Highly enantioselective epoxidation of 2,4-diarylenones by using dimeric cinchona phase-transfer catalysts: Enhancement of enantioselectivity by surfactants

Article abstract of DOI:10.1002/anie.200462254

Dramatic increases in reaction rates and enantioselectivities can be effected by the use of surfactants for the phase-transfer catalytic epoxidation of aromatic enones. Based on the X-ray crystal structure of the most effective catalyst-a modified cinchona alkaloid-a plausible transition state of the reaction has been modeled (see picture; HOO^- yellow, C gray, H white, N blue, O red).

Full text of DOI:10.1002/anie.200462254

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Angewandte
Chemie
Phase-Transfer Catalysis
Highly Enantioselective Epoxidation of 2,4-
Diarylenones by Using Dimeric Cinchona Phase-
Transfer Catalysts: Enhancement of
Enantioselectivity by Surfactants**
Sang-sup Jew,* Jeong-Hee Lee, Byeong-Seon Jeong,
Mi-Sook Yoo, Mi-Jeong Kim, Yeon-Ju Lee, Jihye Lee,
Sea-hoon Choi, Kyungjae Lee, Myoung Soo Lah, and
Hyeung-geun Park*
and 50% aqueous KOH (3 equiv) in diisopropyl ether at
Since the asymmetric epoxidation of allylic alcohols, which
was reported by the Sharpless group in 1980, catalytic
asymmetric epoxidation has been one of the most important
asymmetric methodologies.[1] A number of methods have
been developed for the epoxidation of both unfunctionalized
olefins and electron-deficient enones.[2] Quite recently, cata-
lytic asymmetric phase-transfer epoxidations by using a
cinchona alkaloid-derived quaternary ammonium salt as a
chiral phase-transfer catalyst (PTC) have been reported by
several research groups.[3] Despite their practical potential,
several shortcomings, such as insufficient enantioselectivity,
long reaction times, and low reaction temperatures, still
remain. Herein we report a highly enantioselective and
practical catalytic epoxidation of enones by using cinchona
alkaloid-derived dimeric quaternary ammonium salts and the
role of surfactants for enantioselectivity.
108C. As shown in Table 1, although the reaction time was
somewhat long (48 h), the dimeric catalyst 3 showed moder-
ate enantioselectivity (48% ee) compared with the corre-
sponding monomeric catalyst 9, which provided virtually no
enantioselectivity (Table 1, entries 1 and 8). Before we
searched for an optimal catalyst for the epoxidation, we
needed to reduce the long reaction time, which might cause
the low enantioselectivity through non-PTC-mediated epox-
idation.
Table 1: Catalytic enantioselective epoxidation of trans-chalcone.
Entry
PTC
Triton X-100 [mol%]
t [h]
Yield [%]
ee [%][a]
Recently, we reported a series of novel meta-dimeric
catalysts, derived from cinchona alkaloids, which were
successfully applied in the enantioselective synthesis of a-
amino acids.[4] As part of our research, we attempted to apply
these catalysts to the asymmetric epoxidation of 2,4-diary-
lenones. As very versatile intermediates,[3b] the epoxides of
2,4-diarylenones have been applied to the synthesis of various
biologically active compounds such as naproxen, ibuprofen,
diltiazem, the side chain of Taxol, (+)-clausenamide, as well
as styryl lactones ((+)-goniotriol and (+)-goniofufurone).[5]
We first performed the enantioselective phase-transfer
epoxidation of trans-chalcone (1a) by using 5 mol% of the
dimeric catalyst 3 along with 30% aqueous H2O2 (30 equiv)
1
2
3
4
5
6
7
8
3
3
4
5
6
7
8
9
0
5
5
5
5
5
5
0
5
5
5
48
10
8
8
8
3
8
56
15
15
8
85
89
85
80
90
95
70
65
80
70
95
48
82
2
92
92
98
6
0
2
3
1
9
10
11
9
10
11
[a] Enantiopurity was determined by HPLC analysis with a chiral column
(DAICEL Chiralpak AD), and absolute configuration was determined by
comparison of the HPLC retention time with reported data.[3]
Recently, Okino and Takemoto reported a phase-transfer
alkylation in a nonorganic solvent as a green chemical
process;[6] the method involved the use of a surfactant,
Triton X-100. As surfactants generally increase the surface
area between the two phases by the formation of micelles,[7]
we expected that the reaction would be accelerated in the
presence of surfactants. Thus, we tentatively tried Triton X-
100 in a phase-transfer epoxidation. Surprisingly, the use of
just 5 mol% of Triton X-100 dramatically increased not only
the rate of the reaction (five times) but also the enantiose-
lectivity (82% ee, Table 1, entry 2). Generally, when the
nucleophile and electrophile were not in the same phase,
the phase-transfer reaction was considerably slower than the
reaction that occurred when both components were in the
organic phase. In the case of such a slow enantioselective
phase-transfer reaction, the low enantioselectivities may not
[*] Prof. Dr. S.-s. Jew, J.-H. Lee, Dr. B.-S. Jeong, M.-S. Yoo, M.-J. Kim,
Y.-J. Lee, J. Lee, S.-h. Choi, Prof. Dr. H.-g. Park
Research Institute of Pharmaceutical Sciences and
College of Pharmacy
Seoul National University
Seoul 151-742 (Korea)
Fax: (+82)2-872-9129
E-mail: ssjew@plaza.snu.ac.kr
hgpk@plaza.snu.ac.kr
K. Lee, Prof. Dr. M. S. Lah
Department of Chemistry and Applied Chemistry
Hanyang University
Ansan, Kyunggi 426-791 (Korea)
[**] This research was supported by a grant (R01-2002-000-0005-0) from
the Basic Research Program of the KOSEF (2004).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2005, 44, 1383 –1385
DOI: 10.1002/anie.200462254
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
Table 2: Optimization of surfactants.
always reflect the low catalytic efficiencies of the employed
catalysts. The low reaction rates might not allow the catalysts to
perform optimally. Therefore, surfactants might effectively
increase enantioselectivity, thus allowing an accurate evaluation
of the catalyst capacity in phase-transfer catalytic reactions.
Once we had decreased the reaction time, we continued
our search for an optimal catalyst. Five new dimeric catalysts
(4–8) along with three monomeric catalysts (9–11) were
prepared,[8] and their catalytic efficiencies for epoxidation
were evaluated in the presence of 5 mol% of Triton X-100. As
shown in Table 1, the catalyst based on the naphthyl ligand, 4,
displayed almost no enantioselectivity (Table 1, entry 3),
which suggests that the length of the spacer between the
two cinchona units influences the binding of the catalyst with
chalcone (1a) and peroxide. In a series of meta-dimeric
catalysts based on a central phenyl ring, introduction of
substituents in 5 (X = F; entry 4, 92% ee) and 6 (Y= OMe;
entry 5, 92% ee) had an equal effect on the enantioselectivity.
These favorable effects were confirmed by an additional
increase in enantioselectivity in the case of catalyst 7 (X = F,
Y= OMe; entry 6, 98% ee). Despite the presence of the Fand
OMe functional groups in the appropriate positions, use of
the corresponding O(9)-allyl catalyst 8 led to lower enantio-
selectivity (entry 7, 6% ee), which implies that the free OH
group on C9 is essential for the binding process. With the
monomeric catalysts (9–11), neither the surfactant effect nor
the effect of the functional groups was observed (Table 1,
entries 9–11). These accumulated findings suggested that the
ortho F group on the phenyl ring, the 6’-methoxy group on the
quinoline moiety, and the free OH group on C9 in catalyst 7
play integral roles in the favorable conformation of the
binding intermediate, which comprises 7, 1a, and the hydro-
gen peroxide anion.
Entry
H2O2
KOH
Surfactant[a]
t [h] Yield [%]
ee [%]
[equiv]
[equiv]
1
2
3
4
5
6
7
10
10
10
10
10
10
5
2
2
2
2
2
1
1
Triton X-100
Tergitol NP 9
Brij 78
Tween 20
Span 20
3.5
3
2.5
2
3
4
80
80
95
95
95
95
93
90
97
94
99
>99
>99
97
Span 20
Span 20
4
[a] The surfactants were purchased from Aldrich Co Ltd. 1 mol% was
used in all reactions.
Table 3: Enantioselective phase-transfer catalytic epoxidation of enones.
Entry
R1
R2
t [h]
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4
4
4
95
94
96
95
96
95
97
96
95
>99
98
97
>99
>99
98
>99
98
4-F-C6H4
4-Me-C6H4
4-MeO-C6H4
2-naphthyl
2-thiophenyl
Ph
1.5
6
0.5
1
2-F-C6H4
3-F-C6H4
3-Me-C6H4
Ph
Ph
1
12
97
Next, we focused our attention on finding an optimal
surfactant. Five commercially available surfactants were
chosen. The epoxidation of 1a was performed by using
1 mol% of 7 along with 30% aqueous H2O2 (10 equiv), 50%
aqueous KOH (2.0 equiv), and the surfactants in diisopropyl
ether at room temperature. Among the surfactants (Table 2,
entries 1–5), Span 20 gave the best results in terms of both
yield (95%) and enantioselectivity (> 99%). The enantiose-
lectivity was preserved even when only a stoichiometric
amount of KOH was present (entry 6), but a decrease in the
initial amount of H2O2 used resulted in a slight decrease in
enantioselectivity (entry 7).
plausible transition state of the catalytic asymmetric epox-
idation (Figure 2). The chalcone is located between the two
cinchona units in 7. The b-phenyl group of chalcone has a p–p
stacking interaction with one of the quinoline moieties. The
carbonyl oxygen atom is placed as close to the N+ center as
permitted by van der Waals forces. The other N+ center is ion-
paired with the hydrogen peroxide ion through hydrogen
bonding with the oxygen of 6’-methoxy group in quinoline. As
a consequence, hydrogen peroxide can only approach the
b carbon atom of chalcone from the upside in the 1,4-addition
to afford the aS,bR isomer 2, which is in agreement with the
observed results.
Under the optimal reaction conditions (as in Table 2,
entry 6), the reaction of various 2,4-diarylenones with hydro-
gen peroxide in the presence of 7 was
In conclusion, we have demonstrated that surfactants can
dramatically increase both the reaction rate and enantiose-
investigated (Table 3). High enantiose-
lectivities (97 to 99% ee) were observed
for a variety of 2,4-diarylenones, which
indicate that the reaction is a very
efficient enantioselective method for
this epoxidation. However, aliphatic-
substituted substrates exhibited rela-
tively low enantioselectivities (data not
shown).
Based on the X-ray crystal structure
of 7 (see Figure 1),[9] we propose a Figure 1. Stereoview of the X-ray crystal structure of 7-PF6.
1384
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Angewandte
Chemie
[4] a) S.-s. Jew, B.-S. Jeong, M.-S. Yoo, H.
Huh, H.-g. Park, Chem. Commun. 2001,
1244; b) H.-g. Park, B.-S. Jeong, M.-S.
Yoo, J.-H. Lee, B.-s. Park, M. G. Kim, S.-s.
Jew, Tetrahedron Lett. 2003, 44, 3497.
[5] a) L. Carde, D. H. Davies, S. M. Roberts,
J. Chem. Soc. Perkin Trans. 1 2000, 2455;
b) B. M. Adger, J. V. Barkley, S. Bergeron,
M. W. Cappi, B. E. Flowerdew, M. P.
Jackson, R. McCague, T. C. Nugent,
S. M. Roberts, J. Chem. Soc. Perkin
Trans. 1 1997, 3501; c) M. W. Cappi, W.-
P. Chen, R. W. Flood, Y.-W. Liao, S. M.
Roberts, J. Skidmore, J. A. Smith, N. M.
Williamson, Chem. Commun. 1998, 1159;
d) W.-P. Chen, S. M. Roberts, J. Chem.
Soc. Perkin Trans. 1, 1999, 103.
[6] T. Okino, Y. Takemoto, Org. Lett. 2001, 3,
1515.
[7] D. J. Shaw, Introduction to Colloid and
Surface Chemistry, Butterworth, Boston,
1980.
Figure 2. Plausible model of the transition state for the asymmetric epoxidation of 1a based
on the X-ray crystal structure of 7 (HOOÀ yellow, C dark gray, H white, N blue, O red).
lectivity of phase-transfer catalytic epoxidation. The best
results were obtained with Span 20. The easy preparation of
the most effective catalyst, 7, and the very mild reaction
conditions make this method promising for industrial appli-
cation. Further modification of the dimeric catalysts to extend
the substrate scope and mechanistic studies are in progress.
[8] a) H.-g. Park, B.-S. Jeong, M.-S. Yoo, J.-H. Lee, M.-k. Park, Y.-J.
Lee, M.-J. Kim, S.-s. Jew, Angew. Chem. 2002, 114, 3162; Angew.
Chem. Int. Ed. 2002, 41, 3036; b) S.-s. Jew, M.-S. Yoo, B.-S. Jeong,
I.-Y. Park, H.-g. Park, Org. Lett. 2002, 4, 4245; c) S.-s. Jew, B.-S.
Jeong, J.-H. Lee, M.-S. Yoo, Y.-J. Lee, B.-s. Park, M.-G. Kim, H.-g.
Park, J. Org. Chem. 2003, 68, 4514.
[9] For detailed crystallographic data, see the Supporting Informa-
tion.
Experimental Section
Aqueous hydrogen peroxide (30%, 0.27 mL; 2.4 mmol) and 50%
aqueous KOH (0.027 mL, 0.24 mmol) were added to a mixture of
chalcone 1a (50 mg, 0.24 mmol), catalyst 7 (2.2 mg, 0.0024 mmol),
and Span 20 (0.003 mL, 0.0024 mmol) in diisopropyl ether (0.8 mL),
and the reaction mixture was stirred vigorously at room temperature
until the starting material had been consumed. The resulting
suspension was diluted with ether (10 mL), washed with water (2 ꢀ
5 mL), dried over MgSO4, filtered, and concentrated in vacuo.
Purification of the residue by flash column chromatography on
silica gel (hexanes/EtOAc = 50:1) afforded the desired product 2a
(51.2 mg, 95% yield) as a white solid. The enantioselectivity was
determined by chiral HPLC analysis (DAICEL Chiralpak AD,
hexanes/ethanol = 90:10, flow rate = 1.0 mLminÀ1
,
238C, l =
254 nm; retention times: 16.6 min (minor), 24.0 min (major);
> 99.9% ee) The absolute configuration was determined by compar-
ison of the HPLC retention time with reported data.[3]
Received: October 9, 2004
Revised: November 16, 2004
Published online: January 21, 2005
Keywords: asymmetric catalysis · enantioselectivity ·
.
epoxidation · phase-transfer catalysis · surfactants
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[2] For recent reviews, see: a) M. J. Porter, J. Skidmore, Chem.
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Acta 2002, 35, 47; c) T. Nemoto, T. Ohshima, M. Shibasaki, J.
Synth. Org. Chem. Jpn. 2002, 60, 94; d) A. Gerlach, T. Geller, Adv.
Synth. Catal. 2004, 346, 1247.
[3] a) B. Lygo, P. G. Wainwright, Tetrahedron 1999, 55, 6289; b) E. J.
Corey, F.-Y. Zhang, Org. Lett. 1999, 1, 1287; c) S. Arai, H. Tsuge,
M. Oku, M. Miura, T. Shioiri, Tetrahedron 2002, 58, 1623; d) T.
Ooi, D. Ohara, M. Tamura, K. Maruoka, J. Am. Chem. Soc. 2004,
126, 6844.
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