Diastereoselective aldol condensation of acylsilane silyl enol ethers with acetals

Article abstract of DOI:10.1016/S0040-4020(02)00787-1

Treatment of E- or Z-acylsilane silyl enol ethers derived from acylsilanes having an enolizable methylene proton with a mixture of aromatic aldehyde dimethyl acetals and TiCl₄ in dichloromethane gives the corresponding 2,3-anti-3-methoxyacylsilanes in high d.e., independent of the geometry of double bond in acylsilane silyl enol ethers. On the other hand, E-acylsilane silyl enol ethers react with acetals of aliphatic aldehydes to afford the corresponding aldol adducts with syn-selectivity, while the reaction of Z-isomers provides the products with anti-selectivity.

Full text of DOI:10.1016/S0040-4020(02)00787-1

Tetrahedron 58 (2002) 6815–6823
Diastereoselective aldol condensation of acylsilane silyl enol ethers
with acetals
*
Mitsunori Honda, Wataru Oguchi, Masahito Segi and Tadashi Nakajima
Department of Chemistry and Chemical Engineering, Faculty of Engineering, Kanazawa University, 2-40-20 Kodatsuno,
Kanazawa 920-8667, Japan
Received 25 April 2002; accepted 2 July 2002
Abstract—Treatment of E- or Z-acylsilane silyl enol ethers derived from acylsilanes having an enolizable methylene proton with a mixture
of aromatic aldehyde dimethyl acetals and TiCl4 in dichloromethane gives the corresponding 2,3-anti-3-methoxyacylsilanes in high d.e.,
independent of the geometry of double bond in acylsilane silyl enol ethers. On the other hand, E-acylsilane silyl enol ethers react with acetals
of aliphatic aldehydes to afford the corresponding aldol adducts with syn-selectivity, while the reaction of Z-isomers provides the products
with anti-selectivity. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Here, we wish to report a convenient method of diastereo-
selective construction of acylsilanes having the contiguous
stereogenic centers using the Lewis acid mediated aldol
reaction of acylsilane silyl enol ethers 1 with acetals and the
details of diastereoselectivity of this aldol reaction.
Acylsilanes have received considerable attention due to
their unusual spectroscopic properties, novel chemical
reactivity, and their utility as useful synthons in organic
synthesis.1 While a number of methods for the preparation
of simple acylsilanes have been developed, more highly
functionalized acylsilanes are much less well known,
especially, it is relatively difficult to introduce substituents
at the a and b positions of the carbonyl group of acylsilanes
diastereoselectively.2,3
2. Results and discussion
2.1. Preparation of acylsilane silyl enol ethers
The E-isomers of acylsilane silyl enol ethers 1 were
prepared by the treatment of enolizable acylsilanes8 with
LDA at 258C in THF/HMPA, followed by reaction of the
resulting enolates with trimethylsilyl chloride (E-1/Z-
1¼99–82:1–18). On the other hand, the corresponding
isomeric silyl enol ethers Z-1 were obtained by the treatment
of acylsilanes with LDA at 2788C in THF, followed by the
addition of trimethylsilyl chloride (E-1/Z-1¼10–11:90–
89). The pure E- or Z-isomer as a starting silyl enol ether is
required to study the stereoselectivity of aldol reaction, but
the products 1 obtained under the above conditions were a
mixture of E- and Z-isomers in most cases as shown in
Scheme 1. The complete separation of these isomers by
column chromatography on silica-gel was difficult. In this
study, E- or Z-isomer containing a small quantity of the
other one was used as a starting material in most cases.
We thought that the a,b-disubstituted acylsilanes can be
synthesized by Mukaiyama aldol reaction.4 Since the
Mukaiyama aldol reaction is one of the most useful method
for the stereoselective construction of carbon–carbon
bond,5 the reaction using enol ethers of simple acyl-
silanes1c,6 with acetals is expected to give the functionalized
acylsilanes. In this reaction, the regeneration of silyl-
carbonyl group and the formation of carbon–carbon bond
would take place at the same time. The resulting a,b-
disubstituted acylsilanes would be useful synthetic inter-
mediates as valuable building blocks. However, only a few
reports have been published for the Mukaiyama aldol
reaction with enol ethers of acylsilanes.7 Kuwajima et al.
have reported that boron trifluoride diethyl etherate
catalyzed coupling of enol ethers of acylsilanes with acetals
provided b-alkoxyacylsilanes,7a without description of
diastereoselectivity of resulting aldol adducts.
Additionally, when phosphonium diylide9 generated by the
treatment of dibenzyldiphenylphosphonium bromide with
n-butyllithium was employed as a base in THF, geome-
trically pure E-isomers were obtained. However, this
method was unsuitable for a large scale synthesis of 1.
Keywords: acetals; aldol reactions; diastereoselection; enol ethers; silicon
and compounds.
*
Corresponding author. Tel.: þ81-76-234-4789; fax: þ81-76-234-4800;
e-mail: honda@t.kanazawa-u.ac.jp
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00787-1

6816
M. Honda et al. / Tetrahedron 58 (2002) 6815–6823
all of the following aldol reactions with acetals were carried
out using titanium tetrachloride in dichloromethane at
2788C for 1 h. In addition, the use of catalytic amounts of
Lewis acid led to the decrease in product yield, and the
reaction using benzaldehyde instead of the corresponding
dimethyl acetal as a starting substrate did not proceed at all.
The aldol reaction of 1 having an aliphatic group with
benzaldehyde dimethyl acetal in the presence of titanium
chloride was carried out in dichloromethane at 2788C under
argon. The results are shown in Table 2. In all cases, the
corresponding 2,3-anti-products 2 were preferentially
obtained in good yields. Both reactions of E- and Z-1b
(R¼cyclohexyl) gave 2,3-anti-2b in good yields with an
anti-selectivity (entries 1 and 2). The reaction of E-1b gave
2,3-anti-2b in high yield relative to that of Z-1b, whereas the
reaction of Z-1b provided the corresponding 2b with high
diastereoselectivity relative to that of E-1b. The reaction
using 1d (R¼ethyl), 1e (R¼methyl) or 1f (R¼benzyl)
showed high diastereoselectivity (entries 4–6), whereas 1b
(R¼cyclohexyl) or 1c (R¼isopropyl) showed little diaster-
eoselectivity (entries 1 and 3). The ratio of anti/syn in 2 was
influenced by the bulkiness of the aliphatic substituent and
the geometry of 1.
Scheme 1. Synthesis of acylsilane silyl enol ethers.
2.2. Aldol reaction of acylsilane silyl enol ethers with
acetals
First, the reaction of E- or Z-1a with benzaldehyde dimethyl
acetal was examined in the presence of various Lewis acids.
The results are summarized in Table 1. As Lewis acids we
employed titanium tetrachloride,10 tin tetrachloride,11 boron
trifluoride diethyl etherate7a and trimethylsilyl triflate.12 All
reactions were carried out in dichloromethane. Using
titanium tetrachloride as an activating agent, the reaction
proceeded smoothly at 2788C to afford the corresponding
2,3-anti-3-methoxyacylsilane 2a in good yields with a high
anti-selectivity, irrespective of the geometry of double bond
in 1a (entries 1 and 2). Higher yields were observed in the
reaction of E-1a using tin tetrachloride or boron trifluoride
diethyl etherate (entries 3 and 5), however, the stereo-
selectivity in these reactions was lower than that in the
reaction using titanium tetrachloride (entry 1). On the other
hand, the similar reaction of Z-1a using these Lewis acids
resulted in the lower yields (entries 2, 4, 6 and 8). The
reaction using trimethylsilyl triflate as a Lewis acid gave the
aldol adducts with the moderate yield and diastereoselec-
tivity (entries 7 and 8). Among several Lewis acids tested,
titanium chloride was suitable for this reaction, and hence
In order to examine the structural effect of acetal on the
stereochemistry of this aldol reaction, the reaction using
cyclic acetal13 was carried out under similar conditions as
above. The reaction of 1 with 2-phenyl-1,3-dioxane 3 gave
the corresponding aldol adducts 4 in good yields. The results
are shown in Table 3. In the reaction of E-1a with 3, anti and
syn aldols were produced in a ratio of 95:5 (entry 1), which
showed higher diastereoselectivity than the reaction of E-1a
with benzaldehyde dimethyl acetal (Table 1, entry 1).
Similarly, the reaction of Z-1a gave a mixture of aldols in a
ratio of 96:4 (entry 2). The reaction of 1d with 3 also
showed higher diastereoselectivity (entry 4) than the
reaction with dimethyl acetal (Table 2, entry 4). On the
other hand, the moderate diastereoselectivity was
observed in the reaction of 1c with 3 (entry 3), whereas
little selectivity was showed in the reaction with dimethyl
acetal as mentioned above (Table 2, entry 3). The
Table 1. Effect of Lewis acids in aldol reaction
Entry
1a E/Z
Lewis acid
Temperature
(8C)
Time
(h)
2a
Yield
(%)a
anti/synb
1
2
3
4
5
6
7
8
96/4
1/99
96/4
13/87
92/8
12/88
92/8
24/76
TiCl4
278
278
230
230
1
1
2
1
86
76
96
50
92
45
76
77
87/13
96/4
81/19
94/6
80/20
89/11
76/24
84/16
SnCl4
BF3·OEt2
CF3SO3SiMe3
Molar ratio: 1a/acetal/Lewis acid¼1:1:1.
a
Isolated yield.
Determined by 1H NMR analysis.
b

M. Honda et al. / Tetrahedron 58 (2002) 6815–6823
6817
Table 2. Aldol reaction of acylsilane silyl enol ethers 1 with benzaldehyde dimethyl acetal using TiCl4
Entry
Substrate
R
E/Z
Product
Yield (%)a
anti/synb
1
2
3
4
5
6
1b
1b
1c
1d
1e
1f
Chxc
Chxc
i-Pr
Et
Me
99/1
1/99
83/17
80/20
99/1
96/4
2b
2b
2c
2d
2e
2f
93
85
98
85
71
84
62/38
73/27
56/44
92/8
96/4
86/14
PhCH2
Molar ratio: 1/acetal/TiCl4¼1:1:1.
a
Isolated yield.
b
Determined by 1H NMR analysis.
c
Chx¼Cyclohexyl.
Table 3. Aldol reaction using 2-phenyl-1,3-dioxane
Entry
Substrate
R
E/Z
Product
Yield (%)a
anti/synb
1
2
3
4
5
1a
1a
1c
1d
1e
Ph
Ph
i-Pr
Et
95/5
15/85
99/1
99/1
99/1
4a
4a
4c
4d
4e
91
76
70
51
84
95/5
96/4
73/27
97/3
95/5
Me
Molar ratio: 1/3/TiCl4¼1:1:1.
a
Isolated yield.
Determined by 1H NMR analysis.
b
diastereoselectivity of the reaction with 3 was, therefore,
higher than that of the similar reaction with dimethyl acetal,
irrespective of the geometry in 1.
aromatic aldehydes afforded the anti aldol adducts
preferentially, irrespective of the geometry in 1a
(entries 1–4). On the other hand, acetals of aliphatic
aldehydes reacted with E-1a to yield the corresponding
adducts with low stereoselectivity (entries 5, 7 and 9),
while high anti-selectivity was observed in the reaction
of acetals of aliphatic aldehydes with Z-1a (entries 6, 8
and 10).
Next, several dimethyl acetals derived from aromatic
and aliphatic aldehydes were examined in the aldol
reaction with 1a, and the results are shown in Table 4.
The reaction of E- or Z-1a with dimethyl acetals of
Table 4. Substituent effect of acetal in aldol reaction of acylsilane silyl enol ether 1a
Entry
1a E/Z
Acetal R
Ph
Ph
o-CH3–C6H4
o-CH3–C6H4
Me
Product
Yield (%)a
anti/synb
1
2
3
4
5
6
7
8
9
10
95/5
15/85
95/5
15/85
95/5
15/85
95/5
15/85
95/5
15/85
2a
2a
2g
2g
2h
2h
2i
2i
2j
2j
86
76
73
15
52
64
69
69
80
76
87/13
96/4
89/11
86/14
49/51
89/11
46/54
87/13
37/63
88/12
Me
n-C7H15
n-C7H15
PhCH2
PhCH2
Molar ratio: 1a/acetal/TiCl4¼1:1:1.
a
Isolated yield.
b
Determined by 1H NMR analysis.

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M. Honda et al. / Tetrahedron 58 (2002) 6815–6823
Table 5. Aldol reaction using 2-phenylpropionaldehyde dimethyl acetal
Entry
Substrate
R
E/Z
Product
Yield (%)a
2,3-anti/2,3-synb
1
2
3
4
5
6
1a
1a
1b
1c
1d
1f
Ph
Ph
95/5
15/85
99/1
83/17
80/20
75/25
6a
6a
6b
6c
6d
6f
84
29
79
60
76
97
25/75
82/18
9/91
10/90
37/63
38/62
Chxc
i-Pr
Et
PhCH2
Molar ratio: 1/acetal/TiCl4¼1:1:1.
a
Isolated yield.
b
Determined by 1H NMR analysis.
c
Chx¼Cyclohexyl.
The aldol reaction using the chiral acetals as the substrate
provides the corresponding aldols containing the contiguous
chiral centers.14 Then we turned out attention to the aldol
reaction of 1 with 2-phenylpropionaldehyde dimethyl acetal
as an acetal having a stereogenic center. The reaction was
carried out in a similar manner as above, and the results are
summarized in Table 5. In all cases, only two isomers (2,3-
anti-3,4-syn-6 and 2,3-syn-3,4-syn-6) among the four
possible diastereomeric products were formed with com-
plete Cram-type (3,4-syn ) selectivity. Similar to the results
of the reaction of 1 with aliphatic acetals (Table 4, entries
5–10), the reaction of E-1 gave 2,3-syn-6, whereas that of Z-
1 gave 2,3-anti-6, respectively. For the reaction of 1 having
aliphatic substituent, the stereoselectivity of the reaction
increased with increasing the bulkiness of the substituent R
(entries 3–6).
following mechanism for the reaction of 1a derived from
benzyl silyl ketone with acetal is proposed (Scheme 2). The
proposed open model assumes that two oxygen atoms are as
remote as possible in order to minimize their electrostatic
repulsion. For the Z isomers, Si group attached to oxygen
atom is on the sp2 plane of the carbon–carbon double bond
apart from Si group because of the steric repulsion between
Si(O) and Si group, so transition structure A is disfavored
compared to B by the large nonbonded steric repulsion
between Si(O) and R. Thus, the reaction of Z-1 leads to anti
products with high stereoselectivity by way of transition
structure B. In contrast, E-1 adopts conformations in which
Si group attached to oxygen atom is below the sp2 plane of
the carbon–carbon double bond because of the steric
repulsion between Si(O) and the phenyl group that is
coplanar to the sp2 plane of the carbon–carbon double
bond.16 In the case of the reaction using acetals of aromatic
aldehydes, transition structure C is disfavored compared to
D by the nonbonded steric repulsion between Si and R. In
addition, transition structure D may be favored by a p–p
stacking between the phenyl group of 1a and the aromatic
group of acetal. As a result, the reaction of E isomers with
acetals of aromatic aldehydes is anti selective. On the other
hand, transition structure D is disfavored due to the gauche
repulsion between the phenyl group of 1a and R where
acetals of aliphatic aldehydes are used. In addition, the
nonbonded steric repulsion between Si and aliphatic group
in C would be smaller than that between Si and aromatic
group. Thus, the reaction of E isomers with acetals of
aliphatic aldehydes proceeded with low diastereoselectivity.
Similarly, the results in Table 2 can also be explained as
mentioned above using the models exchanged between Ph
and R. On the whole, approach of acetal moiety to 1 in
transition structure C or D would be easier than that in
transition structure A or B, so higher yields were observed
in the reaction of E-1 with acetals of aromatic aldehydes.
2.3. Mechanistic considerations
In general, the stereoselection of Lewis acid mediated aldol
reactions of silyl enol ether with aldehyde is understood by
assuming acyclic extended transition structures.15 Thus, the
2.4. Stereochemical assignment
Stereochemical assignment of the resulting aldol adduct 4c
was performed by conversion into the corresponding
acetone ketal (Scheme 3). Treatment of a diastereomeric
mixture 4c (73:27), obtained by the reaction of 2-phenyl-
1,3-dioxane with silyl enol ether 1c (Table 3, entry 3),
with PCC in dichloromethane followed by ether cleavage
Scheme 2.

M. Honda et al. / Tetrahedron 58 (2002) 6815–6823
6819
Scheme 3. Conversion of aldol adduct 4c into cyclic ketal.
(b-elimination) with dibenzylammonium trifluoroacetate
gave 3-hydroxyacylsilane 8.13c,17 Reduction of the carbonyl
group of the resulting acylsilane 8 with LAH yielded the
1,3-dihydroxypropylsilane derivative 9, which was then
subjected to treatment with acetone dimethyl acetal,18
affording the 2-silyl-1,3-dioxane derivative 10. Protiodesi-
lylation of the resulting cyclic acetal 10 by tetrabutylam-
monium fluoride gave a mixture of two diastereomers (11A/
11S¼73:27).19
with a stereogenic center was used, complete b,g-diaster-
eoselectivity of aldol adducts was observed. Further
applications of the resulting acylsilanes are now in progress
in our laboratory. The results will be reported in due course.
4. Experimental
4.1. General
The vicinal coupling constant of 10.6 Hz observed between
1
the protons on C-2 and C-3 in the H NMR spectrum of
IR spectra were recorded on a JASCO A-202 or
SHIMADZU FTIR-8300 infrared spectrometer.1H and 13C
NMR spectra were recorded on a JEOL JNM FX-100s, LA-
400 spectrometer, and tetramethylsilane (TMS) served as
the internal standard. Mass spectra were recorded on a JEOL
JMS-SX102A, JMS-AM50 or Hitachi M-80 mass
spectrometer.
major product 11A indicates an axial–axial arrangement of
these two protons, which is correlated to 2,3-anti configur-
ation in major isomer of aldol 4c. On the other hand, the
corresponding vicinal coupling constant of 3.4 Hz for 11S
indicates an axial–equatorial arrangement of these two
protons, so the minor isomer of aldol 4c is assigned to 2,3-
syn configuration (Scheme 4). Thus, the stereoconfiguration
of other aldol adducts 2 and 4 was predicted by comparing
Thin layer chromatography and flash-column chromatog-
raphy were performed by the use of Merck’s silica-gel 60F
254 and silica-gel BW-127ZH (Fuji Silysia), respectively.
3
with the J(H2,H3) coupling constants of 4c.
All the solvents were distilled and stored over a drying
agent. n-Butyllithium (1.6 M solution in hexane) was
purchased from Aldrich Chemical Co., Inc.
3. Conclusion
In summary, TiCl4-catalyzed aldol reaction of acylsilane
silyl enol ethers and acetals has been described. Silyl enol
ethers derived from enolizable acylsilanes reacted with
acetals of aromatic aldehydes to afford the corresponding
aldol adducts in high yields with good anti-selectivity,
irrespective of the double bond stereochemistry in acylsi-
lane silyl enol ethers. On the other hand, E-isomers of silyl
enol ethers reacted with acetals of aliphatic aldehydes to
afford the corresponding adducts with syn-selectivity, while
the reaction of Z-isomers with acetals of aliphatic aldehydes
gave the corresponding adducts with anti-selectivity. In
particular, when 2-phenylpropionaldehyde dimethyl acetal
All reactions were carried out under argon atmosphere in
dried glassware.
Acylsilanes were prepared according to the literature
procedures.
4.2. A typical procedure for the preparation of E-1-
trimethylsiloxy-1-trimethylsilyl-2-phenylethylene
A 300 ml, four-necked, round-bottomed flask equipped with
an argon inlet adapter, rubber septum, thermometer, drop-
Scheme 4.

6820
M. Honda et al. / Tetrahedron 58 (2002) 6815–6823
funnel, and magnetic stirring bar was charged with 150 ml
of dry THF and diisopropylamine (2.8 ml, 20 mmol), cooled
to 2788C and n-butyllithium (1.6 M solution in hexane,
12.5 ml, 20 mmol) was added slowly over several minutes.
After 30 min, 20 ml of hexamethylphosphoric triamide and
a solution of 20 ml of acylsilane in THF were added. After
5 min, the reaction mixture was warmed to room tempera-
ture. After stirring for 1.5 h, a solution of Me3SiCl (2.6 g,
24 mmol) was added, and then stirred further 30 min.
Saturated NaCl solution was then added, and aqueous layer
was extracted with diethyl ether. The combined organic
phase were washed with saturated NaCl solution, and dried
over Na2SO4, filtered, concentrated. Column chromatog-
raphy on a silica-gel afforded E-1-trimethyloxy-1-trimethyl-
silyl-2-phenylethylene as pale yellow oils.
7.19 (m, 10H), 4.79 (d, J¼9.0 Hz, 1H), 4.53 (d, J¼9.0 Hz,
1H), 3.04 (s, 3H), 20.19 (s, 9H).
4.4.2. 2-Cyclohexyl-3-methoxy-3-phenyl-1-trimethylsi-
lyl-1-propanone (2b). IR (neat) 3080, 3050, 3020, 2920,
2840, 2810, 1705, 1635, 1450, 1245, 1200, 1090, 840 cm21
.
HRMS calcd for C18H26OSi ([M2CH3OH]þ) 286.1753,
1
found 286.1760. anti-2b: H NMR (CDCl3) d 7.38–6.98
(m, 5H), 4.33 (d, J¼10.3 Hz, 1H), 3.68 (dd, J¼10.3, 3.9 Hz,
1H), 3.10 (s, 3H), 1.97–0.72 (m, 11H), 20.23 (s, 9H). syn-
2b: 1H NMR (CDCl3) d 7.95–7.10 (m, 5H), 4.44 (d,
J¼9.5 Hz, 1H), 3.37 (dd, J¼9.5, 4.6 Hz, 1H), 2.98 (s, 3H),
1.95–0.50 (m, 11H), 0.18 (s, 9H).
4.4.3. 2-Isopropyl-3-methoxy-3-phenyl-1-trimethylsilyl-
1-propanone (2c). IR (neat) 3090, 3070, 3040, 2970,
2905, 2890, 2820, 1635, 1495, 1465, 1455, 1385, 1365,
1255, 1135, 1105, 1085, 845 cm21. HRMS calcd for
4.3. A typical procedure for the preparation of Z-1-
trimethylsiloxy-1-trimethylsilyl-2-phenylethylene
1
C16H26O2Si (Mþ) 278.1702, found 278.1710. anti-2c: H
A 300 ml, four-necked, round-bottomed flask equipped with
an argon inlet adapter, rubber septum, thermometer, drop-
funnel, and magnetic stirring bar was charged with 150 ml
of dry THF and diisopropylamine (2.8 ml, 20 mmol), cooled
to 2788C and n-butyllithium (1.6 M solution in hexane,
12.5 ml, 20 mmol) was added slowly over several minutes.
After 30 min, a solution of 20 ml of acylsilane in THF was
added. After 30 min, a solution of Me3SiCl (2.6 g, 24 mmol)
was added, The reaction mixture was stirred 30 min and
then allowed to warm to room temperature. Saturated NaCl
solution was then added, and aqueous layer was extracted
with diethyl ether. The combined organic phase were
washed with saturated NaCl solution, and dried over
Na2SO4, filtered, concentrated. Column chromatography
on a silica-gel afforded Z-1-trimethyloxy-1-trimethylsilyl-2-
phenylethylene as pale yellow oils.
NMR (CDCl3) d 7.32–7.01 (m, 5H), 4.32 (d, J¼10.3 Hz,
1H), 3.69 (dd, J¼10.3, 4.2 Hz, 1H), 3.11 (s, 3H), 2.27–2.01
(m, 1H), 1.03 (d, J¼6.8 Hz, 3H), 1.00 (d, J¼7.1 Hz, 3H),
1
20.22 (s, 9H). syn-2c: H NMR (CDCl3) d 7.33 (br, 5H),
4.40 (d, J¼9.5 Hz, 1H), 3.39 (dd, J¼9.5 Hz, 5.5 Hz, 1H),
2.99 (s, 3H), 1.65–1.40 (m, 1H), 0.78 (d, J¼6.8 Hz, 6H),
0.19 (s, 9H).
4.4.4. 2-Ethyl-3-methoxy-3-phenyl-1-trimethylsilyl-1-
propanone (2d). IR (neat) 3120, 3100, 3065, 3005, 2970,
2945, 2920, 2850, 1655, 1510, 1465, 1260, 1215, 1140,
1105, 965, 849 cm21. HRMS calcd for C13H19O2Si
([M2C2H5]þ) 235.1154, found 235.1171. anti-2d: 1H
NMR (CDCl3) d 7.36–7.23 (m, 5H), 4.13 (d, J¼10.0 Hz,
1H), 3.31 (dt, J¼10.0, 3.4 Hz, 1H), 2.99 (s, 3H), 1.67–1.34
1
(m, 2H), 0.58 (t, J¼7.1 Hz, 3H), 0.24 (s, 9H). syn-2d: H
NMR (CDCl3) d 3.14 (s, 3H), 20.14 (s, 9H).
4.4. Aldol reaction of acylsilane silyl enol ether with
acetal
4.4.5. 2,3-anti-2-Methyl-3-methoxy-3-phenyl-1-tri-
methylsilyl-1-propanone (anti-2e). IR (neat) 3086, 3063,
A 30 ml of, three-necked, round-bottomed flask equipped
with argon adapter, rubber septum, thermometer and
magnetic stirring bar was charged with 5 ml of dichlor-
omethane and 0.5 mmol of Lewis acid. This solution was
cooled to 2788C and acetal solution (0.5 mmol in 1 ml of
dichloromethane) was added rapidly via syringe. After
5 min, a solution of acylsilane silyl enol ether (0.5 mmol)
was added. After completion of the reaction evidenced by
GC (usually after being stirred for 1 h at 2788C), saturated
NaCl solution was then added, and the resulting mixture
was separated. The aqueous layer was extracted with
diethyl ether. The combined organic phase was washed
with saturated NaCl solution, and dried over Na2SO4,
filtered, concentrated. Column chromatography on a
silica-gel afforded 3-alkoxyacylsilanes as pale yellow
oils.
3030, 2963, 2932, 2903, 1643, 1454, 1248, 1096 cm21
.
HRMS calcd for C14H22O2Si (Mþ) 250.1389, found
1
250.1381. H NMR (CDCl3) d 7.90–7.23 (m, 5H), 4.18
(d, J¼9.9 Hz, 1H), 3.35 (dq, J¼9.9, 7.1 Hz, 1H), 3.03 (s,
3H), 0.59 (d, J¼7.1 Hz, 3H), 0.25 (s, 9H).
4.4.6. 2-Benzyl-3-methoxy-3-phenyl-1-trimethylsilyl-1-
propanone (2f). IR (neat) 3095, 3075, 3045, 2970, 2945,
2920, 2830, 1645, 1605, 1498, 1455, 1255, 1205, 1105,
1090, 845 cm21
.
HRMS calcd for C19H22OSi
([M2CH3OH]þ) 294.1440, found 294.1441. anti-2f: 1H
NMR (CDCl3) d 7.78–6.82 (m, 10H), 4.17 (d, J¼10.0 Hz,
1H), 3.96–3.71 (m, 1H), 3.00 (s, 3H), 2.74 (dd, J¼12.9,
11.5 Hz, 1H), 2.06 (dd, J¼12.9, 3.4 Hz, 1H), 20.09 (s, 9H).
syn-2f: 1H NMR (CDCl3) d 3.19 (s, 3H), 20.58 (s, 9H).
4.4.7. 3-Methoxy-2-phenyl-3-(2-tolyl)-1-trimethylsilyl-1-
4.4.1. 3-Methoxy-2,3-diphenyl-1-trimethylsilyl-1-propa-
none (2a). IR (neat) 3100, 3090, 3060, 2990, 2960, 2930,
propanone (2g). IR (neat) 2920, 1661, 1249, 1100 cm21
.
HRMS calcd for C20H26O2Si (Mþ) 326.1702, found
326.1722. anti-2g: 1H NMR (CDCl3) d 7.40–6.82 (m,
9H), 5.12 (d, J¼10.0 Hz, 1H), 4.57 (d, J¼10.0 Hz, 1H), 3.11
(s, 3H), 1.94 (s, 3H), 0.09 (s, 9H). syn-2g: 1H NMR (CDCl3)
d 7.40–6.82 (m, 9H), 5.03 (d, J¼8.3 Hz, 1H), 4.60 (d,
J¼8.3 Hz, 1H), 3.00 (s, 3H), 2.44 (s, 3H), 20.17 (s, 9H).
2850, 1655, 1595, 1500, 1460, 1260, 1110, 840 cm21
.
HRMS calcd for C18H20OSi ([M2CH3OH]þ) 280.1283,
found 280.1275. anti-2a: 1H NMR (CDCl3) d 7.23–6.79 (m,
10H), 4.79 (d, J¼10.0 Hz, 1H), 4.45 (d, J¼10.0 Hz, 1H),
3.16 (s, 3H), 0.08 (s, 9H). syn-2a: 1H NMR (CDCl3) d 7.44–

M. Honda et al. / Tetrahedron 58 (2002) 6815–6823
6821
4.4.8. 3-Methoxy-2-phenyl-1-trimethylsilyl-1-butanone
1250, 1090 cm21
.
HRMS calcd for C13H18OSi
(2h). IR (neat) 2900, 1653, 1250, 1100 cm21. HRMS
calcd for C13H18OSi ([M2CH3OH]þ) 218.1127, found
218.1131. anti-2h: 1H NMR (CDCl3) d 7.25–7.15 (m, 5H),
4.10 (d, J¼9.5 Hz, 1H), 3.96 (dq, J¼9.5, 9.3 Hz, 1H), 3.20
(s, 3H), 0.82 (d, 3H), 0.00 (s, 9H). syn-2h: 1H NMR (CDCl3)
d 7.35–7.10 (m, 5H), 4.05 (d, J¼8.5 Hz, 1H), 3.96 (dq,
J¼8.5, 6.1 Hz, 1H), 3.01 (s, 3H), 1.08 (d, 3H), 20.06 (s,
9H).
([M2C3H8O2]þ) 218.1127, found 218.1131. 1H NMR
(CDCl3) d 7.47–7.24 (m, 5H), 4.38 (d, J¼9.9 Hz, 1H),
3.63 (t, J¼5.3 Hz, 2H), 3.38 (dq, J¼9.9, 7.1 Hz, 1H), 3.32
(t, J¼5.8 Hz, 2H), 2.02 (br, 1H), 1.75–1.57 (m, 2H), 0.59
(d, J¼7.1 Hz, 3H), 0.26 (s, 9H).
4.4.15. 3-Methoxy-2,4-diphenyl-1-trimethylsilyl-1-pen-
tanone (6a). IR (neat) 2900, 1655, 1255, 1100 cm21
.
HRMS calcd for C20H24OSi ([M2CH3OH]þ) 308.1596,
found 308.1609. 2,3-anti-6a: 1H NMR (CDCl3) d 7.54–7.16
(m, 10H), 4.49 (d, J¼10.0 Hz, 1H), 4.09 (dd, J¼10.0,
2.2 Hz, 1H), 2.86 (s, 3H), 2.50 (m, 1H), 1.25 (d, 3H), 0.07 (s,
4.4.9. 3-Methoxy-2-phenyl-1-trimethylsilyl-1-decanone
(2i). IR (neat) 3063, 3028, 2928, 2856, 1643, 1454,
1250, 1099 cm21. HRMS calcd for C20H34O2Si (Mþ)
1
1
334.2328, found 334.2333. anti-2i: H NMR (CDCl3) d
7.31–7.13 (m, 5H), 4.34 (d, J¼9.6 Hz, 1H), 3.98–3.93
9H). 2,3-syn-6a: H NMR (CDCl3) d 7.31–7.12 (m, 10H),
4.14 (d, J¼6.8 Hz, 1H), 3.96 (dd, J¼6.8, 5.6 Hz, 1H), 2.88
(m, 1H), 3.32 (s, 3H), 1.30–1.03 (m, 12H), 0.84 (t,
1
(s, 3H), 1.45 (m, 1H), 1.28 (d, 3H), 20.09 (s, 9H).
J¼6.9 Hz, 3H), 0.06 (s, 9H). syn-2i: H NMR (CDCl3)
d 7.38–7.19 (m, 5H), 4.16 (d, J¼8.2 Hz, 1H), 3.82–
3.75 (m, 1H), 3.00 (s, 3H), 1.48–1.16 (m, 12H), 0.88 (t,
J¼6.9 Hz, 3H), 0.00 (s, 9H).
4.4.16. 2-Cyclohexyl-3-methoxy-4-phenyl-1-trimethylsi-
lyl-1-pentanone (6b). IR (neat) 3060, 3035, 2980, 2940,
2850, 1632, 1498, 1450, 1248, 1094, 842 cm21. HRMS
calcd for C21H34O2Si (Mþ) 346.2328, found 346.2321. 2,3-
1
4.4.10. 3-Methoxy-2,4-diphenyl-1-trimethylsilyl-1-buta-
none (2j). IR (neat) 2920, 1640, 1250, 1100 cm21. HRMS
calcd for C19H22OSi ([M2CH3OH]þ) 294.1440, found
294.1439. anti-2j: 1H NMR (CDCl3) d 7.32–7.01 (m, 10H),
4.30 (d, J¼9.5 Hz, 1H), 4.16 (ddd, J¼9.5, 8.0, 2.9 Hz, 1H),
3.10 (s, 3H), 2.64 (dd, J¼14.0, 2.9 Hz, 1H), 2.36 (dd,
J¼14.0, 8.0 Hz, 1H), 0.03 (s, 9H). syn-2j: 1H NMR (CDCl3)
d 7.44–7.12 (m, 10H), 4.03 (d, J¼6.9 Hz, 1H), 4.03 (ddd,
J¼6.9, 6.3, 3.3 Hz, 1H), 2.90 (s, 3H), 2.87 (dd, J¼14.0,
3.3 Hz, 1H), 2.71 (dd, J¼14.0, 6.3 Hz, 1H), 0.03 (s, 9H).
anti-6b: H NMR (CDCl3) d 7.46–6.98 (m, 5H), 3.62 (dd,
J¼8.1, 3.4 Hz, 1H), 3.43 (dd, J¼8.1, 4.4 Hz, 1H), 3.08 (s,
3H), 2.66 (dq, J¼7.0, 3.4 Hz, 1H), 1.88–0.63 (m, 11H),
1
1.27 (d, J¼7.0 Hz, 3H), 0.14 (s, 9H). 2,3-syn-6b: H NMR
(CDCl3) d 2.96 (s, 3H), 0.16 (s, 9H).
4.4.17. 2-Isopropyl-3-methoxy-4-phenyl-1-trimethylsi-
lyl-1-pentanone (6c). IR (neat) 3080, 3060, 3035, 2970,
2940, 2905, 2880, 2830, 1642, 1498, 1452, 1250, 1090,
845 cm21. HRMS calcd for C18H30O2Si (Mþ) 306.2015,
found 306.2025. 2,3-anti-6c: 1H NMR (CDCl3) d 7.41–7.02
(m, 5H), 3.63 (dd, J¼8.2, 3.7 Hz, 1H), 3.42 (dd, J¼8.2,
4.9 Hz, 1H), 3.07 (s, 3H), 2.67 (dq, J¼7.1, 3.7 Hz, 1H),
2.13–1.92 (m, 1H), 1.24 (d, J¼7.1 Hz, 3H), 0.93 (t,
J¼7.1 Hz, 3H), 0.15 (s, 9H). 2,3-syn-6c: 1H NMR
(CDCl3) d 2.65 (s, 3H), 1.31 (d, J¼7.0 Hz, 3H), 0.17 (s, 9H).
4.4.11. 2,3-anti-3-(30-Hydroxypropyloxy)-2,3-diphenyl-1-
trimethylsilyl-1-propanone (anti-4a). IR (neat) 3555,
2890, 1640, 1250, 1110 cm21
.
HRMS calcd for
C18H20OSi ([M2CH3OH]þ) 280.1283, found 280.1283.
1H NMR (CDCl3) d 7.34–6.83 (m, 10H), 4.88 (d, J¼9.9 Hz,
1H), 4.45 (d, J¼9.9 Hz, 1H), 3.70 (t, 2H), 3.47 (m, 2H), 2.73
(br, 1H), 1.72 (m, 2H), 0.09 (s, 9H).
4.4.18. 2-Ethyl-3-methoxy-4-phenyl-1-trimethylsilyl-1-
pentanone (6d). IR (neat) 3080, 3060, 3040, 2970, 2970,
2945, 2880, 2840, 1640, 1499, 1455, 1380, 1255, 1097,
845 cm21. HRMS calcd for C17H28O2Si (Mþ) 292.1859,
4.4.12. 3-(30-Hydroxypropyloxy)-2-isopropyl-3-phenyl-
1-trimethylsilyl-1-propanone (4c). IR (neat) 3461, 1633,
1250, 1100 cm21. HRMS calcd for C18H30O2Si (Mþ)
1
found 292.1843. 2,3-anti-6d: H NMR (CDCl3) d 7.31–
1
322.1964, found 322.1963. anti-4c: H NMR (CDCl3) d
7.35–7.16 (m, 5H), 4.42 (d, J¼10.2 Hz, 1H), 3.70 (m, 2H),
7.19 (m, 5H), 3.43 (dd, J¼9.2, 3.4 Hz, 1H), 3.29 (ddd,
J¼10.1, 9.2, 3.7 Hz, 1H), 2.89 (dq, J¼7.0, 3.4 Hz, 1H), 2.74
(s, 3H), 1.73–1.65 (m, 1H), 1.38–1.32 (m, 1H), 1.34 (d,
J¼7.0 Hz, 3H), 0.77 (t, J¼7.0 Hz, 3H), 0.17 (s, 9H). 2,3-
3.47 (m, 2H), 3.36 (t, 1H), 1.80 (br, 1H), 1.55 (m, 3H), 1.05
1
(d, 3H), 1.00 (d, 3H), 20.23 (s, 9H). syn-4c: H NMR
1
(CDCl3) d 7.37–7.20 (m, 5H), 4.52 (d, J¼9.0 Hz, 1H), 3.61
(m, 2H), 3.49 (dd, 2H), 3.28 (t, 1H), 2.17 (br, 1H), 1.57 (m,
2H), 1.71 (m, 1H), 0.81 (d, 3H), 0.76 (d, 3H), 0.15 (s, 9H).
syn-6d: H NMR (CDCl3) d 7.33–7.21 (m, 5H), 3.52 (dd,
J¼6.1, 5.8 Hz, 1H), 3.15 (s, 3H), 3.00 (ddd, J¼9.2, 5.8,
4.0 Hz, 1H), 2.76 (dq, J¼7.0, 6.7 Hz, 1H), 1.85–1.74 (m,
1H), 1.57–1.45 (m, 1H), 1.31 (d, J¼7.0 Hz, 3H), 0.76 (t,
J¼7.5 Hz, 3H), 0.12 (s, 9H).
4.4.13. 2,3-anti-2-Ethyl-3-(30-hydroxypropyloxy)-3-phe-
nyl-1-trimethylsilyl-1-propanone (anti-4d). IR (neat)
3440, 1645, 1252, 1100 cm21
.
HRMS calcd for
4.4.19. 2-Benzyl-3-methoxy-4-phenyl-1-trimethylsilyl-1-
pentanone (6f). IR (neat) 3075, 3055, 3020, 2970, 2960,
C14H20OSi ([M2C3H8O2]þ) 232.1283, found 232.1270.
1H NMR (CDCl3) d 7.38–7.26 (m, 5H), 4.32 (d, J¼9.8 Hz,
1H), 3.61 (ddd, 2H), 3.38 (dt, J¼9.8 Hz, 1H), 3.26 (t, 2H),
1.87 (br, 1H), 1.66 (m, 2H), 1.41 (m, 2H), 0.60 (t, 3H), 0.24
(s, 9H).
2895, 2820, 1638, 1602, 1497, 1449, 1245, 1083, 835 cm21
.
HRMS calcd for C22H30O2Si (Mþ) 354.2015, found
1
354.2015. 2,3-anti-6f: H NMR (CDCl3) d 7.31–7.01 (m,
10H), 3.78 (ddd, J¼11.3, 9.5, 4.0 Hz, 1H), 3.46 (dd, J¼9.5,
3.4 Hz, 1H), 3.04 (dq, J¼7.0, 3.4 Hz, 1H), 2.93–2.72 (m,
1H), 2.70 (s, 3H), 2.56 (dd, J¼13.1, 4.0 Hz, 1H), 1.44 (d,
J¼7.0 Hz, 3H), 20.16 (s, 9H). 2,3-syn-6f: 1H NMR
(CDCl3) d 7.35–7.02 (m, 10H), 3.52 (ddd, J¼10.4, 4.9,
4.4.14. 2,3-anti-3-(30-Hydroxypropyloxy)-2-methyl-3-
phenyl-1-trimethylsilyl-1-propanone (anti-4e). IR (neat)
3483, 3094, 3065, 3030, 2959, 2930, 2874, 1643, 1454,

6822
M. Honda et al. / Tetrahedron 58 (2002) 6815–6823
4.0 Hz, 1H), 3.47 (dd, J¼6.3, 4.9 Hz, 1H), 3.22 (s, 3H), 2.98
(dq, J¼13.4, 10.4 Hz, 1H), 2.83 (dd, J¼13.4, 3.7 Hz, 1H),
2.76 (qu, J¼6.7 Hz, 1H), 1.37 (d, J¼7.0 Hz, 3H), 20.16 (s,
9H).
derivative (10) in 64% yield. IR (neat) 3033, 2956, 2930,
2915, 2901, 2818, 2341, 1952, 1361, 1100, 1030 cm21
.
HRMS calcd for C15H21O2 ([M2SiMe3]þ) 233.1542, found
233.1537. Major isomer: 1H NMR (CDCl3) d 7.42–7.23 (m,
5H), 4.66 (d, J¼8.1 Hz, 1H), 3.92 (d, J¼5.4 Hz, 1H), 2.23
(m, 1H), 1.99 (m, 1H), 1.43 (s, 3H), 1.26 (s, 3H), 1.19 (d,
4.5. Conversion of aldol adducts into cyclic ketals (11)
1
3H), 0.59 (d, 3H), 0.11 (s, 9H). Minor isomer: H NMR
4.5.1. 2-Isopropyl-3-(30-oxopropyloxy)-3-phenyl-1-tri-
methylsilylpropanone (7).13c A 30 ml of, three-necked,
round-bottomed flask equipped with argon adapter, rubber
septum, thermometer and magnetic stirring bar was charged
with dichloromethane (5 ml) and 1.05 mmol of the diaster-
eomeric mixture of aldol adducts (73:27) and pyridinium
chlorochromate (3.2 mmol) added. This mixture was stirred
at room temperature in a flask protected from light. 10 ml of
ether was then added and the product filtered through
Florisil. The residue was washed with 100 ml of ether and
the triturant was then passed through the column. The
solvent was evaporated to give diastereomeric mixture of
keto aldehyde 7 (73:27) in 75% yield. This material was
used directly without purification.
(CDCl3) d 7.41–7.18 (m, 5H), 5.23 (d, J¼3.1 Hz, 1H), 3.98
(d, J¼2.9 Hz, 1H), 1.83 (m, 1H), 1.66 (m, 1H), 1.49 (m,
1H), 1.43 (s, 3H), 1.11 (d, 3H), 0.44 (d, 3H), 0.10 (s, 9H).
4.5.5. 5-Isopropyl-2,2-dimethyl-4-phenyl-1,3-dioxane
(11). The diastereomeric mixture of dioxane derivative 10
(0.1 mmol) was dissolved in hexamethylphosphoric tria-
mide (1 ml) and tetrabutylammonium fluoride solution
(0.5 mmol in THF) was added and reacted at 408C for 8 h.
It was poured on NaCl solution, and the resulting mixture
was partitioned between H2O and diethyl ether. The
aqueous layer was extracted with diethyl ether. The
combined organic phase were washed with saturated NaCl
solution, and dried over Na2SO4, filtered, concentrated.
Column chromatography on a silica-gel afforded the
corresponding dioxane derivative 11A/S in 99% yield
(73:27). IR (neat) 2960, 1380, 1369, 1230, 1196, 1165,
1107, 1021 cm21. HRMS calcd for C15H22O2 (Mþ)
4.5.2. 3-Hydroxy-2-isopropyl-3-phenyl-1-trimethylsilyl-
propanone (8).13c The diastereomeric mixture of keto
aldehyde (0.93 mmol) was dissolved in benzene (12 ml). To
this stirred solution at 508C was added dibenzylammonium
trifluoroacetate (3.86 mmol). After 10 min the solution was
applied to a silica-gel column and eluted successively with
hexane (100 ml), ether (200 ml). The corresponding 3-
hydroxy acylsilane 8 (73:27) was thus obtained in 81%
yield. This material was used directly without purification.
1
234.1620, found 234.1624. Major isomer 11A: H NMR
(CDCl3) d 7.40–7.25 (m, 5H), 4.75 (d, J¼0.6 Hz, 1H), 3.94
(dd, 1H), 3.88 (dd, 1H), 1.90 (m, 1H), 1.55 (s, 3H), 1.45 (s,
3H), 1.41 (m, 1H), 1.19 (d, 3H), 0.59 (d, 3H). Minor isomer
11S: 1H NMR (CDCl3) d 7.40–7.21 (m, 5H), 5.27 (d,
J¼3.5 Hz, 1H), 4.18 (dd, J¼12.0, 3.5 Hz, 1H), 4.05 (dd,
J¼12.0, 1.5 Hz, 1H), 1.59 (m, 1H), 1.53 (s, 3H), 1.49 (s,
3H), 1.47 (m, 1H), 1.04 (d, 3H), 0.67 (d, 3H).
4.5.3. 1,3-Dihydroxy-2-isopropyl-3-phenyl-1-trimethyl-
silylpropane (9). The diastereomeric mixture of 3-hydroxy
acylsilane (1 mmol) was dissolved THF (5 ml). This
solution was cooled to 2788C and lithium aluminum
hydride solution (2 mmol in THF) was added slowly.
After 30 min, 5 ml of methanol was added to quench, and
the resulting mixture was partitioned between H2O and
diethyl ether. The aqueous layer was extracted with diethyl
ether. The combined organic phase were washed with
saturated NaCl solution, and dried over Na2SO4, filtered,
concentrated. Column chromatography on a silica-gel
afforded dihydroxytrimethylsilylpropane 9 (73:27) in 71%
yield. IR (neat) 3381, 3313, 3302, 1493, 1452, 1251, 1035,
1025, 1002, 996 cm21. HRMS calcd for C15H26O2Si (Mþ)
266.1702, found 266.1686. Major isomer: 1H NMR (CDCl3)
d 7.23–7.18 (m, 5H), 5.09 (d, J¼7.2 Hz, 1H), 3.39 (s, 1H),
3.14 (s, 1H), 2.20 (m, 1H), 1.53 (ddd, 1H), 1.17 (d, 3H), 1.08
Acknowledgments
This work was partially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education,
Science, Sports and Culture, Japan.
References
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1
(d, 3H), 0.04 (s, 9H). Minor isomer: H NMR (CDCl3) d
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