Straightforward synthesis of indolizidine alkaloid 167B

Article abstract of DOI:10.1016/j.tetlet.2010.09.105

The synthetic access to indolizidines, substituted in C-5 position, was reported with good diastereoselectivity. The strategy developed was based on a key step of Michael addition associated with a Clauson-Kaas condensation.

Full text of DOI:10.1016/j.tetlet.2010.09.105

Tetrahedron Letters 51 (2010) 6290–6293
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Tetrahedron Letters
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Straightforward synthesis of indolizidine alkaloid 167B
⇑
⇑
Stéphanie Gracia, Rudolf Jerpan, Stéphane Pellet-Rostaing , Florence Popowycz, Marc Lemaire
Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, UMR-CNRS 5246, Equipe Catalyse Synthèse Environnement, Université de Lyon,
Université Claude Bernard—Lyon 1, Bâtiment Curien, 43 Bd du 11 Novembre 1918, F-69622 Villeurbanne, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 July 2010
Revised 21 September 2010
Accepted 21 September 2010
Available online 26 September 2010
The synthetic access to indolizidines, substituted in C-5 position, was reported with good diastereoselec-
tivity. The strategy developed was based on a key step of Michael addition associated with a Clauson-
Kaas condensation.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Alkaloids
Indolizidines
Michael addition
Multi-step synthesis
1. Introduction
H
N
H
N
8
1
8a
7
6
2
Indolizidine alkaloids1, bearing an azabicyclic ring skeleton,
have been mainly isolated in small quantities from the skin ex-
tracts of neotropical frogs (Dendrobatidae, Mantellinae, Myobatr-
achidae, and Bufonidae)2 and have displayed a wide range of
biological properties, especially as non-competitive nicotinic
inhibitors. These molecules are potent blockers of nicotinic acetyl-
choline receptor channels (nAChRs), suggesting their potential effi-
ciency as lead compounds for the design of drugs to address
cholinergic disorders in the central nervous system.3 Synthetic ac-
cess to izidines substituted in C-5 position has raised great interest
from the chemistry community and a large number of racemic4
and enantiomeric5 strategies have been reported to provide these
natural alkaloids (Fig. 1).
Herein, we proposed a general and straightforward access to
indolizidine derivatives substituted in C-5 position with good
diastereoselectivity. The racemic synthetic methodology has been
developed to target 5-methylindolizidine. Exemplification has
been performed to address the most known congener indolizidine
167B bearing a propyl chain on the C-5 position (Fig. 1). Depending
on the accessibility of nitroalkanes as starting materials, the meth-
odology pointed out the rapid and potentially efficient access to a
large number of non-natural indolizidines compared to previously
reported literature.4,5
N
4
3
5
R1 R2
Indolizidine
R1 = Me, R2 = H
R1 = Me, R2 = Me
Indolizidine 167B
Figure 1. Indolizidine scaffolds targeted.
O
NH2
N
N
R
COOH
OBn
R
COOH
R
NO2
N
+
R
O
R
Scheme 1. Retrosynthetic analysis of C-5 substituted indolizidine.
The key step consisted in a Michael type addition of nitroalkane
on benzyl acrylate. Subsequent hydrogenation provided the -ami-
c
noacid that would be engaged in a Clauson-Kaas condensation.
Acidic intramolecular cyclization followed by final hydrogenation
of ketone and pyrrole nucleus afforded the expected indolizidine
(Scheme 1). In a preliminary investigation for optimization of the
⇑
Corresponding authors. Tel.: +3 346 633 9308; fax: +3 346 679 7611 (S.P.-R.);
tel.: +3 347 243 1409; fax: +3 347 243 1408 (M.L.).
E-mail addresses: stephane.pellet-rostaing@cea.fr (S. Pellet-Rostaing), marc.
lemaire@univ-lyon1.fr (M. Lemaire).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.105

S. Gracia et al. / Tetrahedron Letters 51 (2010) 6290–6293
6291
synthetic strategy, the methodology has been depicted on nitroe-
thane as the standard molecule.
TMG (2 eq.)
CH3CN
30 min., r.t.
O2N
O2N
OBn
BnO
OBn
84%
2. Results and discussion
O
O
O
2a
(1 eq)
(2 eq)
Different conditions for Michael addition of nitroethane on ben-
zyl acrylate (1 equiv) were screened to assess the experimental
procedure and make it adaptable to multistep synthesis. The
choice of the benzyl acrylate in comparison with other commer-
cially available acrylates was validated by the facility of hydrogen-
olysis of the benzyl protecting group as well as the easiness to
follow the reaction conversion by TLC. The addition of nitroethane
on benzyl acrylate promoted by phase-transfer conditions was
examined, especially the nature of the base, the nitroethane/benzyl
acrylate ratio, and the method of activation (Scheme 2, Table 1).
The reaction was carried out with equimolar quantity of nitroe-
thane and benzyl acrylate in the presence of potassium fluoride
(1 equiv) and quaternary ammonium salt such as benzyltrimethy-
lammonium chloride (0.5 equiv) in different polar solvents. (Table
1).6 The best result was obtained with DMF allowing the isolation
of compound 1a in 55% yield (entry 1). Other solvents (water, THF,
and acetonitrile) led to complex mixtures containing mono- and
di-addition products (1a and 2a) (entries 2, 3, 4) which were sys-
tematically detected and evaluated on crude 1H NMR spectra.
The number of equivalents of nitroethane was evaluated ranging
from 3 equiv to 7 equiv (entries 5, 6, 7). A higher number of nitroe-
thane equivalents led to an increased yield of nitro-ester 1a with
minor double addition. One major advantage of this 1,4-conjugate
addition concerned this solventless characteristics of this process.
Under the conditions of entry 5, the side product 2a was isolated
in 28% yield. The activation by ultrasounds (entry 8) represented
a fruitful optimization in comparison with no activation (entry 7)
with an excellent yield of 90% (vs 72% without activation).7 The
reaction rate was significantly improved in comparison with clas-
sical conditions, which again reveals the potential still few have
exploited in sonochemical syntheses.8
Scheme 3. Double Michael addition.
H2, 20 bar
Pd/C 5%, MeOH
NO2
NH2
24 h, t.a.
OBn
quantitative
COOH
O
1a
3a
MeO
O
1.1 eq.
solvent
additive
OMe
2 h, 80°C
N
COOH
4a
Scheme 4. Construction of the pyrrolic nucleus.
Table 2
Optimization of Clauson-Kaas reaction conditions
Entry
Solvent
Additive
Yield 4a
1
2
3
DCE/H2O/AcOH (4/4/1)
DCE/H2O (1/1)
AcOH
NaOAc (1 equiv)
—
NaOAc (1 equiv)
37%
55%
87%
compound 2a as a pure derivative facilitated the optimization
study described in Table 1.
Catalytic hydrogenation allowed simultaneously the reduction
of the nitro and the hydrogenolysis of the benzylic ester. The
Parallel to this work the conjugate di-addition reaction was car-
ried out in acetonitrile in the presence of tetramethylguanidine as
a base affording di-ester 2a in 84% yield (Scheme 3). Isolation of
c-
aminoacid was obtained almost quantitatively in the presence of
5% of palladium on carbon in anhydrous methanol under a 20 bar
pressure of H2. The crude aminoacid was subjected, without puri-
fication, to Clauson-Kaas reaction conditions (Scheme 4, Table 2).9
Treatment of compound 3a under the Müller–Polleux conditions
with dimethoxytetrahydrofuran (1.1 equiv) and sodium acetate
(1 equiv) in a biphasic medium composed of dichloroethane/
water/acetic acid (4/4/1) afforded pyrrolic derivative 4a in an iso-
lated yield of 37% (Table 2, entry 1).10 This result was consistent
with the studies reported by Jefford describing a comparison of for-
mation of the pyrrole between amino-acid and amino-ester with
better conversions and yields obtained in the latter case.5b,d The
conditions already used by Jefford with dimethoxytetrahydrofuran
reacting in a simple biphasic medium composed of ClCH2CH2Cl and
water without additive led to a moderate yield of 55% (entry 2).11
Significant improvement was performed, by using the Pereira con-
ditions, in the presence of sodium acetate in acetic acid as the sol-
PhCH2N+Me3,Cl- (0.5 eq.)
base : KF (1 eq.)
NO2
or
K2CO3 (0.6 eq.)
OBn
NO2
OBn
solvent, r.t., 30 min-1 h
O
O
1a
O2N
1 eq.
BnO
OBn
O
O
2a
Scheme 2. Michael addition reaction.
Table 1
Optimization of Michael addition reaction conditions
vent (entry 3).5w The -pyrrolic acid was obtained in 87% yield.12
c
Entry
EtNO2
Base
Solvent
Activation
Yielda
1
2
3
4
5
6
7
8
1 equiv
1 equiv
1 equiv
1 equiv
3 equiv
5 equiv
7 equiv
7 equiv
KF
KF
KF
KF
K2CO3
K2CO3
K2CO3
K2CO3
DMF
H2O
THF
MeCN
—
—
—
—
—
ꢀ)))
ꢀ)))
—
ꢀ)))
1a (55%)
1a+2a
1a+2a
H
PPA
H2 (10 bar), Pd/C
AcOH, 24 h, r.t.
O
30 min, r.t.
N
N
N
1a+2a
76%
91%
1a (53%)
1a (67%)
1a (72%)
1a (90%)
COOH
—
—
4a
5a
( ) 6a
dr = 88%
a
Isolated yield after purification by flash column chromatography.
Scheme 5. Access to 5-methyl indolizidine.

6292
S. Gracia et al. / Tetrahedron Letters 51 (2010) 6290–6293
PhCH2NMe3,Cl
H2 (20 bars)
Pd/C (5%)
K2CO3
NH2
R2
NO2
NO2
R2
)))
MeOH, 24 h, r.t.
30 min, r.t.
OH
OBn
R1
R2
R1
R1
O
OBn
O
R1 =R2 = Me
1b : 84%
R1 =R2 = Me
3b : Q
O
R
1 = Pr, R2 = H 1c : 98%
R
1 = Pr, R2 = H 3c : Q
MeO
O
OMe (1.1 eq.)
NaOAc (1 eq.), AcOH
2 h, 80°C
H2 (10 bars),
Pd/C (5%)
H
O
PPA
N
AcOH
N
N
30 min., r.t.
24 h, r.t.
OH
R1
R2
R1
R1
R2
R2
1 =R2 = Me
O
R
1 =R2 = Me
6b : 41%
R
5b : 47%
R1 =R2 = Me
R1 = Pr, R2 = H 4c : 73%
4b : 91%
R1 = Pr, R2 = H 6c : 91%
R1 = Pr, R2 = H 5c : 80%
Scheme 6. Synthesis of indolizidine 167B and derivative.
Intramolecular cyclization proceeded in good yield (76%) in the
References and notes
presence of polyphosphoric acid according to a modified procedure
originally reported by Dinsmore.13,14 Subsequent hydrogenation in
acetic acid of bicyclic adduct 5a in the presence of palladium on
carbon under 10 bar of hydrogen provided the indolizidine ( ) 6a
in excellent yield (Scheme 5).15
Hydrogenation was performed with good diastereoselectivity
under classical conditions. This stereochemical outcome is consis-
tent with addition of hydrogen to a chair-like conformation in
which the methyl group adopts an equatorial position. The diaste-
reoselectivity of the hydrogenation and the relative substituent po-
sition were evaluated by proton NMR and 2D correlations of the
crude reaction mixture. The 5-methylindolizidine 6a was obtained
in a five-step sequence from commercially available nitroethane
and benzyl acrylate in global yield of 54%. Using the previously de-
scribed strategy, other substituted izidines were obtained also in
five-steps bearing dimethyl in C-5 position 6b as well as indolizi-
dine 167B 6c (Scheme 6).16
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3. Conclusion
The synthesis of ( ) 5-methyl indolizidine 6a was achieved in
five-steps and an overall yield of 54% through a key step of Michael
addition reaction between nitroethane and benzyl acrylate. The
diastereoselectivity of the hydrogenation reaction was evaluated
to 88%. The proposed synthetic scheme is, for the moment, not
an enantioselective pathway. The synthetic approach developed
in our laboratory is closely related to the strategies developed by
Smith4a and Lazzaroni5ab for the access to izidines substituted in
C-5 position. This synthesis is quite attractive due to the short
length of the sequence (only five-steps in comparison with other
strategies reported in the literature4,5), the accessibility of the reac-
tants/reagents and can also focus on other C-5 substituted alka-
loids opening the wide range of functionality.
Acknowledgment
The Ministère de l’Enseignement Supérieur et de la Recherche is
gratefully acknowledged for a grant to S.G.

S. Gracia et al. / Tetrahedron Letters 51 (2010) 6290–6293
6293
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mixture was cooled down to room temperature and evaporated. The residue
was diluted with dichloromethane (15 ml) and washed with saturated aq.
sodium carbonate (10 ml  3). The combined aqueous extracts were acidified
with hydrochloric acid (1 M) and extracted with dichloromethane (15 ml  3).
The organic layers were dried over Na2SO4, and evaporated to afford 4-pyrrol-
1-yl-pentanoic acid 4a as
a
colorless oil (124 mg, 87%). 1H NMR (CDCl3,
400 MHz): d (ppm) = 6.56 (dd, 2H, J = 2.3 Hz, J = 4.3 Hz, Harom); 6.03 (dd, 2H,
J = 2.3 Hz, J = 4.3 Hz, Harom); 4.04–3.94 (m, 1H, H4); 2.08–2.04 (m, 2H); 1.97–
1.84 (m, 2H); 1.36 (d, 3H, J = 5.1 Hz, H5). 13C NMR (CDCl3, 100 MHz):
d
(ppm) = 179.3 (Cq); 118.4 (2CHarom); 108.0 (2CHarom); 54.4 (CH); 32.9 (CH2);
30.9 (CH2); 22.1 (CH3).
6. (a) Brettle, R.; Cummings, D. P. J. Chem. Soc., Perkin Trans. 1 1977, 19, 2177–
2180; (b) Chittari, P.; Thomas, A.; Rajappa, S. Tetrahedron Lett. 1994, 35, 3793–
3796.
13. Dinsmore, A.; Mandy, K.; Michael, J. P. Org. Biomol. Chem. 2006, 4, 1032–
1037.
14. General procedure for cyclization reaction
7. Experimental procedure for Michael addition
c-Pyrrolic acid 4a (437 mg, 2.61 mmol, 1 equiv) was mechanically stirred in
Nitroethane (718
l
l, 10 mmol, 7 equiv) was added under argon atmosphere to
polyphosphoric acid (>84% phosphate as P2O5) (ꢁ4 ml) for 30 min at room
temperature. The reaction mixture was cautiously quenched with water
(75 ml) and the resulting solution was extracted with dichloromethane
(25 ml  3). The combined organic extracts were dried over Na2SO4 and
evaporated to afford a crude solid. The residue was recrystallized from Et2O to
furnish 5-methyl-6,7-dihydro-5H-indolizin-8-one 5a as a white solid (296 mg,
76%).1H NMR (CDCl3, 400 MHz): d (ppm) = 6.98 (dd, 1H, J = 2.0 Hz, J = 5.2 Hz,
anhydrous potassium carbonate (829 mg, 6 mmol, 0.6 equiv) and
benzyltrimethylammonium chloride (133 mg, 0.72 mmol, 0.5 equiv). Benzyl
acrylate (217 mg, 1.43 mmol, 1 equiv) was added dropwise. The mixture was
irradiated during 30 min under ultrasound activation, and then extracted with
dichloromethane (10 ml  4) and water (3 ml). The combined organic extracts
were dried over Na2SO4, and evaporated to afford a crude oil. The residue was
purified by column chromatography (pentane/EtOAc: 95/5 as eluant)
H
arom); 6.90 (m, 1H, Harom); 6.22 (dd, 1H, J = 3.5 Hz, J = 5.5 Hz, Harom); 4.23 (m,
1H, CHN); 2.66–2.47 (m, 2H); 2.32–2.24 and 2.06–1.97 (m, 2H); 1.54 (d, 3H,
J = 5.0 Hz, CH3). 13C NMR (CDCl3, 100 MHz):
(ppm) = 187.2 (Cq); 130.4
furnishing 4-nitro-pentanoic acid benzyl ester 1a as
a yellow oil (1.51 g,
90%). Rf (pentane/EtOAc: 95/5) = 0.26. 1H NMR (CDCl3, 400 MHz):
d
d
(ppm) = 7.40–7.31 (m, 5H, Harom); 5.13 (s, 2H, OCH2Ph); 4.69–4.61 (m, 1H,
H4); 2.49–2.33 (m, 2H); 2.31–2.04 (m, 2H); 1.54 (d, 3H, J = 5.1 Hz, H5). 13C NMR
(CDCl3, 100 MHz): d (ppm) = 171.8 (Cq); 135.6 (Cqarom); 128.7 (2CHarom); 128.5
(CHarom); 128.3 (2CHarom); 82.4 (CH); 66.7 (CH2); 30.2 (CH2); 29.9 (CH2); 19.3
(CH3). HRMS (EI) calcd for [C12H15NO4]+Å: 237.1001, found 237.1001.
8. Mason, T. J. Chem. Soc. Rev. 1997, 26, 443–451.
9. (a) Clauson-Kaas, N.; Tyle, Z. Acta Chem. Scand. 1952, 6, 667–670; (b) Elming,
N.; Clauson-Kaas, N. Acta Chem. Scand. 1952, 6, 867–874.
10. Müller, P.; Polleux, P. Helv. Chim. Acta 1998, 81, 317–323.
(Cqarom); 124.1 (CHarom); 114.1 (CHarom); 110.4 (CHarom); 50.5 (CH); 34.5 (CH2);
30.8 (CH2); 20.6 (CH3). HRMS (EI) calcd for [C9H11NO]+Å: 149.0841, found
149.083715.
15. General procedure for reduction reaction
Indolizinones 5a–c (1 equiv) were dissolved in acetic acid [0.06 M] in
a
stainless steel reactor. Then Pd/C (5%) was added and the mixture was stirred
overnight under a 10 bar pressure of hydrogen at room temperature. The
palladium was removed by filtration through a pad of CeliteÒ and washed with
acetic acid (10 ml  3). The solvent was evaporated to give a residue, which
was diluted in dichloromethane (20 ml) and then washed with a saturated
solution of potassium carbonate (10 ml  3). The combined organic extracts
were dried over Na2SO4, and evaporated to afford indolizidines 6a–c.
16. 5-Propylindolizidine 6c (Indolizidine 167B) was obtained as a colorless oil
(yield 91%; dr = 85% measured by NMR) and analytical data were found to
correspond with data reported in the literature.
11. Jefford, C. W. Pure Appl. Chem. 1996, 68, 799–804.
12. General procedure for Clauson-Kaas reaction
Aminoacid 3a (100 mg, 0.85 mmol, 1 equiv) and sodium acetate (70 mg,
0.85 mmol,
1 equiv)
were
dissolved
in
acetic
acid
(3.5 ml).
Dimethoxytetrahydrofuran (124 mg, 0.94 mmol, 1.1 equiv) was added and
the mixture was stirred for 2 h at 80 °C. After completion of the reaction, the