A selective direct aldol reaction in aqueous media catalyzed by zinc-proline

Article abstract of DOI:10.1002/ejoc.200500352

The Zn-proline complex is shown to catalyze the aldol reaction of acetone and a wide range of arenecarbaldehydes in aqueous media, accepting even deactivated arenecarbaldehydes such as methoxybenzaldehydes in good yields. Enantiomeric excesses of up to 56

Full text of DOI:10.1002/ejoc.200500352

FULL PAPER
DOI: 10.1002/ejoc.200500352
A Selective Direct Aldol Reaction in Aqueous Media Catalyzed by
Zinc–Proline
Ruben Fernandez-Lopez,[a] Jacob Kofoed,[a] Miguel Machuqueiro,[a] and Tamis Darbre*[a]
Keywords: Aldol reactions / Green chemistry / Aqueous catalysis / Proline / Zinc
The Zn–proline complex is shown to catalyze the aldol reac-
tion of acetone and a wide range of arenecarbaldehydes in
aqueous media, accepting even deactivated arenecarbal-
dehydes such as methoxybenzaldehydes in good yields. En-
antiomeric excesses of up to 56% could be obtained with
5 mol-% of the catalyst at room temperature, and up to 66%
at –15 °C. The aldol reaction is regio- and stereoselective
with hydroxyacetone (moderate yields) and dihydroxyace-
tone (excellent donor, 80–90% yields with 5 mmol-equiv.).
Plausible mechanisms for the reaction are discussed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Enantioselectivity has been achieved, although the silyl
ether substrate requires a substantial amount of organic
solvent due to its poor stability in water. It is surprising
that, in general, asymmetric reactions in water, especially
formation of carbon–carbon bonds, have not been devel-
oped in an extensive manner in spite of the advantages of-
fered by water as a solvent.[14]
We have already reported the aldol reaction of acetone
and 4-nitrobenzaldehyde catalyzed by Zn–proline [Zn-
(Pro)2] and other Zn–amino acid complexes in the presence
of water.[15] This method has been further extended to the
aldolization of glycolaldehyde to give tetroses and the cross-
aldolization of glycolaldehyde and glyceraldehydes to give
pentoses.[16] Here we describe the scope of the Zn(Pro)2-
catalyzed reaction with a variety of aromatic aldehydes and
ketones. The aldol reaction was also extended to HA and
dihydroxyacetone (DHA) as donors.
Introduction
The aldol reaction is of central importance for the con-
struction of C–C bonds in organic chemistry. Consequently,
a large number of catalysts and reagents have been devel-
oped in order to achieve efficient addition with high dia-
stereomeric and enantiomeric selectivity.[1] The direct aldol
reaction is an attractive method since it avoids the pre-for-
mation of silyl enol ethers or other enol derivatives, and
therefore methods to achieve addition with high yields and
enantioselectivities are desired. Two strategies have been
employed in order to catalyze the asymmetric direct aldol
reaction: 1) organocatalysts, including proline[2] and small
peptides,[3] which give good yields and impressive enantio-
selectivities and 2) metal-catalyzed direct aldol reactions
with transition metals, particularly zinc complexes.[4,5] An-
hydrous organic solvents are often required for high selec-
tivities.
In contrast to the above-described transformations, di-
rect aldol reactions in water have been studied to a lesser
extent. This reaction can be accomplished with aldolase en-
zymes[6] and catalytic antibodies,[7] and an aqueous aldol
reaction catalyzed by proline[8] or nornicotine[9] to give ra-
cemic products appeared recently. Enantioselective direct
aldol reactions of aldehydes with hydroxyacetone (HA) cat-
alyzed by small peptides in mixed solvents have also been
reported.[10] Recently, addition of water to organic solvents
has been shown to accelerate the proline[11] or tetrazole-
pyrrolidine[12] catalyzed aldol reaction. Lewis acid catalysis
in water has been investigated with silyl enol ethers and
rare-earth metal triflates, as well as other metals.[13]
Results and Discussion
Zn–Amino Acid Complexes as Water-Compatible Catalysts
The reactivity of metal complexes in water is limited be-
cause water can compete with the substrate for metal coor-
dination. Criteria for water-compatible Lewis acids have
been developed based on a correlation between the catalyst
activity and two parameters, namely the hydrolysis constant
and water-exchange rate constant.[17] Among several metals
that can be considered as suitable for catalysis in water, zinc
looked the most appealing to us as it is not redox-active, it
can accommodate several coordination geometries, it forms
stable complexes with nitrogen-containing ligands, and it is
abundant in nature. Zinc is also present in the active site of
Class II aldolases, making the Zn(Pro)2 approach aldolase
mimics. Therefore we have developed zinc–amino acid com-
[a] Department of Chemistry and Biochemistry, University of
Berne,
Freiestrasse 3, 3012 Berne, Switzerland
E-mail: tamis.darbre@ioc.unibe.ch
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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A Selective Direct Aldol Reaction Catalyzed by Zinc–Proline
FULL PAPER
1
Figure 1. H NMR spectrum of Zn(Pro)2 in D2O compared with the spectrum of -proline.
plexes as catalysts for aldol recations in water, and further Table 1. Conversion yields and ee values for the reaction of ni-
trobenzaldehyde (1a) with acetone in H2O (2:1) to give 2a, with
zinc acetate and amino acids as catalysts at room temp.
studied the zinc–proline-catalyzed direct aldol reaction.
Indeed, the Zn(Pro)2 complex can be readily prepared in
Entry
Catalyst
Time [h] Conv.
ee
methanol from proline and zinc acetate in the presence of
triethylamine. The complex is stable in water, as shown by
the H NMR spectrum (Figure 1), and is easily isolated by
1
2
3
4
Zn(CH3COO)2 (5%)
Zn(CH3COO)2 (5%)
-proline (10%)
24
96
24
24
0%
6%
6%
–
–
1
21% (R)
6% (R)
filtration.
-lysine (5%)
74%
According to the same procedure, a series of Zn–amino
acid complexes containing Lys, Arg, His, Glu, Ser, Ile, and
t-Leu were prepared in good to moderate yields (30–80%).
The yields were not optimized and correspond to the
amount of product precipitated from the reaction mixture.
The complexes were characterized by 1H and 13C NMR
spectroscopy.[11]
gated. While Zn–lysine and Zn–arginine proved to be ef-
ficient catalysts, Zn–serine, Zn–histidine, and Zn–cysteine
failed to provide significant amounts of 2a at room temp.
after 24 h. Lysine can act as a general base catalyst and, in
fact, when the aldol reaction was run in the presence of
5 mol-% of lysine, in the absence of zinc, product 2a was
obtained in 74% yield and 6% ee with the (R)-2a enanti-
omer in excess (Table 1).
The Zn(Pro)2-Catalyzed Aldol Reaction of Acetone and
Aromatic Aldehydes
The ability of Zn(Pro)2 to act as a catalyst for the aldol
reaction in water was first explored with 4-nitrobenzalde-
hyde and acetone. When 4-nitrobenzaldehyde (1a) was
stirred in the presence of Zn(Pro)2 (10 mol-%) in acetone/
H2O (2:1) for 24 h, product 2a was obtained in quantitative
yield (Scheme 1). When proline was the catalyst, in acetone/
H2O (2:1), the yield of 2a after 24 h was 6% and the enan-
tiomeric excess (ee) 21%. The zinc complex gave the (S)
enantiomer in excess (32%), whereas with proline alone the
(R) enantiomer predominates. We did not observe the for-
mation of 2a in the presence of zinc acetate or in the ab-
sence of the zinc salt or proline (Table 1). Unsaturated
ketones derived from water elimination were not detected
When the Zn(Pro)2-catalyzed aldol reaction was carried
out with different amounts of water, the ee obtained de-
creased with a corresponding decrease in the water content
(Figure 2). A higher enantioselectivity was obtained for 2a
with 66 vol.-% of water [the Zn(Pro)2 complex is not soluble
in less then 5% water]. The studies described in this paper
were consequently performed with a 1:2 ratio of acetone
and water.
The Cu–proline complex also catalyzes the aldol reac-
tion, although in much lower yield. The reaction with ace-
tone and 4-nitrobenzaldehyde gave 2a with 10% conversion
after 96 h.
The scope of the reaction was further investigated with a
series of aldehydes and acetone in the presence of Zn(Pro)2
as catalyst. The results are summarized in Table 2.
The results indicate that not only activated arenecarbal-
dehydes bearing electron-withdrawing groups but also benz-
aldehyde as well as aldehydes with methoxy substituents un-
dergo the aldol reaction with very good yields and moder-
ate ee values. Although the methoxy group should reduce
1
by H NMR spectroscopy in the crude product.
Scheme 1.
The catalytic ability of other Zn–-amino acid complexes the conversion, we observed a 75% conversion after 36 h in
[5 mol-% of catalyst, H2O/acetone (1:2)] was also investi- the case of the ortho isomer (Entry 10, Table 2). We assume
Eur. J. Org. Chem. 2005, 5268–5276
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R. Fernandez-Lopez, J. Kofoed, M. Machuqueiro, T. Darbre
FULL PAPER
Table 2. Direct aqueous aldol reaction of aromatic aldehydes and
acetone in water (66 vol.-%) catalyzed by Zn(Pro)2.
En-
try
Alde-
hyde
Aldol
product
Time
[h]
Conv.
[%][a]
X
ee[b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
4-NO2
2-NO2
2-Br
4-F
4-CN
H
2-CH3
2-Cl
4-Cl
2-OCH3
3-OCH3
4-OCH3
4-CF3
naphthyl
18
18
18
36
22
48
72
36
36
36
36
36
48
45
Ͼ95
94
89
Ͼ95
91
32
56%
Ͻ5%
30%
37%
27%
Ͻ5%
Ͻ5%
Ͻ5%
24%
32%
22%
38%
35%
31%
25
Ͼ95
Ͼ95
75
40
48
93
75
Figure 2. Excess of (S) enantiomer of 2a vs. H2O (vol%).
that coordination of the OMe group to Zn2+ facilitates the
reaction. The ee of the reaction was not higher than with
the other two isomers. The ortho-substituted aldehydes 1b
and 1i, in contrast, gave lower ee values than the corre-
[a] Determined by 1H NMR spectroscopy. [b] The ee was deter-
mined by chiral HPLC with a Daicel Chiralpak AS. Conditions:
aldehyde (0.75 mmol), acetone (5 mL), Zn(Pro)2 (10 mg), water
(10 mL), room temperature.
1
Figure 3. H NMR spectrum (300 MHz, CDCl3) of the crude product 2a from the aldol reaction of acetone and 1a after removal of the
catalyst by filtration.
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A Selective Direct Aldol Reaction Catalyzed by Zinc–Proline
FULL PAPER
easily achieved, even during column chromatography,[18] so
sponding para isomers. When the reaction of 2-nitrobenzal- that the ratio obtained may not correspond to that of the
dehyde (1b) was run at –15 °C, the ee increased from Ͻ 5% reaction product.[19] Cyclohexanone and 2-butanone under-
to 27%. For the reaction with activated aldehydes (1a, 1d, went aldol reaction with 1a (Figure 5). The reaction with 2-
1h, 1i), no chromatography with organic solvents was neces- butanone is regioselective, with only the linear product 8
1
sary, and, after lyophilization, the catalyst was removed by being detected by H NMR spectroscopy.
addition of methanol or ethyl acetate and filtration to give
only the corresponding aldol products (Figure 3 for 2a). It
is therefore possible to obtain pure aldol products without
employing an organic solvent either for preparation of the
reagents or purification of the products.
Variation of the Aldehyde and the Ketone Components
Heterocyclic aldehydes were also found to be suitable
substrates for the aldol reaction with acetone, as shown in
Figure 4. Furfuraldehyde gave the aldol product in quanti-
tative yield after 6 h, and at –15 °C full conversion occurred
with 63% ee in 22 h. Cinnamaldehyde acts as an electro-
phile in the reaction.
Figure 5. Aldol reaction with 1a catalyzed by Zn(Pro)2. Conditions:
1a (1 mmol), ketone (4 mmol), Zn(Pro)2 (5mol-%), THF (8 mL),
water (8 mL), room temperature for 48 h.
Reaction with Hydroxyacetone and Dihydroxyacetone
The zinc–proline-catalyzed reaction was extended to HA
and DHA. The reaction was first investigated with 5 equiv.
of ketone and tetrahydrofuran as co-solvent. The results ob-
tained are shown in Table 3. The reaction of HA gave re-
gioselective formation of the more stable enolate; the linear
regioisomer could not be detected by 1H NMR spec-
troscopy. The syn selectivities observed contrast with the
Figure 4. a): Zn(Pro)2 (5 mol-%.), aldehyde (0.75 mmol), acetone
results obtained with proline[2b] but are consistent with the
(5 mL), water (10 mL).
results with the catalytic antibody 38C2[20] and the Lewis
Variations in the ketone component were also made, and acid catalyzed reactions in organic solvents.[4c,5c] DHA is a
quantitative yields were obtained with cyclopentanone, with much better donor than DH, giving aldol products in excel-
a syn/anti ratio of 3:1, after 18 h. The stereochemistry of lent yields with a preference for the syn stereoisomer
the aldol product is rather labile and isomerization can be (Table 3).
Table 3. Aldol reaction of HA and DHA with aromatic aldehydes catalyzed by Zn(Pro)2.
Aldol product
R
H
X
Time [h]
Co-solvent
Conv.[a] [%]
dr (syn/anti)[b]
9a
4-NO2
96
66
48
96
48
66
48
20% THF
50% HA
none
10% THF
20% THF
5% THF
10% THF
25
45
16
35
80
88
90
2:1
1:8
3:2
5:1
1:1
1:1
3:1
9b
9c
10a
10b
10c
H
H
OH
OH
OH
2-NO2
2-Br
4-NO2
2-NO2
2-Br
[a] Determined by 1H NMR spectroscopy; dr = diastereomeric ratio. Conditions: 5 mol-equiv. of HA or DHA, room temp. [b] Determined
1
by H NMR spectroscopy.
Eur. J. Org. Chem. 2005, 5268–5276
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R. Fernandez-Lopez, J. Kofoed, M. Machuqueiro, T. Darbre
FULL PAPER
Table 4. Aldol reaction of HA and 4-nitrobenzaldehyde.
Entry
Co-solvent [vol.-%]
HA [mol-equiv.]
Co-solvent
Conversion [%][a]
1
2
3
4
40
30
50
50
4
10
4
THF
THF
MeOH
MeOH
23
60
35
53
10
1
[a] Determined by H NMR spectroscopy. Reactions at room temp.
The reaction of HA and 4-nitrobenzaldehyde was investi- noncoordinated aldehyde. We have, however, observed that
gated with 4 and 10 equiv. of the ketone component and zinc acetate does not catalyze the aldol reaction, which indi-
different co-solvents. The results presented in Table 4 show cates that both zinc and proline are necessary for catalysis.
that the reaction takes place in good yield with 10 equiv. of The fact that proline alone does not act as a catalyst here
HA. Methanol or tetrahydrofuran as co-solvents gave sim- indicates that the enamine formation should be unfavorable
ilar results. We also observed inversion and increase in the under our reaction conditions.[21] Moreover, the (S) enanti-
diastereomeric selectivity, with dr = 1:8 (syn/anti) when the omer of 2a was formed in excess with Zn(Pro)2, whereas the
reaction was run with a 1:1 mixture of HA and water (R) enantiomer was favored with proline. We can, however,
(Table 3). The reaction was further investigated with only postulate a mechanism involving a zinc-assisted enamine,
5 mol-equiv. of HA or DHA.
where zinc complexation stabilizes the enamine intermedi-
ate. In this case, zinc dissociation from the amine group
provides a nucleophile for addition to the carbonyl group.
Coordination to zinc stabilizes the enamine in water, mak-
ing the condensation with the aldehyde possible (proposed
intermediates shown in Figure 7).[22] Further studies of the
reaction mechanism are still necessary and currently un-
derway.
Mechanistic Considerations
The new catalyst developed incorporates a metal that can
act as a Lewis acid in water, and in this respect Zn(Pro)2
can be seen as mimic of class II aldolases. On the other
hand, the proline could also form an enamine, reacting ac-
cording to a mechanism similar to class I aldolases. If the
metal is acting as a Lewis acid, we can assume that the
Zn2+ ion coordinates to the ketone in order to facilitate the
enolate formation while the proline ligand provides the chi-
ral environment for enantioselectivity (Figure 6). The car-
bon–carbon bond formation takes place with concomitant
coordination of the carbonyl group of the aldehyde or with
Figure 7. Proposed intermediates for the zinc-assisted enamine
mechanism of the zinc–proline-catalyzed aldol reaction.
Conclusions
The direct aldol reaction catalyzed by Zn(Pro)2 complex
in aqueous media has been investigated with respect to the
structure of the aldehyde and the ketone donor. The reac-
tion takes place at room temperature and is complete, in
some cases, after only 6 h. HA and DHA proved to be suit-
able partners for the reaction with aromatic aldehydes. The
enantioselectivity can be improved by running the reaction
at –15 °C. Although the ee values obtained are low to mod-
erate, it is remarkable that any enantioselectivity can be at-
tained in water and mostly at ambient temperature. To date,
these are the best results reported for the direct aldol reac-
tion catalyzed by small metal complexes in water.
Figure 6. Proposed mechanism of the zinc–proline-catalyzed aldol
reaction with zinc acting as Lewis acid.
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A Selective Direct Aldol Reaction Catalyzed by Zinc–Proline
FULL PAPER
1
could be isolated (98 mg, 94%). H NMR (CDCl3): δ = 8.00 (d, J
= 8.2 Hz, 1 H), 7.93 (d, J = 8.3 Hz, 1 H), 7.70 (t, J = 8.0 Hz, 1 H),
7.46 (t, J = 8.0 Hz, 1 H), 5.71 (d, J = 4.6 Hz, 1 H), 3.76 (s, 1 H),
3.17 (d, J = 4.9 Hz, 1 H), 2.81 (dd, J = 4.9, 2.6 Hz, 1 H), 2.22 (s,
3 H) ppm. 13C NMR (CDCl3): δ = 209.56, 139.11, 134.56, 128.94,
125.20, 66.40, 51.79, 31.19 ppm.
In the case of activated aldehydes, quantitative yields and
pure products were obtained without the need for chroma-
tographic separation with organic solvents, thus making the
Zn(Pro)2-catalyzed aldol reaction a truly green method. A
mechanistic pathway involving formation of a zinc-stabi-
lized enamine in water is proposed for the new reaction.
4-(2-Bromophenyl)-4-hydroxybutan-2-one (2c):[23] According to the
general procedure and starting from 1c (93 mg, 0.50 mmol), 2c
1
could be isolated after column chromatography (74 mg, 61%). H
Experimental Section
NMR (CDCl3): δ = 7.54–7.35 (m, 4 H), 5.47 (d, J = 5.2 Hz, 1 H),
3.60 (s, 1 H), 3.03 (d, J = 5.4 Hz, 1 H), 2.72–2.62 (dd, J = 5.2,
2.7 Hz, 1 H), 2.24 (s, 3 H) ppm. 13C NMR (CDCl3): δ = 209.74,
142.38, 133.36, 129.71, 128.61, 128.10, 121.93, 69.58, 50.84,
31.33 ppm. ee = 30%, determined by HPLC [Daicel Chiralpak AS,
iPrOH/hexane (20:80), UV 254 nm, flow rate 2.0 mLmin–1]:
tR(major) = 2.50 min and tR(minor) = 3.32 min.
4-(4-Fluorophenyl)-4-hydroxybutan-2-one (2d):[2f] According to the
general procedure and starting from 1d (106 mg, 0.85 mmol), 2d
could be isolated (154 mg, 91%). 1H NMR (CDCl3): δ = 7.38–7.33
(m, 2 H), 7.09–7.03 (m, 2 H), 5.16 (d, J = 4.6 Hz, 1 H), 3.35 (s, 1
H), 2.87 (t, J = 5.5 Hz, 2 H), 2.23 (s, 3 H) ppm. 13C NMR (CDCl3):
δ = 208.93, 162.23 (d, JC,F = 245.26 Hz), 138.50 (d, JC,F = 3.12 Hz),
127.32 (d, JC,F = 8.11 Hz), 115.36 (d, JC,F = 21.22 Hz), 69.24,
51.93, 30.73 ppm. ee = 37%, determined by HPLC [Daicel Chi-
ralpak AS, iPrOH/hexane (20:80), UV 254 nm, flow rate
2.0 mLmin–1]: tR(minor) = 2.13 min; tR(major) = 2.78 min.
General: Chemicals and solvents were purchased of the best pos-
sible quality from commercial suppliers. For thin-layer chromatog-
raphy (TLC), Merck 60 F254 silica-gel plates were used and com-
pounds were visualized by treatment with a solution of phos-
phomolybdic acid (25 g), Ce(SO4)2·H2O (10 g), concd. H2SO4
(60 mL), and H2O (940 mL) followed by heating. Flash chromatog-
raphy was performed using Merck 60 silica gel (particle size 0.040–
0.063 mm). Solvents were distilled before use. 1H NMR spectra
were recorded with a Bruker AVANCE300 (300 MHz) or Bruker
DRX500 (500 MHz). Chemical shifts are given in ppm relative to
solvent residual peak. Coupling constants (J) are reported in Hz.
Preparative RP-HPLC was performed with HPLC-grade acetoni-
trile and MilliQ deionized water in Waters prepak cartridge 500 g
(RP-C18 20 mm, 300 Å pore size) installed on a Waters Prep
LC4000 system from Millipore. The compounds were eluted from
the column starting from 90% A and 10% D with a gradient of
1% D min–1 [eluent A: H2O with 0.1% TFA; eluent D: CH3CN/
H2O (60:40) with 0.1% TFA] with a flow rate of 100 mLmin–1 and
UV detection (214 or 254nm). Chiral HPLC was performed with
a Waters 600E System Controller and a Waters 996 Photodiode
Array Detector operating a Chiralpak AS column from Daicel
Chemical Industries Ltd., eluting with n-hexane and 2-propanol.
Analytical HPLC was performed with the same system as above
on a Chromolith Performance column and eluting with A and D.
Melting points were determined with a Büchi 510 apparatus and
are not corrected. Mass spectra were recorded by the MS service
(University of Bern, Switzerland).
4-(4-Cyanophenyl)-4-hydroxybutan-2-one (2e):[3b] According to the
general procedure and starting from 1e (39 mg, 0.30 mmol), 2e
1
could be isolated after column chromatography (52 mg, 91%). H
NMR (CDCl3): δ = 7.68 (d, J = 8.2 Hz, 2 H), 7.51 (d, J = 8.2 Hz,
2 H), 5.23 (s, 1 H), 3.55 (s, 1 H), 2.86 (t, J = 5.1 Hz, 2 H), 2.24 (s,
3 H) ppm. 13C NMR (CDCl3): δ = 209.25, 148.71, 133.12, 127.07,
69.83, 52.25, 31.45 ppm. ee = 27%, determined by HPLC [Daicel
Chiralpak AS, iPrOH/hexane (20:80), UV 254 nm, flow rate
2.0 mLmin–1]: tR(major) = 5.12 min; tR(minor) = 8.17 min.
4-Hydroxy-4-phenylbutan-2-one (2f):[3a] According to the general
procedure and starting from 1f (106 mg, 1.0 mmol), 2f could be
isolated after column chromatography (54 mg, 32%). 1H NMR
(CDCl3): δ = 7.30–7.20 (m, 4 H), 5.20 (d, J = 4.9 Hz, 1 H), 3.48
(s, 1 H), 2.82 (t, J = 5.1 Hz, 2 H), 2.24 (s, 3 H) ppm. 13C NMR
General Procedure for the Preparation of Aldol Products from Alde-
hydes and Acetone: In a typical experiment, a mixture of aldehyde
(0.75 mmol), acetone (5 mL), and Zn(Pro)2 (10 mol-%, 25 mg) was
dissolved in water (10 mL). The reaction mixture was stirred for
48 h, filtered, and water was added. The final product was extracted
with ethyl acetate (3×50 mL), and the combined extracts were
dried with MgSO4. The solvent was removed in vacuo to give the
resulting oily or solid products. The conversion was determined
(CDCl3):
31.50 ppm.
δ = 209.79, 129.28, 128.43, 126.37, 70.61, 52.71,
4-Hydroxy-4-(o-tolyl)butan-2-one (2g):[24] According to the general
procedure and starting from 1g (84 mg, 0.70 mmol), 2g could be
isolated after column chromatography (13 mg, 11%). 1H NMR
(CDCl3): δ = 7.28–7.17 (m, 4 H), 5.41 (d, J = 5.2 Hz, 1 H), 2.85
(t, J = 5.5 Hz, 1 H), 2.73 (d, J = 5.4 Hz, 1 H), (s, 3 H), 2.24 (s, 3
H) ppm. 13C NMR (CDCl3): δ = 210.74, 131.62, 129.39, 128.88,
128.23, 127.18, 125.98, 69.79, 51.69, 28.54, 20.52 ppm.
4-(2-Chlorophenyl)-4-hydroxybutan-2-one (2h):[2a] According to the
general procedure and starting from 1h (63 mg, 0.45 mmol), 2h
could be isolated in quantitative yield (89 mg, Ͼ95%). 1H NMR
(CDCl3): δ = 7.34 (m, 4 H), 5.13 (t, J = 4.9 Hz, 1 H), 3.39 (s, 1 H),
2.88 (dd, J = 4.9, 2.5 Hz, 2 H), 2.22 (s, 3 H) ppm. 13C NMR
(CDCl3): δ = 209.62, 141.96, 134.12, 129.43, 127.78, 69.95, 52.55,
31.50 ppm.
1
from the H NMR spectrun of the crude product. For identifica-
tion, the products were isolated by flash chromatography (ethyl
acetate/hexane mixtures) and the spectroscopic data compared with
the literature values.
4-Hydroxy-4-(4-nitrophenyl)butan-2-one (2a):[2f] According to the
general procedure and starting from 1a (113 mg, 0.75 mmol), 2a
was isolated in quantitative yield (152 mg, Ͼ95%) after solvent
evaporation and catalyst precipitation with ethyl acetate. 1H NMR
(CDCl3): δ = 8.20 (d, J = 8.5 Hz, 1 H), 7.55 (d, J = 8.5 Hz, 1 H),
5.25 (m, 1 H), 3.56 (d, J = 3.2 Hz, 1 H), 2.85 (m, 2 H), 2.25 (s, 3
H) ppm. 13C NMR (CDCl3): δ = 208.51, 150.04, 147.22, 126.37,
123.71, 123.57, 68.94, 51.43, 30.67 ppm. ee = 56%, determined by
HPLC [Daicel Chiralpak AS, iPrOH/hexane (20:80), UV 254 nm,
4-(4-Chlorophenyl)-4-hydroxybutan-2-one (2i):[3b] According to the
general procedure and starting from 1i (73 mg, 0.50 mmol), 2i
flow rate 2.0 mLmin–1]: tR(minor)
= 8.47 min; tR(major) =
10.02 min.
1
could be isolated in quantitative yield (104 mg, Ͼ95%). H NMR
4-Hydroxy-4-(2-nitrophenyl)butan-2-one (2b):[2f] According to the
general procedure and starting from 1b (76 mg, 0.50 mmol), 2b
(CDCl3): δ = 7.36–7.32 (m, 4 H), 5.51 (d, J = 4.4 Hz, 1 H), 3.56
(s, 1 H), 3.00 (d, J = 5.5 Hz, 1 H), 2.69 (dd, J = 5.5, 4.2 Hz, 1 H),
Eur. J. Org. Chem. 2005, 5268–5276
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5273

R. Fernandez-Lopez, J. Kofoed, M. Machuqueiro, T. Darbre
FULL PAPER
2.23 (s, 3 H) ppm. 13C NMR (CDCl3): δ = 209.96, 140.83, 131.88,
130.09, 127.99, 67.37, 50.74, 31.34 ppm. ee = 24%, determined by
HPLC [Daicel Chiralpak AS, iPrOH/hexane (20:80), UV 254 nm,
(br. s, 1 H), 3.18 (d, J = 5.3 Hz, 1 H), 2.92 (dd, J = 5.4, 3.2 Hz, 1
H), 2.24 (s, 3 H) ppm. 13C NMR (CDCl3): δ = 209.96, 163.95,
141.80, 139.94, 127.42, 119.92, 70.53, 50.55, 31.55 ppm. MS (EI):
m/z (%) = 245 (20) [M+], 243 (20) [M+], 210 (70), 212 (70), 200
(100), 202 (100), 188 (85), 186 (95), 158 (55), 106 (45), 104 (60), 78
(100), 51 (45), 43 (65). HR ESI MS(+): calcd. for C9H10BrNNaO2
265.9792; found 265.9786.
flow rate 1.5 mLmin–1]: tR(minor)
= 4.68 min; tR(major) =
5.15 min.
4-Hydroxy-4-(2-methoxyphenyl)butan-2-one (2j):[25] According to
the general procedure and starting from 1j (68 mg, 0.50 mmol), 2j
1-(Furan-2-yl)-1-hydroxypropan-2-one (4):[27] According to the ge-
neral procedure and starting from furan-2-carbaldehyde (192 mg,
2.0 mmol), 4 could be isolated after column chromatography
1
could be isolated after column chromatography (68 mg, 70%). H
NMR (CDCl3): δ = 7.46 (d, J = 8.2 Hz, 1 H), 7.28 (d, J = 8.3 Hz,
1 H), 7.06 (t, J = 8.0 Hz, 2 H), 5.43 (t, J = 4.9 Hz, 1 H), 3.86 (s, 3
H), 3.43 (s, 1 H), 2.96 (d, J = 4.9 Hz, 1 H), 2.82 (dd, J = 4.9,
2.5 Hz, 1 H), 2.22 (s, 3 H) ppm. 13C NMR (CDCl3): δ = 209.94,
158.76, 134.58, 128.71, 126.90, 66.02, 55.95, 50.41, 30.61 ppm. ee
= 32%, determined by HPLC [Daicel Chiralpak AS, iPrOH/hexane
(20:80), UV 254 nm, flow rate 1.5 mLmin–1]: tR(minor) = 8.05 min;
tR(major) = 8.63 min.
1
(166 mg, 56%). H NMR (CDCl3): δ = 7.36 (d, J = 8.3 Hz, 1 H),
6.59 (t, J = 8.0 Hz, 1 H), 6.32 (d, J = 8.3 Hz, 1 H), 5.20 (d, J =
5.2 Hz, 1 H), 3.26 (s, 1 H), 3.12 (dd, J = 5.4, 2.9 Hz, 1 H), 3.99 (d,
J = 5.5 Hz, 1 H), 2.24 (s, 3 H) ppm. 13C NMR (CDCl3): δ = 209.47,
155.63, 142.89, 111.04, 107.05, 64.54, 52.66, 31.44 ppm.
(E)-4-Hydroxy-6-phenylhex-5-en-2-one (5):[28] According to the ge-
neral procedure and starting from cinnamaldehyde (238 mg,
1.8 mmol), 5 could be isolated after column chromatography
(83 mg, 30%). 1H NMR (CDCl3): δ = 7.49–7.33 (m, 5 H), 7.96 (dd,
J = 6.9 Hz, 1 H), 6.30 (d, J = 7.5 Hz, 1 H) 4.79 (d, J = 5.4 Hz, 1
H), 3.11 (s, 1 H), 2.77 (d, J = 5.2 Hz, 2 H), 2.24 (s, 6 H) ppm. 13C
NMR (CDCl3): δ = 209.72, 164.24, 144.28, 131.24, 129.33, 128.51,
127.24, 69.22, 50.68, 31.58 ppm.
4-Hydroxy-4-(3-methoxyphenyl)butan-2-one (2k):[26] According to
the general procedure and starting from 1k (68 mg, 0.50 mmol), 2k
1
could be isolated after column chromatography (39 mg, 40%). H
NMR (CDCl3): δ = 7.47 (d, J = 8.3 Hz, 1 H), 7.39 (s, 1 H), 7.28
(t, J = 5.3 Hz, 1 H), 7.06 (d, J = 8.3 Hz, 2 H), 5.15 (t, J = 4.9 Hz,
1 H), 3.82 (s, 3 H), 3.49 (s, 1 H), 2.83 (t, J = 4.8 Hz, 2 H), 2.21 (s,
3 H) ppm. 13C NMR (CDCl3): δ = 209.06, 160.61, 130.35, 113.99,
111.89, 70.55, 56.00, 52.71, 31.51 ppm. ee = 37%, determined by
HPLC [Daicel Chiralpak AS, iPrOH/hexane (20:80), UV 254 nm,
General Procedure for the Preparation of Aldol Products from Alde-
hydes and Hydroxy Ketones or Ketones: In a typical experiment, a
mixture of aldehyde (1 mmol), THF (2 mL), ketone or hydroxy
ketone (5 mmol), and Zn(Pro)2 (5 mol-%, 10 mg) was dissolved in
water (10 mL). The reaction mixture was stirred for 48 h, filtered
and water was added. The product was extracted with ethyl acetate
(3×50 mL), and the combined extracts were dried with MgSO4.
After solvent removal, the residue was purified by medium pressure
chromatography (elution with 20–40% ethyl acetate/hexane), and
the solvent was removed in vacuo to give the resulting oily or solid
products.
flow rate 1.5 mLmin–1]: tR(minor)
= 6.81 min; tR(major) =
7.32 min.
4-Hydroxy-4-(4-methoxyphenyl)butan-2-one (2l):[25] According to
the general procedure and starting from 1l (136 mg, 1.0 mmol), 2l
1
could be isolated after column chromatography (80 mg, 41%). H
NMR (CDCl3): δ = 7.47 (d, J = 8.3 Hz, 1 H), 7.39 (s, 1 H), 7.27
(t, J = 5.3 Hz, 1 H), 7.06 (d, J = 8.3 Hz, 2 H), 5.15 (t, J = 4.9 Hz,
1 H), 3.82 (s, 3 H), 3.49 (s, 1 H), 2.83 (t, J = 4.8 Hz, 2 H), 2.21 (s,
3 H) ppm.
2-[Hydroxy(4-nitrophenyl)methyl]cyclopentanone (6):[2f] According
to the general procedure and starting from 1a (91 mg, 0.60 mmol)
and cyclopentanone (169 mg, 2.0 mmol), 6 could be isolated after
4-Hydroxy-4-[4-(trifluoromethyl)phenyl]butan-2-one (2m):[25] Ac-
cording to the general procedure and starting from 1m (134 µL,
1.0 mmol), 2m could be isolated after column chromatography
1
1
column chromatography (139 mg, Ͼ95%). H NMR (CD3OD): δ
(220 mg, 93%). H NMR (CDCl3): δ = 7.77 (d, J = 8.3 Hz, 2 H),
= 8.19 (d, J = 8.6 Hz, 2 H), 7.59 (d, J = 8.6 Hz, 2 H), 5.31 (s, 1
H), 5.08 (d, J = 7.0 Hz, 1 H), 2.65–1.70 (m, 6 H) ppm. 13C NMR
(CD3OD): δ = 220.78, 128.65, 128.18, 127.77, 127.17, 124.04, 70.76,
56.65, 42.79, 39.69, 25.10, 22.85 ppm.
2-[Hydroxy(4-nitrophenyl)methyl]cyclohexanone (7):[2f] According
to the general procedure and starting from 1a (453 mg, 3.0 mmol)
and cyclohexanone (588 mg, 6.0 mmol), 7 could be isolated after
column chromatography (300 mg, 45%). 1H NMR (CDCl3): δ =
8.26 (d, J = 8.3 Hz, 2 H), 7.51 (d, J = 8.3 Hz, 2 H), 5.48 (s, 1 H),
4.91 (d, J = 6.9 Hz, 1 H), 2.56–1.33 (m, 8 H) ppm. 13C NMR
(CDCl3): δ = 221.22, 128.35, 128.64, 127.65, 125.84, 124.78, 124.19,
70.86, 56.45, 42.45, 40.76, 35.46, 27.46, 25.73 ppm.
7.56 (d, J = 8.3 Hz, 2 H), 5.30 (q, J = 4.4 Hz, 1 H), 2.90 (d, J =
4.9 Hz, 2 H), 2.24 (s, 3 H) ppm. 13C NMR (CDCl3): δ = 208.65,
146.91, 129.72 (q, JC,F = 32.45 Hz), 34, 125.94, 125.41 (q, JC,F
=
3.74 Hz), 124.12 (q, JC,F = 272.10 Hz), 69.15, 51.74, 30.61 ppm. ee
= 35%, determined by HPLC [Daicel Chiralpak AS, iPrOH/hexane
(20:80), UV 254 nm, flow rate 2.0 mLmin–1]: tR(minor) = 2.02 min;
tR(major) = 2.95 min.
4-Hydroxy-4-(2-naphthyl)butan-2-one (2n):[2a] According to the ge-
neral procedure and starting from 1n (200 mg, 1.3 mmol), 2n could
be isolated after column chromatography (149 mg, 53%). 1H NMR
(CDCl3): δ = 8.37 (s, 1 H), 7.97–7.49 (m, 6 H), 5.34 (d, J = 5.4 Hz,
1 H), 3.43 (s, 1 H), 3.00 (t, J = 5.5 Hz, 2 H), 2.24 (s, 3 H) ppm. 13
C
1-Hydroxy-1-(4-nitrophenyl)pentan-3-one (8):[2f] According to the
general procedure and starting from 1a (193 mg, 1.3 mmol) and
2-butanone (368 mg, 5.1 mmol), 8 could be isolated after column
NMR (CDCl3): δ = 209.77, 130.28, 129.85, 129.12, 128.42, 127.95,
127.22, 126.98, 125.86, 125.11, 124.47, 70.75, 52.66, 31.55 ppm. ee
= 31%, determined by HPLC [Daicel Chiralpak AS, iPrOH/hexane
(20:80), UV 254 nm, flow rate 2.0 mLmin–1]: tR(minor) = 3.56 min;
tR(major) = 4.46 min.
1
chromatography (115 mg, 40%). H NMR (CDCl3): δ = 8.24 (d, J
= 8.6 Hz, 2 H), 7.57 (d, J = 8.6 Hz, 2 H), 5.28 (s, 1 H), 3.68 (s, 1
H), 2.87 (dd, J = 6.4, 2.4 Hz, 1 H), 2.83 (dd, J = 6.4, 2.4 Hz, 1 H),
2.46 (q, J = 7.1 Hz, 2 H), 1.11 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR
(CDCl3): δ = 211.68, 128.23, 127.46, 127.16, 124.46, 124.28, 76.19,
69.83, 54.01, 14.87 ppm.
4-(6-Bromopyridin-3-yl)-4-hydroxybutan-2-one (3): According to the
general procedure and starting from 6-bromopyridine-2-carbal-
dehyde (95 mg, 0.50 mmol), 3 could be isolated after column
chromatography as a yellow oil (91 mg, 74%). IR (neat): ν = 3386,
˜
1
2918, 2848, 2360, 1680, 1203, 1203, 1138, 725, 631 cm–1. H NMR
3,4-Dihydroxy-4-(4-nitrophenyl)butan-2-one (9a) as a syn/anti Mix-
ture:[8] According to the general procedure and starting from 1a
(CDCl3): δ = 7.62–7.48 (m, 3 H), 5.17 (d, J = 5.4 Hz, 1 H), 3.88
5274
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2005, 5268–5276

A Selective Direct Aldol Reaction Catalyzed by Zinc–Proline
FULL PAPER
(151 mg, 1.0 mmol) and HA (370 mg, 5.0 mmol), 9a could be iso-
(d, J = 6.6 Hz, 1 H), 7.55 (app. t, 1 H), 7,38 (app. t, 1 H), 5.48 (d,
J = 6.22 Hz, 1 H), 4.46 (d, J = 19.4 Hz, 1 H), 4.32 (d, J = 19.4 Hz,
lated after column chromatography (47 mg, 21%). 1H NMR
(CDCl3): δ = 8.25 (d, J = 8.3 Hz, 3 H), 7.67 (d, J = 8.3 Hz, 3 H), 1 H), 4.11 (d, J = 6.22 Hz, 1 H) ppm. 13C NMR (CD3OD): δ =
5.24 (d, J = 2.6 Hz, 1 H), 5.12 (d, 0.5 H, J = 4.7 Hz), 4.50 (d, 0.5 212.35, 138.13, 134.24, 130.65, 129.83, 125.45, 79.79, 71.86,
H, J = 4.7 Hz), 4.44 (d, J = 2.6 Hz, 1 H), 3.01 (br. s, 0.5 H), 2.83
68.60 ppm. HR ESI MS(+): calcd. for C10H11NNaO6 264.0484;
(br. s, 1 H), 2.39 (s, 3 H), 2.00 (s, 1.5 H) ppm. 13C NMR (CD3OD): found 264.0475. Anal. HPLC (254 nm; gradient 90% A, 10% D to
δ = 211.53, 129.27, 128.69, 124.05, 82.01, 74.53, 27.60, 26.00 ppm.
50% A, 50% D in 10 min): tR = 3.377 min.
3,4-Dihydroxy-4-(2-nitrophenyl)butan-2-one (9b) as a syn/anti Mix-
ture: According to the general procedure and starting from 1a
(151 mg, 1.0 mmol) and HA (370 mg, 5.0 mmol), 9b could be iso-
lated in low yield after column chromatography (8 mg, 4%) in a
syn/anti ratio of 1:0.6. 1H NMR (CDCl3): δ = 8.15–7.51 (several
4-(2-Bromophenyl)-1,3,4-trihydroxybutan-2-one (10c): Starting from
1c (185 mg, 1.0 mmol) and DHA (450 mg, 5.00 mmol), 10c was
obtained according to the general procedure with the following
modifications: the aqueous solution was lyophilized and the crude
product purified by preparative RP-HPLC to separate the two dia-
signals, 6.4 H), 5.92 (d, J = 1.3 Hz, 1 H), 5.56 (d, J = 6.2, 0.6 H), stereoisomers. syn-10c: Yield: 170 mg (62%), oil. IR (neat): ν =
˜
1
4.59 (s, J = 1.3 Hz, 1 H), 4.47 (d, J = 6.2 Hz, 0.6 H), 2.54 (s, 3 H),
2.20 (s, 1.8 H) ppm.
3253, 1734, 1468, 1439, 1103, 1066, 1022, 750, 654 cm–1. H NMR
(CD3OD): δ = 7.70 (d, J = 8.3 Hz, 1 H), 7.56 (d, J = 8.3 Hz, 1 H),
7.39 (app. t, 1 H), 7.16–7.21 (m, 1 H), 5.45 (d, J = 2.07 Hz, 1 H),
4.59 (s, 2 H), 4.41 (d, J = 2.07 Hz, 1 H) ppm. 13C NMR (CD3OD):
δ = 213.31, 142.09, 133.79, 131.35, 130.54, 128.72, 122.67, 79.00,
74.72, 68.44 ppm. HR ESI MS(+): calcd. for C10H11BrNaO4
296.9738; found 296.9749. Anal. HPLC (254 nm; gradient 90% A,
10% D to 50% A, 50% D in 10 min): tR = 4.963 min. anti-10c:
4-(2-Bromophenyl)-3,4-dihydroxybutan-2-one (9c): Starting from 1c
(185 mg, 1.0 mmol) and HA (370 mg, 5.0 mmol), 9c was obtained
according to the general procedure and with the following modifi-
cations: the aqueous solution was lyophilized and the crude prod-
uct purified by preparative RP-HPLC to separate the two dia-
stereoisomers. syn-9c: Yield: 70 mg (27%); oil. IR (neat): ν = 3379,
˜
Yield: 71 mg (26%), white solid, m.p. 66–69 °C. IR (neat): ν = 3282,
˜
1676, 1437, 1199, 1140, 845 cm–1. 1H NMR (CD3OD): δ = 7.73
(app. d, 1 H), 7.60 (app. d, 1 H), 7.43 (app. t, 1 H), 7.15–7.25 (m,
1 H), 5.50 (d, J = 1.69 Hz, 1 H), 4.38 (d, J = 1.69 Hz, 1 H), 2.40
(s, 3 H) ppm. 13C NMR (CD3OD): δ = 210.31, 143.19, 132.85,
130.37, 129.97, 128.36, 122.39, 79.29, 74.29, 29.75 ppm. HR ESI
MS(+): calcd. for C10H11BrNaO3 280.9789; found 280.9784. Anal.
RP-HPLC (254 nm, gradient 90% A, 10% D to 50% A, 50% D in
10 min): tR = 5.161 min. anti-9c: Yield: 16 mg (6%); white solid,
1722, 1464, 1369, 1323, 1188, 1074, 1018, 737 cm–1. 1H NMR
(CD3OD): δ = 7.50–7.77 (m, 2 H), 7.35 (app. t, 1 H), 7.1–7.2 (m,
1 H), 5.22 (d, J = 4.9 Hz, 1 H), 4.35–4.50 (m, 3 H) ppm. 13C NMR
(CD3OD): δ = 212.17, 141.69, 133.91, 130.66, 130.60, 128.86,
124.16, 79.47, 75.89, 68.79 ppm. HR ESI MS(+): calcd. for
C10H11BrNaO4 296.9738; found 296.9732. Anal. HPLC (254 nm;
gradient 90% A, 10% D to 50% A, 50% D in 10 min): tR
=
4.366 min.
m.p. 85–87 °C. IR (neat): ν = 3379, 1701, 1462, 1365, 1319, 1234,
˜
1
1190, 1120, 1086, 1064, 1018, 756, 681 cm–1. H NMR (CD3OD):
Supporting Information (see footnote on the first page of this arti-
δ = 7.58–7.68 (m, 2 H), 7.40 (app. t, 1 H), 7.12–25 (m, 1 H), 5.29
(d, J = 4.9 Hz, 1 H), 4.40 (d, J = 4.9 Hz, 1 H), 2.13 (s, 3 H) ppm.
13C NMR (CD3OD): δ = 210.03, 141.69, 133.91, 132.12, 128.78,
128.62, 126.99, 79.59, 73.85, 26.54 ppm. HR ESI MS(+): calcd. for
C10H11BrNaO3 280.9789; found 280.9783. Anal. HPLC (254 nm;
cle): Selected NMR spectra and HPLC traces.
Acknowledgments
This work was supported by the University of Berne and the Swiss
National Science Foundation. We thank Sandra Zima for assist-
ance in preparing the aldol products.
gradient 90% A, 10% D to 50% A, 50% D in 10 min): tR
=
5.585 min.
1,3,4-Trihydroxy-4-(4-nitrophenyl)butan-2-one (10a) as a syn/anti
Mixture:[8] According to the general procedure and starting from
1a (151 mg, 1.0 mmol) and DHA (450 mg, 5.0 mmol), 10a could
be isolated after column chromatography (185 mg, 77%). 1H NMR
(CD3OD): δ = 8.25 (m, 2 H), 7.7 (m, 2 H), 5.3 (d, J = 2.4 Hz, 0.5
H), 5.05 (d, J = 5.8 Hz, 0.5 H), 4.55 (m, 1 H), 4.40 and 4.30 (2br.
d, 1 H) ppm. 13C NMR (DMSO): δ = 211.76, 146.22, 131.09,
128.63, 128.14, 124.66, 123.26, 79.29, 73.76, 66.83 ppm.
[1] For review articles and references, see: a) T. D. Machajewski,
C.-H. Wong, Angew. Chem. Int. Ed. 2000, 39, 1352–1375; b) C.
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Jiang, Y.-D. Wu, Proc. Natl. Acad. Sci. USA 2004, 101, 5755; c)
H. J. Martin, B. List, Synlett 2003, 1901; d) J. Kofoed, J. Niel-
sen, J.-L. Reymond, Bioorg. Med. Chem. Lett. 2003, 13, 2445.
[4] a) Y. M. A. Yamada, N. Yoshikawa, H. Sasai, M. Shibasaki,
Angew. Chem. Int. Ed. Engl. 1997, 36, 1871–1873; b) N. Yoshi-
kawa, Y. M. A. Yamada, J. Das, M. Sasai, H. Shibasaki, J. Am.
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aga, N. Yoshikawa, T. Ohshima, M. Shibasaki, Org. Lett. 2001,
3, 1539–1542.
1,3,4-Trihydroxy-4-(2-nitrophenyl)butan-2-one (10b): Starting from
1b (151 mg, 1.0 mmol) and DHA (450 mg, 5.0 mmol), 10b was ob-
tained according to the general procedure with the following modi-
fications: the aqueous solution was lyophilized and the crude prod-
uct purified by preparative RP-HPLC to separate the two dia-
stereoisomers. syn-10b: Yield: 103 mg (43%); oil. IR (neat): ν =
˜
3327, 1726, 1523, 1342, 1230, 1053, 717, 631 cm–1. 1H NMR
(CD3OD): δ = 8.0 (m, 2 H), 7.75 (app. t, 1 H), 7.52 (app. t, 1 H),
5.71 (d, J = 2.07 Hz, 1 H), 4.66 (s, 2 H), 4.48 (d, J = 2.07 Hz, 1 H)
ppm. 13C NMR (CD3OD): δ = 212.61, 149.41, 138.80, 134.38,
132.09, 129.82, 125.45, 79.80, 71.00, 68.24 ppm. HR ESI MS(+):
calcd. for C10H11NNaO6 264.0484; found 264.0486. Anal. HPLC
(254 nm; gradient 90% A, 10% D to 50% A, 50% D in 10 min):
tR = 3.096 min. anti-10b: Yield: 91 mg (38%); yellowish solid, m.p.
58–61 °C. IR (neat): ν = 3271, 1724, 1529, 1040, 1082, 834, 793,
˜
732 cm–1. 1H NMR (CD3OD): δ = 7.83 (d, J = 7.16 Hz, 1 H), 7.75
Eur. J. Org. Chem. 2005, 5268–5276
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5275

R. Fernandez-Lopez, J. Kofoed, M. Machuqueiro, T. Darbre
FULL PAPER
[5] a) B. M. Trost, H. Ito, J. Am. Chem. Soc. 2004, 122, 12003–
12004; b) B. M. Trost, E. R. Silcoff, H. Ito, Org. Lett. 2001, 3,
2497–2500; c) B. M. Trost, H. Ito, E. R. Silcoff, J. Am. Chem.
Soc. 2001, 123, 3367–3368.
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a) J. Kofoed, M. Machuqueiro, J.-L. Reymond, T. Darbre,
Chem. Commun. 2004, 1540–1541; b) J. Kofoed, J.-L. Re-
ymond, T. Darbre, Org. Biol. Chem. 2005, 1850–1855.
S. Kobayashi, S. Nagayama, T. Busujima, J. Am. Chem. Soc.
1998, 120, 8287–8288.
M. T. Konieczny, P. H. Toma, M. Cushiman, J. Org. Chem.
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A syn/anti ratio of 4:1 has been reported for the same reaction
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Published Online: October 25, 2005
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Eur. J. Org. Chem. 2005, 5268–5276