A simple and efficient enantioselective route to 2,6-disubstituted piperidines: synthesis of (2R,6S)-isosolenopsin A and (2S,6R)-isosolenopsin

Article abstract of DOI:10.1016/j.tetasy.2009.03.030

The enantioselective synthesis of 2,6-cis-disubstituted piperidine alkaloids, (2R,6S)-isosolenopsin A 2 and (2S,6R)-isosolenopsin 5 from fire ant venom is described. Starting from the dodecanal and decanal, the synthesis presents two key steps. The first

Full text of DOI:10.1016/j.tetasy.2009.03.030

Tetrahedron: Asymmetry 20 (2009) 1160–1163
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A simple and efficient enantioselective route to 2,6-disubstituted
piperidines: synthesis of (2R,6S)-isosolenopsin A and (2S,6R)-isosolenopsin
R. Sateesh Chandra Kumar, Eppakayala Sreedhar, G. Venkateswar Reddy, K. Suresh Babu,
*
J. Madhusudana Rao
Natural Products Laboratory, Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective synthesis of 2,6-cis-disubstituted piperidine alkaloids, (2R,6S)-isosolenopsin A 2 and
(2S,6R)-isosolenopsin 5 from fire ant venom is described. Starting from the dodecanal and decanal, the
synthesis presents two key steps. The first step involves Keck allylation to afford the chiral homoallylal-
cohol with the required stereochemistry and the second key step consists of Grubbs olefin cross metath-
esis. The synthesis was achieved in five steps with 44% overall yield.
Received 26 February 2009
Accepted 27 March 2009
Available online 22 April 2009
Ó 2009 Published by Elsevier Ltd.
1. Introduction
Owing to the challenges posed by the substitution pattern and
also due to the remarkable biological properties, the synthesis of
Piperidine-containing alkaloids are widespread in Nature and
possess a broad spectrum of interesting biological activities.
Among the numerous naturally occurring piperidines, cis and trans
2,6-disubstituted piperidine scaffolds constitute an important class
of alkaloids.1 This 2,6-disubstituted pattern is found in many ani-
mal alkaloids2 and representative members of this family are de-
picted in Figure 1. Particularly, 2,6-cis-disubstituted piperidines
(isosolenopsins) attract considerable attention due to their broad
range of biological activities.3 Isosolenopsin A 2 and isosolenopsin
5 are perhaps the best example of these interesting compounds
that have been isolated from the venom of fire ants of the genus
Solenopsis.4 These compounds exhibit cytotoxic, haemolytic, necro-
tic, antibacterial, insecticidal, antifungal and anti-HIV properties.5
In addition, these compounds were also found to block neuromus-
cular transmissions, while isosolenopsin A at low concentrations
reduces mitochondrial respiration and uncouples oxidative phos-
phorylation through the inhibition of Na+ and K+ATPases.5,6
these compounds has attracted much attention. As a consequence,
a number of total syntheses of these compounds in racemic and
optically active forms have been established.7 However, many of
the reported methods either make use of chiral building blocks
or require longer reaction sequences; often accompanied with
low yields. The lack of efficient synthesis as well as our own inter-
est in the synthesis of enantiopure bioactives8 prompted us to
investigate the total synthesis of isosolenopsin A. Herein, we report
a short stereoselective synthesis of isosolenopsin and isosolenop-
sin A based upon the Keck allylation as the key asymmetry induc-
ing reaction.
2. Results and discussion
Duringthecourseof oursyntheticstudiesonbioactives, wefound
that Keck allylation of aldehyde derivatives using (S)-BINOL and
(R)-BINOL proceeded smoothly to provide homoallylic alcohols with
the desired enantioselectivity. Thus, our retrosynthetic strategy
(Scheme 1) relies on the Keck allylation approach starting from the
dodecanal and a well-known Grubbs cross metathesis. As shown in
Scheme 1, disconnection of 2 revealed a key fragment 13, which
could be subjected to reductive amination and diastereoselective
cyclization to realize the target molecule. The key fragment 13 was
obtained by cross metathesis of chiral homoallyl tosyl ester 11 and
methyl vinyl ketone followed by the azidation. Compound 10 could
be made from aldehyde (dodecanal) via Keck allylation.
N
N
n
n
H
H
n = 8, (2R,6S)-Isosolenopsin 1
n = 10, (2R,6S)-Isosolenopsin A 2
n = 12, (2R,6S)-Isosolenopsin B 3
n = 14, (2R,6S)-Isosolenopsin C 4
n = 8, (2S,6R)-Isosolenopsin 5
n = 10, (2S,6R )-Isosolenopsin A 6
n = 12, (2S,6R)-Isosolenopsin B 7
n = 14, (2S,6R)-Isosolenopsin C 8
Figure 1. Representative examples of isosolenopsins.
Our synthesis (Scheme 2) started with dodecanal 9, which was
subjected to Keck allylation with allyltributyltin in the presence of
(S)-BINOL and Ti(OiPr)4 to produce homoallylalcohol 10 in 84%
* Corresponding author. Tel.: +91 40 27193166; fax: +91 40 27160512.
E-mail address: janaswamy@iict.res.in (J. Madhusudana Rao).
0957-4166/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2009.03.030

R. Sateesh Chandra Kumar et al. / Tetrahedron: Asymmetry 20 (2009) 1160–1163
1161
O
N3
O
OH
N
H
n
n
n
n
H
18
n = 8, (2S,6R) Isosolenopsin, 5
n = 8, (6R),
n = 8, (4S), 15
n = 10, (4R), 10
n = 8, 14
n = 10, 9
n = 10, (2R,6S) Isosolenopsin A, 2 n = 10, (6S), 13
Scheme 1. Retrosynthetic analysis of isosolenopsins.
O
OTs
OH
c
b
a
H
10 9
10
10
11
10
OTs
O
N3
O
e
d
2
10
10
13
12
Scheme 2. Reagents and conditions: (a) I, allyltributyl tin, TI(OiPr)4, DCM, ꢀ20 °C; (b) TsCl, 1:1 pyridine, DCM; (c) Grubb’s second generation catalyst (5 mol %), DCM, 40 °C,
6 h; (d) NaN3, DMF, 70 °C, 6 h; (e) (i) Pd/C (10%), H2 (balloon); (ii) ethanolicꢁHCl.
yield. The enantiomeric purity of 10 was found to be 92% ee by
chiral HPLC.9 Protection of 2° hydroxyl group as a tosyl ester
(OTs)10 followed by a cross metathesis reaction with methyl vinyl
ketone using Grubb’s second generation catalyst (5 mol %) in DCM
lylic alcohol. The free hydroxyl group was then transformed into
the tosylate 16 in 98% yield. Treatment of this tosylate with methyl
vinyl ketone in the presence of Grubb’s second generation catalyst
(5 mol %) at 40 °C temperature yielded a,b-unsaturated ketone 17,
at 40 °C afforded
a
,b-unsaturated ketone 1211 in good yield. The
whose stereochemistry was deduced as E from its 1H NMR spec-
trum. Reaction of 17 with sodium azide in DMF afforded 18, which
finally on reductive amination followed by diastereoselective cycli-
zation using Pd/C (10%) afforded (2S,6R)-isosolenopsin (see
Scheme 3).
stereochemistry of the double bond of compound 12 was con-
firmed as E by the large coupling constant (J = 16 Hz) from the 1H
NMR spectrum. The treatment of
a,b-unsaturated ketone 12 with
NaN3 in DMF at 70 °C afforded azido compound 1310 in excellent
yield (80%). Finally, one-pot reductive amination followed by dia-
stereoselective cyclization11 using Pd/C (10%) afforded (2R,6S)-iso-
solenopsin A 2 in good yield, which was isolated and characterized
as its hydrochloride.
N
N
Cl
Ru
Cl
Ph
P(Cy)3
OH
OH
OH
OH
Grubb’s catalyst
3. Conclusion
In conclusion, the present report describes short and efficient
total syntheses of isosolenopsin and isosolenospsin A with high
enantioselectivity. Important features of this approach include (a)
Keck allylation to establish the required stereocenter and (b) Grub-
bs cross metathesis strategy for the construction of the key frag-
ment. This method allows access to both enantiomers of
isosolenopsin and isosolenopsin A depending on whether (R) or
(S)-BINOL was used as a catalyst. Thus, this flexible, efficient and
I-(S)-BINOL
II-(R)-BINOL
2.1. Synthesis of (2S,6R)-isosolenospsin
Decanal 14 was subjected to Keck allylation using (R)-BINOL
and Ti (OiPr)4 to give the homoallyl alcohol 15 with virtually com-
plete inversion of the configuration and gave the desired homoal-
OH
O
OTs
b
a
c
H
8
8
8
15
16
14
N3
O
OTs
O
e
d
5
8
8
17
18
Scheme 3. Reagents and conditions: (a) II, allyltributyl tin, TI(OiPr)4, DCM, ꢀ20 °C; (b) TsCl, 1:1 pyridine, DCM; (c) Grubb’s second generation catalyst (5 mol %), DCM, 40 °C,
6 h; (d) NaN3, DMF, 70 °C, 6 h; (e) (i) Pd/C (10%), H2 (balloon); (ii) ethanolicꢁHCl.

1162
R. Sateesh Chandra Kumar et al. / Tetrahedron: Asymmetry 20 (2009) 1160–1163
high yielding protocol developed in the present study paves the
way for the construction of related isosolenopsin derivatives for
further biological studies.
24.61, 22.63, 21.55, 14.06. HRESIMS m/z [M]+ found380.2432; cal-
culated 380.2385 for C22H36O3S.
4.1.3. (R,E)-2-Oxoheptadec-3-en-6-yl 4-methylbenzenesulfo-
nate 12
4. Experimental
In a two-necked flask equipped with nitrogen inlet, a magnetic
stirring bar and a rubber septum was placed Grubb’s second gener-
ation catalyst (0.123 g, 5 mol %). A solution of tosylate 11 (1.140 g,
3 mmol) and methyl vinyl ketone (1.050 g, 15 mmol) in CH2Cl2
(20 mL) was introduced at 40 °C temperature and the resultant
pink solution was stirred for 6 h. When TLC analysis indicated com-
plete consumption of 11, the reaction mixture was exposed to air
and concentrated to give the crude product, which was purified
by flash column chromatography on silica gel using hexane/EtOAc
4.1. General information
All commercially available reagents were used without further
purification unless otherwise stated. The solvents used were all
of AR grade and were distilled under a positive pressure of dry
nitrogen atmosphere where necessary. All reactions were per-
formed in pre-dried apparatus under an atmosphere of nitrogen
unless otherwise stated. The progress of the reactions was moni-
tored by analytical thin layer chromatography (TLC) performed
on Merck Silica Gel 60F254 plates. Visualization was performed
using 5% H2SO4 solution followed by heating. Column chromatog-
raphy was carried out using silica gel 60–120 mesh (Qingdao Mar-
ine Chemical, China). High-resolution mass spectra were obtained
on LC-MSD-Trap-SL instrument. NMR spectra were recorded on
Bruker 300 MHz spectrometers, with tetramethylsilane as an inter-
nal standard, using CDCl3. The chemical shifts are expressed as d
values in parts per million (ppm) and the coupling constants (J)
are given in hertz (Hz). Yields that were of purified compounds
were not optimized. Optical rotations were measured with JASCO
DIP 300 digital polarimeter at 25 °C.
(8:2) as eluent to give
pale yellow liquid. TLC: Rf = 0.58 (hexane/EtOAc, 80:20);
¼ þ9:0 (c 0.25, CHCl3); IR (KBr): 2925, 2855, 1677, 1458,
1360, 1178, 900, 667 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.79 (d,
a,b-unsaturated ketone 12 (1.063 g, 84%) as
a
½ ꢂ
a 2D5
.
2H, J = 8.3 Hz), 7.34 (d, 2H, J = 8.1 Hz), 6.54–6.68 (m, 1H), 6.02 (d,
1H, J = 16.0 Hz), 4.57–4.68 (m, 1H), 2.48–2.64 (m, 2H), 2.45 (s,
3H), 2.20 (s, 3H), 1.05–1.37 (m, 20H), 0.88 (t, 3H, J = 6.4 Hz). 13C
NMR (75 MHz, CDCl3): d 198.30, 144.78, 141.24, 134.23, 129.78,
127.71, 81.62, 37.37, 34.22, 31.88, 29.58, 29.49, 29.32, 29.07,
26.83, 24.74, 22.66, 21.61, 14.10. HRESIMS m/z [M+1]+ found
423.2554; calculated 423.2569 for C24H38O4S.
4.1.4. (S,E)-6-Azidoheptadec-3-en-2-one 13
To a stirred solution of
a,b-unsaturated ketone 12 (0.844 g,
4.1.1. (R)-Pentadec-1-en-4-ol 10
2 mmol) in dry DMF (10 mL) at 70 °C temperature under nitrogen
atmosphere was added sodium azide (1.300 g, 20 mmol). The reac-
tion mixture was then allowed to stir at 70 °C for 6 h and subse-
quently extracted with ethyl acetate after being quenched with
water. The combined organic extracts were washed with water,
brine, dried over anhydrous Na2SO4 and concentrated to get the
crude product, which was purified by flash column chromatogra-
phy on silica gel using hexane/EtOAc (8:2) as eluent to give azide
13 (0.468 g) as a pale yellow liquid in 80% yield. TLC: Rf = 0.70 (hex-
A mixture of (S)-BINOL (0.5 mmol, 0.143 g), 1.0 M TI(OiPr)4 in
DCM (0.5 mmol, 0.1 equiv) and over dried 4-Å molecular sieves
(2 g) in DCM (10 mL) was refluxed for 1 h. The red brown mixture
was cooled to room temperature and aldehyde 9 (5 mmol, 0.920 g)
was added. After being stirred for 10 min the contents were cooled
to ꢀ78 °C and allyltributyl tin (5.5 mmol, 1.76 mL) was added. The
reaction mixture was stirred for 10 min and then placed in a
ꢀ20 °C freezer for 70 h. Saturated NaHCO3 1.5 mL was then added
and contents were stirred for 1 h, dried over anhydrous Na2SO4 and
concentrated. The residue was purified by flash column chroma-
tography on silica gel using hexane/EtOAc (9:1) as eluent to give
10 (0.947 g, 84%) as a colourless oil.
ane/EtOAc, 80:20); ½a D25
ꢂ
¼ ꢀ2:6 (c 1.00, CHCl3); IR (KBr): 2924,
2855, 2101, 1679, 1459, 1254, 982 cmꢀ1
.
1H NMR(300 MHz,
CDCl3): d 6.70–6.83 (m, 1H), 6.16 (d, 1H, J = 16.0 Hz), 3.38–3.50
(m, 1H), 2.35–2.53 (m, 2H), 2.28 (s, 3H), 1.10–1.40 (m, 20H), 0.88
(t, 3H, J = 6.2 Hz). 13C NMR (75 MHz, CDCl3): d 198.09, 142.72,
133.73, 61.57, 37.32, 34.20, 31.88, 29.69, 29.59, 29.51, 29.45,
29.31, 27.05, 25.99, 22.67, 14.11. HRESIMS m/z [M+1]+ found
294.250; calculated 294.2545 for C17H32N3O.
TLC: Rf = 0.55 (hexane/EtOAc, 90:10); ½a D25
¼ þ4:5 (c 1.0, CHCl3);
ꢂ
IR (KBr): 3343, 2924, 2855, 1460 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d 5.75–5.92 (m, 1H), 5.07–5.20 (m, 2H), 3.57–3.70 (m, 1H), 2.07–
2.36 (m, 2H), 1.16–1.53 (m, 20H), 0.88 (t, 3H, J = 6.2 Hz). 13C NMR
(75 MHz, CDCl3): d 134.88, 117.96, 70.65, 41.87, 36.76, 31.87,
29.61, 29.57, 29.31, 25.62, 22.64, 14.07. HRESIMS m/z [M]+ found
226.2254; calculated 226.2297 for C15H30O.
4.1.5. (2R,6S)-2-Methyl-6-undecylpiperidine 2 (isosolenopsin
AꢁHCl)
To a solution of 13 (0.293 g, 1 mmol) in ethyl acetate (10 mL)
was added 10% palladium on carbon, and hydrogenated under
1 atm pressure of hydrogen at rt for 12 h. The reaction mixture
was filtered through Celite, and the filtrate was concentrated. After
addition of a few drops of ethanolic-HCl, white solid was formed.
To the resultant white solid was added ether, the insoluble part
was separated and recrystallized from CH2Cl2–ether to give
(2R,6S)-isosolenopsin A hydrochloride 2ꢁHCl as colourless crystals
4.1.2. (R)-Pentadec-1-en-4-yl 4-methylbenzenesulfonate 11
To a stirred solution of homoallyl alcohol 10 (0.904 g, 4 mmol)
in dry DCM (8 mL) at 0 °C temperature, were added pyridine
(8 mL) and tosyl chloride (0.915 g, 4.8 mmol) under a nitrogen
atmosphere. Resultant mixture was allowed to stir at room tem-
perature for overnight. The reaction mixture was then quenched
with saturated CuSO4 solution and extracted with DCM. The com-
bined organic extracts were washed with water, brine, dried over
anhydrous Na2SO4 and concentrated to yield the tosylate 11
(1.48 g) as a pale yellow liquid in 98% yield. TLC: Rf = 0.68 (hex-
in 80% yield. ½a 2D5
¼ þ7:6 (c 1.00, CHCl3); Data were in full agree-
ꢂ
ment with those reported in the literature.7a
ane/EtOAc, 90:10); ½a D25
ꢂ
¼ þ9:6 (c 1.00, CHCl3); IR (KBr): 2925,
4.1.6. (S)-Tridec-1-en-4-ol 15
2855, 1361, 1178, 903, 665 cmꢀ1
.
1H NMR (300 MHz, CDCl3): d
A mixture of (R)-BINOL (0.5 mmol, 0.143 g), 1.0 M TIP in DCM
(0.5 mmol, 0.1 equiv) and over dried 4-Å molecular sieves (2 g) in
DCM (10 mL) was heated at reflux for 1 h. The red brown mixture
was cooled to room temperature and aldehyde 14 (5 mmol,
0.780 g) was added. After being stirred for 10 min the contents
were cooled to ꢀ78 °C and allyltributyl tin (5.5 mmol, 1.76 mL)
7.79 (d, 2H, J = 8.3 Hz), 7.32 (d, 2H, J = 8.1 Hz), 5.55–5.72 (m, 1H),
4.97–5.08 (m, 2H), 4.50–4.61 (m, 1H), 2.44 (s, 3H), 2.36 (t, 2H,
J = 6.8 Hz), 1.04–1.38 (m, 20H), 0.88 (t, 3H, J = 6.2 Hz). 13C
NMR(75 MHz, CDCl3): d 144.35, 134.46, 132.25, 129.58, 127.71,
118.52, 83.03, 38.71, 33.56, 31.85, 29.56, 29.42, 29.31, 29.12,

R. Sateesh Chandra Kumar et al. / Tetrahedron: Asymmetry 20 (2009) 1160–1163
1163
was added. The reaction was stirred for 10 min and then placed in
a ꢀ20 °C freezer for 70 h. Saturated NaHCO3 1.5 mL was then
added and contents were stirred for 1 h, dried over Na2SO4 and
concentrated. The residue was purified by flash column chroma-
tography on silica gel using hexane/EtOAc (9:1) as eluent to give
15 (0.811 g, 82%) as a colourless oil. TLC: Rf = 0.54 (hexane/EtOAc,
atmosphere was added sodium azide (1.300 g, 20 mmol). After stir-
ring for 6 h at 70 °C the reaction mixture was quenched with water
and extracted with ethyl acetate. The combined organic extracts
were washed with water, brine, dried over anhydrous Na2SO4
and concentrated to give the crude product, which was purified
by flash column chromatography on silica gel using hexane/EtOAc
(8:2) as eluent to give azide 18 (0.424 g) as a pale yellow liquid in
90:10); ½a 2D5
ꢂ
¼ ꢀ7:5 (c 1.00, CHCl3); IR (KBr): 3311, 2925, 2855,
1461 cmꢀ1
.
1H NMR (300 MHz, CDCl3): d 5.74–5.90 (m, 1H),
80% yield; TLC: Rf = 0.72 (hexane/EtOAc, 80:20); ½a D25
¼ ꢀ3:6 (c
ꢂ
5.18–5.08 (m, 2H), 3.57–3.67 (m, 1H), 2.07–2.35 (m, 2H), 1.22–
1.50 (m, 16H), 0.91 (t, 3H, J = 6.0 Hz). 13C NMR (75 MHz, CDCl3):
d 134.88, 117.88, 70.62, 41.87, 36.75, 31.84, 29.60, 29.57, 29.54,
29.27, 25.62, 22.62, 14.05. HRESIMS m/z [M]+ found 198.1962; cal-
culated 198.1984 for C13H26O.
1.00, CHCl3); IR (KBr): 2926, 2857, 2102, 1678, 1459, 1255,
981 cmꢀ1 1H NMR (300 MHz, CDCl3): d 6.70–6.84 (m, 1H), 6.16
.
(d, 1H, J = 15.8 Hz), 3.38–3.51 (m, 1H), 2.35–2.54 (m, 2H), 2.28 (s,
3H), 1.19–1.64 (m, 18H), 0.88 (t, 3H, J = 6.0 Hz). 13C NMR
(75 MHz, CDCl3): d 198.01, 142.69, 133.64, 61.48, 37.23, 34.11,
31.76, 29.37, 29.20, 29.17, 26.94, 25.90, 22.57, 14.01. HRESIMS m/
z [M]+ found 265.2183; calculated 265.2154 for C15H27N3O.
4.1.7. (S)-Tridec-1-en-4-yl 4-methylbenzenesulfonate 16
To a stirred solution of homoallyl alcohol 15 (0.792 g, 4 mmol) in
dryDCM (8 mL)at0 °C temperature, wereadded pyridine(8 mL)and
tosyl chloride (0.915 g, 4.8 mmol) under a nitrogen atmosphere. The
resultant mixture was allowed to stir at room temperature for over-
night. The reaction mixture was then quenched with saturated
CuSO4 solution and extracted with DCM. The combined organic ex-
tracts were washed with water, brine, dried over anhydrous Na2SO4
and concentrated to yield the tosylate 16 (1.38 g) as a pale yellow li-
quid in 98% yield; TLC: Rf = 0.65 (hexane/EtOAc, 90:10);
4.2. (2S,6R)-2-Methyl-6-nonylpiperidine 5 (isosolenopsinꢁHCl)
To a solution of 18 (0.265 g) in ethyl acetate (10 mL) was
added 10% palladium on carbon, and hydrogenated under
1 atm pressure of hydrogen at room temperature for 12 h. The
reaction mixture was filtered through Celite, and the filtrate
was concentrated. After addition of a few drops of ethanolic-
HCl, a white solid was formed. To the resultant white solid
was added ether, the insoluble part was separated and recrystal-
lized from CH2Cl2–ether to give (2S,6R)-isosolenopsin hydrochlo-
½
a 2D5
ꢂ
¼ ꢀ13:5 (c 1.00, CHCl3); IR (KBr): 3076, 2926, 2857, 1598,
1457, 1360, 1179, 904, 665 cmꢀ1 1H NMR (300 MHz, CDCl3): d
.
7.79 (d, 2H, J = 8.1 Hz), 7.33 (d, 2H, J = 8.1 Hz), 5.55–5.72 (m, 1H),
5.08–5.97 (m, 2H), 4.50–4.61 (m, 1H), 2.44 (s, 3H), 2.35 (t, 2H,
J = 6.0 Hz), 1.49–1.63 (m, 2H), 1.05–1.63 (m, 16H), 0.88 (t, 3H,
J = 6.4 Hz). 13C NMR (75 MHz, CDCl3): d 144.34, 134.39, 132.20,
129.5, 127.66, 118.47, 82.97, 38.66, 33.51, 31.77, 29.32, 29.28,
29.17, 29.06, 24.56, 22.57, 21.49, 14.01. HRESIMS m/z [M]+ found
352.2018; calculated 352.2072 for C20H32O3S.
ride 5ꢁHCl as colourless crystals in 80% yield; ½a D25
¼ ꢀ10:1 (c
ꢂ
1.00, CHCl3); data were in full agreement with those reported
in the literature.7g
Acknowledgements
The authors thank Dr. J.S. Yadav, Director IICT for this constant
encouragement. RSCK thanks CSIR, New Delhi for financial support.
4.1.8. (S,E)-2-Oxopentadec-3-en-6-yl 4-methylbenzenesulfo-
nate 17
References
In a two-necked flask equipped with nitrogen inlet, a magnetic
stirring bar and a rubber septum was placed Grubbs second gener-
ation catalyst (0.123 g, 5 mol %). A solution of tosylate 16 (1.056 g,
3 mmol) and methyl vinyl ketone (1.050 g, 15 mmol) in CH2Cl2
(20 mL) was introduced at 40 °C temperature and the resultant
pink solution was stirred for 6 h. When TLC analysis indicated com-
plete consumption of 16, the reaction mixture was exposed to air
and concentrated to give the crude product, which was purified
by flash column chromatography on silica gel using hexane/EtOAc
1. Bailey, P. D.; Millwood, P. A.; Smith, P. D. J. Chem. Soc., Chem. Commun. 1998,
633–640.
2. Struntz, G. M.; Findlay, J. A.. In The Alkaloids; Brossi, A., Ed.; Academic: New
York, 1985; Vol. 26, pp 89–193.
3. Schneider, M.. In Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W.,
Ed.; Pergamon: Oxford, 1996; Vol. 10, pp 155–299.
4. Leclerq, S.; Thirionet, I.; Broeders, F.; Daloze, D.; Vander Meer, R.; Braeckman, J.
C. Tetrahedron 1994, 50, 8465–8478.
5. Jones, T. H.; Blum, M. S.; Fales, H. M. Tetrahedron 1982, 38, 1949–1958.
6. (a) Jefford, C. W.; Wang, J. B. Tetrahedron Lett. 1991, 34, 2911–2914; (b)
Numata, A.; Ibuka, T.. In The Alkaloids; Brossi, A., Ed.; Academic Press: New
York, 1987; Vol. 31, pp 193–317.
7. For previous stereoselective synthesis of isosolenopsin A: (a) Monfray, J.;
Mialhe, Y. J.; Gramain, J. C.; Remuson, R. Tetrahedron: Asymmetry 2005, 16,
1025–1034; (b) Jefford, C. W.; Wang, J. B. Tetrahedron Lett. 1993, 34, 2911–
2914; (c) Poerwono, H.; Higashiyama, K.; Yamauchi, T.; Kubo, H.; Ohmiya, S.;
Takahashi, H. Tetrahedron 1998, 54, 13955–13970; (d) Ciblat, S.; Besse, P.;
Papastergiou, V.; Veschambre, H.; Canet, J.-L.; Troin, Y. Tetrahedron: Asymmetry
2000, 11, 2221–2229; (e) Gonzalez, G. J. C.; Francisco, F.; Miguel, Y. Synlett
2008, 18, 2777–2780; (f) Bandara Herath, H. M. T.; Dhammika Nanayakkara, N.
P. J. Heterocycl. Chem. 2008, 45, 129–136; (g) Wang, X.; Dong, Y.; Sun, J.; Xu, X.;
Li, R.; Hu, Y. J. Org. Chem. 2005, 70, 1897–1900.
8. Sreedhar, E.; Kumar, R. S. C.; Reddy, G. V.; Robinson, A.; Babu, K. S.; Rao, J. M.;
Srinivas, P. V. Tetrahedron: Asymmetry 2009, 20, 440–448.
9. (a) Yadav, J. S.; Sridhar Reddy, M.; Prasad, A. R. Tetrahedron Lett. 2006, 47, 4995–
4998; (b) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115,
8467–8468.
(8:2) as eluent to give
pale yellow liquid; TLC: Rf = 0.60 (hexane/EtOAc, 80:20);
¼ ꢀ22:9 (c 0.75, CHCl3); IR (KBr): 2925, 2855, 1677, 1458,
1359, 1177, 899, 667 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.79 (d,
a,b-unsaturated ketone 17 (0.991 g, 84%) as
a
½ ꢂ
a 2D5
.
2H, J = 8.3 Hz), 7.34 (d, 2H, J = 8.3 Hz), 6.02 (d, 1H, J = 15.8 Hz),
5.97–6.07 (m, 2H), 4.57–4.68 (m, 1H), 2.48–2.63 (m, 2H), 2.45 (s,
3H), 2.20 (s, 3H), 1.45–1.70 (m, 2H), 1.06–1.37 (m, 16H), 0.88 (t,
3H, J = 6.6 Hz). 13C NMR (75 MHz, CDCl3): d 197.92, 144.72,
141.20, 134.15, 129.71, 127.62, 81.57, 37.27, 34.12, 31.74, 29.28,
29.23, 29.14, 28.96, 26.73, 24.63, 22.55, 21.51, 14.01. HRESIMS m/
z [M]+ found 394.2199; calculated394.2178 for C22H34O4S.
4.1.9. (R,E)-6-Azidopentadec-3-en-2-one 18
10. Capaccio, C. A. I.; Varela, O. Tetrahedron: Asymmetry 2000, 11, 4945–4954.
11. Randl, S.; Blechert, S. Tetrahedron Lett. 2004, 45, 1167–1169.
To a stirred solution of
a,b-unsaturated ketone 17 (0.788 g,
2 mmol) in dry DMF (10 mL) at 70 °C temperature under nitrogen