Convergent synthesis of the ABCDE ring system of ciguatoxin CTX3C

Article abstract of DOI:10.1016/S0040-4020(02)00041-8

Ciguatoxin CTX3C is a representative congener of the ciguatoxins, which are known to be the principal causative-agents of ciguatera seafood poisoning. The structure of CTX3C spans over three nanometers and is characterized by thirteen ether rings. To attain a practical construction of this molecule, efficient supplies of the structural fragments are crucial. Herein we report the convergent synthesis of the ABCDE ring fragment featuring (i) alkylative coupling of the AB ring and E ring, and (ii) ring-closing olefin metathesis.

Full text of DOI:10.1016/S0040-4020(02)00041-8

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 1835±1851
Convergent synthesis of the ABCDE ring system of
ciguatoxin CTX3C
²
Megumi Maruyama, Masayuki Inoue, Tohru Oishi, Hiroki Oguri, Yoshihiro Ogasawara,
Yumi Shindo and Masahiro Hiramap
Department of Chemistry, Graduate School of Science, Tohoku University, and CREST, Japan Science and Technology Corporation (JST),
Sendai 980-8578, Japan
Received 27 September 2001; accepted 27 October 2001
AbstractÐCiguatoxin CTX3C is a representative congener of the ciguatoxins, which are known to be the principal causative-agents of
ciguatera seafood poisoning. The structure of CTX3C spans over three nanometers and is characterized by thirteen ether rings. To attain a
practical construction of this molecule, ef®cient supplies of the structural fragments are crucial. Herein we report the convergent synthesis of
the ABCDE ring fragment featuring (i) alkylative coupling of the AB ring and E ring, and (ii) ring-closing ole®n metathesis. q 2002 Elsevier
Science Ltd. All rights reserved.
1. Introduction
¯exible and convergent synthetic route to construct the
highly complex polycyclic structure, in which the ®nal
stage of the total synthesis would involve the coupling of
ABCDE ring fragment 3 and HIJKLM ring fragment 411
with the simultaneous construction of the central FG ring
system.8f,10 In this full account, we report an ef®cient and
improved synthesis of the left wing 3, which can be utilized
not only for the total synthesis, but also for the preparation
of anti-ciguatoxin antibodies.12
Ciguatera is a major human poisoning that is caused by the
consumption of tropical and subtropical ®sh, and is
estimated to affect more than 20,000 persons annually.1
The symptoms of ciguatera are manifested in a combination
of gastrointestinal, neurological, and cardiovascular
disturbances, which can persist for months or even years.
The causative toxins, such as ciguatoxin (1)2 and CTX3C
(2),3 are produced by marine dino¯agellate Gambierdiscus
toxicus living on macro algae, and are accumulated in ®sh
through the food chain (Scheme 1).4,5 Since ciguateric ®sh
look, taste, and smell normal, immunochemical methods for
detecting ciguatoxins prior to consumption have been
highly desirable for a long time.6 Biological studies have
revealed that ciguatoxins exert their toxicity through the
activation of voltage-sensitive sodium channels (VSSC).7
In order to prepare anti-ciguatoxin antibodies and to study
the detailed biological pro®les of these ciguatoxins, chemi-
cal synthesis has been the only plausible solution due to the
extremely low concentrations of the toxins in ®sh,8,9 and
therefore we have undertaken the total synthesis of
CTX3C (2).10
2. Results and discussions
2.1. Synthesis of AB ring and E ring
Retrosynthetically, ABCDE ring fragment 3 was dissected
into two parts, AB ring 5 and E ring 6, which could be
assembled by alkylative coupling/ring-closing ole®n
metathesis strategy (RCM)13,14 (Scheme 1).15 We
envisioned that the medium-sized ring ethers in structural
fragments 5 and 6 could be constructed using RCM from
acyclic substrates, in which the stereocenters could originate
from those of d-glucose.
As shown in Scheme 2, the synthesis of 5 was started from
Kishi's intermediate 7.16 The C6-secondary alcohol of 7 was
selectively deprotected using Nicotra's two-step protocol
(I2; Zn, AcOH, 70%) to afford 8,17 which was then
converted to allyl ether 9 in 83% yield. RCM reaction of
9 using Grubbs catalyst13c ef®ciently constructed the
bicyclic AB ring system of 10 (97% yield).12,18 The three
benzyl groups of 10 were removed under carefully controlled
Birch conditions (Na, NH3, EtOH), and the resulting 1,3-
diol portion was protected as a p-methoxybenzylidene
The structures of ciguatoxins are characterized by 12 fused
six- to nine-membered cyclic ethers, together with a spirally
attached ®ve-membered ketal (Scheme 1). We planned a
Keywords: alkylative coupling; ring-closing ole®n metathesis; CTX3C;
polyether; ciguatoxin.
p
Corresponding author. Tel.: 181-22-217-6563; fax: 181-22-217-6566;
e-mail: hirama@ykbsc.chem.tohoku.ac.jp
Present address: Department of Chemistry, Graduate School of Science,
Osaka University, Osaka 560-0043, Japan.
²
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00041-8

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M. Maruyama et al. / Tetrahedron 58 (2002)1835±1851
Scheme 1. Structure of ciguatoxins and synthetic strategy for the total synthesis of CTX3C. Bnˆbenzyl; BOMˆbenzyloxy methyl; MPˆp-methoxyphenyl;
MPMˆp-methoxybenzyl; RCMˆring closing ole®n metathesis; TIPDSˆtetraisopropyl disiloxyl.
acetal to afford 11 in 59% yield (two steps) after a single
recrystalization. In the Birch reduction step, partial cleavage
of the allylic ether was observed, and the byproduct was
puri®ed and characterized after protecting of 14 as the
benzyl ether (15, 21% yield from 10). Subsequent benzyl-
ation of the secondary alcohol of 11 led to 12 in 84% yield.
Finally, the p-methoxybenzylidene acetal of 12 was regio-
selectively cleaved by DIBALH to furnish primary alcohol
13 (82% yield),19 which was converted to the desired AB
ring iodide 5 by a reagent combination of I2, PPh3, and
imidazole in 82% yield.20
As summarized in Scheme 3, construction of the E ring
started with the oxidative cleavage of the protected deriva-
tive of d-glucose 16,21 followed by Wittig reaction to
produce ole®n 17 in 72% yield (two steps). Treatment of
17 with t-butyl bromoacetate under basic conditions gave 18
in 99% yield. Subsequent aldol condensation of ester
enolate of 18 with 3-butenal22 furnished diene 19 as an
inseparable mixture of three diastereomers (91%, combined
yield).23 This mixture was subjected to RCM conditions
using Grubbs catalyst,13c to smoothly yield the eight-
membered cyclic ethers 20±22 in 28, 38, and, 19% yields,
respectively. The stereochemistries of these compounds
Scheme 2. Reagents and conditions: (a) I2, CH2Cl2; (b) Zn, AcOH±Et2O±
were assigned from their coupling constants and NOEs, as
shown in Scheme 3. The low yield of isomer 20, which has
the correct con®guration, was not problematic since all
isomers (20±22) were readily converted to common inter-
mediate 25, which was used for further synthetic operations.
The secondary alcohol of 20 was protected as a TBS ether,
MeOH, 70% (two steps); (c) allyl bromide, KH, THF, 08C, 83%;
(d) (PCy3)2Cl2RuvCHPh (1 mol%), CH2Cl2, rt, 97%; (e) Na, NH3,
THF±EtOH, 2788C; (f) p-methoxybenzylaldehyde dimethylacetal,
p-TsOH, DMF, rt, 59%; (g) BnBr, NaH, THF±DMF, 08C to rt, 84%;
(h) DIBALH, CH2Cl2, 278 to 2208C, 82%; (i) I2, PPh3, imidazole, toluene,
82%. Cyˆcyclohexyl; Bnˆbenzyl; MPˆp-methoxyphenyl; MPMˆp-
methoxybenzyl.

M. Maruyama et al. / Tetrahedron 58 (2002)1835±1851
1837
Scheme 3. Reagents and conditions: (a) NaIO4, MeOH; (b) Ph3PMeBr, KOt-Bu, THF, 72% (two steps); (c) t-butyl bromoacetate, NaH, THF±DMF, 99%;
(d) LDA, then CHvCH2CH2CHO, THF, 2788C, 91%; (e) (PCy3)2Cl2RuvCHPh (7 mol%), CH2Cl2, re¯ux, 2 days, total yield 85%; (f) TBSCl, imidazole,
DMF, 93%; (g) DIBALH, 278 to 2508C; (h) Ph3PMeBr, KOt-Bu, THF, 53% (two steps); (i) LiAlH4, Et2O, 95% from 21, 95% from 22; (j) TBDPSCl, Et3N,
DMAP, CH2Cl2, 87% from 21, 85% from 22; (k) Dess±Martin periodinane, CH2Cl2, 88% (24), 83% (23); (l) imidazole (5 equiv.), toluene, 708C, 1 day, 100%;
(m) TBAF, AcOH, THF, 64%; (n) NaBH(OAc)3, AcOH, MeCN, 93%; (o) TBSCl, imidazole, DMF, 98%; (p) neutral alumina, H2O, hexane, 81%; (q) Dess±
Martin periodinane, CH2Cl2; (r) Ph3PMeBr, KOt-Bu, THF, 85% (two steps); (s) TBAF, THF, 99%; (t) t-butyl bromoacetate, NaH, THF±DMF, 75%.
Cyˆcyclohexyl; DIBALHˆdiisobutylaluminum hydride; DMAPˆ4-(dimethylamino)pyridine; DMFˆN,N-dimethylformamide; TBAFˆtetrabutyl-
ammonium ¯uoride; TBDPSˆt-butyldiphenylsilyl; TBSˆt-butyldimethylsilyl.
and subsequent reduction of the ester to the aldehyde,
followed by Wittig ole®nation, furnished 25. Ketones 23
and 24 were prepared from 22 and 21, respectively, via a
three step procedure: (i) LiAlH4 reduction, (ii) TBDPS
protection, and (iii) Dess±Martin oxidation.24 Subjecting
ketone 23 to heat (1108C) in toluene with imidazole
provided 24 in a quantitative yield via C15-epimerization.25
It is worth noting that isomerization of the b,d-unsaturated
ketones (23,24) to the a,b-unsaturated ketones were not
observed presumably due to the intrinsic ring strain of the
transfused eight-membered ring. Following deprotection of
the TBDPS group of 24, stereoselective reduction26 of the
ketone using NaBH(OAc)3 completed the stereochemical
adjustment to produce a diol, which was converted to ole®n
25 via standard synthetic manipulations. In preparation for
the coupling reaction, glycolic acid ester was introduced
after the removal of TBS, leading to the appropriately
functionalized E ring 6 in 75% yield (two steps).12
C11Sˆ6:1) in favor of the undesired stereoisomer. In effort
to improve the stereoselectivity of this alkylation, we
screened the reaction conditions as well as the substrates.
However, satisfactory results were not obtained; for
instance, attachment of a chiral auxiliary to the glycolate
portion completely retarded the alkylation reaction.27 Thus,
to obtain suf®cient amount of the correct stereoisomer,
epimerization of C-11 was deemed necessary. Acid-
catalyzed removal of the p-methoxy benzyl acetal of 26,
followed by TIPDS protection and MPM deprotection,
produced secondary alcohol 28, which was converted to
the corresponding lactone 29 by the action of a catalytic
amount of CSA (29-R/29-Sˆ6:1). After considerable
experimentation, this mixture of stereoisomers of 29
(R/Sˆ6:1) was found to undergo epimerization, upon treat-
ment with imidazole in toluene at 1108C,25 resulting in an
increased amount of 29-S (R/Sˆ1.8:1). However, the
separation of these isomers was not trivial. At the tens of
milligram scale (approx. 50 mg trials), the desired 29-S was
isolated using preparative TLC in 24% yield, whereas the
undesired 29-R was recovered in 48% yield. The instability
of the lactones on preparative TLC complicated the
problem, especially with large-scale operations. Typically,
scale-up of the preparative TLC separation (approx.
300 mg) resulted in a lower yield [29-R (14%) and 29-S
(7%)], and the carboxylic acid was obtained due to hydro-
lysis of 29 on the silica plate. Although this problem was not
solved at this stage (vide supra), we decided to proceed with
the synthesis of the ABCDE ring fragment. Lactone 29-S
2.2. Synthesis of ABCDE ring fragment12
Following the syntheses of AB ring 5 and E ring 6, we
focused our attention to the coupling of these fragments
and the subsequent construction of the CD ring system
(Scheme 4). The coupling of the fragments was carried
out by the attack of the lithium enolate of 6, which was
generated by treatment with LDA in THF±HMPA, on
iodide 5 at 2788C to give alkylated adduct 26 in 51%
yield as an inseparable mixture of epimers (C11R/

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M. Maruyama et al. / Tetrahedron 58 (2002)1835±1851
Scheme 4. Reagents and conditions: (a) LDA, THF±HMPA, then 5, 2788C, 51%; (b) PPTS, MeOH, 83%; (c) 1,3-dichlorotetraisopropyldisiloxane, pyridine,
92%; (d) DDQ, CH2Cl2, 76%; (e) CSA, toluene, 708C, 82%; (f) imidazole, toluene, 1108C, 48% (29-R), 24% (29-S); (g) vinylmagnesium bromide, Et2O,
2788C, 78%; (h) CH(OMe)3, CSA, CH2Cl2, 86%; (i) Et3SiH, BF3´Et2O, 2508C, 87%; (j) TBAF, THF; (k) Ac2O, py, 82% (two steps); (l) (PCy3)2Cl2-
RuvCHPh (2.8 mol equiv.), CDCl3, 458C, 98%. CSAˆ10-camphorsulfonic acid; Cyˆcyclohexyl; DDQˆ2,3-dichloro-5,6-dicyano-1,4-benzoquinone;
HMPAˆhexamethylphosphoric triamide; PPTSˆpyridinium p-toluenesulfonate; TBAFˆtetrabutylammonium ¯uoride; TIPDSˆtetraisopropyldisiloxyl.
was converted to diene 32, a potential RCM substrate in
three steps: (i) addition of vinylmagnesium bromide, (ii)
conversion of the resulting hemiacetal 30 to the methyl
acetal 31, and (iii) reduction of the acetal using Et3SiH in
the presence of BF3´OEt2.8d,16,28 Ring-closure to the seven-
membered D ring from diene 32 using Grubbs catalyst13c did
not proceed, with only the recovery of the starting material.
We suspected that the bulky TIPDS group might be attribut-
able to the inertness of 32 toward RCM, and to test this
possibility, the TIPDS group of 32 was converted to
diacetate 33 in 82% yield (two steps). By treating 33 with
Grubbs reagent,13c the cyclization proceeded smoothly and
selectively, despite the presence of potentially reactive
ole®ns in rings A and E, to produce the ABCDE ring frag-
ment 34 of CTX3C in excellent yield (98%). The structure
of the product is supported by the indicated NOEs and the
coupling constant (J11,12ˆ9.2 Hz). Although this synthetic
route demonstrated the effectiveness of our alkylation/RCM
sequence15 within a complex chemical context, the supply
of 34 in multi-gram quantities remained to be overcome.
avoiding the chemically unstable lactone intermediate (29)
seemed reasonable, and therefore we modi®ed our synthetic
route with a change in the order of construction of the CD
ring system (from C!D to D!C, Scheme 5). The dia-
stereomeric mixture of ester 27 (R/Sˆ6:1) was reduced to
the aldehyde in 89% yield (35-R/35-Sˆ6:1). Epimerization
of the aldehyde with the use of imidazole in toluene at
1108C gave an inseparable 3:1 mixture of 35-R and
35-S,25 which was reacted with vinyl lithium at 2788C to
afford 36 as a mixture of four diastereomers in 94% yield.
RCM reaction13 of 36 gave a mixture of four diastereomeric
cyclized products, from which desired diastereomer 37 was
chromatographically isolated in 30% yield, along with the
remaining three diastereomers (collectively 38) in 66%
yield. The structure of 37 was unambiguously determined
1
by H±1H coupling constant (J11,12ˆ8.8 Hz) and NOEs, as
indicated in Scheme 5. Compound 37 was oxidized using
Swern conditions to give enone 39-S. On the other hand, the
diastereomers 38 were subjected to an oxidation/thermo-
dynamic-isomerization sequence to produce a 1:4 mixture
of ketones 39-R and 39-S, which were chemically stable and
chromatographically separable. Formation of the desired
39-S as the major isomer in the basic treatment was
particularly favorable for our synthetic operation. Final
2.3. Modi®cation of the construction of CD ring system
For the practical synthesis of the ABCDE ring fragment,

M. Maruyama et al. / Tetrahedron 58 (2002)1835±1851
1839
Scheme 5. Reagents and conditions: (a) DIBALH, CH2Cl2, 278 to 2608C, 89%; (b) imidazole, toluene, 1008C, 99%; (c) tetravinyltin, MeLi, Et2O, 2788C,
94%; (d) (PCy3)2Cl2RuvCHPh (7 mol%), CH2Cl2, 358C, 2.5 h, total yield 96%; (e) (COCl)2, DMSO, Et3N, 278 to 2358C, 78%; (f) (COCl)2, DMSO, Et3N,
278 to 2358C, 88%; (g) DBU, toluene, 958C, 14 h, 95% (39-R/39-Sˆ1: 4); (h) DDQ, CH2Cl2, 94%; (i) CSA, CH(OMe)3, CH2Cl2, 64%; (j) Et3SiH, BF3´Et2O,
CH2Cl2, 278 to 2308C, 98%. CSAˆcamphorsulfonic acid; Cyˆcyclohexyl; DBUˆ1,8-diazabicyclo[5.4.0]undec-7-ene; DDQˆ2,3-dichloro-5,6-dicyano-
1,4-benzoquinone; DIBALHˆdiisobutylaluminum hydride; DMSOˆdimethyl sulfoxide; TIPDSˆtetraisopropyldisiloxyl.
construction of ring C was achieved in three steps: (i)
removal of the MPM group in 39-S using DDQ (94%
yield), (ii) conversion of 40 to the methyl ketal 41 under
acidic conditions in 64% yield, and (iii) Lewis acid-
mediated reductive etheri®cation of 41 to afford ABCDE
ring fragment 3 in 98% yield.8d,16 This synthetic route is
superior to the initial route in terms of yield, ef®ciency,
and applicability to large-scale operations (typical overall
yield from 27: initial route, 11% vs modi®ed route, 25%).
4. Experimental
All reactions sensitive to air or moisture were carried out
under argon or nitrogen atmosphere in dry, freshly distilled
solvents under anhydrous conditions, unless otherwise
noted. Diethyl ether (Et2O) and THF were distilled from
sodium/benzophenone, acetonitrile, benzene, dichloro-
methane (CH2Cl2), diisopropylamine, pyridine, triethyl-
amine, and toluene from calcium hydride, and DMF,
DMSO, HMPA and DMPU from calcium hydride under
reduced pressure. All other reagents were used as supplied
unless otherwise stated.
3. Conclusion
We have achieved an ef®cient construction of the ABCDE
ring system of CTX3C by coupling AB ring 5 and E ring 6,
both of which were prepared from d-glucose. It is particu-
larly noteworthy that all the medium-sized ring ethers of 3
were constructed through a RCM reaction. The results
described herein demonstrate the ef®ciency and applic-
ability of our alkylative coupling/RCM strategy for the
synthesis of fused polycyclic ether. Further studies toward
the ef®cient synthesis of CTX3C as well as other ciguatoxin
congeners are currently underway in this laboratory.
Analytical thin-layer chromatography (TLC) was
performed using E. Merck Silica gel 60 F254 precoated
plates. Column chromatography was performed using
100±210 mm Silica Gel 60N (Kanto Chemicals Co., Inc.),
and for ¯ash column chromatography 40±50 mm Silica Gel
60N (Kanto Chemicals Co., Inc.) was used.
1H and 13C NMR spectra were recorded on a Varian Gemini
200 (200 MHz), Varian Mercury 200 (200 MHz), Varian
INOVA 500 (500 MHz), JOEL GX-400 (400 MHz), JOEL

1840
M. Maruyama et al. / Tetrahedron 58 (2002)1835±1851
a-500 (500 MHz), or Brucker AM-600 (600 MHz) spectro-
meter and referenced to residual CHCl3 [1H NMR (7.26),
13C NMR (77.00)] as an internal standard unless otherwise
noted. IR spectra were recorded on JASCO FT/IR-7000, or
Perkin±Elmer Spectrum BX FT-IR spectrometer. Optical
rotations were recorded on a JASCO DIP-370 polarmeter.
Low- and high-resolution mass spectra (MS, HRMS) were
recorded on a JOEL HX-110, JMS-DX 303, JMS-AX 500,
or HITACHI M-2500-S instrument. Time of ¯ight mass
spectra (MALDI-TOF MS) were recorded on a PerSeptive
Biosystem Voyager DE STR SI-3 instrument. Elemental
analysis was conducted with a Yanako CHN corder MT-5.
Melting points were measured on Yanagimoto micro-
melting point apparatus, and uncorrected.
Jˆ9.5 Hz), 3.64 (1H, dd, Jˆ10.0, 5.0 Hz), 3.65 (1H, t,
Jˆ9.5 Hz), 3.73 (1H, d, Jˆ10.0 Hz), 4.03 (1H, dd,
Jˆ15.0, 1.5 Hz), 4.29 (1H, dd, Jˆ15.0, 6.0 Hz), 4.53 (1H,
d, Jˆ10.5 Hz), 4.56 (1H, d, Jˆ12.0 Hz), 4.61 (1H, d,
Jˆ12.0 Hz), 4.81 (1H, d, Jˆ11.0 Hz), 4.85 (1H, d,
Jˆ10.5 Hz), 5.85±5.95 (1H, m), 7.14±7.42 (15H, m); 13C
NMR (50 MHz, CDCl3) d 35.08, 68.34, 69.73, 73.98, 75.52,
76.15, 76.47, 78.22, 78.90, 86.25, 88.62, 127.94, 128.01,
128.13, 128.18, 128.38, 138.50, 128.87, 138.65, 139.64;
MALDI-TOF MS calcd for C31H34O5Na (M1Na1)
509.23, found 509.28.
4.1.3. Alcohol (11). To a solution of 10 (26.5 g, 54.5 mmol)
in THF/EtOH (5:1, 240 mL) at 2788C was added liquid
NH3 (ca. 50 mL). Then sodium (8.1 g, 0.35 mol) was
added, and the resultant mixture was stirred for 2 h. The
reaction mixture was quenched with solid NH4Cl (50 g)
and allowed to warm to room temperature. After removal
of ammonia completely, salt was ®ltered and washed with
EtOH. Filtration and concentration of the resultant solution
gave crude mixture of the triol along with the monocyclic
4.1. Synthesis of AB ring and E ring
4.1.1. Allyl ether (9). A solution of 8 (63 g, 132 mmol) and
allyl bromide (13.8 mL, 159 mmol) in THF (660 mL) at 08C
was treated with NaH (6.3 g, 60% suspension in mineral oil,
159 mmol). The mixture was stirred for 13 h at room
temperature. The reaction mixture was then quenched
with saturated aqueous NH4Cl. The organic layer was
separated, and the aqueous layer was extracted with
EtOAc. The combined organic extracts were washed with
brine. After being dried over MgSO4, the solution was
concentrated under reduced pressure. The residue was
puri®ed by ¯ash silica gel column chromatography (hexane/
EtOAcˆ3:1) to give 57.0 g (110.0 mol, 83%) of 9 as a
1
tetraol. The ratio of products was determined by H NMR
analysis (triol/tetraolˆ79:21).
The above residue was dissolved in DMF (50.0 mL). The
solution was treated with 4-methoxybenzylaldehyde
dimethylacetal (14.9 mL, 81.8 mmol) and 4-toluenesulfonic
acid monohydrate (1.0 g, 5.5 mmol) at 08C. The mixture
was stirred at room temperature for 1 day. The reaction
mixture was quenched with triethylamine (50 mL) and
saturated aqueous NaHCO3, and diluted with CH2Cl2. The
organic layer was separated, and the aqueous layer was
extracted with CH2Cl2. The combined organic extracts
were washed with brine. After being dried over MgSO4,
the mixture was concentrated under reduced pressure. The
resultant precipitate was recrystalized from EtOAc to give
10.8 g (32.3 mmol, 59%) of 11 as colorless plates, and the
concentration of mother liquor gave mixture of 11 and 14
29
yellow oil. [a]D ˆ19.18 (c 1.0, CHCl3); IR (®lm) n
3098, 3034, 2864, 1644, 1497, 1209 cm21 1H NMR
;
(500 MHz, CDCl3) d 2.32 (1H, dt, Jˆ14.0, 7.5 Hz), 2.56±
2.62 (1H, m), 3.19 (1H, t, Jˆ9.0 Hz), 3.30 (1H, ddd, Jˆ9.0,
7.5, 3.0 Hz), 3.40 (1H, ddd, Jˆ9.0, 4.5, 2.0 Hz), 3.56 (1H, t,
Jˆ9.0 Hz), 3.63 (1H, t, Jˆ9.0 Hz), 3.67 (1H, dd, Jˆ11.0,
4.5 Hz), 3.72 (1H, dd, Jˆ11.0, 2.0 Hz), 4.15 (1H, dd,
Jˆ12.0, 6.0 Hz), 4.34 (1H, dd, Jˆ12.0, 6.0 Hz), 4.57 (1H,
d, Jˆ12.0 Hz), 4.57 (1H, d, Jˆ11.0 Hz), 4.62 (1H, d,
Jˆ12.0 Hz), 4.81 (1H, d, Jˆ11.0 Hz), 4.87 (2H, s), 5.08
(1H, dd, Jˆ10.0, 1.5 Hz), 5.14 (1H, dd, Jˆ17.0, 1.5 Hz),
5.17 (1H, dd, Jˆ10.0, 1.0 Hz), 5.26 (1H, dd, Jˆ17.0,
1.0 Hz), 5.88±5.99 (2H, m), 7.16±7.19 (2H, m), 7.26±
7.37 (13H, m); 13C NMR (50 MHz, CDCl3) d 36.03,
69.02, 73.40, 73.98, 74.96, 75.51, 78.49, 78.77, 79.04,
81.57, 87.19, 116.89, 117.09, 127.51, 127.60, 127.70,
127.76, 127.90, 128.31, 128.40, 134.78, 134.85, 138.20,
138.34, 138.64; MALDI-TOF MS calcd for C33H38O5Na
(M1Na1) 537.26, found 537.19.
29
(1:10, 3.3 g, 22%). Data for 11: [a]D ˆ214.48 (c 1.0,
CHCl3); IR (®lm) n 3493, 3028, 2873, 1614, 1515,
1
1215 cm21; H NMR (500 MHz, CDCl3) d 2.38 (1H, ddq,
Jˆ16.0, 9.5, 3.0 Hz), 2.63 (1H, ddd, Jˆ16.0, 8.0, 3.0 Hz),
2.76 (1H, d, Jˆ2.0 Hz), 3.30 (1H, t, Jˆ9.5 Hz), 3.37 (1H, td,
Jˆ9.5, 3.0 Hz), 3.46 (1H, td, Jˆ9.5, 5.0 Hz), 3.55 (1H, t,
Jˆ9.5 Hz), 3.68 (1H, t, Jˆ9.5 Hz), 3.80 (3H, s), 3.84 (1H,
td, Jˆ9.5, 2.0 Hz), 4.05 (1H, dq, Jˆ16.0, 3.0 Hz), 4.30 (1H,
dd, Jˆ9.5, 5.0 Hz), 4.36 (1H, td, Jˆ16.0, 6.0 Hz), 5.50 (1H,
s), 5.83 (1H, ddt, Jˆ11.5, 8.0, 3.0 Hz), 5.93 (1H, ddt,
Jˆ11.5, 6.0, 3.0 Hz), 6.88 (2H, m), 7.43 (2H, m); 13C
NMR (50 MHz, CDCl3) d 34.26, 55.28, 68.42, 68.77,
69.85, 73.58, 76.37, 80.76, 87.66, 101.70, 113.62, 127.19,
127.62, 129.60, 131.59, 160.16; MALDI-TOF MS calcd for
C18H22O6Na (M1Na1) 357.13, found 357.13.
4.1.2. Bicyclic system (10). To a stirred solution of 9
(57.0 g, 111.0 mmol) in CH2Cl2 (2.8 L) was added Grubbs
catalyst (1.4 g, 1.7 mmol), and the resultant solution was
stirred at room temperature for 3 h. The reaction mixture
was treated with triethyl amine (16 mL) and stirred for 20 h
at room temperature. The mixture was then concentrated
under reduced pressure. The resultant residue was puri®ed
by ¯ash silica gel column chromatography (hexane/
EtOAcˆ3:1) to give 52.0 g (107.0 mmol, 97%) of 10 as a
4.1.4. Benzyl ether (12). To a solution of 11 (5.3 g,
15.8 mmol) in THF/DMF (4:1, 51 mL) was added sodium
hydride (1.0 g, 60% mineral oil, 23.7 mmol) and then
benzylbromide (2.3 mL, 18.9 mmol) dropwise at 08C.
After being stirred at room temperature for 3 h, the reaction
mixture was quenched with MeOH (10 mL) and diluted
with EtOAc and water. The organic layer was separated,
and the aqueous layer was extracted with EtOAc. The
combined organic extracts were washed with brine. After
28
brown oil. [a]D ˆ113.28 (c 1.0, CHCl3); IR (®lm) n 3064,
1
3032, 2866, 1605, 1497, 1210 cm21; H NMR (500 MHz,
CDCl3) d 2.44 (1H, ddd, Jˆ16.0, 9.5, 3.0 Hz), 2.71 (1H,
ddd, Jˆ16.0, 8.0, 4.0 Hz), 3.26 (1H, td, Jˆ9.5, 4.0 Hz), 3.44
(1H, t, Jˆ9.5 Hz), 3.48 (1H, dd, Jˆ9.5, 5.0 Hz), 3.57 (1H, t,

M. Maruyama et al. / Tetrahedron 58 (2002)1835±1851
1841
being dried over Na2SO4, the mixture was concentrated
under reduced pressure. The residue was puri®ed by ¯ash
silica gel column chromatography (hexane/EtOAcˆ4:1) to
give 5.7 g (13.3 mmol, 84%) of 12 as a colorless oil.
with brine. After being dried over Na2SO4, the mixture was
concentrated under reduced pressure. The residue was
puri®ed by ¯ash silica gel column chromatography (hexane/
EtOAcˆ4:1) to give 690 mg (1.6 mmol, 3%) of 12 and 5.8 g
(11.3 mmol, 21% from 10) of 15 as a colorless oil. Data for
29
[a]D ˆ227.48 (c 1.0, CHCl3); IR (®lm) n 2892, 1616,
1517, 1254 cm21
;
1H NMR (500 MHz, CDCl3) d 2.29
15: IR (®lm) n 3029, 2866, 1615, 1518, 1454, 1103 cm21
;
(1H, m), 2.65 (1H, ddd, Jˆ16.0, 8.0, 3.0 Hz), 3.40 (1H,
td, Jˆ9.0, 3.0 Hz), 3.67 (1H, dd, Jˆ10.0, 9.0 Hz), 3.69
(1H, t, Jˆ9.0 Hz), 3.81 (3H, s), 4.05 (1H, dq, Jˆ15.5,
3.0 Hz), 4.30 (1H, dd, Jˆ10.0, 5.0 Hz), 4.32 (1H, dd,
Jˆ15.5, 6.0 Hz), 4.84 (1H, d, Jˆ11.5 Hz), 4.90 (1H, d,
Jˆ11.5 Hz), 5.53 (1H, s), 5.77 (1H, ddt, Jˆ11.5, 8.0,
3.0 Hz), 5.87 (1H, ddt, Jˆ11.5, 6.0, 3.0 Hz), 6.90 (2H, d,
Jˆ8.0 Hz), 7.26 (1H, t, Jˆ8.0 Hz), 7.31 (1H, t, Jˆ8.0 Hz),
7.39 (1H, d, Jˆ8.0 Hz), 7.41 (1H, d, Jˆ8.0 Hz); 13C NMR
(50 MHz, CDCl3) d 34.50, 55.16, 68.46, 68.69, 69.89,
74.91, 77.10, 81.16, 81.24, 87.34, 100.97, 113.43, 126.21,
127.27, 127.34, 127.69, 128.09, 129.87, 131.20, 138.91,
159.86; MALDI-TOF MS calcd for C25H28O6Na
(M1Na1) 447.18, found 447.17.
1H NMR (500 MHz, CDCl3) d 1.61 (3H, d, Jˆ6.0 Hz), 2.28
(1H, dt, Jˆ15.0, 8.0 Hz), 2.56 (1H, dt, Jˆ15.0, 3.0 Hz), 3.38
(1H, t, Jˆ9.0 Hz), 3.42 (1H, td, Jˆ10.0, 5.0 Hz), 3.46 (1H,
tdd, Jˆ10.0, 8.0, 3.0 Hz), 3.66 (1H, t, Jˆ9.0 Hz), 3.70 (1H,
t, Jˆ10.0 Hz), 3.82 (3H, s), 3.84 (1H, t, Jˆ9.0 Hz), 4.33
(1H, dd, Jˆ10.0, 5.0 Hz), 4.63 (1H, d, Jˆ11.0 Hz), 4.79
(1H, d, Jˆ11.0 Hz), 4.97 (1H, d, Jˆ11.0 Hz), 5.00 (1H, d,
Jˆ11.0 Hz), 5.51 (1H, dtd, Jˆ10.5, 6.0, 1.5 Hz), 5.55 (1H,
s), 5.58 (1H, m), 6.92 (2H, d, Jˆ9.0 Hz), 7.28±7.38 (10H,
m), 7.43 (2H, d, Jˆ9.0 Hz); 13C NMR (125 MHz, CDCl3) d
13.22, 29.36, 55.43, 69.08, 70.33, 75.13, 77.36, 79.75,
81.23, 82.68, 83.47, 101.16, 113.72, 125.81, 126.25,
127.43, 127.79, 127.92, 128.09, 128.19, 128.22, 128.51,
128.56, 130.12, 138.36, 138.72, 160.10; MALDI-TOF MS
calcd for C32H36O6Na (M1Na1) 539.24, found 539.25.
4.1.5. Alcohol (13). To a solution of 12 (5.7 g, 13.2 mmol,
89.3 mmol) in CH2Cl2 (27 mL) at 2788C was added
DIBALH (94 mL, 0.95 M hexane, 36 mmol) dropwise.
The reaction mixture was allowed to warm to 2208C, and
stirred for 6 h. The reaction mixture was then quenched with
EtOAc (20 mL). Saturated aqueous solution of potassium
sodium (1)-tartrate was added, and the resultant mixture
was stirred for 2 h. The organic layer was separated, and
the aqueous layer was extracted with EtOAc. The combined
organic extracts were washed with brine. After being dried
over Na2SO4, the solution was concentrated under reduced
pressure. The residue was puri®ed by ¯ash silica gel column
4.1.7. Iodide (5). A solution of 13 (5.29 g, 12.4 mmol) was
treated with imidazole (2.53 g, 37.2 mmol) and PPh3 (6.5 g,
24.8 mmol) in toluene (50 mL) at room temperature. To this
mixture was added I2 (9.44 g 18.6 mmol) portionwise. The
resulting mixture was stirred for 90 min and quenched by
saturated aqueous Na2S2O3. The organic layer was sepa-
rated, and the aqueous layer was extracted with EtOAc.
The combined organic extracts were washed with saturated
aqueous NaHCO3, saturated aqueous NH4Cl and brine.
After being dried over MgSO4, the mixture was concen-
trated under reduced pressure. The residue was puri®ed by
silica gel column chromatography (hexane/EtOAcˆ16:1±
12:1) to give 5 (5.36 g, 10.1 mmol, 82%) as a white powder.
chromatography (hexane/EtOAcˆ6:1) to give 4.6 g
28
(10.8 mmol, 82%) of 13 as a colorless solid. [a]D
17.938 (c 1.0, CHCl3); IR (®lm) n 3480, 3029, 2885,
ˆ
30
[a]D ˆ123.88 (c 1.0, CHCl3); IR (®lm) n 3031, 2868,
1613, 1514, 1249 cm21; H NMR (500 MHz, CDCl3) d
1517, 1253, 1180 cm21; H NMR (500 MHz, CDCl3) d
1
1
1.83 (1H, bs), 2.35 (1H, ddq, Jˆ16.0, 9.5, 3.0 Hz), 2.64
(1H, ddd, Jˆ16.0, 8.0, 4.0 Hz), 3.28 (1H, td, Jˆ9.5,
4.0 Hz), 3.30 (1H, ddd, Jˆ9.5, 5.0, 3.0 Hz), 3.37 (1H, t,
Jˆ9.5 Hz), 3.48 (1H, t, Jˆ9.5 Hz), 3.59±3.66 (1H, m),
3.64 (1H, t, Jˆ9.5 Hz), 3.78±3.85 (1H, m), 3.79 (3H, s),
4.02 (1H, bq, Jˆ16.0, 3.0 Hz), 4.29 (1H, dd, Jˆ16.0,
6.0 Hz), 4.57 (1H, d, Jˆ10.5), 4.81 (1H, d, Jˆ10.5 Hz),
4.83 (1H, d, Jˆ11.0 Hz), 4.97 (1H, d, Jˆ11.0 Hz), 5.79
(1H, ddt, Jˆ11.5, 8.0, 3.0 Hz), 5.90 (1H, ddt, Jˆ11.5, 6.0,
3.0 Hz), 6.86 (2H, m), 7.22 (2H, m), 7.29 (1H, m), 7.35 (2H,
m), 7.40 (2H, m); 13C NMR (50 MHz, CDCl3) d 34.47,
55.18, 62.35, 67.86, 74.57, 75.52, 75.80, 77.21, 78.50,
85.51, 88.05, 113.82, 126.88, 127.43, 127.75, 128.26,
129.70, 130.31, 131.49, 139.07, 159.31; MALDI-TOF MS
calcd for C25H30O6Na (M1Na1) 449.19, found 449.21.
2.39 (1H, ddq, Jˆ16.0, 9.0, 3.0 Hz), 2.68 (1H, ddd,
Jˆ16.0, 8.0, 4.0 Hz), 3.04 (1H, ddd, Jˆ9.0, 6.0, 2.5 Hz),
3.30 (1H, td, Jˆ9.0, 4.0 Hz), 3.30 (1H, dd, Jˆ11.0,
6.0 Hz), 3.38 (1H, t, Jˆ9.0 Hz), 3.40 (1H, t, Jˆ9.0 Hz),
3.47 (1H, dd, Jˆ11.0, 2.5 Hz), 3.66 (1H, t, Jˆ9.0 Hz),
3.80 (3H, s), 4.02 (1H, dq, Jˆ16.0, 3.0 Hz), 4.28 (1H, dd,
Jˆ16.0, 6.0 Hz), 4.64 (1H, d, Jˆ10.5 Hz), 4.81 (1H, d,
Jˆ11.0 Hz), 4.87 (1H, d, Jˆ10.5 Hz), 4.97 (1H, d,
Jˆ11.0 Hz), 5.80 (1H, ddt, Jˆ11.0, 8.0, 3.0 Hz), 5.89
(1H, ddt, Jˆ11.0, 6.0, 3.0 Hz), 6.86 (2H, m), 7.21 (2H,
m), 7.29 (1H, m), 7.35 (2H, m), 7.39 (2H, m); 13C NMR
(50 MHz, CDCl3) d 7.81, 34.36, 55.28, 67.94, 75.00, 75.61,
75.72, 76.30, 76.84, 80.73, 85.19, 88.15, 113.92, 127.15,
127.57, 127.86, 128.37, 129.75, 130.30, 131.44, 138.94,
159.40; MALDI-TOF MS calcd for C25H29NaO5I
(M1Na1) 559.10, found 559.06.
4.1.6. Structure determination of the monocyclic
product (15). A mixture of 11 and 14 (1:10, 5.3 g,
15.8 mmol) was dissolved in THF/DMF (4:1, 44 mL). The
solution was treated with sodium hydride (1.2 g, 60%
mineral oil, 29.2 mmol) and benzylbromide (2.3 mL,
19.4 mmol) at 08C. After being stirred at room temperature
for 3 h, the reaction mixture was quenched with MeOH
(10 mL), and diluted with EtOAc and water. The organic
layer was separated, and the aqueous layer was extracted
with EtOAc. The combined organic extracts were washed
4.1.8. Ester (18). To a solution of the triol (16) (150.0 g,
503.1 mmol) in MeOH (2.0 L) and H2O (150 mL) was
added NaOAc´3H2O (205.4 g, 1.5 mol), acetic acid
(4.3 mL, 75.5 mmol) and then NaIO4 (322.8 g, 1.6 mol) at
08C. The resultant mixture was stirred for 2 h at room
temperature. The solution was then cooled to 08C, and the
reaction was quenched with saturated aqueous NaHCO3
(100 mL) and NaHCO3 (95 g). After the ®ltration, the
organic layer was separated, and the aqueous layer was

1842
M. Maruyama et al. / Tetrahedron 58 (2002)1835±1851
extracted with EtOAc. The combined organic extracts were
washed with brine. After being dried over MgSO4, the
mixture was concentrated under reduced pressure to give
128.4 g of the crude aldehyde.
1H NMR (500 MHz, CDCl3) d 1.49±1.50 (9H, m), 2.26±
2.34 (3H, m), 3.37 (0.25H, td, Jˆ9.4, 4.8 Hz), 3.41 (0.25H,
td, Jˆ9.4, 5.2 Hz), 3.51 (0.25H, td, Jˆ9.3, 4.6 Hz), 3.54
(0.25H, td, Jˆ9.1, 4.5 Hz), 3.61 (0.25H, t, Jˆ10.8 Hz),
3.63 (0.25H, t, Jˆ10.8 Hz), 3.72 (0.25H, t, Jˆ10.8 Hz),
3.73 (0.25H, t, Jˆ10.8 Hz), 3.78 (1.5H, s), 3.79 (1.5H, s),
3.80 (0.25H, d, Jˆ6.8 Hz), 3.83 (0.25H, d, Jˆ12.4 Hz), 3.89
(0.25H, d, Jˆ5.2 Hz), 3.87±3.91 (1H, m), 3.96 (0.25H, d,
Jˆ4.2 Hz), 4.10±4.17 (1H, m), 4.39 (0.25H, dd, Jˆ10.8,
4.8 Hz), 4.42 (0.25H, dd, Jˆ10.8, 4.8 Hz), 4.45 (0.5H, dd,
Jˆ10.8, 5.2 Hz), 5.11±5.18 (2H, m), 5.27 (0.25H, dt,
Jˆ10.5, 1.6 Hz), 5.28 (0.25H, dt, Jˆ12.4, 1.6 Hz), 5.34
(0.25H, dd, Jˆ9.8, 1.0 Hz), 5.36 (0.25H, dd, Jˆ9.6,
1.0 Hz), 5.45 (0.125H, t, Jˆ1.4 Hz), 5.46 (0.125H, t,
Jˆ1.3 Hz), 5.46±5.50 (0.5H, m), 5.48±5.50 (1H, m), 5.51
(0.125H, t, Jˆ1.2 Hz), 5.53 (0.125H, t, Jˆ1.3 Hz), 5.78±
5.89 (1H, m), 5.59 (0.2H, dd, Jˆ17.0, 6.5 Hz), 6.01 (0.2H,
td, Jˆ10.6, 6.3 Hz), 6.03 (0.2H, dd, Jˆ17.0, 6.5 Hz), 6.16
(0.2H, td, Jˆ11.5, 5.2 Hz), 6.20 (0.2H, td, Jˆ10.0, 5.2 Hz),
6.86±6.89 (2H, m), 7.39±7.43 (2H, m); 13C NMR
(125 MHz, CDCl3) d 28.25, 28.29, 37.09, 37.19, 37.77,
37.83, 55.49, 55.80, 60.61, 69.04, 69.15, 69.93, 71.68,
71.98, 72.25, 72.35, 72.52, 72.78, 74.69, 74.83, 79.69,
80.36, 80.43, 80.52, 81.82, 81.86, 82.42, 82.76, 82.84,
82.90, 100.93, 101.02, 113.83, 114.53, 117.33, 117.47,
118.24, 118.37, 118.69, 119.49, 119.89, 127.69, 130.19,
130.24, 132.23, 134.04, 134.18, 134.29, 134.39, 134.88,
135.27, 135.34, 160.27, 169.31, 169.56, 170.06, 170.48,
171.38; HRMS (EI, 70 eV) calcd for C23H32O7 420.2148,
found 420.2149.
A solution of the above aldehyde in THF (900 mL) was
added to a slurry of methyltriphenylphosphonium bromide
(539.2 g, 1.5 mol) and t-BuOK (84.7 g, 754.8 mmol) in
THF (1 L) at 08C and stirred for 2 h. The reaction mixture
was quenched with saturated aqueous NH4Cl. The organic
layer was separated, and the aqueous layer was extracted
with EtOAc. The combined organic extracts were washed
with brine. The solution was concentrated under reduced
pressure. The resultant precipitate was recrystalized from
hexane/EtOAc (2:1) to give 85.5 g (362.1 mmol, 72%) of
17 as a colorless solid.
A solution of 17 (13.2 g, 55.8 mmol) in THF (200 mL) and
DMF (80 mL) was treated with NaH (2.7 g of 60% in oil,
66.9 mmol) at 08C. The reaction mixture was stirred for
20 min at room temperature, and then cooled to 08C before
the addition of t-butyl bromoacetate (10.7 mL, 72.5 mmol).
The mixture was allowed to warm to room temperature and
stirred for 1 day. The reaction was quenched with saturated
aqueous NH4Cl. The organic layer was separated, and the
aqueous layer was extracted with EtOAc. The combined
organic extracts were washed with NaHCO3 and brine.
After being dried over MgSO4, the mixture was concen-
trated under reduced pressure. The residue was puri®ed by
open silica gel column chromatography (hexane/EtOAcˆ
20:1±14:1) to give 19.3 g (55.2 mmol, 99%) of 18 as a
24
colorless oil. [a]D ˆ229.68 (c 1.04, CHCl3); IR (®lm) n
4.1.10. Ring-closing metathesis of diene 19. To a stirred
solution of 19 (1.4 g, 3.2 mmol) in CH2Cl2 (500 mL,
0.006 M) was added Grubbs catalyst (79.3 mg,
96.4 mmol), and the resultant solution was stirred at re¯ux
for 36 h. The reaction mixture was quenched with triethyl-
amine (10 mL), and stirred for 20 h at room temperature.
The mixture was concentrated under reduced pressure. The
resultant residue was puri®ed by ¯ash silica gel column
chromatography (hexane/EtOAcˆ15:1±6:1) to give
352 mg (897.5 mmol, 28%) of desired 20 as colorless plates,
along with 477 mg (1.2 mmol, 38%) of 21 as a colorless oil,
and 238 mg (608 mmol, 19%) of undesired 22 as a colorless
1035, 1139, 1250, 1519, 1748, 2978 cm21 1H NMR
;
(600 MHz, CDCl3) d 1.47 (9H, s), 3.36 (1H, ddd, Jˆ10.0,
9.4, 5.0 Hz), 3.69 (1H, dd, Jˆ10.9, 10.0 Hz), 3.79 (3H, s),
4.01 (1H, d, Jˆ16.3 Hz), 4.08 (1H, d, Jˆ16.3 Hz), 4.12 (1H,
ddd, Jˆ9.4, 6.2, 1.0 Hz), 4.48 (1H, dd, Jˆ10.9, 5.0 Hz),
5.31 (1H, ddd, Jˆ10.6, 1.5, 1.2 Hz), 5.48 (1H, s), 5.51
(1H, ddd, Jˆ17.2, 1.5, 1.3 Hz), 6.07 (1H, ddd, Jˆ17.2,
10.6, 6.2 Hz), 6.86±6.90 (2H, m), 7.40±7.43 (2H, m); 13C
NMR (150 MHz, CDCl3) d 28.07, 55.27, 68.77, 69.38,
74.53, 81.20, 100.71, 113.58, 118.19, 127.46, 130.49,
134.86, 160.01, 169.26; HRMS (EI, 70 eV) calcd for
C19H26O6 350.1728, found 350.1728.
28
oil. Data for 20: mp 130±1328C; [a]D ˆ257.38 (c 1.01,
CHCl3); IR (®lm) n 3510, 2976, 1736, 1616, 1518, 1250,
1
4.1.9. Aldol adduct (19). A solution of n-butyllithium
(7.6 mL, 1.56 M in hexane, 11.8 mmol) in THF (30 mL)
was treated with diisopropylamine (2.2 mL, 15.7 mmol) at
2788C, and the resultant solution was stirred for 15 min. To
a solution mixture was added dropwise a solution of 18
(2.8 g, 7.9 mmol) in THF (10 mL) through cannula and
then a solution of 3-butenal (10.2 mmol) in CH2Cl2
(80 mL) dropwise through cannula over 5 min. After
being stirred for 5 min, the reaction mixture was quenched
with saturated aqueous NH4Cl. The organic layer was sepa-
rated, and the aqueous layer was extracted with EtOAc. The
combined organic extracts were washed with NaHCO3 and
brine. After being dried over MgSO4, the mixture was
concentrated under reduced pressure. The residue was
puri®ed by silica gel column chromatography (hexane/
EtOAcˆ12:1±8:1) to give 3.0 g (7.2 mmol, 91%) of 19 as
a colorless oil. IR (®lm) n 3483, 2979, 2360, 2341, 1742,
1105, 832 cm21; H NMR (500 MHz, CDCl3) d 1.50 (9H,
s), 2.41±2.46 (1H, m), 2.65±2.68 (1H, m), 3.06 (1H, t,
Jˆ2.0 Hz), 3.53 (1H, ddd, Jˆ10.5, 9.2, 5.0 Hz), 3.67 (1H,
t, Jˆ10.5 Hz), 3.80 (3H, s), 3.87 (1H, d, Jˆ9.5 Hz), 4.15
(1H, ddd, Jˆ9.5, 3.0, 2.7 Hz), 4.33 (1H, dd, Jˆ10.5,
5.0 Hz), 4.45 (1H, ddd, Jˆ9.2, 3.5, 1.0 Hz), 5.46 (1H, s),
5.85±5.88 (2H, m), 6.88±6.90 (2H, m), 7.40±7.42 (2H, m);
13C NMR (125 MHz, CDCl3) d 27.96, 31.45, 55.25, 69.09,
72.28, 76.43, 79.23, 80.75, 82.79, 100.81, 113.62, 126.64,
127.38, 129.87, 133.37, 160.05, 172.20; HRMS (EI, 70 eV)
calcd for C21H28O7 392.1835, found 392.1829. Data for 21:
28
[a]D ˆ22.38 (c 1.00, CHCl3); IR (®lm) n 3456, 2933,
1
1749, 1616, 1518, 1250, 1126, 831, 731 cm21; H NMR
(500 MHz, CDCl3) d 1.49 (9H, s), 2.44±2.54 (2H, m),
3.39±3.45 (1H, td, Jˆ9.4, 5.0 Hz), 3.79 (3H, s), 3.79 (1H,
d, Jˆ11.0 Hz), 4.20 (1H, d, Jˆ2.4 Hz), 4.23 (1H, ddd,
Jˆ10.6, 5.7, 2.4 Hz), 4.42 (1H, dd, Jˆ11.0, 5.0 Hz), 4.56
(H, dd, Jˆ9.0, 5.0 Hz), 5.46 (1H, s), 5.72±5.79 (1H, m),
1616, 1519, 1393, 1369, 1250, 1137, 1034, 924, 831 cm21
;

M. Maruyama et al. / Tetrahedron 58 (2002)1835±1851
1843
5.81 (1H, dd, Jˆ11.0, 4.8 Hz), 6.86±6.90 (2H, m), 7.39±
7.43 (2H, m); 13C NMR (125 MHz, CDCl3) d 28.05, 33.28,
55.28, 69.23, 73.42, 75.83, 79.28, 81.22, 82.23, 100.79,
113.62, 126.43, 127.40, 129.87, 131.97, 134.03, 160.04,
170.08; HRMS (EI, 70 eV) calcd for C21H28O7 392.1835,
7.8 Hz), 3.55 (1H, ddd, Jˆ9.7, 9.4, 5.3 Hz), 3.79 (1H, dd,
Jˆ11.0, 9.4 Hz), 3.82 (3H, s), 3.83 (1H, dd, Jˆ11.2,
6.8 Hz), 3.95 (1H, dd, Jˆ11.2, 2.5 Hz), 4.03 (1H, ddd,
Jˆ8.7, 4.4, 2.0 Hz), 4.16 (1H, dd, Jˆ6.8, 2.5 Hz), 4.44
(1H, dd, Jˆ11.0, 5.3 Hz), 4.63 (1H, ddd, Jˆ8.7, 4.4,
2.0 Hz), 5.52 (1H, s), 5.61 (1H, dddd, Jˆ11.0, 9.4, 7.8,
2.0 Hz), 5.95 (1H, ddd, Jˆ10.8, 4.9, 1.3 Hz), 6.90±6.92
(2H, m), 7.40±7.42 (2H. m); 13C NMR (50 MHz, CDCl3)
d 19.17, 26.54, 26.76, 41.72, 55.31, 65.26, 69.99, 77.19,
79.54, 86.56, 100.56, 113.70, 121.43, 127.44, 127.82,
129.64, 134.78, 135.25, 135.54, 135.59, 177.29, 209.06;
HRMS (EI, 70 eV) calcd for C33H38O6Si (M1) 558.2448,
found 558.2448.
29
found 392.1833. Data for 22: [a]D ˆ284.28 (c 0.66,
CHCl3); IR (®lm) n 3490, 2695, 1735, 1617, 1518, 1251,
1
1105, 832 cm21; H NMR (500 MHz, CDCl3) d 1.51 (9H,
s), 2.35±2.39 (1H, m), 2.52 (1H, ddd, Jˆ13.5, 8.7, 2.8 Hz),
3.14 (1H, d, Jˆ3.3 Hz), 3.60 (1H, ddd, Jˆ10.8, 10.0,
5.0 Hz), 3.80 (3H, s), 3.85 (1H, d, Jˆ11.5 Hz), 3.85±3.88
(1H, m), 3.99 (1H, t, Jˆ10.8 Hz), 4.38 (1H, dd, Jˆ10.8,
5.5 Hz), 4.61 (1H, ddd, Jˆ10.0, 7.0, 1.0 Hz), 5.54 (1H, s),
5.75 (1H, ddd, Jˆ11.0, 7.0, 1.5 Hz), 5.87±5.91 (1H, m),
6.87±6.90 (2H, m), 7.42±7.45 (2H, m); 13C NMR
(125 MHz, CDCl3) d 27.93, 34.41, 55.26, 68.48, 70.32,
70.39, 76.88, 78.54, 82.92, 101.22, 113.64, 126.13,
127.40, 126.69, 130.73, 160.09, 170.70; HRMS (EI,
70 eV) calcd for C21H28O7 392.1835, found 392.1838.
4.1.12. Ketone (24). Compound 24 was synthesized by the
same three-step sequence as that for 23 (73% from 21).
28
[a]D ˆ2243.78 (c 1.00, CHCl3); IR (®lm) n 702, 824,
1
1113, 1251, 1428, 1518, 1720, 2360, 2931 cm21; H NMR
(500 MHz, CDCl3) d 1.04 (9H, s), 2.88 (1H, dd, Jˆ11.0,
7.8 Hz), 3.55 (1H, ddd, Jˆ9.7, 9.4, 5.3 Hz), 3.79 (1H, dd,
Jˆ11.0, 9.4 Hz), 3.82 (3H, s), 3.83 (1H, dd, Jˆ11.2,
6.8 Hz), 3.95 (1H, dd, Jˆ11.2, 2.5 Hz), 4.03 (1H, ddd,
Jˆ11.0, 9.4, 1.5 Hz), 4.16 (1H, dd, Jˆ6.8, 2.5 Hz), 4.44
(1H, dd, Jˆ11.0, 5.3 Hz), 4.63 (1H, ddd, Jˆ8.7, 4.4,
2.0 Hz), 5.52 (1H, s), 5.61 (1H, dddd, Jˆ11.0, 9.4, 7.8,
2.0 Hz), 5.95 (1H, ddd, Jˆ10.8, 4.9, 1.3 Hz), 6.90±6.92
(2H, m), 7.40±7.42 (8H, m), 7.65±7.68 (4H, m); 13C
NMR (50 MHz, CDCl3) d 19.17, 26.54, 26.76, 41.72,
55.31, 65.26, 69.99, 77.19, 79.54, 86.56, 100.56, 113.70,
121.43, 127.44, 127.82, 129.64, 134.78, 135.25, 135.54,
135.59, 177.29, 209.06; MALDI-TOF MS calcd for
C33H38O6Si2Na (M1Na1) 581.23, found 581.14.
4.1.11. Ketone (23). To a solution of 22 (331.3 mg,
844.7 mmol) in Et2O (6.0 mL) at 08C was added LiAlH4
(64.0 mg, 1.7 mmol) in two equal portions over 7 min,
and the resultant mixture was stirred for 30 min at room
temperature. The reaction mixture was quenched with
H2O (64 mL), and then 15% NaOH aqueous (128 mL) and
H2O (64 mL) was added. The mixture was ®ltered through a
sintered glass funnel, and washed with EtOAc. The ®ltrate
was concentrated under reduced pressure, and the resultant
residue was puri®ed by silica gel column chromatography
(hexane/EtOAcˆ5:1±1:8) to give 257.2 mg (798.4 mmol,
95%) of the diol as a colorless oil.
To a solution of the above diol (379.0 mg, 1.1 mmol) in
CH2Cl2 (6.0 mL) was added TBDPSCl (310.0 mL,
1.7 mmol), triethylamine (247.0 mL, 1.7 mmol) and
DMAP (15.0 mg, 120.0 mmol) at 08C, and the resultant
mixture was stirred for an hour at room temperature. The
reaction mixture was quenched with saturated aqueous
NH4Cl. The organic layer was separated, and the aqueous
layer was extracted with EtOAc. The combined organic
extracts were washed with NaHCO3 and brine. After
being dried over MgSO4, the mixture was concentrated
under reduced pressure. The residue was puri®ed by silica
gel column chromatography (hexane/EtOAcˆ18:1±14:1) to
give 560.0 mg (1.0 mmol, 85%) of the mono TBDPS ether
as a colorless oil.
4.1.13. Epimerization of ketone (23!24). A solution of 23
(30.9 mg, 57.8 mmol) in toluene (3.0 mL) was treated with
imidazole (19.6 mg, 289.0 mmol) at room temperature, and
the resultant mixture was heated to 708C for 20 h. The
solvent was removed under reduced pressure, and the
residue was puri®ed by silica gel column chromatography
(hexane/EtOAcˆ20:1±16:1) to give 30.9 mg (57.8 mmol,
100%) of 24 as a colorless oil.
4.1.14. Ole®n (25) from 20. To a solution of 20 (545.6 mg,
1.39 mmol) in DMF (14.0 mL) was added TBSCl
(629.3 mg, 4.17 mmol) and imidazole (378.1 mg,
5.56 mmol) at 08C, and the resultant mixture was stirred
for 9 h at room temperature. The solvent was removed
under reduced pressure, and the residue was puri®ed by
¯ash column chromatography (hexane/EtOAcˆ30:1±16:1)
to give 653.8 mg (1.29 mmol, 93%) of the TBS ether as a
colorless solid.
A solution of the above mono TBDPS ether (2.8 g,
5.0 mmol) in CH2Cl2 (25 mL) was treated with Dess±
Martin reagent (4.3 g, 10.0 mmol) at 08C. The mixture
was warmed to room temperature and stirred for 40 min.
Then the reaction was quenched with saturated aqueous
Na2S2O3. The organic layer was separated, and the aqueous
layer was extracted with EtOAc. The combined organic
extracts were washed with NaHCO3 and brine. After
being dried over MgSO4, the mixture was concentrated
under reduced pressure. The residue was puri®ed by silica
gel column chromatography (hexane/EtOAcˆ20:1±16:1) to
give 2.2 g (4.2 mmol, 83%) of 23 as a colorless oil.
A solution of the above TBS ether (653.8 mg, 1.29 mmol) in
CH2Cl2 (8.0 mL) was treated with DIBALH (2.72 mL,
0.95 M in hexane, 2.58 mmol) at 2788C,2508C for
35 min. The reaction mixture was quenched with saturated
aqueous NH4Cl. The organic layer was separated, and the
aqueous layer was extracted with EtOAc. The combined
organic extracts were washed with NaHCO3 and brine.
After being dried over MgSO4, the solution was concen-
trated under reduced pressure. The residue was puri®ed by
silica gel column chromatography (hexane/EtOAcˆ16:1±
12:1) to give the aldehyde as a colorless oil.
28
[a]D ˆ2243.78 (c 1.00, CHCl3); IR (®lm) n 2931, 2360,
1
1720, 1518, 1428, 1251, 1113, 824, 702 cm21; H NMR
(500 MHz, CDCl3) d 1.04 (9H, s), 2.88 (1H, dd, Jˆ11.0,

1844
M. Maruyama et al. / Tetrahedron 58 (2002)1835±1851
A solution of the above aldehyde in THF (5 mL) was added
to a slurry of methyltriphenyl phosphonium bromide
(4.61 g, 12.9 mmol) and t-BuOK (724.0 mg, 6.45 mmol)
in THF (16.0 mL) at 08C, and stirred for 10 min. Then,
the reaction mixture was quenched with H2O. The organic
layer was separated, and the aqueous layer was extracted
with Et2O. The combined organic extracts were washed
with NH4Cl and brine. After being dried over MgSO4, the
mixture was concentrated under reduced pressure. The
residue was puri®ed by silica gel column chromatography
(hexane/EtOAcˆ30:1±12:1) to give 293 mg (678.5 mmol,
53%) of 25 as a colorless oil, along with over-reduced
primary alcohol 223.0 mg (511.2 mmol, 40%). Data for
to give 849.6 mg (1.13 mmol, 98%) of the bis-TBS ether as
a colorless solid.
To a solution of the above bis-TBS ether (780.7 mg,
1.44 mmol) in hexane (300 mL) was added activated neutral
alumina. The slurry was stirred at room temperature for 2
days. The mixture was ®ltered through a sintered glass
funnel and washed with EtOAc. The ®ltrate was concen-
trated under reduced pressure, and residue was puri®ed by
silica gel column chromatography (hexane/EtOAcˆ100:1±
10:1) to give 513.7 mg (1.18 mmol, 81%) of the mono-TBS
ether along with 93.9 mg (215.2 mmol, 15%) of recovered
the bis-TBS ether.
28
25: [a]D ˆ2121.28 (c 1.65, CHCl3); IR (®lm) n 2931,
1
2361, 1250, 1101, 832 cm21; H NMR (500 MHz, CDCl3)
A solution of the above mono-TBS ether (513.7 mg,
1.18 mmol) in CH2Cl2 (5.0 mL) was treated with Dess±
Martin reagent (1.0 g, 2.36 mmol) at 08C. The reaction
mixture was allowed to warm to room temperature. After
being stirred for 40 min, the mixture was diluted with Et2O
(2.0 mL), and saturated aqueous Na2S2O3 was added. The
organic layer was separated, and the aqueous layer was
extracted with EtOAc. The combined organic extracts
were washed with NaHCO3 and brine, and dried over
MgSO4. Concentration and ®ltration through a plug of
¯orisil (hexane/EtOAcˆ10:1±6:1) gave the aldehyde.
d 20.03 (3H, s), 0.02 (3H, s), 0.82 (9H, s), 2.18±2.21 (1H,
m), 2.64±2.66 (1H, m), 3.36 (1H, ddd, Jˆ10.7, 8.5, 4.8 Hz),
3.59 (1H, t, Jˆ10.7 Hz), 3.64±3.66 (1H, m), 3.73 (3H, s),
3.77±3.80 (1H, m), 4.24 (1H, dd, Jˆ10.7, 4.8 Hz), 4.36±
4.39 (1H, m), 5.05 (1H, dd, Jˆ10.5, 1.5 Hz), 5.18 (1H, dd,
Jˆ16.8, 1.5 Hz), 5.38 (1H, s), 5.70±5.74 (1H, m), 5.80±
5.82 (1H, m), 5.84 (1H, dd, Jˆ16.8, 10.5, 4.9 Hz), 6.80±
6.85 (2H, m), 7.42±7.46 (2H, m); 13C NMR (125 MHz,
CDCl3) d 24.46, 17.95, 25.74, 33.39, 55.29, 69.56, 75.05,
75.86, 79.94, 82.75, 100.83, 113.63, 114.72, 126.67, 127.45,
130.12, 133.09, 137.16, 160.03; HRMS (EI, 70 eV) calcd
for C24H36O5Si (M1) 432.2332, found 432.2324.
A solution of the above aldehyde in THF (5.0 mL) was
added to a slurry of methyltriphenylphosphonium bromide
(4.2 g, 6.61 mmol) and t-BuOK (661.0 mg, 5.89 mmol) in
THF (16.0 mL) at 08C, and the resultant mixture was stirred
for 3 min. Then, the reaction mixture was quenched with
H2O. The organic layer was separated, and the aqueous
layer was extracted with EtOAc. The combined organic
extracts were washed with NH4Cl and brine. After being
dried over MgSO4, the mixture was concentrated under
reduced pressure. The residue was puri®ed by silica gel
column chromatography (hexane/EtOAc ˆ30:1±12:1) to
give 438.2 mg (1.00 mmol, 85%) of 25 as a colorless oil.
4.1.15. Ole®n (25) from ketone 24. A solution of 24
(108.5 mg, 194 mmol) in THF (1.0 mL) was treated with
TBAF (291 mL, 1.0 M in THF, 291 mmol) and acetic acid
(1.7 mL, 291.5 mmol) at 08C, and stirred at room tempera-
ture for 50 min. The reaction mixture was concentrated
under reduced pressure, and the residue was puri®ed by
¯ash silica gel chromatography (hexane/EtOAcˆ10:1±
6:1) to give 40.0 mg (124.9 mmol, 64%) of the alcohol as
a colorless oil.
The solution of the above alcohol (13.5 mg, 42.2 mmol) in
CH3CN (3.0 mL) was treated with NaBH(OAc)3 (44.7 mg,
211.0 mmol) and acetic acid (43.5 mL, 759.6 mmol) at
2458C. The solution was allowed to warm to 2108C and
stirred for an hour. Then, the reaction mixture was quenched
with saturated aqueous NH4Cl. The organic layer was
separated, and the aqueous layer was extracted with
EtOAc. The combined organic extracts were washed with
NaHCO3 and brine. After being dried over MgSO4, the
mixture was concentrated under reduced pressure. The
residue was puri®ed by silica gel column chromatography
(hexane/EtOAcˆ6:1±1:8) to give 12.7 mg (39.4 mmol,
93%) of the diol as a colorless oil.
4.1.16. tert-Butyl ester (6). A solution of 25 (438.2 mg,
1.01 mmol) in THF (5.0 mL) was treated with TBAF
(1.32 mL, 1.0 M in THF, 1.32 mmol) at room temperature
for 90 min. The solvent was removed under reduced
pressure, and the resultant residue was puri®ed by silica
gel column chromatography (hexane/EtOAcˆ14:1±6:1) to
give 317.7 mg (998.5 mmol, 99%) of the alcohol as a
colorless oil.
A solution of the above alcohol (312.1 mg, 980.9 mmol) in
THF (5.0 mL) and DMF (2.0 mL) was treated with NaH
(40.5 mg of 98% in oil, 1.5 mmol) at 08C. The mixture
was stirred for 20 min at room temperature, and then cooled
to 08C before the addition of t-butyl bromoacetate (192 mL,
1.3 mmol). The solution was allowed to warm to room
temperature and stirred for 1 day. The reaction was then
quenched with saturated aqueous NH4Cl. The organic
layer was separated, and the aqueous layer was extracted
with EtOAc. The combined organic extracts were washed
with NaHCO3 and brine. After being dried over MgSO4, the
solution was concentrated under reduced pressure. The
residue was puri®ed by silica gel column chromatography
(hexane/EtOAcˆ20:1±10:1) to give 319.6 mg (739.4 mmol,
To a solution of the above diol (369.8 mg, 1.14 mmol) in
DMF (6.0 mL) was added TBSCl (1.73 g, 11.48 mmol) and
imidazole (310.0 mg, 4.56 mmol) at 08C, and the resultant
mixture was stirred at room temperature for 10 h. Then, the
reaction mixture was quenched with saturated aqueous
NH4Cl. The organic layer was separated, and the aqueous
layer was extracted with EtOAc. The combined organic
extracts were washed with NaHCO3 and brine. After
being dried over MgSO4, the mixture was concentrated
under reduced pressure. The residue was puri®ed by silica
gel column chromatography (hexane/EtOAcˆ100:1±50:1)
28
75%) of 6 as a colorless oil. [a]D ˆ292.48 (c 1.00,

M. Maruyama et al. / Tetrahedron 58 (2002)1835±1851
1845
CHCl3); IR (®lm) n 2977, 2360, 1748, 1518, 1250,
132.20, 132.47, 133.71, 137.65, 139.59, 159.75, 160.54,
173.42; MALDI-TOF MS calcd for C49H60O12Na
(M1Na1) 863.94, found 863.27.
1
830 cm21; H NMR (500 MHz, CDCl3) d 1.48 (9H, s),
2.56 (1H, ddd, Jˆ13.0, 6.2, 3.0 Hz), 2.63 (1H, ddd,
Jˆ13.0, 9.8, 3.0 Hz), 3.44 (1H, dt, Jˆ9.0, 3.0 Hz), 3.46
(1H, dd, Jˆ8.3, 5.2 Hz), 3.66 (1H, t, Jˆ10.5 Hz), 3.80
(3H, s), 3.97±3.90 (1H, m), 4.02 (2H, d, Jˆ1.3 Hz), 4.31
(1H, dd, Jˆ10.5, 5.2 Hz), 4.46 (1H, ddd, Jˆ8.3, 4.7,
2.0 Hz), 5.16 (1H, dt, Jˆ10.4, 1.6 Hz), 5.31 (1H, dt,
Jˆ16.7, 1.6 Hz), 5.44 (1H, s), 5.82 (1H, dddd, Jˆ11.6,
9.8, 6.2, 2.0 Hz), 5.90 (1H, dd, Jˆ11.6, 4.7 Hz), 6.09 (1H,
ddd, Jˆ16.7, 10.4, 4.3 Hz), 6.88±6.91 (2H, m), 7.40±7.42
(2H, m); 13C NMR (50 MHz, CDCl3) d 28.04, 28.85, 55.23,
68.08, 69.42, 75.48, 79.73, 80.78, 81.66, 84.42, 100.75,
113.58, 114.52, 126.17, 127.40, 130.01, 135.52, 136.99,
159.99, 169.35; HRMS (EI, 70 eV) calcd for C24H32O7
(M1) 432.2148, found 432.2149.
4.2.2. TIPDS ether (27). A solution of 26 (277.4 mg,
330.0 mmol) in MeOH (10.0 mL) was treated with
pyridinium p-toluenesulfonate (91.2 mg, 363.0 mmol), and
stirred at room temperature for 20 h. The mixture was
concentrated, and the residue was puri®ed by silica gel
column chromatography (hexane/EtOAcˆ3:1±1:5) to give
197.1 mg (272.8 mmol, 83%) of the diol as a colorless oil.
To a solution of the above diol (271.1 mg, 375.3 mmol) in
pyridine (3.0 mL) was added 1,3-dichlorotetraisopropyl-
disiloxane (600 mL, 1.88 mmol) at 2408C. After being stir-
red for 1 day at room temperature, the reaction mixture was
quenched by the addition of MeOH (1.0 mL), diluted with
Et2O, and washed with saturated aqueous NaHCO3. The
organic layer was separated, and the aqueous layer was
extracted with Et2O. The combined organic extracts were
washed with saturated aqueous NH4Cl and brine. After
being dried over MgSO4, the solution was concentrated
under reduced pressure. The residue was puri®ed by ¯ash
silica gel column chromatography (hexane/EtOAcˆ15:1±
10:1) to give 333.0 mg (345.0 mmol, 92%) of 27 as a color-
4.2. Synthesis of ABCDE ring fragment
4.2.1. Coupling adduct (26). A solution of n-butyllithium
(1.09 mL, 1.56 M hexane, 1.69 mmol) in THF (4.0 mL) was
treated with diisopropylamine (475.0 mL, 3.39 mmol) at
2788C, and the resultant solution was stirred for 30 min.
Then, a solution of 6 (488.1 mg, 1.13 mmol) in THF
(3.0 mL) was added dropwise through cannula over 4 min.
After being stirred for 11 min, a solution of 5 (667.6 mg,
1.24 mmol) in THF (3.0 mL) and HMPA (1.3 mL) was
added to the solution dropwise through cannula over
5 min, and the resultant solution was stirred for 15 min.
The reaction was quenched with saturated aqueous
NH4Cl. The organic layer was separated, and the aqueous
layer was extracted with EtOAc. The combined organic
extracts were washed with saturated aqueous NaHCO3 and
brine. After being dried over MgSO4, the mixture was
concentrated under reduced pressure. The residue was
puri®ed by ¯ash silica gel column chromatography (hexane/
EtOAcˆ12:1±8:1) to give 487.4 mg (579.9 mmol, 51%) of
26 as a colorless oil, along with recovered 5 195.5 mg
(354.4 mmol, 29%) and 6 107.8 mg (249.5 mmol, 22%).
IR (®lm) n 2933, 2360, 1742, 1515, 1250, 1098,
less oil. IR n 697, 885, 1089, 1250, 1746, 2360, 2944 cm21
;
1H NMR (500 MHz, CDCl3, major isomer) d 1.02±1.06
(28H, m), 1.47 (9H, s), 2.08 (1H, ddd, Jˆ13.7, 11.2,
2.0 Hz), 2.26±2.35 (2H, m), 2.55 (1H, td, Jˆ8.0, 4.0 Hz),
2.59 (1H, dd, Jˆ10.5, 2.8 Hz), 3.13 (1H, td, Jˆ10.2,
4.0 Hz), 3.14 (1H, t, Jˆ9.0 Hz), 3.23 (1H, d, Jˆ9.0 Hz),
3.35 (1H, t, Jˆ8.7 Hz), 3.40 (1H, dt, Jˆ9.2, 3.0 Hz), 3.44
(1H, dd, Jˆ9.0, 2.5 Hz), 3.57 (1H, t, Jˆ8.3 Hz), 3.78 (3H,
s), 3.88±3.93 (3H, m), 3.97±4.02 (1H, m), 4.16 (1H, dd,
Jˆ11.0, 1.6 Hz), 4.27 (1H, dd, Jˆ15.0, 5.8 Hz), 4.53 (1H,
d, Jˆ11.0 Hz), 4.72 (1H, d, Jˆ9.0, 4.4 Hz), 4.74 (1H, d,
Jˆ10.4 Hz), 4.78 (1H, d, Jˆ11.0 Hz), 4.93 (1H, d,
Jˆ11.3 Hz), 5.12 (1H, dt, Jˆ10.4, 1.2 Hz), 5.32 (1H, dt,
Jˆ16.7, 1.7 Hz), 5.74±5.81 (2H, m), 5.74±5.81 (2H, m),
5.81 (1H, dd, Jˆ10.5, 4.3 Hz), 5.88±5.94 (1H, m), 5.93
(1H, ddd, Jˆ17.5, 10.2, 5.4 Hz), 6.80±6.83 (2H, m),
7.16±7.20 (2H, m), 7.32±7.36 (2H, m), 7.37±7.40 (2H,
m); 13C NMR (50 MHz, CDCl3) d 12.17, 12.40, 13.02,
13.17, 13.29, 17.05, 17.09, 17.24, 17.29, 17.40, 27.95,
28.01, 29.68, 29.78, 34.47, 36.09, 55.18, 63.73, 67.22,
67.79, 73.37, 74.43, 75.28, 75.68, 76.14, 81.12, 81.21,
81.36, 84.46, 84.64, 85.79, 88.40, 113.69, 115.84, 125.59,
127.41, 127.47, 127.86, 128.30, 129.01, 130.35, 131.62,
137.49, 139.14, 159.20, 173.17: MALDI-TOF MS calcd
for C53H80O12Si2Na (M1Na1) 987.51, found 987.31.
1
828 cm21; H NMR (500 MHz, CDCl3) d 1.48 (9H, s),
2.11 (1H, ddd, Jˆ13.8, 11.0, 2.2 Hz), 2.33 (1H, ddd,
Jˆ15.5, 13.6, 2.5 Hz), 2.43 (1H, ddd, Jˆ13.5, 5.0,
2.5 Hz), 2.56 (1H, ddd, Jˆ11.0, 7.8, 3.7 Hz), 2.61 (1H,
ddd, Jˆ13.4, 6.0, 3.0 Hz), 3.15 (1H, td, Jˆ9.3, 4.0 Hz),
3.17 (1H, t, Jˆ9.0 Hz), 3.36 (1H, dd, Jˆ9.4, 2.8 Hz), 3.37
(1H, t, Jˆ9.0 Hz), 3.40±3.46 (1H, m), 3.43 (1H, t,
Jˆ9.2 Hz), 3.59 (1H, t, Jˆ8.7 Hz), 3.66 (1H, t,
Jˆ10.0 Hz), 3.78 (3H, s), 3.94 (1H, dd, Jˆ11.0, 2.5 Hz),
3.96±3.99 (1H, m), 4.00 (1H, dd, Jˆ15.0, 2.7 Hz), 4.29 (1H,
dd, Jˆ15.0, 5.7 Hz), 4.30 (1H, dd, Jˆ11.0, 5.2 Hz), 4.43
(1H, dd, Jˆ9.0, 2.7 Hz), 4.55 (1H, d, Jˆ10.5 Hz), 4.77
(1H, d, Jˆ10.3 Hz), 4.80 (1H, d, Jˆ10.3 Hz), 4.95 (1H, d,
Jˆ11.0 Hz), 5.13 (1H, dt, Jˆ10.6, 1.5 Hz), 5.32 (1H, dt,
Jˆ17.0, 1.7 Hz), 5.44 (1H, s), 5.75±5.82 (2H, m), 5.88±
5.98 (3H, m), 6.81±6.84 (2H, m), 6.87±6.90 (2H, m),
7.18±7.21 (2H, m), 7.32±7.36 (2H, m), 7.38±7.44 (5H,
m). 13C NMR (50 MHz, CDCl3) d 28.29, 30.66, 34.98,
36.52, 55.69, 55.78, 68.29, 68.98, 74.02, 75.01, 75.91,
75.95, 76.09, 76.19, 76.74, 77.71, 80.32, 81.18, 81.55,
85.85, 86.24, 86.31, 88.75, 101.30, 114.14, 114.22,
114.80, 115.22, 127.27, 127.63, 127.95, 128.02, 128.28,
128.29, 128.38, 128.76, 128.83, 130.40, 130.61, 130.80,
4.2.3. Alcohol (28). A solution of 27 (63.5 mg, 65.8 mmol)
in CH2Cl2 (1.0 mL) and H2O (50 mL) was treated with DDQ
(22.4 mg, 98.7 mmol) at 08C. The reaction mixture was
allowed to warm to room temperature, and stirred for 1 h.
The solution was diluted with Et2O (1.0 mL) and saturated
aqueous Na2S2O3 was added. The organic layer was sepa-
rated, and the aqueous layer was extracted with EtOAc. The
combined organic extracts were washed with saturated
aqueous NaHCO3 and brine. After being dried over
MgSO4, the solution was concentrated under reduced
pressure. The residue was puri®ed by silica gel column
chromatography (hexane/EtOAcˆ10:1±6:1) to give

1846
M. Maruyama et al. / Tetrahedron 58 (2002)1835±1851
41.8 mg (49.5 mmol, 76%) of 28 (C11R/C11Sˆ6:1) as a
colorless oil. Analytical sample of 28-R was obtained by
the further puri®cation with silica gel column. Data for
7.30 (1H, m), 7.34±7.36 (2H, m), 7.39±7.41 (2H, m); 13C
NMR (50 MHz, CDCl3) d 12.38, 13.11, 17.08, 17.23, 30.25,
31.89, 34.28, 63.73, 67.16, 68.34, 70.22, 72.18, 75.57,
76.70, 78.21, 81.43, 81.69, 82.21, 84.43, 86.87, 116.58,
125.68, 126.32, 127.72, 127.95, 128.33, 128.55, 131.38,
137.32, 137.72, 138.37, 171.39; MALDI-TOF MS calcd
for C41H62O10Si2Na (M1Na1) 793.38, found 793.30. Data
29
28-R: [a]D ˆ277.68 (c 1.00, CHCl3); IR (®lm) n 3437,
1
2943, 2867, 2361, 1745, 1367, 1090, 885, 698 cm21; H
NMR (500 MHz, CDCl3) d 1.04±1.06 (28H, m), 1.47
(9H, s), 2.16 (1H, ddd, Jˆ13.0, 10.8, 1.8 Hz), 2.21 (1H, d,
Jˆ1.4 Hz), 2.31±2.38 (2H, m), 2.57 (1H, dd, Jˆ8.0,
3.0 Hz), 2.60 (1H, dd, Jˆ8.0, 4.2 Hz), 3.18 (1H, td,
Jˆ9.0, 4.0 Hz), 3.24 (1H, t, Jˆ8.0 Hz), 3.34±3.40 (1H,
dd, Jˆ9.0, 2.9 Hz), 4.71 (1H, d, Jˆ11.6 Hz), 4.99 (1H, d,
Jˆ11.3 Hz), 5.09 (1H, d, Jˆ11.2 Hz), 5.64 (1H, d,
Jˆ17.0 Hz), 5.73±5.83 (3H, m), 5.89±5.93 (1H, m), 5.90
(1H, ddd, Jˆ15.6, 10.2, 4.3 Hz), 7.35±7.37 (5H, m). 13C
NMR (50 MHz, CDCl3) d 12.17, 12.40, 17.41, 29.88,
34.49, 60.38, 63.73, 67.21, 67.74, 67.77, 73.67, 75.20,
76.15, 76.37, 77.37, 77.64, 81.33, 84.39, 85.12, 87.99,
112.34, 115.93, 125.65, 127.61, 127.80, 128.54, 129.10,
131.61, 137.46, 137.59, 173.05; MALDI-TOF MS calcd
for C45H72O11Si2Na (M1Na1) 867.45, found 867.21.
28
for 29-S: [a]D ˆ2105.08 (c 1.00, CHCl3); IR (®lm) n
1
2944, 2867, 1759, 1465, 1089, 787, 748 cm21; H NMR
(500 MHz, CDCl3) d 1.03±1.06 (28H, m), 1.91 (1H, ddd,
Jˆ14.8, 9.0, 3.0 Hz), 2.30±2.41 (2H, m), 2.55±2.67 (3H,
m), 3.25 (1H, d, Jˆ9.0 Hz), 3.29 (1H, td, Jˆ9.2, 4.0 Hz),
3.34 (1H, t, Jˆ8.0 Hz), 3.48 (1H, dd, Jˆ18.0, 8.2 Hz), 3.56
(1H, t, Jˆ8.2 Hz), 3.77±3.81 (2H, m), 3.90 (1H, dd, Jˆ11.6,
1.0 Hz), 4.01 (1H, dd, Jˆ15.0, 2.5 Hz), 4.10 (1H, dd, Jˆ7.0,
3.4 Hz), 4.15 (1H, dd, Jˆ11.6, 1.4 Hz), 4.30 (1H, dd,
Jˆ15.0, 5.5 Hz), 4.48 (1H, t, Jˆ9.3 Hz), 4.71±4.73 (1H,
m), 4.81 (1H, d, Jˆ11.5 Hz), 4.87 (1H, d, Jˆ11.5 Hz),
5.09 (1H, dd, Jˆ10.2, 1.5 Hz), 5.26 (1H, dd, Jˆ16.5,
1.5 Hz), 5.57 (1H, dddd, Jˆ17.0, 10.5, 6.5, 2.0 Hz), 5.75±
5.78 (1H, m), 5.84 (1H, dd, Jˆ10.5, 4.8 Hz), 5.86±5.90 (1H,
m), 5.95 (1H, ddd, Jˆ16.5, 10.2, 5.7 Hz), 7.35±7.38 (2H,
m), 7.38±7.42 (2H, m); 13C NMR (50 MHz, CDCl3) d
12.42, 13.29, 17.24, 17.29, 28.00, 33.15, 34.33, 63.60,
70.92, 72.06, 75.27, 76.53, 78.93, 81.66, 81.73, 81.88,
84.06, 86.63, 117.26, 124.41, 126.34, 127.50, 127.75,
128.19, 128.55, 131.45, 136.39, 138.38, 138.59, 168.27;
MALDI-TOF MS calcd for C41H62O10Si2Na (M1Na1)
793.30, found 793.21.
4.2.4. Lactone (29). A solution of 28 (C11R/C11Sˆ6:1,
41.8 mg, 49.5 mmol) in toluene (1.0 mL) was treated with
CSA (11.5 mg, 49.5 mmol) at room temperature. The
mixture was heated to 708C for 15 h. The reaction mixture
was quenched with a saturated aqueous NaHCO3, and
diluted with EtOAc. The organic layer was separated, and
the aqueous layer was extracted with EtOAc. The combined
organic extracts were washed with saturated aqueous NH4Cl
and brine. After being dried over MgSO4, the mixture was
concentrated under reduced pressure. The residue was
quickly puri®ed by open silica gel column chromatography
(hexane/EtOAcˆ15:1±10:1) to give 31.3 mg (40.6 mmol,
82%) of 29 (C11R/C11Sˆ6:1) as a colorless oil.
4.2.6. Diene (32). To a solution of 29-S (9.9 mg, 12.8 mmol)
in Et2O (700 mL) at 2788C was added vinylmagnesium
bromide (79.0 mL, 1.0 M in THF, 79.0 mmol) dropwise
over 70 min. The reaction mixture was quenched with
saturated aqueous NH4Cl, and diluted with EtOAc. The
organic layer was separated, and the aqueous layer was
extracted with EtOAc. The combined organic extracts
were washed with saturated aqueous NaHCO3 and brine.
After being dried over MgSO4, the solution was concen-
trated under reduced pressure. The residue was puri®ed by
silica gel column chromatography (hexane/EtOAcˆ15:1±
10:1) to give 8.0 mg (10.0 mmol, 78%) of 30 as a colorless
oil.
4.2.5. Epimerization of lactone 29. A solution of 29
(C11R/C11Sˆ6:1, 31.3 mg, 40.6 mmol) in toluene (2.5 mL)
was treated with imidazole (27.6 mg, 406 mmol) at room
temperature. The mixture was heated to 1108C for 14 h.
The reaction mixture was quenched with saturated aqueous
NH4Cl, and diluted with EtOAc. The organic layer was
separated, and the aqueous layer was extracted with
EtOAc. The combined organic extracts were washed with
saturated aqueous NaHCO3 and brine. After being dried
over MgSO4, the mixture was concentrated under reduced
A solution of 30 (15.8 mg, 19.7 mmol) in CH2Cl2 (700 mL)
was treated with methyl orthoformate (32.3 mL,
295.5 mmol) and CSA (2.3 mg, 9.9 mmol), and stirred for
11 h at room temperature. The reaction mixture was
quenched by saturated aqueous NaHCO3 and diluted with
Et2O. The organic layer was separated, and the aqueous
layer was extracted with EtOAc. The combined organic
extracts were washed with saturated aqueous NaHCO3 and
brine. After being dried over MgSO4, the mixture was
concentrated under reduced pressure. The residue was
puri®ed by silica gel column chromatography (hexane/
EtOAcˆ20:1±16:1) to give 13.7 mg (16.8 mmol, 86%) of
31 as a colorless oil.
1
pressure. The isomer ratio was determined by H NMR
analysis of crude mixture (C11R/C11Sˆ1.8:1). The residue
was puri®ed by preparative TLC (hexane/EtOAcˆ4:1) to
give 15.0 mg (19.4 mmol, 48%) of 29-R as a colorless oil
and 7.5 mg (9.7 mmol, 24%) of 29-S as a colorless oil. Data
27
for 29-R: [a]D ˆ2121.88 (c 1.00, CHCl3); IR (®lm) n
1
2944, 2867, 1771, 1464, 1090, 886, 697 cm21; H NMR
(500 MHz, CDCl3) d 1.03±1.06 (28H, m), 1.57±1.63 (1H,
m), 2.14±2.19 (2H, m), 2.31 (1H, ddd, Jˆ16.2, 9.5, 2.6 Hz),
2.62±2.66 (2H, m), 3.25 (1H, d, Jˆ9.0 Hz), 3.30 (1H, td,
Jˆ9.5, 4.0 Hz), 3.35 (1H, t, Jˆ8.2 Hz), 3.51 (1H, dd, Jˆ8.7,
2.7 Hz), 3.51±3.54 (1H, m), 3.61 (1H, t, Jˆ8.2 Hz), 3.85
(1H, dd, Jˆ8.7, 6.7 Hz), 3.89 (1H, d, Jˆ11.4 Hz), 3.96±
3.90 (2H, m), 4.15±4.18 (2H, m), 4.29 (1H, dd, Jˆ15.3,
5.9 Hz), 4.71 (1H, dd, Jˆ9.5, 4.0 Hz), 4.84 (1H, d,
Jˆ11.0 Hz), 4.87 (1H, d, Jˆ11.0 Hz), 5.14 (1H, dd,
Jˆ10.0, 1.5 Hz), 5.28 (1H, dd, Jˆ16.8, 1.5 Hz), 5.75±
5.91 (4H, m), 5.92 (1H, ddd, Jˆ16.8, 10.0, 6.5 Hz), 7.28±
A solution of 31 (13.7 mg, 16.8 mmol) and triethylsilane
(108.0 mL, 674 mmol) in CH2Cl2 (1.0 mL) was treated
with boron tri¯uoride diethyl etherate (12.8 mL,
112 mmol) at 2508C. The mixture was allowed to warm
to 2308C, and stirred for 30 min. The reaction mixture

M. Maruyama et al. / Tetrahedron 58 (2002)1835±1851
1847
was quenched with triethylamine (5.0 mL), and diluted with
Et2O and saturated aqueous NaHCO3. The organic layer was
separated, and the aqueous layer was extracted with EtOAc.
The combined organic extracts were washed with saturated
aqueous NaHCO3 and brine. After being dried over MgSO4,
the mixture was concentrated under reduced pressure. The
residue was puri®ed by silica gel column chromatography
(hexane/EtOAcˆ20:1±16:1) to give 10.5 mg (13.4 mmol,
tube was added Grubbs catalyst 16.6 mg (20.1 mmol) in
nine equal portions over 11 h at 458C, and the reaction
mixture was quenched with triethylamine (100 mL) in
CHCl3 (1.0 mL). Concentration and silica gel column
chromatography (hexane/EtOAcˆ16:1±12:1) gave 4.2 mg
29
(7.04 mmol, 98%) of 34 as a colorless oil. [a]D ˆ254.08 (c
0.28, CHCl3); IR (®lm) n 2932, 1749, 1508, 1243,
1
1092 cm21; H NMR (500 MHz, CDCl3) d 1.43 (1H, q,
30
87%) of 32 as a colorless oil. [a]D ˆ258.08 (c 0.53,
Jˆ11.3 Hz), 2.05 (3H, s), 2.06 (3H, s), 2.30 (1H, dt,
Jˆ11.3, 3.8 Hz), 2.30±2.35 (1H, m), 2.33 (1H, dd,
Jˆ14.0, 9.0 Hz), 2.64 (1H, ddd, Jˆ16.1, 7.8, 3.5 Hz), 2.80
(1H, ddd, Jˆ14.0, 10.0, 3.3 Hz), 3.06 (1H, t, Jˆ9.0 Hz),
3.11 (1H, dt, Jˆ9.0, 3.6 Hz), 3.28 (1H, td, Jˆ9.2, 3.8 Hz),
3.28±3.33 (1H, m), 3.33 (1H, t, Jˆ8.3 Hz), 3.47 (1H, t,
Jˆ8.3 Hz), 3.67 (1H, dt, Jˆ9.0, 3.0 Hz), 3.71 (1H, ddd,
Jˆ10.0, 6.3, 2.1 Hz), 3.80 (1H, ddd, Jˆ9.2, 4.3, 2.5 Hz),
4.01 (1H, ddd, Jˆ15.4, 6.2, 3.0 Hz), 4.11 (1H, dt, Jˆ9.0,
2.2 Hz), 4.16 (1H, dd, Jˆ10.9 Hz), 4.22 (1H, dt, Jˆ10.9,
6.3 Hz), 4.29 (1H, dd, Jˆ15.4, 5.8 Hz), 4.82 (2H, d,
Jˆ11.6 Hz), 4.87 (2H, d, Jˆ11.6 Hz), 5.57 (1H, dd,
Jˆ11.0, 5.2 Hz), 5.62 (1H, dt, Jˆ12.5, 2.4 Hz), 5.75±5.79
(2H, m), 5.80 (1H, dt, Jˆ12.5, 2.7 Hz), 5.83±5.89 (2H, m),
7.30±7.35 (3H, m), 7.38±7.41 (2H, m); 13C NMR (50 MHz,
CDCl3) d 20.91, 21.03, 32.58, 34.64, 36.82, 64.67, 68.37,
70.48, 73.15, 74.81, 75.17, 75.49, 75.69, 75.96, 80.51,
81.76, 81.82, 82.08, 84.39, 87.39, 126.50, 126.73, 127.42,
127.52, 127.73, 128.19, 131.08, 131.34, 132.16, 134.42,
139.15, 168.61, 169.56; MALDI-TOF MS calcd for
C33H40O10Si2Na (M1Na1) 619.25, found 619.18.
CHCl3); IR (®lm) n 2945, 2868, 2361, 1465, 1087, 913,
1
788, 747 cm21; H NMR (500 MHz, CDCl3) d 1.03±1.06
(28H, m), 1.62±1.69 (1H, m), 2.25±2.37 (2H, m), 2.29 (1H,
td, Jˆ6.2, 4.0 Hz), 2.46 (1H, dt, Jˆ11.3, 3.8 Hz), 2.60±2.66
(2H, m), 3.14 (1H, dd, Jˆ10.6, 3.8 Hz), 3.16±3.23 (2H, m),
3.31 (1H, dd, Jˆ8.7, 4.7 Hz), 3.34 (1H, t, Jˆ7.2 Hz), 3.49
(1H, t, Jˆ8.2 Hz), 3.54 (1H, dt, Jˆ8.2, 2.4 Hz), 3.65 (1H,
dd, Jˆ9.2, 4.9 Hz), 3.80 (1H, dd, Jˆ9.0, 5.6 Hz), 3.91 (1H,
dd, Jˆ11.6, 4.4 Hz), 4.03 (1H, dt, Jˆ15.3, 2.6 Hz), 4.16
(1H, dd, Jˆ11.2, 1.4 Hz), 4.30 (1H, dd, Jˆ14.0, 5.6 Hz),
4.72 (1H, ddd, Jˆ9.0, 4.3, 2.1 Hz), 4.80 (1H, d, Jˆ11.3 Hz),
4.89 (1H, d, Jˆ11.3 Hz), 5.12 (1H, dd, Jˆ11.0, 1.4 Hz),
5.20 (1H, dd, Jˆ10.0, 1.3 Hz), 5.30 (1H, dd, Jˆ17.0,
1.6 Hz), 5.37 (1H, dd, Jˆ17.0, 1.2 Hz), 5.58±5.65 (1H,
m), 5.74±5.90 (4H, m), 5.97 (1H, ddd, Jˆ17.0, 10.3,
5.0 Hz), 7.30±7.34 (3H, m), 7.38±7.41 (2H, m); 13C NMR
(50 MHz, CDCl3) d 12.43, 13.26, 17.24, 17.31, 30.49,
34.66, 63.63, 67.23, 68.41, 73.11, 74.99, 75.39, 75.79,
76.18, 76.76, 80.34, 81.06, 81.94, 87.18, 112.30, 115.77,
124.91, 126.55, 127.39, 127.85, 128.16, 131.37, 135.39,
137.22, 137.96, 139.12; MALDI-TOF MS calcd for
C43H66O9Si2Na (M1Na1) 805.41, found 805.12.
4.3. Modi®cation of the construction of CD ring system
4.2.7. Diacetate (33). A solution of 32 (6.9 mg, 8.82 mmol)
in THF (700 mL) was treated with TBAF (27.0 mL, 1.0 M in
THF, 27.0 mmol) and stirred for 20 min at room tempera-
ture. The reaction mixture was concentrated under reduced
pressure, and dissolved in pyridine (500 mL). The solution
was then treated with acetic acid anhydride (80.0 mL), and
stirred at room temperature for an hour. The reaction
mixture was concentrated under reduced pressure. The resi-
due was puri®ed by ¯ash column chromatography (hexane/
EtOAcˆ10:1±6:1) to give 4.5 mg (7.20 mmol, 82%) of 33
n 2983, 1745, 1598, 1244, 1101 cm21; 1H NMR (500 MHz,
CDCl3) d 1.70 (1H, q, Jˆ11.6 Hz), 2.05 (3H, s), 2.06 (3H,
s), 2.32±2.39 (2H, m), 2.47 (1H, dt, Jˆ11.6, 3.9 Hz), 2.65
(1H, ddd, Jˆ15.9, 8.2, 3.7 Hz), 2.73 (1H, ddd, Jˆ11.7, 9.8,
2.4 Hz), 3.13±3.17 (2H, m), 3.21 (1H, t, Jˆ9.6 Hz), 3.30
(1H, td, Jˆ9.7, 4.0 Hz), 3.35 (1H, t, Jˆ8.0 Hz), 3.48 (1H, t,
Jˆ8.2 Hz), 3.54 (1H, dt, Jˆ9.1, 2.7 Hz), 3.63±3.68 (2H, m),
3.79 (1H, dd, Jˆ8.6, 4.2 Hz), 4.03 (1H, ddd, Jˆ15.6, 5.0,
2.4 Hz), 4.20±4.24 (1H, m), 4.31 (1H, dd, Jˆ11.0, 4.8 Hz),
5.74±5.79 (3H, m), 5.87 (1H, ddd, Jˆ11.3, 5.5, 2.8 Hz),
5.97±5.99 (2H, m), 7.29±7.34 (2H, m), 7.38±7.41 (2H,
m); 13C NMR (50 MHz, CDCl3) d 16.86, 30.70, 36.64,
37.38, 64.49, 68.43, 70.49, 73.00, 75.09, 76.16, 76.79,
80.35, 81.04, 81.18, 81.90, 81.97, 82.93, 87.18, 115.39,
116.76, 126.41, 127.85, 128.17, 131.31, 131.37, 132.80,
135.27, 136.74, 139.07, 169.61, 170.83; MALDI-TOF MS
calcd for C35H44O10Si2Na (M1Na1) 647.28, found 647.17.
4.3.1. Aldehyde (35). A solution of 27 (331.8 mg,
344.0 mmol) in CH2Cl2 (7.0 mL) was treated with DIBALH
(398.0 mL, 0.95 M in hexane, 378.4 mmol) at 2788C, and
stirred for an hour at 2608C. Then, the reaction mixture was
quenched with EtOAc. A saturated aqueous solution of
potassium sodium (1)-tartrate was added to the mixture,
and the resultant solution was stirred vigorously for an
hour. The organic layer was separated, and the aqueous
layer was extracted with EtOAc. The combined organic
extracts were washed with NaHCO3 and brine. After
being dried over MgSO4, the mixture was concentrated
under reduced pressure. The residue was puri®ed by silica
gel column chromatography (hexane/EtOAcˆ16:1±8:1) to
give 273.2 mg (306.1 mmol, 89%) of 35 (C11R/C11Sˆ6:1) as
a colorless oil. IR (®lm) n 699, 1028, 1090, 1250, 1466,
29
as a colorless oil. [a]D ˆ267.18 (c 0.35, CHCl3); IR (®lm)
;
1514, 1736, 2867, 2944 cm21 1H NMR (500 MHz,
CDCl3, major isomer) d 1.05 (28H, m), 1.49 (1H, ddd,
Jˆ14.7, 10.8, 3.8 Hz), 2.00 (1H, ddd, Jˆ13.8, 10.8,
2.0 Hz), 2.24 (1H, ddd, Jˆ14.2, 7.0, 2.9 Hz), 2.27±2.33
(1H, m), 2.55 (1H, ddd, Jˆ15.9, 8.0, 4.0 Hz), 2.66 (1H,
ddd, Jˆ14.2, 10.7, 2.1 Hz), 3.13 (1H, td, Jˆ10.0, 4.0 Hz),
3.17 (1H, t, Jˆ9.0 Hz), 3.26 (1H, bd, Jˆ8.9 Hz), 3.35 (1H, t,
Jˆ8.7 Hz), 3.40±3.46 (2H, m), 3.57 (1H, t, Jˆ8.7 Hz), 3.89
(1H, dd, Jˆ9.0, 5.8 Hz), 3.92 (1H, dd, Jˆ11.6, 1.0 Hz), 3.96
(1H, ddd, Jˆ15.2, 3.8, 2.0 Hz), 4.00 (1H, dd, Jˆ15.4,
2.8 Hz), 4.17 (1H, dd, Jˆ11.6, 1.7 Hz), 4.28 (1H, dd,
Jˆ15.4, 5.8 Hz), 4.51 (1H, d, Jˆ10.5 Hz), 4.73 (1H, ddd,
Jˆ8.9, 5.0, 2.1 Hz), 4.79 (2H, d, Jˆ10.5 Hz), 4.95 (1H, d,
Jˆ10.8 Hz), 5.15 (1H, d, Jˆ10.4 Hz), 5.33 (1H, d,
Jˆ16.9 Hz), 5.66±5.73 (1H, m), 5.81 (1H, ddt, Jˆ11.3,
8.0, 2.8 Hz), 5.87 (1H, dd, Jˆ11.0, 5.0 Hz), 5.91 (1H,
4.2.8. ABCDE ring system (34). To a solution of 33
(4.5 mg, 7.2 mmol) in CDCl3 (800 mL, 0.009 M) in NMR

1848
M. Maruyama et al. / Tetrahedron 58 (2002)1835±1851
ddd, Jˆ11.0, 5.8, 2.8 Hz), 5.94 (1H, ddd, Jˆ16.9, 10.4,
5.8 Hz), 6.82±6.86 (2H, m), 7.15±7.18 (2H, m), 7.28±
7.31 (1H, m), 7.32±7.36 (2H, m), 7.37±7.40 (2H, m), 9.66
(1H, d, Jˆ2.0 Hz); 13C NMR (50 MHz, CDCl3) d 12.43,
12.66, 13.41, 13.54, 30.42, 33.48, 34.68, 55.49, 63.93,
67.47, 68.12, 73.57, 74.95, 75.65, 75.92, 81.57, 81.81,
81.83, 84.78, 84.84, 85.85, 88.59, 114.03, 116.44, 125.10,
127.43, 127.78, 128.09, 128.58, 129.94, 130.53, 131.87,
137.45, 138.46, 139.31, 159.58, 203.05; MALDI-TOF MS
calcd for C49H72O11Si2Na (M1Na1) 915.45, found 915.36.
Jˆ9.8 Hz), 3.80 (3H, s), 3.92 (1H, bd.Jˆ11.0 Hz), 4.00
(1H, dd, Jˆ14.9, 2.0 Hz), 4.12±4.16 (3H, m, H12), 4.20
(1H, d, Jˆ11.0 Hz), 4.29 (1H, dd, Jˆ15.6, 6.0 Hz), 4.57
(1H, d, Jˆ10.5 Hz), 4.71 (1H, dd, Jˆ8.9, 4.2 Hz), 4.81
(1H, d, Jˆ11.3 Hz), 4.84 (1H, d, Jˆ10.5 Hz), 4.96 (1H, d,
Jˆ11.3 Hz), 5.64 (1H, dt, Jˆ12.6, 2.4 Hz), 5.68±5.72 (1H,
m), 5.76 (1H, dd, Jˆ11.0, 4.8 Hz), 5.78 (1H, dt, Jˆ8.3,
2.6 Hz), 5.84 (1H, dt, Jˆ12.6, 2.4 Hz), 5.92 (1H, ddd,
Jˆ11.0, 5.8, 2.0 Hz), 6.86±6.89 (2H, m), 7.23±7.26 (2H,
m), 7.29±7.31 (1H, m), 7.34±7.38 (2H, m), 7.39±7.42 (2H,
m); 13C NMR (50 MHz, CDCl3) d 12.09, 12.40, 13.18,
13.29, 29.68, 32.65, 34.56, 34.93, 55.27, 64.08, 67.07,
67.86, 72.47, 74.55, 75.69, 80.80, 80.91, 81.59, 83.98,
84.96, 85.31, 88.03, 113.79, 125.96, 126.61, 127.53,
127.83, 128.34, 129.30, 130.45, 131.62, 131.83, 133.29,
135.13, 136.95, 139.09, 139.57, 159.24; MALDI-TOF MS
calcd for C49H72O11Si2Na (M1Na1) 915.45, found 915.31.
4.3.2. Epimerization of aldehyde 35. A solution of 35
(C11R/C11Sˆ6:1, 115.6 mg, 129.5 mmol) in toluene
(16 mL) was treated with imidazole (132 mg, 1.94 mmol),
and heated to 1008C for 16 h. The reaction mixture was
poured into a vigorously stirred solution of saturated
aqueous NH4Cl (100 mL). The organic layer was separated,
and the aqueous layer was extracted with EtOAc. The
combined organic extracts were washed with NaHCO3
and brine. After being dried over MgSO4, the mixture was
concentrated under reduced pressure. The residue was puri-
®ed by silica gel column chromatography (hexane/
EtOAcˆ16:1±8:1) to give 114.4 mg (128.2 mmol, 99%)
of 35 (C11R/C11Sˆ3:1) as a colorless oil.
4.3.5. Enone (39-S) from 37. A solution of (COCl)2
(52.0 mL, 599.0 mmol) in CH2Cl2 (1.0 mL) was treated
with DMSO (68.0 mL, 960.0 mmol) at 2788C for 10 min.
A solution of 37 (10.7 mg, 12.0 mmol) in CH2Cl2 (1.0 mL)
was added dropwise through cannula over 1 min. After an
hour at 2788C, Et3N (200 mL, 1.4 mmol) was added at
2478C. After being stirred at 2358C for 30 min, the reac-
tion was quenched with saturated aqueous NH4Cl. The
organic layer was separated, and the aqueous layer was
extracted with EtOAc. The combined organic extracts
were washed with NaHCO3 and brine. After being dried
over MgSO4, the mixture was concentrated under reduced
pressure. The residue was puri®ed by ¯ash silica gel column
chromatography (hexane/EtOAcˆ20:1±14:1) to give
8.3 mg (9.3 mmol, 78%) of 39-S as a colorless oil.
4.3.3. Diene (36). A solution of tetravinyltin (32.0 mL,
176 mmol) in Et2O (1.0 mL) was treated with methyllithium
(460.0 mL, 1.14 M hexane, 847 mmol) at 2788C, and stirred
for 1 min. Then, a solution of 35 (C11R/C11Sˆ3:1, 125.5 mg,
140.6 mmol) in Et2O (1.0 mL) was added dropwise through
cannula over 1 min. After being stirred for 13 min, the reac-
tion mixture was quenched with saturated aqueous NH4Cl,
and diluted with EtOAc. The organic layer was separated,
and the aqueous layer was extracted with EtOAc. The
combined organic extracts were washed with NaHCO3
and brine. After being dried over MgSO4, the mixture was
concentrated under reduced pressure. The residue was puri-
®ed by ¯ash silica gel column chromatography (hexane/
EtOAcˆ16:1±8:1) to give 121.5 mg (131.9 mmol, 94%)
of 36 as a colorless oil as a mixture of four diastereomers.
IR (®lm) n 698, 1090, 1249, 1466, 1514, 1612, 2338, 2362,
2867, 2943, 3377 cm21; MALDI-TOF MS calcd for
C51H76O11Si2Na (M1Na1) 943.48, found 943.32.
29
[a]D ˆ231.78 (c 0.91, CHCl3); IR (®lm) n 698, 1089,
1249, 1514, 1665, 2360, 1867, 1944 cm21 1H NMR
;
(500 MHz, CDCl3) d 1.05 (28H, m), 1.88 (1H, ddd,
Jˆ13.4, 9.2, 3.3 Hz), 2.20±2.26 (1H, m), 2.29 (1H, ddd,
Jˆ13.4, 6.2, 3.1 Hz), 2.39 (1H, ddd, Jˆ12.8, 5.3, 1.2 Hz),
2.51 (1H, ddd, Jˆ16.3, 7.7, 4.0 Hz), 2.68 (1H, ddd, Jˆ12.8,
10.0, 3.0 Hz), 3.11 (1H, td, Jˆ9.9, 4.0 Hz), 3.22 (1H, t,
Jˆ8.8 Hz), 3.30 (1H, t, Jˆ8.7 Hz), 3.42 (1H, bd,
Jˆ9.2 Hz), 3.48 (1H, td, Jˆ9.5, 3.1 Hz), 3.56 (1H, t,
Jˆ8.8 Hz), 3.71 (1H, dt, Jˆ8.9, 3.0 Hz), 3.94 (1H, bd,
Jˆ12.2 Hz), 3.98 (1H, bd, Jˆ15.3 Hz), 4.22±4.28 (4H,
m), 4.55 (1H, d, Jˆ10.3 Hz), 4.69±4.73 (1H, m), 4.79
(2H, bd, Jˆ10.7 Hz), 4.93 (1H, d, Jˆ11.0 Hz), 5.70±5.78
(2H, m), 5.82±5.88 (3H, m), 6.46 (1H, dd, Jˆ12.3, 1.9 Hz),
6.84±6.87 (2H, m), 7.19±7.22 (2H, m), 7.27±7.31 (1H, m),
7.32±7.35 (2H, m), 7.37±7.39 (2H, m); 13C NMR (50 MHz,
CDCl3) d 12.12, 12.41, 13.12, 13.29, 31.59, 34.23, 35.87,
55.25, 63.67, 67.02, 67.97, 69.24, 74.75, 75.55, 75.93,
79.65, 81.06, 83.19, 84.63, 85.76, 88.21, 113.82, 125.61,
126.92, 127.09, 127.48, 127.83, 128.31, 129.75, 130.36,
131.27, 138.08, 139.12, 145.62, 159.29, 203.97; MALDI-
TOF MS calcd for C49H70O11Si2Na (M1Na1) 913.44, found
913.81.
4.3.4. Ring-closing metathesis reaction of diene 36. To a
solution of 36 (140.6 mg, 152.7 mmol) in CH2Cl2 (16 mL,
0.009 M) was added Grubbs catalyst (8.8 mg, 10.7 mmol,
7 mol%) at 358C, and the resultant mixture was stirred for
2.5 h. The reaction was then quenched with triethylamine
(100 mL). Concentration and silica gel column chromato-
graphy
(hexane/EtOAcˆ16:1±6:1)
gave
40.9 mg
(45.87 mmol, 30%) of 37 as a colorless oil, along with
90.2 mg (101.0 mmol, 66%) of 38 as a mixture of three
29
diastereomers. Data for 37: [a]D ˆ299.58 (c 0.892,
CHCl3); IR (®lm) n 1090, 1249, 1466, 1612, 2338, 2868,
2943, 3378 cm21; 1H NMR (500 MHz, CDCl3) d 1.04±1.06
(28H, m), 1.80 (1H, ddd, Jˆ15.4, 8.8, 3.2 Hz), 2.16 (1H, dd,
Jˆ15.4, 3.4 Hz), 2.21 (1H, ddd, Jˆ13.2, 6.7, 2.2 Hz), 2.30±
2.37 (1H, m), 2.60 (1H, ddd, Jˆ15.3, 8.0, 3.9 Hz), 2.70 (1H,
ddd, Jˆ13.2, 9.3, 3.9 Hz), 3.20 (1H, t, Jˆ9.4 Hz), 3.28 (1H,
bd, Jˆ8.9 Hz), 3.32 (1H, td, Jˆ9.7, 3.9 Hz), 3.37 (1H, t,
Jˆ9.0 Hz), 3.41 (1H, dt, Jˆ8.8, 3.4 Hz), 3.62 (1H, dt,
Jˆ8.7, 2.9 Hz). 3.66 (1H, t, Jˆ8.4 Hz), 3.68 (1H, bt,
4.3.6. Enone (39-S) from 38. A solution of (COCl)2
(194.0 mL, 2.2 mmol) in CH2Cl2 (2.0 mL) was treated
with DMSO (252.0 mL, 3.5 mmol) at 2788C, and stirred
for 10 min. Then, a solution of 38 (39.6 mg, 44.4 mmol) in
CH2Cl2 (2.0 mL) was added dropwise through cannula over
1 min. After an hour at 2788C, Et3N (743.0 mL, 5.3 mmol)

M. Maruyama et al. / Tetrahedron 58 (2002)1835±1851
1849
was added to this mixture at 2508C, and the resultant solu-
tion was stirred at 2358C for 30 min. The reaction was
quenched with saturated aqueous NH4Cl. The organic
layer was separated, and the aqueous layer was extracted
with EtOAc. The combined organic extracts were washed
with NaHCO3 and brine. After being dried over MgSO4, the
mixture was concentrated under reduced pressure. The
residue was puri®ed by ¯ash silica gel column chromato-
graphy (hexane/EtOAcˆ20:1±14:1) to give 34.9 mg
(39.2 mmol, 88%) of 39 (C11R/C11Sˆ5:1) as a colorless
give 52.8 mg (68.5 mmol, 94%) of 40 as a colorless oil.
29
[a]D ˆ247.48 (c 0.57, CHCl3); IR (®lm) n 886, 1027,
1
1089, 1466, 1665, 2364, 2867, 2944, 3469 cm21; H NMR
(500 MHz, CDCl3) d 1.05 (28H, m), 1.91 (1H, ddd, Jˆ14.0,
8.6, 4.6 Hz), 2.30 (1H, ddd, Jˆ14.0, 5.6, 2.5 Hz), 2.30±2.35
(1H, m), 2.41 (1H, ddd, Jˆ13.2, 6.2, 2.0 Hz), 2.52 (1H, ddd,
Jˆ11.2, 7.9, 4.0 Hz), 2.70 (1H, ddd, Jˆ13.2, 10.0, 3.7 Hz),
3.15 (1H, td, Jˆ9.4, 3.8 Hz), 3.31 (1H, t, Jˆ8.6 Hz), 3.32
(1H, r, Jˆ8.3 Hz), 3.38 (1H, t, Jˆ8.5 Hz), 3.40±3.44 (2H,
m), 3.74 (1H, ddd, Jˆ8.6, 3.7, 2.0 Hz), 3.94 (1H, dd,
Jˆ11.4, 1.6 Hz), 3.98 (1H, dd, Jˆ15.3, 3.0 Hz), 4.22±
4.30 (4H, m), 4.71 (1H, d, Jˆ11.3 Hz), 4.73 (1H, ddd,
Jˆ9.1, 4.9, 1.8 Hz), 4.97 (1H, d, Jˆ11.3 Hz), 5.75±5.79
(2H, m), 5.83±5.89 (3H, m), 6.48 (1H, dd, Jˆ12.5,
2.4 Hz), 7.35±7.37 (5H, m); 13C NMR (50 MHz, CDCl3)
d 12.12, 12.42, 13.13, 13.31, 31.56, 34.26, 36.02, 63.67,
67.03, 67.89, 73.38, 74.31, 75.06, 75.97, 79.60, 82.83,
83.25, 84.61, 84.92, 87.76, 125.53, 126.98, 127.19,
127.76, 127.82, 128.53, 131.31, 138.18, 138.97, 145.82,
203.78; MALDI-TOF MS calcd for C41H62O10Si2Na
(M1Na1) 793.39, found 793.26.
1
oil. Data for 39-R: H NMR (500 MHz, CDCl3) d 1.05
(28H, m), 1.95 (1H, ddd, Jˆ14.7, 10.7, 1.9 Hz), 2.07 (1H,
ddd, Jˆ14.7, 12.2, 1.9 Hz), 2.29±2.42 (2H, m), 2.60 (1H,
ddd, Jˆ16.6, 9.2, 4.4 Hz), 2.70 (1H, ddd, Jˆ13.8, 10.9,
4.0 Hz), 3.24 (1H, btd, Jˆ9.7, 4.9 Hz), 3.26 (1H, t,
Jˆ9.8 Hz), 3.40 (1H, t, Jˆ8.9 Hz), 3.41±3.44 (1H, m),
3.51 (1H, bt, Jˆ9.2 Hz), 3.65 (1H, t, Jˆ8.9 Hz), 3.79 (3H,
s), 3.78±3.81 (1H, m), 3.96 (2H, bd, Jˆ11.0 Hz), 4.02 (1H,
dd, Jˆ15.3, 2.7 Hz), 4.23 (1H, bd, Jˆ11.0 Hz), 4.29 (1H,
dd, Jˆ15.3, 4.9 Hz), 4.36±4.41 (2H, m), 4.55 (2H, d,
Jˆ10.5 Hz), 4.72 (1H, dd, Jˆ7.8, 4.0 Hz), 4.80 (2H, d,
Jˆ11.0 Hz), 4.83 (2H, d, Jˆ10.5 Hz), 4.98 (2H, d,
Jˆ11.0 Hz), 5.72±5.76 (1H, m), 5.77±5.82 (1H, m),
5.85±5.92 (2H, m), 5.92 (1H, dd, Jˆ12.3, 2.3 Hz), 6.63
(1H, dd, Jˆ12.3, 2.8 Hz), 6.81±6.84 (2H, m), 7.15±7.17
(2H, m), 7.29±7.31 (1H, m), 7.34±7.37 (2H, m), 7.39±
7.42 (2H, m); 13C NMR (50 MHz, CDCl3) d 12.11, 12.39,
13.08, 13.27, 31.83, 32.85, 34.49, 55.20, 63.62, 67.00,
67.84, 74.27, 74.95, 75.59, 75.71, 78.72, 79.25, 79.97,
81.25, 84.68, 85.87, 88.24, 113.81, 125.33, 127.12,
127.25, 127.50, 127.81, 128.32, 129.53, 130.31, 138.16,
139.08, 131.51, 147.66, 159.29, 203.12; MALDI-TOF MS
calcd for C49H70O11Si2Na (M1Na1) 913.44, found 913.79.
4.3.8. The ABCDE ring fragment of CTX3C (3). A solu-
tion of 40 (6.3 mg, 8.2 mmol) in CH2Cl2 (1 mL) was treated
with methyl orthoformate (18.0 mL, 163.0 mmol) and CSA
(6.6 mg, 28.6 mmol), and stirred for an hour at room
temperature. The reaction mixture was quenched with satu-
rated aqueous NaHCO3, and diluted with Et2O. The organic
layer was separated, and the aqueous layer was extracted
with Et2O. The combined organic extracts were washed
with NaHCO3 and brine. After being dried over MgSO4,
the mixture was concentrated under reduced pressure. The
residue was puri®ed by silica gel column chromatography
(hexane/EtOAcˆ20:1±14:1) to give 4.1 mg (5.3 mmol,
29
A solution of 39 (C11R/C11Sˆ5:1, 76.8 mg, 86.2 mmol) in
toluene (50 mL) was treated with DBU (177 mL,
1.18 mmol) at room temperature, and heated to 958C for
14 h. The solution was poured into a vigorously stirred solu-
tion of saturated aqueous NH4Cl (140 mL) at 08C. The
organic layer was separated, and the aqueous layer was
extracted with EtOAc. The combined organic extracts
were washed with NaHCO3 and brine. After being dried
over MgSO4, the mixture was concentrated under reduced
pressure. The epimers ratio of the crude mixture was
64%) of methyl acetal 41 as a colorless oil. [a]D
ˆ
291.38 (c 1.01, CHCl3). IR (®lm) n 697, 886, 1028, 1090,
1457, 2867, 2944 cm21; 1H NMR (500 MHz, CDCl3) d 1.05
(28H, m), 1.81 (1H, q, Jˆ11.2 Hz), 2.03 (1H, dt, Jˆ10.3,
4.1 Hz), 2.24 (1H, ddd, Jˆ12.9, 5.8, 1.7 Hz), 2.34 (1H, ddd,
Jˆ16.0, 10.0, 2.7 Hz), 2.64 (1H, ddd, Jˆ15.0, 12.3, 3.7 Hz),
2.69 (1H, ddd, Jˆ12.9, 8.2, 3.0 Hz), 3.14 (1H, td, Jˆ10.2,
4.2 Hz), 3.23 (3H, s), 3.27 (1H, td, Jˆ10.0, 3.7 Hz), 3.33
(1H, t, Jˆ7.7 Hz), 3.34 (1H, d, Jˆ9.0 Hz), 3.35 (1H, t,
Jˆ8.9 Hz), 3.45 (1H, t, Jˆ8.7 Hz), 3.47 (1H, dd, Jˆ12.0,
4.1 Hz), 3.73 (1H, dt, Jˆ8.4, 2.7 Hz), 3.93 (1H, d,
Jˆ11.0 Hz), 4.01 (1H, dd, Jˆ15.3, 1.7 Hz), 4.21 (1H, d,
Jˆ11.3 Hz), 4.30 (1H, dd, Jˆ15.3, 5.6 Hz), 4.30±4.34
(1H, m), 4.70 (1H, dd, Jˆ9.0, 3.5 Hz), 4.84 (1H, d,
Jˆ13.0 Hz), 4.86 (1H, d, Jˆ13.0 Hz), 5.51 (1H, dd,
Jˆ12.0, 2.0 Hz), 5.76±5.81 (3H, m), 5.86 (1H, ddd,
Jˆ10.7, 5.3, 2.8 Hz), 6.07 (1H, ddd, Jˆ12.0, 2.2, 0.8 Hz),
7.24±7.27 (1H, m), 7.30±7.34 (2H, m), 7.38±7.41 (2H, m);
13C NMR (50 MHz, CDCl3) d 12.09, 12.39, 13.13, 13.29,
32.38, 32.83, 34.61, 48.70, 64.10, 67.00, 68.39, 72.88,
73.26, 73.28, 75.20, 79.33, 80.28, 81.83, 84.72, 85.45,
87.59, 98.64, 125.75, 126.84, 127.38, 127.67, 128.15,
129.70, 131.28, 137.08, 139.22, 140.63; MALDI-TOF MS
Calcd for C42H64O10Si2Na (M1Na1) 807.39, found 807.29.
1
determined by H NMR analysis (39-R/39-Sˆ1:4). The
residue was puri®ed by ¯ash silica gel column chromato-
graphy (hexane/etherˆ6:1±4:1) to give 32.0 mg (39-R/39-
Sˆ1:12, 35.9 mmol, 42%), 10.0 mg (39-R/39-Sˆ1:6,
11.2 mmol, 13%), and 25.8 mg (39-R/39-Sˆ1:1,
29.0 mmol, 40%) as colorless oil.
4.3.7. Alcohol (40). A solution of 39-S (65.0 mg,
73.0 mmol) in CH2Cl2 (8.0 mL) and H2O (400 mL) was
treated with DDQ (40.0 mg, 175.2 mmol) at 08C, and stirred
for 10 min. The mixture was allowed to warm to room
temperature, and stirred for 10 min. The solution was
diluted with Et2O (5.0 mL) and saturated aqueous
Na2S2O3. The organic layer was separated, and the aqueous
layer was extracted with EtOAc. The combined organic
extracts were washed with NaHCO3 and brine. After
being dried over MgSO4, the mixture was concentrated
under reduced pressure. The residue was puri®ed by silica
gel column chromatography (hexane/EtOAcˆ16:1±8:1) to
A solution of methyl acetal 41 (43.5 mg, 55.5 mmol) and
triethylsilane (85.0 mL, 529.2 mmol) in CH2Cl2 (3.0 mL)
was treated with boron tri¯uoride diethyl etherate
(17.0 mL, 112.0 mmol) at 2788C. The mixture was allowed

1850
M. Maruyama et al. / Tetrahedron 58 (2002)1835±1851
M.; Tsumuraya, T.; Tomioka, Y.; Mizugaki, M. Synthesis
1999, 1431. (b) Nagumo, Y.; Oguri, H.; Shindo, Y.; Sasaki,
S.-y.; Oishi, T.; Hirama, M.; Tomioka, Y.; Mizugaki, M.;
Tsumuraya, T. Bioorg. Med. Chem. Lett. 2001, 11, 2037.
(c) Hokama, Y.; Takenaka, W. E.; Nishimura, K. L.; Ebesu,
J. S. M.; Bourke, R.; Sullivan, P. K. J. AOAC Int. 1998, 81,
727. (d) Pauillac, S.; Sasaki, M.; Inoue, M.; Naar, J.; Branaa,
P.; Chinain, M.; Tachibana, K.; Legrand, A.-M. Toxicon 2000,
38, 669.
to warm to 2308C, and stirred for 15 min. The reaction
mixture was quenched with triethylamine (60.0 mL), and
diluted with Et2O and saturated aqueous NaHCO3. The
organic layer was separated, and the aqueous layer was
extracted with Et2O. The combined organic extracts were
washed with NaHCO3 and brine. After being dried over
MgSO4, the mixture was concentrated under reduced
pressure. The residue was puri®ed by silica gel column
chromatography (hexane/EtOAcˆ20:1±10:1) to give
41.1 mg (54.4 mmol, 98%) of 3 as a colorless oil.
7. (a) Lombet, A.; Bidard, J.-N.; Lazdunski, M. FEBS Lett. 1987,
219, 355. For a review, see: (b) Dechraoui, M.-Y.; Naar, J.;
Pauillac, S.; Legrand, A.-M. Toxicon 1999, 37, 125.
8. For recent synthetic studies from our laboratory, see: (a) Oishi,
T.; Maruyama, M.; Shoji, M.; Maeda, K.; Kumahara, N.;
Tanaka, S.; Hirama, M. Tetrahedron 1999, 55, 7471.
(b) Oguri, H.; Sasaki, S.; Oishi, T.; Hirama, M. Tetrahedron
Lett. 1999, 40, 5405. (c) Oguri, H.; Tanaka, S.; Oishi, T.;
Hirama, M. Tetrahedron Lett. 2000, 41, 975. (d) Oishi, T.;
Nagumo, Y.; Shoji, M.; Le Brazidec, J.-Y.; Uehara, H.;
Hirama, M. Chem. Commun. 1999, 2035. (e) Oishi, T.;
Tanaka, S.-i.; Ogasawara, Y.; Maeda, K.; Oguri, H.; Hirama,
M. Synlett 2001, 952. (f) Imai, H.; Uehara, H.; Inoue, M.;
Oguri, H.; Oishi, T.; Hirama, M. Tetrahedron Lett. 2001, 42,
6219.
29
[a]D ˆ296.68 (c 1.00, CHCl3); IR (®lm) n 698, 1027,
;
1087, 1467, 2868, 2944 cm21 1H NMR (500 MHz,
CDCl3) d 1.05 (28H, m), 1.51 (1H, q, Jˆ11.8 Hz), 2.24
(1H, ddd, Jˆ13.3, 6.2, 2.7 Hz), 2.29 (1H, dt, Jˆ11.8,
4.1 Hz), 2.30±2.37 (1H, m), 2.64 (1H, ddd, Jˆ16.0, 7.8,
3.8 Hz), 2.71 (1H, ddd, Jˆ13.3, 9.9, 4.0 Hz), 3.05 (1H, t,
Jˆ9.2 Hz), 3.11 (1H, td, Jˆ9.1, 4.1 Hz), 3.22 (1H, ddd,
Jˆ11.4, 9.1, 4.3 Hz), 3.27 (1H, td, Jˆ9.6, 3.8 Hz), 3.30
(1H, d, Jˆ8.6 Hz), 3.33 (1H, t, Jˆ8.3 Hz), 3.46 (1H, t,
Jˆ8.2 Hz), 3.65 (1H, dt, Jˆ8.9, 3.7 Hz), 3.78 (1H, ddd,
Jˆ9.1, 3.7, 2.3 Hz), 3.93 (1H, d, Jˆ11.6 Hz), 4.01 (1H,
dd, Jˆ15.2, 2.2 Hz), 4.16 (1H, ddd, Jˆ8.9, 4.8, 2.6 Hz),
4.21 (1H, dd, Jˆ11.6, 1.5 Hz), 4.28 (1H, dd, Jˆ15.2,
5.4 Hz), 4.70 (1H, ddd, Jˆ8.6, 4.6, 1.7 Hz), 4.81 (1H, d,
Jˆ11.5 Hz), 4.87 (1H, d, Jˆ11.5 Hz), 5.55 (1H, dt,
Jˆ12.7, 3.6 Hz), 5.67±5.73 (1H, m), 5.76±5.81 (2H, m),
5.84±5.88 (1H, m), 5.87 (1H, dt, Jˆ12.7, 2.3 Hz), 7.26±
7.29 (1H, m), 7.31±7.34 (2H, m), 7.38±7.42 (2H, m); 13C
NMR (50 MHz, CDCl3) d 12.09, 12.40, 13.14, 13.29, 31.57,
32.48, 34.61, 64.05, 67.03, 68.33, 73.21, 75.17, 78.02,
80.53, 80.83, 80.98, 82.16, 84.41, 84.42, 85.07, 87.38,
125.68, 126.76, 127.38, 127.72, 128.16, 130.04, 131.34,
135.66, 137.25, 139.36; MALDI-TOF MS calcd for
C41H62O9Si2Na (M1Na1) 777.38, found 777.28.
9. For recent synthetic studies of ciguatoxins from other groups,
see: (a) Sasaki, M.; Fuwa, H.; Ishikawa, M.; Tachibana, K.
Org. Lett. 1999, 1, 1075. (b) Sasaki, M.; Noguchi, K.; Fuwa,
H.; Tachibana, K. Tetrahedron Lett. 2000, 41, 1425.
(c) Takakura, H.; Noguchi, K.; Sasaki, M.; Tachibana, K.
Angew. Chem., Int. Ed. Engl. 2001, 40, 1090. (d) Fujiwara,
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Acknowledgements
We thank Dr Kenji Maeda for contributing to the pre-
liminary phase of this work. A fellowship to M. M. from
the Japanese Society for the Promotion of Science is
gratefully acknowledged.
10. Very recently, we achieved the total synthesis of ciguatoxin
CTX3C. Hirama, M.; Oishi, T.; Uehara, H.; Inoue, M.;
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M. Maruyama et al. / Tetrahedron 58 (2002)1835±1851
1851
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