Chemoenzymatic synthesis of β-hydroxyl-sulfoxides by a two-step reaction of enzymatic reduction using Pseudomonas monteilii species and sulfoxidation with chiral titanium complexe

Article abstract of DOI:10.1016/j.tet.2017.07.014

A two-step enantioselective synthetic strategy for the preparation of β-hydroxyl-sulfoxides has been described. With the enzymatic reduction of β-ketosulfides using Pseudomonas monteilii ZMU-T04 followed by the asymmetric sulfoxidation with Ti(OⁱPr)₄/(S)-BINOL complexe, a wide range of corresponding β-hydroxyl-sulfoxide derivatives were smoothly obtained with excellent stereoselectivities (up to 99:1 dr and >99% ee). A plausible chelate structure of titanium complexe in the asymmetric sulfoxidation of β-hydroxyl-sulfides was also proposed on the basis of control experiments.

Full text of DOI:10.1016/j.tet.2017.07.014

Tetrahedron xxx (2017) 1e7
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chemoenzymatic synthesis of b-hydroxyl-sulfoxides by a two-step
reaction of enzymatic reduction using Pseudomonas monteilii species
and sulfoxidation with chiral titanium complexe
Baodong Cui, Min Yang, Jing Shan, Lei Qin, Ziyan Liu, Nanwei Wan, Wenyong Han,
Yongzheng Chen*
Generic Drug Research Center of Guizhou Province, School of Pharmacy, Zunyi Medical University, Zunyi, 563000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A two-step enantioselective synthetic strategy for the preparation of b-hydroxyl-sulfoxides has been
Received 31 May 2017
Received in revised form
6 July 2017
Accepted 8 July 2017
Available online xxx
described. With the enzymatic reduction of
lowed by the asymmetric sulfoxidation with Ti(OiPr)4/(S)-BINOL complexe, a wide range of corre-
sponding -hydroxyl-sulfoxide derivatives were smoothly obtained with excellent stereoselectivities (up
to 99:1 dr and >99% ee). A plausible chelate structure of titanium complexe in the asymmetric sulfox-
idation of -hydroxyl-sulfides was also proposed on the basis of control experiments.
© 2017 Published by Elsevier Ltd.
b-ketosulfides using Pseudomonas monteilii ZMU-T04 fol-
b
b
Keywords:
Biocatalysis
Titanium complexe
Two-step reaction
Sulfoxidation
b
-Hydroxyl-sulfoxides
1. Introduction
sulfur atom placed at an appropriate position from the hydroxyl
group.5
-Hydroxyl-sulfoxides with the sulfoxide and hydroxyl
b
Endeavors toward the creation of chiral functional molecules
from readily available materials are of continuing interest in
organic chemistry. Particularly, asymmetric synthesis achieved by
either chemocatalysis or biocatalysis is a highly active research field
and has presented great success.1 However sometimes either of
these synthetic strategies might be hindered by the need for
specially designed starting materials or by the intrinsic limiting
reactivity of the single catalyst applied. This problem associated
with the low efficiency of the single catalytic system can be
compensated by the application of two-step reaction with two
different catalysts. In this context, the two-step reaction with
chemo-enzymatic catalysis have gained increasing attention due to
its unprecedented level of efficiency in the asymmetric synthesis.2,3
Literature survey reveals that sulfur-containing chiral alcohols
can serve as intermediates in the synthesis of biologically active
compounds and naturally occurring products,4 and this unique
synthetic versatility is usually determined by the presence of a
groups at 1,3-positions well represent the privileged sulfur-
containing chiral alcohols that have been widely used as key syn-
thons in the asymmetric synthesis. Therefore, considerable efforts
have focused on the development of creative strategies to access
hydroxyl-sulfoxide derivatives. These strategies mainly include the
biotransformation of
-ketosulfides,6 chemical sulfoxidation fol-
lowed by reduction of
-ketosulfides,7 and the stereoselective
reduction of chiral
b-
b
b
b
-ketosulfoxides promoted by samarium diio-
dide.4e,8 However, the two-step reaction involving enzymatic
reduction followed by organometal promoted asymmetric sulfox-
idation of
b-ketosulfides for the synthesis of chiral b-hydroxyl-
sulfoxides has not been exploited although a few chemo-enzymatic
protocols have been reported.5b,9
Inspired by these achievements and the sulfoxidation promoted
by titanium complexe,7,10 as well as our successful exploration of
oxidation and reduction reactions mediated by Pseudomonas
monteilii species,11 we envisioned an alternative chemo-enzymatic
strategy for preparation of the chiral
rivatives. Firstly, the Pseudomonas monteilii ZMU-T04 mediated
asymmetric reduction of -ketosulfides produced the chiral -hy-
droxyl-sulfide intermediates.
b-hydroxyl-sulfoxide de-
b
b
* Corresponding author. Tel.: þ86 851 28642336; fax: þ86 851 28609726.
E-mail address: yzchen@zmc.edu.cn (Y. Chen).
http://dx.doi.org/10.1016/j.tet.2017.07.014
0040-4020/© 2017 Published by Elsevier Ltd.
Please cite this article in press as: Cui B, et al., Chemoenzymatic synthesis of b-hydroxyl-sulfoxides by a two-step reaction of enzymatic
reduction using Pseudomonas monteilii species and sulfoxidation with chiral titanium complexe, Tetrahedron (2017), http://dx.doi.org/
10.1016/j.tet.2017.07.014

2
B. Cui et al. / Tetrahedron xxx (2017) 1e7
T04 in the model reaction could be sustainable for the asym-
metric reduction of a broad range of -ketosulfides. Generally, ar-
omatic -ketosulfides bearing substituents at the ortho-, meta-, and
para-positions gave the desired -hydroxyl-sulfides with excellent
b
b
b
Scheme 1. Design for the synthesis of chiral
b
-hydroxyl-sulfoxides.
enantioselectivities (products 2a, c-q). The electronic nature of the
aromatic substituents had no obvious impact on efficiencies and
enantioselectivities. Products were generated with similar results
when b-ketosulfides with electron-donating (1c-f and 1k-m) and
electron-withdrawing substituents (1a, 1g-j and 1n-q) on the
Subsequently, the chiral b-hydroxyl-sulfides were oxidized to
the final enantiomerically pure
b-hydroxyl-sulfoxides with
Ti(OiPr)4/(S)-BINOL complexe (Scheme 1). Herein, we will disclose
phenyl moiety were applied. Notably, the bulky 2-naphthyl
our research results on this subject.
substituted
b-ketosulfide 1r also participated successfully in the
reaction and gave rise to the corresponding
b
-hydroxyl-sulfide 2r
with 92% ee and >99% conversion of 1r (entry 18).
2. Results and discussion
Having ascertained the scope of the asymmetric bio-reduction
of a variety of
tigate the generality of the asymmetric sulfoxidation of
sulfides 2 promoted by Ti(OiPr)4/(S)-BINOL complexe with tBuOOH
as the oxidant. As shown in Table 3, all the chiral -hydroxyl-sul-
fides 2 could be employed successfully into the following asym-
metric sulfoxidation reaction and furnished the optically active
hydroxyl-sulfoxides with moderate to excellent diaster-
eoselectivities and overall excellent enantioselectivities. However,
lower yields for products 3e and 3k-o were provided due to the
excessive sulfoxidation to sulfones (entries 5 and 11e15). In addi-
b
-ketosulfides 1, we turned our attention to inves-
Initial experiments were performed with 1-((4-chlorophenyl)
thio)propan-2-one 1a, cell suspension of Pseudomonas monteilii
species and Na2HPO4-KH2PO4 buffer for 24 h, and selected reac-
tion results for the asymmetric reduction of b-ketosulfides 1 are
shown in Table 1. The screening of our laboratory's different
b-hydroxyl-
b
b
-
strains from Pseudomonas monteilii ZMU-T01 to ZMU-T17 revealed
that ZMU-T04 strain gave the best results, providing (S)-b-hy-
3
droxyl-sulfide 2a with 97% ee and 96% conversion of model sub-
strate 1a (entry 2). Other strains, including ZMU-T05, ZMU-T06
and ZMU-T17, showed lower activity for the asymmetric reduction
of 1a despite showing satisfactory enantioselectivities (entries 3, 4
and 7). A boost in enantioselectivity was not achieved by replacing
the medium from M9 to LB (entry 8). Then the effect of substrate
concentration of 1a was explored. The reaction results revealed
that increasing of the substrate concentration of 1a had slight
positive effect on the enantioselectivity but was not beneficial for
the conversion of substrate 1a to 2a (entries 9e11). The following
investigation of cell concentration of Pseudomonas monteilii ZMU-
T04 identified 50 cdw g/L as the optimal catalyst loading, and the
desired product 2a was obtained in >99% ee with >99% conversion
of substrate 1a (entry 12).
tion, the sterically demanding
gave the inferior diastereoselectivities (entries 3, 4 and 6e10).
Similarly, the bulky 2-naphthyl substituted -hydroxyl-sulfide 2r
also participated well in the reaction and offered the corresponding
-hydroxyl-sulfoxide 3r in 91% yield with >99% ee but only 84:16 dr
(entry 18).
The absolute configuration of the major stereoisomer 3b could
b-hydroxyl-sulfides 2c, 2d and 2f-j
b
b
be assigned as (CS, SS) by HPLC comparison with the previous
literature report.9 Interesting, another diastereomer 3a' also could
be obtained in 71% yield with 99:1 dr and 99% ee by changing the
absolute configuration of BINOL (Scheme 2).
To explain the transition state of titanium complexe in the
After establishment of the optimal reaction conditions (Table 1,
entry 12), we moved on to explore the scope of the asymmetric bio-
reduction of b-ketosulfides 1 (Table 2). We were pleased to find that
asymmetric sulfoxidation of
b-hydroxyl-sulfides 2, three control
experiments were performed. Firstly, the asymmetric sulfoxidation
of 2a (99% ee) provided the b-hydroxyl-sulfoxide 3a in 61% yield
the high efficiency demonstrated by Pseudomonas monteilii ZMU-
Table 1
Optimization of Reaction Conditions for Asymmetric Reduction of b
-ketosulfides 1.a
Entry
Strain species
Cell concentration (cdw g/L)
Concentration of 1a (mM)
Conversion of 1ab (%)
2a/eec (%)
1
2
3
4
5
6
ZMU-T01
ZMU-T04
ZMU-T05
ZMU-T06
ZMU-T07
ZMU-T14
ZMU-T17
ZMU-T04
ZMU-T04
ZMU-T04
ZMU-T04
ZMU-T04
ZMU-T04
30
30
30
30
30
30
30
30
30
30
30
50
70
5
5
5
5
5
5
5
5
10
20
40
5
67
96
5
48
99
89
7
97
90
80
63
>99
94
94
97
90
85
94
99
73
87
7
8d
9
98
10
11
12
13
>99
>99
>99
99
5
a
Unless otherwise noted, mixtures of 1a, cell suspension of Pseudomonas monteilii species, Na2HPO4-KH2PO4 buffer (100 mM, pH 7) in 5.0 mL reaction system were shaken
at 250 rpm and 30 ꢀC for 24 h.
b
Determined by HPLC analysis.
Determined by chiral HPLC analysis.
LB medium was used.
c
d
Please cite this article in press as: Cui B, et al., Chemoenzymatic synthesis of b-hydroxyl-sulfoxides by a two-step reaction of enzymatic
reduction using Pseudomonas monteilii species and sulfoxidation with chiral titanium complexe, Tetrahedron (2017), http://dx.doi.org/
10.1016/j.tet.2017.07.014

B. Cui et al. / Tetrahedron xxx (2017) 1e7
3
Table 2
Scope of Asymmetric Reduction of b
-Ketosulfides 1.a
Scheme 2. Asymmetric synthesis of another diastereomer 3a'.
obvious steric induction in this oxidative transformation [Scheme
3, Eq. (a)]. Additionally, the chemo-enzymatic synthesis of -hy-
Entry
1
Conversion of 1b (%)
2/eec (%)
b
1
2
3
4
5
6
7
8
R ¼ 4-ClC6H4 (1a)
R ¼ Ph (1b)
2a/>99
2b/>99
2c/96
2d/94
2e/93
2f/99
2g/99
2h/95
2i/79
2j/92
2k/>99
2l/92
2m/93
2n/>99
2o/95
2p/92
2q/92
2r/>99
>99
97
>99
99
97
97
>99
97
>99
97
99
99
93
98
96
97
98
92
droxyl-sulfoxide 3a could also be achieved by exchanging the bio-
reduction of ketone and chemical oxidation of sulfide, but giving
inferior total yield and slightly lower dr of 3a [Scheme 3, Eq. (b)]. It
was speculated that the function of free hydroxyl in 2a may be
necessary for the acceleration and stereocontrol of the oxidation
process. In order to further confirm our speculation, the methyl
protected intermediate 5 was employed into the asymmetric sul-
foxidation. Not surprisingly, the product 6 was just obtained in 15%
yield with 72:28 dr [Scheme 3, Eq. (c)].
R ¼ 2-MeC6H4 (1c)
R ¼ 2-EtC6H4 (1d)
R ¼ 2,4-Me2C6H3 (1e)
R ¼ 2,5-Me2C6H3 (1f)
R ¼ 2,4-F2C6H3 (1g)
R ¼ 2-ClC6H4 (1h)
R ¼ 2,3-Cl2C6H3 (1i)
R ¼ 2,4-Cl2C6H3 (1j)
R ¼ 3-MeC6H4 (1k)
R ¼ 4-MeC6H4 (1l)
R ¼ 3,5-Me2C6H3 (1m)
R ¼ 3,4-F2C6H3 (1n)
R ¼ 3-ClC6H4 (1o)
R ¼ 3-BrC6H4 (1p)
R ¼ 4-BrC6H4 (1q)
R ¼ 2-naphthyl (1r)
9
10
11
12
13
14
15
16
17
18
On the basis of the above control experiments and the previous
literature report,12 a plausible chelate structure of the titanium
complexe in the asymmetric sulfoxidation of b-hydroxyl-sulfides 2
was proposed in Scheme 4. Firstly, Ti(OiPr)4 coordinated with (S)-
BINOL via the ligand exchange. In addition, the hydroxyl group and
sulfur atom of
b-hydroxyl-sulfides 2 might also combine with the
a
Unless otherwise noted, mixtures of 1 (5 mM), cell suspension of Pseudomonas
monteilii species (50 cdw g/L), Na2HPO4-KH2PO4 buffer (100 mM, pH 7) in 5.0 mL
reaction system were shaken at 250 rpm and 30 ꢀC for 24 h.
titanium centre to form the chelate transition structure. Finally, the
t
asymmetric sulfoxidation with BuOOH gave the b-hydroxyl-sulf-
b
Determined by HPLC analysis.
Determined by chiral HPLC analysis.
oxides 3.
c
3. Conclusion
with 56:44 dr and 98% ee in the absence of (S)-BINOL, which
revealed the chiral ligand played an important role in the stereo-
control, but the merely inherent chirality of hydroxyl in 2a had no
In summary, we have developed an efficient complementary
methodology for the stereoselective synthesis of -hydroxyl-sulf-
oxides by a two-step reaction of enzymatic reduction using Pseu-
domonas monteilii ZMU-T04 and sulfoxidation with Ti(OiPr)4/(S)-
BINOL complexe. Under the mild reaction conditions, a wide range
b
Table 3
Scope of Asymmetric Sulfoxidation of b
-Hydroxyl-Sulfides 2.a
of
from the starting
(up to 99:1 dr and >99% ee). Moreover, a plausible chelate titanium
b-hydroxyl-sulfoxide derivatives were smoothly synthesized
b-ketosulfides with excellent stereoselectivities
complexe for the asymmetric sulfoxidation of
was presented.
b-hydroxyl-sulfide
Entry
2
3/yieldb (%)
drc
eed (%)
4. Experimental section
1
2
3
4
5
6
7
8
R ¼ 4-ClC6H4 (2a)
R ¼ Ph (2b)
3a/88
3b/62
3c/66
3d/64
3e/41
3f/70
3g/70
3h/93
3i/98
3j/90
3k/38
3l/44
3m/34
3n/51
3o/41
3p/59
3q/64
3r/91
99:1
94:6
>99
>99
99
>99
>99
>99
>99
94
>99
98
>99
>99
97
4.1. General methods
R ¼ 2-MeC6H4 (2c)
R ¼ 2-EtC6H4 (2d)
R ¼ 2,4-Me2C6H3 (2e)
R ¼ 2,5-Me2C6H3 (2f)
R ¼ 2,4-F2C6H3 (2g)
R ¼ 2-ClC6H4 (2h)
R ¼ 2,3-Cl2C6H3 (2i)
R ¼ 2,4-Cl2C6H3 (2j)
R ¼ 3-MeC6H4 (2k)
R ¼ 4-MeC6H4 (2l)
R ¼ 3,5-Me2C6H3 (2m)
R ¼ 3,4-F2C6H3 (2n)
R ¼ 3-ClC6H4 (2o)
R ¼ 3-BrC6H4 (2p)
R ¼ 4-BrC6H4 (2q)
R ¼ 2-naphthyl (2r)
87:13
81:19
99:1
76:24
79:21
77:23
88:12
76:24
98:2
90:10
96:4
90:10
92:8
Reagents were purchased from commercial sources and were
directly used unless otherwise noted. H NMR and 13C NMR (400
1
and 100 MHz, respectively) spectra were recorded in CDCl3. 1H
9
10
11
12
13
14
15
16
17
18
>99
99
>99
>99
>99
96:4
99:1
84:16
a
Unless otherwise noted, all reactions were performed with substrates
2
L,
(0.25 mmol), Ti(OiPr)4 (0.025 mmol), (S)-BINOL (0.05 mmol), H2O (4.5
m
0.25 mmol) and tBuOOH (70% of aqueous solution, 0.5 mmol) in 5.0 mL of CCl4 at
30 ꢀC for 12 h.
b
Isolated yields of 3.
Determined by chiral HPLC analysis.
Enantiomeric excess for major diastereoisomers determined by chiral HPLC
c
d
analysis.
Scheme 3. Control experiments.
Please cite this article in press as: Cui B, et al., Chemoenzymatic synthesis of b-hydroxyl-sulfoxides by a two-step reaction of enzymatic
reduction using Pseudomonas monteilii species and sulfoxidation with chiral titanium complexe, Tetrahedron (2017), http://dx.doi.org/
10.1016/j.tet.2017.07.014

4
B. Cui et al. / Tetrahedron xxx (2017) 1e7
4.4.1. (S)-1-((S)-(4-chlorophenyl)sulfinyl)propan-2-ol (3a)
25
Yellow oil; 88% yield; 99:1 dr, >99% ee, [
a
]
¼ ꢂ164.7 (c 0.97,
D
CHCl3). The ee was determined by HPLC analysis (Chiralcel OJ-H,
iPrOH/hexane
¼
5/95, flow rate 0.8 mL/min,
l
¼
254 nm,
tmajor ¼ 19.1 min). 1H NMR (300 MHz, CDCl3)
d (major) 7.61e7.58
(m, 2H), 7.53e7.51 (m, 2H), 4.49e4.45 (m, 1H), 3.63 (s, 1H), 2.97 (dd,
J ¼ 9.0 Hz, 13.1 Hz, 1H), 2.78 (dd, J ¼ 2.7 Hz, 13.1 Hz, 1H), 1.32 (d,
Scheme 4. Speculated structure of titanium complexe in the asymmetric sulfoxidation
of b-hydroxyl-sulfides 2.
J ¼ 6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d (major) 142.4, 137.8,
129.9, 125.4, 65.2, 63.9, 23.4. HRMS (ESI-TOF): calcd for
C9H11ClNaO2S [M þ Na]þ: 241.0060; found: 241.0070.
NMR chemical shifts are reported in ppm (d) relative to tetrame-
thylsilane (TMS) with the solvent resonance employed as the in-
ternal standard (CDCl3 at 7.26 ppm). Data were reported as the
follows: chemical shift, multiplicity (s ¼ singlet, br s ¼ broad
singlet, d ¼ doublet, dd ¼ doublet of doublets, t ¼ triplet and
m ¼ multiplet), coupling constants (Hz) and integration. 13C NMR
4.4.2. (S)-1-((S)-phenylsulfinyl)propan-2-ol (3b)
25
Yellow solid; 62% yield; 94:6 dr, >99% ee, [
a
]
¼ ꢂ320.8 (c 0.61,
D
CHCl3); mp 62.8e64.1 ꢀC. The ee was determined by HPLC analysis
(Chiralcel OD, iPrOH/hexane ¼ 10/90, flow rate 0.7 mL/min,
l
¼ 254 nm, tmajor ¼ 24.8 min). 1H NMR (300 MHz, CDCl3)
d (major)
chemical shifts were reported in ppm (
d
) relative to tetrame-
7.67e7.64 (m, 2H), 7.55e7.53 (m, 3H), 4.53e4.48 (m, 1H), 3.81 (s,
1H), 2.98 (dd, J ¼ 9.1 Hz, 13.1 Hz, 1H), 2.78 (dd, J ¼ 2.6 Hz, 13.1 Hz,
thylsilane (TMS) with the solvent resonance as the internal stan-
dard (CDCl3 at 77.16 ppm).
1H), 1.31 (d, J ¼ 6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d (major)
144.0, 131.6, 129.6, 124.0, 65.3, 63.8, 23.4. HRMS (ESI-TOF): calcd for
4.2. Process for the strain cultivation
C9H12NaO2S [M þ Na]þ: 207.0450; found: 207.0456.
The cells of Pseudomonas monteilii strain were transferred from
M9 agar plate into 10 mL LB medium (10 g tryptone, 5 g yeast
extract and 5 g NaCl in 1 L deionized water), and the mixture was
shaken at 30 ꢀC and 250 rpm for 8 h. Then 1 mL of solution collected
from the above mixture was added into 50 mL M9 liquid medium
(17.09 g NaHPO4$12H2O, 3.00 g KH2PO4, 0.50 g NaCl, 1.00 g NH4Cl in
1000 mL deionized water) containing trace elements [HCl (1 mol/
L), FeSO4$7H2O (4.87 g/L), CaCl2$2H2O (4.12 g/L), MnCl2$4H2O
(1.50 g/L), ZnSO4 (1.05 g/L), H3BO3 (0.3 g/L), Na2MoO4$2H2O (0.25 g/
4.4.3. (S)-1-((S)-o-tolylsulfinylpropan-2-ol (3c)
25
Pale yellow solid; 66% yield; 87:13 dr, 99% ee, [
a
]
¼ ꢂ144.1 (c
D
0.62, CHCl3); mp 65.8e67.2 ꢀC. The ee was determined by HPLC
i
analysis (Chiralpak AD-H, PrOH/hexane ¼ 5/95, flow rate 1.0 mL/
min,
(400 MHz, CDCl3)
l
¼ 254 nm, tminor ¼ 28.9 min, tmajor ¼ 35.9 min). 1H NMR
d
(major þ minor) 7.92e7.88 (m, 1H), 7.44e7.35
(m, 2H), 7.18 (d, J ¼ 7.4 Hz, 1H), 4.49e4.37 (m, 1.4H), 4.18 (s, 0.6H),
2.97 (dd, J ¼ 9.9 Hz, 13.4 Hz, 0.4H), 2.78e2.90 (m, 1.6H), 2.34 (d,
J ¼ 8.9 Hz, 3H), 1.31 (d, J ¼ 6.3 Hz, 2H), 1.24 (d, J ¼ 6.4 Hz, 1H); 13
C
L), CuCl2$2H2O (0.15 g/L), Na2EDTA$2H2O (0.84 g/L)] 50
(1 mol/L) 100 L and toluene 50 L in a 250 mL shaking flask to
adjust the initial cell concentration to 0.1 g cdw/L (cell dry weight/
L). 15 mL of plastic tube with 500 L of toluene was put into the
mL, Mg2SO4
NMR (100 MHz, CDCl3)
d
(major þ minor) 142.0, 140.9, 134.4, 134.2,
m
m
131.1, 130.9, 130.8, 127.6, 127.3, 123.9, 123.6, 65.1, 62.6, 62.0, 61.2,
23.3, 23.2, 18.2, 18.1. HRMS (ESI-TOF): calcd for C10H14NaO2S [M þ
Na]þ: 221.0607; found: 221.0605.
m
flask and the vapor of toluene was used as carbon source. The
mixture was incubated at 30 ꢀC and 250 rpm for 24 h. After incu-
bation, the bacterium cells were harvested by centrifugation and
used for the following biotransformation.
4.4.4. (S)-1-((S)-2-ethylphenylsulfinylpropan-2-ol (3d)
25
Yellow oil; 64% yield; 81:19 dr, >99% ee, [
CHCl3). The ee was determined by HPLC analysis (Chiralpak AD-H,
a
]
¼ ꢂ182.2 (c 0.89,
D
iPrOH/hexane
¼
5/95, flow rate 0.5 mL/min,
l
¼
254 nm,
4.3. General procedure for the asymmetric reduction of
b
-
tmajor ¼ 42.3 min). 1H NMR (400 MHz, CDCl3)
d
(major þ minor)
ketosulfides 1
7.96e7.94 (m, 1H), 7.45e7.43 (m, 2H), 7.26e7.25 (m, 1H), 4.52e4.49
(m, 0.7H), 4.43e4.39 (m, 0.3H), 4.20 (s, 0.3H), 4.12 (s, 0.7H),
2.99e2.80 (m, 2H), 2.78e2.60 (m, 3H), 1.32e1.30 (m, 2H), 1.28e1.24
Whole cells of Pseudomonas monteilii ZMU-T04 (50 g cdw/L) was
resuspended in 5 mL phosphate buffer (50 mM Na2HPO4/KH2PO4,
(m, 3H); 13C NMR (100 MHz, CDCl3)
d
(major þ minor) 141.7, 140.8,
pH 7). Then the solution of
b
-ketosulfides 1 (0.025 mmol, 5 mM) in
140.6, 140.4, 131.5, 131.3, 129.0, 128.9, 127.8, 127.4, 124.1, 123.8, 65.4,
62.9, 62.7, 61.9, 24.8, 24.6, 23.4, 23.3, 15.4, 15.1. HRMS (ESI-TOF):
calcd for C11H16NaO2S [M þ Na]þ: 235.0763; found: 235.0755.
100 L of EtOH was added into the above solution and the mixture
m
was shaken at 30 ꢀC and 250 rpm for 24 h. After completion of the
reaction, the mixture was extracted with EtOAc (3 ꢁ 5 mL) and the
combined organic layers were dried over anhydrous Na2SO4,
filtered, concentrated and the residue was purified by flash chro-
matography on silica gel (petroleum ether/ethyl acetate ¼ 5:1). It
was noted that 30 parallel experiments were performed for col-
lecting the pure compounds 2.
4.4.5. (S)-1-((S)-(2,4-dimethylphenyl)sulfinylpropan-2-ol (3e)
25
Pale yellow solid; 41% yield; 99:1 dr, >99% ee, [
a
]
¼ ꢂ127.2 (c
D
0.62, CHCl3); mp 166.1e167.0 ꢀC. The ee was determined by HPLC
i
analysis (Chiralcel OJ-H, PrOH/hexane ¼ 5/95, flow rate 0.8 mL/
min,
l
¼ 254 nm, tmajor ¼ 13.0 min). 1H NMR (400 MHz, CDCl3)
d
(major) 7.80 (d, J ¼ 8.1 Hz, 1H), 7.25 (d, J ¼ 8.5 Hz, 1H), 7.02 (s, 1H),
4.4. General procedure for the asymmetric sulfoxidation of
b
-
4.52 (s, 1H), 4.03 (s,1H), 2.86e2.77 (m, 2H), 2.37 (s, 3H), 2.33 (s, 3H),
hydroxyl-sulfides 2
1.31 (d, J ¼ 4.5 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d (major) 141.7,
138.9, 134.3, 131.6, 128.5, 123.8, 65.5, 61.6, 23.4, 21.4, 18.2. HRMS
(ESI-TOF): calcd for C11H16NaO2S [M þ Na]þ: 235.0763; found:
235.0761.
The mixture with
(0.025 mmol), (S)-BINOL (0.05 mmol), H2O (4.5
b
-hydroxyl-sulfides 2 (0.25 mmol), Ti(OiPr)4
L, 0.25 mmol) and
m
tBuOOH (70% of aqueous solution, 0.5 mmol) in 5.0 mL of CCl4 was
stirred at 30 ꢀC for 12 h. After completion of the reaction, the sol-
vent was removed in vacuo and the residue was directly purified by
column chromatography on silica gel (petroleum ether/
EtOAc ¼ 2:1) to give the title products 3.
4.4.6. (S)-1-((S)-(2,5-dimethylphenyl)sulfinylpropan-2-ol (3f)
25
Yellow solid; 70% yield; 76:24 dr, >99% ee, [
a
]
¼ ꢂ178.9 (c 0.88,
D
CHCl3); mp 83.6e85.5 ꢀC. The ee was determined by HPLC analysis
(Chiralpak IA-3, iPrOH/hexane ¼ 5/95, flow rate 0.8 mL/min,
Please cite this article in press as: Cui B, et al., Chemoenzymatic synthesis of b-hydroxyl-sulfoxides by a two-step reaction of enzymatic
reduction using Pseudomonas monteilii species and sulfoxidation with chiral titanium complexe, Tetrahedron (2017), http://dx.doi.org/
10.1016/j.tet.2017.07.014

B. Cui et al. / Tetrahedron xxx (2017) 1e7
5
l
d
¼ 254 nm, tmajor ¼ 21.7 min). 1H NMR (400 MHz, CDCl3)
(major þ minor) 7.73 (d, J ¼ 7.8 Hz, 1H), 7.20 (d, J ¼ 7.6 Hz, 1H),
13.2 Hz, 0.7H), 2.84e2.75 (m, 1H), 1.34 (d, J ¼ 6.3 Hz, 2H), 1.25 (d,
J ¼ 6.3 Hz, 1H); 13C NMR (100 MHz, CDCl3)
(major þ minor) 140.7,
d
7.11e7.08 (m, 1H), 4.57e4.50 (m, 0.7H), 4.43e4.36 (m, 0.3H),
4.13e4.08 (m, 1H), 3.06e3.00 (m, 0.4H), 2.87e2.77 (m, 1.6H), 2.40
(d, J ¼ 5.2 Hz, 3H), 2.30 (d, J ¼ 10.8 Hz, 3H), 1.31 (d, J ¼ 6.3 Hz, 2H),
139.1, 138.1, 138.0, 130.6, 130.4, 130.1, 129.9, 128.8, 128.6, 127.8,
126.9, 65.2, 63.4, 60.8, 58.7, 23.4. HRMS (ESI-TOF): calcd for
C9H10Cl2NaO2S [M þ Na]þ: 274.9671; found: 274.9672.
1.25 (d,
d
J
¼
6.3 Hz, 1H); 13C NMR (100 MHz, CDCl3)
(major þ minor) 141.6, 140.1, 137.8, 137.3, 132.1, 131.9, 131.1, 131.0,
4.4.11. (S)-1-((S)-m-tolylsulfinylpropan-2-ol (3k)
25
130.9, 130.8, 124.3, 123.7, 65.5, 63.1, 61.3, 59.7, 23.4, 23.3, 21.2, 21.1,
17.8, 17.7. HRMS (ESI-TOF): calcd for C11H16NaO2S [M þ Na]þ:
235.0763; found: 235.0764.
Yellow oil; 38% yield; 98:2 dr, >99% ee, [
a
]
¼ ꢂ168.8 (c 0.77,
D
CHCl3). The ee was determined by HPLC analysis (Chiralcel OD-H,
iPrOH/hexane ¼ 10/90, flow rate 1.0 mL/min,
l
¼ 254 nm,
tmajor ¼ 14.6 min). 1H NMR (400 MHz, CDCl3)
d (major) 7.48 (s, 1H),
4.4.7. (S)-1-((S)-(2,4-difluorophenyl)sulfinylpropan-2-ol (3g)
7.40 (d, J ¼ 4.3 Hz, 2H), 7.32e7.31 (m, 1H), 4.51e4.47 (m,1H), 3.90 (s,
1H), 2.97 (dd, J ¼ 9.2 Hz, 13.2 Hz, 1H), 2.76 (dd, J ¼ 2.0 Hz, 13.2 Hz,
1H), 2.42 (s, 3H), 1.30 (d, J ¼ 6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3)
25
Pale yellow solid; 70% yield; 79:21 dr, >99% ee, [
a]
¼ ꢂ130.4 (c
D
0.66, CHCl3); mp 83.1e84.5 ꢀC. The ee was determined by HPLC
i
analysis (Chiralcel OD-H, PrOH/hexane ¼ 8/92, flow rate 0.5 mL/
d
(major) 143.6, 139.9, 132.4, 129.4, 124.2,121.1, 65.3, 63.7, 23.4, 21.6.
¼ 254 nm, tmajor ¼ 36.1 min). 1H NMR (400 MHz, CDCl3)
HRMS (ESI-TOF): calcd for C10H14NaO2S [M þ Na]þ: 221.0607;
min,
d
l
(major þ minor) 7.86e7.81 (m, 1H), 7.17e7.13 (m, 1H), 6.93e6.88
found: 221.0604.
(m, 1H), 4.59e4.55 (m, 0.8H), 4.32 (s, 0.2H), 3.67 (s, 0.2H), 3.48 (s,
0.8H), 3.26e3.21 (m, 0.2H), 3.07e3.03 (m, 0.8H), 2.98e2.92 (m,
0.8H), 2.76 (d, J ¼ 13.7 Hz, 0.2H), 1.35 (d, J ¼ 6.4 Hz, 2.4H), 1.27e1.25
4.4.12. (S)-1-((S)-p-tolylsulfinylpropan-2-ol (3l)
25
Yellow oil; 44% yield; 90:10 dr, >99% ee, [
a
]
¼ ꢂ207.5 (c 0.90,
D
(m, 0.6H); 13C NMR (100 MHz, CDCl3)
d
(major þ minor) 165.2 (d,
CHCl3). The ee was determined by HPLC analysis (Chiralcel OJ-H,
J ¼ 253.0 Hz, 1C), 165.1 (d, J ¼ 253.2 Hz, 1C), 157.9 (d, J ¼ 248.5 Hz,
1C), 157.8 (d, J ¼ 248.5 Hz, 1C), 128.0 (dd, J ¼ 4.0 Hz, 10.0 Hz, 1C),
127.2 (dd, J ¼ 3.9 Hz, 10.2 Hz, 1C), 113.3 (dd, J ¼ 3.4 Hz, 21.9 Hz),
105.0, 104.9 (d, J ¼ 50.1 Hz, 1C), 104.8 (d, J ¼ 50.2 Hz, 1C), 104.7, 65.0,
63.5, 61.8, 59.8, 23.4, 23.3. HRMS (ESI-TOF): calcd for C9H10F2NaO2S
[M þ Na]þ: 243.0262; found: 243.0252.
iPrOH/hexane ¼ 10/90, flow rate 0.5 mL/min,
l
¼ 254 nm,
tmajor ¼ 14.8 min). 1H NMR (300 MHz, CDCl3)
d (major) 7.54 (d,
J ¼ 8.2 Hz, 2H), 7.34 (d, J ¼ 8.0 Hz, 2H), 4.53e4.49 (m, 1H), 3.82 (s,
1H), 2.95 (dd, J ¼ 9.3 Hz, 13.1 Hz, 1H), 2.75 (dd, J ¼ 2.3 Hz, 13.1 Hz,
1H), 2.42 (s, 3H), 1.30 (d, J ¼ 6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d
(major) 142.2, 140.7, 130.3, 124.0, 65.4, 63.6, 23.5, 21.6. HRMS (ESI-
TOF): calcd for C10H14NaO2S [M þ Na]þ: 221.0607; found: 221.0614.
4.4.8. (S)-1-((S)-(2-chlorophenyl)sulfinyl)propan-2-ol (3h)
25
White solid; 93% yield; 77:23 dr, 94% ee, [
a
]
¼ ꢂ153.3 (c 0.80,
D
4.4.13. (S)-1-((S)-(3,5-dimethylphenyl)sulfinylpropan-2-ol (3m)
CHCl3); mp 108.1e109.9 ꢀC. The ee was determined by HPLC anal-
25
Yellow oil; 34% yield; 96:4 dr, 97% ee, [
a
]
¼ ꢂ182.2 (c 0.90,
i
D
ysis (Chiralpak AD-H, PrOH/hexane ¼ 8/92, flow rate 0.8 mL/min,
CHCl3). The ee was determined by HPLC analysis (Chiralcel OD-H,
l
¼ 254 nm, tminor ¼ 22.0 min, tmajor ¼ 25.5 min). 1H NMR (400 MHz,
iPrOH/hexane ¼ 10/90, flow rate 1.0 mL/min,
l
¼ 254 nm,
CDCl3)
d
(major þ minor) 7.97e7.92 (m, 1H), 7.58e7.52 (m, 1H),
tminor ¼ 12.5 min, tmajor ¼ 10.5 min). 1H NMR (400 MHz, CDCl3)
7.49e7.39 (m, 2H), 4.63e4.57 (m, 0.7H), 4.33e4.30 (m, 0.3H), 3.97
(s, 0.3H), 3.76 (s, 0.7H), 3.30 (dd, J ¼ 9.6 Hz, 13.6 Hz, 0.3H), 3.22 (dd,
J ¼ 2.2 Hz, 13.2 Hz, 0.7H), 2.81 (dd, J ¼ 8.3 Hz, 13.2 Hz, 1H), 1.34 (d,
J ¼ 6.4 Hz, 2H), 1.24 (d, J ¼ 6.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
(major) 7.24 (s, 2H), 7.12 (s, 1H), 4.52e4.48 (m, 1H), 3.91 (s, 1H),
2.95 (dd, J ¼ 9.2 Hz, 13.2 Hz, 1H), 2.75 (dd, J ¼ 2.4 Hz, 13.2 Hz, 1H),
2.37 (s, 6H), 1.30 (d, J ¼ 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
(major) 143.5, 139.7, 133.3, 121.3, 65.4, 63.6, 23.4, 21.4. HRMS (ESI-
d
(major þ minor) 142.0, 140.2, 135.2, 132.4, 131.0, 130.2, 130.0,
TOF): calcd for C11H16NaO2S [M þ Na]þ: 235.0763; found: 235.0754.
129.8, 128.4, 128.1, 126.7, 125.6, 65.4, 63.6, 60.6, 58.1, 23.3, 22.8.
HRMS (ESI-TOF): calcd for C9H11ClNaO2S [M þ Na]þ: 241.0060;
found: 241.0058.
4.4.14. (S)-1-((S)-(3,4-difluorophenyl)sulfinylpropan-2-ol (3n)
25
Yellow oil; 51% yield; 90:10 dr, >99% ee, [
a]
¼ ꢂ39.2 (c 0.90,
D
CHCl3). The ee was determined by HPLC analysis (Chiralpak AD-H,
4.4.9. (S)-1-((S)-(2,3-dichlorophenyl)sulfinylpropan-2-ol (3i)
iPrOH/hexane
¼
5/95, flow rate 1.0 mL/min,
l
¼
254 nm,
25
Brown solid; 98% yield; 88:12 dr, >99% ee, [
a
]
¼ ꢂ145.1 (c 1.03,
D
tmajor ¼ 19.6 min). 1H NMR (400 MHz, CDCl3)
d (major) 7.57e7.53
CHCl3); mp 77.7e79.4 ꢀC. The ee was determined by HPLC analysis
(Chiralcel OJ-H, iPrOH/hexane ¼ 5/95, flow rate 0.8 mL/min,
(m, 1H), 7.41e7.32 (m, 2H), 4.46e4.43 (m, 1H), 3.53 (s, 1H), 2.98 (dd,
J ¼ 8.9 Hz, 13.2 Hz, 1H), 2.79 (dd, J ¼ 2.8 Hz, 13.2 Hz, 1H), 1.33 (d,
l
d
¼ 254 nm, tmajor ¼ 17.1 min). 1H NMR (400 MHz, CDCl3)
(major þ minor) 7.85e7.82 (m, 1H), 7.62e7.59 (m, 1H), 7.52e7.47
J ¼ 6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d (major) 152.3 (dd,
J ¼ 12.5 Hz, 252.9 Hz, 1C), 151.2 (dd, J ¼ 13.7 Hz, 253.8 Hz, 1C), 140.4,
120.7, 118.7 (d, J ¼ 18.4 Hz, 1C), 113.8 (d, J ¼ 19.4 Hz), 64.7, 64.5, 23.4.
HRMS (ESI-TOF): calcd for C9H10F2NaO2S [M þ Na]þ: 243.0262;
found: 243.0256.
(m, 1H), 4.59 (s, 0.8H), 4.33 (s, 0.2H), 3.88 (d, J ¼ 25.4 Hz, 0.2H), 3.67
(d, J ¼ 11.6 Hz, 0.8H), 3.33e3.22 (m, 1H), 2.84e2.76 (m, 1H),
1.36e1.33 (m, 2.4H), 1.27e1.25 (m, 0.6H); 13C NMR (100 MHz,
CDCl3)
d
(major þ minor) 144.5, 134.0, 133.8, 132.8, 132.7, 132.7,
128.9, 128.6, 128.0, 127.8, 124.8, 123.9, 65.2, 63.3, 60.6, 58.8, 23.3.
HRMS (ESI-TOF): calcd for C9H10Cl2NaO2S [M þ Na]þ: 274.9671;
found: 274.9670.
4.4.15. (S)-1-((S)-3-chlorophenylsulfinylpropan-2-ol (3o)
25
Yellow oil; 41% yield; 92:8 dr, 99% ee, [
a
]
¼ ꢂ119.7 (c 1.27,
D
CHCl3). The ee was determined by HPLC analysis (Chiralpak AD-H,
4.4.10. (S)-1-((S)-(2,4-dichlorophenyl)sulfinylpropan-2-ol (3j)
iPrOH/hexane ¼ 10/90, flow rate 1.0 mL/min,
l
¼ 254 nm,
25
White solid; 90% yield; 76:24 dr, 98% ee, [
a
]
¼ ꢂ154.9 (c 1.00,
tminor ¼ 15.6 min, tmajor ¼ 21.1 min). 1H NMR (400 MHz, CDCl3)
D
CHCl3); mp 210.4e211.8 ꢀC. The ee was determined by HPLC anal-
d (major) 7.66 (s, 1H), 7.49e7.47 (m, 3H), 4.48e4.45 (m, 1H), 3.67 (s,
i
ysis (Chiralpak AD-H, PrOH/hexane ¼ 8/92, flow rate 0.8 mL/min,
1H), 2.99 (dd, J ¼ 8.8 Hz, 13.2 Hz, 1H), 2.81 (dd, J ¼ 2.6 Hz, 13.2 Hz,
l
¼ 254 nm, tminor ¼ 16.4 min, tmajor ¼ 15.7 min). 1H NMR (400 MHz,
1H), 1.32 (d, J ¼ 6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d (major)
CDCl3)
d
(major þ minor) 7.90e7.85 (m, 1H), 7.54e7.51 (m, 1H),
145.9, 136.0, 131.7, 130.8, 124.0, 122.0, 65.1, 64.0, 23.4. HRMS (ESI-
7.44e7.42 (m,1H), 4.59e4.57 (m, 0.7H), 4.32 (s, 0.3H), 3.82 (s, 0.3H),
3.62 (s, 0.7H), 3.28 (dd, J ¼ 9.8 Hz,13.7 Hz, 0.3H), 3.19 (dd, J ¼ 2.8 Hz,
TOF): calcd for C9H11ClNaO2S [M
241.0054.
þ
Na]þ: 241.0060; found:
Please cite this article in press as: Cui B, et al., Chemoenzymatic synthesis of b-hydroxyl-sulfoxides by a two-step reaction of enzymatic
reduction using Pseudomonas monteilii species and sulfoxidation with chiral titanium complexe, Tetrahedron (2017), http://dx.doi.org/
10.1016/j.tet.2017.07.014

6
B. Cui et al. / Tetrahedron xxx (2017) 1e7
4.4.16. (S)-1-((S)-3-bromophbbenylsulfinylpropan-2-ol (3p)
cdw/L) was resuspended in 5 mL phosphate buffer (50 mM
Na2HPO4/KH2PO4, pH 7). Then the solution of (5.4 mg,
0.025 mmol, 5 mM) in 100 L of EtOH was added into the above
25
Yellow oil; 59% yield; 96:4 dr, >99% ee, [
a
]
¼ ꢂ122.9 (c 0.90,
4
D
CHCl3). The ee was determined by HPLC analysis (Chiralpak AD-H,
m
iPrOH/hexane
¼
5/95, flow rate 1.0 mL/min,
l
¼
254 nm,
solution and the mixture was shaken at 30 ꢀC and 250 rpm for 24 h.
After completion of the reaction, the mixture was extracted with
EtOAc (3 ꢁ 5 mL) and the combined organic layers were dried over
anhydrous Na2SO4, filtered, concentrated and the residue was pu-
rified by flash chromatography on silica gel (petroleum ether/ethyl
acetate ¼ 5:1) to give product 3a with 93:7 dr and 99% ee and 99%
conversion of 4. It was noted that the above extracted organic phase
was used for chiral HPLC analysis and 30 parallel experiments were
performed for collecting the pure compound 3a.
tmajor ¼ 48.3 min). 1H NMR (400 MHz, CDCl3)
d (major) 7.80 (d,
J ¼ 1.6 Hz, 1H), 7.63 (d, J ¼ 7.9 Hz, 1H), 7.55 (d, J ¼ 7.8 Hz, 1H),
7.42e7.40 (m, 1H), 4.46 (s, 1H), 3.68 (s, 1H), 3.02e2.96 (m, 1H),
2.82e2.78 (m, 1H), 1.33e1.31 (m, 3H); 13C NMR (100 MHz, CDCl3)
d
(major) 146.1, 134.6, 131.0, 126.8, 123.8, 122.5, 65.1, 64.0, 23.4.
HRMS (ESI-TOF): calcd for C9H11BrNaO2S [M þ Na]þ: 284.9555;
found: 284.9550.
4.4.17. (S)-1-((S)-4-bromophenylsulfinylpropan-2-ol (3q)
25
Pale yellow solid; 64% yield; 99:1 dr, >99% ee, [
a]
¼ ꢂ173.5 (c
D
4.6.1. (S)-1-((4-chlorophenyl)sulfinyl)propan-2-one 4
1.01, CHCl3); mp 107.3e108.5 ꢀC. The ee was determined by HPLC
25
Pale yellow solid; 34% yield; 91% ee, [
a
]
¼ ꢂ96.2 (c 0.60,
D
i
analysis (Chiralpak AD-H, PrOH/hexane ¼ 5/95, flow rate 1.0 mL/
CHCl3). The ee was determined by HPLC analysis (Chiralcel OJ-H,
¼ 254 nm, tmajor ¼ 25.6 min). 1H NMR (300 MHz, CDCl3)
iPrOH/hexane
¼
5/95, flow rate 0.8 mL/min,
l
¼
254 nm,
min,
l
tminor ¼ 68.6 min, tmajor ¼ 54.3 min). 1H NMR (400 MHz, CDCl3)
d
(major) 7.70e7.67 (m, 2H), 7.54e7.51 (m, 2H), 4.50e4.45 (m, 1H),
3.61 (s, 1H), 2.96 (dd, J ¼ 9.0 Hz, 13.1 Hz, 1H), 2.78 (dd, J ¼ 2.6 Hz,
d
7.61e7.58 (m, 2H), 7.53e7.50 (m, 2H), 3.88e3.80 (m, 2H), 2.25 (s,
13.1 Hz, 1H), 1.32 (d, J ¼ 6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3)
3H); 13C NMR (100 MHz, CDCl3)
68.6, 32.2.
d 199.4, 141.4, 138.1, 129.9, 125.6,
d
(major) 143.1, 132.9, 126.0,125.6, 65.2, 63.8, 23.5. HRMS (ESI-TOF):
calcd for C9H11BrNaO2S [M þ Na]þ: 284.9555; found: 284.9554.
4.7. Procedure for the synthesis of compound 6
4.4.18. (S)-1-((S)-naphthalen-2-ylsulfinylpropan-2-ol (3r)
25
Pale yellow solid; 91% yield; 84:16 dr, >99% ee, [
a
]
¼ ꢂ80.7 (c
To the mixture of (S)-BINOL (14.3 mg, 0.05 mmol), Ti(OiPr)4
(7.5 mL, 0.025 mmol) and H2O (4.5 mL, 0.25 mmol) in CCl4 (3 mL) was
D
1.05, CHCl3); mp 132.1e133.9 ꢀC. The ee was determined by HPLC
i
analysis (Chiralpak AD-H, PrOH/hexane ¼ 5/95, flow rate 1.0 mL/
added a solution of 5 (50.2 mg, 0.25 mmol) in 2 mL of CCl4. The
min,
(400 MHz, CDCl3)
l
¼ 254 nm, tminor ¼ 41.9 min, tmajor ¼ 49.4 min). 1H NMR
resulting solution was stirred at 30 ꢀC for 10 min, and then tBuOOH
d
(major þ minor) 8.24 (s, 0.2H), 8.20 (s, 0.8H),
(70% aqueous solution, 70.6
mL, 0.5 mmol) was added and the
8.01e7.98 (m, 1H), 7.95e7.90 (m, 2H), 7.64e7.52 (m, 3H), 4.57e4.53
(m, 0.8H), 4.38 (m, 0.2H), 3.98 (s, 0.2H), 3.86 (s, 0.8H), 3.18 (dd,
J ¼ 9.8 Hz, 13.7 Hz, 0.2H), 3.05 (dd, J ¼ 9.1 Hz, 13.2 Hz, 0.8H), 2.87
(dd, J ¼ 1.8 Hz, 13.2, 0.8H), 2.72 (d, J ¼ 13.6 Hz, 0.2H), 1.33 (d,
J ¼ 6.2 Hz, 2.4H), 1.23 (d, J ¼ 6.4 Hz, 0.6H); 13C NMR (100 MHz,
mixture was subsequently stirred at 30 ꢀC for 12 h. After comple-
tion of the reaction, the solvent was removed in vacuo and the
residue was subjected to column chromatography on silica gel
(EtOAc/petroleum ether ¼ 1:2) to give the product 6 in 15% yield
with 72:28 dr and 99% ee.
CDCl3)
d
(major þ minor) 140.8, 134.7, 133.0, 129.9, 129.7, 128.7,
128.6, 128.3, 128.2, 128.1, 128.0, 127.6, 124.9, 124.7, 119.8, 119.7, 65.4,
63.5, 63.3, 23.5, 23.4. HRMS (ESI-TOF): calcd for C13H14NaO2S [M þ
Na]þ: 257.0607; found: 257.0604.
4.7.1. (S)-(4-chlorophenyl)(2-methoxypropyl)sulfane 5
25
Yellow solid; 88% yield; 98% ee, [
a]
¼ ꢂ10.5 (c 1.00, CHCl3). The
D
ee was determined by HPLC analysis (Chiralpak AY-H, iPrOH/
hexane ¼ 5/95, flow rate 0.5 mL/min, ¼ 254 nm, tminor ¼ 10.7 min,
l
4.5. Procedure for the sulfoxidation of 2a to 3a without (S)-BINOL
tmajor ¼ 10.1 min). 1H NMR (400 MHz, CDCl3)
d
7.29 (d, J ¼ 8.6 Hz,
2H), 7.24 (d, J ¼ 8.6 Hz, 2H), 3.48 (dd, J ¼ 6.1 Hz, 12.1 Hz, 1H), 3.34 (s,
3H), 3.10 (dd, J ¼ 5.8 Hz, 13.2 Hz, 1H), 2.90 (dd, J ¼ 6.1 Hz, 13.1 Hz,
To the mixture of Ti(OiPr)4 (7.5
mL, 0.025 mmol) and H2O (4.5 mL,
0.25 mmol) in CCl4 (3 mL) was added a solution of 2a (99% ee,
50.7 mg, 0.25 mmol) in 2 mL of CCl4. The resulting solution was
stirred at 30 ꢀC for 10 min, and then tBuOOH (70% aqueous solution,
1H), 1.25 (s, 3H); 13C NMR (100 MHz, CDCl3)
129.1, 75.9, 56.7, 40.1, 19.0.
d 135.4, 132.1, 130.7,
70.6 mL, 0.5 mmol) was added and the mixture was subsequently
stirred at 30 ꢀC for 12 h. After completion of the reaction, the sol-
vent was removed in vacuo and the residue was subjected to col-
umn chromatography on silica gel (EtOAc/petroleum ether ¼ 1:2)
to give the product 3a in 61% yield with 56:44 dr and 98% ee.
4.7.2. 1-Chloro-4-((S)-((S)-2-methoxypropyl)sulfinyl)benzene 6
25
Yellow solid; 15% yield; 72:28 dr, >99% ee, [
CHCl3). The ee was determined by HPLC analysis (Chiralcel OD-H,
a
]
¼ ꢂ22.9 (c 0.75,
D
iPrOH/hexane
¼
5/95, flow rate 1.0 mL/min,
l
¼
254 nm,
tminor ¼ 18.6 min, tmajor ¼ 16.7 min). 1H NMR (400 MHz, CDCl3)
d
(major þ minor) 7.60e7.56 (m, 2H), 7.51e7.46 (m, 2H), 3.96e3.91
4.6. Procedure for the synthesis of product 3a via the exchange of
the bio-reduction of ketone and chemical oxidation of sulfide
(m, 0.6H), 3.59e3.54 (m, 0.4H), 3.45e3.44 (m, 1.7H), 3.22e3.21 (m,
1.3H), 3.19e3.14 (m, 0.4H), 2.78e2.72 (m, 1.6H), 1.32e1.30 (m, 1.4H),
1.24e1.22 (m, 1.6H); 13C NMR (100 MHz, CDCl3)
d
(major þ minor)
To the mixture of (S)-BINOL (14.3 mg, 0.05 mmol), Ti(OiPr)4
(7.5 mL, 0.025 mmol) and H2O (4.5 mL, 0.25 mmol) in CCl4 (3 mL) was
143.3, 142.3, 137.4, 137.2, 129.7, 129.6, 125.7, 125.3, 71.7, 70.8, 66.4,
63.8, 56.9, 56.0, 19.0, 18.8.
added a solution of substrate 1a (50.2 mg, 0.25 mmol) in 2 mL of
CCl4. The resulting solution was stirred at 30 ꢀC for 10 min, and then
tBuOOH (70% aqueous solution, 70.6
mL, 0.5 mmol) was added and
Acknowledgments
the mixture was subsequently stirred at 30 ꢀC for 12 h. After
completion of the reaction, the solvent was removed in vacuo and
the residue was subjected to column chromatography on silica gel
(EtOAc/petroleum ether ¼ 1:2) to give the intermediate 4 in 34%
yield with 91% ee.
We are grateful for financial support from National Nature Sci-
ence Foundation of China (21262051), Science and Technology
Department of Guizhou Province (QKHRCTD-2014-4002, QKHRC-
2016-4029, QKHPTRC-2016-5801), and New Century Excellent
Talent of the Ministry of Education (NCET-13-1069).
After that, whole cells of Pseudomonas monteilii ZMU-T04 (50 g
Please cite this article in press as: Cui B, et al., Chemoenzymatic synthesis of b-hydroxyl-sulfoxides by a two-step reaction of enzymatic
reduction using Pseudomonas monteilii species and sulfoxidation with chiral titanium complexe, Tetrahedron (2017), http://dx.doi.org/
10.1016/j.tet.2017.07.014

B. Cui et al. / Tetrahedron xxx (2017) 1e7
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7
Appendix A. Supplementary data
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Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2017.07.014.
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