Asymmetric Mannich-type reaction of aromatic α-amido sulfone with malonate using guanidine-thiourea bifunctional organocatalyst

Article abstract of DOI:10.1055/s-0029-1217193

Asymmetric Mannich-type reaction of aromatic α-amido sulfone with malonate, catalyzed by a guanidine-thiourea bifunctional organocatalyst, affords β-amino acid derivatives in high yield with good to excellent enantioselectivity. Georg Thieme Verlag Stuttg

Full text of DOI:10.1055/s-0029-1217193

CLUSTER
1643
Asymmetric Mannich-Type Reaction of Aromatic a-Amido Sulfone with
Malonate Using Guanidine–Thiourea Bifunctional Organocatalyst
A
symmetric Mann
e
ic
h
Reactio
i
n
of
A
r
s
omatic
a
-
u
A
mido Sulfo
k
ne e Takada, Shinji Tanaka, Kazuo Nagasawa*
Department of Biotechnology and Life Science, Faculty of Technology, Tokyo University of Agriculture and Technology,
Koganei, Tokyo 184-8588, Japan
Fax +81(42)38872953; E-mail: knaga@cc.tuat.ac.jp
Received 4 February 2009
amido sulfone under phase-transfer conditions using
guanidine–thiourea bifunctional organocatalysts 1. Then,
the generated imine should interact effectively with the
thiourea group, and stereoselective nucleophilic attack
with malonate should be guided by interaction with the
guanidine group. Herein, we report the asymmetric Man-
nich-type reaction of a variety of aromatic a-amido sul-
fones with malonates using catalyst 1.
Abstract: Asymmetric Mannich-type reaction of aromatic a-amido
sulfone with malonate, catalyzed by a guanidine–thiourea bifunc-
tional organocatalyst, affords b-amino acid derivatives in high yield
with good to excellent enantioselectivity.
Key words: organocatalyst, bifunction, guanidine, thiourea, Man-
nich-type reaction
Bifunctional catalysts have received considerable atten-
tion in the field of asymmetric synthesis and have been ap-
plied to various reactions, including carbon–carbon bond-
forming reactions, over the last few decades. Chiral bi-
functional catalysts are especially attractive, since they
can activate multiple reactants simultaneously, and the
reaction center is highly controlled. Therefore, high reac-
tion rates and excellent stereoselectivity of the product
can be obtained. We have recently developed guanidine–
thiourea bifunctional organocatalysts 1 (Figure 1) and ap-
plied them to a series of asymmetric Henry and aza-Henry
reactions.1 In these reactions, the guanidinium group and
thiourea group selectively coordinate to nucleophiles (ni-
troalkanes) and electrophiles (aldehydes or imines)
through ionic and hydrogen-bonding interaction, respec-
tively, and the transition state is controlled by the amino
acid derived chiral spacer. This concept is expected to be
applicable to a wide range of catalytic asymmetric reac-
tions, with the use of appropriate combinations of electro-
philes and nucleophiles.
R1 R2
Ar = 3,5-(CF3)2C6H3
+N
Cl–
H
H
H
H
N
N
N
N
Ar
N
N
Ar
H
H
S
R3
R3
S
1
1a R1 = C18H37, R2 = H, R3 = Bn
1b R1 = n-Bu, R2 = H, R3 = Bn
1c R1 = n-Bu, R2 = n-Bu, R3 = Bn
1d R1, R2 = CH2(CH2)3CH2, R3 = Bn
1e R1, R2 = CH2(CH2)2CH2, R3 = Bn
1f R1, R2 = CH2(CH2)2CH2, R3 = Me
1g R1, R2 = CH2(CH2)2CH2, R3 = i-Pr
+N
Cl–
BocHN
NHBoc
N
H
N
H
Me
Me
Ar = 3,5-(CF3)2C6H3
1h
S
H
H
H
H
N
N
N
N
Ar
N
H
N
H
Ar
The catalytic asymmetric Mannich-type reaction is one of
the most important carbon–carbon bond-forming reac-
tions in organic synthesis.2 In this reaction, an enolizable
carbonyl compound attacks an imine acceptor, affording
synthetically useful b-amino acid derivatives.3 In this con-
text, a number of studies have been reported on asymmet-
ric Mannich-type reaction using metal catalysts4 and/or
organocatalysts.5 During these studies, it was found that
a-amido sulfone is a useful and stable precursor for in situ
preparation of the imine acceptor.6 Thus, practical catalyt-
ic asymmetric Mannich-type reactions using a-amido sul-
fone have been investigated, for example with Cinchona
alkaloid and proline-type catalysts, though with only lim-
ited success so far.7 We envisaged that imine acceptors
might be easily generated from the corresponding a-
S
Me
Me
S
1i
Figure 1 Structures of guanidine–thiourea bifunctional catalyst 1
In an initial study, we investigated the catalytic activity
and enantioselectivity in the reaction of a-amido sulfone
2a with malonate 3a catalyzed by 1 in the presence of
Cs2CO3 in toluene (Table 1).7a First, we focused on the ef-
fects of the R1 and R2 groups of 1 on guanidine. Both the
monosubstituted guanidine 1a and 1b, and the bis-substi-
tuted guanidine 1c and 1d gave 4a in good yield with
moderate enantioselectivity (entries 1–4). A marked im-
provement of enantioselectivity was obtained with cata-
lyst 1e, which has a pyrrolidine substituent on guanidine
(entry 5). Encouraged by these results, we next explored
the chiral spacer, that is, the R3 group. We found that
catalyst 1f, having an alanine-derived chiral spacer
(R3 = Me), gave the best results in terms of enantioselec-
tivity (entry 6). On the other hand, the catalyst 1g (R3 =
SYNLETT 2009, No. 10, pp 1643–1646
x
x
.x
x
.2
0
0
9
Advanced online publication: 02.06.2009
DOI: 10.1055/s-0029-1217193; Art ID: Y00809ST
© Georg Thieme Verlag Stuttgart · New York

1644
K. Takada et al.
CLUSTER
yield, but the enantioselectivity was only 31% and 6% ee,
respectively. Therefore, the guanidine and thiourea
groups in catalyst 1f appear to act cooperatively in the
asymmetric reaction (entries 8 and 9). The reaction condi-
tions were further optimized, focusing on the solvent and
base, and we found that the enantioselectivity was im-
proved under biphasic solvent conditions. In the case of
toluene–H2O (4:1) with Cs2CO3 (1 equiv), the Mannich
product 4a was obtained in 89% yield with 94% ee
(Table 2, entry 5).
Table 1 Mannich-type Reaction of 2a and 3a in the Presence of
(S,S)-1a
NHBoc
CO2Me
(S,S)-1 (10 mol%)
toluene
NHBoc
SO2Ph
CO2Me
CO2Me
Ph
+
Cs2CO3 (100 mol%)
40 h, –10 °C
Ph
CO2Me
2a
3a
4a
(1.2 equiv)
Entry
Catalyst
1a
Yield (%)b
ee (%)c
33
1
2
3
4
5
6
7
8
9
88
86
86
89
96
89
98
92
84
With optimal reaction conditions in hand, we then evalu-
ated the generality of this protocol. The results for the
Mannich-type reaction of selected aromatic a-amido sul-
fones 2 and malonates 3a or 3b are summarized in
Table 3. Excellent enantioselectivity and yield were ob-
tained for a series of a-amido sulfones bearing para sub-
stituents on the aromatic ring (entries 4, 5, 8, and 9). The
reactions with meta- or ortho-toluyl-, naphthyl- and furyl-
group-substituted a-amido sulfones also gave products in
high yield with good enantioselectivity (entries 2, 3, and
10–12). In some cases, selectivities were varied depend-
ing on the solvents ratio. As shown in entries 5, 9, and 10
(in Table 3), the selectivities were increased up to 90%,
85%, and 80% ee, respectively, by changing the ratio of
solvents (toluene–H2O) from 4:1 to 19:1. Interestingly,
1b
36
1c
50
1d
40
1e
76
1f
84
1g
51
1h
31
1i
6
a Reaction were carried out on 0.1 mmol scale in toluene (1 mL).
b Isolated yield.
c Determined by chiral HPLC analysis.
Table 3 Mannich-type Reaction of 2 and 3 in the Presence (S,S)-1fa
NHBoc
CO2R2
(S,S)-1f (10 mol%)
NHBoc
SO2Ph
2a–j
CO2R2
CO2R2
3a,b
i-Pr) gave only moderate enantioselectivity (entry 7). To
confirm the bifunctional role of the guanidine and thio-
urea groups in catalyst 1f, catalysts 1h and 1i, lacking the
thiourea or guanidine group, were examined. In these cas-
es, the Mannich product 4a was obtained in 92% and 84%
toluene–H2O
+
R1
R1
Cs2CO3 (100 mol%)
CO2R2
4b–m
(1.2 equiv)
Entry R1
R2
Time Temp Yield
ee
Table 2 Screening Reaction Conditions of 2a and 3a with (S,S)-1fa
(h)
(°C)
(%)b
(%)c
(S,S)-1f (10 mol%)
NHBoc
SO2Ph
NHBoc
CO2Me
solvent
1
2
2a Ph
3b Bn
3a Me
3a Me
3a Me
3b Bn
3a Me
3a Me
3a Me
3b Bn
3a Me
3a Me
3a Me
120 –10
4b 86
4c 84
4d 96
4e 89
4f 87
4g 84
4h 83
4i 95
4j 90
4k 87
4l 86
81
80
86
97
90
52
59
92
85
80
90
CO2Me
CO2Me
+
Ph
Ph
base (100 mol%)
40 h, –10 °C
2b 2-MeC6H4
2c 3-MeC6H4
2d 4-MeC6H4
2d 4-MeC6H4
2e 2-ClC6H4
2f 3-ClC6H4
2g 4-ClC6H4
2g 4-ClC6H4
2h 1-naphthyl
2i 2-naphthyl
2j 2-furyl
46
48
r.t.
r.t.
CO2Me
3
2a
3a
4a
4d
5d
6
43 –10
(1.2 equiv)
Entry
Solvent
Base
Yield (%)b ee (%)c
120
44
0
1
2
3
4d
5
6
7
8
CH2Cl2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
CsOH
85
85
92
82
89
81
77
54
35
1
r.t.
THF
7
67 –10
45 –10
MeCN
5
8
9d
10d
11
12
120
72
0
0
toluene
83
94
92
91
90
toluene–H2O = 4:1
toluene–H2O = 4:1
toluene–H2O = 4:1
toluene–H2O = 4:1
72 –15
72
0
4m 92 80
KOH
a Reaction were carried out on 0.1 mmol scale in toluene (0.8 mL) and
H2O (0.2 mL).
a Reaction were carried out on 0.1 mmol scale.
b Isolated yield.
b Isolated yield.
c Determined by chiral HPLC analysis.
d MS 4 Å (50 mg) was added.
c Determined by chiral HPLC analysis.
d Reaction were carried out in toluene (0.95 mL) and H2O (0.05 mL).
Synlett 2009, No. 10, 1643–1646 © Thieme Stuttgart · New York

CLUSTER
Asymmetric Mannich-Type Reaction of Aromatic a-Amino Sulfone
1645
–10 °C for 40 h. To the reaction mixture was added sat. aq NH4Cl,
and the organic layer was extracted with EtOAc. The extracts were
dried over MgSO4, filtered, and concentrated in vacuo. The residue
was purified by column chromatography on SiO2 (n-hexane–
EtOAc = 30:1 to 8:1) to give 4a (29.3 mg, 89%). The ee of 4a {94%
only moderate enantioselectivity was obtained in the case
of meta- or ortho-chloro-substituted aromatic a-amido
sulfones 2e and 2f (entries 6 and 7), which presumably in-
teract poorly with the thiourea group because of the steric
and electronic effects.
25
ee, [a]D +16.9 (c 1.1, CHCl3)} was determined by means of
chiral HPLC analysis (Chiral AD-H, 0.46 cm × 25 cm, n-hexane–
2-PrOH = 80:20, 0.75 mL/min, tR (major) = 14.9 min; tR (minor) =
18.9 min). The absolute configuration of 4a was assigned as the S
isomer by comparison of its optical rotation with a literature value.7c
(S,S)-1f (10 mol%)
NHBoc
NBoc
toluene–H2O (4:1)
CO2Me
CO2Me
+
Ph
Ph
Cs2CO3 (100 mol%)
40 h, –10 °C
CO2Me
CO2Me
5
3a
4a
Acknowledgment
(1.2 equiv)
86% yield
91% ee
This research was supported in part by grants from the Uehara Me-
morial Foundation and the Nagase Science and Technology Found-
ation.
Scheme 1 Mannich-type reaction of 5 with 3a in presence of (S,S)-1f
In this reaction, we found that the benzaldehyde N-(tert-
butoxycarbonyl)imine (5) from the a-amido sulfone with
malonate 3a also gave 4a in 86% yield with 91% ee under
the same reaction conditions as in Table 2, entry 5
(Scheme 1). The absolute stereochemistry of 4 was found
to be 2S, and a possible transition state for this reaction
was proposed to account for this enantioselectivity. As
shown in Figure 2, malonate coordinates with guanidine
as an enolate form, at the same time, the thiourea part of
the catalyst interacts with imine, which is generated in situ
from a-amido sulfone, and is activated via a double
hydrogen-bonding interaction. Then, nucleophilic attack
of the malonate on the imine from the preferential transi-
tion state TS-1, which avoids the steric repulsion between
the methyl group in the chiral spacer and the R2 group in
malonate, results in the formation of (2S)-4.
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Cl–
Cl–
N+
O
N+
O
Me
H
H
N
H
N
H
N
H
N
H
Me
N
N
R2
O
S
S
H
H
O
O
–
R2
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–
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N
N
O
N
R1
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H
H
t-BuO
H
H
Ot-Bu
TS-1 (favored)
TS-2 (unfavored)
Figure 2 Plausible transition state of the Mannich-type reaction
catalyzed by 1f
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type reaction of aromatic a-amido sulfone 2 with mal-
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Experimental Section
Typical Procedure for the Asymmetric Mannich-type Reaction
To a mixture of (S,S)-1f (8.0 mg, 10 mmol), Cs2CO3 (32.6 mg, 0.1
mmol), and a-amido sulfone 2a (34.7 mg, 0.1 mmol) in toluene–
H2O (0.8/0.2 mL) was added methyl malonate (3a, 15.8 mL, 0.12
mmol) at –10 °C. The resulting mixture was stirred vigorously at
Synlett 2009, No. 10, 1643–1646 © Thieme Stuttgart · New York

1646
K. Takada et al.
CLUSTER
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