Aqua-organocatalyzed direct asymmetric aldol reaction with acyclic amino acids and organic bases with control of diastereo- and enantioselectivity

Article abstract of DOI:10.1016/j.tetasy.2007.01.025

An effective aqua-organocatalytic direct aldol reaction is described. Aromatic amino acids can be a bifunctional catalyst system, which demonstrate excellent reactivity, diastereoselectivity, and enantioselectivity (up to 96% ee) in water without the addi

Full text of DOI:10.1016/j.tetasy.2007.01.025

Tetrahedron: Asymmetry 18 (2007) 390–395
Aqua-organocatalyzed direct asymmetric aldol reaction
with acyclic amino acids and organic bases with control
of diastereo- and enantioselectivity
Mohamed Amedjkouh*
Organic Chemistry, Department of Chemistry, Go¨teborg University, SE-412 96 Go¨teborg, Sweden
Received 20 December 2006; accepted 23 January 2007
Available online 27 February 2007
Abstract—An effective aqua-organocatalytic direct aldol reaction is described. Aromatic amino acids can be a bifunctional catalyst
system, which demonstrate excellent reactivity, diastereoselectivity, and enantioselectivity (up to 96% ee) in water without the addition
of organic solvents. Furthermore, the present study demonstrates that both diastereo- and enantioselectivity can be easily modulated by
the appropriate combination of an organocatalyst together with an organic base as a co-catalyst.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Recently, small chiral amines have become attractive and
powerful organocatalysts for C–C bond forming reactions
and yield aldol products with excellent enantioselectivities.5
Proline and short peptides incorporating N-terminal pro-
line residues are capable of catalyzing direct aldol reactions
in organic solvents, such as DMSO or DMF, under mild
conditions. Although several chiral organocatalysts pro-
vide aldols enantioselectively in aqueous organic solvents,
they still require the use of an organic solvent, and large
amounts of buffer or surfactant.6
Reactions, in which water is used as the solvent, have at-
tracted a great deal of attention because water is a desirable
solvent with respect to environmental concerns, safety, and
cost, and which avoids the problems of pollution that are
inherent with organic solvents.1 Although the development
of enantioselective reactions in water is an extensively
investigated topic,2 it has long been considered as a realm
of enzymes.
Water often inhibits the catalyst’s activity or alters enantio-
selectivity by interfering in the transition states of the reac-
tions. Thus, the development of small organic molecules
that catalyze enantioselective reactions in water is currently
a highly challenging goal in chemistry.
More recently, the artificially designed organocatalysts 1
and 2 (Fig. 1) were found to be efficient for direct aldol
reactions in water with high enantioselectivity.7 These
organocatalysts are based on proline with appropriate
hydrophobic groups.
In Nature aldol condensations are promoted by two dis-
tinct classes of aldolases: Class I aldolases contain an active
site lysine involved in the formation of a nucleophilic en-
amine intermediate, and Class II aldolases that contain
an active site zinc co-factor facilitating enolate formation
by coordinating to the carbonyl oxygen of the ketone
donor.3 Natural Class I aldolase enzymes and aldolase
catalytic antibodies catalyze enantioselective aldol reac-
tions in water, in a hydrophobic pocket.4
Natural amino acids can be divided in three different
groups: hydrophobic, hydrophilic, and neutral. Six of them
possess hydrocarbon-like side chains.8 This results in a ten-
dency for nonpolar groups to contact each other, with an
accompanying decrease in their interactions with water,
and engage in hydrophobic bonds.
Thus, we reasoned that such hydrophobic amino acid cat-
alysts would balance the influence of hydrophobic interac-
tion and hydrogen bonding in the transition state in water.9
*
Furthermore, the present study would assess the influence
of such hydrophobic amino acids on a water-based
Tel.: +46 31 772 2895; fax: +46 31 772 3840; e-mail: mamou@
chem.gu.se
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.01.025

M. Amedjkouh / Tetrahedron: Asymmetry 18 (2007) 390–395
391
after 96 h. However, at higher concentration (0.5 M), high-
er conversion was achieved after 48 h. Further increase of
the concentration to 1 M allowed the generation of an
aldol adduct in high yield.
TBDPSO
C9H19
C9H19
N
CO2H
N
H
TFA
N
H
L-Valine and L-leucine are considered as very hydrophobic
amino acids, however, little to no reaction progress was ob-
served after 3 days in water (entries 1 and 2). As would be
expected, neutral amino acids did not show any success in
catalyzing the reaction either in water or in a buffered med-
ium (entries 3–6).
1
2
Ph
Ph
Ph
NH2
Me
HO
NH2
4
3
Most notably, the reaction with aromatic amino acid L-
phenylalanine led to an interesting result, the asymmetric
aldol reaction proceeded efficiently in the presence of water
and the anti-aldol product was obtained with excellent dia-
stereoselectivity in a high enantioselectivity of 76% ee (entry
7). The effect of water as the reaction solvent is very impor-
tant. Thus, reaction in a buffered aqueous medium resulted
in a decrease in both diastero- and enantioselectivity for the
anti aldol product, despite the rate acceleration (entry 8).
The reaction scarcely proceeded with L-phenylalanine in
the presence of sodium dodecylsulfate (SDS) in water, even
at a high concentration of the catalyst (entries 9 and 10). L-
Phenylglycine was unable to promote the aldol reaction.
H
N
HO
NH
N
H2N
CO2H
L-His
H2N
CO2H
L-Trp
H2N
L-Tyr
CO2H
Figure 1.
prebiotic model of aldolase catalysis. Chiral amino acids
were possibly present in the prebiotic period, either formed
on earth or from an extraterrestrial origin. Amino acid
catalysis may hold significant clues to the evolution of
homochirality in aqueous prebiotic chemistry.10
L-Tryptophan, bearing a larger aromatic group, led to the
best results in terms of yield, diastereo- and enantioselectiv-
ity in water. Thus, a smooth reaction proceeded in 62%
yield to afford the anti-aldol as a major product with
88% ee (entry 16). Both L-Phe and L-Trp afforded excellent
diastereoselectivities favoring the anti isomers (>18:2 dr).
Previously, we and others, have reported that the addition
of organic bases significantly improves the rate of the direct
aldol reaction in organic solvents.11 In particular, we have
shown that organic bases can be employed as co-catalysts
to enforce syn-selectivity, while retaining a high level of
enantioselectivity. In stark contrast, amino acids alone,
and proline in particular, usually favor the formation of
anti-aldol adducts.
The major aldol isomer 5a resulting from L-amino acid
catalyzed reactions had a (2S,10R)-absolute configuration.
The observed stereoselectivity is in line with that of L-pro-
line and its derived catalysts, thus favoring the re-facial
attack on the aldehyde.12
Perhaps most interestingly, the reactions catalyzed by L-
histidine led to a switch in the enantioselectivity, with the
formation of equal amounts of anti and syn isomers (entries
12 and 13), although in a rather slow reaction. The major
aldol products, both anti and syn, were generated with an
absolute configuration opposite to that obtained with other
L-amino acids as catalysts. A similar trend in the inversion
of absolute stereochemistry was also observed for L-threo-
nine in PBS, but with a lower reactivity (entry 15).
This observation raises the possibility of modulating the
anti–syn selectivity by the appropriate combination of an
organocatalyst together with an organic base as a co-cata-
lyst in water. Herein, we report a highly diastereo- and
enantioselective aldol reaction promoted by hydrophobic
amino acids in water and the influence of added organic
bases on selectivities.
Simple primary amine (S)-phenylethylamine 3 and amino
alcohol (1S,2R)-2-amino-1,2-diphenylethanol 4 were also
tested as organocatalysts. Consequently, chiral primary
amine 3, lacking the hydroxy group adjacent to the stereo-
genic center, produced the syn aldol as the major product
in 92% yield and with 22% ee (entry 17). However, catalyst
4 in water gave equal amounts of anti and syn aldol prod-
uct in 90% yield and with low enantioselectivity (entry 18).
The drop in selectivity may arise from competing general
base catalysis of the aldol reaction.
2. Results and discussion
To verify this assumption, the aldol reaction of cyclohexa-
none and 4-nitrobenzaldehyde to afford 5a was performed
in water, using several amino acid catalysts (20 mol %) in
the presence or absence of additives. An examination of
the ability of hydrophobic amino acids to catalyze the
model reaction indicated that amino acids bearing an aro-
matic substituent gave better results, in terms of both yield
and enantioselectivities as shown in Table 1. Reactions car-
ried out with 0.2 M 4-nitrobenzaldehyde required the use
of a 2-fold excess of cyclohexanone with a low conversion
L-Tryptophan was chosen for further studies of asymmetric
aldol reactions with a variety of different aromatic

392
M. Amedjkouh / Tetrahedron: Asymmetry 18 (2007) 390–395
Table 1. Amino acid catalyzed aldol reaction of cyclohexanone and 4-nitrobenzaldehydea
O
O
OH
O
Cat. 20 mol%
H2O, r.t
H
+
NO2
NO2
5a
Entry
Amino acid
Time (h)
Yieldsb (%)
anti:sync
eed anti:syn (%)
1
2
L-Val
L-Leu
L-Asp
L-Asp
L-Ser
72
72
72
72
110
21
72
72
48
55
48
72
72
72
72
24
16
48
24
0
7
0
0
0
9:1
99:—
3e
4
5
6e
L-Ser
<5
52
79
0
<5
<5
60
30
0
20
62
92
90
<5
7
L-Phe
L-Phe
L-Phe
L-Phe
L-Phg
L-His
L-His
L-Thr
L-Thr
L-Trp
(S)-3
19:1
4:1
76:—
54:—
8e
9f
10f,g
11
12
13e
14
15e
16
17
18
19
1:1
1:1
ent- 62:ent- 84
ent- 60:ent- 80
1:1
18:2
2:3
1:1
ent- 72:ent- 85
88:—
ent- 20:ent- 22
ent- 12:ent- 39
(1S,2R)-4
L-Tyr
a Unless otherwise stated, all reactions were carried out using 1.0 M aldehyde and 2.0 M ketone in the presence of 20 mol % catalyst in water.
b The yields are for isolated products.
c Determined by 1H NMR of the crude product.
d The ee was determined by chiral HPLC analysis. The enantiomers were assigned by comparison to those obtained L-proline.
e Phosphate buffer at pH 7.1 was the solvent used.
f 1 equiv SDS was added.
g 50 mol % catalyst was used.
aldehydes under the optimized conditions for the model
reaction. The reaction appears to be quite general with re-
spect to aldehyde acceptor. Generally, excellent diastereo-
and enantioselectivities were observed, as shown in Table
2. Typically, anti-aldol products are formed with enantiose-
lectivities ranging from 53% to 96% ee. In contrast, a reac-
tion with water miscible ketone provided aldol product
with lower diastereo- and enantioselectivity (42% ee),
Table 2. L-Trp-catalyzed aldol reaction of cyclohexanone with aldehydes in watera
O
X
OH
O
O
R
R
L-Trp 20 mol%
H2O, r.t
H
+
X
(2S,1'R)-5
Entry
Aldol product
R
X
Time (h)
Yieldb (%) (anti:syn)c
ee anti d (%)
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
4-NO2
2-NO2
4-CN
4-Cl
2-Cl
4-Br
4-CF3
4-NO2
4-NO2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
O
24
96
48
66
66
66
72
96
48
62 (91:9)
78 (92:8)
82 (86:14)
87 (88:12)
83 (89:11)
57 (90:10)
64 (89:11)
74 (62:38)
0
88
94
70
87
84
53
96
42
—
5g
5h
5i
S
a Unless otherwise stated, all reactions were carried out using 1.0 M aldehyde and 2.0 M ketone in the presence of 20 mol % catalyst in water.
b The yields are for isolated products.
c Determined by 1H NMR of the crude product.
d The ee was determined by chiral HPLC analysis.

M. Amedjkouh / Tetrahedron: Asymmetry 18 (2007) 390–395
393
O-
although with good yield (entry 8). However, the solid ke-
tone tetrahydro-4-thiopyranone did not participate in the
aldol reaction (entry 9).
N
O
N
N
Ar
O
H
H
The effectiveness of the aromatic amino acids as catalysts
compared to proline and other acyclic amino acids can
be attributed to the solubility of the catalysts. While pro-
lines dissolve in water, aromatic and aliphatic amino acids
are mainly hydrophobic and are only partially soluble in
water, which results in heterogeneous mixtures.
N
N
H
Ar
O
H
O
N+
O
H
B
H
A
Figure 2. The proposed intermediates in the aldol reaction catalyzed by
histidine in water. (A) Disfavored Re-facial attack on carbonyl. (B)
Favored Si-facial attack on carbonyl.
Although Tyr did not display any catalytic property in the
present study, an important implication of the cation–p
interaction and the related ‘polar–p’ interactions is that
Phe, Tyr, and Trp should not be considered simply ‘hydro-
phobic’ amino acids. They are in fact distinct from the con-
ventional hydrophobic residues, such as Val, Leu, and Ile.
Recent studies have shown that cation–p interactions, the
electrostatically favorable attraction between a cation and
a p-system, are not only quite strong in aqueous media
but also commonly found in protein structures.13
ate the reaction. Interestingly, we have found that organic
bases (DBU, DBN, TMG, or Imidazole) can be also em-
ployed to improve the rate of the reaction catalyzed by his-
tidine with inversion of enantioselectivity. Perhaps most
importantly, these organic bases promoted the aldol reac-
tion by tryptophan. As shown in Table 3, a combination
of histidine and one of the organic bases in 20 mol % of
each allowed the addition of cyclohexanone to 4-nitrobenz-
aldehyde with syn-selectivity. In contrast, a similar combi-
nation with tryptophan catalyst favored the anti-selectivity.
We then turned our attention to histidine catalysis. The
observed inversion of enantioselectivity with L-His as a cata-
lyst in water, suggests the formation of the Si-face enamine
intermediate approached by the Re-face of the acceptor
(Fig. 2). The hydrogen bonding involving the imidazolium
ring rather than the carboxylate group would facilitate this
situation. In this case the imidazole ring functions as a
base, which contributes to the deprotonation of the carbox-
ylic acid. The participation of water—forming the first
hydration shell—can be characterized in providing a pro-
ton shuffle through a hydrogen bond network that might
enable proton transfer and aldehyde activation by the
imidazolium.
Whereas similar enantioselctivities for the syn-aldol were
provided with histidine or tryptophan, higher enantioselec-
tivities were obtained for the anti-aldol in the presence of
histidine.
In the case of histidine catalysis, participation of these or-
ganic bases can be characterized in providing assistance in
the formation of an enamine. Thus, intermediate B (Fig. 2)
still favored for the formation of aldol adduct: the lower
enantioselectivity observed may be attributed to competing
general base catalysis. On the other hand, deprotonation of
the carboxylic group of tryptophan might in turn result in a
Si-face enamine approaching the Re-face of the acceptor,
probably activated by the protonated base.
As mentioned above, catalysis with histidine resulted in a
slow reaction. We presumed that the addition of an organic
base would facilitate enamine formation and thus acceler-
Table 3. Effect of added organic base on the L-Trp- and L-His-catalyzed aldol reaction of cyclohexanone with aldehydes in watera
O
OH
O
O
OH
O
L-Cat 20 mol%
Base 20 mol%
H
+
+
H2O, r.t
NO2
NO2
(2R,1'R)-syn-5a
NO2
(2R,1'S)-anti-5a
Entry
Catalyst–base
Time (h)
Yieldsb (%)
anti:sync
eed (%) anti:syn
1
2
3
4
5
6
7
8
L-Trp–DBU
L-Trp–DBN
L-Trp–TMG
L-Trp–Im
L-His–DBU
L-His–DBN
L-His–TMG
L-His–Im
16
16
16
24
24
24
24
24
97
95
86
97
66
91
89
84
2:1
2:1
2:1
2:1
1:1
1:1
1:2
2:3
<5:60
<5:46
<5:—
<5:65
31:48
31:50
30:52
nd:56
a Unless otherwise stated, all reactions were carried out using 1.0 M aldehyde and 2.0 M ketone in the presence of 20 mol % catalyst and 20 mol % organic
base in water.
b The yields are for isolated products.
c Determined by 1H NMR of the crude product.
d The ee was determined by chiral HPLC analysis.

394
M. Amedjkouh / Tetrahedron: Asymmetry 18 (2007) 390–395
Table 4. Base assisted aldol reaction of cyclohexanone with aldehydes in watera
O
OH
O
OH
O
O
L-Cat 20 mol%
DBU 20 mol%
R
R
R
H
+
+
H2O, r.t
(2R,1'S)-anti-5
(2R,1'R)-syn-5
Entry
R
Time (h)
Yieldb (%) (anti:syn)c
eed (%) anti:syn
1
2
3
4
4-NO2
2-NO2
4-CN
24
24
24
24
66 (1:1)
66 (2:3)
90 (2:3)
92 (1:1)
31:48
39:50
20:44
46:30
4-CF3
a Unless otherwise stated, all reactions were carried out using 1.0 M aldehyde and 2.0 M ketone in the presence of 20 mol % catalyst and 20 mol % organic
base in water.
b The yields are for isolated products.
c Determined by 1H NMR of the crude product.
d The ee was determined by chiral HPLC analysis.
The scope of the aldol reaction, under these new condi-
tions, has been examined. Similar trends were observed
for the histidine–DBU catalytic system with respect to
the enantioselectivities and yields when varying the
structure of aromatic aldehydes (Table 4). Other aromatic
aldehydes such as 2-chloro-, 4-chloro-, and 4-bromobenz-
aldehyde were also suitable for the present aldol reaction,
however, enantioselectivities could not be determined.
d = doublet, t = triplet, m = multiplet), coupling constants
(Hz), and integration.
13C NMR spectra were recorded on Varian Unity 400
(100 MHz) with complete proton decoupling (CDCl3:
77.23 ppm). Chiral HPLC was performed using a Varian
9012 pumping system and Varian 9050 UV detector series
with a chiral column (Chiralcel OD, 0.46 cm (/) · 25 cm,
Daicel Chemical Ind., Ltd.). The racemic samples were pre-
pared by either using racemic proline or pyrrolidine-acid as
the catalyst. The major enantiomer was assigned by com-
parison of racemic aldol products with those reported in
the literature using L-proline.
3. Conclusion
In conclusion, we have developed an aqua-organocatalyzed
asymmetric aldol reaction. Aromatic amino acids acting as
a bifunctional catalyst system demonstrated excellent reac-
tivity, diastereoselectivity, and enantioselectivity in water
without the addition of organic solvents. Furthermore,
conceptually, these results demonstrate that both diastereo-
and enantioselectivity can be easily modulated by the
appropriate combination of an organocatalyst together
with an organic base as a co-catalyst. The present results
suggest that aldol catalysis with aromatic amino acids
under hydrophobic conditions could have provided a
chiral influence in prebiotic chemistry.
4.2. General procedure for the aldol reaction
The following procedure for the reaction of cyclohexanone
with p-nitrobenzaldehyde in water is representative.
To a mixture of the bifunctional catalyst (0.2 mmol) and p-
nitrobenzaldehyde (150 mg, 1.0 mmol) were added cyclo-
hexanone (208 lL, 2.0 mmol) and water (0.8 mL) at room
temperature under air (0.2 mmol of organic base was
added, see Tables 3 and 4). The reaction mixture (emul-
sion) was stirred for 24–96 h. The water phase was
extracted with ethyl acetate (3 · 2 mL), and the organic
extracts dried over Na2SO4, filtered, and concentrated to
give pure aldol adduct 5a through flash column chromato-
graphy on silica gel (hexane/ethyl acetate (3:1)).
Further investigations focusing on the full scope of this
aqua-organocatalysis and related systems are currently
underway and will be reported in due course.14
4. Experimental
Diastereoselectivity and conversion were determined by 1H
NMR analysis of the crude aldol product after removal of
the catalyst on a short pad of silica. The enantiomeric
excess (ee) of 5a was determined by chiral-phase HPLC
analysis. The absolute configuration of aldol products 5
was extrapolated by comparison of the HPLC-data with
the literature.
4.1. General information
Unless otherwise noted, materials were purchased from
commercial suppliers and used without further purifica-
tion. Flash column chromatography was performed using
1
200–300 mesh silica gel. H NMR spectra were recorded
on a Varian Unity 400 (400 MHz) spectrometer. Chemical
shifts are reported in ppm from the solvent resonance
as the internal standard (CDCl3: 7.27 ppm). Data are
reported as follows: chemical shift, multiplicity (s = single,
All compounds gave satisfactory analytical and spectral
data. Compounds 5 are already known.5a,7a Characteriza-
tion data for selected examples are given below:

M. Amedjkouh / Tetrahedron: Asymmetry 18 (2007) 390–395
395
6. For amino acid catalyzed aldol reactions in aqueous media
see: (a) Tanaka, F.; Thayumanavan, R.; Mase, N.; Barbas, C.
F., III. Tetrahedron Lett. 2004, 45, 325–328; (b) Torii, H.;
Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew.
Chem., Int. Ed. 2004, 43, 1983–1986; (c) Amedjkouh, M.
Tetrahedron: Asymmetry 2005, 16, 1411–1414; (d) Nyberg, A.
I.; Usano, A.; Pihko, P. M. Synlett 2004, 1891–1896; (e)
Cordova, A.; Notz, W.; Barbas, C. F., III. Chem. Commun.
2002, 3024–3025; (f) Darbre, T.; Machuqueiro, M. Chem.
Commun. 2003, 1090–1091; (g) Pihko, P. M.; Laurikainen, K.
M.; Usano, A.; Nyberg, A. I.; Kaavi, J. A. Tetrahedron 2006,
62, 317–328; Small peptides were used to catalyze asymmetric
aldol reactions in aqueous media: (a) Tang, Z.; Yamg, Z.-H.;
Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Org. Lett.
2-[Hydroxy-(4-nitro-phenyl)-methyl]-cyclohexanone
5a:
Reaction time: 24 h; yield: 62%; anti:syn = 90:10. anti-
diastereomer: 1H NMR (400 MHz, CDCl3) d (ppm)
1.55–2.16 (m, 6H), 2.37–2.50 (m, 2H), 2.59 (m, 1H), 4.98
(d, J = 8.4 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 8.20 (d,
J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) d (ppm)
24.5, 27.5, 30.6, 42.5, 57.0, 73.8, 123.4, 127.8, 147.4,
148.4, 214.6; HPLC analysis Chiralcel OD (hexane/
i-PrOH = 95:5, 1.5 mL/min, 254 nm, 20 ꢁC) tR (major)
12.8 min and tR (minor) 16.4 min, ee: 88%.
Syn-diastereomer (determined only for reactions catalyzed
by histidine and when organic bases are used as co-cata-
1
´
2004, 6, 2285–2287; (b) Dziedzic, P.; Zou, W.; Hafren, J.;
lysts, see Tables 3 and 4) H NMR (400 MHz, CDCl3)
´
Cordova, A. Org. Biomol. Chem. 2006, 4, 38–40; Janda
d = 8.20 (2H, d, J = 8.7 Hz, ArH), 7.51 (2H, d,
J = 8.7 Hz, ArH), 5.49 (1H, m, CHCHOH), 2.63 (1H, m,
CHCHOH), 2.47–2.30 (2H, m, CH2C(O)), 2.13–1.36
(6H, m, chex-H). HPLC: Chiralcel-OD. Hexane/i-PrOH,
95:5, 1.5 mL minꢀ1, 254 nm: tR (major) = 11.5 min; tR
(minor) = 12.4 min.
reported that the aqueous direct aldol reaction can be
catalyzed by a nicotine metabolite enantiomerically: (a)
Dickerson, T. J.; Janda, K. D. J. Am. Chem. Soc. 2002,
124, 3220; (b) Rogers, C. J.; Dickerson, T. J.; Brogan, A. P.;
Janda, K. D. J. Org. Chem. 2005, 70, 3705.
7. (a) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.;
Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128,
734; (b) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.;
Urushima, T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45,
958–961; During the course of the present work, a report
using water under different conditions has been published,
see: (c) Jiang, Z.; Liang, Z.; Wu, X.; Lu, Y. Chem. Commun.
2006, 2801–2803.
Acknowledgments
This work was supported by the Swedish Research Council
˚
(Veteskapsradet), The Wilhelm and Martina Lundgrens
8. (a) Sereda, T. J.; Mant, C. T.; So¨nnichsen, F. D.; Hodges,
Vetenskapsfond, and The Royal Society of Arts and
Sciences (KVVS).
´
R. S. J. Chromatogr., A 1994, 676, 139–153; (b) Nemethy,
G.; Scheraga, H. A. J. Phys. Chem. 1962, 66, 1773–1789.
9. (a) Breslow, R. Acc. Chem. Res. 1991, 24, 159–164; (b) Otto,
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