A new strategy for the synthesis of (±)-Lupinine and (±)-epilupinine via cyclization of α-sulfinyl carbanions

Article abstract of DOI:10.1055/s-2008-1067027

(±)-Lupinine and (±)-epilupinine have been prepared starting from commercially available δ-valerolactam. The synthetic route involves the advantages of the cyclization based on α-sulfmyl carbanions.

Full text of DOI:10.1055/s-2008-1067027

PAPER
1733
A New Strategy for the Synthesis of ( )-Lupinine and ( )-Epilupinine via
Cyclization of a-Sulfinyl Carbanions
Synthesis of
(
)-Lupin
a
ine and (
)
-
n
Epilupinine at Pohmakotr,* Anusorn Seubsai, Pornthep Numeechai, Patoomratana Tuchinda
Department of Chemistry, Faculty of Science, Mahidol University, Rama VI Road, Bangkok 10400, Thailand
Fax +66(2)6445126; E-mail: scmpk@mahidol.ac.th
Received 12 February 2008
Dedicated to Professor Dieter Seebach on the occasion of his 70th birthday
O
O
Abstract: ( )-Lupinine and ( )-epilupinine have been prepared
starting from commercially available d-valerolactam. The synthetic
route involves the advantages of the cyclization based on a-sulfinyl
carbanions.
a, b
NH
N
SPh
(O)n
3, n = 0
4, n = 1
Key words: ( )-lupinine, ( )-epilupinine, a-sulfinyl carbanion,
cyclization
c
SOPh
SOPh
H
N
d
Quinolizidine alkaloids are important class of compounds
as they are frequently encountered in a large number of
natural products. Among these compounds, the lupin al-
kaloids are of particular interest due to their wide range of
biological activities. Lupinine and epilupinine belonging
to this class of alkaloid have been isolated from the aerial
parts of plants in genus Lupinus, such as Lupinus leteus,
Lupinus albu.1 growing wild in North Africa, South Eu-
rope, North America, and Australia. Their relatively sim-
ple bicyclic quinolizidine structures and the interesting
biological activities have challenged organic chemists to
find an efficient approach to the synthesis of lupinine and
epilupinine.2
N
6
5
e
SOPh
CO2Et
H
N
H
N
CO2Et
f
8
7
i
g
CO2Et
CO2Et
H
H
N
We have recently developed a general route to 1-azabicy-
clo[m.n.0]alkanes including the quinolizidine skeleton via
cyclization based on a-sulfinyl carbanions.3 It is anticipat-
ed that the use of this method would permit a simple prep-
aration of ( )-lupinine (1) and ( )-epilupinine (2). As
summarized in Scheme 1, our strategy involves an in-
tramolecular nucleophilic addition of a-sulfinyl carbanion
onto the carbonyl group of the amide moiety leading to the
key intermediate quinolizidine containing a phenylsulfi-
nyl group. The synthesis started with N-alkylation of the
readily available d-valerolactam with 4-bromo-1-phenyl-
sulfanylbutane employing NaH in DMF at 0 °C to room
temperature to give sulfide 3 in 91% yield. This was fol-
lowed by oxidation with NaIO4 in aqueous methanol at
0 °C to room temperature to provide the corresponding
sulfoxide 4 in 91% yield. The key cyclization step for the
construction of the quinolizidine derivative 5 was carried
out by treatment of the sulfoxide 4 with 2.2 equivalents of
N
9
j
h
CH2OH
CO2Et
H
N
H
N
10
( )-lupinine (1)
k
CH2OH
H
N
( )-epilupinine (2)
Scheme 1 Reagents and conditions: (a) NaH, DMF, PhS(CH2)4Br,
0 °C to r.t.; (b) NaIO4, MeOH, H2O, 0 °C; (c) LiHMDS, THF, –78 °C
to r.t.; (d) NaBH4, MeOH, 0 °C; (e) LDA (1.5 equiv), THF, –78 °C
(1 h); ethyl chloroformate (2.2 equiv), –78 °C, 2 h and r.t., 1 h; (f)
toluene, reflux; (g) H2, PtO2, MeOH; (h) LiAlH4, Et2O; (i) Mg,
MeOH, 2 h; (j) NaOEt, EtOH, reflux, overnight; (k) LiAlH4, Et2O.
SYNTHESIS 2008, No. 11, pp 1733–1736
Advanced online publication: 16.04.2008
x
x.
x
x
.
2
0
0
8
DOI: 10.1055/s-2008-1067027; Art ID: P02008SS
© Georg Thieme Verlag Stuttgart · New York

1734
M. Pohmakotr et al.
PAPER
60H and 60 PF245 were used for column chromatography and pre-
parative TLC, respectively.
lithium hexamethyldisilazide (LiHMDS) in THF over-
night at –78 °C to room temperature, followed by reduc-
tion of the labile unsaturated quinolizidine 5 with NaBH4
in methanol at 0 °C. The expected quinolizidine 6 was ob-
tained in 94% overall yield as a mixture of two diaste-
reomers, the ratio of which ratio could not be determined
by H NMR spectroscopy. However, the major 1,8a-cis-
isomer could be obtained by fractional crystallization
from ethyl acetate.
1-(4-Phenylsulfanylbutyl)piperidin-2-one (3)
To a suspension of NaH (2.42 g, 55 mmol, 55% suspension in min-
eral oil) in DMF (100 mL) was slowly added a DMF (8 mL) solu-
tion of d-valerolactam (5.0 g, 50 mmol) at 0 °C under argon. The
mixture was stirred for 1 h until the generation of H2 ceased, and 1-
bromo-4-phenylsulfanylbutane (1.594 g, 55 mmol) was then added.
After stirring the mixture overnight (15 h) at 0 °C to r.t., it was
quenched with H2O (2 × 50 mL) and extracted with EtOAc (4 × 100
mL). The combined organic layers were washed with H2O (2 × 50
mL) and brine (50 mL), and dried (Na2SO4). Filtration followed by
evaporation in vacuo afforded a residue, which was purified by col-
umn chromatography (SiO2, 80% in hexanes) to give 3 as a pale yel-
low liquid; yield: 12.09 g (91%).
1
The formation of compound 5 resulted from the intramo-
lecular nucleophilic addition of the a-sulfinyl carbanion
derived from the sulfoxide lactam 4 onto the amide group
followed by dehydration during workup.
The key starting intermediate 8 was prepared in two steps
by carboethoxylation of the sulfinylquinolizidine 6 and
sulfoxide elimination. Thus, lithiation of the diastereo-
meric mixture of 6 with lithium diisopropylamide (LDA)4
in THF followed by treatment with ethyl chloroformate
gave compound 7, which was subjected to sulfoxide elim-
ination by refluxing in anhydrous toluene to give the re-
quired compound 8 in 48% yield after chromatographic
purification.
IR (neat): 1638, 1584, 1494, 1481, 1466, 1353, 1300, 741, 692 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.26–7.17 and 7.10–7.06 (2 m, 5
H), 3.28 (t, J = 6.8 Hz, 2 H), 3.15 (br s, 2 H), 2.87 (t, J = 6.5 Hz, 2
H,), 2.27 (br s, 2 H, CH2CON), 1.67–1.58 (m, 8 H).
13C NMR (75 MHz, CDCl3): d = 169.6 (C=O), 136.3 (C), 129.0 (2
CH), 128.7 (2 CH), 125.7 (CH), 47.6 (CH2), 46.2 (CH2), 33.2 (CH2),
32.2 (CH2), 26.2 (CH2), 25.9 (CH2), 23.1 (CH2), 21.2 (CH2).
MS: m/z (%) = 264 (M+ + 1), 154 (100), 112 (77), 84 (71), 56 (18).
Anal. Calcd for C15H21NOS: C, 68.63; H, 8.04; N, 5.32. Found: C,
68.33; H, 8.22; N, 5.02.
Having compound 8 in hand, the preparation of ( )-lupin-
ine (1) and ( )-epilupinine (2) was performed as summa-
rized in Scheme 1. Catalytic hydrogenation of unsaturated
ester 8 using PtO2 as a catalyst in methanol afforded cis-
quinolizidine ester 9 in 80% yield as the sole isomer. Re-
duction of the ester group of 9 with LiAlH4 in anhydrous
diethyl ether furnished ( )-lupinine (1) in 80% yield.5a,b
On the other hand, the reaction of 8 with Mg in methanol
under reflux provided a mixture of cis- and trans-isomers
of the corresponding mixture of methyl and ethyl ester de-
1-(4-Phenylsulfinylbutyl)piperidin-2-one (4)
A solution of 3 (6.32 g, 24 mmol) in MeOH (15 mL) was slowly
added to a cooled (0 °C) suspension of NaIO4 (5.6487 g, 26 mmol)
in MeOH (58 mL) and H2O (14 mL). The mixture was stirred vig-
orously and slowly warmed up overnight (16 h) from 0 °C to r.t. The
precipitate of NaIO3 was filtered and washed with EtOAc (4 × 70
mL). The combined extracts were washed with H2O (2 × 25 mL)
and brine (25 mL), and dried (Na2SO4). Filtration followed by evap-
oration in vacuo gave a residue, which was purified by column chro-
rivatives of 10. Treatment of 10 with sodium ethoxide in matography (SiO2, 100% EtOAc to 2% MeOH in EtOAc) to
provide 4 as a colorless viscous liquid; yield: 6.073 g (91%).
IR (neat): 1634, 1496, 1467, 1444, 1044, 753, 694 cm–1.
refluxing ethanol was done in order to equilibrate the less
stable cis-isomer to the thermodynamically more stable
trans-isomer of the quinolizidine ester 10 and to perform
transesterification of the methyl ester into the ethyl ester
(78% yield).6 Finally, ( )-epilupinine (2) was prepared in
71% yield by reduction of trans-quinoline ester 10 with
LiAlH4 in diethyl ether.5a
1H NMR (300 MHz, CDCl3): d = 7.52–7.48 and 7.42–7.38 (2 m, 5
H), 3.2 (app t, J = 5.9 Hz, 2 H), 3.12 (br s, 2 H), 2.74 (q, J = 8.8 Hz,
2 H), 2.20 (br s, 2 H), 1.67–1.58 (m, 8 H).
13C NMR (75 MHz, CDCl3): d = 169.4 (C=O), 143.2 (C), 130.6
(CH), 128.8 (2 CH), 123.6 (2 CH), 55.9 (CH2), 44.4 (CH2), 45.4
(CH2), 31.8 (CH2), 25.5 (CH2), 22.8 (CH2), 20.9 (CH2), 18.9 (CH2).
In summary, we have demonstrated a short entry to ( )-lu-
pinine (1) and ( )-epilupinine (2) starting from commer-
cially available d-valerolactam by using the synthetic
utilities of cyclization based on a-sulfinyl carbanions.
MS: m/z (%) = 279 (M+, 2), 262 (78), 165 (47), 154 (86), 112 (69),
84 (100), 56 (44).
HRMS (ESI-TOF): m/z calcd for C15H21NO2S: 279.1298; found:
279.1291.
1
The H and 13C NMR spectra were recorded on Bruker DPX-300
1-Benzenesulfinyloctahydroquinolizidine (6)
(300 MHz) spectrometer in CDCl3 using tetramethylsilane as an in-
ternal standard. Melting points were recorded on a Büchi 501 Melt-
ing Point Apparatus and were uncorrected. The IR spectra were
recorded on a GX FT-IR system Perkin-Elmer IR spectrometer. The
mass spectra were recorded by using a Thermo Finnigan Polaris Q
mass spectrometer. The high-resolution mass spectra were recorded
on HR-TOF-MS Micromass spectrometer. The elemental analyses
were performed by a Perkin-Elmer Elemental Analyzer 2400 CHN.
All glassware and syringes were oven-dried and kept in a desiccator
before use. The molarity of n-BuLi (in hexane) was determined by
titration with diphenylacetic acid in THF at 0 °C. THF was distilled
from sodium benzophenone ketyl. i-Pr2NH, hexamethyldisilazane,
and toluene were dried by distilling over CaH2. Merck silica gel
n-BuLi (1.35 M in hexane; 52.93 mL, 71.45 mmol) was added to a
cooled (–78 °C) THF (292 mL) solution of hexamethyldisilazane
(HMDS) (1 mL, 4.8 mmol) under argon. After stirring at –78 °C for
40 min, a THF (64 mL) solution of 4 (9.061 g, 32 mmol) was added
dropwise. The resulting mixture was allowed to stir and slowly
warmed up overnight (15 h) from –78 °C to r.t. The resulting yellow
solution was quenched with H2O (100 mL) and extracted with
EtOAc (4 × 100 mL). The combined organic layers were washed
with H2O (2 × 50 mL) and brine (50 mL) and dried (Na2SO4). Fil-
tration followed by evaporation in vacuo to dryness afforded a vis-
cous yellow liquid of crude 9-benzenesulfinyl-1,3,4,6,7,8-
hexahydro-2H-quinolizine (5; yield: 8.22 g, 31 mmol), which was
Synthesis 2008, No. 11, 1733–1736 © Thieme Stuttgart · New York

PAPER
Synthesis of ( )-Lupinine and ( )-Epilupinine
1735
directly subjected to reduction by using NaBH4 as follows. To a so-
lution of the crude product 5 in MeOH (160 mL) at 3–5 °C under
argon, was added NaBH4 (7.614 g, 201 mmol) in a small portion
over 4 h. The mixture was stirred for 1 h at the same temperature,
diluted with aq 1 N NaOH (100 mL) and extracted with EtOAc (3 ×
100 mL). The combined extracts were washed with H2O (2 × 50
mL) and brine (50 mL), and dried (Na2SO4). Filtration followed by
evaporation in vacuo gave a residue, which was purified by column
chromatography (SiO2, 2% MeOH in EtOAc containing 0.15%
NH4OH) to afford a white semi-solid of 6 as a mixture of two dia-
stereomers; yield: 8.034 g (94%). The major diastereomer could be
obtained by fractional crystallization from EtOAc to give 1,9-cis-6
as a white solid; mp 112–113 °C). The minor diastereomer could
not be separated.
Ethyl (1R*,9aR*)-Octahydro-2H-quinolizine-1-carboxylate (9)
To a solution of 8 (70 mg, 0.364 mmol) in anhyd MeOH (2 mL) was
added PtO2 (8.25 mg, 0.0364 mmol). The reaction flask was con-
nected via a two-way tap connected to a balloon of H2 at atmospher-
ic pressure and a vacuum pump. It was evacuated and flushed with
H2 several times to remove the air. Then it was stirred for 16 h while
maintaining an atmosphere of H2 at a slight positive pressure. At the
end of this time, the H2 was disconnected and the reaction flask was
flushed with N2. The catalyst was removed by filtration, followed
by evaporation in vacuo to provide a residue, which was purified by
TLC (SiO2, 0.15% NH4OH in EtOAc) to give 9 as a pale yellow liq-
uid; yield: 61 mg (80%).
IR (neat): 1733, 1444, 1373, 1318, 1146, 1035 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.11 (m, 2 H, OCH2), 2.87–2.84
(m, 2 H), 2.05 (t, J = 4.1 Hz, 1 H), 2.15–1.93 (m, 4 H), 1.90–1.80
(m, 1 H), 1.75–1.65 (m, 1 H), 1.65–1.40 (m, 6 H), 1.30–1.15 (m, 1
H), 1.18 (t, J = 7.0 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 173.4 (C=O), 62.6 (CH), 59.8
(CH2), 56.9 (CH2), 54.6 (CH2), 44.4 (CH), 28.5 (CH2), 26.1 (CH2),
24.8 (CH2), 24.2 (CH2), 22.1 (CH2), 14.2 (CH3).
IR (Nujol): 2749, 1463, 1446, 1302, 1084, 1034, 752, 690 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.66–7.63 and 7.53–7.43 (2 m, 5
H), 3.01 (m, 2 H), 2.73 (t, J = 4.0 Hz, 1 H), 2.41 (app d, J = 11.9 Hz,
1 H), 2.30–2.18 (m, 2 H), 2.20–2.10 (m, 1 H), 2.14–2.06 (m, 1 H),
2.06–1.93 (m, 1 H), 1.89–1.80 (m, 1 H), 1.79–1.63 (m, 1 H), 1.55–
1.46 (m, 3 H), 1.49–1.40 (m, 1 H), 1.38–1.27 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 145.9 (C), 130.5 (CH), 129.0 (2
CH), 124.7 (2 CH), 66.3 (CH), 62.9 (CH), 56.8 (CH2), 54.4 (CH2),
28.5 (CH2), 24.9 (CH2), 23.9 (CH2), 22.9 (CH2), 21.9 (CH2).
MS: m/z (%) = 211 (M+, 14), 182 (60), 137 (100), 110 (57), 98 (40),
82 (39).
These spectroscopic data are in agreement with those reported in the
literature.5a,b
MS: m/z (%) = 264 (M+ + 1, 8), 246 (100), 136 (93), 110 (30).
Anal. Calcd for C15H21NOS: C, 68.04; H, 8.04; N, 5.32. Found: C,
68.26; H, 8.15; N, 5.67.
1R*,9aR*)-Octahydro-2H-quinolizine-1-ylmethanol [( )-Lupi-
nine (1)]
3,6,7,8,9,9a-Hexahydro-4H-quinolizine-1-carboxylic Acid
Ethyl Ester (8)
A solution of 9a (83 mg, 0.393 mmol) in anhyd Et2O (3 mL) was
added to a stirred suspension of LiAlH4 (33 mg, 0.865 mmol) in an-
hyd Et2O (2 mL) at 0 °C under argon. The resulting mixture was re-
fluxed for 4 h, cooled to 0 °C, and quenched by sequential addition
of EtOAc (5 mL) and H2O (0.5 mL). The mixture was filtered
through Celite. The filtrate was evaporated to give a crude product,
which was purified by TLC on silica gel (SiO2, 0.15% NH4OH in
EtOAc) to give ( )-lupinine (1) as a pale yellow solid; yield: 49 mg
(74% yield); mp 55–56 °C (EtOAc) (Lit.5a mp 55–57 °C).
A solution of 6 (3.95 g, 15 mmol) in THF (30 mL) was added drop-
wise at –78 °C to a THF solution of LDA [prepared by reacting i-
Pr2NH (3.50 mL, 24.75 mmol) in THF (90 mL) with n-BuLi (1.35
M in hexane, 16.7 mL. 22.5 mmol) at –78 °C for 30 min ] under ar-
gon. After stirring for 30 min, ethyl chloroformate (3.15 mL, 33
mmol) was added dropwise. The resulting mixture was stirred at
–78 °C for 2 h and at r.t. for 1 h. It was quenched with H2O (50 mL)
and extracted with EtOAc (4 × 50 mL). The combined organic lay-
ers were washed with H2O (50 mL) and brine (50 mL) and dried
(Na2SO4). The organic phase was concentrated to give a yellow vis-
cous liquid of the crude product 1-benzenesulfinyloctahydroquino-
lizine-1-carboxylic acid ethyl ester (7), which was directly
subjected to sulfoxide elimination by refluxing in toluene as fol-
lows. A solution of the crude product 7 (3.954 g, 12 mmol) in anhyd
toluene (140 mL) in the presence of CaCO3 (0.5 g) was stirred at re-
flux under argon for 16 h. The mixture was filtered and the filtrate
was evaporated to dryness to give a crude product, which was puri-
fied by column chromatography (SiO2, 80% EtOAc in hexanes) to
provide 85a as a yellow liquid; yield: 1.52 g (48%).
IR (neat): 3391, 1468, 1445, 1351, 1296, 1067 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.12 (br s, 1 H, OH), 4.07 (d,
J = 7.0 Hz, 1 H), 3.63 (d, J = 10.8 Hz, 1 H), 2.81–2.74 (m, 2 H),
2.12–1.64 (m, 7 H), 1.60–1.45 (m, 6 H), 1.30–1.25 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 65.6 (CH2), 64.9 (CH), 56.9 (2
CH2), 38.2 (CH), 30.9 (CH), 29.4 (CH2), 25.3 (CH2), 24.5 (CH2),
22.8 (CH2).
MS: m/z (%) = 169 (M+, 42), 168 (89), 152 (94), 138 (82), 110 (61),
98 (100), 83 (50).
These spectroscopic data are in agreement with those reported in the
literature.7
IR (neat): 1714, 1466, 1255, 1173, 1097, 1051 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.78–6.76 (m, 1 H), 4.19–1.03 (m,
2 H), 2.98–2.94 (m, 1 H), 2.89–2.84 (m, 1 H), 2.78–2.73 (m, 1 H),
2.48–2.33 (m, 1 H), 2.46–2.33 (m, 1 H), 2.17–2.11 (m, 1 H), 2.11–
2.05 (m, 1 H), 2.02–2.01 (m, 1 H), 1.76–1.71 (m, 1 H), 1.64–1.45
(m, 2 H), 1.45–1.31 (m, 1 H,), 1.21 (t, J = 7.1 Hz, 3 H), 1.20–1.06
(m, 1 H).
13C NMR (75 MHz, CDCl3): d = 166.4 (C=O), 136.7 (CH), 133.8
(C), 60.2 (CH), 59.9 (CH2), 55.9 (CH2), 48.8 (CH2), 28.5 (CH2),
26.3 (CH2), 24.9 (CH2), 24.4 (CH2), 14.1 (CH3).
Ethyl (1R*,9aS*)-Octahydro-2H-quinolizine-1-carboxylate
(10)6a,b
A solution of 8 (1.033 g, 0.48 mmol) in MeOH (5 mL) and Mg turn-
ings (0.12 g, 4.80 mmol) were stirred and refluxed under argon for
3 h, then cooled to r.t. and diluted with H2O (50 mL). The white pre-
cipitate was filtered and washed with EtOAc (4 × 50 mL). The com-
bined organic layers were washed with H2O (2 × 25 mL) and brine
(25 mL), and dried (Na2SO4). The organic phase was concentrated
to give a pale yellow viscous liquid of a crude product containing a
mixture of ethyl and methyl octahydro-2H-quinolizine-1-ylmeth-
anol (90.1 mg), which was directly subjected to epimerization and
transesterification by using in NaOEt in EtOH as follows. A solu-
tion of the crude product in EtOH (2 mL) at r.t. under argon was
added to a NaOEt solution in EtOH [2 mL, prepared by reacting Na
(40 mg, 1.74 mmol) with EtOH (2 mL)]. The mixture was stirred
MS: m/z (%) = 210 (M+ + 1, 100), 209 (M+, 39), 180 (94), 137 (53),
136 (40), 124 (47).
These spectroscopic data are in agreement with those reported in the
literature.5a
Synthesis 2008, No. 11, 1733–1736 © Thieme Stuttgart · New York

1736
M. Pohmakotr et al.
PAPER
under reflux overnight (16 h). After cooling the mixture to r.t., it
was diluted with H2O (10 mL) and extracted with EtOAc (3 × 20
mL). The combined organic layers were washed with H2O (15 mL)
and brine (15 mL) and dried (Na2SO4). The organic phase was con-
centrated to give a pale yellow viscous liquid of the crude product,
which was purified by TLC on silica gel (SiO2, 0.15% NH4OH in
EtOAc) to give 10 as a pale yellow liquid of; yield: 79 mg (78%).
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IR (neat): 1733, 1445, 1259, 1172, 1131, 1035 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.07 (q, J = 7.1 Hz, 2 H), 2.75 (t,
J = 11.3 Hz, 2 H), 2.24–2.16 (m, 1 H), 2.07–1.92 (m, 3 H), 1.88–
1.83 (m, 1 H), 1.64–1.37 (m, 7 H), 1.28–1.13 (m, 2 H), 1.19 (t,
J = 7.2 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 174.8 (C=O), 63.5 (CH), 60.2
(CH2), 56.6 (CH2), 55.9 (CH2), 49.3 (CH), 30.7 (CH2), 28.6 (CH2),
25.6 (CH2), 24.4 (CH2), 24.2 (CH2), 14.2 (CH3).
MS: m/z (%) = 211 (M+, 20), 182 (100), 178 (31), 138 (69), 110
(62), 96 (60), 83 (43).
These spectroscopic data are in agreement with those reported in the
literature.6a,b
(1R*,9aS*)-Octahydro-2H-quinolizine-1-ylmethanol [( )-Epi-
lupinine (2)]
As described for ( )-lupinine (1), a solution of 10 (80 mg, 0.38
mmol) in anhyd Et2O (3 mL) was added to a stirred suspension of
LiAlH4 (32 mg, 0.83 mmol) in anhyd Et2O (2mL) at 0 °C under ar-
gon to give ( )-epilupinine (2) as a colorless solid; yield. 45 mg
(71%); mp 80–81 °C (Lit.7a mp 79–80 °C.
IR (neat): 3347, 1466, 1358, 1296, 1113, 1067 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.56 (dq, J = 15.7, 3.2 Hz, 2 H),
2.77 (t, J = 11.9 Hz, 2 H), 2.03–1.44 (m, 3 H), 1.86–1.55 (m, 8 H),
1.45–1.35 (m, 1 H), 1.30–1.10 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 64.3 (CH), 64.1 (CH2), 56.5 (CH2),
56.1 (CH2), 43.1 (CH), 28.9 (CH2), 27.7 (CH2), 24.8 (CH2), 24.2
(CH2), 24.1 (CH2).
(3) Pohmakotr, M.; Numechai, P.; Prateeptongkum, S.;
Tuchinda, P.; Reutrakul, V. Org. Biomol. Chem. 2002, 1,
3495.
(4) Lithiation of p-tolylsulfinyl-substituted quinolizidine: Hua,
D. H.; Bharathi, S. N.; Robinson, P. D.; Tsujimoto, A.
J. Org. Chem. 1990, 55, 2128.
(5) (a) Kurihara, T.; Matsubara, Y.; Osaki, H.; Harusawa, S.;
Yoneda, R. Heterocycles 1990, 30, 885. (b) Bohlmann, F.;
Habeck, D.; Poetsch, E.; Schumann, D. Chem. Ber. 1967,
100, 2742.
MS: m/z (%) = 169 (M+, 44), 168 (93), 152 (91), 138 (84), 124 (68),
110 (64), 96 (100), 82 (83).
These spectroscopic data are in agreement with those reported in the
literature.7
(6) (a) Tufariello, J. J.; Tegeler, J. T. Tetrahedron Lett. 1976, 45,
4037. (b) Goldberg, S. F.; Lipkin, A. H. J. Org. Chem. 1970,
35, 4037.
(7) (a) Takahara, H.; Yamabe, K.; Suzuki, T.; Yamazaki, T.
Chem. Pharm. Bull. 1986, 34, 4523. (b) Hua, D. H.; Miao,
S. W.; Bravo, A. A.; Takemoto, D. J. Synthesis 1991, 970.
(c) Haung, H.-L.; Sung, W.-S.; Liu, R.-S. J. Org. Chem.
2001, 66, 6193.
Acknowledgment
We thank the Center for Innovation in Chemistry: Postgraduate
Education and Research Program in Chemistry (PERCH-CIC), the
Thailand Research Fund (BRG49800005), and the Commission of
Higher Education (CHE-RES-RG) for financial support.
Synthesis 2008, No. 11, 1733–1736 © Thieme Stuttgart · New York