Practical and robust method for stereoselective preparations of ketene silyl (thio)acetal derivatives and NaOH-catalyzed crossed-Claisen condensation between ketene silyl acetals and methyl esters

Article abstract of DOI:10.1016/j.tet.2009.02.084

We developed an efficient, practical, and robust method for stereoselective preparations of (Z)-ketene trimethylsilyl (TMS) thioacetals from thioesters and alkyl (1Z)- or (1Z,3E)-1,3-bis(TMS)dienol ethers from alkyl β-ketoesters. The former preparation was performed by convenient procedure (LDA-TMSCl, 0-5 °C, 2.5 h), while the latter preparation involved convenient method A (2NaHMDS-2TMSCl) and cost-effective method B (NaH, NaHMDS-2TMSCl). The first catalytic NaOH-catalyzed crossed-Claisen condensation between ketene silyl acetals and methyl esters proceeded successfully to give a variety of α-monomethyl β-ketoesters and inaccessible α,α-disubstituted β-ketoesters. For further extension, a couple of Claisen-aldol tandem reactions of the obtained β-ketoester analogues utilizing TiCl₄ and TiCl₄-Bu₃N reagents smoothly proceeded with good to excellent stereoselectivity.

Full text of DOI:10.1016/j.tet.2009.02.084

Tetrahedron 65 (2009) 5596–5607
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Tetrahedron
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Practical and robust method for stereoselective preparations of ketene silyl
(thio)acetal derivatives and NaOH-catalyzed crossed-Claisen condensation
between ketene silyl acetals and methyl esters
*
Kenta Takai, Yuuya Nawate, Tomohito Okabayashi, Hidefumi Nakatsuji, Akira Iida, Yoo Tanabe
Department of Chemistry, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo 669-1337, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We developed an efficient, practical, and robust method for stereoselective preparations of (Z)-
ketene trimethylsilyl (TMS) thioacetals from thioesters and alkyl (1Z)- or (1Z,3E)-1,3-bis(TMS)-
Received 15 December 2008
Received in revised form 19 February 2009
Accepted 20 February 2009
Available online 14 April 2009
dienol ethers from alkyl
procedure (LDA–TMSCl, 0–5 ꢀC, 2.5 h), while the latter preparation involved convenient method A
(2NaHMDS–2TMSCl) and cost-effective method (NaH, NaHMDS–2TMSCl). The first catalytic
NaOH-catalyzed crossed-Claisen condensation between ketene silyl acetals and methyl esters
proceeded successfully to give variety of -monomethyl -ketoesters and inaccessible
disubstituted -ketoesters. For further extension, a couple of Claisen-aldol tandem reactions of the
obtained -ketoester analogues utilizing TiCl4 and TiCl4–Bu3N reagents smoothly proceeded with
good to excellent stereoselectivity.
b-ketoesters. The former preparation was performed by convenient
B
a
a
b
a,a-
b
b
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
for regio- and stereoselective preparation of (E)-TMS-KSAs and
b
-ketoester-derived tert-butyl (1Z,3E)-1,3-bis(TMS)dienol ethers
Ketene silyl acetals (KSAs) as well as enol silyl ethers are
widely employed as reactive precursors of carboxylic esters in
a broad range of organic syntheses, e.g., the Mukaiyama aldol and
Michael reactions, the Diels–Alder reaction, Ireland–Claisen
rearrangement, etc.1 The most conventional preparations of these
silyl ethers from ketones and aldehydes use an R3SiCl(or OTf)–
amine (e.g., Et3N) or R3SiCl–amide (e.g., LDA) agent. We pre-
viously described the first catalytic base-promoted preparation of
enol silyl ethers; NaH functioned for ketones and DBU did for
aldehydes (Scheme 1).2 Recently, a practical and robust method
was reported (Scheme 2).3 As a synthetic application of these silyl
enolates, methyl and tert-butyl ester-derived KSAs were utilized
for the first base-catalyzed crossed-Claisen condensation with
simple methyl esters (Scheme 3).4
In connection with these topics, we present herein three sub-
jects: (i) a new practical preparation of relevant (Z)-ketene silyl
thioacetals (KSTAs), (ii) that of alkyl (1Z)- or (1Z,3E)-1,3-bis(TMS)-
dienol ethers, (iii) full details of NaOH-catalyzed crossed-Claisen
condensation,4 and (iv) titanium-mediated Claisen–aldol tandem
reactions of the obtained b-ketoester analogues.
cat. NaH
N-Si
O
OSi
OSi
(0.05 equiv)
LDA (1.1 eq.),
R2
R2
R1
R3
R1
OTMS
O
TMSCl (1.2 eq.)
R1
R1
t
t
O Bu
Si = TMS or TBDMS
/ CPME, 0 - 5 °C
O Bu
R2
cat. DBU
N-Si
R2
O
(E)-KSAs
(0.05 equiv)
(R2 > R1)
R3
CHO
H
NaHMDS (2.2 eq.),
TMSCl (2.4 eq.)
TMSO
OTMS
O
1
3
Scheme 1. Base-catalyzed preparation of enol silyl ethers from ketones and aldehydes.
R
t
t
O Bu
O Bu
/ CPME, 0 - 5
to 20 - 25 °C
R
(1Z,3E)-1,3-bis(TMS)
dienol ethers
* Corresponding author.
Scheme 2. Practical and robust method for preparing (E)-KSAs and tert-butyl (1Z,3E)-
1,3-bis(TMS)dienol ethers.
E-mail address: tanabe@kwansei.ac.jp (Y. Tanabe).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.084

K. Takai et al. / Tetrahedron 65 (2009) 5596–5607
5597
OTMS
CO2R4
2.2. Practical and robust preparation of alkyl (1Z)- and
(1Z,3E)-1,3-bis(TMS)dienol ethers
R1
R3
2 Me
OTMS
OR4
R1
CO2Me
R
Cat. NaOH
(0.05 equiv)
R3
b
-Ketoester-derived 1,3-bis(TMS)-dienol ethers 3 are useful and
attractive KSA derivatives. Extensive studies by Langer’s group
revealed the utility of various 1,3-bis(TMS)dienol ethers of -dicar-
+
+
R2
Me
O
b
R3 = H, Me, Et
R1
CO2R4
R3
bonyl compounds. The impressive progress in this areawas reviewed:7
precursors for Mukaiyama aldol reaction,8 cyclopentannulation,9
benzannulation,10 oxabicyclo[3.2.1]octan-3-one formation,11 tetrahy-
drofuran formation,12 furanone formation,13 Michael addition,14
[4þ2]- or [3þ3]-cycloaddition,15 Claisen-type reactions,16 etc.17
As depicted in Scheme 4, Soriente’s group disclosed a notable
Ti(OiPr)4-BINOL-catalyzed asymmetric aldol addition of 3a to
aldedydes,18 which is a promising candidate for the process route to
synthesize the key common component of HMG-CoA reductase
inhibitors (statin drugs)19 such as pravastatin, simvastatin, ator-
vastatin, and pitavastatin.
t
R4 = Me, Bu
2 Me
R
Scheme 3. NaOH-catalyzed crossed-Claisen condensation of KSAs with simple methyl
esters.
2. Results and discussion
2.1. Practical and robust preparation of ketene silyl
thioacetals (KSTAs)
(S)-binaphthol,
Ti(OPr)4
KSTAs 1 are relevant isosteres of KSAs. Since parent car-
boxylic thioesters have several characteristic features com-
pared with the corresponding esters due to mild reactivity and
specific useful functionalization,5 practical preparations of 1
are therefore desirable for natural product synthesis and pro-
cess chemistry. Initially, we examined the reaction using
S-tert-butyl thioesters to prepare KSTA 1a–e following the
standard procedure for preparing KSAs under identical condi-
tions [LDA, TMSCl, CPME (cyclopentyl methyl ether) solvent,6
0–25 ꢀC].3 As expected, the desired reaction proceeded
smoothly to give 1a–e (Table 1, entries 1–5). Further favorable
features are as follows. (i) n-Octyl and phenyl thioester sub-
strates could be used with the present method (entries 6–14);
undesirable side self-Claisen condensation between two thio-
esters was sufficiently suppressed, in clear contrast to the case
of methyl, ethyl, and phenyl esters. (ii) Consistent Z-stereo-
selectivity was obtained in every case examined, especially for
the substrates bearing bulky R2 group. (iii) In the case of
i
TMSO
OTMS
OEt
RCHO
+
OH OH
O
OH
O
R
OH
common structure of
CO2Et
5S
3R
R
statin drugs
Scheme 4. Synthesis of statin drugs utilizing asymmetric aldol addition using alkyl
(1Z)-1,3-bis(TMS)dienol ethers as the key step.
The most general method for preparing 3 involves a two-step
sequence: TMSCl–Et3N and TMSCl–LDA at ꢁ78 ꢀC.10,20 Although
our previous method (Scheme 2) involved the use of tert-butyl
b
-ketoesters, we reinvestigated the possibility of using other, more
accessible alkyl (Me and iPr)
b
-ketoesters 2. This objective is based
on the conventional Weiler’s protocol for dianion generation using
2,21 which can be performed at a practical temperature (0–5 ꢀC);
initial monoanion formation of the active methylene position
a,a-disubstituted substrates, a couple of practical purification
suppresses the side self-Claisen condensation between b-ketoesters
procedures, distillation, and column chromatography using
FlorisilÒ were applicable.
2 due to intermolecular anion–anion repulsion. As anticipated, the
desired methyl and isopropyl (1Z)-1,3-bis(TMS)-KSAs 3 were suc-
cessfully produced from 2; Table 2 lists the successful results. The
salient features are as follows. (i) Two methods, A (2 equiv of
NaHMDS) and B (each 1 equiv of NaH and NaHMDS), are available.
(ii) Both methods were performed under practical conditions
(CPME solvent,6 0–25 ꢀC). (iii) The more cost-effective method B
produced a slightly better yield than method A in every case ex-
amined. (iv) The reaction using methyl and isopropyl 3-oxopenta-
noates was slightly less 1Z-selective (entries 1–3) than that using
the tert-butyl analogue. (v) Consistent and excellent 1Z/3E-stereo-
selectivity was obtained in the case of R1-substituted 1,3-bis(TMS)-
KSAs 3d–3i (entries 4–9). (vi) R1-, R2-Disubstituted KSA 3j also
exhibited an excellent 1Z/3E ratio (>99:1) based on the chemical
shift data of 3g and NOESY measurement (entry 10). (vii) The
plausible mechanism for 1Z/3E-stereoselectivity is consistent with
the reported speculation.3 (viii) Several trials to prepare 1,3-
bis(TMS)-KSTAs, however, failed.
Table 1
Stereoselective preparation of (Z)-KSTAs 1
OTMS
O
LDA (1.1 eq.), TMSCl (1.2 eq.)
/ CPME, 20 - 25 °C, 2.5 h
R1
R1
SR3
SR3
(R2 > R1)
R2
R2
1
Entry
R1, R2, R3
Product
Yielda/%
Z/Eb
Distillation
FlorisilÒ
1
2
3
H, Me, tBu
1a
1b
1c
78
70
73
89:11
97:3
93:7
t
H, nBu, Bu
t
H, nOct, Bu
t
4
H,
, Bu
1d
78
88:12
7
5
6
7
8
Me, Me, tBu
H, Me, nOct
H, nBu, nOct
H, iPr, nOct
1e
1f
1g
1h
1i
1j
1k
1l
78
85
74
80
74
77
86
79
68
d
93:7
73:27
98:2
dc
Thus, the present simple, practical, and robust method will
provide an easy access for preparing various (1Z)- and (1Z/3E)-1,3-
bis(TMS)-KSAs 3.
9
H, Allyl, nOct
Me, Me, Ph
Me, Me, nOct
10
11
12
13
14
73
85
74
73
94
d
d
2.3. NaOH-catalyzed crossed-Claisen condensation between
ketene silyl acetals (KSAs) and methyl esters
–(CH2)5–, nOct
Et, nBu, nOct
d
dc
1m
1n
Me, OTBS nOct
99:1
Our longstanding interests in Ti(Zr)-Claisen condensations22
a
Isolated.
b
c
Determined by 1H NMR of the crude product.
Not determined.
prompted us to investigate catalytic crossed-Claisen condensa-
tions.23 This section describes full details of
a previous

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K. Takai et al. / Tetrahedron 65 (2009) 5596–5607
Table 2
Stereoselective preparation of (1Z)- and (1Z,3E)-1,3-bis(TMS)dienol
O
O
TMSO
3
OTMS
OR3
base, TMSCl (2.4 eq.)
1
R1
OR3
/ CPME-THF, 0 to 20 - 25 °C, 2.5 h
R2
R1 R2
2
3
Entry
R1, R2, R3
H, H, Me
Product
Method Aa
Method Bb
Yieldc/%
60
1Z/1Ed
1Z, 3E/1Z, 3Zd
Yieldc/%
1Z/1Ed
1Z, 3E/1Z, 3Zd
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
90:10
69
85
87
91
92
94
81
91:9
94:6
>99:1
i
H, H, Pr
t
H, H, Bu
76
75
>99:1e
Me, H, Me
Me, H, iPr
Me, H, tBu
Et, H, Me
>99:1
93:7
93:7
>99:1
>99:1
90
96:4e
3g
8
, H, Me
3h
71
72
63:37
68
91:9
7
iPr, H, Me
Et, Et, Me
9
10
3i
3j
>99:1
>99:1f
78
88
>99:1
>99:1
a
NaHMDS (2.8 equiv) was used as the base.
b
c
d
e
f
NaH (1.4 equiv) and NaHMDS (1.4 equiv) were used as the base.
Isolated.
Determined by 1H NMR of the crude product.
Reported data.3
Not determined.
communication of NaOH-catalyzed crossed-Claisen condensation
the yield (entry 3), because the undesirable self-Claisen conden-
sation was sufficiently circumvented. Thus, the reaction using 4b
with some methyl esters proceeded in moderate to good yields
(entries 3–6).
using KSAs4 and a new extension on the reaction using an
substituted KSA.
a-TBSO-
The major problem of the traditional Claisen condensation lies
in the difficulty in controlling the direction of the reaction; the
reaction of a mixture of two different esters, each of which pos-
Next, we focused our attention on the reaction of KSAs 5 derived
from
-disubstituted
reversible equilibrium barely shifts from the parent esters to
ketoesters due to the fact that -ketoesters lack the ability to force
the formation of the stable -ketoester enolate.
To overcome this problem, we examined the reaction be-
tween KSAs 5a–c derived from -dialkylated esters and
methyl esters. Table 4 lists the successful results for the prep-
aration of a variety of inaccessible -ketoesters 6–17. The salient
a,
a
-disubstituted esters. The retro-Claisen condensation of
sesses
a
-hydrogens, generally affords all four products. This crucial
a,
a
b
-ketoesters usually predominates, because the
issue was resolved by Ti-crossed-Claisen condensations between
methyl esters and acid chlorides,22c,d,f and between KSAs and acid
chlorides.22e,23 As depicted in Scheme 3, the present NaOH-cata-
lyzed crossed-Claisen condensation using KSAs derived from both
b-
b
b
a
-monomethyl and
a
,a
-disubstituted esters afforded a variety of
a,a
the corresponding
b
-ketoesters.
The initial base screening was guided by the reaction of KSA 4a
with methyl decanoate (Table 3). Among alkali metal hydroxides
(MOH, M¼Li, Na, K; 0.05 equiv), NaOH had the best result. In con-
trast, no reaction proceeded using K2CO3 and TBAF (entries 1 and 2).
The use of the KSA 4b derived from tert-butyl propanoate increased
b
features are as follows. (i) Surprisingly, the crossed-Claisen
condensation using KSAs 5a–c, which looked like less reactive
nucleophiles than KSAs 4a, b, proceeded smoothly and the
yields were good to excellent in every case examined. (ii) As an
apparent tendency, the reaction using linear esters (R2¼H)
predominantly gave silyl enolates A of the parent b-ketoesters B,
whereas that of branched esters (R1 and R2sH) exclusively
afforded B. (iii) Silyl enolates A was easily converted to B on
treatment with TBAF or aqueous 1 M HCl. (iv) Several func-
tionalities, such as an acetal, an epoxide, a tert-butyl ester,
a cyclopropane, and an indole, and a benzyloxy, tolerated the
reaction conditions (entries 12–20). (v) Feature (ii) ensures that
the use of optically active methyl lactate and alanine methyl
ester analogs will not racemize during the reaction, because the
sp3 stereogenic center will be maintained. Indeed, two optically
active substrates underwent the reaction without racemization
(entries 23 and 24).
Table 3
Crossed-Claisen condensation between methyl esters and KSAs 4a and 4b derived
from methyl and tert-butyl propanoates
O
OTMS
cat. Base
R1
CO2Me
R1
CO2R4
(0.05 equiv)
Me
OR4
+
R2
4a (R4 = Me)
R2 Me
/ DMF, 15 -
20 °C, 1 h
t
4b (R4 = Bu)
(3.0 equiv)
Entry
Ester
CO2Me
KSA
Base
Yielda /%
1
2
3
4a
4a
4b
LiOH, KOH, K2CO3, TBAF,
Trace
48
64
Scheme 5 shows a plausible reaction mechanism (catalytic cycle)
NaOH
NaOH
7
as exemplified by the reaction between KSA 5a and
stituted linear methyl ester 18. First, the ester enolate 19 generated
by HOꢁ condenses with 18 to give the
-ketoester 20 with the
a-unsub-
CO2Me
4
5
4b
4b
NaOH
NaOH
58
61
b
elimination of MeOꢁ. Next, MeOꢁ attacks 5a to give 19, which in
turn condenses with 20 to give ketone enolate 21. Ketone enolate
21 receives the TMS group from 5a to give the desired TMS enolate
22 by reforming 19. Thus, more than 2 equiv of KSA was required to
complete the reaction.
PhCO2Me
O
O
6
4b
NaOH
57
CO2Me
a
Isolated.

K. Takai et al. / Tetrahedron 65 (2009) 5596–5607
5599
Table 4
NaOH-catalyzed crossed-Claisen condensation between methyl esters and KSAs 4
OTMS
CO2R4
O
OTMS
R1
R1
R1
CO2R4
CO2Me
NaOH (0.05 eq.)
+
+
OR4
R3
R3
R2
R2
R2
/ DMF, 15 -
20 °C, 1 h
R3
5a (R3 = Me, R4 = Me)
5b (R3 = Et, R4 = Me)
5c (R3 = OTBS, R4 = Me)
A
B
(2.4 eq.)
Entry
Ester
KSA
Yielda/%
Product (A/B)
1
5a
5b
5c
99
98
89
6a (82:18)
6b (92:8)
6c (1:>99)
CO2Me
2
7
3b
4
5a
5b
5c
88
87
76
7a (59:41)
7b (93:7)
7c (1:>99)
5
CO2Me
CO2Me
6b
7
8
PhCO2Me
5a
5b
85c
94c
8a —
8b —
9
10
11b
5a
5b
5c
83
82
71
9a (1:>99)
9b (1:>99)
9c (1:>99)
12
5a
5b
5c
88d
91d
76
10a (77:23)
10b (86:14)
10c (>99:1)
O
O
13
14b
CO2Me
CO2Me
15
16
5a
5b
83
92
11a (42:58)
11b (27:73)
7
O
17
18
5a
5b
85
90
12a (51:49)
12b (54:46)
CO2Me
CO2Me
t
BuO2C
5
Cl
Cl
19
20
5a
5b
89
88
13a (1:>99)
13b (1:>99)
CO2Me
21
5a
67e
14
N
TBS
BnO
22
23
CO2Me
CO2Me
NBn2
CO2Me
OTBDPS
5a
5a
83
15 (98:2)
85f,g
16 (1:>99)
24
5a
89f,h
17 (1:>99)
a
Isolated.
b
c
KSA (3.0 equiv), NMP solvent, 20–25 ꢀC, 3 h.
KSA (1.2 equiv). TBAF was added to the crude product to deprotect TMS and TBS groups.
Reaction time is 3 h.
d
e
f
Because the products A and B were not separable, the mixture was treated with 1 M HCl to convert A to B.
Reaction temperature is 0–5 ꢀC.
97% ee by HPLC analysis.
95% ee by HPLC analysis.
g
h
2.4. Titanium-mediated aldol reactions of newly produced
(entries 3 and 4). Scheme 6 depicts our syn and anti switch proposal
that the syn mechanism utilizes the conventional six-membered
chair transition state in the case of 6a, whereas the anti mechanism
utilizes a benzoyloxy-coordination boat mechanism in the case of
15a.25
b-ketoesters and their TMS enolates
For further useful functionalization of both the obtained
a,a-
dialkylated
b-ketoesters B and their TMS enolates A in Table 4,
Mukaiyama aldol reaction using A (method A) and Ti-direct aldol
reaction24 using B (method B) were performed. Table 5 lists these
successful results. All six reactions smoothly proceeded to give the
desired adducts 23–25; R1¼octyl substrate predominantly gave syn
aldol adducts (entries 1–4), whereas R1¼benzyloxy substrate gave
anti aldol adducts (entries 5 and 6). This stereoselectivity were
significantly enhanced by the Ti-direct method using hexanal
In conclusion, we developed (i) practical preparations of
ketene silyl thioacetals (KSTAs) and alkyl (1Z)- or (1Z,3E)-1,3-
bis(TMS)dienol ethers, (ii) a mild, catalytic, practical NaOH-catalyzed
crossed-Claisen condensation giving a variety of
b-ketoesters,
and (iii) further functionalization utilizing two Ti-aldol reactions.
These studies will provide new useful protocols for organic
synthesis.

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K. Takai et al. / Tetrahedron 65 (2009) 5596–5607
OTMS
OMe
Butyl propanethioate (2.19 g, 15 mmol) in CPME (4 mL) was added
to the mixture at the same temperature for 6 min, followed by
being stirred for 0.5 h. TMSCl (2.28 mL, 18.0 mmol) was added to
the mixture for 2 min, followed by being stirred for 0.5 h. Then, the
mixture was warmed up to 20–25 ꢀC, followed by being stirred at
same temperature for 1.5 h. The reaction mixture was poured into
ice-water and hexane, which was extracted with hexane. The or-
ganic phase was washed with brine, dried (Na2SO4), and concen-
trated. The obtained crude oil was purified by distillation to give the
desired product (2.56 g, 78%).
R
CO2Me
18
-OH
5a
TMSOH
O-
O
R
CO2Me
OMe
19
20
OTMS
-
+
MeO
5a
R
CO2Me
(Z Isomer) Colorless oil; bp 47–48 ꢀC/1.5 mmHg; 1H NMR
19
22
TMSOMe
(300 MHz, CDCl3):
d
0.21 (9H, s), 1.37 (9H, s), 1.73 (3H, d, J¼6.9 Hz),
O-
5a
5.28 (1H, q, J¼6.9 Hz); 13C NMR (75 MHz, CDCl3):
d 0.3, 14.7, 31.7,
CO2Me
CO2Me
46.7, 115.3, 145.6; IR (neat) 2963, 2922, 1628, 1363, 1254, 1168, 1140,
1113, 1067, 943, 874, 758 cmꢁ1
.
21
3.1.2. 1-tert-Butylthio-1-(trimethylsiloxy)-1-hexene (1b)27
Following the procedure for preparing KSTA 1a, the reaction of
S-tert-butyl hexanethioate (7.53 g, 40 mmol) gave the desired
product 1b (7.29 g, 70%).
Scheme 5. Proposed reaction mechanism of NaOH-catalyzed crossed-Claisen
condensation.
3. Experimental
3.1. General
(Z Isomer) Colorless oil; bp 45–48 ꢀC/0.2 mmHg; 1H NMR
(300 MHz, CDCl3):
d
0.21 (9H, s), 0.89 (3H, t, J¼6.9 Hz),1.24–1.38 (4H,
m), 1.37 (9H, s), 2.09–2.25 (2H, m), 5.20 (1H, t, J¼7.6 Hz); 13C NMR
(75 MHz, CDCl3): d 0.3,14.0, 22.3, 28.9, 31.7, 32.2, 46.3,121.0,145.0; IR
NMR spectra were recorded on a JEOL DELTA300 spectrometer,
operating at 300 MHz for 1H NMR and 75 MHz for 13C NMR.
(neat) 2961, 2924, 2861, 1620, 1458, 1251, 1167, 1124, 878, 847 cmꢁ1
.
Chemical shift (d ppm) were reported downfield from tetramethyl-
silane (0 ppm) for 1H NMR and were reported in the scale relative to
CDCl3 (77.00 ppm) for 13C NMR. IR spectra were recorded on JASCO
FT/IR-8000 and/or FT/IR-5300 spectrophotometer. Mass spectra
were measured on a JEOL JMS-T100LC spectrometer.
3.1.3. 1-tert-Butylthio-1-(trimethylsiloxy)-1-decene (1c)
Following the procedure for preparing KSTA 1a, the reaction of
S-tert-butyl decanethioate (9.78 g, 40 mmol) gave the desired
product 1e (9.25 g, 73%).
(Z Isomer) Colorless oil; bp 94–97 ꢀC/0.4 mmHg; 1H NMR
3.1.1. 1-tert-Butylthio-1-(trimethylsiloxy)propene (1a)26
(300 MHz, CDCl3):
d
0.21 (9H, s), 0.87 (3H, t, J¼6.5 Hz), 1.16–1.39
(12H, m), 1.36 (9H, s), 2.08–2.23 (2H, m), 5.21 (1H, t, J¼7.6 Hz); 13C
BuLi (1.58 M in hexane, 10.4 mL, 16.5 mmol) was added to
i
NMR (75 MHz, CDCl3):
d 0.3, 14.1, 22.7, 29.2, 29.3, 29.5, 30.0, 31.7,
a stirred solution of Pr2NH (2.53 mL, 18.0 mmol) in cyclopentyl
methyl ether (CPME) (11 mL) at 0–5 ꢀC under an Ar atmosphere,
31.9, 46.3, 121.1, 144.9; IR (neat) 2959, 2924, 2855, 1620, 1458, 1363,
1252, 1125, 874, 845, 756 cmꢁ1
.
followed by being stirred at the same temperature for 0.5 h. S-tert-
3.1.4. 1-tert-Butylthio-1-(trimethylsiloxy)-1,10-undecadiene (1d)
Following the procedure for preparing KSTA 1a, the reaction of
S-tert-butyl 10-undecenethioate (7.70 g, 30 mmol) gave the desired
product 1d (7.69 g, 78%).
Table 5
Ti-Aldol reactions of crossed-Claisen adduct A and B with aldehydesa,b
a
Method A (Mukaiyama Aldol Reaction)
(Z Isomer) Colorless oil; bp 96–99 ꢀC/0.2 mmHg; 1H NMR
OTMS
TiCl4
OH
O
(300 MHz, CDCl3):
d 0.21 (9H, s), 1.20–1.42 (10H, m), 1.36 (9H, s),
R1
CO2Me
R2CHO
+
CO2Me
1.93–2.08 (2H, m), 2.09–2.24 (2H, m), 4.84–5.04 (2H, m), 5.20 (1H, t,
R2
/ CH2Cl2,
-45 °C, 1 h
J¼7.6 Hz), 5.81 (1H, ddt, J¼6.5 Hz, 10.3 Hz, 17.2 Hz); 13C NMR
R1
(75 MHz, CDCl3):
d 0.3, 28.9, 29.1, 29.1, 29.2, 29.3, 29.9, 31.7, 33.8,
15a-A: R1 = OBn
6a-A: R1 = n-Oct
46.3, 114.1, 121.0, 139.2, 145.0; IR (neat) 2961, 2926, 2857, 1620,
1252, 1362, 1167, 1126, 909, 872 cmꢁ1
.
b
Method B (Ti - Direct Aldol Reaction)
3.1.5. 1-tert-Butylthio-2-methyl-1-(trimethylsiloxy)propene (1e)28
Following the procedure for preparing KSTA 1a, the reaction of
S-tert-butyl 2-methylpropanethioate (3.58 g, 22.3 mmol) gave the
desired product 1e (3.06 g, 78%).
O
OH
O
TiCl4 - Bu3N
R1
CO2Me
R2CHO
+
CO2Me
R2
R1
/ CH2Cl2, 0 - 5
°C, 2 h
6a-B 15a-B
Colorless oil; bp 63–65 ꢀC/6.8 mmHg. 1H NMR (300 MHz,
CDCl3):
(75 MHz, CDCl3):
2963, 2861, 1628, 1456, 1363, 1254, 1148, 1055, 901, 864 cmꢁ1
d
0.19 (9H, s), 1.32 (9H, s), 1.73 (3H, s), 1.88 (3H, s); 13C NMR
Entry
R1
Octyle
R2
Method
Product
Yieldc/%
syn/antid
d
0.8, 18.8, 22.2, 31.6, 47.4, 126.4, 138.2; IR (neat)
1
2
3
4
5
6
Ph
A
B
A
B
A
B
23
23
24
24
25
25
73
78
80
83
67
80
93:7
93:7
72:28
>99:1
25:75
2:98
.
Pentyl
Ph
3.1.6. 1-Trimethylsiloxy-1-octylthio-1-propene (1f)
Following the procedure for preparing KSTA 1a, the reaction of
S-octyl propanethioate (2.02 g, 10 mmol) gave the desired product
1f (2.14 g, 85%).
BnOf
a
b
c
d
e
f
Molar ratio; A/aldehydes/TiCl4¼1.0:1.2:1.2.
(Z Isomer) Colorless oil; bp 58–60 ꢀC/0.2 mmHg; 1H NMR
Molar ratio ; 9B/aldehydes/TiCl4/Bu3N¼1.0:1.2:1.2:1.4.
Isolated.
(300 MHz, CDCl3):
d
0.21 (9H, s), 0.87 (3H, t, J¼6.5 Hz), 1.13–1.50
Determined by 1H NMR.
(10H, m), 1.50–1.67 (2H, m), 1.65 (3H, d, J¼6.9 Hz), 2.64 (2H, t,
Compound 9A (E/Z¼1:>99) was used.
J¼7.2 Hz), 4.98 (1H, q, J¼6.9 Hz); 13C NMR (75 MHz, CDCl3):
d
ꢁ0.1,
Compound 9A (E/Z¼5:95) was used.

K. Takai et al. / Tetrahedron 65 (2009) 5596–5607
5601
Ph
CO2Me
OH
O
CO2Me
TiCl3
O
Ph
Oct
O
H
Oct
PhCHO
TiCl4
anti
Chair TS
6a
CO2Me
OH
O
TiCl3
Ph
O
CO2Me
Ph
O
H
Oct
Oct
syn
BnO
OH
O
CO2Me
TiCl3
Ph
Ph
O
OBn
anti
O
PhCHO
TiCl4
CO2Me
15a
Boat TS
Ph
OH
O
BnO
TiCl3
CO2Me
Ph
O
O
OBn
syn
CO2Me
Scheme 6. Proposed mechanism of stereoselective Ti-mediated aldol addition.
13.3, 14.1, 22.6, 28.8, 29.1, 30.1, 30.6, 31.8, 107.9, 145.0; IR (neat)
d
0.1, 14.1, 22.6, 28.7, 29.1, 30.1, 30.6, 31.8, 32.4, 43.2, 110.8, 114.2,
137.2, 145.9; IR (neat) 2959, 2928, 2855, 1698, 1638, 1624, 1509,
1458, 1252, 1150, 868, 847 cmꢁ1
2959, 2857, 1698, 1636, 1458, 1252, 1159, 1064, 947, 873, 846 cmꢁ1
.
.
3.1.7. 1-Trimethoxysiloxy-1-octylthio-1-hexene (1g)
Following the procedure for preparing KSTA 1a, the reaction of
S-octyl butanethioate (2.44 g, 10 mmol) gave the desired product 1f
(2.36 g, 74%).
3.1.10. 2-Methyl-1-trimethylsiloxy-1-phenylthio-1-propene (1j)29
Following the procedure for preparing KSTA 1a, the reaction of
S-phenyl 2-methylpropanethioate (1.80 g, 10 mmol) gave the de-
sired product 1j (1.93 g, 77%) by distillation. FlorisilÒ column
chromatography (hexane) purification gave 1j (1.84 g, 73%).
Colorless oil; bp 58–60 ꢀC/0.2 mmHg; 1H NMR (300 MHz,
(Z Isomer) Colorless oil; bp 81–83 ꢀC/0.2 mmHg; 1H NMR
(300 MHz, CDCl3):
m), 1.49–1.64 (2H, m), 2.64 (2H, t, J¼7.2 Hz), 4.97 (1H, t, J¼7.2 Hz);
13C NMR (75 MHz, CDCl3):
0.6,14.0,14.1, 22.2, 22.4, 22.6, 27.8, 28.8,
29.2, 30.1, 30.7, 31.8, 32.3, 114.2, 144.3; IR (neat) 2957, 2926, 2855,
1624, 1508, 1458, 1252, 874, 847 cmꢁ1
d 0.22 (9H, s), 0.79–0.96 (6H, m), 1.15–1.44 (14H,
d
CDCl3): d 0.11 (9H, s), 1.18 (3H, s), 1.92 (3H, s), 7.09–7.16 (1H, m),
7.22–7.29 (4H, m); 13C NMR (75 MHz, CDCl3):
127.4, 128.7, 135.3, 135.9.
d 0.4,18.7,124.1,125.2,
.
3.1.8. 1-Trimethylsiloxy-3-methyl-1-octylthio-1-butene (1h)
Following the procedure for preparing KSTA 1a, the reaction of
S-octyl 3-methylbutanethioate (2.30 g, 10 mmol) gave the desired
product 1h (2.42 g, 80%).
3.1.11. 2-Methyl-1-trimethylsiloxy-1-octylthio-1-propene (1k)22d
Following the procedure for preparing KSTA 1a, the reaction of
S-octyl 2-methylpropanethioate (1.95 g, 9 mmol) gave the desired
product 1k (2.23 g, 86%) by distillation. FlorisilÒ column chroma-
tography (hexane) purification gave 1k (2.21 g, 85%).
(Z Isomer) Colorless oil; bp 79–81 ꢀC/0.2 mmHg; 1H NMR
(300 MHz, CDCl3):
d
0.23 (9H, s), 0.88 (3H, t, J¼6.9 Hz), 0.96 (6H, d,
Colorless oil; bp 58–60 ꢀC/0.2 mmHg; 1H NMR (300 MHz,
J¼9.7 Hz), 1.11–1.43 (10H, m), 1.45–1.64 (2H, m), 2.50 (3H, m), 4.82
CDCl3):
d
0.22 (9H, s), 0.88 (3H, t, J¼6.5 Hz), 1.08–1.43 (10H, m),
(1H, d,J¼9.7 Hz);13CNMR(75 MHz,CDCl3):
d
0.0,14.1, 22.6, 23.4, 28.2,
1.47–1.59 (2H, m), 1.68 (3H, s), 1.83 (3H, s), 2.60 (2H, t, J¼7.2 Hz); 13C
28.7, 29.2, 30.1, 30.6, 31.8, 122.1, 142.6; IR (neat) 2959, 2928, 2857,
NMR (75 MHz, CDCl3):
31.7, 31.8, 120.2.
d 0.4, 14.0, 18.6, 20.9, 22.7, 28.7, 29.2, 29.7,
1626, 1466, 1419, 1379, 1362, 1252, 1161, 1117, 881, 849, 756 cmꢁ1
.
3.1.9. 1-Trimethoxysiloxy-1-octylthio-1,4-pentadiene (1i)
Following the procedure for preparing KSTA 1a, the reaction of
S-octyl 4-pentenethioate (2.84 g, 10 mmol) gave the desired prod-
uct 1i (2.36 g, 74%).
3.1.12. 1-Trimethylsiloxy-1-octylthiomethylenecyclohexane (1l)
Following the procedure for preparing KSTA 1a, the reaction of
S-octyl cyclohexanethiocarboxylate (1.80 g, 7 mmol) gave the de-
sired product 1l (1.82 g, 79%) by distillation. FlorisilÒ column
chromatography (hexane) purification gave 1l (1.70 g, 74%).
Colorless oil; bp 66–68 ꢀC/0.2 mmHg; 1H NMR (300 MHz,
(Z Isomer) Colorless oil; bp 71–73 ꢀC/0.1 mmHg; 1H NMR
(300 MHz, CDCl3):
d
0.24 (9H, s), 0.88 (3H, t, J¼6.9 Hz), 1.11–1.42
(10H, m), 1.44–1.65 (2H, m), 2.53–2.69 (2H, m), 2.72–2.94 (2H, m),
4.86–5.10 (3H, m), 5.66–5.88 (1H, m); 13C NMR (75 MHz, CDCl3):
CDCl3):
d
0.22 (9H, s), 0.88 (3H, t, J¼6.9 Hz), 1.17–1.42 (10H, m),
1.42–1.58 (2H, m), 2.16–2.25 (2H, m), 2.31–2.40 (2H, m), 2.61 (2H, t,

5602
K. Takai et al. / Tetrahedron 65 (2009) 5596–5607
J¼7.2 Hz); 13C NMR (75 MHz, CDCl3):
d
0.3, 14.1, 22.6, 26.7, 28.0,
Colorless oil; bp 43–45 ꢀC/0.2 mmHg; 1H NMR (300 MHz,
28.5, 28.7, 29.2, 31.4, 31.6, 31.8, 128.4; IR (neat) 2926, 2855, 1630,
CDCl3):
d
0.21 (9H, s), 0.24 (9H, s), 3.55 (3H, s), 3.94 (1H, d, J¼1.4 Hz),
1449, 1252, 1130, 1091, 918, 846 cmꢁ1
.
4.14 (1H, d, J¼1.4 Hz), 4.47 (1H, s); 13C NMR (75 MHz, CDCl3):
d 0.2,
0.4, 54.9, 77.57, 89.2, 153.4, 158.6; IR (neat) 2964, 1708, 1652, 1444,
3.1.13. 2-Ethyl-1-trimethylsiloxy-1-octylthio-1-hexene (1m)
Following the procedure for preparing KSTA 1a, the reaction of
S-octyl 2-ethylhexanethioate (2.72 g, 10 mmol) gave the desired
product 1m (2.52 g, 73%) by distillation. FlorisilÒ column chroma-
tography (hexane) purification gave 1m (2.34 g, 68%).
1388, 1252, 1196, 1093 cmꢁ1
.
3.2.4. 1,3-Bis(trimethylsiloxy)-1-isopropoxybuta-1,3-diene (3b)
[Method B] The reaction of isopropyl 3-oxobutanoate (1.44 g,
10 mmol) gave the desired product 3b (2.45 g, 85%).
Colorless oil; bp 87–89 ꢀC/0.2 mmHg; 1H NMR (300 MHz,
Colorless oil; bp 46–47 ꢀC/0.2 mmHg; 1H NMR (300 MHz,
CDCl3):
d
0.23 (9H, s), 0.79–1.00 (9H, m), 1.16–1.42 (14H, m), 1.47–
CDCl3):
J¼1.4 Hz), 4.12 (1H, d, J¼1.4 Hz), 4.22 (1H, sep, J¼6.2 Hz), 4.47 (1H,
s); 13C NMR (75 MHz, CDCl3):
0.2, 0.6, 21.7, 70.2, 78.6, 88.9, 153.6,
156.1; IR (neat) 2978, 2961, 1716, 1649, 1385, 1252, 1221, 1188, 1113,
1064, 1014, 922, 847 cmꢁ1
d
0.17 (9H, s), 0.25 (9H, s), 1.26 (6H, d, J¼6.2 Hz), 3.91 (1H, d,
1.61 (2H, m), 2.01–2.15 (2H, m), 2.16–2.30 (2H, m), 2.61 (2H, t,
J¼7.2 Hz); 13C NMR (75 MHz, CDCl3):
d
0.3,12.5,13.8,14.1, 22.7, 22.9,
d
25.4, 28.8, 29.2, 29.3, 30.1, 31.2, 31.5, 31.7, 31.9, 130.8; IR (neat) 2959,
2928, 2856, 1686, 1624, 1458, 1252, 1150, 1092, 882, 845 cmꢁ1
.
.
3.1.14. 2-(tert-Butyldimethylsiloxy)-1-trimethylsiloxy-1-octylthio-
1-propene (1n)
3.2.5. 1,3-Bis(trimethylsiloxy)-1-tert-butoxybuta-1,3-diene (3c)3
[Method A] Ref. 3. [Method B] The reaction of methyl 3-oxo-
butanoate (1.58 g, 10 mmol) gave the desired product 3c (2.63 g,
87%).
Following the procedure for preparing KSTA 1a, the reaction of
S-octyl 2-(tert-butyldimethylsiloxy)propanethioate (665 mg, 2 mmol)
gave the desired product 1n (762 mg, 94%) by FlorisilÒ column
chromatography (hexane).
Colorless oil; bp 65–67 ꢀC/0.5 mmHg; 1H NMR (300 MHz,
CDCl3):
d
0.15 (9H, s), 0.21 (9H, s), 1.38 (9H, s), 4.21 (1H, d, J¼1.0 Hz),
(Z Isomer) Colorless oil; 1H NMR (300 MHz, CDCl3):
d
0.15 (6H,
4.25 (1H, d, J¼1.0 Hz), 4.54 (1H, s); 13C NMR (75 MHz, CDCl3):
d 0.2,
s), 0.22 (9H, s), 0.88 (3H, t, J¼6.9 Hz), 0.96 (9H, s), 1.16–1.43 (10H, m)
0.6, 28.7, 79.0, 85.9, 103.4, 146.3, 152.4; IR (neat) 2978, 2912, 1657,
1.46–1.62 (2H, m), 1.85 (3H, s), 2.62 (2H, t, J¼7.2 Hz); 13C NMR
1612, 1368, 1300, 1254, 1136, 1107, 1053, 939, 908, 852 cmꢁ1
.
(75 MHz, CDCl3):
d
ꢁ4.0, 0.4,1.6,14.1,18.1, 22.6, 25.9, 28.9, 29.2, 29.7,
31.7, 31.8, 129.8, 140.7; IR (neat) 2928, 2856, 1686, 1464, 1372, 1252,
1154, 833 cmꢁ1
3.2.6. 1,3-Bis(trimethylsiloxy)-1-methoxypenta-1,3-diene (3d)
[Method A] The reaction of methyl 3-oxopentanoate (1.30 g,
10 mmol) gave the desired product 3 (2.06 g, 75%). [Method B]
(2.50 g, 91%).
.
3.2. General procedure for the preparation of
derived 1,3-bis(TMS)-dienol ethers 3
b-ketoester-
Colorless oil; bp 78–80 ꢀC/0.2 mmHg; 1H NMR (300 MHz,
CDCl3):
d
0.16 (9H, s), 0.17 (9H, s), 1.50 (3H, d, J¼6.9 Hz), 3.58 (3H, s),
3.2.1. Method A of Table 2
4.04 (1H, s), 4.64 (1H, q, J¼6.9 Hz); 13C NMR (75 MHz, CDCl3):
d 0.4,
A
b
-ketoester (10.0 mmol) was added to a stirred suspension of
0.6, 12.8, 55.0, 73.7, 102.7, 126.9, 146.1, 157.6; IR (neat) 2959, 1665,
NaH (14.0 mmol) in CPME (50 mL) at 0–5 ꢀC under an Ar atmo-
sphere, followed by being stirred at the same temperature for 0.5 h.
After evolution of H2 gas ceased, NaHMDS (1.9 M in THF, 7.4 mL,
14 mmol) was added to the mixture for 5–8 min, followed by being
stirred at the same temperature for 0.5 h. TMSCl (3.0 mL,
24.0 mmol) was added to the mixture for 5–8 min., followed by
being stirred for 0.5 h. Then, the mixture was warmed up to 20–
25 ꢀC, followed by being stirred at same temperature for 1.5 h. The
reaction mixture was poured into ice-water and hexane, which was
extracted with hexane. The organic phase was washed with brine,
dried (Na2SO4), and concentrated. The obtained crude oil was pu-
rified by distillation to give the desired product.
1252, 1219, 1088, 978, 845 cmꢁ1
.
3.2.7. 1,3-Bis(trimethylsiloxy)-1-isopropoxypenta-1,3-diene (3e)
[Method B] The reaction of isopropyl 3-oxopentanoate (1.58 g,
10 mmol) gave the desired product 3e (2.78 g, 92%).
Colorless oil; bp 80–82 ꢀC/0.2 mmHg; 1H NMR (300 MHz,
CDCl3):
d
0.15 (9H, s), 0.21 (9H, s), 1.28 (6H, d, J¼6.2 Hz), 1.49 (3H, d,
J¼6.9 Hz), 4.02 (1H, s), 4.26 (1H, sep, J¼6.2 Hz), 4.62 (1H, q,
J¼6.9 Hz); 13C NMR (75 MHz, CDCl3):
d 0.4, 0.8, 12.8, 21.7, 70.0, 74.9,
102.5, 146.4, 154.9; IR (neat) 2963, 2912, 1655, 1373, 1309, 1252,
1217, 1159, 1107, 1065, 920, 845 cmꢁ1
.
3.2.8. 1,3-Bis(trimethylsiloxy)-1-tert-butoxypenta-1,3-diene (3f)
[Method A] Ref. 3. [Method B] The reaction of tert-butyl 3-
oxopentanoate (1.72 g,10 mmol) gave the desired product 3 (2.98 g,
94%).
3.2.2. Method B of Table 2
A b-ketoester (10.0 mmol) was added to a stirred solution of
NaHMDS (1.9 M in THF, 14.7 mL, 28.0 mmol) in CPME (20 mL) at
0–5 ꢀC under an Ar atmosphere, followed by being stirred at same
temperature for 0.5 h. TMSCl (3,0 mL, 24.0 mmol) was added to the
mixture for 5–8 min, followed by being stirred for 0.5 h. Then, the
mixture was warmed up to 20–25 ꢀC, followed by being stirred at
same temperature for 1.5 h. The reaction mixture was poured into
ice-water and hexane, which was extracted with hexane. The or-
ganic phase was washed with brine, dried (Na2SO4), and concen-
trated. The obtained crude oil was purified by distillation to give the
desired product.
Colorless oil; bp 56–57 ꢀC/0.3 mmHg; 1H NMR (300 MHz,
CDCl3):
d
0.15 (9H, s), 0.21 (9H, s), 1.38 (9H, s), 1.50 (3H, d, J¼6.9 Hz),
4.41 (1H, s), 4.63 (1H, t, J¼6.9 Hz), 4.62 (1H, q, J¼6.9 Hz); 13C NMR
(75 MHz, CDCl3): d 0.4, 0.7, 12.7, 28.6, 79.0, 85.9, 103.4, 146.3, 152.4;
IR (neat) 2978, 2912, 1657, 1368, 1300, 1254, 1136, 1107, 1053, 939,
908, 852 cmꢁ1
.
3.2.9. 1,3-Bis(trimethylsiloxy)-1-methoxy hexa-1,3-diene (3g)
[Method B] The reaction of methyl 3-oxohexanoate (1.44 g,
10 mmol) gave the desired product 3 (2.34 g, 81%).
(Note: after finishing this work, hexane or heptane solvent
instead of CPME was found to be available.)
Colorless oil; bp 45–46 ꢀC/0.2 mmHg; 1H NMR (300 MHz,
CDCl3):
d
0.16 (9H, s), 0.21 (9H, s), 0.94 (3H, t, J¼7.6 Hz), 1.92 (2H,
3.2.3. 1,3-Bis(trimethylsiloxy)-1-methoxybuta-1,3-diene (3a)
[Method A] The reaction of methyl 3-oxobutanoate (1.16 g,
10 mmol) gave the desired product 1 (1.56 g, 60%). [Method B]
(1.79 g, 69%).
quin, J¼7.6 Hz), 3.57 (3H, s), 4.06 (1H, s), 4.57 (1H, t, J¼7.6 Hz); 13C
NMR (75 MHz, CDCl3):
d 0.3, 0.6, 14.8, 20.8, 55.0, 73.8, 110.9, 144.8,
157.6; IR (neat) 2961, 2908, 1718, 1655, 1387, 1252, 1221, 1165, 1127,
1092, 982, 920, 847, 760 cmꢁ1
.

K. Takai et al. / Tetrahedron 65 (2009) 5596–5607
5603
3.2.10. 1,3-Bis(trimethylsiloxy)-1-methoxy-trideca-1,3,12-
triene (3h)
Compound 6b-A. colorless oil; 1H NMR:
d
0.16 (9H, s), 0.80 (3H, t,
J¼7.6 Hz), 0.88 (3H, t, J¼6.9 Hz), 1.23–1.35 (12H, m),1.24 (3H, s),1.71
[Method A] The reaction of methyl 3-oxodec-12-enoate (2.40 g,
10 mmol) gave the desired product 3h (2.73 g, 71%). [Method B]
(2.59 g, 68%).
(1H, dq, J¼7.6, 13.4 Hz), 1.78 (1H, dq, J¼7.6, 13.4 Hz), 1.88–2.07 (2H,
m), 3.65 (3H, s), 4.56 (1H, t, J¼6.9 Hz); 13C NMR:
d 0.9, 8.8, 14.1, 20.5,
22.7, 26.1, 28.7, 29.3, 29.4, 29.5, 29.8, 31.9, 51.7, 52.5, 107.5, 151.4,
176.1.; IR (neat) 2926, 2855, 1738, 1665, 1252, 1148, 1125, 1103,
Colorless oil; bp 87–89 ꢀC/0.1 mmHg; 1H NMR (300 MHz,
CDCl3):
d
0.16 (9H, s), 0.18 (9H, s), 1.11–1.55 (10H, m), 1.78–2.13 (4H,
847 cmꢁ1
.
m), 3.56 (3H, ꢂ7/10, s), 3.68 (3H, ꢂ3/10, s), 4.07 (1H, s), 4.57 (1H,
Compound 6b-B. Colorless oil; 1H NMR:
d
0.82 (3H, t, J¼7.6 Hz),
ꢂ7/10, d, J¼7.6 Hz), 4.81, (1H, –3/10, d, J¼7.6 Hz) 4.83–5.05 (2H, m),
0.88 (3H, t, J¼6.9 Hz), 1.21–1.28 (12H, m), 1.31 (3H, s), 1.53–1.61 (2H,
m), 1.80 (1H, dq, J¼7.6, 14.1 Hz), 1.94 (1H, dq, J¼7.6, 14.1 Hz), 2.36
(1H, dt, J¼6.9, 17.2 Hz), 2.43 (1H, dt, J¼6.9, 17.2 Hz), 3.72 (3H, s); 13C
5.80 (1H, ddt, J¼6.9, 10.3, 16.9 Hz); 13C NMR (75 MHz, CDCl3):
d 0.2,
0.3, 0.6, 27.1, 27.4, 28.9, 29.1, 29.2, 29.3, 29.4, 30.2, 33.8, 51.8, 55.0,
73.9, 76.6, 77.0, 77.4, 109.0, 110.9, 114.1, 139.1, 139.2, 144.2, 145.2,
NMR: d 8.6,14.1,18.3, 22.7, 23.8, 27.7, 29.1, 29.3, 29.4, 29.4, 31.9, 38.3,
157.5; IR (neat) 2926, 2855, 1655, 1252, 1211, 1091, 978, 849 cmꢁ1
.
52.2, 60.0, 173.8, 208.0; IR (neat) 2928, 2856, 1745, 1715, 1460, 1244,
1148 cmꢁ1
.
3.2.11. 1,3-Bis(trimethylsiloxy)-1-methoxy-5-methylhexa-1,3-
diene (3i)
3.2.15. Methyl 2-hydroxy-2-methyl-3-oxododecanoate (6c)
[Method A] The reaction of methyl 5-methyl-3-oxohexanoate
(1.58 g, 10 mmol) gave the desired product 3i (2.18 g, 72%). [Method
B] (2.36 g, 78%).
2-(tert-Butyldimethylsiloxy)-1-methoxy-1-(trimethylsiloxy)-1-pro-
pene (5c, 436 mg, 1.5 mmol) was added to a stirred solution of methyl
decanoate (93 mg, 0.5 mmol) and NaOH (1 mg, 0.03 mmol) in
N-methylpyrrolidone (NMP) (0.1 mL) at 20–25 ꢀC under an Ar atmo-
sphere, followed by being stirred for 3 h. Water was added to the
mixture, which was extracted with diethyl ether. The organic phase
was washed with water, brine, dried (Na2SO4), and concentrated. To
the obtained crude product in THF (0.5 mL), 1 M TBAF solution in THF
(1 mL) was added at 0–5 ꢀC under an Ar atmosphere, followed by being
stirred for 1 h. Water was added to the reaction mixture, which was
extracted with AcOEt. The organic phase was washed with water,
brine, dried (Na2SO4), and concentrated. The obtained crude product
was purified by silica gel column chromatography (hexane/AcOEt¼4:1)
to give the desired product 6c (119 mg, 89%).
Colorless oil; bp 63–69 ꢀC/0.1 mmHg; 1H NMR (300 MHz,
CDCl3):
d
0.16 (9H, s), 0.22 (9H, s), 0.94 (6H, d, J¼6.5 Hz), 2.21–2.46
(1H, m), 3.56 (3H, s), 4.10 (1H, s), 4.42 (1H, d, J¼9.6 Hz); 13C NMR
(75 MHz, CDCl3):
d 0.3, 0.7, 23.6, 26.9, 55.0, 73.7, 117.1, 143.6, 157.5;
IR (neat) 2959, 2869, 1665, 1252, 1208, 1088, 978, 845 cmꢁ1
.
3.2.12. 1,3-Bis(trimethylsiloxy)-1-methoxy-2-ethylhexa-1,3-
diene (3j)
[Method B] The reaction of methyl 2-ethyl-3-oxohexanoate
(2.40 g, 10 mmol) gave the desired product 3i (2.79 g, 88%).
Colorless oil; bp 63–69 ꢀC/0.1 mmHg; 1H NMR (300 MHz,
CDCl3):
d
0.14 (9H, s), 0.21 (9H, s), 0.94 (3H, t, J¼7.2 Hz), 0.95 (3H, t,
Colorless oil; 1H NMR:
d
0.87 (3H, t, J¼6.9 Hz), 1.17–1.36 (12H,
J¼7.6 Hz), 2.05 (2H, q, J¼7.2 Hz), 2.06 (2H, quin, J¼7.6 Hz), 3.52 (3H,
m), 1.52–1.65 (2H, m), 1.59 (3H, s), 2.53 (1H, dt, J¼17.9, 7.2 Hz), 2.64
s), 4.57 (1H, t, J¼7.2 Hz); 13C NMR (75 MHz, CDCl3):
d
0.2, 0.4, 13.8,
(1H, dt, J¼17.9, 7.2 Hz), 3.79 (3H, s), 4.21 (1H, br s); 13C NMR:
d 14.1,
14.4, 18.9, 20.9, 56.2, 102.2, 114.0, 145.3, 151.0; IR (neat) 2963, 2934,
2903, 2874, 1655, 1252, 1211, 1173, 1115, 1084, 1046, 961, 920, 845,
21.9, 22.6, 23.5, 29.0, 29.2, 29.3, 29.4, 31.8, 36.3, 53.2, 80.9, 171.9,
207.2; IR (neat) 3470, 2986, 2926, 2856, 1750, 1456, 1265,
666 cmꢁ1
.
1159 cmꢁ1
.
3.2.13. Methyl 2,2-dimethyl-3-(trimethylsiloxy)dodec-3-enoate
(6a-A) and methyl 2,2-dimethyl-3-oxododecanoate (6a-B)
3.2.16. Methyl 2,2,5,5-tetramethyl-3-(trimethylsiloxy)hept-3,6-
dienoate (7a-A) and methyl 2,2,5,5-tetramethyl-3-oxohept-6-
enoate (7a-B)
1-Methoxy-1-trimethylsiloxy-2-methyl-1-propene (5a, 418 mg,
2.4 mmol) was added to a stirred solution of methyl decanoate
(186 mg, 1.0 mmol) and NaOH (2 mg, 0.05 mmol) in DMF (0.2 mL)
at 20–25 ꢀC under an Ar atmosphere, followed by being stirred at
the same temperature for 1 h. The mixture was quenched with
water, which was extracted twice with ether. The combined organic
phase was washed with water, brine, dried (Na2SO4), and concen-
trated. The obtained crude product was purified by SiO2 column
chromatography (hexane/AcOEt¼80:1) to give the desired products
6a-A (267 mg, 81%) and 6a-B (46 mg, 18%).
Following the procedure for preparing 6a-A and 6a-B, the re-
action between methyl 3,3-dimethyl-4-pentenoate (142 mg,1.0 mmol)
and 5a (418 mg, 2.4 mmol) gave the desired products 7a-A (147 mg,
52%) and 7a-B (76 mg, 36%).
Compound 7a-A. Colorless oil; 1H NMR:
d 0.16 (9H, s),1.16 (6H, s),
1.31 (6H, s), 3.66 (3H, s), 4.52 (1H, s), 4.86 (1H, dd, J¼1.4, 10.7 Hz),
4.96 (1H, dd, J¼1.4, 17.5 Hz), 5.95 (1H, dd, J¼10.7, 17.5 Hz); 13C NMR:
d
1.7, 25.2, 28.5, 36.8, 49.0, 52.0, 109.5, 114.1, 147.9, 151.6, 176.6; IR
(neat) 2957, 1717, 1468, 1264, 1150 cmꢁ1
.
Compound 6a-A. Colorless oil; 1H NMR:
d
0.17 (9H, s), 0.88 (3H, t,
Compound 7a-B. Colorless oil; 1H NMR:
d 1.11 (6H, s), 1.32 (6H, s),
J¼6.9 Hz), 1.21–1.36 (12H, m), 1.30 (6H, s), 1.97 (2H, q, J¼6.9 Hz),
2.45 (2H, s), 3.71 (3H, s), 4.90 (1H, dd, J¼1.4, 10.7 Hz), 4.93 (1H, dd,
3.66 (3H, s), 4.60 (1H, t, J¼6.9 Hz); 13C NMR:
d
0.8, 14.1, 22.7, 24.4,
J¼1.4, 17.5 Hz), 5.91 (1H, dd, J¼10.7, 17.5 Hz); 13C NMR:
d 21.9, 26.9,
26.1, 29.3, 29.4, 29.5, 29.7, 31.8, 48.4, 51.9, 106.6, 152.6, 176.5; IR
35.9, 48.7, 52.3, 56.1, 110.4, 147.2, 174.2, 206.1; IR (neat) 2959, 1738,
(neat) 2924, 2857, 1740, 1667, 1252, 1153, 845 cmꢁ1
Compound 6a-B. Colorless oil; 1H NMR:
0.88 (3H, t, J¼6.9 Hz),
.
1655, 1252, 1148, 1121, 845 cmꢁ1
.
d
1.14–1.32 (12H, m), 1.36 (6H, s), 1.52–1.61 (2H, m), 2.43 (2H, t,
3.2.17. Methyl 2-ethyl-2,5,5-trimethyl-3-(timethylsiloxy)hept-3,6-
dienoate (7b-A) and methyl 2-ethyl-2,5,5-trimethyl-3-oxohept-6-
enoate (7b-B)
J¼7.2 Hz), 3.72 (3H, s); 13C NMR:
d 14.1, 20.3, 21.9, 22.6, 23.8, 29.1,
29.3, 29.4, 31.85, 37.9, 52.4, 55.6, 174.3, 208.1; IR (neat) 2921, 2857,
1747, 1716, 1466, 1267, 1150 cmꢁ1
.
Following the procedure for preparing 6a-A and 6a-B, the re-
action between methyl 3,3-dimethyl-4-pentenoate (142 mg,
1.0 mmol) and 5b (452 mg, 2.4 mmol) gave the desired products
7b-A (242 mg, 81%) and 7b-B (14 mg, 6%).
3.2.14. Methyl 2-ethyl-2-methyl-3-(trimethylsiloxy)dodec-3-enoate
(6b-A) and methyl 2-ethyl-2-methyl-3-oxododecanoate (6b-B)
Followingtheprocedureforpreparing6a-Aand6a-B, thereaction
between methyl decanoate (186 mg, 1.0 mmol) and 1-methoxy-1-
trimethylsiloxy-2-methyl-1-butene (5b, 452 mg, 2.4 mmol) gave the
desired products 6b-A (309 mg, 90%) and 6b-B (21 mg, 8%).
Compound 7b-A. Colorless oil; 1H NMR:
d 0.15 (9H, s), 0.80 (3H, t,
J¼7.6 Hz),1.16 (3H, s, J¼6.9 Hz),1.67 (3H, s),1.24 (3H, s),1.72 (1H, dq,
J¼7.6, 13.8 Hz), 1.77 (1H, dq, J¼7.6, 13.8 Hz), 4.86 (1H, dd, J¼1.4,
10.7 Hz), 4.97 (1H, dd, J¼1.4, 17.4 Hz), 5.96 (1H, dd, J¼10.7, 17.4 Hz);

5604
K. Takai et al. / Tetrahedron 65 (2009) 5596–5607
13C NMR:
d
1.8, 8.5, 21.5, 28.3, 28.7, 28.8, 37.0, 51.8, 52.9, 109.5, 115.6,
Yellow oil; 1H NMR:
d 1.12–1.48 (5H, m), 1.51–1.84 (5H, m), 1.58
148.0, 149.9, 176.3; IR (neat) 2965, 1736, 1651, 1252, 1115, 847 cmꢁ1
.
(3H, s), 2.85 (1H, tt, J¼11.4, 3.4 Hz), 3.77 (3H, s), 4.24 (1H, br s); 13C
Compound 7b-B. Colorless oil; 1H NMR:
d
0.81 (3H, t,
NMR: d 21.8, 25.4, 25.4, 25.5, 29.4, 29.5, 45.0, 53.1, 80.8, 171.8, 210.0;
J¼7.6 Hz), 0.87 (3H, t, J¼6.9 Hz), 1.11 (6H, s), 1.28 (3H, s), 1.75 (1H,
dq, J¼7.6, 13.8 Hz), 1.92 (1H, dq, J¼7.6, 13.8 Hz), 2.40 (1H, d,
J¼17.6 Hz), 2.48 (1H, dd, J¼17.6 Hz), 3.71 (3H, s), 4.90 (1H, dd,
J¼1.4, 10.7 Hz), 4.93 (1H, dd, J¼1.4, 17.5 Hz), 5.92 (1H, dd, J¼10.7,
IR (neat) 3474, 2934, 1720, 1450, 1265, 1149, 1114, 1059, 993 cmꢁ1
.
3.2.24. Methyl 2,2-dimethyl-5-(2-methyl-1,3-dioxolane-2-yl)-3-
(trimethylsiloxy)pent-3-enoate (10a-A) and methyl 2,2-dimethyl-5-
(2-methyl-1,3-dioxolane-2-yl)-3-oxopentanoate (10a-B)
17.5 Hz); 13C NMR:
d 8.6, 18.1, 26.9, 27.7, 35.9, 49.2, 52.2, 60.5,
110.4, 147.3, 173.6, 205.9; IR (neat) 2971, 2883, 1716, 1460, 1242,
Following the procedure for preparing 6a-A and 6a-B, the re-
action between methyl 3-(2-methyl-1,3-dioxolane-2-yl)propa-
noate (174 mg, 1.0 mmol) and 5a (418 mg, 2.4 mmol) gave the
desired products 10a-A (214 mg, 68%) and 10a-B (63 mg, 20%).
1150 cmꢁ1
.
3.2.18. Methyl 2-hydroxy-2,5,5-trimethyl-3-oxohept-6-enoate (7c)
Following the procedure for preparing 6c, the reaction between
methyl 3,3-dimethyl-4-pentenoate (71 mg, 0.5 mmol) and 5c
(436 mg, 1.5 mmol) gave the desired product 7c (81 mg, 76%).
Compound 10a-A. Colorless oil; 1H NMR:
d 0.18 (9H, s), 1.30 (3H,
s),1.32 (6H, s), 2.32 (2H, d, J¼6.9 Hz), 3.65 (3H, s), 3.89–3.96 (4H, m),
4.73 (1H, t, J¼6.9 Hz); 13C NMR:
d 0.9, 23.6, 24.4, 36.0, 48.5, 51.9,
64.7, 101.1, 110.0, 154.7, 176.2; IR (neat) 2982, 2882, 1738, 1254, 1136,
Colorless oil; 1H NMR:
d
1.13 (6H, s), 1.56 (3H, s), 2.56 (1H, d,
J¼17.5 Hz), 2.68 (1H, d, J¼17.5 Hz), 3.78 (3H, s), 4.20 (1H, br s, OH),
845 cmꢁ1
Compound 10a-B. Colorless oil; 1H NMR:
s), 1.93–1.98 (2H, m) 2.51–2.56 (2H, m), 3.71 (3H, s), 3.86–3.97 (4H,
m); 13C NMR:
22.1, 23.8, 32.5, 32.7, 52.4, 55.6, 64.6, 109.2, 174.2,
207.6; IR (neat) 2982, 2882, 1738, 1254, 1136, 845 cmꢁ1
.
4.93 (1H, dd, J¼10.7, 1.0 Hz), 4.95 (1H, dd, J¼17.5, 1.0 Hz), 5.89 (1H,
d
1.30 (3H, s), 1.37 (6H,
dd, J¼17.5, 10.7 Hz); 13C NMR:
d 21.8, 26.8, 27.0, 36.0, 47.0, 53.2, 81.3,
110.9, 146.6, 171.8, 205.3; IR (neat) 3478, 2961, 1755, 1732, 1451,
d
1263, 1163, 1041, 916 cmꢁ1
.
.
3.2.19. Methyl 2,2-dimethyl-3-oxo-3-phenylpropanoate (8a)
Following the procedure for preparing 6a-B, the reaction be-
tween methyl benzoate (136 mg, 1.0 mmol) and 5a (214 mg,
1.2 mmol) gave the desired product 8a (175 mg, 85%).
3.2.25. Methyl 2-ethyl-2-methyl-5-(2-methyl-1,3-dioxolane-2-yl)-
3-(trimethylsiloxy)pent-3-enoate (10b-A) and methyl 2-ethyl-2-
methyl-5-(2-methyl-1,3-dioxolane-2-yl)-3-oxopentanoate (10b-B)
Following the procedure for preparing 6a-A and 6a-B, the re-
action between methyl 3-(2-methyl-1,3-dioxolane-2-yl)propa-
noate (174 mg, 1.0 mmol) and 5b (452 mg, 2.4 mmol) gave the
desired products 10b-A (259 mg, 78%) and 10b-B (34 mg, 13%).
Colorless oil; 1H NMR:
d
1.55 (6H, s), 3.64 (3H, s), 7.39–7.45 (2H,
m), 7.49–7.55 (1H, m), 7.80–7.84 (2H, m); 13C NMR:
23.9, 52.5,
53.2, 128.5, 132.7, 135.1, 137.3, 175.6, 197.5; IR (neat) 2996, 2951,
1740, 1686, 1271, 1142, 708 cmꢁ1
d
.
Compound 10b-A. Colorless oil; 1H NMR:
d 0.17 (9H, s), 0.81 (3H,
t, J¼7.6 Hz), 1.25 (3H, s), 1.30 (3H, s), 1.74 (1H, dq, J¼7.6, 13.4 Hz),
1.80 (1H, dq, J¼7.6, 13.4 Hz), 2.29 (1H, dd, J¼6.5, 14.6 Hz), 2.38 (1H,
dd, J¼7.6, 14.6 Hz), 3.65 (3H, s), 3.92–3.95 (4H, m), 4.69 (1H, dd,
3.2.20. Methyl 2-ethyl-2-methyl-3-oxo-3-phenylpropanoate (8b)
Following the procedure for preparing 6a-B, the reaction
between methyl benzoate (136 mg, 1.0 mmol) and 5b (226 mg,
1.2 mmol) gave the desired product 8b (194 mg, 94%).
J¼6.5, 7.6 Hz); 13C NMR:
d 0.9, 8.8, 20.5, 23.7, 28.7, 36.0, 51.7, 52.6,
64.7, 102.2, 110.4, 153.5, 175.9; IR (neat) 2978, 2884, 1736, 1667,
Colorless oil; 1H NMR:
d
0.82 (3H, t, J¼7.6 Hz), 1.51 (3H, s), 2.05
1252, 1123, 849 cmꢁ1
.
(1H, dq, J¼7.6, 14.1 Hz), 2.10 (1H, dq, J¼7.6, 14.1 Hz), 3.63 (3H, s),
Compound 10b-B. Colorless oil; 1H NMR:
d
0.82 (3H, t, J¼7.6 Hz),
7.38–7.44 (2H, m), 7.49–7.54 (1H, m), 7.80–7.84 (2H, m); 13C NMR:
1.30 (3H, s), 1.32 (3H, s), 1.81 (1H, dq, J¼7.6, 14.1 Hz), 1.90–2.02 (2H,
m), 1.95 (1H, dq, J¼7.6, 14.1 Hz), 2.42–2.61 (2H, m), 3.65 (3H, s),
d
8.2, 20.5, 29.3, 52.3, 57.3, 128.4, 128.5, 132.6, 135.7, 174.9, 197.5; IR
(neat) 2976, 2951, 1738, 1684, 1449, 1250, 1130, 702 cmꢁ1
.
3.86–3.97 (4H, m); 13C NMR:
d 8.6, 18.4, 23.9, 27.8, 32.7, 33.0, 52.3,
60.0, 64.6, 109.2, 173.6, 207.4; IR (neat) 2982, 2883, 1743, 1715, 1246,
3.2.21. Methyl 3-cyclohexyl-2,2-dimethyl-3-oxopropanoate (9a)21
Following the procedure for preparing 6a-B, the reaction be-
tween methyl cyclohexanoate (142 mg, 1.0 mmol) and 5a (418 mg,
2.4 mmol) gave the desired product 9a (176 mg, 83%).
1150, 1055 cmꢁ1
.
3.2.26. Methyl 2-hydroxy-2-methyl-5-(2-methyl-1,3-dioxolane-2-
yl)-3-oxopentanoate (10c)
Following the procedure for preparing 6c, the reaction
between methyl 3-(2-methyl-1,3-dioxolane-2-yl)propanoate
(87 mg, 0.5 mmol) and 5c (436 mg, 1.5 mmol) gave the desired
product 10c (92 mg, 76%).
Colorless oil; 1H NMR:
d
1.17–1.48 (5H, m), 1.35 (6H, s), 1.58–1.79
(5H, m), 2.58 (1H, tt, J¼3.4, 11.4 Hz), 3.71 (3H, s); 13C NMR:
d 21.7,
25.6, 30.2, 47.4, 52.2, 56.0, 174.3, 211.2; IR (neat) 2936, 1746, 1711,
1453, 1265, 1150, 993 cmꢁ1
.
Pale yellow oil; 1H NMR:
d
1.30 (3H, s), 1.59 (3H, s), 1.99 (2H, t,
J¼7.2 Hz), 2.63 (1H, dt, J¼17.9, 7.2 Hz), 2.73 (1H, dt, J¼17.9, 7.2 Hz),
3.76 (3H, s), 3.82–3.96 (4H, m), 4.24 (1H, br s); 13C NMR:
22.1, 23.8,
31.0, 32.6, 53.3, 64.6, 81.1, 109.0, 171.9, 206.9; IR (neat) 3470, 2986,
2957, 1724, 1452, 1381, 1261, 1149, 1045, 862 cmꢁ1
3.2.22. Methyl 3-cyclohexyl-2-ethyl-2-methyl-3-
oxopropanoate (9b)
Following the procedure for preparing 6a-B, the reaction be-
tween methyl cyclohexanoate (142 mg, 1.0 mmol) and 5b (452 mg,
2.4 mmol) gave the desired product 9b (186 mg, 82%).
d
.
Colorless oil; 1H NMR:
d
0.81 (3H, t, J¼7.6 Hz), 1.16–1.47 (5H, m),
3.2.27. Methyl 2,2-dimethyl-11-(oxirane-2-yl)-3-(trimethylsiloxy)-
undec-3-enoate (11a-A) and methyl 2,2-dimethyl-11-(oxirane-
2-yl)-3-oxoundecanoate (11a-B)
1.31 (3H, s), 1.58–1.78 (5H, m) 1.76 (1H, dq, J¼7.6, 14.1 Hz), 1.96 (1H,
dq, J¼7.6, 14.1 Hz), 2.56 (1H, tt, J¼3.4, 11.4 Hz), 3.71 (3H, s); 13C
NMR:
d
8.6,17.9, 25.6, 27.3, 29.9, 30.4, 47.5, 52.0, 60.4,173.6, 211.1; IR
Followingtheprocedureforpreparing6a-Aand6a-B, thereaction
between methyl 9-(oxiran-2-yl)nonanoate (214 mg, 1.0 mmol) and
5a (418 mg, 2.4 mmol) gave the desired products 11a-A (124 mg,
35%) and 11a-B (137 mg, 48%).
(neat) 2936, 1744, 1709, 1453, 1244, 1148 cmꢁ1
.
3.2.23. Methyl 3-cyclohexyl-2-hydroxy-2-methyl-3-
oxopropanoate (9c)
Compound 11a-A. Colorless oil; 1H NMR:
d 0.17 (9H, s), 1.22–1.61
Following the procedure for preparing 6c, the reaction between
methyl cyclohexanoate (71 mg, 0.5 mmol) and 5c (436 mg,
1.5 mmol) gave the desired product 9c (76 mg, 71%).
(12H, m), 1.30 (6H, s), 1.93–2.00 (2H, m), 2.46 (1H, dd, J¼5.2, 2.8 Hz),
2.74 (1H, dd, J¼5.2, 4.1 Hz), 2.87–2.93 (1H, m), 3.66 (3H, m), 4.59
(1H, t, J¼6.9 Hz); 13C NMR:
d 0.8, 24.4, 25.9, 26.0, 29.3, 29.4, 29.6,

K. Takai et al. / Tetrahedron 65 (2009) 5596–5607
5605
32.5, 47.1, 48.4, 51.9, 52.4, 106.5, 152.6, 176.5; IR (neat) 2930, 2856,
1738, 1666, 1460, 1253, 1155, 1099, 898, 848 cmꢁ1
Compound 11a-B. Colorless oil; 1H NMR:
1.21–1.60 (14H, m),
Compound 12b-B. Colorless oil; 1H NMR:
d
0.81 (3H, t, J¼7.6 Hz),
.
1.18–1.34 (4H, m), 1.30 (3H, s), 1.43 (9H, s), 1.49–1.62 (4H, m), 1.79
(1H, dq, J¼14.1, 7.6 Hz), 1.94 (1H, dq, J¼14.1, 7.6 Hz), 2.18 (2H, t,
J¼7.6 Hz), 2.37 (1H, dt, J¼19.6, 7.2 Hz), 2.43 (1H, dt, J¼19.6, 7.2 Hz),
d
1.35 (6H, s), 2.42 (2H, t, J¼7.2 Hz), 2.45 (1H, dd, J¼2.8, 5.2 Hz), 2.74
(1H, dd, J¼3.8, 5.2 Hz), 2.85–2.92 (1H, m), 3.71 (3H, s); 13C NMR:
3.71 (3H, s); 13C NMR:
d 8.6, 18.3, 23.6, 24.9, 27.7, 28.1, 28.8, 28.8,
d
21.9, 23.8, 25.9, 29.1, 29.3, 29.3, 32.5, 37.9, 47.1, 52.4, 55.6, 174.3,
35.5, 38.2, 52.2, 59.9, 79.9, 173.1, 173.7, 207.8; IR (neat) 2969, 2946,
208.1; IR (neat) 2984, 2930, 2856, 1745, 1714, 1466, 1267, 1194,
1149 cmꢁ1
1716, 1460, 1367, 1248, 1153 cmꢁ1
.
.
3.2.31. Methyl 3-[3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropyl]-
2,2-dimethyl-3-oxopropnoate (13a-B)
3.2.28. Methyl 2-ethyl-2-methyl-11-(oxirane-2-yl)-3-
(trimethylsiloxy)undec-3-enoate (11b-A) and methyl 2-ethyl-2-
methyl-11-(oxirane-2-yl)-3-oxoundecanoate (11b-B)
Followingtheprocedureforpreparing6a-Aand6a-B, thereaction
between methyl 9-(oxiran-2-yl)nonanoate (214 mg, 1.0 mmol) and
5b (452 mg, 2.4 mmol) gave the desired products 11b-A (92 mg, 25%)
and 11b-B (200 mg, 67%).
Following the procedure for preparing 6a-B, the reaction be-
tween methyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-
carboxylate (223 mg, 1.0 mmol) and 5a (418 mg, 2.4 mmol) gave
the desired product 13a-B (261 mg, 89%).
Diastereomixture (ca. trans/cis 3:2); colorless oil; 1H NMR:
d 1.11
(trans, 3Hꢂ3/5, s), 1.13 (cis, 3Hꢂ2/5, s), 1.18 (trans, 3Hꢂ3/5, s), 1.23
(cis, 3Hꢂ2/5, s), 1.34 (cis, 3Hꢂ2/5, s), 1.35 (trans, 3Hꢂ3/5, s), 1.36
(cis, 3Hꢂ2/5, s), 1.38 (trans, 3Hꢂ3/5, s), 1.86 (trans, 1Hꢂ3/5, d,
J¼5.5 Hz), 2.06 (cis, 1Hꢂ2/5, d, J¼8.26 Hz), 2.12 (cis, 1Hꢂ2/5, dd,
J¼8.3, 8.3 Hz), 2.40 (trans, 1Hꢂ3/5, dd, J¼5.5, 7.9 Hz), 3.73 (3H, s),
5.62 (trans, 1Hꢂ3/5, d, J¼7.9 Hz), 6.32 (cis, 1Hꢂ2/5, d, J¼8.3 Hz); 13C
Compound 11b-A. Colorless oil; 1H NMR:
d 0.16 (9H, s), 0.80 (3H,
t, J¼7.6 Hz), 1.23 (3H, s), 1.23–1.57 (12H, m), 1.70 (1H, dq, J¼13.4,
7.6 Hz),1.78 (1H, dq, J¼13.4, 7.6 Hz), 1.87–2.06 (2H, m), 2.46 (1H, dd,
J¼5.2, 2.8 Hz), 2.74 (1H, dd, J¼5.2, 4.0 Hz), 2.86–2.93 (1H, m), 3.65
(3H, s), 4.55 (1H, t, J¼6.9 Hz); 13C NMR:
d 0.9, 8.8, 20.5, 25.9, 26.1,
28.7, 29.2, 29.4, 29.7, 32.5, 47.1, 51.7, 52.4, 52.5, 107.4, 151.4, 151.5,
176.0; IR (neat) 2928, 2856, 1736, 1664, 1460, 1350, 1251, 1149, 941,
NMR: d 14.3, 19.2, 21.4, 21.7, 21.8, 22.5, 28.4, 30.8, 32.6, 33.6, 35.7,
36.7, 39.7, 52.5, 55.8, 56.4, 120.5, 122.0, 124.7, 126.7, 174.1, 174.2,
203.0, 203.7; IR (neat) 2980, 2955, 2937, 1741, 1699, 1462, 1386,
850, 756 cmꢁ1
.
Compound 11b-B. Colorless oil; 1H NMR:
d
0.82 (3H, t, J¼7.6 Hz),
1263, 1149, 1101, 918, 881 cmꢁ1
.
1.16–1.62 (14H, m), 1.30 (3H, s), 1.80 (1H, dq, J¼14.1, 7.6 Hz), 1.94
(1H, dq, J¼14.1, 7.6 Hz), 2.39 (1H, t, J¼7.2 Hz), 2.31–2.48 (1H, m),
2.45 (1H, dd, J¼5.2, 2.8 Hz), 2.74 (1H, dd, J¼5.2, 4.1 Hz), 3.71 (3H, s);
3.2.32. Methyl 2-[3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropne-
carbonyl]-2-methylbutanoate (13b-B)
13C NMR:
d
8.6, 18.3, 23.8, 25.9, 27.7, 29.0, 29.3, 29.3, 32.4, 38.3, 47.1,
Following the procedure for preparing 6a-B, the reaction be-
tween methyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-
carboxylate (223 mg, 1.0 mmol) and 5b (452 mg, 2.4 mmol) gave
the desired product 13b-B (261 mg, 89%).
52.2, 52.3, 59.9, 173.7, 207.9; IR (neat) 2930, 2856, 1741, 1712, 1460,
1246, 1147, 1057, 835 cmꢁ1
.
3.2.29. 10-tert-Butyl 1-methyl 2,2-dimethyl-3-(trimethylsiloxy)dec-
3-enedioate (12a-A) and 10-tert-butyl 1-methyl 2,2-dimethyl-3-
oxodecanedioate (12a-B)
Diastereomixture (ca. major/minor 3:2); colorless oil; 1H NMR:
d
0.76–0.90 (3Hꢂ3/5, m, þ3Hꢂ2/5, m), 1.08–1.23 (6Hꢂ3/5, m,
þ6Hꢂ2/5, m), 1.30–1.38 (3Hꢂ3/5, m, þ3Hꢂ2/5, m), 1.71–2.04
(1Hꢂ3/5, m, þ2Hꢂ3/5, m, þ2Hꢂ2/5, m), 2.05–2.17 (1Hꢂ2/5, m,
þ1Hꢂ2/5, m), 2.34–2.45 (1Hꢂ3/5, m), 3.73 (3H, s), 5.62 (1Hꢂ3/5, d,
Following the procedure for preparing 6a-A and 6a-B, the re-
action between 8-tert-butyl 1-methyl octanoate (244 mg,
1.0 mmol) and 5a (418 mg, 2.4 mmol) gave the desired products
12a-A (168 mg, 44%) and 12a-B (129 mg, 41%).
J¼7.91 Hz), 6.25–6.35 (1Hꢂ2/5, m); 13C NMR:
d 8.5, 8.6; 14.3, 17.8,
17.9, 18.2, 19.1, 22.5, 22.6, 27.5, 27.7, 28.4, 30.8, 30.8, 32.5, 32.7, 33.6,
34.0, 35.6, 35.7, 36.9, 37.0, 39.8, 40.0, 52.3, 60.1, 60.3, 60.6, 60.7,
120.4, 120.4, 122.2, 124.7, 126.8, 173.5, 173.6, 173.6, 173.7, 202.8,
203.3, 203.5, 203.7; IR (neat) 2955, 2881, 1739, 1699, 1458, 1244,
Compound 12a-A. Colorless oil; 1H NMR:
d 0.17 (9H, s), 1.23–1.37
(4H, m), 1.30 (6H, s), 1.44 (9H, s), 1.50–1.65 (2H, m), 1.94–2.01 (2H,
m), 2.20 (2H, t, J¼7.9 Hz), 3.66 (3H, s), 4.59 (1H, t, J¼6.9 Hz); 13C
NMR:
d
0.8, 24.4, 25.0, 25.9, 28.1, 28.8, 29.4, 35.6, 48.3, 51.8, 79.9,
1149, 1099, 1051, 914, 879 cmꢁ1
.
106.2, 152.7, 173.2, 176.4; IR (neat) 2978, 2935, 2858, 1736, 1666,
1253, 1155, 846 cmꢁ1
Compound 12a-B. Colorless oil; 1H NMR:
.
3.2.33. Methyl 5-(1H-indol-3-yl)-2,2-dimethyl-3-oxo-
pentanoate (14)
d
1.18–1.38 (4H, m),1.35
(6H, s), 1.43 (9H, s), 1.49–1.64 (4H, m), 2.19 (2H, t, J¼7.6 Hz), 2.42
Following the procedure for preparing 6a-B, the reaction be-
tween 3-[(1-tert-butyldimethylsilyl)indol-3-yl]propanoate (318 mg,
1.0 mmol) and 5a (418 mg, 2.4 mmol) gave the desired crude
product, which was added to a stirred solution of TBAF (2.0 mmol)
in THF (3.0 mL) at 0–5 ꢀC, followed by being stirred at 20–25 ꢀC for
1 h. A similar work up gave the desired product 14 (183 mg, 67%).
(2H, t, J¼7.2 Hz), 3.72 (3H, s); 13C NMR:
d 21.9, 23.6, 24.8, 28.0, 28.7,
28.8, 35.4, 37.7, 52.3, 55.5, 79.9, 173.1, 174.2, 207.9; IR (neat) 2980,
2937, 2864, 1712, 1460, 1367, 1259, 1157, 848, 734 cmꢁ1
.
3.2.30. 10-tert-Butyl 1-methyl 2-ethyl-2-methyl-3-(trimethylsiloxy)-
dec-3-enedioate (12b-A) and 10-tert-butyl 1-methyl 2-ethyl-
2-methyl-3-oxodecanedioate (12b-B)
Yellow oil; 1H NMR:
d
1.33 (6H, s), 2.85 (2H, d, J¼7.2 Hz), 3.07
(2H, d, J¼7.2 Hz), 3.57 (3H, s), 6.98 (1H, d, J¼2.0 Hz), 7.09–7.21 (2H,
m), 7.35 (1H, d, J¼7.9 Hz), 7.56 (1H, d, J¼7.91 Hz), 7.91–8.06 (1H, br);
Following the procedure for preparing 6a-A and 6a-B, the re-
action between 8-tert-butyl 1-methyl octanoate (44 mg, 1.0 mmol)
and 5b (452 mg, 2.4 mmol) gave the desired products 12b-A
(195 mg, 49%) and 12b-B (135 mg, 41%).
13C NMR:
d 14.2, 19.6, 21.8, 38.8, 52.3, 55.6, 60.4, 111.1, 115.1, 118.6,
119.3, 121.6, 122.0, 127.1, 136.3, 174.1, 207.6; IR (neat) 3412, 2988,
2951, 1711, 1458, 1271, 1149, 1068, 744 cmꢁ1
.
Compound 12b-A. Colorless oil; 1H NMR:
d 0.16 (9H, s), 0.79
(3H, t, J¼7.6 Hz), 1.22 (3H, s), 1.25–1.39 (4H, m), 1.43 (9H, s),
1.50–1.65 (2H, m), 1.69 (1H, dq, J¼13.8, 7.6 Hz), 1.77 (1H, dq,
J¼13.8, 7.6 Hz), 1.87–2.06 (2H, m), 2.19 (2H, t, J¼7.2 Hz), 3.65
3.2.34. Methyl 4-(benzyloxy)-2,2-dimethyl-3-(trimethylsiloxy)-3-
butenoate (15)
Following the procedure for preparing 6a-A, the reaction be-
tween methyl 2-(benzyloxy)acetate (180 mg, 1.0 mmol) and 5a
(418 mg, 2.4 mmol) gave the desired product 15 (268 mg, 83%).
(3H, s), 4.55 (1H, t, J¼7.2 Hz); 13C NMR:
d 0.9, 8.8, 20.5, 25.0,
25.9, 28.1, 28.7, 28.8, 29.4, 35.6, 51.7, 52.5, 79.9, 107.2, 151.6,
173.2, 176.0; IR (neat) 2976, 2938, 1732, 1664, 1460, 1251, 1152,
(Z/E¼95:5); colorless oil; 1H NMR:
d
0.11 (9Hꢂ19/20, s, Z), 0.17
1119, 844 cmꢁ1
.
(9Hꢂ1/20, s, E), 1.27 (6H, s), 3.66 (3H, s), 4.58 (2Hꢂ1/20, s, E), 4.73

5606
K. Takai et al. / Tetrahedron 65 (2009) 5596–5607
(2Hꢂ19/20, s, Z), 5.73 (1Hꢂ19/20, s, Z), 5.84 (1Hꢂ1/20, s, E), 7.21–
7.40 (5H, m); 13C NMR:
0.6, 23.5, 46.3, 51.9, 73.9,127.2,127.6,127.9,
128.3, 137.2, 139.0, 176.3; IR (neat) 2978, 1738, 1157, 848, 752 cmꢁ1
3.2.40. Methyl 4-(1-hydroxyhexyl)-2,2-dimethyl-3-
d
oxododecanoate (24)
.
Colorless oil; 1H NMR:
d
0.78 (6H, m), 1.10–1.73 (22H, m), 1.40
(6H, s), 2.20–2.64 (1H, br s), 2.78–2.95 (1H, m), 3.62–3.76 (1H, m)
3.72 (3H, s); 13C NMR:
13.99, 14.03, 22.00, 22.21, 22.27, 22.31,
3.2.35. (S)-Methyl 4-(dibenzylamino)-2,2-dimethyl-3-
oxopentanoate (16)
Following the procedure for preparing 6a-B, the reaction be-
tween methyl (S)-methyl 2-(dibenzylamino)propanoate (142 mg,
0.5 mmol) and 5a (209 mg, 1.2 mmol) at 0–5 ꢀC for 30 min gave the
desired product 16 (150 mg, 85%).
d
22.54, 22.60, 25.73, 25.90, 26.23, 27.30, 28.33, 29.19, 29.33, 29.59,
29.73, 30.00, 31.70, 31.77, 34.39, 35.73, 51.60, 51.87, 52.35, 56.65,
56.90, 71.62, 72.02, 173.46, 173.50, 213.06, 213.79; IR (neat) 3524,
2928, 1739, 1703, 1466, 1149 cmꢁ1
.
HPLC analysis [flow rate 0.30 mL /min, solvent: hexane/2-
3.2.41. Methyl 4-(benzyloxy)-5-hydroxy-2,2-dimethyl-3-oxo-5-
propanol¼99:1, tR(racemic)¼19.99 and 20.70 min, tR(16)¼
phenylpentanoate (25)
23
19.27 min] 95% ee. Pale yellow oil; [
a
]
ꢁ1.3 (c 1.16, CHCl3); 1H
syn/anti 25:75; colorless oil; 1H NMR:
d
1.19 (anti, 0.75ꢂ3H, s),
D
NMR:
d
1.20 (3H, d, J¼6.9 Hz), 1.26 (3H, s), 1.28 (3H, s), 3.53 (3H, s),
1.24 (syn, 0.25ꢂ3H, s), 1.30 (syn, 0.25ꢂ3H, s), 1.31 (anti, 0.75ꢂ3H, s),
3.37 (anti, 0.75ꢂ3H, s), 3.42 (syn, 0.25ꢂ3H), 3.99 (syn, 0.25ꢂ1H, d,
J¼10.7 Hz), 4.09 (anti, 0.75ꢂ1H, d, J¼10.7 Hz), 4.22 (anti, 0.75ꢂ1H,
d, J¼6.2 Hz), 4.32 (anti, 0.75ꢂ1H, d, J¼10.7 Hz), 4.34 (syn, 0.25ꢂ1H,
d, J¼10.7 Hz), 4.36 (syn, 0.25ꢂ1H, d, J¼2.8 Hz), 5.06 (anti, 0.75ꢂ1H,
d, J¼6.2 Hz), 5.25 (syn, 0.25ꢂ1H, d, J¼2.8 Hz), 7.01–7.17 (2H, m),
3.55 (1H, d, J¼13.8 Hz), 3.83 (1H, d, J¼13.8 Hz), 3.90 (1H, q,
J¼6.9 Hz), 7.20–7.37 (10H, m); 13C NMR:
d 10.4, 22.6, 22.7, 52.1, 54.1,
55.2, 57.4, 127.0, 128.2, 129.0, 139.3, 173.9, 209.1; IR (neat) 3028,
2982, 2939, 2841, 1743, 1709, 1454, 1383, 1267, 1151, 981 cmꢁ1
.
3.2.36. (S)-Methyl 4-(tert-butyldiphenylsiloxy)-2,2-dimethyl-3-
oxopentanoate (17)
Following the procedure for preparing 6a-B, the reaction be-
tween methyl (S)-methyl 2-(tert-butyldiphenylsiloxy)propanoate
(171 mg, 0.5 mmol) and 5a (209 mg, 1.2 mmol) at 0–5 ꢀC for 30 min
gave the desired product 17 (184 mg, 89%).
7.19–7.45 (8H, m); 13C NMR:
d 20.9, 21.1, 22.2, 22.4, 51.8, 52.0, 53.3,
53.5, 73.1, 74.2, 74.5, 75.8, 86.2, 87.3, 126.1, 127.5, 127.5, 127.6, 127.9,
128.1, 128.1, 128.3, 136.6, 136.9, 139.7, 140.8, 173.3, 173.8, 208.3,
210.1; IR (neat) 3499, 2949, 1749, 1714, 1454, 1151, 702 cmꢁ1
.
Acknowledgements
HPLC analysis [flow rate 0.50 mL/min, solvent: hexane/2-prop-
anol¼99.5:0.5, tR(racemic)¼11.71 and 12.64 min, tR(17)¼11.57 and
This research was partially supported by Grant-in-Aids for Sci-
entific Research on Basic Areas (B) ‘18350056’, Priority Areas (A)
‘17035087’ and ‘18037068’, and Exploratory Research ‘17655045’
from MEXT. We also thank Nissan Chemical Industries Ltd for
a helpful discussion.
24
12.45 min] 97% ee. Colorless oil; [
a]
þ21.7 (c 1.11, CHCl3); 1H NMR:
D
d
1.07 (9H, s), 1.18 (3H, d, J¼6.9 Hz), 1.33 (3H, s), 1.39 (3H, s)3.67 (3H,
s), 4.46 (1H, q, J¼6.9 Hz), 7.32–7.48 (6H, m), 7.60–7.73 (4H, m); 13C
NMR: d 19.2, 21.8, 22.4, 22.7, 26.9, 52.1, 53.1, 74.5, 127.5, 127.8, 129.8,
130.0, 132.5, 133.8, 135.9, 135.9, 173.7, 209.6; IR (neat) 3073, 3051,
2936, 2893, 2860, 1750, 1711, 1589, 1473, 1383, 1263, 1190 cmꢁ1
.
References and notes
3.2.37. Mukaiyama aldol reaction (Table 5, method A): general
procedure
1. (a) Smith, M. B.; March, J. Advanced Organic Chemistry, 6th ed.; Wiley: New
York, NY, 2007; p 1351; (b) Gennari, C. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2, pp 630–657.
2. Tanabe, Y.; Misaki, T.; Kurihara, M.; Iida, A. Chem. Commun. 2002, 1628.
3. Okabayashi, T.; Iida, A.; Takai, K.; Nawate, Y.; Misaki, T.; Tanabe, Y. J. Org. Chem.
2007, 72, 8142.
4. Iida, A.; Takai, K.; Okabayashi, Y.; Misaki, T.; Tanabe, Y. Chem. Commun. 2005,
3171.
5. (a) Ref. 1a, p 1132; (b) Fukuyama, T.; Lin, S. C.; Li, L. J. Am. Chem. Soc. 1990, 112,
7050; (c) Tokuyama, H.; Yokoyama, S.; Lin, S.; Lin, L.; Fukuyama, T. Tetrahedron
Lett. 2002, 8, 1121; (d) Tokuyama, H.; Miyazaki, T.; Yokoyama, S.; Fukuyama, T.
Synlett 2003, 1512.
TiCl4 (40 mL, 0.36 mmol) was added to a stirred solution of an
enol silyl ether (0.30 mmol) and an aldehyde (0.36 mmol) in CH2Cl2
(0.9 mL) at ꢁ45 ꢀC under an Ar atmosphere, followed by being
stirred at same temperature for 1 h. Water was added to the re-
action mixture, which was extracted with AcOEt. The organic phase
was washed with water, brine, dried (Na2SO4), and concentrated.
The obtained crude product was purified by silica gel column
chromatography to give the desired product.
6. Commercially available. Compared with ether solvents such as THF, dioxolane,
DME, etc. there are several advantages for process chemistry: Watanabe, K.;
Yamagiwa, N.; Torisawa, Y. Org. Process Res. Dev. 2007, 11, 251.
7. Langer, P. Synthesis 2002, 441.
3.2.38. Ti-direct aldol reaction (Table 5, method B)
TiCl4 (67
mL, 0.60 mmol) and Bu3N (130 mg, 0.70 mmol) were
8. Chan, T.-H.; Brownbridge, P. J. Chem. Soc., Chem. Commun. 1979, 578; (b) Dan-
ishefsky, S.; Harvey, D. F.; Quallich, G.; Uang, B. J. J. Org. Chem. 1984, 49, 393; (c)
Hagiwara, H.; Kimura, K.; Uda, H. J. Chem. Soc., Chem. Commun. 1986, 860; (d)
Enders, D.; Burkamp, F.; Runsink, J. Chem. Commun. 1996, 609; (e) Evans, D. A.;
Murry, J. A.; Kozlowski, M. C. J. Am. Chem. Soc. 1996, 118, 5814; (f) Kru¨ger, J.;
Carreira, E. M. J. Am. Chem. Soc. 1998, 120, 837; (g) Evans, D. A.; Kozlowski, M. C.;
Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem.
Soc. 1999, 121, 669.
9. (a) Langer, P.; Ko¨hler, V. Org. Lett. 2000, 1597; (b) Chan, T. H.; Brook, M. A.
Tetrahedron Lett. 1985, 26, 294; (c) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc.
1980, 3534; (d) Kan, G. J.; Chan, T. H. J. Org. Chem. 1985, 50, 452.
10. (a) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980, 3534; (b) Brownbridge,
P.; Chan, T.-H.; Brook, M. A.; Kang, G. J. Can. J. Chem. 1983, 61, 688; (c) Lee, S. D.;
Chan, T. H. Tetrahedron 1984, 40, 3611.
11. (a) Molander, G. A.; Siedem, C. S. J. Org. Chem. 1995, 60, 130; (b) Molander, G. A.;
Bessie`res, B.; Eastwood, P. R.; Nool, B. C. J. Org. Chem. 1999, 64, 4124.
12. (a) Langer, P.; Eckardt, T. Angew. Chem., Int. Ed. 2000, 39, 4343; (b) Langer, P.;
Freifeld, I.; Holtz, E. Synlett 2000, 501; (c) Langer, P.; Freifeld, I. Chem.dEur. J.
2001, 7, 565; (d) Langer, P.; Armbrust, H.; Eckardt, T.; Magull. Chem. Eur. J. 2002,
8, 1443.
13. (a) Langer, P.; Krummel, T. Chem. Commun. 2000, 967; (b) Langer, P.; Stoll, M.
Angew. Chem., Int. Ed. 1999, 38, 1803; (c) Langer, P.; Saleh, N. N. R. Org. Lett. 2000,
3333; (d) Langer, P.; Schneider, T.; Stoll, M. Chem.dEur. J. 2000, 6, 3204; (e)
Langer, P.; Eckardt, T. Synlett 2000, 844; (f) Langer, P.; Eckardt, T.; Schneider, T.;
Go¨bel, C.; Herbst-Irmer, R. J. Org. Chem. 2001, 66, 2222.
successively added to
a
stirred solution of -ketoester
a b
(0.50 mmol) in CH2Cl2 (1.5 mL) at 0–5 ꢀC under an Ar atmosphere,
followed by being stirred at the same temperature for 0.5 h. Alde-
hyde (0.60 mmol) was added to the mixture at the same temper-
ature. After stirring for 2 h, water was added to the mixture, which
was extracted with AcOEt. The organic phase was washed with
water, brine, dried (Na2SO4), and concentrated. The obtained crude
product was purified by silica gel column chromatography to give
the desired product.
3.2.39. Methyl 4-(hydroxy(phenyl)methyl)-2,2-dimethyl-3-
oxododecanoate (23)
Colorless oil; 1H NMR:
d
0.77–0.97 (1H, m), 0.85 (3H, t, J¼6.9 Hz),
0.99–1.53 (12H, m), 1.33 (3H, s), 1.35 (3H, s), 1.53–1.75 (1H, m),
3.08–3.26 (1H, m), 3.73 (3H, s), 4.94 (1H, d, J¼3.4 Hz), 7.20–7.40
(5H, m); 13C NMR:
d 14.0, 21.7, 21.9, 22.0, 22.6, 26.3, 27.7, 29.1, 29.2,
29.8, 31.7, 52.5, 53.5, 54.0, 56.7, 73.0, 75.2, 125.9, 126.3, 127.4, 127.8,
128.3, 128.4, 141.6, 173.4, 212.7; IR (neat) 3520, 2928, 1736, 1703,
1265, 1030, 702 cmꢁ1
.

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5607
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