Catalytic asymmetric epoxidation of α,β-unsaturated esters using an yttrium-biphenyldiol complex

Article abstract of DOI:10.1021/ja052466t

We succeeded in a catalytic asymmetric epoxidation reaction of α,β-unsaturated esters via a conjugate addition of an oxidant using 2-10 mol % of the yttirium-chiral biphenyldiol catalyst. A variety of substrates with β-aryl and β-alkyl substituents were epoxidized efficiently, yielding the corresponding α,β-epoxy esters in up to 97% yield and 99% ee. Copyright

Full text of DOI:10.1021/ja052466t

Published on Web 06/07/2005
Catalytic Asymmetric Epoxidation of r,â-Unsaturated Esters Using an
Yttrium-Biphenyldiol Complex
Hiroyuki Kakei, Riichiro Tsuji, Takashi Ohshima, and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku Tokyo 113-0033, Japan
Received April 15, 2005; E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Table 1. Optimization of the Reaction Conditions
Catalytic asymmetric epoxidation of R,â-unsaturated esters is a
synthetically useful reaction in organic synthesis.1 The resulting
enantiomerically enriched epoxy esters can be easily converted to
many types of useful chiral compounds. There are only a few reports
of general and efficient catalytic asymmetric epoxidations of R,â-
unsaturated esters using chiral ketones2,3 or (salen)Mn catalysts.4
These catalysts, however, cannot be applied to substrates that have
functional groups such as a C-C double bond and a ketone, due
to the poor chemoselectivity. Thus, there is room for improvement,
particularly in terms of substrate generality. In this communication,
we report a catalytic asymmetric epoxidation of R,â-unsaturated
esters via conjugate addition of an oxidant using chiral yttrium
catalysts.
yield (%)
3ac
4a
ee (%)
catalyst
concn.b
(Y M)
time
(h)
entry
REa
ligand
(X mol %)
+
5ac
3ad
1
2
3
4
5
6
7
8
9
Pr
Y
Y
Y
Y
Y
Y
Y
Y
Y
BINOL
BINOL
1a
1b
1c
1d
1d
1d
1d
10
10
10
10
10
10
5
3
2
2
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.33
0.5
1.0
72 24
72 36
-
88
95
92
98
99
99
99
99
99
99
5
144
4
120 45
120 49
48 61
48 65
50 79
50 77
65 81
14
26
33
25
21
11
12
8
We previously reported that alkali-metal free lanthanide-
BINOL-Ph3AsdO complexes, generated from Ln(O-i-Pr)3, BINOL,
and Ph3AsdO in a ratio of 1:1:1 were useful catalysts for
asymmetric epoxidation of enones,5 R,â-unsaturated amides,6 and
ester surrogates.6b,7 Thus, we initiated our studies of a catalytic
asymmetric epoxidation using methyl (E)-cinnamate (2a) as a
substrate and Ln-BINOL-Ph3AsdO complexes as a catalyst. The
use of Ln such as Pr was very unsatisfactory in terms of yield (Table
1, entry 1). On the other hand, we were pleased to find that Y
gave a better yield with high enantiomeric excess (entry 2).8 Next,
to overcome the problem of low reactivity, we hypothesized that
6,6′-disubstituted 2,2′-biphenyldiols 19 would give higher reactivity
than BINOL due to less steric hindrance. As expected, 6,6′-
disubstituted 2,2′-biphenyldiol 1b gave higher yield than BINOL
without decreasing the enantiomeric excess (entry 4). On the basis
of this finding, the effects of the dihedral angles of ligands were
carefully investigated by changing the linker length.10 Ligands with
a shorter linker 1a or longer linker 1c (see Figure 1) did not
dramatically increase the reactivity (entries 3,5). These results led
us to examine the effects of heteroatoms on the linker, because
heteroatoms on ligands often change the coordinating natures of
rare earth catalysts and dramatically increase the reactivity.11
Intensive investigation of ligands indicated that ligand 1d linked
by diethylene ether had dramatically greater reactivity (entries
6-10). Transesterification from R,â-epoxy methyl ester to iso-
propyl ester 4a or tert-butyl ester 5a, which were derived from
Y(O-i-Pr)3 and TBHP, remained a significant problem, however,
due to the high reactivity of the catalyst derived from ligand 1d.
To prevent the formation of byproducts, we very carefully examined
the reaction conditions. First, by reducing catalyst loading, the
formation of byproducts was suppressed (entries 7-9). Moreover,
under highly concentrated conditions (1.0 M), the reaction pro-
ceeded very well with as little as 2 mol % catalyst loading, affording
the product in 81% yield and 99% ee (entry 9). Having optimized
the reaction conditions,8 substrate generality was investigated (Table
2). The Y-ligand 1d-Ph3AsdO catalyst system had a broad
generality for epoxidation of various â-aromatic R,â-unsaturated
esters (Table 2). It was also applicable to ethyl (E)-cinnamate (2b),
10
1d
a RE ) rare earth metals. b Concentration of 2a. c Isolated yield. d De-
termined by chiral HPLC.
Figure 1. Structure of ligands 1a-d.
and product 3b was obtained with high yield and high enantiomeric
excess (entry 1). The reaction of substrates with both electron-
donating and electron-withdrawing substituents 2c-f proceeded
smoothly to afford 3c-f in good yield and good enantioselectivity
in the presence of 2-5 mol % of the catalyst (entries 3-6).
Substrate with an acetyl substituent 2g was smoothly epoxidized.
Acetyl functionality remained intact under this epoxidation condition
(entry 7). The reactions of substrates with bulkier â-naphthyl
moieties proceeded well (entries 8,9). The catalyst was also
applicable to â-heteroaromatic substrates 2j-l. Heteroaromatic rings
are easily decomposed under general oxidative conditions. In this
epoxidation system, however, the reactions of these substrates
proceeded to afford the corresponding epoxides 3j-l without
decomposition of heteroaromatic rings (entries 10-12). To the best
of our knowledge, there are no reports of a catalytic asymmetric
epoxidation of â-heteroaromatic substituted R,â-unsaturated esters.
In addition, Y-ligand 1d-Ph3PdO complex was also effective,
yielding products with slightly lower enantioselectivity (entry 2).12
To apply the developed catalyst system to â-alkyl-substituted
substrates, we further examined the reaction conditions. We
determined that 0.5 M was a suitable condition for these substrates.
Various substrates were smoothly epoxidized in good yield and
9
8962
J. AM. CHEM. SOC. 2005, 127, 8962-8963
10.1021/ja052466t CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Catalytic Asymmetric Epoxidation of â-Aromatic
R,â-Unsaturated Esters Using Y-1d-Ph3AsdO Complex
Acknowledgment. This work was supported by RFTF, Grant-
in-Aid for Encouragement for Young Scientists (A), and a Grant-
in-Aid for Specially Promoted Research from the Japan Society
for the Promotion of Science (JSPS) and Ministry of Education,
Culture, Sports, Science, and Technology (MEXT). R.T. thanks
the JSPS Research Fellowships for Young Scientists.
Supporting Information Available: Experimental procedures and
characterization of the products; other detailed results and discussion.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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Table 3. Catalytic Asymmetric Epoxidation of â-Aliphatic
R,â-Unsaturated Esters Using Y-1d-Ph3AsdO Complex
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(8) See Supporting Information for details.
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good enantioselectivity (Table 3, entries 1-5). Also in this case,
Ph3PdO can be utilized as shown in entry 2. Particularly noteworthy
is that this reaction was applicable to substrates that were func-
tionalized with a C-C double bond or ketone, without overoxidation
(entries 3,4).13,14
In conclusion, we developed a catalytic asymmetric epoxidation
reaction of R,â-unsaturated esters via conjugate addition of an
oxidant using a Y-chiral biphenyldiol complex. The success of the
reaction depends on the properties of the newly developed dieth-
ylene ether-linked biphenyldiol ligand 1d. Detailed mechanistic
studies of the present reaction, especially to clarify the properties
of the ligand, are currently in progress.
(11) (a) Matsunaga, S.; Das, J.; Roels, J.; Vogl, E. M.; Yamamoto, N.; Iida,
T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 2252.
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Sakamoto, S.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2003,
125, 2169. (c) Majima, K.; Takita, R.; Okada, R.; Ohshima, T.; Shibasaki,
M. J. Am. Chem. Soc. 2003, 125, 15837. The role of oxygen in this case
is very different from that in the previous case. Clarification of the oxygen
role is actively ongoing
(12) Daikai, M.; Kamaura, M.; Inanaga, J. Tetrahedron Lett. 1998, 39, 7321.
(13) Preliminary studies showed cis- and trisubstituted R,â-unsaturated esters
were not suitable for the newly developed catalyst.
(14) Absolute configurations of 3a, 3b, 3d, and 3m were determined to be
2R, 3S. For the detailed data, see the Supporting Information.
JA052466T
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J. AM. CHEM. SOC. VOL. 127, NO. 25, 2005 8963