Asymmetric syntheses of N-acetyl-(R)-coniine and N-Boc-(2R,6R)-solenopsin A via ring-closing metathesis

Article abstract of DOI:10.1016/S0957-4166(01)00411-6

Asymmetric syntheses of piperidine alkaloids N-acetyl-(R)-coniine and (2R,6R)-trans-solenopsin were achieved utilizing stereoselective additions of allylphenylsulfone to chiral alkyl-N-sulfinylimines and ring-closing olefin metathesis.

Full text of DOI:10.1016/S0957-4166(01)00411-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2269–2276
Asymmetric syntheses of N-acetyl-(R)-coniine and
N-Boc-(2R,6R)-solenopsin A via ring-closing metathesis†
Ramaiah Kumareswaran and Alfred Hassner*
Department of Chemistry, Bar Ilan University, Ramat Gan 52 900, Israel
Received 10 May 2001; accepted 18 September 2001
Abstract—Asymmetric syntheses of piperidine alkaloids N-acetyl-(R)-coniine and (2R,6R)-trans-solenopsin were achieved utilizing
stereoselective additions of allylphenylsulfone to chiral alkyl-N-sulfinylimines and ring-closing olefin metathesis. © 2001 Elsevier
Science Ltd. All rights reserved.
1. Introduction
Optically active piperidine alkaloids bearing a stereo-
genic carbon in the 2-position are an important group
of natural products due to their potent biological activ-
ities and hence they have been the target of numerous
synthetic strategies.1 In our previous reports2 we have
described efficient protocols for the synthesis of
homochiral 2-aryl substituted piperidines such as (S)-
anatabine2b via stereoselective additions of functional-
ized allylsulfone carbanions to chiral aryl-N-
sulfinylimines followed by substitution-induced ring
closure. To further demonstrate the utility of our
method, we undertook the synthesis of (R)-coniine 1,
the poisonous hemlock alkaloid and (2R,6R)-trans-
solenopsin A 2, a constituent of fire-ant venom. Except
for some catalyst based asymmetric syntheses3 of these
alkaloids, most known strategies start from amino acids
or substrates bearing chiral auxiliaries derived from the
natural chiral pool.4
2. Results and discussion
An efficient retrosynthetic analysis (Fig. 1) leading to 1
and 2 suggested the use of non-racemic 3 or 4 and a
ring-closing metathesis reaction (RCM). While Davis et
al. have shown5 that formation of chiral sulfinylimines,
when R=aromatic, can be readily achieved, prepara-
tion of the alkyl analogs (R=alkyl) is more problem-
atic. In fact, in our hands their previously reported
procedure5 for the condensation of (S)-p-toluenesulfon-
amide and laurinaldehyde yielded only a trace of 4. The
Figure 1.
* Corresponding author. Fax: 972-3-5351250; e-mail: hassna@mail.biu.ac.il
†
Synthetic Methods 54. For paper 53, see Basel, Y.; Hassner, A. Synthesis 2001, 550.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00411-6

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R. Kumareswaran, A. Hassner / Tetrahedron: Asymmetry 12 (2001) 2269–2276
in Scheme 1. Monoallylation followed by protection of
the secondary amine 7 to afford the acetamide 8 set the
stage for metathesis ring closure. While neither amine 7
nor its hydrochloride salt underwent clean metathesis,
treatment of a 0.1 M CH2Cl2 solution of the acetamide
derivative 8 with 5 mol% of Grubbs catalyst 10 at room
temperature for 2.5 h afforded 9 in excellent yield. In
order to determine the absolute configurations of 9, it
was first necessary to establish the relative stereochem-
presence of Ti Lewis acids improved the yield of 4 to
about 20% and the best yield of 45% was achieved
when the condensation was carried out in the presence
,
of 1 equivalent of BF3·OEt2 and 4 A molecular sieves.
In our hands, following the Davis procedure using
(S)-p-toluenesulfonamide, butanal and molecular sieves
gave only 14% of 3.6 On the other hand, the one-pot
procedure5 improved the yield to 70%.
1
istry of the alkyl and phenylsulfonyl groups. H NMR
Our synthesis of coniine commences with the stereose-
lective addition of allylphenylsulfone, not bearing any
additional functions, to sulfinylimine 3. Allylphenylsul-
fone was deprotonated by lithium diisopropylamide
(LDA) in THF at −100°C, followed by the addition of
sulfinylimine 3 in THF to afford the product as a 1:1:3
mixture of three diastereomers of which the major
isomer 5 was separated by flash column chromatogra-
phy (Eq. (1)). Variation of the reaction conditions did
not alter the diastereoselectivity appreciably. The 1H
NMR spectrum of 5 showed that the a-phenylsulfonyl
proton appeared as a dd (J=10, 2.4 Hz). This fact,
coupled with the 2D NOESY spectrum which showed a
strong NOE effect between the hydrogens at C(3) and
C(4), indicated the major isomer of 5 to possess the
anti-stereochemistry in accordance with our earlier
reports.2
and NOESY experiments on 9 indicated a trans rela-
tionship, with the alkyl and PhSO2 groups occupying
pseudo diaxial positions since the C(5)H and C(6)H
protons are in a gauche relationship (J5,6 <1 Hz) in
accordance with our previously reported arylpiperidi-
nes.2 Reduction of the double bond to afford 11 and
further reductive desulfonation afforded N-acetyl-(R)-
coniine 12 whose absolute configuration as well as its
enantiopurity were determined by comparing the opti-
cal rotation (vide experimental) value with that of the
authentic sample prepared from (S)-coniine·HCl. Since
we obtained compound 12 in enantiopure form, it is
reasonable to assume that precursors 5–11 were also
enantiopure. We did not attempt to hydrolyze the
amide function due to the high volatility of 1.3a
Next we decided to extrapolate the above reaction
sequence to trans-solenopsin A, a 2,6-dialkylsubstituted
piperidine by taking advantage of the known stereose-
lective C(6) methylation of the 2-substituted piperidine
223 following Beak’s a-lithiation procedure.7 Addition
of allylphenylsulfone to sulfinylimine 4 under the condi-
tions described for 3 yielded the adduct as a mixture of
three isomers whose ratio could not be ascertained
because of the overlapping of the proton signals in the
1H NMR spectrum. However, flash column chromatog-
raphy afforded 13 as an inseparable 1:1.94 mixture of
(1)
Desulfinylation of 5 by treatment with trifluoroacetic
acid in methanol at 0°C afforded the amine 6, as shown
Scheme 1.

R. Kumareswaran, A. Hassner / Tetrahedron: Asymmetry 12 (2001) 2269–2276
2271
the major diastereomers in 52% isolated yield (Eq. (2)).
Based on the coupling constants of C(3)H and C(4)H
and also since both the isomers in mixture 13 showed
similar 2D NOE patterns, we concluded that they are
both anti-C(3)/C(4) diastereoisomers. The third isomer
was isolated in 18% yield. The ratio of the major
diastereomeric mixture was further confirmed from
HPLC analysis of the carbamate derivative of the
amine 14 by comparison with that of the racemic
sample prepared via a different route. The diastereose-
lectivity during the allylphenylsulfone addition could
not be improved further by varying the reaction
conditions.
one of the sulfonyl oxygens, rendering the amine more
basic than nucleophilic. Hence, we resorted to
protection of the amine group as the acetamide 16,
which was then subjected to metathesis ring closure
using 5 mol% of catalyst 10 at room temperature.
Using these conditions, the ring-closing metathesis reac-
tion afforded tetrahydropyridine derivative 17 in 92%
yield. Hydrogenation of the olefin using 10% Pd/C
produced amide 18. Since the Boc group on nitrogen is
vital for the stereoselective methylation of 22 at C(6), it
was necessary to hydrolyze amide 18 and re-protect the
product amine as the tert-butyl carbamate derivative.
Unfortunately, however, our attempts to hydrolyze the
(2)
amide function in 18 using 40% H2SO4 in MeOH at
110°C for 1 week led only to the recovery of starting
material. On the other hand, we were pleased to find
that the hydrolysis of 17 under the above reaction
conditions afforded piperidine 19 in good yield. Treat-
ment of 19 with N-tert-butoxycarbonyloxybenzotria-
zole (TBCBT)8 in CH2Cl2 at room temperature yielded
carbamate 20 in quantitative yield. All the above con-
Desulfinylation followed by monoallylation of the
amine 14 as for 6, afforded compound 15 (Scheme 2).
Treatment of either amine 15 or its hydrochloride salt
with Grubbs catalyst did not lead to a clean metathesis
reaction. Also, all our attempts to protect the sec-
ondary nitrogen in 15 using several Boc transfer
reagents were not successful, presumably due to the
extensive hydrogen bonding of the amino proton with
Scheme 2. N-TBCBT=N-tert-butoxycarbonyloxybenzotriazole.

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R. Kumareswaran, A. Hassner / Tetrahedron: Asymmetry 12 (2001) 2269–2276
versions 13 through 20 were carried out on the insepa-
rable ca. 1:1.9 mixture of isomers. Further, reductive
removal of the sulfonyl group in 21 using Na/Hg
provided the known 22 whose enantiomeric purity was
found to be nearly 30% by comparing the specific
rotation with that of the known compound.3a Lithia-
tion of 22 with sec-BuLi/TMEDA, followed by treat-
ment with dimethylsulfate following the procedure of
Buchwald et al.,3a afforded N-Boc-(2R,6R)-solenopsin
23 with an e.e. of 30%. The optical purity and the
absolute configuration were determined by comparing
the specific rotation value with that of the known
literature value.
water (1 mL) and filtered on a pad of MgSO4 to remove
the molecular sieves, and the filtrate was extracted with
CH2Cl2 (3×15 mL). The combined organic layers were
washed with brine, dried (MgSO4), and concentrated to
afford a crude product which was purified by flash
column chromatography (8% EtOAc in n-hexane) to
1
afford 4 (145 mg, 45%). [h]2D5 +176.3 (c 1.9, CHCl3); H
NMR (CDCl3) l 8.22 (t, J=6 Hz, 1H), 7.55 (d, J=8.15
Hz, 2H), 7.29 (d, J=8.15 Hz, 2H), 2.51–2.42 (m, 2H),
2.4 (s, 3H), 1.62–1.55 (m, 2H), 1.4–1.2 (m, 16H), 0.88 (t,
J=8 Hz, 3H); 13C NMR l 167.4, 141.6, 141.5, 129.8,
124.6, 35.9, 31.9, 29.6, 29.5, 29.4, 29.3, 29.1, 28.9, 25.4,
22.7, 21.4, 14.1.
4.3. (3S)-Phenylsulfonyl-(4R)-[N-(p-tolylsulfinyl)-
amino]hept-1-ene 5
3. Conclusions
In a two-necked, round-bottomed flask equipped with
an argon inlet, rubber septum and a stirring bar was
placed diisopropylamine (0.27 mL, 1.9 mmol) in THF
(3 mL). At −50°C, n-BuLi (1.6 M in hexane, 1.08 mL,
1.73 mmol) was added and stirred for 15 min at the
same temperature. The flask was further cooled to
−100°C and a solution of allylphenylsulfone (315 mg,
1.73 mmol) in THF (9 mL) was added dropwise. After
15 min a solution of sulfinylimine 3 (300 mg, 1.44
mmol) in THF (5 mL) was introduced dropwise along
the sides of the flask. After stirring the mixture for 45
min, the reaction was quenched with aq. NH4Cl (1 mL)
and extracted thoroughly with CH2Cl2 (3×20 mL). The
combined organic part was washed with brine, dried
(MgSO4) and concentrated. Purification of the crude
product by flash column chromatography (22% EtOAc
in hexane) yielded the major isomer 5 as a viscous oil
A straightforward synthesis of both (R)-coniine and
(2R,6R)-trans-solenopsin A derivatives 12 and 23 was
achieved utilizing stereoselective additions of simple
allylphenylsulfone to chiral non-racemic alkyl-N-sulfi-
nylimines and ring-closing metathesis reactions as key
steps. This methodology, which does not rely on amino
acids as a chirality source, should also be applicable to
procure the enantiomers of 12 and 23 by employing
(R)-sulfinylimines.
4. Experimental
4.1. General
All air and moisture sensitive reactions were carried out
in flame-dried, argon-flushed, two necked flasks sealed
with rubber septa, and the dry solvents, reagents were
introduced with a syringe. Tetrahydrofuran (THF) was
freshly distilled from sodium/benzophenone. Reactions
with cooling at −100°C were performed using a mixture
of liquid nitrogen and MeOH. Flash column chro-
matography was carried out on Merck silica gel 60
(230–400 mesh), and pre-coated Merck silica gel plates
(60F-25H) were used for TLC. Unless otherwise men-
tioned 1H and 13C NMR spectra were recorded in
CDCl3 on a Bruker AM-300 spectrometer. Coupling
constants were determined directly from 1H NMR spec-
tra. Mass spectra (CI) were recorded at 60–70 eV.
Optical rotations were measured on a Perkin Elmer 141
polarimeter with path length of 0.1 dm. Sulfinylimine 3
was prepared by following the Davis procedure.5
1
(293 mg, 52%). [h]D25 +141.4 (c 1.4, CHCl3); H NMR
(CDCl3) l 7.92–7.85 (m, 2H), 7.65 (d, J=8.4 Hz, 1H),
7.64 (tt, J=8.2, 1.5 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H),
7.3 (d, J=8.4 Hz, 2H), 5.85 (dt, J=16.8, 10.2 Hz, 1H),
5.26 (dd, J=10.2, 1.2 Hz, 1H), 5.04 (d, J=10.2 Hz, 1H,
exchangeable with D2O), 4.95 (d, J=16.8 Hz, 1H), 4.27
(dd, J=9.9, 2.4 Hz, 1H), 3.73 (tdd, J=9.6, 4.8, 2.7 Hz,
1H), 2.41 (s, 3H), 1.87–1.77 (m, 1H), 1.65–1.57 (m, 1H),
1.48–1.35 (m, 1H), 1.05–0.9 (m, 1H), 0.74 (t, 3H); 13C
NMR (CDCl3) l 141.4, 140.9, 138.7, 133.7, 129.7,
128.9, 128.8, 127.8, 126.1, 124.6, 73.4, 55.7, 34.9, 21.4,
19.5, 13.5. HRMS observed mass=392.133469 (for
MH+, calculated value=392.135413). Two minor
diastereomers were obtained only in impure form and
were not further characterized.
4.4. (4R)-Amino-(3S)-phenylsulfonylhept-1-ene 6
4.2. Preparation of (S)-(+)-N-dodecylidene-p-toluene-
sulfinamide 4
In a single-necked, round-bottomed flask equipped with
a magnetic stirring bar and a rubber septum was placed
a solution of the sulfinylimine 4 (250 mg, 0.64 mmol) in
MeOH (6 mL) at 0°C under an Ar atmosphere. Tri-
fluoroacetic acid (0.2 mL, 2.56 mmol) was added drop-
wise and the resultant solution was stirred at the same
temperature for 3 h until a total disappearance of the
starting material. The reaction mixture was then con-
centrated and the residual oil was dissolved in CH2Cl2
In a two-necked, round-bottomed flask equipped with a
magnetic stirring bar, rubber septum and an argon inlet
,
was placed powdered, freshly activated 4 A molecular
sieves (2 g) and (S)-(+)-p-toluenesulfinamide6 (155 mg,
1 mmol). A solution of laurinaldehyde (184 mg, 1
mmol) in CH2Cl2 (6 mL) was introduced and the
resultant mixture was cooled at −5°C. BF3·OEt2 was
introduced neat and the reaction mixture was stirred
for 1 h, while maintaining the temperature between 0
and −5°C. The reaction mixture was quenched with
and transferred into
a beaker. The beaker was
immersed in an ice bath and a saturated aqueous
NaHCO3 was added until the pH rose to 8. The con-

R. Kumareswaran, A. Hassner / Tetrahedron: Asymmetry 12 (2001) 2269–2276
2273
tents of the beaker was transferred into a separatory
funnel and extracted thoroughly with CH2Cl2 (3×20
mL). The combined organic extract was then washed
with brine, dried (MgSO4) and concentrated. Purifica-
tion of the crude product by flash column chromatogra-
phy (80% EtOAc in hexane) afforded the title
compound as a colorless oil (140 mg, 87%). [h]2D5 −73.1
mixture of two rotamers (200 mg, 80%, sticky solid).
1
[h]2D5 −30 (c 2, CHCl3); H NMR (CDCl3, 600 MHz) l
7.81 (d, J=7.8 Hz, 2H), 7.64 and 7.62 (2t, 7.5 Hz, 1H),
7.54 and 7.52 (2t, J=7.8 Hz, 2H), 5.88 and 5.54 (m, dt,
J=18, 10.2 Hz, 1H), 5.76 (m, 1H), 5.23 (br d, J=13
Hz, 1H), 5.15 (d, J=10.2 Hz, 1H), 5.13 and 4.82 (2d,
J=18, 17 Hz), 5.06 (d, J=10.2 Hz, 1H), 4.08 and 4.49
(dd and dt, J=15.2, 4.8 Hz and 8.46, 2.76 Hz, 1H),
3.77 (br, 2H), 3.09 and 3.63 (2dd, J=15.2, 7.5 and 10.4,
8.4 Hz, 1H), 2.18 (m, 1H), 2.2 and 2 (2s, 3H), 1.78 (m,
1H), 1.33 (m, 2H), 0.93 (t, J=7.4 Hz, 3H). 13C NMR
(CDCl3) l 171.1, 139.8, 135.6, 134 and 133.4, 123, 129.7
and 128.6, 127.7 and 127.3, 125.8, 126.5, 73.7 and 73.6,
57, 46, 37.1, 34.2, 22.9 and 22.6, 14.6. HRMS observed
mass=336.162590 (for MH+ calculated value=
336.163341).
1
(c 1.3, CHCl3); H NMR (CDCl3) l 7.87–7.83 (m, 2H),
7.64 (tt, J=7.8, 2.1 Hz, 1H), 7.54 (tt, J=7.8, 2.1 Hz,
2H), 6.04 (dt, J=17.1, 10.2 Hz, 1H), 5.36 (dd, J=10.2,
0.6 Hz, 1H), 4.96 (dt, J=17.1, 0.6 Hz, 1H), 3.76 (td,
J=5.7, 2.1 Hz, 1H), 3.42 (dd, 10.2, 1.8 Hz, 1H), 1.76
(br, exchangeable with D2O, 2H), 1.39–1.32 (m, 4H),
0.87 (t, J=7 Hz, 3H); 13C NMR (CDCl3) l 141.1,
138.3, 134.1, 129.3, 126.6, 125.7, 74.2, 49.4, 38.1, 19.5,
14.2. HRMS observed mass=254.121693 (for MH+,
calculated value=254.121476).
4.7. N-Acetyl (5S)-phenylsulfonyl-(6R)-n-propyl-
1,2,5,6-tetrahydropyridine 9
4.5. (4R)-N-(2-Propenyl)amino-(3S)-phenylsulfonylhept-
1-ene 7
In a two-necked flask equipped with an argon inlet, a
magnetic stirring bar and a rubber septum was placed
Grubbs catalyst 10 (24 mg, 0.029 mmol, 5 mol%). A
solution of 8 (191 mg, 0.57 mmol) in CH2Cl2 (6 mL)
was introduced at room temperature and the resultant
pink solution was stirred for 2.5 h when TLC analysis
indicated complete consumption of 8. The reaction
mixture was exposed to air and concentrated. Purifica-
tion by flash column chromatography (50% EtOAc in
hexane) afforded 9 (160 mg, 92%). [h]2D5 +196 (c 1.2,
Into a single-necked round-bottomed flask equipped
with a magnetic stirring bar and a rubber septum was
placed K2CO3 (135 mg, 0.98 mmol) in DMF (2 mL) at
0°C under an Ar atmosphere. Solutions of amine 6 (124
mg, 0.49 mmol), allyl bromide (71 mg, 0.59 mmol) in
DMF (2, 0.5 mL) were added successively and the
reaction mixture was brought to room temperature and
stirred overnight. The mixture was quenched by adding
water (0.5 mL) and then extracted with ether (3×15
mL). The combined ethereal part was washed with
brine, dried (MgSO4) and concentrated. Purification of
the crude product by flash column chromatography
(20% EtOAc in hexane) gave 7 as a colorless oil (104
mg, 73%). [h]2D5 −48.2 (c 0.85, CHCl3); 1H NMR
(CDCl3) l 7.87–7.83 (m, 2H), 7.64 (tt, J=7.2, 1.8 Hz,
1H), 7.53 (tt, J=8.4, 1.2 Hz, 2H), 6 (dt, J=17.1, 10.2
Hz, 1H), 5.9 (ddt, J=17.1, 10.2, 6 Hz, 1H), 5.35 (dd,
J=10.2, 1.2 Hz, 1H), 5.2 (dq, J=17.1, 1.2 Hz, 1H),
5.12 (dt, J=10.2, 1.5 Hz, 1H), 4.96 (dt, J=17.1, 1.5 Hz,
1H), 3.57 (dd, J=10, 2.4 Hz, 1H), 3.46–3.25 (m, 3H),
1.7–1.5 (m, 2H), 1.31–1.24 (m, 2H), 0.89 (t, J=7 Hz,
3H); 13C NMR (CDCl3) l 139.5, 136.5, 133.6, 129,
128.4, 127.3, 125, 116.3, 72.5, 55.6, 50.4, 34.6, 19.3,
13.9. HRMS observed mass=293.144964 (for MH+,
calculated value=293.144951).
1
CHCl3); H NMR (CDCl3) l 7.88, 7.77 (2t, J=7 Hz,
2H), 7.64–7.6 (m, 1H), 7.56–7.5 (m, 2H), 6.08–6.02 (m,
1H), 5.45–5.41 (m, 1H), 5.28 and 4.75 (2t, J=6 Hz,
1H), 4.25 and 3.26 (2m, 1H), 3.6–3.75 (m, 2H), 2.25
and 1.76 (2s, 3H), 1.5–1.1 (m, 4H), 0.94 and 0.83 (2t,
J=7 Hz, 3H). 13C NMR (CDCl3) l 169.6 and 169.4,
137.1 and 136.7, 134 and 133.7, 132.1, 130 and 129.7,
128.9 and 128.6, 116.8 and 115.4, 73.5 and 73, 50.6 and
44.9, 42 and 38.5, 35 and 34.1, 30 and 21.6, 19.3 and
19.1, 13.8 and 13.6. HRMS observed mass=307.124416
(for MH+, calculated mass=307.124216).
4.8. N-Acetyl (2R)-n-propyl-(3S)-phenylsulfonylpipe-
ridine 11
In a two-necked flask equipped with a one way stop-
cock attached to a H2 balloon, and a rubber septum
was placed 10% Pd-C (50 mg). A solution of 10 (126
mg, 0.41 mmol) in MeOH (5 mL) was introduced and
the resultant black suspension was stirred under a H2
atmosphere for 2 h, when total disappearance of the
starting material with formation of a non-polar spot
was seen by TLC analysis. The reaction mixture was
exposed to air and filtered through a pad of MgSO4
and concentrated. Purification by flash column chro-
matography (50% EtOAc in hexane) afforded 11 as a
mixture of two rotamers (110 mg, 87%). [h]2D5 −16 (c
4.6. (4R)-N-(2-Propenyl)-N-acetylamino-(3S)-phenylsul-
fonylhept-1-ene 8
To a stirred solution of 7 (0.75 mmol, 220 mg) in
CH2Cl2 (5 mL) at 0°C under an Ar atmosphere was
added dropwise Et3N (0.16 mL, 1.13 mmol) followed
by freshly distilled CH3COCl (60 ml, 0.9 mmol). The
resultant mixture was allowed to warm to room tem-
perature, stirred for 3 h, when complete disappearance
of 7 with appearance of a polar spot on TLC was
observed. Cold water (1 mL) was added to quench the
reaction and the mixture was extracted with EtOAc
(3×20 mL). The combined organic part was washed
with brine, dried (MgSO4) and concentrated. Purifica-
tion of the crude product by flash column chromatogra-
phy (50% EtOAc in hexane) afforded pure 8 as a 1:1
1
2.25, CHCl3); H NMR (CDCl3) l 8.02–7.99 (m, 2H),
7.88 (t, J=1.5 Hz, 1H), 7.66–7.58 (m, 2H), 5.17, 4.74
and 4.59 (t, J=7.8 Hz, dd, J=8.7, 6 Hz, and dt,
J=13.2, 4.8 Hz, 1H), 3.69 and 3.13 (br d, J=13.2 Hz,
and td, J=12.3, 3.3 Hz, 1H), 2.98–2.5 (m, 2H), 2.28
and 2.12 (2s, 3H), 2.05–1.89 (m, 4H), 1.6–1.3 (m, 3H),

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R. Kumareswaran, A. Hassner / Tetrahedron: Asymmetry 12 (2001) 2269–2276
1.2–0.98 (m, 1H), 0.92 and 0.73 (2t, J=7.2 Hz, 3H); 13
C
4.11. (4R)-Amino-(3S)-phenylsulfonylpentadec-1-ene 14
NMR (CDCl3) l 170.4 and 170, 138.3 and 138.2, 134.4
and 134.1, 129.8 and 129.7, 129.5 and 128.8, 62.1 and
61, 50.8 and 45.8, 41.3 and 33.1, 35.5 and 34.7, 22.1 and
21.4, 20.1 and 19.8, 19.6, 19.2 and 18.9, 14.1 and 13.7.
HRMS observed mass=310.150597 (for MH+, calcu-
lated mass=310.147691).
The experimental procedure used for 6 led to 14 (125
mg, 96%) from reaction of 13 (181 mg, 0.36 mmol) in
MeOH (4 mL) and TFA (0.12 mL) at 0–10°C after 3 h.
[h]2D5 −15.3 (c 1.5, CHCl3); 1H NMR (CDCl3) l 7.85 (dt,
J=7.2, 1.2 Hz, 2H), 7.64 (tt, J=7.5 Hz, 1.2 Hz, 1H),
7.54 (tt, J=7.2, 1.2 Hz, 2H), 6.04 (dt, J=17.1, 10.2 Hz,
1H), 5.37 (dd, J=10.2, 1.5 Hz, 1H), 4.96 (dd, J=17.1,
1.5 Hz, 1H), 3.7 (br, 1H), 3.44 (dd, J=10.2, 1.5 Hz,
1H), 1.96 (d, J=5 Hz, 2H, exchangeable with D2O),
1.36–1.24 (m, 20H), 0.88 (t, J=7 Hz, 3H); 13C NMR
(CDCl3) l 138.3, 134.1, 129.3, 129.2, 126.6, 125.7, 74.1,
49.7, 35.9, 32.3, 30, 29.9, 29.8, 29.7, 29.5, 29.2, 26.3,
23.1, 14.5. HRMS observed mass=366.246036 (for
MH+, calculated mass=366.246677).
4.9. N-Acetyl (R)-coniine 12
In a two-necked flask equipped with a rubber septum,
an Ar inlet and a magnetic stirring bar was placed 11
(87 mg, 0.28 mmol) and anhydrous Na2HPO4 (159 mg,
1.12 mmol) in MeOH (4 mL) at −10°C under an Ar
atmosphere. Freshly prepared Na(Hg) (6%, 150 mg)
was added in one portion and the resultant mixture was
stirred at 0°C for 2 h, when total disappearance of the
starting material was seen by TLC analysis. Ice-cold
water (1 mL) was added to quench the reaction mix-
ture, which was then filtered through a pad of MgSO4
and concentrated under reduced pressure. The residue
was dissolved in CH2Cl2 (30 mL), washed with brine
and dried (MgSO4). Evaporation of the solvent
afforded the crude product, which was purified by flash
column chromatography (25% EtOAc in hexane) to
afford a colorless oil of 12 as a mixture of two rotamers
(29 mg, 62%). [h]2D5 −48.6 (c 0.72, CHCl3); [an authentic
N-acetyl S-coniine sample prepared from S-coni-
ine·HCl had [h]D25 +46.9 (c 0.4, CHCl3)]. 1H NMR
(CDCl3) l 4.78 and 4.54–4.46 (br and m, 1H), 3.85 and
3.59–3.55 (br and m, 1H), 3.11 and 2.58 (2br t, J=12
Hz, 1H), 2.23 and 2.09 (2s, 3H), 1.62–1.26 (m, 10H),
0.94 and 0.92 (2t, J=7 Hz, 3H); 13C NMR (CDCl3) l
169.8 and 169, 52.9 and 46.8, 40.9 and 35.4, 31.4 and
30.6, 28.1 and 27, 25.3 and 24.4, 20.8 and 20.5, 18.6 and
18.4, 18, 13.1. HRMS observed mass=169.146002 (for
M+, calculated mass=169.146664).
4.12. (4R)-N-(2-Propenyl)amino-(3S)-phenylsulfonylpen-
tadec-1-ene 15
Experimental procedure was the same as in the case of
7 to afford 15 (95 mg, 70%) from reaction of 14 (122
mg, 0.334 mmol), allyl bromide (48 mg, 0.4 mmol),
K2CO3 (92 mg, 0.668 mol) in DMF (4 mL) after
overnight stirring. The product was isolated by flash
column chromatography (22% EtOAc in hexane). [h]D25
−15.8 (c 1.9, CHCl3); 1H NMR (CDCl3) l 7.84 (dt,
J=7, 1.5 Hz, 2H), 7.63 (tt, J=7.5, 1.2 Hz, 1H), 7.53 (tt,
6.3, 1.5 Hz, 2H), 6 (dt, J=17.1, 10.2 Hz, 1H), 5.89 (ddt,
J=17.1, 10.2, 6 Hz, 1H), 5.41 (dd, J=10.2, 1.2 Hz,
1H), 5.19 (dq, J=17.1, 1.5 Hz, 1H), 5.1 (dq, J=10.2,
1.5 Hz, 1H), 4.97 (dd, J=17.1, 0.6 Hz, 1H), 3.57 (dd,
J=9.9, 2.4 Hz, 1H), 3.42–3.99 (m, 1H), 3.33 (qdt,
J=16.2, 6.3, 1.5 Hz, 2H), 1.9–1.6 (2m, 2H), 1.36–1.24
(m, 18H), 0.88 (t, J=6.9 Hz, 3H); 13C NMR (CDCl3) l
138.7, 137, 133.9, 129.4, 129.1, 127.7, 125.3, 116.5, 72.9,
56.2, 50.7, 32.8, 32.3, 30, 29.9, 29.8, 29.7, 29.4, 29, 26.3,
23.1, 14.5. HRMS observed mass=405.270253 (for M+,
calculated mass=405.270152).
4.10. (3S)-Phenylsulfonyl-(4R)-[N-(p-tolylsulfinyl)-
amino]pentadec-1-ene 13
4.13. (4R)-N-(2-Propenyl)acetamido-(3S)-phenylsulfonyl-
pentadec-1-ene 16
A similar procedure was followed as in the case of 5
starting from 4 (401 mg, 1.25 mmol), allylphenylsulfone
(273 mg, 1.5 mmol), n-BuLi (1.6 M, 0.94 mL, 1.5
mmol) and diisopropylamine (0.23 mL, 1.65 mmol) to
obtain 13 (327 mg, 52%, inseparable mixture of two
diastereomers in a 1:1.94 ratio) as the major product
after flash column chromatographic purification (14%
A similar experimental procedure was followed as in
the case of 8 to afford 16 (160 mg, 81%) as a mixture of
two rotamers from 15 (178 mg, 0.44 mmol), CH3COCl
(52 mg, 0.66 mmol) and Et3N (89 mg, 0.88 mmol) in
CH2Cl2 (4 mL) at 0°C to room temperature. The
product was purified by flash column chromatography
1
EtOAc in hexane). [h]2D5 +108 (c 1.5, CHCl3); H NMR
1
(CDCl3) l 7.88 (tt, J=7, 1.2 Hz, 2H×2), 7.67–7.62 (m,
3H×2), 7.57–7.5 (m, 2H×2), 7.32 and 7.29 (2d, J=8 Hz,
2H×2), 5.92 and 5.87 (2dt, J=16.2, 10.2 Hz, 1H×2),
5.41 and 5.12 (d, J=9 Hz, 1H×2, exchangeable with
D2O), 5.31 and 5.25 (dd, J=10.2 Hz, 1.2 Hz, 1H×2),
4.95 and 4.93 (d, J=16.5 Hz, 1H×2), 4.29 and 4.2 (2dd,
J=9.9, 2.1 Hz, 1H×2, ratio 1:1.94), 3.73–3.68 (m, 1H×
2), 2.3–2 (m, 1H×2), 1.85–1.8 (m, 1H×2), 1.7–1.55 (m,
1H×2), 1.4–1.1 (m, 19H×2), 1.1–0.95 (m, 1H×2), 0.89
(br t, J=7 Hz, 3H×2); 13C NMR (CDCl3) l 139.9, 138,
137, 131.9, 128.1, 127.4, 127.2, 125.3, 124.9, 124.6, 72.7,
49.9, 30.4, 29.7, 28.1, 28, 27.8, 27.3, 24.2, 21.1, 19.8,
12.5. HRMS observed mass=503.252688 (for M+, cal-
culated mass=503.252688).
(30% EtOAc in hexane). [h]2D5 −3.6 (c 3.9, CHCl3); H
NMR (CDCl3) l 7.84 (dt, J=7, 1.5 Hz, 2H), 7.62 (tt,
J=7.5, 1.2 Hz, 1H), 7.51 (tt, 6.3, 1.5 Hz, 2H), 5.93–5.71
(m, 1H), 5.53 (dt, J=17.1, 10.2 Hz, 1H), 5.22 (br d,
J=16 Hz, 1H), 5.13 (d, J=10.2 Hz, 1H), 5.08 (d,
J=10.2 Hz, 1H), 4.82 (d, J=17.1 Hz, 1H), 4.48 (td,
J=10, 2.7 Hz, 1H), 4.06 and 3.1 (2dd, J=15.3 and 4.8
Hz, J=15.3 and 7.5 Hz, 1H), 3.76 (br, 1H), 3.64 (dd,
J=10.2, 8.4 Hz, 1H), 2.2 and 2 (2s, 3H), 1.8–1.6 (m,
2H), 1.4–1.15 (m, 18H), 0.88 (t, J=7 Hz, 3H); 13C
NMR (CDCl3) l 172, 138.2, 134.6 and 134, 133.7,
129.9, 129.1 and 128.9, 128.7 and 128.6, 124.8 and
123.5, 116, 73.7 and 73.5, 57.5, 46.2, 33.9, 31.9, 29.6,
29.5, 29.4, 29.3, 29, 28.7, 28.6, 26.1, 22.7 and 22.4, 14.1.

R. Kumareswaran, A. Hassner / Tetrahedron: Asymmetry 12 (2001) 2269–2276
2275
HRMS observed mass=447.280626 (for M+, calcu-
lated value=447.280716).
benzotriazole (35 mg, 0.15 mmol), and the resulting
mixture was stirred at rt under an Ar atmosphere for
1 h when total disappearance of the starting material
with formation of a non-polar TLC spot was observed.
Concentration of the reaction mixture under reduced
pressure followed by flash column chromatographic
purification (17% EtOAc in hexane) afforded pure 20
as a mixture of two rotamers as a colorless oil (57
mg, quantitative). [h]2D5 +29.6 (c 2.6, CHCl3); 1H
NMR (CDCl3) l 7.85 (dt, J=7.2, 0.6 Hz, 2H), 7.61–
7.45 (2m, 3H), 6–5.7 (2m, 2H), 4.9–4.75 (m, 1H),
3.85–3.6 (m, 2H), 3.3 (td, J=6.9, 0.6 Hz, 1H), 1.62
and 1.52 (2s, 9H), 1.35–1.05 (m, 20H), 0.88 (t, J=7
Hz, 3H); 13C NMR (CDCl3) l 156, 137.8 and 137.2,
134.1 and 133.8, 132.1 and 131.7, 130 and 129.8, 129
and 128.9, 116, 80.9 and 80.4, 65.8 and 65.2, 48.8
and 47.5, 40.6 and 39.7, 33.2 and 32.7, 32.3, 30 and
29.9, 29.7, 29.6, 28.9, 28.8, 27.9, 26.3, 26.1, 23.1, 14.5.
4.14. N-Acetyl-(5S)-phenylsulfonyl-(6R)-n-undecyl-
1,2,5,6-tetrahydropyridine 17
The experimental procedure as used for 9 led, after
stirring a solution of 16 (99 mg, 0.22 mmol) with
Grubbs catalyst (9 mg, 0.011 mmol) in CH2Cl2 (2.5
mL) at room temperature for 2 h under an Ar atmo-
sphere, to 17 (85 mg, 92%) as a mixture of two
rotamers (ratio=1:1.1 at room temperature) after
flash column chromatography (56% EtOAc in hex-
ane). [h]2D5 +52.5 (c 1.6, CHCl3); l 7.84 (dt, J=7, 1.5
Hz, 2H), 7.62 (tt, J=7.5, 1.2 Hz, 1H), 7.51 (tt, J=
6.3, 1.5 Hz, 2H), 6.08–6.01 and 5.7–5.6 (2m, 2H),
5.23 and 4.7 (2t, J=6 Hz, 1H), 4.2 and 3.2 (2br d,
J=3 Hz, 1H), 3.7–3.64 (m, 2H), 2.25 and 1.76 (2s,
3H), 1.65–1.5 (m, 2H), 1.4–1.05 (m, 18H), 0.88 (t,
J=7 Hz, 3H); 13C NMR (CDCl3) l 170.2 and 169.8,
137.4 and 137, 134.3 and 133.9, 132.4 and 130.4, 130
and 128.9, 129.3 and 129.2, 117 and 115.7, 65.5 and
64.5, 51 and 45.4, 42.3, 38.8, 33.2, 32.2, 32.1, 29.8,
29.7, 29.6, 29.5, 29.3, 26.2 and 26.1, 22.9, 22.2 and
21.8. HRMS observed mass=419.249317 (for M+,
calculated mass=419.249416).
4.17. N-Boc-(2R)-n-undecyl-(3S)-phenylsulfonylpipe-
ridine 21
An experimental procedure as used in the case of 11
to afford 21 (56 mg, 93%) from 20 (60 mg, 0.126
mmol) and 10% Pd-C (30 mg). After stirring the reac-
tion mixture under a H2 atmosphere for 3 h, filtration
and evaporation, purification by flash column chro-
matography (20% EtOAc in hexane) afforded 21 as a
mixture of two rotamers. [h]2D5 −6.7 (c 0.75, CHCl3);
1H NMR (CDCl3) l 8–7.92 (m, 2H), 7.68–7.54 (2m,
3H), 4.75–4.65 (2m, 1H), 4.15–3.9 (2m, 1H), 2.87–2.5
(3m, 2H), 2.3–1.85 (2m, 2H), 1.8–1.55 (m, 2H), 1.65
and 1.5 (2s, 9H), 1.3–1 (m, 20H), 0.88 (t, J=6 Hz,
3H); 13C NMR (CDCl3) l 156.1, 138, 133.9, 129.5,
129, 80.2 and 80.1, 61.9 and 61.3, 48.5, 38, 32.2, 31.9,
29.9, 29.8, 29.7, 29.3, 28.8, 27.2, 26, 23, 20.4, 18.3,
18, 14.5.
4.15. (5S)-Phenylsulfonyl-(6R)-n-undecyl-1,2,5,6-tetra-
hydropyridine 19
In a single-necked round-bottomed flask equipped
with a reflux condenser and a magnetic stirring bar
was placed a methanolic solution of 17 (72 mg, 0.17
mmol in 1.5 mL of MeOH) and aq. 40% H2SO4 (3
mL) and the mixture was heated at 110°C for 4 days
under an Ar atmosphere. TLC analysis indicated for-
mation of a non-polar spot characteristic of an amine
in addition to a small amount of the starting mate-
rial, which did not reduce further with time. The
reaction mixture was cooled to 0°C, and a saturated
solution of aq. NaHCO3 was added dropwise until
the pH rose to 8. Extraction with CH2Cl2 (3×15 mL),
washing of the organic layer with brine and drying
over MgSO4 afforded a crude mass, which was
purified by flash column chromatography (22%
EtOAc in hexane) to afford 19 (36 mg) and starting
material (20 mg). Yield=77%, based on recovered
4.18. N-Boc-(2R)-n-undecylpiperidine 22
A similar experimental procedure was followed as in
the case of 12 to afford 22 (20 mg, 56%) from 21 (29
mg, 0.06 mmol), Na(Hg) (30 mg) and Na2HPO4 (34
mg, 0.12 mmol) in MeOH (3 mL). The product was
isolated by flash column chromatography (15%
1
1
starting material. [h]2D5 +38 (c 1.05, CHCl3); H NMR
EtOAc in hexane). The H and 13C NMR spectra of
(CDCl3) l 7.9 (dq, J=7.8, 0.6 Hz, 2H), 7.68 (tt, J=
7.2, 0.6 Hz, 1H), 7.58 (td, J=6.9, 0.6 Hz, 2H), 6.22
(br d, J=9.6 Hz, 1H), 5.65 (m, 1H), 3.46 (t, J=7 Hz,
1H), 3.35 (br, 1H), 3.23 (br, 2H), 2.28 (br, 1H,
exchangeable with D2O), 1.59–1.54 (m, 1H), 1.42–1.2
(m, 19H), 0.88 (t, J=7 Hz, 3H); 13C NMR (CDCl3)
l 137.4, 134.9, 134.1, 129.3, 128.9, 116.1, 61.5, 53.4,
49.7, 39.6, 31.9, 30.9, 29.7, 29.6, 29.5, 29.3, 29.1, 26,
22.7, 14.1.
this compound matched the reported literature values.
[h]D25 −6.4 (c 1.5, CH2Cl2), 30% e.e.; lit.3a for 22 with
99% e.e., [h]2D5 −21.2 (c 4.4, CH2Cl2).
4.19. (2R,6R)-(−)-trans-N-(tert-Butoxycarbonyl)-2-
undecyl-6-methylpiperidine [(2R,6R)-(−)-trans-N-Boc-
solenopsin A] 23
This compound was prepared by methylation of 22
according to the procedure of Buchwald et al.3a The
product was isolated by flash column chromatography
(10% EtOAc in hexane). Yield=81%. [h]2D5 −7.9 (c 2,
CH2Cl2) 30% e.e.; lit.3a for 23 with 99% e.e., [h]2D5
−26.3 (c 4.7, CH2Cl2).
4.16. N-Boc-(5S)-phenylsulfonyl-(6R)-n-undecyl-1,2,5,6-
tetrahydropyridine 20
To a stirred solution of 19 (45 mg, 0.12 mmol) in
CH2Cl2 (2 mL) was added tert-butoxycarbonyloxy-

2276
R. Kumareswaran, A. Hassner / Tetrahedron: Asymmetry 12 (2001) 2269–2276
2127–2130; (c) Munchhof, M. J.; Meyers, A. I. J. Org.
Acknowledgements
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foot, A.; Gallagher, P. J. Org. Chem. 1997, 62, 746–748; (f)
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N. J. Org. Chem. 1999, 64, 8594–8601; (k) Eskici, M.;
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Support of this research by a grant from the US–Israel
Binational Science Foundation and from the Marcus
Center for Medicinal and Pharmaceutical Chemistry is
gratefully acknowledged. We thank Professor A. I.
Meyers for providing (S)-coniine·HCl as well as HPLC
analysis of 12 and 13, and Dr. H. E. Gottlieb for
valuable help with NMR spectra.
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