Synthesis of optically active 2,5-dialkylcyclohexane-1,4-diols and their application in the asymmetric oxidation of sulfides

Article abstract of DOI:10.1055/s-2008-1067185

A simple and efficient approach to obtain optically pure 1,4-diols was established. The asymmetric oxidation of sulfides to sulfoxides with cumyl hydroperoxide in moderate yields and moderate to high enantioselectivities (up to 84%) catalyzed by chiral Ti/ 1,4-diols complexes has been achieved. A 76% ee value was obtained in the asymmetric synthesis of esomeprazole. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067185

PAPER
2513
Synthesis of Optically Active 2,5-Dialkylcyclohexane-1,4-diols and Their
Application in the Asymmetric Oxidation of Sulfides
A
symmetr
i
ic
O
xid
a
ation of Su
n
lfides gtao Sun,*a,b Minghua Yang,a Zhenya Dai,a Chengjian Zhu,*a,c Hongwen Hua
a
b
c
Department of Chemistry, Nanjing University, Nanjing 210093, P. R. of China
E-mail: cjzhu@nju.edu.cn
Department of Chemistry, Sundia MediTech (Shanghai) Co, Ltd., Shanghai 201203, P. R. of China
E-mail: jtsun@sundia.com
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. of China
Fax +86(21)51903505
Received 4 April 2008; revised 7 May 2008
Dedicated to Professor Jintang Wang on the occasion of his 70th birthday
displayed good selectivities in many asymmetric reac-
tions.20,21 In order to obtain the optically active 2,5-dialkyl-
cyclohexane-1,4-diols, Halterman and co-workers
reported their synthetic study involving the use of the ex-
Abstract: A simple and efficient approach to obtain optically pure
1,4-diols was established. The asymmetric oxidation of sulfides to
sulfoxides with cumyl hydroperoxide in moderate yields and mod-
erate to high enantioselectivities (up to 84%) catalyzed by chiral Ti/
1,4-diols complexes has been achieved. A 76% ee value was ob- pensive IpcBH2 as the chiral hydroboration reagent.22
tained in the asymmetric synthesis of esomeprazole.
Two equivalents of IpcBH2 were required for a single
transformation, and this reagent is very inconvenient to be
handled. Although the asymmetric catalysis affords a di-
rect way to obtain the optically active compounds, some-
times the optical resolution of the racemic compounds
with cheap and natural chiral small molecules still re-
mains an important way due to its simplicity and econo-
my. Herein, we report a simple and efficient approach to
obtain the enantiomerically pure 1,4-diols and its success-
ful application in the asymmetric oxidation of sulfides.
Key words: asymmetric oxidation, sulfide, sulfoxide, titanium,
resolution
Enantiopure sulfoxides are important intermediates in or-
ganic synthesis and used as bioactive ingredients in the
pharmaceutical industry. Many efficient approaches have
been developed to obtain the enantiomerically pure sulf-
oxides.1 Among them, enzymes,2 chiral oxaziridines, and
chiral hydroperoxides3 afford the valuable methods to
achieve this target. Another approach consists of the syn-
thesis of a sulfinylating agent with an electrophilic sulfur
of known configuration, followed by the reaction with an
organometallic reagent providing highly enantiopure sulf-
oxides.4 Amongst all the procedures, asymmetric oxida-
tion of prochiral sulfides with chiral metal complexes is
undoubtedly the most attractive way because of its sim-
plicity and atom economy. Since the initial reports by Ka-
gan and Modena in the use of a modified Sharpless
reagent5 in the reaction, many efforts have been devoted
to search for an efficient catalytic system. Metal complex-
es such as Ti,6 V,7 Mn,8 Fe,9 Nb,10 Zr,11 Mo,12 W,13 Cu,14
Al,15 Pt,16 and Os17 have been widely investigated during
the past decades. However, few catalytic systems have
been applied in the industry.1e The development of a prac-
tical and efficient catalytic procedure remains a challenge.
The racemic 1,4-diols could be readily prepared by the hy-
droboration of 1,4-dialkylcyclohexa-1,4-diene with
BH3·SMe2 followed by oxidation with basic hydrogen
peroxide.22 After screening various resolution reagents, an
efficient resolution approach was finally achieved by
treating ( )-3 with d-camphorsulfonyl chloride in CH2Cl2
at 0 °C (Scheme 1). The two diastereoisomers were readi-
ly separated by flash chromatography on silica gel. Treat-
ment of a single diastereomer (such as 4a) with Na/
naphthalene in THF provided the corresponding enan-
tiopure (1R,2R,4R,5R)-2,5-dimethylcyclohexane-1,4-diol
(6a) as white solid in 35% yield after two steps. In the
same manner, 6b, 7a, and 7b were also obtained as white
solid in similar yields. The absolute configuration of the
diols was assigned by comparison of optical rotation with
literature values.21,22
Since Uemura et al.6a reported the utilization of chiral Ti–
BINOL complexes in the asymmetric sulfoxidation, sev-
eral other approaches using chiral titanium–diol complex-
es have been investigated.6,23,24 However, many of these
can not be considered truly catalytic because stoichiomet-
ric amounts of chiral complexes have been used, or the
high enantioselectivities mainly attributed to a kinetic res-
olution process. Very recently, Rosini and co-workers re-
ported the successful application of 1,2-diarylethane-1,2-
diols in the asymmetric sulfoxidation with high enantiose-
lectivities and good chemical yields.6e
Chiral diols are widely employed both as intermediates
and as chiral auxiliaries in asymmetric synthesis.18 Also,
optically pure diols are constituents of many natural com-
pounds.19 Besides the wide utilizations of 1,2-diols, the
C2-symmetric chiral 2,5-dialkylcyclohexane-1,4-diol can
also be converted into a wide diversity of ligands, which
SYNTHESIS 2008, No. 16, pp 2513–2518
x
x.
x
x
.
2
0
0
8
Advanced online publication: 24.07.2008
DOI: 10.1055/s-2008-1067185; Art ID: F08308SS
© Georg Thieme Verlag Stuttgart · New York

2514
J. Sun et al.
PAPER
R
HO
R
R
R
a
b
R
OH
R
2
( )-3
1a R = Me
1b R = i-Pr
O
O
S
O
O
O
R
O
O
S
c
O
R
O
R
+
R
O
O O
O
S
O
S
O
O
5
4
d
d
HO
R
R
R
OH
R
OH
HO
7a: (+)-(1S,2S,4S,5S), R = Me
7b: (+)-(1S,2R,4S,5R), R = i-Pr
6a: (–)-(1R,2R,4R,5R), R = Me
6b: (–)-(1R,2S,4R,5S), R = i-Pr
Scheme 1 Reagents and conditions: (a) Li/NH3 (liq)–EtOH, –40 °C; (b) (i) BH3·SMe2, Et2O, –25 °C, (ii) H2O2, NaOH; (c) d-camphorsulfonyl
chloride, pyridine, CH2Cl2, 0 °C; (d) Na/naphthalene, THF, 0 °C, 4 h.
In view of the good asymmetric induction of the chiral in carbon tetrachloride at 0 °C as the standard conditions
1,4-diols derived ligands in various reactions, we wish to for further investigations.
broaden their use in asymmetric catalysis. Using methyl
phenyl sulfide as the model substrate and Ti(Oi-Pr)4 as the
precatalyst, we examined the oxidation reaction by using
7b as the chiral ligand. The influence of parameters such
as the nature of hydroperoxide, the reaction temperature,
the solvent, and the additive has been investigated. The re-
sults are summarized in Table 1. Among the four hydro-
peroxides investigated, we found cumyl hydroperoxide
(CHP) gave the best selectivity in comparison to tert-butyl
hydroperoxide (TBHP) (entry 2), urea-hydrogen peroxide
adduct (UHP) (entry 4), and hydrogen peroxide (entry 1).
Of all the five solvents we investigated, CCl4 proved to be
the best choice in terms of enantioselectivity. The addition
of molecular sieves was revealed to have remarkable im-
provement on the enantioselectivity. However, addition
To study the influence of the steric effects and the config-
urations of the ligands, we next examined the oxidation
reaction using 6a, 6b, 7a, and 7b under the standard reac-
tion conditions mentioned above. The results are summa-
rized in Table 2. The oxidation of methyl phenyl sulfide
with 6a gave the sulfoxide in comparable yield and with
the same ee value, but in the opposite configuration with
respect to 7a (entry 1 vs entry 3). The similar situation was
observed in the comparison of 6b with 7b (entry 2 vs entry
4). It should be noted that 6a and 6b furnished the S-enan-
tiomer of the sulfoxide, on the contrary, 7a and 7b gave
the opposite R-enantiomer. All of the four chiral ligands
displayed similar reactivities. Compounds 6b and 7b are
superior to 6a and 7a in terms of enantioselectivities,
which is probably attributed to the larger hindrance of iso-
of a small amount of water did not improve, but decreased
propyl group on the cyclohexane skeleton offering a better
both the selectivity and the reactivity (entry 6). A varia-
discrimination than the methyl group.
tion of the reaction temperature from 0 to 25 °C caused
Under the standard reaction conditions, the oxidation of a
variety of aryl alkyl sulfides catalyzed by Ti(Oi-Pr)4/7b
negative influence on the selectivity (entry 12). No signif-
icant change of the selectivity was observed when the re-
was investigated. The results are summarized in Table 3.
action was carried out at –20 °C (entry 11). Increasing the
Moderate to high yields were obtained in all the cases.
catalyst’s loading resulted in a slight increase in reactivity
The enantioselectivities of sulfoxides varied from 51 to
84%. The highest ee value was observed for the oxidation
of 4-chlorophenyl methyl sulfide (entry 6) and 3-meth-
oxyphenyl methyl sulfide gave the corresponding sulfox-
and enantioselectivity (entries 13 and 14). Considering the
economy of the catalytic system, we chose Ti(Oi-Pr)4/7b/
CHP in a ratio of 0.05:0.1:1.5:1 in the presence of MS 4A
Synthesis 2008, No. 16, 2513–2518 © Thieme Stuttgart · New York

PAPER
Asymmetric Oxidation of Sulfides
2515
Table 1 Enantioselective Oxidation of Methyl Phenyl Sulfide with
(1S,2R,4S,5R)-7ba
Table 2 Enantioselective Oxidation of Methyl Phenyl Sulfide with
Diolsa
diol (10 mol%)
O
HO
S
S
Ti(Oi-Pr)4 (5 mol%)
Me
Me
CHP (1.5 equiv), MS 4A, 0 °C
OH
O
7b (10 mol%)
S
Yield (%)b ee (%)c
Configd
S
Entry
Diols
Ti(Oi-Pr)4 (5 mol%)
Me
Me
1
2
3
4
6a
6b
7a
7b
74
72
75
73
65
76
65
77
S
oxidant (1.5 equiv), 0 °C
Entry Oxidant
Solvent
CCl4
Additive
MS 4A
MS 4A
MS 4A
MS 4A
–
Yield (%)b ee (%)c
S
R
R
1
2
H2O2
TBHP
CHP
UHP
CHP
CHP
CHP
CHP
CHP
CHP
CHP
CHP
CHP
CHP
21
62
71
70
60
48
49
55
56
72
63
74
75
79
<5
57
77
65
36
22
64
58
37
14
76
62
78
83
CCl4
a Reaction conditions: Ti(Oi-Pr)4/diol/CHP/methyl phenyl
sulfide = 0.05:0.1:1.5:1, in the presence of MS 4A, 0 °C, 36 h.
b Isolated yields.
3
CCl4
4
CCl4
c Determined by chiral HPLC with a Daicel Chiralcel OD-H column.
d Absolute configuration of the products was assigned by comparison
of optical rotation reported in the literature.24
5
CCl4
6
CCl4
H2O
7
CH2Cl2
CHCl3
toluene
THF
MS 4A
MS 4A
MS 4A
MS 4A
MS 4A
MS 4A
MS 4A
MS 4A
Table 3 Ti(Oi-Pr)4/(1S,2R,4S,5R)-7b Catalyzed Asymmetric Oxi-
dation of Sulfides to Sulfoxidesa
8
9
HO
10
11d
12e
13f
14g
OH
CCl4
7b (10 mol%)
O
CCl4
Ti(Oi-Pr)4 (5 mol%)
S
S
R1
R2
CHP (1.5 equiv), MS 4A
CCl4, 0 °C
R2
R1
CCl4
CCl4
Entry
R1
R2
Yield (%)b ee (%)c
a Reaction conditions: Ti(Oi-Pr)4/7b/oxidant/methyl phenyl
sulfide = 0.05:0.1:1.5:1. Unless otherwise noted, all reactions were
1
2
Ph
Me
Me
71
53
58
72
55
66
49
57
60
67
71
77
72
68
75
54
84
81
66
51
72
65
carried out at 0 °C for 36 h.
4-Tol
b Isolated yields of sulfoxide.
c Determined by HPLC with a Daicel Chiralcel OD-H column. Abso-
lute configuration of the products R was assigned by comparison of
optical rotation reported in the literature.24,
3
4-i-PrC6H4
2-BrC6H4
3-BrC6H4
4-ClC6H4
4-O2NC6H4
4-MeOC6H4
3-MeOC6H4
Ph
Me
Me
Me
Me
Me
Me
Me
Bn
4
d Reaction performed at –20 °C for 48 h.
e Reaction performed at 25 °C for 24 h.
5
f Molar ratio: Ti(Oi-Pr)4/7b/CHP/sulfide = 0.1:0.15:1.5:1.
g Molar ratio: Ti(Oi-Pr)4/7b/CHP/sulfide = 0.15:0.2:2.0:1.
6
7
ide with the lowest ee value (entry 9). The change of the
aryl group in the methyl sulfide to probe electronic effects
displayed no regular trends in the selectivity. Moreover,
moderate yields and enantioselectivities were obtained for
the oxidation of aryl benzyl sulfides with a slight higher
catalyst loading (entries 10 and 11). In addition, all of the
sulfoxides were obtained as R-configured.
8
9
10d
11d
4-Tol
Bn
a Unless otherwise noted, all reactions were carried out under the fol-
lowing conditions: Ti(Oi-Pr)4/7b/CHP/substrate = 0.05:0.1.1.5:1, in
the presence of MS 4A, 0 °C, 36 h.
In most of the reported cases, the enantioselective oxida-
tion of sulfides involved two independent processes,
namely, the asymmetric oxidation produced the sulfoxide
and its subsequent kinetic resolution was accomplished
via further oxidation to sulfone. As good enantioselectiv-
ities in the enantioselective oxidation of sulfides with tita-
nium–diol complexes were obtained mostly on account of
a kinetic resolution process,23e a further study on the rela-
b Isolated yields of sulfoxides.
c Determined by HPLC with a Daicel Chiralcel OD-H or OB-H col-
umn. Absolute configuration of the products R was assigned by com-
parison of optical rotation reported in the literature.24,
d Molar ratio Ti(Oi-Pr)4/7b/CHP/substrate = 0.1:0.15.1.5:1.
Synthesis 2008, No. 16, 2513–2518 © Thieme Stuttgart · New York

2516
J. Sun et al.
PAPER
tionship between enantiomeric excess of sulfoxide and the
yield of sulfone under standard reaction conditions was
carried out. From the time profile of the oxidation of
methyl phenyl sulfide (Figure 1), it can be found that the
ee values of sulfoxide did not change significantly during
the reaction process, that is, the independence of the enan-
tiomeric excess of the sulfoxide on the amount of sulfone
formation. On the basis of this study, we concluded that
the ee value of the sulfoxide did not arise from a selectiv-
ity enhancement caused by kinetic resolution of the chiral
sulfoxide, but by a direct result of the enantioselective ox-
idation.
OH
HO
6b (15 mol%)
MeO
Me
Me
Ti(Oi-Pr)4 (10 mol%)
CHP (1.5 equiv), CCl4, 0 °C
OMe
H
N
N
S
N
MeO
Me
Me
H
N
N
S
O
N
OMe
esomeprazole (76% ee, 72% yield)
Scheme 2 Synthesis of esomeprazole
1H NMR data were recorded on a Bruker AMX-300 spectrometer
with chemical shifts referenced to SiMe4 as internal standard. Elec-
trospray ionization mass spectra were recorded on Finnigan LCQ
Electrospray Mass Spectrometer. Optical rotations were recorded
on a PerkinElmer 241 Polarimeter. The ee values were determined
by a PerkinElmer 200 HPLC on a chiral Chiralcel OD-H or OB-H
column with UV detection at 254 nm. Elemental analyses were car-
ried out on a PerkinElmer 240 C elemental analyzer. All reagents
were obtained from commercial suppliers and used without further
purification unless otherwise stated. Toluene and THF were dis-
tilled from sodium/benzophenone. CCl4 and CH2Cl2 were distilled
from CaH2. CHCl3 was dried with K2CO3 and distilled from P2O5.
Petroleum ether (PE) used had bp 60–90 °C. All reactions were car-
ried out under N2. All catalytic reactions were carried out in Schlenk
tubes. The enantioselectivities of the chiral 2,5-diisopropylhexane-
1,4-diols were determined by HPLC analysis and comparison of op-
tical rotation data with literature values.
Figure 1 Time profile of the enantioselectivity (% ee of sulfoxide)
and the chemoselectivity (% sulfone)
In pharmaceutical industry, the most remarkable utiliza-
tion of metal-catalyzed asymmetric oxidation of sulfide is
the synthesis of esomeprazole, which is the S-enantiomer
of omeprazole, a powerful antiulcer agent serving as effi-
cient proton pump inhibitor.25 A modified Kagan’s proce-
dure is the only efficient metal-catalyzed approach to
obtain the enantiomeric pure product. We applied our ap-
proach in the asymmetric synthesis of (S)-esomeprazole.
After optimization of the reaction conditions (Ti/6b/CHP/
sulfide = 0.1:0.15:1.5:1, MS 4A, 0 °C, 36 h), we obtained
(S)-esomeprazole in a moderate enantiomeric excess
(76% ee, yield 72%) (Scheme 2).
Esterification of Racemic 2,5-Dialkylcyclohexane-1,4-diols
( )-3; General Procedure
A 50 mL round-bottomed flask was charged with the 1,4-diol ( )-3
(1.5 mmol) and anhyd pyridine (2 mL) in CH2Cl2 (20 mL). The mix-
ture was stirred at 0 °C and a solution of d-camphorsulfonyl chlo-
ride (1.25 g, 5 mmol) in CH2Cl2 (10 mL) was added dropwise under
N2. The mixture was stirred for 4 h at 0 °C and then quenched with
aq sat. NH4Cl (50 mL). The aqueous layer was extracted with
CH2Cl2 (3 × 20 mL) and the combined organic phases were dried
(Na2SO4). Flash chromatography of the residue obtained after evap-
oration of the solvent on silica gel (PE–CH2Cl2–EtOAc, 3:1:1) gave
first the diastereomer 4a (0.39 g, 45%) and then the other diaste-
reomer 5a (0.39 g, 45%) from ( )-3a. Similarly 4b (0.42 g, 44%)
and then 5b (0.43 g, 45%) were obtained from ( )-3b.
In summary, a simple and efficient resolution of racemic
1,4-dialkylcyclohexane-2,5-diols has been realized. The
asymmetric oxidation of sulfides with CHP in the pres-
ence of MS 4A catalyzed by Ti(Oi-Pr)4/1,4-diols has been
investigated. The main advantage of our approach resided
in the use of a catalytic amount of the metal complex and
the sulfoxides were obtained in moderate to high enantio-
selectivities under mild reaction conditions. No kinetic
resolution was observed in the oxidation process. More-
over, we employed our catalytic system in the asymmetric
synthesis of esomeprazole, which was obtained in 72%
yield with 76% ee.
(1R,2R,4R,5R)-1,4-Di-d-camphorsulfonato-2,5-dimethylcyclo-
hexane (4a)
White solid; mp 46–48 °C; [a]D10 +23.6 (c 0.7, CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 4.86–4.90 (m, 2 H), 3.62–3.58 (m,
2 H), 3.04–2.96 (m, 2 H), 2.51–2.48 (m, 4 H), 2.41–2.09 (m, 8 H),
1.98–1.96 (m, 2 H), 1.94–1.91 (m, 4 H), 1.73–1.68 (m, 2 H), 1.21–
0.95 (m, 18 H).
MS (ES): m/z = 573.8 [M + 1].
Anal. Calcd for C28H44O8S2: C, 58.71; H, 7.74. Found: C, 58.82; H,
7.89.
Synthesis 2008, No. 16, 2513–2518 © Thieme Stuttgart · New York

PAPER
Asymmetric Oxidation of Sulfides
2517
(1R,2S,4R,5S)-1,4-Di-d-camphorsulfonato-2,5-diisopropylcy-
clohexane (4b)
(1R,2S,4R,5S)-(–)-2,5-Diisopropylcyclohexane-1,4-diol (6b)
White solid; mp 119–120 °C; [a]D25 –36.1 (c 0.5, CH2Cl2); >99% ee
(by comparison of optical rotation reported in the literature22).
White solid; mp 37–39 °C; [a]D10 +25.6 (c 0.8, CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 4.90 (m, 2 H), 3.66–3.61 (d,
J = 15 Hz, 2H), 3.06–3.01(d, J = 15 Hz, 2 H), 2.53 (m, 4 H), 2.39–
2.03 (m, 8 H), 1.95 (m, 2 H), 1.89–1.85 (m, 4 H), 1.70–1.62 (m, 2
H), 1.45 (m, 2 H), 1.17–0.90 (m, 24 H).
1H NMR (300 MHz, CDCl3): d = 3.53 (m, 2 H), 1.91 (m, 2 H), 1.79
(m, 2 H), 1.6 (m, 2 H), 1.48 (m, 2 H), 1.35 (m, 2 H), 0.88 (d, J = 7.2
Hz, 6 H), 0.86 (d, J = 7.2, 6 H).
(1S,2S,4S,5S)-(+)-2,5-Dimethylcyclohexane-1,4-diol (7a)
White solid; mp 121–123 °C; [a]D25 +32.9 (c 0.5, CH2Cl2); >99% ee
(by comparison of optical rotation reported in the literature22).
1H NMR (300 MHz, CDCl3): d = 3.57–3.50 (m, 2 H), 1.92–1.88 (m,
2 H), 1.78–1.69 (m, 4 H), 1.59–1.54 (m, 2 H), 1.02–1.00 (d, J = 6.6
Hz, 6 H).
MS (ES): m/z = 629.8 [M + 1].
Anal. Calcd for C32H52O8S2: C, 61.15; H, 8.27. Found: C, 61.57; H,
8.57.
(1S,2S,4S,5S)-1,4-Di-d-camphorsulfonato-2,5-dimethylpropyl-
cyclohexane (5a)
White solid; mp 62–64 °C; [a]D10 +42.4 (c 0.6, CH2Cl2).
Asymmetric Oxidation of Sulfides to Sulfoxides; Methyl Phenyl
Sulfoxide; Typical Procedure (Table 3, Entry 1)
1H NMR (300 MHz, CDCl3): d = 4.64–4.58 (m, 2 H), 3.41–3.38 (m,
2 H), 2.95–2.88 (m, 2 H), 2.46–2.43 (m, 4 H), 2.28–2.02 (m, 8 H),
1.92–1.85 (m, 2 H), 1.82–1.76 (m, 4 H), 1.65–1.57 (m, 2 H), 1.22–
0.96 (m, 18 H).
A solution of Ti(Oi-Pr)4 (14.8 mL, 0.05 mmol) in CCl4 (2 mL) was
added to a Schlenk tube containing MS 4A (50 mg) and 7b (20 mg,
0.1 mmol). The mixture was stirred for 2 h at r.t. Then the solution
was cooled to 0 °C, and methyl phenyl sulfide (1 mmol, 0.13 mL)
was added. The above mixture was stirred for another 30 min, then
80% cumyl hydroperoxide (270 mL, 1.5 mmol) was added. After
stirring for 36 h at 0 °C, H2O (10 mL) was added. The aqueous layer
was extracted with EtOAc (3 × 20 mL). The combined organic lay-
ers were washed with brine (100 mL) and dried (Na2SO4). The sol-
vent was removed under reduced pressure. The crude products were
purified by column chromatography on silica gel (EtOAc–PE,
1.5:1) to give methyl phenyl sulfoxide; yield: 100 mg (71%); oil at
r.t. (Lit.26 mp 29–30 °C).
MS (ES): m/z = 573.8 [M + 1].
Anal. Calcd for C28H44O8S2: C, 58.71; H, 7.74. Found: C, 58.85; H,
7.91.
(1S,2R,4S,5R)-1,4-Di-d-camphorsulfonato-2,5-diisopropylcy-
clohexane (5b)
White solid; mp 81–83 °C; [a]D10 +33.6 (c 0.3, CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 4.95 (m, 2 H), 3.61–3.56 (d,
J = 15 Hz, 2 H), 3.0–2.95 (d, J = 15 Hz, 2 H), 2.50–2.45 (m, 4 H),
2.32–2.0 (m, 8 H), 1.92 (m, 2 H), 1.86–1.80 (m, 4 H), 1.71–1.58 (m,
2 H), 1.42 (m, 2 H), 1.21–0.87 (m, 24 H).
The rest of the sulfoxides listed in Table 3 were identified by com-
parison of their analytical and spectral data with the corresponding
authentic samples.
MS (ES): m/z = 629.9 [M + 1].
Anal. Calcd for C32H52O8S2: C, 61.15; H, 8.27. Found: C, 61.35; H,
8.32.
Esomeprazole
A solution of Ti(Oi-Pr)4 (30 mL, 0.10 mmol) in CCl4 (3 mL) was
added to a Schlenk tube containing MS 4A (50 mg) and 6b (30 mg,
0.15 mmol). The mixture was stirred for 2 h at r.t. Then the mixture
was cooled to 0 °C, and the precursor sulfide (330 mg, 1 mmol) was
added. The mixture was stirred for another 30 min, then 80% cumyl
hydroperoxide (0.4 mL, 1.5 mmol) was added. After stirring for 36
h at 0 °C, H2O (20 mL) was added to the mixture. The aqueous layer
was separated and extracted with EtOAc (3 × 50 mL). The com-
bined organic layers were washed with brine (100 mL) and dried
(Na2SO4). The solvent was removed under reduced pressure. The
crude product was purified by column chromatography on silica gel
(EtOAc–PE, 1:1) to give esomeprazole (250 mg, 72%) as a clear oil;
Cleavage of the d-Camphorsulfonato Group from the Sulfo-
nates 4 and 5; (1S,2R,4S,5R)-(+)-2,5-Diisopropylcyclohexane-
1,4-diol (7b); Typical Procedure
A 100 mL three-necked flask was charged with 5b (1.53 g, 2.44
mmol) and anhyd THF (20 mL). While stirring the mixture at 0 °C,
a solution of sodium naphthalide [prepared by treating Na (2 g) with
naphthalene (11.4 g) in anhyd THF (200 mL) in a sealed system un-
der N2 for 1 h at r.t.] was added dropwise. The mixture was stirred
at 0 °C for 10 h and then warmed to r.t. After several hours, ice wa-
ter (50 mL) was added. The mixture was extracted with EtOAc (5 ×
20 mL) and the combined organic extracts were dried (Na2SO4).
The solvent were removed by rotary evaporation. After purification
by column chromatography on silica gel (PE–EtOAc, 2:1), 0.36 g
of the desired 1,4-diol 7b was obtained as a white solid (total yield
35% after two steps); mp 120–122 °C; [a]D25 +36.2 (c 0.5, CH2Cl2);
>99% ee (by comparison of optical rotation reported in the
literature22).
20
[a]D –118 (c 0.1, CHCl3); 76% ee. Chiralcel OD-H, hexane–
i-PrOH (9:1); flow rate = 0.5 mL/min.
1H NMR (300 MHz, CDCl3): d = 8.21 (s, 1 H), 7.50 (s, 1 H), 6.94
(d, J = 8.6 Hz, 1 H), 6.92 (d, J = 8.6 Hz, 1 H), 4.71 (s, 2 H), 3.84 (s,
3 H), 3.60 (s, 3 H), 2.19 (s, 3 H), 2.11 (s, 3 H).
1H NMR (300 MHz, CDCl3): d = 3.53 (m, 2 H), 1.91 (m, 2 H), 1.79
(m, 2 H), 1.6 (m, 2 H), 1.48 (m, 2 H), 1.35 (m, 2 H), 0.87 (d, J = 7.2
Hz, 6 H), 0.85 (d, J = 7.2 Hz, 6 H).
Acknowledgment
We gratefully acknowledge the National Natural Science Founda-
tion of China, the 863 High Technology Program, Science Founda-
tion of Jiangsu Province, and the Key Laboratory of Fine
Petrochemical Technology of Jiangsu Province for the financial
support.
(1R,2R,4R,5R)-(–)-2,5-Dimethylcyclohexane-1,4-diol (6a)
White solid; mp 121–122 °C; [a]D25 –32.9 (c 0.6, CH2Cl2); >99% ee
(by comparison of optical rotation reported in the literature22).
1H NMR (300 MHz, CDCl3): d = 3.58–3.51 (m, 2 H), 1.92–1.89 (m,
2 H), 1.79–1.68 (m, 4 H), 1.59–1.54 (m, 2 H), 1.02–1.00 (d, J = 6.6
Hz, 6 H).
Synthesis 2008, No. 16, 2513–2518 © Thieme Stuttgart · New York

2518
J. Sun et al.
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Synthesis 2008, No. 16, 2513–2518 © Thieme Stuttgart · New York