Practical synthesis of chiral cis-cyclohex-4-ene-1,2-dicarboxylic acid derivatives by utilizing (4S)-isopropyl-1,3-thiazolidine-2-thione

Article abstract of DOI:10.3987/COM-05-10356

Both enantiomers of chiral cis-cyclohex-4-ene-1,2-dicarboxylic acid derivatives were synthesized by optical resolution of the corresponding enantiomeric mixtures by utilizing (4S)-isopropyl-1,3-thiazolidine-2-thione followed by mild aminolysis, methanolys

Full text of DOI:10.3987/COM-05-10356

HETEROCYCLES, Vol. 65, No. 5, 2005
1139
HETEROCYCLES, Vol. 65, No. 5, 2005, pp. 1139 - 1157
Received, 31st January, 2005, Accepted, 11th March, 2005, Published online, 11th March, 2005
PRACTICAL SYNTHESIS OF CHIRAL CIS-CYCLOHEX-4-ENE-1,2-
DICARBOXYLIC ACID DERIVATIVES BY UTILIZING (4S)-
ISOPROPYL-1,3-THIAZOLIDINE-2-THIONE†
Tinh Van Dang,a Motoyuki Miyamoto,a Shigeki Sano,a Motoo Shiro,b and
Yoshimitsu Nagaoa*
a Graduate School of Pharmaceutical Sciences, The University of Tokushima,
Sho-machi, Tokushima 770-8505, Japan
b Rigaku Corporation, 3-9-12 Matsubara-cho, Akishima, Tokyo 196-8666, Japan
Abstract – Both enantiomers of chiral cis-cyclohex-4-ene-1,2-dicarboxylic acid
derivatives were synthesized by optical resolution of the corresponding
enantiomeric mixtures by utilizing (4S)-isopropyl-1,3-thiazolidine-2-thione
followed by mild aminolysis, methanolysis, and hydrolysis.
INTRODUCTION
Chiral differentiation between two identical carbonyl groups of prochiral s-symmetric dicarboxylic
acids utilizing an enzymatic or a nonenzymatic procedure should be a rational strategy for asymmetric
syntheses of biologically active compounds, because the resultant chiral products can be subjected to
further “enantioconvergent and enantiodivergent” transformation on the basis of latent s-symmetry.1
Previously, we reported a novel nonenzymatic chiral induction into prochiral s-symmetric dicarboxylic
acids by utilizing a functional heterocycle, (4R or 4S)-methoxycarbonyl-1,3-thiazolidine-2-thione.1-4 In
the course of our series of studies on the chiral induction utilizing C4-chiral 1,3-thiazolidine-2-thiones,2-6
we achieved a highly enantioselective aminolysis of cis-cyclohex-4-ene-1,2-dicarboxylic anhydride (1) by
employing the sodium salt of (4S)-isopropyl-1,3-thiazolidine-2-thione [(4S)-IPTT]6 in THF-DMSO.7 This
particular meso compound (1) is a useful prochiral precursor for asymmetric synthesis of biologically
active compounds such as carbapenems, (+)-carbacyclin, and enzyme inhibitors (vide infra).8,9 (4S)-
IPTT seemed to be available not only for asymmetric aminolysis of prochiral dicarboxylic anhydrides but
†ꢀDedicated to Dr. Pierre Potier, Emeritus Director of C.N.R.S., in celebration of his 70th birthday.

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HETEROCYCLES, Vol. 65, No. 5, 2005
also practically useful for optical resolution of the enantiomeric mixtures of various chiral carboxylic
acids, due to the easy crystallization of its carboxylic amides and easy separation of both the yellow
diastereomers by monitoring their yellow bands on a silica gel column. Acylamides of N-methoxy-N-
methylamine (Weinreb amine) have been widely used as versatile synthetic intermediates in organic
synthesis since they react with Grignard and other organometallic reagents to give the corresponding
ketones.10 Here, we report the practical syntheses of chiral cis-cyclohex-4-ene-1,2-dicarboxylic acid
derivatives by utilizing asymmetric aminolysis or optical resolution with (4S)-IPTT followed by
aminolysis of the (4S)-IPTT amides with the Weinreb amine and other amines. Both enantiomers of chiral
cis-cyclohex-4-ene-1,2-dicarboxylic acid derivatives should be useful for development of new enzyme
inhibitors (vide infra).
RESULTS AND DISCUSSION
Asymmetric aminolysis of dicarboxylic anhydride (1) with sodium salt of (4S)-IPTT in THF-DMSO at
–50 - –40 °C gave a crude monocarboxylic acid (2), which was treated with TMSCHN2 in MeOH-
benzene (2:7) to afford methyl ester (3) in 80% yield and 94% ee as shown in Scheme 1. The
stereochemistry of 3 was determined by its chemical conversion to the antipodal compound (6) of the
known lactone via reduction of 3 with NaBH4 in EtOH-H2O (2:1) followed by lactonization of the
resulting hydroxymethyl derivative with a catalytic amount of TsOH in toluene at 110 °C for 1 h as
shown in Scheme 2.9 The crude (4S)-IPTT amide (2) was allowed to react with N-methoxy-N-
methylamine hydrochloride in the presence of Et3N to afford the optically active amide (4). However, the
chiral Weinreb monoamide (4) could not be furnished; instead, racemic amide (4) was obtained in 56%
yield from 1. This outcome can be explained as follows. In the presence of a small excess of Et3N and N-
methoxy-N-methylamine, the resulting carboxylate would attack to the carbonyl group of the (4S)-IPTT
amide moiety bearing an “active amide structure” to generate anhydride (1), which has been shown to
react with the Weinreb amine to afford racemic amide (4). When dicarboxylic anhydride (1) was
subjected to aminolysis with the Weinreb amine followed by methylation with TMSCHN2, a racemic
methyl ester (5a and 5b) was obtained in 63% yield from 1. Thus, the chiral Weinreb monoamide (5a) (>
93% ee) could be obtained in 90% yield by reaction of 3 (94% de, 80% yield from 1) with N-methoxy-N-
methylamine. In this reaction (3Æ5a), no cyclization and no epimerization occurred as shown in Scheme
1.
Optical resolution of racemic amide (4) obtained from 1 in 71% yield was carried out by utilizing (4S)-
IPTT. Dehydrative condensation of 4 with (4S)-IPTT in the presence of 1-ethyl-3-(3-

HETEROCYCLES, Vol. 65, No. 5, 2005
1141
H
S
NaN
O
S
H
O
O
Me
H
H
O
O
O
HNEt3
S
H
H
S
H
H
HCl·HN
OMe
(1.5 mol eq.)
OH
N
S
(1.1 mol eq.)
O
O
S
O
S
N
S
-50 - -40 °C
THF, 1 h
Et3N (3 mol eq.)
CH2Cl2, rt, 30 min
H
O
H
O
H
1
2
1
1)
2) TMSCHN2
(2 mol eq.)
MeOH:Benzene
(2:7)
Me
HCl·HN
OMe
(1.1 mol eq.)
MeOH:Benzene
(2:7)
rt, 30 min
TMSCHN2
(2 mol eq.)
Me
HN
Et3N (2 mol eq.)
CH2Cl2, rt, 12 h
OMe
rt, 30 min
Me
O
H
O
H
O
H
H
HCl·HN
OMe
(2 mol eq.)
S
OMe
Me
OMe
OH
Me
N
S
N
N
Et3N (3 mol eq.)
DMAP (0.5 mol eq.)
CH2Cl2, rt, 24 h
S
OMe
OMe
H
O
H
O
O
H
5a
4
3
63% from 1, racemate
90% from 3, >93% ee
80% from 1, 94% de
56% from 1, racemate
Scheme 1
O
O
O
H
H
NaBH4
(1 mol eq.)
cat. p-TsOH
toluene
110 °C, 1 h
OMe
OH
3
EtOH:H2O
(2:1)
rt, 1 h
H
H
6
75% from 3
Scheme 2
dimethylaminopropyl)carbodimide hydrochloride (WSCD·HCl) in CH2Cl2 gave a mixture of two
diasteromers (7a and 7b); these compounds could not be separated on a silica gel column. When the
mixture of diasteromers (7a and 7b) was treated with hexane, one of them completely dissolved in hexane
at room temperature. After removing the solvent by filtration, chiral monoamide (7a) remained as a
yellow solid (37% yield, > 99% de) and then another chiral monoamide (7b) was obtained as a yellow oil
(43% yield, 94% de) from the filtrate. Diasteromers (7a and 7b) were converted to the corresponding
enantiomers [5a (82% yield, > 99% ee) and 5b (81% yield, 94% ee)] by methanolysis with K2CO3/MeOH,
respectively.
The stereochemistries of compounds (7a,b and 5a,b) were precisely established by X-Ray
crystallographic analysis of 7a (Figure 1) and chemical conversion of 7a to the known chiral monoamide
(5a), as shown in Scheme 3. Based on the above results, (4S)-IPTT is not only available for asymmetric

1142
HETEROCYCLES, Vol. 65, No. 5, 2005
1
H
O
Me
O
Et3N (2 mol eq.)
CH2Cl2, rt, 12 h
H
H
K2CO3
(5 mol eq.)
S
H
HCl·HN
S
OMe
(1.2 mol eq.)
H
H
OMe
Me
N
Me
1)
S
MeOH
rt, 2 h
N
S
OMe
N
HN
S
O
OMe
H
O
5a
O
OH
N
S
(1.3 mol eq.)
Me
"yellow solid"
7a
82%, >99% ee
37%, >99% de
OMe
WSCD·HCl
(2 mol eq.)
CH2Cl2, rt, 8 h
H
O
O
O
H
H
4
71%, racemate
OMe
S
K2CO3
(5 mol eq.)
OMe
N
2) hexane
3) filtration
N
Me
OMe
Me
N
MeOH
rt, 2 h
S
S
H
H
O
5b
O
H
81%, 94% ee
"yellow oil"
7b
43%, 94% de
Scheme 3
7a
Figure 1. Computer-generated drawing from the X-Ray coordinates of compound (7a)
aminolysis of prochiral dicarboxylic acid anhydride (1) with an excellent diastereoselectivity but also
practically useful for optical resolution.
Subsequently, we attempted an optical resolution of racemic cis-6-benzoylcyclohex-3-enecarboxylic acid
(8) (72% yield) that was obtained by treatment of 4 with PhMgBr in THF at 0 °C. Namely, dehydrative
condensation of 8 with (4S)-IPTT in the presence of WSCD·HCl and 4-dimethylaminopyridine (DMAP)
in CH2Cl2 gave a diasteromeric mixture of 9a and 9b. These mixtures were completely separated on a
silica gel column [hexane-AcOEt (5:1)] to give pure (4S)-IPTT amide (9a) or (9b) as a yellow solid in
40% or 24% yield with each excellent diasteromer excess (> 99% de).

HETEROCYCLES, Vol. 65, No. 5, 2005
1143
4
O
H
O
O
O
O
1)
H
H
H
TMSCHN2
(2 mol eq.)
LiOH
(2 mol eq.)
THF
0 °C
12 h
S
H
Ph
PhMgBr
(3 mol eq.)
Ph
Ph
OMe
S
N
S
S
OH MeOH:Benzene
(2:7)
rt, 30 min
HN
S
MeCN: H2O
(9:1)
0 °C, 4 h
S
H
O
H
O
H
2
5
H
S
(2 mol eq.)
1
3
4
9a
40%, >99% de
10a
70%, >99% ee
11a
90%, >99% ee
OH
Ph
6
WSCD·HCl
(2 mol eq.)
DMAP
(0.5 mol eq.)
CH2Cl2, rt, 1 h
H
O
H
O
H
H
O
H
O
TMSCHN2
(2 mol eq.)
LiOH
(2 mol eq.)
S
8
72%, racemate
OH
Ph
OMe
Ph
N
MeOH:Benzene
(2:7)
rt, 30 min
MeCN: H2O
(9:1)
0 °C, 4 h
Ph
S
2) silica gel column
H
O
H
H
O
O
9b
24%, >99% de
10b
70%, >99% ee
11b
91%, >99% ee
Scheme 4
O
H
O
H
H
K2CO3
(5 mol eq.)
K2CO3
(5 mol eq.)
Ph
OMe
Ph
OMe
MeOH
rt, 9 h
MeOH
rt, 9 h
H
O
12b
O
12a
83%, >99% ee
82%, >99% ee
9a 9b
Me
Me
HCl·HN
OMe
O
H
O
HCl·HN
H
H
OMe
Me
N
OMe
Ph
Ph
Me
N
(2 mol eq.)
(2 mol eq.)
Et3N (3 mol eq.)
DMAP (0.5 mol eq.)
CH2Cl2, rt, 24 h
Et3N (3 mol eq.)
DMAP (0.5 mol eq.)
CH2Cl2, rt, 24 h
OMe
H
O
13a
O
13b
92%, 99% ee
91%, 99% ee
Scheme 5
The stereochemistries of 9a and 9b were established by their X-Ray crystallographic analyses (Figure 2)
and by hydrolysis of 9a with LiOH in MeCN-H2O (9:1) at 0 °C to afford a known carboxylic acid, (1S,
6R)-6-benzoylcyclohex-3-enecarboxylic acid (10a)11 [mp 122–123.5 °C (hexane—CHCl3), [a]D24 -41.4°
(c 0.5, CHCl3); lit.,11 91% ee, mp 106–108 °C (MeOH—CH2Cl2), [a]D -31.9° (c 0.48, CHCl3)] in 70%
23
yield and >99% ee as shown in Scheme 4. The similar hydrolysis of 9b with LiOH furnished another
chiral carboxylic acid (10b) in 70% yield and >99% ee. Methylation of enantiomers (10a and 10b) with
TMSCHN2 gave the corresponding cis-methyl esters (11a) (>99% ee) and (11b) (>99% ee) in 90% and
91% yields, respectively. Interestingly, methanolysis of (4S)-IPTT amides (9a) and (9b) with K2CO3 in
MeOH at room temperature furnished the corresponding trans-methyl esters [12a (82% yield, >99% ee)
and 12b (83% yield, >99% ee)], respectively, as shown in Scheme 5. The trans geometry of 12a,b was
confirmed by comparing their spectroscopic data with those of the cis-methyl esters (11a,b) having the

1144
HETEROCYCLES, Vol. 65, No. 5, 2005
9a
9b
Figure 2. Computer-generated drawing from the X-Ray coordinates of compounds (9a and 9b)
O
O
O
O
H
H
H
H
Me
HN
HN
N
N
N
N
OMe
(4 mol eq.)
(4 mol eq.)
Me
OMe
CH2Cl2, rt, 3 h
CH2Cl2, rt, 3 h
14b
14a
7a
7b
91%, 91% ee
93%, >99% ee
HN
O
O
H
O
HN
O
H
Me
N
O
N
(4 mol eq.)
(4 mol eq.)
OMe
Me
N
CH2Cl2, rt, 5 h
CH2Cl2, rt, 5 h
N
O
OMe
H
H
O
O
15a
15b
91%, >99% ee
90%, 92% ee
Scheme 6
O
H
O
H
HN
HN
N
Ph
N
(4 mol eq.)
(4 mol eq.)
Ph
CH2Cl2, rt, 3 h
CH2Cl2, rt, 3 h
H
O
16a
92%, 99% ee
H
O
16b
91%, 99% ee
O
H
9a 9b
HN
O
O
H
HN
O
N
O
Ph
N
(4 mol eq.)
(4 mol eq.)
CH2Cl2, rt, 6 h
CH2Cl2, rt, 6 h
Ph
O
H
O
H
O
17a
93%, 99% ee
17b
94%, 99% ee
Scheme 7

HETEROCYCLES, Vol. 65, No. 5, 2005
1145
same elemental analysis data. In this reaction (9a,bÆ12a,b), epimerization occurred at the enolizable
chiral carbon atom bearing the benzoyl group.12
The (4S)-IPTT group of the amides bearing an “active amide structure” can be readily removed by the
reactions with a variety of nucleophiles, which allows the products to be transformed into a wide range of
derivatives.6,13 Thus, the (4S)-IPTT amides (7a,b and 9a,b) were subjected to mild aminolyses with the
Weinreb amine and some amines to obtain the corresponding enantiomerically pure Weinreb amides
(13a,b), piperidine amides (14a,b and 16a,b), and morpholine amides (15a,b and 17a,b) in excellent
yields, respectively, as shown in Schemes 5, 6 and 7. In all cases, the end point of the aminolysis could be
monitored by disappearance of the original yellow color of the (4S)-IPTT amides. The (4S)-IPTT was
recovered by flash column chromatography of each reaction mixture in a good yield.
In conclusion, we have developed practically useful procedures for the syntheses of several
enantiomerically pure amides of cis-cyclohex-4-ene-1,2-dicarboxylic acid utilizing diastereoselective
aminolysis of a prochiral dicarboxylic anhydride and optical resolution of some enantiomeric mixtures of
monocarboxylic acids by the efficient use of (4S)-IPTT. The resulting chiral amides can be useful for the
development of new enzyme inhibitors.14 The chiral compounds (9a,b and 10a,b) should specifically be
useful for syntheses of specific enzyme inhibitors and biologically active compounds such as chiral cis-
tetra- and cis-hexahydrophthalazinone (18),14 chiral 3-phenylhexahydro-1(3H)-isobenzofuranone (19),15
chiral 5-methyl-1-phenyl-1H-2,5-benzoxacine (20),16 and other biologically active natural products and
drugs.
Me
H
H
N
R
H
N
O
H
O
O
Ph
Ph
N
R
H
H
H
H
18
19
Scheme 8
20
EXPERIMENTAL
All melting points were determined on a Yanaco micro melting point apparatus and are uncorrected. IR
spectra were obtained using a JASCO FT/IR-420 IR Fourier transform spectrophotometer. 1H NMR (400
13
MHz) and C NMR (100 MHz) spectra were recorded on a JEOL JNM-AL400 spectrometer. Chemical
shifts are given in d value (ppm) using tetramethylsilane (TMS) as an internal standard. EI-MS spectrum
was recorded on a JEOL JMS SX-102A spectrometer. Elementary combustion analyses were performed
using a YANACO CHN CORDER MT-5. All reactions were monitored by TLC employing 0.25 mm

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HETEROCYCLES, Vol. 65, No. 5, 2005
silica gel plates (Merck 5715; 60 F254). Preparative TLC (PTLC) was performed on 0.5 mm silica gel
plates (Merck 5744; 60 F254). Column chromatography was carried out on silica gel [Kanto chemical 60N
(spherical, neutral); 63-210 mm]. Analytical high performance liquid chromatography (HPLC) was
performed on a JASCO model 807-IT HPLC equipped with a JASCO UV-970 intelligent UV/VIS
detector. Optical rotations were measured on a DIP-370 digital polarimeter in a 1 dm cell. Anhydrous
THF and anhydrous CH2Cl2 were used as purchased from Kanto chemical. All other reagents were used
as purchased. All reactions were carried out under argon.
Methyl (1R, 6S)-6-[(4S)-4-Isopropyl-1,3-thiazolidine-2-thion-3-yl]carbonylcyclohex-3-
enecarboxylate (3)
A suspension of 60% NaH (coated type with mineral oil, 220 mg, 5.5 mmol) in THF (6 mL) was added to
a solution of (4S)-IPTT (805 mg, 5 mmol) in THF (5 mL) at 0 °C with stirring. The mixture was stirred at
0 °C for 10 min and then anhydrous DMSO (0.43 mL, 6 mmol) was added at rt. After being stirred at rt
for 1 h, the reaction mixture was added to a solution of 1 (836.8 mg, 5.5 mmol) in THF (6 mL) at -50 oC.
The mixture was stirred at –50 - –40 °C for 1 h. The reaction was quenched with an aqueous solution (20
mL) saturated with NaHSO4 and extracted with CH2Cl2. The extract was washed with brine, dried over
MgSO4, and filtered. The filtrate was evaporated in vacuo to give a crude carboxylic acid (2), which was
treated with TMSCHN2 in ether affording methyl ester (3) (1.30 g, 80%) as a yellow oil after purification
by column chromatography on silica gel with hexane-AcOEt (4:1). [a]D18 +544.8° (c 0.90, CHCl3). IR
(neat) 3029, 1731, 1691 cm-1; 1H-NMR (400 MHz, CDCl3) d 0.95-0.97 (d, 3H, J = 7.08 Hz), 1.05-1.07 (d,
3H, J = 6.84 Hz), 2.05-2.18 (m, 1H), 2.31-2.35 (m, 1H), 2.48-2.52 (m, 1H), 2.82-2.88 (m, 1H), 3.02-3.05
(d, 1H, J = 11.47 Hz), 3.06-3.12 (m, 1H), 3.64-3.70 (m, 1H), 3.68 (s, 3H), 4.39-4.46 (ddd, 1H, J = 16.12,
10.99, 5.13 Hz), 5.02-5.05 (t, 1H, J = 7.57 Hz), 5.68-5.72 (m, 2H); HREI-MS calcd for C15H21NO3S2 MW
327.0963, found m/z 327.0955 (M+); Anal. Calcd for C15H21NO3S2 : C, 55.02; H, 6.46; N, 4.28. Found: C,
55.27; H, 6.57; N, 4.49. HPLC analysis [TSK-gel Silica 60, hexane—AcOEt (9:1), 1.0 mL/min, 305 nm;
tR (minor) = 13.22 min, tR (major) = 15.47 min] gave the isomeric composition of the product: 94% de.
Racemic cis-6-(N-Methoxy-N-methylaminocarbonyl)cyclohex-3-enecarboxylic Acid (4)
Method 1: A crude carboxylic acid (2), obtained by the synthetic method described for 3, was treated with
N-methoxy-N-methylamine hydrochloride (731 mg, 7.5 mmol) and Et3N (2.08 mL, 15 mmol) in CH2Cl2
(30 mL) at rt for 30 min. The reaction mixture was acidified with 10% HCl, and extracted with CHCl3
(3¥100 mL). The usual work-up of the CHCl3 extract followed by purification on a silica gel column with
hexane—EtOAc (1:3) afforded racemic amide (4) (0.59 g, 56%) as a white solid.

HETEROCYCLES, Vol. 65, No. 5, 2005
1147
Method 2: To a solution of 1 (3.35 g, 20 mmol) in CH2Cl2 (60 mL) were added N-methoxy-N-
methylamine hydrochloride (2.34 g, 24 mmol) and Et3N (5.5 mL, 40 mmol) at rt. The mixture was stirred
at rt for 12 h. The reaction mixture was acidified with 10% HCl and then extracted with CHCl3 (3¥100
mL). The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo.
The residue was purified by column chromatography on silica gel with hexane—EtOAc (1:3) to give
racemic amide (4) (3.02 g, 71%) as a white solid. mp 96-97 °C (CHCl3—hexane); IR (KBr) 1702, 1651
cm-1; 1H-NMR (400 MHz, CDCl3) d 2.28-2.29 (m, 1H), 2.36-2.38 (m, 2H), 2.82-2.89 (m, 1H), 2.99-3.01
(m, 1H), 3.28 (s, 3H), 3.39-3.40 (m, 1H), 3.78 (s, 3H), 5.69-5.71 (m, 1H), 5.77-5.79 (m, 1H); HREI-MS
calcd for C10H15NO4 MW 213.1001, found m/z 213.1000 (M+); Anal. Calcd for C10H15NO4 : C, 56.33; H,
7.09; N, 6.57. Found: C, 56.21; H, 7.04; N, 6.47.
Methyl (1R, 6S)-6-(N-Methoxy-N-methylaminocarbonyl)cyclohex-3-enecarboxylate (5a)
Method 1: To a solution of 3 (327 mg, 1 mmol) and N-methoxy-N-methylamine hydrochloride (195 mg, 2
mmol) in CH2Cl2 (6 mL) were added 4-dimethylaminopyridine (61 mg, 0.5 mmol) and Et3N (0.45 mL, 3
mmol) at rt. After being stirred at rt for 24 h, the reaction mixture was acidified with 10% HCl and then
extracted with CHCl3 (3¥20 mL). The extract was washed with brine, dried over MgSO4, and filtered. The
filtrate was evaporated in vacuo to give an oily residue, which was purified by column chromatography
on silica gel with hexane—EtOAc (1:1) to afford chiral amide (5a) (204 mg, 90%; >93% ee) as a
colorless oil. [a]D24 -14° (c 0.63, CHCl3). IR (neat) 1738, 1666 cm-1; 1H-NMR (400 MHz, CDCl3) d 2.36-
2.48 (m, 3H), 2.68-2.78 (m, 1H), 2.89-2.93 (m, 1H), 3.18 (s, 3H), 3.34-3.41 (m, 1H), 3.70 (s, 3H), 3.74 (s,
3H), 5.70-5.75 (m, 2H); HREI-MS calcd for C11H17NO4 MW 227.1158, found m/z 227.1161 (M+); Anal.
Calcd for C11H17NO4 : C, 58.14; H, 7.54; N, 6.16. Found C, 57.97; H, 7.54; N, 6.14.
Method 2: A mixture of 7a (vide infra) (356 mg, 1 mmol) and K2CO3 (691 mg, 5 mmol) in methanol (9
mL) was stirred at rt for 2 h. The reaction was quenched with 10% HCl and then the mixture was
extracted with CHCl3 (3¥20 mL). The extract was washed with brine, dried over MgSO4, and filtered. The
filtrate was evaporated in vacuo to give an oily residue, which was purified by column chromatography
on silica gel with hexane—EtOAc (2:1) to afford chiral amide (5a) (186 mg, 82%; > 99% ee) as a
colorless oil. [a]D23 -16° (c 0.78, CHCl3). HPLC analysis [Chiralcel OD-H, hexane—i-PrOH (5:1), 0.3
mL/min, 225 nm; tR (minor) = 20.9 min, tR (major) = 29.5 min] gave the isomeric composition of the
product: >93% ee (Method 1) and >99% ee (Method 2).
Racemic Methyl cis-6-(N-Methoxy-N-methylaminocarbonyl)cyclohex-3-enecarboxylate (5)

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To a solution of racemic compound (4) (213 mg, 10 mmol) in MeOH—benzene (2:7) (4.5 mL) was added
TMSCHN2 (2.0 M in diethyl ether: 1 mL, 2 mmol) at rt. After being stirred at rt for 30 min, the reaction
mixture was treated with 10% HCl and then extracted with CHCl3 (3 ¥20 mL). The extract was washed
with brine, dried over MgSO4, and filtered. The filtrate was evaporated in vacuo to give an oily residue,
which was purified by column chromatography on silica gel with hexane—EtOAc (2:1) to afford racemic
methyl ester (5a) (202 mg, 89%) as a colorless oil.
Methyl (1S, 6R)-6-(N-Methoxy-N-methylaminocarbonyl)cyclohex-3-enecarboxylate (5b)
The similar metahnolysis of 7b (356 mg, 1 mmol) to the case (Method 2) of 5a afforded chiral methyl
ester (5b) as a colorless oil (184 mg, 81% yield) in 94% ee. [a]D23 +15.6° (c 0.71, CHCl3). IR (neat) 1732,
1659 cm-1; 1H-NMR (400 MHz, CDCl3) d 2.36-2.48 (m, 3H), 2.68-2.78 (m, 1H), 2.89-2.93 (m, 1H), 3.18
(s, 3H), 3.34-3.41 (m, 1H), 3.70 (s, 3H), 3.74 (s, 3H), 5.70-5.75 (m, 2H); HREI-MS calcd for C11H17NO4
MW 227.1158, found m/z 227.1163 (M+). HPLC analysis [Chiralcel OD-H, hexane—i-PrOH (5:1), 0.3
mL/min, 225 nm; tR (major) = 20.85 min, tR (minor) = 29.48 min] gave the isomeric composition of the
product: 94% ee.
(1R, 5S)-2-Oxo-3-oxabicyclo[4.3.0]non-7-ene (6)
To a solution of 3 (600 mg, 1.83 mmol) in EtOH—H2O (2:1) (14.6 mL) was added NaBH4 (77.1 mg, 1.83
mmol) under ice cooling. After being stirred at rt for 1 h, the reaction mixture was treated with an
aqueous solution saturated with NaHSO4 and then EtOH was evaporated in vacuo. The aqueous residue
was extracted with Et2O and the extract was concentrated in vacuo to give an oily residue, which was
treated with toluene (6.1 mL) and a catalytic amount of p-TsOH under heating at 110 °C for 1 h. After
toluene was evaporated in vacuo, the residue was purified by column chromatography on silica gel with
20
hexane—CHCl3—acetone (20:19:1) to afford chiral lactone (6) (90 mg, 75%) as a colorless oil. [a]D
1
+79.8° (c 1.1, acetone) [lit.,9 [a]D20 -85.4° (c 2.63, acetone)]. IR (CHCl3) 1770 cm-1; H-NMR (90 MHz,
CDCl3) d 1.68-2.88 (m, 6H), 4.02 (dd, 1H, J = 8.79, 1.76 Hz), 4.33 (dd, 1H, J = 8.79, 4.62 Hz), 5.56-5.88
(m, 2H); HREI-MS calcd for C8H10O2 MW 138.0680, found m/z 138.0646 (M+); Anal. Calcd for
C8H10O2·1/9H2O C, 68.55; H, 7.35. Found: C, 68.51; H, 7.39.
Optical Resolution of Racemic cis-6-(N-Methoxy-N-methylaminocarbonyl)cyclohex-3-enecarboxylic
Acid (4)
To a solution of racemic carboxylic acid (4) (213 mg, 1 mmol) and (4S)-IPTT (218 mg, 1.3 mmol) in
CH2Cl2 (6 mL) were added DMAP (61 mg, 0.5 mmol) and WSCD·HCl (400 mg, 2 mmol) at rt. The

HETEROCYCLES, Vol. 65, No. 5, 2005
1149
mixture was stirred at rt for 8 h. The reaction mixture was acidified with 10% HCl and then extracted
with CHCl3 (3¥20 mL). The extract was subjected to the usual work-up to give an oily residue, which was
chromatographed on a silica gel column with hexane—EtOAc (2:1) to afford a diasteromer mixture of
7a,b as a yellow oil (285 mg, 80%). The diastereomeric mixture of 7a,b was treated with hexane and then
a yellow precipitation was filtered off. Crystallization of the precipitation in CHCl3—hexane gave (4S)-
IPTT amide (7a) (132 mg, 37%) as yellow prisms. The resulting filtrate was evaporated in vacuo to give
another (4S)-IPTT amide (7b) (153 mg, 43%) as a yellow oil.
(1S, 6R)-6-[(4S)-4-Isopropyl-1,3-thiazolidine-2-thion-3-yl]carbonyl-N-methoxy-N-methylcyclohex-3-
enecarboxamide (7a)
Yellow prisms, mp 135-136.5 °C (CHCl3—hexane); [a]D24 +314.7° (c 1.05, CHCl3). IR (neat) 3381, 1701,
1657 cm-1; 1H-NMR (400 MHz, CDCl3) d 0.98-1.00 (d, 3H, J = 7.18 Hz), 1.06-1.07 (d, 3H, J = 7.08 Hz),
2.25-2.32 (m, 1H), 2.35-2.41 (m, 1H), 2.48-2.55 (m, 1H), 2.62-2.68 (m, 1H), 2.99-3.03 (d, 1H, J = 12.21
Hz), 3.15 (s, 3H), 3.44-3.50 (dd, 1H, J = 11.47, 8.54 Hz), 3.64-3.67 (m, 1H), 3.68 (s, 3H), 4.70-4.75 (m,
1H), 5.06-5.09 (dd, 1H, J = 8.30, 4.64 Hz), 5.70-5.73 (m, 2H); HREI-MS calcd for C16H24N2O3S2 MW
356.1228, found m/z 356.1238 (M+); Anal. Calcd for C16H24N2O3S2 : C, 53.90; H, 6.79; N, 7.86. Found: C,
53.76; H, 6.76; N, 7.82. HPLC analysis [TSK-gel Silica 60, hexane—AcOEt (4:1), 1.5 mL/min, 305 nm;
tR (minor) = 27.07 min, tR (major) = 32.77 min] gave the isomeric composition of the product: >99% de.
(1R, 6S)-6-[(4S)-4-Isopropyl-1,3-thiazolidine-2-thion-3-yl]carbonyl-N-methoxy-N-methylcyclohex-3-
enecarboxamide (7b)
Yellow oil; [a]D24 +269.2° (c 1.05, CHCl3). IR (neat) 3181, 1776, 1650 cm-1; 1H-NMR (400 MHz, CDCl3)
d 0.96-0.98 (d, 3H, J = 7.08 Hz), 1.04-1.06 (d, 3H, J = 6.84 Hz), 2.25-2.55 (m, 4H), 2.98-3.00 (d, 1H, J =
12.20 Hz), 3.18 (s, 3H), 3.19-3.26 (m, 1H), 3.64-3.69 (dd, 1H, J = 10.99, 7.81 Hz), 4.86-4.89 (m, 1H),
5.0-5.01 (dd, 1H, J = 7.81, 6.59 Hz), 5.70-5.75 (m, 1H), 5.78-5.84 (m, 1H); HREI-MS calcd for
C16H24N2O3S2 MW 356.1228, found m/z 356.1204 (M+); Anal. Calcd for C16H24N2O3S2 : C, 53.90; H, 6.79;
N, 7.86. Found: C, 53.72; H, 6.70; N, 7.85. HPLC analysis [TSK-gel Silica 60, hexane—AcOEt (4:1), 1.5
mL/min, 305 nm; tR (major) = 27.06 min, tR (minor) = 33.06 min] gave the isomeric composition of the
product: 94% de.
Racemic cis-6-Benzoylcyclohex-3-enecarboxylic Acid (8)
To a solution of racemic carboxylic acid (4) (213 mg, 1 mmol) in anhydrous THF (6 mL) was added
PhMgBr (1.0 M in THF : 3 mL, 3 mmol) at 0 °C. After being stirred at 0 °C for 12 h, the reaction mixture

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HETEROCYCLES, Vol. 65, No. 5, 2005
was treated with 10% HCl, and extracted with CHCl3 (3¥20 mL). The extract was washed with brine,
dried over MgSO4, and filtered. Evaporation of the filtrate in vacuo gave a solid residue, which was
purified by column chromatography on silica gel with hexane—EtOAc (1:1) to afford benzoyl derivative
(8) (165 mg, 72%) as a white solid. mp 131-132 °C (CHCl3—hexane), (lit.,17 mp 130-131 °C); IR (KBr)
1
1690, 1669 cm-1; H-NMR (400 MHz, CDCl3) d 2.49-2.50 (m, 3H), 2.78-2.83 (m, 1 H), 3.02-3.03 (m,
1H), 3.96-3.97 (m, 1H), 5.60-5.65 (m, 1H), 5.75-5.92 (m, 1H), 7.43-7.48 (m, 2H), 7.53-7.56 (m, 1H),
7.85-7.88 (m, 2H); HREI-MS calcd for C14H14O3 MW 230.0943, found m/z 230.0946 (M+); Anal. Calcd
for C10H15NO4 : C, 73.03; H, 6.13. Found: C, 72.96; H, 6.20.
Optical Resolution of Racemic cis-6-Benzoylcyclohex-3-enecarboxylic Acid (8)
To a solution of 8 (230 mg, 1 mmol) and (4S)-IPTT (335 mg, 2 mmol) in CH2Cl2 (6 mL) were added
DMAP (61 mg, 0.5 mmol) and WSCD·HCl (400 mg, 2 mmol) at rt. After being stirred at rt for 1 h, the
reaction mixture was allowed to treat with the usual work-up to give a yellow solid residue, which was
subjected to column chromatography on silica gel with hexane—EtOAc (5:1) to furnish (4S)-IPTT amide
(9a) (149 mg, 40%) as a yellow solid and then another (4S)-IPTT amide (9b) (90 mg, 24%) as a yellow
solid.
(1S, 6R)-6-Benzoyl-1-[(4S)-4-isopropyl-1,3-thiazolidine-2-thion-3-yl]carbonylcyclohex-3-ene (9a)
Yellow prisms, mp 84-86 °C (hexane); [a]D +354.8° (c 0.5, CHCl3). IR (neat) 3323, 1698, 1671 cm-1; 1H-
24
NMR (400 MHz, CDCl3) d 0.96-0.98 (d, 3H, J = 7.08 Hz), 1.06-1.07 (d, 3H, J = 6.84 Hz), 2.40-2.65 (m,
5H), 3.03-3.06 (d, 1H, J = 12.45 Hz), 3.68-3.73 (dd, 1H, J = 11.48, 8.06 Hz), 3.84-3.89 (m, 1H), 4.80-
4.82 (m, 1H), 5.00-5.05 (m, 1H), 5.75-5.88 (m, 2 H), 7.40-7.50 (m, 2H), 7.55-7.58 (m, 1H), 7.85-7.90 (m,
2H); HREI-MS calcd for C20H23NO2S2 MW 373.1170, found m/z 373.1150 (M+); Anal. Calcd for
C20H23NO2S2 : C, 64.31; H, 6.21; N, 3.75. Found: C, 63.96; H, 6.23; N, 3.73. HPLC analysis [TSK-gel
Silica 60, hexane—AcOEt (15:1), 0.5 mL/min, 305 nm; tR (major) = 34.6 min, tR (minor) = 49.2 min]
gave the isomeric composition of the product: >99% de.
(1R, 6S)-6-Benzoyl-1-[(4S)-4-isopropyl-1,3-thiazolidine-2-thion-3-yl]carbonylcyclohex-3-ene (9b)
Pale yellow prisms, mp 98-100 °C (hexane); [a]D +291° (c 0.5, CHCl3). IR (neat) 3031, 1701, 1679 cm-1;
24
1H-NMR (400 MHz, CDCl3) d 0.89-0.91 (d, 3H, J = 6.84 Hz), 0.98-1.00 (d, 3H, J = 6.83 Hz), 2.25-2.30
(m, 1H), 2.45-2.55 (m, 3H), 2.70-2.78 (m, 1H), 2.96-2.99 (d, 1H, J = 12.69 Hz), 3.43-3.48 (dd, 1H, J =
11.47, 8.30 Hz), 4.10-4.15 (m, 1H), 5.02-5.07 (m, 1H), 5.09-5.13 (m, 1H), 5.72-5.76 (m, 2H), 7.40-7.50
(m, 2H), 7.55-7.58 (m, 1H), 7.85-7.90 (m, 2H); HREI-MS calcd for C20H23NO2S2 MW 373.1170, found

HETEROCYCLES, Vol. 65, No. 5, 2005
1151
m/z 373.1172 (M+); Anal. Calcd for C20H23NO2S2 : C, 64.31; H, 6.21; N, 3.75. Found: C, 64.13; H, 6.25; N,
3.71. HPLC analysis [TSK-gel Silica 60, hexane—AcOEt (15:1), 0.5 mL/min, 305 nm; tR (minor) = 34.6
min, tR (major) = 49.2 min] gave the isomeric composition of the product: >99% de.
(1S, 6R)-6-Benzoylcyclohex-3-enecarboxylic Acid (10a)
To a solution of LiOH (47 mg, 2 mmol) in MeCN—H2O (9:1) (9 mL) was added 9a (373 mg, 1 mmol) at
0 °C. After being stirred at 0 °C for 4 h, the reaction was quenched 10% HCl and then the mixture was
extracted with CHCl3 (3¥20 mL). The extract was washed with brine, dried over MgSO4, and filtered. The
filtrate was evaporated in vacuo and then the resulting residue was purified by column chromatography
on silica gel with hexane—EtOAc (2:1) to afford chiral carboxylic acid (10a) (162 mg, 70%) as a white
solid. mp 122-123.5 °C (CHCl3—hexane); [a]D -41.4° (c 0.5, CHCl3); [lit.,11 mp 106-108 °C
24
(MeOH—CH2Cl2); [α]D23 -31.9° (c 0.48, CHCl3)]; IR (KBr) 1694, 1680 cm-1; 1H-NMR (400 MHz, CDCl3)
d 2.48-2.51 (m, 3H), 2.78-2.83 (m, 1H), 3.02-3.04 (m, 1H), 3.96-3.97 (m, 1H), 5.64-5.65 (m, 1H), 5.75-
5.76 (m, 1H), 7.43-7.48 (m, 2H), 7.53-7.55 (m, 1H), 7.85-7.88 (m, 2H); HREI-MS calcd for C15H16O3,
MW 230.0943, found m/z 230.0930 (M+); Anal. Calcd for C14H14O3 : C, 73.03; H, 6.13. Found: C, 72.90;
H, 6.13. The corresponding methyl ester (11a) was exploited for the ee determination of 10a: >99% ee.
(1R, 6S)-6-Benzoylcyclohex-3-enecarboxylic Acid (10b)
The similar alkaline hydrolysis of 9b (373 mg, 1 mmol) with LiOH (47 mg, 2 mmol) utilizing the
procedure described for 10a gave chiral carboxylic acid (10b) (162 mg, 70%) as a white solid. mp 122-
123.5 °C (CHCl3—hexane); [a]D24 +41.2° (c 0.5, CHCl3). IR (KBr) see 10a; 1H-NMR (400 MHz, CDCl3)
see 10a; HREI-MS calcd for C14H14O3 MW 230.0943, found m/z 230.0930 (M+). Anal. Calcd for
C14H14O3 : C, 73.03; H, 6.13. Found: C, 72.91; H, 6.18. The corresponding methyl ester (11b) was
exploited for the ee determination of 10b: >99% ee.
Methyl (1S, 6R)-6-Benzoylcyclohex-3-enecarboxylate (11a)
To a solution of 10a (230 mg, 1 mmol) in MeOH—benzene (2:7) (4.5 mL) was added TMSCHN2 (2.0 M
in ether: 1 mL, 2 mmol) at rt. The mixture was stirred at rt for 30 min and then subjected to the usual
work-up to obtain a crude product, which was purified by column chromatography on silica gel with
hexane—EtOAc (2:1). The pure chiral methyl ester (11a) (219 mg, 90%) was obtained as a white solid.
1
mp 66-68 °C (CHCl3—hexane); [a]D24 -23.8° (c 0.8, CHCl3); IR (KBr) 1710, 1689 cm-1; H-NMR (400
MHz, CDCl3) d 2.49-2.50 (m, 3H), 2.68-2.81 (m, 1H), 3.02-3.05 (m, 1H), 3.63 (s, 3H), 3.96-4.01 (m, 1H),
5.61-5.69 (m, 1H), 5.72-5.80 (m, 1H), 7.44-7.48 (m, 2H), 7.53-7.55 (m, 1H), 7.85-7.88 (m, 2H); HREI-
MS calcd for C15H16O3, MW 244.1099, found m/z 244.1097 (M+); Anal. Calcd for C15H16O3 : C, 73.75; H,

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HETEROCYCLES, Vol. 65, No. 5, 2005
6.60. Found: C, 73.54; H, 6.68. HPLC analysis [Chiralcel OD-H, hexane—i-PrOH (97:3), 0.5 mL/min,
254 nm; tR (minor) = 31.39 min, tR (major) = 36.12 min] gave the isomeric composition of the product:
>99% ee.
Methyl (1R, 6S)-6-Benzoylcyclohex-3-enecarboxylate (11b)
The similar methylation of 10b (230 mg, 1 mmol) with TMSCHN2 (2.0 M in ether: 1 mL, 2 mmol)
utilizing the procedure described for 11a gave chiral methyl ester (11b) (221 mg, 91%) as white solid. mp
66-68 °C (CHCl3—hexane); [a]D24 +25.1° (c 0.8, CHCl3). IR (KBr) see 11a; 1H-NMR (400 MHz, CDCl3)
see 11a; HREI-MS calcd for C13H16O3 MW 244.1099, found m/z 244.1089 (M+). HPLC analysis
[Chiralcel OD-H, hexane—i-PrOH (97:3), 0.5 mL/min, 254 nm; tR (major) = 31.39 min, tR (minor) =
36.12 min] gave the isomeric composition of the product: >99% ee.
Methyl (1S, 6S)-6-Benzoylcyclohex-3-enecarboxylate (12a)
A mixture of 9a (373 mg, 1 mmol) and K2CO3 (691 mg, 5 mmol) in methanol (9 mL) was stirred at rt for
9 h. The reaction was quenched with 10% HCl, and the mixture was extracted with CHCl3 (3¥20 mL).
The extract was washed with brine, dried over MgSO4, and filtered. The filtrate was evaporated in
vacuo and then the residue was purified by column chromatography on silica gel with hexane—EtOAc
(1:1) to afford chiral methyl ester (12a) (200 mg, 82%) as a colorless oil. [a]D24 +91.4° (c 0.7, CHCl3). IR
1
(neat) 1733, 1680 cm-1; H-NMR (400 MHz, CDCl3) d 2.03-2.12 (m, 1H), 2.20-2.30 (m, 1H), 2.41-2.48
(m, 1H), 2.50-2.57 (m, 1H), 3.12-3.14 (m, 1H), 3.60 (s, 3H), 3.85-3.87 (m, 1H), 5.74-5.75 (m, 2H), 7.45-
7.49 (m, 2H), 7.55-7.57 (m, 1H), 7.99-8.01 (m, 2H); HREI-MS calcd for C15H16O3 MW 244.1099, found
m/z 244.1098 (M+); Anal. Calcd for C15H16O3 : C, 73.75; H, 6.60. Found: C, 73.37; H, 6.61. HPLC
analysis [Chiralcel OD-H, hexane—EtOH (100:1), 0.5 mL/min, 254 nm; tR (major) = 18.80 min, tR
(minor) = 19.69 min] gave the isomeric composition of the product: >99% ee.
Methyl (1R, 6R)-6-Benzoylcyclohex-3-enecarboxylate (12b)
The similar methanolysis of 9b (373 mg, 1 mmol) utilizing the procedure described for 12a gave chiral
methyl ester (12b) (202 mg, 83%) as a colorless oil. [a]D20 -94.1° (c 2.35, CHCl3). IR (neat) see 12a; 1H-
NMR (400 MHz, CDCl3) see 12a; HREI-MS calcd for C15H16O3 MW 244.1099, found m/z 244.1076 (M+).
HPLC analysis [Chiralcel OD-H, hexane—EtOH (100:1), 0.5 mL/min, 254 nm; tR (minor) = 18.90 min, tR
(major) = 19.62 min] gave the isomeric composition of the product: >99% ee.
(1S, 6R)-6-Benzoyl-N-methoxy-N-methylcyclohex-3-enecarboxamide (13a)

HETEROCYCLES, Vol. 65, No. 5, 2005
1153
To a solution of 9a (373 mg, 1 mmol) and N-methoxy-N-methylamine hydrochloride (195 mg, 2 mmol)
in CH2Cl2 (6 mL) were added DMAP (61 mg, 0.5 mmol) and Et3N (0.4 mL, 3 mmol) at rt. After being
stirred at rt for 24 h, the reaction mixture was acidified with 10% HCl and then extracted with CHCl3
(3¥20 mL). The extract was washed with brine, dried over MgSO4, and filtered. The filtrate was
evaporated in vacuo to give an oily residue, which was purified by column chromatography on silica gel
with hexane—EtOAc (2:1) to afford chiral amide (13a) (251 mg, 92%) as a colorless oil. [a]D24 -67.9°(c
1
0.8, CHCl3). IR (neat) 1681, 1660 cm-1; H-NMR (400 MHz, CDCl3) d 2.38-2.50 (m, 3H), 2.65-2.72 (m,
1H), 3.51 (s, 3H), 3.38-3.42 (m, 1H), 3.65 (s, 3H), 3.85-3.89 (m, 1H), 5.81-6.02 (m, 2H), 7.42-7.44 (m,
2H), 7.52-7.53 (m, 1H), 7.87-7.89 (m, 2H); HREI-MS calcd for C16H19NO3 MW 273.1365, found m/z
273.1342 (M+); Anal. Calcd for C16H19NO3 : C, 70.31; H, 7.01; N, 5.12. Found: C, 70.73; H, 7.13, N, 5.08.
HPLC analysis [Chiralcel OD, hexane—EtOH (5:1), 1.0 mL/min, 254 nm; tR (major) = 7.28 min, tR
(minor) = 8.45 min] gave the isomeric composition of the product: 99% ee.
(1R, 6S)-6-Benzoyl-N-methoxy-N-methylcyclohex-3-enecarboxamide (13b)
The similar aminolysis of 9b (373 mg, 1 mmol) with N-methoxy-N-methylamine hydrochloride (195 mg,
2 mmol) based on the procedure described for 13a gave amide (13b) (248 mg, 91%) as a colorless oil.
[a]D24 +67.3° (c 1.3, CHCl3). IR (neat) see 13a; 1H-NMR (400 MHz, CDCl3) see 13a; HREI-MS calcd for
C16H19NO3 MW 273.1365, found m/z 273.1390 (M+); Anal. Calcd for C16H19NO3 : C, 70.31; H, 7.01; N,
5.12. Found: C, 69.85; H, 7.04, N, 4.99. HPLC analysis [Chiralcel OD, hexane—EtOH (5:1), 1.0 mL/min,
254 nm; tR (minor) = 7.6 min, tR (major) = 9.0 min] gave the isomeric composition of the product: 99%
ee.
(1S, 6R)-6-Piperidinocarbonyl-N-methoxy-N-methylcyclohex-3-enecarboxamide (14a)
To a solution of 7a (356 mg, 1 mmol) in CH2Cl2(6 mL) was added piperidine (0.4 mL, 4 mmol) at rt.
After being stirred at rt for 3 h, the reaction mixture was treated with 10% HCl and extracted with CHCl3
(3¥20 mL). The extract was washed with brine, dried over MgSO4, and filtered. The filtrate was
evaporated in vacuo and the oily residue was purified by column chromatography on silica gel with
24
hexane—EtOAc (3:97) to afford chiral piperidine amide (14a) (261 mg, 93%) as a colorless oil. [a]D
+16° (c 1.1, CHCl3). IR (neat) 3498, 1643 cm-1; 1H-NMR (400 MHz, CDCl3) d 1.45-1.60 (m, 6H), 2.15-
2.25 (m, 1H), 2.35-2.42 (m, 2H), 2.81-2.86 (m, 1H), 3.05-3.08 (m, 1H), 3.20 (s, 3H), 3.30-3.40 (m, 3H),
3.45-3.55 (m, 1H), 3.73 (s, 3H), 5.74-5.76 (m, 1H), 5.79-5.83 (m, 1H); 13C-NMR (100 MHz, CDCl3) d
175.6, 171.9, 125.7, 124.0, 60.9, 46.6, 42.6, 37.4, 33.9, 32.1, 27.2, 26.5, 26.2, 25.4, 24.5; HREI-MS calcd
for C15H24N2O4 MW 280.1787, found m/z 280.1786 (M+). HPLC analysis [Chiralcel OD-H,

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HETEROCYCLES, Vol. 65, No. 5, 2005
hexane—i–PrOH (5:1), 0.5 mL/min, 225 nm; tR (minor) = 15.30 min, tR (major) = 22.54 min] gave the
isomeric composition of the product: >99% ee.
(1R, 6S)-6-Piperidinocarbonyl-N-methoxy-N-methylcyclohex-3-enecarboxamide (14b)
The similar aminolysis of 7b (356 mg, 1 mmol) based on the procedure described for 14a gave chiral
piperidine amide (14b) (255 mg, 91%) as a colorless oil. [a]D24 -13.6° (c 1.1, CHCl3). IR (neat) see 14a;
1H-NMR (400 MHz, CDCl3) see 14a; C-NMR (100 MHz, CDCl3) see 14a; HREI-MS calcd for
13
C15H24N2O4 MW 280.1787, found m/z 280.1804 (M+). HPLC analysis [Chiralcel OD-H, hexane—i-PrOH
(5:1), 0.5 mL/min, 225 nm; tR (major) = 14.73 min, tR (minor) = 23.41 min] gave the isomeric
composition of the product: 91% ee.
(1S, 6R)-6-Morpholinocarbonyl-N-methoxy-N-methylcyclohex-3-enecarboxamide (15a)
To a solution of 7a (356 mg, 1 mmol) in CH2Cl2(6 mL) was added morpholine (0.35 mL, 4 mmol) at rt.
After being stirred at rt for 5 h, the reaction mixture was subjected to the usual work-up to give a crude
product, which was purified by column chromatography on silica gel with hexane—EtOAc (3:97) to
afford chiral morpholine amide (15a) (257 mg, 91%) as a white solid. mp 86-87.5 °C (CHCl3—hexane);
1
[a]D24 +8.2° (c 1.08, CHCl3). IR (KBr) 3498, 1659, 1643 cm-1; H-NMR (400 MHz, CDCl3) d 2.18-2.25
(m, 1H), 2.33-2.50 (m, 2H), 2.71-2.78 (m, 1H), 3.02-3.08 (m, 1H), 3.18 (s, 3H), 3.28-3.33 (m, 1H), 3.42-
3.69 (m, 8H), 3.71 (s, 3H), 5.74-5.76 (m, 2H);13C-NMR (100 MHz, CDCl3) d 175.2, 172.3, 125.0, 124.4,
66.7, 66.6, 66.5, 61.0, 46.1, 41.9, 36.4, 32.1, 26.8, 26.3;HREI-MS calcd for C14H22N2O4 MW 282.1580,
found m/z 282.1566 (M+); Anal. Calcd for C14H22N2O4: C, 59.56; H, 7.85; N, 9.92. Found: C, 59.31; H,
7.82; N, 9.81. HPLC analysis [Chiralcel OD-H, hexane—i-PrOH (5:1), 0.5 mL/min, 225 nm; tR (minor) =
28.49 min, tR (major) = 35.24 min] gave the isomeric composition of the product: >99% ee.
(1R, 6S)-6-Morpholinocarbonyl-N-methoxy-N-methylcyclohex-3-enecarboxamide (15b)
The similar aminolysis of 7b (356 mg, 1 mmol) with morpholine (0.35 mL, 4 mmol) based on the
24
procedure described for 15a gave chiral morpholine amide (15b)(254 mg, 90%) as a colorless oil. [a]D
1
-8.3° (c 1.1, CHCl3). IR (neat) see 15a; H-NMR (400 MHz, CDCl3) see 15a; 13C-NMR (100 MHz,
CDCl3) see 15a; HREI-MS calcd for C14H22N2O4 MW 282.1580, found m/z 282.1589 (M+). HPLC
analysis [Chiralcel OD-H, hexane—i-PrOH (5:1), 0.5 mL/min, 225 nm; tR (major) = 28.49 min, tR (minor)
= 35.81 min] gave the isomeric composition of the product: 92% ee.
(1S, 6R)-6-Benzoyl-1-piperidinocarbonylcyclohex-3-ene (16a)

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1155
To a solution of 9a (373 mg, 1 mmol) in CH2Cl2(6 mL) was added piperidine (0.4 mL, 4 mmol) at rt.
After being stirred at rt for 3 h, the reaction mixture was subjected to the usual work-up to give a crude
product, which was purified by column chromatography on silica gel with hexane—EtOAc (2:1) to afford
chiral piperidine amide (16a) (273 mg, 92%) as a colorless oil. [a]D24 -67.9° (c 1.17, CHCl3). IR (neat)
1
3477, 1681, 1633 cm-1; H-NMR (400 MHz, CDCl3) d 1.52-1.63 (m, 6H), 2.35-2.48 (m, 3H), 2.72-2.82
(m, 1H), 3.22-3.26 (m, 1H), 3.41-3.53 (m, 4H), 3.82-3.86 (m, 1H), 5.74-5.76 (m, 1H), 5.82-5.86 (m, 1H),
13
7.41-7.45 (m, 2H), 7.46-7.52 (m, 1H), 7.89-7.92 (m, 2H); C-NMR (100 MHz, CDCl3) d 201.8, 172.1,
137.6, 131.9, 128.2, 128.0, 125.6, 124.3, 46.9, 42.9, 39.8, 38.2, 27.0, 26.7, 26.6, 25.5, 24.6; HREI-MS
calcd for C19H23NO2 MW 297.1729, found m/z 297.1721 (M+). HPLC analysis [Chiralcel OD,
hexane—EtOH (5:1), 1.0 mL/min, 254 nm; tR (major) = 6.56 min, tR (minor) = 8.91 min] gave the
isomeric composition of the product: 99% ee.
(1R, 6S)-6-Benzoyl-1-piperidinocarbonylcyclohex-3-ene (16b)
The similar aminolysis of 9b (373 mg, 1 mmol) with piperidine (0.4 mL, 4 mmol) based on the procedure
described for 16a gave chira piperidine amide (16b) (270 mg, 91%) as a colorless oil. [a]D24 +69.2° (c
1
1.22, CHCl3). IR (neat) see 16a; H-NMR (400 MHz, CDCl3) see 16a; 13C-NMR (100 MHz, CDCl3) see
16a; HREI-MS calcd for C19H23NO2 MW 297.1729, found m/z 297.1720 (M+). HPLC analysis [Chiralcel
OD, hexane—EtOH (5:1), 1.0 mL/min, 254 nm; tR (minor) = 6.56 min, tR (major) = 8.91 min] gave the
isomeric composition of the product: 99% ee.
(1S, 6R)-6-Benzoyl-1-morpholinocarbonylcyclohex-3-ene (17a)
To a solution of 9a (373 mg, 1 mmol) in CH2Cl2 (6 mL) was added morpholine (0.35 mL, 4 mmol) at rt.
The mixture was stirred at rt for 6 h and then subjected to the usual work-up to give a crude product,
which was purified by column chromatography on silica gel with hexane—EtOAc (2:1) to afford chiral
morpholine amide (17a) (321 mg, 93%) as a colorless oil. [a]D24 -60.4° (c 2.2, CHCl3). IR (neat) 3498,
1680, 1632 cm-1; 1H-NMR (400 MHz, CDCl3) d 2.42-2.71 (m, 4H), 3.22-3.24 (m, 1H), 3.51-3.67 (m, 8H),
3.81-3.83 (m, 1H), 5.76-5.80 (m, 2H), 5.76-5.80 (m, 2H), 7.42-7.46 (m, 2H), 7.88-7.90 (m, 2H); 13C-
NMR (100 MHz, CDCl3) d 201.6, 172.5, 137.1, 132.2, 128.3, 128.0, 127.9, 124.8, 124.7, 66.8, 66.7, 66.6,
66.5, 46.4, 42.0, 40.4, 36.8, 26.8; HREI-MS calcd for C18H21NO3 MW 299.1521, found m/z 299.1521
(M+). HPLC analysis [Chiralcel OD, hexane—EtOH (5:1), 1.0 mL/min, 254 nm; tR (major) = 12.60 min,
tR (minor) = 15.26 min] gave the isomeric composition of the product: 99% ee.
(1R, 6S)-6-Benzoyl-1-morpholinocarbonylcyclohex-3-ene (17b)

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The similar aminolysis of 9b (373 mg, 1 mmol) with morpholine (0.35 mL, 4 mmol) based on the
24
procedure described for 17a gave chira morpholine amide (17b) (281 mg, 94%) as a colorless oil. [a]D
1
+59.7° (c 1.9, CHCl3). IR (neat) see 17a; H-NMR (400 MHz, CDCl3) see 17a; 13C-NMR (100 MHz,
CDCl3) see 17a;HREI-MS calcd for C18H21NO3 MW 299.1521, found m/z 299.1509 (M+). HPLC analysis
[Chiralcel OD, hexane—EtOH (5:1), 1.0 mL/min, 254 nm; tR (minor) = 12.60 min, tR (major) = 15.26
min] gave the isomeric composition of the product: 99% ee.
Crystal Data for X-Ray Crystallographic Analysis of Compounds (7a, 9a, and 9b)
7a: C16H24N2O3S2, MW = 356.50, yellow block, monoclinic, space group P21(#4), a = 8.738(3)Å, b =
11.399(5)Å, c = 10.074(4)Å, V = 899.2(6)Å3, b = 116.35(1)°, Z = 2, R = 0.026, Rw = 0.068; 9a:
C20H23NO2S2, MW = 373.53, yellow block, orthorhombic, P212121(#19), a = 9.842(3)Å, b = 10.807(3)Å, c
= 17.396(3)Å, V = 1850.4(8)Å3, Z = 4, R = 0.031, Rw = 0.067; 9b: C20H23NO2S2, MW = 373.53, pale
yellow block, monoclinic, P21(#4), a = 9.009(3)Å, b = 10.882(4)Å, c = 9.532(4)Å, V = 932.3(6)Å3, b =
94.00(2)°, Z = 2, R = 0.025, Rw = 0.071. Structure factors are available from author (e-mail :
ynagao@ph.tokushima-u.ac.jp) upon request.
ACKNOWLEDGEMENTS
This work was supported by a Grant-in-Aid from the Tokyo Biochemical Research Foundation (TBRF).
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