Asymmetric induction via short-lived chiral enolates with a chiral C-O axis

Article abstract of DOI:10.1021/ja4018122

A novel method has been developed for the asymmetric cyclization of alkyl aryl ethers. The reactions were assumed to proceed via short-lived chiral enolate intermediates with a chiral C-O axis to give cyclic ethers with tetrasubstituted carbon in up to 99% ee. The half-life of racemization of the chiral enolate intermediate was roughly estimated to be ～1 s at -78 C.

Full text of DOI:10.1021/ja4018122

Subscriber access provided by Cape Breton University | Library
Communication
Asymmetric Induction via Short-Lived Chiral Enolates with a Chiral C-O Axis
Tomoyuki Yoshimura, Keisuke Tomohara, and Takeo Kawabata
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja4018122 • Publication Date (Web): 22 Apr 2013
Downloaded from http://pubs.acs.org on April 28, 2013
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Asymmetric Induction via Short-Lived Chiral Enolates with a Chiral
C-O Axis
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Tomoyuki Yoshimura, Keisuke Tomohara and Takeo Kawabata*
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611ꢀ0011, Japan
Supporting Information Placeholder
racemization of enolate B. Enolates A and B have suffiꢀ
cient configurational stability for the asymmetric reacꢀ
tions to take place at the reaction temperatures before
they undergo significant racemization. On the other
hand, asymmetric induction via chiral enolate intermediꢀ
ates with a chiral CꢀO axis such as C (Figure 1c) was
expected to be difficult because of their extremely short
halfꢀlives of racemization. Here, we report the first exꢀ
ample of asymmetric induction via shortꢀlived chiral
enolate intermediates with a chiral CꢀO axis.4
ABSTRACT: A novel method for the asymmetric cyꢀ
clization of alkyl aryl ethers has been developed. The
reactions were assumed to proceed via shortꢀlived chiral
enolate intermediates with a chiral CꢀO axis to give cyꢀ
clic ethers with tetrasubstituted carbon in up to 99% ee.
The halfꢀlife of racemization of the chiral enolate interꢀ
mediate was roughly estimated to be ~1 sec at –78 °C.
We have been interested in asymmetric reactions that
proceed via enolate intermediates with intrinsic axial
chirality.1,2 In 1991, we developed an asymmetric inducꢀ
tion via enolate intermediate A with a chiral CꢀC axis
(Figure 1a).3 The halfꢀlife of racemization of the axially
chiral enolate A at the reaction temperature (–20 °C)
was estimated to be ~24 days based on the racemization
behavior of the corresponding enol methyl ether 1.2b,3 In
2000, we developed an asymmetric induction via enolate
intermediate B with a chiral CꢀN axis (Figure 1b).1a The
halfꢀlife of racemization of the axially chiral enolate B at
the reaction temperature (–78 °C) was determined to be
22 h based on a measurement of the timeꢀdependent
Scheme 1. Strategy for Asymmetric Alkylation via
Chiral Enolates with a Chiral C-O Axis
To realize asymmetric induction via rapidly racemizꢀ
ing chiral enolates with a chiral CꢀO axis, we chose the
fiveꢀmembered cyclization of chiral alkyl aryl ethers
(Scheme 1), in which the chiral enolate intermediate is
expected to undergo intramolecular alkylation immediꢀ
ately after it is generated. We anticipated that the choice
of the R group at C(6) might be critical for the asymmetꢀ
ric induction, since this could increase the rotational
barrier around the chiral CꢀO axis.5 We initiated the
study with alkyl aryl ethers 2 (Table 1). Substrates 2
were readily prepared in optically pure form from readiꢀ
ly available and inexpensive Lꢀethyl lactate and the corꢀ
responding phenols by Mitsunobu etherification. Treatꢀ
ment of 2a (R=H) with potassium hexamethyldisilazide
(KHMDS) in THF at –78 ˚C gave 3a (R=H) in 61%
yield as a racemate (Table 1, entry 1). Other conditions
that used various bases (KHMDS, NaHMDS, and
LiHMDS) and solvents (DMF and toluene) also gave 3a
as a racemate (data not shown). We then investigated
substrates 2 with a substituent (R≠H) at C(6). Treatment
of 2b (R=Me) with KHMDS in THF at –78 ˚C gave 3b
in 62% yield and 56% ee (entry 2). The reaction in toluꢀ
ene or DMF/THF (2:1) resulted in a decrease in ee (28%
ee) or both ee and yield (38% ee, 38% yield), respectiveꢀ
Figure 1. Enolates with a) a chiral CꢀC axis, A, b) a chiꢀ
ral CꢀN axis, B, and c) a chiral CꢀO axis, C (this work),
respectively, as intermediates for asymmetric reactions.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
ly (entries 3 and 4). While the asymmetric cyclization of the bromodesilylation of 3d. The absolute configuration
1
2
3
4
5
6
7
8
2b with LiHMDS in THF resulted in the recovery of 2b
(entry 5), that with NaHMDS gave 3b in 66% yield and
84% ee (entry 6). The corresponding reaction at –90 ˚C
slightly improved the ee (87% ee), but diminished the
yield (37%, entry 7).6 Treatment of 2c (R=i-Pr) with
NaHMDS in THF at –78 ˚C gave 3c in 82% yield and
99% ee (Table 1, entry 8). These results indicated that
the bulkiness of the substituent R at C(6) critically afꢀ
fects the efficiency of the asymmetric cyclization.
Asymmetric cyclization of 2d (R=SiMe3) and 2e (R=Ph)
proceeded in a highly enantioselective manner to give
3d in 97% ee (70% yield) and 3e in 94% ee (60% yield),
respectively (entries 9 and 10). Substrate 2f (R=Br) unꢀ
derwent asymmetric cyclization with high enantioselecꢀ
tivity (96% ee), but in a low yield (20%) (entry 11). Altꢀ
hough dihydrobenzofuran 3a (R=H) was obtained as a
racemate by the present method, it could be alternatively
obtained in 97% ee by protodesilylation of 3d (Scheme
2). Similarly, 3f was obtained in an acceptable yield by
of 3d was determined to be S by its chemical correlation
with (S)ꢀ4 (Scheme 2).7 Dihydrobenzofuran 4 prepared
20
from 3d showed, [α]D = –78 (c 0.15, CHCl3) {lit7 (S)ꢀ
20
4: [α]D = –83 (c 0.23, CHCl3)}. The absolute configuꢀ
rations of 3b, 3c, and 3f were deduced to be S by the
comparison of their CD spectra with that of 3d. These
results indicate that the present fiveꢀmembered cyclizaꢀ
tion proceeded with retention of configuration.
9
To gain insights into the mechanism of asymmetric
induction, the racemization behavior of the supposed
chiral enolate C’ (Scheme 1) was investigated. We preꢀ
viously determined the barrier for the racemization of
axially chiral enolate B (Figure 1b) by periodic quenchꢀ
ing of the chiral enolate with methyl iodide.1a,d However,
this protocol cannot be applied to enolate C’ because it
would undergo cyclization immediately after it is generꢀ
ated. Silyl ketene acetal 6 was used as an enolate equivaꢀ
lent to estimate the rotational barrier of the CꢀO bond as
a measure of the racemization barrier of chiral enolate
C’. Compound 5, which has a methoxy group instead of
a bromo group in 2c, was chosen as the precursor beꢀ
cause its enolate does not undergo cyclization, and inꢀ
stead, could be trapped as a silyl ketene acetal. Comꢀ
pound 5 was treated under conditions identical to those
for the asymmetric cyclization of 2c (entry 8 of Table 1)
except for the presence of TBSOTf, to give Zꢀ6 in 79%
yield. The formation of only Zꢀisomer (as determined
from NOESY spectra) indicates that the enolate also has
a Zꢀgeometry. The two methyl groups of the isopropylꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Asymmetric Five-Membered Cyclization of
Alkyl Aryl Ethers 2a
entry
substrate:R base,b solvent
product,
ee(%)c,
yield (%) abs. configd
1
1
2
3
4
2a: H
KHMDS, THF
KHMDS, THF
KHMDS, toluene
KHMDS,
DMF/THF(2:1)
3a, 61
3b, 62
3b, 60
3b, 38
0
groups of Zꢀ6 appeared as two doublets in its H NMR
2b: Me
2b: Me
2b: Me
56,S
28,S
38,S
spectrum measured at –90 °C in d8ꢀtoluene, which sugꢀ
gested restricted rotation around the CꢀO bond. The rotaꢀ
tional barrier was determined to be 11.5 kcal/mol by
VNMR measurement {ꢀν (28.6 Hz) and the coalescence
temperature (–42 ˚C)}. It is not clear whether the rotaꢀ
tional barrier in 6 corresponds to the rotation around the
C(1’)ꢀO bond (red curved arrow) or the C(1)ꢀO bond
(blue curved arrow). However, the restricted rotation
around the CꢀO axis in C’ must be the origin of the preꢀ
sent asymmetric induction because it is the only chiral
element in enolate C’. The halfꢀlife of racemization of
chiral enolate C’ is roughly estimated to be ~1 sec at –
78 ˚C, based on the assumption that the racemization
barrier of chiral enolate C’ is comparable to the rotaꢀ
tional barrier of the CꢀO bond of 6, and that ꢀS≠ of the
unimolecular process for bond rotation is nearly zero.8
5
6
2b: Me
2b: Me
2b: Me
2c: iꢀPr
2d: Me3Si
2e: Ph
LiHMDS, THF
3b, trace –e, –e
NaHMDS, THF
NaHMDS, THF
NaHMDS, THF
NaHMDS, THF
NaHMDS, THF
NaHMDS, THF
3b, 66
3b, 37
3c, 82
3d, 70
3e, 60
3f, 20
84,S
87,S
99,S
97,S
94, –e
96,S
f
7
8
9
10
11
a
2f: Br
b
Reactions were run at a substrate concentration of 0.1 M.
1.1~2.0 Equivalents of the base was used. For the experimental
c
details, see Supporting Information. Ee’s were determined by
HPLC analysis with a chiral stationary phase; see Supporting
Information. d The absolute configuration of 3d was determined
by chemical correlation with known compound (S)ꢀ4. The absoꢀ
lute configurations of 3b, 3c and 3f were deduced based on their
f
CD spectra. See Supporting Information. e Not determined. Run
at –90 ˚C.
Scheme 2. Transformation of 3d into 3a, 3f, and (S)-4
Figure 2. Rotational barriers of the CꢀO bond of silyl
ketene acetals 6 and its precursor 5.
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
A hypothetical model for asymmetric cyclization of
via the βꢀelimination of hydrogen iodide (Table 2, entry
2). The use of KHMDS gave dihydrobenzopyran 8b via
sixꢀmembered cyclization in 40% yield as a racemate
together with 9b in 24% yield (entry 3). Racemic 8c
(R1=iꢀPr) was also obtained by treatment of 7c with
KHMDS in 17% yield, along with the concomitant forꢀ
mation of 9c in 54% yield (entry 4). The formation of
racemic products in the sixꢀmembered cyclization under
the conditions for the highly enantioselective fiveꢀ
membered cyclization indicates that the sixꢀmembered
cyclization proceeds slower than the corresponding fiveꢀ
membered cyclization (Table 2, entries 3 and 4 vs. Table
1, entries 2, 6, and 8) (A similar tendency was observed
for the relative rates of the fiveꢀ vs. sixꢀmembered cyꢀ
clization of axially chiral enolates with a chiral CꢀN axꢀ
is. See reference 1d). We then examined substrate 7d,
and anticipated that the introduction of an additional
substituent at C(3) would increase the rate of sixꢀ
membered cyclization by a buttressing effect.12 The reꢀ
action of 7d possessing two methyl substituents at C(6)
and C(3) with NaHMDS gave 8d in 15% yield and 52%
ee and 9d in 16% yield (entry 5). Although the use of
KHMDS as a base gave racemic 8d in 35% yield, the
use of LDA gave 8d via sixꢀmembered cyclization in
77% yield and 43% ee (entry 7). The substituents at C(6)
and C(3) were further examined. Treatment of 7e bearꢀ
ing an isopropyl group at C(6) and a methyl group at
C(3) with LDA gave 8e in 74% ee and 88% yield withꢀ
out formation of the product from βꢀelimination (entry
8). With the use of a bulky base, TMS(tꢀBu)NLi,13 8e
was obtained from 7e in 85% ee and 66% yield (entry9).
Treatment of 7f possessing a methyl group at C(6) and
an isopropyl group at C(3) with TMS(tꢀBu)NLi gave 8f
in 66% ee (entry 10). The best result was obtained in the
1
2c is shown in Scheme 3. Deprotonation of conformer
2c-I would give enantiomerically enriched enolate C(2c)
with a chiral CꢀO axis,9 which would give 3c with retenꢀ
tion of configuration. On the other hand, deprotonation
of conformer 2c-II would give the product with inverꢀ
sion of configuration via enolate ent-C(2c). Although
deprotonation of conformer 2c-II seems more accessible
due to the steric reasons, preferential deprotonation of
conformer 2c-I might be ascribed to the conformational
preference of 2c-I over 2c-II10 and/or a chelating effect
(CH2Br–NaOC(OEt)=C) in the deprotonation step from
2c-I.11 The chiral enolate C(2c) is assumed to undergo
intramolecular alkylation immediately after it is generatꢀ
ed to minimize its own racemization. This merely proꢀ
vides hypothical understanding without experimental
proof.
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. A Hypothetical Model for the Asymmetric
Cyclization of 2c
Asymmetric sixꢀmembered cyclization was examined.
According to the results of asymmetric fiveꢀmembered
cyclization (Table 1, entries 6 and 8), 7b (R1=Me) was
treated under the optimum conditions for fiveꢀmembered
cyclization (NaHMDS in THF at –78 ˚C, Table 1, entry
8) to give 9b as the only detectable product in 86% yield
Table 2. Asymmetric Six-Membered Cyclization of Aryl Alkyl Ethera
entry
1
2
3
4
5
6
7
8
substrate: R1, R2
7a: H,
7b: Me, H
7b: Me, H
7c: iꢀPr, H
7d: Me, Me
7d: Me, Me
7d: Me, Me
7e: iꢀPr, Me
7e: iꢀPr, Me
7f: Me, iꢀPr
7g: tꢀBu, Me
base
product8(%yield)
8a(27)
%eeof8b,c
0
product9(%yield)
9a(39)
H
NaHMDS
NaHMDS
KHMDS
KHMDS
NaHMDS
KHMDS
LDA
8b(~0)
8b(40)
–
0
9b(86)
9b(24)
8c(17)
0
9c(54)
8d(15)
8d(35)
52
0
9d(16)
9d(27)
8d(77)
8e(88)
8e(66)
8f(44)
43
74
85
66
91
9d (~0)
9e(~0)
9e(~0)
9f(~0)
9g(~0)
LDA
9
10
11
TMS(tꢀBu)NLi
TMS(tꢀBu)NLi
TMS(tꢀBu)NLi
8g(89)
a Reactions were run at a substrate concentration of 0.1 M. b Ee’s were determined by HPLC analysis with a chiral stationary phase; see
Supporting Information. c The absolute configuration of 8e was determined to be R by the PGME method. See Supporting Information. The
absolute configurations of 8d, 8f, and 8g were not determined.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
Viswambharan, B.; Gori, D.; Kouklovsky, C.; Alezra, V. J. Org.
asymmetric cyclization of substrate 7g possessing a tertꢀ
butyl group at C(6) and a methyl group at C(3) (entry
11). Treatment of 7g with TMS(tꢀBu)NLi in THF at –78
˚C gave 8g in 91% ee and 89% yield without formation
of the product from βꢀelimination. These results indicate
that both a bulky substituent at C(6) and an additional
substituent at C(3) are indispensible for highly enantiꢀ
oselective sixꢀmembered cyclization. The absolute conꢀ
figuration of 8e was determined to be R by the PGME
method14 (see Supporting Information). This indicates
that the sixꢀmembered cyclization of 7e proceeds with
inversion of configuration.
Chem. 2012, 77, 8797ꢀ8801. (e) Mai, T. T.; Branca, M.; Gori, D.;
Guillot, R.; Kouklovsky, C.; Alezra, V. Angew. Chem. Int. Ed. 2012,
51, 4981ꢀ4984. (f) Fletcher, S. P.; Solá, J.; Holt, D.; Brown, R. A.;
Clayden, J. Beilstein J. Org. Chem. 2011, 7, 1304ꢀ1309. (g) Branca,
M.; Pena, S.; Guillot, R.; Gori, D.; Alezra, V.; Kouklovsky, C. J. Am.
Chem. Soc. 2009, 131, 10711ꢀ10718. (h) Kolaczkowski, L.; Barnes,
D. M. Org. Lett. 2007, 9, 3029ꢀ3032. (i) MacQuarrieꢀHunter, S.; Carꢀ
lier, P. R. Org. Lett. 2005, 7, 5305ꢀ5308. (j) GeronaꢀNavarro, G.;
Bonache, M. A.; Hernz, R.; GarcíaꢀLópez, M. T.; GonzálezꢀMuñiz, R.
J. Org. Chem. 2001, 66, 3538ꢀ3547.
1
2
3
4
5
6
7
8
(3) Kawabata, T.; Yahiro, K.; Fuji, K. J. Am. Chem. Soc. 1991,
114, 9694ꢀ9696.
(4) Asymmetric alkylation of configurationally stable αoxyꢀ
carbanions has been extensively developed. See: (a) Still, W. C.;
Streekumar, C. J. Am. Chem. Soc. 1980, 102, 1201ꢀ1202. (b) Hoppe,
D.; Hense, T. Angew. Chem. Int. Ed. 1997, 36, 2282ꢀ2316. (c) Baek,
P.; Basu, A.; Gallagher, D. J.; Pack, Y. S.; Thayumanavan, S. Acc.
Chem. Res. 1996, 29, 552ꢀ560.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(5) Configurationally stable biaryl ethers have been developed.
See: (a) Fuji, K.; Oka, T.; Kawabata, T.; Kinoshita, T.; Tetrahedron
Lett. 1998, 39, 1373ꢀ1374. (b) Betson, M. S.; Clayden, J.; Worrall, C.
P. Peace, S. Angew. Chem. Int. Ed. 2006, 45, 5803ꢀ5807.
(6) Dramatic temperature effects in alkylation reactions of benzoꢀ
diazepine enolates via memory of chirality has been reported. See:
reference 2i and Carlier, P. R.; Zhao, H.; MacQarrieꢀHunter S. L.;
DeGuzman, J. C.; Hsu, D. C. J. Am. Chem. Soc. 2006, 128, 15215ꢀ
15220.
(7) Uozumi, Y.; Kato, K.; Hayashi, T. J. Am. Chem. Soc. 1997,
119, 5063ꢀ5064.
In conclusion, we have developed a novel method for
asymmetric synthesis via shortꢀlived axially chiral enoꢀ
lates based on the restricted rotation of the CꢀO bond.
This method provides a unique entry to chiral cyclic
ethers with a tetrasubstituted chiral center. These comꢀ
pounds were prepared via asymmetric CꢀC bond forꢀ
mation by the present method, while they have usually
been constructed via asymmetric CꢀO bond formation.15
(8) The racemization barrier of the chiral sodium enolate derived
from 2c could be quite different from the rotational barrier of 6 beꢀ
cause of the aggregation of the sodium enolate. However, we previꢀ
ously observed that the racemization barrier of a chiral potassium
enolate with a CꢀN axis generated from an amino acid derivative,
which was determined experimentally by periodic quenching of the
enolate, was found to be comparable with the rotational barrier of the
CꢀN axis of the the corresponding silyl ketene acetal, which was deꢀ
termined by VNMR measurement. See reference 1a.
(9) Chiral enolate structure C(2c) based on the restricted rotation of
the C(1’)ꢀO bond was shown tentatively. While that based on the
restricted rotation of the C(1)ꢀO bond cannot to be excluded, we preꢀ
fer the former because asymmetric cyclization of 2 either with a
smaller (Me) or a larger (Me3Si) substituent at C(6) than CH2Br at
C(2) gave the product with the same absolute configuration (Table 1).
(10) A conformational search for 2c was performed by a molecular
modeling search (MCMM 50,000 steps) with an OPLS 2005 force
field using MacroModel (V. 9.0). Conformer 2c-II was suggested to
be 5.8 kcal/mol less stable than the most stable conformer 2c-I. For
details, see Supporting Information.
(11) The importance of the chelation may be suggested by the deꢀ
crease in the enantioselectivity of the asymmetric cyclization of 2b in
the presence of 15ꢀcrownꢀ5. Treatment of 2b under the conditions
identical to those in entry 6 of Table 1, except for the addition of 15ꢀ
crownꢀ5 (3.0 equivalents), gave 3b in 30% ee and 72% yield. The
similar chelating effect affecting stereochemistry of enolate alkylation
was reported. See: Willimas, R. M.; Glinka, T.; Kwast, E. J. Am.
Chem. Soc. 1988, 110, 5927ꢀ5929.
Readily available and abundant Lꢀethyl lactate is used
not only as a functionalized carbon resource but also as a
chiral source for the construction of chiral benzofuran
and chroman derivatives with tetrasubstituted carbon,
which frequently appear in biologically active prodꢀ
ucts.16,17
ASSOCIATED CONTENT
Supporting Information. Experimental procedures and
spectroscopic data for all new compounds. Variableꢀ
temperature NMR of 6. This material is available free of
charge via Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
kawabata@scl.kyotoꢀu.ac.jp
(12) The electrophilic center (C(2)ꢀCH2ꢀCH2ꢀI) of the chiral enoꢀ
lates generated from 7dꢀg may be in close proximity to the nucleoꢀ
philic enolate moiety due to the buttressing effect of the substituent at
C(3), which facilitates intramolecular alkylation before complete
racemization of the chiral enolate takes place. For the detailed discusꢀ
sion, see Supporting Information (Scheme SIꢀ1). The rate acceleration
by the buttressing effect of the ortho substituent in carbene CꢀH insertion
has been reported. See: Tomioka, H.; Kimoto, K.; Murata, H.; Izawa, Y. J.
C. S. Perkin I, 1991, 471ꢀ477.
ACKNOWLEDGMENT
We thank Professor Kiyosei Takasu, Faculty of Pharmaceuꢀ
tical Sciences, Kyoto University, for the valuable discusꢀ
sion. This work was partially supported by a grantꢀinꢀaid
for Young Scientists (B) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
(13) Xie, L.; Isenberger, K. M.; Held, G.; Dahl, L. M. J. Org.
Chem. 1997, 62, 7516ꢀ7519.
(14) Yabuuchi, T.; Kusumi, T. J. Org. Chem. 2000, 65, 397ꢀ404.
(15) For examples of methods for the synthesis of benzofuran and
chroman derivatives via CꢀO bond formation, see (a) reference 7. (b)
Uozumi, Y.; Kyota, H. Kato, K.; Ogasawara, M.; Hayashi, T. J. Org.
Chem. 1999, 64, 1620ꢀ1625. (c) Torraca, K. E.; Kuwabe, S.; Buchꢀ
wald, S. L. J. Am. Chem. Soc. 2000, 122, 12907ꢀ12908. (d) Trost, B.
M.; Shen, H. C.; Dong, L.; Surivet, J.ꢀP. J. Am. Chem. Soc. 2003, 125,
9276ꢀ9277.
REFERENCES
(1) For selected references, see: (a) Kawabata, T.; Suzuki, H.; Naꢀ
gae, Y.; Fuji, K. Angew. Chem. Int. Ed. 2000, 39, 2155ꢀ2157. (b)
Kawabata, T.; Kawakami, S.; Majumdar, S. J. Am. Chem. Soc. 2003,
125, 13012ꢀ13013. (c) Kawabata, T.; Matsuda, S.; Kawakami, S.;
Monguchi, D.; Moriyama, K. J. Am. Chem. Soc. 2006, 128, 15394ꢀ
15395. (d) Kawabata, T.; Moriyama, K.; Kawakami, S.; Tsubaki, K.
J. Am. Chem. Soc. 2008, 130, 4153ꢀ4157. (e) Watanabe, H.; Yoshiꢀ
mura, T.; Kawakami, S.; Sasamori, T.; Tokitoh, N.; Kawabata, T.
Chem. Commun. 2012, 48, 5346ꢀ5348.
(2) For reviews on asymmetric synthesis via axially chiral enolates
with a dynamic nature, see: (a) Zhao, H.; Hsu, D. C.; Carlier, P. R.
Synthesis 2005, 1ꢀ16. (b) Kawabata, T. ACS Symposium Series 1009.
“Asymmetric Synthesis and Application of αꢀAmino Acids”. 2009,
pp. 31ꢀ56. (c) Carlier, P. R.; Hsu, D. C.; Bryson, S. A.; Topics in
Stereochemistry; Denmark, S. E., Ed.; John Wiley & Sons: New
York, 2010; Vol. 26, pp53ꢀ92. For recent reports on the asymmetric
reactions via axially chiral enolates, see: (d) Mai, T. T.;
(16) For examples of biologically active benzofuran derivatives
with tetrasubstituted carbon, see: (a) Mayer, G.; Taberner, P. V. Eur.
J. Pharmacol. 2002, 454, 95ꢀ102. (b) Cohen, J. L.; Limon, A.; Miledi,
R.; Chamberlin, A. R. Bioorg. Med. Chem. Lett. 2006, 16, 2189ꢀ2194.
(17) For examples of biologically active chroman derivatives with
tetrasubstituted carbon at C(2), see: (a) Grisar, J. M.; Petty, M. A.;
Bolkenius, F. N.; Dow, J.; Wagner, J.; Wagner, E. R.; Haegele, K. D.;
De Jong, W. J. Med. Chem. 1991, 34, 257ꢀ260. (b) Grisar, J. M.;
Marciniak, G.; Bolkenius, F. N.; VerneꢀMismer, J.; Wagner, J.; Wagꢀ
ner, E. R. J. Med. Chem. 1995, 38, 2880ꢀ2886.
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
1
2
Insert Table of Contents artwork here
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment