 (70e230 mesh). Preparative
thin layer chromatography (PLC) was performed with silica
gel 60 PF254. Analytical TLC was performed with silica gel
60 PF254 aluminium sheet with 0.2 mm layer of silica gel.
The plates of radial chromatography were prepared by using
silica gel 60 PF254 with CaSO4$1/2H2O.
106 (16), 95 (11), 81 (10), 79 (7), 67 (12). Anal. Calcd for
C16H20O3S: C, 65.72; H, 6.89. Found: C, 65.83; H, 6.75.
4.3. 2-(3-Phenylsulfanylpropyl)cyclopentanone (8)
A mixture of methyl 1-(3-phenylsulfanylpropyl)-2-oxocy-
clopentanecarboxylate (7) (5.84 g, 20.0 mmol), sodium cya-
nide (1.18 g, 24.0 mmol) and DMSO (40 mL) was stirred at
160 ꢁC for 3 h under an argon atmosphere. After cooling,
the reaction mixture was poured into ice-water and extracted
with hexanes (4ꢃ100 mL). The combined organic layers were
washed with brine (50 mL), dried over anhydrous Na2SO4, fil-
tered and concentrated (in vacuo). The residue was purified by
column chromatography on silica gel (25ꢃ3.5 cm, 1:3 ethyl
acetate/hexanes eluent) to afford 8 (4.07 g, 87% yield) as
colourless oil: analytical TLC on silica gel, 1:3 ethyl acetate/
hexanes, Rf¼0.38. IR (neat): nmax 2938 (CeH), 1736 (C]
4.2. Methyl 1-(3-phenylsulfanylpropyl)-2-oxocyclo-
pentanecarboxylate (7)
1
O) cmꢂ1. H NMR (300 MHz, CDCl3): d 7.34e7.22 (4H, m),
To a suspension of NaH (6.28 g, 144.0 mmol; 55e65% sus-
pension in mineral oil) in DMF (100 mL), methyl 2-oxocyclo-
pentanecarboxylate (15.2 mL, 120.0 mmol) was slowly added
at room temperature under an argon atmosphere. The reaction
mixture was further stirred until the evolution of hydrogen gas
ceased (2 h) before 1,3-dibromopropane (36 mL, 360.0 mmol)
was added. After the reaction mixture was stirred at room tem-
perature for 20 h, it was poured into ice-water and extracted
with hexanes (4ꢃ200 mL). The combined organic layers
were washed with water (2ꢃ100 mL), brine (2ꢃ100 mL),
dried over anhydrous Na2SO4 and filtered. The filtrate was
evaporated and distilled under reduced pressure to remove
the unreacted 1,3-dibromopropane (32 ꢁC, 0.8 mmHg). The
resulting bromide was obtained as an orange liquid (27.78 g,
ca. 105.6 mmol), which was used in the next step without fur-
ther purification. Thiophenol (11.3 mL, 110.0 mmol) was
added dropwise at 0 ꢁC to a solution of Et3N (18.4 mL,
132.0 mmol) in THF (340 mL) under an argon atmosphere.
The resulting mixture was stirred at 0 ꢁC for 0.5 h. To this
mixture, was slowly added a solution of crude bromide
(27.78 g, ca. 105.6 mmol) in THF (60 mL). After being stirred
and slowly warmed up to room temperature for 24 h, the reac-
tion mixture was diluted with water (100 mL) and extracted
with hexanes (4ꢃ100 mL). The combined organic layers
were washed with brine (100 mL), water (100 mL) and dried
over anhydrous Na2SO4. Filtration followed by evaporation
gave a crude yellow liquid, which was purified by column
chromatography on silica gel (30ꢃ8.0 cm, 1:4 ethyl acetate/
hexanes eluent) to provide 7 (19.87 g, 57% yield) as a pale
yellow liquid: analytical TLC on silica gel, 1:4 ethyl acetate/
hexanes, Rf¼0.25. IR (neat): nmax 2953 (CeH), 1750 (C]O,
7.19e7.14 (1H, m), 2.99e2.84 (2H, m), 2.35e1.65 (9H, m),
1.55e1.34 (2H, m). 13C NMR (75 MHz, CDCl3): d 220.8,
136.5, 128.97, 128.8, 125.7, 48.6, 38.0, 33.5, 29.5, 28.8, 27.1,
20.6. MS (EI): m/z (%) relative intensity 235 (Mþþ1, 31), 234
(Mþ, 45), 125 (100), 110 (8), 95 (10), 79 (7), 67 (6), 55 (7).
Anal. Calcd for C14H18OS: C, 71.75; H, 7.74. Found: C,
71.55; H, 7.94.
4.4. 2-(3-Phenylsulfanylpropyl)cyclopentanone oxime (9)
A solution of 2-(3-phenylsulfanylpropyl)cyclopentanone
(8) (3.78 g, 16.18 mmol) in EtOH (30.0 mL) was added to a so-
lution of hydroxylamine hydrochloride (1.35 g, 19.42 mmol)
and sodium acetate (2.30 g, 27.96 mmol) in water (20.0 mL).
This mixture was stirred for 4 h at reflux and then for 18 h
at room temperature. The reaction mixture was evaporated
to remove EtOH, extracted with ethyl acetate (3ꢃ100 mL),
washed with brine (50 mL), dried over anhydrous Na2SO4
and filtered. Evaporation of the solvent left thick oil, which
was crystallized from ethyl acetate/hexanes, yielding 9
(4.03 g, quantitatively) as a white solid: analytical TLC on sili-
ca gel, 1:4 ethyl acetate/hexanes, Rf¼0.28, mp¼79e81 ꢁC. IR
(KBr): nmax 3261 (OeH), 2952 (CeH) cmꢂ1 1H NMR
.
(300 MHz, CDCl3): d 7.33e7.24 (4H, m), 7.18e7.13 (1H,
m), 6.50e5.50 (1H, br), 2.98e2.85 (2H, m), 2.63e2.34 (2H,
m), 2.10e1.30 (9H, m). 13C NMR (75 MHz, CDCl3): d 169.2,
136.7, 129.0, 128.8, 125.7, 42.7, 33.6, 31.6, 31.3, 27.3, 27.1,
22.4. MS (EI): m/z (%) relative intensity 250 (Mþþ1, 14),
233 (16), 232 (83), 149 (29), 140 (10), 123 (19), 122 (36),
109 (7), 105 (8), 97 (100), 94 (11), 79 (11), 77 (8), 67 (6),
65 (6). Anal. Calcd for C14H19NOS: C, 67.43; H, 7.68; N,
5.62. Found: C, 67.58; H, 7.63; N, 5.36.
ester), 1725 (C]O, ketone) cmꢂ1 1H NMR (500 MHz,
.
CDCl3): d 7.32e7.26 (4H, m), 7.19e7.15 (1H, m), 3.67 (3H,
s), 2.95e2.85 (2H, m), 2.53e2.48 (1H, m), 2.40 (1H, ddd,
J¼18.9, 8.7, 5.4 Hz), 2.25 (1H, dt, J¼18.9, 8.4 Hz), 2.11e
1.50 (7H, m). 13C NMR (125 MHz, CDCl3): d 214.3, 171.2,
136.3, 129.2, 128.8, 125.9, 60.1, 52.4, 37.7, 33.8, 32.9, 32.8,
24.5, 19.5. MS (EI): m/z (%) relative intensity 293 (Mþþ1,
29), 292 (Mþ, 25), 215 (100), 183 (35), 123 (62), 109 (7),
4.5. 6-(3-Phenylsulfanylpropyl)piperidin-2-one (10)
A solution of 2-(3-phenylsulfanylpropyl)cyclopentanone
oxime (9) (0.75 g, 3.0 mmol) in acetone (7.0 mL) was treated
with 1 N NaOH (3.3 mL, 3.3 mmol) at 0 ꢁC. To this stirred
mixture was added benzenesulfonyl chloride (0.42 mL,

C. Kuhakarn et al. / Tetrahedron 64 (2008) 1663e1670
1667
3.3 mmol) dropwise, and the resulting mixture was stirred at
room temperature (24 h). The reaction mixture was poured
into water and extracted with ethyl acetate (3ꢃ50 mL). The
combined organic layer was washed with brine (20 mL), dried
over anhydrous Na2SO4, filtered, and concentrated to afford
crude mixture as yellow oil. The crude material was purified
by column chromatography on silica gel (30ꢃ4.0 cm, 1%
MeOH/CH2Cl2 eluent) to afford 10 (0.48 g, 64% yield) as
a white solid: analytical TLC on silica gel, 2% MeOH/
CH2Cl2, Rf¼0.34, mp¼106e108 ꢁC. IR (KBr): nmax 3194
55 (38), 51 (13). Anal. Calcd for C14H19NO2S: C, 63.36; H,
7.22; N, 5.28. Found: C, 63.55; H, 7.05; N, 5.40.
4.7. 3-(Phenylsulfanyl)hexahydro-indolizin-5-one (5)
A solution of ZnI2 (40 mg, 0.12 mmol) in CH3CN (5 mL)
was added to a solution of 6-(3-benzenesulfinylpropyl)piperi-
din-2-one (6) (0.253 g, 0.952 mmol) in CH3CN (20 mL) at
room temperature under an argon atmosphere. Subsequen-
tly, tert-butyl-1-(methoxyvinyloxy)dimethylsilane (0.42 mL,
1.91 mmol) was added to the reaction mixture. The solution
was stirred at room temperature for 24 h before it was
quenched by the addition of a saturated NaHCO3 (20 mL).
The mixture was extracted with CH2Cl2 (3ꢃ30 mL). The com-
bined organic layers were washed with brine (30 mL), dried
over anhydrous Na2SO4. Filtration followed by evaporation
gave a crude product, which was purified by radial chromato-
graphy (chromatotron; 1 mm plate, gradient 20e50% ethyl
acetate/hexanes eluent) to provide 5 (0.200 g, 85% yield,
trans/cis¼5:1 determined by 1H NMR) as a colourless oil: an-
alytical TLC on silica gel, 3:2 ethyl acetate/hexanes, Rf¼0.30.
(NeH), 2950 (CeH), 1663 (C]O) cmꢂ1
.
1H NMR
(300 MHz, CDCl3): d 7.34e7.26 (4H, m), 7.21e7.16 (1H, m),
6.48 (1H, br s), 3.37 (1H, br m), 2.93 (2H, t, J¼6.0 Hz), 2.42e
2.22 (2H, m), 1.90e1.87 (2H, m), 1.73e1.60 (5H, m), 1.39e
1.25 (1H, m). 13C NMR (75 MHz, CDCl3): d 172.7, 136.0,
129.3, 128.9, 126.1, 52.8, 35.7, 33.5, 31.0, 28.0, 24.9, 19.4.
MS (EI): m/z (%) relative intensity 250 (Mþþ1, 19), 249
(Mþ, 21), 216 (22), 185 (16), 174 (26), 141 (10), 140 (100),
135 (17), 126 (35), 113 (22), 112 (40), 98 (54), 96 (25), 84
(14), 83 (18), 82 (34), 79 (5), 77 (6), 71 (32), 55 (31). Anal.
Calcd for C14H19NOS: C, 67.43; H, 7.68; N, 5.62. Found: C,
67.56; H, 7.82; N, 5.52.
1
IR (CHCl3): nmax 3003 (CeH), 1635 (C]O) cmꢂ1. H NMR
(500 MHz, CDCl3, minor isomer marked*): d 7.58e7.50 (4H,
m, o-ArH of major and minor isomers), 7.33e7.25 (6H, m, m-
and p-ArH of major and minor isomers), 5.66 (1H, dd, J¼7.8,
5.4 Hz, C3eH), 5.31* (1H, d, J¼6.3 Hz, C3eH), 3.45e3.34
(2H, m, C8aeH of major and minor isomers), 2.49e2.38
(2H, m, C6eH of major and minor isomers), 2.37e2.19 (4H,
m, C2eH and C6eH of major and minor isomers), 2.15e
2.02 (4H, m, C1eH and C8eH of major and minor isomers),
2.00e1.82 (4H, m, C2eH and C7eH of major and minor iso-
mers), 1.69e1.53 (2H, m, C7eH of major and minor isomers),
1.45e1.37 (2H, m, C1eH of major and minor isomers), 1.32*
(1H, qd, J¼12.1, 4.6 Hz, C8eH), 1.22 (1H, qd, J¼12.5,
3.0 Hz, C8eH). 13C NMR (125 MHz, CDCl3, minor isomer
marked*): d 169.7*, 168.3 (C]O), 134.8, 134.1* (2ꢃCH,
C-20 and C-60), 132.8, 131.2* (C, C-10), 128.8*, 128.7
(2ꢃCH, C-30 and C-50), 128.1, 127.8* (CH, C-40), 65.1*,
63.0 (CH, C-3), 60.1*, 58.1 (CH, C-8a), 32.6*, 32.0 (CH2,
C-1), 31.5, 31.4* (CH2, C-6), 30.5, 30.3* (CH2, C-2), 29.3,
29.0* (CH2, C-8), 20.9*, 20.5 (CH2, C-7). MS (EI): m/z
(%) relative intensity 248 (Mþþ1, 35), 247 (Mþ, 2), 139
(10), 138 (MþꢂSPh, 100), 120 (7), 111 (7), 110 (18), 96 (14),
82 (11), 67 (5). Anal. Calcd for C14H17NOS: C, 67.98; H,
6.93; N, 5.66. Found: C, 67.58; H, 6.64; N, 5.32. HRMS
(ESI) calcd for C14H18NOS [MþH]þ: 248.1109; found:
248.1107.
4.6. 6-(3-Benzenesulfinylpropyl)piperidin-2-one (6)
A solution of 6-(3-phenylsulfanylpropyl)piperidin-2-one
(10) (1.37 g, 5.50 mmol) in MeOH (25 mL) was slowly added
at 0 ꢁC to a solution of NaIO4 (1.35 g, 6.33 mmol) in water
(15 mL). The mixture was stirred vigorously and slowly
warmed up to room temperature for 20 h. The white precipi-
tates of NaIO3 were filtered and washed several times with
CH2Cl2. The filtrate was diluted with water and extracted
with CH2Cl2 (3ꢃ100 mL). The combined extracts were
washed with water (50 mL), brine (50 mL) and dried over an-
hydrous Na2SO4. Filtration followed by evaporation gave
a crude product, which was purified by radial chromatography
(chromatotron; 2 mm plate, gradient 0e10% MeOH/ethyl ace-
tate eluent) to provide a white solid of 6 (1.39 g, 95% yield)
as a 1:1 mixture of two diastereomers: analytical TLC on silica
gel, 5% MeOH/CHCl3, Rf¼0.26, mp¼115.0e115.2 ꢁC. IR
(KBr): nmax 3204 (NeH), 2940 (CeH), 1660 (C]O), 1480,
1447, 1409, 1301, 1145, 1088, 1036 (S]O) cmꢂ1. H NMR
1
(500 MHz, CDCl3): d 7.64e7.60 (2ꢃ2H, m, ArH), 7.56e
7.49 (2ꢃ3H, m, ArH), 6.79 (1H, br s, eCONH), 6.73 (1H,
br s, eCONH), 3.44e3.33 (2ꢃ1H, br m, CONHCHe), 2.87e
2.75 (2ꢃ2H, m, eCH2SOPh), 2.41e2.32 (2ꢃ1H, m, eCH2e),
2.31e2.23 (2ꢃ1H, m, eCH2e), 1.93e1.78 (2ꢃ3H, m,
eCH2e), 1.76e1.50 (2ꢃ4H, m, eCH2e), 1.40e1.29 (2ꢃ1H,
m, eCH2e). 13C NMR (125 MHz, CDCl3): d 172.65 (C]
O), 172.59 (C]O), 143.6 (C), 143.5 (C), 131.05 (CH), 131.0
(CH), 129.2 (4ꢃCH), 123.9 (4ꢃCH), 56.6 (CH2), 56.4 (CH2),
52.63 (CH), 52.57 (CH), 35.64 (CH2), 35.58 (CH2), 31.1
(2ꢃCH2), 27.83 (CH2), 27.80 (CH2), 19.44 (CH2), 19.40
(CH2), 18.1 (CH2), 17.9 (CH2). MS (EI): m/z (%) relative inten-
sity 266 (Mþþ1, 7), 248 (33), 140 (67), 139 (10), 138 (82), 136
(25), 135 (12), 126 (18), 112 (14), 110 (15), 98 (27), 97 (26), 96
(100), 84 (11), 82 (18), 79 (11), 78 (25), 77 (11), 70 (24), 67 (9),
4.8. 5-Oxoindolizidine (12)
3-(Phenylsulfanyl)hexahydro-indolizin-5-one (5) (0.978 g,
3.95 mmol) was dissolved in toluene (15 mL) and tri-n-butyl-
tin hydride (2.83 mL, 9.88 mmol) was added. Subsequently,
a solution of azo(bis)isobutyronitrile (0.195 g, 1.19 mmol) in
toluene (5 mL) was added to the reaction mixture. The result-
ing mixture was refluxed at 120 ꢁC (20 h). After cooling to
room temperature, toluene was removed in vacuo and the

1668
C. Kuhakarn et al. / Tetrahedron 64 (2008) 1663e1670
residue was dissolved in acetonitrile (100 mL). This solution
was washed with hexanes (4ꢃ30 mL) and dried over anhy-
drous Na2SO4. Filtration followed by evaporation gave a crude
product, which was purified by column chromatography on
silica gel (20ꢃ2.5 cm, 2% MeOH/CH2Cl2 eluent) to afford
12 (0.410 g, 75% yield) as a colourless oil: analytical TLC
on silica gel, 2% MeOH/CH2Cl2, Rf¼0.21. IR (neat): nmax
temperature and further stirred for additional 4 h. The reaction
mixture was cooled to 0 ꢁC (ice-water bath) and glacial acetic
acid (0.2 mL) was added, followed by NaBH4 (0.050 g,
1.31 mmol). The ice-bath was removed and the mixture was
stirred for 1 h. Subsequently, diethyl ether (40 mL) was added
and the solution was washed with 7.5% KOH (20 mL). The
aqueous layer was extracted with diethyl ether (40 mL), and
the combined organic layer was washed with brine (20 mL),
dried over anhydrous Na2SO4. Filtration followed by evapora-
tion gave a crude product, which was purified by column chro-
matography on Al2O3 (type 507 C neutral, 8ꢃ0.7 cm, 1:6
diethyl ether/hexanes eluent) to afford 3 (0.060 g, 51% yield)
as a colourless oil: IR (neat): nmax 2932 (CeH), 2860, 2781
1
1635 (C]O) cmꢂ1. H NMR (500 MHz, CDCl3): d 3.63e
3.50 (1H, m), 3.50e3.30 (2H, m), 2.50e2.20 (2H, m),
2.16e2.03 (2H, m), 2.00e1.83 (2H, m), 1.82e1.55 (2H, m),
1.50e1.15 (2H, m). 13C NMR (125 MHz, CDCl3): d 169.1,
59.2, 44.7, 33.4, 30.8, 29.0, 22.0, 21.0. MS (EI): m/z (%) rela-
tive intensity 141 (Mþþ2, 28), 139 (Mþ, 54), 111 (54), 105
(28), 99 (49), 97 (61), 85 (48), 83 (55), 81 (55), 71 (82), 69
(49), 67 (48), 57 (100), 55 (58). HRMS (ESI) calcd for
C8H13NONa [MþNa]þ: 162.0895; found: 162.0925. The
spectral characteristics (1H and 13C NMR) of 12 are identical
with those reported in the literature.11a,b
(Bohlmann band), 2709, 1457 cmꢂ1 1H NMR (300 MHz,
.
CDCl3): d 3.20 (1H, td, J¼8.6, 1.9 Hz), 1.90 (1H, q, J¼
8.9 Hz), 1.81e1.52 (9H, m), 1.43e1.01 (9H, m), 0.83 (3H,
t, J¼6.8 Hz). 13C NMR (125 MHz, CDCl3): d 65.2, 63.9,
51.4, 34.1, 30.7, 30.6, 30.4, 28.0, 24.6, 23.0, 20.3, 14.0. MS
(EI): m/z (%) relative intensity 182 (Mþþ1, 1), 181 (Mþ, 3),
180 (18), 149 (2), 138 (3), 125 (10), 124 (100), 122 (4), 97
(2), 96 (20), 94 (2), 81 (2), 79 (2), 77 (1), 67 (2). HRMS (ESI)
calcd for C12H24N [MþH]þ: 182.1908; found: 182.1941.
4.9. (ꢀ)-Indolizidine 167B (2)
5-Oxoindolizidine (12) (0.182 g, 1.31 mmol) was dissolved
in dry THF (4.0 mL) and the solution was brought to 0 ꢁC (ice-
bath). To this solution, was slowly added n-propylmagnesium
bromide (2.0 mL of a 2.0 M solution in THF, 4.0 mmol). The
reaction mixture was warmed to room temperature and further
stirred for additional 4 h. The reaction mixture was cooled to
0 ꢁC (ice-water bath) and glacial acetic acid (0.4 mL) was
added, followed by NaBH4 (0.100 g, 2.62 mmol). The ice-
bath was removed and the mixture was stirred for 1 h. Subse-
quently, diethyl ether (20 mL) was added and the solution was
washed with 7.5% KOH (10 mL). The aqueous layer was ex-
tracted with diethyl ether (20 mL), and the combined organic
layer was washed with brine (10 mL), dried over anhydrous
Na2SO4. Filtration followed by evaporation gave a crude prod-
uct, which was purified by column chromatography on Al2O3
(type 507 C neutral, 8ꢃ0.7 cm, 1:6 diethyl ether/hexanes elu-
ent) to afford (ꢀ)-indolizidine 167B (2) (0.072 g, 33% yield)
as a colourless oil: IR (neat): nmax 2957 (CeH), 2857, 2782
4.11. trans-3-(Benzenesulfonyl)hexahydroindolizin-5-one
(trans-13)
A solution of 3-(phenylsulfanyl)hexahydro-indolizin-5-one
(5) (1.044 g, 4.22 mmol) in CH2Cl2 (20 mL) was slowly added
to a solution of m-CPBA (1.52 g, 8.86 mmol) in CH2Cl2
(30 mL) at 0 ꢁC. The mixture was stirred vigorously and
slowly warmed up to room temperature for 16 h before it
was quenched by the addition of saturated NaHCO3
(20 mL). The mixture was extracted with CH2Cl2 (3ꢃ
30 mL). The combined organic layers were washed with water
(30 mL), brine (30 mL) and dried over anhydrous Na2SO4. Fil-
tration followed by evaporation gave a crude product, which
was purified by column chromatography on silica gel
(30ꢃ3.0 cm, 4:1 ethyl acetate/hexanes eluent) followed by
crystallization from ethyl acetate/hexanes to provide trans-
13 (0.355 g, 30% yield) as a white solid (Fig. 2): analytical
TLC on silica gel, 4:1 ethyl acetate/hexanes, Rf¼0.25, mp¼
116e118 ꢁC. IR (KBr): nmax 2978 (CeH), 1651 (C]O),
1585, 1435, 1406, 1331, 1309 (O]S]O), 1152 (O]S]O),
1
(Bohlmann band), 2710 cmꢂ1. H NMR (300 MHz, CDCl3):
d 3.20 (1H, td, J¼8.6, 2.2 Hz), 1.90 (1H, q, J¼8.9 Hz), 1.82e
1.48 (9H, m), 1.45e1.00 (7H, m), 0.84 (3H, t, J¼7.1 Hz). 13
C
NMR (125 MHz, CDCl3): d 65.0, 63.7, 51.6, 36.9, 31.1, 30.9,
30.6, 24.7, 20.4, 19.1, 14.5. MS (EI): m/z (%) relative intensity
168 (Mþþ1, 5), 167 (Mþ, 49), 166 (5), 150 (11), 149 (10), 125
(8), 124 (100), 121 (6), 97 (5), 95 (6), 83 (6), 81 (7), 71 (8), 57
(7). The spectral characteristics (1H and 13C NMR) of (ꢀ)-
indolizidine 167B (2) are identical with those reported in the
literature.15
1
1084, 733, 690 cmꢂ1. H NMR (500 MHz, CDCl3): d 7.91e
7.89 (2H, m), 7.67e7.64 (1H, m), 7.56e7.53 (2H, m), 5.63
(1H, dd, J¼9.1, 4.2 Hz), 3.99e3.93(1H, m), 2.69e2.62(1H, m),
2.42e2.35 (1H, m), 2.31e2.23 (1H, m), 2.21e2.14 (2H, m),
2.11e2.03 (1H, m), 1.88e1.82 (1H, m), 1.74e1.63 (1H, m),
1.60e1.52 (1H, m), 1.27e1.18 (1H, m). 13C NMR (125 MHz,
Hb
Hb
4.10. (ꢀ)-5-Butylindolizidine (3)
Ha
Ha
1
2
Ha
Ha
8
N
H
He
7
8a
3
5
5-Oxoindolizidine (12) (0.091 g, 0.654 mmol) was dis-
solved in dry THF (2.0 mL) and the solution was brought to
0 ꢁC (ice-bath). To this solution, was slowly added n-butyl-
magnesium chloride (1.0 mL of a 2.0 M solution in THF,
2.0 mmol). The reaction mixture was warmed to room
He
6
eHa
O
O
S
Ha
H
Ph
trans-13
O
Figure 2.

C. Kuhakarn et al. / Tetrahedron 64 (2008) 1663e1670
1669
CDCl3): d 169.5, 138.3, 134.9, 130.1, 129.8, 76.0, 60.1, 33.1,
32.0, 30.1, 23.1, 21.0. MS (EI): m/z (%) relative intensity 279
(Mþ, 2), 168 (2), 167 (13), 150 (4), 149 (36), 139 (11), 138
(MþꢂSO2Ph, 100), 137 (6), 120 (12), 111 (7), 110 (25), 109
(7), 95 (28), 82 (25), 81 (10), 80 (17), 71 (10), 67 (15), 57
(11), 55 (13). HRMS (ESI) calcd for C14H18NO3S [MþH]þ:
280.1007; found: 280.1005.
a solution of 14 (a mixture of cis/trans¼3:2, 0.033 g,
0.17 mmol) in THF (4 mL) at room temperature under an ar-
gon atmosphere. The mixture was brought to refluxing temper-
ature for 5 h. The reaction was cooled to 0 ꢁC followed by the
addition of glacial acetic acid (0.2 mL) and NaBH4 (0.076 g,
2.0 mmol) in MeOH (2 mL). After being stirred at 0 ꢁC for
2 h, the mixture was diluted with water (20 mL), and made al-
kaline with saturated aqueous NaHCO3 before it was extracted
with CH2Cl2 (3ꢃ10 mL). The combined organic layers were
dried over anhydrous Na2SO4. Filtration followed by evapora-
tion gave a crude product, which was purified by column chro-
matography on Al2O3 (8ꢃ0.7 cm, 1:6 diethyl ether/hexanes
eluent) to afford (ꢀ)-monomorine I (4) (0.010 g, 50% yield
(based on cis-14)) as colourless oil: 1H NMR (300 MHz,
CDCl3): d 2.50e2.30 (1H, m), 2.28e2.10 (1H, m), 2.08e
1.95 (1H, m), 1.85e1.52 (5H, m), 1.50e1.00 (11H, m), 1.08
(3H, d, J¼6.1 Hz), 0.82 (3H, t, J¼6.8 Hz). 13C NMR
(125 MHz, CDCl3): d 67.2, 62.9, 60.3, 39.7, 35.9, 31.0,
30.3, 29.8, 29.4, 24.9, 22.9, 22.8, 14.1. MS (EI): m/z (%) rela-
tive intensity 196 (Mþþ1, 3), 195 (Mþ, 1), 180 (MþꢂMe, 11),
139 (11), 138 (MþꢂBu, 100), 124 (8), 110 (4), 95 (6), 70 (17).
The spectral characteristics (1H and 13C NMR) of (ꢀ)-mono-
morine I ((ꢀ)-4) are identical with those reported in the
literature.19
4.12. 3-(Butyl)hexahydroindolizin-5-one (14)
A solution of n-butylmagnesium chloride (2.0 M solution in
THF, 1.1 mL, 2.18 mmol) was slowly added to a solution of
anhydrous zinc chloride (1 M solution in THF, 1.31 mL,
1.31 mmol) in dry CH2Cl2 (6.5 mL) at 0 ꢁC and the mixture
was stirred under argon for 30 min to afford the organozinc
species. A solution of trans-13 (0.304 g, 1.089 mmol) in dry
CH2Cl2 (5.5 mL) was then slowly added to the organozinc
species and stirring was continued at 0 ꢁC to room temperature
for 24 h. The reaction was quenched with saturated aqueous
NH4Cl (5 mL) and extracted with CH2Cl2 (3ꢃ20 mL). The
combined organic extracts were dried over anhydrous
Na2SO4. Filtration followed by evaporation gave a crude prod-
uct, which was purified by column chromatography on silica
gel (15ꢃ1.5 cm, 60% ethyl acetate/hexanes eluent) to afford
14 (0.130 g, 63% yield, cis/trans¼3:2 determined by 1H
NMR) as a colourless oil: analytical TLC on silica gel, 60%
ethyl acetate/hexanes, Rf¼0.37. IR (neat): nmax 2955 (CeH),
2933, 2861, 1623 (C]O), 1466, 1451, 1413, 1373,
Acknowledgements
1
We gratefully acknowledge financial support from the Cen-
ter for Innovation in Chemistry, Postgraduate Education and
Research Program in Chemistry (PERCH-CIC) and the Com-
mission on Higher Education (CHE-RES-RG).
1328 cmꢂ1. H NMR (500 MHz, CDCl3): d 4.12e4.04 (1H,
m, C3eH of trans-14), 3.96 (1H, t, J¼7.6 Hz, C3eH of cis-
14), 3.46e3.40 (1H, m, C8aeH of trans-14), 3.37 (1H, tdd,
J¼11.3, 5.0, 3.0 Hz, C8aeH of cis-14), 2.45 (1H, dd,
J¼18.0, 6.2 Hz, C6eH of trans-14), 2.39e2.21 (3H, m; 2H
for C6eH of cis-14 and 1H for C6eH of trans-14), 2.12e
1.85 (9H, m; 4H for cis-14 and 5H for trans-14), 1.83e1.62
(6H, m; 3H for each isomer), 1.61e1.52 (1H, m, cis-14),
1.49e1.42 (1H, m, trans-14), 1.39e1.14 (11H, m; 6H for
cis-14 and 5H for trans-14), 0.90 (3H, t, J¼7.1 Hz, eCH3 of
trans-14), 0.89 (3H, t, J¼7.2 Hz, eCH3 of cis-14). 13C
NMR (125 MHz, CDCl3, minor isomer marked*): dC 169.4,
168.7* (C]O), 59.9, 58.7* (CH, C-8a), 57.3, 57.0* (CH,
C-3), 34.1* (CH2), 33.0* (CH2), 32.4 (CH2), 31.6* (CH2),
31.3 (CH2), 31.0 (CH2), 29.4* (CH2), 29.3 (CH2), 28.8
(CH2), 28.7* (CH2), 27.6* (CH2), 27.5 (CH2), 22.7* (CH2),
22.6 (CH2), 21.1 (CH2), 20.8* (CH2), 14.0 (CH3 of both iso-
mers). MS (EI): m/z (%) relative intensity 197 (Mþþ2, 14),
196 (Mþþ1, 96), 195 (Mþ, 14), 166 (6), 152 (6), 139 (29),
138 (MþꢂBu, 100), 120 (11), 111 (6), 110 (26), 95 (20), 82
(19), 67 (9). HRMS (ESI) calcd for C12H22NO [MþH]þ:
196.1701; found: 196.1715. The spectral characteristics (1H
and 13C NMR) of cis-14 are identical with those reported in
the literature.18
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