Asymmetric aldol reaction of enol trichloroacetate catalyzed by tin methoxide and BINAP·silver(I) complex

Article abstract of DOI:10.1016/S0040-4020(02)00984-5

Enol trichloroacetate of cyclohexanone has been found to react with benzaldehyde in the presence of a catalytic amount of tributyltin methoxide and stoichiometric amount of MeOH to give an aldol adduct. Methanolysis of the in situ generating tin alkoxide of aldol adduct regenerates the tin methoxide, and thus the aldol reaction can proceed catalytically. The use of BINAP·silver(I) complex as an additional catalyst results in formation of optically active aldol products. This catalytic method has been further applied to the asymmetric reaction of diketene with benzaldehyde.

Full text of DOI:10.1016/S0040-4020(02)00984-5

Tetrahedron 58 (2002) 8331–8339
Asymmetric aldol reaction of enol trichloroacetate catalyzed
by tin methoxide and BINAP·silver(I) complex
†
Akira Yanagisawa,a Yukari Matsumoto,b Kenichi Asakawab and Hisashi Yamamotob
, ,
*
aDepartment of Chemistry, Faculty of Science, Chiba University, Inage, Chiba 263-8522, Japan
bGraduate School of Engineering, SORST, Japan Science and Technology Corporation (JST), Nagoya University, Furo-cho, Chikusa,
Nagoya 464-8603, Japan
Received 3 June 2002; accepted 7 June 2002
Abstract—Enol trichloroacetate of cyclohexanone has been found to react with benzaldehyde in the presence of a catalytic amount of
tributyltin methoxide and stoichiometric amount of MeOH to give an aldol adduct. Methanolysis of the in situ generating tin alkoxide of aldol
adduct regenerates the tin methoxide, and thus the aldol reaction can proceed catalytically. The use of BINAP·silver(I) complex as an
additional catalyst results in formation of optically active aldol products. This catalytic method has been further applied to the asymmetric
reaction of diketene with benzaldehyde. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
a catalytic amount of tin enolate and the asymmetric process
of this reaction with BINAP·silver(I) catalyst.11
Organotin(IV) enolates, existing commonly in O–Sn form
and/or C–Sn form, are known as versatile reagents which
show high nucleophilicity toward electrophiles1 and have
been utilized in various organic reactions, e.g. alkylation,2
acylation,3 aldol reaction,4 palladium-catalyzed cross-
coupling reaction,5 etc. Among them, aldol reaction is a
beneficial method to prepare b-hydroxy carbonyl com-
pounds, and has caught much attention from organic
chemists.6 Transmetallation of lithium enolates with tri-
alkyltin halides is a simple and popular method of
generating tin enolates.7 In contrast, reaction of enol
acetates with trialkyltin methoxide is a convenient alterna-
tive which can provide tin enolates without a contamination
of lithium halides.8 Trialkyltin enolates prepared from
cyclohexanone by this way have been reported to undergo
aldol condensation with aldehydes at 2788C, showing anti
selectivity.9 The diastereoselectivity is highly temperature
dependent and the syn adduct predominates at higher
temperature (458C). The aldol reaction has such an
interesting characteristic on diastereoselectivity markedly
different from that of ordinary Mukaiyama type aldol
reaction using silyl enol ethers,10 however, the former aldol
process possesses the disadvantage of requiring the
stoichiometric use of toxic trialkyltin compounds. We
describe here an example of the aldol condensation using
2. Results and discussion
Fig. 1 shows an our original idea on the catalytic aldol
reaction. Reaction of enol ester 1 with trialkyltin
methoxide generates the corresponding trialkyltin enolate
2 which is anticipated to smoothly add to an aldehyde to
produce aldol product 3. We envisaged that if the tin
alkoxide of aldol adduct 3 could successively react with the
starting enol ester 1 to form ester of the aldol product 4 and
regenerate the tin enolate 2, the aldol reaction might
advance catalytically.
Keywords: asymmetric aldol reaction; enol trichloroacetate; diketene;
aldehyde; BINAP·silver(I) complex; tin methoxide.
*
Corresponding author. Tel.: þ81-52-789-3331; fax: þ81-52-789-3222;
e-mail: yamamoto@cc.nagoya-u.ac.jp; yamamoto@uchicago.edu
Present address: Department of Chemistry, University of Chicago, 5735
South Ellis Avenue, Chicago, 60637, USA.
†
Figure 1. A possible catalytic cycle of tin methoxide-catalyzed aldol
reaction.
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00984-5

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A. Yanagisawa et al. / Tetrahedron 58 (2002) 8331–8339
First of all, we studied the exchange reaction between enol
acetate of cyclohexanone and tributyltin methoxide8 to find
out the optimum reaction conditions (Eq. (1)). In the
reaction at 220 to 08C, however, the desired tin enolate was
not formed at all. In contrast, the corresponding enol
trichloroacetate12 was almost quantitatively converted to the
tributyltin enolate within 30 min at 2208C (Eq. (1))13
trichloroacetate 5 generates methyl trichloroacetate and the
trialkyltin enolate 2, which is then allowed to react with an
aldehyde. Finally, protonation of the resulting tin alkoxide 3
by MeOH reproduces the tin methoxide. The rate of
methanolysis is considered to be the key to success in the
catalytic cycle
ð1Þ
ð2Þ
In fact, when a similar reaction was performed in the
presence of MeOH (100 mol%), the aldol adduct was
obtained in 71% yield with an anti/syn ratio of 29/71, which
obviously showed the occurrence of the catalytic reaction
(Eq. (3)). From this result, the in situ-generated tin enolate
was found to react selectively with the aldehyde even
though the presence of an equal amount of MeOH and
thus, tributyltin methoxide was shown to be effectively
regenerated by the following reaction of the resulting tin
alkoxide of aldol adduct with MeOH
Accordingly, we selected the 1-trichloroacetoxy cyclo-
hexene as a substrate for the tin-catalyzed aldol reaction.
Although a mixture of the enol trichloroacetate and
benzaldehyde was treated with a 10 mol% of tributyltin
methoxide in dry THF at 2208C for 8 h and successively at
room temperature for 12 h, the targeted aldol product was
formed in an unacceptable yield with syn selectivity
(Eq. (2)). As a result, the exchange reaction between the
tin alkoxide of aldol product 3 and the enol trichloroacetate
1 (R¼CCl3) was found to proceed very slowly. We
thereupon attempted an alternative possible tin-catalyzed
reaction in the presence of MeOH. The catalytic cycle is
shown in Fig. 2. Reaction of R3SnOMe with an enol
ð3Þ
The aforementioned results further provoked us to employ
BINAP·silver(I) complex14 as a chiral catalyst for the tin
alkoxide-catalyzed aldol reaction. We have previously
shown that BINAP·AgOTf complex is a good chiral catalyst
for asymmetric aldol reaction of tributyltin enolates.15
Various methods for the catalytic asymmetric aldol reaction
have been developed; however, most of these are the chiral
Lewis acid-catalyzed Mukaiyama aldol reactions using silyl
enol ethers or ketene silyl acetals,16–18 and there has been
no example using enol esters as the latent enolates.
Yamagishi and co-workers independently examined the
Figure 2. An alternative possible catalytic cycle of tin methoxide-catalyzed
aldol reaction.
Table 1. BINAP·Ag(I) and tin methoxide catalyzed enantioselective aldol reaction of enol trichloroacetate of cyclohexanone
Entry
(R)-BINAP·AgOTf
(mol%)
R3SnOMe
(mol%)
MeOH
(mol%)
Product
Yield
(%)a
anti/synb
ee%c
1
2
3
4
5
10
10
5
5
5d
10 (R¼Bu)
10 (R¼Bu)
5 (R¼Bu)
5 (R¼Me)
5 (R¼Me)
100
200
200
200
200
62
94
82
88
86
84/16
92/8
92/8
93/7
94/6
93
95
95
94
96
Unless otherwise noted, the reaction was carried out using (R)-BINAP·AgOTf (5 or 10 mol%), trialkyltin methoxide (5 or 10 mol%), enol trichloroacetate of
cyclohexanone (1 equiv.), and benzaldehyde (1 equiv.) in THF containing MeOH (100 or 200 mol%) at 2208C for 8 h and then at room temperature for 12 h.
Isolated yield.
a
b
Determined by 1H NMR analysis.
c
The value corresponds to the anti isomer. Determined by HPLC analysis (Chiralcel OD-H, Daicel Chemical Industries Ltd).
(R)-p-Tol-BINAP·AgOTf was used.
d

A. Yanagisawa et al. / Tetrahedron 58 (2002) 8331–8339
8333
Table 2. anti- and enantioselective aldol reaction of enol trichloroacetate of cyclohexanone with various aldehydes catalyzed by (R)-p-Tol-BINAP·AgOTf and
Me3SnOMe
Entry
Aldehyde
Yield (%)a
anti/synb
ee%c
1
2
PhCHO
4-MeOC6H4CHO
86
66
94/6
94/6
96
95
3
49
80/20
77
4
5
6
1-Naphthyl-CHO
(E)-PhCHvCHCHO
(E)-CH3(CH2)2CHvCHCHO
Ph(CH2)2CHO
CH3(CH2)4CHO
i-PrCHO
74
76
61
29
,1
,1
96/4
78/22
76/24
84/16
–
92
90
83
79
–
7
8d
9e
–
–
Unless otherwise noted, the reaction was carried out using (R)-p-Tol-BINAP·AgOTf (5 mol%), trimethyltin methoxide (5 mol%), enol trichloroacetate of
cyclohexanone (1 equiv.), and aldehyde (1 equiv.) in THF containing MeOH (2 equiv.) at 2208C for 8 h and then at room temperature for 12 h.
Isolated yield.
a
b
Determined by 1H NMR analysis.
c
The value corresponds to the anti isomer. Determined by HPLC analysis (Chiralcel OD-H or Chiralpak AD, Daicel Chemical Industries Ltd).
The reaction was performed at 2208C for 4 h and then at room temperature for 21 h.
The reaction was performed using isobutyraldehyde (5 equiv.) at 2208C for 5 h and then at room temperature for 15 h.
d
e
BINAP·Ag(I)-catalyzed asymmetric Mukaiyama aldol reac-
tion using trimethylsilyl enol ethers and found that the
reaction was accelerated by BINAP·AgPF6 in DMF
containing a small amount of water to give the aldol
product with high enantioselectivity.19 In contrast, we
studied diverse reaction conditions of the BINAP·Ag(I)
and tin methoxide-catalyzed aldol reaction of enol trichlor-
oacetate of cyclohexanone and found that a combination of
p-Tol-BINAP·AgOTf and trimethyltin methoxide (Me3-
SnOMe) gave the highest enantioselectivity and a satisfac-
tory chemical yield (Table 1). When benzaldehyde was
treated with the enol trichloroacetate under the influence of
(R)-BINAP·AgOTf complex (10 mol%), tributyltin meth-
oxide (Bu3SnOMe, 10 mol%), and MeOH (100 mol%) in
dry THF at 2208C for 8 h and then at room temperature for
12 h, a 84/16 mixture of optically active anti and syn aldol
adduct was formed in 62% combined yield (entry 1). The
anti isomer revealed 93% ee with (2S,10R)-configuration,
a level of enantioselectivity similar to that observed for a
BINAP·silver(I) catalyzed aldol reaction of tributyltin
enolates.15 An increase in the amount of MeOH to
200 mol% caused much improvement in the chemical
yield and diastereoselectivity (entry 2). Since it was
necessary to reduce the amount of toxic organostannanes
from a practical point of view, we further attempted the
reaction using less than 10 mol% of the tin methoxide and
found that 82% yield of the product was still obtained even
in the presence of 5 mol% of both catalysts (entry 3). Alkyl
substituents of tin methoxide somewhat affected the
catalytic activity, and Me3SnOMe20 provided a higher
yield without lowering diastereo- and enantioselectivities
(entry 4). Finally, a change of (R)-BINAP for (R)-p-Tol-
BINAP21 resulted in slightly better selectivities (anti/syn¼
94/6, anti-isomer: 96% ee) with an analogous yield (86%
yield, entry 5).
We further performed the Me3SnOMe and (R)-p-Tol-
BINAP·AgOTf catalyzed aldol reaction with various
aromatic and a,b-unsaturated aldehydes under the optimum
reaction conditions and the corresponding aldol adducts
were obtained with satisfactory diastereo- and enantio-
selectivities (entries 1–6, Table 2). In the reaction with an
a,b-unsaturated aldehyde, a 1,2-adduct was obtained
exclusively (entries 5 and 6). Aliphatic aldehydes showed
low or no reactivity even at room temperature (entries 7–9).
A probable catalytic cycle of this asymmetric aldol reaction
is indicated in Fig. 3. First, R3SnOMe reacts with enol
trichloroacetate 5 to generate trialkyltin enolate 2 as
described in Fig. 2. Subsequently, the tin enolate 2 adds to
an aldehyde enantioselectively under the influence of
(R)-BINAP·AgOTf complex to give the tin alkoxide of
aldol adduct 7. Finally, methanolysis of 7 furnishes the
Figure 3. A proposed catalytic mechanism for the asymmetric aldol
reaction catalyzed by (R)-BINAP·AgOTf and tin methoxide.

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A. Yanagisawa et al. / Tetrahedron 58 (2002) 8331–8339
optically active aldol product 8 and regenerates the tin
methoxide.
attempted NMR studies on the aldol reaction of benzalde-
hyde with tributyltin enolate of cyclohexanone followed by
protonation by MeOH to examine the reactivity of the in situ
generating tributyltin alkoxide of aldol adduct, and the tin
alkoxide was found to react with MeOH below 2208C by
1H NMR analysis (Fig. 5). We further performed 119Sn
NMR experiments to investigate whether a pentacoordinate
structure of the tin aldol product exists and contributes to its
higher reactivity toward MeOH or not. The 119Sn NMR
spectrum (111.9 MHz, CDCl3, rt, Me4Sn; d 0.0 ppm) of the
tin alkoxide showed two peaks at d 101.9 ppm (anti) and
100.7 ppm (syn) with an anti/syn ratio of 23/77.9c These
signals, however, appeared at field almost similar to that of
tributyltin methoxide (d 108–110 ppm) or tributyltin
enolate of cyclohexanone (d 98.1 ppm) which is regarded
as a tetracoodinate tin compound.1b A typical example of
pentacoordinate tin compound has been reported to show a
high field shifted peak at 43.5 ppm.24 As a consequence,
contribution of the pentacoordinate tin species to the
catalytic cycle is not significant. However, an intramolecu-
larly weakly coordinated tin alkoxide is a possible
alternative.
With this mechanistic guidance it became of interest to
apply the present asymmetric catalytic process to a reaction
of diketene with an aldehyde in which a tin enolate,
generated from a trialkyltin methoxide and diketene, might
be recycled in the presence of MeOH (Eq. (4)).22 However,
the reactivity of Bu3SnOMe (n¼1) toward diketene was low
and the reaction required a temperature of more than 08C. In
contrast, under the influence of 10 mol% of dibutyltin
dimethoxide [Bu2Sn(OMe)2, n¼2], the reaction took place
catalytically even at 2208C and the desired aldol adduct
was obtained in 25% yield after 4 h of stirring. Then, we
attempted the asymmetric version of the reaction using a
BINAP·Ag(I) catalyst. Various reaction conditions and
amounts of the catalysts were examined and as a result,
the highest enantioselectivity (84% ee) was gained along
with a satisfactory chemical yield when a mixture of
diketene (5 equiv.) and benzaldehyde (1 equiv.) was
exposed to 20 mol% of Bu2Sn(OMe)2 and 22 mol% of
(R)-p-Tol-BINAP·AgOTf in THF containing MeOH
(200 mol%) at 2208C for 72 h (Eq. (5))
The mechanism of the BINAP·AgOTf-catalyzed aldol
reaction of trialkyltin enolate, generated from enol tri-
chloroacetate and trialkyltin methoxide, has not been
fully elucidated; however, the BINAP·AgOTf complex is
considered to act as a chiral Lewis acid catalyst rather than a
silver enolate, based on the following NMR results. When
tributyltin enolate of cyclohexanone was treated with an
equimolar mixture of (R)-BINAP·AgOTf complex and
DMF in THF-d8 at room temperature, peaks of the tin
enolate disappeared and a set of new peaks assignable to
1-cyclohexenyl group appeared, while peaks of tributyltin
triflate were not observed at all (Fig. 6). These observations
are positive proof that the silver enolate was not generated.
From the above NMR results and the facts that the
diastereoselectivity of the BINAP·AgOTf-catalyzed aldol
reaction of trialkyltin enolate depends on the geometry of
enol stannane,15 the cyclic transition-state structure shown
in Fig. 6 can be viewed as a possible model for the aldol
reaction.
ð4Þ
ð5Þ
One possible reason why MeOH reacts with the aldol
adduct, faster than with in situ generating tin enolate, is that
probably because the tin alkoxide exists as a pentacoordi-
nate structure rather than a tetracoordinate structure (Fig. 4).
Corriu et al. have reported that pentacoodinate silicates
show higher reactivity than that of tetracoordinate silanes
toward nucleophiles and in fact, t-BuMgBr is known to
react with a pentacoordinate silicate, [PhMeSiF3]2
[K,18-Crown-6]þ, a hundred times faster than the corre-
sponding tetracoodinate silane, PhMeSiF2.23 So, we
3. Conclusion
We have demonstrated an example of aldol reaction of enol
Figure 4. Reactivity of pentacoordinate silicon and tin compounds.

A. Yanagisawa et al. / Tetrahedron 58 (2002) 8331–8339
8335
Figure 5. NMR studies on the aldol adducts.
Figure 6. NMR studies on BINAP·AgOTf-catalyzed aldol reaction of tin enolate.
trichloroacetate of cyclohexanone or diketene catalyzed by
tin methoxide in the presence of MeOH and the asymmetric
version using BINAP·AgOTf or p-Tol-BINAP·AgOTf
complex as a chiral catalyst. The main features of the
present method are: (1) the procedure is operationally
simple using readily available chemicals and can provide
optically active anti b-hydroxy ketones with high enantio-
selectivity up to 96% ee; (2) diketene can be converted to an
optically active methyl 5-hydroxy-3-oxopentanoate
derivative by applying this method; (3) the in situ
generating tin enolate reacts with an aldehyde much faster
than with MeOH and the resulting tin alkoxide of aldol
adduct is readily protonated by MeOH to regenerate tin
methoxide; (4) this process is environmentally friendlier
because the amount of toxic trialkyltin compounds is
reduced to a catalytic amount. Hence, this catalytic
procedure is useful and should be broadly applicable in
organic synthesis.
4. Experimental
4.1. General methods
Analytical TLC was done on E. Merck precoated (0.25 mm)
silica gel 60 F254 plates. Column chromatography was
conducted using silica gel 60 (E. Merck 9385, 230–400
mesh). Infrared (IR) spectra were recorded on a Shimadzu
1
FTIR-8100 spectrometer. H NMR spectra were measured
on a Varian Gemini-300 (300 MHz) spectrometer.
1
Chemical shifts of H NMR spectra were reported relative
to tetramethylsilane (d 0) or chloroform (d 7.26). Splitting
patterns are indicated as s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br, broad. 13C NMR spectra were
measured on a Varian Gemini-300 (75 MHz) spectrometer.
Chemical shifts of 13C NMR spectra were reported relative
to CDCl3 (d 77.0). Analytical high-performance liquid
chromatography (HPLC) was done with a Shimadzu 10A

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A. Yanagisawa et al. / Tetrahedron 58 (2002) 8331–8339
instrument using a chiral column (4.6 mm£25 cm, Daicel
CHIRALCEL OD-H or CHIRALPAK AD). Optical rotation
was measured on a JASCO DIP-1000 polarimeter.
(300 MHz, CDCl3) d 1.22–1.37 (m, 1H, one proton of
CH2), 1.47–1.81 (m, 4H, 2 CH2), 2.05–2.13 (m, 1H, one
proton of CH2), 2.31–2.42 (m, 1H, one proton of CH2),
2.45–2.52 (m, 1H, one proton of CH2), 2.57–2.67 (m, 1H,
CH), 3.96 (d, 1H, J¼2.8 Hz, OH), 4.79 (dd, 1H, J¼2.8,
8.8 Hz, CH(OH)), 7.28–7.40 (m, 5H, aromatic); 13C NMR
(75 MHz, CDCl3) d 24.5, 27.6, 30.6, 42.4, 57.3, 74.5, 126.9
(2 C), 127.7, 128.3 (2 C), 140.9, 215.3; [a]3D2¼þ19.78 (c 1.0,
CHCl3); elemental analysis calcd for C13H16O2: C 76.44, H
7.90%; found: C 76.35, H 7.96%. Spectral data of the syn
isomer (white solids, 18% ee): TLC Rf 0.13 (1/5 ethyl
acetate/hexane); IR (KBr) 3600–3125, 2940, 2855, 1701,
All experiments were carried out under an atmosphere of
standard grade argon gas (oxygen,10 ppm) and exclusion
of direct light. Dry THF was used as purchased from Wako
Pure Chemical (dehydrated, .99.5%, water: ,0.005%).
MeOH was purified by distillation over Mg turnings. Silver
triflate (99þ%) was used as purchased from Aldrich.
(R)-BINAP (guaranteed reagent) was used as purchased
from Nacalai Tesque. (R)-p-Tol-BINAP was donated by the
Takasago International Corporation. Aldehydes were puri-
fied by distillation before use. 1-Trichloroacetoxy cyclo-
hexene was prepared by treatment of cyclohexanone with
trichloroacetic anhydride in the presence of a catalytic
amount of p-toluenesulfonic acid and purified by distillation
before use.12 Tributyltin methoxide (Aldrich), dibutyltin
dimethoxide (Aldrich), and diketene (Wako) were purified
by distillation before use. Trimethyltin methoxide was
prepared by treatment of (dimethylamino)trimethyltin
(Aldrich) with MeOH and purified by distillation before
use.20 Other chemicals were used as purchased.
1603, 1495, 1449, 1406, 1320, 1132, 1063, 986, 696 cm21
;
1H NMR (300 MHz, CDCl3) d 1.47–1.80 (m, 4H, 2 CH2),
1.81–1.91 (m, 1H, one proton of CH2), 2.04–2.15 (m, 1H,
one proton of CH2), 2.32–2.51 (m, 2H, CH2), 2.56–2.65
(m, 1H, CH), 3.01 (d, 1H, J¼3.2 Hz, OH), 5.40 (d, 1H,
J¼2.4, 3.2 Hz, CH(OH)), 7.25–7.37 (m, 5H, aromatic); 13C
NMR (75 MHz, CDCl3) d 24.7, 25.9, 27.8, 42.5, 57.1, 70.5,
125.7 (2 C), 126.8, 128.0 (2 C), 141.5, 214.5; [a]3D3¼þ37.68
(c 1.0, CHCl3); elemental analysis calcd for C13H16O2:
C 76.44, H 7.90%; found: C 76.10, H 8.23%. Spectral
1
data (TLC, IR, H NMR, and 13C NMR) of the anti and
syn isomers indicated good agreement with reported
data.11,25,26
4.2. Typical experimental procedure for asymmetric
reaction of benzaldehyde with 1-trichloroacetoxy
cyclohexene catalyzed by (R)-p-Tol-BINAP·AgOTf
complex and tributyltin methoxide
4.2.2. 2-[Hydroxy(4-methoxyphenyl)methyl]cyclohexa-
none (entry 2 in Table 2).27 The anti/syn ratio was
determined to be 94/6 by 1H NMR analysis. Spectral data of
the anti isomer (white solids, 95% ee): TLC Rf 0.17 (1/3
ethyl acetate/hexane); IR (KBr) 3700–3250, 2932, 1705,
4.2.1. Synthesis of (2S,10R)-2-(hydroxyphenylmethyl)-
cyclohexanone (anti-isomer, entry 5 in Table 1 and
entry 1 in Table 2).25 A mixture of AgOTf (12.9 mg,
0.050 mmol) and (R)-p-Tol-BINAP (37.3 mg, 0.055 mmol)
was dissolved in dry THF (6 mL) under argon atmosphere
and with direct light excluded, and stirred at 208C for
10 min. To the resulting solution were added dropwise
MeOH (81 mL, 2.00 mmol), benzaldehyde (100 mL,
0.98 mmol), 1-trichloroacetoxy cyclohexene (243.2 mg,
1.00 mmol), and trimethyltin methoxide (0.52 M in THF,
100 mL, 0.052 mmol) successively at 2208C. After being
stirred for 4 h at this temperature and then for 12 h at room
temperature, the mixture was treated with MeOH (2 mL).
The mixture was then treated with brine (2 mL) and solid
KF (ca. 1 g) at ambient temperature for 30 min. The
resulting precipitate was filtered off by a glass filter funnel
filled with Celitew and silica gel. The filtrate was dried over
Na2SO4 and concentrated in vacuo after filtration. The
residual crude product was purified by column chroma-
tography on silica gel to afford a mixture of the aldol
adducts (172.8 mg, 86% yield) as a colorless oil. The
anti/syn ratio was determined to be 94/6 by 1H NMR
analysis. The enantioselectivities of the anti and syn isomers
were determined to be 96% ee and 18% ee, respectively, by
HPLC analysis using a chiral column (Chiralcel OD-H,
Daicel Chemical Industries Ltd, hexane/i-PrOH¼9/1, flow
1
1686, 1516, 1250, 1173, 1129, 1028, 830 cm21; H NMR
(300 MHz, CDCl3) d 1.23–1.33 (m, 1H, one proton of
CH2), 1.48–1.81 (m, 4H, 2 CH2), 2.04–2.12 (m, 1H, one
proton of CH2), 2.30–2.41 (m, 1H, one proton of CH2),
2.44–2.52 (m, 1H, one proton of CH2), 2.55–2.64 (m, 1H,
CH), 3.80 (s, 3H, CH3), 3.94 (d, 1H, J¼2.5 Hz, OH), 4.74
(dd, 1H, J¼1.9, 8.8 Hz, CH(OH)), 6.88 (d, 2H, J¼8.5 Hz,
aromatic), 7.24 (d, 2H, J¼8.8 Hz, aromatic); 13C NMR
(75 MHz, CDCl3) d 24.7, 27.8, 30.8, 42.6, 55.2, 57.5, 74.2,
113.7 (2C), 128.1 (2C), 133.1, 159.2, 215.7; [a]2D9¼þ20.58
(c 1.2, CHCl3); elemental analysis calcd for C14H18O3: C
71.77, H 7.74%; found: C 71.70, H 7.86%. The enantio-
selectivity was determined to be 95% ee by HPLC analysis
using a chiral column (Chiralcel OD-H, Daicel Chemical
Industries Ltd, hexane/i-PrOH¼9/1, flow rate¼0.5 mL/
min): tmajor¼20.5 min, tminor¼27.7 min. Specific rotation
of the syn isomer (white solids, 12% ee): [a]3D0¼þ22.08
(c 0.5, CHCl3); elemental analysis calcd for C14H18O3: C
71.77, H 7.74%; found: C 71.61, H 7.78%. The enantio-
selectivity was determined to be 12% ee by HPLC analysis
using a chiral column (Chiralcel OD-H, Daicel Chemical
Industries Ltd, hexane/i-PrOH¼9/1, flow rate¼0.5 mL/
min): tmajor¼16.9 min, tminor¼17.7 min. Spectral data
(TLC, IR, 1H NMR, and 13C NMR) of the syn isomer
indicated good agreement with reported data.26,27
rate¼0.5 mL/min): tsyn-minor¼14.2 min (2S,10S), tsyn-major
15.7 min (2R,10R), tanti-major¼17.4 min (2S,10R), tanti-minor
¼
¼
24.2 min (2R,10S). The absolute configurations of all
stereoisomers were unambiguously established by Denmark
and co-workers.25d Spectral data of the anti isomer (oil,
96% ee): TLC Rf 0.11 (1/5 ethyl acetate/hexane); IR (neat)
3700–3140, 2940, 2863, 1700, 1605, 1497, 1453, 1401,
4.2.3. 2-[Hydroxy(2,3-methylenedioxyphenyl)methyl]-
cyclohexanone (entry 3 in Table 2). The anti/syn ratio
1
was determined to be 80/20 by H NMR analysis. Spectral
data of the anti isomer (white solids, 77% ee): TLC Rf 0.13
(1/3 ethyl acetate/hexane); IR (KBr) 3550–3200, 2931,
2852, 1717, 1684, 1559, 1541, 1509, 1489, 1456, 1254,
1
1312, 1296, 1227, 1204, 1130, 1042, 702 cm21; H NMR

A. Yanagisawa et al. / Tetrahedron 58 (2002) 8331–8339
8337
1127, 1048, 976 cm21; 1H NMR (300 MHz, CDCl3) d 1.39
(m, 1H, one proton of CH2), 1.54–1.74 (m, 3H, CH2 and
one proton of CH2), 1.82 (m, 1H, one proton of CH2), 2.11
(m, 1H, one proton of CH2), 2.31–2.54 (m, 2H, CH2), 2.78–
2.90 (m, 1H, CH), 3.98 (s, 1H, OH), 4.95 (d, 1H, J¼8.7 Hz,
CH(OH)), 5.95 (s, 1H, one proton of CH2), 5.98 (s, 1H, one
proton of CH2), 6.79 (m, 1H, aromatic), 6.85 (m, 2H,
aromatic); 13C NMR (75 MHz, CDCl3) d 24.7, 27.8, 30.5,
42.6, 55.9, 70.4, 100.0, 100.8, 108.0, 120.6 (2 C), 121.8 (2
C), 215.5; [a]3D1¼þ8.98 (c 1.0, CHCl3); elemental analysis
calcd for C14H16O4: C 67.72, H 6.51%; found: C 67.78, H
6.73%. The enantioselectivity was determined to be 70% ee
by HPLC analysis using a chiral column (Chiralcel OD-H,
Daicel Chemical Industries Ltd, hexane/i-PrOH¼9/1,
flow rate¼0.5 mL/min): tmajor¼23.5 min, tminor¼28.3 min.
Spectral data of the syn isomer (white solids, 10% ee): TLC
Rf 0.21 (1/3 ethyl acetate/hexane); IR (KBr) 3670–3160,
2954, 1698, 1636, 1559, 1541, 1509, 1489, 1458, 1252,
1115, 1050, 967, 928 cm21; 1H NMR (300 MHz, CDCl3) d
1.52–1.89 (m, 5H, one proton of CH2 and 2 CH2), 2.08 (m,
1H, one proton of CH2), 2.33–2.50 (m, 2H, CH2), 2.75 (m,
1H, CH), 3.06 (s, 1H, OH), 5.50 (br s, 1H, CH(OH)), 5.90 (s,
1H, one proton of CH2), 5.98 (s, 1H, one proton of CH2),
6.76 (d, 1H, J¼8.1 Hz, aromatic), 6.84 (t, 1H, J¼7.8 Hz,
aromatic), 6.76 (d, 1H, J¼7.8 Hz, aromatic); [a]2D9¼þ1.28
(c 1.2, CHCl3); elemental analysis calcd for C14H16O4: C
67.72, H 6.51%; found: C 67.65, H 6.71%. The enantio-
selectivity was determined to be 10% ee by HPLC analysis
using a chiral column (Chiralcel OD-H, Daicel Chemical
Industries Ltd, hexane/i-PrOH¼9/1, flow rate¼0.5 mL/
min): tmajor¼15.9 min, tminor¼17.4 min.
hexane); IR (neat) 3630–3130, 2938, 2863, 1700, 1599,
1
1495, 1449, 1130, 1055, 970, 750, 695 cm21; H NMR
(300 MHz, CDCl3) d 1.37–1.73 (m, 3H, CH2 and one
proton of CH2), 1.83–1.93 (m, 1H, one proton of CH2),
2.05–2.17 (m, 2H, CH2), 2.30–2.55 (m, 3H, CH2 and CH),
3.65 (d, 1H, J¼3.4 Hz, OH), 4.44 (ddd, 1H, J¼3.4, 7.4,
7.9 Hz, CH(OH)), 6.19 (dd, 1H, J¼7.4, 15.9 Hz, CH), 6.62
(d, 1H, J¼15.9 Hz, CH), 7.22–7.40 (m, 5H, aromatic); 13C
NMR (75 MHz, CDCl3) d 24.5, 27.5, 30.4, 42.4, 56.0, 72.8,
126.3 (2C), 127.5, 128.3 (2C), 128.8, 131.8, 136.4, 214.7;
[a]2D7¼228.78 (c 0.51, CHCl3); elemental analysis calcd for
C15H18O2: C 78.23, H 7.88%; found: C 78.22, H 8.14%.
Spectral data of the syn isomer (white solids, 43% ee): TLC
Rf 0.18 (1/3 ethyl acetate/hexane); IR (KBr) 3580–3250,
2934, 2857, 1698, 1599, 1495, 1451, 1424, 1314, 1130,
1123, 970, 760, 739, 696 cm21 1H NMR (300 MHz,
;
CDCl3) d 1.52–1.78 (m, 3H, CH2 and one proton of
CH2), 1.86–1.96 (m, 1H, one proton of CH2), 2.05–2.17
(m, 2H, CH2), 2.30–2.49 (m, 2H, CH2), 2.53–2.62 (m, 1H,
CH), 2.96 (d, 1H, J¼5.0 Hz, OH), 4.77 (ddt, J¼1.8, 5.0,
6.0 Hz, 1H, CH(OH)), 6.22 (dd, 1H, J¼6.0, 16.0 Hz, CH),
6.64 (dd, 1H, J¼1.3, 16.0 Hz, CH), 7.21–7.40 (m, 5H,
aromatic); 13C NMR (75 MHz, CDCl3) d 24.8, 27.3, 27.5,
42.5, 55.5, 70.5, 126.3 (2C), 127.5, 128.5 (2C), 129.0,
130.8, 136.7, 214.2; [a]D27¼234.98 (c 1.0, CHCl3); elemen-
tal analysis calcd for C15H18O2: C 78.23, H 7.88%; found: C
78.12, H 8.12%. Spectral data (TLC, IR, 1H and 13C NMR)
of the anti and syn isomers indicated good agreement with
reported data.11,25b–d,26b
4.2.6. 2-[(E)-1-Hydroxy-2-hexenyl]cyclohexanone (entry
6 in Table 2).27b The anti/syn ratio was determined to be
76/24 by 1H NMR analysis. Spectral data of the anti isomer
(colorless oil, 83% ee): TLC Rf 0.20 (1/3 ethyl acetate/
4.2.4. 2-[(1-Naphthyl)hydroxymethyl]cyclohexanone
(entry 4 in Table 2).25c,d The anti/syn ratio was determined
to be 96/4 by 1H NMR analysis. The enantioselectivities of
the anti and syn isomers were determined to be 92% ee and
42% ee, respectively, by HPLC analysis using a chiral
column (Chiralcel OD-H, Daicel Chemical Industries Ltd,
1
hexane); H NMR (300 MHz, CDCl3) d 0.90 (t, 3H, J¼
7.5 Hz, CH3), 1.30–1.47 (m, 3H, CH2 and one proton of
CH2), 1.61–1.74 (m, 2H, CH2), 1.87 (m, 1H, one proton of
CH2), 1.96–2.11 (m, 4H, 2 CH2), 2.27–2.44 (m, 3H, CH2
and CH), 3.59 (s, 1H, OH), 4.19 (t, 1H, J¼8.0 Hz, CH(OH)),
5.40 (dd, 1H, J¼7.8, 15.3 Hz, CH), 5.68 (dt, 1H, J¼6.9,
15.6 Hz, CH); [a]2D6¼23.18 (c 0.82, CHCl3). The enantio-
selectivity was determined to be 83% ee by HPLC analysis
using a chiral column (Chiralpak AD, Daicel Chemical
Industries Ltd, hexane/i-PrOH¼40/1, flow rate¼0.5 mL/
min): tmajor¼32.6 min, tminor¼34.7 min. Spectral data of the
syn isomer (colorless oil, 48% ee): TLC Rf 0.25 (1/3 ethyl
acetate/hexane); IR (neat) 3650–3120, 2960, 2932, 2869,
hexane/i-PrOH¼9/1, flow rate¼0.5 mL/min): tsyn-minor
¼
15.9 min, tsyn-major¼20.0 min, tanti-minor¼33.7 min (2R,10S),
tanti-major¼35.3 min (2S,10R). The absolute configurations
of the anti isomers were assigned by Denmark and
co-workers.25c,d Specific rotation of the anti isomer (92%
ee): [a]2D7¼þ8.48 (c 1.0, CHCl3); elemental analysis calcd
for C17H18O2: C 80.28, H 7.13%; found: C 80.29, H 7.31%.
Specific rotation of the anti isomer (42% ee): [a]2D7¼þ54.38
(c 0.58, CHCl3); elemental analysis calcd for C17H18O2: C
80.28, H 7.13%; found: C 80.27, H 7.27%. Other spectral
data (TLC, IR, 1H and 13C NMR) of the anti and syn isomers
indicated good agreement with reported data.25c,d,26b
1
1706, 1456, 1312, 1129, 972 cm21; H NMR (300 MHz,
CDCl3) d 0.90 (t, 3H, J¼7.4 Hz, CH3), 1.34–1.46 (m, 2H,
CH2), 1.53–1.77 (m, 3H, CH2 and one proton of CH2),
1.83–2.13 (m, 5H, 2 CH2 and one proton of CH2), 2.27–
2.50 (m, 3H, CH2 and CH), 2.82 (d, 1H, J¼4.8 Hz, OH),
4.49 (br s, 1H, CH(OH)), 5.47 (dd, 1H, J¼6.6, 15.6 Hz,
CH), 5.68 (dt, 1H, J¼6.8, 15.6 Hz, CH); [a]2D6¼211.58 (c
0.87, CHCl3). The enantioselectivity was determined to be
48% ee by HPLC analysis using a chiral column (Chiralpak
AD, Daicel Chemical Industries Ltd, hexane/i-PrOH¼40/1,
flow rate¼0.5 mL/min): tminor¼27.5 min, tmajor¼31.3 min.
Spectral data (IR and 1H NMR) of the anti and syn isomers
indicated good agreement with reported data.27b
4.2.5. 2-[(E)-1-Hydroxy-3-phenyl-2-propenyl]cyclohexa-
none (entry 5 in Table 2).11,25b–d The anti/syn ratio
was determined to be 78/22 by 1H NMR analysis. The
enantioselectivities of the anti and syn isomers were
determined to be 90% ee and 43% ee, respectively, by
HPLC analysis using a chiral column (Chiralpak AD, Daicel
Chemical Industries Ltd, hexane/i-PrOH¼40/1, flow
rate¼0.5 mL/min): tsyn-minor¼36.7 min, tsyn-major¼46.1 min,
t
¼49.6 min (2S,10R), tanti-minor¼57.3 min (2R,10S). The
anti-major
absolute configurations of the anti isomers were assigned by
Denmark and co-workers.25b–d Spectral data of the anti
isomer (oil, 90% ee): TLC Rf 0.14 (1/3 ethyl acetate/
4.2.7. 2-(1-Hydroxy-3-phenylpropyl)cyclohexanone
(entry 7 in Table 2).25c,d The anti/syn ratio was determined

8338
A. Yanagisawa et al. / Tetrahedron 58 (2002) 8331–8339
to be 84/16 by 1H NMR analysis. The enantioselectivities of
the anti and syn isomers were determined to be 79% ee and
60% ee, respectively, by HPLC analysis using two chiral
columns (Chiralcel OD-H and Chiralpak AD, Daicel
Chemical Industries Ltd, hexane/i-PrOH¼20/1, flow rate¼
0.5 mL/min): tanti-major¼46.4 min, tsyn-minor¼48.5 min,
tanti-minor¼54.1 min, tsyn-major¼58.7 min. Spectral data of a
84/16 mixture of the anti and syn isomers (colorless oil):
TLC Rf 0.21 (1/3 ethyl acetate/hexane); IR (neat) 3630–
3125, 3027, 2938, 2863, 1698, 1603, 1497, 1453, 1312,
4.4. Experimental procedure for the NMR studies on
aldol reaction of benzaldehyde with tributyltin enolate of
cyclohexanone followed by protonation with MeOH
(Fig. 5)
A solution of tributyltin enolate of cyclohexanone (175 mL,
0.50 mmol)15 in dry CDCl3 (0.7 mL, distilled from CaH2)
was placed into a dried 5 mm NMR tube. After addition of
benzaldehyde (50 mL, 0.49 mmol) at room temperature
under an argon stream, the resulting mixture was shaken for
a few minutes followed by measurement of the 119Sn NMR
spectrum (111.9 MHz, rt, Me4Sn; d 0.0 ppm) to show
two peaks of the in situ generating tributyltin alkoxide of
aldol adduct at d 101.9 ppm (anti-isomer) and 100.7 ppm
(syn-isomer) with an anti/syn ratio of 23/77. To the mixture,
dry MeOH (25 mL, 0.62 mmol) was added at 2408C and
then, 1H NMR (300 MHz) measurement of the mixture
was performed at 240, 2208C, and room temperature to
indicate the formation of the protonated product at 2408C
and the disappearance of the tin alkoxide at room
temperature.
1130, 749, 700 cm21 1H NMR (300 MHz, CDCl3) d
;
1.35–1.97 (m, 6H, 3CH2), 2.03–2.14 (m, 2H, CH2),
2.25–2.45 (m, 3H, CH2 and CH), 2.64–2.75 (m, 1H, one
proton of CH2), 2.85–2.94 (m, 1H, one proton of CH2),
3.56 (d, 0.84H, J¼3.6 Hz, OH), 3.70 (m, 0.16H, OH),
3.76 (m, 0.84H, CH(OH)), 4.12 (m, 0.16H, CH(OH)),
7.16–7.32 (m, 5H, aromatic); [a]2D5¼214.58 (c 1.68,
CHCl3); elemental analysis calcd for C15H20O2:
C
77.55, H 8.68%; found: C 77.44, H 8.92%. Spectral
1
data (TLC, IR, and H NMR) of the mixture of the anti
and syn isomers indicated good agreement with reported
data.25c,d
4.5. Experimental procedure for the 13C NMR
measurement of a 1:1 mixture of (R)-BINAP·AgOTf and
DMF in THF-d8 (Fig. 6)
4.3. Typical experimental procedure for asymmetric
reaction of benzaldehyde with diketene catalyzed by
(R)-p-Tol-BINAP·AgOTf complex and dibutyltin
dimethoxide
AgOTf (51.3 mg, 0.20 mmol) and (R)-BINAP (125.3 mg,
0.20 mmol) were placed into a dried 5 mm NMR tube and
the mixture was dissolved in dry THF-d8 (0.5 mL) under
argon atmosphere and with direct light excluded, and stirred
at room temperature for 10 min. To the resulting clear
solution, dry DMF (15 mL, 0.19 mmol, distilled from
MgSO4) was added at room temperature and 13C NMR
(75 MHz) measurement of the mixture was performed at
this temperature, showing a shifted peak of DMF at d
163.9 ppm (uncomplexed DMF: d 162.5 ppm). Subse-
quently, tributyltin enolate of cyclohexanone (70 mL,
0.20 mmol)15 was added to the mixture at room temperature
followed by measurement of the 13C NMR spectrum to
reveal a peak of DMF at d 163.4 ppm and set of shifted
peaks attributable to (1-cyclohexenyloxy)tributyltin shown
in Fig. 6.
4.3.1. Synthesis of optically active methyl 5-hydroxy-3-
oxo-5-phenylpentanoate (Eq. (5)).28 A mixture of AgOTf
(56.5 mg, 0.22 mmol) and (R)-p-Tol-BINAP (162.9 mg,
0.24 mmol) was dissolved in dry THF (6 mL) under argon
atmosphere and with direct light excluded, and stirred at
208C for 10 min. To the resulting solution were added
dropwise MeOH (80 mL, 2.00 mmol), benzaldehyde
(100 mL, 0.98 mmol), diketene (385 mL, 4.99 mmol), and
dibutyltin dimethoxide (47 mL, 0.20 mmol) successively at
2208C. After being stirred for 72 h at this temperature, the
mixture was treated with MeOH (2 mL). After warming to
room temperature, the mixture was treated with brine
(2 mL) and solid KF (ca. 1 g) at ambient temperature for
30 min. The resulting precipitate was filtered off by a glass
filter funnel filled with Celitew and silica gel. The filtrate
was dried over Na2SO4 and concentrated in vacuo after
filtration. The residual crude product was purified by
column chromatography on silica gel to afford the aldol
adduct (129.4 mg, 59% yield) as a colorless oil. The
enantioselectivity was determined to be 84% ee by HPLC
analysis using a chiral column (Chiralpak AD, Daicel
Chemical Industries Ltd, hexane/i-PrOH¼9/1, flow
rate¼0.5 mL/min): tmajor¼29.6 min, tminor¼33.2 min. The
absolute configuration of the major enantiomer is not
known. Spectral data of the product: TLC Rf 0.09 (1/3
ethyl acetate/hexane); IR (neat) 3700–3125, 2955, 1742,
Acknowledgements
This work was supported in part by CREST and SORST,
Japan Science and Technology Corporation (JST). We
thank Takasago International Corporation for its generous
gift of (R)-p-Tol-BINAP. A. Yanagisawa also acknowl-
edges financial support from the Sumitomo Foundation.
1710, 1495, 1437, 1320, 750, 702 cm21
;
1H
NMR (300 MHz, CDCl3) d 2.92 (dd, 1H, J¼3.5, 17.4 Hz,
one proton of CH2), 2.98 (br s, 1H, OH), 3.02 (dd,
1H, J¼8.9, 17.4 Hz, one proton of CH2), 3.52 (s, 2H,
CH2), 3.75 (s, 3H, CH3), 5.20 (dd, 1H, J¼3.5, 8.9 Hz,
CH(OH)), 7.28–7.38 (m, 5H, aromatic); 13C NMR
(75 MHz, CDCl3) d 49.7, 51.5, 52.4, 69.7, 125.6 (2C),
127.8, 128.5 (2C), 142.5, 167.2, 202.6; [a]3D0¼þ51.88 (c 1.0,
CHCl3).
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