Synthesis of enantiomerically pure fire ant venom alkaloids: Solenopsins and isosolenopsins A, B and C

Article abstract of DOI:10.1002/jhet.5570450112

(Chemical Equation Presented) Concise and efficient methods for the synthesis of enantiomers of fire ant venom alkaloids solenopsin and isosolenopsin A, B, and C are described. These syntheses are based on diastereoselective electrophilic substitution of enatiomerically-pure α-lithiated 2-alkylpiperidine.

Full text of DOI:10.1002/jhet.5570450112

Jan-Feb 2008
129
Synthesis of Enantiomerically Pure Fire Ant Venom Alkaloids:
Solenopsins and Isosolenopsins A, B and C
H. M. T. Bandara Herath and N. P. Dhammika Nanayakkara*
National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences,
School of Pharmacy, The University of Mississippi, University, MS 38677, USA
*E-mail: dhammika@olemiss.edu
Received March 23, 2007
1. (Boc)2O
2. s-BuLi, TMEDA
Ph3P(CH2R')Br
NaH
Rh/C
TFA, CH2Cl2
R
R'
(+)-Mandelic
acid
3. CH3I
N
N
CHO
N
N
R
N
H
R
R
H
Boc
TMEDA
s-BuLi
1. (-)-Mandalic
acid
R'
1. Pd/H2
Ph3PCH2R'Br
CHO
NaH
N
N
N
N
2. TFA,
CH2Cl2
DMF
2. (Boc)2O
N
H
Boc
H
Boc
Boc
Concise and efficient methods for the synthesis of enantiomers of fire ant venom alkaloids solenopsin
and isosolenopsin A, B, and C are described. These syntheses are based on diastereoselective electrophilic
substitution of enatiomerically-pure ꢀ-lithiated 2-alkylpiperidine.
J. Heterocyclic Chem., 45, 129 (2008).
short and simple procedure to prepare trans-2-methyl-6-
alkylpiperidine on a medium scale. We chose to explore
the application of this synthesis, and experimental details
and results are described in this paper.
INTRODUCTION
The imported fire ant Solenopsis invicta, an aggressive
and venomous pest, has had a major impact on
agriculture, public safety, and environment in the southern
United States [1]. Since their accidental introduction in
the 1920’s fire ants have spread in both rural and urban
areas and pose a threat to young animals or small,
confined pets, children, the elderly, and unconscious or
injured accident victims [1]. Massive fire ant sting
attacks, especially in the case of the elderly and those
acutely sensitive to fire ant venom, can lead to severe
medical complications, including death [1].
N
(CH2)nCH3
N
(CH2)nCH3
H
H
1. n = 10, (2R, 6R)-Solenopsin A
4. n = 10, (2S, 6S)-Solenopsin A
2. n = 12, (2R, 6R) -Solenopsin B 5. n = 12, (2S, 6S)-Solenopsin B
3. n = 14, (2R, 6R) -Solenopsin C 6. n = 14, (2S, 6S)-Solenopsin C
The imported fire ant venom is mainly comprised of
three trans-2-methyl-6-alkylpiperidines [solenopsin A (1),
B (2), and C (3)] and two trans-2-methyl-6-alkenylpiper-
idines [dehydrosolenopsin B (13) and C (14)] [2]. Varying
amounts of three cis-2-methyl-6-alkylpiperidines
[isosolenopsin A (7), B (8) and C (9)] are also found to be
present in the venom of different types of ants [3].
In a previous communication, we reported that racemic
isosolenopsin A and solenopsin A possess robust cardio-
respiratory depressant activity in rats [4]. In order to
investigate individual enantiomers of fire ant venom
alkaloids on cardiorespiratory depressant activity, a
simple and efficient procedure for their synthesis needed
to be developed.
A number of methods have been reported for the stereo-
specific synthesis of solenopsins and 2,6-dialkyl-
piperidines [5-9]. Many of these methods involve multi-
step routes or require expensive starting materials.
However, an introduction of the 6-methyl group to
enatiomerically-pure ꢀ-lithiated 2-alkylpiperidins provides a
N
(CH2)nCH3
N
(CH2)nCH3
H
H
7. n = 10, (2R, 6S)-Isosolenopsin A 10. n = 10, (2S, 6R)-Isosolenopsin A
8. n = 12, (2R, 6S)-Isosolenopsin B 11. n = 12, (2S, 6R)-Isosolenopsin B
9. n = 14, (2R, 6S)-Isosolenopsin C 12. n = 14, (2S, 6R)-Isosolenopsin C
N
(CH2)nCH=CHC8H17
H
13. n = 3, (2R, 6R)-Dehydrosolenopsin B
14. n = 5, (2R, 6R)-Dehydrosolenopsin C
RESULTS AND DISCUSSION
Formation of ꢀ-carbanion and subsequent electrophilic
substitution of piperidines with various nitrogen-
activating groups has been studied extensively [10-12].
Though this process is known to proceed through the
lithiation of the equatorial position followed by
electrophilic substitution with retention of the
conformation, stereospecificity and yields are highly

130
H. M. T. Bandara Herath, N. P. Dhammika Nanayakkara
Vol 45
dependent on the nature of the electrophile and the groups
present on the piperidine ring [10,11]. Unsubstituted
piperidines with N-activating groups provide higher yields
and stereospecificity with electrophiles that are not readily
reducible via electron-transfer processes such as with
aldehydes and ketones [10-12]. However, alkyl halides
that are reducible via electron-transfer processes afford
poor yields and diastereoselectivity [11,12]. The electron
transfer to readily reducible electrophiles appears to be
facilitated by free conformational motion of the piperidine
ring. The retardation of this process by introduction of
bulky substituents at certain positions on the ring can
increase the yield and the stereospecificity of the reaction
[10,11].
undecylpiperidinemandelate with 85-95% ee, and two
subsequent crystallizations afforded an enantiomerically-
pure salt of 2(R)-undecylpiperidine (18a) in 36% yield (ee
> 99%). The amine rich in 2(S)- enantiomer was
regenerated from the combined mother liquor and was
crystallized as a salt of (-)-mandelic acid to afford an
enantiomerically-pure salt of 2(S)-undecylpiperidine
(18b) (Scheme-1).
Scheme 1
(a)
(d)
(b)
R'
N
N
N
R
N
CHO
R
+
18b
H2
H
15
16
17
PhCHOHCOO-
(c)
Axially substituted 2-piperidides are known to be more
stable than their equatorially substituted isomers due to
(f)
(e)
(e), 20b
(f), 21b
(g)
N
BoC
R
N
BoC
N
R
R
+
H2
A
1,3 strain [10]. Lithiation of 2-piperidides would provide
21a
20a
18a
the 6-equatorially lithiated species, which undergo
electrophilic substitution with retention of conformation
to yield preferentially the trans isomer [10]. Hence,
lithiation and subsequent alkylation of 2-alkylpiperidines
is expected to yield trans-2, 6-dialkylpiperidines, the type
of major alkaloids present in fire ant venoms [10].
PhCHOHCOO-
(g)
1. R = C11H23
2. R = C13H27
3. R = C15H31
4. R = C11H23
5. R = C13H27
6. R = C15H31
N
R
H
N
R
H
(a). Ph3P+(CH2R')Br-, NaH(60%), CH2Cl2 (b). Rh/C, Pd/C, H2, EtOH
(c). (+)-Mandelic acid, MeOH, Et2O (d). (-)-Mandalic acid, MeOH, Et2O
(e). NaOH (10%), (t-Boc)2O, THF (f). TMEDA, BuLi, -78 °C, MeI
(g). TFA, CH2Cl2, NaOH
There are three previous reports of the stereospecific
synthesis of trans-2-methyl-6-alkylpiperidines by
employing electrophilic substitution of ꢀ-lithiated
enantiomerically-pure 2-alkylpiperidine analogs [5,6,13].
In the first method, (+)-trans-2,6-dimethylpiperidine and
(+)-trans-2-methyl-6-propylpiperidine have been prepared
by the introduction of methyl and propyl side-chains,
respectively, to enantiomerically pure 2-methylalkyl-
piperidine [13]. However, our attempt to introduce a long
side-chain to lithiated N-Boc-2(S)-methylpiperidine
afforded low yield and diastereoselectivity. In the other
two methods [5,6], (-)-solenopsin A was prepared by the
Treatment of 2(S)-undecylpiperidine and 2(R)-undecyl-
piperidine with di-tert-butyldicarbonate [(Boc)2O] gave
their respective N-Boc amines in high yields. These N-
Boc-2-undecylpiperidines after lithiation were treated
with methyl iodide to yield N-Boc-2(R)-methyl-6(R)-
undecylpiperidine and N-Boc-2(S)-methyl-6(S)-undecyl-
piperidine. Removal of protecting groups of these
compounds yielded (+)-solenopsin A and (-)-solenopsin
A. In a similar manner, racemic 2-tridecylpiperidine and
2-pentadecylpiperidine were resolved to their enantiomers
as diastereomeric salts of mandelic acid and subsequently
converted to (+)-solenopsin B, (-)-solenopsin B, (+)-
solenopsin C, and (-)-solenopsin C by stereospecific
introduction of the 6-methyl group.
Isosolenopsin A, B, and C were synthesized using (R)-
and (S)-2-methylpiperidines as precursors which were
obtained by resolving racemic 2-methylpiperidines (22)
by diastereoisomeric fractional crystallization of their
mandelates [13,14]. (R)- and (S)-2-Methylpiperidines
were converted to their N-Boc-derivatives by reacting
with (Boc)2O. N-Boc-2(R)-methylpiperidine (23a) was
lithiated and treated with DMF to afford a mixture of
trans-N-Boc-2(R)-methylpiperidine-6(S)-carboxaldehyde
and cis-N-Boc-2(R)-methylpiperidine-6(R)-carboxalde-
hyde. This mixture was reacted with ylide of decyl-
triphenylphosphonium bromide in the presence of sodium
hydride to yield cis-N-Boc-2(R)-methyl-6(R)-(2-
undecenyl)piperidine (25) as the only product.
introduction of
a
methyl group to N-Boc-2(R)-
undecylpiperidine. In these cases, it appears that the large
alkyl group at C-2 adopts the more stable axial
conformation and hinders conformational motion, thereby
increasing the yield and stereospecificity of the reaction.
A practical method for the preparation of N-Boc-2(R)-
undecylpiperidine would lead to an efficient procedure for
the medium-scale synthesis of solenopsin A. Both Comins
et al. [5] and Beak et al. [6] used multi-step procedures to
synthesize this intermediate.
To achieve this goal, a method was developed to
resolve racemic 2-undecylpiperidine by fractional crystal-
lization as diastereomeric salts. Racemic 2-undecyl-
piperidine was prepared in high yields by reacting
pyridine-2-carboxaldehyde (15) with the ylide of n-decyl-
triphenylphosphonium bromide followed by catalytic
reduction of the resulting pyridine-2-(undecyl-1-ene) (16).
Racemic 2-undecylpiperidine (17) was resolved by
diastereoisomeric fractional crystallization as a salt of (+)-
mandelic acid. The first crystallization yielded 2(R)-

Jan-Feb 2008
Synthesis of Solenopsins and Isosolenopsins A, B & C.
131
Scheme-2
(c)
and detector temperatures were set up at 225° C and 250° C
respectively and the column temperature was began by holding
at 100° C for 5 min, then rising from 100° C to 180° C at 4°
C/min, holding at 180° C for 5 min. The enantiomeric purities of
compounds 1 – 12 were determined by HPLC analysis after
(a)
N
N
N
H
22
H
22a
23a
BoC
derivartization
with
(R)-(-)-1-(1-napthyl)ethylisocyanate.
(b) 22b
(c) 23b
(d) 24b
(e) 25b
(f) 26b
(g)
Derivatization was carried out by treating amines in toluene with
equimolar amounts of (R)-(-)-1-(1-napthyl)ethylisocyanate in
toluene at room temperature. Analyses of the derivartized
compounds were performed on an Agilent 1100 series
instrument equipped with a photodiode array detector operating
at 240 mm and a Chiralcel OD column (250x4.6 mm) with 0.5%
isopropyl alcohol in hexane as the mobile phase.
2-(Undecyl-1-ene)-pyridine (16, R' = C9H19). A solution of
n-decyltriphenylphosphonium bromide (48.4 g, 0.1 mol) in
anhydrous dichloromethane (500 ml) was treated with NaH
(60%, 4.0 g, 0.1 mol) at room temperature. The mixture was
stirred for 30 min, treated with pyridine-2-carboxaldehyde (15)
(10.7 g, 0.1 mol) and refluxed for 3 h. The reaction mixture was
allowed to cool, filtered, concentrated and chromatographed on
short silica gel column to give a mixture of cis- and trans-2-
(undecyl-1-ene) pyridine (17.1 g, 74%).
2-Undecylpiperidine (17, R = C11H23). The above mixture of
cis- and trans-2-(undecyl-1-ene)-pyridine (15.0 g, 65 mmol) was
dissolved in absolute ethanol (60 ml) and hydrogenated with
Pd/C (10% on carbon, 300 mg) and Rh/C (1.5 g) at 30 lbs/in2 for
12 h. The reaction mixture was filtered through Celite® and
evaporated to give a racemic mixture of 2-undecylpiperidine
(14.9 g, 96%).
(d)
N
CHO
N
CHO
BoC
BoC
N
R
24a
(e)
H
10. R = C11H23
11. R = C13H27
12. R = C15H31
(g)
(f)
N
R
N
R'
N
R
H
BoC
BoC
26a
25a
7. R = C11H23
8. R = C13H27
9. R = C15H31
(a). (+)-Mandelic acid (b). (-)-Mandelic acid (c).10% NaOH, BoC
(d).TMEDA, BuLI, DMF, -78o C (e). Ph3PCH2R'Br, NaH, CH2Cl2
(f). Pd/H2, EtOH (g). TFA, CH2Cl2
This indicates that trans-N-Boc-2(R)-methylpiperidine-
6(S)-carboxaldehyde readily isomerized to its more
thermodynamically stable 6(R)-epimer before reacting
with ylide [10]. Catalytic reduction followed by
deprotection of the amine group yielded (2R,6S)-
isosolenopsin A in good overall yield. In a similar
manner, other enantiomer of isosolenopsin A and both
enantiomers of isosolenopsin B and C were also prepared
(Scheme-2).
2(R)-Undecylpiperidine mandelate (18a, R = C11H23). A
mixture of racemic 2-undecylpiperidine (10.0 g, 41.8 mmol) and
(+)-mandelic acid (6.4 g, 42 mmol) in methanol (40 ml) was
diluted with anhydrous ether (300 ml) and left overnight at 0 °C.
The resulting fine colorless crystals of 2(R)-undecylpiperidine
mandelate were separated by filtration and recrystallized twice
from methanol/ether to afford the pure enantiomer ee >99% (5.8
g, 36%) yield. The optical purity of the amine was determined as
its N-Boc derivative by HPLC. mp 103-104 °C; [ꢀ]D24 = +53.1 (c
3.0, CHCl3).
2(R)-Undecylpiperidine (19a, R = C11H23). A solution of
2(R)-undecylpiperidine mandelate (100 mg, 0.25 mmol) in water
(3 ml) was treated with aqueous NaOH (10%, 2.0 ml) and
extracted with ether (3x5.0 ml). The organic solution was dried
EXPERIMENTAL
All air and moisture sensitive reactions were carried out under
nitrogen in either two or three necked flasks sealed with rubber
septa. Reactions at -78° C were performed using dry ice in
acetone. Column chromatography was carried out on Merck
silica gel 60 (230-400 mesh). Melting points were measured in
Uni-melt, Thomas Hoover capillary melting point apparatus and
the optical rotations were recorded on Rudolph Research
Analytical, Autopol IV polarimeter with path length 0.5 dm. The
nmr spectra were recorded on Bruker Avance DRX-400 (400
MHz for 1H nmr and 100 Mz for 13C nmr) spectrometer in
deuteriochloroform. The mass spectrometric analysis was
performed on an Agilent Series 1100 SL equipped with an ESI
source. HPLC analysis were carried out in Hewlett Packard
1100 series instrument with Chiralcel OD column using 0.1%
isopropyl alcohol in hexane as mobile phase at the rate of 0.7
ml/min. GC experiments were performed on a Hewlett-Packard
5890 gas chromatograph with FID and autosampler. Cyclodex B
capillary column (0.25 mm ID, 30m length, 0.25μm film
thickness; J & W Scientific, Folsom, CA) was used. The injector
and evaporated to give 2(R)-undecylpiperidine (58 mg). [ꢀ]D2 4
=
1
-2.9 (c 2.0, CHCl3). H nmr: ꢁ 3.01 (brd, 1H, J = 12.0 Hz), 2.58
(ddd, 1H, J = 12.0 11.6, 2.8 Hz), 2.35 (m, 1H), 1.72 (brd, 1H J =
11.2 Hz), 1.54 (m, 3H), 1.52 (m, 1H), 1.23(brs, 21H), 0.83 (t,
3H, J = 6.8 Hz). Anal. Calcd. for C16H33N: C, 80.26; H, 13.89;
N, 5.85. Found; C, 80.31; H, 13.84; N, 5.87.
N-Boc-2(R)-Undecylpiperidine (20a,
R = C11H23). A
solution of 2(R)-undecylpiperidine mandelate (4.0 g, 10.2 mmol)
in 10% NaOH (60 ml) was treated with di-tert-butyldicarbonate
(2.5 g, 11.5 mmol) in THF (40 ml) dropwise. The solution was
stirred for 6 h at room temperature, concentrated in vacuum and
extracted with diethyl ether (3x100 ml). The organic layer was
dried over MgSO4, concentrated, and chromatographed on silica
gel to give N-Boc-2(R)-undecylpiperidine as colorless oil (3.1 g,
89%). [ꢀ]D2 4 = -19.8 (c 4.4, CH2Cl2), lit [15] [ꢀ]D24 = -21.2 (c 4.4,
CH2Cl2). 1H nmr: ꢁ 4.16 (brs, 1H), 3.93 (m, 1H), 2.70 (brt, J =
12.8 Hz, 1H), 1.62 (m, 2H), 1.52 (m, 4H), 1.42 (s, 9H), 1.23
(brs, 20H), 0.84 (t, J = 6.4 Hz, 3H).

132
H. M. T. Bandara Herath, N. P. Dhammika Nanayakkara
Vol 45
N-Boc-2(R)-Methyl-6(R)-undecylpiperidine (21a,
R
=
preparation of (20a) to yield N-Boc-2(S)-undecylpiperidine as
1
C11H23). A solution of N-Boc-2(R)-undecylpiperidine (3.0 g, 8.8
mmol) in anhydrous ether (75 ml) was cooled to -78 °C and
treated with tetramethylethylenediamine (TMEDA) (2.0 ml) and
s-BuLi (10.5 ml, 13.5 mmol) sequentially. The mixture was
slowly warmed to -20 °C, stirred for 30 min and cooled again to
-78 °C. MeI (2.0 ml) was added dropwise to the mixture, stirred
for 15 min at -78 °C, and allowed to slowly warm to room
temperature. The reaction mixture was quenched with water (50
ml) and extracted with ether (3x 100 ml). The ether extract was
dried, evaporated and chromatographed on silica gel to give N-
colorless oil (2.94 g, 84%). [ꢀ] D26 = +19.3 (c 4.7, CHCl3). H
nmr: ꢁ 4.16 (brs, 1H), 3.92 (m, 1H), 2.71 (brt, 1H, J = 12.4 Hz),
1.62 (m, 2H), 1.52 (m, 4H), 1.42 (s, 9H), 1.23 (brs, 20H), 0.85
(t, 3H, J= 6.4 Hz).
N-Boc-2(S)-Methyl-6(S)-undecylpiperidine (21b,
R =
C11H23). N-Boc-2(S)-Undecylpiperidine (2.8 g, 8.2 mmol)
reacted with MeI (2.0 ml) as described previously in (21a) to
give N-Boc-2(S)-methyl-6(S)-undecylpiperidine (2.23 g, 79%).
[ꢀ]D26 = +29.1 (c 3.0, CHCl3). H nmr: ꢁ 3.90 (m, 1H), 3.77 (m,
1
1H), 1.80 (m, 2H), 1.62 (m, 4H), 1.52 (m, 2H), 1.45 (s, 9H),
1.25 (brs, 28H), 1.22 (d, 3H, J = 7.8 Hz), 0.87 (t, 3H, J = 6.4
Hz).
Boc-2(R)-methyl-6(R)-undecylpiperidine (2.51 g, 80%). [ꢀ]D2 4
=
1
-28.3 (c 4.7, CH2Cl2), lit [15] [ꢀ]D2 4 = -26.3 (c 4.7, CH2Cl2). H
nmr: ꢁ 3.91 (m, 1H), 3.78 (m, 1H), 1.82 (m, 2H), 1.62(m, 4H),
1.51 (m, 2H), 1.46 (s, 9H), 1.25 (brs, 28H), 1.23(d, 3H, J = 7.8
Hz), 0.88 (t, 3H, J = 6.4 Hz).
2(S)-Methyl-6(S)-undecylpiperidine [(2S,6S)-solenopsin A]
(4, R = C11H23). N-Boc-2(S)-Methyl-6(S)-undecylpiperidine
(2.20 g, 6.2 mmol) was treated with TFA as described earlier
preparation of (1) to give 2(S)-methyl-6(S)-undecylpiperidine as
colorless oil (1.53 g, 97%, ee > 99%). [ꢀ]D26 = +0.88 (c 3.0,
2(R)-Methyl-6(R)-undecylpiperidine [(2R, 6R)-solenopsin
A] (1, R = C11H23). A solution of N-Boc-2(R)-methyl-6(R)-
undecylpiperidine (2.5 g, 7.0 mmol) in CH2Cl2 (50 ml) was
treated with TFA (5.0 g) for 6 h at room temperature. The
solvent was removed under vacuum and the oil obtained was
dissolved in anhydrous ether (30 ml) and neutralized with NaOH
powder (2.0 g). The mixture was filtered and evaporated to give
trans-2(R)-methyl-6(R)-undecylpiperidine as colorless oil (1.7g,
96%, ee > 99%) [ꢀ]D26 = -0.87 (c 1.2, CHCl3), lit[15] [ꢀ]D2 4 = -1.2
1
CHCl3), lit [3] [ꢀ]D20 = +2.5 (c 3.0, CHCl3). H nmr: ꢁ 3.07 (m,
1H), 2.88 (m, 1H), 1.66 (m, 2H), 1.56 (m, 1H), 1.43 (m, 1H),
1.26 (brs, 22H), 1.08 (d, 3H, J = 6.4 Hz), 0.89 (t, 3H, J = 6.8
Hz). Anal. Calcd. for C17H35N: C, 80.56; H, 13.92; N, 5.53.
Found; C, 80.54; H, 13.90; N, 5.56.
(2S,6S)-Solenopsin A. HCl. (2S,6S)-Solenopsin A (1.0 g)
was treated with HCl, as described earlier in (2R,6R)-Solenopsin
A to give colorless crystals of (2S,6S)-solenopsin A.HCl (0.95 g,
83%); mp = 144-146 °C, lit [16] mp 146 °C; [ꢀ]D26 = +7.7 (c 1.5,
CHCl3), lit [3,16] [ꢀ]D20 = +7.5 (c, 1.3, CHCl3). 1H nmr: ꢁ 3.49
(brs, 1H), 3.23 (brs, 1H), 1.93 (m, 4H), 1.60 (m, 6H), 1.43 (d,
3H, J = 6.4, 3H), 1.20 (brs, 16H), 0.83 (t, 3H, J = 7.2 Hz).
1
(c 1.2, CHCl3). H nmr: ꢁ 3.06 (m, 1H), 2.87 (m, 1H), 1.63 (m,
2H), 1.54(m, 1H), 1.43 (m, 1H), 1.25 (brs, 22H), 1.07 (d, 3H, J =
6.4 Hz), 0.87 (t, 3H, J = 6.8 Hz). Anal. Calcd. for C17H35N: C,
80.56; H, 13.92; N, 5.53. Found; C, 80.53; H, 13.89; N, 5.57.
(2R,6R)-Solenopsin A. HCl. A solution of (2R, 6R)-
solenopsin A (1.0 g) in ethanol (5.0 ml), was treated with HCl
(0.5 ml) and diluted with diethyl ether (20 ml) to give colorless
crystals of solenopsin A.HCl. (0.97 g, 85%). mp 142-143 °C, lit
[5] mp 141-142 °C, [ꢀ]D2 4 = -7.6 (c 1.5, CHCl3), lit [5] [ꢀ]D2 4 = -
7.6 (c 0.5, CHCl3). 1H nmr: ꢁ 3.47 (brs, 1H), 3.21 (brs, 1H),
1.91 (m, 4H), 1.58 (m, 6H), 1.41 (d, 3H, J = 6.8), 1.18 (br.s,
16H), 0.81 (t, 3H, J = 6.8 Hz).
cis- and trans-2-(Tridecyl-1-ene)-pyridine (16, R' =
C11H23). n-Dodecyltriphenylphosphonium bromide (51.2
g, 0.1 mol) and pyridine-2-carboxaldehyde (22) (10.7 g,
0.1 mol) were reacted as described earlier (16, R' = C9H19)
to give a mixture of cis- and tran-2-(tridecyl-1-ene)-
pyridine (18.7 g, 72%).
2-Tridecylpiperidine (17, R = C13H27). The mixture of cis-
and trans-2-(tridecyl-1-ene)pyridine (18.2 g, 70 mmol) was
hydrogenated with Pd/C (350 mg) and Rh/C (1.5 g), as
described earlier in preparation of (17, R = C11H23) to yield
racemic 2-tridecylpiperidine (17.8 g, 95%).
2(R)-Tridecylpiperidine mandelate (18a, R = C13H27). The
racemic mixture of 2-tridecylpiperidine (15.0 g, 56 mmol) was
crystallized with (+)-mandelic acid (8.5 g, 56 mmol) as
described in (18a, R = C11H23) to give (+)-2(R)-tridecylpiperi-
dine mandelate (8.6 g, 37%, ee > 99%). mp 106 – 107 °C, [ꢀ]D2 4
= +45.3 (c 3.0, CHCl3).
2(S)-Undecylpiperidine mandelate (18b, R = C11H23). The
combined mother liquors from 4.2.3. was evaporated to dryness,
treated with aqueous NaOH (10%, 50 ml) and extracted with
ether (3x 100 ml). The ether layer was evaporated to give an
amine rich in 2(S)-undecylpiperidine (6.25 g, 26 mmol). This
amine was treated with (-)-mandelic acid (4.2 g, 27.5 mmol) in
methanol (25 ml), diluted with ether (150 ml) and kept at 0° C
overnight. The resulting fine colorless crystals were separated by
filtration and recrystallized two more times with methanol/ether
to afford pure 2(S)-undecylpiperidine mandelate (4.6 g, 45.5%).
mp 103 – 104° C, [ꢀ]D26 = -52.7 (c 3.0, CHCl3).
2(R)-Tridecylpiperidine (19a, R = C13H27). 2(R)-Tridecyl-
piperidine mandelate (100 mg, 0.24 mmol) was treated with
10% NaOH (2.0 ml) to give 2(R)-tridecylpiperidine as a gum (61
mg, 95%). [ꢀ]D24 = -3.1 (c 2.0, CHCl3). 1H nmr: ꢁ 3.00 (brd, 1H, J
= 12.0 Hz), 2.56 (ddd, 1H, J = 12.0 11.2, 2.8 Hz), 2.36 (m, 1H),
1.71(brd, 1H, J = 10.8 Hz), 1.58 (brd, 1H, J = 12.4 Hz), 1.52
(brd, 1H, J = 11.6 Hz), 1.36 (m, 2H), 1.23 (brs, 25H), 0.82 (t,
3H, J = 6.8 Hz). Anal. Calcd. for C18H37N: C, 80.82; H, 13.94;
N, 5.24. Found; C, 80.83; H, 13.91; N, 5.27.
N-Boc-2(R)-Tridecylpiperidine (20a, R = C13H27). 2(R)-
Tridecylpiperidine mandelate (8.4 g, 20 mmol) was treated with
di-tert-butyldicarbonate (4.8 g, 22 mmol) to afford N-Boc-2(R)-
tridecylpiperidine (6.2 g, 84%). [ꢀ]D2 4 = -18.3 (c 4.6, CHCl3). 1H
nmr: ꢁ 4.17 (brs, 1H), 3.93 (m, 1H), 2.72 (dd, 1H, J = 12.4, 13.2
2(S)-Undecylpiperidine (19b, R = C11H23). A solution of
(-)-2-undecylpiperidine mandelate (100 mg, 0.25 mmol) in water
(3 ml) was treated with aqueous NaOH (10%, 2.0 ml) and
extracted with ether (3x5.0 ml). The organic solution was dried
and evaporated to give 2(S)-undecylpiperidine (56 mg). [ꢀ]D26
=
1
+3.0 (c 3.9, CHCl3). H nmr: ꢁ 3.00 (brd, 1H, J = 12.0 Hz), 2.54
(ddd, 1H, J = 11.6 11.6, 2.4 Hz), 2.35 (m, 1H), 1.70 (brd, 1H, J =
10.8 Hz), 1.57 (brd, 1H, J = 12.4 Hz), 1.50 (brd, 1H, J = 11.6
Hz), 1.36 (m, 2H), 1.21 (brs, 21H), 0.81 (t, 3H, J = 6.8 Hz).
Anal. Calcd. for C16H33N: C, 80.26; H, 13.89; N, 5.85. Found; C,
80.29; H, 13.86; N, 5.88.
N-Boc-2(S)-Undecylpiperidine (20b, R = C11H23). 2(S)-
Undecylpiperidine mandelate (4.0 g, 10.2 mmol) was treated
with di-tert-butyldicarbonate (2.5 g, 11.5 mmol) as described in

Jan-Feb 2008
Synthesis of Solenopsins and Isosolenopsins A, B & C.
133
Hz), 1.63 (m, 2H), 1.53 (m, 4H), 1.43 (s, 9H), 1.24 (brs, 24H),
0.86 (t, 3H, J = 6.4 Hz).
similar work up procedure described in the synthesis of
compound 1 to give 2(S)-methyl-6(S)-tridecylpiperidine (1.26 g,
85%, ee > 99%): [ꢀ]D26 = +0.82 (c 4.6, CHCl3). H nmr: ꢁ 3.06
1
N-Boc-2(R)-Methyl-6(R)-tridecylpiperidin (21a,
R
=
C13H27). N-Boc-2(R)-Tridecylpiperidine (5.0 g, 13.6 mmol) was
reacted with MeI (4.0 ml) as described earlier in preparation of
(21a, R = C11H23) to give N-Boc-2(R)-methyl-6(R)-tridecyl-
piperidine (3.91 g, 75%). [ꢀ]D26 = -27.1 (c 3.0, CHCl3). 1H nmr: ꢁ
3.89 (m, 1H), 3.75 (m, 1H), 1.79 (m, 2H), 1.60 (m, 4H), 1.43 (s,
9H), 1.22 (brs, 24H), 1.20 (d, 3H, J = 6.8 Hz), 0.85 (t, 3H, J =
7.2 Hz).
(m, 1H), 2.88 (m, 1H), 1.63 (m, 2H), 1.53 (m, 1H), 1.44 (m,
1H), 1.25 (brs, 26H), 1.08 (d, 3H, J = 6.4 Hz), 0.87 (t, 3H, J =
6.8 Hz). Anal. Calcd. for C19H39N: C, 81.06; H, 13.96; N, 4.98.
Found; C, 81.03; H, 13.98; N, 5.01.
(2S, 6S) Solenopsin B. HCl. (2S, 6S)-Solenopsin B (1.0 g,
3.47 mmol) was treated with HCl to give solenopsin B.HCl
1
(0.89 g, 81%). mp 145-146 °C; [ꢀ]D26 = +7.4 (c 3.5, CHCl3). H
2(R)-Methyl-6(R)-tridecylpiperidine [(2R,6R)-solenopsin
B] (2, R = C13H27). N-Boc-2(R)-Methyl-6(R)-tridecylpiperidine
(3.5 g, 9.2 mmol) was reacted with TFA (6.0g) to give 2(R)-
nmr: ꢁ 3.48 (brs, 1H), 3,22 (brs, 1H), 1.91 (m, 3H), 1.66 (m,
1H), 1.59 (m, 3H), 1.44 (d, 3H, J = 6.8 Hz), 1.21(brs, 23H), 0.81
(t, 3H, J = 6.8 Hz).
methyl-6(R)-tridecylpiperidine (2.45 g, 94%, ee > 99%): [ꢀ]D26
=
Cis- and trans-2-(Pentadecyl-1-ene)-pyridine (16, R' =
C13H27). n-Tetradecyltriphenylphosphonium bromide (64 g,
0.1 mol) reacted with pyridine-2-carboxaldehyde (22)
(10.7 g, 0.1 mol) as described in the synthesis of 16 to give
a mixture of cis- and trans-2-(pentadecyl-1-ene)pyridine
(19.8, 69%).
2-Pentadecylpiperidine (17, R = C15H31). The above mixture
of cis- and trans-2-(pentadecyl-1-ene)pyridine (19.0 g, 66 m
mol) was reduced with Pd/C (500 mg) and Rh/C (1.5 g) at 30
lbs/in2 to give (+)-2-pentadecylpiperidine (18.8 g, 96%).
2(R)-Pentadecylpiperidine mandelate (18a, R = C15H31).
2(R)-Pentadecylpiperidine (18.0 g, 61 m mol) was crystallized
with (+)-mandelic acid (9.27g, 61 m mol) to afford (+)-2-
pentadecyl piperidine mandelate (8.95g, 33%, ee > 99%). mp
108-109 °C; [ꢀ]D24 = +42.2 (c 3.5, CHCl3).
1
-0.63 (c 2.0, EtOH), lit [17] [ꢀ] D23 = -0.51 (c 1.97, EtOH). H
nmr: ꢁ 3.06 (m, 1H), 2.8 8(m, 1H), 1.63 (m, 2H), 1.55 (m, 1H),
1.43 (m, 1H), 1.25 (brs, 26H), 1.08 (d, 3H, J = 6.4 Hz), 0.88 (t,
3H, J = 6.8 Hz). ). Anal. Calcd. for C19H39N: C, 81.06; H, 13.96;
N, 4.98. Found; C, 81.03; H, 13.94; N, 5.03.
(2R,6R)-Solenopsin B. HCl. (2R,6R)-Solenopsin B (1.0 g,
3.47 mmol) in ethanol (5 ml) was treated with Conc. HCl (0.5
ml) to give solenopsin B.HCl (0.94 g, 85%); mp 146-147 °C;
[ꢀ]D24 = -7.3 (c 3.5, CHCl3). H nmr: ꢁ 3.50 (brs, 1H), 3.24 (brs,
1
1H), 1.93 (m, 2H), 1.69 (m, 2H), 1.60(m, 2H), 1.44 (d, 3H, J =
6.8 Hz), 1.21 (brs, 24H), 0.84 (t, 3H, J = 6.8 Hz).
2(S)-Tridecylpiperidine mandelate (18b, R = C13H27). The
combined mother liquors from preparation of (18a, R = C13H27)
was concentrated, basified with 10% NaOH (50 ml) and
extracted with diethyl ether (3x100 ml) to yield a base rich in
2(S)-tridecylpiperidine (6.72 g). This base was treated with (-)-
mandelic acid (4.5 g) in methanol (30 ml), added ether (150 ml)
and left overnight at 0 °C to afford 2(S)-tridecylpiperidine
2(R)-Pentadecylpiperidine (19a, R = C15H31). 2(R)-Penta-
decylpiperidine mandelate (100 mg, 0.22 mmol) was basified
with NaOH as described earlier to give 2(R)-pentadecyl-
piperidine (54 mg, 83%). [ꢀ]D24 = -3.3 (c 2.0, CHCl3). 1H nmr: ꢁ
3.00 (brd, 1H, J = 12.0 Hz), 2.56 (ddd, 1H, J = 11.6, 11.2, 2.4
Hz), 2.36 (m, 1H), 1.72 (brd, 1H, J = 11.2 Hz), 1.56 (m, 3H),
1.34 (m, 3H), 1.23 (brs, 27H), 0.82 (t, 3H, J=6.8 Hz). Anal.
Calcd. for C20H41N: C, 81.28; H, 13.98; N, 4.74. Found; C,
81.30; H, 13.94; N, 4.77.
mandelate 28, (5.81, 42%, ee > 99). mp 106-107 °C; [ꢀ]D26
=
-45.0 (c 3.0, CHCl3).
2(S)-Tridecylpiperidine (19b, R = C13H27). 2(S)-Tridecyl-
piperidine mandelate (100 mg, 0.24 mmol) was converted to
2(S)-tridecylpiperidine (59 mg, 92%) as described in
preparation of 19b (R = C11H23). [ꢀ]D26 = +3.2 (c 2.0, CHCl3).
1H nmr: ꢁ 2.99 (brd, 1H, J = 11.6 Hz), 2.55 (ddd, 1H, J = 11.6
11.2, 2.4 Hz), 2.34(m, 1H), 1.70 (brd, 1H, J = 10.8 Hz), 1.57
(brd, 1H, J = 12.4 Hz), 1.50 (brd, 1H, J = 11.6 Hz), 1.35 (m,
2H), 1.25 (brs, 25H), 0.81(t, 3H, J = 6.8 Hz). ). Anal. Calcd.
for C18H37N: C, 80.82; H, 13.94; N, 5.24. Found; C, 80.86; H,
13.92; N, 5.24.
N-Boc-2(S)-Tridecylpiperidine (20b, R = C13H27). 2(S)-
Tridecylpiperidine mandelate (5.0 g, 12 mmol) was treated with
di-tert-butyldicarbonate (3.0 g, 14 mmol), followed by the
similar work up procedure given in 20a (R = C11H23) to give N-
Boc-2(S)-tridecylpiperidine (3.56 g, 81%). [ꢀ]D26 =18.5 (c 4.0,
CHCl3), 1H nmr: ꢁ 4.15 (brs, 1H), 3.91 (m, 1H), 2.70 (dd, 1H, J
= 12.0, 13.2 Hz), 1.61 (m, 2H), 1.51 (m, 4H), 1.41 (s, 9H), 1.22
(brs, 24H), 0.84 (t, 3H, J = 6.4 Hz).
N-Boc-2(R)-Pentadecylpiperidine (20a, R = C15H31). 2(R)-
Pentadecylpiperidine mandelate (8.5 g, 19 mmol) reacted with
di-tert-butyldicarbonate (4.1 g, 19 mmol) in THF (40 ml) as
described in the synthesis of 20a (R = C11H23) to give N-Boc-
2(R)-pentadecylpiperidine (6.42 g, 85%). [ꢀ] D24 = -17.1 (c 5.5,
CHCl3). 1H nmr: ꢁ 4.17(brs, 1H), 3.93 (m, 1H), 2.72(dd, 1H, J =
12.8, 12.4 Hz), 1.63(m, 2H), 1.54(m, 4H), 1.44(s, 9H), 1.24(brs,
24H), 0.86(t, 3H, J = 6.4 Hz).
N-Boc-2(R)-Methyl-6(R)-pentadecylpiperidine (21a, R =
C15H31). N-Boc-2(R)-pentadecylpiperidine (6.0 g, 15.2 mmol)
was reacted with MeI (3 ml) under the similar conditions used in
the preparation of 20a (R = C11H23), to give N-Boc-2(R)-methyl-
6(R)-pentadecyl piperidine (4.21, 67%). [ꢀ] D26 = -23.0 (c 2.5,
1
CHCl3). H nmr: ꢁ 3.83 (m, 1H), 3.70 (m, 1H), 1.74 (m, 2H),
N-Boc-2(S)-Methyl-6(S)-tridecylpiperidine (21b,
R
=
1.54 (m, 4H), 1.36 (s, 9H), 1.1 6 (brs, 28H), 1.13 (d, 3H, J = 6.6
Hz), 0.78 (t, 3H, J = 6.8 Hz).
C13H27). N-Boc-2(S)-Tridecylpiperidine (3.0 g, 8.17 mmol) was
reacted with MeI (2 ml) as described in preparation of 21b (R =
C11H23) to give N-Boc-2(S)-Methyl-6(S)-tridecylpiperidine (2.21
g, 71%). [ꢀ]D26 = +26.9 (c 3.0, CHCl3). 1H nmr: ꢁ 3.89 (m, 1H),
3.76 (m, 1H), 1.79 (m, 2H), 1.60 (m, 4H), 1.43(s, 9H), 1.23 (brs,
24H), 1.20 (d, 3H, J = 6.8 Hz), 0.85 (t, 3H, J = 7.2 Hz).
2(S)-Methyl-6(S)-tridecylpiperidine [(2S, 6S)-solenopsin
B] (5, R = C13H27). N-Boc-2(S)-Methyl-6(S)-tridecylpiperidine
(2.0 g, 5.25 mmol) was treated with TFA (4.0 g) followed by the
2(R)-Methyl-6(R)-pentadecylpiperidine [(2R,6R)-solenop-
sin C] (3, R = C15H31). N-Boc-2(R)-Methyl-6(R)-pentadecyl-
piperidine (4.0 g, 9.78 mmol) was reacted with TFA (4.0 g) as
described in the final step of the synthesis of compound 1, to
give trans-2(R)-methyl-6(R)-pentadecylpiperidine (2.63 g, 87%,
ee > 99%). [ꢀ]D26 = -0.63 (c 5.0, CHCl3). 1H nmr: ꢁ 3.05 (m, 1H),
2.87(m, 1H), 1.62(m, 2H), 1.54 (m, 2H), 1.44 (m, 1H), 1.37 (m,
1H), 1.25 (brs, 28H), 1.07(d, 3H, J = 6.8 Hz), 0.87 (t, 3H, J = 6.8

134
H. M. T. Bandara Herath, N. P. Dhammika Nanayakkara
Vol 45
Hz). Anal. Calcd. for C21H43N: C, 81.48; H, 14.00; N, 4.52.
Found; C, 81.50; H, 13.98; N, 4.51.
methylpiperidine mandelate were separated by filtration and
recrystallized twice from methanol/ether to afford 2(R)-
methylpiperidine mandelate ee > 99% (35.6 g, 39%). The
enantiomeric purity of compounds was determined by retention
time and the peak area of GC chromatogram of the acetylated
derivative of each enantiomer.
(2R,6R)-Solenopsin C. HCl. (2R,6R)-Solenopsin C (1.0g,
3.23 m mol) was treated with HCl, to give colorless crystals of
solenopsin C. HCl (0.91 g, 81%). mp 136-138 °C; [ꢀ]D24 = -7.1 (c
2.0, CHCl3). 1H nmr: ꢁ 3.49 (brs, 1H), 3,23(br.s, 1H), 1.92 (m,
2H), 1.68 (m, 2H), 1.59 (m, 2H), 1.42 (d, 3H, J = 6.4 Hz), 1.19
(brs, 28H), 0.82 (t, 3H, J = 6.8 Hz).
2(S)-Pentadecylpiperidine mandelate (18b, R = C15H31).
The combined mother liquors after the recrystallization of 18a
(R = C15H31) was basified and extracted as described earlier in
method (18b, R = C11H23) to yield a base rich in 2(S)-penta-
decylpiperidine. This base was crystallized with (-)-mandelic
acid to afford 2(S)-pentadecylpiperidine mandelate (7.1g, 46%,
ee > 99). mp 108-109 °C; [ꢀ]D24 = -42.1 (c 3.0, CHCl3).
2(S)-Pentadecylpiperidine (19b, R = C15H31). 2(S)-Penta-
decylpiperidine mandelate (100 mg, 0.22 mmol) was basified
with 10% NaOH (2.0 ml) and extracted with ether (3x 5.0 ml) to
give 2(S)-pentadecylpiperidine (56 mg, 86%). [ꢀ] D24 = +3.4 (c
5.0, CHCl3). 1H nmr: ꢁ 3.00 (brd, 1H, J = 12.0 Hz), 2.57 (dd, 1H,
J = 11.2, 10.4Hz), 2.36 (m, 1H), 1.72 (brd, 1H, J = 11.6 Hz),
1.56(m, 3H), 1.34(m, 3H), 1.20(brs, 27H), 0.83(t, 3H, J = 6.4
Hz). Anal. Calcd. for C20H41N: C, 81.28; H, 13.98; N, 4.74.
Found; C, 81.29; H, 13.99; N, 4.73.
N-Boc-2(S)-Pentadecylpiperidine (20b, R = C15H31). 2(S)-
Pentadecylpiperidine mandelate (6.5 g, 14.6 mmol) was
derivatized with di-tert-butyldicarbonate (3.2 g, 14.6 mmol)
followed by the similar procedure used in the synthesis of 20a
(R = C11H23), to give N-Boc-2(S)-pentadecylpiperidine (5.02,
87%). [ꢀ] D24 = +17.3 (c 4.8, CHCl3). 1H nmr: ꢁ 4.17 (brs, 1H),
3.93(m, 1H), 2.72 (dd, 1H, J = 12.8, 12.4 Hz), 1.63 (m, 2H),
1.53 (m, 4H), 1.43 (s, 9H), 1.23 (brs, 24H), 0.86 (t, 3H, J = 6.4
Hz).
2(R)-methylpiperidine mandelate. mp 119-120 °C; [ꢀ]D24
+60.0 (c 2.5, MeOH). Lit [13] [ꢀ]D24 = +60.0 (c 2.5, MeOH).
N-Boc-2(R)-Methylpiperidine (22a). A solution of di-tert-
=
butyldicarbonate (21.8, 100 mmol) in THF (100 ml) was added
dropwise to
a stirred mixture of 2(R)-methylpiperidine
mandelate (25.1 g, 100 mmol) and 10% aqueous NaOH (100
ml). The reaction mixture was stirred for 6 h at room
temperature, concentrated in vacuum and extracted with diethyl
ether (3x150 ml). The ether extract was dried over MgSO4,
evaporated and chromatographed over silica gel to give N-Boc-
2(R)-methylpiperidine (18.3 g, 92%). [ꢀ]D2 4 = -50.7 (c 1.0,
CHCl3). Lit [13] [ꢀ]D = -51.0 (c 0.83, CHCl3). 1H nmr: ꢁ 4.22
(m, 1H), 3.77 (brd, 1H, J = 13.2 Hz), 2.66 (ddd, 1H, J = 13.2,
12.8, 2.8 Hz), 1.44 (m, 4H), 1.30 (s, 9H), 1.25 (m, 2H), 0.97 (d,
3H, J = 7.2 Hz).
N-Boc-2(R)-Methylpiperidine-6-carboxaldehyde (24a). A
solution of N-Boc-2(R)-methylpiperidine (10 g, 50.2 mmol) in
anhydrous ether (200 ml) was cooled to -78 °C and treated with
TMEDA (8.0 ml) and s-BuLi (20 ml, 1.4 M) sequentially. The
mixture was slowly warmed to -20 °C, stirred for 30 min, cooled
again to -78 °C and treated with DMF (4.4 g, 60 mmol)
dropwise. The reaction mixture was stirred for 15 min at -78 °C,
and allowed to warm to room temperature. The reaction was
quenched with water (100 ml) and extracted with ether. The
ether extract was dried, evaporated and chromatographed on
silica gel to give the mixture of cis- and trans-N-Boc-2(R)-
methylpiperidine-6-caboxaldehyde (10.2 g, 89%). N-Boc-2(R)-
Methylpiperidine-6(S)-carboxaldehyde (61%). 1H nmr: ꢁ 9.28
(1H, s), 4.26 (m, 1H), 3.61(m, 1H), 1.63 (m, 6H), 1.45 (s, 9H),
1.11 (d, 3H, J = 6.8 Hz).
N-Boc-2(S)-Methyl-6(S)-pentadecylpiperidine (21b, R =
C15H31). N-Boc-2(S)-Pentadecylpiperidine (4.5 g, 11.4 mmol)
was reacted with MeI (2 ml) as described in 21a (R = C11H23), to
give N-Boc-2(S)-methyl-6(S)-pentadecylpiperidine (2.98 g,
64%). [ꢀ]D26 = +24.1 (c 2.0, CHCl3). 1H nmr: ꢁ 3.84 (m, 1H), 3.71
(m, 1H), 1.74 (m, 2H), 1.55 (m, 4H), 1.38 (s, 9H), 1.18 (brs,
28H), 1.14 (d, 3H, J = 6.6 Hz), 0.80 (t, 3H, J = 6.8 Hz).
2(S)-Methyl-6(S)-pentadecylpiperidine [(2S,6S)-solenopsin
N-Boc-2(R)-Methylpiperidine-6(R)-carboxaldehyde (26%).
1H nmr: ꢁ 9.56 (s, 1H), 4.52 (m, 1H), 4.34 (m, 1H), 2.27 (brd,
1H, J = 12.8 Hz), 1.58 (m, 5H), 1.43 (s, 9H), 1.02 (d, 3H, J = 6.8
Hz).
N-Boc-2(R)-Methylpiperidine-6(S)-undecan-1-ene (25a,
R'= C9H19). A solution of n-decyltriphenyl phosphonium
bromide (12.8 g) in dichloromethane (100 ml) was treated with
equal molar amount of NaH (60%) at room temperature for 30
min. An equal molar amount of N-Boc-2(R)-methylpiperidine-
6(S)-caboxaldehyde (6.0 g) was added to the reaction mixture
and refluxed for 3 h. The reaction mixture was allowed to cool,
filtered through Celite® and chromatographed on silica gel to
give N-Boc-2(R)-methylpiperidine-6-(S)-undecan-1-ene (6.8 g,
73%). N-Boc-2(R)-Methylpiperidine-6(R)-caboxaldehyde also
yielded N-Boc-2(R)-methylpiperidine-6(S)-undecan-1-ene under
C] (6,
R = C15H31). N-Boc-2(S)-Methyl-6(S)-pentadecyl-
piperidine (2.5 g, 6.1 mmol) was treated with TFA (2.5 g) and
neutralized with NaOH powder (2.0 g) to give 2(S)-methyl-6(S)-
pentadecylpiperidine (1.62 g, 86%, ee > 99%). [ꢀ]D26 = +0.60 (c
5.0, CHCl3). 1H nmr: ꢁ 3.07 (m, 1H), 2.88 (m, 1H), 1.64 (m, 2H),
1.55 (m, 2H), 1.45 (m, 1H), 1.37 (m, 1H), 1.25 (brs, 28H), 1.08
(d, 3H, J = 6.8 Hz), 0.88 (t, 3H, J = 6.8 Hz). Anal. Calcd. for
C21H43N: C, 81.48; H, 14.00; N, 4.52. Found; C, 81.52; H,
13.97; N, 4.51.
(2S,6S)-Solenopsin C. HCl. (2S,6S)-Solenopsin C (1.0 g,
3.23 mmol) in ethanol (5.0 ml) was treated with Conc. HCl (0.5
ml) and recrystalized with ethanol/ether to give colorless needles
of (2S,6S)-solenopsin C. HCl (0.93, 83%). mp 138-140 °C; [ꢀ]D24
= +7.2 (c 2.0, CHCl3). 1H nmr: ꢁ 3.47 (brs, 1H), 3,21 (brs, 1H),
1.91 (m, 2H), 1.66 (m, 2H), 1.58 (m, 2H), 1.41(d, 3H, J = 6.4
Hz), 1.18 (brs, 28H), 0.80 (t, 3H, J = 6.8 Hz).
1
identical conditions. H nmr: ꢁ 5.61 (dd, 1H, J = 10.8, 9.2 Hz),
5.27 (m, 1H), 4.90 (m, 1H), 4.28 (m, 1H), 2.07 (m, 2H), 1.63 (m,
6H), 1.45 (s, 9H), 1.25 (brs, 14H), 1.18 (d, 3H, J = 7.2 Hz), 0.89
(t, 3H, J = 6.8 Hz).
N-Boc-2(R)-Methyl-6(S)-undecylpiperidine (26a,
R =
C11H23). A solution of N-Boc-2(R)-methylpiperidine-6(S)-
undecan-1-ene (6.0 g) in ethanol (50 ml) was hydrogenated with
Pd/C (10%) catalyst (0.70 g) to give N-Boc-2(R)-methyl-6(S)-
undecylpiperidine (5.7 g, 96%). 1H nmr: ꢁ 3.04 (m, 1H), 2.87(m,
1H), 1.87 (m, 4H), 1.72 (m, 2H), 1.55 (m, 2H), 1.50 (d, 3H, J =
6.0 Hz), 1.18 (brs, 30H), 0.82 (t, 3H, J = 6.8 Hz).
2(R)-Methylpiperidine mandelate. Racemic 2-methyl-
piperidine (36.0 g, 36.2 mmol) was dissolved in methanol (125
ml) added equimolar amount of (+) mandelic acid (55 g) and the
mixture was cooled to 0 °C, added ether (700 ml) to the mixture
and kept at 0 °C overnight. The fine colorless crystals of (+)-2-

Jan-Feb 2008
Synthesis of Solenopsins and Isosolenopsins A, B & C.
135
2(R)-Methyl-6(S)-undecylpiperidine. (7) [(2R,6S)-isosolen-
opsin A]. N-Boc-2(R)-Methyl-6(S)-undecyl piperidine (2.5 g,
7.0 mmol )in CH2Cl2 (50 ml) was treated with TFA (5.0 g) for 6
h at room temperature and the similar work up procedure was
followed up as described in the synthesis of Solenopsin A, B and
N-Boc-2(R)-Methylpiperidine-6(S)-tridecan-1-ene (25a, R'
= C11H23). A mixture of cis- and trans-N-Boc-2-methyl-
piperidine-6-carboxaldehyde (3.0 g) (24a) was treated with
n-dodecyltriphenylphosphonium bromide (6.8 g) in the presence
of NaH (0.5 g) as described in 25a, (R' = C9H19) to yield N-Boc-
2(R)-methylpiperidine-6(S)-tridecan-1-ene (3.45 g, 69%). 1H
nmr: ꢁ 5.63 (dd, 1H, J = 10.8, 9.2 Hz), 5.32 (m, 1H), 4.92 (m,
1H), 4.31(m, 1H), 2.12 (m, 2H), 1.64 (m, 8H), 1.45 (s, 9H), 1.25
(brs, 16H), 1.20 (d, 3H, J = 7.2 Hz), 0.87 (t, 3H, J = 6.8 Hz).
(2R,6S)-Isosolenopsin B (8). Hydrogenation of N-Boc-2(R)-
methylpiperidine-6(S)-tridecan-1-ene (3.2 g) (25a) followed by
deprotection with TFA (1 ml) yielded trans-2(R)-methyl-6(S)-
tridecylpiperidine as a pale yellow oil (2.06 g, ee > 98%). [ꢀ]D24
C
to give trans-2(R)-methyl-6(S)-undecylpiperidine as a
colorless oil (1.7g. 96%, ee > 99%). [ꢀ]D24 = -3.6 (c 2.5, CHCl3),
1H nmr: ꢁ 2.58 (m, 1H), 2.44 (m, 1H), 1.73 (m, 1H), 1.55 (m,
2H), 1.30 (m, 4H), 1.23 (brs, 19H), 1.03 (d, 3H, J = 6.4 Hz),
0.85 (t, 3H, J = 6.8 Hz). Anal. Calcd. for C17H35N: C, 80.56; H,
13.92; N, 5.53. Found; C, 80.54; H, 13.96; N, 5.51.
(2R,6S)-Isosolenopsin A. HCl. (2R,6S)-Isosolenopsin A
(1.0 g) in ethanol (5 ml) was treated with HCl (0.5 ml) as
described earlier and crystallized from methanol/ether to yield
(2S,6R)-isosolenopsin A.HCl (0.92 g, 83%) as white needles. mp
150 - 152 °C; Lit [9] mp 152 - 153 °C; [ꢀ] D24 = +9.9 (c, 1.5,
1
= -4.6 (c 1.25, CHCl3). H nmr: ꢁ 2.73 (m, 1H), 2.58 (m, 1H),
1.81 (m, 1H), 1.69 (m, 2H), 1.55 (m, 2H), 1.41-1.31 (m, 8H),
1.26 (brs, 17H), 1.13 (d, 3H, J = 6.4 Hz), 0.89 (t, 3H, J = 6.8
Hz), Anal. Calcd. for C19H39N: C, 81.06; H, 13.96; N, 4.98.
Found; C, 81.04; H, 13.99; N, 4.96.
1
CHCl3), Lit[9] [ꢀ]D = +10.0 (c 1.1, CHCl3). H nmr: ꢁ 2.97 (m,
1H), 2.79(m, 1H), 1.99 (m, 1H), 1.79 (m, 2H), 1.67 (m, 2H),
1.50 (m, 2H), 1.43 (d, 3H, J = 6.4 Hz), 1.25 (m, 2H), 1.11(brs,
17H), 0.74 (t, 3H, J = 6.4 Hz).
2(S)-Methylpiperidine mandelate. Racemic 2-methyl-
piperidine (18.0 g) was recrystallized with equimolar amount of
(-) mandelic acid (27.5 g) to give 2(S)-methylpiperidine
mandelate (17.6 g, 38%). mp 118-119 °C, Lit[13] mp 118-119
°C; [ꢀ]D24 = -60.2 (c 3.0, MeOH).
N-Boc-2(S)-Methylpiperidine (23b). N-Boc-2(S)-Methyl-
piperidine (10.6 g, 94%) was prepared by treatment of 2(S)-
methylpiperidine mandelate (12.5 g) with di-tert-butyl-dicar-
bonate (11.0 g) as in 22a. [ꢀ]D24 = +50.4 (c 4.3, CHCl3). 1H nmr:
ꢁ 4.27 (m, 1H), 3.82 (brd, 1H, J = 13.2 Hz), 2.71 (ddd, 1H, J =
13.2, 12.8, 2.8 Hz), 1.49 (m, 4H), 1.36 (s, 9H), 1.27 (m, 2H),
1.02 (d, 3H, J = 7.2 Hz).
N-Boc-2(S)-methylpiperidine-6-carboxaldehyde (24b) N-
Boc-2(S)-Methylpiperidine (10.0 g) was lithiated and treated
with DMF (4.4 g) as in 24a to yield a mixture of N-Boc-2(S)-
methylpiperidine-6(R)-carboxaldehyde and N-Boc-2(S)-methyl-
piperidine-6(S)-carboxaldehyde (9.8 g).
(2R,6S)-Isosolenopsin B. HCl. (2R, 6S)-Isosolenopsin B (1.0
g) in methanol (5 ml) was treated with HCl (0.5 ml) (4.2.8) to
yield its hydrochloride (92%). mp 144 - 145 °C; [ꢀ]D24 = +10.7 (c
1
1.5, CHCl3). H nmr: ꢁ 3.00 (m, 1H), 2.82 (m, 1H), 2.03 (m,
1H), 1.84 (m, 2H), 1.70 (m, 2H), 1.47 (d, J = 6.4 Hz, 3H), 1.34
(m, 3H), 1.16 (brs, 22H), 0.78 (t, J = 6.4 Hz, 3H).
N-Boc-2(S)-Methylpiperidine-6(R)-tridecan-1-ene (25b, R'
= C11H23). A mixture of cis- and trans-N-Boc-2-methyl-
piperidine-6-carboxaldehyde (3.0 g) (24a) was treated with n-
dodecyltriphenylphosphonium bromide (6.8 g) in the presence
of NaH (0.5 g) as described in 25a, (R' = C9H19) to yield N-Boc-
2(S)-methylpiperidine-6(R)-tridecan-1-ene (3.51 g).
2(S)-Methyl-6(R)-tridecylpiperidine [(2S,6R)-isosolenopsin
B] (11). Catalytic hydrogenation of (25b, R' = C11H23) (3.0 g)
followed by the deprotection with TFA gave (2S, 6R)-
isosolenopsin B as a pale yellow oil (1.86 g, ee > 99%). [ꢀ]D24
=
+4.7 (c 1.5, CHCl3). 1H nmr: ꢁ 2.71 (m, 1H), 2.56 (m, 1H), 1.78
(m, 1H), 1.68 - 1.58 (m, 3H), 1.39-1.31 (m, 8H), 1.26 (brs, 17H),
1.11 (d, 3H, J = 6.4 Hz), 0.87 (t, 3H, J = 6.8 Hz), Anal. Calcd.
for C19H39N: C, 81.06; H, 13.96; N, 4.98. Found; C, 81.07; H,
13.94; N, 5.01.
N-Boc-2(S)-methylpiperidine-6(R)-undecan-1-ene (25b, R'
= C9H19). The above mixture of N-Boc-2(S)-methylpiperidine-
6(R)-carboxaldehyde and N-Boc-2(S)-methylpiperidine-6(S)-
carboxaldehyde. (3.0 g) was treated with n-decyltriphenyl-
phosphonium bromide (6.4 g) in the presence of 60% NaH (0.5
g) similar to that of 25a to give N-Boc-2(S)-methylpiperidine-
6(R)-undecan-1-ene (3.24 g, 70%).
(2S,6R)-Isosolenopsin B. HCl. (2S,6R)-Isosolenopsin B (1.0
g) in methanol (5 ml) was treated with HCl (0.5 ml) to yield its
hydrochloride (89%) mp 146 - 147 °C; [ꢀ] D24 = -10.5 (c 2.5,
1
CHCl3); H nmr: ꢁ 3.06 (m, 1H), 2.87 (m, 1H), 2.13 (m, 1H),
1.91 (m, 2H), 1.78 (m, 2H), 1.55 (d, 3H, J = 6.4 Hz), 1.35 (m,
3H), 1.28 (brs, 22H), 0.85 (t, 3H, J = 6.4 Hz).
(2S, 6R)-Isosolenopsin A (10). Catalytic hydrogenation of N-
Boc-2(S)-methylpiperidine-6(R)-undecan-1-ene (3.0 g) with
Pd/C (10%) (0.4 g) followed by deprotection with TFA as
described in solenopsin A (1), yielded (2S,6R)-isosolenopsin A
N-Boc-2(R)-Methylpiperidine-6(S)-pentadecan-1-ene (25a,
R' = C13H27). A mixture of cis- and trans-N-Boc-2-methyl-
piperidine-6-carboxaldehyde (3.0 g) (24a) was treated with
n-tetradecyltriphenylphosphonium bromide (7.2 g) as described
in 25a, (R' = C9H19) to yield N-Boc-2(R)-methylpiperidine-6(S)-
pentadecan-1-ene (3.6 g, 67%). 1H nmr: ꢁ 5.64 (dd, 1H, J = 10.8,
9.6 Hz), 5.33 (dt, 1H, J = 9.6, 7.2 Hz), 4.93 (m, 1H), 4.31(m,
1H), 2.11 (m, 2H), 1.64 (m, 8H), 1.44 (s, 9H), 1.25 (brs, 22H),
1.20 (d, 3H, J = 7.2 Hz), 0.87 (t, 3H, J = 6.8 Hz).
(1.9 g, 87%, ee > 99%). [ꢀ]D24 = +3.7 (c 2.0, CHCl3), H nmr: ꢁ
1
2.57 (m, 1H), 2.41 (m, 1H), 1.70 (m, 1H), 1.55 (m, 2H), 1.28 (m,
4H), 1.23 (brs, 19H), 1.01 (d, 3H, J = 6.4 Hz), 0.83 (t, 3H, J =
6.8 Hz). Anal. Calcd. for C17H35N: C, 80.56; H, 13.92; N, 5.53.
Found; C, 80.56; H, 13.93; N, 5.51.
(2S,6R)-Isosolenopsin A.HCl. (2S,6R)-Isosolenopsin A (1.0
g) in ethanol (5.0 ml) was treated with HCl (0.5 ml) and
recrystallized with ethanol ether to yield colorless crystals of
(2S,6R)-isosolenopsin A.HCl (85%). mp 150 - 151 °C, Lit [9]
2(R)-Methyl-6(S)-pentadecylpiperidine [(2R,6S)-isosolen-
opsin C] (9). Catalytic hydrogenation of 25a, (R' = C13H27) (3.0
g) followed by the deprotection as described in gave (2R, 6S)-
isosolenopsin C (1.93 g) as a pale yellow oil. (ee > 99%). [ꢀ]D24
mp 152 - 153 °C, [ꢀ]D2 4 = -9.8 (c, 2.5, CHCl3), Lit [9] [ꢀ]D24
=
-10.1 (c 1.0, CHCl3). 1H nmr: ꢁ 3.01 (m, 1H), 2.82 (m, 1H), 2.05
(m, 1H), 1.85 (m, 2H), 1.71 (m, 2H), 1.48 (d, 3H, J = 6.0 Hz),
1.34 (m, 4H), 1.16 (brs, 17H), 0.79 (d, 3H, J = 6.8 Hz).
1
= -5.1 (c 2.1, CHCl3), H nmr : ꢁ 2.75 (m, 1H), 2.59 (m, 1H),
1.83 (m, 1H), 1.71-1.54 (m, 6H), 1.43-1.30 (m, 8H), 1.26 (brs,
19H), 1.14 (d, 3H, J = 6.4 Hz), 0.88 (t, 3H, J = 6.8 Hz), Anal.

136
H. M. T. Bandara Herath, N. P. Dhammika Nanayakkara
Vol 45
REFERENCES
Calcd. for C21H43N: C, 81.48; H, 14.00; N, 4.52. Found; C,
81.46; H, 13.99; N, 4.56.
(2R,6S)-Isosolenopsin C. HCl. (2R,6S)-Isosolenopsin C (1.0
g) in methanol (5 ml) was treated with HCl (0.5 ml) followed by
recrystallization to yield its hydrochloride. mp 145 - 146 °C;
[1] Taber, W. T. Fire Ants, Texas A & M University Press,
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[2] MacConnell, J. G.; Blum, M. S.; Fales, H. M. Tetrahedron
1971, 26, 1129.
24
1
[ꢀ]D = +8.3 (c 1.0, CHCl3), H nmr: ꢁ 3.03 (m, 1H), 2.84 (m,
1H), 2.08 (m, 1H), 1.87 (m, 2H), 1.73 (m, 2H), 1.51 (d, 3H, J =
6.4 Hz), 1.35 (m, 3H), 1.19 (brs, 26H), 0.82 (t,3H, J = 6.4 Hz).
N-Boc-2(S)-methylpiperidine-6(R)-pentadecan-1-ene (25b,
R' = C13H27). A mixture of cis- and trans-N-Boc-2-methyl-
piperidine-6-carboxaldehyde (3.2 g) (24a) was treated with
n-tetradecyltriphenylphosphonium bromide (7.4 g) in the
presence of NaH (0.5 g) by similar procedure used in 25a,
(R' = C13H27) to yield N-Boc-2(S)-methylpiperidine-6(R)-
pentadecan-1-ene (3.7 g).
[3] Leclerq, S.; Thirionet, I.; Broeders, F.; Daloze, D.; van der
Meer, R.; Braekman, J. C. Tetrahedron 1994, 50, 8465.
[4] Howell, G.; Butler, J.; de Shazo, R. D.; Farley, J. M.; Liu, H.
L.; Nanayakkara, N. P. D.; Yates, A.; Yi, G. B.; Rockhold, R. W. Ann.
Allergy Asthma Immunol. 2005, 94, 380.
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155.
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Org. Chem. 2003, 68, 1919.
[9] Poerwono, H.; Higashiyama, K.; Yamauchi, T.; Kubo, H.;
Ohmiya, S.; Takahashi, H. Tetrahedron 1998 54, 13955.
[10] Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109.
[11] Meyers, A. I.; Edwards, P. D.; Rieker, W. F.; Bailey, T. R. J.
Am. Chem. Soc. 1984, 106, 3270.
[12] Gawley, R. E.; Hart, G. C.; Bartolotti, L. J. J. Org. Chem.
1989, 54, 175.
[13] Adamo, M. F. A.; Aggarwal, V. K.; Sage, M. A. Synthetic
Communications 1999, 29, 1747.
2(S)-Methyl-6(R)-pentadecylpiperidine [(2S,6R)-isosolen-
opsin C] (9). Catalytic hydrogenation of 25b (R' = C13H27), (3.0
g) followed by the deprotection with TFA gave (2S, 6R)-
isosolenopsin C as a pale yellow oil (2.01 g, ee > 99%). [ꢀ]D24
=
+4.9 (c 1.5, MeOH), 1H nmr: ꢁ 2.71 (m, 1H), 2.56 (m, 1H), 1.79
(m, 1H), 1.70 - 1.56 (m, 3H), 1.37-1.29 (m, 10H), 1.25 (brs,
19H), 1.12 (d, 3H, J = 6.4 Hz), 0.87 (t, 3H, J = 6.8 Hz), Anal.
Calcd. for C21H43N: C, 81.48; H, 14.00; N, 4.52. Found; C,
81.44; H, 14.03; N, 4.54.
[14] Klun, J. A.; Khrimian, A.; Margaryan, A.; Kramer, M.;
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Chem. 1986, 51, 4475.
(2S,6R)-Isosolenopsin C. HCl. (2S,6R)-Isosolenopsin C (1.0
g) in methanol (5 ml) was treated with HCl (0.5 ml) to yield its
hydrochloride on recrystallization with methanol/ether, mp 144 -
145 °C; [ꢀ]D24 = -8.2 (c 1.5, CHCl3). 1H nmr: ꢁ 2.87 (m, 1H), 2.69
(m, 1H), 1.70 (m, 2H), 1.60 (m, 2H), 1.34-1.21 (m, 4H), 1.15 (d,
3H, J = 6.4 Hz), 1.00 (brs, 26H), 0.61 (t, 3H, J = 6.8 Hz).
[17] Taber, D.F.; Deker, P.B.; Fales, H.M.; Jones, T.H.; Lloyd,
H.A. J. Org. Chem. 1988, 53, 2968.