Synthesis and stereochemical assignment of (+)-Cladospolide D

Article abstract of DOI:10.1016/j.tet.2008.10.059

Cladospolides A-D are 12-membered, α,β-unsaturated lactones isolated from various species of Cladosporium. Cladospolide D is unique in its γ-keto functionality and possesses antifungal activity; however, the stereochemistry of Cladoapolide D was unknown.

Full text of DOI:10.1016/j.tet.2008.10.059

Tetrahedron 65 (2009) 225–231
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and stereochemical assignment of (þ)-Cladospolide D
*
Ke-Jhen Lu, Chia-Hsiu Chen, Duen-Ren Hou
Department of Chemistry, National Central University, 300 Jhong-Da Road, Jhong-Li, Taoyuan, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Cladospolides A–D are 12-membered,
a
,b
-unsaturated lactones isolated from various species of Clado-
Received 22 September 2008
Received in revised form 21 October 2008
Accepted 21 October 2008
Available online 25 October 2008
sporium. Cladospolide D is unique in its
g
-keto functionality and possesses antifungal activity; however,
the stereochemistry of Cladoapolide D was unknown. We report the asymmetric syntheses to generate
both possible diastereomers of Cladospolide D. Two regioselective cross-metatheses were applied to
form the carbon skeleton, and the two olefins were differentiated by Michael addition, hydrogenation,
and elimination. Later, the macrocycle was achieved through the Yamaguchi protocol. After comparing
the spectroscopic data of the synthetic Cladospolide D with the reported values, the stereochemistry of
Cladospolide D is confirmed as (2E,5R,11S).
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Cladopsolide D (1) was isolated from the fermentation broth
of Cladosporium sp. FT0012 in 2001.1 All the reported Cladop-
The synthesis of Cladospolide D started with the monopro-
tection of the C2-symmetric (3R,4R)-1,5-hexadiene-3,4-diol (2) as
the silyl ether 3.8 Cross-metathesis (CM) between the diene 3 and
methyl acrylate was catalyzed by the second generation Grubbs
solides (A–D) are 12-membered
only Cladospolide D has the -keto functionality and possesses
antifungal activity against Mucor racemosus.1 Indeed, many
unsaturated- -keto lactones, such as 12-membered Patulolide A
a,b
-unsaturated lactones,2 but
g
a
,
b
-
catalyst9 (4) to give the (E)-
a,b-unsaturated ester 5 in 66% yield. The
g
regioselectivity of CM in this case is consistent with Michaelis and
Blechert’s observation,10 and the regioselective reaction of the
olefin with an allylic hydroxy group for cross-metathesis has di-
rected the following steps of the synthesis. Thus, the hydroxy group
of 5 was further protected as (2-methoxyethoxy)methyl (MEM)
ether 6, and the tert-butyldimethylsilyl group was removed to fa-
cilitate the second metathesis at the terminal olefin.11 The second
cross-metathesis between the allylic alcohol 7 and both enantio-
merically pure (R)- and (S)-2-(6-heptenyl) acetates12 (8a and 8b,
respectively) proceeded well to form 9a and 9b. The large coupling
constant (15.0 Hz) between the new formed vinylic hydrogens in-
dicates the formation of an E-olefin. Thus, the required carbon
skeleton for Cladospolide D was assembled (Scheme 1).
and 16-membered A26771B, have been synthetic targets because
these compounds hold antifungal, antibacterial, and antiin-
flammatory activities.3,4 Although Cladospolides A, B, and C have
been synthesized and reported,5–7 the synthesis of Cladospolide
D remained elusive probably due to the unknown stereochemi-
stry at C5 and C11. Here, we report our work in asymmetrically
synthesizing the two possible diastereomers of Cladospolide D.
After comparing the reported spectroscopic data with that of the
synthetic counterparts, the absolute stereochemistry of 1 is de-
termined.
We found that the selective hydrogenation of the allylic alcohol
in 9 is difficult to achieve,13 and attempted to utilize Michael ad-
dition to differentiate the two olefins here. However, no Michael
adduct directly derived from the ester 9 and 1-butanethiol could be
obtained. We suspected that the alkoxide anion, generated from 9
under the basic condition, leads to the undesired reaction channels
and byproducts at 80 ꢀC. On the other hand, the Michael addition
of the re-protected 10 and 1-butanethiol went smoothly to give
the sulfides 11 in good yields.14 The remaining olefin was hydro-
OH
O
O
O
Cladospolide D (1)
genated, and the (E)-
oxidation of sulfide 12, and then elimination.15 This route is
more efficient than regenerating the -unsaturated ester by
a,b-unsaturated ester was regenerated after
* Corresponding author.
E-mail address: drhou@cc.ncu.edu.tw (D.-R. Hou).
a,b
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.059

226
K.-J. Lu et al. / Tetrahedron 65 (2009) 225–231
OH
TBDMSCl
imidazole
71%
(HF/Py).19,20 Although the product 1a could be formed by both re-
HO
HO
HO
OTBDMS
Methyl acrylate
agents with reasonable yields (42 and 30%, respectively), we no-
ticed that the diastereomer 1b is only generated by HF-Py (46%).
The diastereomer 1b, whose methyl and hydroxyl groups are lo-
cated on the opposite face of the macrolactone, seems more sus-
ceptible under the basic condition of TBAF. Indeed, the 1H NMR of
the crude product showed the presence of aldehyde, probably
generated from the retro-Aldol condensation. The overall yields in
synthesizing the two diastereomers 1a and 1b are 3%. We also
attempted to apply the Mitsunobu reaction21 to form the macro-
lide; however, the yield is much lower when preparing the C11
inverted product 15b from 14a (Eq. 1).
Grubbs cat. 4
66%
3
2
OTBDMS
MEMO
OTBDMS
i
MEMCl, Pr2NEt
Bu4NF
88%
ClCH2CH2Cl, 77%
CO2CH3
5
CO2CH3
6
MEMO
OH
(R)-8a
(S)-8b
OAc
OTBDPS
TBDPSO
DIAD, PPh3
HO2C
Grubbs cat. 4
MesN
Cl
NMes
OMEM
CO2CH3
7
OH
5
ð1Þ
rt, toluene
Ru
O
OMEM
Cl
Ph
15b, 5%
14a
PCy3
MEMO
OH
(Eq. 1)
O
(4R, 5R, 11R), 9a, 60%
(4R, 5R, 11S), 9b, 60%
CO2CH3
OAc
Cl
Scheme 1. Two cross-metatheses to form 9.
TBDPSO
COCl
Cl
HO2C
OH
5
Cl
OMEM
selenylation/deselenylation in our hands.7c Both ester groups were
hydrolyzed under basic conditions to give acid 14 (Scheme 2).
14a
14b
DMAP, Et3N
OTBDPS
OMEM
O
O
MEMO
TBDPSCl
imidazole
OTBDPS
(CH2)3
BBr
n-BuSH
cat. DBU
80 °C
OAc
O
O
9
15a, 73%
15b, 78%
CO2CH3
10a, 93%
10b, 86%
OTBDPS
OTBDPS
n
BuS
OTBDPS
Dess-Martin
periodinane
O
OH
H2, Pd/C
H3CO2C
O
OAc
O
O
3
CH2Cl2
17a, 85%
17b, 78%
OMEM
16a, 93%
16b, 98%
O
11a, 88%
11b, 97%
n
OH
O
BuS
OTBDPS
(i) mCPBA
(2.1 equiv.)
H3CO2C
fluoride
OAc
3
(ii) DBU, CH2Cl2
OMEM
12a, 88%
12b, 99%
O
O
(5R, 11R), 1a, 42%, TBAF
(5R, 11S), 1b, 46%, HF-Py
TBDPSO
Scheme 3. Lactonization to form Cladospolide D.
(i) LiOH
H3CO2C
OAc
5
(ii) HCl(aq)
OMEM
13a, 86%
13b, 71%
The key spectroscopic data to identify the natural Cladospolide
D as 1b are shown in Table 1. The diastereomer 1b not only matches
the reported Cladopolide D well in NMR, but it is also consistent
with its optical rotation. Thus, both the relative and absolute con-
figurations of (þ)-Cladospolide D is established as (5R,11S).
TBDPSO
HO2C
OH
5
OMEM
14a, 99%
14b, 99%
3. Conclusions
Scheme 2. Formation of 14.
We have achieved the first synthesis of Cladospolide D by ap-
plying two cross-metatheses to provide the carbon skeleton, Mi-
chael addition/elimination to generate the a,b-unsaturated ester,
and the Yamaguchi protocol to form the macrolide. Comparing to
our previous synthesis of Cladospolide C,7c the protecting groups
applied in this synthesis allow selective deprotection and oxidation
Lactone formation and further modifications to achieve Clado-
spolide D are summarized in Scheme 3. The Yamaguchi protocol
was applied to form the 12-membered lactone 14.16 The MEM
group was removed with B-bromocatechol-borane,17 and the
resulting alcohol was oxidized by Dess–Martin periodinane to give
the g
-keto lactone 17.18 Diastereomers 1a and 1b were produced
to form the
g-ketone. The stereochemistry of Cladospolide D is
after removing the tert-butyldiphenyl silyl (TBDPS) groups by tet-
established after comparing the reported characterization data
rabutylammonium fluoride (TBAF) or hydrogen fluoride/pyridine
with that of both diastereomers 1a and 1b.

K.-J. Lu et al. / Tetrahedron 65 (2009) 225–231
227
Table 1
Spectroscopic data of natural Cladospolide D, 1a and 1b
5
OH
O
5
OH
O
11
O
3
2
11
O
3
2
O
1a
1b
O
Cladospolide D1
1a
1b
[
a
]
þ56.0 (c 0.1, methanol)
ꢂ6.2 (c 0.20, methanol)
þ56.9 (c 0.15, methanol)
D
NMR (
2-CH
3-CH
5-CH
11-CH
d
)
13C
1H
13C
1H
13C
1H
130.9
133.3
73.46
71.50
20.59
6.31
6.41
4.66
5.23
1.31
130.2
134.6
75.9
73.9
21.5
6.21
6.56
4.96
4.44
1.27
130.9
133.3
73.5
71.5
20.6
6.31
6.41
4.67
5.22
1.30
12-CH3
4. Experimental section
a sealable tube at 0 ꢀC. The reaction mixture was sealed, microwave
irradiated (120 ꢀC, 150 W) for 40 min. After cooled to room tem-
perature, the reaction mixture was added with satd NaHCO3(aq)
(4 mL) and water (16 mL), extracted with dichloroethane
(20 mLꢁ3). The combined organic layer was dried over Na2SO4,
filtered, and concentrated. The crude product was purified by
4.1. (3R,4R)-3-(tert-Butyldimethylsilyloxy)-
1,5-hexadien-4-ol (3)8c,22
tert-Butyldimethylsilyl chloride (TBSCl, 10.14 g, 67.29 mmol)
was added to a solution of diol 2 (5.12 g, 44.9 mol), imidazole
(4.57 g, 67.29 mmol), and dichloromethane (256 mL) at 0 ꢀC. The
solution was refluxed for 16 h, quenched with water (150 mL), and
diluted with ether (300 mL). The aqueous layer was further
extracted with ether (50 mLꢁ3), and the combined organic layer
was washed with HCl(aq) (0.1 N, 250 mL), satd NaCl(aq) (250 mL),
dried over Na2SO4, filtered, and concentrated. The crude product
column chromatography (SiO2, EtOAc/hexanes, 1:5; Rf 0.40) to give
20
6 (503 mg, 1.35 mmol, 77%) as a light brown oil. [
a]
þ18.8 (c 2.0,
D
CHCl3); 1H NMR (CDCl3, 500 MHz)
d
0.01 (s, 3H), 0.04 (s, 3H), 0.87
(s, 9H), 3.34 (s, 3H), 3.50 (t, 2H, J¼5.0 Hz), 3.60–3.65 (m, 1H), 3.70
(s, 3H), 3.71–3.75 (m, 1H), 4.18–4.23 (m, 2H), 4.70 (d, 1H, J¼6.9 Hz),
4.76 (d, 1H, J¼6.9 Hz), 5.13 (dd, 1H, J¼10.5 and 1.5 Hz), 5.22 (dd, 1H,
J¼17.5 and 1.5 Hz), 5.77 (ddd, 1H, J¼16.0 Hz, 10.5 and 5.0 Hz), 5.99
(dd, 1H, J¼15.0 and 1.0 Hz), 6.86 (dd, 1H, J¼15.0 and 5.0 Hz); 13C
was purified by column chromatography (SiO2, EtOAc/hexanes, 1:9;
20
Rf 0.60) to give 3 (7.27 g, 31.85 mmol, 71%) as a colorless oil. [
a
]
NMR (CDCl3, 125 MHz)
d
ꢂ5.0, ꢂ4.7, 18.2, 25.8, 51.5, 59.0, 67.2, 71.6,
D
þ8.9 (c 2.05, CHCl3); 1H NMR (CDCl3, 500 MHz)
d
0.03 (s, 3H), 0.06
75.0, 78.9, 94.6, 116.7, 122.4, 136.6, 145.0, 166.5;IR (neat): 3093,
2953, 1728, 1271, 1136, 1032 cmꢂ1; HRMS (ESI) calcd for [MþNa]þ
(C18H34NaO6Si) 397.2022, found 397.2023.
(s, 3H), 0.88 (s, 9H), 2.52 (d, 1H, J¼4.5 Hz), 3.88–3.97 (m, 2H), 5.14–
5.34 (m, 4H), 5.74–5.87 (m, 2H); 13C NMR (CDCl3, 125 MHz)
d
ꢂ4.9,
ꢂ4.2, 18.2, 25.8, 75.7, 77.5, 116.5, 117.0, 136.9, 137.8; IR (neat): 3465,
3080, 2930, 2857, 1245, 836 cmꢂ1; HRMS (ESI) calcd for [MþNa]þ
(C12H24NaO2Si) 251.1443, found 251.1440.
4.4. E-(4R,5R)-Methyl 5-hydroxy-4-((2-methoxyethoxy)-
methoxy)-2,6-heptadienoate (7)
4.2. E-(4R,5R)-Methyl 5-(tert-butyldimethylsilyloxy)-
4-hydroxy-2,6-heptadienoate (5)
Compound 6 (190.0 mg, 0.51 mmol) in THF (6 mL) was added
with TBAF (1.5 mL, 1.52 mmol, 1 M in THF). After stirred at room
temperature for 2 h, the reaction mixture was added with water
(5 mL) and extracted with ethyl acetate (10 mLꢁ3). The combined
organic layer was dried over Na2SO4, filtered, and concentrated. The
crude product was purified by column chromatography (SiO2, EtOAc/
Grubbs catalyst second generation (74.0 mg, 0.09 mmol) was
added to the solution of diene 3 (400.0 mg, 1.75 mmol), 2,6-di-tert-
butyl-4-methylphenol (BHT, 193.0 mg, 0.88 mmol), and methyl
acrylate (1.51 g, 17.53 mmol) in toluene (4 mL). After being heated at
reflux for 3 h, the reaction mixture was concentrated and the crude
product was purified by column chromatography (SiO2, EtOAc/
hexanes, 1:1; Rf 0.60) to give 7 (117 mg, 0.45 mmol, 88%) as a light
yellow oil. [
d
a
]
ꢂ55.1 (c 1.95, CHCl3); 1H NMR (CDCl3, 500 MHz)
20
D
3.05 (d, 1H, J¼4.0 Hz), 3.35 (s, 3.0H), 3.51 (t, 2H, J¼5.0 Hz), 3.64–
hexanes, 1:5; Rf 0.40) to give 5 (331 mg, 1.16 mmol, 66%) as a light
3.68 (m, 1H), 3.71 (s, 3H), 3.78–3.82 (m, 1H), 4.04–4.10 (m, 1H), 4.11–
4.14 (m,1H), 4.69 (d,1H, J¼7.0 Hz), 4.74 (d,1H, J¼7.0 Hz), 5.21 (dd, 1H,
J¼10.5 and 1.5 Hz), 5.34 (dd, 1H, J¼17.0 and 1.0 Hz), 5.79 (ddd, 1H,
J¼17.0 Hz, 10.5 and 6.0 Hz), 6.02 (dd, 1H, J¼16.0 and 1.0 Hz), 6.79 (dd,
20
yellow oil. [
d
a
]
þ14. 8 (c 2.35, CHCl3); 1H NMR (CDCl3, 500 MHz)
D
0.02 (s, 3H), 0.04 (s, 3H), 0.87 (s, 9H), 2.61 (d, 1H, J¼5.0 Hz), 3.72 (s,
3H), 3.99 (dd, 1H, J¼5.8, 6.7 Hz), 4.11 (ddd, 1H, J¼9.0, 4.0 and 2.0 Hz),
5.22 (dd, 1H, J¼10.5 and 1.0 Hz), 5.26 (dd, 1H, J¼17.5 and 1.0 Hz),
5.80 (ddd, 1H, J¼17.5, 10.5 and 7.0 Hz), 6.11 (dd, 1H, J¼15.5 and
2.0 Hz), 6.90 (dd, 1H, J¼15.5 and 4.0 Hz); 13C NMR (CDCl3, 125 MHz)
1H, J¼16.0 and 6.0 Hz); 13C NMR (CDCl3, 125 MHz)
d 51.7, 58.9, 67.7,
71.6, 74.5, 79.7, 94.3, 117.7, 123.6, 135.9, 144.0, 166.2; IR (neat): 3446,
3081, 2950, 1725, 1278, 1114, 1023 cmꢂ1; HRMS (ESI) calcd for
[MþNa]þ (C12H20NaO6) 283.1158, found 283.1157.
d
ꢂ5.0, ꢂ4.2,18.1, 25.7, 51.6, 74.0, 76.8, 118.0, 121.5, 137.1, 146.6, 166.7;
IR (neat): 3495, 3081, 2953, 2857, 1726, 1255 cmꢂ1; HRMS (FAB)
calcd for [MþH]þ(C14H27O4Si) 287.1679, found 287.1673.
4.5. (2E,6E)-(4R,5R,11R)-Methyl 11-acetoxy-5-hydroxy-
4-((2-methoxyethoxy)methoxy)-2,6-dodecadienoate (9a)
4.3. E-(4R,5R)-Methyl 5-(tert-butyldimethylsilyloxy)-
4-((2-methoxyethoxy)methoxy)-2,6-heptadienoate (6)
Grubbs catalyst 4 (17 mg, 0.02 mmol) was added to the solution of
compound 7 (100.0 mg, 0.38 mmol), (R)-8a (90.0 mg, 0.58 mmol),
and p-cresol (20.0 mg, 0.19 mmol) in dichloromethane (2 mL). The
reaction mixture was refluxed for 16 h under nitrogen, concentrated,
and purified by column chromatography (SiO2, EtOAc/hexanes, 1:1;
Methoxyethoxylmethyl chloride (MEMCl, 433.0 mg, 3.49 mmol)
was added to the solution of 5 (500.0 mg, 1.75 mmol), diisopropyl-
ethylamine (1.13 g, 8.74 mmol), and 1,2-dichloroethane (4 mL) in

228
K.-J. Lu et al. / Tetrahedron 65 (2009) 225–231
20
Rf 0.35) to give 9a (90.0 mg, 0.23 mmol, 60%) as a light brown oil. [
a
]
500 MHz)
d
1.04 (s, 9H), 1.14 (d, 3H, J¼6.5 Hz), 1.17–1.24 (m, 2H),
D
ꢂ43.3 (c 1.99, CHCl3); 1H NMR (CDCl3, 500 MHz)
d
1.17 (d, 3H,
1.28–1.48 (m, 2H), 1.81–1.88 (m, 2H), 2.00 (s, 3H), 3.30 (s, 3H), 3.38
(t, 2H, J¼5.0 Hz), 3.51 (t, 2H, J¼5.0 Hz), 3.72 (s, 3H), 4.10–4.12 (m,
1H), 4.22 (t, 1H, J¼5.5 Hz), 4.53 (d, 1H, J¼7.0 Hz), 4.56 (d, 1H,
J¼7.0 Hz), 4.77–4.83 (m, 1H), 5.26–5.35 (m, 2H), 5.97 (dd, 1H, J¼16.0
and 1.5 Hz), 6.95 (dd, 1H, J¼16.0 and 5.5 Hz), 7.30–7.40 (m, 6H),
J¼6.5 Hz), 1.31–1.55 (m, 4H), 2.00 (s, 3H), 2.00–2.05 (m, 2H), 3.02 (d,
1H, J¼4.0 Hz), 3.36 (s, 3H), 3.52 (t, 2H, J¼4.5 Hz), 3.65–3.70 (m, 1H),
3.72 (s, 3H), 3.77–3.82 (m, 1H), 4.00–4.03 (m, 1H), 4.08–4.11 (m, 1H),
4.70 (d, 1H, J¼7.0 Hz), 4.75 (d, 1H, J¼7.0 Hz), 4.82–4.87 (m, 1H), 5.39
(dd, 1H, J¼15.0 and 6.5 Hz), 5.68–5.76 (m, 1H), 6.00 (dd, 1H, J¼16.0
and 1.5 Hz), 6.76 (dd, 1H, J¼16.0 and 6.0 Hz); 13C NMR (CDCl3,
7.59–7.66 (m, 4H); 13C NMR (CDCl3, 125 MHz)
d 19.3, 19.9, 21.4, 24.6,
26.9, 31.8, 35.2, 51.5, 58.9, 67.0, 70.8, 71.5, 75.3, 78.6, 94.4, 122.5,
127.4, 127.6, 128.0, 129.6, 129.8, 133.7, 133.8, 133.9, 135.9, 135.9,
145.2, 166.6, 170.7; IR (neat): 3052, 2930, 1731, 1245, 1111,
125 MHz) d 19.9, 21.3, 24.7, 32.0, 35.3, 51.7, 59.0, 67.8, 70.8, 71.7, 74.4,
80.1, 94.4, 123.4, 127.9, 134.6, 144.3, 166.2, 170.8; IR (neat): 3446 (br),
2937, 1730, 1653, 1247, 1023 cmꢂ1; HRMS (APCI) calcd for [MþNa]þ
(C19H32NaO8) 411.1995, found 411.1992.
1044 cmꢂ1
649.3173, found 649.3188.
;
HRMS (ESI) calcd for [MþNa]þ (C35H50NaO8Si)
4.6. (2E,6E)-(4R,5R,11S)-Methyl 11-acetoxy-5-hydroxy-4-
((2-methoxyethoxy)methoxy)-2,6-dodecadienoate (9b)
4.9. E-(4S,5R,11R)-Methyl 11-acetoxy-5-(tert-
butyldiphenylsilyloxy)-3-(butylthio)-4-((2-
methoxyethoxy)methoxy)-6-dodecenoate (11a)
The procedure to prepare 9a was followed. Starting with com-
pound 7 (100.0 mg, 0.38 mmol), p-cresol (20.0 mg, 0.19 mmol), (S)-
A
reaction mixture of 10a (489.0 mg, 0.78 mmol), 1,8-di-
8b (90.0 mg, 0.58 mmol) and Grubbs catalyst
4
(17.0 mg,
azabicyclo[4.3.0]undec-7-ene (DBU, 24.0 mg, 0.16 mmol), and 1-
butanethiol (211.0 mg, 2.34 mmol) was heated in a 80 ꢀC oil bath for
3 h. The excess reagents were removed under vacuum, and the
crude product was purified by column chromatography (SiO2,
EtOAc/hexanes, 1:3; Rf 0.46) to give 11a (491 mg, 0.69 mmol, 88%)
0.02 mmol), the diene 9b (90.0 mg, 0.23 mol, 60%) was prepared.
20
[a]
ꢂ29.9 (c 2.20, CHCl3); 1H NMR (CDCl3, 500 MHz)
d 1.15 (d, 3H,
D
J¼6.0 Hz), 1.28–1.56 (m, 4H), 1.98 (s, 3H), 2.00–2.05 (m, 2H), 3.08 (d,
1H, J¼3.5 Hz), 3.35 (s, 3H), 3.51 (t, 2H, J¼4.0 Hz), 3.63–3.68 (m, 1H),
3.70 (s, 3H), 3.76–3.81 (m,1H), 3.96–4.02 (m,1H), 4.06–4.11 (m,1H),
4.68 (d, 1H, J¼7.0 Hz), 4.73 (d, 1H, J¼7.0 Hz), 4.80–4.86 (m, 1H), 5.38
(dd, 1H, J¼16.5 and 8.0 Hz), 5.66–5.74 (m, 1H), 5.99 (dd, 1H, J¼16.0
and 1.5 Hz), 6.75 (dd, 1H, J¼16.0 and 6.0 Hz); 13C NMR (CDCl3,
as a colorless oil. 1H NMR (CDCl3, 500 MHz)
d
0.85 (t, 3H, J¼7.0 Hz),
1.00 and 1.03 (s, 9H), 1.13 (d, 3H, J¼6.5 Hz), 1.21–1.51 (m, 8H), 1.63–
1.80 (m, 2H), 1.99 (s, 3H), 2.33–2.50 (m, 2H), 2.33–2.50 and 2.70–
2.76 (m, 2H), 3.32 and 3.35 (s, 3H), 3.36–3.40 (m, 1H), 3.40–3.59 (m,
4H), 3.64 and 3.66 (s, 3H), 3.68–3.73 (m, 1H), 3.76–3.83 (m, 1H),
4.68 (d,1H, J¼7.0 Hz), 4.12 (d,1H, J¼7.0 Hz), 4.73–4.81 (m,1H), 5.19–
5.35 (m, 2H), 7.29–7.40 (m, 6H), 7.60–7.70 (m, 4H); 13C NMR (CDCl3,
125 MHz)
d 19.8, 21.3, 24.6, 31.9, 35.2, 51.6, 58.9, 67.7, 70.6, 71.6,
74.3, 80.0, 94.3, 123.3, 127.9, 134.5, 144.3, 166.2, 170.7; IR (neat):
3447 (br), 2916, 1727, 1247, 1022 cmꢂ1; HRMS (ESI) calcd for
[MþNa]þ (C19H32NaO8) 411.1995, found 411.1996.
125 MHz) d 13.7, 19.3, 19.9, 21.3, 21.9, 24.4, 27.0, 31.5, 31.7, 31.9, 35.4,
36.5, 41.8, 51.6, 59.0, 67.3, 70.8, 71.7, 75.5, 83.3, 96.8, 127.2, 127.3,
127.5, 127.5, 128.8, 129.5, 129.7, 133.5, 135.9, 136.0, 136.0, 136.1,
170.7, 172.5; HRMS (ESI) calcd for [MþNa]þ (C39H60NaO8SSi)
739.3676, found 739.3683.
4.7. (2E,6E)-(4R,5R,11R)-Methyl 11-acetoxy-5-(tert-
butyldiphenylsilyloxy)-4-((2-methoxyethoxy)methoxy)-2,6-
dodecadienoate (10a)
The solution of compound 9a (358.0 mg, 0.92 mmol) in
dichloromethane (8.3 mL) was added with tert-butyldiphenyl-
chlorosilane (506.8 mg, 1.84 mmol) and imidazole (188.0 mg,
2.77 mmol) at 0 ꢀC. The reaction mixture was refluxed for 16 h,
quenched with water (15 mL), and extracted with ether (15 mLꢁ3).
The combined organic layer was dried over Na2SO4, filtered and
concentrated. The crude product was purified by column chroma-
4.10. E-(4S,5R,11S)-Methyl 11-acetoxy-5-(tert-
butyldiphenylsilyloxy)-3-(butylthio)-4-((2-
methoxyethoxy)methoxy)-6-dodecenoate (11b)
The procedure to prepare 11a was followed. Starting with 10b
(784.0 mg, 1.25 mmol), DBU(38.0 mg, 0.25 mmol), and 1-butane-
thiol (339.0 mg, 3.76 mmol), compound 11b (872.0 mg, 1.22 mol,
tography (SiO2, EtOAc/hexanes, 1:3; Rf 0.46) to give 10a (539.0 mg,
97%) was harvested. 1H NMR (CDCl3, 500 MHz)
d 0.84 (t, 3H,
20
0.86 mmol, 93%) as a colorless oil. [
(CDCl3, 500 MHz)
a]
ꢂ2.9 (c 2.20, CHCl3); 1H NMR
J¼7.0 Hz), 1.00 and 1.03 (s, 9H), 1.13 and 1.11(d, 3H, J¼6.5 Hz), 1.25–
1.50 (m, 8H), 1.71–1.78(m, 2H), 1.99(s, 3H), 2.33–2.50 (m, 2H), 2.33–
2.50 and 2.70–2.76 (m, 2H), 3.32 and 3.35 (s, 3H), 3.35–3.40 (m, 1H),
3.40–3.60 (m, 4H), 3.64 and 3.66 (s, 3H), 3.69–3.71 (m, 1H), 3.77–
3.82 (m, 1H), 4.68 (d, 1H, J¼7.0 Hz), 4.81 (d, 1H, J¼7.0 Hz), 4.74–4.80
(m,1H), 5.19–5.34 (m, 2H), 7.29–7.40 (m, 6H), 7.61–7.70 (m, 4H); 13C
D
d
1.04 (s, 9H), 1.14 (d, 3H, J¼6.0 Hz), 1.15–1.22 (m,
2H), 1.29–1.47 (m, 2H), 1.81–1.89 (m, 2H), 2.00 (s, 3H), 3.30 (s, 3H),
3.38 (t, 2H, J¼5.0 Hz), 3.50 (t, 2H, J¼5.0 Hz), 3.72 (s, 3H), 4.08–4.12
(m, 1H), 4.22 (t, 1H, J¼5.5 Hz), 4.53 (d, 1H, J¼7.0 Hz), 4.56 (d, 1H,
J¼7.0 Hz), 4.77–4.83 (m, 1H), 5.27–5.33 (m, 2H), 5.97 (dd, 1H, J¼15.5
and 1.5 Hz), 6.95 (dd, 1H, J¼15.5 and 5.0 Hz), 7.30–7.42 (m, 6H),
NMR (CDCl3, 125 MHz)
d 13.7, 19.3, 19.9, 21.3, 21.9, 24.4, 27.0, 31.5,
7.60–7.67 (m, 4H); 13C NMR (CDCl3, 125 MHz)
d
19.3, 19.9, 21.4, 24.7,
31.7, 31.9, 35.4, 36.5, 41.8, 51.6, 59.0, 67.3, 70.7, 71.7, 75.5, 83.2, 96.8,
127.2,127.3,127.4,127.5,128.8,129.5,129.7,133.5,135.9,136.0,136.0,
136.0, 170.7, 172.5; HRMS (ESI) calcd for [MþNa]þ (C39H60NaO8SSi)
739.3676, found 739.3669.
27.0, 31.8, 35.3, 51.5, 59.0, 67.1, 70.8, 71.5, 75.4, 78.6, 94.4, 122.5,
127.4,127.6,128.1,129.6,129.8,133.7,133.7,133.9,135.9,136.0,145.3,
166.6, 170.7; IR (neat): 3071, 2933, 1730, 1245, 1111 cmꢂ1; HRMS
(ESI) calcd for [MþNa]þ (C35H50NaO8Si) 649.3173, found 649.3174.
4.11. (4S,5R,11R)-Methyl 11-acetoxy-5-(tert-
butyldiphenylsilyloxy)-3-(butylthio)-4-((2-
methoxyethoxy)methoxy)-dodecanoate (12a)
4.8. (2E,6E)-(4R,5R,11S)-Methyl 11-acetoxy-5-(tert-
butyldiphenylsilyloxy)-4-((2-methoxyethoxy)methoxy)-2,6-
dodecadienoate (10b)
The suspension of palladium (5% on activated carbon, 414 mg)
and compound 11a (491.0 mg, 0.69 mmol) in methanol (5 mL) was
stirred under hydrogen (1 atm) for 30 h. The suspension was
filtered, and the filtrate was concentrated to give 12a (432.0 mg,
The procedure to prepare 10a was followed. Starting with 9b
(615.0 mg, 1.58 mmol in 15 mL dichloromethane), tert-butyldiphe-
nylchlorosilane (871.0 mg, 3.17 mmol), and imidazole (323.0 mg,
4.75 mmol), compound 10b (850.0 mg, 1.36 mol, 86%) was pre-
0.60 mmol, 88%) as a colorless oil. 1H NMR (CDCl3, 500 MHz)
d
0.85
20
pared as a colorless oil. [
a
]
ꢂ7.6 (c 1.60, CHCl3); 1H NMR (CDCl3,
(t, 3H, J¼7.0 Hz), 1.02 (s, 9H), 1.02–1.05 (m, 3H), 1.18 (d, 3H,
D

K.-J. Lu et al. / Tetrahedron 65 (2009) 225–231
229
J¼6.0 Hz), 1.20–1.42 (m, 6H), 1.42–1.50 (m, 2H), 1.98 (s, 3H), 2.45–
2.56 (m, 2H), 2.45–2.56 and 2.76–2.82 (m, 2H), 3.35 (s, 3H), 3.39–
3.44 (m, 1H), 3.44–3.64 (m, 4H), 3.66 and 3.68 (s, 3H), 3.70–3.73 (m,
1H), 3.73–3.82 (m, 1H), 4.71 (d, 1H, J¼7.0 Hz), 4.82 (d, 1H, J¼7.0 Hz),
4.72–4.79 (m, 1H), 7.31–7.41 (m, 6H), 7.61–7.71 (m, 4H); 13C NMR
0.23 mmol), the sulfone intermediate (82.2 mg, 0.109 mmol, 98%)
was produced. Then, the elimination of the sulfone (82.21 mg,
0.109 mmol) by DBU (50.88 mg, 0.33 mmol) provided 13b (50.0 mg,
20
0.08 mmol, 71%) as a colorless oil. [
a]
þ9.4 (c 2.41, CHCl3); 1H
D
NMR (CDCl3, 500 MHz)
d
0.97–1.12 (m, 4H), 1.04 (s, 9H), 1.13 (d, 3H,
(CDCl3, 125 MHz)
d
13.6, 19.4, 19.9, 21.3, 22.0, 24.9, 25.1, 27.1, 29.3,
J¼6.0 Hz), 1.16–1.32 (m, 4H), 1.35–1.45 (m, 2H), 1.99 (s, 3H), 3.32 (s,
3H), 3.39 (t, 2H, J¼5.5 Hz), 3.50 (t, 2H, J¼5.5 Hz), 3.73 (s, 3H), 3.75–
3.80 (m, 1H), 4.17–4.21 (m, 1H), 4.91 (d, 1H, J¼7.0 Hz), 4.51 (d, 1H,
J¼7.0 Hz), 4.74–4.81 (m, 1H), 6.00 (dd, 1H, J¼16.0 and 1.5 Hz), 7.04
(dd, 1H, J¼16.0 and 5.0 Hz), 7.31–7.44 (m, 6H), 7.63–7.67 (m, 4H);
31.2, 31.6, 33.0, 35.7, 37.2, 42.4, 51.6, 59.0, 67.6, 70.9, 71.7, 74.0, 82.1,
97.0, 127.4, 127.4, 127.5, 129.5, 129.6, 133.6, 134.6, 135.9, 135.9, 136.0,
170.7, 172.6; HRMS (ESI) calcd for [MþNa]þ (C39H62NaO8SSi)
741.3832, found 741.3835.
13C NMR (CDCl3, 125 MHz)
d 19.4, 19.9, 21.3, 25.1, 25.4, 27.0, 29.4,
4.12. (4S,5R,11S)-Methyl 11-acetoxy-5-(tert-
butyldiphenylsilyloxy)-3-(butylthio)-4-((2-
methoxyethoxy)methoxy)-dodecanoate (12b)
32.3, 35.7, 51.6, 59.0, 67.0, 71.0, 71.4, 74.4, 78.2, 94.4, 122.0, 127.3,
127.4, 127.6, 129.6, 129.7, 133.4, 133.8, 135.8, 135.9, 135.9, 145.5,
166.6, 170.7; IR (neat): 3073, 2932, 1730, 1245, 1011 cmꢂ1; HRMS
(ESI) calcd for [MþNa]þ (C35H52NaO8Si) 651.3329, found 651.3315.
The procedure to prepare 12a was followed. Starting with 11b
(859.0 mg, 1.19 mmol) and palladium (359.0 mg), compound 12b
(854.0 mg, 1.19 mmol, 99%) was produced. 1H NMR (CDCl3,
4.15. E-(4R,5R,11R)-5-(tert-Butyldiphenylsilyloxy)-11-
hydroxy-4-((2-methoxyethoxy)methoxy)-2-dodecenoic
acid (14a)
500 MHz)
d
0.85 (t, 3H, J¼7.0 Hz),1.02 (s, 9H),1.02–1.06 (m, 3H),1.12
(d, 3H, J¼6.5 Hz), 1.20–1.42 (m, 6H), 1.42–1.51 (m, 2H), 1.99 (s, 3H),
2.45–2.56 (m, 2H), 2.45–2.56 and 2.75–2.81 (m, 2H), 3.35 (s, 3H),
3.38–3.42 (m, 1H), 3.44–3.64 (m, 4H), 3.66 and 3.68 (s, 3H), 3.70–
3.72 (m, 1H), 3.77–3.83 (m, 1H), 4.71 (d, 1H, J¼7.0 Hz), 4.82 (d, 1H,
J¼7.0 Hz), 4.72–4.79 (m, 1H), 7.30–7.40 (m, 6H), 7.60–7.73 (m, 4H);
The solution of 13a (93.0 mg, 0.15 mmol) and lithium hydroxide
(62.2 mg, 1.48 mmol) in THF/water (1:1, 2.4 mL) was stirred at room
temperature for 16 h. The reaction mixture was neutralized
(pHw4) by adding HCl(aq) (1 N), and extracted with ethyl acetate
(5 mLꢁ3). The combined organic layer was dried over Na2SO4, fil-
13C NMR (CDCl3, 125 MHz)
d 13.7, 19.4, 19.9, 21.4, 22.0, 24.8, 25.1,
27.0, 29.2, 31.2, 31.6, 33.0, 35.7, 37.2, 42.4, 51.7, 59.0, 67.5, 71.0, 71.7,
74.0, 82.0, 97.0, 127.4, 127.4, 127.5, 129.5, 129.6, 133.6, 134.6, 135.9,
136.0, 170.7, 172.6; HRMS (FAB) calcd for [M]þ (C39H62O8SSi)
718.3933, found 718.3938.
tered, and concentrated to give the acid 14a (85.0 mg, 0.15 mmol,
20
99%) as a colorless oil. [
500 MHz)
a
]
D
þ12.6 (c 1.60, CHCl3); 1H NMR (CDCl3,
d
0.99–1.09 (m, 4H), 1.04 (s, 9H), 1.12 (d, 3H, J¼6.0 Hz),
1.14–1.34 (m, 6H), 3.32 (s, 3H), 3.40 (t, 2H, J¼5.0 Hz), 3.51(t, 2H,
J¼5.0 Hz), 3.65–3.73(m, 1H), 3.76–3.84 (m, 1H), 4.18–4.23 (m, 1H),
4.50 (d,1H, J¼7.0 Hz), 4.51 (d,1H, J¼7.0 Hz), 6.01 (dd,1H, J¼16.0 and
1.5 Hz), 7.15 (dd, 1H, J¼16.0 and 4.5 Hz), 7.32–7.45 (m, 6H), 7.63–
4.13. E-(4R,5R,11R)-Methyl 11-acetoxy-5-(tert-
butyldiphenylsilyloxy)-4-((2-methoxyethoxy)methoxy)-2-
dodecenoate (13a)
7.68 (m, 4H); 13C NMR (CDCl3, 125 MHz)
d 19.3, 20.7, 23.2, 25.3, 27.0,
29.4, 32.3, 39.0, 59.0, 67.1, 68.1, 71.4, 74.4, 78.3, 94.5, 121.7, 127.4,
127.6, 129.6, 129.7, 133.4, 133.8, 135.9, 135.9, 147.7, 170.5; IR (neat)
3404 (br), 3071, 2929, 1702, 1110, 1040 cmꢂ1; HRMS (ESI) calcd for
[MþNa]þ (C32H48NaO7Si) 595.3067, found 595.3078.
m-Chloroperbenzoic acid (312.0 mg, 1.26 mmol) in dichloro-
methane (3.2 mL) was added to the solution of 12a (432.0 mg,
0.60 mmol) in dichloromethane (1.5 mL) at 0 ꢀC. The reaction
mixture was stirred at 0 ꢀC for 2 min, at room temperature for
another 1 h, quenched with satd NaHCO3(aq) (10 mL), and extracted
with dichloromethane (10 mLꢁ3). The combined organic layer was
dried over Na2SO4, filtered, and concentrated to give the sulfone
intermediate (450.0 mg, 0.60 mmol, 99%). The crude sulfone
was redissolved in dichloromethane (30 mL), cooled to 0 ꢀC, and
added with 1,8-diazabicyclo[4.3.0]undec-7-ene (DBU, 274.0 mg,
1.80 mmol). After stirred at 0 ꢀC for 1 h, the reaction mixture was
concentrated. The crude product was purified by column chroma-
4.16. E-(4R,5R,11S)-5-(tert-Butyldiphenylsilyloxy)-11-hydroxy-
4-((2-methoxyethoxy)methoxy)-2-dodecenoic acid (14b)
The procedure to prepare 14a was followed. Starting with
13b (258.0 mg, 0.41 mmol) and lithium hydroxide (172.0 mg,
4.10 mmol, in water and THF, 3 mL each), the acid 14b (235.0 mg,
20
4.10 mmol, 99%) was produced. [
(CDCl3, 500 MHz)
a
]
D
þ15.3 (c 1.98, CHCl3); 1H NMR
d
1.03–1.07 (m, 4H), 1.04 (s, 9H), 1.12 (d, 3H,
tography (SiO2, EtOAc/hexanes, 1:3; Rf 0.40) to give 13a (325 mg,
J¼6.0 Hz), 1.15–1.36 (m, 6H), 3.32 (s, 3H), 3.40 (t, 2H, J¼5.0 Hz), 3.52
(t, 2H, J¼5.0 Hz), 3.66–3.73 (m, 1H), 3.78–3.83 (m, 1H), 4.19–4.23
(m, 1H), 4.50 (d, 1H, J¼7.0 Hz), 4.52 (d, 1H, J¼7.0 Hz), 6.02 (dd, 1H,
J¼16.0 and 1.5 Hz), 7.15 (dd, 1H, J¼16.0 and 4.5 Hz), 7.32–7.44 (m,
20
0.52 mmol, 86%) as a colorless oil. [
NMR (CDCl3, 500 MHz)
a
]
þ14.2 (c 1.39, CHCl3); 1H
D
d
1.02–1.12 (m, 4H), 1.04 (s, 9H), 1.14 (d, 3H,
J¼6.0 Hz), 1.15–1.34 (m, 4H), 1.35–1.47 (m, 2H), 1.99 (s, 3H), 3.32 (s,
3H), 3.39 (t, 2H, J¼5.0 Hz), 3.51 (t, 2H, J¼5.0 Hz), 3.74 (s, 3H), 3.76–
3.80 (m, 1H), 4.17–4.21 (m, 1H), 4.49 (d, 1H, J¼7.0 Hz), 4.51 (d, 1H,
J¼7.0 Hz), 4.75–4.82 (m, 1H), 6.00 (dd, 1H, J¼16.0 and 1.5 Hz), 7.04
(dd,1H, J¼16.0 and 5.0 Hz), 7.32–7.43 (m, 6H), 7.63–7.67(m, 4H); 13C
6H), 7.63–7.68 (m, 4H); 13C NMR (CDCl3, 125 MHz)
d 19.4, 23.2, 25.4,
27.0, 27.0, 29.4, 32.3, 39.0, 58.9, 67.1, 68.1, 71.5, 74.4, 78.4, 94.5, 121.8,
127.3, 127.5, 127.6, 129.6, 129.8, 133.4, 133.8, 135.8, 135.9, 136.0,
147.8, 170.6; HRMS (ESI) calcd for [MþNa]þ (C32H48NaO7Si)
595.3067, found 595.3067.
NMR (CDCl3, 125 MHz)
d 19.4, 19.9, 21.4, 25.1, 25.4, 27.1, 29.3, 32.3,
35.7, 51.6, 59.0, 67.1, 71.0, 71.5, 74.5, 78.3, 94.4, 122.5, 127.5, 127.6,
129.5, 129.6, 129.7, 129.8, 133.5, 133.9, 135.9, 136.0, 145.5, 166.6,
170.7; IR (neat): 2933, 1730, 1245, 1010 cmꢂ1; HRMS (ESI) calcd for
[MþNa]þ (C35H52NaO8Si) 651.3329, found 651.3320.
4.17. E-(5R,6R,12R)-6-(tert-Butyldiphenylsilyloxy)-5-((2-
methoxyethoxy)methoxy)-12-methyloxacyclododec-3-en-2-
one (15a)
4.14. E-(4R,5R,11S)-Methyl 11-acetoxy-5-(tert-
butyldiphenylsilyloxy)-4-((2-methoxyethoxy)methoxy)-2-
dodecenoate (13b)
2,4,6-Trichlorobenzoyl chloride (54.90 mg, 0.23 mmol) was
added to the solution of 14a (85.0 mg, 0.15 mmol), triethylamine
(23.0 mg, 0.23 mmol), and THF (2.4 mL). The solution was stirred at
room temperature for 3 h, diluted with toluene (6 mL), and added
into a refluxing solution of 4-dimethylaminopyridine (91 mg,
0.74 mmol) and toluene (20 mL). The reaction mixture was refluxed
The procedure to prepare 13a was followed. Starting with 12b
(80.0 mg, 0.11 mmol) and m-chloroperbenzoic acid (58.0 mg,

230
K.-J. Lu et al. / Tetrahedron 65 (2009) 225–231
for 3 h, cooled to room temperature, added with satd NaHCO3(aq)
(10 mL). The organic layer was separated, and the aqueous layer
was further extracted with ethyl acetate (10 mLꢁ3). The combined
organic layer was washed with satd CuSO4(aq), water (10 mL), and
satd NaCl(aq) (10 mL), dried over Na2SO4, filtered, and concentrated.
The crude product was purified by column chromatography (SiO2,
0.63 mmol, 0.2 M in DCM) in dichloromethane (4 mL), alcohol 16b
20
(57.6 mg, 0.12 mmol, 98%) was produced. [
a
]
ꢂ7.8 (c 1.15, CHCl3);
D
1H NMR (CDCl3, 500 MHz)
d
1.06 (s, 9H), 1.08–1.22 (m, 4H), 1.24 (d,
3H, J¼7.0 Hz), 1.30–1.57 (m, 6H), 2.40 (br, 1H), 3.39–3.46 (m, 1H),
4.22–4.27 (m, 1H), 4.98–5.06 (m, 1H), 6.03 (dd, 1H, J¼16.0 and
2.0 Hz), 6.94 (dd, 1H, J¼16.0 and 4.5 Hz), 7.35–7.44 (m, 6H), 7.64–
EtOAc/hexanes, 1:3; Rf 0.60) to give 15a (60 mg, 0.11 mmol, 73%) as
7.67 (m, 4H); 13C NMR (CDCl3, 125 MHz)
d 19.0, 19.3, 22.8, 23.8, 27.0,
20
a colorless oil. [
d
a
]
D
ꢂ0.4 (c 1.60, CHCl3); 1H NMR (CDCl3, 500 MHz)
27.9, 32.5, 33.0, 72.7, 77.2, 79.8,121.6,127.7,127.9,129.8,130.0,133.3,
133.6, 135.7, 135.7, 146.9, 166.9; HRMS (ESI) calcd for [MþNa]þ
(C28H38NaO4Si) 489.2437, found 489.2434.
1.01–1.22 (m, 6H), 1.06 (s, 9H), 1.25 (d, 3H, J¼6.5 Hz), 1.22–1.50 (m,
4H), 3.31 (s, 3H), 3.38 (t, 2H, J¼5.0 Hz), 3.45 (t, 2H, J¼5.0 Hz), 3.93–
3.98 (m, 1H), 4.03–4.08 (m, 1H), 4.45 (d, 1H, J¼7.0 Hz), 4.50 (d, 1H,
J¼7.0 Hz), 5.07–5.16 (m, 1H), 6.09 (dd, 1H, J¼16.0 and 1.5 Hz), 6.89
(dd,1H, J¼16.0 and 6.5 Hz), 7.32–7.42 (m, 6H), 7.59–7.69 (m, 4H); 13C
4.21. E-(6R,12R)-6-(tert-Butyldiphenylsilyloxy)-12-
methyloxacyclododec-3-ene-2,5-dione (17a)
NMR (CDCl3, 125 MHz) d 19.2, 19.3, 22.2, 23.7, 26.9, 28.5, 30.0, 32.8,
58.9, 66.9, 71.4, 72.9, 74.5, 79.4, 94.0, 123.2, 127.5, 127.6, 129.6, 129.7,
133.7, 133.8, 135.7, 135.8, 145.4, 167.4; IR (neat): 3071, 2932, 1719,
1212, 1042 cmꢂ1; HRMS (ESI) calcd for [MþNa]þ (C32H46NaO6Si)
577.2961, found 577.2965.
Dess–Martin periodinane (60.0 mg, 0.14 mmol) was added to
the solution of 16a (33.0 mg, 0.07 mmol) and dichloromethane
(2 mL). The reaction mixture was stirred at room temperature for
2.5 h, added with satd NaHCO3(aq) (5 mL), and extracted with
dichloromethane (5 mLꢁ3). The combined organic layer was
washed with water (5 mL), dried over Na2SO4, filtered, and con-
centrated. The crude product was purified by column chromatog-
4.18. E-(5R,6R,12S)-6-(tert-Butyldiphenylsilyloxy)-5-((2-
methoxyethoxy)methoxy)-12-methyloxacyclododec-3-
en-2-one (15b)
raphy (SiO2, EtOAc/hexanes, 1:3; Rf 0.80) to give 17a (28 mg,
20
0.06 mmol, 85%) as a colorless oil. [
NMR (CDCl3, 500 MHz)
a
]
D
ꢂ21.4 (c 0.65, CHCl3); 1H
The procedure to prepare 15a was followed. Starting with 14b
(235.0 mg, 0.41 mmol), triethylamine (62.2 mg, 0.62 mmol), 2,4,6-
trichlorobenzoyl chloride (149.0 mg, 0.62 mmol), and DMAP
d
1.09 (s, 9H), 1.21–1.36 (m, 6H), 1.20 (d, 3H,
J¼6.0 Hz), 1.39–1.48 (m, 2H), 1.58–1.73 (m, 2H),4.36–4.40 (m, 1H),
4.83–4.90 (m, 1H), 6.62 (d, 1H, J¼16.0 Hz), 6.99 (d, 1H, J¼16.0 Hz),
7.32–7.46 (m, 6H), 7.60–7.66 (m, 4H); 13C NMR(CDCl3, 125 MHz)
(250.0 mg, 2.05 mmol) in toluene (72 mL), the lactone 15b
20
(178.0 mg, 0.32 mmol, 78%) was harvested as a colorless oil. [a]
D
d
19.2, 20.6, 24.0, 26.5, 26.9, 27.6, 34.0, 35.0, 75.4, 78.8, 127.7, 127.7,
ꢂ1.7 (c 1.55, CHCl3); 1H NMR (CDCl3, 500 MHz)
d 1.04–1.25 (m, 6H),
127.8, 130.0, 130.0, 131.1, 132.7, 133.3, 134.8, 135.7, 135.9, 137.9, 166.7,
200.1; HRMS (ESI) calcd for [MþNa]þ (C28H36NaO4Si) 487.2281,
found 487.2274.
1.07 (s, 9H), 1.27 (d, 3H, J¼6.5 Hz), 1.36–1.55 (m, 4H), 3.32 (s, 3H),
3.41 (t, 2H, J¼5.0 Hz), 3.57 (t, 2H, J¼5.0 Hz), 3.75–3.82 (m, 1H), 4.15–
4.21 (m, 1H), 4.56 (d, 1H, J¼7.0 Hz), 4.59 (d, 1H, J¼7.0 Hz), 4.94–5.02
(m, 1H), 6.02 (dd, 1H, J¼16.0 and 2.0 Hz), 7.05 (dd, 1H, J¼16.0 and
4.0 Hz), 7.33–7.42 (m, 6H), 7.62–7.70 (m, 4H); 13C NMR (CDCl3,
4.22. E-(6R,12S)-6-(tert-Butyldiphenylsilyloxy)-12-
methyloxacyclododec-3-ene-2,5-dione (17b)
125 MHz) d 19.3,19.8, 22.6, 23.8, 27.0, 27.9, 31.8, 32.7, 58.9, 67.1, 71.5,
73.1, 76.0, 80.8, 94.8, 121.7, 127.5, 127.6, 129.7, 129.7, 133.6, 134.1,
135.8, 135.8, 146.5, 166.9; IR (neat): 3071, 2931, 1715, 1212,
The procedure to prepare 17a was followed. Starting with Dess–
Martin periodinane (58.0 mg, 0.14 mmol) and 16b (32.0 mg,
0.07 mmol) in dichloromethane (2 mL), the ketone 17b (25.0 mg,
1039 cmꢂ1
;
HRMS (ESI) calcd for [MþNa]þ (C32H46NaO6Si)
577.2961, found 577.2964.
0.05 mmol, 78%; Rf 0.80, EtOAc/hexanes) was produced as a color-
20
less oil. [
a]
ꢂ13.2 (c 1.10, CHCl3); 1H NMR (CDCl3, 500 MHz)
d 1.10
D
4.19. E-(5R,6R,12R)-6-(tert-Butyldiphenylsilyloxy)-5-hydroxy-
12-methyloxacyclododec-3-en-2-one (16a)
(s, 9H), 1.17–1.47 (m, 6H), 1.33 (d, 3H, J¼6.0 Hz), 1.47–1.57 (m, 2H),
1.60–1.81 (m, 2H), 4.36–4.40 (m, 1H), 4.48–4.57 (m, 1H), 6.73 (d, 1H,
J¼16.5 Hz), 7.34 (d, 1H, J¼16.5 Hz), 7.32–7.46 (m, 6H), 7.52–7.57 (m,
B-Bromocatechol-borane (3.9 mL, 0.78 mmol, 0.2 M in DCM)
was added to the solution of 15a (42.0 mg, 0.08 mmol) and
dichloromethane (2 mL). The reaction mixture was stirred at room
temperature for 20 h, quenched with water (5 mL), and extracted
with dichloromethane (5 mLꢁ3). The combined organic layer was
washed with satd NaCl(aq) (5 mL), dried over Na2SO4, filtered, and
concentrated. The crude product was purified by column chroma-
2H), 7.61–7.64 (m, 2H); 13C NMR (CDCl3, 125 MHz)
d 19.2, 20.5, 21.5,
24.0, 26.9, 27.2, 33.9, 34.6, 74.8, 76.7, 127.7, 127.8, 130.0, 130.1, 131.4,
132.4, 133.0, 134.6, 135.6, 135.7, 167.3, 200.7; HRMS (ESI) calcd for
[MþNa]þ (C28H36NaO4Si) 487.2281, found 487.2287.
4.23. E-(6R,12R)-6-Hydroxy-12-methyloxacyclododec-3-ene-
tography (SiO2, EtOAc/hexanes, 1:3; Rf 0.60) to give 16a (33 mg,
2,5-dione (1a)
20
0.07 mmol, 93%) as a colorless oil. [
NMR (CDCl3, 500 MHz)
a
]
D
þ25.0 (c 0.80, CHCl3); 1H
d
1.06 (s, 9H), 1.08–1.22 (m, 4H), 1.24 (d, 3H,
Tetrabutylammonium fluoride (0.16 mL, 0.16 mmol, 1 M in THF)
was slowly added to the solution of 17a (25.0 mg, 0.05 mmol),
acetic acid (32.0 mg, 0.54 mmol), and THF (1 mL) in 6 h. The re-
action mixture was stirred at room temperature for another 16 h
and concentrated. The crude product was purified by column
J¼6.5 Hz), 1.26–1.46 (m, 6H), 2.07–2.12 (br, 1H), 3.70–3.76 (m, 1H),
4.07–4.13 (m, 1H), 4.96–5.04 (m, 1H), 6.05 (dd, 1H, J¼16.0 and
1.5 Hz), 6.83 (dd, 1H, J¼16.0 and 7.5 Hz), 7.35–7.45 (m, 6H), 7.63–
7.69 (m, 4H); 13C NMR (CDCl3,125 MHz)
d 19.2, 20.0, 22.7, 24.0, 26.5,
26.9, 31.0, 33.1, 73.4, 76.4, 77.6, 123.2, 127.6, 127.9, 129.8, 129.9,
133.5,134.7,135.7, 135.7,145.4, 167.3; HRMS (ESI) calcd for [MþNa]þ
(C28H38NaO4Si) 489.2437, found 489.2431.
chromatography (SiO2, EtOAc/hexanes, 1:1; Rf 0.40) to give 1a
20
(5.0 mg, 0.02 mmol, 42%) as a colorless oil. [
a
]
ꢂ27.2 (c 0.2,
D
20
CHCl3); [
a]
ꢂ6.2 (c 0.2, MeOH); 1H NMR (CDCl3, 500 MHz)
d 1.15–
D
1.35 (m, 6H), 1.27 (d, 3H, J¼6.5 Hz), 1.51–1.73 (m, 4H), 2.90 (br,
1H),4.41–4.47 (m, 1H), 4.92–5.02 (m, 1H), 6.21 (d, 1H, J¼13.0 Hz),
4.20. E-(5R,6R,12S)-6-(tert-Butyldiphenylsilyloxy)-5-hydroxy-
12-methyloxacyclododec-3-en-2-one (16b)
6.57 (d, 1H, J¼13.0 Hz); 13C NMR(CDCl3, 125 MHz)
d 18.7, 18.8, 21.5,
27.3, 31.0, 31.2, 74.0, 76.0, 130.3, 134.8, 164.6, 203.2; IR (neat): 3445
(br), 2925, 2855, 1717, 1625, 1259, 1114 cmꢂ1; HRMS (ESI) calcd for
[MþNa]þ (C12H18NaO4) 249.1103, found 249.1103.
The procedure to prepare 16a was followed. Starting with 15b
(70.0 mg, 0.13 mmol) and B-bromocatechol-borane (3.16 mL,

K.-J. Lu et al. / Tetrahedron 65 (2009) 225–231
231
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Hydrogen fluoride/pyridine (65–70%, 0.05 mL) diluted with
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EtOAc/hexanes, 1:1; Rf 0.40) to give 1b (2 mg, 0.013 mmol, 46%) as
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20
20
a colorless oil. [
a
]
þ56.9 (c 0.15, MeOH); [
a
]
D
þ22.6 (c 0.1, CHCl3);
D
1H NMR(CDCl3, 500 MHz)
d
1.30 (d, 3H, J¼6.0 Hz), 1.32–1.52 (m,
6H), 1.63–1.75 (m, 4H), 3.18 (d, 1H, J¼5.5 Hz), 4.63–4.69 (m, 1H),
5.20–5.26 (m, 1H), 6.31 (d, 1H, J¼13.5 Hz), 6.41 (d, 1H, J¼13.5 Hz);
13C NMR (CDCl3, 125 MHz)
d 20.6, 21.5, 21.6, 23.0, 31.0, 33.2, 71.5,
73.5, 130.9, 133.3, 165.4, 203.5; IR (neat): 3458 (br), 2928, 2855,
1721, 1623, 1226, 1083 cmꢂ1; HRMS (FAB) calcd for [M]þ (C12H18O4)
226.1205, found 226.1206.
Acknowledgements
This research was supported by the National Science Council
(NSC 95-2113-M-008-007), Taiwan. We are grateful to Ms. Ping-Yu
Lin at the Institute of Chemistry, Academia Sinica, and Valuable
Instrument Center in National Central University for obtaining
mass analysis. Thanks are also due to the National Center for High-
performance Computing for computer time and facilities.
11. The free hydroxyl group enhances the reactivity of the olefin in CM: Chat-
terjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360.
12. (a) Lin, W.; Zercher, C. K. J. Org. Chem. 2007, 72, 4390; (b) Uenishi, J.; Ohmi, M.;
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13. A very related example showed that the regio-selective hydrogenation is dif-
ficult to achieve: Trost, B. M.; Aponick, A. J. Am. Chem. Soc. 2006, 128, 3931 and
Ref. 7c.
Supplementary data
1H NMR and 13C NMR spectra for all the synthesized compounds
are available. Supplementary data associated with this article can
be found in the online version, at doi:10.1016/j.tet.2008.10.059.
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