Chiral ligand-controlled catalytic asymmetric epoxidation of α,β-unsaturated carbonyl compounds with peroxide

Article abstract of DOI:10.1016/S0040-4020(03)00658-6

Asymmetric epoxidation reaction of α,β-unsaturated carbonyl compounds with alkylperoxide was catalyzed by an external chiral tridentate aminodiether-lithium peroxide giving epoxides with good enantiomeric excess. Slow addition of alkylhydroperoxide was beneficial for a catalytic asymmetric reaction. Lone pair electron-differentiating coordination of a carbonyl oxygen to lithium is another critical factor for high enantioselectivity.

Full text of DOI:10.1016/S0040-4020(03)00658-6

Tetrahedron 59 (2003) 4549–4556
Chiral ligand-controlled catalytic asymmetric epoxidation of
a,b-unsaturated carbonyl compounds with peroxide
*
Yoshihito Tanaka, Katsumi Nishimura and Kiyoshi Tomioka
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Received 2 April 2003; accepted 24 April 2003
Abstract—Asymmetric epoxidation reaction of a,b-unsaturated carbonyl compounds with alkylperoxide was catalyzed by an external chiral
tridentate aminodiether–lithium peroxide giving epoxides with good enantiomeric excess. Slow addition of alkylhydroperoxide was
beneficial for a catalytic asymmetric reaction. Lone pair electron-differentiating coordination of a carbonyl oxygen to lithium is another
critical factor for high enantioselectivity. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
tion reaction of a,b-unsaturated carbonyl compounds using
an external chiral ligand and lithium alkylperoxide as an
oxygen nucleophile (Scheme 1). Our strategy for the
nucleophilic asymmetric epoxidation relies on the double
activation of a peroxide by lithiation and subsequent chelate
formation with a chiral ligand.13
Reflecting the importance of chiral epoxides in chemical
synthesis of biologically active compounds, many asym-
metric epoxidation reactions of olefins have been reported.
These reactions are categorized into two types: one is an
electrophilic addition of chirally modified oxygen reagents
to olefins, and the other is a nucleophilic addition of chirally
modified oxygen reagents to electron-deficient olefins such
as a,b-unsaturated carbonyl compounds. The typical
examples of the former type reaction are Sharpless–Katsuki
asymmetric epoxidation of allylic alcohol1 and asymmetric
epoxidation using chiral salen complexes2 as well as chiral
ketones in situ convertible to dioxirane species.3 Recently,
the latter type asymmetric epoxidation of an electron-
deficient olefin has attracted widespread attention,4 and
efficient methods using highly reactive oxygen-equivalent
reagents have been reported. The characteristic of such
oxygen-equivalent active reagents is a combined use of
external chiral ligands and peroxides activated by zinc,5
magnesium,6 and lanthanides.7,8
2. Results and discussion
2.1. Synthesis of chiral ligands
The tridentate ligands having a methoxyphenyl group, 114
and 2,15 were prepared according to previously reported our
procedure (Fig. 1). Chiral ligand 5 was prepared from
proline-derived chloride 316 and guaiacol 4.17 Chiral ligand
9 having a cyclohexane ring was prepared from amino
alcohol 618 and chromium complex 719 through O-arylation
and subsequent dechromination of 8 with iodine.
The bidentate ligands 10–13 were prepared according to
previously reported our procedure (Fig. 2).20
We have been involved in development of methodologies
for the catalytic asymmetric conjugate addition and 1,2-
addition reactions of organolithiums and lithium ester
enolates with a,b-unsaturated carbonyl compounds, ketones
and imines under the catalysis of external chiral ligands.9,10
We have also found that these methodologies are applicable
to asymmetric conjugate addition reactions of heteroatom
nucleophiles such as lithium thiolate11 and lithium amide.12
In this paper, we describe a catalytic asymmetric epoxida-
A chiral ligand having a methoxyethyl side chain 17 was
synthesized according to our previously reported procedure
(Fig. 3).21 The ligands having a chiral side chain, 18r and
18s, were synthesized by an alkylation of 1422 with the
corresponding chiral styrene oxides 1523 and subsequent
methylation of 16 with methyl tosylate.
Keywords: conjugate addition; lithium cumene hydroperoxide;
enantioselectivity; slow addition; chiral ligand.
*
Corresponding author. Tel.: þ81-75-753-4553; fax: þ81-75-753-4604;
Scheme 1. Asymmetric conjugate addition-type epoxidation with chiral
ligand-lithium hydroperoxide catalysis.
e-mail: tomioka@pharm.kyoto-u.ac.jp
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00658-6

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Y. Tanaka et al. / Tetrahedron 59 (2003) 4549–4556
Figure 3. Synthesis of bidentate ligands having a methoxyethyl side chain.
lithium peroxide but also controls the stereochemistry of the
nucleophilic epoxidation reaction. The absolute configur-
ation of optically active 27 was determined to be (2R,3S) by
reducing 27 with lithium aluminum hydride in THF to the
corresponding diols of the established absolute stereochem-
istry (R)-3-phenylpropane-1,2-diol,29 and (R)-1-phenylpro-
pane-1,3-diol30 in 65 and 24% yields, respectively. It is
important to note that the chiral ligand 1 was quantitatively
recovered without any loss of optical purity, and was
reusable.
Figure 1. Synthesis of chiral ligands having a methoxyphenyl group.
Chiral ligands 19 and 20 having a methoxypropyl and a
methoxybenzyl side chains were synthesized by direct
alkylation of 14 with the corresponding tosylate24 or
chloride.25 The methoxymethylphenyl ligand 24 was
synthesized from 14 through arylation with fluorobenzene-
carboxylate,26 reduction of the ester 22, and finally
methylation of the hydroxy group of 23 (Fig. 4).
The reaction of 25 with more bulky lithium cumene
peroxide 28-Li31 gave 27 in an improved 82% yield with
the same 72% ee (Fig. 6). More bulky lithium tritylperoxide
29-Li32 gave 27 in 82% yield with a diminished 59% ee,
perhaps due to the partial prevention of chelate formation
with a chiral ligand by a bulky trityl group.
2.2. Asymmetric epoxidation of BHA cinnamate
We began our study by the examination of an asymmetric
epoxidation reaction of an a,b-unsaturated BHA (3,5-di-
tert-butyl-4-hydroxyanisole) ester 25, which was a highly
effective acceptor for the chiral ligand-controlled catalytic
asymmetric conjugate addition of organolithiums.10d,e We
also expected that the bulkiness of the BHA group prevents
transesterification with lithium alkoxide which is generated
as a side product from lithium peroxide during progress of
the reaction. The reaction of 25 with 1.5 equiv. of lithium
tert-butylperoxide 26-Li, generated by treating tert-butyl-
hydroperoxide with butyllithium, in the absence of a chiral
ligand in toluene gave a desired epoxide 27 only in 10%
yield after stirring at 08C for 36 h (Fig. 5). On the other
hand, the reaction of 25 with 1.5 equiv. of 26-Li in the
presence of 1.8 equiv. of a chiral ligand 1 in toluene at 08C
for 36 h gave 27 in 62% yield without contamination of
transesterificated tert-butyl ester.27 This enhancement effect
on the reaction rate well indicates the applicability of our
strategy in the catalytic asymmetric epoxidation reaction.
The rate-enhancement with chiral ligand is probably due to
deaggregation of lithium tert-butylperoxide as has been
known for the reactivity of organolithiums.28 The enantio-
selectivity was determined to be 72% by a chiral stationary
phase HPLC analysis (Daicel Chiralpak AD). These results
clearly indicate that the chiral ligand 1 not only activates the
2.3. Catalytic asymmetric epoxidation of chalcone by a
slow addition procedure
The reaction of chalcone 30, which has higher reactivity
than the enoate 25, with 1.5 equiv. of lithium cumene
Figure 2. The bidentate ligands having a diphenylethane unit.
Figure 4. Synthesis of ligands having a methoxypropyl-type side chain.

Y. Tanaka et al. / Tetrahedron 59 (2003) 4549–4556
4551
Figure 7. Asymmetric epoxidation of chalcone 30 under 28-Li-1 catalysis.
Figure 5. Epoxidation of an enoate 25 in the presence and absence of 1.
peroxide 28-Li in the presence of 1.8 equiv. of 1 in toluene
at 08C proceeded smoothly within 0.5 h to give an epoxide
31 in 75% yield with 47% ee (Fig. 7). Encouraged by the
rapid reaction as well as relatively high enantioselectivity, a
catalytic reaction was examined. However, the reaction of
30 with 0.15 equiv. of 28-Li in the presence of 0.2 equiv. of
1 and 1.35 equiv. of cumene hydroperoxide resulted in 31
only in 15% ee.
indicates that a methoxy group attached on a phenoxy group
is not mere steric hindrance unit, but coordinates to lithium
forming bicyclo[3.3.0] complex as shown in Figure 8.
The coordinating ability of the chiral ligand also affected the
enantioselectivity. The tridentate ligands 17, 18r and 18s
bearing an alkyl ether side chain, which have stronger
coordinating ability than a phenolic ether, were expected to
form bicyclo[3.3.0] complexes more firmly (entries 9–11).
However, the opposite enantiofacial selection was observed
by the use of 17 and 18s. The ligand 18r gave 31 with
decreased selectivity of 16% ee. The change of enantio-
selectivity was presumably caused by difficulty in the
coordination of a carbonyl oxygen of chalcone to lithium
because of strong coordination to satisfy tetravalency of
lithium by the methoxy group of these chiral ligands 17 and
18s, though the highest 44% ee was realized by 18s.
The decreased enantioselectivity is ascribable to the
coordination of an excess of hydroperoxide to lithium
kicking out a chiral ligand from coordination. Suppression
of the influence of an excess of the hydroperoxide is
possible by a slow addition of cumene hydroperoxide. Thus,
a solution of the hydroperoxide in toluene was slowly added
over 3 h to a mixture of chalcone 30, 0.15 equiv. of lithium
cumene peroxide 28-Li, and 0.2 equiv. of chiral ligand 1 in
toluene at 08C. The reaction completed within another 1 h to
give 31 in 99% yield with an improved 40% ee, indicating
the effectiveness of the slow addition procedure for the
catalytic reaction.
The influence by the length of the side chain connecting two
ether oxygens was examined. The tridentate ligands 19, 20
and 24 bearing the methoxypropyl-type side chains were
expected to form stable bicyclo[4.3.0] complexes (entries
12–14). The chiral ligands 19 and 20 gave 31 with 15 and
23% ee of the opposite absolute configuration. The
enantioselectivity by 24 was nearly marginal.
2.4. Structural requirements of a chiral ligand
The chiral ligand 2, which has no substituent on the carbon
attached to a methoxyphenoxy group, gave an epoxide 31 in
74% yield and 15% ee (Table 1, entry 2). An analogous
ligand 5 gave 31 in 69% yield, but in marginal ee (entry 3).
The ligand 9 having two stereocenters on a cyclohexane
ring, gave 31 in 72% yield and 18% ee of the opposite
absolute configuration (entry 4). These results indicate that
two adjacent trans-phenyl substituents on an ethylene
bridge of the chiral ligand are important for reasonably
high enantioselectivity. We then examined the bidentate
chiral ligands 10–13 having a diphenylethane unit (entries
5–8). The enantioselectivity was ranged and increased from
7 to 42% as the increased bulkiness of the substituent on an
ether oxygen. It is noteworthy that these bidentate chiral
ligands gave an epoxide 31 of the opposite absolute
configuration. The difference of the sense of enantiofacial
selection between the tridentate and bidentate chiral ligands
Table 1. Catalytic asymmetric epoxidation of 30 in the presence of various
chiral ligands
Entry
Chiral ligand
Yield (%)
ee (%)
Configuration
1
2
3
4
5
6
7
8
1
2
5
9
99
74
69
72
97
69
88
85
97
88
56
86
95
70
40
15
0
2R,3S
2R,3S
2R,3S
2S,3R
2S,3R
2S,3R
2S,3R
2S,3R
2S,3R
2R,3S
2S,3R
2S,3R
2S,3R
2R,3S
ent-18
ent-7
ent-7
ent-22
ent-42
ent-19
16
ent-44
ent-15
ent-23
2
10
11
12
13
17
18r
18s
19
20
24
9
10
11
12
13
14
Figure 6. Asymmetric epoxidation of 25 to 27 with use of 28- and 29-Li.

4552
Y. Tanaka et al. / Tetrahedron 59 (2003) 4549–4556
Table 2. Catalytic asymmetric epoxidation of tert-butyl enones
Figure 8. Anticipated bicyclo[3.3.0] complex of lithium peroxide and 1.
Entry
R
Temperature Addition Time Yield
(8C)
ee
(%)
(h)
(h)
(%)
These results indicate the following structural requirements
of a chiral ligand in this epoxidation reaction: (1) vicinal-
trans-diphenyl groups on the ethylene bridge connecting an
amino group and an ether oxygen, (2) a tridentate ligand
which forms bicyclo[3.3.0] complex by the coordination to
lithium, and (3) a hemilabile33 methoxyphenyl side chain
which allows a coordinating atom exchange with a carbonyl
oxygen of an enone.
1
2
3
4
5
6
Ph
0
0
rt
0
3
3
24
3
24
3
1
1
12
1
12
1
76
55
74
81
68
55
71a
56
1-naphthyl
2-naphthyl
4-ClC6H4
4-MeOC6H4 rt
Ph(CH2)2
58
66
64a
37b
0
a
The absolute configuration was determined according to the Ref. 5.
b
The absolute configuration was determined according to the Ref. 34. The
absolute configuration of other products was tentatively assigned by
analogy.
2.5. The structural factor of substituent on ketone for
high enantioselectivity
investigated. Our findings in this work are (1) a chiral
ligand not only activates the lithium peroxide, but also
controls the absolute stereochemistry of the epoxidation
reaction, (2) a tridentate aminodiether ligand having a
hemilabile methoxyphenyl side chain is effective for high
enantioselectivity, (3) the lone pair electron-differentiating
coordination of a carbonyl oxygen to lithium is operative,
and (4) a slow addition procedure is effective for the
catalytic asymmetric reaction. These become a certain basis
of the development of more sophisticated conjugate
addition-type, ligand-controlled catalytic asymmetric
epoxidation reaction of a,b-unsaturated carbonyl
compounds.
The lone pair electron-differentiating coordination of a
carbonyl oxygen to lithium is responsible for the high
enantioselectivity.14 A bulky substituent on a ketone
carbonyl group prevents the lone-pair electron coordination
at this side and directs the coordination to lithium
predominantly at the side of a CvC double bond, opposite
to that bulky substituent. The results of asymmetric
epoxidation of two ketones having tert-butyl and trityl
groups are shown in Figure 9.
The reaction of a tert-butyl enone 32a gave a desired
epoxide 33a in 76% yield with improved 71% ee as
compared with 40% ee of chalcone. Trityl enone 32b also
improved the selectivity to give 33b in 62% yield with 51%
ee. These selectivity improvements indicate that the lone
pair electron-differentiating coordination of a carbonyl
oxygen is operative in this asymmetric epoxidation reaction.
Good selectivity observed in the reaction of a bulky BHA
enoate 25 would also based on this lone pair-differentiating
coordination (Fig. 5).
4. Experimental
4.1. General
1H and 13C NMR spectra were taken in CDC13. Chemical
shift values are expressed in ppm relative to internal
tetramethylsilane. Abbreviations are as follows: s, singlet; d,
doublet; t, triplet; m, multiplet. Purification was carried out
using silica gel column chromatography unless otherwise
noted. All reactions were carried out under an argon
atmosphere unless otherwise stated.
2.6. Generality of the reaction
Some enones bearing an aromatic substituent at the
b-position were oxidized in a selectivity ranging from 56
to 71% ee under the catalytic reaction conditions (Table 2,
entries 1–5). An exception is an enone having sp3
substituent at the b-position, giving an epoxide with a
diminished ee of 37% (entry 6).
4.2. Synthesis of chiral ligands
4.2.1. (S)-2-(2-Methoxyphenoxymethyl)-1-methylpyrro-
lidine (5). A mixture of 2-methoxyphenol 4 (8.80 mL,
80 mmol), NaH (60%, 3.20 g, 80 mmol, washed with
hexane) in DMF (15 mL) was stirred at rt for 40 min. A
solution of N-methyl(2-chloromethyl)pyrrolidine hydro-
chloride 3 (3.40 g, 20 mmol) in DMF (130 mL) was added
over 40 min at 08C. The whole was stirred at rt for 4 h and
then quenched with water, and then extracted with EtOAc.
Organic layers were washed successively with 10% NaOH,
and brine, and then dried over K2CO3. Concentration
followed by chromatography (CHCl3/MeOH¼10:1) gave 5
(3.05 g, 69%) as a pale yellow oil of bp 1608C/4 mm Hg and
3. Conclusion
A conjugate addition-type catalytic asymmetric epoxidation
reaction of a,b-unsaturated carbonyl compounds was
[a]2D5¼259.8 (c 1.00, CHCl3). IR (neat): 1590, 1500 cm21
.
1H NMR: 1.69–1.88 (3H, m), 2.07 (1H, m), 2.27 (1H, m),
2.50 (3H, s), 2.74 (1H, m), 3.09 (1H, m), 3.85 (3H, s), 3.90
Figure 9. Catalytic asymmetric epoxidation of tert-butyl and trityl enones.

Y. Tanaka et al. / Tetrahedron 59 (2003) 4549–4556
4553
(1H, dd, J¼6.7, 9.5 Hz), 4.03 (1H, dd, J¼5.5, 9.5 Hz),
6.87–6.94 (4H, m). 13C NMR: 23.0, 29.0, 41.7, 56.0, 57.7,
64.2, 72.4, 112.0, 113.5, 120.8, 121.1, 148.7, 149.6. MS (EI)
m/z: 221 [Mþ]. Anal. calcd for C13H19NO2: C, 70.56; H,
8.65; N, 6.33. Found: C, 70.81: H, 8.86: N, 6.34.
and then extracted with MTBE. Organic layers were washed
with brine and then dried over K2CO3. Concentration and
Kugelrohr distillation gave a colorless gum (1.20 g, 80%) of
bp 2508C/1 mm Hg and [a]2D5¼260.7 (c 1.07, CHCl3). IR
(neat): 1600, 1490 cm21. 1H NMR: 2.24 (6H, s), 3.24 (3H,
s), 3.37 (1H, dd, J¼4.6, 11 Hz), 3.60 (1H, dd, J¼7.0,
11 Hz), 3.68 (1H, d, J¼8.2 Hz), 4.42 (1H, dd, J¼4.6,
7.0 Hz), 4.69 (1H, d, J¼8.2 Hz), 6.92–6.94 (2H, m), 7.02–
7.11 (8H, m), 7.27–7.35 (5H, m). 13C NMR: 42.7, 56.8,
73.2, 74.9, 82.5, 83.2, 126.8, 127.1, 127.2, 127.4, 127.6,
127.8, 128.0, 128.3, 129.5, 137.0, 139.6, 139.8. MS (CI) m/
z: 376 [MþHþ], 224, 134. Anal. calcd for C25H29NO2: C,
79.96; H, 7.78; N, 3.73. Found: C, 80.17; H, 7.81; N, 3.63.
4.2.2. (1R,2R)-[2-(2-Methoxyphenoxy)cyclohexyl]di-
methylamine (9). A mixture of amino alcohol 6 (616 mg,
4.3 mmol) and NaH (60%, 206 mg, 5.16 mmol) in DMF
(11 mL) was stirred for 1 h at 708C. Fluoroanisole-
chromiumtricarbonyl 7 (1.35 g, 5.16 mmol) in DMF
(3 mL) was added at 08C. The whole was stirred for 0.5 h
at rt and quenched with water at 08C, and then extracted
with EtOAc. Organic layers were washed with brine and
dried over K2CO3. Concentration followed by chromato-
graphy (EtOAc/Et3N¼50:1) gave a yellow oil (1.53 g,
92%). A solution of I2 (4.04 g, 15.9 mmol) in THF (25 mL)
was added to a solution of the above oil in THF (25 mL) at
2788C over 1 h, and the mixture was stirred for 0.5 h at
2788C. After stirring for 0.5 h at 08C, 10% Na2S2O3 was
added, and the mixture was extracted with MTBE. To the
aqueous layer was added 30% K2CO3 (pH.10) and
extracted with MTBE. Combined organic layers were
washed with 30% K2CO3 and brine, and then dried over
4.2.5. (1R,2R)-[2-((S)-2-Hydroxy-2-phenylethoxy)-1,2-
diphenylethyl]dimethylamine (16s). By the same pro-
cedure for 16r, 16s was prepared with (S)-styrene oxide 15
in 32% yield as colorless rods of mp 117–117.58C (hexane)
and [a]2D5¼228.5 (c 1.00, CHCl3). IR (nujol): 3200, 1600,
1
1490 cm21. H NMR: 2.33 (6H, s), 3.36 (1H, dd, J¼10,
10 Hz), 3.86 (1H, dd, J¼2.7, 10 Hz), 4.02 (1H, d, J¼10 Hz),
4.77 (1H, d, J¼10 Hz), 4.96 (1H, dd, J¼2.7, 10 Hz), 6.55
(1H, brs), 6.98–7.39 (15H, m). 13C NMR: 41.7, 73.7, 74.5,
78.0, 84.1, 126.1, 127.3, 127.4, 127.6, 127.8, 128.1, 128.2,
130.0, 133.1, 139.8, 140.6. MS (CI) m/z: 362 [MþHþ], 224,
134. Anal. calcd for C24H27NO2: C, 79.74; H, 7.53; N, 3.87.
Found: C, 79.92; H, 7.53; N, 3.77.
K2CO3.
Concentration,
chromatography
(EtOAc/
MeOH¼10:1–1:1), and then Kugelrohr distillation gave
colorless oil (518 mg, 52%) of bp 1858C/1.5 mm Hg and
[a]2D5¼259.5 (c 1.91, CHCl3). IR (neat): 1590, 1500 cm21
.
1H NMR: 1.15–1.44 (4H, m), 1.63–1.72 (2H, m), 1.89 (1H,
m), 2.10 (1H, m), 2.42 (6H, s), 2.73 (1H, ddd, J¼3.7, 9.5,
11 Hz), 3.84 (3H, s), 4.22 (1H, ddd, J¼4.3, 9.5, 9.5 Hz),
6.85–6.95 (4H, m). 13C NMR: 24.1, 24.8, 26.0, 30.8, 41.3,
55.8, 66.2, 78.1, 112.3, 117.0, 120.7, 121.5, 147.0, 150.9.
MS (EI) m/z: 249 [Mþ], 126. Anal. calcd for C15H23NO2: C,
72.25; H, 9.30; N, 5.62. Found: C, 72.05; H, 9.06; N, 5.66.
4.2.6. (1R,2R)-[2-((S)-2-Methoxy-2-phenylethoxy)-1,2-
diphenylethyl]dimethylamine (18s). By the same pro-
cedure for 18r, 18s was prepared from 16s in 92% yield as a
colorless oil of bp 2408C/0.7 mm Hg and [a]2D5¼þ73.0 (c
1
1.06, CHCl3). IR (neat): 1600, 1490 cm21. H NMR: 2.36
(6H, s), 3.31 (3H, s), 3.37 (1H, dd, J¼3.4, 11 Hz), 3.44 (1H,
dd, J¼8.6, 11 Hz), 3.77 (1H, d, J¼9.2 Hz), 4.48 (1H, dd,
J¼3.4, 8.6 Hz), 4.97 (1H, d, J¼9.2 Hz), 6.99–7.30 (15H,
m). 13C NMR: 41.9, 56.8, 73.2, 74.8, 83.1, 84.2, 126.77,
126.80, 127.1, 127.4, 127.6, 127.7, 128.0, 128.2, 129.5,
136.2, 138.9, 140.1. MS (CI) m/z: 376 [MþHþ], 224, 134.
Anal. calcd for C25H29NO2: C, 79.96; H, 7.78; N, 3.73.
Found: C, 79.71; H, 7.96; N, 3.56.
4.2.3. (1R,2R)-[2-((R)-2-Hydroxy-2-phenylethoxy)-1,2-
diphenylethyl]dimethylamine (16r). A solution of amino
alcohol 14 (724 mg, 3 mmol) and NaH (60%, 144 mg,
3.6 mmol) in DMF (10 mL) was stirred for 1 h at 708C. A
solution of (R)-styrene oxide 15 (721 mg, 6 mmol) in DMF
(5 mL) was added at 08C, and the whole was stirred for 20 h
at 708C and then quenched with water at 08C, and then
extracted with EtOAc. Organic layers were washed with
brine and then dried over K2CO3. Concentration and
chromatography (EtOAc/MeOH¼10:1–3:1) gave a color-
less gum (491 mg, 46%) of bp 2508C/1 mm Hg and
[a]2D5¼243.1 (c 1.63, CHCl3). IR (neat): 3300, 1600,
4.2.7. (1R,2R)-[2-(3-Methoxypropoxy)-1,2-diphenyl-
ethyl]dimethylamine (19). A solution of 14 (2.41 g,
10 mmol) and NaH (480 mg, 12 mmol) in DMF (25 mL)
was stirred at 608C for 2 h. 3-Methoxypropyl tosylate
(2.93 g, 12 mmol) in DMF (5 mL) was added over 10 min at
08C. The mixture was stirred at 1008C for 2.5 h and
quenched with ice water, and then extracted with toluene.
Organic layers were washed with brine and then dried over
K2CO3. Concentration and chromatography gave a colorless
oil (2.70 g, 86%) of bp 2108C/0.7 mm Hg and [a]2D5¼þ17.5
(c 1.24, CHCl3). IR (neat): 1600, 1490 cm21. 1H NMR: 1.87
(2H, tt, J¼6.4, 6.4 Hz), 2.33 (6H, s), 3.29 (3H, s), 3.35–3.43
(3H, m), 3.51 (1H, dt, J¼6.4, 9.2 Hz), 3.72 (1H, d,
J¼8.9 Hz), 4.67 (1H, d, J¼8.9 Hz), 6.97–7.14 (10H, m).
13C NMR: 30.0, 42.4, 58.5, 65.8, 69.8, 74.8, 82.9, 126.8,
127.1, 127.5, 127.6, 127.9, 129.5, 137.0, 140.4. MS (CI) m/
z: 314 [MþHþ], 224, 134. Anal. calcd for C20H27NO2: C,
76.64; H, 8.68; N, 4.47. Found: C, 76.47; H, 8.62; N, 4.38.
1
1490 cm21. H NMR: 2.33 (6H, s), 3.45 (1H, dd, J¼9.2,
11 Hz), 3.53 (1H, dd, J¼3.4, 11 Hz), 4.06 (1H, d, J¼10 Hz),
4.95 (1H, d, J¼10 Hz), 5.00 (1H, dd, J¼3.4, 9.2 Hz), 6.98–
7.40 (15H, m). 13C NMR: 41.5, 71.3, 72.5, 73.3, 79.7, 126.1,
127.3, 127.62, 127.65, 128.0, 128.3, 130.0, 133.1, 138.7,
140.9. MS (CI) m/z: 362 [MþHþ], 224, 134. HRMS (CI) m/
z: calcd for C24H28NO2: 362.2120 [MþH]. Found:
362.2116.
4.2.4. (1R,2R)-[2-((R)-2-Methoxy-2-phenylethoxy)-1,2-
diphenylethyl]dimethylamine (18r). A solution of 16r
(1.45 g, 4.0 mmol) and NaH (60%, 192 mg, 4.8 mmol) in
DMF (10 mL) was stirred for 0.5 h at rt. Methyl toluene-
sulfonate (0.72 mL, 4.8 mmol) was added at 08C, and the
whole was stirred for 0.5 h at 08C and quenched with water,
4.2.8. (1R,2R)-[2-(2-Methoxybenzyloxy)-1,2-diphenyl-
ethyl]dimethylamine (20). A solution of 14 (121 mg,

4554
Y. Tanaka et al. / Tetrahedron 59 (2003) 4549–4556
0.5 mmol) and NaH (30 mg, 0.75 mmol) in DMF (1 mL)
was stirred at 708C for 1 h. A solution of 4-methoxy-
benzylchloride (118 mg, 0.75 mmol) in DMF (0.5 mL) was
added at 08C. The mixture was stirred at 808C for 0.5 h and
quenched with ice water, and then extracted with toluene.
Organic layers were washed with brine and then dried over
K2CO3. Concentration and Kugelrohr distillation (200–
2508C/0.8 mm Hg) gave a colorless oil (130 mg, 72%) of
[a]2D5¼227.3 (c 0.99, CHCl3). IR (neat): 1600, 1590,
1490 cm21. 1H NMR: 2.26 (6H, s), 3.77 (1H, d, J¼8.5 Hz),
3.78 (3H, s), 4.36 (1H, d, J¼12 Hz), 4.52 (1H, d, J¼12 Hz),
4.78 (1H, d, J¼8.5 Hz), 6.84–7.41 (14H, m). 13C NMR:
42.4, 54.9, 65.3, 75.0, 81.3, 109.9, 120.1, 126.5, 126.7,
127.0, 127.3, 127.5, 128.1, 128.6, 129.4, 129.7, 136.9,
140.2, 157.3. MS (CI) m/z: 362 [MþHþ], 134. Anal. calcd
for C24H27NO2: C, 79.73; H, 7.53; N, 3.88. Found: C, 79.47;
H, 7.49; N, 3.90.
Filtration, concentration, and chromatography (benzene/
acetone¼1:0 to 4:1) gave a colorless gum (1.63 g, 99%) of
bp 2408C/0.2 mm Hg. [a]2D5¼þ88.6 (c 1.00, CHCl3). IR
1
(neat): 3200 cm21. H NMR: 2.18 (6H, s), 4.09 (1H, d,
J¼11 Hz), 4.26 (1H, d, J¼12 Hz), 5.19 (1H, d, J¼12 Hz),
5.43 (1H, d, J¼11 Hz), 6.73–7.30 (14H, m). 13C NMR:
40.5, 62.8, 75.3, 79.9, 112.8, 120.9, 127.2, 127.6, 127.7,
128.2, 128.8, 129.3, 130.0, 131.2, 131.7, 139.5, 158.1. MS
(FAB) m/z: 348 [MþHþ], 134. HRMS (FAB) m/z: calcd for
C23H26NO2: 348.1964 [MþH]. Found: 348.1970.
4.2.12. (1R,2R)-[2-(2-Methoxymethylphenoxy)-1,2-
diphenylethyl]dimethylamine (24). A solution of 23
(105 mg, 0.3 mmol) and NaH (60%, 18 mg, 0.45 mmol) in
THF (0.7 mL) was stirred at rt for 1 h. The mixture was
cooled to 08C, methyl iodide (0.02 mL, 0.33 mmol) was
added. After stirring at rt for 3 h, cold water was added, and
the mixture was extracted with Et2O. Organic layers were
washed with brine and then dried over K2CO3. Concen-
tration and chromatography (benzene/acetone¼4:1) gave a
colorless gum (87 mg, 80%) of bp 2408C/1 mm Hg and
4.2.9. 2,4-Dimethyl-3-pentyl 2-fluorobenzoate (21). A
mixture of 2-fluorobenzoic acid (14 g, 100 mmol), 2,4-
dimethyl-3-pentanol (42 mL, 300 mmol), and p-TsOH·H2O
(190 mg, 1 mmol) in toluene (15 mL) was heated under
reflux with Dean–Stark trap for 48 h. Usual workup and
distillation (125–1268C/7 mm Hg) afforded colorless oil
[a]2D5¼þ56.8 (c 0.80, CHCl3). IR (neat): 1600, 1490 cm21
.
1H NMR: 2.37 (6H, s), 3.46 (3H, s), 3.83 (1H, d, J¼6.4 Hz),
4.59 (1H, d, J¼13 Hz), 4.67 (1H, d, J¼13 Hz), 5.66 (1H, d,
J¼6.4 Hz), 6.71–7.35 (14H, m). 13C NMR: 43.9, 58.3, 69.6,
75.8, 80.3, 113.1, 120.5, 127.1, 127.3, 127.4, 127.5, 127.7,
128.2, 128.6, 129.6, 137.4, 138.8, 155.0. MS (CI) m/z: 362
[MþHþ], 134. Anal. calcd for C24H27NO2: C, 79.74; H,
7.53; N, 3.87. Found: C, 79.91; H, 7.25; N, 3.81.
1
(6.33 g, 27%). IR (neat): 1710 cm21. H NMR: 0.96 (12H,
d, J¼6.7 Hz), 2.02 (2H, dq, J¼6.1, 6.7 Hz), 4.88 (1H, t,
J¼6.1 Hz), 7.14 (1H, ddd, J¼0.9, 8.2, 10.7 Hz), 7.21 (1H,
ddd, J¼0.9, 7.3, 8.2 Hz), 7.50 (1H, m), 7.95 (1H, dd, J¼1.8,
7.3 Hz). 13C NMR: 17.5, 19.8, 29.8, 84.1, 117.2 (d,
J¼22.6 Hz), 119.6 (d, J¼10.3 Hz), 124.1 (d, J¼4.1 Hz),
132.3, 134.3 (d, J¼9.3 Hz), 162.1 (d, J¼257 Hz), 164.8 (d,
J¼4.1 Hz). MS (EI) m/z: 238 [Mþ], 195. Anal. calcd for
C14H19FO2: C, 70.56; H, 8.04. Found: C, 70.77; H, 8.03.
4.3. Asymmetric epoxidation of BHA enoate
4.3.1. 2,6-Di-tert-butyl-4-methoxyphenyl 3-phenyloxir-
ane-2-carboxylate (27). A hexane solution of BuLi
(0.96 mL, 1.5 mmol) was added to cumene hydroperoxide
28 (228 mg, 1.5 mmol) in toluene (1 mL) at 2788C, and the
mixture was stirred for 10 min. After an addition of a
solution of 1 (625 mg, 1.8 mmol) in toluene (3 mL), the
mixture was stirred for 10 min at 08C. A solution of 25
(367 mg, 1.0 mmol) in toluene (3 mL) was added at 2788C.
The whole was stirred for 36 h at 08C, and quenched with
satd NH4Cl, and then extracted with Et2O. Organic layers
were successively washed with 10% Na2SO3, 10% HCl,
satd NaHCO3 and brine, and then dried over Na2SO4.
Concentration and chromatography (hexane/Et2O¼10:1)
gave 27 (372 mg, 82%) as a colorless gum of 72% ee
(Daicel Chiralpak AD, hexane/2-PrOH¼200:1, 0.5 mL/
min, 254 nm, 30.5 min and 51.2 min for major and minor
4.2.10. (1R,2R)-2,4-Dimethyl-3-pentyl 2-(2-dimethyl-
amino-1,2-diphenylethoxy)benzoate (22). A solution of
14 (2.41 g, 10 mmol) and NaH (60%, 480 mg, 12 mmol) in
DMF (10 mL) was stirred at 708C for 1 h. The mixture was
cooled to 08C and 21 (3.57 g, 15 mmol) was added. After
stirring at rt for 2 h, cold water was added, and the mixture
was extracted with toluene. Organic layers were washed
with water and brine, and then dried over K2CO3.
Concentration and chromatography (benzene/acetone¼1:0
to 4:1) afforded colorless gum (4.33 g, 94%) of bp 2408C/
0.7 mm Hg and [a]2D5¼þ114.6 (c 1.22, CHCl3). IR (neat):
1
1720, 1600 cm21. H NMR: 1.04–1.06 (total 12H, four d,
J¼6.7 Hz), 2.08 (2H, m), 2.35 (6H, s), 3.89 (1H, d,
J¼7.0 Hz), 4.96 (1H, dd, J¼6.1, 6.1 Hz), 5.67 (1H, d,
J¼7.0 Hz), 6.83–6.87 (2H, m), 7.00–7.10 (10H, m), 7.13
(1H, m), 7.71 (1H, dd, J¼1.8, 7.6 Hz). 13C NMR:17.5, 17.7,
19.68, 19.70, 29.6, 29.7, 43.9, 75.5, 81.4, 82.8, 114.2, 119.8,
122.1, 126.9, 127.2, 127.5, 127.6, 127.7, 129.5, 131.0,
132.4, 138.0, 138.7, 156.6, 166.2. MS (CI) m/z: 460
[MþHþ]. Anal. calcd for C30H37NO3: C, 78.40; H, 8.11;
N, 3.05. Found: C, 78.14; H, 8.15; N, 3.07.
1
enantiomers). IR (nujol): 1760 cm21. H NMR: 1.35 (9H,
s), 1.38 (9H, s), 3.74 (1H, d, J¼1.7 Hz), 3.81 (3H, s), 4.33
(1H, d, J¼1.7 Hz), 6.87 (1H, d, J¼3.0 Hz), 6.88 (1H, d,
J¼3.0 Hz), 7.33–7.43 (5H, m). 13C NMR: 31.4, 31.5, 35.6,
35.7, 55.2, 57.4, 58.3, 111.8, 125.7, 128.8, 129.1, 134.8,
141.0, 143.3, 143.4, 156.6, 168.8. MS (EI) m/z: 382 [Mþ].
Anal. calcd for C24H30O4: C, 75.36; H, 7.91. Found: C,
75.47: H, 8.19. Aqueous layer was made alkaline with 40%
NaOH (pH.11), and extracted with Et2O, which was
washed with brine, and dried over K2CO3. Concentration
afforded 1 as colorless needles (613 mg, 98% recovery).
4.2.11. (1R,2R)-[2-(2-Hydroxymethylphenoxy)-1,2-
diphenylethyl]dimethylamine (23). A solution of 22
(2.15 g, 4.7 mmol) in THF (5 mL) was added to a
suspension of lithium aluminum hydride (267 mg,
7 mmol) in THF (5 mL) at 08C. The whole was heated
under reflux for 0.5 h. Water (0.3 mL), 15% aq. NaOH
(0.3 mL), and water (0.9 mL) were added successively.
Determination of the absolute configuration of 27. A
solution of 27 (58% ee, 975 mg, 2.5 mmol) in THF
(14 mL) was added to a suspension of lithium aluminum

Y. Tanaka et al. / Tetrahedron 59 (2003) 4549–4556
4555
hydride (296 mg, 7.8 mmol) in THF (60 mL) at 08C, and the
mixture was heated under reflux for 5 h. Water (0.3 mL),
15% NaOH (0.3 mL), and water (0.9 mL) were successively
added, and then filtered. Concentration and chromatography
(benzene/Et2O¼1:1) gave (R)-3-phenylpropane-1,2-diol
(224 mg, 59%, 160–1908C/2 mm Hg) and (R)-1-phenyl-
propane-1,3-diol (85 mg, 22%, 160–1908C/2 mm Hg).
51% (Daicel Chiralpak AD, hexane/2-PrOH¼95:5, 1.0 mL
min, 254 nm, 19.6 min and 22.2 min for minor and major
enantiomers). IR (nujol): 1730 cm21. 1H NMR: 3.56 (1H, d,
J¼1.5 Hz), 3.75 (1H, d, J¼1.5 Hz), 6.89 (2H, m), 7.17–
7.35 (18H, m). 13C NMR: 61.0, 61.9, 125.5, 127.2, 128.2,
128.4, 128.5, 130.2, 140.9, 201.5. MS (CI) m/z: 391
[MþHþ], 243. HRMS (CI) m/z: calcd for C28H23O2:
391.1698 [MþH]. Found: 391.1700.
4.3.2. (R)-3-Phenylpropane-1,2-diol.29 [a]D20¼þ19.9 (c
1
1.03 EtOH). IR (neat): 3300 cm21. H NMR: 1.95 (1H,
4.4.4. 2,2-Dimethyl-1-((2R,3S)-3-naphthalen-1-yloxir-
anyl)propan-1-one (35, R51-naphthyl). By the same
procedure for 33a, 35 was obtained in 55% as a white
solid of mp 53–548C and [a]2D5¼225.2 (c 1.03, CHCl3).
The ee was determined to 56% (Daicel Chiralpak AD,
hexane/2-PrOH¼99:1, 1.0 mL/min, 230 nm, 13.6 min and
18.2 min for major and minor enantiomers). IR (nujol):
1710 cm21. 1H NMR: 1.29 (9H, s), 3.86 (1H, d, J¼1.8 Hz),
4.55 (1H, d, J¼1.8 Hz), 7.46–7.57 (4H, m), 7.85 (1H, d,
J¼7.9 Hz), 7.91 (1H, m), 7.98 (1H, m). 13C NMR: 25.8,
43.8, 57.8, 58.2, 122.3, 125.4, 126.1, 126.7, 128.8, 128.9,
131.2, 131.8, 133.3, 208.4. MS (EI) m/z: 254 [Mþ], 169.
Anal. calcd for C17H18O2: C, 80.28; H, 7.13. Found: C,
80.29; H, 7.13.
brs), 2.06 (1H, brs), 2.78 (1H, dd, J¼7.6, 14 Hz), 2.80 (1H,
dd, J¼5.6, 14 Hz), 3.53 (1H, dd, J¼7.3, 11 Hz), 3.71 (1H,
dd, J¼3.0, 11 Hz), 3.95 (1H, m), 7.22–7.38 (5H, m). MS
(EI) m/z: 152 [Mþ], 121.
4.3.3. (R)-1-Phenylpropane-1,3-diol.30 [a]D25¼þ36.0 (c
1
0.84, CHCl3). IR (neat): 3240 cm21. H NMR: 2.00 (2H,
m), 2.31 (1H, brs), 2.77 (1H, brs), 3.88 (2H, t, J¼5.3 Hz),
4.97 (1H, dd, J¼4.0, 8.6 Hz), 7.24–7.38 (5H, m). MS (EI)
m/z: 152 [Mþ], 107.
4.4. Catalytic asymmetric epoxidation of enones
4.4.1. Phenyl((2R,3S)-3-phenyloxiranyl)methanone (31).
Under the same procedure for 33a. 31 as a white solid of mp
74–768C and [a]2D0¼279.4 (c 2.79, THF) was obtained in
99% yield and 40% ee (Shiseido chiral RU-1, MeOH,
0.3 mL/min, 254 nm, 24.3 min and 28.1 min for minor and
major enantiomers). IR (nujol): 1680 cm21. 1H NMR: 4.08
(1H, d, J¼1.8 Hz), 4.31 (1H, d, J¼1.8 Hz), 7.36–7.43 (5H,
m), 7.49 (2H, m), 7.63 (1H, m), 8.01 (2H, m). MS (EI) m/z:
224 [Mþ].
4.4.5. 2,2-Dimethyl-1-((2R,3S)-3-naphthalen-2-yloxir-
anyl)propan-1-one (35, R52-naphthyl). By the same
procedure for 33a, 35 was obtained in 74% as a white
solid of mp 94.5–968C and [a]2D5¼2149.2 (c 1.06, CHCl3).
The ee was determined to 58% (Daicel Chiralpak AD,
hexane/2-PrOH¼99:1, 1.0 mL/min, 230 nm, 17.4 min and
41.5 min for major and minor enantiomers). IR (nujol):
1700 cm21. 1H NMR: 1.25 (9H, s), 3.95 (1H, d, J¼1.8 Hz),
4.02 (1H, d, J¼1.8 Hz), 7.35 (1H, dd, J¼1.8, 8.5 Hz), 7.49–
7.53 (2H, m), 7.82–7.87 (4H, m). 13C NMR: 25.7, 43.6,
59.3, 59.6, 122.4, 125.5, 126.5, 126.6, 127.80, 127.83,
128.7, 133.00, 133.04, 133.6, 208.1. MS (EI) m/z: 254 [Mþ],
141. Anal. calcd for C17H18O2: C, 80.28; H, 7.13. Found: C,
80.27; H, 6.86.
4.4.2. Typical procedure for the catalytic reaction. 2,2-
Dimethyl-1-((2R,3S)-3-phenyloxiranyl)propan-1-one
(33a). A hexane solution of BuLi (1.59 M, 0.28 mL,
0.45 mmol) was added to a solution of cumene hydroper-
oxide (68 mg, 0.45 mmol) in toluene (0.3 mL) at 2788C,
and the mixture was stirred for 10 min at 2788C. A solution
of 1 (208 mg, 0.6 mmol) in toluene (1.5 mL) was added, and
the mixture was stirred for 10 min at 08C. A solution of 32a
(565 mg, 3 mmol) in toluene (3.5 mL) was added over
6 min at 2788C. A solution of cumene hydroperoxide
(617 mg, 4.05 mmol) in toluene (2.7 mL) was added
dropwise over 3 h at 08C. The whole was stirred for another
1 h at 08C and quenched with satd NH4Cl, and then
extracted with toluene. Combined organic layers were
successively washed with 10% Na2SO3 and brine, and then
dried over Na2SO4. Concentration and chromatography
(benzene/acetone¼10:1) gave 33a (466 mg, 76%) as a
white solid of mp 57–588C and [a]2D0¼2182.5 (c 1.06,
CH2Cl2) and 1 (183 mg, 88% recovery). The ee was
determined to 71% (Daicel Chiralpak AD, hexane/2-
PrOH¼99:1, 1 mL/min, 230 nm, 14.0 min and 17.6 min
4.4.6. 1-((2R,3S)-4-Chlorophenyloxiranyl)-2,2-dimethyl-
propan-1-one (35, R54-ClC6H4). By the same procedure
for 33a, 35 was obtained in 81% as a white solid of mp 46–
498C and [a]2D5¼2170.5 (c 1.03, CHCl3). The ee was
determined to 66% ee (Daicel Chiralpak AD, hexane/2-
PrOH¼99:1, 1.0 mL/min, 230 nm, 12.8 min and 22.0 min
for major and minor enantiomers). IR (nujol): 1700 cm21
.
1H NMR: 1.24 (9H, s), 3.80 (1H, d, J¼1.8 Hz), 3.84 (1H, d,
J¼1.8 Hz), 7.24 (2H, d, J¼8.5 Hz), 7.35 (2H, d, J¼8.5 Hz).
13C NMR: 26.1, 44.1, 59.1, 59.5, 127.4, 129.4, 134.6, 135.2,
208.2. MS (EI) m/z: 238 [Mþ]. Anal. calcd for C13H15ClO2:
C, 65.41; H, 6.33. Found: C, 65.29; H, 6.29.
4.4.7. 1-((2R,3S)-4-Methoxyphenyloxiranyl)-2,2-
dimethylpropan-1-one (35, R54-MeOC6H4). By the
same procedure for 33a, 35 was obtained in 68% as a
colorless oil and [a]2D0¼2155.4 (c 2.32, CHCl3). The ee was
determined to 64% (Daicel Chiralpak AD, hexane/
EtOH¼98:2, 1.0 mL/min, 230 nm, 21.3 min and 25.8 min
for major and minor enantiomers). IR (neat): 1720 cm21. 1H
NMR: 1.23 (9H, s), 3.80 (1H, d, J¼1.8 Hz), 3.82 (3H, s),
3.85 (1H, d, J¼1.8 Hz), 6.90 (2H, d, J¼8.5 Hz), 7.23 (2H, d,
J¼8.5 Hz). 13C NMR: 25.7, 43.5, 55.4, 59.2, 59.4, 114.2,
127.0, 127.5, 160.2, 208.3. MS (EI) m/z: 234 [Mþ].
for major and minor enantiomers). IR (nujol): 1700 cm21
1H NMR: 1.24 (9H, s), 3.86 (2H, s), 7.30–7.40 (5H, m). 13
NMR: 25.7, 43.6, 59.1, 59.3, 125.6, 128.7, 128.9, 135.6,
.
C
208.1. MS (EI) m/z: 204 [Mþ], 147.
4.4.3. 2,2,2-Triphenyl-1-((2R,3S)-3-phenyloxiranyl)etha-
none (33b). By the same procedure for 33a, 33b was
obtained in 62% as a white solid of mp 109–109.58C and
[a]2D5¼265.8 (c 1.03, CHCl3). The ee was determined to

4556
Y. Tanaka et al. / Tetrahedron 59 (2003) 4549–4556
1989, 111, 8266–8268. (b) Shindo, M.; Koga, K.; Tomioka,
K. J. Am. Chem. Soc. 1992, 114, 8732–8733. (c) Fujieda, H.;
Kanai, M.; Kambara, T.; Iida, A.; Tomioka, K. J. Am. Chem.
Soc. 1997, 119, 2060–2061. (d) Asano, Y.; Iida, A.; Tomioka,
K. Tetrahedron Lett. 1997, 38, 8973–8976. (e) Asano, Y.;
Iida, A.; Tomioka, K. Chem. Pharm. Bull. 1998, 46, 184–186.
(f) Mizuno, M.; Fujii, K.; Tomioka, K. Angew. Chem., Int. Ed.
1998, 37, 515–517. (g) Taniyama, D.; Hasegawa, M.;
Tomioka, K. Tetrahedron Lett. 2000, 41, 5533–5536. (h)
Iguchi, M.; Tomioka, K. Org. Lett. 2002, 4, 4329–4331.
11. Nishimura, K.; Ono, M.; Nagaoka, Y.; Tomioka, K. J. Am.
Chem. Soc. 1997, 119, 12974–12975.
4.4.8. 2,2-Dimethyl-1-((2R,3S)-3-phenethyloxiranyl)pro-
pan-1-one (35, R5Ph(CH2)2). By the same procedure for
33a, 35 was obtained in 55% as a colorless oil and
[a]2D6¼216.0 (c 1.34, CH2Cl2). The ee was determined to
37% (Daicel Chiralpak AD, hexane/2-PrOH¼99:1, 1.0 mL/
min, 220 nm, 11.6 min and 22.7 min for major and minor
enantiomers). IR (neat): 1710 cm21. 1H NMR: 1.17 (9H, s),
1.93–2.04 (2H, m), 2.73–2.86 (2H, m), 2.99 (1H, dt, J¼1.8,
6.1 Hz), 3.62 (1H, d, J¼1.8 Hz), 7.19–7.31 (5H, m). 13C
NMR: 25.7, 31.9, 33.5, 43.6, 55.4, 59.3, 126.3, 128.30,
128.34, 140.6, 209.3. MS (EI) m/z: 175 [Mþ2t-Bu], 147.
12. Doi, H.; Sakai, T.; Iguchi, M.; Yamada, K.; Tomioka, K. J. Am.
Chem. Soc. 2003, 125, 2886–2887.
Acknowledgements
13. Preliminarily communication of this work Tanaka, Y.;
Nishimura, K.; Tomioka, K. Heterocycles 2002, 58, 71–73.
14. Nishimura, K.; Tomioka, K. J. Org. Chem. 2002, 67,
431–434.
This research was supported by a Grant-in-Aid for Scientific
Research on Priority Areas (A) ‘Exploitation of Multi-
Element Cyclic Molecules’ from the Ministry of Education,
Culture, Sports, Science and Technology, Japan. K. N. was
supported by a fellowship from the JSPS.
15. Tomioka, K.; Sudani, M.; Shinmi, Y.; Koga, K. Chem. Lett.
1985, 329–332.
16. Chavdarian, C. G.; Sanders, E. B.; Bassfield, R. L. J. Org.
Chem. 1982, 47, 1069–1073.
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