Synthesis of enantiomerically pure (R)- and (S)-2-ethoxycarbonylmethyl- 2-hydroxy-cyclohexanones

Article abstract of DOI:10.1016/S0957-4166(98)00367-X

Sulfenylation of 2-p-tolylsulfinyl cyclohexanone can be achieved at - 78°C with thiosulfonates. The in situ aldol reaction of these compounds with ethyl acetate enolate is highly stereoselective (1,2-asymmetric induction) and yields diastereomeric mixture

Full text of DOI:10.1016/S0957-4166(98)00367-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3445–3453
Synthesis of enantiomerically pure (R)- and (S)-2-
ethoxycarbonylmethyl-2-hydroxy-cyclohexanones
José L. García Ruano,a David Barros,a M. Carmen Maestro,a,∗ Ana Alcudia b and
Inmaculada Fernández b
aDpto de Química Orgánica, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
bDpto de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad de Sevilla, Spain
Received 5 August 1998; accepted 11 September 1998
Abstract
Sulfenylation of 2-p-tolylsulfinyl cyclohexanone can be achieved at −78°C with thiosulfonates. The in situ aldol
reaction of these compounds with ethyl acetate enolate is highly stereoselective (1,2-asymmetric induction) and
yields diastereomeric mixtures of β-hydroxyesters (the configuration of the major one being dependent on the
sulfenylating agent) that can be readily separated and transformed into the enantiomerically pure title ketones.
© 1998 Published by Elsevier Science Ltd. All rights reserved.
1. Introduction
The α-hydroxy keto functional moieties are commonly found in natural products.1 Consequently,
efficient methods for the construction of such compounds in their enantiomerically pure form are in
demand.2 The Pummerer reaction,3 one of the most valuable procedures for sulfinyl group exploitation,
has been successfully used to obtain enantiomerically pure α-hydroxyaldehydes and 1,2-diols4,5 from
the appropriate acyclic unsubstituted β-hydroxysulfoxides. In a previous paper we have described the
asymmetric aldol reaction between lithium enolates derived from esters and enantiomerically pure α-
sulfinyl cyclohexanone (1),6 to obtain the corresponding β-hydroxyesters (2) in good yields and high
diastereoselectivities at the hydroxylic center. All attempts to transform these products into the corres-
ponding α-hydroxyketones under Pummerer conditions, did not give satisfactory results (Scheme 1).7
The introduction of a sulfenyl group at the α position of the cyclic β-ketosulfoxide would provide
a good alternative to obtain the desired ketone by hydrolysis of the resulting monothioketal S-oxide.
Open-chain monothioketal S-oxides derived from α-diketones have not been reported to our knowledge,8
probably because of the instability of these compounds which are prone to yield the corresponding
∗
Corresponding author. E-mail: carmen.maestro@uam.es
0957-4166/98/$ - see front matter © 1998 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00367-X

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Scheme 1.
α-sulfenyl α,β-unsaturated ketones by pyrolytic elimination of the sulfinyl group.9 In this paper we
report the successful preparation of monothioketal S-oxides of 1,2-cyclohexanedione, taking advantage
of the restrictions imposed by the cyclic ketone structure to the pyrolytic elimination, their use in situ as
substrates of asymmetric aldol reactions with lithium ethyl acetate enolate, and the deprotection of the
obtained adducts into the enantiomerically pure title compounds.
2. Results and discussion
The first step of the proposed strategy consists of the asymmetric introduction of a sulfenyl group at
the α position of the β-ketosulfoxide (1) (as a 75:25 diastereomeric mixture at C-2), in order to generate
a non-epimerizable stereogenic center. Among the usual sulfenylating reagents, such as disulfides,
sulfenyl chlorides or thiosulfonates,10,11 the first attempts were carried out with p-tolyldisulfide under the
conditions previously reported for acyclic α-alkyl β-ketosulfoxides (NaH, DMF, 0°C).12,13 The reaction
of the resulting compound 3 with the lithium ethyl acetate enolate yielded hydroxyester 4, which was
transformed into the racemic ketone 5 by reaction with NBS.14 This result indicates that a thioketal
(but not a thioketal S-oxide) structure must be assumed for compounds 3 and 4 (Scheme 2).15 We
presumed that this evolution was a result of the strong nucleophilic character of the p-tolylthiolate group16
and hence we decided to use thiosulfonates as the sulfenylating agents, because they do not liberate
nucleophilic species, thus precluding the undesired nucleophilic attack with sulfinyl group removal (see
Scheme 2). Additionally, their enhanced reactivity would allow a decrease in the reaction temperature
and therefore open the possibility to perform the aldol step in situ, and to prevent the easy elimination of
the sulfinyl group from 6.
Three different acyl thioketal S-oxides (6–8) (R=p-Tol, Me, i-Pr) were synthesized starting from the
corresponding thiosulfonates and the lithium enolate of the β-ketosulfoxide (1).17 As compounds 6–8
could not be isolated and characterized because of their easy decomposition, they were treated in situ
with 4 equiv. of the ethyl acetate enolate, affording the corresponding hydroxy esters derivatives 9–11,
as a mixture of diastereoisomers. As can be seen, only two diastereoisomers, easily separable by column
chromatography, are obtained starting from 6 and 8. The composition and the yields for the two-steps
sequence (1-→9–11) of the diastereoisomeric mixtures are indicated in Scheme 3.

J. L. García Ruano et al. / Tetrahedron: Asymmetry 9 (1998) 3445–3453
3447
Scheme 2. Reagents: (i) NaH, DMF, p-TolS2, 88%; (ii) LiCH2CO2Et, 86%; (iii) NBS, 90%
Scheme 3. Reagents: (i) LHMDS, HMPA, RSSO2R; (ii) LiCH2CO2Et; (iii) NBS diastereomers A and A0 (and B and B0) are
epimers at the thioketal S-oxide stereogenic center
The reaction of diastereoisomeric mixtures of 9–11 with NBS yielded ketone 5, the enantiomeric
excess of which was established by the use of chiral lanthanide shift reagents.18 As can be seen, the
enantiomeric ratios of 5 are identical to those of the starting diastereoisomers, which suggests that 9A
and 9B (as well as 11A and 11B) must exhibit the opposite configuration at the hydroxylic center.
In order to confirm the configurational assignment of these compounds, 9B was correlated with
compound 2, of known absolute configuration,6 by transformation of both into the enantiomers of
compound 12 (Scheme 4). Such a correlation allowed us to assign the R configuration to the hydroxylic
center of 9B and therefore the S configuration to that of 11A (Scheme 3).
Scheme 4. Reagents: (i) toluene, NaHCO3 (40 equiv.), 100°C, 85%; (ii) TMSOTf, 85%; (iii) TFAA, 45%; (iv) HF, CH3CN

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J. L. García Ruano et al. / Tetrahedron: Asymmetry 9 (1998) 3445–3453
The described compound (1S,2S,RS)-2, was protected as its trimethylsilyl derivative and submitted to
Pummerer conditions to afford the corresponding O-TMS protected vinyl thioether 16, which was easily
desilylated to pure (S)-12. In parallel, adduct 9B was transformed, by pyrolytic elimination of the sulfinyl
group, in the same hydroxy thioether 12, but of opposite configuration.
Similarly to 9B, and in order to complete the characterization of aldolic adducts, 10A and 11A were
transformed into the more stable enantiomerically pure methylthioether (S)-13 and isopropylthioether
(S)-14, respectively.
As we can see from Scheme 3, the major configuration induced at the hydroxylic center is the opposite,
starting from compounds 6 (R=p-Tol) and 8 (R=i-Pr). Taking into account that configuration at sulfinylic
sulfur is identical at both substrates, we proposed that these aldol reactions are 1,2-asymmetric induction
processes, controlled by the configuration of the thioketal S-oxide carbon, which must be different in
compounds 5 and 7. Despite this dependence being crucial from a synthetic perspective, the reasons
of this configurational change, associated to the starting thiosulfonate, are not clear. Separation of
diastereoisomeric mixtures 9A+9B and 11A+11B allows pure diastereomers 9B and 11A to be obtained,
which were further transformed into enantiomerically pure (R)-5 and (S)-5, respectively, by hydrolysis
in the presence of NBS (Scheme 5).
Scheme 5.
In conclusion, we have described a two step synthesis of the enantiomerically pure (R)- and (S)-α-
substituted α-hydroxy cyclohexanones (5) from sulfinylcyclohexanone (1) (as a 75:25 diastereomeric
mixture at C-2), by sulfenylation and in situ aldol reaction followed by hydrolysis of the resulting
thioketal S-oxide. The configuration of the obtained hydroxy ketone (5) can be selected by the proper
choice of the introduced sulfenyl moiety. The absence of the strongly acidic proton in the sulfenylated β-
ketosulfoxides, which avoids the enolization of the substrates, has allowed us to extend this methodology
to the addition of other nucleophiles. The results of this research will be published in due course.
3. Experimental
Diastereoisomeric aldol ratios were established by integration (1H NMR) of well separated signals
of the diastereoisomers in the crude reaction mixtures. Mass spectra were obtained in the electron
impact mode (EI) at 70 eV unless stated otherwise. All reactions were monitored by TLC, that was
performed on precoated sheets of silica gel 60 (F254), and flash chromatography was effected with
silica gel 60 (230–400 mesh). The apparatus for inert atmosphere experiments was dried by flaming
in a stream of dry argon. THF was distilled from sodium/benzophenone under argon. Diisopropylamine
and diisopropylethyl amine were distilled from potassium hydroxide. HMPA was distilled from calcium
hydride. LHMDS, 1 M solution in THF and n-butyl lithium 2.5 M solution in hexanes were purchased
from Aldrich.

J. L. García Ruano et al. / Tetrahedron: Asymmetry 9 (1998) 3445–3453
3449
3.1. Sulfenylation reagents
3.1.1. p-Tolyl p-toluenethiosulfonate
This was obtained following the previously described procedure.9 The crude product was purified by
1
crystallization (CHCl3). Yield 86%. Mp 75°C. H NMR δ 7.5 (2H, m), 7.3–7.0 (6H, m), 2,43 (3H, s),
2.39 (3H, s); 13C NMR δ 144.6, 142.0, 140.7, 136.3, 130.1, 129.3, 127.4, 124.3, 21.5, 21.4. Anal. calcd
for C14H14S2O2: C, 60.42; H, 5.07; S, 23.0. Found C, 60.63; H, 5.40; S, 23.16.
3.2. Isopropylthio isopropanethiosulfonate
This was obtained following the previously described procedure.9 The crude product was purified by
1
flash chromatography on silica gel (CH2Cl2) to yield pure compound as a colorless liquid. H NMR δ
3.69 (1H, m, J=7.2 Hz), 3.35 (1H, m, J=7.2 Hz), 1.50 (6H, d), 1.49 (6H, d); 13C NMR δ 63.5, 43.0, 24.3
(2C), 16.3 (2C).
3.3. 2,2-Bis-(p-tolylthio)cyclohexanone 3
To a DMF (5 ml) suspension of NaH (1.1 mmol, 26 mg) cooled in an ice–salt bath (−15°C), a DMF
solution of 2-(p-tolylsulfinyl)-cyclohexanone (1) (1.0 mmol, 236 mg) was added dropwise. After 30 min
at the same temperature, a solution of p-tolyl disulfide (292 mg, 1.05 mmol) was added to the above
sodium enolate. After 10 min, the reaction was quenched with a NH4Cl saturated solution (20 ml) and
the mixture was extracted with ethyl ether (2×40 ml). The organic extracts were washed with brine (2×15
ml) and dried (MgSO4). The solvent was removed under vacuum and the product was isolated by flash
chromatography (hexane:acetate=4:1). Yield 88%. The product was further purified by crystallization
1
from ether:hexane. H NMR δ 7.6–7.15 (8H, m), 2.68 (2H, m), 2.38 (3H, s), 2.12 (3H, s), 2.0–0.9 (4H,
m); 13C NMR δ 202.1, 139.0 (2C), 135.6 (2C), 129.2, 126.8 (2C), 72.1, 40.0, 37.8, 26.1, 21.6, 20.9 (2C).
3.4. Sulfenylation of β-ketosulfoxides and condensation with lithium ethyl acetate enolate. General
procedure
A THF solution of β-ketosulfoxide 1 (1 mmol) was added dropwise to a 0.3 M THF solution of
LHMDS (3.33 ml, 1 mmol) cooled at −78°C. After 30 min at the same temperature, 3 ml of HMPA was
added and the temperature was raised to 0°C in a 15 min period. The reaction mixture was introduced to
a bath at −78°C and a THF solution of the corresponding thiosulfonate was added dropwise at the same
temperature. Once the addition has finished, the reaction was kept at the appropriate temperature (−78°C
for compound 6, R=p-Tol and 7, R=Me and −20°C for 8, R=i-Pr) until the complete disappearance of
1 (TLC). Then, the reaction mixture containing the thioketal S-oxide was added dropwise at −78°C,
via cannula over a THF solution (−78°C) of lithium ethyl acetate enolate, prepared from LHMDS (3.5
mmol) and ethyl acetate (341 µl, 3.5 mmol). After 5 min at −78°C, the reaction was quenched with a
NH4Cl saturated solution (40 ml) and the mixture was extracted with ethyl ether (2×40 ml). The organic
extracts were washed with water (2×20 ml) and dried (MgSO4). The solvent was removed under vacuum
without heating, and the crude product purified by flash chromatography or recrystallization to afford the
corresponding hydroxyester.

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3.4.1. 1-[(Ethoxycarbonyl)methyl]-2,2-bis-(p-tolylthio)cyclohexanol 4
This was obtained from 3 (342 mg, 1 mmol) and lithium acetate enolate (3.5 mmol equiv.), following
the general procedure for the aldol reaction. The crude product was purified by flash chromatography
(hexane:acetate=4:1). Yield 86%. Recrystallized from hexane, mp 145°C. 1H NMR δ 7.62 and 7.21 (4H,
AA0BB0 system), 7.28 and 6.99 (4H, AA0BB0 system), 4.22 (2H, q, J=7.0 Hz), 3.9 (1H, s, OH), 3.42
and 2.66 (2H, AB system, JAB=14.5 Hz, ∆ν=153 Hz), 2.40 (3H, s), 2.29 (3H, s), 2.30–1.10 (8H, m),
1.32 (3H, t, J=7.0 Hz). 13C NMR δ 173.0, 139.5, 139.0, 137.5 (2C), 129.3, 129.1, 127.3 (2C), 76.6, 75.6,
60.7, 42.3, 33.9, 31.7, 21.9, 21.3, 21.2, 20.6, 14.19. Anal. calcd for C24H30S2O3: C, 66.95; H, 7.03; S,
14.87. Found C, 67.34; H, 7.15; S, 14.42.
3.4.2. 1-[(Ethoxycarbonyl)methyl]-2-(p-tolylthio)-2-(p-tolylsulfinyl)cyclohexanol 9
This was obtained following the general procedure starting from 1 and p-tolyl p-toluenethiosulfonate,
as an 18:82 mixture of diastereomers 9A:9B (global yield 78%). Column chromatography on silica gel
(hexane:ethyl acetate=3:1) affords pure 9B (45%). Isolation of isomer 9A has not been accomplished
and is described from an enriched mixture. 9A: 1H NMR δ 7.89–6.80 (8H, m), 4.22 (2H, q, J=7.1 Hz),
4.0 (1H, s, OH), 3.42 and 3.13 (2H, AB system, JAB=14.5 Hz, ∆ν=58 Hz), 2.45 (3H, s), 2.27 (3H, s),
2.5–1.7 (8H, m), 1.29 (3H, t, J=7.1 Hz). 9B: 1H NMR δ 7.72 and 6.90 (4H, AA0BB0 system), 7.38 and
6.75 (4H, AA0BB0 system), 5.20 (1H, s, OH), 4.18 (2H, q, J=7.1 Hz), 3.78 and 2.87 (2H, AB system,
J
AB=16 Hz, ∆ν=182 Hz), 2.48 (3H, s), 2.30 (3H, s), 2.3–0.7 (8H, m), 1.27 (3H, t, J=7.1 Hz). 13C NMR
δ 173.6, 141.8, 139.2, 137.5 (2C), 129.5, 129.3, 129.0 (2C), 83.1, 72.1, 60.9, 40.0, 35.2, 34.1, 21.6, 21.4,
21.2, 19.7, 14.1.
3.4.3. 1-[(Ethoxycarbonyl)methyl]-2-(methylthio)-2-(p-tolylsulfinyl)cyclohexanol 10
This was obtained following the general procedure starting from 1 and methyl methanethiosulfonate, as
a 41:5:46:6 mixture of diastereomers 10A:10A0:10B:10B0 (global yield 58%). Column chromatography
1
on silica gel (hexane:ethyl acetate:acetone=3:1:0.1) affords pure 10A: H NMR δ 7.69 and 7.30 (4H,
AA0BB0 system), 4.34 (1H, s, OH), 4.17 (2H, q, J=7.1 Hz), 3.39 and 3.16 (2H, AB system, JAB=13 Hz,
∆ν=46 Hz), 2.41 (3H, s), 2.5–1.4 (8H, m), 1.27 (3H, t, J=7.0 Hz), 1.1 (3H, s). 13C NMR δ 172.8, 142.8,
134.5, 129.1, 127.1, 80.6, 78.1, 60.7, 40.6, 33.7, 26.7, 21.8, 21.6, 21.5, 14.2, 11.3. Isolation of the other
isomers has not been accomplished, and their 1H NMR data are obtained from enriched mixtures. 10A0:
1H NMR δ 7.62 and 7.33 (4H, AA0BB0 system), 5.34 (1H, s, OH), 4.05 (2H, q, J=7.0 Hz), 3.18 and
2.73 (2H, AB system, JAB=13.5 Hz, ∆ν=90 Hz), 2.38 (3H, s), 2.5–1.2 (8H, m), 1.26 (3H, s), 1.23 (3H,
t, J=7.0 Hz). 10B: 1H NMR δ 7.79 and 7.26 (4H, AA0BB0 system), 4.94 (1H, s, OH), 4.20 (2H, q, J=7.1
Hz), 3.38 and 2.90 (2H, AB system, JAB=16 Hz, ∆ν=120 Hz), 2.41 (3H, s), 2.5–1.2 (8H, m), 1.28 (3H,
t, J=7.1 Hz), 1.0 (3H, s). 10B0: 1H NMR δ 7.62 and 7.30 (4H, AA0BB0 system), 5.12 (1H, s, OH), 4.15
(2H, q, J=6.9 Hz), 3.39 and 3.16 (2H, AB system, JAB=16 Hz, ∆ν=272 Hz), 2.41 (3H, s), 2.5–1.4 (8H,
m), 1.24 (3H, s), 1.27 (3H, t, J=6.9 Hz).
3.4.4. 1-[(Ethoxycarbonyl)methyl]-2-(isopropylthio)-2-(p-tolylsulfinyl)cyclohexanol 11
This was obtained following the general procedure from 1 and isopropyl isopropanethiosulfonate, as
an 89:11 mixture of diastereoisomers 11A:11B (global yield 72%). Column chromatography on silica
25
gel (hexane:ethyl acetate=3:1) affords diastereomerically pure isomers. 11A (64%): [α]D +112 (c 1;
CHCl3); 1H NMR δ 7.70 and 7.22 (4H, AA0BB0 system), 4.06 (2H, q, J=6.9 Hz), 3.52 (1H, s, OH), 3.14
and 2.89 (2H, AB system, JAB=14.5 Hz, ∆ν=50 Hz), 2.33 (3H, s), 2.5–1.6 (9H, m), 1.17 (3H, t, J=6.9
Hz), 1.17 (3H, d, J=6.7 Hz), 1.03 (3H, d, J=6.9 Hz); 13C NMR δ 171.7, 141.8, 137.1, 128.8, 128.5, 78.9,
75.3, 60.7, 41.8, 34.4, 34.3, 27.3, 26.3, 24.2, 22.2, 21.3, 20.8, 14.1. 11B: [α]D −25 (c 1.2; CHCl3); 1H
25

J. L. García Ruano et al. / Tetrahedron: Asymmetry 9 (1998) 3445–3453
3451
NMR δ 7.70 and 7.22 (4H, AA0BB0 system), 4.06 (2H, q, J=6.9 Hz), 3.52 (1H, s, OH), 3.14 and 2.89
(2H, AB system, JAB=14.5 Hz, ∆ν=50 Hz), 2.33 (3H, s), 2.5–1.6 (9H, m), 1.17 (3H, t, J=6.9 Hz), 1.17
(3H, d, J=6.7 Hz), 1.03 (3H, d, J=6.9 Hz); 13C NMR δ 171.4, 142.0, 136.7, 128.7, 127.2, 84.2, 82.7,
60.3, 41.4, 33.7, 33.3, 28.9, 25.9, 24.8, 21.9, 21.1 (2C), 14.2.
3.5. Thioketal and thioketal-S-oxide hydrolysis in the presence of NBS
3.5.1. 2-[(Ethoxycarbonyl)methyl]-2-hydroxycyclohexanone 5
To a solution of NBS (9 mmol equiv.) in an acetone:water (90:10) mixture at 0°C, an acetone solution
of thioketal or thioketal-S-oxide was slowly added. The mixture turned orange and after 5 min was
poured into a separation funnel containing 20 ml of hexane, 20 ml of dichloromethane and 20 ml of
saturated Na2SO3 solution. The organic layer was succesively washed with saturated NaHCO3 (20 ml)
and brine (20 ml), dried (MgSO4), concentrated and purified by flash chromatography (hexane:ethyl
1
acetate:acetone=4:1:0.1) to yield 5 as colorless oil. Racemic 5 was obtained from 4. Yield: 90%. H
NMR δ 5.58 (1H, s), 4.23 (2H, q, J=7.1 Hz), 2.93 and 2.47 (2H, AB system, JAB=16 Hz), 2.8–1.5 (8H,
m) 1.24 (3H, t, J=7.1 Hz). 13C NMR δ 211.78, 171.5, 77.4, 60.8, 41.5, 41.4, 37.8, 28.3, 21.7, 14.0. Anal.
calcd for C10H16O3: C, 65.14; H, 8.75. Found C, 64.76; H, 9.10. From pure 9B, (R)-5 was obtained in
25
25
78% yield: [α]D −28 (c 1; CHCl3), and from pure 11A, (S)-5 was prepared in 75% yield: [α]D +28
(c 1; CHCl3).
3.6. Sulfinyl group pyrolysis. General procedure
To a flame-dried flask equipped with a reflux condenser containing sodium bicarbonate (3.5 g, 40.6
mmol) was added via cannula a solution of the hydroxythioketal S-oxide (1.06 mmol). The mixture was
heated in an oil bath under vigorous stirring at the temperature and in the solvent indicated in each
case. The reaction progress was monitored by TLC (CH2Cl2:hexane=3:1). The mixture was cooled to
room temperature, and the crude product was filtered and washed with a saturated NH4Cl solution (20
ml). The organic layer was separated, and the aqueous layer was extracted with ethyl ether (2×30 ml).
The combined organic extracts were finally washed with brine and dried (MgSO4). The ethyl ether was
evaporated under vacuum.
3.6.1. (1R)-1-[(Ethoxycarbonyl)methyl]-2-(p-tolylthio)-cyclohex-2-en-1-ol 12
This was obtained from 9B following the general procedure, by heating 2 h at 100°C in toluene.
The crude product was extracted as above, the ether was removed under vacuum and the crude toluene
solution was directly chromatographed using sucessively as eluents, hexane (to remove toluene) and
25
CH2Cl2:hexane (3:1). [α]D −12 (c 1; CHCl3); 1H NMR δ 7.29 and 7.09 (4H, AA0BB0 system), 5.80
(1H, 7, J=4Hz), 4.16 (2H, q, J=7.0 Hz), 3.80 (1H, s, OH), 3.07 and 2.56 (2H, AB system, JAB=15.2
Hz, ∆ν=10 Hz), 2.31 (3H, s), 2.2–1.6 (6H, m), 1.26 (3H, t, J=7.0 Hz); 13C NMR δ 172.4, 137.7, 136.9,
134.8, 131.7, 131.4, 129.8, 72.1, 60.7, 43.6, 36.2, 21.0, 18.9, 14.1; MS m/z; 306 (20) M+, 288 (9), 218
(37), 124 (100). HRMS calcd for C17H22SO3 306.12896; found 306.12766.
3.6.2. (1S)-1-[Ethoxycarbonyl)methyl]-2-(methylthio)-cyclohex-2-en-1-ol 13
This was obtained from 10A by heating for 2 h in refluxing CHCl3. The reaction mixture was filtered
and the solvent evaporated at reduced pressure. Purification was effected by flash chromatography
(CH2Cl2:hexane=3:1). Yield 90%: [α]D +7 (c 0.75; CHCl3); 1H NMR δ 5.54 (1H, t, J=4.0 Hz), 4.17
25
(2H, q, J=7.2 Hz), 3.89 (1H, s, OH), 3.04 and 2.56 (2H, AB system, JAB=15.4 Hz, ∆ν=95 Hz), 2.22 (3H,

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J. L. García Ruano et al. / Tetrahedron: Asymmetry 9 (1998) 3445–3453
s), 2.2–1.5 (6H, m), 1.27 (3H, t, J=7.2 Hz); 13C NMR δ 172.6, 135.8, 128.5, 71.9, 60.7, 43.6, 36.3, 26.5,
19.1, 15.9, 14.2. MS m/z; 230 (20) M+, 212 (48), 185 (5), 165 (34), 143 (41), 91 (100). HRMS calcd for
C11H18SO3 230.09766; found 230.09784.
3.6.3. (1S)-1-[(Ethoxycarbonyl)methyl]-2-(isopropylthio)-cyclohex-2-en-1-ol 14
14 was obtained from 11A by heating for 2 h in refluxing CHCl3. The reaction mixture was filtered
and the solvent evaporated at reduced pressure. Purification was effected by flash chromatography.
25
1
(CH2Cl2:hexane=3:1). Yield 95%. [α]D +11 (c 1; CHCl3). H NMR δ 5.97 (1H, t, J=4.0 Hz), 4.16
(2H, q, J=6.9 Hz), 3.78 (1H, s, OH), 3.22 (1H, sept, J=6.6 Hz), 3.03 and 2.49 (2H, AB system, JAB=15.2
Hz, ∆ν=160 Hz), 2.3–0.7 (6H, m), 1.27 (3H, t, J=7.2 Hz), 1.25 (6H, two d, J=6.6 Hz); 13C NMR δ
172.6, 136.5, 134.1, 72.1, 60.7, 43.9, 37.3, 36.1, 27.0, 23.1, 22.8, 18.9, 14.1; MS m/z; 258 (4) M+, 240
(17), 151 (86), 124, 91 (100). HRMS calcd for C13H22SO3 258.12896; found 258.12936.
3.7. [1S,2S,RS]-1-[(Ethoxycarbonyl)methyl]-2-(p-tolylsulfinyl)-1-trimethylsilyloxycyclohexane 15
To a flame dried flask containing a cooled solution (−10°C) of 2 (485 mg, 1.5 mmol), in dry
dichloromethane (5 ml) and diisopropyl ethylamine (697 µl, 6 mmol) a dichloromethane solution of
TMSOTf (879 µl, 4.5 mmol) was added dropwise. The reaction mixture turned to red and after 30 min,
the reaction was quenched by addition of 10 ml of saturated NaCl. The organic layer was separated and
the aqueous layer was extracted with hexane (3×50 ml). The combined organic extracts were finally
washed with brine and dried (MgSO4). The solvent was removed and the crude product purified by flash
25
chromatography (hexane:ethyl acetate=3:1 with 5% of NEt3). Yield 90%. [α]D +107 (c 0.42; CHCl3).
1H NMR δ 7.54 and 7.28 (4H, AA0BB0 system), 4.16 (2H, q, J=7.0 Hz), 3.42 and 2.73 (2H, AB system,
J
AB=14 Hz, ∆ν=131 Hz), 2.34 (3H, s), 2.2–1.3 (8H, m), 1.28 (3H, t, J=7.0 Hz), 0.23 (9H, m); 13C
NMR δ 170.5, 141.5, 140.0, 129.5, 124.3, 75.8, 68.7, 60.7, 53.4, 45.9, 37.8, 24.2, 21.3 (2C), 17.0, 14.3,
2.4; MS m/z; 397 (3) M+, 381 (11), 257 (94), 212 (49), 183 (49), 139 (84), 73 (100). HRMS calcd for
C20H32SO4Si 396.17906; found 396.17758.
3.8. [1S]-1-[(Ethoxycarbonyl)methyl]-2-(p-tolylthio)-1-trimethylsilyloxy-2-cyclohexene 16
To a solution of 15 (204 mg, 0.5 mmol) and 2,6-lutidine (235 µl, 2 mmol) in CH3CN (5 ml) at
−78°C was added dropwise a cooled CH3CN solution of TFAA (143 µl, 1 mmol). The mixture was
gradually warmed to −20°C. After 1 h, the mixture was quenched with 10 ml of water and extracted with
hexane (3×20 ml). The combined organic extracts were finally washed with brine, dried (MgSO4) and
concentrated. Purification by flash chromatography (CH2Cl2:hexane=1:1) yielded pure 16 as a colorless
oil (90 mg, 48%). [α]D −40 (c 1; CHCl3). 1H NMR δ 7.32 and 7.10 (4H, AA0BB0 system), 5.38 (1H,
25
7, J=4Hz), 4.13 (2H, m), 3.0 and 2.74 (2H, AB system, JAB=13.5 Hz, ∆ν=52 Hz), 2.33 (3H, s), 2.5–1.6
(6H, m), 1.27 (3H, t, J=6.9 Hz), 0.18 (9H, m); 13C NMR δ 170.7, 136.1, 134.8, 133.2, 131.2, 129.8,
128.3, 75.5, 60.1, 45.2, 36.0, 26.6, 19.7, 14.3, 2.1; MS m/z; 378 (11) M+, 291 (37), 201 (12), 124 (100),
73 (66). HRMS calcd for C20H30SO3Si 378.16849; found 378.16800.
3.9. (1S)-1-[(Ethoxycarbonyl)methyl]-2-(p-tolylthio)-cyclohex-2-en-1-ol 12
This was prepared by treatment of a CH3CN solution of 16 with HF (48% in water) at 0°C for 20 min.
The mixture was treated with saturated NaHCO3 solution (10 ml). The crude was extracted with ethyl
ether (2×30 ml). The organic extracts were finally washed with brine and dried (MgSO4). The solvent

J. L. García Ruano et al. / Tetrahedron: Asymmetry 9 (1998) 3445–3453
3453
was evaporated under vacuum, and chromatographed (CH2Cl2:hexane=3:1) to yield pure (S)-12 (92%):
25
[α]D +10 (c 0.7; CHCl3).
Acknowledgements
We thank Dirección General de Investigación Científica y Técnica (PB-93-0257) for financial support.
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17. LHMDS was preferred as the base used in enolate generation, to prevent a possible attack of the amine to the monothioketal
S-oxide.
18. 0.25 equiv. Eu (tfc)3 was necessary to observe completely separated signals of the ester ethoxy group.