Short total synthesis of (-)-lupinine and (-)-epiquinamide by double Mitsunobu reaction

Article abstract of DOI:10.1055/s-0030-1258356

Alternative total syntheses of (-)-lupinine (1) and (-)-epiquinamide (2) have been described via the key intermediate 3 obtained from the addition of 2-trialkylsilyloxyfuran 5 to N-acyliminium intermediate derived from 4. The major R,R-isomer 8 obtained from the Mannich reaction was converted into its R,S-isomer through Mitsunobu reaction. Then, a second Mitsunobu reaction of 3 led to cyano 9 and azido 11 derivatives, which were converted into 1 and 2 in 33 and 36% overall yield from 4, respectively. The synthetic route is amenable for the generation of several quinolizidine alkaloids. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1258356

PAPER
51
Short Total Synthesis of (–)-Lupinine and (–)-Epiquinamide by Double
Mitsunobu Reaction
S
hor
t
Total Syn
e
thesis of (–
o
)-Lupinine and (–)-Epiqu
a
inamide rdo Silva Santos,*a Yaneris Mirabal-Gallardo,a Nagula Shankaraiah,a,b Mario J. Simirgiotisc
a
Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources, University of Talca, P.O. Box 747, Talca, Chile
Fax +56(71)200448; E-mail: lssantos@utalca.cl
b
c
National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India
Laboratory of Natural Products, Department of Chemistry, Faculty of Basic Sciences, University of Antofagasta,
P.O. Box 170, Antofagasta, Chile
Received 20 July 2010; revised 13 September 2010
chiral quinolizidines based on 8-phenylmenthyl induc-
tion.
Abstract: Alternative total syntheses of (–)-lupinine (1) and (–)-
epiquinamide (2) have been described via the key intermediate 3
obtained from the addition of 2-trialkylsilyloxyfuran 5 to N-
acyliminium intermediate derived from 4. The major R,R-isomer 8
obtained from the Mannich reaction was converted into its R,S-iso-
mer through Mitsunobu reaction. Then, a second Mitsunobu reac-
tion of 3 led to cyano 9 and azido 11 derivatives, which were
converted into 1 and 2 in 33 and 36% overall yield from 4, respec-
tively. The synthetic route is amenable for the generation of several
quinolizidine alkaloids.
As part of our efforts in the field of biologically relevant
quinolizidines, attention was turned toward an alternative
synthetic route for (–)-lupinine4 and (1R,9aR)-epiquin-
amide,5 figured out through the addition of siloxyfuran 5
to key iminium intermediate derived from 4. Recently, we
reported enantioselective total syntheses of arborescidine
alkaloids,6a (–)-quinolactacin B antibiotic,6b PDE5 inhibi-
tors,6c noscapine, bicuculline, and egenine, as well as cap-
noidine and corytensine alkaloids.3e
Key words: quinolizidine alkaloids, azido reduction, nickel boride,
microwave irradiation, Mitsunobu reaction
Structurally, compounds 1 and 2 comprise a common
quinoline core. Our approach to lupinine (1) and epiquin-
amide (2) is based on the preparation of azabicyclo com-
pound 3 through the addition of silyloxyfuran 5 to an N-
acyliminium ion derived from 4, followed by the intro-
duction of the CH2OH and NHAc groups based on double
stereoselective Mitsunobu reactions (Scheme 1). Al-
though demonstrated as a useful synthetic method, these
asymmetric additions remain to be fully explored in the
arena of total syntheses of alkaloid natural products.
The search towards efficient stereoselective methodolo-
gies for the construction of organic molecules with en-
hanced complexity and functions continues to challenge
chemists. Over the last few years 2-trialkylsilyloxyfurans1
have been used as versatile reagents for the preparation of
several enantiomerically pure compounds of biological
interest.2 We have investigated the nucleophilic addition
of carbon nucleophiles to cyclic N-acyliminium ions and
found the relevant role played by the N-acyliminium ring
size in the stereochemical outcome of the reaction.3 As
studies involving the intermolecular nucleophilic addition
of 2-trialkylsilyloxyfurans to cyclic N-acyliminium ions
are so far restricted to five-membered N-acyliminium ion
rings and mainly to N-carbobenzyloxy derivatives,2 it was
decided to explore these studies for the construction of
Our investigation began by examining the addition of dif-
ferent silyloxyfurans 5 (R = Me, Bu, i-Pr) to the N-
acyliminium ion derived from chiral 2-methoxypiperidine
carbamate 42g,3c (Scheme 2). Previously, D’oca and co-
workers reported the addition of 2-tributylsilyloxyfuran to
4 achieving a low diastereoselectivity of 6 (2:1, threo/
erythro) in 73% yield.2g Furthermore, it was observed that
H
CH2OH
N
H
1
OH
+
N
OMe
OSiR3
N
O
O
O
5
H
3
Ph
NHAc
4
N
2
Scheme 1 Retrosynthetic analysis of (–)-lupinine and (1R,9aR)-epiquinamide based on the key intermediate 3
SYNTHESIS 2011, No. 1, pp 0051–0056
x
x
.
x
x
.2
0
1
1
Advanced online publication: 08.12.2010
DOI: 10.1055/s-0030-1258356; Art ID: M05210SS
© Georg Thieme Verlag Stuttgart · New York

52
L. S. Santos et al.
PAPER
the nature of solvent, Lewis acids, and additives have
great influence on selectivities in this kind of reactions.3
Thus, the scope of the addition of 5 to the N-acyliminium
ion derived from carbamate 4 was investigated with and
without additives in different conditions (Table 1). First,
TMSOTf as Lewis acid was used in a mixture of solvent
(THF–CH2Cl2), which proved to improve selectivities for
the addition of silyloxyfurans to cyclic N-acyliminium
ions.3,6 Table 1 shows the addition of nucleophiles 5a–c in
the absence of additives affording threo-6 isomer in dia-
stereoisomeric ratios ranging from 4.5–8.1:1 (threo/erythro)
when TMSOTf was used as Lewis acid. The reactions
proceeded in reaction times of around 7 hours in 75–76%
yields (Table 1, entries 1–3). Then, 5c was selected as nu-
cleophile and TiCl4 and TIPSOTf were used as Lewis acid
(Table 1, entries 4, 5). After 7 hours of reaction, neither
the diastereoselection was improved favoring the threo-
isomer nor the yields. Finally, the addition of CsF3e
(Table 1, entry 6) and butylmethylimidazolinium
tetrafluoroborate3e (BMI·BF4, Table 1, entry 7) as additive
was tested in the reaction of TMSOTf with 5c. The dia-
stereoselectivity of the reaction was significantly affected
by the nature of the additive (BMI·BF4), which improved
yields and selectivities. In fact, in the presence of
BMI·BF4 the preference for the threo-isomer 6 increased
to 9.7:1 (Table 1, entry 7) when compared with no addi-
tive. The diastereoisomeric ratios of threo/erythro 6 ob-
tained were determined by capillary GC analysis.
Table 1 Asymmetric Addition of 5 to N-Acyliminium Precursor
from 4a
Entry 5, R
Lewis acid
Additive 6,
Yield
threo/erythrob (%)c
1
2
3
4
5
6
7
5a, Bu
TMSOTf
TMSOTf
TMSOTf
TiCl4
–
5:1
75
76
75
72
74
73
80
5b, Me
5c, i-Pr
5c, i-Pr
5c, i-Pr
5c, i-Pr
5c, i-Pr
–
4.5:1
8:1
–
–
5:1
TIPSOTf
TMSOTf
TMSOTf
–
8:1
CsF
7.5:1
BMI·BF4 9.7:1
a All reactions were performed in THF–CH2Cl2 (1:1) as solvent at
–78 °C for 7 h.
b Diastereomeric ratio (dr) was calculated based on GC analysis.
c Isolated yields.
97% yield. This route provides enantiomerically pure 1-
azabicyclo[4.4.0]decane 3.7 These results reveal the ex-
clusive addition of silyloxyfuran 5 to the Si face of the N-
acyliminium ions derived from 4, as depicted in Figure 1.
R3SiO
H
O
O
N
O
H
+
Table 1
+
Si-face selectivity
N
OMe
O
OSiR3
N
O
O
H
H
Figure 1 Facial selectivity for the addition of 5 to N-acyliminium
precursor 4
O
O
5
CO2R*
6
Ph
4
Next, efforts were directed to the preparation of cyano
compound 9. The first approach was to convert the alco-
hol 3 via the mesylate affording 9 in 71% overall yield us-
ing 18-crown-6 ether. In the absence of crown ether, the
yields of the reaction were lower (15%). Furthermore, it
was observed that temperatures higher than 70 °C caused
epimerization at C-10 (Scheme 3). Then, it was attempted
to carry out this transformation in one-step applying the
synthetic versatility of the Mitsunobu reaction. First,
KCN, DEAD, and Ph3P were tested, which afforded 9 in
disappointing 31% yield, without epimerization. Then, 3
MeONa
MeOH
reflux
93%
H
H2, Pd/C
OH
O
N
N
O
EtOAc
99%
H
H
O
CO2R*
7
(R,R)-8
AlH3
THF
1) ClCH2CO2H
Ph3P, DEAD
H
H
OH
OH
N
N
2) K2CO3, MeOH
75%
97%
O
3
(R,S)-8
Scheme 2 Synthesis of 3 (R* denotes the 1-(1R,2S,5R)-8-phe- was subjected to Mitsunobu reaction by using acetone cy-
anohydrin, DEAD, and Ph3P in toluene–THF as solvent,8
nylmenthylpiperidine part of the structure; cf. 4).
which converted the C-10 hydroxy group into the homolo-
gated nitrile group in 9 in 81% yield. The reaction pro-
ceeded very clean affording 9 with no epimerization as
determined by GC analysis (Scheme 3).
Then, compound 6 was converted into quinolizidinone
(R,R)-8 in 92% overall yield according to previously stud-
ied methodologies.2g,3b,c Having prepared (R,R)-8, the
next step was the inversion of configuration at C-10 in
(R,R)-8 via Mitsunobu reaction (ClCH2CO2H, DEAD,
Ph3P) to give the corresponding chloroacetate, which was
hydrolyzed with K2CO3 in MeOH to afford the diastereo-
meric alcohol (R,S)-8 in 75% yield. Reduction of (R,S)-8
with alane (AlH3) gave after silica gel purification 3 in
The cyano compound 9 was then hydrolyzed to acid 10
using 6 M HCl in refluxing CHCl3 in 93% yield. Interest-
ingly, compound 10 showed differences in chemical shifts
and coupling constants in CDCl3, probably due to the acid
content of the solvent, for hydrogens on carbons 1, 4, 5
and 10, suggesting an equilibrium among the iminium,
Synthesis 2011, No. 1, 51–56 © Thieme Stuttgart · New York

PAPER
Short Total Synthesis of (–)-Lupinine and (–)-Epiquinamide
53
1. MsCl, Et3N
CH2Cl2
2. KCN, 18-crown-6
DMF, 65 °C
71%
1. MsCl, Et3N
CH2Cl2, 0 °C
30 min
2. NaN3, DMF
75 °C, 18 h
H
CN
Ni2B
N
3
H
H
MeOH, H2O
or
75%
N3
OH
N
N
HO
CN
or
DEAD, Ph3P
HN3
MW, 2 min
95%
9
DEAD, Ph3P
toluene–THF, 81%
95%
11
3
AcOH, Et3N
MeO(CH2)2OMe
silica gel
AlH3, THF
0 °C to r.t.
H
H
HCl–CHCl3
H
+
N
H
CO2H
CH2OH
(6.0 M)
NH2
NHAc
N
9
35 min
91%
N
N
H
Cl–
reflux
93%
MW, 2 min
81%
10
1
12
2
Scheme 3 Synthesis of (–)-lupinine (1).
Scheme 4 Synthesis of (–)-equiquinamide (2)
zwitterion and hydrochloride salt.9 Finally, (–)-lupinine
(1) was obtained in 91% yield by alane reduction of 10, as
depicted in Scheme 3.
safe to handle, stable, does not require inert atmosphere,
and not pyrophoric. Interestingly, the microwave-assisted
irradiation reactions enhanced yields with very short reac-
tion times in contrast to the conventional thermal reac-
tions. The reaction conditions are particularly attractive
and are an example of green chemistry approach.
For the synthesis of epiquinamide, the alcohol 3 was con-
verted via the mesylate into azido 11 in 75% overall
yield.10 However, Cohen and Overman, in their synthesis
of batzelladine F, used the Mitsunobu reaction with hy-
drazoic acid to install an azide group.11 Thus, testing
Mitsunobu reaction of 3 with DEAD, Ph3P, and hydrazoic
acid afforded 11 in yields of around 90–95%. Then, nickel
boride (Ni2B) reduction of azide 11 afforded 1212 in 85%
yield after two hours at 65 °C.13 The nickel boride (amor-
phous fine black granules) was freshly prepared by mix-
ing Ni(OAc)2 and NaBH4.14 With the aim of increasing
the yields along with shortening the reaction times, we de-
cided to explore microwave irradiation in the reduction of
11.15 The same reaction as described above was carried
out under microwave-assisted conditions in a sealed ves-
sel. Reaction times were reduced to two minutes for azide
11, the yields (93–95%) were better than using thermal
heating. Further, it was also observed that by applying the
described protocol, temperatures of the reaction mixture
inside the reaction vessel reached values of 39 °C (2 min)
for the microwave-assisted reductions at a power of 70 W.
These temperatures were lower than used in the thermal
conditions, preventing in this way degradation of reac-
tants and products, and favoring the enhancement of
yields. Finally, a mixture of acetic acid, Et3N and 1,2-
dimethoxyethane (DME) in silica gel using microwave ir-
radiation converted crude 12 into (–)-epiquinamide (2) in
81% yield after two minutes5,16 (Scheme 4).
Commercially available chemical reagents were used without fur-
ther purification. HN3, DEAD, NaN3, DME, and acetone cyanohy-
drin were purchased from Sigma-Aldrich. Ph3P was purchased from
Merck. Anhyd THF, CH2Cl2, MeOH, and DMF were prepared by
distillation under N2 over Na/benzophenone, CaH2, Na/P2O5, and
CaH2/molecular sieves, respectively. Solvents for extraction and
column chromatography were distilled prior to use. NaN3 was han-
dled with care by wearing safety glasses, facemask, gloves, and the
reactions were performed in a fume hood. All the microwave reac-
tions were performed in CEM Discover LabMate equipment in a
closed vessel (built-in infrared sensor) with cooling system. IR
spectra were recorded as film on KBr cells and the wave numbers
are expressed in cm–1. Melting points were measured with an Ele-
trothermal apparatus and are uncorrected. 1H and 13C NMR spectra
were recorded on Bruker WH Avance 300, and Varian Unity 400
MHz spectrometers using TMS as the internal standard. Chemical
shifts are reported in parts per million (ppm) downfield from TMS.
Spin multiplicities are described as s (singlet), br s (broad singlet),
d (doublet), dd (double doublet), t (triplet), q (quartet), or m (mul-
tiplet). Coupling constants are reported in Hertz (Hz). Mass spectra
were recorded on a Qtof Micro (Waters-Micromass). Column chro-
matography was performed using silica gel 100–200 mesh. TLC
analyses were performed with silica gel plates using I2, KMnO4, or
UV-lamp for visualization.
1-(1R,2S,5R)-8-Phenylmenthylpiperidine
This compound was prepared following the experimental procedure
according to reference 3c; mp 55.3–56.6 °C; Rf = 0.5 (hexane–
EtOAc, 1:1); [a]D20 –40 (c 1.07, CHCl3).
In conclusion, these results reveal an attractive route to
enantiomerically pure piperidine derivatives through
quinolididinone 8, which is a potentially useful intermedi-
ate for the asymmetric synthesis of quinolizidine alka-
loids. Although the Mitsunobu reaction is a classical one,
its use continues to be interesting and should not be dis-
carded when asymmetry is required in systems featuring
chiral OH groups. An efficient microwave-assisted meth-
odology employing Ni2B for the preparation of amine 12
is described. Ni2B reagent is easy to prepare, inexpensive,
FTIR (KBr film): 2927, 2854, 1691, 1599, 1429, 1261, 1232, 1149,
1092, 1026, 764, 700 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.75–0.84 (m, 3 H), 0.85 (d, J =
6.7 Hz, 1 H), 0.87–0.93 (m, 1 H), 1.15–1.18 (m, 1 H), 1.21 (s, 3 H),
1.34 (s, 3 H), 1.37–1.67 (m, 9 H), 1.89–2.03 (m, 2 H), 3.03–3.09 (m,
4 H), 4.77 (dt, J = 4.5, 11.0 Hz, 1 H), 7.13–7.17 (m, 1 H), 7.21–7.32
(m, 4 H).
13C NMR (75 MHz, CDCl3): d = 21.3, 24.1, 25.3 (2C), 25.9 (2C),
26.4, 26.5, 31.1, 34.3, 39.3, 42.3, 43.9, 50.5, 75.0, 124.7, 125.3
(2C), 127.9 (2C), 151.9, 154.9.
Synthesis 2011, No. 1, 51–56 © Thieme Stuttgart · New York

54
L. S. Santos et al.
PAPER
HRMS (EI) m/z [M]+· calcd for C22H33NO2: 343.2511; found:
343.2515.
13C NMR (75 MHz, CDCl3): d = 176.0, 154.7, 154.2, 128.3, 127.6,
127.4, 126.4, 121.2, 80.0, 77.1, 52.2, 50.2, 42.9, 41.1, 39.5, 33.7,
33.0, 32.7, 26.0, 25.8, 24.8, 24.7, 24.1, 21.9 (2 × CH3), 19.7.
1-(1R,2S,5R)-8-Phenylmenthyl-2-(R/S)-methoxypiperidine (4)
This compound was prepared following the experimental procedure
according to reference 3c.
HRMS (ESI-MS): m/z calcd for [C26H37NO4 + H]+: 428.2801;
found: 428.2811.
FTIR (KBr film): 3023, 2917, 2952, 2829, 1702, 1602, 1402, 1180,
1083, 755, 700 cm–1.
(1R,9aR)-1-Hydroxyoctahydro-4H-quinolizin-4-one [(R,R)-8]
A solution of NaOMe in MeOH (1.1 mol/L, 5.2 mL) was added to
7 (384 mg, 0.90 mmol) at 0 °C, and the mixture was stirred at r.t.
After 2 h, a 2 mol/L HCl–MeOH solution (10.0 mL) was carefully
added. The organic layer was concentrated under reduced pressure,
providing (R,R)-8 in 93% yield as a colorless oil; yield: 142 mg
(93%, 0.84 mmol); [a]D20 +17 (c 1.5, MeOH).
1H NMR (300 MHz, CDCl3): d = 0.82–0.87 (m, 1 H), 0.91–1.20 (m,
2 H), 1.20 (s, 3 H), 1.22 (s, 3 H), 1.38 (s, 3 H), 1.39–1.81 (m, 9 H),
1.92–1.96 (m, 1 H), 2.01–2.10 (m, 2 H), 2.39, 2.43, 2.74, 2.80, and
2.94 (5 × m, 1 H), 3.07, 3.19, 3.26, and 3.48 (4 × s, 3 H), 4.70–4.92
(m, 1 H), 3.94, 4.45, 5.33, and 5.40 (4 × m, 1 H), 7.10–7.17 (m, 1
H), 7.22–7.30 (m, 4 H).
FTIR (KBr film): 1780, 1680 cm–1.
13C NMR (75 MHz, CDCl3): d = 19.1, 21.9, 24.3, 26.0, 27.7, 30.5,
32.1, 35.1, 38.4, 39.4, 40.9, 42.7, 50.8, 54.8, 75.0, 82.0, 125.3,
125.6 (2C), 128.2 (2C), 152.3, 155.0.
HRMS (EI): m/z [M]+· calcd for C23H35NO3: 373.2617; found:
373.2601.
1H NMR (400 MHz, CDCl3): d = 1.37–1.50 (m, 1 H), 1.51–1.58 (m,
1 H), 1.65 (br s, 1 H), 1.65–1.70 (m, 1 H), 1.70–1.77 (m, 1 H), 1.79–
1.89 (m, 1 H), 1.89–2.03 (m, 1 H), 2.36 (t, J = 5.4 Hz, 1 H), 2.44 (dt,
J = 11.5, 4.2 Hz, 1 H), 2.60 (ddd, J = 17.1, 10.7, 5.6 Hz, 1 H), 3.30
(br dd, J = 11.5, 2.5 Hz, 1 H), 4.04 (br s, 1 H), 4.73 (br d, J = 17.1
Hz, 1 H).
Compound 6
13C NMR (100 MHz, CDCl3): d = 24.2, 25.3, 26.9, 27.2, 28.0, 42.8,
To a solution of methoxycarbamate 4 (672 mg, 1.80 mmol) in anhyd
CH2Cl2–THF (1:1, 10.0 mL) at –78 °C was added BMI·BF4 (0.020
mL, 1.80 mmol) and the mixture was stirred for 30 min under argon
atmosphere, followed by slow addition of 2-triisopropylsilyloxyfu-
ran (460 mg, 1.80 mmol) in CH2Cl2–THF (1:1, 1.00 mL). After 7 h,
sat. aq NH4Cl (10.0 mL) was added and the layers were separated.
The aqueous phase was extracted with CH2Cl2 (2 × 50 mL), and the
combined organic phases were dried (MgSO4) and concentrated un-
der reduced pressure. The crude (9.7:1 diastereoisomeric mixture)
was submitted to flash column chromatography purification (hex-
ane–EtOAc, 2:1) affording pure threo-6 (557 mg, 1.31 mmol) in
73% yield and erythro-6 (61 mg, 0.144 mmol) in 8% yield.
60.6, 66.4, 168.5.
HRMS (ESI-MS): m/z calcd for [C9H15NO2 + H]+: 170.1181; found:
170.1175.
(1R,9aS)-1-Hydroxyoctahydro-4H-quinolizin-4-one [(R,S)-8]
Compound (R,R)-8 (135 mg, 0.80 mmol), Ph3P (378 mg, 1.45
mmol), and ClCH2CO2H (137 mg, 1.45 mmol) were dissolved in
anhyd CH2Cl2 (10 mL). DEAD (0.23 mL, 1.45 mmol) was added
dropwise to the solution and the resulting pale yellow solution was
stirred at r.t. for 6 h. The reaction mixture was concentrated and the
residue was purified by flash chromatography (CHCl3–MeOH,
95:5) to give a mixture of chloroacetate contaminated with trace
amounts of Ph3PO. The chloroacetate was hydrolyzed using K2CO3
(331 mg, 2.4 mmol) in MeOH (10 mL). The MeOH was evaporated
and CH2Cl2 (10 mL) was added to the residue. The mixture was fil-
tered through a column of Celite and the filtrate was concentrated.
The crude product was purified by flash chromatography (CHCl3–
MeOH–NH4OH, 95:4.5:0.5; Rf = 0.42) to give (R,S)-8; yield: 102
mg (75%); [a]D20 –10.5 (c 1.0, CHCl3).
threo-6
[a]D20 –22 (c 1.05, CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.81 (d, J = 6.6 Hz, 3 H), 0.75–1.0
(m, 2 H), 1.07–1.65 (m, 10 H), 1.23 (s, 3 H), 1.39 (s, 3 H), 1.93–2.10
(m, 2 H), 2.68 (dt, J = 3.4, 12.5 Hz, 1 H), 3.35–3.42 (m, 1 H), 4.28
(q, J = 4.1 Hz, 1 H), 4.46 (m, 1 H), 4.96 (dt, J = 4.5, 10.1 Hz, 1 H),
5.61 (br d, J = 6.6 Hz, 1 H), 6.99 (d, 1 H, J = 6.6 Hz, 1 H), 7.00–7.38
(m, 5 H).
13C NMR (75 MHz, CDCl3): d = 172.8, 155.6, 155.3, 152.3, 151.7,
127.9, 125.3, 125.0, 121.4, 120.5, 88.2, 81.4, 75.8, 52.5, 51.9, 50.3,
42.1, 39.9, 34.5, 31.2, 27.3, 26.7, 24.7, 24.6, 21.8, 19.5.
FTIR (KBr film): 3374, 2934, 2857, 1610, 1445, 1048 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.15–1.25 (m, 1 H), 1.31–1.43 (m,
1 H), 1.43–1.55 (m, 1 H), 1.67 (br d, J = 13.0 Hz, 1 H), 1.77–2.01
(m, 4 H), 2.31 (ddd, J = 17.1, 7.8, 6.0 Hz, 1 H), 2.38 (dt, J = 12.8,
2.5 Hz, 1 H), 2.54 (ddd, J = 17.1, 7.8, 6.0 Hz, 1 H), 3.15 (ddd, J =
12.0, 4.5, 2.5 Hz, 1 H), 3.19 (br s, 1 H), 3.68–3.74 (m, 1 H), 4.68–
4.75 (m, 1 H).
HRMS (ESI-MS): m/z calcd for [C26H35NO4 + H]+: 426.2644;
found: 426.2601.
13C NMR (75 MHz, CDCl3): d = 24.4, 25.2, 26.9, 28.5, 31.5, 42.9,
Compound 7
63.7, 69.6, 168.4.
To a solution of threo-6 (510 mg, 1.20 mmol) in EtOAc (12.0 mL)
was added 10% Pd/C (38 mg) and the mixture was stirred under H2
(1 atm) for 4 h. The mixture was then filtered through Celite, and
the pad was rinsed with EtOAc–MeOH (4:1, 200 mL). The organic
layer was concentrated under reduced pressure to furnished pure 7
as a colorless oil; yield: 508 mg (99%, 1.19 mmol); [a]D –55 (c
1.5, CHCl3).
FTIR (KBr film): 1780, 1680 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.79–1.00 (m, 2 H), 0.89 (d, J =
6.5 Hz, 3 H), 1.12–1.29 (m, 3 H), 1.33 (s, 3 H), 1.39–1.81 (m, 12 H),
1.98–2.12 (m, 2 H), 2.22–2.28 (m, 1 H), 2.41–2.46 (m, 1 H), 2.48–
2.54 (m, 1 H), 2.57–2.67 (m, 1 H), 2.89, 3.10 and 3.30 (3 × m, 1 H),
4.14, 4.24, and 4.31 (3 × m, 1 H), 4.60–4.67 (m, 1 H), 4.68–4.80 (m,
1 H), 7.10–7.17 (m, 1 H), 7.19–7.33 (m, 1 H).
HRMS (ESI-MS): m/z calcd for [C9H15NO2 + H]+: 170.1181; found:
170.1188.
(1R,9aR)- 1-Hydroxyoctahydro-1H-quinolizine (3)
20
To a solution of (R,S)-8 (220 mg, 1.30 mmol) in THF (10.0 mL) was
added a solution of AlH3 (1.55 M, 2.50 mL, 3.90 mmol; previously
prepared by mixing 1 equiv of AlCl3 and 3 equiv of LiAlH4 solution
in THF) at r.t. After 10 min, the reaction was quenched with sat. aq
Na2SO4 (3.0 mL) and filtered. The solids were washed with CH2Cl2
(200 mL) and acidified with HCl–MeOH (10%) to effect complete
conversion into the hydrochloride salt. Evaporation at reduced pres-
sure afforded crude 3, which was purified by flash chromatography
eluting with CHCl3–MeOH–NH4OH (95:4.5:0.5, Rf = 0.42) to af-
ford pure 3 as an oil; yield: 196 mg (97%). The spectroscopic data
Synthesis 2011, No. 1, 51–56 © Thieme Stuttgart · New York

PAPER
Short Total Synthesis of (–)-Lupinine and (–)-Epiquinamide
55
are in accordance with previously described for 37; [a]D20 –22.7 (c
1.05, CHCl3).
13C NMR (75 MHz, CDCl3): d = 23.0, 24.5, 25.7, 29.8, 31.3, 38.3,
57.0, 57.2, 65.0, 65.9.
1H NMR (400 MHz, CDCl3): d = 1.24–1.39 (m, 10 H), 2.17–2.38
(m, 5 H), 3.48–3.56 (m, 1 H).
HRMS (ESI-MS): m/z calcd for [C10H19NO + H]+: 170.1545; found:
170.1551.
(1R,9aR)- 1-Cyanooctahydro-1H-quinolizine (9)
(1R,9aR)-1-Azidooctahydro-1H-quinolizine (11)
To a stirred solution of 3 (105 mg, 0.68 mmol), acetone cyanohy-
drin (1.38 mL, 1.36 mmol) and Ph3P (232 mg, 0.88 mmol) in THF
(5.0 mL) was added a 2.2 M solution of diethyl azodicarboxylate in
toluene (0.372 mL, 0.82 mmol) over 1 h at 0 °C, and then the reac-
tion mixture was allowed to warm to r.t. After stirring for 40 min,
the solvent was evaporated under reduced pressure. The residue was
diluted with EtOAc (5.0 mL) and hexane (3.0 mL), and then filtered
to remove Ph3PO. The filtrate was evaporated under reduced pres-
sure and purified by silica gel column chromatography to give 9
containing some Ph3P=O as impurity; yield: 90 mg (81%). Further
purification was not done at this stage; [a]D20 –18.8 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.20–1.42 (m, 9 H), 2.15–2.45 (m,
5 H), 2.68–2.74 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 20.2, 23.4, 24.5, 27.0, 28.4, 38.3,
54.5, 55.8, 63.0, 122.4.
Diethyl azodicarboxylate (DEAD, 0.20 mL, 1.25 mmol) was added
dropwise to solution of 3 (50 mg, 0.32 mmol), H3N (0.53 mL, 2.7
M in toluene, 1.45 mmol), Ph3P (332 mg, 1.27 mmol), and THF (4.0
mL) at 0 °C over 15 min using a syringe pump. After an additional
30 min, hexanes (5.0 mL) were added, and Ph3PO was filtered off.
The residue was purified by flash chromatography to provide 11;
yield: 39.5–41.6 mg (90–95%);10 [a]D20 –36.1 (c 1.5, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.20–1.42 (m, 10 H), 2.10–2.33
(m, 5 H), 3.35–3.39 (m, 1 H).
HRMS (ESI-MS): m/z calcd for [C9H16N4 – N3]+: 138.1277; found:
138.1274.
(1R,9aR)-1-Aminooctahydro-1H-quinolizine (12)
Compound 11 (13.7 mg, 0.10 mmol) was dissolved in MeOH (2.0
mL), and then Ni2B (25 mg, 0.30 mmol) and aq 1 M HCl (0.4 mL)
were added. The mixture was irradiated at 70 W using CEM Dis-
cover LabMate equipment in a closed vessel with the temperature
monitored by a built-in infrared sensor for 2 min at 39 °C with cool-
ing. The resulting mixture was filtered, and then the MeOH was
evaporated under vacuum. Then, sat. aq NaHCO3 (2.0 mL) was add-
ed to the mixture and extracted with CH2Cl2 (3 × 5.0 mL). The com-
bined organic layers were dried (Na2SO4), then evaporated under
reduced pressure to afford crude compound 12; yield: 15 mg (95%).
HRMS (ESI-MS): m/z calcd for [C10H16N2 + H]+: 165.1392; found:
165.1398.
(1R,9aR)-Octahydro-1H-quinolizine-1-carboxylic Acid (10)
Compound 9 (90 mg, 0.55 mmol) was dissolved in a 6 M HCl–
CHCl3 solution (2.0 mL) and stirred under reflux (60 °C) for 2 h.
The mixture was washed with sat. aq NaHCO3 (4.0 mL), and the or-
ganic extract separated. The aqueous layer was extracted with
CHCl3 (2 × 10 mL). The solvents from the combined organic layers
were evaporated under vacuum and the crude product was purified
by flash chromatography to afford the amino acid 10 as a white sol-
id; yield: 93 mg (93%); mp 242–244 °C (Lit.17 mp 255 °C); Rf = 0.3
(CHCl3–MeOH–NH4OH, 4:1:0.1); [a]D20 +9.0 (c 0.5, CHCl3).
HRMS (ESI-MS): m/z calcd for [C9H18N2 + H]+: 155.1548; found:
155.1552.
(–)-Epiquinidine (2)
The crude amine 12 (11 mg, 0.07 mmol) was mixed with silica gel
(100 mg, 100–200 mesh). To the mixture was added in the follow-
ing order: DME (0.09 mL, 1.25 equiv), Et3N (0.50 mL, 51 equiv),
and AcOH (0.0135 mL, 0.176 mmol). The reaction mixture was
heated by microwave-assisted irradiation at 70 W using a CEM Dis-
cover LabMate equipment in a closed vessel with the temperature
monitored by a built-in infrared sensor for 2 min at 39 °C with cool-
ing. The resulting mixture was diluted with CHCl3 (4.0 mL) and fil-
tered; then the organic solvent evaporated under vacuum to afford
the pure compound 2 as a colorless solid; yield: 11.1 mg (81%). The
spectroscopic data were in accordance with the data described pre-
viously;5,16 mp 133–135 °C (Lit.9 mp 131–133 °C; [a]D20 –22 (c 0.5,
CHCl3) {Lit.10 for (+)-2: [a]D22 +26.2 (c 0.25, CHCl3)}.
1H NMR (400 MHz, CDCl3): d = 1.18–1.62 (m, 7 H), 1.73 (br d, J
= 13.0 Hz, 2 H), 1.85 (br d, J = 13.0 Hz, 1 H), 1.91–1.95 (m, 3 H),
2.02 (s, 3 H), 2.74–2.80 (m, 2 H), 3.90–3.95 (br dd, J = 9.0, 2.0 Hz,
1 H), 6.25 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 20.3, 23.4, 24.0, 25.4, 28.8, 29.5,
47.9, 56.6, 56.7, 64.3, 168.9.
FT-IR (KBr film): 3410 (br), 2940, 2868, 1593 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.33 (tq, J = 4.1, 12.5 Hz, 1 H),
1.60–1.80 (m, 6 H), 1.86 (d, J = 13.8 Hz, 1 H), 2.04 (dd, J = 4.7,
13.8 Hz, 1 H), 2.13 (d, J = 12.9 Hz, 1 H), 2.30 (dt, J = 2.8, 12.5 Hz,
2 H), 2.41 (dt, J = 2.3, 12.5 Hz, 1 H), 2.43 (m, 1 H), 2.62 (br s, 1 H),
3.20 (ddd, J = 2.0, 4.7, 12.1 Hz, 1 H), 3.30 (dd, J = 2.0, 12.1 Hz, 1
H), 8.0 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 176.3, 63.9, 56.0, 54.7, 46.1, 29.4,
27.3, 24.2, 23.0, 20.9.
HRMS (ESI-MS): m/z calcd for [C10H17NO2 + H]+: 184.1338;
found: 184.1338.
(–)-Lupinine (1)
To a solution of 10 (24 mg, 0.13 mmol) in THF (2.0 mL) was added
a solution of AlH3 (1.55 M, 0.25 mL, 0.39 mmol, previously pre-
pared by mixing 1 equiv of AlCl3 and 3 equiv of LiAlH4 solution in
THF) at r.t. After 20 min, the reaction was quenched with sat. aq
Na2SO4 (0.70 mL) and filtered. The solids were washed with
CH2Cl2 and acidified with HCl–MeOH (10%) to effect complete
conversion into the hydrochloride salt. Evaporation at reduced pres-
sure afforded the crude 1, which was purified by flash chromatog-
raphy eluting with MeOH–NH4OH (99.5:0.5, Rf = 0.8) to afford
pure 1; yield: 20 mg (91%). The spectroscopic data are in accor-
dance with the data described previously;18 mp 59–60 °C (Lit.18 mp
58–59 °C); [a]D20 –21.5 (c 1.05, CHCl3) {Lit.19 [a]D20 –21.0 (c 0.25,
EtOH)}.
HRMS (ESI-MS): m/z calcd for [C11H20N2O + H]+: 197.1654;
found: 197.1650.
Acknowledgment
L.S.S. thanks FONDECYT (Project 1085308) for support of
research activity. Programa de Doctorado en Ciencias Mención
Investigación y Desarrollo de Productos Bioactivos (Universidad de
Talca) is also acknowledged for financial support to Y.M.G.
1H NMR (300 MHz, CDCl3): d = 1.20–1.25 (m, 1 H), 1.43–1.91 (m,
10 H), 1.99–2.02 (m, 1 H), 2.13–2.16 (m, 2 H), 2.78–2.83 (m, 2 H),
3.66 (d, J = 10.5 Hz, 1 H), 4.14 (ddd, J = 10.5, 5.5, 1.4 Hz, 1 H).
Synthesis 2011, No. 1, 51–56 © Thieme Stuttgart · New York

56
L. S. Santos et al.
PAPER
(7) The spectroscopic data obtained are in accordance with the
previously described data for (R,S)-8: (a) Aaron, H. S.;
Wicks, G. E.; Rader, C. P. J. Org. Chem. 1964, 29, 2248.
(b) Aaron, H. S.; Wicks, G. E.; Rader, C. P. J. Org. Chem.
1964, 29, 2252. (c) Moehrle, H.; Karl, C.; Scheidegger, U.
Tetrahedron 1968, 24, 6813. (d) Srivastava, A. K.; Das, S.
K.; Panda, G. Tetrahedron 2009, 65, 5322.
(8) Uchida, K.; Yokoshima, S.; Kan, T.; Fukuyama, T. Org.
Lett. 2006, 8, 5311.
(9) Fitch, R. W.; Sturgeon, G. D.; Patel, S. R.; Spande, T. F.;
Garraffo, H. M.; Daly, J. W.; Blaauw, R. H. J. Nat. Prod.
2009, 72, 243.
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Synthesis 2011, No. 1, 51–56 © Thieme Stuttgart · New York