Stereospecific synthesis of trans -5,6-dihydropyridinones

Article abstract of DOI:10.1055/s-0030-1258415

An efficient synthesis of trans-5,6-dihydropyridinones bearing a heteroatom (Br, OH) at C-5 has been achieved. The formal synthesis of (±)- epiquinamide and (±)-homopumiliotoxin 223G has also been accomplished through the formation of (±)-trans-1-hydroxyq

Full text of DOI:10.1055/s-0030-1258415

PAPER
759
Stereospecific Synthesis of trans-5,6-Dihydropyridinones
Stereospecific
h
Synthesis of
a
trans-5,6-D
n
ihydropyrid
g
inones -Shing P. Chou,* Tsung-Han Yang, Wan-Shiuan Wu, Tzu-Han Chiu
Department of Chemistry, Fu Jen Catholic University, Taipei 24205, Taiwan, R. O. C.
Fax +886(2)29023209; E-mail: 002181@mail.fju.edu.tw
Received 15 December 2010; revised 29 December 2010
reaction with 1-chloro-4-iodobutane gave the alkylated
product 2.12 Treatment of compound 2 with p-toluene-
sulfonyl isocyanate (PTSI) in refluxing toluene in the
presence of hydroquinone (HQ) and sodium bicarbonate
afforded the cycloaddition product 3 in good yield. The
reaction of compound 3 with 1.1 equivalents of N-bromo-
succinimide (NBS) in refluxing acetonitrile provided the
allylic bromide 4 in excellent yield (Scheme 1). The X-ray
crystal structure of compound 4 (Figure 2)13 shows that
the bromo group and the alkyl side chain are trans to each
other, and both are at the axial positions. We propose that
NBS approaches compound 3 from the opposite side of
the 4-chlorobutyl group, resulting in the formation of
trans-product 4. The diaxial conformations of the bromo
and chlorobutyl groups are attributed mainly to the mini-
mization of A1,3-type strain of the N-tosyl group with the
chlorobutyl side chain.14 The coupling constant (J5,6 = 1.8
Hz) of compound 4 agrees with the equatorial positions of
H-5 and H-6.
Abstract: An efficient synthesis of trans-5,6-dihydropyridinones
bearing a heteroatom (Br, OH) at C-5 has been achieved. The for-
mal synthesis of ( )-epiquinamide and ( )-homopumiliotoxin 223G
has also been accomplished through the formation of ( )-trans-1-
hydroxyquinolizidin-4-one.
Key words: aza-Diels–Alder reaction, trans-5,6-dihydropyridi-
nones, trans-1-hydroxyquinolizidin-4-one, epiquinamide, homopu-
miliotoxin 223G
Many alkaloids have been isolated from amphibian skin.1
Some of them have the indolizidine or quinolizidine struc-
tures, which often show interesting biological activities.2
We have recently developed a new aza-Diels–Alder reac-
tion of thio-substituted 3-sulfolenes with p-toluenesulfo-
nyl isocyanate (PTSI) to synthesize piperidine
derivatives.3 This method was also used by us to prepare
some indolizidines and quinolizidines,4 and other hetero-
cyclic compounds.5 Some of these compounds showed
novel biological activities.6 Herein a new method for the
synthesis of trans-5,6-dihydropyridinones bearing a het-
eroatom at C-5 is reported. There are only a few synthetic
methods known in the literature for such structures.7 In
addition, we have also completed a formal synthesis of
( )-epiquinamide8 and ( )-homopumiliotoxin 223G9
through a common intermediate, ( )-trans-1-hydroxy-
quinolizidin-4-one10 (Figure 1).
Subsequent reaction of bromide 4 with sodium azide in
tetrahydrofuran or N,N-dimethylformamide at room tem-
perature or under heating did not lead to the expected SN2
SPh
SPh
SPh
ii
i
Cl(H2C)4
S
S
Cl(H2C)4
N
O
O2
O2
Ts
1
2
AcHN
3
HO
SPh
N
SPh
N
N
HO
Br
5
iv
iii
v
Cl(H2C)4
O
(+)-epiquinamide
(+)-homopumiliotoxin 223G
Cl(H2C)4
SPh
N
O
6
Ts
Ts
HO
5
4
N
O
SPh
HO
HO
HO
vi
vi
(–)-trans-1-hydroxyquinolizidin-4-one
Cl(H2C)4
N
H
O
N
O
N
O
Figure 1
6
8
7
Deprotonation of 3-(phenylthio)-3-sulfolene (1)11 in tet-
rahydrofuran with butyllithium at –78 °C in the presence
of hexamethylphosphoric amide (HMPA), followed by
Scheme 1 Synthesis of 1-hydroxyquinolizidin-4-one (8). Reagents
and conditions: (i) a) BuLi (1.1 equiv), HMPA (4 equiv), THF, –78
°C, b) Cl(CH2)4I (4 equiv), –78 to –50 °C, 50%; (ii) PTSI (3 equiv),
NaHCO3 (1 equiv), HQ (cat.), toluene, reflux, 6 h, 77%; (iii) NBS (1.1
equiv), MeCN, reflux, 2 h, 96%; (iv) Et3N–H2O–MeCN (1:1.5:3.3),
70 °C, 24 h, 82%; (v) Bu3SnH (1.2 equiv), AIBN (0.6 equiv), toluene,
reflux, 1 h, 80%; (vi) BuLi (2 equiv), THF, –78 °C to r.t., then reflux,
7 h, 88%; (vii) Ra-Ni (10 equiv), 95% EtOH, reflux, 2 h, 83%.
SYNTHESIS 2011, No. 5, pp 0759–0763
x
x
.
x
x
.2
0
1
1
Advanced online publication: 21.01.2011
DOI: 10.1055/s-0030-1258415; Art ID: F03610SS
© Georg Thieme Verlag Stuttgart · New York

760
S.-S. P. Chou et al.
PAPER
version of compound 4 to compound 5 proceeds with re-
tention of configuration, this reaction does not occur via
an SN2 mechanism. We propose that compound 4 under-
goes an SN1 reaction to generate an allylic carbocation,
which is then attacked by water from the opposite side of
the chlorobutyl group to give the trans-product 5.
The tosyl group of compound 5 was effectively cleaved
by Bu3SnH/AIBN16 to give the amide 6. The X-ray crystal
structure of compound 6 (Figure 4)13 shows that the hy-
droxy group and the alkyl side chain are trans to each
other, but both are now at the equatorial positions. The
coupling constant (J5,6 = 4.2 Hz) of compound 6 is consid-
erably larger than those of compounds 4 (1.8 Hz) and 5
(2.1 Hz), confirming that H-5 and H-6 of compound 6 are
both at the axial positions. This indicates that preference
for the diequatorial conformations of the hydroxy group
and the alkyl side chain of compound 6 outweighs the al-
ternative A1,3-type strain of the phenylthio group with the
hydroxy group, since the bulky tosyl group has been
cleaved from the nitrogen atom of compound 5.
Figure 2 X-ray crystal structure of compound 4
product. Instead, complex mixtures of elimination, SN2¢
substitution and N- to O-tosyl migration products were
obtained. It seems that the azido nucleophile is difficult to
approach from the back side of compound 4 due to steric
hindrance with the chlorobutyl group. Our attention was
then turned to SN1 reaction conditions. Indeed, treatment
of compound 4 with 28% aqueous ammonia in
acetonitrile15 at 50 °C gave the substitution product 5 in
48% yield. The best reaction condition found was to heat
compound 4 with triethylamine in aqueous acetonitrile to
give the allylic alcohol 5 in 82% yield. The X-ray crystal
structure of compound 5 (Figure 3)13 shows that the hy-
droxy group and the alkyl side chain are trans to each oth-
er, and both are at the axial positions. The coupling
constant (J5,6 = 2.1 Hz) of compound 5 confirms that both
H-5 and H-6 are at the equatorial positions. Since the con-
Figure 4 X-ray crystal structure of compound 6
Treatment of compound 6 with butyllithium in refluxing
tetrahydrofuran led to the quinolizidine 7 in good yield. It
is important to note that the amount of base has significant
influence on the yields of product 7. The best yield (88%)
was obtained with 2.0 equivalents of butyllithium, much
higher than with 1.0 equivalent (53%) or 3.5 equivalents
(45%) of butyllithium. Further reaction of compound 7
with the W-2 type Raney nickel resulted in both cleavage
of the phenylthio group and reduction of the C=C bond to
give ( )-trans-1-hydroxyquinolizidin-4-one (8).10 It has
recently been reported that (–)-trans-1-hydroxyquinolizi-
din-4-one is an efficient precursor to the synthesis of
(–)-epiquinamide and (–)-homopumiliotoxin 223G.17
To further demonstrate that our method for stereospecific
synthesis of trans-5,6-dihydropyridinones 4 and 5 is not
restricted to structures bearing a long alkyl chain at C-6 of
compound 3, similar reactions were also carried out with
6-methyl derivatives 9 and 10 (Scheme 2). The X-ray
crystal structure of compound 10 (Supporting Informa-
tion)13 not only shows that the bromo and methyl groups
are trans to each other, but also that these two groups are
both at the axial positions. The coupling constant
(J5,6 = 1.6 Hz) of compound 10 confirms that H-5 and H-
6 are both at the equatorial positions. The trans diaxial
transpositions of the methyl and hydroxy groups in com-
pound 11 is proven by its X-ray structure (Supporting In-
Figure 3 X-ray crystal structure of compound 5
Synthesis 2011, No. 5, 759–763 © Thieme Stuttgart · New York

PAPER
Stereospecific Synthesis of trans-5,6-Dihydropyridinones
761
ried out with Heraeus Vario III-NCSH, Heraeus CHN-O-S-Rapid
Analyzer or Elementar Vario EL III. Flash column chromatographic
purifications were performed using Merck 60 H silica gel.
SPh
SPh
SPh
Br
HO
i
ii
N
O
N
O
N
O
6-(4-Chlorobutyl)-4-(phenylthio)-1-tosyl-1,6-dihydropyridin-
2(3H)-one (3)
Ts
Ts
10
Ts
11
A mixture of compound 212b (820 mg, 2.59 mmol), NaHCO3 (217.9
mg, 2.59 mmol), hydroquinone (28.5 mg, 0.26 mmol), and PTSI
(1.2 mL, 7.78 mmol) in toluene (15 mL) was heated at reflux under
N2 for 6 h. After cooling in an ice bath, 5% aq NaOH (50 mL) was
slowly added to decompose the excess PTSI. The mixture was then
extracted with EtOAc (3 × 30 mL), the combined organic extracts
dried (MgSO4), and evaporated under vacuum. The crude product
was purified by flash chromatography using EtOAc–hexanes (1:6)
as eluent; yield: 903 mg (77%); white solid; mp 121.6–122.0 °C.
9
Scheme 2 Synthesis of allylic alcohol 11. Reagents and conditions:
(i) NBS (1.1 equiv), MeCN, reflux, 1 h, 97%; (ii) Et3N–H2O–MeCN
(1:1.2:4), 70 °C, 24 h, 74%.
formation),13 and the coupling constant of J5,6 (2.1 Hz) is
identical with that of compound 5.
Compound 7 was oxidized with MCPBA to produce the
sulfone 12 (Scheme 3). The X-ray crystal structure of
compound 12 (Supporting Information)13 shows not only
that the hydroxy group and the fused ring are trans to each
other, but also that these two groups are both at the axial
IR (ATR, film): 2944, 1697, 1386, 1357, 1169, 1237, 1186, 1169,
1126, 1084, 840 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.89 (2 H, d, J = 8.4 Hz), 7.40–
7.29 (7 H, m), 5.85 (1 H, dd, J = 6.0, 2.8 Hz), 5.06–5.03 (1 H, m),
3.57–3.49 (2 H, m), 3.17 (1 H, dt, J = 21.0, 2.4 Hz), 2.92 (1 H, dd,
positions. The coupling constant (J1,9a = 2.1 Hz) of com- J = 21.0, 0.9 Hz), 2.43 (3 H, s), 1.96–1.75 (4 H, m), 1.54–1.34 (2 H,
m).
pound 12 confirms that H-1 and H-9a are at the equatorial
13C NMR (75 MHz, CDCl3): d = 167.1, 145.1, 136.1, 133.3, 130.6,
130.3, 129.6, 129.3, 129.1, 128.8, 123.7, 58.1, 44.6, 38.3, 36.3,
32.0, 21.7 (2 ×).
positions. It is interesting to note that the corresponding
coupling constant (J1,9a = 5.1 Hz) for compound 7 indi-
cates that the hydroxy group and the fused ring are both at
the equatorial positions. It seems that the bulkier phenyl-
sulfonyl group in compound 12 has a more significant
A1,3-type strain with the hydroxy group than that between
the phenylthio group and the hydroxy group in compound
7.
EI-MS: m/z (%) = 449 (M+, 0.5), 359 (21), 358 (100), 155 (24), 91
(47), 86 (45), 84 (71).
EI-HRMS: m/z calcd for C22H24ClNO3S2: 449.0886; found:
449.0889.
Anal. Calcd for C22H24ClNO3S2: C, 58.72; H, 5.38; N, 3.11. Found:
C, 58.70; H, 5.36; N, 3.46.
SPh
SO2Ph
trans-5-Bromo-6-(4-chlorobutyl)-4-(phenylthio)-1-tosyl-5,6-di-
hydropyridin-2(1H)-one (4)
A mixture of compound 3 (1000 mg, 2.23 mmol) and NBS (372 mg,
2.45 mmol) in MeCN (15 mL) was heated at reflux under N2 for 2
h. The solvent was evaporated under vacuum, and the crude product
was purified by flash chromatography using EtOAc–hexanes (1:6)
as eluent; yield: 1123 mg (96%); white solid; mp 156.7–157.2 °C.
1
HO
1
HO
MCPBA (2.5 equiv)
CH2Cl2, r.t., 2 h
9a
9a
N
O
N
O
12 (75%)
7
Scheme 3 Synthesis of sulfone 12
IR (ATR, film): 3063, 2947, 2866, 1671, 1584, 1357, 1333, 1236,
1166, 1087, 910 cm–1.
In summary, we have developed an efficient synthesis of 1H NMR (300 MHz, CDCl3): d = 8.02 (2 H, d, J = 8.4 Hz), 7.51–
7.42 (5 H, m), 7.27 (2 H, d, J = 8.4 Hz), 5.29 (1 H, d, J = 0.3 Hz),
4.92 (1 H, td, J = 6.6, 1.8 Hz), 4.56 (1 H, dd, J = 1.8, 0.3 Hz), 3.56
(2 H, t, J = 6.3 Hz), 2.41 (3 H, s), 1.88–1.74 (4 H, m), 1.65–1.52 (2
H, m).
trans-bromo compounds 4 and 10, and used the steric ef-
fect of the C-6 substituent (methyl or 4-chlorobutyl) to
control its stereospecific conversion to allylic alcohols 5
and 11 with retention of configuration. It was demonstrat-
13C NMR (75 MHz, CDCl3): d = 159.0, 156.8, 145.1, 135.5, 135.1,
ed that the axial/equatorial conformations of the 5,6-sub-
130.9, 130.2, 129.7, 129.0, 126.7, 116.1, 62.8, 44.4, 44.2, 33.7,
stituents are significantly affected by the A1,3-type strain
32.0, 23.7, 21.7.
of the N-tosyl group with the C-6 substituent. We have
also achieved a facile synthesis of ( )-1-hydroxyquinoliz-
idin-4-one (8), which is known to be an efficient precursor
for the synthesis of ( )-epiquinamide and ( )-homopumil-
FAB-MS: m/z (%) = 530 (M+ + 3, 73), 528 (M+ + 1, 55), 358 (32),
221 (38), 207 (36), 155 (53), 136 (62), 107 (42), 91 (100), 57 (58),
55 (53), 41 (42).
FAB-HRMS: m/z calcd for C22H23BrClNO3S2: 526.9991; found:
526.9998.
iotoxin 223G.
Anal. Calcd for C22H23BrClNO3S2: C, 49.96; H, 4.38; N, 2.65.
Melting points were determined with a SMP3 melting apparatus. IR
Found: C, 49.92; H, 4.24; N, 2.91.
spectra were recorded with a PerkinElmer 100 series FTIR spec-
1
trometer. H and 13C NMR spectra were recorded on a Bruker
trans-6-(4-Chlorobutyl)-5-hydroxy-4-(phenylthio)-1-tosyl-5,6-
dihydropyridin-2(1H)-one (5)
To a solution of compound 4 (50 mg, 0.45 mmol) in MeCN (1 mL)
was added Et3N (0.3 mL) and H2O (0.45 mL). The mixture was
heated at 70 °C under N2 for 24 h. After cooling, EtOAc (30 mL)
was added and the mixture was washed with brine (2 × 30 mL),
Avance 300 spectrometer operating at 300 and at 75 MHz, respec-
tively. Chemical shifts (d) are reported in parts per million (ppm)
and the coupling constants (J) are given in Hertz. High-resolution
mass spectra (HRMS) were measured with a Finnigan/Thermo
Quest MAT 95XL mass spectrometer. Elemental analyses were car-
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762
S.-S. P. Chou et al.
PAPER
dried (MgSO4), and evaporated under vacuum. The crude product
was purified by flash chromatography using EtOAc–hexanes (1:4)
as eluent; yield: 36 mg (82%); white solid; mp 160.2–160.6 °C.
EI-HRMS: m/z calcd for C15H17NO2S: 275.0980; found: 275.0982.
trans-1-Hydroxy-2,3,7,8,9,9a-hexahydro-1H-quinolizin-4(6H)-
one (8)
IR (ATR, film): 3281, 3063, 2952, 2861, 1640, 1596, 1348, 1240,
1163, 900 cm–1.
A mixture of compound 7 (20 mg, 0.09 mmol) and W-2 Raney Ni
(192.5 mg, 1.8 mmol) in 95% EtOH (1.5 mL) was heated at reflux
under N2 for 2 h. The reaction mixture was then passed through a
short pad of Celite, rinsed with MeOH (20 mL), and the solvent was
evaporated under vacuum. The residue was washed with EtOAc–
hexanes (1:95) several times to remove the unwanted top layer ma-
terial. After evaporation of the solvent under vacuum in an ice bath,
product 8 (12 mg, 83%) was obtained as a yellow oil. Its spectral
data were identical with the literature values.10
1H NMR (300 MHz, CDCl3): d = 7.94 (2 H, d, J = 8.4 Hz), 7.49–
7.41 (5 H, m), 7.26 (2 H, d, J = 8.4 Hz), 5.18 (1 H, d, J = 0.6 Hz),
4.81 (1 H, td, J = 6.6, 2.1 Hz), 4.15 (1 H, ddd, J = 5.8, 2.1, 0.6 Hz),
3.57 (2 H, t, J = 6.6 Hz), 2.75 (1 H, d, J = 5.8 Hz), 2.39 (3 H, s),
1.87–1.82 (3 H, m), 1.66–1.62 (3 H, m).
13C NMR (75 MHz, CDCl3): d = 159.8, 158.0, 144.8, 136.2, 135.3,
130.7, 130.2, 129.3, 129.1, 126.9, 115.0, 68.2, 61.8, 44.6, 32.3,
32.2, 23.6, 21.7.
6-Methyl-4-(phenylthio)-1-tosyl-1,6-dihydropyridin-2(3H)-one
(9)
EI-MS: m/z (%) = 465 (M+, 0.1), 315 (23), 314 (100), 210 (21), 91
(43).
A mixture of 2-methyl-4-(phenylthio)-3-sulfolene (1.44 g, 5.99
mmol),12a NaHCO3 (502.1 mg, 5.99 mmol), hydroquinone (33 mg,
0.3 mmol), and PTSI (2.7 mL, 17.97 mmol) in toluene (14 mL) was
heated at reflux under N2 for 2.5 h. After cooling in an ice bath, 5%
aq NaOH (100 mL) was slowly added to decompose the excess of
PTSI. The mixture was then extracted with EtOAc (3 × 40 mL),
dried (MgSO4), and evaporated under vacuum. The crude product
was purified by flash chromatography using EtOAc–hexanes (1:6)
as eluent; yield: 1.58 g (71%); white solid; mp 120.3–121.7 °C.
EI-HRMS: m/z calcd for C22H24ClNO4S2: 465.0835; found:
465.0845.
trans-6-(4-Chlorobutyl)-5-hydroxy-4-(phenylthio)-5,6-dihydro-
pyridin-2(1H)-one (6)
To a refluxing solution of compound 5 (100 mg, 0.22 mmol) in de-
gassed toluene (22 mL) was added slowly a solution of Bu3SnH
(0.07 mmol, 0.26 mmol) and AIBN (21.2 mg, 0.13 mmol) in toluene
(4 mL) over 1 h. The solvent was then evaporated under vacuum,
and the crude product was purified by flash chromatography using
EtOAc–hexanes (1:1) containing 5% Et3N and 5% CH2Cl2 as elu-
ent; yield: 53.2 mg (80%); white solid; mp 112.4–113.1 °C.
IR (ATR, film): 3055, 2988, 1687, 1594, 1476, 1441, 1376, 1341,
1265, 1248, 1186, 1168, 1153, 1088, 1025 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.92 (2 H, d, J = 8.4 Hz), 7.40–
7.30 (7 H, m), 5.88 (1 H, dd, J = 5.7, 2.7 Hz), 5.11–5.07 (1 H, m),
3.18 (1 H, dt, J = 21.0, 2.6 Hz), 2.94 (1 H, dd, J = 21.0, 0.6 Hz), 2.43
(3 H, s), 1.51 (3 H, d, J = 6.6 Hz).
13C NMR (75 MHz, CDCl3): d = 167.7, 145.0, 136.3, 133.1, 130.7,
130.0, 129.3, 129.1, 128.9, 128.7, 125.9, 54.5, 37.9, 23.2, 21.7.
EI-MS: m/z (%) = 373 (M+, 5), 358 (62), 218 (36), 200 (43), 155
(38), 91 (47), 17 (100).
IR (ATR, film): 3269, 3214, 3055, 2951, 2870, 1631, 1571, 1439,
1412, 1266, 1096, 842 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.54–7.42 (5 H, m), 7.03 (1 H, br
s), 5.29 (1 H, d, J = 1.5 Hz), 4.30 (1 H, d, J = 9.3 Hz), 3.95 (1 H, dd,
J = 9.3, 4.2 Hz), 3.53–3.48 (3 H, m), 1.78–1.74 (2 H, m), 1.57–1.42
(4 H, m).
13C NMR (75 MHz, CDCl3): d = 164.3, 157.8, 135.5, 130.2, 130.1,
128.1, 114.7, 69.2, 57.5, 44.6, 32.2 (2 ×), 23.0.
HRMS: m/z calcd for C19H19NO3S2: 373.0806; found: 373.0803.
EI-MS: m/z (%) = 313 (M+ + 2, 2.4), 311 (M+, 6), 164 (22), 135 (34),
122 (32), 120 (100).
trans-5-Bromo-6-methyl-4-(phenylthio)-1-tosyl-5,6-dihydropy-
ridin-2(1H)-one (10)
A mixture of compound 9 (1.00 g, 2.68 mmol) and NBS (524.7 mg,
2.95 mmol) in MeCN (12 mL) was heated at reflux under N2 for 1
h. The solvent was evaporated under vacuum, and the crude product
was purified by flash chromatography using EtOAc–hexanes (1:6)
as eluent; yield: 1.17 g (97%); white solid; mp 189.1–190.0 °C.
EI-HRMS: m/z calcd for C15H18ClNO2S: 311.0747; found:
311.0742.
trans-1-Hydroxy-2-(phenylthio)-7,8,9,9a-tetrahydro-1H-quino-
lizin-4(6H)-one (7)
To a solution of compound 6 (30 mg, 0.10 mmol) in THF (3 mL) at
–78 °C under N2 was added dropwise a solution of BuLi (2.5 M in
hexane, 77 mL, 0.19 mmol). After slowly warming to r.t. in 1 h, the
reaction mixture was heated at reflux for 7 h, and then poured into
sat. aq NH4Cl (20 mL). The mixture was extracted with EtOAc (3 ×
30 mL), dried (MgSO4), and evaporated under vacuum. The crude
product was purified by flash chromatography using EtOAc–hex-
anes (1:4-1:2) containing 5% Et3N and 5% CH2Cl2 as eluent; yield:
23.4 mg (88%); yellow oil.
IR (ATR, film): 2966, 1665, 1587, 1475, 1442, 1384, 1346, 1306,
1245, 1190, 1161, 1085 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.00 (2 H, d, J = 8.4 Hz), 7.50–
7.39 (5 H, m), 7.29 (2 H, d, J = 8.4 Hz), 5.28 (1 H, s), 5.07 (1 H, qd,
J = 6.9, 1.7 Hz), 4.44 (1 H, d, J = 1.7 Hz), 2.40 (3 H, s), 1.51 (3 H,
d, J = 6.9 Hz).
13C NMR (75 MHz, CDCl3): d = 159.0, 156.8, 145.0, 136.0, 135.5,
130.8, 130.2, 129.4, 129.2, 128.1, 126.9, 116.0, 58.8, 45.9, 21.7,
20.2.
IR (ATR, film): 3275, 3058, 2936, 2856, 2709, 1619, 1579, 1468,
1439, 1419, 1266 cm–1.
FAB-MS: m/z (%) = 454 (M + 2 + H, 42), 452 (M + H, 37), 155 (41),
1H NMR (300 MHz, CDCl3): d = 7.52–7.40 (5 H, m), 5.30 (1 H, d,
J = 2.1 Hz), 4.43 (1 H, br d, J = 13.0 Hz), 4.04 (1 H, d, J = 5.1 Hz),
3.44 (1 H, ddd, J = 11.5, 5.1, 2.4 Hz), 2.53 (1 H, td, J = 13.0, 3.1
Hz), 1.90–1.86 (2 H, m), 1.67 (1 H, d, J = 11.1 Hz), 1.58–1.26 (3 H,
m).
13C NMR (75 MHz, CDCl3): d = 162.9, 155.1, 135.5, 130.0 (2 ×),
128.2, 115.9, 70.5, 63.0, 44.1, 30.6, 25.1, 24.1.
136 (56), 91 (80), 73 (100).
FAB-HRMS: m/z calcd for C19H1979BrNO3S2: 451.9989; found:
452.0002.
trans-5-Hydroxy-6-methyl-4-(phenylthio)-1-tosyl-5,6-dihydro-
pyridin-2(1H)-one (11)
To a solution of compound 10 (25 mg, 0.06 mmol) in MeCN (1 mL)
was added Et3N (0.25 mL) and H2O (0.30 mL). The mixture was
heated at 70 °C under N2 for 24 h. After cooling, EtOAc (30 mL)
EI-MS: m/z (%) = 275 (M+, 45), 164 (35), 135 (66), 97 (20), 91 (24),
85 (33), 84 (100), 59 (20), 55 (36).
Synthesis 2011, No. 5, 759–763 © Thieme Stuttgart · New York

PAPER
Stereospecific Synthesis of trans-5,6-Dihydropyridinones
763
was added and the mixture was washed with brine (2 × 30 mL),
dried (MgSO4), and evaporated under vacuum. The crude product
was purified by flash chromatography using EtOAc–hexanes (1:4)
as eluent; yield: 16 mg (74%); white solid; mp 129.2–131.1 °C.
(4) (a) Chou, S. S. P.; Chiu, H. C.; Hung, C. C. Tetrahedron Lett.
2003, 44, 4653. (b) Chou, S. S. P.; Ho, C. W. Tetrahedron
Lett. 2005, 46, 8551. (c) Chou, S. S. P.; Liang, C. F.; Lee, T.
M.; Liu, C. F. Tetrahedron 2007, 63, 8267.
(5) (a) Chou, S. S. P.; Hsieh, H. I.; Hung, C. C. J. Chin. Chem.
Soc. 2006, 53, 891. (b) Chou, S. S. P.; Chen, P. W.
Tetrahedron 2008, 64, 1879. (c) Chou, S. S. P.; Wang, H.
C.; Chen, P. W.; Yang, C. H. Tetrahedron 2008, 64, 5291.
(6) (a) Wang, S. J.; Chou, S. H.; Kuo, Y. C.; Chou, S. S. P.;
Tzeng, W. F.; Leu, J. Y.; Huang, R. F. S.; Liew, Y. F. Acta
Pharmacol. Sin. 2008, 29, 1289. (b) Chou, S. H.; Chou, S.
S. P.; Liew, Y. F.; Leu, J. Y.; Wang, S. J.; Huang, R. F. S.;
Tzeng, W. F.; Kuo, Y. C. Molecules 2009, 14, 2345.
(c) Liew, Y. F.; Huang, C. T.; Chou, S. S. P.; Kuo, Y. C.;
Chou, S. H.; Leu, J. Y.; Tzeng, W. F.; Wang, S. J.; Tang, M.
C.; Huang, R. F. S. Molecules 2010, 15, 1632.
IR (ATR, film): 3354, 3260, 3056, 2926, 1671, 1598, 1386, 1341,
1298, 1265, 1158, 1095, 813, 703 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.94 (2 H, d, J = 7.8 Hz), 7.49–
7.38 (5 H, m), 7.26 (2 H, d, J = 7.8 Hz), 5.20 (1 H, s), 4.92 (1 H, qd,
J = 6.9, 2.1 Hz), 4.04 (1 H, br, s), 2.72 (1 H, d, J = 5.1 Hz), 2.40 (3
H, s), 1.38 (3 H, d, J = 6.9 Hz).
13C NMR (75 MHz, CDCl3): d = 159.7, 158.0, 144.7, 136.5, 135.3,
130.7, 130.2, 129.3, 129.0, 127.1, 115.0, 70.1, 57.8, 21.7, 18.7.
EI-MS: m/z (%) = 325 (20), 155 (24), 135 (31), 134 (100), 91 (51).
EI-HRMS: m/z calcd for C19H19NO4S2: 389.0755; found: 389.0760.
(7) For stereoselective syntheses of trans-5-hydroxy-5,6-
dihydropyridinones, see: (a) Humphries, M. E.; Murphy, J.;
Phillips, A. J.; Abell, A. D. J. Org. Chem. 2003, 68, 2432.
(b) Niida, A.; Tanigaki, H.; Inokuchi, E.; Sasaki, Y.; Oishi,
S.; Ohno, H.; Tamamura, H.; Wang, Z.; Peiper, S. C.;
Kitaura, K.; Otaka, A.; Fujii, N. J. Org. Chem. 2006, 71,
3942. (c) Tinarelli, A.; Paolucci, C. J. Org. Chem. 2006, 71,
6630. (d) Fu, R.; Chen, J.; Guo, L.-C.; Ye, J.-L.; Ruan,
Y.-P.; Huang, P.-Q. Org. Lett. 2009, 11, 5242.
(8) For some representative syntheses of epiquinamide, see:
(a) Tong, S. T.; Barker, D. Tetrahedron Lett. 2006, 47,
5017. (b) Suyama, T. L.; Gerwick, W. H. Org. Lett. 2006, 8,
4541. (c) Kanakubo, A.; Gray, D.; Innocent, N.; Wonnacott,
S.; Gallagher, T. Bioorg. Med. Chem. Lett. 2006, 16, 4648.
(d) Wijdeven, M. A.; Wijtmans, R.; van den Berg, R. J. F.;
Noorduin, W.; Schoemaker, H. E.; Sonke, T.; van Delft, F.
L.; Blaauw, R. H.; Fitch, R. W.; Spande, T. F.; Daly, J. W.;
Rutjes, F. P. J. T. Org. Lett. 2008, 10, 4001.
(9) For some representative syntheses of homopumiliotoxin
223G, see: (a) Aoyagi, S.; Hasegawa, Y.; Hirashima, S.;
Kibayashi, C. Tetrahedron Lett. 1998, 39, 2149. (b) Santos,
L. S.; Pilli, R. A. Tetrahedron Lett. 2001, 42, 6999.
(c) Wang, B.; Fang, K.; Lin, G. Q. Tetrahedron Lett. 2003,
44, 7981. (d) Chen, B. F.; Tsai, M. R.; Yang, C. Y.; Chang,
J. K.; Chang, N. C. Tetrahedron 2004, 60, 10223.
(10) For previous syntheses of trans-1-hydroxyquinolizidin-4-
one, see: (a) Voituriez, A.; Ferreira, F.; Pérez-Luna, A.;
Chemla, F. Org. Lett. 2007, 9, 4705. (b) Chandrasekhar, S.;
Parida, B. B.; Rambabu, Ch. Tetrahedron Lett. 2009, 50,
3294. (c) Tuan, L. A.; Pyeon, H.; Kim, G. Tetrahedron Lett.
2010, 51, 157.
trans-1-Hydroxy-2-(phenylsulfonyl)-7,8,9,9a-tetrahydro-1H-
quinolizin-4(6H)-one (12)
To a solution of compound 7 (19.7 mg, 0.08 mmol) in CH2Cl2 (1
mL) at 0 °C was slowly added a solution of MCPBA (30% in H2O,
42 mg, 0.48 mmol) in CH2Cl2 (1 mL). The mixture was stirred at r.t.
for 2 h, diluted with CH2Cl2 (20 mL), and then sequentially washed
with sat. aq Na2S2O3 (20 mL) and sat. aq NaHCO3 (20 mL). The or-
ganic layer was dried (K2CO3), evaporated, and the residue was re-
crystallized from EtOAc; yield: 16.5 mg (75%); white solid; mp
131–132 °C.
IR (ATR, film): 3340, 3063, 2926, 2856, 2724, 1719, 1663, 1613,
1468, 1447, 1373, 1309, 1152, 1033 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.96–7.93 (2 H, m), 7.74–7.59 (3
H, m), 6.66 (1 H, s), 4.52 (1 H, br d, J = 13.0 Hz), 4.28 (1 H, d,
J = 2.1 Hz), 3.63 (1 H, dt, J = 12.4, 2.1 Hz), 3.34 (1 H, br, s), 2.63
(1 H, td, J = 13.0, 2.7 Hz), 1.87–1.37 (5 H, m), 1.14–1.00 (1 H, m).
13C NMR (75 MHz, CDCl3): d = 159.8, 148.9, 137.6, 134.7, 129.7,
129.4, 128.8, 64.9, 64.5, 45.1, 30.7, 25.4, 24.4.
FAB-MS: m/z (%) = 307 (M+, 3), 281 (16), 221 (13), 207 (19), 154
(40), 136 (76), 107 (30), 91 (50), 73 (97), 55 (100), 41 (86), 39 (39),
29 (29).
FAB-HRMS: m/z calcd for C15H17NO4S: 307.0878; found:
307.0877.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are 1H and 13C NMR spectra for compounds 3–12, and X-ray crystal
structures for compounds 10–12.
(11) (a) Gundermann, K. D.; Holtman, P. Angew. Chem., Int. Ed.
Engl. 1966, 5, 668. (b) Hopkins, P. B.; Fuchs, P. L. J. Org.
Chem. 1978, 43, 1208.
(12) (a) Chou, S. S. P.; Liou, S. Y.; Tsai, C. Y.; Wang, A. J.
J. Org. Chem. 1987, 52, 4468. (b) Chou, S. S. P.; Tsao, H.
J.; Lee, C. M.; Sun, C. M. J. Chin. Chem. Soc. 1993, 40, 53.
(13) Crystallographic data (excluding structure factors) for
compounds 4, 5, 6, 10, 11, and 12 have been deposited with
the Cambridge Crystallographic Data Centre as
Acknowledgment
Financial support of this work by the National Science Council of
the Republic of China (NSC 97-2113-M-030-001-MY3) and Fu Jen
Catholic University (9991A15/10973104995-4) is gratefully
acknowledged.
supplementary publication CCDC 796324–796329 as well
as their corresponding CIF files. Copies of the data can be
obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax: +44 (1223)336033 or
e-mail: deposit@ccdc.cam.ac.uk].
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Synthesis 2011, No. 5, 759–763 © Thieme Stuttgart · New York