Synthetic studies of quinolizidine 195C and derivatives

Article abstract of DOI:10.1016/j.tet.2012.12.017

Sulfur-substituted dihydropyridones prepared by aza-Diels-Alder reactions were converted to the cis-2,6-disubstituted derivatives, which could then proceed through ring-closing metathesis (RCM) and cross metathesis (CM) reactions to give many quinolizidin

Full text of DOI:10.1016/j.tet.2012.12.017

Tetrahedron 69 (2013) 1499e1508
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Synthetic studies of quinolizidine 195C and derivatives
*
Shang-Shing P. Chou , Jun-Wei Zhang, Kuan-Hua Chen
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 9 October 2012
Received in revised form 1 December 2012
Accepted 7 December 2012
Available online 14 December 2012
Sulfur-substituted dihydropyridones prepared by aza-DielseAlder reactions were converted to the cis-
2,6-disubstituted derivatives, which could then proceed through ring-closing metathesis (RCM) and
cross metathesis (CM) reactions to give many quinolizidine derivatives, including two epimers of
(ꢀ)-195C.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Quinolizidines
Quinolizidine 195C
Ring-closing metathesis
Cross metathesis
1. Introduction
2. Results and discussion
Many quinolizidine alkaloids have been isolated from amphibian
skin,1 some of which show interesting biological activities.2 Many
methods have been developed for the synthesis of these novel
compounds.3,4 We have previously developed a new aza-Diel-
seAlder reaction of thio-substituted 3-sulfolenes with p-toluene-
sulfonyl isocyanate (PTSI) to synthesize tetrahydropyridones 2 and 3
(Scheme 1),5 and have used this method to prepare some indolizi-
dines and quinolizidines.6 We now report the use of ring-closing
metathesis (RCM)7,8 and cross-metathesis (CM)9 as key steps for
the synthesis of many quinolizidine derivatives, including two epi-
mers of quinolizidine 195C. Quinolizidine 195C was first isolated
from a Panamanian poison frog, Dendrobates speciosus.10 It was also
detected in an extract of a Brazilian myrmicine ant (Solenopsis picea),
and its structure was determined by chemical synthesis.11
Treatment of a solution of compounds 3aec5 in CH2Cl2 se-
quentially with Et3N, DMAP, and Boc2O at room temperature gave
the Boc-protected amides 4aec. Hydrogenation of the allyl group in
compound 4c provided the propyl-substituted product 4d. Further
oxidation of sulfides 4a,b and 4d with mCPBA afforded the corre-
sponding sulfones 5aec, which were then reduced with LiEt3BH in
CH2Cl2 at ꢁ78 ꢂC to give the aminals 6aec in excellent yields.
Compounds 6b and 6c were obtained as a diastereomeric mixture
of isomers (10.5:1, and 4.4:1, respectively, as judged from the 1H
NMR integrations). Without separation, this mixture of compounds
6aec was treated sequentially with boron trifluoride etherate and
allyltrimethylsilane12 to give products 7aec. The Boc group was
conveniently removed during the workup. The stereochemistry of
the 2,6-disubstituted compounds 7b and 7c was established to be
cis from the X-ray crystal structures of compound 7b and the Cbz-
protected derivative 8b, respectively. Presumably, the allyl nucle-
ophile preferentially approaches the iminium ion intermediate
from the axial direction due to the stereoelectronic effect. It is in-
teresting to note that the X-ray crystal structure of compound 7b
(Fig. 1)13 shows that the 2,6-disubstituents are at the equatorial
position whereas the X-ray crystal structure of compound 8b
(Fig. 2)13 shows that the 2,6-disubstituents are both at the axial
position. Apparently, the Cbz group of compound 8b would suffer
serious A1,3 strains with the 2,6-disubstituents if they were both in
the equatorial position (Scheme 2).
SPh
SPh
SPh
Bu3SnH
TsN=C=O
R
N
Ts
O
R
N
H
O
R
NaHCO3, HQ
Tol, reflux
S
AIBN, Tol
reflux
O2
1
2
3
Scheme 1.
Heating compounds 7a,b with allyl bromide or 3-bromo-2-
methylpropene in the presence of Et3N gave the N-allylated prod-
ucts 9aec. Ring-closing metathesis (RCM) of compounds 9aec with
* 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.2012.12.017

1500
S.-S.P. Chou et al. / Tetrahedron 69 (2013) 1499e1508
SPh
SPh
Boc2O (1.5 eq), Et3N (1 eq)
mCPBA
CH2Cl2, 0 oC to rt
DMAP (0.1 eq), CH2Cl2, rt
R
N
H
O
R
N
Boc
O
4a, R = H (70%)
4b, R = Me (87%)
4c, R = allyl (92%)
4d, R = Pr (99%)
3a, R = H
3b, R = Me
3c, R = allyl
H2 (1 atm), Pd/C, EtOAc, rt, 14 h
SO2Ph
1) BF3.OEt2 (5 eq)
SO2Ph
CH2Cl2, -78 oC, 30 min
LiEt3BH
CH2Cl2, 78 o
C
2) allyltrimethylsilane (5 eq)
CH2Cl2, 78 oC to rt, 24 h
R
N
Boc
O
R
N
Boc
OH
6a, R = H (93%)
5a, R = H (91%)
6b, R = Me (90%)
6c, R = Pr (90%)
5b, R = Me (96%)
5C, R = Pr (88%)
SO2Ph
SO2Ph
CbzCl (2 eq), base (2.1 eq)
CH2Cl2
R
N
H
R
N
Cbz
7a, R = H (65%)
7b, R = Me (56%)
7c, R = Pr (61%)
8a, R = Me (71%)
8b, R = Pr (92%)
Scheme 2.
Fig. 1. X-ray crystal structure of compound 7b.
SO2Ph
SO2Ph
SO2Ph
R'
Br
Grubbs' II (5 mol%)
Tol, reflux
H
N
R
N
R
R
N
H
Et3N
R'
R'
7a, R = H
9a, R = H, R' = H (77%)
9b, R = H, R' = Me (70%)
9c, R = Me, R' = H (83%)
10a, R = H, R' = H (65%)
10b, R = H, R' = Me (67%)
10c, R = Me, R' = H (71%)
7b, R = Me
SO2Ph
SO2Ph
H2 (1 atm)
H2 (1 atm)
Ms
N
N Ms
10% Pd/C (5 mol%)
10% Pd/C (5 mo%)
H
N
Cl
Cl
10a
Ru
N
EtOAc, rt, 48 h
95% EtOH, rt, 24 h
Ph
PCy3
G2
12 (80%)
11 (83%)
Scheme 3.
and p-cresol15 in refluxing toluene to give the
a,b-unsaturated ke-
tone 14, the 1H and 13C NMR spectra of which showed that only the
trans isomer was obtained. Atmospheric hydrogenation of com-
pound 14 gave the ketone 15, which was treated sequentially with
trifluoroacetic acid to remove the Boc group and then with sodium
borohydride in methanol to afford the cis-6,9a-quinolizidine 16.
The stereochemistry of compound 16 was established by NOESY.
Fig. 2. X-ray crystal structure of compound 8b.
0
5 mol % of Grubbs’ II catalyst (G2) in refluxing toluene provided the
cis-4,9a-quinolizidines 10aec.
There are cross signals between H9a and H6 and H4 , as well as
between H4 and the methyl group (Scheme 4).
Atmospheric pressure hydrogenation of compound 10a with
10% Pd/C in EtOAc reduced only the disubstituted C]C double bond
to give product 11, whereas similar reaction using 95% EtOH as the
solvent reduced both C]C double bonds to give the cis-2,9a-qui-
nolizidine 12. The IR spectra of compounds 11 and 12 show
a Bohlmann band at 2757 cmꢁ1 and 2765 cmꢁ1, respectively, in-
Compound 8a underwent cross metathesis (CM) with
propyl vinyl ketone (10 equiv) in the presence of Grubbs’ II catalyst
(G2) and p-cresol in refluxing toluene to give the E-a,b-unsaturated
ketone 17. We intended to synthesize a quinolizidine structure
from compound 17 through a one-pot hydrogenolysis/hydro-
genationecyclizationehydrogenation sequence16 (Scheme 5).
However, we tried many reaction conditions without success
(Table 1).
With the most commonly used catalyst Pd/C for the atmo-
spheric pressure hydrogenation (entry 1), only the exocyclic C]C
double bond of compound 17 was reduced to give product 18. Using
PtO2 as the catalyst (entry 2), product 18 was obtained in quanti-
tative yield. The use of Pd(OH)2 as the catalyst in methanol (entry 3)
cleaved the Cbz group as well as reduced both the endocyclic and
exocyclic C]C double bonds to give product 19 in excellent yield. In
dicating the presence of one or more
biaxially to the nitrogen lone pair.14 The 1H NMR of compound 12
shows a resonance for the H-2 at
a-hydrogens oriented trans-
d
2.99 (tt, J¼3.3,12.3 Hz). Thus, the
H-2 must be at the axial position of the ring. This means that hy-
drogenation occurs from the less hindered side of compound 10a
(cis to H-9a) to give product 12 (Scheme 3).
Compound 7a was protected as the Boc derivative 13. Cross
metathesis (CM) was successfully achieved by treatment of methyl
vinyl ketone (20 equiv) in the presence of Grubbs’ II catalyst (G2)

S.-S.P. Chou et al. / Tetrahedron 69 (2013) 1499e1508
1501
SO2Ph
SO2Ph
order to promote further cyclization of compound 19, trifluoro-
acetic acid (entry 4) or Et3N (entry 5) was added, but with no
success. Increasing the pressure of hydrogen (entry 6) or addition of
1 M HCl under high pressure of hydrogen (entry 7) did not result in
the formation of the expected quinolizidine product. We also used
Raney nickel as the catalyst (entries 8e9) in refluxing 95% EtOH,
with or without external hydrogen, but a complex mixture of
products was obtained. The 1H NMR of compound 19 shows a res-
Boc2O (1.5 eq), Et3N (1 eq)
N
H
DMAP (0.1 eq), CH2Cl2, reflux, 4 h
N
Boc
7a
13 (79%)
SO2Ph
SO2Ph
methyl vinyl ketone (20 eq)
Grubbs' II (5 mol%)
p-cresol (0.5 eq)
H2 (1 atm)
O
O
PtO2 (15 mol%)
onance for the H-4 at
d
3.05 (tt, J¼3.6, 12.6 Hz). Thus, the H-4 must
N
Boc
N
Boc
EtOAc, rt, 21 h
be at the axial position of the ring, and the phenylsulfonyl group is
at the more stable equatorial position. It seems reasonable that
hydrogenation occurs from the less hindered side of compound 17
to give product 19.
Tol, reflux, 4 h
14 (79%)
15 (93%)
NOE
SO2Ph
PhO2S
H4'
H9a
We then tried to carry out the reductive amination of compound
19 to give the quinolizidine product, but again without success
(Table 2). If compound 19 was first dissolved in a mixture of
CF3CO2H and CH2Cl2, followed by treatment with NaBH4 in meth-
anol, only the carbonyl group was reduced to give the alcohol 20 as
a 1:1 diastereomeric mixture (entry 1). The same result was ob-
tained when NaCNBH3 was used (entry 2), or with further control of
the pH (entry 3). We also added CeCl3$7H2O to activate the carbonyl
group (entry 4), but the product 20 was obtained in even lower
yield. The use of NaBH(OAc)3 in HOAc/MeOH at room temperature
(entry 5) or at reflux (entry 6) only gave the recovered starting
material.
1) TFA/CH2Cl2 (1 : 2), 0 oC, 4 h
2) NaBH4 (10 eq), MeOH
H6
H
N
6
9a
N
0
oC to rt, 1 h
H4
Me
16
16 (74%)
NOE
Scheme 4.
SO2Ph
SO2Ph
propyl vinyl ketone (10 eq)
p-cresol (0.5 eq)
O
N
Cbz
N
Cbz
G2 (5 mol%), Tol, reflux, 5 h
Table 2
Reduction of compound 19
8a
17 (68%)
SO2Ph
SO2Ph
OH
O
SO2Ph
hydrogenolysis-
hydrogenation
cyclization
(Table 2)
N
H
N
H
O
N
H
19
20
Entry
1
Reaction conditions
TFA/CH2Cl2 (1:2), 0 ꢂC; NaBH4, MeOH,
ꢂC to rt, 2 h
NaCNBH3, TFA/MeOH (1:10), 0 ꢂC to rt, 4 h
NaCNBH3, TFA/MeOH, pH 6, 0 ꢂC to rt, 4 h
CeCl3$7H2O, THF, reflux, 2 h; HOAc, 0 ꢂC; NaBH4,
MeOH, 0 ꢂC to rt, 5 h
Yield (%)
SO2Ph
N
SO2Ph
N
20 (87)
0
hydrogenation
2
3
4
20 (92)
20 (90)
20 (59)
5
6
NaBH(OAc)3 (10 equiv), HOAc/MeOH (1:40),
NRb
ꢂC to rt, 24 h
Scheme 5.
0
NaBH(OAc)3, HOAc/MeOH (1:40), reflux, 24 h
NRb
aAn inseparable 1:1 diastereomeric mixture of product 20 was obtained.
b
No reaction was observed.
Table 1
Hydrogenation of compound 17
Alcohol 20 was first converted to its mesylate by standard
procedure, and the crude product was then directly heated with
Et3N in toluene to give two diastereomeric quinolizidines 21a and
21b (Scheme 6), which were separated by flash column chroma-
tography. The structure of crystalline compound 21a was de-
termined by X-ray crystallography (Fig. 3).13 The stereochemistry of
liquid compound 21b was established by NOESY (Fig. 4). There are
SO2Ph
SO2Ph
SO2Ph
4
O
O
O
or
N
Cbz
2
N
H
6
N
Cbz
(Table 1)
17
18
19
0
cross signals between H9a and H2, H4 and H6 , but there is no cross
Entry Catalyst (mol %)
H2
Conditions
Yield (%)
signal between H9a and the methyl group.
1
2
3
4
5
6
7
8
9
Pd/C (10)
PtO2 (15)
1 atm MeOH, rt, 24 h
1 atm EA, rt, 20 h
1 atm MeOH, rt, 24 h
1 atm TFA/MeOH (1:5), rt, 24 h
1 atm Et3N (5 equiv), MeOH, rt, 48 h 19 (90)
100 psi MeOH, rt, 24 h 19 (80)
18 (90)
18 (99)
19 (90)
19 (95)
Pd(OH)2 (10)
Pd(OH)2 (10)
Pd(OH)2 (10)
Pd(OH)2 (10)
Pd(OH)2 (10)
SO2Ph
SO2Ph
SO2Ph
1) MsCl (1.1 eq), Et3N (2.1 eq)
CH2Cl2, 0 oC to rt, 17 h
H
N
H
N
5 bar 1 M HCl(aq)/MeOH (1:5), rt, 48 h 19 (84)
+
N
H
Raney-Ni (20 equiv)a None 95% EtOH, reflux, 22 h
Raney-Ni (20 equiv)a 1 atm 95% EtOH, reflux, 60 h
NDb
NDc
2) Et3N/Tol (1:3), reflux, 24 h
a
OH
20 (1:1)
Catalyst (20 equiv) was used.
A complex mixture of products together with recovered compound 17 (22%)
b
21a (48%)
21b (43%)
was obtained.
c
A complex mixture of products was obtained.
Scheme 6.

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S.-S.P. Chou et al. / Tetrahedron 69 (2013) 1499e1508
3. Conclusions
Starting from simple 6-substuted 5,6-dihydro-2-pyridones 3, the
cis-2,6-disubstituted derivatives 7e8 were readily prepared. Further
elaboration through ring-closing metathesis (RCM) and other re-
actions provided the quinolizidines 10e12 with complete stereo-
control. Cross metathesis (CM) of compounds 8a and 13 with
a suitable enone afforded the a,b-unsaturated ketones 17 and 14,
respectively. cis-6,9a-Quinolizidine 16 was then obtained from com-
pound 14, whereas synthetic transformations of compound 17 led to
quinolizidine 6-epi-195C (22) and quinolizidine 9a-epi-195C (23).
4. Experimental section
4.1. General
Melting points were determined with a SMP3 melting appara-
tus. 1H and 13C NMR spectra were recorded on a Bruker Avance 300
spectrometer operating at 300 and at 75 MHz, respectively.
Fig. 3. X-ray crystal structure of compound 21a.
Chemical shifts (d) are reported in parts per million (ppm) from the
NOE
internal reference standard tetramethylsilane (TMS), and the cou-
pling constants (J) are given in Hertz. High resolution mass spectra
(HRMS) were measured with a mass spectrometer Finnigan/
Thermo Quest MAT 95XL. Elemental analyses were carried out with
Heraeus Vario III-NCSH, Heraeus CHNeOeS-Rapid Analyzer, or
Elementar Vario EL III. Flash column chromatographic purifications
were performed using Merck 60H silica gel. The microwave re-
actions were carried out with a CEM FocusedÔ Discover-S system.
H2
H9a
H6
H4
PhO2S
N
Me
4.2. General procedure for protection of compounds 3
Fig. 4. NOESY correlations of compound 21b.
To
a solution of amide 3 (4.88 mmol) and 4-dimethyl-
aminopyridine (0.49 mmol) in CH2Cl2 (20 mL) under nitrogen
were added sequentially Et3N (0.68 mL) and di-tert-butyl dicar-
bonate (7.32 mmol). After stirring at room temperature for 3 h, the
reaction mixture was quenched with saturated sodium bicarbonate
(20 mL). The aqueous solution was extracted with CH2Cl2, dried
(MgSO4), and evaporated under vacuum. The crude product was
purified by flash chromatography using ethyl acetate/hexane (1:9)
containing 5% Et3N as eluent to give product 4.
We can convert compounds 21a and 21b to two epimers of
quinolizidine (ꢀ)-195C (Scheme 7). Treatment of compounds 21a
and 21b individually with 6% Na/Hg in refluxing THF gave the
corresponding products 22 and 23. The spectral data of compound
23 were the same as the literature report, which used NOESY
technique to determine its structure.16d Although the IR and MS
data of compound 22 have been reported and used to elucidate its
stereochemisty,11 we have now fully characterized it by 1H and 13
C
4.2.1. 1-(tert-Butoxycarbonyl)-4-(phenylthio)-1,2,5,6-tetrahydro-2-
NMR spectroscopy. Furthermore, since the structure of crystalline
compound 21a has been established by X-ray crystallography
(Fig. 3), its conversion by reductive cleavage of the phenylsulfonyl
group to compound 22 would confirm the relative stereochemistry
of compound 22. It should be noted that compounds 22 and 23
differ from the stereochemistry of natural product quinolizidine
195C at C6 and C9a, respectively.
pyridinone (4a). Yield (70%); colorless liquid; IR (neat)
n 3059, 2981,
2935, 2891, 1761, 1711, 1598, 1475, 1388, 1318, 1155, 1101, 968, 939,
750, 705, 692 cmꢁ1; 1H NMR (CDCl3)
d 7.52e7.36 (5H, m), 5.32 (1H,
s), 3.87 (2H, t, J¼6.3 Hz), 2.53 (2H, t, J¼6.3 Hz), 1.51 (9H, s); 13C NMR
(CDCl3)
d 162.0, 158.4, 151.9, 134.9, 129.9, 129.6, 127.5, 115.4, 82.2,
43.1, 28.9, 27.7; EI-MS (rel intensity) m/z 305 (Mþ, 7), 244 (52), 205
(38), 172 (22), 86 (64), 84 (100); EI-HRMS m/z calcd for C16H19NO3S
305.1086, found 305.1092.
SO2Ph
H
H
4.2.2. 1-(tert-Butoxycarbonyl)-6-methyl-4-(phenylthio)-1,2,5,6-
tetrahydro-2-pyridinone (4b). Yield (87%); white solid mp
6% Na/Hg (40 eq)
THF, reflux, 7 h
6
N
N
83.1e84.1 ꢂC; IR (ATR, film)
n
3060, 2979, 2933, 1760, 1683, 1456,
1391, 1225, 1156, 1114, 1075, 1024, 822, 751, 706 cmꢁ1 1H NMR
(CDCl3)
;
22 (69%)
d
7.55e7.48 (5H, m), 5.34 (1H, d, J¼2.4 Hz), 4.59 (1H, qdd,
21a
quinolizidine (¡Ó)-6-epi-195C
J¼6.9, 6.0, 1.5 Hz), 2.97 (1H, ddd, J¼17.4, 6.0, 2.4 Hz), 2.20 (1H, dd,
J¼17.4, 1.5 Hz), 1.52 (9H, s), 1.31 (3H, d, J¼6.9 Hz); 13C NMR (CDCl3)
SO2Ph
d
161.8, 155.9, 152.4, 135.4, 130.3, 130.0, 128.0, 115.3, 82.7, 49.9, 35.0,
H
H
28.1, 18.7; EI-MS (rel intensity) m/z 319 (Mþ, 36), 246 (26), 219
(100), 204 (74), 177 (24), 86 (39), 84 (59), 57 (45); EI-HRMS m/z
calcd for C17H21NO3S 319.1242, found 319.1249.
6% Na/Hg (40 eq)
THF, reflux, 7 h
N
N
9a
21b
23 (65%)
quinolizidine (¡Ó)-9a-epi-195C
4.2.3. 6-Allyl-1-(tert-butoxycarbonyl)-4-(phenylthio)-1,2,5,6-tetrah-
ydro-2-pyridinone (4c). Yield (92%); light yellow oil; IR (neat)
n
Scheme 7.
3076, 3062, 2979, 2931, 1760, 1710, 1601, 1583, 1441, 1224, 1156,

S.-S.P. Chou et al. / Tetrahedron 69 (2013) 1499e1508
1503
1117, 1075, 835, 751, 705, 692 cmꢁ1
;
1H NMR (CDCl3)
d
7.58e7.47
(CDCl3) d 161.0, 151.5, 150.5, 136.7, 134.6, 129.6, 128.6, 128.1, 83.7,
(5H, m), 5.84e5.66 (1H, m), 5.35 (1H, d, J¼2.4 Hz), 5.19e5.06 (2H,
53.6, 34.4, 27.8, 25.9, 19.1, 13.5; FAB-MS (rel intensity) m/z 380
(MþH, 1), 325 (19), 324 (100), 280 (19); FAB-HRMS m/z calcd for
C19H25NO5S 379.1453, found 379.1448.
m), 4.54e4.46 (1H, m), 2.83 (1H, ddd, J¼17.4, 6.0, 2.4 Hz), 2.53e2.30
(3H, m), 1.52 (9H, s); 13C NMR (CDCl3)
d 161.4, 155.8, 152.0, 135.1,
133.6, 130.0, 129.7, 127.6, 118.6, 115.2, 82.4, 53.0, 36.7, 31.3, 27.8; EI-
MS (rel intensity) m/z 345 (Mþ, 0.18), 205 (15), 204 (100); EI-HRMS
m/z calcd for C19H23NO3S 345.1399, found 345.1406.
4.4. General procedure for reduction of amides 5
To a solution of compound 5 (0.3 mmol) in CH2Cl2 (10 mL)
at ꢁ78 ꢂC was added dropwise LiEt3BH (1 M in THF, 0.33 mmol).
The reaction mixture was stirred at ꢁ78 ꢂC for another 1 h, and was
quenched with saturated NaHCO3 solution. The aqueous solution
was extracted with CH2Cl2, dried (MgSO4), and evaporated under
vacuum. The crude product was purified by flash chromatography
using ethyl acetate/hexane (1:2) containing 5% Et3N as eluent to
give pure product. If necessary, the solid crude product could be
purified by recrystallization from CH2Cl2/hexane.
4.2.4. 1-(tert-Butoxycarbonyl)-4-(phenylthio)-6-propyl-1,2,5,6-tetra-
hydro-2-pyridinonoe (4d). To a solution of compound 4c (110 mg,
0.32 mmol) in ethyl acetate (5 mL) was added 10% Pd/C (16.9 mg).
Then the reaction mixture was stirred vigorously under a balloon of
hydrogen at room temperature for 22 h, filtered with Celite, washed
with ethyl acetate, dried (MgSO4), and evaporated under vacuum to
give pure product 4d (111 mg, 99%). Colorless liquid; IR (neat)
3060, 2962, 2933, 2873, 1760, 1710, 1602, 1457, 1392, 1157, 1119,
1089, 1075, 827, 751, 706 cmꢁ1 1H NMR (CDCl3)
7.55e7.46 (5H,
n
;
d
m), 5.33 (1H, d, J¼2.4 Hz), 4.54e4.42 (1H, m), 2.89 (1H, ddd, J¼17.4,
4.4.1. 1-(tert-Butoxycarbonyl)-2-hydroxy-4-(phenylsulfonyl)-1,2,5,6-
6.0, 2.4 Hz), 2.32 (1H, dd, J¼17.4,1.5 Hz),1.76e1.56 (2H, m),1.52 (9H,
tetrahydro-2-pyridinone (6a). Yield (93%); white solid mp
s), 1.44e1.21 (2H, m), 0.93 (3H, t, J¼7.2 Hz); 13C NMR (CDCl3)
d 161.8,
103e104 ꢂC; IR (film)
n
3415, 3068, 2978, 1685, 1447, 1419, 1394,
1367, 1306, 1286, 1212, 1151, 1123, 1092, 1062, 1046, 1021, 986, 948,
913, 855, 827, 755, 727, 687 cmꢁ1; 1H NMR (CDCl3)
7.90e7.87 (2H,
156.0, 152.2, 135.2, 130.1, 129.8, 127.8, 115.3, 82.4, 53.5, 34.5, 32.4,
27.9, 19.5, 13.8; EI-MS (rel intensity) m/z 347 (Mþ, 4), 205 (14), 204
(100), 86 (14), 84 (22); EI-HRMS m/z calcd for C19H25NO3S 347.1555,
found 347.1560.
d
m), 7.69e7.54 (3H, m), 6.93e6.91 (1H, m), 5.91 (1H, br s), 4.13e4.03
(2H, m), 3.02 (1H, br s), 2.36e2.23 (2H, m), 1.46 (9H, s); 13C NMR
(CDCl3)
d 154.7, 142.8, 138.3, 133.9, 133.3, 129.4, 128.4, 81.6, 72.4,
4.3. General procedure of oxidation of sulfides 4
36.5, 28.4, 23.5; ESI-MS (rel intensity) m/z 339 (Mꢁ-H, 62), 338 (15),
274 (31), 272 (100); ESI-HRMS m/z calcd for C16H21NO5S 339.1140,
found 339.1131.
To a solution of compound 4 (3.28 mmol) in CH2Cl2 (40 mL) at
0
ꢂC was added mCPBA (70e75% in H2O, 8.19 mmol) in small por-
tions. The reaction mixture was stirred at room temperature for 2 h,
and was washed sequentially with 5% aqueous Na2S2O3 and satu-
rated NaHCO3, dried (MgSO4) and concentrated under reduced
pressure to give pure product. If necessary, the solid crude product
could be purified by recrystallization from CH2Cl2/hexane.
4.4.2. cis- and trans-1-(tert-Butoxycarbonyl)-2-hydroxy-6-methyl-4-
(phenylsulfonyl)-1,2,5,6-tetrahydro-2-pyridinone (6b). Yield (90%);
yellow liquid; IR (neat)
1341, 1308, 1156, 1116, 1054, 851, 737, 705 cmꢁ1
7.98e7.85 (2H, m), 7.72e7.52 (3H, m), 7.03e6.88 (1H, m),
n
3455, 3057, 2982, 2934, 1686, 1447, 1393,
;
1H NMR (CDCl3)
d
5.92e5.72 (1H, m), 4.65e4.22 (1H, m), 2.51e2.34 (1H, m),
2.30e2.13 (1H, m), 2.00 (1H, br s), 1.48 (9H, s), 0.97 (3H, d,
4.3.1. 1-(tert-Butoxycarbonyl)-4-(phenylsulfonyl)-1,2,5,6-tetrahydro-
2-pyridinone (5a). Yield (91%); white solid mp 151.6e152.9 ꢂC; IR
J¼6.6 Hz); 13C NMR (CDCl3)
d 154.7, 139.5, 138.5, 137.9, 133.8, 133.6,
(ATR, film)
968, 899, 751, 724, 690 cmꢁ1; 1H NMR (CDCl3)
7.75e7.51 (3H, m), 6.63 (1H, t, J¼1.3 Hz), 3.87 (2H, t, J¼6.3 Hz),
2.59e2.54 (2H, m), 1.52 (9H, s); 13C NMR (CDCl3)
161.4, 153.2,
n
2985, 2934, 1764, 1706, 1476, 1388, 1219, 1155, 1078,
132.9,129.3,129.0,128.7,128.4, 81.5, 81.3, 72.5, 43.5, 29.7, 28.9, 28.6,
28.3, 19.1, 18.8; ESI-MS (rel intensity) m/z 376 (MþþNa, 58), 280
(39), 258 (18), 236 (100); ESI-HRMS m/z calcd for C17H23NO5S
353.1297, found 353.1294.
d
8.01e7.81 (2H, m),
d
151.5, 137.0, 134.6, 129.7, 128.5, 128.4, 83.9, 43.3, 27.8, 23.0; EI-MS
(rel intensity) m/z 338 (Mþþ1, 1), 283 (22), 282 (95), 264 (20),
238 (80), 208 (28), 125 (43), 96 (24), 86 (23), 77 (24), 67 (30), 57
(100); EI-HRMS m/z calcd for C16H19NO5S 337.0984, found
337.0982.
4.4.3. cis- and trans-1-(tert-Butoxycarbonyl)-2-hydroxy-4-(phenyl-
sulfonyl)-6-propyl-1,2,5,6-tetrahydro-2-pyridinone (6c). Yield (90%);
yellow liquid; IR (neat)
1320, 1125, 1092, 1064, 1042, 813, 759, 689 cmꢁ1; 1H NMR (CDCl3)
7.95e7.87 (2H, m), 7.72e7.51 (3H, m), 7.01e6.89 (1H, m),
n 3446, 3064, 2962, 2933, 2873, 1695, 1368,
d
4.3.2. 1-(tert-Butoxycarbonyl)-6-methyl-4-(phenylsulfonyl)-1,2,5,6-
5.93e5.68 (1H, m), 4.42e4.05 (1H, m), 2.47e2.31 (1H, m),
2.30e2.19 (1H, m), 1.47 (9H, s), 1.23e0.82 (4H, m), 0.81e0.63 (3H,
tetrahydro-2-pyridinone (5b). Yield (96%); white solid mp
123.5e124.5 ꢂC; IR (ATR, film)
n
2972, 2941, 1757, 1687, 1368, 1324,
m); 13C NMR (CDCl3)
d 156.0, 155.1, 140.9, 139.3, 137.8, 137.7, 133.8,
1229, 1115, 1070, 817, 765, 725 cmꢁ1; 1H NMR (CDCl3)
d
7.91 (2H, d,
133.7, 133.2, 132.3, 129.3, 129.2, 128.3, 128.2, 81.5, 81.3, 73.3, 72.2,
51.8, 47.5, 46.4, 35.0, 34.8, 28.2, 27.2, 25.6, 19.4, 13.6; ESI-MS (rel
intensity) m/z 364 (MþꢁH2OþH, 12), 308 (100), 265 (13), 264 (80);
ESI-HRMS m/z calcd for C19H25NO4S 363.1504, found 363.1517.
J¼7.5 Hz), 7.78e7.56 (3H, m), 6.73e6.65 (1H, m), 4.66 (1H, qd, J¼6.6,
6.6 Hz), 2.77 (1H, ddd, J¼17.7, 6.0, 2.7 Hz), 2.47 (1H, d, J¼17.7 Hz),
1.52 (9H, s), 1.14 (3H, d, J¼6.6 Hz); 13C NMR (CDCl3)
d 161.0, 151.5,
150.6, 136.8, 134.6, 134.6, 129.7, 128.6, 127.8, 83.9, 49.9, 28.9, 27.9,
18.7; FAB-MS (rel intensity) m/z 352 (MþH, 3), 297 (17), 296 (100),
252 (17), 57 (46); FAB-HRMS m/z calcd for C17H21NO5S 351.1140,
found 351.1143.
4.5. General procedure for the reaction of aminals 6 with
allyltrimethylsilane
4.3.3. 1-(tert-Butoxycarbonyl)-4-(phenylsulfonyl)-6-propyl-1,2,5,6-
tetrahydro-2-pyridinone (5c). Yield (88%); colorless liquid; IR (neat)
To a solution of compound 6 (0.3 mmol) in CH2Cl2 (10 mL)
at ꢁ78 ꢂC was added BF3$OEt2 (1.5 mmol). After stirring at ꢁ78 ꢂC
for 30 min, allyltrimethylsilane (1.5 mmol) was then added drop-
wise. The reaction mixture was slowly warmed to room tempera-
ture, and was quenched with saturated NaHCO3. The aqueous
solution was extracted with CH2Cl2, dried (MgSO4), and evaporated
under vacuum. The crude product was purified by flash
n
3067, 2964, 2934, 2875, 1766, 1718, 1369, 1292, 1120, 1095, 1079,
817, 759, 730 cmꢁ1; 1H NMR (CDCl3)
d
7.91e7.82 (2H, m), 7.73e7.51
(3H, m), 6.69e6.64 (1H, m), 4.52e4.39 (1H, m), 2.66 (1H, ddd,
J¼18.0, 6.0, 3.0 Hz), 2.51 (1H, dd, J¼18.0, 1.5 Hz), 1.51e1.39 (10H, m),
1.34e1.19 (1H, m),1.12e0.83 (2H, m), 0.71 (3H, t, J¼7.2 Hz); 13C NMR

1504
S.-S.P. Chou et al. / Tetrahedron 69 (2013) 1499e1508
chromatography using ethyl acetate/hexane (1:1e1:3) containing
5% Et3N as eluent to give pure product.
1303, 1149, 1118, 1093, 1068, 884, 840, 767, 728, 691 cmꢁ1; 1H NMR
(CDCl3) 7.95e7.78 (2H, m), 7.72e7.49 (3H, m), 7.44e7.25 (5H, m),
d
7.02 (1H, br s), 5.84 (1H, br s), 5.29e4.99 (4H, m), 4.79e4.38 (2H, m),
2.78e2.45 (1H, m), 2.41e2.11 (3H, m), 1.41e1.22 (1H, m), 1.22e0.98
4.5.1. 2-Allyl-4-(phenylsulfonyl)-1,2,5,6-tetrahydropyridine (7a). Yield
(65%); yellow liquid; IR (film)
n
3058, 2931, 1641, 1446, 1303, 1149,
(3H, m), 0.77 (3H, t, J¼7.2 Hz); 13C NMR (CDCl3)
d 155.0, 138.7, 136.3
1124,1091, 1033,1016, 997, 924, 755, 729, 688 cmꢁ1; 1H NMR (CDCl3)
(ꢃ2), 135.0, 133.6 (ꢃ3), 129.3, 128.6, 128.2, 128.1, 119.0, 67.6, 52.3,
48.2, 40.0, 35.5, 27.0, 19.8, 13.8; FAB-MS (rel intensity) m/z 440
(MþþH, 91), 438 (24), 399 (25), 398 (91), 355 (23), 354 (89), 348
(69), 332 (27), 308 (90), 140 (62), 105 (59), 88 (43), 67 (54), 51 (100);
FAB-HRMS m/z calcd for C25H29NO4S 439.1817, found 439.1812.
d
7.86e7.83 (2H, m), 7.64e7.51 (3H, m), 6.96 (1H, d, J¼1.8 Hz),
5.81e5.70 (1H, m), 5.18e5.13 (2H, m), 3.59e3.54 (1H, m), 3.13 (1H, dt,
J¼12.3, 4.4 Hz), 2.83e2.75 (1H, m), 2.39e2.19 (5H, m); 13C NMR
(CDCl3) d 139.4,139.1, 138.8, 133.7, 133.2, 129.0, 127.9,118.5, 53.5, 41.2,
38.9, 23.5; FAB-MS (rel intensity) m/z 264 (MþþH,100), 262 (28), 222
(38), 125 (33), 122 (25), 80 (22), 30 (53); FAB-HRMS m/z calcd for
C14H17NO2S m/z 263.0980, found 263.0980.
4.7. 1,2-Bis(allyl)-4-(phenylsulfonyl)-1,2,5,6-tetrahydropyrid-
ine (9a)
4.5.2. cis-2-Allyl-6-methyl-4-(phenylsulfonyl)-1,2,5,6-tetrahydropy-
To a solution of compound 7a (100 mg, 0.38 mmol) in THF
(10 mL) was added sequentially Et3N (0.16 mL, 1.14 mmol) and
allyl bromide (0.1 mL, 1.14 mmol). The reaction mixture was then
refluxed for 4 h. The solvent was evaporated under vacuum, and
the residue was purified by flash chromatography using ethyl
acetate/hexane (1:6) containing 5% Et3N as eluent to give
ridine (7b). Yield (56%); yellow solid mp 71.7e73.3 ꢂC; IR (ATR,
film)
n ;
3055, 2988, 1645, 1443, 1422, 1265, 1127, 896, 739, 705 cmꢁ1
1H NMR (CDCl3)
d
7.92e7.79 (2H, m), 7.68e7.58 (1H, m), 7.58e7.48
(2H, m), 6.93 (1H, s), 5.78 (1H, ddt, J¼17.1, 9.9, 7.2 Hz), 5.26e5.09
(2H, m), 3.69e3.57 (1H, m), 2.94e2.77 (1H, m), 2.44e2.21 (3H, m),
1.85e1.67 (1H, m), 1.13 (3H, d, J¼6.6 Hz); 13C NMR (CDCl3)
d
139.2,
product 9a (88.7 mg, 77%). Red-brown liquid; IR (film)
2937, 2810, 1641, 1555, 1446, 1381, 1354, 1304, 1208, 1150, 1091,
1063, 997, 958, 918, 802, 755, 723, 688 cmꢁ1 1H NMR (CDCl3)
7.86e7.84 (2H, m), 7.59e7.50 (3H, m), 6.94 (1H, t, J¼1.2 Hz),
5.85e5.70 (2H, m), 5.20e5.07 (4H, m), 3.32e3.25 (2H, m),
3.03e2.90 (2H, m), 2.55e2.12 (5H, m); 13C NMR (CDCl3)
139.4,
n 3071,
138.9,138.6,133.4 (ꢃ2),129.2,128.0,119.1, 54.8, 48.7, 39.0, 31.1, 21.4;
FAB-MS (rel intensity) m/z 278 (MþþH, 55), 228 (33), 147 (37), 137
(48),136 (87),107 (33), 95 (31), 89 (34), 77 (36), 73 (100), 51 (61), 30
(35); FAB-HRMS m/z calcd for C15H19NO2S 277.1136, found 277.1139.
;
d
d
4.5.3. cis-2-Allyl-4-(phenylsulfonyl)-6-propyl-1,2,5,6-tetrahydropy-
139.1, 138.5, 134.6, 134.0, 133.2, 129.1, 127.9, 118.0, 117.6, 58.3,
56.2, 45.7, 36.2, 22.2; FAB-MS (rel intensity) m/z 304 (MþþH, 31),
302 (39), 262 (100); FAB-HRMS m/z calcd for C17H21NO2S
303.1293, found 303.1288.
ridine (7c). Yield (61%); yellow liquid; IR (neat)
2874, 1686, 1369, 1307, 1155, 1094, 1073, 758, 725 cmꢁ1
(CDCl3) 7.99e7.78 (2H, m), 7.73e7.59 (1H, m), 7.58e7.42 (2H, m),
n
3062, 2957, 2931,
;
1H NMR
d
6.93 (1H, s), 5.78 (1H, ddt, J¼17.1, 10.2, 7.2 Hz), 5.27e5.11 (2H, m),
3.73e3.52 (1H, m), 2.81e2.66 (1H, m), 2.47e2.21 (3H, m), 1.85e1.60
(2H, m), 1.49e1.24 (4H, m), 0.89 (3H, t, J¼7.2 Hz); 13C NMR (CDCl3)
4.8. 2-Allyl-1-(2-methyl-2-propenyl)-4-(phenylsulfonyl)-1,2,5,6-
tetrahydropyridine (9b)
d
139.7, 139.4, 139.2, 133.8, 133.4, 129.2, 128.1, 118.9, 54.9, 52.9, 39.5,
38.5, 30.0, 19.0, 14.1; FAB-MS (rel intensity) m/z 306 (MþþH, 100),
304 (40), 264 (34), 162 (17); FAB-HRMS m/z calcd for C17H23NO2S
305.1449, found 305.1460.
To a solution of compound 7a (100 mg, 0.38 mmol) in toluene
(10 mL) was added sequentially Et3N (0.16 mL, 1.14 mmol) and 3-
bromo-2-methylpropene (0.12 mL, 1.14 mmol). The reaction
mixture was then refluxed for 4 h. The solvent was evaporated
under vacuum, and the residue was purified by flash chroma-
tography using ethyl acetate/hexane (1:6) containing 5% Et3N as
eluent to give product 9b (84.4 mg, 70%). Red-brown liquid; IR
4.6. General procedure for the conversion of compounds 7 to
compounds 8
To
a
mixture of compound
7
(0.50 mmol) and K2CO3
(film)
n
3074, 2939, 2806, 1642, 1446, 1355, 1304, 1207, 1150, 1092,
(1.05 mmol) in CH2Cl2 (10 mL) under nitrogen was added CbzCl
(0.142 mL, 1.0 mmol) in one portion. The reaction mixture was
refluxed for 4 h, and was then quenched with water (10 mL). The
aqueous solution was extracted with CH2Cl2, dried (MgSO4), and
evaporated under vacuum. The crude product was purified by flash
chromatography using ethyl acetate/hexane (1:3) containing 5%
Et3N as eluent to give pure product.
1063, 1024, 998, 908, 802, 755, 726, 687 cmꢁ1
;
1H NMR (CDCl3)
d
7.87e7.84 (2H, m), 7.64e7.51 (3H, m), 6.95 (1H, t, J¼1.2 Hz),
5.84e5.71 (1H, m), 5.12e5.04 (2H, m), 4.83 (2H, br s), 3.22e3.17
(2H, m), 2.93e2.85 (1H, m), 2.75 (1H, d, J¼13.5 Hz), 2.39e2.09
(5H, m), 1.67 (3H, s); 13C NMR (CDCl3)
d 142.6, 139.6, 139.0, 138.3,
134.1, 133.2, 129.0, 127.8, 117.2, 112.9, 59.9, 58.9, 45.1, 36.5, 21.9,
20.4; FAB-MS (rel intensity) m/z 318 (MþþH, 22), 316 (39), 276
(100), 55 (27); FAB-HRMS m/z calcd for C18H23NO2S 317.1449,
found 317.1449.
4.6.1. cis-2-Allyl-1-(benzyloxycarbonyl)-6-methyl-4-(phenylsulfonyl)-
1,2,5,6-tetrahydropyridine (8a). Yield (71%); colorless liquid; IR
(neat)
1308, 1071, 1055, 890, 758, 729, 690 cmꢁ1
7.92e7.88 (2H, m), 7.67e7.58 (1H, m), 7.58e7.48 (2H, m), 7.41e7.22
n
3065, 3034, 2977, 2934, 1693, 1656, 1447, 1383, 1358, 1328,
4.9. cis-1,2-Bis(allyl)-6-methyl-4-(phenylsulfonyl)-1,2,5,6-tetr-
ahydropyridine (9c)
;
1H NMR (CDCl3)
d
(5H, m), 7.05 (1H, s), 5.93e5.71 (1H, m), 5.22e5.03 (4H, m), 4.76 (1H,
br s), 4.60 (1H, br s), 2.56 (1H, br s), 2.49e2.17 (3H, m), 1.00 (3H, d,
To a solution of compound 7b (22 mg, 0.08 mmol) in toluene
(5 mL) was added sequentially Et3N (0.03 mL, 0.24 mmol) and allyl
bromide (0.04 mL, 0.48 mmol). The reaction mixture was heated in
a sealed tube at 150 ꢂC for 3 d. The solvent was evaporated under
vacuum, and the residue was purified by flash chromatography
using ethyl acetate/hexane (1:6) containing 5% Et3N as eluent to
J¼6.9 Hz); 13C NMR (CDCl3)
d
154.3 (ꢃ2), 138.3, 136.1, 134.7, 133.4
(ꢃ2), 129.1, 128.3, 127.9, 127.8, 127.7, 118.6, 67.2, 51.8, 43.5, 39.5, 28.4,
19.7; FAB-MS (rel intensity) m/z 412 (MþþH, 4), 370 (6), 326 (7), 124
(6), 79 (100), 69 (5), 66 (7); FAB-HRMS m/z calcd for C23H25NO4S
411.1504, found 411.1501.
give product 9c (21 mg, 83%). Yellow-brown liquid; IR (neat)
2975, 2930, 1627, 1546, 1479, 1378, 1306, 1216, 1018, 894, 846, 737,
690 cmꢁ1; 1H NMR (CDCl3)
7.93e7.79 (2H, m), 7.65e7.59 (1H, m),
n 3060,
4.6.2. cis-2-Allyl-1-(benzyloxycarbonyl)-4-(phenylsulfonyl)-6-propyl-
d
1,2,5,6-tetrahydropyridine (8b). Yield (90%); white solid mp
7.59e7.48 (2H, m), 6.92 (1H, s), 5.53e5.68 (2H, m), 5.28e5.05 (4H,
m), 3.52e3.25 (3H, m), 2.92e2.75 (1H, m), 2.55e2.41 (1H, m),
101.1e102.8 ꢂC; IR (ATR, film)
n 3059, 2950, 2915, 2863, 1698, 1343,

S.-S.P. Chou et al. / Tetrahedron 69 (2013) 1499e1508
1505
2.39e2.25 (2H, m), 1.98e1.83 (1H, m), 1.16 (3H, d, J¼6.0 Hz); 13C
13C NMR (CDCl3)
d
139.6, 139.2, 138.0, 133.4, 129.2, 128.2, 61.4, 55.5,
NMR (CDCl3)
d
139.4, 139.3, 137.4, 134.2, 133.5, 133.3, 129.2, 128.1,
51.5, 31.1, 25.6, 25.0, 24.1; FAB-MS (rel intensity) m/z 278 (MþþH,
17), 147 (33), 136 (17), 73 (100), 41 (20); FAB-HRMS m/z calcd for
C15H19NO2S 277.1136, found 277.1141.
118.2, 117.8, 58.1, 51.8, 51.2, 37.4, 30.9, 20.1; FAB-MS (rel intensity)
m/z 318 (MþþH, 47), 316 (35), 276 (76), 145 (34), 137 (38), 135 (32),
133 (37), 131 (31), 123 (38), 121 (46), 119 (60), 109 (50), 107 (47), 105
(57), 95 (76), 93 (54), 91 (54), 83 (38), 81 (100), 79 (35); FAB-HRMS
m/z calcd for C18H23NO2S 317.1449, found 317.1441.
4.12. (2S*,9aS*)-2-(Phenylsulfonyl)-2,3,4,6,7,8,9,9a-octahydro-
1H-quinolizine (12)
4.10. General procedure for RCM of compounds 9
A mixture of compound 10a (100 mg, 0.33 mmol) and 10%
palladium on carbon (17.5 mg) in 95% EtOH (10 mL) was stirred
vigorously under a balloon of hydrogen at room temperature for
24 h. The reaction mixture was then filtered with Celite, washed
with ethyl acetate, dried (MgSO4), and evaporated under vacuum.
The crude product was purified by flash chromatography using
ethyl acetate/hexane (1:4) containing 5% Et3N as eluent to give
A mixture of compound 9 (0.33 mmol) and G2 (14 mg,
0.0165 mmol) in toluene (10 mL) was refluxed for 3e4 h. The sol-
vent was removed under vacuum, and the crude product was pu-
rified by flash chromatography using ethyl acetate/hexane
(1:5e1:4) containing 5% Et3N as eluent to give pure product.
product 12 (79 mg, 80%). Light yellow liquid; IR (film)
2805, 2765, 1586, 1447, 1353, 1304, 1277, 1224, 1178, 1146, 1126,
1084, 999, 895, 809, 794, 722, 689 cmꢁ1 1H NMR (CDCl3)
7.88e7.85 (2H, m), 7.69e7.54 (3H, m), 2.99 (1H, tt, J¼3.3, 12.3 Hz),
2.91e2.86 (1H, m), 2.78 (1H, br d, J¼11.7 Hz), 2.05e1.91 (4H, m),
1.76e1.51 (6H, m), 1.43e1.20 (3H, m); 13C NMR (CDCl3)
136.6,
133.8, 129.3, 129.2, 62.1, 61.2, 55.8, 54.7, 33.0, 32.3, 25.6 (ꢃ2), 24.2;
FAB-MS (rel intensity) m/z 280 (MþþH, 100), 278 (42), 138 (69), 136
(58); FAB-HRMS m/z calcd for C15H21NO2S 279.1293, found
279.1291.
n 3060, 2935,
4.10.1. 2-(Phenylsulfonyl)-4,6,9,9a-tetrahydro-3H-quinolizine
(10a). Yield (65%); yellow-brown solid mp 83e84 ꢂC; IR (film)
n
;
3053, 2913, 2756, 1651, 1446, 1304, 1288, 1148, 1085, 1067, 999, 880,
859, 794, 732, 715, 688, 663 cmꢁ1; 1H NMR (CDCl3)
7.87e7.84 (2H,
d
d
m), 7.64e7.50 (3H, m), 6.83 (1H, s), 5.79e5.68 (2H, m), 3.28 (1H, d,
J¼16.8 Hz), 3.05e2.89 (3H, m), 2.45e2.11 (5H, m); 13C NMR (CDCl3)
d
d
139.0, 138.4, 138.3, 133.4, 129.2, 128.1, 125.4, 124.8, 56.5, 53.9, 50.1,
31.4, 23.9; FAB-MS (rel intensity) m/z 276 (MþþH, 100), 275 (21),
274 (64), 134 (43), 132 (24), 130 (23); FAB-HRMS m/z calcd for
C15H17NO2S 275.0980, found 275.0977.
4.13. 2-Allyl-1-(tert-butoxycarbonyl)-4-(phenylsulfonyl)-1,2,5,6-
tetrahydropyridine (13)
4.10.2. 7-Methyl-2-(phenylsulfonyl)-4,6,9,9a-tetrahydro-3H-quinoli-
zine (10b). Yield (67%); yellow-brown solid mp 87e88 ꢂC; IR (film)
n
3058, 2913, 2761, 1734, 1652, 1446, 1369, 1303, 1263, 1218, 1151,
1098, 1080, 1019, 997, 968, 883, 805, 784, 732, 688 cmꢁ1 1H NMR
(CDCl3) 7.88e7.84 (2H, m), 7.64e7.49 (3H, m), 6.84 (1H, s), 5.45
To a solution of 7a (412 mg, 1.57 mmol) and 4-dimethy-
laminopyridine (19 mg, 0.16 mmol) in CH2Cl2 (10 mL) under ni-
trogen were added sequentially Et3N (0.218 mL, 1.57 mmol) and di-
tert-butyl dicarbonate (0.554 mL, 2.35 mmol). After refluxing for
4 h, the reaction mixture was quenched with saturated sodium
bicarbonate (10 mL). The aqueous solution was extracted with
CH2Cl2, dried (MgSO4), and evaporated under vacuum. The crude
product was purified by flash chromatography using ethyl acetate/
hexane (1:2) as eluent to give product 13 (449 mg, 79%). Yellow-
;
d
(1H, d, J¼1.8 Hz), 3.11 (1H, d, J¼15.6 Hz), 2.99e2.82 (3H, m),
2.44e2.33 (3H, m), 2.25e1.99 (2H, m), 1.65 (3H, s); 13C NMR (CDCl3)
d
139.1, 138.5, 138.1, 133.4, 132.6, 129.2, 128.0, 118.9, 58.0, 56.4, 50.0,
31.3, 24.0, 20.6; FAB-MS (rel intensity) m/z 290 (MþþH, 100), 289
(23), 288 (73), 148 (51), 146 (28), 144 (34); FAB-HRMS m/z calcd for
C16H19NO2S 289.1136, found 289.1131.
brown liquid; IR (neat)
1123, 1092, 1057, 953, 925, 758, 727, 690 cmꢁ1
7.93e7.82 (2H, m), 7.72e7.49 (3H, m), 7.00 (1H, s), 5.91e5.72 (1H,
n
3067, 2977, 2933, 1690, 1413, 1318, 1154,
4.10.3. (4R*,9aS*)-4-Methyl-2-(phenylsulfonyl)-4,6,9,9a-tetrahydro-
;
1H NMR (CDCl3)
3H-quinolizine (10c). Yield (71%); yellow-brown liquid; IR (neat)
3038, 2966, 2929, 1651, 1447, 1351, 1305, 1155, 1125, 1086, 829, 737,
718, 689 cmꢁ1; 1H NMR (CDCl3)
8.05e7.78 (2H, m), 7.75e7.48 (3H,
n
d
m), 5.21e5.07 (2H, m), 4.69 (1H, br s), 4.26 (1H, br s), 2.79 (1H, br s),
d
2.49e2.28 (3H, m), 2.16 (1H, br s), 1.44 (9H, s); 13C NMR (CDCl3)
m), 6.81 (1H, s), 5.90e5.65 (2H, m), 3.53 (1H, br d, J¼15.0 Hz), 3.12
d
153.7, 139.0, 138.6, 137.2, 133.5, 133.2, 129.2, 128.0, 118.4, 80.2,
(1H, br s), 2.75 (1H, br d, J¼15.0 Hz), 2.58e1.92 (5H, m), 1.16 (3H, d,
52.0, 37.6, 35.9, 28.2, 23.2; ESI-MS (rel intensity) m/z 364 (MþþH,
6), 266 (25), 264 (10), 221 (16), 125 (100), 122 (19); ESI-HRMS m/z
calcd for C19H25NO4S m/z 363.1504, found 363.1501.
J¼6.0 Hz); 13C NMR (CDCl3)
d 139.2, 138.5, 137.6, 133.4, 129.3, 128.1,
125.6, 124.6, 57.6, 54.1, 50.0, 32.3, 32.2, 19.4; FAB-MS (rel intensity)
m/z 290 (MþþH, 40), 288 (33), 148 (25), 147 (41), 144 (74), 73 (100);
FAB-HRMS m/z calcd for C16H19NO2S 289.1136, found 289.1132.
4.14. 1-(tert-Butoxycarbonyl)-2-[(E)-4-oxopent-2-enyl]-4-(phe-
4.11. 2-(Phenylsulfonyl)-4,6,7,8,9,9a-hexahydro-3H-quinoli-
nylsulfonyl)-1,2,5,6-tetrahydropyridine (14)
zine (11)
A mixture of compound 13 (250 mg, 0.69 mmol), G2 (29 mg,
0.034 mmol), p-cresol (0.036 mL, 0.34 mmol), and methyl vinyl
ketone (1.13 mL, 13.77 mmol) in toluene (10 mL) was refluxed for
7 h. The solvent was evaporated under vacuum, and the residue was
purified by flash chromatography using ethyl acetate/hexane (1:4)
containing 5% Et3N as eluent to give product 14 (214 mg, 77%). Red-
A mixture of compound 10a (100 mg, 0.33 mmol) and 10%
palladium on carbon (17.6 mg) in ethyl acetate (10 mL) was stirred
vigorously under a balloon of hydrogen at room temperature for
48 h. The reaction mixture was then filtered with Celite, washed
with ethyl acetate, dried (MgSO4), and evaporated under vacuum.
The crude product was purified by flash chromatography using
ethyl acetate/hexane (1:4) containing 5% Et3N as eluent to give
brown liquid; IR (neat)
1317, 1307, 1154, 1119, 981, 953, 760, 727 cmꢁ1
7.91e7.83 (2H, m), 7.71e7.61 (1H, m), 7.61e7.52 (2H, m), 6.96 (1H,
n
3062, 2978, 2932, 1691, 1629, 1478, 1366,
;
1H NMR (CDCl3)
product 11 (84 mg, 83%). Light yellow liquid; IR (film)
2757, 1650, 1554, 1446, 1359, 1303, 1292, 1216, 1179, 1132, 1098,
1016, 997, 885, 789, 734, 717, 689 cmꢁ1 1H NMR (CDCl3)
7.87e7.84 (2H, m), 7.63e7.50 (3H, m), 6.75 (1H, s), 2.91e2.81 (2H,
n
3061, 2937,
d
s), 6.82e6.71 (1H, m), 6.11 (1H, br s), 4.90 (1H, br s), 4.44e4.02 (1H,
m), 2.76 (1H, br s), 2.67e2.42 (2H, m), 2.39e2.28 (1H, m), 2.24 (3H,
;
d
s), 2.19e2.10 (1H, m), 1.42 (9H, s); 13C NMR (CDCl3)
d 198.2, 153.7,
m), 2.66e2.63 (1H, m), 2.42e2.28 (3H, m), 2.19 (1H, dt, J¼3.6,
142.6, 140.0, 138.4, 136.4, 133.7 (ꢃ2), 129.4, 128.1, 80.8, 51.8, 36.2
11.0 Hz), 1.85e1.78 (2H, m), 1.64e1.56 (2H, m), 1.46e1.26 (2H, m);
(ꢃ2), 28.2, 27.1, 23.3; ESI-MS (rel intensity) m/z 406 (MþþH, 5), 361

1506
S.-S.P. Chou et al. / Tetrahedron 69 (2013) 1499e1508
(29), 306 (100), 222 (45); ESI-HRMS m/z calcd for C21H27NO5S
405.1610, found 405.1617.
1.02 (3H, d, J¼7.2 Hz), 0.93 (3H, t, J¼7.5 Hz); 13C NMR (CDCl3)
d 199.9, 154.5, 140.8, 138.2, 137.0, 136.0, 134.1, 133.7, 133.0, 129.3,
128.5, 128.2, 128.1, 128.0, 67.6, 51.4, 43.6, 42.2, 38.4, 28.6, 20.0, 17.4,
13.7; ESI-MS (rel intensity) m/z 480 (Mꢁ-H, 40), 370 (100), 326 (64),
297 (37), 150 (17); ESI-HRMS m/z calcd for C27H31NO5S 481.1923,
found 481.1931.
4.15. 1-(tert-Butoxycarbonyl)-2-(4-oxopentyl)-4-(phenylsulfon-
yl)-1,2,5,6-tetrahydropyridine (15)
A mixture of compound 14 (160 mg, 0.39 mmol) and PtO2 (13 mg,
0.06 mmol) in EtOAc (4 mL) was stirred vigorously under a balloon of
hydrogen at room temperature for 21 h. The reaction mixture was
then filtered with Celite, washed with ethyl acetate, dried (MgSO4),
and evaporated under vacuum to give product 15 (150 mg, 93%).
4.18. cis-1-(Benzyloxycarbonyl)-6-methyl-2-(4-oxoheptyl)-4-
(phenylsulfonyl)-1,2,5,6-tetrahydropyridine (18)
A mixture of compound 17 (119 mg, 0.25 mmol) and PtO2 (8 mg)
in EtOAc (5 mL) was stirred vigorously under a balloon of hydrogen
at room temperature for 24 h. The reaction mixture was then fil-
tered with Celite, washed with ethyl acetate, dried (MgSO4), and
evaporated under vacuum to give product 18 (119 mg, 99%). Light
Yellow liquid; IR (neat)
n
3061, 2977, 2935, 1712, 1683, 1478, 1447,
1367, 1307, 1152, 1118, 1058, 758, 735, 690 cmꢁ1
;
1H NMR (CDCl3)
d
7.86 (2H, d, J¼7.8 Hz), 7.70e7.50 (3H, m), 6.98 (1H, s), 4.62 (1H, br s),
4.40e3.99 (1H, m), 2.76 (1H, br s), 2.63e2.39 (2H, m), 2.34e2.22 (1H,
m), 2.21e2.02 (4H, m), 1.74e1.49 (4H, m), 1.44 (9H, s); 13C NMR
yellow liquid; IR (film)
1447, 1380, 1334, 1306, 1154, 1111, 1072, 752, 725, 691 cmꢁ1
NMR (CDCl3) 7.98e7.79 (2H, m), 7.74e7.49 (3H, m), 7.48e7.23 (5H,
n
3064, 3034, 2962, 2934, 2875, 1700, 1655,
(CDCl3)
d
208.0,154.0,138.6,137.6,133.6 (ꢃ2),129.3,128.0, 80.4, 51.3,
;
1H
42.9, 35.5, 32.2, 29.9, 28.3, 23.2, 20.1; FAB-MS (rel intensity) m/z 408
(MþþH, 38), 308 (48), 271 (30),159 (30),147 (32),145 (39),143 (31),
137 (35), 133 (38), 131 (34), 123 (36), 121 (44), 119 (70), 109 (50), 107
(47) 105 (64), 95 (77), 93 (53), 91 (62), 83 (43), 81 (97), 79 (41), 77
(33), 69 (95), 67 (47), 57 (74), 55 (100), 43 (69), 41 (70); FAB-HRMS
m/z calcd for C21H29NO5S 407.1766, found 407.1773.
d
m), 7.07 (1H, s), 5.26e5.02 (2H, m), 4.76 (1H, br s), 4.54 (1H, br s),
2.71e2.12 (6H, m), 1.89e1.45 (6H, m), 0.99 (3H, d, J¼6.9 Hz), 0.90
(3H, t, J¼7.5 Hz); 13C NMR (CDCl3)
d 210.2, 154.6, 138.4, 136.2, 135.9,
135.1, 133.5 (ꢃ2), 129.2, 128.4, 128.1, 128.0, 67.4, 52.0, 44.5, 43.6,
41.8, 34.8, 28.5, 20.4, 19.8, 17.1, 13.6; ESI-MS (rel intensity) m/z 482
(MꢁꢁH, 34), 402 (21), 325 (26), 311 (13), 283 (100); ESI-HRMS m/z
calcd for C27H33NO5S 483.2079, found 483.2093.
4.16. (6S*,9aS*)-6-Methyl-2-(phenylsulfonyl)-4,6,7,8,9,9a-hex-
ahydro-3H-quinolizine (16)
4.19. (2R*,4S*,6S*)-2-Methyl-6-(4-oxoheptyl)-4-(phenylsulfo-
A solution of compound 15 (13 mg, 0.032 mmol) in CF3CO2H/
CH2Cl2 (1:2, 1 mL) was stirred in an ice bathe for 4 h. Then NaBH4
(13 mg, 0.32 mmol) was added, followed by dropwise addition of
MeOH (2 mL). The reaction mixture was further stirred at room
temperature for 1 h. The solvent was evaporated under vacuum,
and then CH2Cl2 (5 mL) and saturated NaHCO3 (5 mL) were added.
The aqueous solution was extracted with CH2Cl2 (5 mLꢃ3), and
the combined organic solution was evaporated under vacuum. The
crude product was purified by flash chromatography using ethyl
acetate/hexane (1:6) containing 5% Et3N as eluent to give product
nyl)piperidine (19)
A mixture of compound 17 (23 mg, 0.05 mmol) and Pd(OH)2
(3 mg) in CF3CO2H/MeOH (1:5, 2 mL) was stirred vigorously under
a balloon of hydrogen at room temperature for 24 h. The reaction
mixture was then filtered with Celite and washed with ethyl acetate.
To this was added 5% NaOH (10 mL), and the aqueous solution was
extracted with CH2Cl2. The combined organic solution was dried
(MgSO4), and evaporated under vacuum to give product 19 (16 mg,
95%) as a light yellow liquid. IR (film)
1708, 1447, 1378, 1303, 1146, 1085, 755, 691 cmꢁ1; 1H NMR (CDCl3)
7.95e7.82 (2H, m), 7.72e7.62 (1H, m), 7.62e7.51 (2H, m), 3.05 (1H,
n 3313, 3064, 2960, 2929, 2873,
16 (7 mg, 75%). Red-brown liquid; IR (neat)
2851, 2795, 1655, 1468, 1331, 1305, 1151, 1125, 1070, 1034, 749,
716 cmꢁ1; 1H NMR (CDCl3)
7.95e7.80 (2H, m), 7.70e7.59 (1H, m),
n 3066, 2967, 2931,
d
d
tt, J¼12.3, 3.6 Hz), 2.72e2.58 (1H, m), 2.58e2.45 (1H, m), 2.45e2.32
(4H, m), 2.08e1.92 (2H, m), 1.81e1.51 (5H, m), 1.42e1.28 (3H, m),
1.21e1.14 (1H, m), 1.09 (3H, d, J¼6.3 Hz), 0.90 (3H, t, J¼7.5 Hz); 13C
7.59e7.47 (2H, m), 6.72 (1H, d, J¼0.9 Hz), 3.42e3.25 (1H, m),
2.84e2.72 (1H, m), 2.42e2.27 (2H, m), 2.27e2.13 (1H, m),
2.13e2.01 (1H, m), 1.87e1.72 (2H, m), 1.69e1.58 (1H, m), 1.52e1.24
NMR (CDCl3) d 210.5, 136.5, 133.6, 128.9, 128.8, 62.1, 55.1, 50.7, 44.5,
(3H, m), 1.09 (3H, d, J¼6.0 Hz); 13C NMR (CDCl3)
d
139.9, 139.2,
42.2, 36.0, 32.9, 30.8, 22.2,19.6,17.0,13.5; FAB-MS (rel intensity) m/z
352 (MþþH,100), 210 (31),126 (23), 52 (22), 51 (26); FAB-HRMS m/z
calcd for C19H29NO3S 351.1868, found 351.1863.
138.0, 133.4, 129.2, 128.2, 61.7, 57.6, 45.7, 34.7, 31.4, 24.8, 24.5, 20.5;
FAB-MS (rel intensity) m/z 292 (MþþH, 63), 271 (41), 165 (42), 157
(41), 155 (40), 143 (49), 141 (41), 133 (40), 129 (48), 128 (52), 119
(77), 115 (50), 109 (43), 107 (46), 105 (79), 95 (63), 93 (54), 91
(100), 81 (76), 79 (47), 77 (60), 73 (57), 69 (75), 67 (44), 57 (40), 55
(89), 43 (51), 41 (67); FAB-HRMS m/z calcd for C16H21NO2S
291.1293, found 291.1297.
4.20. cis- and trans-(2S*,4S*,6R*)-6-Methyl-2-(4-hydroxyhe-
ptyl)-4-(phenylsulfonyl)piperidine (20)
To a solution of compound 19 (85 mg, 0.24 mmol) in CF3CO2H/
MeOH (1:10, 11 mL) at 0 ꢂC was added NaCNBH3 (152 mg,
2.42 mmol). The reaction mixture was stirred at room tempera-
ture for 4 h, and the solvent was evaporated under vacuum. To this
were added CH2Cl2 (10 mL) and saturated NaHCO3 (10 mL). The
aqueous solution was extracted with CH2Cl2 (5 mLꢃ3). The com-
bined organic solution was dried (MgSO4), evaporated under
vacuum, and the crude product was purified by flash chroma-
tography using ethyl acetate containing 5% Et3N as eluent to give
product 20 (79 mg, 92%). Light yellow liquid (1:1 diastereomeric
4.17. cis-1-(Benzyloxycarbonyl)-6-methyl-2-[(E)-4-oxohept-2-
enyl]-4-(phenylsulfonyl)-1,2,5,6-tetrahydropyridine (17)
A mixture of compound 8a (50 mg, 0.12 mmol), G2 (5 mg,
0.006 mmol), p-cresol (0.006 mL, 0.06 mmol) and 1-hexen-3-one
(0.142 mL, 1.20 mmol) in toluene (5 mL) was refluxed for 5 h. The
solvent was evaporated under vacuum, and the residue was puri-
fied by flash chromatography using ethyl acetate/hexane (1:2) as
eluent to give product 17 (40 mg, 68%). Red-brown liquid; IR (neat,
mixture as judged from 13C NMR); IR (neat)
2931, 2870, 1447, 1379, 1303, 1085, 894, 753, 719, 690 cmꢁ1
NMR (CDCl3) 7.93e7.83 (2H, m), 7.73e7.51 (3H, m), 3.59 (1H, br
n
3401, 3065, 2957,
film)
n
3061, 2965, 2935,1695,1631,1360, 1306,1155,1110, 982, 736,
7.89e7.78 (2H, m), 7.71e7.61 (1H, m),
;
1H
700 cmꢁ1; 1H NMR (CDCl3)
d
d
7.61e7.49 (2H, m), 7.42e7.22 (5H, m), 6.96 (1H, s), 6.91e6.72 (1H,
m), 6.12 (1H, d, J¼15.9 Hz), 5.12 (2H, s), 4.75 (2H, br s), 2.75e2.60
(1H, m), 2.59e2.41 (3H, m), 2.35e2.19 (2H, m), 1.72e1.43 (2H, m),
s), 3.06 (1H, tt, J¼12.5, 3.6 Hz), 2.73e2.61 (1H, m), 2.61e2.49 (1H,
m), 2.13e1.92 (2H, m), 1.65e1.28 (11H, m), 1.23e1.13 (1H, m), 1.11
(3H, d, J¼6.0 Hz), 0.92 (3H, t, J¼6.0 Hz); 1H NMR (DMSO-d6)

S.-S.P. Chou et al. / Tetrahedron 69 (2013) 1499e1508
1507
d
7.32e7.10 (5H, m), 3.71 (1H, br s), 2.92e2.68 (2H, m), 2.10e1.81
(Mþþ1, 1), 152 (9), 77 (100), 69 (8), 57 (11); EI-HRMS m/z calcd for
(2H, m), 1.42e1.05 (2H, m), 0.98e0.55 (10H, m), 0.53e0.38 (5H,
C13H25N 195.1987, found 195.1987.
m), 0.31 (3H, t, J¼6.0 Hz); 13C NMR (CDCl3)
d 136.9, 133.8, 129.3,
129.2, 71.5, 62.6, 55.8, 55.6, 51.2, 39.8, 37.5, 37.3, 36.9, 36.8, 33.4,
4.22.2. (4R*,6S*,9aS*)-4-Methyl-6-propyl-2,3,4,6,7,8,9,9a-octahydro-
31.3, 22.5, 22.0, 21.9, 18.9, 14.2; 13C NMR (DMSO-d6)
d
136.9, 133.8,
1H-quinolizine (23). Yield (65%); light yellow liquid; IR (neat, film)
3059, 2929, 2859, 2789, 2708,1456, 1376, 1274, 1160, 1105, 876, 755,
727 cmꢁ1; 1H NMR (CDCl3)
2.65e2.55 (1H, m), 2.54e2.47 (2H, m),
n
129.3, 128.6, 69.2, 60.8, 54.6, 50.1, 37.4, 36.4, 32.8, 30.4, 22.1, 21.5,
21.4, 18.4, 14.1; ESI-MS (rel intensity) m/z 354 (MþþH, 100), 336
(5); ESI-HRMS m/z calcd for C19H31NO3S 353.2025, found
353.2015.
d
1.84e1.72 (1H, m), 1.72e1.59 (3H, m), 1.55e1.42 (5H, m), 1.38e1.18
(7H, m), 1.11 (3H, d, J¼6.3 Hz), 0.90 (3H, t, J¼7.2 Hz); 13C NMR
(CDCl3) d 58.1, 57.1, 55.8, 39.8, 34.4, 33.5, 30.6, 23.6, 22.7, 22.5, 20.2,
4.21. (2S*,4R*,6R*,9aS*)-4-Methyl-2-(phenylsulfonyl)-6-prop-
yl-2,3,4,6,7,8,9,9a-octahydro-1H-quinolizine (21a) and
(2S*,4R*,6S*,9aS*)-4-methyl-2-(phenylsulfonyl)-6-propyl-
2,3,4,6,7,8,9,9a-octahydro-1H-quinolizine (21b)
17.6, 14.4; ESI-MS (rel intensity) m/z 196 (MþþH, 100); ESI-HRMS
m/z calcd for C13H25N 195.1987, found 195.1981.
Acknowledgements
To a solution of compound 20 (110 mg, 0.31 mmol) in CH2Cl2
(5 mL) at 0 ꢂC were added sequentially Et3N (0.091 mL, 0.65 mmol)
and MsCl (0.027 mL, 0.34 mmol). The reaction mixture was then
stirred at room temperature for 17 h, and saturated NaHCO3 (5 mL)
was added. The aqueous solution was extracted with CH2Cl2
(5 mLꢃ3). The combined organic solution was dried (MgSO4) and
evaporated under vacuum. The residue was dissolved in Et3N/tol-
uene (1:3, 20 mL), and refluxed under nitrogen for 1 d. The solvent
was removed under vacuum, and the residue was purified by flash
chromatography using ethyl acetate/hexane (1:4) containing 5%
Et3N as eluent to give compound 21a (50 mg, 48%) and compound
21b (45 mg, 43%). Compound 21a: yellow solid mp 108.1e109.5 ꢂC;
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.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2012.12.017.
References and notes
1. Daly, J. W.; Spande, T. S.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556e1575.
2. (a) Daly, J. W.; Spande, T. F. In Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; Wiley: New York, NY, 1986; Vol. 3; Chapter 1, pp 1e274; (b)
Daly, J. W.; Garraffo, H. M.; Spande, T. F. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Pergamon: New York, NY, 1999; Vol. 13,
pp 1e161.
3. For a recent review, see: Michael, J. P. Nat. Prod. Rep. 2008, 25, 139e165.
4. For some selected recent examples, see: (a) Rueping, M.; Hubener, L. Synlett
2011, 1243e1246; (b) Belanger, G.; O’Brien, G.; Larouche-Gauthier, R. Org. Lett.
2011, 13, 4268e4271; (c) Yang, D.; Micalizio, G. C. J. Am. Chem. Soc. 2009, 131,
17548e17549; (d) Amorde, S. M.; Jewett, I. T.; Martin, S. F. Tetrahedron 2009, 65,
3222e3231; (e) Furman, B.; Lipner, G. Tetrahedron 2008, 64, 3464e3470; (f)
Amorde, S. M.; Judd, A. S.; Martin, S. F. Org. Lett. 2005, 7, 2031e2033.
5. (a) Chou, S. S. P.; Hung, C. C. Tetrahedron Lett. 2000, 41, 8323e8326; (b) Chou, S.
S. P.; Hung, C. C. Synthesis 2001, 2450e2462.
IR (ATR, film)
n
3054, 2936, 2863, 2796, 1445, 1377, 1297, 1279, 1144,
1083, 1024, 755, 690 cmꢁ1
;
1H NMR (CDCl3)
d
7.91e7.80 (2H, m),
7.72e7.61 (1H, m), 7.61e7.50 (2H, m), 3.09 (1H, d, J¼8.7 Hz), 2.98
(1H, tt, J¼12.6, 3.3 Hz), 2.61e2.45 (1H, m), 2.44e2.31 (1H, m),
2.70e1.90 (2H, m), 1.83e1.67 (2H, m), 1.67e1.56 (1H, m), 1.53e1.16
(9H, m), 1.07 (3H, d, J¼6.3 Hz), 0.91 (3H, t, J¼6.9 Hz); 13C NMR
(CDCl3)
d
136.7, 133.7, 129.3, 129.1, 61.8, 53.0, 52.8, 52.2, 34.3 (ꢃ2),
33.9, 27.7, 22.5, 20.3, 19.9, 18.3, 14.4; EI-MS (rel intensity) m/z 336
(Mþþ1, 1), 293 (22), 292 (100), 150 (25); EI-HRMS m/z calcd for
C19H29NO2S 335.1919, found 335.1916. Compound 21b: yellow liq-
uid; IR (neat)
n
3065, 2951, 2935, 2870, 2791, 1638, 1447, 1378, 1306,
6. (a) Chou, S. S. P.; Chiu, H. C.; Hung, C. C. Tetrahedron Lett. 2003, 44, 4653e4655;
(b) Chou, S. S. P.; Ho, C. W. Tetrahedron Lett. 2005, 46, 8551e8554; (c) Chou, S. S.
P.; Liang, C. F.; Lee, T. M.; Liu, C. F. Tetrahedron 2007, 63, 8267e8273; (d) Chou,
S. S. P.; Liu, C. F. J. Chin. Chem. Soc. 2010, 57, 811e819; (e) Chou, S. S. P.; Cai, Y. L.
Tetrahedron 2011, 67, 1183e1186; (f) Chou, S. S. P.; Yang, T. H.; Wu, W. S.; Chiu, T.
H. Synthesis 2011, 759e763; (g) Chou, S. S. P.; Chung, Y. C.; Chen, P. A.; Chiang, S.
L.; Wu, C. J. J. Org. Chem. 2011, 76, 692e695; (h) Chou, S. S. P.; Huang, C. W.;
Chang, C. C. Tetrahedron 2011, 67, 4505e4513; (i) Chou, S. S. P.; Lee, B. H.; Ni, C.
H.; Lin, Y. C. Tetrahedron 2011, 67, 5395e5401; (j) Chou, S. S. P.; Lu, C. L.; Hsu, Y.
H. J. Chin. Chem. Soc. 2012, 59, 365e372; (k) Chou, S. S. P.; Wu, C. J. Tetrahedron
2012, 68, 5025e5030; (l) Chou, S. S. P.; Huang, J. L. Tetrahedron Lett. 2012, 53,
5552e5554; (m) Chou, S. S. P.; Chiang, S. L.; Huang, G. L.; Chiang, B. S.; Yu, Y. C.
Tetrahedron 2013, 69, 274e283.
1147, 1086, 1021, 750, 690 cmꢁ1
;
1H NMR (CDCl3)
d
7.92e7.81 (2H,
m), 7.72e7.62 (1H, m), 7.61e7.50 (2H, m), 3.03 (1H, tt, J¼12.6,
3.6 Hz), 2.77e2.64 (1H, m), 2.53e2.38 (2H, m), 1.93 (1H, dq, J¼12.6,
3.0 Hz), 1.88e1.77 (1H, m), 1.73e1.54 (4H, m), 1.51e1.36 (4H, m),
1.35e1.20 (4H, m), 1.12 (3H, d, J¼6.0 Hz), 0.87 (3H, t, J¼6.9 Hz); 13C
NMR (CDCl3)
d 137.0, 133.7, 129.3, 129.2, 62.2, 57.2, 55.5, 54.7, 40.4,
34.5, 33.1, 29.5, 21.6, 21.4, 20.1, 15.3, 14.3; ESI-MS (rel intensity) m/z
336 (MþþH, 100), 190 (12); ESI-HRMS m/z calcd for C19H29NO2S
335.1919, found 335.1916.
€
7. (a) Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012e3043; (b) Trnka, T. M.;
4.22. General procedure for reductive cleavage of sulfones 21
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18e29; (c) Grubbs, R. H.; Chang, S. Tet-
rahedron 1998, 54, 4413e4450.
8. For some selected examples of synthesis of indolizidines and quinolizidines via
RCM (other than Ref. 6c and 6m), see: (a) Overkleeft, H. S.; Bruggeman, P.; Pandit,
U. K. Tetrahedron Lett. 1998, 39, 3869e3872; (b) Barluenga, J.; Mateos, C.; Aznar,
A
mixture of compound 21 (0.10 mmol) and 6% Na/Hg
(2.09 mmol) in dried THF (5 mL) was refluxed for 3.5 h. Additional
6% Na/Hg (2.09 mmol) was added, and refluxed for another 3.5 h.
The reaction mixture was then filtered through Celite, washed with
ethyl acetate, and evaporated under vacuum. The residue was pu-
rified by flash chromatography using hexane containing 5% Et3N as
eluent to give pure product.
ꢀ
F.; Valdes, C. J. Org. Chem. 2004, 69, 7114e7122; (c) Wijdeven, M. A.; Botman, P. N.
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Berg, R. J. F.; Noorduin, W.; Schoemaker, H. E.; Sonke, T.; van Delft, F. L.; Blaauw,
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4.22.1. (4R*,6R*,9aS*)-4-Methyl-6-propyl-2,3,4,6,7,8,9,9a-octahydro-
1H-quinolizine (22). Yield (69%); light yellow liquid; IR (neat)
2929, 2861, 2792, 2709,1455, 1375, 1319, 1262, 1104, 1052, 880, 750,
724 cmꢁ1; 1H NMR (CDCl3)
3.19e3.06 (1H, m), 2.54e2.40 (1H, m),
n
10. Edwards, M. W.; Daly, J. W. J. Nat. Prod. 1988, 51, 1188e1197.
d
11. Jones, T. H.; Gorman, J. S. T.; Snelling, R. R.; Delabie, J. H. C.; Blum, M. S.; Garraffo,
H. M.; Jain, P.; Daly, J. W.; Spande, T. F. J. Chem. Ecol. 1999, 25, 1179e1193.
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13. Crystallographic data (excluding structure factors) for compounds 7b, 8b, and
21a in this paper have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication CCDC 904865e904867. Copies of the
2.37e2.25 (1H, m), 1.99 (1H, s), 1.81e1.69 (1H, m), 1.66e1.50 (5H,
m), 1.49e1.37 (4H, m), 1.34e1.17 (5H, m), 1.05 (3H, d, J¼6.3 Hz), 0.93
(3H, t, J¼7.2 Hz); 13C NMR (CDCl3)
d 54.1, 53.1, 53.0, 35.7, 35.4, 34.7,
28.0, 24.6, 22.5, 20.5, 20.1, 18.7, 14.6; EI-MS (rel intensity) m/z 196

1508
S.-S.P. Chou et al. / Tetrahedron 69 (2013) 1499e1508
data can be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: þ44-(0)1223-336033 or e-mail: deposit@ccdc.
cam.ac.uk).
(b) Chou, C.-Y.; Hou, D.-R. J. Org. Chem. 2006, 71, 9887e9890; (c) Chen, L.-J.;
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