A catalytic asymmetric synthesis of chiral glycidic acid derivatives through chiral dioxirane-mediated catalytic asymmetric epoxidation of cinnamic acid derivatives

Article abstract of DOI:10.1021/jo049893u

A novel and practical asymmetric synthesis of chiral glycidic acid derivatives involving methyl (2R,3S)-3-(4-methoxyphenyl)glycidate ((2R,3S)-2a), a key intermediate for diltiazem hydrochloride (1), was developed. Treatment of methyl (E)-4-methoxycinnamate ((E)-3a) with chiral dioxirane, generated in situ from a catalytic amount (5 mol %) of an 11-membered C₂-symmetric binaphthyl ketone (R)-7a, provided (2R,3S)-2a in 92% yield and 80% ee. Other cinnamic acid esters and amides were epoxidized by the use of the same procedure to give the corresponding chiral glycidic acid derivatives with up to 95% yield and 92% ee. Higher enantioselectivities in the asymmetric epoxidation of (E)-cinnamates than that of (E)-stilbene derivatives were observed and were proposed to be attributed to a dipole-dipole repulsion between oxygen atoms of an ester group in the cinnamates and those of the lactone moieties in the binaphthyl dioxirane.

Full text of DOI:10.1021/jo049893u

A Ca ta lytic Asym m etr ic Syn th esis of Ch ir a l Glycid ic Acid
Der iva tives th r ou gh Ch ir a l Dioxir a n e-Med ia ted Ca ta lytic
Asym m etr ic Ep oxid a tion of Cin n a m ic Acid Der iva tives
Ritsuo Imashiro† and Masahiko Seki*,‡
Medicinal Research Laboratories, Tanabe Seiyaku Co., Ltd., 3-16-89, Kashima, Yodogawa-ku,
Osaka 532-8505, J apan and Export & Import Group, Purchasing Department, Logistics Division,
Tanabe Seiyaku Co., Ltd., 3-2-10, Dosho-Machi, Chuo-ku, Osaka 541-8505, J apan
m-seki@tanabe.co.jp
Received J anuary 19, 2004
A novel and practical asymmetric synthesis of chiral glycidic acid derivatives involving methyl
(2R,3S)-3-(4-methoxyphenyl)glycidate ((2R,3S)-2a ), a key intermediate for diltiazem hydrochloride
(1), was developed. Treatment of methyl (E)-4-methoxycinnamate ((E)-3a ) with chiral dioxirane,
generated in situ from a catalytic amount (5 mol %) of an 11-membered C2-symmetric binaphthyl
ketone (R)-7a , provided (2R,3S)-2a in 92% yield and 80% ee. Other cinnamic acid esters and amides
were epoxidized by the use of the same procedure to give the corresponding chiral glycidic acid
derivatives with up to 95% yield and 92% ee. Higher enantioselectivities in the asymmetric
epoxidation of (E)-cinnamates than that of (E)-stilbene derivatives were observed and were proposed
to be attributed to a dipole-dipole repulsion between oxygen atoms of an ester group in the
cinnamates and those of the lactone moieties in the binaphthyl dioxirane.
In tr od u ction
as well.3 While a current industrial production of (2R,3S)-
2a has relied upon kinetic resolution of racemates
(()-2a through a lipase-catalyzed asymmetric hydroly-
sis,4 it suffers from such drawbacks as a poor yield (42%)
of (2R,3S)-2a as well as waste materials (ca. 200 t/year)
arising from the unwanted enantiomer (2S,3R)-2a . A
catalytic asymmetric synthesis of the chiral glycidic acid
derivatives involving (2R,3S)-2a has therefore been
highly desirable.
Diltiazem hydrochloride (1) is one of the most potent
calcium antagonists and has been used for over 20 years
as a drug for the treatment of angina and hypertension.1
Among a number of synthetic approaches to 1, a method
utilizing methyl (2R,3S)-4-methoxyglycidate ((2R,3S)-2a )
While the asymmetric synthesis of the chiral glycidic
acid derivatives has so far been extensively investigated,5-9
an approach based on catalytic asymmetric epoxidation
of cinnamates is considered to be the most efficient one,
since the chiral glycidates can be obtained in a single step
from the readily available cinnamates.9 J acobsen and co-
(3) (a) Gou, D.-M.; Liu, Y.-C.; Chen, C.-S. J . Org. Chem. 1993, 58,
1287-1289. (b) Srivastava, R. P.; Zjawiony, J . K.; Peterson, J . R.;
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1998, 39, 5575-5578. (d) Rao, A. V. R.; Rao, S. P.; Bhanu, M. N. J .
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K. B. Tetrahedron 1992, 48, 10515-10530. (f) Flisak, J . R.; Gombatz,
K. J .; Holmes, M. M.; J armas, A. A.; Lantos, I.; Mendelson, W. L.;
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6254. (g) Inoue, H.; Konda, M.; Hashiyama, T.; Otsuka, H.; Watanabe,
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Pharm. Bull. 1997, 45, 1008-1026.
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Shibatani, T. J . Ferment. Bioeng. 1993, 75, 93-98. (c) Matsumae, H.;
Shibatani, T. J . Ferment. Bioeng. 1994, 77, 152-158. (d) Matsumae,
H.; Furui, M.; Shibatani, T.; Tosa, T. J . Ferment. Bioeng. 1994, 78,
59-63. (e) Furutani, T.; Furui, M.; Mori, T.; Shibatani, T. Appl.
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21-25. (g) Matsumae, H.; Akatsuka, H.; Furui, M.; Shibatani, T.; Tosa,
T. Seibutsukougakukaishi 1995, 74, 273-288.
as a key intermediate has been recognized to be the most
efficient one.2 The chiral glycidates are key intermediates
crucial for synthesizing other drugs and natural products
† Medicinal Research Laboratories.
‡ Export & Import Group, Purchasing Department, Logistics Divi-
sion.
(1) (a) Inoue, H.; Takeo, S.; Kawazu, M.; Kugita, H. Yakugaku Zasshi
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A. Chem. Pharm. Bull. 1973, 21, 92-97. (c) Abe, K.; Inoue, H.; Nagao,
T. Yakugaku Zasshi 1988, 108, 716-732.
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10.1021/jo049893u CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/19/2004
4216
J . Org. Chem. 2004, 69, 4216-4226

Synthesis of Chiral Glycidic Acid Derivatives
workers have reported catalytic asymmetric epoxidation
of (Z)-cinnamates employing a chiral salen-manganese
complex as the catalyst.9a Although excellent enantiose-
lectivities (up to 96% ee) were achieved, the synthetic
method requires poorly accessible (Z)-cinnamates as the
starting materials, and the products are obtained as a
mixture of (E)- and (Z)-epoxides. Shibasaki and co-
workers have recently reported that catalytic asymmetric
epoxidation of (E)-R,â-unsaturated carboxylic acid imi-
dazolides, followed by the decomposition of the peroxides
with MeOH, gave optically active glycidates with high
yields and enantioselectivities (up to 93% ee).9i,j However,
it requires highly toxic triphenylarsine as an additive and
an expensive phenylimidazolide as the starting material.
Chiral dioxiranes, generated in situ from chiral ketones
and Oxone, have been reported as the promising oxidizing
reagents for asymmetric epoxidation of olefins.9b-h,10-12
Nonetheless, the enantioselective epoxidation of R,â-
unsaturated acid derivatives with chiral dioxirane still
remaines a challenging issue. As the dioxiranes are
electrophilic oxidants, they are generally inert to electron-
deficient olefins such as R,â-unsaturated acid deriva-
tives.12 For instance, epoxidation of cinnamates with
chiral dioxirane, derived either from R-fluoro-N-ethoxy-
carbonyltropinone (4)9d or chiral R-fluoro cyclohexanones
5,9f proceeds in only moderate yields and enantioselec-
tivities. Although Shi and co-workers have accompolished
excellent enantioselectivities in the catalytic asymmetric
epoxidation of cinnamates employing fructose-derived
ketone 6, yields of the chiral glycidates were only
moderate to good even by the use of excess Oxone (5
equiv) and a subequimolar amount of the chiral ketone
(30 mol %).9g
Meanwhile, Yang and co-workers have developed 11-
membered C2-symmetric biaryl ketones (R)-7a -d that
catalyze epoxidation of various (E)-di- and trisubstituted
olefins with high yields and high enantioselectivities.11
We envisioned a possible use of the biaryl ketones (R)-
7a -d as catalysts for the asymmetric epoxidation of
methyl (E)-4-methoxycinnamate ((E)-3a) to obtain (2R,3S)-
2a . In contrast to 4-6, the catalysts (R)-7a -d might
induce both high reactivity and enantioselectivity in the
epoxidation of (E)-3a due to the presence of the two
electron-withdrawing lactone moieties in (R)-7a -d and
π-π interactions between the aromatic groups in (R)-
7a -d and (E)-3a . An enhanced stereocontrol should be
expected as well on (R)-7a -d over 4-6, since the epoxi-
dation employing (R)-7a -d may proceed with homotopic
ring opening of the dioxiranes, while that employing 4-6
must involve heterotopic cleavage. The ketones (R)-7a -d
have an additional and significant advantage of easy
preparation by using our reported procedure.13
(5) For asymmetric Darzens reaction, see: (a) Corey, E. J .; Choi, S.
Tetrahedron Lett. 1991, 32, 2857-2860. (b) Schwartz, A.; Madan, P.
B.; Mohacsi, E.; O’Brien, J . P.; Todaro, L. J .; Coffen, D. L. J . Org Chem.
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Kojima, S.; Ohkata, K. J . Chem. Soc., Perkin Trans. 1 1998, 689-698.
(f) Wang, Y.-C.; Li, C.-L.; Tseng, H.-K.; Chuang, S.-C.; Yan, T.-H.
Tetrahedron: Asymmetry 1999, 10, 3249-3251. (g) Kiyooka, S.-i.;
Shahid, K. A. Tetrahedron: Asymmetry 2000, 11, 1537-1542. (h)
Imashiro, R.; Kuroda, T. Tetrahedron Lett. 2001, 42, 1313-1315. (i)
Imashiro, R.; Kuroda, T. J . Org. Chem. 2003, 68, 974-979.
(6) For asymmetric dihydroxylation, see: Watson, K. G.; Fung, Y.
M.; Gredley, M.; Bird, G. J .; J ackson, W. R.; Gountzos, H.; Matthews,
B. R. J . Chem. Soc., Chem Commun. 1990, 1018-1019.
(7) For asymmetric reduction, see: (a) Matsuki, K.; Sobukawa, M.;
Kawai, A.; Inoue, H.; Takeda, M. Chem. Pharm. Bull. 1993, 41, 643-
648. (b) Geneˆt, J .-P.; Canˇo de Andrade, M. C.; Ratovelomanana-Vidal,
V. Tetrahedron Lett. 1995, 36, 2063-2066.
(8) For asymmetric epoxidation of aldehydes, see: (a) Zhou, Y.-G.;
Hou, X.-L.; Dai, L.-X.; Xia, L.-J .; Tang, M.-H. J . Chem. Soc., Perkin
Trans. 1 1999, 77-80. (b) Imashiro, R.; Yamanaka, T.; Seki, M.
Tetrahedron: Asymmetry 1999, 10, 2842-2851. (c) Aggarwal, V. K.;
Hynd, G.; Picoul, W.; Vasse, J .-L. J . Am. Chem. Soc. 2002, 124, 9964-
9965.
We report herein a novel synthesis of (2R,3S)-2a 14 and
other chiral glycidic acid derivatives through catalytic
asymmetric epoxidation of cinnamaic acid derivatives
with chiral C2-symmetric biaryl ketone (R)-7a used as a
catalyst. The origin of the stereocontrol in the asymmetric
epoxidation will be discussed as well.
(9) For asymmetric epoxidation of cinnamic acid derivatives, see:
(a) J acobsen, E. N.; Deng, L.; Furukawa, Y.; Mart´ınez, L. E. Tetrahe-
dron 1994, 50, 4323-4334. (b) Adger, B. M.; Barkley, J . V.; Bergeron,
S.; Cappi, M. W.; Flowerdew, B. E.; J ackson, M. P.; McCague, R.;
Nugent, T. C.; Roberts, S. M. J . Chem. Soc., Perkin Trans. 1 1997,
3501-3507. (c) Wang, Z.-X.; Shi, Y. J . Org. Chem. 1997, 62, 8622-
8623. (d) Armstrong, A.; Hayter, B. R. Chem. Commun. 1998, 621-
622. (e) Wang, Z.-X.; Miller, S. M.; Anderson, O. P.; Shi, Y. J . Org.
Chem. 1999, 64, 6443-6458. (f) Solladie´-Cavallo, A.; Boue´rat, L. Org.
Lett. 2000, 2, 3531-3534. (g) Wu, X.-Y.; She, X.; Shi, Y. J . Am. Chem.
Soc. 2002, 124, 8792-8793. (h) Armstrong, A.; Ahmed, G.; Dominguez-
Fernandez, B.; Hayter, B. R.; Wailes, J . S. J . Org. Chem. 2002, 67,
8610-8617. (i) Nemoto, T.; Ohshima, T.; Shibasaki, M. J . Am. Chem.
Soc. 2001, 123, 9474-9475. (j) Nemoto, T.; Tosaki, S.; Ohshima, T.;
Shibasaki, M. Chirality 2003, 15, 306-311. (k) Nemoto, T.; Kakei, H.;
Gnanadesikan, V.; Tosaki, S.; Shibasaki, M. J . Am. Chem. 2002, 124,
14544-14545.
Resu lts a n d Discu ssion
Scr een in g of Ch ir a l Bia r yl Keton e Ca ta lysts (R)-
7a -d . The chiral binaphthyl ketones (R)-7a ,b were
efficiently prepared by conducting our previously reported
procedure.13c,d Other chiral biphenyl ketones (R)-7c,d
were synthesized according to the literature.11c Treatment
of (E)-3a with Oxone (5 equiv) and NaHCO3 (15.5 equiv)
in the presence of (R)-7a -d (10 mol %) in DME-aq 0.4
µM Na2EDTA [2:1, 60 volume (mL) per weight (g) of (E)-
3a (v/w)] at 27 °C for 27 h provided the desired glycidate
(2R,3S)-2a in both good yields and enantioselectivities
(52-87% yield, 67-85% ee, Table 1). It should be noted
J . Org. Chem, Vol. 69, No. 12, 2004 4217

Imashiro and Seki
TABLE 1. Ca ta lytic Asym m etr ic Ep oxid a tion of (E)-3a
w ith Ch ir a l Dioxir a n es Gen er a ted in Situ fr om Ca ta lysts
(R)-7a -d
TABLE 2. Effect of Solven ts in th e Ca ta lytic Aym m etr ic
Ep oxid a tion of (E)-3a w ith Ca ta lyst (R)-7a
assay
assay
entryb
solvent
DME
DME
t (h)c
yield (%)d
ee (%)d
entryb
catalyst
yield (%)c
ee (%)c
1e
2
3
4
5
6
7
8
9
10
11
12f
13f
14
15
2
2
22.5
4.5
4
3.5
21
22
4
2
7
24
22
5.5
4.5
83
86
33
67
62
2
27
19
45
93
0
78
78
72
71
73
31
63
73
70
49
1
2
3
4
(R)-7a
(R)-7b
(R)-7c
(R)-7d
87
74
52
86
76
85
67
68
CH3CN
EtOCH2CH2OH
MeOCH2CH2OH
HOCH2CH2OH
MeOH
a
b
Volume (mL) per weight (g) of (E)-3a . Reactions were
conducted on a 10-mmol scale. c Determined by HPLC analysis.
iPrOH
DMF
acetone
that any cis-glycidates were not detected at all in the
reaction mixture by HPLC. The binaphthyl ketones (R)-
7a ,b proved to be more effective than the biphenyl
counterparts (R)-7c,d (Table 1, entries 1 and 2 versus
entries 3 and 4). 3,3′-Dichloro-1,1′-binaphthyl ketone (R)-
7b provided (2R,3S)-2a in higher enantioselectivity (85%
ee) than the corresponding unsubstituted one (R)-7a (76%
ee) (Table 1, entries 1 and 2). The stereochemical outcome
tBuOMe
toluene
CH2Cl2
1,4-dioxane
1,3-dioxorane
0
0
81
23
76
75
a
b
Volume (mL) per weight (g) of (E)-3a . Reactions were
conducted on a 10-mmol scale. Oxone and NaHCO3 were added
portionwise every 5 min over 1.5 h. c Reaction time after addition
of reagents. Determined by HPLC analysis. e Na2EDTA was
d
added. f 1 mol % of Bu4NHSO4 was added.
(10) (a) Curci, R.; Fiorentino, M.; Serio, M. R. J . Chem. Soc., Chem.
Commun. 1984, 155-156. (b) Curci, R.; D’Accolti, L.; Fiorentino, M.;
Rosa, A. Tetrahedron Lett. 1995, 36, 5831-5834. (c) Brown, D. S.;
Marples, B. A.; Smith, P.; Walton, L. Tetrahedron 1995, 51, 3587-
3606. (d) Tu, Y.; Wang, Z.-X.; Shi, Y. J . Am. Chem. Soc. 1996, 118,
9806-9807. (e) Wang, Z.-X.; Tu, Y.; Frohn, M.; Shi, X. J . Org. Chem.
1997, 62, 2328-2329. (f) Denmark, S. E.; Wu, Z.; Crudden, C. M.;
Matsuhashi, H. J . Org. Chem. 1997, 62, 8288-8289. (g) Wang, Z.-X.;
Shi, Y. J . Org. Chem. 1997, 62, 8622-8623. (h) Wang, Z.-X.; Tu, Y.;
Frohn, M.; Zhang, J .-R.; Shi, Y. J . Am. Chem. Soc. 1997, 119, 11224-
11235. (i) Song, C. E.; Kim, Y. H.; Lee, K. C.; Lee, S.-g.; J in, B. W.
Tetrahedron: Asymmetry 1997, 8, 2921-2926. (j) Adam, W.; Zhao, C.-
G. Tetrahedron: Asymmetry 1997, 8, 3995-3998. (k) Yang, D.; Yip,
Y.-C.; Chen, J .; Cheung, K.-K. J . Am. Chem. Soc. 1998, 120, 7659-
7660. (l) Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-X.; Shi, Y. J . Org.
Chem. 1998, 63, 2948-2953. (m) Wang, Z.-X.; Shi, Y. J . Org. Chem.
1998, 63, 3099-3104. (n) Tu, Y.; Wang, Z.-X.; Frohn, M.; He, M.; Yu,
H.; Tang, Y.; Shi, Y. J . Org. Chem. 1998, 63, 8475-8485. (o) Cao, G.-
A.; Wang, Z.-X.; Tu, Y.; Shi, Y. Tetrahedron Lett. 1998, 39, 4425-4428.
(p) Zhu, Y.; Tu, Y.; Yu, H.; Shi, Y. Tetrahedron Lett. 1998, 39, 7819-
7822. (q) Adam, W.; Fell, R. T.; Saha-Mo¨ller, C. R.; Zhao, C.-G.
Tetrahedron: Asymmetry 1998, 9, 397-401. (r) Frohn, M.; Zhou, X.;
Zang, J .-R.; Tang, Y.; Shi, Y. J . Am. Chem. Soc. 1999, 121, 7718-
7719. (s) Wang, Z.-X.; Miller, S. M.; Anderson, O. P.; Shi, Y. J . Org.
Chem. 1999, 64, 6443-6458. (t) Wang, Z.-X.; Cao, G.-A.; Shi, Y. J . Org.
Chem. 1999, 64, 7646-7650. (u) Shu, L.; Shi, Y. Tetrahedron Lett.
1999, 40, 8721-8724. (v) Denmark, S. E.; Wu, Z. Synlett 1999, 847-
859. (w) Armstrong, A.; Hayter, B. R. Tetrahedron 1999, 55, 11119-
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is consistent with the reported epoxidation of (E)-stilbene
derivatives.11a-c Because of the much higher yield in the
epoxidation with (R)-7a (87%) than that with (R)-7b
(74%) and the easier preparation of (R)-7a over (R)-7b,
the binaphthyl ketone (R)-7a was used in the subsequent
optimization.
Effect of Solven ts. Screening of the solvent for the
reaction was then undertaken, and the proper choice of
solvents was found to be significant for obtaining good
yields and enantioselectivities (Table 2). To develop a
process for a practical large-scale preparation of (2R,3S)-
2a , reduction of the amount of the reagents, catalyst, and
solvent was intensively studied. The reactions were
conducted with use of 1 equiv of Oxone, 3.1 equiv of
NaHCO3, and 5 mol % of (R)-7a in DME-H2O. Although
addition of Na2EDTA has been reported to be essential
to prevent the decomposition of Oxone with the concomi-
tant metal in water,15 it was not important in this
reaction (Table 2, entry 1 versus entry 2), and thus
Na2EDTA was not added for further optimization. While
a mixed solvent, CH3CN-H2O, has often been employed
for the dioxirane-mediated asymmetric epoxidation, it
resulted in a poor yield (33%) with a little decrease of
enantioselectivity (72% ee) (Table 2, entry 3). The use of
alcoholic solvents, EtOCH2CH2OH-H2O and MeOCH2-
CH2OH-H2O, led to reduction in both the yield and the
enantioselectivity (Table 2, entry 4, 67% yield, 72% ee;
entry 5, 62% yield, 71% ee). The use of more polar protic
solvents, HOCH2CH2OH-H2O, iPrOH-H2O, and MeOH-
H2O, or aprotic solvent DMF-H2O provided much poorer
yields (Table 2, entry 6, 2% yield; entry 7, 27% yield;
entry 8, 19% yield; entry 9, 45% yield, respectively). It is
worth noteing that the reaction rate was remarkably
accelarated in acetone-H2O to provide (2R,3S)-2a in
(11) (a) Yang, D.; Yip, Y.-C.; Tang, M.-W.; Wong, M.-K.; Zheng, J .-
H.; Cheung, K.-K. J . Am. Chem. Soc. 1996, 118, 491-492. (b) Yang,
D.; Wang, X.-C.; Wong, M.-K.; Yip, Y.-C.; Tang, M.-W. J . Am. Chem.
Soc. 1996, 118, 11311-11312. (c) Yang, D.; Wong, M.-K.; Yip, Y.-C.;
Wang, X.-C.; Tang, M.-W.; Zheng, J .-H.; Cheung, K.-K. J . Am. Chem.
Soc. 1998, 120, 5943-5952. (d) Yang, D.; J iao, G.-S.; Yip, Y.-C.; Lai,
T.-H.: Wong, M.-K. J . Org. Chem. 2001, 66, 4619-4624.
(12) For a recent review, see; Porter, M. J .; Skidmore, J . Chem.
Commun. 2000, 1215-1225.
(13) (a) Furutani, T.; Hatsuda, M.; Imashiro, R.; Seki, M. Tetrahe-
dron: Asymmetry 1999, 10, 4763-4768. (b) Kuroda, T.; Imashiro, R.;
Seki, M. J . Org. Chem. 2000, 65, 4213-4216. (c) Seki, M.; Furutani,
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(d) Seki, M.; Yamada, S.; Kuroda, T.; Imashiro, R.; Shimizu, T.
Synthesis 2000, 12, 1677-1680.
(14) A part of this work has been published as preliminary com-
munications: (a) Seki, M.; Furutani, T.; Imashiro, R.; Kuroda, T.;
Yamanaka, T.; Harada, N.; Arakawa, H.; Kusama, M.; Hashiyama, T.
Tetrahedron Lett. 2001, 42, 8201-8205. (b) Furutani, T.; Imashiro, R.;
Hatsuda, M.; Seki, M. J . Org. Chem. 2002, 67, 4599-4601.
(15) Curci, R.; Fiorentino, M.; Troisi, L. J . Org. Chem. 1980, 45,
4758-4760.
4218 J . Org. Chem., Vol. 69, No. 12, 2004

Synthesis of Chiral Glycidic Acid Derivatives
TABLE 3. Op tim iza tion of th e Rea ction Con d ition s
vol of solvent
temp
(°C)
addition
time (h)
reaction
time (h)
assay
entrya
base (equiv)
(v/w)b
yield (%)c
ee (%)c
1d
NaHCO3 (3.1)
NaHCO3 (4)
15
15
15
15
15
20
20
27
27
27
27
15-27
15-27
5
1.5
1.5
1.5
1.5
1.5
1.5
<0.1
5.5
3.5
5.5
6.5
3.5
5
81
80
74
74
85
88
92
76
76
76
78
76
77
80
2d
3d
KHCO3 (3.1)
K2CO3 (1.55)
NaHCO3 (3:1)
NaHCO3 (3.1)
NaHCO3 (3.1)
4d
5d,e
6d,e
7f
48
a
b
d
Reactions were conducted on a 10-mmol scale. Volume (mL) per weight (g) of (E)-3a . c Determined by HPLC analysis. Reagents
were added every 5 min over 1.5 h. After addition of reagents at 15 °C, the reactions were conducted at 27 °C. f Reagents were added
e
at one time.
TABLE 4. Asym m etr ic Ep oxid a tion of
excellent yield albeit with a moderate enantioselectivity
4-Meth oxycin n m a tes a n d 4-Meth oxycin n a m id es
(93%, 49% ee) (Table 2, entry 10). Even if competing
epoxidation with achiral dimethyldioxirane generated
in situ from acetone should take place in the reaction,
the moderate enantioselectivity (49% ee) may reflect
the easier formation of the dioxirane from (R)-7a than
from acetone and/or the higer reactivity of the chiral
dioxirane derived from (R)-7a than dimethyldioxirane.
The use of biphasic systems, tBuOMe-H2O, toluene-H2O,
and CH2Cl2-H2O, did not furnish (2R,3S)-2a at all even
in the presence of a phase transfer catalyst (Table 2,
entries 11-13). The use of inexpensive 1,4-dioxane-H2O
afforded (2R,3S)-2a in 81% yield with 76% ee, which were
comparable to the values observed in DME-H2O. Al-
though 1,3-dioxorane, having a similar structure to 1,4-
dioxane, provided a good enantioselectivity (75% ee), the
yield was poor (23%). Considering the cost together with
the yield and ee, the inexpensive mixed solvent, 1,4-
dioxane-H2O, was chosen as a reaction solvent for
further optimization.
Op tim iztion of th e Rea ction Con d ition s. Shi and
a
b
Volume (mL) per weight (g) of (E)-3a . Reaction was con-
co-workers have reported that the catalytic turnover was
dramatically improved upon raising the pH value in the
reaction system.10e Addition of K2CO3 in place of NaHCO3
was thus tested in expectation of higher basicity as well
as higher solubility in H2O than those of NaHCO3.
Although a slightly higher enantioselectivity of (2R,3S)-
2a (78% ee) was obtained when K2CO3 was employed,
the yield decreased (74%) (Table 3, entry 4). The use of
KHCO3, which is less basic than K2CO3, provided the
same yield and a slightly lower enantioselectovity (74%
yield and 76% ee, Table 3, entry 3). Decomposition of
(2R,3S)-2a , Oxone, and/or chiral dioxirane under the
basic conditions might result in the decrease of the yield
of (2R,3S)-2a . While the use of an excess amount (4 equiv)
of NaHCO3 accelerated the epoxidation, the yield was
almost the same as the case when employing 3.1 equiv
of NaHCO3, which is a slightly excess amount for neutral-
izing the acids generated from Oxone (Table 3, entry 1
versus entry 2). The reaction conditions were further
optimized for attaining higher yield and higher enantio-
selectivity. When the addition temperature for Oxone and
NaHCO3 was lowered from 27 to 15 °C, the yield of
(2R,3S)-2a was improved from 81% to 85% (Table 3, entry
1 versus entry 5). Increasing solvent volume from 15 v/w
of (E)-3a to 20 v/w led to an increase of both yield and
ducted on
a
10-mmol scale. c Reactions were conducted on
a
d
1-mmol scale. Determined by HPLC analysis.
enantioselectivity, whcih is as well possibly due to an
increase of the solubility of Oxone and NaHCO3 (88%,
77% ee, Table 3, entry 6 versus entry 1). Although chang-
ing the reaction temperature from 27 to 5 °C resulted in
a longer reaction period (48 h) to complete the reaction,
the best result (92% yield and 80% ee) was achieved
(Table 3, entry 7). Although the ee value of the present
protocol is inferior to the result reported by Shi and co-
workers (80% ee versus 92% ee), it is much superior in
terms of yield (92% versus 57%), the use of a smaller
amount of Oxone (1 equiv versus 5 equiv), and the lower
chiral catalyst loading (5 mol % versus 30 mol %).
Ap p lica tion to th e Asym m etr ic Ep oxid a tion of
Oth er Cin n a m ic Acid Der iva tives. The asymmetric
epoxidation catalyzed by (R)-7a was applied to the
epoxidation of various cinnamic acid derivatives other
than (E)-3a . As shown in Table 4, the bulkiness of ester
moieties did not affect the yield and the enantioselectivity
in the asymmetric epoxidation (Table 4, entries 1-4).
Asymmetric epoxidation of cinnamamides, prepared from
ammonia or primary amine, proceeded with good enan-
J . Org. Chem, Vol. 69, No. 12, 2004 4219

Imashiro and Seki
TABLE 5. Asym m etr ic Ep oxid a tion of Cin n a m a tes Ca r r yin g Va r iou s Su bstitu en ts on th e P h en yl Rin g
Oxone
(equiv)
NaHCO3
(equiv)
assay
ee
entry
substrate
R
solventd
DME/H2O
DME/H2O
DME/H2O
t (h)
product
yield (%)f
(%)f
1c
2b
(E)-3m
(E)-3n
(E)-3n
(E)-3n
(E)-3o
(E)-3p
(E)-3q
(E)-3r
(E)-3s
(E)-3t
(E)-3u
(E)-3v
(E)-3w
(E)-3x
(E)-3y
4-OtBu
4-Me
4-Me
4-Me
4-H
1
1
3.1
3.1
24
24
48
48
48
48
48
48
48
48
48
48
48
48
48
(2R,3S)-2m
(2R,3S)-2n
(2R,3S)-2n
(2R,3S)-2n
(2R,3S)-2o
(2R,3S)-2p
(2R,3S)-2q
(2R,3S)-2r
(2R,3S)-2s
(2R,3S)-2t
(2R,3S)-2u
(2R,3S)-2v
(2R,3S)-2w
(2R,3S)-2x
(2R,3S)-2y
83
52
71
95
75
74
45
6
14
51
81
55
11
55
47
85
76
75
72
74
72
73
81
86
91
92
53
47
75
63
3b
2e
2e
2e
2e
2e
2e
2e
2e
2e
2e
2e
2e
2e
6.2e
6.2e
6.2e
6.2e
6.2e
6.2e
6.2e
6.2e
6.2e
6.2e
6.2e
6.2e
6.2e
4b
1,4-dioxane/H2O
1,4-dioxane/H2O
1,4-dioxane/H2O
1,4-dioxane/H2O
1,4-dioxane/H2O
1,4-dioxane/H2O
1,4-dioxane/H2O
1,4-dioxane/H2O
1,4-dioxane/H2O
1,4-dioxane/H2O
1,4-dioxane/H2O
1,4-dioxane/H2O
5b
6c
4-F
4-Cl
7c
8c
4-CO2Me
4-CF3
4-Ph
9c
10c
11c
12c
13c
14c
15c
4-tBu
2-OMe
3-OMe
2,3-benzo
3,4-benzo
a
b
Volume (mL) per weight (g) per (E)-3m -w . Reactions were conducted on a 10-mmol scale. c Reactions were conducted on a 1-mmol
scale. The ratios 1,4-dioxane/H2O and DME/H2O were 10:6 and 2:1, respectively. e Oxone (1 equiv) and NaHCO3 (3.1 equiv) were added
d
after 24 h. f Determined by HPLC analysis.
TABLE 6. Asym m etr ic Ep oxid a tion of (Z)- a n d Tr isu bstitu ted 3-Ar yl-r,â-Un sa tu r a ted Ester s
assay
ee
entryb
substrate
R1
R2
R3
product
yield (%)c
(%)c
1
2
3
4
5
(Z)-3a
(Z)-3v
(Z)-8a
(E)-8b
(E)-8c
H
H
H
Ph
4-MeOC6H4
2-MeOC6H4
Ph
Me
H
Me
Me
Et
Et
Me
(2R,3R)-2a e
(2R,3R)-2ve
(2R,3R)-9a d
(2R,3S)-9bd
(2R,3S)-9c
71
32
57
93
5
16
15
26
40
60
2-thienyl
a
b
d
Volume (mL) per weight (g) of the cinnamates. Reactions was conducted on a 1-mmol scale. c Determined by HPLC analysis. The
absolute configurations of (2R,3R)-9a and (2R,3S)-9b were determined by comparing the optical rotations with the reported ones. e The
absolute configurations of (2R,3R)-2a and (2R,3R)-2v were confirmed by comparing the HPLC patterns with those of (2R,3R)-9a .
tioselectivities (Table 4, entries 5-7). In contrast, in the
case of cinnamamides, prepared from secondary amines,
considerably poor enantioselectivities were observed
(Table 4, entries 8-11).
stituent (from alkyl, H, fluoro, phenyl, chloro, and tri-
fluoromethyl to methoxycarbonyl) on the phenyl group
was employed, the yield of the epoxide decreased from
95% to 6% (Table 5, entries 4-11). Substitution at the
2- or 3-position of the phenyl group reduced the yields
and the enantioselectivities of the epoxides (Table 5,
entries 12 and 13), while 2- or 3-naphthyl groups
provided moderate enantioselectivities (Table 5, entries
14 and 15). The glycidates (2R,3S)-2n and (2R,3S)-2o are
a key intermediate for a platelet aggregation inhibitor3g
and Taxol side chain,3a-c respectively.
The asymmetric epoxidation of (Z)-cinnamates employ-
ing (R)-7a gave low to good yields and much poorer
enantioselectivities compared to (E)-cinnamates (Table
6, entries 1-3 versus Tables 4 and 5). Trisubstituted
cinnamate (E)-8b was epoxidized very rapidly to give
(2R,3S)-9b in an excellent yield and with a moderate
enantioselectivity (Table 6, entry 4). A cinnamate (E)-8c
involving the 2-thienyl group provided only a trace
(5%) of the epoxide (2R,3S)-9c, which might be attrib-
uted to easy oxidation of the sulfur atom in (E)-8c
and/or (2R,3S)-9c under the reaction conditions (Table
6, entry 5).
The asymmetric epoxidation was further applied to the
cinnamates carrying various substituents on the phenyl
ring. A higher ee was obtained in the asymmetric
epoxidation of (E)-3m bearing a 4-tert-butoxy substituent
on the phenyl group, which is more bulky and has more
electron-donating property than the methoxy group
(Table 5, entry 1). The rate of epoxidation of (E)-3n
carrying the 4-methyl group, which furnish a somewhat
weak electron-donating effect, was slower and the yield
of (2R,3S)-2n was poorer than those observed in the case
of 4-alkoxy derivatives (Table 5, entry 2). Change of
solvent from DME to 1,4-dioxane and further addition
of Oxone (1 equiv) and NaHCO3 (3.1 equiv) considerably
improved the yield of (2R,3S)-2n (Table 5, entry 4 versus
entries 2 and 3). When the 4-substituent on the phenyl
group became larger (from H, fluoro, methyl, chloro,
trifluoromethyl, and methoxycarbonyl phenyl to tert-
butyl), the enantioselectivitiy elevated from 72% to 92%
ee. In contrast, when a more electron-withdrawing 4-sub-
4220 J . Org. Chem., Vol. 69, No. 12, 2004

Synthesis of Chiral Glycidic Acid Derivatives
F IGURE 1. Plausible transition states for the asymmetric epoxidation of (E)-3o.
A P lau sible Mech an ism for th e Asym m etr ic Epox-
id a tion . It is reported that epoxidation of olefins by
dioxiranes is mediated by an electrophilic oxygen atom
transfer from dioxiranes to the nucleophilic double bond
of olefins, and therefore electron-defficient olefins, espe-
cially cinnamates, are resistant to be epoxidized by the
dioxiranes.16 Despite the difficulty, we found that (R)-7a
developed by Yang and co-workers can be a powerful
catalyst for asymmetric epoxidation of not only cinnama-
tes but also cinnamamides. Yang and co-workers sug-
gested that the asymmetric epoxidation of stilbene
derivatives mediated by chiral dioxirane derived from
(R)-7a occurs through a spiro transition state rather than
a planar one.11c,17 On the basis of this assumption, four
possible spiro transition states A-D are expected for the
present reaction (Figure 1).18 It is considered that the
major (2R,3S)-enantiomers (2R,3S)-2a -w were produced
through the transition states A or B in Figure 1 in that
the aryl moietiy and the ester group of cinnamates may
be apart from binaphthyl groups in the dioxirane. Tran-
sition state C has been claimed to be less favorable
because of the steric interaction between the 4-substitu-
ent in the (E)-stilbenes and the 3,3′-substituents in the
binaphthyl dioxiranes.11c The proposal was further sup-
ported by our results in that the larger the substituent
at 3,3′-positions in the binaphthyl ketone or the 4-sub-
stituent on the phenyl ring of cinnamates becomes, the
higher the enantioselectivities will be (Tables 1 and 5).
Transition state D, which may alternatively lead to the
minor product, is considered to have less steric interac-
tion between the ester group of cinnamates and the 3,3′-
substituents of the binaphthyl dioxiranes. However, it
is of interest that epoxidations of 4-substituted cinnama-
tes proceeded more enantioselectively than (E)-stilbenes
carrying substituents at the 4-position (Scheme 1).11c This
might be attributed to stereoelectronic effects involving
a dipole-dipole repulsion10z between an ester group of
cinnamates and lactone moieties of the binaphthyl diox-
irane. In the case of cinnamamides, prepared from
secondary amines, considerably poor enantioselectivities
were obtained (Table 4, entries 8-11). Yang and co-
workers have suggested that the existence of much larger
steric sensors at the 3,3′-positions of the binaphthyl
dioxirane resulted in poorer enantioselectivities and
slower epoxidation.11c N,N-Disubstituted amides should
be more sterically demanding than esters, which might
be responsible for the significant decrease of the enan-
tioselectivities and the somewhat decrease of the yields.
The low enantioselectivities obtained for the (Z)-cin-
namates might be accounted for by considering the
transition states models such as Figure 1.
(16) (a) Baumstark, A. L.; McCloskey, C. J . Tetrahedron Lett. 1987,
28, 3311-3314. (b) Baumstark, A. L.; Vasquez, P. C. J . Org. Chem.
1988, 53, 3437-3439. (c) Baumstark, A. L.; Harden, D. B., J r. J . Org.
Chem. 1993, 58, 7615-7618. (d) Murray, R. W.; Shiang, D. L. J . Chem.
Soc., Perkin Trans. 2 1990, 349-352. (e) Curci, R.; Dioni, A.; Rubino,
M. F. Pure Appl. Chem. 1995, 67, 811-822.
(17) (a) Bach, R. D.; Andre´s, J . L.; Owensby, A. L.; Schlegel, H. B.;
McDouall, J . J . W. J . Am. Chem. Soc, 1992, 114, 7207-7217. (b) Houk,
K. N.; Liu, J .; DeMello, N. C.; Condroski, K. R. J . Am. Chem. Soc. 1997,
119, 10147-10152. (c) J enson, C.; Liu, J .; Houk, K. N.; J orgensen, W.
L. J . Am. Chem. Soc. 1997, 119, 12982-12983.
(18) The stable conformer of the dioxirane derived from (R)-7a was
created as follows: The coordinates of the X-ray structure of (R)-7a ,
reported by Yang and co-workers, was exchanged into the correspond-
ing dioxirane and then the stable conformer of the dioxirane was
calculated by the MOPAC PM3 method.
Con clu sion
As described above, a novel and efficient asymmetric
synthesis of chiral glycidic acid derivatives, involving a
key intermediate for diltiazem, was accomplished through
catalytic asymmetric epoxidation of cinnamates and
cinnamamides with 5 mol % of chiral binaphthyl ketone
J . Org. Chem, Vol. 69, No. 12, 2004 4221

Imashiro and Seki
SCHEME 1. Com p a r ison of th e En a n tioselectivities in th e Asym m etr ic Ep oxid a tion of 4-Su bstitu ted
Stilben e Der iva tives w ith Th a t of 4-Su bstitu ted Cin n m a tes Em p loyin g th e Ca ta lyst (R)-7a a
a
Condition a: The reactions were carried out with use of (R)-7a (10 mmol %), Oxone (5 equiv), and NaHCO3 (15.5 equiv) in CH3CN-
Na2EDTA (20:17) at room temperature. Condition b: The reactions were conducted with (R)-7a (5 mmol %), Oxone (1 equiv), and NaHCO3
(3.1 equiv) in 1,4-dioxane-H2O (10:6) at 10 °C.
(t, J ) 8.0 Hz, 2H), 5.51 (d, J ) 15.3 Hz, 2H), 4.20 (d, J ) 15.3
Hz, 2H); IR (KBr) ν 3080, 2925, 1758, 1730, 1603, 1560, 1531,
(R)-7a used as a catalyst. The present method was
applied to the asymmetric epoxidation of a wide variety
of cinnamic acid derivatives, especially (E)-cinnamates
and cinnamamides bearing a substituent at the 4-position
of the phenyl group to give the corresponding chiral
glycidic acid derivatives in up to 95% yield and 92% ee.
The enhanced enantioselectivities in the epoxidation of
cinnamates over stilbene derivatives can be attributed
to the dipole-dipole repulsion between an ester group
of cinnamates and lactone moieties of dioxiranes derived
from the binaphthyl ketones.
1478, 1418, 1344, 1265, 1198, 1155, 1129 cm-1
.
Gen er a l P r oced u r e for Cin n a m a tes: Syn th esis of (E)-
ter t-Bu tyl 4-Meth oxycin n a m a te ((E)-3d ). To a solution of
4-methoxycinnamic acid (2.67 g, 15 mmol) in CH2Cl2 (30 mL,
stabilized with amylenes) was added (COCl)2 (1.57 mL, 18
mmol) and DMF (3 drops) at room temperature, and the
mixture was stirred at room temperature for 1 h. The mixture
was evaporated and azeotroped with CHCl3 (30 mL, stabilized
with amylenes). To a solution of the corresponding acid
chloride in CH2Cl2 (30 mL, stabilized with amylenes) were
t
added BuOH (4.30 mL, 45 mmol) and pyridine (3.84 mL, 45
mmol) successively at room temperature, and the mixture was
stirred at room temperature overnight. The mixture was
poured into H2O and extracted with AcOEt. The extracts were
washed with saturated aqueous NaHCO3 and brine, dried over
MgSO4, and evaporated. The residue was purified by silica gel
column chromatography (hexane/AcOEt ) 10:1) to give (E)-
tert-butyl 4-methoxycinnamate ((E)-3d ) (3.29 g, 94%) as color-
less crystals. Mp 34-35 °C; 1H NMR (CDCl3, 400 MHz) δ 7.54
(d, J ) 16.0 Hz, 1H), 7.46 (d, J ) 8.6 Hz, 2H), 6.89 (d, J ) 8.8
Hz, 2H), 6.24 (d, J ) 16.0 Hz, 1H), 3.83 (s, 3H), 1.53 (s, 9H);
MS (GC) m/z 234 (M+); IR (ATR) ν 2977, 1701, 1634, 1604,
1576, 1511, 1458, 1421 cm-1. Anal. Calcd for C14H18O3: C,
71.77; H, 7.74. Found: C, 71.50; H, 7.87.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. 1H and
13C NMR spectra were recorded with tetramethylsilane used
as an internal standard. Optical rotations were measured at
the indicated temperature with a sodium lamp (D line, 589
nm). Silica gel column chromatography was performed with
Kieselgel 60 (E. Merck). Thin-layer chromatography (TLC) was
carried out on E. Merck 0.25-mm precoated glass-backed plates
(60 F254). Development was accomplished with 5% phospho-
molybdic acid in ethanol-heat or visualized by UV light where
feasible. All solvents and reagents were used as received.
(R)-5H-Din a p h th o[2,1-g:1′,2′-i][1,5]d ioxa cyclou n d ecin -
3,6,9(7H)-tr ion e ((R)-7a ). The compound (R)-7a was prepared
according to our previously reported procedure.13d Colorless
(E)-Isop r op yl 4-m eth oxycin n a m a te ((E)-3c): yield 98%;
1
colorless oil; H NMR (CDCl3, 400 MHz) δ 7.62 (d, J ) 15.9
Hz, 1H), 7.47 (d, J ) 8.6 Hz, 2H), 6.90 (d, J ) 8.8 Hz, 2H),
6.29 (d, J ) 15.9 Hz, 1H), 5.13 (hept, J ) 6.3 Hz, 1H), 3.84 (s,
3H), 1.81 (d, J ) 6.3 Hz, 6H); MS (GC) m/z 220 (M+); IR (ATR)
ν 2980, 1702, 1634, 1603, 1576, 1511 cm-1. Anal. Calcd for
crystals; mp 300 °C dec; [R]25 +10.9 (c, 1.0, CHCl3); >99% ee
D
(Chiralcel OD, hexane/iPrOH ) 10:1, 1 mL/min, 40 °C, 224
1
nm); H NMR (CDCl3, 200 MHz) δ 8.04 (d, J ) 8.5 Hz, 2H),
7.97 (d, J ) 8.2 Hz, 2H), 7.66 (d, J ) 8.5 Hz, 2H), 7.56 (dd, J
) 1.5, 6.6 Hz, 2H), 7.30-7.37 (m, 2H), 7.25 (d, J ) 14.1 Hz,
2H), 5.56 (d, J ) 15.4 Hz, 2H), 4.20 (d, J ) 15.4 Hz, 2H); MS
(EI) m/z 396 (M+); IR (KBr) ν 3550, 3430, 3050, 2970, 2925,
1755, 1730, 1593 cm-1. Anal. Calcd for C25H16O5: C, 75.71; H,
4.07. Found: C, 75.42; H, 3.99.
C
13H16O3: C, 70.89; H, 7.32. Found: C, 70.68; H, 7.27.
(E)-Ben zyl 4-m eth oxycin n a m a te ((E)-3e): yield 90%;
colorless crystals; mp 53-54 °C; 1H NMR (CDCl3, 400 MHz) δ
7.69 (d, J ) 15.9 Hz, 1H), 7.47 (d, J ) 8.6 Hz, 2H), 7.43-7.32
(m, 5H), 6.90 (d, J ) 8.6 Hz, 2H), 6.36 (d, J ) 15.9 Hz, 1H),
5.24 (s, 2H), 3.83 (s, 3H); MS (GC) m/z 268 (M+); IR (ATR) ν
(R)-2,10-Dich lor od in a p h t h o[2,1-g:1′,2′-i]-4,8-d ioxa cy-
clou n d eca n e-3,6,9-t r ion e ((R)-7b ). The compound (R)-7b
was prepared according to our previously reported procedure.13c
Colorless crystals; mp 257-259 °C; 1H NMR (CDCl3, 200 MHz)
δ 8.08 (s, 2H), 7.88 (d, J ) 8.2 Hz, 2H), 7.56 (t, J ) 7.6 Hz,
2H), 7.31 (t, J ) 7.8 Hz, 2H), 6.94 (d, J ) 8.5 Hz, 2H), 5.57 (d,
J ) 15.7 Hz, 2H), 4.34 (d, J ) 15.3 Hz, 2H); MS (EI) m/z 464
([M]+), 466 ([M + 2]+); IR (KBr) ν 3050, 2920, 1741, 1613, 1580,
2958, 2838, 1704, 1630, 1600, 1575, 1509, 1447, 1421 cm-1
.
Anal. Calcd for C17H16O3: C, 76.10; H, 6.01. Found: C, 76.1;
H, 5.96.
(Z)-Meth yl 2-m eth oxycin n a m a te ((Z)-3v): yield 95%;
1
colorless oil; H NMR (CDCl3, 400 MHz) δ 7.54 (dd, J ) 1.5,
7.6 Hz, 1H), 7.32 (dt, J ) 1.5, 7.8 Hz, 1H), 7.18 (d, J ) 12.6
Hz, 1H), 6.94 (dt, J ) 0.8, 7.6 Hz, 1H), 6.88 (dd, J ) 0.8, 8.3
Hz, 1H), 5.98 (d, J ) 12.4 Hz, 1H), 3.84 (s, 3H), 3.67 (s, 3H);
MS (GC) m/z 192 (M+); IR (ATR) ν 2950, 1721, 1630, 1600,
1488, 1462, 1435 cm-1. Anal. Calcd for C11H12O3: C, 68.74; H,
6.29. Found: C, 68.68; H, 6.36.
1559 cm-1; [R]22 +92.0 (c, 0.100, CHCl3).
D
(R )-3,19-Dic h lor o-9,13-d ioxa -t r ic yc lo[13.4.0.0.2,7]-
n on a d eca -1(15),2(7),3,5,16,18-h exa n e-8,11,14-tr ion e ((R)-
7c). The compound (R)-7c was prepared according to the
literature.11c Yellow crystals; 1H NMR (CDCl3, 200 MHz) δ 7.68
(dd, J ) 2.7, 6.6 Hz, 2H), 7.50-7.40 (m, 4H), 5.50 (d, J ) 15.4
Hz, 2H), 4.19 (d, J ) 15.3 Hz, 2H), 3.39 (br, 2H).
(R )-3,19-D in it r o -9,13-d io x a -t r ic y c lo [13.4.0.0.2,7]-
n on a d eca -1(15),2(7),3,5,16,18-h exa n e-8,11,14-tr ion e ((R)-
7d ). The compound (R)-7c was prepared according to the
literature.11c Yellow crystals; 1H NMR (CDCl3, 200 MHz) δ 8.39
(dd, J ) 1.3, 8.1 Hz, 2H), 7.88 (dd, J ) 1.3, 7.8 Hz, 2H), 7.72
Gen er a l P r oced u r e for Cin n a m a m id s: Syn th esis of
(E)-4-Meth oxycin n a m a ic Acid Dieth yl Am id e ((E)-3i). To
a solution of 4-methoxycinnamic acid (2.67 g, 15 mmol) in
CH2Cl2 (30 mL, stabilized with amylenes) was added N,N-
carbonyldiimidazole (2.92 g, 18 mmol) at room temperature
and the mixture was stirred at room temperature for 0.5 h.
To the solution was added diethylamine (5 mL) at room
temperature and the mixture was stirred at room temperature
4222 J . Org. Chem., Vol. 69, No. 12, 2004

Synthesis of Chiral Glycidic Acid Derivatives
for 1 h. The mixture was poured into H2O and extracted with
AcOEt. The extracts were washed with saturated aqueous
NaHCO3 and brine, dried over MgSO4, and evaporated. The
residue was purified by silica gel column chromatography
(hexane/AcOEt ) 2:1) to give (E)-4-methoxycinnamaic acid
diethyl amide ((E)-3i) (2.16 g, 62%) as a colorless oil. 1H NMR
(CDCl3, 400 MHz) δ 7.67 (d, J ) 15.2 Hz, 1H), 7.48 (d, J )
8.8 Hz, 2H), 6.90 (d, J ) 8.8 Hz, 2H), 6.70 (d, J ) 15.2 Hz,
1H), 3.83 (s, 3H), 3.52-3.42 (m, 4H), 1.26 (t, J ) 7.1 Hz, 3H),
1.19 (t, J ) 7.1 Hz, 3H); MS (APCI) m/z 234 ([M + H]+); IR
(ATR) ν 2973, 1644, 1595, 1509,1429 cm-1. Anal. Calcd for
C14H19NO2: C, 72.07; H 8.21; N, 6.00. Found: C, 71.72; H, 8.20;
N, 5.83.
(E)-4-Meth oxycin n a m ic a m id e ((E)-3f): yield 73%; color-
less crystals; 199-201 °C; 1H NMR (DMSO-d6, 400 MHz) δ
7.50 (d, J ) 8.6 Hz, 2H), 7.45 (br, 1H), 7.36 (d, J ) 15.9 Hz,
1H), 7.01 (br, 1H), 6.97 (d, J ) 8.7 Hz, 2H), 6.46 (d, J ) 15.9
Hz, 1H), 3.79 (s, 3H); MS (APCI) m/z 178 ([M + H]+); IR (ATR)
ν 3461, 3355, 3145, 1661, 1592, 1509, 1423 cm-1. Anal. Calcd
for C10H11NO2: C, 67.78; H 6.26; N, 7.90. Found: C, 67.73; H,
6.21; H, 7.88.
(E)-4-Meth oxycin n a m ic a cid eth yla m id e ((E)-3g): yield
67%; colorless crystals; mp 128-129 °C; 1H NMR (CDCl3, 400
MHz) δ 7.58 (d, J ) 15.7 Hz, 1H), 7.44 (d, J ) 8.6 Hz, 2H),
6.88 (d, J ) 8.6 Hz, 2H), 6.26 (d, J ) 15.7 Hz, 1H), 5.66 (br,
1H), 3.82 (s, 3H), 3.46-3.39 (m, 2H), 1.20 (t, J ) 7.3 Hz, 3H);
MS (APCI) m/z 206 ([M + H]+); IR (ATR) ν 3293, 2965, 2877,
1664, 1653, 1604, 1575, 1537, 1513, 1422 cm-1. Anal. Calcd
for C12H15NO2: C, 70.22; H 7.37; N, 6.82. Found: C, 69.91; H,
7.35; N, 6.72.
was purified by silica gel column chromatography (hexane/
AcOEt ) 5:1) to give methyl (E)-3-methoxycinnamate ((E)-3w )
1
(8.70 g, 84%) as a colorless oil. Yield 84%; H NMR (CDCl3,
400 MHz) δ 7.66 (d, J ) 15.9 Hz, 1H), 7.30 (t, J ) 7.9 Hz, 1H),
7.12 (d, J ) 7.6 Hz, 1H), 6.94 (dd, J ) 2.9, 8.1 Hz, 1H), 7.04 (t,
J ) 1.8 Hz, 1H), 6.43 (d, J ) 15.9 Hz, 1H), 3.83 (s, 3H), 3.81
(s, 3H); MS (GC) m/z 192 (M+); IR (ATR) ν 2951, 1713, 1638,
1579, 1489, 1435 cm-1. Anal. Calcd for C11H12O3: C, 68.74; H,
6.29. Found: C, 68.92; H, 6.33.
(E)-Meth yl 4-ter t-bu toxycin n a m a te ((E)-3m ): yield 44%;
colorless crystals; mp 60-61 °C; 1H NMR (CDCl3, 400 MHz) δ
7.66 (d, J ) 15.9 Hz, 1H), 7.44 (d, J ) 8.6 Hz, 2H), 6.99 (d, J
) 8.6 Hz, 2H), 6.34 (d, J ) 15.9 Hz, 1H), 3.80 (s, 3H), 1.38 (s,
9H); MS (GC) m/z 234 (M+); IR (ATR) ν 2975, 1706, 1630, 1598,
1505, 1432 cm-1. Anal. Calcd for C14H18O3: C, 71.77; H, 7.74.
Found: C, 71.9; H, 7.77.
(E)-Meth yl 4-m eth ylcin n a m a te ((E)-3n ): yield 70%; col-
1
orless crystals; mp 50-52 °C; H NMR (CDCl3, 400 MHz) δ
7.67 (d, J ) 16.2 Hz, 1H), 7.42 (d, J ) 8.1 Hz, 2H), 7.19 (d, J
) 8.1 Hz, 2H), 6.40 (d, J ) 16.2 Hz, 1H), 3.80 (s, 3H), 2.37 (s,
3H); MS (GC) m/z 176 (M+); IR (ATR) ν 2948, 1702, 1632, 1606,
1515, 1435 cm-1. Anal. Calcd for C11H12O2: C, 74.98; H, 6.86.
Found: C, 75.07; H, 6.88.
(E)-Meth yl 4-flu or ocin n a m a te ((E)-3p ): yield 85%; color-
less crystals; mp 45-47 °C; 1H NMR (CDCl3, 400 MHz) δ 7.66
(d, J ) 15.9 Hz, 1H), 7.51 (m, 2H), 7.08 (t, J ) 8.6 Hz, 2H),
6.37 (d, J ) 15.9 Hz, 1H), 3.14 (s, 3H); MS (GC) m/z 180 (M+);
IR (ATR) ν 2956, 1705, 1632, 1599, 1509, 1435 cm-1. Anal.
Calcd for C10H9FO2: C, 66.66; H, 5.03; F, 10.54. Found: C,
66.56; H, 5.06; F, 10.40.
(E)-Meth yl 4-ch lor ocin n a m a te ((E)-3q): yield 67%; color-
less crystals; mp 74-75 °C; 1H NMR (CDCl3, 400 MHz) δ 7.64
(d, J ) 15.9 Hz, 1H), 7.45 (d, J ) 8.6 Hz, 2H), 7.36 (d, J ) 8.6
Hz, 2H), 6.41 (d, J ) 15.9 Hz, 1H), 3.81 (s, 3H); MS (GC) m/z
196 (M+), 198 ([M + 2]+); IR (ATR) ν 2952, 1702, 1634, 1592,
1490, 1432, 1407 cm-1. Anal. Calcd for C10H9ClO2: C, 61.08;
H, 4.61; Cl, 18.03. Found: C, 60.94; H, 4.59; Cl, 17.69.
(E)-4-Met h oxycin n a m ic a cid b en zyla m id e ((E)-3h ):
1
yield 87%; colorless crystals; mp 52 °C; H NMR (CDCl3, 400
MHz) δ 7.64 (d, J ) 15.2 Hz, 1H), 7.44 (d, J ) 8.6 Hz, 2H),
7.36-7.26 (m, 5H), 6.87 (d, J ) 8.6 Hz, 2H), 6.28 (d, J ) 15.7
Hz, 1H), 5.93 (br, 1H), 4.56 (d, J ) 5.8 Hz, 2H), 3.82 (s, 3H);
MS (APCI) m/z 268 ([M + H]+); IR (ATR) ν 3283, 2836, 1644,
1602, 1510, 1454, cm-1. Anal. Calcd for C17H17NO2: C, 76.38;
H 6.41; N, 5.24. Found: C, 76.39; H, 6.31; N, 5.20.
(E)-Meth yl 4-m eth oxyca r bon ylcin n a m a te ((E)-3r ): yield
68%; colorless crystals; mp 122-123 °C; 1H NMR (CDCl3, 400
MHz) δ 8.05 (d, J ) 8.3 Hz, 2H), 7.71 (d, J ) 16.0 Hz, 1H),
7.58 (d, J ) 8.3 Hz, 2H), 6.52 (d, J ) 16.0 Hz, 1H), 3.93 (s,
3H), 3.83 (s, 3H); MS (GC) m/z 220 (M+); IR (ATR) ν 2958,
1717, 1639, 1565, 1433 cm-1. Anal. Calcd for C12H12O4: C,
65.45; H, 5.49. Found: C, 65.35; H, 5.43.
(E)-4-Meth oxycin n a m ic a cid d iben zyla m id e ((E)-3j):
yield 73%; colorless crystals; mp 103-104 °C; 1H NMR (CDCl3,
400 MHz) δ 7.82 (d, J ) 15.3 Hz, 1H), 7.42 (d, J ) 8.8 Hz,
2H), 7.38-7.22 (m, 10H), 6.86 (d, J ) 8.8 Hz, 2H), 6.77 (d, J
) 15.3 Hz, 1H), 4.71 (s, 2H), 4.60 (s, 2H), 3.81 (s, 3H); MS
(APCI) m/z 358 ([M + H]+); IR (ATR) ν 3000, 2929, 1644, 1595,
1573, 1509, 1492, 1454, 1437, 1421 cm-1. Anal. Calcd for
C24H23NO2: C, 80.64; H 6.49; N, 3.92. Found: C, 80.46; H, 6.38;
N, 3.95.
(E)-Meth yl 4-tr iflu or om eth ylcin n a m a te ((E)-3s): yield
42%; colorless crystals; mp 77-79 °C; 1H NMR (CDCl3, 400
MHz) δ 7.71 (d, J ) 15.9 Hz, 1H), 7.64 (dd, J ) 3.0, 8.7 Hz,
4H), 6.52 (d, J ) 15.9 Hz, 1H), 3.83 (s, 3H); MS (GC) m/z 230
(E)-4-Meth oxycin n a m ic a cid p yr r olid in oa m id e ((E)-
1
3k ): yield 79%; colorless crystals; mp 117-118 °C; H NMR
(M+); IR (ATR) ν 2958, 1709, 1639, 1616, 1438, 1418 cm-1
.
(CDCl3, 400 MHz) δ 7.67 (d, J ) 15.2 Hz, 1H), 7.48 (d, J ) 8.6
Hz, 2H), 6.61 (d, J ) 15.2 Hz, 1H), 6.89 (d, J ) 8.8 Hz, 2H),
3.83 (s, 3H), 3.64-3.58 (m, 4H), 2.05-1.97 (m, 2H), 1.93-1.86
(m, 2H); MS (APCI) m/z 232 ([M + H]+); IR (ATR) ν 2955, 2875,
1642, 1593, 1509, 1428 cm-1. Anal. Calcd for C14H17NO2: C,
72.70; H 7.41; N, 6.06. Found: C, 72.61; H, 7.36; N, 6.01.
(E)-4-Met h oxycin n a m ic a cid m or p h olin oa m id e ((E)-
3l): yield 92%; colorless crystals; mp 105-107 °C; 1H NMR
(CDCl3, 400 MHz) δ 7.67 (d, J ) 15.3 Hz, 1H), 7.48 (d, J ) 8.8
Hz, 2H), 6.90 (d, J ) 8.8 Hz, 2H), 6.71 (d, J ) 15.3 Hz, 1H),
3.88 (s, 3H), 3.84-3.72 (br, 8H); MS (APCI) m/z 248 ([M +
Anal. Calcd for C11H9FO2: C, 57.40; H, 3.94; F, 24.76. Found:
C, 57.33; H, 3.89; F, 24.41.
(E)-Meth yl 4-p h en ylcin n a m a te ((E)-3t): yield 78%; col-
orless crystals; mp 147-148 °C; 1H NMR (CDCl3, 400 MHz) δ
7.74 (d, J ) 16.2 Hz, 1H), 7.64-7.59 (m, 6H), 7.49-7.43 (m,
2H), 7.36 (tt, J ) 1.3, 7.3 Hz, 1H), 6.48 (d, J ) 15.9 Hz, 1H),
3.82 (s, 3H); MS (APCI) m/z 239 ([M + H]+); IR (ATR) ν 2945,
1711, 1635, 1600, 1487, 1437, 1409 cm-1. Anal. Calcd for
C
16H14O2: C, 80.65; H, 5.92. Found: C, 80.63; H, 5.70.
(E)-Meth yl 4-ter t-bu tylcin n a m a te ((E)-3u ): yield 65%;
colorless crystals; mp 34 °C; 1H NMR (CDCl3, 400 MHz) δ 7.68
(d, J ) 16.0 Hz, 1H), 7.47 (d, J ) 8.3 Hz, 2H), 7.41 (d, J ) 8.6
Hz, 2H), 6.41 (d, J ) 16.0 Hz, 1H), 3.80 (s, 3H), 1.33 (s, 9H);
MS (GC) m/z 218 (M+); IR (ATR) ν 2957, 1712, 1632, 1606,
1504, 1438, 1412 cm-1. Anal. Calcd for C14H18O2: C, 77.03; H,
8.31. Found: C, 76.77; H, 8.42.
H]+); IR (ATR) ν 2863, 1646, 1603, 1575, 1511, 1432 cm-1
.
Anal. Calcd for C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found:
C, 67.96; H, 6.91; N, 5.75.
Gen er a l P r oced u r e for th e Syn th esis of Cin n a m tes
w ith 4-Su bstitu ted P h en yl Gr ou p : Syn th esis of (E)-
Meth yl 3-Meth oxycin n a m a te ((E)-3w ). To a solution of
m-anisaldehyde (6.81 g, 50 mmol) in AcOMe (50 mL) was
added 28% NaOMe/MeOH (12.5 g, 65 mmol), and the mixture
was refluxed for 3 h. The mixture was cooled to room
temperature, quenched with 6 N aqueous HCl (11 mL, 66
mmol), and extracted with AcOEt. The extracts were washed
with brine, dried over MgSO4, and evaporated. The residue
(E)-Meth yl 2-m eth oxycin n a m a te ((E)-3v): yield 89%;
1
colorless oil; H NMR (CDCl3, 400 MHz) δ 8.00 (d, J ) 16.2
Hz, 1H), 7.51 (dd, J ) 1.5, 7.6 Hz, 1H), 7.35 (ddd, 1.5, 7.3, 8.8
Hz, 1H), 6.96 (dt, J ) 0.8, 7.6 Hz, 1H), 6.92 (d, J ) 8.3 Hz,
1H), 6.53 (d, J ) 15.9 Hz, 1H), 3.89 (s, 3H), 3.80 (s, 3H); MS
(GC) m/z 192 (M+); IR (ATR) ν 2951, 1713, 1639, 1579, 1489,
J . Org. Chem, Vol. 69, No. 12, 2004 4223

Imashiro and Seki
1435 cm-1. Anal. Calcd for C11H12O3: C, 68.74; H, 6.29.
Found: C, 68.43; H, 6.19.
2965, 2843, 1748, 1614, 1587, 1519 cm-1. MS (EI) m/z 208 (M+).
Anal. Calcd for C11H12O4: C, 63.45; H, 5.81. Found: C, 63.14;
H, 5.50.
(E)-Meth yl 3-(1-n a p h th yl)-2-p r op en oa te ((E)-3x): yield
1
69%; colorless syrup; H NMR (CDCl3, 400 MHz) δ 8.54 (d, J
Gen er a l P r oced u r e for Ca ta lytic Asym m etr ic Ep oxi-
d a tion of Cin n a m ic Acid Der iva tives: Syn th esis of Eth yl
(2R,3S)-3-(4-Meth oxyp h en yl)glycid a te ((2R,3S)-2b). To a
solution of methyl (E)-4-methoxycinnamate ((E)-3a ) (206 mg,
1 mmol) and ketone catalyst (R)-7a (20 mg, 0.05 mmol) in a
mixed solvent of DME (4 mL) and H2O (2 mL) were succes-
sively added Oxone (615 mg, 1 mmol) and NaHCO3 (260 mg,
3.1 mmol) at 10 °C. The suspension was stirred at 10 °C for
24 h. The mixture was then warmed to 27 °C and stirring was
continued for 2 h. The resulting suspension was treated with
H2O and the mixture was extracted three times with CHCl3.
The combined extracts were washed with saturated aqueous
NaCl and dried over anhydrous MgSO4. After evaporation of
the solvent, the residue was purified through flash NH silica
gel column chromatography (AcOEt). The yield and ee of
(2R,3S)-2b were determined by Chiral HPLC analysis: yield
85%, 77% ee [HPLC: Chiralcel OD, hexane/iPrOH ) 98:2, 1
mL/min, 220 nm, 40 °C, (2R,3S)-2b 9.6 min, (2S,3R)-2b 10.8
) 15.9 Hz, 1H), 8.20 (d, J ) 8.1 Hz, 1H), 7.89 (t, J ) 8.1 Hz,
2H), 7.76 (d, J ) 7.1 Hz, 1H), 7.61-7.47 (m, 3H), 6.54 (d, J )
15.7 Hz, 1H), 3.86 (s, 3H); MS (GC) m/z 212 (M+); IR (ATR) ν
2941, 1710, 1630, 1510, 1433 cm-1. Anal. Calcd for C14H12O2:
C, 79.22; H, 5.70. Found: C, 78.86; H, 5.58
(E)-Meth yl 3-(2-n a p h th yl)-2-p r op en oa te ((E)-3y): yield
69%; colorless crystals; mp 89-91 °C; 1H NMR (CDCl3, 400
MHz) δ 7.93 (s, 1H), 7.88-7.82 (m, 4H), 7.67 (dd, J ) 1.5, 8.6
Hz, 1H), 7.54-7.49 (m, 2H), 6.56 (d, J ) 15.9 Hz, 1H), 3.84 (s,
3H); MS (APCI) m/z 213 ([M + H]+); IR (ATR) ν 2961, 1712,
1646, 1505, 1435 cm-1. Anal. Calcd for C14H12O2: C, 79.22; H,
5.70. Found: C, 79.03; H, 5.53.
(E)-Meth yl 3-(3-th ien yl)-2-p r op en oa te ((E)-8c): yield
74%; colorless crystals; mp 48-49 °C; 1H NMR (CDCl3, 400
MHz) δ 7.68 (d, J ) 15.9 Hz, 1H), 7.50 (dd, J ) 1.3, 2.8 Hz,
1H), 7.34 (dd, J ) 5.1, 8.0 Hz, 1H), 7.29 (dd, J ) 1.3, 5.1 Hz,
1H), 6.27 (d, J ) 15.9 Hz, 1H), 3.79 (s, 3H); MS (GC) m/z 168
(M+); IR (ATR) ν 3096, 2948, 1702, 1634, 1436 cm-1. Anal.
Calcd for C8H8O2S: C, 57.12; H, 4.79; S, 19.06. Found: C,
57.13; H, 4.61.
1
min]. H NMR (CDCl3, 400 MHz) δ 7.21 (d, J ) 8.8 Hz, 2H),
6.89 (d, J ) 8.8 Hz, 2H), 4.33-4.24 (m, 2H), 4.04 (d, J ) 1.8
Hz, 1H), 3.81 (s, 3H), 3.50 (d, J ) 1.8 Hz, 1H), 1.33(t, J ) 7.1
Hz, 3H); IR (ATR) 2996, 1744, 1612, 1585, 1515, 1469, 1442,
1411 cm-1; MS (EI) m/z 222 (M+). Anal. Calcd for C12H14O4:
C, 64.85; H, 6.35. Found: C, 64.93; H, 6.57.
Gen er a l P r oced u r e of (Z)-Cin n a m a tes: Syn th esis of
(Z)-Eth yl Cin n a m a te ((Z)-8a ). To a solution of ethyl 3-phen-
ylpropiolate (1.74 g, 10 mmol) in hexane (66 mL) and 1-hexene
(33 mL) were added quinoline (2.0 g) and palladium on calcium
carbonate (Lindler reagent, purchased from Aldrich, 340 mg),
and the mixture was stirred under hydrogen (1 atm) at room
temperature overnight. The mixture was filtered, and the
filtrate was washed with 2 N aqueous HCl, H2O, and brine
successively, dried over MgSO4, and evaporated. The residual
mixture was purified by silica gel columun chromatography
(hexane/AcOEt ) 95:5) to give (Z)-ethyl cinnamate ((Z)-8a ) as
The racemic material (()-2b as standard compound was
prepared as below. To a solution of (E)-3b in acetone (4 mL)
and H2O (2 mL) were successively added Oxone (1.23 g, 2
mmol) and NaHCO3 (520 mg, 6.2 mmol) at room temperature,
and the mixture was stirred at room temperature for 24 h.
The mixture was diluted with H2O and extracted with AcOEt.
The extracts were washed with H2O and brine, dried over
MgSO4, and evaporated. The residue was purified by silica gel
column chromatography (hexane/AcOEt ) 5:1) to give (()-2b.
1
a colorless oil (1.24 g, 89%). Yield 89%; H NMR (CDCl3, 400
MHz) δ 7.59-7.57 (m, 2H), 7.38-7.33 (m 3H), 6.95 (d, J )
12.6 Hz, 1H), 5.95 (d, J ) 12.6 Hz, 1H), 4.18 (q, J ) 7.1 Hz,
2H), 1.24 (t, J ) 7.1 Hz, 3H); MS (GC) m/z 192 (M+); IR (ATR)
ν 2982, 1718, 1630, 1495, 1449 cm-1. Anal. Calcd for
Isop r op yl
(2R,3S)-3-(4-m et h oxyp h en yl)glycid a t e
((2R,3S)-2c): yield 85%, 80% ee [HPLC: Chiralcel OG, hexane/
EtOH ) 99:1, 1 mL/min, 220 nm, 40 °C, (2R,3S)-2c 45.4 min,
(2S,3R)-2c 40.6 min]; 1H NMR (CDCl3, 400 MHz) δ 7.22 (d, J
) 8.8 Hz, 2H), 6.89 (d, J ) 8.8 Hz, 2H), 5.14 (hept, J ) 6.3
Hz, 1H), 4.02 (d, J ) 1.8 Hz, 1H), 3.81 (s, 3H), 3.47 (d, J ) 1.8
Hz, 1H), 1.31 (d, J ) 6.3 Hz, 3H), 1.29 (d, J ) 6.3 Hz, 3H); IR
(ATR) 2982, 1742, 1614, 1517, 1440, 1409 cm-1; MS (EI) m/z
236 (M+). Anal. Calcd for C13H16O4: C, 66.09; H, 6.83. Found:
C, 65.98; H, 6.76.
C
11H12O3: C, 74.98; H, 6.86. Found: C, 74.72; H, 7.05.
(Z)-Meth yl 4-m eth oxycin n a m a te9a ((Z)-3a ): yield 89%;
colorless oil; 1H NMR (CDCl3, 400 MHz) δ 7.70 (d, J ) 8.8 Hz,
2H), 6.88 (d, J ) 8.8 Hz, 2H), 6.86 (d, J ) 12.9 Hz, 1H), 5.84
(d, J ) 12.9 Hz, 1H), 3.83 (s, 3H), 3.73 (s, 3H); MS (GC) m/ z
192 (M+); IR (ATR) ν 2951, 1717, 1601, 1509, 1442 cm-1. Anal.
Calcd for C11H12O3: C, 68.74; N, 6.29. Found: C, 68.66; H,
6.33.
ter t-Bu t yl
(2R,3S)-3-(4-m et h oxyp h en yl)glycid a t e
((2R,3S)-2d ): yield 89%, 77% ee [HPLC: Chiralcel OG, hex-
ane/EtOH ) 99:1, 1 mL/min, 220 nm, 40 °C, (2R,3S)-2d 13.7
min, (2S,3R)-2d 10.5 min]; 1H NMR (CDCl3, 400 MHz) δ 7.21
(d, J ) 8.8 Hz, 2H), 6.89 (d, J ) 8.8 Hz, 2H), 3.97 (d, J ) 1.8
Hz, 1H), 3.81 (s, 3H), 3.40 (d, J ) 1.8 Hz, 1H), 1.51 (s, 9H); IR
(ATR) 2990, 1733, 1612, 1515, 1434, 1402 cm-1; MS (EI) m/z
250 (M+). Anal. Calcd for C14H18O4: C, 67.18; H, 7.25. Found:
C, 66.17; H, 7.20.
Asym m etr ic Ep oxid a tion of (E)-3a : Syn th esis of Meth -
yl (2R,3S)-3-(4-Meth oxyp h en yl)glycid a te ((2R,3S)-2a ). To
a solution of methyl (E)-4-methoxycinnamate ((E)-2a ) (1.92 g,
10 mmol) and ketone catalyst (R)-7a (198 mg, 0.5 mmol) in a
mixed solvent of 1,4-dioxane (24.4 mL) and H2O (14.4 mL) were
successively added Oxone (6.14 g, 10 mmol) and NaHCO3 (2.6
g, 31 mmol) at 5 °C. The suspension was mechanically stirred
at 5 °C for 48 h. The mixture was then warmed to 27 °C and
stirring was continued for 2 h. The resulting suspension was
treated with H2O and the mixture was extracted three times
with CHCl3. The combined extracts were washed with satu-
rated aqueous NaCl and dried over anhydrous MgSO4. Evapo-
ration of the solvent provided the crude mixture of (2R,3S)-
2a and (R)-7a . The yield and the ee value of (2R,3S)-2a were
determined by Chiral HPLC analysis: yield 92%, 80% ee
[Chiralcel OD, hexane/iPrOH ) 10:1, 220 nm, 40 °C, (2R,3S)-
2a 8.1 min, (2S,3R)-2a 9.8 min]. The separation of (2R,3S)-2a
and (R)-7a was accomplished by using our previously reported
contituous dissolution and crystallizaition method.14 Mp 87-
88 °C; [R]24D -205 (c 1.00, MeOH); 1H NMR (400 MHz, CDCl3)
δ 7.21 (d, J ) 8.7 Hz, 2H), 6.89 (d, J ) 8.7 Hz, 2H), 4.05 (d, J
) 1.7 Hz, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.51 (d, J ) 1.7 Hz,
1H); 13C NMR (200 MHz, CDCl3) δ 168.7, 160.2, 127.1, 126.9,
126.6, 114.3, 114.0, 57.8, 56.4, 55.2, 52.4; IR (KBr) ν 3029,
Ben zyl (2R,3S)-3-(4-m eth oxyp h en yl)glycid a te ((2R,3S)-
2e): yield 84%, 78% ee [HPLC: Chiralcel OD, hexane/iPrOH
) 98:1, 1 mL/min, 220 nm, 40 °C, (2R,3S)-2e 17.7 min, (2S,3R)-
2e 19.5 min]; 1H NMR (CDCl3, 400 MHz) δ 7.40-7.36 (m, 5H),
7.20 (d, J ) 8.8 Hz, 2H), 6.88 (d, J ) 8.8 Hz, 2H), 5.25 (q, J )
12.4 Hz, 2H), 4.06 (d, J ) 1.8 Hz, 1H), 3.80 (s, 3H), 3.55 (d, J
) 1.8 Hz, 1H); IR (ATR) 3379, 2941, 1727, 1613, 1586, 1515,
1442, 1405 cm-1; MS (EI) m/z 284 (M+). Anal. Calcd for
C
17H16O4: C, 71.82; H, 5.67. Found: C, 72.17; H, 5.74.
(2R,3S)-3-(4-Meth oxyp h en yl)glyid ic a m id e ((2R,3S)-2f):
yield 80%, 71% ee [HPLC: Chiralcel OJ , hexane/EtOH ) 90:
10, 1 mL/min, 220 nm, 40 °C, (2R,3S)-2f 16.3 min, (2S,3R)-2f
1
14.5 min]; H NMR (CDCl3, 400 MHz) δ 7.20 (d, J ) 8.8 Hz,
2H), 6.89 (d, J ) 8.8 Hz, 2H), 6.18 (br, 1H), 6.50 (br, 1H), 4.92
(d, J ) 2.0 Hz, 1H), 3.82 (s, 3H), 3.51 (d, J ) 2.0 Hz, 1H); IR
(ATR) 3448, 3208, 1695, 1663, 1613, 1584, 1515, 1442, 1410
4224 J . Org. Chem., Vol. 69, No. 12, 2004

Synthesis of Chiral Glycidic Acid Derivatives
cm-1; MS (EI) m/z 193 (M+). Anal. Calcd for C10H11NO3: C,
62.17; H, 5.74; N, 7.25. Found: C, 61.93; H, 5.60; N, 7.20.
(2R,3S)-3-(4-Meth oxyp h en yl)glyid ic a cid eth yla m id e
((2R,3S)-2g): yield 93%, 65% ee [HPLC: Chiralcel OJ -H,
hexane/EtOH ) 90:10, 1 mL/min, 220 nm, 40 °C, (2R,3S)-2g
14.8 min, (2S,3R)-2g 10.6 min]; 1H NMR (CDCl3, 400 MHz) δ
7.19 (d, J ) 8.8 Hz, 2H), 6.89 (d, J ) 8.8 Hz, 2H), 6.22 (br,
1H), 3.82 (d, J ) 2.0 Hz, 1H), 3.81 (s, 3H), 3.52 (d, J ) 2.0 Hz,
1H), 3.41-3.26 (m, 2H), 1.18 (t, J ) 7.3 Hz, 3H); IR (ATR)
3273, 3095, 2982, 1652, 1612, 1558, 1516 cm-1; MS (APCI) m/z
222 ([M + H]+). Anal. Calcd for C12H15NO3: C, 65.14; H, 6.83;
N, 6.33. Found: C, 64.92; H, 6.72; N, 6.31.
Gen er a l P r oced u r e for Ca ta lytic Asym m etr ic Ep oxi-
d a tion of Cin n a m ic Acid Der iva tives: Syn th esis of
Mth yl (2R,3S)-3-(4-ter t-Bu tylp h en yl)glycid a te ((2R,3S)-
2u ). To methyl 4-tert-butyl cinnamate ((E)-3u ) (234 mg, 1
mmol) and ketone catalyst (R)-7a (20 mg, 0.05 mmol) in a
mixed solvent of DME (2 mL) and H2O (1 mL) were succes-
sively added Oxone (615 mg, 1 mmol) and NaHCO3 (260 mg,
3.1 mmol) at 10 °C. The suspension was stirred at 10 °C for
24 h. To the mixture were added Oxone (615 mg, 1 mmol) and
NaHCO3 (260 mg, 3.1 mmol) at 10 °C. The mixture was stirred
at 10 °C for 24 h, then warmed to 27 °C, and stirring was
continued for 2 h. The resulting suspension was treated with
H2O and the mixture was extracted three times with CHCl3.
The combined extracts were washed with saturated aqueous
NaCl and dried over anhydrous MgSO4. After evaporation of
the solvent, the residue was purified through flash NH silica
gel column chromatography (AcOEt). The yield and ee of
(2R,3S)-2b were determined by Chiral HPLC analysis: yield
81%, 92% ee [HPLC: Chiralcel OJ -H, hexane/iPrOH ) 90:10,
0.5 mL/min, 220 nm, 40 °C, (2R,3S)-2u 15.7 min, (2S,3R)-2u
(2R,3S)-3-(4-Meth oxyp h en yl)glyid ic a cid ben zyla m id e
((2R,3S)-2h ): yield 93%, 65% ee [HPLC: Chiralcel OJ -H,
hexane/EtOH ) 90:10, 1 mL/min, 220 nm, 40 °C, (2R,3S)-2h
14.8 min, (2S,3R)-2h 10.6 min]; 1H NMR (CDCl3, 400 MHz) δ
7.39-7.28 (m, 5H), 7.19 (d, J ) 8.8 Hz, 2H), 6.89 (d, J ) 8.8
Hz, 2H), 6.54 (br, 1H), 4.48 (q, J ) 3.0 Hz, 2H), 3.85 (d, J )
2.0 Hz, 1H), 3.81 (s, 3H), 3.59 (d, J ) 2.0 Hz, 1H); IR (ATR)
3271, 1653, 1618, 1558, 1519, 1456, 1438, 1409 cm-1; MS
(APCI) m/z 284 ([M + H]+). Anal. Calcd for C17H17NO3: C,
72.07; H, 6.05; N, 4.94. Found: C, 71.80; H, 6.01; N, 4.93.
(2R,3S)-3-(4-Meth oxyp h en yl)glyid ic a cid d ieth yla m id e
((2R,3S)-2i): yield 80%, 10% ee [HPLC: Chiralcel OJ -H,
hexane/EtOH ) 80:20, 0.5 mL/min, 220 nm, 40 °C, (2R,3S)-2i
1
14.4 min]; H NMR (CDCl3, 400 MHz) δ 7.40 (d, J ) 8.3 Hz,
2H), 7.23 (d, J ) 8.3 Hz, 2H), 4.08 (d, J ) 1.8 Hz, 1H), 3.83 (s,
3H), 3.53 (d, J ) 1.8 Hz, 1H), 1.32 (s, 9H); IR (ATR) 2945,
2903, 1745, 1514, 1446, 1400 cm-1; MS (EI) m/z 234 (M+). Anal.
Calcd for C14H18O5: C, 71.77; H, 7.74. Found: C, 71.76; H,
7.80
1
16.7 min, (2S,3R)-2i 14.7 min]; H NMR (CDCl3, 400 MHz) δ
Meth yl (2R,3S)-3-(4-m eth ylp h en yl)glycid a te ((2R,3S)-
2n ): yield 95%, 72% ee [HPLC: Chiralcel OJ -H, hexane/iPrOH
) 80:20, 0.5 mL/min, 220 nm, 40 °C, (2R,3S)-2n 11.6 min,
7.25 (d, J ) 8.8 Hz, 2H), 6.90 (d, J ) 8.8 Hz, 2H), 4.03 (d,
J ) 2.0 Hz, 1H), 3.82 (s, 3H), 3.58 (d, J ) 2.0 Hz, 1H), 3.52-
3.37 (m, 4H), 1.21 (t, J ) 7.0 Hz, 3H), 1.17 (t, J ) 7.0 Hz,
3H); IR (ATR) 2973, 1642, 1585, 1511, 1485, 1468, 1439, 1411
1
(2S,3R)-2n 10.4 min]; H NMR (CDCl3, 400 MHz) δ 7.18 (br,
cm-1; MS (APCI) m/z 250 ([M + H]+). Anal. Calcd for C14H19
-
4H), 4.06 (d, J ) 1.8 Hz, 1H), 3.83 (s, 3H), 3.51 (d, J ) 1.8 Hz,
1H), 2.36 (s, 3H); IR (ATR) 2956, 1731, 1519, 1439 cm-1; MS
(EI) m/z 168 (M+). Anal. Calcd for C11H12O5: C, 68.74; H, 6.29.
Found: C, 68.45; H, 6.07.
NO3: C, 67.45; H, 7.68; N, 5.62. Found: C, 67.48; H, 7.67; N,
5.66.
(2R,3S)-3-(4-Met h oxyp h en yl)glyid ic a cid d ib en zyl-
a m id e ((2R,3S)-2j): yield 69%, 20% ee [HPLC: Chiralcel
OJ -H, hexane/iPrOH ) 90:10, 1 mL/min, 220 nm, 40 °C,
(2R,3S) 40.8 min, (2S,3R) 34.5 min]; 1H NMR (CDCl3, 400
MHz) δ 7.36-7.25 (m, 8H), 7.15 (d, J ) 6.8 Hz, 2H), 7.11 (d,
J ) 8.7 Hz, 2H), 6.83 (d, J ) 8.7 Hz, 2H), 4.65 (s, 2H), 4.54 (s,
2H), 4.07 (d, J ) 2.0 Hz, 1H), 3.78 (s, 3H), 3.68 (d, J ) 2.0 Hz,
1H); IR (ATR) 3030, 1655, 1613, 1516, 1495, 1451 cm-1; MS
(APCI) m/z 284 ([M + H]+). Anal. Calcd for C24H23NO3: C,
77.19; H, 6.21; N, 3.75. Found: C, 76.39; H, 6.15; N, 3.80.
(2R,3S)-3-(4-Meth oxyp h en yl)glyid ic a cid p yr r olid in o-
a m id e ((2R,3S)-2k ): yield 69%, 20% ee [HPLC: Chiralcel
OJ -H, hexane/EtOH ) 80:20, 0.5 mL/min, 220 nm, 40 °C,
Meth yl (2R,3S)-3-p h en ylglycid a te ((2R,3S)-2o): yield
75%, 74% ee [HPLC: Chiralcel OD-H, hexane/iPrOH ) 90:
10, 1 mL/min, 220 nm, 40 °C, (2R,3S)-2o 7.4 min, (2S,3R)-2o
9.1 min]; 1H NMR (CDCl3, 400 MHz) δ 7.39-7.35 (m, 3H),
7.30-7.26 (m, 2H), 4.10 (d, J ) 1.8 Hz, 1H), 3.83 (s, 3H), 3.52
(d, J ) 1.8 Hz, 1H); IR (ATR) 3037, 2956, 1753, 1497, 1460,
1441, 1417 cm-1; MS (GC) m/z 178 (M+). Anal. Calcd for
C
10H10O5: C, 67.41; H, 5.66. Found: C, 67.19; H, 5.59.
Met h yl (2R,3S)-3-(4-flu or op h en yl)glycid a t e ((2R,3S)-
2p ): yield 74%, 72% ee [HPLC: Chiralcel OD-H, hexane/iPrOH
) 98:2, 1 mL/min, 220 nm, 40 °C, (2R,3S)-2p 9.7 min, (2S,3R)-
2p 11.0 min]; 1H NMR (CDCl3, 400 MHz) δ 7.27 (dd, J ) 5.1,
8.8 Hz, 2H), 7.06 (t, J ) 8.8 Hz, 2H), 4.09 (d, J ) 1.8 Hz, 1H),
3.86 (s, 3H), 3.48 (d, J ) 1.8 Hz, 1H); IR (ATR) 2955, 1748,
1606, 1513, 1447, 1401 cm-1; MS (EI) m/z 196 (M+). Anal.
Calcd for C10H9FO5: C, 61.22; H, 4.62; F, 9.68. Found: C,
61.65; H, 4.52; F, 9.74.
1
(2R,3S)-2k 51.1 min, (2S,3R)-2k 46.5 min]; H NMR (CDCl3,
400 MHz) δ 7.24 (d, J ) 8.8 Hz, 2H), 6.89 (d, J ) 8.8 Hz, 2H),
4.08 (d, J ) 2.0 Hz, 1H), 3.81 (s, 3H), 3.68-3.50 (m, 5H), 2.03-
1.86 (m, 4H); IR (ATR) 2967, 2878, 1633, 1609, 1517, 1451
cm-1; MS (APCI) m/z 248 ([M + H]+). Anal. Calcd for C14H17
-
Meth yl (2R,3S)-3-(4-ch lor op h en yl)glycid a te ((2R,3S)-
2q): yield 45%, 73% ee [HPLC: Chiralcel OD-H, hexane/i-
PrOH ) 90:10, 1 mL/min, 220 nm, 40 °C, (2R,3S)-2q 7.6 min,
NO3: C, 68.00; H, 6.93; N, 5.66. Found: C, 67.76; H, 6.90; N,
5.66.
(2R,3S)-3-(4-Met h oxyp h en yl)glyid ic a cid m or p h oli-
n oa m id e ((2R,3S)-2l): yield 75%, 18% ee [HPLC: Chiralcel
OJ -H, hexane/EtOH ) 80:20, 1 mL/min, 220 nm, 40 °C,
(2R,3S)-2l 25.8 min, (2S,3R)-2l 22.6 min]; 1H NMR (CDCl3,
400 MHz) δ 7.23 (d, J ) 8.6 Hz, 2H), 6.90 (d, J ) 8.7 Hz, 2H),
4.04 (d, J ) 2.0 Hz, 1H), 3.82 (s, 3H), 3.72-3.67 (m 8H), 3.62
(d, J ) 2.0 Hz, 1H); IR (ATR) 2858, 1648, 1613, 1516, 1462
1
(2S,3R)-2q 8.8 min]; H NMR (CDCl3, 400 MHz) δ 7.35 (d, J
) 8.5 Hz, 2H), 7.23 (d, J ) 8.5 Hz, 2H), 4.08 (d, J ) 1.8 Hz,
1H), 3.37 (s, 3H), 3.47 (d, J ) 1.8 Hz, 1H); IR (ATR) 3036,
2954, 1751, 1601, 1497, 1444 cm-1; MS (EI) m/z 212 (M+), 214
([M + 2]+). Anal. Calcd for C10H9ClO5: C, 56.49; H, 4.27; Cl,
16.67. Found: C, 56.29; H, 4.16; Cl, 16.27.
cm-1; MS (APCI) m/z 264 ([M + H]+). Anal. Calcd for C14H17
-
Meth yl (2R,3S)-3-(4-m eth oxyca r bon ylp h en yl)glycid a te
((2R,3S)-2r ): yield 6%, 81% ee [HPLC: Chiralcel OJ -H,
hexane/iPrOH ) 90:10, 1 mL/min, 220 nm, 40 °C, (2R,3S)-2r
NO4: C, 63.87; H, 6.51; N, 5.32. Found: C, 64.09; H, 6.34; N,
5.23.
1
11.0 min, (2S,3R)-2r 9.5 min]; H NMR (CDCl3, 400 MHz) δ
Met h yl
(2R,3S)-3-(4-ter t-b u t oxyp h en yl)glycid a t e
8.04 (d, J ) 8.3 Hz, 2H), 7.37 (d, J ) 7.37, 2H), 4.16 (d, J )
1.8 Hz, 1H), 3.93 (s, 3H), 3.84 (s, 3H), 3.51 (d, J ) 1.8 Hz,
1H); IR (ATR) 2964, 1756, 1720, 1615, 1440 cm-1; MS (EI) m/z
236 (M+). Anal. Calcd for C12H12O5: C, 61.01; H, 5.12. Found:
C, 60.90; H, 5.00.
Meth yl (2R,3S)-3-(4-tr iflu or om eth ylp h en yl)glycid a te
((2R,3S)-2s): yield 14%, 86% ee [HPLC: Chiralcel OJ -H,
hexane/EtOH ) 80:20, 0.5 mL/min, 220 nm, 40 °C, (2R,3S)-
((2R,3S)-2m ): yield 80%, 84% ee [HPLC: Chiralcel OD-H,
hexane/EtOH ) 99:1, 1 mL/min, 220 nm, 40 °C, (2R,3S)-2m
12.0 min, (2S,3R)-2m 13.7 min]; 1H NMR (CDCl3, 400 MHz) δ
7.19 (d, J ) 8.6 Hz, 2H), 6.98 (d, J ) 8.6 Hz, 2H), 4.06 (d, J )
1.8 Hz, 1H), 3.83 (s, 3H), 3.53 (d, J ) 1.8 Hz, 1H), 1.35 (s,
9H); IR (ATR) 2978, 1752, 1610, 1510, 1442 cm-1; MS (APCI)
m/z 251 ([M + H]+). Anal. Calcd for C14H18O4: C, 67.18; H,
7.25. Found: C, 66.91; H, 7.16.
J . Org. Chem, Vol. 69, No. 12, 2004 4225

Imashiro and Seki
2s 51.1 min, (2S,3R)-2s 46.5 min]; 1H NMR (CDCl3, 400 MHz)
δ 7.64 (d, J ) 8.3 Hz, 2H), 7.42 (d, J ) 8.3 Hz, 2H), 4.17 (d, J
) 1.8 Hz, 1H), 3.85 (s, 3H), 3.49 (d, J ) 1.8 Hz, 1H); IR (ATR)
2960, 1746, 1621, 1447, 1407 cm-1; MS (EI) m/z 246 (M+). Anal.
Calcd for C11H9FO3: C, 53.67; H, 3.68; F, 23.15. Found: C,
53.46; H, 3.56; F, 22.82.
Met h yl (2R,3S)-3-(4-b ip h en yl)glycid a t e ((2R,3S)-2t ):
yield 51%, 91% ee [HPLC: Chiralcel OD-H, hexane/iPrOH )
90:10, 1 mL/min, 254 nm, 40 °C, (2R,3S)-2t 7.4 min, (2S,3R)-
2t 8.7 min]; 1H NMR (CDCl3, 400 MHz) δ 7.61-7.57 (m, 4H),
7.47-7.43 (m, 2H), 7.38-7.35 (m, 3H), 4.15 (d, J ) 1.8 Hz,
1H), 3.85 (s, 3H), 3.57 (d, J ) 1.8 Hz, 1H); IR (ATR) 3034,
1725, 1489, 1436 cm-1; MS (EI) m/z 254 (M+). Anal. Calcd for
) 90:10, 1 mL/min, 220 nm, 40 °C, (2R,3R)-2a 17.8 min,
(2S,3S)-2a 20.2 min]; 1H NMR (CDCl3, 400 MHz) δ 7.34 (d, J
) 8.6 Hz, 2H), 6.87 (d, J ) 8.8 Hz, 2H), 4.22 (d, J ) 4.6 Hz,
1H), 3.81 (d, J ) 4.6 Hz, 1H), 3.80 (s, 3H), 3.58 (s, 3H); IR
(ATR) 2998, 1749, 1611, 1584, 1515, 1442, 1401 cm-1; MS (EI)
m/z 208 (M+). Anal. Calcd for C11H12O4: C, 63.45; H, 5.81.
Found: C, 63.37; H, 5.78.
Meth yl (2R,3R)-3-(2-m eth oxyph en yl)glycidate ((2R,3R)-
2v): yield 57%, 26% ee [HPLC: Chiralcel OJ -H, hexane/iPrOH
) 90:10, 1 mL/min, 220 nm, 40 °C, (2R,3R)-2v 13.3 min,
1
(2S,3S)-2v 14.5 min]; H NMR (CDCl3, 400 MHz) δ 7.41 (dd,
J ) 1.8, 7.6 Hz, 1H), 7.30 (dt, J ) 1.8, 7.6 Hz, 1H), 6.95 (t, J
) 7.6 Hz, 1H), 6.84 (d, J ) 8.3 Hz, 1H), 4.41 (d, J ) 4.6 Hz,
1H), 3.87 (d, J ) 4.6 Hz, 1H), 3.84 (s, 3H), 3.54 (s, 3H); IR
(ATR) 2977, 1752, 1603, 1496, 1456, 1409 cm-1; MS (EI) m/z
208 (M+). Anal. Calcd for C11H12O4: C, 63.45; H, 5.81. Found:
C, 63.50; H, 5.85.
C
16H14O3: C, 75.57; H, 5.55. Found: C, 75.10; H, 5.40.
Meth yl (2R,3S)-3-(2-m eth oxyp h en yl)glycid a te ((2R,3S)-
2v): yield 55%, 53% ee [HPLC: Chiralcel OJ -H, hexane/iPrOH
) 90:10, 1 mL/min, 220 nm, 40 °C, (2R,3S)-2v 11.9 min,
(2S,3R)-2v 10.4 min]; 1H NMR (CDCl3, 400 MHz) δ 7.30 (dt, J
) 1.8, 8.1 Hz, 1H), 7.15 (dd, J ) 1.8, 7.6 Hz, 1H), 6.95 (t, J )
7.5 Hz, 1H), 6.89 (d, J ) 8.3 Hz, 1H), 4.43 (d, J ) 1.8 Hz, 1H),
3.86 (s, 3H), 3.84 (s, 3H), 3.44 (d, J ) 1.8 Hz, 1H); IR (ATR)
2948, 1740, 1603, 1589, 1495, 1437, 1417 cm-1; MS (EI) m/z
208 (M+). Anal. Calcd for C11H12NO4: C, 63.45; H, 5.81.
Found: C, 63.39; H, 5.64.
Eth yl (2R,3R)-3-ph en ylglycidate ((2R,3R)-9a): yield 57%,
26% ee [HPLC: Chiralcel OD-H, hexane/iPrOH ) 99:1, 0.5 mL/
min, 220 nm, 40 °C, (2R,3R)-9a 42.0 min, (2S,3S)-9a 24.6 min];
[R]26 +0.64 (c 1.03, CHCl3) [[R]25 +25.0 (c 1.1, CHCl3) for
D
D
(2R,3R)-form]; 1H NMR (CDCl3, 400 MHz) δ 7.42 (dd, J ) 1.8,
7.6 Hz, 2H), 7.36-7.30 (m, 3H), 4.27 (d, J ) 4.6 Hz, 1H), 4.07-
3.82 (m, 2H), 3.83 (d, J ) 4.6 Hz, 1H), 1.02 (t, J ) 7.1 Hz,
3H); IR (ATR) 2984, 1751, 1730, 1456 cm-1; MS (EI) m/z 192
(M+). Anal. Calcd for C11H12O3: C, 68.74; H, 6.29. Found: C,
68.53; H, 6.29.
Meth yl (2R,3S)-3-(3-m eth oxyp h en yl)glycid a te ((2R,3S)-
2w ): yield 11%, 47% ee [HPLC: Chiralcel OD-H, hexane/iPrOH
) 90:10, 1 mL/min, 220 nm, 40 °C, (2R,3S)-2w 8.8 min,
(2S,3R)-2w 11.0 min]; 1H NMR (CDCl3, 400 MHz) δ 7.29 (d, J
) 8.0 Hz, 1H), 6.91-6.87 (m, 2H), 6.81-6.80 (m, 1H), 4.08 (d,
J ) 1.8 Hz, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.50 (d, J ) 1.8 Hz,
1H); IR (ATR) 2955, 1748, 1587, 1493, 1438, 1415 cm-1; MS
(EI) m/z 208 (M+). Anal. Calcd for C11H12NO4: C, 63.45; H,
5.81. Found: C, 63.20; H, 5.61.
Eth yl (2R,3S)-3-m eth yl-3-p h en ylglycid a te ((2R,3S)-9b):
yield 93%, 40% ee [HPLC: Chiralcel OD-H, hexane/iPrOH )
98:2, 1 mL/min, 220 nm, 40 °C, (2R,3S)-9b 7.8 min, (2S,3R)-
9b 6.0 min]; [R]26 -5.81 (c 1.03, CHCl3) [[R]25 +121.3 (c 1.0,
D
D
CHCl3) for (2S,3R)- form (96% ee)]; 1H NMR (CDCl3, 400 MHz)
δ 7.39-7.30 (m, 5H), 4.35-4.26 (m, 2H), 3.46 (s, 1H), 1.77 (s,
Meth yl (2R,3S)-3-(1-n a p h th yl)glycid a te ((2R,3S)-2x):
yield 55%, 75% ee [HPLC: Chiralcel OD-H, hexane/iPrOH )
90:10, 1 mL/min, 220 nm, 40 °C, (2R,3S)-2x 11.0 min, (2S,3R)-
3H), 1.33 (t, J ) 7.2 Hz, 3H); IR (ATR) 2982, 1748, 1448 cm-1
;
MS (EI) m/z 206 (M+). Anal. Calcd for C12H14O3: C, 69.88; H,
1
2x 13.6 min]; H NMR (CDCl3, 400 MHz) δ 8.04 (d, J ) 8.3
6.84. Found: C, 69.81 H, 6.91.
Hz, 1H), 7.91 (dd, J ) 1.8, 7.6 Hz, 1H), 7.84 (dd, 2.0, 7.3 Hz,
1H), 7.60-7.52 (m, 2H), 7.50-7.45 (m, 2H), 4.74 (d, J ) 1.8
Hz, 1H), 3.91 (s, 3H), 3.55 (d, J ) 1.8 Hz, 1H); IR (ATR) 2954,
1738, 1598, 1510, 1444 cm-1; MS (EI) m/z 228 (M+). Anal.
Calcd for C14H12O3: C, 73.67; H, 5.30. Found: C, 73.36; H,
5.25.
Meth yl (2R,3S)-3-(2-n a p h th yl)glycid a te ((2R,3S)-2y):
yield 47%, 63% ee [HPLC: Chiralcel OJ -H, hexane/iPrOH )
90:10, 0.5 mL/min, 220 nm, 40 °C, (2R,3S)-2y 30.0 min,
(2S,3R)-2y 25.7 min]; 1H NMR (CDCl3, 400 MHz) δ 7.86-7.82
(m, 4H), 7.53-7.49 (m, 2H), 7.32 (dd, J ) 1.8, 8.6 Hz, 1H),
4.27 (d, J ) 1.8 Hz, 1H), 3.86 (s, 3H), 3.62 (d, J ) 1.8 Hz, 1H);
IR (ATR) 2957, 1736, 1601, 1509, 1449, 1415 cm-1; MS (EI)
m/z 228 (M+). Anal. Calcd for C14H12O3: C, 73.67; H, 5.30.
Found: C, 73.49; H, 5.18.
Meth yl (2R,3S)-3-(3-th ien yl)glycid a te ((2R,3S)-9c): yield
5%, 60% ee [HPLC: Chiralcel OD-H, hexane/iPrOH ) 90:10,
1 mL/min, 220 nm, 40 °C, (2R,3S)-9c 12.6 min, (2S,3R)-9c 8.8
1
min]; H NMR (CDCl3, 400 MHz) δ 7.36-7.32 (m, 2H), 6.97
(dd, J ) 1.5, 5.0 Hz, 1H), 4.17 (d, J ) 1.8 Hz, 1H), 3.83 (s,
3H), 3.61 (d, J ) 1.8 Hz, 1H); IR (ATR) 2955, 1737, 1440 cm-1
;
MS (EI) m/z 184 (M+). Anal. Calcd for C8H8O3S: C, 52.16; H,
4.38; S, 17.41. Found: C, 51.77; H, 4.33.
Ack n ow led gm en t. The authors are indebted to Dr.
Kazuya Nakao Medicinal Research Laboratories, Tanabe
Seiyaka Co., Ltd., for the calculation of the stable
conformation of the dioxirane derived from catalyst
(R)-7a .
Meth yl (2R,3R)-3-(4-m eth oxyph en yl)glycidate ((2R,3R)-
2a ): yield 71%, 16% ee [HPLC: Chiralcel OJ -H, hexane/iPrOH
J O049893U
4226 J . Org. Chem., Vol. 69, No. 12, 2004