N-tert -Butanesulfinyl Imines in Alkaloid Synthesis: Stereoselective Synthesis of (R)-Coniine and Formal Synthesis of (S)-Coniceine 1

Article abstract of DOI:10.1055/s-0030-1260117

A stereoselective synthesis of the hemlock alkaloid (R)-coniine and a formal synthesis of the indolizidine alkaloid (S)-δ-coniceine were achieved by means of a highly diastereoselective Barbier-type indium-mediated allylation strategy involving (S)-(N-ter

Full text of DOI:10.1055/s-0030-1260117

2478
PAPER
N-tert-Butanesulfinyl Imines in Alkaloid Synthesis: Stereoselective Synthesis
of (R)-Coniine and Formal Synthesis of (S)-d-Coniceine1
N-
tert-Butanesulfi
o
nyl Imines in
n
Alkaloid Sy
g
nthesis ara Damodar, Maram Lingaiah, Nisith Bhunia, Biswanath Das*
Organic Chemistry Division-1, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: biswanathdas@yahoo.com
Received 14 April 2011
alized biologically active derivatives, such as swainsonine
Abstract: A stereoselective synthesis of the hemlock alkaloid (R)-
coniine and a formal synthesis of the indolizidine alkaloid (S)-d-
coniceine were achieved by means of a highly diastereoselective
Barbier-type indium-mediated allylation strategy involving (S)-(N-
tert-butanesulfinyl)imines.
(4) or castanospermine (5) (Figure 1).6
Many stereoselective syntheses of optically active coniine
(1) and d-coniceine (3) have been documented in the liter-
ature. Except for some catalyst-based asymmetric synthe-
ses of these alkaloids,7 most of the known strategies start
from substrates bearing chiral auxiliaries or from amino
acids.8
Key words: alkaloids, stereoselective synthesis, piperidines
The piperidine skeleton is an important structural feature
of various secondary metabolites and biologically active
compounds.2 In particular, simple 2-alkylpiperidines,3
such as coniine (1) and pipecolic acid (2) (Figure 1), and
indolizidine alkaloids,4 such as d-coniceine (3), have be-
come important targets for synthesis over the past few de-
cades because of their scarcity in natural sources, their
wide range of structural diversity, and their physiological
effects.5 Coniine is found in large amounts in hemlock
(Conium maculatem L.) and in the leaves of the elder
(Sambucus nigra). It is a highly toxic alkaloid that induces
curare-type paralysis. Hemlock was used by the ancient
Greeks for state executions, Socrates (469–399 BCE) be-
ing the best-known victim of poisoning by this plant.
Other reported methods involve a chiral lithiation–in-
tramolecular reaction sequence of appropriate N-(tert-bu-
toxycarbonyl)-N-(3-halopropyl)allylamines,9 an enzy-
matic resolution,10 or a nucleophilic addition to an N-acyl-
iminium ion.11 Many of these routes cannot be efficiently
scaled up and or they require relatively inaccessible start-
ing materials. Therefore, the development of an efficient
route to 2-substituted piperidines is highly desirable.
N-(tert-Butanesulfinyl)imines, which can be prepared
from readily available chiral N-tert-butanesulfinamide
and an aldehyde or ketone, exhibit unique reactivity, hy-
drolytic stability, and stereoselectivity in various reac-
tions, and they have proved to be extremely versatile as
chiral reagents.12 In a continuation of our work13 on the
synthesis of natural bioactive compounds, we describe a
convenient route for the stereoselective synthesis of (R)-
coniine and a formal synthesis of (S)-d-coniceine by using
a highly diastereoselective, Barbier-type, indium-mediat-
ed, allylation strategy using (S)-(N-tert-butanesulfin-
yl)imines.
H
N
H
(R)-1
N
H
(S)-2
COOH
N
(S)-3
OH
OH
OH
OH
H
H
Our retrosynthetic analysis of these alkaloids is outlined
in Scheme 1. The natural products were envisioned as
arising from the key cyclic intermediate 12. The interme-
diate 12 would then be generated by deprotection of the
tert-butanesulfinyl group and the p-methoxybenzyl
(PMB) group of homoallylamine 10, followed by base cy-
clization of the corresponding hydroxy homoallylamine.
Finally, the N-(tert-butanesulfinyl)homoallylamine 10
would be prepared by a Barbier-type indium-mediated al-
lylation of N-tert-butanesulfinime 9, which, in turn, would
be prepared from commercially available (S)-N-tert-bu-
tanesulfinamide 8 and pentane-1,5-diol (6).
HO
HO
OH
N
N
5
4
Figure 1 Selected examples of 2-alkylpiperidine and indolizidine
alkaloids
Coniceine is not regarded as a true alkaloid, as it has not
been isolated from natural sources; however, it can be de-
rived from the hemlock alkaloid coniine by means of syn-
thetic transformations. Although d-coniceine is the
simplest member of the class of indolizidine alkaloids, it
has gained much importance as it provides a foundation The synthesis of (R)-coniine and (S)-d-coniceine was ini-
for extension to more complex and more highly function- tiated by converting pentane-1,5-diol (6) into its mono(p-
methoxybenzyl) ether 7 by treating with p-methoxyben-
zyl bromide (Scheme 2). The ether 7 underwent oxidation
with pyridinium chlorochromate (PCC) followed by an-
hydrous copper(II) sulfate mediated condensation with
SYNTHESIS 2011, No. 15, pp 2478–2482
Advanced online publication: 14.07.2011
DOI: 10.1055/s-0030-1260117; Art ID: Z39911SS
x
x.
x
x
.
2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

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N-tert-Butanesulfinyl Imines in Alkaloid Synthesis
2479
H
N
NHCbz
3 (S)-coniceine
HO
N
Cbz
12
11
N
H
1 (R)-coniine
S
O
S
O
N
HN
HO
OH
PMBO
PMBO
10
9
6
Scheme 1 Retrosynthetic analysis of (R)-coniine and (S)-d-coniceine
••
(S)-N-tert-butanesulfinamide (8) to give the correspond-
ing (S)-(N-tert-butanesulfinyl)imine 9 in 88% yield.14 In
this reaction, anhydrous copper(II) sulfate was found to
serve as both a Lewis acid catalyst and an effective scav-
enger of water. The sulfinimine 9 was then subjected to
indium-mediated allylation under Barbier conditions.15
The reaction was run on a 10-mmol scale, and the corre-
sponding N-tert-butanesulfinyl homoallylamine 10 was
obtained in 85% yield with excellent diastereoselectivity
t-Bu
H
S
N
O
[In]
R
Figure 2 Chelation control model of indium-mediated Barbier-type
allylation of (S)-(N-tert-butylsulfinyl)imine 9 [R = (CH2)4OPMB]
chiral HPLC). Amine 11 was mesylated, and the crude
product was subjected to ring closure by treatment with
potassium tert-butoxide without further purification.16
This gave the 2-allylpiperidine 12 in 93% yield over the
two steps. Compound 12 was divided into two fractions,
and one fraction was subjected to reduction of the olefinic
double bond and deprotection of the benzyloxycarbonyl
group with hydrogen over palladium-on-carbon in ethyl
acetate solution to give a 2-propylpiperidine whose hy-
drochloride salt showed identical analytical data to those
reported for (R)-(–)-coniine.8e
1
(92:8 dr by H NMR). A six-membered-ring chelation-
control model (Figure 2) is consistent with the high level
of stereocontrol and with the configuration of the newly
created stereogenic center. Coordination of indium to the
nitrogen atom increases the reactivity of the electrophilic
center of the imine, while coordination of the metal to the
oxygen of the sulfinyl group responsible for allylation
takes place at the re face of the (S)-N-tert-butanesulfinyl
imine 9. Removal of the sulfinyl group and the p-meth-
oxybenzyl group under conventional acidic conditions,
followed by selective N-protection with benzyloxycarbo-
nyl chloride gave the hydroxyhomoallylamine 11 in mod-
erate yield (64%) and excellent optical purity (97% ee by
The second fraction of 2-allylpiperidine 12 was selective-
ly hydrated17 by using borane–dimethyl sulfide complex
and hydrogen peroxide to produce the protected 3-pipe-
S
O
N
b
a
PMBO
OH
HO
OH
PMBO
NHCbz
6
7
9
S
O
HN
e
c
d
PMBO
HO
10
11
f
N
N
Cbz
H
•HCl
1 (R)-coniine
12
Scheme 2 Reagents and conditions: a) PMBBr, NaH, THF, 0 °C to r.t., 8 h, 79%; b) i) PCC, CH2Cl2, r.t., 2 h, 90%; ii) (S)-t-BuSONH2, CuSO4
(anhyd), CH2Cl2, r.t., 24 h, 88%; c) CH2=CHCH2Br, In, THF, 66 °C, 4 h, 85%; d) i) 4 M HCl/dioxane, MeOH, r.t., 45 min; ii) CbzCl, K2CO3,
THF–H2O (1:1), 24 h, 64% (two steps); e) i) MsCl, Et3N, CH2Cl2, 0 °C, 1 h; ii) t-BuOK, THF, 0 °C to r.t., 3 h, 93% (two steps); f) i) H2 (1 atm),
Pd/C (10%), EtOAc, r.t., 24 h; ii) HCl, Et2O, r.t., 10 min, 80% (two steps).
Synthesis 2011, No. 15, 2478–2482 © Thieme Stuttgart · New York

2480
K. Damodar et al.
PAPER
CH2Cl2 (60 mL) at 0 °C. The mixture was stirred for 2 h at r.t. then
diluted with Et2O (45 mL) and passed through a silica gel column
with elution by EtOAc–hexane (1:4) to afford the corresponding al-
dehyde as a colorless liquid; yield; 2.765 g (90%).
ridinylpropanol 13 (Scheme 3) in high yield (88%). The
spectral properties and optical rotation of the product were
in agreement with reported data.7e The protected 3-pipe-
ridinylpropanol 13 can be converted into (S)-d-coniceine
(3) by using a previously reported method.7e
To a 0.5 M soln of sulfinamide 8 (1.508 g, 12.46 mmol) in CH2Cl2
was added anhyd CuSO4 (4.358 g, 27.4 mmol, 2.2 equiv) followed
by the aldehyde (2.765 g, 12.46 mmol). The mixture was stirred at
r.t. for 24 h then filtered through a pad of Celite. The filter cake was
washed well with CH2Cl2, and the filtrate was concentrated to give
a residue that was purified by column chromatography [silica gel,
hexane–EtOAc (4:1)] to the sulfinimine as a pale yellow liquid;
yield: 3.562 g (88%); [a]D25 +145.4 (c 1.0, CHCl3).
H
ref. 6e
a
OH
N
N
N
Cbz
Cbz
12
13
3 (S)-coniceine
IR (neat): 2932, 1617, 1512, 1458, 1246, 1082 cm–1.
Scheme 3 Reagents and conditions: a) BH3⋅SMe2, H2O2, 3 M
NaOH, THF, 0 °C, 5 h, 88%.
1H NMR (200 MHz, CDCl3): d = 8.02 (t, J = 4.5 Hz, 1 H), 7.19 (d,
J = 8.5 Hz, 2 H), 6.81 (d, J = 8.5 Hz, 2 H), 4.39 (s, 2 H), 3.78 (s, 3
H), 3.42 (t, J = 6.0 Hz, 2 H), 2.57–2.47 (m, 2 H), 1.79–1.57 (m, 4
H), 1.18 (s, 9 H).
13C NMR (50 MHz, CDCl3): d = 169.3, 159.0, 130.4, 129.1, 113.7,
72.5, 69.3, 56.4, 55.2, 35.8, 29.2, 22.3, 22.2.
In conclusion, we developed a stereoselective synthesis of
the piperidine alkaloid (R)-coniine and a formal synthesis
of the indolizidine alkaloid (S)-d-coniceine by using a
highly diastereoselective Barbier-type indium-mediated
allylation strategy applying (S)-(N-tert-butanesulfin-
yl)imine.
ESI-MS: m/z 326 [M + H]+, 348 [M + Na]+.
(S)-N-((1S)-1-{4-[(4-Methoxybenzyl)oxy]butyl}but-3-en-1-yl)-
2-methylpropane-2-sulfinamide (10)
Unless otherwise stated, all reactions were carried out under an inert
atmosphere by using standard syringe/septa techniques. The sol-
vents were dried and purified by standard techniques before use.
The progress of the reactions was monitored by TLC on glass plates
precoated with silica gel-60 F254 to a thickness of 0.5 mm (Merck).
The TLC plates were visualized by using a UV lamp, I2, anisalde-
hyde, or ninhydrin. Column chromatography was performed on sil-
ica gel (60–120 mesh or 100–200 mesh) with EtOAc and hexane as
eluents. Yields refer to analytically pure samples. IR spectra were
recorded on a Perkin–Elmer Fourier-transform IR spectrophotome-
ter. 1H NMR spectra with CHCl3 (d = 7.26) or TMS (d = 0.00) as in-
ternal standards, were recorded on Varian Gemini 200 MHz, Bruker
Avance 300 MHz, Varian Unity 400 MHz, or Varian Inova 500
MHz spectrometers. Mass spectra were recorded on a VG Micro-
mass 7070 H (EI) or a Thermo Finnigan ESI ion-trap spectrometer.
A mixture of In powder (1.495 g, 13 mmol) and CH2=CHCH2Br
(1.2 mL, 13 mmol) in THF (15 mL) was heated at 66 °C for 15 min
under N2, and then a soln of imine 9 (3.25 g, 10 mmol) in THF (30
mL) was added dropwise. The mixture was stirred at 66 °C for 4 h
while the progress of the reaction was monitored by TLC. The reac-
tion was then quenched with sat. aq NH4Cl and the mixture was fil-
tered through a pad of MgSO4 that was washed well with EtOAc.
The layers were separated and the aqueous layer was extracted with
EtOAc (2 × 100 mL). The combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure to give a residue
that was purified by column chromatography [silica gel, hexane–
EtOAc (3:2)] to give a pale yellow liquid; yield: 3.12 g (85%);
[a]D25 +31.6 (c 1.0, CHCl3).
IR (neat): 3449, 2936, 1612, 1513, 1458, 1248, 1099 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.20 (d, J = 8.5 Hz, 2 H), 6.83 (d,
J = 8.5 Hz, 2 H), 5.74 (m, 1 H), 5.21–5.08 (m, 2 H), 4.39 (s, 2 H),
3.79 (s, 3 H), 3.40 (t, J = 6.0 Hz, 2 H), 3.28 (m, 1 H), 3.16 (m, 1 H),
2.40 (m, 1 H), 2.29 (m, 1 H), 1.66–1.34 (m, 6 H), 1.18 (s, 9 H).
13C NMR (50 MHz, CDCl3): d = 159.0, 134.1, 130.6, 129.1, 118.9,
113.7, 72.5, 69.7, 55.7, 55.2, 54.8, 40.3, 34.7, 29.5, 22.6, 22.2.
5-[(4-Methoxybenzyl)oxy]pentan-1-ol (7)
A 60% dispersion of NaH in mineral oil (0.932 g, 38.83 mmol) was
added portionwise to a soln of pentane-1,5-diol (1.8 g, 17.65 mmol)
in anhyd THF (50 mL) at 0 °C, and the mixture was stirred at 0 °C
for 30 min. Bu4I (0.065 g, 0.18 mmol) and PMBBr (3.371 g, 16.77
mmol) in THF (5 mL) were added sequentially, and the mixture was
stirred for a further 8 h at r.t. H2O was added carefully to the mixture
to quench any excess NaH. The mixture was then extracted with a
large volume of EtOAc. The organic soln was washed with H2O and
brine, dried (Na2SO4), and concentrated. The residue was purified
by column chromatography [silica gel, hexane–EtOAc (3:2)] to
give a colorless liquid; yield: 3.123 g (79%).
ESI-MS: m/z 368 [M + H]+, 390 [M + Na]+.
Benzyl [(1S)-1-(4-Hydroxybutyl)but-3-en-1-yl]carbamate (11)
A dry, 50-mL, round-bottomed flask was charged with a soln of the
protected amino alcohol 10 (1.468 g, 4.0 mmol) in MeOH (8 mL)
under an inert atmosphere. To this soln was added 4 M HCl/dioxane
(8.0 mL, 32.0 mmol), and the soln was stirred for 45 min at r.t. The
soln was then concentrated under reduced pressure. The residue was
dissolved in Et2O (20 mL), and 4 M NaOH (60 mL) was slowly add-
ed with stirring. The layers were separated and the aqueous layer
was extracted with Et2O (2 × 100 mL). The combined organic lay-
ers were dried (Na2SO4) and concentrated under reduced pressure to
give a crude product that was dissolved in THF (2.5 mL). H2O (2.5
mL) and K2CO3 (1.656 g, 12 mmol) were added, and the mixture
was cooled to 0 °C. CbzCl (0.69 mL, 4.8 mmol) was added drop-
wise, and the mixture was stirred for 24 h. The reaction was then
quenched with sat. aq NaHCO3 (3 mL) and the mixture was stirred
for 15 min. The phases were separated and the aqueous layer was
extracted with EtOAc (3 × 20 mL). The combined organic layers
were washed with brine, dried (Na2SO4), and concentrated under re-
duced pressure. The residue was purified by column chromatogra-
IR (neat): 3412, 2936, 1612, 1513, 1460, 1246, 1093 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.22 (d, J = 8.6 Hz, 2 H), 6.84 (d,
J = 8.6 Hz, 2 H), 4.41 (s, 2 H), 3.80 (s, 3 H), 3.61 (t, J = 6.7 Hz, 2
H), 3.43 (t, J = 5.7 Hz, 2 H), 1.65–1.53 (m, 4 H), 1.47–1.40 (m, 2
H).
13C NMR (50 MHz, CDCl3): d = 159.0, 130.5, 129.1, 113.7, 72.5,
69.9, 62.6, 55.2, 32.4, 29.4, 22.4.
ESI-MS: m/z 247 [M + Na]+.
(S)-N-{5-[(4-Methoxybenzyl)oxy]pentylidene}-2-methylpro-
pane-2-sulfinamide (9)
Celite (4.65 g) and PCC (4.474 g, 20.76 mmol) were added to a
stirred soln of the monoprotected diol 7 (3.1 g, 13.84 mmol) in dry
Synthesis 2011, No. 15, 2478–2482 © Thieme Stuttgart · New York

PAPER
N-tert-Butanesulfinyl Imines in Alkaloid Synthesis
2481
phy [silica gel, hexane–EtOAc (1:1)] to give a pale yellow liquid;
column chromatography [silica gel, hexane–EtOAc (3:2)] to give a
pale yellow liquid; yield: 0.061 g (88%); [a]D25 –27.3 (c 1.99,
CHCl3) {Lit.7e [a]D25 –27.99 (c 4.2, CHCl3)}.
IR (neat): 3410, 2930, 1672, 1496, 1425, 1349, 1261 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.38–7.22 (m, 5 H), 5.12 (d,
J = 12.0 Hz, 1 H), 5.03 (d, J = 12.0 Hz, 1 H), 4.32 (m, 1 H), 4.02 (br
d, J = 8.0 Hz, 1 H), 3.66–3.52 (m, 2 H), 2.82 (br t, J = 8.0 Hz, 1 H),
1.88–1.73 (m, 2 H), 1.69–1.40 (m, 7 H), 1.31–1.22 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 155.7, 136.9, 128.4, 127.9, 127.8,
66.9, 62.5, 50.4, 39.1, 29.1, 28.5, 26.0, 25.5, 18.8.
ESI-MS: m/z 278 [M + H]+, 300 [M + Na]+.
yield: 0.710 g (64%); [a]D25 –25.9 (c 1.1, CHCl3).
IR (neat): 3324, 2934, 1698, 1535, 1450, 1252, 1069 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.39–7.22 (m, 5 H), 5.75 (m, 1 H),
5.16–5.01 (m, 4 H), 4.60 (d, J = 6.5 Hz, 1 H), 3.71 (m, 1 H), 3.65–
3.52 (m, 2 H), 2.28 (m, 1 H), 2.20 (m, 1 H), 1.70 (br s, 1 H), 1.61–
1.38 (m, 6 H).
13C NMR (50 MHz, CDCl3): d = 156.2, 136.6, 134.2, 128.5, 128.1,
128.0, 118.0, 66.6, 62.5, 50.6, 39.5, 34.4, 32.4, 22.1.
ESI-MS: m/z 278 [M + H]+, 300 [M + Na]+.
Benzyl (2S)-2-Allylpiperidine-1-carboxylate (12)
Et3N (0.65 mL, 4.7 mmol) and MsCl (0.3 mL, 3.53 mmol) were
added sequentially to a soln of hydroxy homoallylamine 11 (0.65 g,
2.35 mmol) in CH2Cl2 (15 mL) immersed in an ice-cooled bath. Af-
ter 1 h at 0 °C, the reaction was quenched with H2O and the mixture
was diluted with CH2Cl2 (20 mL), washed with brine, dried
(Na2SO4), filtered, and concentrated under reduced pressure. To a
cooled (0 °C) soln of the resulting crude mesylate in THF (15 mL)
was added t-BuOK (0.526 g, 4.7 mmol). The mixture was warmed
to r.t. over 1 h and stirred at r.t. for another 3 h. The reaction was
then quenched with sat. aq NH4Cl, and the mixture was extracted
with CH2Cl2 (2 × 30 mL). The combined organic phases were
washed with brine, dried (Na2SO4), filtered, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy [silica gel, hexane–EtOAc (19:1)] to give a colorless liquid;
yield: 0.565 g (93%); [a]D25 –48.3 (c 0.87, CHCl3).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are 1H and 13C NMR spectra for all compounds.
Acknowledgment
The authors thank CSIR and UGC, New Delhi, for financial assi-
stance.
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6 H).
13C NMR (50 MHz, CDCl3): d = 155.5, 137.0, 135.2, 128.4, 127.8,
127.7, 116.8, 66.8, 50.3, 39.2, 34.4, 27.5, 25.4, 18.7.
ESI-MS: m/z 260 [M + H]+, 282 [M + Na]+.
(R)-(–)-Coniine Hydrochloride (1)
10% Pd/C (30 mg) was added to a soln of allylpiperidine 12 (0.3 g,
1.16 mmol) in EtOAc (6 mL), and the mixture was hydrogenated at
1 atm pressure and r.t. for 24 h. The soln was filtered through Celite,
which was washed with MeOH. The filtrate was treated with 1 M
HCl in Et2O (2.5 mL, 2.5 mmol), and the mixture was stirred for 10
min. The solvent was then evaporated under reduced pressure and
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0.152 g (80%); mp 208–210 °C (Lit.8e 212–213 °C); [a]D25 –6.1 (c
0.5, EtOH) {Lit.8e [a]D20 –7.6 (c 1.0, EtOH)}.
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IR (neat): 3448, 2961, 1260, 1092, 1028 cm–1.
1H NMR (200 MHz, CDCl3): d = 8.80 (br s, 1 H), 8.34 (br s, 1 H),
3.45 (br d, J = 8.0 Hz, 1 H), 3.12–2.90 (m, 2 H), 2.01–1.70 (m, 6 H),
1.62–1.53 (m, 2 H), 1.50–1.32 (m, 2 H), 0.89 (t, J = 7.0 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 57.1, 45.0, 35.5, 28.2, 22.4, 22.2,
18.4, 13.7.
ESI-MS: m/z 128 [M + H]+.
Benzyl (2S)-2-(3-Hydroxypropyl)piperidine-1-carboxylate (13)
BH3·SMe2 (0.1 mL, 0.5 mmol) was added to a stirred soln of ester
12 (0.065 g, 0.25 mmol) in dry THF (4 mL) while the temperature
was kept at 0 °C. The mixture was stirred 0 °C for 5 h then 3 M aq
NaOH was added very slow at 0 °C until the mixture became basic.
30% aq H2O2 (0.1 mL, 0.66 mmol) was added and the mixture was
stirred for 1.5 h then extracted with EtOAc (3 × 15 mL). The com-
bined organic layers were washed with brine, dried (Na2SO4), and
concentrated under reduced pressure. The residue was purified by
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