First total synthesis and determination of the absolute configuration of mueggelone

Article abstract of DOI:10.1016/S0040-4020(01)00279-4

All the four possible stereoisomers of mueggelone, an inhibitor of fish development, were efficiently synthesized in a stereoselective manner starting from D-arabinose, and the absolute configuration was determined to be 9R, 12S, 13S.

Full text of DOI:10.1016/S0040-4020(01)00279-4

TETRAHEDRON
Pergamon
Tetrahedron 57 02001) 3899±3908
First total synthesis and determination of the absolute
con®guration of mueggelone
Hajime Motoyoshi, Ken Ishigami and Takeshi Kitaharap
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi,
Bunkyo-ku, Tokyo 113-8657, Japan
Received 15 February 2001;accepted 5 March 2001
AbstractÐAll the four possible stereoisomers of mueggelone, an inhibitor of ®sh development, were ef®ciently synthesized in a stereo-
selective manner starting from d-arabinose, and the absolute con®guration was determined to be 9R, 12S, 13S. q 2001 Elsevier Science Ltd.
All rights reserved.
1. Introduction
2. Results and discussion
Mueggelone 01) has attracted the keen interest of scientists
for its unique activity and structure since it was isolated
from a bloom-foaming strain of Aphanizomenon ¯os-aquae
in 1995 0Fig. 1).1 With mueggelone at a concentration of
10 mg/mL, zebra ®sh larvae showed 45% mortality and the
surviving larvae showed edema in the heart region and
thrombosis. This compound is thought to play an eco-
logically important role in inhibition of the development
of herbivorous ®sh. Mueggelone was found to have a
10-membered lactone and trans epoxide by spectroscopic
analysis;however, no information has been obtained on the
absolute con®guration of the three stereocenters. Therefore,
we undertook the synthesis of all the four possible stereo-
isomers of mueggelone 01, ent-1, 2, ent-2) to determine the
absolute con®guration and to provide samples for further
biological assay. We have already published a rapid
communication,2 and here we wish to report a full account
of our work.
Our synthetic strategy is illustrated in Scheme 1. We
decided to utilize the key intermediate A, which could be
transformed into any of the four stereoisomers via asym-
metric reduction of a ketone, macrolactonization and ®nally,
epoxide formation. Compound A would be constructed by
Horner±Wadsworth±Emmons 0HWE) reaction of the side
chain part B with the lactone part C. Aldehyde B and phos-
phonate C would be derived from commercially available
compounds, d-arabinose and azelaic acid dimethyl ester,
respectively.
The synthesis of the side chain part is outlined in Scheme 2.
d-Arabinose was converted into alcohol 3 according to the
known procedure.3 Protection of the hydroxyl group
followed by hydrolysis of thioacetal with mercuric salt
gave aldehyde 5, which was submitted to the Wittig
reaction to afford Z-ole®n 6. The best ratio 0E/Zˆ1:10)
was provided by using NaHMDS as a base, and these
isomers were easily separated by AgNO3-impregnated silica
gel column chromatography. The Z-ole®n 6 was simply
transformed into the corresponding primary alcohol 10 in
4 steps, which was then mildly oxidized4 to give the desired
aldehyde 11.
O
1
O
Phosphonate 12 0prepared from azelaic acid dimethyl ester,
dimethyl methylphosphonate, n-BuLi, THF, 2788C, 22%)
was subjected to HWE reaction with the aldehyde 11
0Scheme 3). Under the condition using n-BuLi as a base,
the E/Z ratio was 96:4;however, partial epimerization
025%) of the TBSO± group was observed. On the other
hand, the procedure employing DBU±LiCl5 resulted in
very little epimerization 01±2%) with excellent E/Z selec-
tivity 0E=Z ˆ. 99 : 1). In the next step, we tried several
conditions for the asymmetric reduction of enone 13, and
the best selectivity 09:1) was obtained with the CBS-
O
18
15
13
9
12
Mueggelone (1)
Figure 1.
Keywords: asymmetric synthesis;reduction;lactonization;epoxides.
Corresponding author. Tel.: 181-03-5841-5119;fax: 181-03-5841-
8019;e-mail: atkita@mail.ecc.u-tokyo.ac.jp
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020001)00279-4

3900
H. Motoyoshi et al. / Tetrahedron 57 42001) 3899±3908
PMBO
B
CHO
OTBS
MeO2C
O
PMBO
Mueggelone (1)
MeO2C
O
OTBS
A
O
P
MeO
MeO
C
Scheme 1. Synthetic strategy toward mueggelone.
HO
O
PMBO
OHC
SEt OR
4 steps, 45%
b
c
O
EtS
O
HO
OH
O
O
OH
3: R = H
4: R = PMB
D-Arabinose
5
a
PMBO
6
PMBO
OR'
PMBO
g
d
R
O
OR
O
OTBS
7: R = H, R' = H
10: R = CH2OH
11: R = CHO
e
f
h
8: R = Piv, R' = H
9: R = Piv, R' = TBS
Scheme 2. 0a) PMBCl, NaH, DMF, 100%;0b) HgCl 2, HgO, CH3CN, H2O, 85%;0c) n-propyltriphenylphosphonium bromide, NaHMDS, Et2O, 2788C, 68%,
E/Zˆ1:10;0d) TFA, THF, H 2O, 408C, 96%;0e) PivCl, pyridine, 93%;0f) TBSCl, imidazole, DMF, 98%;0g) DIBAL, CH 2Cl2, 250 to 2108C, 93%;0h) Dess±
Martin periodinane, CH2Cl2, 96%.
MeO2C
O
PMBO
O
P
O
a
MeO
MeO
CO2Me
OTBS
13
12
MeO2C
OH
MeO2C
OH
PMBO
PMBO
Reduction (Table 1)
+
OTBS
OTBS
14β
14α
O
HO2C
OH
PMBO
PMBO
O
b
c
14α
OTBS
OTBS
15α
16α
Scheme 3. 0a) DBU, LiCl, 11, CH3CN, 93%, E=Z . 99 : 1;0b) LiOHH 2O, MeOH, 91%;0c) 2,4,6-trichlorobenzoyl chloride, NEt 3, THF, then DMAP, toluene,
0.6 mM, re¯ux, 12 h, 68%.
reagent6 and borane±THF complex 0Table 1). The resultant
two isomers and other minor and undesired isomers 010Z-
isomers, C-12 epimers) were cleanly separated by prepara-
tive HPLC and the stereochemistry of each isomer
was con®rmed by modi®ed Mosher's method 0Table 2).7
Hydrolysis of 14a with LiOH furnished pure hydroxy-
carboxylic acid 15a. Lactonization of 15a was successfully
achieved by Yamaguchi's method8 to provide 16a in satis-
factory yield, together with a small amount of a dimeric
lactone 05±10%). On the other hand, Corey±Mukaiyama's
method9 was found to give only several unassignable
compounds.

H. Motoyoshi et al. / Tetrahedron 57 42001) 3899±3908
3901
Table 1. Reduction of enone 13
O
Entry
Conditions of reduction
Yield 0%)
Ratio 014a:14b)
PMBO
O
1
2
3
NaBH4, CeCl3, MeOH
l-Selectride, THF
0S)±CBS reagent,
BH3´SMe2, THF
0R)±CBS reagent,
BH3´SMe2, THF
0S)±CBS reagent,
BH3´THF, THF
80
±
±
1:2
1:2
3:1
OMs
21α
4
5
6
58
66
65
1:2
9:1
1:9
Figure 2.
Table 3. 13C NMR 075.5 Hz, CDCl3) data for natural mueggelone, 1/ent-1
and 2/ent-2
0R)±CBS reagent,
BH3´THF, THF
Carbon
natural1
1/ent-1
2/ent-2
Table 2. 1H NMR 0300 MHz, CDCl3) data for 0S)- and 0R)-MTPA ester of
14b
1
2
3
4
5
6
7
8
173.5
35.1
29.9
27.1
24.2
23.7
23.4
20.7
74.9
132.8
128.6
57.4
59.9
29.6
122.3
135.0
20.7
14.2
173.4
35.0
29.8
27.0
24.1
23.6
23.3
20.7
74.8
132.7
128.5
57.4
59.9
29.5
122.2
134.9
20.7
14.2
173.4
35.1
29.9
27.0
24.2
23.6
23.4
20.7
75.1
132.8
129.1
57.3
59.9
29.5
122.2
134.9
20.7
14.2
MTPA
PMBO
O
13
CO2Me
10
8
2
OTBS
14β MTPA ester
1H chemical shift 0d)
9
10
11
12
13
14
15
16
17
18
position
0S)-MTPA
0R)-MTPA
dS 2 dR
2
8
10
11
12
13
2.28
1.63
5.68
5.94
4.14
3.32
2.29
1.64
5.60
5.83
4.12
3.30
20.01
20.01
10.08
10.11
10.02
10.02
In the following epoxide formation stage 0Scheme 4), we
anticipated that stereochemistry of the epoxide could be
controlled by the direction of elimination. Initially, we
decided to synthesize the 012R,13R)-isomer such as 2.
Removal of the PMB group with DDQ10 proceeded without
complication. Mesylation of alcohol 17a followed by treat-
ment with TBAF provided the desired epoxylactone 2 in
good yield. Next, we tried to obtain the 012S,13S)-isomer
by changing the position of the leaving group. So, allylic
mesylate 21a 0Fig. 2) was prepared from 16a;however, it
O
O
O
OR
O
a
c
O
16α
2
OTBS
[α]D = 68.7
17α: R = H
b
18α: R = Ms
O
O
TBDPSO
O
O
O
d
f
17α
1
OR
[α]D = 28.7
19α: R = TBS
20α: R = H
e
O
O
O
O
O
O
14β
ent-2
ent-1
[α]D = –67.3
[α]D = –28.2
Scheme 4. 0a) DDQ, NaHCO3, CH2Cl2, H2O, 99%;0b) Ms 2O, NEt3, DMAP, CH2Cl2, rt, 90%;0c) TBAF, THF, 87%;0d) TBDPSCl, imidazole, DMF, 91%;
0e) HF, CH3CN, 51%;0f) MsCl, NEt , DMAP, CH2Cl2, 08C, then TBAF, THF, 94%.
3

3902
H. Motoyoshi et al. / Tetrahedron 57 42001) 3899±3908
readily decomposed under the conditions of PMB deprotec-
tion. Therefore, we had to change the PMB group for
another protecting group. Masking the hydroxyl group of
17a with TBDPSCl was followed by selective removal of
the TBS group with HF/acetonitrile to give the correspond-
ing alcohol 20a. It was mesylated and then treated with
TBAF without puri®cation to furnish 1. Similarly, ent-1
and ent-2 were synthesized in the same way from 14b.
25.2, 26.5, 38.8, 47.6, 55.3, 66.0, 73.1, 76.5, 78.4, 109.2,
113.8, 129.5, 130.6, 159.3;Anal. Calcd. for C 20H32O4S2: C,
59.96;H, 8.05. Found: C, 60.13;H, 8.06.
3.1.2. )3S,40R)-3-)20,20-Dimethyl-10,30-dioxolan-40-yl)-3-
p-methoxybenzyloxypropanal )5). A solution of 4 05.5 g,
14.2 mmol) in acetonitrile 02 mL) was added dropwise to a
stirred mixture of HgCl2 08.5 g, 31.3 mmol) and yellow
HgO 03.4 g, 15.7 mmol) in acetonitrile±water 04:1,
125 mL) at 08C. The mixture was stirred for 40 min at this
temperature and ®ltered through Celitew. The ®ltrate was
diluted with dichloromethane±hexane 01:1, 100 mL) and
washed with 5 M sodium acetate solution and brine. The
organic layer was dried with MgSO4 and evaporated. The
residue was puri®ed by column chromatography on silica
gel 03:1±1:1 hexanes/EtOAc) to yield aldehyde 5 as a color-
With the four stereoisomers in hand, we analyzed the NMR
spectra and speci®c rotations carefully. As for the 1H NMR,
there was little difference between 1/ent-1 and 2/ent-2 to
distinguish them. However, in the 13C NMR spectra
0Table 3), an obvious difference was observed at the C-11
position 0natural: 128.6 ppm,1 1/ent-1: 128.5 ppm, 2/ent-2:
129.1 ppm) which suggested that 1 or ent-1 should be the
natural isomer. In addition, the value of speci®c rotation
0natural: 128.3, synthetic 1: 128.7, synthetic ent-1:
228.2) showed that 1 must be the natural product, i.e.,
mueggelone has the absolute con®guration of 9R, 12S, 13S.
26
27
less oil 03.4 g, 85%);n D ˆ1:5028; ‰aŠ ˆ112:3 0cˆ0.76,
D
CHCl3);IR 0®lm): nmax 2987, 1728, 1613, 1514, 848 cm21
;
1H NMR 0300 MHz, CDCl3): d 0ppm) 1.34, 1.40 06H, two s,
isopropylidene CH3), 2.72 02H, m, H-2), 3.80 03H, s,
±OMe), 3.80±4.15 04H, m, H-30, 4, 5), 4.51, 4.57 02H,
two d, Jˆ11.1 Hz, CH2 of PMB), 6.87, 7.23 04H, two d,
Jˆ8.6 Hz, Ar of PMB), 9.81 01H, t, Jˆ1.8 Hz, H-1); 13C
NMR 075.5 MHz, CDCl3): d 0ppm) 25.1, 26.5, 45.8, 55.3,
66.9, 72.2, 75.0, 77.2, 109.6, 113.9, 129.6, 129.7, 159.4,
200.6;Anal. Calcd. for C 16H22O5: C, 65.29;H, 7.53.
Found: C, 65.43;H, 7.51.
In conclusion, we have completed the ®rst synthesis of
mueggelone 0and its stereoisomers) in 3.3% overall yield
from d-arabinose and determined the absolute con®guration
of mueggelone to be 9R, 12S, 13S.
3. Experimental
3.1. General
3.1.3. )10S,30Z,4R)-4-)10-p-Methoxybenzyloxyhex-30-enyl)-
2,2-dimethyl-1,3-dioxolane )6). To a cooled 02788C)
suspension of n-propyltriphenylphosphonium bromide
05.1 g, 13.2 mmol) in ether 0100 mL) under argon atmos-
phere was added NaHMDS 012.6 mL of 1 M in THF,
12.6 mmol) and the mixture was stirred for 1 h. To the
resulting orange solution was added a cooled 02788C) solu-
tion of aldehyde 5 03.4 g, 12.6 mmol) in ether 040 mL) via a
cannula at 2788C and stirred for 1 h. The reaction mixture
was poured into water and extracted with ether. The
combined organic layer was washed with water and brine,
dried with MgSO4 and concentrated under reduced pressure.
Puri®cation on silica gel 020:1 hexanes/EtOAc) gave an
ole®n mixture as a colorless oil 02.5 g, 68%, E/Zˆ1:10).
E- and Z-isomers were separated by AgNO3-impregnated
silica gel column chromatography 09:1 hexanes/EtOAc);
Optical rotations were recorded with a JASCO DIP-1000
polarimeter. IR spectra were measured with a JASCO FT/
IR-230 spectrophotometer. 1H and 13C NMR were recorded
on JEOL JNM AL300. Mass spectra were recorded on JEOL
JMS SX102. Column chromatography was performed using
Merck silica gel 60 00.060±0.200 mm). TLC was carried out
on Merck glass plates precoated with silica gel 60 F254
00.25 mm). HPLC was performed using SHOWA DENKO
shodex DS-4 equipped with Senshu Pak Silica-1251-N
04.6f x 250 mm) or Senshu Pak silica-5251-N 020f x
250 mm).
3.1.1. )10S,4R)-4-)30,30-Bisethylthio-10-p-methoxybenzyl-
oxypropyl)-2,2-dimethyl-1,3-dioxolane )4). To a cooled
008C) solution of alcohol 3 0500 mg, 1.8 mmol) in DMF
010 mL) was added NaH 080 mg of 60% in mineral oil,
2.0 mmol) and PMBCl 0320 mg, 2.0 mmol) and the mixture
was stirred for 2 h under argon atmosphere. The reaction
mixture was poured into water and extracted with EtOAc.
The organic layer was washed with water and brine, and
dried with MgSO4. The solvent was removed under reduced
pressure. The residue was puri®ed by silica gel column
chromatography 06:1 hexanes/EtOAc) to provide 4 as a
25
26
nD ˆ1:4986; ‰aŠ ˆ137:9 0cˆ0.49, CHCl3);IR 0®lm):
D
nmax 2962, 1613, 1514, 855, 822 cm21
;
1H NMR
0300 MHz, CDCl3): d 0ppm) 0.97 03H, t, Jˆ7.5 Hz, H-60),
1.34, 1.42 06H, two s, isopropylidene CH3), 2.07 02H, m,
H-50), 2.36 02H, m, H-20), 3.53 01H, q, Jˆ5.5 Hz, H-10),
3.80 03H, s, ±OMe), 3.87 01H, m, H-5a), 3.99±4.10 02H,
m, H-4, 5b), 4.51, 4.59 02H, two d, Jˆ11.3 Hz, CH2 of
PMB), 5.44 01H, dt, Jˆ10.8, 5.3 Hz, H-30), 5.50 01H, dt,
Jˆ10.8, 4.6 Hz, H-40) 6.87, 7.25 04H, two d, Jˆ8.7 Hz, Ar
of PMB); 13C NMR 075.5 MHz, CDCl3): d 0ppm) 14.1, 20.7,
25.4, 26.6, 28.9, 55.2, 66.5, 72.2, 77.2, 78.9, 109.0, 113.7,
124.0, 129.4, 130.6, 134.0, 159.2;Anal. Calcd. for
C19H28O4: C, 71.22;H, 8.81. Found: C, 71.21;H, 8.81.
25
26
colorless oil 0712 mg, 100%);n
0cˆ0.87, CHCl3);IR 0®lm): nmax 2981, 1613, 1513, 856,
ˆ1:5166; ‰aŠ ˆ21:5
D
D
822 cm21 1H NMR 0300 MHz, CDCl3): d 0ppm) 1.23
;
06H, t, Jˆ7.5Hz, ethyl CH3), 1.36, 1.44 06H, two s, iso-
propylidene CH3), 1.86±2.02 02H, m, H-20), 2.52±2.74
04H, m, ethyl CH2), 3.80 03H, s, ±OMe), 3.76±4.14 05H,
m, H-10, 30,4,5), 4.56, 4.69 02H, two d, Jˆ11.0 Hz, CH2 of
PMB), 6.87, 7.26 04H, two d, Jˆ8.6 Hz, Ar of PMB); 13C
NMR 075.5 MHz, CDCl3): d 0ppm) 14.4, 14.4, 23.4, 24.4,
3.1.4. )2R,3S,5Z)-3-p-Methoxybenzyloxyoct-5-ene-1,2-
diol )7). To a stirred solution of 6 050 mg, 0.16 mmol) in
THF±water 04:1, 2 mL) at 08C was added TFA 00.1 mL).
The resulting solution was allowed to warm to 408C and
stirred for 30 h. The reaction was then neutralized by the

H. Motoyoshi et al. / Tetrahedron 57 42001) 3899±3908
3903
addition of saturated NaHCO3 solution and extracted with
EtOAc. The combined organic layer was washed with
water, saturated NaHCO3 solution and brine before drying
with MgSO4. The solvent was removed and the residue was
puri®ed by column chromatography on silica gel 03:1±1:1
hexanes/EtOAc) to yield diol 7 as a colorless oil 042 mg,
133.7, 159.1, 178.4;Anal. Calcd. for C 27H46O5Si: C, 67.74;
H, 9.68. Found: C, 67.74;H, 9.69.
3.1.7. )2R,3S,5Z)-2-t-Butyldimethylsilyloxy-3-p-methoxy-
benzyloxyoct-5-en-1-ol )10). A stirred solution of 9
0500 mg, 1.1 mmol) in dichloromethane 010 mL) was
cooled to 2508C, treated with diisobutylaluminum hydride
02.2 mL of 0.95 M in hexanes, 2.1 mmol), warmed gradu-
ally to 2108C during 1 h and quenched with saturated
aqueous potassium sodium tartrate solution 010 mL). The
reaction mixture was stirred for 1 h at ambient temperature
before extraction with ether. The combined organic layer
was washed with water and brine, dried with MgSO4 and
evaporated to leave a residue which was puri®ed by column
chromatography on silica gel 020:1±5:1 hexanes/EtOAc).
Obtained was the desired primary alcohol 10 as a colorless
30
29
96%);n
ˆ1:5168; ‰aŠ ˆ141:6 0cˆ1.09, CHCl3);IR
D
D
0®lm): nmax 3417, 2962, 1614, 1515, 1250, 822 cm21; H
NMR 0300 MHz, CDCl3): d 0ppm) 0.97 03H, t, Jˆ7.5 Hz,
H-8), 2.07 02H, m, H-7), 2.25±2.50 02H, m, H-4), 3.58±3.80
04H, m, H-1, 2, 3), 3.80 03H, s, ±OMe), 4.44, 4.61 02H, two
d, Jˆ11.1 Hz, CH2 of PMB), 5.30±5.60 02H, m, H-5, 6),
6.88, 7.25 04H, two d, Jˆ8.6 Hz, Ar of PMB); 13C NMR
075.5 MHz, CDCl3): d 0ppm) 14.1, 20.7, 28.4, 55.3, 63.3,
72.2, 72.3, 80.8, 113.9, 123.8, 129.5, 130.1, 134.3, 159.3;
FAB MS m/z 0M1) calcd 280.1675, obsd 280.1635.
1
24
25
oil 0383 mg, 93%);n
ˆ1:4937; ‰aŠ ˆ25:47 0cˆ1.51,
D
D
3.1.5. )2R,3S,5Z)-2-Hydroxy-3-p-methoxybenzyloxyoct-
5-enyl pivalate )8). To a cooled 008C) solution of diol 7
0512 mg, 1.83 mmol) in pyridine 030 mL) was added
PivCl 00.34 mL, 2.74 mmol) and the mixture was stirred
for 1 h. The reaction mixture was poured into water and
extracted with EtOAc. The organic layer was washed with
saturated CuSO4 solution, water, saturated NaHCO3 solu-
tion and brine, and then dried with MgSO4 and evaporated.
Puri®cation of the residue on silica gel 06:1 hexanes/EtOAc)
furnished secondary alcohol 8 as a colorless oil 0621 mg,
CHCl3);IR 0®lm): nmax 3466, 2956, 1613, 1514, 1250, 836,
777 cm21; 1H NMR 0300 MHz, CDCl3): d 0ppm) 0.09, 0.10
06H, two s, ±SiMe), 0.92 09H, s, ±SiBut), 0.97 03H, t, Jˆ
7.5 Hz, H-8), 2.07 02H, m, H-7), 2.31 01H, m, Ha-4), 2.41
01H, m, Hb-4), 3.51±3.79 04H, m, H-1, 2, 3), 3.80 03H, s,
±OMe), 4.55 02H, s, CH2 of PMB), 5.41±5.54 02H, m, H-5,
6), 6.87, 7.26 04H, two d, Jˆ8.4 Hz, Ar of PMB); 13C NMR
075.5 MHz, CDCl3): d 0ppm) 24.6, 24.5, 14.1, 18.0, 20.8,
25.8, 29.2, 55.2, 64.1, 72.6, 74.0, 80.8, 113.7, 124.7, 129.5,
130.5, 133.7, 159.2;Anal. Calcd. for C 22H38O4Si: C, 66.96;
H, 9.71. Found: C, 66.82;H, 9.69.
25
26
93%);n
0®lm): nmax 3449, 2962, 1727, 1612, 1514, 1249,
ˆ1:4961; ‰aŠ ˆ138:0 0cˆ0.80, CHCl3);IR
D
D
822 cm21
;
1H NMR 0300 MHz, CDCl3): d 0ppm) 0.97
3.1.8. )2S,3S,5Z)-2-t-Butyldimethylsilyloxy-3-p-methoxy-
benzyloxy-5-octenal )11). To a solution of alcohol 10
0383 mg, 0.97 mmol) in dichloromethane 06 mL) was
added the Dess±Martin periodinane 0620 mg, 1.46 mmol)
and the mixture was stirred for 20 min. The reaction mixture
was diluted with ether 010 mL), washed twice with a 1:1
mixture of saturated NaHCO3 solution and 10% sodium
thiosulfate solution and then washed with water and brine.
The combined organic layer was dried with MgSO4 and
concentrated. After column chromatography on silica gel
020:1 hexanes/EtOAc), the aldehyde 11 was isolated as a
03H, t, Jˆ7.5 Hz, H-8), 1.21 09H, s, pivaloyl CH3), 2.08
02H, m, H-7), 2.41 02H, m, H-4), 3.50 01H, q, Jˆ5.6 Hz,
H-3), 3.80 03H, s, ±OMe), 3.87 01H, m, H-2), 4.17 01H, dd,
Jˆ6.5, 11.6 Hz, Ha-1), 4.28 01H, dd, Jˆ3.5, 11.6 Hz, Hb-1),
4.44, 4.59 02H, two d, Jˆ11.0 Hz, CH2 of PMB), 5.48 02H,
m, H-5, 6), 6.87, 7.25 04H, two d, Jˆ8.4 Hz, Ar of PMB);
13C NMR 075.5 MHz, CDCl3): d 0ppm) 14.1, 20.7, 27.2,
27.7, 38.8, 55.3, 65.7, 71.3, 71.9, 79.1, 113.8, 124.0,
129.5, 130.2, 134.2, 159.3, 178.9;Anal. Calcd. for
C21H32O5: C, 69.20;H, 8.85. Found: C, 69.16;H, 8.84.
27
28
colorless oil 0366 mg, 96%);n
ˆ1:4908; ‰aŠ ˆ215:7
D
D
3.1.6. )2R,3S,5Z)-2-t-Butyldimethylsilyloxy-3-p-methoxy-
benzyloxyoct-5-enyl pivalate )9). To a solution of alcohol
8 0140 mg, 0.38 mmol) in DMF 01.5 mL) was added imida-
zole 0260 mg, 3.84 mmol) and TBSCl 0174 mg, 1.15 mmol)
and the mixture was stirred for 15 h at room temperature.
The reaction mixture was poured into water and extracted
with ether. The organic layer was washed with water, satu-
rated NaHCO3 solution and brine, and then dried with
MgSO4. After removal of the solvent, puri®cation of the
residue on silica gel 030:1 hexanes/EtOAc) provided 9 as
0cˆ0.97, CHCl3);IR 0®lm): nmax 2931, 1735, 1613, 1514,
1250, 839, 780 cm21; 1H NMR 0300 MHz, CDCl3): d 0ppm)
0.08, 0.09 06H, two s, ±SiMe), 0.93 09H, s, ±SiBut), 0.95
03H, t, Jˆ7.5 Hz, H-8), 2.05 02H, m, H-7), 2.34 01H, m,
Ha-4), 2.42 01H, m, Hb-4), 3.66 01H, dt, Jˆ3.2, 6.8 Hz,
H-3), 3.80 03H, s, ±OMe), 4.12 01H, dd, Jˆ1.4, 3.2 Hz,
H-2), 4.51, 4.57 02H, two d, Jˆ11.4 Hz, CH2 of PMB),
5.26 01H, m, H-5), 5.47 01H, m, H-6), 6.87, 7.25 04H, two
d, Jˆ9.2 Hz, Ar of PMB), 9.61 01H, d, Jˆ1.4 Hz, H-1); 13C
NMR 075.5 MHz, CDCl3): d 0ppm) 24.9, 24.9, 14.0, 18.2,
20.7, 25.7, 28.4, 55.2, 71.8, 79.2, 81.2, 113.7, 123.8, 129.3,
130.2, 134.9, 159.2, 203.3;Anal. Calcd. for C 22H36O4Si: C,
67.30;H, 9.24. Found: C, 67.30;H, 9.27.
27
28
a colorless oil 0180 mg, 98%);n D ˆ1:4761; ‰aŠ ˆ29:40
D
0cˆ0.45, CHCl3);IR 0®lm): nmax 2960, 1731, 1614, 1515,
835, 777 cm21; 1H NMR 0300 MHz, CDCl3): d 0ppm) 0.08,
0.09 06H, two s, ±SiMe), 0.90 09H, s, ±SiBut), 0.96 03H, t,
Jˆ7.5 Hz, H-8), 1.21 09H, s, pivaloyl CH3), 2.06 02H, m,
H-7), 2.31 01H, m, Ha-4), 2.39 01H, m, Hb-4), 3.50 01H, m,
H-3), 3.80 03H, s, ±OMe), 3.89 01H, m, H-2), 4.12 01H, dd,
Jˆ4.7, 11.7 Hz, Ha-1), 4.25 01H, dd, Jˆ3.6, 11.7 Hz, Hb-1),
4.52 02H, s, CH2 of PMB), 5.46 02H, m, H-5, 6), 6.86, 7.24
04H, two d, Jˆ8.9 Hz, Ar of PMB); 13C NMR 075.5 MHz,
CDCl3): d 0ppm) 24.6, 14.1, 18.0, 20.7, 25.8, 27.3, 28.8,
38.8, 55.3, 65.7, 72.4, 72.5, 80.3, 113.7, 125.0, 129.3, 130.7,
3.1.9. Trimethyl 9-oxo-10-phosphonodecanoate )12). To
a cooled 02788C) solution of dimethyl methylphosphonate
01.55 g, 12.5 mmol) in THF 030 mL) under argon was added
n-BuLi 08.5 mL of 1.5 M in n-hexane, 12.8 mmol) and the
mixture was stirred for 20 min. To the resultant solution was
slowly added azelaic acid dimethyl ester 03.0 g, 13.9 mmol)
in THF 010 mL) and stirred for 1 h at 2788C. The reaction
was quenched with saturated NH4Cl solution and extracted

3904
H. Motoyoshi et al. / Tetrahedron 57 42001) 3899±3908
1
with ether. The combined organic layer was washed with
brine, dried with MgSO4, and then evaporated. Puri®cation
of the residue on silica gel 03:1±1:10 hexanes/EtOAc)
3448, 2930, 1740, 1612, 1513, 1249, 836, 776 cm21; H
NMR 0300 MHz, CDCl3): d 0ppm) 0.02, 0.06 06H, two s,
±SiMe), 0.90 09H, s, ±SiBut), 0.94 03H, t, Jˆ7.5 Hz, H-18),
1.20±1.70 012H, m, H-3, 4, 5, 6, 7, 8), 2.02 02H, m, H-17),
2.15±2.40 02H, m, H-14), 2.29 02H, t, Jˆ7.5 Hz, H-2), 3.37
01H, m, H-13), 3.66 03H, s, ±CO2Me), 3.79 03H, s, ±OMe of
PMB), 4.09±4.16 02H, m, H-9, 12), 4.49, 4.62 02H, two d,
Jˆ11.1 Hz, CH2 of PMB), 5.30±5.50 02H, m, H-15, 16),
5.60±5.80 02H, m, H-10, 11), 6.85, 7.25 04H, two d,
Jˆ8.3 Hz, Ar of PMB); 13C NMR 075.5 MHz, CDCl3): d
0ppm) 24.8, 24.2, 14.1, 18.1, 20.7, 24.9, 25.3, 25.8, 29.0,
29.2, 29.3, 34.0, 37.1, 51.4, 55.2, 72.4, 72.6, 75.2, 83.1,
113.6, 125.3, 129.3, 130.8, 131.0, 133.3, 134.8, 159.0,
174.3;Anal. Calcd. for C 33H56O6Si: C, 68.71;H, 9.78.
Found: C, 68.56;H, 9.79.
furnished phosphonate 12 as a colorless oil 0940 mg,
20
22%);n
ˆ1:4505;IR 0®lm): nmax 3474, 2934, 1732,
D
1714, 1256, 1031, 814 cm21
;
1H NMR 0300 MHz,
CDCl3): d 0ppm) 1.15±1.30 06H, m, H-4, 5, 6), 1.45±1.60
04H, m, H-3, 7), 2.22 02H, t, Jˆ7.5 Hz, H-2), 2.54 02H, t,
Jˆ7.5 Hz, H-8), 3.02 02H, d, Jˆ22.8 Hz, H-10), 3.59 03H, s,
±CO2Me), 3.70 06H, d, Jˆ11.1 Hz, ±P0O)0OMe)2); 13C
NMR 075.5 MHz, CDCl3): d 0ppm) 23.1, 24.7, 28.5, 28.7,
28.8, 33.8, 41.1 0d, Jˆ128 Hz, C-10), 43.9 0d, Jˆ1.8 Hz,
C-8), 51.3, 52.9 0d, Jˆ6.2 Hz, ±P0O)0OMe)2), 174.0, 201.8
0d, Jˆ6.2 Hz, C-9);FAB MS m/z 0M1) calcd 309.1467,
obsd 309.1420.
3.1.10. Methyl )10E,12R,13S,15Z)-12-t-butyldimethyl-
silyloxy-13-p-methoxybenzyloxy-9-oxooctadeca-10,15-
dienoate )13). To a stirred suspension of LiCl 036 mg,
0.83 mmol) in acetonitrile 04 mL) under argon at room
temperature, was added phosphonate 12 0257 mg,
0.83 mmol), DBU 00.1 mL, 0.69 mmol) and ®nally alde-
hyde 11 0272 mg, 0.69 mmol). After being stirred for
90 min, the reaction mixture was poured into water and
extracted with ether. The combined organic layer was
washed with water and brine, dried with MgSO4, and then
evaporated. The residue was puri®ed by silica gel column
chromatography 020:1±6:1 hexanes/EtOAc) to provide
enone 13 as a colorless oil 0372 mg, 93%, E/Zˆ.99:1);
3.1.12. Methyl )9S,10E,12R,13S,15Z)-12-t-butyldimethyl-
silyloxy-9-hydroxy-13-p-methoxybenzyloxyoctadeca-10,15-
dienoate )14b). As described for the synthesis of 14a, 13
0370 mg, 0.64 mmol) was converted into 14b 0240 mg,
27
65%, colorless oil) with 0R)-CBS reagent;n
27
ˆ1:4918;
D
‰aŠ ˆ218:4 0cˆ0.60, CHCl3);IR 0®lm): nmax 3450,
D
2930, 1740, 1613, 1514, 1249, 835, 776 cm21; H NMR
1
0300 MHz, CDCl3): d 0ppm) 0.03, 0.06 06H, two s,
±SiMe), 0.91 09H, s, ±SiBut), 0.94 03H, t, Jˆ7.5 Hz,
H-18), 1.2±1.7 012H, m, H-3, 4, 5, 6, 7, 8), 2.02 02H, m,
H-17), 2.15±2.35 02H, m, H-14), 2.29 02H, t, Jˆ7.5 Hz,
H-2), 3.38 01H, m, H-13), 3.66 03H, s, ±CO2Me), 3.79
03H, s, ±OMe of PMB), 4.10 01H, q, Jˆ6.0 Hz, H-9),
4.15 01H, t, Jˆ4.8 Hz, H-12), 4.49, 4.63 02H, two d, Jˆ
11.1 Hz, CH2 of PMB), 5.3±5.5 02H, m, H-15, 16), 5.6±
5.8 02H, m, H-10, 11), 6.85, 7.25 04H, two d, Jˆ8.1 Hz, Ar of
PMB); 13C NMR 075.5 MHz, CDCl3): d 0ppm) 24.8, 24.2,
14.1, 18.1, 20.7, 24.9, 25.4, 25.9, 29.1, 29.2, 29.2, 29.3, 34.1,
37.1, 51.4, 55.2, 72.4, 72.7, 75.2, 83.0, 113.6, 125.3, 129.4,
130.6, 131.0, 133.3, 134.7, 159.0, 174.3;Anal. Calcd. for
C33H56O6Si: C, 68.71;H, 9.78. Found: C, 68.47;H, 9.76.
26
27
nD ˆ1:4952; ‰aŠ ˆ28:22 0cˆ0.44, CHCl3);IR 0®lm):
D
nmax 2932, 1739, 1680, 1514, 1250, 837, 778 cm21; H
1
NMR 0300 MHz, CDCl3): d 0ppm) 0.02, 0.07 06H, two s,
±SiMe), 0.92 09H, s, ±SiBut), 0.95 03H, t, Jˆ7.5 Hz, H-18),
1.25±1.35 06H, m, H-4, 5, 6), 1.50±1.70 04H, m, H-3, 7),
2.02 02H, m, H-17), 2.20±2.40 02H, m, H-14), 2.29 02H, t,
Jˆ7.5 Hz, H-2), 2.53 02H, t, Jˆ7.4 Hz, H-8), 3.41 01H, m,
H-13), 3.66 03H, s, ±CO2Me), 3.79 03H, s, ±OMe of PMB),
4.33 01H, m, H-12), 4.48, 4.56 02H, two d, Jˆ11.3 Hz, CH2
of PMB), 5.30±5.50 02H, m, H-15, 16), 6.28 01H, dd, Jˆ1.4,
16.1 Hz, H-10), 6.84 01H, dd, Jˆ5.3, 16.1 Hz, H-11), 6.85,
7.22 04H, two d, Jˆ8.6 Hz, Ar of PMB); 13C NMR
075.5 MHz, CDCl3): d 0ppm) 24.8, 24.5, 14.1, 18.2,
20.7, 24.1, 24.9, 25.8, 28.9, 29.0, 29.1, 34.0, 40.4, 51.4,
55.2, 72.6, 74.4, 82.5, 113.7, 124.8, 129.4, 129.8, 130.5,
133.8, 145.9, 159.1, 174.2, 200.5;Anal. Calcd. for
C33H54O6Si: C, 68.95;H, 9.47. Found: C, 68.94;H, 9.51.
3.1.13. )9R,10E,12R,13S,15Z)-12-t-Butyldimethylsilyl-
oxy-9-hydroxy-13-p-methoxybenzyloxyoctadeca-10,15-
dienoic acid )15a). To a solution of methyl ester 14a
0192 mg, 0.33 mmol) in methanol 010 mL) was added
LiOH´H2O 0500 mg) and the mixture was stirred for 12 h
at room temperature. The reaction mixture was neutralized
with 3N HCl and extracted with EtOAc. The organic layer
was washed with brine, dried with MgSO4 and evaporated.
Puri®cation of the residue on silica gel 06:1±1:1 hexanes/
EtOAc) provided carboxylic acid 15a as a colorless oil
3.1.11. Methyl )9R,10E,12R,13S,15Z)-12-t-butyldimethyl-
silyloxy-9-hydroxy-13-p-methoxybenzyloxyoctadeca-10,15-
dienoate )14a). To a solution of enone 13 0240 mg,
0.42 mmol) in THF 05 mL) under argon was added
0S)-CBS reagent 042 mL of 1 M in toluene, 0.042 mmol).
The mixture was cooled to 2208C and BH3´THF 0410 mL
of 1 M in THF, 0.42 mmol) was added. The resultant solu-
tion was stirred for 90 min with elevating temperature up to
08C, and then quenched with 1 mL of methanol. The reac-
tion mixture was warmed to ambient temperature and stirred
for 4 h. The solvent was removed in vacuo. Puri®cation by
column chromatography on silica gel 09:1±6:1 hexanes/
EtOAc) gave a mixture of isomers. These were isolated by
30
30
0170 mg, 91%);n
CHCl3);IR 0®lm): nmax 2930, 1712, 1613, 1514, 1249,
ˆ1:4973; ‰aŠ ˆ216:3 0cˆ1.16,
D
D
836, 777 cm21 1H NMR 0300 MHz, CDCl3): d 0ppm)
;
0.03, 0.06 06H, two s, ±SiMe), 0.90 09H, s, ±SiBut), 0.94
03H, t, Jˆ7.5 Hz, H-18), 1.2±1.7 012H, m, H-3, 4, 5, 6, 7, 8),
2.02 02H, m, H-17), 2.1±2.4 02H, m, H-14), 2.32 02H, t,
Jˆ7.5 Hz, H-2), 3.38 01H, m, H-13), 3.79 03H, s, ±OMe),
4.0±4.2 02H, m, H-9, 12), 4.50, 4.63 02H, two d, Jˆ11.3 Hz,
CH2 of PMB), 5.3±5.5 02H, m, H-15, 16), 5.6±5.8 02H, m,
H-10, 11), 6.85, 7.25 04H, two d, Jˆ8.6 Hz, Ar of PMB);
13C NMR 075.5 MHz, CDCl3): d 0ppm) 24.8, 24.2, 14.1,
18.1, 20.7, 24.6, 25.3, 25.9, 28.9, 29.1, 29.2, 29.3, 33.9,
37.1, 55.2, 72.5, 72.7, 75.2, 83.1, 113.6, 125.2, 129.4,
130.8, 131.0, 133.4, 134.8, 159.0, 179.1;Anal. Calcd. for
C32H54O6Si: C, 68.28;H, 9.67. Found: C, 67.98;H, 9.65.
preparative HPLC 03.9:1 hexanes/EtOAc) to furnish the
26
desired 09R)-methyl ester 14a 0159 mg, 66%). nD
27
ˆ
1:4908; ‰aŠ ˆ216:6 0cˆ0.66, CHCl3);IR 0®lm): nmax
D

H. Motoyoshi et al. / Tetrahedron 57 42001) 3899±3908
3905
3.1.14.
)9S,10E,12R,13S,15Z)-12-t-Butyldimethylsilyl-
6.2, 15.0 Hz, H-2b), 3.35 01H, dt, Jˆ7.5, 4.9 Hz, H-13), 3.80
03H, s, ±OMe), 4.15 01H, t, Jˆ4.9 Hz, H-12), 4.48, 4.59
02H, two d, Jˆ11.0 Hz, CH2 of PMB), 5.3±5.5 03H, m,
H-9, 15, 16), 5.7±5.9 02H, m, H-10, 11), 6.85, 7.25 04H,
two d, Jˆ8.9 Hz, Ar of PMB); 13C NMR 075.5 MHz,
CDCl3): d 0ppm) 24.8, 24.3, 14.2, 18.2, 20.7, 20.7, 23.3,
23.4, 24.1, 25.9, 27.1, 29.1, 29.7, 35.1, 55.2, 72.6, 75.1,
75.3, 83.0, 113.6, 125.4, 129.4, 129.4, 131.0, 132.0, 133.3,
159.0, 173.4;Anal. Calcd. for C 32H52O5Si: C, 70.54;H,
9.62. Found: C, 70.60;H, 9.62.
oxy-9-hydroxy-13-p-methoxybenzyloxyoctadeca-10,15-
dienoic acid )15b). As described for the synthesis of 15a,
14b 0119 mg, 0.21 mmol) was converted into 15b 0106 mg,
30
32
91%, colorless oil);n
ˆ1:4971; ‰aŠ ˆ215:6 0cˆ0.84,
D
D
CHCl3);IR 0®lm): nmax 2931, 1713, 1613, 1514, 1249, 836,
776 cm21; 1H NMR 0300 MHz, CDCl3): d 0ppm) 0.03, 0.06
06H, two s, ±SiMe), 0.91 09H, s, ±SiBut), 0.94 03H, t,
Jˆ7.5 Hz, H-18), 1.2±1.7 012H, m, H-3, 4, 5, 6, 7, 8),
2.02 02H, m, H-17), 2.1±2.4 02H, m, H-14), 2.32 02H, t,
Jˆ7.5 Hz, H-2), 3.39 01H, m, H-13), 3.79 03H, s, ±OMe),
4.0±4.2 02H, m, H-9, 12), 4.50, 4.64 02H, two d, Jˆ11.3 Hz,
CH2 of PMB), 5.3±5.5 02H, m, H-15, 16), 5.6±5.8 02H, m,
H-10, 11), 6.85, 7.25 04H, two d, Jˆ8.4 Hz, Ar of PMB);
13C NMR 075.5 MHz, CDCl3): d 0ppm) 24.8, 24.2, 14.1,
18.1, 20.7, 24.6, 25.3, 25.9, 28.9, 29.1, 29.2, 29.3, 34.0,
37.0, 55.2, 72.4, 72.6, 75.1, 83.0, 113.6, 125.2, 129.4,
130.6, 131.0, 133.4, 134.7, 159.0, 179.2;Anal. Calcd. for
C32H54O6Si: C, 68.28;H, 9.67. Found: C, 68.16;H, 9.65.
3.1.17. )9R,10E,12R,13S,15Z)-12-t-Butyldimethylsilyl-
oxy-13-hydroxyoctadeca-10,15-dien-9-olide )17a). To a
solution of 16a 013 mg, 0.024 mmol) in dichloromethane±
water 020:1, 0.5 mL) was added sodium bicarbonate 020 mg,
0.239 mmol) and DDQ 027 mg, 0.119 mmol) at room
temperature and the mixture was stirred for 1 h. The reac-
tion mixture was poured into a 1:1 mixture of saturated
NaHCO3 solution and 10% sodium thiosulfate solution
and extracted with ether. The organic layer was washed
with water, saturated NaHCO3 solution and brine, and
then dried with MgSO4. After removal of the solvent, puri-
®cation of the residue on silica gel 040:1±10:1 hexanes/
EtOAc) provided alcohol 17a as a colorless oil 010 mg,
3.1.15. )9R,10E,12R,13S,15Z)-12-t-Butyldimethylsilyl-
oxy-13-p-methoxybenzyloxyoctadeca-10,15-dien-9-olide
)16a). Triethylamine 0205 mL, 1.47 mmol) and 2,4,6-
trichlorobenzoyl chloride 0192 mL, 1.23 mmol) were
added to a solution of the hydroxy acid 15a 0138 mg,
0.25 mmol) in THF 03 mL). The reaction mixture was
stirred for 1 h at room temperature and then diluted with
dry toluene 018 mL). The resultant solution was slowly
added over 12 h using a syringe pump to a re¯uxing and
vigorously stirred solution of DMAP 0720 mg, 5.88 mmol)
in dry toluene 0420 mL). After the addition of the substrate
was complete, the reaction was stirred for an additional 2 h
and then concentrated in vacuo. Column chromatography of
the crude product on silica gel 030:1±5:1 hexanes/EtOAc)
29
29
99%);n
ˆ1:4806; ‰aŠ ˆ117:9 0cˆ0.45, CHCl3);IR
D
D
0®lm): nmax 3499, 2933, 1731, 1470, 1256, 836 cm21; H
NMR 0300 MHz, CDCl3): d 0ppm) 0.04, 0.07 06H, two s,
±SiMe), 0.90 09H, s, ±SiBut), 0.96 03H, t, Jˆ7.5 Hz, H-18),
1.0±1.8 010H, m, H-3a, 4, 5, 6, 7, 8a), 2.0±2.3 07H, m, H-2a,
3b, 8b, 14, 17), 2.52 01H, ddd, Jˆ2.7, 6.3, 15.3 Hz, H-2b),
3.59 01H, dt, Jˆ3.9, 6.7 Hz, H-13), 4.10 01H, m, H-12),
5.3±5.6 03H, m, H-9, 15, 16), 5.7±5.8 02H, m, H-10, 11);
13C NMR 075.5 MHz, CDCl3): d 0ppm) 24.9, 24.2, 14.2,
18.1, 20.7, 20.7, 23.2, 23.4, 24.0, 25.8, 27.1, 29.5, 29.9,
35.0, 74.7, 75.1, 75.8, 124.5, 130.0, 130.7, 134.3, 173.3;
Anal. Calcd. for C24H44O4Si: C, 67.87;H, 10.44. Found:
C, 67.84;H, 10.42.
1
afforded the desired lactone 16a 091 mg, 68%, colorless oil)
30
together with a dimeric lactone 012.4 mg, 5%);n
30
ˆ
D
1:5012; ‰aŠ ˆ114:0 0cˆ0.3, CHCl3);IR 0®lm): nmax
D
2932, 1728, 1613, 1514, 1250, 836, 758 cm21; H NMR
1
0300 MHz, CDCl3): d 0ppm) 0.03, 0.06 06H, two s,
±SiMe), 0.91 09H, s, ±SiBut), 0.95 03H, t, Jˆ7.5 Hz,
H-18), 1.0±1.8 010H, m, H-3a, 4, 5, 6, 7, 8a), 2.0±2.3 06H,
m, H-2a, 3b, 8b, 14a, 17), 2.35 01H, m, H-14b), 2.49 01H, ddd,
Jˆ2.7, 6.3, 15.2 Hz, H-2b), 3.34 01H, dt, Jˆ7.5, 4.8 Hz,
H-13), 3.80 03H, s, ±OMe), 4.16 01H, t, Jˆ4.8 Hz, H-12),
4.47, 4.58 02H, two d, Jˆ11.1 Hz, CH2 of PMB), 5.3±5.5
03H, m, H-9, 15, 16), 5.7±5.9 02H, m, H-10, 11), 6.84, 7.25
04H, two d, Jˆ8.9 Hz, Ar of PMB); 13C NMR 075.5 MHz,
CDCl3): d 0ppm) 24.8, 24.2, 14.2, 18.2, 20.7, 20.7, 23.3,
23.4, 24.1, 25.9, 27.1, 29.1, 29.6, 35.1, 55.3, 72.6, 75.0,
75.5, 82.9, 113.6, 125.4, 129.3, 129.4, 131.0, 132.2, 133.3,
159.0, 173.3;Anal. Calcd. for C 32H52O5Si: C, 70.54;H,
9.62. Found: C, 70.48;H, 9.60.
3.1.18.
)9S,10E,12R,13S,15Z)-12-t-Butyldimethylsilyl-
oxy-13-hydroxyoctadeca-10,15-dien-9-olide )17b). As
described for the synthesis of 17a, 16b 062 mg,
0.11 mmol) was converted into 17b 048 mg, 99%, colorless
29
31
oil);n
ˆ1:4805; ‰aŠ ˆ246:7 0cˆ0.51, CHCl3);IR
D
D
0®lm): nmax 3492, 2930, 1731, 1470, 1254, 837 cm21; H
NMR 0300 MHz, CDCl3): d 0ppm) 0.05, 0.07 06H, two s,
±SiMe), 0.90 09H, s, ±SiBut), 0.96 03H, t, Jˆ7.5 Hz, H-18),
1.0±1.8 010H, m, H-3a, 4, 5, 6, 7, 8a), 2.0±2.3 07H, m, H-2a,
3b, 8b, 14, 17), 2.52 01H, ddd, Jˆ2.8, 6.2, 15.4 Hz, H-2b),
3.58 01H, dt, Jˆ3.6, 6.8 Hz, H-13), 4.10 01H, m, H-12),
5.3±5.6 03H, m, H-9, 15, 16), 5.7±5.8 02H, m, H-10, 11);
13C NMR 075.5 MHz, CDCl3): d 0ppm) 24.9, 24.3, 14.2,
18.1, 20.7, 20.7, 23.3, 23.4, 24.1, 25.8, 27.1, 29.6, 29.9,
35.0, 74.7, 75.0, 75.8, 124.5, 130.0, 130.6, 134.2, 173.3;
Anal. Calcd. for C24H44O4Si: C, 67.87;H, 10.44. Found:
C, 67.62;H, 10.43.
1
3.1.16.
)9S,10E,12R,13S,15Z)-12-t-Butyldimethylsilyl-
oxy-13-p-methoxybenzyloxyoctadeca-10,15-dien-9-olide
)16b). As described for the synthesis of 16a, 15b 42 mg,
0.075 mmol) was converted into 16b 26 mg, 63%, colorless
3.1.19. )9R,10E,12R,13S,15Z)-12-t-Butyldimethylsilyl-
oxy-13-methanesulfonyloxyoctadeca-10,15-dien-9-olide
)18a). To a solution of alcohol 17a 031 mg, 0.073 mmol) in
dichloromethane 00.3 mL) was added triethylamine
0153 mL, 1.09 mmol) and DMAP 0134 mg, 1.09 mmol).
The mixture was cooled to 08C and methanesulfonic anhy-
dride 039 mg, 0.219 mmol) was added. The reaction was
27
30
oil);n
ˆ1:5022; ‰aŠ ˆ243:9 0cˆ0.43, CHCl3);IR
D
D
0®lm): nmax 2931, 1730, 1613, 1514, 1250, 836, 777 cm21
;
1H NMR 0300 MHz, CDCl3): d 0ppm) 0.04, 0.06 06H, two s,
±SiMe), 0.91 09H, s, ±SiBut), 0.95 03H, t, Jˆ7.5 Hz, H-18),
1.0±1.8 010H, m, H-3a, 4, 5, 6, 7, 8a), 2.0±2.3 06H, m, H-2a,
3b, 8b, 14a, 17), 2.34 01H, m, H-14b), 2.51 01H, ddd, Jˆ2.7,

3906
H. Motoyoshi et al. / Tetrahedron 57 42001) 3899±3908
allowed to warm up to room temperature and stirred for 3 h.
The reaction mixture was poured into cold water and
extracted with ether. The combined organic layer was
washed with water, saturated NH4Cl solution, saturated
NaHCO3 solution and brine, and then dried with MgSO4
and concentrated. The residue was puri®ed by silica gel
3.1.22. )9S,10E,12R,13R,15Z)-12,13-Epoxyoctadeca-10,15-
dien-9-olide )ent-1). As described for the synthesis of 2,
18b 026 mg, 0.052 mmol) was converted into ent-1
29
27
014 mg, 94%, colorless oil);n
ˆ1:4958; ‰aŠ ˆ228:2
D
D
0cˆ0.77, CHCl3);IR 0®lm): nmax 2932, 1731, 1468, 1237,
1067, 966 cm21; 1H NMR 0300 MHz, CDCl3): d 0ppm) 0.97
03H, t, Jˆ7.5 Hz, H-18), 1.0±1.8 010H, m, H-3a, 4, 5, 6, 7,
8a), 1.95±2.15 04H, m, H-3b, 8b, 17), 2.20 01H, ddd, Jˆ2.6,
11.9, 15.5 Hz, H-2a), 2.36 02H, m, H-14), 2.52 01H, ddd,
Jˆ3.0, 6.2, 15.5 Hz, H-2b), 2.87 01H, dt, Jˆ2.2, 5.3 Hz,
H-13), 3.15 01H, dd, Jˆ2.2, 7.8 Hz, H-12), 5.30±5.42
02H, m, H-9, 15), 5.46 01H, ddd, Jˆ1.4, 7.8, 15.6 Hz,
H-11), 5.54 01H, m, H-16), 5.94 01H, dd, Jˆ5.1, 15.6 Hz,
H-10); 13C NMR 075.5 MHz, CDCl3): d 0ppm) 14.2, 20.7,
20.7, 23.3, 23.6, 24.1, 27.0, 29.5, 29.8, 35.0, 57.4, 59.9,
74.8, 122.2, 128.5, 132.7, 134.9, 173.4;Anal. Calcd. for
C18H28O3: C, 73.93;H, 9.65. Found: C, 73.75;H, 9.62.
column chromatography 020:1 hexanes/EtOAc) to provide
28
18a as a colorless oil 032 mg, 90%);n
26
ˆ1:4815;
D
‰aŠ ˆ123:0 0cˆ0.63, CHCl3);IR 0®lm): nmax 2933,
D
1731, 1470, 1361, 1255, 1175, 911, 837 cm21; H NMR
1
0300 MHz, CDCl3): d 0ppm) 0.05, 0.11 06H, two s,
±SiMe), 0.91 09H, s, ±SiBut), 0.97 03H, t, Jˆ7.5 Hz,
H-18), 1.0±1.8 010H, m, H-3a, 4, 5, 6, 7, 8a), 1.95±2.13
04H, m, H-3b, 8b, 17), 2.21 01H, m, H-2a), 2.35 01H, m,
H-14a), 2.43±2.60 02H, m, H-2b, 14b), 3.02 03H, s,
±SO2Me), 4.42 01H, dd Jˆ2.3, 5.3 Hz, H-12), 4.58 01H,
m, H-13), 5.25±5.45 02H, m, H-9, 15), 5.55 01H, m,
H-16), 5.65±5.85 02H, m, H-10, 11); 13C NMR 075.5
MHz, CDCl3): d 0ppm) 24.9, 24.5, 14.0, 18.2, 20.6,
20.7, 23.3, 23.4, 24.0, 25.8, 27.1, 27.6, 29.6, 35.0, 38.6,
74.2, 74.9, 85.8, 122.8, 128.9, 131.4, 135.5, 173.3;FAB
MS m/z 0M1) calcd 502.2784, obsd 502.2747.
3.1.23. )9R,10E,12R,13S,15Z)-12-t-Butyldimethylsilyl-
oxy-13-t-butyldiphenylsilyloxyoctadeca-10,15-dien-9-
olide )19a). To a solution of alcohol 17a 066 mg,
0.16 mmol) and imidazole 0106 mg, 1.55 mmol) in DMF
00.4 mL) under argon was added TBDPSCl 0203 mL,
0.78 mmol) and the mixture was stirred for 12 h at room
temperature. The reaction mixture was poured into water
and extracted with ether. The organic layer was washed
with water and brine, dried with MgSO4 and concentrated
under reduced pressure. The crude product was puri®ed by
3.1.20.
)9S,10E,12R,13S,15Z)-12-t-Butyldimethylsilyl-
oxy-13-methanesulfonyloxyoctadeca-10,15-dien-9-olide
)18b). As described for the synthesis of 18a, 17b 026 mg,
0.061 mmol) was converted into 18b 027 mg, 87%, color-
29
28
less oil);n D ˆ1:4806; ‰aŠ ˆ238:0 0cˆ1.34, CHCl3);IR
D
0®lm): nmax 2959, 1731, 1470, 1360, 1256, 1175, 911,
chromatography on silica gel 030:1 hexanes/EtOAc) gave
29
1
837 cm21; H NMR 0300 MHz, CDCl3): d 0ppm) 0.06,
19a 094 mg, 91%) as a colorless oil;n
29
ˆ1:5171;
1H NMR
D
0.10 06H, two s, ±SiMe), 0.91 09H, s, ±SiBut), 0.97 03H,
t, Jˆ7.5 Hz, H-18), 1.0±1.8 010H, m, H-3a, 4, 5, 6, 7, 8a),
1.95±2.13 04H, m, H-3b, 8b, 17), 2.21 01H, m, H-2a), 2.34
01H, m, H-14a), 2.44±2.60 02H, m, H-2b, 14b), 3.02 03H, s,
±SO2Me), 4.40 01H, m, H-12), 4.58 01H, m, H-13), 5.25±
5.45 02H, m, H-9, 15), 5.55 01H, m, H-16), 5.65±5.85 02H,
m, H-10, 11); 13C NMR 075.5 MHz, CDCl3): d 0ppm) 24.9,
24.6, 14.0, 18.2, 20.7, 20.7, 23.4, 23.5, 24.1, 25.8, 27.1,
27.6, 29.7, 35.0, 38.6, 74.3, 74.9, 85.9, 122.8, 129.0,
131.4, 135.5, 173.3;FAB MS m/z 0M1) calcd 502.2784,
obsd 502.2783.
‰aŠ ˆ138:4 0cˆ1.10, CHCl3);IR 0®lm): nmax 2931,
D
1731, 1470, 1254, 1112, 836, 703 cm21
;
0300 MHz, CDCl3): d 0ppm) 20.03 06H, s, ±SiMe), 0.79
03H, t, Jˆ7.5 Hz, H-18), 0.85 09H, s, ±SiButof TBS), 1.06
09H, s, ±SiButof TBDPS), 1.2±1.9 012H, m, H-3a, 4, 5, 6, 7,
8a, 17), 2.0±2.3 05H, m, H-2a, 3b, 8b, 14), 2.52 01H, m, H-2b),
3.75 01H, m, H-13), 4.09 01H, dd, Jˆ2.0, 6.9 Hz, H-12),
5.14 01H, m, H-15), 5.24 01H, m, H-16), 5.42 01H, m, H-
9), 5.61 01H, dd, Jˆ5.7, 15.6 Hz, H-10), 5.91 01H, dd, Jˆ
6.9, 15.6 Hz, H-11), 7.3±7.8 010H, m, Ar of TBDPS); 13C
NMR 075.5 MHz, CDCl3): d 0ppm) 24.7, 24.3, 14.0, 18.2,
19.5, 20.5, 20.6, 23.0, 23.9, 25.9, 27.0, 27.1, 27.2, 28.7,
31.7, 35.1, 75.2, 75.8, 77.7, 124.3, 127.4, 129.1, 129.4,
129.4, 131.6, 133.5, 133.9, 136.0, 136.2, 173.3;FAB MS
m/z 0M1) calcd 662.4187, obsd 662.4132.
3.1.21. )9R,10E,12R,13R,15Z)-12,13-Epoxyoctadeca-10,15-
dien-9-olide )2). To a solution of 18a 031 mg, 0.062 mmol) in
THF 00.5 mL) was added TBAF 0185 mL of 1 M in THF,
0.185 mmol) and the mixture was stirred for 2 h. The mixture
was diluted with water and extracted with ether. The organic
layer was washed with water and brine, and then dried with
MgSO4 and evaporated. Puri®cation of the residue on silica
gel 030:1±15:1 hexanes/EtOAc) afforded epoxylactone 2 as a
3.1.24.
)9S,10E,12R,13S,15Z)-12-t-Butyldimethylsilyl-
oxy-13-t-butyldiphenylsilyloxyoctadeca-10,15-dien-9-
olide )19b). As described for the synthesis of 19a, 17b
077 mg, 0.18 mmol) was converted into 19b 0109 mg,
27
28
28
27
colorless oil 015 mg, 87%);n
0cˆ0.39, CHCl3);IR 0®lm): nmax 2934, 1730, 1468, 1237,
ˆ1:4951; ‰aŠ ˆ168:7
91%, colorless oil);n
CHCl3);IR 0®lm): nmax 2931, 1731, 1470, 1254, 1112,
ˆ1:5162; ‰aŠ ˆ26:4 0cˆ0.75,
D
D
D
D
967 cm21; H NMR 0300 MHz, CDCl3): d 0ppm) 0.97 03H,
836, 702 cm21 1H NMR 0300 MHz, CDCl3): d 0ppm)
;
1
t, Jˆ7.5 Hz, H-18), 1.0±1.8 010H, m, H-3a, 4, 5, 6, 7, 8a),
1.95±2.15 04H, m, H-3b, 8b, 17), 2.20 01H, ddd, Jˆ2.6,
12.1, 15.5 Hz, H-2a), 2.37 02H, m, H-14), 2.51 01H, ddd,
Jˆ3.0, 6.2, 15.5 Hz, H-2b), 2.88 01H, dt, Jˆ2.0, 5.3 Hz,
H-13), 3.15 01H, dd, Jˆ2.0, 7.7 Hz, H-12), 5.25±5.65 04H,
m, H-9, 11, 15, 16), 5.95 01H, dd, Jˆ6.0, 15.6 Hz, H-10); 13C
NMR 075.5 MHz, CDCl3): d 0ppm) 14.2, 20.7, 20.7, 23.4,
23.6, 24.2, 27.0, 29.5, 29.9, 35.1, 57.3, 59.9, 75.1, 122.2,
129.1, 132.8, 134.9, 173.4;FAB MS m/z 0M11H) calcd
293.2117, obsd 293.2117.
20.02, 20.01 06H, two s, ±SiMe), 0.81 03H, t, Jˆ7.5 Hz,
H-18), 0.87 09H, s, ±SiButof TBS), 1.07 09H, s, ±SiButof
TBDPS), 1.2±1.9 012H, m, H-3a, 4, 5, 6, 7, 8a, 17), 2.0±2.3
05H, m, H-2a, 3b, 8b, 14), 2.50 01H, m, H-2b), 3.75 01H, m,
H-13), 4.07 01H, dd, Jˆ2.0, 6.9 Hz, H-12), 5.15 01H, m,
H-15), 5.25 01H, m, H-16), 5.41 01H, m, H-9), 5.62 01H,
dd, Jˆ5.6, 15.8 Hz, H-10), 5.89 01H, dd, Jˆ6.9, 15.8 Hz,
H-11), 7.3±7.8 010H, m, Ar of TBDPS); 13C NMR
075.5 MHz, CDCl3): d 0ppm) 24.7, 24.4, 14.0, 18.2,
19.5, 20.5, 20.6, 23.2, 23.3, 24.1, 25.9, 27.0, 27.2, 29.3,

H. Motoyoshi et al. / Tetrahedron 57 42001) 3899±3908
3907
31.7, 35.1, 75.2, 75.7, 77.8, 124.3, 127.3, 129.2, 129.4,
131.6, 133.5, 133.9, 134.6, 136.0, 136.2, 173.3;FAB MS
m/z 0M1) calcd 662.4187, obsd 662.4164.
reaction mixture was diluted with water and extracted with
ether. The organic layer was washed with water and brine,
dried with MgSO4 and evaporated. Puri®cation of the
residue on silica gel 030:1±15:1 hexanes/EtOAc) afforded
the desired epoxylactone 1 as a colorless oil 013 mg, 94%);
3.1.25. )9R,10E,12R,13S,15Z)-13-t-Butyldiphenylsilyl-
oxy-12-hydroxyoctadeca-10,15-dien-9-olide )20a). The
compound 19a 021 mg, 0.032 mmol) was dissolved in 2%
HF/acetonitrile 01 mL) at 08C and stirred for 1 h at room
temperature. The reaction mixture was neutralized with
saturated NaHCO3 solution and extracted with ether. The
combined organic layer was washed with water, saturated
NaHCO3 solution and brine. After drying with MgSO4, the
solvent was removed in vacuo. The residue was puri®ed by
silica gel column chromatography 015:1 hexanes/EtOAc) to
furnish alcohol 20a as a colorless oil 08.9 mg, 51%);
29
28
nD ˆ1:4948; ‰aŠ ˆ128:7 0cˆ0.63, CHCl3);IR 0®lm):
D
1
nmax 2932, 1731, 1468, 1237, 1067, 966 cm21; H NMR
0300 MHz, CDCl3): d 0ppm) 0.97 03H, t, Jˆ7.5 Hz,
H-18), 1.0±1.8 010H, m, H-3a, 4, 5, 6, 7, 8a), 1.95±2.15
04H, m, H-3b, 8b, 17), 2.20 01H, ddd, Jˆ2.6, 11.9, 15.5
Hz, H-2a), 2.36 02H, m, H-14), 2.52 01H, ddd, Jˆ3.0, 6.2,
15.5 Hz, H-2b), 2.87 01H, dt, Jˆ2.2, 5.3 Hz, H-13), 3.15
01H, dd, Jˆ2.2, 7.8 Hz, H-12), 5.30±5.42 02H, m, H-9,
15), 5.46 01H, ddd, Jˆ1.4, 7.8, 15.6 Hz, H-11), 5.54 01H,
m, H-16), 5.94 01H, dd, Jˆ5.1, 15.6 Hz, H-10); 13C NMR
075.5 MHz, CDCl3): d 0ppm) 14.2, 20.7, 20.7, 23.3, 23.6,
24.1, 27.0, 29.5, 29.8, 35.0, 57.4, 59.9, 74.8, 122.2, 128.5,
132.7, 134.9, 173.4;Anal. Calcd. for C 18H28O3: C, 73.93;H,
9.65. Found: C, 73.72;H, 9.67.
27
28
nD ˆ1:5166; ‰aŠ ˆ146:9 0cˆ0.81, CHCl3);IR 0®lm):
D
nmax 3449, 2930, 1726, 1111, 822, 703 cm21; H NMR
1
0300 MHz, CDCl3): d 0ppm) 0.81 03H, t, Jˆ7.5 Hz,
H-18), 1.08 09H, s, ±SiBut), 1.2±1.8 012H, m, H-3a, 4, 5,
6, 7, 8a, 17), 2.0±2.3 05H, m, H-2a, 3b, 8b, 14), 2.51 01H, dm,
Jˆ15.6 Hz, H-2b), 3.83 01H, m, H-13), 4.09 01H, m, H-12),
5.16 01H, m, H-15), 5.29 01H, m, H-16), 5.41 01H, m, H-9),
5.70 01H, dd, Jˆ5.3, 15.9 Hz, H-10), 5.87 01H, dd, Jˆ6.0,
15.9 Hz, H-11), 7.3±7.8 010H, m, Ar of TBDPS); 13C NMR
075.5 MHz, CDCl3): d 0ppm) 14.0, 19.4, 20.5, 20.6, 23.1,
23.1, 24.0, 27.0, 27.2, 29.1, 30.6, 35.1, 74.4, 75.2, 76.6,
123.9, 127.6, 127.8, 129.6, 129.8, 129.9, 130.0, 133.4,
133.6, 133.9, 135.8, 135.9, 173.3;FAB MS m/z 0M1)
calcd 548.3322, obsd 548.3325.
3.1.28. )9S,10E,12S,13S,15Z)-12,13-Epoxyoctadeca-10,15-
dien-9-olide )ent-2). As described for the synthesis of 1,
20b 019 mg, 0.034 mmol) was converted into ent-2
28
28
07.5 mg, 75%, colorless oil);n
ˆ1:4949; ‰aŠ ˆ267:3
D
D
0cˆ0.56, CHCl3);IR 0®lm): nmax 2934, 1730, 1468, 1237,
967 cm21; 1H NMR 0300 MHz, CDCl3): d 0ppm) 0.97 03H,
t, Jˆ7.5 Hz, H-18), 1.0±1.8 010H, m, H-3a, 4, 5, 6, 7, 8a),
1.95±2.15 04H, m, H-3b, 8b, 17), 2.20 01H, ddd, Jˆ2.6, 12.1,
15.5 Hz, H-2a), 2.37 02H, m, H-14), 2.51 01H, ddd, Jˆ3.0,
6.2, 15.5 Hz, H-2b), 2.88 01H, dt, Jˆ2.0, 5.3 Hz, H-13), 3.15
01H, dd, Jˆ2.0, 7.7 Hz, H-12), 5.25±5.65 04H, m, H-9, 11,
15, 16), 5.95 01H, dd, Jˆ6.0, 15.6 Hz, H-10); 13C NMR
075.5 MHz, CDCl3): d 0ppm) 14.2, 20.7, 20.7, 23.4, 23.6,
24.2, 27.0, 29.5, 29.9, 35.1, 57.3, 59.9, 75.1, 122.2, 129.1,
132.8, 134.9, 173.4;FAB MS m/z 0M11H) calcd 293.2117,
obsd 293.2091.
3.1.26.
)9S,10E,12R,13S,15Z)-13-t-Butyldiphenylsilyl-
oxy-12-hydroxyoctadeca-10,15-dien-9-olide )20b). As
described for the synthesis of 20a, 19b 044 mg,
0.66 mmol) was converted into 20b 019 mg, 51%, colorless
28
28
oil);n
ˆ1:5168; ‰aŠ ˆ16:4 0cˆ0.83, CHCl3);IR
D
D
0®lm): nmax 3478, 2931, 1730, 1111, 822, 704 cm21; H
NMR 0300 MHz, CDCl3): d 0ppm) 0.82 03H, t, Jˆ7.5 Hz,
H-18), 1.08 09H, s, ±SiBut), 1.2±1.8 012H, m, H-3a, 4, 5, 6,
7, 8a, 17), 2.0±2.3 05H, m, H-2a, 3b, 8b, 14), 2.50 01H, dm,
Jˆ15.3 Hz, H-2b), 3.84 01H, m, H-13), 4.08 01H, m, H-12),
5.18 01H, m, H-15), 5.29 01H, m, H-16), 5.39 01H, m, H-9),
5.72 01H, dd, Jˆ4.7, 15.7 Hz, H-10), 5.80 01H, dd, Jˆ5.1,
15.7 Hz, H-11), 7.3±7.8 010H, m, Ar of TBDPS); 13C NMR
075.5 MHz, CDCl3): d 0ppm) 14.0, 19.4, 20.5, 20.6, 23.2,
23.4, 24.1, 27.0, 27.1, 29.6, 30.5, 35.0, 74.3, 75.3, 76.6,
124.0, 127.6, 127.7, 129.5, 129.8, 129.9, 129.9, 133.5,
133.6, 133.8, 135.8, 135.9, 173.3;FAB MS m/z 0M1)
calcd 548.3322, obsd 548.3332.
1
Acknowledgements
This work was ®nancially supported by a Grant-in-Aid for
Scienti®c Research for Encouragement of Young Scientists
and a Grant-in-Aid for Scienti®c Research from the
Ministry of Education, Science, Sports, and Culture,
È
Japan. We sincerely thank Professor Gabriele M. Konig,
University of Bonn, for the kind gift of the spectral charts
of natural mueggelone. We also thank Ms Hiroko Naito,
University of Tokyo, for elemental analyses.
3.1.27. )9R,10E,12S,13S,15Z)-12,13-Epoxyoctadeca-10,15-
dien-9-olide )Mueggelone, 1). To a solution of alcohol 20a
025 mg, 0.046 mmol) in dichloromethane 00.5 mL) was
added triethylamine 058 mL, 0.401 mmol) and DMAP
049 mg, 0.401 mmol). The mixture was cooled to 08C and
methanesulfonyl chloride 010.6 mL, 0.137 mmol) was
added. Stirring was continued for 4 h and then the reaction
mixture was poured into cold water and extracted with ether.
The combined organic layer was washed with water, satu-
rated NH4Cl solution, saturated NaHCO3 solution and brine,
and then dried with MgSO4. After removal of the solvent,
the residue was taken up into THF 00.5 mL). To this solution
was added TBAF 0100 mL of 1.0 M in THF, 0.1 mmol) and
the mixture was stirred for 2 h at ambient temperature. The
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