Organocatalytic enantioselective synthesis of quinolizidine alkaloids (+)-myrtine, (-)-lupinine, and (+)-epiepiquinamide

Article abstract of DOI:10.1016/j.tet.2011.07.017

The organocatalytic synthesis of quinolizidine alkaloids (+)-myrtine, (-)-lupinine, and (+)-epiepiquinamide is described. It involved, as the key step, an enantioselective intramolecular aza-Michael reaction (IMAMR) catalyzed by J?rgensen catalyst I, affording the common precursor with high enantioselectivity. This compound was subsequently transformed into the three alkaloids in a highly diastereoselective manner.

Full text of DOI:10.1016/j.tet.2011.07.017

Tetrahedron 67 (2011) 7412e7417
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Organocatalytic enantioselective synthesis of quinolizidine alkaloids (þ)-myrtine,
(
ꢀ)-lupinine, and (þ)-epiepiquinamide
a,
b,
a
b
a
a
*
ꢀ
ꢀ
ꢀ
Santos Fustero
Carlos del Pozo
, Javier Moscardo , María Sanchez-Rosello , Sonia Flores , Marta Guerola ,
a,
*
a
Departamento de Química Org aꢀ nica, Universidad de Valencia, E-46100 Burjassot, Spain
Laboratorio de Mol ꢀe culas Org aꢀ nicas, Centro de Investigaci oꢀ n Príncipe Felipe, E-46012 Valencia, Spain
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 May 2011
Received in revised form 4 July 2011
Accepted 6 July 2011
Available online 14 July 2011
The organocatalytic synthesis of quinolizidine alkaloids (þ)-myrtine, (ꢀ)-lupinine, and (þ)-epi-
epiquinamide is described. It involved, as the key step, an enantioselective intramolecular aza-Michael
reaction (IMAMR) catalyzed by Jørgensen catalyst I, affording the common precursor with high enan-
tioselectivity. This compound was subsequently transformed into the three alkaloids in a highly dia-
stereoselective manner.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalysis
Quinolizidine alkaloids
Intramolecular aza-Michael reaction
Myrtine
Lupinine
Epiquinamide
1. Introduction
enantioselection, giving rise to the corresponding enantiomerically
enriched nitrogen heterocycles.
4
c,e
The azabicyclic skeleton of quinolizidine is a relevant structural
subunit present in numerous alkaloids. The wide range of biological
activities found in this family of natural products make them ideal
The synthetic utility of our approach is now illustrated with the
total synthesis of three quinolizidine alkaloids, namely (þ)-myrtine
1, (ꢀ)-lupinine 2, and (þ)-epiepiquinamide 3 (Fig. 1).
1
targets for total synthesis.
In the past decade organocatalysis has become a thriving area of
2
widely applicable asymmetric reactions, thereby accelerating the
H
N
CH OH
NHAc
2
O
H
H
N
3
development of new methods to assemble useful molecules with
high enantiomeric purity. On the other hand, the aza-Michael re-
action constitutes one of the best methods for the formation of CeN
bonds and has emerged as a very powerful tool for the synthesis of
nitrogen-containing heterocycles in its intramolecular version.
Despite the synthetic utility of this transformation, the catalytic
enantioselective aza-Michael reaction remained undeveloped until
N
1
2
[
(+)-myrtine]
[(−)-lupinine]
[(+)-epiepiquinamide]
Fig. 1. Quinolizidine alkaloids.
3
very recently. Furthermore, most of the examples reported in this
field are intermolecular reactions, while the intramolecular version
4
has remained almost unexplored. In this context, we have recently
2. Results and discussion
developed a catalytic enantioselective intramolecular aza-Michael
reaction (IMAMR). Thus, when carbamates bearing a remote a,b-
unsaturated aldehyde moiety were treated with chiral diary-
lprolinol ethers, the IMAMR took place with high levels of
A common carbamate precursor, N-Boc 2-[(R)-piperidin-2-yl]
acetaldehyde (5), was assembled by means of an organocatalytic
IMAMR. Accordingly, conjugated aldehyde 4 was treated with
ꢁ
Jørgensen diarylprolinol I in CHCl
3
at ꢀ50 C in the presence of
benzoic acid as an additive, thus affording the piperidine aldehyde
5 in 63% yield and 94% ee (Scheme 1). The synthesis of compound
4
e
*
Corresponding authors. E-mail address: santos.fustero@uv.es (S. Fustero).
0
040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.017

S. Fustero et al. / Tetrahedron 67 (2011) 7412e7417
7413
5
was also described by Carter et al. starting from 4 in a MeOHeDCE
MgBr
THF, 0 ºC
Boc
Boc
ꢁ
4d
N
N
DMP
mixture at ꢀ25 C by using the same catalyst. This aldehyde was
used as the starting substrate for the synthesis of alkaloids 1e3. The
retrosynthetic analysis is depicted in Scheme 1.
OH
O
DCM, rt
5
6
63% (two steps)
Ar
Boc
Boc
OTMS
N
Et
MeOH, rt
8%
3
N
O
N
N
H
Ar
O
I
O
[
Ar = 3,5-(CF
3
)
2
-C
2 6
H ]
CHO
Boc
9
H
N
7
8
N
CHCl , PhCO H
50 ºC, 20 h
3
2
Boc
5 (63%, 94% ee)
Me
−
4
1
. TFA, DCM, 0 ºC
. K CO , THF, 0 ºC
or ref. 4d
N
H
2
2
3
Scheme 1. Synthesis of the common precursor 5.
O
87%
1
In our approach, the key step in the synthesis of 1 involved
a highly diastereoselective IMAMR on the appropriate precursor
that was in turn prepared from piperidine 5. On the other hand, the
Scheme 3. Synthesis of (þ)-myrtine 1.
key intermediate for the synthesis of 2 and 3 was the bicyclic
b
-
As a result, we have performed the second organocatalytic
synthesis of (þ)-myrtine in six steps and 34% overall yield starting
from the N-Boc protected aldehyde 4.
(ꢀ)-Lupinine 2 (see Fig. 1) is one of the parent members of the
quinolizidine group of alkaloids isolated from the yellow lupin
seeds (Lupinus luteus) and it was first reported over a hundred years
ago. Several asymmetric syntheses of this alkaloid have been
devised, most of them based on chiral pool-derived starting ma-
terials. Only one synthesis reported by Ma and Ni in 2004 took
amino ester 12. In these cases, the second chiral center was in-
stalled by means of a highly diastereoselective allylation reaction
followed by further cyclization onto the nitrogen atom through an
S
N
2-type displacement (Scheme 2).
1
2
S 2
N
Boc
N
13
N
H
advantage of the Sharpless asymmetric epoxidation in order to
O
H
Allylation
14
generate the corresponding chiral centers of the molecule.
CO Et
0
2
On the other hand, (ꢀ)-epiquinamide 3 (Fig. 2) was isolated in
12
5
2003 from the poison frog Epipedobates tricolor and it was claimed to
15
act as an agonist of the nicotinic receptors. This alkaloid has
attracted considerable attention from the synthetic community, and
several asymmetric syntheses have been recently reported. Again,
most of them made use of starting materials coming from the chiral
IMAMR
Me
N
H
2
N
H
1
6
N
and
OH
pool. Optically active precursors obtained by enzymatic resolution
17
have also been employed in the preparationof 3. Very recently, two
more asymmetric syntheses of (ꢀ)-epiquinamide involving an
asymmetric hydroxylation reaction as the key step have been
O
H
NHAc
1
3
18
reported in the literature. However, only one report deals with the
Scheme 2. Retrosynthetic analysis.
17
preparation of the epiquinamide C1-epimer 3 (Fig. 2).
NHAc
NHAc
(
þ)-Myrtine 1 (see Fig. 1) is a naturally occurring quinolizi-
H
H
N
dine alkaloid isolated from Vaccinium myrtillus. Although it was
discovered more than three decades ago -its structure and ab-
solute configuration were determined in 1978-, only six asym-
metric synthesis of this alkaloid have been described to date.
Two of them relied on the use of enantiomerically pure starting
N
5
3
3´
[(−)-epiquinamide]
[
(+)-epiepiquinamide]
6
materials derived from the chiral pool. Two more syntheses
Fig. 2. Epiquinamide epimers.
employed either sulfoxides or 8-phenylmenthol as chiral
auxiliaries.7 The last one was based on a copper-catalyzed
8
enantioselective conjugated addition reaction. Finally, an orga-
In accordance with the retrosynthetic analysis shown in Scheme
2, we have performed the first organocatalytic synthesis of
(ꢀ)-lupinine 2 and (þ)-epiepiquinamide 3 from a common pre-
cursor 12. Thus, aldehyde 5 was transformed into the correspond-
ing methyl ester 9 through oxidation followed by treatment with
nocatalytic enantioselective synthesis of (þ)-myrtine appeared in
9
the literature early this year.
In our strategy, aldehyde 5 reacted with allylmagnesium bro-
mide to afford a diastereomeric mixture of alcohols 6, which were
readily oxidized with DesseMartin periodinane (DMP). The
TMSCHN . The installation of the second stereocenter of the mol-
2
resulting ketone 7 was then treated with Et
3
N in MeOH, thus
ecule was achieved by treatment of the lithium enolate of 9 with
ꢁ
promoting a highly efficient double bond isomerization that gave
allyl iodide at ꢀ100 C, thus affording compound 10 in 94% yield
10
19
access to the
a
,b
-unsaturated ketone 8. Removal of the Boc N-
and excellent diastereoselectivity (96:4 dr). Next, the double bond
protecting group provided the substrate for the IMAMR. Complete
was transformed into the corresponding alcohol 11 by means of the
sequence hydroborationeoxidation. After mesylation of the hy-
droxyl functionality and removal of the Boc protecting group,
selectivity was achieved in this cyclization step when K
2
CO
3
was
ꢁ
employed as a base in THF at 0 C. In this manner, the desired al-
11
kaloid 1 was obtained in 87% yield (Scheme 3).
a smooth cyclization through an S 2-type process took place upon
N

7414
S. Fustero et al. / Tetrahedron 67 (2011) 7412e7417
basification, giving rise to the bicyclic derivative 12 in good yield
Scheme 4).
the organocatalytic enantioselective IMAMR previously developed
in our group, which allows the preparation of the common piper-
idine precursor 5 in high yield and enantioselectivity. The key step
in the synthesis of 1 was a highly diastereoselective IMAMR that
gave access to the second cycle of the natural product. For the
syntheses of 2 and 3, a highly diastereoselective allylation reaction
allowed to install the second stereocenter.
(
LDA, Et O
1
. KH PO4
2
Boc
2
Boc
N
N
I
NaClO2, H O2
2
CO Me
2
O
2. TMSCHN2
2%
−100 ºC
H
9
6
94%
5
4
4
. Experimental section
Boc
Boc
1
. (Me) S·BH3
N
N
H
2
OH
.1. General experimental methods
2
. H O NaOH
2
2,
H
Reactions were carried out under argon atmosphere unless
CO Me
91%
CO Me
2
2
otherwise indicated. The solvents were purified prior to use: THF,
diethyl ether, and toluene were distilled from sodium/benzophe-
none, dichloromethane, and acetonitrile were distilled from cal-
cium hydride. The reactions were monitored with the aid of thin-
layer chromatography (TLC) on 0.25 mm precoated silica gel
plates. Visualization was carried out with UV light and aqueous
ceric ammonium molybdate solution or potassium permanganate
stain. Flash column chromatography was performed with the in-
1
0 (96:4 dr)
11
1
2
. MeSO Cl
2
N
. TFA
3. NaOH
H
CO Me
2
6
5%
1
2
1
Scheme 4. Synthesis of the bicyclic b-amino ester 12.
dicated solvents on silica gel 60 (particle size 0.040e0.063 mm). H
13
and C NMR spectra were recorded on a 300 or 400 MHz spec-
trometers. Chemical shifts are given in ppm ( ), with reference to
the residual proton resonances of the solvents. Coupling constants
J) are given in hertz (Hz). The letters m, s, d, t, and q stand for
d
With intermediate 12 in hand, reduction of the ester moiety
with LiAlH
afforded the desired natural product (ꢀ)-lupinine 2
Scheme 5) in 20% overall yield starting from aldehyde 4.
4
(
(
multiplet, singlet, doublet, triplet, and quartet, respectively. The
letters br indicate that the signal is broad. Aldehyde 4 was pre-
4
e
N
H
LiAlH4
N
H
viously reported.
N
H
0
9
ºC
ref. 21
4.2. Synthesis of (R)-N-tert-butoxycarbonyl-2-[(R)-piperidin-
2-yl]acetaldehyde (5)
COOMe
0%
NHAc
OH
1
2
2
3´
In a flame-dried, 10 mL round bottomed flask, (E)-(7-tert-
butoxycarbonylamino)-2-heptenal (43 mg, 0.20 mmol) was dis-
2
LiOH, THF-H O
solved in dry chloroform (1.6 mL) and the solution was cooled
ꢁ
N
Ac
2
O
N
toꢀ50 C. Over this solution,
a mixture of (S)-2-[bis(3,5-
N
H
DPPA, Et
Toluene, Δ
COOH
3
N
bis(trifluoromethyl)phenyl)-(trimethylsilyloxy) methyl]pyrrolidine
(I) (23.8 mg, 0.04 mmol), and benzoic acid (4.9 mg, 0.04 mmol) in
chloroform (0.4 mL) was added and the resulting solution was
Py
H
H
NH
2
NHAc
1
3
14
ꢁ
3
stirred at ꢀ50 C for 22 h. After the mixture was allowed to reach
3
7%, three steps
ꢁ
0
4
C, it was quenched with aqueous saturated NH Cl and extracted
Scheme 5. Synthesis of (ꢀ)-lupinine 2 and (þ)-epiepiquinamide 3.
with dichloromethane (3ꢂ5 mL). The organic extracts were washed
with brine, dried over anhydrous Na SO , and concentrated to
2
4
dryness under vacuum. After flash chromatography over silica gel
using n-hexane/ethyl acetate (10:1) as eluent, 29 mg of aldehyde 5
Additionally, the ester functionality of the bicyclic derivative 12
25
was hydrolyzed by treatment with lithium hydroxide. During this
process, a complete epimerization of the ester-containing stereo-
were obtained as a colorless oil (63% yield, 94% ee). ½
a
ꢃ
þ48.4 (c
D
22
2
5
1
.0, CHCl
are in agreement with those previously reported in literature.
NMR (300 MHz, CDCl 1.44 (s, 9H), 1.37e1.73 (m, 6H), 2.48e2.56
3
) [lit.
½
a
ꢃ
þ48.0 (c 1.0, CHCl
3
)]. The spectroscopic data
D
2
0
center occurred affording the corresponding carboxylic acid 13.
This compound was subjected to a Curtius-type rearrangement
by reaction with diphenylphosphoryl azide (DPPA) and Et N under
22 1
H
3
) d
3
(
9
d
m, 1H), 2.69e2.78 (m, 2H), 3.98 (br d, J¼13Hz, 1H), 4.83 (br s, 1H),
refluxing toluene. The resulting amine 14 was acylated in situ to
afford the desired alkaloid 3 in 37% yield (three steps). Therefore, by
13
.72 (dd, J
1
¼3.2 Hz, J
2
¼2.2 Hz, 1H). C NMR (75.5 MHz, CDCl
3
)
18.9 (CH
2
), 25.2 (CH
2
), 28.3 (3CH
3
), 28.9 (CH
2
), 39.3 (CH
2
), 44.6
using this strategy, (þ)-epiepiquinamide
3
(Scheme 5) was
þ
(
C
CH
2
), 45.9 (CH), 79.9 (C), 154.7 (C), 200.8 (C). HRMS (EI ) calcd for
obtained in 8% overall yield starting from aldehyde 4.
þ
12
H22NO
3
[MþH ] 228.1584, found 228.1594. After reduction of
0
Finally, the transformation of lupinine 2 into epiquinamide 3
4
the aldehyde with NaBH (3 equiv) in MeOH, the enantiomeric ratio
has been recently described following the sequence oxidation of
the hydroxyl functionality to the corresponding carboxylic acid-
of the corresponding p-chlorobenzoate was determined with the
aid of HPLC analysis: Chiracel IC (25 cmꢂ0.46 cm column), hexane/
2
1
Curtius rearrangement -nitrogen acetylation.
Therefore, our
isopropanol 90:10, flow¼1.0 mL/min,
major¼14.7 min.
t
R
minor¼11.5 min,
t
R
0
synthetic route also constitutes a formal synthesis of 3 .
3
. Conclusion
4.3. Synthesis of (R)-tert-butyl 2-(2-oxopent-4-en-1-yl)
piperidine-1-carboxylate (7)
In conclusion, an organocatalytic asymmetric synthesis of the
quinolizidine alkaloids (þ)-myrtine 1, (ꢀ)-lupinine 2, and (þ)-epi-
Allylmagnesium bromide (2.1 mL of freshly prepared 0.5 M
solution in THF, 1.04 mmol) was added dropwise to a solution of
epiquinamide 3 has been described. The process takes advantage of

S. Fustero et al. / Tetrahedron 67 (2011) 7412e7417
7415
ꢁ
2.75e2.87 (m, 2H), 3.41e3.36 (m, 1H). 13C NMR (75.5 MHz, CDCl
11.0 (CH ), 23.4 (CH ), 25.8 (CH ), 34.2 (CH ), 48.0 (CH ), 48.7
(CH ), 51.4 (CH
for C10
aldehyde 5 (214 mg, 0.94 mmol) in THF (10 mL) at 0 C. The
3
)
mixture was allowed to reach room temperature and stirred for
d
3
2
2
2
2
þ
1
h. Then, a saturated aqueous NH
quenched reaction mixture was extracted with ethyl acetate
3ꢂ10 mL) and the combined organic layers were dried over an-
hydrous Na SO . Solvents were removed under reduced pressure
4
Cl solution was added, the
2
2
), 53.4 (CH), 57.1 (CH), 209.7 (C). HRMS (EI ) calcd
þ
H
17NO [M ] 167.1310, found 167.1314.
(
2
4
4.6. Synthesis of (R)-tert-butyl 2-[(methoxycarbonyl)methyl]
to afford a diastereomeric mixture of alcohols 6 that were used
without further purification. To a solution of 6 in dichloromethane
piperidine-1-carboxylate (9)
(
15 mL) DesseMartin periodinane (DMP) (477 mg, 1.2 mmol), and
To a solution of aldehyde 5 (234 mg, 1.03 mmol) in a mixture of
ꢁ
NaHCO
3
(100.8 mg, 1.2 mmol) were added at 0 C. The reaction
methanol (1 mL), acetonitrile (1 mL), and water (1 mL), KH
2
PO
30%
4
mixture was allowed to warm until room temperature and stirred
for 5 h. Saturated aqueous NH Cl solution was added, the
quenched reaction mixture was extracted with dichloromethane
3ꢂ10 mL) and the combined organic layers were dried over an-
hydrous Na SO . Solvents were removed under reduced pressure
(
387 mg, 2.84 mmol), NaClO
2
(1.95 mL, 2.15 mmol), and H
2
O
2
4
ꢁ
sol (0.23 mL, 2.05 mmol) were added at 0 C. The reaction was
allowed to reach room temperature and stirred for 2 h. Then, 1 M
HCl solution was added until pH 3 and a saturated solution of
(
2
4
Na
extracted with dichloromethane (3ꢂ10 mL) and the combined or-
ganic layers were dried over anhydrous Na SO . Solvents were re-
2 3
SO was added (2 mL). The quenched reaction mixture was
and the crude mixture was purified by flash chromatography on
silica gel using n-hexane/ethyl acetate (6:1) as eluent to afford
1
2
5
2
4
58 mg of ketone 7 (63% yield, two steps) as a light yellow oil. ½ ꢃ
a
D
moved under reduced pressure and the crude mixture was
dissolved in toluene (5 mL) and methanol (15 mL). Then, a solution
1
þ11.9 (c 1.0, CHCl
3
). H NMR (300 MHz, CDCl
.50e1.69 (m, 6H), 2.65 (d, J¼6.0 Hz, 2H), 2.72e2.81 (m, 1H),
.15e3.27 (m, 2H), 3.93e3.97 (m, 1H), 4.70e4.72 (m, 1H),
3
) d 1.43 (s, 9H),
1
of trimethylsilyldiazomethane (2 M in diethyl ether, 1.1 mL,
3
5
d
ꢁ
2
.06 mmol) was added dropwise at 0 C and the reaction was
13
.10e5.19 (m, 2H), 5.82e5.96 (m, 1H). C NMR (75.5 MHz, CDCl
18.9 (CH ), 25.2 (CH ), 28.3 (CH ), 28.4 (3CH ), 39.4 (CH ), 42.8
), 47.2 (CH
3
)
allowed to reach room temperature and stirred for 3 h. Acetic acid
0.5 mL) was added to the reaction mixture and then it was con-
centrated to dryness. The crude mixture was diluted with diethyl
ether (15 mL) and H O (15 mL), extracted with diethyl ether
3ꢂ15 mL) and the combined organic layers were dried over an-
hydrous Na SO . Solvents were removed under reduced pressure
2
2
2
3
2
(
(
(
CH
2
2
), 47.7 (CH), 79.6 (C), 118.9 (CH
2
), 130.5 (CH), 154.7
þ
þ
C), 206.8 (C). HRMS (EI ) calcd for C15
H26NO
3
[MþH ] 268.1907,
2
found 268.1901.
(
2
4
4
.4. Synthesis of (R,E)-tert-butyl 2-(2-oxopent-3-en-1-yl)
and the crude mixture was purified by flash chromatography on
silica gel using n-hexane/ethyl acetate (5:1) as eluent to afford
piperidine-1-carboxylate (8)
2
5
23
1
65 mg (62% yield) of a colorless oil. ½
a
ꢃ
þ8.6 (c 2.0, CHCl
3
) [lit.
D
To a solution of ketone 7 (158 mg, 0.59 mmol) in methanol
3
N (3 mL) was added and the mixture was stirred for
0 h. Solvents were removed under reduced pressure and the
2
5
½
a
ꢃ
þ8.1 (c 2.0, CHCl
3
)]. The spectroscopic data are in agreement
D
(
15 mL), Et
2
3 1
with those previously reported in literature.
CDCl 1.37e1.63 (m, 6H), 1.44 (s, 9H), 2.53 (dd, J
¼7.8 Hz, 1H), 2.62 (dd, J ¼14.2 Hz, J ¼7.3 Hz, 1H), 2.74e2.82 (m,
H), 3.65 (s, 3H), 3.96e4.00 (m, 1H), 4.68e4.69 (m, 1H). C NMR
75.5 MHz, CDCl 18.9 (CH ), 25.3 (CH ), 28.3 (CH ), 28.4 (3CH ),
), 47.9 (CH), 51.7 (CH
H NMR (300 MHz,
1
3
)
d
1
¼14.2 Hz,
crude mixture was purified by flash chromatography on silica gel
using n-hexane/ethyl acetate (6:1) as eluent to afford 154 mg of 8
J
2
1
2
13
1
(
3
(
2
5
1
(
(
98% yield) as a colorless oil. ½
a
ꢃ
þ7.0 (c 1.0, CHCl
3
). H NMR
1.42 (s, 9H), 1.53e1.63 (m, 5H), 1.88 (dd,
¼1.5 Hz, 3H), 2.71e2.75 (m, 3H), 3.95e3.99 (m, 1H),
.66 (m, 1H), 6.12 (dd, J ¼1.5 Hz, 1H), 6.87 (dq,
¼15.8 Hz, J
¼6.9 Hz, 1H). C NMR (75.5 MHz, CDCl 18.3 (CH ),
), 25.2 (CH ), 28.0 (CH ), 28.3 (3CH ), 39.2 (CH ), 40.5
), 47.8 (CH), 79.5 (C), 131.9 (CH), 143.2 (CH), 154.7 (C), 198.5
D
3
)
d
2
2
2
3
3
300 MHz, CDCl ) d
5.1 (CH
2
), 39.1 (CH
2
3
), 79.5 (C), 154.7 (C), 171.9
J
1
¼6.8 Hz, J
2
þ
þ
C). HRMS (EI ) calcd for C13
H
24NO
4
[MþH ] 258.1704, found
4
1
2
2
58.1700.
1
3
J
1
(
(
1
¼15.8 Hz, J
8.8 (CH
CH
C). HRMS (EI ) calcd for C15
2
3
)
d
3
2
2
2
3
2
2
4.7. Synthesis of (R)-tert-butyl 2-[(R)-1-(methoxycarbonyl)
but-3-enyl]piperidine-1-carboxylate (10)
þ
þ
H
25NO
3
[M ] 267.1834, found
2
67.1832.
A solution of 5 (122 mg, 0.47 mmol) in diethyl ether (2 mL) was
ꢁ
4
.5. Synthesis of (4R,9aR)-hexahydro-4-methyl-1H-
cooled to ꢀ100 C and then it was treated with lithium diisopropyl
quinolizin-2(6H)-one [(D)-myrtine, 1]
amide (LDA) (0.57 mL, 1 M solution in diethyl ether) and the mix-
ture was stirred for 1 h. Then, a solution of allyl iodide (0.05 mL,
0.5 mmol) in diethyl ether (2 mL) was added and the resulting
A solution of TFA (0.6 mL) in dichloromethane (4 mL) was added
ꢁ
ꢁ
at 0 C to a solution of 8 (68 mg, 0.25 mmol) in dichloromethane
reaction mixture was stirred for 1 h and warmed until 0 C. A
(
2 mL). After 1 h, TLC showed total consumption of the starting
saturated aqueous NH
reaction mixture was extracted with diethyl ether (3ꢂ25 mL). The
combined organic layers were dried over anhydrous Na SO . Sol-
4
Cl solution was added and the quenched
material and the crude reaction mixture was concentrated to dry-
ness. The residue was dissolved in methanol (4 mL) and K
2
CO
3
2
4
ꢁ
(
105 mg, 0.76 mmol) was added at 0 C. The reaction mixture was
vents were removed under reduced pressure and the crude mixture
was purified by flash chromatography on silica gel (n-hexane/ethyl
acetate, 8:1) to afford 132 mg (94% yield) of 10 as a colorless oil.
stirred for 1 h and then concentrated to dryness. A saturated
aqueous NH Cl solution was added, the quenched reaction mixture
was extracted with dichloromethane (3ꢂ5 mL) and the combined
organic layers were dried over anhydrous Na SO . Solvents were
removed under reduced pressure and the crude was purified by
4
2
5
13f
½
a
ꢃ
þ8.2 (c 3.0, CHCl
3
) [lit.
½
a
ꢃ
ꢀ7.5 (c 2.84, CHCl
3
)]. The spec-
D
D
2
4
troscopic data are in agreement with those previously reported in
literature.
13f 1
3
H NMR (300 MHz, CDCl ) d 1.35e1.76 (m, 6H), 1.42 (s,
flash chromatography on silica gel (n-hexane/ethyl acetate/E
3
N,
9H), 2.20e2.39 (m, 2H), 2.86e3.03 (m, 2H), 3.60 (s, 3H), 3.96e3.99
2
:1:0.1) to afford 37 mg (87% yield) of (þ)-myrtine (1) as a light
(m, 1H), 4.37e4.40 (br d, J¼9.6 Hz, 1H), 4.99e5.09 (m, 2H),
2
5
8
25
D
13
yellow oil. ½
a
ꢃ
þ10.1 (c 1.5, CHCl
3
) [lit. ½
a
ꢃ
þ10.2 (c 1.8, CHCl
3
)].
5.67e5.80 (m, 1H). C NMR (75.5 MHz, CDCl
3
)
d
18.9 (CH
2
), 25.2
D
The spectroscopic data are in agreement with those previously
2
(CH ), 25.8 (CH
2
), 28.3 (2CH
3
), 28.4 (CH
3
), 33.9 (CH
2
), 39.4 (CH ),
2
8
1
reported in literature. H NMR (300 MHz, CDCl
J¼6.8 Hz, 3H), 1.18e1.37 (m, 2H), 1.67e1.72 (m, 5H), 2.21e2.26 (m,
H), 2.47 (dt, J ¼2.8 Hz, 1H), 2.60e2.69 (m, 1H),
¼11.5 Hz, J
3
)
d
0.96 (d,
45.2 (CH), 51.4 (CH
154.3 (C), 173.6 (C). HRMS (EI ) calcd for C16
298.2020, found 298.2013.
3
), 52.6 (CH), 79.4 (C), 116.9 (CH
2
), 134.9 (CH),
þ
þ
H28NO
4
[MþH ]
2
1
2

7416
S. Fustero et al. / Tetrahedron 67 (2011) 7412e7417
4
.8. Synthesis of (R)-tert-butyl 2-[(R)-1-(methoxycarbonyl)-4-
4.11. Synthesis of [(9R,9aR)-octahydro-1H-quinolizin-9-yl]
hydroxybutyl]piperidine-1-carboxylate (11)
methanol [(L)-lupinine, 2]
To a solution of ester 10 (89 mg, 0.3 mmol) in hexane (2 mL)
A solution of quinolizidine ester 12 (78 mg, 0.396 mmol) in THF
borane-methyl sulphide complex (9.41
m
l, 0.1 mmol) was added
(1 mL) was added dropwise to a suspension of lithium aluminum
ꢁ
dropwise at 0 C. After 30 min, the cooling bath was removed and
stirring was continued for 3 h. Ethanol (0.6 mL), aqueous sodium
hydroxide (1% solution; 0.5 mL), and hydrogen peroxide (30% so-
lution; 0.06 mL) were then added to the reaction mixture. The
resulting solution was heated under reflux for 1 h, then cooled,
diluted with water (5 mL), and extracted with diethyl ether
hydride (21 mg, 0.60 mmol) in Et
was refluxed for 3 h, then cooled and Na
2
O (7 mL). The resulting mixture
SO $10H O was added
2
4
2
under vigorous stirring until aluminum salts turned white. The
Ò
suspension was filtered through a short pad of Celite washing
with small portions of diethyl ether. The filtrate was concentrated
under vacuum and the residue was purified by flash chromatog-
(
4ꢂ15 mL). The combined extracts were washed with brine (10 mL),
raphy (CH
2
Cl
2
/MeOH/NH
4
OH, 97:3:0.1 to 95:5:0.1) to give
Ò
ꢁ
dried over anhydrous Na
the filtrate was evaporated to afford the hydroxy ester 11 (86 mg,
9
2
SO
4
, filtered through a pad of Celite and
(ꢀ)-lupinine 2 as a white solid (60 mg, 90% yield). Mp 66e68
C
14
ꢁ
25
D
14
20
D
[lit. mp 70e71 C]. ½
a
ꢃ
ꢀ20.1 (c 1.0, EtOH) [lit.
½
a
ꢃ
ꢀ21.0 (c
2
5
13f
25
D
1% yield) as a colorless oil. ½
a
ꢃ
þ4.0 (c 2.0, CHCl
3
) [lit.
½
a
ꢃ
ꢀ4.7
0.25, EtOH)]. The spectroscopic data are in agreement with those
D
14 1
(c 2.34, CHCl
3
)]. The spectroscopic data are in agreement with those
previously reported in the literature. H NMR (300 MHz, CDCl
1.15e1.30 (m, 1H), 1.52e1.58 (m, 6H), 1.74e1.80 (m, 4H), 1.99e2.14
(m, 3H), 2.77e2.81 (m, 2H), 3.67 (d, J¼10.8 Hz, 1H), 4.09e4.14 (m,
3
)
13f 1
previously reported in literature.
d
H NMR (300 MHz, CDCl
3
)
d
1.39 (s, 9H), 1.42e1.53 (m, 10H), 1.96 (br s, 1H), 2.88e2.95 (m, 2H),
.59 (m, 5H), 3.92 (br s, 1H), 4.32e4.36 (br d, J¼9.8 Hz, 1H).
13
3
1H), 4.75 (br s, 1H). C NMR (75.5 MHz, CDCl
3
)
d
22.8 (CH
2
), 24.5
), 65.0
(
CH
(CH), 65.7 (CH
found 170.1542.
2
), 25.5 (CH
2
), 29.5 (CH
). HRMS (EI ) calcd for C10
2
), 31.2 (CH
2
), 38.1 (CH), 57.0 (2CH
2
þ
þ
4
1
.9. Synthesis of (1R,9aR)-methyl octahydro-1H-quinolizine-
-carboxylate (12)
2
H
20NO [M þH] 170.1545,
Methanesulfonyl chloride (23
wise to an ice-cold, stirred solution of hydroxy ester 11 (86 mg,
.27 mmol), and triethylamine (42 l, 0.30 mmol) in dichloro-
m
l, 0.30 mmol) was added drop-
4.12. Synthesis of N-[(9S,9aR)-octahydro-1H-quinolizin-9-yl]
acetamide [(D)-epiepiquinamide, 3]
0
m
methane (2 mL). After 2 h, the mixture was diluted with
To a solution of acid 13 (45 mg, 0.25 mmol) in toluene (8 mL)
dichloromethane (10 mL), washed with water (2ꢂ5 mL), dried over
diphenylphosphoryl azide (0.15 mL, 0.70 mmol), and Et N (0.11 mL,
3
anhydrous Na
2
SO
4
, and filtered. The filtrate was concentrated to
0.8 mmol) were successively added. The reaction was heated under
2
mL and trifluoroacetic acid (0.4 mL) was added. The resulting
reflux and stirred overnight. The solvent was removed in vacuo and
1 N HCl (0.5 mL) was added. The resulting suspension stirred
30 min. The solvent was again removed in vacuo and the residue
washed with EtOAc (2ꢂ2 mL). The residue was dissolved in pyri-
dine (1.5 mL) and acetic anhydride (1.5 mL) and the mixture stirred
overnight. After evaporation of solvents, the residue was twice flash
chromatographed on silica gel on a gradient of CH Cl /MeOH (19:1
solution was stirred at room temperature for 1.5 h and then evap-
orated and the residue finally dried under high vacuum. The dry
residue was then treated with ice-cold, aqueous sodium hydroxide
(
0.78 mL) in dichloromethane (2 mL). After mixing, the layers were
separated and the aqueous layer was extracted with dichloro-
methane (4ꢂ5 mL). Solvents were removed under reduced pres-
sure and the crude mixture was purified by flash chromatography
2
2
to 1:1) to afford 3 as an off-white solid (24 mg, 48% for two steps).
ꢁ
2
1
ꢁ
25
D
17
on silica gel (dichloromethane/methanol/triethylamine, 20:1:0.1)
Mp 169e171
C [lit. mp 170e171 C]. ½
a
ꢃ
þ2.7 (c 0.5, CHCl ) [lit.
3
D
25
to afford 35 mg (65% yield) of 12 as a colorless oil. ½
a
ꢃ
ꢀ18.4 (c 0.5,
½
a
ꢃ
ꢀ2.9 (c 0.5, CH Cl )]. The spectroscopic data are in agreement
2
5
D
2
2
) [lit.24
½
a
ꢃ
20
D
ꢀ18.0 (c 0.42, CHCl
)]. The spectroscopic data are
21 1
CHCl
in agreement with those previously reported in the literature.
NMR (300 MHz, CDCl3) 1.23e1.76 (m, 9H), 1.88e2.13 (m, 4H),
.52e2.56 (m, 1H), 2.84e2.92 (m, 2H), 3.65 (s, 3H). C NMR
3
3
with those previously reported in the literature.
H NMR
2
3 1
H
(300 MHz, CDCl3) 1.20e2.05 (m, 13H), 1.97 (s, 3H), 2.74e2.83 (m,
d
1
3
d
2H), 3.89 (dd, J ¼10.0 Hz, J ¼4.1 Hz, 1H), 5.31 (br s, 1H). C NMR
1
2
13
2
(75.5 MHz, CDCl )
d
23.5 (CH ), 24.0 (CH ), 24.4 (CH ), 25.6 (CH ),
3
3
2
2
2
(
2
1
1
75.5 MHz, CDCl
3
)
d
22.0 (CH
2
), 24.3 (CH
2
), 24.8 (CH
2
), 26.9 (CH
), 62.6 (CH
2
),
),
2 2 2 2
29.0 (CH ), 32.2 (CH ), 51.1 (CH ), 55.8 (CH), 56.5 (CH ), 67.5 (CH),
þ
þ
8.9 (CH
2
), 44.4 (CH), 51.1 (CH), 54.9 (CH
2
), 57.0 (CH
2
3
169.3 (C). HRMS (EI ) calcd for C11H21N O [M þH] 197.1648, found
2
þ
þ
73.8 (C). HRMS (EI ) calcd for C11
97.1490.
H19NO
2
[MþH ] 198.1494, found
197.1655.
Acknowledgements
4
.10. Synthesis of (1S,9aR)-octahydro-1H-quinolizine-1-
carboxylic acid (13)
We would like to thank MICINN (CTQ2010-19774) of Spain and
Generalitat Valenciana (PROMETEO/2010/061) for financial sup-
port. M.S.-R. expresses her thanks to MICINN for a Juan de la Cierva
contract, J.M. to Generalitat Valenciana for a predoctoral fellowship
and S.F. expresses her gratitude to MICINN for a predoctoral
fellowship.
2
LiOH$H O (41 mg, 1.0 mmol) was added to a solution of ester 12
ꢁ
(
96 mg, 0.33 mmol) in a mixture of THF/H
2
O (4:1, 3 mL) at 0 C. The
reaction was allowed to reach room temperature and stirred for 4 h.
Then, solvents were removed and the crude was dissolved in
methanol and filtered through a short pad of Celite washing with
Ò
small portions of methanol. Solvents were again removed under
reduced pressure and the crude mixture purified by flash chro-
References and notes
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2
Cl
2
/MeOH, 90:10 to 50:50) to give 13 as a white
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ꢁ
25
D
solid (45 mg, 74% yield). Mp 250e252 C ½
a
ꢃ
þ55.2 (c 1.0, EtOH).
1
H NMR (300 MHz, CDCl
3
)
d
1.24e1.32 (m, 1H), 1.69e1.81 (m, 7H),
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2
2
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13
3
)
d
21.1 (CH
2
), 23.1 (CH
2
), 24.3 (CH
2
2
),
),
7.3 (CH ), 29.5 (CH ), 46.2 (CH), 54.8 (CH
2
2
2
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3. For recent reviews on asymmetric enantioselective aza-Michael reactions, see:
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7
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3
10. A different way to access compound 8 involved the addition of (E)eCH eCH]
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trans diastereoisomers.
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s 3
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yield.
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1
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1
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