Total synthesis of (±)-protoemetinol

Article abstract of DOI:10.1016/j.tet.2008.07.110

A new approach to the benzo[a]quinolizidine alkaloid was described. Total synthesis of (±)-protoemetinol (1) was reported.

Full text of DOI:10.1016/j.tet.2008.07.110

Tetrahedron 64 (2008) 9685–9688
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of (ꢀ)-protoemetinol
Jung-Kai Chang, Bo-Rui Chang, Yu-Hsiu Chuang, Nein-Chen Chang
*
Department of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2008
Received in revised form 31 July 2008
Accepted 31 July 2008
A new approach to the benzo[a]quinolizidine alkaloid was described. Total synthesis of (ꢀ)-protoe-
metinol (1) was reported.
Ó 2008 Elsevier Ltd. All rights reserved.
Available online 6 August 2008
1. Introduction
of their benzo[a]quinolizidine constituents have exhibited potent
biological activity.2 For instance, it was reported that psychotrine
(ꢁ)-Protoemetinol (1) is a benzo[a]quinolizidine alkaloid iso-
lated from Alangium lamarckii by Battersby and co-workers.1 This
heterocyclic template is found in a number of alkaloids, such as
psychotrine (2), emetine (3), and tubulosine (4) (Fig. 1). A number
(2) is potent inhibitor of HIV-1 reverse transcriptase3 and exhibit an
unusual four-fold more potent inhibition of HIV-2 RT (9–10 mM)
compared to HIV-1 RT.4 Emetine (3) also shows antiamoebic
properties,5 shows activity against breast tumor cells,6 and can be
used as an emetic.7
(ꢁ)-Protoemetinol (1) is an attractive synthetic target. Discon-
nection of psychotrine (2), emetine (3), and related alkaloids re-
veals the protoemetinol structure as essentially constituting the
upper half of the molecular. A number of elegant syntheses of
benzo[a]quinolizidine alkaloids have been reported.8 Presently, we
wish to report a new route to the benzo[a]quinolizidine alkaloids
from glutarimide derivatives. Total synthesis of (ꢀ)-protoemetinol
was also reported.
MeO
MeO
MeO
N
MeO
A
B
H
H
H
N
N
C
H
H
H
OH
MeO
Protoemetinol (1)
2. Results and discussion
OMe
Psychotrine (2)
2.1. Retrosynthesis of ( )-protoemetinol (1)
MeO
MeO
MeO
MeO
Our strategy for the synthesis of (ꢀ)-protoemetinol (1) was
shown in Scheme 1. The benzo[a]quinolizidine alkaloid 1 was en-
visaged to arise from benzo[a]quinolizinone 5b. The benzo[a]quino-
lizinone skeleton could then be formed via acid-catalyzed
intramolecular cyclization of 6. The enlactam 6 was anticipated to
derive from [3þ3] annulation adduct 7.
N
N
H
H
H
H
H
H
N
H
H
H
N
H
HN
2.2. Synthesis of enlactam 6
MeO
OMe
Emetine (3)
OH
Tubulosine (4)
As shown in Scheme 2, glutarimide 7 was easily prepared via
stepwise [3þ3] annulation9 of
a-sulfonyl acetamide 8 with a,b-
unsaturated ester 9. Regioselective reduction of C-2 carbonyl group
at 7 with sodium borohydride gave hydroxylactam 10.8k,10 Mesy-
lation and elimination of 10 with methanesulfonyl chloride and
triethylamine furnished 11, which then further desulfonated with
sodium amalgam to yield the corresponding enlactam 6.
Figure 1. The benzo[a]quinolizidine alkaloids.
* Corresponding author.
E-mail address: ncchang@mail.nsysu.edu.tw (N.-C. Chang).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.110

9686
MeO
MeO
J.-K. Chang et al. / Tetrahedron 64 (2008) 9685–9688
isomer 5b could be obtained through the isomerization of the 11b-
-H isomer 5a on treatment with Lewis acid.
MeO
MeO
A
B
H
b
N
C
N
O
H
H
H
H
MeO
MeO
MeO
MeO
H
N
O
N
O
EtI, LHMDS
5b
OH
OBn
THF, -78 °C
93%
Protoemetinol (1)
6
12
MeO
MeO
MeO
OBn
OBn
N
O
O
N
O
MeO
MeO
MeO
MeO
MeO
11b
H
11b
N
2
O
H
N
O
H
Ts
BF3 OEt2
H
H
3
3
CH2Cl2, -15 °C
83%
2
6
7
H
OBn
OBn
Scheme 1. Retrosynthesis of (ꢀ)-protoemetinol (1).
5a
5b
OBn
OBn
dr 5a : 5b = 1 : 6
Scheme 3. Synthesis of benzo[a]quinolizinone 5b.
MeO
O
OEt
O
N
O
MeO
MeO
MeO
2
[ 3+3 ]
no NOE
NOE
HN
O
NaH, THF
90%
Ts
Ts
OBn
7
MeO
MeO
MeO
8
OBn
O
9
11b
11b
N
O
H
N
2
O
H
MeO
MeO
MeO
MeO
MeO
H
H
3
3
2
HO
Ts
N
N
O
no NOE
H
H
H
H
14
14
NaBH4
MsCl
NOE
Ts
MeOH, -10 °C
88%
Et3N, 0 °C
86%
OBn
OBn
5a
5b
11
10
OBn
OBn
MeO
MeO
MeO
MeO
11b
N
2
O
H
N
O
Na-Hg
H
3
X
MeOH
96%
H
H
S
S
6
OBn
5a
Scheme 2. Synthesis of enlactam 6.
Figure 2. Selected NOE enhancements for 5a and 5b.
Finally, treatment of benzo[a]quinolizinone 5b with palladium
on carbon and hydrogen provided debenzylation product 13, which
was further reduced with lithium aluminum hydride to produce
the desired reduced product (ꢀ)-protoemetinol (1) in 85% yield
(Scheme 4).
2.3. Total synthesis of ( )-protoemetinol (1)
With the key intermediate 6 in hand, we then focused our at-
tention on the construction of ring B and three chiral centers in
(ꢀ)-protoemetinol (1) (Scheme 3). Treatment of 6 with LHMDS and
iodoethane provided alkylation product 12 as a single diastereomer
in 93% yield. The stereochemistry of 12 was assigned as trans on the
basis of NOESY data of the next reaction products 5a and 5b. Acid-
catalyzed cyclization of 12 produced a 1:6 mixture of 5a and 5b in
83% yield. Their structures were determined by NOESY studies
(Fig. 2). The NOESY experimental results of 5a are similar to 5a0 as
reported by Lete and co-workers.11 Thus, for 5a, an NOE enhance-
ment between H-11b, H-3, and H-14 was observed. On the other
hand, diastereomer 5b showed an NOE enhancement between
H-11b and H-2, whereas no NOE was observed between H-11b, H-3,
and H-14. The diastereoselectivity observed in the cyclization of 12
could be rationalized on the basis of Takano’s hypothesis.12 The
approach of the dimethoxyphenyl group to the 6-position of 12
from a pseudoaxial direction (a less hindered side) should give 5a
MeO
MeO
MeO
MeO
11b
H
N
O
H
N
2
O
H
H2
H
H
3
Pd/C
H
97%
13
5b
OH
OBn
MeO
MeO
N
LAH
H
H
THF, 0 °C
85%
H
OH
Protoemetinol (1)
Scheme 4. Completion of the total synthesis of (ꢀ)-protoemetinol (1).
instead of 5b as a main product. However, the 11b-
5a) isomerized to the 11b- -H isomer (as 5b) via a B/C seco in-
termediate. Therefore, the thermodynamically more stable 11b- -H
b-H isomer (as
a
a

J.-K. Chang et al. / Tetrahedron 64 (2008) 9685–9688
9687
3. Conclusion
4.51 (AB, 2H), 3.99–3.95 (m, 1H), 3.97 (s, 3H), 3.94 (s, 1H), 3.92 (s,
3H), 3.56–3.50 (m, 3H), 3.07–2.84 (m, 5H), 2.54 (s, 3H), 2.36 (dd,
J¼3.5, 16.5 Hz, 1H), 1.82–1.76 (m, 1H), 1.55–1.49 (m, 1H); 13C NMR
Starting from easily available a-sulfonyl acetamide 8, a concise
eight-step synthesis of (ꢀ)-protoemetinol (1) has been achieved in
a total of 35.7% yield. Further application of the present strategy to
the synthesis of benzo[a]quinolizidine alkaloids are currently un-
derway in our laboratory and will be reported in future.
(125 MHz, CDCl3): d 170.3, 149.0, 147.7, 145.2, 138.1, 135.0, 131.3,
129.8 (2C), 128.7 (2C), 128.3 (2C), 127.56 (2C), 127.53, 120.8, 111.7,
111.2, 79.9, 72.8, 67.8, 66.8, 55.9, 55.7, 48.4, 35.2, 35.0, 33.9, 26.5,
21.6; IR (CHCl3, cmꢁ1): 3459, 1647, 1596; HRMS (ESI, Mþþ1) calcd
for C31H38NO7S 568.2369, found 568.2370.
4. Experimental
4.1. General
4.2.3. 4-(2-Benzyloxyethyl)-1-[2-(3,4-dimethoxyphenyl)-ethyl]-5-
(toluene-4-sulfonyl)-3,4-dihydro-1H-pyridin-2-one (11)
Triethylamine (0.60 mL, 4.20 mmol) was added to the solution
of 10 (990 mg, 1.70 mmol) in dry THF (10.0 mL) and the mixture
was stirred at room temperature. After 0.5 h, the resulting mixture
was poured into methanesulfonyl chloride (205 mg, 1.80 mmol) in
an ice bath for 12 h. Saturated sodium bicarbonate solution
(10.0 mL) was added to the mixture and concentrated under re-
duced pressure. The residue was diluted with water (15.0 mL) and
extracted with ethyl acetate (3ꢂ40.0 mL). The combined organic
layers were washed with brine, dried over anhydrous MgSO4, fil-
tered, and evaporated. Purification on silica gel (n-hexane/ethyl
acetate¼4:1 to 2:1) produced 11 (800 mg, 86%) as a yellow oil; 1H
Melting points were determined with melting point apparatus
and are uncorrected. 1H NMR and 13C NMR were recorded on Varian
VRX 500 spectrometer. NMR spectra were recorded in CDCl3 (1H at
500 MHz and 13C at 125 MHz), and chemical shifts are expressed in
parts per million (d) relative to internal Me4Si.
Tetrahydrofuran was distilled prior to use. All other reagents and
solvents were obtained from commercial sources and were used
without any further purification. Reactions were routinely carried
out under an atmosphere of dry nitrogen with magnetic stirring.
Solutions of products in organic solvents were dried over anhy-
drous magnesium sulfate before concentration under vacuum.
NMR (500 MHz, CDCl3):
d
7.61 (d, J¼8.5 Hz, 2H), 7.35–7.27 (m, 7H),
7.16 (s, 1H), 6.82 (d, J¼8.0 Hz, 1H), 6.74 (dd, J¼2.0, 8.0 Hz, 1H), 6.67
(d, J¼2.0 Hz, 1H), 4.46 (d, J¼12.0 Hz, 1H), 4.39 (d, J¼12.0 Hz, 1H),
3.94–3.88 (m, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.71–3.65 (m, 1H), 3.41
(t, J¼6.0 Hz, 2H), 2.90–2.81 (m, 2H), 2.74–2.72 (m, 1H), 2.59 (d,
J¼16.5 Hz, 1H), 2.42 (s, 3H), 2.35 (dd, J¼7.5, 16.5 Hz, 1H), 1.75–1.71
4.2. Preparation of a key intermediate, enlactam 6
4.2.1. 4-(2-Benzyloxyethyl)-1-[2-(3,4-dimethoxyphenyl)-ethyl]-3-
(toluene-4-sulfonyl)piperidin-2,6-dione (7)
A solution of
a
-toluenesulfonyl acetamide 8 (1.50 g, 4.00 mmol)
(m, 1H), 1.44–1.39 (m,, 1H); 13C NMR (125 MHz, CDCl3):
d 168.07,
in dry THF (40.0 mL) was added to a rapidly stirred suspension of
sodium hydride (336 mg, 8.40 mmol, 60%) in dry THF (20.0 mL).
After the reaction mixture was stirred at room temperature for
149.02, 147.89, 144.08, 138.86, 138.19, 137.39, 129.90, 129.84 (2C),
128.31 (2C), 127.61 (2C), 127.54 (3C), 120.87, 120.72, 111.99, 111.43,
72.49, 66.48, 55.88, 55.81, 48.71, 33.55, 34.39, 31.17, 28.56, 21.56; IR
(CHCl3, cmꢁ1): 3030, 1649; HRMS (EI, Mþ) calcd for C31H35NO6S
549.2180, found 549.2185.
30 min, a solution of a,b-unsaturated ester 9 (731 mg, 4.20 mmol)
in dry THF (20.0 mL) was slowly added over 1 h. The resulting
mixture was stirred for 4 h, quenched with saturated ammonium
chloride solution (25.0 mL) in an ice bath, and concentrated under
reduced pressure. The residue was diluted with water (25.0 mL)
and extracted with ethyl acetate (3ꢂ70.0 mL). The combined or-
ganic layers were washed with brine, dried over anhydrous MgSO4,
filtered, and evaporated. Purification on silica gel (n-hexane/ethyl
acetate¼4:1 to 2:1) produced glutarimide 7 (2.02 g, 90%) as a yel-
4.2.4. 4-(2-Benzyloxyethyl)-1-[2-(3,4-dimethoxyphenyl)-ethyl]-
3,4-dihydro-1H-pyridin-2-one (6)
Sodium amalgam (6%, Na/Hg, 3.00 g) and sodium phosphate
(40.0 mg) were added to
a stirred solution of 11 (853 mg,
1.55 mmol) in MeOH (40.0 mL), and vigorously stirred for 2 h at
room temperature. The residue was filtered and washed with
MeOH (2ꢂ10.0 mL). The combined organic layers were concen-
trated to obtain the crude product. The crude product was purified
by silica gel chromatography (hexane/ethyl acetate¼4:1 to 2:1) to
afford enlactam 6 (590 mg, 96%) as colorless oil; 1H NMR (500 MHz,
low oil; 1H NMR (500 MHz, CDCl3):
d
7.63 (d, J¼8.5 Hz, 2H), 7.35–
7.26 (m, 7H), 6.76 (s, 3H), 4.44 (s, 2H), 4.22 (s, 1H), 4.09–3.96 (m,
2H), 3.86 (s, 3H), 3.83 (s, 3H), 3.51–3.45 (m, 2H), 3.40 (dd, J¼6.0,
18.0 Hz, 1H), 3.18 (dd, J¼6.5, 13.0 Hz, 1H), 2.79 (t, J¼8.0 Hz, 2H), 2.62
(d, J¼18.0 Hz, 1H), 2.46 (s, 3H), 1.56–1.53 (m, 2H); 13C NMR
CDCl3):
d
7.36–7.27 (m, 5H), 6.79 (d, J¼8.5 Hz, 1H), 6.72 (d, J¼8.5 Hz,
(125 MHz, CDCl3):
d
170.26, 164.41, 148.80, 147.65, 145.62, 137.67,
1H), 6.69 (s, 1H), 5.79 (dd, J¼3.0, 8.0 Hz, 1H), 5.06 (dd, J¼2.0, 8.0 Hz,
1H), 4.52 (dd, J¼3.5, 15.5 Hz, 2H), 3.77–3.74 (m, 1H), 3.68–3.60 (m,
2H), 3.59–3.56 (m, 1H), 2.82 (dd, J¼7.0, 14.5 Hz, 2H), 2.58–2.54 (m,
1H), 2.19–2.12 (m, 1H), 1.76–1.71 (m, 1H); 13C NMR (125 MHz,
135.18, 130.68, 129.87 (2C), 128.79 (2C), 128.51 (2C), 127.80, 127.66
(2C), 121.02, 111.17, 111.11, 73.27, 70.30, 67.28, 55.86, 41.23, 34.79,
33.51, 33.25, 29.69, 27.15, 21.78; IR (CHCl3, cmꢁ1): 3027,1689; HRMS
(EI, Mþ) calcd for C31H35NO7S 565.2129, found 565.2111.
CDCl3):
d 171.18, 148.94, 147.76, 138.38, 130.63, 128.35 (2C), 127.94,
127.62 (2C),127.54,120.78,112.03,111.30,110.23, 72.91, 70.87, 67.95,
55.88, 55.86, 48.33, 36.78, 34.32, 31.49; IR (CHCl3, cmꢁ1): 3027,
1641; HRMS (ESI, Mþþ1) calcd for C24H30NO4 396.2175, found
396.2175.
4.2.2. 4-(2-Benzyloxyethyl)-1-[2-(3,4-dimethoxyphenyl)-ethyl]-6-
hydroxy-5-(toluene-4-sulfonyl)piperidin-2-one (10)
A solution of glutarimide 7 (1.13 g, 2.00 mmol) in a co-solvent of
THF (10.0 mL) and HPLC-grade MeOH (40.0 mL) was stirred at
ꢁ10 ꢃC. Sodium borohydride (136 mg, 4.00 mmol) was added at
ꢁ10 ꢃC. The mixture was stirred for 2 h at that temperature. Satu-
rated sodium bicarbonate solution (10.0 mL) was added to the
mixture and concentrated under reduced pressure. The residue was
diluted with water (15.0 mL) and extracted with ethyl acetate
(3ꢂ40.0 mL). The combined organic layers were washed with brine,
dried over anhydrous MgSO4, filtered, and evaporated. Purification
on silica gel (n-hexane/ethyl acetate¼2:1 to 1:1) produced 10
4.3. Total synthesis of ( )-protoemetinol (1)
4.3.1. 4-(2-Benzyloxyethyl)-1-[2-(3,4-dimethoxyphenyl)-ethyl]-3-
ethyl-3,4-dihydro-1H-pyridin-2-one (12)
A solution of lithium bis(triethylsilyl)amide (LHMDS, 1.06 M,
2.70 mL, 2.70 mmol) in THF was added to the solution of enlactam 6
(530 mg,1.30 mmol) in dry THF (15.0 mL) at ꢁ78 ꢃC, and the mix-
ture was stirred for 0.5 h. Iodoethane (310 mg, 2.00 mmol) was
added; the resulting mixture was stirred for 10 h at ꢁ78 ꢃC. Satu-
rated ammonium chloride solution (15.0 mL) was added to the
(1.02 g, 90%) as a yellow oil; 1H NMR (500 MHz, CDCl3):
d
7.75 (d,
J¼8.0 Hz, 2H), 7.47–7.36 (m, 7H), 6.87–6.74 (m, 3H), 5.06 (br, 1H),

9688
J.-K. Chang et al. / Tetrahedron 64 (2008) 9685–9688
mixture and concentrated under reduced pressure. The residue was
diluted with water (10.0 mL) and extracted with ethyl acetate
(3ꢂ40.0 mL). The combined organic layers were washed with brine,
dried over anhydrous MgSO4, filtered, and evaporated. Purification
on silica gel (n-hexane/ethyl acetate¼4:1 to 2:1) produced 12
4.3.4. 2-(3-Ethyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-
pyrido[2,1-a]isoquinolin-2-yl)ethanol (1)
A solution of 13 (170 mg, 0.50 mmol) in dry THF (10.0 mL) was
added to the solution of lithium aluminum hydride (76.0 mg,
2.00 mmol) in dry THF (5.00 mL) in an ice bath. The resulting
mixture was stirred for 24 h at 0 ꢃC, quenched with saturated
ammonium chloride solution (10.0 mL), and concentrated under
reduced pressure. The residue was diluted with water (10.0 mL)
and extracted with ethyl acetate (3ꢂ30.0 mL). The combined or-
ganic layers were washed with brine, dried over anhydrous MgSO4,
filtered, and evaporated. Purification on silica gel (n-hexane/ethyl
acetate¼2:1 to 1:1) produced protoemetinol (1) (138 mg, 85%) as
(530 mg, 93%) as a yellow oil; 1H NMR (500 MHz, CDCl3):
d 7.34–
7.25 (m, 5H), 6.79–6.69 (m, 3H), 5.80 (d, J¼7.5 Hz, 1H), 4.96–4.91
(m, 1H), 4.48 (AB, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 3.60–3.71 (m, 2H),
3.46 (t, J¼6.0 Hz, 2H), 2.83–2.73 (m, 2H), 2.40–2.34 (m, 1H), 2.21–
2.17 (m, 1H), 1.65–1.45 (m, 4H), 0.93 (t, J¼7.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d 171.4,148.8,147.6,138.3,131.1,128.3 (2C),128.2,
127.6, 127.6, 120.8, 112.0, 111.1, 108.2, 72.9, 67.2, 55.84, 55.79, 48.5,
47.7, 34.4, 34.0, 32.9, 23.7, 11.7; IR (CHCl3, cmꢁ1): 1655, 1516, 1237;
HRMS (ESI, Mþþ1) calcd for C26H34NO4 424.2488, found 424.2484.
a colorless oil; 1H NMR (500 MHz, CDCl3):
d 6.69 (s, 1H), 6.57 (s, 1H),
3.92–3.73 (m, 4H), 3.85 (s, 3H), 3.84 (s, 3H), 3.14–3.03 (m, 3H), 2.99–
2.95 (m, 1H), 2.64–2.60 (m, 1H), 2.47 (td, J¼11.5, 4.0 Hz, 1H), 2.35–
2.33 (m, 1H), 2.04–2.00 (m, 1H), 1.97–1.92 (m, 1H), 1.70–1.64 (m,
4.3.2. 2-(2-Benzyloxyethyl)-9,10-dimethoxy-3-methyl-
1,2,3,6,7,11b-hexahydropyrido[2,1-a]isoquinolin-4-ones
(5a) and (5b)
1H), 1.44–1.41 (m, 2H), 1.28–1.09 (m, 2H), 0.92 (t, J¼7.5 Hz, 3H); 13
C
NMR (125 MHz, CDCl3): d 147.4, 147.1, 130.0, 126.6, 111.4, 108.2, 62.6,
A solution of 12 (440 mg, 1.00 mmol) in dry dichloromethane
(20.0 mL) was treated with BF3$OEt2 (0.15 mL, 1.10 mmol) at
ꢁ15 ꢃC. After 15 h, the resulting mixture was quenched with satu-
rated sodium bicarbonate solution (20.0 mL) and extracted with
dichloromethane (2ꢂ20.0 mL). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered, and
evaporated. Purification on silica gel (n-hexane/ethyl acetate¼6:1
to 2:1) produced 5a (51.0 mg, 12%) and 5b (300 mg, 71%). Com-
61.4, 60.4, 56.1, 55.8, 52.4, 41.2, 37.6, 37.2, 35.8, 29.1, 23.4, 11.1; IR
(CHCl3, cmꢁ1): 3450, 1426, 1292; HRMS (ESI, Mþþ1) calcd for
C19H30NO3 320.2226, found 320.2223.
Acknowledgements
The authors would like to thank the National Science Council of
the Republic of China for financial support.
pound 5a: colorless oil; 1H NMR (500 MHz, CDCl3):
d 7.35–7.27 (m,
5H), 6.61 (s, 1H), 6.58 (s, 1H), 4.88–4.84 (m, 1H), 4.65 (dd, J¼5.0,
11.0 Hz, 1H), 4.54 (s, 2H), 3.86 (s, 3H), 3.79 (s, 3H), 3.67–3.58 (m,
2H), 2.90–2.76 (m, 2H), 2.64–2.61 (m, 1H), 2.29 (td, J¼4.0, 13.5 Hz,
1H), 2.21–2.18 (m, 1H), 2.13–2.11 (m, 1H), 1.95–1.73 (m, 4H), 1.55–
1.46 (m, 1H), 0.96 (t, J¼7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3):
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2008.07.110.
d
171.7, 147.7, 147.6, 138.2, 129.4, 128.4 (2C), 127.63, 127.58 (2C),
References and notes
127.2, 111.5, 107.8, 73.1, 68.2, 56.0, 55.8, 52.5, 47.8, 39.7, 33.0, 30.7,
29.9, 28.6, 25.5, 12.3; IR (CHCl3, cmꢁ1): 1656, 1513; HRMS (ESI,
Mþþ1) calcd for C26H34NO4 424.2488, found 424.2491.
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7. Endo, T.; Nemoto, M.; Ogawa, T.; Tamakai, H.; Hamaue, N.; Hirafuji, M.; Takeda,
Y.; Hasegawa, M.; Fujii, Y.; Minami, M. Res. Commun. Mol. Pathol. Pharmacol.
2000, 108, 187.
Compound 5b: colorless oil; 1H NMR (500 MHz, CDCl3):
d 7.53–
7.27 (m, 5H), 6.60 (s, 1H), 6.57 (s, 1H), 4.88–4.85 (m, 1H), 4.58–4.55
(m, 1H), 4.53 (AB, 2H), 3.86 (s, 3H), 3.79 (s, 3H), 3.65–3.58 (m, 2H),
2.88–2.74 (m, 2H), 2.62–2.59 (m, 1H), 2.48 (td, J¼3.5, 13.5 Hz, 1H),
2.16–2.02 (m, 3H), 1.96–1.90 (m, 1H), 1.71–1.66 (m, 1H), 1.49–
1.43(m, 1H), 1.32 (AB, 1H), 0.91 (t, J¼7.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3):
d 171.4, 147.6, 138.4, 129.1, 128.3 (2C), 127.62, 127.59, 127.5
(2C), 127.3, 111.4, 108.4, 72.9, 67.7, 56.1, 55.8, 55.7, 48.0, 39.5, 37.2,
34.0, 31.3, 28.5, 22.2, 10.0; HRMS (ESI, Mþþ1) calcd for C26H34NO4
424.2488, found 424.2489.
8. (a) Takano, S.; Hatakeyama, S.; Ogasawara, K. Tetrahedron Lett. 1978, 28, 2519;
(b) Ihara, M.; Yasui, K.; Taniguchi, N.; Fukumoto, K. J. Chem. Soc., Perkin Trans. 1
1990, 1469; (c) Ihara, M.; Yasui, K.; Taniguchi, N.; Fukumoto, K.; Kametani, T.
Tetrahedron Lett. 1988, 29, 4963; (d) Hirai, Y.; Terada, T.; Hagiwara, A.; Yamazaki,
T. Chem. Pharm. Bull. 1988, 36, 1343; (e) Bhattacharjya, A.; Mukhopadhyay, R.;
Sinha, R. R.; All, E.; Pakrashi, S. C. Tetrahedron 1988, 44, 3477; (f) Fujii, T.; Ohba,
M.; Yoshifuji, S. Heterocycles 1988, 27, 1009; (g) Takacs, J. M.; Boito, S. C. Tet-
rahedron Lett. 1995, 36, 2941; (h) Tietze, L. F.; Rackelmann, N.; Sekar, G. Angew.
Chem., Int. Ed. 2003, 42, 4254; (i)Tietze, L. F.; Rackelmann, N.;Muller, I. Chem.dEur.
J. 2004,10, 2722; (j) Itoh, T.; Miyazaki, M.; Fukuoka, H.; Nagata, K.; Ohsawa, A. Org.
Lett. 2006, 8,1295; (k) Chang, B. R.; Chen, C. Y.; Chang, N. C. Tetrahedron Lett. 2002,
43, 3233.
9. (a) Chang, M. Y.; Chang, B. R.; Tai, H. M.; Chang, N. C. Tetrahedron Lett. 2000, 41,
10273; (b) Huang, C. G.; Chang, B. R.; Chang, N. C. Tetrahedron Lett. 2002, 43,
2721; (c) Chang, M. Y.; Chen, S. T.; Chang, N. C. Tetrahedron 2002, 58, 5075; (d)
Chang, M. Y.; Chen, S. T.; Chang, N. C. Heterocycles 2002, 57, 2321; (e) Lin, C. H.;
Tsai, M. R.; Wang, Y. S.; Chang, N. C. J. Org. Chem. 2003, 68, 5688; (f) Chang, M.
Y.; Chen, S. T.; Chang, N. C. Heterocycles 2003, 60, 99; (g) Chang, M. Y.; Chen, S.
T.; Chang, N. C. Synth. Commun. 2003, 33, 1375; (h) Chen, B. F.; Tasi, M. R.; Yang,
C. Y.; Chang, J. K.; Chang, N. C. Tetrahedron 2004, 60, 10223.
4.3.3. 3-Ethyl-2-(2-hydroxyethyl)-9,10-dimethoxy-1,2,3,6,7,11b-
hexahydropyrido[2,1-a]isoquinolin-4-one (13)
Palladium on activated carbon (10%, 10.0 mg) was added to the
solution of 5b (80.0 mg, 0.20 mmol) in EtOH (15.0 mL) Hydrogen
was bubbled into the mixture for 10 min, and the reaction mixture
was continued to stir for 12 h at room temperature. The catalyst was
filtered through a short plug of Celite and washed with EtOH
(2ꢂ10.0 mL). The combined organic layers were concentrated to
obtain the crude product. The crude product was purified by silica
gel chromatography (hexane/ethyl acetate¼4:1 to 2:1) to afford 13
(58.0 mg, 97%) as colorless oil; 1H NMR (500 MHz, CDCl3):
d 6.66 (s,
1H), 6.61 (s, 1H), 4.88–4.85 (m, 1H), 4.60 (dd, J¼3.5, 11.5 Hz, 1H),
3.87 (s, 6H), 3.84–3.78 (m, 2H), 2.89–2.75 (m, 2H), 2.63–2.60 (m,
1H), 2.53 (td, J¼3.5, 13.0 Hz, 1H), 2.17–2.05 (m, 3H), 1.91–1.84 (m,
1H), 1.74–1.65 (m, 2H), 1.46–1.41 (m, 1H), 1.36 (AB, 1H), 0.91 (t,
10. (a) Chang, M. Y.; Chen, S. T.; Chang, N. C. Tetrahedron 2002, 58, 3623; (b) Hsu, R.
T.; Cheng, L. M.; Chang, N. C.; Tai, H. M. J. Org. Chem. 2002, 67, 5044; (c) Chen, C.
Y.; Chang, B. R.; Tsai, M. R.; Chang, M. Y.; Chang, N. C. Tetrahedron 2003,
59, 9383.
11. Garcia, E.; Lete, E.; Sotomayor, N. J. Org. Chem. 2006, 71, 6776.
12. Takano, S.; Hatakeyama, S.; Takashi, Y.; Ogasawara, K. Heterocycles 1982, 17, 263.
J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3):
d 171.5, 147.7, 138.4,
129.0, 127.3, 111.4, 108.5, 60.2, 56.2, 55.9, 55.7, 48.0, 39.6, 37.3, 37.1,
30.8, 28.6, 22.3,10.0; IR (CHCl3, cmꢁ1): 3459,1653,1597; HRMS (ESI,
Mþþ1) calcd for C19H28NO4 334.2018, found 334.2020.