Stereoselective reactions. Part 31: Catalytic asymmetric alkylation of achiral lithium enolates using a chiral tetradentate amine in the presence of an achiral bidentate amine

Article abstract of DOI:10.1016/S0040-4020(99)00995-3

Catalytic asymmetric alkylation of achiral lithium enolates of 1- tetralone and cyclohexanone with reactive alkyl halides was realized by using a combination of a chiral tetradentate amine (~0.05 equiv.) and an achiral bidentate amine (2 equiv.).

Full text of DOI:10.1016/S0040-4020(99)00995-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 179–185
Stereoselective Reactions. Part 31:1 Catalytic Asymmetric
Alkylation of Achiral Lithium Enolates Using a Chiral
Tetradentate Amine in the Presence of an
Achiral Bidentate Amine
,†
*
Mitsuko Imai, Atsushi Hagihara, Hisashi Kawasaki, Kei Manabe and Kenji Koga
Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 12 October 1999; accepted 8 November 1999
Abstract—Catalytic asymmetric alkylation of achiral lithium enolates of 1-tetralone and cyclohexanone with reactive alkyl halides was
realized by using a combination of a chiral tetradentate amine (ϳ0.05 equiv.) and an achiral bidentate amine (2 equiv.). ᭧ 1999 Elsevier
Science Ltd. All rights reserved.
Introduction
of ligands to the lithium in situ,6 efforts were made to
achieve catalytic version of this enantioselective
a
alkylation reaction using a catalytic amount of a tetradentate
amine ((R)-1) in the presence of 2 equiv. of an achiral
bidentate amine as an additive.7
Lithium enolates play a central role in organic synthesis,
because they react with various electrophiles to undergo
many synthetically important reactions, such as alkylation,
acylation, aldolization, protonation, etc.2 It is also known
that the lithium enolate prepared from a carbonyl compound
and a lithium amide forms a complex in solution with the
amine coming from the lithium amide employed.3 It is
therefore reasonable to assume that the achiral lithium
enolate prepared by using a chiral lithium amide forms a
complex with the chiral amine coming from the chiral
lithium amide employed, where the symmetrical p-system
of the enolate is expected to exist in a chiral environment,
and reacts with electrophiles enantioselectively.
Results and Discussion
As shown in Scheme 1, the trimethylsilyl enol ether (2) of
1-tetralone was treated with 1.0 equiv. of MeLi–LiBr in
ether to give the corresponding lithium enolate (3) containing
LiBr. After addition of (R)-1 and an achiral additive in a
given solvent, benzyl bromide (10 equiv.) was added and
the whole was stirred at Ϫ45ЊC for 18 h. Some results
using N,N,N0,N0-tetramethylethylenediamine (TMEDA), an
achiral bidentate amine, as an additive are summarized in
Table 1.
Based on this strategy, we have previously reported enantio-
selective alkylation of achiral lithium enolates of six-
membered cyclic ketones using a stoichiometric amount
of a chiral tetradentate amine in the presence of lithium
bromide (LiBr) in toluene.1,4 It is suggested that the for-
mation of a ternary complex comprising lithium enolate,
chiral tetradentate amine, and LiBr is responsible for high
asymmetric induction. It is also shown that the rate of the
alkylation reaction of the lithium enolate of 1-tetralone is
slow in the absence and in the presence of a bidentate amine,
but is enhanced significantly in the presence of a tetra-
dentate amine.1,5 Expecting the fast exchange of two kinds
First, the reaction was examined in toluene. Without (R)-1
and TMEDA, the reaction practically did not proceed (run
1) with 86% recovery of 1-tetralone, while in the presence
of 2 equiv. of TMEDA, racemic 4a was obtained in 12%
yield (run 2). In the presence of 1 equiv. of (R)-1, (R)-4a
was obtained with 97% ee in 56% isolated yield (run 3).
These results demonstrate that (R)-1 accelerates the reaction
of 3, presumably due to the deaggregation of the lithium
enolate and formation of the complex with (R)-1 and LiBr.
However, on reducing the amount of (R)-1 to a substoichio-
metric amount (0.2 equiv.), the product was obtained in less
than 1% yield with 87% recovery of 1-tetralone (run 4). We
assumed that this result might come from the deactivation of
(R)-1 by complexation with LiBr, because of the presence
of LiBr in a large excess relative to (R)-1 at the beginning of
* Corresponding author. Tel.: ϩ81-743-72-6170; fax: ϩ81-743-72-6179;
e-mail: kkoga@ms.aist-nara.ac.jp
†
Present address: Research and Education Center for Materials Science,
Nara Institute of Science and Technology, Ikoma-shi, Nara 630-0101,
Japan.
0040–4020/00/$ - see front matter ᭧ 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)00995-3

180
M. Imai et al. / Tetrahedron 56 (2000) 179–185
Scheme 1.
Table 1. Benzylation of 3 using (R)-1 in the absence and in the presence of TMEDA (typical procedures are described in the experimental section)
Run
(R)-1 (equiv.)
TMEDA (equiv.)
Solvent
Product ((R)-4a)
Isolated yield (%)
ee (%)
1
2
3
4
0
0
0
2.0
0
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DME
DME
DME
DME
DME
Cyclopentane
Ether
THF
Ͻ1
12
56
Ͻ1
68
89
90
87
80
37
28
32
92
82
79
38
40
42
–
–
1.0
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0
97
52
87
86
78
87
79
52
–
0
5
1.0
2.0
2.0
3.0
4.0
8.0
0
2.0
0
0
6
7a
8
9
10
11
12
13
14
15
16
17
18
0
–
1.0
0.2
0.2
0.2
0.2
0.2
94
82
92
50
78
77
2.0
2.0
2.0
2.0
a The result using a halide-free solution of MeLi in ether for the generation of 3.
the reaction. Therefore, TMEDA was added as an additive
with the intention of trapping LiBr. Both the chemical yield
and ee were then increased greatly (runs 5–10). The best
result was obtained by using 2.0 or 3.0 equiv. of TMEDA
(runs 6 and 8). As was observed previously,4a the ee of the
product decreased when LiBr was absent at the beginning of
the reaction (run 7).
The effect of various achiral additives (2.0 equiv.) on the
benzylation of 3 using 0.2 equiv. of (R)-1 was then
examined in toluene. The results are shown in Table 2. Of
linear terminal diamines (runs 1–7), TMEDA and
N,N,N0,N0-tetramethylpropylenediamine (5) were found to
be excellent additives with respect to both chemical and
optical yields of the product (runs 2 and 3), probably
The situation is somewhat different in DME. Thus, without
(R)-1 and TMEDA, the product was obtained in 28% yield
Table 2. Effect of additives (2 equiv.) on the benzylation of 3 using
0.2 equiv. of (R)-1 in toluene (a typical procedure is described in the
experimental section)
(run 11), which is higher than that obtained in toluene (run
1). This result suggests that the lithium enolate is deaggre-
gated to some extent in DME. In the presence of 2 equiv. of
TMEDA, the chemical yield of the product was not
improved (run 12). However, in the presence of 1.0 equiv.
of (R)-1, (R)-4a was obtained in reasonably good chemical
and optical yields (run 13). Contrary to the reaction in tolu-
ene, reducing the amount of (R)-1 to 0.2 equiv. gave (R)-4a
in still higher chemical and optical yields (run 14), but a
better result was obtained in the presence of 0.2 equiv. of
(R)-1 and 2.0 equiv. of TMEDA (run 15). It is reasonable to
assume that DME can work, to some extent, to trap LiBr.
The chemical yield and ee of the product were found to be
dependent on the solvent used (runs 6, 15–18). Among the
solvents examined, toluene and DME were most effective
for the present catalytic asymmetric benzylation.
Run Additive
Product ((R)-4a)
Isolated yield (%) ee (%)
1
2
3
4
5
6
7
8
9
Me2N–CH2–NMe2
Ͻ3
89
83
42
63
38
30
15
9
83
86
92
93
86
96
88
86
95
95
47
Me2N–(CH2)2–NMe2 (TMEDA)
Me2N–(CH2)3–NMe2 (5)
Me2N–(CH2)4–NMe2
(CH2)5N–(CH2)2–N(CH2)5
(CH2)5N–(CH2)3–N(CH2)5
H2N–(CH2)2–NH2
MeO–(CH2)2–OMe (DME)
Me2N–CH2CH3
10a Me2N–CH2CH3
9
11
Me2N–(CH2)2–N(Me)–(CH2)2–NMe2 87
a The result using 4.0 equiv. of an additive.

M. Imai et al. / Tetrahedron 56 (2000) 179–185
181
Table 3. Benzylation of 3 with catalytic amount of (R)-1 in the presence of
5 (2.0 equiv.) (typical procedures are described in the experimental section)
because they trap LiBr effectively by the formation of a five-
or six-membered chelated structure. Changing the two
terminal dimethylamino groups to the more hindered
piperidino groups (runs 5 and 6), or to the less hindered
amino groups (run 7) and methoxy groups (run 8) gave
poorer yields, while the ee of the product remained high.
The results using monodentate and tridentate ligands (runs
9–11) suggest that the bidentate ligands function more
effectively.
Run
(R)-1 (equiv.)
Solvent
Product ((R)-4a)
Isolated yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
0.2
0.1
Toluene
Toluene
Toluene
Toluenea
Toluene
Toluene
DME
DME
DME
DME
83
78
76
82
69
29
86
91
91
55
92
95
96
95
97
89
92
93
90
48
0.05
0.05
0.025
0.01
0.2
0.1
0.05
0.01
Selecting 5 as an achiral bidentate additive in the present
catalytic asymmetric benzylation reaction using (R)-1, the
effect of decreasing the amount of (R)-1 was examined. The
results obtained with 2.0 equiv. of 5 in toluene and in DME
are summarized in Table 3. In both toluene (runs 1–6) and
DME (runs 7–10), good chemical and optical yields were
a In toluene containing DME (32 equiv.).
Scheme 2.
Table 4. Benzylation of 7 using (R)-1 and 5 in toluene (a typical procedure
is described in the experimental section)
retained, up to 0.05 equiv. of (R)-1. It is generally
recognized that chemical yields are a little higher in
DME, while the ees of the product are a little higher in
toluene under the present catalytic conditions.
Run
(R)-1 (equiv.)
5 (equiv.)
Product ((R)-8)
Isolated yield (%)
ee (%)
Benzylation reaction of the lithium enolate (7) of cyclo-
hexanone was also examined using (R)-1 and 5 in toluene.
The results are shown in Table 4. These results demonstrate
that (R)-1 also functions as a catalyst for the benzylation of 7
(Scheme 2).
1a
2
3
1.0
0.2
0.1
0.05
0
43
52
52
47
91
92
90
75
2.0
2.0
2.0
4
a Data taken from Ref. 1.
Scheme 3.
Based on these data, catalytic asymmetric alkylation of 3
with reactive alkyl halides was examined in toluene using
0.05 equiv. of (R)-1 and 2.0 equiv. of 5. The results are
summarized in Table 5. It is again shown that chiral (R)-1
turns over efficiently by addition of achiral 5 (Scheme 3).
Table 5. Catalytic asymmetric alkylation of 3
Run
R–X
Product
4
Isolated yield (%)
ee (%)
1
2
CH2yCH–CH2Br
Me2CyCH–CH2Br
PhCHyCHCH2Br
MeO2C–CH2Br
MeI
(R)-4b
(R)-4c
(R)-4d
(R)-4e
(S)-4f
69
62
69
84
28
96
97
91
81
77
The absolute configurations of (R)-4a,4a (R)-4d,4a (S)-4f,8
and (R)-88 are already known. As shown in Scheme 4,
(R)-4b and (R)-4c were chemically correlated to (R)-4e,
whose absolute configuration was determined by circular
dichroism.4a,9,10
3
4a
5
a Alkylation time was 40.5 h.

182
M. Imai et al. / Tetrahedron 56 (2000) 179–185
Scheme 4.
Conclusion
hexane/2-propanolˆ9/1)) as a colorless oil. [a]2D5 ϩ18.1
identical to those reported previously.1
(cˆ1:81; MeOH). Spectral data (IR, 1H NMR) were
Catalytic asymmetric alkylation of the lithium enolates of
1-tetralone and cyclohexanone with reactive alkyl halides in
the presence of LiBr was realized by the turnover of a chiral
tetradentate amine ((R)-1) (ϳ0.05 equiv.) by addition of an
achiral bidentate amine (5) (2.0 equiv.) as an additive. It is
assumed that 5 works to prevent deactivation of (R)-1 by
trapping LiBr, which exists in a large excess relative to
(R)-1 at the beginning of the reaction. Since the reactions
of lithium enolates with electrophiles constitute the most
fundamental and widely used processes in synthesis, the
method mentioned here should provide a useful strategy
for catalytic asymmetric reactions of achiral lithium
enolates.
(b) (Table 1, run 4) Under argon atmosphere, a solution of
MeLi–LiBr in ether (1.17N, 0.87 mL, 1.02 mmol) was
added to 2 (223.0 mg, 1.02 mmol), and the whole was
stirred at room temperature for 1.5 h. After addition of
toluene (7 mL) at Ϫ20ЊC, a solution of (R)-1 (68.0 mg,
0.20 mmol) in toluene (5 mL) was added, and the whole
was stirred at Ϫ20ЊC for 30 min. A solution of benzyl bro-
mide (1.21 mL, 10.2 mmol) in toluene (2 mL) was added at
Ϫ78ЊC, and the whole was treated as in (a) above to give a
residue after evaporation of the dried ethereal extracts. This
residue was subjected to column chromatography (silica gel,
hexane/etherˆ50/1) to give (R)-4a (1.0 mg, 0.4%, 52% ee
by HPLC analysis) as a colorless oil. Further elution using
hexane/ether (10/1) gave 1-tetralone (130.3 mg, 87%) as a
colorless oil.
Experimental
General
(c) (Table 1, run 6) Under argon atmosphere, a solution of
MeLi–LiBr in ether (1.17N, 0.83 mL, 0.97 mmol) was
added to 2 (212.8 mg, 0.97 mmol), and the whole was
stirred at room temperature for 1.5 h. After addition of
toluene (7 mL) at Ϫ20ЊC, a solution of (R)-1 (65.4 mg,
0.20 mmol) in toluene (5 mL) and then TMEDA
(0.29 mL, 1.95 mmol) were added, and the whole was
stirred at Ϫ20ЊC for 30 min. A solution of benzyl bromide
(1.16 mL, 9.7 mmol) in toluene (2 mL) was added at
Ϫ78ЊC, and the whole was treated as in (a) above to give
a residue after evaporation of the dried ethereal extracts.
The residue was subjected to column chromatography
(silica gel, hexane/etherˆ50/1) to give (R)-4a (203.8 mg,
89%, 86% ee by HPLC analysis) as a colorless oil.
IR spectra were recorded on a JASCO Report-100 spectro-
1
meter. H NMR (270 MHz) and 13C NMR (67.80 MHz)
spectra were recorded in CDCl3 on a JEOL EX-270 spectro-
meter. Chemical shifts are given in d (ppm) using tetra-
methylsilane as an internal standard. Coupling constants
(J) are given in hertz. Mass spectra (MS, HRMS) were
recorded on a JEOL JMS-D 300 or JEOL JMS-SX 102
spectrometer. Optical rotations were measured by a Jasco
DIP-370 polarimeter. For anhydrous solvents, toluene,
ether, THF, DME, and cyclopentane were distilled from
sodium/benzophenone ketyl under argon atmosphere.
(R)-1,11 2,1 and 61 were prepared as reported.
(R)-2-Benzyl-1-tetralone ((R)-4a). (a) (Table 1, run 3)
Under argon atmosphere, a solution of MeLi–LiBr in
ether (1.17N, 0.89 mL, 1.05 mmol) was added to 2
(228.2 mg, 1.05 mmol), and the whole was stirred at room
temperature for 1.5 h. After addition of toluene (7 mL) at
Ϫ20ЊC, a solution of (R)-1 (347.5 mg, 1.05 mmol) in
toluene (5 mL) was added, and the whole was stirred at
Ϫ20ЊC for 30 min. A solution of benzyl bromide
(1.24 mL, 10.5 mmol) in toluene (2 mL) was added at
Ϫ78ЊC, and the whole was stirred at Ϫ45ЊC for 18 h.
After the reaction mixture was cooled to Ϫ78ЊC, 10%
aqueous citric acid (10 mL) was added, and the whole was
allowed to warm to room temperature. The reaction mixture
was extracted with ether (20 mL) twice, and the ethereal
extracts were combined and washed with satd. aqueous
NaHCO3 (20 mL) and brine (20 mL). After drying
(MgSO4), the solvent was evaporated to dryness to give a
residue, which was purified by column chromatography
(silica gel, hexane/etherˆ50/1) to give (R)-4a (137.2 mg,
56%, 97% ee by HPLC analysis (Waters Opti-Pak TA,
(d) (Table 1, run 15) Under argon atmosphere, a solution of
MeLi–LiBr in ether (1.16N, 0.93 mL, 1.07 mmol) was
added to 2 (234.7 mg, 1.07 mmol), and the whole was
stirred at room temperature for 1.5 h. After addition of
DME (7 mL) at Ϫ20ЊC, a solution of (R)-1 (70.9 mg,
0.21 mmol) in DME (5 mL) and then TMEDA (0.32 mL,
2.15 mmol) were added, and the whole was stirred at Ϫ20ЊC
for 30 min. A solution of benzyl bromide (1.28 mL,
10.7 mmol) in DME (2 mL) was added at Ϫ78ЊC, and the
whole was treated as in (a) above to give a residue after
evaporation of the dried ethereal extracts. The residue was
subjected to column chromatography (silica gel, hexane/
etherˆ60/1) to give (R)-4a (200.6 mg, 79%, 92% ee by
HPLC analysis) as a colorless oil. Further elution using
hexane/ether (10/1) gave 1-tetralone (14.9 mg, 9%) as a
colorless oil.
(e) (Table 2, run 3) Under argon atmosphere, a solution of
MeLi–LiBr in ether (1.17N, 0.86 mL, 1.00 mmol) was

M. Imai et al. / Tetrahedron 56 (2000) 179–185
183
added to 2 (218.9 mg, 1.00 mmol), and the whole was
less oil. [a]2D5 Ϫ29.9 (c ˆ 1:29; MeOH). IR (neat) cmϪ1
:
stirred at room temperature for 1.5 h. After addition of
toluene (7 mL) at Ϫ20ЊC, a solution of (R)-1 (66.7 mg,
0.20 mmol) in toluene (5 mL) and then 5 (0.34 mL,
2.0 mmol) were added, and the whole was stirred at
Ϫ20ЊC for 30 min. A solution of benzyl bromide
(1.19 mL, 10.0 mmol) in toluene (2 mL) was added at
Ϫ78ЊC, and the whole was treated as in (a) above to give
a residue after evaporation of the dried ethereal extracts.
The residue was subjected to column chromatography
(silica gel, hexane/etherˆ50/1) to give (R)-4a (196.5 mg,
83%, 92% ee by HPLC analysis) as a colorless oil.
1675, 1635, 1600. 1H NMR: 1.78–1.95 (1H, m, CH2–
CHH–CH), 2.18–2.82 (4H, m, CH2–CHH–CH, CH2–
CHyCH), 3.0 (2H, m, Ar-CH2), 5.07 (1H, d, Jˆ9.9,
–CHyCHH), 5.11 (1H, d, Jˆ11.9, –CHyCHH), 5.77–
5.93 (1H, m, –CHyCH2), 7.15–7.35 (2H, m, ArH), 7.46
(1H, t, Jˆ11,9, ArH), 8.04 (1H, Jˆ7.9, ArH). Racemic 4b
is reported.12
(R)-2-Prenyl-1-tetralone ((R)-4c). Under argon atmos-
phere, a solution of MeLi–LiBr in ether (1.07N, 0.95 mL,
1.02 mmol) was added to 2 (224.4 mg, 1.02 mmol), and the
whole was stirred at room temperature for 1.5 h. After
addition of toluene (7 mL), a solution of (R)-1 (17.2 mg,
0.051 mmol) in toluene (5 mL) and then 5 (0.34 mL,
2.0 mmol) were added, and the whole was stirred at
(f) (Table 3, run 3) Under argon atmosphere, a solution of
MeLi–LiBr in ether (1.16N, 0.88 mL, 1.02 mmol) was
added to 2 (222.4 mg, 1.02 mmol), and the whole was
stirred at room temperature for 1.5 h. After addition of
toluene (7 mL) at Ϫ20ЊC, a solution of (R)-1 (17.1 mg,
0.051 mmol) in toluene (5 mL) and then 5 (0.34 mL,
2.0 mmol) were added, and the whole was stirred at
Ϫ20ЊC for 30 min. A solution of benzyl bromide
(1.21 mL, 10.2 mmol) in toluene (2 mL) was added at
Ϫ78ЊC, and the whole was treated as in (a) above to give
a residue after evaporation of the dried ethereal extracts.
The residue was subjected to column chromatography
(silica gel, hexane/etherˆ60/1) to give (R)-4a (182.3 mg,
76%, 96% ee by HPLC analysis) as a colorless oil. Further
elution using hexane/ether (10/1) gave 1-tetralone (20.7 mg,
14%) as a colorless oil.
Ϫ20ЊC for 30 min.
A solution of prenyl bromide
(1.17 mL, 10.2 mmol) in toluene (2 mL) was added at
Ϫ78ЊC, and the whole was treated as in (a) for the synthesis
of (R)-4a above to give a residue after evaporation of the
dried ethereal extracts. The residue was subjected to column
chromatography (silica gel 50 g, hexane/etherˆ60/1) to
give (R)-4c (136.3 mg, 62%, 97% ee by HPLC analysis
(Waters Opti-Pak TA, hexane/2-propanolˆ500/1)) as a
colorless oil. [a]2D5 Ϫ17.9 (c ˆ 1:51; MeOH). IR (neat)
1
cmϪ1: 1680, 1600. H NMR: 1.64 (3H, s, –CH3), 1.72
(3H, s, –CH3), 1.75–1.95 (1H, m, –CH2–CHH–CH2–),
2.15–2.30 (2H, m, –CH2–CHH–CH2– and –CHH–CHy),
2.45–2.55 (1H, m, –CO–CH), 2.60–2.75 (1H, m, –CHH–
CHy), 2.98 (2H, dd, Jˆ7.4, 7.6, Ar-CH2), 5.18 (1H, dd,
Jˆ7.9, 7.6, –CH2–CHyC), 7.23 (1H, d, Jˆ7.6, ArH),
7.30 (1H, t, Jˆ7.3, ArH), 7.46 (1H, t, Jˆ7.3, ArH), 8.04
(1H, d, Jˆ7.6, ArH). 13C NMR: 17.88, 25.86, 27.98, 28.10,
28.64, 48.07, 121.80, 126.54, 127.44, 128.68, 132.61,
133.10, 133.53, 144.13, 200.00. MS m/z: 214 (Mϩ).
HRMS m/z: Calcd for C15H18O: 214.1358. Found:
214.1359.
(R)-2-Benzylcyclohexanone ((R)-8). (Table 4, run 3) Under
argon atmosphere, a solution of MeLi–LiBr in ether (1.16N,
0.94 mL, 1.09 mmol) was added to
6
(185.1 mg,
1.09 mmol), and the whole was stirred at room temperature
for 1.5 h. After addition of toluene (7 mL) at Ϫ20ЊC, a
solution of (R)-1 (36.6 mg, 0.11 mmol) in toluene (5 mL)
and then 5 (0.36 mL, 2.2 mmol) were added, and the whole
was stirred at Ϫ20ЊC for 30 min. A solution of benzyl bro-
mide (1.29 mL, 10.9 mmol) in toluene (2 mL) was added at
Ϫ78ЊC, and the whole was treated as in (a) for the synthesis
of (R)-4a above to give a residue after evaporation of the
dried ethereal extracts. The residue was subjected to column
chromatography (silica gel, hexane/etherˆ20/1) to give
(R)-8 (107.0 mg, 52%, 90% ee by HPLC analysis (Waters
Opti-Pak TA, hexane/2-propanolˆ300/1)) as a colorless oil.
Spectral data (IR, 1H NMR) were identical to those reported
previously.1
(R)-2-Cinnamyl-1-tetralone ((R)-4d). Under argon atmos-
phere, a solution of MeLi–LiBr in ether (1.16N, 0.81 mL,
0.94 mmol) was added to 2 (204.0 mg, 0.93 mmol), and the
whole was stirred at room temperature for 1.5 h. After
addition of toluene (7 mL), a solution of (R)-1 (15.8 mg,
0.047 mmol) in toluene (5 mL) and then 5 (0.31 mL,
1.9 mmol) were added, and the whole was stirred at
Ϫ20ЊC for 30 min. A solution of cinnamyl bromide
(1.84 g, 9.34 mmol) in toluene (2 mL) was added at
Ϫ78ЊC, and the whole was treated as in (a) for the synthesis
of (R)-4a above to give a residue after evaporation of the
dried ethereal extracts. The residue was subjected to column
chromatography (silica gel, hexane/etherˆ50/1 to 10/1) to
give (R)-4d (179.5 mg, 69%, 91% ee by HPLC analysis
(Waters Opti-Pak TA, hexane/2-propanolˆ100/1)) as a
pale yellow oil. [a]2D5 ϩ15.0 (cˆ1:00; EtOH) (reported1
[a]2D5 ϩ16.0 (cˆ1:02; EtOH) for (R)-4d of 88% ee).
Spectral data (IR, 1H NMR) were identical to those
reported.1
(R)-2-Allyl-1-tetralone ((R)-4b). Under argon atmosphere,
a solution of MeLi–LiBr in ether (1.16N, 0.82 mL,
0.95 mmol) was added to 2 (207.7 mg, 0.95 mmol), and
the whole was stirred at room temperature for 1.5 h. After
addition of toluene (7 mL) at Ϫ20ЊC, a solution of (R)-1
(16.2 mg, 0.048 mmol) in toluene (5 mL) and then 5
(0.32 mL, 1.9 mmol) were added, and the whole was stirred
at Ϫ20ЊC for 30 min. A solution of allyl bromide (0.82 mL,
9.51 mmol) in toluene (2 mL) was added at Ϫ78ЊC, and the
whole was treated as in (a) for the synthesis of (R)-4a above
to give a residue after evaporation of the dried ethereal
extracts. The residue was subjected to column chroma-
tography (silica gel, hexane/etherˆ60/1) to give (R)-4b
(122.3 mg, 69%, 96% ee by HPLC analysis (Daicel
Chiralcel OD-H, hexane/2-propanolˆ2000/1)) as a color-
(R)-2-Carbomethoxymethyl-1-tetralone ((R)-4e). (a) Under
argon atmosphere, a solution of MeLi–LiBr in ether (1.07N,
0.95 mL, 1.02 mmol) was added to
2
(221.4 mg,
1.01 mmol), and the whole was stirred at room temperature
for 1.5 h. After addition of toluene (7 mL), a solution of

184
M. Imai et al. / Tetrahedron 56 (2000) 179–185
(R)-1 (17.0 mg, 0.051 mmol) in toluene (5 mL) and then 5
(0.34 mL, 2.0 mmol) were added, and the whole was stirred
at Ϫ20ЊC for 30 min. A solution of methyl bromoacetate
(0.96 mL, 10.1 mmol) in toluene (2 mL) was added at
Ϫ78ЊC, and the whole was treated as in (a) for the synthesis
of (R)-4a above to give a residue after evaporation of the
dried ethereal extracts. The residue was subjected to column
chromatography (silica gel, hexane/etherˆ15/2) to give (R)-
4e (185.0 mg, 84%, 81% ee by HPLC analysis (Waters
Opti-Pak XC, hexane/2-propanolˆ100/1)) as a pale yellow
oil, which solidified on scratching. [a]2D5 Ϫ20.0 (cˆϪ1.07,
(41.9 mg, 28%, 77% ee by HPLC analysis (Daicel Chiralcel
1
OD-H, hexane/2-propanolˆ600/1)). Spectral data (IR, H
NMR) were identical to those reported.1
(R)-2-Formylmethyl-1-tetralone ((R)-9). Dried ozone-
oxygen gas was passed through a colorless solution of
(R)-4b ([a]2D5ˆϪ29.9 (cˆ1:29; MeOH), 96% ee by HPLC
analysis) (39.2 mg) in CH2Cl2 (1 mL) at Ϫ80ЊC for 5 min
until the resulting solution became blue-white. After
addition of CH2Cl2 (5 mL), argon gas was passed through
at Ϫ80ЊC until the resulting solution became colorless.
Dimethyl sulfide (0.2 mL) was added at Ϫ80ЊC, and the
resulting solution was stirred at 0ЊC for 10 min, and at
room temperature for 1.5 h. The whole was mixed with
CH2Cl2 (5 mL) and water (10 mL), and the aqueous layer
was extracted with CH2Cl2 (20 mL) twice. The organic
extracts were combined, washed with brine (10 ml), dried
over MgSO4, and evaporated to dryness. The residue was
subjected to column chromatography (silica gel, hexane/
etherˆ20/1) to give crude (R)-9 (24.0 mg, 61%) as a color-
less oil. This sample was used for the next step without
1
MeOH). IR (neat) cmϪ1: 1730, 1680. H NMR: 1.97 (1H,
dddd, Jˆ12.9, 12.7, 12.5, 4.6, CH–CHH–CH2), 2.2–2.3
(1H, m, CH–CHH–CH2), 2.44 (1H, dd, Jˆ17.7, 7.9, CH–
CHH–CO), 2.92–3.20 (4H, m, CO–CH–CHH–CO, Ar–
CH2), 3.37 (3H, s, OCH3), 7.22–7.33 (2H, m, ArH, 7.47
(1H, t, Jˆ7.6, ArH), 8.02 (1H, d, Jˆ7.6, ArH). 13C NMR:
29.27, 34.88, 44.80, 51.73, 126.66, 127.46, 128.75, 132.13,
133.42, 144.01, 173.01, 198.31. MS m/z: 218 (Mϩ). Race-
mic (R)-4e is reported.13 A sample ([a]2D5 Ϫ16.5 (cˆ1:20;
MeOH), 67% ee by HPLC analysis (Waters Opti-Pak XC,
hexane/2-propanolˆ100/1)) showed [u]365ˆϪ424 (cˆ1:20;
MeOH), indicating R-configuration.4a,9,10
1
further purification. IR (neat) cmϪ1: 1720, 1680. H NMR:
1.95 (1H, m, CH2–CHH–CH), 2.15–2.35 (1H, m, CH2–
CHH–CH), 2.55 (1H, m, CH–CHH–CO), 2.9–3.2 (4H,
m, CO–CH, Ar-CH2, CH–CHH–CO), 7.20–7.35 (2H,
ArH), 7.49 (1H, t, Jˆ7.6, ArH), 8.02 (1H, d, Jˆ7.6, ArH),
9.92 (1H, s, CHO). 13C NMR: 29.29, 29.45, 43.24, 44.26,
126.70, 127.48, 128.77, 131.95, 133.57, 144.01, 198.38,
200.63.
(b) A stirred suspension of nitrosomethylurea (1 g,
10 mmol) in ether (10 mL) was mixed with 50% aqueous
KOH (10 mL) at 0ЊC. The ethereal phase was separated and
dried over KOH. This CH2N2 solution (5 mL) was added
dropwise to a solution of (R)-10 (19 mg, 0.093 mmol)
obtained as described below in ether (10 mL) to give a
yellow solution. After quenching the reaction mixture
with AcOH (0.5 mL), H2O (20 mL) was added. The ethereal
phase was separated and the aqueous phase was extracted
with ether (20 mL) twice. The ethereal extracts were
combined, washed with satd. aqueous NaHCO3 (20 mL)
and brine (20 mL), dried over MgSO4, and evaporated to
dryness to give a residue. This residue was subjected to
column chromatography (silica gel, hexane/etherˆ60/1) to
give the product (9.7 mg, 48%). Spectral data (IR, 1H NMR)
were identical to those obtained in (a). By HPLC analysis,
this sample was found to have R-configuration of 82% ee.
(R)-2-Carboxymethyl-1-tetralone ((R)-10). A solution of
(R)-9 (24.0 mg, 0.13 mmol) obtained above in t-BuOH
(0.78 mL) was mixed with 5% aqueous NaH2PO4
(0.52 mL). Under vigorous stirring, aqueous KMnO4 (1N,
1.3 mL, 0.13 mmol) was slowly added, and the whole was
stirred at room temperature for 1.5 h. After addition of satd.
aqueous Na2SO3 (6 mL), the whole was mixed with 10%
aqueous HCl (11 mL) to pH 1, and was extracted with ether
(20 mL) four times. The organic extracts were combined,
washed with water (20 mL) and brine (20 mL), dried over
MgSO4, and evaporated to dryness to give crude (R)-10
(19.0 mg, 73%) as a yellow oil. This sample was used for
(c) (R)-4c (52.1 mg, 97% ee by HPLC analysis) described
above was converted to (R)-4e (30.8 mg, 58% yield) by the
sequence of reactions described below for the conversion of
(R)-4b to (R)-10, followed by treatment with CH2N2 to (R)-
4e described above in (b). Spectral data (IR, 1H NMR) were
identical to those obtained in (a). By HPLC analysis, this
sample was found to have R-configuration of 72% ee.
the next step without further purification. IR (neat) cmϪ1
:
1
1710, 1680. H NMR: 1.85–2.1 (1H, m, CH2–CHH–CH),
2.2–2.35 (1H, m, CH2–CHH–CH), 2.50 (1H, dd, Jˆ18.3,
8.3, CH–CHH–CO), 2.9–3.2 (4H, m, CH–CH2, Ar-CH2,
CH–CHH–CO), 7.2–7.35 (2H, m, ArH), 7.49 (1H,
t, Jˆ7.6, ArH), 8.03 (1H, d, Jˆ7.6, ArH).
(S)-2-Methyl-1-tetralone ((S)-4f). Under argon atmos-
phere, a solution of MeLi–LiBr in ether (1.16N, 0.81 mL,
0.94 mmol) was added to 2 (205.0 mg, 0.94 mmol), and the
whole was stirred at room temperature for 1.5 h. After
addition of toluene (7 mL), a solution of (R)-1 (15.6 mg,
0.047 mmol) in toluene (5 mL) and then 5 (0.31 mL,
1.9 mmol) were added, and the whole was stirred at
Ϫ20ЊC for 30 min. A solution of methyl iodide (0.58 mL,
9.4 mmol) in toluene (2 mL) was added at Ϫ78ЊC, and the
whole was treated as in (a) for the synthesis of (R)-4a above
to give a residue after evaporation of the dried ethereal
extracts. The residue was subjected to column chroma-
tography (silica gel, hexane/etherˆ60/1) to give (S)-4f
Acknowledgements
Financial support from the Ministry of Education, Science,
Sports and Culture of the Japanese Government is gratefully
acknowledged.
References
1. Part 30: Murakata, M.; Yasukata, T.; Aoki, T.; Nakajima, M.;
Koga, K. Tetrahedron 1998, 54, 2449.
2. (a) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry,
Part B: Reactions and Synthesis; Plenum: New York, 1990;

M. Imai et al. / Tetrahedron 56 (2000) 179–185
185
Chapters 1 and 2. (b) Mekelburger, H. B.; Wilcox, C. S. Compre-
hensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 3, Chapter 1.4. (c) Caine, D.
Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I.,
Eds.; Pergamon: Oxford, 1991; Vol. 3, Chapter 1.1.
Tetrahedron Lett. 1996, 37, 8195. (b) Yamashita, T.; Sato, D.;
Kiyoto, T.; Kumar, A.; Koga, K. Tetrahedron 1997, 53, 16987.
7. A part of this paper has been reported as a communication:
Imai, M.; Hagihara, A.; Kawasaki, H.; Manabe, K.; Koga, K.
J. Am. Chem. Soc. 1994, 116, 8829.
3. (a) Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624.
(b) Juaristi, E.; Beck, A. K.; Hansen, J.; Matt, T.; Mukhopadhyay,
T.; Simson, M.; Seebach, D. Synthesis 1993, 1271.
8. Meyers, A. I.; Williams, D. R.; Erickson, G. W.; White, S.;
Druelinger, M. J. Am. Chem. Soc. 1981, 103, 3081.
9. Snatzke, G.; Snatzke, F. In Fundamental Aspects and Recent
Developments in Optical Rotatory Dispersion and Circular
Dichroims; Ciardelli, F.; Salvadori, P., Eds.; Heyden: London,
1973; Chapter 3.2.
10. We thank Dr. M. Murakata for the measurement.
11. Shirai, R.; Aoki, K.; Sato, D.; Kim, H.-D.; Murakata, M.;
Yasukata, T.; Koga, K. Chem. Pharm. Bull. 1994, 42, 690.
12. Shea, K. J.; Stoddard, G. J.; England, W. P.; Haffner, C. D.
J. Am. Chem. Soc. 1992, 114, 2635.
4. (a) Murakata, M.; Nakajima, M.; Koga, K. J. Chem. Soc., Chem.
Commun. 1990, 1657. (b) Hasegawa, Y.; Kawasaki, H.; Koga, K.
Tetrahedron Lett. 1993, 34, 1963. (c) Yasuda, K.; Shindo, M.;
Koga, K. Tetrahedron Lett. 1996, 37, 6343. (d) Yasuda, K.;
Shindo, M.; Koga, K. Tetrahedron Lett. 1997, 38, 3531. (e)
Matsuo, J.; Kobayashi, S.; Koga, K. Tetrahedron Lett. 1998, 39,
9723. (f) Yamashita, Y.; Odashima, K.; Koga, K. Tetrahedron Lett.
1999, 40, 2803.
5. Goto, M.; Akimoto, K.; Aoki, K.; Shindo, M.; Koga, K.
Tetrahedron Lett. 1999, 40, 8129.
6. (a) Yamashita, T.; Sato, D.; Kiyoto, T.; Kumar, A.; Koga, K.
13. Bachmann, W. E.; Johnson, G. D. J. Am. Chem. Soc. 1949, 71,
3467.