The cleavage of meso-epoxides with homochiral thiols: Synthesis of (+)- and (-)-trans-1-mercaptocyclohexan-2-ol

Article abstract of DOI:10.1016/S0957-4166(99)00446-2

The synthesis of (+)- and (-)-trans-1-mercaptocyclohexan-2-ol is described. Ring opening of cyclohexene oxide with (-)-4-methoxybenzylnopan- 3(R)-thiol 1a followed by oxidation gives two readily separable diastereomeric sulfoxides. These sulfoxides display very different thermal stability but both undergo regio-specific syn-elimination to give cyclohexan- 1-ol-2-sulfenic acid that can be reacted in situ with 3,5-dimethylthiophenol to give a mixed disulfide. Reduction of these disulfides with lithium aluminium hydride gives the title compounds in enantiomerically pure form.

Full text of DOI:10.1016/S0957-4166(99)00446-2

Pergamon
Tetrahedron: Asymmetry 10 (1999) 4129–4142
The cleavage of meso-epoxides with homochiral thiols: synthesis
of (+)- and (−)-trans-1-mercaptocyclohexan-2-ol
Harry Adams,b Richard Bell,c Yiu-Yin Cheung,a D. Neville Jones a,∗ and
Nicholas C. O. Tomkinsona,†
aDepartment of Chemistry, University of Sheffield, Sheffield S3 7HF, UK
bCrystallographic Department, University of Sheffield, Sheffield S3 7HF, UK
cGlaxo Wellcome Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
Received 10 September 1999; accepted 7 October 1999
Abstract
The synthesis of (+)- and (−)-trans-1-mercaptocyclohexan-2-ol is described. Ring opening of cyclohexene oxide
with (−)-4-methoxybenzylnopan-3(R)-thiol 1a followed by oxidation gives two readily separable diastereomeric
sulfoxides. These sulfoxides display very different thermal stability but both undergo regio-specific syn-elimination
to give cyclohexan-1-ol-2-sulfenic acid that can be reacted in situ with 3,5-dimethylthiophenol to give a mixed di-
sulfide. Reduction of these disulfides with lithium aluminium hydride gives the title compounds in enantiomerically
pure form. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
The cleavage of meso-epoxides with homochiral nucleophiles and bases has proven to be a versatile
means of synthesising enantio-enriched compounds. The challenge of discriminating between identical
enantiotopic groups, attached to centres of opposite configuration, has led to ingenious chemical methods
for the synthesis of compounds such as β-azido alcohols,1 allylic alcohols,2 hydroxy sulfides3 and
halohydrins.4 This success prompted our own investigations into the cleavage of cyclohexene oxide with
the homochiral thio-nucleophiles 1a and 1b.
Cleavage of cyclohexene oxide 2 with a chiral thiol can give rise to two possible diastereomeric
hydroxy sulfides 3, oxidation of which can lead to four possible hydroxy sulfoxides 4 (Scheme 1).
Providing these diastereomeric sulfoxides were separable then their thermolysis should lead to either
homochiral allylic alcohols or hydroxy sulfenic acids.
∗
†
Corresponding author.
Current address: Department of Chemistry, Cardiff University, Cardiff CF10 3TB, Wales, UK. E-mail: tomkinsonnc@
cardiff.ac.uk
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00446-2

4130
H. Adams et al. / Tetrahedron: Asymmetry 10 (1999) 4129–4142
Scheme 1.
It is well established that sulfoxides bearing a β-hydrogen can thermolyse via a syn-elimination to give
an alkene and the corresponding sulfenic acid.5 Sulfoxide 5 is one of the four possible diastereomeric
sulfoxides formed from the cleavage of cyclohexene oxide with pinane thiol 1b, followed by oxidation.
This compound has three available syn β-hydrogens, two on the cyclohexane ring and one on the
bicyclic moiety. Elimination into the cyclohexane ring could lead to either cyclohexanone 6, formed
by tautomerisation of the corresponding enol, or the allylic alcohol 7. Elimination into the pinane ring
system would generate the hydroxysulfenic acid 8 (Scheme 2). By analogy with β-selenoxides,6 it would
be expected that the sulfoxide 5 would eliminate away from the hydroxy group, thus from the thermolysis
of 5 we would expect to produce homochiral allylic alcohols 7 and/or hydroxysulfenic acids 8. Herein
we report a short synthetic route to the homochiral thiols 1a and 1b starting from inexpensive and readily
available (−)-nopol and (−)-α-pinene, the regio and stereochemical course of the thermolysis of hydroxy
sulfoxides of the general type 5, and the synthesis of (+)- and (−)-trans-1-mercaptocyclohexan-2-ol.
Scheme 2.
2. Results and discussion
(−)-Nopol 9a was converted to its 4-methoxybenzyl ether under standard conditions,7 followed by
hydroboration with borane–dimethyl sulfide complex to give the alcohol 10a as a single diastereoisomer
(Scheme 3).8 Attempts to introduce sulfur functionality to 10a via the corresponding sulfonate ester
were complicated by loss of enantiomeric purity, elimination and rearrangement of the pinane skeleton.
Success was achieved, however, via a modified Misunobu procedure as reported by Rollin.9 Treatment
of the alcohol 10a with zinc N,N-dimethyldithiocarbamic acid in the presence of triphenylphosphine
and diethylazodicarboxylate (DEAD) proceeded with inversion of configuration at C3 to give the
dithiocarbamate 11a in 75% yield after chromatography. Reduction of 11a with lithium aluminium

H. Adams et al. / Tetrahedron: Asymmetry 10 (1999) 4129–4142
4131
hydride gave (−)-4-methoxybenzyl-nopan-3(R)-thiol 1a as a colourless oil (Scheme 3). Similarly, (−)-
pinan-3(R)-thiol 1b was obtained in three steps from (−)-α-pinene 10b in 55% overall yield as a
colourless oil.10
Scheme 3. Reagents: (i) (a) NaH, PMBCl, THF, ∆; (b) BH3·Me2S, THF, then H2O2, NaOH, EtOH, ∆; (ii) BH3·Me2S, THF,
then H2O2, NaOH, EtOH, ∆; (iii) PPh3, DEAD, Zn(CS2NMe2)2, PhMe; (iv) LiAlH4, Et2O, ∆
The pinane thiolate anion, generated by treatment of 1b with one equivalent of sodium ethoxide in
ethanol, cleaved cyclohexene oxide to give two diastereomeric hydroxy sulfides 12 in the ratio of 1:1.
These sulfides were chromatographically identical, and the ratio of the diastereoisomers was established
by interpretation of the 1H NMR spectrum of the mixture. The hydroxy directed oxidation of this mixture
with one equivalent of meta-chloroperoxybenzoic acid (mCPBA) at 0°C gave a mixture of hydroxy
sulfoxides (1R,2R,Ss)-2-pinanylsulfinylcyclohexanol 13b and the (1S,2S,Rs) isomer 14b which were
readily separable by virtue of their relative chromatographic mobilities on silica. Similarly, the thiol
1a was converted into the sulfoxides 13a and 14a (Scheme 4). Independent oxidation of the sulfoxides
13a and 14a to their corresponding sulfones with one equivalent of mCPBA gave two diastereomeric
sulfones. These sulfones had different specific rotations and 1H NMR characteristics, indicating that the
sulfoxides have opposite absolute configurations at the cyclohexyl hydroxyl group.
Scheme 4.
The absolute configuration assigned to the sulfoxides 13a, 13b, 14a and 14b was confirmed by X-ray
crystallography and 1H NMR spectroscopy. The single crystal X-ray crystal structure of the sulfoxide 13b
is shown in Fig. 1, where the absolute configuration at sulfur is (Ss). Thus, the absolute configuration at
sulfur in the hydroxy sulfoxide 14b was assigned as (Rs), on the basis of the X-ray structure of 13b
and the known directing power of hydroxy groups in the mCPBA oxidation of sulfides.11 Comparison
of the 1H NMR resonance of the C3 proton in the pinane ring system enabled us to assign the absolute
configuration of 13a and 14a to that shown in Scheme 4 (Table 1).
The thermolysis of sulfoxide 13a in refluxing xylenes was complete after 1.5 h. The alkene 15 was
isolated in 83% yield, which indicated that syn-elimination had occurred into the bicyclic moiety rather
than the cyclohexane ring and therefore the hydroxysulfenic acid 16 must have been formed. However,

4132
H. Adams et al. / Tetrahedron: Asymmetry 10 (1999) 4129–4142
Figure 1. Chem. 3D representation of the X-ray crystal structure of sulfoxide 13b
Table 1
Salient 1H NMR (CDCl3, 250 MHz) resonances of the sulfoxides 13a, 13b, 14 and 14b
the expected dihydroxythiosulfinate 17 was not detected, instead the disulfide 18 was isolated in 32%
yield (Scheme 5).
Scheme 5.
This initially surprising result may be rationalised in terms of an unforeseen Pummerer type rearran-
gement of the initially formed dihydroxythiosulfinate 17 under the acidic conditions of the thermolysis
(Scheme 6).12
Scheme 6.
This problem was circumvented by the use of the sulfenic acid trapping agent 3,5-
dimethylthiophenol.13 Thermolysis of 13a in the presence of 5 equivalents of 3,5-dimethylthiophenol

H. Adams et al. / Tetrahedron: Asymmetry 10 (1999) 4129–4142
4133
in xylenes for 1.5 h gave the mixed disulfide (−)-19 in 53% isolated yield. Reduction of this disulfide
(−)-19 with lithium aluminium hydride in diethyl ether gave (−)-trans-1-mercaptocyclohexan-2-ol
(−)-20 (Scheme 7). The sulfoxide 14a proved to be a lot more thermally stable than 13a; however,
thermolysis in refluxing xylenes for 18 h gave the mixed disulfide (+)-19, along with (+)-trans-1-
mercaptocyclohexan-2-ol (+)-20. We attribute the direct formation of the hydroxythiol (+)-20 to the
reaction of excess 3,5-dimethylthiophenol with the expected mixed disulfide (+)-19 under the reaction
conditions.
Scheme 7.
The thermolysis of the pinane thiol derived sulfoxides 13b and 14b proved to be more troublesome.
After considerable experimentation, consistent results were realised with the use of tert-butylthiol
as a sulfenic acid trapping agent. Treatment of sulfoxide 13b with a boiling diglyme/tert-butylthiol
mixture for 2 h gave the disulfide (−)-21 in 68% yield, which was reduced with lithium aluminium
hydride to give (−)-trans-1-mercaptocyclohexan-2-ol (−)-20 (Scheme 8). Thermolysis of the sulfoxide
14b in a boiling diglyme/tert-butylthiol mixture for 48 h gave the mixed disulfide (+)-21; no trans-1-
mercaptocyclohexan-2-ol (+)-20 was detected under these conditions.
Scheme 8.
In order to determine the enantiomeric excess of the hydroxythiols (−)- and (+)-20 and their disulfide
precursors racemic modifications of the compounds were prepared. Treatment of cyclohexene oxide
2 with sulfurated sodium borohydride, prepared in situ from sodium borohydride and sulfur, gave a
pungent crude disulfide, which on reduction with lithium aluminium hydride provided racemic trans-
1-mercaptocyclohexan-2-ol (ꢀ)-20 in 92% yield.14 Base catalysed conjugate addition of (ꢀ)-20 to
acrylonitrile in the presence of trimethylbenzylammonium hydroxide gave a sulfide, which was oxidised
to the sulfoxide 22 by treatment with mCPBA. Thermolysis of 22 in the presence of either tert-butylthiol
or 3,5-dimethylthiophenol gave the disulfides (ꢀ)-21 and (ꢀ)-19 in good yield (Scheme 9).

4134
H. Adams et al. / Tetrahedron: Asymmetry 10 (1999) 4129–4142
Scheme 9.
Table 2
Enantiomeric excesses for the disulfides 19 and 21
1
Spectroscopic examination of the disulfides (−)- and (+)-19 and (−)- and (+)-21 by H NMR tech-
niques in conjunction with the chiral shift reagent tris-[3-(heptafluoropropylhydroxymethylene)-(+)-
camphorato]-europium(III) (Eu(hfc)3), examining the proton adjacent to sulfur on the cyclohexane ring,
revealed the enantiomeric excesses for the disulfides as shown in Table 2. The disulfides (−)- and (+)-19
and (−)-21 had an enantiomeric excess >95% which was not compromised in the reduction with lithium
aluminium hydride.15 The low and somewhat disappointing enantiomeric excess for the disulfide (+)-21
suggests that the optical purity is diminished under the harsh conditions of thermolysis, which involved
long reaction times (48 h) and high temperatures (140°C).
3. Conclusions
In summary, we have found a short and valuable route to both enantiomers of trans-1-
mercaptocyclohexan-2-ol. This involves the base catalysed opening of cyclohexene oxide with the
homochiral thiol 1a, oxidation with mCPBA, thermolysis of the sulfoxides in the presence of 3,5-
dimethylthiophenol and reduction of the resulting disulfides to give enantiomerically pure (+)- and
(−)-trans-1-mercaptocyclohexan-2-ol. This route is not viable for pinane thiol 1b which only gives one
enantiomer of 20 in enantiomerically pure form.
4. Experimental
Proton magnetic resonance spectra were recorded on a Bruker ACF-250 and on a Bruker WH-400
spectrometer supported by an Aspect 2000 data system. Mass spectra were obtained on a Kratos MS 25
instrument operating in E.I., C.I. mode and on a Kratos MS 80 in +ve FAB mode. Melting points were
determined on a Kofler Hot Stage Micro Melting Point Apparatus and are uncorrected. Elemental micro-
analyses were carried out using a Perkin–Elmer 2400 Elemental Analyser CHN. Sulfur content was

H. Adams et al. / Tetrahedron: Asymmetry 10 (1999) 4129–4142
4135
determined by oxygen combustion followed by wet titration. Infrared spectra were recorded in the range
4000–600 cm−1 using a Perkin–Elmer 157G Grating Infrared Spectrophotometer. Optical rotations were
measured on an Optical Activity AA-1000 polarimeter at room temperature. Thin layer chromatography
(TLC) was performed on Merck 5554 60F silica gel coated aluminium plates and detection was effected
with a solution of 10% ceric sulfate in 10% sulfuric acid, followed by heating the plates. Purification of
compounds was achieved by medium pressure chromatography using Merck 9385 60 silica gel.
4.1. (4-Methoxybenzyl)-nop-2-ene
Sodium hydride (7.0 g, 50%, 146 mmol) was added to a stirred solution of (−)-nopol (22 g, 132 mmol)
in dry THF (200 mL) under nitrogen and the resulting solution was stirred for 10 min. A solution of 4-
methoxybenzyl chloride (19.5 g, 124 mmol) in dry THF (20 mL) was added dropwise under nitrogen and
the solution was stirred for 20 min and then refluxed for 1.5 h. The solvent was removed under reduced
pressure and the residue was dissolved in ether (350 mL), washed with water (3×150 mL) and dried
(MgSO4). The solvent was removed under reduced pressure and the crude product was chromatographed
on silica eluting with ether/light petroleum (10%) to give the product (31.5 g, 88%) as a yellow oil; [α]D
−23 (c 5.2, CHCl3); νmax cm−1 (CHCl3) 3030 (C_C), 2920 (OCH3), 1620 (aromatic), 1070 (OCH2Ar);
1H NMR (250 MHz, CDCl3) δ 7.28 (2H, d, J=9 Hz, Ar), 6.84 (2H, d, J=9 Hz, Ar), 5.26 (1H, m, CH), 4.42
(2H, s, CH2Ar), 3.80 (3H, s, OCH3), 3.45 (2H, t, J=7 Hz, C-11 protons), 2.38–1.97 (7H, m, aliphatic),
1.24 (3H, s, CH3), 0.81 (3H, s, CH3); (found: C, 79.5; H, 9.2; m/z 286. C19H26O2 requires: C, 79.7; H,
9.2; M+ 286).
4.2. (3S)-(4-Methoxybenzyl)-nopan-3-ol 10a
A solution of (4-methoxybenzyl)-nop-2-ene (31.1 g, 0.11 mol) in light petroleum (55 mL) was cooled
to 0°C under nitrogen and treated cautiously with borane–dimethyl sulfide (35 mL, 2 M in THF), the
solution was allowed to warm to room temperature and stirring was continued overnight. The reaction
mixture was cooled to 0°C and ethanol (75 mL) was added dropwise followed by sodium hydroxide
solution (35 mL, 2 M) and aqueous hydrogen peroxide (18 mL, 30% w/v). After addition was complete
the reaction mixture was refluxed for 1 h and cooled to room temperature. The organic phase was
separated and the aqueous layer was extracted with ether (2×150 mL). The combined organics were
dried over MgSO4 and the solvent was removed under reduced pressure. The crude product was purified
on silica eluting with ether/light petroleum (40%) to give 10a (21.9 g, 71%) as a yellow oil; [α]D 0 (c
5.25, CHCl3); νmax cm−1 (liquid film) 3420 (OH), 2920 (OCH3), 1620 (aromatic), 1070 (CH2OCH2);
1H NMR (250 MHz, CDCl3) δ 7.26 (2H, d, J=9 Hz, Ar), 6.82 (2H, d, J=9 Hz, Ar), 4.44 (2H, J=11 Hz,
CH2Ar), 4.14 (1H, br s, CHOH), 3.78 (3H, s, OCH3), 3.60 (2H, m, C11 protons), 3.39 (1H, d, J=3 Hz,
CHOH), 1.98–1.50 (6H, m, aliphatic), 1.18 (3H, s, CH3), 0.88 (3H, s, CH3); (found: C, 74.9; H, 9.4; m/z
305. C19H28O3 requires: C, 75.0; H, 9.3; M+ 305).
4.3. (3R)-(4-Methoxybenzyl)-nopan-3-N,N-dimethyldithiocarbamate 11a
Zinc N,N-dimethyldithiocarbamate (7.24 g, 23.7 mmol) was added to a stirred solution of triphenyl-
phosphine (33.0 g, 126 mmol) and the alcohol 10a (12.0 g, 39.5 mmol) in dry toluene (50 mL). The
reaction flask was protected from light and cooled to 0°C under nitrogen. Diethylazodicarboxylate (19
mL, 126 mmol) was carefully added and the suspension dissolved to give a light brown solution which
was stirred overnight and loaded directly onto a silica gel column eluting with first light petroleum (500

4136
H. Adams et al. / Tetrahedron: Asymmetry 10 (1999) 4129–4142
mL) followed by ethyl acetate/light petroleum (10%) to give the crude product 11a as a pink oil (12.1
g, 75%). A sample was re-chromatographed on silica eluting with ether/light petroleum (5–20%) for
characterisation; [α]D +52 (c 1.00, CHCl3); νmax cm−1 (CHCl3) 1612 (aromatic), 1140, 1090 (C_S);
1H NMR (400 MHz, CDCl3) δ 7.28 (2H, d, J=9 Hz, Ar), 6.84 (2H, d, J=9 Hz, Ar), 4.73 (1H, dt, J=10
and 10 Hz, CHS), 4.39 (2H, J=11 Hz, CH2Ar), 3.56 (3H, s, OCH3), 3.50 (3H, s, NCH3), 3.38 (2H, m,
OCH2CH), 3.36 (3H, s, NCH3), 2.76–1.49 (9H, m, aliphatic), 1.17 (3H, s, CH3), 0.97 (3H, s, CH3);
(found: C, 64.8; H, 8.3; N, 3.5; S, 15.6; m/z 408. C22H33O2S2N requires: C, 64.8; H, 8.2; N, 3.4, S; 15.7;
M+ 408).
4.4. (3R)-(4-Methoxybenzyl)-nopan-3-thiol 1a
Lithium aluminium hydride (6 g, 0.16 mol) was carefully added to a stirred solution of the dithio-
carbamate 11a (12 g, 29 mmol) in dry ether (250 mL) and the resulting solution was heated at reflux
overnight under nitrogen. The solution was cooled to 0°C and lithium aluminium hydride was quenched
with careful addition of wet ether followed by dropwise addition of water. The reaction mixture was
filtered through Celite and the filtrate was dried over MgSO4. Removal of solvent under reduced pressure
gave the crude product which was chromatographed on silica eluting with ethyl acetate/light petroleum
1
(5%) to give the product 1a as a pungent colourless oil (8.06 g, 85%); [α]D −11 (c 1.00, CHCl3); H
NMR (400 MHz, CDCl3) δ 7.28 (2H, d, J=9 Hz, Ar), 6.84 (2H, d, J=9 Hz, Ar), 4.42 (2H, s, CH2Ar),
3.80 (3H, s, OCH3), 3.45 (2H, m, OCH2CH), 2.45–1.41 (9H, m, aliphatics), 1.17 (3H, s, CH3), 0.95 (3H,
s, CH3); (found C, 71.2; H, 8.7; S, 10.2; m/z 320. C19H28O2S requires: C, 71.2; H, 8.8; S, 10.0; M+ 320).
4.5. (1R,2R,10R,20S,30R)-trans-2-Pinanylthiocyclohexanol and (1S,2S,10R,20S,30R)-trans-2-pinanyl-
thiocyclohexanol 12b
Pinane thiol (12 g, 70.6 mmol) was added to a stirred solution of sodium (1.62 g, 70.5 mmol) in
absolute ethanol (400 mL) under argon, and stirring was continued for 10 min. Cyclohexene oxide (7.14
mL, 70.6 mmol) was added and the solution was stirred at room temperature overnight (18 h). The
reaction mixture was diluted with ether (10 mL) and washed with water (3×50 mL). The organic layer
was separated and dried (MgSO4). Removal of solvent under reduced pressure gave the crude product
which was chromatographed on silica eluting with ether/light petroleum (5%) to give the products 12b as
a mixture of diastereoisomers (14.66 g, 78%); νmax cm−1 (thin film) 3456 (OH), 2981 (C-H); 1H NMR
(250 MHz, CDCl3) δ 3.66 (1H, dt, J=10 and 10 Hz, CHS), 3.63 (1H, dt, J=10 and 10 Hz, CH0S), 3.30
(2H, m, CHOH and CH0OH), 2.63–1.26 (16H, m, aliphatics), 1.21 (3H, d, J=8 Hz, CHCH3), 1.18 (6H,
s, CH3 and CH0 ), 1.18 (3H, d, J=8 Hz, CHCH0 ), 1.10 (3H, s, CH3), 1.09 (3H, s, CH0 ) (H and H0
3
3
3
denote different isomers); (found: C, 71.8; H, 10.5; S, 12.1; m/z 268. C16H28O1S1 requires: C, 71.6; H,
10.5; S, 11.9; M+ 268).
4.6. (−)-(1R,2R,Ss,10R,20S,30R)-trans-2-Pinanylsulfinylcyclohexanol 13b and (+)-(1S,2S,Rs,10R,20S,
30R)-trans-2-pinanylsulfinylcyclohexanol 14b
meta-Chloroperoxybenzoic acid (10.23 g, 58 mmol) was added to a stirred solution of hydroxy sulfides
12b (14.4 g, 53.7 mmol) in dry dichloromethane (200 mL) at 0°C. The solution was stirred for 30 min
and TLC showed the reaction was complete. Anhydrous potassium fluoride (9.52 g, 3 equiv.) was added
followed by Celite (5 g). The solution was filtered and reduced to give the crude product which was
chromatographed on silica eluting with ethyl acetate/light petroleum first (30%), followed by (50%) to

H. Adams et al. / Tetrahedron: Asymmetry 10 (1999) 4129–4142
4137
give the product 13b as a white crystalline solid (5.87 g, 40%); mp 96°C (ethyl acetate/light petroleum);
[α]D −100 (c 0.87, CHCl3); νmax cm−1 (thin film) 3380 (OH), 1065 (S_O); 1H NMR (250 MHz, CDCl3)
δ 4.10 (1H, ddd, J=10, 10 and 4 Hz, CHOH), 3.81 (1H, dt, J=10 and 10 Hz, CHSO), 2.84 (1H, m,
SOCH), 2.74 (1H, ddq, J=10, 8 and 4 Hz, CHCH3), 1.48 (3H, d, J=8 Hz, CHCH3), 1.20 (3H, s, CH3),
1.00 (3H, s, CH3); (found: C, 67.5; H, 9.8; S, 11.5; m/z 285. C16H28O2S1 requires: C, 67.6; H, 9.9; S,
11.3; M+ 285). Followed by the product 14b as a white crystalline solid (5.34 g, 36%); mp 166°C (ethyl
acetate/light petroleum); [α]D +29 (c 0.84, CHCl3); νmax cm−1 (thin film) 3380 (OH), 1065 (S_O); 1H
NMR (250 MHz, CDCl3) δ 4.08 (1H, ddd, J=10, 10 and 4 Hz, CHOH), 3.22 (1H, dt, J=9 and 9 Hz,
CHSO), 2.85 (1H, ddd, J=12, 9 and 4 Hz, CHSO), 2.74 (1H, m, CHCH3), 2.33–1.54 (11H, m, ring
protons), 1.47 (3H, d, J=8 Hz, CHCH3), 1.22 (3H, s, CH3), 0.99 (3H, s, CH3); (found: C, 67.7; H, 9.8;
S, 11.4; m/z 285. C16H28O2S1 requires: C, 67.6; H, 9.9; S, 11.3; M+ 285).
4.7. (1R,2R,10R,20S,30R)-trans-2-(4-Methoxybenzyl)-nopylthiocyclohexanol and (1S,2S,10R,20S,30R)-
trans-2-4-methoxybenzyl)-nopylthiocyclohexanol 12a
4-Methoxybenzylnopan-3(R)-thiol (1 g; 3.12 mmol) was added to a stirred solution of sodium ethoxide
(67 mg, in 20 mL of absolute ethanol), and stirring was continued for 15 min. Cyclohexene oxide (0.32
mL, 3.12 mmol) was added and the reaction mixture was stirred for 2.5 h and refluxed for 0.5 h. The
solution was diluted with ether (20 mL), washed with water (3×10 mL) and dried over MgSO4. Removal
of the solvent under reduced pressure gave the crude product which was chromatographed on silica
eluting with ether/light petroleum (15%) to give a mixture of two diastereoisomeric hydroxy sulfides 12a
as a colourless oil (1.19 g, 91%). High performance liquid chromatography on a small sample gave a 90%
separation of the diastereoisomers; first diastereoisomer: νmax cm−1 (liquid film) 3456 and 2981 (OH),
2860 (OMe), 1610 (aromatic); 1H NMR (250 MHz, CDCl3) δ 7.28 (2H, d, J=9 Hz, Ar), 6.84 (2H, d, J=9
Hz, Ar), 4,42 (2H, s, CH2Ar), 3.90 (3H, s, OCH3), 3.64 (1H, dt, J=10 and 10 Hz, H-3), 3.43 (2H, t, J=7
Hz, OCH2), 3.28 (1H, dt, J=9.5 and 4 Hz, CHS), 3.03 (1H, br s, CHOH), 2.52–1.21 (17H, m, aliphatic),
1.17 (3H, s, CH3), 0.95 (3H, s, CH3); m/z 418 (M+); second diastereoisomer: νmax cm−1 3456 and 2981
(OH), 2860 (OMe), 1610 (aromatic); 1H NMR (250 MHz, CDCl3) δ 7.29 (2H, d, J=9 Hz, Ar), 6.85 (2H,
d, J=9 Hz, Ar), 4.42 (2H, s, CH2Ar), 3.81 (3H, s, OCH3), 3.63 (1H, dt, J=10 and 10 Hz), 3.45 (2H, m,
OCH2), 3.25 (1H, br s, OH), 3.03 (1H, ddd, J=11, 9 and 4 Hz, CHS), 2.49–1.23 (17H, m, aliphatic), 1.21
(3H, s, CH3), 0.94 (3H, s, CH3); m/z 418 (M+).
4.8. (−)-(1R,2R,Ss,10R,20S,30R)-trans-2-(4-Methoxybenzyl)-nopylsulfinylcyclohexanol 13a and (+)-
(1S,2S,Rs,10R,20S,30R)-trans-2-(4-methoxybenzyl)-nopylsulfinylcyclohexanol 14a
meta-Chloroperoxybenzoic acid (451 mg, 2.62 mmol) was added to a stirred solution of sulfides 12a
(1.093 g, 2.62 mmol) in dichloromethane (20 mL) at 0°C. The solution was stirred for 20 min after
which time the reaction was complete. Na2SO3 solution was added, and the organic layer was separated
and washed with saturated NaHCO3 solution (3×30 mL) and dried over MgSO4. The solvent was
removed under reduced pressure and the crude product was chromatographed on silica eluting with ethyl
acetate/light petroleum (40%) to give the product 13a as a colourless viscous oil (388 mg, 34%); [α]D
−95 (c 0.104, CHCl3); νmax cm−1 (liquid film) 3645, 3450 (OH), 1607 (aromatic), 1060 (S_O); 1H NMR
(250 MHz, CDCl3) δ 7.32 (2H, d, J=9 Hz, Ar), 6.88 (2H, d, J=9 Hz, Ar), 5.39 (1H, br s, OH), 4.42 (2H,
s, CH2Ar), 4.05 (1H, m, CHOH), 3.81 (1H, s, OCH3), 3.50 (2H, m, OCH2), 3.21 (1H, dt, J=9 and 9 Hz,
H-3), 1.17 (3H, s, CH3), 1.01 (3H, s, CH3); (found: C, 67.8; H, 8.7; S, 7.2; m/z 424. C25H38SO4·0.5H2O
requires: C, 67.7; H, 8.9; S, 7.2; M+ 424). Further elution with ethyl acetate/light petroleum (70%) gave

4138
H. Adams et al. / Tetrahedron: Asymmetry 10 (1999) 4129–4142
product 14a as a white crystalline solid (364 mg, 32%); [α]D +15 (c 0.100, CHCl3); νmax cm−1 (CHCl3)
1
3645, 3450 (OH), 1608 (aromatic), 1050 (S_O); H NMR (250 mHz, CDCl3) δ 7.29 (2H, d, J=9 Hz,
Ar), 6.85 (2H, d, Ar), 4.42 (2H, s, CH2Ar), 4.09 (1H, m, CHOH), 3.82 (1H, dt, 9.5 and 9.5 Hz, H-3), 3.80
(3H, s, OCH3), 3.52 (2H, m, OCH2), 2.88 (1H, ddd, J=13, 9 and 4 Hz, cyclohexyl SOCH), 2.75–1.24
(17H, m, aliphatics), 1.19 (3H, s, CH3), 0.97 (3H, s, CH3); (found: C, 68.7; H, 8.9; S, 7.4; m/z 424.
C25H38SO4 requires: C, 69.1; H, 8.8; S, 7.4; M+ 424).
4.9. (−)-(1R,2R,10R,20S,30R)-trans-2-(4-Methoxybenzyl)-nopylsulfonylcyclohexanol
meta-Chloroperbenzoic acid (32 mg, 0.18 mmol) was added to a stirred solution of the hydroxy
sulfoxide 10a (74 mg, 0.17 mmol) in dichloromethane (2 mL) at 0°C. After 5 min the reaction mixture
was washed with NaHCO3 solution (3×10 mL), and the organic layer was separated and dried over
MgSO4. Removal of the solvent under reduced pressure gave the crude product which was purified on
silica eluting with ethyl acetate/light petroleum (30%) to give the product (67 mg, 83%); [α]D −20 (c
1
0.88; CHCl3); νmax cm−1 3614 and 3512 (OH), 2871 (OMe), 1614 (aromatic), 1126, 1317 (SO2); H
NMR (CDCl3) (250 mHz, CDCl3) δ 7.29 (2H, d, J=9 Hz, aromatic), 6.85 (2H, d, J=9 Hz, aromatic),
4.42 (2H, J=12 Hz, CH2Ar), 4.05 (1H, m, CHOH), 3.94 (1H, dt, J=9.5 and 9.5 Hz, H-3), 3.81 (3H, s,
OCH3), 3.71 (1H, d, J=3 Hz, OH), 3.47 (2H, m, OCH2), 3.11 (1H, ddd, J=12, 9 and 4 Hz, SO2CH), 1.19
(3H, s, CH3), 1.07 (3H, s, CH3); m/z 450 (MH+).
4.10. (+)-(1S,2S,10R,20S,30R)-trans-2-(4-Methoxybenzyl)-nopylsulfonylcyclohexanol
meta-Chloroperbenzoic acid (32 mg, 0.18 mmol) was added to a stirred solution of hydroxy sulfoxide
13a (71 mg, 0.164 mmol) in dichloromethane (2 mL) at 0°C. The solution was stirred for 5 min and
diluted with diethyl ether (20 mL). The reaction mixture was washed with NaHCO3 solution (3×10
mL), and the organic layer was separated and dried over MgSO4. Removal of the solvent under reduced
pressure gave the crude product which was purified on silica eluting with ethyl acetate/light petroleum
(30%) to give the product (35 mg, 46%); [α]D +19 (c 0.151, CHCl3); νmax cm−1 3615 (OH), 2871
(OMe), 1614 (aromatic), 1328, 1143 and 1126 (SO2); 1H NMR (250 mHz, CDCl3) δ 7.25 (2H, d, J=10
Hz, aromatic), 6.81 (2H, d, J=10 Hz, aromatic), 4.38 (2H, J=12 Hz, CH2Ar), 4.01 (1H, m, CHOH), 3.89
(1H, dt, J=10 and 10 Hz, H-3), 3.85 (3H, s, OCH3), 3.45 (2H, m, OCH2), 3.06 (1H, ddd, 14, 10 and 4
Hz, SO2CH), 1.14 (3H, s, CH3), 1.02 (3H, s, CH3); m/z 450 (MH+).
4.11. (−)-(1R,2R)-trans-2-(3,5-Dimethylphenyl)-dithiocyclohexanol 19
3,5-Dimethylthiophenol (831 mg, 6.01 mmol) was added to a stirred solution of the hydroxy sulfoxide
13a (522 mg, 1.20 mmol) in dry xylenes (5 mL). The resulting solution was heated at 140–150°C for 2 h
and then allowed to cool to ambient temperature. The solvent was removed under reduced pressure and
the crude product was purified on silica eluting with ether/light petroleum (20%) to give the product (−)-
19 (167 mg, 53%); [α]D −53 (c 0.415; CHCl3). All other spectral properties as for racemic modification.
4.12. (1R,2R)-(−)-trans-1-Mercaptocyclohexan-2-ol 20
Lithium aluminium hydride (65 mg, 1.71 mmol) was added to a stirred solution of disulfide (−)-19
(154 mg, 0.58 mmol) in dry ether (5 mL). The solution was stirred at room temperature for 1 h. Excess
lithium aluminium hydride was quenched with first ‘wet’ ether followed by careful dropwise addition of

H. Adams et al. / Tetrahedron: Asymmetry 10 (1999) 4129–4142
4139
water. 2 M HCl (3 mL) was added and the ethereal layer was decanted off and dried (MgSO4). The crude
product was chromatographed on silica eluting with light petroleum followed by ether/light petroleum
(40%) to give the product (−)-20 (38 mg, 50%); [α]D −42 (c 0.68, CHCl3). All other spectral properties
as for racemic modification.
4.13. (1S,2S)-(+)-trans-2-(3,5-Dimethylphenyl)-dithiocyclohexanol 19 and (1S,2S)-(+)-trans-1-mer-
captocyclohexan-2-ol 20
A solution of the sulfoxide 14b (1.18 g, 2.73 mmol) and 3,5-dimethylthiophenol (1.89 g, 13.6 mmol)
in xylenes (20 mL) was heated at reflux overnight under nitrogen. The reaction mixture was cooled to
room temperature and the solvent removed under reduced pressure to give the crude product which was
purified on silica eluting with first ether/light petroleum (10%) followed by ether/light petroleum (20%)
to give product (+)-19 (151 mg, 21%); [α]D +52 (c 1.67, CHCl3). All other spectral properties as for
racemic modification. Followed by the product (+)-20 (179 mg, 50%); [α]D +39 (c 1.43, CHCl3). All
other spectral properties as for racemic modification.
4.14. (−)-(1R,2R)-trans-2-tert-Butyldithiocyclohexanol 21
To a boiling mixture of diglyme:tert-butylthiol (4:1, v/v) (10 mL) under argon was added the sulfoxide
13b (200 mg, 0.73 mmol). The solution was refluxed for 12 h and TLC showed no starting sulfoxide to be
present. The reaction mixture was diluted with ether (20 mL) and washed with aqueous sodium hydroxide
solution (3×15 mL, 2 M) and water (2×15 mL). The organic layer was dried (MgSO4) and reduced under
reduced pressure to give the crude product which was chromatographed on silica eluting with ether/light
petroleum (20%) to give the product (−)-21 (109 mg, 68%) as a white solid; mp 30–32°C (ether); [α]D
−37 (c 0.82, CHCl3). All other spectral properties as for racemic modification.
4.15. (1R,2R)-(−)-trans-1-Mercaptocyclohexan-2-ol 20
Lithium aluminium hydride (51 mg, 1.36 mmol) was added to a stirred solution of disulfide 23 (100
mg, 0.45 mmol) in dry ether (5 mL). The solution was stirred at room temperature for 3 h. Excess lithium
aluminium hydride was destroyed with first wet ether followed by careful dropwise addition of water.
Dilute hydrochloric acid (3 mL, 2 M) was added, followed by vigorous stirring, and the ether layer
was decanted off and dried (MgSO4). The crude product was chromatographed on silica eluting with
ether/light petroleum (20%) to give the product (−)-20 (38 mg, 63%), as a colourless oil; [α]D −40 (c
0.56, CHCl3). All other spectral properties as for racemic modification.
4.16. (1S,2S)-(+)-trans-2-tert-Butyldithiocyclohexanol 21
To a boiling mixture of diglyme:tert-butylthiol (4:1, v/v) (10 mL) under argon was added the sulfoxide
11b (200 mg, 0.73 mmol). The solution was refluxed for 48 h and TLC showed no starting sulfoxide to be
present. The reaction mixture was diluted with ether (20 mL) and washed with aqueous sodium hydroxide
solution (3×15 mL, 2 M) and water (2×15 mL). The organic layer was dried (MgSO4) and reduced to
give the crude product which was chromatographed on silica eluting with ether/light petroleum to give
the product 24 (106 mg, 66%) as a white solid; mp 31–32°C (ether/light petroleum); [α]D +7 (c 0.97,
CHCl3). All other spectral properties as for racemic modification.

4140
H. Adams et al. / Tetrahedron: Asymmetry 10 (1999) 4129–4142
4.17. (ꢀ)-trans-1-Mercaptocyclohexan-2-ol 20
Dry tetrahydrofuran (300 mL) was added rapidly to an ice cooled mixture of sulfur (35.52 g, 1.11
mmol) and sodium borohydride (14.06 g, 0.38 mmol) under argon. After evolution of hydrogen had
ceased (ca. 30 min), cyclohexene oxide (18.5 g, 0.19 mmol) was added and the mixture was heated at
reflux for 14 h, after which no epoxide was detected by TLC. The solvent was removed under reduced
pressure, and the residue separated between NaOH (200 mL, 2 M) and dichloromethane (200 mL). Re-
extraction of the aqueous phase with dichloromethane (3×150 mL), followed by drying of the combined
organics (MgSO4) and removal of the solvent, gave a very pungent crude disulfide (25.6 g) as a white
solid.
A solution of the disulfide (25.6 g) in tetrahydrofuran (200 mL) was added dropwise with stirring to
lithium aluminium hydride (6.22 g, 86 mmol) in dry ether (200 mL). The reaction was stirred at room
temperature for 3 h and the excess lithium aluminium hydride was quenched with wet ether followed by
careful dropwise addition of water. The ether was decanted off and the white precipitate was dissolved
in dilute hydrochloric acid (250 mL, 2 M). Extraction of the aqueous phase with ether (4×200 mL) and
drying of the combined organics afforded the product (ꢀ)-20 (24.25 g) as a colourless oil which was
purified by vacuum distillation at 56–60°C, 0.3 mmHg (22.3 g, 90%); νmax cm−1 (thin film) 3480 (OH);
1H NMR (250 mHz, CDCl3) δ 3.21 (1H, dddd, J=10, 10, 4 and 2 Hz, CHOH), 2.76 (1H, bd, J=2 Hz,
OH), 2.52 (1H, dddd, J=12, 10, 7 and 4 Hz, CHSH), 1.43 (1H, d, J=10 Hz, SH); (found: C, 54.6; H, 9.1;
S, 24.3; m/z 132. C6H12O1S1 requires: C, 54.5; H, 9.1; S, 24.2; M+ 132).
4.18. (ꢀ)-trans-2-(2-Cyanoethylthio)cyclohexanol
Trimethylbenzyl ammonium hydroxide B (0.14 mL, 40% solution in methanol) was added to a stirred
solution of racemic hydroxythiol (ꢀ)-20 (500 mg, 3.82 mmol) in dry tetrahydrofuran (10 mL) at −78°C.
The solution was stirred for 15 min and acrylonitrile (0.28 mL, 4.2 mmol) was added. After 20 min
the reaction was allowed to warm up to room temperature over 45 min. The solvent was removed
under reduced pressure leaving a yellow oil which was separated between ether (20 mL) and water
(20 mL). The ether layer was washed with a further 20 mL of water before being dried (MgSO4) and
reduced. Purification by chromatography on silica eluting with ethyl acetate/light petroleum (30%) gave
the product (629 mg, 87%) as a colourless oil which was crystallised from ethyl acetate/light petroleum;
1
mp 51–52°C (ethyl acetate/light petroleum); νmax cm−1 (thin film) 3540 (OH), 2250 (CN); H NMR
(250 mHz, CDCl3) δ 3.35 (1H, m, CHOH), 2.90 (2H, m, SCH2), 2.69 (1H, br d, J=7 Hz, CHOH), 2.66
(2H, dd, J=9 and 7 Hz, CH2CN, 2.47 (1H, m, CHS); (found: C, 58.0; H, 8.1; N, 7.5; S, 17.1; m/z 185.
C9H15O1N1S1 requires: C, 58.3; H, 8.2; N, 7.6; S, 17.3; M+ 185).
4.19. (ꢀ)-trans-2-(2-Cyanoethylsulfinyl)cyclohexanol 22
meta-Chloroperbenzoic acid (0.511 g, 1.1 equiv.) was added to a stirred solution of the sulfide prepared
above (0.5 g, 2.7 mmol) in dry dichloromethane (10 mL) at 0°C. The solution was stirred for a further
2 h. The reaction mixture was diluted with dichloromethane (15 mL) and potassium fluoride (173 mg)
and stirring was continued for 1.5 h to allow precipitation of 3-chlorobenzoic acid. The reaction mixture
was filtered through Celite and the solvent removed under reduced pressure. The crude product was
chromatographed on silica eluting with methanol/dichloromethane (5%) to give the product 22 (443 mg,
82%) as a white solid which was recrystallised from ethyl acetate/light petroleum; mp 88–90°C; νmax
1
cm−1 (thin film) 3430 (OH), 2250 (CN), 1070 (S_O); H NMR (250 mHz, CDCl3) δ 4.10 (1H, ddd,

H. Adams et al. / Tetrahedron: Asymmetry 10 (1999) 4129–4142
4141
J=10, 10 and 5 Hz, CHOH), 3.52 (1H, br s, OH), 3.14 (2H, dt, J=7 and 2 Hz, SOCH2), 2.92 (2H, dt, J=7
and 2 Hz, CH2CN), 2.78 (1H, ddd, J=12, 10 and 4 Hz, CHSO), 2.16–1.15 (8H, m, aliphatics); (found:
C, 53.7; H, 7.5; N, 6.9; S, 16.1; m/z 201. C9H15N1O2S1 requires: C, 53.7; H, 7.5; S, 16.1; M+ 201).
4.20. (ꢀ)-trans-2-tert-Butyldithiocyclohexanol 21
To a boiling mixture of diglyme:tert-butylthiol (4:1, v/v) (10 mL) was added the cyanosulfoxide 22
(200 mg, 1 mmol), and the mixture was refluxed for 45 min. After cooling to room temperature the
reaction mixture was diluted with ether (50 mL). The organic phase was washed with sodium hydroxide
solution (3×50 mL, 2 M), water (2×50 mL), dried (MgSO4) and reduced to give the crude product which
was purified by column chromatography on silica, eluting with ether/light petroleum (20%) to afford the
product (ꢀ)-21 (202 mg, 92%) as a white solid, which was recrystallised from ether; mp 29–31°C; νmax
cm−1 (CHCl3) 3480 (OH); 1H NMR (250 mHz, CDCl3) δ 3.45 (1H, ddd, J=10, 10 and 5 Hz, CHOH),
t
3.52 (1H, bs, OH), 2.5 (1H, ddd, J=12, 10 and 4 Hz, CHS), 1.3 (9H, s, Bu), 1.98–1.05 (8H, m, ring
protons); (found: C, 54.6; H, 9.3; S, 28.3; m/z 220. C10H20O1S2 requires: C, 54.5; H, 9.2; S, 29.1; M+
220).
4.21. (ꢀ)-trans-3,5-Dimethylphenyldithiocyclohexanol 19
3,5-Dimethylthiophenol (1.16 g, 8.41 mmol) was added to a stirred solution of cyanosulfoxide 22 (338
mg, 1.68 mmol) in dry xylenes (10 mL), and the reaction mixture was heated at 110°C for 0.5 h under
nitrogen. The reaction mixture was allowed to cool to ambient temperature and the solvent was removed
under reduced pressure to give the crude disulfide which was purified on silica eluting with ether/light
1
petroleum (30%) to give the product (ꢀ)-19 (281 mg, 62%); H NMR (250 mHz, CDCl3) δ 7.19 (2H,
s, aromatic), 6.85 (1H, s, aromatic), 3.48 (1H, m, CHOH), 2.59 (1H, ddd, J=12, 9 and 4 Hz, CHS),
2.43 (1H, d, J=2 Hz, OH), 2.31 (6H, s, ArCH3); (found: C, 62.9; H, 7.6; S, 23.6; m/z 268. C14H20S2O
requires: C, 62.6; H, 7.5; S, 23.9; M+ 268).
Acknowledgements
The authors would like to express their gratitude to Courtaulds and the SERC for a CASE studentship
(Y.Y.C.) and Glaxo Wellcome for a research studentship (N.C.O.T.).
References
1. Martinez, L. E.; Leighton, J. L.; Carsten, D. H.; Jacobsen, E. N. J. Am. Chem. Soc. 1995, 117, 5897; Nugent, W. A. J. Am.
Chem. Soc. 1992, 114, 2768.
2. Asami, M.; Inoue, S. Tetrahedron 1995, 51, 11725.
3. Wu, M. H.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 5252; Iida, T.; Yamamoto, N.; Sasai, H.; Shibasaki, M. J. Am. Chem.
Soc. 1997, 119, 4783; Yamashita, H. Bull. Soc. Chem. Jpn. 1988, 61, 1213.
4. Joshi, N. N.; Srebnik, M.; Brown, H. C. J. Am. Chem. Soc. 1988, 110, 6246.
5. Shelton, K. R.; Davis, K. E. Internat. J. Sulfur Chem. 1973, 8, 205; Bateman, L.; Cain, M.; Colclough, T.; Cunneen, J. I.
J. Chem. Soc. 1962, 3570; Kingsbury, C. A.; Cram, D. J. J. Am. Chem. Soc. 1960, 82, 1810.
6. Hori, T.; Sharpless, K. B. J. Org. Chem. 1978, 43, 1689; Sharpless, K. B.; Lauer, J. Am. Chem. Soc. 1973, 95, 2697.
7. Marco, J. L.; Hueso-Rodriquez, J. A. Tetrahedron Lett. 1988, 29, 2459.
8. Lane, C. J. Org. Chem. 1974, 39, 1437.

4142
H. Adams et al. / Tetrahedron: Asymmetry 10 (1999) 4129–4142
9. Rollin, P. Tetrahedron Lett. 1986, 27, 4169.
10. Since completion of this work the use of 1b has been reported in an asymmetric epoxidation process: Aggarwal, V. K.;
Kalomiri, M.; Thomas, A. P. Tetrahedron: Asymmetry 1994, 5, 723.
11. Furukawa, N.; Fujihara, H. In The Chemistry of Sulfones and Sulfoxides; Patai, S.; Rapport, Z.; Stirling, C. J. M., Eds.;
Wiley: Chichester, 1988.
12. De Lucchi, O.; Miotti, U.; Modena, G. Org. React. 1991, 40, 157.
13. Barton, D. H. R.; Sammes, P. G.; Taylor, M. V.; Cooper, C. M.; Hewitt, G.; Looker, B. E.; Underwood, W. G. E. J. Chem.
Soc., Chem. Commun. 1971, 1137.
14. Lalancette, J. M.; Freche, A. Can. J. Chem. 1971, 49, 4047.
15. Further chiral shift 1H NMR experiments on the hydroxythiols (+)- and (−)-19 in conjunction with Eu(Hfc)3 showed them
to be >95% ee.