One-pot synthesis of α-siloxy esters using a silylated masked acyl cyanide

Article abstract of DOI:10.1055/s-0028-1083219

Synthesis of α-siloxy esters via a one-pot reaction from various aldehydes and alcohols using a masked acyl cyanide (MAC) reagent bearing tert-butyldimethylsilyl group is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083219

PAPER
3819
One-Pot Synthesis of a-Siloxy Esters Using a Silylated Masked Acyl Cyanide
O
ne-PotSynthesis
i
of
a
-S
s
ars o Nemoto,* Rujian Ma, Tomoyuki Kawamura, Kenji Yatsuzuka, Masaki Kamiya, Masayuki Shibuya
Division of Pharmaceutical Chemistry, Institute of Health Biosciences, Graduate School of the University of Tokushima,
1-78 Sho-machi, Tokushima 770-8505, Japan
Fax +81(88)6337284; E-mail: nem@ph.tokushima-u.ac.jp
Received 22 July 2008; revised 1 September 2008
conventional means of preparing such vicinal functional
Abstract: Synthesis of a-siloxy esters via a one-pot reaction from
various aldehydes and alcohols using a masked acyl cyanide (MAC)
reagent bearing tert-butyldimethylsilyl group is described.
groups consists of a carbon–carbon bond-formation reac-
tion between two oxygenated functionalities, as summa-
rized in Scheme 1.2
Key words: acyl anion equivalents, masked acyl cyanide, a-hy-
droxy esters, one-pot, intramolecular migration
Both routes A and B generally require multiple steps,
which include delicate carbanion chemistry under anhy-
drous conditions. However, as shown in Scheme 2, there
is one unique exception to route A, a reaction using sily-
lated masked acyl cyanide (MAC) reagents.3 This one-pot
reaction proceeds with neither delicate anhydrous condi-
a-Hydroxycarboxylic acid and their derivatives have been
found in a number of artificial medicinal chemicals and
naturally occurring biologically active molecules.1 The
X
OH
Y
unmasked
R1
R2
Z
R1
R2
CO2H
route A
OH
unmasked
O
R1
R2
Y
OR
OH
Y
route B
oxidation
R1
R1
R2
OR
O
H
R1
R2
CO2R
– HY
R2
OH
Scheme 1 Typical general routes for the synthesis of a-hydroxycarboxylic acids or esters with one-carbon homologation
CN
SiR'3
O
H
OSiR'3
O
one-pot
XR3
R1
R2
CN
R1
R2
MAC reagent
HXR3
O
hydrolysis
HXR3
OSiR'3
O
SiR'3
O
R1
R2
CN
R1
OH
R2
X = O or NR4
O
R1
R2
CO2H
NC CN
O
Passerini reaction
R5CO2H
cf.
O
hydrolysis
R5
O
H
one-pot
N
R1
R2
R1
R6
R2
R6
O
C
N
each time
H2N R6
Scheme 2 One-pot reaction using MAC reagents and the Passerini reaction
SYNTHESIS 2008, No. 23, pp 3819–3827
x
x.
x
x
.
2
0
0
8
Advanced online publication: 14.11.2008
DOI: 10.1055/s-0028-1083219; Art ID: F16508SS
© Georg Thieme Verlag Stuttgart · New York

3820
H. Nemoto et al.
PAPER
tions nor vigorous unmasking conditions. The efficiency Table 1 One-Pot Reaction with Various Aldehydesa
is as high as that of Passerini reaction,4 which is a well-
known and pervasive one-pot reaction using an isonitrile
as a key reagent.
Entry R1CHO
Base
Temp Time Yield
of 4 (%)
1
4-MeC6H4CHO
(2a)
DMAP (0.1) r.t.
5 min 96 (4a)
Esters and tertiary amides, which cannot be directly syn-
thesized by the Passerini reaction, can be synthesized
with MAC reagents.5–7 Also, whenever the Passerini reac-
tion is carried out, an isonitrile must be prepared from
each amine. In contrast, amines can be used directly with
MAC reagents. MAC reagents thus have these two advan-
tages over isonitrile chemistry.
2
3
2a
pyridine (1.0) r.t.
pyridine (1.0) r.t.
2 h
2 h
91 (4a)
94 (4b)
2-HOC6H4CHO
(2b)
4
5
6
7
2-furaldehyde
(2c)
pyridine (1.0) r.t.
pyridine (1.0) r.t.
2 h
2 h
2 h
2 h
97 (4c)
98 (4d)
95 (4e)
79 (4f)
90 (4f)
We have already reported the one-pot reaction from vari-
ous aldehydes/ketones and amines to afford a-siloxy
amides (X = NR4).5 Its counterpart, the reaction to afford
a-siloxy esters (X = O), has not yet been reported except
for the example of methyl N-protected 3-amino-2-siloxy-
4-phenylbutanoate.6
4-NCC6H4CHO
(2d)
(E)-PhCH=CHCHO pyridine (1.0) r.t.
(2e)
(E)-MeCH=CHCHO pyridine (1.0) r.t.
(2f)
In this paper, we report a one-pot reaction to form a-siloxy
esters 4 starting from various substrates using H–MAC–
TBS (1) (Scheme 3) in order to illustrate the generality of
the above synthetic route of Scheme 2. The results are list-
ed in Table 1 for various aldehydes, in Table 2 for various
ketones, and in Table 3 for various alcohols.
8
9
2f
DMAP (0.1) –25 °C 2 h
DMAP (0.1) r.t.
PhCH2CH2CHO
(2g)
5 min 63b (4g)
10 2g
DMAP (0.1) –40 °C 2 h
DMAP (0.1) –25 °C 12 h
78 (4g)
51 (4h)
TBS
11 Me2CHCHO
O
CN
CN
O
3° amine
one-pot
(2h)
+
OR3
R3OH
+
H
OTBS
R1
R2
R1
R2
12 2h
DMAP (3.0) –25 °C 12 h
68c (4h)
30 (4i)
O
2
1
3
4
13 Me3CCHO
DMAP (0.1) r.t.
5 h
Scheme 3
(2i)
a Reaction conditions: aldehyde 2 (R2 = H, 1 equiv), 1 (1.1. equiv) in
MeOH (R3 = Me).
At first, the reaction of p-tolaldehyde (2a) with 1 and
methanol (5.0 equiv) was examined in acetonitrile or tet-
rahydrofuran by using triethylamine as a base. Although
the desired product 4a was obtained, the yield was moder-
ate and several unidentified by-products were produced.
After examining various reaction conditions, the use of
methanol as a solvent in the presence of a catalytic amount
of 4-(N,N-dimethylamino)pyridine (DMAP) gave satis-
factory results. The pure desired product 4a was obtained
in 96% isolated yield within 5 minutes (Table 1, entry 1).
Although a longer period is required, one equivalent of
pyridine can be used instead of DMAP (entry 2). The con-
ditions in entry 2 were applied to various aromatic alde-
hydes and conjugated aldehydes to afford the desired
products 4b–e in excellent yields (entries 3–6). Accord-
ingly, the electron density of the aromatic ring did not sig-
nificantly influence the desired reactions. In the case of 2f
(entry 7), some side-reactions such as self-condensation
occurred under the same condition as entries 2–6. This
problem was solved when DMAP was used instead of py-
ridine at –25 °C (entry 8). In the case of aliphatic aldehyde
2g, the reason for the low yield was the formation of the
cyanohydrin, PhCH2CH2CH(CN)OH, which was derived
from 2g and the cyanide anion generated from 1 (entry 9).
Fortunately, other side-reactions were also inhibited in a
manner similar to entry 8 (entry 10). Next, we attempted
the reaction with aldehydes bearing bulky group (entries
b Cyanohydrin, PhCH2CH2CH(CN)OH, was obtained in 35% yield.
c Amount of 1 used = 3.0 equiv.
11, 13). Beyond expectation, the desired products were
obtained in moderate yields. As listed in entry 12, the use
of excess 1 improved the chemical yield.
The results using ketones are listed in Table 2. As a repre-
sentative electron-deficient aromatic ketone, 4-nitroace-
tophenone (2j) with 1 in methanol in the presence of a
catalytic amount of DMAP afforded 4j in 90% yield
(Table 2, entry 1). In contrast, under similar conditions,
the reaction of 4-methylacetophenone (2k), a representa-
tive electron-rich aromatic ketone, afforded 4k in 24%
yield (entry 2). The yield was optimized to 77% by the use
of excess 1 and DMAP at low temperature (entries 3, 4).
However, the use of triethylamine instead of DMAP de-
creased the yield of 4k to 36% (entry 5). The best condi-
tions for 4k (entry 4) were applied to acetophenone (2l) to
give 4l in 90% yield (entry 6).
The reaction of cyclohex-2-enone (2m) afforded the de-
sired compound 4m in 32% yield and the double-alkylat-
ed by-product 5 in 38% yield (Table 2, entry 7)
(Scheme 4). This is in contrast with the report that H–
MAC–EE3 (EE = 1-ethoxyethyl group) and 2m gave only
1,4-adducts 6 in 82% yield.8 It is considered that the 1,2-
Synthesis 2008, No. 23, 3819–3827 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of a-Siloxy Esters
3821
Table 2 One-Pot Reaction with Various Ketonesa
As a representative example of aliphatic ketones, cyclo-
hexanone (2n), which has a similar reactivity to 8, afforded
4n in 63% yield (entry 8), which was improved to 88%
when an excess of DMAP and 1 were used (entry 9). In the
case of pentan-3-one (2o), the desired product 4o was ob-
tained only in 35% yield even when optimized conditions
as described above were applied (entry 10). Finally, the
reaction of a sterically hindered substrate, 3,3-dimethyl-
butan-2-one (2p) was attempted, but no desired compound
was detected (entry 11). In cases such as entries 10 and 11
in Table 2 as well as entry 13 in Table 1, the reaction rate
to produce the desired compounds was most likely com-
petitive with the decomposition rate of 1, since not all of
starting substrate 2 was completely consumed nor was 1
recovered.
Entry R1COR2
DMAP Temp
(equiv)
Time Yield of 4
(h)
(%)
1
2
3
4-O2NC6H4COMe 0.1
(2j)
r.t.
0.5
90 (4j)
4-MeC6H4COMe 0.1
(2k)
r.t.
24
24 (4k) (54)b
2k
0.1
3.0
3.0d
3.0
–25 °C
–25 °C
–25 °C
–25 °C
72
24
24
24
67 (4k) (20)b
77 (4k) (11)b
36 (4k) (24)b
90 (4l)
4c 2k
5c 2k
6c PhCOMe
(2l)
In Table 3, one-pot reactions of 2a with various alcohols
are listed. The a-siloxy esters 4p–s were obtained in ex-
cellent yields (entries 1–4). In the case of tert-butyl alco-
hol, the desired a-siloxy ester was not produced (entry 5).
7
8
cyclohex-2-enone 3.0
(2m)
–25 °C
r.t.
24
32 (4m)e
63 (4n)
cyclohexanone
0.1
0.5
(2n)
9c 2n
3.0
3.0
–25 °C
–25 °C
24
24
88 (4n)
35 (4o)
Table 3 One-Pot Reaction of 2a, DMAP, and 1 with Various Alco-
holsa
10c pentan-3-one
Entry
R3
Yield of 4 (%)
90 (4p)
88 (4q)
92 (4r)
93 (4s)
0c
(2o)
11c Me3CCOMe
3.0
–25 °C
48
0
1
2
3
4
5
i-Pr
Bn
(2p)
a Reaction conditions: ketone 2 (1 equiv), 1 (1.1 equiv) in MeOH
(R3 = Me).
allyl
Phb
t-Bu
b Recovered yield of 2.
c Amount of 1 used = 3.0 equiv.
d Et3N was used instead of DMAP.
e The double-alkylated product 5 (Scheme 4) was obtained in 38%
yield.
a Reaction conditions: 2a (R1 = 4-MeC6H4, R2 = H, 1 equiv), DMAP
(0.1 equiv), and 1 (1.1 equiv) with alcohols (R3OH) at r.t.
b A mixture of phenol and MeCN (1:1) was used.
c The nonmigratory adduct 9 was obtained as a major by-product
(Figure 1).
addition is competitive with 1,4-addition to give a mixture
of 4m and 7 in the case of entry 7. It was found that 7 can
be easily transformed to 5 since reaction rate of saturated
ketone 7 with 1 is probably much faster than the reaction
rate of unsaturated ketone 2m and 1 as illustrated by the
results in entries 8 and 9. In contrast, the proposed inter-
mediate 8 by H–MAC–EE can be reversibly converted
back into 2m and H–MAC–EE since EE is not migratory,9
and only 1,4-adduct 6 is obtained.
OH
OTBS
CN
NC
9
Figure 1 Structure of 9
OTBS
O
CN
O
TBSO
CO2Me
CN
OEE
CN
OTBS
CN
OTBS
CN
6
NC
7
NC
migratory
OTBS
5
NC
OEE
CN
OTBS
CN
not migratory
2m
CN
CN
OEE
CN
O
O
CN
CN
CN
4m
8
Scheme 4
Synthesis 2008, No. 23, 3819–3827 © Thieme Stuttgart · New York

3822
H. Nemoto et al.
PAPER
OTBS
tected a-aminal 116 derived from D-phenylalanine was
transformed to the b-cholesteryl ester 12 (12a/
12b = 83:17) in 52% yield in diethyl ether at 0 °C for 12
hours by using 2.0 equivalents of 1 and 10 equivalents of
b-cholesterol in the presence of 1.0 equivalent of PPY
(Scheme 6). The excess b-cholesterol was quantitatively
recovered. The stereochemistry of the newly formed
asymmetric centers of 12a and 12b were determined by
the methanolysis of the ester moiety to afford the deriva-
1 (1.1 equiv)
DMAP (0.1 equiv)
CHO
OH
O
MeCN, r.t., 2 h, 71% yield
O
10
Scheme 5
Instead, formation of 9, a simple adduct without silyl mi-
gration, was observed (Figure 1).
Our attempts to prepare an a-siloxy thioester did not yield tive 13a and its 2S-isomer 13b,6 respectively.
any positive result. Thus, a mixture of 2a, 1 and 3–5
The final example described in this paper is the one-car-
equivalents of thiophenol in acetonitrile did not afford the
bon homologation of a pyranose derivative. The reaction
desired a-siloxy thioester. We observed that 1 was gradu-
of 14 with 1 (2.0 equiv) and methanol (3.0 equiv) in dieth-
ally decomposed to unidentified polar materials in the
yl ether at 0 °C for 12 hours in the presence of PPY (1.0
presence of thiophenol.
equiv) gave the desired products 15 (15a/15b = 92:8) in
Finally, three synthetic applications are introduced. In the 85% yield (Scheme 7). The TBS group from a mixture of
presence of a catalytic amount of DMAP, the reaction of 15a and 15b was removed by tetrabutylammonium fluo-
salicylaldehyde with 1 in acetonitrile at room temperature ride (Bu4NF) in THF to afford heptose derivatives 16a2
gave the 2-coumaranone derivative 10 in 71% isolated and 16b2 (92:8) in 97% yield. The multiple-step proce-
yield (Scheme 5).
dures using most of acyl anion equivalents with one-car-
bon homologation10 involve an independent unmasking
step, which has been often carried out in protic acidic con-
ditions. Accordingly, it is noteworthy that two of ace-
In the following two cases, 4-(pyrrolidin-1-yl)pyridine
(PPY) gave much better results than DMAP. The N-pro-
CHO
PPY (1.0 equiv), Et2O, 0 °C, 12 h 1 (2.0 equiv)
NHCbz
11
HO
10 equiv
OTBS
+
OTBS
O
O
12a
12b
CbzHN
O
CbzHN
O
K2CO3, MeOH, r.t., 36 h
K2CO3, MeOH, r.t., 36 h
OTBS
52% yield
OTBS
CO2Me
CO2Me
NHCbz
NHCbz
13b
13a
83% yield
68% yield
Scheme 6
OTBS
H
H
O
TBSO
H
H
H
1 (2.0 equiv),
MeOH (3.0 equiv)
O
O
O
O
O
O
OHC
O
O
O
O
MeO2C
MeO2C
+
PPY (1.0 equiv)
Et2O, 0 °C, 12 h
85% yield
O
O
O
O
14
15a
15b
H
OH
H
HO
H
H
Bu4NF in THF
36 h, r.t.
O
O
O
O
O
MeO2C
MeO2C
+
97% yield
O
O
O
O
O
16a
16b
Scheme 7
Synthesis 2008, No. 23, 3819–3827 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of a-Siloxy Esters
3823
IR (CHCl3): 2955, 2931, 2859, 1753, 1256, 1131, 840 cm–1.
tonide moieties were retained here during the one-pot
reaction.
1H NMR (400 MHz): d = 7.35 (d, J = 8.0 Hz, 2 H), 7.14 (d, J = 8.0
Hz, 2 H), 5.20 (s, 1 H), 3.67 (s, 3 H), 2.34 (s, 3 H), 0.91 (s, 9 H),
0.10 (s, 3 H), 0.03 (s, 3 H).
13C NMR (100 MHz): d = 172.7 (C=O), 137.8 (C), 136.2 (C), 129.0
(2 × CH), 126.3 (2 × CH), 74.3 (CH), 52.1 (OCH3), 25.7 (3 × CH3),
21.2 (ArCH3), 18.3 (CMe3), –5.10 (CH3Si), –5.13 (CH3Si).
In conclusion, one-pot reactions to afford a-siloxy esters
using H–MAC–TBS 1 were described. For the title reac-
tion, the choice of a tertiary amine was important. If the
starting substrate, either an aldehyde (a ketone) or an al-
cohol, is a large molecule or possesses sterically hindered
skeleton, PPY or DMAP can improve the chemical yield
of the desired compounds. In contrast, trialkylamines such
as triethylamine are generally unsuitable for this reaction
since such bases caused the MAC reagents to decompose
to unidentified polar materials. If a methyl ester is the tar-
get molecule, use of methanol as a solvent is generally the
best condition for this reaction. However, when several
side reactions such as formation of cyanohydrin or the oli-
gomerization of aldehydes were observed, lower temper-
atures such as –25 to –40 °C in diethyl ether are
recommended. We believe that one-pot reactions with
MAC reagents are one of most efficient and facile meth-
ods for the synthesis of a-hydroxy carbonyl compounds
since MAC reagents are the only reagents that allow one-
pot reactions among all the reported acyl anion equiva-
lents with one-carbon homologation. We hope that this
paper and our previously reported related papers are of
use when a-siloxy esters and amides are the target mole-
cules.
EI-HRMS: m/z calcd for C16H27O3Si [M + H]+: 295.1729; found:
295.1725.
Methyl 2-[(tert-Butyldimethylsilyl)oxy]-2-(2-hydroxyphe-
nyl)acetate (4b)
Colorless needles; mp 103–104 °C (hexane–EtOAc).
IR (CHCl3): 3397, 2956, 2932, 1751, 1244, 1100, 841 cm–1.
1H NMR (300 MHz): d = 7.79 (s, 1 H), 7.21 (dd, J = 7.6, 7.6 Hz, 1
H), 7.13 (d, J = 7.6 Hz, 1 H), 6.88 (d, J = 7.6 Hz, 1 H), 6.85 (dd,
J = 7.6, 7.6 Hz, 1 H), 5.24 (s, 1 H), 3.72 (s, 3 H), 0.92 (s, 9 H), 0.15
(s, 3 H), 0.07 (s, 3 H).
13C NMR (75 MHz): d = 172.0 (C=O), 155.9 (C–O), 130.0 (CH),
128.3 (CH), 122.4 (C), 119.8 (CH), 117.5 (CH), 75.1 (CH), 52.6
(OCH3), 25.5 (3 × CH3), 18.1 (CMe3), –5.3 (SiCH3), –5.5 (SiCH3).
Anal. Calcd for C15H24O4Si: C, 60.78; H, 8.16. Found: C, 60.57; H,
8.23.
Methyl 2-[(tert-Butyldimethylsilyl)oxy]-2-(2-furyl)acetate (4c)
Colorless oil.
IR (CHCl3): 2956, 2932, 2859, 1757, 1260, 1153, 1119, 841 cm–1.
1H NMR (400 MHz): d = 7.39 (s, 1 H), 6.34 (s, 2 H), 5.28 (s, 1 H),
3.77 (s, 3 H), 0.90 (s, 9 H), 0.11 (s, 3 H), 0.04 (s, 3 H).
13C NMR (100 MHz): d = 170.6 (C=O), 151.6 (C), 142.6 (CH),
110.4 (CH), 108.1 (CH), 68.7 (CH), 52.4 (OCH3), 25.6 (3 × CH3),
18.4 (CMe3), –5.2 (SiCH3), –5.3 (SiCH3).
Melting points were determined using Yanagimoto Micro Melting
Point Apparatus and are uncorrected. IR spectra were recorded on
PerkinElmer 1720 or Jasco FT-IR/420 Infrared Fourier Transfer
1
Spectrometer. H and 13C NMR spectra were measured with Jeol
JMN-AL300 Spectrometer at 300 MHz and 75 MHz, respectively,
or with Jeol GSX400 Spectrometer at 400 MHz and 100 MHz, re-
spectively, in CDCl3, and chemical shifts are given as d value in
ppm from internal TMS at 25 °C unless otherwise noted. High-res-
olution mass spectra were measured with Jeol JMS-DX303 spec-
trometer. Elementary analyses were performed on Yanagimoto
CHN-corder MT-3. HPLC analyses were preformed on Hitachi L-
7000 instrument equipped with Hitachi L-7400 UV detector. Opti-
cal rotations were measured with Jasco DIP-370 digital polarimeter.
MeOH was distilled over Mg(OMe)2. Pyridine and Et3N were dis-
tilled over KOH. MeCN was distilled over calcium hydride. Et2O
was distilled over sodium/benzophenone. Anhyd THF was pur-
chased from Kanto Chemicals. All aldehydes and ketones 2 were
distilled or recrystallized before use. All the reactions were carried
out under N2, unless otherwise noted.
EI-HRMS: m/z calcd for C13H23O4Si [M + H]+: 271.1366; found:
271.1386.
Methyl 2-[(tert-Butyldimethylsilyl)oxy]-2-(4-cyanophenyl)ace-
tate (4d)
Colorless oil.
IR (CHCl3): 2955, 2932, 2860, 2232, 1757, 1261, 1136, 841 cm–1.
1H NMR (300 MHz): d = 7.65 (d, J = 8.8 Hz, 2 H), 7.60 (d, J = 8.8
Hz, 2 H), 5.27 (s, 1 H), 3.70 (s, 3 H), 0.92 (s, 9 H), 0.13 (s, 3 H),
0.06 (s, 3 H).
13C NMR (75 MHz): d = 171.4 (C=O), 144.1 (C), 132.1 (CH), 126.9
(CH), 118.5 (C≡N), 111.9 (C), 73.7 (CH), 52.4 (OCH3), 25.5 (3 ×
CH3), 18.2 (CMe3), –5.2 (SiCH3), –5.4 (SiCH3).
EI-HRMS: m/z calcd for C16H24NO3Si [M + H]+: 306.1525; found:
One-Pot Reaction of 2 with the Masked Acyl Cyanide 1 in the
Presence of Alcohols; General Procedure
306.1502.
To a solution of an aldehyde (or a ketone) 2 (1.0 mmol) and 1 (216
mg, 1.1 mmol) in alcohol 3 (5 mL) was added a tertiary amine. The
amount of tertiary amine, the temperature, and time applied are
specified in Tables 1 and 2. Then the mixture was concentrated in
vacuo. The residue was purified by silica gel column chromatogra-
phy to give a-siloxy esters 4. When aliphatic aldehydes or ketones
were the starting substrates, the alcohol 3 (3.0 mmol) in Et2O (5 mL)
was used instead of the pure alcohol 3 (5 mL).
Methyl (3E)-2-[(tert-Butyldimethylsilyl)oxy]-4-phenylbut-3-
enoate (4e)
Colorless oil.
IR (CHCl3): 2955, 2931, 2859, 1752, 1472, 1259, 1152, 839 cm–1.
1H NMR (400 MHz): d = 7.39 (d, J = 7.3 Hz, 2 H), 7.32 (dd,
J = 7.3, 7.3 Hz, 2 H), 7.24 (dd, J = 7.3, 7.3 Hz, 1 H), 6.75 (d,
J = 15.6 Hz, 1 H), 6.31 (dd, J = 15.6, 5.6 Hz, 1 H), 4.89 (d, J = 5.6
Hz, 1 H), 3.75 (s, 3 H), 0.95 (s, 9 H), 0.15 (s, 3 H), 0.12 (s, 3 H).
13C NMR (100 MHz): d = 172.3 (C=O), 136.4 (C), 131.6 (CH),
128.6 (2 × CH), 127.9 (CH), 126.7 (CH), 126.6 (2 × CH), 73.2
(CH), 52.2 (OCH3), 25.8 (3 × CH3), 18.5 (CMe3), –5.0 (SiCH3),
–5.1 (SiCH3).
Methyl 2-[(tert-Butyldimethylsilyl)oxy]-2-(4-methylphenyl)ace-
tate (4a)
Colorless oil.
Synthesis 2008, No. 23, 3819–3827 © Thieme Stuttgart · New York

3824
H. Nemoto et al.
PAPER
EI-HRMS: m/z calcd for C17H27O3Si [M + H]+: 307.1729; found:
EI-HRMS: m/z calcd for C9H19O3Si [M – t-Bu]+: 203.1103; found:
307.1766.
203.1087.
Methyl (3E)-2-[(tert-Butyldimethylsilyl)oxy]pent-3-enoate (4f)
Colorless oil.
Methyl 2-[(tert-Butyldimethylsilyl)oxy]-2-(4-nitrophenyl)pro-
panoate (4j)
Colorless needles; mp 65–66 °C (hexane–EtOAc).
IR (CHCl3): 2956, 1735, 1524, 1351, 1262, 1167, 840 cm–1.
1H NMR (400 MHz): d = 8.18 (d, J = 8.8 Hz, 2 H), 7.70 (d, J = 8.8
Hz, 2 H), 3.69 (s, 3 H), 1.82 (s, 3 H), 0.98 (s, 9 H), 0.17 (s, 3 H),
0.13 (s, 3 H).
IR (CHCl3): 2955, 2931, 2859, 1751, 1257, 1156, 840 cm–1.
1H NMR (400 MHz): d = 5.83 (dqd, J = 15.1, 6.8, 1.5 Hz, 1 H), 5.57
(ddq, J = 15.1, 5.8, 1.5 Hz, 1 H), 4.66 (br d, J = 5.8 Hz, 1 H), 3.73
(s, 3 H), 1.72 (ddd, J = 6.8, 1.5, 1.5 Hz, 3 H), 0.91 (s, 9 H), 0.10 (s,
3 H), 0.07 (s, 3 H).
13C NMR (100 MHz): d = 172.8 (C=O), 128.3 (=CH), 128.3 (=CH),
73.1 (CH), 52.0 (OCH3), 25.8 (3 × CH3), 18.4 (CMe3), 17.6
(CH3CH=), –5.0 (SiCH3), –5.1 (SiCH3).
EI-HRMS: m/z calcd for C12H25O3Si [M + H]+: 245.1573; found:
245.1596.
13C NMR (100 MHz): d = 173.6 (C=O), 151.4 (C), 147.4 (C), 126.0
(2 × CH), 123.4 (2 × CH), 78.5 (C), 52.6 (OCH3), 28.3 (CH3), 25.8
(3 × CH3), 18.5 (CMe3), –2.8 (SiCH3), –3.6 (SiCH3).
Anal. Calcd for C16H25NO5Si: C, 56.61; H, 7.42; N, 4.13. Found: C,
56.55; H, 7.50; N, 4.12.
Methyl 2-[(tert-Butyldimethylsilyl)oxy]-4-phenylbutanoate (4g)
Colorless oil.
Methyl 2-[(tert-Butyldimethylsilyl)oxy]-2-(4-methylphenyl)pro-
panoate (4k)
Colorless oil.
IR (CHCl3): 2955, 2931, 2859, 1751, 1259, 1132, 839 cm–1.
IR (CHCl3): 2955, 2931, 1735, 1261, 1163, 1122, 1006, 839 cm–1.
1H NMR (400 MHz): d = 7.32–7.25 (m, 2 H), 7.20–7.13 (m, 3 H),
4.26 (t, J = 5.8 Hz, 1 H), 3.70 (s, 3 H), 2.80–2.64 (m, 2 H), 2.10–
1.98 (m, 2 H), 0.93 (s, 9 H), 0.09 (s, 3 H), 0.07 (s, 3 H).
13C NMR (100 MHz): d = 174.0 (C=O), 141.5 (C), 128.4 (2 × CH),
128.4 (2 × CH), 125.9 (CH), 71.7 (CH), 51.8 (OCH3), 36.9 (CH2),
31.4 (CH2), 25.8 (3 × CH3), 18.4 (CMe3), –4.9 (SiCH3), –5.3
(SiCH3).
1H NMR (400 MHz): d = 7.40 (d, J = 8.0 Hz, 2 H), 7.13 (d, J = 8.0
Hz, 2 H), 3.65 (s, 3 H), 2.33 (s, 3 H), 1.78 (s, 3 H), 0.96 (s, 9 H),
0.12 (s, 3 H), 0.07 (s, 3 H).
13C NMR (100 MHz): d = 174.9 (C=O), 141.4 (C), 137.1 (C), 128.8
(2 × CH), 124.9 (2 × CH), 78.4 (C), 52.1 (OCH3), 28.3 (CH3), 25.9
(3 × CH3), 21.0 (CH3), 18.5 (CMe3), –2.9 (SiCH3), –3.5 (SiCH3).
EI-HRMS: m/z calcd for C17H29O3Si [M + H]+: 309.1886; found:
EI-HRMS: m/z calcd for C13H19O3Si [M – t-Bu]+: 251.1103; found:
309.1847.
251.1135.
Methyl 2-[(tert-Butyldimethylsilyl)oxy]-3-methylbutanoate (4h)
Colorless oil.
Methyl 2-[(tert-Butyldimethylsilyl)oxy]-2-phenylpropanoate
(4l)
Colorless oil.
IR (CHCl3): 2960, 2932, 2859, 1748, 1259, 1146, 838 cm–1.
IR (CHCl3): 2955, 2931, 2858, 1733, 1261, 1166, 839 cm–1.
1H NMR (300 MHz): d = 7.58–7.47 (m, 2 H), 7.40–7.22 (m, 3 H),
3.66 (s, 3 H), 1.80 (s, 3 H), 1.00 (s, 9 H), 0.13 (s, 3 H), 0.08 (s, 3 H).
1H NMR (300 MHz): d = 3.97 (d, J = 5.0 Hz, 1 H), 3.71 (s, 3 H),
2.13–1.94 (m, 1 H), 0.93 (d, J = 7.0 Hz, 3 H), 0.91 (s, 9 H), 0.90 (d,
J = 7.0 Hz, 3 H), 0.05 (s, 3 H), 0.04 (s, 3 H).
13C NMR (75 MHz): d = 174.0 (C=O), 77.1 (CH), 51.5 (OCH3),
32.9 (CH), 25.7 (3 × CH3), 19.0 (CH3), 18.3 (CMe3), 17.0 (CH3),
–5.0 (SiCH3), –5.4 (SiCH3).
13C NMR (100 MHz): d = 174.8 (C=O), 144.4 (C), 128.1 (2 × CH),
127.4 (CH), 125.0 (2 × CH), 78.6 (C), 52.2 (OCH3), 28.3 (CH3),
25.9 (3 × CH3), 18.5 (CMe3), –2.8 (SiCH3), –3.5 (SiCH3).
EI-HRMS: m/z calcd for C8H17O3Si [M – t-Bu]+: 189.0947; found:
EI-HRMS: m/z calcd for C12H17O3Si [M – t-Bu]+: 237.0947; found:
189.0952.
237.0937.
2-Hydroxy-4-phenylbutanenitrile
This was a major by-product of entry 9 in Table 1; colorless oil.
Methyl 1-[(tert-Butyldimethylsilyl)oxy]cyclohex-2-enecarboxy-
late (4m)
Colorless oil.
IR (CHCl3): 3360, 2936, 2244, 1449, 1077 cm–1.
1H NMR (300 MHz): d = 7.52–6.99 (m, 5 H), 4.40 (br t, J = 6.6 Hz,
1 H), 3.01 (br s, 1 H), 2.83 (t, J = 7.5 Hz, 2 H), 2.25–1.97 (m, 2 H).
13C NMR (75 MHz): d = 139.5 (C), 128.7 (2 × CH), 128.4 (2 × CH),
126.5 (CH), 119.8 (C≡N), 60.3 (CHC≡N), 36.5 (CH2), 30.6 (CH2).
IR (CHCl3): 2953, 2857, 1733, 1256, 1038, 838 cm–1.
1H NMR (300 MHz): d = 5.94 (dt, J = 10.2, 3.6 Hz, 1 H), 5.78 (br
d, J = 10.2 Hz, 1 H), 3.72 (s, 3 H), 2.20–1.60 (m, 6 H), 0.87 (s, 9 H),
0.09 (s, 3 H), 0.05 (s, 3 H).
13C NMR (75 MHz): d = 175.4 (C=O), 131.5 (CH=), 128.4 (CH=),
74.0 (C), 52.0 (OCH3), 34.7 (CH2), 25.7 (3 × CH3), 24.8 (CH2), 18.3
(CMe3), 18.2 (CH2), –2.9 (SiCH3), –3.0 (SiCH3).
EI-HRMS: m/z calcd for C10H11NO [M]+: 161.0841; found:
161.0853.
Methyl 2-[(tert-Butyldimethylsilyl)oxy]-3,3-dimethylbutanoate
(4i)
EI-HRMS: m/z calcd for C14H26O3Si [M]+: 270.1651; found:
270.1642.
Colorless oil.
Methyl 1-(tert-Butyldimethylsilyloxy)-3-[(tert-butyldimethyl-
silyloxy)dicyanomethyl]cyclohexanecarboxylate (5)
Colorless needles; mp 71–73 °C (hexane–EtOAc).
IR (CHCl3): 2956, 2246, 1740, 1257, 1139, 841 cm–1.
1H NMR (300 MHz): d = 3.74 (s, 3 H), 2.42 (tt, J = 12.3, 3.4 Hz, 1
H), 2.19 (br d, J = 12.8 Hz, 1 H), 2.04 (br d, J = 12.3 Hz, 1 H), 1.89
IR (CHCl3): 2957, 2859, 1747, 1260, 1230, 1122, 839 cm–1.
1H NMR (400 MHz): d = 3.83 (s, 1 H), 3.69 (s, 3 H), 0.94 (s, 9 H),
0.91 (s, 9 H), 0.03 (s, 3 H), 0.00 (s, 3 H).
13C NMR (100 MHz): d = 173.2 (C=O), 80.1 (CH), 51.1 (OCH3),
35.3 (C), 25.9 (3 × CH3), 25.7 (3 × CH3), 18.2 (CMe3), –5.3
(SiCH3), –5.5 (SiCH3).
Synthesis 2008, No. 23, 3819–3827 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of a-Siloxy Esters
3825
(br d, J = 13.4 Hz, 1 H), 1.85–1.72 (m, 2 H), 1.72–1.54 (m, 2 H),
1.36–1.17 (m, 1 H), 0.93 (s, 9 H), 0.91 (s, 9 H), 0.36 (s, 6 H), 0.09
(s, 3 H), 0.09 (s, 3 H).
EI-HRMS: m/z calcd for C18H21O3Si [M – t-Bu]+: 313.1260; found:
313.1251.
Allyl 2-[(tert-Butyldimethylsilyl)oxy]-2-(4-methylphenyl)ace-
tate (4r)
Colorless oil.
IR (CHCl3): 2956, 2859, 1751, 1255, 1177, 864, 840 cm–1.
1H NMR (400 MHz): d = 7.36 (d, J = 8.0 Hz, 2 H), 7.14 (d, J = 8.0
Hz, 2 H), 5.90–5.78 (m, 1 H), 5.22 (s, 1 H), 5.26–5.14 (m, 2 H), 4.57
(dt, J = 5.2, 1.2 Hz, 2 H), 2.34 (s, 3 H), 0.91 (s, 9 H), 0.10 (s, 3 H),
0.03 (s, 3 H).
13C NMR (75 MHz): d = 174.5 (C=O), 114.7 (C≡N), 114.4 (C≡N),
75.9 (C), 67.8 (C), 52.2 (OCH3), 44.2 (CH2), 35.7 (CH2), 35.0
(CH2), 26.0 (3 × CH3), 25.8 (3 × CH3), 25.2 (CH), 19.9 (CH2), 18.7
(CMe3), 18.1 (CMe3), –3.4 (SiCH3), –4.6 (SiCH3), –4.6 (SiCH3),
–4.6 (SiCH3).
Anal. Calcd for C23H42N2O4Si2: C, 59.18; H, 9.07; N, 6.00. Found:
C, 59.18; H, 9.10; N, 5.97.
Methyl 1-[(tert-Butyldimethylsilyl)oxy]cyclohexanecarboxy-
late (4n)
Colorless oil.
IR (CHCl3): 2936, 2857, 1733, 1250, 1156, 1084, 1062, 839 cm–1.
13C NMR (100 MHz): d = 172.0 (C=O), 137.8 (C), 136.2 (C), 131.8
(CH=), 129.0 (2 × CH2), 126.3 (2 × CH2), 118.2 (H2C=), 74.3 (CH),
65.5 (CH2), 25. 7 (3 × CH3), 21.2 (CH3), 18.3 (CMe3), –5.0 (SiCH3),
–5.1 (SiCH3).
1H NMR (400 MHz): d = 3.70 (s, 3 H), 1.86–1.74 (m, 2 H), 1.74–
1.60 (m, 4 H), 1.57–1.42 (m, 3 H), 1.35–1.23 (m, 1 H), 0.90 (s, 9 H),
0.06 (s, 6 H).
EI-HRMS: m/z calcd for C14H19O3Si [M – t-Bu]+: 263.1103; found:
263.1096.
Phenyl 2-[(tert-Butyldimethylsilyl)oxy]-2-(4-methylphenyl)ace-
tate (4s)
Colorless oil.
IR (CHCl3): 2931, 1772, 1493, 1256, 1192, 1126, 872, 840 cm–1.
1H NMR (400 MHz): d = 7.46 (d, J = 8.0 Hz, 2 H), 7.37–7.28 (m, 2
H), 7.23–7.13 (m, 3 H), 6.98 (d, J = 8.0 Hz, 2 H), 5.41 (s, 1 H), 2.36
(s, 3 H), 0.95 (s, 9 H), 0.17 (s, 3 H), 0.09 (s, 3 H).
13C NMR (100 MHz): d = 175.5 (C=O), 76.5 (C), 51.6 (OCH3), 36.0
(2 × CH2), 26.0 (3 × CH3), 25.3 (CH2), 21.7 (CH2), 18.6 (CH2), –3.2
(2 × SiCH3).
EI-HRMS: m/z calcd for C14H29O3Si [M + H]+: 273.1886; found:
273.1872.
Methyl 2-[(tert-Butyldimethylsilyl)oxy]-2-ethylbutanoate (4o)
Colorless oil.
13C NMR (100 MHz): d = 170.8 (C=O), 150.7 (C), 138.1 (C), 135.8
(C), 129.3 (2 × CH2), 129.2 (2 × CH2), 126.4 (2 × CH2), 125.8
(CH2), 121.2 (2 × CH2), 74.4 (CH), 25. 7 (3 × CH3), 21.2 (CH3), 18.3
(CMe3), –5.0 (SiCH3), –5.1 (SiCH3).
EI-HRMS: m/z calcd for C21H29O3Si [M – t-Bu]+: 357.1886; found:
357.1876.
IR (CHCl3): 2955, 2931, 1740, 1252, 1188, 1147, 1088, 838 cm–1.
1H NMR (300 MHz): d = 3.70 (s, 3 H), 1.84–1.60 (m, 4 H), 0.89 (s,
9 H), 0.85 (t, J = 7.5 Hz, 6 H), 0.12 (s, 6 H).
13C NMR (75 MHz): d = 175.5 (C=O), 81.7 (C), 51.6 (OCH3), 32.2
(CH2), 26.0 (CH2), 18.8 (CH3), 8.4 (CH3), –2.7 (2 × SiCH3).
EI-HRMS: m/z calcd for C9H19O3Si [M – t-Bu]+: 203.1103; found:
203.1118.
2-(tert-Butyldimethylsilyloxy)-2-[hydroxy(p-tolyl)methyl]mal-
ononitrile (9)
To a solution of 2a (120 mg, 1.0 mmol) and 1 (216 mg, 1.1 mmol)
in t-BuOH (5.0 mL) was added DMAP (12.2 mg, 0.1 mmol) at r.t.
After stirring for 24 h at r.t., the mixture was concentrated in vacuo.
Although NMR indicated that 9 was the main product, isolation of
9 by silica gel column chromatography failed because of the revers-
ible reaction back to 1 and 2a.
1H NMR (300 MHz): d = 7.43 (d, J = 8.0 Hz, 2 H), 7.22 (d, J = 8.0
Hz, 2 H), 4.97 (s, 1 H), 2.38 (s, 3 H), 0.90 (s, 9 H), 0.35 (s, 3 H),
0.24 (s, 3 H).
Isopropyl 2-[(tert-Butyldimethylsilyl)oxy]-2-(4-methylphe-
nyl)acetate (4p)
Colorless oil.
IR (CHCl3): 2931, 2859, 1742, 1256, 1104, 874, 839 cm–1.
1H NMR (400 MHz): d = 7.35 (d, J = 8.0 Hz, 2 H), 7.13 (d, J = 8.0
Hz, 2 H), 5.14 (s, 1 H), 5.03–4.93 (m, 1 H), 2.33 (s, 3 H), 1.22 (d,
J = 6.4 Hz, 3H), 1.15 (d, J = 6.4 Hz, 3 H), 0.92 (s, 9 H), 0.11 (s, 3
H), 0.04 (s, 3 H).
13C NMR (75 Hz): d = 139.8 (C), 131.2 (C), 129.0 (2 × CH2), 128.8
(2 × CH2), 114.6 (C≡N), 113.7 (C≡N), 78.4 (CH), 69.0 (C), 25.2 (3
× CH3), 21.2 (CH3), 18.0 (CMe3), –4.6 (SiCH3), –4.8 (SiCH3).
13C NMR (100 MHz): d = 171.9 (C=O), 137.6 (C), 136.5 (C), 128.9
(2 × CH), 126.2 (2 × CH), 74.4 (CH), 68.4 (CH), 25.8 (3 × CH3),
21.7 (CH3), 21.6 (CH3), 21.2 (CH3), 18.4 (CMe3), –5.0 (SiCH3),
–5.1 (SiCH3).
EI-HRMS: m/z calcd for C17H24N2O2Si [M]+: 316.1607; found:
EI-HRMS: m/z calcd for C14H21O3Si [M – t-Bu]+: 265.1260; found:
316.1611.
265.1271.
3-[(tert-Butyldimethylsilyl)oxy]-2-coumaranone (10)
A mixture of salicylaldehyde (54.9 mg, 0.45 mmol), 1 (97 mg, 0.49
mmol), and pyridine (107 mg, 1.35 mmol) in MeCN (10 mL) was
stirred at r.t. for 2 d, and then was concentrated in vacuo. The resi-
due was purified by silica gel column chromatography using hex-
ane–EtOAc (20:1) as the eluent to afford 10 (84.8 mg, 0.32 mmol,
71%) as colorless needles; mp 58–59 °C (hexane–EtOAc).
Benzyl 2-[(tert-Butyldimethylsilyl)oxy]-2-(4-methylphenyl)ace-
tate (4q)
Colorless oil.
IR (CHCl3): 2957, 2931, 1751, 1256, 1168, 1130, 867, 840 cm–1.
1H NMR (400 MHz): d = 7.35 (d, J = 8.0 Hz, 2 H), 7.33–7.26 (m, 2
H), 7.26–7.19 (m, 3 H), 7.14 (d, J = 8.0 Hz, 2 H), 5.23 (s, 1 H), 5.11
(s, 2 H), 2.34 (s, 3 H), 0.89 (s, 9 H), 0.06 (s, 3 H), 0.00 (s, 3 H).
13C NMR (100 MHz): d = 172.1 (C=O), 137.8 (C), 136.1 (C), 135.7
(C), 129.0 (2 × CH2), 128.4 (2 × CH2), 128.1 (2 × CH2), 128.0
(CH2), 126.4 (2 × CH2), 74.3 (CH), 66.6 (CH2), 25.7 (3 × CH3), 21.2
(CH3), 18.3 (CMe3), –5.1 (SiCH3), –5.2 (SiCH3).
IR (CHCl3): 2932, 2860, 1821, 1466, 1107, 1068, 840 cm–1.
1H NMR (300 MHz): d = 7.39–7.30 (m, 2 H), 7.17 (t, J = 7.5 Hz, 1
H), 7.07 (d, J = 8.7 Hz, 1 H), 5.31 (s, 1 H), 0.97 (s, 9 H), 0.27 (s, 3
H), 0.25 (s, 3 H).
Synthesis 2008, No. 23, 3819–3827 © Thieme Stuttgart · New York

3826
H. Nemoto et al.
PAPER
13C NMR (75 MHz): d = 174.4 (C=O), 153.5 (C), 130.5 (C), 126.5
(CH), 125.1 (CH), 124.5 (CH), 111.2 (CH), 68.8 (CH), 25.6 (3 ×
CH3), 18.3 (CMe3), –4.3 (SiCH3), –5.0 (SiCH3).
EI-HRMS: m/z calcd for C14H21O3Si [M + H]+: 265.1260; found:
265.1245.
(20 mL), and then concentrated. The residue was purified with pre-
parative TLC using hexane–EtOAc (4:1) as the eluent to give 13a6
(8.3 mg, 0.018 mmol, 68%) and a detectable but trace amount of
13b probably because of partial epimerization), and 12a (2.6 mg,
12% recovered yield).12
Anal. Calcd for C14H20O3Si: C, 63.60; H, 7.62. Found: C, 63.36; H,
7.59.
Conversion of 12b into 13b
The structure of 12b was confirmed by converting it into 13b. A
mixture of 12b (24 mg, 0.030 mmol) and K2CO3 (50 mg) in MeOH
(1 mL) was stirred at 35 °C for 24 h. The mixture was filtered
through a silica gel pad (1 × 3 cm), washed with EtOAc (20 mL),
and then concentrated. The residue was purified with preparative
TLC using hexane–EtOAc (4:1) as the eluent to give 13b (11.2 mg,
0.025 mmol, 83%) and a detectable, but trace amount of 13a prob-
ably because of partial epimerization), and b-cholesterol (10.8 mg,
0.028 mmol, 94%).
b-Cholesteryl (2R,3R)-3-N-Benzyloxycarbonylamino-2-[(tert-
butyldimethylsilyl)oxy]-4-phenylbutanoate (12a) and the 2S-
Isomer (12b)
To a solution of D-1111 (102.9 mg, 0.364 mmol), 1 (143 mg, 0.730
mmol), and b-cholesterol (1.41 g, 3.653 mmol) in Et2O (24 mL) was
added PPY (53.8 mg, 0.364) at 0 °C, and the mixture was stirred for
12 h at 0 °C. Et3N (1 mL) was added and the mixture stirred for 5 h
to destroy the excess of 1. The mixture was concentrated in vacuo
and the residue was purified by silica gel column chromatography
using hexane–EtOAc (10:1–2:1) as the eluent to give 12a and 12b
(156 mg, 0.193 mmol, 52%), and b-cholesterol (1.29 g, 3.342
mmol, 91% recovered yield). A mixture of 12a and 12b (156 mg)
was further purified by preparative TLC on silica gel (PTLC) using
hexane–EtOAc (20:1) as the eluent to give 12a (116 mg, 0.143
mmol, 39%) and 12b (24 mg, 0.030 mmol, 8%).
Methyl 2-[(2S,6S,1R,9R)-4,4,11,11-Tetramethyl-3,5,8,10,12-
pentaoxatricyclo[7.3.0.02,6]dodec-7-yl)-2-hydroxyacetate (15a)
and its 2R-Isomer (15b)
To a solution of aldehyde 1413 (93.7 mg, 0.363 mmol), 1 (142 mg,
0.724 mmol), and MeOH (35 mg, 44.3 mL, 1.09 mmol) in Et2O (18
mL) was added PPY (53.8 mg, 0.364 mmol) at 0 °C. After stirring
for 12 h at 0 °C, the mixture was directly purified by silica gel col-
umn chromatography using hexane–EtOAc (20:1–3:1) as the eluent
to give a mixture of (2S)-15a and (2R)-15b (133 mg, 0.308 mmol,
85%). The ratio of 15a and 15b (92:8) was determined by 1H NMR
spectroscopy.
12a
Amorphous solid; [a]D22 +8.3 (c 2.3, CHCl3).
IR (CHCl3): 3437, 2951, 2861, 1744, 1721, 1503, 1143, 839 cm–1.
1H NMR (300 MHz): d = 7.41–7.05 (m, 10 H), 5.31 (d, J = 4.4 Hz,
1 H), 5.17 (d, J = 9.7 Hz, 1 H), 5.00 (d, J = 12.4 Hz, 1 H), 4.97 (d,
J = 12.4 Hz, 1 H), 4.67–4.52 (m, 1 H), 4.43–4.28 (m, 1 H), 4.22 (d,
J = 2.0 Hz, 1 H), 2.95–2.72 (m, 2 H), 2.36–2.14 (m, 2 H), 2.08–1.71
(m, 5 H), 1.70–0.79 (m, 27 H), 0.96 (s, 9 H), 0.92 (d, J = 6.2 Hz, 3
H), 0.87 (d, J = 6.6 Hz, 6 H), 0.11 (s, 3 H), 0.06 (s, 3 H).
13C NMR (75 MHz): d = 171.2 (C=O), 155.5 (C=O), 139.3 (C= at
C-5), 137.6 (C), 136.6 (C), 129.2, 128.4, 128.0, 127.9, 126.5 (aro-
matic 10 × CH), 122.8 (CH = at C-6), 75.1 (OCH), 72.5 (CH at C-
3), 66.5 (CH2 of Cbz), 56.7 (CH at C-14), 56.1 (CH at C-17), 55.6
(CH–N), 50.0 (CH at C-9), 42.3 (C at C-13), 39.7 (CH2 at C-16),
39.5 (CH2 at C-24), 38.2 (CH2 at C-4), 37.7 (CH2 at C-1), 36.9 (CH2
at C-10), 36.5 (CH2 at C-22), 36.2 (CH at C-20), 35.8 (CH2Ph), 31.9
(CH2 at C-7), 31.8 (CH at C-8), 28.2 (CH2 at C-2), 28.0 (CH at C-
25), 27.6 (CH2 at C-12), 25.8 (3 × CH3), 24.3 (CH2 at C-15), 23.8
(CH2 at C-23), 22.8 (CH3 at C-27), 22.5 (CH3 at C-26), 21.0 (CH2
at C-11), 19.3 (CH3 at C-19), 18.7 (CH3 at C-21), 18.3 (CMe3), 11.8
(CH3 at C-18), –4.5 (SiCH3), –5.2 (SiCH3) [The assignments in ital-
ics belong to the PhCH2NH(Cbz)CH(OTBS)CO2 moiety].
Major Isomer (2S)-15a
1H NMR (300 MHz): d = 5.54 (d, J = 5.1 Hz, 1 H), 4.58 (dd,
J = 8.1, 2.3 Hz, 1 H), 4.42–4.23 (m, 3 H), 3.92 (dd, J = 7.6, 1.4 Hz,
1 H), 3.75 (s, 3 H), 1.57 (s, 3 H), 1.45 (s, 3 H), 1.32 (s, 3 H), 1.31 (s,
3 H), 0.88 (s, 9 H), 0.11 (s, 3 H), 0.10 (s, 3 H).
13C NMR (75 MHz): d = 171.2 (C=O), 109.4 (O–C–O), 108.7 (O–
C–O), 96.3 (anomeric CH), 72.2 (CH), 70.8 (CH), 70.8 (CH), 70.6
(CH), 69.8 (CH), 51.8 (OCH3), 25.9 (3 × CH3), 25.6 (CH3), 25.6
(CH3), 25.0 (CH3), 24.5 (CH3), 18.3 (CMe3), –4.9 (SiCH3), –5.3
(SiCH3).
Minor Isomer (2R)-15b
1H NMR (400 MHz): d = 5.45 (d, J = 4.6 Hz, 1 H), 4.62 (dd,
J = 8.1, 2.0 Hz, 1 H), 4.42–4.23 (m, 3 H), 4.05 (dd, J = 9.4, 1.6 Hz,
1 H), 3.75 (s, 3 H), 1.53 (s, 3 H), 1.43 (s, 3 H), 1.33 (s, 3 H), 1.31 (s,
3 H), 0.89 (s, 9 H), 0.10 (s, 3 H), 0.08 (s, 3 H).
13C NMR (75 MHz): d = 172.2 (C=O), 108.9 (O–C–O), 108.8 (O–
C–O), 95.8 (anomeric CH), 71.1 (CH), 71.0 (CH), 70.3 (CH), 69.3
(CH), 68.8 (CH), 51.8 (OCH3), 25.9 (3 × CH3), 25.8 (CH3), 25.5
(CH3), 25.0 (CH3), 23.8 (CH3), 18.1 (CMe3), –5.4 (SiCH3), –5.6
(SiCH3).
FAB-HRMS: m/z calcd for C51H77NO5Si + Na [M + Na]+:
834.5469; found: 834.5459.
12b
Methyl (2RS,2¢S,3¢R,4¢R,5¢R,6¢R)-2-Hydroxy-2-[2¢ (3¢,4¢,5¢,6¢-di-
O-isopropylidene)tetrahydropyranyl]acetates (16a and 16b)
A mixture of 15 (128 mg, 0.296 mmol) and TBAF (1.0 M solution
in THF, 0.35 mL, 0.350 mmol) in THF (8 mL) was stirred at r.t. for
36 h. The mixture was directly purified by silica gel column chro-
matography using hexane–EtOAc (2:1) as the eluent to give a mix-
ture of (2S)-16a and (2R)-16b (91.4 mg, 0.287mmol, 97%). The
ratio of 16a and 16b (92:8) was determined by 1H NMR spectros-
copy. The stereochemistry of 16a and 16b was confirmed with the
known compounds2 by 1H and 13C NMR spectroscopy.
Several broad peaks were observed in both 1H and 13C NMR spectra
of 12b probably because of slow rotation due to steric hindrance.
However, the structure of 12b was confirmed via transformation to
13b6 by methanolysis; [a]D22 +9.3 (c 0.3, CHCl3).
IR (CHCl3): 3444, 2951, 2933, 2858, 1743, 1720, 1508, 1469, 1283,
1255, 1149, 838 cm–1.
FAB-HRMS: m/z calcd for C51H77NO5Si + Na [M + Na]+:
834.5469; found: 834.5447.
Conversion of 12a into 13a
The stereochemistry of 12a was determined by converting it into
13a. A mixture of 12a (21.7 mg, 0.027 mmol) and K2CO3 (50 mg)
in MeOH (1 mL) was stirred at r.t. for 36 h. The resulting mixture
was filtered through a silica gel pad (1 × 3 cm), washed with EtOAc
Acknowledgment
This work was partly supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science and
Synthesis 2008, No. 23, 3819–3827 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of a-Siloxy Esters
3827
Technology of Japan (Grant No. 18550094 in 2006–2008 and
15510177 in 2003–2005).
(7) Nemoto, H. Yuki Gosei Kagaku Kyokaishi 2004, 62, 347;
Chem. Abstr. 2004, 141, 206541.
(8) Kubota, Y.; Nemoto, H.; Yamamoto, Y. J. Org. Chem. 1991,
56, 7195.
(9) (a) Nemoto, H.; Kubota, Y.; Yamamoto, Y. J. Chem. Soc.,
Chem. Commun. 1994, 1665. (b) Nemoto, H.; Ma, R.;
Ibaragi, T.; Suzuki, I.; Shibuya, M. Tetrahedron 2000, 56,
1463.
(10) For selected examples of homologating carbohydrate-
derived hexoses like 16, see: (a) Khare, N. K.; Sood, R. K.;
Aspinall, G. O. Can. J. Chem. 1994, 72, 237. (b) Dondoni,
A.; Fantin, G.; Fogagnolo, M.; Medici, A. Tetrahedron
1987, 43, 3533. (c) Kato, K.; Chen, C. Y.; Akita, H.
Synthesis 1998, 1527.
(11) Fehrentz, J.-A.; Castro, B. Synthesis 1983, 676.
(12) The difference in the reaction rate of methanolysis can be
reasonably explained as follows. The broad peaks in NMR
spectrum of 12b infer a larger steric repulsion between the b-
cholesteryl and C-3 side chain moieties of 12b than that of
12a. Thus, the ester bond of 12b was cleaved faster than that
of 12a due to the difference of constraint energies of the ester
bonds.
References
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Synthesis 2008, No. 23, 3819–3827 © Thieme Stuttgart · New York