Enantioselective ring-opening reaction of meso-epoxides with ArSH catalyzed by heterobimetallic Ti-Ga-Salen system

Article abstract of DOI:10.1016/j.tetlet.2008.11.060

The enantioselective ring-opening reaction of meso-epoxides with aryl thiols catalyzed by a chiral heterobimetallic Ti-Ga-Salen complex was realized, and the 1,2-mercapto alcohols were obtained in good yields and moderate to high enantioselectivities (up

Full text of DOI:10.1016/j.tetlet.2008.11.060

Tetrahedron Letters 50 (2009) 548–551
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Enantioselective ring-opening reaction of meso-epoxides with ArSH catalyzed
by heterobimetallic Ti–Ga–Salen system
Jiangtao Sun a, Fang Yuan a,b, Minghua Yang a, Yi Pan a, Chengjian Zhu a,c,
*
a School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210093, PR China
b Enzmed (Nanjing) Co., Ltd, Nanjing 210046, PR China
c State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective ring-opening reaction of meso-epoxides with aryl thiols catalyzed by a chiral hetero-
bimetallic Ti–Ga–Salen complex was realized, and the 1,2-mercapto alcohols were obtained in good
yields and moderate to high enantioselectivities (up to 92% ee). A strong synergistic cooperation between
different Lewis acids in the system was exhibited in the catalytic process.
Received 16 September 2008
Revised 14 November 2008
Accepted 18 November 2008
Available online 21 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
Epoxides
Thiols
Ring-opening
Enantioselectivity
The enantioselective desymmetrization of meso-epoxides with
nucleophiles has proven to be a valuable tool for the straightfor-
ward synthesis of enantiomerically highly enriched 1,2-difunction-
alized organic compounds.1 In general, nucleophiles such as RNH2,2
tion of a mixed complex which exhibited high catalytic properties
derived from both homometallic species.9 Moreover, since the suc-
cessful application of the first heterometallic multifunctional cata-
lyst in the asymmetric Michael reaction,8a Shibasaki et al. have
developed various hetero- or homo- bimetallic complexes, such as
La–Li–Pybox, Pd–La–Schiff base, Cu–Sm–Schiff base, and Ni2–Schiff
base in various reactions with excellent enantioselectivities.10
Recently, we reported a highly enantioselective desymmetriza-
tion of meso-epoxides by aryl selenols using a heterometallic Ti–
Ga–Salen complex as catalyst11 in which the catalyst displayed
excellent reactivity and enantioselectivity. Herein, we wish to re-
port the enantioselective ring-opening reaction of meso-epoxides
with aryl thiols catalyzed by the heterobimetallic Ti–Ga–Salen
complex.
The catalysts were synthesized straightforward as shown in
Scheme 1. The commercially available Salen compounds (R,R)-1
were selected as the requisite ligands. Treatment of 1 with 1 equiv
of GaMe3 provided monometallic complexes 2 in high yields.12
Reactions of 2 with another equivalent of Ti(OiPr)4 gave the hetero-
bimetallic complexes 3, which were directly used in the reactions.
Using hexane as solvent, we initially tested the ring-opening of
cyclohexene oxide with thiophenol at 0 °C catalyzed by the
in situ prepared complex 3a or 3b. To our delight, the reaction gave
the b-hydroxy sulfide in 76% ee and 96% chemical yield when 3b
was used, while 62% ee was obtained with 3a (entries 1 and 2).
Utilizing 3b as catalyst, the reaction conditions were then
optimized, and the results are summarized in Table 1. Among the
5
ROH,3 TMSCN,4 and RN3 have been widely investigated in the
reaction catalyzed by various chiral catalysts.6 However, since
the first useful example reported by Yamashida and Mukaiyama
using zinc tartrate as catalyst,7a only a few practical methods have
been realized using thiols as nucleophiles so far.7 In 1997, Shibasa-
ki and co-workers developed a heterobimetallic Ga–Li–BINOL
(GaLB) complex as highly efficient catalyst for this reaction.7b
Hou and co-workers reported the use of Ti–Salen complex with
moderate enantioselectivities.7c Recently, Kobayashi and co-work-
ers7d,e and Schneider and co-workers7f reported their investiga-
tions independently using Scandium-bipyridine and Indium-
bipyridine as highly enantioselective catalysts in the ring-opening
reaction with excellent results. Although the asymmetric thiolysis
of aromatic meso-epoxides gave excellent enantioselectivities in
several reports, however, the aliphatic meso-epoxides afforded
unsatisfied results except the utilization of GaLB complex.7b
The design and use of bimetallic complexes for asymmetric
catalysis have seen significant progress and are emerging as a rap-
idly developing area.8 For example, Belcokon et al. showed that a
mixture of two chiral VV and TiIV complexes resulted in the forma-
* Corresponding author. Tel.: +86 25 83594886; fax: +86 25 83317761.
E-mail address: cjzhu@nju.edu.cn (C. Zhu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.060

J. Sun et al. / Tetrahedron Letters 50 (2009) 548–551
549
N
N
O
c
Me2Ga
O
t-Bu
t-Bu
GaMe2
t-Bu
t-Bu
5
N
N
N
N
a
R
O
HO
R
R
OH HO
R
GaMe2
R
R
R
R
1a R = H
1b R = t-Bu
2a R = H
2b R = t-Bu
d
b
N
N
N
O
N
(
i-PrO)3Ti
Ti
R
O
GaMe2
O
R
t-Bu
O
-Pr)2
t-Bu
(Oi
R
R
t-Bu
t-Bu
3a R = H
3b R = t-Bu
4
Scheme 1. Reagents and conditions: (a) GaMe3, hexane, 0 °C, 1 h. (b) Ti(OiPr)4, hexane, 25 °C, 1 h. (c) GaMe3 (2.1 equiv), toluene, 80 °C to reflux, 2 h. (d) Ti(OiPr)4 (1 equiv),
hexane, 0 °C, 1 h.
solvents investigated, hexane was proved to be the best one in
terms of the reactivity and enantioselectivity. A variation of the
reaction temperature from 0 to À20 °C caused a significant in-
crease in the ee value (entry 6), but a slight decrease was observed
when the reaction was carried out at À40 °C (entry 9). Further
investigation showed that there was no significant change when
the amount of 3b was decreased to 5 mol % (entry 10). The reaction
still showed good results even with only 2 mol % catalyst loading
(entry 11). For comparison, titanium complex 47c and homobime-
tallic gallium complex 512 were also examined. However, complex
5 gave poor asymmetric induction (entry 8), while the cyclic tita-
nium complex 4, as reported by Hou et al., provided moderate
enantioselectivity (entry 7).7c Those results demonstrated that
the Ti–Ga–Salen heterobimetallic catalyst was very efficient and
showed significant margins over other catalysts.
Next, the asymmetric ring-opening of a variety of meso-epox-
ides with thiophenol, 4-methyl thiophenol, and 4-chloro thiophe-
nol were investigated under the optimized reaction conditions.13
As shown in Table 2, it can be found that most of the reactions pro-
ceeded smoothly to furnish the b-hydroxy sulfides in high yields
and moderate to high enantiomeric excesses (65–92% ee) except
8j. We also found that cyclic meso-epoxides displayed better asym-
metric induction than acyclic ones under the same conditions.
Unfortunately, for more sterically hindered epoxides 6e and 6f,
the results are far from satisfying (entries 9 and 10). On the other
hand, the para-chloro or -methyl substituted thiophenol gave bet-
ter results than thiophenol in terms of reactivity and selectivity. It
is also worth noting that the results represent a considerable
improvement comparable to the results of the reaction catalyzed
by complex 4.7c
Table 1
Asymmetric ring-opening reactions of cyclohexene oxide with thiolphenola
OH
catalyst
+
PhSH
O
SPh
Entry
Catalyst
Solvent
T (°C)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
3a
3b
3b
3b
3b
3b
4
Hexane
Hexane
Toluene
Et2O
CH2Cl2
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
0
0
0
0
1
1
1
1
1
1
4
4
1
1
1
93
96
93
92
90
96
93
72
93
95
88
62
76
70
63
45
87
63
22
86
87
86
0
À20
À20 to 40
À20
À40
À20
À20
5
3b
3b
3b
10d
11e
a
Unless otherwise noted, the reaction condition: cyclohexene oxide (1 mmol),
PhSH (1.2 mmol), catalyst (10 mol %).
b
Isolated yields.
c
Determined by HPLC with a Daicel Chiralcel OD column. Absolute configura-
tions of the major enantiomers (1S,2S) were assigned by comparison of the rotation
values in the literature.
d
5 mol % of 3b.
2 mol % of 3b
e

550
J. Sun et al. / Tetrahedron Letters 50 (2009) 548–551
As mentioned in Shibasaki’s report,7b the heterobimetallic cata-
Table 2
Asymmetric thiolysis of meso-epoxides catalyzed by 3ba
lyst GaLB appears to act as multifunctional catalyst, with a lithium
binaphthoxide moiety functioning as a Brønsted base, activating
thiol and a gallium metal function as a Lewis acid, activating and
also controlling the orientation of epoxide, as a result high asym-
metric induction was realized. In our case, the current catalyst sys-
tem has two Lewis acid centers to activate both the epoxides and
the thiols, or to control the orientation of epoxides and the nucle-
ophiles, respectively. Considering the lower asymmetric induction
of Ti–Salen (4) and Ga–Salen (5), it is most likely that the high cat-
alytic activity of Ti–Ga–3b can be accounted for the two different
Lewis acids should work complementally in the catalytic system.
Also, 1H NMR study showed that the chemical shifts of the dimeth-
ylgallium hydrogens of complex 3b appear at a higher field (d
À0.25 and À0.36 ppm) in comparison with those of complex 2b
(d À0.22 and À0.31 ppm), which may be due to the coordination
of the oxygen in the isopropoxyl group to the gallium, as a result
the change of bond angle between the Lewis acids and the sub-
strates is probably the crucial factor.
In summary, we developed a highly enantioselective ring-
opening reaction of meso-epoxides with aryl thiols using a hetero-
bimetallic Ti–Ga–Salen complex as catalyst, which furnishes
1,2-mercapto alcohols in good yields (up to 97%) and high enantio-
meric excesses (up to 92% ee). Both Ti and Ga metals were essential
to realize high enantioselectivity. Further mechanistic studies as
well as applications of this Ti–Ga heterobimetallic catalyst to other
reactions are in progress.
R
R
OH
R
catalyst 3b
+
ArSH
O
SPh
R
8a-m
6a-e
7a-c
Entry
1
Epoxide
Ar
Ph
Product
Yieldb (%)
eec (%)
O
8a
95
84
87
92
71
82
6a
6a
O
O
O
O
2
3
4
5
4-Me–Ph
4-Cl–Ph
Ph
8b
8c
8d
8e
95
97
96
95
6a
6b
4-Me–Ph
Acknowledgments
6b
We gratefully acknowledge the National Natural Science Foun-
dation of China (20672053, 20832001) and the National Basic Re-
search Program of China (2007CB925103) for their financial
support. The Program for New Century Excellent Talents in the
University of China (NCET-06-0425) is also acknowledged.
Ph
O
6
7
Ph
8f
91
95
90
83
23
50
74
84
85
65
53
80
Ph
6c
Ph
References and notes
O
O
4-Me–Ph
4-Cl–Ph
Ph
8g
8h
8i
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8j
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6e
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11d
Ph
8k
6f
a
Reaction conditions: epoxide (1.0 mmol), ArSH (1.2 mmol), catalyst (5 mol %),
hexane (3 mL), À20 °C, 1 h.
b
Isolated yields.
c
Determined by HPLC with a Daicel Chiralcel OD column. Absolute configura-
tions of the major enantiomers (1S,2S) were assigned by comparison of the rotation
values in the literature or by analogy.
d
Reaction was conducted at 0 °C for 24 h.

J. Sun et al. / Tetrahedron Letters 50 (2009) 548–551
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13. General procedure for the ring-opening of the meso-epoxides by aromatic thiols:
GaMe3 (0.05 mmol, 0.5 M in hexane) was added dropwise to 3 mL of hexane
solution of ligand (R,R)-3b (28 mg, 0.05 mmol) under argon at 0 °C. After the
solution was stirred for 1 h at room temperature,
a
solution of Ti(OiPr)4
(0.05 mmol, 0.2 M in hexane) was then added and stirred for another 1 h to
form the Ti–Ga–3b complex. The resultant yellow solution was cooled to
À20 °C. The epoxide (1.0 mmol) and thiol (1.2 mmol) were added successively.
The mixture was stirred for 1 h at the same temperature before being
quenched with a saturated NH4Cl solution and extracted with ether. The
organic phase was dried over anhydrous sodium sulfate, and the solvent was
removed. After being separated by preparative silica gel TLC, the b-hydroxy
sulfide was obtained and the ee value was determined by chiral HPLC with a
Daicel Chiralcel OD column.