Synthesis of trans-fused polycyclic ethers with angular methyl groups using sulfonyl-stabilized oxiranyl anions

Article abstract of DOI:10.1016/j.tet.2003.09.016

An efficient method has been developed for the synthesis of trans-fused tetrahydropyrans with angular methyl groups adjacent to the ring oxygen. The procedure involves the coupling reaction of a sulfonyl-stabilized oxiranyl anion with an appropriate triflate followed by 6-endo cyclization, and is effective for the construction of 6/6- and 6/7/6-cyclic ether ring systems with sterically congested 1,3-diaxial methyl groups.

Full text of DOI:10.1016/j.tet.2003.09.016

Tetrahedron 59 (2003) 9767–9777
Synthesis of trans-fused polycyclic ethers with angular methyl
groups using sulfonyl-stabilized oxiranyl anions
†
Hiroki Furuta,a Toyohisa Takase,a Hisafumi Hayashi,a Ryoji Noyorib and Yuji Moria
,
,
*
aFaculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan
bDepartment of Chemistry, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan
Received 11 June 2003; accepted 5 September 2003
Abstract—An efficient method has been developed for the synthesis of trans-fused tetrahydropyrans with angular methyl groups adjacent to
the ring oxygen. The procedure involves the coupling reaction of a sulfonyl-stabilized oxiranyl anion with an appropriate triflate followed by
6-endo cyclization, and is effective for the construction of 6/6- and 6/7/6-cyclic ether ring systems with sterically congested 1,3-diaxial
methyl groups.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
(Scheme 1). We report herein the details of the synthesis of
6/6- and 6/7/6-cyclic ether ring systems having angular
methyl groups based on an oxiranyl anion strategy.8
Metalated oxiranes, considered as fleeting unstable inter-
mediates, are emerging as useful synthons.1 Their potential
was first demonstrated by Eisch and Galle, who found that
epoxides with anion-stabilizing groups can be metalated
with strong bases at low temperatures and trapped by
electrophiles.2 Among them, the generation of sulfonyl-
stabilized oxiranyl anions and their synthetic utility as a
functionalized acyl anion equivalent have been extensively
studied by Jackson and co-workers.3 As a part of our
program directed to the synthesis of polycyclic ether natural
products, we have developed a general and iterative
procedure for the synthesis of polytetrahydropyrans based
on an oxiranyl anion strategy, in which alkylation of a
sulfonyl-stabilized oxiranyl anion and the subsequent
6-endo cyclization were employed as key reactions.4 The
6-endo cyclization directed by the electron-withdrawing
ability of a sulfonyl group is complementary to that of the
p-orbital-assisted cyclization developed by Nicolaou.5
Taking advantage of our methodology, we envisioned a
way to synthesize the 6-membered ether ring systems, I-III,
containing angular methyl groups adjacent to the ring
oxygen. Such ring systems are often encountered as
structural units of polycyclic ether marine toxins,6 and
several synthetic efforts have been reported.7 A particularly
attractive feature of our approach is that the methyl-
substituted keto tetrahydropyran 5 could be easily accessed
by assembling triflate 1 and epoxy sulfone 2 followed by
6-endo cyclization of 3 via hydroxy epoxy sulfone 4
Scheme 1.
2. Results and discussion
Since oxiranyl anions stabilized by a sulfonyl group are
unstable even at low temperatures, the reaction of triflate 1
and oxiranyl anion 2 was carried out by an in situ trapping
method in order to minimize decomposition of the transient
lithiated epoxides prior to electrophile trapping.9 Thus, a
mixture of a triflate and an epoxy sulfone in THF at 21008C
in the presence of DMPU or HMPA was treated with n-BuLi
to afford a cyclization precursor in high yield (Table 1). The
Keywords: tetrahydropyrans; oxiranes; oxiranyl anions; 6-endo cyclization.
*
Corresponding author. Tel.: þ81-52-832-1781; fax: þ81-52-834-8090;
e-mail: mori@ccmfs.meijo-u.ac.jp
Visiting Professor of Meijo University.
†
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.016

Table 1. Reaction of triflate 1 with the oxiranyl anion generated from epoxy sulfone 2
Entry
Triflate
Epoxy sulfone
Reaction conditions
Product
Yield (%)
90
1
1a
1a
1b
6
2a
2b
2b
2b
2a
2b
n-BuLi, THF-DMPU, 21008C, 30 min
3a
3b
3c
7
2
3
5
6
7
n-BuLi, THF-DMPU, 21008C, 40 min
n-BuLi, THF-HMPA, 21008C, 25 min
n-BuLi, THF-HMPA, 21008C, 30 min
n-BuLi, THF-HMPA, 21008C, 45 min
n-BuLi, THF-HMPA, 21008C, 90 min
90
94
95
97
71
1c
1c
3d
3e

Table 2. 6-endo Cyclization of monomethyl-substituted silyloxy epoxy sulfones
Entry
Epoxy sulfone
Cyclization conditions
Product
Yield (%)
80
1
3a
3b
TsOH·H2O (1.3 equiv.), CHCl3, 558C, 3 h
5a
2
3
4
TsOH·H2O (1.3 equiv.), CHCl3, 558C, 4 h
BF3·OEt2 (2.0 equiv.), CHCl3, rt, 4.5 h
TsOH·H2O (1.5 equiv.), CHCl3, 08C, 16 h
9a
9b
5c
R¼H
52
58
90
R¼TBS
3c
5
7
TsOH·H2O (1.5 equiv.), CHCl3, 08C, 13 h
8
89
6
7
3d
TsOH·H2O (1.3 equiv.), CHCl3, 558C, 8 h
5d
48
89
BF3·OEt2 (5.0 equiv.), CHCl3, 08C, 30 min, rt, 30 min

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H. Furuta et al. / Tetrahedron 59 (2003) 9767–9777
oxiranyl anions generated from epoxy sulfones 2a and 2b
are configurationally stable under these conditions. In the
case of the reaction of 1c and 2b, HMPA was necessary
rather than DMPU as a co-solvent to obtain 3e in good yield
(entry 7). The monocyclic triflates 1a-c and 6 were prepared
from the corresponding diols by regioselective O-triflation
and O-silylation by a one-pot procedure.4 The optically
active epoxy sulfones 2a and 2b were synthesized from (S)-
O-pentylideneglyceraldehyde10 and (R)-(2)-chloromethyl
p-tolyl sulfoxide,11 respectively.
protected epoxy sulfone 3c was prepared and subjected to
the cyclization reaction. Exposure of 3c to TsOH·H2O in
CHCl3 at 08C led to detriethylsilylation within 30 min and
the following cyclization proceeded smoothly to give the
bicyclic ketone 5c in 90% yield (entry 4). Under these
reaction conditions the silylene derivative 7 could be
transformed to the keto tetrahydropyran 8 without any
deprotection of the silylene group (entry 5).
Cyclization of 3d was then examined, where a tertiary
alcohol and a trisubstituted epoxy sulfone participate. In this
case, a TMS group was employed for the protection of the
tertiary alcohol because of its easier deprotection than that
of the TES group. Heating a solution of 3d with TsOH·H2O
in CHCl3 at 558C for 8 h resulted in the formation of the
bicyclic ketone 5d in moderate yield (entry 6). In order to
improve the yield, several Lewis acids which are not
potential sources of nucleophilic halide ions were examined
as a stronger activator for cyclization. Among them,
BF3·OEt2 was found to be an excellent activator and the
cyclization proceeded rapidly to afford the ketone 5d in high
yield (entry 7).
Construction of a new ether ring by 6-endo cyclization
requires the conversion of the coupling product 3 to hydroxy
epoxide 4 before the 6-endo cyclization reaction. We
explored the reaction conditions that induce both desilyl-
ation of a secondary or a tertiary alcohol and 6-endo
cyclization (Table 2). Entry 1 demonstrates the originally
reported cyclization conditions employed for the non-
methyl-substituted precursor 3a.4,10 Initial attempts to
cyclize epoxy sulfone 3a were conducted with TsOH·H2O
in CH2Cl2 at various temperatures. These conditions,
however, were unable to deprotect the TBS group and
then 3a was heated with TsOH·H2O in CHCl3 at 558C. We
were pleased to find that deprotection of the TBS group and
the following 6-endo cyclization proceeded simultaneously
to give, after 3 h, the bicyclic ketone 5a in 80% yield (entry
1). It is worthy to note that treatments with Lewis acids
containing halogens such as MgBr2·OEt2, ZnCl2, and AlCl3
caused the formation of the corresponding a-halo ketones
by the nucleophilic attack of a halogen to the epoxy sulfone
moiety as previously reported.12
Construction of a tetrahydropyran of type III is a
challenging synthetic issue because it contains sterically
congested 1,3-diaxial methyl groups adjacent to the ring
oxygen. Considering the 1,2-migration of the sulfonyl group
observed in the case of the methyl-substituted epoxy sulfone
3b (Table 2, entries 2 and 3), the cyclization of 3e that
requires reaction between a less reactive tertiary alcohol and
a more reactive methyl-substituted epoxy sulfone would be
difficult. It is, however, very interesting to construct such
ring system by the 6-endo cyclization methodology. In fact,
treatments of 3e with TsOH·H2O and camphorsulfonic acid
at room temperature caused only the rearrangement of the
epoxy sulfone to a-sulfonyl ketone 10 as a single isomer
(Table 3, entries 1 and 2). Deprotection of the TMS group
was rapid but the subsequent cyclization reaction was very
slow under the conditions. However, BF3·OEt2 did promote
the cyclization of 3e to the bicyclic ketone 5e, albeit in low
yield (entry 3). This result encouraged us to carry out the
reaction with a larger amount of BF3·OEt2 at below room
temperature to suppress the 1,2-sulfonyl shift and to
accelerate the cyclization. Thus, cyclization with 7.5 equiv
In the case of the 6-endo cyclization of the substrates having
a methyl group on an oxirane ring, reaction temperature was
found to be critical. Reaction of the TBS-protected epoxy
sulfone 3b with TsOH·H2O in CHCl3 at 558C induced a 1,2-
shift of the sulfonyl group,13 rather than 6-endo cyclization,
to give a-sulfonyl ketone 9a in 52% yield as a single isomer
(entry 2). The stereochemistry of the sulfone-attached
carbon was tentatively assigned based on the migration of
the sulfonyl group to the back side of the cleaved epoxide
center, but no further proof was carried out. In order to
achieve the cyclization at or below room temperature to
avoid the migration of the sulfonyl group, the TES-
Table 3. 6-endo Cyclization of dimethyl-substituted silyloxy epoxy sulfone 3e
Entry
Cyclization conditions
Yield (%)
Acid
Equiv.
Temperature
Time (h)
5e
10
1
2
3
4
5
6
TsOH
CSA
BF3·OEt2
BF3·OEt2
Tl(TFA)3
BF3·OEt2/Tl(TFA)3
1.5
5.0
5.0
7.5
4.0
1.0/3.0
rt
rt
rt
08C
rt
72
60
72
1
4
2
–
–
25
47
52
62
28a
59
51
30
b
–
b
08C
–
a
Detrimethylsilylated 3e was obtained in 31% yield.
Trace amount (,5%).
b

H. Furuta et al. / Tetrahedron 59 (2003) 9767–9777
9771
Now, stereocontrolled synthesis of the three types of
methyl-substituted tetrahydropyrans I-III was accom-
plished by choosing suitable cyclization conditions
depending upon the type of methyl-substitution. The
stereochemistry of the cyclization products 5a and 5c-e
1
was equivocally assigned on the basis of H NMR NOE
experiments as shown in Figure 1. These results indicate
that the cyclization proceeded stereoselectively with
inversion of the stereogenic center of the epoxide
through the chair-like transition state 4 shown in
Scheme 1.
In an effort to extend the 6-endo cyclization reaction to
a 7-membered ring alcohol, the bicyclic ketone 11 was
prepared from the keto tetrahydropyran 5a by ring
expansion reaction with trimethylsilyldiazomethane
(Scheme 2).10 Attempts to direct installation of an
a-oriented methyl group to the ketone 11 with
MeMgBr, MeLi, or Me3Al were unsuccessful, resulting
in the formation of the undesired b-methyl isomer as a
major product. Then, the required a-methyl isomer 12
was prepared by a four-step manipulation in 69%
overall yield: methylenation with Tebbe reagent, epoxi-
dation with m-CPBA (a/b¼3:1), reduction with LiEt3-
BH, and desilylation with TBAF. Subsequent O-triflation
and O-triethylsilylation in one pot gave triflate 13 in
88% yield. Reaction of 13 with the oxiranyllithium
generated from 2b gave the cyclization precursor 14 in
91% yield.
Figure 1. NOE in bicyclic ketones 5a and 5c-e.
of BF3·OEt2 at 08C increased the yield of 5e up to 47% yield,
but the formation of a considerable amount of 10 was still
problematic. It is likely that addition of a metal ion which
traps the sulfonyl group as a sulfinate salt would prevent the
1,2-sulfonyl shift and hence the cyclization would become a
major reaction pathway. After many attempts with various
metal compounds, a thallium ion was found to be effective
to quench the sulfinate by forming insoluble salts in the
reaction medium. Thus, treatment of 3e with Tl(TFA)3 gave
a 52% yield of cyclization product 5e along with a trace
amount of the rearranged product. A combination of
BF3·OEt2 and Tl(TFA)3 was more effective and the yield
of 5e was improved up to 62%.
Scheme 2.
Table 4. 6-endo Cyclization of dimethyl-substituted silyloxy epoxy sulfone 14
Entry
BF3·OEt2 (equiv.)
Additive (equiv.)a
Temperature
Time (h)
Yield (%)
˚
1
2
3
4
5
6
1.0
1.0
3.0
5.0
5.0
7.0
Tl(TFA)3 (3.0), 4 A MS
08C
rt
rt
rt
rt
18
20
7.5
3.5
17
1
30
45
60
74
59
64
˚
Tl(TFA)3 (3.0), 4 A MS
CH2(COOTl)2 (3.0), 4 A MS
˚
CH2(COOTl)2 (3.0), 4 A MS
˚
–
–
rt
a
Molecular sieves were added to remove a trace amount of water in a reaction media.

9772
H. Furuta et al. / Tetrahedron 59 (2003) 9767–9777
Scheme 3.
Exposure of 14 to BF3·OEt2 in the presence of Tl(TFA)3 at
08C and at room temperature gave 15 only in 30 and 45%
yields, respectively (Table 4, entries 1 and 2). As the
oxidative and acidic nature of Tl(TFA)3 might be causative
of the low yields of cyclization, Tl(I) salts were then
reexamined. A substantial improvement was achieved by
employing a combination of dithallium malonate and
BF3·OEt2, providing the tricyclic ketone 15 in 74% yield
(entries 3 and 4). Moreover, we found that the cyclization
occurred only with BF3·OEt2 in good yields (entries 5 and
6). This is an interesting result compared with the case of the
6/6-membered ether ring formation in which a thallium ion
was indispensable to prevent 1,2-shift of the sulfonyl group
(Table 3). The different reactivity between 3e and 14 could
be explained by the flexibility of the existing rings of the
cyclization precursors. The seven-membered ring is more
flexible than the 6-membered ring and, therefore, the steric
repulsion of two methyl groups in a 6-membered chair-like
transition state would be reduced in the case of 14.
cyclization conditions depending upon the substituted
positions of the methyl groups of silyloxy epoxy sulfones.
The present method was proved very efficient to construct a
tetrahydropyran that has sterically congested 1,3-diaxial
angular methyl groups.
4. Experimental
4.1. General
IR spectra were recorded in CHCl3 solution on a JASCO
FTIR-420 spectrometer. 1H and 13C NMR spectra were
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. All air- and moisture-sensitive reactions were
carried out under an argon atmosphere in dry, freshly
distilled solvents under anhydrous conditions. 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 filtration.
Finally, we applied the BF3-promoted cyclization con-
ditions to epoxy sulfone 18, which has a silylene protective
group and was prepared by the reaction of triflate 1614 and
the oxiranyl anion generated from epoxy sulfone 17
(Scheme 3).15 Treatment of 18 with BF3·OEt2 in the
˚
presence of 4 A MS led to the formation of the 6/6/7/6-
4.1.1. 2-[(2R,3R)-3-(tert-Butyldiphenylsilyloxymethyl)-3-
methyl-2-(toluene-4-sulfonyl)-oxiranylmethyl]-3-
(triethylsilyloxy)-tetrahydropyran (3c). A solution of
triflate 1b (260 mg, 0.688 mmol) and epoxy sulfone 2b
(495 mg 1.032 mmol) in HMPA (0.480 mL, 2.752 mmol)
and THF (7 mL) was cooled to 21008C and n-BuLi
(0.645 mL of a 1.6 M solution in hexane, 1.032 mmol)
was added dropwise. After stirring at 21008C for 30 min,
the reaction was quenched with saturated aqueous NH4Cl.
The reaction mixture was warmed to room temperature and
extracted with EtOAc. The extract was washed with water
and brine, dried, and concentrated in vacuo. Purification by
flash chromatography (8% EtOAc in hexane) gave 3c
(459 mg, 94%) as a colorless oil. [a]2D4¼þ32.8 (c 1.0,
CHCl3); IR (CHCl3) 1597, 1319, 1151, 1103, 813,
tetracyclic ketone 19 in 58% yield and the partially
deprotected tricyclic ketone 20 in 36% yields, respectively.
Although the silylene protective group was not compatible
under these reaction conditions, the total yield of the
cyclization was very high. Fortunately, the by-product 20
could be transformed into the desired ketone 19 in 79%
yield by heating with TsOH·H2O in benzene.
3. Conclusion
Our results demonstrated that alkylation of an oxiranyl
anion and the following 6-endo cyclization provide a
powerful method to construct trans-fused 6/6- and 6/7/6-
cyclic systems having angular methyl groups adjacent to the
ring oxygen. The cyclization precursors were synthesized
by coupling reaction of a suitable triflate and an oxiranyl
anion stabilized with a sulfonyl group. The stereocontrolled
6-endo cyclization was accomplished by choosing suitable
704 cm21 1H NMR (400 MHz, CDCl3) d 0.59 (6H, q,
;
J¼7.8 Hz), 0.95 (9H, t, J¼7.8 Hz), 1.08 (9H, s), 1.28 (1H,
m), 1.57 (2H, m), 1.58 (3H, s), 1.99 (1H, br d, J¼12.7 Hz),
2.12 (1H, dd, J¼15.6, 9.3 Hz), 2.38 (3H, s), 2.59 (1H, dd,
J¼15.6, 2.0 Hz), 2.99 (1H, ddd, J¼9.3, 8.3, 2.0 Hz), 3.09

H. Furuta et al. / Tetrahedron 59 (2003) 9767–9777
9773
(1H, ddd, J¼11.7, 11.2, 4.4 Hz), 3.16 (1H, ddd, J¼10.3, 8.3,
4.4 Hz), 3.76 (1H, br d, J¼11.2 Hz), 4.24 (1H, d,
J¼11.7 Hz), 4.30 (1H, d, J¼11.7 Hz), 7.17–7.71 (14H,
Ar); 13C NMR (100 MHz, CDCl3) d 5.10 (3£C), 6.84
(3£C), 17.16, 19.38, 21.66, 25.83, 26.88 (3£C), 31.41,
33.48, 64.77, 67.36, 69.10, 71.32, 79.86, 81.05, 127.63,
127.68, 129.18, 129.31, 129.60, 129.69, 133.21, 133.36,
135.64, 135.68, 135.97, 144.08; HRFABMS calcd for
C39H57O6SSi2 (MHþ) 709.3411, found 709.3425.
1.09 (9H, s), 1.12 (3H, s), 1.55 (1H, m), 1.57 (3H, s), 1.61
(2H, m), 1.87 (1H, m), 2.04 (1H, dd, J¼15.6, 9.8 Hz), 2.33
(1H, dd, J¼15.6, 1.0 Hz), 2.38 (3H, s), 3.18 (1H, br d,
J¼9.8 Hz), 3.21 (1H, ddd, J¼10.2, 10.2, 2.0 Hz), 3.82 (1H,
dd, J¼10.2, 4.4 Hz), 4.23 (1H, d, J¼11.7 Hz), 4.30 (1H, d,
J¼11.7 Hz), 7.17–7.71 (14H, Ar); 13C NMR (100 MHz,
CDCl3) d 2.66 (3£C), 17.29, 19.34, 20.05, 21.62, 24.68,
26.88 (3£C), 28.97, 40.13, 64.69, 67.92, 68.86, 72.79,
81.38, 83.12, 127.63, 127.68, 129.11, 129.24, 129.62,
129.70, 133.18, 133.31, 135.64, 135.68, 136.07, 144.13;
HRFABMS calcd for C37H53O6SSi2 (MHþ) 681.3098,
found 681.3062.
4.1.2. (4R,5S)-2,2-Di-tert-butyl-4-[(2R,3R)-3-(tert-butyl-
diphenylsilyloxymethyl)-3-methyl-2-(toluene-4-sul-
fonyl)-oxiranylmethyl]-5-(triethylsilyloxy)-1,3,2-dioxa-
silinane (7). According to the procedure for the preparation
of 3c, the reaction of 6 (127 mg, 0.250 mmol) and 2b
(180 mg, 0.375 mmol) gave 7 (200 mg, 95%) as a colorless
oil after flash chromatography (5% EtOAc/hexane).
[a]2D4¼þ67.1 (c 0.85, CHCl3); IR (CHCl3) 1599, 1473,
4.1.5. 4-(tert-Butyldiphenylsilyloxy)-1-[(2R,3S)-3-
hydroxy-tetrahydropyran-2-yl]-3-methyl-3-(toluene-4-
sulfonyl)-butan-2-one (9a). A solution of 3b (6.2 mg,
0.009 mmol) and TsOH·H2O (2.6 mg, 0.0137 mmol) in
CHCl3 (0.3 mL) was stirred at 558C for 4 h. After cooling to
room temperature, Et3N (0.05 mL) was added to the
solution and the reaction mixture was concentrated in
vacuo. Purification by flash chromatography (30% EtOAc in
hexane) gave 9a (3.5 mg, 52%) as a colorless oil. IR
(CHCl3) 3525, 1712, 1427, 1302, 1146, 818 cm21; 1H NMR
(400 MHz, CDCl3) d 1.09 (9H, s), 1.37 (1H, m), 1.55 (3H,
s), 1.63 (2H, m), 1.70 (1H, br, OH), 2.10 (1H, br d,
J¼11.7 Hz), 2.45 (3H, s), 3.04 (1H, dd, J¼18.3, 7.4 Hz),
3.16 (1H, dd, J¼18.3, 3.7 Hz), 3.24–3.33 (2H, m), 3.51
(1H, ddd, J¼17.1, 11.0, 6.6 Hz), 3.76 (1H, br d, J¼11.7 Hz),
3.91 (1H, d, J¼10.3 Hz), 4.40 (1H, d, J¼10.3 Hz), 7.22–
7.61 (14H, Ar); HRFABMS calcd for C33H43O6SSi (MHþ)
595.2547, found 595.2521.
1
1313, 1219, 1105, 825, 733 cm21; H NMR (400 MHz,
CDCl3) d 0.62 (6H, q, J¼7.8 Hz), 0.94 (9H, s), 0.96 (9H, s),
0.97 (9H, t, J¼7.8 Hz), 1.08 (9H, s), 1.61 (3H, s), 2.20 (1H,
dd, J¼15.6, 9.8 Hz), 2.38 (3H, s), 2.70 (1H, dd, J¼15.6,
2.0 Hz), 3.36 (1H, ddd, J¼13.2, 9.8, 4.4 Hz), 3.45 (1H, t,
J¼10.2 Hz), 3.47 (1H, ddd, J¼13.2, 9.8, 2.0 Hz), 3.92 (1H,
dd, J¼10.2, 4.4 Hz), 4.31 (1H, d, J¼11.7 Hz), 4.35 (1H, d,
J¼11.7 Hz), 7.17–7.79 (14H, Ar); 13C NMR (100 MHz,
CDCl3) d 4.95 (3£C), 6.77 (3£C), 17.09, 19.81, 21.58,
22.57, 26.88 (3£C), 26.93, 27.37, 31.98, 64.82, 69.37,
70.02, 70.98, 75.72, 80.44, 127.60, 127.68, 129.31, 129.39,
129.59, 129.67, 133.04, 133.39, 135.64, 135.69, 144.24;
HRFABMS calcd for C45H71O7SSi3 (MHþ) 839.4224,
found 839.4220.
4.1.6. (2R,4aR,8aS)-2-(tert-Butyldiphenylsilyloxy-
methyl)-2-methyl-hexahydro-pyrano[3,2-b]pyran-3-one
(5c). A solution of 3c (219 mg, 0.309 mmol) and TsOH·H2O
(88 mg, 0.463 mmol) in CHCl3 (3.0 mL) was stirred at 08C
for 16 h. The reaction mixture was diluted with EtOAc and
washed successively with saturated aqueous NaHCO3,
water, and brine. The organic layer was dried and
concentrated in vacuo. Purification by flash chromatography
(6% EtOAc in hexane) gave ketone 5c (122 mg, 90%) as
colorless crystals. Mp 73–748C. [a]2D5¼þ3.95 (c 0.78,
CHCl3); IR (CHCl3) 1718, 1464, 1427, 1093, 823,
4.1.3. (2R,3S)-2-[(2R,3R)-3-(tert-Butyldiphenylsilyl-
oxymethyl)-2-(toluene-4-sulfonyl)-oxiranylmethyl]-
3-methyl-3-(triethylsilyloxy)-tetrahydropyran (3d).
According to the procedure for the preparation of 3c, the
reaction of 1c (111 mg, 0.317 mmol) and 2a (244 mg,
0.540 mmol) gave 3d (201 mg, 97%) as a colorless oil after
flash chromatography (10% EtOAc/hexane). [a]2D5¼þ44.8
(c 0.79, CHCl3); IR (CHCl3) 1427, 1324, 1220, 1113, 840,
1
731 cm21; H NMR (400 MHz, CDCl3) d 20.09 (9H, s),
1.10 (9H, s), 1.10 (3H, s), 1.46–1.68 (3H, m), 1.80 (1H, m),
2.02 (1H, dd, J¼15.1, 0.9 Hz), 2.08 (1H, dd, J¼15.1,
9.3 Hz), 2.76 (1H, dd, J¼9.3, 0.9 Hz), 3.17 (1H, ddd,
J¼11.7, 11.7, 2.4 Hz), 3.69 (1H, dd, J¼6.3, 2.4 Hz), 3.79
(1H, dd, J¼11.7, 5.4 Hz), 4.38 (1H, dd, J¼13.2, 2.4 Hz),
4.51 (1H, dd, J¼13.2, 6.3 Hz), 7.36–7.85 (15H, Ar); 13C
NMR (100 MHz, CDCl3) d 2.41(3£C), 19.26, 20.48, 24.61,
26.82 (3£C), 28.28, 39.87, 61.47, 66.14, 67.56, 71.83,
75.44, 77.31, 78.79, 127.71, 129.06, 129.69, 133.31, 133.49,
133.95, 135.59, 137.37; HRFABMS calcd for
C35H49O6SSi2 (MHþ) 653.2786, found 653.2769.
1
706 cm21; H NMR (400 MHz, CDCl3) d 1.01 (9H, s),
1.17 (3H, s), 1.58 (1H, m), 1.80 (2H, m), 2.18 (1H, br d,
J¼12.2 Hz), 2.41 (1H, dd, J¼18.1, 10.3 Hz), 2.96 (1H, dd,
J¼18.1, 6.3 Hz), 3.42 (1H, ddd, J¼10.7, 9.3, 4.4 Hz), 3.43
(1H, ddd, J¼11.2, 11.2, 4.4 Hz), 3.51 (1H, ddd, J¼10.3, 9.3,
6.3 Hz), 3.58 (1H, d, J¼10.4 Hz), 3.91 (1H, d, J¼10.4 Hz),
3.93 (1H, br d, J¼11.2 Hz), 7.35–7.76 (10H, Ar); 13C NMR
(100 MHz, CDCl3) d 18.70, 19.23, 25.24, 26.63 (3£C),
29.60, 43.83, 67.39, 69.69, 71.06, 75.68, 85.28, 127.56,
127.63, 129.56, 129.64, 133.16, 133.34, 135.64, 135.69,
210.46; HRFABMS calcd for C26H35O4Si (MHþ) 439.2303,
found 439.2315.
4.1.4. (2R,3S)-2-[(2R,3R)-3-(tert-Butyldiphenylsilyloxy-
methyl)-3-methyl-2-(toluene-4-sulfonyl)-oxiranyl-
methyl]-3-methyl-3-(triethylsilyloxy)-tetrahydropyran
(3e). According to the procedure for the preparation of 3c,
the reaction of 1c (55 mg, 0.157 mmol) and 2b (128 mg,
0.540 mmol) gave 3e (76 mg, 71%) as a colorless oil after
flash chromatography (10% EtOAc/hexane). [a]2D5¼þ17.2
(c 0.75, CHCl3); IR (CHCl3) 1569, 1427, 1319, 1149, 1106,
840, 779 cm21; 1H NMR (400 MHz, CDCl3) d 0.11 (9H, s),
4.1.7. (4aR,8aS,6R)-2,2-Di-tert-butyl-6-(tert-butyldi-
phenylsilyloxymethyl)-6-methyl-tetrahydro-1,3,5-
trioxa-2-sila-naphthalen-7-one (8). According to the
procedure for the preparation of 5c, treatment of epoxy
sulfone 7 (164 mg, 0.196 mmol) with TsOH·H2O (56 mg,
0.293 mmol) in CHCl3 (2.0 mL) at 08C for 13 h and
purification by flash chromatography (5% EtOAc in hexane)

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H. Furuta et al. / Tetrahedron 59 (2003) 9767–9777
gave ketone 8 (99 mg, 89%). [a]2D5¼þ15.3 (c 0.53, CHCl3);
4.1.10. (2R,4aR,8aS)-2-(tert-Butyldiphenylsilyloxy-
methyl)-2,8a-dimethyl-hexahydro-pyrano[3,2-b]pyran-
3-one (5e) (Table 3, entry 6). To a stirred mixture of 3e
1
IR (CHCl3) 1720, 1471, 1223, 1113, 825, 723 cm21; H
NMR (400 MHz, CDCl3) d 1.00 (9H, s), 1.01 (9H, s), 1.05
(9H, s), 1.17 (3H, s), 2.42 (1H, dd, J¼18.1, 10.2 Hz), 3.08
(1H, dd, J¼18.1, 6.3 Hz), 3.54 (1H, d, J¼9.8 Hz), 3.67 (1H,
ddd, J¼10.2, 10.2, 4.9 Hz), 3.89 (1H, d, J¼9.8 Hz), 3.96
(1H, dd, J¼10.2, 10.2 Hz), 4.24 (1H, dd, J¼10.2, 4.9 Hz),
4.32 (1H, ddd, J¼10.2, 10.2, 4.9 Hz), 7.35–7.70 (10H, Ar);
13C NMR (100 MHz, CDCl3) d 18.51, 19.85, 26.60 (3£C),
27.00 (3£C), 27.44 (3£C), 46.81, 67.13, 69.48, 70.85,
71.67, 127.60, 127.65, 129.64, 129.69, 135.61, 210.10;
HRFABMS calcd for C32H49O5Si2 (MHþ) 569.3116, found
569.3110.
˚
(29 mg, 0.0428 mmol) and 4 A MS (60 mg) in CH2Cl2
(0.9 mL) at 08C were added Tl(TFA)3 (70 mg,
0.1284 mmol) and BF3·OEt2 (5.3 mL, 0.0428 mmol), and
the reaction mixture was stirred at 08C for 2 h. The reaction
was quenched with saturated aqueous NaHCO3 and the
reaction mixture was extracted with EtOAc. The extract was
washed with water and brine, dried, and concentrated in
vacuo. Purification by flash chromatography (12!30%
EtOAc in hexane) gave ketone 5e (12 mg, 62%).
[a]2D5¼þ28.8 (c 0.17, CHCl3); IR (CHCl3) 1714, 1222,
1
1088, 788, 705 cm21; H NMR (400 MHz, CDCl3) d 1.03
4.1.8. (2R,4aR,8aS)-2-(tert-Butyldiphenylsilyloxy-
methyl)-8a-methyl-hexahydro-pyrano[3,2-b]pyran-3-
one (5d). To a stirred solution of 3d (142 mg, 0.218 mmol)
in CH2Cl2 (4.4 mL) at 08C was added BF3·OEt2 (134 mL,
1.091 mmol), and the reaction mixture was stirred at 08C for
30 min and then at room temperature for 30 min. 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 in
vacuo. Purification by flash chromatography (12% EtOAc in
hexane) gave ketone 5d (85 mg, 89%). [a]2D5¼þ50.2 (c
0.25, CHCl3); IR (CHCl3) 1720, 1211, 1113, 779, 769,
750 cm21; 1H NMR (400 MHz, CDCl3) d 1.02 (9H, s), 1.27
(3H, s), 1.71 (2H, m), 1.89 (1H, m), 1.99 (1H, m), 2.40 (1H,
dd, J¼18.5, 11.7 Hz), 2.82 (1H, dd, J¼18.5, 6.8 Hz), 3.47
(1H, ddd, J¼11.7, 11.7, 2.0 Hz), 3.68 (1H, dd, J¼11.7,
6.8 Hz), 3.85 (1H, dd, J¼12.9, 2.9 Hz), 3.99 (1H, dd,
J¼11.7, 5.4 Hz), 4.06 (1H, dd, J¼9.8, 2.9 Hz), 4.07 (1H, dd,
J¼12.7, 9.8 Hz), 7.36–7.76 (10H, Ar); 13C NMR (100 MHz,
CDCl3) d 14.25, 19.20, 24.13, 26.67 (3£C), 37.00, 41.31,
65.15, 68.35, 71.50, 76.59, 79.75, 127.61, 127.66, 129.60,
129.69, 135.63, 135.66, 208.63; HRFABMS calcd for
C26H35O4Si (MHþ) 439.2303, found 439.2348.
(9H, s), 1.19 (3H, s), 1.23 (3H, s), 1.66 (1H, m), 1.76 (1H,
ddd, J¼12.7, 11.7, 3.9 Hz), 1.86 (1H, m), 2.00 (1H, br d,
J¼12.7 Hz), 2.36 (1H, dd, J¼19.0, 11.2 Hz), 2.86 (1H, dd,
J¼19.0, 7.3 Hz), 3.41 (1H, ddd, J¼12.2, 11.7, 2.4 Hz), 3.53
(1H. d, J¼9.8 Hz), 3.64 (1H, d, J¼9.8 Hz), 3.95 (1H, m),
3.96 (1H, dd, J¼11.2, 7.3 Hz), 7.36–7.64 (10H, Ar); 13C
NMR (100 MHz, CDCl3) d 17.40, 19.10, 23.34, 24.15,
26.73 (3£C), 37.31, 40.78, 68.25, 71.69, 72.38, 76.28,
83.98, 127.75, 127.79, 129.72, 129.84, 132.57, 132.83,
135.59, 135.63, 212.48; HRFABMS calcd for C27H37O4Si
(MHþ) 453.2459, found 453.2481
4.1.11. (4aS,6R,7S,9aR)-6-Hydroxymethyl-7-methyl-
octahydro-1,5-dioxa-benzocyclohepten-7-ol (12). (i)
Methylenation. To a stirred solution of 11 (668 mg,
1.525 mmol) in THF (15 mL) at 08C was added the Tebbe
reagent (3.11 mL of
a 0.5 M solution in toluene,
1.55 mmol), and the reaction mixture was stirred at room
temperature for 30 min. The reaction mixture was diluted
with Et2O (20 mL) and treated with 0.1N NaOH (1.0 mL)
until orange-yellow precipitates were formed. The mixture
was extracted with Et2O and the extract was washed with
water and brine, dried, and concentrated in vacuo. Flash
chromatography (7% EtOAc in hexane) gave an exocyclic
methylene (633 mg, 95%) as an oil. [a]2D5¼þ53.2 (c 1.0,
CHCl3); IR (CHCl3) 1471, 1427, 1219, 1093, 1030, 904,
825 cm21; 1H NMR (400 MHz, CDCl3) d 1.05 (9H, s), 1.27
(1H, m), 1.44 (1H. m), 1.62 (2H, m), 2.06 (1H, m), 2.10–
2.19 (3H, m), 3.04 (1H, ddd, J¼9.3, 9.3, 4.9 Hz), 3.08 (1H,
ddd, J¼9.3, 9.3, 4.9 Hz), 3.29 (1H, ddd, J¼10.7, 10.7,
2.9 Hz), 3.51 (1H, dd, J¼10.7, 5.4 Hz), 3.70 (1H, d, J¼10.7,
6.8 Hz), 3.83 (1H, ddd, J¼10.7, 3.9, 2.0 Hz), 4.16 (1H, dd,
J¼6.4, 5.4 Hz), 4.74 and 4.97 (each 1H, s), 7.34–7.70 (10H,
Ar); 13C NMR (100 MHz, CDCl3) d 19.23, 25.61, 26.82
(3£C), 28.00, 31.21, 36.61, 66.91, 67.31, 76.80, 81.21,
83.76, 112.84, 127.52, 129.52, 133.70, 133.83, 135.74,
150.63; HRFABMS calcd for C27H37O3Si (MHþ) 437.2510,
found 437.2527.
4.1.9. 4-(tert-Butyldiphenylsilyloxy)-1-[(2R,3S)-3-
hydroxy-3-methyl-tetrahydropyran-2-yl]-3-methyl-3-
(toluene-4-sulfonyl)-butan-2-one (10) (Table 3, entry 2).
To a stirred solution of 3e (6.3 mg, 0.0093 mmol) in CH2Cl2
(0.1 mL) at 08C was added CSA (5.4 mg, 0.023 mmol), and
the mixture was stirred at room temperature for 60 h. The
reaction was quenched with saturated aqueous NaHCO3 and
the reaction mixture was extracted with EtOAc. The extract
was washed with water and brine, dried, and concentrated in
vacuo. Purification by flash chromatography (12% EtOAc in
hexane) gave ketone 10 (3.3 mg, 59%). [a]2D5¼þ10.0 (c
0.23, CHCl3); IR (CHCl3) 1718, 1597, 1220, 1105, 779,
750 cm21; 1H NMR (400 MHz, CDCl3) d 1.01 (9H, s), 1.22
(3H, s), 1.54 (1H, m), 1.56 (3H, s), 1.58 (1H, m), 1.70 (1H,
br s, OH), 1.72 (1H, m), 1.89 (1H, m), 2.42 (3H, s), 3.04
(1H, dd, J¼18.1, 7.8 Hz), 3.19 (1H, dd, J¼18.1, 2.9 Hz),
3.39 (1H. ddd, J¼11.7, 11.2, 2.9 Hz), 3.69 (1H, dd, J¼7.8,
2.9 Hz), 3.86 (1H, ddd, J¼11.7, 3.4, 2.0 Hz), 3.91 (1H, d,
J¼10.3 Hz), 4.40 (1H, d, J¼10.3 Hz), 7.22–7.61 (14H, Ar);
13C NMR (100 MHz, CDCl3) d 15.38, 19.28, 20.28,
21.65, 24.92, 26.77 (3£C), 39.95, 40.97, 64.36, 67.93,
69.38, 77.08, 79.49, 127.78, 129.36, 129.90, 130.08, 132.34,
132.48, 132.55, 132.64, 135.71, 145.22, 202.00;
HRFABMS calcd for C34H43O5SSi (MHþ2H2O)
591.2598, found 591.2591.
(ii) Epoxidation. To a stirred solution of the exocyclic
methylene (655 mg, 1.502 mmol) in CH2Cl2 (12 mL) and
pH 7 phosphate buffer (12 mL) was added m-CPBA (80%,
972 mg, 4.506 mmol). The reaction mixture was stirred at
room temperature for 6 h and then extracted with EtOAc.
The extract was washed successively with saturated aqueous
Na2S2O3, saturated aqueous NaHCO3, water, and brine. The
organic layer was dried and concentrated in vacuo.
Purification by flash chromatography (10!15% EtOAc in
hexane) gave a b-epoxide (475 mg, 70%) and an a-epoxide

H. Furuta et al. / Tetrahedron 59 (2003) 9767–9777
9775
(175 mg, 26%). b-Epoxide: [a]2D5¼þ52.1 (c 1.0, CHCl3); IR
(CHCl3) 1471, 1427, 1306, 1182, 1093, 1028, 823 cm21; 1H
NMR (400 MHz, CDCl3) d 1.05 (9H, s), 1.22 (1H, ddd,
J¼14.2, 4.9, 2.9 Hz), 1.40 (1H, m), 1.64 (2H, m), 1.74 (1H,
dddd, J¼13.6, 13.6, 11.2, 2.9 Hz), 1.89 (1H, dddd, J¼13.6,
4.9, 4.9, 2.9 Hz), 2.05 (1H, m), 2.09 (1H, ddd, J¼14.2, 14.2,
2.9 Hz), 2.68 and 2.88 (each 1H, d, J¼4.4 Hz), 3.07 (1H,
ddd, J¼10.7, 9.3, 5.4 Hz), 3.29 (1H, m), 3.32 (1H, t,
J¼5.4 Hz), 3.38 (1H, ddd, J¼11.2, 9.3, 5.4 Hz), 3.63 (1H,
dd, J¼10.7, 5.9 Hz), 3.68 (1H, dd, J¼10.7, 4.9 Hz), 3.85
(1H, m), 7.36–7.68 (10H, Ar); 13C NMR (100 MHz,
CDCl3) d 19.13, 25.40, 25.75, 26.80 (3£C), 29.71, 31.22,
52.09, 60.43, 62.25, 67.23, 75.90, 80.92, 83.48, 127.65,
129.72, 133.21, 135.63; HRFABMS calcd for C27H37O4Si
(MHþ) 453.2459, found 453.2443.
added and the reaction mixture was stirred for 30 min. 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 in
vacuo. Purification by flash chromatography (3% EtOAc in
hexane) gave triflate 13 (1.46 g, 88%) as a pale yellow oil.
[a]2D5¼þ19.6 (c 0.53, CHCl3); IR (CHCl3) 1413, 1245,
1
1223, 1145, 1083, 955, 842 cm21; H NMR (400 MHz,
CDCl3) d 0.12 (9H, s), 1.13 (3H, s), 1.44 (1H, ddd, J¼11.2,
8.8, 6.8 Hz), 1.68 (3H, m), 1.80 (2H, m), 1.99 (1H, m), 2.15
(1H, m), 2.92 (1H, ddd, J¼8.8, 8.8, 4.4 Hz), 3.12 (1H, ddd,
J¼11.2, 9.3, 4.4 Hz), 3.31 (1H, ddd, J¼11.2, 8.8, 5.9 Hz),
3.69 (1H, dd, J¼9.3, 2.0 Hz), 3.88 (1H, m), 4.45 (1H, t,
J¼9.3 Hz), 4.63 (1H, dd, J¼10.3, 2.0 Hz); 13C NMR
(100 MHz, CDCl3) d 2.30 (3£C), 24.63, 25.91, 27.72,
30.68, 38.50, 68.10, 76.39, 83.96, 84.49, 84.68, 85.94;
FABMS m/z 421 (MHþ).
(iii) Reduction. To a stirred solution of the b-epoxide
(1.52 g, 3.36 mmol) in THF (37 mL) at 08C was added
lithium triethylborohydride (6.72 mL of a 1.0 M solution in
THF, 6.72 mmol), and the reaction mixture was stirred at
08C for 30 min. The reaction was quenched with water and
the reaction mixture was extracted with EtOAc. The extract
was washed with water and brine, dried, and concentrated.
Purification by flash chromatography (30% EtOAc in
4.1.13. (4aS,6R,7S,9aR)-6-[(2R,3S)-3-(tert-Butyldi-
phenylsilyloxymethyl)-3-methyl-2-(toluene-4-sulfonyl)-
oxiranylmethyl]-7-methyl-7-(trimethylsilyloxy)-octa-
hydro-1,5-dioxa-benzocycloheptene (14). A solution of
triflate 13 (1.46 g, 3.476 mmol) and epoxy sulfone 2b
(2.0 g, 4.166 mmol) in THF (69 mL) and HMPA (6.21 mL)
was cooled to 21008C, and n-BuLi (2.6 mL of a 1.6 M
solution in hexane, 4.166 mmol) was added dropwise. After
stirring at 21008C for 30 min, the reaction was quenched
with saturated aqueous NH4Cl and the reaction mixture was
extracted with EtOAc. The extract was washed with water
and brine, dried, and concentrated in vacuo. Purification by
flash chromatography (10% acetone in hexane) gave epoxy
sulfone 14 (2.38 g, 91%) as a colorless oil. [a]2D5¼þ41.8 (c
0.79, CHCl3); IR (CHCl3) 1427, 1319, 1151, 1111, 1078,
842, 782 cm21; 1H NMR (400 MHz, CDCl3) d 0.13 (9H, s),
1.07 (3H, s), 1.09 (9H, s), 1.27 (1H, m), 1.57 (3H, s), 1.62
(5H, m), 1.91 (1H, m), 2.10 (1H, dd, J¼15.6, 10.2 Hz), 2.21
(1H, m), 2.37 (1H, d, J¼14.2 Hz), 2.40 (3H, s), 2.79 (1H,
m), 2.94 (1H, ddd, J¼10.7, 9.3, 3.9 Hz), 3.27 (1H, m), 3.30
(1H, d, J¼10.2 Hz), 3.85 (1H, m), 4.27 (1H, d, J¼11.7 Hz),
4.34 (1H, d, J¼11.7 Hz), 7.20–7.70 (14H, Ar); 13C NMR
(100 MHz, CDCl3) d 2.30 (3£C), 17.16, 19.38, 21.66,
24.36, 26.06, 26.90 (3£C), 27.46, 28.49, 30.60, 38.58,
64.89, 68.28, 70.12, 77.63, 81.05, 83.91, 84.52, 84.64,
127.63, 127.71, 129.19, 129.49, 129.65, 129.74, 133.26,
135.69, 135.81, 144.46; HRFABMS calcd for C34H51O5Si2
(MHþ2TolSO2H) 595.3272, found 595.3287.
hexane) gave
a
tertiary alcohol (1.51 g, 99%).
[a]2D5¼218.5 (c 0.15, CHCl3); IR (CHCl3) 3500, 1469,
1427, 1221, 1209, 1088, 791, 725 cm21 1H NMR
;
(400 MHz, CDCl3) d 1.06 (9H, s), 1.22 (3H, s), 1.36 (1H,
m), 1.60–1.68 (3H, m), 1.75–1.83 (3H, m), 2.87 (1H, ddd,
J¼9.8, 9.8, 3.9 Hz), 3.07 (1H, br s, OH), 3.08 (1H, m), 3.30
(1H, ddd, J¼11.2, 7.8, 4.4 Hz), 3.64 (1H, t, J¼6.8 Hz), 3.72
(1H, dd, J¼9.8, 6.8 Hz), 3.76 (1H, dd, J¼10.3, 6.8 Hz), 3.87
(1H, m), 7.38–7.70 (10H, Ar); 13C NMR (100 MHz,
CDCl3) d 19.03, 24.36, 25.60, 26.88 (3£C), 27.85, 31.22,
38.83, 64.10, 68.02, 74.57, 84.32, 84.60, 84.64, 127.86,
129.95, 130.05, 135.51, 135.63; HRFABMS calcd for
C27H39O4Si (MHþ) 455.2615, found 455.2641.
(iv) Deprotection of the TBDPS group. To a stirred solution
of the tertiary alcohol (1.95 g, 4.295 mmol) in THF (42 mL)
was added Bu4NF (6.44 mL of a 1.0 M solution in THF,
6.44 mmol), and the solution was stirred at room tempera-
ture for 1.5 h. The solvent was removed in vacuo and the
residue was purified by flash chromatography (4% MeOH in
EtOAc) to give 12 (926 mg, 100%). [a]2D5¼þ9.28 (c 0.56,
CHCl3); IR (CHCl3) 3600, 3473, 1454, 1439, 1221, 1209,
1
1088, 791, 725 cm21; H NMR (400 MHz, CDCl3) d 1.17
(3H, s), 1.46 (1H, m), 1.69 (2H, m), 1.74–1.94 (6H, m), 2.08
(1H, m), 2.94 (1H, ddd, J¼8.8, 8.8, 3.9 Hz), 3.19 (1H, ddd,
J¼11.2, 9.3, 3.9 Hz), 3.32 (1H, ddd, J¼11.2, 9.3, 6.8 Hz),
3.55 (1H, dd, J¼7.8, 5.4 Hz), 3.66 (1H, dd, J¼10.7, 7.8 Hz),
3.75 (1H, dd, J¼10.7, 5.4 Hz), 3.89 (1H, m); 13C NMR
(100 MHz, CDCl3) d 24.45, 25.91, 27.84, 31.24, 39.45,
62.39, 67.95, 74.29, 84.08, 84.13, 86.82; HRFABMS calcd
for C11H21O4 (MHþ) 217.1439, found 217.1430.
4.1.14. (2R,4aR.5aS,9aR,11aS)-2-(tert-Butyldiphenyl-
silyloxymethyl)-2,11a-dimethyl-decahydro-1,5,9-trioxa-
dibenzo[a,d]cyclohepten-3-one (15). To a mixture of 14
˚
(100 mg, 0.133 mmol) and 4 A MS (190 mg) in CH2Cl2
(2.7 mL) was added dithallium malonate (204 mg,
0.400 mmol) at 08C. After stirring at 08C for 30 min,
BF3·OEt2 (82 mL, 0.666 mmol) was added. The reaction
mixture was stirred at 08C for 30 min and then at room
temperature for 3.5 h. The reaction was quenched with
saturated aqueous NaHCO3 and the reaction mixture was
extracted with EtOAc. The extract was washed with water
and brine, dried, and concentrated in vacuo. Purification by
flash chromatography (6% acetone in hexane) gave ketone
15 (52 mg, 74%) as a colorless oil. [a]2D5¼þ32.9 (c 0.89,
CHCl3); IR (CHCl3) 1714, 1429, 1211, 1088, 706 cm21; 1H
NMR (400 MHz, C6D6) d 0.98 (3H, s), 1.07 (3H, s), 1.11
4.1.12. (4aS,6R,7S,9aR)-Trifluoromethanesulfonic acid
7-methyl-7-(trimethylsilyloxy)-octahydro-1,5-dioxa-
benzocyclohepten-6-ylmethyl ester (13). To a stirred
solution of 12 (850 mg, 3.935 mmol) in CH2Cl2 (39 mL)
and 2,6-lutidine (1.82 mL, 15.74 mmol) at 2788C was
added Tf2O (0.675 mL, 4.013 mmol). After stirring at
2788C for 30 min, TMSOTf (1.06 mL, 5.902 mmol) was

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H. Furuta et al. / Tetrahedron 59 (2003) 9767–9777
(9H, s), 1.16 (1H, m), 1.35 (2H, m), 1.70 (1H, ddd, J¼15.1,
10.7, 2.4 Hz), 1.92 (1H, m), 1.99 (1H, m), 2.18 (1H, m), 2.27
(1H, ddd, J¼15.1, 8.3, 2.4 Hz), 2.54 (1H, dd, J¼19.0,
11.2 Hz), 2.85 (1H, ddd, J¼8.8, 8.8, 4.4 Hz), 2.98 (1H, ddd,
J¼11.2, 11.2, 2.0 Hz), 3.04 (1H, dd, J¼19.0, 6.8 Hz), 3.16
(1H, ddd, J¼10.7, 9.3, 4.4 Hz), 3.63 (1H, d, J¼9.3 Hz), 3.67
(1H, m), 3.81 (1H, d, J¼9.3 Hz), 4.42 (1H, dd, J¼11.2,
6.8 Hz), 7.17–7.86 (10H, Ar); 13C NMR (100 MHz, CDCl3)
d 19.20, 20.66, 23.47, 25.84, 26.86 (3£C), 28.90, 31.26,
38.60, 42.18, 67.85, 72.46, 76.69, 78.17, 81.53, 83.48,
83.63, 127.76, 127.83, 129.75, 129.87, 132.48, 132.94,
135.53, 135.61, 213.16; HRFABMS calcd for C31H43O5Si
(MHþ) 523.2877, found 523.2886.
d 0.97 (9H, s), 1.04 (9H, s), 1.05 (9H, s), 1.14 (6H, s), 1.48
(1H, q, J¼11.2 Hz), 1.77–1.98 (3H, m), 2.20 (1H, m), 2.35
(1H, ddd, J¼11.2, 3.9, 3.9 Hz), 2.40 (1H, dd, J¼19.5,
10.7 Hz), 2.85 (1H, dd, J¼19.5, 6.8 Hz), 3.01 (1H, ddd,
J¼11.2, 9.3, 3.9 Hz), 3.11 (1H, m), 3.22 (1H, ddd, J¼10.2,
10.2, 4.9 Hz), 3.56 (1H, d, J¼9.8 Hz), 3.64 (1H, m), 3.66
(1H, d, J¼9.8 Hz), 3.75 (1H, dd, J¼10.2, 10.2 Hz), 4.10
(1H, dd, J¼10.2, 4.9 Hz), 4.17 (1H, dd, J¼10.7, 6.8 Hz),
7.36–7.71 (10H, Ar); 13C NMR (100 MHz, C6H6) d 19.45,
20.14, 20.55, 22.79, 23.52, 26.97 (3£C), 27.37 (3£C), 27.63
(3£C), 28.55, 38.85, 40.73, 42.37, 67.38, 72.88, 73.34,
76.89, 77.78, 78.87, 80.02, 83.34, 83.59, 127.89, 128.13,
130.07, 130.24, 132.95, 133.69, 135.88, 136.00;
HRFABMS calcd for C40H61O7Si2 (MHþ) 709.3952,
found 709.3935. 20: colorless oil. IR (CHCl3) 3686, 3425,
1724, 1472, 1208, 1113 cm21; 1H NMR (400 MHz, CDCl3)
d 1.01 (9H, s), 1.03 (9H, s), 1.04 (9H, s), 1.15 (6H, s), 1.55
(1H, q, J¼11.3 Hz), 1.80 (1H, m), 1.87 (1H, m), 1.94 (1H,
m), 2.18 (1H, br s, OH), 2.22 (1H, m), 2.40 (1H, dd, J¼19.0,
11.2 Hz), 2.43 (1H, ddd, J¼11.3, 4.1, 4.1 Hz), 2.86 (1H, dd,
J¼19.0, 6.8 Hz), 2.99 (1H, ddd, J¼11.7, 9.7, 4.4 Hz), 3.06
(1H, t, J¼2.9 Hz, OH), 3.08 (2H, m), 3.52 (1H, d,
J¼9.8 Hz), 3.66 (1H, d, J¼9.8 Hz), 3.82 (2H, br s), 3.88
(1H, ddd, J¼11.2, 9.3, 4.9 Hz), 4.20 (1H, dd, J¼11.2,
6.8 Hz), 7.36–7.70 (10H, Ar); FABMS m/z 727 (MHþ).
4.1.15. (4aR,5aS,8R,9S,10aR,11aS)-2,2-Di-tert-butyl-9-
[(2S,3R)-3-(tert-butyldiphenylsilyloxymethyl)-3-methyl-
2-(toluene-4-sulfonyl)-oxiranylmethyl]-8-methyl-8-(tri-
methylsilyloxy)-decahydro-1,3,5,10-tetraoxa-2-sila-
cyclohepta[b]naphthalene (18). According to the
procedure for the preparation of 14, treatment of triflate
16 (438 mg, 0.724 mmol) and epoxy sulfone 17 (521 mg,
1.090 mmol) in HMPA (1.3 mL) and THF (14.4 mL) with
n-BuLi (0.68 mL of a 1.58 M solution in hexane,
1.074 mmol) and purification by flash chromatography
(6% EtOAc in hexane) gave 18 (635 mg, 94%) as a
colorless oil. [a]D25¼236.8 (c 2.45, CHCl3); IR (CHCl3)
1472, 1318, 1252, 1088 cm21; 1H NMR (400 MHz, CDCl3)
d 0.13 (9H, s), 0.97 (9H, s), 1.03 (9H, s), 1.05 (3H, s), 1.11
(9H, s), 1.39 (1H, q, J¼11.2 Hz), 1.57–1.73 (3H, m), 1.58
(3H, s), 1.93 (1H, m), 1.98 (1H, dd, J¼15.6, 10.3 Hz), 2.40
(3H, s), 2.41 (1H, d, J¼15.6 Hz), 2.59 (1H, ddd, J¼11.2,
4.4, 4.4 Hz), 2.93 (1H, ddd, J¼9.3, 9.3, 3.9 Hz), 2.99 (1H,
m), 3.24 (1H, ddd, J¼10.2, 9.3, 4.9 Hz), 3.35 (1H, d,
J¼10.3 Hz), 3.75 (1H, m), 3.78 (1H, dd, J¼10.2, 10.2 Hz),
4.11 (1H, dd, J¼10.2, 4.9 Hz), 4.29 (1H, d, J¼11.2 Hz),
4.42 (1H, d, J¼11.2 Hz), 7.21–7.72 (14H, Ar); 13C NMR
(100 MHz, CDCl3) d 2.46 (3£C), 17.39, 19.39, 19.92,
21.66, 22.62, 24.38, 26.72, 26.96 (3£C), 27.09 (3£C), 27.42
(3£C), 28.07, 38.49, 39.50, 64.77, 67.03, 70.01, 73.13,
77.63, 77.79, 80.72, 81.94, 84.26, 84.85, 127.68, 127.71,
129.21, 129.52, 129.72, 133.19, 133.32, 135.66, 135.74,
144.55; HRFABMS calcd for C50H77O9SSi3 (MHþ)
937.4663, found 937.4641.
4.2. Transformation of 20 to 19
A solution of 20 (35 mg, 0.048 mmol) and TsOH·H2O
(18.3 mg, 0.096 mmol) in benzene (0.5 mL) was heated at
758C for 3 h. After cooling to room temperature, the
reaction was quenched with triethylamine (0.1 mL) and the
reaction mixture was concentrated in vacuo. Purification by
flash chromatography (10% EtOAc in hexane) gave 19
(27 mg, 79%).
Acknowledgements
This work was aided by Grant-in-Aid for Creative Scientific
Research (No. 14GS0214) from the Japan Society for the
Promotion of Science.
4.1.16. (2S,4aS,5aR,6aS,10aR,11aS,13aR)-8,8-Di-tert-
butyl-2-(tert-butyldiphenylsilyloxymethyl)-2,13a-
dimethyl-decahydro-1,5,7,9,11-pentaoxa-8-sila-benzo-
[4,5]cyclohepta[1,2-b]naphthalen-3-one (19) and
(2S,4aS,5aR,7S,8R,9aS,11aR)-2-(tert-butyldiphenylsilyl-
oxymethyl)-7-(di-tert-butyl-hydroxy-silyloxy)-8-hydro-
xymethyl-2,11a-dimethyl-decahydro-1,5,9-trioxa-di-
benzo[a,d]cyclohepten-3-one (20). To a stirred mixture of
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