A chemo-enzymatic synthesis of chiral secondary alcohols bearing sulfur-containing functionality

Article abstract of DOI:10.1039/b820192g

A facile method for the preparation of chiral secondary alcohols bearing a sulfur-containing functionality using a chemo-enzymatic approach is described, with the aid of baker's yeast and Candida Antarctica lipase B. A complete set of four stereoisomers o

Full text of DOI:10.1039/b820192g

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LETTER
www.rsc.org/njc | New Journal of Chemistry
A chemo-enzymatic synthesis of chiral secondary alcohols bearing
sulfur-containing functionalityw
Qihui Chen, Ke Wang and Chengye Yuan*
Received (in Montpellier, France) 12th November 2008, Accepted 17th December 2008
First published as an Advance Article on the web 12th January 2009
DOI: 10.1039/b820192g
A facile method for the preparation of chiral secondary alcohols
bearing a sulfur-containing functionality using a chemo-enzymatic
approach is described, with the aid of baker’s yeast and Candida
Antarctica lipase B. A complete set of four stereoisomers of two
substituted phenylsulfinylpropan-2-ols were synthesized from
b-sulfinyl ketones with excellent enantioselectivity for the
first time.
yeast. After trials, we found that 1 g of baker’s yeast was most
effective in a mixture of 10 mL diisopropyl ether and 0.7 mL
water. (S)-Phenylsulfonylpropan-2-ol was obtained in 99%
yield and 99% ee in 4 h (Scheme 1).
There have been reports concerning the baker’s yeast-
mediated reduction of 1-(phenylsulfonyl)propan-2-one in an
aqueous system.2a–c The best result was obtained by using 6 g
yeast per mmol substrate;2a while in our system, only 1 g yeast
per mmol substrate was utilized, and the time for such a
biotransformation was significantly shortened (Table 1). It is
worth noting that the work-up was greatly simplified by
avoiding a tedious extraction.
In recent years, a variety of sulfur-containing chiral alcohols
have been utilized as key chiral synthons in asymmetric
synthesis.1 Many transformations have been used in their
preparation by employing whole-cell biocatalysts,2 enzymatic
transformations3 and transition metal catalysis.4 However, the
drawbacks of these reactions are also obvious. For bioreduction
in water, a relatively large volume of water is required as the
solvent, which makes the work-up procedure more difficult,
particularly since the product is difficult to isolate from the
huge amounts of biomass.2 For enzymatic kinetic resolution
(KR), as a rule, no more than a 50% yield of the enantiomer
needed can be obtained.3a,b Using transition metal complexes
needs harsh conditions4a,c–e and expensive reagents,4 or is less
effective.4b Furthermore, because b-hydroxysulfoxides bear
two chiral centers, four stereoisomers are thus expected.
Unfortunately, none of the reported methods provide all of
four stereoisomers of b-hydroxysulfoxides simultaneously
with excellent enantioselectivity.2,3c,d Herein, we wish to
report an alternative and convenient biotransformation
system. With the aid of this system, both b-hydroxysulfones
and b-hydroxysulfides were synthesized in medium-to-high
yields and excellent enantioselectivities. Moreover, four
stereoisomers of substituted phenylsulfinylpropan-2-ols were
prepared with excellent enantioselectivities with the aid of
Candida Antarctica lipase B (CALB).
Recently, several protocols for the preparation of other
chiral b-hydroxysulfones via enantioselective reduction have
been documented (Scheme 2).2f,4d,e However, as shown in
Table 2, as a non-popular enzyme, P. minuta IAM 12215 is
not easily available. Furthermore, this bioreduction system
also suffers from the same intrinsic limitations of biotransfor-
mations in water. Nevertheless, enantioselective reductions
catalyzed by transition metals such as Rh and Ru are highly
efficient. However, expensive chiral metallic catalysts and
harsh operating conditions for the removal of water and
oxygen are usually required. Besides these operations with
hydrogen under pressure are also inconvenient.
To further study the scope of this diisopropyl ether/limited
water system, a variety of sulfur-containing ketones were
prepared, as shown in Scheme 3. Various sulfur-containing
ketones were reduced enantioselectively by baker’s yeast in
this system.
As shown in Table 3, when R2 was methyl, all the sulfur-
containing alcohols were obtained with excellent enantio-
selectivity. Electronic effects do not seem to have any significant
influence on the enantioselectivity of the products. When R2
was methyl, substituted phenylsulfonylpropan-2-ols were
obtained in medium-to-high yield with excellent enantio-
selectivities, except for 1d; this is probably due to the poor
solubility of 1d in diisopropyl ether (Table 3, entries 1–5). With
the increasing steric hindrance of R2, both the yield and ee
dropped (Table 3, entries 6–7). When phenyl deactivated the
carbonyl group, the reaction was blocked (Table 3, entry 8).
Due to the intrinsic limitations of biotransformations
undertaken in water, a variety of organic solvents, such as
benzene, petroleum ether, toluene and carbon tetrachloride,
were used to replace water in yeast-catalyzed reactions.5
Diisopropyl ether, as a substitute for water, worked well with
enzymes in our previous studies.6 Herein, we investigated
whether it could be used as an appropriate organic solvent
for the bioreduction of sulfur-containing ketones by baker’s
State Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Feng-Lin Lu, Shanghai 200032, China.
E-mail: yuancy@mail.sioc.ac.cn; Fax: +86 21-5492-5379
w Electronic supplementary information (ESI) available: Experimental
procedures and data, and other material. See DOI: 10.1039/b820192g
Scheme 1 The bioreduction of b-ketosulfones by baker’s yeast.
ꢀc
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Table 1 The bioreduction of 1-(phenylsulfonyl)propan-2-one
Entry
Solvent
Yeast/g mmolꢁ1
Reaction time/h
Yield (%)
ee (%)
1a
2b
iPr2O
H2O
1
6
4
24
99
99
99
495
a
b
1 g baker’s yeast, 10 mL diisopropyl ether and 0.7 mL water with 1 mmol substrate. 6 g baker’s yeast and 6 g sucrose in 18 mL water with
1 mmol substrate.2a
Scheme 2 Transformations for the preparation of chiral b-hydroxy-
sulfones.
Scheme
3 The enantioselective reduction of sulfur-containing
ketones.
specific rotations and 1H NMR spectra with the literature,z in
addition to HPLC with a chiral column.y Compared with
other reported methods,2b–e,3c,d our strategy is of unique
significance since, for the first time, the four stereoisomers of
two b-hydroxysulfoxides could be prepared simultaneously
with excellent enantioselectivities by using commercial available
reagents, rather than expensive or uncommon materials, or
special skills in biology.2c–e
Enantiopure b-hydroxysulfides serve as synthons in asymmetric
synthesis.1 For substituted phenylthiopropan-2-ones, the
baker’s yeast in diisopropyl ether system also works well
(Table 3, entries 9, 11–15) as smaller amounts of substrates
can be reduced, and longer reaction times are required because
of the poor electron-withdrawing ability of the phenylthio
group. It has been reported that in an aqueous system, the
baker’s yeast-mediated reduction of phenylthiopropan-2-one
(1i) occurs in only a 35% yield at low concentrations (Table 3,
entry 10).2b
Compared with bioreductions in water,2a–d,f our biotrans-
formation system has advantages. The procedure is easily
undertaken, the product can be isolated efficiently and the
reaction time is shorter. In addition, the biotransformation
system can also be applied to larger reaction scales. What’s
more, the system developed by us is more atom-economical
than the KR system (for KR, the yield is r50 %).3a,b Besides
this, the method is economical and can be carried out under
very mild conditions relative to transformations catalyzed by
transition metal complexes.4
In summary, chiral b-hydroxysulfones and b-hydroxysulfides
were prepared using baker’s yeast in a diisopropyl ether/
limited water solvent system with medium-to-high yields and
excellent enantioselectivities. By combined this biotransformation
system with CALB, a complete set of four stereoisomers
of two substituted phenylsulfinylpropan-2-ols was prepared
simultaneously for the first time with highly efficiency.
Experimental
General procedure for the bioreduction of sulfur-containing
alcohols using baker’s yeast in a diisopropyl ether/limited
water solvent system
In recent years, many transformations for the preparation
of chiral b-hydroxysulfoxides have been introduced; however,
not all of the stereoisomers of b-hydroxysulfoxides can be
obtained by one single method.2,3c,d Herein, we wish to report
a novel method for the preparation of the four stereoisomers
of b-hydroxysulfoxides based on a combination of baker’s
yeast and CALB with excellent enantioselectivities (Scheme 4).
As shown in Table 4, the four stereoisomers of two
b-hydroxysulfoxides have been prepared by combining our
biotransformation system with CALB, with excellent enantio-
selectivities and high syn/anti ratios. The absolute configuration
of each stereoisomer was determined by comparisons of their
To a 25 mL round-bottomed flask equipped with a magnetic
stirring bar was added 1 g baker’s yeast, 10 mL diisopropyl
ether and 0.7 mL water. The solution was stirred for
5 min, after which time each b-keto sulfone (1a) (198 mg,
1 mmol) was added. The mixture was stirred at 30 1C
and monitored by TLC. 4 h later, the mixture was filtered,
the filtrate removed under reduced pressure and the
residue subjected to flash chromatography over silica gel
(petroleum : EtOAc = 1 : 1) to afford a colourless oil (2a)
(198 mg, yield: 99%, ee: 99%).
Table 2 Comparison of literature data related to the catalytic transformations leading to chiral b-hydroxysulfones
Entry
Solvent (1 mmol)
Catalyst (1 mmol)
Reaction time/h
Yield (%)
ee (%)
1
2
3
113 mL H2O
4 mL EtOH
4 mL PrOH
2 g P. minuta IAM 12215
0.25% Ru*Cl2/(H2)
1% Rh*SbF6/(H2)
28
20
24
92a
100b
99b
97
99
95
i
a
b
(a) Isolated yield. (b) Conversion. For more detailed information, please refer to 2f, 4d and e.
ꢀc
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Table 3 The enantioselective reduction of sulfur-containing ketones
Substrates
Products
R1
R2
Yield (%)a
ee (%)b
Entry
Reaction time/h
Configurationc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1b
1c
1d
1e
1f
C6H5SO2
CH3
CH3
CH3
CH3
CH3
C2H5
C3H7
C6H5
CH3
–CH3
CH3
CH3
CH3
CH3
CH3
4
5
5
4
4
10
17
20d
12
24
12
12
18
22
17
2a
2b
2c
2d
2e
2f
2g
2h
2i
2i
2j
2k
2l
2m
2n
99f
95
85
47
77
91
74
99
99
99
96
99
92
70
—
95
—
99
99
98
96
97
S
S
S
S
S
S
S
—
S
—
S
S
S
S
S
4-CH3C6H4SO2
4-CH3OC6H4SO2
4-NO2C6H4SO2
4-ClC6H4SO2
C6H5SO2
C6H5SO2
C6H5SO2
C6H5S
C6H5S
4-CH3C6H4S
4-CH3OC6H4S
4-ClC6H4S
4-NO2C6H4S
4-BrC6H4S
1g
1h
1i
—
97e
35
1ig
1j
96e
86e
67e
92e
73e
1k
1l
1m
1n
a
b
Isolated yield. Determined by HPLC with a chiral column. Determined by comparison with the optical rotation of known compounds.
c
d
e
f
No reaction. 1 g baker’s yeast can only catalyze 0.2–0.3 mmol b-ketosulfides, which is also indicated in the Experimental section. When the
amount of 1a was increased up to 10 mmol, the reaction also proceeded successfully. 0.5 g 1i in 600 mL baker’s yeast suspension (water).2b
g
Scheme 4 Preparation of the four stereoisomers of substituted phenylsulfinylpropan-2-ols. Reagents and reaction conditions: (a) Baker’s
yeast/iPr2O/limited water. (b) Triacetoxyperiodinane/CH2Cl2. (c) NaBH4/MeOH. (d) CALB, CH3COOCHCH2/iPr2O. (e) BF3ꢂEt2O/MeOH,
reflux.
General procedure for the preparation of the four stereoisomers
of substituted phenylsulfinylpropan-2-ols
(420 mg, 2.3 mmol) was added. The mixture was stirred at
30 1C and the reaction monitored by TLC. 80 min later, the
mixture was filtered, the solvent removed under reduced
pressure and the residue subjected to flash chromatography
over silica gel (petroleum : EtOAc = 1 : 1 B 1 : 2) to afford the
desired products (SS)-phenylsulfinylpropan-2-one (4a) and
To a 25 mL round-bottomed flask equipped with a magnetic
stirring bar was added 3 g baker’s yeast, 30 mL diisopropyl
ether and 2.1 mL water. The solution was stirred for
5 min, after which time phenylsulfinylpropan-2-one (3a)
ꢀc
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Table 4 Preparation of the four stereoisomers of substituted phenyl-
sulfinylpropan-2-ols
1 (a) K. Tanaka, K. Ootake, K. Imai, N. Tanaka and A. Kaji, Chem.
Lett., 1983, 12, 633; (b) G. Solladie, C. Frechou, G. Demailly and
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(e) R. Sanchez-Obregon, B. Ortiz, F. Walls, F. Yuste and J. L.
G. Ruano, Tetrahedron: Asymmetry, 1999, 10, 947; (f) L. D. Nunno,
C. Franchini, A. Nacci, A. Scilimati and M. S. Sinicropi,
Tetrahedron: Asymmetry, 1999, 10, 1913; (g) M. Gruttadauria,
P. Meo and R. Noto, Tetrahedron, 1999, 55, 14097;
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M. Ishiguro, J. Chem. Soc., Chem. Commun., 1991, 662;
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2000, 41, 4189; (k) T. Naka, N. Minakawa, D. Kaga and
A. Matsuda, J. Am. Chem. Soc., 2000, 122, 7233; (l) S. Raghavan,
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Product
ee (%)a syn/antia
(SS,SC)-Phenylsulfinylpropan-2-ol (9a)
(SS,RC)-Phenylsulfinylpropan-2-ol (10a)
(RS,SC)-Phenylsulfinylpropan-2-ol (13a)
(RS,RC)-Phenylsulfinylpropan-2-ol (14a)
(SS,SC)-4-Chlorophenylsulfinylpropan-2-ol (9b)
(SS,RC)-4-Chlorophenylsulfinylpropan-2-ol (10b) 499
(RS,SC)-4-Chlorophenylsulfinylpropan-2-ol (13b)
(RS,RC)-4-chlorophenylsulfinylpropan-2-ol (14b)
499
99
99
499
499
26 : 1
1 : 38
1 : 29
12 : 1
53 : 1
1 : 19
1 : 8915
12 : 1
93
98
a
The ee values and syn/anti ratios of 9a–14a were determined by
HPLC (WATERS) using a chiral column. The four stereoisomers of
racemic phenylsulfinylpropan-2-ol were distinguished by HPLC (using
a
CHIRALPAK OD column, hexane : = 90 : 10,
iPrOH
0.7 mL minꢁ1; retention times: 14.02, 18.14, 21.18 and 24.57 min).
The ee values and syn/anti ratios of 9b–14b were determined by HPLC
(WATERS) using a chiral column. The four stereoisomers of racemic
4-chlorophenylsulfinylpropan-2-ol were distinguished by HPLC (using
2 (a) S. Robin, F. Huet, A. Fauve and H. Veschambre, Tetrahedron:
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17, 3358.
a CHIRALPAK OJ column, hexane : iPrOH = 98 : 2, 0.7 mL minꢁ1
retention times: 38.03, 43.24, 61.90 and 71.51 min).
;
(RS,SC)-phenylsulfinylpropan-2-ol (5a), respectively. Oxidation
by triacetoxyperiodinane of compound (5a) gave (RS)-phenyl-
sufinylpropan-2-one (6a).
3 (a) R. Chinchilla, C. Najera, J. Pardo and M. Yus, Tetrahedron:
Asymmetry, 1990, 1, 575; (b) U. Goergens and M. P. Schneider,
J. Chem. Soc., Chem. Commun., 1991, 1064; (c) S. Singh, S. Kumar
and S. S. Chimni, Tetrahedron: Asymmetry, 2001, 12, 2457;
(d) M. Medio-Simon, J. Gil, P. Aleman, T. Varea and G. Asensio,
Tetrahedron: Asymmetry, 1999, 10, 561.
(SS)-Phenylsulfinylpropan-2-ol (7a) was obtained by reducing
(SS)-phenylsulfinylpropan-2-one (4a) with NaBH4. The
CALB-catalyzed kinetic resolution of 7a afforded acetate 8a
and (SS,SC)-phenylsulfinylpropan-2-ol (9a) (general procedure
for the kinetic resolution of phenylsulfinylpropan-2-ol: 100 mg
CALB, 5 mL iPr2O and 1 mL CH3COOCHCH2 were used for
1 mmol substrate; 24 h later, acetate 8a and alcohol 9a were
obtained). The transesterification of 8a catalyzed by BF3ꢂEt2O
in methanol afforded (SS,RC)-phenylsulfinylpropan-2-ol
(10a). Similarly, (RS,SC)-phenylsulfinylpropan-2-ol (13a) and
(RS,RC)-phenylsulfinylpropan-2-ol (14a) were prepared.
This project was supported by the Chinese Academy of
Sciences and the National Natural Science Foundation of
China (Grant nos. 20672132 and 20872165).
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z A clear distinction between the two diastereomers could be observed
from their 1H NMR spectra (see ref. 3c); the methyl protons in 9a
resonate at d 1.33, and in case of 10a at d 1.27. Therefore, 9a was
(SS,SC)-phenylsulfinylpropan-2-ol and 10a was (SS,RC)-phenylsulfinyl-
propan-2-ol. The specific rotation of 9a was ꢁ2481 (c 1.00 in
CHCl3), while the specific rotation of 10a was +3171 (c 0.60 in
CHCl3), which also proved to be the absolute configuration
of 9a and 10a. In the same way, the other two stereoisomers of
phenylsulfinylpropan-2-ol also could be distinguished.
y The retention time of each stereoisomer synthesized by the above
method was in accordance with the value for the stereosiomer
prepared by known methods.
ꢀc
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