Short synthesis of stenusine and norstenusine, two spreading alkaloids from Stenus beetles (Coleoptera: Staphylinidae)

Article abstract of DOI:10.1016/j.tet.2007.01.024

Each of the both spreading alkaloids stenusine and norstenusine could be synthesized starting from commercially available 3-picoline in a two-step synthesis in yields of 74% and 67% in gram scale. The stereoisomeric ratio of the synthesized (+)-stenusine is similar to that of stenusine from Stenus comma.

Full text of DOI:10.1016/j.tet.2007.01.024

Tetrahedron 63 (2007) 2670–2674
Short synthesis of stenusine and norstenusine, two spreading
alkaloids from Stenus beetles (Coleoptera: Staphylinidae)
Thomas Gedig,a Konrad Dettnerb and Karlheinz Seiferta,
*
aLehrstuhl fu€r Organische Chemie, NW II, Universita€t Bayreuth, D-95440 Bayreuth, Germany
bLehrstuhl fu€r Tiero€kologie II, Universita€t Bayreuth, D-95440 Bayreuth, Germany
Received 5 December 2006; revised 9 January 2007; accepted 14 January 2007
Available online 17 January 2007
Abstract—Each of the both spreading alkaloids stenusine and norstenusine could be synthesized starting from commercially available 3-
picoline in a two-step synthesis in yields of 74% and 67% in gram scale. The stereoisomeric ratio of the synthesized (+)-stenusine is similar
to that of stenusine from Stenus comma.
Ó 2007 Elsevier Ltd. All rights reserved.
7
7
9
1. Introduction
10
2
2
11
10
N
N
The rove beetle genus Stenus comprises 1990 species world-
wide1 and about 120 species in Central Europe. Stenus comma
LeConte, the most common species of the genus, lives in
sandy banks of ponds and sluggishly flowing rivers.2 The
beetle has no ability to swim, but during its hunting for its
prey, it often falls into the water. In order to avoid drowning,
the beetle releases a surface-active fluid from the pygidial
glands. This fluid propels the beetle over the water with a
speed up to 75 cm/s. The Schildknecht group found that sten-
usine exhibits a high spreading capacity.2 The surface-active
oil contains some other compounds such as 1,8-cineol, iso-
piperitenol and 6-methyl-5-hepten-2-one.3 Norstenusine4
and actinidine5 could be detected in other Stenus species.
Actinidine shows a knock-down effect to other insects.
13
12
Figure 1. Stenusine (1) and norstenusine (2). The numbering of the N- and
C-atoms of 1 and 2 is used for the NMR assignments.
determined by chiral GC: 13%:40%:43%:4%. These four
stenusine isomers in a ratio of 9%:36%:43%:12% could
also be obtained in a two-step biomimetic route with a yield
of 26% starting from (R)-phenylglycinol and glutaraldehyde.
Since the found ratio of stereoisomers is similar to that of
natural stenusine from S. comma, the authors consider this
as a confirmation of their hypothesis for the biosynthesis of
stenusine.8
Our objectives are the determination of the repellent activity
of stenusine and norstenusine against predators and the anal-
ysis of their surface activity. For these reasons we were inter-
ested in the synthesis of stenusine (1) and norstenusine (2)
(Fig. 1).
2. Results and discussion
As we could demonstrate other Stenus species show com-
pletely different stenusine stereoisomer ratios.9 Stenusine
from Stenus juno possesses mainly (20R,3R)-configuration
(88%), whereas in Stenus clavicornis, Stenus providus and
Stenus bimaculatus the (20S,3R)-stereoisomer dominates
(95%, 95%, 76%). For Stenus fulvicornis (20R,3S)-stenusine
was found as the main peak (90%). This shows that the bio-
synthesis of stenusine in other Stenus species than S. comma
is highly enantio- and diastereoselective.
Numerous preparations of stenusine have been developed.
The enantioselective 12-step synthesis of Enders et al.6
started from 5-tert-butyldimethylsilyloxypentanol7 and gave
(20S,3S)- and (20S,3R)-stenusine in total yields of 7.8% and
5.7%. By means of the both diastereomeric compounds, the
ratio of the four stereoisomers (20R,3R):(20S,3R):(20S,3S):
(20R,3S) of natural stenusine from S. comma could be
Although our synthesis of stenusine (1) is not based on a
biomimetic route, it leads also to a stereoisomer ratio
(20R,3R):(20S,3R):(20S,3S):(20R,3S) of 10%:29%:54%:7%,
which is similar to the natural stenusine from S. comma
(Fig. 2).
Keywords: Alkaloids; Asymmetric synthesis; Stenusine; Stenus comma;
Staphylinidae.
* Corresponding author. Tel.: +49 0921 553396; fax: +49 0921 555358;
e-mail: karlheinz.seifert@uni-bayreuth.de
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.024

T. Gedig et al. / Tetrahedron 63 (2007) 2670–2674
2671
rel. int. [%]
rel. int [%]
100
90
80
70
60
50
40
30
20
10
(2’S,3R)
37%
(2’S,3S)
43%
100
90
80
70
60
50
40
30
20
10
(2’S,3S)
54%
(2’S,3R)
29%
(2’R,3R)
17%
(2’R,3S)
7%
(2’R,3R)
10%
(2’R,3S)
3%
69.0
70.0
71.0
72.0
retention time [min]
73.0
69.0
70.0
71.0
72.0
retention time [min]
73.0
Figure 2. Gas chromatogram of synthetic (left) and natural (right) stenusine (1) from S. comma, fused with silica capillary column (30 m, 0.25 mm ID), coated
with 0.25 mm film of 0.4% heptakis(2,3-di-O-methyl-6-O-tert-butyldimethylsilyl)b-cyclodextrin (30%) in SE 52 (70%), carrier gas He, temperature program
60 ꢀC (20 min isothermal), heating rate 2 ꢀC/min to 200 ꢀC. Capillary column was self-prepared by D. Burkhardt and A. Mosandl, University of Frankfurt am
Main.
The alkylation of the methyl group of 3-picoline (3) with
(R)-2-bromobutane gives 82% yield with 66% ee (S)-3-(20-
methylbutyl)pyridine (4, 83%) and its (R)-enantiomer (4,
17%). This enantiomeric mixture reacts with ethyl iodide
quantitatively to yield 1-ethyl-3-(20-methylbutyl)pyridinium
iodide (5). Reduction of 5 with NaBH4 leads to 3,4-dide-
hydrostenusine (6), which can be transformed by catalytic
hydrogenation under normal pressure to four stereoisomers
of stenusine (1). Catalytic hydrogenation of the pyridinium
salt 5 at a hydrogen pressure of 10 bar gives 90% yield of
the four stenusine isomers (1) and so the total yield over
three steps starting from 3-picoline is 74% (Scheme 1).
In order to demonstrate that stenusine (1) and norstenusine
(2) are surface-activecompounds, the surface tension was de-
termined by means of the pendant drop tensiometry at 22 ꢀC.
At a concentration of 0.125% of stenusine (1) or norstenusine
(2) in an aqueous 0.1 M phosphate buffer, a surface tension of
about 60 mN/m is observed (Fig. 3). Even at 0.05% stenusine
concentration, a distinct lowering of the surface tension
(65 mN/m) compared with water (72.8 mN/m) is observed.
Sodium phosphate is as electrolyte surface inactive, so that
the comparison of the surface tensions of stenusine (1) and
norstenusine (2) in phosphate buffer with water is justified.
3. Experimental
a
N
N
3.1. Alkylation of 3-picoline (3)
3
4
b
3.1.1. Alkylation with (R)-2-bromobutane. A mixture of
diisopropylamine (7.4 ml, 5.3 g, 52.5 mmol) in abs THF
(120 ml) under argon is cooled to ꢁ30 ꢀC. To this mixture
n-BuLi (21.0 ml, 2.5 M, 52.5 mmol) is added under stirring.
After 1 h, 3-picoline (3, 4.8 ml, 4.7 g, 50 mmol) is slowly
added and stirring is continued for 1 h at 0 ꢀC. (R)-2-Bromo-
butane (5.5 ml, 6.9 g, 50 mmol) is slowly added to the deep
brown solution at ꢁ78 ꢀC and the mixture is warmed to
room temperature overnight. The reaction mixture is diluted
with half saturated NH4Cl solution, the organic phase is
separated and the aqueous phase extracted three times with
EtOAc. The combined organic phases are washed with satu-
rated NaCl solution and dried with MgSO4. After filtration
through CeliteÒ and removing the solvent under vacuum,
3-(20-methylbutyl)pyridine (4, 6.95 g, 47 mmol, 93%, crude
product) is obtained. Distillation gives 4 (6.10 g, 40.9 mmol,
82%) as colourless oil. [a]2D3 +5.8 (c 2.10, CHCl3); 1H NMR
f
N
I
5
e
c
3
2'
d
N
N
6
1
Scheme 1. Synthesis of stenusine (1). Reagents and conditions: (a) LDA,
THF, 0 ꢀC; (R)-2-bromobutane, THF, ꢁ78 ꢀC to room temperature, 82%;
(b) EtI, 90 ꢀC, 0.5 h, 100%; (c) NaBH4, MeOH/THF 2:1, ꢁ78 ꢀC to room
temperature, 96%; (d) H2 (normal pressure), Pd/C, EtOAc, 35 ꢀC, 89%;
(e) H2 (10 bar), Pd/C, MeOH, room temperature, 16 h, 90%; (f) H2
(20 bar), Pd/C, MeCHO, MeCOOH, 30 ꢀC, 24 h, 90%.
A further distinct improvement of the stenusine synthesis can
beachievedbyreactionof3-(20-methylbutyl)pyridine(4)with
acetaldehyde under hydrogenating conditions. In this way 1
can be synthesized in two steps with 74% yield (Scheme 1).
(300 MHz, CDCl3):
d
(ppm)¼8.38 (dd, 1H, 6-H,
3J6,5¼4.9 Hz, 4J6,4¼1.6 Hz), 8.36 (br s, 1H, 2-H), 7.40 (dd,
3
4
1H, 4-H, J4,5¼7.8 Hz, J4,6¼1.6 Hz), 7.14 (ddd, 1H, 5-H,
3
5
3J5,4¼7.8 Hz, J5,6¼4.9 Hz, J5,2¼1.0 Hz), 2.58 (dd, 1H,
2
3
The use of 2-bromopropane instead of (R)-2-bromobutane
for the alkylation of 3-picoline methyl group gives 81%
yield of 3-isopropylpyridine (7), which can be transformed
in an analogous way as 4 with comparable yields in a three-
or two-step reaction sequence to racemic norstenusine (2).
7-Ha, J7a,7b¼13.7 Hz, J7a,8¼6.1 Hz), 2.32 (dd, 1H, 7-Hb,
3
2J7a,7b¼13.7 Hz, J7b,8¼8.2 Hz), 1.59 (mc, 1H, 8-H), 1.34,
3
1.14 (2mc, 2H, 9-H), 0.87 (dd, 3H, 10-H, J10,9¼7.5 Hz),
3
0.80 (d, 3H, 11-H, J11,8¼6.6 Hz); 13C NMR (75 MHz,
CDCl3): d (ppm)¼150.3 (2-C), 146.9 (6-C), 136.5 (3-C),

2672
T. Gedig et al. / Tetrahedron 63 (2007) 2670–2674
72
72
67
62
57
52
47
42
37
67
0.05
62
0.125
0.125
0.25
57
0.25
0.5
0.5
52
1.0
47
42
1.0
37
-50
-50
950
1950
2950
950
1950
2950
Age (s)
Age (s)
Figure 3. Surface tension of stenusine (1) (left) and norstenusine (2) (right) in 0.1 M phosphate buffer (pH 6) determined by means of pendant drop tensiometry
at 22 ꢀC.
136.2 (4-C), 122.9 (5-C), 40.0 (7-C), 36.2 (8-C), 28.8 (9-C),
18.5 (11-C), 11.1 (10-C); GC–MS, EI+: m/z (%)¼150 (4)
[M+H+], 149 (28) [M+], 118 (5), 93 (100) [C6H7N+], 92
(18), 65 (13), 57 (21) [C4H+9], 41 (20) [C3H5+]; HRMS
(70 eV): 149.1204 [C10H15N+] (calcd 149.1205), 93.0579
[C6H7N+] (calcd 93.0579), 57.0704 [C4H+9] (calcd 57.0704).
3J13,12¼7.4 Hz), 1.18, 1.01 (2mc, je 1H, 9-H), 0.69 (dd, 3H,
3
3
10-H, J10,9¼7.3 Hz), 0.66 (d, 3H, 11-H, J11,8¼6.5 Hz);
13C NMR (75 MHz, CDCl3): d (ppm)¼145.1 (2-C), 143.5
(6-C), 142.7 (3-C), 141.5 (4-C), 127.5 (5-C), 56.4 (12-C),
38.9 (7-C), 35.3 (8-C), 28.3 (9-C), 18.0 (11-C), 16.9 (13-C),
10.7 (10-C).
3.1.2. Alkylation with isopropyl bromide. 3-Picoline
(3, 4.8 ml, 4.7 g, 50 mmol), isopropyl bromide (4.7 ml,
6.15 g, 50 mmol). Yield of 3-isobutylpyridine (7): 6.26 g,
46.3 mmol, 93%, crude product; after distillation 5.48 g,
3.2.2. N-Ethylation of 3-isobutylpyridine (7) with ethyl
iodide. 3-Isobutylpyridine (7, 3.92 g, 29.0 mmol), ethyl
iodide (3.50 ml, 6.74 g, 43.2 mmol). Yield of 1-ethyl-3-iso-
butylpyridinium iodide (8): 8.44 g, 29.0 mmol, 100%, crude
product. 1H NMR (300 MHz, CDCl3): d (ppm)¼9.03 (br s,
1
40.5 mmol, 81%. H NMR (300 MHz, CDCl3): d (ppm)¼
3
4
3
8.28 (dd, 1H, 6-H, J6,5¼4.9 Hz, J6,4¼1.7 Hz), 8.26 (br s,
1H, 2-H), 8.99 (d, 1H, 6-H, J6,5¼6.1 Hz), 7.94 (d, 1H,
3
4
3
3
1H, 2-H), 7.30 (dd, 1H, 4-H, J4,5¼7.8 Hz, J4,6¼1.7 Hz),
4-H, J4,5¼7.9 Hz), 7.80 (dd, 1H, 5-H, J5,6¼6.1 Hz,
3
3
3
7.04 (dd, 1H, 5-H, J5,4¼7.8 Hz, J5,6¼4.9 Hz), 2.32 (d,
3J5,4¼7.9 Hz), 4.63 (q, 2H, 11-H, J11,12¼7.2 Hz), 2.50 (d,
3
3
2H, 7-H, J7,8¼7.5 Hz), 1.72 (mc, 1H, 8-H), 0.73 (d, 6H,
2H, 7-H, J7,8¼7.6 Hz), 1.76 (mc, 1H, 8-H), 1.43 (t, 3H,
3
3
3
9-H, 10-H, J8,9/10¼6.8 Hz); 13C NMR (75 MHz, CDCl3):
12-H, J12,11¼7.2 Hz), 0.72 (2d, 6H, 9-H, 10-H, J9/10,8¼
d (ppm)¼150.2 (2-C), 146.9 (6-C), 136.3 (3-C), 136.0
(4-C), 122.7 (5-C), 42.0 (7-C), 29.7 (8-C), 21.8 (9-C, 10-
C); GC–MS, EI+: m/z (%)¼135 (41) [M+], 118 (3), 93
(100) [C6H7N+], 92 (27), 66 (6), 65 (14), 51 (4), 43 (20),
41 (10) [C3H+5], 39 (13); HRMS (70 eV): 135.1048
[C9H13N+] (calcd 135.1048), 93.0578 [C6H7N+] (calcd
93.0579), 41.0391 [C3H+5] (calcd 41.0391).
6.7 Hz); 13C NMR (75 MHz, CDCl3): d (ppm)¼144.6
(2-C), 144.5 (6-C), 142.8 (3-C), 142.3 (4-C), 127.7 (5-C),
56.8 (11-C), 41.0 (7-C), 29.3 (8-C), 21.6 (9-C, 10-C), 16.9
(12-C).
3.3. Partial reduction of the pyridinium salts
to the tetrahydropyridines
3.2. N-Ethylation
3.3.1. Reduction of 1-ethyl-3-(20-methylbutyl)pyridinium
iodide (5). Compound 5 (3.51 g, 11.5 mmol) is dissolved
under argon in MeOH/THF (2:1, 120 ml) and cooled to
ꢁ78 ꢀC. NaBH4 (1.30 g, 34.5 mmol) is added, the mixture
is stirred for 20 min at ꢁ78 ꢀC, warmed to room temperature
overnight and cooled again to ꢁ78 ꢀC. NaBH4 (0.87 g,
23 mmol) is added and the reaction mixture is warmed to
room temperature for 5 h. To stop the reaction, 2 N HCl
(125 ml, 250 mmol) is added and stirred for 1 h at room tem-
perature. To prevent the oxidation of iodide by air, a small
amount of Na2SO3 is added, the volume of the reaction mix-
ture is reduced to about 1/5 and 2 N KOH (about 100 ml) is
added (pH>10). The mixture is extracted three times with
EtOAc (50 ml), the combined organic layers are washed
with saturated NaCl solution and dried with MgSO4. After
filtration through CeliteÒ and removing the solvent crude
3.2.1. N-Ethylation of 3-(20-methylbutyl)pyridine (4) with
ethyl iodide. Under argon, ethyl iodide (2.90 ml, 5.57 g,
35.7 mmol) is added to 3-(20-methylbutyl)pyridine (4,
3.55 g, 23.8 mmol) and heated for 30 min under reflux (tem-
perature of the oil bath 90 ꢀC). The surplus ethyl iodide is
distilled off under vacuum and 1-ethyl-3-(20-methylbutyl)-
pyridinium iodide (5) is obtained in quantitative yield
1
(7.27 g, 23.8 mmol, 100%) as viscous pale yellow oil. H
NMR (300 MHz, CDCl3): d (ppm)¼9.23 (br s, 1H, 2-H), 9.13
(d, 1H, 6-H, 3J6,5¼6.1 Hz), 8.10 (d, 1H, 4-H, 3J4,5¼8.0 Hz),
7.91 (dd, 1H, 5-H, 3J5,6¼6.1 Hz, 3J5,4¼8.0 Hz), 4.79 (q, 2H,
12-H, 3J12,13¼7.4 Hz), 2.73 (dd, 1H, 7-Ha, 2J7a,7b¼13.8 Hz,
3J7a,8¼6.1 Hz), 2.50 (dd, 1H, 7-Hb, J7b,7a¼13.8 Hz,
2
3J7b,8¼8.3 Hz), 1.61 (mc, 1H, 8-H), 1.52 (t, 3H, 13-H,

T. Gedig et al. / Tetrahedron 63 (2007) 2670–2674
2673
product (2.09 g, 11.5 mmol, 100%), from which 5 (91 mg,
3.5. Hydrogenation and N-ethylation of the 3-alkyl-
pyridines
0.30 mmol, 3%) is separated as viscous oil. The resulting
1-ethyl-3-(20-methylbutyl)-1,2,5,6-tetrahydropyridine (6,
3,4-didehydrostenusine, 2.00 g, 11.0 mmol, 96%) is not fur-
3.5.1. Hydrogenation and N-ethylation of 3-(20-methyl-
butyl)pyridine (4). Since the acid amount is critical for a
fast reaction the amount of 3-(20-methylbutyl)pyridine (4,
6.95 g, 46.6 mmol) is divided into two parts and each of
them (4, 3.47 g, 23.3 mmol) is dissolved in concentrated
acetic acid (80 ml). After the addition of palladium on
charcoal (10%, 620 mg, 0.58 mmol, 2.5 mol %) and acetal-
dehyde (2.0 ml, 1.54 g, 35.0 mmol), the mixture is hydroge-
nated for 24 h in an autoclave at a hydrogen pressure of
20 bar and 30 ꢀC. The two reaction mixtures are combined,
filtered through CeliteÒ and evaporated under vacuum to a
volume of about 20 ml. Solid KOH is added until pH value
of 10 is reached. The mixture is extracted four times with
EtOAc (100 ml), the organic layer is dried with MgSO4,
evaporated and the crude product (8.36 g, 45.6 mmol, 98%)
is degassed (inhibition of foam formation) by cooling three
times with liquid nitrogen and slow heating to room temper-
ature under vacuum. Distillation gives stenusine (1, 7.70 g,
42.0 mmol, 90%) as colourless oil. Bp 75 ꢀC (15 Torr); [a]D26
+10.3 (c 2.01, CH3OH); 1H NMR (500 MHz, CDCl3):
d (ppm)¼2.83 (mc, 2H, 6-Ha), 2.81 (mc, 1H, 2-Ha, (20S,3S)-
diastereomer), 2.77 (mc, 1H, 2-Ha, (20S,3R)-diastereomer),
2.32 (mc, 4H, 12-H), 1.71 (mc, 2H, 6-Hb), 1.70 (mc, 1H, 4-
Ha, (20S,3R)-diastereomer), 1.64 (mc, 1H, 4-Ha, (20S,3S)-dia-
stereomer), 1.58 (mc, 2H, 8-H), 1.56 (mc, 2H, 5-Ha), 1.52(mc,
2H, 5-Hb), 1.42 (mc, 1H, 2-Hb, (20S,3R)-diastereomer), 1.40
(mc, 1H, 2-Hb, (20S,3S)-diastereomer), 1.33 (mc, 2H, 3-H),
1.23 (mc, 2H, 9-Ha), 1.07 (mc, 2H, 7-Ha), 1.05 (mc, 2H, 9-Hb),
1.00 (t, 6H, 13-H, 3J13,12¼7.3 Hz), 0.88 (mc, 2H, 7-Hb), 0.78
(mc, 12H, 11-H, 10-H), 0.77 (mc, 1H, 4-Hb, (20S,3S)-diaste-
reomer), 0.73 (mc, 1H, 4-Hb, (20S,3R)-diastereomer); 13C
NMR (125 MHz, CDCl3): (20S,3S)-diastereomer: d (ppm)¼
60.3 (2-C), 53.8 (6-C), 52.8 (12-C), 42.1 (7-C), 33.5 (8-C),
31.9 (4-C), 31.1 (3-C), 29.5 (9-C), 25.6 (5-C), 19.4 (11-C),
12.0 (13-C), 11.1 (10-C); (20S,3R)-diastereomer: d (ppm)¼
61.0 (2-C), 53.8 (6-C), 52.8 (12-C), 41.8 (7-C), 33.6 (8-C),
31.1 (3-C), 31.0 (4-C), 29.9 (9-C), 25.5 (5-C), 19.2 (11-C),
12.0 (13-C), 11.2 (10-C); GC–MS, EI+: m/z (%)¼183 (23)
[M+], 182 (23) [M+ꢁH], 168 (100) [M+ꢁCH3], 154 (14)
[M+ꢁC2H5], 126 (7) [M+ꢁC4H9], 124 (9), 112 (10)
[M+ꢁC5H11], 110 (4), 98 (14) [M+ꢁCH3ꢁC5H10], 96 (8),
85 (10) [C5H11N+], 84 (9) [C5H10N+], 72 (33) [C4H10N+],
58 (44) [C3H8N+], 57 (13) [C4H+9], 44 (5), 42 (10), 41 (11);
HRMS (70 eV): 183.1987 [C12H25N+] (calcd 183.1987),
168.1752 [C11H22N+] (calcd 168.1752), 126.1283 [C8H16N+]
(calcd 126.1283), 112.1126 [C7H14N+] (calcd 112.1126),
98.0969 [C6H12N+] (calcd 98.0970), 85.0892 [C5H11N+]
(calcd 85.0892), 72.0813 [C4H10N+] (calcd 72.0813).
1
ther purified. H NMR (300 MHz, CDCl3): d (ppm)¼5.35
(mc, 1H, 4-H), 2.74 (mc, 2H, 2-H), 2.41 (mc, 2H, 6-H), 2.40
(q, 2H, 12-H, 3J12,13¼7.3 Hz), 2.10 (mc, 2H, 5-H), 1.89 (dd,
1H, 7-Ha, 2J7a,7b¼13.6, 3J7a,8¼6.3 Hz), 1.65 (dd, 1H, 7-Hb,
3
2J7b,7a¼13.6, J7b,8¼8.2 Hz), 1.40 (mc, 1H, 8-H), 1.30,
3
1.02 (2mc, 2H, 9-H), 1.06 (t, 3H, 13-H, J13,12¼7.3 Hz),
3
0.80 (dd, 3H, 10-H, J10,9a¼3J10,9b¼7.5 Hz), 0.76 (d, 3H,
3
11-H, J11,8¼6.2 Hz); 13C NMR (75 MHz, CDCl3):
d (ppm)¼135.0 (3-C), 120.1 (4-C), 55.5 (2-C), 52.2
(12-C), 49.7 (6-C), 43.3 (7-C), 32.4 (8-C), 29.3 (9-C), 26.0
(5-C), 19.0 (11-C), 12.2 (13-C), 11.3 (10-C); GC–MS, EI+:
m/z (%)¼181 (17) [M+], 180 (7) [M+ꢁH], 166 (19)
[M+ꢁCH3], 152 (3) [M+ꢁC2H5], 124 (100) [M+ꢁC4H9],
110 (35) [M+ꢁC5H11], 96 (7) [C6H10N+], 82 (4) [C5H8N+],
68 (13) [C5H+8], 56 (7) [C3H6N+], 42 (12) [C2H4N+], 41 (11);
HRMS (70 eV): 181.1831 [C12H23N+] (calcd 181.1831),
166.1596 [C11H20N+] (calcd 166.1596), 124.1126
[C8H14N+] (calcd 124.1126), 110.0970 [C7H12N+] (calcd
110.0970), 68.0628 [C5H+8] (calcd 68.0626).
3.3.2. Reduction of 1-ethyl-3-isobutylpyridinium iodide
(8). 1-Ethyl-3-isobutylpyridinium iodide (8, 4.22 g,
14.5 mmol). Yield of 1-ethyl-3-isobutyl-1,2,5,6-tetrahydro-
pyridine (9, 3,4-didehydronorstenusine): 2.27 g, 13.6 mmol,
94%, crude product. 1H NMR (300 MHz, CDCl3): d (ppm)¼
5.30 (mc, 1H, 4-H), 2.70 (mc, 2H, 2-H), 2.36 (mc, 2H, 6-H),
3
2.36 (q, 2H, 11-H, J11,12¼7.3 Hz), 2.06 (mc, 2H, 5-H),
3
1.70 (d, 2H, 7-H, J7,8¼6.8 Hz), 1.60 (mc, 1H, 8-H), 1.01
3
(t, 3H, 12-H, J12,11¼7.3 Hz), 0.76 (d, 6H, 9-H, 10-H,
3J9/10,8¼6.5 Hz); 13C NMR (75 MHz, CDCl3): d (ppm)¼
135.0 (3-C), 119.9 (4-C), 55.3 (2-C), 52.0 (11-C), 49.6
(6-C), 45.2 (7-C), 26.0 (8-C), 25.9 (5-C), 22.3 (9-C, 10-C),
12.1 (12-C); GC–MS, EI+: m/z (%)¼167 (32) [M+], 166
(23) [M+ꢁH], 152 (11) [M+ꢁCH3], 136 (3) [M+ꢁCH2CH3],
124 (100) [M+ꢁC3H7], 122 (9), 110 (83) [M+ꢁCH3ꢁC3H6],
108 (13), 95 (23) [C7H+11], 81 (13), 68 (33) [C4H6N+], 67
(18), 58 (12), 56 (7) [C3H6N+], 55 (9), 42 (34) [C2H4N+],
41 (23), 39 (8).
3.4. Catalytic hydrogenation of the tetrahydropyridines
3.4.1. Hydrogenation of 3,4-didehydrostenusine (6).
Compound 6 (2.00 g, 11.0 mmol) is dissolved in EtOAc
(30 ml) and palladium on charcoal (10%, 585 mg,
0.55 mmol, 5 mol %) is added under argon. After four evac-
uations and fillings with hydrogen, the mixture is heated to
35 ꢀC and stirred until the appropriate amount of hydrogen
(250 ml) is consumed. The reaction mixture is filtered
through CeliteÒ, the solvent is removed and the crude prod-
uct (1.97 g, 10.7 mmol, 98%) is purified by column chroma-
tography on silica gel with EtOAc as solvent to yield
stenusine (1, 1.79 g, 9.8 mmol, 89%) as a colourless oil.
3.5.2. Hydrogenation and N-ethylation of 3-isobutylpyri-
dine (7). 3-Isobutylpyridine (7, 6.26 g, 46.3 mmol) is divided
into two parts and to each of them (7, 3.13 g, 23.1 mmol)
acetaldehyde (2.0 ml, 1.54 g, 35.0 mmol) is added. Yield
of 1-ethyl-3-isobutylpiperidine (2, norstenusine): 7.46 g,
44.0 mmol, 95%, crude product; after distillation 6.52 g,
1
3.4.2. Hydrogenation of 3,4-didehydronorstenusine (9).
3,4-Didehydronorstenusine (9, 4.54 g, 27.2 mmol). Yield
of 1-ethyl-3-isobutylpiperidine (2, norstenusine): 4.47 g,
26.4 mmol, 97%, crude product; after distillation 3.64 g,
21.5 mmol, 79%.
38.5 mmol, 83%. Bp 69 ꢀC (15 Torr); H NMR (300 MHz,
CDCl3): d (ppm)¼2.83 (mc, 1H, 6-Ha), 2.78 (mc, 1H, 2-Ha),
2.31 (mc, 2H, 11-H), 1.73 (mc, 1H, 6-Hb), 1.66 (mc, 1H, 4-
Ha), 1.57 (mc, 3H, 3-H, 5-Ha, 8-H), 1.48 (mc, 1H, 5-Hb),
2
1.42 (dd, 1H, 2-Hb, J2b,2a¼3J2b,3¼10.8 Hz), 1.02 (t, 3H,

2674
T. Gedig et al. / Tetrahedron 63 (2007) 2670–2674
3
3
12-H, J12,11¼7.3 Hz), 0.97 (dd, 2H, 7-H, J7,8¼3J7,3
¼
¼
We would like to thank Dipl.-Chem. D. Burkhardt and
Prof. A. Mosandl from the University of Frankfurt am
Main, Germany, for GC measurements at chiral phase.
6.8 Hz), 0.81, 0.79 (2d, 6H, 9-H, 10-H, J9,8¼3J10,8
3
6.3 Hz), 0.74 (mc, 1H, 4-Hb); 13C NMR (75 MHz, CDCl3):
d (ppm)¼60.6 (2-C), 53.8 (6-C), 52.8 (11-C), 44.2 (7-C),
33.7 (3-C), 31.4 (4-C), 25.6 (5-C), 24.7 (8-C), 23.0 (9-C),
22.7 (10-C), 12.0 (12-C); GC–MS, EI+: m/z (%)¼169 (32)
[M+], 168 (31) [M+ꢁH], 154 (100) [M+ꢁCH3], 140 (5)
[M+ꢁC2H5], 126 (8) [M+ꢁC3H7], 112 (7) [M+ꢁC4H9], 110
(5), 98 (14) [M+ꢁCH3ꢁC4H8], 96 (8), 85 (11) [C5H11N+],
84 (10) [C5H10N+], 72 (39) [C4H10N+], 69 (10), 58 (73)
[C3H8N+], 57 (17) [C4H9+], 55 (11), 42 (15) [C2H4N+],
41 (15); HRMS (70 eV): 169.1830 [C11H23N+] (calcd
169.1831), 154.1596 [C10H20N+] (calcd 154.1596),
126.1283 [C8H16N+] (calcd 126.1283), 112.1126 [C7H14N+]
(calcd 112.1126), 98.0969 [C6H12N+] (calcd 98.0970).
References and notes
1. Herman, L. A. Bull. Am. Mus. Nat. Hist. 2001, 265, 2007–2439.
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€
4. Kohler, P. Dissertation, Ruprecht-Karl-Universitat Heidelberg,
1979.
5. Dettner, K. Biochem. Syst. Ecol. 1993, 21, 143–162.
6. Enders, D.; Tiebes, J.; De Kimpe, N.; Keppens, M.; Stevens, C.;
Smagghe, G.; Betz, O. J. Org. Chem. 1993, 58, 4881–4884.
7. Enders, D.; Tiebes, J. Liebigs Ann. Chem. 1993, 173–177.
8. Poupon, E.; Kunesch, N.; Husson, H.-P. Angew. Chem., Int. Ed.
2000, 39, 1493–1495.
Acknowledgements
Support of this research by the Deutsche Forschungsgemein-
schaft (graduate college 678) is gratefully acknowledged.
9. Lusebrink, I.; Burkhardt, D.; Gedig, T.; Dettner, K.; Seifert, K.;
Mosandl, A. Naturwissenschaften, in press.