Combined proline-surfactant organocatalyst for the highly diastereo- and enantioselective aqueous direct cross-aldol reaction of aldehydes

Article abstract of DOI:10.1002/anie.200601156

(Chemical Equation Presented) Why not combine the two? The asymmetric direct aldol reaction of two different aldehydes was catalyzed by a combined proline-surfactant organic catalyst in the presence of water. A stable emulsion was formed in the reaction mixture, and the aldols were obtained with excellent diastereo- and enantioselectivities (see scheme).

Full text of DOI:10.1002/anie.200601156

Angewandte
Chemie
Organocatalysis
DOI: 10.1002/anie.200601156
Combined Proline–Surfactant Organocatalyst for
the Highly Diastereo- and Enantioselective
Aqueous Direct Cross-Aldol Reaction of
Aldehydes**
Yujiro Hayashi,* Seiji Aratake, Tsubasa Okano,
Junichi Takahashi, Tatsunobu Sumiya, and
Mitsuru Shoji
Scheme 1. Organocatalysts examined in this study. TBDPS=tert-butyl-
diphenylsilyl.
As water offers several advantages over organic solvents,
reactions in aqueous media have received a great deal of
attention in recent years.[1] However, the asymmetric aldol
reaction in water has proved very difficult to achieve.[2] While
proline has been reported to catalyze aldol reactions effi-
ciently in polar solvents such as dimethyl sulfoxide (DMSO)
and N,N-dimethylformamide (DMF),[3] and while a small
amount of water is beneficial in some proline-mediated aldol
reactions,[4] only low enantioselectivities have been obtained
in water even in the presence of a surfactant.[5] There have
been no successful asymmetric aldol reactions performed
using organocatalysts in water in the absence of an organic
cosolvent or other additives. Recently, we reported that a
siloxyproline effectively catalyzes the highly diastereo- and
enantioselective aldol reaction of ketones and aldehydes in
the presence of water.[6] Barbas and co-workers reported the
asymmetric aldol reaction of ketones and aldehydes in water
catalyzed by a combination of a diamine and an acid.[7]
Herein, we describe how combined proline–surfactant organ-
ocatalysis promotes the asymmetric direct aldol reaction of
two different aldehydes in the presence of water and no other
additives, with high diastereo- and enantioselectivity. The
original version of this reaction reported by MacMillan and
Northup was carried out in a polar organic solvent under
proline catalysis, with introduction of the aldehyde donor by
syringe pump.[8]
(Table 1). No reaction proceeded when proline (1), hydrox-
yproline (2), or proline-tetrazol (3)[4a,9] were employed. With
Table 1: Effect of the organocatalyst and amount of water on the aldol
reaction of o-chlorobenzaldehyde and propanal.[a]
Entry
Catalyst
Amount of
water [equiv]
Yield
[%][b]
anti/syn[c]
ee
[%][d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18[e]
19[f]
1
2
3
4
5
6
7
8
9
10
11
12
13
10
10
10
10
10
10
18
18
18
18
18
18
18
18
18
18
18
18
18
0
<5
<5
<5
30
50
14
17
39
57
60
54
15
32
71
58
65
58
92
97
–
–
–
2:1
8:1
–
–
–
71
98
96
95
96
97
99
96
96
94
97
97
94
95
99
99
18:1
20:1
14:1
18:1
20:1
17:1
>20:1
11:1
16:1
17:1
12:1
13:1
19:1
19:1
5
54
125
18
18
The reaction of o-chlorobenzaldehyde and propanal
(5 equiv) was selected as a model and performed in the
presence of 18 equivalents of water and several putative
organocatalysts (10 mol%, 24 h; see Scheme 1). The aldols
were isolated after reduction to the corresponding diols
[a] The reaction was conducted with 0.4 mmol of o-chlorobenzaldehyde
and 2.0 mmol of propanal at 08C for 24 h. [b] Isolated yield. [c] Deter-
mined by 1H NMR spectroscopy. [d] ee value of anti isomer, determined
by chiral HPLC after conversion into the benzoyl ester (see Supporting
Information). [e] The reaction was performed for 70 h. [f] The reaction
was performed with 15 mmol of o-chlorobenzaldehyde and 45 mmol of
propanal for 96 h.
[*] Prof. Dr. Y. Hayashi, S. Aratake, T. Okano, J. Takahashi, T. Sumiya,
Dr. M. Shoji
Department of Industrial Chemistry
Faculty of Engineering
Tokyo University of Science
Kagurazaka, Shinjuku-ku, Tokyo 162-8601 (Japan)
Fax: (+81)3-5261-4631
E-mail: hayashi@ci.kagu.tus.ac.jp
Homepage: http://www.ci.kagu.tus.ac.jp/lab/org-chem1/
siloxyproline,[6,10] two phases were formed as previously
described[6] and the aldols were obtained with excellent
diastereo- and enantioselectivities. The moderate yield can be
ascribed to insufficient mixing of the reagents, as propanal is
water-soluble while o-chlorobenzaldehyde is not. Emulsions
may be the ideal reaction medium for achieving effective
mixing, as demonstrated by Kobayashi et al. for several
surfactant-combined organometallic catalysts, which promote
organic reactions in water or aqueous organic solvents.[2]
[**] This work was partially supported by the Toray Science Foundation
and a Grand-in-Aid for Scientific Research on Priority Areas
16073219 from MEXT.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2006, 45, 5527 –5529
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5527

Communications
Table 2: Enantioselective direct aldehyde cross-aldol reaction in the presence of water.[a]
First, we examined proline N-
sulfonyl amides 6 and 7 containing
long alkyl chains (Scheme 1).
Though similar N-arylsulfonyl
amides are excellent aldol catalysts
in organic solvents, as reported by
Berkessel et al.[11] and Ley and co-
workers,[9] 6 and 7 were found to be
poor catalysts: an emulsion did not
form in the reaction mixture, and
the products were obtained in low
yield. Next, we developed the
novel catalysts 8–13, which contain
both a proline unit and a long alkyl
chain and which were easily pre-
pared in large quantities from
Entry
R1
R2
t [h]
Yield
[%][b]
anti/syn[c]
ee
[%][d]
1
2
3
4
5
o-chlorophenyl
p-chlorophenyl
p-fluorophenyl
phenyl
2-naphtyl
1-naphtyl
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
iPr
70
110
110
73
110
80
68
72
70
118
68
92
90
76
88
54
49
65
83
38
29
58
61
57
35
35
18:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
20:1
>20:1
10:1
8:1
10:1
99
99
99
99
99
98
99
95
97
92
92
73
92
93
89
6
7[e]
8
p-tolyl
o-methoxyphenyl
p-methoxyphenyl
cyclohexyl
9
10
11[f]
12[e]
13[e]
14[g]
15[f,g]
2-furyl
o-chlorophenyl
o-chlorophenyl
dimethoxymethyl
ethyl
68
93
62
96
commercially
available
l-4-
Bn
Bn
Me
14:1
4:1
10:1
hydroxyproline. An emulsion was
formed in the reaction mixture and
excellent diastereo- and enantiose-
lectivities were attained using cat-
alysts 8–13, while the chain length
dramatically affected the yield.
Neither very long nor very short
chains were effective, whereas cat-
alyst 10 with a decanoate moiety
was found to be the most efficient.
[a] Unless otherwise shown, the reactions were conducted with 0.4 mmol of acceptor aldehyde and
2.0 mmol of donor aldehyde and water (130 mL) in the presence of 10 mol% of 10 at 08C. [b] Isolated
yield. [c] Determined by 1H NMR spectroscopy. [d] ee value of anti isomer (see Supporting Information).
[e] 20 mol% of 10 was employed. [f] The reaction was performed at room temperature. [g] 3.8 equiv of
water was employed.
The yield was increased to 92% on prolonging the reaction
time (70 h). Diastereo- and enantioselectivities decreased
slightly as the amount of water in the reaction was increased.
The reaction also proceeded efficiently under neat reaction
conditions, though slight decreases in diastereo- and enantio-
selectivities were observed. This result provides evidence that
the reaction proceeds in the organic phase, created inside the
emulsion when the reaction is performed in the presence of
water. Note also that the reaction can be performed on a 15-
mmol scale with 3 equivalents of propanal to afford 2.9 g of
aldol with 99% ee and 19:1 anti diastereoselectivity.
The generality of the reaction was also investigated
(Table 2). The reaction was highly diastereo- and enantiose-
lective, and hardly any dehydration products were generated
in every case investigated. Not only propanal but also
isovaleraldehyde and 3-phenylpropanal were successfully
employed as the donor. Note the excellent diastereoselectiv-
ity obtained in entries 4 and 15 (Table 2), which is in marked
contrast to the low d.r. (3:1) reported for the corresponding
proline-mediated aldol reactions in DMF.[8] The low yield
obtained with aliphatic aldehydes such as cyclohexylcarbal-
dehyde and propanal can be ascribed to inefficient mixing due
to insufficient hydrophobicity of the acceptor aldehydes, as
only in these cases was an emulsion not formed. Commer-
cially available aqueous dimethoxyacetaldehyde was also a
successful acceptor (Table 2, entry 14). In their procedure
using benzaldehyde as the acceptor, MacMillan and Northup
employed an excess amount of benzaldehyde (10 equiv) with
slow addition of propanal over 16 h.[8] In the present protocol,
the nucleophilic aldehyde (5 equiv) was used without slow
addition. Although the self-aldol products of propanal were
formed (ca. 30%), they could easily be removed by column
chromatography. The same predominant enantiomer was
formed as with l-proline in DMF,[8] which indicates the
involvement of a similar transition state to that reported.
In summary, we have developed a catalytic, direct
asymmetric cross-aldol reaction of two different aldehydes
in the presence of water, catalyzed by a novel combined
proline–surfactant organocatalyst 10. Neither organic cosol-
vent nor additional acid is necessary. Though the precise
reaction mechanism is not clear at the moment, emulsions
seem to offer an ideal reaction environment in the presence of
water, in which organic molecules can be assembled through
hydrophobic interactions thus enabling the aldol reaction to
proceed efficiently.
Experimental Section
General procedure (Table 1, entry 19): o-Chlorobenzaldehyde
(1.69 mL, 15.0 mmol), and then propanal (3.25 mL, 45 mmol) were
added to a mixture of (2S,4R)-4-decanoyloxypyrrolidine-2-carboxylic
acid (10; 413 mg, 1.5 mmol) and water (4.9 mL) at 08C. The reaction
mixture was stirred at 08C for 96 h, then MeOH (60 mL) and NaBH4
(5.67 g, 150 mmol) were added. The reaction mixture was stirred for a
further 1 h at 08C and was then quenched with pH 7.0 phosphate
buffer solution. The organic materials were extracted with chloroform
three times, and the combined organic extracts were dried over
anhydrous Na2SO4 and concentrated in vacuo after filtration.
Purification by column chromatography (silica gel; hexane/AcOEt
20:1 to 3:1) gave (1R,2R)-1-(o-chlorophenyl)-2-methylpropane-1,3-
diol (2.9 g, 14.5 mmol, 97%) as a colorless oil: anti/syn 19:1 (by
1H NMR spectroscopy of the crude mixture). Enantioselectivity was
determined after conversion into the corresponding monobenzoyl
ester: 99% ee (by HPLC on a Chiralpak AS-H column, l = 254 nm,
5528
www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 5527 –5529

Angewandte
Chemie
iPrOH/hexane 1:100, 1.2 mLminÀ1; tR = 15.2 min (major), 17.2 min
(minor)).
Received: March 23, 2006
Revised: June 7, 2006
Published online: July 20, 2006
Keywords: aldol reaction · asymmetric synthesis ·
.
green chemistry · organocatalysis · surfactants
[1] a) Organic Synthesis in Water (Ed.: P. A. Grieco), Blackie,
London, 1998; b) U. M. Lindstrom, Chem. Rev. 2002, 102, 2751;
c) C.-J. Li, Chem. Rev. 2005, 105, 3095; d) M. C. Pirrung, Chem.
Eur. J. 2006, 12, 1312.
[2] a) S. Kobayashi, K. Manabe, Acc. Chem. Res. 2002, 35, 209; b) T.
Hamada, K. Manabe, S. Kobayashi, J. Syn. Org. Chem. Jpn. 2003,
61, 445.
[3] a) B. List, R. A. Lerner, C. F. Barbas III, J. Am. Chem. Soc. 2000,
122, 2395; for Reviews, see: b) B. List in Modern Aldol
Reactions, Vol. 1 (Ed.: R. Mahrwald), Wiley-VCH, Weinheim,
2004, pp. 161 – 200.
[4] a) H. Torii, M. Nakadai, K. Ishihara, S. Saito, H. Yamamoto,
Angew. Chem. 2004, 116, 2017; Angew. Chem. Int. Ed. 2004, 43,
1983; b) A. I. Nyberg, A. Usano, P. M. Pihko, Synlett 2004, 1891;
c) Z. Tang, Z.-H. Yang, L.-F. Cun, L.-Z. Gong, A.-Q. Mi, Y.-Z.
Jiang, Org. Lett. 2004, 6, 2285; d) J. Casas, H. Sunden, A.
Cordova, Tetrahedron Lett. 2004, 45, 6117; e) D. E. Ward, V.
Jheengut, Tetrahedron Lett. 2004, 45, 8347; f) I. Ibrahem, A.
Cordova, Tetrahedron Lett. 2005, 46, 3363; g) M. Amedjkouh,
Tetrahedron: Asymmetry 2005, 16, 1411; h) P. Dziedzic, W. Zou,
J. Hafren, A. Cordova, Org. Biomol. Chem. 2006, 4, 38; i) P. M.
Pihko, K. M. Laurikainen, A. Usano, A. I. Nyberg, J. A. Kaavi,
Tetrahedron 2006, 62, 317.
[5] A. Cordova, W. Notz, C. F. Barbas III, Chem. Commun. 2002,
3024.
[6] Y. Hayashi, T. Sumiya, J. Takahashi, H. Gotoh, T. Urushima, M.
Shoji, Angew. Chem. 2006, 118, 972; Angew. Chem. Int. Ed. 2006,
45, 958.
[7] N. Mase, Y. Nakai, N. Ohara, H. Yoda, K. Takabe, F. Tanaka,
C. F. Barbas III, J. Am. Chem. Soc. 2006, 128, 734.
[8] A. B. Northup, D. W. C. MacMillan, J. Am. Chem. Soc. 2002, 124,
6798.
[9] A. J. A. Cobb, D. M. Shaw, D. A. Longbottom, J. B. Gold, S. V.
Ley, Org. Biomol. Chem. 2005, 3, 84.
[10] Y. Hayashi, J. Yamaguchi, K. Hibino, T. Sumiya, T. Urushima, M.
Shoji, D. Hashizume, H. Koshino, Adv. Synth. Catal. 2004, 346,
1435.
[11] A. Berkessel, B. Koch, J. Lex, Adv. Synth. Catal. 2004, 346, 1141.
Angew. Chem. Int. Ed. 2006, 45, 5527 –5529
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5529