A new route for the preparation of succinates

Article abstract of DOI:10.1055/s-0028-1083140

Succinates of the tertiary hydroxy group having a formyl group in the structure were conveniently synthesized by oxidative cleavage of dihydropyrans prepared from lactones via coupling of ketene acetal triflates and zinc homoenolates.

Full text of DOI:10.1055/s-0028-1083140

PAPER
3209
A New Route for the Preparation of Succinates
A
N
ewRoute fo
a
r
the Prepa
k
r
ation of Suc
e
cinates shi Shimizu,* Katsunori Murakoshi, Koji Yasui, Mikiko Sodeoka
RIKEN (The Institute of Physical and Chemical Research), Hirosawa 2-1,Wako, Saitama 351-0198, Japan
Fax +81(48)4679375; E-mail: tshimizu@riken.jp
Received 20 May 2008; revised 27 June 2008
CO2R3
O
Abstract: Succinates of the tertiary hydroxy group having a formyl
group in the structure were conveniently synthesized by oxidative
cleavage of dihydropyrans prepared from lactones via coupling of
ketene acetal triflates and zinc homoenolates.
O
n
CO2R3
O
n
O
O
R1
R1
R1
m
m
m
O
R2
R2
R2
Key words: succinates, dihydropyrans, esters, lactones, dihydroxy-
lations
m = 1–8
n = 1–5
5
6
7
Scheme 2 Synthetic plan for dicarboxylic acid diesters 7
Butanedioic acid monoesters, namely the hemisuccinates,
are found in several biologically active natural products
such as punctatin C,1 (–)-A26771B,2 gamahonolide B,3
and reveromycins.4 It was reported that the hemisuccinyl
group of reveromycin A, a selective isoleucyl-tRNS syn-
thetase inhibitor, is important for its strong activity.5 In
addition, hemisuccinates attract much attention as the pro-
drugs of steroids,6 anthracyclins,7,8 and taxol9–11 because
of their water-soluble properties. Several methods for
their preparation with succinic anhydride, succinic acid
monoester, succinyl chloride, and the carboxylate anion
have been reported.6–11 However, few methods are known
for the acylation of sterically hindered alcohols.12,13 We
have already reported an efficient preparation of the suc-
cinates 3 of hindered tertiary alcohols 1 with succinic acid
monoesters 2 in dichloromethane in the presence of N,N¢-
dicyclohexylcarbodiimide or 1,3-diisopropylcarbodiim-
ide and 4-(dimethylamino)pyridine under high pressure
(1.5 GPa) and the conversion of the succinates 3 into the
hemisuccinates 4 (Scheme 1).14
Oxidative cleavage of olefinic double bonds to give dicar-
bonyl compounds is one of the most useful chemical con-
versions. It was expected that the cyclic vinyl ethers 6
having an a-substituent with a terminal ester group might
be converted into the dicarboxylic acid diesters 7 that in-
clude a formyl group in their structure by oxidative cleav-
age of the double bond (Scheme 2). The cyclic vinyl
ethers 6 could be prepared by palladium-catalyzed cou-
pling of the ketene acetal triflate derived from the lactone
5 and w-(ethoxycarbonyl)alkylzinc bromide. For confir-
mation of the hypothesis, d-lactones 5 (m = 2) were con-
verted into the succinates 7 (m = 2, n = 2) via the
dihydropyrans 6 (m = 2, n = 2). The succinate 18 was se-
lected as a model compound, which could be the key com-
pounds for the synthesis of reveromycin A (Scheme 4).15
Lactone 13 was prepared as the model compound from
but-3-yn-1-ol in 14% overall yield in eleven steps
(Scheme 3). Namely, the propargyl alcohol 8, prepared
from but-3-yn-1-ol, was successively treated with lithium
aluminum hydride/sodium methoxide and iodine to fur-
nish the (Z)-vinyl iodide (61%), which was alkylated by
treatment with lithium dibutylcuprate and then butyl
iodide16 to give the allyl alcohol 9 (70%). After protection
of the hydroxy group in 9 by the tert-butyldiphenylsilyl
group, the tetrahydropyran group was hydrolyzed with
pyridinium 4-toluenesulfonate in ethanol at 55 °C to give
the alcohol (84%, two steps), which was then converted
into the iodide (97%). Alkylation of the iodide with tert-
This procedure was successfully applied as a key step in
the first asymmetric total synthesis of reveromycin A.15 In
this paper, we report a new general methodology for the
preparation of succinates of tertiary alcohols without us-
ing high pressure (Scheme 2).
R1
DCC, DMAP
CH2Cl2, 1.5 GPa
CO2R4
R2
OH
O
+
HO2C
R3
1
2a: R4 = Me
butyl
acetate/lithium
N-isopropylcyclohexylamide
b: R4 = allyl
(LNICA) followed by deprotection of the tert-butyldiphe-
nylsilyl group with tetrabutylammonium fluoride gave the
tert-butyl ester 10 (88%, two steps). The Sharpless asym-
metric epoxidation17 of the allyl alcohol 10 with tert-butyl
hydroperoxide in the presence of (+)-diethyl tartrate and
titanium(IV) isopropoxide afforded the epoxide 11 (67%,
92% ee) and the bicyclo derivative 12 (30%, 92% ee). The
enantiomeric excess of both 11 and 12 were determined
on the basis of the 1H NMR spectra of the corresponding
MTPA esters. Hydrolysis of the tert-butyl ester group in
11 with trifluoroacetic acid resulted in simultaneous cy-
O
R1
R1
n-PrSLi, HMPA
(R4 = Me)
OR4
OH
R2
O
R2
O
R3
O
Pd(PPh3)4, Ph3P
pyrrolidine
R3
O
3a: R4 = Me
b: R4 = allyl
4
(R4 = allyl)
Scheme 1 Succinylation of tertiary alcohols 1 under high pressure
SYNTHESIS 2008, No. 20, pp 3209–3218
x
x.
x
x
.
2
0
0
8
Advanced online publication: 25.09.2008
DOI: 10.1055/s-0028-1083140; Art ID: F11508SS
© Georg Thieme Verlag Stuttgart · New York

3210
T. Shimizu et al.
PAPER
1) DHP, p-TsOH
Et2O, r.t., 92%
that if 17 and 19 are in a state of equilibrium, the treatment
of 17 with lead(IV) acetate might afford the succinate 18
via the oxidative cleavage of 19. In fact, the treatment of
17 with lead(IV) acetate in benzene at room temperature
promptly gave 18 in good yield (89%).
OH
OTHP
OTHP
2) n-BuLi, (HCHO)n
THF, 0 °C, 65%
OH
8
but-3-yn-1-ol
This new procedure for the preparation of the succinate of
a tertiary alcohol was applied to the synthesis of deriva-
tives having other protecting groups such as benzylidene
acetal or silyl groups (Scheme 5). The treatment of the
lactone diol 13 with benzaldehyde dimethyl acetal in the
presence of 4-toluenesulfonic acid gave the benzylidene
acetal 20 as a 1:1 mixture (90%). The ketene acetal triflate
prepared from 20 by treatment with potassium hexameth-
yldisilazanide and N-phenylbis(trifluoromethanesulfon-
imide) in the presence of hexamethylphosphoramide was
converted into the cyclic enol ether 21 via palladium-cat-
alyzed coupling with the zinc homoenolate. The oxidation
of dihydropyran 21 with osmium tetroxide/N-methylmor-
pholine N-oxide in acetone and water (78%, three steeps)
followed by treatment with lead(IV) acetate afforded the
succinate 22 (84%), which also included the formyl
group. The lactone diol 13 was then silylated with tert-bu-
tylchlorodiphenylsilane followed by the addition of chlo-
rotriethylsilane in the presence of imidazole in N,N-
dimethylformamide to give the silyl ether 23 (88%) in a
one-pot procedure. Then, 23 was reacted with potassium
1) LAH, NaOMe, THF, 0 °C to reflux
then I2, –78 °C to r.t., THF, 61%
2) n-Bu2CuLi, Et2O, –30 °C
then n-BuI, -30 °C ~ r.t., 70%
9
OH
1) TBDPSCl, imidazole
DMF, r.t., 99%
O
2) PPTS, EtOH, 55 °C, 84%
O
3) I2, Ph3P, imidazole
benzene, r.t., 97%
10
OH
4) t-BuOAc, LNICA, HMPA
THF, –78 °C, 88%
5) TBAF, THF, r.t., 99%
O
O
Ti(Oi-Pr)4, (+)-DET, TBHP, 4 Å MS
CH2Cl2, –26 °C, 97%
O
OH
11 (67%)
O
O
TFA, CH2Cl2
+
O
O
78%
O
OH
OH
12 (30%)
OH
13
hexamethyldisilazanide
and
N-phenylbis(trifluoro-
Scheme 3 Synthesis of lactone 13
O
O
LHMDS, PhNTf2
HMPA, THF
Me2C(OMe)2
PPTS, CH2Cl2
clization to give the lactone 13. The bicyclo derivative 12
was also treated with trifluoroacetic acid to afford 13 as
the sole product. Practically, the mixture of 11 and 12
directly produced the lactone diol 13 (78%) by treatment
with trifluoroacetic acid.
13
94%
O
O
14
CO2Et
Next, the lactone 13 was converted into the succinate 18
of the tertiary hydroxy group, which includes a formyl
group in the structure, in 74% overall yield in five steps
(Scheme 4). The hydroxy groups in 13 were protected as
an acetonide to afford 14 (94%). The acetonide 14 was
then treated with lithium hexamethyldisilazanide/N-phe-
nylbis(trifluoromethanesulfonimide)18 to give the ketene
acetal triflate 15, which was coupled with zinc homoeno-
late, 3-ethoxy-3-oxopropylzinc bromide, in the presence
of tetrakis(triphenylphosphine)palladium19 to afford the
cyclic enol ether 16 (99%, two steps). Ozonolysis of 16
followed by reduction with dimethyl sulfide or triphe-
nylphosphine afforded a mixture of the succinate 18
(10~51%) and the ketone diol 17 (~50%). The Lemieux–
Johnson oxidation20 of 16 with osmium tetroxide/sodium
periodate also afforded a mixture of 17 and 18. The succi-
nate 18 might be a useful intermediate for the synthesis of
reveromycin A. However, these oxidations were not re-
producible. On the other hand, the oxidation of 16 with os-
mium tetroxide (0.1 equiv)/N-methylmorpholine N-oxide
(14 equiv) in acetone–water (4:1) constantly gave 17 in
good yield (89%), which is the ring-opened derivative of
the desired dihydroxytetrahydropyran 19. We anticipated
OTf
CO2Et
O
O
BrZn
Pd(Ph3P)4,benzene
99% (2 steps)
O
O
O
O
16
15
OH
OH
OsO4, NMO
Pb(OAc)4
benzene
CO2Et
acetone–H2O
O
89%
89%
O
O
17
O
O
CO2Et
OH
HO
O
O
CO2Et
O
O
O
O
18
19
Scheme 4 Synthesis of succinate 18
Synthesis 2008, No. 20, 3209–3218 © Thieme Stuttgart · New York

PAPER
A New Route for the Preparation of Succinates
3211
methanesulfonimide) in the presence of hexamethylphos- group were conveniently prepared via the oxidative cleav-
phoramide to afford the triflate (99%), while no reaction age of the corresponding dihydropyrans.
occurred when lithium hexamethyldisilazanide was used
in place of potassium hexamethyldisilazanide. The palla-
dium-catalyzed coupling reactions of the triflate and zinc
homoenolate in the presence of Pd(PPh3)4, Pd(dppf)Cl2, or
PdCl2(PPh3)2 did not take place and the dihydropyran 24
was not obtained. It was assumed that the reason for no re-
action is due to the steric hindrance resulting from both si-
lyl groups. Next, another attempt to prepare the succinate
Next, this new procedure for the preparation of the succi-
nate of the tertiary alcohol was applied to a g-lactone 29,2,1
(5, m = 1) (Scheme 6). The acetonide 29 was treated with
lithium hexamethyldisilazanide and N-phenylbis(trifluo-
romethanesulfonimide) in the presence of hexamethyl-
phosphoramide to recover 29, although the acetonide 14
was quantitatively converted into the triflate 15. However,
treatment of 29 with potassium hexamethyldisilazanide
and N-phenylbis(trifluoromethanesulfonimide) afforded a
25 was made, because the Weinreb amide corresponding
to the aldehyde 25 was conveniently used in the total syn-
thesis of 1.15 The lactone diol 13 was protected with chlo-
rotriethylsilane to afford the bis(triethylsilyl) ethers 26.
The triflate prepared from 26 using potassium hexamethyl-
disilazanide and N-phenylbis(trifluoromethanesulfon-
imide) reacted with zinc homoenolate to afford the
dihydropyran 27 unlike the triflate of 23. Deprotection of
the silyl groups in 27 with tetrabutylammonium fluoride
followed by silylation with tert-butylchlorodiphenylsi-
lane and successive treatment with chlorotriethylsilane af-
forded the dihydropyran 24 (81%, two steps) having the
triethylsilyl and tert-butyldiphenylsilyl groups. The treat-
ment of 24 with osmium tetroxide/N-methylmorpholine
N-oxide followed by oxidation with lead(IV) acetate
formed the succinate 25 (75%, two steps). The dihydropy-
ran 27 having bis(triethylsilyl) groups was also oxidative-
ly cleaved by successive treatment with osmium
tetroxide/N-methylmorpholine and lead(IV) acetate to af-
ford the succinate 28 (77%, two steps). As a result, four
succinates 18, 22, 25, and 28 having a different protecting
labile triflate,18 which was directly converted into the cy-
clic enol ether 30 via palladium-catalyzed coupling with
the zinc homoenolate in low yield (16%, two steps). On
the other hand, the use of the Commins’ reagent in place
of N-phenylbis(trifluoromethanesulfonimide) increased
the yield (31%, two steps). The oxidation of the dihydro-
furan 30 with osmium tetroxide/N-methylmorpholine in
acetone and water followed by treatment with lead(IV) ac-
etate afforded the succinate 31 (68%, two steps), which
also include the formyl group.
In conclusion, the succinates 18, 22, 25, 28 (7, m = 2,
n = 2), and 31 (7, m = 1, n = 2) of the tertiary hydroxy
group having a formyl group in the structures were gener-
ally synthesized by oxidative cleavage of the dihydropyr-
ans 16, 21, 24, and 27 and the dihydrofuran 30, prepared
from the lactones 13 and 29, respectively, via coupling of
the ketene acetal triflates and w-(ethoxycarbonyl)alkyl-
zinc bromide. This protocol would be applicable to the
preparation of the dicarboxylic acid diesters 7 (m = 3–8,
O
O
O
CO2Et
1) OsO4, NMO
O
CO2Et
O
acetone–H2O
78%, (3 steps)
PhCH(OMe)2
1) KHMDS, PhNTf2
HMPA, THF
p-TsOH
13
DMF, 90%
2) Pb(OAc)4
benzene, 84%
CO2Et
O
O
O
2)
O
BrZn
Pd(PPh3)4, benzene
O
O
O
Ph
Ph
Ph
21
22
20
O
CO2Et
1) OsO4, NMO
O
O
CO2Et
O
O
TBDPSCl, imidazole
DMF then TESCl
1) KHMDS, PhNTf2
HMPA, THF
acetone–H2O
76%
13
19
OTES
88%
20
2)
2) Pb(OAc)4
benzene, 99%
CO2Et
O
OTES
OTES
BrZn
OTBDPS
OTBDPS
OTBDPS
Pd(PPh3)4, benzene
25
24
23
1) TBAF, THF, 92%
2) TBDPSCl, imidazole, DMF
then TESCl, 88%
O
O
EtO2C
O
O
1) OsO4, NMO
acetone–H2O
82%
CO2Et
O
TESCl, imidazole
DMF
1) KHMDS, PhNTf2
HMPA, THF
13
95%
CO2Et
2) Pb(OAc)4
benzene, 94%
2)
O
OTES
BrZn
OTES
OTES
Pd(PPh3)4, benzene
93% (2 steps)
OTES
OTES
OTES
26
27
28
Scheme 5 Synthesis of succinates 22, 25, and 28
Synthesis 2008, No. 20, 3209–3218 © Thieme Stuttgart · New York

3212
T. Shimizu et al.
PAPER
NTf2
1)
2)
O
CO2Et
N
O
Cl
KHMDS, THF
O
CO2Et
BrZn
O
O
Pd(Ph3P)4, HMPA
benzene, 31% (2 steps)
O
O
29
30
O
O
CO2Et
1) OsO4, NMO
acetone–H2O
O
O
2) Pb(OAc)4, benzene
68% (2 steps)
O
31
Scheme 6 Synthesis of succinate 31
1H NMR (500 MHz, CDCl3): d = 1.5–2.1 (m, 6 H), 2.53 (m, 2 H),
3.52 (m, 1 H), 3.57 (dt, J = 9.6, 7.3 Hz, 1 H), 3.82 (dt, J = 9.6, 7.3
Hz, 1 H), 3.88 (m, 1 H), 4.24 (br s, 2 H), 4.64 (dd, J = 4.1, 3.2 Hz,
1 H).
13C NMR (125 MHz, CDCl3): d = 19.5, 20.3, 25.4, 30.6, 51.3, 62.4,
65.7, 79.5, 83.2, 98.9.
n = 1, 3–5) because zinc reagents [EtO2C(CH2)nZnBr:
n = 1–5] are commercially available or known.
All reactions were carried out under N2 with anhydrous solvents un-
der anhydrous conditions, unless otherwise noted. Anhyd Et2O,
CH2Cl2, THF, and DMF were purchased from Kanto Chemical Co.,
Ltd, and purified with the GlassContour solvent dispensing system.
Kanto chemical silica gel 60 N (spherical, neutral) (40–100 mm)
was used for flash chromatography. NMR spectra were recorded on
a Jeol JNM-ECP-500 or a JNM-AL-400 spectrometer in CDCl3
with TMS d = 0 (1H NMR) or CDCl3 d = 77.1 (13C NMR) as internal
standard. IR spectra were recorded on a Jasco VALOR-III FT-IR
spectrophotometer. Optical rotations were recorded on a Jasco DIP-
370 digital polarimeter. HRMS were recorded on a Jeol MStation
JMS-700 mass spectrometer under FAB conditions.
(E)-3-[2-(Tetrahydro-2H-pyran-2-yloxy)ethyl]hept-2-en-1-ol
(9)
(Z)-3-Iodo-5-(tetrahydro-2H-pyran-2-yloxy)pent-2-en-1-ol
To a stirred soln of 8 (7.18 g, 39.0 mmol) in THF (325 mL) at 0 °C
was added NaOMe (5.05 g, 93.6 mmol) and suspension of LiAlH4
(1.78 g, 46.8 mmol) in THF (40 mL) over 20 min. The mixture was
heated under reflux for 3 h and then cooled to 0 °C. EtOAc (1.52
mL) was added and the mixture was stirred for 20 min. The mixture
was cooled to –78 °C and I2 (14.8 g, 58.5 mmol) in THF (65 mL)
was added. The mixture was allowed to warm to r.t., quenched with
aq Na2S2O3, and diluted with Et2O. The organic layer was washed
with brine, dried (MgSO4), and concentrated. The resulting oil was
purified by flash chromatography (n-hexane–EtOAc, 2:1) to pro-
vide the vinyl iodide (7.42 g, 61%) as a yellow oil.
1H NMR (500 MHz, CDCl3): d = 1.5–1.9 (m, 7 H), 2.80 (t, J = 6.6
Hz, 2 H), 3.54 (m, 1 H), 3.57 (dt, J = 10.2, 6.6 Hz, 1 H), 3.86 (m, 1
H), 3.87 (dt, J = 10.2, 6.6 Hz, 1 H), 4.18 (d, J = 5.6 Hz, 2 H), 4.61
(dd, J = 3.3, 2.6 Hz, 1 H), 5.95 (tt, J = 5.6, 1.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 19.4, 25.3, 30.5, 45.2, 62.4, 65.9,
67.2, 98.9, 104.7, 135.8.
5-(Tetrahydro-2H-pyran-2-yloxy)pent-2-yn-1-ol (8)
4-(Tetrahydro-2H-pyran-2-yloxy)but-1-yne
To a stirred soln of but-3-yn-1-ol (10.0 g, 143 mmol) and 3,4-dihy-
dro-2H-pyran (14.4 g, 171 mmol) in Et2O (200 mL) at r.t. was added
p-TsOH (0.400 g, 2.10 mmol). The mixture was stirred for 1 d,
quenched with aq NaHCO3 (40 mL), and diluted with Et2O. The or-
ganic layer was washed with H2O and brine, dried (MgSO4), and
concentrated. The resulting oil was purified by flash chromatogra-
phy (n-hexane–EtOAc, 20:1) to provide the product (20.3 g, 92%)
as a colorless oil.
1H NMR (500 MHz, CDCl3): d = 1.5–1.9 (m, 6 H), 1.98 (t, J = 2.6
Hz, 1 H), 2.50 (dt, J = 6.9, 2.6 Hz, 2 H), 3.52 (m, 1 H), 3.57 (dt,
J = 9.6, 6.9 Hz, 1 H), 3.84 (dt, J = 9.6, 6.9 Hz, 1 H), 3.89 (m, 1 H),
4.66 (dd, J = 4.0, 3.0 Hz, 1 H).
(E)-3-[2-(Tetrahydro-2H-pyran-2-yloxy)ethyl]hept-2-en-1-ol
(9)
To a suspension of CuI (9.27 g, 48.7 mmol) in Et2O (100 mL) at
–20 °C was added 1.52 M n-BuLi in hexane (64.1 mL, 97.4 mmol)
over 20 min, and then the mixture was stirred for 30 min at this tem-
perature. To the cooled mixture at –30 °C was added the vinyl
iodide (3.04 g, 9.74 mmol) in Et2O (30 mL) over 20 min. After 5 h,
n-BuI (2.21 mL, 19.4 mmol) was added and the mixture was stirred
at r.t. for 1 d. The mixture was diluted with Et2O and H2O and fil-
tered through a pad of Celite. The organic layer was washed with
H2O and brine, dried (MgSO4), and evaporated. The residue was pu-
rified by flash chromatography (n-hexane–EtOAc, 2:1) to provide 9
(1.65 g, 70%) as a yellow oil.
13C NMR (125 MHz, CDCl3): d = 19.4, 19.9, 25.4, 30.5, 62.2, 65.5,
69.2, 81.4, 98.8.
5-(Tetrahydro-2H-pyran-2-yloxy)pent-2-yn-1-ol (8)
To a soln of 4-(tetrahydro-2H-pyran-2-yloxy)but-1-yne (4.30 g,
27.9 mmol) in THF (100 mL) at 0 °C was added 1.52 M n-BuLi in
n-hexane (22.0 mL, 33.5 mmol). The mixture was stirred at this
temperature for 30 min. To the mixture was added (HCHO)n (1.10
g, 36.3 mmol) in one portion, and the mixture was allowed to warm
to r.t. After 2.5 h, the mixture was added to aq NH4Cl (10 mL) and
diluted with Et2O. The organic layer was washed with brine, dried
(MgSO4), and concentrated. The residue was purified by flash chro-
matography (n-hexane–EtOAc, 2:1) to provide 8 (3.32 g, 65%) as a
yellow oil.
IR (neat): 3407, 2933, 2867, 1662, 1025, 498 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.90 (t, J = 6.9 Hz, 3 H), 1.2–1.9
(m, 10 H), 2.08 (t, J = 7.3 Hz, 2 H), 2.33 (t, J = 7.3 Hz, 2 H), 3.49
(dt, J = 9.9, 7.3 Hz, 1 H), 3.50 (m, 1 H), 3.82 (dt, J = 9.9, 7.3 Hz, 1
IR (neat): 3415, 2940, 2870, 1440, 1352, 1134, 1118, 1018, 969
cm–1.
Synthesis 2008, No. 20, 3209–3218 © Thieme Stuttgart · New York

PAPER
A New Route for the Preparation of Succinates
3213
H), 3.85 (m, 1 H), 4.15 (d, J = 6.6 Hz, 2 H), 4.59 (dd, J = 5.1, 2.8
Hz, 1 H), 5.45 (t, J = 6.6 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 14.0, 19.6, 22.7, 25.4, 30.5, 30.7,
30.9, 36.7, 59.1, 62.4, 66.4, 98.8, 125.2, 140.9.
HRMS (FAB): m/z [M + Na]+ calcd for C14H26NaO3: 265.1780;
found: 265.1775.
mixture was stirred at this temperature for 15 min. The mixture was
cooled to –78 °C, and t-BuOAc (445 mL, 3.30 mmol) was added.
The mixture was stirred for 10 min and then HMPA (555 mL, 3.00
mmol) and the iodide (506 mg, 1.00 mmol) were added. The mix-
ture was stirred for 1 h and then slowly warmed to r.t. The mixture
was quenched with aq NH4Cl and diluted with Et2O. The organic
layer was washed with 1 M HCl, 1 M NaHCO3, and brine, dried
(MgSO4), and the solvent evaporated. The residue was purified by
flash chromatography (n-hexane–EtOAc, 50:1) to provide the tert-
butyl ester (435 mg, 88%) as a colorless oil.
tert-Butyl (E)-5-(2-Hydroxyethylidene)nonanoate (10)
(E)-3-[2-(tert-Butyldiphenylsiloxy)ethylidene]-1-(tetrahydro-
2H-pyran-2-yloxy)heptane
To a mixture of 9 (2.95 g, 12.2 mmol) and imidazole (1.82 g, 26.8
mmol) in DMF (12 mL) at r.t. was added TBDPSCl (3.43 mL, 13.4
mmol). The mixture was stirred for 2 h and then diluted with Et2O.
The organic layer was washed with H2O, 1 M HCl, aq NaHCO3, and
then brine, dried (MgSO4), and concentrated. The residue was puri-
fied by flash chromatography (n-hexane–EtOAc, 10:1) to provide
the silyl ether (5.80 g, 99%) as a yellow oil.
1H NMR (500 MHz, CDCl3): d = 0.80 (t, J = 7.0 Hz, 3 H), 1.03 (s,
9 H), 1.1–1.9 (m, 10 H), 1.85 (t, J = 7.6 Hz, 2 H), 2.29 (t, J = 7.3 Hz,
2 H), 3.45 (dt, J = 9.8, 7.3 Hz, 1 H), 3.51 (m, 1 H), 3.79 (dt, J = 9.8,
7.3 Hz, 1 H), 3.88 (m, 1 H), 4.21 (d, J = 6.1 Hz, 2 H), 4.60 (dd,
J = 4.0, 3.1 Hz, 1 H), 5.42 (t, J = 6.1 Hz, 1 H), 7.39 (m, 6 H), 7.68
(m, 4 H).
13C NMR (125 MHz, CDCl3): d = 14.0, 19.2, 19.7, 22.7, 25.6, 26.9,
30.7, 30.8, 36.7, 60.8, 62.4, 66.6, 98.8, 125.9, 127.7, 129.6, 134.1,
135.6, 135.7, 138.6.
IR (neat): 2932, 2859, 1731, 1147, 1112, 702 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.81 (t, J = 7.0 Hz, 3 H), 1.05 (s,
9 H), 1.18 (m, 4 H), 1.46 (s, 9 H), 1.67 (m, 2 H), 1.80 (t, J = 7.5 Hz,
2 H), 1.99 (t, J = 7.7 Hz, 2 H), 2.20 (t, J = 7.7 Hz, 2 H), 4.21 (d,
J = 6.2 Hz, 2 H), 5.37 (t, J = 6.3 Hz, 1 H), 7.39 (m, 6 H), 7.69 (m, 4
H).
13C NMR (125 MHz, CDCl3): d = 13.9, 19.1, 22.6, 23.3, 26.8, 28.1,
29.9, 30.6, 35.0, 35.8, 60.7, 79.9, 124.9, 127.6, 129.5, 134.0, 135.5,
140.7, 173.1.
tert-Butyl (E)-5-(2-Hydroxyethylidene)nonanoate (10)
To a soln of the tert-butyl ester (864 mg, 1.75 mmol) in THF (15
mL) was added TBAF (915 mg, 3.50 mmol) at r.t. and the mixture
was stirred for 1 h. The mixture was diluted with Et2O and washed
with H2O. The aqueous layer was extracted with Et2O. The com-
bined extracts were washed with brine, dried (MgSO4), and concen-
trated. The resulting oil was purified by flash chromatography (n-
hexane–EtOAc, 5:1) to provide 10 (443 mg, 99%) as a colorless oil.
(E)-3-[2-(tert-Butyldiphenylsiloxy)ethylidene]heptan-1-ol
To a stirred soln of the silyl ether (4.81 g, 10.0 mmol) in EtOH (100
mL) was added PPTS (251 mg, 1.00 mmol). After heating at 55 °C
for 2 h, the mixture was cooled. Et3N (202.4 mL, 2.0 mmol) was
added to the mixture and the solvent was evaporated. The residue
was diluted with Et2O and the organic layer was washed with H2O,
1 M HCl, 1 M NaHCO3, and brine. The organic layer was dried
(MgSO4) and concentrated. The residue was purified by flash chro-
matography (n-hexane–EtOAc, 10:1) to provide the alcohol (3.33 g,
84%) as a yellow oil.
1H NMR (400 MHz, CDCl3): d = 0.81 (t, J = 7.3 Hz, 3 H), 1.04 (s,
9 H), 1.1–1.4 (m, 4 H), 1.81 (br t, J = 7.3 Hz, 2 H), 2.24 (br t, J = 6.0
Hz, 2 H), 3.63 (br t, J = 6.0 Hz, 2 H), 4.23 (d, J = 6.6 Hz, 2 H), 5.44
(br t, J = 6.6 Hz, 1 H), 7.40 (m, 6 H), 7.69 (m, 4 H).
IR (neat): 3386, 2958, 2933, 2873, 1731, 1457, 1368, 1256, 1147,
1001, 847 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.90 (t, J = 7.0 Hz, 3 H), 1.2–1.4
(m, 5 H), 1.45 (s, 9 H), 1.71 (m, 2 H), 2.03 (t, J = 6.9 Hz, 2 H), 2.05
(t, J = 6.9 Hz, 2 H), 2.21 (t, J = 7.3 Hz, 2 H), 4.15 (dd, J = 6.9, 5.0
Hz, 2 H), 5.40 (t, J = 6.9 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 14.0, 22.8, 23.4, 28.2, 30.0, 31.0,
35.2, 36.0, 59.2, 80.2, 124.3, 143.2, 173.0.
HRMS (FAB): m/z [M + Na]+ calcd for C15H28NaO3: 279.1936;
found: 279.1937.
tert-Butyl 4-[(2S,3S)-2-Butyl-3-(hydroxymethyl)oxiran-2-yl]bu-
tanoate (11) and [(1R,5S,7S)-5-tert-Butoxy-1-butyl-6,8-dioxabi-
cyclo[3.2.1]octan-7-yl]methanol (12)
13C NMR (100 MHz, CDCl3): d = 13.9, 19.1, 22.6, 30.0, 30.7, 39.6,
60.4, 60.5, 127.2, 127.6, 129.6, 133.8, 135.6, 137.8.
To a stirred suspension of MS4A (523 mg) in CH2Cl2 (10 mL) at
–26 °C was added Ti(Oi-Pr)4 (387 mL, 1.32 mmol) and (+)-DET
(282 mL, 1.65 mmol). After 15 min, allyl alcohol 10 (843 mg, 3.29
mmol) in CH2Cl2 (5 mL) was added and the mixture was stirred for
20 min. 5 M TBHP in decane (0.99 mL, 4.94 mmol) was added and
the mixture was kept at –26 °C for 1 d. The mixture was quenched
with aq Na2SO4 (16.5 mL) and diluted with EtOAc. The mixture
was filtered through a pad of Celite and the solvent was evaporated.
The residue was purified by flash chromatography (n-hexane–
EtOAc, 5:1) to provide epoxide 11 (600 mg, 67%) as a colorless oil
and bicyclo derivative 12 (269 mg, 30%) as a colorless oil:
(E)-3-[2-(tert-Butyldiphenylsiloxy)ethylidene]-1-iodoheptane
To a stirred soln of the alcohol (4.11 g, 10.4 mmol) in benzene (30
mL) at r.t. was added imidazole (1.06 g, 15.6 mmol), Ph3P (4.09 g,
15.6 mmol), and I2 (3.96 g, 15.6 mmol). The mixture was stirred for
15 min then it was diluted with Et2O. The organic layer was washed
with H2O, aq Na2S2O3, and brine, dried (MgSO4), and concentrated.
The resulting oil was purified by flash chromatography (n-hexane–
EtOAc, 10:1) to provide the iodide (5.11 g, 97%) as a colorless oil.
IR (neat): 2958, 2931, 2858, 1428, 1112 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.81 (t, J = 6.9 Hz, 3 H), 1.04 (s,
9 H), 1.18 (m, 4 H), 1.80 (t, J = 7.3 Hz, 2 H), 2.53 (t, J = 7.6 Hz, 2
H), 3.16 (t, J = 7.6 Hz, 2 H), 4.21 (d, J = 6.3 Hz, 2 H), 5.41 (br t,
J = 6.3 Hz, 1 H), 7.40 (m, 6 H), 7.69 (m, 4 H).
Epoxide 11
[a]D27 –7.7 (c 1.58, CHCl3).
IR (neat): 3436, 2957, 2932, 2871, 1727, 1367, 1146, 1034 cm–1.
13C NMR (125 MHz, CDCl3): d = 4.1, 13.9, 19.1, 22.6, 26.8, 29.8,
1H NMR (500 MHz, CDCl3): d = 0.91 (t, J = 6.9 Hz, 3 H), 1.2–1.7
(m, 10 H), 1.45 (s, 9 H), 2.24 (m, 2 H), 2.96 (dd, J = 6.9, 4.6 Hz, 1
H), 3.69 (ddd, J = 11.9, 6.9, 3.2 Hz, 1 H), 3.84 (ddd, J = 11.9, 6.0.
4.6 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 14.1, 20.4, 23.0, 27.5, 28.2, 30.1,
34.4, 35.4, 61.2, 62.9, 63.9, 80.4, 172.8.
30.6, 41.0, 60.6, 126.8, 127.6, 129.5, 133.9, 135.6, 140.0.
tert-Butyl (E)-5-[2-(tert-Butyldiphenylsiloxy)ethylidene]nona-
noate
To a soln of i-PrNHCy (602 mL, 3.30 mmol) in THF (5 mL) at 0 °C
was added 1.53 M n-BuLi in hexane (1.96 mL, 3.00 mmol). The
Synthesis 2008, No. 20, 3209–3218 © Thieme Stuttgart · New York

3214
T. Shimizu et al.
PAPER
HRMS (FAB): m/z [M + H]+ calcd for C15H29O4: 273.2066; found:
273.2062.
To the mixture was added Et3N (221 mL, 1.59 mmol) and it was then
diluted with hexane. The organic layer was washed with brine, dried
(MgSO4), and concentrated. The resulting oil was purified by flash
chromatography (n-hexane–EtOAc, 10:1, 1% Et3N) to provide 15
(30.3 mg) as a colorless oil.
Bicyclo Derivative 12
[a]D27 +26.0 (c 3.80, CHCl3).
IR (neat): 3433, 2933, 2873, 1730, 1389, 1236, 1101, 1026 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.92 (t, J = 6.8 Hz, 3 H), 1.2–1.8
(m, 8 H), 1.35 (2 s, 3 H), 1.43 (s, 3 H), 2.11 (m, 2 H), 3.93 (dd,
J = 8.7, 6.3 Hz, 1 H), 4.02 (dd, J = 8.7, 6.9 Hz, 1 H), 4.29 (dd,
J = 6.9, 6.3 Hz, 1 H), 4.68 (dd, J = 4.0, 3.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.4, 17.8, 23.7, 24.7, 25.5, 25.5,
26.5, 31.6, 65.0, 76.5, 84.8, 86.9, 110.0, 118.8, 149.3.
1H NMR (500 MHz, CDCl3): d = 0.91 (t, J = 6.8 Hz, 3 H), 1.3–2.0
(m, 12 H), 1.40 (s, 9 H), 3.61 (br, 1 H), 3.96 (dd, J = 11.0, 8.7 Hz, 1
H), 4.01 (ddd, J = 8.7, 3.2, 1.4 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 14.0, 18.9, 23.2, 25.9, 28.6, 30.6,
34.2, 36.3, 61.4, 77.0, 82.0, 83.4, 121.4.
HRMS (FAB): m/z [M + Na]+ calcd for C15H28NaO4: 295.1885;
found: 295.1887.
Ethyl 3-{(R)-6-Butyl-6-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-5,6-
dihydro-4H-pyran-2-yl}propanoate (16); Typical Procedure
To a soln of the enol triflate 15 (30.3 mg, 78 mmol) in benzene (1
mL) was successively added Pd(PPh3)4 (4.6 mg, 4 mmol) and 0.5 M
3-ethoxy-3-oxopropylzinc bromide in THF (312 mL, 156 mmol) at
r.t. The mixture was stirred for 2 h and Et3N (174 mL, 1.25 mmol)
was added. The mixture was filtered through a pad of silica gel and
concentrated. The resulting oil was purified by flash chromatogra-
phy (n-hexane–EtOAc, 10:1) to provide 16 (26.3 mg, 99%) as a col-
orless oil.
(R)-6-Butyl-6-[(S)-1,2-dihydroxyethyl]tetrahydro-2H-pyran-2-
one (13)
To a stirred soln of 11 and 12 (272 mg, 1.00 mmol) in CH2Cl2 (6
mL) was added TFA (7.7 mL, 0.10 mmol) at r.t. and the mixture was
stirred at this temperature for 1 d. To the mixture was added Et3N
(27.9 mL, 0.2 mmol) and then it was diluted with Et2O. The organic
layer was washed with H2O and brine, dried (MgSO4), and concen-
trated. The resulting oil was purified by flash chromatography (n-
hexane–EtOAc, 1:1) to provide 13 (169 mg, 78%) as a colorless oil.
[a]D27 –3.9 (c 1.00, CHCl3).
IR (neat): 2956, 2932, 2873, 1736, 1678, 1456, 1370, 1250, 1210,
1155, 1069, 1044, 855 cm–1.
[a]D27 +18.3 (c 1.00, CHCl3).
IR (neat): 3401, 2958, 2873, 1706, 1256, 1042 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.91 (t, J = 7.2 Hz, 3 H), 1.2–2.1
(m, 10 H), 2.32 (br, 1 H), 2.48 (m, 2 H), 3.10 (br, 1 H), 3.56 (dd,
J = 11.2, 3.0 Hz, 1 H), 3.72 (dd, J = 11.2, 3.0 Hz, 1 H), 3.88 (dd,
J = 8.4, 3.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 14.0, 16.9, 23.1, 25.1, 26.0, 29.9,
36.9, 62.1, 75.5, 87.4, 172.9.
HRMS (FAB): m/z [M + H]+ calcd for C11H21O4: 217.1440; found:
217.1434.
1H NMR (400 MHz, CDCl3): d = 0.91 (t, J = 7.3 Hz, 3 H), 1.2–1.7
(m, 8 H), 1.25 (t, J = 7.3 Hz, 3 H), 1.35 (s, 3 H), 1.43 (s, 3 H), 1.99
(m, 2 H), 2.32 (t, J = 7.8 Hz, 2 H), 2.43 (m, 2 H), 3.91 (dd, J = 8.2,
6.4 Hz, 1 H), 3.96 (dd, J = 8.2, 6.8 Hz, 1 H), 4.12 (q, J = 7.3 Hz, 2
H), 4.25 (t, J = 6.4 Hz, 1 H), 4.49 (dd, J = 3.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.3, 14.5, 17.5, 23.6, 25.3, 25.5,
25.5, 26.3, 30.1, 31.8, 32.4, 60.4, 64.8, 77.1, 77.4, 94.6, 109.2,
150.7, 173.0.
HRMS (FAB): m/z [M + Na]+ calcd for C19H32NaO5: 363.2147;
found: 363.2150.
(R)-6-Butyl-6-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]tetrahydro-
2H-pyran-2-one (14)
Ethyl (R)-8-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-5,8-dihy-
droxy-4-oxododecanoate (17); Typical Procedure
To a mixture of 13 (108 mg, 0.50 mmol) and acetone dimethyl ace-
tal (306 mL, 2.50 mmol) in CH2Cl2 (7 mL) was added PPTS (12.6
mg, 0.05 mmol) at r.t. The mixture was stirred for 3 h and quenched
with Et3N (13.9 mL, 0.10 mmol). The mixture was diluted with Et2O
and the organic layer was washed with H2O and brine, dried
(MgSO4), and concentrated. The resulting oil was purified by flash
chromatography (n-hexane–EtOAc, 2:1) to provide 14 (120 mg,
94%) as a colorless oil.
[a]D27 +6.0 (c 1.00, CHCl3).
IR (neat): 2958, 2933, 1735, 1255, 1065, 756 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.91 (t, J = 6.6 Hz, 3 H), 1.2–2.0
(m, 10 H), 1.33 (s, 3 H), 1.45 (s, 3 H), 2.45 (m, 2 H), 3.81 (dd,
J = 8.8, 6.4 Hz, 1 H), 4.02 (dd, J = 8.8, 7.1 Hz, 1 H), 4.25 (dd,
J = 7.1, 6.4 Hz, 1 H).
To a soln of 16 (30.0 mg, 88 mmol) in acetone–H2O (4:1, 1 mL) was
added 2.5 wt% OsO4 in t-BuOH (2.9 mL, 0.2 mmol) and NMO (15.5
mg, 130 mmol) at r.t. The mixture was stirred for 1 d and diluted
with Et2O. To the mixture was added aq Na2S2O3 and it was stirred
for 10 min. After the addition of H2O, the mixture was stirred for 40
min and diluted with EtOAc. The organic layer was washed with
brine, dried (MgSO4), and concentrated. The resulting oil was puri-
fied by flash chromatography (n-hexane–EtOAc, 2:1) to afford 17
(29.0 mg, 89%) as a colorless oil.
IR (neat): 3469, 2956, 2935, 1716, 1371, 1209, 1069, 859 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.92 (m, 3 H), 1.2–2.1 (m, 10 H),
1.25 (m, 3 H), 1.35 (m, 3 H), 1.42 (m, 3 H), 2.18 (br, 1 H), 2.64 (m,
2 H), 2.80 (m, 2 H), 3.70 (br, 1 H), 3.86 (m, 1 H), 3.94 (m, 1 H), 4.03
(m, 1 H), 4.13 (m, 2 H), 4.22 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.4, 14.2, 23.5, 25.6, 25.6, 26.1,
26.6, 27.5, 28.0, 32.7, 36.5, 60.9, 64.7, 73.0, 76.7, 79.5, 108.9,
172.3, 210.5.
13C NMR (125 MHz, CDCl3): d = 14.1, 17.1, 23.1, 24.7, 25.1, 25.9,
26.1, 30.1, 36.3, 64.8, 79.3, 85.2, 109.7, 171.3.
HRMS (FAB): m/z [M + H]+ calcd for C14H25O4: 257.1753; found:
257.1751.
HRMS (FAB): m/z [M + Na]+ calcd for C19H34NaO7: 397.2202;
found: 397.2206.
(R)-6-Butyl-6-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-5,6-dihydro-
4H-pyran-2-yl Trifluoromethanesulfonate (15)
(R)-1-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-1-(3-oxopropyl)pen-
tyl Ethyl Succinate (18); Typical Procedure
To a soln of 17 (29 mg, 77 mmol) in benzene (1 mL) was added
Pb(OAc)4 (51 mg, 0.166 mmol) at r.t. The mixture was stirred for
30 min, diluted with Et2O, and filtered through Celite. After evapo-
To a soln of 14 (20.0 mg, 78 mmol) in THF (1 mL) was added 1.0
M LHMDS in THF (234 mL, 234 mmol) and HMPA (20.3 mL, 117
mmol) at –78 °C and the mixture was stirred at this temperature for
2 h. A soln of PhNTf2 (33.2 mg, 93 mmol) in THF (1 mL) was added,
and the mixture was stirred for 7 h, and then slowly warmed to r.t.
Synthesis 2008, No. 20, 3209–3218 © Thieme Stuttgart · New York

PAPER
A New Route for the Preparation of Succinates
3215
ration of the solvents, the resulting oil was purified by flash chro-
matography (n-hexane–EtOAc, 2:1) to afford 18 (25.4 mg, 89%) as
a colorless oil.
[a]D27 –1.4 (c 0.80, CHCl3).
Ethyl 3-{(R)-6-Butyl-6-[(S)-2-phenyl-1,3-dioxolan-4-yl]-5,6-di-
hydro-4H-pyran-2-yl}propanoate (21)
Following the typical procedure for 16 using enol triflate (169 mg,
<53 mmol) in benzene (1 mL), Pd(PPh3)4 (4.6 mg, 4 mmol), and 0.5
M 3-ethoxy-3-oxopropylzinc bromide in THF (212 mL, 106 mmol).
Work up used Et3N (105 mL, 0.85 mmol) to give crude dihydropyr-
an 21 (46 mg) as a colorless oil as a 1:1 mixture of diastereomers.
IR (neat): 2959, 2931, 1729, 1460, 1371, 1270, 1160, 1071, 859
cm–1.
1H NMR (400 MHz, CDCl3): d = 0.90 (t, 3 H), 1.2–1.6 (m, 4 H),
1.26 (t, J = 7.3 Hz, 3 H), 1.32 (s, 3 H), 1.41 (s, 3 H), 1.84 (t, 2 H),
2.13 (m, 1 H), 2.35 (m, 1 H), 2.57 (s, 4 H), 2.62 (m, 2 H), 3.88 (dd,
J = 8.5, 7.0 Hz, 1 H), 3.96 (dd, J = 8.5, 7.0 Hz, 1 H), 4.14 (q, J = 7.3
Hz, 2 H), 4.55 (t, J = 7.0 Hz, 1 H), 9.76 (t, J = 1.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.2, 14.4, 23.5, 24.9, 25.6, 26.3,
27.2, 29.3, 30.1, 33.0, 39.0, 60.9, 65.4, 78.5, 85.6, 109.3, 172.1,
172.3, 201.6.
IR (neat): 2956, 2930, 2871, 1734, 1678, 1458, 1373, 1293 cm–1.
1H NMR (500 MHz, CDCl3) (both diastereomers): d = 0.89 (t,
J = 7.3 Hz, 3 H), 0.91 (t, J = 7.3 Hz, 3 H), 1.2–2.1 (m, 20 H), 1.24
(t, J = 7.3 Hz, 3 H), 1.25 (t, J = 7.3 Hz, 3 H), 2.3–2.5 (m, 8 H), 4.00
(dd, J = 8.2, 7.8 Hz, 1 H), 4.05 (dd, J = 8.7, 6.8 Hz, 1 H), 4.13 (m,
6 H), 4.32 (dd, J = 6.8, 6.8 Hz, 1 H), 4.37 (dd, J = 7.8, 6.0 Hz, 1 H),
4.51 (m, 2 H), 5.80 (s, 1 H), 5.96 (s, 1 H), 7.3–7.5 (m, 10 H).
HRMS (FAB): m/z [M + Na]+ calcd for C23H32NaO5: 411.2147;
found: 411.2144.
HRMS (FAB): m/z [M + Na]+ calcd for C19H32NaO7: 395.2046;
found: 395.2049.
Ethyl (R)-1-(3-Oxopropyl)-1-[(S)-2-phenyl-1,3-dioxolan-4-
yl]pentyl Succinate (22)
Ethyl (R)-5,8-Dihydroxy-4-oxo-8-[(S)-2-phenyl-1,3-dioxolan-4-
yl]dodecanoate
To a soln of the crude 21 (46.0 mg, <53 mmol) in acetone–H2O (4:1,
1 mL) was added 2.5 wt% OsO4 in t-BuOH (107 mL, 5.3 mmol) and
NMO (9.3 mg, 80 mmol) at r.t. The mixture was stirred for 2 h and
diluted with EtOAc. To the mixture was added aq Na2S2O3 and it
was stirred for 10 min. After the addition of H2O, the mixture was
stirred for 40 min and diluted with EtOAc. The organic layer was
washed with brine, dried (MgSO4), and concentrated. The resulting
oil was purified by flash chromatography (n-hexane–EtOAc, 2:1) to
afford dihydroxy ketone (17.5 mg, 78%, 3 steps from 20) as a col-
orless oil as a 2:2:1:1 mixture of diastereomers.
(R)-6-Butyl-6-[(S)-2-phenyl-1,3-dioxolan-4-yl]tetrahydro-2H-
pyran-2-one (20)
To a mixture of 13 (46.0 mg, 210 mmol) and benzaldehyde dimethyl
acetal (64.0 mL, 430 mmol) in DMF (1 mL) was added p-TsOH (4.0
mg, 21 mmol) at r.t. The mixture was stirred for 3 h and quenched
with Et3N (7.0 mL, 0.05 mmol). The mixture was diluted with Et2O
and the organic layer was washed with H2O and brine, dried
(MgSO4), and concentrated. The resulting oil was purified by flash
chromatography (n-hexane–EtOAc, 2:1) to provide 20 (58.3 mg,
90%) as a colorless oil as a 1:1 mixture of diastereomers.
IR (neat): 2995, 2872, 1729, 1458, 1401, 1329, 1251 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.91 (t, J = 7.3 Hz, 3 H), 0.92 (t,
J = 6.8 Hz, 3 H), 1.2–2.1 (m, 20 H), 2.42 (m, 2 H), 2.50 (m, 2 H),
3.97 (dd, J = 8.1, 6.9 Hz, 1 H), 4.09 (m, 2 H), 4.18 (dd, J = 8.7, 6.9
Hz, 1 H), 4.33 (dd, J = 6.9, 6.9 Hz, 1 H), 4.37 (dd, J = 7.3, 5.9 Hz,
1 H), 5.76 (s, 1 H), 6.05 (s, 1 H), 7.3–7.5 (m, 10 H).
13C NMR (125 MHz, CDCl3): d = 14.0, 16.7, 17.0, 23.1, 23.1, 25.0,
25.4, 26.0, 26.1, 30.0, 30.0, 35.9, 36.1, 65.9, 66.1, 79.3, 79.8, 85.4,
86.1, 104.3, 104.7, 125.7, 126.1, 128.4, 129.3, 129.5, 136.4, 137.9,
171.1, 171.4.
IR (neat): 3476, 2956, 2933, 2872, 1715, 1459, 1399, 1376, 1206,
1090 cm–1.
1H NMR (500 MHz, CDCl3) (both diastereomers): d = 0.91 (m, 18
H), 1.2–2.1 (m, 60 H), 1.25 (m, 18 H), 2.18 (br, 2 H), 2.22 (br, 2 H),
2.29 (br, 2 H), 2.65 (m, 12 H), 2.80 (m, 12 H), 3.64 (br s, 2 H), 3.69
(br s, 4 H), 4.02 (m, 6 H), 4.12 (m, 12 H), 4.17 (m, 12 H), 4.18 (m,
6 H), 4.23 (m, 3 H), 4.28 (m, 3 H), 5.79 (s, 2 H), 5.80 (s, 1 H), 5.97
(s, 2 H), 5.98 (s, 1 H), 7.3–7.5 (m, 30 H).
HRMS (FAB): m/z [M + Na]+ calcd for C18H24NaO4: 327.1572;
found: 327.1565.
HRMS (FAB): m/z [M + Na]+ calcd for C23H34NaO7: 445.2202;
found: 445.2200.
Ethyl 3-{(R)-6-Butyl-6-[(S)-2-phenyl-1,3-dioxolan-4-yl]-5,6-di-
hydro-4H-pyran-2-yl}propanoate (21)
(R)-6-Butyl-6-[(S)-2-phenyl-1,3-dioxolan-4-yl]-5,6-dihydro-4H-
pyran-2-yl Trifluoromethanesulfonate
Ethyl (R)-1-(3-Oxopropyl)-1-[(S)-2-phenyl-1,3-dioxolan-4-
yl]pentyl Succinate (22)
Following the typical procedure for 18 using dihydroxy ketone
(14.6 mg, 35 mmol) in benzene (1 mL) and Pb(OAc)4 (23.0 mg, 52
mmol) with stirring for 10 min. Flash chromatography (n-hexane–
EtOAc, 3:1) afforded succinate 22 (12.2 mg, 84%) as a colorless oil
as a 1:1 mixture of diastereomers.
To a soln of 20 (16.1 mg, 53 mmol) in THF (1 mL) was added 0.5
M KHMDS in THF (528 mL, 264 mmol) and HMPA (45.0 mL, 264
mmol) at –78 °C and the mixture was stirred at this temperature for
30 min. A soln of PhNTf2 (94.0 mg, 264 mmol) in THF (1 mL) was
added and the mixture was stirred for 30 min. To the mixture was
added Et3N (336 mL, 2.64 mmol) and the mixture was diluted with
hexane. The organic layer was washed with brine, dried (MgSO4),
and concentrated. The resulting oil was purified by flash chroma-
tography (n-hexane–EtOAc, 2:1, 1% Et3N) to provide crude enol
triflate (169 mg) as a colorless oil as a 1:1 mixture of diastereomers.
1H NMR (500 MHz, CDCl3) (both diastereomers): d = 0.88 (t,
J = 7.3 Hz, 3 H), 0.88 (t, J = 7.3 Hz, 3 H), 1.2–2.3 (m, 20 H), 4.05
(dd, J = 8.7, 6.9 Hz, 1 H), 4.07 (dd, J = 7.8, 7.8 Hz, 1 H), 4.17–4.28
(m, 2 H), 4.37 (dd, J = 6.9, 6.9 Hz, 1 H), 4.44 (dd, J = 7.8, 5.0 Hz,
1 H), 4.71 (m, 1 H), 4.72 (m, 1 H), 5.75 (s, 1 H), 5.93 (s, 1 H), 7.3–
7.5 (m, 10 H).
IR (neat): 2958, 2929, 2873, 1725, 1460, 1376, 1270, 1158, 1069
cm–1.
1H NMR (500 MHz, CDCl3) (both diastereomers): d = 0.89 (t,
J = 6.9 Hz, 3 H), 0.92 (t, J = 6.9 Hz, 3 H), 1.2–2.7 (m, 20 H), 1.25
(t, J = 7.3 Hz, 6 H), 2.58 (m, 8 H), 4.03 (m, 2 H), 4.13 (m, 6 H), 4.61
(dd, J = 6.9, 6.9 Hz, 1 H), 4.72 (dd, J = 6.8, 6.8 Hz, 1 H), 5.72 (s, 1
H), 5.74 (s, 1 H), 7.3–7.5 (m, 10 H).
13C NMR (125 MHz, CDCl3): d = 14.0, 14.1, 14.3, 23.2, 23.3, 25.5,
25.6, 26.9, 27.1, 29.2, 29.2, 29.8, 30.0, 33.0, 33.1, 38.8, 39.1, 60.8,
60.9, 66.4, 66.5, 79.2, 79.5, 85.7, 86.0, 104.1, 104.3, 126.3, 126.7,
128.4, 128.5, 129.2, 129.6, 136.6, 138.2, 171.4, 171.5, 172.3, 201.6,
201.7.
HRMS (FAB): m/z [M + Na]+ calcd for C23H32NaO7: 443.2046;
found: 443.2048.
Synthesis 2008, No. 20, 3209–3218 © Thieme Stuttgart · New York

3216
T. Shimizu et al.
PAPER
(R)-6-Butyl-6-[(S)-2-(tert-butyldiphenylsiloxy)-1-(triethylsi-
loxy)ethyl]tetrahydro-2H-pyran-2-one (23)
Ethyl 3-{(R)-6-[(S)-1,2-Bis(triethylsiloxy)ethyl]-6-butyl-5,6-di-
hydro-4H-pyran-2-yl}propanoate (27)
(R)-6-[(S)-1,2-Bis(triethylsiloxy)ethyl]-6-butyl-5,6-dihydro-4H-
pyran-2-yl Trifluoromethanesulfonate
To a soln of 26 (200.0 mg, 0.45 mmol) in THF (5 mL) was added
0.5 M KHMDS in THF (2.70 mL, 1.35 mmol) and HMPA (234 mL,
1.35 mmol) at –78 °C and the mixture was stirred at this temperature
for 30 min. A soln of PhNTf2 (560 mg, 1.57 mmol) in THF (1 mL)
was added and the mixture was allowed to increase to r.t. and stirred
for 1 h. To a mixture was added Et3N (1.11 mL, 9.0 mmol) and the
mixture was diluted with hexane. The organic layer was washed
with brine, dried (MgSO4), and concentrated. The resulting oil was
purified by flash chromatography (n-hexane, 1% Et3N) to provide
crude enol triflate (423 mg) as a colorless oil.
To a mixture of 13 (250 mg, 1.16 mmol) and imidazole (236 mg,
3.47 mmol) in DMF (500 mL) was added TBDPSCl (296 mL, 1.16
mmol) at 0 °C. After the mixture was stirred for 15 min, TESCl (290
mL, 1.73 mmol) was added and the mixture was stirred for 30 min.
The mixture was diluted with Et2O and the organic layer was
washed with H2O, brine, dried (MgSO4), and concentrated. The re-
sulting oil was purified by flash chromatography (n-hexane–
EtOAc, 10:1) to provide 23 (577 mg, 88%) as a colorless oil.
[a]D27 +13.5 (c 0.7, CHCl3).
IR (neat): 3447, 2954, 2932, 2857, 1735, 1428, 1242, 1106, 793,
701 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.57 (q, J = 8.0 Hz, 6 H), 0.86 (t,
J = 7.2 Hz, 3 H), 0.89 (t, J = 8.0 Hz, 9 H), 1.06 (s, 9 H), 1.2–2.1 (m,
10 H), 2.36 (m, 2 H), 3.57 (dd, J = 10.9, 5.1 Hz, 1 H), 3.64 (dd,
J = 10.9, 5.1 Hz, 1 H), 3.87 (t, J = 5.1 Hz, 1 H), 7.42 (m, 6 H), 7.66
(m, 4 H).
1H NMR (500 MHz, CDCl3): d = 0.61 (m, 12 H), 0.90 (t, J = 7.3 Hz,
3 H), 0.95 (m, 18 H), 1.2–2.0 (m, 8 H), 2.13 (m, 2 H), 3.52 (dd,
J = 10.5, 6.9 Hz, 1 H), 3.75 (dd, J = 10.5, 3.2 Hz, 1 H), 3.86 (dd,
J = 6.9, 3.2 Hz, 1 H), 4.64 (t, J = 4.1 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 5.0, 6.1, 6.8, 7.1, 14.2, 17.7, 19.3,
23.4, 25.2, 26.4, 27.0, 30.4, 38.4, 65.6, 77.4, 87.1, 127.7, 127.7,
129.8, 129.8, 132.9, 132.9, 135.7, 135.7, 171.7.
HRMS (FAB): m/z [M + Na]+ calcd for C33H52NaO4Si2: 591.3302;
found: 591.3301.
Ethyl 3-{(R)-6-[(S)-1,2-Bis(triethylsiloxy)ethyl]-6-butyl-5,6-di-
hydro-4H-pyran-2-yl}propanoate (27)
Following the typical procedure for 16 using enol triflate (423 mg,
<0.45 mmol) in benzene (5 mL), Pd(PPh3)4 (4.6 mg, 4 mmol), and
0.5 M 3-ethoxy-3-oxopropylzinc bromide in THF (1.80 mL, 0.90
mmol) with stirring for 12 h; workup used Et3N (808 mL, 1.56
mmol). Flash chromatography (n-hexane–EtOAc, 10:1) provided
27 (221 mg, 93%, 2 steps) as a colorless oil.
(R)-6-Butyl-6-[(S)-2-(tert-butyldiphenylsiloxy)-1-(triethylsi-
loxy)ethyl]-5,6-dihydro-4H-pyran-2-yl Trifluoromethane-
sulfonate
[a]D24 –12.3 (c 1.00, CHCl3).
To a soln of 23 (10.0 mg, 18 mmol) in THF (200 mL) was added 0.5
M KHMDS in THF (48 mL, 24 mmol) and HMPA (4.7 mL, 27 mmol)
at –78 °C and the mixture was stirred at this temperature for 30 min.
A soln of PhNTf2 (7.9 mg, 22 mmol) in THF (200 mL) was added and
the mixture was allowed to increase to r.t. and it was stirred for 6 h.
To a mixture was added Et3N (46.8 mL, 0.36 mmol) and the mixture
was diluted with hexane. The organic layer was washed with brine,
dried (MgSO4), and concentrated. The resulting oil was purified by
flash chromatography (n-hexane, 1% Et3N) to provide crude enol
triflate (33 mg) as a colorless oil.
1H NMR (500 MHz, CDCl3): d = 0.63 (q, J = 7.9, 6 H), 0.90 (t,
J = 6.9 Hz, 3 H), 0.94 (t, J = 7.9 Hz, 9 H), 1.06 (s, 9 H), 1.2–2.1 (m,
8 H), 2.21 (m, 2 H), 3.58 (dd, J = 10.6, 6.0 Hz, 1 H), 3.71 (dd,
J = 10.6, 3.1 Hz, 1 H), 4.00 (dd, J = 6.0, 3.1, 1 H), 4.62 (t, J = 4.1,
3 H), 7.40 (m, 6 H), 7.66 (m, 4 H).
IR (neat): 2954, 2875, 1739, 1678, 1237, 1133, 1064, 1009, 727
cm–1.
1H NMR (400 MHz, CDCl3): d = 0.61 (m, 12 H), 0.89 (t, J = 7.2 Hz,
3 H), 0.95 (m, 18 H), 1.2–1.9 (m, 8 H), 1.25 (t, J = 7.0, 3 H), 1.92
(m, 2 H), 2.29 (m, 2 H), 2.44 (m, 2 H), 3.50 (dd, J = 10.4, 8.0 Hz, 1
H), 3.79 (m, 2 H), 4.12 (q, J = 7.0 Hz, 2 H), 4.46 (dd, J = 3.6, 3.4
Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 5.4, 5.6, 7.0, 7.3, 14.3, 14.5, 17.5,
23.7, 25.0, 25.4, 25.5, 30.1, 32.5, 32.6, 60.3, 64.7, 76.3, 79.0, 94.4,
150.6, 173.1.
HRMS (FAB): m/z [M + Na]+ calcd for C28H56NaO5Si2: 551.3564;
found: 551.3560.
Ethyl 3-{(R)-6-Butyl-6-[(S)-2-(tert-butyldiphenylsiloxy)-1-(tri-
ethylsiloxy)ethyl]-5,6-dihydro-4H-pyran-2-yl}propanoate (24)
3-{(R)-6-Butyl-6-[(S)-1,2-dihydroxyethyl]-5,6-dihydro-4H-pyr-
an-2-yl}propanoate
(R)-6-[(S)-1,2-Bis(triethylsiloxy)ethyl]-6-butyltetrahydro-2H-
pyran-2-one (26)
To a mixture of 13 (490 mg, 2.27 mmol) and imidazole (516 mg,
7.49 mmol) in DMF (980 mL) was added TESCl (1.14 mL, 6.81
mmol) at 0 °C. The mixture was stirred for 1.5 h and then diluted
with Et2O. The organic layer was washed with H2O and brine, dried
(MgSO4), and concentrated. The resulting oil was purified by flash
chromatography (n-hexane–EtOAc, 10:1) to provide silyl ether 26
(934 mg, 95%) as a colorless oil.
To a soln of 27 (40.0 mg, 76 mmol) in THF (2 mL) was added 1 M
TBAF in THF (224 mL, 224 mmol) at r.t. and the mixture was stirred
at this temperature for 30 min. The mixture was diluted with Et2O.
The organic layer was washed with H2O and brine, dried (MgSO4),
and concentrated. The resulting oil was purified by flash chroma-
tography (n-hexane–EtOAc, 1:1) to provide the diol (20.0 mg, 92%)
as a colorless oil.
[a]D27 +9.9 (c 1.00, CHCl3).
[a]D22 +7.0 (c 1.00, CHCl3).
IR (neat): 3431, 2957, 2872, 1737, 1679, 1249, 967, 950 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.90 (t, J = 7.3 Hz, 3 H), 1.2–2.5
(m, 14 H), 1.25 (t, J = 7.0, 3 H), 2.25 (br, 1 H), 2.66 (br, 1 H), 3.64
(m, 1 H), 3.71 (m, 1 H), 3.81 (m, 1 H), 4.13 (q, J = 7.0 Hz, 2 H),
4.51 (m, 1 H).
IR (neat): 3460, 2956, 2913, 2877, 1738, 1459, 1415, 1379, 1330,
1194, 975, 960, 815 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.62 (m, 12 H), 0.90 (t, J = 7.3 Hz,
3 H), 0.95 (m, 18 H), 1.2–2.1 (m, 10 H), 2.39 (m, 2 H), 3.81 (m, 1
H), 3.54 (dd, J = 10.6, 6.0 Hz, 1 H), 3.67 (dd, J = 10.6, 3.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 4.5, 5.2, 7.0, 7.1, 14.2, 17.4, 23.4,
25.3, 26.5, 30.0, 37.9, 64.2, 77.6, 87.0, 171.7.
13C NMR (125 MHz, CDCl3): d = 14.2, 14.5, 17.4, 23.2, 24.1, 25.3,
31.9, 32.9, 60.6, 63.6, 74.0, 79.4, 94.3, 150.0, 173.5.
HRMS (FAB): m/z [M + Na]+ calcd for C23H48NaO4Si2: 467.2989;
HRMS (FAB): m/z [M + Na]+ calcd for C16H28NaO5Si2: 323.1834;
found: 467.2971.
found: 323.1835.
Synthesis 2008, No. 20, 3209–3218 © Thieme Stuttgart · New York

PAPER
A New Route for the Preparation of Succinates
3217
Ethyl 3-{(R)-6-Butyl-6-[(S)-2-(tert-butyldiphenylsiloxy)-1-(tri-
ethylsiloxy)ethyl]-5,6-dihydro-4H-pyran-2-yl}propanoate (24)
To a mixture of the diol (16.7 mg, 57 mmol) and imidazole (11 mg,
0.17 mmol) in DMF (50 mL) was added TBDPSCl (16 mL, 62 mmol)
at 0 °C. The mixture was stirred for 15 min and then TESCl (14.4
mL, 85 mmol) was added and it was stirred for 30 min. The mixture
was diluted with Et2O and the organic layer was washed with H2O
and brine, dried (MgSO4), and concentrated. The resulting oil was
purified by flash chromatography (n-hexane–EtOAc, 20:1) to pro-
vide silyl ether 24 (31.9 mg, 88%) as a colorless oil.
13C NMR (100 MHz, CDCl3): d = 5.3, 7.2, 14.1, 14.4, 19.3, 23.3,
26.0, 26.6, 27.1, 29.2, 30.0, 34.7, 39.2, 60.8, 66.4, 77.0, 87.0, 127.7,
127.7, 129.8, 129.8, 132.9, 133.0, 135.6, 135.7, 171.0, 172.1, 202.2.
HRMS (FAB): m/z [M + Na]+ calcd for C38H60NaO7Si2: 707.3775;
found: 707.3775.
(R)-1-[(S)-1,2-Bis(triethylsiloxy)ethyl]-1-(3-oxopropyl)pentyl
Ethyl Succinate (28)
Ethyl (R)-8-[(S)-1,2-Bis(triethylsiloxy)ethyl]-5,8-dihydroxy-4-
oxododecanoate
Following the typical procedure for 17 using 27 (145 mg, 0.274
mmol) in acetone–H2O (4:1, 2 mL), 2.5 wt% OsO4 in t-BuOH (376
mL, 30 mmol) and NMO (48 mg, 0.411 mmol) and dilution with
Et2O. Flash chromatography (n-hexane–EtOAc, 5:1) to afford the
dihydroxy ketone (126 mg, 82%) as a colorless oil.
[a]D26 –0.4 (c 1.00, CHCl3).
IR (neat): 2956, 2934, 2874, 2860, 1737, 1678, 1428, 1112, 740,
700 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.69 (m, 6 H), 0.82 (t, J = 6.8 Hz,
3 H), 0.96 (m, 9 H), 1.0–2.0 (m, 10 H), 1.05 (s, 9 H), 1.24 (t, J = 6.8,
3 H), 2.17 (m, 2 H), 2.30 (m, 2 H), 3.59 (m, 1 H), 3.79 (m, 1 H), 3.94
(m, 1 H), 4.11 (q, J = 6.8 Hz, 2 H), 4.41 (m, 1 H), 7.38 (m, 6 H),
7.67 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 5.6, 7.3, 14.2, 14.7, 17.4, 19.3,
23.6, 25.0, 25.3, 25.8, 30.1, 32.2, 32.4, 60.3, 66.3, 76.6, 79.0, 94.2,
127.6, 127.6, 129.5, 132.5, 135.6, 135.7, 150.5, 173.1.
IR (neat): 3491, 2954, 2876, 1737, 1716, 1069, 1005, 727 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.63 (m, 12 H), 0.90 (m, 3 H), 0.97
(m, 18 H), 1.2–2.1 (m, 10 H), 1.25 (t, J = 7.3 Hz, 3 H), 2.64 (m, 2
H), 2.84 (m, 2 H), 3.40 (br, 0.6 H), 3.48 (br, 0.4 H), 3.59 (m, 1 H),
3.72 (m, 1 H), 3.72 (m, 1 H), 3.90 (br, 0.6 H), 4.04 (br, 0.4 H), 4.13
(m, 2 H), 4.19 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 4.2, 5.2, 5.3, 6.8, 7.0, 14.1, 14.2,
23.6, 25.7, 27.4, 27.5, 28.0, 28.0, 31.0, 31.1, 32.9, 35.4, 35.5, 60.8,
64.4, 64.5, 75.5, 75.5, 76.0, 76.2, 77.3, 77.4, 172.5, 211.3, 211.4.
HRMS (FAB): m/z [M + Na]+ calcd for C38H60NaO5Si2: 675.3877;
found: 675.3859.
(R)-1-[(S)-2-(tert-Butyldiphenylsiloxy)-1-(triethylsiloxy)ethyl]-
1-(3-oxopropyl)pentyl Ethyl Succinate (25)
HRMS (FAB): m/z [M + Na]+ calcd for C28H58NaO7Si2: 585.3619;
found: 585.3618.
Ethyl (R)-8-[(S)-2-(tert-Butyldiphenylsiloxy)-1-(triethylsi-
loxy)ethyl]-5,8-dihydroxy-4-oxododecanoate
Following the typical procedure for 17 using 24 (21 mg, 32 mmol)
in acetone–H2O (4:1, 1 mL), 2.5 wt% OsO4 in t-BuOH (38mL, 3
mmol), and NMO (5.9 mg, 45 mmol). Flash chromatography (n-hex-
ane–EtOAc, 5:1) afforded the dihydroxy ketone (16 mg, 76%) as a
colorless oil .
(R)-1-[(S)-1,2-Bis(triethylsiloxy)ethyl]-1-(3-oxopropyl)pentyl
Ethyl Succinate (28)
Following the typical procedure for 18 using dihydroxy ketone (9.3
mg, 17 mmol) in benzene (1 mL) and Pb(OAc)4 (11.0 mg, 25 mmol).
Flash chromatography (n-hexane–EtOAc, 10:1) afforded 28 (8.7
mg, 94%) as a colorless oil.
IR (neat): 3456, 2957, 2932, 2875, 2859, 1734, 1157, 1112, 740,
702 cm–1.
[a]D27 –3.0 (c 0.60, CHCl3).
IR (neat): 2955, 2876, 1731, 1413, 1159, 1005, 963, 740 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.47 (m, 6 H), 0.85 (m, 9 H), 0.89
(m, 3 H), 1.06 (s, 9 H), 1.2–2.1 (m, 10 H), 1.25 (m, 3 H), 2.63 (m, 2
H), 2.80 (m, 2 H), 3.33 (br, 1 H), 3.57 (m, 1 H), 3.72 (m, 1 H), 3.73
(m, 1 H), 3.95 (br, 1 H), 4.12 (m, 2 H), 4.17 (m, 1 H), 7.43 (m, 6 H),
7.66 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 5.2, 5.2, 7.0, 14.3, 14.4, 19.2,
23.7, 25.8, 25.9, 27.0, 27.5, 27.6, 31.1, 32.9, 35.6, 35.7, 60.8, 65.7,
75.6, 75.6, 75.9, 77.3, 77.4, 127.8, 129.9, 135.6, 135.6, 172.3,
211.0, 211.1.
1H NMR (500 MHz, CDCl3): d = 0.51 (m, 12 H), 0.80 (m, 3 H), 0.96
(m, 18 H), 1.1–1.4 (m, 4 H), 1.26 (t, J = 7.3 Hz, 3 H), 1.84 (m, 2 H),
2.13 (m, 1 H), 2.35 (m, 1 H), 2.57 (m, 4 H), 2.62 (m, 2 H), 3.52 (dd,
J = 10.5, 6.4 Hz, 1 H), 3.70 (dd, J = 10.5, 3.2 Hz, 1 H), 4.14 (q,
J = 7.3 Hz, 2 H), 4.22 (dd, J = 6.3, 3.2 Hz, 1 H), 9.74 (t, J = 1.4 Hz,
1 H).
13C NMR (125 MHz, CDCl3): d = 4.3, 5.2, 6.8, 7.1, 14.0, 14.3, 23.3,
26.0, 26.5, 29.2, 30.0, 34.6, 39.3, 60.4, 64.7, 77.3, 87.0, 171.4,
172.2, 202.5.
HRMS (FAB): m/z [M + Na]+ calcd for C38H62NaO7Si2: 709.3932;
found: 709.3933.
HRMS (FAB): m/z [M + Na]+ calcd for C28H56NaO7Si2: 583.3462;
found: 583.3461.
(R)-1-[(S)-2-(tert-Butyldiphenylsiloxy)-1-(triethylsiloxy)ethyl]-
1-(3-oxopropyl)pentyl Ethyl Succinate (25)
Following the typical procedure for 18 using dihydroxy ketone (27
mg, 40 mmol) in benzene (2 mL) and Pb(OAc)4 (27 mg, 60 mmol)
with stirring for 10 min. Flash chromatography (n-hexane–EtOAc,
10:1) afforded 25 (27 mg, 99%) as a colorless oil.
[a]D27 +0.7 (c 0.30, CHCl3).
IR (neat): 2956, 2933, 2875, 1731, 1427, 1160, 1112, 740, 703 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.62 (m, 6 H), 0.82 (t, J = 6.9 Hz,
3 H), 0.92 (t, J = 8.0 Hz, 9 H), 1.05 (s, 9 H), 1.1–1.9 (m, 6 H), 1.25
(t, J = 7.3 Hz, 3 H), 2.07 (m, 1 H), 2.25 (m, 1 H), 2.48 (s, 4 H), 2.60
(m, 2 H), 3.58 (dd, J = 11.2, 6.0 Hz, 1 H), 3.67 (dd, J = 11.2, 4.0 Hz,
1 H), 4.13 (q, J = 7.3 Hz, 2 H), 4.37 (dd, J = 6.0, 4.0 Hz, 1 H), 7.41
(m, 6 H), 7.66 (m, 4 H), 9.70 (s, 1 H).
Ethyl 3-{(R)-5-Butyl-4,5-dihydro-5-[(S)-2,2-dimethyl-1,3-di-
oxolan-4-yl]furan-2-yl}propanoate (30)
(R)-5-Butyl-5-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-4,5-dihydro-
furan-2-yl Trifluoromethanesulfonate
To a stirred soln of 29 (20.3 mg, 83 mmol) and N-(5-chloro-2-py-
ridyl)triflimide (181 mg, 460 mmol) in THF (1 mL) was dropwise
added 0.5 M KHMDS in toluene (840 mL, 420 mmol) over 30 min
at –78 °C. The mixture was stirred at this temperature for 30 min
and then allowed to warm to r.t. and stirred for 15 min. Et3N (234
mL, 1.68 mmol) was added and the mixture was diluted with hexane.
The organic layer was washed with H2O and brine and dried
(MgSO4). To the mixture was added HMPA (73 mL, 150 mmol),
which was concentrated to give crude enol triflate and HMPA as a
yellow oil.
1H NMR (300 MHz, CDCl3): d = 0.93 (t, J = 7.0 Hz, 3 H), 1.2–1.8
(m, 6 H), 1.36 (s, 3 H), 1.43 (s, 3 H), 2.62 (m, 2 H), 3.79 (dd, J = 8.4,
Synthesis 2008, No. 20, 3209–3218 © Thieme Stuttgart · New York

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T. Shimizu et al.
PAPER
6.6 Hz, 1 H), 4.03 (dd, J = 8.4, 6.6 Hz, 1 H), 4.22 (dd, J = 6.6, 6.6
Hz, 1 H), 4.59 (t, J = 2.6 Hz, 1 H).
ence, Sport, and Culture, Japan, and by the Special Project Funding
for Basic Science (Chemical Biology) from RIKEN. We thank Dr.
H. Koshino for the NMR measurements, and Ms. K. Harata for the
mass spectral measurements.
Ethyl 3-{(R)-5-Butyl-4,5-dihydro-5-[(S)-2,2-dimethyl-1,3-di-
oxolan-4-yl]furan-2-yl}propanoate (30)
To the crude triflate in benzene (2 mL) was successively added
Pd(PPh3)4 (4.8 mg, 4.2 mmol) and 0.5 M 3-ethoxy-3-oxopropylzinc
bromide in THF (670 mL, 335 mmol) at 0 °C and allowed to warm
to r.t. The mixture was stirred for 2.5 h and then Et3N (234 mL, 1.68
mmol) was added. The mixture was filtered through a pad of silica
gel and concentrated. The resulting oil was purified by flash chro-
matography (n-hexane–EtOAc, 10:1, 1% Et3N) to provide 30 (8.6
mg, 31%, 2 steps) as a colorless oil.
References
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[a]D27 –176.05 (c 1.17, CHCl3).
IR (neat): 2982, 2956, 2872, 1737, 1674, 1370, 1256, 1212, 1184,
1158, 1073, 857 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.91 (t, J = 6.9 Hz, 3 H), 1.2–1.6
(m, 5 H), 1.25 (t, J = 7.3 Hz, 3 H), 1.36 (s, 3 H), 1.44 (s, 3 H), 1.69
(m, 1 H), 2.42 (m, 4 H), 2.50 (m, 2 H), 3.75 (dd, J = 8.3, 6.9 Hz, 1
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13C NMR (125 MHz, CDCl3): d = 14.2, 14.3, 23.3, 23.6, 24.8, 25.4,
26.3, 31.7, 36.1, 36.3, 60.5, 65.1, 80.1, 87.7, 93.6, 109.5, 156.5,
172.8.
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327.2163.
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Ethyl (R)-1-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-1-(2-oxoeth-
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To a soln of dihydrofuran 30 (8.6 mg, 26 mmol) in acetone–H2O
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and NMO (4.6 mg, 39.5 mmol) at r.t. The mixture was stirred for 2
h. To the mixture was added aq Na2S2O3 and the mixture was stirred
for 10 min. After the addition of H2O, the mixture was stirred for 40
min and diluted with EtOAc. The aqueous layer was extracted with
EtOAc (3 ×). The combined organic layers were washed with brine,
dried (MgSO4), and concentrated to afford a colorless oil. To a
stirred soln of the colorless oil in benzene (500 mL) was added
Pb(OAc)4 (23.3 mg, 52.6 mmol) at 0 °C and allowed to warm to r.t.
The mixture was stirred for 1.5 h, diluted with Et2O, and filtered
through Celite. After evaporation of the solvents, the resulting oil
was purified by flash chromatography (n-hexane–EtOAc, 10:1) to
afford 31 (6.6 mg, 68%, 2 steps) as a colorless oil.
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IR: 2983, 2960, 2935, 2873, 1733, 1458, 1372, 1212, 1162, 1072,
858 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.90 (t, J = 6.9 Hz, 3 H), 1.2–1.4
(m, 3 H), 1.26 (t, J = 7.3 Hz, 3 H), 1.33 (s, 3 H), 1.38 (s, 3 H), 1.88
(m, 2 H), 2.61 (m, 3 H), 2.66 (m, 3 H), 3.00 (dd, J = 16.0, 1.4 Hz, 1
H), 3.73 (dd, J = 8.7, 6.9 Hz, 1 H), 4.01 (dd, J = 8.7, 6.9 Hz, 1 H),
4.15 (q, J = 7.3 Hz, 2 H), 4.73 (dd, J = 6.9, 6.9 Hz, 1 H), 9.79 (dd,
J = 3.2, 1.4 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 13.9, 14.3, 23.0, 24.9, 25.2, 25.7,
29.2, 30.0, 33.6, 46.8, 60.9, 65.2, 78.3, 84.9, 110.3, 171.7, 172.2,
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359.2176.
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Acknowledgment
This work was supported in part by a Grant-in-Aid for Scientific
Research (18590027) to T.S. from the Ministry of Education, Sci-
Synthesis 2008, No. 20, 3209–3218 © Thieme Stuttgart · New York