Studies of substituent effect on asymmetric epoxidation of chromenes by chiral dioxirane

Article abstract of DOI:10.1021/jo0604179

A series of 6- and 8-substituted chromenes has been investigated for asymmetric epoxidation using chiral ketone catalysts. Up to 93% ee was achieved. Higher ee's are obtained when substrates are substituted at the 6-position. The enhanced enantioselectivity is likely due to the beneficial interaction between the 6-substituent of the substrate and the N-aryl or alkyl group of the ketone catalyst.

Full text of DOI:10.1021/jo0604179

Studies of Substituent Effect on Asymmetric
Epoxidation of Chromenes by Chiral Dioxirane
O. Andrea Wong and Yian Shi*
Department of Chemistry, Colorado State UniVersity,
Fort Collins, Colorado 80523
FIGURE 1. Ketone catalysts for asymmetric epoxidation.
yian@lamar.colostate.edu
ReceiVed February 27, 2006
FIGURE 2. Transition states for the epoxidation of cis-â-methylsty-
renes.
A series of 6- and 8-substituted chromenes has been
investigated for asymmetric epoxidation using chiral ketone
catalysts. Up to 93% ee was achieved. Higher ee’s are
obtained when substrates are substituted at the 6-position.
The enhanced enantioselectivity is likely due to the beneficial
interaction between the 6-substituent of the substrate and the
N-aryl or alkyl group of the ketone catalyst.
FIGURE 3. Two reacting approaches for the epoxidation of 3-sub-
stituted cis-â-methylstyrenes.
SCHEME 1. Synthesis of 2,2-Dimethylchromenes
Chiral dioxiranes have recently been shown to be effective
asymmetric epoxidation reagents, and a variety of chiral ketones
have been extensively investigated in various laboratories. In
1
our earlier studies, fructose-derived ketone 1 (Figure 1) has been
shown to be a very effective catalyst for the epoxidation of trans-
2
and trisubstituted olefins. Subsequently, we have found that
an oxazolidinone-bearing ketone 2 provided encouragingly high
ee’s in the epoxidation of cis-olefins and styrenes. Our recent
3
further enhance the interaction between the phenyl group of
the olefin and the phenyl group of the ketone catalyst, thus
further favoring spiro transition state A and increasing the
enantioselectivty (Figure 2). However, in the case of 3-substi-
tuted cis-â-methylstyrenes, there are two possible reacting
approaches for the favored spiro transition state (A-1 and A-2)
studies have also shown that readily available N-aryl-substituted
ketone 3 is an effective catalyst for asymmetric epoxidation of
4
a variety of cis-â-methylstyrenes. Interestingly, it was observed
that substituents on the phenyl group of cis-â-methylstyrenes
have a significant positive effect on the enantioselectivity of
the epoxidation. Our earlier studies suggested that the asym-
metric induction during the epoxidation with ketone 3 is likely
due to an attraction between the phenyl group of the olefin and
the oxazolidinone moiety of the catalyst in the transition state,
(Figure 3). We decided to probe the difference between
transition states A-1 and A-2 using cyclic olefins, so that the
reacting approach can be defined. Thus, a series of 6- and
8
-substituted 2,2-dimethylchromenes were examined for the
5
,6
3,4
epoxidation. Herein we report our studies on this subject.
causing spiro A to be more favorable than spiro B (Figure 2).
It appears that substituents on the phenyl group of the olefin
Substituted chromenes were prepared on the basis of a
7
reported procedure (Scheme 1). The epoxidation was initially
8
*
To whom correspondence should be addressed. Phone: 970-491-7424.
Fax: 970-491-1801.
1) For reviews, see: (a) Denmark, S. E.; Wu, Z. Synlett 1999, 847. (b)
Shi, Y. Acc. Chem. Res. 2004, 37, 488. (c) Yang, D. Acc. Chem. Res. 2004,
7, 497.
2) (a) Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806.
b) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem.
Soc. 1997, 119, 11224. (c) Shu, L.; Shi, Y. Tetrahedron 2001, 57, 5213.
3) (a) Tian, H.; She, X.; Shu, L.; Yu, H.; Shi, Y. J. Am. Chem. Soc.
investigated using ketone 4 as a catalyst (Figure 4). Subjecting
(
(5) For leading reviews on highly enantioselective epoxidation of
chromenes by chiral salen catalysts, see: (a) Jacobsen, E. N. Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993; p 159. (b)
Katsuki, T. Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New
York, 2000; p 287.
(6) For a recent report on highly enantioselective epoxidation of
chromenes by chiral iminium salts, see: Page, P. C. B.; Buckley, B. R.;
Heaney, H.; Blacker, A. J. Org. Lett. 2005, 7, 375.
3
(
(
(
2
1
6
000, 122, 11551. (b) Tian, H.; She, X.; Xu, J.; Shi, Y. Org. Lett. 2001, 3,
929. (c) Tian, H.; She, X.; Yu, H.; Shu, L.; Shi, Y. J. Org. Chem. 2002,
7, 2435.
(7) Godfrey, J. D., Jr.; Mueller, R. H.; Sedergran, T. C.; Soundararajan,
N.; Colandrea, V. J. Tetrahedron Lett. 1994, 35, 6405.
(4) Shu, L.; Shi, Y. Tetrahedron Lett. 2004, 45, 8115.
1
0.1021/jo0604179 CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/15/2006
J. Org. Chem. 2006, 71, 3973-3976
3973

FIGURE 4. Ketone catalysts used for the asymmetric epoxidation of
chromenes.
FIGURE 5. Two competing spiro transition states for the epoxidations
of 6-substituted 2,2-dimethylchromenes.
TABLE 1. Asymmetric Epoxidation of Chromenes Catalyzed by
Ketones 4 and 5
FIGURE 6. Chem3D molecular modeling of TS spiro C for the
epoxidation of 6-methyl-2,2-dimethyl chromene with ketone 4 (ste-
reoview).
to investigate the effect of the gem-dimethyl groups on
enantioselectivity (Table 1, entry 11). The epoxidation of this
substrate gave 90% ee, only slightly lower than 2,2-dimethyl-
6
-methylchromene (Table 1, entry 3), suggesting the gem-
dimethyl groups do not have a significant effect on enantio-
selectivity. On the other hand, when the substituent is at the
8
-position, the ee’s increase with electron-withdrawing groups,
a
such as cyano, but decrease with electron-donating groups, such
as methoxy and methyl (Table 1, entries 12-17).
The effect of substituents at the 8-position on the enantio-
selectivity is likely to be electronic in nature. In the case of
All reactions were carried out with olefin (0.40 mmol), ketone 4 (0.08
mmol), Oxone (1.07 mmol), K2CO3 (4.23 mmol), Bu4NHSO4 (0.003 mmol)
in DME/DMM (3:1 v/v) (6.0 mL), and buffer (0.1 M K2CO3-AcOH, pH
.3) (4.0 mL) at 0 °C (bath temperature). All reactions were carried out
b
9
with olefin (0.20 mmol), ketone 5 (0.04 mmol), Oxone (0.53 mmol), K2CO3
2.12 mmol), Bu4NHSO4 (0.0015 mmol) in DME/DMM (3:1 v/v) (3.0 mL),
and buffer (0.1 M K2CO3-AcOH, pH 9.3) (2.0 mL) at 0 °C (bath
temperature). Reaction time 6 h. Reaction time 12 h. The conversion
was determined by NMR. The yield is the isolated yield. The epoxides
were purified by flash chromatography (buffered with 1% NEt3) and gave
satisfactory spectroscopic characterization. For entry 11, a diol resulting
from the opening of the epoxide was also isolated in 42% yield.
6
-substituted chromenes, besides the electronic effect, the
(
proximity of substitutents on chromenes to the phenyl group of
the catalyst in spiro transition state C might cause additional
beneficial nonbonding interactions between the substituent at
the 6-position of the substrate and the phenyl group of the
catalyst, further favoring spiro transition state C (Figure 5)
(examples of Chem3D molecular modeling of transition states
spiro C and D for the epoxidation of 6-methyl-2,2-dimethyl-
chromene with ketone 4 are shown in Figures 6 and 7). On the
other hand, such interaction is not feasible for 8-substituted
substrates (Figure 8) (examples of Chem3D molecular modeling
of transition states spiro E and F for the epoxidation of 8-methyl-
c
d
e
f
Enantioselectivity was determined by chiral HPLC (Chiralcel OD).
Enantioselectivity was determined by chiral GC (Chiraldex B-DM).
Enantioselectivity was determined by chiral HPLC (Chiralcel OJ). The
g
h
i
epoxides have (3R,4R) configurations as determined by comparing the
measured optical rotations with reported ones (ref 9). j The epoxides were
isolated in 52-83% yields.
2
,2-dimethylchromene with ketone 4 are shown in Figures 9
2
%
,2-dimethylchromene to the epoxidation conditions with 20 mol
and 10). To further probe this interaction, the epoxidation of
some chromenes was also carried out with N-hexyl-substituted
ketone 5 (Figure 4). As shown in Table 1, a similar trend was
of ketone 4 at 0 °C gave (3R,4R)-(+)-2,2-dimethylchromene
9
oxide with 100% conversion and 84% ee (Table 1, entry 1).
Introducing an electron-donating or electron-withdrawing sub-
stituent at the 6-position increases the ee by 5-9%, with
electron-withdrawing groups giving generally higher ee’s (Table
(9) The absolute configuration was determined by comparing the
measured optical rotations with reported ones; see: (a) Jacobsen, E. N.;
1
, entries 2-10). Furthermore, 6-methylchromene was studied
Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L. J. Am. Chem. Soc. 1991,
113, 7063. (b) Lee, N. H.; Muci, A. R.; Jacobsen, E. N. Tetrahedron Lett.
1
991, 32, 5055. (c) Hashihayata, T.; Ito, Y.; Katsuki, T. Tetrahedron 1997,
(
8) Goeddel, D.; Shu, L.; Yuan, Y.; Wong, O. A.; Wang, B.; Shi, Y. J.
53, 9541. (d) Scheurer, A.; Mosset, P.; Spiegel, M.; Saalfrank, R. W.
Tetrahedron 1999, 55, 1063. (e) Reference 6.
Org. Chem. 2006, 71, 1715.
3
974 J. Org. Chem., Vol. 71, No. 10, 2006

FIGURE 7. Chem3D molecular modeling of TS spiro D for the
epoxidation of 6-methyl-2,2-dimethyl chromene with ketone 4 (ste-
reoview).
FIGURE 10. Chem3D molecular modeling of TS spiro F for the
epoxidation of 8-methyl-2,2-dimethylchromene with ketone 4 (stereo-
view).
to 93% ee was obtained. Similar results obtained with both
N-aryl- and alkyl-substituted ketone catalysts suggest that van
der Waals forces and/or hydrophobic interactions play important
roles in the beneficial interaction between the substitutent of
the substrate and the N-substituent of the ketone catalyst. The
information obtained could be useful for the prediction of
stereochemical outcome for given substrates and the design of
new ketone catalysts in the future.
FIGURE 8. Two competing spiro transition states for the epoxidations
of 6-substituted 2,2-dimethylchromenes.
Experimental Section
General Procedure for the Aysmmetric Epoxidation of 2,2-
Dimethylchromenes. To a mixture of 2,2-dimethylchromene (0.4
mmol), Bu
.08 mmol) was added DME/DMM (v/v 3:1) (6.0 mL). After the
mixture was stirred at rt for 20 min, buffer (0.1 M K CO -AcOH
4 4
NHSO (0.001 g, 0.003 mmol), and ketone 4 (0.028 g,
0
2
3
-
4
in 4 × 10 M aqueous EDTA, pH 9.3) (4.0 mL) was added. After
being stirred at rt for 10 more min, the mixture was cooled by an
-
4
ice bath (0 °C). Oxone (5.04 mL, 0.212 M in 4 × 10 M aqueous
-
4
EDTA) and K
2
CO
3
(5.04 mL, 0.84 M in 4 × 10 M aqueous
EDTA) were added simultaneously and separately via a syringe
pump over the period of time indicated. The reaction was quenched
by the addition of diethyl ether and extracted with diethyl ether.
The combined organic layers were washed with brine, dried with
2 4
Na SO , filtered, concentrated, and purified by flash chromatog-
3
raphy (silica gel was buffered with 1% NEt ) to afford the
corresponding epoxide.
2,2-Dimethylchromene (Table 1, Entry 1). The reaction mixture
was purified by flash chromatography (silica gel was buffered with
FIGURE 9. Chem3D molecular modeling of TS spiro E for the
epoxidation of 8-methyl-2,2-dimethylchromene with ketone 4 (stereo-
view).
1
% NEt
3
) to give the epoxide as a yellow solid (0.060 g, 86% yield,
20
8
4% ee): mp 27-29 °C; [R]
D
) +28.0 (c 0.82, THF) (84% ee);
observed (the ee’s of 6-substituted chromenes are higher than
that of 8-substituted chromenes), suggesting that a nonaromatic
group on the nitrogen could also provide the beneficial
interaction between the 6-substituent of the substrate and the
N-substituent of the ketone catalyst. The fact that both electron-
donating and electron-withdrawing groups enhance the enan-
tioselectivity of the epoxidation with ketones 4 and 5 suggests
that nonbonding interactions, such as van der Waals forces and/
or hydrophobic interactions, are important components of the
interaction between the substituent on the phenyl group of the
olefin and the N-substituent of the ketone catalyst.
-1 1
IR (film) 1491 cm ; H NMR (400 MHz, CDCl
3
) δ 7.35 (dd, J )
7.2, 1.6 Hz, 1H), 7.25 (td, J ) 7.6, 1.6 Hz, 1H), 6.94 (td, J ) 7.2,
0.8 Hz, 1H), 6.82 (d, J ) 8.0 Hz, 1H), 3.92 (d, J ) 4.2 Hz, 1H),
1
3
3.51, (d, J ) 4.2 Hz, 1H), 1.59 (s, 3H), 1.27 (s, 3H); C NMR
(
100 MHz, CDCl
3.1, 51.2, 25.9, 22.8. Anal. Calcd for C11
Found: C, 75.20; H, 6.92.
-Methoxy-2,2-dimethylchromene (Table 1, Entry 2). The
reaction mixture was purified by flash chromatography (silica gel
was buffered with 1% NEt ) to give the epoxide as a white solid
3
) δ 152.8, 130.5, 129.8, 121.3, 120.1, 118.2, 73.2,
6
12 2
H O : C, 74.98; H, 6.86.
6
3
20
(
0
0.053 g, 65% yield, 90% ee): mp 61-64 °C; [R]
D
) +12.4 (c
) (90% ee); IR (film) 1159 cm ; H NMR (400 MHz,
) δ 6.90 (d, J ) 3.2 Hz, 1H), 6.80 (dd, J ) 8.8, 2.8 Hz, 1H),
.75 (dd, J ) 8.8 Hz, 1H), 3.87 (d, J ) 4.2 Hz, 1H), 3.79 (s, 3H),
-1
1
.66, CHCl
3
In summary, asymmetric epoxidation of various chromenes
using N-substituted oxazolidinone-containing ketones 4 and 5
has shown that 6-substituents on the phenyl group of the olefin
have significant beneficial effects on the enantioselectivity. Up
CDCl
6
3
1
3
3.48 (d, J ) 4.2 Hz, 1H), 1.57, (s, 3H), 1.23 (s, 3H); C NMR
(100 MHz, CDCl
3
) δ 154.0, 146.4, 120.8 118.9, 115.8, 114.9, 72.9,
J. Org. Chem, Vol. 71, No. 10, 2006 3975

6
3.0, 56.0, 51.3, 25.9, 22.5. Anal. Calcd for C12
H
14
O
3
: C, 69.88;
Supporting Information Available: Characterization of ketone
5 and epoxides along with data for the determination of the
enantiomeric excess of the epoxides obtained with ketone 4. This
material is available free of charge via the Internet at http://
pubs.acs.org.
H, 6.84. Found: C, 70.02; H, 6.89.
Acknowledgment. We are grateful for the generous financial
support from the General Medical Sciences of the National
Institutes of Health (GM59705-07). We thank Drs. Lianhe Shu
and Yi Yuan for the synthesis of ketone 5.
JO0604179
3
976 J. Org. Chem., Vol. 71, No. 10, 2006