New synthesis and reactions of indolizidine 167E and indolizidine derivatives

Article abstract of DOI:10.1016/j.tet.2012.10.026

Two new methods of synthesizing indolizidines via ring-closing metathesis (RCM) have been developed. One method utilizes an alkene-isomerization, and the other method uses N-vinylation of an amide as the key step. Indolizidine 167E and many derivatives ha

Full text of DOI:10.1016/j.tet.2012.10.026

Tetrahedron 69 (2013) 274e283
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New synthesis and reactions of indolizidine 167E and indolizidine
derivatives
*
Shang-Shing P. Chou , Shan-Lun Chiang, Guan-Lin Huang, Bi-Shan Chiang, Ya-Chien Yu
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:
Received 14 August 2012
Received in revised form 21 September 2012
Accepted 9 October 2012
Available online 16 October 2012
Two new methods of synthesizing indolizidines via ring-closing metathesis (RCM) have been developed.
One method utilizes an alkene-isomerization, and the other method uses N-vinylation of an amide as the
key step. Indolizidine 167E and many derivatives have also been synthesized.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Indolizidines
Indolizidine 167E
Ring-closing metathesis
Alkene-isomerization
N-Vinylation
1. Introduction
2. Results and discussion
The piperidine ring is among the most abundant molecular
fragments in both natural and synthetic compounds with various
biological activities.1 The aza-DielseAlder reaction is one of the
most versatile routes to substituted piperidines.2 In general, the use
of strongly electron-deficient imines is a prerequisite. We have
reported a new aza-DielseAlder reaction of thio-substituted 3-
sulfolenes (1) with p-toluenesulfonyl isocyanate (PTSI) to give the
cyclized products 2, which upon treatment with acid or base afford
the conjugated products 3 (Scheme 1).3 We have also used this
method to prepare some indolizidines and quinolizidines,4 which
are important framework of many natural products.5 We now re-
port some new synthetic transformations of indolizidines as well as
two new methods of synthesizing indolizidines via ring-closing
metathesis (RCM).6 There are only a few examples in the litera-
ture for making indolizidines via RCM of piperidine derivatives.7
2.1. Reactions of indolizidines
The thio-substituted indolizidine 44b could be converted to the
alkyl-substituted compounds 5a4f and 5b by treatment with an
organocopper reagent8 in the presence of boron trifluoride ether-
ate. Catalytic hydrogenation of compounds 5 was efficiently carried
out to give products 6 (Scheme 2). Compound 6a is identical with
the literature report,9 and compound 6b has similar spectral data as
compound 6a. Thus, hydrogenation of indolizidines 5 occurs pref-
erentially from the less hindered exo face.
R
N
R
N
SPh
RLi (7 eq), CuI (3.5 eq)
.
H
2 (1 atm)
BF3 EtO2 (5.5 eq)
H
THF, 78 oC to rt, 24 h
PtO2 (15 mol%)
EtOAc, rt, 1 d
O
O
N
O
SPh
SPh
Ts
N C O
5a, R = CH3 (96%)
5b, R = Bu (76%)
6a, R = CH3 (96%)
6b, R = Bu (95%)
SPh
4
NaHCO3
acid
or base
R
N
Ts
O
hydroquinone (cat.)
Tol, reflux, 4.5 h
R
N
Ts
O
R
Scheme 2.
S
O2
1
3
Compound 4 was oxidized by mCPBA to the sulfone 7. Further
treatment with 5% sodium amalgam gave indolizidine 8 (Scheme
3), which had been prepared by a different route in the literature.10
Compound 8 underwent conjugate addition with an organo-
copper reagent in the presence of boron trifluoride etherate to give
products 9a and 9b in good yield (Scheme 4). Diastereomeric pairs
6a/9a, and 6b/9b have distinctive 13C NMR absorptions especially at
2
Scheme 1.
* 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.
http://dx.doi.org/10.1016/j.tet.2012.10.026

S.-S.P. Chou et al. / Tetrahedron 69 (2013) 274e283
275
R1
R1
SPh
R2Li
R1
SO2Ph
mCPBA (6 eq)
5% Na/Hg (8 eq)
H
R2
O
R2
OH2
H
H
H
CH2Cl2, rt, 3.5 h
THF, H3PO4
reflux, 30 min
N
O
N
O
N
O
N
N
O
N
8 (73%)
7 (89%)
6
A
B
4
R1
Scheme 3.
R1
N
H
from above
-H2O
H
H
R2
N
R2
C-7 and C-8a (Experimental section). Thus, we can stereoselectively
synthesize both the cis- and trans-7,8a-disubstituted indolizidi-
nones 6 and 9, respectively. The stereospecific formation of products
9 from compound 8 is probably due to both steric (from the less
hindered convex side) and stereoelectronic (axial attack) effects.
C
11
Scheme 7.
structure of its benzoate 14 (Fig. 1).14 Thus, the hydride attacks the
ketone 13 from the less hindered exo face.
R
RLi (7 eq), CuI (3.5 eq)
7
H
8a
O
N
SPh
BF3 . OEt2 (5.5 eq)
THF, 78 oC to rt, 24 h
N
O
N
O
c.HBr (excess)
NaBH4 (10 eq)
9a, R = CH3 (76%)
9b, R = Bu (72%)
MeOH, 50 oC to rt, 4 h
O
8
95% EtOH
75 oC, 10 h
N
O
Scheme 4.
12 (92%)
4
OH
N
OBz
Following the literature method of using N-methylmorpholine
oxide (NMO) and a catalytic amount of OsO4 for dihydroxylation of
alkenes,11 compound 8 was converted to the cis-diol 10 (Scheme 5).
The stereochemistry of compound 10 was determined by the NOESY
spectrum. This also agrees with the expectation that the dihydrox-
ylation occurs from the less hindered exo face of compound 8.
BzCl (3 eq), Et3N (3 eq)
CH2Cl2, reflux, 12 h
H
H
O
N
O
13 (86%)
14 (51%)
Scheme 8.
OH
OH
NMO (1.2 eq), OsO4 (cat.)
H
N
O
acetone/t-butanol/H2O, rt, 8 h
N
O
8
10 (85 %)
Scheme 5.
The reaction of compounds 6a and 6b with an alkyllithium re-
agent, followed by sequential treatment with acetic acid and
methanolic NaBH4, provided (ꢀ)-8a-epi-dendroprimine (11a) and
cis-5,7-disubstituted indolizidines 11b and 11c, respectively
(Scheme 6). The spectral data of compound 11a is identical with the
literature report,9a,12 and those of compounds 11b and 11c are also
consistent with the literature trends.13
R1
N
R1
7
1) R2Li (3 eq), THF, rt, 5 h
2) CH3CO2H (5 eq), 0 oC, 10 min
H
H
5
R2
O
N
3) NaBH4 (10 eq), CH3OH
0 oC, 3 h
11a, R1, R2 = CH3 (68%)
6a, R1 = CH3
6b, R1 = Bu
11b, R1 = CH3 , R2 = Bu (53%)
11c, R1 = Bu, R2 = CH3 (78%)
Scheme 6.
The stereoselective formation of products 11 from compounds 6
can be explained as in Scheme 7. The organolithium reagent attacks
the amide 6 to form the intermediate A, which upon treatment
with an acid would give the intermediate B. Further dehydration
generates the iminium ion C, which is then attacked by the hydride
from the less hindered convex side to give products 11.
Treatment of compound 4 with hot concentrated HBr hydro-
lyzed the vinyl sulfide group to provide the ketone product 12.
Further reduction with NaBH4 afforded the alcohol 13 (Scheme 8),
the stereochemistry of which was determined from the X-ray
Fig. 1. X-ray crystal structure of compound 14.
2.2. New synthesis of indolizidines via RCM
Although we were successful in synthesizing the quinolizidines
16a and pyridoazepines 16b,c fromthe piperidines 15 via ring-closing
metathesis (RCM) (Scheme 9),4c the corresponding indolizidine
structures (16, m¼1, n¼0; or m¼0, n¼1) could not be made because

276
S.-S.P. Chou et al. / Tetrahedron 69 (2013) 274e283
our methodology could not provide the piperidines 15 with m¼0 or
n¼0. We now report two new methods of synthesizing indolizidines
from structurally modified piperidines 15 (m¼0 or n¼0).
the C]C bond. Presumably, the ring strain of the expected epoxide
product would disfavor its formation.
SO2Ph
SPh
mCPBA (2.3 eq)
PCy3
Cl2Ru
PCy3
Ph
SPh
N
SPh
N
CH2Cl2, rt, 1 h
N
O
N
O
21a
22 (81%)
(
)
O
( )
O
(5 mol%)
m
m
(
)
R2
Scheme 11.
(
)
R1
R1
n
n
R2
Reaction of compound 21a with CH3Li/CuI (2:1) with the acti-
vation17 of BF3$OEt2 led to a good yield of the methyl-substituted
product 23 (Scheme 12). It should be emphasized that, without
the BF3$OEt2 or with insufficient amounts of BF3$OEt2, this reaction
did not proceed at all or gave very low yields of the product 23.
15
16a, m = 1, n = 1
16b, m = 1, n = 2
16c, m = 2, n = 1
Scheme 9.
Our synthesis of new sulfur-substituted indolizidines 21 is
shown in Scheme 10. Following a literature method,15a treat-
ment of the allyl-substituted dihydropyridone 173b with vinyl-
oxytrimethylsilane in the presence of Grubbs’ catalyst (G1) in
refluxing toluene gave the 1-propenyl-substituted product 18 in
excellent yield. We propose that under the reaction conditions
a ruthenium hydride complex is first generated,15b which then
undergoes an insertion reaction with the terminal double bond
SPh
N
CH3
N
CH3Li (7 eq), CuI (3.5 eq), THF
BF3.OEt2 (5.5 eq), 78 oC to rt, 1.5 h
O
O
21a
23 (67%)
Scheme 12.
Following a reported procedure,18 treatment of compound 21a
with methylmagnesium bromide, followed by sequential acidifi-
cation with acetic acid and reduction with sodium borohydride,
gave stereospecifically the cis product 24 (Scheme 13). Its stereo-
chemistry was confirmed by NOESY spectrum.
of compound 17. Subsequent b-hydride elimination would then
give the alkene-isomerized product 18. Compound 18 was
detosylated by Parson’s method16 of Bu3SnH/AIBN to give the
amide 19. Treatment of compound 19 with BuLi at low tem-
perature, followed by reactions with allylic bromides in the
presence of HMPA, gave the N-allylated products 20a and 20b. It
was found that compound 20a reacted with Grubbs’ catalyst G1
at room temperature to yield the indolizidine product 21a.
However, the RCM reaction of the methyl-substituted compound
20b required the use of Grubbs’ catalyst G2 at higher tempera-
tures; the best reaction condition was to use microwave heating
at 170 ꢁC.
SPh
N
SPh
1) MeMgBr (4 eq), THF, 60 oC, 2.5 h
2) HOAc (5 eq), 0 oC, 10 min
H
H
N
O
3) NaBH4 (4 eq), CH3OH, 0 o
C
24 (67%)
21a
Scheme 13.
SPh
SPh
Our second new method of constructing the indolizidine skel-
eton via RCM is shown in Scheme 14. Modifying the literature re-
action conditions,19 amide 253b underwent N-vinylation with vinyl
bromides in the presence of CuI (1 or 2 equiv), base (K2CO3 or
Cs2CO3) and N,N0-dimethylethylenediamine (1 or 2 equiv) to give
the substitution products 26 in fair to excellent yields. The RCM was
efficiently carried out with Grubbs’ catalyst G2 in refluxing CH2Cl2
to afford the indolizidines 27a and 27b. It should be noted that if
the RCM of compound 26b was carried out with the G2 catalyst in
toluene in a sealed tube at 120 ꢁC, the exocyclic alkene 28 was
obtained instead of compound 27b. This is probably because
Bu3SnH (2.2 eq)
AIBN (0.2 eq)
(10 eq)
OSiMe3
Tol, reflux, 2 h
G1 (10 mol%)
Tol, reflux, 10 h
N
Ts
O
N
Ts
O
18 (93%)
17
SPh
N
SPh
1) BuLi (1.3 eq), HMPA (4 eq)
THF, 78 oC, 30 min
O
R
N
H
O
R
2)
(4 eq), 78 oC to rt, 2 h
Br
20a, R = H (77%)
20b, R = Me (54%)
19 (92%)
Br
SPh
SPh
SPh
(2 eq), CuI
NHMe
for 20a, G1 (5 mol%)
CH2Cl2, rt, 24 h
PCy3
Ru
PCy3
Ms
N
N
Ms
R
Ph
Cl
Cl
Cl
Cl
N
R
O
N
O
N
H
O
Ru
PCy3
MeHN
for 20b, G2 (5 mol%)
Ph
tol, M.W. 170 oC, 2 h
K2CO3, Tol, heat
R
G1
25
26a, R = Me (77%)
26b, R = Et (80%)
G2
21a, R = H (67%)
21b, R = Me (52%)
SPh
SPh
Scheme 10.
G2 (5 mol%)
CH2Cl2, reflux, 5 h
N
O
N
O
R
We have also carried out some functional group transformations
of indolizidine 21a. Treatment of compound 21a with mCPBA gave
the sulfone 22 in good yield (Scheme 11). Further reaction of
compound 22 with additional 2.3 equiv of mCPBA did not oxidize
27a, R = Me (77%)
27b, R = Et (80%)
28 (79%)
Scheme 14.

S.-S.P. Chou et al. / Tetrahedron 69 (2013) 274e283
277
compound 27b is more strained than compound 28, and at higher
temperature the RCM reaction is reversible to give the more stable
product 28. The X-ray crystal structure of compound 28 (Fig. 2)14
shows the E configuration of the exocyclic double bond. Com-
pound 27b as compared to compound 28 is quite easily hydrolyzed
by aqueous acid. Thus, we would use compound 28 for further
synthetic transformations.
Treatment of compound 30 with hot concentrated HBr hy-
drolyzed the vinyl sulfide group to provide the ketone product
32. Further reduction with NaBH4 afforded the alcohol 32
(Scheme 17), the stereochemistry of which was proven by X-ray
crystallography (Fig. 3).14 Thus, the hydride attacks the ketone 32
from the less hindered exo face. Since the structure of compound
33 has now been established by X-ray crystallography, the
structure of indolizidine 167E (Scheme 16) is further confirmed
other than by the spectroscopic method provided in the
literature.20
O
N
SPh
N
HBr (excess)
H
H
95 EtOH, 70 oC, 14 h
3
30 (57%)
32 (67%)
OH
N
NaBH4 (10 eq), MeOH
78 oC to rt, 6 h
H
Fig. 2. X-ray crystal structure of compound 28.
Catalytic hydrogenation of compound 27a gave a mixture of cis
and trans isomers, 29a and 29b in a ratio of 3:1 (Scheme 15). This
stereoselectivity is probably due to steric effect. Previously, we
reported that mercuric ion promoted the intramolecular cyclization
of a secondary amide with the alkene side chain to give a 1:1
mixture of 29a and 29b.4a Thus, we can now slightly improve the
stereoselectivity of the indolizidine formation.
33 (72%)
Scheme 17.
SPh
N
SPh
SPh
H2 (1 atm)
H
H
+
PtO2 (15 mol%)
EtOAc, rt, 1 d
O
N
O
N
O
27a
29a
29b
3:1 (66%)
Scheme 15.
The reaction of compound 28 with methylmagnesium bromide,
followed by sequential treatment with acetic acid and methanolic
NaBH(OAc)3, led to product 30 (Scheme 16), the stereochemistry of
which was proven by its further reaction with Raney nickel to give
compound 31, indolizidine 167E. If NaBH4 or NaCNBH3 were used as
SPh
N
SPh
N
1) MeMgBr (4 eq), THF, 60 oC, 2 h
H
2) HOAc (5 eq), 0 oC, 10 min
3) NaBH(OAc)3 (10 eq), MeOH
O
3
0
oC, 2 h; rt, 2 h
30 (57%)
28
Fig. 3. X-ray crystal structure of compound 33.
Raney-Ni (20 eq)
H
N
95 EtOH, reflux, 2 h
3. Conclusions
31 (88%)
indolizidine 167E
We have extended our previously developed method of aza-
DielseAlder reaction to construct new indolizidine structures. We
have also established two new methods of synthesizing indolizi-
dines via ring-closing metathesis (RCM). One method utilizes an
alkene-isomerization of compound 17 to compound 18, and the
other method uses N-vinylation of amide 25 as the key step. Ster-
eoselective synthesis of indolizidine 167E (31) and many de-
rivatives have been achieved.
Scheme 16.
the reducing agent, a C-3 epimer would also be obtained. Indoli-
zidine 167E was isolated from the venom of the ant Solenopsis
conjurata,20 and has only been synthesized twice before.21 We have
recently reported a tandem cross metathesis and intramolecular
aza-Michael reaction to synthesize indolizidine 167E.22

278
S.-S.P. Chou et al. / Tetrahedron 69 (2013) 274e283
4. Experimental section
1228, 1217, 908, 730, 704 cmꢂ1 1H NMR (CDCl3)
; d 5.96 (1H, dq,
J¼6.3, 2.1 Hz), 5.81 (2H, dq, J¼6.3, 2.1 Hz), 5.78 (1H, d, J¼1.5 Hz),
4.70e4.57 (1H, m), 4.41 (1H, ddt, J¼16.5, 4.8, 2.4 Hz), 4.15 (1H, ddt,
J¼16.5, 3.6, 2.4 Hz), 2.36e2.24 (1H, m),1.93 (3H, s); 13C NMR (CDCl3)
4.1. General
Melting points were determined with a SMP3 melting appa-
ratus. 1H and 13C NMR spectra were recorded on a Bruker Avance
300 spectrometer operating at 300 and at 75 MHz, respectively.
d 163.1, 149.3, 128.9, 127.4, 121.3, 62.2, 51.4, 35.1, 22.9; EI-MS (rel
intensity) m/z 149 (Mþ, 89), 148 (50), 82 (100), 68 (50), 54 (24), 39
(32), 17 (32); EI-HRMS calcd for C9H11NO m/z 149.0841 (Mþ), found
149.0841.
Chemical shifts (d) are reported in parts per million (ppm) from the
internal reference standard tetramethylsilane (TMS), and the
coupling constants (J) are given in Hertz. High resolution mass
spectra (HRMS) were measured with a mass spectrometer Fin-
nigan/Thermo Quest MAT 95XL. Elemental analyses were carried
out with Heraeus Vario III-NCSH, Heraeus CHNeOeS-Rapid Ana-
lyzer, or Elementar Vario EL III. Flash column chromatographic
purifications were performed using Merck 60 H silica gel. The
microwave reactions were carried out with a CEM FocusedÔ
Discover-S system.
4.3. cis-7-Methyl-1,2,3,5,6,7,8,8a-octahydro-5-indolizinone
(6a)
To a solution of compound 5a (54.2 mg, 0.358 mmol) in ethyl
acetate (2 mL) in an Erlenmyer flask was added PtO2 (12.0 mg). A
hydrogen balloon was attached to the flask through a needle. The
reaction mixture was vigorously stirred for 1 d, and more ethyl
acetate was added to filter the reaction mixture through Celite. The
filtrate was dried (MgSO4) and concentrated to give pure product
4.2. General procedure for the BF3$OEt2-promoted cuprate
addition reactions
6a (52.5 mg, 96%) as a colorless oil: IR (neat)
n
2955, 1619, 1455,
1413, 1324, 920, 727 cmꢂ1 1H NMR (CDCl3)
;
d 3.62e3.50 (1H, m),
3.50e3.38 (2H, m), 2.50 (1H, d, J¼15.3 Hz), 2.15e2.00 (2H, m),
2.00e1.70 (4H, m), 1.52e1.35 (1H, m), 1.15e0.95 (4H, m); 13C NMR
4.2.1. 7-Butyl-1,2,3,5,8,8a-hexahydro-5-indolizinone (5b). To a mix-
ture of CuI (407 mg, 2.13 mmol) in THF (1.5 mL) at 0 ꢁC was added
dropwise a solution of BuLi (2.5 M in THF,1.71 mL, 4.28 mmol). After
stirring at 0 ꢁC for 30 min, the mixture was cooled to ꢂ78 ꢁC, and
BF3$OEt2 (0.43 mL, 3.36 mmol) was added and stirred for 5 min.
Then a solution of compound 4 (150 mg, 0.61 mmol) in THF
(1.5 mL), precooled at ꢂ78 ꢁC, was added dropwise. The reaction
mixture was slowly warmed to room temperature, stirred for an-
other 24 h, and quenched with saturated ammonium chloride. The
aqueous solution was extracted with CH2Cl2, combined with the
organic layer, dried (MgSO4), and concentrated under vacuum. The
crude product was purified by flash chromatography using ethyl
acetate/hexane (1:4e1:2) as eluent to give product 5b (89 mg, 76%)
(CDCl3) d 168.8, 58.9, 44.4, 39.6, 37.4, 33.1, 28.3, 22.1, 21.4; EI-MS (rel
intensity) m/z 153 (Mþ, 99), 152 (70), 111 (31), 83 (95), 70 (55), 41
(22); EI-HRMS calcd for C9H15NO m/z 153.1154 (Mþ), found
153.1149.
4.4. cis-7-Butyl-1,2,3,5,6,7,8,8a-octahydro-5-indolizinone (6b)
A similar procedure as for compound 6a was used. Starting from
compound 5b (89.0 mg, 0.46 mmol), product 6b (84.9 mg, 95%) was
obtained as a colorless oil: IR (neat)
n
2854, 1621, 1455, 1412, 1377,
3.65e3.51 (1H, m),
1339, 755, 726, 699 cmꢂ1 1H NMR (CDCl3)
;
d
3.50e3.35 (2H, m), 2.53 (1H, dd, J¼16.5, 4.2 Hz), 2.15e2.02 (2H, m),
as a yellow oil: IR (neat)
n
3053, 2959, 2932, 2874, 1658, 1606, 1455,
1265, 895, 867, 736, 703 cmꢂ1
;
1H NMR (CDCl3)
d
5.22 (1H, s),
2.02e1.80 (2H, m), 1.80e1.70 (2H, m), 1.50e1.35 (1H, m), 1.35e1.22
(6H, m), 1.05e0.85 (4H, m); 13C NMR (CDCl3)
d 169.2, 59.1, 44.7,
3.77e3.58 (2H, m), 3.50e3.47 (1H, m), 2.40e2.29 (1H, dd, J¼16.8,
5.1 Hz), 2.25e2.15 (3H, m), 2.12e1.95 (1H, m), 1.90e1.70 (1H, m),
1.70e1.50 (1H, m), 1.49e1.20 (5H, m), 0.95e0.85 (3H, m); 13C NMR
38.2, 36.1, 35.7, 33.5, 33.5, 28.9, 22.8, 22.4, 14.1; EI-MS (rel intensity)
m/z 195 (Mþ, 76), 194 (55), 139 (28), 138 (100), 111 (39), 83 (81), 70
(93), 55 (24), 41 (26), 18 (23); EI-HRMS calcd for C12H21NO m/z
195.1623 (Mþ), found 195.1626.
(CDCl3)
d 164.3, 153.8, 119.9, 56.5, 43.8, 36.1, 34.5, 33.4, 28.9, 22.9,
22.2, 13.7; EI-MS (rel intensity) m/z 193 (Mþ, 83), 193 (83), 192 (43),
150 (20), 96 (22), 82 (100), 70 (75); EI-HRMS calcd for C12H19NO m/z
193.1467 (Mþ), found 193.1468.
4.5. 7-(Phenylsulfonyl)-1,2,3,5,8,8a-hexahydro-5-indolizinone
(7)
4.2.2. trans-7-Methyl-1,2,3,5,6,7,8,8a-octahydro-5-indolizinone
(9a). Yellow oil: IR (neat)
n
3054, 2986, 1625, 1550, 1421, 1264,
3.70e3.40 (3H, m), 2.45 (1H, dd,
To a solution of compound 4 (150 mg, 0.61 mmol) in CH2Cl2
(3 mL) at 0 ꢁC was added a solution of mCPBA (1.27 g, 50% in H2O,
3.67 mmol) in CH2Cl2 (3 mL) in small portions. The reaction mixture
was stirred at room temperature for 3.5 h, and saturated aqueous
Na2S2O3 and saturated aqueous NaHCO3 were added sequentially.
The mixture was then extracted with CH2Cl2, dried (MgSO4), and
evaporated. The crude product was purified by flash chromatog-
raphy using ethyl acetate/hexane (1:2e1:1) as eluent to give
product 7 (143 mg, 85%) as a white solid: mp 96e97 ꢁC (recryst
from ethyl acetate/hexane); IR (film) 3054, 2976, 2893, 1657, 1611,
896 cmꢂ1 1H NMR (CDCl3)
;
d
J¼17.4, 6.3 Hz), 2.30e2.20 (1H, m), 2.19e2.04 (2H, m), 2.03e1.72
(3H, m), 1.55e1.35 (2H, m), 1.05 (3H, d, J¼6.3 Hz); 13C NMR (CDCl3)
d
169.3, 54.4, 44.7, 38.5, 34.9, 33.6, 25.8, 22.3, 20.0; EI-MS (rel in-
tensity) m/z 153 (Mþ, 23),138 (60), 86 (22), 84 (40), 83 (42), 49 (28);
EI-HRMS calcd for C9H15NO m/z 153.1154 (Mþ), found m/z 153.1153.
4.2.3. trans-7-Butyl-1,2,3,5,6,7,8,8a-octahydro-5-indolizinone
(9b). Yellow oil: IR (neat)
n
2955, 2926, 2859, 2622, 1456,
1057 cmꢂ1 1H NMR (CDCl3)
;
d
3.71e3.58 (1H, m), 3.58e3.37 (2H,
1446, 1308, 1153, 1082, 1019, 741, 689 cmꢂ1
;
1H NMR (CDCl3)
m), 2.44 (1H, dd, J¼17.4, 6.3 Hz), 2.19 (1H, d, J¼17.4 Hz), 2.11e2.05
d 7.83e7.80 (2H, m), 7.65e7.60 (1H, m), 7.54e7.50 (2H, m), 6.64 (1H,
(1H, m), 2.05e1.92 (2H, m), 1.88e1.70 (2H, m), 1.50e1.30 (8H, m),
d, J¼3.0 Hz), 3.74e3.62 (1H, m), 3.58e3.50 (1H, m), 3.39e3.30 (1H,
m), 2.78 (1H, dd, J¼16.8, 5.0 Hz), 2.21e2.04 (2H, m), 2.01e1.92 (1H,
0.93e0.88 (3H, m); 13C NMR (CDCl3)
d 169.5, 54.6, 44.7, 37.1, 33.8,
33.7, 33.2, 31.0, 29.7, 22.8, 22.3, 14.1; EI-MS (rel intensity) m/z 195
(Mþ, 59), 194 (55), 139 (22), 138 (74), 111 (38), 83 (91), 82 (24), 70
(100), 55 (27); EI-HRMS calcd for C12H21NO m/z 195.1623 (Mþ),
found 195.1617.
m), 1.83e1.68 (1H, m), 1.61e1.47 (1H, m); 13C NMR (CDCl3)
d 160.6,
149.4, 137.5, 134.4, 129.6, 129.4, 128.5, 56.9, 44.2, 33.0, 28.7, 22.9;
FAB-MS (rel intensity) m/z 278 (MþþH, 100), 154 (62), 149 (24), 147
(25), 137 (40), 136 (63), 91 (25), 73 (100), 69 (28), 55 (24); FAB-
HRMS calcd for C14H16NO3S m/z 278.0851 (MþþH), found
278.0859. Anal. Calcd for C14H15NO3S: C, 60.63; H, 5.45; N, 5.05.
Found: C, 60.37; H, 5.46; N, 4.83.
4.2.4. 7-Methyl-3,5,8,8a-tetrahydro-5-indolizinone (23). Colorless
oil: IR (neat) n 3075, 2985, 2942, 2909,1667, 1609, 1445, 1372, 1264,

S.-S.P. Chou et al. / Tetrahedron 69 (2013) 274e283
279
4.6. 1,2,3,5,8,8a-Hexahydro-5-indolizinone (8)
(70), 41 (73); FAB-HRMS calcd for C13H25N m/z 195.1987 (Mþ),
found 195.1986.
To a solution of compound 7 (25 mg, 0.09 mmol) in dried THF
(3 mL) was added 5% sodium amalgam (349 mg, 0.72 mmol) and
two drops of concentrated phosphoric acid. The mixture was
heated under nitrogen at 80 ꢁC for 30 min. Upon cooling the mix-
ture was filtered through Celite, rinsed with THF, and evaporated
under vacuum. The residue was purified by flash chromatography
using ethyl acetate/hexane (1:1e2:1) to give product 8 (9.0 mg,
73%) as a colorless liquid. Its 1H NMR and 13C NMR data were
identical with the literature report.10
4.8.3. (5S*,7R*,8aR*)-7-Butyl-5-methyl-1,2,3,5,6,7,8,8a-octahy-
droindolizine (11c). Colorless oil: IR (neat)
n 3054, 2986, 1421, 1265,
896, 738, 705 cmꢂ1 1H NMR (CDCl3)
;
d
3.22 (1H, td, J¼8.7, 1.8 Hz),
2.10e1.73 (6H, m), 1.73e1.60 (2H, m), 1.50e1.20 (8H, m), 1.10 (3H, d,
J¼6.3 Hz), 1.02e0.80 (5H, m); 13C NMR (CDCl3)
d 64.8, 58.3, 51.6,
41.3, 37.5, 36.5, 36.4, 30.5, 29.2, 23.0, 21.1, 20.8, 14.2; EI-MS (rel
intensity) m/z 195 (Mþ, 49), 194 (54), 180 (44), 138 (100), 83 (43), 70
(65), 55 (30); EI-HRMS calcd for C13H25N m/z 195.1987 (Mþ), found
195.1989.
4.7. (6R*,7R*,8aR*)-6,7-Dihydroxy-1,2,3,5,6,7,8,8a-octahydro-
5-indolizinone (10)
4.8.4. cis-5-Methyl-7-(phenylthio)-3,5,8,8a-tetrahydro-indolizidine
(24). Colorless oil: IR (neat)
n
3084, 2985, 2943, 2908, 1645, 1447,
To a solution of compound 8 (36 mg, 0.26 mmol) in t-BuOH
(1 mL), acetone (1 mL), and H2O (0.1 mL) was added N-methyl-
morpholine oxide (53 mg, 0.39 mmol). Then a solution of OsO4 (2.5%
in tert-butanol, three drops, 3.84ꢃ10ꢂ3 mmol) was added, and stir-
red at room temperature for 8 h. The reaction mixture was quenched
with 10% aqueous NaHSO3, stirred for 1 h, and then extracted with
CH2Cl2 (10 mLꢃ3). The solvent was evaporated under vacuum, and
the crude product was purified by flash chromatography using ethyl
acetate as eluent to give product 10 (38.0 mg, 85%) as a colorless oil:
1372, 1372, 1300, 1234, 1044, 847, 736 cmꢂ1
;
1H NMR (CDCl3)
d
7.29e7.19 (5H, m), 5.95 (1H, dq, J¼6.0, 1.5 Hz), 5.89 (1H, d,
J¼1.2 Hz), 5.81 (1H, dq, J¼6.0, 1.5 Hz), 3.85 (1H, ddq, J¼12.9, 4.5,
1.5 Hz), 3.36e3.33 (1H, m), 3.26e3.21 (1H, m), 3.08 (1H, ddq,
J¼12.9, 6.9, 1.5 Hz), 2.40e2.28 (2H, m), 1.21 (3H, d, J¼6.9 Hz); 13C
NMR (CDCl3)
d 136.2, 134.4, 131.7, 131.6, 131.0, 129.1, 128.8, 126.9,
65.9, 56.6, 56.1, 35.8, 20.1; EI-MS (rel intensity) m/z 243 (Mþ, 8), 176
(20), 134 (100), 132 (27), 118 (32), 117 (35); EI-HRMS calcd for
C15H17NO m/z 243.1076 (Mþ), found 243.1082.
IR (neat)
n
3397, 2968, 2887, 1622, 1481, 1130, 1101, 1060, 730 cmꢂ1
4.35e4.30 (1H, m), 4.09 (1H, s, OH), 4.01e3.94
;
1H NMR (CDCl3)
d
4.8.5. (3R*,5S*,8aR*)-3-Ethyl-5-methyl-7-(phenylthio)-1,2,3,5,8,8a-
(1H, m), 3.91e3.78 (1H, m), 3.60e3.40 (2H, m), 3.05 (1H, s, OH), 2.40
(1H, dt, J¼14.1, 4.2 Hz), 2.12e1.95 (2H, m), 1.95e1.77 (1H, m),
hexahydroindolizine (30). Yellow oil: IR (neat)
n 3053, 2985, 2959,
2855, 1454, 1378, 1156, 1078, 1026, 739, 705 cmꢂ1; 1H NMR (CDCl3)
1.65e1.40 (2H, m); 13C NMR (CDCl3)
d
169.1, 70.4, 66.1, 54.8, 44.1,
d
7.33e7.18 (5H, m), 5.71 (1H, d, J¼1.2 Hz), 3.16e3.10 (1H, m),
32.8, 32.4, 22.6; ESI-MS (rel intensity) m/z 194 (MþþNa, 100), 172
(MþþH, 22), 140 (18), 136 (38); ESI-HRMS calcd for C8H14NO3 m/z
172.0973 (MþþH), found 172.0961.
2.60e2.44 (2H, m), 2.19e2.15 (2H, m), 1.91e1.85 (1H, m), 1.79e1.69
(2H, m), 1.56e1.28 (3H, m), 1.21 (3H, d, J¼6.9 Hz), 0.85 (3H, t,
J¼7.3 Hz); 13C NMR (CDCl3)
d 136.4, 134.3, 131.0, 130.6, 129.0, 126.7,
65.3, 63.7, 59.9, 36.7, 31.7, 29.7, 29.2, 22.3,11.1; ESI-MS (rel intensity)
m/z 274 (MþþH, 39), 270 (100), 168 (21); ESI-HRMS calcd for
C17H23NS m/z 273.1551 (Mþ), found 273.1541.
4.8. General procedure for the reaction of amides with an
organometallic reagent followed by reduction
To a solution of compound 6a (33.3 mg, 0.22 mmol) in THF
(3 mL) at room temperature was added slowly another solution of
MeLi (2.2 M in hexane, 0.30 mL, 0.66 mmol). The reaction mixture
was stirred at room temperature for 5 h, and then cooled in an ice
bath. Acetic acid (0.06 mL, 1.1 mmol) was then added dropwise. The
mixture was stirred for 10 min, and NaBH4 (82.3 mg, 2.2 mmol) was
added, followed by a dropwise addition of methanol (2 mL). After
stirring for 3 h, the solvent was removed under vacuum, and sat-
urated sodium bicarbonate was added. The mixture was extracted
with ethyl acetate, dried (MgSO4), and evaporated. The crude
product was purified by column chromatography on silica gel using
ethyl acetate/hexane (1:4) as eluent to give the pure product.
4.9. 7-Oxo-1,2,3,5,6,7,8,8a-octahydro-5-indolizinone (12)
To a solution of compound 4 (100 mg, 0.408 mmol) in 95% EtOH
(10 mL) was added dropwise a 50% aqueous HBr (10 mL). The
mixture was heated at 75 ꢁC under nitrogen for 10 h. After cooling,
the reaction was carefully quenched with saturated sodium bi-
carbonate. The solution was extracted with CH2Cl2 (30 mLꢃ3),
dried (MgSO4), and evaporated under vacuum. The crude product
was purified by flash chromatography using ethyl acetate/hexane
(1:1) as eluent to give product 12 (57.4 mg, 92%) as a colorless oil: IR
(neat)
NMR (CDCl3)
n
3054, 2979, 2884,1726, 1654, 1449,1266, 736, 702 cmꢂ1; 1H
3.92e3.81 (1H, m), 3.70e3.50 (2H, m), 3.36e3.19
d
(2H, m), 2.85 (1H, dd, J¼16.6, 3.3 Hz), 2.40e2.25 (2H, m), 2.15e2.01
4.8.1. (5S*,7R*,8aR*)-5,7-Dimethyl-1,2,3,5,6,7,8,8a-octahydroindolizine
(1H, m), 2.0e1.85 (1H, m), 1.78e1.60 (1H, m); 13C NMR (CDCl3)
(11a). Colorless oil: IR (neat)
1375, 1265, 739, 703 cmꢂ1 1H NMR (CDCl3)
2.1 Hz), 2.10e1.40 (11H, m), 1.10 (3H, d, J¼6.3 Hz), 1.05e0.85 (4H, m);
n
2962, 2926, 2873, 2793, 2698, 1457,
d 204.2, 164.8, 54.3, 47.7, 45.5, 45.1, 33.5, 23.1; EI-MS (rel intensity)
;
d
3.25 (1H, td, J¼8.4,
m/z 153 (Mþ, 100), 83 (25), 70 (89); EI-HRMS calcd for C8H11NO2 m/
z 153.0790 (Mþ), found 153.0793.
13C NMR (CDCl3)
d 64.8, 58.2, 51.4, 43.1, 39.4, 31.4, 30.4, 22.0, 21.0,
20.8; EI-MS (rel intensity) m/z 153 (Mþ, 44), 152 (47), 138 (100), 119
(31), 105 (31), 91 (34), 70 (34), 55 (35), 43 (37), 41 (40); EI-HRMS
calcd for C10H19N m/z 153.1517 (Mþ), found 153.1513.
4.10. cis-7-Hydroxy-1,2,3,5,6,7,8,8a-octahydro-5-indolizinone
(13)
To a solution of compound 12 (50 mg, 0.33 mmol) in methanol
(5 mL) at ꢂ50 ꢁC was added in one portion NaBH4 (122 mg,
3.26 mmol). After stirring for 2 h, the solvent was evaporated under
vacuum and quenched with saturated aqueous NaHCO3. The mix-
ture was extracted with CH2Cl2 (10 mLꢃ3), dried (MgSO4), and
evaporated. The crude product was purified by flash chromatog-
raphy using ethyl acetate and then methanol as eluent to give
4.8.2. (5S*,7R*,8aR*)-5-Butyl-7-methyl-1,2,3,5,6,7,8,8a-octahy-
droindolizine (11b). Colorless oil: IR (neat)
1422, 1377, 1265, 1183, 1132, 1107, 1081, 1032, 895, 739, 705 cmꢂ1
1H NMR (CDCl3)
3.25 (1H, td, J¼8.4, 1.5 Hz), 2.00e1.60 (9H, m),
1.50e1.20 (8H, m), 0.97e0.85 (7H, m); 13C NMR (CDCl3)
64.9, 63.1,
n 2955, 2927, 2871, 1457,
;
d
d
51.3, 39.9, 39.7, 34.4, 31.4, 30.5, 28.2, 23.2, 22.2, 20.9, 14.2; FAB-MS
(rel intensity) m/z 196 (MþþH, 23), 138 (47), 138 (47), 95 (47), 91
(30), 83 (39), 81 (56), 71 (31), 69 (79), 67 (45), 57 (66), 55 (100), 43
product 13 (43.5 mg, 86%) as a yellow oil: IR (neat)
n 3390, 2953,
2923, 2877, 1614, 1474, 1324, 1049 cmꢂ1 1H NMR (CDCl3)
;

280
S.-S.P. Chou et al. / Tetrahedron 69 (2013) 274e283
d
4.20e4.00 (1H, m), 3.72 (1H, s, OH), 3.60e3.45 (1H, m), 3.44e3.33
4.13. 4-(Phenylthio)-6-(E-1-propenyl)-1,2,5,6-tetrahydro-2-
(2H, m), 2.80 (1H, dd, J¼17.4, 6.0 Hz), 2.40e2.20 (2H, m), 2.15e2.05
pyridinone (19)
(1H, m), 2.05e1.91 (1H, m), 1.88e1.71 (1H, m), 1.55e1.32 (2H, m);
13C NMR (CDCl3)
d
167.9, 65.5, 56.3, 44.5, 40.9, 38.4, 33.0, 22.4; ESI-
To a solution of compound 18 (570 mg, 1.43 mmol) in degassed
toluene (15 mL) at reflux was added dropwise another solution of
Bu3SnH (0.84 mL, 3.58 mmol) and AIBN (47 mg, 0.29 mmol) in
toluene (34 mL). The mixture was refluxed for 2 h, and the solvent
was removed under vacuum. The crude product was purified by
flash chromatography on silica gel prewashed with Et3N using ethyl
acetate/hexane (1:4e1:1) as eluent to give product 19 (323 mg,
92%) as a white solid: mp 139e140 ꢁC (recryst from EA/hexane); IR
MS m/z 178 (MþþNa), 156 (MþþH); ESI-HRMS calcd for C8H14NO2
m/z 156.1024 (MþþH), found 156.1017.
4.11. cis-7-Benzoyloxy-1,2,3,5,6,7,8,8a-octahydro-5-indolizi-
none (14)
To a solution of compound 13 (10 mg, 6.4ꢃ10ꢂ2 mmol) in
CH2Cl2 (2 mL) were added sequentially Et3N (25
m
L, 0.19 mmol)
(film)
1130, 1067, 966, 936, 851, 822, 778, 753, 691, 656 cmꢂ1
(CDCl3)
n
3070, 2938, 2850, 1645, 1587, 1473, 1393, 1328, 1295, 1217,
and benzoyl chloride (10
m
L, 0.19 mmol). The mixture was refluxed
;
1H NMR
for 12 h, and was poured into saturated aqueous NaHCO3,
extracted with CH2Cl2 (10 mLꢃ3), and dried (MgSO4). The solvent
was evaporated and the crude product was purified by flash
chromatography using ethyl acetate/hexane (1:1) as eluent to give
product 14 (8.6 mg, 51%) as a white solid: mp 142.5e143.5 ꢁC
d
7.50e7.39 (5H, m), 5.72 (1H, ddq, J¼15.3, 0.6, 6.6 Hz), 5.45
(1H, ddq, J¼15.3, 7.5, 1.5 Hz), 5.38 (1H, s), 5.27 (1H, d, J¼1.8 Hz), 4.09
(1H, q, J¼7.5 Hz), 2.48e2.45 (2H, m), 1.74e1.68 (3H, m); 13C NMR
(CDCl3)
d 165.8, 154.4, 135.3, 129.9, 129.8, 129.7, 129.0, 128.2, 114.4,
53.3, 35.2,17.6; EI-MS (rel intensity) m/z 245 (Mþ, 59), 244 (39), 243
(40), 242 (42), 230 (34), 204 (65), 176 (84), 148 (41), 147 (49), 136
(60), 110 (54), 109 (46), 108 (38), 91 (68), 77 (55), 67 (100), 65 (37);
EI-HRMS calcd for C14H15NOS m/z 245.0874 (Mþ), found 245.0872.
Anal. Calcd for C14H15NOS: C, 68.54; H, 6.16; N, 5.71. Found: C, 68.13;
H, 6.12; N, 5.36.
(recryst from CH2Cl2/hexane); IR (film)
n
2978, 2886, 1714, 1638,
8.05e8.00 (2H, m),
1451, 1284, 1113, 719 cmꢂ1 1H NMR (CDCl3)
;
d
7.62e7.54 (1H, m), 7.49e7.42 (2H, m), 5.42e5.28 (1H, m),
3.68e3.42 (3H, m), 3.00 (1H, dd, J¼17.4, 6.6 Hz), 2.68e2.47 (2H, m),
2.22e2.10 (1H, m), 2.10e1.95 (1H, m), 1.90e1.79 (1H, m), 1.65e1.48
(2H, m); 13C NMR (CDCl3)
d 166.6, 165.9, 133.3, 130.0, 129.7, 128.5,
68.4, 55.7, 44.7, 37.4, 35.2, 33.1, 22.5; EI-MS (rel intensity) m/z 259
(Mþ, 67), 138 (21), 137 (100), 136 (66), 109 (40), 105 (100), 83 (43),
77 (65), 70 (57), EI-HRMS calcd for C15H17NO3 m/z 259.1208 (Mþ),
found 259.1211. Crystallographic data: C15H17NO3, formula
4.14. 1-Allyl-4-(phenylthio)-6-(E-1-propenyl)-1,2,5,6-tetrahy-
dro-2-pyridinone (20a)
To a solution of compound 19 (250 mg, 1.02 mmol) and HMPA
(0.71 mL, 4.08 mmol) in THF (5 mL) at ꢂ78 ꢁC was added dropwise
a solution of BuLi (2.5 M in hexane, 0.53 mL, 1.33 mmol). The
mixture was stirred at ꢂ78 ꢁC for 30 min, and allyl bromide
(0.35 mL, 4.08 mmol) was added in one portion. After slowly
warming to room temperature and further stirring for 2 h, the re-
action mixture was quenched with saturated ammonium chloride.
The aqueous solution was extracted with ethyl acetate, combined
with the organic layer, dried (MgSO4), and concentrated under
vacuum. The crude product was purified by flash chromatography
using ethyl acetate/hexane (1:5) as eluent to give product 20a
ꢀ
weight¼259.30, temperature¼293(2) K, wavelength¼0.71073 A,
ꢀ
crystal system¼triclinic, space group¼P ꢂ1, a¼7.8489(3) A,
ꢀ
ꢀ
a
b¼9.1149(3) A, c¼10.2047(4) A,
¼93.142(2)ꢁ,
b
¼108.134(2)ꢁ,
3
ꢁ
ꢀ
g
¼105.880(3) , volume¼659.45(4) A , Z¼2, density (calculated)¼
1.306 Mg/m3, absorption coefficient¼0.091 mmꢂ1, F(000)¼276,
crystal size¼0.78ꢃ0.62ꢃ0.4 mm3, theta range for data collection¼
2.13e25.02ꢁ, index ranges: ꢂ9ꢄhꢄ9, ꢂ10ꢄkꢄ10, ꢂ10ꢄlꢄ12, re-
flections collected¼4112, independent reflections¼2267 [R(int)¼
0.0559], completeness to theta¼25.02ꢁ (97.2%), absorption cor-
rection: multi-scan, refinement method: full-matrix least-squares
on F2, data/restraints/parameters¼2267/0/172, goodness-of-fit on
F2¼1.031, final R indices: [I>2sigma(I)] R1¼0.0495, wR2¼0.1307, R
(225 mg, 77%) as a yellow oil: IR (neat)
1453, 1441, 1415, 1353, 1264, 993, 966, 907, 853, 727, 704, 691,
646 cmꢂ1; 1H NMR (CDCl3)
7.59e7.45 (5H, m), 5.83e5.70 (1H, m),
n 3078, 2984, 1634, 1592,
indices (all data) R1¼0.0684, wR2¼0.1462, largest diff. peak and
d
ꢀꢂ3
hole¼0.215 and ꢂ0.298 e A
.
5.62e5.41 (2H, m), 5.38 (1H, d, J¼2.1 Hz), 5.17e5.12 (2H, m), 4.67
(1H, ddt, J¼15.6, 4.5, 1.5 Hz), 3.95 (1H, td, J¼6.9, 3.0 Hz), 3.30 (1H,
dd, J¼15.6, 7.2 Hz), 2.85 (1H, ddd, J¼16.8, 6.9, 2.1 Hz), 2.28 (1H, dd,
4.12. 4-(Phenylthio)-6-(E-1-propenyl)-1-(toluenesulfonyl)-1,2,
5,6-tetrahydro-2-pyridinone (18)
J¼16.8, 2.4 Hz), 1.70 (3H, d, J¼5.7 Hz); 13C NMR (CDCl3)
d 162.7,
150.2, 134.9, 133.7, 129.4 (ꢃ2), 128.4, 127.6, 116.6, 116.5, 115.3, 56.0,
45.7, 34.3, 17.3; EI-MS (rel intensity) m/z 285 (Mþ, 18), 244 (24), 88
(30), 73 (34), 61 (100); EI-HRMS calcd for C17H19NO m/z 285.1187
(Mþ), found 285.1191.
To a solution of compound 173b (250 mg, 0.63 mmol) in toluene
(5 mL) was added vinyloxytrimethylsilane (0.94 mL, 6.30 mmol) and
G1 (25.0 mg, 0.03 mmol). The mixture was heated at reflux for 5 h,
and another portion of G1 (25.0 mg, 0.03 mmol) was added and
refluxed for an additional 5 h. The solvent was removed under
vacuum, and the crude product was purified by flash chromatog-
raphy using ethyl acetate/hexane (1:6) as eluent to give product 18
(232 mg, 93%) as a yellow solid: mp 126e127 ꢁC (recryst from ethyl
4.15. 1-(2-Methylallyl)-4-(phenylthio)-6-(E-1-propenyl)-1,2,5,
6-tetrahydro-2-pyridinone (20b)
acetate/hexane); IR (film)
1357, 1307, 1212, 1102, 1009, 854, 834, 751, 699, 688, 653 cmꢂ1; 1H
NMR (CDCl3)
n
3081, 2872, 1638, 1612,1574, 1438, 1425,
A similar procedure as for compound 20a was used. Starting
from compound 19 (70 mg, 0.29 mmol), product 20b (38 mg, 54%)
d
7.85 (2H, d, J¼8.4 Hz), 7.49e7.38 (5H, m), 7.22 (2H, d,
was obtained as a yellow oil: IR (neat)
n
3054, 1637, 1422, 1365,
J¼8.4 Hz), 5.78 (1H, ddq, J¼13.8, 0.6, 6.3 Hz), 5.50 (1H, ddq, J¼13.8,
7.5,1.5 Hz), 5.29 (1H, t, J¼6.6 Hz), 5.17 (1H, d, J¼2.4 Hz), 3.12 (1H, ddd,
J¼17.6, 6.3, 2.4 Hz), 2.40 (1H, dd, J¼17.6,1.8 Hz), 2.38 (3H, s),1.69 (3H,
1264, 1228, 1217, 908, 730, 704, 650 cmꢂ1
;
1H NMR (CDCl3)
d
7.52e7.40 (5H, m), 5.59e5.50 (2H, m), 5.39 (1H, d, J¼2.1 Hz),
4.87e4.81 (2H, m), 4.65 (1H, br d, J¼15.6 Hz), 3.81 (1H, td, J¼6.6,
2.4 Hz), 3.13 (1H, br d, J¼15.6 Hz), 2.88 (1H, ddd, J¼16.8, 6.6, 2.1 Hz),
2.29 (1H, dd, J¼16.8, 2.4 Hz),1.72 (3H, br d, J¼6.6 Hz),1.70 (3H, br s);
dd, J¼6.3, 1.5 Hz); 13C NMR (CDCl3)
d 161.0, 157.4, 144.4, 136.4, 135.2,
130.33,130.27, 129.9, 129.3, 128.8, 127.6, 127.3, 113.9, 56.5, 35.5, 21.6,
17.5; FAB-MS (rel intensity) m/z 400 (MþþH,100), 229 (66),155 (23),
91 (62), 77 (23), 73 (22), 42 (22); FAB-HRMS calcd for C21H22NO3S2
m/z 400.0963 (MþþH), found 400.0956. Anal. Calcd for
C21H21NO3S2: C, 63.13; H, 5.30. Found: C, 63.18; H, 5.41.
13C NMR (CDCl3)
d 163.1, 150.3, 141.4,135.3, 135.1, 129.8, 129.7, 128.6,
127.5,115.5,111.9, 55.9, 48.8, 34.5, 20.0,17.5; EI-MS (rel intensity) m/
z 299 (Mþ, 17), 258 (30), 89 (31), 88 (29), 73 (33), 70 (52), 61 (100);
EI-HRMS calcd for C18H21NO m/z 299.1344 (Mþ), found 299.1347.

S.-S.P. Chou et al. / Tetrahedron 69 (2013) 274e283
281
4.16. 7-(Phenylthio)-3,5,8,8a-tetrahydro-5-indolizinone (21a)
K2CO3 (40.0 mg, 0.2 mmol) and toluene (1.2 mL). Then CuI (23.0 mg,
0.1 mmol) and N,N0-dimethylethylenediamine (13.2
L, 0.1 mmol)
m
To a solution of compound 20a (46.0 mg, 0.16 mmol) and G1
(6.6 mg, 0.0079 mmol) in CH2Cl2 (2 mL) was stirred at room tem-
perature for 24 h. The solvent was then evaporated under vacuum,
and the crude product was purified by flash chromatography on
silica gel prewashed with Et3N using ethyl acetate/hexane
(1:3e1:1) as eluent to give product 21a (26 mg, 67%) as a white
were added. The mixture was heated at 160 ꢁC for 2 h. The solvent
was removed under vacuum, and the crude product was purified by
flash chromatography using ethyl acetate/hexane (1:3e1:2) as el-
uent to give the pure product.
4.19.1. 6-Allyl-1-(1-methylvinyl)-4-(phenylthio)-1,2,5,6-tetrahydro-
solid: mp 88e89 ꢁC (recryst from EA/hexane); IR (film)
2872, 1638, 1612, 1574, 1438, 1425, 1357, 1307, 1212, 1102, 1009, 854,
834, 751, 699, 688, 653 cmꢂ1; 1H NMR (CDCl3)
7.42e7.37 (5H, m),
n
3081,
2-pyridinone (26a). Colorless liquid: IR (neat)
n
3075, 2974, 2926,
7.46e7.27
1646, 1420, 1257, 1154, 998, 918 cmꢂ1; 1H NMR (CDCl3)
d
d
(5H, m), 5.78e5.64 (1H, m), 5.36 (1H, d, J¼2.1 Hz), 5.18e5.11 (2H,
m), 4.99 (1H, q, J¼1.2 Hz), 4.89 (1H, s), 3.78e3.71 (1H, m), 2.79 (1H,
ddd, J¼17.1, 6.3, 2.1 Hz), 2.48e2.38 (3H, m), 2.01 (3H, d, J¼1.2 Hz);
5.98 (1H, dq, J¼6.3, 2.1 Hz), 5.80 (1H, dq, J¼6.3, 2.1 Hz), 5.40 (1H, d,
J¼1.8 Hz), 4.74e4.63 (1H, m), 4.39 (1H, ddt, J¼16.5, 5.0, 2.1 Hz), 4.13
(1H, ddt, J¼16.5, 3.6, 1.8 Hz), 2.54e2.51 (2H, m); 13C NMR (CDCl3)
13C NMR (CDCl3)
d 162.1, 151.6, 144.9, 135.3, 133.6, 129.9, 129.7,
d
161.9, 152.1, 135.3, 130.0, 129.9, 128.8, 128.3, 128.0, 116.3, 62.4, 51.5,
128.2, 118.8, 115.3, 110.9, 57.1, 36.7, 32.0, 21.5; EI-MS (rel intensity)
m/z 285 (Mþ, 2), 244 (14), 205 (13), 204 (100), 67 (19); EI-HRMS
calcd for C17H19NOS m/z 285.1187 (Mþ), found 285.1190.
34.8; EI-MS (rel intensity) m/z 243 (Mþ, 94), 242 (23), 177 (20), 176
(100), 148 (26), 147 (27), 68 (21), 67 (82); EI-HRMS calcd for
C14H13NOS m/z 243.0718 (Mþ), found 243.0715.
4.19.2. 6-Allyl-1-(but-2-enyl)-1,2,5,6-tetrahydro-2-pyridinone
4.17. 2-Methyl-7-(phenylthio)-3,5,8,8a-tetrahydro-5-indolizi-
none (21b)
(26b). Yellow oil: IR (neat)
n
3060, 2934, 2968, 1647, 1595, 1440,
1304, 1149, 1068, 919, 852, 731, 692, 534 cmꢂ1
;
1H NMR (CDCl3)
d
7.49e7.39 (5H, m), 5.69 (1H, ddt, J¼17.3, 9.9, 7.2 Hz), 5.37 (1H, d,
A solution of compound 20b (33.0 mg, 0.11 mmol) and G2
(4.7 mg, 0.005 mmol) in toluene (2 mL) was heated at 170 ꢁC in
a microwave reactor for 2 h. The solvent was then evaporated
under vacuum, and the crude product was purified by flash
chromatography on silica gel prewashed with Et3N using ethyl
acetate/hexane (1:3e1:1) as eluent to give product 21b (15 mg,
J¼2.1 Hz), 5.17e5.11 (2H, m), 5.07 (1H, t, J¼1.5 Hz), 4.94 (1H, s),
3.69e3.61 (1H, m), 2.79 (1H, ddd, J¼17.2, 5.9, 2.1 Hz), 2.49e2.20
(5H, m), 1.06 (3H, t, J¼7.5 Hz); 13C NMR (CDCl3)
d 162.4, 151.5, 150.0,
135.6, 134.0, 130.0, 129.9, 128.4, 119.0, 115.7, 110.0, 57.1, 36.9, 32.0,
27.5, 11.9; EI-MS (rel intensity) m/z 299 (Mþ, 27), 298 (74), 284 (29),
271 (69), 258 (100), 257 (42), 256 (53), 242 (53), 216 (72), 204 (45),
86 (31), 84 (48), 55 (66); EI-HRMS calcd for C18H21NOS m/z
299.1344 (Mþ), found 299.1339.
52%) as a yellow oil: IR (neat)
n
2985, 2942, 2908, 1447, 1372, 1234,
1097, 1043, 938, 847, 786 cmꢂ1
;
1H NMR (CDCl3)
d
7.48e7.39 (5H,
m), 5.41e5.37 (2H, m), 4.68e4.63 (1H, m), 4.28e4.21 (1H, m),
4.06e4.01 (1H, m), 2.48e2.42 (2H, m), 1.81 (3H, s); 13C NMR
4.20. 3-Methyl-7-(phenylthio)-1,5,8,8a-tetrahydro-5-indolizi-
none (27a)
(CDCl3)
d
161.9, 152.2, 137.9, 135.3, 129.9 (ꢃ2), 129.8, 122.2, 116.2,
62.7, 54.6, 35.0, 14.5; EI-MS (rel intensity) m/z 257 (Mþ, 100), 256
(36), 255 (38), 148 (43), 147 (45), 118 (21), 109 (23), 82 (83), 67
(97), 65 (21); EI-HRMS calcd for C15H15NOS m/z 257.0874 (Mþ),
found 257.0878.
A mixture of compound 26a (45.0 mg, 0.16 mmol) and G2
(6.7 mg, 5 mol %) in CH2Cl2 (2 mL) was refluxed under nitrogen for
8 h. The solvent was then removed under vacuum, and the crude
product was purified by flash chromatography using ethyl acetate/
hexane (1:4) as eluent to give product 27a (31.3 mg, 77%) as a yel-
4.18. 7-(Phenylsulfonyl)-3,5,8,8a-tetrahydro-5-indolizinone
(22)
low oil: IR (neat)
848, 751, 688 cmꢂ1; 1H NMR (CDCl3)
d, J¼1.8 Hz), 4.84 (1H, t, J¼1.3 Hz), 4.01e3.98 (1H, m), 2.67e2.57
(3H, m), 2.39e2.28 (4H, m); 13C NMR (CDCl3)
160.7, 152.4, 141.8,
n
3075, 2925, 1661, 1629, 1409, 1353, 1148, 1123,
d
7.44e7.31 (5H, m), 5.37 (1H,
To a solution of compound 21a (50.0 mg, 0.21 mmol) in CH2Cl2
(3 mL) in an ice bath was added slowly another solution of mCPBA
(50% in H2O, 158 mg, 0.48 mmol) in CH2Cl2 (3 mL). The reaction
mixture was then stirred at room temperature for 1 h, and was then
added sequentially saturated Na2S2O3 and saturated sodium bi-
carbonate. The mixture was extracted with CH2Cl2, dried (K2CO3),
and evaporated under vacuum. The crude product was purified by
flash chromatography using ethyl acetate/hexane (1:2e1:1) as el-
uent to give product 22 (46 mg, 77%) as a white solid: mp
d
135.2, 129.9, 129.8, 128.8, 117.6, 106.6, 57.8, 35.6, 34.6, 16.1; EI-MS
(rel intensity) m/z 257 (Mþ, 7), 162 (33), 128 (100), 61 (18); EI-
HRMS calcd for C15H15NOS m/z 257.0874 (Mþ), found 257.0868.
4.21. 3-Ethyl-7-(phenylthio)-1,5,8,8a-tetrahydro-5-indolizi-
none (27b)
107e108 ꢁC (recryst from ethyl acetate/hexane); IR (film)
2970, 2857, 1661, 1600, 1439, 1356, 1286, 1216, 1152, 1079, 992, 952,
750, 717, 649 cmꢂ1 1H NMR (CDCl3)
n
3052,
A mixture of compound 26b (48.8 mg, 0.16 mmol) and G2
(13.8 mg, 5 mol %) in CH2Cl2 (5 mL) was refluxed under nitrogen for
5 h. The solvent was then removed under vacuum, and the crude
product was purified by flash chromatography using ethyl acetate/
hexane (1:5) containing 5% EtN as eluent to give product 27b
;
d
7.90 (2H, br d, J¼7.5 Hz),
7.72e7.68 (1H, m), 7.62e7.51 (2H, m), 6.76 (1H, d, J¼3.0 Hz),
6.00e5.98 (1H, m), 5.81e5.79 (1H, m), 4.72e4.67 (1H, m), 4.41 (1H,
ddt, J¼16.2, 7.2, 1.8 Hz), 4.18 (1H, ddt, J¼16.2, 3.6, 1.8 Hz), 2.92 (1H,
dd, J¼16.8, 4.5 Hz), 2.23 (1H, ddd, J¼16.8, 14.4, 3.0 Hz); 13C NMR
(38.2 mg, 86%) as a light yellow oil: IR (neat)
1628, 1588, 1476, 1409, 1358, 1330, 1266, 1149, 1088, 1024, 896, 855,
737, 705 cmꢂ1 1H NMR (CDCl3)
7.50e7.39 (5H, m), 5.38 (1H, d,
n 3054, 2986, 1659,
(CDCl3)
d
160.0, 149.5, 137.6, 134.5, 129.7, 129.4, 128.6, 128.1, 127.8,
;
d
62.6, 51.7, 28.2; ESI-MS (rel intensity) m/z 276 (MþþH, 28), 258
(100); ESI-HRMS calcd for C14H13NO3S m/z 275.0616 (Mþ), found
275.0606.
J¼2.1 Hz), 4.90e4.87 (1H, m), 4.10e3.98 (1H, m), 2.75e2.53 (5H, m),
2.31e2.20 (1H, m), 1.10 (3H, t, J¼7.3 Hz); 13C NMR (CDCl3)
d 160.4,
152.1, 148.0, 135.1, 129.8 (ꢃ2), 128.7, 117.7, 104.8, 58.0, 35.5, 34.6,
22.8, 12.5; EI-MS (rel intensity) m/z 271 (Mþ, 71), 180 (57), 179 (50),
178 (33), 176 (29), 117 (32), 105 (51), 97 (47), 91 (41), 84 (34), 83
(57), 82 (31), 81 (34), 71 (41), 69 (61), 68 (37), 67 (39), 57 (83), 56
(33), 55 (100); EI-HRMS calcd for C16H17NOS m/z 271.1031 (Mþ),
found 271.1035.
4.19. General procedure for the N-vinylation of amides
In a sample vial for the microwave reaction were added com-
pound 253b (30.0 mg, 0.1 mmol), a vinyl bromide (0.2 mmol) and

282
S.-S.P. Chou et al. / Tetrahedron 69 (2013) 274e283
4.22. (E)-3-Ethylidene-7-(phenylthio)-1,2,3,5,8,8a-hexahydro-
5-indolizinone (28)
167E (29.0 mg, 88%) as a yellow oil, the spectral data of which were
identical with the literature values.19
A mixture of compound 26b (163.3 mg, 0.55 mmol) and G2
(23.1 mg, 5 mol %) in toluene (2 mL) was heated in a sealed tube at
120 ꢁC for 5 h. The solvent was then removed under vacuum, and the
crude product was purified by flash chromatography using ethyl ac-
etate/hexane (1:5) containing 5% EtN as eluent to give product 28
(117.3 mg, 79%) as a white solid: mp 135.2e136.8 ꢁC (recryst from
4.25. (3R*,5S*,8aR*)-3-Ethyl-5-methy-1,2,3,5,6,7,8,8a-octahy-
dro-5-indolizinone (32)
To a solution of compound 30 (70.2 mg, 0.26 mmol) in 95% EtOH
(3 mL) was added dropwise a 50% aqueous HBr (3 mL). The mixture
was heated at 70 ꢁC under nitrogen for 14 h. The reaction was
quenched with saturated sodium bicarbonate, extracted with
CH2Cl2 (10 mLꢃ3), and dried (MgSO4). The solvent was removed
under vacuum, and the crude product was purified by flash chro-
matography using ethyl acetate/hexane (1:6) containing 5% Et3N as
eluent to give product 32 (31.1 mg, 67%) as a colorless oil (29 mg,
CH2Cl2/hexane); IR (ATR, neat)
n
3045, 2919, 2853, 1630, 1590, 1408,
7.51e7.41
1389,1321,1163, 990, 849, 753, 691 cmꢂ1; 1H NMR (CDCl3)
d
(5H, m), 6.48e6.44 (1H, m), 5.36 (1H, d, J¼1.8 Hz), 3.98 (1H, tt, J¼11.1,
5.7Hz), 2.67(1H,dd,J¼15.6, 8.4Hz),2.48e2.34(3H, m),2.20e2.13 (1H,
m), 1.66e1.57 (4H, m); 13C NMR (CDCl3)
d 162.6, 151.6, 138.3, 135.2,
129.9 (ꢃ2), 128.8, 117.8, 104.2, 59.3, 35.8, 29.8, 26.5, 13.9; EI-MS (rel
intensity) m/z 272 (MþþH, 5), 245 (22), 244 (100), 68 (12); EI-HRMS
calcd for C16H17NOS m/z 271.1031 (Mþ), found 271.1024. Crystallo-
graphic data: C16H17NOS, formula weight¼271.37, temperature¼
91%): IR (neat)
n
2964, 2876, 2793,1721,1555,1461,1380,1196,1124,
932, 825, 734, 618 cmꢂ1
;
1H NMR (CDCl3)
d
2.68e2.51 (2H, m),
2.50e2.44 (2H, m), 2.36e2.18 (3H, m), 2.04e1.91 (1H, m), 1.81e1.73
(1H, m), 1.71e1.47 (3H, m), 1.42e1.30 (1H, m), 1.20 (3H, d, J¼6.3 Hz),
0.89 (3H, t, J¼7.5 Hz); 13C NMR (CDCl3)
d 209.7, 65.4, 62.6, 57.4, 50.1,
ꢀ
100(2) K, wavelength¼0.71073 A, crystal system¼monoclinic, space
ꢀ
ꢀ
ꢀ
group¼P 121/c 1, a¼12.3340(17) A, b¼11.8593(16) A, c¼9.7249(13) A,
47.4, 32.0, 30.9, 29.8, 22.7, 10.6; FAB-MS (rel intensity) m/z 182
(MþþH, 14), 146 (38), 145 (24), 139 (24), 66 (100); FAB-HRMS calcd
for C11H19NO m/z 181.1467 (Mþ), found 181.1467.
3
ꢁ
¼90ꢁ,
b
¼103.183(3)ꢁ,
g
¼90 , volume¼1385.0(3) A , Z¼4, density
ꢀ
a
(calculated)¼1.301 Mg/m3, absorption coefficient¼0.225 mmꢂ1
,
F(000)¼576, crystal size¼0.17ꢃ0.06ꢃ0.05 mm3, theta range for data
collection¼1.70e26.38ꢁ, index ranges: ꢂ15ꢄhꢄ15, ꢂ14ꢄkꢄ11,
ꢂ12ꢄlꢄ12, reflections collected¼10,231, independent reflections¼
2832 [R(int)¼0.0338], completeness to theta¼26.38ꢁ (99.9%), max.
and min. transmission¼0.9486 and 0.8487, refinement method: full-
matrix least-squares on F2, data/restraints/parameters¼2832/0/173,
goodness-of-fit on F2¼1.034, final R indices [I>2sigma(I)]: R1¼0.0550,
4.26. (3R*,5S*,7R*,8aR*)-3-Ethyl-5-methy-7-hydroxy-
1,2,3,5,6,7,8,8a-octahydroindolizine (33)
To a solution of compound 32 (27.3 mg, 0.15 mmol) in methanol
(5 mL) at ꢂ78 ꢁC was added dropwise a solution of NaBH4 (57 mg,
1.5 mmol) in methanol (5 mL). The reaction mixture was slowly
warmed to room temperature and stirred for 6 h. The solvent was
then evaporated under vacuum and quenched with saturated
aqueous NaHCO3. The mixture was extracted with CH2Cl2
(10 mLꢃ3), dried (K2CO3), and evaporated. The crude product was
purified by recrystallization from CH2Cl2/hexane to give product 33
wR2¼0.1229, R indices (all data) R1¼0.0753, wR2¼0.1354, largest diff.
ꢀꢂ3
peak and hole¼0.939 and ꢂ0.695 e A
.
4.23. cis-3-Methyl-7-(phenylthio)-1,2,3,5,8,8a-hexahydro-5-
indolizinone (29a) and trans-3-methyl-7-(phenylthio)-
1,2,3,5,8,8a-hexahydro-5-indolizinone (29b)
(20.0 mg, 72%) as a white solid: mp 69.2e70.2 ꢁC; IR (film)
2967, 2872, 1734, 1560, 1459, 1382, 1312, 1142, 1097, 1040, 947, 824,
618 cmꢂ1; 1H NMR (CDCl3)
n 3239,
A mixture of compound 27 (14.0 mg, 0.05 mmol) and PtO2
(4.9 mg) in ethyl acetate (2 mL) was stirred vigorously under a bal-
loon of hydrogen for 24 h. The solvent was evaporated under vac-
uum, and the crude product was purified by flash chromatography
using ethyl acetate/hexane (1:4) as eluent to give an inseparable 3:1
mixture (determined by 1H NMR) of products 29a and 29b (9.2 mg,
d
3.70e3.63 (1H, m), 2.43 (1H, tt, J¼9.6,
2.4 Hz), 2.36e2.25 (1H, m), 2.23e2.14 (1H, m), 2.11e2.04 (1H, m),
1.94e1.80 (2H, m), 1.73e1.61 (3H, m), 1.51e1.42 (2H, m), 1.37e1.21
(3H, m), 1.15 (3H, d, J¼6.6 Hz), 0.85 (3H, t, J¼7.3 Hz); 13C NMR
(CDCl3) d 69.7, 64.8, 63.3, 57.0, 45.2, 40.3, 32.1, 30.0, 29.9, 22.6, 10.9;
EI-MS (rel intensity) m/z 183 (Mþ, 14), 184 (100), 182 (75), 166 (23),
149 (74), 139 (31), 82 (18), 71 (25), 66 (28), 63 (45), 62 (23), 55 (37),
53 (48); EI-HRMS calcd for C11H21NO m/z 183.1623 (Mþ), found
65%)4a: IR (neat)
1426, 1367, 1344, 1305, 1257, 1230, 1175, 1126, 1075, 1022, 1000, 984,
956, 914, 851, 751, 691 cmꢂ1; 1H NMR (CDCl3)
7.52e7.36 (m), 5.34
n 3055, 2963, 2926, 2871, 1643, 1582, 1474, 1439,
d
183.1622.
Crystallographic
data:
C11H23NO2,
formula
ꢀ
(d, J¼2.4 Hz), 4.20e4.11 (m), 3.92e3.83 (m), 3.76e3.65 (m),
2.52e2.31 (m), 2.12e1.89 (m), 1.80e1.42 (m), 1.29 (d, J¼6.3 Hz), 1.23
(d, J¼6.3 Hz); EI-MS (rel intensity) m/z 259 (Mþ, 38), 244 (100), 176
(21), 147 (14), 67 (14); EI-HRMS calcd for C15H17NOS m/z 259.1031
(Mþ), found 259.1030. Most of the 1H NMR signals for compounds
weight¼201.30, temperature¼200(2) K, wavelength¼0.71073 A,
ꢀ
crystal system¼triclinic, space group¼P ꢂ1, a¼7.1773(4) A,
ꢀ
ꢀ
b¼8.3584(6)ꢁ A, c¼11.7370(7) A,
a
3
¼71.092(4)ꢁ,
b
¼75.568(4)ꢁ,
ꢀ
g
¼64.714(4) , volume¼597.22(6) A , Z¼2, density (calculated)¼
1.119 Mg/m3, absorption coefficient¼0.076 mmꢂ1, F(000)¼224,
crystal size¼0.69ꢃ0.25ꢃ0.08 mm3, theta range for data
collection¼2.78e25.03ꢁ, index ranges: ꢂ8ꢄhꢄ8, ꢂ9ꢄkꢄ9,
29a and 29b overlap, but
belong to compound 29a, whereas
d
3.76e3.65 (m) and 1.23 (d, J¼6.3 Hz)
d
3.92e3.83 (m) and 1.29 (d,
J¼6.3 Hz) belong to compound 29b. The 13C NMR absorptions are
distinctive. Compound 29a: 162.8, 152.6, 135.2, 129.74, 129.71, 128.9,
116.9, 57.9, 51.3, 36.2, 30.8, 30.6, 20.9. Compound 29b: 162.1, 150.7,
135.1, 129.74, 129.71, 128.9, 117.1, 55.4, 52.5, 35.4, 31.6, 31.5, 19.9.
ꢂ12ꢄlꢄ13,
reflections
collected¼4813,
independent
reflections¼2061 [R(int)¼0.0573], completeness to theta¼25.03ꢁ
(97.9%), absorption correction: multi-scan, max. and min. trans-
mission¼0.9940 and 0.9497, refinement method: full-matrix least-
squares on F2, data/restraints/parameters¼2061/0/128, goodness-
of-fit on F2¼1.090, Final R indices [I>2sigma(I)]: R1¼0.0987,
4.24. (3S*,5R*,8aR*)-3-Ethyl-5-methyl-1,2,3,5,6,7,8,8a-octahy-
droindolizine (31, indolizidine 167E)
wR2¼0.2674, R indices (all data): R1¼0.1329, wR2¼0.2919, largest
ꢀꢂ3
diff. peak and hole¼0.982 and ꢂ0.432 e A
.
A mixture of compound 30 (54 mg, 0.20 mmol) and a W-2
Raney-Ni (451 mg, 3.95 mmol) in 95% EtOH (3 mL) was heated at
reflux under nitrogen for 2 h. The solid was filtered off, washed
with methanol, and the residue was evaporated under vacuum in
an ice bath. The crude product was purified by flash chromatog-
raphy using ethyl acetate/hexane (1:4) as eluent to give indolizidine
Acknowledgements
Financial support of this work by the National Science Council of
the Republic of China (NSC 97-2113-M-030-001-MY3 and NSC 100-
2113-M-030-007) is gratefully acknowledged.

S.-S.P. Chou et al. / Tetrahedron 69 (2013) 274e283
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Supplementary data
NMR spectra (1H, 13C) for all new compounds and indolizidine
167E, and X-ray data for compounds 14, 28 and 33. Supplementary
data related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2012.10.026.
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