Synthesis of the C1-C12 acid fragment of amphidinolide T marine macrolides via SmI2-mediated enantioselective reductive coupling of aldehydes with a chiral crotonate

Article abstract of DOI:10.1016/j.tet.2009.06.070

A new strategy for enantioselective assembly of the trisubstituted tetrahydrofuran ring has been established for synthesis of the C1-C12 acid fragment of amphidinolide T series marine macrolides. The key steps involve the SmI₂-mediated highly e

Full text of DOI:10.1016/j.tet.2009.06.070

Tetrahedron 65 (2009) 6828–6833
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Synthesis of the C1–C12 acid fragment of amphidinolide T marine macrolides
via SmI2-mediated enantioselective reductive coupling of aldehydes with
a chiral crotonate
,b,
Jialu Luo a, Huoming Li a, Jinlong Wu a, Xinglong Xing b, Wei-Min Dai a
*
a Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, China
b Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 May 2009
Received in revised form 14 June 2009
Accepted 19 June 2009
Available online 24 June 2009
A new strategy for enantioselective assembly of the trisubstituted tetrahydrofuran ring has been
established for synthesis of the C1–C12 acid fragment of amphidinolide T series marine macrolides. The
key steps involve the SmI2-mediated highly enantioselective reductive coupling of an aldehyde with
the (1S,2R)-N-methylephedrine-derived crotonate to form the cis-3,4-disubstituted
g-butyrolactone
and the subsequent BF3-mediated 1,3-anti-selective allylation of the five-membered-ring oxocarbenium
ion with allyltrimethylsilane. The desired C1–C12 acid fragment was obtained in >25% overall yield via
a 9-step sequence.
Keywords:
Allylation
Amphidinolide
Ó 2009 Elsevier Ltd. All rights reserved.
g-Butyrolactone
Macrolide
Samarium
1. Introduction
hydroxy ketone subunit at C12 and C13 and the absolute configu-
rations of the C12/C13-hydroxy and the C14-methyl groups.
Amphidinolides are a large family of bioactive macrolides from
symbiotic marine dinoflagellates Amphidinium sp. and the amphi-
dinolide T congeners consist of five structurally related 19-mem-
bered macrolides (Fig.1).1,2 They commonly possess a trisubstituted
tetrahydrofuran (THF) ring and a C16-exo-methylene group. Their
Moreover, amphidinolide T2 is the only homologue which has an
extra chiral hydroxy group at C21. Up to date amphidinolide T1 and
T3–T5 have been synthesized by Fu¨rstner,3 Ghosh,4 Jamison,5
Zhao,6 and Yadav.7 Ring-closing metathesis (RCM),3,8 Yamaguchi
macrolactonization,4,6,7,9 and nickel-catalyzed alkyne–aldehyde
reductive macrocyclization5 have been applied in the formation of
the 19-membered ring macrocycle.10 Another focus of these total
syntheses is on the strategies toward stereoselective assembly of
the trisubstituted THF ring. The syn aldol intermediates 1a–c were
prepared by the diastereoselective Brown allylation3 and crotyla-
tion,5 and the diastereoselective aldol reaction4 of the titanium
enolate of a chiral propionate (Scheme 1). It was followed by the
cyclization reactions of the advanced intermediates derived from
structural differences are reflected on the relative position of the a-
OH
O
Me
HO
Me
O
13
12
14
12
14
*
*
CH2
CH2
X
8
10
O
Me
Me
18
Me
O
21 R
Me
21
Me
7
O
O
1a–c to afford the
g
-butyrolactone4,5 and the lactol 2b,3,5 which
2
could be transformed into the sulfone 2a.3,4 Under the Lewis acid
catalysis, the sulfone 2a, the lactol 2b and the lactolether 2c7 can
serve as the precursors of the five-membered-ring oxocarbenium
ions to undergo alkylation reactions with allyltrimethylsilane,5,7
silyl enol ethers,3,4 and allenylsilane or allenylstannane,5 resulting
in the formation of the C8/C10-trans 3a–c in a highly stereoselective
manner.11 Zhao et al. established an intramolecular O-alkylation of
the C10-alkoxide generated in situ from the acetate 4b which was
derived from the anti-aldol 4a.6 The desired trisubstituted THF
product was obtained with inversion of the configuration at C7.6
O
O
T2: 12 -OH, 14 -Me, R = Me, X = OH
T3: 12 -OH, 14 -Me, R = X = H
T4: 12 -OH, 14 -Me, R = X = H
T5: 12 -OH, 14 -Me, R = X = H
amphidinolide T1
Figure 1. Structures of the 19-membered marine macrolides amphidinolide T1, T2, T3,
T4, and T5.
* Corresponding author. Tel./fax: þ86 (571) 87953128.
E-mail addresses: chdai@ust.hk, chdai@zju.edu.cn (W.-M. Dai).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.070

J. Luo et al. / Tetrahedron 65 (2009) 6828–6833
6829
Iqbal et al. used an intramolecular oxy-Michael addition within 5 to
Me
TBDPSO
CHO
construct the THF ring with a 82:18 diastereomeric ratio.12 In our
previous total synthesis of amphidinolide X and Y, we employed
a 5-endo epoxide ring-opening cyclization to build up the 1,1,4,5-
tetrasubstituted THF subunit.13 We report here on synthesis of the
C1–C12 acid fragment of amphidinolide T macrolides by utilizing
an enantioselective reductive coupling of an aldehyde with the
(1S,2R)-N-methylephedrine-derived crotonate14–16 to install the
requisite absolute configurations at C7 and C8 in the trisubstituted
THF ring.
OPMB
OHC
9
7
DMP, NaHCO3
RO
99%
ref. 17
Me
OH
8a: R = H
8b: R = TBDPS
TBDPSCl
imidazole
(59%)
OH
MeO2C
6
MsCl, Et3N; NaI
84%
R2
10
X
ref. 21
OH
8
8
O10
R1
O
R1
TBDPSO
Me
Me
8
7
I
Y
Me
7
7
10
Me
OPMB
R1
I
1. PPh3, MeNO2, reflux
2. KHMDS, THF, 0 °C; 7
3a: R2 = allyl
12
1a: Y = OTs, H
1b: Y = OH, H
1c: Y = CH2
2a: X = SO2Ph
2b: X = OH
2c: X = OEt
79%
Me
3b: R2 = 2-oxoalkyl
3c: R2 = propargyl
TBDPSO
1. PPh3, MeNO2
140 °C, MW, 2 h
OPMB
OR
OH
2. KHMDS, THF, 0 °C
then 9, 0 °C, 2 h (86%)
10
8
8
11
7
TrO
7
EtO2C
Ac
O
M
e
Me
5
4a: R = H
4b: R = Ts
1. Pd/C, H2, EtOH
Me
2. TBAF, THF
O
OPMB
Scheme 1. Stereoselective formation of the trisubstituted THF ring of amphidinolide T
3. DMP, NaHCO3
(80% for 3 steps)
macrolides.
13
Scheme 2. Preparation of the C1–C7 aldehyde 13.
2. Results and discussion
(1S,2R)-N-methylephedrine-derived crotonate 14 (Table 1).14 We
first performed the known reaction of 14 with cyclohexane-
carbaldehyde at different temperatures (Table 1, entries 1–3). The
The chiral aldehyde (R)-7,17 easily derived from (R)-methyl 3-
hydroxy-2-methylpropionate 6, and its antipode have been used in
diastereoselective reactions such as aldol17a,c,d and crotylation17b
and the TBDPS- and Tr-protected analogues18 have been subjected
desired cis-3,4-disubstituted g-butyrolactone 15a was obtained in
high diastereomeric selectivity as reported14 but the yield was low.
By applying the conditions we established for the reactions of the
crotonates derived from atropisomeric 1-naphthamides,15c 15a was
obtained in 56% yield (entry 3). Use of 3 equiv of SmI2 was found
beneficial in the reaction of octanal as well and the product 15b was
produced in 45% yield (entries 4 and 5). Similarly, the reaction of the
chiral aldehyde 13 with 14 afforded the product 15c in 53–67% after
shortening the reaction time to 3 h between ꢁ20 to ꢁ15 ꢀC on small
scales (entry 6). The yield of 15c dropped slightly to 46% on average
for the preparative scales (entry 7). These results suggest that the
to the reaction with Takai’s (g-methoxyallyl)chromium reagent.
Racemization at the stereogenic center of these aldehydes was not
revealed in the above reactions. We initially carried out the Wittig
olefination of (R)-7 for the synthesis of the aldehyde 13 (Scheme 2).
The iodide 10,19 prepared from 1,4-butanediol 8a, was reacted with
PPh3 in refluxing MeNO2 for 21 h to give the phosphonium salt
(92%), which was deprotonated using KHMDS to form the requisite
ylide. The latter, without isolation, reacted with (R)-7 in THF at 0 ꢀC
22
for 1 h, providing the (Z)-alkene 11 {[
a]
þ0.77 (c 3.80, acetone)} in
D
86% yield. The optical rotation of 11 is rather lower but we could not
realize loss of stereochemistry during the Wittig olefination till 11
20
was transformed into the known C1–C12 acid fragment 18 {[a]
D
Table 1
23
ꢁ0.3 (c 4.44, CH2Cl2); lit.5b
[
a]
þ8.4 (c 4.5, CH2Cl2)} (vide infra). At
SMI2-Mediated enantioselective reductive coupling
D
that stage, we decided to prepare the alkene 11 via the Wittig re-
action starting from the achiral aldehyde 920 and the chiral iodide
12.21 The alkylation of PPh3 with 12 was first carried out in
refluxing MeNO2 for 23 h followed by washing the residue with
Et2O, giving a yellow oil with ca. 75% conversion of 12 presumably
due to steric hindrance of the iodide 12. When the oil was used for
the Wittig reaction with 9 the alkene 11 was produced in 32% yield.
Fortunately, under microwave heating22 for 2 h in a closed vial at
140 ꢀC in MeNO2 the iodide 12 was mostly reacted with PPh3 to
form the phosphonium salt. The latter was then deprotonated by
Me2N
Me
O
O
R
SmI2
CHO
R
O
Me
+
t-BuOH, THF
-20 to -15 °C
Ph
O
Me
14
15
Entry
RCHO
SmI2 (eq)
T (ꢀC); t (h)
15; Yield (%)
15a; 34a
15a; 45
15a; 56
15b; 33
1
2
3
4
5
6
7
CyCHO
CyCHO
CyCHO
Octanal
Octanal
13
2
2
3
2
3
3
3
ꢁ78; 1 and then ꢁ78 to rt; 2–3
ꢁ20 to ꢁ15; 6
ꢁ20 to ꢁ15; 6
ꢁ20 to ꢁ15; 6
KHMDS and the resultant ylide reacted with 9 to furnish the alkene
ꢁ20 to ꢁ15; 6
15b; 45
20
ꢁ20 to ꢁ15; 3
15c; 53–67b
15c; 46c,d
11 {[a
]
þ29.8 (c 3.75, acetone)} in 86% overall yield from 12.
D
13
ꢁ20 to ꢁ15; 3
Hydrogenation of 11 over Pd/C in EtOH (rt, 1 h; 99%) and removal of
the TBDPS protection group by TBAF in THF (rt, 1 h; 95%) gave the
saturated primary alcohol, which was oxidized to the aldehyde 13
by DMP–NaHCO3 (rt, 0.5 h; 85%).
a
A GC yield of 74% was reported for formation of 15a at ꢁ78 ꢀC and a 71% isolated
yield was given for 15a prepared at 0 ꢀC (Ref. 14).
b
For the runs of 0.2–0.25 mmol.
Average yield for three runs of ca. 3 mmol of 13.
A 97.1:2.9 diastereomer ratio was obtained by HPLC analysis over a chiral sta-
c
d
With the aldehyde 13 in hand, we next investigated the SmI2-
mediated reductive coupling reactions of aldehydes with the
tionary phase (see Supplementary data for details).

6830
J. Luo et al. / Tetrahedron 65 (2009) 6828–6833
SmI2-mediated reductive coupling reaction is sensitive to the re-
action conditions. The byproduct of the reaction seems related to
the reduced aldehyde but the exact structure has not been deduced
yet. Nevertheless, the straight-chain aldehydes gave low yields of
55–59% by GC analysis in Fukuzawa’s work.14 Our results for the
reductive coupling reactions of octanal and 13 are consistent with
this trend.15b,d
other chiral auxiliaries.15c,d Research toward this goal is in progress
in our laboratories.
4. Experimental
4.1. General methods
The cis-3,4-disubstituted
g
-butyrolactone 15 prepared from 14
1H and 13C NMR spectra were recorded on a 400 MHz spec-
trometer in CDCl3 (400 MHz for 1H and 100 MHz for 13C, re-
spectively) with CHCl3 as the internal reference. IR spectra were
taken on a FTIR spectrophotometer. Mass spectra (MS) were mea-
sured by the þESI or ꢁESI method at 70 eV. High-resolution mass
spectra (HRMS) were measured by the þESI. Optical rotation data
were recorded on a polarimeter with a cylindrical quartz cell
(thermostattable, 3.5 mm IDꢃ10 mm). Silica gel plates pre-coated
on glass were used for thin-layer chromatography using UV light, or
7% ethanolic phosphomolybdic acid and heating as the visualizing
methods. Silica gel and petroleum ether (PE; bp 60–90 ꢀC) were
used for flash column chromatography. Yields refer to chromato-
graphically and spectroscopically (1H NMR) homogeneous mate-
rials. Anhydrous Et2O, THF and PhMe were freshly distilled from
sodium benzophenone ketyl under N2. Anhydrous CH2Cl2 and
MeNO2 were freshly distilled from CaH2. Dess–Martin periodinane
is expected to have ꢂ97:3 cis:trans ratio with ꢂ94% ee for the cis
isomer according to Fukuzawa’s work.14 Due to lack of stereo-
chemical communication with the remote chirality in the aldehyde
13, the stereochemical course of the reductive coupling reaction of
13 is controlled by the chiral crotonate 14, preferentially affording
the cis diastereomer 15c. However, the pair of cis diastereomers of
15c, being different at the C3 and C4 stereogenic centers on the g-
butyrolactone ring, are not distinguishable by 1H NMR spectros-
copy. By using HPLC analysis over a chiral stationary phase, we
were able to estimate a diastereomer ratio of 97.1:2.9 for 15c (see
Supplementary data). Moreover, the corresponding trans isomers
of 15c were not detected by 1H NMR spectroscopy, indicating that
the reductive coupling of 13 with 14 offers high diastereo-
selectivity.
As depicted in Scheme 3, 15c was first reduced by Dibal-H at
ꢁ78 ꢀC to give the lactol 16, which was subjected to the allylation
with allyltrimeyhlsilane in the presence of BF3$OEt2 at ꢁ78 ꢀC.5b,7
The 3,5-trans-2,3,5-trisubstituted THF product 17 was formed in
91% overall yield from 15c. Under the Lewis acidic conditions, the
PMB protecting group was cleaved spontaneously. The primary
alcohol 17 was finally oxidized to the known carboxylic acid 185b in
90% yield by treating with PDC in DMF–H2O.23 All spectral data and
(DMP) was prepared according to the literature procedure.24
23
(1S,2R)-N-Methylephedrinyl crotonate 14 {[
a
]
ꢁ2.8 (c 1.35,
D
CDCl3)} was prepared according to Fukuzawa’s procedure.14 The
solution of SmI2 (0.1 M in THF) from a commercial source was used
in this work. The reductive coupling reactions using in situ pre-
pared SmI2 from Sm metal and diiodoethane25 gave similar results.
The microwave reactions were carried out in closed pressurized
process vials on a technical microwave reactor (EmrysÔ creator
from Personal Chemistry AB, Uppsala, Sweden) with the reaction
temperature measured by an IR sensor. The reaction time is the
holding time after reaching the set reaction temperature. Other
reagents were obtained commercially and used as received. Am-
bient temperature ranges from 10–30 ꢀC.
17
23
optical rotation {[
a]
þ11.9 (c 4.3, CH2Cl2); lit.5b
[a
]
þ8.4 (c 4.5,
D
D
CH2Cl2)} of our sample 18 are consistent with those reported by
Jamison.5b
Me
O
OPMB
Dibal-H
HO
15c
CH2Cl2, -78 °C, 1 h
4.2. Preparation of known intermediates
Me
16
4.2.1. Synthesis of (R)-(ꢁ)-3-(4-methoxybenzyloxy)-2-
methylpropanal (7)17
CH2=CHCH2SiMe3
BF3•OEt2, CH2Cl2
-78 °C, 2 h
91% for
2 steps
To a solution of (S)-(ꢁ)-3-(40-methoxybenzyloxy)-2-methyl-
propan-1-ol26 (3.88 g, 18.47 mmol) in CH2Cl2 (370 mL) at rt was
added solid NaHCO3 (15.5 g, 185 mmol) followed by carefully add-
ing a solution of Dess–Martin periodinane (DMP)24 in CH2Cl2
(0.3 M, 74 mL, 22 mmol). The resultant mixture was stirred at room
temperature for 0.5 h followed by treating with saturated aqueous
Na2S2O3 and NaHCO3. The reaction mixture was extracted with
CH2Cl2 (3ꢃ200 mL). The combined organic layer was washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash column
chromatography (eluting with 20% EtOAc in PE) to give the alde-
hyde (R)-7 (3.77 g, 98%) as a colorless oil. Rf¼0.56 (20% EtOAc in PE);
Me
O
OH
PDC, DMF-H2O
rt, overnight
(90%)
Me
17
Me
O
OH
O
Me
18
20
25
[a
]
ꢁ27.8 (c 1.9, CHCl3); lit.17d
[
a]
þ29.4 (c 9.06, CH2Cl2; ca. 95%
Scheme 3. Synthesis the C1–C12 acid fragment 18.
D
D
purity) for (S)-7; 1H NMR (400 MHz, CDCl3)
d 9.71 (s, 1H), 7.24 (d,
J¼8.0 Hz, 2H), 6.88 (d, J¼7.6 Hz, 2H), 4.46 (s, 2H), 3.81 (s, 3H), 3.67–
3. Conclusion
3.58 (m, 2H), 2.69–2.61 (m, 1H), 1.12 (d, J¼7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3)
46.7, 10.7.
d 203.9, 159.2, 129.9, 129.2, 113.8, 72.9, 69.8, 55.2,
In summary, we have established a one-step stereoselective
synthesis of the cis-3,4-disubstituted -butyrolactone 15c via the
g
SmI2-mediated reductive coupling of the chiral aldehyde 13 with
the know chiral crotonate 14.14 The reaction is reproducible on
preparative (sub-gram) scales in the average yield of 46%, which is
comparable to those multiple-step approaches reported in the lit-
erature.3–7,10 Improvement over the product yield of the reductive
coupling is considered by using the chiral crotonates derived from
4.2.2. Synthesis of 4-[(tert-butyldiphenylsilyl)oxy]butan-
1-ol (8b)19b,20
To a solution of 1,4-butanediol 8a (8.86 mL, 100.0 mmol) and
imidazole (8.850 g, 130.0 mmol) in dry CH2Cl2 (300 mL) was added
t-BuPh2SiCl (52.0 mL, 200.0 mmol) dropwise under a nitrogen at-
mosphere at room temperature followed by stirring at same

J. Luo et al. / Tetrahedron 65 (2009) 6828–6833
6831
temperature for 4 h. The reaction mixture was concentrated under
reduced pressure and the residue was purified by flash column
chromatography (eluting with 9% EtOAc in PE) to give, along with
the bis-silylated byproduct, the monoalcohol 8b19b,20 (18.50 g,
59%) as a colorless oil. Rf¼0.17 (9% EtOAc in PE); 1H NMR (400 MHz,
6.88 (d, J¼8.4 Hz, 2H), 4.44 (s, 2H), 3.81 (s, 3H), 3.38–3.24 (m, 4H),
1.74–1.80 (m, 1H), 0.98 (d, J¼6.8 Hz, 3H).
4.3. Synthesis of (2S,3Z)-7-[(tert-butyldiphenylsilyl)oxy]-1-
(40-methoxybenzyloxy)-2-methylhept-3-ene (11)
CDCl3)
d
7.76–7.72 (m, 4H), 7.48–7.39 (m, 6H), 3.76 (t, J¼6.0 Hz, 2H),
3.68 (t, J¼6.0 Hz, 2H), 2.68 (br s, 1H), 1.77–1.65 (m, 4H), 1.12 (s, 9H).
4.3.1. The Wittig olefination starting from the iodide 10 and the
chiral aldehyde 7 (Method A)
4.2.3. Synthesis of 4-(tert-butyldiphenylsilyloxy)butanal (9)20
To a solution of the iodide 10 (36.80 g, 84 mmol) in MeNO2
(200 mL) was added PPh3 (22.00 g, 84 mmol) followed by stirring
at reflux in an oil bath for 21 h. After cooling to room temperature,
the reaction mixture was diluted with Et2O (260 mL). The pre-
cipitate was collected by filtration and was washed with Et2O. The
solid was dried under reduced pressure to give the phosphonium
salt 10a (52.90 g, 92%) as a pale yellow solid.
To a solution of the phosphonium salt 10a (687.0 mg, 1.0 mmol)
in dry THF (4 mL) cooled at 0 ꢀC was added KHMDS (0.7 M in tol-
uene, 2.57 mL, 1.8 mmol) dropwise under a nitrogen atmosphere.
After stirring at the same temperature for 30 min, a solution of the
aldehyde 7 (104.0 mg, 0.5 mmol) in dry THF (2 mL) was added
dropwise via a syringe. The resultant mixture was stirred at 0 ꢀC for
1 h and the reaction was quenched by adding water. The reaction
mixture was extracted with EtOAc (3ꢃ10 mL) and the combined
organic layer was dried over anhydrous Na2SO4, filtered, and con-
centrated under reduced pressure. The residue was purified by
To a solution of the alcohol 8b (12.56 g, 40.2 mmol) in CH2Cl2
(200 mL) at room temperature was added solid NaHCO3 (33.80 g,
402 mmol) followed by carefully adding a solution of Dess–Martin
periodinane (DMP)24 in CH2Cl2 (0.3 M, 160 mL, 48 mmol). The re-
sultant mixture was stirred at room temperature for 0.5 h followed
by treating with saturated aqueous Na2S2O3 and NaHCO3. The re-
action mixture was extracted with CH2Cl2 (3ꢃ50 mL). The com-
bined organic layer was washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash column chromatography (eluting
with 9% EtOAc in PE) to give the aldehyde 920 (12.40 g, 99%) as
a colorless oil. Rf¼0.56 (9% EtOAc in PE); 1H NMR (400 MHz, CDCl3)
d
9.80 (s, 1H), 7.67–7.64 (m, 4H), 7.50–7.30 (m, 6H), 3.70 (t,
J¼6.0 Hz, 2H), 2.56 (t, J¼6.8 Hz, 2H), 1.90 (quintet, J¼6.4 Hz, 2H),
1.05 (s, 9H).
4.2.4. Synthesis of 4-[(tert-butyldiphenylsilyl)oxy]-1-
flash column chromatography (eluting with 3% EtOAc in PE) to give
22
iodobutane (10)19
11 (216.0 mg, 86%) as a colorless oil. [
a
]
þ0.77 (c 3.80, acetone)
D
20
To a solution of the alcohol 8b (2.01 g, 6.43 mmol) in dry CH2Cl2
(10 mL) cooled at 0 ꢀC was added Et3N (1.34 mL, 9.65 mmol) and
MeSO2Cl (0.60 mL, 7.7 mmol) under a nitrogen atmosphere. The
resultant mixture was allowed to warm to room temperature and
was stirred at same temperature for 1 h. The reaction was quenched
by adding EtOAc (50 mL). The organic layer was washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure to give the crude mesylate which, without puri-
fication, was dissolved in acetone (30 mL) followed by adding solid
NaI (9.638 g, 64.3 mmol). The resultant suspension was stirred at
reflux for 4 h. The reaction mixture was allowed to cool to room
temperature and was then concentrated under reduced pressure.
The residue was dissolved in EtOAc (30 mL) and washed with sat-
urated aqueous Na2S2O3. The aqueous layer was extracted with
EtOAc (2ꢃ30 mL), dried over anhydrous Na2SO4, filtered, and con-
centrated under reduced pressure. The residue was purified by
flash column chromatography (eluting with PE) to give the iodide
1019 (2.357 g, 84% over 2 steps from 8b) as a colorless oil. Rf¼0.52
and [
a]
þ2.09 (c 3.0, CHCl3).
D
Note. Racemization at the stereogenic carbon of the aldehyde 7
during the Wittig reaction was confirmed after transforming 11 into
the target acid 18.
4.3.2. The Wittig olefination starting from the chiral iodide 12
and the aldehyde 9 (Method B)
A 10 mL pressurized process vial was charged the iodide 12
(160.0 mg, 0.5 mmol) and PPh3 (197.0 mg, 0.75 mmol) followed by
adding MeNO2 (2 mL). The vial was sealed with a cap containing
a silicon septum. The loaded vial was placed into the microwave
reactor cavity and, after being heated at 140 ꢀC for 2 h, the iodide 12
was found to be mostly converted. The reaction mixture was con-
centrated under reduced pressure to give the crude phosphonium
salt 12a which, without purification, was used for the next step.
To a solution of the above phosphonium salt 12a in dry THF
(4 mL) cooled at 0 ꢀC was added KHMDS (0.5 M in toluene, 1 mL,
0.5 mmol) dropwise under a nitrogen atmosphere. After stirring at
the same temperature for 30 min, a solution of the aldehyde 9
(279.0 mg, 0.9 mmol) in dry THF (2 mL) was added dropwise via
a syringe. The resultant mixture was stirred at 0 ꢀC for 2 h and the
reaction was quenched by adding water. The reaction mixture was
extracted with EtOAc (3ꢃ10 mL) and the combined organic layer
was dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash column chro-
(PE); 1H NMR (400 MHz, CDCl3)
6H), 3.70 (t, J¼6.0 Hz, 2H), 3.21 (t, J¼6.8 Hz, 2H), 2.01–1.92 (m, 2H),
1.71–1.63 (m, 2H), 1.07 (s, 9H); 13C NMR (100 MHz, CDCl3)
135.6
d 7.69–7.66 (m, 4H), 7.45–7.38 (m,
d
(4ꢃ), 133.8 (2ꢃ), 129.6 (2ꢃ), 127.6 (4ꢃ), 62.7, 33.3, 30.1, 26.9, 19.2,
7.01; MS (ꢁESI) m/z (relative intensity) 423 (MꢁCH3, 100).
4.2.5. Synthesis of (R)-(ꢁ)-1-[(30-iodo-20-methylpropoxy)methyl]-
4-methoxybenzene (12)26
matography (eluting with 4% EtOAc in PE) to give 11 (217.0 mg, 86%
20
To a solution of (S)-(ꢁ)-3-(40-methoxybenzyloxy)-2-methyl-
propan-1-ol26 (6.80 g, 32.3 mmol) in dry PhMe (200 mL) at room
temperature was added PPh3 (21.20 g, 80.9 mmol), imidazole
(5.50 g, 80.9 mmol), and I2 (16.40 g, 64.7 mmol). The resultant
mixture was stirred at room temperature for 3 h followed by
treating with saturated aqueous Na2S2O3. The reaction mixture was
extracted with Et2O (3ꢃ50 mL) and the combined organic layer was
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
from 12) as a colorless oil. [
a
]
þ29.8 (c 3.75, acetone); Rf¼0.49 (4%
D
EtOAc in PE); IR (film) 2931, 1612, 1513, 1247, 1111 cmꢁ1
(400 MHz, CDCl3)
;
1H NMR
d
7.68 (d, J¼6.4 Hz, 4H), 7.44–7.36 (m, 6H), 7.25
(d, J¼8.4 Hz, 2H), 6.87 (d, J¼8.8 Hz, 2H), 5.38 (dt, J¼10.4, 7.2 Hz,
1H), 5.19 (dd, J¼10.8, 9.6 Hz, 1H), 4.45 and 4.41 (ABq, J¼12.0 Hz,
2H), 3.80 (s, 3H), 3.68 (t, J¼6.8 Hz, 2H), 3.31–3.20 (m, 2H), 2.84–
2.76 (m, 1H), 2.23–2.09 (m, 2H), 1.67–1.57 (m, 2H), 1.06 (s, 9H), 0.97
(d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
159.0, 135.5 (4ꢃ),
134.0 (2ꢃ), 132.9, 130.8, 129.7, 129.5 (2ꢃ), 129.0 (2ꢃ), 127.6 (4ꢃ),
113.7 (2ꢃ), 75.0, 72.5, 63.4, 55.2, 32.8, 32.2, 26.8 (3ꢃ), 23.9, 19.2,
17.8; MS (þESI) m/z (relative intensity) 525 (MþNaþ, 100); HRMS
(þESI) calcd for C32H42O3SiNaþ (MþNaþ) 525.2795, found
525.2782.
flash column chromatography (eluting with 4% EtOAc in PE) to give
20
the iodide (R)-(ꢁ)-1226 (9.30 g, 90%) as a colorless oil. [
a
]
ꢁ14.1 (c
D
20
20
1.23, acetone) and [
a]
ꢁ13.5 (c 2.9, CH2Cl2); lit.26
[a]
D
ꢁ13.5 (c
D
1.15, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d
7.27 (d, J¼8.4 Hz, 2H),

6832
J. Luo et al. / Tetrahedron 65 (2009) 6828–6833
4.4. Synthesis of (S)-7-[(tert-butyldiphenylsilyl)oxy]-2-
CDCl3)
d
9.75 (s, 1H), 7.25 (d, J¼8.8 Hz, 2H), 6.87 (d, J¼9.2 Hz, 2H),
methylhept-1-yl 40-methoxybenzyl ether
4.43 and 4.40 (ABq, J¼12.4 Hz, 2H), 3.80 (s, 3H), 3.27 (dd, J¼8.8,
6.4 Hz, 1H), 3.21 (dd, J¼8.8, 6.8 Hz, 1H), 2.41 (td, J¼7.2, 1.6 Hz, 2H),
1.78–1.68 (m, 1H), 1.66–1.56 (m, 2H), 1.50–1.22 (m, 3H), 1.17–1.07 (m,
To a solution of the alkene 11 (239.0 mg, 0.48 mmol) in EtOH
(2 mL) was added Pd/C (10% w/w, 50.5 mg, 4.7ꢃ10ꢁ2 mmol Pd). The
loaded reaction flask was charged with a hydrogen gas balloon and
was then gently evacuated and backfilled with hydrogen gas (re-
peated for three times). The mixture was vigorously stirred at room
temperature for 1 h under a hydrogen atmosphere. The reaction
mixture was filtered through a Celite plug with washing by EtOH
(10 mL) and the combined filtrate was concentrated under reduced
pressure. The residue was purified by flash column chromatogra-
1H), 0.90 (d, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 202.7, 159.0,
130.8, 129.1 (2ꢃ), 113.7 (2ꢃ), 75.4, 72.6, 55.2, 43.8, 33.3, 33.2, 26.4,
22.3, 17.0; MS (ꢁESI) m/z (relative intensity) 263 (MꢁH, 100); HRMS
(þESI) calcd for C16H24O3Naþ (MþNaþ) 287.1618, found 287.1628.
4.7. General procedure for SmI2-mediated reductinve
coupling reactions of aldehydes with the chiral crotonate 14
phy (eluting with 3% EtOAc in PE) to afford the saturated chiral silyl
To a solution of the chiral crotonate 1414 (59.0 mg, 0.24 mmol),
the aldehyde (0.20 mmol), and t-BuOH (0.24 mmol) in THF (1 mL)
cooled at ꢁ20 ꢀC under a nitrogen atmosphere was added a THF
solution of SmI2 (0.40 or 0.60 mmol). The resultant mixture was
stirred at ꢁ20 to ꢁ15 ꢀC for 3–6 h. The reaction was quenched with
saturated aqueous NH4Cl and extracted with EtOAc (3ꢃ10 mL). The
combined organic layer was washed with brine, dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography (eluting with
20
ether (237.0 mg, 99%) as a colorless oil. [
a
]
ꢁ21.6 (c 0.66, CH2Cl2);
D
Rf¼0.49 (4% EtOAc in PE); IR (film) 2931,1613,1513,1247,1111 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
7.68 (d, J¼7.2 Hz, 4H), 7.39–7.34 (m,
6H), 7.25 (d, J¼8.0 Hz, 2H), 6.86 (d, J¼8.4 Hz, 2H), 4.43 and 4.40
(ABq, J¼12.4 Hz, 2H), 3.76 (s, 3H), 3.66 (t, J¼6.0 Hz, 2H), 3.28 (dd,
J¼9.2, 6.0 Hz, 1H), 3.19 (dd, J¼9.2, 6.8 Hz, 1H), 1.77–1.66 (m, 1H),
1.61–1.51 (m, 2H), 1.43–1.18 (m, 6H), 1.06 (s, 9H), 0.90 (d, J¼6.4 Hz,
3H); 13C NMR (100 MHz, CDCl3)
d
159.0, 135.5 (ꢃ4), 134.1 (2ꢃ),
130.9, 129.4 (2ꢃ), 129.0 (2ꢃ), 127.5 (4ꢃ), 113.6 (2ꢃ), 75.6, 72.5, 63.9,
55.1, 33.6, 33.4, 32.5, 26.8 (3ꢃ), 26.7, 26.1, 19.2, 17.1; MS (þESI) m/z
(relative intensity) 522 (MþNHþ4 , 100), 527 (MþNaþ, 71); HRMS
(þESI) calcd for C32H44O3SiNaþ (MþNaþ) 527.2953, found 527.2964.
25% EtOAc in PE) to give the g-butyrolactones 15a–c. The yields of
15a–c are found in Table 1 of the main text.
4.7.1. (4S,5S)-5-Cyclohexyl-4-methyldihydrofuran-2(3H)-one
(15a)14,15c
4.5. Synthesis of (S)-7-(40-methoxybenzyloxy)-6-
methylheptan-1-ol
A white solid; 1H NMR (400 MHz, CDCl3)
d
4.00 (dd, J¼10.0,
4.8 Hz, 1H), 2.70 (dd, J¼16.4, 6.8 Hz, 1H), 2.56–2.50 (m, 1H), 2.17 (d,
J¼16.8 Hz, 1H), 2.02 (br d, J¼12.8 Hz, 1H), 1.80–1.55 (m, 4H), 1.30–
0.80 (m, 6H), 0.97 (d, J¼7.2 Hz, 3H).
To a solution of the above chiral silyl ether (10.40 g, 20.6 mmol)
in THF (200 mL) was added TBAF (1.0 M in THF, 30.9 mL,
30.9 mmol) followed by stirring at room temperature for 1 h. The
reaction was then quenched by adding saturated aqueous NH4Cl.
The reaction mixture was extracted with EtOAc (3ꢃ200 mL). The
combined organic layer was washed with brine, dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash column chromatography (eluting
4.7.2. (4S,5S)-5-Heptyl-4-methyldihydrofuran-2(3H)-one (15b)
A colorless oil; 1H NMR (400 MHz, CDCl3)
d 4.45–4.37 (m, 1H),
2.67 (dd, J¼17.2, 8.0 Hz, 1H), 2.62–2.50 (m, 1H), 2.17 (dd, J¼16.8,
3.2 Hz, 1H), 1.70–1.40 (m, 3H), 1.40–1.20 (m, 9H), 0.99 (d, J¼6.8 Hz,
3H), 0.86 (t, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 176.9, 83.7,
37.5, 33.0, 31.7, 29.8, 29.4, 29.1, 25.8, 22.6, 14.0, 13.8.
with 25% EtOAc in PE) to give the chiral alcohol (5.20 g, 95%) as
20
a colorless oil. [
a
]
ꢁ7.2 (c 0.71, CH2Cl2); Rf¼0.27 (25% EtOAc in PE);
4.7.3. (4S,5S,50S)-5-[60-(400-Methoxybenzyloxy)-50-methylhexyl]-4-
methyldihydrofuran-2(3H)-one (15c)
D
IR (film) 3404 (br), 2931, 1613,1513,1248,1090,1036 cmꢁ1; 1H NMR
(400 MHz, CDCl3)
17
d
7.25 (d, J¼8.0 Hz, 2H), 6.87 (d, J¼8.4 Hz, 2H),
A colorless oil. [
a
]
D
ꢁ31.2 (c 2.7, CH2Cl2); Rf¼0.46 (25% EtOAc in
4.44 and 4.41 (ABq, J¼12.4 Hz, 2H), 3.79 (s, 3H), 3.60 (t, J¼6.4 Hz,
2H), 3.28 (dd, J¼8.8, 6.0 Hz, 1H), 3.20 (dd, J¼8.8, 6.4 Hz, 1H), 1.90–
1.67 (m, 2H), 1.60–1.50 (m, 2H), 1.47–1.20 (m, 5H), 1.15–1.05 (m, 1H),
PE); IR (film) 2934, 1777, 1514, 1248, 1171, 1093, 1035 cmꢁ1; 1H NMR
(400 MHz, CDCl3)
d
7.25 (d, J¼6.8 Hz, 2H), 6.88 (d, J¼8.8 Hz, 2H),
4.42 (s, 2H), 4.45–4.39 (m, 1H), 3.80 (s, 3H), 3.27 and 3.22 (Abqd,
J¼8.8, 6.4 Hz, 2H), 2.68 (dd, J¼17.2, 8.0 Hz, 1H), 2.61–2.53 (m, 1H),
2.19 (dd, J¼17.2, 4.0 Hz, 1H), 1.78–1.60 (m, 2H), 1.54–1.25 (m, 6H),
1.16–1.07 (m, 1H), 1.00 (d, J¼6.8 Hz, 3H), 0.91 (d, J¼6.4 Hz, 3H); 13C
0.91 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 159.0, 130.8,
129.0 (2ꢃ), 113.6 (2ꢃ), 75.6, 72.5, 62.8, 55.2, 33.5, 33.3, 32.6, 26.6,
25.9, 17.1; MS (þESI) m/z (relative intensity) 289 (MþNaþ, 100);
HRMS (þESI) calcd for C16H26O3Naþ (MþNaþ) 289.1774, found
289.1776.
NMR (100 MHz, CDCl3)
d
176.9, 159.1, 130.8, 129.1 (ꢃ2), 113.7 (ꢃ2),
83.6, 75.6, 72.6, 55.3, 37.5, 33.5, 33.4, 33.0, 29.8, 26.7, 26.2, 17.1, 13.8;
MS (þESI) m/z (relative intensity) 357 (MþNaþ, 100); HRMS (þESI)
calcd for C20H30O4Naþ (MþNaþ) 357.2036, found 357.2037.
4.6. Synthesis of (S)-7-(40-methoxybenzyloxy)-6-
methylheptanal (13)
4.8. A preparative scale synthesis of 15c
To a solution of the above chiral alcohol (4.00 g, 15.0 mmol) in
CH2Cl2 (300 mL) at room temperature was added solid NaHCO3
(12.60 g, 150 mmol) followed by carefully adding a solution of
Dess–Martin periodinane1 in CH2Cl2 (0.3 M, 60 mL, 18 mmol). The
resultant mixture was stirred at room temperature for 1 h followed
by treating with saturated aqueous Na2S2O3 and NaHCO3. The re-
action mixture was extracted with CH2Cl2 (3ꢃ50 mL). The com-
bined organic layer was washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash column chromatography (eluting with
To a solution of SmI2 in THF (0.1 M, 89.0 mL, 8.9 mmol) cooled at
ꢁ20 to ꢁ15 ꢀC, was added a solution of the chiral crotonate 1414
(885.0 mg, 3.58 mmol), the aldehyde 13 (789.0 mg, 2.98 mmol) and
t-BuOH (0.34 mL, 3.62 mmol) in THF (5 mL) via a syringe under
a nitrogen atmosphere. The resultant mixture was stirred at ꢁ20 to
ꢁ15 ꢀC for 3 h and the reaction was quenched with saturated
aqueous NH4Cl. The reaction mixture was extracted with EtOAc
(3ꢃ50 mL) and the combined organic layer was washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by column chroma-
25% EtOAc in PE) to give the aldehyde 13 (3.40 g, 85%) as a colorless
20
oil. [
a]
ꢁ6.7 (c 0.95, CH2Cl2); Rf¼0.62 (25% EtOAc in PE); IR (film)
tography (eluting with 16% EtOAc in PE) to give the g-butyrolactone
15c (463.0 mg, 46%).
D
2933, 1724, 1612, 1513, 1247, 1092, 1035 cmꢁ1
;
1H NMR (400 MHz,

J. Luo et al. / Tetrahedron 65 (2009) 6828–6833
6833
4.9. Synthesis of (2S,20S,30S,50R)-6-(50-allyl-30-
grants from The National Natural Science Foundation of China
(Grant No. 20772107), Zhejiang University, and Zhejiang University
Education Foundation. The authors thank Prof. T. F. Jamison of MIT,
USA for providing a copyof the 13C NMR spectrum of the acid 18, and
Lijie Sun for his assistance on the HPLC analysis of 15c.
methyltetrahydrofuran-20-yl)-2-methylhexanol (17)7
To a solution of 15c (500.0 mg, 1.50 mmol) in dry CH2Cl2 (15 mL)
cooled at ꢁ78 ꢀC was added dropwise a solution of diisobutyl-
aluminum hydride in hexane (1 M, 1.8 mL, 1.8 mmol) followed by
stirring for 1 h at the same temperature. The reaction was
quenched by carefully adding EtOAc (10 mL) and the mixture was
allowed to warm to 0 ꢀC. Saturated aqueous sodium potassium
tartrate was added and the resultant mixture was diluted with Et2O
(50 mL) with vigorous stirring. The organic layer was separated and
the aqueous layer was extracted with Et2O (2ꢃ30 mL). The com-
bined organic layer was dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure to give the crude lactol 16.
To a solution of the above crude lactol 16 and allyltrimethylsilane
(0.48 mL, 3.0 mmol) in dry CH2Cl2 (30 mL) cooled at ꢁ78 ꢀC was
added BF3$OEt2 (0.57 mL, 4.5 mmol) via a syringe. The resultant
mixture was stirred for 2 h at ꢁ78 ꢀC and allowed to warm to room
temperature slowly. The reactionwas quenched by saturated NaHCO3
and the reaction mixture was extracted with CH2Cl2 (3ꢃ25 mL). The
combined organic layers were dried overanhydrous Na2SO4, filtrated,
and concentrated under reduced pressure. The residue was purified
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.06.070.
References and notes
1. For reviews, see: (a) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77–93; (b)
Kobayashi, J.; Kubota, T. J. Nat. Prod. 2007, 70, 451–460; (c) Kobayashi, J.
J. Antibiot. 2008, 61, 271–284.
2. For isolation and structures of amphidinolide T1–T5, see: (a) Tsuda, M.; Endo,
T.; Kobayashi, J. J. Org. Chem. 2000, 65, 1349–1352; (b) Kobayashi, J.; Kubota, T.;
Endo, T.; Tsuda, M. J. Org. Chem. 2001, 66, 134–142; (c) Kubota, T.; Endo, T.;
Tsuda, M.; Shiro, M.; Kobayashi, J. Tetrahedron 2001, 57, 6175–6179.
3. (a) Fu¨ rstner, A.; Aı¨ssa, C.; Riveiros, R.; Ragot, J. Angew. Chem., Int. Ed. 2002, 41,
4763–4766; (b) Aı¨ssa, C.; Riveiros, R.; Ragot, J.; Fu¨rstner, A. J. Am. Chem. Soc.
2003, 125, 15512–15520.
4. Ghosh, A. K.; Liu, C. J. Am. Chem. Soc. 2003, 125, 2374–2375.
5. (a) Colby, E. A.; O’Brien, K. C.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 998–999;
(b) Colby, E. A.; O’Brien, K. C.; Jamison, T. F. J. Am. Chem. Soc. 2005, 127, 4297–
4307; For synthesis of C13–C22 fragment of amphidinolide T2, see: O’Brien, K.
C.; Colby, E. A.; Jamison, T. F. Tetrahedron 2005, 61, 6243–6248.
6. Deng, L.-S.; Huang, X.-P.; Zhao, G. J. Org. Chem. 2006, 71, 4625–4635.
7. Yadav, J. S.; Reddy, C. S. Org. Lett. 2009, 11, 1705–1708.
8. For selective reviews on RCM, see: (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998,
54, 4413–4450; (b) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012–3043;
(c) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29; (d) Schrock, R. R.;
Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4592–4633; (e) Deiters, A.; Martin,
S. F. Chem. Rev. 2004, 104, 2199–2238; (f) Grubbs, R. H. Tetrahedron 2004, 60,
7117–7140; (g) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005,
by column chromatography (eluting with 20% EtOAc in PE) to give the
alcohol 17 (328.0 mg, 91%) as a colorless oil. [
20
a]
ꢁ10.9 (c 2.7,
D
CH2Cl2); lit.7 [
(film) 3391 (br), 2933, 1464, 1091, 1043 cmꢁ1
CDCl3)
a]
D
ꢁ6.0 (c 1.0, CHCl3); Rf¼0.28 (25% EtOAc in PE); IR
25
;
1H NMR (400 MHz,
d
5.83–5.73 (m, 1H), 5.06 (br d, J¼18.0 Hz, 1H), 5.02 (br d,
J¼10.0 Hz, 1H), 4.09 (quintet, J¼6.8 Hz, 1H), 3.86–3.80 (m, 1H), 3.48
and 3.39 (ABqd, J¼10.8, 6.0 Hz, 2H), 2.35–2.28 (m, 1H), 2.23–2.14 (m,
2H), 1.94–1.80 (br s, 1H), 1.78–1.65 (m, 2H), 1.65–1.53 (m, 2H), 1.50–
1.21 (m, 6H), 1.15–1.04 (m, 1H), 0.89 (d, J¼6.8 Hz, 3H), 0.88 (d,
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 135.0, 116.7, 81.3, 75.9,
´
44, 4490–4527; (h) Gradillas, A.; Perez-Castells, J. Angew. Chem., Int. Ed. 2006, 45,
6086–6101; (i) Schrodi, Y.; Pederson, R. L. Aldrichimica Acta 2007, 40, 45–52;
(j) Hoveyda, A. H.; Zhugralin, A. R. Nature 2007, 450, 243–251; Also see: Handbook
of Metathesis; Grubbs, R. H., Ed.; Wiley–VCH: Weinheim, 2003; Vols. 1–3.
9. For a review on macrolactonization, see: Parenty, A.; Moreau, X.; Campagne,
J.-M. Chem. Rev. 2006, 106, 911–939.
68.2, 41.0, 39.2, 35.8, 35.7, 33.0, 30.3, 27.1, 26.8,16.6,13.9; MS (þCI) m/z
(relative intensity) 199 (MꢁC3Hþ5 ,100), 241 (MþHþ,10); HRMS (þESI)
calcd for C15H28O2Naþ (MþNaþ) 263.1982, found 263.1988.
10. For a comparative analysis, see: Colby, E. A.; Jamison, T. F. Org. Biomol. Chem.
2005, 3, 2675–2684.
4.10. Synthesis of (2S,20S,30S,50R)-6-(50-allyl-30-
methyltetrahydrofuran-20-yl)-2-methylhexanoic acid (18)5b
11. (a) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am. Chem. Soc. 1999,
121, 12208–12209; (b) Schmitt, A.; Reissig, H.-U. Synlett 1990, 40–42.
12. For synthesis of C1–C12 fragment of amphidinolide T1, see: Abbineni, C.;
Sasmal, P. K.; Mukkanti, K.; Iqbal, J. Tetrahedron Lett. 2007, 48, 4259–4262.
13. (a) Chen, Y.; Jin, J.; Wu, J.; Dai, W.-M. Synlett 2006, 1177–1180; (b) Jin, J.; Chen,
Y.; Li, Y.; Wu, J.; Dai, W.-M. Org. Lett. 2007, 9, 2585–2588; (c) Dai, W.-M.; Chen,
Y.; Jin, J.; Wu, J.; Lou, J.; He, Q. Synlett 2008, 1737–1741.
To a solution of the alcohol 17 (335.0 mg, 1.4 mmol) in DMF
(14 mL) was added 28 drops of water. Then, pyridinium dichromate
(3.41 g, 9.0 mmol) was added and the resultant mixture was stirred
overnight at room temperature.24 The reaction mixture was directly
transferred to a silica gel column followed byeluting with 25% EtOAc
in PE to give the pure acid 18 (228.0 mg) and a mixed fraction with
DMF and pyridine. The latter was dissolved in EtOAc and washed
with 5% aqueous HCl for twice. The organic layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure to give
14. Fukuzawa, S.; Seki, K.; Tatsuzawa, M.; Mutoh, K. J. Am. Chem. Soc.1997,119,1482–1483.
15. For SmI2-mediated enantioselective synthesis of cis-3,4-disubstituted
g-bu-
tyrolactones, see: (a) Kerrigan, N. J.; Hutchison, P. C.; Heightman, T. D.; Procter,
D. J. Chem. Commun. 2003, 1402–1403; (b) Kerrigan, N. J.; Hutchison, P. C.;
Heightman, T. D.; Procter, D. J. Org. Biomol. Chem. 2004, 2, 2476–2482; (c)
Zhang, Y.; Wang, Y.; Dai, W.-M. J. Org. Chem. 2006, 71, 2445–2455; (d) Vogel, J.
C.; Butler, R.; Procter, D. J. Tetrahedron 2008, 64, 11876–11883.
16. For reviews, see: (a) Molander, G. A.; Harries, C. R. Chem. Rev. 1996, 96, 307–
338; (b) Krief, A.; Laval, A.-M. Chem. Rev. 1999, 99, 745–778; (c) Edmonds, D. J.;
Johnston, D.; Procter, D. J. Chem. Rev. 2004, 104, 3371–3403; (d) Gopalaiah, K.;
Kagan, H. B. New J. Chem. 2008, 32, 607–637.
17. (a) Smith, A. B., III; Qiu, Y.; Jones, D. R.; Kobayashi, K. J. Am. Chem. Soc. 1995, 117,
12011–12012; (b) Scheidt, K.A.; Bannister, T.D.; Tasaka, A.; Wendt, M.D.; Savall, B.
M.; Fegley, G.J.; Roush, W.R. J. Am. Chem. Soc. 2002, 124, 6981–6990; For the (S)-
enantiomer, see: (c) Mulzer, J.; Mantoulidis, A. Tetrahedron Lett. 1996, 37, 9179–
9182; (d) Walkup, R. D.; Kahl, J. D.; Kane, R. R. J. Org. Chem. 1998, 63, 9113–9116.
18. (a) Guan, Y.; Wu, J.; Sun, L.; Dai, W.-M. J. Org. Chem. 2007, 72, 4953–4960; (b)
Toshima, K.; Jyojima, T.; Yamaguchi, H.; Noguchi, Y.; Yoshida, T.; Murase, H.;
Nakata, M.; Matsumura, S. J. Org. Chem. 1997, 62, 3271–3284.
an additional 91.0 mg of the acid 18. The acid 18 was obtained
20
(319.0 mg, 90%) as a colorless oil. [
a
]
þ11.9 (c 4.3, CH2Cl2); lit.5b
D
23
[
a]
þ8.4 (c 4.5, CH2Cl2); Rf¼0.25 (25% EtOAc in PE); IR (film) 3076,
D
2937, 1705, 1464, 1235, 1091 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
5.84–5.74 (m, 1H), 5.07 (dd, J¼17.6, 2.0 Hz, 1H), 5.03 (d, J¼10.2 Hz,
1H), 4.11 (quintet, J¼6.8 Hz, 1H), 3.87–3.82 (m, 1H), 2.49–2.40 (m,
1H), 2.37–2.29 (m, 1H), 2.27–2.14 (m, 2H), 1.80–1.63 (m, 3H), 1.53–
1.22 (m, 7H), 1.16 (d, J¼7.2 Hz, 3H), 0.89 (d, J¼7.2 Hz, 3H) (The acidic
proton is not seen.); 13C NMR (100 MHz, CDCl3)
d 182.7, 135.0, 116.8,
´
19. (a) Lakanen, J. R.; Pegg, A. E.; Coward, J. K. J. Med. Chem.1995, 38, 2714–2727; (b) Perez,
81.3, 76.0, 40.9, 39.3, 39.2, 35.8, 33.5, 30.2, 27.3, 26.5, 16.8, 14.0; MS
(ꢁESI) m/z (relative intensity) 253 (MꢁH, 100), 254 (M, 11); HRMS
(þESI) calcd for C15H26O3Naþ (MþNaþ) 277.1774, found 277.1776.
M.; Canoa, P.; Go´mez, G.; Tera´n, C.; Fall, Y. Tetrahedron Lett. 2004, 45, 5207–5209.
20. Freeman, F.; Kim, D. S. H. L. J. Org. Chem. 1992, 57, 1722–1727.
21. (a) Heckrodt, T. J.; Mulzer, J. Synthesis 2002, 1857–1866; (b) Bailey, W. F.;
Punzalan, E. R. J. Org. Chem. 1990, 55, 5404–5406.
22. (a) Kiddle, J. J. Tetrahedron Lett. 2000, 41, 1339–1341; (b) Dai, W.-M.; Wu, A.;
Wu, H. Tetrahedron: Asymmetry 2002, 13, 2187–2191.
Acknowledgements
23. Williams, D. R.; Meyer, K. G. J. Am. Chem. Soc. 2001, 123, 765–766.
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26. Heckrodt, T. J.; Mulzer, J. Synthesis 2002, 1857–1866.
The Laboratory of Asymmetric Catalysis and Synthesis is estab-
lished under the Cheung Kong Scholars Program of The Ministry of
Education of China. This work is supported in part by the research