The asymmetric synthesis of (-)-pumiliotoxin C using tandem catalysis

Article abstract of DOI:10.1016/j.tet.2004.06.148

The potent neurotoxin (-)-pumiliotoxin C has been prepared in 8 steps starting from 2-cyclohexenone. Key steps are a tandem asymmetric conjugate addition-allylic substitution reaction and a tandem Heck-allylic substitution reaction. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.06.148

Tetrahedron 60 (2004) 9687–9693
The asymmetric synthesis of (K)-pumiliotoxin C using
tandem catalysis
Ewold W. Dijk, Lavinia Panella, Pedro Pinho, Robert Naasz, Auke Meetsma,
*
*
Adriaan J. Minnaard and Ben L. Feringa
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute, University of Groningen, Nijenborgh 4,
9747 AG Groningen, The Netherlands
Received 28 April 2004; revised 8 June 2004; accepted 12 June 2004
Available online 21 August 2004
Abstract—The potent neurotoxin (K)-pumiliotoxin C has been prepared in 8 steps starting from 2-cyclohexenone. Key steps are a tandem
asymmetric conjugate addition–allylic substitution reaction and a tandem Heck-allylic substitution reaction.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Tandem8 or domino9 catalytic reactions comprise a rapidly
growing field in organic synthesis. Especially the use of
reactive intermediates, formed in the first step, for a
subsequent reaction in a multistep conversion allows the
preparation of complicated structures in a limited number
of steps. The catalytic asymmetric synthesis of (K)-
pumiliotoxin C (1) presented here is based on two tandem
catalytic reactions elaborated upon in our laboratory. In the
retrosynthetic scheme (Scheme 1), it is shown that the
nitrogen containing six-membered ring in 1 can be
constructed by a tandem Heck-allylic substitution reaction
starting from 2. Reduction of the double bond and
detosylation leads directly to 1. In turn, 2 can be prepared
starting from 2-cyclohexenone 3 by a tandem asymmetric
conjugate addition–allylic substitution reaction, followed
by conversion of the carbonyl group into the required
N-tosylamine.
Among the alkaloids isolated from Dendrobates spp.
(poison dart frogs), pumiliotoxin C (1), first isolated from
Dendrobates pumilio, is one of the most prominent
members.1 Pumiliotoxin C is a potent neurotoxin that acts
as a noncompetitive blocker for acetylcholine receptor-
channels and therefore has attracted considerable attention
from a pharmaceutical standpoint.2 Because of its structure,
a cis-fused perhydroquinoline skeleton featuring four
stereogenic centers, an impressive effort has been devoted
to the synthesis of 1.3 A number of total syntheses has been
reported either of the racemate,4 the natural enantiomer,5 or
its antipode.6 The strategies applied for the synthesis of
(K)-1 until now relied on starting materials from the chiral
pool, the use of chiral auxiliaries, for example, in the
concise synthesis by Comins and coworkers,7 or the
application of a (enzymatic) kinetic resolution. No catalytic
asymmetric synthesis of pumiliotoxin C is known (Fig. 1).
Figure 1. (K)-Pumiliotoxin (1).
Keywords: Alkaloids; Heck-allylic substitution; Pumiliotoxin C.
* Corresponding authors. Tel.: C31-50-3634258; fax: C31-503634296;
e-mail addresses: minnaard@chem.rug.nl; feringa@chem.rug.nl
Scheme 1. Retrosynthesis of 1.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.148

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E. W. Dijk et al. / Tetrahedron 60 (2004) 9687–9693
Scheme 2. Tandem asymmetric conjugate addition–allylic substitution reaction.
2. Results and discussion
Ph3P and Hu¨nig’s base) the reaction with N-tosyl t-butoxy-
carbamate was successful, whereas N-tosyl formamide
showed no reaction. Using 5 as the substrate, however,
only a very slow reaction was observed and therefore these
nucleophiles were abandoned.
The synthesis started with the copper-phosphoramidite
catalyzed addition of dimethylzinc to 2-cyclohexenone (3,
Scheme 2).10 Using the depicted phosphoramidite ligand,
this reaction proceeds with an excellent enantioselectivity of
96%. The resulting zinc enolate reacted with catalytic
Pd(PPh3)4 and allyl acetate to give 4.11 This reaction was
carried out on 5 g scale using 0.5 mol% of copper catalyst
and 2 mol% of palladium catalyst and afforded 4 in 84%
yield as a mixture of trans/cis isomers (ratio 8:1).
Contrary, using phthalimide as the nucleophile, 6 was
obtained in a reasonable yield (66%) and after hydrazino-
lysis and subsequent reaction of the amine 7 with tosyl
chloride, 2 was obtained as a crystalline compound. In order
to ascertain the correct 1,2-cis-2,3-trans stereochemistry of
2, crystals were grown from heptane and an X-ray structure
was obtained.16 As can be seen in Figure 2, 2 possesses the
desired relative and absolute stereochemistry. In addition,
the crystallization increased the ee of 2 to O99.5%
according to chiral HPLC analysis.
In order to convert ketone 4 into its corresponding amine 7
with the correct stereochemistry, several methods were
applied. Whereas reduction of the corresponding oxime
with LiAlH4 led predominantly to the undesired isomer,
reductive amination using Leuckart’s method12 was
accompanied by the formation of side products. It was
therefore decided to reduce 4 to alcohol 5 and use this in a
subsequent Mitsunobu amination reaction (Scheme 3).
With 2 in hand, the tandem Heck-allylic substitution
reaction was studied using 1-bromopropene as the alkenyl
halide.17,18 This palladium-catalyzed reaction was per-
formed using the conditions initially developed by Larock
and coworkers using tri-o-tolylphosphine as the ligand
(Scheme 4).
Reduction of 4 with LiAlH4 at low temperature afforded 5 in
virtually quantitative yield as a 2:1 mixture of diastereomers
together with the residual diastereomer at C2. After
purification by flash chromatography, 5 was isolated in
46% yield and 90% diastereomeric purity.
In this mechanistically quite complicated reaction, the
alkylpalladium species resulting from the Heck reaction
rearranges to the corresponding allylic palladium inter-
mediate by a b-hydride elimination–readdition mechanism
(Fig. 3).19
Alcohol 5 was subjected to Mitsunobu-type reactions.13 As
an N-tosyl functionality was required, initially both N-tosyl
formamide14 and N-tosyl t-butoxycarbamate15 were
explored as nucleophiles. After reaction, mild cleavage of
the formyl or BOC group, respectively, would afford the
corresponding tosyl amide. With cyclohexanol as a model
substrate and using standard Mitsunobu conditions (DEAD,
Intramolecular attack of the deprotonated N-tosylamide
affords the six-membered ring, thereby liberating the
palladium catalyst. At the outset of the synthesis it was
not clear which stereochemistry would result from this
Scheme 3.

E. W. Dijk et al. / Tetrahedron 60 (2004) 9687–9693
9689
Figure 2. Ortep plot of the structure of 2.
Scheme 4.
Figure 3. The Heck-allylic substitution reaction (ligands are omitted for clarity).

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E. W. Dijk et al. / Tetrahedron 60 (2004) 9687–9693
Scheme 5.
reaction and molecular models did not give a conclusive
answer.
acetone and upon removal of the solvents dried at 70 8C
under vacuum for 32 h. The needed volume of dry CH3CN
to afford a 1 M solution was then added and the reagent kept
and used as such. Dry Na2CO3 was purchased from
commercial suppliers and stored in a Schlenk flask after
further drying under vacuum at 120 8C for 24 h. Flash
chromatography was performed on silica gel Merck Type
9385 230–400 mesh. All NMR spectra were recorded on a
Varian XL 300 MHz in CDCl3 solutions using the residual
solvent peak as internal reference. Mass spectra and HRMS
data were obtained using an AEI MS-902. Melting points
were determined on a Mettler FP1.
Inspection of the crude product mixture by GC-MS revealed
that several stereoisomers of 8 had been formed in the
reaction. As cis,trans isomers of the olefin moiety could not
be excluded, it was decided to take the crude product
through the next step without purification. Hydrogenation of
the double bond with H2 and Pd/C afforded a mixture that
consisted mainly of two stereoisomers of 9, according to
GC-MS, and a number of side products that could not be
identified (Scheme 5). One of the two stereoisomers of 9
could be purified by flash chromatography. After removal of
the tosyl group by treatment with Na/naphthalene this
isomer could tentatively be identified as 2-epi-pumiliotoxin
according to GC-MS.20
3.1.1. (2S, 3R)-2-Allyl-3-methylcyclohexanone (4).
Cu(OTf)2 (94 mg, 0.26 mmol, 0.5 mol%) and (R,S,S)-
phosphoramidite ligand10a (280 mg, 0.52 mmol, 1.0 mol%)
were dissolved in dry toluene in a flame-dried Schlenk tube
under an atmosphere of nitrogen. After stirring for 1 h at
room temperature, the solution was cooled to K30 8C and
freshly distilled 2-cyclohexenone (5.03 mL, 52 mmol) was
added. After stirring for an additional 10 min at the same
temperature, Me2Zn (31.2 mL of a 2 M solution in toluene,
62.4 mmol, 1.2 equiv) was added dropwise to the solution
which turned bright yellow. After stirring for an additional
3 h at K30 8C, Pd(PPh3)4 (1.20 g, 1.04 mmol, 2.0 mol%)
and allyl acetate (6.17 mL, 57.2 mmol, 1.14 equiv) were
added. The resulting mixture was warmed to 0 8C and stirred
overnight at this temperature. GC analysis of a reaction
mixture aliquot on a DB-1 column showed complete
conversion to the product with a trans/cis ratio of 8.5:1
(trans: TrZ12.28 min, cis: TrZ13.40 min). The reaction
mixture was quenched by pouring it into 200 mL of 2 M
aqueous HCl. The layers were separated, the aqueous layer
was extracted with diethyl ether (4!100 mL), the combined
organic layers were washed with brine, dried over MgSO4,
filtered and concentrated under reduced pressure. The
residual zinc and palladium salts were removed by flash
chromatography of the resulting yellow oil over a small
column of silica, eluted with toluene. Crude yield: 7.51 g
(49.3 mmol, 95%) of a yellowish oil, which was used
without further purification. 1H NMR of a sample purified by
flash chromatography (SiO2, hexanes:diethyl ether 3:1): dH
0.81 (3H, d, JZ6.9 Hz, of minor diastereomer), 1.05 (3H, d,
JZ6.2 Hz), 1.43–1.59 (1H, m), 1.64–2.11 (6H, m), 2.21–
2.40 (5H, m), 4.95–5.05 (2H, m), 5.74–5.85 (1H, m); dC 20.2
(q), 25.4 (t), 30.8 (t), 33.4 (t), 37.8 (d), 41.5 (t), 56.7 (d),
115.8 (t), 136.5 (d), 212.1 (s); m/z (EI) 152 (MC, 23), 137
(100), 97 (54). An ee of 96.2% was determined by chiral GC
As the other isomer of 9 could not be obtained pure by flash
chromatography, preparative HPLC was applied. This
afforded a pure isomer of 9 which, after removal of the
tosyl group and purification by acid/base extraction,
afforded (K)-1 in 48% yield. All spectral data are in
accordance with those reported in the literature.21
To conclude; a short, catalytic asymmetric synthesis of (K)-
pumiliotoxin C has been developed that is based on two
tandem catalytic reactions. Starting with an asymmetric
conjugate addition–allylic substitution reaction, two stereo-
centers are created in high yield with excellent enantio-
selectivity and high diastereoselectivity. After functional
group modification, a tandem Heck-allylic substitution
reaction creates the perhydroquinoline skeleton, albeit in
moderate yield, with both the natural and unnatural
configuration at the C2 stereocenter. Two additional steps
complete the synthesis of (K)-pumiliotoxin C.
3. Experimental
3.1. General
General experimental information: Unless noted otherwise,
all materials were obtained from commercial suppliers and
used without further purification. THF was dried and
distilled from sodium/benzophenone, CH3CN and DME
were dried and distilled from CaH2 and ether was dried and
distilled from P2O5. The n-Bu4NCl was crystallized by
addition of dry ether to a saturated solution in reagent grade

E. W. Dijk et al. / Tetrahedron 60 (2004) 9687–9693
9691
on a Chiraldex G-TA column, 30 m!0.25 mm, He-flow:
1.0 mL/min, 100 8C, 15 min, 10 8C/min, 150 8C, 30 min;
TrZ13.14 min (major enantiomer), TrZ14.96 min (minor
enantiomer), TrZ15.54 min (both enantiomers of the minor
diastereomer).
({MKphthaloyl-H}C,100), 95 (44). HRMS 283.1565,
C18H21NO2 requires 283.1572.
3.1.4. (1R,2S,3R)-2-Allyl-3-methylcyclohexylamine (7).
To a solution of 6 (2.94 g, 10.38 mmol) and 1-hexene
(6.5 mL, 51.5 mmol, 5 equiv) in 55 mL of ethanol in a 3-
necked roundbottom flask under a nitrogen atmosphere,
hydrazine hydrate (2.5 mL, 48.4 mmol, 4.7 equiv) was
added. This mixture was heated at reflux overnight. After
cooling, the solvent was removed under reduced pressure,
and the remaining oil was taken up in 50 mL of ethyl acetate
and extracted with 50 mL of 0.1 M aqueous NaOH. The
aqueous layer was extracted with ethyl acetate (3!50 mL).
The combined organic layers were washed with brine
(50 mL), dried over Na2SO4, filtered and evaporated. 1.24 g
(8.12 mmol, 78%) of 7 was obtained which was used
without further purification. dH 0.80–1.02 (1H, m), 0.88
(3H, d, JZ6.4 Hz), 1.12–1.23 (1H, m), 1.48–1.53 (6H, m),
1.58–1.63 (2H, br d, JZ12.8 Hz), 1.87–1.98 (1H, m), 2.29–
2.33 (1H, m), 3.05 (1H, m), 4.96–5.08 (2H, m), 5.72–5.82
(1H, m); dC 19.9 (t), 20.1 (q), 30.3 (d), 33.9 (t), 34.1 (t), 34.8
(t), 47.1 (d), 47.4 (d), 115.3 (t), 138.0 (d); m/z (CI) 154
(MCH)C.
3.1.2. (1S,2S,3R)-2-Allyl-3-methylcyclohexanol (5). To a
stirred suspension of LiAlH4 (3.74 g, 98.6 mmol) in 100 mL
of THF at K80 8C in flame-dried glassware under a nitrogen
atmosphere, was added in a dropwise fashion 7.5 g
(49.3 mmol) crude 4 as a solution in 20 mL of THF. The
reaction mixture was stirred at this temperature until the
reaction was completed as indicated by TLC (approx. 3 h).
The reaction was quenched by adding 2 mL of water, 1 mL
of 15% aqueous NaOH after 15 min and 1 mL of water after
an additional 30 min. This procedure avoids problems with
aluminum salts. The resulting slurry was then divided
between water and diethyl ether and the aqueous layer was
extracted with diethyl ether (3!100 mL). After drying the
combined organic layers over MgSO4, the solvent was
removed under reduced pressure yielding 7.26 g
(47.1 mmol, 99%) of the crude product. The diastereomeric
mixture was separated by flash chromatography (SiO2,
heptanes:diethyl ether 2:1) yielding 5 as a colorless oil
which solidified upon standing at 5 8C. 3.5 g (22.6 mmol) of
crystalline 5 was obtained, melting at ambient temperature.
3.1.5. N-[(1R,2S,3R)-2-Allyl-3-methylcyclohexyl]-4-
toluenesulfonamide (2). To a solution of 7 (682 mg,
4.45 mmol) in 15 mL of dichloromethane was added
p-toluenesulfonyl chloride (933 mg, 4.94 mmol, 1.1 equiv)
and triethylamine (1.34 mL, 9.6 mmol, 2.2 equiv). The
mixture was stirred for 60 h under a nitrogen atmosphere.
After removal of the solvent, the residue was dissolved in
diethyl ether (50 mL), and sequentially washed with 2 M
aqueous HCl (2!50 mL), aqueous saturated sodium
bicarbonate (2!50 mL) and brine (50 mL). After drying
over MgSO4, filtration and evaporation, an oil (1.39 g,
4.52 mmol) was isolated. Crystallisation from heptane
afforded 2 (900 mg 2.93 mmol, 66%) as colorless crystals;
mp 92–94 8C. A second crop of 395 mg (29%, 1.28 mmol)
proved to be equally pure. dH 0.89 (3H, d, JZ6.0 Hz), 0.95–
1.01 (1H, m), 1.13–1.64 (8H, m), 1.91–2.01 (1H, m), 2.11–
2.19 (1H, m), 2.43 (3H, s), 3.56–3.58 (1H, m), 4.79–4.82
(1H, m), 4.86–4.92 (2H, m), 5.56–5.71 (1H, m), 7.29 (2H, d,
JZ8.0 Hz), 7.78 (2H, d, JZ7.3 Hz). dC 19.9 (t), 20.1 (q),
21.5 (q), 30.6 (t), 31.3 (d), 33.0 (t), 33.6 (t), 47.2 (d), 51.5
(d), 116.1 (t), 127.0 (d), 129.6 (d), 137.0 (d), 138.5 (s), 143.1
(s); m/z (EI) 307 (MC,18), 155 (TsC, 44), 152 ({MK
Ts}C,100), 91 (tropyliumC, 57). HRMS 307.1599,
C17H25NO2S requires 307.1606. Anal. Found: C, 66.26;
H, 8.22; N, 4.56; S, 10.11. C17H25NO2S requires C, 66.41;
H, 8.20; N, 4.56; S, 10.41. [a]DZK36.88 (cZ1.01, CHCl3).
An ee of 99.5% was determined by chiral HPLC on a
Chiralpak AS column, 250!4.6 mm, eluted with n-
heptane: i-propanol 95:5, flow: 1 mL/min, at 40 8C.
1
1H NMR showed 90% diastereomeric purity. H NMR: dH
0.86–1.09 (3H, m), 0.96 (3H, d, JZ5.3 Hz), 1.22–1.30
(4H, m), 1.58–1.79 (4H, m), 1.94–1.96 (1H, m), 2.22–2.30
(1H, m), 2.51–2.58 (1H, m), 3.38–3.44 (1H, m), 4.94–5.15
(2H, m), 5.82–5.97 (1H, m); dC 19.7 (q), 23.9 (t), 32.3 (t),
33.7 (d), 35.1 (t), 35.7 (t), 50.9 (d), 72.4 (d), 116.3 (t), 136.3
(d); m/z (CI) 172 (MCNH4)C. [a]DZK88 (cZ1.01,
CHCl3).
3.1.3. 2-[(1R,2S,3R)-2-Allyl-3-methylcyclohexyl]-1H-iso-
indole-1,3(2H)-dione (6). To a solution of 5 (3.13 g,
20.3 mmol), triphenylphosphine (10.64 g, 40.58 mmol,
2 equiv), phthalimide (5.97 g, 40.58 mmol, 2 equiv) and
distilled di-i-propylethylamine (7.1 mL, 40.58 mmol,
2 equiv) in 200 mL of THF in a flame-dried Schlenk tube
under a nitrogen atmosphere was added dropwise via
syringe diethyl azodicarboxylate (6.4 mL, 40.58 mmol,
2 equiv) over 15 min, allowing the reaction temperature to
rise to 30 8C. After 3.5 h of stirring, no starting material
remained as indicated by TLC. After evaporation of the
solvent, 14.4 g of a viscous bright orange oil was obtained.
After adding 100 mL of heptane, a yellow semi-solid,
consisting of diethyl 1,2-hydrazinedicarboxylate and tri-
phenylphosphine oxide, remained. After filtration and
evaporating the mixture, 3.2 g of a yellow oil was obtained.
Further extraction of the residue with heptane yielsded an
additional 0.6 g of crude product. Purification by flash
chromatography (SiO2, heptanes:diethyl ether 5:1) yielded
3.79 g (13.38 mmol, 66%) of 6 as a colorless oil. dH 0.81–
0.89 (2H, m), 1.16 (3H, d, JZ7.0 Hz), 1.21–1.28 (2H, m),
1.57–1.81 (5H, m), 2.07–2.18 (2H m), 2.30–2.41 (1H, m),
2.60–2.72 (1H, m), 4.53–4.59 (1H, m), 4.58–4.96 (2H, m),
5.53–5.67 (1H, m), 7.67–7.72 (2H, m), 7.77–7.83 (2H, m);
dC 19.2 (q), 21.0 (t), 25.6 (t), 26.5 (t), 30.3 (d), 34.7 (t), 44.2
(d), 50.9 (d), 115.6 (t), 122.8 (d), 131.8 (s), 133.6 (d),
137.5 (d), 169.2 (s); m/z (EI) 283 (MC, 42), 186 (25), 136
Selected X-ray data of 2.16 C17H25NO2S, MrZ307.45,
monoclinic, P21, aZ11.3300(5), bZ10.9724(5),
3
˚
˚
cZ13.7035(7) A, bZ98.732(1)8, VZ1683.84(14) A ,
ZZ4, DxZ1.213 g cmK3, F(000)Z664, mZ1.96 cmK1
,
˚
l(Mo Ka)Z0.71073 A, TZ100(1) K, 16062 reflections
measured, GooFZ1.029, wR(F2)Z0.1700 for 8539 unique
reflections and 392 parameters, 23 restraints and R(F)Z
0.0629 for 8285 reflections obeying FoR4.0s(Fo) criterion

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E. W. Dijk et al. / Tetrahedron 60 (2004) 9687–9693
of observability. The asymmetric unit consists of two
molecules of the title compound.
dichloromethane (4!5 mL). After drying over MgSO4 and
evaporation of the solvent, 7 mg (0.036 mmol, 48%) of pure
(K)-pumiliotoxin C (1) was obtained. All spectroscopic
data were in accordance with the literature. Comparison of
the mass spectrum with the NIST Mass Spectral Library
(1995) showed 94% correspondence.
3.1.6. (2S,4aS,5R,8aR)-5-Methyl-1-(4-toluenesulfonyl)-2-
n-propyl decahydro-quinoline (10). A flame-dried reseal-
able tube with a teflon cap was loaded with dry Na2CO3
(268 mg, 2.53 mmol, 3 equiv) and suspended in 1.41 mL of
dry, distilled CH3CN under a nitrogen atmosphere. To the
stirring mixture was then sequentially added tri-o-tolylphos-
phine (154 mg, 0.51 mmol, 0.6 equiv), palladium acetate
(5.08 mL of a 0.05 M stock solution in CH3CN, 0.25 mmol,
0.3 equiv), tetra-n-butylammonium chloride (1.69 mL of a
1 M solution in CH3CN, 1.69 mmol, 2 equiv), 2 (260 mg,
0.85 mmol), and 1-bromo-1-propene (0.29 mL, 3.39 mmol,
4 equiv, mixture of cis and trans). The amount of solvent
was adapted so as to afford a 0.1 M solution of 2. The
mixture was then frozen at K40 8C, sealed under vacuum
and slowly heated to 86 8C. After stirring at this temperature
for 68 h, the mixture was flashed over a plug of silica with
pentanes:ethyl acetate 1:1 and concentrated to afford
384 mg of a yellow oil. GC-MS analysis showed a 1:1
mixture of diastereomers with the correct mass (m/zZ347)
together with some unidentified side products. The product
mixture was hydrogenated without further purification:
500 mg of the mixture was dissolved in 10 mL of ethanol,
placed in an autoclave and 50 mg of 10% Pd/C was added.
The mixture was stirred overnight at room temperature
under 45 bar of hydrogen pressure. After filtration over a
plug of silica with ethanol 132 mg (0.38 mmol, 26%) of a
mixture of two epimers (9) with an m/z of 349 (GC-MS) was
obtained together with a number of side products that could
not be identified. Purification by flash chromatography
(SiO2, hexanes:diethyl ether 10:1) afforded a pure compound
that after removal of the tosyl group by Na/naphthalene (vide
infra) gave 2-epi-pumiliotoxin C (epi-1).20
1H NMR: d 0.85 (d, JZ6.3 Hz, 3H), 0.91 (t, JZ6.5 Hz, 3H),
1.08–1.18 (m, 2H), 1.26–1.49 (m, 8H), 1.52–1.69 (m, 5H),
1.81–1.98 (m, 2H), 2.53–2.56 (m, 1H), 2.85–2.86 (m, 1H).
13C NMR: d 57.74 (d), 55.98 (d), 42.56 (d), 39.68 (t), 35.91
(t), 33.37 (t), 27.37 (d), 27.32 (t), 27.04 (t), 21.25 (t), 19.91
(q), 19.15 (t), 14.31 (q). The free amine was converted into
its hydrochloride by bubbling HCl gas through a solution in
i-propanol, giving a temperature rise to about 50 8C. After
cooling in ice and no further observation of heat develop-
ment, the solvent was removed under reduced pressure
giving 5 mg of a yellowish solid. Crystallisation from
i-propanol gave a tiny amount of small colorless needles,
mp 190–191 8C (dec., lit.5j 220–225 8C).
Acknowledgements
T. Tiemersma is gratefully acknowledged for the assistance
with HPLC separations.
References and notes
1. (a) Daly, J. W.; Tokuyama, T.; Habermehl, G.; Karle, I. L.;
Witkop, B. Lieb. Ann. Chem. 1969, 729, 198. For an overview
of the natural occurence of pumiliotoxin C and analogues, see
(b) Spande, T. F.; Jain, P.; Garraffo, H. M.; Pannell, L. K.; Yeh,
H. J. C.; Daly, J. W.; Fukumoto, S.; Imamura, K.; Tokuyama,
T.; Torres, J. A.; Snelling, R. R.; Jones, T. H. J. Nat. Prod. 1999,
62, 5. (c) Michael, J. P. Nat. Prod. Rep. 1998, 15, 595.
Separation of the remaining mixture by preparative HPLC
yielded 26 mg (0.075 mmol) of 10 as a colorless solid. dH
0.93 (3H, d, JZ4.0 Hz), 0.95 (3H, t, JZ4.0 Hz), 1.07–1.83
(16H, m), 2.42 (3H, s), 3.95–4.04 (2H, m), 7.27 (2H, d,
JZ8.1 Hz), 7.71 (2H, d, JZ8.1 Hz). dC 14.0 (q), 18.4 (q),
18.9 (q), 20.5 (t), 20.6 (t), 20.9 (t), 21.4 (d), 26.3 (t), 28.2 (t),
29.9 (t), 34.4 (d), 38.3 (t), 51.7 (d), 52.5 (d), 126.6 (d), 129.4
(d), 139.2 (s), 142.4 (s): m/z (EI) 349 (MC, 1.1), 306 ({MK
n-Pr}C, 100), 155 (TsC, 6), 135 (20), 91 (tropyliumC, 12).
HRMS 349.2087. C20H31NO2S requires 349.2075.
2. (a) Daly, J. W.; Nishizawa, Y.; Padgett, W. L.; Tokuyama, T.;
McCloskey, P. J.; Waykole, L.; Schulz, A. G.; Aronstam,
R. S. Neurochem. Res. 1991, 16, 1207. (b) Schulz, A. G.; Wang,
A. H.; Alva, C.; Sebastian, A.; Glick, S. D.; Deecher,
D. C.; Bidlack, J. M. J. Med. Chem. 1996, 39, 1956.
3. For a review of the literature until 1976 see: Inubushi, Y.;
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3.1.7. (2S,4aS,5R,8aR)-5-Methyl-2-n-propyl decahydro-
quinoline, (K)-pumiliotoxin C (1). Naphthalene (47.7 mg,
0.37 mmol, 5 equiv) was dissolved in 2 mL of dry and
degassed DME under an argon atmosphere. To this solution
was added metallic sodium (approx. 9 mg, 0.39 mmol,
5.2 equiv) in small slices and the mixture was sonicated
until a deep-green solution of sodium naphthalenide had
formed (5 min). The solution was then stirred for an
additional 2 h at room temperature under argon, cooled to
0 8C and 26 mg of 10 (0.075 mmol) was added as a solution
in 1 mL of dry DME. The mixture was stirred for 60 min at
0 8C and then quenched by adding 1 mL of saturated
aqueous NH4Cl. Subsequently, 5 mL of 2 M aqueous HCl
was added and the aqueous layer was washed with heptane
(3!5 mL). The aqueous layer was brought to pH 14 by
addition of 10% aqueous NaOH followed by extraction with

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J. Org. Chem. 1996, 61, 5440.
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20. Ref. 4d. The compound showed 45–90% correspondence with
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