Stereoselective total synthesis of the piperidine alkaloids, (+)-coniine, (+)-pseudoconhydrine, and (+)-sedamine through a common intermediate

Article abstract of DOI:10.1016/j.tetasy.2011.06.011

The stereoselective total synthesis of the piperidine alkaloids, (+)-coniine, (+)-pseudoconhydrine and (+)-sedamine has been achieved through a common intermediate generated from butane-1,4-diol. The synthetic sequence involves a Maruoka asymmetric allylation and ring-closing metathesis as the key steps.

Full text of DOI:10.1016/j.tetasy.2011.06.011

Tetrahedron: Asymmetry 22 (2011) 1000–1005
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective total synthesis of the piperidine alkaloids, (+)-coniine,
(+)-pseudoconhydrine, and (+)-sedamine through a common intermediate q
⇑
Gandham Satyalakshmi, Kanaparthy Suneel, Digambar Balaji Shinde, Biswanath Das
Organic Chemistry 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:
Received 19 April 2011
Accepted 9 June 2011
The stereoselective total synthesis of the piperidine alkaloids, (+)-coniine, (+)-pseudoconhydrine and (+)-
sedamine has been achieved through a common intermediate generated from butane-1,4-diol. The syn-
thetic sequence involves a Maruoka asymmetric allylation and ring-closing metathesis as the key steps.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
imidazole (Scheme 2). The silylated ether 7 underwent oxidation
with PCC followed by Maruoka allylation8 with allyltributylstann-
Piperidine alkaloids are widespread in Nature and many of
these compounds are known to possess interesting biological prop-
erties.1 Much effort has been devoted to the isolation and charac-
terization of these bases. However, these compounds are
generally obtained in small quantities from natural sources. As a
result, several synthetic methods have been discovered for the
preparation of these alkaloids.2 In a continuation of our work3 on
asymmetric routes to the natural bioactive compounds, we herein
report the total synthesis of three piperidine alkaloids, (+)-coniine
1, (+)-pseudoconhydrine 2 and (+)-sedamine 3. The first two com-
pounds 1 and 2 were isolated from Conium maculatum4a while the
other three from Sedum acre.4b,4c All of these three alkaloids, 1,5 26
and 37 have attracted the attention of organic chemists.
ane in the presence of the (S)-Binol complex (S,S)-I to produce the
chiral homoallylic alcohol 5 (96% ee). The latter was treated with
MsCl and this mesylate underwent nucleophilic displacement by
a SN2 process with allylamine in DMF at 50 °C to afford the amine
derivative 8 (92% ee) with an inverse configuration of the required
stereocenter of the target molecule 1. This was supported by its
opposite specific rotation value, ½a D25
¼ þ11:6 (c 0.5, CHCl3), com-
ꢀ
pared to that of homoallylic alcohol 5, ½a D25
¼ ꢁ5:4 (c 0.5, CHCl3).
ꢀ
Amine 8 was treated with (Boc)2O to form 9 and the TBS ether
group of the latter was deprotected. The resulting compound 10
was subjected to a ring-closing metathesis (RCM) reaction9 using
a Grubbs’ second generation catalyst to give the cyclic tetrahydro-
pyridine derivative 4, a common intermediate useful for the syn-
thesis of 1–3. Compound 4 was treated with I2 and imidazole to
form the corresponding iodide derivative, which was reduced with
Zn/AcOH10 to produce (+)-coniine derivative 11. The reduction of
the olefinic double bond of 11 with H2/Pd–C followed by treatment
with aqueous HCl and washing with NaOH solution afforded (+)-
coniine 1.4a This compound was treated with a 2 M solution of
dry HCl in EtOH and the resulting residue was recrystallized from
ether. The melting point of this hydrochloride salt of 1 was 195–
OH
N
HN
HN
OH
Ph
3
2
1
197 °C (lit. mp 195 °C) and
½
a 2D5
ꢀ
¼ þ8:6 (c 0.8, EtOH) {lit.
½
a 2D2
ꢀ
¼ þ8:3 (c 0.7, EtOH)}. Its spectroscopic data also matched well
2. Results and discussion
with those of the reported compound.5c
Compound 11 derived from the common intermediate 4 was
used for the synthesis of (+)-pseudoconhydrine 2 (Scheme 3).
The double bond of 11 was selectively hydrated11 using BH3ꢂDMS
and H2O2 to produce the Boc-protected (+)-pseudoconhydrine 13
and its diastereoisomer in a 9:1 ratio. Both diastereoisomers were
separated. Compound 13 upon treatment with aqueous HCl, fol-
lowed by washing with a NaOH solution yielded (+)-pseudoconhy-
drine 2. By following the above procedure, the hydrochloride salt of
2 was prepared. The melting point of this compound was 204–
The retrosynthetic analysis of compounds 1–3 (Scheme 1) re-
vealed that these compounds can be prepared from a common
intermediate 4 which, in turn, can be obtained from the homoal-
lylic alcohol 5 generated from readily available butane-1,4-diol 6.
The synthesis of (+)-coniine was initiated by converting butane-
1,4-diol 6 into mono-silylated ether 7 by treatment with TBSCl and
q
Part 46 in the series ‘Synthetic studies on natural products’.
⇑
Corresponding author.
E-mail address: biswanathdas@yahoo.com (B. Das).
206 °C (lit. mp 208 °C) and
½
a 2D5
ꢀ
¼ þ3:0 (c 0.4, MeOH) {lit.
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.06.011

G. Satyalakshmi et al. / Tetrahedron: Asymmetry 22 (2011) 1000–1005
1001
OiPr
Ti
O
O
N
N
O
O
O
Cl
Ti
iPrO
Ru
Cl
Ph
P(Cy)3
I
Grubbs' II generation catalyst
(S,S)-
HN
1
OH
OH
BocN
HN
TBSO
HO
5
2
4
OH
N
HO
OH
3
6
Scheme 1. Retrosynthetic analysis of 1–3.
OH
R'N
b
RO
c
TBSO
OR'
RO
6
7
R = R' = H
R = TBS, R' = H
a
5
8
9
R = TBS, R' = H
d
e
R = TBS, R' = Boc
10
R = H, R' = Boc
BocN
BocN
RN
f
g
h
HO
4
12 R = Boc
1 R = H
11
i
Scheme 2. Synthesis of (+)-coniine 1. Reagents and conditions: (a) TBSCl, imidazole, DCM, 0 °C to rt, 0.5 h, 90%; (b) (i) PCC, DCM, 0 °C to rt, 0.5 h, 90%, (ii) (S,S)-I,
CH2@CHCH2SnBu3, DCM, ꢁ15 to 0 °C, 72 h, 85%; (c) (i) MsCl, Et3N, DMAP, DCM, 0 °C to rt, 1 h, (ii) allylamine, DMF, H2O, 50 °C, 30 h, 78% (over two steps); (d) (Boc)2O, Et3N,
DCM, rt, 3 h, 92%; (e) pTSA, THF/H2O (3:1), rt, 0.5 h; 89%; (f) Grubbs’ II catalyst (10 mol %), DCM, reflux at 50 °C, 4 h, 90%; (g) (i) I2, TPP, imidazole, CH3CN/ether (1:3), 0 °C to rt
15 min; (ii) Zn, DCM, rt, 30 min, then AcOH, 0 °C to rt, 0.5 h, 80% (over two steps); (h) H2/Pd–C, EtOAc, rt, 2 h, 91%; (i) 5 M HCl, THF, rt, 89%.
with H2/Pd–C to afford product 14 (Scheme 4). Treatment of 14
with I2 and imidazole and subsequently with tBuOK generated
OH
the olefinic compound 15.12 The latter was treated with RuCl3
and NaIO4 and the resulting aldehyde with PhMgBr to produce
alcohol 16 and its diastereoisomer in a 95:5 ratio.13 The major
product 16 was separated and then treated with LiAlH4 to afford
(+)-sedamine 3 with a melting point of 56–58 °C (lit. mp 54–
RN
a
11
13 R = Boc
R = H
b
2
56 °C), ½a 2D5
ꢀ
¼ þ86:3 (c 1.0, EtOH) {lit. ½a D20
¼ þ86:8 (c 1.0, EtOH)}.
ꢀ
Scheme 3. Synthesis of (+)-pseudoconhydrine 2. Reagents and conditions: (a)
BH3.SMe2, THF, ꢁ78 °C to rt, 20 h, then H2O, 20% NaOH, 30% H2O2, rt, 2 h, 90%; (b)
5 N HCl, THF, rt, 0.5 h, 87%.
The spectroscopic properties of 3 were identical to those reported
in the literature.7e
½
a 2D0
ꢀ
¼ þ2:6 (c 0.47, MeOH)}. The spectroscopic data of this com-
3. Conclusion
pound matched well with the previous report.6c
Finally, the synthesis of (+)-sedamine 3 was achieved from the
common intermediate 4 by saturating its olefinic double bond
In conclusion, we have synthesized the piperidine alkaloids, (+)-
coniine, (+)-pseudoconhydrine and (+)-sedamine starting from a

1002
G. Satyalakshmi et al. / Tetrahedron: Asymmetry 22 (2011) 1000–1005
BocN
BocN
OH RN
c
b
a
4
HO
Ph
d
16 R = Boc
14
15
3
R = Me
Scheme 4. Synthesis of (+)-sedamine 3. Reagents and conditions: (a) H2/ Pd–C, EtOAc, rt, 2 h, 91%; (b) (i) I2, TPP, imidazole, CH3CN/ether (1:3), 15 min, (ii) tBuOK, THF, 0 °C to
rt, 15 min, 85% (over two steps); (c) (i) RuCl3, NaIO4, CH3CN/H2O (6:1), 1 h; (ii) PhMgBr, THF, ꢁ78 °C, 56% (over two steps); (d) LiAlH4, THF, rt, 8 h, 78%.
common intermediate generated from butane-1,4-diol, involving
Maruoka allylation and RCM as the key steps. This method can
be utilized for the synthesis of several other related piperidine
alkaloids.
lowed to warm to 0 °C and stirred for 20 h. The mixture was
quenched with aqueous saturated NaHCO3 (25 mL) and extracted
with CH2Cl2 (3 ꢃ 50 mL). The organic extracts were dried over anhy-
drous Na2SO4. Evaporation of the solvents and purification of the
residue by column chromatography(ethyl acetate/hexane, 2:8) gave
pure (R)-7-(tert-butyldimethylsilyloxy)hept-1-en-4-ol 5 (4.148 g,
4. Experimental
4.1. General
85%) as a colorless liquid. ½a D25
ꢀ
¼ ꢁ5:4 (c 0.5, CHCl3); IR:
m 3449,
1619, 1457, 1401, 1250 cmꢁ1
;
1H NMR (200 MHz, CDCl3): d 5.79
(1H, m), 5.12–5.03 (2H, m), 3.67–3.56 (3H, m), 2.51 (1H, br s),
2.25–2.10 (2H, m), 1.68–1.52 (3H, m), 1.41 (1H, m), 0.89 (9H, s),
0.02 (6H, s); 13C NMR (50 MHz, CDCl3): d 135.2, 117.5, 70.7, 63.5,
42.2, 34.0, 29.2, 26.1, 18.5, ꢁ5.2; ESIMS: m/z 245 [M+H]+ Anal. Calcd
for C13H28NOSi: C, 63.87; H, 11.55%. Found: C, 63.94; H, 11.49%.
Silica gel F254 plates were used for thin layer chromatography
(TLC) in which the spots were examined under UV light and then
developed by an iodine vapor. Column chromatography was per-
formed with silica gel (BDH 100–200 mesh). Solvents were purified
according to standard procedures. The spectra were recorded with
the following instruments; IR: Perkin-Elmer RX FT-IR spectropho-
tometer; NMR: Varian Gemini 200 MHz (1H) and 50 MHz (13C)
spectrometer; ESIMS: VG-Autospec micromass. Organic extracts
were dried over anhydrous Na2SO4. Optical rotations were mea-
sured with JASCO DIP 300 digital polarimeter at 25 °C.
4.1.3. (S)-N-allyl-7-(tert-Butyldimethylsilyloxy)hept-1-en-4-
amine 8
To a stirred solution of alcohol 5 (4.1 g, 16.8 mmol) in CH2Cl2
(30 mL) was added dried Et3N (2.206 g, 21.84 mmol) at room tem-
perature under a nitrogen atmosphere. To this solution, a catalytic
amount of DMAP was added and the mixture was stirred for
15 min. The reaction mixture was cooled to 0 °C, after which mesyl
chloride (2.298 g, 20.16 mmol) was added and stirred for 1 h. The
reaction mixture was quenched with saturated aqueous NaHCO3
(30 mL) and extracted with CH2Cl2 (3 ꢃ 40 mL). The extract was
dried over anhydrous Na2SO4 and concentrated in vacuo. The crude
mesylate (4.97 g, 92%) thus obtained was used without further
purification. The crude mesylate (4.97 g, 15.2 mmol) was dissolved
in dry DMF (60 mL) and to this was added allylamine (17.33 g,
304 mmol) at room temperature. This reaction mixture was
warmed to 50 °C and refluxed for 36 h. The reaction mixture was
allowed to cool to room temperature and extracted with ether
(3 ꢃ 50 mL). The combined organic extracts were washed with
brine (2 ꢃ 20 mL), dried over anhydrous Na2SO4 and concentrated
in vacuo. The residue on purification by column chromatography
(ethyl acetate/hexane, 4:6) afforded pure (S)-N-allyl-7-(tert-butyl-
dimethylsilyloxy)hept-1-en-4-amine 8 (3.66 g, 85%) as a yellow li-
4.1.1. 4-(tert-Butyldimethylsilyloxy)butan-1-ol 7
To a stirred solution of butanediol 6 (2.25 g, 25 mmol) in CH2Cl2
(50 mL) was added imidazole (2.04 g, 30 mmol) at room tempera-
ture. After 15 min, to this stirred solution, TBDMS–Cl (3.75 g,
25 mmol) was added. The reaction mixture was stirred for
30 min. It was then concentrated in vacuo and the reaction mixture
purified by column chromatography (ethyl acetate/hexane, 2:8) to
afford pure 4-(tert-butyldimethylsilyloxy)butan-1-ol
7
(4.59 g,
90%) as a colorless liquid. IR:
m
3387,1467, 1255, 1117 cmꢁ1
;
1H
NMR (200 MHz, CDCl3): d 3.61 (2H, t, J = 7.0 Hz), 3.54 (2H, t,
J = 7.0 Hz), 2.75 (1H, br s), 1.62–1.51 (4H, m), 0.83 (9H, s), 0.01
(6H, s); 13C NMR (50 MHz, CDCl3): d 63.5, 62.6, 30.0, 29.7, 25.8,
18.2, ꢁ3.8; ESIMS: m/z 205 [M+H]+ Anal. Calcd for C10H24O2Si: C,
58.77; H, 11.84. Found: C, 58.67; H, 11.89.
4.1.2. (R)-7-(tert-Butyldimethylsilyloxy)hept-1-en-4-ol 5
To a stirred suspension of Celite in CH2Cl2 (20 mL) was added a
solution of compound 7 (4.56 g, 22.3 mmol) in CH2Cl2 (30 mL) at
room temperature. To this suspension pyridinium chlorochromate
(8.63 g, 40.14 mmol) was added at 0 °C and the mixture was
warmed to room temperature. After 1 h, the reaction mixture
was filtered off through a Celite pad. The filtrate was concentrated
under reduced pressure and the residue was purified by column
chromatography (1:9). The purified aldehyde (4.059 g, 90%) was
directly subjected to allylation.
quid. ½a 2D5
ꢀ
¼ þ11:6 (c 0.5, CHCl3); IR:
m 3425, 1639, 1560, 1459,
1220 cmꢁ1
;
1H NMR (200 MHz, CDCl3): d 5.89 (1H, m), 5.72 (1H,
m), 5.28–5.07 (2H, m), 3.68-3.55 (3H, m), 3.39–3.32 (2H, m), 2.72
(1H, m), 2.30–2.22 (2H, m), 1.62–1.51 (3H, m), 1.38 (1H, m), 0.83
(9H, s), 0.02 (6H, s); 13C NMR (50 MHz, CDCl3): d 137.0, 136.2,
117.4, 115.9, 63.0, 55.1, 46.0, 38.9, 29.8, 27.7, 26.2, 18.8, ꢁ5.1;
ESIMS: m/z 284 [M+H]+ Anal. Calcd for C16H33NOSi: C, 67.78; H,
11.73; N, 4.94. Found: C, 67.84; H, 11.67; N, 4.86%.
To a stirred solution of TiCl4 (0.189 g, 1 mmol) in CH2Cl2 (15 mL)
was added dried Ti(OiPr)4 (0.852 g, 3 mmol) at 0 °C under a nitrogen
atmosphere and the mixture was allowed to warm to room temper-
ature. After 1 h, silver(I) oxide (0.462 g, 2 mmol) was added and the
reaction was continued for 5 h under the exclusion of direct light.
The mixture was diluted with CH2Cl2 (30 mL) and treated with (S)-
BINOL (1.144 g, 4 mmol) at room temperature for 2 h to furnish
the chiral bis-Ti(IV)oxide (S,S)-I. This complex was cooled to
ꢁ15 °C and treated sequentially with a solution of aldehyde
(4.04 g, 20 mmol) in dry CH2Cl2 (20 mL) and allyltributyltin
(8.606 g, 26 mmol) at the same temperature. The mixture was al-
4.1.4. (S)-tert-Butyl allyl(7-(tert-butyldimethylsilyloxy)hept-1-
en-4-yl)carbamate 9
To a stirred solution of amine 8 (3.6 g, 12.7 mmol) in dry CH2Cl2
(25 mL) under a nitrogen atmosphere at room temperature was
added Et3N (1.67 g, 16.5 mmol). The reaction mixture was stirred
for 15 min, after which was added (Boc)2O (3.045 g, 13.97 mmol)
and further stirred for 3 h. The reaction mixture was quenched
with aqueous saturated NH4Cl (15 mL) and extracted with EtOAc
(3 ꢃ 30 mL). The combined organic extracts were dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue on

G. Satyalakshmi et al. / Tetrahedron: Asymmetry 22 (2011) 1000–1005
1003
purification by column chromatography (ethyl acetate/hexane,
4.1.7.1. Activation of zinc.
Zinc dust was treated with 10%
0.5:9:5) afforded pure (S)-tert-butyl allyl(7-(tert-butyldimethylsi-
lyloxy)hept-1-en-4-yl)carbamate 9 (4.48 g, 92%) as a colorless li-
HCl for 10 min, then the dark solution was filtered, washed with
water and acetone. The solid collected was dried at 50–60 °C for
30 min and stored in desiccators.
quid.
½
a 2D5
ꢀ
¼ þ45:4 (c 0.6, CHCl3); IR:
m 1693, 1457, 1365,
1250 cmꢁ1
;
1H NMR (200 MHz, CDCl3): d 5.91–5.62 (2H, m),
To a stirred solution of iodide (0.34 g, 0.97 mmol) in dry CH2Cl2
(2 mL) at room temperature was added zinc dust (0.252 g,
3.88 mmol) under nitrogen. The suspension was stirred for
30 min and at 0 °C, after which 0.4 mL of glacial acetic acid was
added slowly. The reaction mixture was warmed to room temper-
ature and stirred for another 30 min. After completion of the reac-
tion (monitored with TLC), the reaction mixture was filtered
through a Celite pad with CH2Cl2. The filtrate was extracted with
CH2Cl2 (3 ꢃ 15 mL) and washed with an aqueous saturated NaH-
CO3 (10 mL) solution and brine solution (8 mL). The organic layer
was dried over anhydrous Na2SO4 and concentrated in vacuo.
The product was purified by column chromatography (ethyl ace-
tate/hexane, 0.1:9.9) to afford (S)-tert-butyl 6-propyl-5,6-dihydro-
pyridine-1(2H)-carboxylate 11 (0.183 g, 84%) as a colorless liquid.
5.16–4.94 (4H, m), 3.70 (1H, m), 3.62–3.51 (4H, m), 2.32–2.11
(2H, m), 1.54–1.50 (2H, m), 1.46 (9H, s), 1.38–1.24 (2H, m), 0.89
(9H, s), 0.02 (6H, s); 13C NMR (50 MHz, CDCl3): d 156.4, 137.4,
136.5, 117.1, 115.5, 79.2, 62.6, 55.1, 45.7, 38.3, 29.6, 28.4, 27.8,
26.0, 18.5, ꢁ0.51; ESIMS: m/z 384 [M+H]+ Anal. Calcd for
C21H41NO3Si: C, 65.75; H, 10.77; N, 3.65. Found: C, 65.81; H,
10.82; N, 3.58%.
4.1.5. (S)-tert-Butyl allyl(7-hydroxyhept-1-en-4-yl)carbamate 10
To a stirred solution of compound 9 (4.44 g, 11.6 mmol) in THF/
H2O (20 mL, 3:1) was added p-TSA (0.199 g, 1.16 mmol) at room
temperature. The reaction mixture was stirred for 15 min and
quenched with aqueous saturated solution of NaHCO3 (15 mL).
The reaction mixture was extracted with EtOAc (2 ꢃ 40 mL) and
the combined organic extracts were dried over anhydrous Na2SO4
and concentrated in vacuo. The residue on purification by column
chromatography (ethyl acetate/hexane, 2:8) afforded pure (S)-tert-
butyl allyl(7-hydroxyhept-1-en-4-yl)carbamate 10 (2.775 g, 89%)
½
a 2D5
ꢀ
¼ þ15:7 (c 0.6, CHCl3); IR:
m 1693, 1460, 1370, 1256,
1119 cmꢁ1 1H NMR (200 MHz, CDCl3): d 5.70–5.49 (2H, m),
;
4.42–4.01(2H, m), 3.40 (1H, m), 2.38 (1H, m), 1.82 (1H, m), 1.46
(9H, s), 1.33–1.12 (4H, m), 0.85 (3H, t, J = 7.0 Hz); 13C NMR
(50 MHz, CDCl3): d 153.4, 123.8, 122.9, 79.3, 64.2, 48.4, 39.3,
33.9, 28.4, 19.5, 14.0; ESIMS: m/z 226 [M+H]+ Anal. Calcd for
as colorless liquid. ½a D25
ꢀ
¼ þ39:6 (c 0.4, CHCl3); IR:
m 3442, 1681,
C13H23NO2: C, 69.29; H, 10.29; N, 6.22%. Found: C, 69.19; H,
1451, 1366, 1247, 1169 cmꢁ1
;
1H NMR (200 MHz, CDCl3): d 5.90–
10.33; N, 6.29%.
5.61 (2H, m), 5.18–4.96 (4H, m), 3.71 (1H, m), 3.64–3.52 (4H, m),
2.38–2.10 (2H, m), 1.64–1.52 (4H, m), 1.46 (9H, s); 13C NMR
(50 MHz, CDCl3): d 156.2, 136.4, 135.8, 117.0, 116.1, 79.4, 62.8,
54.9, 45.2, 38.1, 29.1, 28.5, 25.8; ESIMS: m/z 270 [M+H]+ Anal.
Calcd for C15H27NO3: C, 66.88; H, 10.10; N, 5.20%. Found: C,
66.81; H, 10.15; N, 5.28%.
4.1.8. (S)-tert-Butyl 2-propylpiperidine-1-carboxylate 12
To a solution of compound 11 (0.08 g, 0.36 mmol) in EtOAc
(3 mL) was added 10% Pd/C under hydrogen. After 2 h the reaction
mixture was filtered through Celite and concentrated in vacuo. The
residue on purification by column chromatography (ethyl acetate/
hexane, 0.1:9.9) afforded (S)-tert-butyl 2-propylpiperidine-1-car-
boxylate 12 (0.074 g, 91%) as colorless liquid. ½a D25
ꢀ
¼ þ16:1 (c 0.4,
4.1.6. (S)-tert-Butyl 6-(3-hydroxypropyl)-5,6-dihydropyridine-
1(2H)-carboxylate 4
CHCl3); IR:
m ;
1683, 1356, 1252, 1112, 952 cmꢁ1 1H NMR
A solution of compound 10 (0.7 g, 2.6 mmol) in dry CH2Cl2
(150 mL) was first bubbled with a nitrogen flow, after which
Grubb’s second generation catalyst (10 mol %) was added and the
resulting mixture was heated under nitrogen at 50 °C for 6 h. After
cooling, the solvent was evaporated in vacuo. The residue on puri-
fication by column chromatography (ethyl acetate/hexane, 0.5:9.5)
afforded pure (S)-tert-butyl 6-(3-hydroxypropyl)-5,6-dihydropyri-
dine-1(2H)-carboxylate 4 (0.564 g, 90%) as a colorless liquid.
(200 MHz, CDCl3): d 3.50 (1H, m), 3.12–2.89 (2H, m), 2.01–1.70
(5H, m), 1.69–1.52 (2H, m), 1.51–1.33 (12H, m), 0.91 (3H, t,
J = 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 152.3, 79.2, 57.2, 44.1,
34.8, 28.3, 22.6, 22.3, 19.4, 13.7; ESIMS: m/z 128 [M+H]+ Anal.
Calcd for
C13H25NO2: C, 68.68; H, 11.08; N, 6.16%. Found:
C,68.55; H, 11.15; N, 6.21.
4.1.9. (S)-2-Propylpiperidine 1
½
a 2D5
ꢀ
¼ þ32:5 (c 0.6, CHCl3); IR:
m 3380, 1697, 1634, 1457,
To a stirred solution of compound 12 (0.05 g, 0.22 mmol) in THF
(1 mL) was added 0.5 mL of 5 M HCl at room temperature. After
completion of the reaction, the reaction mixture was basified with
5% NaOH solution. The reaction mixture was extracted with EtOAc
(3 ꢃ 10 mL) and washed with brine solution. The organic layers
were dried over anhydrous Na2SO4 and concentrated under re-
duced pressure. The obtained residue was free amine 1 (0.026 g,
89%). This free amine was used to prepare a HCl salt by adding
dry ethanolic HCl. After 10 min., the reaction was completed and
the reaction mixture was filtered through Wattman filter paper.
The white solid obtained (0.033 g) was the HCl salt of coniine 1.
The spectroscopic data of the compound were found to be identical
to those reported earlier.5c
1364 cmꢁ1 1H NMR (200 MHz, CDCl3): d 5.76–5.53 (2H, m),
;
4.47–4.08 (3H, m), 3.69–3.55 (2H, m), 3.46 (1H, m), 2.50–2.33
(2H, m), 1.91 (1H, m), 1.66 (1H, m), 1.59–1.43 (2H, m), 1.41 (9H,
s); 13C NMR (50 MHz, CDCl3): d 156.2, 123.5, 122.9, 80.0, 62.3,
60.1, 48.1, 29.7, 29.0, 28.3, 27.7; ESIMS: m/z 242 [M+H]+ Anal.
Calcd for C13H23NO3: C, 64.70; H, 9.61; N, 5.80. Found: C, 64.78;
H, 9.55; N, 5.88.
4.1.7. (S)-tert-Butyl 6-propyl-5,6-dihydropyridine-1(2H)-
carboxylate 11
To a stirred solution of alcohol 4 (0.25 g, 1.04 mmol) in acetoni-
trile/ether (8 mL, 3:1) were added imidazole (0.163 g, 2.39 mmol),
TPP (0.545 g, 2.08 mmol) and iodine (0.526 g, 2.08 mmol) sepa-
rately at 0 °C under nitrogen. After 15 min the reaction was
quenched by an aqueous saturated sodium thiosulfate (Na2S2O3)
solution (4 mL). The organic portions were extracted with CH2Cl2
(3 ꢃ 20 mL) and the extract was washed with brine solution
(20 mL). The organic layer was dried over Na2SO4 and concentrated
under reduced pressure. The product was purified by column chro-
matography (ethyl acetate/hexane, 0.2:9.8) to afford iodide
(0.349 g, 96%) as a yellow viscous liquid. This iodide was used for
the next step without characterization.
4.1.10. (2S,5S)-tert-Butyl 5-hydroxy-2-propylpiperidine-1-
carboxylate 13
To a stirred solution of compound 11 (0.08 g, 0.36 mmol) in dry
THF (33 mL) was added BH3.DMS (2.7 g, 36 mmol) under nitrogen
at ꢁ78 °C. The reaction mixture was warmed to room temperature
and stirred for 36 h. Next, were added H2O (0.55 mL), 20% aq NaOH
(0.8 mL) and 30% aq H2O2 (0.8 mL) and stirred for 2 h, after which
H2O (4 mL) was added. The organic layer was extracted with EtOAc
(3 ꢃ 10 mL) and dried over anhydrous Na2SO4. The organic layer

1004
G. Satyalakshmi et al. / Tetrahedron: Asymmetry 22 (2011) 1000–1005
was concentrated in vacuo and the residue on purification by
column chromatography (ethyl acetate/hexane, 4:6) afforded
(2S,5S)-tert-butyl 5-hydroxy-2-propylpiperidine-1-carboxylate 13
4.1.14. (R)-tert-Butyl 2-((R)-2-hydroxy-2-phenylethyl)piperid-
ine-1-carboxylate 16
To a stirred solution of compound 15 (0.150 g, 0.67 mmol) and
RuCl3 (1 mL, 0.0235 mmol, 3.5 mol %) in CH3CN (4 mL) and distilled
water (0.67 mL) was added NaIO4 (0.286 g, 1.34 mmol) at room
temperature. After 1 h, the reaction was quenched with an aq sat-
urated solution of hypo (5 mL). The aqueous layer was extracted
with EtOAc (3 ꢃ 15 mL) and washed with brine solution (6 mL).
The combined organic layers were dried over anhydrous Na2SO4
and concentrated in vacuo. The residue was purified by column
chromatography (ethyl acetate/hexane, 0.2:9.8) to afford (0.106 g,
70%) as a colorless liquid. Without characterization this aldehyde
was used for the next step.
(0.077 g, 90%) as a colorless liquid. ½a D25
ꢀ
¼ þ9:3 (c 0.4, CHCl3); IR:
m
3446, 1689, 1459, 1369, 1247 cmꢁ1
;
1H NMR (200 MHz, CDCl3):
d 5.12 (1H, br s), 4.28 (1H, m), 4.08 (1H, m), 3.92–3.48 (2H, m),
1.94 (1H, m), 1.72–1.52 (4H, m), 1.48 (9H, s), 1.39–1.25 (3H, m),
0.91 (3H, t, J = 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 155.5, 79.8,
68.9, 62.0, 49,1, 37.0, 31.8, 28.4, 25.5, 19.2, 13.9; ESIMS: m/z 266
[M+Na]+ Anal. Calcd for C13H25NO3: C, 64.16; H, 10.36; N, 5.76%.
Found: C, 64.21; H, 10.25; N, 5.69%.
4.1.11. (3S,6S)-6-Propylpiperidin-3-ol 2
Magnesium metal turnings (0.027 g, 1.125 mmol) were placed
into a two necked round bottom flask after which were added
dry THF (2 mL) and then bromobenzene (0.118 g, 0.75 mmol)
slowly under nitrogen at room temperature. The reaction mixture
was stirred until the solution became an ash color. The solution of
the aldehyde (0.106 g, 0.47 mmol) in dry THF (2 mL) was added
dropwise to the above freshly prepared Grignard reagent at
ꢁ78 °C. The reaction mixture was stirred for 4 h at ꢁ78 °C. The
reaction was quenched with aqueous saturated NH4Cl solution
(3 mL). The aqueous layer was extracted with EtOAc (3 ꢃ 15 mL)
and washed with a brine solution (8 mL). The combined organic
layers were dried over anhydrous Na2SO4 and concentrated in va-
cuo. The residue was purified by column chromatography (ethyl
acetate/hexane, 2:8) to afford (R)-tert-butyl 2-((R)-2-hydroxy-2-
phenylethyl)piperidine-1-carboxylate 16 (0.114 g, 80%) as a color-
The HCl salt of pseudoconhydrine 2 (0.031 g, 87%, white precip-
itate) was prepared from 13 following the same procedure as that
described for the synthesis of the HCl salt of coniine 1. The spectro-
scopic data of the compound were found to be identical to those
reported earlier.6c
4.1.12. (R)-tert-Butyl 2-(3-hydroxypropyl)piperidine-1-
carboxylate 14
To a solution of compound 4 (0.280 g, 1.16 mmol) in EtOAc
(5 mL) was added 10% Pd/C under hydrogen. After 2 h the reaction
mixture was filtered through Celite and concentrated in vacuo. The
residue on purification by column chromatography (ethyl acetate/
hexane, 2:8) afforded (R)-tert-butyl 2-(3-hydroxypropyl)piperi-
dine-1-carboxylate 14 (0.57 g, 91%) as
¼ þ33:8 (c 0.5, CHCl3); IR: 3422, 1676, 1420, 1368,
1266 cmꢁ1
a colorless liquid.
½
a 2D5
ꢀ
m
less liquid. ½a 2D5
ꢀ
¼ þ63:6 (c 0.5, CHCl3); IR:
m 3408, 1673, 1606,
;
1H NMR (200 MHz, CDCl3): d 4.52–4.25 (2H, m), 3.95
1504, 1205 cmꢁ1
;
1H NMR (200 MHz, CDCl3): d 7.41–7.20 (5H,
(1H, m), 3.80–3.62 (2H, m), 1.86–1.52 (10H, m), 1.48 (9H, s); 13C
NMR (50 MHz, CDCl3): d 153.5, 79.8, 62.2, 56.3, 40.8, 29.6, 29.4,
28.5, 26.4, 25.7, 19.1; ESIMS: m/z 244 [M+H]+ Anal. Calcd for
m), 4.86 (1H, dd, J = 7.0, 2.0 Hz), 4.71 (1H, br s), 3.19–2.96 (2H,
m), 2.68 (1H, m), 2.12 (1H, m), 1.81 (1H, m), 1.73–1.38 (15H, m);
13C NMR (50 MHz, CDCl3): d 156.2, 145.1, 128.9, 127.8, 126.3,
78.4, 73.0, 61.9, 53.0, 29.9, 29.1, 26.5, 22.3, 21.2; ESIMS: m/z 306
[M+H]+ Anal. Calcd for C18H27NO3: C, 70.79; H, 8.91; N, 4.59%.
Found: C, 70.85; H, 8.88; N, 4.66%.
C13H25NO3: C, 64.16; H, 10.36; N, 5.76%. Found: C, 64.22; H,
10.33; N, 5.68%.
4.1.13. (R)-tert-Butyl 2-allylpiperidine-1-carboxylate 15
To a stirred solution of alcohol 14 (0.230 g, 0.95 mmol) in aceto-
nitrile/ether (5 mL, 3:1) were added imidazole (0.148 g,
2.18 mmol), TPP (0.498 g, 1.9 mmol) and iodine (0.481 g,
1.9 mmol) separately at 0 °C under nitrogen. After 15 min. the
reaction was quenched by an aq saturated hypo solution (6 mL).
The organic portions were extracted with CH2Cl2 (3 ꢃ 20 mL) and
washed with brine solution (10 mL). The organic layer was dried
over anhydrous Na2SO4 and concentrated under reduced pressure.
The residue was purified by column chromatography (ethyl ace-
tate/hexane, 0.2:9.8) to afford the iodide (0.32 g, 96%) as a yellow
viscous liquid. This iodide was used for the next step without
characterization.
4.1.15. (R)-2-((R)-1-Methylpiperidin-2-yl)-1-phenylethanol 3
To a suspension of LiAlH4 (0.053 g, 1.4 mmol) in dry THF (4 mL)
was added a solution of 16 (0.086 g, 0.28 mmol) in dry THF at room
temperature under nitrogen. The reaction mixture was stirred for
6 h at reflux. After completion, the reaction was quenched with
an aqueous saturated solution of Na2SO4 (6 mL) followed by the
addition of 15% aqueous NaOH solution (1 mL). The reaction mix-
ture was filtered through Celite and the filtrate was extracted into
EtOAc (3 ꢃ 15 mL). The combined organic layers were dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography (ethyl acetate/hexane, 3:7)
to afford sedamine 3 (0.048 g, 78%) as white solid. The spectro-
scopic data of the compound were found to be identical to those
reported earlier.7e
To a stirred solution of the iodide (0.32 g, 0.91 mmol) in dry THF
was added tBuOK (0.254 g, 2.27 mmol) at 0 °C under nitrogen. The
reaction was warmed to room temperature and stirred for 20 min.
After completion of reaction, it was quenched with aqueous satu-
rated NH4Cl (6 mL). The reaction mixture was extracted with
EtOAc (3 ꢃ 20 mL) and the combined organic layers were dried
over anhydrous Na2SO4. The organic portion was concentrated un-
der reduced pressure and the residue was purified by column chro-
matography (ethyl acetate/hexane, 0.2:9.8) to afford (R)-tert-butyl
2-allylpiperidine-1-carboxylate 15 (0.179 g, 88%) as a light yellow
Acknowledgments
The authors thank CSIR and UGC, New Delhi for their financial
assistance.
References
m ;
1684, 1444, 1249 cmꢁ1 1H NMR (200 MHz,
1. (a) Strunzard, G. M.; Finlay, J. A. The Alkaloids In Brossi, A., Ed.; Academic Press:
New York, 1986. Vol. 26, pp 89–174; (b) Jones, T. H.; Blum, M. S.; Robertson, H.
G. J. Nat. Prod. 1990, 53, 429; (c) Davies, F. A.; Santhanaram, M. J. Org. Chem.
2006, 71, 4222; (d) Voituriez, A.; Ferreira, F.; Perez-Luna, A.; Chemla, F. Org.
Lett. 2007, 9, 4705.
2. Davies, S. G.; Bhalay, G. Tetrahedron: Asymmetry 1595, 1996, 7; (b) Bailey, P. D.;
Millwood, P. A.; Smith, P. D. Chem. Commn. 1998, 633; (c) Felpin, F.-X.;
Lebreton, J. Eur. J. Org. Chem. 2003, 3693; (d) Weintraub, P. M.; Sabol, J. S.; Kane,
J. A.; Borcherding, D. R. Tetrahedron 2003, 59, 2953; (e) Buffat, M. G. P.
viscous liquid. IR:
CDCl3): d 5.73 (1H, m), 5.12–4.96 (2H, m), 4.28 (1H, m), 4.16–
3.91 (2H, m), 2.48–2.17 (2H, m), 1.78–1.50 (6H, m), 1.47 (9H, s);
13C NMR (50 MHz, CDCl3): d 153.4, 135.4, 116.3, 79.6, 53.4, 45.1,
34.2, 32.0, 28.6, 25.6, 19.2; ESIMS: m/z 226 [M+H]+ Anal. Calcd
for C13H23NO2: C, 69.29; H, 10.29; N, 6.22%. Found: C, 69.38; H,
10.23; N, 6.29%.

G. Satyalakshmi et al. / Tetrahedron: Asymmetry 22 (2011) 1000–1005
1005
Tetrahedron 2004, 60, 1701; (f) Toure, B. B.; Hall, D. G. Angew. Chem., Int. Ed.
2004, 43, 2001; (g) Zheng, G.; Dwoskin, L. P.; Deaciuc, A. G.; Norrholm, S. D.;
Crooks, P. A. J. Med. Chem. 2005, 48, 5551; (h) Adriaenssens, L. V.; Austin, C. A.;
Gibson, M.; Smith, D.; Hartley, R. C. Eur. J. Org. Chem. 2006, 4998; (i) Sax, M.;
Ebert, K.; Schepmann, D.; Wibbeling, B.; Wunsch, B. Bioorg. Med. Chem. 2006,
14, 5955; (j) Sax, M.; Frohlich, R.; Schepmann, D.; Wunsch, B. Eur. J. Org. Chem.
2008, 6015; (k) Wang, G.; Vedejs, E. Org. Lett. 2009, 11, 1059; (l) Davies, S. G.;
Nicholson, R.; Price, P. D.; Roberts, P. M.; Russel, A. J.; Savory, E. D.; Smith, A. D.;
Thomson, J. E. Tetrahedron: Asymmetry 2009, 20, 758; (m) Davies, S. G.; Fletcher,
A. M.; Roberts, P. M.; Smith, A. D. Tetrahedron 2009, 65, 10192; (n) Etayo, P.;
Badorry, R.; Diaz-de-Villegas, M. D.; Galvez, J. A.; Lopez-Ram-de-Viu, P. Synlett
2010, 1775; (o) Bagal, S. K.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Russell, A. J.;
Scott, P. M.; Thomson, J. E. Org. Lett. 2010, 12, 136; (p) Bagal, S. K.; Davies, S. G.;
Lee, J. A.; Roberts, P. M.; Scott, P. M.; Thomson, J. E. J. Org. Chem. 2010, 75, 8133;
(q) Lahiri, R.; Kokatla, H. P.; Vankar, Y. D. Tetrahedron Lett. 2011, 52, 781.
3. (a) Das, B.; Laxminarayana, K.; Krishnaiah, M.; Kumar, D. N. Bioorg. Med. Chem.
Lett. 2009, 19, 6396; (b) Das, B.; Suneel, K.; Satyalakshmi, G.; Kumar, D. N.
Tetrahedron: Asymmetry 2009, 20, 1536; (c) Das, B.; Kumar, D. N. Tetrahedron
Lett. 2010, 51, 6011.
Synthesis 2010, 3105; (g) Airiau, E.; Girard, N.; Pizzeti, M.; Salvadori, J.; Taddei,
M.; Mann, A. J. Org. Chem. 2010, 75, 8670; (h) Davies, S. G.; Hughes, D. G.; Price,
P. D.; Roberts, P. M.; Russel, A. J.; Smith, A. D.; Thomson, J. E.; Williams, O. M. H.
Synlett 2010, 567.
6. (a) Oppolzer, W.; Bochet, C. G. Tetrahedron Lett. 1995, 36, 2959; (b) Fry, D. F.;
Brown, M.; McDonald, J. C. Tetrahedron Lett. 1996, 37, 6227; (c) Agami, C.;
Couty, F.; Lain, H.; Mathieu, H. Tetrahedron 1998, 54, 8783; (d) Lofstedt, J.;
Pettersson-Fasth, H.; Backvall, J. E. Tetrahedron 2000, 56, 2225; (e) Hedley, S. J.;
Moran, W. J.; Prenzel, A. H. G. P.; Price, D. A.; Harrity, J. P. A. Synlett 2001, 1596;
(f) Lovick, H. M.; Michael, F. E. J. Am. Chem. Soc. 2010, 132, 1249.
7. (a) Compere, D.; Maranzano, C.; Das, B. C. J. Org. Chem. 1999, 64, 4528; (b)
Cossy, J.; Wllis, C.; Bellosta, V.; Bouzbouz, S. J. Org. Chem. 2002, 67, 1982; (c)
Angoli, M.; Barilli, A.; Lesma, G.; Passarella, D.; Riva, S.; Silvani, A.; Danieli, B. J.
Org. Chem. 2003, 68, 9525; (d) Zheng, G.; Dwoskin, L. P.; Crooks, P. A. J. Org.
Chem. 2004, 69, 8514; (e) Yadav, J. S.; Reddy, M. S.; Rao, P. P.; Prasad, A. R.
Synthesis 2006, 4005; (f) Birman, V. B.; Jiang, H.; Li, X. Org. Lett. 2007, 9, 3237;
(g) Bates, R. W.; Nemeth, J. A.; Snell, R. H. Synthesis 2008, 1033; (h)
Spangenberg, T.; Berit, B.; Mann, A. Org. Lett. 2009, 11, 261; (i) Shaik, T. M.;
Sudalai, A. Eur. J. Org. Chem. 2010, 3437.
4. (a) Ladenberg, A.; Adam, G. Chem. Ber. 1891, 24, 1671; (b) Marion, L.; Lavigre,
R.; Lemay, L. Cand. J. Chem. 1951, 29, 347; (c) Franck, B. Chem. Ber. 1958, 91,
2803.
8. (a) Hanawa, H.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 1708;
(b) Das, B.; Laxminarayana, K.; Krishnaiah, M.; Kumar, D. N. Helv. Chem. Acta
2009, 92, 1840.
5. (a) Davies, S. G.; Iwamoto, K.; Smethurst, C. A. P.; Smith, A. D.; Rodriguez-Solla,
H. Synlett 2002, 1146; (b) Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58, 5957; (c)
Chippindale, A. M.; Davies, S. G.; Iwamoto, K.; Parkin, R. M.; Smethurst, C. A. P.;
Smith, A. D.; Rodriguez-Solla, H. Tetrahedron 2003, 59, 3253; (d) Burke, A. J.;
Davies, S. G.; Garner, A. C.; Mc Carthy, T. D.; Roberts, P. M.; Smith, A. D.;
Rodriguez-Solla, H.; Vickers, R. J. Org. Biomol. Chem. 2004, 2, 1387; (e) Nomura,
H.; Richards, C. J. Org. Lett. 2009, 11, 2892; (f) Kondekar, N. B.; Kumar, P.
9. (a) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc.
2000, 122, 3783; (b) Tranka, T.; Gruble, R. H. Acc. Chem. Res. 2001, 34, 18.
10. Das, B.; Damodar, K.; Kanth, B. S. Tetrahedron Lett. 2009, 50, 2072.
11. Plehiers, M.; Hootele, C. Tetrahedron Lett. 1993, 34, 7569.
12. Chandrasekhar, S.; Mahipal, B.; Kavitha, M. J. Org. Chem. 2009, 74, 9531.
13. (a) Yang, D.; Zhang, G. J. Org. Chem. 2001, 66, 4814; (b) Fustero, S.; Iimenez, D.;
Moscardo, J.; Catakan, S.; del Pozo, C. Org. Lett. 2007, 9, 5283.