Diastereoselective synthesis of β-hydroxy sulfoxides: Enzymatic and biomimetic approaches

Article abstract of DOI:10.1002/ejoc.200600624

Stereoselectivities of up to 98 % have been found in the enzymatic synthesis of β-hydroxy sulfoxides catalyzed by cyclohexanone monooxygenase (CHMO). The diastereoselectivity of the "one-pot" preparation of the title compounds in the presence of bovine se

Full text of DOI:10.1002/ejoc.200600624

FULL PAPER
DOI: 10.1002/ejoc.200600624
Diastereoselective Synthesis of β-Hydroxy Sulfoxides: Enzymatic and
Biomimetic Approaches
[
a]
[a]
[b]
[b]
Stefano Colonna,* Vincenza Pironti, Francesca Zambianchi, Gianluca Ottolina,
[a]
[a]
Nicoletta Gaggero, and Giuseppe Celentano
Keywords: Sulfoxides / Cyclohexanone monooxygenase / Kinetic resolution / Bovine serum albumin / Enzyme catalysis /
Asymmetric oxidation
Stereoselectivities of up to 98% have been found in the enzy-
presence of bovine serum albumin has also been investi-
matic synthesis of β-hydroxy sulfoxides catalyzed by cyclo- gated.
hexanone monooxygenase (CHMO). The diastereoselectivity
of the “one-pot” preparation of the title compounds in the
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
exquisite selectivity with a wide variety of natural and syn-
thetic substrates. Furthermore these biocatalytic oxidation
reactions are less hazardous and polluting than conven-
tional chemistry-based methodologies. Thus this enzyme
has been used as a chemoenzymatic reagent for the large-
Chiral β-hydroxy sulfoxides are well known for their use-
fulness as chiral auxiliaries in asymmetric synthesis either
[
1]
as ligands or as building blocks for the preparation of a
[
2]
great variety of compounds such as cyclic sulfides, benz-
[
14]
scale synthesis of a variety of key chiral products.
[
3]
[4]
[5]
oxathiepines, benzothiazepines, allylic alcohols, mac-
With the same purpose in mind, the asymmetric oxi-
dation of β-hydroxy sulfides in the presence of bovine se-
rum albumin (BSA) in a one-pot procedure was investigated
[
6]
[7]
rolides and leukotrienes.
So far, optically active β-hydroxy sulfoxides have been
obtained either by aldol-type reactions of α-sulfinyl anions
with carbonyl compounds[ or by reduction of β-keto sulf-
oxides with various hydride transfer agents.[ Another pro-
cedure involves optically active β-hydroxy sulfides, obtained
by addition of thiolates to enantiomerically pure epox-
(BSA/tBuOOH). BSA is an abundant carrier protein with
8]
no known catalytic function that possesses well-defined
hydrophobic binding sites for a variety of hydrophobic sub-
9]
[
15]
strates. This makes such a readily available and inexpen-
sive protein an attractive template for asymmetric oxi-
dation. Indeed, BSA, like other carrier proteins, specifically
binds and transfers a solute molecule across lipid mem-
branes similarly to a specialized membrane-bound enzyme.
In the last few years our research group has investigated
some enantioselective reactions with BSA in water as sol-
vent, in particular, the oxidation of sulfides to sulfoxides,[
the catalytic asymmetric Weitz–Scheffer epoxidation of 1,4-
[
10]
ides,
followed by chemical oxidation with tBuOOH. A
more direct approach is the asymmetric oxidation of
racemic β-hydroxy sulfides; Modena and Kagan and their
co-workers used systems based on titanium(IV), diethyl tar-
trate and an alkyl hydroperoxide as oxidizing agent and ob-
[
11]
tained fairly good enantiomeric excesses (20–80%).
16]
In view of the synthetic importance of optically pure β-
hydroxy sulfoxides we have investigated the possibility of
the asymmetric oxidation of β-hydroxy sulfides with cyclo-
hexanone monooxygenase (CHMO) from Acinetobacter
calcoaceticus. CHMO is a bacterial Baeyer–Villigerase that
[
17]
naphthoquinones
and the kinetic dynamic resolution of
[
18]
tertiary amines to amine N-oxides.
The choice of water
as solvent presents several advantages: water is cheap, read-
ily available and nontoxic. The resulting process is econ-
omic and clearly constitutes an environmentally friendly
solvent-alternative in organic synthesis.
[
12]
converts cyclic ketones into the corresponding lactones.
CHMO also catalyzes the oxygenation of boronic acids as
well as cyclic and aryl alkyl sulfides, selenides and tertiary
[
13]
alkylamines. What makes CHMO attractive for synthetic
purposes is the fact that these reactions can proceed with
Results and Discussion
[
[
a] Istituto di Chimica Organica “A. Marchesini”, Facoltà di Farm-
acia, Università degli Studi di Milano,
The oxidation of different β-hydroxy sulfides was investi-
gated using cyclohexanone monooxygenase as the catalyst
or under biomimetic conditions. All the trans β-hydroxy
sulfides were easily synthesized according to a standard
Via Venezian 21, 20133 Milano, Italy
Fax: +39-0250314476
E-mail: Stefano.Colonna@unimi.it
b] Istituto di Chimica del Riconoscimento Molecolare, CNR,
Via Mario Bianco 9, 20131 Milano, Italy
[
19]
procedure.
Eur. J. Org. Chem. 2007, 363–368
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
363

S. Colonna et al.
FULL PAPER
The asymmetric sulfoxidation of racemic trans β-hydroxy absolute configuration (1S,2S,S ). Note that the optical pu-
S
sulfides (Ϯ)-1–7 catalyzed by CHMO led to kinetic resolu- rities of both the major 2a (eeՆ98%) and the minor 2b
tion (see Scheme 1). The diastereomeric ratios were deter- (eeՆ95%) diastereomers were very high (Table 1). The un-
mined by comparison of the NMR spectra with those re- reacted sulfide 2 was recovered with a good ee and its abso-
[
20]
ported in literature.
lute configuration was identified as (1R,2R) by comparison
Excellent results were obtained in the oxidation of sulfide of its optical rotation value with that reported in the litera-
(
Ϯ)-2 (Table 1); the enzyme-catalyzed oxidation in fact ture: ee = 47%, [α] = –31.3 (c = 0.5, CHCl ) (see the Exp.
D
3
[
22]
showed remarkable enantio- and diastereoselectivity. The Sect.).
The absolute configurations of the two products
[
21]
enantiomeric ratio E, calculated according to Chen et al.,
was about 299, which implies that the sulfide enantiomer elution of appropriate samples synthesized according to a
1S,2S) was almost exclusively recognised and transformed. well-known procedure.
Similarly, the high diastereomeric ratio of up to 99:1 indi- CHMO discriminated poorly the enantiomeric substrates
2a and 2b were established by comparison of the order of
(
cates that oxygen was introduced almost solely in the pro-S of the sulfides (Ϯ)-1 and (Ϯ)-3 (1.6 Ͻ E Ͻ 4.3) (Table 1);
position of the sulfur atom to give the sulfoxide with the with these substrates the diastereomeric ratios were also
Scheme 1. Oxidation of β-hydroxy sulfides (Ϯ)-trans-1–7 to β-hydroxy sulfoxides catalyzed by CHMO.
Table 1. Oxidation of β-hydroxy sulfides (Ϯ)-trans-1–7 to β-hydroxy sulfoxides catalyzed by CHMO.
Sulfides
Time [h]
C [%][a]
ee Sulfides [%][a]
Diastereomeric ratio[a]
major/minor
eemajor [%][a]
eeminor [%][a]
(Ϯ)-1
(Ϯ)-2
(Ϯ)-3
(Ϯ)-4
(Ϯ)-5
(Ϯ)-6
n = 0
24
97
69 (1.6)[b]
83:17
53
91
1
R = H,
2
R = OH
47 (261)[
87 (299)
b]
Ͼ99:1
99:1
Ն98
Ն98
(1S,2S,S
–
Ն95
(1R,2R,S )
S
n = 1
1
5
36
47
1
[b]
R = H,
2
R = OH
S
)
50 (4.3)[
79 (3.3)
b]
89:11
82:18
63
45
56
78
n = 2
1
3
52
78
1
[b]
R = H,
2
R = OH
8 (2.0)[b]
3 peaks 4:1.5:1 ratio
3 peaks 8:3:1 ratio
[c]
n = 1
5
48
21
95
1
[b]
[c]
R = OCH
3
3
13 (1.1)
2
R = OH
n = 1
48
48
n.r.[d]
1
R = H
2
R = OCH
n = 1
n.r.[d]
1
R = H
2
R = OC-
OCH
3
(
Ϯ)-7
n = 1
48
n.r.[d]
1
R = NO
2
2
R = OH
[
a] The conversions, C, diastereomeric ratios and enantiomeric excesses were determined by HPLC analysis using an OD CHIRALCEL
column. [b] Enantiomeric ratio, E. [c] Configuration not assignable. [d] n.r.: no reaction.
364
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 363–368

Diastereoselective Synthesis of β-Hydroxy Sulfoxides
FULL PAPER
rather modest, but the enantiomeric excesses fairly good as chiral auxiliary was almost completely diastereoselective
45–91%). These results show that for enzymatic sulfoxid- (95:5). However the prevailing diastereoisomer was ob-
ation mediated by CHMO the presence of a six-membered tained in a racemic form.
(
ring is essential for obtaining optically pure β-hydroxy sulf-
oxides.
Replacement of thiophenol by p-methoxythiophenol
again provided the corresponding β-hydroxy sulfoxides (4a,
With the sulfide (Ϯ)-2, the crucial role, in terms of reac- 4b) with a very high diastereomeric ratio and low ee. When
tivity, played by the hydroxy group in the β position and p-nitrothiophenol was used the reaction proceeded with low
the hydrogen atom in the para position must be stressed. diastereoselectivity and the products obtained (7a, 7b) were
Indeed, when the hydroxy group was replaced by a methoxy in a racemic form.
[
(Ϯ)-5] or an acetoxy group [(Ϯ)-6], the sulfides were not
Cycloheptene oxide was not reactive enough and so we
transformed by the enzyme. When the hydrogen atom in the decided to use a different strategy involving the introduc-
para position was replaced by a methoxy group [(Ϯ)-4] the tion of a Lewis acid such as ZnCl into the reaction mixture
2
diastereomeric ratio decreased noticeably whereas the nitro in order to promote the formation of the β-hydroxy sulfide
[
23]
compound (Ϯ)-7 did not act as a substrate at all with (Ϯ)-3, in accord with a well-known procedure. ZnCl in-
2
CHMO.
creased the rate of epoxide opening, the yield and the con-
The same β-hydroxy sulfides (Ϯ)-1–4 and (Ϯ)-7 were also version of the one-pot procedure. It had however detrimen-
studied by a biomimetic approach based on a one-pot in tal effects on the diastereoselectivity of the reaction when
situ thiolysis of the parent epoxides according to known carried out in the presence of BSA. This is possibly due
[
20]
methods, followed by BSA/tBuOOH oxidation. The thi- to conformational changes to the protein induced by the
2+
olysis of the epoxides was a stereospecific process that pro- chelation of Zn ions to the external histidine group of the
[
24]
ceeded in an anti fashion and led to (Ϯ)-trans-β-hydroxy polypeptide.
sulfides as the only products.[ This reaction was carried
20]
Also, for the BSA-mediated oxidation reactions, the role
out in a water/buffer solution at pH 9.0 and then a BSA/ of the hydroxy group in the β position was significant. In-
tBuOOH solution was added. Ring-opening of cyclopen- deed, the reactions of sulfides (Ϯ)-5 and 8 with BSA/
tene oxide with thiophenol gave the β-hydroxy sulfoxides 1a tBuOOH gave higher conversions but lower diastereoselec-
and 1b with high conversion and low ee (Table 2).
tivities in the case of 5a,5b (Table 3) with respect to sulfox-
The control reactions carried out without BSA gave dia- ides 2a,2b. Furthermore, in contrast with the enzyme-cata-
stereomeric ratios lower than those obtained in the biomi- lyzed reaction, racemic products were obtained.
metic reactions with the exception of the cyclopentenyl de-
rivative 1 for which the diastereomeric ratio was higher vestigated in a one-pot reaction as an example of an α-
78:22) than that obtained with BSA (Table 2).
substituted 1,2-epoxide. Nucleophilic attack occurred pre-
When cyclohexene oxide and thiophenol were used as the dominantly at the benzylic position due to electronic effects
The thiolysis of styrene oxide by thiophenol was also in-
(
starting materials in the one-pot procedure the dia- and the primary alcohol (Ϯ)-10 was obtained in a 2:1 ratio
stereomeric ratio of the β-hydroxy sulfoxides 2a/2b was with respect to the secondary alcohol (Ϯ)-9 (Scheme 2).
2:28, similar to that reported by Fringuelli et al.[ Note Subsequent sulfoxidation to give compounds 9a,b and 10a,b
20]
7
that the same reaction performed in the presence of BSA occurred again with low enantioselectivity.
Table 2. One-pot synthesis of β-hydroxy sulfoxides 1–7a,b by thiolysis of the corresponding epoxides and subsequent oxidation with BSA/
tBuOOH.
Sulfoxides
BSA [mol. equiv.]
ZnCl
2
[mol. equiv.]
C [%][a]
Diastereomeric ratio[b]
major/minor
eemajor [%][a]
eeminor [%][a]
1
a,b
a,b
–
.025
–
.025
–
.025
–
.025
–
.025
–
.025
–
–
–
–
85
95
70
45
95
65
78:22
69:31
72:28
95:5
69:31
74:26
–
–
15
–
Ͻ3
–
Ͻ3
–
–
–
Ͻ3
–
5
–
–
10
–
Ͻ3
–
Ͻ3
–
–
0
0
0
0
0
0
0
2
–
0.10
0.10
–
[
[
c]
c]
3
a,b
n.r.
n.r.
–
–
0.10
0.10
–
–
–
23
43
85
95
35
45
75:25
85:15
75:25
Ͼ98:2
63:37
74:26
–
Ͻ3
–
4
a,b
a,b
n.d.[
d]
7
–
Ͻ3
.025
–
Ͻ3
1
[
a] Determined by H NMR spectroscopy. [b] The diastereomeric ratios and the enantiomeric excesses were determined by HPLC analysis
using an OD CHIRALCEL column. [c] n.r.: no reaction. [d] n.d.: not determined.
Eur. J. Org. Chem. 2007, 363–368
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
365

S. Colonna et al.
FULL PAPER
Table 3. Oxidation of sulfides (Ϯ)-5 and 8 with BSA/tBuOOH.
Sulfide
BSA [mol. equiv.]
C [%][a]
Diastereomeric ratio[b]
major/minor
eemajor [%][a]
eeminor [%][a]
5
n = 1
–
15
52
57:43
68:32
–
Ͻ3
–
Ͻ3
1
R = H
0.025
2
R = OCH
3
n.a.[
c]
–
Ͻ3
–
Ͻ3
8
n = 1
–
34
59
1
[c]
R = H
0.025
n.a.
2
R = H
1
[
a] Determined by H NMR spectroscopy. [b] The diastereomeric ratios and the enantiomeric excesses were determined by HPLC analysis
using an OD CHIRALCEL column. [c] n.a. = not applicable.
Scheme 2. One-pot sulfoxidation using styrene oxide and thiophenol as the starting materials.
at 254 nm. Melting points were recorded with a Stuart Scientific
apparatus. Infrared spectra were recorded with an FT-IR Perkin-
Conclusions
The kinetic resolution of β-hydroxy sulfides mediated by Elmer SPECTRUM ONE spectrophotometer using thin films be-
CHMO provided an excellent result in the case of sulfide tween NaCl plates in the cases of liquid samples and as KBr tablets
(
Ϯ)-2 and moderate results with (Ϯ)-1 and (Ϯ)-3. Indeed, for solid samples. Chemical reactions were monitored by analytical
TLC performed with Merck silica gel 60 F254 plates and visualized
the enzyme-catalyzed oxidation to sulfoxide 2a showed re-
markable enantio- and diastereoselectivity with an enantio-
meric ratio E = 299 and with an ee Ն 98% (C = 47%).
CHMO did not transform those substrates having a pro-
tected hydroxy group [(Ϯ)-5, (Ϯ)-6].
In the one-pot procedure, the presence of BSA as chiral
auxiliary led to a substantial improvement in the diastereo-
selectivity of the β-hydroxy sulfoxides formed, but the prod-
ucts were practically racemic. Such results could possibly be
a consequence of the poor immobilization of the β-hydroxy
sulfides onto the binding site of BSA.
by UV irradiation or by iodine. For column chromatography, col-
umns were packed with Merck silica gel 60 (230–400 mesh) as the
stationary phase and eluted using the flash chromatographic tech-
nique. All commercially available compounds were used without
further purification. CHMO was obtained from Acinetobacter cal-
[13b]
coaceticus as already described.
β-Hydroxy sulfides 1–4 and 7
[19]
were synthesized according to known methods.
Preparation of trans-2-Methoxycyclohexyl Phenyl Sulfide [(؎)-5]:
nBuLi (1.5 mmol, 1.6  in hexane) was added under N to a solu-
2
tion of the hydroxy sulfide (Ϯ)-2 (1.5 mmol) in dry THF (20 mL)
at –78 °C. The solution was stirred for 5 min and then iodomethane
Addition of ZnCl to the one-pot procedure with the re- was added (1.5 mmol). The reaction mixture was stirred for 20 h
2
calcitrant starting oxirane (cycloheptene oxide) had a posi- at –78 °C and then allowed warm to room temperature. Then a
tive effect on the reaction rates and chemical yields.
mixture of 1:1 H
was extracted with diethyl ether (3ϫ20 mL) and then washed with
brine. The combined organic layers were dried with MgSO , filtered
and evaporated under reduced pressure to provide the desired prod-
uct. The crude product was purified by column chromatography
2 3
O/Et N (5 mL) was added. The reaction mixture
4
Experimental Section
General Methods: 1H and 13C NMR spectra were recorded with a
(
elution with hexane/ethyl acetate, 9:1) to give the product as a
3
Bruker AC 300 or AC 200 instrument in CDCl solutions and
1
1
colourless oil. Yield 80 mg, 24%. H NMR (CDCl
1.21–1.29 (m, 4 H, 3-H, 4-H), 1.72–1.80 (m, 2 H, 6-H), 1.95–
.02 (m, 2 H, 3-H), 2.10–2.20 (m, 1 H, 2-H), 3.13 (m, 1 H, 1-H),
.38 (s, 3 H, CH ), 7.25 (m, 3 H, Ar-H), 7.44 (m, 2 H, Ar-H) ppm.
3
, 300 MHz): δ
chemical shifts are given in ppm relative to TMS ( H, 0.0 ppm).
Low-resolution mass spectra were recorded with a Fisons MD 800
spectrometer using the EI method. Analytical HPLC analyses were
performed with a Jasco HPLC instrument (model 980-PU pump,
model 975-UV detector) on a chiral stationary phase using a Daicel
Chiralcel OD column and hexane/2-propanol in various ratios as
=
2
3
3
+
EI-MS: m/z (%) = 222 (100) [M] .
Preparation of trans-2-Acetoxycyclohexyl Phenyl Sulfide [(؎)-6]:
Acetic anhydride (1.5 mmol, 0.142 mL) was added to a stirred solu-
–1
the mobile phase at a flow rate of 1 mLmin ; readings were taken
366
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 363–368

Diastereoselective Synthesis of β-Hydroxy Sulfoxides
FULL PAPER
, 200 MHz): δ = 1.19–1.90 (m, 10 H,
–
1 1
tion of 2 (312 mg, 1.5 mmol) in pyridine (5 mL). The reaction mix-
ture was stirred overnight and then evaporated under reduced pres-
sure. The crude was redissolved in diethyl ether (5 mL) and washed
with a 1% HCl solution (2 mL) and brine (2 mL). The organic
1014 cm . H NMR (CDCl
3
3-H, 4-H, 5-H, 6-H, 7-H), 2.85 (br. s, 1 H, OH), 2.94 (m, 1 H, 2-
H), 4.32 (m, 1 H, 1-H), 7.56 (m, 3 H, Ar-H), 7.76 (2 H, m, Ar-
+
H) ppm. EI-MS: m/z (%) = 238 (100) [M] .
layers were dried with Na
duced pressure to give the product 6 without the need of further
purification. Yield 257 mg, 65%. H NMR (CDCl
2 4
SO , filtered and evaporated under re-
trans-2-(Phenylsulfinyl)cycloheptan-1-ol (3b): Minor diastereoiso-
mer. The crude product was purified by column chromatography
1
3
, 200 MHz): δ
, 2.04–2.08
(
elution with hexane/ethyl acetate, 2:8) to give the product as a
=
1.36–1.74 (m, 6 H, 4-H, 5-H, 6-H), 1.91 (s, 3 H, CH
3
white solid; m.p. 125 °C. IR (KBr): ν˜ = 3358, 3057, 1638, 1050,
(
(
m, 2 H, 3-H), 3.14 (m, 1 H, 2-H), 4.78 (m, 1 H, 1-H), 7.21–7.46
m, 5 H, Ar-H) ppm. EI-MS: m/z (%) = 264 (100) [M] .
–1 1
1
014 cm . H NMR (CDCl
3
, 200 MHz): δ = 1.24–1.89 (m, 10 H,
+
3-H, 4-H, 5-H, 6-H, 7-H), 2.16 (br. s, 1 H, OH), 2.99 (m, 1 H, 2-
Analytical Biotransformations with CHMO: Sulfides (Ϯ)-1–7 H), 4.16 (m, 1 H, 1-H), 7.53 (m, 3 H, Ar-H), 7.88 (2 H, m Ar-
–
1
+
(
1 mgmL ) were bio-oxidized, at 25 °C and under gentle stirring,
H) ppm. EI-MS: m/z (%) = 238 (100) [M] .
+
in 50 m Tris/HCl buffer (pH 8.6) containing 0.5 m NADP ,
0 m glucose 6-phosphate, partially purified CHMO (1 UmL )
and glucose 6-phosphate dehydrogenase from Leuconostoc mesen-
trans-2-[(4-Methoxyphenyl)sulfinyl]cyclohexan-1-ol (4a): Major dia-
stereoisomer. The crude product was purified by column
chromatography (elution with hexane/ethyl acetate, 4:6) to give the
product as a white solid; m.p. 166 °C. IR (KBr): ν˜ = 3358, 2934,
3
, 200 MHz): δ = 1.11–1.73
m, 7 H, 3Ј-H, 4-H, 5-H, 6-H), 2.07 (m, 1 H, 3ЈЈ-H), 2.69 (m, 1 H,
3
), 4.03 (m, 1 H, 1-H), 5.18 (br. s, 1 H, OH),
.00 (d, JH,H = 8.8 Hz, 2 H, Ar-H), 7.62 (d, JH,H = 8.8 Hz, 2 H,
Ar-H) ppm. EI-MS: m/z (%) = 254 (100) [M] .
–
1
5
–1
teroides (G6PDH) (18 UmL ). The biotransformation process was
monitored by withdrawing samples at different times from the reac-
tion medium and extracting them with diethyl ether (1:1 volume).
The degree of oxidation and the enantiomeric excesses of the prod-
ucts were determined on the extracts, evaporated and redissolved
in propan-2-ol, by chiral HPLC on a Chiralcel OD column (Daicel,
Illkirch, France) using the appropriate ratio of n-hexane/propan-2-
ol as the mobile phase; readings were taken at 254 nm.
–1
1
1
594, 1254, 1025 cm . H NMR (CDCl
(
2-H), 3.83 (s, 3 H, CH
7
+
trans-2-[(4-Methoxyphenyl)sulfinyl]cyclohexan-1-ol (4b): Minor dia-
stereoisomer. The crude product was purified by column
chromatography (elution with hexane/ethyl acetate, 4:6) to give the
product as a white solid; m.p. 152 °C. IR (KBr): ν˜ = 3390, 2936,
3
, 200 MHz): δ = 1.04–1.49
m, 6 H, 4-H, 5-H, 6-H), 1.92–2.09 (m, 2 H, 3-H), 2.67 (m, 1 H,
3
), 3.88 (m, 1 H, 1-H), 4.74 (br. s, 1 H, OH),
.02 (d, JH,H = 9.7 Hz, 2 H, Ar-H), 7.51 (d, JH,H = 9.7 Hz, 2 H,
Ar-H) ppm. EI-MS: m/z (%) = 254 (100) [M] .
trans-2-(Phenylsulfinyl)cyclopentan-1-ol (1a): Major diastereoiso-
mer. The crude product was purified by column chromatography
elution with hexane/ethyl acetate, 2:8) to give the product as a
(
–1 1
1
594, 1251, 1025 cm . H NMR (CDCl
white solid; m.p. 102 °C. IR (KBr): ν˜ = 3390, 3058, 1651, 1085,
(
–
1 1
1
3
4
3
028 cm . H NMR (CDCl , 200 MHz): δ = 1.62–1.83 (m, 5 H,
2-H), 3.84 (s, 3 H, CH
Ј-H, 4-H, 5-H), 2.07 (m, 1 H, 3ЈЈ-H), 3.02 (m, 2 H, 2-H, OH),
.64 (m, 1 H, 1-H), 7.50 (m, 3 H, Ar-H), 7.77 (2 H, m Ar-H) ppm.
EI-MS: m/z (%) = 210 (100) [M] .
7
+
+
Preparation of Enantiopure Sulfide (1S,2S)-2: A mixture of racemic
sulfide 2 (0.5 mmol), isopropenyl acetate (1 mmol) and lipase PS
Amano) (250 mg) in diisopropyl ether was stirred at 23 °C over-
night. When about half of the substrate had been acetylated, the
mixture was filtered and the solvent evaporated. The crude product
was purified by column chromatography (elution with hexane/ethyl
trans-2-(Phenylsulfinyl)cyclopentan-1-ol (1b): Minor diastereoiso-
mer. The crude product was purified by column chromatography
elution with hexane/ethyl acetate, 2:8) to give the product as a
(
(
white solid; m.p. 97 °C. IR (KBr): ν˜ = 3295, 3058, 1637, 1085,
–
1 1
1
4
(
(
012 cm . H NMR (CDCl
3
, 200 MHz): δ = 1.53–1.71 (m, 4 H,
-H, 5-H), 1.84–2.06 (m, 3 H, 3-H, OH), 3.03 (m, 1 H, 2-H), 4.56
1
acetate, 8:2) to give the product as an oil. H NMR (200 MHz,
m, 1 H, 1-H), 7.85 (m, 5 H, Ar-H) ppm. EI-MS: m/z (%) = 210
CDCl
H, 3-H), 3.40 (dt, JH,H = 7.1, 14.1 Hz, 1 H, 2-H, 4.10 (dt, JH,H
.0, 13.9 Hz, 1 H, 1-H), 7,17–7.44 (m, 5 H, Ar-H) ppm. EI-MS:
3
): δ = 1.79–1.84 (m, 6 H, 3-H, 4-H, 5-H), 2.00–2.31 (m, 2
+
100) [M] .
=
7
trans-2-(Phenylsulfinyl)cyclohexan-1-ol (2a): Major diastereoisomer
1S,2S,S ). The crude product was purified by column chromatog-
+
20
[22]
m/z (%) = 208 (100) [M] . [α]
[α] = +71.9 (c = 1.21, CHCl )].
D
= +69.0 (c = 1.5, CHCl
3
) [ref.
(
S
2
0
raphy (elution with hexane/ethyl acetate, 4:6) to give the product
D
3
as a white solid; m.p. 156–157 °C. IR (KBr): ν˜ = 3444, 2931, 1628,
Preparation of Enantiopure Sulfoxides (1S,2S,S )-2a and
S
–1 1
1077, 1002 cm . H NMR (CDCl
3
, 300 MHz): δ = 1.11–1.40 (m,
(1S,2S,R )-2b: The sulfide (1S,2S)-2 (0.25 mmol) was dissolved in
S
6
H, 4-H, 5-H, 6-H), 1.73 (m, 2 H, 3-H), 2.75 (m, 1 H, 2-H), 3.03 dichloromethane (2 mL) and then oxidized with MCPBA
(m, 1 H, 1-H), 4.16 (br. s, 1 H, OH), 7.55 (m, 3 H, Ar-H), 7.74 (m,
(0.25 mmol) at 0 °C for 1 h. The reaction mixture was washed with
+
20
2
H, Ar-H) ppm. EI-MS: m/z (%) = 224 (100) [M] . [α]
).
D
= –134
a saturated solution of Na SO (1 mL) and brine. The recovered
2
3
(c = 1.5, CHCl
3
2 4
organic layers were dried with Na SO , filtered and evaporated un-
der reduced pressure. The sulfoxides (1S,2S,S
S S
)-2a and (1S,2S,R )-
trans-2-(Phenylsulfinyl)cyclohexan-1-ol (2b): Minor diastereoisomer
1R,2R,S ). The crude product was purified by column chromatog-
2b were characterized, giving the data as shown above.
(
S
raphy (elution with hexane/ethyl acetate, 4:6) to give the product
as a white solid; m.p. 138–139 °C. IR (KBr): ν˜ = 3450, 2931, 1648,
Analytical HPLC analyses were performed on a chiral stationary
phase using a Daicel Chiralcel OD column and hexane/2-propanol
in a ratio of 95:5 as the mobile phase. Retention times: (1R,2R)-2
–
1 1
1
7
3
077, 1012 cm . H NMR (CDCl , 300 MHz): δ = 1.09–1.71 (m,
H, 3Ј-H, 4-H, 5-H, 6-H), 2.11 (m, 1 H, 3ЈЈ-H), 2.66 (m, 1 H, 2- 6.69 min, (1S,2S)-2 10.76 min, (1S,2S,R )-2b 12.10 min,
S
H), 3.93 (m, 1 H, 1-H), 4.01 (br. s, 1 H, OH), 7.58 (m, 5 H, Ar- (1R,2R,S )-2b 15.38 min, (1R,2R,R )-2a 19.03 min, (1S,2S,S )-2a
S
S
S
+
20
H) ppm. EI-MS: m/z (%) = 224 (100) [M] . [α]
D
= +100.9 (c = 1.5,
21.31 min.
CHCl ).
3
General Procedure for the One-Pot Preparation of β-Hydroxy Sulf-
oxides 1–4, 7 and 9,10a,b: The appropriate thiol (1.0 mmol) was
added at room temperature to a phosphate buffer (2 mL) at
pH 9.00. The resulting pH was adjusted to 9.00 by adding an aque-
ous 5  solution of NaOH (20 µL) and then the epoxide
trans-2-(Phenylsulfinyl)cycloheptan-1-ol (3a): Major diastereoiso-
mer. The crude product was purified by column chromatography
(elution with hexane/ethyl acetate, 4:6) to give the product as a
white solid; m.p. 148 °C. IR (KBr): ν˜ = 3353, 3059, 1579, 1050,
Eur. J. Org. Chem. 2007, 363–368
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
367

S. Colonna et al.
FULL PAPER
(
0.66 mmol) was added. During the reaction the pH was kept con-
Cyclohexyl Phenyl Sulfoxide (8a): The crude product was purified
by column chromatography (elution with hexane/ethyl acetate, 6:4)
to give the product as a colourless oil. Yield 30%. IR (NaCl): ν˜ =
stant at 9.00 by adding a 1% aqueous H SO solution. After 3–6 h
2
4
BSA (0.025 mol. equiv.) was added. The reaction mixture was
stirred magnetically for 2 h and then tBuOOH (6.0 mol. equiv.) was
added. The mixture was stirred for 15 h, chloroform (20 mL) was
then added and the mixture left to stand overnight. The resulting
–
1 1
3
3055, 2930, 1742, 1444, 1040 cm . H NMR (CDCl , 200 MHz):
δ = 1.17–1.84 (m, 10 H), 2.60 (m, 1 H, 1-H), 7.47–7.61 (m, 5 H,
+
Ar-H) ppm. EI-MS: m/z (%) = 208 (100) [M] .
4
slurry was filtered through a cake of Celite, dried with MgSO and
the solvent evaporated. The organic phase was purified by flash
chromatography using the appropriate eluent.
Acknowledgments
1
-Phenyl-2-(phenylsulfinyl)ethanol (9a): Minor diastereoisomer. The
We thank MURST (Programmi di Ricerca Scientifica di Interesse
Nazionale) for financial support.
crude product was purified by column chromatography (elution
with hexane/ethyl acetate, 2:8) to give the product as a white solid.
Yield 8 mg, 5%. H NMR (CDCl
3
1
3
, 300 MHz): δ = 2.95 (m, 1 H),
[
1] P. E. Broutin, F. Colobert, Org. Lett. 2003, 5, 3281–3284.
[2] J. Eames, S. Warren, J. Chem. Soc., Perkin Trans. 1 1999, 2783–
790.
.30 (m, 1 H), 3.43 (br. s, 1 H, OH), 5.37 (m, 1 H), 7.20–7.70 (m,
+
1
0 H, Ar-H) ppm. EI-MS: m/z (%) = 246 (100) [M] .
2
1
-Phenyl-2-(phenylsulfinyl)ethanol (9b): Major diastereoisomer. The
[3] A. C. Gelebe, P. T. Kaye, Synth. Commun. 1996, 26, 4459–4475.
[4] A. Schwatz, P. B. Madan, E. Mohacsi, J. P. O’Brien, L. J. Tod-
aro, D. L. Coffen, J. Org. Chem. 1992, 57, 851–856.
crude product was purified by column chromatography (elution
with hexane/ethyl acetate, 2:8) to give the product as a white solid.
Yield 45 mg, 28%. H NMR (CDCl
H), 3.20 (m, 1 H), 3.43 (br. s, 1 H, OH), 5.27 (m, 1 H), 7.20–7.70
1
[5] V. Kesavan, D. Bonnet-Delpon, J. P. Bégué, Tetrahedron Lett.
3
, 300 MHz): δ = 2.90 (m, 1
2
000, 41, 2895–2898.
[
6] G. Solladiè, A. Almario, C. Dominguez, Pure Appl. Chem.
+
(m, 10 H, Ar-H) ppm. EI-MS: m/z (%) = 246 (100) [M] .
1994, 66, 2159–2162.
2-Phenyl-2-(phenylsulfinyl)ethanol (10a): Major diastereoisomer.
[7] E. J. Corey, D. A. Clark, G. Goto, A. Marfat, C. Mioskowski,
B. Samuelsson, S. Hammarstrom, J. Am. Chem. Soc. 1980, 102,
The crude product was purified by column chromatography (elu-
tion with hexane/ethyl acetate, 4:6) to give the product as a white
solid. Yield 16 mg, 10%. H NMR (CDCl
1436–1438.
1
[8] G. Demailly, C. Greck, G. Solladiè, Tetrahedron Lett. 1984, 25,
113–4115.
9] S. Nakamura, T. Suzuki, K. Tada, J. Org. Chem. 2003, 68,
766–5768, and references cited therein.
3
, 200 MHz): δ = 3.68
4
(br. s, 1 H, OH), 4.09 (m, 2 H), 5.25 (m, 1 H), 6.77–7.75 (m, 10 H,
[
[
[
+
Ar-H) ppm. EI-MS: m/z (%) = 246 (100) [M] .
5
10] T. Hashiyama, H. Inoue, M. Konda, M. Takeda, J. Chem. Soc.,
Perkin Trans. 1 1984, 1725–1732.
11] a) V. Conte, F. Di Furia, G. Licini, G. Modena, G. Sbampato,
G. Valle, Tetrahedron: Asymmetry 1991, 2, 257–276; b) P.
Pitchen, H. B. Kagan, Tetrahedron Lett. 1984, 25, 1049–1051.
12] N. K. Donoghue, D. B. Norris, P. W. Trudgill, Eur. J. Biochem.
2-Phenyl-2-(phenylsulfinyl)ethanol (10b): Minor diastereoisomer.
The crude product was purified by column chromatography (elu-
tion with hexane/ethyl acetate, 4:6) to give the product as a white
solid. Yield 13 mg, 8%. H NMR (CDCl
s, 1 H, OH), 3.92 (dd, JH,H = 3.7, 7.8 Hz, 1 H), 4.20 (dd, JH,H
1
3
, 200 MHz): δ = 3.68 (br.
=
[
3
.7, 12.3 Hz, 1 H), 4.60 (dd, JH,H = 7.8, 12.3 Hz, 1 H), 6.77–7.75
1
976, 63, 175–192.
[13] a) C. T. Walsh, Y.-C. Chen, Angew. Chem. Int. Ed. Engl. 1988,
7, 333–343; b) F. Secundo, F. Zambianchi, G. Crippa, G. Car-
+
(m, 10 H, Ar-H) ppm. EI-MS: m/z (%) = 246 (100) [M] .
2
Oxidation of β-Hydroxy Sulfides (؎)-5 and 8 in the Presence of
BSA: The β-hydroxy sulfide (1.0 mmol) and tBuOOH (3 equiv.
mol.) were added to a well stirred solution of BSA (0.025 mol.
equiv.) in a buffer solution (3 mL) at pH 9.00. The mixture was
stirred for 15 h and then stirred overnight with chloroform
rea, G. Tedeschi, J. Mol. Catal. B 2005, 34, 1–6, and references
cited therein.
[
14] I. Hilker, R. Wohlgermuth, V. Alphand, R. Furstoss, Biotech-
nol. Bioeng. 2005, 92, 702–710.
[15] S. V. Dzyuba, A. M. Klibanov, Tetrahedron: Asymmetry 2004,
15, 2771–2777.
(20 mL). The resulting slurry was filtered through a cake of Celite,
dried with MgSO and the solvent evaporated. The organic phase
was purified by flash chromatography using the appropriate eluent.
4
[16] a) S. Colonna, S. Banfi, F. Fontana, M. Sommaruga, J. Org.
Chem. 1985, 50, 769–771; b) S. Colonna, N. Gaggero, Tetrahe-
dron Lett. 1989, 30, 6233–6236.
trans-[(2-Methoxycyclohexyl)sulfinyl]benzene (5a): Major dia-
stereoisomer. The crude product was purified by column
chromatography (elution with hexane/ethyl acetate, 9:1) to give the
product as a white solid. Yield 33%; m.p. 136–137 °C. IR (KBr): ν˜
[
17] a) S. Colonna, A. Manfredi, R. Annunziata, M. Spadoni, Tet-
rahedron 1987, 43, 257–2164; b) S. Colonna, N. Gaggero, A.
Manfredi, M. Spadoni, L. Casella, G. Carrea, P. Pasta, Tetra-
hedron 1988, 44, 5169–5178.
–1
1
[18] S. Colonna, N. Gaggero, J. Drabowicz, P. Lyzwa, M. Miko-
=
3447, 2940, 1638, 1057, 1014 cm . H NMR (CDCl
δ = 1.14–1.85 (m, 6 H, 4-H, 5-H, 6-H), 2.13–2.36 (m, 2 H, 3-H),
.91 (m, 1 H, 2-H), 3.29 (s, 3 H, CH ), 3.45 (m, 1 H, 1-H), 7.50
3
, 200 MHz):
lajczyk, Chem. Commun. 1999, 1787–1788.
[
[
19] V. Pironti, S. Colonna, Green Chem. 2005, 7, 43–45.
20] F. Fringuelli, F. Pizzo, S. Tortoioli, L. Vaccaro, Adv. Synth.
Catal. 2002, 344, 379–384.
2
3
(
m, 3 H, Ar-H), 7.86 (m, 2 H, Ar-H) ppm. EI-MS: m/z (%) = 238
+
(100) [M] .
[
[
[
[
21] C. S. Chen, Y. Fujimoto, G. Girdaukas, C. J. Sih, J. Am. Chem.
Soc. 1982, 104, 7294–7299.
trans-[(2-Methoxycyclohexyl)sulfinyl]benzene (5b): Minor dia-
stereoisomer. The crude product was purified by column
chromatography (elution with hexane/ethyl acetate, 9:1) to give the
product as a white solid. Yield 15%; m.p. 129–130 °C. IR (KBr): ν˜
22] T. Fukazawa, Y. Shinoji, T. Hashimoto, Tetrahedron: Asym-
metry 1996, 7, 1649–1658.
23] F. Fringuelli, F. Pizzo, S. Tortoioli, L. Vaccaro, J. Org. Chem.
2003, 68, 8248–8251.
–1 1
=
3455, 2951, 1657, 1027, 1004 cm . H NMR (CDCl
δ = 1.14–1.85 (m, 6 H, 4-H, 5-H, 6-H), 2.13–2.36 (m, 2 H, 3-H),
.03 (m, 1 H, 2-H), 3.11 (s, 3 H, CH ), 3.47 (m, 1 H, 1-H), 7.57
m, 5 H, Ar-H) ppm. EI-MS: m/z (%) = 238 (100) [M] .
3
, 200 MHz):
24] J. Masuoka, J. Hegenauer, B. R. Van Dyke, P. Saltman, J. Biol.
Chem. 1993, 268, 21533–21685.
3
(
3
Received: July 19, 2006
+
Published Online: October 27, 2006
368
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 363–368