A formal total synthesis of securinine via an intramolecular [4+2] cycloaddition reaction

Article abstract of DOI:10.3987/COM-02-S11

An intramolecular Diels-Alder reaction of the enol ester derived from 2-acetylpyridine and sorbic anhydride gave the cycloaddition product, stereoselectively, which was further converted into the key intermediate for the synthesis of securinine.

Full text of DOI:10.3987/COM-02-S11

HETEROCYCLES, Vol. 59, No. 1, 2003, pp. 169 - 187, Received, 17th May, 2002
A FORMAL TOTAL SYNTHESIS OF SECURININE VIA AN
†
INTRAMOLECULAR [4+2] CYCLOADDITION REACTION
Toshio Honda,* Hidenori Namiki, Mika Kudoh, Hiromasa Nagase, and
Hirotake Mizutani
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41,
Shinagawa-ku, Tokyo 142-8501, Japan
Abstract – An intramolecular Diels-Alder reaction of the enol ester derived
from 2-acetylpyridine and sorbic anhydride gave the cycloaddition product,
stereoselectively, which was further converted into the key intermediate for the
synthesis of securinine.
Securinine,1 a member of the Securinega family of alkaloids having a tetracyclic indolizidine skeleton
with an α,β-unsaturated γ-lactone, was originally isolated from Securinega suffruticasa,2 and its structure
was determined by chemical and spectroscopic studies,3,4 and also by X-Ray crystallographic analysis5 as
shown in Figure 1.
O
O
H
N
Figure 1. The structure of securinine.
Since this alkaloid has been shown to exhibit a stereospecific GABAA receptor antagonist activity, a
number of syntheses and synthetic approaches were developed with the hope of understanding the shape

of the GABAA receptor site.6 To date, only two total syntheses of securinine have been reported.7 The
first total synthesis of securinine was published by Horii and co-workers in 1967,7a where
cyclohexane-1,2-dione was employed as the A-ring precursor and 2-lithiopyridine was introduced as the
C-ring moiety. Although a number of synthetic approaches to this alkaloid were developed after Horii’s
synthesis, most of them could not reach to its total synthesis. Very recently, a concise total synthesis of
securinine was achieved by using a ring closing metathesis leading to the construction of the A-ring, as a
key reaction by Liras and co-workers.7b Due to the attractive biological activity and also its unique
structural feature, we are also interested in developing a novel strategy for the synthesis of securinine, in
which we planned to utilize an intramolecular Diels-Alder reaction of an enol ester to construct the A and
D rings in one-step.8 Our retrosynthetic strategy was depicted in Figure 2.9
O
O
D
O
O
O
B
H
H
N
ref.
O
A
C
N
R
NH
H
H
Securinine
[4+2] cycloaddition
isomerization
N
R
N
R
H
O
O
O
O
+
sorbic anhydride
N
R
O
Figure 2. Retrosynthesis for securinine.
Thus, we investigated the preparation of the enol ester (8), a precursor for Diels-Alder reaction, as
follows.
The ketal (2), derived from 2-acetylpyridine (1) and ethylene glycol, was alkylated with benzyl bromide in

acetonitrile to afford the quaternary salt, which on successive reduction with sodium borohydride, then
over platinum oxide under an atmospheric pressure of hydrogen gave the piperidine derivative (5). After
removal of the ketal group of 5 by acid treatment, the resulting acetyl compound (6) was treated with
sorbic anhydride in the presence of lithium hexamethyldisilazide in THF to give the conjugated enol ester
(7). Deconjugation reaction of 7 was achieved by treatment with lithium hexamethyldisilazide, followed
by protonation with acetic acid10 to provide the enol ester (8) (Scheme 1).
-
b
a
c
Br
+
N
N
N
O
O
O
O
O
O
Bn
2
3
1
e
f
d
N
N
N
O
O
O
Bn
Bn
O
Bn
4
5
6
O
O
g
N
N
N
Bn
O
Bn
Bn
O
O
O
7
8
9
Scheme 1. a) HO(CH2)2OH, p-TsOH, benzene; b) BnBr, MeCN; c) NaBH4, MeOH;
d) H2, PtO2, EtOAc; e) aq. TFA; f) LDA, then sorbic anhydride, THF; g) LiHMDS,
then AcOH, THF-HMPA.
Attempted Diels-Alder reaction of 8, however, afforded none of the desired product under the various
reaction conditions, unfortunately.
Although the similar synthetic approach was applied to
1-tert-butoxycarbonyl-2-acetylpiperidine11 to synthesize an enol ester, the C-acylated product (12) was
only isolated (Scheme 2).
We therefore decided to use a pyridine derivative (14) instead of a piperidine derivative for an
intramolecular cycloaddition reaction, although a stereoselective reduction of the pyridine ring would be
required to synthesize the target molecule, at a later stage of this synthesis.

N
N
Boc O
Boc O
O
10
11
1) LDA, THF
2) sorbic anhydride
N
Boc O
O
12
Scheme 2.
Again, treatment of 2-acetylpyridine with sorbic anhydride in the presence of lithium
hexamethyldisilazide in THF gave the conjugated enol ester (13), whose deconjugation was achieved by
adopting the procedure as described above10 to afford the precursor for Diels-Alder reaction. Heating of
14 in toluene at 180 °C in a sealed tube for 12 h gave the cycloaddition products (15 and 16) in 70 and 8%
yields, respectively (Scheme 3).
a
b
N
N
O
N
O
O
O
O
O
1
13
14
O
c
O
O
+
H
H
N
N
16
15
Scheme 3. a) LDA, then sorbic anhydride, THF; b) LiHMDS, then AcOH, THF-HMPA;
c) toluene, 180ºC in a sealed tube.
Although the stereochemistry of the products could not be determined at this stage, the major product was

assumed to have cis configuration based on the examination of the transition states as shown in Figure 3.
In the endo-transition, the steric repulsion between the pyridine ring and the diene moiety was observed.
On the contrary, none of such steric repulsion could be observed in the exo-transition state, which leads to
the cis-fused compound.
O
O
O
O
N
N
endo-TS
exo-TS
Figure 3. Transition states for the cycloaddition.
Since we could succeed in the synthesis of the rings A and D unit in one-step by an intramolecular
cycloaddition reaction, our attention was focused on the construction of the basic skeleton for securinine
according to the synthetic path as shown in Figure 2. Treatment of the major cycloadduct (15) with
phenylselenenyl chloride in the presence of LDA afforded the selenide (17), which on oxidation with 30%
hydrogen peroxide in the presence of sodium hydrogen carbonate in ethyl acetate-THF (1:1) gave the
conjugated olefin (18) (Scheme 4).
O
O
O
O
SePh
O
O
O
O
a
b
H
H
Py
N
N
N
X
15
17
18
X = halogen
or OH
Scheme 4. a) LDA, then PhSeCl, THF; b) 30% H2O2, EtOAc-THF, NaHCO3.
Attempted allylic oxidation with selenium dioxide or allylic bromination with N-bromosuccinamide,

however, gave none of the desired product, unfortunately. In order to accomplish the synthesis of
securinine, a stereoselective reduction of the pyridine ring was, therefore, investigated prior to the
introduction of the diene system. The olefin moiety of 15 was protected as the acetonide (20) prior to the
reduction of the pyridine ring by dihydroxylation, followed by acetonization of the diol (19). Catalytic
hydrogenation of 20 over platinum oxide under an atmospheric pressure of hydrogen furnished the
piperidine derivatives (21 and 22), which on acetylation with acetic anhydride, gave the inseparable
acetonides (23 and 24) in a ratio of ca. 2:3, respectively, in 91% yield from 20. Acid hydrolysis of the
mixture gave the diols, which were separated by column chromatography on silica gel to provide 25 and
26 in 55 and 36% yields, respectively. The structure of the later compound (26) was determined by
X-Ray analysis unambiguously confirming the stereochemistry of the cycloadduct to be cis as proposed
(Figure 4). Although the expected high stereoselectivity for the catalytic reduction of the pyridine ring in
20 could not be obtained, unfortunately, we used the major compound in further conversion into the key
intermediate for the synthesis of securinine (Scheme 5).
O
O
O
O
O
O
a
b
c
H
H
H
N
N
N
O
OH
OH
O
19
15
20
O
O
O
O
O
O
O
O
d
H
H
H
H
+
+
N
N
N
Ac
N
H
H
H
H
Ac
R
O
R
O
OH
OH
OH
O
O
OH
22: R = H
24: R = Ac
26
21: R = H
23: R = Ac
25
d
d
Scheme 5. a) OsO4, NMO, tert-BuOH; b) 2,2-dimethoxypropane, CSA, DMF; c) H2, PtO2,
AcOH; d) Ac2O, Py, DMAP; d) 1N HCl, THF.
Treatment of the diol (26) with thiocarbonyldiimidazole afforded the thionocarbonate (27) in 85% yield.

Reductive deoxygenation of 27 with bis(1,5-cyclooctadiene)nickel(0) [Ni(COD)2],12 provided the olefin
(28), mp 138°C, in 90% yield. Finally, the diene system was introduced by phenylselenylation of 28 in
the presence of lithium diisopropylamide, followed by oxidative elimination of the selenide (Scheme 6).
Since the compound (29) was already converted into securinine by Horii and co-workers,7a this synthesis
constitutes its formal synthesis.
O
O
O
O
O
O
O
O
a
b
c
H
H
H
N
Ac
N
N
Ac
N
H
H
Ac
OH
OH
O
H
H
Ac
O
S
26
27
28
29
Scheme 6. a) 1,1'-thiocarbonyldiimidazole, toluene; b) Ni(COD)2, DMF; c) LDA, PhSeCl,
THF, then 30% H2O2, EtOAc-THF, NaHCO3.
As means to confirm the stereochemistry of the minor reduction product (25), it was also converted into
thionocarbonate (30) by employing the same procedure as for the synthesis of 27 (Scheme 7).
O
O
O
O
O
a
O
H
N
H
H
N
Ac
N
H
H
Ac
OH
OH
O
O
S
Allosecirinine
25
30
Scheme 7. a) 1,1'-thiocarbonyldiimidazole, toluene.
Again, X-Ray crystallographic analysis of 30 showed this compound to be a diastereoisomer of 27, which
might be a potential intermediate for the synthesis of allosecurinine (Figure 5).
In summary, we could achieve a formal total synthesis of securinine by using an intramolecular [4+2]
cycloaddition reaction of the enol ester as a key step. Although the conversion of 29 to securinine

proceeded in quite low yield in the literature, the intramolecular cycloaddition reaction of enol ester
developed here would be a useful synthetic strategy for the synthesis of polycyclic natural products having
a lactone ring in their molecules in relatively short steps.
Figure 4. ORTEP drawing for 26.
Figure 5. ORTEP drawing for 30.
EXPERIMENTAL
Melting points were measured with a Yanagimoto MP apparatus and are uncorrected. IR spectra were
obtained using a JASCO FT/IR-200 spectrophotometer. 1H- and 13C-NMR spectra were obtained on JEOL
LAMBDA-270 (1H-NMR: 270 MHz, 13C-NMR: 67.8 MHz) instrument for solutions in CDCl3, and
chemical shifts are reported on the δ scale from internal TMS. MS spectra were measured with a JEOL
JMS-D 300 spectrometer. Elemental analyses were performed on a Yanaco-MT5.
2,4-Hexadienoic Acid Anhydride (Sorbic Anhydride): A solution of sorbic acid (8.4 g, 75 mmol) and
Et3N (10.5 mL, 75 mmol) in CH2Cl2 (500 mL) was stirred for 30 min at 0 °C. To this solution was added
diphenyl phosphorochloride (7.9 mL, 37.5 mmol) at the same temperature, and the resulting mixture was
stirred for further 10 h at rt. After treatment with saturated aq. NH4Cl solution, the mixture was extracted
with CH2Cl2, and the extract was washed with brine and dried (Na2SO4), and concentrated to leave the
residue, which was purified by column chromatography on silica gel. Elution with hexane-EtOAc (20:1)
gave sorbic anhydride (5.7 g, 73%) as a colorless oil; IR: νmax 1780 and 1660 cm-1; 1H-NMR: δ 1.82 (6H,

m, 2×Me), 5.74 (2H, d, J=15.3 Hz, 2×2-CH), 6.27 (4H, m, 2×4-CH and 2×5-CH), 7.30 (2H, m, 2×3-CH).
2-(1’,1’-Ethylenedioxy)ethylpyridine (2): A stirred solution of 2-acetylpyridine ( ) (20 g, 165 mmol) and
1
ethylene glycol (27.6 mL, 495 mmol) in benzene (150 mL) was heated at reflux in the presence of p-TsOH
(6.28 g, 33 mmol) for 10 h. After cooling to rt, the mixture was diluted with EtOAc, and washed with
saturated aq. NaHCO3 solution. The organic layer was dried (Na2SO4) and evaporated to leave the residue,
which was purified by column chromatography on silica gel. Elution with hexane-EtOAc (10:1) gave the
ketal (2) (25 g, 92%) as a colorless oil; bp 85-87 °C/2 mmHg; IR: νmax 1020 cm-1; 1H-NMR: δ 1.74 (3H,
s, Me), 3.85-3.95 and 4.08-4.13 (each 2H, each m, OCH2CH2O), 7.21 (1H, ddd, J=1.2, 4.9 and 7.3 Hz,
5-CH), 7.55 (1H, dt, J=1.2 and 7.9 Hz, 3-CH), 7.69 (1H, ddd, J=1.8, 7.3 and 7.9 Hz, 4-CH), 8.64 (1H, dd,
J=1.8 and 4.9 Hz, 6-CH); HRMS m/z calcd for C9H12NO2 (M++1): 166.0868. Found: 166.0863.
1-Benzyl-2-(1’,1’-ethylenedioxy)ethylpyridine (5): A stirred solution of 2 (25 g, 151.5 mmol) and
benzyl bromide (180 mL, 1.52 mol) in MeCN (250 mL) was heated at 100 °C for 4 days. After
evaporation of the solvent, the residue was dissolved into MeOH (250 mL), and NaBH4 (22.9 g, 606
mmol) was added portionwise to this solution at 0 °C. The resulting mixture was stirred at rt for 4 days,
and then treated with saturated aq. NH4Cl solution. After removal of the solvent, the residue was
extracted with EtOAc, and the extract was washed with brine, and dried (Na2SO4). Evaporation of the
solvent gave the residue, which was again dissolved into EtOAc. The organic layer was treated with 10%
KHSO4 solution, and the aqueous layer was basified with 10% NaOH solution, and extracted with EtOAc.
The extract was dried (Na2SO4) and concentrated to leave the residue, which was purified by column
chromatography on silica gel. Elution with hexane gave the ketal (16.9 g, 51%) as a mixture of olefinic
isomers, which was used in next step without further separation. A solution of the mixture obtained above
in EtOAc was hydrogenated over PtO2 (542 mg) under an atmospheric pressure of hydrogen for 1 h. After
removal of the insoluble material by filtration, the filtrate was concentrated to give the residue, which was
purified by column chromatography on silica gel to provide the piperidine derivative (5) (14.9 g, 87%) as
a colorless oil; bp 137 °C/2 mmHg; IR: νmax 1162 cm-1; 1H-NMR: δ 1.42 (3H, s, Me), 1.33-1.50 (4H, m,
4- and 5-CH2), 1.77-2.05 (3H, m, 3-CH2 and 6-CHH), 2.41 (1H, dd, J=3.1 and 10.4 Hz, 6-CHH), 2.86 (1H,
m, 2-CH), 3.23 and 4.46 (each 1H, each d, J=14.7 Hz, CH2Ph), 3.85-3.98 (4H, m, OCH2CH2O), 7.16-7.36

(5H, m, aromatic protons); HRMS m/z calcd for C16H23NO2 (M+): 261.1729. Found: 261.1729. Anal.
Calcd for C16H23NO2: C, 73.56; H, 8.82; N, 5.37. Found: C, 73.43; H, 8.86; N, 5.36.
2-Acetyl-1-benzylpiperidine (6): A solution of the ketal (5) (13.68 g, 52.4 mmol) in CF3CO2H-H2O (100
mL; 9:1, v/v) was stirred at ambient temperature for 2 days. After evaporation of the solvent, the residue
was treated with 25% NH4OH at 0 °C, and extracted with CHCl3. The extract was washed with brine and
dried (Na2SO4), and concentrated to leave the residue, which was purified by column chromatography on
silica gel. Elution with hexane-EtOAc (20:1) gave 6 (9.73 g, 91%) as a colorless oil; bp 140 °C/2 mmHg;
IR: νmax 1712 cm-1; 1H-NMR: δ 1.21-1.80 (6H, m, 3-, 4- and 5-CH2), 1.91 (1H, ddd, J=3.7, 11.0 and 11.6
Hz, 6-CHH), 2.25 (3H, s, Me), 2.85-2.94 (2H, m, 2-CH and 6-CHH), 3.18 and 3.65 (each 1H, each d,
J=14.0 Hz, CH2Ph), 7.21-7.33 (5H, m, aromatic protons); HRMS m/z calcd for C14H19NO (M+): 217.1467.
Found: 217.1461.
1’-[2”-(N-Benzylpiperidyl)]ethenyl 2,4-Hexadienoate (7): To a stirred solution of LDA [prepared from
diisopropylamine (0.34 mL, 2.4 mmol) and n-BuLi (1.45 mL of 1.65M hexane solution, 2.4 mmol)] in
THF (7.5 mL) was added HMPA (0.43 mL, 2.46 mmol) at –78 °C. To this solution was added a solution
of 6 (300 mg, 1.33 mmol) in THF (5 mL), and the resulting mixture was stirred for further 2 h at the same
temperature. A solution of sorbic anhydride (495 mg, 2.4 mmol) in THF (10 mL) was added slowly to the
solution and the whole mixture was stirred for 1 h at the same temperature. After treatment with saturated
aq. NH4Cl solution, the mixture was extracted with EtOAc. The extract was dried (Na2SO4) and
evaporated to leave the residue, which was purified by column chromatography on silica gel. Elution with
hexane-EtOAc (20:1) gave the enol ester (7) (312 mg, 75%) as a colorless oil; bp 190 °C/2 mmHg; IR:
1
νmax 1732, 1645, 1261, 1125, and 999 cm-1; H-NMR: δ 1.22-1.92 (7H, m, 3”-, 4”-, 5”-CH2 and
6”-CHH), 1.88 (3H, d, J=5.5 Hz, Me), 2.75 (1H, dd, J=3.1 and 10.4 Hz, 2”-CH), 2.87 (1H, m, 6”-CHH),
2.98 and 4.35 (each 1H, each d, J=14.0 Hz, CH2Ph), 4.96 and 5.14 (each 1H, each d, J=1.5 Hz, 2’-CH2),
5.89 (1H, d, J=15.3 Hz, 2-CH), 6.11-6.31 (2H, m, 4- and 5-CH), 7.18-7.39 (6H, m, 3-CH and aromatic
protons); HRMS m/z calcd for C20H25NO2 (M+): 311.185. Found: 311.1885.
1’-[2”-(N-Benzylpiperidyl)]ethenyl 3,5-Hexadienoate (8): To a stirred solution of LiHMDS (1.05 mL of
1.0M hexane solution, 1.05 mmol) and HMPA (0.27 mL, 1.54 mmol) in THF (7.5 mL) was added a

solution of the conjugated enol ester (7) (280 mg, 0.90 mmol) in THF (1.75 mL) at –78 °C, and the
resulting mixture was stirred for further 2 h at the same temperature. The reaction was quenched by
addition of AcOH-H2O (1:2, v/v)(3 mL), and the mixture was extracted with EtOAc. The extract was
washed with brine, dried (Na2SO4), and evaporated to leave the residue, which was purified by column
chromatography on silica gel. Elution with CHCl3 gave the deconjugated enol ester (8) (280 mg, 100%) as
1
a colorless oil; IR: νmax 1768 and 1125 cm-1; H-NMR: δ 1.18-1.90 (7H, m, 3”-, 4”-, 5”-CH2 and
6”-CHH), 2.72 (1H, dd, J=3.1 and 10.4 Hz, 2”-CH), 2.82-2.89 (1H, m, 6”-CHH), 2.94 and 4.31 (each 1H,
each d, J=13.4 Hz, CH2Ph), 3.27 (2H, br d, J=7.0 Hz, 2-CH2), 4.94 and 5.13 (each 1H, each d, J=1.8 Hz,
2’-CH2), 5.09 (1H, d, J=10.4 Hz, 6-CHH), 5.19 (1H, d, J=15.9 Hz, 6-CHH), 5.84 (1H, dt, J=7.0 and 14.7
Hz, 3-CH), 6.17-6.40 (2H, m, 4- and 5-CH), 7.22-7.29 (5H, m, aromatic protons).
1’-(2”-Pyridyl)ethenyl 2,4-Hexadienoate (13): The enol ester was prepared from 2-acetylpyridine (1)
(1.1 mL, 10 mmol), sorbic anhydride (3.7 g, 18 mmol), and LDA (18 mmol) by using the same procedure
as for the preparation of 7 to give the product (13) (1.01 g, 47%) as a pale yellowish oil; IR: νmax 1725
1
and 1705 cm-1; H-NMR: δ 1.90 (3H, d, J=5.5 Hz, 6-Me), 5.25 (1H, d, J=1.8 Hz, 2’-CHH), 6.00 (1H, d,
J=15.3 Hz, 2-CH), 6.11 (1H, d, J=1.8 Hz, 2’-CHH), 6.18-6.34 (2H, m, 4- and 5-CH), 7.20 (1H, m, 5”-CH),
7.37-7.48 (2H, m, 3-CH and 3”-CH), 7.66 (1H, dt, J=1.8 and 7.9 Hz, 4”-CH), 8.59 (1H, dd, J=1.8 and 4.9
Hz, 6”-CH); HRMS m/z calcd for C13H13NO2 (M+): 215.0933. Found: 215.0939.
1’-(2”-Pyridyl)ethenyl 3,5-Hexadienoate (14): Deconjugation of 13 (1.72 g, 8 mmol) was carried out by
using the same procedure as for the preparation of 8 to give the ester (14) (1.4 g, 81%) as a pale yellowish
1
oil; IR: νmax 1770 and 1745 cm-1; H-NMR: δ 3.40 (2H, d, J=7.3 Hz, 2-CH2), 5.11 (1H, ddd, J=0.8, 1.8
and 9.9 Hz, 6-CHH), 5.22 (1H, dt, J=0.8 and 16.2 Hz, 6-CHH), 5.24 (1H, d, J=1.8 Hz, 2’-CHH), 5.90 (1H,
dt, J=7.3 and 14.7 Hz, 3-CH), 6.04 (1H, d, J=1.8 Hz, 2’-CHH), 6.21-6.46 (2H, m, 4- and 5-CH), 7.20 (1H,
ddd, J=1.2, 4.8 and 7.6 Hz, 5”-CH), 7.38 (1H, ddd, J=1.0, 1.2 and 7.9 Hz, 3”-CH), 7.66 (1H, ddd, J=1.8,
7.6 and 7.9 Hz, 4”-CH), 8.57 (1H, ddd, J=1.0, 1.8 and 4.8 Hz, 6”-CH); HRMS m/z calcd for C13H13NO2
(M+): 215.0930. Found: 215.0937.
7-Oxa-6-(2’-pyridyl)bicyclo[4.3.0]non-2-en-8-ones (15 and 16): A solution of the enol ester (14) (860
mg, 4 mmol) in toluene (50 mL) in a sealed tube was heated at 180 °C for 12 h. After evaporation of the

solvent, the residue was subjected to column chromatography on silica gel. Elution with hexane-EtOAc
(10:1) gave the cis isomer (15) (593 mg, 69%) as colorless prisms; mp 66-67.5 °C
(EtOAc-Et2O-hexane=1:2:4); IR: νmax 1770 cm-1; 1H-NMR: δ 2.07-2.41 (5H, m, 4-, 5-CH2 and 9-CHH),
2.57 (1H, dd, J=8.4 and 17.3 Hz, 9-CHH), 3.69 (1H, m, 1-CH), 5.61 (1H, m, 3-CH), 5.94 (1H, m, 2-CH),
7.24 (1H, ddd, J=1.2, 4.8 and 7.9 Hz, 5’-CH), 7.59 (1H, dt, J=1.8 and 7.9 Hz, 3’-CH), 7.74 (1H, dt, J=1.8
and 7.9 Hz, 4’-CH), 8.60 (1H, ddd, J=1.0, 1.8 and 4.8 Hz, 6’-CH); HRMS m/z calcd for C13H13NO2 (M+):
215.0931. Found: 215.0938. Anal. Calcd for C13H13NO2: C, 72.54; H, 6.09; N, 6.51. Found: C, 72.37; H,
6.11; N, 6.45.
Further elution with the same solvent gave the trans isomer (16) (59 mg, 8%) as a colorless oil; IR: νmax
1
1770 cm-1; H-NMR: δ 2.07-2.62 (6H, m, 4-, 5- and 9-CH2), 3.40 (1H, m, 1-CH), 5.46 (1H, m, 2-CH),
6.02 (1H, m, 3-CH), 7.22 (1H, m, 5’-CH), 7.49 (1H, d, J=7.9 Hz, 3’-CH), 7.69 (1H, dt, J=1.8 and 7.9 Hz,
4’-CH), 8.52 (1H, dd, J=1.8 and 4.9 Hz, 6’-CH).
7-Oxa-9-phenylselenenyl-6-(2’-pyridyl)bicyclo[4.3.0]non-2-en-8-one (17): To a stirred solution of LDA
[prepared from diisopropylamine (1.4 mL, 10 mmol) and 1.62 M hexane solution of n-butyllithium (6.2
mL, 10 mmol)] in THF (20 mL) in the presence of HMPA (1 mL) was added a solution of the lactone (15)
(860 mg, 4 mmol) in THF (10 mL) at –78 °C, and the resulting solution was stirred for further 1 h at the
same temperature. To this mixture was added a solution of phenylselenenyl chloride (1.5 g, 8 mmol) in
THF (15 mL) at –78 °C and the whole mixture was stirred for further 1 h. After treatment with brine, the
mixture was extracted with EtOAc, and the extract was washed with brine, dried (Na2SO4), and
evaporated to leave the residue, which was purified by column chromatography on silica gel. Elution with
hexane-EtOAc (10:1) gave the selenide (17) (1.26 g, 85%) as white solid; mp 143-144 °C; IR: νmax 1765
1
cm-1; H-NMR: δ 2.03-2.53 (5H, m, 4-, 5-CH2 and 9-CH), 3.61-3.93 (1H, m, 1-CH), 5.60-5.79 (1H, m,
2-CH), 5.94-6.06 (1H, m, 3-CH), 7.09-7.81 (8H, m, aromatic protons), 8.36-8.61 (1H, m, 6’-CH); Anal.
Calcd for C19H17NO2Se: C, 61.63; H, 4.63; N, 3.78. Found: C, 61.67; H, 4.70; N, 3.77.
7-Oxa-6-(2’-pyridyl)bicyclo[4.3.0]nona-2,9-dien-8-one (18): To a stirred solution of the selenide (17)
(370 mg, 1 mmol) in EtOAc-THF (1:1, 10 mL) in the presence of NaHCO3 (840 mg, 10 mmol) was added
30% H2O2 (5.7 mL, 50 mmol) at 0 °C, and the mixture was stirred for further 30 min at the same

temperature. After treatment with saturated aq. Na2S2O3 solution, the mixture was extracted with ether and
the ethereal layer was washed with brine, dried (Na2SO4), and evaporated to leave the residue, which was
purified by column chromatography on silica gel. Elution with hexane-EtOAc (5:1) gave the olefin (18)
(202 mg, 95%) as white needles; mp 110-110.5 °C (hexane-EtOAc); IR: νmax 1740 and 1640 cm-1;
1H-NMR: δ 2.15-2.25 (2H, m, 4-HH and 5-CHH), 2.44 (1H, m, 4-CHH), 5.61 (1H, m, 5-CHH), 5.89 (1H,
s, 9-CH), 6.21 (1H, m, 2-CH), 6.66 (1H, m, 3-CH), 7.31 (2H, m, 3’- and 5’-CH), 7.69 (1H, m, 4’-CH),
8.58 (1H, m, 6’-CH); HRMS m/z calcd for C13H11NO2 (M+): 213.0792. Found: 213.0791. Anal. Calcd for
C13H11NO2: C, 73.22; H, 5.20; N, 6.57. Found: C, 73.33; H, 5.36; N, 6.49.
2,3-Dihydroxy-7-oxa-6-(2’-pyridyl)bicyclo[4.3.0]nonan-8-one (19): To a stirred solution of 15 (540 mg,
2.51 mmol) in tert-BuOH-H2O (1:2, 15 mL) were added NMO (883 mg, 7.53 mmol) and a solution of
OsO4 in tert-BuOH (5 mg/mL; 3.8 mL, 0.75 mmol) at ambient temperature, and the resulting solution was
stirred for further 6 h. To this solution was added NaHSO3 (1.31 g, 12.6 mmol) and the mixture was stirred
for 30 min. After treatment with brine, the mixture was extracted with EtOAc, and the extract was washed
with brine, dried (Na2SO4), and evaporated to leave the residue, which was purified by column
chromatography on silica gel. Elution with EtOAc gave the diol (19) (625 mg, 100%) as a colorless oil;
1
IR: νmax 3440 and 1778 cm-1; H-NMR: δ 1.57 (1H, m, 5-CHH), 1.73 (1H, m, 5-CHH), 2.01 (1H, m,
4-CHH), 2.14 (1H, m, 4-CHH), 2.68 (1H, dd, J=12.2 and 17.6 Hz, 9-CHH), 2.78 (1H, dd, J=9.1 and 17.6
Hz, 9-CHH), 2.84 (1H, d, J=9.9 Hz, OH), 3.20 (1H, m, 1-CH), 3.87 (1H, m, 3-CH), 3.98 (1H, m, 2-CH),
7.15 (1H, d, J=9.4 Hz, OH), 7.36 (1H, ddd, J=1.2, 5.0 and 7.6 Hz, 5’-CH), 7.69 (1H, ddd, J=1.0, 1.2 and
7.9 Hz, 3’-CH), 7.86 (1H, ddd, J=1.6, 7.6 and 7.9 Hz, 4’-CH), 8.54 (1H, ddd, J=1.0, 1.6 and 5.0 Hz,
6’-CH); 13C-NMR: δ 24.7, 31.6, 33.1, 43.4, 67.4, 70.1, 88.0, 120.1, 122.9, 137.7, 147.5, 160.5, 175.8;
HRMS m/z calcd for C13H15NO4 (M+): 249.1001. Found: 249.0975.
2,3-Isopropylidenedioxy-7-oxa-6-(2’-pyridyl)bicyclo[4.3.0]nonan-8-one (20): A solution of the diol
(19) (109 mg, 0.44 mmol) and 2,2-dimethoxypropane (0.08 mL, 0.66 mmol) in DMF (1.5 mL) in the
presence of CSA (0.51 mg, 0.22 mmol) was stirred at rt for 12 h. The reaction was quenched by addition
of saturated aq. NaHCO3 solution and the mixture was extracted with EtOAc. The extract was washed
with brine, dried (Na2SO4), and evaporated to leave the residue, which was purified by column

chromatography on silica gel. Elution with hexane-EtOAc (3:1) gave the acetonide (20) (122 mg, 96%) as
1
colorless prisms; mp 95-95.5 °C (CHCl3-hexane); IR: νmax 1778 cm-1; H-NMR: δ 1.38 and 1.53 (each
3H, each s, Me), 1.88-2.02 (3H, m, 4-CHH and 5-CH2), 2.05-2.33 (1H, m, 4-CHH), 2.46 (1H, dd, J=4.0
and 18.1 Hz, 9-CHH), 2.73 (1H, dd, J=9.6 and 18.1 Hz, 9-CHH), 3.47 (1H, ddd, J=4.0, 5.9 and 9.6 Hz,
1-CH), 4.21 (1H, dd, J=5.9 and 6.3 Hz, 2-CH), 4.49 (1H, m, 3-CH), 7.23 (1H, ddd, J=1.0, 4.6 and 7.3 Hz,
5’-CH), 7.52 (1H, dd, J=1.0 and 7.6 Hz, 3’-CH), 7.72 (1H, ddd, J=1.6, 7.3 and 7.6 Hz, 4’-CH), 8.61 (1H,
dd, J=1.6 and 4.6 Hz, 6’-CH); 13C-NMR: δ 22.9, 24.5, 26.8, 28.7, 33.3, 39.7, 71.5, 75.5, 88.0, 108.3, 119.2,
122.5, 136.6, 149.0, 161.5, 175.4; HRMS m/z calcd for C16H19NO4 (M+): 289.1314. Found: 289.1336.
Anal. Calcd for C16H19NO4: C, 66.42; H, 6.62; N, 4.84. Found: C, 66.15; H, 6.48; N, 4.74.
2,3-Isopropylidenedioxy-7-oxa-6-(2’-piperidyl)bicyclo[4.3.0]nonan-8-ones (21 and 22): A suspension
of 20 (476 mg, 1.65 mmol) and PtO2 (10 mg) in AcOH (5 mL) was stirred at rt for 2 h under an
atmospheric pressure of hydrogen. After filtration of the catalyst, the filtrate was concentrated to leave the
residue, which was basified with saturated aq. NaHCO3 solution, and extracted with EtOAc. The extract
was washed with brine, dried (Na2SO4), and evaporated to leave the residue, which was purified by
column chromatography on silica gel. Elution with CHCl3-MeOH (19:1) gave the inseparable piperidine
1
derivatives (21 and 22) (474 mg, 98%) as colorless oil; IR: νmax 1770 and 1260 cm-1; H-NMR: δ
1.22-1.87 (10H, m, 4-, 5-, 3’-, 4’-CH2, 5’-CHH and NH), 1.32 and 1.47 (each 3H, each s, Me), 2.06 (1H,
m, 5’-CHH), 2.23 (1H, dd, J=8.1 and 18.7 Hz, 9-CHH), 2.62 (2H, m, 6’-CH2), 2.89 (1H, dd, J=12.3 and
18.7 Hz, 9-CHH), 3.08 (1H, m, 2’-CH), 3.15 (1H, ddd, J=2.1, 8.1 and 12.3 Hz, 1-CH), 4.32 (1H, dd, J=2.1
13
and 7.3 Hz, 2-CH), 4.43 (1H, m, 3-CH); C-NMR: δ 23.0, 23.3, 23.7, 24.4, 25.7, 25.9, 33.7, 33.8, 47.8,
63.2, 70.8, 73.7, 90.3, 107.4, 175.0; HRMS m/z calcd for C16H25NO4 (M+): 295.1783. Found: 295.1791.
2,3-Isopropylidenedioxy-7-oxa-6-[2’-(N-acetyl)piperidyl]bicyclo[4.3.0]nonan-8-ones (23 and 24): A
solution of the amines (21 and 22) (440 mg, 1.49 mmol), 4-dimethylaminopyridine (18 mg) and Ac2O (6
mL) in pyridine (3 mL) was stirred at ambient temperature for 1 h. After treatment with brine, the mixture
was extracted with EtOAc, and the extract was washed with brine, dried (Na2SO4), and evaporated to
leave the residue, which was purified by column chromatography on silica gel. Elution with
CHCl3-MeOH (19:1) gave the acetate (23 and 24) (467 mg, 93%) as colorless needles; mp 152-152.5 °C

1
(CHCl3-hexane); IR: νmax 1770 and 1634 cm-1; H-NMR: δ 1.26-2.28 (10.4H, m, 4-, 5-, 3’-, 4’- and
5’-CH2 for the mixture, and 9-CHH for 23), 1.32 and 1.59 (3H, s, Me for the mixture), 2.14 (1.8H, s, Ac
for 24), 2.18 (1.2H, s, Ac for 23), 2.25 (0.6H, dd, J=9.2 and 18.5 Hz, 9-CHH for 24), 2.69 (0.4H, dd,
J=11.9 and 18.5 Hz, 9-CHH for 23), 2.80 (0.6H, dd, J=11.9 and 18.7 Hz, 9-CHH for 24), 2.95 (0.6H, m,
1-CH for 24), 3.16 (0.4H, m, 1-CH for 23), 3.34-3.49 (1H, m, 6’-CHH for the mixture), 3.62-3.73 (1H, m,
6’-CHH for the mixture), 4.37-4.70 (2H, m, 2- and 3-CH for the mixture), 4.79 (0.4H, dd, J=5.6 and 5.9
Hz, 2’-CH for 23), 4.86 (0.6H, m, 2’-CH for 24); 13C-NMR: δ 20.4, 21.8, 22.8, 23.2, 24.0, 24.7, 25.4, 25.9,
32.1, 36.8, 43.4, 54.5, 70.6, 73.7, 91.0, 108.3, 169.8, 174.7; HRMS m/z calcd for C17H24NO5 (M+-15):
322.1653. Found: 322.1655.
2,3-Dihydroxy-7-oxa-6-[2’-(N-acetyl)piperidyl]bicyclo[4.3.0]nonan-8-ones (25 and 26): To a stirred
solution of the acetates (23 and 24) (123 mg, 0.42 mmol) in THF (3 mL) was added 1N HCl (1 mL) at rt
and the resulting solution was stirred for further 2 days at the same temperature. The solution was basified
with saturated aq. NaHCO3 solution, and extracted with CHCl3. The extract was washed with brine, dried
(Na2SO4), and evaporated to leave the residue, which was purified by column chromatography on silica
gel. Elution with CHCl3-MeOH (19:1) gave the diol (26) (59.4 mg, 55%) as colorless prisms; mp 190 °C
(CHCl3-EtOAc); IR: νmax 3404, 1772 and 1618 cm-1; 1H-NMR: δ 1.41-2.21 (10H, m, 4-, 5-, 3’-, 4’- and
5’-CH2), 2.16 (3H, s, Ac), 2.47 (1H, dd, J=2.2 and 17.6 Hz, 9-CHH), 2.68 (1H, dd, J=8.9 and 17.6 Hz,
9-CHH), 2.93 (1H, m, 1-CH), 3.34-3.47 (3H, m, 6’-CH2 and OH), 3.61 (1H, m, 2-CH), 3.87 (1H, m,
3-CH), 3.99 (1H, d, J=2.5 Hz, OH), 5.25 (1H, dd, J=2.5 and 4.2 Hz, 2’-CH); 13C-NMR: δ 19.8, 21.8, 23.1,
24.4, 24.9, 29.0, 31.6, 42.6, 43.3, 51.2, 67.7, 70.0, 89.9, 171.0, 175.0; HRMS m/z calcd for C15H23NO5
(M+): 297.1576. Found: 297.1585. Anal. Calcd for C15H23NO5: C, 60.59; H, 7.80; N, 4.71. Found: C,
60.59; H, 7.61; N, 4.83.
Further elution with the same solvent system gave the diol (25) (39.2 mg, 36%) as colorless prisms; mp
1
178-181 °C (CHCl3-EtOAc); IR: νmax 3380, 1772, 1615, 1429, 1426, 1252, and 1196 cm-1; H-NMR: δ
1.23-2.05 (9H, m, 5-, 3’-, 4’-, 5’-CH2 and 4-CHH), 2.21 (3H, s, Ac), 2.26 (1H, m, 4-CHH), 2.49 (1H, dd,
J=12.4 and 17.3 Hz, 9-CHH), 2.61 (1H, dd, J=8.4 and 17.3 Hz, 9-CHH), 2.72 (1H, m, 1-CH), 3.07 (1H, d,
J=9.7 Hz, OH), 3.47 (1H, ddd, J=7.1, 10.2 and 14.5 Hz, 6’-CHH), 3.63 (1H, m, 6’-CHH), 3.78 (1H, m,

3-CH), 3.92 (1H, m, 2-CH), 4.81 (1H, dd, J=6.3 and 6.9 Hz, 2’-CH), 5.49 (1H, d, J=3.1 Hz, OH);
13C-NMR: δ 18.4, 22.0, 23.3, 23.4, 24.5, 29.0, 32.1, 42.2, 43.2, 53.4, 68.0, 68.8, 88.8, 173.0, 174.1. Anal.
Calcd for C15H23NO5: C, 60.59; H, 7.80; N, 4.71. Found: C, 60.56; H, 7.86; N, 4.65.
Crystal Data of 26: C15H23NO5, M=297.35, monoclinic, space group P 21/n, a=7.406(2), b=20.818(2),
c=9.688(2) Å, β=107.94(1)°, V=1431.21(1) Å3, Z=4, Dc=1.390 g cm-3; 2111 reflections with
4.24<2θ<120.02° were recorded on a four-circle diffractometer using graphite-monochromated Cu-Kα
radiation. Of those, 1911 with I>3σ(I) were judged as observed. The structure was solved using
MALTAN88. R=0.0385, Rw=0.0328.
6-[2’-(N-Acetyl)piperidyl]-7-oxa-2,3-thionocarbonyldioxybicyclo[4.3.0]nonan-8-one (27): A stirred
solution of the diol (26) (443 mg, 1.49 mmol) and 1,1’-thiocarbonyldiimidazole (161 mg, 1.49 mmol) in
toluene (2 mL) was heated at 110 °C for 24 h. The solution was treated with water and extracted with
CHCl3. The extract was washed with brine, dried (Na2SO4), and evaporated to leave the residue, which
was purified by column chromatography on silica gel. Elution with CHCl3-MeOH (19:1) gave the
thionocarbonate (27) (448 mg, 89%) as colorless prisms; mp 218-218.5 °C (CHCl3); IR: νmax 1772, 1630,
1
1288, 1271 and 1196 cm-1; H-NMR: δ 1.51-2.17 (10H, m, 4-, 5-, 3’-, 4’- and 5’-CH2), 2.17 (3H, s, Ac),
2.27 (1H, dd, J=8.6 and 19.0 Hz, 9-CHH), 2.98 (1H, dd, J=12.1 and 19.0 Hz, 9-CHH) 3.28-3.42 (2H, m,
1-CH and 6’-CHH), 3.70 (1H, m, 6’-CHH), 4.82 (1H, m, 2’-CH), 5.12 (1H, dd, J=2.5 and 8.3 Hz, 2-CH),
5.24 (1H, m, 3-CH); 13C-NMR: δ 20.2, 22.1, 22.2, 22.7, 24.4, 24.9, 31.7, 35.6, 43.4, 54.4, 77.7, 79.4, 89.1,
170.9, 173.1, 190.2; HRMS m/z calcd for C16H21NO5S (M+): 339.1140. Found: 339.1167.
6-[2’-(N-Acetyl)piperidyl]-7-oxabicyclo[4.3.0]non-2-en-8-one (28):
A
stirred solution of the
thionocarbonate (27) (20 mg, 0.06 mmol) and Ni(COD)2 (34 mg, 0.12 mmol) in DMF (1 mL) was heated
at 60 °C for 3 h under argon. After the insoluble material was filtered off by filtration through the pad of
Celite, the filtrate was concentrated to give a residue, which was purified by column chromatography on
silica gel. Elution with CHCl3-MeOH (49:1) gave the olefin (28) (14 mg, 90%) as colorless needles; mp
138 °C (hexane-EtOAc); IR: νmax 1778, 1635, 1425 and 1205 cm-1; 1H-NMR: δ 1.44-2.25 (10H, m, 4-, 5-,
3’-, 4’- and 5’-CH2), 2.25 (3H, s, Ac), 2.27 (1H, dd, J=8.1 and 17.6 Hz, 9-CHH), 2.71 (1H, dd, J=9.4 and
17.6 Hz, 9-CHH), 2.96 (1H, m, 1-CH), 3.42 (1H, ddd, J=4.9, 12.1 and 14.3 Hz, 6’-CHH), 3.62 (1H, m,

6’-CHH), 4.80 (1H, dd, J=6.1 and 6.3 Hz, 2’-CH), 5.60 (1H, m, 3-CH), 5.84 (1H, m, 2-CH); 13C-NMR: δ
20.2, 21.7, 21.9, 23.4, 25.4, 28.1, 36.1, 37.6, 43.4, 50.8, 89.9, 125.4, 128.3, 175.9, 179.5; HRMS m/z calcd
for C15H21NO3 (M+): 263.1521. Found: 263.1513. Anal. Calcd for C15H21NO3• 1/4H2O: C, 67.27; H, 8.09;
N, 5.23. Found: C, 67.33; H, 8.08; N, 5.27.
6-[2’-(N-Acetyl)piperidyl]-7-oxabicyclo[4.3.0]nona-2,9-dien-8-one (29): To a stirred solution of
LiHMDS [prepared from hexamethyldisilazane (0.35 mL, 1.65 mmol) and n-BuLi (1.6M solution in
hexane, 0.99 mL, 1.59 mmol)] in THF (3.3 mL) were added HMPA (0.14 mL, 0.79 mmol) and a solution
of the lactone (28) (174 mg, 0.66 mmol) in THF (1 mL) at –78 °C, and the resulting solution was stirred at
the same temperature for further 1 h. To this mixture was added a solution of PhSeCl (253 mg, 1.32
mmol) in THF (1 mL) and the whole mixture was stirred at –78 °C for 1 h. The mixture was treated with
brine and extracted with EtOAc. The extract was dried (Na2SO4), and evaporated to leave the crude
selenide, which, without further purification, was used to the next step.
To a stirred solution of the selenide in CH2Cl2 (2.4 mL) were added pyridine (0.11 mL, 1.38 mmmol) and
30% H2O2 (0.09 mL, 0.76 mmol) at 0 °C, and the resulting mixture was stirred at the same temperature for
further 30 min. The mixture was treated with 10% sodium thiosulfate solution, and extracted with ether.
The ethereal solution was dried (Na2SO4), and evaporated to leave the residue, which was purified by
column chromatography on silica gel. Elution with hexane-EtOAc (1:1) gave the unsaturated lactone (29)
(69.1 mg, 40% from 27) as colorless prisms; mp 162-163 °C (EtOAc-hexane); IR: νmax 1747, 1637, 1423,
1
1272 and 1209 cm-1; H-NMR: δ 1.41-1.85 (7H, m, 3’-, 4’-, 5’-CH2 and 5-CHH), 2.20 (3H, s, Ac),
2.26-2.38 (2H, m, 4-CHH and 5-CHH), 2.95 (1H, m, 4-CHH), 3.63-3.77 (2H, m, 6’-CH2), 5.01 (1H, dd,
J=3.6 and 5.4 Hz, 2’-CH), 5.76 (1H, s, 9-CH), 6.32 (1H, m, 3-CH), 6.49 (1H, ddd, J= 0.5, 2.5 and 11.9 Hz,
2-CH); 13C-NMR: δ 20.2, 22.1, 23.2, 25.1, 25.5, 30.9, 43.4, 90.0, 110.0, 119.2, 141.0, 166.9, 171.0, 172.8;
HRMS m/z calcd for C15H20NO3 (M++1): 262.1443. Found: 262.1465. Anal. Calcd for C15H19NO3: C,
68.94; H, 7.33; N, 5.36. Found: C, 68.79; H, 7.54; N, 5.23.
Thionocarbonate (30): The thionocarbonate was synthesized from 25 (560 mg, 1.89 mmol) by the same
procedure as for the preparation of 27 to give 30 (494 mg, 77%); mp 235-236 °C (CH2Cl2-acetone); IR:

1
νmax 1772, 1734, 1636, 1456, 1261 and 1196 cm-1; H-NMR: δ 1.44-2.17 (10H, m, 4-, 5-, 3’-, 4’- and
5’-CH2), 2.17 (3H, s, Ac), 2.18 (1H, dd, J=12.0 and 19.0 Hz, 9-CHH), 2.97 (1H, dd, J=12.2 and 19.0 Hz,
9-CHH), 3.38 (1H, ddd, J=5.1, 11.9 and 14.3 Hz, 6’-CHH), 3.53 (1H, ddd, J=2.7, 12.0 and 12.2 Hz,
1-CH), 3.64 (1H, ddd, J=0.2, 4.9 and 14.3 Hz, 6’-CHH), 4.70 (1H, t, J=6.1 Hz, 2’-CH), 5.20 (1H, m,
3-CH), 5.29 (1H, dd, J=2.7 and 8.3 Hz, 2-CH); 13C-NMR: δ 18.7, 21.5, 22.1, 22.8, 24.0, 25.0, 30.8, 33.3,
42.6, 54.7, 78.2, 80.3, 88.5, 171.5, 174.1, 191.2; HRMS m/z calcd for C16H21NO5S (M+): 339.1140.
Found: 339.1158. Anal. Calcd for C16H21NO5S: C, 56.52; H, 6.24; N, 4.13. Found: C, 56.56; H, 6.34; N,
4.05.
Crystal Data of 30: C16H20NO5S, M=338.40, monoclinic, space group P 21/a, a=11.878(2), b=11.178(2),
c=12.950(1) Å, β=113.21(7)°, V=1580.4(3) Å3, Z=4, Dc=1.422 g cm-3; 2360 reflections with
4.24<2θ<120.02° were recorded on a four-circle diffractometer using graphite-monochromated Cu-Kα
radiation. Of those, 1571 with I>3σ(I) were judged as observed. The structure was solved using
MALTAN88. R=0.0889, Rw=0.1333.
ACKNOWLEDGMENT
This work was supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and
Technology of Japan, and also by The Takeda Science Foundation.
REFERENCES AND NOTE
This paper is dedicated to Professor Yuichi Kanaoka on occasion of his 75th birthday.
†
1. V. Snieckus, “The Alkaloids”, Vol. 14, ed. by R. H. F. Manske, Academic Press, New York, 1973, pp.
425-503 and references cited therein.
2. V. I. Murav’eva and A. I. Ban’kovskii, Dokl. Akad. Nauk SSSR, 1956, 110, 998.
3. S. Saito, K. Kotera, N. Shigematsu, A. Ide, N. Sugimoto, Z. Horii, M. Hanaoka, Y. Yamawaki, and Y.
Tamura, Tetrahedron, 1963, 19, 2085; Z. Horii, M. Ikeda, N. Sugimoto, Y. Tamura, S. Saito, and K.
Kotera, Tetrahedron, 1963, 19, 2101; I. Sakoda, M. Maruyama, J. Tsuji, and E. Yoshii, Tetrahedron
Lett., 1962, 1199; J. Parello, A. Melera, and R. Goutarel, Bull. Soc. Chim. Fr., 1963, 898; S. –F. Chen,

C. –H. Hsieh, and H. –T. Liang, Scientia Sinica, 1963, 12, 1525.
4. T. Nakano, T. H. Yang, and S. Terao, Tetrahedron, 1963, 19, 609; T. Nakano, T. H. Yang, and S. Terao,
J. Org. Chem., 1963, 28, 2619.
5. S. Imado, M. Shiro, and Z. Horii, Chem. Pharm. Bull., 1965, 13, 643.
6. J. A. Beutler, E. W. Karbon, A. N. Brubaker, R. Malik, D. R. Curtis, and S. J. Enna, Brain Res., 1985,
330, 135.
7. (a) Z. Horii, M. Hanaoka, Y. Yamawaki, Y. Tamura, S. Saito, N. Shigematsu, K. Kotera, H. Yoshikawa,
Y. Sato, H. Nakai, and N. Sugimoto, Tetrahedron, 1967, 23, 1165; (b) S. Liras, J. E.Davoren, and J.
Bordner, Org. Lett., 2001, 3, 703.
8. Some examples of intramolecular Diels-Alder reactions of enol esters in natural product synthesis: S.
J. Baily and E. J. Thomas, J. Chem. Soc., Chem. Commun., 1978, 474; K. Takeda, M. Sato, and E.
Yoshii, Tetrahedron Lett., 1986, 27, 3903.
9. A part of this work was published as a preliminary communication: T. Honda, H. Namiki, M. Kudoh,
N. Watanabe, H. Nagase, and H. Mizutani, Tetrahedron Lett., 2000, 41, 5927. The references for total
synthesis or synthetic approaches of Securinega alkaloids are cited therein.
10. R. V. Stevens, R. E. Cherpeck, B. L. Harrison, J. Lai, and R. Lapalme, J. Am. Chem. Soc., 1976, 98,
6317.
11. S. Aoyagi, T. C. Wang, and C. Kibayashi, J. Am. Chem. Soc., 1993, 115, 11393.
12. M. F. Semmelhack and R. D. Stauffer, Tetrahedron Lett., 1973, 2667.