Chiral base-catalyzed aldol reaction of trimethoxysilyl enol ethers: Effect of water as an additive on stereoselectivities

Article abstract of DOI:10.1016/j.tet.2005.09.074

An aldol reaction of trimethoxysilyl enol ether catalyzed by lithium binaphtholate is described. The aldol reaction of trimethoxysilyl enol ether derived from cyclohexanone under anhydrous conditions predominantly afforded the anti-aldol adduct with moder

Full text of DOI:10.1016/j.tet.2005.09.074

Tetrahedron 62 (2006) 390–400
Chiral base-catalyzed aldol reaction of trimethoxysilyl enol
ethers: effect of water as an additive on stereoselectivities
Yuya Orito,a Shunichi Hashimoto,b Tadao Ishizukaa and Makoto Nakajimaa,
*
aFaculty of Medical and Pharmaceutial Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862 0973, Japan
bGraduate School of Pharmaceutical Schiences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo 060 0812, Japan
Received 5 July 2005; revised 30 August 2005; accepted 16 September 2005
Available online 10 October 2005
Abstract—An aldol reaction of trimethoxysilyl enol ether catalyzed by lithium binaphtholate is described. The aldol reaction of
trimethoxysilyl enol ether derived from cyclohexanone under anhydrous conditions predominantly afforded the anti-aldol adduct with
moderate enantioselectivity, whereas the reaction under aqueous conditions predominantly resulted in the syn-adduct and the
enantioselectivity of the syn-adduct was considerably improved. The best enantioselectivity was obtained in the reaction of trimethoxysilyl
enol ether derived from 1-indanone with cyclohexanecarboxaldehyde (97% ee (syn)). This is the first example of an aldol reaction of
trimethoxysilyl enol ether catalyzed by a chiral base.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
wherein BINAP–silver(I) complex was employed as a
Lewis acid catalyst.7b However, base-catalyzed aldol
reactions of trimethoxysilyl enol ethers have yet to be
developed, although hypervalent silicates derived from
trimethoxysilyl compounds are well-investigated.5,7c In our
pursuit to develop base-catalyzed reactions involving
hypervalent silicate intermediate,6,8 herein we describe the
details of an enantioselective aldol reaction of trimethoxy-
silyl enol ethers catalyzed by chiral base, wherein water as
an additive played a pivotal role in stereoselectivities.9,10
The asymmetric aldol reaction is well-recognized as one of
the most important methods for constructing optically active
b-hydroxy carbonyl compounds.1 Recent significant
developments in asymmetric aldol reactions are mostly
based on the principles of conventional Mukaiyama-type
catalysis, in which aldol acceptors are activated by chiral
Lewis acid catalysts.2,3 In 1996, Denmark and co-workers
reported the first Lewis base-catalyzed enantioselective
aldol reactions of trichlorosilyl enol ethers employing chiral
phosphoramides4 as organocatalysts, wherein the aldol
donors were activated to form hypervalent silicate inter-
mediates.5 We have also reported asymmetric aldol reaction
of trichlorosilyl enol ethers catalyzed by chiral N-oxides.6
These base-catalyzed reactions afforded the corresponding
adducts with high diastereo- and enantioselectivities,
however, aldol reactions of trichlorosilyl enol ethers are
not widely utilized in organic synthesis since the enol ethers
are extremely water sensitive.
2. Results and discussion
2.1. Synthesis of trialkoxysilyl enol ethers
Trialkoxysilyl enol ethers that were sufficiently stable to
survive an aqueous work-up or silica gel column chroma-
tography were easily prepared from the corresponding
enones or ketones. Starting from the corresponding
conjugated enones, trimethoxysilyl enol ethers 1a and 1b
were prepared by hydrosilylation with trimethoxysilane
catalyzed by Rh(PPh3)3Cl using a literature procedure
(Eq. 1).7b Trimethoxysilyl enol ethers 1c–1g and triethoxy-
silyl enol ether 1h17 were prepared by silylation of lithium
enolates from the corresponding ketones with chloro-
trimethoxysilane11 (or chlorotriethoxysilane) in THF or
silylation of ketones with iodotrimethoxysilane prepared
in situ in acetonitrile in the presence of triethylamine
(Eq. 2). An aqueous work-up followed by distillation in
vacuo gave pure silyl enol ethers in moderate to good yields.
Trialkoxysilyl compounds,7 which are more stable than its
trichlorosilyl derivatives, are expected to form reactive
hypervalent silicates with bases. In 2001, Yamamoto and
co-workers reported an asymmetric aldol reaction of
trimethoxysilyl enol ethers with high enantioselectivity
Keywords: Chiral catalyst; Enantioselectivity; Aldol reaction; Silyl enol
ether; Binaphthol.
Corresponding author. Tel.: C81 96 371 4680; fax: C81 96 362 7692;
e-mail: nakajima@gpo.kumamoto-u.ac.jp
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.074

Y. Orito et al. / Tetrahedron 62 (2006) 390–400
391
(1)
(2)
Since dilithium salt and monolithium salt of 9 may form
different reactive species,7c we then examined the stoichio-
metry of lithium to 9 (Table 2). Surprisingly, a slight
difference in the equivalents of BuLi extensively influenced
the reaction rate and stereoselectivities. Catalysts prepared
with 10–14 mol% of BuLi predominantly afforded the syn-
adduct in a moderate chemical yield with a decreased
reaction rate (entries 1–3), while anti-adduct was pre-
dominantly formed using 16–20 mol% of BuLi (entries
4–6). Although the origin of the dramatic change in
stereoselectivity is unclear, the catalyst in following studies
was a dilithium salt. Screening of binaphthols revealed that
dibromide 9 and dichloride 13 were superior in terms of
diastereo- and enantioselectivity (Table 3).
2.2. Aldol reaction of trimethoxysilyl enol ether under
anhydrous condition
Our initial studies examined the addition of trimethoxysilyl
enol ether 1a derived from cyclohexanone with benzal-
dehyde using various bases (10 mol%) in THF (Table 1).
Although aromatic N-oxides efficiently catalyzed the aldol
reaction of trichlorosilyl enol ethers, N-oxide 3 did not
afford the aldol adduct for trimethoxysilyl enol ether (entry
1). On the other hands, lithium salts of chiral alcohol 5,
amines 6, 7, and binaphthol 8 gave silyl ether of
corresponding adduct in moderate to high yield (entries 3–
6). Further catalyst screenin0g based on binaphthol revealed
that the dilithium salt of 3,3 -dibromobinaphthol 9 gave the
most promising result (entry 7, 16% ee (syn), 12% ee (anti)).
Decreasing the reaction temperature to K23 8C with 9
significantly improved the stereoselectivities (entry 8, syn/
anti 1:3.7, 51% ee (anti)) without eroding the reaction
rate.12
Table 2. Effect of molar equivalent of nBuLi
Entry
nBuLi
(mol%)
Time
(h)
Yield
(%)a
syn:antib
ee (%)
(syn/
anti)b
1
2
3
4
5
6
7
10
12
14
16
18
20
22
100
30
30
0.5
0.5
0.5
0.5
42c
59c
66c
98
98
97
1.8:1
2.4:1
2.2:1
1:2.7
1:2.8
1:3.7
1:3.5
27/14
51/31
55/38
12/50
7/47
Table 1. Screening the catalyst
8/51
18/49
98
a Isolated as alcohol.
b Determined by HPLC analysis.
c Not completed.
Entry
Ligand
nBuLi
(mol%)
Time Yield syn:antib ee (%)
(h)
Table 3. Screening binaphthol derivatives
(%)a
(syn/anti)b
Entry
Substituent
on 3,3-
positon
Yield (%)a
syn:antib
ee (%)
(syn/anti)b
1
2
3
4
5
6
7
8c
3
4
5
6
7
8
9
9
0
24
24
24
5
0.5
0.5
0.5
0.5
0
0
—
—
w0/9
w0/w0
w0/w0
w0/w0
16/12
20
20
10
10
20
20
20
46
59
59
98
83
97
1:1.1
1:1.5
1:1.4
1:1.3
1:1.9
1:3.7
1
2
3
4
5
6
Me (10)
Ph (11)
CF3 (12)
Cl (13)
Br (9)
91
98
98
87
97
89
1:1.4
1:2.3
1:2.1
1:3.8
1:3.7
1:3.7
14/29
5/33
24/13
20/56
8/51
8/51
I (14)
4/31
a Isolated as alcohol.
b Determined by HPLC analysis.
a Isolated as alcohol.
b Determined by HPLC analysis.
c At K23 8C.

392
Y. Orito et al. / Tetrahedron 62 (2006) 390–400
Table 4. Aldol reaction of various silyl enol ethers with benzaldehyde
Entry
Ligand
Enol ether
Product
Yield (%)a
syn: antib
ee (%) (syn/anti)b
1
2
3
4
5
6
13
13
13
9
13
13
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
87
91
98
93
98
87c
1:3.8
1.4:1
—
3.4:1
1:1.7
1.8:1
20/56
39/42
50
46/30
w0/w0
w0/w0
a Isolated as alcohol.
b Determined by HPLC analysis.
c At room temperature (45 h).
Table 5. Aldol reaction of 1a with aldehydes catalyzed by dilithium salt of 13
Entry
Aldehyde
Product
Time (h)
Yield (%)a
syn:antib
ee (%) (syn/anti)b
1
2
3
PhCHO
PhCH]CHCHO
PhCH2CH2CHO
2a
2h
2i
0.5
0.5
3c
87
98
14
1:3.8
1:1.5
2.9:1
20/56
44/6
40/16
a Isolated as alcohol.
b Determined by HPLC analysis.
c Not completed.
Table 4 shows the results of the aldol reaction of
trimethoxysilyl enol ethers derived from various ketones
with benzaldehyde using the optimized catalyst at K23 8C.
(E)-Enolates and enolate without substituents at the
a-position afforded the corresponding aldol adducts in
good to high yields, although the diastereo- and enantio-
selectivities were moderate (entries 1–4). On the other hand,
(Z)-enolates gave low selectivities (entries 5 and 6), and the
enolate with bulky substituent slowed the reaction rate
(entry 6), probably due to steric hindrance.
proceeded smoothly, but the stereoselectivity decreased
(entry 2). The unconjugate aldehyde was much less reactive
(entry 3), as is often observed in the base-catalyzed aldol
reactions involving hypervalent silicate intermediate.
2.3. Aldol reaction of trimethoxysilyl enol ether under
aqueous condition
To enhance the stereoselectivity, we then examined the
effect of the additives. As shown in Table 6, the additive
structure strongly affected both diastereo- and enantio-
selectivities. Among various additives surveyed, water gave
the best result and predominantly afforded the syn-adduct as
the alcohol in good enantioselectivity. (entry 10).
The aldol reactions of other aldehydes with 1a were
investigated (Table 5). The reaction of conjugate aldehyde
Table 6. Screening the additives
Table 7 summarizes more detailed studies on the equivalent
of water. Interestingly, the ratio of syn to anti and the
enantioselectivity of syn-adduct increased as a function of
the increasing amount of water. Equimolar amounts of
water to silyl enol ether (1.5 equiv to aldehyde, i.e.,
1.0 equiv to silyl enol ether) were sufficient to optimize
the diastereo- and enantioselectivity (entry 5, syn/anti 3.2:1,
80% ee (syn), 51% ee (anti)), which suggests that water (or
the hydroxy ion) may strongly coordinate to the silicon atom
Entry
Additive
Time (h)
Yield (%)a syn:antib
ee (%)
(syn/
anti)b
1
2
3
4
5
6
7
8
9
10
None
EtCN
0.5
1
1
1
5
5
2
1
0.5
0.5
97
97
91
80
63
71
59
70
98
93
1:3.7
1:1.7
1.1:1
1.1:1
1.8:1
2.0:1
1.4:1
1.7:1
1.2:1
3.0:1
8/51
12/47
9/3
30/56
41/32
48/19
25/16
52/39
39/40
78/47
13,14
of silyl enol ether.
HMPA
IQNOc
TMEDA
iPr2NEt
nPrNH2
NH3
Table 7. Effect of equivalent of H2O
Entry
H2O
(equiv)
Yield
(%)
syn:antia
ee (%)
(syn/anti)a
1
2
3
4
5
0
97
93
97
93
94
1:3.7
1:1.1
1.7:1
3.0:1
3.1:1
8/51
MeOH
H2O
0.1
0.5
1.0
1.5
15/46
60/44
78/47
80/50
a Isolated as alcohol.
b Determined by HPLC analysis.
c Isoquinoline N-oxide.
a Determined by HPLC analysis.

Y. Orito et al. / Tetrahedron 62 (2006) 390–400
393
Table 8. Screening binaphthol derivatives
Entry
Substituent on
3,30-
position
Yield
(%)
syn:antia
ee (%)
(syn/anti)a
(3)
1
2
3
4
5
6
7
8
9
H (8)
Me (10)
Ph (11)
CF3 (12)
Cl (13)
Br (9)
I (14)
CH2OMe (15)
CO2Me (16)
76
98
98
95
98
94
98
98
76
1.2:1
2.3:1
2.0:1
2.6:1
3.0:1
3.1:1
2.9:1
1.6:1
1:1.1
24/5
55/15
34/5
69/38
78/48
80/50
73/35
14/1
(4)
Control experiments showed that the trimethoxysilyl enol
ether, which was stable under anhydrous conditions even in
the presence of lithium binaphtholate, quickly decomposed
into the corresponding ketone in aqueous conditions in the
presence of lithium binaphtholate (Eqs. 3 and 4).15 This
suggests that the coordination of water (or hydroxy ion) to
silicon atom may increase the nucleophilicity of the silicate
complex to predominantly afford the syn-adduct via an
acyclic transition state, while under anhydrous conditions
the reaction may proceed via a cyclic chairlike transition
state4,5 to predominantly yield the anti adduct, but the
details of reaction mechanism are unclear.
17/46
a Determined by HPLC analysis.
Table 9. Aldol reaction of various silyl enol ethers with benzaldehyde
under hydrous condition
An evaluation of the binaphthol derivatives is shown in
Table 8. Although both steric and electronic factor
influenced the selectivity, binaphthols with halogen sub-
stituents at 3,30-position gave relatively superior results.
Consequently, dibromide 9 gave the best result in terms of
diastereo- and enantioselectivity.
Entry
Silyl enol Product
ether
Yield
(%)
syn:antia
ee (%)
(syn/
anti)a
1
2
3
4
5
6
1a
1c
1d
1e
1g
1h
2a
2c
2d
2f
2g
2a
94
88
98
91
78
83b
3.1:1
—
2.9:1
1.9:1
2.9:1
2.9:1
80/50
75
72/6
19/38
83/48
77/45
Table 9 shows the results of the aldol reactions of
trimethoxysilyl enol ethers derived from various ketones
and benzaldehyde under optimal conditions. In all cases, the
corresponding syn-adducts were predominantly obtained in
good to excellent yields. Enantioselectivities of (E)-enolates
(entries 2, 3 and 5) were comparable to that of 1a (entry 1),
while (Z)-enolate demonstrated relatively low selectivity,
similar to anhydrous conditions (entry 4). Among various
silyl enol ethers, indanone derivative 1g gave the best
enantioselectivity (entry 5). Triethoxysilyl enol ether 1h
a Determined by HPLC analysis.
b Eighteen hours.
Table 10. Aldol reaction of 1g with various aldehydes under hydrous condition
Entry
Aldehyde
Product
Yield (%)
syn:antia
ee (%) (syn/anti)a
1
2
3
4
5
6
PhCHO
2g
2j
2k
2l
2m
2n
78
89
88
98
90
94
2.9:1
2.4:1
2.1:1
3.4:1
2.6:1
1.4:1
83/48
70/25
48/39
73/10
92/47
97/84
p-MeOC6H4CHO
p-CF3C6H4CHO
PhCH]CHCHO
PhCH2CH2CHO
cHexCHO
a Determined by HPLC analysis.
Table 11. Aldol reaction of 1a with various aldehyde under hydrous condition
Entry
Aldehyde
Product
Yield (%)
syn:antia
ee (%) (syn/anti)a
1
2
3
4
5
PhCHO
2a
2o
2p
2h
2i
94
90
94
96
75
3.1:1
1.4:1
1.6:1
1.4:1
1.2:1
80/50
81/65
72/45
75/5
1-NaphCHO
2-NaphCHO
PhCH]CHCHO
PhCH2CH2CHO
91/40
a Determined by HPLC analysis.

394
Y. Orito et al. / Tetrahedron 62 (2006) 390–400
showed a significantly decreased reactivity, although the
yield and stereoselectivities were about the same (entry 6).
of new compounds were assigned based on the splitting
pattern of the hydroxyl bearing methine.4b
Table 10 summarizes the aldol reactions of indanone
derivative 1g with various aldehydes. Introducing both
electron donating/withdrawing groups decreased the
enantioselectivity (entries 2 and 3). Interestingly, rather
high enantioselectivities were observed in the reaction of
unconjugate aldehydes (entries 5–7), which showed quite
low reactivities under anhydrous conditions (Table 5, entry
3). The best enantioselectivity (97% ee) was obtained in the
reaction of cyclohexenecarboxaldehyde, though the dia-
stereoselectivity decreased (entry 6).
Column chromatography was conducted on Silica Gel 60 N
(spherical, neutral, 60–210 mm, Kanto Chemical Co.).
Analytical thin-layer chromatography was carried out on
Merck Kieselgel 60 F254 plates with visualization by
ultraviolet and stains. TLC stains were prepared as follows;
p-anisaldehyde stain: EtOH (460 mL), p-anisaldehyde
(13 mL), AcOH (5 mL), concd H2SO4 (17 mL).; PMA
stain: EtOH solution of phosphomolybdic acid (5% wt);
PMA/H2SO4 stain: H2O (400 mL), phosphoric acid (6 mL),
concd H2SO4 (20 mL), phosphomolybdic acid (9.6 g).
Table 11 shows the reaction of cyclohexanone derivative 1a
with various aldehydes. Though diastereoselectivities are
not satisfactory, modest to high enantioselectivities were
generally obtained. The best enantioselectivity was
observed in the reaction of unconjugate aldehyde 2i (entry
7, 91% ee). It is noteworthy that the aldol reaction of
unconjugate aldehydes, which often gives inferior results
under Lewis base-catalyzed condition, afforded adducts in
high yield and with high enantioselectivity.
Reagents and solvents were purchased and purified by
standard means or used as received unless otherwise noted.
Dehydrated stabilizer free THF and dichloromethane were
purchased from Kanto Chemical Co., Inc. and used as
received. Concentration of n-butyllithium was estimated by
titrating with diphenylacetic acid in THF.16
4.2. Representative procedures for the synthesis of
trimethoxysilyl enol ethers by hydrosilylation
Trimethoxysilyl enol ethers 1a and 1b were prepared by
modifying a literature procedure.
3. Conclusion
4.2.1. 1-Trimethoxysilyloxycyclohexene (1a).7b To an
orange solution of Rh(PPh3)3Cl (20.5 mg, 23 mmol,
0.025 mol%) in 2-cyclohexen-1-one (8.6 g, 90 mmol) was
added trimethoxysilane (14.3 g, 117 mmol, 1.3 equiv) under
an argon atmosphere at room temperature. After heating at
90 8C for 30 min, the reaction mixture was cooled to room
temperature. Ice-cooled satd NaHCO3 (15 mL) was added
and the mixture was vigorously stirred. After removing the
cloudy material by Celite filtration and washing with
hexane, the combined organic layer was washed with
brine, dried over Na2SO4, and evaporated to give the crude
product as a pale yellow oil. Distillation in vacuo (118–
119 8C, 20 mmHg) gave the silyl enol ether as a colorless oil
(15.1 g, 77%); 1H NMR (CDCl3, 270 MHz) d 1.46–1.54 (m,
2H), 1.59–1.70 (m, 2H), 1.97–2.10 (m, 2H), 3.58 (s, 9H),
5.05–5.07 (m, 1H).
An aldol reaction of trimethoxysilyl enol ether catalyzed by
lithium binaphtholate was developed, wherein water served
as an additive and played a pivotal role in stereoselectivities.
This is the first example of an aldol reaction of
trimethoxysilyl enol ether catalyzed by a chiral base.
Mechanistic studies as well as designing a new chiral
catalyst to enhance the stereoselectivities are currently
underway.
4. Experimental
4.1. General
Melting points were measured using a Bu¨chi 535 melting
point apparatus and were not corrected. Optical rotations
were obtained on a JASCO P-1030 digital polarimeter.
Infrared spectra were recorded on a JASCO FT/IR-5300. 1H
NMR and 13C NMR spectra were recorded on a JEOL
EX-270 (1H, 270 MHz; 13C, 68 MHz) spectrometer in
deuteriochloroform. Chemical shift values are expressed in
ppm relative to internal tetramethylsilane. Coupling
constants (J) are reported in Hertz (Hz). NMR data are
presented as follows: chemical shift, multiplicity, inte-
gration, coupling constant. Abbreviations are as follows: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br,
broad. Mass spectra were obtained on JEOL JMS-DX303 or
JEOL FABmate. HPLC was performed on a JASCO
PU-1580 with a JASCO UV-1575 (lZ254 nm) and chiral
separations were performed using Daicel chiralpak or
chiralcel columns (4 0.46!25 cm). Hexane and 2-propanol
for HPLC were HPLC grade and filtered and degassed
before use. HPLC peaks of syn/anti isomers were assigned
by the comparing to authentic samples prepared with
racemic binaphthol as a catalyst. The relative configurations
4.2.2.
1-Trimethoxysilyloxycycloheptene
(1b).7b
Following the representative procedure, silyl enol ether 1b
was obtained from 2-cyclohepten-1-one (0.28 g, 2.5 mmol)
as a colorless oil (0.32 g, 56%); 1H NMR (CDCl3,
270 MHz) d 1.47–1.81 (m, 6H), 1.91–2.02 (m, 2H), 2.28–
2.32 (m, 2H), 3.58 (s, 9H), 5.21 (t, 1H, JZ6.5 Hz).
4.3. Representative procedure for the synthesis of
trimethoxysilyl enol ethers via enolate
4.3.1. 1-Trimethoxysilyloxy-1-phenylethylene (1c).
Method A. To a solution of diisopropylamine (2.9 g,
28.8 mmol, 1.15 equiv) in THF (50 mL) was added
n-butyllithium in hexane (1.6 M, 17.2 mL, 27.5 mmol,
1.1 equiv) at K78 8C. After stirring for 15 min, aceto-
phenone (3.0 g, 25 mmol) was added dropwise to the pale
yellow mixture via a cannula over a 30 min period. After
stirring an additional 15 min, chlorotrimethoxysilane11
(4.31 g, 27.5 mmol, 1.1 equiv) was added dropwise and

Y. Orito et al. / Tetrahedron 62 (2006) 390–400
395
the entire mixture was stirred for 30 min. The mixture was
evaporated and the resulting white precipitate was removed
by Celite filtration and washed with hexane. Ice-cooled satd
NaHCO3 (30 mL) was added to the filtrate and the mixture
was stirred vigorously. After removing the cloudy material
by Celite filtration, the organic layer was dried over Na2SO4
and evaporated to give the crude product as a brown oil.
Distillation in vacuo (122–124 8C, 14 mmHg) gave the silyl
enol ether as a colorless oil (2.7 g, 45% yield).
4.3.5. 1-Trimethoxysilyloxy-3H-indene (1g). Following
the representative procedure A, silyl enol ether 1g was
obtained from 1-indanone (3.3 g, 25 mmol) as a colorless oil
(1.7 g, 62%). Bp 125 8C, 4 mmHg; 1H NMR (CDCl3,
270 MHz) d 3.27 (d, 2H, JZ2.5 Hz), 3.65 (s, 9H), 5.67 (t,
1H, JZ2.5 Hz), 7.1–7.5 (m, 4H); 13C NMR (CDCl3,
68 MHz) d 151.6, 142.6, 140.5, 126.0, 125.2, 123.8,
118.0, 107.3, 51.5, 33.8; IR (neat) 2948, 2847, 1605,
1578, 1366, 1181, 1082, 901, 837 cmK1; LR-EIMS 252
(MC), 236 (bp), 121, 91; HR-EIMS calcd for C12H16O4Si
252.0818, found 252.0806.
Method B. To a solution of anhydrous sodium iodide
(8.25 g, 55 mmol, 1.1 equiv; dried over 5 mmHg, 150 8C,
6 h) in acetonitrile (60 mL) was added chlorotrimethoxy-
silane11 (8.61 g, 55 mmol, 1.1 equiv) at room temperature
under an argon atmosphere. After stirring for 5 min,
acetophenone (6.0 g, 50 mmol) was added and the mixture
was stirred for additional 5 min. Triethylamine (12.6 g,
125 mmol, 2.5 equiv) was added dropwise to the pale
yellow mixture. After refluxing for 3 h, the mixture was
extracted with hexane (5!80 mL). The organic layer was
evaporated and the precipitates were removed by Celite
filtration. Ice-cooled satd NaHCO3 was added to the filtrate
and the mixture was vigorously stirred. After removing the
cloudy material by Celite filtration, the organic layer was
dried over Na2SO4 and evaporated to give the crude product
as a brown oil. Distillation in vacuo (108–110 8C, 9 mmHg)
gave the silyl enol ether as a colorless oil (5.0 g, 42% yield).
4.3.6. 1-Triethoxysilyloxycyclohexene (1h).17 Following
the representative procedure A, silyl enol ether 11 was
obtained from cyclohexanone (0.98 g, 10 mmol) and
chlorotriethoxysilane (2.2 g, 11 mmol) as a colorless oil
1
(1.6 g, 62%). Bp 87–89 8C, 9 mmHg; H NMR (CDCl3,
270 MHz) d 1.22 (t, 9H, JZ6.5 Hz), 1.47–1.56 (m, 2H),
1.63–1.67 (m, 2H), 1.97–2.10 (m, 4H), 3.85 (q, 6H, JZ
6.5 Hz), 5.07 (m, 1H).
4.4. Synthesis of 3,30-disubstituted binaphthol
derivatives
Binaphthol derivatives 10–16 were prepared by literature
procedure.
4.4.1. (R)-3,30-dimethyl-1,10-binaphthalene-2,20-diol
(10).18 TLC RfZ0.5 (benzene, PMA/H2SO4); 1H NMR
(CDCl3, 270 MHz) d 2.49 (s, 6H), 5.10 (s, 2H), 7.05 (d, 2H,
JZ8.6 Hz), 7.20 (d, 2H, JZ7.3 Hz), 7.32 (t, 2H, JZ
6.5 Hz), 7.79–7.81 (m, 4H); mp 199–201 8C; [a]D C33.7 (c
1.0, CHCl3); [a]546 C43.9 (c 1.0, CHCl3).
1
Compound 1c. H NMR d 3.62 (s, 9H, SiOCH3), 4.72 (d,
1H, JZ2.2 Hz), 5.00 (d, 1H, JZ2.2 Hz), 7.34–7.28 (m, 3H),
7.65–7.60 (m, 2H); 13C NMR d 51.6, 92.0, 125.1, 128.2,
128.4, 136.3, 153.8; IR (neat) 2945, 2840, 1692, 1621, 1573,
1492, 1317, 1201, 1096, 1037, 828, 775, 743, 715 cmK1
;
LR-EIMS 241 ((MCH)C), 120, 105, 77; HR-EIMS calcd
for C11H16O4Si 241.0896, found 241.0892.
4.4.2. (R)-3,30-diphenyl-1,10-binaphthalene-2,20-diol
1
(11).19 TLC RfZ0.4 (hexane/AcOEt 4:1, UV); H NMR
4.3.2. (Z)-tert-butylpropenyloxytrimethoxysilane (1f).7b
Following the representative procedure A, silyl enol ether 1f
was obtained from 2,2-dimethyl-3-pentanone (0.57 g,
5 mmol) as a colorless oil (0.87 g, 74%); 1H NMR
(CDCl3, 270 MHz) d 1.09 (s, 9H), 1.57 (d, 3H, JZ
6.5 Hz), 3.68 (s, 9H), 4.64 (q, 1H, JZ6.6 Hz).
(CDCl3, 270 MHz) d 5.34 (s, 2H), 7.20–7.51 (m, 12H),
7.70–7.74 (m, 4H), 7.91 (d, 2H, JZ7.8 Hz), 8.01 (s, 2H);
mp 197–199 8C; [a]D C104.3 (c 1.0, CHCl3).
4.4.3. (R)-3,30-dichloro-1,10-binaphthalene-2,20-diol
1
(13).20 TLC RfZ0.4 (hexane/AcOEt 4:1, UV); H NMR
(CDCl3, 270 MHz) d 5.55 (s, 2H), 7.09 (d, 2H, JZ8.4 Hz),
7.28–7.40 (m, 8H), 7.80 (d, 2H, JZ8.6 Hz), 8.06 (s, 2H);
mp 167–170 8C; [a]D C90.3 (c 1.0, CHCl3).
4.3.3.
1-Trimethoxysilyloxycyclopentene
(1d).7b
Following the representative procedure A, silyl enol ether
4.4.4. (R)-3,30-diiodo-1,10-binaphthalene-2,20-diol (14).20
TLC RfZ0.5 (hexane/AcOEt 4:1, UV); H NMR (CDCl3,
270 MHz) d 5.41 (s, 2H), 7.05 (d, 2H, JZ8.6 Hz), 7.26–7.38
(m, 8H), 7.77 (d, 2H, JZ8.6 Hz), 8.50 (s, 2H); mpO300 8C;
[a]D C100.9 (c 1.0, THF).
1d was obtained from cyclopentanone (2.1 g, 25 mmol) as a
colorless oil (2.7 g, 53%); H NMR (CDCl3, 270 MHz) d
1.86–1.95 (m, 2H), 2.26–2.38 (m, 4H), 3.62 (s, 9H), 4.84–
4.86 (m, 1H).
1
1
4.3.4. (Z)-trimethoxy-(1-phenylpropenyloxy)silane (1e).
Following the representative procedure A, silyl enol ether
1e was obtained from propiophenone (3.4 g, 25 mmol) as a
colorless oil (1.7 g, 27%, E/Z 1:34). Bp 116 8C, 11 mmHg;
1H NMR (CDCl3, 270 MHz) d 1.80 (d, 3H, JZ6.5 Hz), 3.49
(s, 9H), 5.37 (q, 1H, JZ6.5 Hz), 7.32–7.18 (m, 3H), 7.51 (d,
2H); 13C NMR (CDCl3, 68 MHz) d 148.0, 137.9, 128.2,
127.4, 125.0, 105.8, 51.4, 11.0; IR (neat) 3057, 2947, 2847,
2361, 1948, 1690, 1659, 1599, 1495, 1447, 1381, 1323,
1267, 1196, 1100, 1032 cmK1; LR-EIMS 254 (MC), 225
(bp), 121; HR-EIMS calcd for C12H17O4Si 254.0974, found
254.0966.
4.4.5. (R)-3,30-bis(methoxycarbonyl)-1,10-binaphthal-
ene-2,20-diol (16).21 TLC RfZ0.4 (hexane/AcOEt 4:1,
PMA/H2SO4); 1H NMR (CDCl3, 270 MHz) d 4.04 (s,
6H), 7.11–7.15 (m, 2H), 7.29–7.35 (m, 4H), 7.88–7.92 (m,
2H), 8.67 (s, 2H); mp 244–246 8C; [a]D C170.5 (c 1.1,
THF).
4.4.6. (R)-3,30-bis(trifluoromethyl)-1,10-binaphthalene-
2,20-diol (12).22 To a double-necked 20 mL round-bottomed
flask equipped with a magnetic stirring bar, septum, and
dry-ice condenser containing activated cadmium (675 mg,

396
Y. Orito et al. / Tetrahedron 62 (2006) 390–400
6 mmol) was added DMF (2.5 mL) under argon atmosphere.
Dibromodifluoromethane (0.28 mL, 3 mmol) was added to
the mixture at 0 8C and the entire mixture was immediately
warmed to room temperature. After stirring for 2 h, the
suspension was filtered with glass filter under argon pressure
and the precipitate was washed with DMF (0.5 mL). To the
resulting brown solution, HMPA (3.0 mL) was added
followed by cuprous bromide (215 mg, 1.5 mmol) in one
portion at 0 8C. After stirring for a few minutes, 3,30-diiodo-
UV); 1H NMR (CDCl3, 270 MHz) d 3.51 (s, 3H), 4.84 (dd,
2H, JZ12.7, 16.4 Hz), 7.11 (d, 1H, JZ8.4 Hz), 7.2–7.4 (m,
2H), 7.82 (s, 1H), 7.85 (s, 1H); 13C NMR (CDCl3, 68 MHz)
d 58.5, 72.5, 113.9, 123.8, 124.5, 125.5, 126.8, 128.1, 128.5,
128.8, 133.5, 151.3; IR (KBr) 3526, 3294, 1626, 1504,
1392, 1194, 1107, 922 cmK1; mp 143–144 8C; [a]D C20.2
(c 0.78, CHCl3); LR-FABMS 374 (MC); HR-FABMS calcd
374.1518 found 374.1505; Anal. Calcd for C24H22O4: C,
76.99; H, 5.92 found C, 77.20; H, 6.02.
2,20-bis(methoxymethoxy)-1,10-binaphthyl
(62.6 mg,
0.1 mmol), which was prepared by the literature pro-
cedure20 was added in one portion and then the reaction
mixture was heated at 70 8C for 6 h. Benzene (10 mL) and
H2O (5 mL) were added to the reaction mixture and the
mixture was vigorously stirred at room temperature for 12 h.
After removing the precipitate by Celite filtration, the
organic layer was washed with H2O and brine, dried over
Na2SO4, and evaporated. The brown residue was purified
with silica gel column chromatography (hexane/benzene,
1:1). Dichloromethane (2 mL), methanol (2 mL), and concd
HCl (0.3 mL) were added to the resulting yellow oil and the
mixture was stirred overnight at room temperature. Then the
organic layer was washed with satd NaHCO3 and brine,
dried over Na2SO4, and evaporated. Purification with silica
gel 0column chromatography (hexane/AcOEt, 20:1) aff0orded
3,3 -bis(trifluoromethyl)-1,10-binaphthalene-2,2 -diol
(34.0 mg, 81% yield) as pale yellow prisms. TLC RfZ0.4
(hexane/AcOEt 8:1, UV); 1H NMR d 5.35 (br, 2H), 7.10 (d,
2H, JZ7.3 Hz), 7.44 (m, 4H), 7.86 (d, 2H, JZ7.3 Hz), 8.36
4.5. General procedure for the aldol reaction of
trimthoxysilyl enol ethers under anhydrous conditions
To a stirred solution of (R)-3,30-dibromo-1,10-binaphtha-
lene-2,20-diol 9 (21.0 mg, 0.047 mmol, 0.1 equiv) in THF
(3 mL) was added n-butyllithium in hexane (0.16 M,
0.6 mL, 0.094 mmol, 0.2 equiv) at K23 8C, and the
resulting yellow mixture was stirred for a few minutes.
Then a solution aldehyde in THF (1.0 M, 0.47 mL,
0.47 mmol) and trimethoxysilyl enol ether (0.70 mmol,
1.5 equiv) were added. The mixture was stirred for 0.5 h at
the same temperature and the reaction was quenched with
KF/KH2PO4 aq (15% KF, 10% KH2PO4 solution, 2 mL).
The entire mixture was stirred for an additional 2 h and the
mixture was diluted with AcOEt (10 mL). The organic layer
was washed three times with brine, dried over Na2SO4, and
then evaporated. The crude product was purified by silica
gel column chromatography (9.0 g SiO2, CH2Cl2/hexane
8:1, then CH2Cl2/AcOEt 160:1/10:1) to give the
corresponding aldol adduct as a syn/anti mixture. The
enantiomeric excess of the adduct was determined by chiral
HPLC.
(s, 2H); IR (KBr) 3549, 3063, 1630, 1332, 1207, 1155 cmK1
;
[a]2D3 C657 (c 1.01, THF); mp 235–237 8C; LR-FABMS
422 (MC); 154, 136; HR-FABMS calcd 422.0742 found
422.0752; Anal. Calcd for C22H12F6O2: C, 62.57; H, 2.86
found C, 62.18; H, 2.96.
4.5.1. 2-(Hydroxyphenylmethyl)cyclohexanone (2a).7b
Following the general procedure, the aldol adduct 2a was
obtained from silyl enol ether 1a and benzaldehyde as a
colorless oil (93.4 mg, 97%, syn/anti 1:3.7, syn 8% ee, anti
51% ee). TLC RfZ0.35 (syn), 0.30 (anti) (hexane/AcOEt
4:1, p-anisaldehyde); 1H NMR (CDCl3, 270 MHz) d 1.4–1.9
(m, 8H), 2.0–2.1 (m, 4H), 2.3–2.7 (m, 4H), 2.99 (d, 1H, JZ
2.7 Hz), 3.93 (m, 1H), 4.79 (d, 1H, JZ8.9 Hz), 5.40 (d, 1H,
JZ2.7 Hz), 7.2–7.4 (m, 10H); HPLC (Daicel chiralcel
OD-H, hexane/IPA 19:1, 1.0 mL/min): tR 9.4 (syn-minor,
2S, 10S), 10.6 (syn-major, 2R, 100R), 12.5 (anti-major, 2S,
10R), 18.5 min (anti-minor, 2R, 1 S).
4.4.7. (R)-3,30-bis(methoxymethyl)-1,10-binaphthalene-
2,20-diol (16). To a 20 mL round-bottomed flask equipped
with magnetic stirring bar containing sodium hydride (65%,
57 mg, 1.5 mmol, 2.4 equiv) and THF (5 mL) was adde0d
THF (5 mL) solution of (R)-3,30-bis(hydroxymethyl)-2,2 -
bis(methoxymethoxy)-1,10-binaphthyl
(277 mg,
0.64 mmol) prepared by the literature procedure23 via a
cannula. After stirring for 1 h, methyl iodide (0.25 mL,
4.0 mmol, 6.3 equiv) was added to the resulting yellow
solution, which was then stirred additional 2 days. After the
reaction was completed, water (10 mL) was added to the
mixture and the entire mixture was extracted with AcOEt
(3!50 mL). The organic layer was washed w0ith brine, dried
over Na2SO4, and evaporated to give (R)-3,3 -bis(methoxy-
methyl)-2,20-bis(methoxymethoxy)-1,10-binaphthyl as a
yellow oil (288 mg, 98% (crude)). Dichloromethane
(5 mL) was added to this crude product, followed by
concd HCl aq (0.3 mL), and the solution was stirred for 2 h
at room temperature. The reaction mixture was neutralized
with satd NaHCO3 and extracted with AcOEt (3!50 mL).
The organic layer was washed with brine, dried over
Na2SO4, and evaporated. The resulting yellow oil was
purified with silica gel column chromatography (12 g SiO2,
CH2Cl2/AcOEt 100:1/20:1). Recrystalization of resulting
yellow solid (hexane/AcOEt 4:1) gave 3,30-bis(methoxy-
methyl)-1,10-binaphthalene-2,20-diol as colorless prisms
(1st crop, 90.2 mg, 38%) and pale yellow prisms (2nd
crop, 55.4 mg, 23%). TLC RfZ0.25 (hexane/AcOEt 1:1,
4.5.2. 2-(Hydroxyphenylmethyl)cycloheptanone (2b).7b
Following the general procedure, the aldol adduct 2b was
obtained from silyl enol ether 1b and benzaldehyde as a
colorless oil (93.0 mg, 91%, syn/anti 1.4:1, syn 39% ee, anti
42% ee). TLC RfZ0.5 (hexane/AcOEt 4:1, p-anis-
aldehyde); 1H NMR (CDCl3, 270 MHz) d 1.2–1.9 (m,
14H), 2.4–2.7 (m, 4H), 2.85 (m, 1H), 3.00 (m, 1H), 3.3–3.5
(m, 2H), 4.82 (d, 1H, JZ8.4 Hz), 5.19 (d, 1H, JZ2.7 Hz),
7.2–7.5 (m, 10H); HPLC (Daicel chiralpak AD-H, hexane/
IPA 19:1, 1.0 mL/min): tR 11.8 (syn-major), 13.4 (syn-
minor), 20.2 (anti-minor), 23.5 min (anti-major).
4.5.3. 2-(Hydroxyphenylmethyl)cyclopentanone (2d).7b
Following the general procedure, the aldol adduct 2d was
obtained from silyl enol ether 1d and benzaldehyde as a
colorless oil (83.0 mg, 93%, syn/anti 3.4:1, syn 46% ee,
anti 30% ee). TLC RfZ0.4 (hexane/AcOEt 4:1,

Y. Orito et al. / Tetrahedron 62 (2006) 390–400
397
p-anisaldehyde); 1H NMR (CDCl3, 270 MHz) d 1.6–2.5 (m,
14H), 4.69 (d, 1H, JZ9.5 Hz), 5.29 (t, 1H, JZ4.0 Hz), 7.2–
7.4 (m, 10H); HPLC (Daicel chiralcel OD-H, hexane/IPA
9:1, 1.0 mL/min): tR 7.9 (syn-minor), 9.5 (syn-major), 11.5
(anti-minor, 2S, 10R), 13.7 min (anti-major, 2R, 10S).
4.6. The general procedure for the aldol reaction of
trimethoxysilyl enol ethers under aqueous conditions. To
a stirred solution of (R)-3,30-dibromo-1,10-binaphthalene-
2,20-diol 9 (21.0 mg, 0.047 mmol, 0.1 equiv) in THF (3 mL)
was added H2O in THF (2.8 M, 0.25 mL, 0.70 mmol,
1.5 equiv) and n-butyllithium in hexane (0.16 M, 0.6 mL,
0.094 mmol, 0.2 equiv) at K23 8C. The resulting yellow
mixture was stirred for a few minutes and then a solution of
aldehyde in THF (1.0 M, 0.5 mL, 0.47 mmol) and
trimethoxysilyl enol ether (0.70 mmol, 1.5 equiv) were
added. The mixture was stirred for 0.5 h at the same
temperature and the reaction was quenched with KF/
KH2PO4 aq (15% KF, 10% KH2PO4 solution, 2 mL). The
mixture was diluted with AcOEt (10 mL) and washed three
times with brine. The organic layer was dried over Na2SO4
and then evaporated. The crude product was purified by
silica gel column chromatography (CH2Cl2/hexane 8:1, then
CH2Cl2/AcOEt 160:1/10:1) to give the corresponding
aldol adduct as a syn/anti mixture. The enantiomeric excess
of the adduct was determined by chiral HPLC.
4.5.4. 3-Hydroxy-1,3-diphenyl-1-propanone (2c).24
Following the general procedure, the aldol adduct 2c was
obtained from silyl enol ether 1c and benzaldehyde as a
colorless oil (98.0 mg, 92%, 50% ee). TLC RfZ0.25
1
(hexane/AcOEt 4:1, UV); H NMR (CDCl3, 270 MHz) d
3.38 (d, 2H, JZ6.1 Hz), 5.36 (t, 1H, JZ6.1 Hz), 7.3–7.6 (m,
8H), 7.9–8.0 (m, 2H); HPLC (Daicel chiralcel OB-H,
hexane/IPA 9:1, 1.0 mL/min) tR 17.8 min (major, R),
25.8 min (minor, S).
4.5.5. 3-Hydroxy-2-methyl-1,3-diphenyl-1-propanone
(2e).4b Following the general procedure, the aldol adduct
2e was obtained from silyl enol ether 1e and benzaldehyde
as a colorless oil (111 mg, 98%, syn/anti 1:1.7, syn w0% ee,
anti w0% ee). TLC RfZ0.20 (hexane/AcOEt 4:1,
1
4.6.1. 2-(Hydroxyphenylmethyl)cyclohexanone (2a).7b
Following the general procedure, the aldol adduct 2a was
obtained from silyl enol ether 1a and benzaldehyde as a
colorless oil (89.2 mg, 93%, syn/anti 3.1:1, syn 80% ee, anti
50% ee). TLC RfZ0.35 (syn), 0.30 (anti) (hexane/AcOEt
4:1, p-anisaldehyde); 1H NMR (CDCl3, 270 MHz) d 1.4–1.9
(m, 8H), 2.0–2.1 (m, 4H), 2.3–2.7 (m, 4H), 2.99 (d, 1H, JZ
2.7 Hz), 3.93 (m, 1H), 4.79 (d, 1H, JZ8.9 Hz), 5.40 (d, 1H,
JZ2.7 Hz), 7.2–7.4 (m, 10H); HPLC (Daicel chiralcel
OD-H, hexane/IPA 19:1, 1.0 mL/min): tR 9.4 (syn-minor,
2S, 10S), 10.6 (syn-major, 2R, 100R), 12.5 (anti-major, 2S,
10R), 18.5 min (anti-minor, 2R, 1 S).
p-anisaldehyde); H NMR (CDCl3, 270 MHz) d 1.06 (d,
3H, JZ7.3 Hz), 1.18 (d, 3H, JZ7.3 Hz), 2.94 (d, 1H, JZ
4.6 Hz), 3.7–3.9 (m, 3H), 4.95 (m, 1H), 5.23 (s, 1H), 7.2–7.6
(m, 17H), 7.9–8.0 (m, 3H); HPLC (Daicel chiralcel OD-H,
hexane/IPA 19:1, 1.0 mL/min): tR 10.5 (syn), 12.3 (syn),
15.2 (anti), 16.9 min (anti).
4.5.6. 1-Hydroxy-2,4,4-trimethyl-1-phenylpentan-3-one
(2f).7b Following the general procedure, the aldol adduct
2f was obtained from silyl enol ether 1f and benzaldehyde as
a colorless oil (91.0 mg, 87%, syn/anti 1.8:1, syn w0% ee,
anti w0% ee). TLC RfZ0.4 (hexane/AcOEt 4:1, KI/I2 aq,
1
4.6.2. 2-(Hydroxyphenylmethyl)cyclopentanone (2d).7b
Following the general procedure, the aldol adduct 2d was
obtained from silyl enol ether 1d and benzaldehyde as a
colorless oil (88 mg, 98%, syn/anti 2.9:1, syn 72% ee, anti
6% ee). TLC RfZ0.4 (hexane/AcOEt 4:1, p-anisaldehyde);
1H NMR (CDCl3, 270 MHz) d 1.6–2.5 (m, 14H), 4.69 (d,
1H, JZ9.5 Hz), 5.29 (t, 1H, JZ4.0 Hz), 7.2–7.4 (m, 10H);
HPLC (Daicel chiralcel OD-H, hexane/IPA 9:1, 1.0 mL/
min): tR 7.9 (syn-minor), 9.5 (syn-major), 11.5 (anti-minor,
2S, 10R), 13.7 min (anti-major, 2R, 10S).
H2SO4); H NMR (CDCl3, 270 MHz) d 0.9–1.1 (m, 24H),
3.1–3.4 (m, 3H), 3.5–3.6 (m, 1H), 4.75 (d, 1H, JZ7.3 Hz),
5.23 (d, 1H, JZ4.1 Hz), 7.1–7.4 (m, 10H); HPLC (Daicel
chiralpak AD-H, hexane/IPA 40:1, 1.0 mL/min): tR 11.1
(syn), 11.7 (syn), 12.8 (anti), 15.1 min (anti).
4.5.7. 2-(1-Hydroxy-3-phenyl-2-propenyl)cyclohex-
anone (2h).4b Following the general procedure, the aldol
adduct 2h was obtained from silyl enol ether 1a and
cinnamaldehyde as a colorless oil (106 mg, 98%, syn/anti
1:1.5, syn 44% ee, anti 6% ee). TLC RfZ0.4 (hexane/
AcOEt 4:1, UV); 1H NMR (CDCl3, 270 MHz) d 1.3–1.8 (m,
8H), 1.8–1.9 (m, 2H), 2.0–2.2 (m, 2H), 2.3–2.6 (m, 6H),
4.43 (t, 1H, JZ8.1 Hz), 4.77 (m, 1H), 6.1–6.3 (m, 2H), 6.5–
6.7 (m, 2H), 7.1–7.4 (m, 10H); HPLC (Daicel chiralcel
AD-H, hexane/IPA 19:1, 1mL/min) tR 32.8 (syn-major),
40.0 (syn-minor), 44.3 (anti-minor), 53.1 min (anti-major).
4.6.3. 3-Hydroxy-1,3-diphenyl-1-propanone (2c).24
Following the general procedure, the aldol adduct 2c was
obtained from silyl enol ether 1c and benzaldehyde as a
colorless oil (94 mg, 88%, 75% ee). TLC RfZ0.25 (hexane/
AcOEt 4:1, UV); 1H NMR (CDCl3, 270 MHz) d 3.38 (d, 2H,
JZ6.1 Hz), 5.36 (t, 1H, JZ6.1 Hz), 7.3–7.6 (m, 8H), 7.9–
8.0 (m, 2H); HPLC (Daicel chiralcel OB-H, hexane/IPA
9:1, 1.0 mL/min) tR 17.8 min (major, R), 25.8 min (minor,
S).
4.5.8. 2-(1-Hydroxy-3-phenylpropyl)cyclohexanone
(2i).4b Following the general procedure, the aldol adduct
2i was obtained from silyl enol ether 1a and hydrocinnam-
aldehyde as a colorless oil (15 mg, 14%, syn/anti 2.9:1, syn
40% ee, anti 16% ee). TLC RfZ0.35 (hexane/AcOEt 4:1,
p-anisaldehyde); 1H NMR (CDCl3, 270 MHz) d 1.5–1.9 (m,
12H), 2.0–2.2 (m, 4H), 2.3–2.5 (m, 4H), 2.5–2.7 (m, 3H),
2.8–3.0 (m, 2H), 3.51 (m, 1H), 3.73 (m, 1H), 4.10 (m, 1H),
7.1–7.3 (m, 10H, Ar-H); HPLC (Daicel chiralcel OJ-H,
hexane/IPA 40:1, 1.0 mL/min): tR 16.1 (syn-major), 20.5
(syn-minor), 23.2 (anti-major), 24.8 min (anti-minor).
4.6.4. 3-Hydroxy-2-methyl-1,3-diphenyl-1-propanone
(2e).4b Following the general procedure, the aldol adduct
2e was obtained from silyl enol ether 1e and benzaldehyde
as a colorless oil (103 mg, 91%, syn/anti 1.9:1, syn 19% ee,
anti 38% ee). TLC RfZ0.20 (hexane/AcOEt 4:1,
1
p-anisaldehyde); H NMR (CDCl3, 270 MHz) d 1.06 (d,
3H, JZ7.3 Hz), 1.18 (d, 3H, JZ7.3 Hz), 2.94 (d, 1H, JZ
4.6 Hz), 3.7–3.9 (m, 3H), 4.95 (m, 1H), 5.23 (s, 1H), 7.2–7.6

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Y. Orito et al. / Tetrahedron 62 (2006) 390–400
(m, 17H), 7.9–8.0 (m, 3H); HPLC (Daicel chiralcel OD-H,
hexane/IPA 19:1, 1.0 mL/min): tR 10.5 (syn-major), 12.3
(syn-minor), 15.2 (anti-minor), 16.9 min (anti-major).
4.6.8. 2,3-Dihydro-2-(1-hydroxy-3-phenyl-2-propen-yl)-
1H-inden-1-one (2l). Following the general procedure, the
aldol adduct 2l was obtained from silyl enol ether 1g and
cinnamaldehyde as a colorless oil (122 mg, 98%, syn/anti
3.4:1, syn 73% ee, anti 10% ee). TLC RfZ0.2 (hexane/
AcOEt 4:1, UV); 1H NMR (CDCl3, 270 MHz) d 2.8–3.0 (m,
2H), 3.1–3.3 (m, 4H), 4.52 (t, 1H, JZ6.5 Hz), 5.02 (m, 1H),
6.2–6.3 (m, 2H), 6.7–6.8 (m, 2H), 7.2–7.8 (m, 18H); 13C
NMR (CDCl3, 68 MHz) d 27.3, 29.6, 52.0, 52.6, 71.6, 74.0,
123.8, 124.1, 126.4, 126.5, 126.6, 127.3, 127.6, 127.7,
127.8, 128.5, 128.7, 129.4, 131.0, 132.2, 135.0, 135.4,
136.3, 136.3, 136.4, 137.0, 154.0, 154.8, 207.8, 209.0 (syn/
anti mixture); [a]2D5 C82.2 (c 0.96, CHCl3); IR (KBr) 3478,
4.6.5. 2,3-Dihydro-2-(hydroxyphenylmethyl)-1H-inden-
1-one (2g).25 Following the general procedure, the aldol
adduct 2g was obtained from silyl enol ether 1g and
benzaldehyde as a colorless oil (88 mg, 78%, syn/anti 2.9:1,
syn 83% ee, anti 48% ee). TLC RfZ0.35 (hexane/AcOEt
1
4:1, UV); H NMR (CDCl3, 270 MHz) d 2.24 (d, 1H, JZ
4.9 Hz), 2.67 (m, 1H), 2.8–3.1 (m, 3H), 3.25 (dd, 1H, JZ
4.0, 16.7 Hz), 4.78 (d, 1H, JZ9.5 Hz), 5.59 (m, 1H), 7.2–
7.4 (m, 14H), 7.5–7.6 (m, 2H), 7.6–7.8 (m, 2H); 13C NMR
(CDCl3, 68 MHz) d 26.6, 54.7, 71.9, 124.1, 126.5, 127.0,
128.5, 135.5, 137.0, 142.6, 154.8, 207.3 (syn); 29.8, 53.1,
75.6, 124.1, 126.5, 127.2, 128.4, 134.9, 136.4, 141.3, 154.0,
209.6 (anti); [a]2D5 C108 (c 1.0, CHCl3); IR (KBr) 3553,
3449, 3055, 2910, 1703, 1605, 1462, 1449, 1329, 1294,
1280, 1095, 765 cmK1; LR-EIMS 238 (MC), 219, 132; HR-
EIMS calcd for C16H14O2 238.0994 found 238.0990; HPLC
(Daicel chiralpak AS-H, hexane/IPA 9:1, 1.0 mL/min): tR
15.4 (anti-minor), 16.9 (anti-major), 22.1 (syn-minor),
34.2 min (syn-major).
1698, 1605, 1464, 1329, 1296, 1205, 963, 765, 705 cmK1
;
LR-EIMS 264 (MC), 246, 132; HR-EIMS calcd for
C18H16O2 264.1150 found 264.1158; HPLC (Daicel
chiralpak AS-H, hexane/IPA 9:1, 1.0 mL/min): tR 22.1
(anti-major), 26.8 (anti-minor), 31.8 (syn-minor), 37.2 min
(syn-major).
4.6.9. 2,3-Dihydro-2-(1-hydroxy-3-phenylpropyl)-1H-
inden-1-one (2m). Following the general procedure, the
aldol adduct 2m was obtained from silyl enol ether 1g and
hydrocinnamaldehyde as a colorless oil (113 mg, 90%, syn/
anti 2.6:1, syn 92% ee, anti 47% ee). TLC RfZ0.3 (hexane/
AcOEt 4:1, UV); 1H NMR (CDCl3, 270 MHz) d 1.7–2.0 (m,
4H), 2.4–2.9 (m, 8H), 3.1–3.3 (m, 2H), 3.84 (m, 1H), 4.38
(m, 1H), 7.1–7.7 (m, 18H); 13C NMR (CDCl3, 68 MHz) d
27.2, 29.6, 29.7, 31.3, 32.4, 36.6, 37.3, 51.9, 53.1, 70.2,
71.7, 123.6, 123.9, 125.8, 125.9, 126.4, 126.5, 127.2, 127.6,
128.3, 128.4, 128.5, 128.7, 134.9, 135.3, 136.4, 137.0,
141.7, 142.0, 153.7, 154.7, 208.4, 209.9 (syn/anti mixture);
[a]2D5 C39.6 (c 0.93, CHCl3); IR (KBr) 3486, 1698, 1605,
1464, 1329, 1296, 1209, 1039, 770 cmK1; LR-EIMS 266
(MC), 248, 161, 132; HR-EIMS calcd for C18H18O2
266.1306 found 266.1299; HPLC (Daicel chiralpak AS-H,
hexane/IPA 9:1, 1.0 mL/min) tR 15.4 (anti-minor), 16.9
(anti-major), 22.1 (syn-minor), 34.2 min (syn-major).
4.6.6. 2,3-Dihydro-2-[hydroxy-(4-methoxyphenyl)-
methyl]-1H-inden-1-one (2j). Following the general
procedure, the aldol adduct 2j was obtained from silyl
enol ether 1g and p-anisaldehyde as a colorless oil (113 mg,
89%, syn/anti 2.4:1, syn 70% ee, anti 25% ee). TLC RfZ0.3
1
(hexane/AcOEt 4:1, UV); H NMR (CDCl3, 270 MHz) d
2.6–2.7 (m, 1H), 2.8–3.0 (m, 4H), 3.2–3.3 (m, 1H), 3.77 (s,
6H), 4.78 (d, 1H, JZ19.1 Hz), 5.51 (s, 1H), 6.8–6.9 (m,
4H), 7.3–7.8 (m, 12H); 13C NMR (CDCl3, 68 MHz) d 26.7,
29.8, 53.1, 54.7, 55.1, 71.4, 75.0, 76.6, 113.6, 113.8, 123.7,
124.0, 126.4, 126.5, 126.6, 127.1, 127.5, 128.1, 133.4,
134.8, 135.3, 136.2, 136.9, 153.9, 154.8, 158.6, 159.3,
207.5, 209.6 (syn/anti mixture); [a]2D5 C143 (c 1.2, CHCl3);
IR (KBr) 3493, 1692, 1609, 1512, 1298, 1256, 1092, 1028,
853 cmK1; LR-EIMS 268 (MC), 132; HR-EIMS calcd for
C17H16O3 268.1099 found 268.1102; HPLC (Daicel
chiralpak AS-H, hexane/IPA 3:1, 1.0 mL/min): tR 10.2
(anti-minor), 13.7 (anti-major), 17.6 (syn-major), 30.2 min
(syn-minor).
4.6.10. 2,3-Dihydro-2-(hydroxycyclohexylmethyl)-1H-
inden-1-one (2n). Following the general procedure, the
aldol adduct 2n was obtained from silyl enol ether 1g and
hydrocinnamaldehyde as a colorless oil (109 mg, 94%, syn/
anti 1.4:1, syn 97% ee, anti 84% ee). TLC RfZ0.4 (hexane/
AcOEt 4:1, UV); 1H NMR (CDCl3, 270 MHz) d 0.9–1.4 (m,
8H), 1.5–1.9 (m, 12H), 2.0–2.1 (m, 2H), 2.8–2.9 (m, 2H),
3.0–3.3 (m, 3H), 3.66 (d, 1H, JZ9.2 Hz), 4.10 (d, 1H, JZ
7.3 Hz), 4.2–4.3 (m, 1H), 7.3–7.8 (m, 8H); 13C NMR
(CDCl3, 68 MHz) d 25.6, 25.8, 26.1, 26.2, 26.4, 26.6, 26.7,
29.3, 29.5, 29.8, 30.1, 41.5, 41.9, 49.3, 50.8, 74.9, 76.4,
123.5, 123.8, 126.4, 126.5, 127.0, 127.5, 134.7, 135.2,
136.5, 137.2, 153.8, 154.9, 209.0, 211.0 (syn/anti mixture);
[a]2D5 C46.8 (c 1.2, CHCl3); IR (KBr) 3409, 2924, 2847,
1678, 1605, 1466, 1296, 1084, 1024, 960 cmK1; LR-EIMS
244 (MC), 161, 132; HR-EIMS calcd for C16H20O2
244.1463 found 244.1455; HPLC (Daicel chiralpak AD-H,
hexane/IPA 19:1, 1.0 mL/min): tR 15.4 (anti-minor), 19.4
(anti-major), 22.4 (syn-major), 28.4 min (syn-minor).
4.6.7.
2,3-Dihydro-2-[hydroxy-(4-trifluoromethyl-
phenyl)methyl]-1H-inden-1-one (2k). Following the
general procedure, the aldol adduct 2k was obtained from
silyl enol ether 1g and p-(trifluoromethyl)benzaldehyde as a
colorless oil (128 mg, 88%, syn/anti 2.1:1, syn 48% ee, anti
1
39% ee). TLC RfZ0.4 (hexane/AcOEt 4:1, UV); H NMR
(CDCl3, 270 MHz) d 2.4–2.7 (m, 1H), 2.7–3.3 (m, 7H), 4.89
(d, 1H, JZ8.9 Hz), 5.67 (br s, 1H), 7.3–7.8 (m, 16H); 13C
NMR (CDCl3, 68 MHz) d 26.5, 29.6, 53.0, 54.7, 71.1, 75.1,
122.3, 123.9, 124.2, 125.3, 125.4, 125.5, 125.6, 125.7,
125.8, 126.5, 126.6, 127.3, 127.4, 127.9, 129.3, 129.7,
130.2, 130.6, 135.2, 135.7, 136.1, 136.8, 145.2, 146.8,
153.7, 154.7, 207.0, 209.1 (syn/anti mixture); [a]2D5 C40.1
(c 1.0, CHCl3); IR (KBr) 3433, 1693, 1604, 1467, 1413,
1325, 1298, 1163, 1109, 1064, 1016 cmK1; LR-EIMS 306
(MC), 288, 173, 132 (bp); HR-EIMS calcd for C17H13O2F3
306.0868 found 306.0858; HPLC (Daicel chiralpak AS-H,
hexane/IPA 9:1, 1.0 mL/min): tR 12.5 (anti-minor), 14.5
(anti-major), 15.6 (syn-major), 22.2 min (syn-minor).
4.6.11. 2-(Hydroxy-1-naphthalenylmethyl)cyclohexan-
one (2o).7b Following the general procedure, the aldol
adduct 2o was obtained from silyl enol ether 1a and
1-naphthaldehyde as a colorless oil (108 mg, 90%, syn/anti

Y. Orito et al. / Tetrahedron 62 (2006) 390–400
399
¨
1998, 9, 357–389. (b) Groger, H.; Vogl, E. M.; Shibasaki, M.
Chem. Eur. J. 1998, 4, 1137–1141. (c) Mahrwald, R. Chem.
Rev. 1999, 99, 1095–1120. (d) Machajewski, T. D.; Wong,
C.-H. Angew. Chem., Int. Ed. 2000, 39, 1352–1374.
1.4:1, syn 81% ee, anti 65% ee). TLC RfZ0.35 (syn), 0.30
(anti) (hexane/AcOEt 4:1, p-anisaldehyde); 1H NMR
(CDCl3, 270 MHz) d 1.3–1.9 (m, 8H), 2.0–2.2 (m, 4H),
2.3–2.6 (m, 4H), 2.77 (m, 1H), 2.97 (m, 1H), 3.08 (d, 1H,
JZ3.3 Hz), 4.11 (d, 1H, JZ3.3 Hz), 5.57 (m, 1H), 6.24 (br
s, 1H), 7.4–7.6 (m, 7H), 7.7–7.9 (m, 6H), 8.25 (m, 1H);
HPLC (Daicel chiralcel OD-H, hexane/IPA 40:1, 0.7 mL/
min): tR 19.0 (syn-minor), 26.3 (syn-major), 44.2 (anti-
minor), 52.7 min (anti-major).
2. (a) Carreira, E. M. In Jacobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds.; Comprehensive asymmetric catalysis; Springer:
Berlin, 1999; Vol. 3, pp 997–1065.
3. Other recent examples of enantioselective aldol reactions: (a)
Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am.
Chem. Soc. 1992, 114, 4418–4420. (b) Sodeoka, M.; Ohrai, K.;
Shibasaki, M. J. Org. Chem. 1995, 60, 2648–2649. (c)
Yanagisawa, A.; Matsumoto, Y.; Nakashima, H.; Asakawa,
K.; Yamamoto, H. J. Am. Chem. Soc. 1997, 119, 9319–9320.
(d) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki,
M. Angew. Chem., Int. Ed. 1997, 36, 1871–1873. (e) Kuwano,
R.; Miyazaki, H.; Ito, Y. Chem. Commun. 1998, 71–72. (f)
List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2000,
122, 2395–2396. (g) Trost, B. M.; Ito, H. J. Am. Chem. Soc.
2000, 122, 12003–12004. (h) Northrup, A. B.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2002, 124, 6798–6799. (i) Evans,
D. A.; Downey, C. W.; Hubbs, J. L. J. Am. Chem. Soc. 2003,
125, 8706–8707.
4.6.12. 2-(Hydroxy-2-naphthalenylmethyl)cyclohexan-
one (2p).26 Following the general procedure, the aldol
adduct 2p was obtained from silyl enol ether 1a and
2-naphthaldehyde as a colorless oil (113 mg, 94%, syn/anti
1.6:1, syn 72% ee, anti 45% ee). TLC RfZ0.30 (syn), 0.25
(anti) (hexane/AcOEt 4:1, p-anisaldehyde); 1H NMR
(CDCl3, 270 MHz) d 1.3–1.8 (m, 8H), 2.0–2.2 (m, 4H),
2.3–2.6 (m, 4H), 2.7–2.8 (m, 2H), 3.13 (d, 1H, JZ3.3 Hz),
4.03 (d, 1H, JZ3.0 Hz), 4.95 (m, 1H), 5.56 (br s, 1H), 7.36
(d, 1H, JZ8.7 Hz), 7.4–7.5 (m, 5H), 7.75 (m, 1H), 7.8–7.9
(m, 7H); HPLC (Daicel chiralcel OD-H, hexane/IPA 9:1,
1.0 mL/min): tR 9.0 (syn-minor), 9.7 (syn-major), 11.0 (anti-
minor), 13.5 min (anti-major).
4. (a) Denmark, S. E.; Winter, S. B. D.; Su, X.; Wong, K.-T.
J. Am. Chem. Soc. 1996, 118, 7404–7405. (b) Denmark, S. E.;
Wong, K.-T.; Stavenger, R. A. J. Am. Chem. Soc. 1997, 119,
2333–2334. (c) Denmark, S. E.; Su, X.; Nishigaichi, Y. J. Am.
Chem. Soc. 1998, 120, 12990–12991. (d) Denmark, S. E.;
Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432–440. (e)
Denmark, S. E.; Gosh, S. K. Angew. Chem., Int. Ed. 2001, 40,
4759–4762. (f) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc.
2002, 124, 4233–4235.
4.6.13. 2-(1-Hydroxy-3-phenyl-2-propenyl)cyclohexa-
none (2h).4b Following the general procedure, the aldol
adduct 2h was obtained from silyl enol ether 1a and
cinnamaldehyde as a colorless oil (104 mg, 95%, syn/anti
1.4:1, syn 75% ee, anti 5% ee). TLC RfZ0.4 (hexane/
AcOEt 4:1, UV); 1H NMR (CDCl3, 270 MHz) d 1.3–1.8 (m,
8H), 1.8–1.9 (m, 2H), 2.0–2.2 (m, 2H), 2.3–2.6 (m, 6H),
4.43 (t, 1H, JZ8.1 Hz), 4.77 (m, 1H), 6.1–6.3 (m, 2H), 6.5–
6.7 (m, 2H), 7.1–7.4 (m, 10H); HPLC (Daicel chiralpak
AD-H, hexane/IPA 19:1, 1.0 mL/min) tR 32.8 (syn-major),
40.0 (syn-minor), 44.3 (anti-minor), 53.1 min (anti-major).
5. For reviews of hypervalent silicate, see: (a) Chuit, C.; Corriu,
´
R. J. P.; Reye, C. J. Organomet. Chem. 1988, 358, 57–66. (b)
Chuit, C.; Corriu, R. J. P.; Reye, C.; Young, J. C. Chem. Rev.
1993, 93, 1371–1448.
6. Nakajima, M.; Yokota, T.; Saito, M.; Hashimoto, S.
Tetrahedron Lett. 2004, 45, 61–64.
4.6.14. 2-(1-Hydroxy-3-phenylpropyl)cyclohexanone
(2i).4b Following the general procedure, the aldol adduct
2i was obtained from silyl enol ether 1a and hydrocinnam-
aldehyde as a colorless oil (83 mg, 75%, syn/anti 1.2:1, syn
92% ee, anti 40% ee). TLC RfZ0.35 (hexane/AcOEt 4:1,
p-anisaldehyde); 1H NMR (CDCl3, 270 MHz) d 1.5–1.9 (m,
12H), 2.0–2.2 (m, 4H), 2.3–2.5 (m, 4H), 2.5–2.7 (m, 3H),
2.8–3.0 (m, 2H), 3.51 (m, 1H), 3.73 (m, 1H), 4.10 (m, 1H),
7.1–7.3 (m, 10H); HPLC (Daicel chiralcel OJ-H, hexane/
IPA 40:1, 1.0 mL/min): tR 16.1 (syn-major), 20.5 (syn-
minor), 23.2 (anti-major), 24.8 min (anti-minor).
7. (a) Yanagisawa, A.; Nakatsuka, Y.; Asakawa, K.; Kageyama,
H.; Yamamoto, H. Synlett 2001, 69–72. (b) Yanagisawa, A.;
Nakatsuka, Y.; Asakawa, K.; Wadamoto, M.; Kageyama, H.;
Yamamoto, H. Bull. Chem. Soc. Jpn. 2001, 74, 1477–1484. (c)
Schiffers, R.; Kagan, H. B. Synlett 1997, 1175–1178. (d)
Yamasaki, S.; Fujii, K.; Wada, R.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2002, 124, 6536–6537. (e) Aoyama, N.;
Hamada, T.; Manabe, K.; Kobayashi, S. Chem. Commun.
2003, 676–677.
8. (a) Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S. J. Am.
Chem. Soc. 1998, 120, 6419–6420. (b) Nakajima, M.; Saito,
M.; Uemura, M.; Hashimoto, S. Tetrahedron Lett. 2002, 43,
8827–8829.
Acknowledgements
9. Some of these results have been described in a preliminary
communication: Nakajima, M.; Orito, Y.; Ishizuka, T.;
Hashimoto, S. Org. Lett. 2004, 6, 3763–3765.
This work was partly supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education,
Science, Sports and Culture of Japan, the Novartis
Foundation for the Promotion of Science, and the SUNBOR
GRANT.
10. Since the catalyst in the present reaction contains lithium
cations, it might not be a true organocatalyst. We categorized
this reaction as an organocatalysis since the metal center does
not participate in the reaction mechanism. See: Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726–3748.
11. Corriu, R. J. P.; Moreau, J. J. E.; Thepot, P.; Man, M. W. C.
Chem. Mater. 1992, 4, 1217–1224.
References and notes
12. Other metal salts did not give better results than the dilithium
salt (Na: 2 h, 91% yield, syn/anti 1:3.0, 46% ee (syn), 45% ee
1. For reviews, see: (a) Nelson, S. G. Tetrahedron: Asymmetry

400
Y. Orito et al. / Tetrahedron 62 (2006) 390–400
(anti); K: 12 h, 66% yield, syn/anti 1:1.5, !10% ee (syn), 28%
ee (anti); Rb: no reaction).
19. Lingenfelter, D. S.; Helgeson, R. C.; Cram, D. J. J. Org. Chem.
1981, 46, 393–406.
13. Lowering the reaction temperature did not increase the
selectivities (K45 8C: 77% yield, syn/anti 3.0:1, 76% ee
(syn), 45% ee (anti)).
20. Cox, P. J.; Wang, W.; Snieckus, V. Tetrahedron Lett. 1992, 33,
2253–2256.
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amounts of product, while excess BuLi (40 mol%) did not
influence the yields or selectivities (98% yield, syn/anti 3.0:1,
80% ee (syn), 50% ee (anti)).
23. Zhang, H.-C.; Hwang, W.-W.; Pu, L. J. Org. Chem. 2001, 66,
481–487.
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Cram, D. J. J. Am. Chem. Soc. 1980, 102, 2043–2052.
26. Yanagisawa, A.; Takahashi, H.; Arai, T. Chem. Commun.
2004, 580–581.