A concise and diastereoselective synthesis of piperidine and indolizidine alkaloids via aza-Prins cyclization

Article abstract of DOI:10.1055/s-0031-1289648

The synthesis of 2-substituted and 2,4-disubstituted piperidine alkaloids such as (±)-coniine, (±)-hydroxypipecolic acid, (±)-pipecolic acid, (±)-coniceine, and (±)-4-hydroxy-2- hydroxy-methyl piperidine have been accomplished in a highly diastereo-selective manner by employing aza-Prins cyclization as a key step to construct the piperidine core of these alkaloids. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289648

PAPER
297
A Concise and Diastereoselective Synthesis of Piperidine and Indolizidine
Alkaloids via Aza-Prins Cyclization
Piperidine and
In
a
dolizidine
A
s
lkaloidsi V. Subba Reddy,*a Dudhmal N. Chaya,a Jhillu S. Yadav,a René Gréeb
a
Discovery Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: basireddy@iict.res.in; E-mail: bvsreddiict@gmail.com
b
Université de Rennes 1, Laboratoire SCR, CNRS UMR 6226, Avenue du Général Leclerc, 35042 Rennes Cedex, France
Received 27 September 2011; revised 15 November 2011
ates in the synthesis of five representative alkaloids. To
the best of our knowledge, this is the first report on the
synthesis of ( )-coniine (A),6 ( )-4-hydroxypipecolic acid
(B),7 ( )-pipecolic acid (C),8 ( )-coniceine (D),9 and ( )-
Abstract: The synthesis of 2-substituted and 2,4-disubstituted pip-
eridine alkaloids such as ( )-coniine, ( )-hydroxypipecolic acid,
( )-pipecolic acid, ( )-coniceine, and ( )-4-hydroxy-2-hydroxy-
methyl piperidine have been accomplished in a highly diastereo-
selective manner by employing aza-Prins cyclization as a key step 4-hydroxy-2-hydroxymethylpiperidine (E)10 using aza-
to construct the piperidine core of these alkaloids.
Prins cyclization (Scheme 1).
Coniine (A)11 is a hemlock alkaloid that was used in an-
cient Greece to execute criminals. Initially, we prepared
Key words: aza-Prins cyclization, diastereoselective, piperidine,
alkaloids, natural products
the piperidine key intermediate 4-iodopiperidine 1 in 92%
yield using aza-Prins cyclization between N-tosylhomo-
allylic amine and n-butyraldehyde,5a which was trans-
Piperidine and indolizidine subunits are common structur-
al motifs in naturally occurring alkaloids and constitute
the basic skeleton of several drug candidates for the treat-
ment of a wide range of diseases.1,2 As a result, various
methods have been developed for the stereo- and enantio-
selective synthesis of piperidine derivatives.3 Of these, the
coupling of homoallylic amines with aldehydes – the so-
called aza-Prins cyclization – is a versatile and direct
method for the synthesis of trans-2,4-disubstituted pipe-
ridines.4 As part of our ongoing research project on the de-
velopment of new chemical entities, recently, we have
reported the synthesis of 4-iodo- and 4-hydroxypipe-
ridines by means of aza-Prins cyclization.5 Herein, we re-
port an extension of this work to the total synthesis of
several piperidine and indolizidine alkaloids. The 4-iodo-
and 4-hydroxypiperidines could be used as key intermedi-
formed into coniine by a known reaction sequence.
Piperidine intermediate 2 was achieved by radical reduc-
tion of 1 in 95% yield by refluxing with n-tributyltinhy-
dride in toluene.12 The exposure of 2 to a dark-green
sodium naphthalenide solution at –78 °C in anhydrous tet-
rahydrofuran resulted in deprotection of the N-tosyl group
to give coniine (A) in 90% yield (Scheme 2).13 The data of
product A was identical to that reported in the literature.6d
The 4-hydroxypipecolic acid (B)14 motif is the most prev-
alent subunit of this type in bioactive molecules such as
SS20846A15 and palinavir,16 which is a highly potent HIV
protease inhibitor. Both pipecolic acid and 4-hydroxy-
pipecolic acid, being unnatural amino acids, are useful in
peptide synthesis.
OH
N
H
COOH
+
(–)-4-hydroxy-
pipecolic acid
N
B
N
COOH
+
(–)-coniceine
H
D
+
(–)-pipecolic acid
C
X
OH
OH
N
H
N
H
+
N
R
N
R
+
(–)-coniine
Ts
Ts
(–)-4-hydroxy-2-
hydroxymethyl piperidine
A
E
aza-Prins
Scheme 1 Retrosynthetic analysis for the synthesis of piperidine and indolizidine alkaloids
SYNTHESIS 2012, 44, 297–303
x
x
.x
x
.2
0
1
1
Advanced online publication: 15.12.2011
DOI: 10.1055/s-0031-1289648; Art ID: Z92911SS
© Georg Thieme Verlag Stuttgart · New York

298
B. V. S. Reddy et al.
PAPER
carboxylic acid 7 in 70% yield.8a,17 Deprotection of the
N-tosyl group was carried out using sodium/naphthalene
at –78 °C in anhydrous tetrahydrofuran to afford ( )-pipe-
colic acid (C) in 89% yield (Scheme 4).13 The data for
product C was in agreement with the those reported in the
literature.8a
I
O
b
a
+
H
N
NHTs
Ts
1
c
I
N
N
H
Ts
O
b
a
2
A
+
H
Ph
N
Ph
N
Ph
Scheme 2 Synthesis of ( )-coniine (A). Reagents and conditions:
(a) GaI3, I2, anhydrous CH2Cl2, 0 °C to r.t., 7 h, 92%; (b) Bu3SnH,
AIBN, toluene, 4 h, reflux, 95%; (c) Na/naphthalene, anhydrous THF,
–78 °C, 6 h, 90%.
NHTs
Ts
5
Ts
6
c
d
N
COOH
N
H
COOH
The key intermediate, 4-hydroxypiperidine 3, was synthe-
sized in 85% yield by means of an aza-Prins cyclization
between N-tosyl homoallylic amine and cinnamalde-
hyde.5b Oxidative cleavage of olefin 3 with RuCl3·2H2O
gave the corresponding carboxylic acid 4 in 68% yield
without affecting the hydroxy group.8a,17 Treatment with
sodium/naphthalene at –78 °C in anhydrous tetrahydrofu-
ran deprotected the tosyl group to give the target product
B in 80% yield (Scheme 3).13 The data of product B was
identical with respect to its 1H NMR spectrum to that re-
ported in the literature.7a
Ts
7
C
Scheme 4 Synthesis of ( )-pipecolic acid (C). Reagents and condi-
tions: (a) GaI3, I2, anhydrous CH2Cl2, 0 °C to r.t., 7 h, 90%; (b)
Bu3SnH, AIBN, toluene, 3 h, reflux, 93%; (c) RuCl3·2H2O, NaIO4,
MeCN–CCl4–H2O (1:1:10), r.t., 8 h, 70%; (d) Na/naphthalene, anhy-
drous THF, –78 °C, 6 h, 89%.
Bicyclic alkaloid coniceine (D)24 is a representative mem-
ber of the biologically active indolizidine alkaloids. It acts
as a non-competitive blocker for muscle and ganglionic
nicotinic receptor channels that have been isolated from
the skin secretions of neotropical amphibians.
OH
O
a
b
+
The synthesis of coniceine (D) began from aldehyde 8,
which was prepared from 1,4-butanediol by mono-benz-
ylation, followed by oxidation of the free hydroxy group
with pyridinium chlorochromate. The resulting aldehyde
was subjected to aza-Prins cyclization with homoallylic
amine using gallium iodide and iodine to give 4-iodopip-
eridine 9 in 85% yield. Radical reduction of 9 was
achieved by treatment of tributyltin hydride in the pres-
ence of AIBN at reflux in toluene to give piperidine 10 in
80% yield.12 Both N-tosyl and O-benzyl groups under-
went smooth cleavage upon treatment with sodium/naph-
thalene at –78 °C in anhydrous tetrahydrofuran to afford
compound 11 in 85% yield.13 Cyclization of 11 was
achieved by treatment with iodine, triphenylphosphine
and imidazole followed by aqueous sodium bicarbonate to
give coniceine (D) in 60% yield (Scheme 5).25 The data of
product D was in agreement with those reported in the lit-
erature.9a
H
Ph
N
Ph
NHTs
Ts
3
OH
OH
N
c
N
H
COOH
COOH
Ts
4
B
Scheme 3 Synthesis of ( )-4-hydroxypipecolic acid (B). Reagents
and conditions: (a) PMA (10 mol%), anhydrous CH2Cl2, reflux, 10 h,
85%; (b) RuCl3·2H2O, NaIO4, MeCN–CCl4–H2O (1:1:10), r.t., 8 h,
68%; (c) Na/naphthalene, anhydrous THF, –78 °C, 6 h, 80%.
Pipecolic acid (C)18 is a naturally occurring non-proteino-
genic a-amino acid that is frequently found in plants, fun-
gi, and human physiological fluids. It is a key structural
unit in many biologically active natural and synthetic mol-
ecules, for instance anticonvulsant pipradol,19 immuno-
suppressants FK 50620 and rapamycin,21 amylo-
glucosidase inhibitor lentiginosine,22 enzyme inhibitors,
and N-methyl-D-aspartic acid (NMDA)23 antagonists.
4-Hydroxy-2-hydroxymethylpiperidine (E) was prepared
from piperidine 13 by tosyl deprotection upon treatment
with sodium/naphthalene at –78 °C. Piperidine 13 was
synthesized in 65% yield by aza-Prins cyclization be-
tween aldehyde 12 and homoallylic amine with PMA at
reflux temperature for 18 hours,5b with concomitant de-
benzylation. It should be noted that the N-tosyl group was
stable under these conditions.26 Aldehyde 12 was pre-
pared in good yield from ethylene glycol through
monobenzylation followed by oxidation of the free alco-
hol with pyridinium chlorochromate (Scheme 6). The
The key precursor, 4-iodopiperidine 5 was also prepared
by means of an aza-Prins cyclization.5a Removal of iodide
with n-tributyltinhydride in the presence of AIBN gave
the (E)-2-styryl-N-tosylpiperidine 6 in 93% yield.12 Oxi-
dative cleavage of the olefin was achieved using
RuCl3·2H2O and NaIO4 to afford the corresponding
Synthesis 2012, 44, 297–303
© Thieme Stuttgart · New York

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Piperidine and Indolizidine Alkaloids
299
silica gel. MS were recorded with a Micromass VG-7070H for EI
and a VG Autospec M for FAB-MS.
O
a
b
OH
OBn
HO
I
H
trans-4-Iodo-2-propyl-N-tosylpiperidine (1)
8
A mixture of N-tosylhomoallylic amine (0.430 g, 1.91 mmol), n-bu-
tyraldehyde (0.178 g, 2.48 mmol), iodine (0.485 g, 1.90 mmol) and
gallium iodide (0.008 g, 0.019 mmol) in CH2Cl2 (25 mL) was stirred
at 0 °C for 10 min and then at r.t. for 7 h. After completion of the
reaction (indicated by TLC), the reaction mixture was extracted
with CH2Cl2 (3 × 20 mL) and the combined organic layers were
dried over anhydrous Na2SO4. Removal of the solvent, followed by
purification on silica gel (EtOAc–hexane, 5:95) gave the product.
c
d
OBn
OBn
N
N
Ts
Ts
10
9
Yield: 0.715 g (92%); colorless oil.
e
IR (neat): 2923, 2853, 1739, 1461, 1374, 1216, 1170, 1119, 759,
668 cm–1.
OH
N
N
H
11
1H NMR (300 MHz, CDCl3): d = 7.67 (d, J = 8.3 Hz, 2 H), 7.30 (d,
J = 7.9 Hz, 2 H), 4.24 (tt, J = 12.4, 3.8 Hz, 1 H), 3.89 (br q, 1 H),
3.63 (ddt, J = 14.6, 4.4, 2.3 Hz, 1 H), 3.02 (ddd, J = 15.2, 12.4,
2.9 Hz, 1 H), 2.40 (s, 3 H), 2.12–2.20 (m, 2 H), 2.02 (ddt, J = 13.4,
4.2, 2.1 Hz, 1 H), 1.87 (dq, J = 4.6, 12.3 Hz, 1 H), 1.25–1.60 (m,
4 H), 0.90 (t, J = 7.1 Hz, 3 H).
D
Scheme 5 Synthesis of ( )-coniceine (D). Reagents and conditions:
(a) (i) NaH, BnBr, DMF, cat. TBAI, 0 °C to r.t., 12 h, 90%; (ii) PCC–
Celite (1:1), anhydrous CH2Cl2, r.t., 12 h, 80%; (b) N-tosyl homoally-
lic amine, GaI3, I2, anhydrous CH2Cl2, 0 °C to r.t., 11 h, 85%; (c)
Bu3SnH, AIBN, toluene, 10 h, reflux, 80%; (d) Na/naphthalene, an-
hydrous THF, –78 °C, 6 h, 85%; (e) I2, TPP, imidazole, r.t., 4 h, then
sat. NaHCO3, 3 h, 60%.
13C NMR (75 MHz, CDCl3): d = 13.6, 19.6, 21.4, 31.6, 37.9, 41.3,
42.2, 55.1, 126.8, 129.6, 138.1, 143.2.
LC-MS: m/z = 408 [M + H], 430 [M + Na].
( )-2-Propyl-N-tosylpiperidine (2)
O
a
b
In an oven-dried, single-neck 25 mL round-bottom flask equipped
with reflux condenser, magnetic stirring bar, rubber septum and ni-
trogen inlet, was placed 1 (0.575 g, 1.41 mmol) and anhydrous tol-
uene (20 mL). Bu3SnH (0.570 mL, 2.12 mmol) was added and the
mixture was heated at reflux for 4 h (130 °C), then AIBN (10 mg)
was added to the reaction mixture at 80 °C. After completion of the
reaction, as indicated by TLC, the mixture was cooled to r.t. and
then concentrated to give a syrup. The resulting crude product was
purified by column chromatography (EtOAc–petroleum ether,
15:85) to give 2.
OH
OBn
HO
H
12
OH
OH
N
c
OH
OH
N
H
Ts
13
E
Yield: 0.378 g (95%); colorless oil.
Scheme 6 Synthesis of ( )-4-hydroxy-2-hydroxymethylpiperidine
(E). Reagents and conditions: (a) (i) NaH, BnBr, DMF, cat. TBAI,
0 °C to r.t., 14 h, 85%; (ii) PCC–Celite (1:1), anhydrous CH2Cl2, r.t.,
10 h, 70%; (b) N-tosylhomoallylic amine, PMA (10 mol%), anhy-
drous CH2Cl2, reflux, 20 h, 65%; (c) Na/naphthalene, anhydrous
THF, –78 °C, 70%.
IR (neat): 2930, 2862, 1734, 1456, 1334, 1156, 1093, 931, 815, 654
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.69 (d, J = 8.3 Hz, 2 H), 7.25 (d,
J = 7.5 Hz, 2 H), 3.97–4.05 (m, 1 H), 3.73 (dd, J = 3.0, 13.6 Hz,
1 H), 2.95 (ddd, J = 15.6, 13.5, 2.2 Hz, 1 H), 2.43 (s, 3 H), 1.20–
1.61 (m, 10 H), 0.90 (t, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 13.7, 18.2, 19.5, 21.3, 24.2, 27.2,
data of product E was in agreement with those reported in
31.4, 40.4, 52.5, 126.7, 129.4, 138.8, 142.5.
the literature.10
LC-MS: m/z = 282 [M + H], 299 [M + NH4].
In summary, we have demonstrated a modular and con-
cise route to the total synthesis of ( )-coniine, ( )-4-hy-
droxypipecolic acid, ( )-pipecolic acid, ( )-coniceine,
and ( )-4-hydroxy2-hydroxymethylpiperidine via aza-
Prins cyclization.
( )-Coniine (A)
To a stirred solution of naphthalene (0.732 g, 5.72 mmol) in anhy-
drous THF (20 mL) in a two-neck 50 mL, round-bottom flask
equipped with magnetic stirring bar, a rubber septum and a nitrogen
inlet, was added sodium (0.132 g, 5.73 mmol) at r.t. and the mixture
was stirred until the formation of sodium naphthalide was complete
(indicated by the formation of a persistent navy-blue color; sodium
naphthalide was formed within 40 min), and then cooled to –78 °C.
A solution of 2 (0.268 g, 0.953 mmol) in anhydrous THF (15 mL)
was added to the above solution at –78 °C and the resulting mixture
was stirred at the same temperature for 45 min. The reaction was
quenched by the addition of sat. aq NH4Cl (15 mL) and the organic
layer was washed with H2O (2 × 10 mL), brine (3 × 10 mL), dried
over anhydrous Na2SO4 and concentrated in vacuo. Purification of
the crude product by column chromatography (EtOAc–petroleum
ether, 35:65) gave the target molecule A.
Commercial reagents were used without further purification and all
solvents were purified by standard techniques. IR spectra were re-
corded with a Perkin–Elmer FT-IR 240-c spectrophotometer using
KBr optics. NMR spectra were recorded in CDCl3 with Varian
Gemini 200, Bruker 300, or Varian Unity 400 NMR spectrometers.
Chemical shifts (d) are quoted in parts per million (ppm) and are ref-
erenced to tetramethylsilane (TMS) as internal standard; coupling
constants (J) are quoted in hertz. Column chromatographic separa-
tions were carried out on silica gel (60–120 mesh) and flash chro-
matographic separations were carried out using 230–400 mesh
© Thieme Stuttgart · New York
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300
B. V. S. Reddy et al.
PAPER
Yield: 0.109 g (90%); syrup.
with naphthalene (0.126 g, 0.984 mmol) and sodium metal (0.023 g,
1 mmol) to give the target molecule B.
IR (neat): 3447, 2925, 2855, 1735, 1458, 1335, 1155, 1093, 927,
687 cm–1.
Yield: 0.019 g (80%); viscous oil.
1H NMR (300 MHz, CDCl3): d = 3.74–3.79 (m, 1 H), 3.65 (dddd,
J = 11.5, 4.0, 2.1, 1.7 Hz, 1 H), 3.50 (ddd, J = 11.5, 11.3, 2.4 Hz,
1 H), 2.30–2.36 (m, 1 H), 2.12–2.17 (m, 1 H), 1.77–1.81 (m, 2 H),
1.57–1.70 (m, 3 H), 1.25–1.36 (m, 4 H), 0.93 (dd, J = 7.0, 6.9 Hz,
3 H).
IR (neat): 3430, 2927, 1630, 1028, 764 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 10.4 (s, 1 H), 5.04–5.07 (m,
2 H), 3.74–3.85 (m, 7 H).
LC-MS: m/z = 168 [M + Na].
13C NMR (75 MHz, CDCl3): d = 13.8, 19.6, 26.1, 32.3, 33.8, 40.6,
46.1, 50.7.
trans-4-Iodo-2-styryl-N-tosylpiperidine (5)
A mixture of N-tosylhomoallylic amine (0.193 g, 0.857 mmol),
trans-cinnamaldehyde (0.147 g, 1.11 mmol), iodine (0.218 g 0.858
mmol) and gallium iodide (0.0038 g, 0.008 mmol) in CH2Cl2 (15
mL) was stirred at 0 °C for 10 min and then at r.t. for 7 h. After com-
pletion of the reaction, as indicated by TLC, the reaction mixture
was extracted with CH2Cl2 (3 × 10 mL) and the combined organic
layers were dried over anhydrous Na2SO4. Removal of the solvent
and purification on silica gel (EtOAc–hexane, 5:95) gave the prod-
uct.
LC-MS: m/z = 150 [M + Na].
trans-2-Styryl-N-tosylpiperidin-4-ol (3)
A mixture of N-tosylhomoallylic amine (0.338 g, 1.50 mmol),
trans-cinnamaldehyde (0.257 g, 1.95 mmol) and phosphomolybdic
acid (0.027 g, 0.015 mmol) in CH2Cl2 (25 mL) was stirred at reflux
temperature for 10 h. After completion of the reaction, as indicated
by TLC, the reaction mixture was extracted with CH2Cl2
(3 × 20 mL) and the combined organic layers were dried over anhy-
drous Na2SO4. Removal of the solvent followed by purification on
silica gel (EtOAc–hexane, 18:82) gave the product.
Yield: 0.360 g (90%); yellow syrup.
IR (KBr): 2918, 2858, 1646, 1492, 1383, 1334, 1189, 1155, 1087,
931, 700, 651 cm–1.
Yield: 0.456 g (85%); white solid; mp 170–173 °C.
1H NMR (300 MHz, CDCl3): d = 7.65 (d, J = 8.7 Hz, 2 H), 7.13–
7.25 (m, 7 H), 6.43 (d, J = 16.2 Hz, 1 H), 5.92 (dd, J = 5.6, 16.1 Hz,
1 H), 4.63–4.73 (m, 1 H), 4.27 (tt, J = 12.3, 3.9 Hz, 1 H), 3.67 (ddt,
J = 14.5, 4.3, 2.3 Hz, 1 H), 3.10 (ddd, J = 15.1, 12.2, 2.8 Hz, 1 H),
2.10–2.55 (m, 7 H).
13C NMR (75 MHz, CDCl3): d = 21.3, 32.1, 33.7, 38.9, 44.3, 55.5,
125.9, 127.2, 128.3, 129.2, 130.5, 133.1, 134.5, 136.2, 137.1, 143.2.
IR (neat): 3452, 2929, 2854, 1598, 1448, 1334, 1156, 1081, 1022,
929, 755, 669 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.64 (d, J = 8.2 Hz, 2 H), 7.00–
7.20 (m, 7 H), 6.34 (d, J = 16.6 Hz, 1 H), 5.85 (dd, J = 5.8, 15.6 Hz,
1 H), 4.78–4.84 (m, 1 H), 3.75–3.83 (m, 2 H), 3.02 (ddd, J = 15.1,
13.2, 2.7 Hz, 1 H), 2.35 (s, 3 H), 2.01 (ddd, J = 13.0, 3.8, 1.8 Hz,
1 H), 1.80 (dddd, J = 11.9, 2.5, 3.7, 3.9 Hz, 1 H), 1.61 (ddd,
J = 12.8, 11.3, 5.5 Hz, 1 H), 1.35 (dddd, J = 12.0, 11.9, 4.5, 3.5 Hz,
1 H).
LC-MS: m/z = 490 [M + Na].
HRMS (ESI): m/z [M + Na] calcd for C20H22NO2SNa: 490.0287;
13C NMR (75 MHz, CDCl3): d = 21.2, 34.0, 38.9, 40.3, 55.0, 64.3,
found: 490.0308.
125.9, 127.1, 127.6, 128.3, 129.4, 130.5, 132.0, 136.5, 137.1, 143.1.
( )-2-Styryl-N-tosylpiperidine (6)
LC-MS: m/z = 358 [M + H].
Compound 5 (0.259 g, 0.555 mmol) was subjected to the same re-
action conditions (synthesis of 2 from 1) with Bu3SnH (0.24 mL,
0.831 mmol) and AIBN (10 mg) to give compound 6.
HRMS (ESI): m/z [M + H] calcd for C20H24NO3S: 358.1478; found:
358.1476.
Yield: 0.176 g (93%); syrup.
trans-4-Hydroxy-N-tosylpiperidine-2-carboxylic Acid (4)
To a stirred solution of NaIO4 (0.209 g, 0.976 mmol) in MeCN–
CCl4–H2O (1:1:10, 12 mL) was added RuCl3·2H2O (0.011 g, 0.048
mmol) and the resulting mixture was stirred at r.t. for 1 h. Com-
pound 3 (0.174 g, 0.488 mmol) was dissolved in MeCN (10 mL)
and this solution was added to the above reaction mixture, followed
by the addition of a second portion of NaIO4 (0.105 g, 0.490 mmol).
The resulting mixture was stirred at r.t. for 30 min and then filtered
through Celite. The organic layer was dried over Na2SO4 and con-
centrated in vacuo. The residue was purified by column chromatog-
raphy (MeOH–CHCl3, 1:9 to 2:8) to yield acid 4.
IR (neat): 2927, 2864, 1709, 1450, 1340, 1213, 1158, 1054, 964,
815, 696 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.64 (d, J = 7.5 Hz, 2 H), 7.10–
7.25 (m, 7 H), 6.38 (d, J = 15.8 Hz, 1 H), 5.93 (dd, J = 6.7, 16.6 Hz,
1 H), 4.69 (dd, J = 11.5, 4.5 Hz, 1 H), 3.72 (dd, J = 12.8, 2.3 Hz,
1 H), 2.98 (ddd, J = 15.8, 12.4, 3.7 Hz, 1 H), 2.34 (s, 3 H), 1.79
(ddd, J = 3.7, 7.5, 18.1 Hz, 2 H), 1.49–1.66 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 18.8, 21.3, 30.1, 34.0, 40.1, 54.9,
125.3, 126.3, 127.1, 128.3, 129.6, 132.7, 143.3.
LC-MS: m/z = 340 [M – H].
Yield: 0.099 g (68%); colorless oil.
IR (neat): 3460, 2924, 2855, 1726, 1454, 1273, 1161, 1097, 708
cm–1.
1H NMR (500 MHz, CDCl3): d = 7.73 (d, J = 7.3 Hz, 2 H), 7.28 (d,
J = 8.2 Hz, 2 H), 5.05 (d, J = 5.4 Hz, 1 H), 4.90–4.99 (br s, 1 H),
3.96–4.00 (m, 1 H), 3.52 (ddd, J = 4.5, 10.9, 13.7 Hz, 1 H), 2.71–
2.75 (m, 2 H), 2.49–2.56 (m, 1 H), 2.40–2.49 (m, 4 H).
( )-N-Tosylpiperidine-2-carboxylic Acid (7)
Compound 6 (0.131 g, 0.384 mmol) was subjected to the same re-
action conditions (synthesis of 4 from 3) with RuCl3·2H2O (0.009 g,
0.040 mmol), NaIO4 (0.171 g, 0.799 mmol), and a second portion of
NaIO4 (0.086 g, 0.401 mmol) to give 7.
Yield: 0.092 g (70%); viscous oil.
13C NMR (75 MHz, CDCl3): d = 20.8, 39.6, 41.5, 41.9, 55.4, 60.3,
127.1, 129.6, 135.8, 143.9, 171.3.
IR (neat): 3430, 2926, 2856, 1724, 1666, 1595, 1411, 1356, 1282,
168, 1092, 1064, 1039, 939, 812, 686 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.52 (br s, 1 H), 7.62 (d,
J = 8.7 Hz, 2 H), 7.22 (d, J = 8.2 Hz, 2 H), 5.19–5.21 (dd, J = 2.9,
5.8 Hz, 1 H), 3.68 (ddt, J = 3.6, 13.1, 17.5 Hz, 1 H), 3.31–3.38 (ddd,
LC-MS: m/z = 300 [M + H], 322 [M + Na].
( )-4-Hydroxypipecolic Acid (B)
Compound 4 (0.049 g, 0.163 mmol) was subjected to tosyl depro-
tection using the procedure described above (synthesis of A from 2)
Synthesis 2012, 44, 297–303
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Piperidine and Indolizidine Alkaloids
301
J = 2.9, 11.7, 16.1 Hz, 1 H), 2.41 (s, 3 H), 2.15 (dddd, J = 2.9, 13.1,
15.3, 18.3 Hz, 1 H), 1.24–1.67 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 13.9, 21.2, 38.8, 40.1, 42.4, 56.3,
127.1, 129.6, 135.2, 143.8, 171.2.
as indicated by TLC, the reaction mixture was extracted with
CH2Cl2 (3 × 20 mL), and the combined organic layers were dried
over anhydrous Na2SO4. Removal of the solvent, followed by puri-
fication on silica gel (EtOAc–hexane, 10:90) gave the product.
Yield: 0.424 g (85%); yellow syrup.
LC-MS: m/z = 282 [M – 1].
IR (neat): 2936, 1722, 1598, 1451, 1334, 1157, 1075, 1031, 931,
814, 722, 676 cm–1.
( )-Pipecolic Acid (C)
Compound 7 (0.042 g, 0.148 mmol) was subjected to tosyl depro-
tection using the same reaction conditions (synthesis of A from 2)
with naphthalene (0.114 g, 0.890 mmol) and sodium metal (0.020 g,
0.869 mmol) to give the target molecule C.
1H NMR (300 MHz, CDCl3): d = 7.67 (d, J = 7.9 Hz, 2 H), 7.21–
7.30 (m, 7 H), 4.44 (s, 2 H), 4.34 (tt, J = 12.2, 3.7 Hz, 1 H), 4.10–
4.25 (m, 1 H), 3.79 (ddt, J = 14.7, 4.6, 2.3 Hz, 1 H), 3.44–3.50 (dd,
J = 4.8, 10.5 Hz, 2 H), 2.96 (ddd, J = 2.5, 9.6, 13.5 Hz, 1 H), 2.40
(s, 3 H), 1.49–1.70 (m, 4 H), 0.82–1.25 (m, 4 H).
Yield: 0.017 g (89%); syrup.
IR (neat): 3452, 2926, 1723, 1655, 1158, 1036, 822 cm–1.
13C NMR (75 MHz, CDCl3): d = 21.4, 26.6, 27.6, 32.4, 36.8, 39.3,
42.1, 56.5, 63.1, 72.7, 126.8, 127.5, 128.3, 129.7, 133.1, 135.2,
138.8, 143.2.
1H NMR (300 MHz, DMSO-d6): d = 9.05 (br s, 1 H), 3.82–3.89 (m,
1 H), 3.71–3.74 (m, 1 H), 3.51–3.54 (m, 1 H), 3.29–3.31 (m, 1 H),
2.78–2.83 (m, 2 H), 2.51–2.63 (m, 3 H).
LCMS: m/z = 514 [M + H].
LC-MS: m/z = 130 [M + H].
( )-2-[3-(Benzyloxy)propyl]-N-tosylpiperidine (10)
Compound 9 (0.302 g, 0.588 mmol) was subjected to the procedure
described (synthesis of 2 from 1) with Bu3SnH (0.257 mL, 0.883
mmol) and AIBN (10 mg) to give compound 10.
4-(Benzyloxy)butanal (8)
To a stirred solution of 1,4-butanediol (0.283 g, 3.14 mmol) in an-
hydrous DMF (35 mL) in a single-necked, round-bottom 100 mL
flask equipped with nitrogen inlet, was added NaH (0.090 g, 3.77
mmol) at 0 °C and stirring was continued for 30 min. To the above
mixture, benzyl bromide (0.27 mL, 3.11 mmol) was added dropwise
at 0 °C, then TBAI (0.0011 g, 0.0031 mmol) was added and the re-
action was stirred at r.t. for 12 h. After completion of the reaction,
as indicated by TLC, the mixture was quenched with H2O (5 mL)
and the aqueous layer was extracted with EtOAc (3 × 15 mL). The
combined organic layers were concentrated in vacuo and the result-
ing syrup was purified by column chromatography (EtOAc–petro-
leum ether, 15:85) to give the mono-protected alcohol.
Yield: 0.183 g (80%); syrup.
IR (neat): 2926, 2855, 1595, 1453, 1336, 1215, 1161, 1058, 934,
735, 660 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.69 (d, J = 8.3 Hz, 2 H), 7.28–
7.33 (m, 7 H), 4.46 (s, 2 H), 4.20 (dd, J = 11.0, 5.5 Hz, 1 H), 3.90
(ddt, J = 3.7, 14.3, 18.1 Hz, 1 H), 3.44–3.50 (m, 2 H), 3.10 (ddd,
J = 2.2, 15.1, 12.8 Hz, 1 H), 2.42 (s, 3 H), 1.99 (dddd, J = 2.2, 4.5,
14.3, 16.6 Hz, 2 H), 1.25–1.65 (m, 8 H).
13C NMR (75 MHz, CDCl3): d = 19.0, 21.5, 26.6, 27.5, 29.8, 32.8,
39.1, 53.5, 69.4, 72.8, 126.9, 127.6, 128.4, 129.8, 138.2, 138.5,
143.3.
Yield: 0.509 g (90%); syrup.
IR (neat): 3383, 2940, 2865, 1714, 1451, 1364, 1275, 1102, 1064,
742, 706, 611 cm–1.
LCMS: m/z = 386 [M – H].
1H NMR (300 MHz, CDCl3): d = 7.25–7.34 (m, 5 H), 4.49 (s, 2 H),
3.61 (t, J = 6.1 Hz, 2 H), 3.49 (t, J = 6.1 Hz, 2 H), 1.61–1.75 (m,
4 H).
13C NMR (75 MHz, CDCl3): d = 26.1, 29.4, 61.9, 70.1, 72.6, 127.7,
128.2, 128.1, 137.8.
Amino Alcohol (11)
Compound 10 (0.133 g, 0.344 mmol) was subjected to tosyl depro-
tection (synthesis of A from 2) using naphthalene (0.264 g, 2.062
mmol) and sodium metal (0.047 g, 2.043 mmol) to give piperidine
11.
LCMS: m/z = 181 [M + H].
Yield: 0.042 g (86%); syrup.
HRMS (ESI): m/z [M + Na] calcd for C11H16O2Na: 203.1042;
IR (neat): 3448, 2923, 2853, 1637, 1460, 1375, 770 cm–1.
found: 203.1042.
1H NMR (300 MHz, CDCl3): d = 6.23–6.91 (br s 1 H), 4.46–4.44
(m, 2 H), 4.09–4.18 (m, 1 H), 3.54–3.60 (m, 1 H), 3.29–3.41 (m,
1 H), 3.11–3.25 (m, 1 H), 3.00–3.12 (m, 1 H), 1.53–2.03 (m, 8 H).
13C NMR (75 MHz, CDCl3): d = 21.1, 26.2, 29.8, 32.2, 32.8, 42.8,
51.9, 63.2.
This product (0.410 g, 2.27 mmol) was directly oxidized over PCC
(0.979 g, 4.55 mmol) and Celite (0.979 g) in CH2Cl2 (40 mL) at r.t.
for about 12 h. After completion of the reaction, as indicated by
TLC, the reaction mixture poured on silica gel and purified by col-
umn chromatography (EtOAc–hexane, 7:93) to give aldehyde 8.
LCMS: m/z = 166 [M + Na].
Yield: 0.324 g (80%); oil.
IR (neat): 2949, 2858, 1720, 1600, 1452, 1274, 1106, 1027, 711,
609 cm–1.
1H NMR (500 MHz, CDCl3): d = 10.04 (s, 1 H), 7.29–7.35 (m, 5 H),
4.50 (s, 2 H), 4.35 (t, J = 6.8 Hz, 2 H), 3.50–3.56 (m, 2 H), 1.79–
1.98 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 26.2, 64.6, 69.6, 72.7, 127.4, 128.8,
129.3, 129.5, 134.2, 138.3, 192.1.
( )-Coniceine (D)
To a stirred solution of 11 (0.021 g, 0.147 mmol) in anhydrous
CH2Cl2 (15 mL) in a 100 mL single-neck round-bottom flask were
added Ph3P (0.115 g, 0.440 mmol), iodine (0.112 g, 0.440 mmol)
and imidazole (0.029 g, 0.440 mmol) at 0 °C. The resulting mixture
was stirred at r.t. for 4 h and then quenched with sat. aq NaHCO3
(10 mL). The aqueous layer was extracted with EtOAc (2 × 10 mL),
the combined organic layers were concentrated in vacuo, and the re-
sulting syrup was purified by column chromatography (EtOAc–pe-
troleum ether, 10:90) to give the target molecule D.
trans-2-[3-(Benzyloxy)propyl]-N-tosyl-piperidine-4-ol (9)
A mixture of N-tosylhomoallylic amine (0.219 g, 0.973 mmol), 4-
(benzoloxy)butanal (8; 0.225 g, 1.26 mmol), iodine (0.247 g, 0.973
mmol) and gallium iodide (0.004 g, 0.009 mmol) in CH2Cl2 (25 mL)
was stirred at 0 °C to r.t. for 11 h. After completion of the reaction,
Yield: 0.011 g (60%); syrup.
1H NMR (300 MHz, CDCl3): d = 4.06–4.13 (m, 1 H), 3.57–3.63 (m,
1 H), 2.26–2.33 (m, 1 H), 2.13–2.17 (m, 1 H), 2.02–2.06 (m, 2 H),
© Thieme Stuttgart · New York
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302
B. V. S. Reddy et al.
PAPER
1.83–1.92 (m, 1 H), 1.61–1.72 (m, 1 H), 1.47–1.55 (m, 1 H), 1.31–
1.41 (m, 1 H), 1.17–1.29 (m, 5 H).
( )-4-Hydroxy-2-hydroxymethylpiperidine (E)
Compound 13 (0.040 g, 0.140 mmol) was subjected to tosyl depro-
tection using the same reaction conditions (synthesis of A) with
naphthalene (0.107 g, 0.842 mmol) and sodium metal (0.019 g,
0.842 mmol) to give the target molecule E.
LCMS: m/z = 124 [M – H].
2-(Benzyloxy)acetaldehyde (12)
To a stirred solution of ethylene glycol (0.150 g, 2.41 mmol) in an-
hydrous DMF (25 mL) in a single-neck, round-bottom 100 mL flask
equipped with a nitrogen inlet, was added NaH (0.071 g, 2.95
mmol) at 0 °C and stirring was continued for 30 min. To the above
mixture, benzyl bromide (0.21 mL, 2.388 mmol) was added drop-
wise at 0 °C, then TBAI (0.0017 g, 0.0048 mmol) was added and the
mixture was stirred at r.t. for 14 h. After completion of the reaction,
as indicated by TLC, the mixture was quenched with H2O (5 mL)
and the aqueous layer was extracted with EtOAc (3 × 15 mL). The
combined organic layers were concentrated in vacuo and the result-
ing syrup was purified by column chromatography (EtOAc–petro-
leum ether, 15:85) to give the mono-protected alcohol.
Yield: 0.009 g (50%); syrup.
IR (neat): 3471, 2923, 1622, 1615, 1051, 1010, 722 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 4.27 (br s, 1 H), 4.19 (dd,
J = 9.06, 11.2 Hz, 1 H), 3.86–3.88 (m, 1 H), 3.62–3.72 (ddd,
J = 13.1, 3.5, 2.3 Hz, 1 H), 2.56–2.69 (m, 2 H), 2.37–2.40 (m, 1 H),
1.74–1.76 (m, 1 H), 1.57–1.59 (m, 1 H), 1.23–1.25 (m, 1 H), 0.86–
0.89 (m, 1 H).
LCMS: m/z = 149 [M + Na].
Acknowledgment
Yield: 0.311 g (85%); syrup.
This research has been performed as part of the Indo-French ‘Joint
Laboratory for Sustainable Chemistry at Interfaces’. We thank
CSIR and CNRS for support. D.N.C. thanks CSIR, New Delhi for
the award of a fellowship. J.S.Y. acknowledges partial support by
King Saud University for Global Research Network for Organic
Synthesis (GRNOS).
IR (neat): 3413, 2926, 2863, 1496, 1453, 1358, 1209, 1112, 1067,
891, 741, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.24–7.27 (m, 5 H), 4.47 (s, 2 H),
3.63 (t, J = 4.7 Hz, 2 H), 3.48 (t, J = 4.9 Hz, 2 H), 3.04 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 61.4, 71.2, 73.2, 127.6, 128.2,
137.7.
References and Notes
LCMS: m/z = 170 [M + NH4], 175 [M + Na].
(1) (a) Jones, T. H.; Blum, M. S. In Alkaloids: Chemical and
Biological Perspectives, Vol. 1; Pelletier, S. W., Ed.; Wiley:
New York, 1983, Chap. 2, 33. (b) Fodor, G. B.; Colasanti,
B. In Alkaloids: Chemical and Biological Perspectives, Vol.
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This product (0.216 g, 1.42 mmol) was directly oxidized over PCC
(0.611 g, 2.84 mmol) and Celite (0.611 g) in CH2Cl2 (30 mL) at r.t.
for about 10 h. After completion of the reaction, as indicated by
TLC, the reaction mixture was passed through a silica gel column
(EtOAc–hexane, 5:95) to give the pure aldehyde 12.
Yield: 0.149 g (70%); oil.
IR (neat): 2867, 1704, 1613, 1498, 1455, 1351, 1310, 1260, 1047,
967, 869, 744, cm–1.
1H NMR (400 MHz, CDCl3): d = 9.28 (s, 1 H), 7.28–7.34 (m, 5 H),
5.14 (d, J = 2.9 Hz, 1 H), 5.09 (d, J = 2.9 Hz, 1 H), 4.90 (s, 2 H).
LCMS: m/z = 149 [M – H].
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A mixture of N-tosylhomoallylic amine (0.2 g, 0.888 mmol), 2-
(benzyloxy)acetaldehyde (12; 0.086 g, 0.575 mmol) and phospho-
molybdic acid (0.008 g, 0.004 mmol) in CH2Cl2 (30 mL) was stirred
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IR (neat): 3448, 2988, 2886, 1595, 1342, 1256, 1161, 1098, 1008,
968, 868, 818, 688 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.62 (d, J = 8.1 Hz, 2 H), 7.29 (d,
J = 7.9 Hz, 2 H), 4.51–4.53 (m, 1 H), 4.36–4.41 (m, 1 H), 3.64–3.70
(m, 1 H), 3.52 (dd, J = 3.5, 9.4 Hz, 1 H), 3.25 (d, J = 9.4 Hz, 1 H),
2.82–2.92 (m, 1 H), 2.45 (s, 3 H), 1.80–1.89 (m, 2 H), 1.63–1.69
(m, 2 H).
13C NMR (75 MHz, CDCl3): d = 21.3, 30.6, 37.2, 39.8, 55.8, 69.1,
73.6, 126.9, 129.5, 134.8, 143.3.
LCMS: m/z = 285 [M+], 268 [M – OH].
Synthesis 2012, 44, 297–303
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PAPER
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