Efficient soluble polymer-supported tartrate/Ti catalyst for asymmetric oxidation of prochiral sulfides

Article abstract of DOI:10.1016/j.tetlet.2007.09.169

A group of soluble polymer-supported chiral tartrate ligands was prepared by liquid-phase synthesis with ligand diversity strategy. Moderate to excellent chemical yields and enantiomeric excesses were obtained by using soluble polymer-supported tartrate ester in asymmetric oxidation of prochiral sulfides using Ti(O-i-Pr)₄/cumyl hydroperoxide, and the workup was greatly simplified. The influence of substituent in chiral tartrate ligands on the enantioselectivities of the reaction was disclosed.

Full text of DOI:10.1016/j.tetlet.2007.09.169

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Tetrahedron Letters 48 (2007) 8453–8455
Efficient soluble polymer-supported tartrate/Ti catalyst
for asymmetric oxidation of prochiral sulfides
Jinshan Gao, Hongchao Guo,* Shangzhong Liu and Min Wang*
College of Science, China Agricultural University, 2 Yuanmingyuan West Road, Beijing 100094, PR China
Received 11 June 2007; revised 25 September 2007; accepted 28 September 2007
Available online 1 October 2007
Abstract—A group of soluble polymer-supported chiral tartrate ligands was prepared by liquid-phase synthesis with ligand diversity
strategy. Moderate to excellent chemical yields and enantiomeric excesses were obtained by using soluble polymer-supported
tartrate ester in asymmetric oxidation of prochiral sulfides using Ti(O-i-Pr)4/cumyl hydroperoxide, and the workup was greatly
simplified. The influence of substituent in chiral tartrate ligands on the enantioselectivities of the reaction was disclosed.
Ó 2007 Elsevier Ltd. All rights reserved.
Optically active sulfoxides are important chiral reagents,
building blocks and pharmaceutical targets.1 As an effi-
cient method for asymmetric synthesis of sulfoxides,
recently chiral metal complexes in combination with
an oxidant have attracted much attention and a variety
of catalytic systems therefore have been developed.2 The
use of chiral complexes involving titanium and tartrate,
first introduced by Modena and Kagan independently, is
one of the most efficient and prominent catalysts for
enantioselective sulfoxidations.2,3
However, there is no report of the immobilization of the
Ti-tartrate ester-based asymmetric sulfoxidation catalyst
using soluble-polymers for catalyst separation and
reuse. Synthetic approaches utilizing soluble polymers
couple the advantages of homogeneous solution chemis-
try such as high reactivity, lack of diffusion phenomena
and ease of analysis with the advantages of solid phase
methods, such as the use of excess of reagents, easy iso-
lation and the purification of products. Therefore, this
approach has been extensively applied in organic syn-
thesis and catalysis in the past 10 years.6 Recently the
synthesis of soluble polymer-supported tartrate esters
and their successful use with [Ti(O-i-Pr)4] and tert-butyl
hydroperoxide (TBHP) as the oxidant in Sharpless
epoxidation with high chemical yield and good to excel-
lent ee had been reported.7 Having interest in the appli-
cation of soluble polymer-supported tartrate esters in
the sulfide oxidations, here we describe the construction
of a library of soluble polymer-bound tartrate ligands
and their use in the asymmetric oxidation of prochiral
sulfide.
Some heterogeneous versions of asymmetric sulfoxida-
tions have also been described. In 2003, Sudalai et al.
developed a heterogeneous catalytic system with WO3
as a catalyst precursor, (DHQD)2-PYR as a ligand
and aqueous hydrogen peroxide as terminal oxidant.4
The catalysis afforded the corresponding oxidation
product with up to 65% ee. WO3 was recovered by sim-
ple filtration and recycled at least five times. In 2005,
Ding et al. described a new strategy with self-supported
concept for the heterogenization of chiral titanium
complexes by the in situ assembly of bridged multitopic
BINOL ligands with [Ti(O-i-Pr)4] without using a sup-
port.5 The assembled heterogeneous titanium catalysts
showed excellent enantioselectivity in the oxidation of
sulfides (up to >99% ee). The catalysts were highly stable
and could be readily recycled and reused for over one
month (at least eight cycles) without significant loss of
activity and enantioselectivity.
In order to increase the loading as much as possible,
polyethylene glycol monomethyl ether (MeOPEGOH,
MW2000) was chosen as soluble support. It possesses
lowest molecular weight in the MeOPEGOHs that are
good solid at room temperature. A small library of
tartrate esters L1–L8 were synthesized from the one-
pot reaction of L-(+)-tartaric acid, MeOPEGOH
(MW2000) and alcohols (ROH) with molar ratio of
MeOPEGOH/ROH = 1:4.25 and acid/(MeOPEGOH +
ROH) = 1:2.10 by the known procedure (Scheme 1).7,8
*
Corresponding authors. Tel.: +86 10 6273 1356; e-mail:
hchguo@gmail.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.169

8454
J. Gao et al. / Tetrahedron Letters 48 (2007) 8453–8455
HO
COOPEGOMe
COOR
HO
HO
COOH
COOH
5% p-TsOH
ROH
MeOPEGOH +
+
toluene, refluxing, 45h
HO
4
L1-L8
1
2
O
O
O
O
HO
HO
HO
HO
HO
OPEGOMe
CH3
OPEGOMe
O CH3
OPEGOMe
O
OPEGOMe
O
O
HO
HO
i-Pr
HO
n-Bu
4
6
O
L2
O
L3
O
L4
O
L1
O
O
O
O
HO
HO
HO
HO
HO
HO
HO
HO
OPEGOMe
O
OPEGOMe
OPEGOMe
OPEGOMe
-Pr
O
Ph
O
n-Pr
O
i
O
O
O
CH3
O
i-Pr
L5
L6
L8
L7
Scheme 1. Synthesis of PEG-supported tartrates.
After the reaction, the solvent toluene was removed by
distillation under reduced pressure; then the resulting
solid was dissolved using a small amount of CH2Cl2.
Diethyl ether was added to the resulting solution to
precipitate tartrate ester under ice-salt cooling, and
tartrate esters were obtained by filtration.
98% ee was achieved with the tartrate ligand L1 pre-
pared from the straight chain alcohols (Table 1, entry
1). Similar ligands L2–L4 also indicated excellent enantio-
selectivity (entries 2, 3 and 8). Although comparing to
the size of PEG monoether group, the effect of another
alkoxyl group, especially the straight chain alkoxyl
groups, on the performance of the ligands should not
be so significant, in fact, it is (entries 2 and 3). When
the catalyst loading was decreased, the enantioselectivity
dramatically went bad (entries 5–7). The steric effects of
R group have big influence on the enantioselectivity of
the oxidation. Ligands L6 and L7 with bulky R substit-
uents in the Ti-catalyzed oxidation reaction gave 8% ee
and 85% ee, respectively (entries 10 and 11). Ligands L8
with aromatic benzyl group could give 88% ee (entry
12). The electronic property of R group appears to have
some influence on the enantioselectivity in the oxidation.
Especially, L5 with another chiral carbon in R group
gave racemic oxidation product in 58% yield (entry 9).
This can be explained by the mechanism proposed by
Kagan.8 In the bimetallic species catalyzed oxidation
reaction, the tartrate acts as a tridentate ligand and
the chiral carbon of ester part may influence the nucleo-
philic attacking direction of sulfide.
With the ligand library mentioned above in hand, brief
screening of the library with eight kinds of MeOPEG-
supported tartrate esters was carried out with the
combination of Ti(O-i-Pr)/L/substrate = 50:200:100 by
Kagan’s procedure9 in the asymmetric oxidation of
methyl phenyl sulfide (Table 1). It was observed that
methyl phenyl sulfide underwent the oxidation with
80% cumyl hydroperoxide (CHP) at À20 °C in the pres-
ence of 50 mol % of L-Ti(IV) complex prepared by
in situ mixing L and Ti(O-i-Pr)4. To our delight, up to
Table 1. Asymmetric oxidation of phenyl methyl sulfide with L/Ti
complex
O
Ti/L, CHP
S
S
Ph
Ph
CH2Cl2, -20 °C, 16h
*
Entry
Ligand
Ti (mol %)
Ti:L
Yielda (%)
eeb (%)
To demonstrate the flexibility of this methodology, the
oxidation of a series of sulfide was studied with Ti/L
complexes under the optimized conditions. The screen-
ing of chiral ligands led us to understand the influence
of R substituent in MeOPEG-supported ligands on the
enantioselectivity. Although L1/Ti and L4/Ti complexes
catalyzed the oxidation of methyl phenyl sulfide to give
the best enantioselectivity (98% ee and 97% ee, respec-
tively) in all catalysts, strangely, both L1/Ti and L4/Ti
complexes showed relative lower enantioselectivity for
other substrates. Finally, we chose ligand L3 to con-
struct the Ti-catalyst. As shown for aryl methyl sulfide
(Table 2, entries 1–7), the oxidation afforded the corre-
sponding chiral products in high yields (62–96%) with
good to excellent enantioselectivities (81–99% ee). Out-
standing selectivity of 99% ee was achieved in the oxida-
tion of p-chlorophenyl methyl sulfide (entry 4). These
1
2
3
4
5
6
7
8
9
L1
L2
L3
L3
L3
L3
L3
L4
L5
L6
L7
L8
50
50
50
50
30
15
10
50
50
50
50
50
1:4
1:4
1:4
1:2
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
63
88
62
52
79
88
90
90
58
54
78
85
98
90
95
39
86
72
59
97
0
10
11
12
8
85
88
a Isolated yield.
b The ees were determined by chiral HPLC analysis using Chiralcel
OD-H (hexane/i-PrOH = 90:10); The absolute configurations were
determined as S by comparison of the HPLC results with the data in
the literature.

J. Gao et al. / Tetrahedron Letters 48 (2007) 8453–8455
8455
Table 2. L3–Ti (IV) catalyzed asymmetric oxidation of prochiral
sulfidesa
synthesis has been extended to the oxidation of prochi-
ral thioethers.
O
Ti(O-i-Pr)4:L3=1:4
S
S
R1
R2
R1
R2
*
Acknowledgement
CHP, CH2Cl2, -20 °C, 16h
Entry
R1
C6H5
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-Br–C6H4
4-NO2
R2
Yieldb (%)
eec (%)
Financial support from the National Natural Science
Foundation of China (Grant No. 20472111) is gratefully
acknowledged.
1
2
3
4
5
6
7
8
9
Me
62
66
77
91
82
70
96
80
78
95d
90d
81d
99e
95f
96f
88d
57d
33d
Me
Me
Me
Me
Me
Me
Et
References and notes
2-Naphthyl
C6H5
C6H5
´
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b Isolated yield.
c Ees were determined by using chiral HPLC analysis. The absolute
configurations were determined as S by comparison of the HPLC
results with the data in the literature.
´
´
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tolerance to the pattern and electronic properties of
the substituent on the phenyl ring of substrates. It
is worth noting that the enantiomeric excesses are in
general compared to the corresponding low molecular
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enantioselectivity than that with methyl (entries 8
and 9).
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principle the soluble polymer-supported ligand might be
reused. Ligand L3 was recycled four times, and the ees
of first recycle to fourth recycle were 95%, 94%, 93%
and 91%, respectively, and the isolated yields remained
at 62–67%. The recovery of catalyst can be carried out
by simple precipitation and filtration. The ligands were
stable and generally the recovery was >97%. During
the work-up, the product can be directly extracted with
diethyl ether after the reaction was quenched, and this
greatly simplifies the isolation of products.
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oethers with cumyl hydroperoxide catalyzed by a soluble
polymer-supported Ti-catalyst provides a simple and
effective procedure for the preparation of chiral sulfox-
ides in good enantiomeric purity. The previous concept
of constructing chiral ligand library by liquid-phase
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