ORGANOCATALYSIS
271
CHIMIA 2007, 61, No. 5
NO2
Table 2. Michael addition of malononitrile to α,β-unsaturated imides 13
CH2(CN)2 14a
O
O
CHO
HO2C
EtO
OEt
O
d-f
a, b
c
O
NH2•HCl
(NC)2HC
H
NO2
2a (10 mol%)
Ph
R
toluene (0.5 M), rt
Cl
Ph
R
Cl
Cl
( R)-(–)-Baclofen
Cl
15A-G
ee [%]
13A-G
Scheme 2. Reagents and Conditions: (a) MeNO2, NaOMe, MeOH, rt, 15 h,
90%; (b) MsCl, Et3N, THF, rt, 1 h, 72%; (c) Diethyl malonate, 2a, toluene, rt,
24 h, 80% (>99% ee after single recrystallization from hexane/AcOEt); (d)
NiCl2·6H2O, NaBH4, MeOH, rt, 7.5 h, 94%; (e) NaOH, EtOH, rt, 45 h; then
toluene, reflux, 6.5 h, 84%; (f) 6N HCl, reflux, 24 h, 94%.
entry
1
product
time [h]
yield (%)
0
substrate [R]
N
15A
13A
48
96
120
60
140
8
-
O
H
O
NO2
O
H
N
NO2
N
O
15B
15C
15D
15E
15F
15G
2
3
4
5
6
7
13B
13C
13D
13E
13F
13G
89
59
93
42
94
97
83
81
87
59
84
86
8
Cl
a
HO
O
N
O
+
OMe
N
O
O
OMe
H
Cl
NO2
allylO
Cl
11
O
MeO
O
10
9
H4
O2
N
Cl
Cl
NO2
N
NMe
H
b-d
e
NO2
H4
H1
H1
+
N
N
N
H
HO
O
O
N
Cl
OH
OH
12A
12B
H
N
Cl
NO2
Cl
N
N
g
f
12A
N
(ꢁ )-epibatidine
OMs
Scheme 3. Reagents and Conditions: (a) 2a, toluene, 0 °C; KOH, EtOH, 0
°C, 77% (75% ee); (b) Pd(OAc)2, PPh3, HCO2H, Et3N, THF, rt, 99%; (c) L-
Selectride, THF, –78 °C, 71%; (d) NaOMe, tert-BuOH, 71%; (e) NaBH3CN,
AcOH, MeOH, –20 °C, 87% (12A/12B = 9/1); (f) MsCl, Et3N, DMAP, CH2Cl2,
0 °C, 91%; (g) Zn, AcOH, THF, rt; CHCl3, 60 °C, 85%.
NHCOPh
NHCO
could be used as a nucleophile to give the
corresponding addition adducts 7 in good
yields with 89–94% ee (Scheme 1, 6A–F).
It should be noted that the reaction with
prochiral nucleophiles such as α-substi-
tuted β-ketoesters also occurred in good
diastereo- and enantioselective manner,
resulting in the construction of contiguous
stereogenic centers containing a chiral qua-
ternary carbon (6G–I).
Baclofen is a lipophilic analogue of
GABA (γ-aminobutylic acid), and it is
widely used as an antispastic agent in race-
mic form. We applied the Michael reaction
for the synthesis of (R)-(–)-baclofen as its
hydrochloric salt (38% overall yield in six
steps from 4-chlorobenzaldehyde) (Scheme
2).
9
OMe
dine, a potent nicotinic acetylcholine recep-
proven to be efficient catalysts for the Mi-
tor agonist (Scheme 3).[12] The subsequent
chaelreactionwithenonesandnitroalkenes,
there have been no reports on their appli-
and nitroalkene 9 with thiourea 2a and KOH cation to α,β-unsaturated acid derivatives.
treatment of γ,δ-unsaturated β-ketoester 8
Therefore, the development of general and
gave rise to 3,4-anti-4,5-syn cycloadduct 11
via Michael adduct 10 with excellent diaste-
reoselectivity, but moderate enantioselectiv-
ity. It is worthy to note that this was the first
report of successful asymmetric synthesis of
three contiguous stereogenic centers by the
tandem Michael reaction with nitroalkenes.
Consequently, we have succeeded in the to-
highly enantioselective versions with α,β-
unsaturated acid derivatives still remains
a challenging goal.[13] We investigated the
thiourea-catalyzed asymmetric Michael
reaction of 1,3-dicarbonyl compounds to
α,β-unsaturated carboxylic acid derivatives
based on our previous results with nitroole-
fins. We expected that an imide moiety
could be activated by bifunctional thiourea
2a through double hydrogen-bonding in-
teraction in a similar manner as the nitro
group (Fig. 3). Although there would be
various types of the hydrogen-bonding in-
teraction between an imide and thiourea 2a
(for example A and B), the reaction should
take place via the transition state such as A,
where a nucleophile, activated by the amino
group of 2a, can attack the β-position of the
imide.
tal synthesis of (−)-epibatidine in six steps
The enantioselective construction of
from the Michael adduct 11.
multiple stereogenic centers in a single
operation has been the subject of recent
research. For this purpose, we planned to
develop a tandem Michael addition of γ,δ-
unsaturated β-ketoesters to nitroalkenes
for the asymmetric synthesis of (−)-epibati-
3.2. Enantioselective Michael
Reaction to α,ꢀ-Unsaturated Imides
Although organocatalysts possessing
chiral secondary amines or thioureas have
S
S
Me
Me
Ar
Ar
N
H
N
H
N
H
N
N
H
N
H
Me
Y
Nu
Me
O
O
O
O
Indeed, among the α,β-unsaturated acid
derivatives 13A–G, N-acyl-2-methoxybenz-
imide 13G exhibited high reactivity in the
Michael addition of malononitrile 14a, that
is, the reaction was complete after only 9 h,
R
N
X
Y
N
X
R
A
B
Fig. 3. Hydrogen-bonding interaction between an imide and 2a