Synthesis of peduncularine

Article abstract of DOI:10.1246/bcsj.79.1552

Peduncularine, the principal alkaloid of the Tasmanian shrub Aristotelia peduncularis, was synthesized via the radical cyclization of 7-oxabicyclo[2.2.1]hept-2-en-5-yl ketone oxime 9 forming the 6-azabicyclo[3.2.1]octane skeleton.

Full text of DOI:10.1246/bcsj.79.1552

1552 Bull. Chem. Soc. Jpn. Vol. 79, No. 10, 1552–1560 (2006)
ꢀ 2006 The Chemical Society of Japan
Synthesis of Peduncularine
ꢀ1
Mitsuru Kitamura, Yuichiro Ihara,2 Kazuyoshi Uera,2 and Koichi Narasaka2
1Department of Applied Chemistry, Faculty of Engineering, Kyushu Institute of Technology,
1-1 Sensui-cho, Tobata-ku, Kitakyushu 804-8550
2Department of Chemistry, Graduate School of Science, The University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033
Received March 20, 2006; E-mail: kita@che.kyutech.ac.jp
Peduncularine, the principal alkaloid of the Tasmanian shrub Aristotelia peduncularis, was synthesized via the rad-
ical cyclization of 7-oxabicyclo[2.2.1]hept-2-en-5-yl ketone oxime 9 forming the 6-azabicyclo[3.2.1]octane skeleton.
Peduncularine (1) (Fig. 1) was isolated from the Tasmanian
R1O
conditions
R1O
shrub Aristotelia peduncularis in 1971 by Bick and co-work-
ers,1 and the structure was determined in 1979.2 Peduncularine
consists of an unusual 6-azabicyclo[3.2.1]octene core with 3-
indolylmethyl group and is reported to show cytotoxic activity
towards breast cancer cell lines.3 The unique structure and the
biological feature make this compound an attractive synthetic
target.4 In 1989, Speckamp et al. reported the first synthesis of
peduncularine (1), showing the synthetic problems of peduncu-
larine: 1) construction of 6-azabicyclo[3.2.1]octene skeleton,
and 2) stereoselective introduction of the exo indolylmethyl
side chain at C(7).4a Weinreb et al. reported a formal total syn-
thesis of peduncularine based on the amidyl radical cycliza-
tion.4c Recently, Woerpel and Roberson reported an efficient
synthesis by [3 þ 2] annulation of cyclohexenylsilanes and
chlorosulfonyl isocyanate as a key step to construct the bicy-
clic skeleton, and the successive stereoselective installation
of the indolylmethyl group at C(7).4d
Previously, we reported that ꢀ,ꢁ-unsaturated oxime de-
rivatives are transformed to a variety of 3,4-dihydro-2H-pyr-
rols having 2-bromo-, phenylthio-, and phenylseleno-methyl
groups via radical cyclization induced by one-electron reduc-
tion.5 In addition, this radical cyclization was improved to a
catalytic process by using copper(I) bromide as a redox cata-
lyst (Scheme 1).6 Herein, we report the synthesis of peduncu-
larine (1) via radical cyclization of oximes as a key step in
constructing 6-azabicyclo[3.2.1]octene framework.
a or b
N
N
R2
R2
2a : R1 = 2,4-dinitrophenyl
2b : R1 = C6F5CO, CH3OCO
3
X
N
4a : X = SePh
4b : X = Br
R2
a for 2a: NaH, 3,4-methylenedioxyphenol, (PhSe)2, 1,4-dioxane
b for 2b: cat. CuBr·SMe2, LiBr, 1,4-dioxane
Scheme 1. Radical cyclization of oximes by one-electron
reduction.
of oximes in the construction of 6-azabicyclo[3.2.1]octane
framework. That is, 6-azabicyclo[3.2.1]octene C is synthe-
sized via radical cyclization of oxime A, which has a 7-oxabi-
cyclo[2.2.1]heptene moiety, followed by reductive ring open-
ing of the resulting tricyclic imine B.7 The stereochemistry
at C(7) is expected to be arranged when the imine moiety of
azabicyclooctene C is reduced.4a
The synthesis of peduncularine (1) was initiated by prepar-
ing ꢀ,ꢁ-unsaturated oxime 9 from the known ester 5
(Scheme 3).8 Ester 5 was reduced to a primary alcohol 6,9
which was then oxidized under Swern oxidation conditions10
to the corresponding aldehyde. Because the aldehyde easily
underwent a retro-Diels–Alder reaction, the crude aldehyde
was alkylated with 2-(1,3-dioxan-2-yl)ethylmagnesium bro-
Results and Discussion
As shown in Scheme 2, our synthetic plan of peduncularine
(1) was inspired by an interest to apply the radical cyclization
O
O
OH
X
e−, X•
8
2e−
N
N
4
N
R'
N
R'
R'
A
B
C
3
OR
7
N
H
O
R' =
O
peduncularine (1)
peduncularine (1)
Fig. 1. Structure of peduncularine (1).
Scheme 2. Synthetic strategy for peduncularine (1).
Published on the web October 10, 2006; doi:10.1246/bcsj.79.1552

M. Kitamura et al.
Bull. Chem. Soc. Jpn. Vol. 79, No. 10 (2006) 1553
1) (COCl)2, DMSO
Et3N, CH2Cl2
O
O
LiAlH4,
Et2O, rt
97%
−60 °C
O
2)
CH2CH2MgBr
CO2Me
CH2OH
O
5
6
THF, −78 °C
2 steps 64%
O
O
1) (COCl)2, DMSO, Et3N,
CH2Cl2, −60 °C
2) NH2OH·HCl, pyridine,
O
O
HO
RO
N
EtOH, rt
O
O
2 steps 72%
8: R = H
7
9a: R = 2,4-dinitrophenyl
9b: R = CH3OCO
a
9c: R = C6F5CO
←
a) 8 9a: 2,4-dinitrofluorobenzene, NaH, DMF, −20 °C (80%);
←
8
8
9b: MeOCOCl, Et3N, DMAP, CH2Cl2, 0 °C (93%);
←
9c: C6F5COCl, Et3N, CH2Cl2, 0 °C (95%).
Scheme 3. Preparation of oximes 9a–9c.
mide11 to yield the secondary alcohol 7. Oxidation of the alco-
CuBr SMe2 proceeded smoothly to afford imine 10b in 98%
ꢁ
hol 7 and successive treatment with NH2OH HCl and pyridine
yield (Run 4) and 75% yield (Run 5), respectively. In the
Cu-mediated reaction, the endo isomer formed as the major
product, possibly via an amino-metallation process.
ꢁ
afforded oxime 8. Oxime 8 was then converted into the corre-
sponding O-2,4-dinitrophenyloxime 9a, O-methoxycarbonyl-
oxime 9b, and O-pentafluorobenzoyloxime 9c.5,6
Having synthesized 10a and 10b, we turned our attention to
the reductive ring opening of cyclic ether 10 to 11, which pos-
sesses the azabicyclo[3.2.1]octene core. Reductive ring open-
ing occurred when 10a and 10b were reacted with lithium
naphthalenide12 to afford the desired 6-azabicyclooctene 11
(Scheme 4). Because imine 11 was easily hydrolyzed, it was
converted to N-Alloc-enamine 12 with allyloxycarbonyl chlo-
ride (AllocCl) and pyridine.13 Enamine 12 was obtained as a
single stereoisomer and was stable enough to be purified by
silica-gel column chromatography.
Radical cyclization of O-2,4-dinitrophenyloxime 9a (DNP
oxime) proceeded smoothly by the treatment with NaH and
3,4-methylenedioxyphenol (sesamol) in the presence of di-
phenyl diselenide at 50 ꢂC for 2 h, and the expected tricyclic
imine exo-10a, which has a phenylseleno group, was obtained
in 77% yield (Table 1, Run 1). The product yield was increas-
ed up to 93% yield by performing the reaction at room temper-
ature for 24 h (Run 2). O-Methoxycarbonyloxime 9b was cy-
clized slowly to form bromotricyclic imine 10b in moderate
yield (65%, exo:endo = 1:3) by the treatment with an equimo-
Next, we explored the stereo selective reduction of enamine
12. A preliminary experiment showed that it is difficult to pro-
duce the desired stereochemistry at C(7). The reduction of N-
lar amount of CuBr SMe2 (Run 3). Both stoichiometric and
catalytic cyclizations of pentafluorobenzoyloxime 9b with
ꢁ
Table 1. Radical Cyclization of Oximes 9a–9c
O
O
reductant
radical trapping
reagent
O
O
1,4-dioxane
RO
N
N
O
O
OR
9a: R = 2,4-dinitrophenyl (DNP)
9b: R = CH3OCO
O
O
N
9c: R = C6F5CO
H
2
X
2
+
X
O
H
O
N
O
O
exo-10
endo-10
Run
R
9
Reagents
Temp
50 ꢂC
rt
Time
X
10
Yield (exo:endo)
1
2
DNP
DNP
9a
9a
sesamol, NaH, (PhSe)2
sesamol, NaH, (PhSe)2
2 h
24 h
PhSe
PhSe
10a
10a
77% (>99:<1)
93% (>99:<1)
3
4
5
CH3OCO
C6F5CO
C6F5CO
9b
9c
9c
CuBr SMe2 (1.0), LiBr (4.0)
ꢁ
rt
rt
40 ꢂC
56 h
2 h
2 h
Br
Br
Br
10b
10b
10b
65% (1:3)
98% (1:2.2)
75% (1:6.5)
CuBr SMe2 (1.0), LiBr (4.0)
ꢁ
CuBr SMe2 (0.2), LiBr (4.0)
ꢁ

1554 Bull. Chem. Soc. Jpn. Vol. 79, No. 10 (2006)
Synthesis of Peduncularine
O
O
H
N
OH
1) lithium naphthalenide
THF
X
SO3·Py
Alloc
Alloc
N
−78 °C for 10a
Et3N, DMSO
O
N
−100 °C for 10b
CH2Cl2, rt
80%
O
10a: X = PhSe
10b: X = Br
2) MeOH
O
O
12
17
OH
O
O
8
OH
Alloc
R3SiCH2
OH
AllocCl
N
7
pyridine
N
Alloc
N
R3SiCH2M
CH2Cl2
−40 °C
O
12
Et2O
11
O
O
−78 °C - rt
O
75% from 10a
73% from 10b
O
18
O
Scheme 4. Synthesis of N-Alloc-enamine 12.
R3SiCH2M
18 yield/%
benzyloxycarbonylenamine 1314 with NaBH3CN under acidic
conditions15 afforded only the endo isomer of 14, which does
not have the desired stereochemistry at C(7) (Eq. 1).
Me3SiCH2MgCl
Et3SiCH2MgCl
18a 77
18b 81
Me2PhSiCH2MgCl 18c 69
OH
Ph3SiCH2Li
i-Pr3SiCH2Li
18d 52
18e 23
PhCH2O2C
N
NaBH3CN, AcOH
7
Scheme 5. Preparation of 18.
CH2Cl2, 0 °C - rt
O
13
O
ð1Þ
Table 2. Reduction of Enecarbamate 18
OH
OH
R3SiCH2
OH
R3SiCH2
OH
PhCH2O2C
PhCH2O2C
N
N
Alloc
N
Alloc
H
+
NaBH3CN
AcOH
O
N
H
O
O
O
CH2Cl2
0 °C - rt
O
O
O
18
19
exo-14 0 %
endo-14 81%
O
The following result, however, gave us a clue to control
stereochemistry of the reduction of the enamine moiety.
Metal-hydrides such as NaBH4 and L-selectride attacked
Alloc
H
Alloc
N
KH
N
ꢀ
+
the Si -face of the C(8)-carbonyl group in Boc derivative
O
16 derived from alcohol 1514 to regenerate 15 exclusively
(Eq. 2),16,17 which implies that a bulky nucleophile would be-
have in the same way to convert compound 17 into alkylated
product such as compound 18. The bulky substituent would
prevent hydride to attack the exo face of the enamine moiety.
THF, rt
H
O
O
O
exo-20
endo-20
Run R3Si
19
Yield
20 Yield (exo:endo)
1
2
3
4
5
Me3Si
Et3Si
Me2PhSi 19c 69%
Ph3Si
i-Pr3Si
19a 80%
70% (1:1.1)
19b 69% (85%)aÞ 87% (2:1)
H
N
OH
57% (1:1.7)
64% (1:3)
47% (1:9)
SO3·Py, DMSO
t-BuO2C
19d 76%
19e 50%
Et3N
CH2Cl2
rt, 4 h
O
O
a) Conversion yield.
70%
15
it can be readily converted to a methylene group by Peterson
olefination.18 Alcohol 12 was oxidized19 and the resulting
ketone 17 was treated with various silylmethylmetal reagents
to give the corresponding alcohols 18a–18e as a single product
(Scheme 5).20,21
The reduction of 18a–18e was performed with NaBH3CN
and acetic acid, and the diastereoselectivity was determined
after the product 19 was converted into the methylenated prod-
uct 20 by Peterson olefination with KH (Table 2).18 As we ex-
pected, the reduction of 18a having trimethylsilylmethyl group
at C(8) gave the desired product exo-20, as well as a similar
O
ð2Þ
8
t-BuO2C
N
H−
15
O
O
16
NaBH4, EtOH, rt
L-selectride, THF, −78 °C
66%
66%
A silylmethyl group was chosen as a substituent because

M. Kitamura et al.
Bull. Chem. Soc. Jpn. Vol. 79, No. 10 (2006) 1555
from Kanto Chemical. 2-Bromoethyl-1,3-dioxane, hydroxylam-
monium chloride, oxalyl dichloride, methyl acrylate, pentafluoro-
benzoyl chloride, and 2,4-dinitrofluorobenzene were purchased
from Tokyo Chemical Industry and were used without purifica-
tion. Naphthalene was recrystallized from benzene. Allyloxycar-
bonyl chloride was distilled from calcium chloride and stored over
MS 4A. Lithium wire, copper powder, CuBr SMe2 and SO3
Alloc
N
1) Pd(PPh3)4, piperidine
CH3CN, rt
O
O
exo-20
2) i-PrI, EtN(i-Pr)2
CH3CN, 50 °C
ꢁ
ꢁ
2 steps 72%
pyridine complex were purchased from Aldrich and were used
without purification. Isopropyl iodide was distilled from calcium
chloride. BF3 Et2O, sodium hydride, lithium aluminum hydride,
N
ꢁ
N
and sodium cyanoborohydride were purchased from Kanto Chem-
ical and were used without purification. Sesamol was recrystal-
lized from benzene and petroleum ether (P.E.).
PhNHNH2·HCl
O
O
cat. H2SO4, H2O
reflux
N
H
21
endo-7-Oxabicyclo[2.2.1]hept-2-ene-5-methanol (6). To a
solution of LiAlH4 (2.48 g, 65.3 mmol) in Et2O (200 mL) was
slowly added ester 5 (8.48 g, 55.0 mmol) in Et2O (75 mL). After
stirring for 2 h at room temperature, to the reaction mixture was
63%
peduncularine (1)
Scheme 6. Synthesis of peduncularine (1).
added Na2SO4 10H2O at 0 ꢂC and was heated to reflux for
ꢁ
amount of endo-20 was formed (Run 1). The exo-20 was ob-
tained predominantly in a 2:1 ratio of exo- and endo-20 from
triethylsilyl-substituted 18b (Run 2). However, reaction with
dimethylphenyl, triphenylsilyl, and triisopropylsilyl derivatives
afforded the undesired endo-20 predominantly (Runs 3–5).
Synthesis of peduncularine (1) was accomplished in the fol-
lowing three steps from exo-20 (Scheme 6). Elimination of the
allyloxycarbonyl group under Pd-catalyzed conditions22 and
successive isopropylation of the resulting secondary amine23
gave cyclic N-propylamine 21, which is an intermediate in
Hiemstra and Speckamp’s synthesis.4a Finally, a 3-indolyl
group was constructed by the Fischer method from acetal 21,
leading to peduncularine (1) in 63% yield.4d,24
15 min. The mixture was dried over anhydrous Na2SO4, filtered,
and was concentrated in vacuo to yield alcohol 6 (6.73 g, 53.3
mmol) in 97% yield as a colorless oil. The spectral data were in
a total agreement with those in Ref. 9.
endo-3-(1,3-Dioxan-2-yl)-1-(7-oxabicyclo[2.2.1]hept-2-en-2-
yl)propan-1-ol (7). To a solution of oxalyl dichloride (9.05 mL,
104 mmol) in CH2Cl2 (250 mL) at ꢃ60 ꢂC was slowly added a so-
lution of DMSO (14.8 mL, 208 mmol) in CH2Cl2 (50 mL) and the
reaction mixture was stirred for 5 min. Subsequently, alcohol 6
(11.9 g, 94.7 mmol) in CH2Cl2 (100 mL) was slowly added over
5 min. After the reaction mixture was stirred for 20 min, triethyl-
amine (65.6 mL, 473 mmol) was slowly added. The reaction mix-
ture was stirred for another 40 min, treated with aq NaHCO3,
and extracted with CH2Cl2. The combined organic extracts were
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo under 10 ꢂC. The residue was dissolved in
THF (300 mL) and cooled to ꢃ78 ꢂC. To the solution was added
2-(1,3-dioxan-2-yl)ethylmagnesium bromide (1.0 M solution in
THF, 97 mL, 97 mmol), and the reaction mixture was allowed to
warm to room temperature and stirred for 14 h. The reaction
was quenched with aq NH4Cl, and the mixture was extracted with
EtOAc. The combined organic extracts were dried over anhydrous
MgSO4, filtered, and evaporated. The residue was purified by col-
umn chromatography (SiO2, CHCl3:MeOH = 25:1) to afford 7
(14.5 g, 64%) as a colorless oil (diastereomer mixture 6:4).
IR (neat) 3438, 3373, 1456, 1379, 1319, 1242, 1146, 1088, 995,
910 cmꢃ1; 1H NMR (500 MHz, CDCl3) ꢁ 0.67 (0.6H, dd, J ¼ 4:1,
11.2 Hz), 1.12 (0.4H, dd, J ¼ 3:9, 11.4 Hz), 1.33 (1H, d, J ¼ 13:6
Hz), 1.44–1.51 (1H, m), 1.62–1.76 (3H, m), 1.92 (0.6H, ddd,
J ¼ 4:8, 9.2, 11.2 Hz), 2.03–2.08 (1.4H, m), 2.18–2.23 (1H, m),
2.45 (0.4H, br), 2.92 (0.6H, br), 2.99 (1H, br dd, J ¼ 9:4, 9.4 Hz),
3.75 (2H, dd, J ¼ 12:1, 12.1 Hz), 4.07–4.10 (2H, m), 4.55 (1H, dd,
J ¼ 4:4, 4.4 Hz), 4.81 (0.4H, d, J ¼ 4:3 Hz), 4.88 (0.6H, d, J ¼
4:8 Hz), 4.91 (0.4H, dd, J ¼ 1:5, 4.8 Hz), 5.04 (0.6H, d, J ¼ 4:4
Hz), 6.17 (0.4H, dd, J ¼ 1:2, 5.9 Hz), 6.34 (1.2H, br), 6.40 (0.4H,
dd, J ¼ 1:5, 5.9 Hz); 13C NMR (125 MHz, CDCl3) ꢁ 25.5, 25.6,
28.5, 28.9, 30.5, 30.8, 31.1, 31.2, 44.9, 45.5, 66.9, 74.3, 75.5,
78.3, 78.7, 78.9, 80.0, 101.9, 102.0, 131.6, 133.0, 136.1, 137.2.
3-(1,3-Dioxan-2-yl)-1-(endo-7-oxabicyclo[2.2.1]hept-2-en-5-
yl)propan-1-one Oxime (8). To a solution of oxalyl dichloride
(9.92 g, 78.1 mmol) in CH2Cl2 (220 mL) at ꢃ60 ꢂC was slowly
added a solution of DMSO (12.2 g, 156 mmol) in CH2Cl2 (45 mL),
and the reaction mixture was stirred for 5 min. Subsequently, alco-
hol 7 (17.1 g, 71.0 mmol) in CH2Cl2 (88 mL) was slowly added
Experimental
General. 1H NMR (500 and 270 MHz) spectra were recorded
on Bruker DRX-500, Bruker Avance-500, and JEOL AL-270
spectrometers in CDCl3, in which CHCl3 was used as an internal
standard (ꢁ ¼ 7:24)] or C6D6, in which case C6HD5 was used as
an internal standard (ꢁ ¼ 7:15). 13C NMR (125 and 67.5 MHz)
spectra were recorded on Bruker DRX-500, Bruker Avance-500,
and JEOL AL-270 spectrometers in CDCl3, which was used as
an internal standard (ꢁ ¼ 77:0) or C6D6, which was used as an in-
ternal standard (ꢁ ¼ 128:0). IR spectra were recorded on a Horiba
FT 300-S by ATR method. High-resolution mass spectra were ob-
tained with a JEOL MS-700M mass spectrometer. Elemental anal-
yses were carried out at The Elemental Analysis Laboratory,
Department of Chemistry, Faculty of Science, The University of
Tokyo. Flash column chromatography was performed on silica
gel [Fuji Silysia silica gel PSQ–100B and Kanto Chemical silica
gel 60N (spherical, neutral)], alumina (WAKO) and florisil
(WAKO). Preparative thin-layer chromatography (PTLC) was
carried out using Wakogel B-5F. N,N-Dimethylformamide (DMF)
was distilled under reduced pressure from P2O5 and then from
CaH2, and stored over molecular sieves 4A (MS 4A) under an
argon atmosphere. Acetonitrile was distilled from CaH2, P2O5,
and CaH2 again and was stored over MS 4A. Dimethyl sulfoxide
(DMSO) was distilled under reduced pressure from CaH2 and
stored over MS 4A. Dichloromethane was distilled from P2O5
and then from CaH2, and was stored over MS 4A. Triethylamine,
ethyldiisopropylamine, furan, and pyridine were distilled from
CaH2 and stored over KOH. 1,4-Dioxane was distilled from
LiAlH4 and used immediately. MeOH was distilled from Mg and
stored with MS 4A. Dry THF and diethyl ether were purchased

1556 Bull. Chem. Soc. Jpn. Vol. 79, No. 10 (2006)
Synthesis of Peduncularine
over 5 min. After the reaction mixture was stirred for 20 min
at ꢃ60 ꢂC, triethylamine (35.9 mL, 355 mmol) was slowly added.
The reaction mixture was stirred for another 40 min, treated with
aq NaHCO3 and extracted with CH2Cl2. The combined organic
extracts were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. The residue was dissolved in
EtOH, and pyridine (16.9 g, 213 mmol) and hydroxylammonium
chloride (7.40 g, 107 mmol) were added to the solution at room
temperature. After stirring for 24 h, the mixture was diluted with
water, and extracted with EtOAc. The combined extracts were
dried over anhydrous Na2SO4, filtered, successively concentrated
in vacuo. The residue was purified by column chromatography
(SiO2) to yield 8 (13.0 g, 72%, E:Z = 7:2) as colorless crystals.
Mp 75–76 ꢂC (Et2O); IR (KBr) 3305, 2954, 2856, 1666, 1651,
1568, 1471, 1240, 1128, 725 cmꢃ1; 1H NMR (500 MHz, CDCl3) ꢁ
1.35E (br d, J ¼ 13:6 Hz) and 1.39Z (dd, J ¼ 4:1, 11.6 Hz) (1H);
1.50E (dd, J ¼ 4:4, 12.6 Hz), 1.66–2.14E;Z (m), 2.33E (ddd, J ¼
6:6, 9.7, 13.0 Hz) and 2.46E (ddd, J ¼ 6:5, 9.5, 13.0 Hz) (5H);
3.02E (ddd, J ¼ 4:3, 4.4, 8.9 Hz) and 3.46Z (ddd, J ¼ 4:1, 4.3,
9.0 Hz) (1H); 3.71–3.79E;Z (m, 2H); 4.06–4.15E;Z (m, 2H); 4.51Z
(dd, J ¼ 5:0, 5.0 Hz) and 4.56E (dd, J ¼ 4:9, 4.9 Hz) (1H); 4.99E
(dd, J ¼ 1:4, 4.7 Hz) and 5.02Z (dd, J ¼ 1:1, 4.4 Hz) (1H); 5.12E
(dd, J ¼ 1:0, 4.3 Hz) and 5.49Z (d, J ¼ 4:3 Hz) (1H); 6.16E (dd,
J ¼ 1:0, 5.8 Hz) and 6.18Z (dd, J ¼ 1:5, 5.8 Hz) (1H); 6.39E (dd,
J ¼ 1:4, 5.8 Hz) and 6.41Z (dd, J ¼ 1:1, 5.8 Hz) (1H); 7.83E (br)
and 8.25Z (br) (1H); 13C NMR (125 MHz, CDCl3) ꢁ 23.4, 25.7,
27.5, 27.5, 27.7, 30.9, 31.4, 37.2, 42.6, 66.8, 66.8, 78.4, 78.9,
79.0, 79.6, 132.4, 133.2, 136.0, 136.1, 158.9, 160.0; Anal. Found:
C, 61.37; H, 7.52; N, 5.49%. Calcd for C13H19NO4: C, 61.64; H,
7.56; N, 5.53%.
aminopyridine (11.7 mg, 0.096 mmol), and methoxycarbonylchlo-
ride (0.070 mL, 1.2 mmol). The solution was stirred at 0 ꢂC for 3 h.
To this solution was added pyridine (0.30 mL, 3.8 mmol) and
methoxycarbonyl chloride (0.23 mL, 3.9 mmol). The reaction mix-
ture was stirred for 24 h at room temperature, and the reaction was
quenched with aq NaHCO3. The mixture was extracted with
CH2Cl2, and the combined organic extracts were washed with
brine, dried over anhydrous Na2SO4, filtered, evaporated. The
residue was purified by column chromatography (SiO2; hexane:
acetone = 2:1) to afford 211 mg of 9b in 93% yield as a colorless
oil (E:Z = 7.7:2.3 mixture).
IR(neat) 2956, 2852, 2360, 1772, 1653, 1506, 1437, 1228,
1128, 1026, 893, 777 cmꢃ1 1H NMR (500 MHz, CDCl3) ꢁ 1.31
;
(1H, dd, J ¼ 1:0, 13.5 Hz), 1.38 (0.23H, dd, J ¼ 4:0, 11.8 Hz),
1.58 (0.77H, dd, J ¼ 4:4, 11.4 Hz), 1.71–1.80 (2H, m), 1.97–2.20
(2.46H, m), 2.34–2.45 (1.54H, m), 3.07–3.11 (0.77H, m), 3.41–
3.45 (0.23H, m), 3.71 (2H, dd, J ¼ 10:8, 13.5 Hz), 3.80 (2.31H,
s), 3.85 (0.69H, s), 4.00–4.10 (2H, m), 4.50 (1H, t, J ¼ 4:8 Hz),
4.97 (0.77H, d, J ¼ 4:6 Hz), 5.00 (0.23H, d, J ¼ 4:5 Hz), 5.15
(0.77H, d, J ¼ 4:2 Hz), 5.34 (0.23H, d, J ¼ 4:5 Hz), 6.14 (0.23H,
d, J ¼ 5:8 Hz), 6.19 (0.77H, dd, J ¼ 1:1, 5.8 Hz), 6.37 (0.77H, dd,
J ¼ 1:5, 5.8 Hz), 6.42 (0.23H, dd, J ¼ 1:5, 5.8 Hz); 13C NMR
(125 MHz, CDCl3) ꢁ 24.6, 25.5, 25.6, 27.3, 27.6, 27.7, 31.1,
31.3, 38.5, 42.8, 55.0, 55.1, 66.8, 78.5, 78.9, 79.3, 79.4, 100.7,
132.5, 132.6, 136.2, 136.8, 154.3, 167.1, 167.7.
3-(1,3-Dioxan-2-yl)-1-(endo-7-oxabicyclo[2.2.1]hept-2-en-5-
yl)propan-1-one O-Pentafluorobenzoyloxime (9c). To a solu-
tion of oxime 8 (2.74 g, 10.8 mmol) in CH2Cl2 at 0 ꢂC was added
triethylamine (2.95 mL, 21.3 mmol) and pentafluorobenzoyl chlo-
ride (1.95 mL, 14.4 mmol). After stirring for 10 min at 0 ꢂC, the re-
action was quenched with aq NaHCO3 and extracted with CH2Cl2.
The combined organic extracts were washed with brine, dried over
anhydrous MgSO4, filtered, and evaporated. The residue was pu-
rified by column chromatography (SiO2) to afford 9c (4.60 g,
95%) as colorless crystals.
3-(1,3-Dioxan-2-yl)-1-(endo-7-oxabicyclo[2.2.1]hept-2-en-5-
yl)propan-1-one O-2,4-Dinitrophenyloxime (9a). A solution of
oxime 8 (603 mg, 2.38 mmol) in DMF (24 mL) was added to NaH
(55.7 mg, 3.57 mmol, washed with P.E.) in a three necked flask at
0 ꢂC. After the solution was stirred for 1 h, to this solution was
added a solution of 2,4-dinitrofluorobenzene (487 mg, 2.62 mmol),
and the mixture was stirred for 24 h at room temperature. The
reaction was quenched with ice water, and the mixture was ex-
tracted with CH2Cl2. The combined organic extracts were washed
with water and brine, dried over anhydrous Na2SO4, filtered, and
evaporated. The residue was purified by column chromatography
(SiO2; hexane:EtOAc = 2:1) to give 784 mg (80%) of 9a as col-
orless crystals.
(E:Z = 7.7:2.3) IR(neat) 2954, 2852, 1757, 1653, 1523, 1506,
1325, 1198, 1147, 1003, 893, 868 cmꢃ1 1H NMR (500 MHz,
;
CDCl3) ꢁ 1.31 (1H, brd, J ¼ 12:3 Hz), 1.42 (0.23H, dd, J ¼ 4:0,
11.9 Hz), 1.58 (0.77H, dd, J ¼ 4:4, 12.2 Hz), 1.76–1.83 (2H, m),
1.97–2.04 (1H, m), 2.05–2.13 (1H, m), 2.17–2.28 (0.46H, m),
2.40–2.51 (1.54H, m), 3.15–3.19 (0.77H, m), 3.48–3.52 (0.23H,
m), 3.71 (2H, dd, J ¼ 10:8, 12.3 Hz), 4.04 (2H, dd, J ¼ 4:9, 10.8
Hz), 4.51 (0.77H, t, J ¼ 4:7 Hz), 4.55 (0.23H, t, J ¼ 4:8 Hz), 5.00
(0.77H, d, J ¼ 4:5 Hz), 5.03 (0.23H, d, J ¼ 3:7 Hz), 5.19 (0.77H,
d, J ¼ 4:1 Hz), 5.24 (0.23H, d, J ¼ 4:4 Hz), 6.18 (0.23H, dd, J ¼
1:3, 5.8 Hz), 6.23 (0.77H, dd, J ¼ 1:2, 5.8 Hz), 6.41 (0.77H, dd,
J ¼ 1:5, 5.8 Hz), 6.47 (0.23H, dd, J ¼ 1:5, 5.8 Hz); 13C NMR
(125 MHz, CDCl3) ꢁ 25.0, 25.4, 25.5, 27.4, 27.6, 27.7, 30.9,
31.0, 38.7, 42.9, 66.7, 78.6, 78.9, 79.2, 79.3, 100.4, 100.5, 107.0,
132.1, 132.4, 136.3, 136.6, 137.1, 138.6, 142.2, 144.2, 146.2,
156.3, 169.6, 170.5; Anal. Found: C, 53.57; H, 4.15; N, 2.99%.
Calcd. for C20H18F5NO5: C, 53.70; H, 4.06; N, 3.13%.
E isomer: mp 97–98 ꢂC (hexane–Et2O); IR (KBr) 1604, 1529,
1
1348, 1273, 1146, 899 cmꢃ1; H NMR (500 MHz, CDCl3) ꢁ 1.36
(1H, d, J ¼ 13:6 Hz), 1.68 (1H, dd, J ¼ 4:3, 11.4 Hz), 1.87–1.96
(2H, m), 2.07 (1H, ddddd, J ¼ 5:0, 5.0, 12.0, 12.0, 13.6 Hz), 2.15
(1H, ddd, J ¼ 4:8, 8.9, 11.4 Hz), 2.58 (1H, ddd, J ¼ 7:0, 8.9,
12.9 Hz), 2.69 (1H, ddd, J ¼ 6:7, 9.0, 12.9 Hz), 3.26 (1H, ddd,
J ¼ 4:3, 4.4, 8.9 Hz), 3.78 (2H, dd, J ¼ 10:0, 12.0 Hz), 4.11 (2H,
d, J ¼ 10:0 Hz), 4.65 (1H, dd, J ¼ 4:8, 4.8 Hz), 5.08 (1H, d, J ¼
4:8 Hz), 5.25 (1H, dd, J ¼ 1:0, 4.4 Hz), 6.22 (1H, dd, J ¼ 1:0,
5.8 Hz), 6.47 (1H, dd, J ¼ 1:4, 5.8 Hz), 7.77 (1H, d, J ¼ 9:3 Hz),
8.38 (1H, dd, J ¼ 2:8, 9.4 Hz), 8.88 (1H, d, J ¼ 2:8 Hz); 13C NMR
(125 MHz, CDCl3) ꢁ 25.6, 25.7, 27.6, 31.2, 43.1, 66.8, 79.0, 79.5,
100.9, 117.1, 122.1, 129.3, 132.2, 136.0, 136.6, 140.6, 157.3,
169.4; Anal. Found: C, 54.31; H, 4.99; N, 10.04%. Calcd for
C19H21N3O8: C, 54.41; H, 5.05; N, 10.02%.
5-[2-(1,3-Dioxan-2-yl)ethyl]-2-phenylseleno-8-oxa-4-azatri-
cyclo[4.2.1.03;7]non-4-ene (10a).
To a solution of sodium
hydride (1.39 g, 5.77 mmol, washed with P.E. three times) in 1,4-
dioxane (10 mL) at room temperature was added a solution of ses-
amol (0.811 g, 5.87 mmol) in 1.4-dioxane (10 mL), a solution of
diphenyl diselenide (5.27 g, 16.9 mmol) in 1,4-dioxane (18 mL),
and O-2,4-dinitrophenyloxime 9a (2.42 g, 5.77 mmol) in 1,4-diox-
ane (10 mL). After stirring for 24 h at room temperature, ice water
was added to the reaction mixture. The mixture was extracted with
Et2O, and the combined organic extracts were washed with brine,
3-(1,3-Dioxan-2-yl)-1-(endo-7-oxabicyclo[2.2.1]hept-2-en-5-
yl)propan-1-one O-Methoxycarbonyloxime (9b). To a solution
of oxime 8 (199 mg, 0.79 mmol) in 1.2-dichloroethane (10 mL)
at 0 ꢂC was added triethylamine (0.29 mL, 2.0 mmol), 4-dimethyl-

M. Kitamura et al.
Bull. Chem. Soc. Jpn. Vol. 79, No. 10 (2006) 1557
dried over anhydrous Na2SO4, filtered, and evaporated. Purifica-
tion by column chromatography (SiO2) gave 10a (1.78 g, 93%)
as pale yellow crystals.
ature and stirred for 3 h. The reaction was quenched with aq
NaHCO3, and the mixture was extracted with CH2Cl2. The com-
bined organic extracts were washed with brine, dried over anhy-
drous Na2SO4 and concentrated in vacuo. The residue was puri-
fied by column chromatography (SiO2; hexane:acetone = 2:1)
to afford enecarbamate 12 (129 mg, 75%) as a colorless oil. Com-
pound 12 was also prepared from imine 10b in a similar manner as
10a, in 73%.
Mp 71–72 ꢂC (hexane–Et2O); IR (KBr) 1626, 1377, 1136,
1022, 964, 879, 742 cmꢃ1 1H NMR (500 MHz, CDCl3) ꢁ 1.33
;
(1H, ddd, J ¼ 0:8, 1.8, 13.5 Hz), 1.65 (1H, dd, J ¼ 1:2, 12.5 Hz),
1.84–1.96 (3H, m), 2.05 (1H, ddddd, J ¼ 4:9, 4.9, 12.6, 12.6,
13.5 Hz), 2.34–2.59 (2H, m), 2.65 (1H, dd, J ¼ 4:6, 9.5 Hz),
3.14 (1H, s), 3.75 (2H, ddd, J ¼ 1:8, 10.9, 12.6 Hz), 4.08 (2H,
ddd, J ¼ 0:8, 4.9, 10.9 Hz), 4.17 (1H, d, J ¼ 4:5 Hz), 4.59 (1H,
dd, J ¼ 4:8, 4.8 Hz), 4.64 (1H, d, J ¼ 5:1 Hz), 5.42 (1H, dd,
J ¼ 4:6, 5.1 Hz), 7.25–7.30 (3H, m), 7.51–7.55 (2H, m); 13C NMR
(125 MHz, CDCl3) ꢁ 25.7, 28.4, 30.8, 36.7, 46.7, 49.5, 66.8, 66.8,
76.7, 84.0, 89.5, 101.1, 127.3, 129.2, 129.9, 133.4, 185.8; Anal.
Found: C, 58.11; H, 5.87; N, 3.57%. Calcd for C19H23NO3Se:
C, 58.16; H, 5.91; N, 3.57%.
IR (neat) 3435, 1711, 1402, 1333, 1277, 1240, 1138, 1014
1
cmꢃ1; H NMR (500 MHz, CDCl3) ꢁ 1.29 (1H, d, J ¼ 13:4 Hz),
1.98–2.08 (1H, m), 2.16–2.20 (1H, m), 2.18 (1H, d, J ¼ 18:6 Hz),
2.24–2.34 (2H, m), 2.49 (1H, dd, J ¼ 4:5, 18.6 Hz), 3.04 (1H, br),
3.71 (2H, dt, J ¼ 2:3, 12.1 Hz), 4.03–4.06 (2H, m), 4.22–4.26
(2H, m), 4.50 (1H, t, J ¼ 5:3 Hz), 4.58 (2H, br), 5.18 (1H, d,
J ¼ 10:4 Hz), 5.27 (1H, d, J ¼ 17:2 Hz), 5.85–5.94 (3H, m), 6.04
(1H, br); 13C NMR (125 MHz, CDCl3) ꢁ 25.7, 28.4, 35.1, 38.9,
54.9, 65.7, 66.9, 67.9, 101.9, 102.9, 117.5, 125.4, 131.7, 132.6,
142.3, 152.0; Anal. Found: C, 63.35; H, 7.38; N, 4.08%. Calcd
for C17H23NO5: C, 63.54; H, 7.21; N, 4.36%.
2-Bromo-5-[2-(1,3-dioxan-2-yl)ethyl]-8-oxa-4-azatricyclo-
[4.2.1.03;7]non-4-ene (10b). To a solution of O-pentafluoroben-
zoyloxime 9c (145 mg, 0.324 mmol) and lithium bromide (110
mg, 1.27 mmol) in 1,4-dioxane (7 mL) at room temperature was
6-Benzyloxycarbonyl-7-[2-(1,3-dioxan-2-yl)ethylidene]-6-aza-
bicyclo[3.2.1]oct-3-en-8-ol (13). IR (neat) 3413, 1711, 1664,
1402, 1277, 1136, 1014 cmꢃ1; 1H NMR (500 MHz, CDCl3) ꢁ 1.29
(1H, ddd, J ¼ 0:6, 2.3, 13.5 Hz), 1.94–2.09 (2H, m), 2.20 (1H, d,
J ¼ 18:8 Hz), 2.25–2.35 (2H, m), 2.50 (1H, dd, J ¼ 4:6, 18.8 Hz),
3.05 (1H, m), 3.71 (2H, ddd, J ¼ 2:3, 12.1, 11.7 Hz), 4.06 (2H,
ddd, J ¼ 0:6, 4.4, 11.7 Hz), 4.23–4.27 (1H, m), 4.29 (1H, br),
4.50 (1H, br), 5.13 (2H, br), 5.94 (1H, br), 6.08 (1H, br), 7.27–
7.37 (5H, m).
added CuBr SMe2 (66.2 mg, 0.322 mmol). After the reaction mix-
ꢁ
ture was stirred for 2 h at room temperature, brine and N,N,N0,N0-
tetramethylethylenediamine was added. The mixture was extract-
ed with EtOAc, and the combined organic extracts were washed
with brine, dried over anhydrous MgSO4, filtered, and evaporated.
The residue was purified by column chromatography (florisil;
hexane:acetone = 4:1) to give 10b (100 mg, 98%, exo:endo =
1:2.2) as a colorless oil. O-Methoxycarbonyloxime 9b also gave
10b in 65% (exo:endo = 1:3 mixture) in a similar manner as 9c.
exo Isomer: IR (neat) 2964, 2852, 1699, 1622, 1377, 1144, 1082,
6-Benzyloxycarbonyl-7-[endo-2-(1,3-dioxan-2-yl)ethyl]-6-aza-
bicyclo[3.2.1]oct-3-en-8-ol (endo-14). IR (neat) 3417, 1693,
;
1415, 1136, 1088 cmꢃ1 1H NMR (500 MHz, CDCl3, 323 K) ꢁ
1043, 1001, 883, 850, 793 cmꢃ1
;
1H NMR (500 MHz, CDCl3) ꢁ
1.32 (1H, dd, J ¼ 1:0, 13.5 Hz), 1.67 (1H, d, J ¼ 12:6 Hz), 1.83–
1.91 (3H, m), 1.98–2.14 (1H, m), 2.37–2.48 (2H, m), 2.63 (1H, dd,
J ¼ 4:6, 9.9 Hz), 3.67 (1H, s), 3.72 (2H, dd, J ¼ 11:9, 13.5 Hz),
4.06 (2H, brd, J ¼ 11:9 Hz), 4.36 (1H, d, J ¼ 4:5 Hz), 4.57 (1H,
t, J ¼ 4:8 Hz), 4.73 (1H, d, J ¼ 5:2 Hz), 5.42 (1H, dd, J ¼ 4:5,
4.6 Hz); 13C NMR (125 MHz, CDCl3) ꢁ 25.7, 28.3, 30.5, 36.5,
46.2, 51.9, 66.8, 66.84, 79.4, 86.1, 89.1, 101.0, 186.8; HRMS
(FABþ) Found: m=z 316.0530, Calcd for C13H19BrNO3: ðM þ
HÞþ, 316.0548.
1.28 (1H, d, J ¼ 13:3 Hz), 1.47–1.52 (3H, br), 1.90 (1H, br d, J ¼
9:0 Hz), 2.03 (1H, ddddd, J ¼ 4:8, 4.8, 12.6, 12.6, 13.3 Hz), 2.25
(1H, br d, J ¼ 18:4 Hz), 2.39–2.43 (3H, br m), 3.69 (2H, br), 3.88
(1H, br), 4.04 (2H, dd, J ¼ 4:8, 10.8 Hz), 4.13 (1H, ddd, J ¼ 4:5,
4.5, 9.0 Hz), 4.21 (1H, br), 4.47 (1H, br), 5.07 (1H, d, J ¼ 12:4
Hz), 5.12 (1H, d, J ¼ 12:4 Hz), 5.89–5.93 (1H, br m), 7.26–7.33
(5H, m).
6-t-Butoxycarbonyl-7-[2-(1,3-dioxan-2-yl)ethylidene)-6-aza-
bicyclo[3.2.1]oct-3-en-8-ol (15). IR (neat) 3442, 1707, 1390,
1
endo Isomer: IR (neat) 2962, 2852, 1699, 1628, 1442, 1377,
1242, 1144, 1028, 1001, 955, 874, 777 cmꢃ1; 1H NMR (500 MHz,
C6D6) ꢁ 0.62 (1H, brd, J ¼ 13:2 Hz), 1.65 (1H, ddd, J ¼ 4:5, 9.2,
10.4 Hz), 1.73–1.84 (1H, m), 1.88 (1H, dd, J ¼ 1:6, 9.2 Hz), 1.94
(1H, dd, J ¼ 4:9, 10.4 Hz), 2.09–2.17 (1H, m), 2.20–2.26 (1H,
m), 2.28–2.35 (1H, m), 2.43–2.49 (1H, m), 3.34–3.42 (2H, m),
3.67–3.83 (4H, m), 4.10 (1H, dd, J ¼ 4:5, 4.5 Hz), 4.69 (1H, t,
J ¼ 5:0 Hz), 4.79 (1H, dd, J ¼ 4:6, 4.9 Hz); 13C NMR (125 MHz,
C6D6) ꢁ 25.7, 28.5, 30.2, 30.6, 47.9, 48.6, 66.8, 66.9, 82.0, 90.3,
100.9, 186.8; HRMS (FABþ) Found: m=z 316.0533, Calcd for
C13H19BrNO3: ðM þ HÞþ, 316.0548.
1138, 669 cmꢃ1; H NMR (500 MHz, CDCl3) ꢁ 1.30 (1H, d, J ¼
13:4 Hz), 1.46 (9H, s), 1.92 (1H, d, J ¼ 10:0 Hz), 2.05 (1H, ddddd,
J ¼ 4:1, 4.1, 12.7, 12.7, 13.4 Hz), 2.19 (1H, d, J ¼ 18:7 Hz),
2.25–2.35 (2H, m), 3.04 (1H, br), 3.72 (2H, ddd, J ¼ 1:8, 11.4,
12.7 Hz), 4.06 (2H, dd, J ¼ 4:1, 11.4 Hz), 4.19 (1H, br), 4.23 (1H,
br quin), 4.52 (1H, dd, J ¼ 5:3, 5.3 Hz), 5.94 (3H, br).
6-t-Butoxycarbonyl-7-[2-(1,3-dioxan-2-yl)ethylidene]-6-aza-
bicyclo[3.2.1]oct-3-ene-8-one (16). IR (neat) 1782, 1711, 1383,
1136, 1014, 862 cmꢃ1; 1H NMR (500 MHz, CDCl3) ꢁ 1.29 (1H, d,
J ¼ 13:4 Hz), 1.46 (9H, s), 2.02 (1H, ddddd, J ¼ 4:7, 4.7, 12.7,
12.7, 13.4 Hz), 2.25 (2H, dd, J ¼ 5:2, 7.7 Hz), 2.84 (1H, d, J ¼
17:6 Hz), 2.92 (1H, dddd, J ¼ 2:3, 3.2, 4.6, 17.6 Hz), 3.31 (1H,
br), 3.71 (2H, dddd, J ¼ 2:6, 2.6, 11.1, 12.7 Hz), 4.04 (2H, dd,
J ¼ 4:7, 11.1 Hz), 4.18 (1H, br), 4.51 (1H, dd, J ¼ 5:2, 5.2 Hz),
5.78 (1H, ddd, J ¼ 3:2, 3.2, 8.9 Hz), 6.13 (2H, br); 13C NMR
(125 MHz, CDCl3) ꢁ 25.7, 28.3, 35.0, 39.9, 47.3, 58.9, 66.9,
81.3, 101.6, 102.8, 130.8, 131.1, 139.2, 151.3, 206.5.
6-Allyloxycarbonyl-7-[2-(1,3-dioxan-2-yl)ethylidene]-6-aza-
bicyclo[3.2.1]oct-3-ene-8-ol (12). To a solution of the selenide
10a (211 mg, 0.537 mmol) in THF (8 mL) at ꢃ78 ꢂC was slowly
added lithium naphthalenide (0.1 M solution in THF, 3 mL, 1.5
mmol). The mixture was stirred for 25 min at ꢃ78 ꢂC, and the re-
action was quenched with MeOH. The mixture was evaporated,
and the residue was diluted in CH2Cl2 (8 mL). The resulting sus-
pension was filtered through a celite pad and the filtrate was
evaporated. To a solution of the residue in CH2Cl2 (8 mL) at
ꢃ20 ꢂC was added pyridine (0.057 mL, 7.1 mmol) and AllocCl
(0.063 mL, 6.0 mmol). The mixture was warmed to room temper-
6-Allyloxycarbonyl-7-[2-(1,3-dioxan-2-yl)ethylidene]-6-aza-
bicyclo[3.2.1]oct-3-ene-8-one (17). To a solution of enecarba-
mate 12 (95.2 mg, 0.296 mmol) in CH2Cl2 (1 mL) and DMSO
(1 mL) was added triethylamine (195 mg, 1.93 mmol), a solution
of SO3 pyridine (142 mg, 0.888 mmol) in DMSO (1 mL) and
ꢁ

1558 Bull. Chem. Soc. Jpn. Vol. 79, No. 10 (2006)
Synthesis of Peduncularine
CH2Cl2 (1 mL). After the mixture was stirred for 17 h at room
temperature, the reaction was quenched by adding water. The
mixture was extracted with CH2Cl2 and the combined organic
extracts were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. Purification by PTLC (SiO2;
hexane:EtOAc = 1:1) gave 78.0 mg (82%) of 17 as a colorless oil.
0.36 (6H, s), 1.29 (3H, m), 2.00–2.05 (1H, m), 2.17–2.25 (4H, m),
2.46 (1H, d, J ¼ 18:8 Hz), 2.72 (1H, brs), 3.71 (2H, dd, J ¼ 11:6,
13.4 Hz), 3.92 (1H, brs), 4.02–4.10 (2H, m), 4.47 (1H, t, J ¼ 5:2
Hz), 4.49–4.55 (2H, m), 5.18 (1H, d, J ¼ 10:1 Hz), 5.24 (1H, d,
J ¼ 17:0 Hz), 5.87–6.05 (4H, m), 7.51–7.54 (3H, m), 7.67 (2H,
brs).
IR (neat) 1780, 1716, 1396, 1281, 1236, 1138, 1014 cmꢃ1
;
6-Allyloxycarbonyl-7-[2-(1,3-dioxan-2-yl)ethylidene]-8-anti-
triphenylsilylmethyl-6-azabicyclo[3.2.1]oct-3-en-8-ol (18d).
To a solution of tributyl(triphenylsilylmethyl)tin (234 mg, 0.415
mmol, prepared from triphenylsilylmethyl chloride and tributyl-
tinlithium) at 0 ꢂC was slowly added butyllithium (1.63 M solution
in hexane, 0.26 mL, 0.42 mmol). After the reaction mixture was
stirred for 30 min at 0 ꢂC, it was cooled to ꢃ78 ꢂC. To this solution
was slowly added ketone 17 (57.6 mg, 0.180 mmol) in THF
(2 mL). The reaction mixture was stirred for 1 h at ꢃ78 ꢂC and
was treated with aq NH4Cl. The mixture was extracted with
CH2Cl2, and the combined organic extracts were washed with
brine, dried with anhydrous MgSO4, filtered, and evaporated. The
residue was purified by PTLC (SiO2; hexane:EtOAc = 1:1) to
yield 18d (62.4 mg, 60%, conv. 82%) as a colorless oil.
1H NMR (270 MHz, CDCl3) ꢁ 1.26 (1H, d, J ¼ 11:6 Hz), 1.99–
2.09 (6H, m), 2.29 (1H, d, J ¼ 13:1 Hz), 2.61 (1H, brs), 3.62–3.73
(2H, m), 3.94–4.07 (3H, m), 4.44 (1H, t, J ¼ 5:4 Hz), 4.46–4.60
(2H, m), 5.15–5.25 (2H, m), 5.81–6.06 (4H, m), 7.29–7.39 (9H,
m), 7.58–7.61 (6H, m).
6-Allyloxycarbonyl-7-[2-(1,3-dioxan-2-yl)ethylidene]-8-anti-
triisopropylsilylmethyl-6-azabicyclo[3.2.1]oct-3-en-8-ol (18e).
Compound 18e was prepared from 17 in a similar manner as 18b
in 23% as a colorless oil.
1H NMR (270 MHz, CDCl3) ꢁ 0.99–1.12 (21H, m), 1.13 (2H,
s), 1.30 (1H, d, J ¼ 13:5 Hz), 1.97–2.04 (1H, m), 2.24–2.33 (4H,
m), 2.54 (1H, brd, J ¼ 13:5 Hz), 2.84 (1H, brs), 3.71 (2H, dd, J ¼
11:2, 13.5 Hz), 4.05 (3H, dd, J ¼ 4:9, 11.2 Hz), 4.50 (1H, t, J ¼
5:1 Hz), 4.60 (2H, brs), 5.19 (1H, dd, J ¼ 0:4, 13.9 Hz), 5.28
(1H, d, J ¼ 13:9 Hz), 5.86–6.06 (4H, m).
1H NMR (500 MHz, CDCl3, 323 K) ꢁ 1.28 (1H, dm, Jd ¼ 13:3
Hz), 2.03 (1H, dm, Jd ¼ 13:3 Hz), 2.26 (2H, dd, J ¼ 5:1, 7.8 Hz),
2.86 (1H, dm, Jd ¼ 17:6 Hz), 2.94 (1H, dm, Jd ¼ 17:6 Hz), 3.32–
3.34 (1H, m), 3.68–3.73 (2H, m), 4.03–4.06 (2H, m), 4.26 (1H, dd,
J ¼ 1:4, 6.0 Hz), 4.51 (1H, t, J ¼ 5:1 Hz), 4.62 (2H, d, J ¼ 5:5
Hz), 5.19–5.22 (1H, m), 5.27–5.31 (1H, m), 5.80 (1H, dm, Jd ¼
9:0 Hz), 5.91 (1H, dm, Jd ¼ 5:5 Hz), 6.13–6.16 (2H, m); 13C NMR
(125 MHz, CDCl3, 323 K) ꢁ 25.7, 35.0, 40.0, 47.1, 58.7, 66.1,
66.9, 101.6, 103.8, 117.9, 130.6, 131.4, 132.4, 138.9, 151.9, 205.7;
HRMS (FABþ) Found: m=z 320.1941, Calcd for C17H22NO5:
ðM þ HÞþ, 320.1498.
6-Allyloxycarbonyl-7-[2-(1,3-dioxan-2-yl)ethylidene]-8-anti-
trimethylsilylmethyl-6-azabicyclo[3.2.1]oct-3-en-8-ol (18a).
Compound 18a was prepared from 17 in a similar manner as 18b
in 80% (conv. 84%) as a colorless oil.
IR (neat) 3487, 1712, 1398, 1304, 1246, 1140, 1018, 845 cmꢃ1
;
1H NMR (500 MHz, CDCl3, 323 K) ꢁ 0.06 (9H, s), 1.28 (1H, dd,
J ¼ 1:8, 13.4 Hz), 2.05 (1H, dtm, Jd ¼ 13:4, Jt ¼ 5:0 Hz), 2.24–
2.35 (3H, m), 2.24 (1H, s), 2.25–2.35 (2H, m), 2.54 (1H, dm,
Jd ¼ 18:8 Hz), 2.81–2.82 (1H, m), 3.72 (2H, dm, Jd ¼ 1:8 Hz),
4.05 (2H, dd, J ¼ 5:0, 10.9 Hz), 4.04–4.07 (1H, m), 4.50 (1H, t,
J ¼ 5:2 Hz), 4.60 (2H, d, J ¼ 4:9 Hz), 5.19 (1H, d, J ¼ 10:6 Hz),
5.28 (1H, d, J ¼ 17:2 Hz), 5.88–6.02 (4H, m); 13C NMR (125
MHz, CDCl3, 323 K) ꢁ 0.2, 25.7, 25.8, 30.8, 35.2, 45.3, 61.5,
65.6, 66.8, 66.8, 74.5, 102.0, 103.5, 117.3, 127.8, 131.4, 132.8,
143.3, 152.3.
6-Allyloxycarbonyl-7-[2-(1,3-dioxan-2-yl)ethylidene]-8-anti-
triethylsilylmethyl-6-azabicyclo[3.2.1]oct-3-en-8-ol (18b). To
a solution of ketone 17 (86.2 mg, 0.27 mmol) in Et2O (3.5 mL)
at ꢃ78 ꢂC was added triethylsilylmethylmagnesium bromide
(0.5 M solution in Et2O, 1.2 mL, 0.66 mmol). The reaction mixture
was stirred for 1 h at room temperature and was treated with aq
NH4Cl. The mixture was extracted with EtOAc, and the combined
organic extracts were washed with brine, dried over anhydrous
MgSO4, filtered, and evaporated. The residue was purified by col-
umn chromatography (SiO2; hexane:EtOAc = 3:1) to give 18b
(75.8 mg, 62%, conv. 81%) as a colorless oil.
6-Allyloxycarbonyl-7-[2-(1,3-dioxan-2-yl)ethyl]-8-anti-trieth-
ylsilylmethyl-6-azabicyclo[3.2.1]oct-3-en-8-ol (19b). To a solu-
tion of 18b (41.8 mg, 0.093 mmol) in CH2Cl2 (2 mL) at room tem-
perature was added an excess amount of sodium cyanoborohy-
dride and acetic acid (0.11 mL). The reaction mixture was stirred
for 48 h at room temperature, poured into aq NaHCO3 and extract-
ed with CH2Cl2. The combined organic extracts were washed with
brine, dried over anhydrous MgSO4, filtered, and evaporated. The
residue was purified by PTLC (SiO2; hexane:EtOAc = 3:1) to
yield 29.1 mg (69%, conv. 85%) of 19b as a colorless oil.
6-Allyloxycarbonyl-7-[2-(1,3-dioxan-2-yl)ethyl]-8-methylene-
6-azabicyclo[3.2.1]oct-3-en (20). To a solution of alcohol 19b
(61.0 mg, 0.135 mmol) in THF (3 mL) at room temperature was
added excess amount of KH. The mixture was stirred for 30 min,
and the reaction was quenched with ice water. The mixture was
extracted with EtOAc, and the combined organic extracts were
washed with brine, dried over anhydrous MgSO4, filtered, and
evaporated. The residue was purified by column chromatography
(SiO2) to yield 20 (37.3 mg, 87%) as a mixture of exo/endo iso-
mers (exo:endo = 2:1). The ratio of endo- and exo-20 was deter-
IR(neat) 2962, 2848, 1780, 1716, 1647, 1398, 1340, 1281,
1236, 1138, 1016, 787, 756 cmꢃ1 1H NMR (500 MHz, CDCl3)
;
ꢁ 0.56 (6H, q, J ¼ 8:0 Hz), 0.90 (9H, t, J ¼ 8:0 Hz), 1.05 (2H, s),
1.30 (1H, d, J ¼ 13:0 Hz), 2.03 (1H, dtt, J ¼ 4:6, 12.2, 13.0 Hz),
2.23–2.35 (4H, m), 2.53 (1H, brd, J ¼ 18:9 Hz), 2.78 (1H, brs),
3.72 (2H, dd, J ¼ 11:3, 13.0 Hz), 4.01 (1H, brs), 4.05 (2H, dd,
J ¼ 4:6, 11.3 Hz), 4.50 (1H, t, J ¼ 5:3 Hz), 4.58 (2H, brs), 5.19
(1H, d, J ¼ 10:4 Hz), 5.28 (1H, d, J ¼ 17:2 Hz), 5.88–6.08 (4H,
m); 13C NMR (125 MHz, CDCl3) ꢁ 4.6, 7.5, 20.6, 25.7, 30.9,
35.2, 45.2, 61.6, 65.5, 66.9, 74.4, 102.0, 103.4, 117.4, 127.8,
131.5, 132.7, 143.4, 152.2; Anal. Found: C, 63.93; H, 8.68; N,
3.00%. Calcd for C24H39NO5Si: C, 64.11; H, 8.74; N, 3.11%.
6-Allyloxycarbonyl-7-[2-(1,3-dioxan-2-yl)ethylidene]-8-anti-
dimethyl(phenyl)silylmethyl-6-azabicyclo[3.2.1]oct-3-en-8-ol
(18c). Compound 18c was prepared from 17 in a similar manner
as 18b in 69% as a colorless oil.
1
mined by H NMR. The mixture was separated by column chro-
matography (SiO2; benzene:EtOAc = 6:1). Since the low polar
material could be transformed to peduncularine, the compound
was assigned as the exo isomer and the high polar material was
assigned as the endo isomer. Compound 20 was also derived from
compounds 19a (70%), 19c (57%), 19d (64%), 19e (47%) in a
similar manner as 19b.
IR(neat) 2954, 2850, 1701, 1525, 1398, 1303, 1244, 1140,
1113, 1016, 831, 723, 700 cmꢃ1 1H NMR (500 MHz, CDCl3) ꢁ
;

M. Kitamura et al.
Bull. Chem. Soc. Jpn. Vol. 79, No. 10 (2006) 1559
exo-20: IR(neat) 2956, 2850, 1697, 1653, 1558, 1506, 1456,
1
was dissolved in CH3CN (4 mL). To this solution at room temper-
ature was added ethyldiisopropylamine (1.7 mL, 0.007 mmol),
isopropyl iodide (0.7 mL, 0.07 mmol), and the mixture was stirred
at 50 ꢂC for 7 h. The mixture was treated with brine containing
10% NaOH and was extracted with CH2Cl2. The combined organ-
ic extracts were washed with brine, dried over MgSO4, filtered,
and evaporated. The residue was purified by column chromatogra-
phy (alumina; EtOAc:hexane = 1:8) to afford 21 (15.8 mg, 72%)
as a colorless oil.
1396, 1254, 1140, 1093, 995 cmꢃ1; H NMR (500 MHz, CDCl3)
ꢁ 1.29 (1H, d, J ¼ 12:8 Hz), 1.39–1.49 (1H, m), 1.51–1.64 (2H,
m), 1.75–1.84 (1H, m), 1.98–2.09 (1H, m), 2.32 (1H, d, J ¼
18:1 Hz), 2.55–2.68 (2H, m), 3.61–3.75 (3H, m), 4.04–4.08 (2H,
m), 4.30 (1H, dd, J ¼ 5:7, 13.9 Hz), 4.58–4.60 (3H, m), 4.82 (1H,
d, J ¼ 4:4 Hz), 4.87 (1H, d, J ¼ 11:8 Hz), 5.17 (1H, d, J ¼ 10:5
Hz), 5.28 (1H, dd, J ¼ 1:4, 17.3 Hz), 5.53 (1H, m), 5.86–5.98
(1H, m), 6.12–6.33 (1H, m); 13C NMR (125 MHz, CDCl3) ꢁ
25.8, 28.4, 32.0, 38.5, 44.5, 56.8, 65.4, 65.5, 66.8, 102.3, 102.4,
116.9, 127.8, 132.7, 133.2, 147.8, 154.7; HRMS (FABþ) Found:
m=z 320.1857; Calcd for C18H26NO4: ðM þ HÞþ 320.1862.
endo-20: 1H NMR (500 MHz, CDCl3, 323 K) ꢁ 1.29 (1H, d,
J ¼ 13:3 Hz), 1.46–1.55 (4H, m), 2.05 (1H, tm, J ¼ 5:0 Hz), 2.41
(1H, dm, J ¼ 18:3 Hz), 2.49 (1H, d, J ¼ 18:3 Hz), 2.80–2.81 (1H,
m), 3.69–3.75 (2H, m), 3.79–3.80 (1H, m), 4.06 (2H, dm, J ¼ 5:0
Hz), 4.47–4.59 (1H, m), 4.51 (1H, t, J ¼ 4:6 Hz), 4.55 (2H, ddd,
J ¼ 1:2, 1.3, 5.4 Hz), 4.75 (1H, s), 5.17 (1H, dd, J ¼ 1:3, 10.5
Hz), 5.27 (1H, dd, J ¼ 1:2, 17.2 Hz), 5.61 (1H, dm, J ¼ 9:1 Hz),
5.88–5.96 (1H, m), 6.05–6.07 (1H, m); 13C NMR (125 MHz,
CDCl3, 323 K) ꢁ 25.9, 32.1, 32.6, 57.0, 61.5, 65.5, 66.9, 100.3,
102.3, 116.9, 128.7, 131.8, 133.4, 148.8.
6-Allyloxycarbonyl-7-[2-(1,3-dioxan-2-yl)ethyl]-8-anti-tri-
methylsilylmethyl-6-azabicyclo[3.2.1]oct-3-en-8-ol (19a). Com-
pound 19a was prepared from 18a in a similar manner as 19b in
74% (conv. 78%) as a colorless oil.
1H NMR (500 MHz, CDCl3, 323 K) ꢁ 0.05–0.08 (9H, m), 0.90–
1.60 (6H, m), 2.00–2.29 (5H, m), 2.41–2.61 (1H, m), 3.36–4.12
(6H, m), 4.48–4.58 (3H, m), 5.15–5.30 (2H, m), 5.86–5.92 (3H, m).
6-Allyloxycarbonyl-7-[2-(1,3-dioxan-2-yl)ethyl]-8-anti-dimeth-
yl(phenyl)silylmethyl-6-azabicyclo[3.2.1]oct-3-en-8-ol (19c).
Compound 19c was prepared from 18c in a similar manner as 19b
in 69% as a colorless oil.
IR(neat) 2964, 2926, 2850, 1734, 1684, 1558, 1507, 1457,
1374, 1146, 996, 755, 729 cmꢃ1 1H NMR (500 MHz, CDCl3) ꢁ
;
1.06 (3H, d, J ¼ 5:4 Hz), 1.07 (3H, d, J ¼ 5:4 Hz), 1.22–1.38 (3H,
m), 1.50–1.60 (2H, m), 1.99–2.08 (1H, m), 2.18 (1H, brd, J ¼
17:6 Hz), 2.34 (2H, brs), 2.53 (1H, brd, J ¼ 17:6 Hz), 2.83 (1H,
septet, J ¼ 5:4 Hz), 3.69–3.73 (3H, m), 4.06 (2H, dd, J ¼ 4:8,
11.1 Hz), 4.46 (1H, t, J ¼ 5:1 Hz), 4.75 (1H, s), 4.85 (1H, s),
5.67 (1H, brd, J ¼ 9:2 Hz), 5.87–5.89 (1H, m); 13C NMR (125
MHz, CDCl3) ꢁ 22.6, 23.3, 25.8, 32.9, 33.1, 40.1, 46.1, 50.8,
60.1, 66.8, 66.9, 69.5, 101.0, 102.3, 130.6, 132.9, 150.1; HRMS
(FABþ) Found: m=z 278.2124, Calcd for C17H28NO2: ðM þ HÞþ,
278.2120.
Peduncularine (1). A solution of 4% aqueous sulfuric acid
(1.4 mL) was heated to 50 ꢂC for 30 min. An excess amount of
phenylhydrazine hydrochloride (20.0 mg) was added to the heated
solution and the solid was allowed to dissolve over 10 min. The
hot solution was transferred to a flask containing 21 (4.8 mg,
0.017 mmol) and H2O (0.1 mL). After stirring for 40 min at reflux,
the reaction mixture was cooled to room temperature. To the mix-
ture was added saturated aqueous NaHCO3 and brine, and then the
mixture was extracted CH2Cl2. The organic extracts were washed
with brine, dried over Na2SO4, filtered, and evaporated. Purifica-
tion by column chromatography (alumina, hexane:EtOAc = 6:1)
gave peduncularine as a white foam (3.2 mg, 63%).
1H NMR (270 MHz) ꢁ 0.34–0.39 (6H, m), 1.55–1.58 (5H, m),
1.98–2.03 (3H, m), 2.10–2.65 (3H, m), 3.30–3.73 (3H, m), 3.82–
3.95 (1H, m), 4.02–4.06 (2H, m), 4.44–4.52 (3H, m), 5.16 (1H, dd,
J ¼ 1:4, 11.0 Hz), 5.26 (1H, d, J ¼ 11:0 Hz), 5.84–5.90 (3H, m),
7.30–7.33 (3H, m), 7.50–7.56 (2H, m).
6-Allyloxycarbonyl-7-[2-(1,3-dioxan-2-yl)ethyl]-8-anti-tri-
phenylsilylmethyl-6-azabicyclo[3.2.1]oct-3-en-8-ol (19d). Com-
pound 19d was prepared from 18d in a similar manner as 19b in
76% as a colorless oil.
1H NMR (270 MHz, CDCl3) ꢁ 1.21–1.50 (2H, m), 1.73–1.85
(3H, m), 1.86–2.17 (3H, m), 2.18–2.45 (3H, m), 3.63–3.90 (4H,
m), 4.03 (2H, d, J ¼ 11:6 Hz), 4.11–4.57 (3H, m), 5.11–5.32 (2H,
m), 5.69–5.91 (3H, m), 7.32–7.37 (9H, m), 7.49–7.66 (6H, m).
6-Allyloxycarbonyl-7-[2-(1,3-dioxan-2-yl)ethyl]-8-anti-triiso-
propylsilylmethyl-6-azabicyclo[3.2.1]oct-3-en-8-ol (19e). Com-
pound 19e was prepared from 18e in a similar manner as 18b in
69% as a colorless oil.
1H NMR (270 MHz, CDCl3) ꢁ 0.88–1.21 (21H, m), 1.28 (1H, d,
J ¼ 15:9 Hz), 1.33–1.56 (3H, m), 2.01–2.19 (3H, m), 2.20–2.32
(3H, m), 2.33–2.48 (1H, m), 3.68–3.92 (4H, m), 4.05 (2H, dd,
J ¼ 5:9, 11.6 Hz), 4.48–4.60 (3H, m), 5.16 (1H, d, J ¼ 10:5 Hz),
5.25 (1H, d, J ¼ 16:5 Hz), 5.84–5.96 (3H, m).
IR (neat) 2964, 2926, 2850, 1734, 1684, 1558, 1507, 1457,
1374, 1146, 996, 755, 729 cmꢃ1 1H NMR (500 MHz, CDCl3) ꢁ
;
1.15 (3H, d, J ¼ 6:2 Hz), 1.29 (3H, d, J ¼ 6:3 Hz), 2.05 (1H, ddt,
J ¼ 1:7, 3.2, 17.6 Hz), 2.44 (1H, ddt, J ¼ 2:3, 4.7, 17.6 Hz), 2.49
(1H, br d, J ¼ 4:3 Hz), 2.69 (1H, dd, J ¼ 11:4, 14.7 Hz), 2.87 (1H,
br d, J ¼ 11:4 Hz), 2.93 (1H, br d, J ¼ 15:0 Hz), 2.98 (1H, septet,
J ¼ 6:3 Hz), 3.83 (1H, d, J ¼ 4:9 Hz), 4.80 (1H, s), 4.94 (1H, s),
5.67 (1H, br d, J ¼ 9:2 Hz), 5.93 (1H, ddt, J ¼ 2:0, 5.3, 9.2 Hz),
6.97 (1H, s), 7.11 (1H, t, J ¼ 7:4 Hz), 7.18 (1H, t, J ¼ 7:4 Hz),
7.35 (1H, d, J ¼ 8:1 Hz), 7.59 (1H, d, J ¼ 7:9 Hz), 7.99 (1H, s);
13C NMR (125 MHz, CDCl3) ꢁ 22.7, 23.6, 34.2, 40.1, 45.8, 50.9,
60.4, 69.8, 101.4, 111.0, 115.1, 119.1, 119.3, 121.3, 122.0, 127.8,
128.5, 130.6, 136.1, 150.0; HRMS (FABþ) Found: m=z 278.2124,
Calcd for C17H28NO2: ðM þ HÞþ 278.2120.
This work was supported by Grant-in-Aid for Scientific
Research on Priority Areas 17035018 from The Ministry of
Education, Culture, Sports, Science and Technology (MEXT).
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2
3
4

1560 Bull. Chem. Soc. Jpn. Vol. 79, No. 10 (2006)
Synthesis of Peduncularine
is temporary employed in the formula 16.
17 Hydride attack to carbonyl group in 16 would be occurred
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16
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ꢀ
ꢀ
16 Although all the compounds are racemic, Si -Re notation