A general strategy for the convergent synthesis of fused polycyclic ethers via B-alkyl Suzuki coupling: Synthesis of the ABCD ring fragment of ciguatoxins

Article abstract of DOI:10.1016/S0040-4020(02)00045-5

A new method for convergent coupling of fused polycyclic ethers has been developed, which relies on B-alkyl Suzuki crosscoupling of lactone-derived enol triflates or phosphates. The strategy was successfully applied to a convergent synthesis of the ABCD r

Full text of DOI:10.1016/S0040-4020(02)00045-5

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 1889±1911
A general strategy for the convergent synthesis of fused polycyclic
ethers via B-alkyl Suzuki coupling: synthesis of the ABCD
ring fragment of ciguatoxins
Makoto Sasaki,a,b,p Makoto Ishikawa,a Haruhiko Fuwaa and Kazuo Tachibanaa
aDepartment of Chemistry, Graduate School of Science, The University of Tokyo, and CREST,
Japan Science and Technology Corporation (JST), Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
bDepartment of Biomolecular Science, Graduate School of Life Science, Tohoku University, Tsutsumidori-Amamiya,
Aoba-ku, Sendai 981-8555, Japan
Received 2 October 2001; accepted 1 November 2001
AbstractÐA new method for convergent coupling of fused polycyclic ethers has been developed, which relies on B-alkyl Suzuki cross-
coupling of lactone-derived enol tri¯ates or phosphates. The strategy was successfully applied to a convergent synthesis of the ABCD ring
fragment 4 of ciguatoxins, the causative toxin for ciguatera ®sh poisoning. The synthetic route includes a convergent union of the B and D
rings (18 and 29c, respectively) by the B-alkyl Suzuki coupling, introduction of a double bond into the D ring followed by reductive closure
of the tetrahydropyran C ring to afford the BCD ring system 51, and, ®nally, ring-closing metathesis reaction to construct the oxepene A ring.
q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
ether at one end. So far, 22 ciguatoxin congeners, including
CTX3C 26 and 51-hydroxyCTX3C 3,7 have been identi®ed
from toxic ®sh and/or G. toxicus, and the structures were
elucidated by extensive NMR analysis and/or CID FAB/
MS/MS experiments using a minute amount of samples.8
More recently, the absolute con®guration of 1 was success-
fully determined as shown in Fig. 1 by Yasumoto and
co-workers.9
The polycyclic ether class of marine natural products,
exempli®ed by brevetoxins, ciguatoxins, and maitotoxin,
has received much attention due to the biological potency
and structural complexity of these molecules.1 Among the
most remarkable polycyclic ethers are ciguatoxin (CTX, 1)
and its congeners. These are the principal toxins for
ciguatera seafood poisoning that is prevalent in circum
tropical areas with more than 20,000 victims annually and
continues to be a serious public health problem.2 The
causative toxins originate in an epiphytic dino¯agellate
Gambierdiscus toxicus3 and are accumulated in ®sh through
the food chain, thus causing human intoxication. These
dino¯agellate toxins undergo oxidative changes in ®sh,
yielding the principal toxins, ciguatoxin and a number of
congeners. Ciguatoxin (1) was ®rst isolated from the moray
The ciguatoxins are extremely potent neurotoxins that bind
to voltage-sensitive Na1-channels (VSSC) and inhibit
depolarization to allow inward Na1 in¯ux to continue;10
however, the mechanism for the binding of ciguatoxins to
VSSC has not yet been clari®ed. The binding site on VSSC
was reported to be shared by brevetoxins, another class of
structurally related marine toxins.11 It is noteworthy that the
binding af®nity of 1 was shown to be some 10 times more
potent than that of brevetoxins, despite their structural
similarity.11b However, the precise location of the receptor
site of the ciguatoxins and brevetoxins on VSSC has not
been fully identi®ed.12 The scarcity of ciguatoxins from
natural sources has also precluded further investigations
on their interactions with VSSC. Thus, a practical total
synthesis currently provides the only potential source of
useful amounts of these intriguing molecules. In addition,
structure±activity relationshipstudies of structural ana-
logues not accessible by degradation or functionalization
of the natural toxins may provide useful information for
understanding the detailed structural basis necessary for
their high-af®nity binding to VSSC.
4
eel Gymnothorax javanicus by Scheuer's groupin 1980.
The structure of 1, except for the absolute con®guration
and relative stereochemistry at C2, was elucidated using
a puri®ed sample of only 0.35 mg by Yasumoto and
co-workers in 1989.5 The ciguatoxin molecule consists of
12 trans-fused polycyclic ethers, ranging from six- to nine-
membered, and a spirally attached ®ve-membered cyclic
Keywords: marine metabolites; polyethers; ring-closing metathesis; Suzuki
reactions; toxins.
Corresponding author. Tel.: 181-3-5841-4357; fax: 181-3-5841-8380;
e-mail: msasaki@chem.s.u-tokyo.ac.jp
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00045-5

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M. Sasaki et al. / Tetrahedron 58 (2002)1889±1911
Figure 1. Structures of ciguatoxin (CTX, 1), its congeners (CTX3C, 2; 51-hydroxyCTX3C, 3), and the ABCD ring fragment 4.
The complex molecular architecture and their potential as
tools for biological studies of ciguatoxins, as well as their
limited availability from natural sources, make these
toxins attractive targets for total synthesis, and thus a
number of synthetic efforts, including ours,13,14 have been
reported.15±17 Our own investigations in this area have
focused on development of a practical methodology for
the convergent assembly of polycyclic ethers.18 We have
recently reported an ef®cient and general strategy for the
convergent synthesis of polycyclic ether frameworks via
palladium-catalyzed Suzuki coupling of alkylboranes with
lactone-derived enol tri¯ates.14a,19±21 However, the B-alkyl
Suzuki coupling of lactone-derived enol tri¯ates was limited
to reactions of six-membered rings, and seven-membered
enol tri¯ates could not be utilized as the coupling partners
due to their instability under the reaction conditions. In
order to overcome this problem, we have disclosed
B-alkyl Suzuki coupling of lactone-derived enol phos-
phates, superior substrates to the corresponding tri¯ates
with respect to their stability and handling.14b±e,22 It was
noteworthy that the method enabled convergent coupling
of medium-ring ethers with a variety of ring sizes. In this
contribution, we describe full details of our B-alkyl Suzuki
coupling of lactone-derived enol phosphates and its success-
ful application to the convergent synthesis of the ABCD
ring fragment 4 of representative ciguatoxin analogues,
CTX3C (2) and 51-hydroxyCTX3C (3).23
2. Results and discussion
2.1. Synthesis plan
We have previously shown that a polytetrahydropyran ring
system, the most frequently encountered structural unit
in polycyclic ether natural products, can be constructed
ef®ciently by B-alkyl Suzuki coupling of lactone-derived
enol tri¯ates followed by stereoselective hydroboration
and reductive ring-closure (Eq. (1)). We envisioned that
such a sequence would provide convenient entry to the
ABCD ring system of the ciguatoxins. Our initial approach
to the ABCD ring fragment 4 is outlined retrosynthetically
in Scheme 1. We reasoned that the oxepene ring A could be
accessed from a precursor triene 5 by a ring-closing meta-
thesis reaction. The ring-closing metathesis reaction has
rapidly become an important and powerful transformation
in organic synthesis,24 and its utility has been demonstrated
in the construction of medium-ring ethers.13f,16,25 We
envisioned that seven-membered ketone 6 would serve as
a key precursor for the synthesis of 5; introduction of a
Scheme 1. Retrosynthetic analysis of ABCD ring fragment 4 of CTX3C.

M. Sasaki et al. / Tetrahedron 58 (2002)1889±1911
1891
Scheme 2. Reagents and conditions: (a) DIBALH, CH2Cl2, 2788C; (b) NaBH4, MeOH, 08C; (c) PivCl, NEt3, DMAP, CH2Cl2, rt, quant. (three steps); (d) H2,
Pd(OH)2/C, EtOAc/MeOH, rt; (e) CSA, PhCH(OMe)2, DMF/CH2Cl2, rt, 80% (two steps); (f) BnBr, NaHMDS, TBAI, DMF, 08C; (g) CSA, MeOH/CH2Cl2, rt,
84% (two steps); (h) TBDMSOTf, 2,6-lutidine, CH2Cl2, 08C; (i) DIBALH, CH2Cl2, 2788C, 87% (two steps); (j) MOMCl, i-Pr2NEt, TBAI, CH2Cl2, rt;
(k) CSA, MeOH/CH2Cl2, 08C, 91% (two steps); (l) I2, PPh3, imidazole, PhH, rt, quant.; (m) t-BuOK, THF, 08C, 96%.
double bond into the D ring of 6 followed by reductive
closure of the C ring would lead to 5. The key intermediate
6 would arise by ring-expansion26 of six-membered ketone
7, which should be readily derived from 8. In turn, enol ether
8 would be obtained by Suzuki coupling of alkylborane
9, generated from the corresponding exo-ole®n, with six-
membered lactone-derived enol tri¯ate 10.
Removal of the benzyl groups by hydrogenolysis and subse-
quent protection as the benzylidene acetal gave diol 13 in
84% yield for the two steps. Benzylation followed by
removal of the benzylidene acetal groupyielded diol 14,
which, upon bis-silylation and reductive removal of the
pivalate ester, provided primary alcohol 15 in 87% overall
yield. Protection as its methoxymethyl (MOM) ether and
selective removal of the primary t-butyldimethylsilyl
(TBS) groupafforded alcohol 16 (91% yield for the two
steps), which upon iodination gave primary iodide 17.
Finally, treatment with a base (KOt-Bu, THF, 08C)
completed the synthesis of the B ring exo-ole®n 18 in
96% overall yield from 16.
The synthesis of enol tri¯ate 10 started with tri-O-acetyl-d-
glucal (19) as summarized in Scheme 3. O-Glycosidation of
19 with 2-propanol in the presence of BF3´OEt2 (CH2Cl2,
08C) and hydrogenation of the double bond,28 followed by
replacement of the acetyl groups with benzyl groups,
afforded bis(benzyl) ether 20. Acidic hydrolysis produced
hemiacetal 21, which was then oxidized with catalytic tetra-
n-propylammonium perruthenate (TPAP)29 and N-methyl-
morpholine-N-oxide (NMO) to afford lactone 22. Finally,
lactone 22 was converted to enol tri¯ate 10 according to the
procedure of Murai (KHMDS, PhNTf2, THF/HMPA,
2788C).30 Due to its unstable nature, the unpuri®ed 10
was immediately used in the next Suzuki coupling.
ꢀ1†
2.2. Synthesis of the BCD ring framework: B-alkyl
Suzuki coupling-ring expansion strategy
The synthesis of exo-ole®n 18, representing the B ring,
began with the known ester 1127 (Scheme 2). Reduction of
the ester in 11 by a two-stepsequence (DIBALH, then
NaBH4) was followed by protection of the resultant primary
alcohol to give pivalate ester 12 in quantitative yield.
Hydroboration of exo-ole®n 18 with 2.6 equiv. of 9-BBN
(THF, rt!608C) afforded the corresponding alkylborane 9,
which was in situ treated with aqueous Cs2CO3 and then
enol tri¯ate 10 in the presence of Pd2(dba)3´CHCl3 (dbaˆ
dibenzylideneacetone) and triphenylarsine in DMF at
room temperature (Scheme 4). The desired cross-coupled
product 8 was obtained in excellent yield. The use of
Pd2(dba)3´CHCl3 as a palladium(0) catalyst instead of
PdCl2(dppf) (dppfˆ1,10-bis(diphenylphosphino)ferrocene)
that was used in the original report14a improved the yield
of the coupling reaction. Further hydroboration of the enol
ether within 8 with thexylborane (THF, 08C) proceeded
stereoselectively to give, after oxidative workup, alcohol
23 in 92% yield as the sole product. Oxidation of the
secondary alcohol with TPAP/NMO29 afforded ketone 7 in
quantitative yield.
Scheme 3. Reagents and conditions: (a) BF3´OEt2, i-PrOH, CH2Cl2,
08C!rt; (b) H2, 10% Pd/C, EtOAc/MeOH, rt; (c) NaOMe, MeOH, rt;
(d) NaH, BnBr, n-Bu4NI, THF/DMF (2:1), 08C, 85% (four steps); (e) 80%
HOAc, 1 M HCl, 50±608C; (f) TPAP, NMO, 4 A molecular sieves, CH2Cl2,
rt, 66% (two steps); (g) KHMDS, PhNTf2, THF/HMPA, 278!08C.
Ê
With the desired 7 in hand, we focused on the possibility of

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M. Sasaki et al. / Tetrahedron 58 (2002)1889±1911
Scheme 4. Reagents and conditions: (a) 18, 9-BBN, THF, rt!608C; then 3 M aq. Cs2CO3, 10, Pd2(dba)3´CHCl3, Ph3As, DMF, rt, 91%; (b) ThexylBH2, THF,
Ê
08C; then 3 M NaOH, 30% H2O2, rt, 92%; (c) TPAP, NMO, 4 A molecular sieves, CH2Cl2, rt, 99%; (d) TMSCHN2, Me3Al, CH2Cl2, 2788C; (e) p-TsOH´H2O,
MeOH/CH2Cl2, 558C; (f) PivCl, Et3N, DMAP, CH2Cl2, rt; (g) Et3SiH, BF3´OEt2, CH3CN, 08C, 78% (four steps); (h) DIBALH, CH2Cl2, 2788C, 96%;
(i) SO3´Pyr, DMSO, Et3N, CH2Cl2, 08C; (j) Ph3PCH3Br, NaHMDS, THF, 08C, 88% (two steps).
ring expansion leading to seven-membered ketone 6.26 This
transformation was best accomplished by treatment with
trimethylsilyldiazomethane (TMSCHN2) in the presence
of trimethylaluminum in CH2Cl2 at 2788C (Scheme 4).
The crude reaction product31 was then treated with
p-toluenesulfonic acid monohydrate (p-TsOH´H2O) in
methanol/CH2Cl2 at 558C to effect removal of the MOM
and TBS protecting groups with concomitant formation of
a mixed methyl ketal.32 Subsequent protection of the
primary alcohol gave pivalate ester 24. Axial hydride reduc-
tion of the methyl ketal at C1233 with Et3SiH and BF3´OEt2
(CH2Cl2, 08C)27 afforded tricyclic ether 25 as the sole
product in 78% overall yield from 7. Reductive removal
of the pivalate ester followed by Parikh±Doering oxi-
dation34 and Wittig methylenation of the derived aldehyde
afforded terminal ole®n 26 in 79% yield for the three
steps.
2.3. Suzuki coupling of lactone-derived enol phosphate
While the BCD ring system 26 was successfully synthesized
via the B-alkyl Suzuki coupling of six-membered enol
tri¯ate 10 and subsequent ring-expansion protocol, overall
ef®ciency was lacking. Accordingly, an alternative and
more direct approach that uses B-alkyl Suzuki coupling of
seven-membered enol tri¯ates was investigated. However,
we encountered dif®culty in using seven-membered enol
tri¯ate 27 as a substrate in the B-alkyl Suzuki coupling
(Eq. (2)), mainly due to its instability under the aqueous
basic conditions. Therefore, we explored B-alkyl Suzuki
coupling of lactone-derived enol phosphates, superior
substrates to the corresponding tri¯ates with respect to
their stability and handling.
Table 1. Suzuki coupling of alkylborane 9 with enol phosphate 29a (Eq.
(3))
ꢀ2†
ꢀ3†
The use of lactone-derived enol phosphates in organic
synthesis was ®rst demonstrated by Kane and co-workers
in their total synthesis of zoapatanol.35 More recently, Nico-
laou and co-workers have reported that six- to nine-
membered enol phosphates derived from the corresponding
lactones undergo palladium-catalyzed Stille coupling,36
which has been used as the key reaction in their total syn-
thesis of brevetoxin A.37 However, at the time that we
initiated our studies, Suzuki coupling of enol phosphates
had not been reported.38
Entry
Basea
Pd cat.
Co-ligand 29a (eq) Yield (%)
1b
2b
3b
4
5
6
Cs2CO3
Cs2CO3
K3PO4
K3PO4
NaHCO3 Pd(PPh3)4
NaHCO3 Pd(PPh3)4
NaHCO3 Pd(PPh3)4
Pd2(dba)3´CHCl3 Ph3As 1.0
Pd2(dba)3´CHCl3 (2-Furyl)3P 1.0
Pd(PPh3)4
Pd(PPh3)4
0
0
±
±
±
±
±
1.0
1.0
1.0
1.4
2.0
46
56
72
84
98
7
All reactions were carried out with aq. base (3 equiv.), Pd(0) cat.
(10 mol%), and co-ligand (0.4 equiv.) in DMF.
a
To test the feasibility of utilizing lactone-derived enol phos-
phates in B-alkyl Suzuki coupling, we ®rst examined the
3 M Cs2CO3; 3 M K3PO4; 1 M NaHCO3.
Reaction was carried out at room temperature.
b

M. Sasaki et al. / Tetrahedron 58 (2002)1889±1911
1893
Table 2. Suzuki coupling of alkylborane 9 with enol phosphates with a variety of ring sizes
Entry
Phosphate
Product (yield)
1
2
3
4
All reactions were carried out with aq. NaHCO3 (3 equiv.) and Pd(PPh3)4 (10 mol%) in DMF at 508C.
See, Ref. 36.
a
reaction of alkylborane 9 with phosphate 29a as a model
system (Eq. (3), Table 1). Enol phosphate 29a was prepared
from lactone 22 following the procedure of Nicolaou
(KHMDS, (PhO)2P(O)Cl, THF/HMPA, 2788C).36 Alkyl-
borane 9, generated in situ from 18 with 9-BBN as described
above, reacted with 29a under the conditions that we have
described for the Suzuki coupling of enol tri¯ate 10
(Cs2CO3, Pd2(dba)3´CHCl3, Ph3As, DMF, room tempera-
ture). However, the desired coupling product 8 could not
be obtained at all (entry 1). Tri(2-furyl)phosphine was also
ineffective in the present coupling reaction (entry 2).
Considering the low reactivity of enol phosphate 29a
compared with tri¯ate 10, it was supposed that phosphate
29a could not undergo oxidative addition to a palladium(0)
species having a less electron-donating ligand such as
triphenylarsine or tri(2-furyl)phosphine.39 In contrast, the
most commonly used system (aqueous K3PO4, Pd(PPh3)4,
DMF) in Suzuki couplings19,20 afforded 8, albeit in modest
yield (46±56%, entries 3 and 4). Presumably, hydrolysis of
29a would occur competitively under these conditions due
to the slow rate of oxidative addition of less reactive 29a to
the palladium(0) complex. Use of NaHCO3 as a weaker base
proved to be the most effective (entry 5). Increasing the
amounts of 29a further improved the yield of coupling
product (entry 6). Finally, the best result was obtained
when 2 equiv. of 29a was employed, giving 8 in nearly
quantitative yield (entry 7).
seven-membered enol tri¯ate decomposed even under
these mild conditions using NaHCO3 as a base,40 the use
of a phosphate leaving group is critical for this coupling
reaction. Moreover, since eight- and nine-membered
lactone-derived enol tri¯ates are known to be rather
unstable and dif®cult to prepare or isolate,41 the present
B-alkyl Suzuki coupling of medium-ring enol phosphates
is promising for the synthesis of polycyclic ether natural
products.
The syntheses of seven- and eight-membered enol phos-
phates 29b±d are outlined in Scheme 5. The synthesis of
seven-membered enol phosphate 29b began with 2-deoxy-
d-ribose (31), which was converted to hydroxy ester 32 in a
three-stepsequence. Hydrolysis of the methyl ester within
32 afforded hydroxy acid 33, which was lactonized under
Yamaguchi conditions42 to give seven-membered lactone
34. Conversion of 34 to enol phosphate 29b was accom-
plished by the procedure of Nicolaou (KHMDS,
(PhO)2P(O)Cl, THF, HMPA, 2788C).36 Another seven-
membered enol phosphate 29c was prepared from 32.
Protection as its MOM ether followed by reduction of the
ester and silylation of the derived alcohol afforded TIPS
ether 35. After removal of the benzylidene acetal by hydro-
genolysis, benzylation of the derived alcohols was followed
by desilylation to afford primary alcohol 36, which was then
converted to hydroxy acid 37 by a three-stepsequence.
Yamaguchi lactonization followed by enol phosphate
formation afforded 29c following the same procedure as
described for the conversion of 33 to 29b. Construction of
eight-membered enol phosphate 29d started with alcohol
36, which was transformed to hydroxy acid 39 by tosylation,
displacement with KCN, and hydrolysis of the cyanide.
Hydroxy acid 39 was readily converted to enol phosphate
29d by the same procedure described earlier.
To ascertain the generality and scope of the B-alkyl Suzuki
coupling of lactone-derived enol phosphates, a variety of
substrates of different ring sizes were allowed to react
with 9 under the optimal conditions described earlier. As
shown in Table 2, seven- to nine-membered enol phosphates
29b±e reacted smoothly with 9 to afford the desired cross-
coupled products 28 and 30c±e in excellent yields. Since the

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M. Sasaki et al. / Tetrahedron 58 (2002)1889±1911
Scheme 5. Reagents and conditions: (a) Ph3PvCHCO2Me, THF, re¯ux; (b) H2, 10% Pd/C, EtOAc/MeOH, rt; (c) PhCH(OMe)2, CSA, CH2Cl2, rt; (d) KOH,
THF/MeOH/H2O, 508C; (e) 2,4,6-Cl3PhCOCl, Et3N, THF, rt; then DMAP, benzene, 808C; (f) KHMDS, (PhO)2P(O)Cl, THF/HMPA, 2788C; (g) MOMCl,
i-Pr2NEt, TBAI, CH2Cl2, rt; (h) LiAlH4, THF, 08C; (i) TIPSOTf, 2,6-lutidine, CH2Cl2, 08C!rt; (j) NaH, BnBr, TBAI, DMF, rt; (k) TBAF, THF, rt; (l) SO3´Pyr,
Et3N, DMSO, CH2Cl2, 08C; (m) BF3´OEt2, Me2S, CH2Cl2, 08C; (n) NaClO2, 2-methyl-2-butene, NaH2PO4, t-BuOH/H2O, rt; (o) p-TsCl, Et3N, DMAP, CH2Cl2,
rt; (p) KCN, DMSO, 808C; (q) aq. HCl, MeOH; then aq. KOH, MeOH, 708C.
Scheme 6. Reagents and conditions: (a) ThexylBH2, THF, 210!08C; then 3 M NaOH, 30% H2O2, rt, 83% (1recovered 30c, 10%); (b) (COCl)2, DMSO,
Et3N, CH2Cl2, 278!08C; (c) p-TsOH, MeOH/CH2Cl2, 558C, 82% (two steps); (d) SO3´Pyr, DMSO, Et3N, CH2Cl2, 08C; (e) Ph3PCH3Br, NaHMDS, THF, 08C,
79% (two steps); (f) Et3SiH, BF3´OEt2, MeCN/CH2Cl2, 08C, 86%; (g) I2, CH2Cl2, 08C; (h) Zn, HOAc, Et2O/MeOH, 08C, 96% (two steps); (i) NaHMDS, allyl
bromide, DMF, 08C!rt, 78%; (j) Grubbs' catalyst 46, CH2Cl2, rt, quant.
2.4. Synthesis of the ABCD ring system 47
hydroboration of 30c can be explained by approach of
the thexylborane onto the double bond from the a-face in
the most stable conformer A (Fig. 2), generated by confor-
mational search using MM2p force ®eld in MacroModel
version 5.5. Oxidation of the secondary alcohol under
Swern conditions provided ketone 6, which upon treatment
with p-TsOH´H2O in methanol afforded hydroxy mixed
methyl ketal 42 in 82% yield for the two steps. Oxidation
of the primary alcohol34 followed by Wittig reaction
afforded ole®n 43 (79%, two steps), which was then reduced
with Et3SiH and BF3´OEt2 to give tricycle 26 as the sole
product in 86% yield.
Hydroboration of the enol ether 30c with thexylborane
(THF, 210!08C), followed by oxidation, afforded the
desired alcohol 41 in 83% yield along with a 10% yield of
recovered 30c (Scheme 6). The stereoselectivity of the
In order to construct the oxepene ring A, we decided to use a
ring-closing metathesis reaction. To this end, regioselective
removal of the benzyl groupat C6 of 26 was carried out
according to the method of Cipolla.43 Thus, treatment of 26
with I2 effected debenzylative iodoetheri®cation to give an
iodoether, which was then treated with zinc powder in the
presence of acetic acid to afford alcohol 44 in 84% overall
yield. Subsequent allylation of the derived secondary
Figure 2.

M. Sasaki et al. / Tetrahedron 58 (2002)1889±1911
1895
Scheme 7. Reagents and conditions: (a) LiHMDS, TMSCl, Et3N, CH2Cl2, 2788C; (b) Pd(OAc)2, MeCN, rt, 96% (two steps).
alcohol gave diene 45 (78% yield), setting the stage for the
ring-closing metathesis reaction. Exposure of 45 to Grubbs'
catalyst 4644 furnished the desired ABCD ring framework
47 in nearly quantitative yield. The relative con®guration of
47 was ®rmly established by NOEs between H-5/H-9, H-8/
H-12, and H-9/H-11. Thus, a concise and rapid synthesis of
the ABCD ring polyether skeleton 47 was achieved in 10
steps and 30% overall yield from 18.
with p-TsOH in methanol did not provide the desired 49
but resulted in decomposition. After extensive experimen-
tation,47 we found that an 83% yield of a 7:1 mixture of
hydroxy ketone 50 and the corresponding hemiketal (not
shown) could be obtained upon treatment of 48 with 46%
aqueous HF in MeCN at room temperature.
Treatment of a mixture of 50 and the hemiketal with Et3SiH
in the presence of BF3´OEt2 afforded less than 50% of the
desired tricyclic ether 51, and diol 52 was signi®cantly
produced (Scheme 8). Hirama and co-workers have reported
that reduction of a mixed methyl ketal rather than that of the
corresponding hemiketal with Et3SiH and BF3´OEt2 gave
reproducibly a higher yield of the reduction product.18e
However, treatment of 50 with HC(OMe)3 in the presence
of PPTS (CH2Cl2, rt) afforded an approximately 1:1 mixture
of 49 and the orthoester 53 in modest yield. Finally, this
problem was addressed by the ®rst selective protection of
the primary alcohol within 50 as the triisopropylsilyl (TIPS)
ether 54 (87%) and subsequent treatment with HC(OMe)3 in
the presence of PPTS, giving mixed methyl ketal 55
(Scheme 9). Exposure of 55 to Et3SiH and BF3´OEt2
effected reduction of the mixed methyl ketal with concomi-
tant desilylation to furnish tricyclic ether 51 as the sole
product in 94% yield from 54.
2.5. Synthesis of the ABCD ring fragment 4
For the synthesis of the ABCD ring fragment 4, we required
introduction of a double bond into the oxepane D ring of 6.
Initial attempts to install the double bond by selenenylation-
oxidative elimination sequence45 proved unsuccessful.
Selenenylation of ketone 6 under acidic or basic conditions
resulted in no reaction or only a low yield of enone 48.
Moreover, separation of the desired 48 from the recovered
ketone 6 was troublesome. Accordingly, we sought an alter-
native method for introduction of the double bond. After
some experimentation, it was discovered that the Ito±
Saegusa protocol46 gave the best result (Scheme 7). Thus,
ketone 6 was converted to the kinetic enol silyl ether
(LiHMDS, CH2Cl2, 2788C, then TMSCl, Et3N), which
was then treated with
a stoichiometric amount of
Pd(OAc)2 in MeCN at room temperature to yield enone
48 in excellent yield. The next stage of our synthetic plan
called for the conversion of 48 to mixed methyl ketal 49 for
the construction of the C ring. However, treatment of 48
Oxidation of the primary alcohol within 51 with SO3´pyri-
dine34 followed by Wittig methylenation of the derived
aldehyde afforded ole®n 56 in 91% overall yield. Removal
Scheme 8.

1896
M. Sasaki et al. / Tetrahedron 58 (2002)1889±1911
Scheme 9. Reagents and conditions: (a) TIPSCl, Et3N, DMAP, CH2Cl2, rt, 87%; (b) PPTS, HC(OMe)3, toluene, 458C; (c) Et3SiH, BF3´OEt2, MeCN/CH2Cl2
(2:1), 08C, 94% (two steps); (d) SO3´Pyr, DMSO, Et3N, CH2Cl2, 08C; (e) Ph3PCH3Br, NaHMDS, THF, 08C, 91% (two steps); (f) LiDBB, THF, 2788C;
(g) CSA, p-MeOC6H4CH(OMe)2, CH2Cl2/DMF (3:1), rt, 59% (two steps); (h) TIPSOTf, 2,6-lutidine, CH2Cl2/DMF (3:1), 08C; (i) NaHMDS, allyl bromide,
DMF, rt, quant. (two steps); (j) Grubbs' catalyst 46, CH2Cl2, rt, 97%.
of the benzyl groups with lithium di-tert-butylbiphenilide
(LiDBB)48 and selective protection of the derived tetraol as
its mono-p-methoxybenzylidene acetal provided 57 in 59%
yield for the two steps. Regioselective protection of the
hydroxyl groupat C7 of diol 57 as its TIPS ether followed
by allylation of the remaining alcohol gave triene 5 in 94%
overall yield. Finally, ring-closing metathesis reaction of 5
with Grubbs' catalyst 46 proceeded cleanly in the presence
of the D ring double bond to furnish the targeted ABCD ring
fragment 4 in 97% yield. The relative con®guration of 4 was
unambiguously established by 1H±1H coupling constant
analysis.49
chromatography was performed using E. Merck silica gel
60 F254 plates (0.25-mm thickness). Column chroma-
tography was performed using Kanto Chemical silica gel
60N (40±100 mesh, spherical, neutral) and for ¯ash column
chromatography Fuji Silysia silica gel BW-300 (200±400
mesh) or E. Merck Kieselgel silica gel 60 (230±400 mesh)
was used. Optical rotations were recorded on a JASCO
DIP-350 digital polarimeter. IR spectra were recorded on
a JASCO FT/IR-420 spectrometer. 1H and 13C NMR spectra
were recorded on a JEOL A500 or Bruker DRX-500 spec-
trometer, and chemical shift values are reported in ppm (d)
down®eld from tetramethylsilane with reference to internal
residual solvent (1H NMR, CHCl3 (7.24), C6HD5 (7.15),
C5HD4N (8.50); 13C NMR, CDCl3 77.0, C6D6 128.0,
C5D5N 135.5). Coupling constants (J) are reported in hertz
(Hz). The following abbreviations are used to designate the
multiplicities: sˆsinglet, dˆdoublet, tˆtriplet, mˆmulti-
plet, brˆbroad. Low- and high-resolution mass spectra
were recorded on a JEOL JMS-SX102 mass spectrometer
under fast atom bombardment (FAB) conditions using
m-nitrobenzyl alcohol (NBA) as a matrix.
3. Conclusion
We have developed a general and high-yielding method for
the convergent synthesis of polycyclic ethers based on
B-alkyl Suzuki reaction of lactone-derived enol phosphates.
The synthesis enables the coupling of medium-ring ethers of
different ring sizes. The potential of the B-alkyl Suzuki
coupling-based approach to the assemblage of polycyclic
ether structures was demonstrated by its successful appli-
cation to the convergent synthesis of the ABCD ring
fragment 4 of ciguatoxin analogues.
4.1.1. Pivalate 12. To a solution of ester 1127 (42.48 g,
69.64 mmol) in CH2Cl2 (400 mL) at 2788C was added
dropwise diisobutylaluminum hydride (1.0 M in toluene,
105 mL, 105 mmol). The resultant solution was stirred at
2788C for 1 h before the reaction was quenched with satu-
rated aqueous potassium sodium tartrate (400 mL). The
mixture was extracted with ethyl acetate (900 mL), washed
with H2O (200 mL) and brine (400 mL), dried over Na2SO4,
®ltered, and concentrated in vacuo. The crude aldehyde was
used in the next reaction without chromatographic puri®-
cation.
4. Experimental
4.1. General methods
All reactions sensitive to air or moisture were carried out
under an atmosphere of argon or nitrogen in freshly
distilled, dry solvents under anhydrous conditions unless
otherwise noted. Anhydrous THF and N,N-dimethylforma-
mide (DMF) were purchased from Kanto Chemical Co. Inc.
and used without further drying. Diethyl ether (Et2O) was
dried from sodium/benzophenone under argon, benzene,
dichloromethane (CH2Cl2), N,N-diisopropylethylamine,
methanol, toluene, triethylamine, and pyridine from calcium
hydride, dimethylsulfoxide (DMSO) and hexamethylphos-
phoric triamide (HMPA) from calcium hydride under
reduced pressure. All other reagents purchased were of the
highest commercial quality and used without further puri®-
cation unless otherwise noted. Analytical thin-layer
To a solution of the above aldehyde in methanol (280 mL) at
08C was added NaBH4 (2.1 g, 56 mmol). The resultant solu-
tion was stirred at 08C for 30 min before the reaction was
quenched with water (10 mL). The solvent was removed in
vacuo, and the residue was dissolved in ethyl acetate
(1.5 L), washed with saturated aqueous NH4Cl (400 mL)
and brine (400 mL), dried over Na2SO4, ®ltered, and
concentrated in vacuo. The crude alcohol was used in the
next reaction without puri®cation.
To a solution of the above alcohol in CH2Cl2 (400 mL) were

M. Sasaki et al. / Tetrahedron 58 (2002)1889±1911
1897
successively added triethylamine (29.1 mL, 209 mmol),
dimethylaminopyridine (2.55 g, 13.9 mmol), and pivaloyl
chloride (17.15 mL, 139.3 mmol). The resultant solution
was stirred at room temperature overnight. The reaction
mixture was extracted with ether (1.5 mL), washed with
1 M HCl (400 mL), saturated aqueous NaHCO3 (400 mL),
and brine (400 mL), dried over Na2SO4, ®ltered, and
concentrated in vacuo. Puri®cation by column chroma-
tography on silica gel (30% ether/hexanes) gave pivalate
12 (45.9 g, quant. for the three steps) as a colorless oil:
138.5 mmol). The resultant solution was stirred at 08C for
1 h and allowed to warm to room temperature. After 3 h, the
reaction was quenched with saturated aqueous NH4Cl. The
mixture was extracted with ether (1.5 L), washed with satu-
rated aqueous NH4Cl (400 mL), water (400 mL), and brine
(400 mL), dried over Na2SO4, ®ltered, and concentrated in
vacuo. The crude bis(benzyl) ether was used in the next
reaction without chromatographic puri®cation.
A solution of the above bis(benzyl) ether in CH2Cl2/metha-
nol (1:1, v/v, 200 mL) was treated with camphorsulfonic
acid (2.6 g, 11 mmol). The resultant solution was stirred at
room temperature for 5 h before the reaction was quenched
with triethylamine. The solvent was removed in vacuo, and
the residue was puri®ed by column chromatography on
silica gel (8% methanol/CHCl3) to provide diol 14
(22.00 g, 84% for the two steps) as a colorless solid:
27
[a]D ˆ263.7 (c 0.81, C6H6); IR (®lm) 3089, 3063, 3030,
2971, 2903, 2869, 1951, 1873, 1808, 1727, 1605, 1586,
1540, 1496, 1479, 1454, 1397, 1361, 1283, 1208, 1158,
1099, 941, 908, 735, 697, 614, 461 cm21 1H NMR
;
(CDCl3, 500 MHz) d 7.33±7.13 (m, 20H), 4.89 (s, 2H),
4.87 (d, Jˆ9.2 Hz, 1H), 4.80 (d, Jˆ10.7 Hz, 1H), 4.64 (d,
Jˆ11.0 Hz, 1H), 4.61 (d, Jˆ12.5 Hz, 1H), 4.55 (d, Jˆ
11.0 Hz, 1H), 4.50 (d, Jˆ12.2 Hz, 1H), 4.22±4.13 (m,
2H), 3.70±3.63 (m, 4H), 3.37±3.24 (m, 3H), 2.16 (m,
1H), 1.69 (m, 1H), 1.16 (s, 9H); 13C NMR (125 MHz,
CDCl3) d 178.4, 138.6, 138.3, 138.2, 138.1, 128.4, 128.3,
128.0, 127.8, 127.7, 127.6, 87.3, 82.2, 79.0, 78.5, 76.1, 75.5,
75.2, 74.9, 73.5, 69.0, 61.1, 38.7, 31.0, 27.2; HRMS (FAB)
calcd for C41H48O7Na [(M1Na)1] 675.3298, found
675.3302.
27
[a]D ˆ239.0 (c 0.36, C6H6); IR (®lm) 3356, 3064, 3032,
2968, 2933, 2871, 1727, 1497, 1479, 1454, 1397, 1361,
1282, 1210, 1153, 1097, 1038, 996, 886, 738, 698, 647,
1
530 cm21; H NMR (500 MHz, CDCl3) d 7.36±7.23 (m,
10H), 4.94 (d, Jˆ11.6 Hz, 1H), 4.87 (d, Jˆ11.0 Hz, 1H),
4.74 (d, Jˆ11.6 Hz, 1H), 4.65 (d, Jˆ11.0 Hz, 1H), 4.20 (m,
1H), 4.14 (m, 1H), 3.80 (m, 1H), 3.67 (m, 1H), 3.55±3.47
(m, 2H), 3.37 (ddd, Jˆ2.4, 9.5, 9.5 Hz, 1H), 3.25±3.19 (m,
2H), 2.19 (m, 1H), 1.62 (m, 1H), 1.17 (s, 9H); 13C NMR
(125 MHz, CDCl3) d 178.6, 138.5, 137.8, 128.7, 128.5,
128.1, 128.0, 127.8, 86.7, 82.1, 79.0, 75.8, 75.3, 75.2,
71.1, 62.8, 60.6, 38.8, 31.1, 27.2; HRMS (FAB) calcd for
C27H36O7Na [(M1Na)1] 495.2359, found 495.2378.
4.1.2. Diol 13. To a solution of pivalate 12 (45.75 g,
70.17 mmol) in ethyl acetate/methanol (1:2, v/v, 500 mL)
was added 20% Pd(OH)2/C (5.0 g), and the resulting
mixture was stirred at room temperature under hydrogen
atmosphere overnight. The catalyst was removed by ®l-
tration through a pad of Celite, and the ®ltrate was concen-
trated to give crude tetraol, which was used in the next
reaction without puri®cation.
4.1.4. Alcohol 15. To a solution of diol 14 (2.00 g,
4.24 mmol) and 2,6-lutidine (1.98 mL, 16.9 mmol) in
CH2Cl2 (42 mL) at 08C was added t-butyldimethylsilyl
tri¯uoromethanesulfonate (2.63 mL, 11.4 mmol). The
resultant solution was stirred at 08C for 2 h before the
reaction was quenched with methanol (2 mL). The mixture
was extracted with ether (200 mL), washed with 1 M HCl
(50 mL), saturated aqueous NaHCO3 (50 mL), and brine
(50 mL), dried over Na2SO4, ®ltered, and concentrated in
vacuo. The crude bis(silyl) ether was used in the next
reaction without puri®cation.
To a solution of the above tetraol in CH2Cl2/DMF (20:7, v/v,
135 mL) were added benzaldehyde dimethylacetal (15.7
mL, 105 mmol) and camphorsulfonic acid (1.61 g, 6.93
mmol). The resultant solution was stirred at room tempera-
ture overnight before the reaction was quenched with
triethylamine. The solvent was removed in vacuo, and the
residue was puri®ed by column chromatography on silica
gel (50±70% ethyl acetate/hexanes) to give diol 13 (21.23 g,
27
80% for the two steps) as a colorless oil: [a]D ˆ236.3 (c
To a solution of the above bis(silyl) ether in CH2Cl2 (42 mL)
at 2788C was added DIBALH (1.0 M solution in toluene,
10.6 mL, 10.6 mmol). The resultant solution was stirred at
2788C for 2 h before the reaction was quenched with
saturated aqueous potassium sodium tartrate. The mixture
was stirred vigorously at room temperature for 1 h. The
mixture was extracted with ethyl acetate (200 mL), washed
with water (50 mL) and brine (50 mL), dried over Na2SO4,
®ltered, and concentrated in vacuo. Puri®cation by column
chromatography on silica gel (10±15% ethyl acetate/
hexanes) gave alcohol 15 (2.27 g, 87% for the two steps)
5.19, C6H6); IR (®lm) 3445, 3069, 3036, 2973, 2872, 1961,
1815, 1727, 1540, 1480, 1455, 1385, 1286, 1165, 1127,
1100, 1015, 971, 940, 916, 876, 762, 737, 699, 680, 654,
1
605, 538 cm21; H NMR (CDCl3, 500 MHz) d 7.51±7.31
(m, 5H), 5.45 (s, 1H), 4.24 (dd, Jˆ10.4, 4.9 Hz, 1H), 4.18
(m, 1H), 4.11 (m, 1H), 3.63±3.57 (m, 3H), 3.37 (dd, Jˆ9.2,
9.2 Hz, 1H), 3.33±3.29 (m, 2H), 3.22 (dd, Jˆ8.8, 8.8 Hz,
1H), 2.12 (m, 1H), 1.66 (m, 1H), 1.19 (s, 9H); 13C NMR
(125 MHz, CDCl3) d 178.6, 137.0, 129.2, 128.2, 126.3,
101.7, 81.0, 77.2, 75.0, 74.3, 70.1, 68.7, 61.0, 38.6, 31.0,
27.1; HRMS (FAB) calcd for C20H28O7Na [(M1Na)1]
403.1733, found 403.1733.
27
as a colorless solid: [a]D ˆ124.7 (c 0.22, C6H6); IR (®lm)
3420, 2960, 2928, 2856, 1497, 1471, 1409, 1359, 1260,
1
1152, 1092, 1027, 939, 859, 835, 800, 732, 696 cm21; H
4.1.3. Diol 14. To a solution of diol 13 (21.06 g,
55.42 mmol) in DMF (300 mL) at 08C were added tetra-n-
butylammonium iodide (2.05 g, 5.54 mmol) and sodium
bis(trimethylsilyl)amide (1.0 M solution in THF, 166.3
mL, 166.3 mmol). After being stirred at 08C for 5 min, the
mixture was treated with benzyl bromide (16.48 mL,
NMR (500 MHz, CDCl3) d 7.34±7.11 (m, 10H), 4.95 (d,
Jˆ11.9 Hz, 1H), 4.80 (d, Jˆ11.9 Hz, 1H), 4.73 (d, Jˆ
10.7 Hz, 1H), 4.54 (d, Jˆ11.0 Hz, 1H), 3.84 (dd, Jˆ11.0,
2.1 Hz, 1H), 3.77 (m, 2H), 3.61 (dd, Jˆ11.0, 6.4 Hz, 1H),
3.56±3.42 (m, 3H), 3.26 (dd, Jˆ9.2, 9.2 Hz, 1H), 2.01 (m,
1H), 1.70 (m, 1H), 0.88 (s, 9H), 0.86 (s, 9H), 20.03 (s, 3H),

1898
M. Sasaki et al. / Tetrahedron 58 (2002)1889±1911
20.07 (s, 3H), 20.27 (s, 3H), 20.33 (s, 3H); 13C NMR
(CDCl3, 125 MHz) d 138.9, 137.8, 128.4, 128.2, 127.9,
127.8, 127.1, 126.6, 86.8, 82.9, 81.2, 80.2, 75.2, 75.0,
71.2, 63.0, 62.1, 33.7, 25.9, 25.8, 18.3, 18.0, 23.8, 24.6,
25.3, 25.34; HRMS (FAB) calcd for C34H56O6Si2Na
[(M1Na)1] 639.3513, found 639.3527.
27
96%) as a colorless oil: [a]D ˆ234.4 (c 0.44, C6H6); IR
(®lm) 3089, 3063, 3031, 2953, 2928, 2884, 2857, 1661,
1497, 1472, 1454, 1388, 1360, 1253, 1210, 1151, 1098,
1
1027, 919, 863, 837, 778, 734, 697, 556 cm21; H NMR
(C6D6, 500 MHz) d 7.33±7.00 (m, 10H), 4.84 (d, Jˆ
11.8 Hz, 1H), 4.81 (s, 1H), 4.75 (d, Jˆ11.2 Hz, 1H), 4.71
(d, Jˆ11.8 Hz, 1H), 4.50±4.46 (m, 3H), 4.14 (d, Jˆ8.2 Hz,
1H), 3.82 (ddd, Jˆ2.7, 9.3, 9.3 Hz, 2H), 3.71 (m, 1H), 3.55
(dd, Jˆ8.2, 8.2 Hz, 1H), 3.36 (dd, Jˆ9.7, 8.2 Hz, 1H), 3.16
(s, 3H), 2.25 (m, 1H), 1.74 (m, 1H), 0.96 (s, 9H), 0.08 (s,
3H), 0.04 (s, 3H); 13C NMR (C6D6, 125 MHz) d 160.9,
139.7, 139.3, 128.9, 128.7, 128.6, 128.2, 127.9, 127.8,
97.0, 94.7, 87.1, 82.9, 77.8, 75.3, 75.2, 73.5, 64.3, 55.3,
33.4, 26.4, 18.6, 24.1, 24.4; HRMS (FAB) calcd for
C30H44O6SiNa [(M1Na)1] 551.2805, found 551.2794.
4.1.5. Alcohol 16. To a solution of alcohol 15 (23.64 g,
38.38 mmol) and tetra-n-butylammonium iodide (2.84 g,
7.69 mmol) in CH2Cl2 (30 mL) at 08C were added diiso-
propylethylamine (23.4 mL, 134.3 mmol) followed by
chloromethyl methyl ether (7.3 mL, 95.9 mmol). The
resultant solution was stirred at room temperature overnight.
The mixture was diluted with ether (1 L), washed with 1 M
HCl (300 mL), saturated aqueous NaHCO3 (300 mL), and
brine (300 mL), dried over Na2SO4, ®ltered, and concen-
trated in vacuo. The crude methoxymethyl ether was used
in the next reaction without puri®cation.
4.1.8. Bis(benzyl) ether 20. To a solution of tri-O-acetyl-d-
glucal 19 (5.10 g, 18.7 mmol) in CH2Cl2 (30 mL) at 08C
were added isopropyl alcohol (5.80 mL, 75.5 mmol) and
boron tri¯uoride etherate (3.20 mL, 25.2 mmol). The resul-
tant mixture was stirred at 08C for 20 min and at room
temperature for 40 min. The reaction was quenched with
saturated aqueous NaHCO3 (30 mL), and the mixture was
diluted with ethyl acetate (200 mL). The organic layer was
washed with saturated aqueous NaHCO3 (80 mL) and brine
(80 mL), dried over Na2SO4, ®ltered, and concentrated in
vacuo. The crude isopropyl glycoside was used in the next
reaction without chromatographic puri®cation.
To a solution of the above methoxymethyl ether in CH2Cl2/
methanol (1:3, v/v, 400 mL) at 08C was added camphor-
sulfonic acid (4.46 g, 19.2 mmol). The resultant solution
was stirred at 08C for 1 h before the reaction was quenched
with triethylamine. The solvent was removed in vacuo, and
the residue was puri®ed by column chromatography on
silica gel (20±40% ethyl acetate/hexanes) to give alcohol
16 (19.09 g, 91% for the two steps) as a colorless oil:
27
[a]D ˆ25.95 (c 0.14, C6H6); IR (®lm) 3483, 3030, 2952,
2927, 2884, 2856, 1497, 1471, 1455, 1359, 1252, 1211,
1153, 1107, 1059, 918, 858, 836, 778, 733, 697, 672,
To a solution of the above glycoside in ethyl acetate/ethanol
(1:1, v/v, 50 mL) was added 10% Pd/C (0.60 g), and the
mixture was stirred at room temperature under hydrogen
atmosphere overnight. The catalyst was removed by ®l-
tration through a pad of Celite, and the ®ltrate was concen-
trated to give crude diacetate, which was used in the next
reaction without puri®cation.
1
411 cm21; H NMR (CDCl3, 500 MHz) d 7.34±7.13 (m,
10H), 4.93 (d, Jˆ11.9 Hz, 1H), 4.81 (d, Jˆ11.9 Hz, 1H),
4.74 (d, Jˆ10.7 Hz, 1H), 4.60±4.56 (m, 3H), 3.80 (m, 1H),
3.79±3.56 (m, 3H), 3.54 (dd, Jˆ8.9, 8.9 Hz, 1H), 3.49±3.44
(m, 2H), 3.33 (s, 3H), 3.27±3.22 (m, 2H), 2.15 (m, 1H), 1.64
(m, 1H), 0.85 (s, 9H), 0.06 (s, 3H), 20.03 (s, 3H); 13C NMR
(CDCl3, 125 MHz) d 138.9, 137.8, 128.4, 128.2, 127.9,
127.8, 127.1, 126.6, 96.3, 87.0, 83.0, 80.3, 76.2, 75.2,
75.1, 71.3, 64.0, 62.5, 55.2, 32.0, 25.9, 18.0, 23.8, 24.7;
HRMS (FAB) calcd for C30H46O7SiNa [(M1Na)1]
569.2911, found 569.2899.
To a solution of the above diacetate in methanol (50 mL)
was added sodium methoxide (1.0 M solution in methanol,
5.69 mL, 5.60 mmol). The resultant solution was stirred at
room temperature for 30 min. The reaction was quenched
with amberlyst-15, and the resin was removed by ®ltration.
The solvent was removed in vacuo to give crude diol, which
was used in the next reaction without puri®cation.
4.1.6. Iodide 17. To a solution of alcohol 16 (1.83 g,
3.35 mmol) and imidazole (342.3 mg, 5.03 mmol) in
benzene (50 mL) were added triphenylphosphine (1.32 g,
5.03 mmol) followed by iodine (1.11 g, 4.36 mmol). The
resultant solution was stirred at room temperature for
45 min before the reaction was quenched with saturated
aqueous Na2SO3 (10 mL). The mixture was extracted with
ether (300 mL), washed with brine (80 mL), dried over
Na2SO4, ®ltered, and concentrated in vacuo. Puri®cation
by column chromatography on silica gel (5±15% ethyl
acetate/hexanes) gave iodide 17 (2.25 g, quant.) as a color-
less oil, which was used in the next reaction without further
puri®cation.
To a solution of the above diol in THF/DMF (2:1, v/v,
150 mL) at 08C were added tetra-n-butylammonium iodide
(0.72 g, 1.9 mmol) and sodium hydride (60% dispersion in
mineral oil, 3.00 g, 75.0 mmol). The resultant mixture was
stirred at 08C for 10 min and then at room temperature for
30 min. The mixture was recooled to 08C and treated with
benzyl bromide (6.10 mL, 51.2 mmol). After 10 min, the
resultant mixture was allowed to warm to room temperature,
and the stirring was continued overnight. The reaction was
quenched with methanol (20 mL) at 08C, and the mixture
was extracted with ether (300 mL), washed with water
(100 mL) and brine (100 mL), dried over Na2SO4, ®ltered,
and concentrated in vacuo. Puri®cation by column chroma-
tography on silica gel (10% ethyl acetate/hexanes) gave
bis(benzyl) ether 20 (5.89 g, 85% for the four steps) as a
colorless oil: 1H NMR (500 MHz, CDCl3) d 4.93 (brs, 1H),
4.64 (d, Jˆ12.2 Hz, 1H), 4.57 (d, Jˆ11.3 Hz, 1H), 4.51 (d,
Jˆ12.2 Hz, 1H), 4.38 (d, Jˆ11.3 Hz, 1H), 3.92 (dd, Jˆ5.8,
4.1.7. exo-Ole®n 18. To a solution of the above iodide 17 in
THF (40 mL) at 08C was added potassium t-butoxide
(940.2 mg, 8.38 mmol). The resultant solution was stirred
at 08C for 4 h. The mixture was diluted with ether, washed
with brine, dried over Na2SO4, ®ltered, and concentrated in
vacuo. Puri®cation by column chromatography on silica gel
(10% ethyl acetate/hexanes) gave exo-ole®n 18 (1.70 g,

M. Sasaki et al. / Tetrahedron 58 (2002)1889±1911
1899
6.3 Hz, 1H), 3.82 (m, 1H), 3.76 (dd, Jˆ3.9, 10.4 Hz, 1H),
3.64 (dd, Jˆ2.1, 10.4 Hz, 1H), 3.53 (ddd, Jˆ4.3, 4.9,
10.1 Hz, 1H), 2.01 (m, 1H), 1.86±1.72 (m, 3H), 1.18 (d,
Jˆ6.3 Hz, 3H), 1.11 (d, Jˆ5.8 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 138.4, 138.4, 93.9, 73.4, 73.1, 71.3,
70.8, 69.3, 67.7, 29.4, 24.0, 23.3, 21.3.
concentrated in vacuo. Puri®cation by column chromato-
graphy on silica gel (10±40% ethyl acetate/hexanes)
provided enol ether 8 (15.35 g, 91%) as a colorless oil:
31
[a]D ˆ153.7 (c 0.55, C6H6); IR (®lm) 3032, 2925, 1684,
1
1458, 1360, 1308, 1254, 1105, 847, 739, 694 cm21; H
NMR (500 MHz, CDCl3) d 7.24±7.11 (m, 20H), 4.83 (d,
Jˆ11.9 Hz, 1H), 4.71 (d, Jˆ11.6 Hz, 1H), 4.63 (d, Jˆ
10.7 Hz, 1H), 4.52 (d, Jˆ11.9 Hz, 1H), 4.49±4.42 (m,
4H), 4.40 (s, 2H), 4.38 (m, 1H), 3.85 (m, 1H), 3.68±3.62
(m, 3H), 3.54 (m, 1H), 3.41 (m, 1H), 3.33 (m, 1H), 3.24 (m,
1H), 3.20±3.16 (m, 4H), 3.13 (dd, Jˆ9.2, 8.9 Hz, 1H), 2.47
(dd, Jˆ14.7, ,1 Hz, 1H), 2.22 (m, 1H), 2.04±1.95 (m, 2H),
1.82 (dd, Jˆ14.7, 9.8 Hz, 1H), 1.52 (m, 1H), 0.82 (s, 9H),
20.05 (s, 3H), 20.13 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 150.6, 143.3, 139.0, 138.5, 138.1, 130.5, 129.0, 128.4,
128.3, 128.1, 127.9, 127.7, 127.6, 127.55, 127.79, 127.0,
126.7, 125.4, 96.5, 94.0, 87.0, 83.5, 77.8, 76.9, 76.0, 75.2,
75.1, 75.0, 73.3, 71.1, 70.6, 69.3, 64.5, 55.0, 41.9, 36.6,
32.4, 27.2, 26.8, 26.0, 25.7, 24.7, 18.0, 23.6, 24.1;
HRMS (FAB) calcd for C50H66O9SiNa [(M1Na)1]
861.4374, found 861.4402.
4.1.9. Lactone 22. A solution of bis(benzyl) ether 20
(3.85 g, 10.4 mmol) in 80% acetic acid/1 M HCl (4:1, v/v,
100 mL) was heated at 608C for 2 days. The reaction
mixture was cooled to room temperature and poured into
cold saturated aqueous NaHCO3 (300 mL). The aqueous
layer was extracted with ethyl acetate (300 mL£3), dried
over Na2SO4, ®ltered, and concentrated in vacuo. Puri®-
cation by column chromatography on silica gel (50±60%
ethyl acetate/hexanes) gave lactol 21 (1.01 g, 78%) as a
white solid.
To a solution of lactol 21 (1.31 g, 4.00 mmol) in acetonitrile
Ê
(10 mL) were added 4 A molecular sieves (2.05 g) and
N-methylmorpholine-N-oxide (0.70 g, 5.9 mmol). After
20 min, tetra-n-propylammonium perruthenate (76.8 mg,
0.218 mmol) was added, and the resultant mixture was
stirred at room temperature for 4.5 h. The solvent was
removed in vacuo and the residue was puri®ed by column
chromatography on silica gel (40% ethyl acetate/hexanes) to
4.1.12. Alcohol 23. To a solution of 2,3-dimethyl-2-butene
(5.06 mL, 42.6 mmol) in THF (5 mL) at 08C was added
borane´THF (1.0 M solution in THF, 42.6 mL, 42.6
mmol). The resultant solution was stirred at 08C for 2 h.
To a solution of enol ether 8 (5.95 g, 7.10 mmol) in THF
(70 mL) at 08C was added the above solution of thexyl-
borane in THF, and the resulting solution was stirred at
08C for 2 h. The reaction was quenched with water
(5 mL), and the mixture was treated with 3 M aqueous
NaOH (40 mL) followed by 30% aqueous H2O2 (30 mL).
The resultant solution was stirred at room temperature for
1.5 h and then heated at 458C for 0.5 h. The reaction mixture
was cooled to room temperature, extracted with ethyl ace-
tate (500 mL), washed with saturated aqueous Na2SO3
(200 mL) and brine (200 mL), dried over Na2SO4, ®ltered,
and concentrated in vacuo. Puri®cation by column chroma-
tography on silica gel (20% ethyl acetate/hexanes) gave
1
give lactone 22 (1.01 g, 78%) as a colorless oil: H NMR
(500 MHz, CDCl3) d 7.28±7.18 (m, 10H), 4.52 (d, 1H,
Jˆ11.9 Hz), 4.92 (d, 1H, Jˆ11.9 Hz), 4.43 (d, 1H, Jˆ
11.9 Hz), 4.43 (d, 1H, Jˆ11.9 Hz), 4.38 (m, 1H), 3.82 (m,
1H), 3.64 (dd, 1H, Jˆ3.7, 10.7 Hz), 3.60 (dd, 1H, Jˆ4.0,
10.7 Hz), 2.63 (ddd, 1H, Jˆ6.4, 9.5, 17.4 Hz), 2.40 (ddd,
1H, Jˆ5.8, 6.1, 17.4 Hz), 2.02 (m, 1H), 1.92 (m, 1H); 13C
NMR (125 MHz, CDCl3) d 170.8, 137.6, 137.5, 128.5,
128.4, 128.4, 127.9, 127.8, 127.8, 127.7, 80.9, 73.6, 71.1,
70.5, 69.3, 26.7, 23.4.
4.1.10. Enol tri¯ate 10. To a solution of lactone 22 (3.40 g,
10.43 mmol) in THF (50 mL) at 2788C were added HMPA
(2.72 mL, 15.6 mmol) followed by potassium bis(trimethyl-
silyl)amide (0.5 M solution in toluene, 27.2 mL, 13.5
mmol). After 30 min at 2788C, N-phenytri¯uoromethane-
sulfonimide (4.47 g, 12.5 mmol) in THF (15 mL) was added
to the solution, and the resultant mixture was stirred at 08C
for 1.5 h. Volatiles were removed in vacuo and the residue
was extracted with hexane (15 mL£6). The organic extracts
were combined and concentrated to give crude enol tri¯ate
10, which was used immediately in the next reaction without
puri®cation.
27
alcohol 23 (5.61 g, 92%) as a colorless oil: [a]D ˆ112.4
(c 0.075, C6H6); IR (®lm) 3458, 3063, 3031, 2927, 2856,
1652, 1496, 1454, 1360, 1310, 1251, 1209, 1107, 1056, 918,
1
858, 836, 777, 734, 697, 668 cm21; H NMR (500 MHz,
C6D6) d 7.37±6.91 (m, 20H), 4.99 (d, Jˆ12.2 Hz, 1H),
4.79 (d, Jˆ12.2 Hz, 1H), 4.66 (d, Jˆ11.1 Hz, 1H), 4.57±
4.42 (m, 6H), 4.30 (d, Jˆ11.8 Hz, 1H), 3.77 (ddd, Jˆ9.4,
9.4, 4.8 Hz, 1H), 3.67±3.57 (m, 4H), 3.53±3.47 (m, 3H),
3.46 (m, 1H), 3.41 (dd, Jˆ8.8, 8.8 Hz, 1H), 3.19 (dd, Jˆ9.4,
9.4 Hz, 1H), 3.18 (s, 3H), 2.67 (ddd, Jˆ11.4, 4.4, 4.4 Hz,
1H), 2.36 (ddd, Jˆ14.7, 5.1, 1.5 Hz, 1H), 2.17 (m, 1H), 2.03
(ddd, Jˆ14.7, 8.9, 3.6 Hz, 1H), 1.62 (ddd, Jˆ11.4, 11.4,
11.4 Hz, 1H), 1.52 (m, 1H), 1.02 (s, 9H), 0.16 (s, 3H),
0.11 (s, 3H); 13C NMR (125 MHz, C6D6) d 139.7, 135.9,
139.2, 138.7, 128.6, 128.5, 128.4, 128.3, 128.0, 127.9,
127.8, 127.7, 127.6, 127.5, 127.2, 126.7, 96.7, 87.1, 83.2,
81.4, 80.0, 77.4, 76.4, 75.0, 74.9, 74.8, 73.6, 73.0, 70.9,
70.2, 69.0, 64.2, 55.1, 38.9, 35.0, 32.3, 26.4, 18.4, 23.2,
24.0; HRMS (FAB) calcd for C50H68O10SiNa [(M1Na)1]
879.4479, found 879.4476.
4.1.11. Enol ether 8. exo-Ole®n 18 (3.72 g, 7.05 mmol) was
treated with 9-BBN (0.5 M solution in THF, 36.6 mL,
18.3 mmol), and the resultant solution was stirred at room
temperature for 1 h and then heated to re¯ux for 2 h. The
solution was cooled to room temperature and treated with
3 M aqueous Cs2CO3 (7.05 mL, 21.2 mmol). After 15 min,
the above enol tri¯ate 10 in DMF (20 mL) followed
by tris(dibenzylideneacetone)dipalladium(0)±chloroform
adduct complex (364.6 mg, 0.352 mmol) and triphenylar-
sine (863.0 mg, 2.82 mmol) were added to the solution.
After being stirred at room temperature for 14 h, the reac-
tion mixture was extracted with ether (500 mL), washed
with brine (200 mL£2), dried over Na2SO4, ®ltered, and
4.1.13. Ketone 7. To a solution of alcohol 23 (5.61 g,
Ê
6.55 mmol) in CH2Cl2 (30 mL) were added 4 A molecular
sieves (2 g) and N-methylmolpholine-N-oxide (1.15 g,

1900
M. Sasaki et al. / Tetrahedron 58 (2002)1889±1911
9.82 mmol), and the solution was stirred at room tempera-
ture for 5 min. Tetra-n-propylammonium perruthenate
(115.2 mg, 0.33 mmol) was added, and the resultant solu-
tion was stirred at room temperature for 1 h. The solvent
was removed in vacuo and the residue was puri®ed by
column chromatography on silica gel (40% ethyl acetate/
hexanes) to give ketone 7 (5.57 g, 99%) as a colorless oil:
(0.25 mL, 1.57 mmol) and boron tri¯uoride etherate
(0.075 mL, 0.59 mmol). The resultant solution was stirred
at 08C for 2 h before the reaction was quenched with satu-
rated aqueous NaHCO3. The reaction mixture was diluted
with ethyl acetate, washed with saturated aqueous NaHCO3
and brine, dried over Na2SO4, ®ltered, and concentrated in
vacuo. Puri®cation by column chromatography on silica gel
(10% ethyl acetate/hexanes) gave tricyclic ether 25
(123.1 mg, 78% for the four steps) as a colorless amorphous
27
[a]D ˆ25.25 (c 0.05, C6H6); IR (®lm) 3030, 2927, 2855,
1734, 1496, 1472, 1453, 1359, 1251, 1207, 1108, 1027, 915,
1
1
858, 836, 777, 733, 697, 674 cm21; H NMR (500 MHz,
solid: H NMR (CDCl3, 500 MHz) d 7.80±7.24 (m, 20H),
C6D6) d 7.37±6.87 (m, 20H), 4.99 (d, Jˆ12.1 Hz, 1H),
4.80 (d, Jˆ12.1 Hz, 1H), 4.71 (d, Jˆ11.0 Hz, 1H), 4.62±
4.50 (m, 3H), 4.38±4.28 (m, 2H), 4.23 (dd, Jˆ6.7, 4.0 Hz,
1H), 4.18 (d, Jˆ11.9 Hz, 1H), 3.94±3.87 (m, 4H), 3.81±
3.70 (m, 3H), 3.55±3.47 (m, 4H), 3.45 (dd, Jˆ8.8, 8.8 Hz,
1H), 3.29 (dd, Jˆ9.2, 9.2 Hz, 1H), 3.19 (s, 3H), 2.86 (dd,
Jˆ14.9, 3.9 Hz, 1H), 2.63 (ddd, Jˆ14.0, 6.9, 2.5 Hz, 1H),
2.57 (dd, Jˆ14.9, 4.8 Hz, 1H), 2.21 (m, 1H), 2.13 (ddd,
Jˆ14.0, 10.1, 4.0 Hz, 1H), 1.76 (m, 1H), 0.98 (s, 9H),
0.11 (s, 3H), 0.09 (s, 3H); 13C NMR (125 MHz, C6D6) d
207.9, 139.7, 138.9, 138.8, 138.5, 128.6, 128.5, 128.4,
128.3, 128.0, 127.9, 127.8, 127.7, 127.2, 126.7, 96.7, 87.3,
83.5, 79.8, 79.0, 77.2, 76.4, 75.9, 75.1, 75.1, 74.9, 73.5,
70.7, 70.6, 64.3, 55.0, 41.3, 33.9, 32.7, 26.3, 18.3, 23.4,
23.9; HRMS (FAB) calcd for C50H66O10SiNa [(M1Na)1]
877.4323, found 877.4343.
4.98±4.90 (m, 2H), 4.74 (d, Jˆ11.3 Hz, 1H), 4.61 (d,
Jˆ10.1 Hz, 1H), 4.54 (m, 1H), 4.32 (d, Jˆ11.9 Hz, 1H),
4.20±4.07 (m, 2H), 3.76 (ddd, Jˆ4.9, 4.9, 4.9 Hz, 1H),
3.69 (m, 1H), 3.57 (dd, Jˆ8.9, 8.9 Hz, 1H), 3.44 (m, 1H),
3.36±3.28 (m, 2H), 3.21 (dd, Jˆ8.9, 8.9 Hz, 1H), 3.16±3.08
(m, 1H), 3.04 (m, 1H), 2.35 (ddd, Jˆ11.6, 4.6, 4.3 Hz, 1H),
2.14 (m, 1H), 2.05 (m, 1H), 1.95±1.85 (m, 2H), 1.71±1.59
(m, 2H), 1.51 (ddd, Jˆ11.6, 11.6, 11.6 Hz, 1H), 1.17 (s,
9H); 13C NMR (CDCl3, 125 MHz) d 178.5, 138.9, 138.4,
138.3, 138.2, 128.4, 128.3, 127.9, 127.7, 127.6, 127.5, 84.1,
83.6, 82.3, 81.8, 81.5, 79.6, 78.2, 77.3, 76.4, 75.2, 74.9,
73.2, 71.4, 70.6, 61.1, 38.7, 37.0, 31.3, 27.2, 26.3, 23.6.
4.1.15. Ole®n 26. To a solution of pivalate ester 25
(58.4 mg, 0.0751 mmol) in CH2Cl2 (1 mL) at 2788C was
added diisobutylaluminum hydride (1.0 M solution in
toluene, 0.23 mL, 0.23 mmol). The resultant solution was
stirred at 2788C for 3 h before the reaction was quenched
with saturated aqueous potassium sodium tartrate. The
mixture was diluted with ethyl acetate and stirred vigorously
at room temperature for 2.5 h. The resultant mixture was
diluted with ethyl acetate, washed with water and brine,
dried over Na2SO4, ®ltered, and concentrated in vacuo.
Puri®cation by column chromatography on silica gel (30±
40% ethyl acetate/hexanes) gave primary alcohol (49.9 mg,
96%) as a colorless oil.
4.1.14. Tricyclic ether 25. To a solution of ketone 7
(173.8 mg, 0.204 mmol) in CH2Cl2 (2 mL) at 2788C were
added trimethylaluminum (0.98 M solution in hexane,
0.26 mL, 0.25 mmol) and trimethylsilyldiazomethane
(2.0 M solution in hexane, 0.15 mL, 0.30 mmol). The resul-
tant solution was stirred at 2788C for 6 h before the reaction
was quenched with saturated aqueous NaHCO3. The
reaction mixture was diluted with ethyl acetate, washed
with saturated aqueous NaHCO3 and brine, dried over
Na2SO4, ®ltered, and concentrated in vacuo. The residue
was dissolved in methanol/CH2Cl2 (3:1, v/v, 2.6 mL) and
treated with p-toluenesulfonic acid monohydrate (58.1 mg,
0.301 mmol). The resultant solution was stirred at room
temperature for 2 days and then heated to re¯ux for 4 h.
The solution was cooled to 08C, and the reaction was
quenched with saturated aqueous NaHCO3. The mixture
was diluted with ethyl acetate, washed with saturated
aqueous NaHCO3 and brine, dried over Na2SO4, ®ltered,
and concentrated in vacuo. The crude alcohol was used in
the next reaction without chromatographic puri®cation.
To a solution of the above alcohol in CH2Cl2/DMSO (4:1,
v/v, 1 mL) at 08C were successively added triethylamine
(0.05 mL, 0.36 mmol) and SO3´pyridine complex (45.8
mg, 0.288 mmol). The resultant solution was stirred at 08C
for 2 h. The mixture was diluted with ethyl acetate, washed
with 1 M HCl, saturated aqueous NaHCO3, and brine, dried
over Na2SO4, ®ltered, and concentrated in vacuo. The crude
aldehyde was used in the next reaction without puri®cation.
To a suspension of methyltriphenylphosphonium bromide
(77.1 mg, 0.216 mmol) in THF (1 mL) at 08C was added
sodium bis(trimethylsilyl)amide (1.0 M solution in THF,
0.2 mL, 0.2 mmol). The resultant solution was stirred at
08C for 30 min. A solution of the above aldehyde in THF/
CH2Cl2 (3:10, v/v, 1.3 mL) was added to the ylide solution,
and the resulting mixture was stirred at 08C for 1 h. The
reaction was quenched with saturated aqueous NH4Cl, and
the mixture was diluted with ethyl acetate, washed with
water and brine, dried over Na2SO4, ®ltered, and concen-
trated in vacuo. Puri®cation by column chromatography on
silica gel (5±20% ethyl acetate/hexanes) gave ole®n 26
(43.9 mg, 88% for the two steps) as a white solid:
To a solution of the above alcohol in CH2Cl2 (2 mL) were
successively added triethylamine (0.09 mL, 0.61 mmol),
dimethylaminopyridine (12.4 mg, 0.102 mmol), and piva-
loyl chloride (0.05 mL, 0.41 mmol). The resultant solution
was stirred at room temperature overnight. The reaction
mixture was diluted with ethyl acetate, washed with 1 M
HCl, saturated aqueous NaHCO3, and brine, dried over
Na2SO4, ®ltered, and concentrated in vacuo. The residue
was ®ltered through a short column chromatography on
silica gel (10±30% ethyl acetate/hexanes) to give mixed
methyl ketal 24, which was used in the next reaction without
further puri®cation.
31
[a]D ˆ14.658 (c 0.97, CHCl3); IR (®lm) 3030, 2866,
1954, 1732, 1643, 1495, 1452, 1363, 1211, 1072, 910,
1
To a solution of the above mixed methyl ketal 24 in aceto-
nitrile (3 mL) at 08C were successively added triethylsilane
741, 698 cm21; H NMR (500 MHz, CDCl3) d 7.36±7.26
(m, 20H), 5.87 (ddt, Jˆ17.2, 10.1, 6.6 Hz, 1H), 5.09±5.04

M. Sasaki et al. / Tetrahedron 58 (2002)1889±1911
1901
(m, 2H), 4.97 (d, Jˆ11.2 Hz, 1H), 4.93 (d, Jˆ10.8 Hz, 1H),
4.75 (d, Jˆ11.2 Hz, 1H), 4.61 (d, Jˆ10.9 Hz, 1H), 4.54 (d,
Jˆ12.6 Hz, 1H), 4.53 (s, 2H), 4.33 (d, Jˆ11.8 Hz, 1H), 3.77
(ddd, Jˆ4.9, 4.9, 4.9 Hz, 1H), 3.70 (m, 1H), 3.59 (dd,
Jˆ8.6, 8.6 Hz, 1H), 3.47±3.44 (m, 2H), 3.37±3.26 (m,
3H), 3.15±3.07 (m, 3H), 2.57 (m, 1H), 2.37 (ddd, Jˆ11.5,
4.3, 4.3 Hz, 1H), 2.25 (m, 1H), 2.05 (m, 1H), 1.91±1.89 (m,
2H), 1.67 (m, 1H), 1.55 (m, 1H); 13C NMR (125 MHz,
CDCl3) d 139.0, 138.5, 138.4, 138.3, 134.7, 128.35,
128.32, 128.27, 128.0, 127.9, 127.62, 127.59, 127.53,
127.45, 116.9, 84.2, 83.7, 82.4, 81.9, 81.0, 79.7, 79.0,
78.3, 75.1, 74.9, 74.0, 73.2, 71.6, 70.7, 37.1, 36.1, 26.4,
23.7; HRMS (FAB) calcd for C44H50O7Na [(M1Na)1]
713.3454, found 713.3450.
ethyl acetate/hexanes) gave coupling product 8 (160.8 mg,
98%) as a colorless clear oil.
4.2.1. Hydroxy ester 32. To a solution of 2-deoxy-d-ribose
(31) (10.00 g, 74.55 mmol) in THF (200 mL) was added
methyl triphenylphosphoranylidene acetate (27.4 g, 82.0
mmol). The resultant solution was heated under re¯ux for
3 h. The solvent was removed in vacuo and the residue was
puri®ed by column chromatography on silica gel (10±15%
methanol/CHCl3) to give a,b-unsaturated ester as a
brownish viscous oil, which was used in the next reaction
without further puri®cation.
To a solution of the above a,b-unsaturated ester in ethyl
acetate/methanol (1:1, v/v, 250 mL) was added 10% Pd/C
(2.0 g). The resulting mixture was stirred at room tempera-
ture under hydrogen atmosphere overnight. The catalyst was
removed by ®ltration through a pad of Celite, and the ®ltrate
was concentrated in vacuo. The residue was dissolved in
CH2Cl2 (400 mL) and treated with benzaldehyde dimethyl-
acetal (16.8 mL, 112 mmol) and camphorsulfonic acid
(5.20 g, 22.4 mmol). The resultant solution was stirred at
room temperature overnight before the reaction was
quenched with triethylamine. The solvent was removed in
vacuo and the residue was puri®ed by column chroma-
tography on silica gel (10±40% ethyl acetate/hexanes) to
give hydroxy ester 32 (16.33 g, 78% for the three steps) as
4.1.16. Enol phosphate 29a. To a solution of lactone 22
(1.19 g, 3.65 mmol) in THF (20 mL) were added HMPA
(1.90 mL, 10.9 mmol) and diphenylphosphoryl chloride
(1.52 mL, 7.30 mmol). The resultant solution was cooled
to 2788C and treated with potassium bis(trimethylsilyl)-
amide (0.5 M solution in toluene, 9.50 mL, 4.75 mmol).
After being stirred at 2788C for 30 min, the reaction
mixture was diluted with ether and 2% NH4OH. The
mixture was stirred at room temperature for 30 min before
dilution with ethyl acetate. The organic layer was separated,
washed with brine, dried over Na2SO4, ®ltered, and concen-
trated in vacuo. Puri®cation by column chromatography on
silica gel (25% ethyl acetate/hexanes) gave enol phosphate
29a (1.52 g, 75%) as a pale yellow oil, which was used in
the next cross-coupling reaction without further puri®ca-
1
a colorless clear oil: H NMR (500 MHz, CDCl3) d 7.36±
7.35 (m, 2H), 7.27±7.21 (m, 3H), 5.35 (s, 1H), 4.15 (dd,
Jˆ10.1, 4.3 Hz, 1H), 3.57±3.42 (m, 6H), 2.30±2.24 (m,
2H), 1.90 (brd, Jˆ5.2 Hz, 1H), 1.86±1.80 (m, 2H), 1.66
(m, 1H), 1.54 (m, 1H); 13C NMR (125 MHz, CDCl3) d
174.2, 137.7, 128.8, 128.4, 128.3, 128.2, 126.0, 100.9,
81.5, 71.2, 65.7, 51.6, 33.8, 30.9, 20.4.
1
tion: H NMR (C6D6) d 7.39±77.34 (m, 4H), 7.28±7.24
(m, 2H), 7.20±7.05 (m, 8H), 6.97±6.90 (m, 4H), 6.83±
6.77 (m, 2H), 4.46 (m, 1H), 4.37 (d, Jˆ11.9 Hz, 1H), 4.31
(d, Jˆ11.9 Hz, 1H), 4.26 (d, Jˆ11.9 Hz, 1H), 4.20 (d, Jˆ
11.9 Hz, 1H), 4.10 (ddd, Jˆ7.6, 4.6, 3.1 Hz, 1H), 3.70±3.61
(m, 2H), 3.52 (dd, Jˆ11.0, 3.1 Hz, 1H), 2.00 (m, 1H), 1.89
(m, 1H); HRMS (FAB) calcd for C32H31O7PNa [(M1Na)1]
581.1705, found 581.1724.
4.2.2. Hydroxy acid 33. To a solution of hydroxy ester 32
(959.4 mg, 3.4264 mmol) in THF/methanol/water (1:1:1,
v/v, 30 mL) was added KOH (340 mg, 6.06 mmol). After
being stirred at 508C for 45 min, the reaction mixture was
acidi®ed with 1 M aqueous HCl. The mixture was diluted
with brine, and the aqueous layer was extracted with ethyl
acetate repeatedly. The combined organic extracts were
dried over Na2SO4 and concentrated in vacuo. The residue
was passed through a short column of silica gel (10% metha-
nol/CHCl3) to give hydroxy acid 33 (904.2 mg, 99%) as a
4.2. General procedure for Suzuki coupling of enol
phosphates
exo-Ole®n 18 (103.7 mg, 0.1964 mmol) was treated with
9-BBN (0.5 M solution in THF, 1.00 mL, 0.500 mmol).
The resultant solution was stirred at room temperature for
1 h and then heated at 608C for 2 h. After being cooled to
room temperature, the reaction mixture was treated with
1 M aqueous NaHCO3 (0.59 mL, 0.59 mmol) and stirred
at room temperature for 15 min. To this mixture were
added a solution of enol phosphate 29a (221.0 mg,
0.3961 mmol) in DMF (2.5 mL) followed by tetrakis(tri-
phenylphosphine)palladium(0) (23.2 mg, 0.0201 mmol).
The resultant solution was stirred at 508C for 20 h. The
mixture was cooled to room temperature and diluted with
ether, washed with brine, dried over Na2SO4, ®ltered, and
concentrated in vacuo. The residue was dissolved in THF
(5 mL), cooled to 08C, and treated with 3 M aqueous NaOH
(0.50 mL) and 30% H2O2 (0.25 mL). The resulting mixture
was stirred at room temperature for 1 h, diluted with ethyl
acetate, washed with saturated aqueous Na2SO3 and brine,
dried over Na2SO4, ®ltered, and concentrated in vacuo.
Puri®cation by column chromatography on silica gel (10%
1
colorless amorphous solid: H NMR (500 MHz, CDCl3) d
7.46±7.45 (m, 2H), 7.36±7.31 (m, 3H), 5.46 (s, 1H), 4.26
(dd, Jˆ10.5, 4.7 Hz, 1H), 3.64±3.52 (m, 3H), 2.46±2.38 (m,
2H), 2.01±1.90 (m, 2H), 1.79 (m, 1H), 1.66 (m, 1H); 13C
NMR (125 MHz, CDCl3) d 178.0, 137.8, 128.9, 128.2,
126.1, 101.0, 81.5, 71.2, 65.8, 33.5, 30.9, 20.3.
4.2.3. Seven-membered lactone 34. To a solution of
hydroxy acid 33 (2.16 g, 8.12 mmol) in THF (50 mL)
were added triethylamine (1.58 mL, 11.3 mmol) and 2,4,6-
trichlorobenzoyl chloride (1.40 mL, 8.96 mmol). After
being stirred at room temperature overnight, the reaction
mixture was diluted with benzene (50 mL) and transferred
via cannula to a re¯uxing solution of dimethylaminopyri-
dine (1.50 g, 12.3 mmol) in benzene (400 mL) over a period
of 4 h. The reaction mixture was cooled to room tempera-
ture and concentrated in vacuo. The residue was diluted with
ethyl acetate, washed with 1 M aqueous HCl, saturated

1902
M. Sasaki et al. / Tetrahedron 58 (2002)1889±1911
aqueous NaHCO3, and brine, dried over Na2SO4, ®ltered,
and concentrated in vacuo. Puri®cation by column chroma-
tography on silica gel (40±50% ethyl acetate/hexanes) gave
lactone 34 (1.56 g, 77%) as a colorless amorphous solid: 1H
NMR (500 MHz, CDCl3) d 7.47±7.42 (m, 2H), 7.38±7.34
(m, 3H), 5.48 (s, 1H), 4.40 (dd, Jˆ11.3, 5.8 Hz, 1H), 4.26
(ddd, Jˆ9.5, 9.5, 5.8 Hz, 1H), 3.83±3.76 (m, 2H), 2.75 (dd,
Jˆ14.4, 7.0 Hz, 1H), 2.60 (m, 1H), 2.32 (m, 1H), 2.01 (m,
1H), 1.84±1.67 (m, 2H); 13C NMR (125 MHz, CDCl3) d
174.2, 132.6, 129.2, 128.3, 128.1, 126.1, 100.7, 78.2, 71.5,
68.1, 35.3, 34.8, 19.9.
4.2.6. Primary alcohol 36. To a solution of silyl ether 35
(20.42 g, 45.22 mmol) in ethyl acetate/methanol (1:1, v/v,
250 mL) was added 20% Pd(OH)2/C (1.97 g), and the
mixture was stirred at room temperature under hydrogen
atmosphere overnight. The catalyst was removed by ®l-
tration, and the solvent was removed in vacuo. The crude
diol was used in the next reaction without chromatographic
puri®cation.
To a solution of the above diol in DMF (200 mL) at 08C was
added sodium hydride (60% dispersion in mineral oil,
7.32 g, 183 mmol). The reaction mixture was stirred at
room temperature for 30 min and then cooled to 08C. To
the mixture were added benzyl bromide (16.2 mL,
136 mmol) and tetra-n-butylammonium iodide (1.67 g,
4.52 mmol). The resultant solution was stirred at room
temperature overnight before the reaction was quenched
with methanol. The mixture was diluted with ether, washed
with water and brine, dried over MgSO4, ®ltered, and
concentrated in vacuo. The crude bis(benzyl) ether was
used in the next reaction without puri®cation.
4.2.4. Enol phosphate 29b. By the same procedure
described above, lactone 34 (370.7 mg, 1.4948 mmol)
afforded enol phosphate 29b (640.6 mg, 89%) as a pale
yellow oil, which was immediately used in the next
coupling reaction: 1H NMR (500 MHz, C6D6) d 7.57±
7.53 (m, 2H), 7.33±7.28 (m, 4H), 7.19±7.07 (m, 5H),
6.97±6.91 (m, 4H), 6.83±6.78 (m, 2H), 5.24 (s, 1H), 4.70
(m, 1H), 4.30 (dd, Jˆ10.7, 5.5 Hz, 1H), 4.01 (ddd, Jˆ10.1,
9.2, 5.5 Hz, 1H), 3.40 (dd, Jˆ10.7, 10.1 Hz, 1H), 3.31 (ddd,
Jˆ10.4, 9.2, 3.4 Hz, 1H), 1.79±1.69 (m, 2H), 1.52 (m, 1H),
1.37 (m, 1H).
To a solution of the above bis(benzyl) ether in THF
(200 mL) was added tetra-n-butylammonium ¯uoride
(1.0 M solution in THF, 67.8 mL, 67.8 mmol). After being
stirred at room temperature overnight, the reaction mixture
was concentrated in vacuo. Puri®cation by column chroma-
tography on silica gel (50% ethyl acetate/hexanes) gave
alcohol 36 (14.03 g, 80% for the three steps) as a colorless
4.2.5. Silyl ether 35. To a solution of ester 32 (16.33 g,
58.32 mmol) in CH2Cl2 (300 mL) at 08C were added diiso-
propylethylamine (40.6 mL, 233 mmol), tetra-n-butyl-
ammonium iodide (2.15 g, 5.82 mmol) and chloromethyl
methyl ether (13.3 mL, 175 mmol). After being stirred at
room temperature for 3 days, the reaction mixture was
diluted with ethyl acetate, washed with 1 M aqeuous HCl,
saturated aqueous NaHCO3 and brine, dried over Na2SO4,
®ltered, and concentrated in vacuo. The crude methoxy-
methyl ether was used in the next reaction without puri®-
cation.
1
clear oil: H NMR (500 MHz, CDCl3) d 7.35±7.23 (m,
10H), 4.77 (d, Jˆ6.7 Hz, 1H), 4.71 (d, Jˆ6.7 Hz, 1H),
4.64 (d, Jˆ11.3 Hz, 1H), 4.54 (d, Jˆ12.2 Hz, 1H), 4.50
(d, Jˆ12.2 Hz, 1H), 4.49 (d, Jˆ11.3 Hz, 1H), 3.90 (dd,
Jˆ9.8, 4.3 Hz, 1H), 3.67±3.55 (m, 5H), 3.36 (s, 3H),
1.65±1.48 (m, 6H), 1.38 (m, 1H); 13C NMR (125 MHz,
CDCl3) d 138.6, 138.2, 128.3, 127.9, 127.64, 127.60,
96.4, 79.1, 77.2, 73.4, 72.4, 70.1, 62.7, 55.6, 32.7, 30.3,
21.7.
To a solution of the above methoxymethyl ether in THF
(300 mL) at 08C was added lithium aluminum hydride
(3.33 g, 87.7 mmol). After being stirred at 08C for 45 min,
the reaction mixture was treated with 3 M aqueous NaOH
(20 mL) and stirred vigorously at room temperature until the
white gel precipitated. Filtration through a pad of Celite
followed by concentration gave crude alcohol, which was
used in the next reaction without puri®cation.
4.2.7. Hydroxy acid 37. To a solution of alcohol 36
(497.6 mg, 1.2891 mmol) in CH2Cl2/DMSO (1:1, v/v,
12 mL) at 08C were successively added triethylamine
(0.900 mL, 6.46 mmol) and SO3´pyridine complex (822.7
mg, 5.17 mmol). After being stirred at 08C for 1 h, the reac-
tion mixture was diluted with ether, washed with 1 M
aqueous HCl, saturated aqueous NaHCO3, and brine, dried
over Na2SO4, ®ltered, and concentrated in vacuo. The crude
aldehyde was used in the next reaction without puri®cation.
To a solution of the above alcohol in CH2Cl2 (250 mL) at
08C were added 2,6-lutidine (9.61 mL, 83.0 mmol) and
triisopropylsilyl tri¯uoromethanesulfonate (16.7 mL, 62.1
mmol). The resultant solution was allowed to warm to
room temperature over 4 h before addition of methanol.
The reaction mixture was diluted with ethyl acetate, washed
with 1 M aqueous HCl, saturated aqueous NaHCO3, and
brine, dried over Na2SO4, ®ltered, and concentrated in
vacuo. Puri®cation by column chromatography on silica
gel (5±10% ethyl acetate/hexanes) gave silyl ether 35
(20.42 g, 78% for the three steps) as a colorless clear oil:
1H NMR (500 MHz, CDCl3) d 7.48±7.45 (m, 2H), 7.36±
7.29 (m, 3H), 5.46 (s, 1H), 4.68±4.64 (m, 2H), 4.40 (dd,
Jˆ10.8, 5.1 Hz, 1H), 3.72±3.67 (m, 2H), 3.65±3.58 (m,
2H), 3.48 (ddd, Jˆ9.8, 9.8, 5.1 Hz, 1H), 3.37 (s, 3H), 1.90
(m, 1H), 1.71±1.44 (m, 5H), 1.15±0.90 (m, 21H); 13C NMR
(125 MHz, CDCl3) d 138.0, 128.7, 128.2, 126.0, 100.7,
96.8, 80.4, 72.3, 70.1, 63.3, 55.7, 33.0, 31.6, 21.4, 18.0, 12.0.
To a solution of the above aldehyde in CH2Cl2/dimethyl
sul®de (3:1, v/v, 16 mL) at 08C was added BF3´OEt2
(0.490 mL, 3.87 mmol). The resultant solution was stirred
at 08C for 30 min before the reaction was quenched with
saturated aqueous NaHCO3. The mixture was diluted with
ethyl acetate, washed with saturated aqueous NaHCO3 and
brine, dried over Na2SO4, ®ltered, and concentrated in
vacuo. The crude hydroxy aldehyde was used in the next
reaction without puri®cation.
To a solution of the above hydroxy aldehyde in t-butanol/
water (4:1, v/v, 15 mL) at 08C were successively added
2-methyl-2-butene (2.70 mL, 25.5 mmol), NaH2PO4
(176.9 mg, 1.474 mmol) and NaClO2 (79% purity,

M. Sasaki et al. / Tetrahedron 58 (2002)1889±1911
1903
517.0 mg, 4.516 mmol). After being stirred at room
temperature for 1 h, the reaction mixture was acidi®ed
with 1 M aqueous HCl and extracted with CHCl3. The
organic layer was dried over Na2SO4, ®ltered, and concen-
trated in vacuo. Puri®cation by ¯ash chromatography on
silica gel (3% methanol/CHCl3) gave hydroxy acid 37
in DMSO (30 mL) was added KCN (1.05 g, 16.1 mmol).
The resultant solution was heated at 808C overnight. After
being cooled to room temperature, the reaction mixture was
diluted with ether, washed with water and brine, dried over
Na2SO4, ®ltered, and concentrated in vacuo. Puri®cation by
¯ash chromatography on silica gel (30% ethyl acetate/
hexanes) gave cyanide (1.283 g, quant.) as a colorless
1
(259.0 mg, 56% for the three steps) as a colorless oil: H
1
NMR (500 MHz, CDCl3) d 7.35±7.24 (m, 10H), 4.56 (s,
2H), 4.52 (s, 2H), 3.88 (ddd, Jˆ6.6, 6.2, 3.7 Hz, 1H), 3.61
(dd, Jˆ9.6, 3.7 Hz, 1H), 3.57 (dd, Jˆ9.6, 6.6 Hz, 1H), 3.49
(m, 1H), 2.38±2.27 (m, 2H), 1.82 (m, 1H), 1.73±1.57 (m,
4H); 13C NMR (125 MHz, CDCl3) d 177.6, 138.3, 137.9,
128.5, 128.4, 127.90, 127.86, 127.7, 79.1, 73.5, 72.3, 71.5,
71.1, 33.6, 29.4, 20.3.
clear oil: H NMR (500 MHz, CDCl3) d 7.40±7.25 (m,
10H), 4.77 (d, Jˆ6.7 Hz, 1H), 4.72 (d, Jˆ6.7 Hz, 1H),
4.65 (d, Jˆ11.3 Hz, 1H), 4.54 (d, Jˆ12.2 Hz, 1H), 4.50
(d, Jˆ12.2 Hz, 1H), 4.47 (d, Jˆ11.3 Hz, 1H), 3.90 (m,
1H), 3.67±3.55 (m, 3H), 3.36 (s, 3H), 2.29±2.21 (m, 2H),
1.67±1.38 (m, 6H); 13C NMR (125 MHz, CDCl3) d 138.3,
138.0, 128.4, 128.0, 127.7, 119.7, 96.4, 78.5, 76.8, 73.4,
72.3, 69.8, 55.6, 29.7, 25.4, 24.8, 17.1; MS (FAB) m/z 420
[(M1Na)1].
4.2.8. Seven-membered lactone 38. By the same procedure
described above, hydroxy acid 37 (765.2 mg, 2.137 mmol)
afforded lactone 38 (465.7 mg, 64%) as a pale yellow oil: 1H
NMR (500 MHz, CDCl3) d 7.35±7.22 (m, 10H), 4.56 (d,
Jˆ11.6 Hz, 1H), 4.56 (s, 2H), 4.38 (d, Jˆ11.6 Hz, 1H), 4.32
(ddd, Jˆ8.2, 5.8, 2.8 Hz, 1H), 3.74 (dd, Jˆ10.7, 2.8 Hz,
1H), 3.72±3.66 (m, 2H), 2.74 (ddd, Jˆ14.3, 10.1, 7.6 Hz,
1H), 2.61 (ddd, Jˆ14.3, 6.7, 4.0 Hz, 1H), 2.00±1.82 (m,
3H), 1.71 (m, 1H); 13C NMR (125 MHz, CDCl3) d 173.8,
137.9, 137.7, 128.5, 128.4, 127.9, 127.8, 127.7, 80.8, 75.5,
73.6, 71.6, 69.8, 32.6, 28.7, 16.6.
To a solution of the above cyanide (131.2 mg, 0.3304
mmol) in methanol (4 mL) was added 6 M aqueous HCl
(2 mL). After being stirred at room temperature overnight,
the reaction mixture was cooled to 08C and treated with 6 M
aqueous KOH (2 mL). Solid KOH (1.31 g, 23.3 mmol) was
added to the mixture, and the resultant solution was heated
at 708C overnight. The reaction mixture was cooled to 08C
and acidi®ed with diluted HCl. The aqueous layer was
extracted with CHCl3 repeatedly. The combined organic
layers were dried over Na2SO4, ®ltered, and concentrated
in vacuo. Puri®cation by ¯ash chromatography on silica gel
(5% methanol/CHCl3) gave hydroxy acid 39 (121.2 mg,
4.2.9. Enol phosphate 29c. By the same procedure
described above, lactone 38 (288.1 mg, 0.847 mmol) in
THF (15 mL) afforded enol phosphate 29c (364.0 mg,
75%) as a pale yellow oil, which was immediately used in
1
99% for the two steps) as a colorless clear oil: H NMR
(500 MHz, CDCl3) d 7.34±7.24 (m, 10H), 4.58±4.48 (m,
4H), 3.89 (m, 1H), 3.61 (dd, Jˆ9.6, 3.8 Hz, 1H), 3.57 (dd,
Jˆ9.6, 6.7 Hz, 1H), 3.49 (m, 1H), 2.37±2.25 (m, 2H), 1.67±
1.46 (m, 5H), 1.38 (m, 1H); 13C NMR (125 MHz, CDCl3) d
179.0, 138.3, 137.8, 128.44, 128.36, 127.9, 127.8, 127.7,
79.3, 73.4, 72.4, 71.6, 71.0, 33.8, 29.7, 24.7, 24.5.
1
the next coupling reaction: H NMR (500 MHz, C6D6) d
7.41±7.33 (m, 4H), 7.28±7.24 (m, 2H), 7.18±7.10 (m,
8H), 6.97±6.90 (m, 4H), 6.82±6.76 (m, 2H), 4.61 (m,
1H), 4.44±4.38 (m, 2H), 4.27 (d, Jˆ12.2 Hz, 1H), 4.23 (d,
Jˆ11.6 Hz, 1H), 4.05 (d, Jˆ11.6 Hz, 1H), 3.86 (m, 1H),
3.78 (dd, Jˆ11.0, 2.4 Hz, 1H), 3.68 (dd, Jˆ11.0, 2.4 Hz,
1H), 2.18 (m, 1H), 1.86 (m, 1H), 1.65±1.52 (m, 2H).
4.2.11. Eight-membered lactone 40. By the same pro-
cedure described above, hydroxy acid 39 (520.0 mg,
1.398 mmol) afforded lactone 40 (361.1 mg, 73%) as a
colorless clear oil: 1H NMR (CDCl3) d 7.34±7.20 (m,
10H), 4.67 (m, 1H), 4.60±4.50 (m, 3H), 4.30 (d, Jˆ
11.3 Hz, 1H), 3.80 (dd, Jˆ10.8, 1.9 Hz, 1H), 3.69 (dd,
Jˆ10.8, 5.9 Hz, 1H), 3.62 (m, 1H), 2.53±2.38 (m, 2H),
1.92±1.72 (m, 4H), 1.67±1.52 (m, 2H); 13C NMR
(CDCl3) d 175.8, 138.1, 137.9, 128.9, 128.7, 128.41,
128.38, 128.0, 127.8, 127.7, 127.6, 78.8, 77.9, 73.4, 71.3,
69.7, 33.0, 28.3, 28.0, 21.1.
4.2.10. Hydroxy acid 39. To a solution of alcohol 36
(1.4874 g, 3.8533 mmol) in CH2Cl2 (35 mL) at 08C were
successively added triethylamine (1.60 mL, 11.5 mmol),
dimethylaminopyridine (47.2 mg, 0.386 mmol) and
p-toluenesulfonyl chloride (1.10 g, 5.77 mmol). After
being stirred at room temperature overnight, the reaction
mixture was diluted with ethyl acetate, washed with 1 M
aqueous HCl, saturated aqueous NaHCO3, and brine, dried
over Na2SO4, ®ltered, and concentrated in vacuo. Puri®-
cation by ¯ash chromatography on silica gel (20±25%
ethyl acetate/hexanes) gave tosylate (1.7550 g, 84%) as a
4.2.12. Enol phosphate 29d. By the same procedure
described above, lactone 40 (224.8 mg, 0.6350 mmol)
afforded enol phosphate 29d (286.4 mg, 77%) as a pale
yellow oil, which was immediately used in the next
coupling reaction: 1H NMR (500 MHz, C6D6) d 7.38±
7.34 (m, 4H), 7.30±7.27 (m, 2H), 7.20±7.05 (m, 8H),
6.97±6.89 (m, 4H), 6.82±6.77 (m, 2H), 4.82 (ddd, Jˆ7.0,
6.7, 2.4 Hz, 1H), 4.48 (m, 1H), 4.41 (d, Jˆ12.2 Hz, 1H),
4.34 (d, Jˆ12.2 Hz, 1H), 4.31 (d, Jˆ11.6 Hz, 1H), 4.15 (d,
Jˆ11.6 Hz, 1H), 3.77±3.60 (m, 3H), 2.00±1.86 (m, 3H),
1.72 (m, 1H), 1.57 (m, 1H), 1.51 (m, 1H).
1
pale yellow oil: H NMR (500 MHz, CDCl3) d 7.67±7.63
(m, 2H), 7.23±7.12 (m, 12H), 4.64 (d, Jˆ6.7 Hz, 1H), 4.58
(d, Jˆ6.7 Hz, 1H), 4.50 (d, Jˆ11.3 Hz, 1H), 4.42 (d, Jˆ
12.2 Hz, 1H), 4.39 (d, Jˆ12.2 Hz, 1H), 4.33 (d, Jˆ11.3 Hz,
1H), 3.89±3.83 (m, 2H), 3.75 (m, 1H), 3.51 (dd, Jˆ10.4,
5.8 Hz, 1H), 3.46 (dd, Jˆ10.4, 4.6 Hz, 1H), 3.41 (m, 1H),
3.24 (m, 3H), 1.54±1.30 (m, 5H), 1.21 (m, 1H); 13C NMR
(125 MHz, CDCl3) d 144.6, 138.4, 138.1, 133.2, 129.8,
128.4, 128.3, 127.92, 127.85, 127.7, 96.4, 78.7, 76.9, 73.3,
72.3, 70.4, 69.9, 55.6, 29.9, 28.9, 21.6; MS (FAB)
[(M1Na)1] m/z 565.
4.2.13. Compound 28. By the same procedure described
above, exo-ole®n 18 (102.4 mg, 0.1903 mmol) and enol
To a solution of the above tosylate (1.755 g, 3.2380 mmol)

1904
M. Sasaki et al. / Tetrahedron 58 (2002)1889±1911
phosphate 29b (180.9 mg, 0.3769 mmol) afforded coupling
ˆ
1685, 1460, 1367, 1107, 1067, 847, 744, 694 cm21; H
128.7, 128.6, 128.5, 128.5, 128.4, 128.3, 128.0, 128.0,
127.8, 127.7, 127.6, 127.5, 127.2, 126.8, 103.5, 96.8, 87.4,
84.0, 80.2, 78.7, 77.8, 76.3, 75.8, 75.1, 75.0, 73.5, 72.4,
70.9, 64.9, 54.9, 39.2, 33.1, 26.3, 25.8, 24.4, 24.0, 18.3,
23.3, 24.0; HRMS (FAB) calcd for C52H70O9SiNa
[(M1Na)1] 889.4687, found 889.4709.
31
product 28 (136.0 mg, 94%) as a colorless oil: [a]D
147.38 (c 0.25, C6H6); IR (®lm) nmaxˆ3033, 2933, 2867,
1
NMR (500 MHz, C6D6) d 7.66±7.64 (m, 3H), 7.38±7.36
(m, 2H), 7.22±7.02 (m, 10H), 5.38 (s, 1H), 5.03±4.95 (m,
2H), 4.79 (d, Jˆ11.9 Hz, 1H), 4.70 (d, Jˆ11.0 Hz, 1H), 4.62
(d, Jˆ10.0 Hz, 1H), 4.60 (d, Jˆ10.0 Hz, 1H), 4.51 (d, Jˆ
11.0 Hz, 1H), 4.42 (m, 1H), 3.85 (ddd, Jˆ9.5, 9.2, 5.5 Hz,
1H), 3.78 (ddd, Jˆ9.5, 6.7, 4.3 Hz, 1H), 3.67 (m, 1H), 3.64±
3.58 (m, 2H), 3.57±3.42 (m, 4H), 3.27 (dd, Jˆ9.2, 8.9 Hz,
1H), 3.24 (s, 3H), 2.73 (dd, Jˆ14.0, ,1 Hz, 1H), 2.29 (m,
1H), 2.15 (m, 1H), 2.08 (dd, Jˆ14.0, 10.0 Hz, 1H), 2.03 (m,
1H), 1.94 (m, 1H), 1.67 (m, 1H), 1.60 (m, 1H), 0.96 (s, 9H),
0.09 (s, 3H), 0.06 (s, 3H); 13C NMR (125 MHz, C6D6) d
156.9, 139.7, 138.8, 138.8, 128.8, 128.53, 128.46, 128.4,
128.3, 127.9, 127.7, 127.2, 126.8, 126.7, 110.4, 101.1,
96.8, 87.3, 83.8, 83.0, 78.1, 76.0, 75.7, 75.2, 75.1, 75.0,
69.5, 64.2, 54.9, 38.8, 32.9, 32.5, 26.1, 21.3, 18.3, 23.3,
24.2; HRMS (FAB) calcd for C44H60O9SiNa [(M1Na)1]
783.3904, found 783.3895.
4.2.16. Compound 30e. By the same procedure described
above, exo-ole®n 18 (106.6 mg, 0.2019 mmol) and enol
phosphate 29e36 (202.8 mg, 0.4008 mmol) afforded
coupling product 30e (155.5 mg, 98%) as a colorless oil:
31
[a]D ˆ131.88 (c 0.47, C6H6); IR (®lm) nmaxˆ3027,
2933, 2860, 1743, 1668, 1458, 1392, 1363, 1298, 1254,
1209, 1103, 847, 769, 742, 694 cm21 1H NMR (500
;
MHz, C6D6) d 7.64±7.62 (m, 3H), 7.38±7.36 (m, 2H),
7.22±7.02 (m, 10H), 5.80±5.70 (m, 2H), 5.35 (s, 1H),
5.07 (dd, Jˆ7.9, 7.3 Hz, 1H), 5.03 (d, Jˆ11.9 Hz, 1H),
4.82 (d, Jˆ11.9 Hz, 1H), 4.70 (d, Jˆ11.0 Hz, 1H), 4.66
(d, Jˆ6.4 Hz, 1H), 4.63 (d, Jˆ6.4 Hz, 1H), 4.56 (dd, Jˆ
10.4, 4.9 Hz, 1H), 4.50 (d, Jˆ11.0 Hz, 1H), 3.94 (ddd,
Jˆ10.4, 10.4, 4.9 Hz, 1H), 3.87±3.74 (m, 3H), 3.68 (dd,
Jˆ10.4, 10.4 Hz, 1H), 3.57 (ddd, Jˆ9.8, 9.8, 2.1 Hz, 1H),
3.54±3.37 (m, 4H), 3.32±3.22 (m, 5H), 2.72 (dd, Jˆ14.7,
,1 Hz, 1H), 2.38±2.26 (m, 2H), 2.03 (dd, Jˆ14.7, 10.7 Hz,
1H), 1.64 (m, 1H), 0.96 (s, 9H), 0.10 (s, 3H), 0.03 (s, 3H);
13C NMR (125 MHz, C6D6) d 156.5, 139.6, 138.8, 138.7,
131.9, 129.0, 128.9, 128.5, 128.5, 128.4, 128.3, 128.2,
128.0, 127.8, 127.3, 126.8, 126.7, 124.4, 113.4, 101.7,
97.0, 87.4, 84.0, 81.2, 77.5, 76.1, 75.8, 75.8, 75.2, 75.1,
71.0, 64.4, 55.0, 39.6, 33.0, 29.7, 26.2, 23.5, 18.2, 23.5,
23.7; HRMS (FAB) calcd for C46H62O9SiNa [(M1Na)1]
809.4061, found 809.4037.
4.2.14. Compound 30c. By the same procedure described
above, exo-ole®n 18 (155.5 mg, 0.2945 mmol) and enol
phosphate 29c (337.6 mg, 0.5902 mmol) afforded coupling
31
product 30c (243.1 mg, 97%) as a colorless oil: [a]D
ˆ
164.38 (c 0.47, C6H6); IR (®lm) 3033, 2927, 1680, 1458,
1363, 1254, 1103, 847, 739, 696 cm21; 1H NMR (500 MHz,
C6D6) d 7.39±7.02 (m, 20H), 5.08 (d, Jˆ12.2 Hz, 1H),
4.85±4.80 (m, 2H), 4.64±4.58 (m, 2H), 4.54 (d, Jˆ
12.5 Hz, 1H), 4.50 (d, Jˆ10.7 Hz, 1H), 4.48 (d, Jˆ12.4,
1H), 4.35 (d, Jˆ11.9 Hz, 1H), 4.34 (m, 1H), 3.96 (d,
Jˆ11.6 Hz, 1H), 3.89±3.82 (m, 2H), 3.75 (m, 1H), 3.70
(d, Jˆ4.3 Hz, 1H), 3.68 (s, 2H), 3.67 (m, 1H), 3.57 (ddd,
Jˆ9.8, 9.8, 2.1 Hz, 1H), 3.53±3.50 (m, 2H), 3.28 (dd, Jˆ
9.8, 8.9 Hz, 1H), 3.23 (s, 3H), 2.90 (dd, Jˆ14.3, ,1 Hz,
1H), 2.61 (m, 1H), 2.32 (m, 1H), 2.22 (dd, Jˆ14.3,
10.1 Hz, 1H), 2.19 (m, 1H), 1.92±1.89 (m, 2H), 1.71 (m,
1H), 0.98 (s, 9H), 0.10 (s, 6H); 13C NMR (125 MHz, C6D6)
d 157.1, 139.8, 139.4, 139.2, 138.9, 128.5, 128.43, 128.36,
128.3, 128.0, 127.8, 127.74, 127.66, 127.54, 127.51, 127.17,
126.7, 106.3, 96.9, 87.4, 84.1, 83.9, 77.74, 77.66, 76.1, 75.8,
75.1, 75.0, 73.2, 71.4, 70.9, 64.6, 54.9, 38.9, 33.0, 29.0,
26.3, 20.9, 18.3, 23.3, 24.0; HRMS (FAB) calcd for
C51H68O9SiNa [(M1Na)1] 875.4530, found 875.4506.
4.2.17. Alcohol 41. To a solution of 2,3-dimethyl-2-butene
(97 mL, 0.82 mmol) in THF (0.5 mL) at 08C was added
BH3´THF (0.98 M solution in THF, 0.83 mL, 0.82 mmol),
and the resultant solution was stirred at 08C for 2 h. To a
solution of enol ether 30c (139.0 mg, 0.163 mmol) in THF
(1 mL) at 2108C was added the above solution of thexyl-
borane in THF. The resultant solution was stirred at 2108C
for 19 h, 258C for 3 h, and then 08C for 3 h. The reaction
was quenched with water (2 mL), and the mixture was
treated with 3 M aqueous NaOH (1.1 mL) followed by
30% aqueous H2O2 (0.6 mL). The resultant mixture was
stirred at room temperature for 2 h, extracted with ethyl
acetate (50 mL), washed with saturated aqueous Na2SO3
(15 mL) and brine (15 mL), dried over Na2SO4, ®ltered,
and concentrated in vacuo. Puri®cation by column chroma-
tography on silica gel (10±40% ethyl acetate/hexanes) gave
alcohol 41 (117.8 mg, 83%) as a colorless oil, along with
4.2.15. Compound 30d. By the same procedure described
above, exo-ole®n 18 (117.1 mg, 0.2218 mmol) and enol
phosphate 29d (256.8 mg, 0.4382 mmol) afforded coupling
31
product 30d (185.2 mg, 96%) as a colorless oil: [a]D
147.58 (c 0.90, C6H6); IR (®lm) nmaxˆ3030, 2931, 2867,
ˆ
31
recovered 30c (14.2 mg, 10%). 41: [a]D ˆ130.3 (c 0.47,
1
1662, 1458, 1363, 1254, 1105, 847, 739, 696 cm21; H
CHCl3); IR (®lm) 3471, 3043, 2929, 1749, 1458, 1362,
NMR (500 MHz, C6D6) d 7.39±7.04 (m, 20H), 5.01 (d,
Jˆ12.0 Hz, 1H), 4.82 (d, Jˆ12.2 Hz, 1H), 4.76 (dd,
Jˆ8.9, 6.7 Hz, 1H), 4.71 (d, Jˆ11.0 Hz, 1H), 4.63±4.58
(m, 3H), 4.53±4.48 (m, 2H), 4.46 (d, Jˆ11.6 Hz, 1H),
4.15 (d, Jˆ11.6 Hz, 1H), 3.89 (m, 1H), 3.82 (m, 1H), 3.75
(dd, Jˆ10.5, 2.3 Hz, 1H), 3.72±3.61 (m, 3H), 3.55±3.43 (m,
3H), 3.27 (dd, Jˆ9.0, 9.0 Hz, 1H), 3.22 (s, 3H), 2.99 (dd,
Jˆ13.9, ,1 Hz, 1H), 2.56 (m, 1H), 2.33 (m, 1H), 2.18±2.08
(m, 2H), 2.02±1.93 (m, 2H), 1.86 (m, 1H), 1.79 (m, 1H),
1.67 (m, 1H), 0.97 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H); 13C
NMR (125 MHz, C6D6) d 153.7, 139.8, 139.4, 139.2, 138.9,
1254, 1101, 847, 739, 696 cm21 1H NMR (500 MHz,
;
CDCl3) d 7.36±7.14 (m, 20H), 4.95 (d, Jˆ11.9 Hz, 1H),
4.82 (d, Jˆ11.9 Hz, 1H), 4.75 (d, Jˆ10.8 Hz, 1H), 4.60±
4.46 (m, 4H), 4.59 (s, 2H), 4.35 (d, Jˆ11.6 Hz, 1H), 3.74
(m, 1H), 3.68 (ddd, Jˆ5.1, 4.9, 4.7 Hz, 1H), 3.64±3.56 (m,
3H), 3.53±3.50 (m, 2H), 3.47±3.43 (m, 3H), 3.40±3.32 (m,
2H), 3.32 (s, 3H), 3.23 (dd, Jˆ9.3, 9.3 Hz, 1H), 2.16±2.10
(m, 2H), 1.97 (m, 1H), 1.86±1.79 (m, 2H), 1.76±1.66 (m,
2H), 1.63±1.55 (m, 1H), 0.87 (s, 9H), 0.07 (s, 3H), 0.02 (s,
3H); 13C NMR (125 MHz, CDCl3) d 139.0, 138.6, 138.5,
138.0, 128.3, 128.1, 127.8, 127.7, 127.6, 127.5, 127.0,

M. Sasaki et al. / Tetrahedron 58 (2002)1889±1911
1905
126.6, 125.7, 96.4, 86.9, 83.1, 82.7, 82.2, 78.5, 76.6, 76.2,
75.0, 74.9, 74.8, 73.3, 73.2, 71.4, 70.7, 64.1, 55.3, 35.5,
31.9, 28.3, 26.0, 23.6, 18.1, 23.4, 24.1; HRMS (FAB)
calcd for C51H70O10SiNa [(M1Na)1] 893.4636, found
893.4620.
methyl ketal 42 (55.4 mg, 82% for the two steps) as a color-
31
less oil: [a]D ˆ247.48 (c 0.23, CHCl3); IR (®lm) 3495,
3030, 2905, 1496, 1453, 1364, 1219, 1088, 737,
1
698 cm21; H NMR (500 MHz, CDCl3) d 7.38±7.22 (m,
20H), 4.96 (d, Jˆ11.1 Hz, 1H), 4.90 (d, Jˆ10.9 Hz, 1H),
4.75 (d, Jˆ11.1 Hz, 1H), 4.58 (d, Jˆ10.9 Hz, 1H), 4.54±
4.48 (m, 3H), 4.37 (d, Jˆ11.9 Hz, 1H), 3.81 (ddd, Jˆ5.9,
5.9, 3.6 Hz, 1H), 3.73±3.70 (m, 3H), 3.57 (dd, Jˆ9.0,
8.9 Hz, 1H), 3.51±3.44 (m, 3H), 3.39±3.35 (m, 2H), 3.26
(m, 1H), 3.26 (s, 3H), 3.12 (ddd, Jˆ11.4, 9.6, 4.4 Hz, 1H),
2.07±1.85 (m, 6H), 1.77±1.65 (m, 2H); 13C NMR
(125 MHz, CDCl3) d 138.8, 138.4, 138.3, 138.1, 128.4,
128.3, 128.03, 128.00, 127.8, 127.7, 126.7, 99.2, 84.6,
83.7, 81.6, 80.5, 79.9, 78.7, 75.4, 75.1, 74.3, 74.2, 73.3,
71.5, 70.7, 61.2, 47.1, 34.2, 32.0, 25.9, 21.6; HRMS calcd
for C44H52O9Na [(M1Na)1] 747.3509, found 747.3502.
4.2.18. Ketone 6. To a solution of alcohol 41 (670.2 mg,
Ê
0.770 mmol) in CH2Cl2 (8 mL) were added 4 A molecular
sieves (385 mg) and N-methylmorpholine-N-oxide (135.4
mg, 1.54 mmol). After 5 min, tetra-n-propylammonium
perruthenate (13.6 mg, 0.039 mmol) was added to the
mixture, and the resultant solution was stirred at room
temperature for 1 h. The solvent was removed in vacuo
and the residue was puri®ed by column chromatography
on silica gel (35% ethyl acetate/hexanes) to give ketone 6
27
(661.4 mg, 99%) as a colorless oil: [a]D ˆ16.0 (c 0.27,
C6H6); IR (®lm) 3063, 3029, 2927, 2883, 2856, 1716, 1496,
1454, 1360, 1321, 1252, 1209, 1107, 1028, 916, 859, 836,
4.2.20. Ole®n 43. To a solution of hydroxy mixed methyl
ketal 42 (49.8 mg, 68.8 mmol) and triethylamine (0.05 mL,
0.358 mmol) in CH2Cl2/DMSO (4:1, v/v, 1 mL) at 08C was
added SO3´pyridine complex (43.8 mg, 0.275 mmol). The
resulting solution was stirred at 08C for 1.4 h and then at
room temperature for 2 h. The reaction mixture was diluted
with ethyl acetate, washed with 1 M HCl, aqueous saturated
NaHCO3, and brine, dried over Na2SO4, ®ltered, and
concentrated in vacuo. The crude aldehyde was used in
the next reaction without puri®cation.
1
777, 734, 697, 676 cm21; H NMR (500 MHz, C6D6) d
7.35±6.86 (m, 20H), 4.98 (d, Jˆ12.2 Hz, 1H), 4.79 (d,
Jˆ12.2 Hz, 1H), 4.70 (d, Jˆ11.0 Hz, 1H), 4.56 (s, 2H),
4.51 (d, Jˆ11.3 Hz, 1H), 4.47±4.40 (m, 2H), 4.23 (dd,
Jˆ7.4, 4.5 Hz, 1H), 4.17 (d, Jˆ11.4 Hz, 1H), 3.83 (m,
1H), 3.77 (m, 1H), 3.67±3.63 (m, 2H), 3.62 (m, 1H),
3.56±3.48 (m, 3H), 3.47 (m, 1H), 3.40 (dd, Jˆ8.7, 8.7 Hz,
1H), 3.28 (dd, Jˆ9.2, 9.2 Hz, 1H), 3.21 (s, 3H), 2.77 (ddd,
Jˆ12.9, 12.8, 3.2 Hz, 1H), 2.47 (ddd, Jˆ13.8, 7.4, 2.6 Hz,
1H), 2.35 (ddd, Jˆ12.9, 7.4, 2.5 Hz, 1H), 2.21 (m, 1H), 2.11
(ddd, Jˆ13.8, 9.2, 4.5 Hz, 1H), 1.97 (m, 1H), 1.79 (m, 1H),
1.46 (dddd, Jˆ12.8, 11.7, 11.7, 2.5 Hz, 1H), 0.98 (s, 9H),
0.15 (s, 3H), 0.11 (s, 3H); 13C NMR (125 MHz, C6D6) d
213.1, 139.8, 139.2, 138.96, 138.92, 128.6, 128.5, 128.4,
128.3, 128.0, 127.8, 127.7, 127.2, 126.7, 96.8, 87.3, 85.5,
83.9, 83.3, 78.0, 76.6, 76.28, 76.25, 75.4, 74.9, 73.5, 71.43,
71.4, 64.3, 55.0, 36.7, 36.0, 32.6, 27.4, 26.3, 18.3, 23.3,
23.9; HRMS (FAB) calcd for C51H68O10SiNa [(M1Na)1]
891.4479, found 891.4470.
To a suspension of methyltriphenylphosphonium bromide
(73.7 mg, 0.206 mmol) in THF (1 mL) at 08C was added
sodium bis(trimethylsilyl)amide (1 M solution in THF,
0.193 mL, 0.193 mmol). After stirring for 30 min, a solution
of the above aldehyde in THF/CH2Cl2 (5:7, v/v, 1.2 mL)
was added to the ylide solution, and the resultant mixture
was stirred at 08C for 1 h before the reaction was quenched
with aqueous saturated NH4Cl. The mixture was diluted
with ethyl acetate, washed with water and brine, dried
over Na2SO4, ®ltered, and concentrated in vacuo. Flash
chromatography on silica gel (10±20% ethyl acetate/
hexanes) afforded ole®n 26 (39.3 mg, 79% for the two
4.2.19. Hydroxy mixed methyl ketal 42. To a solution of
oxalyl chloride (0.25 mL, 0.287 mmol) in CH2Cl2 (1 mL)
at 2788C was added dropwise DMSO (0.027 mL,
0.380 mmol). After 10 min, a solution of 41 (81.2 mg,
0.0933 mmol) in CH2Cl2 (1 mL) was added to the mixture,
and the resulting solution was stirred at 2788C for 40 min
before addition of triethylamine (0.104 mL, 0.747 mmol).
After being stirred at 2788C for 10 min, the reaction
mixture was allowed to warm to 08C over 1 h. The mixture
was diluted with ethyl acetate, washed with 1 M HCl, satu-
rated aqueous NaHCO3, water, and brine, dried over
Na2SO4, ®ltered, and concentrated in vacuo. The crude
ketone was used in the next reaction without chromato-
graphic puri®cation.
31
steps) as a colorless oil: [a]D ˆ223.48 (c 0.69, CHCl3);
IR (®lm) 3024, 2902, 1637, 1495, 1454, 1363, 1215, 1080,
1
912, 741, 698 cm21; H NMR (500 MHz, CDCl3) d 7.35±
7.23 (m, 20H), 5.88 (ddt, Jˆ17.2, 10.2, 6.6 Hz, 1H), 5.08±
5.03 (m, 2H), 4.96 (d, Jˆ11.1 Hz, 1H), 4.90 (d, Jˆ10.8 Hz,
1H), 4.75 (d, Jˆ11.1 Hz, 1H), 4.59 (d, Jˆ10.8 Hz, 1H),
4.55±4.47 (m, 3H), 4.38 (d, Jˆ11.8 Hz, 1H), 3.82 (ddd,
Jˆ6.0, 5.9, 3.8 Hz, 1H), 3.69 (m, 1H), 3.54 (dd, Jˆ6.7,
6.5 Hz, 1H), 3.49 (dd, Jˆ10.2, 6.0 Hz, 1H), 3.48 (dd, Jˆ
12.1, 4.5 Hz, 1H), 3.39 (dd, Jˆ10.2, 5.9 Hz, 1H), 3.38±3.31
(m, 2H), 3.28 (m, 1H), 3.27 (s, 3H), 3.08 (ddd, Jˆ11.3, 9.7,
4.3 Hz, 1H), 2.55 (m, 1H), 2.26 (m, 1H), 2.08 (ddd, Jˆ11.0,
4.5, 4.3 Hz, 1H), 2.01±1.85 (m, 4H), 1.75 (m, 1H); 13C
NMR (125 MHz, CDCl3) d 138.9, 138.5, 138.42, 138.36,
134.7, 128.4, 128.3, 128.0, 127.9, 127.64, 127.60, 127.5,
116.9, 99.1, 84.7, 84.0, 81.3, 80.8, 79.1, 78.7, 75.2, 75.1,
74.5, 74.1, 73.3, 71.6, 70.6, 47.1, 36.1, 32.0, 26.1, 21.6;
HRMS (FAB) calcd for C44H52O8Na [(M1Na)1]
743.3560, found 743.3558.
To a solution of the above ketone in methanol/CH2Cl2 (4:1,
v/v, 1 mL) was added p-toluenesulfonic acid monohydrate
(35.5 mg, 0.187 mmol). The resultant solution was stirred at
room temperature for 18 h and then heated at 558C for 4 h.
After cooling to room temperature, the reaction was
quenched with aqueous saturated NaHCO3. The solution
was diluted with ethyl acetate, washed with aqueous satu-
rated NaHCO3 and brine, dried over Na2SO4, ®ltered, and
concentrated in vacuo. Flash chromatography on silica gel
(30±40% ethyl acetate/hexanes) afforded hydroxy mixed
4.2.21. Tricyclic ether 26. To a solution of ole®n 43
(29.1 mg, 40.4 mmol) in CH3CN/CH2Cl2 (5:3, v/v,
0.8 mL) at 08C were added triethylsilane (0.052 mL,

1906
M. Sasaki et al. / Tetrahedron 58 (2002)1889±1911
0.326 mmol) followed by boron tri¯uoride etherate
(0.015 mL, 0.118 mmol). The resultant solution was stirred
at 08C for 1.5 h before the reaction was quenched with
aqueous saturated NaHCO3. The mixture was diluted with
ethyl acetate, washed with aqueous saturated NaHCO3 and
brine, dried over Na2SO4, ®ltered, and concentrated in
vacuo. Flash chromatography on silica gel (15±20% ethyl
acetate/hexanes) afforded tricyclic ether 26 (24.1 mg, 86%).
(FAB) calcd for C40H48O7Na [(M1Na)1] 663.3298, found
663.3290.
4.2.24. ABCD ring system 47. To a solution of diene 45
(8.2 mg, 0.013 mmol) in CH2Cl2 (2 mL) was added Grubbs'
catalyst 46 (2.1 mg, 2.55 mmol) in CH2Cl2 (0.5 mL) via
cannula, and the resultant solution was stirred at room
temperature for 2.5 h. The solvent was removed in vacuo
and the residue was puri®ed by column chromatography on
4.2.22. Alcohol 44. To a solution of tricyclic ether 26
(24.5 mg, 35.5 mmol) in CH2Cl2 (1 mL) at 08C was added
iodine (90.1 mg, 0.355 mmol). The resultant solution was
stirred at room temperature for 6 h before the reaction was
quenched with saturated aqueous Na2S2O3 (2 mL). The
mixture was extracted with ethyl acetate (10 mL), washed
with brine (3 mL), dried over Na2SO4, ®ltered, and concen-
trated in vacuo. Puri®cation by column chromatography on
silica gel (5±20% ethyl acetate/hexanes) gave iodide
(22.3 mg, 87%) as a colorless solid, which was used in the
next reaction without further puri®cation.
silica gel (20% ethyl acetate/hexanes) to give ABCD ring
31
system 47 (10.2 mg, quant.) as a colorless solid: [a]D
20.12 (c 0.41, CHCl3); IR (®lm) 3028, 2865, 1739, 1450,
ˆ
1365, 1086, 741, 698 cm21; H NMR (500 MHz, C6D6) d
1
740±7.15 (m, 15H), 5.63±5.53 (m, 2H), 5.23±5.10 (m, 2H),
4.45±4.38 (m, 3H), 4.25 (d, Jˆ11.9 Hz, 1H), 4.16 (dd, Jˆ
15.6, 5.3 Hz, 1H), 4.01 (m, 1H), 3.84 (dd, Jˆ15.6, 2.4 Hz,
1H), 3.73 (m, 1H), 3.67 (dd, Jˆ8.9, 8.6 Hz, 1H), 3.52±3.38
(m, 3H), 3.35±3.29 (m, 2H), 3.15 (ddd, Jˆ10.7, 9.2, 4.3 Hz,
1H), 2.93 (ddd, Jˆ11.6, 9.5, 4.3 Hz, 1H), 2.64 (ddd, Jˆ16.2,
7.6, 4.0 Hz, 1H), 2.51 (ddd, Jˆ11.6, 4.6, 4.3 Hz, 1H), 2.33
(m, 1H), 2.16 (dddd, Jˆ11.9, 11.9, 11.9, ,1 Hz, 1H), 1.97±
1.86 (m, 2H), 1.78 (ddd, Jˆ11.6, 11.3, 11.3 Hz, 1H), 1.60
(dddd, Jˆ14.3, 13.4, ,1, ,1 Hz, 1H); 13C NMR (125 MHz,
C6D6) d 140.6, 139.11, 139.10, 131.7, 128.6, 128.4, 128.3,
127.91, 127.89, 127.8, 127.7, 127.4, 126.5, 87.9, 83.8, 82.7,
82.2, 82.1, 79.4, 78.8, 77.2, 75.2, 73.8, 73.3, 72.0, 70.8,
68.5, 38.0, 35.2, 26.7, 23.5; HRMS (FAB) calcd for
C38H44O7Na [(M1Na)1] 635.2985, found 635.2977.
To a solution of the above iodide (22.3 mg, 30.7 mmol) in
ether/methanol (2:1, v/v, 1.5 mL) were added zinc powder
(18.1 mg, 0.277 mmol) and acetic acid (3 mL, 0.06 mmol).
The resultant solution was stirred at room temperature
overnight. Insoluble solids were ®ltered through a pad of
Celite, and the ®ltrate was concentrated in vacuo. Puri®-
cation by column chromatography on silica gel (5±20%
ethyl acetate/hexanes) gave alcohol 44 (17.7 mg, 96%) as
a colorless solid: 1H NMR (CDCl3, 270 MHz) d 7.15±7.37
(m, 15H), 5.81 (m, 1H), 4.90±5.08 (m, 3H), 4.60 (d, Jˆ
11.6 Hz, 1H), 4.48 (d, Jˆ10.0 Hz, 1H), 4.46 (s, 2H), 4.28
(d, Jˆ11.9 Hz, 1H), 3.61±3.74 (m, 2H), 3.17±3.43 (m, 6H),
2.98±3.15 (m, 3H), 2.50 (m, 1H), 2.10±2.36 (m, 2H), 1.98
(m, 1H), 1.78±1.89 (m, 2H), 1.47±1.65 (m, 2H).
4.2.25. Enone 48. To a solution of ketone 6 (661.4 mg,
0.762 mmol) in THF (7 mL) at 2788C was added lithium
bis(trimethylsilyl)amide (1.0 M solution in THF, 1.53 mL,
1.53 mmol). After 20 min, triethylamine (0.21 mL,
1.53 mmol) and trimethylsilyl chloride (0.193 mL, 1.53
mmol) were added, and the resultant solution was stirred
at 2788C for 10 min before the reaction was quenched
with water (0.5 mL). The mixture was extracted with ethyl
acetate (50 mL), washed with water (15 mL) and brine
(15 mL), dried over Na2SO4, ®ltered, and concentrated in
vacuo. The crude silyl enol ether was used immediately in
the next reaction without puri®cation.
4.2.23. Diene 45. To a solution of alcohol 44 (17.7 mg,
0.0295 mmol) in DMF (0.5 mL) at 08C was added sodium
bis(trimethylsilyl)amide (1.0 M solution in THF, 0.12 mL,
0.12 mmol). After 1 h, allyl bromide (8 mL, 0.09 mmol) was
added, and the resultant solution was stirred at 08C for 4 h
before the reaction was quenched with saturated aqueous
NH4Cl (1 mL). The mixture was extracted with ethyl acetate
(10 mL), washed with water (3 mL) and brine (3 mL), dried
over Na2SO4, ®ltered, and concentrated in vacuo. Puri®-
cation by column chromatography on silica gel (10%
ethyl acetate/hexanes) gave diene 45 (14.7 mg, 78%) as a
To a solution of the above silyl enol ether in acetonitrile
(7 mL) was added palladium(II) acetate (427.7 mg, 1.90
mmol). The resultant solution was stirred at room tempera-
ture for 30 min. The mixture was ®ltered through a pad of
Celite, and the ®ltrate was concentrated in vacuo. Puri®-
cation by column chromatography on silica gel (20±30%
ethyl acetate/hexanes) gave enone 48 (632.5 mg, 96% for
31
colorless solid: [a]D ˆ25.38 (c 0.22, CHCl3); IR (®lm)
3028, 2864, 1643, 1452, 1362, 1074, 914, 741, 696 cm21
;
1H NMR (500 MHz, CDCl3) d 7.37±7.24 (m, 15H), 5.93±
5.82 (m, 2H), 5.22 (dd, Jˆ17.0, 2.0 Hz, 1H), 5.14±5.02 (m,
3H), 4.91 (d, Jˆ11.0 Hz, 1H), 4.71 (d, Jˆ11.0 Hz, 1H), 4.53
(d, Jˆ13.0 Hz, 1H), 4.52 (s, 2H), 4.36 (dddd, Jˆ12.0, 5.8,
1.3, 1.3 Hz, 1H), 4.31 (d, Jˆ11.5 Hz, 1H), 4.09 (dddd, Jˆ
12.0, 5.8, 1.3, 1.3 Hz, 1H), 3.74 (m, 1H), 3.67 (m, 1H), 3.48
(dd, Jˆ8.8, 8.8 Hz, 1H), 3.46±3.39 (m, 2H), 3.33±3.26 (m,
2H), 3.13±3.01 (m, 4H), 2.54 (m, 1H), 2.34 (m, 1H), 2.23
(ddd, Jˆ7.3, 7.3, 7.3 Hz, 1H), 2.03 (m, 1H), 1.91±1.84 (m,
2H), 1.64 (m, 1H), 1.54 (m, 1H); 13C NMR (125 MHz,
CDCl3) d 139.0, 138.4, 138.3, 135.0, 134.7, 128.3,
128.26, 127.9, 127.63, 127.60, 127.55, 127.46, 116.9,
84.0, 83.7, 82.2, 81.8, 81.0, 79.8, 79.0, 78.2, 74.9, 74.2,
74.0, 73.2, 71.5, 70.6, 37.1, 36.1, 26.3, 23.6; HRMS
the two steps) as a colorless oil: [a]D ˆ171.7 (c 0.97,
27
C6H6); IR (®lm) 3087, 3062, 3029, 2927, 2884, 2856,
1671, 1557, 1540, 1496, 1471, 1454, 1387, 1360, 1309,
1251, 1209, 1107, 1028, 917, 859, 836, 777, 734, 697,
1
677 cm21; H NMR (500 MHz, C6D6) d 7.35±7.06 (m,
20H), 6.20±6.13 (m, 2H), 4.97 (d, Jˆ12.2 Hz, 1H), 4.77
(d, Jˆ12.2 Hz, 1H), 4.70 (d, Jˆ11.0 Hz, 1H), 4.56 (s,
2H), 4.59±4.50 (m, 2H), 4.44 (d, Jˆ12.2 Hz, 1H), 4.38 (d,
Jˆ12.2 Hz, 1H), 4.33 (d, Jˆ11.5 Hz, 1H), 4.22 (d, Jˆ
11.5 Hz, 1H), 4.18 (dd, Jˆ3.0, 7.7 Hz, 1H), 3.88±3.73 (m,
3H), 3.70 (ddd, Jˆ9.2, 9.2, 2.1 Hz, 1H), 3.58±3.55 (m, 2H),
3.53 (m, 1H), 3.51 (dd, Jˆ9.2, 9.2 Hz, 1H), 3.41 (dd, Jˆ9.2,
9.2 Hz, 1H), 3.28 (dd, Jˆ9.2, 9.2 Hz, 1H), 3.21 (s, 3H), 2.55
(ddd, Jˆ13.9, 7.0, 2.1 Hz, 1H), 2.27±2.18 (m, 2H), 1.80 (m,

M. Sasaki et al. / Tetrahedron 58 (2002)1889±1911
1907
1H), 0.97 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR
(125 MHz, C6D6) d 204.1, 141.3, 139.8, 139.0, 138.9,
138.4, 129.8, 128.6, 128.5, 128.4, 128.3, 128.0, 127.9,
127.8, 127.7, 127.6, 127.2, 126.7, 96.7, 87.3, 83.3, 83.2,
81.8, 76.9, 76.7, 76.5, 75.5, 75.0, 74.9, 73.6, 71.7, 70.8,
64.5, 54.9, 36.5, 32.5, 26.3, 18.3, 23.3, 23.9; HRMS
(FAB) calcd for C51H66O10SiNa [(M1Na)1] 889.4323,
found 889.4343.
1H), 4.92 (d, Jˆ11.4 Hz, 1H), 4.82 (d, Jˆ11.6 Hz, 1H),
4.63±4.59 (m, 2H), 4.42 (d, Jˆ12.0 Hz, 1H), 4.32 (d, Jˆ
12.0 Hz, 1H), 4.23 (d, Jˆ11.6 Hz, 1H), 4.14 (d, Jˆ11.6 Hz,
1H), 4.11±3.96 (m, 2H), 3.92 (m, 1H), 3.70 (m, 1H), 3.65±
3.62 (m, 2H), 3.58 (m, 1H), 3.54 (dd, Jˆ8.9, 9.0 Hz, 1H),
3.46 (m, 1H), 3.32 (dd, Jˆ9.0, 9.1 Hz, 1H), 2.91 (brd, Jˆ
4.6 Hz, 1H), 2.50 (ddd, Jˆ14.8, 3.8, 3.8 Hz, 1H), 2.30±2.17
(m, 2H), 1.73 (m, 1H); 13C NMR (125 MHz, C6D6) d 203.4,
141.9, 139.9, 139.4, 138.5, 138.2, 129.2, 128.7, 128.6,
128.54, 128.51, 128.4, 128.3, 128.2, 128.0, 127.91,
127.86, 127.83, 127.6, 127.5, 87.2, 83.3, 82.8, 81.4, 76.7,
76.5, 76.2, 75.3, 75.2, 74.9, 73.6, 71.7, 70.4, 60.1, 36.13,
36.10, 18.3, 18.2, 12.4; HRMS (FAB) calcd for C52H68O9Na
[(M1Na)1] 887.4530, found 887.4526.
4.2.26. Keto diol 50. To a solution of enone 48 (1.61 g,
1.853 mmol) in acetonitrile (25 mL) at 08C was added
46% aqueous HF (4.2 mL). The resultant solution was
stirred at room temperature overnight. Another portion of
46% aqueous HF (2.0 mL) was added, and the stirring was
continued overnight. Another portion of 46% aqueous HF
(1.5 mL) was added, and the reaction mixture was stirred
overnight before the reaction was quenched with saturated
aqueous NaHCO3 (100 mL). The mixture was extracted
with ethyl acetate, washed with brine, dried over Na2SO4,
®ltered, and concentrated in vacuo. Puri®cation by column
chromatography on silica gel (40±60% ethyl acetate/
hexanes) gave a 7:1 equilibrium mixture of keto diol 50
and the corresponding hemiketal (1.12 g, 85%) as a color-
4.2.28. Alcohol 51. A solution of a mixture of hydroxy
ketone 54 and its hemiketal (1.08 g, 1.25 mmol) in toluene
(13 mL) was treated with trimethyl orthoformate (2.73 mL,
25.0 mmol) and pyridinium p-toluenesulfonate (62.8 mg,
0.250 mmol). The resultant solution was stirred at 458C
overnight before the reaction was quenched with saturated
aqueous NaHCO3 (30 mL) at room temperature. The
mixture was extracted with ethyl acetate (100 mL), washed
with brine (30 mL), dried over Na2SO4, ®ltered, and concen-
trated in vacuo. The crude mixed methyl ketal 55 was used
in the next reaction without chromatographic puri®cation.
26
less oil. 50: [a]D ˆ126.8 (c 0.73, CHCl3); IR (®lm) 3458,
3087, 3062, 3030, 2870, 1667, 1496, 1453, 1361, 1311,
1
1208, 1090, 1027, 911, 736, 698, 681, 609 cm21; H NMR
(500 MHz, CDCl3) d 7.21±7.11 (m, 20H), 6.41 (m, 1H),
5.89 (m, 1H), 4.75±4.71 (m, 3H), 4.49±4.33 (m, 6H), 4.10
(ddd, Jˆ7.9, 3.6, 1.6 Hz, 1H), 3.72 (ddd, Jˆ8.2, 5.7, 2.6 Hz,
1H), 3.61±3.53 (m, 5H), 3.34±3.13 (m, 3H), 3.12 (dd,
Jˆ9.0, 8.9 Hz, 1H), 2.68 (brd, Jˆ3.9 Hz, 1H), 2.13 (ddd,
Jˆ14.9, 3.9, 3.9 Hz, 1H), 1.93±1.78 (m, 2H); 13C NMR
(125 MHz, CDCl3) d 204.4, 142.6, 138.7, 138.1, 137.8,
137.3, 128.8, 128.53, 128.49, 128.47, 128.4, 128.3, 128.1,
128.0, 127.9, 127.8, 127.7, 80.5, 83.3, 81.8, 81.2, 78.8, 76.5,
76.3, 75.3, 75.0, 74.4, 73.5, 71.9, 70.2, 60.6, 35.6, 34.1;
HRMS (FAB) calcd for C43H48O9Na [(M1Na)1]
731.3196, found 731.3185.
To a solution of the above mixed methyl ketal 55 in aceto-
nitrile/CH2Cl2 (2:1, v/v, 19 mL) at 08C were added triethyl-
silane (1.60 mL, 10.0 mmol) and boron tri¯uoride etherate
(0.64 mL, 5.00 mmol). The resultant solution was stirred at
08C for 1.5 h before the reaction was quenched with satu-
rated aqueous NaHCO3 (10 mL). The mixture was extracted
with ethyl acetate (80 mL), washed with saturated aqueous
NaHCO3 (30 mL) and brine (30 mL), dried over Na2SO4,
®ltered, and concentrated in vacuo. Puri®cation by column
chromatography on silica gel (30±40% ethyl acetate/
hexanes) gave alcohol 51 (817.0 mg, 94% for the two
26
steps) as a colorless solid: [a]D ˆ27.17 (c 0.84, CHCl3);
4.2.27. TIPS ether 54. To a solution of a mixture of
hydroxyketone 50 and its hemiketal (3.03 g, 4.28 mmol)
in CH2Cl2 (50 mL) at 08C were successively added triethyl-
amine (2.38 mL, 17.1 mmol), dimethylaminopyridine
(104.5 mg, 0.285 mmol), and triisopropylsilyl chloride
(1.10 mL, 5.13 mmol). The resultant solution was stirred
at 08C for 2 h and then allowed to warm to room tempera-
ture. After 20 h, additional dimethylaminopyridine (104.5
mg, 0.285 mmol) and triisopropylsilyl chloride (0.36 mL,
1.71 mmol) were added, and the stirring was continued for
further 2 days. Additional dimethylaminopyridine (52.2 mg,
0.142 mmol) was added, and the mixture was stirred for 1 h
before the reaction was quenched with methanol (3 mL).
The mixture was extracted with ethyl acetate (400 mL),
washed with saturated aqueous NH4Cl (100 mL), dried
over Na2SO4, ®ltered, and concentrated in vacuo. Puri®-
cation by column chromatography on silica gel (10±40%
ethyl acetate/hexanes) gave a 7:1 mixture of TIPS ether 54
and the corresponding hemiketal (3.20 g, 87%) as a color-
IR (®lm) 3289, 3061, 3030, 2872, 1496, 1453, 1365, 1327,
1292, 1209, 1095, 1027, 908, 736, 696, 613 cm21; 1H NMR
(500 MHz, C6D6) d 7.31±6.99 (m, 20H), 5.82±5.74 (m,
2H), 5.09 (d, Jˆ11.6 Hz, 1H), 4.96 (d, Jˆ11.6 Hz, 1H),
4.81 (d, Jˆ11.6 Hz, 1H), 4.51 (d, Jˆ11.3 Hz, 1H), 4.47±
4.41 (m, 3H), 4.30 (d, Jˆ11.6 Hz, 1H), 4.18 (dd, Jˆ8.7,
1.9 Hz, 1H), 3.76±3.64 (m, 6H), 3.58 (dd, Jˆ9.2, 9.2 Hz,
1H), 3.42 (m, 1H), 3.21 (dd, Jˆ9.2, 9.2 Hz, 1H), 3.14 (ddd,
Jˆ11.4, 9.2, 4.3 Hz, 1H), 3.05 (dd, Jˆ9.2, 9.2 Hz, 1H), 2.73
(ddd, Jˆ11.6, 9.4, 4.2 Hz, 1H), 2.13 (ddd, Jˆ11.4, 4.3,
4.3 Hz, 1H), 1.98 (m, 1H), 1.60 (m, 1H), 1.52 (ddd, Jˆ
11.4, 11.4, 11.4 Hz, 1H); 13C NMR (125 MHz, C6D6) d
139.7, 139.3, 139.2, 138.7, 132.5, 132.3, 128.6, 128.5,
128.3, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 84.4, 84.0,
82.5, 81.8, 80.9, 79.1, 78.7, 78.0, 75.4, 75.0, 73.9, 73.7,
71.9, 71.4, 60.5, 37.2, 35.0; HRMS (FAB) calcd for
C43H48O8Na [(M1Na)1] 715.3247, found 715.3262.
4.2.29. Ole®n 56. To a solution of alcohol 51 (105.2 mg,
0.152 mmol) and triethylamine (0.106 mL, 0.760 mmol) in
CH2Cl2/DMSO (3:1, v/v, 2.7 mL) at 08C was added
SO3´pyridine (96.8 mg, 0.608 mmol). The resultant solution
was stirred at 08C for 2 h. The mixture was extracted with
ethyl acetate (10 mL), washed with 1 M HCl (3 mL),
26
less oil. 54: [a]D ˆ118.5 (c 0.94, CHCl3); IR (®lm) 3447,
3062, 3030, 2868, 1663, 1496, 1453, 1361, 1310, 1207,
;
1089, 1027, 912, 736, 697, 610 cm21 1H NMR
(500 MHz, C6D6) d 7.33±7.07 (m, 20H), 6.04 (dd, Jˆ3.4,
12.6 Hz, 1H), 5.98 (d, Jˆ12.6 Hz, 1H), 4.99 (d, Jˆ11.6 Hz,

1908
M. Sasaki et al. / Tetrahedron 58 (2002)1889±1911
saturated aqueous NaHCO3 (3 mL), and brine (3 mL), dried
over Na2SO4, ®ltered, and concentrated in vacuo. The crude
aldehyde was used in the next reaction without puri®cation.
5.36 (s, 1H), 5.14 (dd, Jˆ17.0, 1.0 Hz, 1H), 5.06 (dd,
Jˆ10.2, 1.0 Hz, 1H), 4.29 (dd, Jˆ8.8, 2.1 Hz, 1H), 4.19
(dd, Jˆ10.8, 5.1 Hz, 1H), 3.88 (dd, Jˆ9.0, 2.0 Hz, 1H),
3.78 (s, 3H), 3.58 (dd, Jˆ9.2, 9.2 Hz, 1H), 3.56±3.46 (m,
2H), 3.38±3.29 (m, 3H), 3.10 (ddd, Jˆ11.7, 9.2, 4.2 Hz,
1H), 2.93 (dd, Jˆ9.2, 9.2 Hz, 1H), 2.59 (m, 1H), 2.38±
2.26 (m, 2H), 1.53 (m, 1H); 13C NMR (125 MHz, CDCl3)
d 160.2, 134.3, 131.9, 131.3, 127.5, 117.3, 113.7, 100.8,
80.7, 80.6, 80.5, 79.0, 77.6, 76.0, 74.1, 73.9, 73.0, 69.2,
55.3, 36.4, 36.1; HRMS (FAB) calcd for C24H30O8Na
[(M1Na)1] 469.1838, found 469.1827.
To a suspension of methyltriphenylphosphonium bromide
(162.9 mg, 0.456 mmol) in THF (3.0 mL) at 08C was added
sodium bis(trimethylsilyl)amide (1.0 M solution in THF,
0.46 mL, 0.46 mmol). The resultant ylide solution was
stirred at 08C for 30 min. To the solution was added a
solution of the above aldehyde in CH2Cl2 (2 mL), and the
resultant mixture was stirred at 08C for 30 min. The reaction
mixture was poured into water (5 mL), extracted with ethyl
acetate (10 mL£2), washed with brine (5 mL), dried over
Na2SO4, ®ltered, and concentrated in vacuo. Puri®cation by
column chromatography on silica gel (10±20% ethyl
acetate/hexanes) gave ole®n 56 (94.9 mg, 91% for the two
4.2.31. Triene 5. To a solution of diol 57 (206.9 mg,
0.464 mmol) and 2,6-lutidine (0.162 mL, 1.39 mmol) in
DMF/CH2Cl2 (1:3, v/v, 4 mL) at 08C was added triisopro-
pylsilyl tri¯uoromethanesulfonate (0.25 mL, 0.93 mmol).
The resultant solution was stirred at 08C for 6 h before the
reaction was quenched with methanol (1 mL). The mixture
was extracted with ethyl acetate (30 mL), washed with
saturated aqueous NH4Cl (10 mL) and brine (10 mL),
dried over Na2SO4, ®ltered, and concentrated in vacuo.
The crude TIPS ether was used in the next reaction without
puri®cation.
26
steps) as a colorless solid: [a]D ˆ20.3 (c 0.33, CHCl3); IR
(®lm) 3067, 3028, 2863, 1496, 1453, 1363, 1325, 1205,
1073, 1027, 997, 913, 734, 696, 611 cm21 1H NMR
;
(500 MHz, C6D6) d 7.44±7.08 (m, 20H), 6.06±6.00 (m,
2H), 5.81±5.77 (m, 2H), 5.14±5.05 (m, 3H), 5.01 (d,
Jˆ11.3 Hz, 1H), 4.82 (d, Jˆ11.5 Hz, 1H), 4.57 (d, Jˆ
11.3 Hz, 1H), 4.48±4.44 (m, 2H), 4.30 (d, Jˆ11.6 Hz,
1H), 4.16 (dd, Jˆ8.5, 1.6 Hz, 1H), 3.76±3.69 (m, 4H),
3.64 (dd, Jˆ9.1, 9.0 Hz, 1H), 3.37±3.31 (m, 2H), 3.19 (m,
1H, 11H), 3.11 (dd, Jˆ9.0, 9.1 Hz, 1H), 2.83 (ddd, Jˆ11.5,
4.3, 9.1 Hz, 1H), 2.62 (m, 1H), 2.37±2.23 (m, 2H), 1.66
(ddd, Jˆ11.5, 11.5, 11.5 Hz, 1H); 13C NMR (125 MHz,
C6D6) d 139.8, 139.4, 138.7, 135.1, 132.4, 132.3, 128.5,
128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7,
127.6, 127.5, 117.1, 84.6, 84.0, 82.7, 81.3, 81.0, 79.4,
78.8, 78.0, 75.2, 75.0, 73.8, 73.6, 71.9, 71.4, 37.4, 36.6;
HRMS (FAB) calcd for C44H48O7Na [(M1Na)1]
711.3298, found 711.3308.
To a solution of the above triisopropylsilyl ether in DMF
(5 mL) at 08C was added sodium bis(trimethylsilyl)amide
(1.0 M solution in THF, 2.3 mL, 2.3 mmol). The resultant
solution was stirred at 08C for 30 min, and then allyl
bromide (0.16 mL, 1.85 mmol) was added. The resultant
solution was stirred at room temperature overnight before
the reaction was quenched with saturated aqueous NH4Cl
(30 mL). The mixture was extracted with ethyl acetate
(50 mL£2), washed with brine (20 mL), dried over
Na2SO4, ®ltered, and concentrated in vacuo. Puri®cation
by column chromatography on silica gel (7% ethyl acetate/
hexanes) gave triene 5 (302.7 mg, quant. for the two steps)
4.2.30. p-Methoxybenzylidene acetal 57. To a solution of
di-tert-butylbiphenyl (1.6 g, 6.0 mmol) in THF (12 mL) at
08C was added lithium metal (60.0 mg, 8.57 mmol), and the
resultant solution was stirred at 0±258C for 5 h. To a solu-
tion of ole®n 56 (126.3 mg, 0.1835 mmol) in THF (8 mL) at
2788C was added the above lithium di-tert-butylbiphenyl-
ide (LiDBB) until the solution became deepblue. The resul-
tant solution was stirred at 2788C for 1 h before the reaction
was quenched with solid NH4Cl (200 mg) and methanol
(1 mL). The solvent was removed in vacuo and the residue
was puri®ed by column chromatography on silica gel (15%
methanol/CHCl3) to give tetraol, which was used in the next
reaction without further puri®cation.
26
as a colorless oil: [a]D ˆ127.6 (c 0.175, CHCl3); IR (®lm)
3076, 2942, 2891, 2864, 1642, 1615, 1588, 1517, 1462,
1382, 1250, 1172, 1095, 1065, 1039, 999, 917, 882, 828,
1
806, 681 cm21; H NMR (500 MHz, C6D6) d 7.57 (d, Jˆ
8.7 Hz, 2H), 6.81 (d, Jˆ8.6 Hz, 2H), 6.05 (m, 2H), 5.93±
5.85 (m, 3H), 5.30 (dd, Jˆ17.6, 1.7 Hz, 1H), 5.28 (s, 1H),
5.15 (dd, Jˆ17.4, 1.5 Hz, 1H), 5.09 (dd, Jˆ10.3, ,1 Hz,
1H), 5.04 (dd, Jˆ10.6, 1.4 Hz, 1H), 4.45 (d, Jˆ12.6, 5.0 Hz,
1H), 4.12 (dd, Jˆ10.1, 4.3 Hz, 1H), 4.07 (dd, Jˆ9.2, ,1 Hz,
1H), 4.04 (dd, Jˆ12.6, 5.5 Hz, 1H), 3.91 (dd, Jˆ9.7, 8.5 Hz,
1H), 3.80 (dd, Jˆ8.1, ,1 Hz, 1H), 3.45 (dd, Jˆ10.1,
10.1 Hz, 1H), 3.41 (ddd, Jˆ10.1, 9.2, 4.3 Hz, 1H), 3.28
(m, 1H), 3.26 (s, 3H), 3.07±3.02 (m, 2H), 2.86 (dd, Jˆ
9.1, 8.7 Hz, 1H), 2.77 (ddd, Jˆ11.5, 9.1, 4.5 Hz, 1H), 2.60
(m, 1H), 2.30 (m, 1H), 2.16 (ddd, Jˆ11.5, 4.5, 4.5 Hz, 1H),
1.55 (ddd, Jˆ11.5, 11.5, 11.5 Hz, 1H), 1.37±1.16 (m, 21H);
13C NMR (125 MHz, C6D6) d 160.6, 135.5, 135.3, 132.6,
131.6, 130.9, 128.5, 128.3, 128.0, 117.0, 115.8, 113.8,
101.1, 83.3, 82.4, 81.1, 80.9, 79.5, 78.0, 77.7, 74.2, 74.1,
73.4, 69.4, 54.7, 37.2, 36.6, 18.6, 18.5, 13.7; HRMS (FAB)
calcd for C36H54O8SiNa [(M1Na)1] 665.3486, found
665.3470.
To a solution of the above tetraol in DMF/CH2Cl2 (1:3, v/v,
4 mL) were added p-anisaldehyde dimethylacetal (62.5 mL,
0.367 mmol) and camphorsulfonic acid (8.5 mg, 37 mmol).
The resultant solution was stirred at room temperature for
6 h before the reaction was quenched with triethylamine.
The solvent was removed in vacuo and the residue was
puri®ed by column chromatography on silica gel (2%
methanol/CHCl3) to give p-methoxybenzylidene acetal 57
(48.2 mg, 59% for the two steps) as a colorless oil:
26
[a]D ˆ23.16 (c 0.11, CHCl3); IR (®lm) 3489, 2859,
1615, 1517, 1457, 1382, 1303, 1284, 1250, 1172, 1089,
4.2.32. ABCD ring fragment 4. To a solution of triene 5
(58.2 mg, 90.7 mmol) in CH2Cl2 (10 mL) was added
Grubbs' catalyst 46 (37.3 mg, 45.3 mmol), and the resultant
solution was stirred at room temperature for 2 h. Another
1040, 1001, 916, 828, 674, 579 cm21
;
1H NMR
(500 MHz, CDCl3) d 7.42 (d, Jˆ8.7 Hz, 2H), 6.87 (d,
Jˆ7.0 Hz, 2H), 5.90 (m, 1H), 5.76 (m, 1H), 5.70 (m, 1H),

M. Sasaki et al. / Tetrahedron 58 (2002)1889±1911
1909
Harada, N.; Yasumoto, T. J. Am. Chem. Soc. 1997, 119,
11325±11326.
portion of 46 (7.5 mg, 9.0 mmol) was added, and the stirring
was continued for further 2 h. The solvent was removed in
vacuo and the residue was puri®ed by column chroma-
tography on silica gel (5±10% ethyl acetate/hexanes) to
give ABCD ring fragment 4 (53.9 mg, 97%) as a colorless
10. Bidard, J.-N.; Vijverberg, H. P. M.; Frelin, C.; Chungue, E.;
Legrand, A.-M.; Bagnis, R.; Lazdanski, M. J. Biol. Chem.
1984, 259, 8353±8357.
26
11. (a) Catteral, W. A.; Risk, M. Mol. Pharmacol. 1981, 19, 345±
348. (b) Lombet, A.; Bidard, J. N.; Lazdanski, M. FEBS Lett.
1987, 219, 355±359.
oil: [a]D ˆ17.54 (c 0.08, CHCl3); IR (®lm) 2942, 2890,
2864, 1615, 1518, 1463, 1381, 1302, 1284, 1250, 1172,
1100, 1038, 1005, 882, 810, 677, 652 cm21 1H NMR
;
(500 MHz, C6D6) d 7.57 (d, Jˆ8.6 Hz, 2H), 6.81 (d, Jˆ
8.7 Hz, 2H), 5.94±5.88 (m, 2H), 5.58±5.51 (m, 2H), 5.28
(s, 1H), 4.14±4.08 (m, 2H), 4.04 (dd, Jˆ15.4, 5.9 Hz, 1H),
3.87 (dd, Jˆ9.0, 8.4 Hz, 1H), 3.82 (dd, Jˆ9.0, ,1 Hz, 1H),
3.70 (dd, Jˆ15.4, 2.5 Hz, 1H), 3.47±3.39 (m, 2H), 3.26 (s,
3H), 3.21 (dd, Jˆ9.6, 3.8 Hz, 1H), 3.12 (dd, Jˆ9.6, 9.0 Hz,
1H), 3.10 (ddd, Jˆ11.3, 9.0, 4.0 Hz, 1H), 2.95 (dd, Jˆ9.2,
8.4 Hz, 1H), 2.86 (ddd, Jˆ11.3, 9.2, 4.3 Hz, 1H), 2.54 (ddd,
Jˆ16.2, 7.9, 3.8 Hz, 1H), 2.25 (m, 1H), 2.22 (ddd, Jˆ11.3,
4.3, 4.0 Hz, 1H), 1.59 (ddd, Jˆ11.3, 11.3, 11.3 Hz, 1H),
1.33±1.16 (m, 21H); 13C NMR (125 MHz, C6D6) d 160.5,
132.4, 132.0, 130.9, 128.3, 128.0, 126.8, 113.8, 101.1, 89.1,
82.3, 81.1, 80.9, 77.8, 77.0, 76.1, 74.2, 72.9, 69.4, 68.5,
54.7, 37.3, 35.2, 18.6, 13.1; HRMS (FAB) calcd for
C34H50O8SiNa [(M1Na)1] 637.3173, found 637.3197.
12. (a) Trainer, V. L.; Thomsen, W. J.; Catterall, W. A.; Baden,
D. G. Mol. Pharmacol. 1991, 40, 988±994. (b) Trainer, V. L.;
Baden, D. G.; Catterall, W. A. J. Biol. Chem. 1994, 269,
19904±19909.
13. (a) Sasaki, M.; Hasegawa, A.; Tachibana, K. Tetrahedron Lett.
1993, 34, 8489±8492. (b) Sasaki, M.; Inoue, M.; Tachibana,
K. J. Org. Chem. 1994, 59, 715±717. (c) Inoue, M.; Sasaki,
M.; Tachibana, K. Tetrahedron Lett. 1997, 38, 1611±1614.
(d) Inoue, M.; Sasaki, M.; Tachibana, K. Angew. Chem. Int.
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(h) Sasaki, M.; Inoue, M.; Takamatsu, K.; Tachibana, K.
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(j) Sasaki, M.; Honda, S.; Noguchi, T.; Takakura, H.;
Tachibana, K. Synlett 2000, 838±840.
Acknowledgements
This work was supported in part by a Grant-in-Aid from
the Ministry of Education, Culture, Sports, Science and
Technology of Japan.
14. (a) Sasaki, M.; Fuwa, H.; Inoue, M.; Tachibana, K.
Tetrahedron Lett. 1998, 39, 9027±9030. (b) Sasaki, M.;
Fuwa, H.; Ishikawa, M.; Tachibana, K. Org. Lett. 1999, 1,
1075±1077. (c) Sasaki, M.; Noguchi, K.; Fuwa, H.;
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(d) Takakura, H.; Noguchi, K.; Sasaki, M.; Tachibana, K.
Angew. Chem. Int. Ed. 2001, 40, 1090±1093.
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Ê
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