Total synthesis of (-)-mniopetal F, a novel inhibitor of RNA-directed DNA-polymerases

Article abstract of DOI:10.1016/S0040-4020(01)00686-X

We have achieved a total synthesis of (-)-mniopetal F, a drimane-type sesquiterpenoid which inhibits the reverse transcriptase activity of the human immunodeficiency virus (HIV)-1. The key step in our enantiospecific synthesis is a stereoselective intramolecular Diels-Alder reaction, in which the π-facial selectivity is controlled by the stereoelectronic effect of a trialkylsilyloxy substituent existing adjacent to the dienophile part.

Full text of DOI:10.1016/S0040-4020(01)00686-X

TETRAHEDRON
Pergamon
Tetrahedron 57 )2001) 7291±7301
Total synthesis of ꢀ2)-mniopetal F, a novel inhibitor of
RNA-directed DNA-polymerases
Yoshikazu Suzuki, Aiko Ohara, Kenji Sugaya, Ken-ichi Takao and Kin-ichi Tadanop
Department of Applied Chemistry, Keio University, 3-14-1 Hiyoshi, Kokoku-ku, Yokohama 223-8522, Japan
Received 8 May 2001;accepted 29 June 2001
AbstractÐWe have achieved a total synthesis of )2)-mniopetal F, a drimane-type sesquiterpenoid which inhibits the reverse transcriptase
activity of the human immunode®ciency virus )HIV)-1. The key step in our enantiospeci®c synthesis is a stereoselective intramolecular
Diels±Alder reaction, in which the p-facial selectivity is controlled by the stereoelectronic effect of a trialkylsilyloxy substituent existing
adjacent to the dienophile part. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
of these products, all consisting of a highly oxygenated
octahydronaphthalene core framework, were elucidated by
a combination of chemical and spectroscopic methods )1H
and 13C NMR, MS, UV, and IR).2 The absolute stereo-
chemistries of 1±6 were proposed as depicted3 based on
the correlation to the stereochemically de®ned 1a,15-
dihydroxylmarasmene )7), which was isolated previously
by Ayer's group.4 In addition, a structurally similar natural
product marasmal )8) was isolated from another fungus.4
Recently, the absolute stereochemistries of )2)-mniopetal
E )5) and )2)-mniopetal F )6) were established through
their total syntheses completed by us5 and by Jauch,6 respec-
tively. Because of their intriguing biological activities and
structural uniqueness, a number of synthetic studies of these
sesquiterpenoids have been conducted by several groups,7
including ours.8 In this paper, we describe an enantiospeci®c
total synthesis of )2)-mniopetal F )6).
In 1994, six novel drimane-type sesquiterpenoids,
mniopetals A±F )1±6) )Fig. 1) were isolated from the
fermentation broth of Canadian Mniopetalum sp. 87256 by
Steglich et al.1 These natural products are known to inhibit
the activity of the RNA-directed DNA-polymerases )RT,
reverse transcriptases) of the human immunode®ciency
virus )HIV)-1, avian myeloblastosis virus )AMV), and
moloney murine leukemia virus )MMuLV).1 The structures
2. Results and discussion
Our retrosynthesis to 6 is shown in Scheme 1, in which the
key step is the intramolecular Diels±Alder )IMDA) reac-
tion9 of a butenolide C, tethering a functionalized )E,E)-5,7-
octadiene at the b-carbon, for the construction of the 6±6±5
angularly fused tricyclic skeleton in 6. The adjustment of
the oxidation states at C-11 and C-15 )mniopetal number-
ing) in the expected Diels±Alder adduct A, accompanying
by the migration of the carbon±carbon double bond, would
eventually provide 6. We anticipated that the IMDA
reaction of the substrate C would proceed favorably via a
chair-like endo-transition state depicted as B, leading to the
desired adduct A. Accordingly, we designed the trienes C
carrying a variety of hydroxy-protecting groups )P in
Scheme 1) at C-1 as the substrates for the directed Diels±
Alder reaction. The synthesis of C could be achieved from a
heptanal derivative D by the introduction of the diene and
Figure 1.
Keywords: biologically active compounds;Diels±Alder reactions;
Katsuki±Sharpless reactions;terpenes and terpenoids.
p
Corresponding author. Tel./fax: 181-45-566-1571;
e-mail: tadano@applc.keio.ac.jp
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020)01)00686-X

7292
Y. Suzuki et al. / Tetrahedron 57 ,2001) 7291±7301
Scheme 1.
dienophile parts. Then the intermediate D could be prepared
from known d-2-deoxy-erythritol derivative 9, which had
been prepared from d-mannitol by Sharpless et al. using
their asymmetric epoxidation strategy.10
The synthesis of substrates 25±33 for the directed IMDA
reaction is summarized in Scheme 2. The primary hydroxyl
group in 9 was protected as a tert-butyldimethylsilyl )TBS)
ether. The secondary hydroxyl group in the resulting 10 was
protected as a methoxymethyl )MOM) ether to provide 11.
De-O-silylation of 11 with tetrabutylammonium ¯uoride
)TBAF) afforded 12. Treatment of 12 with I2, PPh3 and
imidazole11 provided iodide 13. The substitution of the
iodo group in 13 by an anion generated from 2-methyl-
Scheme 2. Reagents and conditions: )a) TBSCl, Et3N, DMAP, CH2Cl2;
)b) MOMCl, DIPEA, CHCl3, 408C;)c) TBAF, THF )89% from 9);)d) I ,
PPh3, imidazole, THF, 2188C )93%);)e) Me CHCN, LDA, THF, 2188C
2
2
)99%);)f) DIBALH, PhMe, 2788C then 1 M HCl;)g) triethyl 4-phos-
phonocrotonate, LiOH´H2O, MS 4A, THF, re¯ux )83% from 14);
)h) DIBALH, CH2Cl2, 2788C;)i) MnO 2, CH2Cl2;)j) HSCH 2CH2SH,
BF3´OEt2, CH2Cl2, 2188C )22% from 16 for 19 and 45% for 20);
)k) AcOH/H2O/THFˆ3:1:1 )93%);)l) TBSCl, Et 3N, DMAP, CH2Cl2
)89%);)m) DMSO, SO 3´pyr., Et3N, CH2Cl2 )70%);)n) CSA, MeOH/
H2O/CH2Cl2 )45:7.5:1) )87%);)o) )EtO) 2P)O)CH2CO2H, WSC´HCl,
Et3N, DMAP, CH2Cl2;)p) K 2CO3, 18-crown-6, PhMe )80% from 23);
)q) 4 M HCl/THF )3:7) )92%);)r) for 27: TMSCl, Et3N, DMAP, THF
)48%, recovery of 26, 48%);for 28: DMIPSCl, imidazole, DMF, 08C
)87%);for 29: TBSOTf, pyr. then 1 M HCl, THF )84%);for 30: TESCl,
DMAP, pyr. )85%);for 31: TIPSOTf, DMAP, pyr. )93%);for 32: Ac2O,
pyr. )99%);for 33: PivCl, DMAP, pyr. )85%).
propionitrile12 provided, quantitatively,
a heptanitrile
derivative 14. Reduction of the nitrile group in 14 with
diisobutylaluminum hydride )DIBALH) followed by acidic
hydrolysis provided aldehyde 15. The Horner±Emmons
reaction of 15 with triethyl 4-phosphonocrotonate using
lithium hexamethyldisilazide as the base in tolune provided
)E,E)-a,b/g,d-unsaturated ester 16 in a 66% yield with high
E,E-selectivity. However, reproducibility of the Horner±
Emmons recation of 15 under these conditions was
problematic. This problem was overcome by conducting
the reaction in the presence of LiOH´H2O and molecular
sieves )4A powder),13 and the yield of 16 was improved to
an 83% yield from 14. Furthermore, the geometric ratio
)E,E-isomer/other isomers) was determined to be .20:1
phosphonoacetic acid by the action of water-soluble
carbodiimide )WSC) provided a-phosphonoacetate 24.
The intramolecular Horner±Emmons reaction of 24 was
ef®ciently conducted in the presence of K2CO3 and
18-crown-6,15 providing the butenolide 25 in an 80% yield
from 23. The substituent at C-1 in 25 was protected by a
variety of functional groups including ®ve trialkylsilyloxy
groups for investigating the effect on the p-facial
selectivity in the directed IMDA reaction. Thus, hydrolysis
of 25 with aqueous HCl followed by protection of the
hydroxyl group in the resulting 26 with a variety of silyl-
ating reagents provided trialkylsilyl ethers 27±31. We
also prepared acetate 32 and pivaloate 33 by respective
acylation.
1
based on the H NMR analysis. DIBALH reduction of 16
followed by MnO2 oxidation of the resulting allylic alcohol
17 provided aldehyde 18. As a masked aldehyde function-
ality, the formyl group in 18 was converted into a 1,3-dithio-
lane form, providing 19. The de-O-isopropylidene
derivative 20 was accompanied by 19. Acid hydrolysis of
19 also provided the additional diol 20. Selective protection
of the primary hydroxyl group14 in 20 provided the TBS
ether 21. Oxidation of 21 with DMSO and SO3´pyridine
and subsequent de-O-silylation of the resulting keto
derivative 22 with camphorsulfonic acid )CSA) provided
a-hydroxy ketone 23. Esteri®cation of 23 with diethyl-

Y. Suzuki et al. / Tetrahedron 57 ,2001) 7291±7301
Table 1. Intramolecular Diels±Alder reactions of 25±33
7293
Entry
Triene
Products
P
Time )h)
Yield )%)a
endo/exob
A/Bb
1
2
3
4
5
6
7
8
9
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
MOM
H
40
40
40
70
50
40
40
40
40
86
66
70
81
84
78
50
74
72
.20:1
.20:1
.20:1
.20:1
.20:1
.20:1
.20:1
.20:1
.20:1
8:12
8:12
13:7
13:7
13:7
12:8
10:10
5:15
7:13
TMS
DMIPS
TBS
TES
TIPS
Ac
Piv
a
Isolated yield of the diastereomeric mixture.
Determined by 300 MHz 1H NMR.
b
the ODMIPS group orients axially. On the other hand, the
H-1 proton for the minor diastereomer 37B appeared as a
doublet of doublets with Jˆ5.3 and 10.6 Hz, indicating the
ODMIPS group orients equatorially. These spectral data
veri®ed the conformations of 37A and 37B as shown.
Based on their NOESY correlations and coupling constants
for ring protons, it was con®rmed that all the IMDA reac-
tions of 25±33 proceeded with high endo/exo selectivity
)A1B/C1D, more than 20 to 1 in every case). In addition,
the p-facial selectivity of the endo-adducts )A/B) depended
on the substituent at C-1. The alkyloxy and acyloxy
substrates at C-1, i.e. 25, 32, and 33, and unprotected
substrate 26 provided the undesired endo-cycloadduct B
preferentially )entries 1, 2, 8, or 9). On the other hand, the
silyl ethers 27±30 provided the desired endo-adducts A
predominantly )entries 3±6). Among them, the subtrates
28 and 29 carrying a bulkier trialkylsilyloxy group at C-1
provided the desired endo-adducts 37 and 38 with the high-
est ratio in comparable yields )entries 4 and 5). In the case of
the bulkiest silyl ether 31, the p-facial selectivity signi®-
cantly decreased, providing two endo-adducts 40A and 40B
equally with a reduced combined yield )entry 7). Although
we have no ®rm explanation for these stereochemical
outcomes, the steric and/or stereoelectronic balance of the
three substituents at the silicon atom seems to be crucial for
the p-facial selectivity and the yield. From the steric point
of view, a substituent neighboring the dienophile part would
generally dispose an equatorial orientation in the transition
state. Plausible transition states TS-A, B, C, and D, leading
to adducts A, B, C, and D, respectively, are depicted in Fig.
3 to explain the preferential formation of the endo-adducts
A and B. As our substrates possesses a butenolide as the
dienophile, the six-membered chair-like transition states are
considered as shown in Fig. 3. The endo-mode cyclization,
as shown in the cases of TS-A and B, proceeds smoothly
because of the presence of preferable secondary orbital
interaction. In the exo-mode cyclizations )TS-C and D),
severe interactions between H-6 )the diene part) and H-3
or OP-1 )or H-1) make the cyclization unfavorable. In fact,
Figure 2.
The results of the thermal IMDA reactions using the
substrates 25±33 are summarized in Table 1. Each solution
²
of the substrate in toluene was heated at 2108C in a sealed
tube in the presence of a catalytic amount of 2,6-di-tert-
butyl-4-methylphenol )BHT). After chromatographic puri-
®cation of the reaction mixture on silica gel, the structures
of the adducts and diastereomeric ratios )endo/exo and the
endo-adducts A/B) of the respective cycloadducts were
1
determined based on H NMR analysis. As shown in Fig.
2, the relative con®gurations for the diastereomeric adducts
were determined by NOESY correlations, exempli®ed by
the diastereomeric adducts 37A and 37B obtained from
the substrate 28 carrying an isopropyldimethylsilyl
)DMIPS) ether at C-1. From these NOESY correlations, it
was established that both 37A and 37B possess a trans-fused
octahydronaphthalene skeleton. Consequently, the cyclo-
addition of 28 predominantly proceeded via the anticipated
endo-mode. Furthermore, the H-1 proton for the major
adduct 37A appeared as a narrow singlet, indicating that
²
We did not conduct the IMDA reactions of 25±33 using a Lewis acid
catalyst, because of our previous unfruitful results with Lewis acids
obtained in the mniopetal E synthesis. See Ref. 5b.

7294
Y. Suzuki et al. / Tetrahedron 57 ,2001) 7291±7301
in the TSs) at the neiboring site of the diene part. This
may accelerate the cyclization, as a number of precedent
papers described the geminal dialkyl effect.18 However,
we could not estimate the magnitude of this effect because
we had no opportunity to conduct the IMDA reaction using
a substrate without this geminal dimethyl substitutent. From
the synthetic point of view, we chose the diastereomeric
mixture 37 as the most suitable IMDA adducts for the
total synthesis of 6.19
Total synthesis of mniopetal F )6) was achieved from 37 as
summarized in Scheme 3. De-O-silylation of 37, as an
approximately 2:1 diastereomeric mixture of 37A and
37B, with TBAF provided 35 as a diastereomeric mixture.
Treatment of 35 with Hg)ClO4)2´3H2O20 provided a dia-
³
stereomeric mixture of dimethylacetal 43A )44%) and
43B )25%), which were cleanly separated by chromato-
graphy on silica gel. The hydroxyl group in the diastereo-
merically pure 43A was protected as an MOM ether. The
g-lactone in the resulting 44 was hydrolyzed under basic
Figure 3.
Scheme 3. Reagents and conditions: )a) TBAF, THF, 08C )92%);)b) Hg)ClO )2´3H2O, CaCO3, MeOH/CHCl3 )3:1), 08C )44% for 43A, 25% for 43B);
4
)c) MOMCl, DIPEA, CH2Cl2, 408C )85%);)d) 1 M KOH, Na 2RuO4, t-BuOH, 808C )100%);)e) DIBALH, PhMe, 2788C )44% for 46, 21% for 44, 21% for
45);)f) TsOH´H 2O, THF/H2O )4:1) )43%);)g) DMSO, Ac 2O )80%);)h) 6 M HCl, THF then Et 3N, PhMe )83%).
in all IMDA reactions using 25±33, only the endo-adducts
were formed substantially. In regard to the p-facial
selectivity in the formation of endo-adducts A and B, we
made the following speculation. As shown in TS-A and C,
previous reports on the stereochemical studies of IMDA
reactions indicated that a trialkylsilyloxy substituent in the
substrates prefers to dispose an axial orientation as a result
of the maximum hyperconjugative interaction between sC±O
conditions, and the resulting open-ring g-hydroxyl
carboxylate was immediately oxidized with Na2RuO4,21
providing g-hydroxyl-g-lactone 45 as an inseparable dia-
stereomeric mixture. Treatment of 45 with 2 equiv. of
DIBALH provided dialdehyde hydrate 46 )44%) along
with 44 )21%) and recovered 45 )21%). Brief treatment of
46 with TsOH provided a tetracyclic hemiacetal mixture 47,
which was oxidized to tetracyclic lactone 48. Finally, acid
hydrolysis of the acetal moiety in 48 and subsequent base-
mediated double-bond migration provided )2)-mniopetal F
)6). In the initial stage of this step, simultaneous acid
hydrolysis )6 M HCl) of the MOM ether and methyl acetal
and pp
of the dienophile, which lowers the dienophile
CvC
LUMO.16,17 As mentioned above, TS-C suffers from a
severe interaction between H-6 and the silyloxy group. In
addition, the A1,3 strain between the ring hydrogen in the
butenolide and equatorially oriented silyloxy group makes
TS-B less favorable, resulting in the preferential formation
of the endo-A isomer as the major product. The present
IMDA substrates possess a geminal dimethyl group )C-4
³
The enantiopurity of 43A ).98% ee) was con®rmed by 1H NMR analyses
of the corresponding )R)- and )S)-O-acetylmandelate derivatives. No
racemization of the C-1 in 28 occurred under the used IMDA conditions.

Y. Suzuki et al. / Tetrahedron 57 ,2001) 7291±7301
7295
in 48 occurred. Isomerization of the double bond in this
intermediary hemiacetal proceeded quite slowly under the
acidic conditions. On the contrary, treatment of this
hemiacetal with triethylamine as the base provided the
thermodynamically favorable double-bond migration
product, i.e. 6, as a sole product in a yield of 83% from
48. The spectroscopic data )1H and 13C NMR, IR, MS) of
the synthetic 6 were well matched with those for natural 6.§
oil;TLC, Rf 0.35 )EtOAc/hexane, 1:5);[ a]21.5 ˆ117.5 )c
D
0.92, CHCl3);IR 3500 cm 21; 1H NMR )300 MHz) d 0.08 )s,
6H), 0.90 )s, 9H), 1.35, 1.41 )2s, 3H£2), 1.59±1.74 )m, 1H),
1.78±1.89 )m, 1H), 3.41±3.68 )br, 1H), 3.76±4.12 )m, 6H);
13C NMR )75 MHz) d 5.6£2, 18.1, 25.3, 25.8£3, 26.6, 34.5,
62.4, 66.4, 72.6, 78.3, 109.1;HRMS calcd for C 13H27O4Si
)M12CH3) 275.1679, found 275.1677.
To a cooled )08C) solution of crude 10 obtained above in
CHCl3 )80 mL) were added diisopropylethylamine
)DIPEA) )40.1 mL, 230 mmol) and chloromethyl methyl
ether )MOMCl) )8.75 mL, 115 mmol). The mixture was
stirred at 408C for 19 h and concentrated in vacuo. The
residue was diluted with EtOAc, washed with 1.0 M
aqueous HCl and saturated aqueous NaHCO3. The organic
layer was dried and concentrated in vacuo to provide crude
11 as a pale yellow oil, which was used in the next step
without further puri®cation. In a small-scale experiment,
pure 11 was obtained by column chromatography on silica
gel )EtOAc/hexane, 1:40) as a colorless oil;TLC, Rf 0.65
In summary, we have completed the total synthesis of )2)-
mniopetal F )6) in its natural form. Our total synthesis
features the highly endo-selective IMDA reaction achieved
by using a variety of substrates 25±33. In addition, the
p-facial selectivity in the IMDA reaction was controlled
by the stereoelectronic effect of the silyloxy group adjacent
to the dienophile part, as in the case of 28.
3. Experimental
)EtOAc/hexane, 1:5);[ a]22 ˆ212.6 )c 0.57, CHCl3);IR
D
3.1. General methods
1
2930 cm21; H NMR )300 MHz) d 0.05 )s, 6H), 0.89 )s,
9H), 1.35, 1.41 )2s, 3H£2), 1.61±1.84 )m, 2H), 3.39 )s,
3H), 3.70±3.77 )m, 2H), 3.78±3.86 )m, 1H), 3.87 )dd,
Jˆ6.9, 7.9 Hz, 1H), 4.03 )dd, Jˆ6.9, 7.9 Hz, 1H), 4.12±
4.18 )m, 1H), 4.71, 4.74 )ABq, Jˆ6.8 Hz, 1H£2); 13C
NMR )75 MHz) 25.43, 25.38, 18.2, 25.2, 25.9£3, 26.3,
34.6, 55.7, 59.2, 65.8, 74.9, 78.1, 96.9, 109.1;HRMS
calcd for C15H31O5Si )M12CH3) 319.1941, found
319.1950.
Speci®c rotations were measured in a 10 mm cell. Infrared
)IR) spectra were determined as neat unless otherwise
1
noted. H NMR spectra were recorded at 270 MHz or at
300 MHz in CDCl3 with tetramethylsilane as an internal
standard. 13C NMR spectra were recorded at 67.5 Hz or at
75 MHz in CDCl3, and signal positions were measured
relative to the signal for CDCl3 )d 77.0). Thin-layer chro-
matography )TLC) was performed with a glass plate coated
with Kieselgel 60F254 )Merck). Extractive materials were
puri®ed by chromatography on Daisogel IR-60 )Daiso
Co., Ltd) or Wakogel C300 )Wako Pure Chemical
Industries). Unless otherwise described, reactions were
carried out at ambient temperature. Combined organic
extracts were dried over anhydrous Na2SO4. Solvents were
removed from reaction mixture or combined organic
extracts by concentration under reduced pressure using an
evaporator with a water bath at 35±458C. Commercially
available solvents were dried )drying reagent in brackets)
and distilled prior to use: tetrahydrofuran )THF) [LiAlH4
and then Na/benzophenone ketyl], N,N-dimethylformamide
)DMF) [CaH2], CH2Cl2 [CaH2], dimethyl sulfoxide
)DMSO) [CaH2], pyridine [NaOH], and toluene [CaH2].
To a cooled )08C) solution of crude 11 obtained above in
THF )80 mL) was added tetrabutylammonium ¯uoride
)TBAF) )30.0 mL, 1.0 M solution in THF, 30.0 mmol).
The mixture was stirred for 1.5 h and concentrated in
vacuo. The residue was puri®ed by column chromatography
on silica gel )EtOAc/hexane, 1:4) to provide 4.51 g )89%
from 9) of 12 as a colorless oil;TLC, Rf 0.27 )acetone/
toluene, 1:3);[ a]22 ˆ240.1 )c 2.50, CHCl3);IR
D
1
3440 cm21; H NMR )300 MHz) d 1.36, 1.41 )2s, 3H£2),
1.61±1.75 )m, 1H), 1.77±1.90 )m, 1H), 2.31 )br-s, 1H), 3.42
)s, 3H), 3.71±3.90 )m, 4H), 4.03±4.15 )m, 2H), 4.70, 4.76
)ABq, Jˆ6.7 Hz, 1H£2); 13C NMR )75 MHz) d 25.3, 26.3,
34.0, 56.0, 59.1, 66.0, 76.2, 77.8, 97.3, 109.3;HRMS calcd
for C9H17O5: )M12CH3) 205.1076, found 205.1078.
3.1.1.
ꢀ2R,3S)-1,2-ꢀIsopropylidenedioxy)-3-ꢀmethoxy-
3.1.2. ꢀ2R,3S)-5-Iodo-1,2-ꢀisopropylidenedioxy)-3-ꢀmeth-
oxymethoxy)pentane ꢀ13). To a cooled )2188C) solution
of 12 )1.49 g, 6.76 mmol) in THF )30 mL) were added PPh3
)2.66 g, 10.1 mmol), imidazole )693 mg, 10.2 mmol), and I2
)2.21 g, 8.70 mmol). After being stirred at 2188C for 1 h,
the organic solvent was removed by evaporation. The resi-
due was diluted with EtOAc, washed with 20 wt% aqueous
Na2S2O3 and saturated aqueous NaHCO3. The organic layer
was dried and concentrated in vacuo. The residue was
puri®ed by column chromatography on silica gel )EtOAc/
hexane, 1:40) to provide 2.07 g )93%) of 13 as a colorless
methoxy)-5-pentanol ꢀ12). To a cooled )08C) solution of
9 )4.06 g, 23.0 mmol) in CH2Cl2 )80 mL) were added Et3N
)16.1 mL, 115 mmol), TBSCl )5.21 g, 34.6 mmol) and
4-dimethylaminopyridine )DMAP) )141 mg, 1.15 mmol).
The mixture was stirred for 3.5 h and concentrated in
vacuo. The residue was diluted with EtOAc, washed with
0.2 M aqueous HCl and saturated aqueous NaHCO3. The
organic layer was dried and concentrated in vacuo to
provide crude 10 as a colorless oil, which was used in the
next step without further puri®cation. In a small-scale
experiment, pure 10 was obtained by column chromato-
graphy on silica gel )EtOAc/hexane, 1:12) as a colorless
oil;TLC, Rf 0.43 )EtOAc/hexane, 1:4);[ a]26.5 ˆ230.9 )c
D
1
1.65, CHCl3);IR 2990 cm 21; H NMR )300 MHz) d 1.35,
1.42 )2s, 3H£2), 1.97±2.19 )m, 2H), 3.22±3.42 )m, 2H),
3.41 )s, 3H), 3.63±3.73 )m, 1H), 3.85 )dd, Jˆ6.1, 7.9 Hz,
1H), 4.05 )dd, Jˆ6.4, 7.9 Hz, 1H), 4.06±4.16 )m, 1H), 4.72,
4.75 )ABq, Jˆ7.0 Hz, 1H£2); 13C NMR )75 MHz) d 2.0,
§
The optical rotation of our synthetic 6 )[a]23 ˆ256, c 0.24, MeOH) was
D
not matched with that for natural 61 )[a]23 ˆ229, c 0.22, MeOH), but
D
was matched well with that reported by Jauch for his synthetic 6
)[a]20 ˆ263, c 0.65, MeOH).6
D

7296
Y. Suzuki et al. / Tetrahedron 57 ,2001) 7291±7301
25.1, 26.3, 35.7, 55.9, 66.1, 77.1, 78.2, 96.9, 109.3;HRMS
calcd for C9H16O4I )M12CH3) 315.0094, found 315.0093.
d 1.05 )s, 6H), 1.29 )t, Jˆ7.2 Hz, 3H), 1.34, 1.39 )2s,
3H£2), 1.35±1.60 )m, 4H), 3.38 )s, 3H), 3.56±3.63 )m,
1H), 3.80±3.90 )m, 1H), 3.98±4.08 )m, 2H), 4.20 )q,
Jˆ7.2 Hz, 2H), 4.64, 4.71 )ABq, Jˆ6.8 Hz, 1H£2), 5.81
)d, Jˆ15.3 Hz, 1H), 6.00±6.15 )m, 2H), 7.21±7.31 )m,
1H); 13C NMR )75 MHz) d 14.3, 25.3, 26.4, 26.5, 26.6,
26.8, 36.6, 37.6, 55.8, 60.1, 66.1, 77.4, 78.0, 96.6, 109.0,
119.6, 124.8, 145.3, 153.4, 167.2;HRMS calcd for
C20H34O6 )M1) 370.2355, found 370.2355.
3.1.3.
ꢀ5S,6R)-6,7-ꢀIsopropylidenedioxy)-5-ꢀmethoxy-
methoxy)-2,2-dimethyl-1-heptanenitrile ꢀ14). The follow-
ing reaction was carried out under argon. To a cooled )08C)
solution of diisopropylamine )1.67 mL, 11.9 mmol) in THF
)40 mL) was added n-BuLi )4.8 mL, 2.46 M solution in
hexane, 11.8 mmol). After being stirred at 08C for 30 min,
isobutyronitrile )1.10 mL, 12.1 mmol) was added to the
solution at 2788C. After being stirred at 2788C for 1 h, a
solution of 13 )1.97 g, 5.97 mmol) in THF )10 mL) was
added to the mixture. The mixture was stirred at 2188C
for 30 min and quenched with saturated aqueous NH4Cl.
The organic solvent was removed by evaporation. The
resulting aqueous solution was diluted with 10 wt% aqueous
Na2S2O3 and the whole was extracted with CH2Cl2. The
combined organic layers were dried and concentrated in
vacuo. The residue was puri®ed by column chromatography
on silica gel )EtOAc/hexane, 1:9) to provide 1.60 g )99%) of
3.1.5. ꢀ2R,3S,7E,9E)-10-ꢀ1,3-Dithiolan-2-yl)-3-ꢀmethoxy-
methoxy)-6,6-dimethyl-7,9-decadiene-1,2-diol ꢀ20). The
following reaction was carried out under argon. To a cooled
)2788C) solution of 16 )11.5 g, 31.0 mmol) in CH2Cl2
)220 mL) was added DIBALH )78.0 mL, 1.0 M solution
in toluene, 78 mmol). The mixture was stirred at 2788C
for 15 min and quenched with H2O. This was diluted with
H2O )150 mL) then with CH2Cl2 )150 mL). To this was
added potassium sodium )1)-tartrate tetrahydrate )40 g).
The whole was stirred vigorously for 15.5 h and the organic
layer was separated. The aqueous layer was extracted with
CH2Cl2. The combined organic layers were dried and
concentrated in vacuo to provide crude 17 )11.0 g) as a
colorless oil, which was used in the next step without puri-
®cation. In a small-scale experiment, pure 17 was obtained
by column chromatography on silica gel )EtOAc/hexane,
1:3) as a colorless oil )E,E-isomer/other isomers)20:1,
14 as a pale yellow oil;TLC, Rf 0.22 )EtOAc/hexane, 1:4);
1
[a]24 ˆ23.5 )c 1.78, CHCl3);IR 2240 cm 21; H NMR
D
)300 MHz) d 1.35 )s, 6H), 1.37, 1.41 )2s, 3H£2), 1.55±
1.86 )m, 4H), 3.39 )s, 3H), 3.62±3.69 )m, 1H), 3.87 )dd,
Jˆ9.0, 10.7 Hz, 1H), 4.02±4.11 )m, 2H), 4.67, 4.72 )ABq,
Jˆ6.8 Hz, 1H£2); 13C NMR )75 MHz) d 25.3, 26.3, 26.5,
26.9£2, 32.2, 36.1, 55.9, 66.4, 77.1, 77.6, 96.6, 109.2,
124.8;HRMS calcd for C 13H22O4N: )M12CH3) 256.1549,
found 256.1552.
1
determined by H NMR analysis);TLC, Rf 0.52 )EtOAc/
hexane, 1:1);[ a]25 ˆ12.4 )c 2.00, CHCl3);IR 3430,
D
1
1660 cm21; H NMR )270 MHz) d 1.02 )s, 6H), 1.24±
3.1.4. Ethyl ꢀ2E,4E,9S,10R)-10,11-ꢀisopropylidenedioxy)-
9-ꢀmethoxymethoxy)-6,6-dimethyl-2,4-undecadienoate
ꢀ16). The following reaction was carried out under argon.
To a cooled )2788C) solution of 14 )1.52 g, 5.60 mmol) in
toluene )30 mL) was added diisobutylaluminium hydride
)DIBALH) )8.7 mL, 1.0 M solution in toluene, 8.7 mmol).
After being stirred at 2788C for 30 min, the mixture was
quenched with H2O. This was diluted with 1.0 M aqueous
HCl and extracted with EtOAc. The combined extracts were
washed with saturated NaHCO3. The organic layer was
dried and concentrated in vacuo to provide crude 15 as a
pale yellow oil, which was used in the next step without
further puri®cation. In a small-scale experiment, pure 15
was obtained by column chromatography on silica gel
)EtOAc/hexane, 1:10) as a colorless oil;TLC, Rf 0.57
1.58 )m, 4H), 1.35, 1.39 )2s, 3H£2), 1.65 )br-s, 1H), 3.38
)s, 3H), 3.58±3.64 )m, 1H), 3.81±3.92 )m, 1H), 3.98±4.13
)m, 2H), 4.16 )dd, Jˆ1.1, 5.9 Hz, 2H), 4.64, 4.72 )ABq,
Jˆ7.0 Hz, 1H£2), 5.63 )d, Jˆ15.4 Hz, 1H), 5.75 )dt,
Jˆ5.9, 15.0 Hz, 1H), 5.96 )dd, Jˆ10.3, 15.4 Hz, 1H), 6.22
)br-dd, Jˆ10.3, 15.0 Hz, 1H); 13C NMR )75 MHz) d 25.3,
26.37, 26.40, 26.9, 27.2, 35.8, 37.9, 55.7, 63.4, 65.9, 77.5,
77.9, 96.5, 109.0, 125.8, 129.7, 132.2, 144.7;HRMS calcd
for C17H29O5 )M12CH3) 313.2015, found 313.2018.
To a cooled )08C) solution of the crude 17 obtained above
)11.0 g) in CH2Cl2 )200 mL) was added MnO2 )79.3 g,
912 mmol). The mixture was stirred for 25 min, and inor-
ganic materials were ®ltered off, washed well with EtOAc.
The combined ®ltrate and washings were concentrated in
vacuo to provide crude 18 )9.66 g) as a colorless oil, which
was used in the next step without further puri®cation. In a
small-scale experiment, pure 18 was obtained by column
chromatography on silica gel )EtOAc/hexane, 1:5) )E,E-
isomer/other isomers)20:1, determined by 1H NMR analy-
1
)EtOAc/hexane, 1:2);IR 1730 cm 21; H NMR )300 MHz)
d 1.07 )s, 6H), 1.34, 1.39 )2s, 3H£2), 1.35±1.75 )m, 4H),
3.39 )s, 3H), 3.57±3.64 )m, 1H), 3.80±3.90 )m, 1H), 4.00±
4.10 )m, 2H), 4.65, 4.72 )ABq, Jˆ6.8 Hz, 1H£2), 9.46 )s, 1H).
The following reaction was carried out under argon. To a
mixture of crude 15 obtained above and molecular sieves
4A powder )8.4 g) in THF )30 mL) were added triethyl
4-phosphonocrotonate )2.1 mL, 8.7 mmol) and LiOH´H2O
)354 mg, 8.4 mmol). The mixture was heated under re¯ux
for 19 h. The reaction mixture was ®ltered through a short
column of silica gel with CHCl3 as eluate, and the eluate
was concentrated in vacuo. The residue was puri®ed by
column chromatography on silica gel )EtOAc/hexane, 1:9)
to provide 1.72 g )83% from 14) of 16 as a colorless oil
sis);TLC,
Rf 0.49 )EtOAc/hexane, 1:2);IR 1680,
,
1H NMR )300 MHz) d 1.09 )s, 6H), 1.35,
1635 cm21
1.39 )2s, 3H£2), 1.37±1.62 )m, 4H), 3.38 )s, 3H), 3.56±
3.63 )m, 1H), 3.82±3.89 )m, 1H), 4.00±4.09 )m, 2H),
4.65, 4.72 )ABq, Jˆ7.0 Hz, 1H£2), 6.11 )dd, Jˆ7.7,
15.4 Hz, 1H), 6.19 )d, Jˆ15.0 Hz, 1H), 6.26 )dd, Jˆ8.4,
15.0 Hz, 1H), 7.09 )ddd, Jˆ1.5, 8.4, 15.4 Hz, 1H), 9.54
)d, Jˆ7.7 Hz, 1H); 13C NMR )75 MHz) d 25.2, 26.2, 26.4,
26.5£2, 36.9, 37.4, 55.7, 66.1, 77.3, 78.0, 96.5, 109.0, 125.1,
130.3, 153.1, 155.9, 193.7.
1
)E,E-isomer/other isomers)20:1, determined by H NMR
analysis);TLC Rf 0.53 )EtOAc/hexane, 1:3);[ a]25 ˆ13.6
To a cooled )2188C) solution of the crude 18 obtained
above )9.66 g) in CH2Cl2 )200 mL) were added
D
)c 1.42, CHCl3);IR 1715, 1640 cm 21; 1H NMR )300 MHz)

Y. Suzuki et al. / Tetrahedron 57 ,2001) 7291±7301
7297
HS)CH2)2SH )5.24 mL, 62.5 mmol) and BF3´OEt2
)1.19 mL, 9.39 mmol). The mixture was stirred at 2188C
for 1 h, and then HS)CH2)2SH )1.30 mL, 15.5 mmol) and
BF3´OEt2 )0.30 mL, 2.37 mmol) were added at 2188C. The
mixture was stirred for an additional 40 min and diluted
with saturated aqueous NaHCO3. This was extracted with
CH2Cl2. The combined organic layers were dried and
concentrated in vacuo. The residue was puri®ed by column
chromatography on silica gel )EtOAc/hexane, 1:13 to 1:1)
to provide 2.73 g )22% from 16) of 19 and 5.11 g )45% from
16) of 20. Compound 19 was obtained as a colorless oil
1H£2), 5.09 )d, Jˆ9.2 Hz, 1H), 5.57±5.66 )m, 2H), 5.92
)dd, Jˆ10.4, 15.4 Hz, 1H), 6.14 )dd, Jˆ10.4, 14.7 Hz, 1H);
13C NMR )75 MHz) d 25.4£2, 18.2, 25.7, 25.9£3, 26.9,
27.1, 35.9, 38.2, 39.5£2, 54.3, 55.8, 63.7, 72.9, 80.1, 96.8,
125.1, 130.1, 131.3, 145.4;HRMS calcd for C 23H44O4SiS2
)M1) 476.2450, found 476.2467.
3.1.7. ꢀ3S,7E,9E)-1-tert-Butyldimethylsilyloxy-10-ꢀ1,3-
dithiolan-2-yl)-3-ꢀmethoxymethoxy)-6,6-dimethyl-7,9-
decadien-2-one ꢀ22). To a stirred solution of 21 )5.69 g,
11.9 mmol) in a mixture of CH2Cl2 and DMSO )2.5:1 v/v,
120 mL) were added Et3N )65.6 mL, 477 mmol) and
SO3´pyridine )38.0 g, 239 mmol). The mixture was stirred
for 1.5 h, then Et3N )33.0 mL, 240 mmol) and SO3´pyridine
)19.0 g, 119 mmol) were added. The mixture was stirred for
2.5 h, then Et3N )33.0 mL, 240 mmol) and SO3´pyridine
)19.0 g, 119 mmol) were added. The mixture was stirred
for an additional 2 h, diluted with EtOAc and washed with
H2O. The organic layer was dried and concentrated in
vacuo. The residue was puri®ed by column chromatography
on silica gel )EtOAc/hexane, 1:20) to provide 4.02 g )70%)
of 22 as a colorless oil )E,E-isomer/other isomers)20:1,
1
)E,E-isomer/other isomers)20:1, determined by H NMR
analysis);TLC, Rf 0.62 )EtOAc/hexane, 1:3);[ a]25.5
ˆ
D
21
12.8 )c 1.77, CHCl3);IR 1650 cm
;
1H NMR )300
MHz) d 1.00 )s, 6H), 1.35, 1.39 )2s, 3H£2), 1.25±1.54
)m, 4H), 3.20±3.38 )m, 4H), 3.38 )s, 3H), 3.58±3.63 )m,
1H), 3.81±3.91 )m, 1H), 3.98±4.09 )m, 2H), 4.64, 4.72
)ABq, Jˆ6.8 Hz, 1H£2), 5.09 )d, Jˆ9.4 Hz, 1H), 5.618
)d, Jˆ15.4 Hz, 1H), 5.622 )dd, Jˆ9.4, 14.9 Hz, 1H), 5.92
)dd, Jˆ10.3, 15.4 Hz, 1H), 6.14 )dd, Jˆ10.3, 14.9 Hz, 1H);
13C NMR )75 MHz) d 25.4, 26.5£2, 26.9, 27.1, 36.0, 37.9,
39.5£2, 54.3, 55.8, 66.0, 77.6, 77.9, 96.6, 109.0, 125.3,
130.2, 131.2, 145.2;HRMS calcd for C 20H34O4S2 )M1)
402.1899, found 402.1899.
1
determined by H NMR analysis);TLC, Rf 0.51 )EtOAc/
hexane, 1:4);[ a]25 ˆ16.9 )c 1.36, CHCl3);IR 1730,
D
1
1650 cm21; H NMR )300 MHz) d 0.09 )s, 6H), 0.92 )s,
Compound 20 was obtained as a colorless oil )E,E-isomer/
9H), 0.99 )s, 6H), 1.24±1.73 )m, 4H), 3.19±3.39 )m, 4H),
3.35 )s, 3H), 4.25 )dd, Jˆ4.4, 7.3 Hz, 1H), 4.34, 4.41 )ABq,
Jˆ18.3 Hz, 1H£2), 4.60, 4.62 )ABq, Jˆ6.8 Hz, 1H£2),
5.08 )d, Jˆ9.2 Hz, 1H), 5.58 )d, Jˆ15.5 Hz, 1H), 5.62
)dd, Jˆ9.2, 14.9 Hz, 1H), 5.90 )dd, Jˆ10.3, 15.5 Hz, 1H),
6.12 )dd, Jˆ10.3, 14.9 Hz, 1H); 13C NMR )75 MHz) d
25.6, 25.5, 18.3, 25.7£3, 26.8, 26.9, 27.2, 35.8, 38.0,
39.5£2, 54.2, 55.9, 67.7, 80.2, 96.4, 125.4, 130.4, 131.0,
144.7, 209.6;HRMS calcd for C 23H42O4SiS2 )M1)
474.2294, found 474.2300.
1
other isomers)20:1, determined by H NMR analysis);
21
TLC, Rf 0.56 )acetone/hexane, 1:1);IR 3420, 1650 cm
;
[a]26.0 ˆ136.6 )c 1.60, CHCl3); H NMR )300 MHz) d
1
D
1.00 )s, 6H), 1.21±1.53 )m, 4H), 2.38 )br, 2H), 3.18±3.41
)m, 4H), 3.42 )s, 3H), 3.51±3.75 )m, 4H), 4.61, 4.71 )ABq,
Jˆ6.7 Hz, 1H£2), 5.09 )d, Jˆ9.2 Hz, 1H), 5.61 )d,
Jˆ15.4 Hz, 1H), 5.63 )dd, Jˆ9.2, 14.6 Hz, 1H), 5.92 )dd,
Jˆ10.3, 15.4 Hz, 1H), 6.14 )dd, Jˆ10.3, 14.6 Hz, 1H); 13C
NMR )75 MHz) d 26.7, 26.9, 27.0, 35.9, 38.7, 39.5£2, 54.2,
55.9, 63.0, 73.0, 83.3, 97.7, 125.4, 130.4, 131.0, 144.9;
HRMS calcd for C17H30O4S2 )M1) 362.1586, found
362.1585.
3.1.8. ꢀ3S,7E,9E)-10-ꢀ1,3-Dithiolan-2-yl)-1-hydroxy-3-
ꢀmethoxymethoxy)-6,6-dimethyl-7,9-decadien-2-one ꢀ23).
To a cooled )08C) solution of 22 )4.02 g, 8.47 mmol) in a
mixture of MeOH, H2O and CH2Cl2 )45:7.5:1 v/v/v,
100 mL) was added CSA )197 mg, 0.848 mmol). The
mixture was stirred for 19 h and diluted with saturated
aqueous NaHCO3, and extracted with CH2Cl2. The
combined organic layers were dried and concentrated in
vacuo. The residue was puri®ed by column chromatography
on silica gel )EtOAc/hexane, 1:4) to provide 2.65 g )87%) of
23 as a colorless oil )E,E-isomer/other isomers)20:1,
Compound 19 )2.73 g, 6.78 mmol) was dissolved in a
mixture of AcOH, H2O, and THF )3:1:1, v/v, 80 mL). The
solution was stirred for 3.5 days then concentrated in vacuo
with the aid of toluene and EtOH. The residue was puri®ed
by column chromatography on silica gel )EtOAc/hexane,
1:1) to provide 2.29 g )93%) of 20.
3.1.6. ꢀ2R,3S,7E,9E)-1-tert-Butyldimethylsilyloxy-10-ꢀ1,3-
dithiolan-2-yl)-3-ꢀmethoxymethoxy)-6,6-dimethyl-7,9-
decadien-2-ol ꢀ21). To a cooled )08C) solution of 20
)4.86 g, 13.4 mmol) in CH2Cl2 )100 mL) were added Et3N
)7.50 mL, 53.8 mmol), TBSCl )3.64 g, 24.1 mmol) and
DMAP )163 mg, 1.34 mmol). The mixture was stirred for
19 h and diluted with saturated brine. This was extracted
with CH2Cl2. The combined organic layers were dried and
concentrated in vacuo. The residue was puri®ed by column
chromatography on silica gel )EtOAc/hexane, 1:17) to
provide 5.69 g )89%) of 21 as a colorless oil )E,E-isomer:-
1
determined by H NMR analysis);TLC, Rf 0.55 )acetone/
hexane, 1:2);[ a]21.5 ˆ216.3 )c 1.26, CHCl3);IR 3460,
D
1
1720, 1650 cm21; H NMR )300 MHz) d 0.99 )s, 6H),
1.31±1.40 )m, 2H), 1.59±1.67 )m, 2H), 3.00 )br, 1H),
3.19±3.42 )m, 4H), 3.37 )s, 3H), 4.09 )t, Jˆ5.9 Hz, 1H),
4.44 )s, 2H), 4.64 )s, 2H), 5.08 )d, Jˆ9.1 Hz, 1H), 5.57 )d,
Jˆ15.5 Hz, 1H), 5.64 )dd, Jˆ9.1, 14.8 Hz, 1H), 5.91 )dd,
Jˆ10.3, 15.5 Hz, 1H), 6.13 )dd, Jˆ10.3, 14.8 Hz, 1H); 13C
NMR )75 MHz) d 26.8, 26.9, 27.6, 35.8, 37.3, 39.5£2, 54.1,
56.1, 66.3, 81.1, 96.5, 125.5, 130.5, 130.8, 144.3, 211.2;
HRMS calcd for C17H28O4S2 )M1) 360.1429, found
360.1427.
1
other isomers)20:1, determined by H NMR analysis);
TLC, Rf 0.42 )EtOAc/hexane, 1:4);[ a]26 ˆ16.4 )c 2.24,
D
1
CHCl3);IR 3470, 1650 cm 21; H NMR )300 MHz) d 0.08
)s, 6H), 0.90 )s, 9H), 1.00 )s, 6H), 1.24±1.58 )m, 4H), 2.68
)br, 1H), 3.19±3.39 )m, 4H), 3.39 )s, 3H), 3.48±3.56 )m,
1H), 3.58±3.77 )m, 3H), 4.62, 4.69 )ABq, Jˆ6.6 Hz,
3.1.9. 3-[ꢀ1S,5E,7E)-8-ꢀ1,3-Dithiolan-2-yl)-1-ꢀmethoxy-
methoxy)-4,4-dimethyl-5,7-octadienyl]-2-buten-4-olide
ꢀ25). To a cooled )08C) solution of 23 )2.65 g, 7.35 mmol) in

7298
Y. Suzuki et al. / Tetrahedron 57 ,2001) 7291±7301
CH2Cl2 )50 mL) were added )EtO)2P)O)CH2CO2H
)2.36 mL, 14.7 mmol), Et3N )2.00 mL, 14.3 mmol),
DMAP )270 mg, 2.21 mmol), and 1-ethyl-3-)3-dimethyl-
aminopropyl)carbodiimide hydrochloride )2.82 g, 14.7
mmol). The mixture was stirred for 2.5 h and diluted with
CH2Cl2. This was washed with 0.1 M aqueous HCl, 0.1 M
aqueous NaOH, and H2O, successively. The organic layer
was dried and concentrated in vacuo to provide crude 24,
which was used in the next step without puri®cation. In a
small-scale experiment, pure 24 was obtained by column
chromatography on silica gel )EtOAc/hexane, 1:1) as a
colorless oil )E,E-isomer/other isomers)20:1, determined
was obtained as a colorless oil )E,E-isomer/other
1
isomers)20:1, determined by H NMR analysis);TLC, Rf
0.38 )EtOAc/hexane, 1:1);[ a]26 ˆ26.4 )c 1.71, CHCl3);
D
1
IR 3440, 1780, 1730, 1640 cm21; H NMR )300 MHz) d
1.02 )s, 6H), 1.30±1.66 )m, 4H), 2.30 )br, 1H), 3.21±3.37
)m, 4H), 4.59 )br t, Jˆ5.7 Hz, 1H), 4.85 )d, Jˆ2.0 Hz, 2H),
5.09 )d, Jˆ9.3 Hz, 1H), 5.58 )d, Jˆ15.6 Hz, 1H), 5.65 )dd,
Jˆ9.3, 14.6 Hz, 1H), 5.93 )dd, Jˆ10.3, 15.6 Hz, 1H), 5.95±
5.97 )m, 1H), 6.13 )dd, Jˆ10.3, 14.6 Hz, 1H); 13C NMR
)75 MHz) d 26.9£2, 31.5, 35.8, 37.7, 39.5£2, 54.1, 68.8,
71.2, 114.7, 125.6, 130.6, 130.7, 144.4, 172.9, 174.0;HRMS
calcd for C17H24O3S2 )M1) 340.1167, found 340.1168.
1
by H NMR analysis);TLC, Rf 0.31 )acetone/hexane, 1:2);
[a]23 ˆ222.1 )c 0.96, CHCl3);IR 1730, 1650 cm 21; H
3.1.11. 3-[ꢀ1S,5E,7E)-1-ꢀDimethylisopropyl)silyloxy-8-
ꢀ1,3-dithiolan-2-yl)-4,4-dimethyl-5,7-octadienyl]-2-buten-
4-olide ꢀ28). To a cooled )08C) solution of 26 )521 mg,
1.53 mmol) in DMF )10 mL) were added imidazole
)564 mg, 8.28 mmol) and dimethylisopropylchlorosilane
)0.680 mL, 4.12 mmol). The mixture was stirred at 08C
for 50 min, diluted with EtOAc, and the whole was washed
with H2O. The organic layer was dried and concentrated in
vacuo. The residue was puri®ed by column chromatography
on silica gel )EtOAc/hexane, 1:12) to provide 588 mg )87%)
of 28 as a colorless oil )E,E-isomer/other isomers)20:1,
1
D
NMR )300 MHz) d 0.99 )s, 6H), 1.36 )t, Jˆ7.1 Hz, 6H),
1.25±1.45 )m, 2H), 1.60±1.68 )m, 2H), 3.10 )d, Jˆ21.7 Hz,
2H), 3.20±3.37 )m, 4H), 3.38 )s, 3H), 4.04 )br-t, Jˆ6.0 Hz,
1H), 4.20 )dq, Jˆ7.1, 7.8 Hz, 4H), 4.64, 4.67 )ABq,
Jˆ6.6 Hz, 1H£2), 4.93, 5.01 )ABq, Jˆ17.6 Hz, 1H£2),
5.08 )d, Jˆ9.3 Hz, 1H), 5.59 )d, Jˆ15.5 Hz, 1H), 5.63
)dd, Jˆ9.3, 14.9 Hz, 1H), 5.91 )dd, Jˆ10.3, 15.5 Hz, 1H),
6.13 )dd, Jˆ10.3, 14.9 Hz, 1H); 13C NMR )75 MHz) d
3
16.3£2 )d, JP,Cˆ6.2 Hz), 26.8, 26.9, 27.4, 33.8 )d,
1JP,Cˆ134.3 Hz), 35.8, 37.3, 39.5£2, 54.2, 56.2, 62.8£2
2
1
)d, JP,Cˆ6.2 Hz), 67.3, 81.7, 96.6, 125.5, 130.5, 131.0,
determined by H NMR analysis);TLC, Rf 0.50 )EtOAc/
2
144.6, 165.1 )d, JP,Cˆ5.0 Hz), 203.6;HRMS calcd for
hexane, 1:3);[ a]22 ˆ21.8 )c 2.53, CHCl3);IR 1780, 1750,
D
C23H39O8PS2 )M1) 538.1824, found 538.1832.
1645 cm21; H NMR )300 MHz) d 0.05, 0.08 )2s, 3H£2),
1
0.73±0.89 )m, 1H), 0.96 )d, Jˆ7.1 Hz, 3H), 0.97 )d,
Jˆ7.3 Hz, 3H), 0.99 )s, 6H), 1.25±1.35 )m, 2H), 1.48±
1.56 )m, 2H), 3.20±3.38 )m, 4H), 4.58 )br t, 5.3 Hz, 1H),
4.79 )d, Jˆ1.5 Hz, 2H), 5.09 )d, Jˆ9.3 Hz, 1H), 5.55 )d,
Jˆ15.5 Hz, 1H), 5.64 )dd, Jˆ9.3, 14.9 Hz, 1H), 5.88±5.90
)m, 1H), 5.90 )dd, Jˆ10.4, 15.5 Hz, 1H), 6.13 )dd, Jˆ10.4,
14.9 Hz, 1H); 13C NMR )75 MHz) d 24.0, 23.9, 14.6,
16.8£2, 26.9, 27.0, 32.4, 35.7, 37.2, 39.5£2, 54.2, 69.5,
70.9, 114.9, 125.6, 130.68, 130.74, 144.4, 172.8, 173.5;
HRMS calcd for C22H36O3SiS2 )M1) 440.1875, found
440.1869.
To a cooled )08C) solution of the crude 24 obtained above in
toluene )80 mL) were added 18-crown-6 )3.50 g,
9.45 mmol) and K2CO3 )653 mg, 4.72 mmol). The mixture
was stirred for 12 h, then 18-crown-6 )870 mg, 2.36 mmol)
was added. The mixture was stirred for 1.5 h, then K2CO3
)162 mg, 1.17 mmol) was added. The mixture was stirred
for an additional 5.5 h, diluted with saturated brine, and
extracted with EtOAc. The combined organic layers were
dried and concentrated in vacuo. The residue was puri®ed
by column chromatography on silica gel )EtOAc/hexane,
1:4) to provide 2.27 g )80% from 23) of 25 as a colorless
oil )E,E-isomer/other isomers)20:1, determined by 1H
NMR analysis);TLC, Rf 0.56 )acetone/hexane, 1:2);
3.1.12. Diastereomeric mixture ꢀ13:7) of ꢀ1S,2S,6S,
9S,10S)-ꢀ37A),ꢀ1R,2S,6R,9R,10R)-2-ꢀdimethylisopropyl)-
silyloxy-5,5-dimethyl-9-ꢀ1,3-dithiolan-2-yl)-12-oxatricy-
clo[8.3.0.01,6]tridec-7-en-11-one ꢀ37B). Compound 28
)577 mg, 1.31 mmol) was dissolved in degassed toluene
)131 mL) and a crystal of 2,6-di-tert-butyl-4-methylphenol
)BHT) was added. The solution was transferred into 14
tubes of 20 mL sealed tube equipped with a screwed stop-
per. All the tubes were ®lled with argon. The tubes were
heated to 2108C for 70 h. After being cooled to ambient
temperature, the combined solutions were concentrated in
vacuo. The residue was puri®ed by column chromatography
on silica gel )EtOAc/hexane, 1:15) to provide 466 mg )81%)
of 37 as an inseparable diastereomeric mixture )the ratio of
diastereomers, 37A/37B/exo-isomersˆca. 13:7:1 was deter-
mined by 1H NMR analysis). The mixture 37 as a colorless
[a]19.5 ˆ232.8 )c 1.85, CHCl3);IR 1780, 1750,
D
1
1640 cm21; H NMR )300 MHz) d 1.00 )s, 6H), 1.24±
1.46 )m, 2H), 1.55±1.63 )m, 2H), 3.20±3.37 )m, 4H), 3.37
)s, 3H), 4.47 )br t, Jˆ5.9 Hz, 1H), 4.62 )s, 2H), 4.80 )br d,
Jˆ1.8 Hz, 2H), 5.09 )d, Jˆ9.1 Hz, 1H), 5.56 )d, Jˆ15.4 Hz,
1H), 5.65 )dd, Jˆ9.1, 14.8 Hz, 1H), 5.92 )dd, Jˆ10.3,
15.4 Hz, 1H), 5.96±5.98 )m, 1H), 6.13 )dd, Jˆ10.3,
14.8 Hz, 1H); 13C NMR )75 MHz) d 26.88, 26.93, 29.7,
35.8, 37.6, 39.5£2, 54.1, 55.9, 70.9, 73.1, 95.2, 116.4,
125.7, 130.7, 130.8, 144.2, 169.8, 173.2;HRMS calcd for
C19H28O4S2 )M1) 384.1429, found 384.1429.
3.1.10. 3-[ꢀ1S,5E,7E)-8-ꢀ1,3-Dithiolan-2-yl)-1-hydroxy-
4,4-dimethyl-5,7-octadienyl]-2-buten-4-olide ꢀ26). To a
cooled )08C) solution of 25 )1.46 g, 3.80 mmol) in THF
)35 mL) was added 4.0 M aqueous HCl )15 mL). The
mixture was stirred for 97 h, diluted with saturated aqueous
NaHCO3, and extracted with CH2Cl2. The combined
organic layers were dried and concentrated in vacuo. The
residue was puri®ed by column chromatography on silica
gel )EtOAc/hexane, 1:4 to 1:2) to provide 1.19 g )92%) of
26 and 93.9 mg )6%) of 25 was recovered. Compound 26
1
oil: TLC, Rf 0.47 )EtOAc/hexane, 1:4);IR 1765 cm 21; H
NMR for the mixture of endo isomers 37A and 37B
)300 MHz) d 0.10 )s, 3H£7/20), 0.11 )s, 3H), 0.15 )s,
3H£13/20), 0.71±0.88 )m, 1H), 0.82 )s, 3H), 0.93 )s,
3H£7/13), 0.94 )s, 3H£7/20), 0.95 )s, 3H£7/20), 0.96 )s,
3H£13/20), 0.99 )s, 3H£13/20), 1.01 )s, 3H£13/20), 1.14±
1.85 )m, 4H), 1.75 )br-s, 1H£7/20), 2.32 )br-s, 1H£13/20),
2.40±2.53 )m, 1H), 2.98 )d, Jˆ7.6 Hz, 1H£7/20),

Y. Suzuki et al. / Tetrahedron 57 ,2001) 7291±7301
7299
1
3.11±3.30 )m, 4H), 3.35 )d, Jˆ7.3 Hz, 1H£13/20), 3.64 )dd,
Jˆ5.3, 10.6 Hz, 1H£7/20), 3.79 )d, Jˆ8.8 Hz, 1H£7/20),
3.81 )br s, 1H£13/20), 3.88, 3.92 )ABq, Jˆ9.5 Hz,
1H£2£13/20), 4.31 )d, Jˆ8.8 Hz, 1H£7/20), 4.99 )d,
Jˆ11.7 Hz, 1H£13/20), 5.00 )d, Jˆ11.2 Hz, 1H£7/20),
5.90±6.04 )m, 2H); 13C NMR for the major endo-isomer
37A )75 MHz) d 24.0, 23.2, 15.0, 16.96, 17.02, 21.3,
25.8, 31.88, 31.94, 33.3, 38.0, 38.3, 43.0, 46.3, 48.7, 53.1,
53.7, 70.8, 72.7, 131.5, 132.1, 177.5;for the minor endo-
isomer 37B d 23.8, 23.1, 14.8, 16.66, 16.71, 21.3, 28.2,
31.3, 31.94, 38.3, 38.4£2, 45.8, 48.2, 50.2, 53.5, 53.7, 70.2,
76.6, 131.7, 131.8, 177.1;HRMS calcd for C 22H36O3SiS2
)M1) 440.1875, found 444.1876.
)KBr disk) 3460, 1740 cm21; H NMR )300 MHz) d 0.83,
0.99 )2s, 3H£2), 1.18±1.30 )m, 1H), 1.65±2.13 )m, 4H),
2.26±2.32 )m, 1H), 2.57±2.67 )m, 1H), 3.32 )d,
Jˆ8.5 Hz, 1H), 3.36, 3.50 )2s, 3H£2), 3.86 )br s, 1H),
3.90, 3.97 )ABq, Jˆ9.4 Hz, 1H£2), 4.88 )d, Jˆ7.8 Hz,
1H), 5.98 )dt, Jˆ3.1, 9.4 Hz, 1H), 6.06 )dt, Jˆ2.8, 9.4 Hz,
1H); 13C NMR )75 MHz) d 21.2, 26.1, 31.7, 32.2, 33.3,
39.2, 42.7, 45.3, 51.4, 53.1, 54.9, 69.3, 72.9, 103.1, 128.5,
131.2, 178.0;HRMS calcd for C 17H26O5 )M1) 310.1780,
found 310.1782. Compound 43B as a colorless oil;TLC,
Rf 0.39 )EtOAc/toluene, 1:1);[ a]26 ˆ128.7 )c 2.38,
D
21
CHCl3);IR 3450, 1760 cm
;
1H NMR )300 MHz) d
0.83, 0.95 )2s, 3H£2), 1.35 )br dt, Jˆ4.2, 13.5 Hz, 1H),
1.52 )br dt, Jˆ3.4, 13.5 Hz, 1H), 1.61±1.83 )m, 3H), 1.87
)br, 1H), 2.53±2.61 )m, 1H), 2.99 )d, Jˆ8.3 Hz, 1H), 3.39,
3.55 )2s, 3H£2), 3.66 )dd, Jˆ5.0, 11.1 Hz 1H), 3.84 )d,
Jˆ9.2 Hz, 1H), 4.29 )d, Jˆ9.2 Hz, 1H), 4.88 )d,
Jˆ8.3 Hz, 1H), 5.99 )dt, Jˆ3.3, 9.3 Hz, 1H), 6.07 )dt,
Jˆ2.9, 9.3 Hz, 1H); 13C NMR )75 MHz) d 21.4, 28.1,
31.2, 32.1, 38.5, 39.2, 47.1, 48.2, 52.2, 53.2, 55.7, 70.0,
75.9, 103.3, 128.8, 131.4, 177.9;HRMS calcd for
C17H26O5 )M1) 310.1780, found 310.1781.
3.1.13. Diastereomeric mixture ꢀ13:7) of ꢀ1S,2S,6S,
9S,10S)-ꢀ35A), ꢀ1R,2S,6R,9R,10R)-2-hydroxy-5,5-dimethyl-
9-ꢀ1,3-dithiolan-2-yl)-12-oxatricyclo[8.3.0.01,6]tridec-7-en-
11-one ꢀ35B). To a cooled )08C) solution of the 13:7 dia-
stereomeric mixture 37 )104 mg, 0.235 mmol) in THF
)2 mL) was added TBAF )0.35 mL of 1.0 M solution in
THF, 0.35 mmol). The mixture was stirred at 08C for
15 min and concentrated in vacuo. The residue was puri®ed
by column chromatography on silica gel )EtOAc/toluene,
1:5) to provide 73.6 mg )92%) of 35 as a diastereomeric
mixture )the ratio of diastereomers, 35A/35B/exo
isomersˆca. 13:7:1, was determined by 1H NMR analysis).
The mixture 35 as amorphous solids;TLC, Rf 0.68 for
isomer 35A, Rf0.62 for isomer 35B )EtOAc/hexane, 1:1);
IR 3450, 1760, 1750 cm21; 1H NMR for the mixture of end
isomers 35A and 35B )300 MHz) d 0.83 )s, 3H), 0.95 )s,
3H£7/20), 0.98 )s, 3H£13/20), 1.23±1.90 )m, 4H), 1.82
)br-s, 1H£7/20), 2.31 )br-s, 1H£13/20), 2.49±2.56 )m,
1H), 3.17 )d, Jˆ7.8 Hz, 1H£7/20), 3.25 )br-s, 4H), 3.51
)d, Jˆ7.6 Hz, 1H£13/20), 3.71 )dd, Jˆ4.8, 11.1 Hz,
1H£7/20), 3.83 )d, Jˆ9.0 Hz, 1H£7/20), 3.89, 3.94 )ABq,
Jˆ9.5 Hz, 1H£2£13/20), 3.90 )br s, 1H£13/20), 4.32 )d,
Jˆ9.0 Hz, 1H£7/20), 4.98 )d, Jˆ11.2 Hz, 1H£7/20), 4.99
)d, Jˆ11.2 Hz, 1H£13/20), 5.96±6.05 )m, 2H); 13C NMR
for the major endo-isomer 35A )75 MHz) d 21.2, 26.2,
31.8, 32.13, 33.2, 38.3, 38.5, 42.8, 46.1, 48.3, 52.4,
53.7, 69.5, 73.1, 131.6, 131.9, 177.8;for the minor endo-
isomer 35B d 21.4, 28.1, 31.3, 32.08, 38.4, 38.5£2, 45.7,
48.1, 49.8, 53.3, 53.6, 70.0, 75.7, 131.7, 131.8, 177.5;
HRMS calcd for C17H24O3S2 )M1) 340.1167, found
340.1160.
3.1.15. ꢀ1S,2S,6S,9S,10S)-9-ꢀDimethoxy)methyl-2-ꢀmeth-
oxymethoxy)-5,5-dimethyl-12-oxatricyclo[8.3.0.01,6]tri-
dec-7-en-11-one ꢀ44). To a cooled )08C) solution of 43A
)96.2 mg, 0.310 mmol) in CH2Cl2 )2 mL) were added
DIPEA )0.870 mL, 4.99 mmol) and MOMCl )0.190 mL,
2.50 mmol). The mixture was stirred at 408C for 19 h and
diluted with saturated aqueous NH4Cl. This was extracted
with CH2Cl2. The combined extracts were dried and concen-
trated in vacuo. The residue was puri®ed by column
chromatography on silica gel )EtOAc/hexane, 1:5) to
provide 93.5 mg )85%) of 44 as a colorless oil;TLC, Rf
0.52 )EtOAc/hexane, 2:3);[ a]23.5 ˆ155.1 )c 1.27,
D
21
CHCl3);IR 1770 cm
;
1H NMR )300 MHz) d 0.84,
0.98 )2s, 3H£2), 1.20±1.31 )m, 1H), 1.60±1.94 )m, 3H),
2.25 )br s, 1H), 2.56±2.64 )m, 1H), 3.22 )d, Jˆ8.1 Hz,
1H), 3.38, 3.44, 3.52 )3s, 3H£3), 3.68 )br s, 1H), 3.91,
3.97 )ABq, Jˆ9.5 Hz, 1H£2), 4.64, 4.77 )ABq, Jˆ7.0 Hz,
1H£2), 4.90 )d, Jˆ7.8 Hz, 1H), 5.97 )dt, Jˆ3.3, 9.4 Hz,
1H), 6.06 )dt, Jˆ2.9, 9.4 Hz, 1H); 13C NMR )75 MHz)
d 21.4, 22.2, 31.7, 32.0, 33.7, 39.5, 43.5, 45.5, 51.0,
53.4, 55.3, 56.2, 72.7, 75.8, 95.6, 103.3, 128.8, 131.0,
177.7;HRMS calcd for C 19H30O6 )M1) 354.2042, found
354.2042.
3.1.14. ꢀ1S,2S,6S,9S,10S)-ꢀ43A) and ꢀ1R,2S,6R,9R,10R)-
2-hydroxy-9-ꢀdimethoxy)methyl-5,5-dimethyl-12-oxatri-
cyclo[8.3.0.01,6]tridec-7-en-11-one ꢀ43B). To a cooled
)08C) solution of the diastereomeric mixture 35 )73.6 mg,
0.216 mmol) in a mixture of MeOH and CHCl3 )3:1 v/v,
6.5 mL) were added CaCO3 )324 mg, 3.24 mmol) and
Hg)ClO4)2´3H2O )267 mg, 0.589 mmol). The mixture was
stirred at 08C for 20 h and diluted with 10 wt% aqueous KI.
This was extracted with CHCl3, and the organic layers were
combined. The resulting inorganic precipitates were ®ltered
off and washed well with CHCl3. The combined ®ltrate and
washings were dried and concentrated in vacuo. The residue
was puri®ed by column chromatography on silica gel
)EtOAc/toluene, 1:6 to 1:4) to provide 29.6 mg )44%) of
43A and 16.8 mg )25%) of 43B. Compound 43A as amor-
phous solids;mp 170±171 8C )decomp.);TLC, Rf 0.35
3.1.16. Diastereomeric mixture of ꢀ1R,2S,6S,9S,10S,13R
and 13S)-9-ꢀdimethoxy)methyl-13-hydroxy-2-ꢀmethoxy-
methoxy)-5,5-dimethyl-12-oxatricyclo[8.3.0.01,6]tridec-
7-en-11-one ꢀ45). To a stirred solution of 44 )107 mg,
0.302 mmol) in t-BuOH )0.5 mL) were added 1.0 M
aqueous KOH )1.5 mL) and a 0.015 M solution of
Na2RuO4 in 1 M aqueous NaOH )38.8 mL, 0.582 mmol).
The mixture was stirred at 808C for 14 h, cooled to 08C,
and quenched with 2-propanol. The resulting insoluble
materials were ®ltered off and washed well with EtOH.
The combined ®ltrate and washings were concentrated in
vacuo to 5 mL and neutralized with 1.0 M aqueous HCl.
This was extracted with CH2Cl2. The combined extracts
were dried and concentrated in vacuo. The residue was
puri®ed by column chromatography on silica gel )EtOAc/
hexane, 1:2) to provide 113 mg )100%) of 45 as a colorless
)EtOAc/hexane, 1:1);[ a]24 ˆ150.0 )c 1.37, CHCl3);IR
D

7300
Y. Suzuki et al. / Tetrahedron 57 ,2001) 7291±7301
oil )the ratio of diastereomers, ca. 5:3, was determined by 1H
NMR analysis);TLC, Rf 0.56 )EtOAc/hexane, 1:1);IR
)d, Jˆ2.4 Hz, 1H), 5.19 )br d, Jˆ9.8 Hz, 1H), 5.85 )d,
Jˆ6.0 Hz, 1H), 5.96 )dt, Jˆ2.9, 9.9 Hz, 1H), 6.20 )dt,
Jˆ2.7, 9.9 Hz, 1H); 13C NMR for the major isomer
)67.5 MHz) d 22.4, 23.3, 31.2, 32.2, 34.4, 41.4, 43.8,
45.8, 53.3, 55.5, 56.1, 75.4, 96.0, 103.9, 108.0, 109.6,
128.2, 132.6;HRMS calcd for C 18H28O6 )M1) 340.1886,
found 340.1882.
1
3350, 1770 cm21; H NMR )300 MHz) d 0.97 )s, 3H),
1.01 )s, 3H£3/8), 1.07 )s, 3H£5/8), 1.22±1.34 )m, 1H),
1.54±1.96 )m, 1H), 2.12±2.27 )m, 1H), 2.24 )br s, 1H£5/
8), 2.33 )br q, Jˆ3.1 Hz, 1H£5/8), 2.55±2.64 )m, 1H£5/8),
2.81±2.90 )m, 1H£3/8), 3.37, 3.40, 3.50 )3s, 3H£3£3/8),
3.40, 3.45, 3.51 )3s, 3H£3£5/8), 3.36±3.49 )m, 1H11H£3/
8), 4.06 )br s, 1H£5/8), 4.22 )br d, Jˆ12.9 Hz, 1H£3/8),
4.61, 4.74 )ABq, Jˆ6.6 Hz, 1H£2£3/8), 4.63, 4.76 )ABq,
Jˆ6.8 Hz, 1H£2£5/8), 4.66 )d, Jˆ3.1 Hz, 1H£3/8), 4.98 )d,
Jˆ9.0 Hz, 1H£5/8), 5.41 )br d, Jˆ12.9 Hz, 1H£3/8), 5.49
)s, 1H£5/8), 5.95 )dt, Jˆ3.1, 9.0 Hz, 1H£5/8), 5.99±6.06
)m, 1H), 6.19 )dt, Jˆ2.9, 10.3 Hz, 1H£3/8); 13C NMR
)75 MHz) for the major isomer; d 20.7, 23.8, 32.4, 34.1,
34.5, 40.9, 44.6, 49.6, 52.0, 53.6, 54.8, 56.1, 73.9, 95.4,
100.2, 103.2, 129.6, 130.8, 176.5;HRMS calcd for
C19H30O7 )M1) 370.1992, found 370.1992.
3.1.19. ꢀ1R,2S,6S,9S,10S,12R,15S)-10-Methoxy-2-ꢀmeth-
oxymethoxy)-5,5-dimethyl-11,13-dioxatetracyclo[10.2.1.01,6.
0
9,15]pentadec-7-en-14-one ꢀ48). To a stirred solution of 47
)10.9 mg, 32.0 mmol) in DMSO )1 mL) was added Ac2O
)1 mL). The mixture was stirred for 6 h and concentrated
in vacuo with the aid of toluene. The residue was diluted
with EtOAc and washed with brine. The organic layer was
dried and concentrated in vacuo. The residue was puri®ed
by column chromatography on silica gel )EtOAc/hexane,
1:7) to provide 8.6 mg )80%) of 48 as a colorless oil;
TLC, Rf 0.47 )EtOAc/hexane, 1:2);[ a]22 ˆ1129 )c0.39,
D
1
3.1.17. Diastereomeric mixture of ꢀ1R,2S,6S,9S,10S, 11R
and 11S,13R and 13S)-9-ꢀdimethoxy)methyl-2-ꢀmeth-
oxymethoxy)-5,5-dimethyl-12-oxatricyclo[8.3.0.01,6]tri-
dec-7-en-11,13-diol ꢀ46). The following reaction was
carried out under argon. To a cooled )2788C) solution of
the mixture 45 )76.4 mg, 0.206 mmol) in toluene )1 mL)
was added DIBALH )0.62 mL, 1.0 M in toluene,
0.62 mmol). The mixture was stirred at 2788C for 25 min
and quenched with H2O. The resulting gels were ®ltered off
and washed well with CH2Cl2. The ®ltrate and washings
were combined and concentrated in vacuo. The residue
was puri®ed by column chromatography on silica gel
)EtOAc/hexane, 1:4 to acetone/hexane, 2:1) to provide
33.9 mg )44%) of 46 as an inseparable diastereomeric
mixture, 18.4 mg )21%) of 44 and 16.4 mg )21%) of 45
was recovered. The diastereomeric mixture 46 as a colorless
oil;TLC, Rf 0.48 )acetone/toluene, 1:1);IR 3420 cm 21; 1H
NMR )300 MHz, CD3OD, d 3.30) d 0.92±1.07 )m, 6H),
1.17±1.88 )m, 4H), 2.12±2.52 )m, 2H), 2.88±4.24 )m,
11H), 4.55±5.37 )m, 5H), 5.67±6.14 )m, 2H);HRMS
)FAB) calcd for C19H31O7 )M12H) 371.2070, found
371.2069.
CHCl3);IR 1780 cm 21; H NMR )300 MHz) d 0.98, 1.28
)2s, 3H£2), 1.32 )dt, Jˆ3.4, 13.4 Hz, 1H), 1.56±1.71 )m,
1H), 1.79 )dq, Jˆ3.4, 14.8 Hz, 1H), 1.98±2.12 )m, 1H),
2.15±2.18 )m, 1H), 2.68±2.76 )m, 1H), 3.44 )s, 6H), 3.72
)br s, 1H), 3.80 )dd, Jˆ5.4, 10.6 Hz, 1H), 4.67, 4.79 )ABq,
Jˆ6.8 Hz, 1H£2), 5.10 )d, Jˆ2.0 Hz, 1H), 5.80 )dt, Jˆ2.5,
9.6 Hz, 1H), 5.94 )d, Jˆ5.4 Hz, 1H), 6.05 )dt, Jˆ3.5,
9.6 Hz, 1H); 13C NMR )67.5 MHz) d 22.0, 22.3, 31.8,
33.1, 33.5, 42.4, 42.6, 47.0, 55.9, 56.0, 56.2, 72.6, 95.5,
104.0, 111.6, 126.7, 132.3, 174.1;HRMS calcd for
C18H26O6 )M1) 338.1729, found 338.1732.
3.1.20. Mniopetal F ꢀ6). To a solution of 48 )8.6 mg,
25 mmol) in THF )1 mL) was added 6.0 M aqueous HCl
)1 mL). The mixture was stirred for 44 h, diluted with
H2O, and extracted with CHCl3. The combined extracts
were dried and concentrated in vacuo. The residue was
dissolved in toluene )1.5 mL) and Et3N )25 mL,
0.18 mmol) was added. The solution was stirred for 20 h
and concentrated in vacuo. The residue was puri®ed by
column chromatography on silica gel )acetone/toluene/
AcOH, 10:100:1) to provide 5.9 mg )83%) of 6 as a color-
less oil;TLC, Rf 0.38 )acetone/toluene/AcOH, 30:70:1),
3.1.18. Diastereomeric mixture ꢀ9:1) of ꢀ1R,2S,6S,9S,
10S,12S,14R and 14S,15S)-10-methoxy-2-ꢀmethoxy-
methoxy)-5,5-dimethyl-11,13-dioxatetracyclo[10.2.1.01,6.
[a]23 ˆ255.6 )c 0.24, MeOH);IR 3430, 1750, 1680,
D
1
1650 cm21; H NMR )300 MHz, CD3OD, d 3.30) d 0.99,
1.23 )2s, 3H£2), 1.18±1.27 )m, 1H), 1.61 )dq, Jˆ3.4,
13.9 Hz, 1H), 1.69 )dd, Jˆ3.4, 12.7 Hz, 1H), 1.85 )dt,
Jˆ2.7, 13.7 Hz, 1H), 2.03±2.20 )m, 2H), 2.50 )ddd,
Jˆ3.4, 6.6, 19.0 Hz, 1H), 3.67 )br s, 1H), 4.36 )br s, 1H),
5.36 )s, 1H), 7.21 )d, Jˆ6.6 Hz, 1H), 9.42 )s, 1H); 13C NMR
)75 MHz, CD3OD, d 49.0) d 23.1, 26.1, 26.4, 33.1, 33.8,
34.1, 41.6, 47.8, 54.1, 68.6, 101.5, 140.4, 156.5, 179.2,
195.3;HRMS calcd for C 15H20O5 )M1) 280.1311, found
280.1310.
0
9,15]pentadec-7-en-14-ol ꢀ47). To a cooled )08C) solution
of the diastereomeric mixture 46 )23.3 mg, 62.6 mmol) in a
mixture of THF and H2O )4:1, 0.5 mL) was added
p-toluenesulfonic acid monohydrate )TsOH) )10.4 mg,
54.7 mmol). The mixture was stirred for 2 h then TsOH
)7.2 mg, 38 mmol) was added. The mixture was stirred for
an additional 30 min and diluted with saturated aqueous
NaHCO3. This was extracted with CH2Cl2. The combined
extracts were dried and concentrated in vacuo. The residue
was puri®ed by column chromatography on silica gel
)acetone/hexane, 1:14) to provide 9.2 mg )43%) of 47 as a
colorless oil )the ratio of diastereomers, ca. 9:1, was deter-
Acknowledgements
mined by 1H NMR analysis);TLC, Rf 0.53 )EtOAc/toluene,
21
1:1);IR 3420 cm
;
1H NMR for the major isomer
We thank Professor W. Steglich )University of MuÈnchen)
for sending us copies of the spectra for natural mniopetal F
)1H and 13C NMR and MS). We are grateful to the Japan
Interaction in Science and Technology Forum )JIST) for
®nancial support.
)300 MHz) d 0.95, 1.01 )2s, 3H£2), 1.20±1.29 )m, 1H),
1.57±1.84 )m, 3H), 2.46±2.50 )m, 1H), 2.70±2.78 )m,
1H), 3.41, 3.42 )2s, 3H£2), 3.62 )dd, Jˆ6.0, 11.0 Hz, 1H),
3.62±3.68 )m, 1H), 4.63, 4.75 )ABq, Jˆ6.8 Hz, 1H£2), 4.94

Y. Suzuki et al. / Tetrahedron 57 ,2001) 7291±7301
7301
11. Garegg, P. J.;Samuelsson, B. J. Chem. Soc., Perkin Trans. 1
1980, 2866±2869.
References
12. Semmelhack, M. F.;Harrison, J. J.;Thebtaranonth, Y. J. Org.
Chem. 1979, 44, 3275±3277.
1. Kuschel, A.;Anke, T.;Velten, R.;Klostermeyer, D.;Steglich,
È
W.;Ko nig, B. J. Antibiot. 1994, 47, 733±739.
13. Takacs, J. M.;Jaber, M. R.;Clement, F.;Walters, C. J. Org.
Chem. 1998, 63, 6757±6760.
2. Velten, R.;Klostermeyer, D.;Steffan, B.;Steglich, W.;
Kuschel, A.;Anke, T. J. Antibiot. 1994, 47, 1017±1024.
3. Velten, R.;Steglich, W.;Anke, T. Tetrahedron: Asymmetry
1994, 5, 1229±1232.
14. Chaudhary, S. K.;Hernandez, O. Tetrahedron Lett. 1979, 99±
102.
15. Aristoff, P. A. J. Org. Chem. 1981, 46, 1954±1957.
16. )a) Funk, R. L.;Zeller, W. E. J. Org. Chem. 1982, 47, 180±
182. )b) MuÈller, G.;Jas, G. Tetrahedron Lett. 1992, 33, 4417±
4420.
4. Ayer, W. A.;Craw, P. A. Can. J. Chem. 1989, 67, 1371±1380.
5. )a) Suzuki, Y.;Nishimaki, R.;Ishikawa, M.;Murata, T.;
Takao, K.;Tadano, K. Tetrahedron Lett. 1999, 40, 7835±
7838. )b) Suzuki, Y.;Nishimaki, R.;Ishikawa, M.;Murata,
T.;Takao, K.;Tadano, K. J. Org. Chem. 2000, 65, 8595±
8607. )c) Jauch, J. Synlett 2001, 87±89.
17. For the IMDA approaches for azadirachtin synthesis adopting
a similar trialkylsilyloxy substituent effect, see: )a) Kanoh, N.;
Ishihara, J.;Murai, A. Synlett 1995, 895±897. )b) Kanoh, N.;
Ishihara, J.;Murai, A. Synlett 1997, 737±739. )c) Ishihara, J.;
Yamamoto, Y.;Kanoh, N.;Murai, A. Tetrahedron Lett. 1999,
40, 4387±-4390. )d) Kanoh, N.;Ishihara, J.;Yamamoto, Y.;
Murai, A. Synthesis 2000, 1878±1893. )e) Yamamoto, Y.;
Ishihara, J.;Kanoh, N.;Murai, A. Synthesis 2000, 1894±1906.
18. For the discussion on the geminal dialkyl effect and the origi-
nal Thorpe-Ingold effect observed in the IMDA reactions, see:
)a) Boeckman, Jr., R. K.;Ko, S. S. J. Am. Chem. Soc. 1982,
104, 1033±1041. )b) Sternbach, D. D.;Rossana, D. M.;Onan,
K. D. Tetrahedron Lett. 1985, 26, 591±594. )c) Jung, M. E.;
Gervay, J. Tetrahedron Lett. 1988, 29, 2429±2432. )d) Jung,
M. E.;Gervay, J. J. Am. Chem. Soc. 1991, 113, 224±232.
19. The preparation of alternative substrate 29 from 26 by
silylation with TBSOTf in pyridine accompanied by the trans-
formation of the butenolide moiety into 2-tert-butyldimethyl-
siloxyfuran. To obtain the substrate 29, it was required an acid
treatment of this intermediate. In the case of the silylation of
26 with DMIPSCl in the presence of imidazole, substrate 28
was obtained ef®ciently without formation of such a furan
intermediate.
6. Jauch, J. Eur. J. Org. Chem., 2001, 473±476.
7. )a) Jauch, J. Synlett 1999, 1325±1327. )b) Allen, Jr., A.;
Gordon, D. M. Indian J. Chem. 1999, 269±273. )c) Reiser,
U.;Jauch, J.;Herdtweck, E. Tetrahedron: Asymmetry 2000,
11, 3345±3349. )d) Jauch, J. Angew. Chem., Int. Ed. Engl.
2000, 39, 2764±2765. )e) Reiser, U.;Jauch, J. Synlett 2001,
90±92.
8. Murata, T.;Ishikawa, M.;Nishimaki, R.;Tadano, K. Synlett
1997, 1291±1293.
9. For representative reviews on IMDA reactions, see: )a) Roush,
W. R. Advances in Cycloaddition;Curran, D. P., Ed.;JAI
Press: Greenwich, 1990;Vol. 2, pp. 91±146. )b) Carruthers,
W. Cycloaddition Reactions in Organic Synthesis;Pergamon:
Oxford, 1990. )c) Roush, W. R. Comprehensive Organic
Synthesis;Trost, B. M., Fleming, I., Paquette, L. A., Eds.;
1991;Vol. 5, pp. 513±550. )d) Kappe, C. O.;Murphree,
S. S.;Padwa, A. Tetrahedron 1997, 42, 14179±14233.
)e) Fallis, A. G. Acc. Chem. Res. 1999, 32, 464±474.
10. )a) Katsuki, T.;Lee, A. W. M.;Ma, P.;Martin, V. S.;
Masamune, S.;Sharpless, K. B.;Tuddenham, D.;Walker,
F. J. J. Org. Chem. 1982, 47, 1373±1380. )b) Ma, P.;Martin,
20. Fujita, E.;Nagao, Y.;Kaneko, K. Chem. Pharm. Bull. 1978,
26, 3743±3751.
V. S.;Masamune, S.;Sharpless, K. B.;Viti, S. M.
J. Org.
Chem. 1982, 47, 1380±1381. For convenient preparation
of the intermediary )R)-glyceraldehyde acetonide, see:
)c) Schmid, C. R.;Bryant, J. D. Org. Synth. 1993, 72, 6±13.
21. )a) Lee, D. G.;Hall, D. T.;Cleland, J. H. Can. J. Chem. 1972,
50, 3741±3743. )b) Corey, E. J.;Myers, A. G. J. Am. Chem.
Soc. 1985, 107, 5574±5576.