Access to the nicotine system by application of a guanidine-catalyzed asymmetric Michael addition of diphenyliminoacetate with 3-pyridyl vinyl ketone

Article abstract of DOI:10.1016/j.tetlet.2010.05.086

A guanidine-based chiral organocatalyst was successfully applied to the Michael addition of diphenyliminoacetate to pyridyl vinyl ketone as a key reaction for the construction of the nicotine system.

Full text of DOI:10.1016/j.tetlet.2010.05.086

Tetrahedron Letters 51 (2010) 3927–3930
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Access to the nicotine system by application of a guanidine-catalyzed
asymmetric Michael addition of diphenyliminoacetate with
3-pyridyl vinyl ketone
*
Gang Zhang, Takuya Kumamoto, Takashi Heima, Tsutomu Ishikawa
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A guanidine-based chiral organocatalyst was successfully applied to the Michael addition of diph-
enyliminoacetate to pyridyl vinyl ketone as a key reaction for the construction of the nicotine system.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 17 April 2010
Revised 15 May 2010
Accepted 21 May 2010
Available online 25 May 2010
Keywords:
Nicotine
Organocatalysis
Michael addition
Pyridyl vinyl ketone
Nicotine (1) and nornicotine (2) are typical alkaloid components
of tobacco (Nicotina tabacum), which play important roles as chem-
ical mediators in the nervous system.1 The first synthesis of 1 was
disclosed by Pictet in 1904,2 and, since then, much attention has
been devoted to the construction of the 2-arylpyrrolidine ring sys-
tem3 because of the widespread occurrence of structurally related
5-arylprolines in nature.4 A variety of these synthetic approaches
to the 2-arylpyrrolidine ring system, including asymmetric ver-
sions, can be classified into four categories (Scheme 1): pyrrolidine
ring construction from 1-functionalized 4-amino-1-arylbutanes
(method I)5, 4-functionalized 1-amino-1-arylbutanes (method
II)6, introduction of an aryl unit onto a pyrrolidine ring by direct
insertion (method III)7, and modification of proline derivatives
(method IV).8 However, there have been no reports of asymmetric
synthesis of 2-arylpyrrolidines using organocatalysis.
Guanidine is a strong organic base and thus plays an important
role as a base catalyst in organic synthesis.9 Recently, we explored
novel preparations of a variety of chiral guanidines10 and observed
that some of the guanidines prepared acted as effective base cata-
lysts in asymmetric reactions such as the Michael reaction, TMS-
cyanation, base-catalyzed epoxidation, alkylative esterification,
and kinetic silylation.11 Among them it was found that (+)-(S,S)-
2-[(R)-1-(2-hydroxymethyl)phenyl ethylimino]-1,3-dimethyl-4,5-
diphenylimidazolidine [(+)-ChibaG] (3) (and its enantiomer)
affords satisfactory product formation with high enantioselectivity
in both inter-11b,e and intramolecular Michael reactions.11f In the
former reaction, using diphenyliminoacetate as a Michael donor,
complex formation with ChibaG has been proposed in the transition
state to rationalize the high asymmetric induction observed (see,
Fig. 1). In order to provide further experimental support for this
hypothesis, (+)-ChibaG was applied to the Michael addition of diph-
enyliminoacetate to 3-pyridyl vinyl ketone as a key reaction for the
construction of optically active 5-pyridylprolines. We herein report
the first example of organobase-catalyzed asymmetric synthesis of
5-(3-pyridyl)proline derivatives using our guanidine catalyst, Chi-
baG, in a formal synthesis of nicotine belonging to method I.
Our retrosynthetic analysis for the construction of the nicotine
system is outlined in Scheme 2, in which (R)-5-tert-butoxycar-
bonyl-2-(3-pyridyl)-1,2-dehydropyrrolidine (4),
a
precursor to
method I
method III
Z
(N)
N
Ar
Y
R
Ar
X
N
R
Y
nicotine (1):
Y
N
method IV
method II
Ar = (S)-3-pyridyl;
R = Me; X = H
nornicotine (2):
Ar = (S)-3-pyridyl;
R = X = H
Ar
(N)
R
* Corresponding author. Tel./fax: +81 43 290 2910.
E-mail address: benti@p.chiba-u.ac.jp (T. Ishikawa).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.086

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G. Zhang et al. / Tetrahedron Letters 51 (2010) 3927–3930
nicotinoyl chloride and N,O-dimethylhydroxylamine hydrochloride
in 87% yield) with vinylmagnesium bromide failed. However, oxi-
dation of allyl alcohol 9 (obtained by Grignard reaction of pyri-
dine-3-carbaldehyde with vinylmagnesium bromide in 98% yield)
with either activated manganese dioxide or 2-iodoxybenzoic acid
(IBX)12 successfully gave vinyl ketone 6, which was found to be
not only sensitive to air but also to polymerize readily during at-
tempted purification by chromatography (Scheme 3). Thus, the
pyridyl vinyl ketone 6 was used as a Michael acceptor in the reac-
tion with diphenyliminoacetate 7 without further purification.
Preliminary examination of (+)-ChibaG (3)-catalyzed Michael
reaction of diphenyliminoacetate 7 using a crude pyridyl vinyl ke-
tone 6 showed that a Michael adduct 5 was partially hydrolyzed to
give a dehydropyrrolidine derivative 4 during purification depen-
dent upon chromatographic conditions. Hopefully, estimation of
enantioselectivity in a crude adduct 5 using chiral HPLC, as ex-
pected, allowed us to deduce high asymmetric induction (93–98%
ee) in the (+)-ChibaG (3)-catalyzed Michael reaction. Therefore,
we decided to directly prepare a dehydropyrrolidine derivative 4
from allyl alcohol 9 in overall three steps (Table 1).
Me
H
N
C
N
N
O
H
Me
H
O
C
N
C
tBuO
R
H
O
Figure 1.
(S)-nicotine (1) and (S)-nornicotine (2), would be afforded by cycli-
zation of the (R)-Michael adduct 5, itself obtained by the reaction
of 3-pyridyl vinyl ketone (6) and tert-butyl diphenyliminoacetate
(7) in the presence of (+)-ChibaG (3).
In the preparation of 3-pyridyl vinyl ketone (6) as a Michael
acceptor, Grignard reaction of Weinreb amide 8 (derived from
Thus, crude 3-pyridyl vinyl ketone 6, obtained by IBX oxidation
of 9 (step 1), was treated with an equimolar amount of diph-
enyliminoacetate 7 in tetrahydrofuran (THF) at À15 °C for 3 days
in the presence of 20 mol % of (+)-ChibaG (3) to give Michael
CO2tBu
N
N
R
N
N
4
R = Me (S)-nicotine (1)
R = H (S)-nornicotine (2)
Ph
Ph
O
N
CO2tBu
N
5
O
Ph
tBuO2C
Ph
Ph
N
OH
+
N
N
effective
asymmetric
induction ?
6
7
MeN
Ph
NMe
Ph
(+)-ChibaG (3)
Scheme 2.
O
O
HN(Me)OMe
DIPEA
Me
MgBr
THF
Cl
N
OMe
CH2Cl2
87%
N
N
8
O
N
OH
O
6
MgBr
H
THF
98%
N
N
IBX or MnO2
9
Scheme 3.

G. Zhang et al. / Tetrahedron Letters 51 (2010) 3927–3930
3929
Table 1
Preparation of dehydropyrrolidine 4 from allyl alcohol 9 through (+)-ChibaG (3)-catalyzed Michael reaction
O
OH
(+)-ChibaG (3)
tBuO2C
oxidant
step 1
Ph
Ph
N
step 2
Ph
N
N
6
9
7
Ph
O
acid
N
CO2tBu
N
CO2tBu
step 3
N
N
4
5
Entry
Step 1a
Step 2
Step 3
Acid
4
Oxidant
3 (mol %)
Temp (°C)
Solvent
Time
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
IBX
IBX
IBX
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
20
20
20
20
10
10
5
À15
À15
À15
À15
rt
À15
À15
À15
À15
THF
THF
THF
THF
THF
CH2Cl2
THF
THF
THF
3 d
2 d
2 d
3 d
16 h
2 d
5 d
3 d
7 d
AcOH/THF/H2Od
33
44
43
53
28
34
35
71
73
81
68
89
91
82
82
87
90
94
AcOH/THF/H2Oe
15% citric acid/THFf
15% citric acid/THFf
15% citric acid/THFf
15% citric acid/THFf
15% citric acid/THFf
15% citric acid/THFf
15% citric acid/THFf
20g
10g
a
b
c
d
e
f
IBX (1.5 M equiv) was used in DMSO at rt for 6 h, whereas MnO2 (10 M equiv) in CH2Cl2 under relux for 1 d.
Isolated yield.
Determined by HPLC.
AcOH/THF/H2O = 1:1:1 at rt for 8 h.
AcOH/THF/H2O = 1:1:1 at rt for 12 h.
15% citric acid/THF = 2:1 at rt for 12 h.
The reaction was carried out in a ratio of 7:9 = 1:2.
g
adduct 5 (step 2), which was hydrolyzed with aqueous acetic acid
and THF (step 3) to afford dehydropyrrolidine 4 in 33% overall yield
and with 81% ee (entry 1). Prolonging the reaction time in step 3
increased the yield, but decreased the ee (entry 2). These results
showed that partial epimerization occurs during acid hydrolysis
using aqueous acetic acid. The use of 15% citric acid in THF slightly
improved the product formation (43%) and enantioselectivity (89%
ee) (entry 3). Oxidation of 9 with MnO2 in the place of IBX in step 1
afforded a better result (entry 4). Optimization of the molar ratios
of (+)-ChibaG (3) and Michael donor 7 resulted in the use of
10 mol % of 3 and 200 mol % of diphenyliminoacetate 7 as the opti-
mum situation, in which dehydropyrrolidine 4 was obtained in 73%
yield with 94% ee (entry 9). From the atom economy viewpoint it
should be noted that the benzophenone could be recovered and
recycled as the starting material for diphenyliminoacetate 7 after
the reaction.
Generation of the stereogenic center of the adduct obtained in
the intermolecular Michael reaction using diphenyliminoacetate
7 is strictly controlled by matched chiral centers of the 2-imino
substituent and imidazolidine ring of the ChibaG catalyst,11b,11e
as shown in a proposed transition state for this reaction (Fig. 1).
Thus, (R)-1,5-dehydroprolinate 4 would be predicted when (+)-
ChibaG (3) is used as a catalyst. In addition, a negative sign in
trifluoroacetic acid afforded 5-(3-pyridyl)proline (11) as a trifluro-
acetic acid salt (Scheme 4) and thus, the formal asymmetric syn-
thesis of nicotine system was achieved as 11 has been previously
converted into nicotine (1).5a
In summary, we have demonstrated the preparation of highly
enantioenriched 5-(3-pyridyl)proline derivatives using guanidine-
catalyzed asymmetric Michael reaction of diphenyliminoacetate
and pyridyl vinyl ketone as the key reaction. This not only provides
additional experimental evidence to support our proposed transi-
tion state for the ChibaG-catalyzed Michael reaction using
diphenyliminoacetate as a Michael donor, but is also the first appli-
cation of organocatalysis to the construction of the nicotine
system.
H2, Pd / C
CO2tBu
N
CO2tBu
N
H
iPrOH
rt, 24 h
N
N
4
10
94%
TFA / CH2Cl2
rt, 20 h
67%
the optical rotation of 4 {[
ported an R configuration of the stereogenic center by comparison
with that of the closely related methyl (S)-5-(3-pyridyl)-3,4-dihy-
a
]
À91.0 (c 0.5, CH2Cl2)} strongly sup-
D
CO2H
N
N
H
R
+82.7 (c 0.5, CH2Cl2)}.5h
N
N
dro-2H-pyrrole-2-carboxylate {[a]
D
11
Catalytic hydrogenation of 1,5-dehydroprolinate 4 smoothly
afforded reduction product 10 as a sole isomer, the cis-configura-
tion of which was assigned by comparison of the 1H NMR spectrum
with literature data. Hydrolysis of the tert-butyl ester of 10 with
R = Me (S)-Nicotine (1)
R = H (S)-Nornicotine (2)
Scheme 4.

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G. Zhang et al. / Tetrahedron Letters 51 (2010) 3927–3930
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