8090
J . Org. Chem. 1998, 63, 8090-8091
Ta ble 1.
Rep r esen ta tive Resu lts for th e Ca ta lytic
Th e F ir st Ca ta lytic En a n tioselective
Syn th esis of cis-Ep oxyk eton es fr om
cis-En on es
Asym m etr ic Ep oxid a tion of cis-En on es
Shizue Watanabe,†,‡ Takayoshi Arai,† Hiroaki Sasai,*,†
Masahiro Bougauchi,‡ and Masakatsu Shibasaki*,‡
The Institute of Scientific and Industrial Research (ISIR),
Osaka University, Mihogaoka, Ibaraki, Osaka 567-0047, J apan,
and Graduate School of Pharmaceutical Sciences, The
University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, J apan
cis-
trans-
Received J uly 30, 1998
epoxidea epoxide
The synthesis of optically active compounds is usually
considered to be much more difficult than that of corre-
sponding racemic compounds. Indeed, almost all develop-
ments of novel asymmetric reactions are based on the
reactions for racemic compounds. However, in our recent
studies on the development of enantioselective reactions
utilizing rare earth and/or group 13 elements (Al or Ga)
containing optically active complexes, we have found several
multifunctional catalytic reactions in which these complexes
not only activate both substrates in intermolecular reactions
but also control the orientation of them.1 The multifunc-
tional catalyst can provide optically active compounds, which
are difficult to synthesize even in a racemic form. This
unique feature of the multifunctional catalyst is believed to
be the result of a synergistic cooperation of metals in the
asymmetric bimetallic complexes. This feature also seems
to be present in the asymmetric epoxidation of cis-enones
(cis-R,â-unsaturated ketones). We report here the first
efficient synthesis of cis-epoxyketones from cis-enones by use
of the catalyst ytterbium-(R)-3-(hydroxymethyl)-1,1′-bi-2-
naphthol complex2a (Yb-3-CH2OH-BINOL; Yb-2).
catalyst
TBHP time
y(%),
ee (%)
y (%),
entry substrate (mol %) (equiv) (h)
ee (%)b
1c
2c
3c
4c
5
3 f 4
3 f 4
3 f 4
3 f 4
3 f 4
5 f 6
5 f 6
7 f 8
7 f 8
9 f 10
BuLi (10)
La-1d (5)
Yb-1d (5)
La-2 (10)
Yb-2 (10)
Yb-1d (10)
Yb-2 (10)
Yb-1d (10)
Yb-2 (10)
Yb-2 (10)
3
22
72
72
8, nd
31, 5
60, 4
43, nd
<10, nd
<10, nd
1.5
1.5
3
72
58, 58 <10, nd
74, 94 trace, nd
56, 21 <10, nd
78, 93 trace, nd
75, 27 trace, nd
80, 96 trace, nd
60, 82 32, 10e
51, 88 19, 58e
3
72
6c
7
3
3
3
3
146
146
127
127
81
8c
9
10
3
11
11 f 12 Yb-2 (10)
3
96
a
Absolute configurations of the major enantiomer were deter-
b
mined to be (RS,âS) other than entries 3, 6, 8 (RR,âR). nd: Not
determined. c The starting material was retained. Prepared from
d
Ln(O-i-Pr)3 and 1 in a ratio of 1:1. e Absolute configurations of the
major enantiomer were determined to be (RS,âR).
hydroperoxide (CMHP).4 It is noteworthy that the reaction
proceeds at room temperature without special care to remove
moisture. As shown in Table 1, the Yb-2 catalyst gave cis-
epoxyketone of a higher ee than the La-2 catalyst and/or
the BINOL (1) derived catalysts. By use of the Yb-2 catalyst,
aliphatic cis-enones were converted into cis-epoxyketones in
a highly enantioselective manner (93-96% ee).5,6 The
absolute configuration of the â-position of cis-epoxyketones
was determined to be S when (R)-Yb-2 was utilized. This
was in direct contrast to what was seen in the epoxidation
of the corresponding trans-enones, in which the major
enantiomer was (RS, âR).2a Attempts to prepare racemic
authentic samples with Ln(O-i-Pr)3 resulted in the formation
of a mixture of cis- and trans-epoxyketones, suggesting the
importance of the multifunctional character of the Yb-2
catalyst.2a,7 For aromatic cis-enones, which isomerize readily
to trans-enones, 10 mol % of the Yb-2 catalyst was effective
to obtain cis-epoxides, though a small amount of trans-
epoxyketones were also formed.8 We also examined asym-
metric epoxidation of trisubstituted enone (CH3)2CdCHCOPh
The stereoselective construction of cis-epoxyketones from
acyclic cis-enones is difficult due to the tendency of cis-
enones to afford the corresponding more stable trans deriva-
tives during the oxidation process. For example, treatment
of cis-3 with TBHP in the presence of BuLi (10 mol %)
provided a mixture of cis- and trans-epoxyketones in 8% and
43% yield, respectively (Table 1, entry 1).3
On the other hand, we were pleased to find that the Ln-2
catalyst (Ln ) Yb or La),2a prepared from Ln(O-i-Pr)3 and 2
in a ratio of 1:1.4, gave cis-epoxides quite efficiently. TBHP
seems to be a more appropriate oxidant than cumene
(4) CMHP was effective for the epoxidation of trans-enones promoted
by either the La-1 or La-2 catalyst (see ref 2a). However, it appeared that
epoxidation of cis-enones using CMHP was quite slow.
(5) Measurements of enantiomeric excess were performed by stationary
phase chiral HPLC. See Supporting Information.
† Osaka University.
‡ The University of Tokyo.
(6) The absolute configurations were determined by Mosher method after
transforming to the corresponding â-hydroxyketones (for 4, 6, 8, 10) or
determined by transformation to the authentic sample (for 12).
(7) By use of 10 mol % of Ln(O-i-Pr)3, the following results were obtained.
La(O-i-Pr)3: cis-6: trans-6 ) 66:18 (rt, 11 h); cis-10: trans-10 ) 60:32 (rt,
2 h); cis-12: trans-12 ) 68:23 (rt, 4 h), Yb(O-i-Pr)3: cis-10: trans-10 ) 51:
34 (rt, 29 h).
(8) Recently, we have revealed that a 2:3 ratio of Yb(O-i-Pr)3 and BINOL
(1) was an efficient catalyst (Yb-1) for the epoxidation of trans-enones in
the presence of both water and MS 4A. See, Watanabe, S.; Kobayashi, Y.;
Arai, T.; Sasai, H.; Bougauchi, M.; Shibasaki, M. Tetrahedron Lett. 1998,
39, 7353-7356. However, the Yb-1 catalyst gave the cis-epoxyketones very
slowly.
(1) (a) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. Engl.
1997, 36, 1236-1256. (b) Sasai, H.; Arai, T.; Satow, Y.; Houk, K. N.;
Shibasaki, M. J . Am. Chem. Soc. 1995, 117, 6194-6198. (c) Arai, T.; Sasai,
H.; Yamaguchi, K.; Shibasaki, M. J . Am. Chem. Soc. 1998, 120, 441-442.
(d) Gro¨ger, H.; Saida, Y.; Sasai, H.; Yamaguchi, K.; Martens, J .; Shibasaki,
M. J . Am. Chem. Soc. 1998, 120, 3089-3103. (e) Emori, E.; Arai, T.; Sasai,
H.; Shibasaki, M. J . Am. Chem. Soc. 1998, 120, 4043-4044.
(2) (a) Bougauchi, M.; Watanabe, S.; Arai, T.; Sasai, H.; Shibasaki, M.
J . Am. Chem. Soc. 1997, 119, 2329-2330. (b) Sasai, H.; Arai, T.; Shibasaki,
M. J . Am. Chem. Soc. 1994, 116, 1571-1572.
(3) Furthermore, use of KF-Al2O3 and TBHP, or NaOH (10 mol %) and
H2O2, did not afford cis-epoxyketones.
10.1021/jo9815047 CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/27/1998
Watanabe
