Facile and short synthesis of (±) 1-hydroxy indolizidine and (±) coniceine from picolinic acid ethyl ester via cross claisen condensation

Article abstract of DOI:10.14233/ajchem.2015.17459

New short synthesis of (±) 1-hydroxy indolizidine (4) and (±) coniceine (5) are described starting from picolinic acid ethyl ester (6). The key steps are the conversion of the picolinic acid ethyl ester into β-keto ester 7 via cross Claisen condensation and hydrogenation of the β-keto ester in to hydroxy bicyclic amide (8) using PtO₂/H₂.

Full text of DOI:10.14233/ajchem.2015.17459

Asian Journal of Chemistry; Vol. 27, No. 5 (2015), 1667-1670
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2015.17459
Facile and Short Synthesis of ( ) 1-Hydroxy Indolizidine and ( ) Coniceine
from Picolinic Acid Ethyl Ester via Cross Claisen Condensation
1,2
1
2
S. VEERASWAMY , A. ANJAIAH , SATYANARAYANA YENNAM1,* and A. JAYASHREE
1Chemistry Services, GVK Biosciences Pvt. Ltd., Plot No. 28A, IDA, Nacharam, Hyderabad-500 076, India
2Chemistry Division, Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500 072, India
*Corresponding author: Fax: +91 40 66281505; Tel: +91 40 66281704; E-mail: satya@gvkbio.com
Received: 24 February 2014;
Accepted: 22 May 2014;
Published online: 20 February 2015;
AJC-16865
New short synthesis of ( ) 1-hydroxy indolizidine (4) and ( ) coniceine (5) are described starting from picolinic acid ethyl ester (6). The
key steps are the conversion of the picolinic acid ethyl ester into β-keto ester 7 via cross Claisen condensation and hydrogenation of the
β-keto ester in to hydroxy bicyclic amide (8) using PtO2/H2.
Keywords: 1-Hydroxy indolizidine, Coniceine, β-keto ester, Cross Claisen condensation.
compound 6 (15 g, 99.3 mmol) in anhydrous THF (150 mL),
LiHMDS (298 mL, 1 M sol. in THF, 298 mmol) was added
quickly at -50 °C and stirred at the same temperature for 0.5 h.
After completion of the reaction (monitored by TLC), reaction
mixture was quenched with acetic acid (15 mL) and water
(150 mL), basified with saturated solution of sodium bicarbonate
(100 mL) and extracted with ethyl acetate (3 × 100 mL). The
combined organic layer washed with water (150 mL), brine
solution (150 mL) and dried over Na2SO4. The solvent was
removed under reduced pressure and crude was purified by
column chromatography (hexane/ethyl acetate 20:80) to afford
compound 7 (16.5 g, 86 %) as a pale yellow liquid. Rf (20 %
ethyl acetate in hexane) 0.4; 1H NMR of compound 7 recorded
as keto enol mixtures. 1H NMR (400 MHz, CDCl3): δ 8.68 (d,
1H, J = 4.4 Hz), 8.64 (d, 0.16H, J = 4.8, Hz), 8.08 (d, 1H, J =
7.6 Hz), 7.92 (d, 0.15H, J = 8 Hz), 7.93 (t, 1H, J = 7.6 Hz),
7.85 (t, 0.17H, J = 7.6 Hz), 7.5 (t, 1H J = 6 Hz), 7.35 (t, 0.15H,
J = 5.6 Hz), 4.32 (q, 0.35H, J = 6.8 Hz), 4.23 (m, 4H), 1.36 (t,
0.49H, J = 6.8 Hz), 1.25 (t, 3H, J = 7.2 Hz); 13C NMR (100
MHz, CDCl3): δ 194.5, 168.1, 152.3, 148.9, 136.9, 127.4,
122.0, 89.3, 61.1, 44.7, 14.0. MS ESI): (m/z) calcd for
C10H11NO3 [M-H]-, 192.05; found 192.05.
INTRODUCTION
Azabicycles such as indolizidines, quinolizidines and
pyrrolizidines are very important, because of their presence
in numerous biologically active natural products.Among these,
synthesis of indolizidine alkaloids and its derivatives received
more attention due to their frequent appearance in the naturally
occurring bioactive molecules1-7. Few indolizidine alkaloids
isolated from plants and animals have shown considerable
biological activities8,9. Particularly hydroxylated indolizidines
such as lentiginosine (1), swainsonine (2) and castanosperimine
(3) (Fig. 1) are potent inhibitors of α and β-glycosidases and
also used in cancer chemotherapy10,11. 1-Hydroxy indolizidines
are considered as key precursors in the biosynthesis of toxic
indolizidine alkaloids salframin and swainsonine in fungus
Rhizoctonia leguminicola12.
There are many racemic and asymmetric synthesis of
1-hydroxy indolizidine13-26 and coniceine27-31 starting from
different racemic and enantio-pure starting materials.Although
numerous racemic and enantio-selective synthesis are known
for these indolizidine alkaloids, the need and development of
new short synthetic routes are of interest. The scope of
synthesizing these indolizidines starting from pyridines has
not been explored extensively. To the best of our knowledge,
there are few reports using pyridine derivatives as starting
materials32-34 in the synthesis of indolizidine natural products.
Preparation of hexahydro-1-hydroxyindolizidin-3-
(5H)one (8): Platinum oxide (200 mg) was added to the
solution of compound 7 (2 g, 10.3 mmol) in ethanol (20 mL),
and heated to 70 °C under 100 Psi hydrogen pressure for 14 h.
After completion of the reaction (monitored by TLC), RM
was filtered through a pad of celite and washed with ethanol
(15 mL). Filtrate was concentrated under reduced pressure to
EXPERIMENTAL
Preparation of ethyl 3-oxo-3-(pyridin-2-yl)propanoate
(7): To the solution of ethyl acetate (59 mL, 596 mmol) and

1668 Veeraswamy et al.
Asian J. Chem.
get compound 8 (1.3 g, 81 %), as light yellow oil, which is
mixture of cis:trans (1:3) isomers. Rf (10 % MeOH/CHCl3)
0.5; H NMR (400 MHz, CDCl3) : δ 4.41 (m, 0.26H), 4.16-
to dryness. Crude was purified by column chromatography
(silica gel, hexane/ethyl acetate 2:8) to afford compound 10
(200 mg, 85 %), as a pale yellow liquid. Rf (5 % MeOH/CHCl3)
0.3; 1H NMR (400 MHz, CDCl3) : δ 7.02 (m, 1H), 6.16 (m,
1H), 4.31 (m, 1H), 3.88 (m, 1H), 2.87-2.80 (m, 1H), 2.14-
2.08 (m, 1H), 1.98-1.90 (m, 1H), 1.55-1.48 (m, 1H) 1.32-1.27
(m, 2H) 1.08-1.01 (m, 1H); 13C NMR (100 MHz, CDCl3): δ
168.8 146.9, 127.2, 61.3, 39.1, 30,6, 25.2, 23.3. MS (ESI):(m/z)
calcd for C8H11NO [M + H]+, 138.08; found : 138.04
1
4.09 (m, 2H), 3.44-3.39 (m, 0.27H), 3.31-3.26 (m, 1H), 2.77-
2.63 (m, 2.5H), 2.39-2.36 (m, 1.2H), 2.12 (br, 1H, OH), 2.05-
2.02 (m, 1.34H), 1.93-1.84 (m, 1.25H), 1.73-1.69 (m, 1.63H),
1.46-1.42 (m, 1.4H), 1.37-1.27 (m, 1.2H), 1.16-1.09 (m, 1H);
13C NMR (100 MHz, CDCl3): δ 172.4, 171.3, 70.4, 65.9, 65.6,
61.8, 40.9, 40.2, 40.1, 39.9, 30.3, 24.5, 24.3, 23.9, 23.3,
23.1.MS (ESI):(m/z) calcd for C8H13NO2 [M + H]+, 156.09;
found 156.22.
Preparation of hexahydroindolizin-3(5H)-one (11):
Pd-C (40 mg) was added to the solution of compound 9 (400
mg 2.9 mmol) in ethanol (10 mL) and stirred at room
temperature under 15 psi of hydrogen pressure for 6 h . After
completion of reaction (monitored by TLC), the mixture was
filtered through a pad of celite and washed with ethanol (10 mL).
Filtrate was evaporated to dryness in vacuum to get compound
11 (314 mg, 80 %), as light brown viscous oil. Rf (10 % MeOH/
Preparation of octahydroindolizin-1-ol (4): To the
suspension of LiAlH4 (176 mg, 4.9 mmol), in dry THF (10
mL), a solution of compound 6 (380 mg 2.4 mmol) in dry
THF (4 mL) was added at 0 °C and stirred at this temperature
for 1 h. After completion of the reaction (monitored by TLC),
RM was quenched slowly by adding 0.2 mL of 10 % aq. NaOH
solution and 0.5 mL of water. The resulting solid was filtered
through a pad of celite and washed with ethyl acetate (10 mL).
Filtrate was dried over Na2SO4 and concentrated. Crude was
purified by column chromatography (silica gel, hexane/ethyl
acetate 3:7) to get compound 4 (290 mg, 84 %), as a colourless
liquid, which is mixture of cis:trans (1:3) isomers. Rf (10 %
MeOH/CHCl3) 0.3; 1H NMR (400 MHz, CDCl3): δ 4.11-4.06
(m, 0.27H), 3.95-3.90 (m, 1H), 3.09-3.03 (m, 0.5H), 3.01-
2.98 (m, 2H), 2.38-2.32 (m, 1.1H), 2.30-2.17 (m, 1.3H), 2.03-
1.97 (m, 3H), 1.83 (m, 2H), 1.55-1.46 (m, 2H) 1.30-1.21 (m,
2H); 13C NMR (100 MHz, CDCl3), 76.0, 72.8, 70.9, 69.0, 53.4,
53.1, 52.7, 52.4, 33.1, 31.7, 25.0, 24.8, 23.9, 23.7. MS
(ESI):(m/z) calcd for C8H15NO [M + H]+, 142.12; found 142.21.
Preparation of octahydro-3-oxoindolizin-1-yl methane
sulfonate (9): To the solution of compound 7 (300 mg, 1.9
mmol) and triethyl amine (0.38 mL 2.7 mmol) in anhydrous
dichloromethane (10 mL), methane sulfonylchloride (266 mg,
2.3 mmol) was added at 0 °C and stirred at RT for 16 h. After
completion of reaction (monitored by TLC), RM was quenched
with cold water (10 mL) and extracted with dichloromethane
(3 × 20 mL). The combined organic layer was washed with
water (10 mL) and saturated brine solution (10 mL) and dried
over Na2SO4. Evaporation of solvent under reduced pressure
gave compound 9 (400 mg, 88 %) as a light brown liquid,
which is mixture of cis:trans (1:3) isomers. Rf (5 % MeOH/
1
CHCl3) 0.4; H NMR (400 MHz, CDCl3): δ 4.12 (m, 1H),
3.43 (m, 1H), 2.64 (m, 1H), 2.37-2.33 (m, 2H), 2.33-2.18 (m,
1H), 1.87 (m, 2H), 1.70-1.67 (m, 1H), 1.63-1.59 (m, 1H), 1.58-
1.57 (m, 1H), 1.39-1.33 (m, 2H), 1.19-1.10 (m, 1H); 13C NMR
(100 MHz, CDCl3): δ 173.6, 57.2, 40.1, 33.5, 29.6, 25.2, 24.3,
23.5. MS (ESI):(m/z) calcd for C8H13NO [M + H]+, 140.10;
found: 140.13.
Preparation of octahydroindolizine (5): To a solution
of compound 11 (100 mg, 0.7 mmol) in THF (5 mL), was
cooled to 0 °C and borane-methyl sulfide complex in THF
(1.05 mL, 2.0 M sol. in THF, 2.1 mmol) was added drop wise
under nitrogen atmosphere. The reaction mixture was allowed
to room temperature and stirred for 16 h. The reaction mixture
was quenched with cold water (5 mL) and extracted with ethyl
acetate (3 × 10 mL). The combined organic layer was washed
with brine solution (5 mL) and dried over Na2SO4 evaporated
to dryness. Purification of crude by column chromatography
(silica gel, methanol/ethyl acetate) affords compound 5 (65
mg, 75 %) as pale yellow liquid. Rf (20 % MeOH/CHCl3) 0.1;
1H NMR (400 MHz, CDCl3): δ 3.3-2.55 (m, 5H), 2.05-1.74
(m, 4H), 1.6-1.3 (m, 6H); 13C NMR (400 MHz, CDCl3): δ
65.4, 60.4, 53.4, 27.0, 24.1, 20.97, 19.3, 18.6. MS (ESI):(m/z)
calcd for C8H15N [M + H]+, 125.12; found 126.01.
RESULTS AND DISCUSSION
In continuation of earlier research work35,36 in the area of
cross Claisen condensation and its use in the synthesis of
β-keto esters, here in we wish to report the first synthesis of
indolizidine alkaloids ( ) 1-hydroxy indolizidine (4) and ( )
coniceine (5) (Fig. 1) starting from commercially available
picolinic acid ethyl ester via cross Claisen condensation.
As shown in the retrosynthetic analysis (Scheme-I), the
key intermediate hydroxy bicyclic amide 8 can be prepared
from the picolinic acid ester in two steps and the reduction of
this hydroxy bicyclic amide using lithium aluminium hydride
gave ( ) 1-hydroxy indolizidine. ( ) Coniceine was obtained
in four steps from hydroxy bicyclic amide 8.
1
CHCl3) 0.7 H NMR (400 MHz, CDCl3): δ 5.3 (s, 0.28H),
4.88-4.81(m, 0.83H), 4.21-4.16 (m, 1.1H), 3.68 (s, 0.7H), 3.65-
3.59 (m, 1H), 3.07 (s, 3H), 2.96-2.84 (m, 1H), 2.76-2.61 (m,
2.2H), 2.14-2.06 (m, 2H), 1.97-1.92 (m, 1H), 1.74-1.67
(m,1H), 1.51-1.23 (m, 4H); 13C NMR (100 MHz, CDCl3): δ
169.9, 168.8, 74.4, 63.2, 60.2, 52.5, 40.4, 40.1, 38.5, 38.1,
37.0, 31.4, 29.7, 25.4, 24.1, 23.6, 23.1, 22.9. MS (ESI):(m/z)
calcd for C9H15NO4S [M + H]+, 234.07; found: 234.08.
Preparation of 6,7,8,8a-tetrahydroindolizin-3(5H)-one
(10): DBU (0.3 mL, 2.06 mmol) was added to the solution of
compound 8 (300 mg, 1.28 mmol) in anhydrous THF (5 mL)
and stirred at room temperature for 16 h. After completion of
reaction (monitored by TLC), RM was quenched with cold
water and extracted with ethyl acetate (3 × 20 mL ). The com-
bined organic layer was washed with water (10 mL), saturated
brine solution (5 mL) and dried over Na2SO4 and evaporated
Our method of preparations is outlined in Scheme-II and
III. As depicted in Scheme-II, the inexpensive commercially
available picolinic acid ethyl ester 6 was converted into the
corresponding β-keto ester using LiHMDS and EtOAc at

Vol. 27, No. 5 (2015)
Synthesis of ( ) 1-Hydroxy Indolizidine and ( ) Coniceine from Picolinic Acid Ethyl Ester 1669
OH
OH
OH
OSO2CH3
OH
OH
H
OH
HO
HO
i
ii
OH
N
N
N
OH
N
N
85%
88%
N
O
O
O
10
8
9
lentiginosine ( )
1
castanopermine ( )
3
swainsonine ( )
2
iii
80%
iv
OH
N
N
75%
O
N
5
N
11
Coniceine ( )
5
(i) Ms-Cl, Et N, DC M, 0°C to RT, 6 h (ii) D BU, THF, 0°C, 6 h (iii) Pd-C, H
3 2
1-Hydroxy indolizidine (4)
(15 Psi),
EtOH, 6 h (iv)
BH .SMe , THF, RT, 15 h
3
2
Fig. 1. Structures of indolizidine alkaloids
Scheme-III: Synthesis of ( ) coniceine
amide 11 using BH3.Me2S in 75 % yield32. 1H NMR values of
OH
OH
( ) coniceine are complied with the reported values.
N
N
Conclusion
N
COOEt
OH
O
In conclusion, an efficient, short and high yielding method
is developed to synthesize hydroxy indolizidine and coniceine
from the inexpensive, commercially available, picolinic acid
ethyl ester.
4
6
8
N
N
N
O
O
5
ACKNOWLEDGEMENTS
10
8
Scheme-1:Retro synthesis path way for ( ) 1-hydroxy indolizidine and ( )
The authors are grateful to GVK Biosciences Pvt. Ltd.,
for the financial support and encouragement. Thanks are also
due to Dr. Sudhir Kumar Singh for his encouragement and
motivation and help from the analytical department.
coniceine
-50 °C37. The β-keto ester 7 was successfully hydrogenated
using PtO2/H2 in ethanol at 100 psi to get the key intermediate
hydroxy bicyclic amide 8 in 81 % yield. Interestingly we did
not observe the complete reduction of keto group in to -CH2
group. Reduction using PtO2/H2 produced the mixture of
diastereomers in the ratio of 1:3 (syn:anti), respectively.
Heimgartner et al.34 reported that increased diastereo-selec-
tivity during the pyridine ring reduction can be achieved when
there is a 3-alkoxy substitution in the pyridine ring. Reduction
of hydroxy bicyclic compound 8 using lithium aluminium
hydride in THF afford 1-hydroxy indolizidine (4) in 84 %
yield14,15. 1H NMR of 1-hydroxy indolizidine (4) complied with
the reported data26. More importantly purifications in any of
the these steps were not perfomed.
Synthesis of ( ) coniceine was outlined in Scheme-III.
Hydroxy bicyclic amide (8) was easily converted into enamide
10 in two steps by following the procedure reported by
Lennartz and E. Steckhan38 Simple hydrogenation of enamide
10 using Pd-C/ethanol at 15 psi produced bicyclic amide 11
in 80 % yield. ( ) Coniceine (5) was obtained by reducing
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