Stereoselective reactions. XXXIV. Enantioselective deprotonation of prochiral 4-substituted cyclohexanones using chiral bidentate lithium amides having a bulky group instead of a phenyl group on the chiral carbon

Article abstract of DOI:10.1248/cpb.49.468

Using chiral bidentate lithium amides having a bulky group instead of a phenyl group on the chiral carbon, enantioselective deprotonation of prochiral 4-substituted cyclohexanones in the presence of excess trimethylsilyl chloride was examined in THF in th

Full text of DOI:10.1248/cpb.49.468

4
68
Chem. Pharm. Bull. 49(4) 468—472 (2001)
Vol. 49, No. 4
1)
Stereoselective Reactions. XXXIV.
Enantioselective Deprotonation of
Prochiral 4-Substituted Cyclohexanones Using Chiral Bidentate Lithium
Amides Having a Bulky Group Instead of a Phenyl Group on the Chiral
Carbon
a
b
a
a
Masaharu TORIYAMA, Keizo SUGASAWA, Shigeyasu MOTOHASHI, Norio TOKUTAKE, and
Kenji KOGA*,
c
a
College of Pharmacy, Nihon University, Narashinodai, Funabashi-shi, Chiba 274–8555, Japan, Institute for Drug
b
Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305–8585, Japan, and
c
Research and Education Center for Materials Science, Nara Institute of Science and Technology, Takayama-cho, Ikoma-
shi, Nara 630–0101, Japan. Received January 5, 2001; accepted February 1, 2001
Using chiral bidentate lithium amides having a bulky group instead of a phenyl group on the chiral carbon,
enantioselective deprotonation of prochiral 4-substituted cyclohexanones in the presence of excess trimethylsilyl
chloride was examined in THF in the absence and in the presence of HMPA. It is shown that enantioselectivity of
the reactions decreases as the substituent on the chiral carbon of the chiral lithium amides and the substituent at
the 4-position of cyclohexanones become reasonably bulky. An eight-membered cyclic transition state model is
proposed for this deprotonation reaction.
6
15
Key words chiral lithium amide; enantioselective deprotonation; Li-NMR; N-NMR; eight-membered cyclic transition state
model
Lithium dialkylamides such as lithium diisopropylamide on the amide nitrogen are summarized in Table 1. It is shown
LDA) are widely used in organic synthesis as strong bases that, except one case (run 20), chiral lithium amides having
(
2
)
with low nucleophilicity. We have previously reported enan- R-configuration give the products rich in R-enantiomer, while
3
)
tioselective deprotonation of prochiral 4-substituted cyclo- that having S-configuration gives the products rich in S-enan-
hexanones (1) using chiral lithium amides in the presence of tiomer. It is also shown that the enantioselectivities of the re-
excess trimethylsilyl chloride (TMSCl) (Corey’s internal actions are dependent on the bulkiness of both the substituent
4
)
quench method ) to isolate the corresponding lithium eno- on the chiral carbon of the chiral lithium amides and the sub-
5
)
lates (2) as trimethylsilyl enol ethers (3). Among various
chiral lithium amides examined, chiral bidentate lithium
amides ((R)-5a, (R)-5b) having a phenyl group on the chiral
carbon, a neopentyl or trifluoroethyl group on the amide ni-
trogen, and a piperidino group as an internal ligation site for
5
b,c,i,l)
the lithium give the products ((R)-3) in high ee’s.
By X-
ray and NMR studies, it is shown that these chiral lithium
amides ((R)-5a, (R)-5b) exist almost entirely as a chelated
monomeric form ((R)-6) having a chiral amide nitrogen in
tetrahydrofuran (THF) or dimethoxyethane (DME), and in
THF, DME, ether, or toluene in the presence of 2 eq of hexa-
5
b,c,i,l)
methylphosphoric triamide (HMPA).
In this structure,
the substituent (a neopentyl or trifluoroethyl group) on the
amide nitrogen and the phenyl group on the chiral carbon are
trans, presumably due to the steric repulsion between them.
It is therefore reasonable to assume that bidentate chiral
lithium amides ((R)-12a, b—(R)-15a, b, (S)-16a, b) having a
bulkier substituent instead of a phenyl group on the chiral
carbon would be more effective as chiral bases for enantiose-
lective deprotonation. Based on this consideration, we pre-
pared chiral bidentate amines ((R)-7a, b—(R)-10a, b, (S)-
1
1a, b) for the preparation of their corresponding lithium
1
)
amides. The present paper describes the results of deproto-
nation reactions of 4-substituted cyclohexanones (1a—d) by
these chiral bidentate lithium amides.
The reactions of 1a—d were carried out under the fixed
conditions, using 1.2 eq of lithium amide and 5 eq of TMSCl
in the presence of 1.2 eq of HMPA in THF at Ϫ78 °C for
6
)
3
0 min. The results using chiral lithium amides ((R)-5a,
(R)-11a—(R)-15a, and (S)-16a) having a neopentyl group
Chart 1
∗
To whom correspondence should be addressed. e-mail: kkoga@ms.aist-nara.ac.jp
© 2001 Pharmaceutical Society of Japan

April 2001
469
a)
Table 1. Enantioselective Deprotonation of 1 Using (R)-5a, (R)-12a—(R)-15a, and (S)-16a
Ketone
Compound
Lithium amide
Product
Run
1
2
R
Compound
R
R
Compound
Chem. y. (%)
E.e. (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
1a
1b
1c
1d
1a
1b
1c
1d
1a
1b
1c
1d
1a
1b
1c
1d
1a
1b
1c
1d
1a
1b
1c
1d
Me
iso-Pr
Ph
t-Bu
Me
iso-Pr
Ph
t-Bu
Me
iso-Pr
Ph
t-Bu
Me
iso-Pr
Ph
t-Bu
Me
iso-Pr
Ph
t-Bu
Me
iso-Pr
Ph
(R)-5a
(R)-5a
(R)-5a
(R)-5a
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
t-Bu
t-Bu
t-Bu
t-Bu
(R)-3a
(R)-3b
(R)-3c
(R)-3d
(R)-3a
(R)-3b
(R)-3c
(R)-3d
(R)-3a
(R)-3b
(R)-3c
(R)-3d
(R)-3a
(R)-3b
(R)-3c
(R)-3d
(R)-3a
(R)-3b
(R)-3c
(S)-3d
(S)-3a
(S)-3b
(S)-3c
(S)-3d
77
91
98
96
87
91
98
87
78
93
97
95
84
95
99
99
67
85
77
85
65
78
86
77
92
89
87
83
94
93
90
85
92
87
85
75
86
80
74
47
66
33
23
16
27
17
6
(R)-12a
(R)-12a
(R)-12a
(R)-12a
(R)-13a
(R)-13a
(R)-13a
(R)-13a
(R)-14a
(R)-14a
(R)-14a
(R)-14a
(R)-15a
(R)-15a
(R)-15a
(R)-15a
(S)-16a
(S)-16a
(S)-16a
(S)-16a
1-Naph
1-Naph
1-Naph
1-Naph
2-Naph
2-Naph
2-Naph
2-Naph
3,5-Me C H
3,5-Me C H
3,5-Me C H
3,5-Me C H
3,5-(t-Bu) C H
3,5-(t-Bu) C H
3,5-(t-Bu) C H
3,5-(t-Bu) C H
H
H
H
H
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
6
3
3
3
3
2
6
2
6
2
6
2
6
3
3
3
3
2
6
2
6
2
6
t-Bu
12
a) A typical procedure is written in the Experimental.
stituent on the 4-position of cyclohexanones. Thus, by using group is almost racemic 3d (run 20). Enantioselectivities of
R)-5a having a phenyl group on the chiral carbon, enantios- the reactions using (S)-16b (runs 21—24) are improved
(
electivities of the reactions decrease as the bulkiness of the compared to those using (S)-16a (runs 21—24, Table 1), but
substituent on the 4-position of cyclohexanones increases are still lower than those using (R)-5b, (R)-12b, (R)-13b, and
(
runs 1—4). The same tendency is observed for the reactions (R)-14b (runs 1—16).
using (R)-12a (runs 5—8), (R)-13a (runs 9—12), (R)-14a These data clearly show that, for the reactions using chiral
runs 13—16), and (R)-15a (runs 17—19), having a 1-naph- lithium amides having an aryl group on the chiral carbon
(
thyl, 2-naphthyl, 3,5-dimethylphenyl, and 3,5-di-tert- ((R)-5a, b, (R)-12a, b—(R)-15a, b), severe steric interactions
butylphenyl group, respectively, on the chiral carbon. It is arise between the bulkier aryl substituent of the chiral
also recognized that enantioselectivities of the reactions are lithium amides and the bulkier 4-substituent of cyclohexa-
generally higher by using chiral lithium amides having a nones at the transition states of the reactions.
phenyl or 1-naphthyl group on the chiral carbon ((R)-5a or
R)-12a), while they become lower by using chiral lithium responding silyl enol ether: the lithium amide and TMSCl
amides having a more bulky substituent on the chiral carbon are premixed prior to the addition of the ketone (internal
Two methods are available to convert the ketone to the cor-
(
4
)
(
(R)-14a, (R)-15a). As a result, the sense of asymmetric in- quench method ) and the lithium amide is allowed to react
duction is reversed in the reaction of 1d having a tert-butyl with the ketone before TMSCl is added (external quench
group by (R)-15a having a 3,5-di-tert-butylphenyl group, method). It is shown that the internal quench method, in gen-
giving (S)-3d in low ee (run 20). On the other hand, the eral, gives higher enantioselectivity than the external quench
lithium amide ((S)-16a) having a tert-butyl group on the chi- method, and that improvement in enantiomeric excess of the
ral carbon is not an efficient chiral base giving the products products under external quench conditions can be achieved
in low ee’s (runs 21—24).
As summarized in Table 2, similar phenomena are ob- the deprotonation step.
by the presence of lithium halides in the reaction mixture at
5
d,9,10)
We have previously observed a
served for the reactions by chiral lithium amides ((R)-5b, similar phenomenon in the deprotonation of 1d using a mon-
R)-12b—(R)-15b, (S)-16b) having a trifluoroethyl group on odentate chiral lithium amide, and shown that the formation
(
the amide nitrogen. Thus, except one case (run 20), the of a 1 : 1 mixed dimer of the lithium amide and LiCl or LiBr
lithium amides having R-configuration give the products rich is responsible for the improvement of enantioselectivities
in R-enantiomer, while the lithium amide having S-configura- under the external quench conditions in the presence of these
5
d)
tion gives the products rich in S-enantiomer, and the enan- lithium halides at the deprotonation step. All the reactions
tioselectivities of the reactions lower as the bulkiness of both shown in Tables 1 and 2 are carried out under the internal
the aryl substituent at the chiral carbon of the chiral lithium quench method. As shown in Table 3, it is again recognized
amides and the substituent on the 4-position of cyclohexa- that enantioselectivities of the reactions of 1d using (R)-5a
nones increases. The product of the reaction of 1d having a and (R)-12a to give (R)-3d change by the reaction conditions
tert-butyl group by (R)-15b having a 3,5-di-tert-butylphenyl employed. Thus, compared to the reactions under the internal

4
70
Vol. 49, No. 4
a)
Table 2. Enantioselective Deprotonation of 1 Using (R)-5b, (R)-12b—(R)-15b, and (S)-16b
Ketone
Compound
Lithium amide
Product
Run
1
2
R
Compound
R
R
Compound
Chem. y. (%)
E.e. (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
1a
1b
1c
1d
1a
1b
1c
1d
1a
1b
1c
1d
1a
1b
1c
1d
1a
1b
1c
1d
1a
1b
1c
1d
Me
iso-Pr
Ph
t-Bu
Me
iso-Pr
Ph
t-Bu
Me
iso-Pr
Ph
t-Bu
Me
iso-Pr
Ph
t-Bu
Me
iso-Pr
Ph
t-Bu
Me
iso-Pr
Ph
(R)-5b
(R)-5b
(R)-5b
(R)-5b
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
t-Bu
t-Bu
t-Bu
t-Bu
(R)-3a
(R)-3b
(R)-3c
(R)-3d
(R)-3a
(R)-3b
(R)-3c
(R)-3d
(R)-3a
(R)-3b
(R)-3c
(R)-3d
(R)-3a
(R)-3b
(R)-3c
(R)-3d
(R)-3a
(R)-3b
(R)-3c
(RS)-3d
(S)-3a
(S)-3b
(S)-3c
(S)-3d
66
85
91
82
90
92
96
91
69
82
90
85
68
77
87
85
49
56
46
54
79
92
95
94
89
90
88
85
89
93
91
87
92
88
86
78
91
80
70
57
66
43
30
~0
70
57
54
53
(R)-12b
(R)-12b
(R)-12b
(R)-12b
(R)-13b
(R)-13b
(R)-13b
(R)-13b
(R)-14b
(R)-14b
(R)-14b
(R)-14b
(R)-15b
(R)-15b
(R)-15b
(R)-15b
(S)-16b
(S)-16b
(S)-16b
(S)-16b
1-Naph
1-Naph
1-Naph
1-Naph
2-Naph
2-Naph
2-Naph
2-Naph
3,5-Me C H
3,5-Me C H
3,5-Me C H
3,5-Me C H
3,5-(t-Bu) C H
3,5-(t-Bu) C H
3,5-(t-Bu) C H
3,5-(t-Bu) C H
H
H
H
H
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
6
3
3
3
3
2
6
2
6
2
6
2
6
3
3
3
3
2
6
2
6
2
6
t-Bu
a) A typical procedure is written in the Experimental.
Table 3. Enantioselective Deprotonation of 1d to Give (R)-3d under Dif-
ferent Conditons
Product ((R)-3d)
Lithium
amide
a)
Run
Conditions
Chem. y. (%)
E.e. (%)
1
2
3
4
5
6
(R)-5a
(R)-5a
(R)-5a
(R)-12a
(R)-12a
(R)-12a
A
B
C
A
B
C
95
88
97
84
88
94
84
77
85
86
76
87
a) All reactions were run in THF in the absence of HMPA. A: Internal quench
method; B: External quench method; C: External quench conditions in the presence of
LiBr at the deprotonation step.
quench method (runs 1 and 4), enantioselectivities of the re-
actions under the external quench method are somewhat
lower (runs 2 and 5), but are improved to the level of the in- a) Without LiCl. b) With LiCl (0.9 eq). c) With LiCl (1.3 eq).
ternal quench method under the external quench conditions
6
15
Fig. 1. NMR spectra of [ Li, N ]-(R)-5a in THF-d (0.05 M, at Ϫ115 °C).
2
8
6
6
6
in the presence of one equivalent of LiBr (runs 3 and 6).
Since LiCl is generated in situ as the silylation proceeds
under the internal quench method, the solution structures of
6
15
5i)
[
Li, N ]-(R)-5a in THF-d in the absence and in the pres-
2
8
6
6
15
ence of LiCl were examined by Li- and N-NMR spectra.
As already reported, [ Li, N ]-(R)-5a exists almost entirely
as a chelated monomeric form (17) in the absence of LiCl,
because the Li-NMR spectrum shows a doublet of doublets, blet and a doublet of doublets for the Li-NMR, while a
indicative of coupling with two N nuclei, while the corre- triplet and a quintet-like triplet of triplets for the N-NMR.
sponding N-NMR spectrum displays two sets of triplets, in- These data mean that one Li couples with one N nucleus
dicating that each nitrogen atom couples with one Li nu- and the other Li couples with two N nuclei, while one
cleus (Fig. 1a). The new signals appear in the presence of couples with one Li nucleus and the other N couples with
6
15
2
6
5i)
6
ence of 1.3 eq of LiCl (Fig. 1c). The new signals are a dou-
6
6
1
5
15
1
5
6
15
6
6
15
15
N
1
1)
6
15
6
6
6
LiCl. They are the major signals in the presence of 0.9 eq of two Li nuclei. Since the coordinating lone pair on the amide
LiCl (Fig. 1b), while they are the sole signals in the pres- nitrogen of the chelated monomer (17) is known to be exclu-

April 2001
471
5
i)
sively cis to the phenyl group in the chelated ring, a 1 : 1 dition of triethylamine (4 ml) and saturated aqueous NaHCO
(10 ml) at
3
Ϫ78 °C, and the whole was allowed to warm to room temperature. The
work-up as described in a) above gave (R)-3d (400 mg, 88%) as a colorless
mixed dimer (18) is proved to be formed in the presence of
LiCl, and is considered to be a responsible species for the
deprotonation reactions under the internal quench method
and under the external quench conditions in the presence of
6
25
365
oil of bp 150 °C (bath temperature). [a] ϩ180° (cϭ1.50), corresponding
1
to be 76% ee.
Rotational Values of the Products (3a—d) by the Reactions in Table 1
Run 1: [a]365 ϩ219° (cϭ1.50); run 2: [a]365 ϩ203° (cϭ1.49); run 3: [a]365
5
e)
25
25
25
LiBr or LiCl.
2
5
25
365
1
2)
ϩ128° (cϭ1.51); run 4: [a]
ϩ197° (cϭ1.51); run 5: [a]
ϩ223°
We previously proposed the mechanism of the present
enantioselective deprotonation reactions based on Ireland’s
365
2
5
25
(
9
cϭ1.51); run 7: [a] ϩ132° (cϭ1.48); run 8: [a] ϩ201° (cϭ1.50); run
3
65
365
25
365
25
365
25
: [a] ϩ219° (cϭ1.50); run 10: [a] ϩ198° (cϭ1.5); run 11: [a]
2
,13)
365
six-membered transition state model.
However, since the
25
3
25
365
ϩ124° (cϭ1.50); run 12: [a] ϩ177° (cϭ1.50); run 13: [a] ϩ204°
65
2
3
5
65
25
dimer (18) is considered to be responsible for the reactions (cϭ1.51); run 14: [a] ϩ182° (cϭ1.51); run 15: [a] ϩ108° (cϭ1.50);
365
2
5
25
365
run 16: [a] ϩ111° (cϭ1.57); run 17: [a] ϩ157° (cϭ1.50); run 18:
under the internal quench method or under the external
quench conditions in the presence of LiCl, it is reasonable to
assume that the eight-membered cyclic transition state model
19) including LiCl is a better explanation for (R)-5a to
give the products (3a—d) rich in R-enantiomer. By this tran- Run 1: [a] ϩ213° (cϭ1.51); run 2: [a] ϩ205° (cϭ1.50); run 3: [a]
sition state model, it is possible to explain the severe steric
interactions between the bulkier aryl substituent of the chiral
bidentate lithium amides and the bulkier 4-substituent of cy-
clohexanones to reduce enantioselectivities of the reactions.
365
2
3
5
65
25
365
25
[
a]
ϩ74° (cϭ1.51); run 19: [a]
ϩ34.0° (cϭ1.51); run 20: [a]
365
2
3
5
65
25
365
Ϫ38.5° (cϭ1.54); run 21: [a] Ϫ64.6° (cϭ1.51); run 22: [a] Ϫ38.0°
25
25
(
cϭ1.51); run 23: [a]3 Ϫ8.3° (cϭ1.50); run 24: [a] Ϫ28.4° (cϭ1.51).
6
5
3
6
5
1
4)
(
Rotational Values of the Products (3a—d) by the Reactions in Table 2
2
3
5
65
25
365
25
365
2
365
5
25
365
ϩ129° (cϭ1.50); run 4: [a]
ϩ202° (cϭ1.44); run 5: [a]
ϩ213°
2
3
5
65
25
(
8
cϭ1.42); run 6: [a] ϩ212° (cϭ1.48); run 7: [a] ϩ133° (cϭ1.50); run
365
2
3
5
65
25
365
25
: [a] ϩ205° (cϭ1.62); run 9: [a] ϩ218° (cϭ1.50); run 10: [a]
365
25
3
25
365
ϩ200° (cϭ1.50); run 11: [a] ϩ125° (cϭ1.50); run 12: [a] ϩ185°
65
2
3
5
65
25
(cϭ1.50); run 13: [a] ϩ216° (cϭ1.49); run 14: [a] ϩ182° (cϭ1.62);
365
2
3
5
65
25
365
run 15: [a] ϩ102° (cϭ1.52); run 16: [a] ϩ135° (cϭ1.56); run 17:
2
3
5
65
25
365
25
Experimental
[a] ϩ158° (cϭ1.43); run 18: [a] ϩ97.8° (cϭ1.51); run 19: [a]
365
6
15
25
3
25
365
General All boiling points are uncorrected. Li- and N-NMR spectra ϩ44.0° (cϭ1.51); run 20: [a] Ϫ0.5° (cϭ1.50); run 21: [a] Ϫ166°
65
2
3
5
65
25
365
were recorded on a JEOL GSX-500 spectrometer (73.45 and 50.55 MHz, re- (cϭ1.49); run 22: [a] Ϫ130° (cϭ1.50); run 23: [a] Ϫ78.3° (cϭ1.51);
6
15
25
65
spectively) as reported, and the Li- and N chemical shifts are given in d run 24: [a]3 Ϫ125° (cϭ1.52).
6
15
(
(
ppm) using LiCl in THF-d8 (dϭ0.0) and using [ N]-aniline in THF-d
Rotational Values of the Products (3d) by the Reactions in Table 3
8
5
i)
25
25
25
365
dϭ52.0) as external standards, respectively, as reported. The following Run 1: [a]3 ϩ199° (cϭ1.51); run 2: [a] ϩ183° (cϭ1.51); run 4: [a]
65
365
2
3
5
65
abbreviations are used: dϭdoublet, ddϭdoublet of doublets, tϭtriplet, ϩ204° (cϭ1.42); run 6: [a] ϩ205° (cϭ1.51).
6
15
6
15
ttϭtriplet of triplets. Optical rotations were measured by a JASCO DIP-360
Li- and N-NMR Spectroscopic Analysis Solutions of [ Li, N ]-
2
6
or a JASCO DIP-370 digital polarimeter using benzene as a solvent. The (R)-5a in THF-d in the presence and in the absence of LiCl were prepared
syntheses of (R)-5a, b, (R)-7a, b—(R)-10a, b, (S)-11a, b, and [ Li, N ]-
8
7
)
1)
1)
6
15
5d,5i)
6
15
according to the reported method.
(R)-5a (Fig. 1a), Li-NMR: 0.85 (dd, J ϭ7.0 and 2.4); N-NMR: 47.5 (t,
Data are as follows. For [ Li, N ]-
2
2
5i)
6
15
(
R)-5a are reported. Maximum rotational values of (R)-3a, (R)-3b, (R)-3c,
Li–N
8
)
25
65
25
365
6
15
and (R)-3d in benzene are reported to be [a]3 ϩ238°, [a] ϩ228°, JN–Liϭ2.4), 53.6 (t, J ϭ7.0). For [ Li, N ]-(R)-5a in the presence of
N–Li
2
2
5
25
365
6
6
[
a]3 ϩ146°, and [a] ϩ237°, respectively.
1.3 eq of LiCl (Fig. 1c), Li-NMR: 0.64 (d, JLi–Nϭ4.9), 1.14 (dd, JLi–Nϭ4.3
65
1
5
Typical Procedures for Deprotonation Reactions a) Internal quench and 2.7). N-NMR: 36.7 (tt, JLi–Nϭ4.3 and 4.9), 46.2 (t, JN–Liϭ2.7).
method (Table 1, run 6): A solution of n-BuLi in hexane (1.55 N, 1.55 ml,
.40 mmol) was added to a solution of (R)-12a (811 mg, 2.50 mmol) in THF
50 ml) at Ϫ78 °C under argon atmosphere. The resulting solution was Culture, Sports, Science and Technology of Japan is acknowledged.
2
Acknowledgment Financial support from the Ministry of Education,
(
stirred for 30 min. After addition of HMPA (0.50 ml, 2.9 mmol), the whole
was stirred at Ϫ78 °C for 20 min. A solution of 1b (280 mg, 2.00 mmol) and References and Notes
TMSCl (1.27 ml, 10.0 mmol) in THF (4 ml) was added during 6 min, and the
1) Part XXXIII: Toriyama M., Tokutake N., Koga K., Chem. Pharm.
whole was stirred at Ϫ78 °C for 30 min. The reaction mixture was quenched
Bull., 49, 330—334 (2001).
by addition of triethylamine (4 ml) and saturated aqueous NaHCO (10 ml)
2) Evans D. A., “Asymmetric Synthesis,” Vol. 3, ed. by Morrison J. D.,
Academic Press, New York, 1984, pp. 1—110.
3
at Ϫ78 °C, and the whole was allowed to warm to room temperature. After
addition of water, the whole was extracted with hexanes (50 mlϫ3). The or-
ganic extracts were combined, washed successively with water (20 mlϫ2),
3) For reviews: a) Koga K., Yuki Gosei Kagaku Kyokai Shi, 48, 463—475
(1990); b) Cox P. S., Simpkins N. S., Tetrahedron: Asymmetry, 2, 1—
26 (1991); c) Waldmann H., Nachr. Chem. Tech. Lab., 39, 413—418
(1991); d) Koga K., Pure Appl. Chem., 66, 1487—1492 (1994); e)
Koga K., Shindo M., Yuki Gosei Kagaku Kyokai Shi, 53, 1021—1032
(1995); f ) Simpkins N. S., Pure Appl. Chem., 68, 691—694 (1996); g)
Idem, “Advanced Asymmetric Synthesis,” ed. by Stephenson G. R.,
Chapman & Hall, London, 1996, pp. 111—125; h) O’Brien P., J.
Chem. Soc., Perkin Trans. 1, 1998, 1439—1457.
0
.1 N aqueous citric acid (80 mlϫ6), water (20 ml), saturated aqueous
NaHCO (20 ml), and brine (50 ml). Evaporation of the dried (Na SO ) ex-
3
2
4
tracts gave a pale yellow oil (650 mg), which was purified by column chro-
matography (silica gel, hexane) followed by bulb-to-bulb distillation to give
(
R)-3b (387 mg, 91%) as a colorless oil of bp 120 °C (bath temperature).
0.4
25
[a]3 ϩ211 (cϭ1.49), corresponding to be 93% ee.
65
b) External quench conditions in the presence of LiBr (Table 3, run 3): A
solution of MeLi–LiBr in ether (1.50 N for MeLi, 1.60 ml, 2.40 mmol) was
added to a solution of (R)-4a (686 mg, 2.50 mmol) in THF (50 ml) at Ϫ78 °C
under argon atmosphere. The resulting solution was stirred for 30 min. A so-
lution of 1d (308 mg, 2.00 mmol) in THF (4 ml) was added during 5 min,
and the whole was stirred at Ϫ78 °C for 10 min. TMSCl (1.27 ml, 10.0
mmol) was added, and the whole was stirred at Ϫ78 °C for 30 min. The reac-
tion mixture was quenched by addition of triethylamine (4 ml) and saturated
4) Corey E. J., Gross A. W., Tetrahedron Lett., 25, 495—498 (1984).
5) a) Shirai R., Tanaka M., Koga K., J. Am. Chem. Soc., 108, 543—546
(1986); b) Sato D., Kawasaki H., Shimada I., Arata Y., Okamura K.,
Date T., Koga K., ibid., 114, 761—763 (1992); c) Aoki K., Noguchi
H., Tomioka K., Koga K., Tetrahedron Lett., 34, 5105—5108 (1993);
d) Sugasawa K., Shindo, M., Noguchi H., Koga K., ibid., 37, 7377—
7380 (1996); e) Yamashita T., Sato D., Kiyoto T., Kumar A., Koga K.,
ibid., 37, 8195—9198 (1996); f ) Toriyama M., Sugasawa K., Shindo
M., Tokutake N., Koga K., ibid., 38, 567—570 (1997); g) Aoki K.,
Koga K., ibid., 38, 2505—2506 (1997); h) Shirai R., Sato D., Aoki K.,
Tanaka M., Kawasaki H., Koga K., Tetrahedron, 53, 5963—5972
(1997); i) Sato D., Kawasaki H., Shimada I., Arata Y., Okamura K.,
Date T., Koga K., ibid., 53, 7191—7200 (1997); j) Sato D., Kawasaki
H., Koga K., Chem. Pharm. Bull., 45, 1399—1402 (1997); k) Chatani
H., Nakajima M., Koga K., Heterocycles, 46, 53—56 (1997); l) Aoki
K., Tomioka K., Noguchi H., Koga K., Tetrahedron, 53, 13641—
13656 (1997); m) Yamashita T., Sato D., Kiyoto T., Kumar A., Koga
K., ibid., 53, 16987—16998 (1997); n) Aoki K., Koga K., Chem.
aqueous NaHCO (10 ml) at Ϫ78 °C, and the whole was allowed to warm to
3
room temperature. The work-up as described in a) above gave (R)-3d (437.5
2
5
mg, 97%) as a colorless oil of bp0.7 160 °C (bath temperature). [a] ϩ201°
365
(cϭ1.50), corresponding to be 85% ee.
c) External quench method (Table 3, run 5): A solution of n-BuLi in
hexane (1.55 N, 1.55 ml, 2.40 mmol) was added to a solution of (R)-7a (811
mg, 2.50 mmol) in THF (50 ml) at Ϫ78 °C under argon atmosphere. The re-
sulting solution was stirred for 30 min. A solution of 1d (308 mg, 2.00
mmol) in THF (4 ml) was added during 5 min, and the whole was stirred at
Ϫ78 °C for 10 min. TMSCl (1.27 ml, 10.0 mmol) was added, and the whole
was stirred at Ϫ78 °C for 30 min. The reaction mixture was quenched by ad-

4
72
Vol. 49, No. 4
Pharm. Bull., 48, 571—574 (2000).
Almost the same results were obtained in the absence of HMPA.
Shirai R., Aoki K., Kim H.-D., Murakata M., Yasukata T., Koga K.,
Chem. Pharm. Bull., 42, 690—693 (1994).
Beck A. K., Hansen J., Natt T., Mukhopadhyay T., Simson M., See-
bach D., Synthesis, 1993, 1271—1290; c) Seebach D., Beck A. K.,
Studer A., “Modern Synthetic Methods,” Vol. 7, VCH, Weinheim,
1995, pp. 1—178.
5
f )
6
7
)
)
6
15
8
)
)
Aoki K., Nakajima M., Tomioka K., Koga K., Chem. Pharm. Bull., 41, 11) Nuclear spins of Li and N are 1 and Ϫ1/2, respectively.
9
94—996 (1993).
12) Koga K., “Stereocontrolled Organic Synthesis,” ed. by Trost B. M.,
Blackwell Scientific Publications, London, 1994, pp. 97—116.
9
a) Majewski M., Gleave D. M., J. Org. Chem., 57, 3599—3605
(
(
1992); b) Bunn B. J., Simpkins N. S., J. Org. Chem., 58, 533—534 13) Ireland R. E., Mueller R. H., Willard A. K., J. Am. Chem. Soc., 98,
1993); c) Bunn B. J., Simpkins N. S., Spavold Z., Crimmin M. J., J. 2868—2877 (1976).
Chem. Soc., Perkin Trans. 1, 1993, 3113—3116; d) Majewski M., 14) The eight-membered cyclic transition state models have already been
Lazny R., Tetrahedron Lett., 35, 3653—3656 (1994); e) Majewski M.,
Lazny R., Nowak P., ibid., 36, 5465—5468 (1995); f ) Busch-Petersen
J., Corey E. J., ibid., 41, 6941—6944 (2000).
discussed. a) Romsberg F. E., Collum D. B., J. Am. Chem. Soc., 117,
2166—2178 (1995); b) Henderson K. W., Dorigo A. E., Liu Q.-Y.,
Williard P. G., Schleyer P. v. R., Bernstein P. R., ibid., 118, 1339—
1347 (1996); c) Bush-Peterson J., Corey E. J., Tetrahedron Lett., 41,
6941—6944 (2000).
1
0) For reviews including discussion of salt effects, see a) Seebach D.,
Angew, Chem. Int. Ed. Engl., 27, 1624—1654 (1988); b) Juaristi E.,