Chiral scandium-catalyzed highly stereoselective ring-opening of meso-epoxides with thiols

Article abstract of DOI:10.1246/cl.2007.34

The desymmetrization of meso-epoxides with thiols proceeded smoothly in dichloromethane or dichloroethane in the presence of a catalytic amount of a chiral scandium complex consisting of Sc(OTf)₃ and chiral bipyridine 1, to afford the correspon

Full text of DOI:10.1246/cl.2007.34

3
4
Chemistry Letters Vol.36, No.1 (2007)
Chiral Scandium-catalyzed Highly Stereoselective Ring-opening
of meso-Epoxides with Thiols
Ã
Chikako Ogawa, Naiwei Wang, and Sh u¯ Kobayashi
Graduate School of Pharmaceutical Sciences, The University of Tokyo, The HFRE Division, ERATO,
Japan Science and Technology Agency (JST), Hongo, Bunkyo-ku, Tokyo 113-0033
(Received October 11, 2006; CL-061195; E-mail: skobayas@mol.f.u-tokyo.ac.jp)
The desymmetrization of meso-epoxides with thiols pro-
Table 1. Optimization of reaction conditions
ceeded smoothly in dichloromethane or dichloroethane in the
presence of a catalytic amount of a chiral scandium complex
consisting of Sc(OTf)3 and chiral bipyridine 1, to afford the cor-
responding sulfides in high yields with high enantioselectivities.
Ligand 1
Ph
Ph
Ph
OH
Sc(OTf)3
t
O
+
4- BuC H SH
6 4
DCM or DCEa
t
Ph
S-4- BuC6H4
(x equiv.)
2
Entry
X
Sc/Lig Time/h Temp/°C Conc/M Yield/% ee/%
1
2
3
4
5
1.5 10/12
7
7
rt
rt
0.2
0.2
0.2
0.4
0.4
42
74
87
78
84
92
94
95
92
93
The ring-opening desymmetrization of meso-epoxides with
nucleophiles provides a powerful and efficient strategy for con-
structing two contiguous stereogenic centers in a single event. In
general, the reactions proceed under Lewis acidic conditions,
and combinations of chiral Lewis acids and nucleophiles such
3
3
10/12
10/12
12
7
rt
1.5 10/12
1.5
5/6
40
40
7
1
as amines and alcohols have been investigated. However, the
use of thiols as nucleophiles is still relatively unexplored and
a
DCM (dichloromethane) at rt and DCE (dichloroethane) at
40 C.
ꢀ
2
only a few examples have been reported. Recently, we have
be noted that no desired product was obtained when Sc(OTf)3
9
developed a novel chiral scandium complex prepared from
Sc(OTf)3 and chiral bipyridine 1, that catalyzes enantioselective
hydroxymethylation reactions of silicon enolates using an aque-
was used alone as a catalyst under the conditions (without 1).
ꢀ
On the other hand, when the reaction was carried out at 40 C
in dichloroethane (DCE), the same levels of yield and enantiose-
lectivity were obtained even using a slight excess of the thiol
3
ous formaldehyde solution. We also reported that a chiral scan-
dium complex prepared from Sc(OSO3C12H25)3 (Sc(DS)3) and 1
was effective for ring-opening reactions of meso-epoxides in
water with aromatic amines, aromatic N-heterocycles, and an
alcohol.4 Interestingly, some thiols also worked well using
(
(
1.5 equiv.) and a smaller amount of the chiral scandium catalyst
Entries 4 and 5). It is noteworthy that the use of 5 mol % of
,5
the catalyst also gave the desired product in high yield with
excellent enantioselectivity (Entry 5).
5
Sc(DS)3 and 1 in water (Scheme 1). As an extension of this
Several meso-epoxides and thiols were then subjected to this
system (Table 2). Benzenethiols having electron-donating and
electron-withdrawing groups worked well in the reaction in the
presence of 10 mol % of Sc(OTf)3-1 to afford the corresponding
sulfides in high yields and with excellent enantioselectivities
work, we further investigated the desymmetrization of meso-
epoxides by ring opening with thiols, and found that efficient
reactions also proceeded not only in water but also in organic
solvents. In this paper, we report the highly enantioselective
ring-opening of meso-epoxides with thiols catalyzed by a chiral
scandium complex.6
(
Entries 1–4). In particular, cis-stilbene oxide (2) reacted with
-chlorobenzenethiol to provide the desired product in 97% ee
Entry 4). The absolute configuration of the product in Entry 3
was determined after oxidizing to the corresponding sulfone
compared the optical rotation of the sulfone with that in litera-
4
(
First, we selected the reaction of cis-stilbene oxide (2) with
-t-butylbenzenethiol as a model, and several reaction condi-
4
tions were examined (Table 1). The reaction proceeded in mod-
erate yield with high enantioselectivity in dichloromethane
(
1
0
ture). Furthermore, not only reactions using benzenethiols pro-
ceeded smoothly but those involving less reactive alkyl thiols
(
(
DCM) at room temperature in the presence of Sc(OTf)3
8
7
10 mol %) and chiral bipyridine 1 (12 mol %) (Entry 1). The
(
Entry 5) also worked well to give the desired adducts in good
yield was improved without loss of enantioselectivity using an
excess amount of the thiol (3.0 equiv., Entries 2 and 3). It should
yields with excellent enantiomeric excesses. As for the scope
of the meso-epoxide, other cis-stilbene oxide derivatives also re-
acted well to give the corresponding sulfides in good to high
yields with excellent enantioselectivities (Entries 6–8). In the re-
action of cis-stilbene oxide derivative 3 with 4-t-butylbenzene-
thiol, epoxide 3 was consumed after 4 h at room temperature,
however some side reactions occurred with the result that the
yield of the desired sulfide was decreased (Entry 6). Notably
however, the reaction of cis-stilbene oxide derivative 4 with 4-
t-butylbenzenethiol proceeded relatively slowly but without side
reactions at room temperature, to afford the desired product in
high yield with excellent enantiomeric excess (Entry 8). While
the reactions proceeded smoothly at room temperature in most
Sc(DS)3 (5—10 mol %)
N
N
tBu
tBu
OH
HO
R
R
R
R
OH
Nu
1
(6—12 mol %)
O
NuH
H O, rt
2
3
4—85% y
NuH: indole, benzotriazole, alcohol, thiol
85—96% ee
Scheme 1. Sc-catalyzed desymmetrization of meso-epoxides in
water.
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.1 (2007)
35
Table 2. Ring-opening of meso-epoxides with thiols
complex. The scandium complex consisting of Sc(OTf)3 and
chiral bipyridine 1, that was recently shown as an efficient
catalyst in asymmetric hydroxymethylation using an aqueous
formaldehyde solution, was also found to be effective in this
asymmetric reaction, and various sulfides were obtained in high
yields with high enantioselectivities. Recently, we have also
reported desymmetrizative ring-opening of meso-epoxides with
thiols in water using Sc(DS)3 and chiral bipyridine 1 as a cata-
Ligand 1 (12 mol %)
R1
R1
R1
OH
Sc(OTf) (10 mol %)
3
2
+
R SH
O
R1
DCM, rt, time
SR2
(3 equiv.)
Entry
Epoxide
Ph
R2
Time/h Yield/% ee/%
1
2
3
4
5
6
7
8
9
O 2
4-t-BuC H
12
12
12
12
12
4
87
79
84
76
68
95
95
6
4
5
lyst. Compared with these reactions, while the present reactions
Ph
in an organic solvent gave the same levels of yields and enantio-
selectivities, it was revealed from our preliminary comparison
experiments that the reaction rates in organic solvents were
lower than that in water. Further investigations to clarify scope
and limitation, kinetics, and reaction environments in these sys-
tems (in both water and organic solvents) are now in progress.
2
2
2
2
4-MeOC H
6
4
C H
90a
97
6
5
4-ClC H
6
4
This work was partially supported by a Grant-in-Aid for
Scientific Research from Japan Society of the Promotion of
Science (JSPS).
PhCH2
96
p
p
-MeC H4
6
64 (69)b 91 (94)b
O 3 4-t-BuC H
6
4
-MeC H4
6
This paper is dedicated to Professor Teruaki Mukaiyama for
his great contribution to this journal on the occasion of his 80th
birthday.
3
4-ClC H
6
4
12
18
24
53
86
41
93
96
50
p
-BrC H4
6
O 4 4-t-BuC H
6
4
4
p
-BrC H
6
4
References and Notes
1
Me
4-t-BuC H
a) M. C. Willis, J. Chem. Soc., Perkin Trans. 1 1999, 1765. b)
D. M. Hodgson, A. R. Gibbs, G. P. Lee, Tetrahedron 1996,
6
O 5
Me
5
2, 14361. c) E. N. Jacobsen, M. H. Wu, in Comprehensive
a
Asymmetric Catalysis, ed. by E. N. Jacobsen, A. Pfaltz, H.
Yamamoto, Springer-Verlag, Berlin, 1999, Vol. 3, p. 1309.
a) T. Iida, N. Yamamoto, H. Sasai, M. Shibasaki, J. Am. Chem.
Soc. 1997, 119, 4783. b) M. H. Wu, E. N. Jacobsen, J. Org.
Chem. 1998, 63, 5252. c) J. Wu, X.-L. Hou, L.-X. Dai, L.-J.
Xia, M.-H. Tang, Tetrahedron: Asymmetry 1998, 9, 3431.
S. Ishikawa, T. Hamada, K. Manabe, S. Kobayashi, J. Am.
Chem. Soc. 2004, 126, 12236.
S. Azoulay, K. Manabe, S. Kobayashi, Org. Lett. 2005, 7, 4593.
M. Boudou, C. Ogawa, S. Kobayahsi, Adv. Synth. Catal., in
press.
Recently, Schneider et al. reported ring opening of meso-
epoxides with alcohols and amines catalyzed by a chiral
scandium complex in an organic solvent. C. Schneider, A. R.
Sreekanth, E. Mai, Angew. Chem., Int. Ed. 2004, 43, 5691.
a) C. Bolm, M. Zehnder, D. Bur, Angew. Chem., Int. Ed. 1990,
The absolute configuration of the product was determined to be
S,3S (see text). 0 C for 7 h.
b
ꢀ
2
2
3
ꢀ
cases, it is possible to conduct the reaction at 0 C to afford the
desired compound in higher enantiometic excess (Entry 6 in pa-
renthesis). It should be noted that excellent levels of enantiose-
lectivity have been attained in the ring-opening desymmetriza-
tion of cis-stilbene oxide derivatives with thiols by using
a relatively simple chiral catalyst prepared from Sc(OTf)3 and
chiral bipyridine 1. In contrast, cis-2,3-epoxybutane (5) reacted
with 4-t-butylbenzenethiol to afford the corresponding sulfide in
moderate yield with moderate enantiomeric excess (Entry 9).
We confirmed that in this case a background reaction (without
the catalyst) is competitive with the enantioselective process
and that this undesired non-catalyzed pathway decreased the
enantioselectivity. A trial to suppress the undesired pathway
and to improve the enantioselectivity is now under investigation.
A typical experimental procedure is described for the de-
symmetrization of cis-stilbene oxide 2 with 4-t-butylbenzene-
thiol. Sc(OTf)3 (19.7 mg, 0.04 mmol) and chiral bipyridine
ligand (S,S)-1 (15.8 mg, 0.048 mmol) in DCM (0.8 mL) were
stirred for 10 min at room temperature. To this solution, an
epoxide (0.4 mmol) in DCM (0.8 mL) and a thiol (1.2 mmol)
in DCM (0.4 mL) were successively added. The mixture was
stirred at the same temperature for 4–24 h. Water was added to
quench the reaction, and the product was extracted with DCM.
After usual work-up, the crude product was purified by prepara-
tive TLC on silica gel to afford the desired sulfide. The enantio-
selectivity of the product was determined by HPLC analysis
using a chiral column.
4
5
6
7
8
29, 205. b) C. Bolm, M. Ewald, M. Felder, G. Schlingloff,
Chem. Ber. 1992, 125, 1169.
A chiral bismuth complex consisting of Bi(OTf)3 and chiral
bipyridine 1 also catalyzed enantioselective ring-opening
desymmetrization of meso-epoxides. a) C. Ogawa, S. Azoulay,
S. Kobayashi, Heterocycles 2005, 66, 201. For a reference to
the bismuth catalyst see: b) S. Kobayashi, T. Ogino, H. Shimizu,
S. Ishikawa, T. Hamada, K. Manabe, Org. Lett. 2005, 7, 4729.
Some side reactions occurred under the conditions. Crotti et al.
reported that lanthanide triflates such as Yb(OTf)3-catalyzed
aminolysis of epoxides effectively. a) M. Chini, P. Crotti, L.
Favero, F. Macchia, M. Pineschi, Tetrahedron Lett. 1994, 35,
433. For lanthanide triflates and scandium triflate as water-
and amine-compatible Lewis acids, see: b) S. Kobayashi, M.
Sugiura, H. Kitagawa, W. W.-L. Lam, Chem. Rev. 2002, 102,
2227. c) S. Kobayashi, Eur. J. Org. Chem. 1999, 15. d) S.
Kobayashi, Synlett 1994, 689.
9
In summary, we have developed a ring-opening desymmet-
rization of meso-epoxides with thiols using a chiral scandium
10 S. Nakamura, R. Nakagawa, Y. Watanabe, T. Toru, J. Am.
Chem. Soc. 2000, 122, 11340.
Published on the web (Advance View) December 2, 2006; doi:10.1246/cl.2007.34