Anodic cyanation of (-)-N-phenyl-2-methylpiperidine: A short synthesis of (+)-Solenopsin A and (+)-isosolenopsin A

Article abstract of DOI:10.1081/SCC-200050370

A convenient method for the preparation of (+)-Solenopsin A 1 (5 steps, 21%) involving regiospecific anodic cyanation of (-)-N-phenyl-2-methylpiperidine 4 is described.

Full text of DOI:10.1081/SCC-200050370

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Anodic Cyanation of
(-)‐N‐Phenyl‐2‐Methylpiperidine: A
Short Synthesis of (+)‐Solenopsin A and
(+)‐Isosolenopsin A
Nicolas Girard a , Jean‐Pierre Hurvois a , Loic Toupet b & Claude Moinet a
a Laboratoire d'électrochimie, UMR 6509, Institut de Chimie, Université de
Rennes I, Rennes Cedex, France
b Groupe Matière Condensée et Matériaux, Université de Rennes I, Rennes
Cedex, France
Published online: 20 Aug 2006.
To cite this article: Nicolas Girard , JeanPierre Hurvois , Loic Toupet & Claude Moinet (2005) Anodic
Cyanation of (-)‐N‐Phenyl‐2‐Methylpiperidine: A Short Synthesis of (+)‐Solenopsin A and (+)‐Isosolenopsin A,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
35:5, 711-723, DOI: 10.1081/SCC-200050370
To link to this article: http://dx.doi.org/10.1081/SCC-200050370
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Synthetic Communicationsw, 35: 711–723, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200050370
Anodic Cyanation of (2)-N-Phenyl-2-
Methylpiperidine: A Short Synthesis of (1)-
Solenopsin A and (1)-Isosolenopsin A
Nicolas Girard and Jean-Pierre Hurvois
´
Laboratoire d’electrochimie, UMR 6509, Institut de Chimie,
´
Universite de Rennes I, Rennes Cedex, France
Loic Toupet
´
` ´ ´
Groupe Matiere Condensee et Materiaux, Universite de Rennes I,
Rennes Cedex, France
Claude Moinet
Laboratoire d’electrochimie, UMR 6509, Institut de Chimie,
´
Universite de Rennes I, Rennes Cedex, France
´
Abstract: A convenient method for the preparation of (þ)-Solenopsin A 1 (5 steps,
21%) involving regiospecific anodic cyanation of (2)-N-phenyl-2-methylpiperidine
4 is described.
Keywords: Solenopsin A, isosolenopsin A, electrolysis
INTRODUCTION
Solenopsin A 1 together with its cis isomer isosolenopsin A 2 (Fig. 1), are
constituents of nonproteinaceous piperidine alkaloids secreted by the fire
ant Solenopsis invicta.[1] Despite a limited systemic toxicity, these substances,
which are injected by massive stings, have pronounced haemolytic, cytotoxic,
Received in Poland 2 November 2004
Address correspondence to Jean-Pierre Hurvois, Laboratoire d’electrochimie, UMR
´
´
6509, Institut de Chimie, Universite de Rennes I, Campus de Beaulieu, F-35042 Rennes
Cedex, France. Fax: þ33(223)235967; E-mail: Jean-Pierre.Hurvois@univ-rennes1.fr

712
N. Girard et al.
Figure 1. Chemical structures for (þ)-solenopsin A and (þ)-isosolenopsin A.
and histamine-releasing properties.[2] In addition a recent study showed that
isosolenopsin A was a potent and a selective inhibitor of three neuronal nitric
oxide synthase isoforms.[3] These interesting biological properties coupled
with their cis/trans isomerism have made 1 and 2 popular synthetic targets
on which to study new synthetic tools.
Therefore, during the last decade, several enantioselective syntheses of
Solenopsin A were developed which include: ex-chiral pool syntheses, chiral
auxilliary controlled methods, and asymmetric catalytic reactions.[4] In this
context, chiral nonracemic aminonitrile systems were soon recognized as
useful synthetic intermediates for the elaboration of piperidine alkaloids substi-
tuted at both the C-2 and C-6 carbon atoms.[5] A recent study performed in our
laboratory shows clearly that any N-phenyl-2-cyano-6-alkylpiperidines could
be prepared by anodic cyanation of the corresponding N-phenyl-2-alkyl-
piperidine.[6] In the continuation of these studies, we felt that our synthetic
approach would be suitable to exploit the innate chirality of 2-methylpiperidine.
Thus, for an efficient synthesis of (þ)-1, the homochiral (S)-2-methylpiperidine
3 was an obvious starting material.[7] In the present paper we describe a con-
[8a]
`
cise synthesis of 1 and 2 that embodies Caubere N-aryl coupling,
cyanation, and Birch reductive dearomatization as key features.
anodic
RESULTS AND DISCUSSION
Our synthetic route (Scheme 1) began with the condensation of the commercially
available (S)-(þ)-2-methylpiperidine 3 with phenylbromide (1.1equiv.) in tetra-
hydrofuran(THF) (508C, 16h)in the presenceofa t-BuONa/NaNH2 mixture.[8a]
Under these conditions, (S)-(–)-N-phenyl-2-methylpiperidine 4 was obtained in
84% yield f[a]D, 226.58, (c ¼ 0.30, CHCl3)g.
Chiral capillary gas chromatography gave ee values up to 98%, and we
were pleased to find that no racemization occurred during the coupling
process.[9a] For the synthesis of aminonitrile 5, a range of conditions was
investigated. When the electrolysis [Ep ¼ þ0.75 V/SCE, MeOH, AcOLi
(20 g/l), NaCN (6 equiv.)] was conducted in a divided cell and in connection
with the amount of electricity (2.3–2.5 Faraday per mol) that was consumed
during theses electrolyses, one can assume that a redox reaction between the
nitrogen-centered cation radical and cyanide anions partially occurred.[10]

(1)-Solenopsin A
713
Scheme 1. Reagents and conditions: (a) NaNH2/t-BuOH, C6H5Br, THF, 508C, 16 h,
84%; (b) 22e, 2Hþ, MeOH, NaCN (6 equiv.), 72%; (c) LDA (1.1 equiv.), C11H23Br,
THF, 2788C to rt, 91%; (d) NaBH4 (4 equiv.), EtOH, 15 h, 90%; (e) Li (75 equiv.),
NH3/THF/EtOH (20:10:6), 10% HCl, EtOH, 608C, 15 min, (þ)-1, 45%, (þ)-2, 28%.
When similar transformations were achieved in an undivided cell, the amount
of electricity was close to the theoretical 2 Faraday per mol process. It seems
likely that using this device, lithium hydroxide is produced at the cathode from
the electrolyte and readily deprotonates the cation radical species. Thus, for
sake of simplicity, the electrolysis of (2)-4 was carried out in an undivided
cell with a glassy carbon electrode as anode and a carbon rod as cathode.
After work-up, the expected cyano adduct, 5, was obtained as a single regioi-
somer (72%). On the other hand, the examination of the 1H NMR spectrum of
5 revealed the presence of a mixture of epimers. In order to determine the
structure of each isomer, separate experiments were undertaken in the
racemic series. In one of these, we observed that treatment of a cis/trans
mixture (30:70) of (+)-5 with a stoichiometric amount of LDA (lithium
diisopropylamide) at 2208C, followed by the subsequent addition of water
onto the resulting anion solution, led to an unexpected trans to cis isomeriza-
tion (.99% de). A further X-ray study performed on (+)-cis-5 revealed that
both the methyl and the cyano groups were axially oriented (Fig. 2).
The incorporation of the requisite n-undecyl side chain was made through
the metallation of the aminonitrile function of 5. The anion formation was
made by treatment at 2788C of a THF solution of a cis/trans mixture
(30:70) of 5 followed by the addition of n-undecylbromide. A 15 h stirring
period at þ58C led to (2)-6 [90%, f[a]D, 29.58, (c ¼ 1.80, CHCl3)g]. It
should be pointed out that no reaction took place when the condensation was

714
N. Girard et al.
Figure 2. Oak Ridge Thermal Ellipsoid Plot (ORTEP) drawing of aminonitrile
(+)-cis-5.
1
carried out at temperatures below 2208C. The H NMR spectrum of (2)-6
revealed the presence of a single adduct and showed H-6 as a multiplet
signal at d ¼ 3.33 with a width at half-height of ca. 20 Hz. Taken together,
these results indicated that the alkylation procedure proceeded with a high
degree of stereoselectivity (.99% de) placing both the alkyl chains in a cis
diequatorial disposition.[6,11] The reductive decyanation of (2)-6 remained
a critical step. In analogy with former investigations, all attempts made to
improve the diastereoselectivity of that transformation were unsuccessful.[6]
However, best yields and reaction rates were obtained upon the exposure of
(2)-6 to NaBH4 in ethanol. Compound 7 was obtained in 90% yield as an
inseparable cis/trans mixture (35:65). The low stereocontrol of this last
step was in agreement with a rapid equilibrium between the two half-chair
conformations A and B (Fig. 3).
Delivery of hydride on A and B (under a stereoelectronically controlled
mode)[12] produced cis- and trans-7, respectively. In contrast to N-Boc[13] or
N-tosyl[14] iminium derivatives, the phenyl group in A does not interfere to a
great extent with the equatorial methyl substituent. As a result, our model is
not susceptible to A1,2 strain and trans-7 was obtained in a moderate 58%
yield. Finally, the cleavage of the N-aryl bond in 7 was carried out through
the reductive dearomatization of the phenyl substituent.[6] For this, 7 was
reduced with Li (75 equiv.) in a NH3/THF/EtOH (20:10:6) mixture. The
unstable dienamine C[15] (Fig. 3) was obtained in nearly quantitative yield,

(1)-Solenopsin A
715
Figure 3. Stereochemistry for the hydride addition on minimum systems A and B.
and was subjected without purification to acid hydrolysis (10% HCl, 608C,
EtOH, 15 min). The oily residue was purified by column chromatography
(silica gel, diethyl ether saturated with gaseous NH3). The (2S,6R)-(þ)-
.
isosolenopsin A 2 f2 HCl mp 1508C; [a]D, 210.38 (c ¼ 1.74, CHCl3)g; lit.
[4 h] mp 152–1538C; [a]D, 210.18, (c ¼ 1.0, CHCl3)g eluted first, followed
by the more polar trans isomer (2S,6S)-(þ)-solenopsin A 1, which was
isolated in an overall 45% yield from 7. The optical rotation of the hydro-
chloride salt of our synthetic solenopsin A was dextrorotatory and was consis-
.
tent with that reported in the literature f1 HCl mp 1488C; [a]D, þ7.48
(c ¼ 1.97, CHCl3)g; lit.[5] mp 1468C; [a]D, þ7.58, (c ¼ 1.3, CHCl3)g.
CONCLUSION
In summary, an efficient process (5 steps, 21%) to (2S,6S)-(þ)-solenopsin A
from the readily available enantiomerically pure (S)-(þ)-2-methylpiperidine
has been developed. Application of a similar strategy to the synthesis of
more complex alkaloids is currently under investigations in our laboratory.
EXPERIMENTAL
General Information
All glassware was oven dried (1208C) over a 24 h period and cooled under an
atmosphere of argon. Tetrahydrofuran (THF) was distilled before use from

716
N. Girard et al.
sodium benzophenone ketyl. Lithium acetate dihydrate was purchased from
Acros. Solution of n-butyllithium (1.6 M) was purchased from Acros. Diiso-
propylamine was distilled over KOH pellets and was stored under argon.
Lithium diisopropylamide solutions were prepared prior to use by the
addition of n-butyllithium (2.0 M in THF/heptane) on a THF solution contain-
ing 1.1 equivalent of diisopropylamine, or were purchased from Aldrich and
used without titration. (S)-(þ)-2-methylpiperidine (98% ee) was purchased
from Aldrich and was used as supplied. Tert-butanol was distilled over
CaH2 and was stored under nitrogen. Air sensitive reagents were transferred
by syringe or with a double-ended canula. Purification by column chromato-
graphy was performed using 70–230 Mesh silica gel (Merck). Thin layer
chromatography (TLC) analyses were carried out on alumina sheets
precoated with silica gel 60F254. Rf values are given for guidance. The
NMR spectra were recorded on a Bruker AH 300 Ft spectrometer [300 MHz
(1H) and 75 MHz (13C) or a Brucker DPI 200 FT [200 MHz (1H) and
50 MHz (13C)]. Chemical shifts are expressed in ppm downfield from TMS
where s, d, dd, t, q, and m designate singlet, doublet, doublet of doublets,
triplet, quartet, and multiplets, respectively, and coupling constants are
expressed in Hz. High Resolution Mass Spectra (HRMS) were obtained
with a MAT 311 double focusing instrument at the CRMPO (Centre
Regional de Mesures Physiques de l’Ouest) with a source temperature of
1708C. An ion accelerating potential of 3 kV and ionizing electrons of
70 eV. were used. Analytical capillary gas chromatography was performed
on a VARIAN CP 3380 gas chromatograph equipped with a programmable
temperature control, a flame ionization detector and a CP-Chirasil-Dex CB
column (25 m ꢀ 0.25 mm ꢀ 0.25 mm). Optical rotations ([a]D)were
recorded on a PERKIN polarimeter and were all conducted at 208C.
(2S)-(2)-1-Phenyl-2-methylpiperidine (4)
To a THF (30 mL) suspension of NaNH2 (1.65 g, 42.30 mmol) was added
dropwise (by syringe) 10 mL of THF containing 1.5 mL (1.16 g,
15.70 mmol) of t-BuOH. The resulting mixture was stirred at room tempera-
ture for 1 h under an atmosphere of argon. (S)-(þ)-2-methylpiperidine 3
(1.40 g, 14.11 mmol in 5 mL of THF) and bromobenzene (2.46 g, 1.65 mL,
15.65 mmol) were successively added over a 15 min period. The resulting
solution was stirred at 508C for 16 h and the reaction mixture was quenched
by the addition of an excess of water, and extracted with ether (50 mL ꢀ 3).
The combined organic layers were extracted by a 10% HCl solution
(50 mL), which was made basic by the addition of NaOH pellets. The oily
residue was extracted with ether (50 mL ꢀ 3) and dried over MgSO4. The
organic phases were concentrated in vacuo and the crude material was purified
by column chromatography (diethyl ether/petroleum ether, 5:95, Rf ¼ 0.50) to

(1)-Solenopsin A
717
afford 4 (2.07 g, 84%) as slightly yellow oil. [a]2D0, 226.58 (c ¼ 0.30 CHCl3).
dH(200MHz, CDCl3) 1.01 (3 H, d, J ¼ 6.6 Hz), 1.52–1.95 (6 H, m), 2.98
(1 H, td, J ¼ 11.0 and 3.0 Hz), 3.21 (1 H, dm, J ¼ 11.0Hz), 3.90 (1 H, m),
6.82 (1 H, t, J ¼ 7.2 Hz), 6.94 (2 H, m), 7.24 (2 H, m). dC(50 MHz, CDCl3)
14.38 (CH3), 20.31, 26.62, 32.30, 45.59, 51.92 (CH), 118.15, 119.70, 129.44,
151.90. HRMS calcd. for C12H17N (Mþ) 175.1361, found 175.1369. VPC:
tR ¼ 5.62min (150–2008C at 58C/min, 98% ee).
(2R,6S)-6-Methyl-1-phenylpiperidine-2-carbonitrile (5)
Compound (2)-4 (1 g, 5.70 mmol) was dissolved in 100 mL of methanol in the
presence of 2 g of lithium acetate and 1.7 g (6 equiv.) of sodium cyanide. The
resulting solution was oxidized at þ0.80 V/SCE in an undivided cell fitted at
a planar vitreous carbon electrode. After the consumption of 1140 coulomb
the electrolysis was stopped. The solution was concentrated under reduced
pressure and the crude material was taken up with water (20 mL) and
extracted with CH2Cl2 (50 mL ꢀ 2). The combined organic layers were dried
over MgSO4 and concentrated. The crude reaction mixture was purified by
column chromatography (diethyl ether/petroleum ether, 1:2 to afford 5
(0.820 g, 72%) as a mixture (30:70) of cis/trans isomers. A further purification
on a silica column using diethyl ether/petroleum ether, 10:90 as eluent
(Rf ¼ 0.33), allowed the partial separation of (2R,6S)-5. Capillary gas chroma-
tography analysis indicated that our sample was contaminated (7%) by the cis
derivative. dH(200 MHz, CDCl3) 0.89 (3 H, d, J ¼ 5.90 Hz), 1.23–1.38 (1 H,
m), 1.71–2.01 (5 H, m), 3.29 (1 H, m), 4.12 (1 H, t, J ¼ 3.5 Hz), 7.09–7.33
(5 H, m). dC(50 MHz, CDCl3) 21.37 (CH3), 21.49, 31.45, 34.70, 50.56 (CH),
57.63 (CH), 121.70 (CN), 126.08, 126.43, 129.91, 149.66. HRMS calcd.
for C13H16N2 (Mþ) 200.1313, found 200.1316, VPC: tR ¼ 8.21 min
(150–2008C at 58C/min).
Cis-6-Methyl-1-phenylpiperidine-2-carbonitrile (5)
To a THF solution containing (+)-5 (cis/trans ¼ 30:70, 1.94 g, 9.70 mmol) at
2788C, were added 1.1 equiv. of LDA. The solution was allowed to warm up
to 2208C and was stirred at that temperature for 2 h. An excess (10 mL) of
water was poured onto the resulting solution, which was extracted with
diethyl ether (100 mL ꢀ 2). The combined organic layers were dried over
MgSO4 and concentrated in vacuo. The crude material was purified by
column chromatography (diethyl ether/petroleum ether, 10:90, Rf ¼ 0.30)
to yield (+)-cis-5 (1.90 g, 97%) as a slightly yellow viscous oil that solidifies
upon cooling, m. p. ¼ 788C. dH(300 MHz, CDCl3) 1.16 (3 H, d, J ¼ 6.80 Hz),
1.65–1.73 (2 H, m), 1.81–2.02 (3 H, m), 2.05–2.14 (1 H, m), 3.96 (1 H, m),

718
N. Girard et al.
4.34 (1 H, t, J ¼ 4.45 Hz), 6.93–7.05 (3 H, m), 7.28–7.35 (2 H, m).
dC(75 MHz, CDCl3) 15.93 (CH3), 17.33, 30.12, 31.10, 46.47 (CH), 51.32
(CH), 117.96, 120.70 (CN), 121.46, 129.46, 147.99. HRMS calcd. for
C13H16N2 (Mþ) 200.1314, found 200.1316.
Crystal Data, X-ray Data Collection, and Refinement Results
of (+)-cis-(5)
C13H16N2, M ¼ 200.28, monoclinic, space group P21/n, a ¼ 9.360(3),
b ¼ 7.525(2), c ¼ 16.409(6) A, b ¼ 104.24(1)8, V ¼ 1120.2(6) A–3, Z ¼ 4,
˚
˚
Dx ¼ 1.188 Mg m–3, l (MoKa) ¼ 0.71073 A, m ¼ 0.71cm21, F(000) ¼ 432,
˚
T ¼ 290 K. The sample (plate: 0.40 ꢀ 0.35 ꢀ 0.35mm) is studied on a
NONIUS Kappa CCD with graphite monochromatized MoKa radiation. The
cell parameters are obtained with Denzo and Scalepack[16] with 10 frames
(psi rotation: 18 per frame). The data collection[17] (2umax ¼ 548, 129 frames
via 28 omega rotation and 20s per frame, range HKL: H 0,12 K 0,9 L–
21,20) gives 7390 integrated reflections. The data reduction with Denzo and
Scalepack[16] leads to 2527 independent reflections [1947 with I . 2.0s(I)].
The structure was solved with SIR-97,[18] which reveals all the nonhydrogen
atoms of the compound and the solvent. After anisotropic refinement, the
hydrogen atoms are found with a Fourier difference. The whole structure was
refined with SHELXL97[19] by the full matrix least-square techniques (use of
F square magnitude; x, y, z, bij for C and N atoms and riding mode for H
atoms; 137 variables and 2527 observations with I . 2.0s(I); calc w ¼ 1/[s2
(Fo2) þ (0.176P)2 þ 0.176P] where P ¼ (Fo2 þ 2Fc2)/3 with the resulting
R ¼ 0.044, Rw ¼ 0.116, and Sw ¼ 1.05 (residual Dr , 0.17eA23). Atomic
˚
scattering factors are available from International Tables for X-ray Crystallogra-
phy.[20] The ORTEP views were realized with PLATON98.[21] All the calcu-
lations were performed on a Pentium NT Server computer. Further details of
the crystal structure analysis are available on request from the Cambridge Crys-
tallographic Data Center as supplementary publication no: 241073. Copies of
the data can be obtained free of charge on application to the director CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (Fax: þ44 1223 336033, E-mail:
deposit@ccdc.cam.ac.uk.)
(2R,6S)-(2)-6-Methyl-2-undecyl-1-phenylpiperidine-2-carbonitrile (6)
To a THF solution (15 mL) containing 0.980 mL (0.707g, 7.0 mmol) of diisopro-
pylamine at 2808C were added (by syringe) 3.1 mL (6.2mmol) of n-BuLi (2M).
The solution was stirred at that temperature for 15min and was allowed to
warmed to 08C over a 30min period. The resulting LDA solution was transferred
(by syringe) to a THF solution (15 mL) cooled at 2808C containing the

(1)-Solenopsin A
719
aminonitrile 5 (0.82 g, 4.10mmol, cis/trans mixture, 30: 70). The solution was
allowed to warm up to 2308C for 1 h and n-bromoundecane (1.64 g, 1.56mL,
7 mmol) was added dropwise. The reaction mixture was stirred at þ58C for
12h, diluted with water (100mL), and extracted with diethyl ether
(100 mL ꢀ 2). The oily residue was purified by rapid filtration over a silica
column with diethyl ether/petroleum ether (5:95, Rf ¼ 0.63) to yield (2)-6
(1.32g, 91%) as a viscous yellow oil. [a]2D0, 29.78 (c ¼ 1.08 CHCl3).
dH(300MHz, CDCl3) 0.72 (3 H, J ¼ 6.10Hz), 0.74 (1 H, m), 0.89 (3 H,
J ¼ 6.50Hz), 1.05–1.50 (21 H, m), 1.62 (1 H, m), 1.80–1.88 (2 H, m), 2.06 (1
H, dm, J ¼ 11.0Hz), 3.33 (1 H, m), 7.22–7.34 (5 H, m). dC(75 MHz, CDCl3)
14.12, 21.67, 22.23 (CH3), 22.68, 23.84, 29.32, 29.37, 29.42, 29.56, 29.61,
31.90, 34.77, 35.64, 39.42, 54.14 (CH), 62.35, 121.22 (CN), 126.85, 128.72,
129.35, 146.49. HRMS calcd. for C24H38N2 (Mþ) 354.3035, found 354.3060.
2-Methyl-1-phenyl-6-undecylpiperidine (7)
To an ethanol solution (15 mL) of (2)-6 (1.27 g, 3.58 mmol) at room tempera-
ture, 0.545 g (14.40 mmol) of NaBH4 was added. The solution was stirred at
that temperature overnight and the solvent was evaporated. The crude
material was taken-up with water (50 mL) and extracted with diethyl ether
(100 mL ꢀ 2). The combined organic portions were dried over MgSO4 and
concentrated to give a crude mixture that was chromatographed on silica
with diethyl ether/petroleum ether (5:95, Rf ¼ 0.4) affording 7 (1.06 g,
90%) as a viscous colorless oil consisting of a mixture of diastereoisomers
(cis/trans ¼ 65:35), as determined by capillary gas chromatography
analysis. dH(300 MHz, CDCl3) 0.84 f3 H (cis isomer), d, J ¼ 6.4 Hzg, 0.90
f6 H (cis and trans isomers), t, J ¼ 6.50 Hzg, 0.97 f3 H (trans isomer), d,
J ¼ 6.20 Hzg, 1.07–1.91 f43 H (cis and trans isomers), mg, 2.93–3.03 f1 H
(cis isomer), mg, 3.05–3.16 f1 H (cis isomer), mg, 3.24–3.31 f1 H (trans
isomer), mg, 3.43–3.53 (1 H (trans isomer), mg, 6.85–7.06 (6 H, m), 7.18–
7.26 (4 H, m). dC(75 MHz, CDCl3) 14.14 (CH3), 17.78 (CH3), 18.37, 21.11,
21.79, 22.70, 26.28, 26.55, 28.44, 29.35, 29.56, 29.63, 29.65, 29.69, 29.78,
30.50, 31.93, 33.56, 33.95, 34.19, 50.56 (CH), 55.29 (CH), 57.03
(CH), 59.53 (CH), 121.51, 122.68, 123.54, 128.21, 128.76, 150.46, 150.82.
HRMS calcd. for C23H39N (Mþ) 329.3082, found 329.3078. VPC:
tR ¼ 23.35 min (cis), tR ¼ 27.46 min (trans) (2008C).
(2S,6S)-(1)-2-Methyl-6-undecylpiperidine (1) and (2S,6R)-(1)-2-
Methyl-6-undecylpiperidine (2)
In a Schlenck tube containing 10 mL of THF at 2408C, 6 mL of absolute
ethanol were added, 0.6 g (1.82 mmol) of 7 (cis/trans ¼ 35:65), and 20 mL

720
N. Girard et al.
of liquid ammonia in that order. Then, 0.830 g (120 mmol) of lithium wire was
added in small pieces over a 2 h period, the solution then became blue. The
solution was stirred for 1 h and quenched with an excess of water (100 mL).
The ammonia was allowed to evaporate, and the resulting solution was
extracted by diethyl ether (100 mL ꢀ 2). The organic layers were dried over
MgSO4 and concentrated to give a mixture of unstable dienamines as
colorless oil. [Selected data only: dH (200 MHz, CDCl3) ¼ 4.81
(d, J ¼ 6 Hz), 4.91 (d, J ¼ 5.60 Hz), 5.26 (m), 5.34 (m), 5.90 (m)]. After
being dissolved in an H2SO4/H2O/EtOH (0.5:5:4.5) mixture, the crude
material was heated at 608C for 15 min. The solvents were evaporated and
the resulting oily residue was dissolved in water (10 mL). The aqueous
mixture was made basic by the addition of NaOH pellets and the aqueous
layer was extracted with diethyl ether (20 mL ꢀ 2). The combined organic
extracts were dried over MgSO4 and the solvent was removed at reduced
pressure. The resulting crude oil was purified by column chromatography
with diethyl ether saturated with gaseous ammonia to afford the cis isomer
(þ)-2 (Rf ¼ 0.85, 0.130 g, 28%) and the trans isomer (þ)-1 (Rf ¼ 0.35,
0.210 g, 45%) as pale yellow oils. (2S,6S)-(þ)-solenopsin A 1: dH(300 MHz,
CDCl3) 0.85 (3 H, t, J ¼ 6.95 Hz), 1.04 (3 H, d, J ¼ 6.50 Hz), 1.11–1.66 (27
H, m), 2.81–2.88 (1 H, m), 2.98–3.08 (1 H, m). dC(75 MHz, CDCl3) 14.07
(CH3), 19.56, 21.24 (CH3), 22.66, 26.45, 29.33, 29.61, 29.64, 29.77, 30.80,
31.89, 33.00, 34.07, 45.78 (CH), 50.80 (CH). HRMS calcd. for C17H35N
(Mþ) 253.2769, found 253.2760. VPC: tR ¼ 14.42 min (150–2008C at 58C/
min). (2S,6R)-(þ)-isosolenopsin A 2: dH(300 MHz, CDCl3) 0.87 (3 H, t,
J ¼ 6.05 Hz), 0.94–1.08 (1 H, m), 1.05 (3 H, d, J ¼ 7.0 Hz), 1.12–1.68 (25
H, m), 1.70–1.79 (1 H, m), 2.41–2.51 (1 H, m), 2.55–2.66 (1 H, m).
dC(75 MHz, CDCl3) 14.09 (CH3), 22.67, 23.10 (CH3), 24.88, 25.99, 29.34,
29.60, 29.62, 29.66, 29.84, 31.90, 32.28, 34.44, 37.47, 52.46 (CH), 57.13
(CH). HRMS calcd. for C17H35N (Mþ) 253.2769, found 253.2767. VPC:
tR ¼ 13.55 min (150–2008C at 58C/min).
.
(2S,6S)-(1)-Solenopsin A Hydrochloride (1) HCl
The amine 1 (0.210g, 0.83mmol) was dissolved in 10mL of dry diethyl ether
and dry gaseous HCl was bubbled through the solution to precipitate the hydro-
chloride salt (0.240g, 100%). M. p. 1488C (diethyl ether); lit.[5] 1468C
(CH2Cl2–diethyl ether). [a]2D0, þ7,48 (c ¼ 1.97 CHCl3), lit.[5] [a]D20, þ7.58
(c ¼ 1.30 CHCl3). dH(300MHz, CDCl3) 0.83 (3 H, t, J ¼ 6.50Hz), 1.11–
1.38 (21 H, m), 1.43 (3 H, d, J ¼ 6.60Hz), 1.50–1.78 (5 H, m), 1.82–20.5
(3 H, m), 3.16–3.31 (1 H, m), 3.41–3.57 (1 H, m), 9.19–9.43 (2 H, s, br).
dC(75 MHz, CDCl3) 14.05 (CH3), 16.81 (CH3), 17.32, 22.62, 25.80, 26.11,
28.85, 29.28, 29.29, 29.45, 29.51, 29.56, 30.67, 31.85, 47.86 (CH), 51.68 (CH).

(1)-Solenopsin A
(2S,6R)-(1)-Isosolenopsin A Hydrochloride (2) HCl
721
.
The amine 2 (0.130 g, 0.51 mmol) was dissolved in 10 mL of dry diethyl ether
and dry gaseous HCl was bubbled through the solution to precipitate the
hydrochloride salt (0.130 g, 87%). M. p. 1508C (diethyl ether), lit.[4h] 152–
1538C (CH2Cl2–diethyl ether). [a]2D0 –10.38 (c ¼ 1.74 CHCl3), lit.[4h]
[a]2D0, –10.18 (c ¼ 1.0 CHCl3). dH(300 MHz, CDCl3) 0.86 (3 H, t,
J ¼ 6.9 Hz), 1.10–1.50 (21 H, m), 1.56 (3 H, d, J ¼ 6.40 Hz), 1.70–2.03
(5 H, m), 2.06–2.21 (1 H, m), 2.80–2.96 (1 H, m), 2.99–3.14 (1 H, m),
8.95–9.16 (1 H, br), 9.43–9.52 (1 H, br). dC(75 MHz, CDCl3) 14.08 (CH3),
19.45 (CH3), 22.65, 22.90, 25.69, 27.46, 29.31, 29.36, 29.54, 29.61, 30.72,
31.88, 33.23, 54.50 (CH), 58.61 (CH).
ACKNOWLEDGMENT
N.G. would like to thank the MENRT for a grant.
REFERENCES
1. (a) Absolute configuration of solenopsins: Leclercq, S.; Thirionet, I.; Broeders, F.;
Daloze, D.; Vander Meer, R.; Braeckman, J. C. Absolute configuration of the sole-
nopsins, venom alkaloids of the fire ants. Tetrahedron 1994, 50, 8465–8478.
(b) For a review see: Leclercq, S.; Daloze, D.; Braekman, J. C. Synthesis of the
fire ant alkaloids, solenopsins. A review. Org. Prep. Proced. Int. 1996, 28,
501–543.
2. Fodor, G. B.; Colasanti, B. The pyridine and piperidine alkaloids: chemistry and
pharmacology. In Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; John Wiley: New York, 1985; Vol. 3, pp. 1–91.
3. Yi, G. B.; McClendon, D.; Desaiah, D.; Goddard, J.; Lister, A.; Moffitt, J.; Vander
Meer, R. K.; deShazo, R.; Lee, K. S.; Rockhold, R. W. Fire ant venom alkaloid,
isosolenopsin A, a potent and selective inhibitor of neuronal nitric oxide
synthase. Int. J. Toxicol. 2003, 22, 81–86.
4. For recent enantioselective syntheses of Solenopsin A see: (a) Amat, M.; Llor, N.;
Hidalgo, J.; Escolano, C.; Bosch, J. Enantioselective synthesis of piperidine, indo-
lizidine, and quinolizidine alkaloids from a phenylglycinol-derived d-lactam.
J. Org. Chem. 2003, 68, 1919–1928; (b) Takahata, H.; Ouchi, H.; Ichinose, M.;
Nemoto, H. A novel C2-symmetric 2,6-diallypiperidine carboxylic acid methyl
ester as a promising chiral building block for piperidine-related alkaloids. Org.
Lett. 2002, 4, 3459–3462; (c) Kumareswaran, R.; Hassner, A. Asymmetric
synthesis of N-acetyl-(R)-coniine and N-Boc-(2R,6R)-solenopsin A via ring-
closing metathesis. Tetrahedron: Asymmetry 2001, 12, 2269–2276;
(d) Wilkinson, T. J.; Stehle, N. W.; Beak, P. Enantioselective synthesis of
2-alkyl- and 2,6-dialkylpiperidine alkaloids: preparation of the hydrochlorides of
(2)-coniine, (2)-solenopsin A, and (2)-dihydropinidine. Org. Lett. 2000, 2,
`
155–158; (e) Guilloteau-Bertin, B.; Compere, D.; Gil, L.; Marazano, C.;

722
N. Girard et al.
Das, B. C. Stereocontrolled alkylation of chiral pyridinium salt toward a short
enantioselective access to 2-alkyl and 2,6-dialkyl-1,2,5,6-tetrahydropyridines.
Eur. J. Org. Chem. 2000, 1391–1399; (f) Amat, M.; Hidalgo, J.; Llor, N.;
Bosch, J. Enantioselective synthesis of the trans-2,6-dialkylpiperidine alkaloids
(2R,6R)-lupetidine and (2R,6R)-solenopsin A. Tetrahedron: Asymmetry 1998, 9,
2419–2422; (g) Redding, M. T.; Buchwald, S. L. Short enantioselective total
synthesis of the piperidine alkaloids (S)-coniine and (2R,6R)-trans-solenopsin A
via catalytic asymmetric imine hydrosilylation. J. Org. Chem. 1998, 63,
6344–6347; (h) Poerwono, H.; Higashiyama, K.; Yamauchi, T.; Kubo, H.;
Ohmiya, S.; Takahashi, H. Stereocontrolled preparation of cis- and trans-2,6-
dialkylpiperidines via diastereoselective reaction of 1-aza-4-oxabicyclo[4.3.0]no-
nane derivatives with Grignard reagents. Tetrahedron 1998, 54, 13955–13970;
(i) Comins, D. L.; Benjelloun, N. R. Enantiopure N-acyldihydropyridones as
synthetic intermediates. An asymmetric synthesis of solenopsin A. Tetrahedron
Lett. 1994, 35, 829–832; (j) Oppolzer, W.; Bochet, C. G.; Merifield, E.
Diastereo- and enantioselective syntheses of (–)-coniine, (–)-solenopsin A,
(–)solenopsis fugax venom and (–)-xenovenine via deoxygenative decarboxyla-
tion of 2-carbonylsultam-substituted N-hydroxy-piperidines and -pyrrolidines.
Tetrahedron Lett. 1994, 38, 7015–7018.
5. Grierson, D. S.; Royer, J.; Guerrier, L.; Husson, H. P. Asymmetric synthesis. 6.
Practical synthesis of (þ)-solenopsin A. J. Org. Chem. 1986, 51, 4475–4477.
6. Girard, N.; Gauthier, C.; Malassene, R.; Hurvois, J. P.; Moinet, C.; Toupet, L.
Dearomatization of N-phenyl-2,6-dialkylpiperidines: practical synthesis of (+)-
solenopsin A and (+)-dihydropinidine. Synlett 2004, 2005–2009.
7. Adamo, M. F. A.; Aggarwal, V. K.; Sage, M. A. An improved resolution of
2-methylpiperidine and its use in the synthesis of homochiral trans-2,6-dialkylpi-
peridines. Synth. Commun. 1999, 29, 1747–1756.
`
8. (a) Caubere, P.; Loubinoux, B. Reactivite des halobenzenes en milieu aprotique.
Les melanges de bases. Bull. Soc. Chim. Fr. 1968, 9, 3857–3861; (b) Bhaskar
´
´
`
´
Kanth, J. V.; Periasamy, M. Convenient procedure for N-phenylation of amines.
J. Org. Chem. 1993, 58, 3156–3157.
9. (a) Wagaw, S.; Rennels, R. A.; Buchwald, S. L. Palladium-catalyzed coupling of
optically active amines with arylbromides. J. Am. Chem. Soc. 1997, 119,
8451–8458; (b) For a review see: Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.;
Buchwald, S. L. Rational development of practical catalysts for aromatic
carbon-nitrogen bond formation. Acc. Chem. Res. 1998, 31, 805–818.
10. Le Gall, E.; Hurvois, J. P.; Renaud, T.; Moinet, C.; Tallec, A.; Uriac, P.; Toupet, L.
Electrosynthesis of a-aminonitriles: anodic cyanation of N-substituted tetrahydro-
quinolines and N-phenylpiperidines. Liebigs Ann./Recueil 1997, 2089–2101.
11. For a review on the reactivity of cyano-stabilized carbanions see: Fleming, F. F.;
Shook, B. C. Nitrile anion cyclizations. Tetrahedron 2002, 58, 1–23.
12. Deslonchamps, P. Stereoelectronic Effects in Organic Chemistry; Pergamon:
New York, 1983, pp. 209–288.
13. Comins, D. L.; Weglarz, M. A. Stereocontrolled preparation of cis- and trans-2,6-
dialkylpiperidines via 1-acyldihydropyridine intermediates. Synthesis of (+)-
solenopsin A and (+)-dihydropinidine. J. Org. Chem. 1991, 56, 2506–2512.
14. Jefford, C. W.; Wang, J. B. An enantiospecific synthesis of solenopsin A. Tetrahe-
dron Lett. 1993, 34, 2911–2914.
15. Leonard, N. J.; Musliner, W. J. The synthesis of substituted tricyclo[6.2.2.0]dode-
canes from 2-cyclohexenones. J. Org. Chem. 1966, 31, 639–646.

(1)-Solenopsin A
723
16. Otwinowski, Z.; Minor, W. Processing of X-ray Data Collected in Oscillation
Mode. In Methods in Enzymology; Macromolecular Crystallography, Part A;
Carter, C. W., Sweet, R. M., Eds.; Academic Press: London, 1997; Vol. 276,
pp. 307–326.
17. Nonius, Kappa CCD Software; Nonius, B. V. Delft, The Netherlands, 1999.
18. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G.; Giacovazzo, C.;
Guargliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna, R. J. Appl. Crystall.
1999, 32, 115–119.
19. Sheldrick, G. M. SHELX97, Program for the Refinement of Crystal Structures.
¨
Univ. of Gottingen: Germany, 1997.
20. International Tables for X-ray Crystallography; A. J. C., Ed.; Kluwer Academic
Publishers: Dordrecht, 1992; Vol. C.
21. Spek, A. L. PLATON. A Multipurpose Crystallographic Tool. Utrech University:
Utrech, The Netherlands, 1998.