Performance of C1-symmetric chiral ammonium betaines as catalysts for the enantioselective Mannich-type reaction of α- nitrocarboxylates

Article abstract of DOI:10.1016/j.tetasy.2010.04.006

The catalytic performance of C₁-symmetric chiral ammonium betaines in the enantioselective direct Mannich-type reaction of α-nitrocarboxylates with N-Boc imines has been investigated. The most effective catalyst structure has been identified; this provides a reliable synthetic route to a variety of enantiomerically enriched α- tetrasubstituted α,β-diamino acid derivatives.

Full text of DOI:10.1016/j.tetasy.2010.04.006

Tetrahedron: Asymmetry 21 (2010) 1189–1190
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Performance of C1-symmetric chiral ammonium betaines as catalysts
for the enantioselective Mannich-type reaction of a-nitrocarboxylates
*
Daisuke Uraguchi, Kyohei Koshimoto, Chisato Sanada, Takashi Ooi
Department of Applied Chemistry, Graduate School of Engineering, Nagoya University, Nagoya 464-8603, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The catalytic performance of C1-symmetric chiral ammonium betaines in the enantioselective direct
Mannich-type reaction of -nitrocarboxylates with N-Boc imines has been investigated. The most effec-
tive catalyst structure has been identified; this provides a reliable synthetic route to a variety of enanti-
omerically enriched -tetrasubstituted ,b-diamino acid derivatives.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 11 March 2010
Accepted 6 April 2010
Available online 11 May 2010
a
a
a
Dedicated to Professor Henri Kagan on the
occassion of his 80th birthday
1. Introduction
a
-amino acid-derived nucleophile that affords certain synthetic
advantage.4
Duringour continuingeffortsto explorethescopeand limitations
of 1 as an organic base catalyst, we were interested in its perfor-
mance in the direct Mannich-type reaction of -nitrocarboxylates
Over the last two decades, chiral quaternary ammonium salts
have been emerging as a useful and reliable organic molecular cata-
lyst for effecting various stereoselective transformations under mild
conditions.1 Previously elaborated chiral quaternary ammonium
salts can be classified as intermolecular ion-pairing ammonium
salts, and they exhibit catalytic activity in either heterogeneous (bi-
phasic) or homogeneous systems. In both cases, the reactivity and
selectivity strongly depend on the three-dimensional structure of
the chiral ammonium cations as well as the properties of the counter
anions. In 2008, we developed a chiral ammonium betaine, an intra-
molecular ion-pairing quaternary ammonium aryloxide, as a new
class of ammonium salts, and successfully demonstrated its ability
to function as a bifunctional organic base catalyst in a homogeneous
system by achieving the highly enantioselective direct Mannich-
a
3 with N-Boc imines 2 (see Table 2), mainlyfor thefollowingtwo rea-
sons: (1) this catalytic asymmetric protocol represents one of the
simplest strategies to access variable precursors of
ed ,b-diamino acids that are potentially valuable intermediates of
biologically active, functionalized molecules; however, only a hand-
ful of effective catalyst systems have been reported in the litera-
tures;5,6 (2) such an investigation offers an appropriate
opportunity for evaluating the validity of having consolidated the
structural featuresof our initially devised, pseudo C2-symmetric chi-
ral ammonium betaine into 1; this would strengthen the basis for
pursuing further molecular design of this type of ammonium beta-
ines. Herein, we report a set of results of this study.
a-tetrasubstitut-
a
type reaction of
a
-nitrocarboxylates with N-Boc imines.2,3 In the
case of ammonium betaine, the entire structure of the organic ion
pair can be fine-tuned by the structural modification of the back-
bone. Moreover, because the conjugate acid of the betaine is a qua-
ternary ammonium cation possessing a phenolic proton, it could
form a structured ion pair with a nucleophilic anion through electro-
static and hydrogen-bonding interactions, which constitutes a key
element for inducing rigorous enantiocontrol. Quite recently, we
introduced the second generation of this class of ammonium salts,
C1-symmetric chiral ammonium betaine of type 1 (Fig. 1), and suc-
ceeded in determining its discrete intramolecular ion-pairing struc-
ture by single-crystal X-ray diffraction analysis. This new,
structurally simple ammonium betaine exhibited high catalytic
and stereocontrolling abilities, enabling the highly stereoselective
Mannich-type reaction of 2-alkoxythiazol-5(4H)-ones, a unique
R1
O
1a: R1 = R2 = Ph
1b: R1 = Ph, R2 = Cl
1c: R1 = p-tBu-C6H4, R2 = Cl
NMe3
1d: R1 = 3,5-(tBu)2-C6H3, R2 = Cl
R2
1
Figure 1. Structure of C1-symmetric chiral ammonium betaine 1.
2. Results and discussion
Initially, the reaction of tert-butyl 2-nitropropionate 3a with
benzaldehyde-derived N-Boc imine 2a was conducted in the pres-
ence of a catalytic amount of 1a (1 mol %) in toluene at 0 °C.
Smooth bond formation occurred, and after 10 h of stirring the de-
* Corresponding author. Tel.: +81 52 789 4501; fax: +81 789 3338.
E-mail address: tooi@apchem.nagoya-u.ac.jp (T. Ooi).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.006

1190
D. Uraguchi et al. / Tetrahedron: Asymmetry 21 (2010) 1189–1190
of 1c possessing a 4-tert-butylphenyl group as R1 led to an
improvement in both the diastereo- and enantioselectivities (entry
3), whereas a substantial decrease in catalytic efficiency and stere-
oselectivities was observed when 3,5-di-tert-butylphenyl-substi-
tuted 1d was tested (entry 4). Consequently, the most
stereoselective catalyst 1c was selected for further investigations.
Since the optimal structure of 1 as a catalyst was thus iden-
tified, we next examined the applicability of the present method.
As shown in Table 2, a series of aromatic N-Boc imines with sub-
stituents having different electronic properties could be em-
ployed, and the general trend of selectivity was the moderate
diastereocontrol and the rigorous enantiofacial discrimination
for the major syn isomer (entries 1–5). It should be added that
the incorporation of the ortho substituent seemed to be associ-
ated with a higher diastereoselectivity (entry 5). This system also
tolerated heteroaromatic imines such as 2-furylaldehyde-derived
one, in which the highest level of enantioselectivity was attained
(entry 7). Moreover, tert-butyl 2-nitrobutanoate 3b appeared to
be a suitable pro-nucleophile for the 1c-catalyzed direct Man-
nich-type protocol (entry 8).
Table 1
Effect of substituent on each naphthyl group of chiral ammonium betaine 1a
Boc
Boc
Ph
N
NH
1 (1 mol%)
t
t
CO2 Bu
Me
CO2 Bu
+
+
anti-4a
Ph
H
toluene
0 ºC, time
Me NO2
syn-4a
NO2
3a
2a
Entry
1
Time (h)
Yieldb (%)
drc (syn/anti)
eed (%)
1
2
3
4
1a
1b
1c
1d
10
8
8
92
89
98
91
2.1:1
2.6:1
3.2:1
1.6:1
90
93
95
47
36
a
Reactions were carried out with 0.22 mmol of 2a, 0.2 mmol of 3a, and
0.002 mmol of 1 in 0.4 mL of toluene at 0 °C under argon atmosphere.
b
Isolated yields were reported.
c
Diastereomeric ratio was determined by 1H NMR analysis of crude mixture.
d
Enantiomeric excess was analyzed by chiral HPLC. Absolute configuration was
assigned based on the previous report.2
3. Conclusion
Table 2
Scope of substrate for 1c-catalyzed Mannich-type reaction of
a
-nitrocarboxylates
with N-Boc iminesa
We have demonstrated that structurally simplified, C1-symmet-
ric chiral ammonium betaines of type 1 can function as effective
catalysts for the enantioselective direct Mannich-type reaction of
Boc
Boc
N
NH
1c (1 mol%)
a-nitrocarboxylates through appropriate tuning of the backbone
t
t
R4
CO2 Bu
+
CO2 Bu
+
anti-4
structure. We believe that the present study not only enhances
the synthetic value of this particular transformation as a reliable
R3
H
R3
toluene
0 ºC, time
R4 NO2
syn-4
NO2
tool for the catalytic asymmetric synthesis of
a-tetrasubstituted
2
3
a,b-diamino acid derivatives but also underscores the potential
Entry 2(R3)
3(R4) Time (h) Yieldb (%) drc (syn/anti) eed (%)
of the intramolecular ion-pairing, chiral quaternary ammonium
salts as an organic molecular catalyst.
1
2
3
4
p-BrÀC6H4
p-ClÀC6H4
Me
Me
6
6
3
95
99
97
99
90
99
99
99
3.1:1
2.8:1
2.8:1
3.8:1
5.9:1
4.4:1
2.3:1
2.1:1
93
95
94
95
90
92
96
94
p-CO2MeÀC6H4 Me
Acknowledgments
p-MeOÀC6H4
o-MeÀC6H4
1-Naph
2-Furyl
Ph
Me
Me
Me
Me
Et
9
5
12
15
6
This work has been supported by the Sumitomo Foundation, the
Global COE program in Chemistry of Nagoya University, and the
Tatematsu Foundation.
6e
7
8e
24
a
Reactions were carried out with 0.22 mmol of 2, 0.2 mmol of 3, and 0.002 mmol
References
of 1c in 0.4 mL of toluene at 0 °C under argon atmosphere.
b
Isolated yields were reported.
c
Diastereomeric ratio was determined by 1H NMR analysis of crude mixture.
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d
Enantiomeric excess was analyzed by chiral HPLC.
e
1.5 equiv of 2 was used.
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diastereomeric ratio was relatively low (syn/anti = 2.1:1), the
enantiomeric excess of the major syn isomer was determined to
be 90% ee (Table 1, entry 1). It was of interest that the replacement
of the phenyl substituent of the naphthyl unit bearing a pendent
ammonium cation moiety (R2) by the sterically less demanding
chlorine atom slightly improved the stereoselectivities (entry 2).
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influence on the catalytic performance of 1. For instance, the use
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