Expedient syntheses of indolizidines (-)-167B and (-)-209D

Article abstract of DOI:10.1016/S0957-4166(01)00369-X

Indolizidine alkaloids (-)-167B and (-)-209D were synthesized via an expedient route using hydroacylation and amination.

Full text of DOI:10.1016/S0957-4166(01)00369-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2073–2076
Expedient syntheses of indolizidines (−)-167B and (−)-209D
Guncheol Kim* and Eun-ju Lee
Department of Chemistry, College of Natural Science, Chungnam National University, Taejon 305-764, South Korea
Received 25 July 2001; accepted 17 August 2001
Abstract—Indolizidine alkaloids (−)-167B and (−)-209D were synthesized via an expedient route using hydroacylation and
amination. © 2001 Published by Elsevier Science Ltd.
1. Introduction
tion of the known chiral intermediate 3, we planned to
use intermediate 5, which was made by modifying the
reported process.5a,5b Condensation of (R)-(−)-2-
phenylglycinol with succinimide afforded imide 4 as
described, which was partially reduced to a hydroxy
imide using SnCl2 and NaBH4 in EtOH.6 Acid treat-
ment, selective allylation, separation of the 9:1
diastereomeric products by column chromatography,
and deprotection of the chiral auxiliary using Na in
NH3 containing EtOH provided 5. LAH reduction of
the amide to pyrrolidine and treatment of the interme-
diate with benzyl chloroformate afforded 3 (Scheme 2).
The indolizidine alkaloids are contained in the toxic
skin secretion of neotropical frogs belonging to the
genus Dendrodates, and display a wide range of biolog-
ical activities.1 Some of the indolizidines in this class are
non-competitive blockers of nicotinic receptor
channels.2
The simplest bicyclic gephyrotoxin alkaloids, 167B and
209D, have a single alkyl substituent at C(5) of the
indolizidine ring, and the limited amount of these com-
pounds available from natural sources as well as their
interesting pharmacological properties has made them
an attractive synthetic subject.3
The allylic compound 3 was then subjected to hydro-
acylation conditions. Recent development of a mild
intermolecular hydroacylation has described the com-
bined use of a Rh(I) complex, 2-amino-3-picoline, ben-
zoic acid, and aniline.7 However, an excess amount of
simple alkenes has been used with mostly reactive ben-
zaldehyde or its congeners. As the alkene 3 must be
We considered the keto-intermediates 1 and 2 to be
appropriate final precursors for the synthesis, as hydro-
genation of the compounds would control the stereo-
chemistry at the developing stereogenic center to afford
the alkaloids,3c,3n respectively, and these compounds
could be prepared from intermediate 3. To elongate the
allylic side chain of 3 and afford the appropriate car-
bonyl compounds, we wanted to perform the process in
a single step using a hydroacylation reaction (Scheme
1). In the related syntheses, manipulation of the allylic
side chain required several steps and costly
chemicals.3n,4
2. Results and discussion
Herein, we describe a concise route to the alkaloids
using hydroacylation and amination. For the prepara-
Scheme 1.
* Corresponding author. E-mail: guncheol@cuvic.cnu.ac.kr
0957-4166/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0957-4166(01)00369-X

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G. Kim, E. Lee / Tetrahedron: Asymmetry 12 (2001) 2073–2076
4. Experimental
4.1. General procedures
All reactions were performed in oven-dried glassware
with magnetic stirring. Commercial grade reagents and
anhydrous solvents were used without further
purification.
4.2. Preparation of the known intermediate (5S)-
propenyl pyrrolidinone 35a,5b
Succinic anhydride (3.64 g, 36.4 mmol) and (S)-phenyl-
glycinol (5 g, 36.4 mmol) were dissolved in toluene (300
mL). The mixture was heated under reflux for 1 h, and
triethylamine (10 mL) was added and the mixture was
heated again at reflux for 17 h. The resulting product
was cooled to rt and concentrated. The crude product
was separated by column chromatography eluting
hex:EtOAc 5:1 to afford (S)-(+)-N-(1-phenyl-2-hydroxy-
ethyl)succinimde 4 as an oil (6.45 g, 84%, [h]2D4 +17.4 (c
1.80, EtOH) [lit.5a [h]D +16.5 (c 1.87, EtOH)]).
Scheme 2. Reagents and conditions: (a) (R)-(−)-2-phenylgly-
cinol, toluene, Et3N; (b) NaBH4, SnCl2, EtOH; (c) CF3CO2H,
CH2Cl2; (d) AllBu3Sn, TiCl4, CH2Cl2; (e) Na, NH3, THF,
EtOH; (f) LAH, THF; (g) ClCO2Bn, THF, Et3N.
To a solution of this imide (3.50 g, 16.0 mmol) and
tin(II) chloride (3.00 g, 16.0 mmol) in ethanol/CH2Cl2
(7:1, 160 mL) was added sodium borohydride (3.0 g,
80.0 mmol) at 0°C. The mixture was stirred at 0°C for
40 min and quenched with saturated aqueous NaHCO3
solution. The resulting grey mixture was extracted with
CH2Cl2 (5×100 mL). The combined organic extracts
were dried over MgSO4 and concentrated to afford a
crude mixture, and this material was directly treated
with trifluoroacetic acid (15 mL) in CH2Cl2 (200 mL).
After stirring the solution for 20 min at rt, the solution
was concentrated and separated by column chromatog-
raphy to afford a bicyclic lactam intermediate (2.64 g,
90%, mp 65–68°C; [h]D24 +153.5 (c 1.60, EtOH) [lit.5a
[h]D +154.1 (c 1.29, EtOH)]).
used as the limiting reagent, we wanted to find the
optimal conditions for this case. When using 1 equiv. of
heptaldehyde at 130°C over 2 h, only 10% of 2 was
obtained with 80% recovery of the starting material 3.
Use of 5 equiv. of heptaldehyde at 150°C over 24 h
increased the yield to 35% (45% recovery of 3). In the
case of butyraldehyde, 30% of 1 (55% recovery of 3)
was obtained under the same conditions. Although the
yields are relatively low even under vigorous reaction
conditions, the single step manipulation using commer-
cially available aldehydes compensates for the moderate
yields.
Finally, hydrogenation of 1 and 2 was carried out
under 1 atm pressure of H2 in MeOH containing 5% Pd
on carbon, providing (−)-167B (80%, [h]2D4 −104.0 (c
0.80, CH2Cl2) [lit.3a [h]D −111.3 (c 1.3, CH2Cl2)]) and
(−)-209D (83%, [h]D24 −81.4 (c 1.15, CH2Cl2) [lit.3a [h]D
−80.4 (c 1, CH2Cl2)]), respectively (Scheme 3).
This lactam intermediate (2.20 g, 11.0 mmol) and
allyltrimethylsilane (6.90 mL, 43.0 mmol) in CH2Cl2 (20
mL) was added to a solution of TiCl4 (1 M solution in
CH2Cl2, 27.0 mL, 27.0 mmol) in CH2Cl2 (100 mL) at
−78°C under an argon atmosphere. The resulting solu-
tion was stirred at −78°C for 1 h and at 0°C for 2 h and
quenched with saturated NaHCO3 solution. The mix-
ture was extracted with CH2Cl2 (3×100 mL), dried over
MgSO4, filtered, concentrated and the crude product
(ꢀ9:1 mixture of epimers) purified by silica gel column
chromatography using hex:EtOAc=5:1 provided N-[2-
(2R-phenyl ethanol)]-5S-propenyl-2-pyrrolidinone as a
clear oil (2.18 g, 81%), [h]2D4 +22.2 (c 1.70, CH2Cl2) [lit.5b
[h]D +21.9 (c 2.0, CH2Cl2)].
3. Conclusion
The present study demonstrates the use of hydro-
acylation of intermediate 3 with commercial aldehydes,
providing precursors 1 and 2 for indolizidines (−)-167B
and (−)-209D in moderate yields, and the following
hydrogenation made the expedient syntheses possible.
Scheme 3. Reagents and conditions: (a) [Rh(PPh3)3Cl](2 mol%), 2-amino-3-picoline (20 mol%), benzoic acid (6 mol%), aniline (60
mol%), RCHO (500 mol%), toluene, 150°C, 24 h, 30% for 1, 35% for 2; (b) H2, 5% Pd on C, MeOH, 80% for 167B, 83% for 209D.

G. Kim, E. Lee / Tetrahedron: Asymmetry 12 (2001) 2073–2076
2075
To a solution of this pyrrolidinone (2.43 g, 13.20 mmol)
in liquid NH3 (70 mL) containing THF/ethanol (8
mL/8 mL) was added Na (1.52 g, 66 mmol) slowly at
−78°C. The blue color persisted more than 3 min, and
then the reaction was quenched by slow addition of
solid NH4Cl. After slow evaporation of liquid NH3, the
mixture was extracted with EtOAc (3×100 mL), washed
with brine (30 mL), and dried over MgSO4. Filtration,
evaporation, and purification by silica gel column chro-
matography afforded 1.97 g of 5 (67%, [h]2D4 +1.95 (c
1.49, CH2Cl2) [lit.5b [h]D +1.4 (c 2.0, CH2Cl2)]).
16H), and 0.85 (t, J=7.1 Hz, 3H); 13C NMR (100
MHz, CDCl3) l 211.8, 155.3, 137.5, 128.8 (3), 128.2 (2),
66.8, 57.7, 46.7, 43.3, 42.8, 34.1, 32.0, 30.5, 29.3, 24.2,
23.8, 22.9, 20.7, 17.9, and 14.4; [h]2D4 −38.0 (c 1.50,
CHCl3); IR (thin film) 2943, 1710, 1700, 1558, 1417,
1358 and 1102 cm−1; ESIMS m/z 360.1 (M+H+,
C22H33NO3 requires 360.2). Anal. calcd for C22H33NO3:
C, 73.50; H, 9.19; N, 3.90. Found: C, 73.45; H, 9.26; N,
3.85%.
4.5. Synthesis of 167B
To a solution of 5 (1.0 g, 8.0 mmol) in THF (15 mL)
was added LAH solution (24 mL of 1.0 M solution in
ether, 24.0 mmol) at 0°C. The solution was heated
under reflux for 5 h, and then 20% NaOH solution (3
mL) was added. The white solid was filtered through
glass filter and the filtrate was concentrated. The crude
product was directly treated with benzyloxycarbonyl
chloride (2.87 g, 16.0 mmol) in THF (15 mL) contain-
ing Et3N (1.0 mL), stirring at rt for 4 h. The reaction
mixture was diluted with EtOAc (15 mL), washed with
satd NH4Cl solution and dried over MgSO4. After
concentration the crude product was purified by
column chromatography to provide 3 (1.50 g, 77%,
[h]D24 −46.9 (c 1.18, CHCl3) [lit.5c [h]D −38.7 (c 1.13,
CHCl3)]).
A solution of 1 (48 mg, 0.151 mmol) in MeOH (2 mL)
containing Pd on carbon (5%, 5 mg) was stirred under
H2 at rt for 10 h. After filtration through Celite, the
mixture was concentrated and filtered through short
path of silica gel using EtOAc as an eluent to afford
167B (20 mg, 80%, [h]2D4 −104.0 (c 0.80, CH2Cl2) [lit.3a
[h]D −111.3 (c 1.3, CH2Cl2)].
4.6. Synthesis of 209D
Similar procedure using 2 as above afforded 209D
(83%, [h]2D4 −81.4 (c 1.15, CH2Cl2) [lit.3a [h]D −80.4 (c 1,
CH2Cl2)].
Acknowledgements
4.3. Preparation of (R)-1-benzyloxycarbonyl-2-
(4-oxo-nonyl)pyrrolidine 1
The authors thank the CMDS in KAIST for generous
funding.
A mixture of 3 (0.20 g, 0.816 mmol), butyraldehyde
(0.294 g, 4.08 mmol), toluene (0.25 mL), 2-amino-3-
picoline (34.6 mg, 0.32 mmol), benzoic acid (12 mg,
0.10 mmol), and aniline (94 mg, 1.0 mmol) in a screwed
vial was stirred at rt for 10 min, and Rh(PPh3)3Cl (30
mg, 0.032 mmol) was added. The combined mixture
was heated at 150°C for 24 h. The mixture was diluted
with EtOAc (10 mL) and washed with 1N H2SO4, satd
NaHCO3 solution, and brine. After drying over
MgSO4, the organic layer was filtered and concentrated.
Silica gel column chromatography afforded 1 (78 mg,
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