A diacetate ketone-catalyzed asymmetric epoxidation of olefins

Article abstract of DOI:10.1021/jo900330n

(Chemical Equation Presented) A fructose-derived diacetate ketone has been shown to be an effective catalyst for asymmetric epoxidation. High ee values have been obtained for a variety of trans and trisubstituted olefins including electron-deficient α,β-unsaturated esters as well as certain cis olefins.

Full text of DOI:10.1021/jo900330n

reactivity and possibly reduces the decomposition via
Baeyer-Villiger oxidation. Herein we wish to report our
detailed studies on epoxidations with ketone 3a and its related
analogues.
A Diacetate Ketone-Catalyzed Asymmetric
Epoxidation of Olefins
Bin Wang, Xin-Yan Wu, O. Andrea Wong, Brian Nettles,
Mei-Xin Zhao, Dajun Chen, and Yian Shi*
Department of Chemistry, Colorado State UniVersity,
Fort Collins, Colorado 80523
yian@lamar.colostate.edu
ReceiVed February 14, 2009
Ketone 3a can be synthesized from ketone 1 in two steps
by selective deketalization with 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ)5 and subsequent acetylation with Ac2O
and a catalytic amount (2 mol %) of DMAP (Scheme 1).4
SCHEME 1
A fructose-derived diacetate ketone has been shown to be
an effective catalyst for asymmetric epoxidation. High ee
values have been obtained for a variety of trans and
trisubstituted olefins including electron-deficient R,ꢀ-unsatur-
ated esters as well as certain cis olefins.
Ketone 3a is highly electrophilic and can easily form a
hydrate with water.6 With this method, ketone 3a can be
obtained largely in ketone form by avoiding moisture. The
ꢀ-acetate of ketone 3a is prone to elimination to form an
enone. To minimize this elimination, it is crucial to use only
a small amount of DMAP (ca. 2 mol %) and to carefully
control the reaction time in the acetylation step. Nevertheless,
it was found that the resulting enone was barely active and
had little impact on the asymmetric epoxidation. Alterna-
tively, ketone 3a can be readily prepared in hydrate form
from ketone 1 by one-pot deketalization and acetylation with
Chiral ketones of various structures have been extensively
investigated for asymmetric epoxidation of olefins in a
number of laboratories.1 In our studies, we have found that
fructose-derived ketone 1 provides high ee values for a wide
variety of trans and trisubstituted olefins,2 and oxazolidinone
ketone 2 can give high ee values for olefins which had not
beeneffectivewithketone1,includingvariouscisolefins,3a,c-e,g,k,l
styrenes,3b-d,f and certain trisubstituted3h,j and tetrasubstituted
olefins.3i,j In our efforts to expand the substrate scope, we
have reported that ketone 3a is an effective epoxidation
catalyst for a variety of electron-deficient R,ꢀ-unsaturated
esters.4 Replacing the fused ketal of 1 with more electron-
withdrawing diacetates significantly enhances the ketone’s
(5) For leading references, see: (a) Fernandez, J. M. G.; Mellet, C. O.; Marin,
A. M.; Fuentes, J. Carbohydr. Res. 1995, 274, 263. (b) Tu, Y.; Wang, Z.-X.;
Frohn, M.; He, M.; Yu, H.; Tang, Y.; Shi, Y. J. Org. Chem. 1998, 63, 8475.
(6) For other examples on ketone/hydrate, see: (a) Denmark, S. E.; Forbes,
D. C.; Hays, D. S.; DePue, J. S.; Wilde, R. G. J. Org. Chem. 1995, 60, 1391.
(b) Denmark, S. E.; Wu, Z.; Crudden, C. M.; Matsuhashi, H. J. Org. Chem.
1997, 62, 8288. (c) Wang, Z.-X.; Shi, Y. J. Org. Chem. 1997, 62, 8622. (d)
Song, C. E.; Kim, Y. H.; Lee, K. C.; Lee, S.-G.; Jin, B. W. Tetrahedron:
Asymmetry 1997, 8, 2921. (e) Denmark, S. E.; Wu, Z. J. Org. Chem. 1998, 63,
2810. (f) Yang, D.; Yip, Y.-C.; Tang, M.-W.; Wong, M.-K.; Cheung, K.-K. J.
Org. Chem. 1998, 63, 9888. (g) Yang, D.; Yip, Y.-C.; Jiao, G.-S.; Wong, M.-K.
J. Org. Chem. 1998, 63, 8952. (h) Reference 5b. (i) Armstrong, A.; Hayter,
B. R. Tetrahedron 1999, 55, 11119. (j) Carnell, A. J.; Johnstone, R. A. W.;
Parsy, C. C.; Sanderson, W. R. Tetrahedron Lett. 1999, 40, 8029. (k) Reference
1a. (l) Wang, Z.-X.; Miller, S. M.; Anderson, O. P.; Shi, Y. J. Org. Chem. 1999,
64, 6443. (m) Armstrong, A.; Washington, I.; Houk, K. N. J. Am. Chem. Soc.
2000, 122, 6297. (n) Tian, H.; She, X.; Shi, Y. Org. Lett. 2001, 3, 715. (o)
Stearman, C. J.; Behar, V. Tetrahedron Lett. 2002, 43, 1943. (p) Reference 3c.
(q) Shu, L.; Shen, Y.-M.; Burke, C.; Goeddel, D.; Shi, Y. J. Org. Chem. 2003,
68, 4963. (r) Chan, W.-K.; Yu, W.-Y.; Che, C.-M.; Wong, M.-K. J. Org. Chem.
2003, 68, 6576. (s) Crane, Z.; Goeddel, D.; Gan, Y.; Shi, Y. Tetrahedron 2005,
61, 6409.
(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.
(4) Wu, X.-Y.; She, X.; Shi, Y. J. Am. Chem. Soc. 2002, 124, 8792.
3986 J. Org. Chem. 2009, 74, 3986–3989
10.1021/jo900330n CCC: $40.75 2009 American Chemical Society
Published on Web 04/23/2009

ZnCl2, AcOH, and Ac2O in water (Scheme 2).7-9 However,
if ketone 3a is desired, it can be obtained from 3a · H2O by
simply dissolving 3a · H2O in solvents such as EtOAc and
stirring with Na2SO4 overnight at rt, followed by filtration
TABLE 1. Asymmetric Epoxidation of Ethyl trans-Cinnamate
with Ketones 3, 5a, 6, 7, and 10a
entry
ketone
conv (%)
ee (%)
1b
2b
3b
4b
5b
6b
7b
8b
9c
3a
3b
3c
3d
3e
5a
6
47
27
16
34
10
1
10
4
5
95
94
94
94
90
29
91
62
42
SCHEME 2
7
10
and concentration or by passing 3a · H2O through a short
column of silica gel. In CDCl3, the hydrate gradually
converted into the ketone as judged by 1H NMR (25% ketone
at 10 min, 50% ketone at 30 min, 67% ketone at 1 h, 90%
ketone at 2 h, 100% ketone at 11 h). In CD3CN-D2O (1.5:
1, v/v), ca. 21% of the ketone was formed from the hydrate
at 1 h (ca. 22% at 7 h). When the ketone was subjected to
the same solvent mixture, ca. 26% of the ketone remained
at 1 h (ca. 25% at 7 h). It appears that a similar amount of
the ketone was present at around 1 h regardless of whether
the ketone or its hydrate was used. Similar conversions and
ee values were also obtained for the epoxidation with ethyl
trans-cinnamate as test substrate when either the ketone or
its hydrate was used. In addition to ketone 3a, several
analogues including diesters 3b-e and 6, as well as mo-
noester ketones 5, 7, and 10, were also prepared for the
epoxidation studies (Schemes 1 and 3).
a Method A: All reactions were carried out with substrate (0.5 mmol),
ketone (0.1 mmol), Bu4NHSO4 (0.03 mmol), Oxone (2.5 mmol), and
NaHCO3 (7.75 mmol) in CH3CN-aq. Na2(EDTA) (4 × 10-4 M) (6.25
mL) (v/v, 1.5/1).
A mixture of Oxone and NaHCO3 was added
portionwise over 4.5 h at 0 °C with stirring then for an additional 5.5 h
at 0 °C. For entry 8, a mixture of Oxone and NaHCO3 was added
portionwise over 4.5 h at 0 °C with stirring then for an additional 7.5 h
at 0 °C and for 12 h at room temperature. b The conversion and ee were
determined by chiral GC (Chiraldex G-TA). c The conversion and ee
were determined by chiral GC (Chiraldex B-DM).
TABLE 2. Asymmetric Epoxidation of Olefins Catalyzed by
Ketone 3aa
SCHEME 3
Ethyl trans-cinnamate was used for initial epoxidations with
each of these ketones (20 mol %). As shown in Table 1,
diacetate ketone 3a was found to be among the most effective
ketones in terms of both conversion and enantioselectivity.
Various R,ꢀ-unsaturated esters were subsequently examined
a Method A: All reactions were carried out with substrate (0.5 mmol),
ketone 3a (0.1-0.15 mmol), Bu4NHSO4 (0.03 mmol), Oxone (2.5
mmol), and NaHCO3 (7.75 mmol) in CH3CN-aq. Na2(EDTA) (4 ×
10-4 M) (6.25 mL) (v/v, 1.5/1). A mixture of Oxone and NaHCO3 was
added portionwise over 4.5 h at 0 °C with stirring then for an additional
7.5 h at 0 °C and for 12 h at rt. For entry 3 a mixture of Oxone and
NaHCO3 was added portionwise over 4.5 h at 0 °C and with stirring
then for an additional 7.5 h at 0 °C. b Isolated yields. c 0.15 mmol 3a
used. d 0.125 mmol 3a used. e 0.10 mmol 3a used. f Determined by
chiral GC (Chiraldex G-TA). g Determined by chiral HPLC (Chiralpak
AD). h Determined by chiral HPLC (Chiralcel OD). i Determined by
chiral HPLC (Chiralcel OB). j Determined by comparing the measured
optical rotations with the reported ones.
(7) For a leading reference on selective deketalization with aqueous AcOH,
see: Kang, J.; Lim, G. J.; Yoon, S. K.; Kim, M. Y. J. Org. Chem. 1995, 60, 564.
(8) For a leading reference on Lewis acid-catalyzed acetylation, see: Orita,
A.; Tanahashi, C.; Kakuda, A.; Otera, J. J. Org. Chem. 2001, 66, 8926.
(9) For a related two-step procedure with AcOH-H2O, Ac2O-ZnCl2 from
ketone 1, see: Nieto, N.; Molas, P.; Benet-Buchholz, J.; Vidal-Ferran, A. J. Org.
Chem. 2005, 70, 10143.
(10) For leading reviews on various effective asymmetric epoxidation of
electron-deficient olefins see: (a) Porter, M. J.; Skidmore, J. Chem. Commun.
2000, 1215. (b) Lauret, C.; Roberts, S. M. Aldrichim. Acta 2002, 35, 47. (c)
Kelly, D. R.; Roberts, S. M. Biopolymers 2006, 84, 74. (d) Shibasaki, M.; Kanai,
M.; Matsunaga, S. Aldrichim. Acta 2006, 39, 31. (e) D´ıez, D.; Nu´n˜ez, M. G.;
Anto´n, A. B.; Garc´ıa, P.; Moro, R. F.; Garrido, N. M.; Marcos, I. S.; Basabe,
P.; Urones, J. G. Curr. Org. Synth. 2008, 5, 186. (f) Lattanzi, A. Curr. Org.
Synth. 2008, 5, 117.
(11) Cabon, O.; Buisson, D.; Larcheveque, M.; Azerad, R. Tetrahedron:
Asymmetry 1995, 6, 2211.
(12) Yamamoto, M.; Hayashi, M.; Masaki, M.; Nohira, H. Tetrahedron:
Asymmetry 1991, 2, 403.
(13) Abidi, S. L.; Wolfhagen, J. L. J. Org. Chem. 1979, 44, 433.
(14) Bougauchi, M.; Watanabe, S.; Arai, T.; Sasai, H.; Shibasaki, M. J. Am.
Chem. Soc. 1997, 119, 2329.
with ketone 3a (20-30 mol %). As shown in Table 2, high
ee values were obtained for substituted cinnamates and a
variety of trisubstituted R,ꢀ-unsaturated esters (for more
examples, see ref 4). While certain enones could give good
J. Org. Chem. Vol. 74, No. 10, 2009 3987

TABLE 3. Asymmetric Epoxidation of Olefins Catalyzed by
Ketone 3aa,b
FIGURE 1. Possible competing spiro transition states for the epoxi-
dation of trans and trisubstituted olefins with ketone 3a.
FIGURE 2. Possible competing spiro transition states for the epoxi-
dation of cis olefins with ketone 3a.
ee values (Table 2, entry 9), ketone 3a is less effective for
enones in general.10
The epoxidation with other types of olefins was also inves-
tigated.15 Studies with trans-ꢀ-methylstyrene showed that a
smaller amount of ketone catalyst (10 mol %) was required when
the epoxidation was carried out at a slightly higher pH (around
8.75 to 9.50) with slow addition of Oxone and K2CO3 solutions
(method B). This protocol is usually effective for relatively
reactive substrates. The epoxidation with ketone 3a gave good
to high ee values for various trans and trisubstituted olefins
including less reactive trans enimides (Table 3, entries 1-9).
High ee values were obtained for certain cis olefins such as
aromatic conjugated olefins with bulky R groups (Table 3,
entries, 14-17). Low ee values were obtained for terminal and
tetrasubstituted olefins tested (Table 3, entries 19-21). Figures
1 and 2 list a few possible competing spiro transition states for
trans, trisubstituted, and cis olefins.16 On the basis of the
determined configurations of some epoxide products in Tables
2 and 3, the epoxidation for trans and trisubstituted olefins likely
proceeds via spiro transition state A with possible contribution
from B (Figure 1) (at least in these cases). For conjugated
aromatic cis olefins, the epoxidation appears to proceed via spiro
transition state E with possible contribution from F based on
the configurations determined (Table 3).
a Method A: All reactions were carried out with olefin (0.5 mmol),
ketone 3a (0.125 mmol), Bu4NHSO4 (0.03 mmol), Oxone (2.5 mmol), and
NaHCO3 (7.75 mmol) in CH3CN-aq. Na2(EDTA) (4 × 10-4 M) (6.25 mL)
(v/v, 1.5/1). For entries 1, 2, 5, and 6, a mixture of Oxone and NaHCO3
was added portionwise over 4.5 h at 0 °C with stirring then for an
additional 7.5 h at 0 °C and for 12 h at rt. For entries 8 and 9, a mixture of
Oxone and NaHCO3 was added portionwise over 3 h at 0 °C with stirring
for another 11 h at 0 °C. b Method B: All epoxidations were carried out
with substrate (0.5 mmol), ketone 3a·H2O (0.046 mmol) (0.1 mmol for
entries 14 and 15), Oxone (1.01 mmol), and K2CO3 (2.02 mmol) in
CH3CN-DMM (9 mL) (v/v, 1/2), and buffer (0.05 M Na2HPO4/0.05 M
KH2PO4, pH 7.0, 3 mL) at 0 °C for 8, 16, or 24 h. c Isolated yields.
d Determined by comparing the measured optical rotations with the reported
ones. e Determined by chiral GC (Chiraldex B-DM). f Determined by chiral
HPLC (Chiralcel OD). g The epoxide was opened (NaOMe-MeOH), the
resulting alcohol was converted to its benzoate, enantioselectivity was
determined by chiral HPLC (Chiralcel OD-H). h Determined by chiral
HPLC (Chiralpak AD-H). i Determined by chiral HPLC (Chiralcel OD-H).
(15) For recent epoxidation examples catalyzed by ketone 3a, see: (a) ref 9.
(b) Nieto, N.; Munslow, I. J.; Ferna´ndez-Pe´rez, H.; Vida-Ferran, A. Synlett 2008,
2856. (c) Hirooka, Y.; Nitta, M.; Furuta, T.; Kan, T. Synlett 2008, 3234.
(16) Some planar transition states may also be competing. However, the extent
of their involvement awaits further studies.
(17) Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 3099.
(18) Zhu, Y.; Shu, L.; Tu, Y.; Shi, Y. J. Org. Chem. 2001, 66, 1818.
(19) Denis, J. N.; Greene, A. E.; Serra, A. A.; Luche, M. J. J. Org. Chem.
1986, 51, 46.
(20) Capriati, V.; Florio, S.; Luisi, R.; Salomone, A. Org. Lett. 2002, 4, 2445.
3988 J. Org. Chem. Vol. 74, No. 10, 2009

3436, 1736 cm-1; 1H NMR (400 MHz, CDCl3) (ketone) δ 5.89 (d,
J ) 4.0 Hz, 1H), 5.60-5.62 (m, 1H), 4.70 (d, J ) 9.6 Hz, 1H),
4.44 (dd, J ) 13.2, 1.2 Hz, 1H), 3.99 (d, J ) 9.6 Hz, 1H), 3.96
(dd, J ) 13.2, 2.0 Hz, 1H), 2.17 (s, 3H), 2.12 (s, 3H), 1.55 (s, 3H),
1.40 (s, 3H); 13C NMR (75 MHz, CDCl3) (ketone) δ 192.0, 170.4,
169.6, 114.1, 105.2, 74.2, 72.3, 69.6, 62.7, 26.6, 26.2, 21.0, 20.6.
Anal. Calcd for C13H20O9 (hydrate): C, 48.75; H, 6.29. Found: C,
49.14; H, 6.12.
Representative Asymmetric Epoxidation Procedure with
Oxone and NaHCO3 (Method A) (Table 2, Entry 2). Aqueous
Na2(EDTA) (1 × 10-4 M, 2.5 mL) and a catalytic amount of
tetrabutylammonium hydrogen sulfate (0.010 g, 0.03 mmol) were
added to a solution of ethyl trans-4-methylcinnamate (0.095 g, 0.5
mmol) in CH3CN (2.5 mL) with vigorous stirring at 0 °C. A mixture
of Oxone (1.537 g, 2.5 mmol) and NaHCO3 (0.651 g, 7.75 mmol)
was pulverized, and a small portion of this mixture was added to
the reaction mixture to bring the pH to >7.0. Then a solution of
ketone 3a (0.038 g, 0.125 mmol) in CH3CN (1.25 mL) was added.
The rest of the Oxone and NaHCO3 was added to the reaction
mixture portionwise over a period of 4.5 h. After being stirred for
an additional 7.5 h at 0 °C and 12 h at rt, the resulting mixture was
diluted with water and extracted with ethyl acetate. The combined
extracts were washed with brine, dried over Na2SO4, filtered,
concentrated, and purified by flash chromatography (silica gel,
hexane/EtOAc ) 1/0 to 95/5) to give the epoxide as a colorless oil
(0.094 g, 91% yield, 97% ee).
In summary, several fructose-derived diester and monoester
ketones were investigated for asymmetric epoxidation. Diacetate
ketone 3a has been found to be the most effective catalyst among
those ketones investigated. High ee values have been obtained
for a variety of trans and trisubstituted olefins as well as certain
cis olefins. While it is generally less enantioselective than ketone
1 for trans and trisubstituted olefins and less enantioselective
than ketone 2 for cis olefins, ketone 3a is more effective than
1 and 2 for electron-deficient olefins, thus providing a comple-
mentary epoxidation system to ketones 1 and 2. Future efforts
will be devoted to further understanding the structural effect of
ketones on catalysis and developing more effective catalytic
systems.
Experimental Section
Representative Synthesis of Ketone 3a. To a solution of ketone
1 (6.90 g, 26.7 mmol) in CH3CN-H2O (v/v, 9/1) (90 mL) was
added DDQ (0.60 g, 2.60 mmol) at rt. Upon being stirred at rt for
7 h, the reaction mixture was concentrated, dissolved in EtOAc
(80 mL), dried (Na2SO4), filtered, concentrated, and purified by
flash chromatography (silica gel, hexane/EtOAc ) 1/0 to 1/1) to
give 4 as a white solid (4.00 g, 69% yield). Mp 107-110 °C; [R]25
D
-140.0 (c 0.80, MeOH); IR (film) 3469, 3402, 1747 cm-1; 1H NMR
(300 MHz, CDCl3) δ 4.74 (d, J ) 4.2 Hz, 1H), 4.68 (d, J ) 9.6
Hz, 1H), 4.39 (m, 1H), 4.32 (d, J ) 12.9 Hz, 1H), 4.00 (d, J ) 9.6
Hz, 1H), 3.98 (dd, J ) 12.9, 2.4 Hz, 1H), 3.29 (m, 2H), 1.54 (s,
3H), 1.39 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 199.0, 113.6,
104.5, 74.4, 73.8, 69.7, 63.6, 26.6, 26.4.
[For Table 2 entry 3, 7.5 mL of CH3CN and 5.0 mL of aqueous
Na2(EDTA) (1 × 10-4 M) were used due to the poorer solubility
of the substrate. For Table 2 entry 3 as well as Table 3, the silica
gel was buffered with 1% Et3N in hexane.]
Representative Asymmetric Epoxidation Procedure with
Oxone and K2CO3 (Method B) (Table 3, Entry 1). To a solution
of olefin (0.059 g, 0.5 mmol), ketone 3a (hydrate form) (0.015 g,
0.046 mmol), and tetrabutylammonium hydrogen sulfate (0.01 g,
0.03 mmol) in MeCN-DMM (v/v, 1/2) (9 mL) was added buffer
(0.05 M aq Na2HPO4-0.05 M aq KH2PO4, pH 7.0) (3 mL) with
stirring. Upon cooling to 0 °C, a solution of Oxone (0.212 M in 4
× 10-4 M aq EDTA, 4.8 mL) and a solution of K2CO3 (0.42 M in
4 × 10-4 M aq EDTA, 4.8 mL) were added dropwise simulta-
neously and 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 over Na2SO4, filtered,
concentrated, and purified by flash chromatography (silica gel was
buffered with 1% Et3N in organic solvent, first pentane, then
pentane/Et2O ) 20/1) to give the epoxide as a colorless oil (0.054
g, 81% yield, 86% ee).
To a solution of 4 (3.51 g, 16.10 mmol) and DMAP (0.039 g,
0.32 mmol) in dry DCM (150 mL) was added dropwise Ac2O (4.97
g, 48.70 mmol) at 0 °C over 20 min. After being stirred at rt for
16 h (monitored by TLC), the reaction mixture was filtered through
a short silica gel column. The filtrate was concentrated and purified
by flash chromatography (silica gel, hexane/EtOAc ) 1/0 to 3/1)
to give ketone 3a as colorless syrup (3.84 g, 79% yield). [R]25
D
-103.0 (c 0.98, CHCl3); IR (film) 1750 cm-1; 1H NMR (400 MHz,
CDCl3) δ 5.89 (d, J ) 3.9 Hz, 1H), 5.62-5.60 (m, 1H), 4.70 (d,
J ) 9.6 Hz, 1H), 4.44 (d, J ) 13.2 Hz, 1H), 3.99 (d, J ) 9.6 Hz,
1H), 3.96 (dd, J ) 13.2, 2.1 Hz, 1H), 2.18 (s, 3H), 2.13 (s, 3H),
1.55 (s, 3H), 1.41 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 192.0,
170.4, 169.6, 114.1, 105.2, 74.2, 72.3, 69.6, 62.7, 26.6, 26.2, 21.0,
20.6; HRMS calcd for C13H19O8 (M + 1) 303.1080, found 303.1087.
One-Pot Synthesis of Ketone 3a. AcOH (17.5 mL) and
deionized water (4.3 mL) were added to a mixture of ketone 1
(12.90 g, 50.0 mmol) and ZnCl2 (0.17 g, 1.25 mmol) in a 250 mL
round-bottomed flask equipped with a Teflon-coated magnetic stir
bar. After the resulting suspension was stirred at rt for 8-10 h,
Ac2O (64.9 g, 635.8 mmol) was added into the reaction flask. After
the resulting mixture was stirred at rt for 16 h, deionized water (30
mL) was added. After being stirred at rt for 20 min, the reaction
mixture was concentrated in vacuo (130 mmHg, 55 °C) until about
20 mL of solution remained. The resulting solution was transferred
to a 100 mL beaker, and 10 mL of deionized water was used to
rinse the flask and transferred to the beaker. After being shaken
slightly for 5 min, the mixture was then placed in an ice bath for
2 h, and the solid (mud-like) precipitated. The solid was filtered
through a Bu¨chner funnel, washed by ice-cold H2O (5 mL) and
ice-cold hexane (20 mL), and dried under vacuum pump (10-20
mmHg) overnight to give ketone 3a·H2O as a white solid (12.2 g,
76% yield). Mp 81-84 °C; [R]25D -112.0 (c 1.05, CHCl3); IR (film)
Acknowledgment. We are grateful to the generous financial
support from the General Medical Sciences of the National
Institutes of Health (GM59705-08). We thank Dr. Yuanming
Zhu for initial studies on the epoxidation of enimides with
ketone 1.
Supporting Information Available: The synthesis and
characterization of ketones 3, 4, 5, 6, 7, 9, and 10; the
characterization of epoxides, the X-ray structure of ketone 5a,
the NMR spectra of ketones and epoxides, and the data for the
determination of the enantiomeric excess of the epoxides
obtained with ketone 3a. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO900330N
J. Org. Chem. Vol. 74, No. 10, 2009 3989