Synthetic studies of yessotoxin, a polycyclic ether implicated in diarrhetic shellfish poisoning: Convergent synthesis of the BCDE ring system via an alkyne intermediate

Article abstract of DOI:10.1016/S0040-4020(02)00038-8

A convergent synthetic route to the BCDE ring system of yessotoxin, a polycyclic ether marine toxin related to diarrhetic shellfish poisoning, has been developed. The key feature of the present synthesis is the alkylation of acetylene with the B and E rin

Full text of DOI:10.1016/S0040-4020(02)00038-8

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 1789±1797
Synthetic studies of yessotoxin, a polycyclic ether implicated in
diarrhetic shell®sh poisoning: convergent synthesis of the BCDE
ring system via an alkyne intermediate
Yuji Morip and Hisafumi Hayashi
Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan
Received 6 September 2001; accepted 24 October 2001
AbstractÐA convergent synthetic route to the BCDE ring system of yessotoxin, a polycyclic ether marine toxin related to diarrhetic
shell®sh poisoning, has been developed. The key feature of the present synthesis is the alkylation of acetylene with the B and E ring units,
which were prepared from a common intermediate. The alkyne functionality was directly converted to a 1,2-diketone by ruthenium
oxidation. Acid treatment of the diketone led to the formation of a tetracyclic dihemiketal structure. O-Methylation of the hydroxyl groups
of the dihemiketal and reductive etheri®cation completed the synthesis of the BCDE ring system of yessotoxin. q 2002 Elsevier Science Ltd.
All rights reserved.
1. Introduction
2. Result and discussion
2.1. Retrosynthetic analysis
Polycyclic ether marine toxins produced by marine dino-
¯agellates consist of bioactive agents, the skeletons of
which incorporate regular oxygenated heterocycles,1 and
their unique architecture and potent biological activities
have attracted the attention of numerous organic
chemists. Yessotoxin (1) was isolated from the digestive
glands of diarrhetic shell®sh poisoning-infested scallops,
Patinopecten yessoensis, in 1993 as one of the causative
toxins of diarrhetic shell®sh poisoning.2 Its planar structure
and relative stereochemistry have been elucidated by
spectroscopic methods to have a ladder-shape polycyclic
skeleton with an unsaturated side-chain and two sulfate
ester groups.2,3 The absolute con®guration was determined
by the NMR method using a chiral anisotropic reagent.4 The
trans-fused polyether skeleton has led researchers to believe
that an iterative5 or convergent approach6 might be the best
way to synthesize the six-membered ring systems contained
in yessotoxin. We have recently reported a convergent
strategy for the synthesis of polytetrahydropyrans using
alkyne intermediates.7 The same approach has also been
reported independently by Murai's8 and Nakata's9 groups
at almost the same time. In this paper, we describe in detail a
stereocontrolled construction of the BCDE ring system of
yessotoxin based on our alkyne strategy.
A synthetic plan to the BCDE ring system 2 of yessotoxin
involves the synthesis of 1,2-diketone 3 (Scheme1). Simul-
taneous double six-membered hemiketal ring formation
from 3 followed by reductive elimination of the two hemi-
ketal hydroxyl groups would be expected to provide the
trans-fused ring system 2. In turn, the 1,2-diketone 3
would be prepared by direct oxidation of the corresponding
acetylene derivative 4. Disassembly of 4 at the indicated
strategic bonds leads to the B-ring 5 and E-ring 6 units
and acetylene. We next envisaged synthesizing the B- and
E-ring units from a common intermediate, ketone 7, which
could be prepared by an oxiranyl anion strategy developed
in our laboratory using tri¯ate 8 and an oxiranyl anion 9.10
These disconnections allow for a highly convergent
approach, and the successful execution of the synthetic
strategy for 2 is described below.
2.2. Synthesis of the B ring
The initial steps for the synthesis of the B ring, based on an
oxiranyl anion strategy5b are shown in Scheme 2. One-pot
regioselective activation and protection of two hydroxyl
groups of 1,3-O-di-t-butylsilylene-l-erythritol (10)11 was
accomplished with tri¯ic anhydride followed by triethylsilyl
tri¯ate to afford the TES-protected tri¯ate 8 in 95% yield.
Reaction of the tri¯ate with the oxiranyl anion generated
from racemic epoxy sulfone 11 (a ca. 1:3 mixture of cis-
and trans-isomers) and n-butyllithium in THF±HMPA at
21008C gave the coupled product 12 in 91% yield. As the
Keywords: acetals; alkynes; polyethers; toxins.
Corresponding author. Tel.: 181-52-832-1781; fax: 181-52-834-8090;
e-mail: mori@ccmfs.meijo-u.ac.jp
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00038-8

1790
Y. Mori, H. Hayashi / Tetrahedron 58 (2002) 1789±1797
Scheme 1. Retrosynthetic analysis of yessotoxin (1).
product is a mixture of four diastereoisomers around the
stereochemistry of the epoxide functionality, cyclization
of 12 to a tetrahydropyran ring was carried out in a stepwise
manner according to the previously reported method.12
Thus, detriethylsilylation of 12 with TsOH followed by
exposure to MgBr2´OEt2 gave a mixture of hydroxy bromo-
ketones, which was then treated with DBU to afford an
equilibrium mixture of cyclized products. The desired,
thermodynamically more stable ketone 7 was isolated in
79% overall yield along with a 9% yield of its epimer having
Scheme 2. Reagents and conditions: (a) Tf2O, 2,6-lutidine, CH2Cl2, 2788C, 30 min, then TESOTf, 95%; (b) n-BuLi, THF±HMPA, 21008C, 40 min, 91%;
(c) TsOH´H2O, MeOH, room temperature, 2 h, 98%; (d) MgBr2´OEt2, CH2Cl2, 08C, 1 h, 97%; (e) DBU, CH2Cl2, 08C, 1 h, 83%; (f) NaBH4, CH2Cl2±MeOH,
2788C, 30 min, 95%; (g) H2, Pd(OH)2±C, EtOAc, 40 min, 100%; (h) Tf2O, 2,6-lutidine, THF, 2788C, 30 min, then TBSOTf, 278!08C, 94%;
(i) Me3SiCuCH, n-BuLi, THF±HMPA, 2788C, 2.5 h; (j) 5% KOH, MeOH, room temperature, 1.5 h, 74% (two steps).

Y. Mori, H. Hayashi / Tetrahedron 58 (2002) 1789±1797
1791
Scheme 3. Reagents and conditions: (a) H2, Pd(OH)2±C, EtOAc, 100%; (b) TBDPSCl, imidazole, DMF, room temperature, 100%; (c) Me3SiCHN2, BF3´OEt2,
MS 3A, CH2Cl2, 2788C; PPTS, MeOH, room temperature, 72%; (d) Tebbe reagent, THF, 08C, 95%; (e) Oxone, CF3COCH3, NaHCO3, 0.4 mM EDTA´Na2,
acetone±MeCN, 08C, 87%; (f) LiBHEt3, THF, 08C, 98%; (g) 10% KOH, MeOH, room temperature, 88%; (h) BnBr, KH, THF, 08C, 96%; (i) Bu4NF, THF,
room temperature, 89%; (j) Tf2O, 2,6-lutidine, CH2Cl2, 2788C, then TBSOTf, 278!08C, 93%.
an axial side chain. Stereoselective reduction of ketone 7
with sodium borohydride in CH2Cl2±MeOH at 2788C and
subsequent debenzylation by hydrogenolysis gave diol 13 in
95% yield. In order to introduce an acetylene unit into 13,
the diol was transformed into the TBS-protected tri¯ate 5.
Coupling reaction of 5 with lithium trimethylsilylacetylide
in THF±HMPA13 followed by selective removal of the
trimethylsilyl group with 5% KOH in methanol led to the
completion of the B-ring unit 14 having a terminal alkynyl
group.
selectivity of ca. 4:1. The desired tertiary alcohol 20 was
obtained as a minor product.
We next explored an alternative method to construct the
methyl group having b-con®guration: spiro-epoxide forma-
tion and reductive opening. The ketone 17 was converted
into exo-methylene 18 in 95% yield using the Tebbe
reagent.15 Epoxidation of 18 with m-CPBA, however, led
to only 3:2 selectivity of a- and b-epoxides, although the
major isomer was the desired product 19. In order to effect a
predominant a-attack, use of a reagent that demands more
steric requirements in a transition state is one way to this
end. In this regard, dioxirane oxidation occurred to us.
Epoxidation of ole®ns with dioxiranes is believed to
proceed via a spiro transition state rather than a planar
transition state.16 The spiro transition state should induce
more steric interactions between the substituents of an ole®n
and a dioxirane and therefore, would favor the approach of
an oxidizing reagent from the less hindered side of the
ole®n. In this case, reaction of 18 with methyl(tri¯uoro-
methyl)dioxirane generated in situ from Oxonew and
1,1,1-tri¯uoroacetone17 led to spiro-epoxide formation
with 10:1 selectivity, and the desired a-epoxide 19 was
isolated in 87% yield. Reductive opening of the oxirane
ring with lithium triethylborohydride gave the desired
tertiary alcohol 20 quantitatively. The TBDPS ether of
20 was then selectively removed in the presence of the
silylene-protective group by exposure to 10% NaOH in
methanol18 to furnish a diol, which was protected as the
benzyl ether by treatment with potassium hydride and
benzyl bromide, giving 21 in 84% yield. With the right-
hand side fully protected, it was possible to begin manipula-
tion of the left side. Thus, the silylene group of 21 was
deprotected with Bu4NF in THF to give diol 22. Regio-
selective tri¯ation of the primary hydroxyl group
followed by silylation of the secondary hydroxyl group in
one-pot yielded the E-ring tri¯ate 6 in 83% overall yield
from 21.
2.3. Synthesis of the E ring
Elaboration of the six-membered ketone 7 to a seven-
membered ketone requires one-carbon homologation of
the tetrahydropyran ring (Scheme 3). The reaction condi-
tions of this ring expansion reaction have been established
previously.14 However, reaction of 7 with trimethylsilyl-
diazomethane in the presence of BF3´OEt2 in CH2Cl2 at
2788C gave the desired seven-membered ketone 16 in
only 43% yield after acid treatment of the intermediary
a-trimethylsilyl ketone. The side-reactions were com-
petitive spiro-epoxide formation on the carbonyl group of
7 and debenzylation by BF3´OEt2, and a debenzylated TMS-
substituted spiro-epoxide derivative was isolated in 38%
yield. Then, the benzyl group of 7 was replaced by a
bulky t-butyldiphenylsilyl group and the resulting 15 was
subjected to the ring expansion reaction. In this case, the
reaction proceeded more satisfactorily to afford 17 in 72%
yield along with 5% yield of its regioisomeric ketone. With
the desired ketone 17 in hand, our attention was directed to
stereoselective installation of a methyl group at the carbonyl
carbon. Unfortunately, direct introduction of the b-oriented
methyl group by nucleophilic addition to the ketone was
unsuccessful. Methylation using trimethylaluminum,
methylmagnesium bromide, and methyllithium took place
mainly from the less hindered a-side of the molecule with

1792
Y. Mori, H. Hayashi / Tetrahedron 58 (2002) 1789±1797
Scheme 4. Reagents and conditions: (a) n-BuLi, THF±HMPA, 2788C, 71%; (b) TsOH´H2O, CH2Cl2±MeOH, room temperature, 93%; (c) TESOTf, 2,6-
lutidine, CH2Cl2, 08C, 95%; (d) RuO2´H2O, NaIO4, CCl4±MeCN±pH 7 buffer, room temperature, 65%; (e) TsOH´H2O, CHCl3, 08C, 89%; (f) MeI, NaH, DMF,
08C, 55%; (g) Et3SiH, TMSOTf, CH2Cl2, 08C, 51%.
2.4. Synthesis of the BCDE ring system
by NOESY experiments. Direct treatment of 26 with
TsOH´H2O and trimethyl orthoformate in chloroform
afforded a lower yield of the desired product 28 and
increased amounts of other isomers. Final reductive
etheri®cation of 28 with triethylsilane in the presence of
trimethylsilyl tri¯ate20 at room temperature resulted in the
formation of the desired trans-fused tetracyclic ether ring
system in 50% yield, but the concomitant elimination of the
benzyloxy group at a quaternary center to an exo-methylene
group was observed. This elimination reaction was
suppressed by carrying out the reduction at 08C, and the
synthesis of the target BCDE ring system 2 of yessotoxin
was accomplished in 55% yield.
Convergent synthesis of the target ring system 2 is shown in
Scheme 4. Coupling reaction of the lithium acetylide
generated from acetylene 14 with tri¯ate 6 gave the
disubstituted acetylene 23 in 71% yield. Oxidation of the
acetylene to the corresponding 1,2-diketone was carried out
according to the reported procedure. Thus, oxidation of the
acetylene 23 with a catalytic amount of RuO2´H2O and
3 equiv. of NaIO4 in CCl4±CH3CN±H2O19 afforded the
1,2-diketone 25 in 74% yield. Selective deprotection of
the TBS group with TsOH in CHCl3 at 558C and the follow-
ing spontaneous double hemiketal ring formation to 27 was
unsuccessful, giving a complex mixture of products. Treat-
ment with trimethyl orthoformate in the presence of TsOH
also led to a mixture of O-methyl ethers of cyclic and
acyclic ketals. The dif®culty in the formation of trans-
fused dihemikatal rings may be attributed to the higher
reaction temperature required for the deprotection of the
TBS groups and the con®gurational problem of the hydroxyl
group on the seven-membered ring which adopts an axial-
like quasi-equatorial con®guration.
3. Conclusion
Stereocontrolled convergent synthesis of the BCDE ring
system of yessotoxin was developed starting from 1,3-O-
di-t-butylsilylene-l-erythritol. In the present synthesis, we
have demonstrated that the six-membered ketone 7 prepared
by an oxiranyl anion strategy is a useful common inter-
mediate for the synthesis of the B- and E-ring units. Con-
nection of both ring units via acetylene, followed by
ruthenium oxidation of the triple bond to the corresponding
1,2-diketone, double hemiketal formation, and reductive
etheri®cation enabled a convergent synthesis of the tetra-
cyclic ether ring system composed of six- and seven-
membered rings. These studies are expected to facilitate
the projected total synthesis of yessotoxin and related
compounds.
In order to carry out the deprotection of the silyl groups and
the following dihemikatal ring formation under mild con-
ditions, the TBS groups of acetylene 23 were replaced with
TES ethers by treatment with TsOH in methanol followed
by triethylsilylation, giving 24 in 88% overall yield.
Ruthenium oxidation of 24 gave diketone 26 in 65%
yield. The expected six-membered dihemiketal formation
proceeded smoothly by the treatment of the diketone with
TsOH in chloroform at 08C to give 27 in 89% yield.
O-Methylation of the two hemiketal hydroxyl groups
under basic conditions with MeI and NaH in DMF gave
the desired di-O-methyl ketal 28 in 55% yield along with
two other stereoisomers (13 and 5% yields) attributed to the
con®guration of the methoxy groups. The stereochemical
assignment of two methoxy groups of 28 was established
4. Experimental
4.1. General
IR spectra were recorded in CHCl3 solution on a JASCO

Y. Mori, H. Hayashi / Tetrahedron 58 (2002) 1789±1797
1793
1
FTIR-420 spectrometer. H and 13C NMR spectra were
(2.14 g, 4.39 mmol) in CH2Cl2 (30 mL) at 08C was added
DBU (0.69 mL, 4.61 mmol). After stirring at 08C for 1 h, the
reaction was quenched with saturated aqueous NH4Cl and
the mixture was extracted with CH2Cl2. The combined
extracts were washed with water, dried, and evaporated.
Puri®cation by ¯ash chromatography (3!15% EtOAc/
hexane) gave 7 (1.49 g, 83%) as a solid and its C(8)-epimer
recorded on a JEOL A-400 or A-600 spectrometer in
CDCl3 solution using TMS and CDCl3 (77.00 ppm) as
internal standards, respectively. Mass spectra were obtained
on JEOL JMS-700 and HX-110 mass spectrometers. Optical
rotations were determined on a JASCO DIP-370 digital
polarimeter. Air- and moisture-sensitive reactions were
carried out under an argon atmosphere in anhydrous condi-
tions. Flash chromatography was carried out with E. Merck
silica gel 60 (230±400 mesh). The term `dried' refers to the
drying of an organic solution over MgSO4 followed by
®ltration.
25
(162 mg, 9%) as an oil. 7: mp 101±1028C; [a]D ˆ212.088
1
(c 0.59, CHCl3); IR (CHCl3) 1725, 1473, 1114 cm21; H
NMR (400 MHz) d 1.00 (9H, s), 1.05 (9H, s), 2.44 (1H,
dd, Jˆ16.1, 10.7 Hz), 3.04 (1H, dd, Jˆ16.1, 5.9 Hz), 3.63
(1H, ddd, Jˆ10.3, 10.3, 4.9 Hz), 3.66 (1H, dd, Jˆ10.7,
5.9 Hz), 3.87 (1H, dd, Jˆ10.7, 2.9 Hz), 3.95 (1H, t,
Jˆ10.3 Hz), 4.06 (1H, dd, Jˆ6.3, 2.9 Hz), 4.18 (1H, ddd,
Jˆ10.7, 10.3, 5.9 Hz), 4.31 (1H, dd, Jˆ10.3, 4.9 Hz), 4.53
and 4.57 (each 1H, d, Jˆ12.1 Hz), 7.27±7.36 (5H, m); 13C
NMR (100 MHz) d 19.90, 22.59, 26.98 (3£C), 27.37 (3£C),
48.22, 66.54, 68.33, 72.49, 73.71, 76.05, 82.61, 127.73
(2£C), 127.76 (2£C), 128.39, 137.83, 203.93; EIMS m/z
406 (M1). Anal. Calcd for C22H34O5Si: C, 64.99; H, 8.43.
Found: C, 64.62; H, 8.69.
4.1.1. Tri¯ate 8. To a stirred solution of diol 1011 (1.40 g,
5.34 mmol) in dry CH2Cl2 (14 mL) at 2788C under argon
was added 2,6-lutidine (1.85 mL, 16.03 mmol) and tri¯ic
anhydride (0.94 mL, 5.61 mmol). After stirring at 2788C
for 30 min, TESOTf (1.42 mL, 6.41 mmol) was added and
stirring was continued for another 30 min. The reaction
mixture was poured into water and extracted with EtOAc.
The combined extracts were washed with saturated aqueous
NaHCO3, water, and brine, dried, and evaporated. Puri®ca-
tion by ¯ash chromatography (3% EtOAc/hexane) gave 8
4.1.3. Diol 13. To a stirred solution of 7 (1.49 g, 3.67 mmol)
in CH2Cl2 (15 mL) and MeOH (15 mL) at 2788C was added
NaBH4 (300 mg, 7.93 mmol), and the reaction mixture was
stirred at 2788C for 30 min. The reaction mixture was
poured into water and extracted with EtOAc. The extract
was washed with water and brine, dried, and concentrated.
Puri®cation by ¯ash chromatography (20% EtOAc/hexane)
gave an alcohol (1.42 g, 95%) as a crystalline solid: mp 77±
25
(2.59 g, 95%) as a pale yellow oil; [a]D ˆ238.58 (c 0.22,
CHCl3); IR (CHCl3) d 1473, 1413, 1225, 1207 cm21; H
1
NMR (600 MHz) d 0.61 (6H, q, Jˆ8.1 Hz), 0.95 (9H, t,
Jˆ8.1 Hz, 1.00 (9H, s), 1.04 (9H, s), 3.79 (2H, m), 4.06
(2H, m), 4.61 (1H, dd, Jˆ10.3, 4.4 Hz), 4.68 (1H, dd,
Jˆ10.3, 2.2 Hz).
25
4.1.2. Ketone 7. Alkylation reaction. A solution of tri¯ate 8
(2.59 g, 5.09 mmol) and a 1:3 mixture of racemic cis- and
trans-epoxy sulfone 11 (2.43 g, 7.65 mmol) in HMPA
(2.66 mL, 15.29 mmol) and dry THF (34 mL) under argon
was cooled to 21008C and treated with n-BuLi (4.78 mL of
1.6 M solution in hexane, 7.65 mmol). After stirring at
21008C for 40 min, the reaction was quenched with satu-
rated aqueous NH4Cl. The mixture was warmed to 08C and
extracted with EtOAc. The combined extracts were washed
with water and brine, dried, and evaporated. Puri®cation by
¯ash chromatography (6% EtOAc/hexane) gave 12 (3.15 g,
91%).
798C; [a]D ˆ26.168 (c 0.53, CHCl3). A mixture of the
alcohol (800 mg, 1.96 mmol) and 20% Pd(OH)2/C
(160 mg) in EtOAc (14 mL) was stirred at room temperature
for 40 min under a hydrogen atmosphere. The reaction
mixture was passed through a short column of Celite and
eluted with EtOAc. Concentration of the eluate gave 13
(622 mg, 100%) as a crystalline solid: mp 211±2128C;
25
[a]D ˆ237.48 (c 0.50, CHCl3); IR (KBr) 3587,
1
3420 cm21; H NMR (600 MHz, acetone-d6) d 0.98 (9H,
s), 1.02 (9H, s), 1.51 (1H, q, Jˆ11.7 Hz), 2.40 (1H, ddd,
Jˆ11.7, 4.4, 4.4 Hz), 3.20 (1H, ddd, Jˆ8.8, 5.9, 2.9 Hz),
3.31 (1H, ddd, Jˆ9.5, 9.5, 5.1 Hz), 3.53 (1H, t, Jˆ6.4 Hz,
OH), 3.55±3.62 (2H, m), 3.74 (1H, t, Jˆ10.3 Hz), 3.77 (2H,
m), 4.07 (1H, dd, Jˆ10.3, 5.1 Hz), 4.10 (1H, d, Jˆ5.1 Hz,
OH); 13C NMR (150 MHz, acetone-d6) d 20.43, 23.11,
27.47 (3£C), 27.79 (3£C), 42.74, 63.13, 66.58, 67.66,
73.43, 77.66, 83.68; EIMS m/z 318 (M1). Anal. Calcd for
C15H30O5Si: C, 56.57; H, 9.50. Found: C, 56.43; H, 9.76.
Detriethylsilylation. The product 12 (3.15 g, 4.65 mmol)
obtained above was dissolved in MeOH (31 mL) and
TsOH´H2O (18 mg, 0.093 mmol) was added. After stirring
at room temperature for 2 h, the reaction was quenched with
Et3N (0.1 mL) and the solvent was evaporated. The residue
was puri®ed by ¯ash chromatography (30% EtOAc/hexane)
to give a 1:1 mixture of hydroxy epoxy sulfones (2.55 g,
98%).
4.1.4. Tri¯ate 5. To a stirred solution of 13 (504 mg,
1.585 mmol) in dry THF (10 mL) and 2,6-lutidine
(740 mL, 6.340 mmol) at 2788C was added Tf2O
(290 mL, 1.743 mmol). After stirring at 2788C for 30 min,
TBSOTf (540 mL, 2.377 mmol) was added, and the reaction
mixture was allowed to warm to 08C over 1 h. The reaction
was quenched with saturated aqueous NaHCO3, and the
mixture was extracted with EtOAc. The extract was washed
with water and brine, dried, and concentrated. The residue
was puri®ed by ¯ash chromatography (3% EtOAc in
hexane) to give tri¯ate 5 (844 mg, 94%) as a pale yellow
oil: 1H NMR (400 MHz, CDCl3) d 0.09 (3H, s), 0.13 (3H, s),
0.89 (9H, s), 0.99 (9H, s), 1.04 (9H, s), 1.54 (1H, q,
Jˆ12.0 Hz), 2.43 (1H, ddd, Jˆ12.0, 4.4, 4.4 Hz), 3.33
Bromoketone formation. To a stirred solution of the hydroxy
epoxy sulfones (2.55 g, 4.54 mmol) in CH2Cl2 (45 mL) was
added MgBr2´OEt2 (1.41 g, 5.44 mmol) at 08C. After stir-
ring at room temperature for 1 h, the reaction mixture was
poured into water and extracted with CH2Cl2. The combined
extracts were washed with saturated aqueous NaHCO3 and
brine, dried, and evaporated. Puri®cation by ¯ash chromato-
graphy (25% EtOAc/hexane) gave a 1:1 mixture of bromo-
ketones (2.14 g, 97%).
Cyclization. To a stirred solution of the bromoketones

1794
Y. Mori, H. Hayashi / Tetrahedron 58 (2002) 1789±1797
(1H, ddd, Jˆ9.9, 9.9, 4.8 Hz), 3.45 (1H, ddd, Jˆ7.3, 5.5,
1.8 Hz), 3.60 (1H, ddd, Jˆ10.6, 9.2, 4.4 Hz), 3.76 (1H, ddd,
Jˆ11.4, 9.5, 4.4 Hz), 3.79 (1H, t, Jˆ10.3 Hz), 4.14 (1H, dd,
Jˆ10.3, 4.8 Hz), 4.50 (1H, dd, Jˆ10.6, 5.5 Hz), 4.69 (1H,
dd, Jˆ10.6, 1.8 Hz).
4.1.7. Ketone 17. To a stirred solution of ketone 15
(894 mg, 1.614 mmol) and molecular sieves 3A (4.5 g) in
dry CH2Cl2 (16 mL) at 2788C were added BF3´OEt2
(218 mL, 1.775 mmol) and Me3SiCHN2 (2.42 mL of a
2.0 M solution in hexane, 4.841 mmol), and the mixture
was stirred at 2788C for 20 min. The reaction was quenched
with saturated aqueous NaHCO3, and the mixture was
extracted with hexane. The extract was washed with water
and brine, dried, and concentrated. The residue was
dissolved in MeOH (20 mL) and PPTS (50 mg) was added
to the solution. After stirring at room temperature for 4 h,
Et3N (0.1 mL) was added, and the mixture was concen-
trated. Flash chromatography (6% Et2O in hexane) gave
4.1.5. Acetylene 14. To a stirred solution of trimethylsilyl-
acetylene (156 mL, 1.106 mmol) in dry THF (2 mL) at 08C
was added n-BuLi (710 mL of a 1.56 M solution in hexane,
1.106 mmol), and the reaction mixture was stirred at 08C for
30 min. After cooling the mixture to 2788C, HMPA
(290 mL, 1.660 mmol) and a solution of 5 (312 mg,
0.553 mmol) in dry THF (2 mL) were added, and the
mixture was warmed gradually to 08C over 2.5 h. The reac-
tion was quenched with saturated aqueous NH4Cl, and the
mixture was extracted with Et2O. The extract was washed
with water and brine, dried, and concentrated. The residue
was dissolved in MeOH (5 mL) and 5% KOH (0.5 mL), and
the solution was stirred at room temperature for 1.5 h. The
reaction mixture was extracted with EtOAc, and the extract
was washed with water and brine, dried, and concentrated.
Puri®cation of the residue by ¯ash chromatography (4%
EtOAc in hexane) gave 14 (180 mg, 74%) as a colorless
25
17 (666 mg, 72%) as an oil: [a]D ˆ275.88 (c 2.09,
CHCl3); IR (CHCl3) 1716, 1472 cm21
;
1H NMR
(600 MHz, CDCl3) d 0.96 (9H, s), 1.01 (9H, s), 1.08 (9H,
s), 1.58 (1H, br q, Jˆ12.5 Hz), 2.28 (1H, m), 2.43 (1H, dd,
Jˆ12.5, 7.3 Hz), 2.97 (1H, br t, Jˆ12.5 Hz), 3.21 (1H, ddd,
Jˆ10.3, 10.3, 5.1 Hz), 3.84±3.95 (4H, m), 4.05 (1H, ddd,
Jˆ10.3, 10.3, 4.4 Hz), 4.10 (1H, dd, Jˆ10.3, 5.1 Hz), 7.36±
7.42 (6H, m), 7.62±7.69 (4H, m); 13C NMR (150 MHz,
CDCl3) d 19.21, 19.87, 22.63, 26.68 (3£C), 27.00 (3£C),
27.47 (3£C), 32.46, 38.28, 65.87, 66.97, 77.41, 81.28,
88.02, 127.60 (2£C), 127.67 (2£C), 129.71, 129.74,
132.93, 133.13, 135.61 (2£C), 135.68 (2£C), 214.87;
HREIMS m/z Calcd for C32H48O5Si2 568.3038. Found
568.3011.
24
oil: [a]D ˆ246.78 (c 0.93, CHCl3); IR (CHCl3) 3309,
2122, 1472 cm21 1H NMR (600 MHz, CDCl3) d 0.11
;
(3H, s), 0.12 (3H, s), 0.89 (9H, s), 0.99 (9H, s), 1.05 (9H,
s), 1.52 (1H, q, Jˆ11.7 Hz), 1.98 (1H, t, Jˆ2.9 Hz), 2.37
(1H, ddd, Jˆ11.7, 4.4, 4.4 Hz), 2.42 (1H, ddd, Jˆ16.9, 5.9,
2.9 Hz), 2.61 (1H, ddd, Jˆ16.9, 2.9, 2.9 Hz), 3.24 (1H, ddd,
Jˆ8.8, 5.9, 3.7 Hz), 3.32 (1H, ddd, Jˆ10.3, 10.3, 5.1 Hz),
3.59 (1H, ddd, Jˆ11.7, 9.5, 5.1 Hz), 3.77 (1H, ddd, Jˆ11.7,
9.5, 4.4 Hz), 3.83 (1H, t, Jˆ10.3 Hz), 4.16 (1H, dd, Jˆ10.3,
5.1 Hz); 13C NMR (150 MHz, CDCl3) d 24.86, 24.07,
17.86, 19.95, 21.59, 22.60, 25.72 (3£C), 27.09 (3£C),
27.46 (3£C), 42.21, 66.87, 68.52, 69.88, 72.23, 77.30,
79.99, 80.73; HREIMS m/z Calcd for C23H44O4Si2 (M1)
440.2776. Found 440. 2749.
4.1.8. exo-Ole®n 18. To a stirred solution of 17 (784 mg,
1.380 mmol) in dry THF (14 mL) at 08C was added the
Tebbe reagent (3.04 mL of a 0.5 M solution in toluene,
1.518 mmol), and the mixture was stirred at 08C for
35 min. The reaction mixture was diluted with Et2O
(20 mL), and 1% NaOH was added until orange±yellow
precipitate formed. The mixture was extracted with Et2O,
and the extract was washed with water and brine, dried, and
concentrated. Flash chromatography (3% EtOAc in hexane)
25
gave 18 (739 mg, 95%) as an oil: [a]D ˆ237.98 (c 2.74,
4.1.6. Ketone 15. A mixture of 7 (924 mg, 2.276 mmol) and
20% Pd(OH)2/C (92 mg) in EtOAc (23 mL) was stirred
under a hydrogen atmosphere for 1 h. The reaction
mixture was ®ltered through a short pad of Celite, and the
®ltrate was concentrated. To a solution of the residue in
DMF (4.5 mL) was added imidazole (310 mg,
4.552 mmol) and TBDPSCl (0.65 mL, 2.504 mmol) at
08C. After stirring at room temperature for 3 h, the reaction
mixture was extracted with Et2O, and the extract was
washed with saturated aqueous NaHCO3 and brine, dried,
and concentrated. Flash chromatography (5% EtOAc in
CHCl3); IR (CHCl3) 1472, 1428 cm21; 1H NMR (600 MHz,
CDCl3) d 0.96 (9H, s), 1.03 (9H, s), 1.04 (9H, s), 1.33 (1H,
m), 2.11 (2H, m), 2.22 (1H, m), 3.23 (1H, ddd, Jˆ10.3, 10.3,
5.1 Hz), 3.51 (1H, dd, Jˆ11.0, 5.1 Hz), 3.66 (1H, dd,
Jˆ11.0, 6.6 Hz), 3.79 (1H, ddd, Jˆ11.0, 11.0, 5.8 Hz),
3.81 (1H, t, Jˆ11.0 Hz), 4.02 (1H, dd, Jˆ11.0, 5.1 Hz),
4.16 (1H, br t, Jˆ5.9 Hz), 4.74 (1H, s), 4.98 (1H, s),
7.35±7.42 (6H, m), 7.65±7.67 (4H, m); 13C NMR
(150 MHz, CDCl3) d 19.21, 19.82, 22.58, 26.82 (3£C),
27.10 (3£C), 27.50 (3£C), 28.02, 39.61, 66.96 (2£C),
76.79, 77.77, 84.25, 113.05, 127.56 (4£C), 129.59 (2£C),
133.62, 133.80, 135.71 (4£C), 150.34; HREIMS m/z Calcd
for C33H50O4Si2 566.3245. Found 566.3271.
25
hexane) gave 15 (1.26 g, 100%) as an oil: [a]D ˆ222.28
1
(c 2.39, CHCl3); IR (CHCl3) 1726, 1472 cm21; H NMR
(600 MHz, CDCl3) d 1.01 (9H, s), 1.02 (9H, s), 1.05 (9H,
s), 2.42 (1H, dd, Jˆ16.9, 11.0 Hz), 3.04 (1H, dd, Jˆ16.9,
5.9 Hz), 3.58 (1H, ddd, Jˆ9.5, 9.5, 5.1 Hz), 3.90 (1H,
t, Jˆ10.2 Hz), 3.95 (2H, m), 4.00 (1H, dd, Jˆ11.0,
2.2 Hz), 4.19 (1H, ddd, Jˆ9.5, 9.5, 5.9 Hz), 4.23 (1H,
dd, Jˆ10.2, 5.1 Hz), 7.35±7.43 (6H, m), 7.65±7.68
(4H, m); 13C NMR (150 MHz, CDCl3) d 19.26, 19.60,
22.63, 26.69 (3£C), 27.00 (3£C), 27.40 (3£C), 48.21,
63.21, 66.61, 72.20, 75.37, 83.58, 127.60 (4£C),
129.66 (2£C), 133.31, 133.39, 135.64 (4£C), 205.15;
HREIMS m/z Calcd for C31H46O5Si2 554.2881. Found
554.2898.
4.1.9. Epoxide 19. To a stirred solution of 18 (610 mg,
1.078 mmol) in acetone (30 mL) and MeCN (10 mL) at
08C were added successively EDTA´Na2 (9 mL of a
0.4 mM aqueous solution), 1,1,1-tri¯uoroacetone (3 mL),
NaHCO3 (1.36 g, 16.166 mmol), and Oxonew (3.31 g,
5.388 mmol). After stirring at 08C for 5 h, the reaction
mixture was diluted with EtOAc and ®ltered. The ®ltrate
was concentrated, and the residue was puri®ed by ¯ash
chromatography (4% EtOAc in hexane) to give 19
(546 mg, 87%) and its epimer (56 mg, 9%). 19:
28
[a]D ˆ228.38 (c 1.26, CHCl3); IR (CHCl3) 1472, 1428,

Y. Mori, H. Hayashi / Tetrahedron 58 (2002) 1789±1797
1795
1
1114 cm21; H NMR (600 MHz, CDCl3) d 0.99 (9H, s),
CDCl3) d 19.97, 20.63, 22.57, 27.18 (3£C), 27.56 (3£C),
30.20, 31.78, 63.38, 67.90, 70.68, 73.10, 78.93, 79.06,
83.75, 86.46, 127.09, 127.22, 127.33 (2£C), 127.40
(2£C), 128.29 (2£C), 128.32 (2£C), 138.62, 139.20;
HREIMS m/z Calcd for C31H46O5Si 526.3112. Found
526.3137.
1.03 (9H, s), 1.04 (9H, s), 1.21 (1H, ddd, Jˆ13.9, 5.1,
2.9 Hz), 1.81 (1H, m), 2.00 (1H, m), 2.05 (1H, ddd,
Jˆ13.9, 13.9, 2.2 Hz), 2.68 (1H, d, Jˆ4.4 Hz), 2.80 (1H,
d, Jˆ4.4 Hz), 3.31 (1H, t, Jˆ5.1 Hz), 3.59±3.66 (3H, m),
3.77 (1H, t, Jˆ10.3 Hz), 3.81 (1H, ddd, Jˆ10.3, 10.3,
5.1 Hz), 4.00 (1H, dd, Jˆ10.3, 5.1 Hz), 7.36±7.44 (6H,
m), 7.62±7.65 (4H, m); 13C NMR (150 MHz, CDCl3) d
19.15, 19.90, 22.53, 25.56, 26.81 (3£C), 27.13 (3£C),
27.45 (3£C), 32.58, 51.98, 60.38, 65.06, 66.79, 75.72,
77.63, 83.95, 127.69 (4£C), 129.81 (2£C), 133.11,
133.23, 135.61 (4£C); HREIMS m/z Calcd for
C33H50O5Si2 582.3194. Found 582.3225.
4.1.12. Diol 22. To a stirred solution of 21 (322 mg,
0.612 mmol) in THF (4 mL) was added Bu4NF (1.83 mL
of a 1.0 M solution in THF, 1.836 mmol), the solution
was stirred at room temperature for 5 h. The solvent was
evaporated, and the residue was puri®ed by ¯ash chromato-
graphy (80% EtOAc in hexane) to give 22 (211 mg, 89%) as
24
an oil: [a]D ˆ211.38 (c 1.0, CHCl3); IR (CHCl3) 3486
1
4.1.10. Alcohol 20. To a stirred solution of 19 (623 mg,
1.070 mmol) in dry THF (9 mL) at 08C was added lithium
triethylborohydride (1.2 mL of a 1.0 M solution in THF,
1.20 mmol), the solution was stirred at 08C for 30 min.
The reaction was quenched with water, and the mixture
was extracted with EtOAc. The extract was washed with
water and brine, dried, and concentrated. Flash
chromatography (10% EtOAc in hexane) gave 20
(br), 1497 cm21; H NMR (600 MHz, CDCl3) d 1.15 (3H,
s), 1.59 (1H, dd, Jˆ14.7, 9.5 Hz), 1.78 (1H, br, OH), 1.82
(1H, m), 1.89 (1H, m), 2.08 (1H, dd, Jˆ14.7, 9.5 Hz), 2.87
(1H, br, OH), 3.44 (1H, ddd, Jˆ8.8, 8.8, 3.7 Hz), 3.53 (2H,
m), 3.59 (1H, dd, Jˆ11.0, 8.1 Hz), 3.73 (1H, dd, Jˆ10.3,
2.2 Hz), 3.80 (1H, dd, Jˆ9.5, 2.2 Hz), 3.83 (1H, dd, Jˆ11.0,
2.9 Hz), 4.39 and 4.43 (each 1H, d, Jˆ11.0 Hz), 4.54 and
4.56 (each 1H, d, Jˆ11.7 Hz), 7.26±7.35 (10H, m); 13C
NMR (150 MHz, CDCl3) d 19.67, 30.24, 31.11, 63.39,
64.74, 70.47, 72.50, 73.20, 78.58, 86.59, 88.87, 127.06
(2£C), 127.26 (2£C), 127.62 (2£C), 128.30 (2£C),
128.41 (2£C), 138.06, 139.15; HREIMS m/z Calcd for
C23H30O5 386.2092. Found 386.2084.
26
(612 mg, 98%) as an oil: [a]D ˆ111.68 (c1.28, CHCl3);
IR (CHCl3) 3507, 1472, 1103 cm21; H NMR (600 MHz,
1
CDCl3) d 0.99 (9H, s), 1.01 (9H, s), 1.06 (9H, s), 1.16 (3H,
s), 1.64 (1H, m), 1.81±1.93 (3H, m), 2.72 (1H, br s, OH),
3.33 (1H, ddd, Jˆ10.3, 10.3, 5.1 Hz), 3.59 (1H, t,
Jˆ7.3 Hz), 3.67 (1H, t, Jˆ10.3 Hz), 3.68 (1H, m), 3.71
(2H, d, Jˆ10.3 Hz), 4.43 (1H, dd, Jˆ10.3, 5.1 Hz), 7.39±
7.46 (6H, m), 7.67±7.69 (4H, m); 13C NMR (150 MHz,
CDCl3) d 19.03, 20.00, 22.52, 24.24, 26.81 (3£C), 27.19
(3£C), 27.48 (3£C), 30.14, 38.09, 63.82, 67.84, 74.49,
79.02, 83.66, 85.32, 127.83 (2£C), 127.87 (2£C), 129.97,
130.04, 132.59, 132.65, 135.55 (2£C), 135.63 (2£C);
HREIMS m/z Calcd for C33H52O5Si2 584.3350. Found
582.3371.
4.1.13. Tri¯ate 6. The procedure for compound 5 was
employed with compound 22 (66 mg, 0.171 mmol) and
CH2Cl2 as a solvent. Puri®cation by ¯ash chromatography
(4% EtOAc in hexane) gave 6 (100 mg, 93%) as a pale
22
yellow oil: [a]D ˆ110.28 (c 0.25, CHCl3); IR (CHCl3)
1497, 1413 cm21 1H NMR (600 MHz, CDCl3) d 0.06
;
(3H, s), 0.07 (3H, s), 0.87 (9H, s), 1.14 (3H, s), 1.50 (1H,
dd, Jˆ15.4, 11.0 Hz), 1.73 (1H, ddd, Jˆ14.2, 8.8, 3.7 Hz),
1.91 (1H, ddd, Jˆ14.2, 10.3, 10.3 Hz), 2.07 (1H, dd,
Jˆ15.4, 9.5 Hz), 3.46 (1H, dd, Jˆ9.5, 8.1 Hz), 3.60 (1H,
ddd, Jˆ8.8, 8.8, 3.7 Hz), 3.64 (1H, ddd, Jˆ8.1, 5.1, 2.2 Hz),
3.77 (1H, dd, Jˆ10.2, 1.5 Hz), 3.81 (1H, d, Jˆ8.8 Hz), 4.40
and 4.42 (each 1H, d, Jˆ11.0 Hz), 4.52 (1H, dd, Jˆ10.3,
5.1 Hz), 4.53 and 4.59 (each 1H, d, Jˆ11.7 Hz), 4.70 (1H,
dd, Jˆ10.3, 2.2 Hz), 7.27±7.36 (10H, m).
4.1.11. Dibenzyl ether 21. To a stirred solution of 20
(592 mg, 1.014 mmol) in MeOH (30 mL) was added 10%
KOH (5.2 mL), and the solution was stirred at room
temperature for 2.5 h. After the reaction was neutralized
with 3N HCl, the mixture was concentrated to one-third of
the volume and extracted with EtOAc. The extract was
washed with water and brine, dried, and concentrated.
Flash chromatography (10% Et2O in hexane) gave a diol
(309 mg, 88%). The diol (221 mg, 0.639 mmol) and benzyl
bromide (0.61 mL, 5.110 mmol) was dissolved in dry THF
(6.4 mL), and then excess KH in mineral oil was added at
08C. After stirring at room temperature for 1 h, the reaction
was quenched carefully with saturated aqueous NH4Cl and
extracted with Et2O. The extract was washed with water and
brine, dried, and concentrated. Flash chromatography (5%
EtOAc in hexane) gave 21 (322 mg, 96%) as an oil:
4.1.14. Alkyne 23. A solution of 14 (62 mg, 0.141 mmol), 6
(45 mg, 0.070 mmol), and HMPA (0.1 mL) in dry THF
(0.9 mL) was cooled to 2788C and treated with n-BuLi
(97 mL of a 1.6 M solution in hexane, 0.155 mmol). After
stirring at 2788C for 30 min, the reaction mixture was
warmed to 2208C over 30 min and stirred for 1 h. The
reaction was quenched with NH4Cl, and the mixture was
extracted with EtOAc. The extract was washed with water
and brine, dried, and concentrated. Flash chromatography
(5% EtOAc in hexane) gave 23 (47 mg, 71%) as an oil:
25
[a]D ˆ110.78 (c 1.0, CHCl3); IR (CHCl3) 1496, 1472,
1
22
1104 cm21; H NMR (400 MHz, CDCl3) d 0.99 (9H, s),
[a]D ˆ232.88 (c 1.69, CHCl3); IR (CHCl3) 1472, 1252,
1
1.04 (9H, s), 1.12 (3H, s), 1.51 (1H, dd, Jˆ15.6, 11.2 Hz),
1.87 (1H, m), 1.95 (1H, m), 2.12 (1H, dd, Jˆ15.6, 7.8 Hz),
3.45 (1H, dd, Jˆ10.2, 8.8 Hz), 3.50 (1H, ddd, Jˆ10.2, 9.8,
4.9 Hz), 3.74 (1H, ddd, Jˆ9.8, 9.8, 3.9 Hz), 3.77 (1H, dd,
Jˆ10.2, 2.0 Hz), 3.82 (1H, t, Jˆ10.2 Hz), 3.84 (1H, dd,
Jˆ8.8, 2.0 Hz), 4.23 (1H, dd, Jˆ10.2, 4.9 Hz), 4.39 and
4.44 (each 1H, d, Jˆ11.2 Hz), 4.55 and 4.57 (each 1H, d,
Jˆ12.2 Hz), 7.23±7.33 (10H, m); 13C NMR (100 MHz,
1093 cm21; H NMR (400 MHz, CDCl3) d 0.07 (3H, s),
0.08 (3H, s), 0.09 (3H, s), 0.10 (3H, s), 0.88 (9H, s), 0.89
(9H, s), 0.99 (9H, s), 1.04 (9H, s), 1.16 (3H, s), 1.50 (2H, q,
Jˆ11.2 Hz), 1.69 (1H, ddd, Jˆ10.2, 9.3, 2.4 Hz), 1.83 (1H,
ddd, Jˆ8.8, 5.4, 5.4 Hz), 2.15 (1H, dd, Jˆ14.2, 9.8 Hz),
2.29 (1H, br dd, Jˆ16.6, 6.8 Hz), 2.36 (1H, ddd, Jˆ12.2,
4.4, 4.4 Hz), 2.43 (2H, m), 2.61 (1H, br dd, Jˆ16.6, 2.4 Hz),
3.20 (1H, ddd, Jˆ8.8, 7.3, 2.9 Hz), 3.30 (1H, ddd, Jˆ10.2,

1796
Y. Mori, H. Hayashi / Tetrahedron 58 (2002) 1789±1797
10.2, 4.9 Hz), 3.51 (3H, m), 3.76 (1H, ddd, Jˆ11.2, 9.3,
4.4 Hz), 3.80 (1H, dd, Jˆ10.3, 2.0 Hz), 3.81 (1H, t,
Jˆ9.8 Hz), 3.86 (1H, m), 3.90 (1H, dd, Jˆ8.3, 2.0 Hz),
4.15 (1H, dd, Jˆ9.8, 4.9 Hz), 4.42 (2H, s), 4.54 and 4.61
(each 1H, d, Jˆ12.7 Hz), 7.23±7.35 (10H, m); 13C NMR
(100 MHz, CDCl3) d 24.79, 24.60, 24.27, 24.09, 17.86
(2£C), 19.77, 19.95, 22.14, 22.59, 24.28, 25.75 (3£C),
25.81 (3£C), 27.09 (3£C), 27.44 (3£C), 28.38, 30.76,
42.30, 63.21 (2£C), 66.96, 68.87, 70.81, 72.28, 73.02,
74.14, 78.05, 78.09, 78.43, 80.88, 83.98, 85.52, 126.99
(2£C), 127.04 (2£C), 127.24, 127.37, 128.19 (2£C),
128.26 (2£C), 138.95, 139.54; HRFABMS m/z Calcd for
C52H87O8Si3 (MH1) 923.5704. Found 923.5743.
ddd, Jˆ14.7, 5.3, 5.3 Hz), 2.07 (1H, dd, Jˆ15.4, 9.5 Hz),
2.35 (1H, ddd, Jˆ11.7, 4.4, 4.4 Hz), 2.85 (1H, dd, Jˆ16.9,
6.8 Hz), 2.94 (1H, dd, Jˆ15.4, 9.5 Hz), 3.01 (1H, dd,
Jˆ15.4, 2.9 Hz), 3.04 (1H, dd, Jˆ16.9, 3.0 Hz), 3.27 (1H,
ddd, Jˆ9.5, 9.5, 5.1 Hz), 3.36 (1H, dd, Jˆ10.3, 8.1 Hz),
3.42 (1H, ddd, Jˆ10.3, 10.3, 4.4 Hz), 3.53 (1H, ddd,
Jˆ8.1, 8.1, 2.9 Hz), 3.62 (1H, dd, Jˆ10.3, 1.5 Hz), 3.66
(1H, t, Jˆ10.3 Hz), 3.69 (2H, m), 3.80 (1H, dd, Jˆ8.1,
2.2 Hz), 3.90 (1H, ddd, Jˆ8.1, 8.1, 2.9 Hz), 4.00 (1H, dd,
Jˆ10.5, 4.4 Hz), 4.38 and 4.40 (each 1H, d, Jˆ11.3 Hz),
4.47 and 4.49 (each 1H, d, Jˆ12.5 Hz), 7.22±7.31 (10H, m);
13C NMR (150 MHz, CDCl3) d 5.01 (3£C), 5.07 (3£C),
6.83 (3£C), 6.86 (3£C), 19.98 (2£C), 22.62, 27.05 (3£C),
27.43 (3£C), 29.59, 31.07, 38.66, 40.57, 42.41, 63.19,
66.66, 70.01, 70.26, 72.22 (2£C), 72.59, 76.15, 78.13,
78.60, 84.27, 84.69, 126.95 (4£C), 127.06, 127.23, 127.49
(2£C), 128.21 (2£C), 138.67, 139.39, 197.28, 197.41;
HRFABMS m/z Calcd for C52H87O10Si3 (MH1) 955.5602.
Found 955.5647.
4.1.15. Alkyne 24. A solution of 23 (63 mg, 0.068 mmol)
and TsOH´H2O (26 mg, 0.136 mmol) in CH2Cl2 (0.3 mL)
and MeOH (0.7 mL) was stirred at room temperature for
7 h. After addition of Et3N (0.1 mL), the reaction mixture
was concentrated. The residue was puri®ed by ¯ash
chromatography (40% EtOAc in hexane) to give a diol
(44.3 mg, 93%). The diol (32.8 mg, 0.047 mmol) was
dissolved in CH2Cl2 (1 mL), and then 2,6-lutidine (28 mL,
0.236 mmol) and TESOTf (43 mL, 0.189 mmol) were added
at 08C. After stirring at 08C for 30 min, the reaction mixture
was extracted with EtOAc. The extract was washed with
saturated aqueous NaHCO3 and brine, dried, and concen-
trated. Flash chromatography (6% EtOAc in hexane) gave
4.1.17. Dimethyl ketal 28. A solution of 26 (24.2 mg,
0.0253 mmol) and TsOH´H2O (9.6 mg, 0.0507 mmol) in
CHCl3 (1.0 mL) was stirred at 08C for 1 h. The reaction
was quenched with three drops of Et3N, and the solvent
was evaporated. Flash chromatography (20% acetone in
hexane) gave 27 (16.9 mg, 89%). To a stirred solution of
27 (15.0 mg) in DMF (1.0 mL) at 08C were added MeI
(0.1 mL) and NaH (60% in mineral oil, 20 mg), the reaction
mixture was stirred at 08C for 35 min. The reaction was
quenched with saturated aqueous NH4Cl, and the mixture
was extracted with EtOAc. The extract was washed with
water and brine, dried, and concentrated. Flash chromato-
graphy (25% Et2O in hexane) gave 28 (8.5 mg, 55%) as a
21
acetylene 24 (41.4 mg, 95%): [a]D ˆ233.88 (c 0.84,
1
CHCl3); H NMR (400 MHz, CDCl3) d 0.58±0.65 (12H,
m), 0.96 (18H, t, Jˆ7.8 Hz), 0.99 (9H, s), 1.04 (9H, s),
1.16 (3H, s), 1.52 (2H, m), 1.70 (1H, m), 1.84 (1H, ddd,
Jˆ14.6, 8.3, 8.3 Hz), 2.16 (1H, dd, Jˆ14.2, 10.3 Hz), 2.28
(1H, br dd, Jˆ16.6, 7.3 Hz), 2.36 (1H, ddd, Jˆ12.2, 4.4,
4.4 Hz), 2.47 (2H, m), 2.64 (1H, dd, Jˆ16.6, 2.4 Hz), 3.20
(1H, ddd, Jˆ8.8, 7.3, 2.9 Hz), 3.29 (1H, ddd, Jˆ10.2, 10.2,
4.9 Hz), 3.47±3.56 (3H, m), 3.74 (1H, ddd, Jˆ11.2, 8.8,
4.4 Hz), 3.81 (1H, t, Jˆ10.3 Hz), 3.82 (1H, dd, Jˆ10.2,
2.0 Hz), 3.85 (1H, m), 3.91 (1H, dd, Jˆ8.3, 2.0 Hz), 4.15
(1H, dd, Jˆ9.8, 4.9 Hz), 4.42 (2H, s), 4.54 and 4.61 (each
1H, d, Jˆ12.7 Hz), 7.21±7.35 (10H, m); 13C NMR
(100 MHz, CDCl3) d 5.03 (6£C), 6.86 (3£C), 6.91 (3£C),
19.74, 19.95, 22.60, 24.38, 27.09 (3£C), 27.46 (3£C),
28.46, 30.85, 42.41, 63.21, 66.95, 69.02, 70.83, 72.31,
73.05 (2£C), 74.27, 77.26, 78.00, 78.05, 78.45, 81.00,
83.91, 85.61, 127.00 (2£C), 127.04, 127.24 (2£C),
127.38, 128.21 (2£C), 128.24 (2£C), 138.98, 139.58;
HRFABMS m/z Calcd for C52H87O8Si3 (MH1) 923.5704.
Found 923.5681.
20
solid: mp 188±1898C; [a]D ˆ217.78 (c 0.71, CHCl3); IR
(CHCl3) 1473, 1365, 1278, 1102 cm21; 1H NMR (600 MHz,
CDCl3) d 0.99 (9H, s), 1.04 (9H, s), 1.16 (3H, s), 1.57 (1H,
m), 1.66 (1H, q, Jˆ11.7 Hz), 1.75 (1H, m), 1.90 (1H, t,
Jˆ12.5 Hz), 2.00 (1H, m), 2.03 (1H, t, Jˆ11.7 Hz), 2.15
(1H, dd, Jˆ12.5, 4.2 Hz), 2.19 (1H, dd, Jˆ15.4, 8.1 Hz),
2.30 (1H, dd, Jˆ12.5, 4.4 Hz), 2.34 (1H, ddd, Jˆ11.7, 4.4,
4.4 Hz), 3.20 (3H, s), 3.25 (3H, s), 3.27 (1H, ddd, Jˆ11.7,
8.8, 5.1 Hz), 3.33 (1H, ddd, Jˆ10.3, 10.3, 5.1 Hz), 3.37±
3.47 (3H, m), 3.50 (1H, dd, Jˆ10.3, 8.1 Hz), 3.78 (1H, dd,
Jˆ10.3, 2.4 Hz), 3.82 (1H, t, Jˆ10.3 Hz), 3.84 (2H, m),
4.13 (1H, dd, Jˆ10.3, 4.4 Hz), 4.40 and 4.46 (each 1H, d,
Jˆ11.7 Hz), 4.57 and 4.59 (each 1H, d, Jˆ11.7 Hz), 7.25±
7.34 (10H, m); 13C NMR (150 MHz, CDCl3) d 19.94, 20.99,
22.60, 26.96, 27.05 (3£C), 27.40 (3£C), 29.11, 30.80,
33.09, 37.82, 47.03, 47.10, 63.27, 66.74, 68.43, 70.70,
72.97, 73.09, 75.62, 76.01, 78.04, 78.99, 81.77, 87.39,
98.13, 98.46, 126.95, 127.14, 127.24, 127.29, 128.23,
128.26, 128.31, 128.36, 129.45, 129.54, 138.80, 139.29;
HRFABMS m/z Calcd for C42H63O10Si (MH1) 755.4187.
Found 755.4162.
4.1.16. 1,2-Diketone 26. To a suspension of 24 (38.8 mg,
0.0421 mmol) in CCl4 (0.4 mL), MeCN (0.4 mL), and pH 7
phosphate buffer (0.6 mL) were added NaIO4 (22.5 mg,
0.1052 mmol) and RuO2´H2O (0.8 mg). After stirring at
room temperature for 4 h, additional NaIO4 (10.4 mg) was
added, and stirring was continued for 4 h. The reaction
mixture was extracted with hexane and the extract was
washed with aqueous Na2S2O3 and brine, dried, and concen-
trated. Flash chromatography (7% EtOAc in hexane) gave
4.1.18. BCDE ring system 2. To a stirred solution of 28
(8.4 mg, 0.0111 mmol) in dry CH2Cl2 (0.2 mL) at 08C were
added Et3SiH (16.5 mL, 0.111 mmol) and TMSOTf (8.8 mL,
0.0446 mmol), the reaction mixture was stirred at 08C
for 45 min. The reaction was quenched with NaHCO3, and
the mixture was extracted with EtOAc. The extract was
washed with water and brine, dried, and concentrated.
Flash chromatography (15% acetone in hexane) gave 2
25
26 (26 mg, 65%) as a yellow oil: [a]D ˆ228.08 (c 0.68,
CHCl3); IR (CHCl3) 1715, 1472, 1093 cm21 1H NMR
;
(600 MHz, CDCl3) d 0.59 (12H, m), 0.94 (18H, m), 0.97
(9H, s), 1.02 (9H, s), 1.09 (3H, s), 1.50 (1H, m), 1.51 (1H, q,
Jˆ11.7 Hz), 1.72 (1H, ddd, Jˆ14.7, 9.5, 3.7 Hz), 1.88 (1H,

Y. Mori, H. Hayashi / Tetrahedron 58 (2002) 1789±1797
1797
21
(3.9 mg, 51%) as a solid: mp 182±1838C; [a]D ˆ225.28 (c
6. For examples of convergent approaches, see: (a) Nicolaou,
K. C.; Postema, M. H. D.; Claiborne, C. F. J. Am. Chem.
0.1, CHCl3); IR (CHCl3) 1454, 1077 cm21 1H NMR
;
Â
Soc. 1996, 118, 1565±1566. (b) Alvarez, E.; Perez, R.; Rico,
(600 MHz, CDCl3) d 0.98 (9H, s), 1.04 (9H, s), 1.13 (3H,
s), 1.44 (1H, q, Jˆ11.0 Hz), 1.54 (3H, q, Jˆ11.8 Hz), 1.82
(1H, m), 1.90 (1H, ddd, Jˆ13.9, 10.3, 10.3 Hz), 2.17 (1H,
dd, Jˆ15.4, 8.1 Hz), 2.30 (1H, ddd, Jˆ8.1, 3.7, 3.7 Hz),
2.44 (1H, ddd, Jˆ11.0, 4.4, 4.4 Hz), 2.48 (1H, ddd,
Jˆ11.0, 3.7, 3.7 Hz), 3.03±3.10 (4H, m), 3.14 (1H, ddd,
Jˆ11.0, 9.5, 4.4 Hz), 3.31 (1H, ddd, Jˆ10.3, 10.3,
3.7 Hz), 3.33 (1H, ddd, Jˆ9.5, 9.5, 5.1 Hz), 3.48 (1H, dd,
Jˆ10.3, 8.8 Hz), 3.77 (1H, dd, Jˆ10.3, 1.5 Hz), 3.81 (2H, t,
Jˆ10.3 Hz), 3.84 (1H, ddd, Jˆ11.0, 8.8, 4.4 Hz), 4.14 (1H,
dd, Jˆ10.3, 5.1 Hz), 4.38 and 4.44 (each 1H, d, Jˆ11.7 Hz),
4.56 and 4.61 (each 1H, d, Jˆ12.5 Hz), 7.24±7.34 (10H, m);
13C NMR (150 MHz, CDCl3) d 19.94, 20.76, 22.65, 23.22,
27.05 (3£C), 27.43 (3£C), 32.40, 35.14, 36.85, 38.35,
63.31, 66.77, 70.77, 72.71 (2£C), 73.20, 76.61, 77.05,
77.38, 77.74, 78.97, 83.15, 84.22, 87.01, 127.01 (2£C),
127.21 (2£C), 127.41 (2£C), 128.28 (2£C), 128.34
(2£C), 138.70, 139.28; HRFABMS m/z Calcd for
C40H59O8Si (MH1) 695.3976. Found 695.3989.
Â
Â
M.; Rodrõguez, R. M.; Martõn, J. D. J. Org. Chem. 1996, 61,
3003±3016. (c) Sasaki, M.; Fuwa, H.; Inoue, M.; Tachibana,
K. Tetrahedron Lett. 1998, 39, 9027±9030. (d) Fujiwara, K.;
Saka, K.; Takaoka, D.; Murai, A. Synlett 1999, 1037±1040.
(e) Maeda, K.; Oishi, T.; Oguri, H.; Hirama, M. Chem.
Commun. 1999, 1063±1065. (f) Sasaki, M.; Fuwa, H.;
Ishikawa, M.; Tachibana, K. Org. Lett. 1999, 1, 1075±1078.
7. Mori, Y.; Mitsuoka, S.; Furukawa, H. Tetrahedron Lett. 2000,
41, 4161±4164.
8. Fujiwara, K.; Morishita, H.; Saka, K.; Murai, A. Tetrahedron
Lett. 2000, 41, 507±510.
9. Matsuo, G.; Hinou, H.; Koshino, H.; Suenaga, T.; Nakata, T.
Tetrahedron Lett. 2000, 41, 903±906.
10. Mori, Y.; Yaegashi, K.; Iwase, K.; Yamamori, Y.; Furukawa,
H. Tetrahedron Lett. 1996, 37, 2605±2608.
11. 1,3-O-Di-t-butylsilylene-l-eryhtritol (10) was prepared from
tri-O-acetyl-d-glucal in four steps. Synthesis of both enantio-
meric 1,3-O-di-t-butylsilylene-d- and l-eryhtritols. Mori, Y.;
Hayashi, H. J. Org. Chem., 2002, 66, 8666±8668.
12. Mori, Y.; Yaegashi, K.; Furukawa, H. Tetrahedron Lett. 1999,
40, 7239±7242.
References
13. Kotsuki, H.; Kadota, I.; Ochi, M. Tetrahedron Lett. 1990, 31,
4609±4612.
1. (a) Shimizu, Y. Marine Natural Products, Vol. 1; Academic:
New York, 1978. (b) Shimizu, Y. Chem. Rev. 1993, 93, 1685±
1698. (c) Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93,
1897±1909.
14. Mori, Y.; Yaegashi, K.; Furukawa, H. Tetrahedron 1997, 53,
12917±12932.
15. Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.
1978, 100, 3611±3613. For a review, see: (b) Pine, S. H. Org.
React. 1993, 43, 1±91.
2. (a) Murata, M.; Kumagai, M.; Lee, J. S.; Yasumoto, T.
Tetrahedron Lett. 1987, 28, 5869±5872. (b) Naoki, H.;
Murata, M.; Yasumoto, T. Rapid Commun. Mass Spectrum
1993, 7, 179±182.
16. (a) Baumstark, A. L.; McCloskey, C. J. Tetrahedron Lett.
1987, 28, 3311±3314. (b) Bach, R. D.; Andres, J. L.;
Owensby, A. L.; Schlegel, H. B.; McDouall, J. J. W. J. Am.
Chem. Soc. 1992, 114, 7207±7217. (c) Houk, K. N.; Liu, J.;
Demello, N. C.; Condroski, K. R. J. Am. Chem. Soc. 1997,
119, 10147±10152.
3. Satake, M.; Terasawa, K.; Kadowaki, Y.; Yasumoto, T.
Tetrahedron Lett. 1996, 37, 5955±5958.
4. Takahashi, H.; Kusumi, T.; Kan, Y.; Satake, M.; Yasumoto, T.
Tetrahedron Lett. 1996, 37, 7087±7090.
5. For examples of iterative approaches, see: (a) Mori, Y. Chem.
Eur. J. 1997, 3, 849±852. (b) Mori, Y.; Yaegashi, K.;
Furukawa, H. J. Am. Chem. Soc. 1996, 118, 8158±8159.
(c) Evans, P. A.; Roseman, J. D.; Garber, L. T. J. Org.
Chem. 1996, 61, 4880±4888. (d) Clark, J. S.; Kettle, J. G.
Tetrahedron Lett. 1997, 38, 123±126. (e) Rainer, J. D.;
Allwein, S. P. Tetrahedron Lett. 1998, 39, 9601±9604.
(f) Bowman, J. L.; McDonald, F. E. J. Org. Chem.
1998, 63, 3680±3682. (g) Hori, N.; Matukura, H.; Matsuo,
G.; Nakata, T. Tetrahedron Lett. 1999, 40, 2811±2814.
(h) Leeuwenburgh, M. A.; Litjens, R. E. J. N.; Codee,
J. D. C.; Overkleeft, H.; van der Marel, G. A.; van
Boom, J. H. Org. Lett. 2000, 2, 1275±1277.
17. Yang, D.; Wong, M.-K.; Yip, Y.-C. J. Org. Chem. 1995, 60,
3887±3889.
18. Kabat, M. M.; Lange, M.; Wovkulich, P. M.; Uskokovic, M. R.
Tetrahedron Lett. 1992, 33, 7701±7704.
19. (a) Charlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless,
K. B. J. Org. Chem. 1981, 46, 3936±3983. (b) Zibuck, R.;
Seebach, D. Helv. Chim. Acta 1988, 71, 237±240.
20. (a) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett.
1979, 4679±4682. (b) Nicolaou, K. C.; Hwang, C.-K.; Nugiel,
D. A. J. Am. Chem. Soc. 1989, 111, 4136±4137.