InCl3-Catalyzed direct aldol reactions of glyoxylic acid monohydrate and glyoxylates with various ketones: Scope and limitations

Article abstract of DOI:10.1016/S0040-4020(01)00309-X

The direct aldol reactions of various ketones with glyoxylic acid and glyoxylates afforded the α-hydroxy acid and α-hydroxy esters in good yields and high regioselectivities.

Full text of DOI:10.1016/S0040-4020(01)00309-X

TETRAHEDRON
Pergamon
Tetrahedron 57 ꢀ2001) 4231±4236
InCl -Catalyzed direct aldol reactions of glyoxylic acid
3
monohydrate and glyoxylates with various ketones:
scope and limitations
p
Teck-Peng Loh, Li-Chun Feng and Lin-Li Wei
National University of Singapore, Department of Chemistry, 3 Science Drive 3, Singapore 117543, Singapore
Received 14 December 2000; revised 19February 2001; accepted 8 March 2001
AbstractÐThe direct aldol reactions of various ketones with glyoxylic acid and glyoxylates afforded the a-hydroxy acid and a-hydroxy
esters in good yields and high regioselectivities. q 2001 Elsevier Science Ltd. All rights reserved.
1
.Introduction
aldol reaction, which provide the biologically and syntheti-
cally important a-hydroxy esters and a-hydroxy acid, are of
3
,7,8
The aldol Reaction is one of the most powerful and useful
tools for the construction of carbon±carbon bonds.
special synthetic value.
the aldol products are obtained in poor yields under very
However, in most of these cases,
1
8
,9
However, the most classical and conventional Aldol reac-
tion which involves the mixed aldol reaction between a
ketone containing a-hydrogen with an aldehyde in the
presence of base or acid has not been well exploited due
to the following reasons: 1) side reactions such as self-
condensation of the ketone or/and dimerization of the
aldehyde can be a problem; 2) the harsh reaction conditions
employed which, usually require a strong acid or base,
makes it unattractive for the complex molecule synthesis
which contains acid or base sensitive functional groups; 3)
the desired aldol product is usually accompanied by
elimination products, dimmers and polymers; 4) low regio-
selectivity is observed in most of cases. Therefore, mild
reaction conditions are much sought after to overcome
some, if not all, the above problems. Recently, it has been
reported that Zn-catalyst ꢀZn ꢀNO ) ´6H O and a-amino
harsh reaction conditions. In this paper, we present the
direct aldol reactions of glyoxylic acid monohydrate and
methyl glyoxylate with aliphatic and aromatic ketones in
the presence of InCl under solvent-free conditions. In
3
addition, the direct aldol reactions of glyoxylate derived
from ꢀ2)-8-phenylmenthol with aliphatic and aromatic
ketones, which provide optically active products, are also
investigated.
2.Results and discussions
2.1. Direct aldol reaction of glyoxylic acid with different
ketones
In our investigation, we found that InCl can effectively
3
3
2
2
2
3
3
4,5
acid ester), BCl and TiCl are useful catalyst to promote
promote the direct aldol reaction of glyoxylic acid mono-
hydrate with different ketones under sonication ꢀScheme 1).
The results are shown in Table 1.
4
the direct aldol reaction. However, the reactions catalyzed
by the latter two Lewis acids must be carried out under
anhydrous conditions due to their moisture sensitivities.
InCl has also been shown to be a mild, ef®cient, recover-
3
As shown in Table 1, InCl is essential for the success of the
3
able, reusable and water-stable Lewis acid to promote
different kinds of C±C or C±X formation. On the other
hand, the glyoxylate aldol reaction and glyoxylic acid
reactions with propiophenone ꢀTable 1, entries 1, 2). In the
presence of 20 mol% InCl under sonication and neat con-
dition, satisfactory yields were obtained in all cases. The
6
3
Scheme 1.
p
Corresponding author. Tel.: 165-874-7851; fax: 165-779-1691; e-mail: chmlohtp@nus.edu.sg
040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020ꢀ01)00309-X
0

4232
T.-P. Loh et al. / Tetrahedron 57 $2001) 4231±4236
Table 1. Direct aldol reaction of glyoxylic acid monohydrate with different ketones
a
b
Entry
Ketones
Conditions
))), 3 d
Yield%
syn:anti
Products
1
2
3
4
5
Propiophenone
Propiophenone
Acetophenone
Cyclohexanone
Cyclopentanone
10
80
94
80
95
73:27
60:40
±
62:38
71:29
1a
1a
1b
1c
1d
InCl
InCl
InCl
InCl
3
3
3
3
ꢀ0.2 equiv.),))), 3d
ꢀ0.2 equiv.),))), 3 d
ꢀ0.2 equiv.),))), 2 d
ꢀ0.2 equiv.),))), 4 d
a
Isolated yield.
Determined by H NMR and C NMR analysis.
b
1
13
10
yields with moderate diastereoselectivities and regio-
selectivities. For unsymmetrical ketones, the thermo-
dynamically controlled products were the major products.
2.2. Direct aldol reactions of methyl glyoxylate with
different ketones
Figure 1.
With the success of carrying out the direct aldol reaction of
glyoxylic acid monohydrate with different ketones, we next
explored the direct aldol reactions of methyl glyoxylate
diastereoselectivities were low to moderate and the syn
products were predominant regardless of the geometry of
the enols. The observed syn diastereoselectivities can be
explained using an open-chain antiperiplanar transition
state ꢀFig. 1).
1
1
instead of glyoxylic acid monohydrate with different
ketones ꢀScheme 3). In the presence of InCl under neat
3
and sonication conditions, methyl glyoxylate can react
with different ketones to give the aldol addition products
in moderate to good yields with low to moderate diastereo-
selectivities. The results are shown in Table 2.
The aldol reaction of unsymmetrical ketones with
glyoxylic acid monohydrate was also investigated. The
regioselectivities were high and the thermodynamically
controlled products were obtained as major products
From table 2, we can see that compared to the high yields
obtained in the reactions of acetophenone, propiophenone,
and cyclopentanone with glyoxylic acid ꢀtable 1, entries 2,
3, 5), the yields of these ketones with methyl glyoxylate in
ꢀ
Scheme 2).
Generally, the direct aldol reactions of various ketones with
glyoxylic acid monohydrate are clean. The possible a,b-
unsaturated acid resulted from the aldol condensation and
double aldol reaction was not detected in most cases. The
reactions proceeded smoothly under extremely mild condi-
tions to give the corresponding a-hydroxy acids in high
the presence of InCl under sonication and neat condition
3
were lower ꢀtable 2, entries 1, 2, 3). However, the yield for
the reaction of cyclohexanone with methyl glyoxylate was
higher than that of cyclohexanone with glyoxylic acid
monohydrate.
Scheme 2.
Scheme 3.

T.-P. Loh et al. / Tetrahedron 57 $2001) 4231±4236
Table 2. Direct aldol reaction of methyl glyoxylate with various ketones
4233
a
b
Entry
Ketones
Conditions
Yields%
Syn:anti
Product
1
2
3
4
Acetophenone
Propiophenone
Cyclopentanone
Cyclohexanone
InCl
InCl
InCl
InCl
3
3
3
3
ꢀ1 equiv.), ))), 5 d
ꢀ1 equiv.), ))), 5 d
ꢀ1 equiv.), ))), 5 d
ꢀ1 equiv.), ))), 5 d
59±
62
80
95
2a
2b
2c
2d
39:61
52:48
51:49
a
Isolated yields.
Determined by H NMR and C NMR.
b
1
13
10
Scheme 4.
As for unsymmetrical ketones 2-butanone and 2-methyl-
cyclopentanone, the regioselectivities were moderate and
also the thermodynamically controlled products were
obtained as major products ꢀScheme 4).
of ꢀ2)-8-phenylmethyl-2-hydroxyl-4-oxo-4-pentenoate
prepared from the known ꢀ2)-8-phenylmethyl-2-hydroxyl-
1
4-methyl-4-pentenoate as shown in Scheme 6.
2
2.3. Direct aldol reactions of chiral glyoxylate with
different ketones
3.Conclusions
In summary, we have developed an easy approach to various
a-hydroxy esters and a-hydroxy acids via the direct aldol
reactions of different ketones with commercially available
monohydrate of glyoxylic acid, methyl glyoxylate and
chiral glyoxylate derived from ꢀ2)-8-phenylmenthol in
the presence of indium trichloride under solvent-free
conditions. Especially worthy of being mentioned is that
the non-protected acid and the hydrated aldehyde can be
The aldol reactions of chiral glyoxylate derived from ꢀ2)-8-
phenylmenthol with different ketones, which provides opti-
cally active products, were also investigated ꢀScheme 5).
The results are summarized in Table 3. From Table 3, we
can see that in all cases the desired products were obtained
in moderate yields with good diastereoselectivities.
The absolute stereochemistry of the major product 2i was
con®rmed after comparing with the H NMR and C NMR
used directly. Since InCl is a mild, ef®cient, recoverable,
3
reusable and water-stable Lewis acid and the products of
1
13
Scheme 5.
Table 3. Direct aldol reaction of chiral glyoxylate with different ketones
a
b
Entry
Ketones
Conditions
Yields%
2S/2R
Product
1
2
3
Acetofuran
Acetone
Acetophenone
InCl
InCl
InCl
3
3
3
ꢀ1 equiv.), ))), 6 d
ꢀ1 equiv.), ))), 6 d
ꢀ1 equiv.), ))), 6 d
50
42
54
73:27
80:20
87:13
2h
2i
2j
a
Isolated yields.
Determined by H NMR and C NMR.
b
1
13

4234
T.-P. Loh et al. / Tetrahedron 57 $2001) 4231±4236
Scheme 6.
these reactions are important and useful intermediates for
natural product synthesis, we can expect that this simple,
highly ef®cient, safe and environmentally friendly method-
ology will ®nd wide applications in industry.
ꢀ4), 176 ꢀ62), 149ꢀ52), 105 ꢀ73), 55 ꢀ82), 45 ꢀ100);
HRMS ꢀEI) calcd. for C H O 194.0579, found 194.0579.
1
0
10
4
4.2.3. ,1c) Hydroxy-,2-oxo-cyclohexyl)-acetic acid. Oil.
1
mixture of two isomers, 62:38). ꢀ69mg, 80%). H NMR
300 MHz, CDCl ) d ꢀppm): major: 4.70 ꢀ1H, br, CHOH),
3
ꢀ
ꢀ
2.85±2.89ꢀ1H, m, C HCHOH), 1.61±2.44 ꢀ8H, m,
OCCH CH CH CH CH); C NMR ꢀ75 MHz, CDCl ): d
4.Experimental
13
2
2
2
2
3
ꢀ
ppm): major: 212.4, 176.5, 68.6, 53.4, 41.7, 26.8, 24.5,
4
.1. General methods and materials
21
0.6; FTIR ꢀneat) 1726.0, 1710.1 cm ; MS ꢀEI) ꢀm/z, rela-
2
tive intensity): 172 ꢀ13), 126 ꢀ59), 69 ꢀ92), 55 ꢀ100); HRMS
NMR spectra were recorded on Bruker ACF 300 NMR and
Bruker DPX 300 NMR. MS spectra were obtained with a
Hewlett±Packard 5890A gas chromatograph. HR-mass
spectra ꢀEI) were obtained with V.G. Micromass 7035. IR
spectra were measured with a Perkin±Elmer 1600 FTIR
spectrometer and Bio-RAD FTS 165 FT-IR spectro-
photometer. Column chromatography was performed on
silica gel, Merck grade 60 ꢀ40±63 mm particle size).
Ketones, indium trichloride and glyoxylic acid mono-
hydrate were purchased ꢀAldrich) and used directly.
ꢀ
EI) calcd. for C H O 172.0736, found 172.0731.
8 12 4
4
ꢀ
.2.4. ,1d) Hydroxy-,2-oxo-cyclopentyl)-acetic acid. Oil.
1
mixture of two isomers, 71:29). ꢀ75 mg, 95%). H NMR
ꢀ300 MHz, CDCl ) d ꢀppm): major: 4.75 ꢀ1H, br, CHOH),
3
4
.70 ꢀ1H, d, Jˆ2.6 Hz, CHOH), 1.45±2.78 ꢀ7H, m,
13
OCCH CH CH CHCHOH); C NMR ꢀ75 MHz, CDCl ):
2
2
2
3
d ꢀppm): major: 219.6, 176.2, 68.2, 51.9, 38.3, 22.9, 20.3;
FTIR ꢀneat) 1726.8 cm ; MS ꢀEI) ꢀm/z, relative intensity):
158 ꢀ2), 140 ꢀ33), 112 ꢀ55), 84 ꢀ77), 42 ꢀ100); HRMS ꢀEI)
calcd. for C H O 158.0579, found 158.0578.
21
7
10
4
4.2. Representative procedure for direct aldol reaction of
various ketones with glyoxylic acid monohydrate
1
4.2.5. ,1e) 2-Hydroxy-4-oxo-hexanoic acid. Oil. H NMR
300 MHz, CDCl ) d ꢀppm): 4.54±4.57 ꢀ1H, m, CHOH),
ꢀ
3
Glyoxylic acid monohydrate ꢀ46 mg, 0.5 mmol), aceto-
phenone ꢀ120 mg, 1mmol) and InCl ꢀ22.1 mg, 0.1 mmol)
were mixed and sonicated for 3 d ꢀ,308C). After normal
acid±base workup, the pure aldol product ꢀ1b) was obtained
as an oil. ꢀ91.2 mg, 94%).
2.96±3.13 ꢀ2H, m, COCH
CH CH
), 1.04 ꢀ3H, t, Jˆ7.2 Hz, CH
ꢀ75 MHz, CDCl ): d ꢀppm): 210.8, 175.7, 66.5, 45.2, 36.4,
7.3; FTIR ꢀneat) 1728.1, 1713.2 cm ; MS ꢀEI) ꢀm/z, rela-
tive intensity): 146 ꢀ3), 101 ꢀ44), 57 ꢀ66), 29ꢀ100); HRMS
2
CH), 2.47 ꢀ2H, q, Jˆ7.2 Hz,
CH ); C NMR
2 3
1
3
3
2
3
3
2
1
ꢀEI) calcd. for C H O 146.0579, found 146.0584.
6 10 4
4.2.1. ,1a) 2-Hydroxy-3-methyl-4-oxo-4-phenyl-butyric
acid. Oil. ꢀmixture of two isomers, 60:40). ꢀ83.2 mg,
4.2.6. ,1f) 2-Hydroxy-3-methyl-4-oxo-pentanoic acid.
Oil. ꢀmixture of two isomers, 56:44). H NMR ꢀ300 MHz,
1
0%). H NMR ꢀ300 MHz, CDCl ) dꢀppm): 7.89±7.91
2H, m, Ph), 7.50±7.55 ꢀ1H, m, Ph), 7.39±7.44 ꢀ2H, m,
1
8
3
ꢀ
CDCl
3
) d ꢀppm): syn: 4.65 ꢀ1H, br, CHOH), 2.96±3.13 ꢀ1H,
), 2.21 ꢀ3H, s, CH
CO), 1.18 ꢀ3H, d, Jˆ7.2 Hz,
); C NMR ꢀ75 MHz, CDCl ): d ꢀppm): 210.2,
175.9, 71.6, 49.4, 28.6, 10.4; anti: 4.27 ꢀ1H, d, Jˆ4.1 Hz,
CHOH), 2.96±3.13 ꢀ1H, m, CHCH ), 2.22 ꢀ3H, s, CH CO),
1.29ꢀ3H, d, Jˆ7.4 Hz, CHCH ); C NMR ꢀ75 MHz,
CDCl ): d ꢀppm): 212.6, 176.5, 70.5, 49.6, 28.2, 12.7;
Ph), 4.64 ꢀ1H, d, Jˆ3.3 Hz, CHOH) ꢀmajor); 4.44 ꢀ1H, d,
m, CHCH
3
1
3
3
Jˆ4.3 Hz, CHOH) ꢀminor); 3.95±4.91 ꢀ1H, m, CHCH ),
CHCH
3
3
3
1
.31 ꢀ3H, d, Jˆ7.4 Hz, CH CH) ꢀminor); 1.22 ꢀ3H, d,
3
Jˆ7.2 Hz, CH CH) ꢀmajor); 13C NMR ꢀ75 MHz, CDCl ):
3
3
3
3
1
3
d ꢀppm): major: 202.7, 175.5, 135.2, 133.5, 128.7, 128.5,
3
7
1
9
1
1.1, 43.8, 11.7; minor: 204.7, 175.8, 135.0, 133.9, 128.8,
3
2
1
28.7, 72.1, 43.9, 14.2; FTIR ꢀneat) 3447.9, 1738.5, 1681.6,
77.2, 703 cm ; MS ꢀEI) ꢀm/z, relative intensity): 208 ꢀ3),
90 ꢀ46), 134 ꢀ76), 105 ꢀ100), 77 ꢀ83), 39 ꢀ66); HRMS ꢀEI)
FTIR ꢀneat) 1728.1, 1713.2 cm ; MS ꢀEI) ꢀm/z, relative
intensity): 146 ꢀ3), 101 ꢀ44), 57 ꢀ66), 29ꢀ100); HRMS
2
1
ꢀEI) calcd. for C H O 146.0579, found 146.0584.
6 10 4
calcd. for C H O 208.0736, found 208.0745.
1
1
12
4
4.2.7. ,1g) Hydroxy-,1-methyl-2-oxo-cyclohexyl)-acetic
acid. ꢀ88.4 mg, 95%). Oil. ꢀmixture of two isomers,
4
.2.2. ,1b) 2-Hydroxy-4-oxo-4-phenyl-butyric acid.
91.2 mg, 94%). Oil. H NMR ꢀ300 MHz, Acetone-d ) d
1
1
ꢀ
ꢀ
7
57:43). H NMR ꢀ300 MHz, CDCl
4.17 ꢀ1H, s, CHOH), 3.04 ꢀ1H, br, CHOH), 1.36±2.51 ꢀ6H,
m, COCH CH CH ), 1.26 ꢀ3H, s, CCH ), 1.01 ꢀ2H, t,
Jˆ6.3 Hz, CCH ); C NMR ꢀ75 MHz, CDCl ): d ꢀppm):
215.4, 176.3, 70.3, 53.8, 45.8, 36.8, 24.8, 24.6, 14.0; FTIR
3
) d ꢀppm): one isomer:
6
ppm): 7.99±8.03 ꢀ2H, m, Ph), 7.60±7.65ꢀ1H, m, Ph),
.48±7.55 ꢀ2H, m, Ph), 4.75 ꢀ1H, t, Jˆ5.4 Hz, CHOH),
2
2
2
13
3
1
3
3
Acetone-d ): d ꢀppm): 198.6, 176.2, 138.6, 134.8, 130.2,
.50 ꢀ2H, d, Jˆ5.4 Hz, CH CHOH); C NMR ꢀ75 MHz,
2
3
2
6
2
1
1
7
29.7, 68.4, 44.1; FTIR ꢀneat) 3341, 1731.0, 1678.1,
55.6, 685.0 cm ; MS ꢀEI) ꢀm/z, relative intensity): 194
ꢀneat) 2943.8, 2869.7, 1759.7, 1713.6 cm ; MS ꢀEI) ꢀm/z,
relative intensity): 186 ꢀ2), 150 ꢀ43), 112 ꢀ76), 55 ꢀ100), 29
2
1

T.-P. Loh et al. / Tetrahedron 57 $2001) 4231±4236
4235
ꢀ
1
55); HRMS ꢀEI) calcd. for C H O 186.0892, found
9
86.0888.
140 ꢀ45), 113 ꢀ53), 67 ꢀ56), 55 ꢀ82), 29ꢀ100); HRMS ꢀEI)
calcd. for C H O 172.0736, found 172.0738.
14
4
8
12
4
4.3.4. ,2d) Hydroxy-,2-oxo-cyclohexyl)-acetic acid
methyl ester. ꢀ88 mg, 95%). Oil. ꢀmixture of two isomers,
4.3. Representative procedure for direct aldol reaction of
various ketones with alkyl glyoxylate
1
1:49). R 0.30 ꢀn-hexane:EtOAc, 2:1). H NMR ꢀ300 MHz,
5
f
CDCl ) d ꢀppm): syn: 4.69ꢀ1H, dd, Jˆ2.5, 4.7 Hz, CHOH),
Methyl glyoxylate ꢀ44 mg, 0.5 mmol) was added to the
suspension of cyclohexanone ꢀ98 mg, 1 mmol) and InCl3
3
3
.79ꢀ3H, s, COO Me), 2.96 ꢀ1H, d, Jˆ4.7 Hz, CHOH),
2.78±2.95 ꢀ1H, m, CHCO), 1.65±2.49ꢀ8H, m,
COCH CH CH CH CH); C NMR ꢀ75 MHz, CDCl ): d
ꢀ
5
¯
110.5 mg, 0.5 mmol). The suspension was sonicated for
d ꢀ,308C). The resultant sticky mixture was puri®ed by
ash silica gel chromatography ꢀn-hexane: EtOAc, 4:1)
1
3
2
2
2
2
3
ꢀ
2
ppm): 210.5, 173.9, 70.8, 53.6, 52.3, 41.7, 29.9, 26.7,
1
4.4; anti: H NMR ꢀ300 MHz, CDCl ) d ꢀppm): 4.03
directly to provide pure product ꢀ2d) in excellent yield
88 mg, 95%). Oil. ꢀmixture of two isomers, 51:49). Rf
3
ꢀ
3
1H, dd, Jˆ3.2, 7.6 Hz, CHOH), 3.76 ꢀ3H, s, COOMe),
ꢀ
.16 ꢀ1H, d, Jˆ7.6 Hz, CHOH), 2.78±2.95 ꢀ1H, m,
C
2 2 2 2
0
.30 ꢀn-hexane:EtOAc, 2:1).
1
3
CHCO), 1.65±2.49ꢀ8H, m, COC H CH CH CH CH);
NMR ꢀ75 MHz, CDCl ): d ꢀppm): 211.2, 173.7, 69.0,
3
4.3.1. ,2a) 2-Hydroxy-4-oxo-4-phenyl-butyric acid
methyl ester. ꢀ61.4 mg, 59%). Oil. R 0.30 ꢀhexane:EtOAc,
2:1). H NMR ꢀ300 MHz, CDCl ) d ꢀppm): 7.97±7.45 ꢀ5H,
3
m, Ph), 4.71±4.66 ꢀ1H, m, CHOH), 3.81 ꢀ3H, s, OMe), 3.55
5
1
1
3.5, 52.3, 41.7, 27.0, 26.7, 24.5; FTIR ꢀneat) 1738.3,
704.3, 1234.2 cm ; MS ꢀEI) ꢀm/z, relative intensity):
86 ꢀ43), 127 ꢀ58), 81 ꢀ68), 43 ꢀ85), 29ꢀ100); HRMS ꢀEI)
f
2
1
1
calcd. for C H O 186.0892, found 186.0895.
4
ꢀ
1H, dd, Jˆ3.9, 17.6 Hz, COCH ), 3.46 ꢀ1H, dd, Jˆ5.8,
9
14
2
1
3
1
NMR ꢀ75 MHz, CDCl ): d ꢀppm): 197.5, 174.2, 136.2,
1
2
7.6 Hz, COCH ), 3.35 ꢀ1H, d, Jˆ5.8 Hz, CHOH);
C
2
4
.3.5. ,2e) 2-Hydroxy-3-methyl-4-oxo-pentanoic acid
methyl ester. Oil. ꢀmixture of two isomers, 66:34). R
f
3
33.5, 128.6, 128.1, 67.0, 52.5, 42.1; FTIR ꢀneat) 3439.9,
953.7, 1741.0, 1683.6, 1215.7 cm ; MS ꢀEI) ꢀm/z, relative
1
2
1
0.22 ꢀn-hexane:EtOAc, 2:1). H NMR ꢀ300 MHz, CDCl )
3
d ꢀppm): syn: 4.60 ꢀ1H, d, Jˆ3.5 Hz, CHOH), 3.80 ꢀ3H, s,
intensity): 208 ꢀ42), 176 ꢀ46), 105 ꢀ100), 43 ꢀ54), 29ꢀ3 9) ;
HRMS ꢀEI) calcd. for C H O 208.0736, found 208.0725.
COOMe), 2.80±3.07 ꢀ1H, m, CHCH ), 2.23 ꢀ3H, s,
3
1
1
12
4
1
3
CH CO), 1.14 ꢀ3H, d, Jˆ7.1 Hz, CHCH ); C NMR
3
3
4.3.2. ,2b) 2-Hydroxy-3-methyl-4-oxo-4-phenyl-butyric
acid methyl ester. ꢀ68.8 mg, 62%). Oil. ꢀmixture of two
ꢀ75 MHz, CDCl
3
): d ꢀppm): 209.3, 173.6, 70.8, 52.6, 49.8,
28.2, 10.3; anti: 4.49ꢀ1H, dd, Jˆ4.1, 6.1 Hz, CHOH), 3.77
ꢀ3H, s, COOMe), 2.80±3.07 ꢀ1H, m, CHCH ), 2.18 ꢀ3H, s,
CH
CO), 1.28 ꢀ3H, d, Jˆ7.3 Hz, CHCH
ꢀ75 MHz, CDCl ): d ꢀppm): 208.9, 173.6, 72.4, 52.4, 49.8,
28.7, 12.8; FTIR ꢀneat) 3446.0, 2955.8, 1740.2, 1711.5,
1
isomers, 39:61). R 0.42 ꢀhexane:EtOAc, 2:1). H NMR
f
3
1
3
ꢀ
300 MHz, CDCl ) d ꢀppm): syn: 7.90±7.97 ꢀ2H, m, Ph),
3
3
); C NMR
3
7
.56±7.62 ꢀ1H, m, Ph), 7.45±7.52 ꢀ2H, m, Ph), 4.62 ꢀ1H, t,
3
Jˆ4.5 Hz, CHOH), 3.89±4.02 ꢀ1H, m, COCHCH ), 3.80
3
2
1
ꢀ
3H, s, OMe), 3.26 ꢀ1H, d, Jˆ4.5 Hz, CHOH); 1.29ꢀ3H,
1224.3 cm ; MS ꢀEI) ꢀm/z, relative intensity): 113 ꢀ26),
57 ꢀ90), 43 ꢀ100), 29 ꢀ39); HRMS ꢀEI) calcd. for C
160.0735, found 160.0738.
1
3
d, Jˆ7.2 Hz, CHCH ); C NMR ꢀ75 MHz, CDCl ): d
H O
7 12 4
3
3
ꢀ
5
ꢀ
9
ppm): 201.8, 173.4, 135.5, 133.3, 128.6, 128.3, 71.6,
2.5, 44.2, 12.0; anti: 7.90±7.97 ꢀ2H, m, Ph), 7.56±7.62
1H, m, Ph), 7.45±7.52 ꢀ2H, m, Ph), 4.39ꢀ1H, dd, Jˆ4.5,
.2 Hz, CHOH), 3.89±4.02 ꢀ1H, m, COCHCH ), 3.70 ꢀ3H,
4.3.6. ,2f) 2-Hydroxy-3-oxo-hexanoic acid methyl ester.
Known compound.
1
3
3
s, OMe), 3.58 ꢀ1H, d, Jˆ9.2 Hz, CHOH); 1.37 ꢀ3H, d,
1
3
Jˆ7.2 Hz, CHCH ); C NMR ꢀ75 MHz, CDCl ): d
4.3.7. ,2g) Hydroxy-,1-methyl-2-oxo-cyclopentyl)-acetic
acid methyl ester. ꢀ42.8, 46%). Oil. ꢀmixture of two
3
3
ꢀ
ppm): 203.3, 173.5, 135.7, 133.44, 128.7, 128.3, 73.1,
1
5
1
2.3, 43.9, 14.3; FTIR ꢀneat) 3477.8, 2953.9, 1738.3,
681.5, 1215.8, 972.9, 704.6 cm ; MS ꢀEI) ꢀm/z, relative
isomers, 56:44). R
ꢀ300 MHz, CDCl
CHOH), 3.75 ꢀ3H, s, COOMe), 3.26 ꢀ1H, br, CHOH),
1.52±2.35 ꢀ6H, m, COCH CH CH CCH ), 1.13 ꢀ3H, s,
); C NMR ꢀ75 MHz, CDCl ): d ꢀppm): 220.6,
73.7, 74.5, 62.0, 52.3, 38.1, 32.5, 19.3, 18.6; anti: H
NMR ꢀ300 MHz, CDCl ) d ꢀppm): 4.20±4.30 ꢀ1H, m,
CHOH), 3.72 ꢀ3H, s, COOMe), 3.26 ꢀ1H, br, CHOH),
1.52±2.35 ꢀ6H, m, COCH CH CH CCH ), 1.05 ꢀ3H, s,
); C NMR ꢀ75 MHz, CDCl ): d ꢀppm): 220.5,
173.3, 74.1, 61.7, 51.6, 37.8, 30.6, 19.9, 18.6; FTIR ꢀneat)
f
0.27 ꢀn-hexane:EtOAc, 2:1). H NMR
2
1
) d ꢀppm): syn: 4.20±4.30 ꢀ1H, m,
3
intensity): 222 ꢀ16), 163 ꢀ53), 134 ꢀ58), 105 ꢀ100), 77 ꢀ87),
5
found 222.0906.
1 ꢀ74), 29ꢀ52); HRMS ꢀEI) calcd. for C 12H O 222.0892,
14
2
2
2
3
4
1
3
CHCH
1
3
3
1
4.3.3. ,2c) Hydroxy-,2-oxo-cyclopentyl)-acetic acid
methyl ester. ꢀ68.8 mg, 80%). Oil. ꢀmixture of two isomers,
3
1
2:48). R 0.27 ꢀn-hexane:EtOAc, 2:1). H NMR ꢀ300 MHz,
5
2
2
2
3
f
1
3
CDCl ) d ꢀppm): syn: 4.71 ꢀ1H, dd, Jˆ2.6, 5.0 Hz, CHOH),
CHCH
3
3
3
3
.79ꢀ3H, s, COO Me), 2.98 ꢀ1H, d, Jˆ5.0 Hz, CHOH), 2.55
2
1
ꢀ1H, dt, Jˆ2.0, 9.3 Hz, CHCO), 1.73±2.37 ꢀ6H, m,
COCH CH CH CH); C NMR ꢀ75 MHz, CDCl ): d
3478.6, 2965.0, 1738.1, 1215.0 cm ; MS ꢀEI) ꢀm/z, relative
intensity): 186 ꢀ2), 154 ꢀ18), 136 ꢀ43), 98 ꢀ57), 55 ꢀ98), 42
1
3
2
2
2
3
ꢀ
anti: H NMR ꢀ300 MHz, CDCl ) d ꢀppm): 4.32 ꢀ1H, t,
ppm): 218.0, 174.4, 68.6, 52.6, 51.8, 38.4, 22.3, 20.3;
ꢀ100); HRMS ꢀEI) calcd. for C
186.0896.
H O 186.0892, found
9 14 4
1
3
Jˆ4.0 Hz, CHOH), 3.81 ꢀ3H, s, COOMe), 3.18 ꢀ1H, d,
Jˆ4.0 Hz, CHOH), 2.70 ꢀ1H, dt, Jˆ3.4, 9.5 Hz, CHCO),
4.3.8. ,2h) 4-Cyclopenta-1ꢀ3-dienyl±2-hydroxy-4-oxo-
butyric acid 5-methyl-2-,1-methyl-1-phenyl-ethyl)-
1
3
1
ꢀ
.73±2.37 ꢀ6H, m, COCH CH CH CH);
C NMR
75 MHz, CDCl ): d ꢀppm): 217.9, 173.8, 69.5, 52.5, 51.6,
2
2
2
cyclohexyl ester. ꢀ99.5 mg, 50%). Oil. R
EtOAc, 4:1). ꢀmixture of two isomers, 73:27). H NMR
ꢀ300 MHz, CDCl ) d ꢀppm): major isomer: 7.57 ꢀ1H, d,
0.32 ꢀn-hexane:
3
f
1
3
1
8.3, 25.7, 20.5; FTIR ꢀneat) 3443.4, 2958.7, 1731.6,
224.6 cm ; MS ꢀEI) ꢀm/z, relative intensity): 172 ꢀ7),
2
1
3

4236
T.-P. Loh et al. / Tetrahedron 57 $2001) 4231±4236
Jˆ1.7 Hz, furan), 7.11±7.37 ꢀ6H, m, Ph& furan), 6.52±
HRMS ꢀEI) calcd. for C H O 408.2300, found
26 32 4
408.2302.
6
CHOH), 3.64±3.67 ꢀ1H, m, CHOCO), 2.90 ꢀ1H, dd,
.54 ꢀ1H, m, furan), 4.85 ꢀ1H, dt, Jˆ4.5, 10.8 Hz,
Jˆ3.8, 17.0 Hz, CH CHOH), 2.64 ꢀ1H, dd, Jˆ5.9,
2
Acknowledgements
1
7.0 Hz,
CH CHOH),
1.56±2.12
ꢀ8H,
m,
CHCH CH CHCH ), 1.29ꢀ3H, s, CC H ), 1.17 ꢀ3H, s,
2
2
2
2
3
1
3
We thank the National University of Singapore for ®nancial
support.
CCH ), 0.87 ꢀ3H, d, Jˆ6.3 Hz, CHCH ); C NMR
3
3
ꢀ
75 MHz, CDCl ): d ꢀppm): major isomer: 185.8, 172.9,
3
1
7
2
52.1, 146.5, 128.0, 125.5, 125.4, 125.2, 117.5, 112.3,
7.2, 66.5, 50.3, 41.6, 41.0, 34.6, 31.3, 29.7, 26.3, 22.8,
1.8; FTIR ꢀneat) 3487, 3023, 1736, 1687, 1248 cm ;
References
2
1
MS ꢀEI) ꢀm/z, relative intensity): 398 ꢀ0.1), 279 ꢀ47), 149
ꢀ
1. ꢀa) Nielsen, A. T.; Houlihan, W. J. Organic Reactions; John
Wiley & Sons: New York, 1968; Vol. 16, p 1. ꢀb) Healthcock,
C. H. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 1, p 133.
2. Nakagawa, M.; Nakao, H.; Watanabe, K. Chem. Lett. 1985,
391.
100), 57ꢀ92), 43 ꢀ91); HRMS ꢀEI) calcd. for C H O
24 30 5
3
98.2093, found 398.2081.
4
.3.9. ,2i) 2-Hydroxy-4-oxo-pentanoic acid 5-methyl-2-
,
4
1-methyl-1-phenyl-ethyl)-cyclohexyl ester. ꢀ72.7 mg,
2%). Oil. R 0.40 ꢀn-hexane:EtOAc, 4:1). ꢀmixture of
two isomers, 80:20). H NMR ꢀ300 MHz, CDCl ) d
3. Chow, H. F.; Seebach, D. Helv. Chim. Acta. 1986, 69, 604.
4. Evans, D. A.; Rieger, D. A.; Bilodeau, M. T.; Urpi, F. J. Am.
Chem. Soc. 1991, 113, 1047 and references cited therein..
5. Mahrwald, R. Chem. Ber. 1995, 128, 919. and references cited
therein. Mahrwald, R.; Gundogan, B. J. Am. Chem. Soc. 1998,
120, 413.
f
1
3
ꢀ
ppm): major isomer: 7.04±7.26 ꢀ5H, m, Ph), 4.76 ꢀ1H,
dt, Jˆ4.4, 10.8 Hz, CHOH), 3.39±3.43 ꢀ1H, m,
CHOCꢀvO)), 2.73 ꢀ1H, br, CHOH), 2.37 ꢀ1H, dd, Jˆ3.5,
1
CH CHOH), 1.98 ꢀ3H, s, CꢀvO)CH ), 1.35±1.86 ꢀ8H, m,
7.4 Hz, CH CHOH), 2.27 ꢀ1H, dd, Jˆ6.3, 17.4 Hz,
2
6. ꢀa) Loh, T. P.; Pei, J.; Lin, M. Chem. Commun. 1996, 2315.
ꢀb) Loh, T. P.; Pei, J.; Cao, G. Q. Chem. Commun. 1996, 1819.
ꢀc) Loh, T. P.; Wei, L. L. Tetrahedron Lett. 1998, 39, 323.
ꢀd) Loh, T. P.; Wei, L. L.; Feng, L. C. Synlett 1999, 07, 1059.
ꢀe) Babu, B.; Perumal, P. T. Tetrahedron Lett. 1998, 39, 3225.
ꢀf) Ranu, B. C.; Jana, U. J. Org Chem. 1998, 63, 8212.
ꢀg) Miyai, T.; Onishi, Y.; Baba, A. Tetrahedron Lett. 1998,
39, 6291. ꢀh) Hirashita, T.; Kamei, T.; Horie, T.; Yamamura,
H.; Kawai, M.; Araki, S. J. Org. Chem. 1999, 64, 172.
ꢀi) Sengupta, S.; Mondal, S. Tetrahedron Lett. 1999, 40,
2
3
CHCH CH CHCH ), 1.21 ꢀ3H, s, CCH ), 1.10 ꢀ3H, s,
2
2
2
3
1
3
CCH ), 0.81 ꢀ3H, d, Jˆ6.6 Hz, CHCH ); C NMR
3
3
ꢀ
75 MHz, CDCl ): d ꢀppm): major isomer: 205.5, 172.9,
3
1
3
3
52.2, 127.9, 125.3, 125.1, 76.0, 66.4, 50.3, 46.4, 41.1,
9.3, 34.5, 31.2, 30.1, 29.6, 26.2, 22.5, 21.7; FTIR ꢀneat)
475, 3017, 1736, 1718, 1217 cm ; MS ꢀEI) ꢀm/z, relative
2
1
intensity): 346 ꢀ0.8), 251 ꢀ47), 214 ꢀ56), 199 ꢀ33), 119 ꢀ95),
91 ꢀ77), 43 ꢀ100); HRMS ꢀEI) calcd. for C H O 346.2144,
21 30 4
found 346.2145.
8
685. ꢀj) Inoue, K.; Yasuda, M.; Shibata, I.; Babe, A.
4
.3.10. ,2j) 2-Hydroxy-4-oxo-4-phenyl-butyric acid 5-
methyl-2-,1-methyl-1-phenyl-ethyl)-cyclohexyl ester.
110.2 mg, 54%). Oil. R 0.37 ꢀn-hexane:EtOAc, 4:1).
Tetrahedron Lett. 2000, 41, 113. ꢀk) Ranu, B. C.; Hajra, A.;
Jana, U. Org Lett. 1999, 1, 1141. ꢀl) Ranu, B. C.; Hara, A.;
Jana, U. Tetrahedron Lett. 2000, 41, 531.
ꢀ
ꢀ
f
1
mixture of two isomers, 87:13). H NMR ꢀ300 MHz,
7. For review: Coppola, G. M., Schuster, H. F. In a-hydroxy
Acids in Enantioselective Synthesis; VCH: Germany; 1997.
8. Bianchi, M.; Butti, A.; Christidis, Y.; Perronnet, J.; Barzaghi,
F.; Cesana; Nencioni, A. Eu. J. Med. Chem. 1988, 23, 45.
9. ꢀa) Kurath, P.; Cole, W. J. Org. Chem. 1961, 26, 4592.
ꢀb) Debono, M.; Molloy, R. M.; Patterson, L. E. J. Org.
Chem. 1968, 34, 3033 and references cited therein.
10. Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem.
1982, 13, 1.
CDCl ) d ꢀppm): major isomer: 7.75 ꢀ2H, d, Jˆ1.4 Hz,
3
PhCꢀvO)), 7.47±7.53 ꢀ3H, m, PhCꢀvO)), 7.04±7.26
ꢀ5H, m, PhCꢀCH ) ), 4.77 ꢀ1H, dt, Jˆ4.3, 10.8 Hz,
CHOH), 3.60±3.62 ꢀ1H, m, CHOCꢀvO)), 2.73 ꢀ1H, br,
3
2
CHOH), 2.94 ꢀ1H, dd, Jˆ3.7, 17.4 Hz, CH CHOH), 2.65
2
ꢀ
CHCH CH CHCH ), 1.22 ꢀ3H, s, CCH ), 1.09ꢀ3H, s,
1H, dd, Jˆ5.7, 17.4 Hz, CH CHOH), 1.36±2.03 ꢀ8H, m,
2
2
2
2
3
1
3
CCH ), 0.79ꢀ3H, d, Jˆ6.6 Hz, CHCH ); C NMR
3
3
ꢀ
75 MHz, CDCl ): d ꢀppm): major isomer: 197.0, 173.0,
3
11. Kelly, T. R.; Schmidt, J. D.; Haggerty, J. K. Synthesis 1972,
554.
1
7
2
1
2
52.2, 136.5, 133.3, 128.5, 128.0, 127.9, 125.1, 125.0,
6.0, 66.5, 50.2, 41.6, 40.9, 39.2, 34.4, 31.1, 29.9, 26.1,
2.3, 21.6; FTIR ꢀneat) 3493, 3060, 1736, 1687,
223 cm ; MS ꢀEI) ꢀm/z, relative intensity): 408 ꢀ0.1),
72 ꢀ24), 214 ꢀ50), 159ꢀ36), 105 ꢀ100), 41 ꢀ54), 43 ꢀ100);
12. Whitesell, J. K.; Bhattacharya, A.; Buchanan, C. M.; Chen,
H. H. et al. Tetrahedron 1986, 11, 2993.
2
1
13. Punniyamurthy, T.; Bhatia, B.; Iqbal J. Org. Chem. 1994, 59,
850±853.