Synthesis of the BCD-ring of ciguatoxin 1B using an acetylene cobalt complex and vinylsilane strategy

Article abstract of DOI:10.1016/S0040-4020(02)00044-3

Synthesis of the tricyclic BCD-ring segment with high stereoselectivity has been achieved starting from a sugar derivative directed toward the synthesis of the left part of ciguatoxin 1B. The central reactions in the synthesis are (i) ether ring formation mediated by an acetylene cobalt complex, (ii) decomplexation of the endo-acetylene cobalt complex to the vinylsilane, and (iii) ring-opening reaction of the epoxysilane into the allylic alcohol.

Full text of DOI:10.1016/S0040-4020(02)00044-3

TETRAHEDRON
Pergamon
Tetrahedron 58 /2002) 1875±1888
Synthesis of the BCD-ring of ciguatoxin 1B using an acetylene
cobalt complex and vinylsilane strategy
Kazunobu Kira, Akinari Hamajima and Minoru Isobep
Laboratory of Organic Chemistry, School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan
Received 1 October 2001; accepted 22 November 2001
AbstractÐSynthesis of the tricyclic BCD-ring segment with high stereoselectivity has been achieved starting from a sugar derivative
directed toward the synthesis of the left part of ciguatoxin 1B. The central reactions in the synthesis are /i) ether ring formation mediated by
an acetylene cobalt complex, /ii) decomplexation of the endo-acetylene cobalt complex to the vinylsilane, and /iii) ring-opening reaction of
the epoxysilane into the allylic alcohol. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
We have been studying various synthetic methodologies
applicable to the 1 class of natural products, that have syn/
trans stereochemistry of polycyclic oxy-ring systems. The
strategy of these studies is based on the chemistry of the
acetylene biscobalthexacarbonyl complex.5 Our synthetic
efforts have recently culminated in both enantiomeric
forms of the left-end segment AB6 or left-middle segment
/D)EF7 or right-middle segment including the /H)IJK
segment8 of CTX-1B. The key issues are stereoselective
ether ring cyclization in syn/trans manner via the pro-
pargylic cation9 5 stabilized by the acetylene biscobalt-
hexacarbonyl complex /Scheme 1).10 The stereochemistry
of cyclic products 6 is governed by the reaction conditions;
the anti isomer being a kinetic product and the syn isomer
being a thermodynamic product.5b The endo-acetylene
cobalt complex 6 would be decomplexed to vinylsilane 7
/hydrosilylation) regioselectively.11 Stereospeci®c ring-
opening reaction of a,b-epoxysilane 8, resulting in the
Ciguatoxin 1B /CTX-1B, 1, Fig. 1), one of the principal
toxins causing ciguatera ®sh poisoning, was ®rst isolated
from the moray eel, Gymnothorax javanicus, by Scheuer
and co-workers at the University of Hawaii and character-
ized as a polyether compound in 1980.1 The gross structure
of CTX-1B, except for the absolute con®guration and the
relative con®guration at C-2, was elucidated by Yasumoto
and co-workers in 1989 using a puri®ed sample of only
0.35 mg.2 Recently, the absolute con®guration of ciguatoxin
was successfully determined by Yasumoto and co-workers
as shown in Fig. 1.3 CTX-1B possesses 33 asymmetric
carbons and 12 trans-fused polycyclic ethers ranging from
six to nine-membered, where another ®ve-membered
oxacycle is spirally attached at one end. Due to the limited
availability of the compound from nature, extensive studies
have been made towards its synthesis.4
Figure 1.
Keywords: ciguatoxin; acetylene cobalt complex; hydrosilylation; vinylsilane; epoxysilane.
Corresponding author. Tel.: 181-52-789-4109; fax: 181-52-789-4111; e-mail: isobem@agr.nagoya-u.ac.jp
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020/02)00044-3

1876
K. Kira et al. / Tetrahedron 58 .2002) 1875±1888
Scheme 1.
formation of allylic alcohol 9,7,12 has also been one of the
key reactions in our synthetic studies. This paper describes
the synthesis of the BCD-ring segment 2 /Fig. 1) directed
toward the synthesis of the left part of CTX-1B based on this
strategy.
ether ring system. The allylic alcohol moiety on the D-ring
of 2 should be transformed from the epoxysilane 10 through
the ring-opening reaction of a,b-epoxysilane. Vinylsilane
11, which would be obtained from the acetylene cobalt
complex 12 through the hydrosilylation reaction, was
de®ned as a precursor to 10. The critical 7-membered ring
cyclization would occur from the precursor propargylic
cation 13 that is stabilized by the acetylene cobalt complex.
This cyclization precursor should be derived from the
BC-acetylene 15 and 3-oxy-propanal 14. BC-acetylene 15
should be transformed from B-ring segment 17 and acyl
anion equivalent 16. Methyl-a-d-glucopyranoside would
access to this B-ring segment 17.
2. Results and discussion
We employed the above methodology for the synthesis of 2
summarized as a retrosynthetic analysis in Scheme 2. The
BCD-ring segment 2, representing the C6±C23 portion of
CTX-1B, consists of a trans-fused tricyclic 6/6/7-membered
Scheme 2.
Scheme 3.

K. Kira et al. / Tetrahedron 58 .2002) 1875±1888
1877
Scheme 4.
Synthesis of the B-ring 17 is summarized in Scheme 3.13
Selective dibenzylation at C-10, 11 was performed in three
steps from methyl-a-d-glucopyranoside to give 18. This
primary alcohol 18 was converted into iodide 19. The result-
ing iodide 19 was transformed into lactone 20 by a four-step
sequence including pivaloylation at C-12, acetolysis,
hydrolysis, and oxidation.14 Treatment of lactone 20 with
allylmagnesium bromide to obtain C-9 ketal, followed by
reduction of this ketal produced the a-allyl-glycoside 21.15
The pivaloyl protecting groups of 21 were changed into the
ethoxy ethyl ether 22 in high yield. Iodine 22 was replaced
with cyanide to provide nitrile 23 which was reduced with
DIBAL to afford the B-ring 17.
ated stereogenic center in 27 at the C16 position was a
mixture with ratio of 2:1. This stereochemistry was
corrected by epimerization through the following 3 steps.
First removal of the acetoxy group followed by oxidation17
to the ketone at C15, and subsequent treatment of the result-
ing ketone with Et3N in MeOH at room temperature gave 28
/syn/antiˆ9:1). Stereoselective reduction of the ketone at
C15 was achieved by NaBH4 in CH2Cl2±MeOH at
2788C18 to give alcohol 29 which has the desired stereo-
chemistry. At this stage, the minor isomer could be sepa-
rated by silica gel column chromatography. With BC-ring
29 in hand, the side chain was required for the conversion
into an acetylene equivalent for the construction of the
D-ring. Removal of the pivaloyl group was followed by
oxidation to aldehyde 31, which was converted into
dibromoole®n19 as BC-acetylene equivalent 32 by Corey's
protocol.
Synthesis of the BC-acetylene equivalent 32 is summarized
in Scheme 4. Lithiation of the dithiane 24 and addition of
the resulting anion to aldehyde 17 in THF at 08C gave a
coupling adduct, which has all the carbons needed to
construct the BC-ring skeleton. Selective protection and
deprotection provided 26. The thioketal moiety of 26 was
hydrolyzed by treatment with bis/tri¯uoroacetoxy)iodo-
benzene16 in CH3CN±H2O to cyclic ketal, which was subse-
quently transformed into cyclic ether 27 by treatment with
Et3SiH and BF3´OEt2 in CH3CN at 08C.15 The newly gener-
Treatment of the dibromoole®n 32 with 2.2 equiv. of
n-BuLi generated the corresponding acetylide, which was
mixed with the protected 3-oxy-propanal 33 to give the
coupling product 34 /Scheme 5). After deprotection of the
hydroxyl group at C15, it was successively treated with
Co2/CO)8 and then BF3´OEt2 in one-pot to afford the
Scheme 5.

1878
K. Kira et al. / Tetrahedron 58 .2002) 1875±1888
Scheme 8.
Scheme 6.
found to prevent the isomerization completely /Scheme 8).
The vinylsilane 37 was a sole product /89%). With this
dummy acetylene, it became possible to raise the reaction
scale to over 1 g. It is noted that the vinylsilanes /44, 45)
which come from propargyl alcohol were also obtained
/Scheme 9). The formation of these vinylsilanes /44, 45)
suggest that propargyl alcohol could trap the active species
39 /step a), then hydrosilylated into vinylsilane 44 or 45
/step b).21
cyclization product 36 as a single stereoisomer having syn
relationship. Hydrosilylation of 36 was conducted with
Et3SiH by heating at 608C in dichloroethane solvent in the
presence of EtOH. EtOH was added to prevent the silylation
of alcohol at C-22.11 But this hydrosilylation reaction
provided a complex mixture of the desired vinylsilane 37
/50±80%) and 38 /10±30%) whose terminal ole®n was
isomerized into inner ole®n, unexpectedly. The ratios of
the position isomers 38/37 were remarkably dependent
on the reaction scale; thus, as the reaction scale became
large, the ratio increased.
According to the route shown in Scheme 10, our attention
was turned to the transformation of the vinylsilane 37 into
the allylic alcohol 49. The terminal ole®n of 37 was
converted into methylketone 46 through Wacker oxidation.
Conversion of the terminal ole®n was due to its reactive
nature during the following iodo-lactonization step to
provide a tetrahydrofuran by-product through an iodo-
etheri®cation22 reaction between the terminal ole®n and
the C10 hydroxy group; thus Wacker oxidation was
employed to protect this ole®n. The terminal hydroxy
group of 46 was oxidized into carboxylic acid, followed
It is likely that this isomerization reaction took place by
an action of `unisolable substance [Co]p 39' /Scheme 6).
This 39 is supposed to be real active species of the catalytic
hydrosilylation reaction /Scheme 7).20 Although the 39
has not been characterized yet, it is likely to be liberated
from the acetylene cobalt complex 36 when hydrosilylated.
It should be assumed that it is possible to inhibit the side
reactions if the `unisolable substance 39' can be trapped by
additives.
23
by treatment with I/collidine)2PF6 to give iode lactone
47 in modest yield, which was converted to epoxysilane
48 by the opening of lactone in the presence of Na2CO3 in
MeOH.24 With the epoxysilane 48 in hand, we tried a ring-
opening reaction of epoxysilane into an allylic alcohol form.
Treatment of epoxysilane 48 with BF3´OEt2 gave a mixture
of the desired allylic alcohol 49 and its lactone analog 50,
unfortunately. The methyl ester moiety of epoxysilane 48
turned out to be changed prior to this step into an inactive
form to prevent lactone formation.
Under these circumstances, large excess hexene was added
as a dummy terminal ole®n to prevent the isomerization of
37. Although the hexene decreased the ratio of the isomer 38
/0±20%), it was not able to stop isomerization completely
/the ratio of the isomer 38 was remarkably dependent on the
reaction scale). Next excess 2-propene-1-ol was added in
place of EtOH and hexene, but it could not completely,
either /0±20%). These results show the importance of trap-
ping the active species 39 to prevent the isomerization. In
order to trap 39, excess propargyl alcohol was added. This
choice turned out to be right; adding propargyl alcohol was
Scheme 7.
Scheme 9.

K. Kira et al. / Tetrahedron 58 .2002) 1875±1888
1879
Scheme 10.
Scheme 11.
The ketone at C7 of iodo-lactone 47 was protected in the
form of dithioketal 51 /Scheme 11). Originally BF3´OEt2
was used instead of Zn/OTf)2,25 but vinylsilane 56 was
reformed by a nucleophilic attack of thiol to iodide as a
side reaction /Scheme 12). It can be presumed that this
retro lactonization reaction took place by the effect of the
silyl group that stabilizes a cation at C-19. DIBAL reduction
of this lactone 51 was followed by DBU treatment in THF to
yield the epoxysilane 52 having the aldehyde side chain.
After converting the aldehyde 52 into the acetylene26 53,
the ring-opening reaction of epoxysilane 53 into the allylic
alcohol 54 was achieved by treatment with BF3´OEt2 in
80%, and its con®guration was corrected under a modi®ed
Mitsunobu condition27 using p-nitrobenzoic acid to afford
BCD-ring 55.28
A possible mechanism of the ring-opening reaction of
epoxysilane 53 is shown in Scheme 13.12 Because of the
Scheme 12.

1880
K. Kira et al. / Tetrahedron 58 .2002) 1875±1888
Scheme 13.
well-known stabilization of the b cations to the silicon
atom, acid-catalyzed reaction of a,b-epoxysilane might be
expected to proceed with ring-opening at the b carbon. But
in the case of an a,b-epoxysilane, the relative orientation of
the a C±Si bond and the b C±O bond is not in the parallel
alignment necessary for the stabilization of a developing
positive charge by the silicon atom. Many ring-opening
reactions of a,b-epoxysilanes are reported to show that
these reactions proceed with strong preference for cleavage
of the a C±O bond under various conditions.29 Treatment of
53 with BF3´OEt2 proceeded with ring-opening at the
a-carbon to give a-cation intermediate 58. Although it is
assumed that the ring-opening reaction would take place in a
concerted manner, the cation intermediates are expressed in
Scheme 13 in stepwise form for simpli®cation. Since
hydride shift should occur to the a-cation 58 from the
pseudo axial hydrogen at the b or b0-carbon that was
oriented antiperiplanar to the generating empty p-orbital,
the b0-hydride shift as illustrated in Newman projection A
occurred predominantly in 58 to give the b0-cation 59,
which might be stabilized by the silyl group. Then the
b0-cation 59 underwent a rapid loss of the silyl group to
result in the formation of allylic alcohol 54.
and are reported in m/z. Elemental analyses were performed
by Analytical Laboratory at School of Bioagricultural
Sciences, Nagoya University. Reactions were monitored
by thin-layer chromatography carried out on 0.25 mm silica
gel coated glass plates 60F254 /Cica Merck, Art 1.05715)
using UV light as visualizing agent and 7% ethanolic phos-
phomolybdic acid, or p-anisaldehyde solution as developing
agents. Cica Merck silica gel 60 /particle size 0.063±
0.2 mm ASTM) was used for open-column chroma-
tography. Unless otherwise noted, nonaqueous reactions
were conducted in oven-dried /2008C) or ¯ame-dried glass-
ware under inert atmosphere of dry nitrogen or argon. Dry
THF was distilled from potassium metal with benzo-
phenone. Dry CH2Cl2 was distilled from CaH2 under
nitrogen atmosphere. BF3´OEt2 were distilled from CaH2.
All other commercially available reagents were used as
received. Hy¯o Super-Celw /nacalai tesque) was used as a
®lter aid.
3.1.1. Diol ,18). To a solution of methyl-a-d-glucopyrano-
side /1.19 kg, 6.13 mol) in 6.0 L of DMF were added
2,2-dimethoxypropane /1.88 L, 15.3 mol) and A-15E
/Amberlyst-15E, 6.0 g) at room temperature. After stirring
mechanically for 3 days at room temperature, the reaction
mixture was ®ltered and concentrated under reduced
pressure to give 1.43 kg of acetonide as a crude oil, which
was used directly for the next reaction without further
puri®cation.
Thus, we have succeeded in the synthesis of the BCD-ring
55 of CTX-1B 1 using an acetylene cobalt complex-
mediated cyclization and the ring-opening reaction of
epoxysilane to allylic alcohol. Further efforts directed
toward the total synthesis of CTX-1B are in progress in
our laboratory.
A solution of the above acetonide /100 g) in 200 mL of
CH2Cl2 was gradually added to a mechanically stirred solu-
tion containing 240 g /4.28 mol) of KOH in 800 mL of BnCl
heated at 908C. After stirring for 2.5 h at 1158C, the
reaction mixture was cooled to room temperature and
poured into an ice-cold sat. NH4Cl solution. The resulting
mixture was extracted with ether /£3). The combined
extract was dried over Na2SO4, and concentrated under
reduced pressure. The residue was ®ltered through a silica
gel short column.
3. Experimental
3.1. General
Melting points /mp) were recorded on a Yanaco MP-S3
melting point apparatus and are not corrected. Infrared
spectra /IR) were recorded on a JASCO FT/IR-8300
spectrophotometer and are reported in wave number
/cm21). Proton nuclear magnetic resonance /1H NMR)
spectra were recorded on Brucker ARX-400 /400 MHz)
and Varian Gemini-2000 /300 MHz) spectrometers. Carbon
nuclear magnetic resonance /13C NMR) spectra were
recorded on Brucker ARX-400 /100 MHz) and Varian
Gemini-2000 /75 MHz) spectrometers. Optical rotations
were measured on a JASCO DIP-370 digital polarimeter.
Mass spectra were recorded on a Micromass Q-TOF /ESI),
A-15E /30.0 g) was added to a solution containing the above
dibenzyl ether in 2.0 L of MeOH at room temperature. After
stirring mechanically for 18 h at room temperature, the
reaction mixture was ®ltered, dried over Na2SO4, and
concentrated in vacuo to leave a viscous oil. The residue
was ®ltered through a silica gel short column and dissolved
in ether containing a small amount of hexane and the
solution was stood still for crystallization. The mother

K. Kira et al. / Tetrahedron 58 .2002) 1875±1888
1881
liquors were decanted and the crystals were collected by
®ltration and then dried under high vacuum to afford
the volatiles in vacuo gave acetal, which was used in next
step without further puri®cation.
27
117 g of diol 18 in three crops /73% in 3 steps). [a]D
116.38 /c 1.01, CHCl3). Mp 77.58C. IR /KBr) nmax 3425,
ˆ
To a solution of the above acetal /139.0 g) in 1260 mL
of DMSO was added 840 mL of acetic anhydride. After
stirring magnetically for 12 h at room temperature, the reac-
tion mixture was poured into a cold H2O, extracted with
ether /£3). The combined extract was dried over Na2SO4
and concentrated in vacuo to leave a viscous oil. The residue
was ®ltered through a silica gel short column and dissolved
in ether±hexane and was stood still for crystallization.
The mother liquors were decanted and the crystals were
collected by ®ltration and then dried under high vacuum
to afford 61.0 g of lactone 20 in three crops /52% in four
2926, 2362, 1749, 1455, 1364, 1052, 740, 698 cm21. H
1
NMR /CDCl3, 300 MHz) d 2.21 /1H, br, ±OH), 2.66 /1H,
br, ±OH), 3.36 /3H, s, ±OCH3), 3.45±3.63 /3H, m, H-10,
12, 13), 3.66±3.83 /3H, m, H-11, 14a, 14b), 4.57±4.78 /4H,
m, ±OCH2Ph, ±OCH2Php), 5.01 /1H, d, Jˆ11.5 Hz, H-9),
7.25±7.40 /10H, m, aromatic). 13C NMR /CDCl3, 75 MHz)
d 55.2, 62.2, 70.3, 70.7, 73.1, 75.3, 79.7, 81.3, 98.2, 127.9,
128.0, 128.1, 128.5, 128.6, 138.0, 138.7. Anal. Calcd for
C21H26O6: C, 67.36; H, 7.00. Found: C, 67.28; H, 6.93.
27
3.1.2. Iodide ,19). To a solution of the diol 18 /63.79 g,
0.170 mol) in 1275 mL of toluene were added imidazole
/29.0 g, 0.426 mol), PPh3 /71.50 g, 0.273 mol) and I2
/69.18 g, 0.273 mol) at room temperature. After stirring
mechanically for 2 h, the reaction mixture was poured into
an ice-cold sat. Na2SO3 solution and extracted with CH2Cl2
/£3). The combined extract was dried over Na2SO4 and
concentrated under reduced pressure. The residue was
chromatographed on a silica gel column /ether/hexaneˆ
80:20). Recrystallization from hexane/ether gave 70.12 g
steps). [a]D ˆ1728 /c 0.66, CHCl3). Mp 95.0±96.58C. IR
/KBr) nmax 3446, 3032, 2972, 2875, 2362, 2341, 1757, 1737,
1481, 1455, 1277, 1231, 1162, 1136, 1041, 743, 698 cm21
.
1H NMR /CDCl3, 300 MHz) d 1.18 /9H, s, ±OPiv), 3.28
/1H, dd, Jˆ11.5, 6.0 Hz, H-14a), 3.46 /1H, dd, Jˆ11.5,
6.0 Hz, H-14b), 3.82 /1H, dd, Jˆ5.5, 4.0 Hz, H-11), 4.16
/1H, d, Jˆ5.5 Hz, H-10), 4.54 /1H, ddd, Jˆ7.5, 6.0, 6.0 Hz,
H-13), 4.62 /1H, d, Jˆ12.0 Hz, ±OCH2Ph), 4.66 /1H, d, Jˆ
12.0 Hz, ±OCH2Php), 4.70 /1H, d, Jˆ12.0 Hz, ±OCH2Php),
4.91 /1H, d, Jˆ12.0 Hz, ±OCH2Ph), 5.22 /1H, dd, Jˆ7.5,
4.0 Hz, H-12), 7.23±7.36 /10H, m, aromatic). 13C NMR
/CDCl3, 75 MHz) d 2.8, 26.8, 38.7, 71.1, 72.7, 73.4, 76.9,
78.9, 127.9, 128.0, 128.2, 128.3, 128.5, 128.6, 136.5, 136.9,
167.6, 177.0. Anal. Calcd for C25H29IO6: C, 54.36; H, 5.29.
Found: C, 54.36; H, 5.10.
26
/85%) of iodide 19 as white crystals. [a]D ˆ1228 /c
0.98, CHCl3). Mp 83.5±84.08C. IR /KBr) nmax 3504,
3030, 2909, 2363, 1455, 1363, 1198, 1063, 985, 738,
698 cm21 1H NMR /CDCl3, 300 MHz) d 2.22 /1H, s,
.
±OH), 3.22±3.34 /2H, m, H-14a, 14b), 3.38±3.55 /3H, m,
H-10, 12, 13), 3.44 /3H, s, ±OCH3), 3.78 /1H, t, Jˆ9.0 Hz,
H-11), 4.63±4.81 /4H, m, ±OCH2Ph, ±OCH2Php), 5.03 /1H,
d, Jˆ11.3 Hz, H-9), 7.25±7.45 /10H, m, aromatic). 13C
NMR /CDCl3, 75 MHz) d 6.9, 55.5, 69.7, 73.1, 73.6,
75.3, 79.8, 80.7, 98.1, 128.0, 128.1, 128.5, 128.7, 137.9,
138.6. Anal. Calcd for C21H25IO5: C, 52.08; H, 5.20.
Found: C, 52.08; H, 5.33.
3.1.4. Allyl glycoside ,21). A solution of allylmagnesium
bromide /1.0 M in ether, 50.5 mL, 0.051 mol) was slowly
added to a solution of the lactone 20 /25.39 g, 0.046 mol) in
460 mL of THF at 2788C. After stirring magnetically for
1 h at 2788C, the reaction mixture was poured into an ice-
cold sat. NH4Cl solution and extracted with ether /£3). The
combined extract was dried over Na2SO4 and concentrated
in vacuo to give ketal as a crude oil, which was ®ltered
through a silica gel short column.
3.1.3. Lactone ,20). To a solution of the iodide 19 /100.0 g,
0.207 mol) in 2070 mL of CH2Cl2 were added pivaloyl
chloride /38.2 mL, 0.310 mol) and DMAP /25.2 g,
0.207 mol) at 08C. After mechanically stirring for 2 days
at room temperature, the reaction mixture was poured into
an ice-cold sat. NH4Cl solution and extracted with CH2Cl2
/£3). The combined extract was dried over Na2SO4 and
concentrated under reduced pressure to give pivaloate as a
crude oil, which was used directly in the next step without
further puri®cation.
To a solution of the above ketal /30.0 g) in 500 mL of
CH3CN were added 24.0 mL of Et3SiH /0.151 mol) and
9.67 mL of BF3´OEt2 /0.076 mol) at 2108C. After stirring
magnetically for 30 min at 210 to 08C, the reaction mixture
was poured into an ice-cold sat. NaHCO3 solution and
extracted with ether /£3). The combined extract was dried
over Na2SO4 and concentrated under reduced pressure to
give a crude oil, which was chromatographed on a silica
gel column /ether/hexaneˆ90:10) to give 21 /22.7 g, 85%
A conc. H2SO4 /6.75 mL) was slowly added to a solution of
above pivaloate /135.0 g) in 1350 mL of acetic anhydride at
258C. After stirring mechanically for 15 min at 25 to 08C,
the reaction mixture was poured into an ice-cold sat.
NaHCO3 solution and extracted with CH2Cl2 /£3). The
combined extract was dried over Na2SO4 and concentrated
under reduced pressure to give 146.0 g of acetate, which was
used directly in the next step without further puri®cation.
27
in 2 steps). [a]D ˆ1238 /c 0.89, CHCl3). IR /KBr) nmax
3066, 3032, 2974, 2905, 2872, 2359, 2342, 1736, 1643,
1480, 1455, 1363, 1278, 1159, 1135, 1084, 996, 737,
698 cm21 1H NMR /CDCl3, 300 MHz) d 1.18 /9H, s,
.
±OPiv), 2.30 /1H, dt, Jˆ16.5, 7.0 Hz, H-8a), 2.60 /1H,
ddt, Jˆ16.5, 7.0, 1.5 Hz, H-8b), 3.06 /1H, dd, Jˆ11.5,
9.0 Hz, H-14a), 3.20 /1H, dd, Jˆ11.5, 2.5 Hz, H-14b),
3.35 /1H, ddd, Jˆ10.0, 9.0, 2.5 Hz, H-13), 3.38±3.48 /2H,
m, H-9, 10), 3.70 /1H, t, Jˆ10.0 Hz, H-11), 4.62 /1H,
d, Jˆ12.0 Hz, ±OCH2Ph), 4.68 /1H, d, Jˆ12.0 Hz,
±OCH2Ph), 4.79 /1H, d, Jˆ12.0 Hz, ±OCH2Ph), 4.80
/1H, d, Jˆ12.0 Hz, ±OCH2Ph), 4.92 /1H, t, Jˆ10.0 Hz,
H-12), 5.10 /1H, dm, Jˆ10.5 Hz, H-6a), 5.13 /1H, dm,
Jˆ18.0 Hz, H-6b), 5.98 /1H, ddt, Jˆ18.0, 10.5, 7.0 Hz,
To a solution of the above acetate /146.0 g) in 2177 mL of
THF and 109.0 mL of H2O was added 109.0 mL of conc.
HCl at 08C. After stirring magnetically for 7 days at room
temperature, the reaction mixture was poured into an ice-
cold sat. NaHCO3 solution and extracted with ether /£3).
The combined extracts was dried over Na2SO4. Removal of

1882
K. Kira et al. / Tetrahedron 58 .2002) 1875±1888
H-7), 7.23±7.36 /10H, m, aromatic). 13C NMR /CDCl3,
75 MHz) d 4.3, 27.0, 35.7, 38.8, 74.0, 75.1, 75.1, 79.0,
81.4, 84.2, 117.4, 128.2, 127.7, 127.9, 128.4, 128.5, 134.4,
138.0, 138.1, 177.3. Anal. Calcd for C28H35IO5: C, 58.14; H,
6.10. Found: C, 58.14; H, 6.14.
reaction mixture was poured into 10% AcOH aq /100 mL)
and extracted with CH2Cl2 /£2). The combined extract was
washed with sat. NaHCO3 solution, brine, dried over
Na2SO4, and concentrated in vacuo. The residue was
puri®ed by silica gel column chromatography /ether/
hexaneˆ80:20) to afford B-ring 17 /6.17 g, 98%). IR
/KBr) nmax 3066, 3032, 2981, 2903, 1728, 1454, 1359,
3.1.5. Nitrile ,23). A solution of diisobutylaluminum
hydride /DIBAL, 1.0 M solution in toluene, 111 mL,
0.111 mol) was slowly added to a solution of the pivaloate
21 /25.65 g, 0.044 mol) in 443 mL of CH2Cl2 at 2788C.
After stirring magnetically for 1 h at 2788C, 60 mL of
ethyl acetate and 28 mL of sat. NH4Cl aq. were added at
2788C. Allowed to warm up to room temperature, this
slurry was diluted with 280 mL of ether and stirred for
further 1 h 40 min. Anhydrous sodium sulfate /98.0 g) was
added to this slurry, then the mixture was ®ltered through
the pad of Super-Cel. The ®ltrate was dried over Na2SO4,
and then concentrated under reduced pressure to give
alcohol /23.69 g), which was used directly in the next step
without further puri®cation.
1
1092, 1057, 736, 698 cm21. H NMR /CDCl3, 300 MHz)
d 1.07, 1.18 /total 3H, each t, Jˆ7.0 Hz, ±OCH2CH3),
1.22, 1.30 /total 3H, each d, Jˆ5.0 Hz, ±OCH/CH3)O±),
2.21 /1H, dt, Jˆ15.0, 7.5 Hz, H-8a), 2.47±2.61 /2H, m,
H-8b, 14a), 2.81, 3.01 /total 1H, each dm, Jˆ16.0 Hz,
H-14b), 3.24±3.51 /4H, m, H-9, 10, 12, 13), 3.64 /1H, t,
Jˆ9.0 Hz, H-11), 3.70±3.81 /2H, m, ±OCH2CH3), 4.62,
4.64 /total 1H, each d, Jˆ11.5 Hz, ±OCH2Ph), 4.76±4.95
/total 4H, ±OCH2Ph, ±OCH2Php, ±OCH/CH3)O±), 5.05
/1H, dm, Jˆ10.5 Hz, H-6a), 5.11 /1H, dm, Jˆ17.0 Hz,
H-6b), 5.76±5.90 /1H, m, H-7), 7.22±7.36 /10H, m,
aromatic), 9.75, 9.76 /total 1H, each t, Jˆ2.5 Hz, ±CHO).
Anal. Calcd for C28H36O6: C, 71.77; H, 7.74. Found: C,
71.77; H, 7.67.
To a solution of the above alcohol /23.69 g) in 443 mL of
CH2Cl2 was added 8.47 mL of ethyl vinyl ether /EVE,
0.087 mol) and pyridinium p-toluenesulufonate /PPTS,
500 mg) at room temperature. After stirring magnetically
for 12 h at room temperature, the reaction mixture was
poured into a cold sat. NaHCO3 aq. and extracted with
CH2Cl2 /£2). The combined extract was dried over
Na2SO4 and concentrated under reduced pressure to give
ethoxyethyl ether, which was used in the next step without
further puri®cation.
3.1.7. Diol ,25). To a solution of the dithiane 24 /4.35 g,
18.4 mmol) in 100 mL of dry THF was added a solution of
n-BuLi /1.60 M in hexane, 11.5 mL, 18.4 mmol) at 2788C.
After stirring for 20 min at 08C, aldehyde 17 /7.01 g,
14.9 mmol) in 25.0 mL of THF was added and the resulting
mixture was stirred for 40 min at 08C. Then the reaction
mixture was poured into an ice-cold sat. NH4Cl solution
and extracted with ether. The combined extract was washed
with brine, dried over Na2SO4, and concentrated in vacuo,
which was used in the next step without further puri®cation.
NaCN /3.26 g, 0.065 mol) was added to a solution of the
above ethoxyethyl ether /26.08 g, 0.041 mol) in 443 mL of
DMSO at room temperature. After raising the temperature
to 658C, the reaction mixture was stirred for 1 h. After
cooling to room temperature, the reaction mixture was
poured into H2O and extracted with ether /£3). The
combined extract was dried over Na2SO4 and concentrated
under reduced pressure to give a crude oil, which was
chromatographed on a silica gel column /ether/hexaneˆ
80:20) to give 23 /20.27 g, 89% in 3 steps). IR /KBr) nmax
2980, 2901, 1645, 1498, 1455, 1379, 1359, 1121, 1089,
The above coupling compound was dissolved in 100 mL of
pyridine and treated with acetic anhydride /2.84 mL,
29.9 mol). After stirring at room temperature for 12 h, the
reaction mixture was quenched with an ice-cold sat. NH4Cl
solution and extracted with ether /£3). The extracts were
dried over Na2SO4, and concentrated under reduced
pressure.
To a solution of the above acetate in 150 mL of MeOH
was added A-15E /1.0 g). After stirring for 48 h at room
temperature, the reaction mixture was ®ltered through a
pad of Celite, the resin was washed thoroughly with ethyl
acetate. The ®ltrate was concentrated in vacuo. The residue
was puri®ed by silica gel column chromatography /ether/
hexaneˆ80:20) to give diol 25 /6.39 g, 70% in 3 steps). IR
/KBr) nmax 3422, 2900, 1741, 1713, 1642, 1498, 1454, 1426,
1
1053, 738, 699 cm21. H NMR /CDCl3, 300 MHz) d 1.09,
1.22 /total 3H, each t, Jˆ7.0 Hz, ±OCH2CH3), 1.24, 1.35
/total 3H, each d, Jˆ5.0 Hz, ±OCH/CH3)O±), 2.30 /1H, dt,
Jˆ15.0, 8.0 Hz, H-8a), 2.58 /1H, dm, Jˆ15.0 Hz, H-8b),
2.66, 2.75 /total 1H, each dd, Jˆ16.5, 5.5 Hz, H-14a),
2.83, 2.90 /total 1H, each dd, Jˆ16.5, 3.5 Hz, H-14b),
3.28±3.64 /5H, m, H-9, 10, 11, 12, 13), 3.76, 3.79 /total
2H, each q, Jˆ7.0 Hz, ±OCH2CH3), 4.63, 4.65 /total 1H,
each d, Jˆ11.0 Hz, ±OCH2Ph), 4.74±4.96 /4H, m,
±OCH2Ph, ±OCH2Php, ±OCH/CH3)O±), 5.09 /1H, dm,
Jˆ10.5 Hz, H-6a), 5.11 /1H, dm, Jˆ17.0 Hz, H-6b),
5.91 /1H, m, H-7), 7.22±7.36 /10H, m, aromatic). Anal.
Calcd for C28H35NO5: C, 72.23; H, 7.58. Found: C, 72.23;
H, 7.55.
1
1372, 1237, 1089, 1043, 1028, 910, 737, 699 cm21. H
NMR /CDCl3, 300 MHz) d 1.72±2.37 /9H, m, H-8a, 14a,
14b, 17a, 17b, ±SCH2CH2CH2S±), 2.08, 2.09 /total 3H,
each s, ±OAc), 2.45±2.80 /3H, m, 8b, ±SCH2CH2CH2S±),
2.97±3.50 /5H, m, H-9, 10, 11, 12, 13), 3.91 /2H, m, H-18a,
18b), 4.67, 4.68 /total 1H, each d, Jˆ11.0 Hz, ±OCH2Ph),
4.72, 4.74 /total 1H, each d, Jˆ11.5 Hz, ±OCH2Php), 4.86,
4.87 /total 1H, each d, Jˆ11.0 Hz, ±OCH2Ph), 4.95, 4.96
/total 1H, each d, Jˆ11.5 Hz, ±OCH2Php), 5.08 /1H, dm,
Jˆ10.5 Hz, H-6a), 5.10 /1H, dm, Jˆ17.0 Hz, H-6b), 5.73,
5.84 /total 1H, dd, Jˆ9.0, 1.5 Hz; d, Jˆ10.0 Hz, H-15),
5.84±6.04 /1H, m, H-7), 7.26±7.38 /10H, m, aromatic).
Anal. Calcd for C32H42O7S2: C, 63.76; H, 7.02. Found: C,
63.58; H, 7.28.
3.1.6. B-ring ,17). A solution of diisobutylaluminum
hydride /DIBAL, 1.0 M in toluene, 14.1 mL, 14.1 mmol)
was slowly added to a solution of 23 /6.25 g, 13.4 mmol)
in 134 mL of CH2Cl2 at 2788C. After stirring for 1 h at 278
to 2208C, 10 mL of AcOEt was added at 2208C. The

K. Kira et al. / Tetrahedron 58 .2002) 1875±1888
1883
3.1.8. Pivaloate ,26). Piv-Cl /1.31 mL, 10.6 mmol) was
added to a solution of the diol 25 /6.39 g, 10.6 mmol) in
200 mL of CH2Cl2 and 8.57 mL of pyridine at 08C. After
stirring at room temperature for 12 h, another Piv-Cl
/0.39 mL, 3.18 mol) was added at 08C. After stirring at
room temperature for additional 12 h, the reaction mixture
was poured into an ice-cold sat. NH4Cl solution and
extracted with CH2Cl2 /£3). The combined extract was
dried over Na2SO4, and concentrated under reduced
pressure. Puri®cation of the residue with silica gel column
chromatography /ether/hexaneˆ50:50) gave the pivaloate
26 /7.5 g, 100%). IR /KBr) nmax 3481, 2974, 2906, 2872,
1728, 1481, 1455, 1426, 1371, 1283, 1236, 1156, 1091,
over Na2SO4, and concentrated under reduced pressure,
which was used in the next step without further puri®cation.
To the solution of above alcohol in 70 mL of DMSO was
added IBX /2.88 g, 10.3 mmol). After stirring at room
temperature for 12 h, the reaction was quenched with H2O
and ®ltered through a pad of Celite, washed thoroughly with
ether. The ®ltrate was extracted with ether /£2). The
extracts were dried over Na2SO4, and concentrated under
reduced pressure. Puri®cation of the residue with silica gel
column chromatography /ether/hexaneˆ40:60) gave the
ketone as a mixture at C-16 /3.37 g, 88% in 2 steps).
1
1064, 1045, 1028, 910, 736, 698 cm21. H NMR /CDCl3,
To a solution of the above ketone /2.00 g, 3.73 mmol) in
75 mL of MeOH was added Et3N /1.04 mL, 7.45 mmol).
After stirring at room temperature for 12 h, the reaction
mixture was poured into an ice-cold sat. NH4Cl solution.
The resulting mixture was extracted with ether /£2). The
combined extract was washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The
residue was ®ltered through a silica gel short column to
give the bicyclic ketone 28 /1.99 g). IR /KBr) nmax 2970,
300 MHz) d 1.18 /9H, s, ±OPiv), 1.68±2.38 /6H, m, H-14a,
14b, 17a, 17b, ±SCH2CH2CH2S±), 2.45±2.82 /4H, m, 8a,
8b, ±SCH2CH2CH2S±), 2.98±3.56 /7H, m, 9, 10, 11, 12, 13,
±SCH2CH2CH2S±), 4.30±4.38 /2H, m, H-18a, 18b), 4.64±
4.97 /4H, m, ±OCH2Ph, ±OCH2Php), 5.07 /1H, dm, Jˆ
10.5 Hz, H-6a), 5.09 /1H, dm, Jˆ17.0 Hz, H-6b), 5.73,
5.85 /total 1H, each d, Jˆ10.0 Hz, H-15), 5.85±6.05 /1H,
m, H-7), 7.26±7.38 /10H, m, aromatic). Anal. Calcd for
C37H50O8S2: C, 64.69; H, 7.34. Found: C, 64.67; H, 7.61.
2904, 1728, 1457, 1364, 1286, 1158, 1100, 737, 698 cm21
.
1H NMR /CDCl3, 300 MHz), d 1.18 /9H, s, ±OPiv), 1.90
/1H, ddt, Jˆ14.5, 8.5, 5.5 Hz, H-17a), 2.25±2.34 /2H, m,
H-8a, 17b), 2.50 /1H, dd, Jˆ15.5, 11.5 Hz, H-14a), 2.57±
2.63 /1H, m, H-8b), 2.97 /1H, dd, Jˆ15.5, 5.5 Hz, H-14b),
3.37 /1H, dd, Jˆ9.0, 8.5 Hz, H-10), 3.42±3.50 /3H, m, H-9,
12, 13), 3.72 /1H, t, Jˆ8.5 Hz, H-11), 3.94 /1H, dd, Jˆ8.5,
4.0 Hz, H-16), 4.18 /1H, ddd, Jˆ11.0, 8.5, 5.5 Hz, H-18a),
4.24 /1H, ddd, Jˆ11.0, 6.5, 5.0 Hz, H-18b), 4.64 /1H,
d, Jˆ10.5 Hz, ±OCH2Ph), 4.78 /1H, d, Jˆ11.0 Hz,
±OCH2Php), 4.95 /1H, d, Jˆ11.0 Hz, ±OCH2Php), 4.96
/1H, d, Jˆ10.5 Hz, ±OCH2Ph), 5.08 /1H, dm, Jˆ10.5 Hz,
H-6a), 5.09 /1H, dm, Jˆ17.0 Hz, H-6b), 5.83 /1H, dddd,
Jˆ17.0, 10.5, 8.0, 6.5 Hz, H-7), 7.26±7.38 /10H, m,
aromatic). 13C NMR /CDCl3, 75 MHz) d 27.2, 28.6, 35.9,
38.7, 44.9, 60.3, 73.9, 75.3, 75.4, 78.8, 79.5, 80.5, 81.9,
83.9, 117.5, 127.7, 127.8, 127.9, 128.0, 128.5, 134.1,
138.1, 138.3, 204.2. Anal. Calcd for C32H40O7: C, 71.62;
H, 7.51. Found: C, 71.70; H, 7.53.
3.1.9. Bicyclic ether ,27). To a solution of 26 /10.84 g,
15.7 mmol) in 300 mL of CH3CN and 30 mL of H2O was
added /CF3CO2)2IPh /13.57 g, 31.6 mol) at room tempera-
ture. After stirring at room temperature for 15 min, the
reaction mixture was poured into an ice-cold sat. NaHCO3
solution and extracted with ether /£3). The extracts were
dried over Na2SO4, and concentrated under reduced
pressure. The residue was ®ltered through a silica gel
short column to give the ketal.
To a solution of the above ketal in 194 mL of CH3CN were
successively added triethylsilane /6.21 mL, 38.9 mmol) and
BF3´OEt2 /2.46 mL, 19.4 mmol) at 08C. After stirring at 08C
for 1 h, the reaction mixture was poured into an ice-cold sat.
NaHCO3 solution. The resulting mixture was extracted with
ether /£2). The combined extract was dried over Na2SO4,
and concentrated under reduced pressure. Puri®cation of the
residue with silica gel column chromatography /ether/
hexaneˆ50:50) gave the 27 /6.60 g, 72% in 2 steps). IR
/KBr) nmax 2975, 2936, 2904, 2874, 1732, 1481, 1455,
1369, 1286, 1237, 1158, 1100, 1068, 1029, 997, 914, 751,
737, 699 cm21. 1H NMR /CDCl3, 300 MHz) d 1.19 /9H, s,
±OPiv), 1.51 /1H, q, Jˆ11.0 Hz, H-14a), 1.62±2.05 /2H, m,
H-17a, 17b), 2.05, 2.12, 2.13 /total 3H, each s, ±OAc),
2.17±2.64 /3H, m, H-8a, 8b, 14b), 3.12±3.76 /6H, m,
H-9, 10, 11, 12, 13, 16), 4.02±4.34 /2H, m, H-18a, 18b),
4.61 /1H, d, Jˆ11.0 Hz, ±OCH2Ph), 4.73 /1H, d, Jˆ
11.0 Hz, ±OCH2Php), 4.93 /1H, d, Jˆ11.0 Hz, ±OCH2Ph),
4.94 /1H, d, Jˆ11.0 Hz, ±OCH2Php), 5.02±5.12 /2H, m,
H-6a, 6b), 5.76±5.94 /1H, m, H-7), 7.26±7.38 /10H, m,
aromatic). Anal. Calcd for C34H44O8: C, 70.32; H, 7.64.
Found: C, 70.32; H, 7.73.
3.1.11. Alcohol ,29). A solution of the ketone 28 in 18 mL
of MeOH and 18 mL of CH2Cl2 was cooled to 2788C and
treated with NaBH4 /351 mg, 9.27 mmol). After stirring at
2788C for 1 h, the reaction mixture was poured into an ice-
cold sat. NH4Cl solution and extracted with ether /£3). The
extracts were dried over Na2SO4, and concentrated under
reduced pressure. Puri®cation of the residue with silica gel
column chromatography /ether/hexaneˆ50:50) gave the
27
alcohol 29 /1.75 g, 87% in 2 steps). [a]D ˆ1288 /c 0.83,
CHCl3). IR /KBr) nmax 3447, 2974, 2935, 2904, 2872, 1727,
1708, 1481, 1456, 1364, 1287, 1162, 1101, 1072, 751, 737,
699 cm21 1H NMR /CDCl3, 400 MHz) d 1.20 /9H, s,
.
±OPiv), 1.50 /1H, q, H-14a), 1.76 /1H, dddd, Jˆ14.5, 9.0,
6.0, 4.5 Hz, H-17a), 2.20±2.31 /2H, m, H-8a, 17b), 2.43
/1H, ddd, Jˆ11.5, 4.0, 4.0 Hz, H-14b), 2.58 /1H, dm,
Jˆ11.5 Hz, H-8b), 3.08±3.16 /2H, m, H-12, 13), 3.24
/1H, td, Jˆ9.0, 3.0 Hz, H-16), 3.29 /1H, dd, Jˆ9.5,
8.5 Hz, H-10), 3.38 /1H, ddd, Jˆ9.5, 7.5, 3.5 Hz, H-9),
3.44 /1H, m, H-15), 3.60 /1H, t, Jˆ8.5 Hz, H-11), 4.18
/1H, ddd, Jˆ11.0, 8.5, 6.0 Hz, H-18a), 4.34 /1H, ddd,
Jˆ11.0, 7.0, 4.5 Hz, H-18b), 4.61 /1H, d, Jˆ10.5 Hz,
3.1.10. Bicyclic ketone ,28). To a solution of 27 /4.13 g,
7.10 mmol) in 71 mL of MeOH was added K2CO3 /197 mg,
1.40 mmol). After stirring at room temperature for 20 h, the
reaction mixture was poured into an ice-cold sat. NH4Cl
solution. The resulting mixture was extracted with ether
/£2). The combined extract was washed with brine, dried

1884
K. Kira et al. / Tetrahedron 58 .2002) 1875±1888
±OCH2Ph), 4.73 /1H, d, Jˆ11.0 Hz, ±OCH2Php), 4.94 /1H,
d, Jˆ10.5 Hz, ±OCH2Ph), 4.95 /1H, d, Jˆ11.0 Hz,
±OCH2Php), 5.07 /1H, dm, Jˆ10.0 Hz, H-6a), 5.08 /1H,
dm, Jˆ17.0 Hz, H-6b), 5.87 /1H, dddd, Jˆ17.0, 10.0, 7.5,
6.5 Hz, H-7), 7.26±7.38 /10H, m, aromatic). 13C NMR
/CDCl3, 75 MHz) d 27.2, 31.2, 36.0, 38.6, 38.7, 61.0,
69.5, 73.5, 75.1, 75.3, 78.8, 78.9, 80.8, 82.6, 84.1, 117.2,
127.7, 127.8, 127.9, 128.1, 128.4, 134.5, 138.3, 138.6,
178.4. Anal. Calcd for C32H42O7: C, 71.35; H, 7.86.
Found: C, 71.35; H, 7.62.
3.84 /6H, m, H-9, 11, 15, 16, ±OCH2CH3), 4.62 /1H, d, Jˆ
11.0 Hz, ±OCH2Ph), 4.68 /1H, d, Jˆ11.0 Hz, ±OCH2Php),
4.68, 4.79 /total 1H, each q, Jˆ5.5 Hz, ±OCH/CH3)O±),
4.84 /1H, d, Jˆ11.0 Hz, ±OCH2Ph), 4.95 /1H, d, Jˆ
11.0 Hz, ±OCH2Php), 5.07 /1H, dm, Jˆ10.0 Hz, H-6a),
5.08 /1H, dm, Jˆ17.0 Hz, H-6b), 5.80±5.95 /1H, m, H-7),
7.26±7.38 /10H, m, aromatic), 9.76, 9.79 /total 1H, each q,
Jˆ1.5 Hz, ±CHO). Anal. Calcd for C31H40O7: C, 70.97; H,
7.68. Found: C, 70.95; H, 7.51.
3.1.14. BC-ring ,32). To a solution of CBr4 /5.01 g,
15.0 mmol) in 30 mL of CH2Cl2 was added a solution of
PPh3 /7.92 g, 30.2 mmol) in 10 mL of CH2Cl2 at 08C. After
stirring for 10 min at 08C, aldehyde 31 /1.98 g, 3.77 mmol)
in 10 mL of CH2Cl2 was added and the resulting mixture
was stirred for 30 min at 08C. Then the reaction mixture was
poured into an ice-cold sat. NaHCO3 solution and extracted
with ether. The combined extract was washed with brine,
dried over Na2SO4, and concentrated in vacuo, which was
®ltered through a silica gel short column.
3.1.12. Alcohol ,30). To a solution of 29 /721 mg,
1.34 mmol) in 15 mL of CH2Cl2 were successively added
ethyl vinyl ether /0.38 mL, 4.02 mmol) and pyridinium
p-toluenesulfonate /25 mg). After stirring for 12 h at room
temperature, the reaction mixture was poured into an ice-
cold sat. NaHCO3 solution. The resulting mixture was
extracted with CH2Cl2 /£2). The extracts were dried over
Na2SO4, and concentrated under reduced pressure, which
was used in the next step without further puri®cation.
To a solution of a above pivaloate /910 mg) in 15 mL of
MeOH was added NaOMe /108 mg, 2.00 mmol). After
stirring for 12 h at 458C, the reaction mixture was poured
into an ice-cold sat. NH4Cl solution. The resulting mixture
was extracted with CH2Cl2 /£3). The extracts were dried
over Na2SO4, and concentrated under reduced pressure. The
crude residue was puri®ed by silica gel column chroma-
tography /ether/hexaneˆ80:20) to give 30 /643 mg, 91%
in 2 steps). IR /KBr) nmax 3393, 2975, 2894, 1456, 1097,
To a solution of the above dibromoole®n in 50 mL of
CH2Cl2 were successively added ethyl vinyl ether
/0.72 mL, 13.1 mmol) and pyridinium p-toluenesulfonate
/50.0 mg). After stirring for 6 h at room temperature, the
reaction mixture was poured into an ice-cold sat. NaHCO3
solution. The resulting mixture was extracted with CH2Cl2
/£2). The combined extract was dried over Na2SO4, and
concentrated under reduced pressure. The residue was puri-
®ed by silica gel column chromatography /ether/hexaneˆ
17:83) to give the BC-ring 32 /2.57 g, 99% in 2 steps). IR
/KBr) nmax 2979, 2889, 1456, 1376, 1098, 1069, 1029, 737,
1
1068, 746, 696 cm21. H NMR /CDCl3, 300 MHz) d 1.20
/3H, t, Jˆ7.0 Hz, ±OCH2CH3), 1.30, 1.32 /total 3H, each d,
Jˆ5.5 Hz, ±OCH/O)CH3), 1.44, 1.56 /total 1H, each q,
Jˆ11.5 Hz, H-14a), 1.68±1.84 /1H, m, H-17a), 2.05±2.62
/4H, m, H-8a, 8b, 14b, 17b), 3.06±3.86 /11H, m, H-9, 10,
11, 12, 13, 15, 16, 18a, 18b, ±OCH2CH3), 4.62 /1H, d,
Jˆ11.0 Hz, ±OCH2Ph), 4.72, 4.81 /total 1H, each q, Jˆ
5.5 Hz, ±OCH/CH3)O±), 4.78 /1H, d, Jˆ11.0 Hz,
±OCH2Php), 4.88 /1H, d, Jˆ11.0 Hz, ±OCH2Php), 4.92
/1H, d, Jˆ11.0 Hz, ±OCH2Ph), 5.07 /1H, dm, Jˆ10.0 Hz,
H-6a), 5.08 /1H, dm, Jˆ17.0 Hz, H-6b), 5.80±5.95 /1H, m,
H-7), 7.26±7.38 /10H, m, aromatic). Anal. Calcd for
C31H42O7: C, 70.70; H, 8.04. Found: C, 70.60; H, 7.70.
1
698 cm21. H NMR /CDCl3, 300 MHz) d 1.20, 1.21 /total
3H, each t, Jˆ7.0 Hz, ±OCH2CH3), 1.30, 1.32 /total 3H,
each q, Jˆ5.5 Hz, ±OCH/O)CH3), 1.44, 1.55 /total 1H,
each q, Jˆ11.5 Hz, H-14a), 2.18±2.34 /2H, m, H-8a,
17a), 2.45±2.76 /3H, m, H-8b, 14b, 17b), 3.04±3.66 /9H,
m, H-9, 10, 11, 12, 13, 15, 16, ±OCH2CH3), 4.62 /1H, d,
Jˆ10.5 Hz, ±OCH2Ph), 4.72, 4.80 /total 1H, each q,
Jˆ5.5 Hz, ±OCH/CH3)O±), 4.74 /1H, d, Jˆ11.0 Hz,
±OCH2Php), 4.95 /1H, d, Jˆ10.5 Hz, ±OCH2Ph), 4.96
/1H, d, Jˆ11.0 Hz, ±OCH2Php), 5.07 /1H, dm, Jˆ
10.0 Hz, H-6a), 5.08 /1H, dm, Jˆ17.0 Hz, H-6b),
5.80±5.95 /1H, m, H-7), 6.55, 6.58 /total 1H, each t,
Jˆ7.0 Hz, H-18), 7.26±7.42 /10H, m, aromatic). Anal.
Calcd for C32H40Br2O6: C, 56.48; H, 5.98. Found: C,
56.48; H, 5.85.
3.1.13. Aldehyde ,31). The alcohol 30 /2.44 g, 4.63 mmol)
was dissolved in 46 mL of DMSO. To this solution was
added IBX /1.56 g, 5.56 mmol). After stirring at room
temperature for 12 h, the reaction was quenched with H2O
and ®ltered through a pad of Celite, washed thoroughly with
ether. The ®ltrate was extracted with ether /£2). The
extracts were dried over Na2SO4, and concentrated under
reduced pressure. Puri®cation of the residue with silica gel
column chromatography /ether/hexaneˆ30:70) gave the
aldehyde 31 /2.33 g, 96%). IR /KBr) nmax 2980, 2933,
2895, 1722, 1498, 1456, 1400, 1380, 1369, 1353, 1339,
3.1.15. Diol ,35). To a solution of the dibromoole®ne 32
/3.97 g, 5.83 mmol) in 50 mL of THF was added a solution
of n-BuLi /1.59 M in hexane, 8.81 mL, 14.0 mmol) at
2788C. After stirring for 15 min at 2788C, aldehyde 33
/1.59 g, 8.17 mmol) in 10 mL of THF was added and the
resulting mixture was stirred for 60 min at 278 to 08C. Then
the reaction mixture was poured into an ice-cold sat. NH4Cl
solution and extracted with ether. The combined extract was
washed with brine, dried over Na2SO4, and concentrated in
vacuo.
1
1218, 1139, 1097, 1047, 1028, 751, 696 cm21. H NMR
/CDCl3, 300 MHz) d 1.20 /3H, t, Jˆ7.0 Hz, ±OCH2CH3),
1.29 /3H, d, Jˆ5.5 Hz, ±OCH/O)CH3), 1.49, 1.60 /total 1H,
each q, Jˆ11.5 Hz, H-14a), 2.20±2.30 /1H, m, H-8a), 2.45±
2.62 /3H, m, H-8b, 14b, 17a), 2.81, 2.93 /total 1H, ddd,
Jˆ16.0, 4.0, 2.0 Hz; Jˆ16.0, 3.5, 1.5 Hz, H-17b), 3.10
/1H, ddd, Jˆ11.5, 9.5, 4.5 Hz, H-13), 3.22 /1H, t, Jˆ
9.0 Hz, H-12), 3.29 /1H, dd, Jˆ9.5, 8.5 Hz, H-10), 3.34±
To a solution of the above coupling product 34 in 50 mL of
MeOH was added Amberlyst-15E /300 mg). After stirring
for 2 h at room temperature, the reaction mixture was
®ltered through a pad of Celite, the resin was washed

K. Kira et al. / Tetrahedron 58 .2002) 1875±1888
1885
thoroughly with ethyl acetate. The ®ltrate was concentrated
in vacuo. The residue was puri®ed by silica gel column
chromatography /ether/hexaneˆ80:20) to give 35 /3.45 g,
92% in 2 steps). IR /KBr) nmax 3418, 3065, 3032, 2933,
2868, 1614, 1514, 1456, 1363, 1303, 1249, 1100, 1072,
3.1.17. Vinylsilane ,37). To a solution of the acetylene
cobalt complex 36 /589 mg, 0.746 mmol) in 75 mL of
C2H4Cl2 were added Et3SiH /2.38 mL, 14.9 mmol) and
propargyl alcohol /2.17 mL, 37.3 mmol). After stirring for
1 h at 608C, another Et3SiH /1.19 mL, 7.46 mmol) was
added. After stirring for additional 30 min at 608C, the reac-
tion mixture was ®ltered through Super-Cel and concen-
trated under reduced pressure. The residue was puri®ed by
silica gel column chromatography /ether/hexaneˆ40:60) to
1
1029, 915, 823, 752, 738, 699 cm21. H NMR /CDCl3,
300 MHz) d 1.48 /1H, q, Jˆ11.5 Hz, H-14a), 1.78±2.00
/2H, m, H-21a, 21b), 2.25 /1H, dt, Jˆ14.5, 7.5 Hz, H-8a),
2.36 /1H, dt, Jˆ11.5, 4.5 Hz, H-14b), 2.47±2.74 /3H, m,
H-8b, 17a, 17b), 3.02±3.28 /2H, m, H-12, 13), 3.15 /1H, td,
Jˆ8.5, 3.5 Hz, H-16), 3.28 /1H, dd, Jˆ9.5, 8.5 Hz, H-10),
3.35 /1H, ddd, Jˆ9.5, 7.5, 3.5 Hz, H-9), 3.43±3.76 /3H, m,
H-15, 22a, 22b), 3.59 /1H, t, Jˆ8.5 Hz, H-11), 3.78 /3H, s,
±OMe), 4.41 /1H, d, Jˆ2.0 Hz, ±OCH2C6H4OMe), 4.50
/1H, m, H-20), 4.60 /1H, d, Jˆ11.0 Hz, ±OCH2Ph), 4.75,
4.76 /total 1H, each d, Jˆ11.5 Hz, ±OCH2Php), 4.92 /1H,
d, Jˆ11.0 Hz, ±OCH2Ph), 5.02 /1H, d, Jˆ11.5 Hz,
±OCH2Php), 5.06 /1H, dm, Jˆ10.0 Hz, H-6a), 5.07 /1H,
dm, Jˆ17.0 Hz, H-6b), 5.87 /1H, dddd, Jˆ17.5, 10.5, 7.5,
6.5 Hz, H-7), 6.86 /2H, d, Jˆ9.0 Hz, aromatic), 7.21±7.40
/12H, m, aromatic). 13C NMR /CDCl3, 75 MHz) d 22.5,
36.0, 36.9, 38.1, 55.2, 61.4, 67.3, 68.9, 72.9, 73.3, 74.6,
75.2, 78.9, 79.8, 80.7, 81.7, 82.5, 82.6, 83.5, 113.9, 117.2,
127.6, 127.7, 127.9, 128.0, 128.3, 128.4, 129.3, 129.4,
129.9, 134.6, 138.3, 138.9, 159.3. Anal. Calcd for
C39H46O8: C, 72.87; H, 7.21. Found: C, 72.80; H, 7.17.
24
give the vinylsilane 37 /407 mg, 89%). [a]D ˆ1218 /c
0.57, CHCl3). IR /KBr) nmax 3484, 3067, 3032, 2953,
2908, 2874, 2053, 2028, 1456, 1362, 1327, 1074, 1029,
1
1003, 913, 733, 698 cm21. H NMR /CDCl3, 400 MHz) d
0.63 /6Hq, Jˆ7.5 Hz, ±SiCH2CH3), 0.95 /9H, t, Jˆ7.5 Hz,
±SiCH2CH3), 1.58 /1H, q, Jˆ11.5 Hz, H-14a), 1.83 /1H,
ddt, Jˆ14.5, 6.5, 4.0 Hz, H-21a), 1.95 /1H, dddd, Jˆ14.5,
9.5, 6.5, 4.5 Hz, H-21b), 2.25 /1H, dt, Jˆ14.5, 7.5 Hz,
H-8a), 2.37 /1H, dt, Jˆ11.5, 4.0 Hz, H-14b), 2.50±2.60
/2H, m, H-8b, 17a), 2.62 /1H, dd, Jˆ14.5, 3.0 Hz, H-17b),
2.98 /1H, ddd, Jˆ11.5, 8.5, 3.0 Hz, H-16), 3.12 /1H, t,
Jˆ8.5 Hz, H-12), 3.12±3.16 /1H, m, H-13), 3.28 /1H, dd,
Jˆ9.5, 8.5 Hz, H-10), 3.37 /1H, ddd, Jˆ9.5, 7.5, 3.0 Hz,
H-9), 3.51 /1H, ddd, Jˆ11.5, 8.5, 4.5 Hz, H-15), 3.60
/1H, t, Jˆ8.5 Hz, H-11), 3.78±3.82 /2H, m, H-22a, 22b),
4.24 /1H, ddd, Jˆ9.5, 4.5, 4.0 Hz, H-20), 4.62 /1H, d, Jˆ
11.0 Hz, ±OCH2Ph), 4.75 /1H, d, Jˆ11.5 Hz, ±OCH2Php),
4.93 /1H, d, Jˆ11.0 Hz, ±OCH2Ph), 4.95 /1H, d, Jˆ
11.5 Hz, ±OCH2Php), 5.05 /1H, dm, Jˆ10.5 Hz, H-6a),
5.07 /1H, dm, Jˆ17.5 Hz, H-6b), 5.86 /1H, dddd, Jˆ17.5,
10.5, 7.5, 6.5 Hz, H-7), 6.02 /1H, dd, Jˆ4.5, 2.5 Hz, H-19),
7.26±7.38 /10H, m, aromatic). 13C NMR /CDCl3, 75 MHz)
d 2.3, 7.4, 35.9, 36.5, 37.0, 37.9, 60.9, 73.9, 75.1, 75.2, 78.9,
80.9, 82.5, 82.9, 84.2, 117.1, 127.8, 128.0, 128.2, 128.4,
128.5, 134.6, 139.4, 138.8, 141.2, 145.9. Anal. Calcd for
C37H52O6Si: C, 71.57; H, 8.44. Found: C, 71.57; H, 8.58.
3.1.16. Cyclic acetylene cobalt complex ,36). To a solution
of the diol 35 /2.45 g, 3.81 mmol) in 40 mL of CH2Cl2 was
added a solution of Co2/CO)8 /1.96 g, 5.72 mmol) in 10 mL
of CH2Cl2. After stirring for 20 min at room temperature,
BF3´OEt2 /0.97 mL, 7.62 mmol) was added at 08C. After
stirring for 15 min at room temperature, the reaction
mixture was poured into an ice-cold sat. NaHCO3 solution
and extracted with CH2Cl2 /£3). The combined extract was
washed with brine, dried over Na2SO4, and concentrated in
vacuo. The residue was puri®ed by silica gel column
chromatography /ether/hexaneˆ40:60) to give 36 /2.36 g,
3.1.18. Methylketone ,46). To a solution of the alcohol 37
/3.35 g, 5.40 mmol) in 50 mL of DMF and 10 mL of H2O
were added PdCl2 /48 mg, 0.27 mmol) and CuCl /7.6 mg,
0.54 mmol). After stirring under O2 atmosphere for 48 h at
room temperature, the reaction mixture was poured into
an ice-cold H2O and extracted with CH2Cl2 /£3). The
combined extract was washed with brine, dried over
Na2SO4, and concentrated in vacuo. The residue was puri-
®ed by silica gel column chromatography /ether/hexaneˆ
80:20) to give the methylketone 46 /2.85 g, 83%).
27
78%) as a dark red oil. [a]D ˆ21978 /c 0.06, CHCl3). IR
/KBr) nmax 3066, 3032, 2935, 2876, 2094, 2053, 2025, 1456,
1433, 1095, 1071, 913, 735, 699, 519 cm21 1H NMR
.
/CDCl3, 400 MHz) d 1.61 /1H, q, Jˆ11.5 Hz, H-14a),
1.95 /1H, dddd, Jˆ14.5, 10.0, 7.0, 4.5 Hz, H-21a), 2.11
/1H, tdd, Jˆ10.5, 7.5, 4.0 Hz, H-21b), 2.26 /1H, dt, Jˆ
15.0, 7.5 Hz, H-8a), 2.45 /1H, ddd, Jˆ11.5, 5.5, 4.0 Hz,
H-14b), 2.57 /1H, dm, Jˆ14.5 Hz, H-8b), 2.89 /1H, dd,
Jˆ16.0, 10.5 Hz, H-17a), 3.08±3.16 /2H, m, H-12, 13),
3.30 /1H, dd, Jˆ9.5, 8.5 Hz, H-10), 3.35 /1H, ddd, Jˆ
10.5, 8.5, 4.5 Hz, H-16), 3.38 /1H, ddd, Jˆ9.5, 7.0,
3.0 Hz, H-9), 3.45±3.52 /1H, m, H-15), 3.51 /1H, dd,
Jˆ16.0, 4.5 Hz, H-17b), 3.58 /1H, t, Jˆ8.5 Hz, H-11),
3.85±3.95 /2H, m, H-22a, 22b), 4.63 /1H, d, Jˆ11.0 Hz,
±OCH2Ph), 4.69 /1H, dd, Jˆ10.0, 3.5 Hz, H-20), 4.80
/1H, d, Jˆ11.5 Hz, ±OCH2Php), 4.94 /1H, d, Jˆ11.0 Hz,
±OCH2Ph), 4.95 /1H, d, Jˆ11.5 Hz, ±OCH2Php), 5.06 /1H,
dm, Jˆ10.0 Hz, H-6a), 5.07 /1H, dm, Jˆ17.0 Hz, H-6b),
5.85 /1H, dddd, Jˆ17.5, 10.5, 7.5, 6.0 Hz, H-7), 7.26±
7.40 /10H, m, aromatic). 13C NMR /CDCl3, 100 MHz) d
36.0, 37.2, 38.7, 39.7, 60.8, 72.3, 74.9, 75.3, 77.7, 78.9,
80.8, 80.9, 81.3, 82.1, 84.2, 92.9, 101.1, 117.2, 127.5,
127.6, 127.8, 128.0, 128.3, 128.4, 134.5, 138.3, 139.0,
199.0, 199.3. ESI Q-TOF MS calcd for C37H36Co2O12Na
[M1Na]1 813.077, found 813.087.
24
[a]D ˆ17.78 /c 1.15, CHCl3). IR /KBr) nmax 3489, 2953,
2874, 1718, 1455, 1418, 1357, 1330, 1086, 733, 699 cm21
.
1H NMR /CDCl3, 300 MHz) d 0.63 /6H, q, Jˆ8.0 Hz,
±SiCH2CH3), 0.95 /9H, t, Jˆ8.0 Hz, ±SiCH2CH3), 1.52
/1H, q, Jˆ11.5 Hz, H-14a), 1.78±2.00 /2H, m, H-21a,
21b), 2.11 /3H, s, H-6), 2.34 /1H, dt, Jˆ11.5, 4.0 Hz,
H-14b), 2.48 /1H, dd, Jˆ16.0, 8.5 Hz, H-8a), 2.54±2.61
/2H, m, H-17a, 17b), 2.69 /1H, dd, Jˆ16.0, 3.0 Hz, H-8b),
2.97 /1H, dt, Jˆ3.0, 9.0 Hz, H-16), 3.12 /1H, t, Jˆ9.0 Hz,
H-12), 3.16±3.24 /1H, m, H-13), 3.24 /1H, t, Jˆ9.0 Hz,
H-10), 3.51 /1H, ddd, Jˆ11.5, 9.0, 4.0 Hz, H-15), 3.63
/1H, t, Jˆ8.5 Hz, H-11), 3.74±3.83 /3H, m, H-9, 22a,
22b), 4.24 /1H, dt, Jˆ9.5, 4.0 Hz, H-20), 4.59 /1H, d, Jˆ
11.0 Hz, ±OCH2Ph), 4.75 /1H, d, Jˆ10.5 Hz, ±OCH2Php),
4.93 /1H, d, Jˆ11.0 Hz, ±OCH2Ph), 4.96 /1H, d, Jˆ
10.5 Hz, ±OCH2Php), 6.02 /1H, dd, Jˆ4.0, 1.5 Hz, H-19),
7.25±7.40 /10H, m, aromatic). 13C NMR /CDCl3, 75 MHz)

1886
K. Kira et al. / Tetrahedron 58 .2002) 1875±1888
d 2.3, 7.3, 30.6, 36.5, 36.8, 37.9, 46.0, 60.7, 74.0, 75.1, 75.1,
75.2, 75.6, 80.7, 82.4, 82.7, 83.9, 127.8, 127.9, 128.1, 128.2,
128.4, 128.5, 138.1, 138.6, 141.1, 146.0, 206.5. Anal. Calcd
for C37H52O7Si: C, 69.78; H, 8.23. Found: C, 69.77; H, 8.23.
added 0.12 mL of DIBAL /1.0 M in toluene, 0.118 mmol)
at 2788C. After stirring for 1 h at 2788C, AcOEt was added
to the reaction mixture at 2788C, then poured into ice-cold
sat. NH4Cl solution and extracted with CH2Cl2 /£3). The
combined extract was dried over Na2SO4 and concentrated
under reduced pressure, which was used directly in the next
step without further puri®cation.
3.1.19. Iodolactone ,51). To a solution of the methylketone
46 /433 mg, 0.68 mmol) in 34 mL of acetone was added
Jones' reagent at 08C over 30 min until the color of reaction
mixture became to orange. The reaction mixture was treated
with 2-propanol and extracted with CH2Cl2 /£3). The
combined extract was concentrated under reduced pressure.
The residue was ®ltered through a silica gel short column to
give the carboxylic acid.
To a solution of the above lactol in 3.0 mL of THF was
added DBU /0.044 mL, 0.30 mmol) at 08C. After stirring
for 3 h at room temperature, the reaction mixture was
poured into ice-cold sat. NH4Cl solution and extracted
with ether /£3). The combined extract was dried over
Na2SO4 and concentrated under reduced pressure to give
64.0 mg of aldehyde 52, which was directly used in the
next step without further puri®cation. IR /KBr) nmax 3567,
3446, 2956, 2876, 1792, 1725, 1559, 1497, 1456, 1419,
The above carboxylic acid was dissolved in 66 mL of
CH2Cl2. To this solution was added I/collidine)2PF6
/514 mg, 1.00 mmol). After stirring at room temperature
for 2 h, the reaction was quenched with 1N HCl aq. and
extracted with CH2Cl2 /£2). The combined extract was
dried over Na2SO4, and concentrated under reduced
pressure. The residue was ®ltered through a silica gel
short column to give the iodolactone.
1
1363, 1333, 1103, 1074, 1028, 735, 700 cm21. H NMR
/CDCl3, 300 MHz) d 0.63 /6H, q, Jˆ7.5 Hz, ±SiCH2CH3),
1.00 /9H, t, Jˆ7.5 Hz, ±SiCH2CH3), 1.50 /1H, q, Jˆ
11.0 Hz, H-14a), 1.51 /3H, s, H-6), 1.72±1.88 /2H, m,
±SCH2CH2CH2S±), 1.80 /1H, dd, Jˆ15.0, 8.5 Hz, H-8a),
1.89 /1H, dd, Jˆ15.0, 10.5 Hz, H-17a), 2.26 /1H, dt, Jˆ11.5,
4.5 Hz, H-14b), 2.60±2.90 /4H, m, ±SCH2CH2CH2S±),
2.54 /1H, d, Jˆ15.0 Hz, H-8b), 2.61 /1H, dd, Jˆ15.0,
3.5 Hz, H-17b), 2.68 /1H, ddd, Jˆ16.0, 4.0, 1.5 Hz,
H-21a), 2.71 /1H, S, H-19), 2.91 /1H, ddd, Jˆ11.0, 9.0,
4.5 Hz, H-15), 3.00 /1H, ddd, Jˆ16.0, 9.0, 1.5 Hz,
H-21b), 3.02±3.10 /2H, m, H-12, 13), 3.23 /1H, dd, Jˆ
9.5, 8.5 Hz, H-10), 3.32 /1H, ddd, Jˆ10.5, 9.5, 3.5 Hz,
H-16), 3.54 /1H, t, Jˆ8.5 Hz, H-9), 3.58 /1H, t, Jˆ8.5 Hz,
H-11), 4.26 /1H, dd, Jˆ9.0, 4.0 Hz, H-20), 4.63 /1H,
d, Jˆ11.5 Hz, ±OCH2Ph), 4.76 /1H, d, Jˆ11.0 Hz,
±OCH2Php), 4.94 /1H, d, Jˆ11.0 Hz, ±OCH2Php), 5.00
/1H, d, Jˆ11.5 Hz, ±OCH2Ph), 7.26±7.39 /10H, m, aro-
matic), 9.82 /1H, t, Jˆ1.5 Hz, ±CHO). 13C NMR /CDCl3,
75 MHz) d 1.3, 7.2, 24.7, 26.0, 26.6, 28.6, 35.4, 36.3, 41.5,
48.3, 49.2, 53.5, 59.8, 71.9, 73.2, 75.0, 75.7, 76.9, 77.8,
79.9, 81.1, 81.7, 84.6, 127.7, 127.9, 128.1, 128.3, 128.4,
128.5, 138.3, 138.9, 200.3.
To a solution of the above ketone in 12 mL of CH2Cl2 were
added ethanedithiol /161 mL, 1.61 mmol) and Zn/OTf)2
/389 mg, 1.07 mmol). After stirring for 2 h at room
temperature, the reaction mixture was poured into an ice-
cold sat. NaHCO3 solution. The resulting mixture was
extracted with CH2Cl2 /£2). The combined extract was
washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The residue was puri®ed by silica
gel column chromatography /ether/hexaneˆ50:50) to give
24
51 /392 mg, 67% in 3 steps). [a]D ˆ15.88 /c 0.11, CHCl3).
IR /KBr) nmax 3447, 2953, 2911, 2876, 1793, 1456, 1418,
1374, 1340, 1209, 1159, 1144, 1097, 1074, 1010, 904, 733,
1
699 cm21. H NMR /CDCl3, 400 MHz) d 0.93 /6H, q, Jˆ
7.5 Hz, ±SiCH2CH3), 1.08 /9H, t, Jˆ8.0 Hz, ±SiCH2CH3),
1.50 /1H, q, Jˆ11.0 Hz, H-14a), 1.51 /3H, s, H-6), 1.72±
1.88 /2H, m, ±SCH2CH2CH2S±), 1.79 /1H, dd, Jˆ15.0,
8.5 Hz, H-8a), 2.35 /1H, dt, Jˆ11.0, 4.5 Hz, H-14b), 2.41
/1H, dd, Jˆ16.0, 2.5 Hz, H-17a), 2.46 /1H, ddd, Jˆ14.5,
5.5, 3.5 Hz, ±SCH2CH2CH2S±), 2.54 /1H, d, Jˆ15.0 Hz,
H-8b), 2.56 /1H, d, Jˆ17.5 Hz, H-21a), 2.58 /1H, ddd,
Jˆ14.5, 5.5, 3.5 Hz, ±SCH2CH2CH2S±), 2.67 /1H, ddd,
Jˆ14.5, 11.5, 3.0 Hz, ±SCH2CH2CH2S±), 2.73 /1H, dd,
Jˆ17.5, 5.0 Hz, H-21b), 2.78 /1H, ddd, Jˆ14.5, 11.0,
3.0 Hz, ±SCH2CH2CH2S±), 2.97 /1H, dd, Jˆ16.0, 7.5 Hz,
H-17b), 3.10 /1H, t, Jˆ8.5 Hz, H-12), 3.15 /1H, ddd,
Jˆ11.0, 9.0, 4.0 Hz, H-13), 3.23 /1H, dd, Jˆ9.5, 8.5 Hz,
H-10), 3.55±3.60 /1H, m, H-9, 16), 3.67 /1H, t, Jˆ8.5 Hz,
H-11), 4.49 /1H, ddd, Jˆ11.5, 9.5, 4.0 Hz, H-15), 4.63 /1H,
d, Jˆ11.5 Hz, ±OCH2Ph), 4.69 /1H, d, Jˆ2.5 Hz, H-19),
4.71 /1H, dd, Jˆ5.0, 2.5 Hz, H-20), 4.81 /1H, d, Jˆ11.5 Hz,
±OCH2Php), 4.98 /1H, d, Jˆ11.5 Hz, ±OCH2Ph), 5.03 /1H,
d, Jˆ11.5 Hz, ±OCH2Php), 7.26±7.39 /10H, m, aromatic).
13C NMR /CDCl3, 100 MHz) d 4.8, 8.3, 24.8, 26.0, 26.7,
28.8, 35.8, 35.9, 37.1, 38.6, 41.6, 48.4, 73.9, 74.5, 74.9,
75.6, 78.2, 79.2, 81.1, 81.5, 83.2, 84.1, 89.7, 127.6, 127.8,
128.1, 128.4, 128.4, 138.4, 138.7, 174.2. Anal. Calcd for
C40H55O7S2Si: C, 55.41; H, 6.39. Found: C, 55.42; H, 6.52.
3.1.21. Epoxysilane±acetylene ,53). To a solution of the
aldehyde 52 /37 mg, 50.0 mmol) and K2CO3 /28 mg,
0.199 mmol) in 2.5 mL of dry MeOH was added
dimethyl-1-diazo-2-oxopropyl phosphonate /29 mg, 0.15
mmol) in 0.5 mL of MeOH at room temperature. After
stirring for 9 h at room temperature, the reaction mixture
was diluted with ether and poured into an ice-cold sat.
NaHCO3 solution and extracted with ether /£3). The
combined extract was washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. Puri®ca-
tion of the residue with silica gel column chromatography
/ether/hexaneˆ30:70) gave the acetylene 53 /27.5 mg, 73%
27
in 3 steps). [a]D ˆ2318 /c 0.21, CHCl3). IR /KBr) nmax
2952, 2911, 2876, 1734, 1456, 1418, 1335, 1103, 1073,
1
1014, 913, 736, 698 cm21. H NMR /CDCl3, 400 MHz) d
0.63 /6H, q, Jˆ8.0 Hz, ±SiCH2CH3), 1.00 /9H, t, Jˆ8.0 Hz,
±SiCH2CH3), 1.51 /3H, s, H-6), 1.52 /1H, q, Jˆ11.0 Hz,
H-14a), 1.72±1.88 /2H, m, ±SCH2CH2CH2S±), 1.81 /1H,
dd, Jˆ14.5, 8.5 Hz, H-8a), 1.87 /1H, dd, Jˆ15.0, 10.5 Hz,
H-17a), 2.05 /1H, t, Jˆ2.5 Hz, H-23), 2.31 /1H,
ddd, Jˆ11.0, 4.5, 4.0 Hz, H-14b), 2.44±2.68 /2H, m,
±SCH2CH2CH2S±), 2.54 /1H, d, Jˆ14.5 Hz, H-8b), 2.59
3.1.20. Epoxysilane-aldehyde ,52). To a solution of the
lactone 51 /85 mg, 98.0 mmol) in 3.0 mL of CH2Cl2 was

K. Kira et al. / Tetrahedron 58 .2002) 1875±1888
1887
/1H, dd, Jˆ15.0, 3.5 Hz, H-17b), 2.59 /1H, ddd, Jˆ16.5,
8.5, 2.5 Hz, H-21a), 2.66 /1H, ddd, Jˆ16.5, 6.5,
2.5 Hz, H-21b), 2.69 /1H, ddd, Jˆ14.5, 11.5, 3.0 Hz,
±SCH2CH2CH2S±), 2.80 /1H, ddd, Jˆ14.5, 11.5, 3.0 Hz,
±SCH2CH2CH2S±), 2.87 /1H, ddd, Jˆ11.0, 9.0, 4.5 Hz,
H-15), 3.03 /1H, ddd, Jˆ11.0, 9.0, 4.0 Hz, H-13), 3.05
/1H, S, H-19), 3.07 /1H, t, Jˆ9.0 Hz, H-12), 3.23 /1H, dd,
Jˆ9.5, 8.5 Hz, H-10), 3.33 /1H, ddd, Jˆ10.5, 9.0, 3.5 Hz,
H-16), 3.54 /1H, dd, Jˆ9.5, 8.5 Hz, H-9), 3.58 /1H, t,
Jˆ8.5 Hz, H-11), 3.80 /1H, dd, Jˆ8.5, 6.5 Hz, H-20),
4.63 /1H, d, Jˆ11.0 Hz, ±OCH2Ph), 4.76 /1H, d, Jˆ
11.0 Hz, ±OCH2Php), 4.94 /1H, d, Jˆ11.0 Hz, ±OCH2Php),
5.00 /1H, d, Jˆ11.5 Hz, ±OCH2Ph), 7.26±7.39 /10H, m,
aromatic). 13C NMR /CDCl3, 100 MHz) d 1.4, 7.4, 24.8,
25.9, 26.1, 26.7, 28.7, 35.5, 36.4, 41.6, 48.4, 53.0, 58.5,
70.4, 73.4, 75.0, 75.3, 75.7, 77.2, 77.8, 80.0, 80.6, 81.2,
81.8, 84.7, 127.7, 127.8, 128.1, 128.2, 128.4, 128.5, 138.4,
138.9. Anal. Calcd for C41H56O6S2Si: C, 66.81; H, 7.66.
Found: C, 66.71; H, 7.87.
washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The residue was ®ltered through a
silica gel short column to give the p-nitrobenzoate.
To a solution of the above p-nitrobenzoate in 1.6 mL of
MeOH was added K2CO3 /4.4 mg, 32.0 mmol). After
stirring for 30 min at room temperature, the reaction
mixture was poured into an ice-cold sat. NH4Cl solution.
The resulting mixture was extracted with CH2Cl2 /£2). The
extracts were dried over Na2SO4, and concentrated under
reduced pressure. Puri®cation of the residue with silica gel
column chromatography /ether/hexaneˆ20:80) gave the
23
BCD-ring 55 /18.7 mg, 94% in 2 steps). [a]D ˆ2348 /c
0.17, CHCl3). IR /KBr) nmax 3449, 3297, 3031, 2883, 1455,
1423, 1368, 1333, 1276, 1101, 1064, 911, 737, 699,
645 cm21 1H NMR /400 MHz, CDCl3) d 1.52 /3H, s,
.
H-6), 1.59 /1H, q, Jˆ11.5 Hz, H-14a), 1.81 /1H, dd, Jˆ
15.0, 8.5 Hz, H-8a), 1.72±1.90 /2H, m, ±SCH2CH2CH2S±
), 2.04 /1H, t, Jˆ3.0 Hz, H-23), 2.35 /1H, dt, Jˆ11.5,
4.5 Hz, H-14b), 2.53 /1H, ddd, Jˆ17.0, 6.5, 3.0 Hz,
H-21a), 2.55 /1H, d, Jˆ15.0 Hz, H-8b), 2.65 /1H, ddd,
Jˆ17.0, 3.5, 3.0 Hz, H-21b), 2.45±2.83 /4H, m,
±SCH2CH2CH2S±), 3.10 /1H, ddd, Jˆ11.5, 9.0, 4.5 Hz,
H-13), 3.13 /1H, dd, Jˆ9.0, 8.5 Hz, H-12), 3.25 /1H, dd,
Jˆ9.5, 8.5 Hz, H-10), 3.34 /1H, ddd, Jˆ11.0, 9.0, 4.5 Hz,
H-15), 3.48 /1H, ddd, Jˆ9.0, 6.5, 3.5 Hz, H-20), 3.57 /1H,
ddm, Jˆ9.5, 8.5 Hz, H-9), 3.64 /1H, t, Jˆ8.5 Hz, H-11),
3.88 /1H, ddd, Jˆ9.0, 3.0, 1.5 Hz, H-16), 4.32 /1H, dbr,
Jˆ9.0 Hz, H-19), 4.61 /1H, d, Jˆ11.5 Hz, ±OCH2Ph),
4.77 /1H, d, Jˆ11.0 Hz, ±OCH2Php), 4.99 /1H, d, Jˆ
11.0 Hz, ±OCH2Php), 5.00 /1H, d, Jˆ11.5 Hz, ±OCH2Ph),
5.67 /1H, dd, Jˆ12.5, 1.5 Hz, H-18), 5.71 /1H, dd, Jˆ12.5,
1.5 Hz, H-17), 7.26±7.38 /10H, m, aromatic). 13C NMR
/CDCl3, 100 MHz) d 23.7, 24.8, 26.1, 26.7, 28.8, 36.7,
41.7, 48.3, 70.3, 73.1, 73.2, 75.1, 75.7, 77.9, 78.8, 80.3,
80.8, 81.2, 82.2, 82.6, 84.4, 127.6, 127.8, 128.0, 128.2,
128.4, 128.4, 131.5, 133.9, 138.3, 138.8. Anal. Calcd for
C35H42O6S2: C, 67.49; H, 6.80. Found: C, 67.52; H, 6.64.
3.1.22. Allylic alcohol ,54). To a solution of the epoxy-
silane 53 /20 mg, 27.1 mmol) in 2.7 mL of CH2Cl2 was
added BF3´OEt2 /0.20 M in C2H4Cl2, 0.069 mL,
54.3 mmol). After stirring for 30 min at room temperature,
the reaction mixture was poured into an ice-cold sat.
NaHCO2 solution. The resulting mixture was extracted
with CH2Cl2 /£2). The combined extract was washed with
brine, dried over Na2SO4, and concentrated under reduced
pressure. The crude residue was puri®ed by silica gel
column chromatography /ether/hexaneˆ50:50) to give the
26
allyl alcohol 54 /13.5 mg, 80%). [a]D ˆ2328 /c 0.12,
CHCl3). IR /KBr) nmax 3444, 3292, 3029, 2924, 1457,
1
1375, 1101, 1086, 1074, 1060, 1028, 737, 699 cm21. H
NMR /300 MHz, CDCl3) d 1.53 /3H, s, H-6), 1.61 /1H, q,
Jˆ11.5 Hz, H-14a), 1.81 /1H, dd, Jˆ15.0, 8.5 Hz, H-8a),
1.72±1.90 /2H, m, ±SCH2CH2CH2S±), 2.02 /1H, t,
Jˆ2.5 Hz, H-23), 2.38 /1H, dt, Jˆ11.5, 4.5 Hz, H-14b),
2.53 /2H, dd, Jˆ7.0, 2.5 Hz, H-21a, 21b), 2.56 /1H, d,
Jˆ15.0 Hz, H-8b), 2.45±2.83 /4H, m, ±SCH2CH2CH2S±),
3.10 /1H, ddd, Jˆ11.0, 9.0, 4.5 Hz, H-13), 3.15 /1H, t,
Jˆ9.0 Hz, H-12), 3.26 /1H, dd, Jˆ9.5, 8.5 Hz, H-10),
3.40 /1H, ddd, Jˆ11.0, 9.0, 4.5 Hz, H-15), 3.58 /1H, ddbr,
Jˆ9.5, 8.5 Hz, H-9), 3.65 /1H, t, Jˆ8.5 Hz, H-11), 3.77
/1H, t, Jˆ7.0 Hz, H-20), 4.02 /1H, ddd, Jˆ9.5, 2.5,
1.5 Hz, H-16), 4.10 /1H, dbr, Jˆ7.5 Hz, H-19), 4.63
/1H, d, Jˆ11.5 Hz, ±OCH2Ph), 4.77 /1H, d, Jˆ11.0 Hz,
±OCH2Php), 4.98 /1H, d, Jˆ11.5 Hz, ±OCH2Ph), 5.02
/1H, d, Jˆ11.0 Hz, ±OCH2Php), 5.81 /1H, dd, Jˆ12.5,
1.5 Hz, H-17), 5.71 /1H, ddd, Jˆ12.5, 7.5, 2.5 Hz, H-18),
7.26±7.38 /10H, m, aromatic). 13C NMR /CDCl3,
100 MHz) d 23.0, 24.7, 25.9, 26.6, 28.7, 36.7, 41.5, 48.3,
68.2, 70.0, 73.0, 75.1, 75.7, 77.9, 79.0, 80.2, 80.8, 81.1,
82.2, 82.3, 84.4, 127.7, 127.9, 128.0, 128.3, 128.4, 128.5,
129.0, 135.8, 138.3, 138.7. Anal. Calcd for C35H42O6S2: C,
67.49; H, 6.80. Found: C, 67.22; H, 6.90.
Acknowledgements
We are grateful to Mr Kitamura /analytical laboratory in this
school) for elemental analyses. This work was supported by
JSPS-RFTF, Grant-In-Aid for Scienti®c Research, and
JSPS-DC fellowship.
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