Synthetic studies on a marine polyether toxin, gambierol: Stereoselective synthesis of the EFGH ring system via B-alkyl Suzuki coupling

Article abstract of DOI:10.1016/S0040-4020(01)00164-8

A synthetic route to the EFGH ring system (3) of gambierol (1), a marine polyether toxin isolated from the dinoflagellate Gambierdiscus toxicus, has been developed. The present synthesis features convergent coupling of the F and H rings followed by ring-closure of the G ring based on the B-alkyl Suzuki reaction of lactone-derived enol phosphates. An angular methyl group at C23 was stereoselectively introduced by treatment of sulfone 32 with trimethylaluminum. Installation of a tertiary alcohol at C21 was accomplished through stereoselcetive dihydroxylation of exo-methylene 36 followed by selective formation of the primary p-toluensulfonate and treatment of the resultant monotosylate 40 with lithium aluminum hydride. Finally, formation of the E ring as a lactone form completed the synthesis of 3.

Full text of DOI:10.1016/S0040-4020(01)00164-8

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 3019±3033
Synthetic studies on a marine polyether toxin, gambierol:
stereoselective synthesis of the EFGH ring system via B-alkyl
Suzuki coupling
Haruhiko Fuwa, Makoto Sasakip and Kazuo Tachibana
Department of Chemistry, Graduate School of Science, The University of Tokyo, CREST, Japan Science and Technology Corporation ꢀJST),
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 12 January 2001; accepted 8 February 2001
AbstractÐA synthetic route to the EFGH ring system (3) of gambierol (1), a marine polyether toxin isolated from the dino¯agellate
Gambierdiscus toxicus, has been developed. The present synthesis features convergent coupling of the F and H rings followed by ring-closure
of the G ring based on the B-alkyl Suzuki reaction of lactone-derived enol phosphates. An angular methyl group at C23 was stereoselectively
introduced by treatment of sulfone 32 with trimethylaluminum. Installation of a tertiary alcohol at C21 was accomplished through stereo-
selcetive dihydroxylation of exo-methylene 36 followed by selective formation of the primary p-toluensulfonate and treatment of the
resultant monotosylate 40 with lithium aluminum hydride. Finally, formation of the E ring as a lactone form completed the synthesis of
3. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
of extensive NMR analysis (Fig. 1).2 Recently, the absolute
con®guration has been unambiguously established by inver-
sion of the C6±OH group and application of the chiral
anisotropic reagent.3 Its characteristic polyether structure,
potent biological activity, and extremely limited availability
from natural sources make gambierol an intriguing synthetic
target molecule.4 We have recently reported a powerful
coupling strategy for the convergent assembly of a polyether
structure based on B-alkyl Suzuki coupling of lactone-
derived enol phosphates and disclosed its potential in the
synthesis of ciguatoxin fragments.5,6 In this paper, we
describe in detail a stereocontrolled construction of the
EFGH ring system (3) of gambierol based on the B-alkyl
Suzuki coupling strategy.7
A variety of polyether natural products that present
extremely potent biological activities have been isolated
from the marine dino¯agellates.1 Gambierol (1) was isolated
as a toxic constituent from cultured cells of the ciguatera
causative dino¯agellate, Gambierdiscus toxicus, and
showed toxicity against mice (LD50 50 mg kg21, mice,
i.p.).2 The symptoms caused in mice resemble those
shown by ciguatoxins, implying the possibility that
gambierol is also implicated in ciguatera ®sh poisoning,
which is one of the most widespread seafood poisonings.
The gross structure, including relative stereochemistry, has
been determined by Yasumoto and co-workers on the basis
HO
Me Me
O
H
H
H
H
O
D
H
H
O
E
20
A
B 10
C
O
HO
H
F
38
H
O
O
Me
O
1
H
H
H
G
H
O
Me
30
H
OH
Me
Gambierol (1)
Figure 1. Structure of gambierol (1).
Keywords: marine metabolites; polyethers; 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±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00164-8

3020
H. Fuwa et al. / Tetrahedron 57 ꢀ2001)3019±3033
2. Results and discussion
known a, b-unsaturated ester 8 (Scheme 2).10 DIBALH
reduction of 8 gave allylic alcohol 9, which was subjected
to sharpless asymmetric epoxidation with (2)-diethyl
tartrate as the chiral auxiliary to provide epoxy alcohol 10
in 87% yield. Oxidation with SO3´pyridine and DMSO
followed by Wittig methylenation generated vinyl epoxide
11 in 86% yield for the two steps, which was desilylated
with tetra-n-butylammonium ¯uoride (TBAF) to give
alcohol 12 in 98% yield. Upon treatment with PPTS tetra-
hydropyran 13 was regio- and stereoselectively formed in
94% yield. The secondary alcohol was then protected as the
benzyl ether 14. Hydroboration of 14 with 9-BBN-H
followed by oxidative workup provided primary alcohol
(95%), which was then benzylated to give bis(benzyl)
ether 15 in 76% yield. Following removal of the benzyl-
idene acetal, the resultant diol 16 was converted to primary
alcohol 17 by silylation of both hydroxyl groups and subse-
quent selective mono-desilylation (camphorsulfonic acid,
methanol±CH2Cl2, 08C). Iodination of the primary hydroxyl
groupin 17 gave primary iodide 18 (95%), which upon
treatment with potassium t-butoxide in THF at 08C
furnished the desired exo-ole®n 6 in 96% yield.
2.1. Synthetic plan
A convergent synthetic approach to gambierol (1) involves
construction of two fragments representing the ABC and
EFGH ring systems (2 and 3, respectively) and their
coupling through B-alkyl Suzuki reaction (Scheme 1). The
latter compound could be readily derived from tricyclic
FGH ring system 4. A formidable challenge in synthesizing
4 was the introduction of the 1,3-diaxial dimethyl groups at
the C21 and C23 positions on the F ring. Although a few
methods have been reported for the synthesis of a trans-
fused tetrahydropyran ring system having axial-oriented
methyl substituents ¯anking the ether oxygen,8 there has
been no report for the synthesis of 1,3-diaxial dimethyl-
substituted terahydropyrans at the angular positions
adjacent to the ring methylene. We envisaged the installa-
tion of a tertiary alcohol at C21 onto a tricyclic substrate
wherein the C23 angular methyl substituent was already in
place. The precursor tricyclic ether 5 could be obtained by
B-alkyl Suzuki coupling of the F and H ring fragments (6
and 7, respectively) followed by ring-closure of the G ring.
2.3. B-Alkyl Suzuki coupling of 6 and 7
2.2. Synthesis of exo-ole®n 6
In our previously reported B-alkyl Suzuki coupling reac-
tions,5b,c excess amounts (2 equiv.) of the phosphate
coupling partners and elevated reaction temperature were
Synthesis of exo-ole®n 6, representing the F ring of 1,
followed the procedure of Nicolaou9 starting from the
HO
Me Me
O
H
H
H
O
D
H
F
H
G
O
E
A
B
C
O
HO
H
H
O
O
Me
O
H
H
H
H
H
O
H
Me
Gambierol (1)
OH
Me
BnO
A
H
O
H
H
H
H
Me Me
O
O
O
F
OTBDMS
+
E
G
H
B
C
O
BnO
BnO
H
O
O
H
O
O
Me Me
H
H
O
2
3
H
O
H
O
O
O
H
H
O
H
H
H
H
H
TIPSO
O
F
O
O
21
23
H
H
BnO
O
Me
HO
O
H
Me Me
5
4
O
H
O
O
H
O
BnO
O
F
(PhO)2PO
+
H
H
BnO
OTBDMS
6
7
Scheme 1. Retrosynthetic analysis of gambierol.

H. Fuwa et al. / Tetrahedron 57 ꢀ2001)3019±3033
3021
TBDMS
TBDMS
O
TBDMS
H
MeO2C
O
O
O
O
HO
O
HO
O
c,d
a
b
O
O
O
Ph
Ph
O
Ph
O
Ph
O
H
H
H
10
8
9
R
O
H
H
H
H
O
BnO
O
h,i
j
O
f
O
RO
O
Ph
BnO
O
Ph
H
H
H
13 : R = H
15
11 : R = TBDMS
12 : R = H
g
e
14 : R = Bn
H
H
H
H
H
BnO
O
BnO
O
BnO
O
n
m
OH
OR
I
OTBDMS
BnO
OTBDMS
BnO
k,l
BnO
6
18
16 : R = H
17 : R = TBDMS
Ê
Scheme 2. Reagents and conditions: (a) DIBALH, CH2Cl2, 2788C, quant.; (b) t-BuOOH, Ti(Oi-Pr)4, (2)-diethyl tartrate, 4 A molecular sieves, CH2Cl2,
2208C, 87%; (c) SO3´pyridine, Et3N, DMSO, CH2Cl2, 08C; (d) Ph3P1CH3Br2, NaHMDS, THF, 08C, 86% (two steps); (e) n-Bu4NF, THF, rt, 98%; (f) PPTS,
CH2Cl2, rt, 94%; (g) NaH, BnBr, Bu4NI, DMF, rt, 97%; (h) 9-BBN-H, THF, rt, then NaOH, H2O2, rt, 95%; (i) KH, BnBr, Bu4NI, THF, re¯ux, 76%;
(j) p-TsOH´H2O, MeOH±CH2Cl2, rt, 90%; (k) TBDMSCl, imidazole, DMF, 508C; (l) CSA, MeOH±CH2Cl2, 08C, 96% (two steps); (m) I2, PPh3, imidazole,
benzene, rt, 95%; (n) t-BuOK, THF, 08C, 96%.
required to realize the coupling reaction in high yield.
These problems prompted us to explore the optimum
reaction conditions for the hydroboration±Suzuki coupling
of exo-ole®n 6 and enol phosphate 7.5b Hydroboration of
the B-alkyl Suzuki coupling partner 6 (9-BBN-H, THF,
room temperature) and direct subjection of the resultant
alkylborane to 1.2 equiv. of enol phosphate 7 under
the previously reported conditions (aqueous 1 M
phosphino)ferrocene]palladium(II) (PdCl2(dppf)) as a cata-
lyst improved the yield of 19 (entry 2) and allowed the
coupling reaction to proceed at room temperature in high
yield (entry 3).11 On the other hand, use of dichlorobis(tri-
cyclohexylphosphine)palladium(II) (PdCl2(PCy3)2)12 with
an electron-rich phosphine ligand lowered the yield of the
coupling reaction (entry 4).13 It has been recently reported
by Buchwald and co-workers that palladium(II) acetate/o-
(di-tert-butylphosphino)biphenyl 20 ef®ciently promotes
the room-temperature Suzuki coupling of less reactive aryl
chlorides;11e,f however, this catalyst system was also less
effective in the present case (entry 5).
NaHCO3
(3 equiv.),
tetrakis(triphenylphosphine)pal-
ladium(0) (Pd(PPh3)4, 10 mol%), DMF, 508C, 20 h)5b
afforded the desired cross-coupled product 19 in 87%
yield (Table 1, entry 1). Use of dichloro[1,10-bis(diphenyl-
Table 1. B-Alkyl Suzuki coupling of exo-ole®n 6 and enol phosphate 7
H
H
H
BnO
O
F
BnO
BnO
O
9-BBN
THF, rt
B
BnO
OTBDMS
O
BnO
BnO
OTBDMS
6
H
O
O
O
(PhO)2PO
H
O
O
H
H
H
O
7
Ph
H
O
H
aq. NaHCO3, Pd catalyst
O
TBDMS
19
Entry
Pd catalyst
Conditions
Yield (%)
1
2
3
Pd(PPh3)4
DMF, 508C, 20 h
DMF, 508C, 20 h
DMF, rt, 24 h
DMF, 508C, 20 h
Dioxane, rt, 24 h
87
93
97
50
58
PdCl2(dppf)
PdCl2(dppf)
PdCl2(PCy3)2
Pd(OAc)2/20
4
5a
Reactions were carried out using 10 mol% of Pd catalyst, 3 equiv. of aqueous 1 M NaHCO3, and 1.2 equiv. of enol phosphate 5; reaction times have not been
minimized.
20 mol% of ligand 20 was used.
a

3022
H. Fuwa et al. / Tetrahedron 57 ꢀ2001)3019±3033
H
H
H
O
O
H
H
H
H
H
O
O
BnO
O
BnO
O
Ph
Ph
Ph
a
b
O
O
H
H
H
BnO
O
BnO
BnO
O
OH
TBDMS
TBDMS
21
19
H
O
O
H
H
H
H
H
H
O
O
BnO
O
BnO
O
Ph
d
e
O
O
H
BnO
OR
OPMB
O
OPMB
24
22 : R = TBDMS
23 : R = H
c
H
H
H
O
O
H
H
H
H
H
H
O
O
BnO
BnO
O
O
BnO
BnO
O
O
Ph
Ph
i,j
f-h
O
O
H
H
BnO
BnO
OH
BnO
BnO
OR
Me
H
Me
OPMB
O
25
26 : R = TMS
H
H
H
OAc
OAc
OAc
OAc
H
H
H
H
O
O
O
O
Me OMe
Me
27
28
Scheme 3. Reagents and conditions: (a) BH3´THF, THF, 2308C, NaOH, H2O2, rt!408C, 77% (isomer, 10%); (b) KH, PMBCl, n-Bu4NI, THF, rt, 88%;
Ê
(c) n-Bu4NF, THF, rt, quant.; (d) TPAP, NMO, 4 A molecular sieves, CH2Cl2, rt, 94%; (e) MeMgBr, toluene, 2788C; (f) TMSOTf, 2,6-lutidine, CH2Cl2, 08C;
Ê
(g) DDQ, CH2Cl2±pH 7.0 phosphate buffer, rt; (h) TPAP, NMO, 4 A molecular sieves, CH2Cl2, rt; (i) p-TsOH´H2O, MeOH±CH2Cl2, rt, 80% (®ve steps);
(j) Ac2O, DMAP, CH2Cl2, rt, 70%.
H
H
O
O
H
H
H
H
H
H
H
O
O
BnO
O
BnO
O
Ph
Ph
a
O
O
H
H
BnO
O
BnO
O
OH
OPMB
24
29
b,c
d
H
H
H
OAc
OAc
OAc
H
H
H
H
H
O
O
BnO
O
BnO
O
OAc
BnO
O
BnO
O
OMe H
X
H
30
31 : X = SEt
32 : X = SO2Et
e
f
H
H
O
O
OAc
OAc
H
H
H
H
H
H
H
H
O
O
BnO
O
BnO
g,h
O
H
BnO
O
BnO
O
Me
Me
28
5
Scheme 4. Reagents and conditions: (a) DDQ, CH2Cl2±pH 7.0 phosphate buffer, rt; (b) p-TsOH´H2O, CHCl3±MeOH, rt; (c) Ac2O, DMAP, Et3N, CH2Cl2, rt,
97% from 24; (d) EtSH, Zn(OTf)2, NaHCO3, CH2Cl2, rt; then Ac2O, DMAP, 88% from 24; (e) m-CPBA, NaHCO3, CH2Cl2, rt, 96%; (f) Me3Al, CH2Cl2,
2788C!rt, 90%; (g) NaOMe, MeOH±CH2Cl2, rt; (h) Me2C(OMe)2, PPTS, DMF± CH2Cl2, rt, 98% (two steps).

H. Fuwa et al. / Tetrahedron 57 ꢀ2001)3019±3033
3023
2.4. Synthesis of tricyclic ether 5
To circumvent this obstacle, we converted 24 to mixed
ethylthio ketal 31. Following removal of the PMB group
of 24, treatment of the resulting hemiketal 29 with
ethanethiol and zinc tri¯ate in the presence of NaHCO3 in
In our ®rst synthetic strategy, we planned to introduce an
angular methyl groupat C23 via hydride reduction of mixed
methyl ketal 27 (Scheme 3). Hydroboration of 19 with
thexylborane (THF, 08C) was very slow, and the desired
alcohol 21 was obtained in 67% yield after 4 days. More
practically, hydroboration of 19 with borane±THF complex
(THF, 2308C, overnight, then NaOH, H2O2) provided 21 in
77% yield along with 10% of its diastereomer, which were
easily separable by column chromatography on silica gel.
Protection of the secondary alcohol as the p-methoxybenzyl
(PMB) ether 22 followed by removal of the silyl groupgave
alcohol 23 in 88% overall yield. Oxidation of the resultant
alcohol with tetrapropylammonium perruthenate (TPAP)
and N-methylmorpholine N-oxide (NMO)14 provided
ketone 24 in 94% yield. Treatment of 24 with methyl-
magnesium bromide in toluene at 2788C provided tertiary
alcohol 25 stereoselectively.15 Protection of the tertiary
alcohol as its trimethylsilyl ether followed by oxidative
removal of the PMB groupwith DDQ and oxidation of
the resulting secondary alcohol with TPAP/NMO provided
ketone 26. Exposure of 26 to p-toluenesulfonic acid in
methanol effected formation of a mixed methyl ketal and
removal of the benzylidene groupto give the diol (80%
overall yield from 24), which was then acetylated to yield
diacetate 27 in 70% yield. However, reduction of 27 with
triethylsilane in the presence of boron tri¯uoride etherate in
CH2Cl2 or CH3CN at low temperature (240!08C) resulted
in no reaction, whereas at room temperature signi®cant
decomposition was observed and the desired product 28
18
CH2Cl2 and in situ acetylation provided mixed thioketal
31 in 88 % overall yield. Oxidation of 31 with m-CPBA then
gave the corresponding sulfone 32 in 96% yield. Reaction of
32 with trimethylaluminum (CH2Cl2, 2788C to rt)19 led
exclusively to the desired 28 in 90% yield. The relative
con®guration of 28 was unambiguously established by
NOE experiments (Fig. 2). Finally, routine protecting
groupmanipulation allowed for conversion of 28 to aceto-
nide 5 in 98% overall yield.
2.5. Installation of tertiary alcohol at C21
With the desired 5 in hand, our attention was next directed
to stereoselective construction of the tertiary alcohol at the
C21 position. Removal of the benzyl groups of 5, followed
by selective silylation of the primary alcohol (TBDMSCl or
TIPSCl, imidazole, CH2Cl2, rt), provided alcohol 33 in high
yield (Scheme 5). Oxidation of the secondary alcohol with
TPAP/NMO gave ketone 34 in near quantitative yield.
Unfortunately, all attempts to install C21 tertiary alcohol
by nucleophilic addition to ketone 34a were unsuccessful.
Direct methylation using methylmagnesium bromide,
methyllithium, and trimethylaluminum occurred from the
topface to yield the undesired isomer 35 exclusively or
as the major product. Nucleophilic epoxidation using
H
O
H
H
H
O
BnO
O
was not obtained. The presence of an angular methyl
a,b
16
groupat C23
nucleophile from the bottom face of the oxocarbenium ion
would hinder the axial attack of hydride
O
H
BnO
HO
O
generated from 27.
Me
H
H
H
5
Having failed to reduce mixed methyl ketal 27 to obtain 28,
we explored the possibility of introduction of the methyl
groupvia methylation of the oxocarbenium ion generated
from mixed methyl ketal 30 (Scheme 4). Oxidative removal
of the PMB groupof 24 followed by acidic treatment in
methanol and subsequent acetylation led to diacetate 30 in
79% overall yield. However, upon treatment of 30 with
trimethylaluminum or dimethylzinc in the presence of
boron tri¯uoride etherate,17 none of the desired methylated
product 28 was obtained.
H
O
H
O
RO
O
c
O
H
O
Me
H
33a : R = TBDMS
33b : R = TIPS
H
O
H
H
H
O
RO
O
O
H
O
O
Me
H
34a : R = TBDMS
34b : R = TIPS
H
O
O
H
H
H
O
TBSO
O
H
HO
O
Me Me
H
35
Scheme 5. Reagents and conditions: (a) H2, Pd(OH)2/C, EtOAc, rt;
(b) TBDMSCl or TIPSCl, imidazole, CH2Cl2, rt, 74% (two steps) for
Ê
33a, 89% (two steps) for 33b; (c) TPAP, NMO, 4 A molecular sieves,
CH2Cl2, rt, 99% for 34a, quant. for 34b.
Figure 2. Stereochemical assignment of tricyclic ether 28. Double-ended
arrows denote NOEs.

3024
H. Fuwa et al. / Tetrahedron 57 ꢀ2001)3019±3033
H
H
H
O
H
H
H
H
H
O
O
O
TIPSO
O
O
O
a
b
O
H
H
H
O
Me
H
H
H
36
O
TIPSO
O
HO
HO
O
Me
H
H
39
O
H
Figure 3.
TIPSO
c
dimethyloxosulfonium methylide20 followed by reduction
with lithium triethylborohydride also provided 35 as a single
stereoisomer. These results can be explained by the serious
steric congestion of the angular methyl groupat C23 (Fig. 3).
O
23
HO
O
Me
H
TsO
40
NOE
H
O
H
H
H
Under these circumstances, we explored an alternative
method for the construction of C21 tertiary alcohol. It was
anticipated that epoxidation of exo-ole®n 37, derived from
ketone 34b, would proceed stereoselectively to give the
b-epoxide which, upon hydride reduction, would furnish
the desired tertiary alcohol 4 (Scheme 6). Thus, methyl-
enation of ketone 34b with Wittig reagent (6 equiv. of
Ph3P1BrCH32, 5.6 equiv. of NaHMDS, THF, 2788C!rt,
3.5 h) provided 36 in 92% yield. However, epoxidation of
36 with m-CPBA (NaHCO3, CH2Cl2, rt, 2 days) yielded an
inseparable mixture of epoxides 37 (37a/37bˆ2:3), which
was reduced with lithium triethylborohydride (THF, rt)
giving an inseparable mixture of the desired tertiary alcohol
4 and its C21 diastereomer 38 (4/38ˆ3:2) in 68% combined
yield along with 28% of recovered 36. Epoxidation at the
elevated temperature in the presence of a radical inhibitor,
4,40-thiobis(6-t-butyl-m-cresol),21 did not improve the facial
selectivity.
O
TIPSO
O
O
H
O
O
Me
37β
H
H
O
H
H
H
O
TIPSO
O
F
G
H
O
H
HO
O
Me Me
H
4
Scheme 7. Reagents and conditions: (a) OsO4 (3 equiv.), NMO (10 equiv.),
t-BuOH±H2O, rt, 1.5 d, then aq. NaHSO3, pyridine, rt, 96%; (b) p-TsCl,
DMAP, (CH2Cl)2, rt, 99%; (c) LiAlH4, THF, 08C!rt, 3 h, 75%.
H
H
O
O
H
H
H
H
H
H
H
H
H
O
O
TIPSO
TIPSO
O
TIPSO
O
a
b
O
O
H
H
O
O
O
Me
Me
36
34b
H
H
O
O
H
H
H
H
H
H
O
O
c
O
TIPSO
TIPSO
O
O
+
+
O
O
H
H
O
O
O
O
Me
H
Me
H
37α (undesired)
37β (desired)
H
H
O
O
H
H
H
H
H
H
H
O
O
TIPSO
O
O
O
21
H
H
HO
O
HO
O
Me Me
Me Me
38
4
Scheme 6. Reagents and conditions: (a) Ph3P1CH3Br2 (6 equiv.), NaHMDS (5.6 equiv.), THF, 2788C!rt, 3.5 h, 92%; (b) m-CPBA, NaHCO3, CH2Cl2, rt,
2 days; (c) LiEt3BH, THF, rt, 68% (two steps, 4/38ˆ3:2).

H. Fuwa et al. / Tetrahedron 57 ꢀ2001)3019±3033
3025
After several experiments, we found that dihydroxylation of
36 proceeded stereoselectively to give diol 39 as a single
stereoisomer in near quantitative yield (Scheme 7). In this
reaction, excess amounts of reagents (3 equiv. of OsO4 and
10 equiv. of NMO) and prolonged reaction time were
required to obtain a high yield of 39. Selective tosylation
of the primary hydroxyl group gave primary monotosylate
40 in virtually quantitative yield. The relative stereo-
chemistry at C21 was established by an NOE between the
oxymethylene and C23 angular methyl groups as shown in
Scheme 7. Reduction of 40 with lithium aluminum
hydride in THF at 08C yielded epoxide 37b which, upon
warming to room temperature, delivered the desired
tertiary alcohol 4 in 75% yield.22 To our knowledge, the
present synthesis of 4 constitutes the ®rst example for the
construction of 1,3-diaxial dimethyl-substituted tetra-
hydropyran at the angular position adjacent to the ring
methylene.
(2,4,6-trichlorobenzoyl chloride, triethylamine, THF±
toluene; then DMAP, toluene, 1108C)23 to furnish the
target EFGH ring system 3 in 93% yield for the two steps.
Stereochemistry at the quaternary center at C21 was
unambiguously established by NOE between the angular
methyl groups at C21 and C23.
3. Conclusions
We have completed the synthesis of the EFGH ring system
of gambierol. In the present synthesis we have demonstrated
that PdCl2(dppf) promotes the room-temperature B-alkyl
Suzuki coupling of lactone-derived enol phosphate in high
yield. The mild reaction conditions described herein should
tolerate the presence of a wide variety of functional
groups and thus enhance the practicality and usefulness of
the B-alkyl Suzuki coupling-based strategy for the synthesis
of a polyether system. Also, 1,3-diaxial dimethyl groups
with serious steric congestion were successfully introduced.
Further efforts directed toward a total synthesis of gambierol
are under way and will be reported in due course.
2.6. Final conversion to the EFGH ring system
Final transformation of 4 into the target EFGH ring system
(3) is outlined in Scheme 8. Protection of the tertiary alcohol
of 4 as its benzyl ether followed by desilylation provided
alcohol 41 in 87% yield for the two steps. Oxidation of the
primary alcohol with SO3´pyridine and DMSO followed by
Wittig homologation using benzyl (triphenylphophoranyl-
idene)acetate provided a,b-unsaturated benzyl ester 42 in
86% overall yield. Removal of the benzyl protecting groups
and hydrogenation of the double bond gave hydroxy acid
43, which was lactonized under Yamaguchi conditions
4. Experimental
4.1. General methods
All moisture and/or air sensitive reactions were conducted
under an atmosphere of argon or nitrogen with dry solvents
under anhydrous conditions unless otherwise noted.
Anhydrous THF and dimethylsulfoxide (DMSO) were
purchased from Kanto Chemical and Aldrich, respectively.
Benzene, toluene, dichloromethane, methanol, triethyl-
amine, and pyridine were distilled from calcium hydride.
Other solvents and reagents purchased were of the highest
commercial quality and used without further puri®cation
unless otherwise noted. All reactions were monitored by
thin-layer chromatography (TLC) with pre-coated silica
gel plates (E. Merck, Silica gel 60 F254). Column chromato-
graphy was performed on Kanto Chemical silica gel 60N
(spherical, neutral). NMR spectra were recorded on a JEOL
A500 or Bruker DRX-500 instrument and referenced to a
residual solvent. Chemical shifts are reported in d (ppm).
Coupling constants are reported in Hertz (Hz). The follow-
ing abbreviations were used to designate the multiplicities:
sˆsinglet, dˆdoublet, tˆtriplet, mˆmultiplet, brˆbroad. IR
spectra were recorded on a JASCO FT/IR-420 instrument.
Low- and high-resolution mass spectra were recorded on a
JEOL JMS-SX102L mass spectrometer under fast atom
bombardment (FAB) conditions with m-nitrobenzyl alcohol
(NBA) as the matrix.
H
O
H
H
H
R1O
O
O
c,d
O
R2O
O
H
Me Me
H
4 : R1 = TIPS, R2 = H
a,b
41 : R1 = H, R2 = Bn
H
O
H
H
H
O
O
e
O
BnO2C
O
H
BnO
O
O
Me Me
H
H
42
H
O
H
H
f
O
HO2C
O
H
O
HO
Me Me
H
O
43
H
H
H
O
H
4.1.1. Allylic alcohol 9. To a solution of a,b-unsaturated
ester 89 (7.92 g, 20.2 mmol) in CH2Cl2 (80 mL) at 2788C
was added DIBALH (1.0 M solution in toluene, 50.5 mL,
50.5 mmol). After being stirred at 2788C for 2 h, the reac-
tion was quenched with saturated aqueous potassium
sodium tartrate. The reaction mixture was diluted with
EtOAc and vigorously stirred at room temperature until
the layers were separated. The organic layer was separated,
washed with brine, dried over Na2SO4, and concentrated.
The residue was puri®ed by column chromatography (silica
E
F
G
O
H
O
21
23
H
O
Me Me
H
O
3
Scheme 8. Reagents and conditions: (a) KH, BnBr, THF, rt; (b) n-Bu4NF,
THF, rt, 87% (two steps); (c) SO3´pyridine, Et3N, DMSO, CH2Cl2, 08C;
(d) Ph3PvCHCO2Bn, (CH2Cl)2, rt, 86% (two steps); (e) H2, Pd(OH)2/C,
EtOAc, rt; (f) 2,4,6-trichlorobenzoyl chloride, Et3N, THF±toluene (1:1), rt,
then DMAP, toluene, 1108C, 93% (two steps).

3026
H. Fuwa et al. / Tetrahedron 57 ꢀ2001)3019±3033
gel, 25!35% EtOAc/hexane) to give allylic alcohol 9
984, 884, 838, 778, 697 cm21; 1H NMR (500 MHz, CDCl3)
d 7.47±7.45 (m, 2H), 7.36±7.32 (m, 3H), 5.58 (ddd, 1H,
Jˆ17.7, 10.1, 7.3 Hz), 5.49 (s, 1H), 5.46 (d, 1H,
Jˆ17.7 Hz), 5.26 (d, 1H, Jˆ10.1 Hz), 4.18 (dd, 1H,
Jˆ10.7, 4.6 Hz), 3.69 (m, 1H), 3.56 (dd, 1H, Jˆ10.7,
9.8 Hz), 3.16±3.07 (m, 2H), 2.04±1.93 (m, 2H), 0.88 (s,
9H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (CDCl3,
125 MHz) d 137.8, 135.7, 128.9, 128.2, 126.0, 119.2,
100.8, 80.0, 71.9, 65.9, 58.2, 57.2, 33.8, 25.7, 17.9;
HRMS calcd for C21H32O4SiNa [(M1Na)1] 399.1968,
found 399.1974.
26
(7.34 g, quant.) as a colorless oil: [a]D ˆ257.6 (c 2.08,
benzene); IR (®lm) 3413, 2954, 2929, 2857, 1462, 1398,
1362, 1254, 1108, 1029, 974, 838, 778, 698 cm21 1H
;
NMR (500 MHz, CDCl3) d 7.47±7.45 (m, 2H), 7.36±7.31
(m, 3H), 5.82 (ddd, 1H, Jˆ15.6, 6.7, 6.7 Hz), 5.74 (ddd, 1H,
Jˆ15.6, 5.5, 5.5 Hz), 5.46 (s, 1H), 4.17 (m, 1H), 4.08 (d, 2H,
Jˆ5.5 Hz), 3.62±3.52 (m, 3H), 2.61 (dd, 1H, Jˆ14.7,
6.7 Hz), 2.30 (dt, 1H, Jˆ14.7, 6.7 Hz), 0.89 (s, 9H), 0.09
(s, 3H), 0.07 (s, 3H); 13C NMR (CDCl3, 125 MHz) d 137.9,
131.6, 128.8, 128.4, 128.2, 126.0, 100.8, 81.9, 71.7, 66.1,
63.6, 34.3, 25.7, 17.9; HRMS calcd for C20H34O4SiNa
[(M1Na)1] 387.1968, found 387.1971.
4.1.4. Hydroxy epoxide 12. To a solution of ole®n 11
(5.38 g, 14.3 mmol) in THF (100 mL) was added TBAF
(1.0 M solution in THF, 21.5 mL, 21.5 mmol). After being
stirred at room temperature for 45 min, the reaction mixture
was diluted with EtOAc, washed with saturated aqueous
NH4Cl and brine, dried over Na2SO4, and concentrated.
The residue was puri®ed by column chromatography (silica
gel, 40!50% EtOAc/hexane) to give hydroxy epoxide 12
4.1.2. Epoxide 10. To a solution of allylic alcohol 9 (4.27 g,
Ê
11.7 mmol) and 4 A molecular sieves (1.63 g) in CH2Cl2
(40 mL) at 2208C were added (2)-DET (0.40 mL,
2.3 mmol) and Ti(Oi-Pr)4 (0.52 mL, 1.8 mmol). After
being stirred at 2208C for 30 min, t-BuOOH (5.7 M solu-
tion in isooctane, 5.10 mL, 29.1 mmol) was added to the
mixture and the resulting mixture was stirred at 2208C
for 4 h. The reaction mixture was allowed to warm to
room temperature and ®ltered through Celite. The ®ltrate
was diluted with EtOAc, washed with saturated aqueous
Na2SO4 and brine, dried over Na2SO4, and concentrated.
The residue was puri®ed by column chromatography (silica
gel, 25!35% EtOAc/hexane) to give epoxide 10 (3.90 g,
25
(3.68 g, 98%) as a colorless oil: [a]D ˆ219.0 (c 0.42,
benzene); IR (®lm) 3444, 2858, 1456, 1397, 1074, 1027,
1
984, 925, 873, 752, 699, 668 cm21; H NMR (500 MHz,
CDCl3) d 7.48±7.46 (m, 2H), 7.37±7.31 (m, 3H), 5.58
(ddd, 1H, Jˆ17.4, 10.1, 7.0 Hz), 5.55 (s, 1H), 5.47 (d, 1H,
Jˆ17.4 Hz), 5.28 (d, 1H, Jˆ10.1 Hz), 4.30 (dd, 1H, Jˆ10.7,
5.2 Hz), 3.88 (m, 1H), 3.75 (m, 1H), 3.60 (m, 1H), 3.24±
3.17 (m, 2H), 2.41 (br, 1H), 2.27 (ddd, 1H, Jˆ15.0, 3.7,
3.4 Hz), 1.93 (ddd, 1H, Jˆ15.0, 7.0, 5.8 Hz); 13C NMR
(CDCl3, 125 MHz) d 137.7, 135.1, 129.0, 128.3, 126.1,
119.8, 101.1, 79.6, 71.1, 65.0, 58.3, 57.0, 34.2; HRMS
calcd for C15H18O4Na [(M1Na)1] 285.1103, found
285.1126.
26
87%) as a colorless oil: [a]D ˆ235.6 (c 0.47, benzene); IR
(®lm) 3445, 2928, 2857, 1460, 1388, 1254, 1106, 1029, 838,
1
778, 698 cm21; H NMR (500 MHz, CDCl3) d 7.48±7.45
(m, 2H), 7.38±7.31 (m, 3H), 5.49 (s, 1H), 4.19 (dd, 1H,
Jˆ10.7, 4.6 Hz), 3.90 (ddd, 1H, Jˆ12.5, 5.5, 4.6 Hz),
3.71±3.59 (m, 3H), 3.56 (dd, 1H, Jˆ10.7, 9.5 Hz), 3.23
(dt, 1H, Jˆ5.5, 2.4 Hz), 2.97 (dt, 1H, Jˆ4.9, 2.4 Hz), 2.02
(m, 1H), 1.64 (dd, 1H, Jˆ7.3, 5.5 Hz), 0.88 (s, 9H), 0.10 (s,
3H), 0.09 (s, 3H); 13C NMR (CDCl3, 125 MHz) d 137.7,
128.9, 128.3, 126.0, 100.8, 80.0, 71.8, 65.9, 61.7, 57.8, 52.9,
33.4, 25.8, 17.9, 24.2, 24.8; HRMS calcd for
C20H32O5SiNa [(M1Na)1] 403.1917, found 403.1945.
4.1.5. Tetrahydropyran 13. To a solution of hydroxy
epoxide 12 (3.62 g, 13.8 mmol) in CH2Cl2 (140 mL) was
added PPTS (1.71 g, 6.80 mmol). After being stirred at
room temperature for 3.5 h, the reaction was quenched
with Et3N and the mixture was concentrated. The residue
was puri®ed by column chromatography (silica gel, 50%
EtOAc/hexane) to give tetrahydropyran 13 (3.40 g, 94%)
as a colorless solid: mp143±145 8C (hexane/EtOAc);
4.1.3. Ole®n 11. To a solution of epoxide 10 (6.30 g,
16.6 mmol) and Et3N (11.6 mL, 83.2 mmol) in CH2Cl2±
DMSO (3:1, 80 mL) at 08C was added SO3´pyridine
(10.55 g, 66.29 mmol) and the resulting mixture was stirred
at 08C for 30 min. The reaction mixture was diluted with
EtOAc, washed with 1 M aqueous HCl, saturated aqueous
NaHCO3 and brine, dried over Na2SO4, and concentrated to
give crude aldehyde, which was used in the next reaction
without further puri®cation.
25
[a]D ˆ225.4 (c 0.07, CHCl3); IR (®lm) 3361, 2873,
1
1456, 1369, 1100, 1011, 750, 697, 668 cm21; H NMR
(500 MHz, CDCl3) d 7.49±7.46 (m, 2H), 7.37±7.34 (m,
3H), 5.84 (ddd, 1H, Jˆ17.4, 10.4, 7.0 Hz), 5.52 (s, 1H),
5.44 (d, 1H, Jˆ17.4 Hz), 5.37 (d, 1H, Jˆ10.4 Hz), 4.33
(dd, 1H, Jˆ10.4, 4.9 Hz), 3.72±3.63 (m, 2H), 3.59 (ddd,
1H, Jˆ11.6, 8.9, 4.3 Hz), 3.51 (m, 1H), 3.42 (ddd, 1H,
Jˆ11.3, 9.2, 4.9 Hz), 2.52 (ddd, 1H, Jˆ11.6, 4.9, 4.3 Hz),
1.73 (ddd, 1H, Jˆ11.6, 11.6, 11.3 Hz); 13C NMR (CDCl3,
125 MHz) d 135.0, 129.1, 128.3, 126.2, 120.0, 101.7, 83.9,
76.6, 73.0, 69.3, 68.9, 37.0; HRMS calcd for C15H18O4Na
[(M1Na)1] 285.1103, found 285.1079.
To a suspension of Ph3P1CH3Br2 (11.85 g, 33.17 mmol) in
THF (50 mL) at 08C was added NaHMDS (1.0 M solution in
THF, 30.0 mL, 30.0 mmol) and the resulting ylide solution
was stirred at 08C for 30 min. To the solution was added
dropwise a solution of the above aldehyde in THF (40 mL).
After being stirred at 08C for 30 min, the reaction was
quenched with saturated aqueous NH4Cl. The resulting
mixture was diluted with ether, washed with water and
brine, dried over MgSO4, and concentrated. The residue
was puri®ed by column chromatography (silica gel, 10%
EtOAc/hexane) to give ole®n 11 (5.38 g, 86% for two
4.1.6. Benzyl ether 14. To a solution of tetrahydropyran 13
(10.69 g, 40.80 mmol) in DMF (300 mL) at 08C was added
NaH (60% oil dispersion, 3.26 g, 81.5 mmol), and the
resulting solution was stirred at room temperature for
30 min. The reaction mixture was cooled to 08C, treated
with BnBr (7.28 mL, 61.2 mmol) and n-Bu4NI (1.51 g,
4.09 mmol), and allowed to warm to room temperature.
After being stirred at room temperature for 100 min, the
26
steps) as a colorless oil: [a]D ˆ249.7 (c 0.45, benzene);
IR (®lm) 2955, 2929, 2857, 1462, 1399, 1254, 1112, 1029,

H. Fuwa et al. / Tetrahedron 57 ꢀ2001)3019±3033
3027
reaction was quenched with MeOH. The reaction mixture
was diluted with ether, washed with water and brine, dried
over MgSO4, and concentrated. The residue was puri®ed by
column chromatography (silica gel, 10% EtOAc/hexane) to
give benzyl ether 14 (13.86 g, 97%) as a colorless solid: mp
Jˆ10.4, 4.9 Hz), 3.62±3.57 (m, 3H), 3.47±3.45 (m, 2H),
3.31±3.29 (m, 2H), 2.60 (ddd, 1H, Jˆ11.4, 4.3, 4.2 Hz),
2.28 (m, 1H), 1.70±1.60 (m, 2H); 13C NMR (125 MHz,
CDCl3) d 138.7, 138.0, 137.6, 129.0, 128.4, 128.3, 127.9,
127.8, 127.6, 127.5, 126.2, 101.7, 78.2, 76.8, 76.4, 73.0,
72.9, 71.0, 69.4, 66.6, 34.9, 32.2; HRMS calcd for
C29H32O5Na [(M1Na)1] 483.2147, found 483.2169.
25
95.5±97.58C (hexane/Et20); [a]D ˆ259.8 (c 1.01, CHCl3);
IR (®lm) 2879, 1454, 1381, 1093, 1012, 990, 930, 755, 697,
1
651 cm21; H NMR (500 MHz, CDCl3) d 7.49±7.47 (m,
2H), 7.36±7.31 (m, 8H), 5.98 (ddd, 1H, Jˆ17.3, 10.7,
5.9 Hz), 5.50 (s, 1H), 5.42 (d, 1H, Jˆ17.3 Hz), 5.28 (d,
1H, Jˆ10.7 Hz), 4.61 (d, 1H, Jˆ11.7 Hz), 4.52 (d, 1H,
Jˆ11.7 Hz), 4.33 (dd, 1H, Jˆ10.3, 4.8 Hz), 3.83 (dd, 1H,
Jˆ9.2, 5.9 Hz), 3.68 (dd, 1H, Jˆ10.3, 10.2 Hz), 3.51 (m,
1H), 3.44 (m, 1H), 3.34 (m, 1H), 2.60 (ddd, 1H, Jˆ11.5, 4.3,
4.3 Hz), 1.73 (ddd, 1H, Jˆ11.5, 11.4, 11.2 Hz); 13C NMR
(125 MHz, CDCl3) d 137.9, 137.4, 135.4, 129.0, 128.4,
128.3, 127.8, 126.1, 117.8, 101.6, 81.3, 76.5, 72.8, 71.4,
69.3, 35.2; HRMS calcd for C22H24O4Na [(M1Na)1]
375.1572, found 375.1569.
4.1.8. Diol 16. To a solution of bis(benzyl) ether 15 (3.76 g,
8.17 mmol) in MeOH±CH2Cl2 (1:1, 80 mL) was added
p-TsOH´H2O (0.46 g, 2.4 mmol) and the resulting mixture
was stirred at room temperature for 3 h. The reaction was
quenched with Et3N, and the reaction mixture was concen-
trated. The residue was puri®ed by column chromatography
(silica gel, 80% EtOAc/hexane) to give diol 16 (2.74 g,
25
90%) as a colorless amorphous solid: [a]D ˆ277.5 (c
0.15, benzene); IR (®lm) 3393, 2925, 2868, 1456, 1097,
1
738, 698 cm21; H NMR (500 MHz, CDCl3) d 7.34±7.24
(m, 10H), 4.60 (d, 1H, Jˆ11.6 Hz), 4.52 (d, 1H,
Jˆ12.1 Hz), 4.47±4.42 (m, 2H), 3.77 (m, 1H), 3.71 (m,
1H), 3.62±3.54 (m, 3H), 3.37 (ddd, 1H, Jˆ9.1, 9.1,
2.6 Hz), 3.20±3.13 (m, 2H), 2.54 (ddd, 1H, Jˆ11.3, 4.6,
4.6 Hz), 2.26 (m, 1H), 1.62 (m, 1H), 1.46 (ddd, 1H,
Jˆ11.3, 11.3, 11.3 Hz); HRMS calcd for C22H28O5Na
[(M1Na)1] 395.1834, found 395.1829.
4.1.7. Bis3benzyl) ether 15. To a solution of benzyl ether 14
(2.45 g, 6.96 mmol) in THF (70 mL) was added 9-BBN
dimmer (2.21 g, 9.06 mmol) and the resulting mixture was
stirred at room temperature for 105 min. After cooling to
08C, the reaction was quenched with water (10 mL) and then
treated with 3 M aqueous NaOH (30 mL) and 30% H2O2
(25 mL) and the resulting mixture was allowed to warm to
room temperature and stirred overnight. The reaction
mixture was diluted with EtOAc, washed with water, satu-
rated aqueous Na2SO3 and brine, dried over Na2SO4 and
concentrated. The residue was puri®ed by column chroma-
tography (silica gel, 50% EtOAc/hexane) to give primary
alcohol (2.43 g, 95%) as a viscous oil, which was used in the
next reaction without further puri®cation. 1H NMR
(500 MHz, CDCl3) d 7.47±7.45 (m, 2H), 7.37±7.27 (m,
8H), 5.50 (s, 1H), 4.65 (d, 1H, Jˆ11.6 Hz), 4.46 (d, 1H,
Jˆ11.6 Hz), 4.27 (dd, 1H, Jˆ10.4, 4.9 Hz), 3.80±3.27 (m,
2H), 3.63 (dd, 1H, Jˆ10.4, 10.1 Hz), 3.56 (ddd, 1H, Jˆ8.9,
8.9, 3.1 Hz), 3.48 (m, 1H), 3.42±3.32 (m, 2H), 2.64 (ddd,
1H, Jˆ11.3, 4.3, 4.0 Hz), 2.16 (m, 1H), 1.75±1.60 (m, 2H);
13C NMR (125 MHz, CDCl3) d 137.5, 137.3, 129.1, 128.5,
128.3, 128.0, 127.9, 126.1, 101.7, 81.1, 76.4, 75.8, 73.1,
70.9, 69.2, 61.0, 34.6, 34.4.
4.1.9. Alcohol 17. To a solution of diol 16 (2.49 g,
6.69 mmol) in DMF (60 mL) were added imidazole
(1.82 g, 26.7 mmol) and TBDMSCl (3.03 g, 20.1 mmol),
and the resulting mixture was stirred at 508C for 9 h. The
reaction mixture was cooled to room temperature, diluted
with ether, washed with 1 M HCl, saturated aqueous
NaHCO3, and brine. The organic layer was dried over
MgSO4 and concentrated to give bis(silyl) ether, which
was used in the next reaction without further puri®cation.
A solution of the above bis(silyl) ether in MeOH±CH2Cl2
(1:1, 80 mL) was treated with CSA (311.4 mg, 1.341 mmol)
at 08C. After being stirred at 08C for 80 min, the reaction
was quenched with Et3N and concentrated. The residue was
puri®ed by column chromatography (silica gel, 20% EtOAc/
hexane) to give alcohol 17 (3.11 g, 96% for two steps) as a
26
colorless oil: [a]D ˆ224.6 (c 0.21, benzene); IR (®lm)
3468, 2928, 2857, 1454, 1362, 1254, 1095, 860, 837, 776,
1
To a suspension of KH (30% oil dispersion, 418.7 mg,
3.132 mmol) in THF at room temperature was added drop-
747, 697 cm21; H NMR (500 MHz, CDCl3) d 7.34±7.24
(m, 10H), 4.58 (d, 1H, Jˆ11.6 Hz), 4.52 (d, 1H,
Jˆ11.9 Hz), 4.46 (d, 1H, Jˆ11.6 Hz), 4.44 (d, 1H,
Jˆ11.9 Hz), 3.75 (m, 1H), 3.62±3.45 (m, 4H), 3.36 (ddd,
1H, Jˆ9.2, 9.2, 2.8 Hz), 3.18±3.10 (m, 2H), 2.36 (ddd, 1H,
Jˆ11.6, 4.6, 4.6 Hz), 2.25 (m, 1H), 1.64 (m, 1H), 1.44 (ddd,
1H, Jˆ11.6, 11.3, 11.3 Hz), 0.85 (s, 9H), 0.03 (s, 6H); 13C
NMR (125 MHz, CDCl3) d 138.5, 138.1, 128.40, 128.35,
127.83, 127.76, 127.6, 127.5, 81.5, 77.5, 76.2, 72.9, 71.1,
66.8, 66.7, 62.7, 39.1, 32.2, 25.7, 17.9, 24.2, 24.9; HRMS
calcd for C28H42O5SiNa [(M1Na)1] 509.2699, found
509.2695.
wise
a solution of the above alcohol (442.4 mg,
1.196 mmol) in THF (7 mL). After being stirred at room
temperature for 20 min, the mixture was treated with
BnBr (213 mL, 1.79 mmol) and n-Bu4NI (44.4 mg,
0.120 mmol) and the resultant solution was re¯uxed for
1 h. The reaction was quenched by careful addition of
MeOH at 08C, and the reaction mixture was diluted with
EtOAc, washed with saturated aqueous NH4Cl and brine,
dried over Na2SO4, and concentrated. The residue was puri-
®ed by column chromatography (silica gel, 10!20%
EtOAc/hexane) to give bis(benzyl) ether 15 (415.8 mg,
25
76%) as a colorless oil: [a]D ˆ284.1 (c 0.18, benzene);
4.1.10. Iodide 18. To a solution of alcohol 17 (2.59 g,
5.33 mmol) in benzene (50 mL) were added imidazole
(547 mg, 8.04 mmol), PPh3 (2.10 g, 8.01 mmol), and I2
(1.76 g, 6.93 mmol), and the resulting mixture was stirred
at room temperature for 25 min. The reaction was quenched
with saturated aqueous Na2SO3, and the resulting mixture
IR (®lm) 3031, 2868, 1496, 1454, 1363, 1096, 1027, 748,
1
697 cm21; H NMR (500 MHz, CDCl3) d 7.47±7.46 (m,
2H), 7.35±7.24 (m, 13H), 5.48 (s, 1H), 4.62 (d, 1H,
Jˆ11.6 Hz), 4.52 (d, 1H, Jˆ12.1 Hz), 4.46 (d, 1H,
Jˆ11.6 Hz), 4.45 (d, 1H, Jˆ12.1 Hz), 4.23 (dd, 1H,

3028
H. Fuwa et al. / Tetrahedron 57 ꢀ2001)3019±3033
was diluted with EtOAc, washed with brine, dried over
Na2SO4, and concentrated. The residue was puri®ed by
column chromatography (silica gel, 5% EtOAc/hexane) to
product 19 (419.6 mg, 97%) as
a
colorless oil:
28
[a]D ˆ122.1 (c 0.56, benzene); IR (®lm) 2928, 2856,
1683, 1455, 1362, 1254, 1092, 837, 748, 697 cm21; H
1
give iodide 18 (3.01 g, 95%) as
a
colorless oil:
[a]D ˆ215.6 (c 0.12, benzene); IR (®lm) 2927, 2856,
1455, 1362, 1254, 1092, 837, 776, 741, 697 cm21 1H
NMR (500 MHz, C6D6) d 7.65±7.63 (m, 2H), 7.36±7.35
(m, 2H), 7.25±7.23 (m, 2H), 7.20±7.06 (m, 9H), 5.35 (s,
1H), 4.98 (dd, 1H, Jˆ7.9, 4.0 Hz), 4.49 (d, 1H, Jˆ11.9 Hz),
4.46 (d, 1H, Jˆ11.9 Hz), 4.41 (d, 1H, Jˆ11.6 Hz), 4.36 (dd,
1H, Jˆ8.9, 3.4 Hz), 4.28 (d, 1H, Jˆ11.6 Hz), 3.76±3.72 (m,
2H), 3.66±3.59 (m, 2H), 3.58±3.49 (m, 2H), 3.42 (ddd, 1H,
Jˆ9.8, 8.9, ,1 Hz), 3.30 (ddd, 1H, Jˆ11.0, 8.9, 4.6 Hz),
3.14 (ddd, 1H, Jˆ11.0, 9.2, 4.6 Hz), 2.73 (dd, 1H, Jˆ14.7,
,1 Hz), 2.48 (m, 1H), 2.40 (ddd, 1H, Jˆ11.9, 4.6, 4.6 Hz),
2.13±1.96 (m, 3H), 1.90 (m, 1H), 1.80 (m, 1H), 1.61±1.48
(m, 2H), 0.94 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H); 13C NMR
(125 MHz, C6D6) d 157.5, 139.6, 139.1, 138.9, 128.8,
128.52, 128.50, 128.3, 128.2, 127.9, 127.7, 127.5, 126.8,
109.4, 101.1, 82.9, 80.2, 77.7, 76.9, 75.1, 73.2, 71.0, 70.9,
69.5, 67.2, 40.1, 38.4, 33.1, 32.6, 25.9, 21.4, 18.1, 23.8,
24.6; HRMS calcd for C42H56O7SiNa [(M1Na)1]
723.3693, found 723.3694.
28
;
NMR (500 MHz, CDCl3) d 7.35±7.24 (m, 10H), 4.58±
4.45 (m, 4H), 3.69±3.64 (m, 2H), 3.44 (dd, 1H, Jˆ10.4,
2.8 Hz), 3.39 (ddd, 1H, Jˆ9.5, 9.5, 2.4 Hz), 3.33 (ddd,
1H, Jˆ11.0, 8.5, 4.6 Hz), 3.18±3.12 (m, 2H), 2.91 (ddd,
1H, Jˆ8.9, 7.3, 2.8 Hz), 2.33 (ddd, 1H, Jˆ11.9, 4.6,
4.6 Hz), 2.25 (m, 1H), 1.65 (m, 1H), 1.45 (ddd, 1H,
Jˆ11.9, 11.0, 11.0 Hz), 0.85 (s, 9H), 0.06 (s, 3H), 0.04 (s,
3H); 13C NMR (125 MHz, CDCl3) d 133.8, 133.7, 128.7,
128.5, 128.4, 128.3, 127.80, 127.77, 127.75, 127.4, 80.3,
77.6, 76.4, 73.0, 71.3, 70.3, 66.7, 39.0, 32.1, 25.7, 8.1,
24.0, 24.5; HRMS calcd for C28H41IO4SiNa [(M1Na)1]
619.1717, found 619.1730.
4.1.11. exo-Ole®n 6. To a solution of iodide 18 (2.95 g,
4.95 mmol) in THF (50 mL) at 08C was added KOt-Bu
(2.78 g, 24.8 mmol), and the resulting solution was stirred
at 08C for 3 h. The reaction mixture was diluted with
EtOAc, washed with water and brine, dried over Na2SO4,
and concentrated. The residue was puri®ed by column chro-
matography (silica gel, 5% EtOAc/hexane containing 2%
Et3N) to give exo-ole®n 6 (2.22 g, 96%) as a colorless oil:
4.1.13. Alcohol 21. To a solution of coupling product 19
(419.6 mg, 0.5994 mmol) in THF (6 mL) at 2308C was
added BH3´THF (1.08 M solution in THF, 2.78 mL,
2.57 mmol), and the resulting solution was stirred at
2308C overnight. The reaction was quenched with water
(1 mL), and the resulting mixture was treated with 3 M
aqueous NaOH (3 mL) and 30% H2O2 (2 mL) and stirred
at room temperature for 1 h and then at 408C for 0.5 h. After
being cooled to room temperature, the reaction mixture was
diluted with EtOAc, washed with saturated aqueous Na2SO3
and brine, dried over Na2SO4, and concentrated. The residue
was puri®ed by column chromatography (silica gel,
10!30% EtOAc/hexane) to give alcohol 21 (329.9 mg,
77%) and its isomer (41.4 mg, 10%) as colorless oils. 21:
27
[a]D ˆ285.8 (c 0.24, benzene); IR (®lm) 2928, 2857,
1661, 1455, 1362, 1254, 1221, 1133, 1095, 1005, 864,
1
837, 776, 746, 697 cm21; H NMR (500 MHz, C6D6) d
7.30±7.29 (m, 2H), 7.20±7.07 (m, 8H), 4.81 (d, 1H,
Jˆ1.6 Hz), 4.78 (d, 1H, Jˆ1.6 Hz), 4.40 (d, 1H, Jˆ
12.2 Hz), 4.35 (d, 1H, Jˆ11.8 Hz), 4.33 (d, 1H, Jˆ
12.2 Hz), 4.20 (d, 1H, Jˆ11.8 Hz), 4.05 (m, 1H), 3.82
(ddd, 1H, Jˆ9.0, 9.0, 2.7 Hz), 3.72±3.69 (m, 2H), 3.28
(ddd, 1H, Jˆ10.5, 9.5, 4.6 Hz), 2.45±2.34 (m, 2H), 1.89
(m, 1H), 1.70 (ddd, 1H, Jˆ11.3, 11.1, 11.1 Hz), 0.96 (s,
9H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 161.9, 138.7, 138.1, 128.4, 128.3, 127.82,
127.76, 127.6, 127.5, 92.1, 79.8, 75.6, 73.0, 71.0, 66.8,
66.6, 39.2, 32.4, 25.8, 18.2, 24.9 (2C); HRMS calcd for
C28H40O4SiNa [(M1Na)1] 491.2594, found 491.2573.
28
[a]D ˆ29.92 (c 0.24, benzene); IR (®lm) 3446, 2929,
2856, 1614, 1513, 1456, 1362, 1288, 1249, 1100, 1031,
1
836, 747, 698 cm21; H NMR (500 MHz, C6D6) d 7.66±
7.65 (m, 2H), 7.34±7.33 (m, 2H), 7.24±7.23 (m, 2H),
7.19±7.09 (m, 9H), 5.33 (s, 1H), 4.42±4.39 (m, 2H),
4.27±4.24 (m, 2H), 3.78±3.74 (m, 2H), 3.69 (ddd, 1H,
Jˆ5.3, 5.3, 3.8 Hz), 3.62±3.46 (m, 5H), 3.42±3.28 (m,
3H), 3.06 (ddd, 1H, Jˆ11.0, 9.3, 4.4 Hz), 2.42±2.37 (m,
2H), 2.09 (m, 1H), 1.98±1.72 (m, 4H), 1.67±1.60 (m,
2H), 1.56±1.48 (m, 2H), 0.95 (s, 9H), 0.03 (s, 3H), 0.02
(s, 3H); 13C NMR (125 MHz, C6D6) d 139.2, 139.1,
139.0, 128.9, 128.8, 128.5, 128.42, 128.37, 128.23,
128.18, 128.0, 127.1, 101.2, 83.9, 82.1, 79.0, 78.1, 76.7,
75.5, 73.3, 73.0, 71.1, 70.6, 70.2, 66.8, 40.1, 37.0, 32.6,
28.7, 27.5, 25.9, 18.1, 23.8, 24.6; HRMS calcd for
C42H58O8SiNa [(M1Na)1] 741.3799, found 741.3770.
4.1.12. Coupling product 19. exo-Ole®n 6 (288.6 mg,
0.6167 mmol) was treated with 9-BBN (0.5 M solution in
THF, 3.21 mL, 3.21 mmol) and the resulting solution was
stirred at room temperature for 3 h. The solution was treated
with 1 M aqueous NaHCO3 (1.85 mL, 1.85 mmol) and the
resultant mixture was stirred at room temperature for
15 min. The mixture was then treated with a solution of
cyclic ketene acetal phosphate 7 (358.7 mg, 0.7473 mmol)
in DMF (6 mL) and PdCl2(dppf)´CH2Cl2 (50.4 mg,
0.0617 mmol). After being stirred at room temperature for
24 h, the reaction mixture was diluted with ether, washed
with brine, dried over Na2SO4, and concentrated. The resi-
due was dissolved in THF (20 mL) and cooled to 08C. The
resultant solution was treated with 3 M aqueous NaOH
(1 mL) and 30% H2O2 (800 mL) and stirred at room
temperature for 30 min. The reaction mixture was diluted
with EtOAc, washed with saturated aqueous Na2SO3 and
brine, dried over Na2SO4, and concentrated. The residue
was puri®ed by column chromatography (silica gel, 5%
EtOAc/hexane containing 2% Et3N) to give coupling
28
Isomer. [a]D ˆ131.4 (c 0.69, benzene); IR (®lm): 3446,
2928, 2857, 1455, 1362, 1286, 1253, 1102, 1028, 837, 775,
748, 698 cm21; 1H NMR (500 MHz, C6D6) d 7.65±7.64 (m,
2H), 7.34±7.33 (m, 2H), 7.24±7.07 (m, 11H), 5.33 (s, 1H),
4.43±4.33 (m, 4H), 4.26 (d, 1H, Jˆ11.6 Hz), 3.82 (m, 1H),
3.70±3.63 (m, 2H), 3.57±3.34 (m, 6H), 3.26 (m, 1H), 3.12
(m, 1H), 2.45±2.34 (m, 2H), 2.26 (m, 1H), 2.07 (m, 1H),
1.95±1.67 (m, 4H), 1.60±1.45 (m, 3H), 0.96 (s, 9H), 0.06
(s, 3H), 0.02 (s, 3H); 13C NMR (125 MHz, C6D6) d
139.2, 139.1, 139.0, 128.8, 128.5, 128.3, 128.2, 127.90,
127.87, 127.7, 127.5, 126.8, 101.0, 81.2, 79.4, 79.3, 77.9,
76.9, 76.6, 73.1, 70.93, 70.86, 70.3, 67.2, 67.1, 39.9, 36.0,

H. Fuwa et al. / Tetrahedron 57 ꢀ2001)3019±3033
3029
32.8, 32.2, 31.6, 25.9, 18.0, 24.0, 24.5; MS m/z
[(M1Na)1] 741.
subjected to column chromatography (silica gel, 40%
EtOAc/hexane) to give ketone 24 (237.6 mg, 94%) as a
28
colorless oil: [a]D ˆ11.39 (c 0.35, benzene); IR (®lm)
4.1.14. PMB ether 22. To a suspension of KH (30% oil
dispersion, 319.0 mg, 2.393 mmol) in THF (5 mL) was
added dropwise a solution of alcohol 21 (318.6 mg,
0.4437 mmol) in THF (5 mL) and the mixture was stirred
at room temperature for 20 min. The mixture was treated
with PMBCl (120 mL, 0.885 mmol) and a catalytic amount
of n-Bu4NI, and stirred at room temperature for 1.5 h. The
reaction was quenched with MeOH at 08C and the mixture
was diluted with ether, washed with water and brine, dried
over Na2SO4, and concentrated. The residue was puri®ed by
column chromatography (silica gel, 10% EtOAc/hexane) to
give PMB ether 22 (325.4 mg, 88%) as a colorless oil:
2931, 2862, 1733, 1611, 1513, 1454, 1364, 1289, 1249,
1099, 1029, 822, 739, 699 cm21 1H NMR (500 MHz,
;
C6D6) d 7.68±7.66 (m, 2H), 7.29±7.27 (m, 2H), 7.19±
7.06 (m, 13H), 6.78±6.76 (m, 2H), 5.38 (s, 1H), 4.34±
4.28 (m, 3H), 4.26 (d, 1H, Jˆ11.9 Hz), 4.20±4.15 (m,
2H), 4.12 (d, 1H, Jˆ11.6 Hz), 4.08 (d, 1H, Jˆ11.9 Hz),
3.87±3.78 (m, 3H), 3.54±3.35 (m, 6H), 3.29 (s, 3H), 2.64
(dd, 1H, Jˆ15.0, 4.3 Hz), 2.37 (dd, 1H, Jˆ15.0, 5.5 Hz),
2.23 (m, 1H), 2.05±1.85 (m, 4H), 1.80±1.65 (m, 2H), 1.52
(m, 1H); 13C NMR (125 MHz, C6D6) d 207.4, 159.7,
139.1(£2), 138.3, 130.8, 129.3, 128.7, 128.61, 128.58,
128.53, 128.3, 128.2, 127.9, 127.8, 127.7, 126.9, 114.1,
101.2, 82.0, 80.44, 80.42, 78.7, 77.8, 77.5, 73.4, 73.1,
70.5, 70.2, 70.0, 66.6, 54.7, 41.2, 35.9, 34.2, 26.6, 22.5;
HRMS calcd for C44H50O9Na [(M1Na)1] 745.3353,
found 745.3362.
28
[a]D ˆ28.33 (c 0.43, benzene); IR (®lm) 2927, 2856,
1541, 1456, 1358, 1251, 1098, 1027, 837, 747, 697 cm21
;
1H NMR (500 MHz, C6D6) d 7.68±7.66 (m, 2H), 7.32±7.09
(m, 15H), 6.82±6.80 (m, 2H), 5.41 (s, 1H), 4.45±4.35 (m,
4H), 4.33±4.15 (m, 4H), 3.94 (ddd, 1H, Jˆ10.1, 9.8,
5.5 Hz), 3.73±3.64 (m, 3H), 3.58±3.43 (m, 3H), 3.34±
3.25 (m, 4H), 3.10±3.00 (m, 2H), 2.46 (m, 1H), 2.40±2.30
(m, 2H), 2.04±1.87 (m, 3H), 1.85±1.74 (m, 2H), 1.67 (m,
1H), 1.48 (ddd, 1H, Jˆ11.6, 11.0, 11.0 Hz), 0.94 (s, 9H),
0.01 (s, 3H), 0.00 (s, 3H); 13C NMR (125 MHz, C6D6) d
159.7, 139.4, 139.2, 139.1, 130.8, 129.6, 128.7, 128.3,
128.2, 127.93, 127.85, 127.78, 127.6, 126.9, 114.2, 101.2,
82.0, 81.5, 79.5, 79.0, 77.8, 76.7, 73.12, 73.07, 71.1, 70.5,
70.2, 70.0, 67.2, 54.8, 40.1, 37.5, 33.0, 26.6, 25.9, 21.9,
18.0, 23.8, 24.6; HRMS calcd for C50H66O9SiNa
[(M1Na)1] 861.4374, found 861.4365.
4.1.17. Mixed methyl ketal 30. To a solution of ketone 24
(47.2 mg, 0.0654 mmol) in CH2Cl2±pH 7 buffer (9:1, 1 mL)
at 08C was added DDQ (27.4 mg, 0.121 mmol). After
being stirred at room temperature for 40 min, the
reaction mixture was cooled to 08C and quenched with
saturated aqueous NaHCO3. The reaction mixture was
diluted with EtOAc, washed with saturated aqueous
NaHCO3, brine, dried over Na2SO4, and concentrated. The
crude hemiketal 29 thus obtained was used without further
puri®cation.
To a solution of the crude 29 in MeOH±CHCl3 (2:1,
1.5 mL) was added a small crystal of p-TsOH´H2O. After
being stirred at room temperature overnight, the reaction
was quenched with Et3N. The resulting mixture was concen-
trated and puri®ed by column chromatography (silica gel,
5Ã10% MeOH/CHCl3) to give dihydroxy mixed methyl
ketal (28.2 mg, 82%) as a colorless foam.
4.1.15. Alcohol 23. To a solution of PMB ether 22
(298.9 mg, 0.3567 mmol) in THF (5 mL) was added
TBAF (1.0 M solution in THF, 1.07 mL, 1.07 mmol), and
the mixture was stirred at room temperature for 1.5 h. The
reaction mixture was concentrated and the residue was puri-
®ed by column chromatography (silica gel, 60% EtOAc/
hexane) to give alcohol 23 (261.0 mg, quant.) as a colorless
28
oil: [a]D ˆ235.6 (c 0.33, benzene); IR (®lm) 3446, 2927,
To a solution of the above diol (26.8 mg, 0.0508 mmol) in
CH2Cl2 (1 mL) at 08C were added DMAP (62.2 mg,
0.509 mmol) and Ac2O (25 mL, 0.26 mmol). After being
stirred at 08C for 30 min, the reaction was quenched with
MeOH. The reaction mixture was diluted with EtOAc,
washed with 1 M aqueous HCl, saturated aqueous
NaHCO3 and brine, dried over Na2SO4, and concentrated.
The residue was puri®ed by column chromatography (silica
gel, 40% EtOAc/hexane) gave mixed methyl ketal 30
(29.5 mg, 97%) as a colorless clear oil: 1H NMR
(500 MHz, C6D6) d 7.32±7.30 (m, 2H), 7.22±7.06 (m,
8H), 5.08 (m, 1H), 4.43±4.34 (m, 3H), 4.27 (d, 1H,
Jˆ11.9 Hz), 4.18 (dd, 1H, Jˆ11.6 6.7 Hz), 4.06 (dd, 1H,
Jˆ11.6, 4.9 Hz), 3.80±3.59 (m, 4H), 3.41 (ddd, 1H,
Jˆ11.0, 9.8, 4.3 Hz), 3.32 (ddd, 1H, Jˆ12.8, 11.9,
4.6 Hz), 3.13 (ddd, 1H, Jˆ11.3, 11.0, 4.9 Hz), 3.04 (dd,
1H, Jˆ12.2, 4.0 Hz), 2.92 (s, 3H), 2.55 (dd, 1H, Jˆ12.8,
4.6 Hz), 2.47 (m, 1H), 2.26 (ddd, 1H, Jˆ12.2, 11.6,
11.3 Hz), 2.03 (m, 1H), 1.90±1.55 (m, 11H), 1.35 (dd,
1H, Jˆ12.8, 11.9 Hz); 13C NMR (C6D6, 125 MHz) d
170.0, 169.3, 139.5, 138.8, 128.53, 128.46, 128.3, 128.2,
127.9, 127.8, 127.5, 95.6, 81.6, 80.5, 78.5, 77.7, 75.5,
73.5, 73.3, 72.9, 71.2, 66.9, 65.1, 46.8, 35.0, 32.7, 31.9,
27.0, 25.2, 20.6, 20.3; MS (FAB) m/z 596 [(M1Na)1].
2863, 1614, 1512, 1456, 1248, 1098, 1027, 820, 748,
1
698 cm21; H NMR (500 MHz, C6D6) d 7.68±7.66 (m,
2H), 7.31±7.08 (m, 15H), 6.82±6.80 (m, 2H), 5.36 (s,
1H), 4.42 (d, 1H, Jˆ11.9 Hz), 4.40±4.37 (m, 2H), 4.34 (d,
1H, Jˆ11.9 Hz), 4.27±4.20 (m, 2H), 4.16 (d, 1H,
Jˆ11.6 Hz), 4.12 (m, 1H), 3.81 (ddd, 1H, Jˆ9.8, 9.5,
5.2 Hz), 3.72±3.63 (m, 2H), 3.54±3.43 (m, 3H), 3.38
(ddd, 1H, Jˆ11.0, 9.2, 5.2 Hz), 3.30 (s, 3H), 3.19 (m,
1H), 3.11±3.02 (m, 2H), 2.45 (m, 1H), 2.39 (ddd, 1H,
Jˆ11.6, 4.0, 4.0 Hz), 1.95±1.70 (m, 6H), 1.54 (m, 1H),
1.37 (ddd, 1H, Jˆ11.6, 11.3, 11.3 Hz); 13C NMR
(125 MHz, C6D6) d 159.8, 139.4, 139.05, 138.98, 130.8,
129.4, 128.8, 128.6, 128.53, 128.49, 128.3, 128.2, 127.9,
127.8, 127.7, 127.5, 126.9, 114.2, 101.2, 82.0, 81.3, 80.4,
79.3, 77.9, 76.8, 74.0, 73.0, 70.7, 70.2, 69.9, 69.3, 67.1,
54.8, 38.7, 38.1, 32.9, 26.7, 22.9; HRMS calcd for
C44H52O9Na [(M1Na)1] 747.3509, found 747.3509.
4.1.16. Ketone 24. To a solution of alcohol 23 (252.8 mg,
Ê
0.3492 mmol) in CH2Cl2 (5 mL) were added 4 A molecular
sieves (211.0 mg), NMO (81.6 mg, 0.697 mmol) and a cata-
lytic amount of TPAP, and the resulting mixture was stirred
at room temperature for 70 min. The mixture was directly

3030
H. Fuwa et al. / Tetrahedron 57 ꢀ2001)3019±3033
4.1.18. Mixed thioketal 31. To a solution of ketone 24
(929.6 mg, 1.286 mmol) in CH2Cl2±pH 7 phosphate buffer
(9:1, 30 mL) at 08C was added DDQ (525.7 mg,
2.316 mmol), and the resulting mixture was stirred at
room temperature for 40 min. The reaction was quenched
with saturated aqueous NaHCO3 at 08C, and the mixture was
diluted with water and extracted with EtOAc (£2). The
organic layer was dried over Na2SO4 and concentrated to
give crude hemiketal 29, which was used in the next
reaction without further puri®cation.
71.6, 66.8, 65.1, 41.3, 33.3, 32.9, 27.0, 25.0, 20.6, 20.3,
20.1, 14.9.
4.1.20. Tricyclic ether 28. To a solution of the above sul-
fone 32 (50.6 mg, 0.0738 mmol) in CH2Cl2 (3.7 mL) at
2788C was added Me3Al (1.0 M solution in hexane,
365 mL, 0.365 mmol), and the resulting mixture was
allowed to warm gradually to room temperature over a
period of 5 h. The reaction was quenched by the addition
of saturated aqueous potassium sodium tartrate, and the
reaction mixture was diluted with EtOAc, washed with satu-
rated aqueous potassium sodium tartrate and brine, dried
over Na2SO4 and concentrated. The residue was puri®ed
by column chromatography (silica gel, 40% EtOAc/hexane)
to give tricyclic ether 28 (39.5 mg, 90%) as a colorless oil:
To a solution of the above crude 29 in CH2Cl2 (30 mL) were
added solid NaHCO3 (109.2 mg, 1.300 mmol), EtSH
(1.91 mL, 25.8 mmol) and Zn(OTf)2 (140.5 mg,
0.3865 mmol). After being stirred at room temperature
overnight, the mixture was treated with Et3N (7.18 mL,
51.5 mmol), DMAP (786.2 mg, 6.435 mmol) and Ac2O
(3.64 mL, 38.6 mmol), and the resulting mixture was stirred
at room temperature for 4 h. The reaction was quenched
with MeOH at 08C, and the mixture was diluted with
EtOAc, washed with 1 M aqueous HCl, saturated aqueous
NaHCO3 and brine, dried over Na2SO4 and concentrated.
The residue was puri®ed by column chromatography (silica
gel, 40% EtOAc/hexane) to give mixed thioketal 31
(723.1 mg, 88% for three steps) as a colorless oil:
28
[a]D ˆ225.2 (c 0.19, benzene); IR (®lm) 3062, 3031,
2945, 2871, 1740, 1496, 1455, 1370, 1236, 1096, 1052,
1
804, 738, 699 cm21; H NMR (500 MHz, C6D6) d 7.31±
7.30 (m, 2H), 7.22±7.21 (m, 2H), 7.17±7.05 (m, 6H), 5.09
(m, 1H), 4.42±4.35 (m, 3H), 4.21±4.15 (m, 2H), 4.06 (dd,
1H, Jˆ11.6, 4.9 Hz), 3.74±3.69 (m, 2H), 3.65 (m, 1H), 3.57
(m, 1H), 3.36 (ddd, 1H, Jˆ9.8, 9.5, 4.9 Hz), 3.27 (ddd, 1H,
Jˆ10.7, 10.7, 4.9 Hz), 3.09 (ddd, 1H, Jˆ11.3, 9.8, 4.9 Hz),
2.95 (dd, 1H, Jˆ12.5, 3.7 Hz), 2.42 (m, 1H), 2.32 (dd, 1H,
Jˆ11.6, 4.9 Hz), 2.05 (m, 1H), 1.85±1.53 (m, 13H), 1.08 (s,
3H); 13C NMR (125 MHz, C6D6) d 169.9, 169.3, 139.4,
138.9, 128.54, 128.51, 128.49, 128.3, 128.0, 127.8, 127.7,
127.5, 81.6, 81.1, 79.3, 78.8, 76.7, 73.7, 73.6, 73.0, 72.4,
70.9, 67.0, 65.1, 43.9, 33.1, 32.9, 27.7, 25.1, 20.6, 20.3,
15.9; HRMS calcd for C34H44O9Na [(M1Na)1] 619.2883,
found 619.2899.
28
[a]D ˆ154.0 (c 0.15, benzene); IR (®lm) 2927, 2868,
1740, 1455, 1370, 1237, 1100, 1068, 1036, 743,
1
699 cm21; H NMR (500 MHz, C6D6) d 7.32±7.31 (m,
2H), 7.24±7.23 (m, 2H), 7.17±7.07 (m, 6H), 5.08 (m,
1H), 4.44±4.38 (m, 2H), 4.36 (d, 1H, Jˆ11.9 Hz), 4.33 (d,
1H, Jˆ11.9 Hz), 4.17 (dd, 1H, Jˆ11.6, 6.4 Hz), 4.07±3.96
(m, 3H), 3.79±3.70 (m, 2H), 3.70±3.62 (m, 2H), 3.14 (m,
1H), 3.06 (m, 1H), 2.63 (dd, 1H, Jˆ12.5, 4.6 Hz), 2.44 (m,
1H), 2.35±2.17 (m, 3H), 2.02 (m, 1H), 1.97±1.53 (m, 12H),
1.09 (t, 3H, Jˆ7.6 Hz); 13C NMR (125 MHz, C6D6) d 170.0,
169.3, 139.5, 139.0, 128.54, 128.47, 128.40, 128.3, 128.1,
127.9, 127.5, 87.5, 81.6, 80.5, 79.7, 79.5, 76.7, 73.6, 73.5,
73.0, 71.6, 66.8, 65.1, 41.3, 33.3, 32.9, 27.0, 25.0, 20.6,
20.3, 20.1, 14.9; HRMS calcd for C35H46O9SNa
[(M1Na)1] 665.2760, found 665.2763.
4.1.21. Acetonide 5. To a solution of tricyclic ether 28
(39.5 mg, 0.0663 mmol) in MeOH±CH2Cl2 (1:1, 4 mL)
was added NaOMe (1 M solution in MeOH, 20 mL,
0.020 mmol), and the resulting mixture was stirred at
room temperature for 35 min. The reaction was quenched
by the addition of Amberlyst ion-exchange resin. Filtration
of the resin followed by concentration gave crude diol,
which was used in the next reaction without further
puri®cation.
4.1.19. Sulfone 32. To a solution of mixed thioketal 31
(628.6 mg, 0.9791 mmol) in CH2Cl2 (25 mL) were added
solid NaHCO3 (404.0 mg, 4.809 mmol) and m-CPBA
(80% purity, 518.8 mg, 2.405 mmol), and the resulting
mixture was stirred at room temperature for 75 min. The
mixture was diluted with EtOAc, washed with saturated
aqueous Na2SO3 and brine, dried over Na2SO4 and concen-
trated. The residue was puri®ed by column chromatography
(silica gel, 50% EtOAc/hexane) to give sulfone 32
(640.4 mg, 96%) as a colorless oil, which was used in the
next reaction without further puri®cation: 1H NMR
(500 MHz, C6D6) d 7.33±7.31 (m, 2H), 7.25±7.23 (m,
2H), 7.18±7.05 (m, 6H), 5.08 (m, 1H), 4.44±4.39 (m,
2H), 4.37 (d, 1H, Jˆ12.2 Hz), 4.34 (d, 1H, Jˆ11.6 Hz),
4.17 (dd, 1H, Jˆ11.6, 6.4 Hz), 4.08±3.97 (m, 3H), 3.79±
3.71 (m, 2H), 3.70±3.63 (m, 2H), 3.14 (ddd, 1H, Jˆ11.3,
9.8, 4.9 Hz), 3.06 (ddd, 1H, Jˆ12.5, 4.0 Hz), 2.67 (dd, 1H,
Jˆ12.5, 4.9 Hz), 2.43 (m, 1H), 2.34±2.19 (m, 3H), 2.02
(ddd, 1H, Jˆ11.6, 4.3, 4.0 Hz), 1.97±1.55 (m, 12H), 1.09
(t, 3H, Jˆ7.6 Hz); 13C NMR (125 MHz, C6D6) d 170.0,
169.3, 139.5, 139.0, 128.53, 128.46, 128.3, 128.2, 127.8,
127.5, 87.5, 81.6, 80.5, 79.7, 79.5, 76.7, 73.6, 73.5, 73.0,
A solution of the above crude diol in CH2Cl2±DMF (2:3,
5 mL) was treated with Me2C(OMe)2 (324 mL, 2.64 mmol)
and a catalytic amount of PPTS, and the resulting mixture
was stirred at room temperature overnight. The mixture was
diluted with ether, washed with saturated aqueous NaHCO3
and brine, dried over Na2SO4 and concentrated. The residue
was puri®ed by column chromatography (silica gel, 30%
EtOAc/hexane) to give acetonide 5 (35.8 mg, 98% for two
28
steps) as a colorless oil: [a]D ˆ232.7 (c 0.87, benzene); IR
(®lm) 2990, 2942, 2873, 1455, 1371, 1268, 1200, 1094,
1
1029, 737, 698 cm21; H NMR (500 MHz, C6D6) d 7.31±
7.29 (m, 2H), 7.24±7.22 (m, 2H), 7.15±7.06 (m, 6H), 4.43±
4.33 (m, 3H), 4.18 (d, 1H, Jˆ11.6 Hz), 3.93 (dd, 1H,
Jˆ11.3, 5.5 Hz), 3.75±3.57 (m, 5H), 3.44 (m, 1H), 3.32±
3.24 (m, 2H), 2.98 (dd, 1H, Jˆ12.8, 4.0 Hz), 2.92 (ddd, 1H,
Jˆ11.0, 9.2, 4.0 Hz), 2.42 (m, 1H), 2.31 (dd, 1H, Jˆ11.3,
4.9 Hz), 2.04 (ddd, 1H, Jˆ11.6, 4.3, 4.3 Hz), 2.03±1.90 (m,
2H), 1.85±1.74 (m, 3H), 1.69 (ddd, 1H, Jˆ12.2, 11.9,
11.6 Hz), 1.57 (dd, 1H, Jˆ11.9, 11.3 Hz), 1.47 (s, 3H),
1.29 (s, 3H), 1.09 (s, 3H); 13C NMR (125 MHz, C6D6) d
139.4, 139.0, 128.52, 128.49, 128.0, 127.8, 127.7, 127.5,

H. Fuwa et al. / Tetrahedron 57 ꢀ2001)3019±3033
3031
98.5, 80.9, 79.3, 78.7, 76.8, 75.8, 73.5, 73.2, 73.0, 72.2,
70.9, 67.0, 63.5, 44.0, 33.2, 32.6, 30.2, 29.8, 28.9, 19.4,
15.7; HRMS calcd for C33H44O7Na [(M1Na)1] 575.2985,
found 575.3016.
1.30 mmol) and the resulting ylide solution was stirred at
08C for 20 min. To the solution cooled to 2788C was added
a solution of ketone 34b (120.8 mg, 0.2297 mmol) in THF
(7 mL), and the mixture was allowed to warm gradually to
room temperature over a period of 3.5 h. The reaction was
quenched with saturated aqueous NH4Cl, and the mixture
was diluted with EtOAc, washed with water and brine, dried
over Na2SO4 and concentrated. The residue was puri®ed by
column chromatography (silica gel, 10% EtOAc/hexane) to
4.1.22. Alcohol 33b. To a solution of acetonide 5
(217.5 mg, 0.3940 mmol) in EtOAc (10 mL) was added
20% Pd(OH)2/C (72.2 mg), and the resulting mixture was
stirred under hydrogen atmosphere overnight. The catalyst
was ®ltered off, and the ®ltrate was concentrated to give
crude diol, which was used in the next reaction without
further puri®cation.To a solution of the above crude diol
in CH2Cl2 (10 mL) were added imidazole (65.6 mg,
0.964 mmol) and TIPSCl (100 mL, 0.467 mmol), and the
resulting mixture was stirred at room temperature for 4 h.
Additional imidazole (85.3 mg, 1.25 mmol) and TIPSCl
(150 mL, 0.701 mmol) were added and the mixture was
stirred at room temperature for 18 h. The reaction mixture
was diluted with EtOAc, washed with 1 M aqueous HCl,
saturated aqueous NaHCO3 and brine, dried over Na2SO4,
and concentrated. The residue was puri®ed by column chro-
matography (silica gel, 35% EtOAc/hexane) to give alcohol
33b (185.5 mg, 89% for two steps) as a colorless oil:
1
give exo-ole®n 36 (110.8 mg, 92%) as a colorless oil: H
NMR (500 MHz, C6D6) d 4.78 (s, 1H), 4.68 (s, 1H), 4.11
(m, 1H), 4.03 (ddd, 1H, Jˆ9.8, 9.2, 4.9 Hz), 3.88 (dd, 1H,
Jˆ11.3, 5.5 Hz), 3.83 (ddd, 1H, Jˆ9.8, 6.4, 4.0 Hz), 3.71
(ddd, 1H, Jˆ9.2, 7.0, 6.7 Hz), 3.62 (dd, 1H, Jˆ11.3,
9.2 Hz), 3.44 (ddd, 1H, Jˆ8.9, 8.5, 4.0 Hz), 3.28±3.20 (m,
2H), 3.06 (ddd, 1H, Jˆ11.3, 8.9, 4.9 Hz), 2.43 (d, 1H,
Jˆ12.5 Hz), 2.35 (d, 1H, Jˆ12.5 Hz), 2.22 (ddd, 1H,
Jˆ11.9, 4.9, 4.0 Hz), 2.10 (m, 1H), 2.00±1.89 (m, 2H),
1.85±1.74 (m, 4H), 1.44 (s, 3H), 1.28 (s, 3H), 1.18±1.05
(m, 24H); 13C NMR (125 MHz, C6D6) d 145.9, 110.3, 98.4,
80.9, 79.1, 75.7, 74.3, 73.3, 73.2, 63.5, 59.9, 48.7, 35.2,
33.1, 30.4, 30.3, 29.8, 28.8, 19.5, 18.3, 15.1, 12.3.
27
[a]D ˆ27.91 (c 0.29, benzene); IR (®lm) 3445, 2943,
4.1.25. Diol 39. To a solution of exo-ole®n 36 (49.4 mg,
0.0943 mmol) in t-BuOH±H2O (1:1, 5 mL) were added
NMO (110.5 mg, 0.9432 mmol) and OsO4 (71.1 mg,
0.280 mmol), and the resulting mixture was stirred at
room temperature for 1.5 days. To the mixture were added
saturated aqueous NaHSO3 (10 mL) and pyridine (3 mL),
and the resultant mixture was stirred at room temperature
for 1 h. The mixture was diluted with EtOAc, washed with
water and brine, dried over Na2SO4, and concentrated. The
residue was puri®ed by column chromatography (silica gel,
50% EtOAc/hexane) to give diol 39 (50.7 mg, 96%) as a
2867, 1462, 1380, 1268, 1093, 1052, 882, 747, 682 cm21
;
1H NMR (500 MHz, C6D6) d 3.89 (dd, 1H, Jˆ11.3, 5.8 Hz),
3.86±3.75 (m, 2H), 3.70 (m, 1H), 3.62 (dd, 1H, Jˆ11.3,
8.9 Hz), 3.52±3.42 (m, 2H), 3.34 (m, 1H), 3.25 (ddd, 1H,
Jˆ9.2, 8.9, 5.8 Hz), 3.08 (dd, 1H, Jˆ12.8, 4.0 Hz), 3.01
(ddd, 1H, Jˆ11.0, 9.2, 4.9 Hz), 2.57 (br, 1H), 2.25 (dd,
1H, Jˆ11.6, 4.9 Hz), 2.17 (ddd, 1H, Jˆ11.9, 4.9, 4.0 Hz),
2.08 (m, 1H), 1.98±1.88 (m, 2H), 1.83±1.72 (m, 4H), 1.64
(dd, 1H, Jˆ11.6, 11.3 Hz), 1.44 (s, 3H), 1.28 (s, 3H), 1.16±
1.00 (m, 24H); 13C NMR (125 MHz, C6D6) d 98.5, 82.3,
80.9, 78.9, 75.8, 73.5, 73.2, 72.3, 69.9, 63.5, 60.7, 47.1,
37.4, 32.8, 30.2, 29.8, 28.8, 19.5, 18.1, 15.7, 12.2; HRMS
calcd for C28H52O7SiNa [(M1Na)1] 551.3380, found
551.3355.
28
colorless oil: [a]D ˆ219.1 (c 0.32, CHCl3); IR (®lm)
3438, 2943, 2867, 1462, 1381, 1268, 1200, 1095, 1067,
1
922, 882, 749, 682, 516 cm21; H NMR (500 MHz, C6D6)
d 3.93±3.81 (m, 3H), 3.70 (m, 1H), 3.67±3.56 (m, 3H),
3.49±3.42 (m, 2H), 3.24 (ddd, 1H, Jˆ9.2, 8.9, 5.5 Hz),
3.10 (dd, 1H, Jˆ12.8, 4.0 Hz), 3.02 (ddd, 1H, Jˆ10.7,
9.2, 5.2 Hz), 2.50 (d, 1H, Jˆ12.8 Hz), 2.16 (ddd, 1H,
Jˆ11.6, 5.2, 4.0 Hz), 2.08 (m, 1H), 1.99±1.87 (m, 2H),
1.81±1.69 (m, 3H), 1.63 (d, 1H, Jˆ12.8 Hz), 1.56 (m,
1H), 1.45 (s, 3H), 1.29 (s, 3H), 1.18 (s, 3H), 1.15±1.05
(m, 21H); 13C NMR (125 MHz, C6D6) d 98.5, 83.7, 81.0,
80.7, 76.0, 73.3, 73.1, 72.1, 71.9, 65.2, 63.5, 61.0, 48.0,
32.44, 32.39, 30.1, 29.8, 28.8, 19.5, 18.2, 15.3, 12.3;
HRMS calcd for C29H54O8SiNa [(M1Na)1] 581.3486,
found 581.3491.
4.1.23. Ketone 34b. To a solution of alcohol 33b (185.5 mg,
Ê
0.3513 mmol) in CH2Cl2 (10 mL) were added 4 A molecu-
lar sieves (167.7 mg), NMO (88.5 mg, 0.755 mmol) and a
catalytic amount of TPAP. The resulting mixture was stirred
at room temperature for 30 min and directly subjected to
column chromatography (silica gel, EtOAc) to give ketone
27
34b (183.5 mg, 99%) as a colorless oil: [a]D ˆ22.70 (c
0.11, benzene); IR (®lm) 2943, 2867, 1718, 1558, 1541,
1
1507, 1457, 1375, 1267, 1095, 881, 747, 682 cm21; H
NMR (500 MHz, C6D6) d 3.98 (dd, 1H, Jˆ8.9, 3.7 Hz),
3.92±3.85 (m, 2H), 3.77 (m, 1H), 3.67 (ddd, 1H, Jˆ9.2,
6.7, 6.7 Hz), 3.61 (dd, 1H, Jˆ11.3, 9.2 Hz), 3.28±3.20 (m,
3H), 2.94 (ddd, 1H, Jˆ11.3, 9.5, 4.9 Hz), 2.78 (d, 1H,
Jˆ15.0 Hz), 2.44 (m, 1H), 2.28 (d, 1H, Jˆ15.0 Hz), 2.18
(ddd, 1H, Jˆ11.9, 4.9, 4.6 Hz), 1.92 (m, 1H), 1.86±1.66 (m,
5H), 1.45 (s, 3H), 1.28 (s, 3H), 1.21±1.00 (m, 24H); 13C
NMR (125 MHz, C6D6) d 205.2, 98.5, 80.4, 80.3, 77.5, 75.8,
73.8, 73.4, 73.2, 63.5, 59.3, 54.4, 33.5, 32.7, 30.0, 29.7,
28.8, 19.4, 18.2, 16.1, 12.3; HRMS calcd for C28H50O7SiNa
[(M1Na)1] 549.3224, found 549.3227.
4.1.26. Monotosylate 40. To a solution of diol 39
(144.3 mg, 0.2586 mmol) in (CH2Cl)2 (10 mL) were added
DMAP (317.9 mg, 2.602 mmol) and p-TsCl (246.9 mg,
1.295 mmol), and the resulting mixture was stirred at
room temperature overnight. The mixture was diluted with
EtOAc, washed with 1 M aqueous HCl, saturated aqueous
NaHCO3 and brine, dried over Na2SO4, and concentrated.
The residue was puri®ed by column chromatography (silica
gel, 20!40% EtOAc/hexane) to give monotosylate 40
27
(182.4 mg, 99%) as a colorless oil: [a]D ˆ238.5 (c 0.07,
4.1.24. exo-Ole®n 36. To a suspension of Ph3P1CH3Br2
(493.5 mg, 1.382 mmol) in THF (10 mL) at 08C was
added NaHMDS (1.0 M solution in THF, 1.30 mL,
benzene); IR (®lm) 2943, 2867, 1457, 1369, 1267, 1177,
1096, 986, 882, 839, 750, 669, 553 cm21 1H NMR
;
(500 MHz, C6D6) d 7.75±7.73 (m, 2H), 6.66±6.64 (m,

3032
H. Fuwa et al. / Tetrahedron 57 ꢀ2001)3019±3033
2H), 4.37 (d, 1H, Jˆ10.7 Hz), 4.33 (d, 1H, Jˆ10.7 Hz), 3.88
(dd, 1H, Jˆ11.3, 5.8 Hz), 3.78 (ddd, 1H, Jˆ10.1, 10.1,
4.3 Hz), 3.72±3.59 (m, 4H), 3.40 (ddd, 1H, Jˆ8.9, 8.5,
4.3 Hz), 3.21 (ddd, 1H, Jˆ8.9, 8.9, 5.8 Hz), 3.04 (dd, 1H,
Jˆ12.8, 3.7 Hz), 2.96 (ddd, 1H, Jˆ10.9, 8.9, 4.9 Hz), 2.62
(d, 1H, Jˆ13.1 Hz), 2.51 (br, 1H), 2.09 (ddd, 1H, Jˆ11.3,
4.9, 3.7 Hz), 1.97±1.85 (m, 3H), 1.79 (s, 3H), 1.79±1.62 (m,
2H), 1.58 (d, 1H, Jˆ13.1 Hz), 1.44 (s, 3H), 1.33 (m, 1H),
1.28 (s, 3H), 1.18±0.97 (m, 24H); HRMS calcd for
C36H60O10SSiNa [(M1Na)1] 735.3574, found 735.3587.
(ddd, 1H, Jˆ11.0, 9.2, 5.2 Hz), 2.08 (d, 1H, Jˆ11.9 Hz),
2.03±1.74 (m, 8H), 1.48 (s, 3H), 1.31 (s, 3H), 1.12 (s, 3H),
1.09 (s, 3H); 13C NMR (125 MHz, C6D6) d 139.5, 128.5,
128.30, 128.26, 127.7, 127.6, 98.5, 85.9, 80.9, 80.3, 76.0,
74.9, 73.3, 73.1, 71.8, 63.53, 63.47, 61.6, 50.5, 32.2 (2C),
30.2, 29.9, 28.9, 21.1, 19.4, 15.9; HRMS calcd for C27H41O7
[(M1H)1] 477.2852, found 477.2896.
4.1.29. a,b-Unsaturated ester 42. To a mixture of alcohol
41 (82.9 mg, 0.174 mmol) and Et3N (120 mL, 0.861 mmol)
in CH2Cl2±DMSO (1:1, 5 mL) at 08C was added SO3´pyr-
idine (111.5 mg, 0.7006 mmol). The resulting mixture was
stirred at 08C for 1.5 h. The mixture was diluted with
EtOAc, and the organic layer was washed with 1 M aqueous
HCl, saturated aqueous NaHCO3 and brine, dried over
Na2SO4, and concentrated to give crude aldehyde, which
was used in the next reaction without further puri®cation.
4.1.27. FGH ring system 4. To a solution of monotosylate
40 (41.6 mg, 0.0584 mmol) in THF (4 mL) at 08C was
added LiAlH4 (22.5 mg, 0.593 mmol). The resulting
mixture was stirred at 08C for 1 h and then allowed to
warm to room temperature for 2 h. The reaction was
quenched with EtOAc at 08C, and the mixture was treated
with 3 M aqueous NaOH (0.3 mL) and vigorously stirred at
room temperature until a white gel was precipitated. Filtra-
tion and concentration followed by column chromatography
(silica gel, 30% EtOAc/hexane) gave FGH ring system 4
A solution of the above aldehyde in (CH2Cl)2 (5 mL) was
treated with Ph3PvCHCO2Bn (107.2 mg, 0.2612 mmol)
and the resulting mixture was stirred at room temperature
overnight. The mixture was directly subjected to column
chromatography (silica gel, 25% EtOAc/hexane) to give
a,b-unsaturated benzyl ester 42 (89.2 mg, 86% for two
27
(23.8 mg, 75%) as a colorless oil: [a]D ˆ239.2 (c 0.20,
benzene); IR (®lm) 3445, 2943, 2867, 1459, 1382, 1270,
1200, 1096, 1065, 930, 882, 749, 682 cm21 1H NMR
;
27
(500 MHz, C6D6) d 3.94±3.86 (m, 2H), 3.84 (m, 1H),
3.71 (m, 1H), 3.64 (dd, 1H, Jˆ11.3, 8.9 Hz), 3.51±3.46
(m, 2H), 3.24 (ddd, 1H, Jˆ8.9, 8.9, 5.4 Hz), 3.07 (dd, 1H,
Jˆ12.8, 4.0 Hz), 3.02 (ddd, 1H, Jˆ11.0, 9.2, 5.2 Hz), 2.17
(ddd, 1H, Jˆ11.6, 5.2, 4.0 Hz), 2.05±1.90 (m, 4H), 1.84±
1.66 (m, 5H), 1.62 (m, 1H), 1.60 (s, 3H), 1.45 (s, 3H), 1.18±
1.03 (m, 27H); 13C NMR (125 MHz, C6D6) d 98.4, 85.1,
80.5, 76.0, 73.2, 73.1, 72.0, 70.1, 63.5, 61.1, 54.6, 33.1,
32.5, 30.2, 29.8, 28.8, 24.7, 19.5, 18.2, 15.8, 12.3; HRMS
calcd for C29H54O7SiNa [(M1Na)1] 565.3537, found
565.3527.
steps) as a colorless oil: [a]D ˆ24.37 (c 0.41, benzene);
IR (®lm) 3445, 2943, 2861, 1718, 1653, 1456, 1381, 1325,
1
1267, 1172, 1096, 738, 697 cm21; H NMR (500 MHz,
C6D6) d 7.30 (ddd, 1H, Jˆ15.6, 7.5, 6.5 Hz), 7.25±7.02
(m, 10H), 5.99 (d, 1H, Jˆ15.6 Hz), 5.09 (s, 2H), 4.17 (d,
1H, Jˆ11.0 Hz), 4.13 (d, 1H, Jˆ11.0 Hz), 3.96 (dd, 1H,
Jˆ11.3, 5.5 Hz), 3.72 (m, 1H), 3.64 (dd, 1H, Jˆ11.3,
8.9 Hz), 3.48±3.40 (m, 2H), 3.27 (ddd, 1H, Jˆ8.9, 8.9,
5.5 Hz), 2.88±2.77 (m, 2H), 2.43 (m, 1H), 2.14±1.73 (m,
8H), 1.57 (ddd, 1H, Jˆ12.2, 11.9, 11.6 Hz), 1.48 (s, 3H),
1.30 (s, 3H), 1.09 (s, 3H), 1.04 (s, 3H); 13C NMR (125 MHz,
C6D6) d 166.0, 147.3, 139.5, 136.9, 128.5, 128.3, 128.1,
127.7, 127.6, 123.0, 98.5, 85.1, 80.9, 80.4, 76.0, 74.8,
73.3, 73.2, 71.8, 66.0, 63.53, 63.48, 50.5, 32.2, 32.0, 30.3,
29.9, 28.9, 20.8, 19.4, 16.0; HRMS calcd for C36H46O8Na
[(M1Na)1] 629.3090, found 629.3047.
4.1.28. Alcohol 41. To a solution of FGH ring system 4
(121.9 mg, 0.2249 mmol) in THF (5 mL) at 08C was
added excess amount of KH (30% oil dispersion, ca.
300 mg) and the resulting mixture was stirred at 08C for
20 min. The mixture was treated with BnBr (135 mL,
1.13 mmol) at 08C, allowed to warm to room temperature,
and stirred for 50 min. The reaction was quenched with
MeOH at 08C, and the reaction mixture was diluted with
EtOAc, washed with water and brine, dried over Na2SO4,
and concentrated to give crude benzyl ether, which was used
in the next reaction without further puri®cation.To a solu-
tion of the above benzyl ether in THF (5 mL) was added
TBAF (1.0 M solution in THF, 680 mL, 0.680 mmol) and
the resulting mixture was stirred at room temperature for
45 min. The reaction mixture was diluted with EtOAc,
washed with saturated aqueous NH4Cl and brine, dried
over Na2SO4, and concentrated. The residue was puri®ed
by column chromatography (silica gel, 30!50% EtOAc/
hexane) to give alcohol 41 (93.3 mg, 87% for two steps)
4.1.30. EFGH ring system 3. To a solution of a,b-unsatu-
rated ester 42 (33.4 mg, 55.1 mmol) in EtOAc (2 mL) was
added a catalytic amount of 20% Pd(OH)2/C, and the result-
ing mixture was stirred at room temperature under hydrogen
atmosphere overnight. The catalyst was removed by ®ltra-
tion through Celite and the ®ltrate was concentrated to give
crude hydroxy carboxylic acid 43, which was azeotropically
dried with toluene and used in the next step.
To a solution of the above hydroxy carboxylic acid 43 in
THF±toluene (1:1, 2 mL) were added Et3N (76 mL,
0.55 mmol) and 2,4,6-trichlorobenzoylchloride (34 mL,
0.22 mmol), and the resulting mixture was stirred at room
temperature for 45 min and then diluted with toluene
(10 mL). The reaction mixture was added dropwise to a
re¯uxing solution of DMAP (80.2 mg, 0.671 mmol) in
toluene (10 mL) over a period of 45 min. The mixture was
stirred under re¯ux for 1 h. The mixture was cooled to room
temperature, concentrated and diluted with EtOAc. The
organic layer was washed with 1 M aqueous HCl, saturated
aqueous NaHCO3 and brine, dried over Na2SO4, and
concentrated. The residue was puri®ed by column
27
as a colorless oil: [a]D ˆ129.1 (c 0.15, benzene); IR
(®lm) 3481, 2942, 2876, 1456, 1382, 1268, 1200, 1096,
1
1066, 878, 736, 698 cm21; H NMR (500 MHz, C6D6) d
7.25±7.08 (m, 5H), 4.20 (d, 1H, Jˆ11.0 Hz), 4.15 (d, 1H,
Jˆ11.0 Hz), 3.96 (dd, 1H, Jˆ11.3, 5.5 Hz), 3.79±3.69 (m,
3H), 3.66 (dd, 1H, Jˆ11.3, 9.2 Hz), 3.60 (dd, 1H, Jˆ9.8,
2.4 Hz), 3.46 (ddd, 1H, Jˆ9.2, 8.9, 4.0 Hz), 3.27 (ddd, 1H,
Jˆ9.2, 9.2, 5.5 Hz), 2.92 (dd, 1H, Jˆ12.8, 3.7 Hz), 2.87

H. Fuwa et al. / Tetrahedron 57 ꢀ2001)3019±3033
3033
J. B.; Danishefsky, S. J. Angew. Chem. Int. Ed. Engl. 1999,
38, 3542±3545. (k) Zhu, B.; Panek, J. S. Org. Lett. 2000, 2,
2575±2578. (l) Kallan, N. C.; Halcomb, R. L. Org. Lett. 2000,
2, 2687±2690. (m) Chelmer, S. R.; Danishefsky, S. J. Org.
Lett. 2000, 2, 2695±2698.
chromatography (silica gel, 50!60% EtOAc/hexane) to
give EFGH ring system 3 (20.9 mg, 93% for two steps) as
28
a colorless amorphous solid: [a]D ˆ129.3 (c 0.79,
CHCl3); IR (®lm) 2947, 2883, 1712, 1456, 1382, 1278,
1
1197, 1110, 1078, 912, 732 cm21; H NMR (500 MHz,
7. Fuwa, H.; Sasaki, M.; Tachibana, K. Tetrahedron Lett. 2000,
41, 8371±8375.
CDCl3) d 3.85 (dd, 1H, Jˆ11.6, 5.5 Hz), 3.70 (m, 1H),
3.56 (dd, 1H, Jˆ11.6, 8.9 Hz), 3.48 (ddd, 1H, Jˆ9.2, 8.9,
4.0 Hz), 3.39 (dd, 1H, Jˆ11.6, 3.1 Hz), 3.32 (ddd, 1H,
Jˆ8.9, 8.9, 5.5 Hz), 3.24 (ddd, 1H, Jˆ11.0, 9.2, 5.2 Hz),
3.09 (dd, 1H, Jˆ12.8, 3.7 Hz), 2.82 (m, 1H), 2.55 (m,
1H), 2.14 (d, 1H, Jˆ12.8 Hz), 2.08 (ddd, 1H, Jˆ11.9, 5.2,
3.7 Hz), 2.06±1.52 (m, 13H), 1.41 (s, 3H), 1.34 (s, 3H), 1.21
(s, 3H); 13C NMR (125 MHz, CDCl3) d 173.3, 98.6, 84.8,
80.7, 80.61, 80.57, 75.9, 72.7, 72.6, 71.5, 63.1, 53.2, 37.1,
31.6, 30.3, 29.6, 29.2, 28.3, 22.2, 20.8, 19.6, 15.9; HRMS
calcd for C22H34O7Na [(M1Na)1] 433.2202; found
433.2211.
8. (a) Nicolaou, K. C.; Duggan, M. E.; Hwang, C.-K. J. Am.
Chem. Soc. 1989, 111, 6676±6682. (b) Mori, Y.; Furuta, H.;
Takase, T.; Mitsuoka, S.; Furukawa, H. Tetrahedron Lett.
1999, 40, 8019±8022.
9. Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang,
C.-K. J. Am. Chem. Soc. 1989, 111, 5330±5334.
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È
Gartner, P.; Yang, Z. Chem. Eur. J. 1999, 5, 618±627.
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