A novel method for asymmetric synthesis of both enantiomers of α-substituted carboxylic acid derivatives from optically active 1-chlorovinyl p-tolyl sulfoxides and lithium ester enolates with 1,4-chiral induction from the sulfur chiral center

Article abstract of DOI:10.1016/j.tetlet.2005.06.172

Treatment of optically active 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from symmetrical ketones and (R)-(-)-chloromethyl p-tolyl sulfoxide in three steps, with lithium enolate of carboxylic acid tert-butyl esters gave optically active addu

Full text of DOI:10.1016/j.tetlet.2005.06.172

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6771–6775
A novel method for asymmetric synthesis of both enantiomers
of a-substituted carboxylic acid derivatives from optically
active 1-chlorovinyl p-tolyl sulfoxides and lithium ester enolates
with 1,4-chiral induction from the sulfur chiral center
Shimpei Sugiyama, Masahiro Kido and Tsuyoshi Satoh*
Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Received 6 June 2005; revised 6 July 2005; accepted 15 July 2005
Available online 11 August 2005
Abstract—Treatment of optically active 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from symmetrical ketones and (R)-
(ꢀ)-chloromethyl p-tolyl sulfoxide in three steps, with lithium enolate of carboxylic acid tert-butyl esters gave optically active
adducts having a substituent at the a-position with high 1,4-chiral induction from the sulfur chiral center in high yields. The adducts
were converted to optically active esters and carboxylic acids having a chiral center at the a-position. When this addition reaction
was carried out with the ester enolate generated from excess carboxylic acid tert-butyl ester with LDA in the presence of HMPA, the
diastereomer of the adduct was obtained. By using the two reaction conditions for the generation of the ester enolates, a new method
for asymmetric synthesis of both enantiomers of carboxylic acid derivatives having a substituent at the a-position from the one
chiral source, (R)-(ꢀ)-chloromethyl p-tolyl sulfoxide, was realized.
Ó 2005 Elsevier Ltd. All rights reserved.
Carboxylic acids, esters, amides, and their derivatives
are obviously among the most important and funda-
mental compounds in organic chemistry,1 bioorganic
chemistry,2 and synthetic organic chemistry. Innumera-
ble studies on the chemistry and preparation of these
compounds have already been reported. On the other
hand, synthesis of optically active carboxylic acids and
esters is quite an interesting and important aspect of
chemistry these days. The optically active compounds
are most important in the science of drugs, bioactive
compounds, and life.
carbon of carboxylic acids and esters at the a-position,
new methods for their synthesis are still very much
desired.
Recently, we reported a novel method for the synthesis
of esters, lactones and amides having a tertiary or a qua-
ternary carbon at the b-position from 1-chlorovinyl
p-tolyl sulfoxides.5 The key reaction was the addition
of the lithium ester enolate of tert-butyl acetate and
N,N-dimethylacetamide to 1-chlorovinyl p-tolyl sulfox-
ides to afford the adducts in almost quantitative yields.
Control of the stereochemistry of the chiral carbon of
carboxylic acids and esters at the a-position is now
extensively studied. For example, the chiral aldol-type
reactions3 and chiral substitution of the a-position of
esters4 are well known. However, in view of the impor-
tance of the stereoselective formation of the chiral
In continuation of our interest in the study of the devel-
opment of new synthetic methods for optically active
carboxylic acid derivatives by using optically active
1-chlorovinyl p-tolyl sulfoxides, we recently investigated
the reaction described below and interesting results were
obtained.
Thus, optically active 1-chlorovinyl p-tolyl sulfoxides 3
were synthesized from symmetrical ketones 1 and opti-
cally pure (R)-(ꢀ)-chloromethyl p-tolyl sulfoxide 2.6
Reaction of the lithium enolate of carboxylic acid
tert-butyl esters, which were generated from the
Keywords: Optically active sulfoxide; Asymmetric synthesis; Optically
active a-substituted ester; 1,4-Chiral induction; Lithium ester enolate.
Corresponding author. Tel.: +81 3 5228 8272; fax: +81 3 3235
*
2214; e-mail: tsatoh@ch.kagu.tus.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.172

6772
S. Sugiyama et al. / Tetrahedron Letters 46 (2005) 6771–6775
O
S
Tol
ClH2C
R1
H
R1
H
R1CH2COOC(CH3)3
R
R
C-COOC(CH3)3
(R)-(-)-2
R
R
R
R
Cl
S
R
R
C-COOC(CH3)3
O
*
CH2SO2Tol
LDA
THF
CHS(O)Tol
Tol
1
Cl
O
5
3
4
R1
H
R1
H
R1CH2COOC(CH3)3
R
R
C-COOC(CH3)3
CH2SO2Tol
R
C-COOC(CH3)3
*
R
CHS(O)Tol
LDA
THF-HMPA
Cl
7
6
Scheme 1.
corresponding esters with LDA, with the optically active
1-chlorovinyl p-tolyl sulfoxides 3 gave optically active
adduct 4 in high yield with high 1,4-chiral induction
from the sulfur chiral center (Scheme 1). Interestingly,
the reaction of the lithium enolate of carboxylic acid
tert-butyl esters generated from the excess esters with
LDA in the presence of HMPA with the optically active
3 gave the diastereomer 6 (corresponding to 4) in high
yield. As the result, both enantiomers of the a-substi-
tuted esters 5 and 7 could be obtained from the same
chiral source (R)-(ꢀ)-2 by choosing the conditions for
the generation of the Z-enolates or E-enolates.
oxide 26 in three steps in 87% overall yield.7 Lithium
enolate (5 equiv) of tert-butyl propionate was generated
from tert-butyl propionate with LDA in THF at
ꢀ75 °C. The addition reaction of 3a with the enolate
was found to be instantaneous and adduct 4a was ob-
tained within one minute in 99% yield. Quite interestingly,
although the adduct 4a has three stereogenic centers, only
1
a single isomer was observed judging from its H NMR
spectrum. This result indicated that the stereochemistry
of both the carbons bearing the chlorine and the methyl
group was induced from the sulfur chiral center.
In order to eliminate two stereogenic centers, 4a was
first treated with Bu3SnH8 to give the reduced 8a in
quantitative yield. The sulfinyl group in 8a was oxidized
with m-chloroperbenzoic acid (m-CPBA) to afford sul-
A representative example is reported as follows (Scheme
2). First, 1-chlorovinyl p-tolyl sulfoxide 3a was synthe-
sized from acetone and (R)-(ꢀ)-chloromethyl p-tolyl sulf-
O
S
Tol
ClH2C
H
CH3
H3C
H3C
C-COOC(CH3)3
5 eq.
CH3CH2COOC(CH3)3
H3C
H3C
Cl
S
(R)-(-)-2
CH3COCH3
LDA / THF
S
3-Steps, 87%
Tol
Tol
-75 ºC
99%
Cl
O
O
4a
3a
H
H
CH3
CH3
Bu3SnH
AIBN
H3C
H3C
C-COOC(CH3)3
SO2Tol
H3C
H3C
C-COOC(CH3)3
m-CPBA
benzene
99%
CH2Cl2
87%
S
Tol
5a
O
8a
[α]D30 -14.3 (c 1.2, ethanol)
H
H
CH3
CH3
H3C
H3C
C-COOH
H3C
H3C
C-COOH
S
TFA
Raney-Ni
ethanol
82%
CH3
CH2Cl2
91%
Tol
10
[α]D27 = -20.8 (c 0.7, ethanol)
O
9
Scheme 2.

S. Sugiyama et al. / Tetrahedron Letters 46 (2005) 6771–6775
6773
fone 5a. The enantiomeric excess of sulfone 5a was
determined to be 96% by HPLC using Chiralpak AD
as a chiral stationary column.
As shown in Table 1, the addition reaction of the lithium
enolates (generated from the esters with LDA in THF at
ꢀ75 °C) to the vinyl sulfoxides 3 proceeded to give the
adducts 4 in high yields, except in one case (entry 7).
Reduction of the chlorine atom in 4 followed by oxida-
tion of the resulting sulfoxide 8 gave sulfone 5 in high
yields. The enantiomeric excess of all the sulfones 5
was determined to be 93–99% by using HPLC with Chir-
alpak AD. All of the signs of the specific rotation of the
sulfones 5 showed minus.
In order to determine the absolute configuration of the
carbon bearing the methyl group, 8a was converted to
known carboxylic acid 10. Thus, 8a was treated with tri-
fluoroacetic acid in dichloromethane to give the carbox-
ylic acid 9. Finally, the sulfinyl group in 9 was reduced
with Raney-Ni to give 2,3,3-trimethylbutyric acid 10.
As the sign of the specific rotation of (S)-10 was re-
ported to be plus,9 the absolute configuration of the syn-
thesized 10, which has a minus sign for the specific
rotation, was determined to be R.
A plausible mechanism of this 1,4-chiral induction from
the sulfur chiral center is proposed as shown in Figure 1.
Previously, we reported a plausible transition state mod-
el for the addition reaction of lithium enolate of tert-
butyl acetate to optically active 1-chlorovinyl p-tolyl
sulfoxides 3.5d Thus, the lithium cation forms a five-
membered chelate between the oxygen of the sulfoxide
and the chlorine atom. In this event, the enolates were
introduced to the vinyl sulfoxides from the less hindered
re face (Fig. 1).
Next, we examined the generality of this reaction and
the results are summarized in Table 1. We selected
1-chlorovinyl p-tolyl sulfoxides 3 synthesized from
acetone, cyclohexanone, and cyclopentadecanone. tert-
Butyl propionate, tert-butyl butyrate, and tert-butyl
hexanoate were selected as the esters.
Table 1. Asymmetric synthesis of carboxylic acid tert-butyl esters having an alkyl group at the a-position 5 from optically active 1-chlorovinyl p-tolyl
sulfoxides 3
R1
H
R1
R1
H
H
R
R
Cl
S
R
R
C-COOC(CH3)3
R
R
C-COOC(CH3)3
R1CH2COOC(CH3)3
Bu3SnH
R
R
C-COOC(CH3)3
m-CPBA
LDA, THF
-75 ˚C
S
AIBN
Benzene
reflux
SO2Tol
CH2Cl2
r. t.
S
Tol
Tol
Tol
Cl
O
3
5
8
4
O
O
Entry
Vinyl sulfoxide 3
Adduct 4a
Sulfoxide 8
Sulfone 5
R1
Yield/%
Yield/%
Yield/%
eeb (%)
[a]D
c
R
R
30
1
2
3
4
5
6
7
3b
–(CH2)5–
–(CH2)14
CH3 CH3
–(CH2)5–
CH3
99
95
96
96
82
99
71
91
92
99
97
97
93
82
5b
5c
5d
5e
5f
96
89
92
94
83
94
97
97
97
93
99
97
96
97
½aꢁD ꢀ5.34 (c 1.8)
28
3c
3a
–
CH3
½aꢁD ꢀ4.34 (c 0.9)
26
CH3CH2
CH3CH2
CH3CH2
n-C4H9
n-C4H9
½aꢁD ꢀ3.00 (c 1.7)
26
½aꢁD ꢀ4.93 (c 1.8)
26
–(CH2)14
–
½aꢁD ꢀ1.74 (c 0.9)
28
CH3
CH3
5g
5h
½aꢁD ꢀ0.47 (c 2.8)
27
–(CH2)14
–
½aꢁD ꢀ1.86 (c 0.9)
a All the adducts were observed as a single isomer determined from their 1H NMR spectra.
b The enantiomeric excess was determined by HPLC using Chiralpak AD.
c The specific rotation was determined in ethanol.
CH3
si
H3C
S(O)Tol
CH3
COOH
H
H
H3C
H3C
S
H3C
H3C
O
Li
Cl
H
Cl
CH3
H3C
3a
CH3
(H3C)3COOC
10
re
OC(CH3)3
H3C
H
4a
-
O
Z-enolate
Figure 1.

6774
S. Sugiyama et al. / Tetrahedron Letters 46 (2005) 6771–6775
R1
H
Bu3SnH
AIBN
Cl
S
20 eq. R1CH2COOC(CH3)3
C-COOC(CH3)3
LDA (5 eq.)
benzene
S
Tol
Tol
THF-HMPA (20 eq.)
-75 ºC ~ -50 ºC
Cl
6a R1=CH3 (93%)
O
O
3c
R1
6b R1=CH3CH2 (62%)
R1
H
H
C-COOC(CH3)3
C-COOC(CH3)3
SO2Tol
m-CPBA
CH2Cl2
S
Tol
[α]D23 +5.05 (c 1.34, ethanol)
[α]D25 +1.75 (c 0.45, ethanol)
O
7a (ent-5c) 74%
7b (ent-5f) 84%
11a 88% (diastereomeric ratio=9:1)
11b 86% (diastereomeric ratio=97:3)
H3C
H3C
H3C
H3C
H
H
C-COOC(CH3)3
C-COOC(CH3)3
1) 20 eq. CH3CH2COOC(CH3)3
H3C
H3C
Cl
S
m-CPBA
LDA (5 eq.)
CH2Cl2
99%
H3C
SO2Tol
H3C
S
Tol
Tol
THF-HMPA (20 eq.)
-75 ºC ~ -50 ºC, 75%
7c (ent-5a)
O
O
12
3a
[α]D28 +9.78 (c 0.84, ethanol); 80% ee
2) Bu3SnH, AIBN in benzene, 82%
Scheme 3.
Treatment of carboxylic esters including tert-butyl pro-
pionate with LDA in THF at low temperature was
reported to give Z-enolate.10a While the real reason is
obscure at present, the Z-enolate of tert-butyl propio-
nate would be placed as shown in Figure 1 by chelation
with lithium and introduced from re face to afford the
adduct 4a with high 1,4-chiral induction from the sulfur
chiral center.
excess was found to be over 99%. The minor diastereo-
mer (corresponding to 11a) was oxidized to sulfone and
it was proved to be 5c.
In order to confirm the generality of this reaction, 3a
was reacted with the E-enolate generated from tert-butyl
propionate under the conditions as above and the ad-
duct was reduced with Bu3SnH to afford 12 in good
yield. Unfortunately, 12 was found to be an inseparable
mixture of two diastereomers. The sulfoxide 12 was oxi-
dized with m-CPBA to give the sulfone 7c in quantita-
tive yield. As anticipated, the product 7c was the
enantiomer of 5a and the enantiomeric excess was mea-
sured to be 80% by using HPLC with Chiralpak AD.
Ireland et al.,10b Tanaka and Fuji,10c and Otera et al.10d
reported that treatment of carboxylic acid esters with
LDA in THF in the presence of HMPA gave E-enolates
predominantly. Moreover, Otera et al.10d reported that
increasing the ester/LDA ratio, more E-enolates were
produced. We thought that if the reaction described
above was conducted with the lithium ester enolates
generated with LDA in the presence of HMPA and ex-
cess of esters, the enantiomer of the a-substituted esters
could be synthesized (Scheme 3).
In conclusion, a new method for asymmetric synthesis of
carboxylic acid derivatives having a substituent at the a-
position from (R)-(ꢀ)-chloromethyl p-tolyl sulfoxide
was realized. Both enantiomers of the a-substituted car-
boxylic acid derivatives can be synthesized from one chi-
ral source by choosing the conditions for the generation
of the lithium ester enolates, which is the most interest-
ing characteristic of this procedure.
First, optically active 1-chlorovinyl p-tolyl sulfoxide 3c
was reacted with the lithium enolates generated from
tert-butyl propionate (20 equiv) or tert-butyl butanoate
(20 equiv) with 5 equiv of LDA in the presence of
20 equiv of HMPA at ꢀ75 °C to ꢀ50 °C. These reac-
tions gave 6a and 6b as an inseparable mixture of two
diastereomers. The adducts 6a and 6b were reduced with
Bu3SnH to give 11a and 11b, respectively, in good
yields. At this stage two diastereomers could be sepa-
rated by silica gel column chromatography, and the dia-
stereomeric ratio is shown in Scheme 3. Finally, the
main products were oxidized with m-CPBA to afford
7a and 7b, respectively, in good yield.
Acknowledgements
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture,
Sports, Science, and Technology of Japan to promote
multi-disciplinary research project, which is gratefully
acknowledged.
References and notes
The sign of the specific rotation of 7a showed plus and
all the other data indicated that 7a is the enantiomer
of 5c. The enantiomeric excess was calculated to be over
99% using Chiralpak AD. In the same manner, 7b was
proved to be the enantiomer of 5f and the enantiomeric
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23
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