Asymmetric epoxidation catalyzed by α,α-dimethylmorpholinone ketone. Methyl group effect on spiro and planar transition states

Article abstract of DOI:10.1021/jo900739q

(Chemical Equation Presented) Asymmetric epoxidation of olefins by using an α,α-dimethylmorpholinone-containing chiral ketone catalyst (4) has been investigated. This ketone, which has the combined features of several previously studied catalysts, is an effective catalyst for trans- and trisubstituted olefins, and up to 97% ee has been achieved. The R, R-dimethyl group has significant impact on spiro and planar transition states.

Full text of DOI:10.1021/jo900739q

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Asymmetric Epoxidation Catalyzed by
r,r-Dimethylmorpholinone Ketone. Methyl Group
Effect on Spiro and Planar Transition States
O. Andrea Wong, Bin Wang, Mei-Xin Zhao, and Yian Shi*
FIGURE 1. Ketones 1-4.
Department of Chemistry, Colorado State University,
Fort Collins, Colorado 80523
yian@lamar.colostate.edu
Received April 7, 2009
FIGURE 2. Proposed competing transition states for the epoxida-
tion of trans- and trisubstituted olefins with ketone 1.
Asymmetric epoxidation of olefins by using an R,R-
dimethylmorpholinone-containing chiral ketone catalyst
(4) has been investigated. This ketone, which has the
combined features of several previously studied catalysts,
is an effective catalyst for trans- and trisubstituted olefins,
and up to 97% ee has been achieved. The R,R-dimethyl
group has significant impact on spiro and planar transi-
tion states.
FIGURE 3. Proposed competing transition states for the epoxida-
tion of cis-olefins with ketone 2.
ketone 3 provides encouragingly high enantioselectivity for
1,1-disubstituted and cis-olefins.4
The enantioselectivity for the epoxidation with ketone 1 is
largely due to the steric effect. Spiro A is likely to be the major
transition state, and transition states such as spiro B are
disfavored by the steric repulsion between the dimethyl ketal
group of the catalyst and the substituent on the reacting
olefin (Figure 2). Earlier studies showed that the methyl
groups on the spiro ketal ring of ketone 1 are crucial to the
high enantioselectivity obtained for trans- and trisubstituted
olefins.5
For the epoxidation of cis-olefins with ketone 2, the
stereodifferentiation likely originates from the apparent
attraction between the Rπ substituent and the oxazolidinone
moiety of the ketone catalyst, causing spiro C to be favored
over spiro D (Figure 3). In the case of trans-olefins, ketone
2 lacks dimethyl groups on its oxazolidinone moiety and
is thus less effective in stereodifferentiating spiro E and F
via the steric repulsion, resulting in more competition
from F (Figure 4) and giving lower enantioselectivity than
ketone 1.3a,3c,5,6
Chiral dioxirane-mediated epoxidation is a very useful
method to synthesize chiral epoxides. A variety of different
ketones have been investigated in various research groups.1
In our laboratory, we found that fructose-derived ketone 1 is
a very effective catalyst for the epoxidation of trans- and
trisubstituted olefins,2 and oxazolidinone-containing ke-
tones 2 are effective catalysts for a wide variety of conjugated
cis-olefins,3a,3c-3e,3g,3k,3l styrenes,3b-3d,3f and certain trisub-
stituted3h,3j and tetrasubstituted olefins3i,3j (Figure 1). Sub-
sequently, we have also found that morpholinone-containing
(1) For leading reviews, see: (a) Denmark, S. E.; Wu, Z. Synlett 1999,
847. (b) Frohn, M.; Shi, Y. Synthesis 2000, 1979. (c) Shi, Y. Acc. Chem. Res.
2004, 37, 488. (d) Yang, D. Acc. Chem. Res. 2004, 37, 497. (e) Wong, O. A.;
Shi, Y. Chem. Rev. 2008, 108, 3958.
(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. 2000,
122, 11551. (b) Tian, H.; She, X.; Xu, J.; Shi, Y. Org. Lett. 2001, 3, 1929. (c)
Tian, H.; She, X.; Yu, H.; Shu, L.; Shi, Y. J. Org. Chem. 2002, 67, 2435. (d)
Shu, L.; Wang, P.; Gan, Y.; Shi, Y. Org. Lett. 2003, 5, 293. (e) Shu, L.; Shi, Y.
Tetrahedron Lett. 2004, 45, 8115. (f) Goeddel, D.; Shu, L.; Yuan, Y.; Wong,
O. A.; Wang, B.; Shi, Y. J. Org. Chem. 2006, 71, 1715. (g) Wong, O. A.; Shi,
Y. J. Org. Chem. 2006, 71, 3973. (h) Shen, Y.-M.; Wang, B.; Shi, Y. Angew.
Chem., Int. Ed. 2006, 45, 1429. (i) Shen, Y.-M.; Wang, B.; Shi, Y. Tetrahedron
Lett. 2006, 47, 5455. (j) Wang, B.; Shen, Y.-M.; Shi, Y. J. Org. Chem. 2006,
71, 9519. (k) Burke, C. P.; Shi, Y. Angew. Chem., Int. Ed. 2006, 45, 4475. (l)
Burke, C. P.; Shi, Y. J. Org. Chem. 2007, 72, 4093. (m) Burke, C. P.; Shi, Y. J.
Org. Chem. 2007, 72, 6320.
Ketone 3 provides similar enantioselectivity for cis-olefins
such as cis-β-methylstyrene (85% ee) and 6-cyano-2,2-
dimethylchromene (84% ee) to ketone 2, indicating that
(4) Wang, B.; Wong, O. A.; Zhao, M.-X.; Shi, Y. J. Org. Chem. 2008, 73,
9539.
(5) Crane, Z.; Goeddel, D.; Gan, Y.; Shi, Y. Tetrahedron 2005, 61, 6409.
(6) trans-7-Tetradecene was epoxidized in 44% yield and 62% ee with
ketone 2 (R = p-Tol) [reaction conditions: olefin (0.5 mmol), ketone 2 (0.15
mmol), tetrabutylammonium hydrogen sulfate (0.003 mmol), Oxone (1.32
mmol, 0.20 M), K2CO3 (5.29 mmol, 0.84 M) in CH3CN-DMM (1:2, v/v)
(7.5 mL) and buffer (0.1 M K2CO3-AcOH, pH 9.3) (5.0 mL) at 0 °C for
3.5 h].
DOI: 10.1021/jo900739q
r
Published on Web 07/16/2009
J. Org. Chem. 2009, 74, 6335–6338 6335
2009 American Chemical Society

Wong et al.
JOCNote
TABLE 1. Asymmetric Epoxidation with Ketones 3 and 4a
FIGURE 4. Proposed competing transition states for the epoxida-
tion of trans-olefins with ketone 2.
FIGURE 5. Proposed competing transition states for the epoxida-
tion of cis-olefins with ketone 3.
FIGURE 6. Proposed competing transition states for the epoxida-
tion of 1,1-disubstituted olefins with ketone 3.
the aforementioned electronic attraction also exists between
the morpholinone moiety and the phenyl group of the olefin
in spiro transition state G, causing spiro G to be favored over
spiro H (Figure 5).4 The six-membered morpholinone moi-
ety of ketone 3 appears to be more favorable for such
attraction in the planar transition state as compared to the
five-membered oxazolidinone moiety of ketones 2. As a
result, ketone 3 gives higher ee values for 1,1-disubstituted
terminal olefins (up to 88% ee) than ketone 2, with planar
I being a possible favored transition state (Figure 6).4
In our continuing efforts to study the structural effect of
ketone catalysts on asymmetric epoxidation and develop
ketone catalysts with a broad substrate scope, we synthesized
ketone 4 to combine the steric and electronic features of
ketones 1 and 3 (Figure 1) with the aim to investigate whether
the dimethylmorpholinone moiety of ketone 4 would pro-
vide a steric environment similar to that of the spiro ketal of
ketone 1 to provide high enantioselectivity for trans- and
trisubstituted olefins in a manner similar to ketone 1, and
whether the dimethylmorpholinone moiety would also inter-
act with the Ar group of the olefin in a manner similar to
ketone 3, thus giving good enantioselectivity for cis- and 1,1-
disubstituted olefins as well. Herein we wish to report our
studies on this subject.
aAll reactions were carried out with olefin (0.2 mmol), ketone (0.03-
0.06 mmol), tetrabutylammonium hydrogen sulfate (0.004 g, 0.01 mmol),
Oxone (0.26 mmol, 0.20 M), K2CO3 (1.16 mmol, 0.89 M) in CH3CN-
DMM (1:2 v/v) (3mL), and buffer (0.1 M K2CO3-AcOH, pH 9.3) (2 mL)
for the indicated time and at the indicated temperature unless otherwise
stated. b0.32 mmol of Oxone (0.20 M) and 1.34 mmol of K2CO3 (0.84 M)
were used, and DME-DMM (3:1) was used as the organic solvent.
c0.32 mmol of Oxone (0.20 M) and 1.34 mmol of K2CO3 (0.84 M) were
used, and 1,4-dioxane was used as the organic solvent. dIsolated yield.
eThe ee was determined by chiral HPLC (Chiralcel OD column). fThe ee
was determined by GC (Chiraldex B-DM). gThe epoxide was opened with
NaOMe-MeOH, the resultingalcohol was converted to its benzoate, and
h
the ee was determined by chiral HPLC (Chiralcel OD-H). The ee was
i
determined by chiral HPLC (Chiralpak AD-H column). The absolute
configurations were determined by comparing the measured optical
rotations, GC trace, and HPLC trace with reported ones. This result
j
was previously reported in ref 4. kThe configuration was assigned by
analogy based on the mechanistic model described in ref 4.
The catalytic property of ketone 4 was evaluated with
various olefins. A comparison of the epoxidation results of
ketones 3 and 4 is presented in Table 1. In contrast to ketone
3, ketone 4 gave generally high enantioselectivities for the
epoxidation of trans- and trisubstituted olefins (Table 1, en-
tries 2, 4, 6, 8, and 10). For example, 90% ee was obtained for
trans-β-methylstyrene with ketone 4 (Table 1, entry 4) while
only 33% ee was obtained with ketone 3 (Table 1, entry 3).
Interestingly, the epoxidation of 1-phenylcyclohexene with
ketone 4 produced the (þ)-(R,R) epoxide in 87% ee (Table 1,
entry 12). The configuration of the resulting epoxide is
opposite to thatof the epoxideproducedfrom the epoxidation
The synthesis of ketone 4 is outlined in Scheme 1. Known
amino diol 5, prepared from D-glucose by Amadori rearran-
gement and ketalization,3d,7 was converted to ketone 4 by the
formation of six-membered morpholinone and subsequent
PDC oxidation (for the X-ray structure of ketone 4, see the
Supporting Information).
(7) Zhao, M.-X.; Goeddel, D.; Li, K.; Shi, Y. Tetrahedron 2006, 62, 8064.
(8) Zhu, Y.; Shu, L.; Tu, Y.; Shi, Y. J. Org. Chem. 2001, 66, 1818.
6336 J. Org. Chem. Vol. 74, No. 16, 2009

Wong et al.
JOCNote
FIGURE 7. Proposed competing transition states for the epoxida-
tion of trans- and trisubstituted olefins with ketones 3 and 4.
FIGURE 9. Proposed competing transition states for the epoxida-
tion of R-isopropylstyrene with ketone 3.
FIGURE 8. Proposed competing transition states for the epoxida-
tion of 1-phenylcyclohexene with ketones 3 and 4.
FIGURE 10. Proposed competing transition states for the epox-
idation of R-isopropylstyrene with ketone 4.
SCHEME 1
FIGURE 11. Proposed competing transition states for the epox-
idation of cis-olefins with ketone 4.
with ketone 3 (Table 1, entry 11) but the same as that of the
epoxide produced from the epoxidation with ketone 1.2a The
epoxidation of R-isopropylstyrene with ketones 3 and 4 also
gave opposite enantiomers (Table 1, entries 13 and 14). The
epoxidation of cis-olefins with ketone 4 is somewhat less
enantioselective compared to that with ketone 3 (Table 1,
entries 15-18).
An overlay of ketones 1 and 4 shows that the two methyl
groups at the R-position of the lactam of ketone 4 are very
close to the methyl groups on the spiro ketal of ketone 1 (for
the structure overlay of ketones 1 and 4, see the Supporting
Information). The dimethyl group on the six-membered
morpholinone of 4 thus reduces the competition from transi-
tion states such as spiro M via the greater steric repulsion as
compared to ketone 3 (R = H) (Figure 7), consequently
increasing the enantioselectivity for the epoxidation.
In the case of 1-phenylcyclohexene, the attraction between
the morpholinone moiety of ketone 3and the phenyl ring of the
olefin favors planar transition state P (Figure 8).4 As a result,
the (S,S) epoxide is obtained in 80% ee (Table 1, entry 11).
However, the dimethyl group on the morpholinone moiety of
ketone 4 disfavors the corresponding planar transition state R,
thus giving the (R,R) epoxide in 87% ee via spiro transition
state Q (Table 1, entry 12, Figure 8).
R-Isopropylstyrene is another case where the dimethyl
group in ketone 4 disfavors the planar transition state.
Planar T is favored when ketone 3 is used for the epoxida-
tion, resulting in the (þ) epoxide in 84% ee (Table 1, entry 13,
Figure 9). However, when ketone 4 is used as the catalyst,
spiro Y may become the major transition state, providing the
(-) epoxide in 45% ee (Table 1, entry 14, Figure 10).
The epoxidation of cis-olefins with ketone 3 and 4 both
provided the same enantiomer for both cis-β-methylstyrene
(Table 1, entries 15 and 16) and 6-cyano-2,2-dimethylchro-
mene (Table 1, entries 17 and 18), indicating there also exists
an attraction between the morpholinone moiety of the
catalyst and the aromatic substituent of the olefin in spiro
transition state AA of ketone 4 (Figure 11). The attraction in
spiro AA may have been weakened by the dimethyl group as
compared to spiro G of ketone 3 (Figure 5), thus giving lower
enantioselectivity for the epoxidation compared to that of
ketone 3.
J. Org. Chem. Vol. 74, No. 16, 2009 6337

Wong et al.
JOCNote
In conclusion, a ketone (4) that possesses the features of
fructose-derived ketone 1 and glucose-derived ketone 3 has
been synthesized and investigated for asymmetric epoxida-
tion. Ketone 4 has proven to be a highly effective catalyst for
the epoxidation of trans- and trisubstituted olefins. The
addition of the dimethyl group onto the morpholinone of
ketone 3 increased the enantioselectivity for trans- and
trisubstituted olefins, presumably by inhibiting competing
transition state(s) via the steric repulsion between the dimeth-
yl group of the catalyst and the olefin substituent. However,
the addition of the dimethyl group onto ketone 3 decreased
the epoxidation enantioselectivity of 1,1-disubstituted and
cis-olefins. The apparent attraction between the aromatic
group and the morpholinone moiety, particularly in planar
transition states, is decreased by the addition of the dimethyl
group, thus reducing the enantioselectivity or even giving the
opposite enantiomer in some cases. The information gained
in this study will be helpful for the future design of new
catalysts with a broader substrate scope.
109.7, 95.7, 77.3, 76.0, 73.3, 71.7, 60.7, 55.8, 28.3, 27.8, 27.0, 25.9,
21.3; HRMS calcd for C20H28NO6 (M þ 1) 378.1917, found
378.1907.
To a slurry of alcohol 6 (1.70 g, 4.5 mmol), PDC (5.12 g,
˚
13.6 mmol), and 3 A MS (3.3 g) in DCM (50 mL) was added
2 drops of AcOH. The resulting mixture was stirred at rt for
3 d (monitored by TLC until no alcohol remained), filtered
through a pad of silica gel, washed with EtOAc, concentrated,
and purified by flash chromatography (silica gel, hexanes/EtOAc
= 2/1) to give ketone 4 as a white solid (1.60 g, 95% yield). Mp
118-119 °C; [R]25 -96.9 (c 1.2, CHCl3); IR (film) 1751, 1677
D
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.23-7.17 (m, 4H), 4.86
(d, J = 5.7 Hz, 1H), 4.61 (dd, J = 5.7, 1.5 Hz, 1H), 4.46 (dd, J =
13.5, 2.4 Hz, 1H), 4.39 (d, J = 13.8 Hz, 1H), 4.18 (d,
J = 13.5 Hz, 1H), 3.78 (d, J = 13.8 Hz, 1H), 2.35 (s, 3H), 1.67
(s, 3H), 1.56 (s, 3H), 1.46 (s, 3H), 1.42 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 197.8, 170.8, 139.2, 137.1, 129.9, 125.7, 110.8,
96.5, 78.6, 78.4, 75.7, 59.6, 52.0, 27.7, 27.3, 26.6, 26.3, 21.3. Anal.
Calcdfor C20H25NO6:C, 63.99; H, 6.71. Found: C,63.75; H, 6.89.
Representative Epoxidation Procedure (Table 1, Entry 4). To a
solution of trans-β-methylstyrene (0.024 g, 0.026 mL, 0.2 mmol),
tetrabutylammonium hydrogen sulfate (0.004 g, 0.012 mmol),
and ketone 4 (0.011 g, 0.03 mmol) in CH3CN-DMM (v/v, 1:2)
Experimental Section
(3.0 mL) was added buffer (0.1 M K2CO3-AcOH in 4ꢀ10-4
M
Synthesis and Characterization of Ketone 4. To a slurry of 5
(3.09 g, 10.0 mmol)(prepared fromD-glucose in two steps)3d,7 and
NaHCO3 (1.68 g, 20.0 mmol) in DCM (400 mL) was added 2-
bromo-2-methylpropanoyl bromide (2.76 g, 1.48 mL, 12.0 mmol)
dropwise at rt. The resulting mixture was stirred at rt for 16 h to
forma brownslurry(monitored by TLCuntil nostartingmaterial
remained, the product and the starting material have similar
Rf values, but can be differentiated by color with anisaldehyde
stain). The reaction was quenched by addition of 0.1 M aqueous
K2CO3 solution (50 mL), and the layers were separated. The
organic layer was dried (Na2SO4), filtered, concentrated, and
dried under vacuum for 3 h to give crude brown syrup (this
intermediate is unstable and should be used without delay), which
was dissolved in THF (200 mL). Upon addition of NaH (60%,
0.8 g, 20.0 mmol), the resulting mixture was stirred at rt for 0.5 h,
quenched with water (0.2 mL), filtered, concentrated, and pur-
ified by flash chromatography (silica gel, hexanes/EtOAc=1/1)
aqueous EDTA, pH 9.3) (2.0 mL) with stirring. After the
mixture was cooled to 0 °C (bath temperature), a solution of
Oxone (0.20 M, in 4ꢀ10-4 M aqueous Na2(EDTA), 1.3 mL) and
a solution of K2CO3 (0.89 M in 4ꢀ10-4 M aqueous Na2(EDTA),
1.3 mL) were added separately and simultaneously with a
syringe pump over a period of 8 h at 0 °C. The reaction mixture
was quenched with hexanes, extracted with hexanes, dried over
Na2SO4, filtered, concentrated, and purified by flash chroma-
tography [the silica gel was buffered with 1% Et3N in organic
solvent; hexanes/Et2O = 50/1 was used as eluent] to give the
epoxide as a colorless oil (0.022 g, 81% yield, 90% ee).
Acknowledgment. We are grateful to the generous financial
support from the General Medical Sciences of the National
Institutes of Health (GM59705-08).
to give alcohol 6 as a light yellow syrup (1.70 g, 45% yield). [R]25
Supporting Information Available: The characterization of
epoxides, the X-ray structure of ketone 4, the structure over-
lay of ketones 1 and 4, the NMR spectra of compound 6
and ketone 4, and the 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.
D
-54.4 (c 1.0, CHCl3); IR (film) 3431, 1659 cm-1 1H NMR
;
(300 MHz, CDCl3) δ 7.22-7.16 (m, 4H), 4.30-4.23 (m, 2H),
4.19 (d, J = 12.9 Hz, 1H), 4.13 (dd, J = 13.2, 1.8 Hz, 1H), 4.00 (d,
J = 13.2 Hz, 1H), 3.71 (d, J = 12.9 Hz, 1H), 3.63-3.61 (m, 1H),
2.34 (s, 3H), 1.60 (s, 3H), 1.57 (s, 3H), 1.51 (s, 3H), 1.38 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 171.2, 139.6, 137.0, 130.0, 125.8,
6338 J. Org. Chem. Vol. 74, No. 16, 2009