L-Proline catalysed asymmetric aldol reactions in PEG-400 as recyclable medium and transfer aldol reactions

Article abstract of DOI:10.1016/j.tet.2005.09.122

L-Proline-catalysed direct asymmetric aldol reaction of acetone with various aldehydes in PEG-400 is described. Recycling of the catalyst and solvent (PEG) was possible up to ten runs without loss of catalyst activity. l-Proline was also found to be an efficient catalyst for the asymmetric transfer aldol reaction between various aldehydes and diacetone alcohol for the first time. Good yields and enantioselectivities were observed with both methods.

Full text of DOI:10.1016/j.tet.2005.09.122

Tetrahedron 62 (2006) 338–345
L-Proline catalysed asymmetric aldol reactions in PEG-400 as
recyclable medium and transfer aldol reactions
S. Chandrasekhar,
*
N. Ramakrishna Reddy, S. Shameem Sultana, Ch. Narsihmulu
and K. Venkatram Reddy
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 31 May 2005; revised 8 September 2005; accepted 16 September 2005
Available online 25 October 2005
Abstract—L-Proline-catalysed direct asymmetric aldol reaction of acetone with various aldehydes in PEG-400 is described. Recycling of the
catalyst and solvent (PEG) was possible up to ten runs without loss of catalyst activity. L-Proline was also found to be an efficient catalyst for
the asymmetric transfer aldol reaction between various aldehydes and diacetone alcohol for the first time. Good yields and
enantioselectivities were observed with both methods.
q 2005 Elsevier Ltd. All rights reserved.
1
3
1
. Introduction
Cordova using organometallic or purely organic catalysts.
Recent work has been attempted by using a recyclable ionic
liquid as the solvent, buffered aqueous media, Zn-
1
4
15
In general, most of the methodologies, which are available
1
,2
16
for the asymmetric aldol reactions fall into one of the
following categories: (a) the chiral auxiliary assisted aldol
reactions based on the use of stoichiometric quantities of
proline complexes in aqueous media or aqueous micelles.
Organocatalysis is the acceleration of chemical reactions
with a substoichiometric amount of an organic compound,
which does not contain a metal atom. The application of
enantiomerically pure ‘small’ organic molecules represents
a promising alternative catalytic concept in addition to other
frequently used syntheses based on metal containing
3
chiral appendage; (b) chiral Lewis acid-catalysed
Mukaiyama type and chiral Lewis-base catalysed aldol
4
reactions; (c) heterobimetallic bifunctional Lewis acid/
5
Bronsted base-catalysed direct aldol reactions ; and
(
d) aldol reactions catalysed by aldolase enzymes and
6
17
antibodies. A significant characteristic of the later two
methodologies is the employment of unmodified carbonyl
compounds as aldol donor substrates, whereas the first two
methodologies require some degree of preactivation of the
substrates involved.
catalysts. Some new direct asymmetric intermolecular
reactions such as Mannich, Michael and other analogous
1
8
19
2
reactions have been reported by Barbas III, and others
0
2
1
using proline as catalyst.
Asymmetric versions of the aldol reaction rely upon the use
of chiral auxiliaries, however, it must be noted that there has
been some success of using asymmetric catalysts, although
they normally rely on a Mukaiyama type process.
2
. Results and discussion
It is always economical if the catalytic reaction is performed
in an ecofriendly solvent, which allows both solvent and
catalyst to recycle. Poly(ethylene glycol) (PEG) is non-toxic
and used as a rapid and recyclable reaction medium for the
The development of catalytic and enantioselective C– bond
forming reactions is currently among the prime objectives in
organic synthesis. Direct catalytic and enantioselective
aldol reactions of unmodified ketones or aldehydes were
2
2
23
Heck reaction, asymmetric dihydroxylation and Baylis–
2
4
Hillman reactions. In continuation of this work, an
efficient synthesis of chiral b-hydroxy ketones from various
aldehydes and acetone in poly (ethylene glycol)-400
7
8
reported by the research groups of Shibasaki, Trost,
10
9
Jorgensen, MacMillan,
11
12
List,
Barbas III
and
2
5
catalysed by L-proline has been developed (Scheme 1).
Keywords: L-Proline; PEG-400; Aldol reaction; Transfer aldol reaction.
*
Several groups studied the mechanism of L-proline
catalysed direct asymmetric aldol reaction and proposed
Corresponding author. Tel.: C91 40 27193434; fax: C91 40 27160512;
e-mail: srivaric@iict.res.in
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.122

S. Chandrasekhar et al. / Tetrahedron 62 (2006) 338–345
339
an enamine mechanism based on the Hajos–Parrish–Eder–
2
Sauer–Wiechert reaction mechanism.
6
We were particularly interested in developing an eco-
friendly approach for the direct aldol reaction using PEG as
a solvent for the following reasons.
Scheme 1.
2
7
(a) PEG is biologically compatible.
Table 1. L-Proline catalysed asymmetric aldol reactions in PEG-400
a
Entry
1
Substrate
Time (min)
30
Product
Yield (%)
94
ee (%)
b
67
1
2
a
a
1
2
b
b
b
2
3
30
30
90
88
64
b
70
3
4
a
a
3
4
b
b
b
4
5
30
30
58
85
58
b
65
5
6
a
a
5
6
b
b
b
6
7
30
30
90
88
61
c
60
7
8
a
a
7
8
b
b
c
8
9
120
180
90
65
84
c
71
9a
9
b
a
Isolated yields after column chromatography; the products were characterised by spectral data.
ee% by chiral HPLC.
ee% by optical rotation.
b
c

340
S. Chandrasekhar et al. / Tetrahedron 62 (2006) 338–345
(
b) The polymer is available at a very low affordable price
[ionic liquid cost 1200 – 2400 USD/kg, as against
PEG-400, which cost 43 USD/kg].
c) Requires only a low concentration of catalyst.
d) Highly practical and a simple work-up procedure.
stirring for 30 min resulted in the formation of the aldol
product 1b in 93% yield with similar enantioselectivity.
Except for the third run, which showed a slight increase in
enantioselectivity (71%), all the runs were similar in
product yields and enantioselectivities. The efficient
recycling was then proved by additional experiments until
the tenth run (Table 2).
(
(
First we initiated our study by using 4-nitrobezaldehyde
entry 1, Table 1), acetone and L-proline (10 mol %) in
(
PEG-400. The reaction was completed in 30 min and
yielded 94% of product 1b with 67% ee. Enantiomeric
excess was determined using chiralcel OB-H column. After
workup (extraction with ether) mother liquor (PEGC
proline) was kept aside for further runs. The transformation
in conventional solvent (DMSO) took 4 h for completion of
the reaction.
2.1. L-Proline catalysed asymmetric transfer aldol
reaction
To further expand the scope of the L-proline catalysed C–
bond forming reaction, we sought to apply this amine
catalysed enamine generation to asymmetric transfer aldol
reaction. The addition of nucleophiles to carbonyl com-
pounds has been under investigation for decades. Examples
include the addition of enolates to aldehydes and
the Meerwein–Ponndorf–Verley reduction of ketones
2
-Nitrobenzaldehyde and 3-nitrobenzaldehydes (entries 2
and 3, Table 1) were reacted with acetone to give the aldol
products 2b and 3b in good yields and enantioselectivities.
Aldol reaction between simple benzaldehyde (entry 4,
Table 1) and acetone afforded the product 4b in 58% yield
and 58% ee. The 4-bromobenzaldehyde, 2-chloro-5-nitro-
benzaldehyde and 2-chlorobenzaldehyde (entries 5, 6 and 7,
Table 1) underwent the aldol reaction smoothly giving the
products 5b, 6b and 7b in 85, 90 and 88% yields with 65, 61
and 60% ee’s, respectively.
(hydride as a nucleophile). Recent achievements in this
area are: alkynyl transfer reactions, allyl transfer
2
8
2
reaction (as proposed to occur by a stepwise ionic
9
3
0
mechanism) and cyanide transfer reactions.
This concept of transfer aldol reaction has originated from
above mentioned reactions. Aldol and retro aldol reactions
are catalysed by either acid or base. The reversibility of the
aldol reaction, that is, equilibrium between aldol and
carbonyl compounds is one of the most important
The aliphatic aldehydes, isobutyraldehyde and cyclohexane
carboxaldehyde (entries 8 and 9, Table 1) have also proved
to be efficient by producing the products 8b and 9b in 90 and
3
1
characteristics of the aldol reaction. The retro aldol
reaction has been recently found to have several new
applications, for instance antibodies and enzymes have been
found to catalyse retro aldol reactions allowing efficient
kinetic resolution of racemic aldols. The retro aldol reaction
has been utilised for the synthesis of bicyclo-[2.2.1]-heptane
and cyclopentane derivatives, which in turn have been
employed in the synthesis of a variety of diterpenoids,
sesquiterpenes, biaryl compounds and bicyclo-[4.3.0]-
6
5% yields, respectively. The optical purity of the products
was determined by their optical rotation (compared with the
literature value). High enantioselectivity of 84% ee was
obtained for the reaction of isobutyraldehyde with acetone
in PEG.
We found L-proline to be an efficient catalyst for the direct
asymmetric aldol reaction of acetone with aromatic and
aliphatic aldehydes in PEG. Enantioselectivities depend on
the aldehyde component and are typically in the seventies
with aromatic aldehydes and in the eighties with aliphatic
a-branched aldehydes.
3
2
nonane derivatives.
Transfer aldol reaction involving diacetone alcohol as a
source of ketone (acetone) is studied with several alkoxides,
in these reactions Aldol–Tischenko reaction is competitive
to get mono protected 1,3-diols and in few cases normal
We have studied the reusability of the catalyst as well as the
solvent. A second run was performed without any
modification. The simple addition of 4-nitrobenzaldehyde
3
3
aldol products were observed.
We initiated this study to explore L-proline as a mild
organocatalyst for asymmetric transfer aldol reaction
(
entry 1, Table 2) and acetone to the mother liquor with
3
4
Table 2. L-Proline catalysed asymmetric aldol reactions in PEG
between diacetone alcohol and various aldehydes.
Interestingly the present procedure not only allowed
to achieve condensation with good selectivity but also
was mild enough to avoid Tischenko–Aldol product A
a
b
Entry
1
Substrate
Time (min) Yield (%)
ee (%)
67
30
94
(Scheme 2) in Lewis acid catalysed transfer aldol
reactions.
2
3
4
5
6
7
8
9
2nd run
3rd run
4th run
5th run
6th run
7th run
8th run
9th run
10th run
30
30
30
30
30
30
30
30
30
93
90
89
90
88
87
88
86
84
68
71
67
66
64
67
65
67
66
First we examined the transfer aldol reaction between
4
-nitrobenzaldehyde (entry 1, Table 3) and diacetone
alcohol in the presence of L-proline (30 mol%) in
DMSO to afford the corresponding b-hydroxy ketone
1b in 86% yield and 71% ee. Even after increasing the
catalyst concentration (100 mol%), there was no differ-
ence in yields and ee’s (entry 2, Table 3). This reaction
was also attempted in PEG-400 as solvent, however,
1
0
a
Isolated yields after chromatography.
ee% by chiral HPLC.
b

S. Chandrasekhar et al. / Tetrahedron 62 (2006) 338–345
341
Since, in principle aldol reactions are reversible, another
question to be addressed in this context is whether the
optical purity varies as a function of time. This is an
important feature to be determined and we found that
the ee of the aldol product in our model reaction (entry
1
) does not vary significantly (eeZ71%) when
monitored at different intervals (4, 8, 12 and 24 h),
however, the formation of dehydrated aldol conden-
sation product was observed after 8 h. In the case of
aliphatic aldehydes having a-hydrogens (phenyl propa-
nol), we have observed that the self-aldolisation of
aldehyde was competitive.
Scheme 2.
product yield and ee were lower compared to the
standard solvent.
3
. Conclusion
There is no direct evidence for the mechanism by which the
reaction proceeds. However, we believe a cyclic transition
state (re-facial attack of aldehyde to proline derivative)
where a retro aldol and aldol reactions are initiated by the
same catalyst (Scheme 3).
In summary, poly(ethylene glycol) (PEG) has been
shown to be a rapid and reusable reaction medium for
L-proline- catalysed asymmetric aldol reaction. The
reusability of this solvent was studied over ten runs
without loss of activity of either the catalyst or the
solvent and we have also developed the first asymmetric
transfer aldol reaction catalysed by L-proline. In this
reaction no Aldol–Tischenko product was observed in
contrast to other reported methods.
Similarly various other aldehydes such as 3-nitrobenz-
aldehyde, 4-bromobenzaldehyde, 2-chloro-5-nitrobenz-
aldehyde and 2-chlorobenzaldehyde (entries 3, 5, 6
and 7, Table 3) were subjected to this transformation
and observed the yields of aldol products up to 88%
and ee’s up to 71%.
Transfer aldol reaction between simple benzaldehyde (entry
4. Experimental
4
5
1
1
, Table 3) and diacetone alcohol gave the product 4b in
0% yield and 57% ee. In the case of anisaldehyde (entry
0, Table 3)(electron rich benzaldehyde) the aldol product
0b was observed only after 5 days stirring at room
4
.1. General
All solvents and reagents were purified by standard
techniques. Crude products were purified by column
chromatography on silica gel of 60–120 meshes. IR spectra
were recorded on Perkin-Elmer 683 spectrometer. Optical
rotations were obtained on Jasco Dip 360 digital polari-
meter. H NMR and C NMR spectra were recorded in
CDCl solvent on a Varian Gemini 200, Bruker 300 or
Varian Unity 400 NMR spectrometers. Chemical shifts
were reported in ppm with respect to internal TMS.
temperature with 48% ee and 40% yield along with the
dehydrated aldol condensation product.
Aliphatic aldehydes (entries 8 and 9, Table 3) were also
good substrates for this reaction, wherein isobutyraldehyde
provided aldol product 8b in 80% yield and 84% ee and
cyclohexane carboxaldehyde furnished 9b in 91% yield
with 86% ee.
1
13
3
Scheme 3.

342
S. Chandrasekhar et al. / Tetrahedron 62 (2006) 338–345
Table 3. L-Proline catalysed asymmetric transfer aldol reaction
a
Yield (%)
Entry
1
Substrate
Time (min)
4
Product
ee (%)
b
71
86
85
88
1
1
a
a
1
1
b
b
b,c
72
2
3
4
6
b
70
3
4
a
a
3
4
b
b
b
4
5
12
12
50
65
57
d
71
5
6
a
a
5
6
b
b
b
6
7
6
8
82
70
60
d
60
7
8
a
a
7
8
b
b
d
8
9
12
12
80
91
84
d
86
9
1
a
9
b
b
48
10
120
40
0a
1
0b
a
b
c
d
Isolated yields after column chromatography; the products were characterised by spectral data.
ee% by chiral HPLC.
L-Proline used 100 mol%.
ee% by optical rotation.

S. Chandrasekhar et al. / Tetrahedron 62 (2006) 338–345
343
Coupling constants (J) are quoted in Hz. Mass spectra were
obtained on Finnegan MAT 1020B or micro mass VG 70-
15:85) UV 262 nm, flow rate 1.0 mL/min; major isomer, tR
12.72 min and minor isomer, t 11.82 min.
R
7
0H spectrometer operating at 70 eV using direct inlet
0
(3b). Yellow viscous oil, H NMR (300 MHz, CDCl ): d
system. HPLC was recorded on SHIMADZU HPLC using
chiralcel OB-H column, hexane and isopropyl alcohol as
eluents.
4.3.3. (4R)-Hydroxy-4-(3 -nitrophenyl)-butan-2-one
2
1
1
3
8.24 (s, 1H. Ar-H), 8.13 (d, JZ8.6 Hz, 1H, Ar-H), 7.71 (d,
JZ7.5 Hz, 1H, Ar-H), 7.53 (t, JZ7.5 Hz, 1H, Ar-H), 5.27–
5.15 (m, 1H, –CHOH), 3.50 (br s, 1H, –OH), 2.82 (d, JZ
12.0 Hz, 2H, –CH CO), 2.23 (s, 3H, –COCH ); Mass (EI):
4.2. General procedure for the aldol reaction:
procedure A
2
3
C
m/z 209 (M ), 43; IR (neat): 3414, 2931, 1715, 1519,
K1
25
To a stirred solution of L-proline (10 mol%) in PEG (2 mL)
was added acetone (4 mmol) at room temperature under
inert atmosphere. After being stirred this mixture for 5 min,
aldehyde (1 mmol) was added and allowed to stir for
1370 cm ; [a] C49.9 (c 1.2, CHCl ) for 70% ee.
D 3
Enantiomeric excess: 70% by procedure A and B, which
was determined by HPLC analysis using chiralcel OB-H
column (isopropyl alcohol/hexane 15:85) UV 262 nm, flow
rate 1.0 mL/min; major isomer, tR 31.55 min and minor
3
0 min. The reaction medium was diluted with anhydrous
ether (5 mL), stirred for 5 min, allowed to separate out and
the ether layer was decanted. This process was repeated
twice to obtain the product in ether where as the mother
liquor (PEGCproline) was kept aside for further runs. This
process was repeated up to ten runs without loss of the
activity of the catalyst. Solvent was removed under vacuo
and purified by silica gel column chromatography to give
the pure product.
isomer, t 36.58 min.
R
3
5,21
4.3.4. (4R)-Hydroxy-4-phenyl-butan-2-one (4b).
Colourless oil, H NMR (200 MHz, CDCl ): d 7.33–7.17
1
3
(m, 5H, Ar-H), 5.15–5.04 (m, 1H, –CHOH), 3.17 (br s, 1H,
–OH), 2.80–2.75 (m, 2H, –CH CO), 2.17 (s, 3H, –COCH );
Mass (EI): m/z 164 (M ), 43; IR (neat): 3413, 2932, 1718,
2
3
C
K1
25
D
1450, 890 cm ; [a] C60.0 (c 1, CHCl ) for 83% ee [lit.
3
value]. Enantiomeric excess: 58% by procedure A and 57%
by procedure B, which was determined by optical rotation
(compared with the literature value).
4.3. General procedure for transfer aldol reaction:
procedure B
0
(5b). Colorless oil, H NMR (300 MHz, CDCl ): d 7.47
To a stirred solution of L-proline (30 mol%) in DMSO was
added diacetone alcohol (4 mmol) at room temperature
under inert atmosphere. After being stirred for 5 min
aldehyde (2 mmol) was added, and allowed to stir for 4 h.
After completion of the reaction (monitored by TLC), water
was added and extracted with ethyl acetate twice (2!
4.3.5. (4R)-Hydroxy-4-(4 -bromophenyl)-butan-2-one
2
1
1
3
(d, JZ8.4 Hz, 2H, Ar-H), 7.22 (d, JZ8.4 Hz, 2H, Ar-H),
5.08 (dd, JZ5.6, 7.8 Hz, 1H, –CHOH), 3.38 (br s, 1H,
–OH), 2.80–2.70 (m, 2H, –CH CO), 2.20 (s, 3H, –COCH );
2
3
C
Mass (EI): m/z 243 (M ), 43; IR (neat): 3418, 2934, 1713,
1489, 1369, 1077, 538 cm ; [a] C53.3 (c 1, CHCl ) for
D 3
K1
25
2
0 mL). The combined organic layers were washed with
brine, dried over anhydrous sodium sulphate. Solvent was
removed under vacuo and purified by silica gel column
chromatography to afford the pure product.
90% ee [lit. value]. Enantiomeric excess: 65% by procedure
A and 71% by procedure B, which was determined by
optical rotation (compared with the literature value).
0
1b). Pale brown viscous oil, H NMR (300 MHz,
0
2-one (6b). Colourless viscous oil, H NMR (200 MHz,
0
4
(
.3.1. (4R)-Hydroxy-4-(4 -nitrophenyl)-butan-2-one
4.3.6. (4R)-Hydroxy-4-(2 -chloro-5 -nitrophenyl)-butan-
2
1
1
1
CDCl ): d 8.20 (d, JZ7.0 Hz, 2H, Ar-H), 7.52 (d, JZ
CDCl ): d 8.66 (s, 1H, Ar-H), 8.10 (dd, JZ1.7, 8.8 Hz, 1H,
3
3
7
–
.0 Hz, 2H, Ar-H), 5.30–5.20(m, 1H, –CHOH), 3.56(brs, 1H,
OH), 2.85–2.80 (m, 2H, –CH CO), 2.21 (s, 3H, -COCH );
Ar-H), 7.44 (d, JZ9.6 Hz, 1H, Ar-H), 5.43 (d, JZ12.0 Hz,
1H, –CHOH), 3.65 (s, 1H, –OH), 3.02 (dd, JZ4.1, 12.5 Hz,
1H, –CH CO), 2.61 (dd, JZ8.3, 16.6 Hz, 1H, –CH CO),
2
3
C
Mass (EI): m/z 209 (M ), 43; IR (neat): 3419, 2930, 1716,
1
2
2
K1
514, 1480, 1370 cm ; [a] C44.3 (c 1, CHCl ) for 67%
25
D
13
2.24 (s, 3H, –COCH3); C NMR (75 MHz, CDCl ): 208.3,
147.1, 142.3, 137.6, 130.2, 123.2, 122.7, 66.1, 49.3, 30.4;
Mass (EI): m/z 243 (M ), 183, 43; HRMS calcd for
3
3
ee. Enantiomeric excess: 67% by procedure A and 71% by
procedure B, which was determined by HPLC analysis
using chiralcel OB-H column (isopropyl alcohol/hexane
C
C
C H ClNO (M ) 243.0928, found 243.0898; IR (KBr):
1
0
10
4
K1
3414, 2932, 1718, 1517, 1373, 1167, 1069 cm ; [a] C
25
D
15:85) UV 262 nm, flow rate 1.0 mL/min; major isomer, tR
28.49 min and minor isomer, t 34.20 min.
84.45 (c 0.5, CHCl ) for 64% ee. Enantiomeric excess: 64%
3
R
by procedure A and 60% by procedure B, which was
determined by HPLC analysis using chiralcel OB-H column
(isopropyl alcohol/hexane 15:85) UV 262 nm, flow rate
0
2b). Pale brown viscous oil, H NMR (300 MHz,
4
(
.3.2. (4R)-Hydroxy-4-(2 -nitrophenyl)-butan-2-one
1
4
1
CDCl ): d 7.96 (dd, JZ1.2, 8.1 Hz, 1H, Ar-H), 7.91 (dd,
JZ1.2, 8.1 Hz, 1H, Ar-H), 7.71 (dt, JZ1.2, 8.1 Hz, 1H, Ar-
H), 7.44 (dt, JZ1.2, 8.1 Hz, 1H, Ar-H), 5.70 (d, JZ9.3 Hz,
1.0 mL/min; major isomer, t
11.82 min.
12.72 min and minor isomer,
R
3
t
R
0
4.3.7. (4R)-Hydroxy-4-(2 -chlorophenyl)-butan-2-one
(7b). Colourless oil, H NMR (300 MHz, CDCl ): d
1
1
2
H, –CHOH), 3.76–3.70 (m, 1H, –OH), 3.15 (dd, JZ2.1,
2
1
1
7.7 Hz, 1H, CH CO), 2.70 (dd, JZ9.6, 18 Hz, 1H, –CH CO),
2
2
3
C
.24 (s, 3H, –COCH ); Mass (EI): m/z 209 (M ), 43; IR
7.60 (d, JZ8.6 Hz, 1H, Ar-H), 7.34–7.14 (m, 3H, Ar-H),
5.46 (d, JZ10.4 Hz, 1H, –CHOH), 3.58 (s, 1H, –OH), 3.05–
2.90 (m, 1H, –CH CO), 2.73–2.53 (m, 1H, –CH CO), 2.22
3
K1
25
(
(
neat): 3416, 2934, 1719, 1512, 1376 cm ; [a] K109.2
c 1, CHCl ) for 64% ee. Enantiomeric excess: 64% by
D
3
2
2
C
procedure A, which was determined by HPLC analysis
using chiralcel OB-H column (isopropyl alcohol/hexane
(s, 3H, –COCH ); Mass (EI): m/z 198 (M ), 43; IR (neat):
3
K1
3410, 2930, 1712, 1440, 840 cm ; [a] C97.0 (c 1,
25
D

344
S. Chandrasekhar et al. / Tetrahedron 62 (2006) 338–345
CHCl ) for 85% ee [lit. value]. Enantiomeric excess: 60%
3
by procedure A and procedure B, which was determined by
optical rotation (compared with the literature value).
1982; Vol. 13, pp 1–116. (b) Heathcock, C. H. In The Aldol
Addition Reaction; Morrison, J. D., Ed.; Asymmetric
Synthesis; Academic: New York, 1984; Vol. 3, Chapter 2,
pp 111–212. (c) Bennani, Y. L.; Hanessian, S. Chem. Rev.
1997, 3161. (d) Enders, D.; Wortmann, L.; Peters, R. Acc.
Chem. Res. 2000, 33, 157.
2
.3.8. (4R)-Hydroxy-5-methyl-hexan-2-one (8b). Col-
1
4
ourless oil, H NMR (200 MHz, CDCl ): d 3.85–3.75 (m,
1
3
1
–
H, –CHOH); 2.90 (br s, 1H, –OH), 2.58–2.50 (m, 2H,
CH CO), 2.20 (s, 3H, –CO CH ), 1.76–1.58 (m, 1H,
4. (a) For reviews see: Carreira, E. M. Mukayama Aldol Reaction
In Comprehensive Asymmetric Catalysis. (b) Jacobsen, E. N.;
Pfaltz, A.; Yamamoto, H.; Springer-Verlag: Heidelberg, 1999,
Vol. 3, chapter 29.1. (c) Groger, H.; Vogl, E. M.; Shibasaki, M.
Chem. Eur. J. 1998, 4, 1137. (d) Nelson, S. G. Tetrahedron:
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Matsukawa, S.; Okano, N.; Imamoto, T. Tetrahedron Lett.
2
3
(
CH ) CH), 1.00–0.85 (m, 6H, –CH(CH ) ); IR (neat):
3 2
3 2
25
K1
3
CHCl ) for 99% ee [lit. value]. Enantiomeric excess: 84%
by procedure A and 84% by procedure B, which was
determined by optical rotation (compared with the literature
value).
410, 2929, 1710, 1350, 702 cm ; [a] C75.5 (c 1.2,
D
3
2
000, 41, 103.
2
1
4
Colourless oil, H NMR (300 MHz, CDCl ): d 3.83–3.76
.3.9. (4R)-4-(Cyclohexyl)-4-hydroxy-2-butanone (9b).
5. Yoshikawa, N.; Yamada, M. A. Y.; Das, J.; Sasai, H.;
Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168 and
references cited therein.
1
3
(
(
m, 1H, –CHOH), 2.60–2.50 (m, 2H, –CH CO), 2.40–2.25
2
m, 1H, –OH), 2.18 (s, 3H, –COCH ), 1.77–1.62 (m, 5H,
3
6. Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am.
Chem. Soc. 2001, 123, 5260 and references cited therein.
7. (a) Yoshikawa, N.; Kumagai, N.; Matsunaga, S.; Moll, G.;
Ohshima, T.; Suzuki, T.; Shibasaki, M. J. Am. Chem. Soc.
2001, 123, 2466. (b) Yamada, M. A. Y.; Shibasaki, M.
Tetrahedron Lett. 1998, 39, 5561.
–
(
CH CH CHCH CH ), 1.25–0.97 (m, 6H, –(CH ) ); Mass
2 2 2 2 2 3
C
EI): m/z 169 (M K1), 87, 43; IR (neat): 3419, 2930,
K1
25
1
715, 1450, 1364, 1165 cm ; [a] C45.9 (c 1.2, CHCl )
D 3
for 97% ee [lit. value]. Enantiomeric excess: 71% by
procedure A and 86% by procedure B, which was
determined by optical rotation (compared with the
literature value).
8
. Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003.
. Bogevig, A.; Kumaragurubaran, N.; Jorgensen, K. A. Chem.
Commun. 2002, 620.
9
0
10b). Colorless oil, H NMR (300 MHz, CDCl ): d 7.27
4
(
.3.10. (4R)-Hydroxy-4-(4 -methoxyphenyl)-butan-2-one
10. Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002,
124, 6798.
3
5
1
3
(
d, JZ8.8 Hz, 2H, Ar-H), 6.88 (d, JZ8.8 Hz, 2H, Ar-H),
1
1. List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc.
000, 122, 2395.
5
–
–
(
1
.10 (dd, JZ9.0, 3.3 Hz, 1H, –CHOH), 3.80 (s, 3H,
OCH ), 3.22 (br s, 1H, –OH), 2.86–2.78 (m, 2H,
CH CO), 2.19 (s, 3H, –COCH ); Mass (EI): m/z 194
2
3
12. Cordova, A.; Notz, W.; Barbas, C. F., III. J. Org. Chem. 2002,
67, 301.
2
3
C
M ), 43; IR (neat): 3424, 2917, 1730, 1450, 1100,
13. Cordova, A. Tetrahedron Lett. 2004, 45, 3949.
14. Kotrusz, P.; Kmentova, I.; Gotov, B.; Toma, S.; Solcaniova, E.
K1
25
070 cm ; [a] C38.5 (c 0.7, CHCl ) for 48% ee.
D 3
Enantiomeric excess: 48% by procedure B, which was
determined by HPLC analysis using chiralcel OB-H column
Chem. Commun. 2002, 2510.
5. (a) Cordova, A.; Notz, W.; Barbas, C. F., III. Chem. Commun.
1
(
isopropyl alcohol/hexane 15:85).
2
2
002, 3024. (b) Nyberg, A. I.; Usano, A.; Pihko, P. M. Synlett
004, 1891. (c) Hartikka, A.; Arvidsson, P. I. Tetrahedron:
Asymmetry 2004, 15, 1831. (d) Peng, Y.-Y.; Ding, Q. P.; Li, Z.;
Wang, P. G.; Cheng, J.-P. Tetrahedron Lett. 2003, 44, 3871.
Acknowledgements
(
e) Hayashi, Y.; Tsuboi, W.; Shoji, M.; Suzuki, N.
Three of us (N.R.R., S.S.S. and C.N.) thank CSIR New
Delhi for financial support. IICT Communication no.
Tetrahedron Lett. 2004, 45, 4353. (f) Wu, Y.; Shao, W.;
Zheng, C.; Huang, Z.; Cai, J.; Deng, Q. Helv. Chim. Acta 2004,
0
50704
8
7, 1377.
1
6. Darbre, T.; Machuqueiro, M. Chem. Commun. 2003, 1090.
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1
5
29. (b) List, B. Synlett 2001, 1675. (c) Jarvo, E. R.; Miller,
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