Syntheses of the AB and EFGH ring segments of gambierol

Article abstract of DOI:10.1016/S0040-4020(02)00039-X

Stereocontrolled syntheses of the AB and EFGH ring systems of gambierol (1) are described. The two key intermediates 3 and 55, representing the AB and EFGH ring frameworks, were prepared from 2-deoxy-D-ribose via linear sequences. Brown's asymmetric allylboration and the intramolecular hetero-Michael reaction were successfully applied to the construction of the A ring moiety. Synthesis of the EFGH ring segment 55 was achieved by the SmI₂ mediated reductive cyclization, constructing the EF ring bearing two 1,3-diaxial methyl groups, and the palladium catalyzed coupling of enol triflate and zinc bishomoenolate, making the GH ring moiety. Attempted convergent approaches toward the EFGH ring framework are also described.

Full text of DOI:10.1016/S0040-4020(02)00039-X

TETRAHEDRON
Pergamon
Tetrahedron 58 12002) 1799±1816
Syntheses of the AB and EFGH ring segments of gambierol
Isao Kadota,a Chie Kadowaki,b Choul-Hong Park,b Hiroyoshi Takamura,b Kumi Sato,b
Philip W. H. Chan,b Stephan Thorandb and Yoshinori Yamamotob,p
aResearch Center for Sustainable Materials Engineering, Institute of Multidisciplinary Research for Advanced Materials, Tohoku University,
Sendai 980-8578, Japan
bDepartment of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Received 7 September 2001; accepted 29 October 2001
AbstractÐStereocontrolled syntheses of the AB and EFGH ring systems of gambierol 11) are described. The two key intermediates 3 and
55, representing the AB and EFGH ring frameworks, were prepared from 2-deoxy-d-ribose via linear sequences. Brown's asymmetric
allylboration and the intramolecular hetero-Michael reaction were successfully applied to the construction of the A ring moiety. Synthesis of
the EFGH ring segment 55 was achieved by the SmI2 mediated reductive cyclization, constructing the EF ring bearing two 1,3-diaxial methyl
groups, and the palladium catalyzed coupling of enol tri¯ate and zinc bishomoenolate, making the GH ring moiety. Attempted convergent
approaches toward the EFGH ring framework are also described. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
synthetic analysis of Scheme 1, we tested the ®rst generation
route toward gambierol 11) as described below.8
Gambierol 11), which has a 6,6,6,6,7,6,6,7-polycyclic ether
skeleton including 18 stereocenters and a triene side chain,
was isolated from the cultured cells of Gambierdiscus
toxicus by Yasumoto in 1993.1 The compound shows
signi®cant toxicity against mice 1LD50 50 mg/kg), and the
symptoms resemble those caused by ciguatoxins inferring
the possibility that it is also implicated in ciguatera poison-
ing.2 In the course of our synthetic effort towards gambierol,
we synthesized the AB, E, and H ring segments in 1998,3,4
based on the absolute stereochemistry proposed by
Yasumoto and co-workers in 1993.1 However, later on in
1999, they revised the absolute stereochemistry;2 it is now
believed to be the opposite to that reported in 1993. Accord-
ingly, we undertook to synthesize those segments having the
correct absolute stereochemistry. Scheme 1 shows our new
synthetic strategy for the convergent synthesis of 1. The
polycyclic ether framework of 1 would be constructed
from 2 via oxidation of the C±C triple bond to an
a-diketone, selective removal of the TBS protective groups,
and subsequent reductive cyclization of the resulting
hydroxy ketone.5 Retrosynthetic disassembly of the alkyne
2 based on a retro-acetylide-tri¯ate coupling6 furnished the
AB ring segment 3 and the EFGH ring segment 4. It was
thought that the later compound 4 would be derived from
the carboxylic acid 5 and the alcohol 6 via an esteri®cation
followed by an ole®n metathesis.7 Based on the retro-
2. Synthesis of the AB ring segment
Protection of the known starting material 79 with TBSCl
followed by ozonolysis gave the aldehyde 8 in 99% yield
1Scheme 2). Brown's asymmetric allylboration of 8 using
allyldiisopinocampheylborane derived from 11)-pinene
afforded the homoallylic alcohol 9 as the sole product in
92% yield.10,11 Deprotection of the silyloxy group of 9
using TBAF and ozonolysis followed by Wittig reaction
gave the a,b-unsaturated ester 10 in 94% yield. The
cyclization precursor 10 was then subjected to an intra-
molecular hetero-Michael reaction. Thus, treatment of 10
with K2CO3 in THF/MeOH gave a 92:8 mixture of the
desired bicyclic compound 11 and its diastereoisomer in
78% combined yield.12 The stereochemistry of the major
product 11 was unambiguously con®rmed by NOE experi-
ments on the corresponding acetate derivative 12 as shown
in Fig. 1.
Further chain elongation and introduction of an alkynyl
group are shown in Scheme 3. Protection of the hydroxy
group of 11 with TIPSOTf followed by reduction of the ester
group of 13 with LiAlH4 gave the alcohol 14 in 94% yield.
One carbon elongation of the hydroxymethyl group of 14
was achieved in the following way. Swern oxidation and
subsequent Wittig reaction of the resulting aldehyde with
Ph3PvCH2 gave the corresponding one carbon elongated
ole®n, which was converted to the alcohol 15 through
hydroboration in 85% yield. Benzyl protection of the
Keywords: stereocontrolled synthesis; AB and EFGH ring segments;
gambierol; polycyclic ether.
p
Corresponding author. Tel.: 181-22-2176581; fax: 181-22-2176784;
e-mail: yoshi@yamamoto1.chem.tohoku.ac.jp
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020102)00039-X

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I. Kadota et al. / Tetrahedron 58.2002) 1799±1816
Scheme 1. Retrosynthesis of gambierol 11).
Scheme 2. 1a) 1i) TBSOTf, 2,6-lutidine, CH2Cl2, 408C, 100%; 1ii) O3, CH2Cl2/MeOH, 2788C, then PPh3, 2788C to rt, 99%; 1b) dIpc2B-allyl, ether, 2788C;
H2O2, NaOH, rt, 92%; 1c) 1i) TBAF, THF, rt, 100%; 1ii) O3, CH2Cl2/MeOH, 2788C, then PPh3, 2788C to rt, 99%; 1iii) Ph3PvCHCO2Me, CH2Cl2, rt, 95%;
1d) K2CO3, THF/MeOH, 408C, 78% 192:8).
hydroxy group of 15 followed by removal of the benzyl-
idene acetal using catalytic CSA in MeOH furnished the
diol 16 in 99% yield. Protection of 16 as a bis-TBS ether
followed by selective deprotection of the primary silyloxy
group gave 17 in 76% yield. Swern oxidation, Wittig
reaction, and hydroboration afforded the alcohol 18 in
72% yield. Conversion of 18 to the alkyne 3 was performed
by oxidation with SO3´py/DMSO/Et3N, reaction with CBr4/
PPh3, followed by treatment of the resulting dibromoole®n
19 with n-BuLi.13 The yield of 3 from 18 was 88%.
Figure 1. Observed NOEs are shown by arrows.

I. Kadota et al. / Tetrahedron 58.2002) 1799±1816
1801
Scheme 3. 1a) TIPSOTf, 2,6-lutidine, DMF, 608C, 98%; 1b) LiAlH4, ether, 08C, 96%; 1c) 1i) 1COCl)2, DMSO, CH2Cl2, 2788C, then Et3N, 2788C to rt;
1ii) Ph3P1CH3Br2, NaHMDS, THF, 08C, 90% 12 steps); 1iii) 1c-Hex)2BH, 08C, then 30% H2O2, 3N NaOH, 08C to rt, 94%; 1d) 1i) BnBr, KH, THF, 608C;
1ii) CSA, MeOH, rt, 99% 12 steps); 1e) 1i) TBSOTf, 2,6-lutidine, CH2Cl2, rt; 1ii) CSA, MeOH/CH2Cl2, rt, 76% 12 steps); 1f) 1i) 1COCl)2, DMSO, CH2Cl2,
2788C, then Et3N, 2788C to rt; 1ii) Ph3P1CH3Br2, NaHMDS, THF, 408C, 97% 12 steps); 1iii) BH3´SMe2, 08C, then 30% H2O2, 3N NaOH, 08C to rt, 74%;
1g) 1i) SO3´py, DMSO, Et3N, CH2Cl2, 08C, 91%; 1ii) CBr4, PPh3, CH2Cl2, 08C, 97%; 1h) n-BuLi, THF, 2788C, 99%.
3. Attempted convergent approaches toward the EFGH
ring framework
stereoselective manner by using Mori's ring expansion
methodology as shown in Scheme 4. The starting material
20, prepared from 2-deoxy-d-ribose via the hydroxy
epoxide cyclization,9 was converted to the ketone 21 in
62% yield via ozonolysis, reductive work up, selective
We next examined the convergent synthesis of the EFGH
ring segment 4. The E ring moiety was constructed in
Scheme 4. 1a) 1i) O3, MeOH, 2788C, then NaBH4, 2788C to rt, 78%; 1ii) TBDPSCl, imidazole, DMF, rt, 86%; 1iii) 1COCl)2, DMSO, CH2Cl2, 2788C, then
Et3N, 2788C to rt, 93%; 1b) 1i) TMSCHN2, BF3´OEt2, CH2Cl2, 2788C; 1ii) PPTS, MeOH, rt, 74% 12 steps); 1c) 1i) TBAF, THF, rt, 89%; 1ii) Me4NBH1OAc)3,
CH3CN/AcOH, 2208C, 89%; 1d) 1i) BnBr, KH, THF, 08C to rt, 68%; 1ii) conc. HCl, MeOH, rt, 86%; 1iii) TBSOTf, 2,6-lutidine, CH2Cl2, 08C to rt, 98%;
1e) 1i) CSA, MeOH, 08C, 89%; 1ii) 1COCl)2, DMSO, CH2Cl2, 2788C, then Et3N, 2788C to rt, 93%; 1f) 1i) Ph3P1CH3Br2, NaHMDS, THF, 08C, 33%;
1ii) 1c-Hex)2BH, THF, 08C, then 30% H2O2, 3N NaOH, 93%; 1g) 1i) Dess±Martin periodinane, CH2Cl2, rt; 1ii) NaClO2, 2-methyl-2-butene, NaH2PO4, t-BuOH/
H2O, rt, 91% 12 steps).

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I. Kadota et al. / Tetrahedron 58.2002) 1799±1816
Scheme 5. 1a) 1i) TBSCl, imidazole, DMF, 508C, 96%; 1ii) 1c-Hex)2BH, THF, 08C, then 30% H2O2, 3N NaOH, 99%; 1b) 1i) 1COCl)2, DMSO, CH2Cl2, 2788C,
then Et3N, 2788C to rt; 1ii) Ph3P1CH2CH3Br2, NaHMDS, THF, 08C, 65% 12 steps); 1iii) TBAF, THF, rt, 99%; 1c) 5, DCC, DMAP, CSA, CH2Cl2, rt, 45%;
1d) Tebbe reagent or Cp2TiMe2, THF, rt to 658C.
protection of the resulting primary alcohol, and Swern
oxidation. Treatment of 21 with TMSCHN2 and BF3´OEt2
followed by the hydrolysis of the resulting silyl enol ether
gave the 7-membered cyclic ketone 22 in 74% yield.14
Desilylation and subsequent stereoselective reduction of
the resulting b-hydroxy ketone afforded the diol 23 as the
sole product in 89% yield.15 Benzyl protection of 23,
hydrolysis of the benzylidene acetal, and TBS protection
gave the bis-TBS ether 24 in 57% yield. Selective deprotec-
tion of the primary silyloxy group followed by Swern
oxidation gave the aldehyde 25 in 83% yield. One carbon
chain elongation of 25 was performed by Wittig reaction
followed by hydroboration to give the alcohol 26 in 31%
yield. Dess±Martin oxidation of 26,16 followed by the treat-
ment of the resulting aldehyde with NaClO2, gave the
carboxylic acid 5 in 91% yield.
TBS protection of 273c followed by hydroboration afforded
28 in 95% yield 1Scheme 5). The alcohol 28 was converted
to the ole®n 6 in 64% yield via Swern oxidation, Wittig
reaction, and desilylation. DCC coupling of 6 with 5 gave
the ester 29 in 45% yield. The coupling product 29 was then
subjected to the metathesis reaction reported by Nicolaou.7
However, all attempts to effect cyclization of 29 resulted in
failure and none of 30 was obtained.
Scheme 6 shows an alternative approach towards the EFGH
ring framework via the intermediate 30. The compound 27
was converted to 31 in quantitative yield via ozonolysis and
Wittig reaction. Hydrogenation of 31 followed by lactoni-
zation gave the lactone 32 in 77% yield. Treatment of 32
with KHMDS and PhNTf2 gave the corresponding ketene
acetal tri¯ate,17 which was converted to the vinylstannane
Scheme 6. 1a) 1i) O3, CH2Cl2, 2788C, then Ph3P, 2788C to rt; 1iii) Ph3PvCH2CO2Me, 100% 12 steps); 1b) 1i) H2, Pd/C, EtOAc, rt, 98%; 1ii) p-TsOH, benzene,
re¯ux, 79%; 1c) 1i) KHMDS, PhNTf2, HMPA, THF, 2788C to rt, 70%; 1ii) 1Me3Sn)2, LiCl, Pd1PPh3)4, THF, re¯ux, 81%; 1d) n-BuLi, THF, 2788C, then 25,
97%; 1e) 1i) KH, CS2, THF, rt, then MeI, 95%; 1ii) n-Bu3SnH, AIBN, benzene, 858C, 64% of 30 and 11% of 35; 1f) RuCl21PPh3)3, benzene, 808C, 61%;
1g) 1i) dimethyldioxirane, CH2Cl2, 2658C; 1ii) Me3Al, CH2Cl2, 2788C to rt.

I. Kadota et al. / Tetrahedron 58.2002) 1799±1816
1803
33 in 57% yield by the palladium catalyzed coupling with
1Me3Sn)2.18 The vinylstannane 33 was then subjected to
condensation with the aldehyde 25 under the conditions
reported by Nicolaou. Thus, the metal exchange with
n-BuLi and addition of the aldehyde 25 gave the coupling
product 34 as a mixture of diastereoisomers in 97% yield.19
Barton deoxygenation of 34 gave an 85:15 mixture of 30
and the exo-ole®n 35 in 75% combined yield.20 The later
compound was converted to the desired enol ether 30 by
heating with RuCl21PPh3)3 in 61% yield.19 Again, however,
all attempts to introduce a methyl group into the ole®n of 30
using the Rainier's protocol failed.21 Finally, therefore, we
decided to abandon the convergent construction of 4 and to
seek a linear approach to the EFGH ring framework.
resulting diol as a bis-TBS ether, and selective removal of
the primarly TBS group afforded 43 in 57% yield. One
carbon elongation of the hydroxymethyl group of 43 was
achieved by Swern oxidation and subsequent Wittig
reaction of the resulting aldehyde followed by hydro-
boration to give alcohol 44 in 77% yield. Swern oxidation
followed by the addition of MeMgBr to the resulting
aldehyde gave the corresponding methyl carbinol, which
was oxidized under Swern conditions, giving the methyl
ketone 45 upon desilylation, in 66% yield. Construction of
the F ring including 1,3-diaxial methyl groups was carried
out by the Nakata protocol.25 Thus, treatment of the alcohol
45 with ethyl propiolate and 4-methylmorphorine gave the
acrylate 46, which was then subjected to the SmI2 mediated
reductive cyclization to give the bicycle 47 as a single
stereoisomer in 97% yield.
4. Synthesis of the EFGH ring segment
Construction of the EFGH ring system is shown in
Scheme 8. Protection of the hydroxy group of 47 with
TMS/imidazole followed by reduction of the ester with
LiAlH4 gave the alcohol 48 in quantitative yield. Swern
oxidation of 48 followed by Wittig reaction gave the enol
ether 49 in 64% yield. After hydrolysis, the resulting
aldehyde was oxidized to the corresponding hydroxy
carboxylic acid, which was allowed to cyclize under
Yamaguchi conditions to give 50 in 74% yield. Treatment
of the lactone 50 with PhNTf2 and KHMDS gave the corre-
sponding ketene acetal tri¯ate, which was allowed to react
with IZn1CH2)3CO2Et in the presence of Pd1PPh3)4 to afford
51 in 87% yield.4c,26,27 Unfortunately, hydroboration of the
Scheme 7 describes the synthesis of the EF ring segment.
The starting material 37,22 derived from 2-deoxy-d-ribose,
was converted into 38 in 67% yield by hydrogenation,
Swern oxidation, methylation, hydrolysis, and Yamaguchi
lactonization.23 The ketene acetal tri¯ate derived from the
lactone 38 was subjected to the palladium catalyzed
carbonylation to give 39 in 92% yield.24 DIBALH reduction
of the ester 39 followed by MPM protection gave 40 in 99%
yield. Hydroboration of the enol ether 40 with BH3´SMe2
gave a 3:2 mixture of the desired alcohol 41 and its stereo-
isomer 42 in 89% yield. Protection of 41 with MPMCl,
hydrolysis of the benzylidene acetal, protection of the
Scheme 7. 1a) 1i) H2, 5% Pd/C, EtOAc, 98%; 1ii) 1COCl)2, DMSO, CH2Cl2, 2788C, then Et3N, 2788C to rt; 1iii) Me3Al, CH2Cl2, 2208C, 70% 12 steps);
1iv) LiOH, THF/H2O, rt, 100%; 1v) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, rt, then DMAP, benzene, rt, 98%; 1b) 1i) PhNTf2, KHMDS, HMPA, THF,
2788C; 1ii) CO, Et3N, Pd1PPh3)4, MeOH, rt, 92% 12 steps); 1c) 1i) DIBALH, CH2Cl2, 2788C, 99%; 1ii) MPMCl, KH, THF, 08C to rt, 95%; 1d) BH3SMe2, THF,
08C to rt, then 30% H2O2, 3N NaOH, 08C, 53% of 41, 36% of 42; 1e) 1i) MPMCl, KH, THF, 08C to rt, 77%; 1ii) CSA, CH2Cl2/MeOH, rt, 84%; 1iii) TBSOTf,
2,6-lutidine, CH2Cl2, 08C to rt, 96%; 1iv) CSA, CH2Cl2/MeOH, 08C, 91%; 1f) 1i) 1COCl)2, DMSO, CH2Cl2, 2788C, then Et3N, 2788C to rt, 95%;
1ii) Ph3P1CH3Br2, NaHMDS, THF, 0 to rt, 96%; 1iii) 1c-Hex)2BH, 08C, then H2O2, 3N NaOH, 08C, 84%; 1g) 1i) 1COCl)2, DMSO, CH2Cl2, 2788C, then
Et3N, 2788C to rt, 86%; 1ii) MeMgI, ether, 08C; 1iii) 1COCl)2, DMSO, CH2Cl2, 2788C, then Et3N, 2788C to rt, 89% 12 steps); 1iv) TBAF, THF, rt, 86%;
1h) ethyl propiolate, 4-methylmorphorine, CH2Cl2, rt, 100%; 1i) SmI2, MeOH, THF, 08C, 97%.

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I. Kadota et al. / Tetrahedron 58.2002) 1799±1816
Scheme 8. 1a) 1i) TMS/imidazole, CH2Cl2, rt; 1ii) LiAlH4, ether, 08C, 100% 12 steps). 1b) 1i) SO3´py, DMSO, Et3N, CH2Cl2, rt, 87%; 1ii) Ph3P1CH2OMeCl2,
NaHMDS, THF, 2788C to rt, 74%; 1c) 1i) CSA, CH3CN/H2O, rt, 83%; 1ii) NaClO2, 2-methyl-2-butene, NaH2PO4, t-BuOH/H2O, rt; 1iii) 2,4,6-trichlorobenzoyl
chloride, Et3N, THF, rt, then DMAP, benzene, rt, 89% 12 steps); 1d) 1i) PhNTf2, KHMDS, HMPA, THF, 2788C; 1ii) IZn1CH2)3CO2Et, Pd1PPh3)4, benzene, rt,
87% 12 steps); 1e) BH3´SMe2, THF, 08C, then 30% H2O2, satd NaHCO3, 94%; 1f) 1i) Dess±Martin periodinane, NaHCO3, CH2Cl2, rt; 1ii) DBU, toluene, rt, 64%
12 steps); 1g) NaBH4, CH2Cl2/MeOH, 2788C, 98%; 1h) 1i) LiOH, THF/H2O, 408C; 1ii) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, rt, then DMAP, benzene, rt,
76% 12 steps).
enol ether 51 gave the undesired stereoisomer 52 as the sole
product, although the yield was quantitative. Stereo-
isomerization of 52 was performed by the following steps;
Dess±Martin oxidation of 52 followed by treatment with
DBU gave 53 in 64% yield, and then reduction of the ketone
53 with NaBH4 gave the desired alcohol 54 as a single
stereoisomer in 98% yield. Hydrolysis of the ester followed
by Yamaguchi lactonization gave the EFGH ring segment
55 in 76% yield. The stereochemistry of 55 was
convergent approaches toward the EFGH ring framework
were examined, all attempts resulted in failure, forcing us to
take a linear strategy for the target molecule. Finally, the
construction of the EFGH ring segment 55 was achieved by
40 steps from 2-deoxy-d-ribose in 1.9% total yield. The
SmI2 mediated reductive cyclization was successfully
applied to the construction of the EF ring bearing two 1,3-
diaxial methyl groups. The palladium catalyzed coupling of
enol tri¯ate and zinc bishomoenolate was very effective and
ef®cient for synthesizing the GH ring moiety. Further
studies toward the total synthesis of gambierol are now in
progress in our laboratories.
1
unambiguously con®rmed by H NMRanalysis and NOE
experiments as shown in Fig. 2.
6. Experimental
6.1. General procedure
All reactions involving air- and/or moisture-sensitive
materials were carried out under argon with dry solvents
purchased from Wako or Kanto chemicals. On workup,
extracts were dried over MgSO4. Reactions were monitored
by thin-layer chromatography carried out on 0.25 mm
Merck silica gel plates 160F-254). Column chromatography
was performed with Kanto Chemical silica gel 160N,
spherical, neutral, particle size 0.100±0.210 mm). Yields
refer to chromatographically and spectroscopically
homogeneous materials.
Figure 2. Observed NOEs are shown by arrows.
5. Conclusion
Synthesis of the AB ring segment 3, having absolute stereo-
chemistry corresponding to natural gambierol 1, was
achieved from 2-deoxy-d-ribose. Brown's asymmetric
allylboration and the intramolecular hetero-Michael
reaction were successfully applied to the construction of
the A ring moiety. Although a signi®cant number of
Chemical shifts are reported in delta 1d) units relative to

I. Kadota et al. / Tetrahedron 58.2002) 1799±1816
1805
tetramethylsilane or to the singlet at 7.26 ppm for chloro-
form. Coupling constants are reported in hertz 1Hz).
HRMS 1EI) calcd for C25H39O5Si 1M2H) 447.2567, found
447.2610.
6.1.1. Aldehyde 8. To a stirred solution of alcohol 7 15.0 g,
17.2 mmol) and 2,6-lutidine 16.0 ml, 51.7 mmol) in CH2Cl2
1170 ml) at 08C was added TBSOTf 17.88 ml, 34.4 mmol)
dropwise, and the mixture was stirred at room temperature.
After 1 h, the reaction mixture was quenched with MeOH,
diluted with ether, then washed with satd NaHCO3 and
brine. The organic layer was concentrated and puri®ed by
chromatography 1hexane/EtOAc, 10:1) to give the silyl
6.1.3. Unsaturated ester 10. To a stirred solution of 9
114.1 g, 31.5 mmol) in THF 1300 ml) at 08C was added
TBAF 138 ml, 1 M in THF, 38 mmol). After 0.5 h, the reac-
tion mixture was concentrated and subjected to chromato-
graphy 1hexane/EtOAc, 2:1) to give the diol 110.5 g, 100%):
colorless oil; Rfˆ0.57 1hexane/EtOAc, 1:1); [a]24 ˆ24.68
D
1c 0.11, CHCl3); IR1neat) 3600±3200, 1155 cm 21; 1H NMR
1300 MHz, CDCl3) d 7.35±7.20 1m, 5H), 5.78 1m, 1H), 5.53
1s, 1H), 5.20±5.10 1m, 2H), 3.84 1dd, Jˆ11.4, 4.8 Hz, 1H),
3.81 1d, Jˆ9.7 Hz, 1H), 3.69 1s, 1H), 3.49 1m, 3H), 2.84 1s,
1H), 2.53 1m, 1H), 2.12±1.85 1m, 3H), 1.51 1s, 3H), 1.26 1s,
ether 17.1 g, quantitative): colorless oil; Rfˆ0.45 1hexane/
21
EtOAc, 10:1); IR1neat) 1471, 1095 cm
;
1H NMR
1300 MHz, CDCl3), d 7.53±7.42 1m, 5H), 6.01 1dd,
Jˆ12.7, 7.0 Hz, 1H), 5.70 1s, 1H), 5.39 1dd, Jˆ12.7,
0.7 Hz, 1H), 5.31 1dd, Jˆ7.0, 0.7 Hz, 1H), 4.06 1d,
Jˆ9.9 Hz, 1H), 3.78 1m, 1H), 2.12 1m, 2H), 1.70 1s, 3H),
1.49 1s, 3H), 1.01 1s, 9H), 0.23 1s, 3H), 0.21 1s, 3H); 13C
NMR175 MHz, CDCl 3) d 144.5, 137.6, 129.1, 128.4, 126.3,
112.6, 103.0, 80.3, 78.5, 74.7, 68.9, 31.3, 25.7, 21.2, 19.1,
17.8, 24.1, 24.9.
3H); 13C NMR175 MHz, CDCl ) d 137.4, 135.2, 129.0,
3
128.2, 126.2, 118.3, 102.8, 80.3, 79.7, 77.6, 76.6, 74.8,
68.8, 35.4, 28.9, 18.8, 15.9; HRMS, calcd for C19H26O5
1M) 334.1780, found 334.1781.
A solution of the diol 110.5 g, 31.5 mmol) in CH2Cl2
1150 ml) and MeOH 1150 ml) was treated with ozone at
2788C until the solution turned to blue. The mixture was
treated with triphenylphosphine 124.8 g, 94.5 mmol) and
stirred at 258C for 1 h. Concentration and chromatography
1hexane/EtOAc, 1:1) gave the hemiacetal 110.5 g, 99%):
A solution of the silyl ether 15.0 g, 12.3 mmol) in CH2Cl2
160 ml) and MeOH 160 ml) was cooled to 2788C. After
passing ozonized oxygen until color of the solution changed
to blue, PPh3 16.48 g, 24.7 mmol) was added and the
mixture was stirred for 30 min at room temperature. The
reaction mixture was concentrated and puri®ed by chroma-
tography 1hexane/EtOAc, 10:1) to give the aldehyde 8
14.9 g, 99%): colorless oil; Rfˆ0.20 1hexane/EtOAc,
white solid; Rfˆ0.19 1hexane/EtOAc, 1:1); IR1neat)
1
3600±3200, 1452 cm21; H NMR1300 MHz, CDCl ) d
3
7.35±7.20 1m, 5H), 5.59 1s, 1H), 5.14 1d, Jˆ3.7 Hz, 1H),
4.43 1m, 1H), 3.94±3.52 1m, 4H), 2.10 1m, 4H), 1.64 1s, 3H),
1.39 1s, 3H); 13C NMR175 MHz, CDCl ) d 129.3, 128.4,
3
10:1); [a]24 ˆ21.88 1c 1.00, CHCl3); IR1neat) 2947,
126.3, 103.3, 92.5, 82.6, 77.2, 76.4, 71.6, 71.4, 33.9, 26.5,
20.5, 20.0, 18.6.
D
1
1741 cm21; H NMR1300 MHz, CDCl ) d 9.39 1s, 1H),
3
7.35±7.20 1m, 5H), 5.57 1s, 1H), 4.03 1dd, Jˆ9.4, 5.8 Hz,
1H), 3.95 1d, Jˆ9.9 Hz, 1H), 3.66±3.58 1m, 2H), 2.18±2.12
1m, 1H), 1.98 1ddd, Jˆ12.3, 12.3, 9.4 Hz, 1H), 1.60 1s, 3H),
1.38 1s, 3H), 0.97 1s, 9H), 0.08 1s, 3H), 0.03 1s, 3H); 13C
NMR175 MHz, CDCl 3) d 199.6, 137.2, 129.2, 128.3, 126.2,
102.9, 81.9, 79.2, 76.6, 69.2, 67.8, 30.8, 25.5, 18.8, 17.7,
17.5, 24.4, 25.2; HRMS 1EI) calcd for C22H34O5Si
406.2174, found 406.2176.
To a solution of the hemiacetal 110.5 g, 31.2 mmol) in
CH2Cl2 1300 ml) was added methyl triphenylphosphor-
anylideneacetate 152.2 g, 156 mmol) at room temperature
and the mixture was stirred for 12 h at 408C. The reaction
mixture was concentrated and diluted with hexane. The
resulting solid was ®ltered off and the ®ltrate was concen-
trated. The residue was puri®ed by chromatography
1hexane/EtOAc, 1:1) to give a,b-unsaturated ester 10
111.9 g, 95%): colorless oil; Rfˆ0.36 1hexane/EtOAc,
6.1.2. Homoallylic alcohol 9. To a stirred solution of alde-
hyde 8 15.0 g, 12.3 mmol) in ether 1110 ml) at 2788C was
added dropwise a solution of allyldiisopinocamphenyl-
borane 1117 ml, 0.21 M in pentane) over 14 min. After
stirring for 5 h at the same temperature, the mixture was
quenched with MeOH. H2O2 130 ml, 30% in H2O) and
aqueous NaOH 129 ml, 3N in H2O) were added to the
reaction mixture at 08C and the mixture was stirred for 1 h
at room temperature. The reaction mixture was diluted with
ethyl acetate, then washed with satd NH4Cl and brine. The
organic layer was concentrated and puri®ed by chromato-
graphy 1hexane/EtOAc, 20:1) to give the homoallylic
alcohol 9 15.08 g, 92%): colorless oil; Rfˆ0.39 1hexane/
1:1); [a]24 ˆ114.28 1c 0.45, CHCl3); IR1neat) 3600±
D
3200, 1728 cm21; H NMR1300 MHz, CDCl ) d 7.35±
1
3
7.20 1m, 5H), 6.98 1ddd, Jˆ15.2, 9.0, 7.0 Hz, 1H), 5.94
1d, Jˆ15.2 Hz, 1H), 5.55 1s, 1H), 3.88 1m, 1H), 3.82 1d,
Jˆ10.3 Hz, 1H), 3.73 1s, 3H), 3.64±3.48 1m, 4H), 3.02
1m, 1H), 2.67 1m, 1H), 2.24 1m, 1H), 2.17±1.86 1m, 2H),
1.53 1s, 3H), 1.31 1s, 3H); 13C NMR175 MHz, CDCl ) d
3
166.8, 146.4, 137.4, 129.2, 128.4, 126.3, 123.5, 103.0, 80.2,
79.6, 77.8, 74.6, 69.1, 51.6, 34.3, 29.3, 18.9, 16.1; HRMS
1EI) calcd for C21H28O7 1M1) 392.1835, found 392.1839.
6.1.4. Ester 11. To a solution of 10 112.8 g, 32.7 mmol) in
THF 115 ml) and MeOH 115 ml) was added K2CO3 190 mg,
0.66 mmol). After stirring for 5 h at 408C, the reaction
mixture was diluted with ether, then washed with satd
NH4Cl, water, and brine. The organic layer was concen-
trated and puri®ed by chromatography 1hexane/EtOAc,
10:1) to give 11 110.0 g, 78%): colorless oil; Rfˆ0.39
EtOAc, 4:1); [a]24 ˆ11.58 1c 1.07, CHCl3); IR1neat)
D
1
3600±3200, 1641 cm21; H NMR1300 MHz, CDCl ) d
3
7.35±7.20 1m, 5H), 5.91 1m, 1H), 5.55 1s, 1H), 5.10 1m,
2H), 4.05 1dd, Jˆ11, 5.1 Hz, 1H), 3.88 1d, Jˆ9.9 Hz, 1H),
3.49±3.34 1m, 3H), 2.55 1m, 1H), 2.41 1dd, Jˆ14.5, 6.2 Hz,
1H), 2.21±1.91 1m, 3H), 1.45 1s, 3H), 1.35 1s, 3H), 0.87 1s,
9H), 0.12 1s, 6H); 13C NMR175 MHz, CDCl ) d 137.4,
1hexane/EtOAc, 5:1); [a]24 ˆ14.98 1c 0.41, CHCl3); IR
3
D
136.4, 129.2, 128.4, 126.3, 116.5, 103.1, 80.1, 78.0, 76.6,
71.7, 68.8, 35.7, 31.1, 25.7, 18.9, 18.85, 17.9, 23.1, 24.7;
1neat) 3600±3200, 1732 cm21
;
CDCl3) d 7.35±7.20 1m, 5H), 5.52 1s, 1H), 4.25 1m, 1H),
1H NMR1300 MHz,

1806
I. Kadota et al. / Tetrahedron 58.2002) 1799±1816
3.91 1dd, Jˆ12.0, 4.0 Hz, 1H), 3.81 1d, Jˆ9.7 Hz, 1H), 3.7
1bs, 1H), 3.64 1s, 3H), 3.58 1dd, Jˆ12.0, 4.0 Hz, 1H), 3.52
1d, Jˆ9.9 Hz, 1H), 2.63 1bs, 1H), 2.51 1dd, Jˆ15.2, 7.3 Hz,
1H), 2.37 1dd, Jˆ15.2, 5.3 Hz, 1H), 2.07±1.81 1m, 4H), 1.56
diluted with ether, then washed with satd NH4Cl, water, and
brine. The organic layer was concentrated to give the crude
aldehyde.
1s, 3H), 1.34 1s, 3H); 13C NMR175 MHz, CDCl ) d 170.8,
To a stirred suspension of methyltriphenylphosphonium
bromide 13.2 g, 8.9 mmol) in THF 120 ml) at 08C was
added NaHMDS 18.9 ml, 1.0 M in THF, 8.9 mmol), and
the resulting mixture was stirred for 10 min at the same
temperature. A solution of the aldehyde obtained above in
THF 130 ml) was added to the mixture, and the stirring was
continued for 1 h. The reaction was quenched with water,
and the mixture was extracted with ether. The organic layer
was washed with brine, dried, and concentrated. The residue
was diluted with hexane, and the resulting solid was ®ltered
off. The ®ltrate was concentrated and puri®ed by chromato-
graphy 1hexane/EtOAc, 10:1) to give the ole®n 12.8 g,
90%): colorless oil; Rfˆ0.42 1hexane/EtOAc, 10:1);
3
137.2, 128.9, 128.1, 126.1, 102.8, 81.8, 76.1, 76.0, 73.4,
71.1, 70.8, 70.7, 70.5, 51.5, 40.1, 34.7, 26.5, 20.0, 19.5;
HRMS 1EI) calcd for C21H28O7 1M1) 392.1835, found
392.1838.
6.1.5. Acetate 12. This material was prepared from 11 with
standard acetylation conditions. 12: colorless oil; Rfˆ0.38
21
1hexane/EtOAc, 2:1); IR1neat) 1732 cm
;
1H NMR
1300 MHz, CDCl3) d 7.35±7.20 1m, 5H), 5.56 1s, 1H),
5.56 1t, Jˆ2.8 Hz, 1H), 4.21 1m, 1H), 3.90 1dd, Jˆ11.7,
4.0 Hz, 1H), 3.85 1d, Jˆ9.9 Hz, 1H), 3.70 1s, 3H), 3.60
1dd, Jˆ11.7, 3.7 Hz, 1H), 3.42 1d, Jˆ10.0 Hz, 1H), 2.57
1dd, Jˆ15.8, 7.7 Hz, 1H), 2.21 1dd, Jˆ15.7, 5.0 Hz, 1H),
2.21 1s, 3H), 2.15±1.94 1m, 3H), 1.78 1m, 1H), 1.57 1s, 3H),
1.42 1s, 3H).
[a]24 ˆ128.58 1c 0.74, CHCl3); IR1neat) 2943,
D
1
1641 cm21; H NMR1300 MHz, CDCl ) d 7.35±7.20 1m,
3
5H), 5.78 1m, 1H), 5.53 1s, 1H), 5.06 1m, 2H), 4.02 1dd,
Jˆ12.0, 4.0 Hz, 1H), 3.92 1m, 1H), 3.88 1m, 1H), 3.77 1d,
Jˆ10.0 Hz, 1H), 3.63 1dd, Jˆ15.6, 4.0 Hz, 1H), 3.63 1s,
1H), 2.33 1m, 1H), 2.17 1m, 1H), 2.12±1.75 1m, 3H), 1.65
1dt, Jˆ14.3, 2.9 Hz, 1H), 1.58 1s, 3H), 1.33 1s, 3H), 1.10
6.1.6. TIPS ether 13. To a stirred solution of alcohol 11
13.3 g, 8.4 mmol) and 2,6-lutidine 14.9 ml, 42 mmol) in
DMF 185 ml) at 08C was added TIPSOTf 19.9 ml,
37 mmol). After stirring for 13 h at 608C, the mixture was
diluted with ether, then washed with satd NH4Cl, water, and
brine. The organic layer was concentrated and puri®ed by
chromatography 1hexane/EtOAc, 10:1) to give 13 14.5 g,
1brs, 21H); 13C NMR175 MHz, CDCl ) d 137.6, 134.3,
3
129.1, 128.3, 126.3, 117.0, 103.2, 103.0, 82.1, 76.8, 73.7,
73.4, 72.0, 70.4, 39.8, 38.0, 27.2, 20.6, 18.2, 12.4; HRMS
1EI) calcd for C30H48O5Si 1M1) 516.3271, found 516.3287.
98%): colorless oil; Rfˆ0.22 1hexane/EtOAc, 10:1);
1
[a]24 ˆ18.68 1c 1.06, CHCl3); IR1neat) 1743 cm 21; H
To a solution of cyclohexene 11.6 ml, 16 mmol) in THF
120 ml) at 08C was added BH3´SMe 1710 ml, 8.0 mmol),
and the mixture was stirred for 20 min at the same tempera-
ture. A solution of the ole®n obtained above 12.76 g,
5.3 mmol) in THF 130 ml) was added, and the stirring was
continued for 0.5 h. Aqueous 3N NaOH 118 ml, 54 mmol)
and 30% H2O2 12 ml, 64 mmol) were added. After stirring
for 1 h at room temperature, the mixture was extracted with
ether. The organic layer was washed with aqueous Na2S2O3
and brine. Concentration and chromatography 1hexane/
EtOAc, 5:1) gave 15 12.68 g, 94%): colorless oil; Rfˆ0.21
D
NMR1300 MHz, CDCl ) d 7.35±7.20 1m, 5H), 5.51 1s,
3
1H), 4.29 1m, 1H), 4.03 1dd Jˆ12.0, 4.0 Hz, 1H), 3.92 1m,
1H), 3.76 1d, Jˆ9.7 Hz, 1H), 3.65 1s, 3H), 3.63 1m, 2H),
2.58 1dd, Jˆ15.0, 7.0 Hz, 1H), 2.37 1dd, Jˆ15.0, 6.0 Hz,
1H), 2.10±1.86 1m, 3H), 1.71 1dt, Jˆ14.0, 2.8 Hz, 1H),
1.56 1s, 3H), 1.32 1s, 3H), 1.09 1brs, 21H); 13C NMR
175 MHz, CDCl3) d 171.1, 137.6, 129.0, 128.3, 126.3,
103.1, 81.9, 76.5, 76.3, 73.4, 71.9, 70.8, 70.5, 51.6, 40.5,
38.1, 27.1, 20.6, 18.2, 18.2, 12.4; HRMS 1EI) calcd for
C30H48O7Si 1M1) 548.3169, found 548.3173.
1hexane/EtOAc, 3:1); [a]24 ˆ14.098 1c 0.21, CHCl3); IR
D
1
6.1.7. Alcohol 14. To a suspension of LiAlH4 1100 mg,
2.64 mmol) in ether 115 ml) at 08C was added a solution
of 13 11.45 g, 2.64 mmol) in ether 110 ml). After stirring
for 1 h, the mixture was diluted with ether and quenched
with brine. The resulting white precipitate was ®ltered off,
and the ®ltrate was concentrated. The crude product was
puri®ed by chromatography 1hexane/EtOAc, 4:1) to give
1neat) 360±3200, 1654 cm21; H NMR1300 MHz, CDCl )
3
d 7.35±7.20 1m, 5H), 5.52 1s, 1H), 4.03 1dd, Jˆ11.7, 4.2 Hz,
1H), 3.93 1m, 1H), 3.87 1m, 1H), 3.77 1d, Jˆ9.9 Hz, 1H),
3.63 1m, 4H), 2.06 1m, 1H), 1.97 1d, Jˆ11.7 Hz, 1H), 1.88
1m, 6H), 1.57 1s, 3H), 1.34 1s, 3H), 1.10 1s, 21H); 13C NMR
175 MHz, CDCl3) d 137.5, 129.0, 128.3, 126.3, 103.0, 81.9,
76.7, 76.3, 74.4, 73.3, 72.0, 70.4, 62.8, 38.7, 32.4, 29.2,
27.1, 20.6, 18.2, 12.4; HRMS 1EI) calcd for C30H50O6Si
1M1) 534.3376, found 534.3349.
14 11.31 g, 96%): colorless oil; Rfˆ0.12 1hexane/EtOAc,
1
4:1); H NMR1300 MHz, CDCl ) d 7.35±7.20 1m, 5H),
3
5.53 1s, 1H), 4.16±4.07 1m, 1H), 4.05 1dd, Jˆ11.9,
4.2 Hz, 1H), 3.94 1brs, 1H), 3.84±3.74 1m, 3H), 3.67±3.60
1m, 2H), 2.56 1t, Jˆ5.1 Hz, 1H), 2.07±1.90 1m, 3H), 1.78±
1.60 1m, 3H), 1.58 1s, 3H), 1.37 1s, 3H), 1.09 1brs, 21H).
6.1.9. Diol 16. To a stirred suspension of KH 11.38 g of a
suspension in mineral oil, 12.1 mmol, prewashed with
hexane) in THF 150 ml) at 08C was added a solution of 15
15.4 g, 10.1 mmol) in THF 150 ml). After 40 min, benzyl
bromide 11.8 ml, 15.1 mmol) was added, and the mixture
was stirred for 14 h at room temperature. The reaction was
quenched with MeOH at 08C, and the mixture was diluted
with ether and washed with water and brine. The organic
layer was concentrated and puri®ed by chromatography
1hexane/EtOAc, 20:1) to give the benzyl ether 16.28 g,
6.1.8. Alcohol 15. To a solution of DMSO 1920 ml,
13 mmol) in CH2Cl2 120 ml) at 2788C was added 1COCl)2
1930 ml, 10.7 mmol), and the mixture was stirred for 10 min
at the same temperature. A solution of 14 13.1 g, 5.92 mmol)
in CH2Cl2 140 ml) was added to the resulting mixture, and
the stirring was continued for 1.5 h. Triethylamine 14.1 ml,
29.6 mmol) was added, and the mixture was allowed to
warm to room temperature with stirring. The mixture was
100%): colorless oil; Rfˆ0.37 1hexane/EtOAc, 20:1);
1
[a]24 ˆ18.788 1c 0.56, CHCl3); IR1neat) 1641 cm 21; H
D

I. Kadota et al. / Tetrahedron 58.2002) 1799±1816
1807
NMR1300 MHz, CDCl 3) d 7.35±7.20 1m, 5H), 5.52 1s, 1H),
4.48 1s, 2H), 3.99 1dd, Jˆ11.7, 4.8 Hz, 1H), 3.91 1s, 1H),
3.84 1m, 1H), 3.77 1d, Jˆ12.5 Hz, 1H), 3.61 1m, 2H), 3.46
1m, 2H), 2.05±1.38 1m, 8H), 1.57 1s, 3H), 1.32 1s, 3H), 1.04
1s, 21H); 13C NMR175 MHz, CDCl 3) d 138.5, 137.7, 129.1,
128.3, 127.6, 127.5, 126.3, 103.2, 82.1, 76.6, 76.4, 74.0,
73.3, 73.0, 72.1, 70.4, 70.3, 38.7, 32.3, 27.3, 25.9, 20.8,
20.6, 18.3, 18.3, 12.5.
1COCl)2 156 ml, 0.64 mmol), and the mixture was stirred
for 10 min at the same temperature. A solution of 17
1232 mg, 0.36 mmol) in CH2Cl2 11.5 ml) was added to the
resulting mixture, and the stirring was continued for 1 h.
Triethylamine 1250 ml, 1.78 mmol) was added, and the
mixture was allowed to warm to room temperature with
stirring. The mixture was diluted with ether, then washed
with satd NH4Cl, water, and brine. The organic layer was
concentrated and puri®ed by chromatography 1hexane/
EtOAc, 10:1) to give the aldehyde 1232 mg, 100%): color-
To a mixture of the benzyl ether 15.8 g, 9.3 mmol) in MeOH
170 ml) and CH2Cl2 130 ml) at 08C was added camphor-
sulfonic acid 10.43 g, 1.9 mmol), and the mixture was stirred
for 22 h at room temperature. The reaction mixture was
quenched with triethylamine, concentrated and puri®ed by
chromatography 1hexane/EtOAc, 2:1) to give 16 14.95 g,
99%): colorless oil; Rfˆ0.34 1hexane/EtOAc, 2:1); IR
less oil; Rfˆ0.37 1hexane/EtOAc, 10:1); IR1neat)
1
1726 cm21; H NMR1300 MHz, CDCl ) d 9.47 1s, 1H),
3
7.35±7.24 1m, 5H), 4.49 1s, 2H), 3.96 1m, 2H), 3.80 1m,
1H), 3.76 1dd, Jˆ12.5, 4.8 Hz, 1H), 3.46 1m, 2H), 2.07
1m, 1H), 1.80±1.43 1m, 7H), 1.30 1s, 3H), 1.26 1s, 3H),
1.07 1s, 21H), 0.85 1s, 9H), 0.06 1s, 3H), 0.01 1s, 3H); 13C
NMR175 MHz, CDCl 3) d 201.7, 138.5, 127.6, 127.5, 81.9,
75.4, 73.0, 72.3, 70.4, 70.3, 67.6, 38.3, 32.3, 31.3, 25.9,
25.7, 19.7, 18.2, 18.2, 17.2, 17.9, 12.6, 0.00, 24.4, 25.1;
HRMS 1EI) calcd for C27H43O6Si 1M2C6H21Si) 491.2825,
found 491.2829.
;
1neat) 3600±3200, 1465 cm21 1H NMR1300 MHz,
CDCl3) d 7.35±7.20 1m, 5H), 4.49 1s, 2H), 3.94 1dd,
Jˆ11.7, 4.8 Hz, 1H), 3.94 1m, 1H), 3.81 1m, 1H), 3.74
1dd, Jˆ12.5, 3.5 Hz, 1H), 3.63±3.32 1m, 4H), 2.58 1brs,
2H), 2.05±1.38 1m, 8H), 1.25 1s, 3H), 1.19 1s, 3H), 1.07
1s, 21H); 13C NMR175 MHz, CDCl 3) d 138.4, 128.3,
128.2, 127.6, 127.5, 127.5, 77.8, 75.0, 73.2, 72.9, 72.5,
71.7, 70.2, 67.9, 37.9, 32.2, 30.2, 25.8, 19.4, 18.1, 18.0,
12.7.
To a stirred suspension of methyltriphenylphosphonium
bromide 1420 mg, 1.17 mmol) in THF 14 ml) at 08C was
added NaHMDS 11.2 ml, 1.0 M in THF, 1.2 mmol), and
the resulting mixture was stirred for 10 min at the same
6.1.10. TBS ether 17. To a mixture of 16 14.96 g, 9.2 mmol)
and 2,6-lutidine 14.33 ml, 37.1 mmol) in CH2Cl2 1100 ml) at
08C was added TBSOTf 15.5 ml, 23.9 mmol). After stirring
for 1 h at room temperature, the mixture was quenched with
MeOH at 08C, diluted with ether, then washed with satd
NaHCO3 and brine. The organic layer was concentrated
and puri®ed by chromatography 1hexane/EtOAc, 20:1) to
give the bis-silyl ether 16.92 g, 98%): colorless oil;
temperature. A solution of the aldehyde 1378 mg,
0.58 mmol) in THF 12 ml) was added to the mixture, and
the mixture was stirred for 0.5 h at 408C. The reaction was
quenched with water, and the mixture was extracted with
ether. The organic layer was washed with brine, dried, and
concentrated. The residue was diluted with hexane, and the
resulting solid was ®ltered off. The ®ltrate was concentrated
and puri®ed by chromatography 1hexane/EtOAc, 20:1) to
give the ole®n 12.8 g, 90%): colorless oil; Rfˆ0.45 1hexane/
1
Rfˆ0.25 1hexane/EtOAc, 20:1); IR1neat) 1641 cm 21; H
1
NMR1300 MHz, CDCl ) d 7.35±7.20 1m, 5H), 4.49 1s,
3
EtOAc, 20:1); IR1neat) 1647 cm 21; H NMR1300 MHz,
2H), 3.88 1m, 1H), 3.78 1m, 1H), 3.75 1dd, Jˆ12.3,
4.2 Hz, 1H), 3.54±3.36 1m, 5H), 1.94±1.40 1m, 8H), 1.21
1s, 3H), 1.20 1s, 3H), 1.07 1s, 21H), 0.87 1s, 9H), 0.85 1s, 9H),
0.06 1s, 3H), 0.02 1s, 3H), 0.02 1s, 6H); 13C NMR175 MHz,
CDCl3) d 128.3, 127.6, 127.5, 79.2, 74.3, 73.0, 72.2, 71.7,
71.4, 71.0, 70.4, 38.4, 32.3, 31.4, 26.0, 25.7, 19.5, 19.3,
18.4, 18.3, 17.8, 12.5, 23.9, 25.1, 25.3, 25.6.
CDCl3) d 7.35±7.24 1m, 5H), 5.85 1dd, Jˆ17.6, 11.0 Hz,
1H), 5.14 1dd, Jˆ17.6, 1.2 Hz, 1H), 4.97 1dd, Jˆ11.0,
1.5 Hz, 1H), 4.49 1s, 2H), 3.90 1m, 1H), 3.84 1dd, Jˆ12.5,
4.4 Hz, 1H), 3.83 1m, 1H), 3.59 1dd, Jˆ10.5, 5.0 Hz, 1H),
3.47 1m, 2H), 1.94±1.43 1m, 8H), 1.30 1s, 3H), 1.25 1s, 3H),
1.07 1s, 21H), 0.85 1s, 9H), 0.05 1s, 3H), 0.00 1s, 3H); 13C
NMR175 MHz, CDCl 3) d 145.2, 138.6, 128.3, 127.6, 127.5,
112.5, 78.3, 74.8, 73.6, 73.1, 72.9, 72.4, 71.2, 70.4, 38.4,
32.3, 31.6, 25.9, 25.8, 20.9, 19.9, 18.3, 17.9, 12.6, 24.1,
24.9.
To a mixture of the bis-silyl ether 16.37 g, 8.32 mmol) in
CH2Cl2 120 ml) and MeOH 160 ml) at 08C was added CSA
10.39 g, 1.7 mmol). After stirring for 18 h at the same
temperature, the mixture was quenched with triethylamine,
concentrated, and puri®ed by chromatography 1hexane/
EtOAc, 10:1) gave 17 14.18 g, 77%): colorless oil;
A stirred solution of the ole®n 1406 mg, 0.63 mmol) in THF
17 ml) at 08C was added BH3´SMe2 189 ml, 1.0 mmol). After
stirring for 1 h at the same temperature, the reaction mixture
was treated with 3N NaOH 12.1 ml, 6.3 mmol) and 30%
H2O2 12.2 ml, 7.6 mmol), and the mixture was stirred for
another 1 h. The reaction mixture was diluted with
ether, washed with satd aqueous Na2SO3 and brine. The
organic layer was concentrated and puri®ed by chromato-
graphy 1hexane/EtOAc, 10:1) to give 18 1309 mg, 74%):
Rfˆ0.32 1hexane/EtOAc, 10:1); IR1neat) 3600±3200,
1
1463 cm21; H NMR1300 MHz, CDCl ) d 7.35±7.20 1m,
3
5H), 4.48 1s, 2H), 3.99 1dd, Jˆ11.2, 5.3 Hz, 1H), 3.94 1m,
1H), 3.80 1m, 1H), 3.69 1dd, Jˆ12.1, 4.0 Hz, 1H), 3.46 1m,
2H), 3.27 1m, 2H), 2.41 1dd, Jˆ9.0, 3.7 Hz, 1H), 1.91±1.34
1m, 8H), 1.24 1s, 3H), 1.12 1s, 3H), 1.07 1s, 21H), 0.85 1s,
9H), 0.09 1s, 3H), 0.07 1s, 3H); 13C NMR175 MHz, CDCl 3)
d 138.5, 128.3, 127.6, 127.5, 78.6, 74.7, 73.1, 72.9, 72.6,
71.4, 70.3, 67.9, 67.5, 37.9, 32.3, 30.8, 25.8, 25.7, 20.0,
19.3, 18.1, 18.0, 17.8, 12.7, 12.5, 24.1, 25.2.
colorless oil; Rfˆ0.42 1hexane/EtOAc, 5:1); IR1neat)
1
3600±3200, 1463 cm21; H NMR1300 MHz, CDCl ) d
3
7.35±7.26 1m, 5H), 4.50 1s, 2H), 3.92 1m, 1H), 3.88 1m,
2H), 3.81 1dd, Jˆ11.7, 4.6 Hz, 1H), 3.73 1m, 1H), 3.57
1dd, Jˆ10.6, 5.1 Hz, 1H), 3.48 1m, 2H), 2.85 1bs, 1H),
1.91±1.45 1m, 10H), 1.31 1s, 3H), 1.23 1s, 3H), 1.11 1s,
21H), 0.86 1s, 9H), 0.10 1s, 3H), 0.06 1s, 3H); 13C NMR
6.1.11. Alcohol 18. To a solution of DMSO 156 ml,
0.78 mmol) in CH2Cl2 12 ml) at 2788C was added

1808
I. Kadota et al. / Tetrahedron 58.2002) 1799±1816
175 MHz, CDCl3) d 138.6, 128.4, 127.6, 127.5, 80.4, 75.6,
74.7, 73.2, 73.0, 72.5, 71.1, 70.3, 59.5, 43.4, 38.4, 32.3,
31.0, 25.9, 25.7, 21.1, 19.4, 18.4, 18.3, 17.8, 13.0, 23.8,
25.0; HRMS 1EI) calcd for C37H68O6Si2 1M1) 664.4550,
found 664.4554.
22.6, 21.4, 19.2, 18.4, 18.3, 17.8, 15.2, 14.1, 12.5, 23.9,
25.1; HRMS 1EI) calcd for C35H59O5Si2 1M2C3H7)
615.3901, found 615.3905.
6.1.14. Ester 29. A stirred solution of the carboxylic acid 5
1159 mg, 0.30 mmol), alcohol 6 1110 mg, 0.30 mmol),
DMAP 111 mg, 0.09 mmol) and CSA 121 mg, 0.09 mmol)
in CH2Cl2 13 ml) at 258C was treated with DCC 193 mg,
0.45 mmol). After 5 h, the reaction mixture was diluted
with ether and ®ltered through a Celite pad. The ®ltrate
was concentration and puri®ed by chromatography 1hexane/
EtOAc, 10:1) to afford 29 1109 mg, 45%): colorless oil;
Rfˆ0.29 1hexane/EtOAc, 10:1); 1H NMR1300 MHz,
CDCl3) d 7.51±7.46 1m, 2H), 7.38±7.22 1m, 13H), 5.56
1m, 1H), 5.45 1s, 1H), 5.42 1m, 1H), 4.97 1m, 1H), 4.51 1s,
2H), 4.50 1d, Jˆ11.7 Hz, 1H), 4.35 1d, Jˆ11.7 Hz, 1H), 4.23
1m, 1H), 3.92 1m, 2H), 3.67±3.40 1m, 7H), 2.53 1m, 2H),
2.25 1m, 2H), 2.02±1.60 1m, 6H), 1.61 1d, Jˆ6.6 Hz, 3H),
1.56 1s, 2H), 1.37 1s, 3H), 0.90 1s, 9H), 0.069 1s, 6H); 13C
NMR175 MHz, CDCl 3) d 170.2, 138.7, 137.8, 128.9, 128.2,
127.6, 127.5, 127.5, 127.4, 127.3, 126.5, 126.2, 125.5,
100.9, 83.6, 81.6, 79.9, 79.6, 78.5, 76.4, 76.0, 75.8, 74.9,
74.7, 74.0, 73.2, 72.1, 70.9, 69.6, 45.9, 32.0, 27.0, 25.9,
25.0, 24.1, 18.0, 18.0, 13.0, 24.2, 25.0.
6.1.12. Dibromoole®n 19. To a mixture of 18 1273 mg,
0.41 mmol), DMSO 11 ml), and triethylamine 1290 ml,
2.0 mmol) in CH2Cl2 14 ml) at 08C was added sulfur trioxide
pyridine complex 1260 mg, 1.6 mmol). After stirring for 2 h,
the reaction mixture was diluted with ether, then washed
with satd NH4Cl and brine. The organic layer was concen-
trated and puri®ed by chromatography 1hexane/EtOAc,
10:1) to give the aldehyde 1247 mg, 91%): colorless oil;
1
Rfˆ0.38 1hexane/EtOAc, 10:1); IR1neat) 1724 cm 21; H
NMR1300 MHz, CDCl ) d 9.89 1t, Jˆ3.1 Hz, 1H), 7.36±
3
7.26 1m, 5H), 4.49 1s, 2H), 3.93 1m, 1H), 3.83 1dd, Jˆ12.1,
4.3 Hz, 2H), 3.55 1dd, Jˆ10.8, 4.9 Hz, 1H), 3.48 1m, 2H),
2.45 1dd, Jˆ15.5, 3.4 Hz, 1H), 2.35 1bd, Jˆ14.5 Hz, 1H),
1.92±1.45 1m, 8H), 1.36 1s, 3H), 1.25 1s, 3H), 1.05 1s, 21H),
0.85 1s, 9H), 0.08 1s, 3H), 0.04 1s, 3H); 13C NMR1300 MHz,
CDCl3) d 203.8, 138.5, 128.4, 127.6, 127.5, 77.6, 77.2, 75.5,
74.7, 73.3, 73.0, 72.2, 71.2, 70.3, 55.2, 38.4, 32.3, 31.0,
30.3, 29.7, 25.9, 25.7, 22.7, 22.1, 19.4, 18.2, 18.2, 17.8,
12.6, 23.8, 25.1.
6.1.15. Vinylatannane 33. A solution of 32 1992 mg,
3.26 mmol) and HMPA 11.14 ml, 6.58 mmol) in THF
130 ml) was treated with KHMDS 113 ml, 0.5 M in toluene,
6.6 mmol) at 2788C. After stirring at 2788C for 2 h,
PhNTf2 12.37 g, 6.58 mmol) was added, and the mixture
was allowed to warm to 258C. After further stirring at
258C for 1 h, the reaction was quenched with water
1containing 1% of triethylamine), and the mixture was
extracted with ether. The organic layer was washed with
brine, concentrated, and subjected to chromatography
1pentane/ether, 10:1±5:1 containing 1% triethylamine) to
give the enol tri¯ate 1995 mg, 70%): colorless oil;
Rfˆ0.17 1hexane/EtOAc, 10:1); 1H NMR1300 MHz,
C6D6) d 7.62 1d, Jˆ6.8 Hz, 2H), 7.23±7.09 1m, 3H), 5.18
1s, 1H), 4.14 1dd, Jˆ5.0, 2.6 Hz, 1H), 4.09 1m, 1H), 3.40±
3.27 1m, 2H), 3.13 1m, 2H), 2.90 1ddd, Jˆ9.3, 9.3, 6.2 Hz,
1H), 1.84±1.54 1m, 6H).
To stirred solution of CBr4 1227 mg, 0.68 mmol) in CH2Cl2
11 ml) at 08C was added triphenylphosphine 1359 mg,
1.4 mmol). After 5 min, a solution of the aldehyde
1113 mg, 0.17 mmol) in CH2Cl2 11 ml) was added. After
stirring for 10 min, the mixture was diluted with CH2Cl2
and washed with brine. The organic layer was concentrated
and puri®ed by chromatography 1hexane/EtOAc, 10:1) to
give 19 1135 mg, 97%): colorless oil; Rfˆ0.45 1hexane/
1
EtOAc, 10:1); H NMR1300 MHz, CDCl ) d 7.34±7.20
3
1m, 5H), 6.61 1m, 1H), 4.48 1s, 2H), 3.90 1m, 1H), 3.81
1m, 1H), 3.76 1dd, Jˆ12.1, 4.2 Hz, 1H), 3.45 1m, 3H),
2.44 1dd, Jˆ15.4, 8.7 Hz, 1H), 1.87±1.38 1m, 8H), 1.19
1s, 3H), 1.17 1s, 3H), 1.06 1s, 21H), 0.87 1s, 9H), 0.08 1s,
6H); 13C NMR175 MHz, CDCl ) d 138.5, 135.9, 128.3,
3
127.6, 127.5, 88.8, 77.8, 75.2, 74.5, 73.2, 72.9, 72.2, 71.3,
70.3, 46.3, 38.4, 32.3, 31.3, 25.9, 25.7, 21.5, 19.3, 18.3,
18.2, 17.8, 12.7, 23.8, 25.1.
A mixture of the enol tri¯ate 1995 mg, 2.28 mmol), hexa-
methylditin 11.10 ml, 3.30 mmol), Pd1PPh3)4 194 mg,
0.08 mmol) and lithium chloride 1763 mg, 18 mmol) in
THF 120 ml) was heated at 808C for 5 h. The resulting
brown suspension was diluted with ether, ®ltered through
a Celite pad. The ®ltrate was concentrated and subjected to
chromatography 1hexane/ether, 300:1±5:1, containing 1%
triethylamine) to provide 33 1833 mg, 81%): colorless oil;
Rfˆ0.20 1hexane/ether, 10:1); 1H NMR1300 MHz, C 6D6) d
7.64±7.59 1m, 2H), 7.22±7.08 1m, 3H), 5.25 1s, 1H), 4.68
1m, 1H), 4.20 1dd, Jˆ8.8, 2.9 Hz, 1H), 3.51±3.28 1m, 5H),
2.28±2.10 1m, 2H), 2.04±1.83 1m, 4H), 0.19 1dd, Jˆ27.0,
6.1.13. Alkyne 3. To a stirred solution of ole®n 19 1225 mg,
0.27 mmol) in THF 13 ml) at 2788C was added n-butyl-
litium 10.36 ml, 1.6 M in hexane, 0.58 mmol), and the
mixture was stirred for 0.5 h at the same temperature. The
mixture was allowed to warm to 08C, quenched with satd
NH4Cl, and extracted with ether. The organic layer was
washed with brine 10.5 ml), concentrated, and puri®ed by
chromatography 1hexane/EtOAc, 10:1) to give the acetylene
3 1184 g, quantitative yield): colorless oil; Rfˆ0.46 1hexane/
EtOAc, 10:1); [a]24 ˆ149.08 1c 0.50, CHCl3); IR1neat)
D
2120, 1463 cm21; H NMR1300 MHz, CDCl ) d 7.35±
1
3
7.22 1m, 5H), 4.48 1s, 2H), 3.91 1s, 1H), 3.83 1m, 1H),
3.76 1dd, Jˆ12.1, 4.2 Hz, 1H), 3.46 1m, 3H), 2.45 1dd,
Jˆ16.3, 2.8 Hz, 1H), 2.45 1dd, Jˆ16.3, 2.8 Hz, 1H), 2.10
1d, Jˆ16.2 Hz, 1H), 1.90 1t, Jˆ2.0 Hz, 1H), 1.88±1.38 1m,
7H), 1.32 1s, 3H), 1.26 1s, 3H), 1.05 1s, 21H), 0.85 1s, 9H),
27.0 Hz, 9H); 13C NMR175 MHz, C D6) d 162.4, 138.8,
6
128.8, 128.2, 126.8, 109.9, 101.3, 82.4, 80.0, 78.9, 75.3,
70.0, 31.3, 29.8, 29.1, 29.79.
6.1.16. Alcohol 34. A solution of azeotropically dried 33
1400 mg, 0.89 mmol) in THF 18.0 ml) was treated dropwise
at 2788C with n-BuLi 10.52 ml, 1.67 M in n-hexane,
0.83 mmol). After stirring at 2788C for 20 min, a solution
0.08 1s, 3H), 0.05 1s, 3H); 13C NMR175 MHz, CDCl ) d
3
138.5, 128.3, 127.6, 127.5, 81.7, 77.7, 75.0, 74.2, 73.2, 72.9,
71.3, 69.7, 65.8, 38.4, 32.9, 32.3, 31.6, 31.4, 25.9, 25.7,

I. Kadota et al. / Tetrahedron 58.2002) 1799±1816
1809
of azeotropically dried aldehyde 25 1237 mg, 0.48 mmol) in
THF 12.0 ml) was added dropwise. After stirring for another
2 h at 2788C, the mixture was quenched with MeOH at this
temperature. The reaction mixture was allowed to warm up
to room temperature, diluted with ether, and washed with
brine. The organic layer was concentrated and subjected to
chromatography 1hexane/EtOAc, 10:1±1:1, containing 1%
triethylamine) to afford 34 1289 mg, 77%) as a mixture of
3H), 1.44±1.16 1m, 3H), 1.04 1s, 9H), 0.15 1s, 3H), 0.11
1s, 3H); 13C NMR175.45 MHz, C 6D6) d 149.0, 139.8,
138.7, 128.9, 128.4, 128.3, 127.8, 127.6, 127.4, 127.3,
126.7, 115.7, 101.2, 81.3, 81.3, 80.6, 79.6, 79.3, 76.4,
74.6, 74.5, 73.4, 72.8, 71.6, 69.8, 30.3, 30.1, 29.3, 28.8,
27.1, 26.2, 21.3, 18.5, 24.19, 24.66; HRMS 1EI) calcd
for C46H62O8Si 1M1) 770.4210, found 770.4192.
diastereomers. 34 1major isomer): colorless oil; Rfˆ0.27
6.1.18. Conversion of 35 to 30. To a solution of 35 168 mg,
0.088 mmol) in benzene 18 ml) was added RuCl21PPh3)3
185 mg, 0.089 mmol) at 258C. After stirring for 3 days at
808C, the mixture was ®ltered through a silica gel pad using
ether as an eluent. The ®ltrate was concentrated and puri®ed
by chromatography 1hexane/EtOAc, 10:1±4:1, containing
1% triethylamine) to give 30 141.6 mg, 61%).
1
1hexane/EtOAc, 2:1); H NMR1300 MHz, C D6) d 7.63
6
1d, Jˆ6.2 Hz, 2H), 7.35±7.04 1m, 13H), 5.26 1s, 1H), 4.82
1bdd, Jˆ2.4, 2.4 Hz, 1H), 4.53±4.28 1m, 6H), 4.18 1bd,
Jˆ8.1 Hz, 2H), 4.07 1s, 1H), 3.71 1bd, Jˆ10.1 Hz, 1H),
3.59 1dd, Jˆ9.6, 6.3 Hz, 1H), 3.54±3.30 1m, 8H), 2.30±
1.77 1m, 8H), 1.47 1s, 3H), 0.96 1s, 9H), 0.065 1d,
Jˆ6.2 Hz, 6H); 13C NMR175 MHz, C D6) d 153.4, 139.5,
6
139.4, 138.8, 128.9, 128.5, 128.3, 127.8, 127.6, 127.5,
126.7, 101.4, 97.5, 82.7, 82.3, 79.7, 79.1, 78.8, 77.2, 75.4,
74.0, 73.5, 72.5, 71.5, 69.9, 29.9, 29.5, 29.0, 27.5, 26.2,
18.4, 17.5, 24.08, 24.82.
6.1.19. Lactone 38. A mixture of 37 132.0 g, 115 mmol) and
5% Pd/C 11.0 g) in EtOAc 1500 ml) was vigorously stirred
under hydrogen atmosphere at room temperature. After
10 h, the catalyst was ®ltered off. The ®ltrate was concen-
trated and puri®ed by chromatography 1hexane/EtOAc, 1:1)
to give the saturated ester 131.5 g, 98%): colorless oil;
Rfˆ0.44 1hexane/EtOAc, 1:1); 1H NMR1300 MHz,
CDCl3) d 7.42±7.27 1m, 5H), 5.45 1s, 1H), 4.23 1dd,
Jˆ9.7, 3.8 Hz, 1H), 3.70±3.50 1m, 3H), 3.64 1s, 3H), 2.46
1d, Jˆ4.4 Hz, 1H), 2.37 1t, Jˆ7.0 Hz, 2H), 1.96±1.53 1m,
4H).
6.1.17. Enol ether 30. A solution of alcohol 34 113 mg,
0.017 mmol) in ether 11.0 ml) was treated with KH
119 mg of 35% in mineral oil, prewashed with hexane,
0.17 mmol) and carbon disul®de 15 ml, 0.083 mmol), and
the mixture was stirred 2 h at 258C. The reaction mixture
was quenched with methyl iodide 120 ml, 0.33 mmol),
diluted with ether, then washed with satd NH4Cl and
brine. The organic layer was concentrated to afford the
xanthate 113.8 mg, 95%) which was used directly for the
next step.
To a solution of DMSO 1510 ml, 7.2 mmol) in CH2Cl2
110 ml) at 2788C was added 1COCl)2 1470 ml, 5.4 mmol),
and the mixture was stirred for 0.5 h at the same tempera-
ture. A solution of the ester 11.0 g, 3.6 mmol) in CH2Cl2
15 ml) was added to the resulting mixture, and the stirring
was continued for 1 h. Triethylamine 12.5 ml, 18 mmol) was
added, and the mixture was allowed to warm to room
temperature with stirring. The mixture was diluted with
ether, then washed with satd NH4Cl, water, and brine. The
organic layer was concentrated to give the crude ketone
which was used for next reaction without puri®cation.
A mixture of xanthate 139 mg, 0.045 mmol), Bu3SnH
160 ml, 0.023 mmol) and AIBN 11 mg) in benzene 13 ml)
was heated at 808C for 30 min. The mixture was concen-
trated and subjected to chromatography 1hexane/EtOAc,
10:1±4:1, containing 1% triethylamine) to give 30 122 mg,
64%) and 35 13.9 mg, 11%).
Compound 30: colorless oil; Rfˆ0.46 1hexane/EtOAc, 4:1);
1H NMR1300 MHz, C D6) d 7.24 1d, Jˆ7.0 Hz, 2H), 7.36
To a mixture of the ketone in CH2Cl2 115 ml) at 2158C was
added AlMe3 14.4 ml, 0.98 M in hexane, 4.3 mmol). After
stirring at the same temperature for 2 h, the mixture was
quenched with MeOH and brine. The resulting white preci-
pitate was removed by ®ltration through a Celite pad. The
®ltrate was concentrated and puri®ed by chromatography
1hexane/EtOAc, 2:1) to give the methylcarbinol 1742 mg,
70%): colorless oil; Rfˆ0.21 1hexane/EtOAc, 2:1); 1H
6
1d, Jˆ7.3 Hz, 2H), 7.29 1d, Jˆ7.4 Hz, 2H), 7.22±7.07 1m,
9H), 5.27 1s, 1H), 4.50 1d, Jˆ11.7 Hz, 1H), 4.95 1s, 2H),
4.48±4.46 1m, 1H), 4.35 1d, Jˆ11.7 Hz, 1H), 4.31±4.20 1m,
2H), 4.09 1bd, Jˆ5.0 Hz, 1H), 3.78 1dd, Jˆ9.9, 2.6 Hz, 1H),
3.68 1dd, Jˆ9.9, 6.2 Hz, 1H), 3.58±3.30 1m, 6H), 2.39 1s,
2H), 2.22±1.60 1m, 8H), 1.50 1s, 3H), 1.42±1.20 1m, 2H),
0.99 1s, 9H), 0.051 1s, 6H); 13C NMR175.45 MHz, C 6D6) d
152.2, 139.6, 138.8, 128.9, 128.5, 127.8, 127.6, 127.5,
127.4, 101.4, 98.0, 82.3, 80.3, 79.6, 79.2, 78.8, 76.2, 75.4,
75.3, 73.4, 72.8, 71.4, 70.0, 45.3, 30.2, 29.7, 29.1, 26.2,
26.0, 25.9, 19.4, 18.3, 24.13, 24.80; HRMS 1EI) calcd
for C46H62O8Si 1M1) 770.4210, found 770.4178.
NMR1300 MHz, CDCl ) d 7.42±7.27 1m, 5H), 5.46 1s,
3
1H), 4.10 1dd, Jˆ14.1, 7.1 Hz, 1H), 3.87 1d, Jˆ10.6 Hz,
1H), 3.70±3.52 1m, 1H), 3.64 1s, 3H), 3.55 1d, Jˆ10.6 Hz,
1H), 2.36 1t, Jˆ6.9 Hz, 2H), 2.00±1.47 1m, 4H), 1.35 1s,
3H).
Compound 35: colorless oil; Rfˆ0.34 1hexane/EtOAc, 4:1);
To a mixture of the methyl ester 12.25 g, 7.64 mmol) in THF
120 ml) and H2O 110 ml) was added LiOH´H2O 1482 mg,
11.5 mmol), and the mixture was stirred at 408C for 1 h.
The mixture was cooled to 08C, acidi®ed by 1N HCl, and
extracted with EtOAc. The organic layer was concentrated
to give the crude carboxylic acid which was used for next
step without puri®cation.
IR1neat) 3032, 1682 cm 21; [a]21 ˆ21.978 1c 1.00,
D
1
CHCl3); H NMR1300 MHz, C D6) d 7.67 1d, Jˆ7.0 Hz,
6
2H), 7.38 1d, Jˆ6.8 Hz, 2H), 7.24±7.03 1m, 11H), 5.27 1s,
1H), 4.81 1s, 1H), 4.60±4.39 1m, 5H), 4.34 1d, Jˆ7.0 Hz,
1H), 4.20 1dd, Jˆ10.6, 4.7 Hz, 1H), 3.89 1dd, Jˆ10.1,
2.4 Hz, 1H), 3.76 1dd, Jˆ10.1, 6.0 Hz, 1H), 3.62 1ddd,
Jˆ14.5, 5.5, 3.7 Hz, 1H), 3.48±3.22 1m, 5H), 2.96 1ddd,
Jˆ14.6, 5.1, 4.2 Hz, 1H), 2.13±1.64 1m, 8H), 1.78 1s,
To a mixture of the carboxylic acid obtained above in THF

1810
I. Kadota et al. / Tetrahedron 58.2002) 1799±1816
150 ml) at 08C were added triethylamine 11.6 ml,
11.5 mmol) and 2,4,6-trichlorobenzoyl chloride 11.9 ml,
12.2 mmol). After stirring at the same temperature for 1 h,
the reaction mixture was diluted with benzene 1300 ml) and
added to a solution of DMAP 11.9 g, 15.3 mmol) in benzene
1150 ml) at room temperature. After 1 h, the mixture was
®ltered through a Celite pad, concentrated, and puri®ed by
chromatography 1hexane/EtOAc, 1:1) to give 38 11.97 g,
98%): colorless oil; Rfˆ0.47 1hexane/EtOAc, 1:1); 1H
1dd, Jˆ9.0, 3.3 Hz, 1H), 4.35 1s, 2H), 4.00 1d, Jˆ10.5 Hz,
1H), 3.79±3.68 1m, 2H), 3.64±3.58 1m, 1H), 3.34 1s, 3H),
1.90±1.40 1m, 4H).
6.1.22. Alcohol 41. To a solution of 40 15.91 g, 14.9 mmol)
in THF 1100 ml) at 08C was added BH3´SMe2 12.8 ml,
29.8 mmol), and the mixture was stirred at the same
temperature for 2 h. An aqueous solution of NaOH 11N,
50 ml) and 30% H2O2 110 ml) were added, and the mixture
was stirred at room temperature for 0.5 h. The mixture was
extracted with ether. The organic layer was washed with
saturated aqueous Na2SO3 and brine, then concentrated.
The residue was puri®ed by chromatography 1hexane/
EtOAc, 2:1) to give 41 13.28 g, 53%) and 42 12.25 g, 36%).
NMR1300 MHz, CDCl ) d 7.43±7.28 1m, 5H), 5.46 1s,
3
1H), 4.00 1d, Jˆ11.0 Hz, 1H), 3.77 1dd, Jˆ11.0, 3.8 Hz,
1H), 3.73 1d, Jˆ11.0 Hz, 1H), 2.78 1dd, Jˆ15.6, 5.9 Hz,
1H), 2.55 1ddd, Jˆ13.5, 13.5, 2.3 Hz, 1H), 2.06±1.65 1m,
4H), 1.64 1s, 3H).
6.1.20. Ester 39. To a stirred solution of 38 12.8 g,
10.7 mmol), PhNTf2 17.5 g, 21 mmol), and DMPU
13.9 ml, 32 mmol) in THF 1200 ml) at 2788C was added
KHMDS 139 ml, 0.7 M in toluene, 27 mmol). After stirring
for 0.5 h, the reaction mixture was quenched with H2O and
extracted with ether. The organic layer was washed with
brine and concentrated to give the crude enol tri¯ate
which was used for next reaction without puri®cation.
Compound 41: colorless oil; Rfˆ0.24 1hexane/EtOAc, 2:1);
1H NMR1300 MHz, CDCl ) d 7.43±7.40 1m, 2H), 7.30±
3
7.25 1m, 3H), 7.20 1d, Jˆ8.6 Hz, 2H), 6.81 1d, Jˆ8.6 Hz,
2H), 5.38 1s, 1H), 4.45 1d, Jˆ11.7 Hz, 1H), 4.38 1d,
Jˆ11.7 Hz, 1H), 3.90 1m, 1H), 3.80±3.70 1m, 2H), 3.75
1s, 3H), 3.54±3.45 1m, 3H), 3.34 1dd, Jˆ9.5, 6.4 Hz, 1H),
2.47 1brs, 1H), 2.00±1.65 1m, 4H).
Compound 42: colorless oil; Rfˆ0.18 1hexane/EtOAc, 2:1);
A mixture of the enol tri¯ate obtained above, Et3N 16.0 ml,
43 mmol), Pd1PPh3)4 1250 mg, 0.21 mmol), and MeOH
117 ml, 430 mmol) in DMF 150 ml) was stirred at room
temperature under the carbon monoxide atmosphere. After
13 h, the mixture was ®ltered through a silica gel pad. The
®ltrate was concentrated and puri®ed by chromatography
1hexane/EtOAc, 4:1) to give 39 13.0 g, 92%): colorless oil;
Rfˆ0.40 1hexane/EtOAc, 4:1); 1H NMR1300 MHz, C 6D6) d
7.58±7.54 1m, 2H), 7.25±7.10 1m, 3H), 6.45 1dd, Jˆ9.2,
3.8 Hz, 1H), 5.34 1s, 1H), 4.18 1d, Jˆ10.5 Hz, 1H), 3.74
1d, Jˆ10.5 Hz, 1H), 3.48 1dd, Jˆ11.2, 3.8 Hz, 1H), 3.37
1s, 3H), 1.90±1.40 1m, 4H).
1H NMR1300 MHz, CDCl ) d 7.43±7.40 1m, 2H), 7.30±
3
7.25 1m, 3H), 7.19 1d, Jˆ8.6 Hz, 2H), 6.82 1d, Jˆ8.6 Hz,
2H), 5.39 1s, 1H), 4.46 1d, Jˆ11.5 Hz, 1H), 4.40 1d,
Jˆ11.5 Hz, 1H), 3.92 1dd, Jˆ10.8, 4.1 Hz, 1H), 3.75±3.40
1m, 6H), 3.74 1s, 3H), 2.75 1brs, 1H), 2.00±1.50 1m, 4H).
6.1.23. TBS ether 43. To a stirred suspension of KH 132 mg
of a suspension in mineral oil, 0.28 mmol, prewashed with
hexane) in THF 11 ml) at 08C were added MPMCl 138 ml,
0.28 mmol) and a solution of 41 158 mg, 0.14 mmol) in THF
11.5 ml), and the mixture was stirred at room temperature
for 1 h. The reaction was quenched with MeOH at 08C,
diluted with ether, then washed with water and brine. The
organic layer was concentrated and puri®ed by chromato-
graphy 1hexane/EtOAc, 4:1) to give the bis-MPM ether
6.1.21. MPM ether 40. To a mixture of 39 14.51 g,
14.8 mmol) in CH2Cl2 1150 ml) at 2788C was added
DIBALH 133 ml, 1.0 M in CH2Cl2, 33 mmol), and the
mixture was stirred at the same temperature for 0.5 h. The
mixture was quenched with MeOH and brine, and the result-
ing white precipitate was removed by ®ltration through a
Celite pad. The ®ltrate was concentrated and puri®ed by
chromatography 1hexane/EtOAc, 2:1) to give the allylic
158 mg, 77%): colorless oil; Rfˆ0.21 1hexane/EtOAc,
1
4:1); H NMR1300 MHz, CDCl ) d 7.43±7.40 1m, 2H),
3
7.30±7.25 1m, 3H), 7.23 1d, Jˆ8.6 Hz, 2H), 7.17 1d,
Jˆ8.6 Hz, 2H), 6.80 1d, Jˆ8.6 Hz, 2H), 6.76 1d,
Jˆ8.6 Hz, 2H), 5.40 1s, 1H), 4.40 1s, 2H), 4.36 1d,
Jˆ11.5 Hz, 1H), 4.25 1d, Jˆ11.5 Hz, 1H), 3.99 1m, 1H),
3.75 1d, Jˆ10.3 Hz, 1H), 3.76 1s, 3H), 3.72 1s, 3H), 3.64
1m, 1H), 3.55 1d, Jˆ10.3 Hz, 1H), 3.46 1dd, Jˆ11.6, 3.7 Hz,
1H), 3.35 1dd, Jˆ9.9, 5.1 Hz, 1H), 3.24 1dd, Jˆ9.9, 5.9 Hz,
1H), 2.02±1.93 1m, 2H), 1.67±1.46 1m, 2H), 1.44 1s, 3H).
alcohol 14.06 g, 99%): colorless oil; Rfˆ0.27 1hexane/
1
EtOAc, 2:1); H NMR1300 MHz, C D6) d 7.58±7.54 1m,
6
2H), 7.25±7.10 1m, 3H), 5.38 1s, 1H), 4.95 1dd, Jˆ8.8,
3.3 Hz, 1H), 3.95 1d, Jˆ10.6 Hz, 1H), 3.71 1m, 2H), 3.69
1d, Jˆ10.6 Hz, 1H), 3.61 1m, 1H), 2.00±1.50 1m, 4H).
To a mixture of the MPM ether obtained above 13.37 g,
6.3 mmol) in MeOH 1100 ml) and CH2Cl2 120 ml) was
added camphorsulfonic acid 1732 mg, 3.15 mmol). After
stirring at room temperature for 27 h, the mixture was
quenched with triethylamine, concentrated, and puri®ed
by chromatography 1hexane/EtOAc, 1:1±0:1) to give the
To a stirred suspension of KH 13.2 g of a suspension in
mineral oil, 27.4 mmol, prewashed with hexane) in THF
170 ml) at 08C were added MPMCl 13.7 ml, 27.4 mmol)
and a solution of the alcohol obtained above 13.78 g,
13.7 mmol) in THF 140 ml), and the mixture was stirred at
room temperature for 1 h. The reaction was quenched with
MeOH at 08C, diluted with ether, then washed with water
and brine. The organic layer was concentrated and puri®ed
by chromatography 1hexane/EtOAc, 10:1±2:1) to give 40
1
diol 12.36 g, 84%): colorless crystal; Rfˆ0.47 1EtOAc); H
NMR1300 MHz, CDCl 3) d 7.25 1d, Jˆ8.6 Hz, 2H), 7.19 1d,
Jˆ8.6 Hz, 2H), 6.90 1d, Jˆ8.6 Hz, 2H), 6.87 1d, Jˆ8.6 Hz,
2H), 4.51±4.40 1m, 3H), 4.26 1d, Jˆ11.4 Hz, 1H), 3.90±
3.40 1m, 6H), 3.82 1s, 6H), 2.10±1.65 1m, 4H), 1.28 1s, 3H).
15.43 g, 100%): colorless oil; Rfˆ0.08 1hexane/EtOAc,
1
10:1); H NMR1300 MHz, C D6) d 7.63±7.56 1m, 2H),
7.23±7.19 1m, 5H), 6.83±6.75 1m, 2H), 5.39 1s, 1H), 5.32
6
To a mixture of the diol obtained above 12.36 g, 5.29 mmol)

I. Kadota et al. / Tetrahedron 58.2002) 1799±1816
1811
in CH2Cl2 160 ml) at 08C were added 2,6-lutidine 11.9 ml,
15.9 mmol) and TBSOTf 12.9 ml, 12.7 mmol), and the
mixture was stirred at room temperature for 1.5 h. The
mixture was quenched with MeOH, diluted with ether,
then washed with satd NaHCO3 and brine. The organic
layer was concentrated and puri®ed by chromatography
1hexane/EtOAc, 8:1) to give the bis-TBS ether 13.44 g,
96%): colorless oil; Rfˆ0.23 1hexane/EtOAc, 8:1); 1H
1m, 4H), 1.26 1s, 3H), 0.91 1s, 9H), 0.040 1s, 6H); 13C NMR
175.45 MHz, CDCl3) d 158.9, 158.8, 144.3, 131.0, 131.0,
129.1, 129.0, 113.6, 113.5, 112.5, 80.3, 78.5, 76.9, 74.4,
72.8, 71.6, 70.8, 55.2, 25.9, 25.4, 25.3, 19.6, 18.1, 24.38,
25.12.
To a mixture of cyclohexene 1100 ml, 1.00 mmol) in THF
10.2 ml) at 08C was added BH3´SMe2 148 ml, 0.50 mmol),
and the mixture was stirred for 15 min at the same tempera-
ture. A solution of the ole®n 1180 mg, 323 mmol) in THF
11.0 ml) was added dropwise. After 30 min, the reaction
mixture was treated with 3N NaOH 10.5 ml, 1.5 mmol)
and 30% H2O2 10.5 ml). The cooling bath was removed,
and the reaction mixture was stirred for another 30 min.
The reaction mixture was diluted with ether and washed
with brine. The organic layer was concentrated and puri®ed
by chromatography 1hexane/ether, 2:1±1:1) to afford 44
1155.9 mg, 84%): colorless oil; Rfˆ0.14 1hexane/ether,
NMR1300 MHz, CDCl ) d 7.22 1d, Jˆ8.6 Hz, 2H), 7.13
3
1d, Jˆ8.6 Hz, 2H), 6.80 1d, Jˆ8.6 Hz, 2H), 6.77 1d,
Jˆ8.6 Hz, 2H), 4.51±4.40 1m, 3H), 4.30 1d, Jˆ11.2 Hz,
1H), 4.00 1m, 1H), 3.81 1m, 1H), 3.75 1s, 6H), 3.53 1dd,
Jˆ10.3, 2.8 Hz, 1H), 3.45 1dd, Jˆ10.2, 5.5 Hz, 1H),
3.34±3.26 1m, 3H), 1.90±1.65 1m, 4H), 0.87 1s, 9H), 0.85
1s, 9H), 20.01 1s, 9H), 20.03 1s, 3H).
To a mixture of the bis-TBS ether 13.44 g, 5.1 mmol) in
MeOH 140 ml) and CH2Cl2 114 ml) at 08C was added
camphorsulfonic acid 1273 mg, 1.02 mmol). After stirring
at 08C for 1.5 h, the mixture was quenched with triethyl-
amine, diluted with ether, then washed with water and brine.
The organic layer was concentrated and puri®ed by
chromatography 1hexane/EtOAc, 4:1) to give 43 12.59 g,
1:1); IR1neat) 3600±3200, 1612 cm 21; [a]24 ˆ220.48 1c
D
1.00, CHCl3); 1H NMR1300 MHz, CDCl 3) d 7.24 1d,
Jˆ8.6 Hz, 2H), 7.15 1d, Jˆ8.6 Hz, 2H), 6.87 1d,
Jˆ8.6 Hz, 2H), 6.84 1d, Jˆ8.6 Hz, 2H), 4.45 1m, 3H),
4.22 1d, Jˆ11.4 Hz, 1H), 3.96±3.47 1m, 4H), 3.79 1s, 6H),
3.44±3.27 1m, 1H), 1.94±1.50 1m, 6H), 1.25 1s, 3H), 0.86 1s,
9H), 0.04 1s, 3H), 0.02 1s, 3H); 13C NMR175 MHz, CDCl3)
d 159.1, 130.4, 130.3, 129.4, 129.2, 113.7, 82.8, 78.8, 77.6,
74.2, 72.7, 71.1, 70.5, 59.4, 55.2, 42.2, 35.5, 26.3, 25.8,
25.4, 17.9, 16.2, 24.11, 25.03; HRMS 1EI) calcd for
C24H41O6Si 1M2C8H9O) 453.2672, found 453.2680.
1
91%): colorless crystal; Rfˆ0.15 1hexane/EtOAc, 4:1); H
NMR1300 MHz, CDCl 3) d 7.20 1d, Jˆ8.6 Hz, 2H), 7.11 1d,
Jˆ8.6 Hz, 2H), 6.84 1d, Jˆ8.6 Hz, 2H), 6.81 1d, Jˆ8.6 Hz,
2H), 4.45 1d, Jˆ11.7 Hz, 1H), 4.43 1d, Jˆ11.2 Hz, 1H), 4.38
1d, Jˆ11.7 Hz, 1H), 4.23 1d, Jˆ11.2 Hz, 1H), 3.81±3.75 1m,
1H), 3.76 1s, 3H), 3.75 1s, 3H), 3.58 1dd, Jˆ10.1, 3.1 Hz,
1H), 3.43±3.32 1m, 5H), 2.27 1brs, 1H), 1.92±1.80 1m, 2H),
1.65±1.47 1m, 2H), 1.18 1s, 3H), 0.84 1s, 9H), 0.01 1s, 3H),
20.02 1s, 3H).
6.1.25. Ketone 45. To a mixture of DMSO 1430 ml,
6.05 mmol) in CH2Cl2 120 ml) at 2788C was added
1COCl)2 1430 ml, 4.94 mmol), and the mixture was stirred
at the same temperature. After 10 min, a solution of alcohol
44 11.38 g, 2.40 mmol) was added dropwise. After stirring
for 1.5 h, triethylamine 11.70 ml, 12.2 mmol) was added,
and the reaction mixture was allowed to warm to room
temperature. The mixture was diluted with ether, then
washed with satd NH4Cl, and brine. The organic layer
was concentrated and puri®ed by chromatography 1hexane/
6.1.24. Alcohol 44. To a solution of DMSO 176 ml,
1.07 mmol) in CH2Cl2 15 ml) at 2788C was added
1COCl)2 176 ml, 0.87 mmol), and the mixture was stirred
for 10 min at the same temperature. A solution of 43
1272 mg, 0.49 mmol) in CH2Cl2 12 ml) was added to the
resulting mixture, and the stirring was continued for 1 h.
Triethylamine 1340 ml, 2.43 mmol) was added, and the
mixture was allowed to warm to room temperature with
stirring. The mixture was diluted with ether, then washed
with satd NH4Cl, water, and brine. The organic layer was
concentrated to give the crude aldehyde which was used for
next reaction without puri®cation.
EtOAc, 2:1) to give the aldehyde 11.18 g, 86%): colorless
oil; Rfˆ0.26 1hexane/EtOAc, 4:1); IR1neat) 1720 cm
21
;
[a]24 ˆ212.88 1c 1.00, CHCl3); 1H NMR1300 MHz,
D
CDCl3) d 9.86 1dd, Jˆ2.9, 2.9 Hz, 1H), 7.22 1d,
Jˆ8.6 Hz, 2H), 7.19 1d, Jˆ8.6 Hz, 2H), 6.86 1d,
Jˆ8.6 Hz, 2H), 6.84 1d, Jˆ8.6 Hz, 2H), 4.44 1m, 3H),
4.28 1d, Jˆ11.1 Hz, 1H), 3.90±3.68 1m, 1H), 3.80 1s, 6H),
3.58±3.36 1m, 4H), 2.49 1dd, Jˆ15.1, 2.4 Hz, 1H), 2.42 1dd,
Jˆ15.1, 3.3 Hz, 1H), 1.98±1.52 1m, 4H), 1.33 1s, 3H), 0.88
1s, 9H), 0.04 1s, 3H), 0.03 1s, 3H); 13C NMR175 MHz,
CDCl3) d 203.6, 159.0, 130.4, 130.5, 129.2, 129.1, 113.7,
80.0, 78.5, 77.8, 74.7, 72.8, 71.6, 70.6, 55.2, 54.3, 26.2,
25.8, 25.1, 17.9, 17.5, 24.12, 25.00; HRMS 1EI) calcd
for C24H39O6Si 1M2C8H9O) 451.2516, found 451.2534.
To a stirred suspension of methyltriphenylphosphonium
bromide 1433 mg, 1.21 mmol) in THF 15 ml) at 08C was
added dropwise NaHMDS 11.20 ml, 1.0 M in THF,
1.20 mmol). After stirring for 10 min, a solution of the
crude aldehyde in THF 12 ml) was added, and the mixture
was stirred for another 1 h. The reaction mixture was
quenched with acetone, diluted with ether, then washed
with water and brine. The organic layer was concentrated
and diluted with hexane. The resulting solid was ®ltered off.
The ®ltrate was concentrated and puri®ed by column
chromatography 1hexane/EtOAc, 4:1) to give the ole®n
To a stirred solution of aldehyde 11.18 g, 2.06 mmol) in
ether 120 ml) at 08C was added MeMgI 14.3 ml, 1.0 M in
THF, 3.54 mmol). After stirring for 0.5 h, the reaction was
quenched with aqueous saturated NH4Cl, and the mixture
was extracted with ether. The organic layer was washed
with brine and concentrated to give the crude alcohol.
1245.7 mg, 91%): colorless oil; Rfˆ0.46 1hexane/EtOAc,
1
4:1); H NMR1300 MHz, CDCl ) d 7.28±7.16 1m, 4H),
3
6.88±6.81 1m, 4H), 5.86 1dd, Jˆ17.3, 10.8 Hz, 1H), 5.27
1dd, Jˆ17.2, 1.8 Hz, 1H), 5.02 1dd, Jˆ10.7, 1.8 Hz, 1H),
4.54±4.44 1m, 3H), 4.34 1d, Jˆ11.2 Hz, 1H), 4.01 1m, 1H),
3.80 1s, 6H), 3.70 1m, 1H), 3.63±3.37 1m, 3H), 1.94±1.58
To a solution of DMSO 10.33 ml, 4.64 mmol) in CH2Cl2

1812
I. Kadota et al. / Tetrahedron 58.2002) 1799±1816
15 ml) at 2788C was added 1COCl)2 1330 ml, 3.80 mmol),
and the mixture was stirred at the same temperature. After
10 min, a solution of the alcohol obtained above in CH2Cl2
115 ml) was added dropwise. After stirring for 1.5 h,
triethylamine 11.48 ml, 10.6 mmol) was added, and the
reaction mixture was allowed to warm to room temperature.
The mixture was diluted with ether, then washed with satd
NH4Cl, and brine. The organic layer was concentrated to
give the crude ketone: colorless oil; Rfˆ0.23 1hexane/
EtOAc, 2:1); 1H NMR1300 MHz, CDCl 3) d 7.22 1d,
Jˆ8.6 Hz, 2H), 7.17 1d, Jˆ8.6 Hz, 2H), 6.86 1d,
Jˆ8.6 Hz, 2H), 6.84 1d, Jˆ8.6 Hz, 2H), 4.44 1m, 3H),
4.27 1d, Jˆ11.4 Hz, 1H), 3.80 1m, 1H), 3.80 1s, 6H), 3.68
1m, 1H), 3.50±3.38 1m, 3H), 2.62 1d, Jˆ12.7 Hz, 1H), 2.45
1d, Jˆ12.7 Hz, 1H), 2.19 1s, 3H), 1.94±1.56 1m, 4H), 1.25
1s, 3H), 0.88 1s, 9H), 0.06 1s, 6H).
concentrated and puri®ed by chromatography 1hexane/
EtOAc, 2:1±1:1) to give 47 1950 mg, 97%): colorless
crystal; Rfˆ0.40 1hexane/EtOAc, 1:1); IR1neat) 3600±
3200, 1732 cm21; [a]27 ˆ211.08 1c 1.00, CHCl3); 1H
D
NMR1300 MHz, CDCl ) d 7.22 1d, Jˆ8.6 Hz, 2H), 7.18
3
1d, Jˆ8.6 Hz, 2H), 6.87 1d, Jˆ8.6 Hz, 2H), 6.83 1d,
Jˆ8.6 Hz, 2H), 4.47 1s, 2H), 4.43 1d, Jˆ11.7 Hz, 1H),
4.33 1d, Jˆ11.7 Hz, 1H), 4.16 1q, Jˆ7.2 Hz, 2H), 3.99 1m,
1H), 3.80 1s, 3H), 3.79 1s, 3H), 3.71±3.63 1m, 2H), 3.42 1dd,
Jˆ9.9, 5.3 Hz, 1H), 3.28 1dd, Jˆ9.9, 6.2 Hz, 1H), 3.14 1dd,
Jˆ11.6, 3.6 Hz, 1H), 2.65 1dd, Jˆ15.6, 3.9 Hz, 1H), 2.40
1dd, Jˆ15.6, 9.3 Hz, 1H), 2.02±1.72 1m, 3H), 1.68±1.52 1m,
3H), 1.39 1s, 3H), 1.27 1t, Jˆ7.2 Hz, 3H), 1.25 1s, 3H); 13C
NMR175 MHz, CDCl 3) d 172.2, 159.1, 130.7, 130.4, 129.2,
128.9, 113.7, 113.6, 86.8, 82.8, 78.3, 76.3, 75.5, 72.9, 72.3,
70.3, 70.0, 60.6, 56.0, 55.3, 35.0, 29.7, 24.9, 23.3, 23.2,
15.5, 14.2; HRMS 1EI) calcd for C24H35O8 1M2C8H9O)
451.2330, found 451.2302.
To a stirred solution of the crude ketone in THF 110 ml) at
room temperature was added TBAF 12.5 ml, 1.0 M in THF,
2.5 mmol). After stirring for 16 h, the reaction mixture was
diluted with EtOAc and washed with brine. The organic
layer was concentrated and puri®ed by chromatography
1hexane/EtOAc, 4:1±1:1) to give 45 1810 mg, 81%): color-
less oil; Rfˆ0.26 1hexane/EtOAc, 1:1); 1H NMR1300 MHz,
CDCl3) d 7.22 1d, Jˆ8.6 Hz, 2H), 7.17 1d, Jˆ8.6 Hz, 2H),
6.86 1d, Jˆ8.6 Hz, 2H), 6.84 1d, Jˆ8.6 Hz, 2H), 4.50±4.38
1m, 3H), 4.23 1d, Jˆ11.2 Hz, 1H), 3.84 1m, 1H), 3.80 1s,
3H), 3.80 1s, 3H), 3.62±3.50 1m, 2H), 3.41±3.37 1m, 2H),
2.73 1d, Jˆ12.7 Hz, 1H), 2.65 1d, Jˆ12.7 Hz, 1H), 2.63 1m,
1H), 2.21 1s, 3H), 2.00±1.86 1m, 2H), 1.72±1.58 1m, 3H),
6.1.28. TMS ether 48. A stirred solution of alcohol 47
118 mg, 0.031 mmol) in CH2Cl2 10.5 ml) at 258C was treated
with 1-1trimethylsilyl)imidazole 10.1 ml, 0.68 mmol). After
stirring for 16 h, the mixture was quenched with MeOH and
concentrated to give the silyl ether 121 mg, 100%): colorless
oil; Rfˆ0.31 1hexane/EtOAc, 4:1); IR1neat) 1738 cm
21
;
[a]27 ˆ28.228 1c 1.00, CHCl3); 1H NMR1300 MHz,
D
CDCl3) d 7.23 1d, Jˆ8.6 Hz, 2H), 7.19 1d, Jˆ8.6 Hz, 2H),
6.87 1d, Jˆ8.6 Hz, 2H), 6.83 1d, Jˆ8.6 Hz, 2H), 4.48 1s,
2H), 4.43 1d, Jˆ11.7 Hz, 1H), 4.30 1d, Jˆ11.7 Hz, 1H),
4.16 1m, 2H), 3.98 1m, 1H), 3.81 1s, 3H), 3.79 1s, 3H),
3.70 1dd, Jˆ10.3, 2.6 Hz, 1H), 3.66 1m, 1H), 3.42 1dd,
Jˆ9.9, 5.3 Hz, 1H), 3.29 1dd, Jˆ9.9, 6.4 Hz, 1H), 3.17
1dd, Jˆ11.8, 3.7 Hz, 1H), 2.60 1dd, Jˆ15.4, 2.6 Hz, 1H),
2.30 1dd, Jˆ15.4, 10.5 Hz, 1H), 2.00±1.75 1m, 4H), 1.64±
1.48 1m, 2H), 1.37 1s, 3H), 1.26 1t, Jˆ7.2 Hz, 3H), 1.26 1s,
1.30 1s, 3H); 13C NMR175 MHz, CDCl ) d 210.0, 159.0,
3
130.4, 130.3, 129.2, 129.2, 113.7, 113.6, 80.0, 77.6, 74.0,
72.7, 71.7, 70.4, 55.3, 55.2, 32.7, 26.2, 25.1, 16.1.
6.1.26. Ester 46. To a stirred solution of 45 1810 mg,
1.71 mmol) in CH2Cl2 18 ml) at room temperature were
added N-methylmorphorine 10.38 ml, 3.42 mmol) and
ethyl propiolate 10.35 ml, 3.42 mmol). After stirring at
308C for 16 h, the reaction mixture was diluted with
EtOAc and washed with brine. The organic layer was
concentrated and puri®ed by chromatography 1hexane/
3H), 0.106 1s, 9H); 13C NMR175 MHz, CDCl ) d 172.3,
3
159.1, 158.9, 130.7, 130.5, 129.2, 128.9, 113.7, 113.6, 86.8,
83.1, 78.3, 76.2, 75.5, 73.1, 72.8, 72.3, 69.9, 60.4, 55.7,
55.2, 34.5, 24.9, 24.5, 23.2, 15.8, 14.2, 2.65; HRMS 1EI)
calcd for C34H49O9Si 1M2CH3) 629.3146, found 629.3142.
EtOAc, 4:1±2:1) to give 46 1978 mg, 100%): colorless oil;
Rfˆ0.47 1hexane/EtOAc, 1:1); IR1neat) 1706 cm
To a suspension of LiAlH4 173.4 mg, 1.78 mmol) in ether
115 ml) at 08C was added a solution of the silyl ether 11.15 g,
1.78 mmol) in Et2O 15 ml). After stirring at 08C for 0.5 h,
the reaction mixture was quenched with MeOH and brine,
and the resulting white precipitate was removed by ®ltration
through a Celite pad. The ®ltrate was concentrated and
puri®ed by chromatography 1hexane/EtOAc, 2:1) to give
48 11.07 g, 100%): colorless oil; Rfˆ0.31 1hexane/EtOAc,
21
;
[a]27 ˆ27.678 1c 1.00, CHCl3); 1H NMR1300 MHz,
D
CDCl3) d 7.46 1d, Jˆ12.5 Hz, 1H), 7.22 1d, Jˆ8.6 Hz,
2H), 7.15 1d, Jˆ8.6 Hz, 2H), 6.86 1d, Jˆ8.6 Hz, 2H), 6.83
1d, Jˆ8.6 Hz, 2H), 5.26 1d, Jˆ12.5 Hz, 1H), 4.48±4.37 1m,
3H), 4.27 1d, Jˆ11.2 Hz, 1H), 4.15 1q, Jˆ7.1 Hz, 2H), 4.03
1dd, Jˆ10.4, 2.7 Hz, 1H), 3.82 1m, 1H), 3.80 1s, 3H), 3.80 1s,
3H), 3.53±3.36 1m, 3H), 2.67 1d, Jˆ12.7 Hz, 1H), 2.50 1d,
Jˆ12.7 Hz, 1H), 2.19 1s, 3H), 2.02±1.64 1m, 4H), 1.31 1s,
3H), 1.26 1t, Jˆ7.1 Hz, 3H); 13C NMR175 MHz, CDCl 3) d
207.8, 167.8, 161.6, 159.1, 159.1, 130.2, 129.3, 129.2,
113.7, 113.7, 98.2, 86.9, 78.8, 74.6, 72.8, 71.4, 70.8, 59.8,
55.2, 53.2, 33.0, 24.8, 22.7, 17.3, 14.3; HRMS 1EI) calcd for
C24H33O7 1M2C8H9O2) 449.2176, found 449.2197.
2:1); IR1neat) 3600±3200 cm 21; [a]28 ˆ29.918 1c 1.00,
D
CHCl3); 1H NMR1500 MHz, CDCl
)
3
d
7.23 1d,
Jˆ8.6 Hz, 2H), 7.19 1d, Jˆ8.6 Hz, 2H), 6.87 1d,
Jˆ8.6 Hz, 2H), 6.83 1d, Jˆ8.6 Hz, 2H), 4.48 1s, 2H), 4.43
1d, Jˆ11.4 Hz, 1H), 4.32 1d, Jˆ11.4 Hz, 1H), 4.00 1m, 1H),
3.82 1m, 1H), 3.81 1s, 3H), 3.79 1s, 3H), 3.77 1m, 1H), 3.67
1m, 1H), 3.42 1dd, Jˆ9.9, 5.2 Hz, 1H), 3.35 1dd, Jˆ9.8,
2.9 Hz, 1H), 3.29 1dd, Jˆ9.9, 6.4 Hz, 1H), 3.16 1dd,
Jˆ11.9, 3.7 Hz, 1H), 1.98±1.92 1m, 2H), 1.90±1.79 1m,
2H), 1.66 1m, 1H), 1.60 1m, 1H), 1.51 1m, 1H), 1.38 1s,
3H), 1.29 1s, 3H), 0.12 1s, 9H); 13C NMR1125 MHz,
CDCl3) d 159.1, 159.0, 130.7, 130.5, 129.2, 128.9, 113.7,
113.7, 87.4, 86.7, 78.3, 76.3, 75.3, 73.7, 72.9, 72.3, 70.0,
62.6, 55.9, 55.2, 30.8, 25.0, 24.6, 23.6, 15.7, 2.67; HRMS
6.1.27. Alcohol 47. To a stirred solution of 46 1978 mg,
1.71 mmol) and MeOH 1210 ml, 5.13 mmol) in THF
117 ml) at 08C was added SmI2 152 ml, 0.1 M in THF,
5.2 mmol). After stirring at 08C for 15 min, the reaction
mixture was diluted with EtOAc, then washed with satu-
rated aqueous Na2S2O3 and brine. The organic layer was

I. Kadota et al. / Tetrahedron 58.2002) 1799±1816
1813
1EI) calcd for C25H41O7Si 1M2C8H9O) 481.2619, found
481.2605.
3.81 1s, 3H), 3.79 1s, 3H), 3.67 1m, 1H), 3.41 1dd, Jˆ9.9,
5.2 Hz, 1H), 3.28 1dd, Jˆ9.9, 6.1 Hz, 1H), 3.09 1dd, Jˆ10.5,
1.7 Hz, 1H), 3.04 1dd, Jˆ11.9, 3.8 Hz, 1H), 2.60 1dddd,
Jˆ17.4, 7.3, 7.3, 1.8 Hz, 1H), 2.55 1dddd, Jˆ17.4, 17.4,
7.3, 7.3 Hz, 1H), 2.10±1.39 1m, 8H), 1.38 1s, 3H), 1.27 1s,
6.1.29. Enol ether 49. To a stirred mixture of 48 1181 mg,
0.30 mmol), DMSO 10.3 ml), and triethylamine 1250 ml,
1.80 mmol) in CH2Cl2 13 ml) at 08C was added sulfur
trioxide/pyridine complex 1143 mg, 0.90 mmol). After stir-
ring at 258C for 3.5 h, the reaction mixture was diluted with
ether and washed with satd NH4Cl. The organic layer was
concentrated and puri®ed by chromatography 1hexane/
EtOAc, 4:1) to give the aldehyde 1153 mg, 85%): colorless
oil; Rfˆ0.29 1hexane/EtOAc, 4:1); 1H NMR1300 MHz,
CDCl3) d 9.74 1dd, Jˆ2.4, 2.4 Hz, 1H), 7.23 1d,
Jˆ8.6 Hz, 2H), 7.19 1d, Jˆ8.6 Hz, 2H), 6.87 1d,
Jˆ8.6 Hz, 2H), 6.83 1d, Jˆ8.6 Hz, 2H), 4.48 1s, 2H), 4.45
1d, Jˆ11.3 Hz, 1H), 4.32 1d, Jˆ11.3 Hz, 1H), 3.99 1dd,
Jˆ4.6, 4.6 Hz, 1H), 3.81 1s, 3H), 3.79 1s, 3H), 3.74 1dd,
Jˆ9.2, 4.6 Hz, 1H), 3.67 1m, 1H), 3.42 1dd, Jˆ9.9,
5.3 Hz, 1H), 3.29 1dd, Jˆ9.8, 6.5 Hz, 1H), 3.18 1dd,
Jˆ11.7, 3.5 Hz, 1H), 2.58 1ddd, Jˆ15.4, 3.3, 3.3 Hz,
1H), 2.43 1ddd, Jˆ15.4, 9.1, 2.1 Hz, 1H), 2.20±1.75 1m,
4H), 1.64±1.48 1m, 2H), 1.38 1s, 3H), 1.27 1s, 3H), 0.10
1s, 9H).
3H); 13C NMR175 MHz, CDCl ) d 203.2, 159.4, 159.3,
3
131.0, 130.8, 129.6, 129.3, 114.0, 114.0, 87.1, 86.0, 78.6,
76.6, 75.9, 73.2, 72.7, 71.0, 70.3, 56.2, 55.6, 41.8, 25.2,
23.8, 23.4, 21.9, 15.8.
To a mixture of the aldehyde 175 mg, 0.14 mmol) in
t-BuOH/H2O 12:1, 0.8 ml) at room temperature were
added 2-methyl-2-butene 164 ml, 0.6 mmol), NaH2PO4
158 mg, 0.48 mmol), and sodium chlorite 155 mg,
0.48 mmol). After vigorous stirring for 1 h, the reaction
mixture was diluted with EtOAc and washed with brine.
The organic layer was concentrated to give the crude
carboxylic acid.
To a mixture of the carboxylic acid obtained above in THF
10.4 ml) at 08C were added triethylamine 130 ml, 0.22 mol)
and 2,4,6-trichlorobenzoyl chloride 135 ml, 0.22 mmol).
After stirring at room temperature for 1.5 h, the reaction
mixture was diluted with benzene 12 ml) and added to a
solution of DMAP 135 mg, 0.29 mmol) in benzene 12 ml).
After 40 min, the mixture was concentrated, diluted with
EtOAc, and ®ltered through a Celite pad. The ®ltrate was
puri®ed by chromatography 1hexane/EtOAc, 2:1) to give 50
166 mg, 89%): colorless crystal; Rfˆ0.40 1hexane/EtOAc,
To a stirred solution of methoxymethyltriphenylphos-
phonium chloride 1318 mg, 0.90 mmol) in THF 11 ml) at
2788C was added NaHMDS 10.9 ml, 1.0 M solution in
THF, 0.9 mmol). After stirring for 30 min, a solution of
the aldehyde 1153 mg) in THF 11.5 ml) was added, and
the mixture was stirred at room temperature for 1 h. The
reaction mixture was quenched with water and extracted
with ether. The organic layer was washed with brine and
concentrated. The residue was diluted with hexane, and the
resulting solid was ®ltered off. The ®ltrate was concentrated
and puri®ed by chromatography 1hexane/EtOAc, 10:1±4:1)
to give 49 1104 mg, 74%): colorless oil; Rfˆ0.34 1hexane/
EtOAc, 4:1); 1H NMR1300 MHz, CDCl 3) d 7.24 1d,
Jˆ8.6 Hz, 2H), 7.20 1d, Jˆ8.6 Hz, 2H), 6.87 1d, Jˆ
8.6 Hz, 2H), 6.82 1d, Jˆ8.6 Hz, 2H), 6.34 1d, Jˆ12.6 Hz,
1H), 4.85 1ddd, Jˆ13.4, 6.7, 6.7 Hz, 1H), 4.48 1s, 2H), 4.43
1d, Jˆ11.7 Hz, 1H), 4.29 1d, Jˆ11.7 Hz, 1H), 3.99 1bdd,
Jˆ4.9, 4.9 Hz, 1H), 3.81 1s, 3H), 3.79 1s, 3H), 3.67 1m,
1H), 3.52 1s, 3H), 3.42 1dd, Jˆ9.9, 5.3 Hz, 1H), 3.66 1m,
1H), 3.42 1dd, Jˆ9.9, 5.3 Hz, 1H), 3.29 1dd, Jˆ9.9, 6.4 Hz,
1H), 3.30 1dd, Jˆ9.9, 6.2 Hz, 1H), 3.08 1bd, Jˆ8.1 Hz, 2H),
2.20 1m, 1H), 2.50±1.80 1m, 5H), 1.68±1.42 1m, 2H), 1.37
1s, 3H), 1.26 1s, 3H), 0.109 1s, 9H); 13C NMR175 MHz,
CDCl3) d 159.1, 158.9, 147.8, 130.8, 130.5, 129.2, 128.9,
113.7, 113.6, 100.7, 87.5, 86.7, 78.4, 76.1, 75.6, 73.9, 72.8,
72.3, 69.9, 56.1, 55.9, 55.2, 29.7, 26.8, 25.0, 24.3, 15.8,
2.72.
1:1); IR1neat) 1732 cm 21; [a]26 ˆ235.48 1c 1.475,
D
CHCl3); 1H NMR1300 MHz, CDCl 3) d 7.22 1d, Jˆ
8.6 Hz, 2H), 7.19 1d, Jˆ8.6 Hz, 2H), 6.86 1d, Jˆ8.6 Hz,
2H), 6.83 1d, Jˆ8.6 Hz, 2H), 4.47 1s, 2H), 4.43 1d,
Jˆ11.6 Hz, 1H), 4.37 1d, Jˆ11.6 Hz, 1H), 4.02 1m, 1H),
3.80 1s, 3H), 3.79 1s, 3H), 3.69 1brd, Jˆ5.2 Hz, 1H), 3.52
1dd, Jˆ12.5, 5.2 Hz, 1H), 3.43 1dd, Jˆ10.0, 5.2 Hz, 1H),
3.30 1dd, Jˆ10.2, 6.7 Hz, 1H), 3.24 1dd, Jˆ11.7, 3.4 Hz,
1H), 2.86±2.61 1m, 2H), 2.11±1.80 1m, 3H), 1.66 1m,
1H), 1.51 1m, 1H), 1.47 1s, 3H), 1.44 1s, 3H); 13C NMR
175 MHz, CDCl3) d 170.3, 159.1, 159.0, 130.5, 130.3,
129.2, 128.9, 113.7, 113.6, 88.0, 78.6, 78.5, 78.1, 76.5,
75.3, 72.9, 72.2, 70.1, 55.2, 52.2, 28.2, 25.1, 23.1, 22.8,
20.8, 16.1; HRMS 1EI) calcd for C23H31O7 1M2C8H9O)
419.2070, found 419.2078.
6.1.31. Ester 51. To a stirred solution of 50 1281 mg,
0.52 mmol), PhNTf2 1372 mg, 1.04 mmol), and DMPU
1190 ml, 1.04 mmol) in THF 15 ml) at 2788C was added
KHMDS 12.1 ml, 0.5 M in toluene, 1.05 mmol). After stir-
ring for 0.5 h, the reaction mixture was quenched with water
containing 1% triethylamine and allowed to warm up to
room temperature. The mixture was diluted with ether and
washed with brine. The organic layer was concentrated to
6.1.30. Lactone 50. To a mixture of 49 1104 mg,
0.16 mmol) in wet CH3CN 11.2 ml) was added CSA
12.3 mg, 0.01 mmol). After stirring at room temperature
for 1.5 h, the reaction was quenched with triethylamine.
The mixture was concentrated and puri®ed by chromato-
graphy 1hexane/EtOAc, 1:1±1:4) to give the aldehyde
give the crude enol tri¯ate: light yellow crystal; Rfˆ0.40
1
1hexane/EtOAc, 2:1); H NMR1300 MHz, C D6) d 7.20
6
1d, Jˆ8.6 Hz, 2H), 7.19 1d, Jˆ8.6 Hz, 2H), 6.81 1d,
Jˆ8.6 Hz, 2H), 6.79 1d, Jˆ8.6 Hz, 2H), 4.36 1s, 3H), 4.33
1s, 3H), 4.15 1m, 2H), 3.80 1d, Jˆ5.3 Hz, 1H), 3.49 1dd,
Jˆ9.4, 4.6 Hz, 1H), 3.30 1s, 3H), 3.29 1s, 3H), 3.26 1m,
1H), 3.10 1dd, Jˆ11.0, 5.7 Hz, 1H), 2.97 1dd, Jˆ11.7,
3.5 Hz, 1H), 2.08±1.56 1m, 6H), 1.39 1m, 2H), 1.38 1s,
174.5 mg, 83%): colorless oil; Rfˆ0.16 1hexane/
1
EtOAcˆ1:1); H NMR1300 MHz, CDCl ) d 9.76 1s, 1H),
3
7.24 1d, Jˆ8.6 Hz, 2H), 7.20 1d, Jˆ8.6 Hz, 2H), 6.87 1d,
Jˆ8.6 Hz, 2H), 6.82 1d, Jˆ8.6 Hz, 2H), 4.46 1s, 2H), 4.43
1d, Jˆ11.6 Hz, 1H), 4.38 1d, Jˆ11.6 Hz, 1H), 3.99 1m, 1H),
3H), 1.11 1s, 3H); 13C NMR175 MHz, C D6) d 159.8,
6
159.7, 147.9, 131.1, 130.8, 129.5, 129.4, 119.11q), 114.1,

1814
I. Kadota et al. / Tetrahedron 58.2002) 1799±1816
114.0, 88.3, 86.5, 79.7, 78.3, 77.7, 76.9, 75.6, 73.2, 72.6,
70.3, 54.7, 52.0, 25.3, 23.6, 23.1, 17.5, 16.3.
ketone: colorless crystal; Rfˆ0.23 1hexane/EtOAc, 2:1);
1H NMR1300 MHz, CDCl ) d 7.23 1d, Jˆ8.6 Hz, 2H),
3
7.20 1d, Jˆ8.6 Hz, 2H), 6.86 1d, Jˆ8.6 Hz, 2H), 6.83 1d,
Jˆ8.6 Hz, 2H), 4.48 1s, 2H), 4.47 1d, Jˆ11.7 Hz, 1H), 4.35
1d, Jˆ11.7 Hz, 1H), 4.12 1q, Jˆ7.1 Hz, 2H), 4.06±3.98 1m,
2H), 3.84 1m, 1H), 3.81 1s, 3H), 3.79 1s, 3H), 3.69 1m, 1H),
3.43 1dd, Jˆ9.9, 4.9 Hz, 1H), 3.31 1dd, Jˆ9.9, 6.2 Hz, 1H),
3.21 1dd, Jˆ11.7, 3.7 Hz, 1H), 2.44 1dd, Jˆ10.7, 8.4 Hz,
1H), 2.36±2.25 1m, 3H), 2.05±1.40 1m, 10H), 1.44 1s,
3H), 1.31 1s, 3H), 1.25 1t, Jˆ7.0 Hz, 3H); 13C NMR
175 MHz, CDCl3) d 208.8, 173.4, 159.1, 158.9, 130.6,
130.4, 129.2, 128.9, 113.7, 113.6, 87.5, 78.8, 78.2, 76.4,
75.4, 73.0, 72.5, 72.4, 70.0, 60.2, 55.2, 53.3, 39.8, 34.0,
32.7, 25.2, 23.2, 21.1, 20.9, 16.3, 14.2.
To a suspension of Zn±Cu couple 1688 mg, 10.4 mmol) in
benzene 13 ml) and DMA 11.5 ml) was added ethyl 3-iodo-
butyrate 1650 ml, 5.2 mmol). The mixture was stirred at
908C for 4 h and cooled to 258C. A solution of the enol
tri¯ate obtained above in benzene 11.5 ml) and a solution
of Pd1PPh3)4 1150 mg, 0.13 mmol) in benzene 11 ml) were
added successively. After stirring at room temperature for
2 h, the reaction mixture was ®ltered through a silica gel
pad. The ®ltrate was concentrated and puri®ed by chromato-
graphy 1hexane/EtOAc, 10:1±4:1, containing 1% triethyl-
amine) to afford 51 1290 mg, 87%): colorless crystal;
1
Rfˆ0.20 1hexane/EtOAc, 4:1); H NMR1300 MHz, C D6)
6
d 7.20 1d, Jˆ8.6 Hz, 2H), 7.19 1d, Jˆ8.6 Hz, 2H), 6.80 1d,
Jˆ8.6 Hz, 2H), 6.78 1d, Jˆ8.6 Hz, 2H), 4.35 1s, 4H), 4.30
1bd, Jˆ3.8 Hz, 1H), 4.21 1bdd, Jˆ5.5, 5.5 Hz, 1H), 3.94 1q,
Jˆ7.2 Hz, 2H), 3.81 1bd, Jˆ5.5 Hz, 1H), 3.51 1dd, Jˆ9.5,
4.7 Hz, 1H), 3.43 1dd, Jˆ11.0, 5.9 Hz, 1H), 3.31 1s, 3H),
3.30 1s, 3H), 3.19 1dd, Jˆ11.9, 3.5 Hz, 1H), 2.22±1.68 1m,
12H), 1.55 1s, 3H), 1.52±1.26 1m, 2H), 1.21 1s, 3H), 0.94 1t,
To a solution of the crude ketone obtained above in toluene
15 ml) was added DBU 1400 ml, 2.73 mmol). After stirring
at room temperature for 0.5 h, the reaction mixture was
diluted with EtOAc, then washed with saturated aqueous
NH4Cl and brine. The organic layer was concentrated and
puri®ed by chromatography 1hexane/EtOAc, 2:1) to give 53
1113 mg, 64%): colorless solid; Rfˆ0.29 1hexane/EtOAc,
Jˆ7.2 Hz, 3H); 13C NMR175 MHz, C D6) d 172.8, 159.7,
2:1); H NMR1300 MHz, CDCl ) d 7.23 1d, Jˆ8.6 Hz,
1
6
3
159.6, 151.0, 131.2, 131.0, 129.5, 129.4, 114.1, 114.0, 88.3,
79.6, 78.6, 76.9, 76.1, 74.0, 73.2, 72.8, 70.2, 60.0, 54.7,
53.3, 33.6, 33.5, 25.5, 24.6, 23.9, 22.8, 18.4, 16.6, 14.3;
HRMS 1EI) calcd for C29H40O8 1M2C8H9O) 517.2802,
found 517.2800.
2H), 7.20 1d, Jˆ8.6 Hz, 2H), 6.86 1d, Jˆ8.6 Hz, 2H), 6.83
1d, Jˆ8.6 Hz, 2H), 4.48 1s, 2H), 4.43 1d, Jˆ11.5 Hz, 1H),
4.32 1d, Jˆ11.5 Hz, 1H), 4.12 1q, Jˆ7.1 Hz, 2H), 4.03 1bs,
2H), 3.84±3.79 1m, 2H), 3.81 1s, 3H), 3.80 1s, 3H), 3.70 1bs,
1H), 3.57 1dd, Jˆ13.2, 5.7 Hz, 1H), 3.44 1dd, Jˆ9.9, 5.2 Hz,
1H), 3.31 1dd, Jˆ9.7, 6.4 Hz, 1H), 3.24 1dd, Jˆ11.5, 3.3 Hz,
1H), 2.74 1dd, Jˆ17.6, 5.5 Hz, 1H), 2.44 1dd, Jˆ17.6,
13.4 Hz, 1H), 2.41±2.24 1m, 3H), 2.05±1.46 1m, 7H), 1.50
1s, 3H), 1.31 1s, 3H), 1.25 1t, Jˆ7.3 Hz, 3H); 13C NMR
175 MHz, CDCl3) d 208.9, 173.3, 159.1, 159.0, 130.6,
130.4, 129.3, 128.9, 113.7, 113.7, 87.9, 78.7, 78.2, 77.2,
76.4, 75.6, 73.0, 72.4, 72.1, 70.1, 60.3, 55.3, 53.1, 41.1,
34.1, 31.2, 30.3, 25.3, 23.2, 20.6, 16.8, 16.7, 14.2.
6.1.32. Alcohol 52. To a stirred solution of 51 124 mg,
0.038 mmol) in THF 10.3 ml) at 08C was added BH3´SMe2
14.6 ml, 0.049 mmol), and the mixture was stirred at the
same temperature for 1.5 h. Satd NaHCO3 11.5 ml) and
30% hydrogen peroxide 175 ml) were added at 08C, and
the mixture was stirred at room temperature for 0.5 h. The
reaction mixture was diluted with EtOAc, then washed with
satd Na2S2O3 and brine. The organic layer was concentrated
and puri®ed by chromatography 1hexane/EtOAc, 1:1) to
give 52 123 mg, 94%): colorless crystal; Rfˆ0.23 1hexane/
EtOAc, 1:1); 1H NMR1300 MHz, C 6D6) d 7.20 1d,
Jˆ8.6 Hz, 2H), 7.19 1d, Jˆ8.6 Hz, 2H), 6.80 1d,
Jˆ8.6 Hz, 2H), 6.78 1d, Jˆ8.6 Hz, 2H), 4.36 1s, 4H), 4.20
1bdd, Jˆ5.3, 5.3 Hz, 1H), 3.95 1q, Jˆ7.2 Hz, 2H), 3.84±
3.79 1m, 1H), 3.76 1dd, Jˆ11.7, 6.4 Hz, 1H), 3.63±3.50
1m, 3H), 3.32 1m, 1H), 3.30 1s, 3H), 3.29 1s, 3H), 3.18
1dd, Jˆ11.8, 3.3 Hz, 1H), 2.24±2.12 1m, 6H), 1.92±1.67
1m, 3H), 1.52 1s, 3H), 1.40±1.24 1m, 3H), 1.18 1s, 3H),
0.95 1t, Jˆ7.2 Hz, 3H); 13C NMR175 MHz, C 6D6) d
173.3, 159.7, 159.6, 131.3, 131.0, 129.5, 129.4, 114.1,
114.0, 88.6, 78.6, 77.7, 76.8, 76.0, 74.8, 73.2, 72.9, 71.9,
70.3, 68.0, 60.0, 34.2, 33.5, 33.1, 25.7, 25.0, 24.0, 20.9,
16.7, 14.3; HRMS 1EI) calcd for C29H41O9 1M2C8H9O)
535.2908, found 535.2942.
6.1.34. Alcohol 54. To a solution of 53 1113 mg,
0.17 mmol) in MeOH 12 ml) and CH2Cl2 12 ml) at 2788C
was added NaBH4 115 mg, 0.40 mmol), and the mixture was
stirred at 2788C for 2 h. The reaction mixture was diluted
with EtOAc and washed with brine. The organic layer was
concentrated and puri®ed by chromatography 1hexane/
EtOAc, 1:1) to give 54 1111 mg, 98%): colorless oil;
Rfˆ0.26 1hexane/EtOAc, 1:1); IR1neat) 3600±3200,
1736 cm21; [a]25 ˆ24.978 1c 0.78, CHCl3); 1H NMR
D
1300 MHz, CDCl3) d 7.23 1d, Jˆ8.6 Hz, 2H), 7.19 1d,
Jˆ8.6 Hz, 2H), 6.86 1d, Jˆ8.6 Hz, 2H), 6.83 1d,
Jˆ8.6 Hz, 2H), 4.47 1s, 2H), 4.46 1d, Jˆ11.9 Hz, 1H),
4.32 1d, Jˆ11.9 Hz, 1H), 4.12 1q, Jˆ7.1 Hz, 2H), 4.00 1m,
1H), 3.81 1m, 1H), 3.80 1s, 3H), 3.79 1s, 3H), 3.67 1m, 1H),
3.48±3.36 1m, 2H), 3.30 1dd, Jˆ9.9, 6.3 Hz, 2H), 3.19 1dd,
Jˆ11.8, 3.3 Hz, 1H), 3.10 1dd, Jˆ12.7, 3.3 Hz, 1H), 2.31
1dd, Jˆ6.9, 6.9 Hz, 2H), 2.10±1.38 1m, 12H), 1.47 1s, 3H),
1.26 1s, 3H), 1.25 1dd, Jˆ9.0, 9.0 Hz, 3H); 13C NMR
175 MHz, CDCl3) d 173.9, 158.9, 158.8, 130.5, 130.3,
129.1, 128.8, 113.5, 88.6, 80.8, 78.0, 76.2, 75.8, 72.9,
72.3, 71.8, 70.5, 69.9, 60.1, 55.0, 53.6, 34.1, 33.6, 31.4,
25.4, 23.2, 20.6, 17.0, 17.0, 16.6, 14.1; HRMS 1EI) calcd
for C29H43O9 1M2C8H9O) 535.2907, found 535.2913.
6.1.33. Ketone 53. To a solution of 52 1180 mg, 0.27 mmol)
in CH2Cl2 13 ml) at room temperature was added Dess±
Martin periodinate 1300 mg, 0.71 mmol) and NaHCO3
1150 mg, 1.79 mmol), and the mixture was stirred for
0.5 h. Aqueous saturated solution of NaHCO3 and
Na2S2O3 11:1, 5 ml) was added, and the mixture was vigor-
ously stirred for 15 min. The mixture was extracted with
ether. The organic layer was washed with aqueous saturated
NaHCO3 and brine, then concentrated to give the crude
6.1.35. Lactone 55. To a solution of 54 129 mg,
0.045 mmol) in THF/H2O 12:1, 0.8 ml) was added

I. Kadota et al. / Tetrahedron 58.2002) 1799±1816
1815
Kadowaki, C.; Yoshida, N.; Yamamoto, Y. Tetrahedron
Lett. 1998, 39, 6369±6372. 1c) Kadota, I.; Ohno, A.;
Matsukawa, Y.; Yamamoto, Y. Tetrahedron Lett. 1998, 39,
6373±6376.
LiOH´H2O 13.5 mg, 0.084 mmol). After stirring at 408C for
1 h, the mixture was acidi®ed with 1 M HCl to pH 2 and
extracted with EtOAc. The organic layer was concentrated
to give the crude carboxylic acid: colorless crystal; Rfˆ0.23
1EtOAc); 1H NMR1300 MHz, CDCl 3) d 7.22 1d, Jˆ8.6 Hz,
2H), 7.19 1d, Jˆ8.6 Hz, 2H), 6.86 1d, Jˆ8.6 Hz, 2H), 6.82
1d, Jˆ8.6 Hz, 2H), 4.47 1s, 2H), 4.45 1d, Jˆ11.2 Hz, 1H),
4.32 1d, Jˆ11.2 Hz, 1H), 4.00 1brs, 1H), 3.80 1s, 3H), 3.79
1s, 3H), 3.78 1m, 1H), 3.66 1bs, 1H), 3.41 1m, 2H), 3.31 1dd,
Jˆ15.6, 6.1 Hz, 1H), 3.19 1d, Jˆ9.2 Hz, 1H), 3.08 1d,
Jˆ11.2 Hz, 1H), 2.36 1m, 2H), 2.17±1.36 1m, 13H), 1.47
4. For other synthetic studies of gambierol, see: 1a) Kadowaki,
C.; Chan, P. W. H.; Kadota, I.; Yamamoto, Y. Tetrahedron
Lett. 2000, 41, 5769±5772. 1b) Fuwa, H.; Sasaki, M.;
Tachibana, K. Tetrahedron Lett. 2000, 41, 8371±8375.
1c) Kadota, I.; Takamura, H.; Sato, K.; Yamamoto, Y.
Tetrahedron Lett. 2001, 42, 4729±4731. 1d) Kadota, I.;
Ohno, A.; Matsuda, K.; Yamamoto, Y. J. Am. Chem. Soc.
2001, 123, 6702±6703. 1e) Sakamoto, Y.; Matsuo, G.;
Matukura, H.; Nakata, T. Org. Lett. 2001, 3, 2749±2752.
1f) Cox, J. M.; Rainier, J. D. Org. Lett. 2001, 3, 2919±2922.
1g) Fuwa, H.; Sasaki, M.; Tachibana, K. Tetrahedron 2001,
57, 3019±3033. 1h) Fuwa, H.; Sasaki, M.; Tachibana, K. Org.
Lett. 2001, 3, 3549±3552.
1s, 3H), 1.26 1s, 3H); 13C NMR175 MHz, CDCl ) d 178.6,
3
159.0, 158.9, 130.6, 130.4, 129.2, 128.9, 113.7, 113.6, 88.7,
80.8, 78.2, 76.8, 76.3, 75.9, 73.0, 72.4, 72.1, 70.8, 70.1,
55.2, 53.6, 33.8, 33.6, 31.4, 25.5, 23.3, 20.5, 17.1, 16.7.
To a mixture of the carboxylic acid obtained above in THF
10.4 ml) at 08C were added triethylamine 120 ml,
0.14 mmol) and 2,4,6-trichlorobenzoyl chloride 124 ml,
0.15 mmol). After stirring at room temperature for 2 h, the
reaction mixture was diluted with benzene 12 ml) and added
to a solution of DMAP 122 mg, 0.18 mmol) in benzene
12 ml). After 0.5 h, the mixture was concentrated, diluted
with EtOAc, and ®ltered through a Celite pad. The ®ltrate
was puri®ed by chromatography 1hexane/EtOAc, 2:1) to
give 55 121 mg, 76%): colorless crystal; mp 1558C 1hexane/
5. 1a) Fujiwara, K.; Morishita, H.; Saka, K.; Murai, A.
Tetrahedron Lett. 2000, 41, 507±508. 1b) Matsuo, G.;
Hinou, H.; Koshino, H.; Suenaga, T.; Nakata, T. Tetrahedron
Lett. 2000, 41, 903±906. 1c) Mori, Y.; Mitsuoka, S.;
Furukawa, H. Tetrahedron Lett. 2000, 41, 4161±4164.
6. Kotsuki, H.; Kadota, I.; Ochi, M. Tetrahedron Lett. 1990, 31,
4609±4612.
7. 1a) Nicolaou, K. C.; Postema, M. H. D.; Claiborne, C. F. J. Am.
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CH2Cl2); Rfˆ0.26 1hexane/EtOAc, 1:1); [a]25 ˆ231.28 1c
D
1
0.99, CHCl3); IR1KBr) 1755 cm 21; H NMR1300 MHz,
8. For preliminary communications on the syntheses of the AB
and EFGH ring segments of gambierol, see: 1a) Kadota, I.;
Park, C.-H.; Sato, K.; Yamamoto, Y. Tetrahedron Lett. 2001,
42, 6195±6197. 1b) Kadota, I.; Kadowaki, C.; Takamura, H.;
Yamamoto, Y. Tetrahedron Lett. 2001, 42, 6199±6202.
9. Nicolaou, K. C.; Nugiel, D. A.; Couladouros, E.; Hwang,
C.-K. Tetrahedron 1990, 46, 4517±4552.
CDCl3) d 7.22 1d, Jˆ8.6 Hz, 2H), 7.19 1d, Jˆ8.6 Hz, 2H),
6.86 1d, Jˆ8.6 Hz, 2H), 6.83 1d, Jˆ8.6 Hz, 2H), 4.47 1s,
2H), 4.46 1d, Jˆ11.8 Hz, 1H), 4.37 1d, Jˆ11.8 Hz, 1H),
4.13 1ddd, Jˆ10.4, 10.4, 5.1 Hz, 1H), 4.00 1bs, 1H), 3.80
1s, 3H), 3.79 1s, 3H), 3.68 1bs, 1H), 3.61 1ddd, Jˆ9.3, 9.3,
3.3 Hz, 1H), 3.42 1dd, Jˆ9.8, 5.0 Hz, 1H), 3.29 1dd, Jˆ9.7,
6.3 Hz, 1H), 3.19 1dd, Jˆ11.8, 3.3 Hz, 1H), 3.13 1dd,
Jˆ13.2, 3.5 Hz, 1H), 2.68 1dd, Jˆ13.5, 7.0 Hz, 1H), 2.55
1dd, Jˆ13.6, 13.6 Hz, 1H), 2.26 1m, 1H), 2.12 1bd,
Jˆ13.2 Hz, 1H), 2.03±1.82 1m, 4H), 1.75±1.48 1m, 6H),
10. Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401±
404.
11. The reaction with allylmagnesium bromide in THF gave a 3:1
mixture of diastereoisomers. See Ref. 3a.
1.47 1s, 3H), 1.29 1s, 3H); 13C NMR175 MHz, CDCl ) d
3
174.4, 159.1, 159.0, 130.6, 130.5, 129.2, 128.9, 113.7,
113.7, 88.8, 79.7, 78.2, 77.8, 76.4, 75.8, 73.0, 72.4, 71.9,
70.4, 70.1, 55.2, 53.4, 36.0, 34.4, 30.7, 25.4, 23.3, 20.6,
17.0, 16.6; HRMS 1EI) calcd for C27H37O8 1M2C8H9O)
489.2488, found 489.2499.
12. For a recent example of the synthesis of cyclic ethers via the
intramolecular hetero-Michael reaction, see: Betancort, J. M.;
Â
Â
Â
Â
Martõn, V. S.; Padron, J. M.; Palazon, J. M.; Ramõrez, M. A.;
Soler, M. A. J. Org. Chem. 1997, 62, 4570±4583 and
references cited therein.
13. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769±3772.
14. 1a) Mori, Y.; Yaegashi, K.; Furukawa, H. J. Am. Chem. Soc.
1997, 119, 4557±4558. 1b) Mori, Y.; Yaegashi, K.; Furukawa,
H. Tetrahedron 1997, 53, 12917±12932. 1c) Mori, Y.;
Yaegashi, K.; Furukawa, H. J. Org. Chem. 1998, 63, 6200±
6209.
Acknowledgements
This work was ®nancially supported by the Grant-in-Aid for
Scienti®c Research from the Ministry of Education, Science
and Culture of Japan. C. K acknowledges the Hayashi
Memorial Foundation for Female Natural Scientists for
®nancial support.
15. 1a) Evans, D. A.; Chapman, K. T. Tetrahedron Lett. 1986, 27,
5939±5942. 1b) Evans, D. A.; Chapman, K. T.; Carreira, E. M.
J. Am. Chem. Soc. 1988, 110, 3560±3578.
16. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277±
7287.
17. Fujiwara, K.; Tsunashima, M.; Awakura, D.; Murai, A.
Tetrahedron Lett. 1995, 36, 8263±8266.
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