Effective asymmetric epoxidation of styrenes by chiral dioxirane

Article abstract of DOI:10.1021/jo0520285

High enantioselectivity (80-92% enantiomeric excess (ee)) has been obtained for the epoxidation of various styrenes using an easily prepared ketone (4) catalyst.

Full text of DOI:10.1021/jo0520285

reagents have been investigated for the epoxidation of styrenes
including chiral porphyrin complexes,4 chiral salen complexes,5
chiral oxaziridines, and oxaziridinium salts.6 Although signifi-
cant progress has been made in this area, the development of a
potentially useful epoxidation method for styrenes has been
elusive.
Effective Asymmetric Epoxidation of Styrenes by
Chiral Dioxirane
David Goeddel, Lianhe Shu, Yi Yuan, O. Andrea Wong,
Bin Wang, and Yian Shi*
Department of Chemistry, Colorado State UniVersity,
Although chiral dioxiranes are effective for asymmetric
epoxidation of trans-, trisubstituted, and certain cis-alkenes,7
styrenes have been challenging substrates.8 During our earlier
studies, we found that fructose-derived ketone 1 (Scheme 1), a
very effective catalyst for trans- and trisubstituted alkenes, gave
only 24% enantiomeric excess (ee) for styrene.9 Encouragingly
high ee’s (74-85%) were subsequently obtained with ketone
2.10 Our recent studies on the conformational and electronic
effects of ketone catalysts on epoxidation have shown that
ketone 3, a carbocyclic analogue of 2, gives high ee for styrenes
(89-93% ee).11 Although ketone 3 is mechanistically informa-
tive, its lengthy synthesis precludes its practical use. Very
recently, we have shown that N-aryl-substituted oxazolidinone
ketone 4a (Ar ) p-MePh) (Scheme 1), which is readily prepared
from glucose and p-toluidine (Scheme 2), provides a potentially
practical catalyst for epoxidation.12 Herein, we wish to report
our studies on the epoxidation of styrenes with this class of
ketones.
Our studies showed that the N-substituents of the ketones
have significant effects on the enantioselectivity of styrene
epoxidation, with the ee varying from 55 to 87% using 15 mol
% ketone catalyst in DME (Scheme 3, Table 1). Generally
speaking, aniline substitution with hydrocarbons consistently
shows higher ee than substitution with ethers or halogens. A
combination of high enantioselectivity and low cost of aniline
starting materials (p-toluidine and 4-ethylaniline) makes 4a and
4b good catalyst choices among all of these ketones. The ee
obtained with ketone 4b for styrene encouraged us to extend
the epoxidation to other styrenes. As shown in Table 2, up to
92% ee was obtained with the observed enantioselectivity being
dependent on the phenyl group substituents of the olefins.
Fort Collins, Colorado 80523
yian@lamar.colostate.edu
ReceiVed September 27, 2005
High enantioselectivity (80-92% enantiomeric excess (ee))
has been obtained for the epoxidation of various styrenes
using an easily prepared ketone (4) catalyst.
Chiral styrene oxides are extremely useful and can be
prepared by a number of methods, such as asymmetric reduction
of R-halo acetophenones,1 asymmetric dihydroxylation of
styrenes,2 and kinetic resolution of racemic epoxides.3 The
asymmetric epoxidation of styrenes has also received a con-
siderable amount of interest.4-6 Various chiral catalysts and
* To whom correspondence should be addressed. Phone: 970-491-7424.
Fax: 970-491-1801.
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Soc. 1991, 113, 6865. (e) Konishi, K.; Oda, K.-I.; Nishida, T.; Aida, T.;
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Tani, F.; Maruyama, K. Bull. Chem. Soc. Jpn. 1993, 66, 158. (g) Collman,
J. P.; Lee, V. J.; Kellen-Yuen, C. J.; Zhang, X.; Ibers, J. A.; Brauman, J.
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Chem. Soc., Perkin Trans. 1 1997, 2265. (i) Collman, J. P.; Wang, Z.;
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1999, 409. (k) Gross, Z.; Ini, S. Org. Lett. 1999, 1, 2077. (l) Zhang, R.;
Yu, W.-Y.; Wong, K.-Y.; Che, C.-M. J. Org. Chem. 2001, 66, 8145. (m)
Rose, E.; Ren, Q.-Z.; Andrioletti, B. Chem.-Eur. J. 2004, 10, 224. (n)
Rose, E.; Andrioletti, B.; Zrig, S.; Quelquejeu-Etheve, M. Chem. Soc. ReV.
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(9) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem.
Soc. 1997, 119, 11224.
(10) Tian, H.; She, X.; Xu, J.; Shi, Y. Org. Lett. 2001, 3, 1929.
(11) Hickey, M.; Goeddel, D.; Crane, Z.; Shi, Y. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5794.
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Jacobsen, E. N. J. Am. Chem. Soc. 1990, 112, 2801. (b) O’Connor, K. J.;
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10.1021/jo0520285 CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/24/2006
J. Org. Chem. 2006, 71, 1715-1717
1715

TABLE 2. Asymmetric Epoxidation of Styrenes with Ketone 4ba
SCHEME 1
SCHEME 2
SCHEME 3
a All reactions were carried out with olefin (0.40 mmol), ketone 4b
(0.06-0.12 mmol), Oxone (1.07 mmol), K2CO3 (4.23 mmol), and Bu4NHSO4
(0.04 mmol) in DME (6.0 mL) and buffer (0.1 M K2CO3-AcOH, pH 9.3)
(4.0 mL) at -10 to -15 °C (bath temperature). For entry 12, the reaction
was carried out at -5 °C. For entry 13, the reaction was carried out in
DME (5.0 mL)/dioxane (1.0 mL) at 0 °C. b Isolated yield. c The conversion
was determined by GC, except for entries 8, 10, 11, and 12 which were
determined by 1H NMR. d The ee was determined by chiral GC (Chiraldex
B-DM). e The ee was determined by chiral HPLC (Chiralcel AD). f The ee
was determined by chiral HPLC (Chiralcel OD). g The ee was determined
by chiral HPLC (Chiralcel OJ). h The absolute configurations were deter-
mined by comparing the measured optical rotations with the reported ones.
i Reaction time of 6 h. j Reaction time of 8 h. k Reaction time of 12 h.
l Reaction time of 16 h. m 0.06 mmol of ketone 4b was used. n 0.12 mmol
of ketone 4b was used. ï The reaction was carried out with 3.24 mmol of
olefin and 0.98 mmol of ketone 4b.
TABLE 1. Asymmetric Epoxidation of Styrene with Ketone 4a
conv. (ee)
(%)b
conv. (ee)
entry
ketone
entry
ketone
(%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
100 (84)
100 (86)
100 (84)
100 (84)
99 (84)
100 (86)
100 (82)
95 (85)
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
4o
4p
4q
4r
4s
4t
4u
4v
4w
4x
4y
4z
100 (82)
97 (85)
100 (87)
100 (80)
100 (79)
100 (81)
77 (70)
49 (78)
52 (55)
98 (83)
98 (69)
87 (84)
78 (78)
89 (79)
100 (86)
SCHEME 4
79 (83)
100 (78)
100 (86)
79 (75)
89 (85)
100 (81)
4aa
4bb
4cc
a All reactions were carried out with olefin (0.10 mmol), ketone 4 (0.015
mmol), Oxone (0.212 M, 0.84 mL), K2CO3 (0.48 M, 0.84 mL), and
Bu4NHSO4 (0.02 mmol) in DME (1.5 mL) and buffer (0.1 M K2CO3-
AcOH, pH 8.0) (1.0 mL) at -10 °C (bath temperature) (NaCl ice bath) for
3.5 h. b The conversion and ee were determined by chiral GC (Chiraldex
B-DM).
8-11), certain substituents on the phenyl group of the olefin
appear to further favor spiro A, resulting in an increase in overall
ee. For para-substituted styrenes (Table 2, entries 3-7), certain
substituents do not significantly affect the competition of the
transition states, thus giving an ee similar to styrene itself.
However, electron-deficient olefins give higher ee’s than their
more electron-rich counterparts, presumably because of en-
hanced secondary orbital interactions further favoring spiro
transition states.11 Styrenes bearing multiple substituents give
ee’s that are consistent with the various electronic and structural
patterns of the simpler monosubstituted styrenes.
In summary, the asymmetric epoxidation of various styrenes
has been investigated with a variety of N-aryl-substituted
oxazolidinone-containing ketones. High enantioselectivity has
been achieved for both electron-rich and electron-poor styrenes.
The availability of these ketone catalysts reveals the potential
of this asymmetric epoxidation as a viable entry into this
important class of molecules. Future studies will be devoted to
Our earlier studies suggest that the asymmetric induction for
ketone class 4 is likely due to an attraction between the aryl
group of the olefin and the oxazolidinone moiety of the ketone
catalyst in the transition state.10-12 For styrenes, spiro A is likely
to be the favored transition state with spiro B and planar C
being competing transition states (Scheme 4). For ortho-
substituted styrenes (Table 2, entry 2), observed enantioselec-
tivity is lower than styrene itself, presumably because of
unfavorable steric interactions between the substituents on the
styrene and the oxazolidinone moiety of the catalyst for spiro
transition state A. As a result, a net decrease in enantioselectivity
is observed. For meta-substituted styrenes (Table 2, entries
1716 J. Org. Chem., Vol. 71, No. 4, 2006

A mixture of the above oil and NaHCO3 (12.2 g) was suspended
in CH2Cl2 (142 mL). While stirring at 0 °C, 20% phosgene solution
in toluene (21.3 mL, 40.5 mmol) was added via a syringe pump
under argon over 2 h. After the mixture was stirred at 0 °C for an
additional 4 h, triethylamine (17.3 mL) was then added. Upon
stirring at room temperature overnight, the mixture was filtered
through a pad of silica gel, concentrated, and purified on silica gel
with hexane/AcOEt (2:1 to 1:2) to give the alcohol product as a
light brown solid (6.78 g, 55% yield over two steps).
further understanding the interactions between olefin substituents
and N-substituents of ketone catalysts and fully exploring the
substrate scope of these effective chiral ketone catalysts.
Experimental
Representative Asymmetric Epoxidation Procedure (Table
2, Entry 3). To a solution of 4-chlorostyrene (0.055 g, 0.4 mmol)
and ketone 4b (0.021 g, 0.06 mmol) in DME (6.0 mL) were added
buffer (0.1 M K2CO3-AcOH in 4 × 10-4 M aq EDTA, pH 9.3)
(4.0 mL) and Bu4NHSO4 (0.010 g, 0.03 mmol) with stirring. After
the mixture was cooled to about -10 to -15 °C (bath temperature)
To a suspension of the alcohol (8.0 g, 22.9 mmol), PDC (12.9
g, 34.4 mmol), and 3A MS (14 g) in CH2Cl2 (23 mL) was added
acetic acid (5 drops). Upon stirring at room temperature overnight,
the reaction mixture was filtered through a pad of silica gel and
washed with hexane/AcOEt (1:2). The filtrate was concentrated and
dried on the high-vacuum line to give the ketone. Recrystallization
(ether/hexanes) gave the product (4b) as a white solid (4.3 g,
54%): mp 135-136 °C; [R]D20 -40.6 (c, 0.32, CHCl3); IR (film)
via a NaCl ice bath, a solution of Oxone (0.212 M in 4 × 10-4
M
aq EDTA, 5.04 mL) and a solution of K2CO3 (0.84 M in 4 × 10-4
M aq EDTA, 5.04 mL) were added dropwise separately over 8 h
via syringe pump. The reaction was quenched by addition of pentane
and extracted with pentane. The combined organic layers were dried
(Na2SO4), filtered, concentrated, and purified by flash chromatog-
raphy [the silica gel was buffered by 1% Et3N in pentane; pentane/
ether (1:0 to 10:1) was used as the eluent] to give 4-chlorostyrene
oxide as a colorless oil (0.0526 g, 85%, 86% ee).
1
1774 cm-1; H NMR (300 MHz, CDCl3) δ 7.42 (d, J ) 8.4 Hz,
2H), 7.21 (d, J ) 8.4 Hz, 2H), 4.87 (d, J ) 5.1 Hz, 1H), 4.74 (d,
J ) 10.2 Hz, 1H), 4.66-4.59 (m, 2H), 4.26 (d, J ) 13.5 Hz, 1H),
3.75 (d, J ) 10.2 Hz, 1H), 2.63 (q, J ) 7.5 Hz, 2H), 1.48 (s, 3H),
1.43 (s, 3H), 1.22 (t, J ) 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 195.1, 151.4, 141.3, 134.7, 128.7, 119.0, 111.2, 99.3, 77.7, 75.7,
61.2, 50.1, 28.5, 27.4, 26.3, 15.9; HRMS calcd for C18H22NO6 (M+
+ 1) 348.1447, found 348.1441.
Representative Ketone Synthesis. To a mixture of D-glucose
(50.0 g, 279.0 mmol) and 4-ethylaniline (40.3 g, 333.0 mmol) was
added water (13.7 mL), followed by AcOH (0.34 g, 5.66 mmol).
After the mixture was stirred at 95 °C (oil bath temperature) for 1
h (the mixture solidified), ether (200 mL) was added. Upon stirring
at room temperature for 2 h and standing in the freezer overnight,
the mixture was filtered. The filter cake was washed to white with
additional ether and dried to give a white solid that was used without
further purification (55.5 g, 70%).
Acknowledgment. We are grateful to the generous financial
support from the General Medical Sciences of the National
Institutes of Health (GM59705-06).
To a suspension of the above product (10.1 g, 35.6 mmol) in
acetone (420 mL) was added HC(OMe)3 (8.9 mL, 81.3 mmol),
followed by H2SO4 (3.1 mL, 55.8 mmol), at 0 °C. Upon stirring at
0 °C for 1 h, the reaction mixture was quenched with concentrated
NH4OH (8.9 mL) and quickly filtered through a pad of silica gel.
The filter cake was washed with additional acetone. The acetone
solution was dried (Na2SO4), filtered, and concentrated to give a
yellow oil (9.32 g) that was used without further purification.
Supporting Information Available: The characterization of
ketone catalysts, data for the determination of the enantiomeric
excess of the epoxides, and NMR data for the ketone catalysts (54
pages). This material is available free of charge via the Internet at
http://pubs.acs.org
JO0520285
J. Org. Chem, Vol. 71, No. 4, 2006 1717