β-aminosulfonamide-catalyzed direct asymmetric aldol reaction in brine

Article abstract of DOI:10.1055/s-0030-1259317

Direct asymmetric aldol reactions of aldehydes with ketones in the presence of a catalytic amount of β-aminosulfonamide 2 and trifluoroacetic acid in brine results in the formation of the corresponding anti-aldol products in high yields with up to 96% ena

Full text of DOI:10.1055/s-0030-1259317

410
LETTER
b-Aminosulfonamide-Catalyzed Direct Asymmetric Aldol Reaction in Brine
S
ulfonamide-Ca
s
talyze
d
A
u
ldol Reactio
y
n
oshi Miura,*a Mariko Ina,a Kie Imai,a Kosuke Nakashima,a Akira Masuda,a Norihiro Tada,a Nobuyuki Imai,b
Akichika Itoha
a
Gifu Pharmaceutical University 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan
Fax +81(58)2308105; E-mail: miura@gifu-pu.ac.jp
Faculty of Pharmacy, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi, Chiba 288-0025, Japan
b
Received 15 October 2010
We have recently reported on direct asymmetric aldol re-
Abstract: Direct asymmetric aldol reactions of aldehydes with ke-
tones in the presence of a catalytic amount of b-aminosulfonamide
2 and trifluoroacetic acid in brine results in the formation of the cor-
responding anti-aldol products in high yields with up to 96% enan-
actions in brine catalyzed by chiral sulfonamide 1 derived
from L-phenylalanine (Scheme 1).5 In addition, we have
also developed a recyclable organocatalyst with a fluo-
tiomeric excess. The anti-aldol products obtained by using rous tag that can promote asymmetric direct aldol reac-
tions in brine.6 We have attempted to find further
applications of b-aminosulfonamide derivatives 1 and
wanted to direct asymmetric aldol reactions in water. In
this letter, we describe that sulfonamide 2 catalyzes the re-
action of aldehydes with ketones in brine to give the anti-
organocatalyst 2 have the opposite absolute configuration to those
obtained using the similar sulfonamide catalyst 1, which was report-
ed previously by us.
Key words: organocatalyst, aldol reaction, sulfonamide, brine,
asymmetric
aldol products with the opposite absolute configuration
compared to those obtained by using the original organo-
catalyst 1 prepared from L-phenylalanine as the same
Organocatalysts play important roles in asymmetric syn-
thesis because enantiopure molecules can be synthesized
under mild, environmentally benign conditions without
toxic metal catalysts.1 Aldol reactions are one of the most
important carbon–carbon bond-forming procedures avail-
able for synthetic reactions involving organocatalysts.2
Especially, organocatalytic aldol reactions in water, as a
safe and an environmentally friendly solvent, have been
developed in recent years.3 However, although one enan-
tiomer can be selectively obtained by various reactions us-
ing an organocatalyst, it is usually difficult to synthesize
the opposite enantiomer because both enantiomeric orga-
nocatalysts are rarely available. Recently, Nakayama and
Maruoka4 have reported an excellent asymmetric synthe-
sis of both enantiomeric aldol products using two different
organocatalysts, which were prepared from common
chiral sources having three chiral centers. Their finding
that the enantioselectivity could be switched by using sep-
arate organocatalysts derived from the same chiral source
was of some interest to us.
chiral source.
As a novel organocatalyst, sulfonamide 2 was prepared as
shown in Scheme 2. Compound 3, as the intermediate for
the synthesis of organocatalyst 1, was prepared from L-
phenylalaninol in three steps.5,7 The Boc group of 3 was
removed by treatment with hydrogen chloride in ethyl ac-
etate, followed by treatment of 4 with tifluoromethane-
sulfonyl anhydride and triethylamine in dichloromethane
to give sulfonamide 5, which was converted into the de-
sired sulfonamide organocatalyst 2 by reduction with
triphenylphosphine in THF–H2O.
The reaction conditions were optimized for the enantiose-
lective direct aldol reactions as shown in Table 1. Aldol
reactions were carried out with aldehyde 6a and cyclohex-
anone (10 equiv) in the presence of a catalytic amount of
the sulfonamide 2 and trifluoroacetic acid (TFA) in brine,
based on the optimal conditions for asymmetric aldol re-
action catalyzed by organocatalyst 1.5 When the reactions
were carried out in the presence of 0.1 equivalent of 2,
O
Ph
H2N
NHTf
O
OH
O
TFA
(0.05 equiv)
(0.1 equiv)
1
(10 equiv)
NO2
H
brine, 0 °C
92%
NO2
7a
6a
anti/syn = 82:18
90% ee
Scheme 1 Our previous work
SYNLETT 2011, No. 3, pp 0410–0414
x
x.
x
x.
2
0
1
1
Advanced online publication: 13.01.2011
DOI: 10.1055/s-0030-1259317; Art ID: U09410ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Sulfonamide-Catalyzed Aldol Reaction
411
8d, and 8g in low to moderate yields with high enantiose-
lectivities (entries 3, 4, and 7). The aldehydes substituted
by nitro groups at either the ortho- or meta-position (6e
and 6f) were converted into the corresponding anti-aldol
products (8e and 8f) in high yields with 93 and 96% ee, re-
spectively (entries 5 and 6). 2,6-Dichlorobenzaldehyde
(6h), as a sterically hindered aldehyde, also reacted with
cyclohexanone to give the corresponding product 8h in
high yield with 92% ee (entry 8). The reaction of penta-
substituted aldehyde 6i was carried out to afford the cor-
responding anti-aldol products 8i in high yield with 84%
ee and low diastereoselectivity (entry 9). We also exam-
ined reactions between other ketones and aldehyde 6a.
The aldol reaction of cyclic ketone cycloheptanone with
p-nitrobenzaldehyde (6a) gave the expected aldol product
8j in 71% yield with 89% ee (entry 10). The reaction of
acyclic ketone acetone with p-nitirobenzaldehyde (6a) af-
forded 8k in low yield with 70% ee (entry 11). Although
the reaction of isobutyl aldehyde acting as either an ali-
phatic donor or acceptor was also examined with acetone
and 6a, respectively, the corresponding aldol products
could not be obtained under these reaction conditions. All
anti-aldol products 8a–k obtained with organocatalyst 2
were determined by HPLC analysis and optical rotation
measurements to be enantiomeric to the anti-aldol prod-
ucts obtained with organocatalyst 1.5
Ph
H2N
Ph
Tf2O, Et3N
HCl
EtOAc, r.t., 4 h
96%
CH2Cl2, r.t., 16 h
81%
N3
Ph
BocHN
N3
4
3
Ph
TfHN
Ph3P, H2O
THF, r.t., 12 h
70%
TfHN
NH2
N3
2
5
Scheme 2 Preparation of the organocatalyst
high enantioselectivities with moderate yields were
achieved (entries 1–4). Both high yield and enantioselec-
tivity were obtained when using 0.2 equivalent of organo-
catalyst 2 (entries 5 and 6). In addition, anti-aldol product
8a, obtained by using organocatalyst 2, had the opposite
absolute configuration to that of 7a obtained by using the
original catalyst 1.5
Table 2 shows the scope and limitations of the direct
asymmetric aldol reaction with various aldehydes 6a–i
under the optimized reaction conditions as mentioned
above.8 We chose nitro, trifluoromethyl, and halogen sub-
stituents as examples of electron-withdrawing groups (en-
tries 1, 2, 5, 6, and 8–11), and a methoxy substituent as a
representative electron-donating group (entries 3 and 7),
in the benzene ring. The aldehydes substituted by an elec-
tron-withdrawing group at the para-position (6a and 6b)
were converted into the corresponding anti-aldol products
in high yields with high enantioselectivities (entries 1 and
2). The reactions of less reactive p-anisaldehyde (6c), ben-
zaldehyde (6d), and m-anisaldehyde (6g) with cyclohex-
anone were also carried out to afford aldol products 8c,
H
N
N
O
Ar
Ph
H
Tf
H
H
Figure 1 Proposed transition state model of the aldol reaction
Table 1 Optimization of Reaction Conditions
O
Ph
O
OH
O
TfHN
NH2
TFA
2
(10 equiv)
H
brine
NO2
NO2
8a
6a
Entry
2 (equiv)
0.1
TFA (equiv)
0.05
Temp (°C)
Time (h)
48
Yield (%)a
anti/synb
95:5
ee (%)c
96
1
2
3
4
5
6
7d
0
49
49
59
55
85
81
78
0.1
0.05
r.t.
0
48
91:9
94
0.1
0.025
0.025
0.05
48
95:5
96
0.1
r.t.
0
28
94:6
95
0.2
48
96:4
96
0.2
0.05
r.t.
r.t.
36
92:8
95
0.2
0.05
48
89:11
93
a 1H NMR yield.
b Determined by 1H NMR spectroscopic analysis.
c Determined by HPLC analysis using Chiralcel AS-H.
d The reaction was carried out with 5 equiv of cyclohexanone.
Synlett 2011, No. 3, 410–414 © Thieme Stuttgart · New York

412
T. Miura et al.
LETTER
Table 2 Direct Asymmetric Aldol Reactions Using Organocatalyst 2
Ph
TFA
(0.05 equiv)
O
O
OH
TfHN
NH2
ketone
(10 equiv)
H
2 (0.2 equiv)
R
R
brine, r.t.
6
8
Entry
1
Product
Time (h)
Yield (%)a
81
anti/synb
ee (%)c
95
O
O
O
OH
OH
36
92:8
NO2
8a
8b
8c
2
3
65
72
12
93:7
95:5
94
80
CF3
OH
OH
137
OMe
O
4
52
136
96
47
80
73
14
79
94:6
95:5
94:6
96:4
88:12
94
93
96
96
92
8d
O
O
O
O
OH NO2
5d
8e
8f
OH
NO2
6
OH
OMe
7e
120
127
8g
OH Cl
8
Cl
8h
O
OH
F
F
F
F
F
9
120
72
56:44
79
8i
Synlett 2011, No. 3, 410–414 © Thieme Stuttgart · New York

LETTER
Sulfonamide-Catalyzed Aldol Reaction
413
Table 2 Direct Asymmetric Aldol Reactions Using Organocatalyst 2 (continued)
Ph
TFA
(0.05 equiv)
O
O
OH
TfHN
NH2
ketone
(10 equiv)
H
2 (0.2 equiv)
R
R
brine, r.t.
6
8
Entry
10
Product
Time (h)
Yield (%)a
71
anti/synb
ee (%)c
89
OH
O
124
80:20
NO2
8j
O
OH
11e,f
120
18
–
70
NO2
8k
a 1H NMR yields.
b Determined by 1H NMR spectroscopic analysis.
c Determined by HPLC analysis.
d Catalyst (0.1 equiv) and TFA (0.025 equiv) were used.
e The reaction was carried out at 0 °C.
f The reaction was carried out with 30 equiv of acetone in brine.
We infer that the b-aminosulfonamide 2 catalyzed direct References and Notes
aldol reactions between aldehydes and ketones proceed
(1) For selected reviews on organocatalysis, see: (a) Dalko,
P. I.; Moisan, L. Angew. Chem. Int. Ed. 2004, 43, 5138.
(b) Pellissier, H. Tetrahedron 2007, 63, 9267.
via a transition state proposed by Córdova’s group,9 based
on the stereochemistry of the aldol products 8 (Figure 1).
We believe it is reasonable to assume that the sulfonamide
proton of 2 coordinates to the oxygen of the aldehyde to
control the direction of approach of the aldehyde to the
enamine intermediate. The addition of TFA to the aldol
reaction accelerates the formation of the enamine interme-
diate.10
(c) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem.
Rev. 2007, 107, 5471. (d) Dondoni, A.; Massi, A. Angew.
Chem. Int. Ed. 2008, 47, 4638. (e) Lattanzi, A. Chem.
Commun. 2009, 1452. (f) Liu, X.; Lin, L.; Feng, X. Chem.
Commun. 2009, 6145.
(2) Modern Aldol Reactions, Vol. 1 and 2; Mahrwald, R., Ed.;
Wiley-VCH: Weinheim, 2004.
(3) For selected reviews on organocatalysis in water, see:
(a) Gruttadauria, M.; Giacalone, F.; Noto, R. Adv. Synth.
Catal. 2009, 351, 33. (b) Paradowska, J.; Stodulski, M.;
Mlynarski, J. Angew. Chem. Int. Ed. 2009, 48, 4288.
(c) Raj, M.; Singh, K. Chem. Commun. 2009, 6687. For
selected recent examples of organocatalyzed aldol reactions
in water, see: (d) An, Y.-J.; Zhang, Y.-X.; Wu, Y.; Liu,
Z.-M.; Pi, C.; Tao, J.-C. Tetrahedron: Asymmetry 2010, 21,
688. (e) Zhang, S.-P.; Fu, X.-K.; Fu, S.-D. Tetrahedron Lett.
2009, 50, 1173. (f) Zhou, H.; Xie, Y.; Ren, L.; Wang, K.
Adv. Synth. Catal. 2009, 351, 1284. (g) Ma, X.; Da C, S.;
Yi, L.; Jia, Y.-N.; Guo, Q.-P.; Che, L.-P.; Wu, F.-C.; Wang,
J.-R.; Li, W.-P. Tetrahedron: Asymmetry 2009, 20, 1419.
(h) Chimni, S. S.; Singh, S.; Kumar, A. Tetrahedron:
Asymmetry 2009, 20, 1722. (i) Fu, S.-D.; Fu, X.-K.; Zhang,
S.-P.; Zou, X.-C.; Wu, X.-J. Tetrahedron: Asymmetry 2009,
20, 2390. (j) Vishnumaya, M. R.; Singh, V. K. J. Org. Chem.
2009, 74, 4289. (k) Nisco, M. D.; Pedatella, S.; Ullah, H.;
Zaidi, J. H.; Naviglio, D.; Ozdamar, O.; Caputo, R. J. Org.
Chem. 2009, 74, 9562. (l) Vishnumaya, M. R.; Singh, V. K.
J. Org. Chem. 2009, 74, 4289. (m) Mase, N.; Noshiro, N.;
Mokuya, A.; Takabe, K. Adv. Synth. Catal. 2009, 351, 2791.
(n) Tea, Y.-C.; Lee, P. P. Synth. Commun. 2009, 39, 3081.
(o) Jia, Y.-N.; Wu, F.-C.; Ma, X.; Zhu, G.-J.; Da C, S.
Tetrahedron Lett. 2009, 50, 3059. (p) Ramasastry, S. S. V.;
In conclusion, the simple sulfonamide 2, with only one
chiral center, works efficiently as a catalyst in the direct
aldol reaction of various aldehydes with ketones in brine11
to give the corresponding anti-aldol products 8 with high
enantioselectivities. The stereochemistry of anti-aldol
products 8, obtained by using organocatalyst 2, had the
opposite absolute configuration to those obtained by using
the original catalyst 1.5 Thus, both enantiomeric anti-aldol
products can be synthesized by applying organocatalysts
2 and 1, which are easily prepared from L-phenylalanine,
a commercially available, inexpensive natural amino acid.
Further application to the synthesis of bioactive com-
pounds is in progress in our laboratory.
Acknowledgment
This work was supported in part by Grants-in-Aid for Scientific Re-
search (C) (No. 22590007) from the Japan Society for the Promoti-
on of Science and the Suzuken Memorial Foundation.
Synlett 2011, No. 3, 410–414 © Thieme Stuttgart · New York

414
T. Miura et al.
LETTER
Albertshofer, K.; Utsumi, N.; Barbas, C. F. Org. Lett. 2008,
10, 1621. (q) Zhu, M.-K.; Xu, X.-Y.; Gong, L.-Z. Adv.
Synth. Catal. 2008, 350, 1390. (r) Zu, L.; Xie, H.; Li, H.;
Wang, J.; Wang, W. Org. Lett. 2008, 10, 1211. (s) Gandhi,
S.; Singh, V. K. J. Org. Chem. 2008, 73, 9411. (t) Zhao,
J.-F.; He, L.; Jiang, J.; Tang, Z.; Cun, L.-F.; Gong, L.-Z.
Tetrahedron Lett. 2008, 49, 3372. (u) Huang, W.-P.; Chen,
J.-R.; Li, X.-Y.; Cao, Y.-J.; Xiao, W.-J. Can. J. Chem. 2007,
85, 208. (v) Huang, J.; Zhang, X.; Armstrong, D. W. Angew.
Chem. Int. Ed. 2007, 46, 9073. (w) Gryko, D.; Saletra, W. J.
Org. Biomol. Chem. 2007, 5, 2148. (x) Hayashi, Y.;
Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji,
M. Angew. Chem. Int. Ed. 2006, 45, 958. (y) Mase, N.;
Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.;
Barbas, C. F. J. Am. Chem. Soc. 2006, 128, 734.
(8) A typical procedure for the aldol condensation using 2 and
6a is as follows: To a colorless suspension of p-nitro-
benzaldehyde (6a; 90.7 mg, 0.600 mmol) and the organo-
catalyst 2 (33.9 mg, 0.120 mmol) in brine (1.2 mL), were
added cyclohexanone (0.62 mL, 6.00 mmol) and TFA (2.2
mL, 0.030 mmol) at r.t. The reaction mixture was stirred at
r.t. for 36 h, and extracted three times with EtOAc. The
organic layers were combined, washed with brine, dried over
anhydrous MgSO4, and evaporated. The residue was purified
by flash column chromatography on silica gel (toluene–
EtOAc, 4:1) to afford pure 8a (121.3 mg, 81%) as a colorless
solid.
(9) (a) Bassan, A.; Zou, W.; Reues, E.; Himo, F.; Córdova, A.
Angew. Chem. Int. Ed. 2005, 44, 7028. (b) Dziedzic, P.;
Zou, W.; Háfren, J.; Córdova, A. Org. Biomol. Chem. 2006,
4, 38.
(4) Nakayama, K.; Maruoka, K. J. Am. Chem. Soc. 2008, 130,
17666.
(10) Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.;
Barbas, C. F. J. Am. Chem. Soc. 2006, 128, 4966.
(11) We assume that the aldol reactions are accelerated by the use
of brine (salting-out effect),10 see: Maya, V.; Singh, V. K.
Org. Lett. 2007, 9, 1117.
(5) Miura, T.; Yasaku, Y.; Koyata, N.; Murakami, Y.; Imai, N.
Tetrahedron Lett. 2009, 50, 2632.
(6) Miura, T.; Imai, K.; Ina, M.; Tada, N.; Imai, N.; Itoh, A. Org.
Lett. 2010, 12, 1620.
(7) Imai, N.; Nokami, J.; Nomura, T.; Ninomiya, Y.; Shinobe,
A.; Matsushiro, S. Bull. Okayama Univ. Sci. 2002, 47.
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