Asymmetric synthesis of 3-substituted 3,4-dihydroisocoumarins via stereoselective addition of laterally lithiated chiral 2-(o-tolyl)oxazolines to aldehydes followed by diastereomer-selective lactonization

Article abstract of DOI:10.1016/j.tet.2005.01.103

Lateral lithiation of (S)-4-isopropyl-2-(o-tolyl)oxazoline in diethyl ether followed by the reaction with aldehydes in the presence of TMEDA produced the addition products with stereoselectivities up to 84% de. Utilization of TMEDA as a ligand is essential for the good selectivity. Rationale for the stereoselectivity is proposed based on ab initio calculation of the lateral lithio species. The major (S,S)-products lactonized faster than the minor (S,R)-products to the corresponding 3,4-dihydroisocoumarins under acidic conditions. Thus, (3S)-3,4-dihydroisocoumarins were obtained in good optical purities up to 97% ee by sequential application of these matched stereoselective reactions.

Full text of DOI:10.1016/j.tet.2005.01.103

Tetrahedron 61 (2005) 3289–3303
Asymmetric synthesis of 3-substituted 3,4-dihydroisocoumarins
via stereoselective addition of laterally lithiated chiral
2-(o-tolyl)oxazolines to aldehydes followed by
diastereomer-selective lactonization
*
Yuji Kurosaki, Tsutomu Fukuda and Masatomo Iwao
Department of Applied Chemistry, Faculty of Engineering, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Received 2 November 2004; revised 30 November 2004; accepted 21 January 2005
Abstract—Lateral lithiation of (S)-4-isopropyl-2-(o-tolyl)oxazoline in diethyl ether followed by the reaction with aldehydes in the presence
of TMEDA produced the addition products with stereoselectivities up to 84% de. Utilization of TMEDA as a ligand is essential for the good
selectivity. Rationale for the stereoselectivity is proposed based on ab initio calculation of the lateral lithio species. The major (S,S)-products
lactonized faster than the minor (S,R)-products to the corresponding 3,4-dihydroisocoumarins under acidic conditions. Thus, (3S)-3,4-
dihydroisocoumarins were obtained in good optical purities up to 97% ee by sequential application of these matched stereoselective
reactions.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
by the presence or absence of TMEDA.4 The selectivity has
been rationalized by steric interaction between TMEDA and
C-4 substituents on the oxazoline ring in the transition states
of deprotonation. This interesting and unique reactivity
has been successfully applied to an efficient synthesis of
3-substituted 8-hydroxy-3,4-dihydroisocoumarins including
the natural products (G)-hydrangenol and (G)-phyllo-
dulcin.5 As an extension of these studies, we planned to
investigate an asymmetric synthesis of optically enriched
3-substituted 3,4-dihydroisocoumarins via stereoselective
addition of laterally lithiated chiral 2-(o-tolyl)oxazolines
to aldehydes followed by acid-catalyzed lactonization
(Scheme 1). Asymmetric syntheses of 3-substituted 3,4-di-
hydroisocoumarins6 have been achieved by using several
A number of functional groups promote ortho-lithiation to
produce relatively stable functionalized aryl- and hetero-
aryllithiums.1 Such functional groups also assist lateral
lithiation at the benzylic position of the ortho-alkyl
substituent.2 These directed lithiations have been exten-
sively studied to produce a variety of regiospecifically
substituted aromatic and heteroaromatic compounds. Utili-
zation of the oxazoline ring as a directing group in aromatic
lithiation was demonstrated by both Gschwend and Meyers
in 1975.3 Recently, we reinvestigated the lithiation of
4,4-dimethyl-2-(o-tolyl)oxazolines and discovered that the
regioselectivity (ortho or lateral) can be simply controlled
Scheme 1.
Keywords: 2-(o-Tolyl)oxazoline; Lateral lithiation; Asymmetric synthesis; 3,4-Dihydroisocoumarin; Ab initio calculation.
* Corresponding author. Tel./fax: C81 95 819 2681; e-mail: iwao@net.nagasaki-u.ac.jp
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.103

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Y. Kurosaki et al. / Tetrahedron 61 (2005) 3289–3303
Table 1. Stereoselective addition of laterally lithiated chiral 2-(o-tolyl)oxazolines 1 to p-tolualdehyde
Entry
1
R
Solvent
Additive
Adduct
Yield (%)a
dr (2:3)b
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1b
1c
1d
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Me
Et2O
THF
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
None
None
TMEDA
PMDTA
MgBr2
MgBr2CTMEDA
TMEDA
TMEDA
TMEDA
2a, 3a
2a, 3a
2a, 3a
2a, 3a
2a, 3a
2a, 3a
2b, 3b
2c, 3c
2d, 3d
93
93
99
66
93
90
91
82
97
1.5:1
2.7:1
7.6:1
1.8:1
1:1.5
1.2:1
6.1:1
4.0:1
5.4:1
Bn
t-Bu
a Isolated yield.
b Determined by HPLC analysis (Daicel Chiralpak AD).
different types of key reactions, such as (1) ring-opening of
chiral epoxides with metallated aromatics,6a–c (2) asym-
metric dihydroxylation of olefinic side-chain of aromatic
substrates,6d–f (3) CBS reduction of aryl o-carbamoylbenzyl
ketones,6g (4) stereoselective addition of laterally metal-
lated o-toluates to chiral aldehydes6h–j or to prochiral
aldehydes in the presence of chiral ligands.6k,l Our approach
using chiral 2-(o-tolyl)oxazolines as the chiral o-toluate
equivalents has not been reported so far.7
under these conditions indicating the poor reactivity of the
PMDTA complex towards the aldehyde. Next, we examined
the metal exchange of lithium to the more Lewis acidic
magnesium. However, the results were disappointing even
in the presence of TMEDA (entries 5 and 6). Finally, effects
of an alkyl substituent on the oxazoline 4-position were
inspected under the diethyl ether–TMEDA conditions.
Although we tested easily synthesized methyl-, benzyl-,
and tert-butyloxazolines 1b–d, all of these substrates
were less selectively reacted with p-tolualdehyde than 1a
(entries 7–9). Thus, we conclude the stereoselective
addition of the laterally lithiated 1 can be most satisfactorily
achieved by using the isopropyl oxazoline as an
auxiliary group, diethyl ether as a solvent, and TMEDA as
an additive.
2. Results and discussion
2.1. Stereoselective addition of laterally lithiated chiral
2-(o-tolyl)oxazolines to aldehydes
Following these preliminary experiments, we surveyed the
scope and limitations of this stereoselective addition using
a variety of aldehydes (Table 2). Common aromatic
aldehydes including cinnamaldehyde reacted with the
lithiated 1a in the presence of TMEDA in excellent yields
to give adducts 4 in over 70% de (entries 1–3, 5–6). The
stereoselectivity, however, decreased in the reactions with
electron-deficient p-chlorobenzaldehyde (entry 4). An
aliphatic and bulky pivalaldehyde was reacted in high
stereoselectivity (entry 8). On the other hand, linear
octylaldehyde gave a disappointing result (entry 9).
Initially, we examined the addition of the lithiated (S)-4-
isopropyl-2-(o-tolyl)oxazoline (1a) to p-tolualdehyde under
a variety of conditions. Thus, (S)-4-isopropyl-2-(o-tolyl)-
oxazoline (1a) was lithiated regioselectively at the lateral
methyl group in diethyl ether or THF by treatment with
1.2 equiv of sec-BuLi at K78 8C for 1 h.4 After injection of
an appropriate additive, the lithiated species8 was reacted
with p-tolualdehyde at K78 8C for 1 h. A diastereomeric
mixture of the addition products, 2a and 3a, was readily
isolated by column chromatography in good yields. The
diastereomer ratio was estimated by HPLC analysis. The
results are summarized in Table 1. When diethyl ether was
used as a solvent without additive, the diastereomer ratio
was found to be only 1.5:1 (entry 1). The ratio was
somewhat improved by using THF as a solvent (entry 2). To
our surprise, when the addition was carried out in diethyl
ether in the presence of TMEDA, the selectivity was
dramatically improved to 7.6:1 (entry 3). These results
suggested that utilization of solvents or ligands possessing
high coordinating ability are advantageous for the stereo-
selective addition. Therefore, we tested tridentate PMDTA
(N,N,N0,N00,N00-pentamethyldiethylenetriamine) as an addi-
tive. In this case, however, both the diastereomer ratio and
the chemical yield decreased considerably (entry 4). The
characteristic deep purple color of the anion did not fade
It is quite interesting that the transfer of chirality from the
oxazoline to the prochiral aldehydes can be effected via
the lateral lithio species only in the presence of TMEDA.
Thus, we tried to reveal the structures of the lithio species
by means of ab initio calculations. All calculations were
performed by the DFT method implemented in the Gaussian
98 program package.9 Geometry optimizations were carried
out at the B3LYP/6-31G(d) level. The optimized structures
of the parent oxazoline 5, the laterally lithiated oxazoline 6,
and the laterally lithiated oxazoline coordinated with two
ammonia molecules 7 as a model of the TMEDA complex
are shown in Figure 1. It has been presumed that the lateral
litho species generated from o-toluic acid derivatives

Y. Kurosaki et al. / Tetrahedron 61 (2005) 3289–3303
3291
Table 2. Stereoselective addition of laterally lithiated chiral 2-(o-tolyl)oxazoline 1a to aldehydes
R0
Entry
Aldehyde
Adducta
Yield (%)b
drc,d
% de
1
2
3
4
5
6
7
8
9
Benzaldehyde
4a
4b
4c
4d
4e
4f
4g
4h
4i
Phenyl
p-Tolyl
94
99
95
97
97
95
87
91
75
8.2:1
7.6:1
6.2:1
3.2:1
5.7:1
5.7:1
7.1:1
11.8:1
2.1:1e
78
77
72
53
70
70
75
84
35
p-Tolualdehyde
p-Anisaldehyde
p-Chlorobenzaldehyde
Veratraldehyde
1-Naphthaldehyde
Cinnamaldehyde
Pivalaldehyde
p-Methoxyphenyl
p-Chlorophenyl
3,4-Dimethoxyphenyl
1-Naphthyl
(E)-Styryl
t-Butyl
Heptyl
Octylaldehyde
a Diastereomeric mixture.
b Isolated yield.
c Diastereomer ratio of (S,S)- to (S,R)-isomer unless otherwise mentioned.
d Determined by HPLC analysis (Daicel Chiralpak AD).
e Diastereomer ratio of (S,R)- to (S,S)-isomer.
possess o-quinodimethane (extended enolate) structures.10
Comparison of the relative bond lengths (C1–C2, C2–C3,
C3–C4, C4–N) of our calculated models 5, 6, and 7 clearly
indicated that the lithiated oxazolines, especially when
lithium is coordinated with ammonia, are nicely represented
as the N-lithio-o-quinodimethane structures. The other
characteristic features of the lithiated species are as follows.
The aromatic and oxazoline rings are twisted with each
other by about 208 in both 6 and 7. The lithium in 6 exists
essentially in the same plane of the oxazoline ring, whereas
the lithium in 7 bends upward about 258 from the oxazoline
plane.
Next, we examined the structures of the TMEDA complex.
For simplification, the calculations were performed on a
complex derived from the (S)-4-methyl-2-(o-tolyl)oxazo-
line. The complex can exists as an anti- or a syn-isomer with
respect to 4-methyl and N-Li-TMEDA. The optimized
structures of the anti-isomer 8a and the syn-isomer 8b are
shown in Figure 2. The calculation indicated the anti-isomer
Figure 1. The optimized structures of 5, 6 and 7.

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Y. Kurosaki et al. / Tetrahedron 61 (2005) 3289–3303
Figure 2. The TMEDA complexes of lithiated chiral oxazoline 1b.
8a is more stable than the syn-isomer 8b by 0.70 kcal molK1
apparently due to unfavorable steric interactions between
the 4-methyl group and TMEDA.11
preferentially to give the (S,S)-product 10a via the transition
state 9a in which unfavorable steric interactions between the
quinodimethane ring and the aromatic ring of the aldehyde
are minimized. The less stable syn-quinodimethane 8b may
attack the re-face preferentially to give (S,R)-product 10b
via a similar chelation-controlled mechanism. In this case,
however, severe steric repulsion between TMEDA and the
substituent of the oxazoline ring must be generated in the
transition state 9b. Thus, the (S,S)-isomer 10a is formed as a
major product through the energetically favorable transition
state 9a. The loss of the stereoselectivity in the presence of
By considering the computer-generated models 8a and 8b,
a plausible mechanism for the stereoselective addition to
p-tolualdehyde is proposed (Scheme 2). The stereoselectivity
can be rationalized by assuming eight-membered ring
transition states, 9a and 9b, in which the lithium is chelated
to the carbonyl oxygen. The more stable anti-quinodi-
methane 8a may attack the si-face of the aldehyde
Scheme 2. Plausible addition mechanism.

Y. Kurosaki et al. / Tetrahedron 61 (2005) 3289–3303
Table 3. Acid-catalyzed lactonization of the addition product 4b
3293
Entry
Time (h)
3,4-Dihydroisocoumarin 11b
Yield (%)a
Unreacted 4b
Yield (%)a
% eeb
% deb
1
2
3
4
5
6
7
8c
1
2
4
6
12
24
48
48
11
15
28
37
63
77
89
99
95
95
94
94
93
91
88
77
86
84
66
62
36
19
9
74
73
70
66
52
25
K34
—
0
a Isolated yield.
b Determined by HPLC analysis (Daicel Chiralpak AD).
c Reaction at room temperature.
tridentate PMDTA strongly supports this chelation-con-
trolled mechanism. The effects of alkyl substituent on the
C-4 position of the oxazoline ring cannot be clearly
understood at the present stage. We suppose, however, the
transition states described above are rather tight and
sensitive to the steric effects. Thus, a very large substituent
such as t-butyl group may exert some unfavorable steric
effects even in the transition state of type 9a and
consequently induce the decrease of stereoselectivity.
out carefully at 0 8C in aqueous THF in the presence of
trifluoroacetic acid (TFA). The reaction was stopped after
appropriate time and the 3,4-dihydroisocoumarin 11b and
the unreacted 4b were isolated by flash chromatography.
The yields of 11b and 4b and their ee or de in each reaction
are summarized in Table 3. The reaction is rather slow under
these conditions, and, to our surprise, the optical purity of
the 3,4-dihydroisocoumarin 11b isolated was found to be
much higher than that expected from the de of the starting
material. For example, a 95% ee sample of 11b was isolated
in 11% yield after 1 h (entry 1). With the elapse of the
reaction time, yield of 11b increased and its optical purity
decreased gradually. These results clearly indicated that the
lactonization rate of the major (S,S)-diastereomer is faster
than that of the minor (S,R)-diastereomer. The cyclization
2.2. Diastereomer-selective lactonization of the addition
products
Lactonization of the addition product 4b (77% de sample) to
the corresponding 3,4-dihydroisocoumarin 11b was carried
Table 4. Synthesis of optically enriched 3,4-dihydroisocoumarins 11 via diastereomer-selective lactonization
Entry
Addition product
3,4-Dihydroisocooumarin
R0
4
% de
11
Yield (%)a
% ee
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
Phenyl
p-Tolyl
78
77
72
53
70
70
75
84
35
11a
11b
11c
11d
11e
11f
11g
11h
11i
84
77
72
83
57
72
67
56
43
89b
91b
86b
73b
82c
92b
88c
97c
79b
p-Methoxyphenyl
p-Chlorophenyl
3,4-Dimethoxyphenyl
1-naphthyl
(E)-styryl
t-Butyl
Heptyl
a Isolated yield.
b Determined by HPLC analysis (Daicel Chiralpak AD).
c Determined by HPLC analysis (Daicel Chiralpak AS).

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Y. Kurosaki et al. / Tetrahedron 61 (2005) 3289–3303
Scheme 3. Rationale for diastereomer-selective lactonization.
rates of both diastereomers fit to the first-order kinetics and
the relative rate [k(S,S)/k(S,R)] is estimated to be approxi-
mately 5 from the data shown in Table 3.
unfavorable. Thus, (S,S)-4 cyclizes faster than (S,R)-4
(Scheme 3).
2.3. Determination of the absolute configurations
The generality of this diastereomer-selective lactonization
was tested using a variety of adducts 4a–i. The reactions
were carried out at 0 8C for 24 h. As shown in Table 4, the
selective cyclization was observed in all cases under these
restricted conditions and the optically enriched (3S)-3,4-
dihydroisocoumarins 11a–i were isolated in 69–97% ee.
The absolute configurations of the 3-substituted 3,4-di-
hydroisocoumarins were determined by unequivocal
syntheses. The chiral epoxides 16a–d were synthesized
using the established procedures (Scheme 4).6j,12,13 Thus,
the olefins 13a–d were converted to the chiral diols 14a–d
using AD-mix-b.12 The diols were transformed to the
(R)-epoxides 16a–d via the tosylate intermediates 15a–d.13
The optical purities of the epoxides varied from 78 to
98% ee depending on the substituent R. The oxazoline 17
was ortho-lithiated with sec-BuLi and, after conversion to
the cyanocuprate, reacted with the epoxides 16a–d. The
crude products were treated with TFA in aq THF to give S
(RZPh, p-Tol) or R (RZ2-phenylethyl, n-heptyl) dihydro-
isocoumarins 18a–d in modest yields (Table 5). The
absolute configurations of the 3,4-dihydroisocoumarins
11a,b,i are shown to be identical with the authentic samples
18a–c, respectively, by comparison of their specific
rotations and HPLC profiles. The configuration of 11g
is correlated to 18d after hydrogenation of its styryl side
chain (Scheme 5). The absolute configurations of
other dihydroisocoumarins 11c–f,h were determined
The preferential lactonization of (S,S)-4 can be explained as
follows. The cyclization may proceed via initial and rate-
determining addition of the hydroxy group to the C]N
bond of the protonated oxazoline. It is reasonable to assume
that the addition proceeds most readily when the oxazoline
ring takes near-perpendicular conformations against
the benzene ring due to deconjugation between oxazoline
C]N and aromatic p-systems. In such conformations,
the hydroxy group attacks the less hindered re-face of
the oxazoline preferentially in order to avoid unfavorable
steric interactions between isopropyl and lateral sub-
stituents. In such mode of cyclization, the transition
state 12a is expected to be more stable in energy than
the transition state 12b in which the gauche interaction
between the aromatic ring and the substituent R0 is
Scheme 4. Synthesis of chiral epoxides 16a–d.

Y. Kurosaki et al. / Tetrahedron 61 (2005) 3289–3303
Table 5. Synthesis of chiral 3,4-dihydroisocoumarins 18a–d
3295
Entry
Epoxide
18
R
Yield (%)a
% ee
[a]2D5
1
2
3
4
16a
16b
16c
16d
18a
18b
18c
18d
Phenyl
p-Tolyl
C7H15
2-Phenylethyl
27
26
38
62
98 (S)b
98 (S)b
84 (R)b
79 (R)c
K151 (c 1.53, MeOH)
K124 (c 1.46, MeOH)
K51.9 (c 1.00, MeOH)
K30.4 (c 1.00, MeOH)
a Isolated yield.
b Determined by HPLC analysis (Daicel Chiralpak AD).
c Determined by HPLC analysis (Daicel Chiralpak AS).
Scheme 5.
by comparison of their CD spectra with those of 11a,b,i
(Figs. 3 and 4).
stereoselectivity has been rationalized by chelation-con-
trolled addition of the TMEDA complexes, which are nicely
represented as N-lithio-o-quinodimethane structures by ab
initio calculations. We have also discovered that the major
addition products lactonize much faster than the minor
adducts under acidic conditions to give optically enriched
3,4-dihydroisocoumarins. The procedure presented herein
is simple and practically useful to produce a variety of
optically active 3-substituted 3,4-dihydroisocoumarins.
3. Conclusion
We have discovered that the stereoselective addition of the
laterally lithiated chiral 2-(o-tolyl)oxazolines to aldehydes
proceeds in diethyl ether in the presence of TMEDA. The
Figure 3. CD spectra of 3,4-dihydroisocoumarins 11a–e.

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Y. Kurosaki et al. / Tetrahedron 61 (2005) 3289–3303
Figure 4. CD spectra of 3,4-dihydroisocoumarins 11a, 11h, 11i and 18d.
4. Experimental
4.1. General
dichloromethane and the extract was washed with brine,
dried over Na2SO4, and evaporated. The residual solid was
dried in vacuo to give the intermediate o-toluamide. Thionyl
chloride (21.5 mL, 295 mmol) was added dropwise to the
amide at 0 8C and mixture was stirred for 1 h. Methanol
(21.5 mL) was added 0 8C to decompose excess of thionyl
chloride. When gas evolution ceased, the solution was made
basic with 10% aqueous KOH. After stirring for 30 min at
room temperature, the mixture was extracted with dichloro-
methane. The extract was washed with brine, dried over
Na2SO4, and evaporated. The residual oil was purified by
bulb-to-bulb distillation to give the oxazoline 1.
Melting points were determined with a Yanagimoto micro
melting points apparatus and are uncorrected. IR spectra
were obtained with a Perkin–Elmer System 2000 instru-
1
ment. H NMR spectra were recorded at 300 MHz on a
Varian Gemini-300 instrument using TMS as an internal
standard. 13C NMR spectra were obtained at 100 MHz on a
JEOL JNM-AL400 instrument using TMS as an internal
standard. High resolution mass spectra were recorded on a
JEOL JMS-DX303 spectrometer. HPLC analyses were
performed on a Shimadzu LC-6A apparatus. Optical
rotations were measured on a JASCO DPI-1000 digital
polarimeter at ambient temperature. Flash chromatography
was conducted on Silica Gel 60N, 40–50 mm (Kanto
Chemical Co., Inc.). Column chromatography was con-
ducted on Silica Gel 60N, 63–210 mm (Kanto Chemical Co.,
Inc.) or Chromatorex NH-DM1020 silica gel (Fuji Silysia
Chemical Ltd). sec-BuLi was purchased from Kanto
Chemical Co., Inc. and used after titration with 2,5-
dimethoxybenzyl alcohol. AD-mix-b was purchased from
Aldrich Chemical Co., Inc. Diethyl ether and THF were
dried over Na-benzophenone ketyl under Ar and distilled
immediately before use. Dichloromethane was distilled
from CaH2.
4.2.1. (S)-4-Isopropyl-2-(o-tolyl)-4,5-dihydrooxazole
(1a). According to the general procedure, (S)-2-amino-3-
methyl-1-butanol (3.50 g, 34 mmol) was reacted to give 1a
as colorless oil (6.02 g, 87%). Bp 90 8C (1.6 mmHg, bulb-
to-bulb); IR (neat): 2960, 1646, 1576, 1493, 1456, 1385,
1348, 1307, 1274, 1246, 1053, 972, 904, 775, 728, 667 cmK1
;
1H NMR (300 MHz, CDCl3): d 0.95 (d, JZ6.8 Hz, 3H),
1.04 (d, JZ6.8 Hz, 3H), 1.80–1.93 (m, 1H), 2.58 (s, 3H),
4.05–4.18 (m, 2H), 4.30–4.42 (m, 1H), 7.17–7.35 (m, 3H),
7.76 (d, JZ7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d
18.20, 18.81, 21.58, 32.86, 69.34, 72.91, 125.33, 127.37,
129.57, 130.15, 130.91, 138.42, 163.63; [a]2D6ZK76.2 (c
1.03, MeOH). HREIMS m/z. Calcd for C13H17NO (MC):
203.1310. Found: 203.1349.
4.2. Synthesis of (S)-4-alkyl-2-(o-tolyl)oxazoline 1.
General procedure
4.2.2. (S)-4-Methyl-2-(o-tolyl)-4,5-dihydrooxazole (1b).
According to the general procedure, (S)-2-amino-1-propa-
nol (1.31 g, 17 mmol) was reacted to give 1b as colorless oil
(2.22 g, 72%). Bp 105 8C (2.0 mmHg, bulb-to-bulb); IR
(neat): 3064, 3027, 2967, 2926, 2894, 1644, 1603, 1574,
1492, 1475, 1454, 1374, 1353, 1337, 1304, 1287, 1248,
1205, 1163, 1140, 1124, 1106, 1065, 1038, 974, 931, 888,
A solution of o-toluoyl chloride (4.90 mL, 38 mmol) in THF
(46 mL) was added dropwise to a mixed solution of (S)-2-
amino-2-alkylethanol (34 mmol) and triethylamine
(5.6 mL, 40 mmol) in THF (46 mL) at 0 8C. After being
stirred for 1 h, saturated aqueous NaHCO3 was added and
the mixture was evaporated. The residue was extracted with
851, 776, 729, 683, 664 cmK1
;
1H NMR (300 MHz,
CDCl3): d 1.36 (d, JZ6.7 Hz, 3H), 2.57 (s, 3H), 3.92 (t,

Y. Kurosaki et al. / Tetrahedron 61 (2005) 3289–3303
3297
JZ6.7 Hz, 1H), 4.32–4.50 (m, 2H), 7.17–7.36 (m, 3H), 7.77
(d, JZ7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 21.54,
21.63, 62.20, 73.31, 125.36, 127.22, 129.63, 130.26, 130.93,
138.40, 163.82; [a]2D7ZK64.9 (c 1.00, MeOH). HREIMS
m/z. Calcd for C11H13NO (MC): 175.0997. Found:
175.0984.
triethylamine for 2b, 3b and 2c, 3c. The diastereoselectivity
was determined by HPLC analysis (Daicel Chiralpak AD,
hexane–i-PrOHZ1:1).
4.3.1. (S)- and (R)-2-{2-[(S)-4-Isopropyl-4,5-dihydrooxa-
zol-2-yl]phenyl}-1-(p-tolyl)ethanol (2a, 3a). According to
the general procedure, 1a (2.03 g, 10 mmol) was reacted
under the conditions shown in Table 1, entry 3, to give a
7.6:1 mixture of 2a and 3a as colorless semisolid (3.21 g,
99%). IR (KBr): 2965, 1645, 1513, 1492, 1358, 1252, 1064,
4.2.3. (S)-4-Benzyl-2-(o-tolyl)-4,5-dihydrooxazole (1c).
According to the general procedure, (S)-2-amino-3-phe-
nyl-1-propanol (709 mg, 4.7 mmol) was reacted to give 1c
as colorless oil (753 mg, 64%). Bp 160 8C (1.0 mmHg,
bulb-to-bulb); IR (neat): 3062, 3027, 2963, 2924, 1770,
1651, 1644, 1604, 1574, 1552, 1494, 1473, 1454, 1383,
1352, 1310, 1270, 1250, 1203, 1178, 1163, 1133, 1123,
1075, 1050, 1031, 970, 916, 776, 753, 728, 700, 682,
958, 853, 806, 747, 557 cmK1 1H NMR (300 MHz,
;
CDCl3): d 1.01 (d, JZ6.7 Hz, 3H, both isomers), 1.08 (d,
JZ6.7 Hz, 3H, both isomers), 1.84–1.98 (m, 1H, both
isomers), 2.34 (s, 0.35H, minor isomer), 2.36 (s, 2.65H,
major isomer), 3.06–3.20 (m, 1H, both isomers), 3.47 (dd,
JZ9.4, 13.3 Hz, 0.12H, minor isomer), 3.58 (t, JZ9.8,
13.3 Hz, 0.88H, major isomer), 4.10–4.30 (m, 2H, both
isomers), 4.36–4.51 (m, 1H, both isomers), 4.95 (br d, JZ
9.1 Hz, 1H, both isomers), 7.10–7.44 (m, 7H, both isomers),
7.73–7.80 (m, 1H, both isomers). Anal. Calcd for
C21H25NO2: C, 77.98; H, 7.79; N, 4.33. Found: C, 77.68;
H, 8.04; N, 4.09.
1
666 cmK1; H NMR (300 MHz, CDCl3): d 2.57 (s, 3H),
2.76 (dd, JZ8.4, 13.7 Hz, 1H), 3.22 (dd, JZ5.2, 13.7 Hz,
1H), 4.11 (dd, JZ7.3, 8.4 Hz, 1H), 4.30 (dd, JZ8.4, 9.2 Hz,
1H), 4.55–4.69 (m, 1H), 7.17–7.36 (m, 8H), 7.76 (d, JZ
7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 21.66, 41.82,
68.11, 70.91, 125.36, 126.30, 127.06, 128.32, 129.17,
129.63, 130.33, 130.97, 137.85, 138.53, 164.27; [a]2D7Z
K15.2 (c 1.00, MeOH). HREIMS m/z. Calcd for C17H17NO
(MC): 251.1310. Found: 251.1297.
4.3.2. (S)- and (R)-2-{2-[(S)-4-Methyl-4,5-dihydrooxazol-
2-yl]phenyl}-1-(p-tolyl)ethanol (2b, 3b). According to the
general procedure, 1b (175 mg, 1.0 mmol) was reacted
under the conditions shown in Table 1, entry 7, to give a
6.1:1 mixture of 2b and 3b as colorless oil (268 mg, 91%).
IR (neat): 3224, 3057, 3022, 2968, 2924, 2867, 1726, 1644,
1600, 1575, 1513, 1493, 1446, 1376, 1358, 1342, 1307,
1252, 1199, 1177, 1127, 1104, 1055, 966, 893, 851, 807,
4.2.4. (S)-4-(t-Butyl)-2-(o-tolyl)-4,5-dihydrooxazole (1d).
According to the general procedure, (S)-2-amino-3,3-
dimethyl-1-butanol (1.00 g, 8.5 mmol) was reacted to give
1d as colorless oil (1.72 g, 93%). Bp 120 8C (1.0 mmHg,
bulb-to-bulb); IR (neat): 3063, 3028, 2957, 2903, 2869,
1651, 1604, 1575, 1493, 1478, 1456, 1393, 1383, 1364,
1352, 1334, 1306, 1288, 1248, 1209, 1194, 1162, 1123,
1
776, 738, 692 cmK1; H NMR (300 MHz, CDCl3): d 1.17
1070, 1049, 1025, 992, 971, 931, 901, 775, 731, 667 cmK1
;
1H NMR (300 MHz, CDCl3): d 0.97 (s, 9H), 2.59 (s, 3H),
4.08 (dd, JZ8.0, 10.2 Hz, 1H), 4.18 (t, JZ8.0 Hz, 1H), 4.30
(dd, JZ8.0, 10.2 Hz, 1H), 7.17–7.35 (m, 3H), 7.75 (d, JZ
7.7 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 21.60, 25.88,
33.90, 67.88, 76.60, 125.33, 127.40, 129.54, 130.11, 130.90,
138.46, 163.53; [a]2D7ZK76.1 (c 1.00, MeOH). HREIMS
m/z. Calcd for C14H19NO (MC): 217.1467. Found:
217.1482.
(d, JZ6.6 Hz, 0.42H, minor isomer), 1.44 (d, JZ6.3 Hz,
2.58H, major isomer), 2.35 (s, 2.58H, major isomer), 2.38
(s, 0.42H, minor isomer), 3.02 (dd, JZ2.9, 16.3 Hz, 0.14H,
minor isomer), 3.09 (dd, JZ3.4, 13.3 Hz, 0.86H, major
isomer), 3.43–3.62 (m, 1H, both isomers), 3.97–4.20
(m, 1H, both isomers), 4.42–4.60 (m, 2H, both isomers),
4.88–4.99 (m, 1H, both isomers), 7.12–7.44 (m, 7H,
both isomers), 7.71–7.80 (m, 1H, both isomers). HREIMS
m/z. Calcd for C19H21NO2 (MC): 295.1572. Found:
295.1554.
4.3. Stereoselective addition of laterally lithiated (S)-4-
alkyl-2-(o-tolyl)oxazolines 1 to p-tolualdehyde (Table 1).
General procedure
4.3.3. (S)- and (R)-2-{2-[(S)-4-Benzyl-4,5-dihydrooxazol-
2-yl]phenyl}-1-(p-tolyl)ethanol (2c, 3c). According to the
general procedure, 1c (251 mg, 1.0 mmol) was reacted
under the conditions shown in Table 1, entry 8, to give a
4.0:1 mixture of 2c and 3c as colorless oil (306 mg, 82%).
IR (neat): 3238, 3061, 3027, 2922, 1726, 1644, 1603, 1575,
1514, 1494, 1454, 1358, 1309, 1274, 1225, 1178, 1118,
1063, 1031, 1001, 967, 914, 878, 852, 808, 776, 737, 700,
Under an argon atmosphere, a hexane-cyclohexane solution
of sec-BuLi (12 mmol) was added dropwise to a solution of
the oxazoline 1 (10 mmol) in diethyl ether or THF (50 mL)
at K78 8C. After being stirred for 1 h, an appropriate
additive (15 mmol) was added as a neat liquid or diethyl
ether solution and the mixture was stirred for 1 h at K78 8C.
A solution of p-tolualdehyde (1.53 mL, 13 mmol) in diethyl
ether or THF (10 mL) was added and the solution was
stirred for an additional 1 h at K78 8C. The reaction mixture
was quenched with H2O at the same temperature and
allowed to warm to room temperature. The products were
extracted with diethyl ether and the extract was washed with
brine, dried over Na2SO4, and evaporated under reduced
pressure. The residue was purified by flash chromatography
over Silica Gel 60N using the following eluents: hexane–
ethyl acetateZ10:1 containing 1% triethylamine for 2a, 3a
and 2d, 3d; hexane–ethyl acetateZ3:1 containing 1%
1
666 cmK1; H NMR (300 MHz, CDCl3): d 2.35 (s, 2.40H,
major isomer), 2.37 (s, 0.60H, minor isomer), 2.76–2.98 (m,
1H, both isomers), 3.00–3.20 (m, 1H, both isomers), 3.31
(dd, JZ5.3, 13.7 Hz, 0.80H, major isomer), 3.41 (dd, JZ
9.5, 13.3 Hz, 0.20H, minor isomer), 3.50–3.68 (m, 1H, both
isomers), 4.14–4.22 (m, 1H, both isomers), 4.41 (t, JZ
9.1 Hz, 0.80H, major isomer), 4.46 (t, JZ8.9 Hz, 0.20H,
minor isomer), 4.61–4.80 (m, 1H, both isomers), 4.85–4.98
(m, 1H, both isomers), 7.00–7.50 (m, 12H, both isomers),
7.68–7.80 (m, 1H, both isomers). HREIMS m/z. Calcd for
C25H25NO2 (MC): 371.1885. Found: 371.1884.

3298
Y. Kurosaki et al. / Tetrahedron 61 (2005) 3289–3303
4.3.4. (S)- and (R)-2-{2-[(S)-4-(t-Butyl)-4,5-dihydrooxa-
zol-2-yl]phenyl}-1-(p-tolyl)ethanol (2d, 3d). According to
the general procedure, 1d (217 mg, 1.0 mmol) was reacted
under the conditions shown in Table 1, entry 9, to give a
5.4:1 mixture of 2d and 3d as colorless solid (326 mg, 97%).
Mp 79–85 8C; IR (KBr): 3224, 3060, 3021, 2959, 2868,
1645, 1600, 1576, 1513, 1494, 1478, 1445,1396, 1358,
1340, 1309, 1252, 1210, 1196, 1176, 1128, 1074, 1056, 997,
reacted. After chromatographic purification over Silica Gel
60N (hexane–ethyl acetateZ5:1 containing 1% triethyl-
amine), 4c was obtained as colorless oil (966 mg, 95%).
HPLC (Daicel Chiralpak AD, hexane–i-PrOHZ1:1):
72% de. IR (neat): 3213, 2961, 1733, 1652, 1646, 1616,
1586, 1516, 1464, 1362, 1247, 1172, 1065, 965, 825, 777,
741, 667 cmK1; 1H NMR (300 MHz, CDCl3): d 1.02 (d, JZ
6.9 Hz, 3H, both isomers), 1.09 (d, JZ6.9 Hz, 2.58H, major
isomer), 1.11 (d, JZ7.1 Hz, 0.42H, minor isomer), 1.84–
1.98 (m, 1H, both isomers), 3.11–3.23 (m, 1H, both
isomers), 3.44 (dd, JZ9.0, 13.3 Hz, 0.14H, minor isomer),
3.54 (dd, JZ9.3, 13.5 Hz, 0.86H, major isomer), 3.82 (s,
3H, both isomers), 4.05–4.30 (m, 2H, both isomers), 4.45–
4.51 (m, 1H, both isomers), 4.90–5.00 (m, 1H, both
isomers), 6.85–6.95 (m, 2H, both isomers), 7.23–7.45 (m,
5H, both isomers), 7.75–7.79 (m, 1H, both isomers). Anal.
Calcd for C21H25NO3: C, 74.31; H, 7.42; N, 4.13. Found: C,
74.24; H, 7.51; N, 4.04.
966, 911, 854, 806, 773, 740, 666 cmK1 1H NMR
;
(300 MHz, CDCl3): d 1.02 (s, 9H, both isomers), 2.36 (s,
3H, both isomers), 3.10 (dd, JZ2.7, 13.5 Hz, 0.84H, major
isomer), 3.20 (dd, JZ3.7, 13.3 Hz, 0.16H, minor isomer),
3.44 (dd, JZ9.2, 13.3 Hz, 0.16H, minor isomer), 3.63 (dd,
JZ9.9, 13.5 Hz, 0.84H, major isomer), 4.15–4.30 (m, 2H,
both isomers), 4.35–4.48 (m, 1H, both isomers), 4.90–5.01
(m, 1H, both isomers), 7.12–7.48 (m, 7H, both isomers),
7.72–7.81 (m, 1H, both isomers). HREIMS m/z. Calcd for
C22H27NO2 (MC): 337.2042. Found: 337.2027.
4.4. Stereoselective addition of laterally lithiated (S)-4-
isopropyl-2-(o-tolyl)oxazoline (1a) to aldehydes (Table 2).
General procedure
4.4.3. (S)- and (R)-2-{2-[(S)-4-Isopropyl-4,5-dihydro-
oxazol-2-yl]phenyl}-1-(4-chlorophenyl)ethanol (4d).
According to the general procedure, 1a (203 mg,
1.0 mmol) and p-chlorobenzaldehyde (182 mg, 1.3 mmol)
were reacted. After chromatographic purification over Silica
Gel 60N (hexane–ethyl acetateZ20:1 containing 1%
triethylamine), 4d was obtained as colorless semisolid
(334 mg, 97%). HPLC (Daicel Chiralpak AD, hexane–i-
PrOHZ1:1): 53% de. IR (KBr): 1641, 1490, 1065, 972,
Under an argon atmosphere, a hexane-cyclohexane solution
of sec-BuLi (2.4 mmol) was added dropwise to a solution of
1a (2.0 mmol) in diethyl ether (10 mL) at K78 8C. After
being stirred for 1 h, TMEDA (452 mL, 3.0 mmol) was
added as a neat liquid and the mixture was stirred for 1 h at
K78 8C. A solution of an appropriate aldehyde (2.6 mmol)
in diethyl ether (2.0 mL) was added and the reaction mixture
was stirred for an additional 1 h at K78 8C. The reaction
mixture was quenched with water at the same temperature
and allowed to warm to room temperature. The products
were extracted with diethyl ether and the extract was
washed with brine, dried over Na2SO4, and evaporated
under reduced pressure. The residue was purified by column
chromatography to give 4 as a diastereomeric mixture.
1
754 cmK1; H NMR (300 MHz, CDCl3): d 1.01 (d, JZ
6.7 Hz, 2.30H, major isomer), 1.02 (d, JZ6.9 Hz, 0.70H,
minor isomer), 1.07 (d, JZ6.7 Hz, 2.30H, major isomer),
1.11 (d, JZ6.9 Hz, 0.70H, minor isomer), 1.82–1.98 (m,
1H, both isomers), 3.16–3.27 (m, 1H, both isomers), 3.37
(dd, JZ8.5, 13.5 Hz, 0.23H, minor isomer), 3.47 (dd, JZ
9.1, 13.5 Hz, 0.77H, major isomer), 4.14–4.27 (m, 2H, both
isomers), 4.46–4.52 (m, 1H, both isomers), 4.99 (br d, JZ
7.4 Hz, 1H, both isomers), 7.08 (dd, JZ1.1, 6.6 Hz, 0.23H,
minor isomer), 7.15 (dd, JZ1.1, 7.7 Hz, 0.77H, major
isomer), 7.25–7.42 (m, 6H, both isomers), 7.55–7.66 (m,
1H, both isomers), 7.75–7.79 (m, 1H, both isomers). Anal.
Calcd for C20H22ClNO2: C, 69.86; H, 6.45; N, 4.07. Found:
C, 69.75; H, 6.64; N, 4.08.
4.4.1. (S)- and (R)-2-{2-[(S)-4-Isopropyl-4,5-dihydrooxa-
zol-2-yl]phenyl}-1-phenylethanol (4a). According to the
general procedure, 1a (407 mg, 2.0 mmol) and benzalde-
hyde (264 mL, 2.6 mmol) were reacted. After chromato-
graphic purification over Chromatorex NH-DM1020 silica
gel (hexane–ethyl acetate Z20:1), 4a was obtained as
colorless powder (584 mg, 94%). HPLC (Daicel Chiralpak
AD, hexane–i-PrOHZ1:1): 78% de. Mp 105–110 8C; IR
(KBr): 3199, 2959, 1647, 1491, 1452, 1358, 1248, 1201,
1164, 1087, 1062, 998, 960, 758, 703, 556 cmK1; 1H NMR
(300 MHz, CDCl3): d 1.01 (d, JZ6.6 Hz, 3H, both isomers),
1.09 (d, JZ6.6 Hz, 2.67H, major isomer), 1.12 (d, JZ
6.7 Hz, 0.33H, minor isomer), 1.82–2.00 (m, 1H, both
isomers), 3.11–3.23 (m, 1H, both isomers), 3.47 (dd, JZ9.3,
13.5 Hz, 0.11H, minor isomer), 3.57 (dd, JZ9.6, 13.5 Hz,
0.89H, major isomer), 4.13–4.28 (m, 2H, both isomers),
4.45–4.51 (m, 1H, both isomers), 4.96–5.02 (m, 1H, both
isomers), 7.15–7.52 (m, 8H, both isomers), 7.76–7.80 (m,
1H, both isomers). Anal. Calcd for C20H23NO2: C, 77.64; H,
7.49; N, 4.53. Found: C, 77.57; H, 7.58; N, 4.48.
4.4.4. (S)- and (R)-2-{2-[(S)-4-Isopropyl-4,5-dihydrooxa-
zol-2-yl]phenyl}-1-(3,4-dimethoxyphenyl)ethanol (4e).
According to the general procedure, 1a (203 mg,
1.0 mmol) and veratraldehyde (216 mg, 1.3 mmol) were
reacted. After chromatographic purification over Silica Gel
60N (hexane–ethyl acetateZ2:1 containing 1% triethyl-
amine), 4e was obtained as colorless oil (358 mg, 97%).
HPLC (Daicel Chiralpak AD, hexane–i-PrOHZ1:1):
70% de. IR (neat): 3208, 2960, 1726, 1652, 1593, 1516,
1464, 1418, 1362, 1265, 1139, 1029, 963, 911, 862, 808,
761, 690 cmK1; 1H NMR (300 MHz, CDCl3): d 1.03 (d, JZ
6.7 Hz, 3H, both isomers), 1.11 (d, JZ6.7 Hz, 2.55H, major
isomer), 1.13 (d, JZ5.6 Hz, 0.45H, minor isomer), 1.81–
1.97 (m, 1H, both isomers), 3.17 (dd, JZ3.0, 13.4 Hz,
0.85H, major isomer), 3.27 (dd, JZ3.8, 13.5 Hz, 0.15H,
minor isomer), 3.41 (dd, JZ8.7, 13.5 Hz, 0.15H, minor
isomer), 3.54 (dd, JZ9.3, 13.4 Hz, 0.85H, major isomer),
3.86 (s, 0.45H, minor isomer), 3.88 (s, 2.55H, major
isomer), 3.89 (s, 3H, both isomers), 4.10–4.28 (m, 2H,
both isomers), 4.42–4.55 (m, 1H, both isomers), 4.91–5.01
4.4.2. (S)- and (R)-2-{2-[(S)-4-Isopropyl-4,5-dihydro-
oxazol-2-yl]phenyl}-1-(4-methoxyphenyl)ethanol (4c).
According to the general procedure, 1a (609 mg,
3.0 mmol) and p-anisaldehyde (531 mg, 3.9 mmol) were

Y. Kurosaki et al. / Tetrahedron 61 (2005) 3289–3303
3299
(m, 1H, both isomers), 6.83–7.12 (m, 3H, both isomers),
7.17–7.49 (m, 4H, both isomers), 7.75–7.80 (m, 1H, both
isomers). HREIMS m/z. Calcd for C22H27NO4 (MC):
369.1940. Found: 369.1940.
isomers), 1.84–1.98 (m, 1H, both isomers), 2.71–2.83 (m,
1H, both isomers), 3.33–3.45 (m, 2H, both isomers), 4.08–
4.27 (m, 2H, both isomers), 4.38–4.45 (m, 1H, both
isomers), 6.42 (br s, 1H, both isomers), 7.21–7.32 (m, 2H,
both isomers), 7.37–7.45 (m, 1H, both isomers), 7.68–7.76
(m, 1H, both isomers). HREIMS m/z. Calcd for C18H27NO2
(MC): 289.2042. Found 289.2018.
4.4.5. (S)- and (R)-2-{2-[(S)-4-Isopropyl-4,5-dihydroox-
azol-2-yl]phenyl}-1-(1-naphthyl)ethanol (4f). According
to the general procedure, 1a (203 mg, 1.0 mmol) and
1-naphthaldehyde (203 mg, 1.3 mmol) were reacted. After
chromatographic purification over Silica Gel 60N (hexane–
ethyl acetateZ10:1 containing 1% triethylamine), 4f was
obtained as colorless oil (341 mg, 95%). HPLC (Daicel
Chiralpak AD, hexane–i-PrOHZ1:1): 70% de. IR (neat):
3202, 2961, 1728, 1645, 1598, 1578, 1494, 1467, 1360,
4.4.8. (R)- and (S)-1-{2-[(S)-4-Isopropyl-4,5-dihydroox-
azol-2-yl]phenyl}nonane-2-ol (4i). According to the gen-
eral procedure, 1a (203 mg, 1.0 mmol) and octylaldehyde
(203 mL, 1.3 mmol) were reacted. After chromatographic
purification over Chromatorex NH-DM1020 silica gel
(hexane–ethyl acetate Z20:1), 4i was obtained as colorless
oil (247 mg, 75%). HPLC (Daicel Chiralpak AD, hexane–i-
PrOHZ9:1): 35% de; IR (neat): 3273, 2927, 1733, 1646,
1601, 1576, 1493, 1467, 1355, 1308, 1249, 1115, 1065, 967,
909, 776, 751 cmK1; 1H NMR (300 MHz, CDCl3): d 0.77–
1.02 (m, 9H, both isomers), 1.16–1.58 (m, 12H, both
isomers), 1.68–1.83 (m, 1H, both isomers), 2.87 (dd, JZ3.2,
13.2 Hz, 0.68H, major isomer), 2.98 (dd, JZ3.8, 13.3 Hz,
0.32H, minor isomer), 3.08 (dd, JZ7.8, 13.3 Hz, 0.32H,
minor isomer), 3.19 (dd, JZ9.1, 13.2 Hz, 0.68H, major
isomer), 3.75 (br s, 1H, both isomers), 4.00–4.13 (m, 2H,
both isomers), 4.30–4.42 (m, 1H, both isomers), 6.30 (br s,
1H, both isomers), 7.14–7.25 (m, 2H, both isomers), 7.33
(dt, JZ1.3, 7.4 Hz, 1H, both isomers), 7.66 (dd, JZ1.1,
7.7 Hz, 1H, both isomers). Anal. Calcd for C21H33NO2: C,
76.09; H, 10.03; N, 4.23. Found: C, 75.94; H, 10.22; N, 4.19.
1254, 1064, 965, 799, 777 cmK1 1H NMR (300 MHz,
;
CDCl3): d 1.04 (d, JZ6.7 Hz, 2.55H, major isomer), 1.09
(d, JZ6.6 Hz, 0.45H, minor isomer), 1.11 (d, JZ6.7 Hz,
2.55H, major isomer), 1.18 (d, JZ6.6 Hz, 0.45H, minor
isomer), 1.85–2.00 (m, 1H, both isomers), 3.37–3.47 (m,
1H, both isomers), 3.55 (dd, JZ8.6, 13.6 Hz, 0.15H, minor
isomer), 3.65 (dd, JZ9.2, 13.6 Hz, 0.85H, major isomer),
4.15–4.33 (m, 2H, both isomers), 4.47–4.54 (m, 1H, both
isomers), 5.77–5.87 (m, 1H, both isomers), 7.08–7.62
(m, 6H, both isomers), 7.67–7.93 (m, 4H, both isomers),
8.21–8.28 (m, 1H, both isomers). HREIMS m/z. Calcd for
C24H25NO2 (MC): 359.1885. Found: 359.1883.
4.4.6. (2S,3E)- and (2R,3E)-1-{2-[(S)-4-Isopropyl-4,5-
dihydrooxazol-2-yl]phenyl}-4-phenyl-3-buten-2-ol (4g).
According to the general procedure, 1a (609 mg,
3.0 mmol) and cinnamaldehyde (515 mg, 3.9 mmol) were
reacted. After chromatographic purification over Chroma-
torex NH-DM1020 silica gel (hexane–ethyl acetate Z5:1),
4g was obtained as colorless solid (877 mg, 87%). HPLC
(Daicel Chiralpak AD, hexane–i-PrOHZ1:1): 75% de. Mp
69–72 8C; IR (KBr): 3211, 2961, 1647, 1600, 1577, 1494,
4.5. Acid-catalyzed lactonization of the addition product
4b (Table 3)
The 77% de sample of 4b (100 mg, 0.309 mmol) was
dissolved in 4.0 mL of a mixed solvent (THF–H2O–TFAZ
10:1.5:0.5) at 0 8C. After being stirred for an appropriate
reaction time, the mixture was quenched with saturated
aqueous NaHCO3 and the product was extracted with
diethyl ether. The extract was washed with brine, dried over
Na2SO4, and evaporated under reduced pressure. The
product 11b and the unreacted 4b were separated by
column chromatography over Silica Gel 60N using hexane–
ethyl acetateZ20:1 containing 1% triethylamine as an
eluent. Both ee of 11b and de of 4b were determined by
HPLC analyses (Daicel Chiralpak AD: hexane–i-PrOHZ
7:3 for 11b, hexane–i-PrOHZ1:1 for 4b). The results are in
Table 3.
1
1446, 1356, 1250, 1104, 1065, 965, 747, 695 cmK1; H
NMR (300 MHz, CDCl3): d 0.99 (d, JZ6.6 Hz, 0.37H,
minor isomer), 1.00 (d, JZ6.9 Hz, 2.63H, major isomer),
1.08 (d, JZ6.9 Hz, 3H, both isomers), 1.75–1.90 (m, 1H,
both isomers), 3.15 (dd, JZ3.6, 13.3 Hz, 1H, both isomers),
3.38 (dd, JZ9.1, 13.3 Hz, 1H, both isomers), 4.10–4.21 (m,
2H, both isomers), 4.44–4.53 (m, 1H, both isomers), 4.53–
4.65 (m, 1H, both isomers), 6.38 (dd, JZ5.6, 15.8 Hz,
0.12H, minor isomer), 6.39 (dd, JZ5.5, 15.8 Hz, 0.88H,
major isomer), 6.68 (d, JZ15.8 Hz, 0.12H, minor isomer),
6.72 (dd, JZ0.8, 15.8 Hz, 0.88H, major isomer), 7.19–7.47
(m, 8H, both isomers), 7.76 (dd, JZ1.2, 7.8 Hz, 1H, both
isomers). Anal. Calcd for C22H25NO2: C, 78.77; H, 7.51; N,
4.18. Found: C, 78.59; H, 7.59; N, 4.03.
4.6. Synthesis of optically enriched 3,4-dihydroiso-
coumarins 11 via diastereomer-selective lactonization
(Table 4). General procedure
4.4.7. (S)- and (R)-1-{2-[(S)-4-Isopropyl-4,5-dihydrooxa-
zol-2-yl]phenyl}-3,3-dimethylbutan-2-ol (4h). According
to the general procedure, 1a (203 mg, 1.0 mmol) and
pivalaldehyde (149 mL, 1.3 mmol) were reacted. After
chromatographic purification over Chromatorex NH-
DM1020 silica gel (hexane–ethyl acetate Z20:1), 4h was
obtained as colorless semisolid (262 mg, 91%). HPLC
(Daicel Chiralpak AD, hexane–i-PrOHZ9:1): 84% de. IR
(KBr): 3267, 2959, 1648, 1480, 1359, 1247, 1065, 965,
The addition product 4 (1.6 mmol) was dissolved in 20 mL
of a mixed solvent (THF–H2O–TFAZ10:1.5:0.5) at 0 8C.
After being stirred for 24 h, the mixture was quenched with
saturated aqueous NaHCO3 and the product was extracted
with diethyl ether. The extract was washed with brine, dried
over Na2SO4, and evaporated under reduced pressure. The
residue was purified by column chromatography over
Silica Gel 60N using the following eluents: toluene–ethyl
acetateZ20:1 for 11a, 11d, 11f, 11g, 11h and 11i; hexane–
ethyl acetateZ10:1 for 11c; toluene–ethyl acetateZ5:1 for
1
738 cmK1; H NMR (300 MHz, CDCl3): d 0.98 (d, JZ
6.8 Hz, 3H, both isomers), 1.00 (s, 0.70H, minor isomer),
1.02 (s, 8.30H, major isomer), 1.03 (d, JZ6.8 Hz, 3H, both

3300
Y. Kurosaki et al. / Tetrahedron 61 (2005) 3289–3303
11e. Recrystallizations of 11a, 11b, 11f, 11g and 11h
afforded the optically pure samples (O99% ee).
PrOHZ7:3): 73% ee. Mp 74.5–75.0 8C; IR (KBr): 3071,
2907, 1725, 1606, 1495, 1461, 1418, 1346, 1271, 1225,
1116, 1084, 1031, 1016, 914, 894, 817, 744, 704, 686, 646,
624 cmK1; 1H NMR (300 MHz, CDCl3): d 3.12 (dd, JZ3.3,
16.4 Hz, 1H), 3.30 (dd, JZ11.8, 16.4 Hz, 1H), 5.54 (dd, JZ
3.3, 11.8 Hz, 1H), 7.29 (d, JZ7.5 Hz, 1H), 7.36–7.43 (m,
4H), 7.44 (t, JZ7.5 Hz, 1H), 7.58 (dt, JZ1.3, 7.5 Hz, 1H),
8.15 (d, JZ7.5 Hz, 1H); 13C NMR (100 MHz, CDCl3): d
35.47, 79.04, 124.80, 127.20, 127.32, 127.83, 128.72,
130.28, 133.86, 134.28, 136.93, 138.42, 164.81; [a]2D6Z
K91.3 (c 1.01, MeOH, 73% ee). Anal. Calcd for
C15H11ClO2: C, 69.64; H, 4.29. Found: C, 69.72; H, 4.72.
4.6.1. (S)-3-Phenyl-3,4-dihydroisocoumarin (11a).
According to the general procedure, 4a (500 mg,
1.6 mmol) was reacted to give 11a as colorless solid
(304 mg, 84%). HPLC (Daicel Chiralpak AD, hexane–i-
PrOHZ7:3): 89% ee. Recrystallization from diethyl ether–
hexane gave an optically pure sample as colorless needles.
Mp 76.5–77.0 8C; IR (KBr): 1717, 1604, 1488, 1458, 1349,
1278, 1226, 1117, 1090, 1072, 1031, 999, 923, 802, 762,
1
748, 701, 640, 575, 511, 433 cmK1; H NMR (300 MHz,
CDCl3): d 3.14 (dd, JZ3.3, 16.5 Hz, 1H), 3.35 (dd, JZ12.0,
16.5 Hz, 1H), 5.56 (dd, JZ3.3, 12.0 Hz, 1H), 7.29 (d, JZ
7.4 Hz, 1H), 7.33–7.52 (m, 6H), 7.57 (dt, JZ1.4, 7.6 Hz,
1H), 8.16 (dd, JZ1.1, 7.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d 35.51, 79.84, 124.93, 125.94, 127.20, 127.69,
128.46, 128.50, 130.21, 133.74, 138.36, 138.75, 165.10;
[a]D26ZK158 (c 0.990, MeOH, O99% ee) {lit.6g [a]DZ
C89 [c 1, CHCl3, ca. 45% ee, (R)-isomer]}. Anal. Calcd for
C15H12O2: C, 80.34; H, 5.39. Found: C, 80.10; H, 5.33.
4.6.5. (S)-3-(3,4-Dimethoxyphenyl)-3,4-dihydroisocou-
marin (11e). According to the general procedure, 4e
(148 mg, 0.40 mmol) was reacted to give 11e as colorless
solid (64.8 mg, 57%). HPLC (Daicel Chiralpak AS,
hexane–EtOHZ3:7): 82% ee. Mp 73.5–74.5 8C; IR (KBr):
2941, 1716, 1607, 1518, 1461, 1427, 1388, 1348, 1278,
1240, 1157, 1142, 1123, 1075, 1024, 996, 909, 866, 822,
1
734, 693 cmK1; H NMR (300 MHz, CDCl3): d 3.11 (dd,
JZ3.0, 16.4 Hz, 1H), 3.37 (dd, JZ12.1, 16.4 Hz, 1H), 3.91
(s, 3H), 3.92 (s, 3H), 5.51 (dd, JZ3.0, 12.1 Hz, 1H), 6.88 (d,
JZ8.2 Hz, 1H), 6.99 (dd, JZ1.9, 8.2 Hz, 1H), 7.04 (d, JZ
1.9 Hz, 1H), 7.29 (d, JZ7.5 Hz, 1H), 7.44 (t, JZ7.5 Hz,
1H), 7.58 (dt, JZ1.4, 7.5 Hz, 1H), 8.16 (d, JZ7.5 Hz, 1H);
13C NMR (100 MHz, CDCl3): d 35.53, 55.88, 55.91, 79.85,
109.26, 110.83, 118.55, 124.96, 127.19, 127.67, 130.23,
130.94, 133.72, 138.86, 148.96, 149.11, 165.22; [a]2D6Z
K85.1 (c 0.995, MeOH, 82% ee). HREIMS m/z. Calcd for
C17H16O4 (MC): 284.1048. Found: 284.1066.
4.6.2. (S)-3-(o-Tolyl)-3,4-dihydroisocoumarin (11b).
According to the general procedure, 4b (102 mg,
0.32 mmol) was reacted to give 11b as colorless solid
(57.9 mg, 77%). HPLC (Daicel Chiralpak AD, hexane–i-
PrOHZ7:3): 91% ee. Recrystallization from diethyl ether–
hexane gave an optically pure sample as colorless needles.
Mp 98.0–98.5 8C; IR (KBr): 1719, 1604, 1516, 1464, 1344,
1276, 1226, 1121, 1083, 1066, 1029, 1006, 913, 820, 747,
692, 530, 508 cmK1; 1H NMR (300 MHz, CDCl3): d 2.38 (s,
3H), 3.11 (dd, JZ3.2, 16.5 Hz, 1H), 3.34 (dd, JZ12.0,
16.5 Hz, 1H), 5.53 (dd, JZ3.2, 12.0 Hz, 1H), 7.22 (d, JZ
8.0 Hz, 2H), 7.28 (d, JZ7.6 Hz, 1H), 7.37 (d, JZ8.0 Hz,
2H), 7.43 (t, JZ7.6 Hz, 1H), 7.57 (dt, JZ1.4, 7.6 Hz, 1H),
8.15 (d, JZ7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): d
21.15, 35.48, 79.80, 125.01, 125.93, 127.19, 127.63, 129.14,
130.20, 133.67, 135.43, 138.28, 138.86, 165.18; [a]2D6Z
K132 (c 1.02, MeOH, O99% ee). Anal. Calcd for
C16H14O2: C, 80.65; H, 5.92. Found: C, 80.41; H, 5.95.
4.6.6. (S)-3-(1-Naphthyl)-3,4-dihydroisocoumarin (11f).
According to the general procedure, 4f (100 mg,
0.28 mmol) was reacted to give 11f as colorless solid
(54.6 mg, 72%). HPLC (Daicel Chiralpak AD, hexane–i-
PrOHZ7:3): 92% ee. Recrystallization from CH2Cl2–
hexane gave an optically pure sample as colorless needles.
Mp 189.0–189.5 8C; IR (KBr): 3041, 1711, 1602, 1514,
1459, 1431, 1343, 1287, 1238, 1123, 1098, 1087, 1032,
1008, 995, 967, 921, 909, 777, 738, 729, 693, 640, 534,
498 cmK1; 1H NMR (300 MHz, CDCl3): d 3.33 (dd, JZ3.2,
16.6 Hz, 1H), 3.48 (dd, JZ11.9, 16.6 Hz, 1H), 6.33 (dd, JZ
3.2, 11.9 Hz, 1H), 7.32 (d, JZ7.6 Hz, 1H), 7.48 (t, JZ
7.6 Hz, 1H), 7.51–7.58 (m, 3H), 7.61 (dt, JZ1.4, 7.6 Hz,
1H), 7.82 (d, JZ7.1 Hz, 1H), 7.88 (d, JZ8.2 Hz, 1H), 7.90–
7.94 (m, 1H), 7.97–8.10 (m, 1H), 8.22 (d, JZ7.6 Hz, 1H);
13C NMR (100 MHz, CDCl3): d 35.06, 77.09, 122.30,
123.79, 125.01, 125.25, 125.65, 126.46, 127.20, 127.80,
128.97, 129.82, 130.37, 133.57, 133.80, 139.01, 165.30;
[a]2D6ZK178 (c 0.100, MeOH, O99% ee); [a]2D6ZK252 (c
1.00, CHCl3, O99% ee). HREIMS m/z. Calcd for C19H14O2
(MC): 274.0994. Found 274.0994.
4.6.3. (S)-3-(4-Methoxyphenyl)-3,4-dihydroisocoumarin
(11c). According to the general procedure, 4c (729 mg,
2.1 mmol) was reacted to give 11c as colorless solid
(393 mg, 72%). HPLC (Daicel Chiralpak AD, hexane–i-
PrOHZ1:1): 86% ee. Mp 84.0–86.0 8C; IR (KBr):
1717,1612, 1516, 1460, 1279, 1249, 1181, 1119, 1072,
1027, 999, 828, 742, 687, 615, 523 cmK1 1H NMR
;
(300 MHz, CDCl3): d 3.09 (dd, JZ3.0, 16.4 Hz, 1H), 3.35
(dd, JZ12.0, 16.4 Hz, 1H), 3.82 (s, 3H), 5.50 (dd, JZ3.0,
12.0 Hz, 1H), 6.93 (d, JZ8.7 Hz, 2H), 7.28 (d, JZ7.5 Hz,
1H), 7.40 (d, JZ8.7 Hz, 2H), 7.42 (t, JZ7.5 Hz, 1H), 7.56
(t, JZ7.5 Hz, 1H), 8.14 (d, JZ7.5 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d 35.37, 55.24, 79.71, 113.85, 124.98,
127.20, 127.48, 127.63, 130.18, 130.46, 133.68, 138.90,
159.62, 165.25; [a]2D6ZK93.8 (c 1.02, MeOH, 86% ee).
Anal. Calcd for C16H14O3: C, 75.57; H, 5.55. Found: C,
75.53; H, 5.57.
4.6.7. (S)-3-[(E)-Styryl]-3,4-dihydroisocoumarin (11g).
According to the general procedure, 4g (700 mg,
2.1 mmol) was reacted to give 11g as colorless solid
(351 mg, 67%). HPLC (Daicel Chiralpak AS, hexane–i-
PrOHZ1:1): 88% ee. Recrystallization from diethyl ether
gave an optically pure sample as colorless needles. Mp
92.0–92.5 8C; IR (KBr): 1707, 1605, 1460, 1378, 1278,
1256, 1223, 1138, 1105, 1084, 995, 971, 914, 804, 762, 747,
4.6.4. (S)-3-(4-Chlorophenyl)-3,4-dihydroisocoumarin
(11d). According to the general procedure, 4d (138 mg,
0.40 mmol) was reacted to give 11d as colorless solid
(85.5 mg, 83%). HPLC (Daicel Chiralpak AD, hexane–i-
1
696, 589, 512 cmK1; H NMR (300 MHz, CDCl3): d 3.11

Y. Kurosaki et al. / Tetrahedron 61 (2005) 3289–3303
3301
(dd, JZ4.1, 16.2 Hz, 1H), 3.19 (dd, JZ9.9, 16.2 Hz, 1H),
5.16–5.26 (m, 1H), 6.34 (dd, JZ6.4, 16.1 Hz, 1H), 6.79 (d,
JZ16.1 Hz, 1H), 7.27–7.44 (m, 7H), 7.56 (dt, JZ1.2,
7.6 Hz, 1H), 8.13 (d, JZ7.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d 33.71, 78.54, 124.99, 125.68, 126.55, 127.29,
127.66, 128.17, 128.51, 130.17, 133.12, 133.68, 135.64,
138.43, 164.89; [a]2D5ZK53.3 (c 1.03, MeOH, O99% ee).
Anal. Calcd for C17H14O2: C, 81.58; H, 5.64. Found: C,
81.38; H, 5.64.
mixture was quenched with water and the product was
extracted with diethyl ether. The extract was washed
successively with 2 M aqueous HCl, water and brine,
dried over Na2SO4, and evaporated under reduced pressure.
The residue was purified by column chromatography over
Silica Gel 60N using the following eluents: hexane–ethyl
acetateZ3:1 for 15a, 15b and 15d; hexane–ethyl acetateZ
5:1 for 15c. Yields of the tosylate intermediates 15 after
chromatography are shown in Scheme 4.
To a solution of the tosylate 15 (3.9 mmol) in diethyl ether
(20 mL) was added 2 M aqueous NaOH (10 mL) at room
temperature. After being stirred for 3 h, the mixture was
extracted with diethyl ether. The extract was washed
successively with water and brine, dried over Na2SO4, and
evaporated under reduced pressure. The residue was
purified by distillation. Yields of the epoxides 16 after
distillation are shown in Scheme 4.
4.6.8. (S)-3-(t-Butyl)-3,4-dihydroisocoumarin (11h).
According to the general procedure, 4h (200 mg,
0.69 mmol) was reacted to give 11h as colorless solid
(79.7 mg, 56%). HPLC (Daicel Chiralpak AS, hexane–
EtOHZ9:1): 97% ee. Recrystallization from diethyl ether–
hexane gave an optically pure sample as colorless needles.
Mp 82.5–83.5 8C (diethyl ether); IR (KBr): 2967, 1716,
1608, 1459, 1346, 1281, 1237, 1121, 1085, 998, 909, 746,
1
694, 639 cmK1; H NMR (300 MHz, CDCl3): d 1.09 (s,
4.7.1. (R)-Phenyloxirane (16a). Bp 85–120 8C (24 mmHg,
bulb-to-bulb); 1H NMR (300 MHz, CDCl3): d 2.80 (dd, JZ
2.5, 5.5 Hz, 1H), 3.15 (dd, JZ4.0, 5.5 Hz, 1H), 3.86 (dd,
JZ2.5, 4.0 Hz, 1H), 7.23–7.40 (m, 5H); HPLC (Daicel
Chiralpak AS, hexane–i-PrOHZ30:1): 98% ee; [a]2D6Z
C45.9 (c 0.652, benzene), {lit.13 [a]D22ZK44.5 (c 1.15,
benzene): (S)-isomer (99% ee)}.
9H), 2.84 (dd, JZ2.7 and 16.1 Hz, 1H), 3.02 (dd, JZ12.6,
16.1 Hz, 1H), 4.17 (dd, JZ2.7, 12.6 Hz, 1H), 7.26 (d, JZ
7.4 Hz, 1H), 7.38 (t, JZ7.4 Hz, 1H), 7.53 (t, JZ7.4 Hz,
1H), 8.09 (d, JZ7.4 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 25.60, 28.41, 33.99, 86.05, 125.09, 127.33, 127.35,
130.01, 133.38, 139.53, 165.81; [a]2D6ZK107 (c 1.04,
MeOH, O99% ee). Anal. Calcd for C13H16O2: C, 76.44; H,
7.90. Found: C, 76.10; H, 8.28.
4.7.2. (R)-(p-Tolyl)oxirane (16b). Bp 105–120 8C
(10 mmHg, bulb-to-bulb); H NMR (300 MHz, CDCl3): d
1
4.6.9. (R)-3-Heptyl-3,4-dihydroisocoumarin (11i).
According to the general procedure, 4i (161 mg,
0.49 mmol) was reacted to give 11i as colorless oil
(51.8 mg, 43%). HPLC (Daicel Chiralpak AD, hexane–i-
PrOHZ9:1): 79% ee. IR (neat): 2927, 2857, 1733, 1609,
1461, 1359, 1277, 1116, 1086, 1031, 914, 802, 745, 716,
694, 604 cmK1; 1H NMR (300 MHz, CDCl3): d 0.89 (t, JZ
6.7 Hz, 3H), 1.24–1.62 (m, 10H), 1.66–1.78 (m, 1H), 1.82–
1.96 (m, 1H), 2.90 (dd, JZ4.1, 16.2 Hz, 1H), 2.99 (dd, JZ
10.6, 16.2 Hz, 1H), 4.47–4.58 (m, 1H), 7.24 (d, JZ7.6 Hz,
1H), 7.38 (t, JZ7.6 Hz, 1H), 7.53 (dt, JZ1.3, 7.6 Hz, 1H),
8.09 (d, JZ7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): d
14.07, 22.60, 24.89, 29.11, 29.32, 31.72, 33.18, 34.94,
78.68, 125.09, 127.19, 127.40, 130.06, 133.45, 139.06,
165.49; [a]2D5ZK50.4 (c 1.01, MeOH, 79% ee). HREIMS
m/z. Calcd for C16H22O2 (MC): 246.1620. Found 246.1624.
2.34 (s, 3H), 2.80 (dd, JZ2.0, 6.0 Hz, 1H), 3.12 (dd, JZ4.0,
6.0 Hz, 1H), 3.83 (dd, JZ2.0, 4.0 Hz, 1H), 7.17 (s, 4H);
HPLC (Daicel Chiralpak AS, hexane–i-PrOHZ30:1):
97% ee; [a]2D6ZC26.7 (c 1.12, benzene), {lit.13 [a]D22Z
K25.9 (c 1.02, benzene): (S)-isomer (97% ee)}.
4.7.3. (R)-Heptyloxirane (16c). Bp 40–50 8C (1.0 mmHg,
1
bulb-to-bulb); H NMR (300 MHz, CDCl3): d 0.87 (t, JZ
6.0 Hz, 3H), 1.20–1.60 (m, 12H), 2.46 (dd, JZ3.5, 6.0 Hz,
1H), 2.75 (t, JZ6.0 Hz, 1H), 2.85–2.95 (m, 1H); [a]2D4Z
C7.21 (c 1.01, CHCl3), {lit.14 [a]D24ZK8.9 (c 1.14,
CHCl3): (S)-isomer (O97% ee)}. Optical purity of 16c
was estimated to be 81% ee from the lit. [a]D.
4.7.4. (R)-(2-Phenylethyl)oxirane (16d). Bp 90–110 8C
(7.0 mmHg, bulb-to-bulb); H NMR (300 MHz, CDCl3): d
1
1.76–1.93 (m, 2H), 2.47 (dd, JZ3.5, 5.0 Hz, 1H), 2.65–2.90
(m, 3H), 2.90–3.00 (m, 1H), 7.12–7.36 (m, 5H); HPLC
(Daicel Chiralcel OD-H, hexane–i-PrOHZ9:1): 78% ee;
[a]D26ZC15.8 (c 1.24, acetone), {lit.15 [a]2D3ZC16.4 (c 1.4,
acetone): (R)-isomer (96% ee)}.
4.7. Synthesis of chiral epoxides 16. General procedure
AD-mix-b (14 g) was dissolved in a mixture of tert-butyl
alcohol (50 mL) and water (50 mL). The olefin 13
(10 mmol) was added dropwise to this mixture at 0 8C.
After being stirred for 18 h at 0 8C, Na2SO3 (15 g,
119 mmol) was added to the mixture. The mixture was
extracted with diethyl ether and the extract was washed
successively with water and brine, dried over Na2SO4, and
evaporated under reduced pressure. The residue was
purified by column chromatography over Silica Gel 60N
using hexane–ethyl acetateZ1:1 as an eluent. Yields of the
diol intermediates 14 after chromatography are shown in
Scheme 4.
4.8. Synthesis of chiral 3,4-dihydroisocoumarins 18.
General procedure
Under an argon atmosphere, a hexane-cyclohexane solution
of sec-BuLi (3.1 mmol) was added dropwise to a solution
of oxazoline 17 (491 mg, 2.8 mmol) in THF (5.0 mL) at
K78 8C. After being stirred for 1 h, the reaction mixture
was added dropwise to a suspension of copper cyanide
(125 mg, 1.4 mmol) at K78 8C. The mixture was gradually
warmed to K20 8C over 3 h, and then cooled to K78 8C.
The epoxide 16 in THF (2.0 mL) was added to the mixture
at K78 8C. The mixture was gradually warmed to 0 8C over
p-Toluenesulfonyl chloride (1.29 g, 6.76 mmol) was added
portionwise to a solution of diol 14 (6.14 mmol) in pyridine
(5 mL) at 0 8C. After being stirred for 13 h at 0 8C, the

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Y. Kurosaki et al. / Tetrahedron 61 (2005) 3289–3303
4 h and then stirred for additional 12 h at 0 8C. The reaction
mixture was quenched with a mixture of 28% aqueous NH3
(10 mL) and saturated aqueous NH4Cl (15 mL) and the
product was extracted with diethyl ether. The extract was
washed successively with water and brine, dried over
Na2SO4, and evaporated under reduced pressure. The
residue was dissolved in 36 mL of a mixed solvent (THF–
H2O–TFAZ10:1.5:0.5) at room temperature. After being
stirred for 14 h, the mixture was quenched with saturated
aqueous NaHCO3 and the product was extracted with
diethyl ether. The extract was washed successively with
water and brine, dried over Na2SO4, and evaporated under
reduced pressure. The residue was purified by column
chromatography over Silica Gel 60N using the following
eluents: hexane–ethyl acetateZ10:1 for 18a and 18b;
hexane–ethyl acetateZ5:1 for 18c and 18d.
evaporated under reduced pressure. The residue was
purified by column chromatography over Silica Gel 60N
(hexane–ethyl acetateZ10:1) to give 19 (14.1 mg, 70%).
HPLC (Daicel Chiralpak AS, hexane–i-PrOHZ7:3):
O99% ee. [a]2D5ZK38.1 (c 0.705, MeOH). Other spectro-
scopic data are identical with those of 18d.
References and notes
1. For reviews, see: (a) Gschwend, H. W.; Rodriguez, H. R. Org.
React. 1979, 26, 1–360. (b) Snieckus, V. Chem. Rev. 1990, 90,
879–933. (c) Queguiner, G.; Marsais, F.; Snieckus, V.;
Epsztajn, J. Adv. Heterocycl. Chem. 1991, 56, 187–304.
(d) Rewcastle, G. W.; Katritzky, A. R. Adv. Heterocycl. Chem.
1993, 52, 155–302. (e) Gray, M.; Tinkl, M.; Snieckus, V. In
McKillop, A., Ed.; Comprehensive Organometallic Chemistry
II; Pergamon: Oxford, 1995; Vol. 11. (f) Clayden, J.
Organolithiums: Selectivity for Synthesis; Pergamon: Oxford,
2002.
4.8.1. (S)-3-Phenyl-3,4-dihydroisocoumarin (18a).
According to the general procedure, 16a (120 mg,
1.0 mmol) was reacted to give 18a as colorless solid
(58.4 mg, 27%). HPLC (Daicel Chiralpak AD, hexane–i-
PrOHZ7:3): 98% ee. Mp 73.0–75.0 8C; [a]2D5ZK151 (c
1.53, MeOH). Other spectroscopic data are identical with
those of 11a.
2. For reviews, see: (a) Clark, R. D.; Jahangir, A. Org. React.
1995, 47, 1–314.(b) Ref. 1e, pp 73–85.
3. (a) Gschwend, H. W.; Hamden, A. J. Org. Chem. 1975, 40,
2008–2009. (b) Meyers, A. I.; Mihelich, E. D. J. Org. Chem.
1975, 40, 3158–3159. For a review, see: (c) Reuman, M.;
Meyers, A. I. Tetrahedron 1985, 41, 837–860.
4.8.2. (S)-3-(p-Tolyl)-3,4-dihydroisocoumarin (18b).
According to the general procedure, 16b (134 mg,
1.0 mmol) was reacted to give 18b as colorless solid
(62.4 mg, 26%). HPLC (Daicel Chiralpak AD, hexane–i-
PrOHZ7:3): 98% ee. Mp 88.0–90.0 8C; [a]2D5ZK124
(c 1.46, MeOH). Other spectroscopic data are identical
with those of 11b.
4. Tahara, N.; Fukuda, T.; Iwao, M. Tetrahedron Lett. 2002, 43,
9069–9072.
5. Tahara, N.; Fukuda, T.; Iwao, M. Tetrahedron Lett. 2004, 45,
5117–5120.
¨
6. (a) Bestmann, H. J.; Kern, F.; Schafer, D.; Witschel, M. C.
4.8.3. (R)-3-Heptyl-3,4-dihydroisocoumarin (18c).
According to the general procedure, 16c (142 mg,
1.0 mmol) was reacted to give 18c as colorless oil
(94.8 mg, 38%). HPLC (Daicel Chiralpak AD, hexane–i-
PrOHZ9:1): 84% ee. [a]D25ZK51.9 (c 1.00, MeOH). Other
spectroscopic data are identical with those of 11i.
Angew. Chem., Int. Ed. Engl. 1992, 31, 795–796.
(b) Choukchou-Braham, N.; Asakawa, Y.; Lepoittenvin, J.-P.
Tetrahedron Lett. 1994, 35, 3949–3952. (c) Ramacciotti, A.;
Fiaschi, R.; Napolitano, E. J. Org. Chem. 1996, 61,
5371–5374. (d) Superchi, S.; Minutolo, F.; Pini, D.; Salvadori,
P. J. Org. Chem. 1996, 61, 3183–3186. (e) Salvadori, P.;
Superchi, S.; Minutolo, F. J. Org. Chem. 1996, 61, 4190–4191.
(f) Uchida, K.; Watanabe, H.; Kitahara, T. Tetrahedron 1998,
54, 8975–8984. (g) Arnoldi, A.; Bassoli, A.; Merlini, L.; Ragg,
E. Gazz. Chim. Ital. 1992, 122, 403–407. (h) Hamada, Y.;
Hara, O.; Kawai, A.; Kohno, Y.; Shioiri, T. Tetrahedron 1991,
47, 8635–8652. (i) Ward, R.; Procter, G. Tetrahedron 1995,
51, 12301–12318. (j) Broady, S. D.; Rexhausen, J. E.; Thomas,
E. J. J. Chem. Soc., Perkin Trans. 1 1999, 1083–1094.
(k) Regan, A. C.; Staunton, J. J. Chem. Soc., Chem. Commun.
1983, 764–765. (l) Regan, A. C.; Staunton, J. J. Chem. Soc.
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4.8.4. (R)-3-(2-Phenylethyl)-3,4-dihydroisocoumarin
(18d). According to the general procedure, 16d (148 mg,
1.0 mmol) was reacted to give 18d as colorless oil (157 mg,
62%). HPLC (Daicel Chiralpak AS, hexane–i-PrOHZ7:3):
79% ee. IR (neat): 3063, 3028, 2948, 1722, 1606, 1496,
1456, 1362, 1280, 1159, 1123, 1030, 942, 913, 803, 745,
1
701, 605 cmK1; H NMR (300 MHz, CDCl3): d 1.96–2.08
(m, 1H), 2.16–2.29 (m, 1H), 2.79–3.07 (m, 4H), 4.47–4.56
(m, 1H), 7.16–7.33 (m, 6H), 7.38 (t, JZ7.6 Hz, 1H), 7.52
(dt, JZ1.4, 7.6 Hz, 1H), 8.10 (dd, JZ1.1, 7.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3): d 30.98, 33.21, 36.57, 77.49,
124.95, 125.95, 127.17, 127.45, 128.31, 128.35, 130.07,
133.51, 138.85, 140.71, 165.32; [a]2D5ZK30.4 (c 1.00,
MeOH). HREIMS m/z. Calcd for C17H16O2 (MC):
252.1150. Found 252.1056.
7. For an achiral version, see: Fu, P. P.; Unruh, L. E.; Miller,
D. W.; Huang, L. W.; Yang, D. T. C. J. Org. Chem. 1985, 50,
1259–1261.
8. The lithiated 1a is extremely reactive towards oxygen to
produce the corresponding benzyl alcohol. Precautions are
necessary to achieve good yields of the desired products. We
used a rather thick rubber tube to connect reaction flask to
argon line to prevent diffusion of aerial oxygen through the
tube. The sensitivity of a similar o-toluamide anion to oxygen
has been reported, see: Davis, F. A.; Mohantly, P. K.; Bums,
D. M.; Andemichael, Y. W. Org. Lett. 2000, 2, 3901–3903.
9. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.;
4.9. Catalytic hydrogenation of 11g
Under a hydrogen atmosphere, a mixture of 3,4-dihydro-
isocoumarin 11g (O99% ee) (20.0 mg, 0.0799 mmol), 5%
palladium carbon (2.0 mg), and ethanol (2.0 mL) was
vigorously stirred at room temperature for 8 h. The mixture
was passed through a pad of Celite and the filtrate was

Y. Kurosaki et al. / Tetrahedron 61 (2005) 3289–3303
3303
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