New, highly efficient syntheses of rac-, (R)- and (S)-4-hydroxy-2-cyclohexenone

Article abstract of DOI:10.1016/S0957-4166(00)00451-1

Both enantiomers of 4-hydroxy-2-cyclohexenone have been synthesised from chiral p-benzoquinone equivalents through very short and simple sequences in good overall yields.

Full text of DOI:10.1016/S0957-4166(00)00451-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4473–4483
New, highly efficient syntheses of rac-, (R)- and
(S)-4-hydroxy-2-cyclohexenone
Pedro de March, Maria Escoda, Marta Figueredo,* Josep Font, Elena Garc´ıa-Garc´ıa and
Sonia Rodr´ıguez
Departament de Qu´ımica, Universitat Auto`noma de Barcelona, 08193 Bellaterra, Spain
Received 21 August 2000; revised 14 November 2000; accepted 15 November 2000
Abstract
Both enantiomers of 4-hydroxy-2-cyclohexenone have been synthesised from chiral p-benzoquinone
equivalents through very short and simple sequences in good overall yields. © 2000 Published by Elsevier
Science Ltd.
1. Introduction
4-Hydroxy-2-cyclohexenone, 1, has been used as a building block in the synthesis of several
bioactive compounds such as the anti-cholesterol agents compactin and ML-236A,1 and the
immunosuppressant FK-506.2 In these syntheses, the relative configuration of the stereogenic
centres of the target molecules is induced by the stereogenic centre at C4 of the hydroxyenone
1.
Several preparations of racemic 1 have been published, usually embodied into wider reactivity
studies.3–6 Some reported syntheses of (S)-1 (or O-protected derivatives of it) make use of
enzymatic6–9 or other catalytic10 transformations as the crucial step. Alternatively, strategies
based on the use of chiral auxiliaries have been employed for the preparation of both
enantiomers of 1,11,12 and two complementary approaches starting from (−)-quinic acid, leading
to (S)-13 and (R)-1,14 have also been developed. Many of these syntheses involve multi-step
sequences with low overall yields or poor enantioselectivities. Moreover, there are some practical
problems associated to the isolation of ketone 1, because it is a volatile compound, highly
soluble in water. As Bru¨ckner pointed out, this can be the cause for the wide dispersion of
published specific rotations of (R)- and (S)-1.14
In previous reports, we have prepared a series of chiral p-benzoquinone derivatives, having
one or both pairs of equivalent functional groups differentiated. In compound 2 (Scheme 1) one
* Corresponding author. Tel: 34 935811853; fax: 34 935811265; e-mail: marta.figueredo@uab.es
0957-4166/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0957-4166(00)00451-1

4474
P. de March et al. / Tetrahedron: Asymmetry 11 (2000) 4473–4483
of the carbonyl groups has been protected as a ketal with a chiral C2-symmetric diol,15 while in
the monoketal 3 one of the double bonds has been also temporarily masked by conjugate
addition of thiophenol.16 These derivatives were successfully used as chiral synthetic equivalents
of p-benzoquinone in cycloaddition reactions.17 (R,R)-2 and racemic 3 are easily available in
multi-gram scale from very inexpensive materials, and resolution of the racemate of 3 is
effectively performed by liquid chromatography on cellulose triacetate.16
O
O
OH
carbonyl reduction
desulfuration
carbonyl reduction
hydrogenation
ketal hydrolysis
ketal hydrolysis
SPh
O
O
O
O
O
Ph
Ph
2
3
1
Scheme 1.
A priori, the conversion of 2 or 3 into 1 would require only a few conventional steps, namely
reduction of the ketone to alcohol, selective hydrogenation of one of the double bonds (from 2)
or desulphurisation (from 3), and hydrolysis of the ketal. We decided to explore both synthetic
approaches, the results of which are described herein.
2. Results and discussion
Partial hydrogenation of 2 to give the desired a,b-unsaturated ketone 4 was accomplished
working in toluene in the presence of Wilkinson’s catalyst (Scheme 2). The reaction evolution
1
was followed by H NMR analysis of aliquot samples, and it was run until 50% conversion of
2. In this way, 4 can be obtained in 75% yield or higher. Further conversion of 2 leads to
hydrogenation of the second double bond and the dihydrogenated product contaminates
recovered 2. The use of Pd/C in several solvents afforded complex mixtures of hydrogenation
1
products. The olefin protons of 4 show H NMR signals at l 6.91 and 6.11.
O
O
OH
1
OH
75%
87%
O
O
O
O
O
O
O
Ph
Ph
Ph
Ph
Ph
Ph
2
4
(1R)-5, 67%
(+)-(R)-1
+
(1S)-5
Scheme 2.

P. de March et al. / Tetrahedron: Asymmetry 11 (2000) 4473–4483
4475
The efficiency of the asymmetric synthesis of 1 depended on the diastereoselectivity of the
reduction of the carbonyl group of 4 or the ability to separate the diastereoisomeric allylic
alcohols formed. Reduction of 4 with NaBH4 in methanol at −78°C proceeded quantitatively to
give a ca. 4:1 mixture of (1R)- and (1S)-5, from which the major diastereoisomer (1R)-5 was
isolated as a solid, [h]2D0=+49.2 (c 0.6, CH2Cl2), in 67% yield by repeated crystallisation of the
mixture in ether/pentane. This crystallisation happens to be quite tedious and its efficiency can
be improved if the reaction crude is previously purified by column chromatography on silica gel.
The olefin proton signals of (1R)-5 have shifted to l 6.04 and 5.91 and the absorption at l 66.6
in the 13C NMR spectrum evidences the presence of the carbinol. The reduction of 4 with other
hydride donors such as DIBALH, L-Selectride®, and LiAl(tBuO)3H gave lower yields without a
significant improvement of the stereoselectivity.
Removal of the ketal and retrieval of the chiral auxiliary was best performed by treatment of
(1R)-5 with montmorillonite K-10 in dichloromethane, according to the method described by
Taylor et al.18 Using these conditions, 91% of (1R,2R)-hydrobenzoin was recovered and the
target enone (R)-1, [h]2D0=+90.0 (c 0.2, CHCl3), was obtained in 87% yield and 97% ee
determined by CGC. The configuration of 1 reveals the relative configuration of the isolated
allylic alcohol (1R)-5. Hence, the conversion of 2 into (+)-(R)-1 had been accomplished in 45%
overall yield through a simple three-step sequence.
The synthetic pathway starting from 3 was then explored (Scheme 3). Provided that the
sulphur substituent was able to exert a good asymmetric induction in the reduction of the
OH
OH
OBz
OBz
+
SPh
SPh
O
O
O
O
O
11
8
cis-10
trans-10
96%
O
OH
OH
OR
O
90%
80%
SPh
SPh
SPh
O
O
O
O
O
3
6
7
1, R=H
9, R=Bz
81%
96%
O
OH
OR
OR
69% from 14
65% from 15
93%
88%
72%
+
SPh
SPh
SPh
SPh
O
O
O
O
O
O
13
12
cis-14, R=H
cis-15, R=Bz
trans-14, R=H
trans-15, R=Bz
Scheme 3.

4476
P. de March et al. / Tetrahedron: Asymmetry 11 (2000) 4473–4483
carbonyl group, another very simple approach could be set up to obtain both (R)- and (S)-1,
starting from each enantiomer of 3. In practice, the envisaged transformations were more
complicated than expected and the synthetic route had to be modified accordingly.
The reduction of ( )-3 with NaBH4 gave exclusively the cis alcohol 6 in 90% yield. The
stereochemistry of 6 was established after hydrolysis of the ketal with a DOWEX® resin,
following a described methodology.19 In both compounds 6 and 7 the a-sulphur proton (l 3.43
in 6 and l 3.80 in 7) presents constant coupling values consistent with a pseudoaxial orientation
(13.2 and 2.9 Hz for 6 and 13.2 and 5.1 Hz for 7). The cis stereochemistry of the hydroxyketone
7 was deduced from the high NOE observed between the a-sulphur and the a-hydroxyl protons,
which demonstrates their proximity, in agreement with a cis-1,3-diaxial relationship. Conse-
quently, the phenylthio and the hydroxyl groups must occupy pseudoequatorial positions.
Compound 7 epimerises slowly to its trans isomer.
Desulphuration of 7 with different reagents in a variety of conditions was unsuccessful. Raney
nickel in ethanol without previous deactivation gave 4-hydroxycyclohexanone,20 8, as the only
identifiable product. Under milder conditions, the starting compound 7 was recovered, along
with its trans epimer, traces of the saturated hydroxyketone 8, the target compound 1 and other
unidentified products. Other reductive systems such as catalytic hydrogenation, Bu3SnH, Zn,
Al/Hg and SmI2 proved ineffective as well. Considering the problems associated with the
isolation of 1 and that its benzoyl derivative 9 was already known,7 we decided to protect the
hydroxyl group of 7 as a benzoate and to test the desulphuration reactions on the benzoate.
Treatment of 7 with benzoyl chloride in pyridine, not surprisingly, gave a mixture of cis- and
1
trans-10 in 96% yield. In the H NMR spectrum of the more stable trans isomer, the a-sulphur
proton H5 absorbs at l 4.02 as a false triplet with J:4.8 Hz, in agreement with a pseudoequa-
torial disposition of this proton; therefore the phenylthio group must be in a pseudoaxial
1
orientation. The H NMR spectrum of the less stable epimer cis-10 is very similar to that of
cis-7, H5 presenting a double doublet at l 3.93 with J values of 11.3 and 4.8 Hz, in agreement
with an axial orientation. This isomer epimerises too fast to be fully characterised, but this
process would not be detrimental to the synthesis, since the configurationally unstable stereo-
genic a-carbonyl centre should disappear in the desulphuration step. Unfortunately, the conven-
tional procedures to remove the sulphur residue were also ineffective for the benzoate 10, and
again either unchanged starting material or unidentified products were obtained. We also
intended the desulphuration of the ketal 6 with the same variety of reagents. The expected
hydroxyketal 11 could only be detected as a minor component in the reaction mixtures of
reductions with Bu3SnH/AIBN in toluene. All the other reducing agents let 6 unchanged.
In view of the difficulty of performing the desulphuration of these substrates, we decided to
attempt an alternative strategy. If the hydrogenation of the carbonꢀcarbon double bond of 6 or
7 could be efficiently performed, later on the double bond could be regenerated at the
enantiotopic position by elimination of thiophenol, and the overall process would be equivalent
to the impossible desulphuration. The hydrogenation of 6 was tried with Pd, Pd(OH)2 and Pt as
catalysts in MeOH or EtOH, at room temperature. In all cases the conversion was low and the
desired hydroxyketal 12 was contaminated by other unidentified products. Under similar
hydrogenation conditions, compound 7 remained unchanged, except for occasional epimerisa-
tion of the a-carbonyl centre.
At this point, the only remaining option was to perform the hydrogenation of the car-
bonꢀcarbon double bond of 3 in the first place, followed by reduction of the ketone to alcohol,
and then elimination of thiophenol. After different trials, the hydrogenation of 3 was effectively

P. de March et al. / Tetrahedron: Asymmetry 11 (2000) 4473–4483
4477
performed using Pearlman’s catalyst in methanol at room temperature. The new ketone 13 was
isolated in 96% yield. Treatment of 13 with NaBH4 gave the alcohol 12 in 93% yield, as the only
reaction product. The a-sulphur proton H3 of 12 presents J values of 12.4 and 4.4 Hz, according
to a preference for the axial orientation and it shows a positive NOE with the a-hydroxyl proton
H1, proving the cis stereochemistry of 12. As in the enone 3, the phenylthio group directs the
anti approach of the hydride. Ketal 12 was recovered unchanged after treatment with DOWEX®
under the same conditions used to hydrolyse 6, but heating 12 in a mixture of THF–H2O with
a trace of p-toluenesulphonic acid gave ketone 14 in 88% yield, as a 1:2.5 mixture of the cis and
trans epimers. The cis stereochemistry of the minor isomer was determined by a positive NOE
between the a-hydroxyl and the a-sulphur protons. 1H NMR analysis of aliquot samples showed
that cis-14 is the only isomer present at the beginning of the hydrolysis, but it evolves to the
more stable trans-14. The mixture 14 was oxidised with m-CPBA in CH2Cl2 at 0°C to the
corresponding sulphoxides, which were submitted to pyrolysis by heating them in chloroform at
reflux temperature without previous purification. After column chromatography, the hydroxy-
enone 1 was isolated in 69% yield. Complementarily, the mixture of cis- and trans-14 was
converted into the corresponding benzoates cis- and trans-15 in 72% yield, which were oxidised
to the sulphoxides with m-CPBA; subsequent pyrolysis furnished the benzoyloxyenone 97 in 65%
yield. Compound 9 was also obtained through benzoylation of 1 in 81% yield. The two epimers
of 15 equilibrated rapidly and we could only isolate a pure analytical sample of the more stable
1
trans isomer, the H NMR spectrum of which resembles closely that of trans-14. The cis
stereochemistry of the minor isomer was again confirmed by the positive NOE between H1 and
H3. In spite of the problems associated with the isolation of 1, the oxidation–pyrolysis step of
15 works similar to that of 14 and we were unable to improve the yield of the benzoylation of
14; therefore, passing through the benzoyl derivative is not advantageous for the overall
synthesis.
The new synthesis of ( )-1 starting from the precursor ( )-3 had been completed in only four
steps and 54% overall yield. Then the same sequence was repeated starting with each enantiomer
of 3. From (−)-3, we arrived at (+)-1, [h]2D0=+92.0 (c 0.96, CHCl3), corresponding to (R)-1, and
from (+)-3 we obtained (−)-1, [h]2D0=−92.3 (c 1.30, CHCl3), according to (S)-1. The enantiomeric
purity of both antipodes was determined by CGC to be 98%. This correlation establishes the
configuration of (−)-3, (−)-13 and (−)-12 as (5R), (3R) and (1R,3R), and that of (+)-3, (+)-13
and (+)-12 as (5S), (3S) and (1S,3S), respectively.
In summary, we have developed two new, stereoselective, very short and simple synthetic
approaches to (R)- and (S)-4-hydroxy-2-cyclohexenone from easily available chiral synthetic
equivalents of p-benzoquinone. The access in multi-gram quantities to compound 1 in both
enantiomeric forms encouraged us to use it in the syntheses of more complex molecules, which
are currently investigated.
3. Experimental
Reaction mixtures were stirred magnetically. TLC was performed using 0.25 mm Alugram Sil
plates, Machery–Nagel. Flash column chromatography was performed using SDS 230–400 mesh
or Baker 40 mm silica gel. CGC were performed with an FS-Lipodex B 20 m×0.25 mm column.
1
Infrared spectra were recorded on a Nicolet 5 ZDX spectrophotometer. H and 13C NMR
spectra were recorded in Servei de Ressona`ncia Magne`tica Nuclear de la Universitat Auto`noma de

4478
P. de March et al. / Tetrahedron: Asymmetry 11 (2000) 4473–4483
Barcelona on Bruker AC-250-WB or AM-400-WB instruments. Mass spectra were performed at
Servei d’Ana`lisi Qu´ımica de la Universitat Auto`noma de Barcelona (SAQ-UAB) on an Hewlett–
Packard 5985B instrument. Elemental analyses were performed at Centre d’Investigacio´ i
Desenvolupament de Barcelona CSIC or at SAQ-UAB.
3.1. 4,4-[(1R,2R)-(1,2-Diphenylethylene)dioxy]-2-cyclohexenone, 4
A solution of 2 (892 mg, 2.93 mmol) and RhCl(PPh3)3 (65 mg, 0.07 mmol) in toluene (36 mL)
was stirred under a hydrogen atmosphere at room temperature. The evolution of the reaction
1
mixture was followed by H NMR analysis of aliquot samples. After 5 h, when the spectrum
showed around 50% conversion, the hydrogen was evacuated and the solvent was removed
under vacuum, giving 900 mg of crude material. Purification of this residue by flash chromatog-
raphy (hexane/CH2Cl2, 3/7) gave 439 mg (1.44 mmol, 49%) of starting material and 343 mg
(1.12 mmol, 38%) of 4. Considering the recovered 2 the yield is 75%. 4: white solid, mp 73–75°C
1
(ether/pentane); IR (KBr): 3065, 3037, 2959, 2924, 2864, 1687, 1455, 1223, 1124, 1019 cm−1; H
NMR (250 MHz, CDCl3): l 7.40–7.25 (m, 6H: 6HAr), 7.25–7.10 (m, 4H: 4HAr), 6.91 (d,
J3,2=10.2 Hz, 1H: H3), 6.11 (d, J2,3=10.2 Hz, 1H: H2), 4.86 (d, J1%,2%=8.4 Hz, 1H: H1%/H2%), 4.79
(d, J1%,2%=8.4 Hz, 1H: H1%/H2%), 2.81 (ddd, J=16.8 Hz, J%=9.3 Hz, J¦=6.4 Hz, 1H: H5/H6), 2.68
(dt, J=16.8 Hz, J%=J¦=5.5 Hz, 1H: H5/H6), 2.60–2.40 (complex absorption, 2H: H5, H6); 13C
NMR (62.5 MHz, CDCl3): l 198.6, 146.7, 135.6, 135.4, 130.8, 128.7, 128.6, 126.6, 104.5, 85.8,
85.2, 35.2, 34.0; MS (CI/NH3) (m/z) 324 (M++18, 13), 307 (M++1, 22), 214 (100), 200 (46), 197
(68). Anal. calcd for C20H18O3: C, 78.41; H, 5.92. Found: C, 78.23; H, 5.96. [h]2D0=+48.0 (c 1.0,
CHCl3).
3.2. (1R)-4,4-[(1R,2R)-(1,2-Diphenylethylene)dioxy]-2-cyclohexenol, (1R)-5
To a solution of 4 (620 mg, 2.02 mmol) in 20 mL of MeOH at −78°C, NaBH4 (48 mg, 1.27
mmol) was added in small portions and the mixture was stirred at the same temperature,
following the reaction evolution by TLC (hexane/EtOAc, 2/1). After 5 h of reaction, the solvent
was removed under vacuum, water (6 mL) was added, the solution was acidified with 3% HCl,
and the aqueous phase extracted with CH2Cl2. Evaporation of the solvent gave 616 mg (2.00
mmol, 99%) of a ca. 4:1 mixture of (1R)- and (1S)-5. Repeated crystallisation from ether/pen-
tane yielded 67% of pure (1R)-5. The crystallisation is more efficient if the reaction crude is
previously purified by flash chromatography on silica gel (hexane/EtOAc, 2/1). (1R)-5: white
solid, mp 117–119°C (ether/pentane); IR (KBr): 3255, 3037, 2952, 2875, 1602, 1455, 1384, 1258,
1
1159, 1110, 1012 cm−1; H NMR (250 MHz, CDCl3): l 7.35–7.25 (m, 6H: 6HAr), 7.23–7.10 (m,
4H: 4HAr), 6.04 (d, J2,3=10.0 Hz, 1H: H2/H3), 5.91 (d, J2,3=10.0 Hz, 1H: H2/H3), 4.78 (d,
J1%,2%=8.5 Hz, 1H: H1%/H2%), 4.68 (d, J1%,2%=8.5 Hz, 1H: H1%/H2%), 4.28 (br s, 1H: H1), 2.25 (m, 2H),
2.07 (m, 1H), 1.87 (m, 1H), 1.55 (m, 1H: OH); 13C NMR (62.5 MHz, CDCl3): l 136.3, 136.2,
135.7, 129.5, 128.5, 128.40, 128.36, 126.83, 126.6, 105.72, 85.5, 85.1, 66.6, 32.8, 31.0; MS
(CI/NH3) (m/z) 309 (M++1, 22), 214 (100), 202 (31). Anal. calcd for C20H20O3: C, 77.90; H, 6.54.
Found: C, 77.98; H, 6.40. [h]2D0=+49.2 (c 0.6, CH2Cl2). (1S)-5: H NMR (250 MHz, CDCl3,
1
observable signals): l 6.06 (d, J2,3=10.0 Hz, 1H: H2/H3), 5.96 (d, J2,3=10.0 Hz, 1H: H2/H3),
4.81 (d, J1%,2%=8.5 Hz, 1H: H1%/H2%), 4.74 (d, J1%,2%=8.5 Hz, 1H: H1%/H2%), 2.35 (m, 1H); 13C NMR
(62.5 MHz, CDCl3, observable signals): l 136.43, 136.39, 134.4, 130.4, 126.76, 105.67, 65.3, 31.7,
30.0.

P. de March et al. / Tetrahedron: Asymmetry 11 (2000) 4473–4483
4479
3.3. Conversion of (1R)-5 into (R)-4-hydroxy-2-cyclohexenone, (R)-1
A mixture of (1R)-5 (92 mg, 0.30 mmol) and montmorillonite K-10 (420 mg) in CH2Cl2 (8
mL) was stirred at room temperature for 29 h. The montmorillonite was filtered off and the
solvent was removed under vacuum. Flash chromatography (hexane/EtOAc, 1/1) of the residue
(115 mg) afforded (1R,2R)-hydrobenzoin (58 mg, 0.27 mmol, 91%) and (+)-1 (58 mg, 0.27
mmol, 87%), [h]2D0=+90.0 (c 0.2, CHCl3).
3.4. cis-4,4-Ethylenedioxy-5-phenylthio-2-cyclohexenol, 6
To a stirred solution of 4,4-ethylenedioxy-5-phenylthio-2-cyclohexenone, 3, (765 mg, 2.9
mmol) in a mixture of CH2Cl2 (8 mL) and MeOH (8 mL) at 0°C was added NaBH4 (31 mg, 0.82
mmol) in small portions. The mixture was stirred at 0°C for 1 h and then at room temperature
until TLC (CH2Cl2/ether, 9/1) showed complete conversion of 3. The solvent was removed under
vacuum, water (10 mL) was added, the solution was acidified with 4% HCl and then extracted
with CH2Cl2 (4×10 mL). The organic extracts were dried over anhydrous MgSO4 and the solvent
evaporated, giving 730 mg of an oily residue. This oil was purified by flash chromatography
(CH2Cl2/ether, 9/1), yielding 680 mg (2.6 mmol, 90%) of 6: white solid, mp 62–64°C (CH2Cl2/
pentane); IR (KBr): 3395, 3055, 2945, 2882, 1680, 1581, 1476, 1441, 1230, 1152, 1061, 1005 cm−1;
1H NMR (250 MHz, CDCl3): l 7.49 (m, 2H), 7.30 (m, 3H), 5.91 (dt, J=10.2 Hz, J2,1:J2,6:1.8
Hz, 1H: H2), 5.66 (dd, J3,2=10.2 Hz, J3,1=2.2 Hz, 1H: H3), 4.15 (m, 5H: OCH2CH2O, H1), 3.43
trans
trans
(dd,
J =13.2 Hz, cisJ5,6=2.9 Hz, 1H: H5), 2.46 (m, 1H: H6), 2.00 (td,
J :J6,6:12.8 Hz,
6,5
5,6
J6,1=9.5 Hz, 1H: H6), 1.80 (br d, J=7.3 Hz, 1H: OH); 13C NMR (62.5 MHz, CDCl3): l 135.3,
134.3, 131.6, 128.8, 128.7, 126.8, 105.7, 67.0, 66.2, 65.9, 52.4, 38.7; MS (m/z) 264 (M+, 1), 128
(100). Anal. calcd for C14H16O3S: C, 63.62; H, 6.11; S, 12.11. Found: C, 63.55; H, 6.06; S, 12.01.
3.5. cis-6-Phenylthio-4-hydroxy-2-cyclohexenone, 7
To a stirred suspension of 6 (135 mg, 0.51 mmol) in water (7 mL) and EtOAc (200 mL) were
added 150 mg of resin DOWEX®-50WX8-400 (previously washed with 2% HCl and then water)
and the mixture was stirred at room temperature for 2.5 h. The resin was filtered off and washed
with EtOAc (4×4 mL). The organic phase was separated, dried with anhydrous MgSO4 and the
solvent evaporated under vacuum. The residue (108 mg) was purified by flash chromatography
(CH2Cl2/ether, 9/1), yielding 90 mg (0.41 mmol, 80%) of 7: oil; IR (film): 3423, 2931, 2957, 2868,
1
1743, 1680, 1588, 1476, 1441, 1378, 1251, 1223, 1061 cm−1; H NMR (250 MHz, CDCl3): l 7.35
(m, 2H), 7.20 (m, 3H), 6.84 (br d, J3,2=10.2 Hz, 1H: H3), 5.92 (dd, J2,3=10.2 Hz, J2,4=2.2 Hz,
trans
cis
1H: H2), 4.48 (m, 1H: H4), 3.80 (dd,
J =13.2 Hz, J5,6=5.1 Hz, 1H: H6), 2.47 (m, 1H: H5),
5,6
1.98 (m, 1H: H5); 13C NMR (62.5 MHz, CDCl3): l 195.1, 153.2, 132.8, 132.5, 128.9, 127.7,
127.6, 66.2, 51.9, 39.1; MS (m/z) 220 (M+, 27), 202 (M+−H2O, 6), 137 (30), 136 (48), 135 (62),
110 (100), 84 (89), 55 (42). Anal. calcd for C12H12O2S: C, 65.44; H, 5.50; S, 14.53. Found: C,
1
65.40; H, 5.56; S, 14.53. Compound 7 epimerises slowly to the trans isomer: H NMR (250
MHz, CDCl3, significant signals): l 6.82 (m, H3), 5.91 (br d, J=10.2 Hz, H2), 4.78 (m, H4), 3.89
(br t, J:4.8 Hz, H6).

4480
P. de March et al. / Tetrahedron: Asymmetry 11 (2000) 4473–4483
3.6. Reaction of 7 with Raney nickel
Compound 7 (20 mg, 0.09 mmol) was added to a suspension of aqueous Raney nickel (W-2,
Aldrich) in ethanol (1.5 mL) and the mixture was stirred at room temperature for 1 h. The
reaction mixture was filtered through Celite, the filtrate was dried with anhydrous Mg2SO4 and
1
the solvent was evaporated under vacuum. H NMR analysis of the oily residue (16 mg) showed
the presence of 4-hydroxycyclohexanone,20 8, as the major compound.
3.7. 4-Oxo-5-phenylthiocyclohex-2-enyl benzoate, 10
To a stirred solution of 7 (235 mg, 1.10 mmol) in pyridine (6 mL) under nitrogen at 0°C,
benzoyl chloride (250 mL, 2.14 mmol) was added and the mixture was stirred for 75 min. Then
CH2Cl2 (10 mL) and water (10 mL) were added and stirring was continued for 30 min. The
organic layer was separated, washed with water (2×10 mL), dried over anhydrous MgSO4 and
the solvent removed. The residue (400 mg) was purified by flash chromatography (hexane/
EtOAc, 9/1), giving 139 mg (0.43 mmol, 40%) of trans-4-oxo-5-phenylthiocyclohex-2-enyl
benzoate, trans-10, and 193 mg (0.59 mmol, 56%) of cis-10. The last isomer epimerised on
standing and therefore it could not be fully characterised. trans-10: yellowish solid, mp 93–96°C
(hexane/EtOAc); IR (KBr): 3058, 2931, 1792, 1715, 1673, 1609, 1588, 1482, 1448, 1314, 1272,
1240, 1216, 1110, 1068, 1026 cm−1; 1H NMR (250 MHz, CDCl3): l 8.02 (d, J=7.3 Hz, 2H), 7.50
(m, 5H), 7.25 (m, 3H), 6.91 (br d, J2,3=9.5 Hz, 1H: H2), 6.09 (d, J3,2=9.5 Hz, 1H: H3), 6.05 (m,
trans
1H: H1), 4.02 (t,
J :cisJ5,6:4.8 Hz, 1H: H5), 2.59 (m, 2H: 2H6); 13C NMR (62.5 MHz,
5,6
CDCl3): l 193.1, 165.5, 146.4, 133.7, 133.4, 129.7, 129.3, 129.1, 128.5, 128.4, 66.6, 50.6, 34.6; MS
(m/z) 218 (M+−PhCHO, 5), 202 (M+−PhCO2H, 13), 122 (67), 105 (100), 77 (72), 51 (39). Anal.
calcd for C19H16O3S: C, 70.35; H, 4.98; S, 9.87. Found: C, 70.26; H, 4.96; S, 9.67. cis-10:
1
yellowish solid; H NMR (250 MHz, CDCl3): l 8.07 (m, 4H), 7.56–7.25 (complex absorption,
6H), 7.02 (d, J2,3=8.9 Hz, 1H: H2), 6.15 (d, J3,2=8.9 Hz, 1H: H3), 5.83 (m, 1H: H1), 3.93 (dd,
trans
cis
J =11.3 Hz, J5,6=4.8 Hz, 1H: H5), 2.70 (dt, J6,6=12.0 Hz, J6,5:J6,1:4.3 Hz, 1H: H6);
5,6
2.31 (dt, J6,6=12.0 Hz, J6,5:J6,1:8.9 Hz, 1H: H6); 13C NMR (62.5 MHz, CDCl3): l 193.6,
171.5, 146.7, 133.5, 133.3–127.8 (several signals), 67.6, 51.6, 35.6; MS (m/z) 218 (M+−PhCHO,
1), 202 (M+−PhCO2H, 24), 122 (75), 105 (100), 77 (75), 51 (39).
3.8. 4,4-Ethylenedioxy-3-phenylthiocyclohexanone, 13
Palladium hydroxide on carbon (20%, 756 mg) was added to a solution of 3 (5.16 g, 19.7
mmol) in methanol (250 mL) and the mixture was stirred under a hydrogen atmosphere at room
1
temperature for 15 h. After this time, H NMR analysis of an aliquot sample still showed a
residual amount of starting material. Therefore, 100 mg of catalyst was added and the mixture
stirred again under hydrogen for 2 h. Then the hydrogen was evacuated and the mixture was
filtered through Celite. Evaporation of the solvent under vacuum furnished 5.09 g of an oily
residue. Purification of this material by flash chromatography (CH2Cl2/ether, 9/1) gave 5.00 g
(18.9 mmol, 96%) of 13: white solid, mp 47–50°C (ether–pentane); IR (KBr): 3058, 2966, 2896,
1
1722, 1581, 1476, 1441, 1265, 1202, 1145, 1117, 1033 cm−1; H NMR (250 MHz, CDCl3): l 7.40
trans
cis
(m, 2H), 7.20 (m, 3H), 4.08 (m, 4H: OCH2CH2O), 3.53 (dd,
J =9.9 Hz, J3,2=5.1 Hz, 1H:
3,2
H3), 2.78–2.45 (complex absorption, 3H), 2.38 (m, 1H), 2.20 (m, 1H), 1.90 (m, 1H); 13C NMR
(62.5 MHz, CDCl3): l 207.4, 133.9, 132.4, 128.9, 127.4, 108.1, 65.8, 53.8, 45.5, 38.0, 32.4; MS

P. de March et al. / Tetrahedron: Asymmetry 11 (2000) 4473–4483
4481
(m/z) 264 (M+, 15), 126 (35), 99 (100). Anal. calcd for C14H16O3S: C, 63.62; H, 6.11; S, 12.11.
Found: C, 63.64; H, 6.10; S, 11.95. (R)-13: oil, [h]2D0=−48.7 (c 5.3, CHCl3). (S)-13: oil,
[h]2D0=+44.7 (c 6.4, CHCl3).
3.9. cis-4,4-Ethylenedioxy-3-phenylthiocyclohexanol, 12
To a stirred solution of 13 (506 mg, 1.9 mmol) in a mixture of CH2Cl2 (6 mL) and MeOH (6
mL) at 0°C was added NaBH4 (22 mg, 0.58 mmol) in small portions and the mixture was stirred
at 0°C for 1 h and then at room temperature until total conversion of 13 (TLC, CH2Cl2/ether,
9/1). The solvent was removed under vacuum, water (8 mL) was added, the solution was
acidified with 4% HCl and then extracted with CH2Cl2. The organic extracts were dried over
anhydrous MgSO4 and the solvent evaporated, giving 600 mg of an oily residue. This oil was
purified by flash chromatography (CH2Cl2/ether, 9/1), yielding 473 mg (1.78 mmol, 93%) of 12:
white solid, mp 88–91°C (EtOAc/pentane); IR (KBr): 3381 (br), 3100, 2959, 2889, 1581, 1476,
1
1441, 1363, 1328, 1265, 1209, 1166, 1131, 1082, 1054 cm−1; H NMR (250 MHz, CDCl3): l 7.37
trans
(m, 2H), 7.14 (m, 3H), 3.98 (m, 4H: OCH2CH2O), 3.59 (m, 1H: H1), 3.18 (dd,
J =12.4 Hz,
3,2
cis
J =4.4 Hz, 1H: H3), 2.17 (m, 1H: H2), 1.82 (m, 3H: H2, H5, H6), 1.47 (m, 3H: H5, H6, OH);
3,2
13C NMR (62.5 MHz, CDCl3): l 135.8, 131.5, 128.7, 126.6, 108.6, 69.1, 65.6, 53.6, 40.8, 32.6,
32.1; MS (m/z) 266 (M+, 14), 99 (100). Anal. calcd for C14H18O3S: C, 63.13; H, 6.82; S, 12.02.
Found: C, 63.06; H, 6.93; S, 11.97. (1R,3R)-12: oil, [h]2D0=−3.4 (c 4.6, CHCl3). (1S,3S)-12: oil,
[h]2D0=+2.9 (c 5.6, CHCl3).
3.10. 2-Phenylthio-4-hydroxycyclohexanone, 14
A stirred mixture of 12 (879 mg, 3.3 mmol), p-TsOH (135 mg, 0.71 mmol), water (118 mL)
and THF (9 mL) was heated at 80°C for 22 h. Then it was neutralised with saturated solution
of NaHCO3 and extracted with CH2Cl2. The organic extracts were dried over anhydrous MgSO4
and evaporation of the solvent furnished 650 mg of an oily residue. Purification of this material
by flash chromatography (CH2Cl2/ether, 9/1) gave 640 mg (2.9 mmol, 88%) of a 1:2.5 mixture
of cis- and trans-14, respectively: IR (KBr): 3338, 2931, 1715, 1588, 1469, 1434, 1258, 1202, 1068
1
cm−1; H NMR (250 MHz, CDCl3): l 7.41 (m), 7.22 (m), 4.32 (m, H4 of trans-14), 4.16 (m, H4
of cis-14), 4.10 (ddd, J2,3=7.6 Hz, J2,3=5.1 Hz, J2,6=1.4 Hz, H2 of trans-14), 3.83 (ddd,
J2,3=7.6 Hz, J2,3=5.8 Hz, J=1.5 Hz, H2 of cis-14), 2.96 (ddd, J6,6=14.6 Hz, J6,5=7.3 Hz,
J6,5=5.1 Hz, 1H6 of cis-14), 2.79 (ddd, J6,6=14.4 Hz, J6,5=8.0 Hz, J6,5=5.8 Hz, 1H6 of
trans-14), 2.60 (dddd, J6,6=14.4 Hz, J6,5=8.5 Hz, J6,5=5.6 Hz, J6,2=1.4 Hz, 1H6 of trans-14),
2.45 (dddd, J3,3=13.9 Hz, J3,2=5.8 Hz, J3,4=3.6 Hz, J3,5=1.5 Hz, 1H3 of cis-14), 2.40–1.90
(complex absorption), 1.72 (br d, J=2.9 Hz, 1H: OH); 13C NMR (62.5 MHz, CDCl3): l 206.5,
206.1, 133.7, 133.3, 132.1, 131.7, 131.3, 128.9, 128.6, 127.5, 127.3, 66.5, 64.8, 53.6, 52.8, 40.8,
40.7, 35.2, 34.1, 34.0; MS (m/z) 222 (M+, 26), 218 (28), 110 (100), 109 (36). Anal. calcd for
C12H14O2S: C, 64.84; H, 6.35; S, 14.42. Found: C, 64.41; H, 6.18; S, 13.91.
3.11. 4-Oxo-3-phenylthiocyclohexyl benzoate, 15
To a stirred solution of 14 (655 mg, 2.9 mmol) and pyridine (315 mL, 3.9 mmol) in CH2Cl2
(5 mL) under nitrogen at 0°C, benzoyl chloride (690 mL, 5.9 mmol) was added and the mixture
was stirred at 0°C for 1.5 h and at room temperature for 30 min. Then CH2Cl2 (4 mL) and water

4482
P. de March et al. / Tetrahedron: Asymmetry 11 (2000) 4473–4483
(8 mL) were added and stirring was continued for 30 min. The organic layer was separated,
washed with water (3×10 mL), dried over anhydrous MgSO4 and the solvent removed. The
residue (1.16 g) was purified by flash chromatography (hexane/EtOAc, 9/1), giving 700 mg (2.1
mmol, 72%) of a 2:1 mixture of trans- and cis-4-oxo-3-phenylthiocyclohexyl benzoate, trans-
and cis-15. The two isomers equilibrate rapidly. An analytical sample of trans-15 could be
obtained by crystallisation (ether/pentane) of an enriched fraction: mp 81–85°C (ether/pentane);
IR (KBr): 3058, 2966, 2945, 2910, 1708, 1602, 1581, 1441, 1321, 1279, 1202, 1173, 1117, 1068,
1026 cm−1; 1H NMR (250 MHz, CDCl3): l 7.98 (d, J=8.1 Hz, 2H), 7.55 (t, J=5.1 Hz, 1H), 7.25
(m, 4H), 7.20 (m, 3H), 5.51 (m, 1H: H1), 4.07 (m, 1H: H3), 2.86 (m, 1H), 2.54 (m, 2H), 2.30 (m,
1H), 2.18 (m, 2H); 13C NMR (62.5 MHz, CDCl3): l 205.4, 165.7, 134.0, 133.1, 132.2, 129.8,
129.4, 129.0, 128.4, 127.8, 68.1, 53.3, 37.2, 34.1, 30.9; MS (m/z) 326 (M+, 8), 204 (M+−PhCO2H,
68), 105 (100), 77 (48). Anal. calcd for C19H18O3S: C, 69.92; H, 5.56; S, 9.80. Found: C, 70.02;
1
H, 5.66; S, 9.54. cis-15: H NMR (250 MHz, CDCl3): l 8.10 (d, J=8.1 Hz, 2H), 7.60–7.18
(complex absorption, 8H), 5.37 (m, 1H: H1), 3.79 (m, 1H: H3), 3.14 (m, 1H); 2.56 (m, 1H), 2.33
(m, 2H), 2.15 (m, 2H); 13C NMR (62.5 MHz, CDCl3): l 205.1, 165.4, 133.2–127.7 (several
signals), 68.2, 53.0, 37.5, 35.5, 30.9.
3.12. Conversion of 14 into 4-hydroxy-2-cyclohexenone, 1
To a solution of 14 (202 mg, 0.91 mmol) in CH2Cl2 (6 mL) at 0°C was added 54% m-CPBA
(289 mg, 0.89 mmol) and the mixture was stirred at 0°C for 2 h. The reaction mixture was
washed with saturated aqueous NaHCO3 and the aqueous layer extracted with CH2Cl2 (5×5
mL). The combined organic extracts were dried over anhydrous MgSO4 and the solvent
removed under vacuum to give 255 mg of a residue. This residue was solved in CHCl3 (7 mL)
and heated at reflux temperature for 25 h. During this time, the reaction evolution was
monitored by TLC (hexane/EtOAc, 7/3). Removal of the solvent under vacuum furnished 209
mg of a residue. Purification of this material by flash chromatography (hexane/EtOAc, 7/3) gave
71 mg (0.63 mmol, 69%) of 1.3–6 The same procedure applied to a mixture of trans- and cis-14
prepared from (1R,3R)-12 gave (R)-1,11,12,14 [h]D20=+94.7 (c 1.1, CHCl3), and from (1S,3S)-12
gave (S)-1,11–13 [h]D20=−92.3 (c 1.3, CHCl3).
3.13. Conversion of 15 into 4-oxocyclohexen-2-yl benzoate, 9
To a solution of 15 (564 mg, 1.7 mmol) in CHCl3 (5 mL) at 0°C was added 41% m-CPBA
(716 mg, 1.7 mmol) and the mixture was stirred at 0°C until TLC analysis (hexane/ether, 2/1)
showed total conversion of 15. The reaction mixture was washed with saturated aqueous
NaHCO3, the aqueous phase was extracted with CHCl3 (5×5 mL), the combined organic
extracts were dried over anhydrous MgSO4 and the solvent removed, giving 841 mg of a residue,
which was solved in CHCl3 (10 mL) and heated at reflux temperature for 19 h. Removal of the
solvent under vacuum furnished 796 mg of crude material. Purification by flash chromatography
(hexane/EtOAc, 7/3) gave 241 mg (1.1 mmol, 65%) of 9.7
3.14. Benzoylation of 1
To a stirred solution of 1 (278 mg, 1.29 mmol) in pyridine (500 mL) and CH2Cl2 (800 mL) at
0°C, benzoyl chloride (270 mL, 2.32 mmol) was added and the mixture was stirred at 0°C for 30

P. de March et al. / Tetrahedron: Asymmetry 11 (2000) 4473–4483
4483
min and at room temperature for 20 h. Then CH2Cl2 (5 mL) and water (5 mL) were added and
stirring was continued for 30 min. The organic layer was separated, washed with water (2×5
mL), dried over anhydrous MgSO4 and the solvent removed. Purification of the residue (481 mg)
by flash chromatography (hexane/ether, 9/1) gave 291 mg (1.35 mmol, 81%) of 9.7
Acknowledgements
We gratefully acknowledge financial support of CIRIT (1997SGR 00003) and DGES (PB97-
0215) and grants of Generalitat de Catalunya (to M.E. and E.G.) and Universitat Auto`noma de
Barcelona (to S.R.).
References
1. Danishefsky, S. J.; Simoneau, B. J. Am. Chem. Soc. 1989, 111, 2599–2604.
2. Jones, A. B.; Yamaguchi, M.; Patten, A.; Danishefsky, S. J.; Ragan, J. A.; Smith, D. B.; Schreiber, S. L. J. Org.
Chem. 1989, 54, 17–19.
3. Suzuki, M.; Oda, Y.; Noyori, R. Tetrahedron Lett. 1981, 22, 4413–4416.
4. Balci, M.; Akbulut, N. Tetrahedron 1985, 41, 1315–1322.
5. Ba¨ckvall, J.-E.; Andreasson, U. Tetrahedron Lett. 1993, 34, 5459–5462.
6. Marchand, A. P.; Xing, D.; Wang, Y.; Bott, S. G. Tetrahedron: Asymmetry 1995, 6, 2709–2714.
7. Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia, L. A. J. Org. Chem. 1991, 56, 2656–2665.
8. Essig, S.; Scheffold, R. Chimia 1991, 45, 30–32.
9. Witschel, M. C.; Bestmann, H. J. Synthesis 1997, 107–112.
10. Chang, S.; Heid, R. M.; Jacobsen, E. N. Tetrahedron Lett. 1994, 35, 669–672.
11. Carren˜o, M. C.; Garc´ıa-Ruano, J. L.; Garrido, M.; Ruiz, M. P.; Solladie´, G. Tetrahedron Lett. 1990, 31,
6653–6656.
12. Bru¨njes, R.; Tilstam, U.; Winterfeldt, E. Chem. Ber. 1991, 124, 1677–1678.
13. (a) Trost, B. M.; Romero, A. G. J. Org. Chem. 1986, 51, 2332–2342; (b) Audia, J. E.; Boisvert, L.; Patten, A.
D.; Villalobos, A.; Danishefsky, S. J. J. Org. Chem. 1989, 54, 3738–3740.
14. Gebauer, O.; Bru¨ckner, R. Liebigs Ann. 1996, 1559–1563.
15. de March, P.; Escoda, M.; Figueredo, M.; Font, J.; Alvarez-Larena, A.; Piniella, J. F. J. Org. Chem. 1995, 60,
3895–3897.
16. (a) de March, P.; Escoda, M.; Figueredo, M.; Font, J. Tetrahedron Lett. 1995, 36, 8665–8668; (b) de March, P.;
Escoda, M.; Figueredo, M.; Font, J.; Medrano, J. An. Quim. Int. Ed. 1997, 93, 81–87.
17. (a) de March, P.; Escoda, M.; Figueredo, M.; Font, J.; Alvarez-Larena, A.; Piniella, J. F. J. Org. Chem. 1997,
62, 7781–7787; (b) de March, P.; Figueredo, M.; Font, J.; Rodr´ıguez, S. Tetrahedron 2000, 56, 3603–3609.
18. Gautier, E. C. L.; Graham, A. E.; McKillop, A.; Standen, S. P.; Taylor, R. J. K. Tetrahedron Lett. 1997, 38,
1881–1884.
19. Bueno, A. B.; Carren˜o, M. C.; Garc´ıa-Ruano, J. L. Tetrahedron Lett. 1995, 36, 3737–3740.
20. Majewski, M.; Irvine, N. M.; MacKinnon, J. Tetrahedron: Asymmetry 1995, 6, 1837–1840.
.