An asymmetric synthesis of carboxylic acid derivatives, including lactic acid and α-amino acid derivatives, from optically active 1-chlorovinyl p-tolyl sulfoxides and ester lithium enolates with creation of chirality at the α-position

Article abstract of DOI:10.1016/j.tetasy.2007.07.033

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

Full text of DOI:10.1016/j.tetasy.2007.07.033

Tetrahedron: Asymmetry 18 (2007) 1934–1947
An asymmetric synthesis of carboxylic acid derivatives, including
lactic acid and a-amino acid derivatives, from optically active
1-chlorovinyl p-tolyl sulfoxides and ester lithium enolates with
creation of chirality at the a-position
Masahiro Kido, Shimpei Sugiyama and Tsuyoshi Satoh*
Department of Chemistry, Faculty of Science, Tokyo University of Science, Ichigaya-Funagawara-Machi, Shinjuku-ku,
Tokyo 162-0826, Japan
Received 10 July 2007; accepted 31 July 2007
Abstract—Treatment of optically active 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from symmetrical ketones or methyl for-
mate 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 (alkyl, alkoxy, or dibenzylamino group) at the a-position with high 1,4-chiral induction from the
sulfur chiral center. The adducts were converted to optically active esters, lactic acid, and a-amino acid derivatives having a chiral center
at the a-position. When this addition reaction was carried out with an 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 gener-
ation of the ester enolate, 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 achieved.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
asymmetric alkylation4 of the a-position of carbonyl com-
pounds are well known.
Carboxylic acids,1 including lactic acid and a-amino acid
derivatives,2 are one of the most important and fundamen-
tal compounds in organic, bioorganic, and synthetic organ-
ic chemistry. Innumerable studies on the chemistry and
synthesis of carboxylic acids and their derivatives have
already been reported; however in view of the importance
of these compounds in organic chemistry, development of
new and practical synthetic methods is still eagerly awaited.
In addition, construction of a carbon stereogenic center at
the a- or b-position of carboxylic acid derivatives is quite
an important aspect of chemistry, because optically active
compounds are most important in the science of drugs, bio-
logically active compounds, and life. Control of the stereo-
chemistry of the chiral carbon of carboxylic acids and
esters at the a-position is now extensively studied. For
example, the asymmetric aldol-type reactions3 and Myers
In the previous studies, we have found that various lithium
enolate of tert-butyl esters, such as tert-butyl propionate,
reacted with 1-chlorovinyl p-tolyl sulfoxides, which were
synthesized from symmetrical ketones, gave adducts of
the esters having a carbon chiral center at the a-position
in high yields.5 The adducts have three chiral centers and
in a theoretical sense, four diastereomers should be pro-
duced. However, in the above-mentioned reactions we ob-
tained only single isomer of the adduct.
From this result, it was expected that, if a-substituted ace-
tate and optically active 1-chlorovinyl p-tolyl sulfoxide
having the same two substituents at the 2-position 3, which
was synthesized from symmetrical ketones 1 and (R)-(ꢀ)-
chloromethyl p-tolyl sulfoxide 2, were used in this reaction,
various optically active adducts of ester 4 with 1,4-chiral
induction from the sulfur chiral center could be synthe-
sized. Furthermore, we anticipated that if a-alkoxy acetate
and a-dialkylamino acetate were used as the nucleophiles, a
new asymmetric synthesis of lactic acid derivatives 4
*
Corresponding author. Tel.: +81 3 5228 8272; fax: +81 3 5261 4631;
e-mail: tsatoh@rs.kagu.tus.ac.jp
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.07.033

M. Kido et al. / Tetrahedron: Asymmetry 18 (2007) 1934–1947
1935
O
S
Tol
ClH2C
R1
H
R1
C COOC(CH3)3
H
R1CH2COOC(CH3)3
LDA / THF
R
R
R
R
Cl
S
(R)-(-)-2
R
R
C
COOC(CH3)3
R
R
O
S(O)Tol
SO2Tol
Tol
5
Cl
1
3
O
R = Alkyl, H
R1
4
H
R1 = Alkyl, OBn, NBn2
O
R
R
O
6
R1
R1
H
H
R1CH2COOC(CH3)3
R
R
C
COOC(CH3)3
R
R
C
COOC(CH3)3
LDA - HMPA / THF
R1 = Alkyl
SO2Tol
S(O)Tol
Cl
8
7
Scheme 1.
(R1 = OH) and a-amino acid derivatives 4 (R1 = NH2)
could be achieved. Adducts 4 were expected to be con-
verted to c-sulfonyl esters 5 and lactones 6 (Scheme 1).
istry 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 (the carbon
bearing a chlorine atom and the sulfinyl group), 10a was
first treated with Bu3SnH under radical conditions (reduc-
tion of the chlorine atom). The sulfinyl group of the prod-
uct was oxidized with m-chloroperbenzoic acid (m-CPBA)
to give sulfone 11a in high overall yield. The enantiomeric
excess of sulfone 11a was determined to be 96% by HPLC
using Chiralpak AD (hexane–i-PrOH = 20:1) as a chiral
stationary column.
Some of these expected reactions have already been inves-
tigated, and we have previously communicated a novel
asymmetric synthesis of both enantiomers of optically ac-
tive adducts of esters 4 and 7 (R = alkyl) having a carbon
chiral center at the a-position (Scheme 1).6 We report here-
in, in detail, a study on the asymmetric synthesis of
a-substituted carboxylic acid derivatives and, as an
application of this method, the asymmetric synthesis of
lactic acid derivatives and a-amino acid derivatives.
In order to determine the absolute configuration of the car-
bon bearing the methyl group, 10a was converted to known
carboxylic acid 12. Thus, the chlorine atom in 10a was re-
duced with Bu3SnH and the tert-butyl ester was converted
to a carboxylic acid with trifluoroacetic acid in dichloro-
methane. Finally, the sulfinyl group was reduced with Ra-
ney-Ni to give 2,3,3-trimethylbutyric acid 12. As the sign of
specific rotation of (S)-12 was reported to be plus,8 the
absolute configuration of the synthesized 12, which has a
minus sign for the specific rotation, was determined to be
(R).
2. Results and discussion
2.1. Synthesis of optically active 1-chlorovinyl p-tolyl sulf-
oxides from symmetrical ketones and reaction with the
lithium enolate of a-alkylated tert-butyl acetate
A representative example is reported as follows (Scheme 2).
First, 1-chlorovinyl p-tolyl sulfoxide 9a was synthesized
from acetone and (R)-(ꢀ)-chloromethyl p-tolyl sulfoxide
27 in three steps in 87% overall yield. The lithium enolate
of tert-butyl propionate (5 equiv) was generated from
tert-butyl propionate with LDA in THF at ꢀ75 °C and
to this reaction mixture was added a THF solution of 1-
chlorovinyl p-tolyl sulfoxide 9a. The addition reaction
was found to be instantaneous and adduct 10a was ob-
tained within one minute in 99% yield. When less than
5 equiv of the lithium enolate of tert-butyl propionate
was used, the reaction was not complete. Quite interest-
ingly, although adduct 10a has three stereogenic centers,
only a single isomer was obtained according to its 1H
NMR spectrum. This result indicated that the stereochem-
Next, the generality of this reaction was examined and the
results are summarized in Table 1. Acetone, cyclohexa-
none, and cyclopentadecanone were selected for the start-
ing ketones and tert-butyl propionate, tert-butyl butyrate
and tert-butyl hexanoate were selected as the esters. As
shown in Table 1, the addition reaction of the lithium eno-
late (generated from the esters with LDA in THF at
ꢀ75 °C) to the vinyl sulfoxides 9 gave adducts 10 in high
yields, except in one case (entry 7). Reduction of the chlo-
rine atom in 10 followed by oxidation of the sulfinyl group
with m-CPBA afforded sulfone 11 in high overall yield. The
enantiomeric excess of all sulfones 11 were determined to

1936
M. Kido et al. / Tetrahedron: Asymmetry 18 (2007) 1934–1947
O
S
Tol
ClH2C
H
5 eq.
CH3
COOC(CH3)3
CH3CH2COOC(CH3)3
H3C
H3C
Cl
S
(R)-(-)-2
H3C
H3C
C
CH3COCH3
LDA / THF
-75 ˚C, 99%
S
3-steps, 87%
Tol
H
Tol
Cl
O
O
9a
10a
CH3
H3C
H3C
C
COOC(CH3)3
1) Bu3SnH, AIBN / benzene
10a
10a
2) m-CPBA / CH2Cl2
SO2Tol
11a
[α]D30 = -14.3 (c 1.2, ethanol); 96%ee
86%; 2-steps
H
CH3
C COOH
H3C
H3C
1) Bu3SnH, AIBN / benzene
2) TFA / CH2Cl2
CH3
3) Raney-Ni / ethanol
12
[α]D28 = -20.8 (c 0.7, ethanol)
74%; 3-steps
Scheme 2.
Table 1. Asymmetric synthesis of carboxylic acid tert-butyl esters having an alkyl group at the a-position 11 from optically active 1-chlorovinyl p-tolyl
sulfoxides 9
R1
R1
H
H
R1CH2COOC(CH3)3
R
R
Cl
S
R
R
C-COOC(CH3)3
R
R
C-COOC(CH3)3
1) Bu3SnH, AIBN / benzene
LDA / THF
-75 °C
2) m-CPBA / CH2Cl2
S
SO2Tol
Tol
Tol
Cl
O
9
11
10
O
Entry
Vinyl sulfoxide 9
Adduct 10a
R1
Sulfone 11
eeb (%)
[a]D
c
R
R
Yield (%)
Yield (%)
26
1
2
3
4
5
6
7
9b
–(CH2)5–
–(CH2)14
CH3 CH3
–(CH2)5–
10b
10c
10d
10e
10f
10g
10h
CH3
99
95
96
96
82
99
71
11b
11c
11d
11e
11f
11g
11h
87
82
91
91
81
81
80
97
97
93
99
97
96
97
½aꢁD ¼ ꢀ5:3 (c 1.8)
24
9c
9a
9b
9c
9a
9c
–
CH3
½aꢁD ¼ ꢀ4:3 (c 0.9)
26
CH3CH2
CH3CH2
CH3CH2
n-C4H9
n-C4H9
½aꢁD ¼ ꢀ3:0 (c 1.7)
26
½aꢁD ¼ ꢀ4:9 (c 1.8)
26
–(CH2)14
–
½aꢁD ¼ ꢀ1:7 (c 0.9)
28
CH3
CH3
½aꢁD ¼ ꢀ0:5 (c 2.8)
27
–(CH2)14
–
½aꢁD ¼ ꢀ1:9 (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.
be 93–99% by using HPLC with Chiralpak AD (hexane–i-
PrOH = 20:1). All of the signs of the specific rotation of
sulfones 11 were minus and, at the same time, the general-
ity of this reaction was verified.
We were interested in the addition reaction of 1-chloro-
vinyl p-tolyl sulfoxide with tert-butyl acetate having an
oxygen atom at the a-position. At first, the addition
reaction of tert-butyl benzyloxyacetate with 1-chlorovinyl
p-tolyl sulfoxide 9a was investigated and the results are
summarized in Table 2.
2.2. Asymmetric synthesis of lactic acid derivatives using
tert-butyl benzyloxyacetate
First, the addition reaction was conducted in a similar way
as described above (5 equiv of lithium enolate of tert-butyl
benzyloxyacetate in THF at ꢀ78 °C for 15 min); however,
Next, an asymmetric synthesis of lactic acid derivatives was
investigated on the basis of our method described above.

M. Kido et al. / Tetrahedron: Asymmetry 18 (2007) 1934–1947
1937
Table 2. Addition of lithium enolate of tert-butyl benzyloxyacetate to optically active 1-chlorovinyl p-tolyl sulfoxide 9a
OBn
H
H3C
H3C
Cl
S
H3C
COOC(CH3)3
BnOCH2COOC(CH3)3
LDA / THF
H3C
S
Tol
Tol
Cl
9a
O
O
13a
Entry
Solvent
Ester/equiv
Conditions
13a
Temp/°C (time/min)
Yielda/%
(Isomeric ratio)b
1
2
3
4
5
6
THF
THF
THF
THF
THF
Toluene
5
5
5
5
7.5
5
ꢀ78 (15)
Trace
11
55
ꢀ78 (60)
(9:1)
(10:1)
(12:1)
ꢀ45 to ꢀ40 (60)
ꢀ78 to rt (10)
ꢀ45 (60)
96
94c
58
ꢀ78 to rt (10)
(8:1)
a Isolated yield after silica gel column chromatography.
b The ratio of isolated two diastereomers (less polar product to more polar product on silica gel TLC).
c Trace of the more polar product was observed on TLC.
only a trace of the desired adduct 13a was obtained (entry
1). Next, as shown in entry 2, the reaction time was pro-
longed to 60 min. In this reaction, the desired adduct 13a
was obtained in low yield as a mixture of two diastereo-
mers. Although the yield was low, asymmetric induction
from the sulfoxide chiral center was observed in this reac-
tion. Next, the reaction was conducted at ꢀ45 °C and the
temperature of the reaction mixture was slowly allowed
to warm to ꢀ40 °C in 60 min. In these conditions, 13a
was obtained in moderate yield as a mixture of two diaste-
reomers with similar asymmetric induction (entry 3).
treatment gave almost a quantitative yield of adduct 13a;
however, although the ratio of the diastereomers was bet-
ter, the product was still a mixture of two diastereomers.
Finally, using 7.5 equiv of the lithium enolate of tert-butyl
benzyloxyacetate at ꢀ45 °C for 60 min was found to be the
conditions of choice (entry 5). In this case, interestingly,
adduct 13a was obtained in high yield and the product
was almost a single isomer. In order to investigate the sol-
vent effect, the reaction was conducted in toluene; however,
no improvement of the yield was obtained (entry 6).
In order to determine the absolute configuration of the car-
bon bearing the benzyloxy group, adduct 13a was con-
verted to known lactone 14a as follows (Scheme 3). Thus,
to a mixture of 13a and NaI in acetone at ꢀ55 °C was
Furthermore, the reaction was conducted at ꢀ78 °C and
the cooling bath was removed immediately after 9a was
added to the reaction mixture (entry 4). Interestingly, this
OBn
H
OBn
H
1) TFAA (5 eq), NaI (5 eq)
O
H3C
H3C
COOC(CH3)3
H3C
H3C
acetone, -55 °C
O
S
2) mCPBA (1.2 eq) / CH2Cl2, r.t.
3) i-PrMgCl (1.6 eq) / THF, -78 °C
Tol
Cl
O
14a
79%; 3-steps
[α]D28 = +112.5 (c 0.22, CHCl3)
13a
99%ee
7.5 eq.
OBn
H
Cl
BnOCH2COOC(CH3)3
COOC(CH3)3
S
LDA / THF, -45 °C
S
Tol
Tol
95%
Cl
O
O
9b
13b
OBn
H
1) TFAA (5 eq), NaI (5 eq)
O
acetone, -55 °C
O
2) mCPBA (1.2 eq) / CH2Cl2, r.t.
3) i-PrMgCl (1.6 eq) / THF, -78 °C
14b
[α]D27 = +101.2 (c 0.91, CHCl3); 97%ee
63%; 3-steps
Scheme 3.

1938
M. Kido et al. / Tetrahedron: Asymmetry 18 (2007) 1934–1947
added TFAA to afford the desired c-sulfanyl c-lactone in
high yield.9 The sulfanyl group was oxidized with m-CPBA
at room temperature to a sulfinyl group, and the resultant
sulfinyl-lactone was treated with 1.6 equiv of i-PrMgCl to
give lactone 14a via a sulfoxide–magnesium exchange reac-
tion10 in 79% overall yield. The enantiomeric excess of 14a
was confirmed to be 99% by HPLC using Chiralpak AD
(hexane–i-PrOH = 9:1). Comparing the sign of the specific
rotation of the product with that of the reported optically
active 14a (the sign of the specific rotation of (S)-14a was
reported to be minus11), the absolute configuration of the
synthesized 14a, which has a plus sign for the specific rota-
tion, was determined to be (R). It is worth noting that the
absolute configuration is the same as that of 11
(see Scheme 2 and Table 1), which implies that the princi-
ple for the chiral induction of the two reactions is the
same.
72% (entries 2 and 3). Interestingly, although adduct 15a
has three chiral centers, only a single isomer was
obtained. The best yield was obtained using 7.5 equiv of
lithium enolate of N,N-dibenzylglycine tert-butyl ester
(entry 4). Again, toluene was not a suitable solvent for this
reaction (entry 5).
For determination of the absolute configuration of the a-
position, adduct 15a was converted to known cyclic a-ami-
no acid derivative 17 again by using our method (see
Scheme 4).9,10 Thus, at first, 15a was transformed to lac-
tone 16a in the same way as described in Scheme 3 in
78% overall yield. The enantiomeric excess of 16a was con-
firmed to be 99% by HPLC using Chiralpak AD (hexane–i-
PrOH = 9:1) as a chiral stationary column. Next, a-amino
c-lactone 16a was converted to known 17. Thus, 16a was
treated with Pd–C in the presence of formic acid in metha-
nol to give debenzylated c-lactone having a free amino
group at the a-position.12 The free amino group was
treated with ethyl chloroformate to give N-methoxy-
carbonylated a-amino c-lactone 17 in 66% overall yield
from 16a. Lactone 17 showed minus sign for the specific
rotation. Versleijen et al. reported that (R)-carbometh-
oxyamino lactone 17 showed a minus sign for the specific
rotation.13 Thus, the absolute configuration at the a-car-
bon of our lactone 17 was determined to be (R). It is note-
worthy that the absolute configuration of the synthesized
17 is the same as that of 11 (see Scheme 2 and Table 1)
and 14 (see Scheme 3), which ascertains that the principle
for chiral induction of the three reactions mentioned above
is the same.
In a similar way, the addition reaction of tert-butyl ben-
zyloxyacetate with vinyl sulfoxide 9b, which was derived
from cyclohexanone and 2, gave adduct 13b in 95% yield
as a single isomer. Adduct 13b was converted to spiro c-
lactone 14b in three steps in moderate overall yield. The
enantiomeric excess of 14b was confirmed to be 99% by
HPLC using Chiralpak IA (hexane–i-PrOH = 9:1). The
sign of the specific rotation of 14b was plus, which indi-
cated that the absolute configuration of 14b must be (R).
2.3. Asymmetric synthesis of a-amino acid derivatives using
N,N-dibenzylglycine tert-butyl ester
We further extended the chemistry mentioned above to an
asymmetric synthesis of a-amino acid derivatives. At
first, the addition reaction of the lithium enolate of
N,N-dibenzylglycine to 1-chlorovinyl p-tolyl sulfoxides
followed by conversion of the adducts to a-amino acid
derivatives was investigated as shown in Table 3, Schemes
4 and 5.
A spiro-cyclic a-amino c-lactone having a quaternary car-
bon at the b-position was also synthesized starting from 9b
(Scheme 4). Thus, vinyl sulfoxide 9b was treated with
7.5 equiv of lithium enolate of N,N-dibenzylglycine tert-
butyl ester as described above to give an optically active
adduct 15b in a quantitative yield. Adduct 15b was
converted to optically active spiro a-amino c-lactone 16b
in good overall yield by using the chemistry described
above. Again, the enantiomeric excess was found to be
99% by using Chiralpak AD (hexane–i-PrOH = 9:1) as a
chiral stationary column.
Table 3. Addition of lithium enolate of N,N-dibenzylglycine tert-butyl
ester to optically active 1-chlorovinyl p-tolyl sulfoxide 9a
NBn2
H
Bn2NCH2COOC(CH3)3
LDA
H3C
H3C
COOC(CH3)3
H3C
H3C
Cl
S
Furthermore, we tried to synthesize optically active a-ami-
no c-lactone without any substituents at the b-position
(Scheme 5). First, the synthesis of optically active 1-chloro-
vinyl p-tolyl sulfoxide 9d was investigated starting from
methyl formate and (R)-(ꢀ)-2. Sulfoxide 2 was treated with
LDA at ꢀ65 °C followed by the addition of methyl formate
to give the desired aldehyde having a chlorine and a p-tol-
ylsulfinyl group, which was observed as a mixture of keto
S
Tol
Tol
Cl
O
O
9a
15a
Ester/equiv Conditions/°C (min) Yielda/%
Entry Solvent
1
2
3
4
5
THF
THF
THF
THF
5
5
5
7.5
5
ꢀ78 (15)
ꢀ45 (15)
ꢀ45 (60)
ꢀ45 (60)
ꢀ45 (15)
N.R.
24
72
99
15
1
and enol form by H NMR and IR analyses. This mixture
Toluene
was reduced without further purification with NaBH4 in
ethanol to afford alcohol 18 in 82% overall yield. Alcohol
18 was treated with methanesulfonyl chloride in the pres-
ence of triethylamine (TEA) in CH2Cl2 at room tempera-
ture to give the desired enantiomerically pure
vinylsulfoxide 9d in high yield. In a similar way as des-
cribed above, the addition reaction of 9d with 7.5 equiv
of the lithium enolate of N,N-dibenzylglycine tert-butyl
ester was conducted; however, the yield and the asymmetric
a The adduct was confirmed to be a single isomer from 1H NMR.
Optically active 1-chlorovinyl p-tolyl sulfoxide 9a was trea-
ted with 5 equiv of the lithium enolate of N,N-dibenzylgly-
cine tert-butyl ester and the reaction mixture was stirred at
ꢀ78 °C for 15 min (Table 3, entry 1); however, the reaction
did not proceed. Raising the reaction temperature and pro-
longing the reaction time gave the desired adduct 15a up to

M. Kido et al. / Tetrahedron: Asymmetry 18 (2007) 1934–1947
1939
NBn2
O
NBn2
H
H
1) TFAA (5 eq), NaI (5 eq)
O
H3C
H3C
H3C
H3C
COOC(CH3)3
acetone, -55 °C
S
2) mCPBA (1.2 eq) / CH2Cl2, r.t.
3) i-PrMgCl (1.6 eq) / THF, -78 °C
Tol
16a
Cl
O
[α]D29 = +137 (c 0.47, ethanol)
78%; 3-steps
15a
99%ee
NHCO2CH3
H
O
1) Pd / C, 4.4% HCOOH / MeOH
H3C
H3C
2) ClCO2Me / K2CO3-H2O
66%; 2-steps
O
17
[α]D28 = -82 (c 1.0, CHCl3); 99%ee
NBn2
COOC(CH3)3
7.5 eq.
Bn2NCH2COOC(CH3)3
H
Cl
S
S
LDA / THF, -45 °C
Tol
Tol
96%
Cl
9b
15b
O
O
NBn2
O
H
1) TFAA (5 eq), NaI (5 eq)
O
acetone, -55 °C
2) mCPBA (1.2 eq) / CH2Cl2, r.t.
3) i-PrMgCl (1.6 eq) / THF, -78 °C
16b
64%; 3-steps
[α]D27 = +91.5 (c 1.0, ethanol); 99%ee
Scheme 4.
O
S
O
OH
LDA / THF
NaBH4 / EtOH
82%; 2-steps
Tol
H
S
H
S
ClH2C
HCOOCH3
Tol
Tol
Cl
Cl
-65 °C
O
O
(R)-(-)-2
NBn2
H
7.5 eq.
OH
H
H
COOC(CH3)3
H
Cl
Bn2NCH2COOC(CH3)3
MsCl / TEA
H
S
S
CH2Cl2
92%
H
S
LDA / THF, -45 °C
H
Tol
Tol
Tol
Cl
Cl
O
74%
O
O
15c
18
9d
NBn2
H
1) TFAA (5 eq), NaI (5 eq)
O
acetone, -55 °C
O
2) mCPBA (1.2 eq) / CH2Cl2, r.t.
3) i-PrMgCl (1.6 eq) / THF, -78 °C
16c
[α]D28 = +26.5 (c 0.22, ethanol); 87%ee
42%; 3-steps
Scheme 5.
induction of the desired product 15c were not satisfactory.
Product 15c was converted to a c-lactone having an N,N-
dibenzylamino group at the a-position 16c in 42% overall
yield. The enantiomeric excess of 16c was found to be

1940
M. Kido et al. / Tetrahedron: Asymmetry 18 (2007) 1934–1947
CH3
si
H3C
S(O)Tol
CH3
COOH
H
H
H3C
H3C
S
H3C
H3C
O
Li
Cl
H
Cl
CH3
H3C
9a
X
(H3C)3COOC
12
re
OC(CH3)3
X
10a
13a
X = CH3
X = OCH2Ph
H
O
H
X
15a
X = N(CH2Ph)2
H3C
H3C
Z-enolate
O
X = CH3,
OCH2Ph,
N(CH2Ph)2
O
14a
16a
X = OCH2Ph
X = N(CH2Ph)2
Figure 1.
87% by using Chiralpak AD (hexane–i-PrOH = 14:1) as a
chiral stationary column. Comparing the results shown in
Scheme 4 and Table 3 with those of in Scheme 5, it is ascer-
tained that the two substituents on the b-position of the 1-
chlorovinyl p-tolyl sulfoxides play an important role for the
high 1,4-asymmetric induction.
oxides from the less hindered re-face (Fig. 1). Treatment of
carboxylic esters including tert-butyl propionate,15a tert-
butyl benzyloxyacetate15b and N,N-dibenzylglycine tert-
butyl ester15c with LDA in THF at low temperature was
reported to give a Z-enolate. While the real reason is not
clear at present, the Z-enolates would be placed as shown
in Figure 1 by chelation with lithium and introduced from
re face to afford adduct 10a, 13a, or 15a with high 1,4-chi-
ral induction from the sulfur chiral center.
A plausible mechanism for this 1,4-chiral induction from
the sulfur chiral center is proposed as shown in Figure 1.
Previously, we reported a plausible transition state model
for the addition reaction of the lithium enolate of tert-butyl
acetate to optically active 1-chlorovinyl p-tolyl sulfoxide
3.14 The lithium cation forms a five-membered chelate be-
tween the oxygen of the sulfoxide and the chlorine atom.
In this event, the enolates were introduced to the vinyl sulf-
Ireland et al.,16a Tanaka and Fuji,16b and Otera et al.16c re-
ported that treatment of carboxylic acid ester with LDA in
THF in the presence of HMPA gave the E-enolate predom-
inantly. Moreover, Otera et al. reported that increasing the
ester/LDA ratio, more E-enolates were produced.16c We
R1
H
Bu3SnH
AIBN
Cl
S
20 eq. R1CH2COOC(CH3)3
C-COOC(CH3)3
LDA (5 eq.)
THF-HMPA (20 eq.)
-75 ~ -50 ºC
benzene
S
Tol
Tol
10
10
H
Cl
O
O
19a R1=CH3 (93%)
9c
19b R1=CH3CH2 (97%)
R1
R1
H
C-COOC(CH3)3
C-COOC(CH3)3
SO2Tol
m-CPBA
CH2Cl2
S
Tol
10
10
O
[α]D23 = +5.05 (c 1.34, ethanol)
[α]D25 = +1.75 (c 0.45, ethanol)
21a (ent-11c) 74%
21b (ent-11f) 84%
20a 88% (diastereomeric ratio=9:1)
20b 95% (diastereomeric ratio=9:1)
H3C
H3C
H
H
H3C
H3C
C-COOC(CH3)3
SO2Tol
H3C
H3C
C-COOC(CH3)3
1) 20 eq. CH3CH2COOC(CH3)3
H3C
H3C
Cl
S
m-CPBA
LDA (5 eq.)
CH2Cl2
99%
S
Tol
Tol
THF-HMPA (20 eq.)
-75 ~ -50 ºC, 75%
23 (ent-11a)
O
O
22
9a
[α]D28 = +9.78 (c 0.84, ethanol); 80% ee
2) Bu3SnH, AIBN in benzene, 82%
Scheme 6.

M. Kido et al. / Tetrahedron: Asymmetry 18 (2007) 1934–1947
1941
thought that if the reaction described above was conducted
with LDA in the presence of HMPA and excess of esters,
the enantiomer of a-substituted esters could be synthesized
(Scheme 6).
column chromatography and the products having UV
absorption were detected by UV irradiation. In experi-
ments requiring a dry reagent, and solvent, benzene,
dichloromethane, N,N-diisopropylamine, triethylamine,
and pyridine were distilled from CaH2. THF was distilled
from diphenylketyl and acetone was dried over CaSO4
and distilled before use.
Optically active 1-chlorovinyl p-tolyl sulfoxide 9c was trea-
ted with 20 equiv of lithium enolates generated from tert-
butyl propionate or tert-butyl butanoate with 5 equiv of
LDA in the presence of 20 equiv of HMPA at ꢀ75 to
ꢀ50 °C. These reactions gave 19a and 19b as an insepara-
ble mixture of two diastereomers. Reduction of adducts
19a and 19b with Bu3SnH gave 20a and 20b, respectively,
in good yields. At this stage two diastereomers could be
separated by silica gel column chromatography, and the
diastereomeric ratios are shown in Scheme 6. Finally, the
main products were oxidized with m-CPBA to afford 21a
and 21b, respectively, in good yield. The sign of the specific
rotation of 21a was plus and all the other data indicated
that 21a is the enantiomer of 11c. The enantiomeric excess
was calculated to be over 99% using Chiralpak AD (hex-
ane–i-PrOH = 9:1). In the same manner, 21b was proved
to be the enantiomer of 11f and the enantiomeric excess
found to be over 99%. The minor diastereomer (corre-
sponding to 20a) was oxidized to a sulfone and it was
proved to be 11c.
3.1. tert-Butyl 4-chloro-2,3,3-trimethyl-4-(p-tolylsulfinyl)-
butanoate 10a
tert-Butyl propionate (0.15 mL; 1.13 mmol) was added to a
solution of LDA (0.66 mmol) in 3 mL of dry THF at
ꢀ78 °C with stirring. The solution was stirred for 10 min,
and a solution of 9a (30 mg; 0.131 mmol) in THF
(0.5 mL) was added. The reaction mixture was stirred for
5 min, and the reaction was quenched by adding satd aq
NH4Cl. The whole was extracted with CHCl3. The organic
layer was dried over MgSO4 and concentrated in vacuo.
The product was purified by silica gel column chromato-
graphy to afford 10a (46.5 mg; 99%) as a colorless oil; IR
(neat) 2977, 1723 (CO), 1457, 1367, 1151, 1057 (SO)
1
cmꢀ1; H NMR d 1.16 (3H, d, J = 7.4 Hz), 1.28 (3H, s),
1.42 (9H, s), 1.47 (3H, s), 2.43 (3H, s), 3.04 (1H, q,
J = 7.0 Hz), 4.75 (1H, s), 7.31, 7.70 (each 2H, d, J =
7.9 Hz). MS m/z (%) 358 (M+, trace), 342 (trace),
318 (trace), 285 (21), 271 (trace), 250 (trace), 229 (1), 212
(1), 196 (2), 163 (25), 140 (100), 139 (22), 127 (21), 91 (9).
Calcd for C18H27ClO3S: M, 358.1369. Found: m/z
358.1375.
In order to confirm the generality of this reaction, 9a was
reacted with the E-enolate of tert-butyl propionate under
the same conditions as above and the adduct was reduced
with Bu3SnH to afford 22 in good yield. Unfortunately, the
product was found to be an inseparable mixture of two dia-
stereomers. Sulfoxide 22 was oxidized with m-CPBA to
give sulfone 23 in quantitative yield. As anticipated, prod-
uct 23 was the enantiomer of 11a; however, the enantio-
meric excess was measured to be 80% by using HPLC
with Chiralpak AD (hexane–i-PrOH = 20:1). Unfortu-
nately, this technique was not useful for a synthesis of
the enantiomers of the lactic acid and a-amino acid deriv-
atives described above.
3.2. tert-Butyl 2-{1-[chloro(p-tolylsulfinyl)methyl]cyclohexyl}-
propionate 10b
Colorless oil; IR (neat) 2930, 1727 (CO), 1596, 1455, 1367,
1
1255, 1145, 1056 (SO), 849 cmꢀ1; H NMR d 1.34 (3H, d,
J = 7.1 Hz), 1.47 (9H, s), 1.26–1.83 (10H, m), 2.44 (3H, s),
3.11 (1H, q, J = 7.1 Hz), 4.96 (1H, s), 7.33, 7.72 (each 2H,
d, J = 8.3 Hz). MS m/z (%) 399 ([M+H]+, trace), 381
(trace), 342 (1), 325 (15), 290 (2), 279 (3), 269 (2), 252 (1),
203 (27), 185 (4), 167 (64), 140 (100), 139 (20), 93 (20), 91
(12). Calcd for C21H32ClO3S: M, 399.1761. Found: m/z
399.1750.
In conclusion, we have developed a new and efficient
method for a synthesis of optically active carboxylic acid
derivatives and lactones, including lactic acid and a-amino
acid derivatives, having a chiral carbon center at the a-
position from (R)-(ꢀ)-chloromethyl p-tolyl sulfoxide. Both
enantiomers of the a-substituted carboxylic acid deriva-
tives can be synthesized from one chiral source by choos-
ing the conditions for the generation of the lithium ester
enolates.
3.3. tert-Butyl 2-{1-[chloro(p-tolylsulfinyl)methyl]cyclopen-
tadecyl}propionate 10c
Colorless oil; IR (neat) 2929, 2875, 1727 (CO), 1459, 1369,
1241, 1150, 1059 (SO) cmꢀ1 1H NMR d 1.37 (3H, d,
;
J = 7.1 Hz), 1.2–1.4 (28H, m), 1.47 (9H, s), 2.43 (3H, s),
3.03 (1H, q, J = 7.1 Hz), 4.60 (1H, s), 7.35, 7.71 (each
2H, d, J = 8.3 Hz). MS m/z (%) 525 ([M+H]+, trace), 451
(10), 329 (27), 293 (77), 275 (15), 219 (48), 140 (100), 95
(18), 57 (86). Calcd for C30H50ClO3S: M, 525.3169. Found:
m/z 525.3185.
3. Experimental
All melting points were measured on Yanaco MP-S3 appa-
ratus and are uncorrected. 1H NMR spectra were measured
in a CDCl3 solution with JEOL JNMLA 500 and Burker
XWIN-600 spectrometer. Electron-impact mass spectra
(MS) were obtained at 70 eV by direct insertion by HIT-
ACHI M-80B mass spectrometer. IR spectra were recorded
on a Perkin–Elmer Spectrum One FT-IR instrument. Silica
gel 60N (KANTO CHEMICAL) containing 0.5% fluores-
cence reagent 254 and a quartz column were used for
3.4. tert-Butyl 4-chloro-2-ethyl-3,3-dimethyl-4-(p-tolylsulfi-
nyl)butanoate 10d
Colorless oil; IR (neat) 2975, 2877, 1722 (CO), 1596, 1458,
1367, 1155, 1056 (SO), 948, 813 cmꢀ1; 1H NMR d 0.95 (3H,
t, J = 7.3 Hz), 1.28 (3H, s), 1.42 (3H, s), 1.45 (9H, s),

1942
M. Kido et al. / Tetrahedron: Asymmetry 18 (2007) 1934–1947
2.43 (3H, s), 2.91 (1H, dd, J = 11.6, 3.4 Hz), 4.51 (1H, s),
7.31, 7.68 (each 2H, d, J = 8.0 Hz). MS m/z (%) 372
(M+, trace), 356 (trace), 322 (trace), 299 (18), 264 (1), 263
(0.5), 229 (1), 196 (3), 177 (27), 159 (5), 140 (100),
139 (20), 91 (7). Calcd for C19H29ClO3S: M, 372.1526.
Found: m/z 372.1532.
fluxed for 30 min. The solvent was removed in vacuo and
the residue was purified by silica gel column chromatogra-
phy to give dechlorinated sulfoxide (65 mg; 99%) as a col-
orless oil. m-CPBA (49.4 mg; 0.2 mmol) was added to a
solution of the sulfoxide in 10 mL of CH2Cl2 at room tem-
perature with stirring. The solution was stirred for 30 min,
and the reaction was quenched by adding satd aq Na2SO3
and satd aq NaHCO3. The whole was extracted with
CH2Cl2. The organic layer was dried over MgSO4 and con-
centrated in vacuo. The product was purified by silica gel
column chromatography to afford 11a (59.2 mg; 87%) as
a colorless oil; IR (neat) 2977, 2932, 1722 (CO), 1462,
3.5. tert-Butyl 2-{1-[chloro(p-tolylsulfinyl)methyl]cyclo-
hexyl}butanoate 10e
Colorless oil; IR (neat) 2930, 2868, 1723 (CO), 1596, 1455,
1
1366, 1259, 1143, 1056 (SO), 811 cmꢀ1; H NMR d 0.98
1
(3H, t, J = 7.0 Hz), 1.49 (9H, s), 1.2–2.0 (12H, m), 2.44
(3H, s), 2.85 (1H, dd, J = 12, 3.1 Hz), 5.00 (1H, s), 7.33,
7.73 (each 2H, d, J = 8.3 Hz). MS m/z (%) 412 (M+, trace),
395 (trace), 339 (16), 217 (33), 181 (90), 140 (100), 93 (24).
Calcd for C22H33ClO3S: M, 412.1839. Found: m/z
412.1837.
1368, 1147, 1087 (SO2), 849, 817 cmꢀ1; H NMR d 1.09–
1.10 (3H, m), 1.28–1.31 (6H, m), 1.41 (9H, s), 2.47 (3H,
s), 2.52 (1H, q, J = 7.1 Hz), 3.07, 3.47 (each 1H, d,
J = 13.8 Hz), 7.34, 7.80 (each 2H, d, J = 8.1 Hz). MS m/z
(%) 340 (M+, 0.2), 308 (trace), 284 (20), 267 (55), 266
(20), 238 (4), 211 (100), 182 (5), 157 (93), 139 (33), 129
(71), 111 (10), 91 (37). Calcd for C18H28O4S: M,
30
340.1709. Found: m/z 340.1710. ½aꢁD ¼ ꢀ14:3 (c 1.2, etha-
28
3.6. tert-Butyl 2-{1-[chloro(p-tolylsulfinyl)methyl]cyclo-
pentadecyl}butanoate 10f
nol). Compound 23: ½aꢁD ¼ þ9:8 (c 0.84, ethanol).
Colorless oil; IR (neat) 2929, 2851, 1727 (CO), 1569, 1455,
3.10. (2R)-(ꢀ)-tert-Butyl 2-{1-[(p-tolylsulfonyl)methyl]-
1
1367, 1256, 1149, 1059 (SO), 811 cmꢀ1; H NMR d 0.96
cyclohexyl}propionate 11b
(3H, t, J = 7.2 Hz), 1.1–1.6 (28H, m), 1.49 (9H, s), 1.9–
2.1 (2H, m), 2.43 (3H, s), 2.78 (1H, dd, J = 12.0, 3.0 Hz),
4.53 (1H, s), 7.31, 7.71 (each 2H, J = 7.8, 8.4 Hz). MS
m/z (%) 539 ([M+H]+, trace), 465 (10), 343 (33), 307
(100), 289 (14), 261 (13), 219 (40), 140 (68). Calcd for
C31H52ClO3S: M, 539.3325. Found: m/z 539.3323.
Colorless oil; IR (neat) 2928, 2870, 1716 (CO), 1597, 1455,
1
1367, 1147 (SO2), 849, 817 cmꢀ1; H NMR d 1.05 (3H, d,
J = 7.0 Hz), 1.43 (9H, s), 1.4–1.7 (10H, m), 2.44 (3H, s),
3.10, 3.58 (each 1H, d, J = 14.7 Hz), 3.17 (1H, q,
J = 7.3 Hz), 7.33, 7.79 (each 2H, d, J = 8.0 Hz). MS m/z
(%) 380 (M+, trace), 350 (trace), 324 (16), 307 (28), 306
(8), 251 (100), 250 (2), 184 (1), 157 (70), 123 (26), 109 (5),
3.7. tert-Butyl 2-{1-[chloro(p-tolylsulfinyl)methyl]-1-methyl-
ethyl}hexanoate 10g
95 (87). Calcd for C21H32O4S: M, 380.2021. Found: m/z
26
380.2012. ½aꢁD ¼ ꢀ5:34 (c 1.8, ethanol).
Colorless oil; IR (neat) 2973, 2921, 1723 (CO), 1494, 1464,
1367, 1146, 1057 (SO) cmꢀ1
;
1H NMR d 0.90 (3H, t,
3.11. (2R)-(ꢀ)-tert-Butyl 2-{1-[(p-tolylsulfonyl)methyl]-
J = 8.0 Hz), 1.28 (3H, s), 1.42 (3H, s), 1.44 (9H, s), 1.2–
1.7 (6H, m), 2.43 (3H, s), 2.99 (1H, dd, J = 11.6, 2.5 Hz),
4.52 (1H, s), 7.31, 7.68 (each 2H, d, J = 8.0, 8.3 Hz). MS
m/z (%) 400 (M+, trace), 385 (trace), 373 (trace), 327
(16), 314 (2), 296 (3), 270 (17), 266 (6), 214 (11), 205 (35),
169 (17), 140 (100), 139 (17), 123 (10), 69 (8). Calcd for
C21H33ClO3S: M, 400.1839. Found: m/z 400.1855.
cyclopentadecyl}propionate 11c
Colorless oil; IR (neat) 2928, 2856, 1719 (CO), 1597, 1458,
1
1367, 1319, 1146 (SO2), 1087, 816 cmꢀ1; H NMR d 1.14
(3H, d, J = 7.4 Hz), 1.2–1.5 (28H, m), 1.43 (9H, s), 2.44
(3H, s), 2.86 (1H, q, J = 7.4 Hz), 3.22, 3.46 (each 1H, d,
J = 14.7 Hz), 7.32, 7.79 (each 2H, d, J = 8.25 Hz). MS
m/z (%) 506 (M+, trace), 450 (3), 433 (7), 377 (35), 295
(15), 277 (30), 263 (100), 221 (84), 157 (40), 109 (42), 83
3.8. tert-Butyl 2-{1-[chloro(p-tolylsulfinyl)methyl]cyclo-
pentadecyl}hexanoate 10h
(79), 55 (96). Calcd for C30H50O4S: M, 506.3430. Found:
24
m/z 506.3431. ½aꢁD ¼ ꢀ4:3 (c 0.9, ethanol). Compound
23
Colorless oil; IR (neat) 2929, 2858, 1727 (CO), 1462, 1367,
1148, 1059 (SO) cmꢀ1; 1H NMR d 0.93 (3H, t, J = 7.3 Hz),
1.2–1.5 (28H, m), 1.48 (9H, s), 1 1.7–1.9 (6H, m), 2.43 (3H,
s), 2.87 (1H, dd, J = 11.3, 4.0 Hz), (1H, s), 7.31, 7.71 (each
2H, d, J = 8.0 Hz). MS m/z (%) 567 ([M+H]+, trace), 493
(21), 371 (69), 335 (100), 289 (45), 267 (19), 219 (100),
140 (100), 57 (100).
21a: ½aꢁD ¼ þ5:05 (c 1.34, ethanol, 99% ee).
3.12. (2R)-(ꢀ)-tert-Butyl 2-ethyl-3,3-dimethyl-4-(p-tolyl-
sulfonyl)butanoate 11d
Colorless oil; IR (neat) 2972, 2877, 1722 (CO), 1598, 1460,
1
1367, 1317, 1147 (SO2), 1087, 949, 815 cmꢀ1; H NMR d
0.86 (3H, t, J = 7.3 Hz), 1.27 (3H, s), 1.31 (3H, s), 1.44
(9H, s), 1.5–1.6 (2H, m), 2.18 (1H, dd, J = 10.1, 4.9 Hz),
2.44 (3H, s), 3.04, 3.41 (each 1H, d, J = 14.0 Hz), 7.33,
7.78 (each 2H, d, J = 8.3 Hz). MS m/z (%) 354 (M+, trace),
341 (trace), 322 (trace), 298 (18), 281 (52), 242 (8), 211
(100), 196 (6), 170 (3), 143 (62), 139 (26), 97 (33), 91 (28).
3.9. (2R)-(ꢀ)-tert-Butyl 2,3,3-trimethyl-4-(p-tolylsulfonyl)-
butanoate 11a
AIBN (9.8 mg; 0.06 mmol) was added to a solution of 10a
(72.2 mg; 0.2 mmol) and Bu3SnH (0.14 mL; 0.3 mmol) in
5 mL of benzene. The atmosphere in the flask was replaced
with argon, and the reaction mixture was stirred and re-
Calcd for C19H30O4S: M, 354.1864. Found: m/z 354.1862.
26
½aꢁD ¼ ꢀ3:0 (c 1.7, ethanol).

M. Kido et al. / Tetrahedron: Asymmetry 18 (2007) 1934–1947
1943
3.13. (2R)-(ꢀ)-tert-Butyl 2-{1-[(p-tolylsulfonyl)methyl]-
the residue was purified by silica gel column chromatogra-
phy to give dechlorinated product as colorless oil. To a
solution of the product in 10 mL of CH2Cl2 was added tri-
fluoroacetic acid (0.09 mL; 15 mmol). The solution was
stirred overnight. The reaction was quenched by satd aq
NaHCO3. After the aqueous layer was acidified by 10%
HCl, the whole was extracted with CH2Cl2 and the organic
layer was evaporated to afford a carboxylic acid.
cyclohexyl}butanoate 11e
Colorless oil; IR (neat) 2930, 2847, 1716 (CO), 1597, 1456,
1
1366, 1316, 1146 (SO2), 1087, 815 cmꢀ1; H NMR d 0.88
(3H, t, J = 7.4 Hz), 1.44 (9H, s), 1.4–1.7 (8H, m), 2.0–2.1
(1H, m), 2.2–2.3 (1H, m), 2.44 (3H, s), 2.87 (1H, dd,
J = 10.1, 4.9 Hz), 3.03, 3.63 (each 1H, d, J = 14.6 Hz),
7.33, 7.79 (each 2H, d, J = 8.3 Hz). MS m/z (%) 394
(M+, trace), 362 (trace), 338 (17), 321 (24), 320 (14), 293
(2), 251 (100), 242 (4), 196 (3), 183 (22), 157 (75), 137
A solution of the carboxylic acid (40 mg; 0.15 mmol) and
excess of Raney-Ni in EtOH was stirred and refluxed for
30 h. The Raney Ni was filtered off, and the filtrate was
evaporated to give a residue, which was purified by silica
gel column chromatography to afford 12 (19.8 mg; 82%)
as a colorless oil; IR (neat) 2927, 1704 (CO), 1463, 1368,
(23), 95 (95), 81 (17). Calcd for C22H34O4S: M, 394.2178.
26
Found: m/z 394.2182. ½aꢁD ¼ ꢀ4:9 (c 1.8, ethanol).
3.14. (2R)-(ꢀ)-tert-Butyl 2-{1-[(p-tolylsulfonyl)methyl]-
1
cyclopentadecyl}butanoate 11f
1287, 1241, 1184, 945 cmꢀ1; H NMR d 1.00 (9H, s), 1.14
27
(3H, d, J = 7.2 Hz), 2.30 (1H, q, J = 7.2 Hz). ½aꢁD
¼
Colorless oil; IR (neat) 2930, 2858, 1721 (CO), 1460, 1367,
ꢀ20:8 (c 0.7, ethanol).
1319, 1147 (SO2), 1087 cmꢀ1 1H NMR d 0.88 (3H, t,
;
J = 7.2 Hz), 1.2–1.6 (28H, m), 1.6–1.7 (2H, m), 2.43 (3H,
s), 2.52 (1H, dd, J = 9.0, 5.4 Hz), 3.24, 3.42 (each 1H, d,
J = 14.4 Hz), 7.32, 7.79 (each 2H, J = 8.4 Hz). MS m/z
(%) 520 (M+, trace), 446 (18), 377 (75), 309 (33), 291
(28), 277 (10), 221 (100), 157 (23), 97 (12). Calcd for
C31H52O4S: M, 520.3587. Found: m/z 520.3593.
3.18. tert-Butyl 2-benzyloxy-4-chloro-3,3-dimethyl-4-
(p-tolylsulfinyl)butanoate 13a
tert-Butyl benzyloxyacetate (142 mg; 0.65 mmol) was
added to a solution of LDA (0.65 mmol) in 3 mL of dry
THF at ꢀ45 °C with stirring. The solution was stirred for
15 min, then a solution of 9a (20 mg; 0.087 mmol) in
THF (0.5 mL) was added. The solution was stirred for
60 min at ꢀ45 °C and the reaction was quenched by adding
satd aq NH4Cl. The whole was extracted with CHCl3. The
organic layer was dried over MgSO4 and concentrated in
vacuo. The product was purified by silica gel column chro-
matography to afford 13a (36 mg; 94%) as a colorless oil;
IR (neat) 2978, 2936, 1732 (CO), 1455, 1393, 1370, 1258,
26
25
½aꢁD ¼ ꢀ1:7 (c 0.9, ethanol). Compound 21b: ½aꢁD ¼ þ1:7
(c 0.45, ethanol, 99% ee).
3.15. (2R)-(ꢀ)-tert-Butyl 2-[1,1-dimethyl-2-(p-tolylsulfonyl)-
ethyl]hexanoate 11g
Colorless oil; IR (neat) 2960, 2872, 1718 (CO), 1598, 1466,
1
1392, 1367, 1317, 1147 (SO2), 1087, 847 cmꢀ1; H NMR d
1
0.87 (3H, t, J = 7.4 Hz), 1.28 (3H, s), 1.31 (3H, s), 1.43 (9H,
s), 1.2–1.5 (6H, m), 2.22 (1H, dd, J = 12.0, 3.1 Hz), 2.44
(3H, s), 3.03, 3.42 (each 1H, d, J = 14.3 Hz), 7.33, 7.79
(each 2H, d, J = 8.0 Hz). MS m/z (%) 382 (M+, trace),
309 (45), 308 (28), 270 (16), 252 (5), 211 (100), 171 (66),
1220, 1159, 1121, 1054 (SO), 812 cmꢀ1; H NMR d 1.24
(3H, s), 1.44 (3H, s), 1.51 (9H, s), 2.39 (3H, s), 4.60 (1H,
d, J = 10.7 Hz), 4.68 (1H, d, J = 10.7 Hz), 4.84 (1H, s),
4.92 (1H, s), 7.21, (2H, d, J = 7.9 Hz), 7.30–7.40 (5H, m).
7.58 (2H, d, J = 8.25 Hz). MS m/z (%) 451 (M+, trace),
435 (trace), 349 (15), 303 (10), 255 (5), 230 (5), 196 (2),
140 (25), 91 (100), 57 (26). Calcd for C24H31O4ClS: M,
450.1632. Found; m/z 450.1636.
157 (47), 139 (25), 91 (27). Calcd for C21H34O4S; M,
28
382.2178. Found: m/z 382.2188. ½aꢁD ¼ ꢀ0:5 (c 2.8,
ethanol).
3.16. (2R)-(ꢀ)-tert-Butyl 2-{1-[(p-tolylsulfonyl)methyl]-
Minor diastereomer: Colorless oil; IR (neat) 2979, 2934,
1739 (CO), 1463, 1393, 1369, 1159, 1112, 1055 (SO),
cyclopentadecyl}hexanoate 11h
811 cmꢀ1 1H NMR d 1.31 (3H, s), 1.51 (9H, s), 1.52
;
Colorless oil; IR (neat) 2929, 2871, 1715 (CO), 1597, 1462,
(3H, s), 2.43 (3H, s), 4.23 (1H, s), 4.36, 4.55 (each 1H, d,
J = 11.0 Hz), 4.87 (1H, s), 7.26–7.37 (7H, m), 7.71 (2H,
d, J = 8.0 Hz).
1
1367, 1316, 1148 (SO2), 1087, 915, 817 cmꢀ1; H NMR d
0.88 (3H, t, J = 7.4 Hz), 1.2–1.5 (28H, m), 1.5–1.7 (4H,
m), 1.9–2.0 (1H, m), 2.44 (3H, s), 2.56–2.58 (1H, m),
3.23, 3.46 (each 1H, d, J = 14.4 Hz), 7.33, 7.79 (each 2H,
d, J = 8.4 Hz). MS m/z (%) 548 (M+, trace), 474 (12),
377 (64), 337 (31), 319 (24), 221 (100), 157 (25), 139 (9),
3.19. (R)-(+)-3-Benzyloxy-4,4-dimethyldihydrofuran-2-one
14a
97 (18), 57 (40). Calcd for C33H56O4S; M, 548.3899.
Found: m/z 548.3903. ½aꢁD ¼ ꢀ1:9 (c 0.9, ethanol).
A solution of NaI (56.5 mg; 0.375 mmol) in 5 mL of dry
acetone was stirred for 15 min at ꢀ55 °C. TFAA
(0.53 mL; 0.375 mmol) was added dropwise to the solution
of NaI with stirring at ꢀ55 °C and the solution was stirred
for 15 min. Adduct 13a (33 mg; 0.075 mmol) in 1.5 mL of
dry acetone was added dropwise to the suspension of
NaI and TFAA at ꢀ55 °C with stirring and the reaction
mixture was stirred for 10 min. The reaction was quenched
by adding satd aq NaHCO3 followed by satd aq Na2SO3.
The whole was extracted with CHCl3. The organic layer
27
3.17. (R)-(ꢀ)-2,3,3-Trimethylbutyric acid 12
AIBN (9.8 mg; 0.06 mmol) was added to a solution of 10a
(72.2 mg; 0.20 mmol) and Bu3SnH (0.14 mL; 0.30 mmol) in
5 mL of benzene. The atmosphere in the flask was replaced
with argon, and the reaction mixture was stirred and re-
fluxed for 30 min. The solvent was removed in vacuo and

1944
M. Kido et al. / Tetrahedron: Asymmetry 18 (2007) 1934–1947
was washed with satd aq NaHCO3 and dried over MgSO4.
The solvent was removed in vacuo and the residue was
purified by silica gel column chromatography to give c-tol-
ylsulfanyl c-lactone as a mixture of two diastereomers. m-
CPBA (49.4 mg; 0.2 mmol) was added to a solution of
the c-tolylsulfanyl c-lactone in 10 mL of CH2Cl2 at 0 °C
with stirring. The solution was stirred for 30 min, and the
reaction was quenched by adding satd aq Na2SO3 and satd
aq NaHCO3. The whole was extracted with CH2Cl2. The
organic layer was washed with satd aq NaHCO3 and dried
over MgSO4. The product was purified by silica gel column
chromatography to give c-sulfinyl c-lactone as a colorless
was washed with satd aq NH4Cl. The product was puri-
fied by silica gel column chromatography to afford 15a
(46.9 mg; 99%) as colorless crystals; mp 84–85 °C (hex-
ane–AcOEt). IR (KBr) 2970, 2935, 2834, 1720 (CO),
1152, 1055, 738 cmꢀ1 1H NMR d 1.00 (3H, s), 1.50
;
(9H, s), 1.59 (3H, s), 2.41 (3H, s), 3.67 (2H, d,
J = 13.7 Hz), 3.75 (1H, s), 4.06 (2H, d, J = 13.7 Hz),
4.92 (1H, s), 7.25–7.29 (4H, m), 7.33, 7.36 (4H, m),
7.39–7.41 (2H, m), 7.64 (2H, d, J = 8.1 Hz). MS m/z (%)
540 (M+, trace), 448 (5), 438 (5), 392 (2), 310 (22), 264
(18), 254 (65), 210 (8), 181 (5), 139 (5), 91 (100). Calcd
for C31H39ClNO3S: M, 540.2340. Found: m/z 540.2332.
Anal. Calcd for C31H39ClNO3S: C, 68.93; H, 7.09; Cl,
6.56; N, 2.59; S, 5.94. Found: C, 68.73; H, 7.22; Cl,
6.40; N, 2.30; S, 5.60.
i
oil. PrMgCl (2.0 mol/L in THF; 0.06 mL, 0.12 mmol)
was added to a solution of the c-tolylsulfinyl c-lactone at
ꢀ78 °C with stirring under argon atmosphere. The solution
was stirred for 15 min at ꢀ78 °C, and the reaction was
quenched by adding satd aq NH4Cl. The whole was ex-
tracted with CHCl3. The product was purified by silica
gel column chromatography to afford 14a (18.9 mg; three
steps 79%) as a colorless oil; IR (neat) 2967, 2916,
3.23. tert-Butyl 2-dibenzylamino-2-{1-[chloro(p-tolylsulfi-
nyl)methyl]cyclohexyl}acetate 15b
Colorless oil; IR (neat) 2929, 2867, 1723 (CO), 1455, 1367,
1788(CO), 1465, 1374, 1199, 1156, 1009, 749 cmꢀ1
;
1H
1143, 1052 (SO), 753 cmꢀ1; H NMR d 1.2–1.5 (10H, m),
1
NMR d 1.10 (3H, s), 1.13 (3H, s), 3.73 (1H, s), 3.87 (1H,
d, J = 8.9 Hz), 4.00 (1H, d, J = 8.9 Hz), 4.75, 5.04 (each
1H, d, J = 12.2 Hz), 7.29–7.40 (5H, m). MS m/z (%) 220
1.52 (9H, s), 1.93 (1H, d, J = 15.0 Hz), 2.42 (3H, s), 2.83
(1H, m), 3.55 (2H, d, J = 13.7 Hz), 4.12 (1H, s), 4.92
(1H, s), 7.2–7.6 (14H, m).
(M+, 0.5), 114 (45), 99 (85), 91 (100). Calcd for
28
C13H16O3: M, 220.1100. Found; m/z 220.1101. ½aꢁD
¼
3.24. (R)-(+)-3-Dibenzylamino-4,4-dimethyldihydrofuran-
2-one 16a
þ112:5 (c 0.22, CHCl3, 99% ee).
3.20. tert-Butyl 2-benzyloxy-2-{1-[chloro(p-tolylsulfinyl)-
methyl]cyclohexyl}acetate 13b
A solution of NaI (96.8 mg; 0.630 mmol) in 4 mL of dry
acetone was stirred for 15 min at ꢀ55 °C. TFAA
(0.092 mL; 0.630 mmol) was added dropwise to a solution
of NaI with stirring at ꢀ55 °C and the solution was stirred
for 15 min. Adduct 15a (68 mg; 0.126 mmol) in 1 mL of dry
acetone was added dropwise to the solution of NaI and
TFAA at ꢀ55 °C dropwise with stirring and the reaction
mixture was stirred for 10 min. The reaction was quenched
by adding satd aq NaHCO3 followed by satd aq Na2SO3.
The whole was extracted with CHCl3. The organic layer
was washed with satd aq NaHCO3 and dried over MgSO4.
The solvent was evaporated and the residue was purified by
silica gel column chromatography to give c-tolylsulfanyl
c-lactone as a mixture of two diastereomers.
Colorless oil; IR (neat) 2978, 2931, 1739 (CO), 1495, 1456,
1
1394, 1368, 1159, 1083, 1060 (SO), 755 cmꢀ1; H NMR d
1.22–1.75 (10H, s), 1.40 (9H, s), 2.40 (3H, s), 4.26 (1H,
s), 4.55, 4.67 (each 1H, d, J = 11.4 Hz), 4.94 (1H, s),
7.22–7.38 (5H, m), 7.44–7.49 (2H, m), 7.58–7.65 (2H,
m). MS m/z (%) 490 (M+, trace), 474 (0.2), 389 (30),
295 (27), 230 (31), 169 (33), 140 (100), 91 (100), 57 (88).
Calcd for C27H35O4ClS: M, 490.1944. Found: m/z
490.1949.
3.21. (R)-(+)-4-Benzyloxy-2-oxaspiro[4.5]decan-3-one 14b
Colorless oil; IR (neat) 2927, 2858, 1791 (CO), 1455, 1163,
m-CPBA (32.8 mg; 0.138 mmol) was added to a solution of
the c-tolylsulfanyl c-lactones in CH2Cl2 at 0°C with stir-
ring. The solution was stirred for 30 min, and the reaction
was quenched by adding satd aq Na2SO3 and satd aq NaH-
CO3. The whole was extracted with CH2Cl2. The product
was purified by silica gel column chromatography to afford
a mixture of c-tolylsulfinyl c-lactones.
1
1146, 736 cmꢀ1; H NMR d 1.23–1.76 (10H, m), 3.71 (1H,
s), 3.87, 4.24 (each 1H, d, J = 8.9 Hz), 4.71, 5.02 (each 1H,
d, J = 11.8 Hz), 7.28–7.42 (5H, m). MS m/z (%) 260 (M+,
0.1), 154 (100), 111 (50), 91 (82), 81 (8). Calcd for
27
C16H20O3: M, 260.1413. Found m/z 260.1418. ½aꢁD
¼
þ101:2 (c 0.91, CHCl3).
3.22. tert-Butyl 2-dibenzylamino-4-chloro-3,3-dimethyl-4-
(p-tolylsulfinyl)butanoate 15a
iPrMgCl (2.0 mol/L, in THF; 0.41 mL) was added to a
solution of the c-tolylsulfinyl c-lactones (60.6 mg;
0.135 mmol) at ꢀ78 °C with stirring under argon atmo-
sphere. The solution was stirred for 15 min at ꢀ78 °C
and the reaction was quenched by adding satd aq NH4Cl.
The whole was extracted with CHCl3. The product was
purified by silica gel column chromatography to afford
16a (37.5 mg; 78%; three steps) as colorless crystals; mp
128–129 °C (hexane); IR (KBr) 2923, 1765 (CO), 1494,
A
solution of N,N-dibenzylglycine tert-butyl ester
(204 mg; 0.656 mmol) in THF was added to a solution
of LDA (0.656 mmol) in 4 mL of dry THF at ꢀ45 °C with
stirring. The solution was stirred for 15 min, then a solu-
tion of 9a (20 mg; 0.0874 mol) in THF (0.5 mL) was
added. The solution was stirred for 1 h at ꢀ45 °C, and
the reaction was quenched by adding satd aq NH4Cl.
The whole was extracted with CHCl3. The organic layer
1
1453, 1365, 1131, 1025, 1015 cmꢀ1; H NMR d 1.21 (3H,
s), 1.84 (3H, s), 3.35 (1H, s), 3.78 (1H, d, J = 9.0 Hz),

M. Kido et al. / Tetrahedron: Asymmetry 18 (2007) 1934–1947
1945
3.86 (2H, d, J = 14.1 Hz), 3.92 (1H, d, J = 9.0 Hz), 3.98
(2H, d, J = 14.1 Hz), 7.26–7.29 (2H, m), 7.34–7.37 (4H,
m), 7.45–7.47 (4H, m). Anal. Calcd for C20H23NO2: C,
m), 4.16–4.22 (1H, m), 4.29–4.36 (1H, m), 4.50 (0.8H, dd,
J = 5.3, 3.7 Hz), 4.65 (0.2H, dd, J = 7.7, 5.3 Hz), 7.36
(2H, d, J = 8.0 Hz), 7.55 (0.4H, d, J = 8.3 Hz), 7.68
(1.6H, d, J = 8.3 Hz). MS m/z (%) 218 (M+, 6), 171 (4),
166 (4), 140 (100), 139 (70), 123 (8), 111 (7), 92 (63), 91
(42). Calcd for C9H11ClO2S: M, 218.0168. Found m/z
218.0167.
77.64; H, 7.49; N, 4.53. Found: C, 77.53; H, 7.35; N,
29
4.28. ½aꢁD ¼ þ137 (c 0.47, ethanol).
3.25. (R)-(ꢀ)-(4,4-Dimethyl-2-oxotetrahydrofuran-3-yl)-
carbamic acid methyl ester 17
3.28. (R)-1-Chloroethenyl p-tolyl sulfoxide 9d
10% Pd on carbon (83 mg) was added to a solution of 16a
(83 mg; 0.268 mmol) in 15 mL of 4.4% formic acid in meth-
anol at room temperature. The solution was stirred for 2 h
at 40 °C. The Pd on carbon was filtered off, and the filtrate
was concentrated in vacuo to give a residue. Methyl chlo-
roformate (0.024 mL; 0.32 mmol) was added to a solution
of the residue in 4 mL of water and 0.3 mL of 1 M
K2CO3 at 0 °C with stirring. The reaction mixture was stir-
red for 3 h at room temperature. The whole was extracted
with diethyl ether. The product was purified by silica gel
column chromatography to afford 17 (33.1 mg; 66%) as
colorless crystals; mp 94–95 °C (hexane); IR (KBr) 3321
(NH), 2960, 2924, 1775 (CO), 1763 (CO), 1728 (CO),
To a solution of 18 (100 mg; 0.46 mmol) in 5 mL of dry
CH2Cl2 was added triethylamine (0.46 mL; 3.45 mmol) fol-
lowed by methanesulfonyl chloride (0.09 mL; 1.15 mmol)
with stirring at 0 °C. The reaction mixture was stirred at
0 °C for 10 min and at room temperature for 6 h. The reac-
tion was quenched with water, and the whole was extracted
with CH2Cl2. The organic layer was washed successively
with 10% HCl and satd NaHCO3. The organic layer was
dried over MgSO4 and concentrated in vacuo. The residue
was purified by silica gel column chromatography to afford
9d (84 mg; 92%) as a colorless oil; IR (neat) 3100, 3008,
2925, 1606 (C@C), 1492, 1454, 1399, 1092, 1063 (SO),
1
1715 (CO), 1554, 1259, 1064 cmꢀ1; H NMR d 1.01 (3H,
906 cmꢀ1 1H NMR d 2.42 (3H, s), 5.96 (1H, d,
;
s), 1.26 (3H, s), 3.73 (3H, s), 4.04 (2H, m), 4.42 (1H, d,
J = 7.8 Hz), 5.04 (1H, s). ½aꢁD ¼ ꢀ82 (c 1.0, CHCl3).
J = 3.0 Hz), 6.44 (1H, d, J = 3.0 Hz), 7.32, 7.60 (each
2H, d, J = 8.1 Hz). MS m/z (%) 200 (M+, 20), 152 (48),
139 (100), 123 (23), 117 (17), 91 (38). Calcd for C9H9ClOS:
M, 200.0053. Found m/z 200.0063.
28
3.26. (R)-(+)-4-Dibenzylamino-2-oxaspiro[4.5]decan-3-one
16b
3.29. tert-Butyl 2-dibenzylamino-4-chloro-4-(p-tolylsulfinyl)-
butanoate 15c
Colorless crystals; mp 116–117 °C (hexane); IR (KBr)
1
3020, 2936, 1765 (CO), 1216, 757, 669 cmꢀ1; H NMR d
1.23–1.81 (10H, m), 3.27 (1H, s), 3.80 (2H, d, J =
13.7 Hz), 3.84 (1H, d, J = 9.3 Hz), 3.87 (2H, d, J =
13.7 Hz), 4.14 (1H, d, J = 9.3 Hz), 7.24–7.29 (2H, m),
7.32–7.38 (4H, m), 7.44–7.48 (4H, m). Anal. Calcd
Colorless oil; IR (neat) 2977, 2930, 1722 (CO), 1494, 1455,
1
1368, 1150, 1086, 1057 (SO), 751 cmꢀ1; H NMR d 1.52
(9H, s), 2.1–2.2 (1H, m), 2.42 (3H, s), 2.6–2.7 (1H, m),
3.53 (1H, dd, J = 8.0, 6.1 Hz), 3.62, 3.80 (each 2H, d,
J = 13.6 Hz), 4.57 (1H, dd, J = 10.7, 6.0 Hz), 7.21–7.37
(12H, m), 7.43–7.47 (2H, m). MS m/z (%) 511 (M+, 0.1),
494 (10), 422 (27), 420 (70), 358 (30), 272 (100), 254 (42),
236 (35), 180 (25), 139 (25), 91 (100). Calcd for
C29H34ClNO3S: M, 511.1948. Found; m/z 511.1941.
for C23H27NO2: C, 79.05; H, 7.79; N, 4.01. Found: C,
27
79.00; H, 7.65; N, 3.77. ½aꢁD ¼ þ91:5 (c 1.0, ethanol, 99%
ee).
3.27. 2-Chloro-2-(p-tolylsulfinyl)ethanol 18
A solution of (R)-(ꢀ)-2 (100 mg; 0.53 mmol) in 1 mL of dry
THF was added dropwise to a solution of LDA
(0.74 mmol) in 4 mL of THF at ꢀ65 °C. The solution
was stirred at ꢀ65 °C for 10 min, and then methyl formate
(0.164 mL; 2.65 mmol) was added. The reaction mixture
was stirred for 10 min and the reaction was quenched with
satd aq NH4Cl. The whole was extracted with CH2Cl2 and
the organic layer was washed with satd aq NH4Cl and
dried over MgSO4. The solvent was evaporated to give a
solid residue. A solution of NaBH4 (19.4 mg) in 2 mL of
ethanol was added dropwise to a solution of the solid res-
idue in 3 mL of ethanol at room temperature for 20 min,
then the reaction was quenched by adding NH4Cl. The sol-
vent was evaporated and the residue was extracted with
CHCl3. The organic layer was washed with satd aq NH4Cl
and dried over MgSO4. The solvent was evaporated and
the residue was purified by silica gel column chromatogra-
phy to give 18 (116 mg; two steps 82%; about 4:1 diastereo-
meric mixture) as a colorless oil; IR (neat) 3391 (OH),
3.30. (R)-(+)-3-Dibenzylaminodihydrofuran-2-one 16c
Colorless oil; IR (neat) 2919, 1770 (CO), 1494, 1455, 1373,
1
1180, 1150, 1022, 750 cmꢀ1; H NMR d 2.2–2.3 (2H, m),
3.68, 3.92 (2H, d, J = 13.7 Hz), 3.76 (1H, t, J = 9.5 Hz),
4.08–4.12 (1H, m), 4.30–4.36 (1H, m), 7.24–7.27 (2H, m),
7.29–7.34 (4H, m), 7.40–7.44 (4H, m). MS m/z (%) 281
(M+, 5), 196 (20), 190 (10), 146 (88), 132 (25), 91 (100).
Calcd for C18H19NO2: M, 281.1416. Found: m/z
28
281.1412. ½aꢁD ¼ þ26:5 (c 0.22, ethanol).
3.31. tert-Butyl 2-{1-[chloro(p-tolylsulfinyl)methyl]cyclo-
pentadecyl}propionate 19a
tert-Butyl propionate (0.36 mL; 2.4 mmol) was added to a
solution of LDA (0.6 mmol) in the presence of HMPA
(0.4 mL; 2.4 mmol) in 5 mL of dry THF at ꢀ78 °C with
stirring. The solution was stirred for 10 min, then a solu-
tion of 9c (47.4 mg; 0.12 mmol) in THF (0.5 mL) was
added. The reaction mixture was stirred at ꢀ78 °C for
5 min and the reaction temperature was allowed to warm
2924, 1651, 1596, 1494, 1455, 1086 (SO), 1039, 813 cmꢀ1
1H NMR d 2.43 (0.6H, s), 2.44 (2.4H, s), 3.75–3.78 (1H,
;

1946
M. Kido et al. / Tetrahedron: Asymmetry 18 (2007) 1934–1947
to ꢀ50 °C, and was stirred for 2 h. The reaction was
quenched by adding satd aq NH4Cl. The whole was ex-
tracted with CHCl3. The organic layer was washed with
satd aq NH4Cl and dried over MgSO4. The product was
purified by silica gel column chromatography to afford
19a (58.6 mg; 93%) as colorless oil (ca. 9:1 diastereomeric
mixture); IR (neat) 2928, 2857, 1728 (CO),1715 (CO),
1.26 (2.4H, s), 1.31 (0.6H, s), 1.32 (2.4H, s), 1.47 (9H, s),
2.41 (3H, s), 2.43 (0.8H, q, J = 7.2 Hz), 2.55 (0.2H,
q, J = 7.2 Hz), 2.66 (0.8H, d, J = 13.8 Hz), 2.82 (0.2H, d,
J = 14.4 Hz), 2.89 (0.2H, d, J = 14.4 Hz), 2.97 (0.8H,
d, J = 13.8 Hz), 7.32 (2H, d, J = 7.8 Hz), 7.51 (1.6H, d,
J = 7.8 Hz), 7.52 (0.4H, d, J = 7.8 Hz). MS m/z (%) 324
(M+, trace), 308 (5), 269 (100), 267 (70), 251 (23), 213
(19), 177 (18), 155 (16), 140 (38), 129 (77). Calcd for
C18H28O3S: M, 324.1759. Found: m/z 324.1768.
1
1597, 1456, 1368, 1256, 1153, 1057 (SO) cmꢀ1; H NMR
d 1.29 (3H, d, J = 7.2 Hz), 1.2–1.5 (28H, m), 1.46 (9H, s),
2.42 (0.3H, s), 2.43 (2.7H, s), 2.87 (0.1H, q, J = 7.2 Hz),
3.04 (0.1H, q, J = 7.2 Hz), 3.21 (0.9H, q, J = 7.2 Hz),
3.42 (0.9H, q, J = 7.2 Hz), 4.60 (0.1H, s), 5.05 (0.9H,
s), 7.31 (1.8H, d, J = 8.4 Hz), 7.71 (0.2H, d, J = 7.8 Hz),
7.74 (1.8H, d, J = 8.4 Hz). MS m/z (%) 524 (M+, trace),
507 (trace), 451 (10), 329 (30), 293 (100), 275 (13), 236
(8), 219 (38), 140 (80), 95 (14). Calcd for C30H49ClO3S:
M, 524.3091. Found: m/z 524.3088.
References
1. Some monographs for the chemistry of carboxylic acids,
amides, lactones, and their derivatives: (a) Patai, S. The
Chemistry of Carboxylic Acids and Esters; John Wiley
and Sons: London, 1969; (b) Zabicky, J. The Chemistry
of Amides; John Wiley and Sons: London, 1970; (c) Patai, S.
The Chemistry of Acid Derivatives, Parts 1 and 2; John Wiley
and Sons: Chichester, 1979; (d) Comprehensive Organic
Chemistry, Part 9; Sutherland, I. O., Ed.; Pergamon Press:
Oxford, 1979; Vol. 2; (e) Patai, S. The Chemistry of Acid
Derivatives, Parts 1 and 2; John Wiley and Sons: Chichester,
1992.
3.32. tert-Butyl 2-{1-[chloro(p-tolylsulfinyl)methyl]cyclopen-
tadecyl}butanoate 19b
Colorless oil (ca. 9:1 diastereomeric mixture); IR (neat)
2929, 2857, 1723 (CO), 1459, 1367, 1148, 1083, 1057
1
(SO), 810 cmꢀ1; H NMR (the main product is reported)
2. Recent monographs and reviews for the chemistry and
synthesis of a-amino acids: (a) Chemistry and Biochemistry
of the Amino Acids; Barrett, G. C., Ed.; Chapman and Hall:
London, 1985; (b) Williams, R. M. Synthesis of Optically
Active a-Amino Acids; Pergamon Press: Oxford, 1989; (c)
Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymme-
try 2000, 11, 645; (d) Beller, M.; Eckert, M. Angew. Chem.,
Int. Ed. 2000, 39, 1010; (e) Groger, H. Chem. Rev. 2003,
103, 2795; (f) Ma, J.-A. Angew. Chem., Int. Ed. 2003, 42,
4290.
d 0.88 (3H, t, J = 7.2 Hz), 1.2–1.5 (30H, m), 1.50 (9H, s),
2.43 (3H, s), 2.76 (1H, dd, J = 9.6, 4.8 Hz), 4.90 (1H, s),
7.31, 7.72 (each 2H, d, J = 8.4 Hz). MS m/z (%) 538
(M+, trace), 465 (8), 343 (43), 307 (100), 289 (15), 261
(11), 219 (32), 140 (57), 139 (18). Calcd for C31H51ClO3S:
M, 538.3248. Found: m/z 538.3248.
3.33. tert-Butyl {1-[(p-tolylsulfinyl)methyl]cyclopentacecyl}-
propionate 20a
3. (a) Heathcock, C. H. The Aldol Addition Reaction. In
Asymmetric Synthesis, Part B; Morrison, J. D., Ed.; Aca-
demic Press: Orland, 1984; Vol. 3, pp 111–212; (b) Nerz-
Stormes, M.; Thornton, E. R. J. Org. Chem. 1991, 56, 2489;
(c) Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1991, 56,
5747; (d) Evans, D. A.; Bilodeau, M. T.; Somers, T. C.;
Clardy, J.; Cherry, D.; Kato, Y. J. Org. Chem. 1991, 56, 5750;
(e) Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000,
33, 432.
4. Some recent papers concerning this chemistry: (a) Myers, A.
G.; Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem. Soc.
1994, 116, 9361; (b) Shioiri, T. Farumashia 1997, 33, 599; (c)
Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.;
Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119,
6496; (d) Horikawa, M.; Busch-Petersen, J.; Corey, E. J.
Tetrahedron Lett. 1999, 40, 3843; (e) Nelson, A. Angew.
Chem., Int. Ed. 1999, 38, 1583; (f) Ooi, T.; Kameda, M.;
Tannai, H.; Maruoka, K. Tetrahedron Lett. 2000, 41, 8339;
(g) Juhl, K.; Jorgensen, K. A. J. Am. Chem. Soc. 2002, 124,
2420; (h) Jew, S.-S.; Jeong, B.-S.; Lee, J.-H.; Yoo, M.-S.; Lee,
Y.-J.; Park, B.-S.; Kim, M. G.; Park, H.-G. J. Org. Chem.
2003, 68, 4514; (i) Trost, B. M.; Jiang, C. Org. Lett. 2003, 5,
1563; (j) Ooi, T.; Maruoka, K. J. Syn. Org. Chem. Jpn. 2003,
61, 1195; (k) Ooi, T.; Uematsu, Y.; Maruoka, K. Tetrahedron
Lett. 2004, 45, 1675; (l) Park, E. J.; Kim, M. H.; Kim, D. Y.
J. Org. Chem. 2004, 69, 6897.
Colorless oil; IR (neat) 2929, 2857, 1717 (CO), 1457, 1367,
1
1249, 1147, 1084, 1048 (SO), 850, 810 cmꢀ1; H NMR d
1.30 (3H, d, J = 7.8 Hz), 1.2–1.5 (28H, m), 1.43 (9H, s),
2.41 (3H, s), 2.65 (1H, q, J = 7.8 Hz), 2.90, 3.05 (each
1H, d, J = 14.4 Hz), 7.31, 7.59 (each 2H, d, J = 7.8 Hz).
MS m/z (%) 490 (M+, trace), 474 (12), 417 (10), 344 (12),
296 (22), 295 (100), 277 (15), 140 (25), 83 (70). Calcd for
C30H50O3S: M, 490.3480. Found: m/z 490.3480.
3.34. tert-Butyl {1-[(p-tolylsulfinyl)methyl]cyclopentadecyl}-
butanoate 20b
Colorless oil; IR (neat) 2391, 2857, 1715 (CO), 1460, 1366,
1
1257, 1147, 1084, 1044 (SO), 811 cmꢀ1; H NMR d 0.93
(3H, t, J = 7.2 Hz), 1.2–1.5 (28H, m), 1.44 (9H, s), 1.6–
1.9 (2H, m), 2.37–2.40 (1H, m), 2.40 (3H, s), 2.85, 3.09
(each 1H, d, J = 14.4 Hz), 7.31, 7.59 (each 2H, d,
J = 7.8 Hz). MS m/z (%) 504 (M+, trace), 488 (10), 431
(12), 344 (13), 309 (100), 291 (23), 140 (23), 97 (11). Calcd
for C31H52O3S: M, 504.3637. Found: m/z 504.3632.
3.35. tert-Butyl 2,3,3-trimethyl-4-(p-tolylsulfinyl)butanoate
22
5. Satoh, T.; Sugiyama, S.; Kamide, Y.; Ota, H. Tetrahedron
2003, 59, 4327.
6. Sugiyama, S.; Kido, M.; Satoh, T. Tetrahedron Lett. 2005, 46,
6771.
7. Satoh, T.; Oohara, T.; Ueda, Y.; Yamakawa, K. J. Org.
Chem. 1989, 54, 3130.
Colorless oil (ca. 4:1 diastereomeric mixture); IR (neat)
2973, 2874, 1721 (CO), 1459, 1367, 1254, 1223, 1146,
1
1085 (SO), 1043, 849, 811 cmꢀ1; H NMR d 1.10 (2.4H,
d, J = 7.2 Hz), 1.12 (0.6H, d, J = 7.2 Hz), 1.25 (0.6H, s),

M. Kido et al. / Tetrahedron: Asymmetry 18 (2007) 1934–1947
1947
8. Rangaishenvi, M. V.; Singaram, B.; Brown, H. C. J. Org.
Chem. 1991, 56, 3286.
9. (a) Satoh, T.; Sugiyama, S.; Ota, H. Tetrahedron Lett. 2002,
43, 3033; (b) Satoh, T.; Sugiyama, S.; Kamide, Y.; Ota, H.
Tetrahedron 2003, 59, 4327.
13. Versleijen, J. P.; Sanders–Hovens, M. S.; Vanhommerig, S.
A.; Vekemans, J. A.; Meijer, E. M. Tetrahedron 1993, 49,
7793.
14. Sugiyama, S.; Satoh, T. Tetrahedron: Asymmetry 2005, 16,
665.
10. Sugiyama, S.; Shimizu, H.; Satoh, T. Tetrahedron Lett. 2006,
47, 8771.
11. Mori, T.; Takahashi, K.; Kashiwabara, M.; Umeura, D.
Tetrahedron Lett. 1985, 26, 1073 (S)-14a, [a]D = ꢀ114 (c 1.9,
CHCl3).
15. (a) Seebach, D.; Amstutz, R.; Laube, T.; Schweizer, W. B.;
Dunitz, J. D. J. Am. Chem. Soc. 1985, 107, 5403; (b) Petersen,
J. B.; Corey, E. J. Tetrahedron Lett. 2000, 41, 2515; (c)
Guanti, G.; Banfi, L.; Narisano, E.; Scolastico, C. Tetra-
hedron 1988, 44, 3671.
12. (a) ElAmin, B.; Anantharamaiah, G. M.; Royer, G. P.;
Means, G. A. J. Org. Chem. 1979, 44, 3442; (b) Davies, S. G.;
Epstein, S. W.; Garner, A. C.; Ichihara, O.; Smith, A. D.
Tetrahedron: Asymmetry 2002, 13, 1555.
16. (a) Ireland, R. E.; Wipf, P.; Armstrong, J. D., III J. Org.
Chem. 1991, 56, 650; (b) Tanaka, F.; Fuji, K. Tetrahedron
Lett. 1992, 33, 7885; (c) Otera, J.; Fujita, Y.; Fukuzumi, S.
Synlett 1994, 213.