Synthesis of the EF-ring segment of ciguatoxin CTX1B based on novel regioselective reduction of unsaturated cyanohydrins and ring-closing olefin metathesis

Article abstract of DOI:10.1016/j.tet.2005.05.073

Aiming at a convergent total synthesis of ciguatoxin CTX1B, its EF-ring segment has been synthesized. During the synthesis, a novel method for the construction of branched ethers, based on regioselective reduction of γ-alkoxy β,γ-unsaturated α-silyloxy ni

Full text of DOI:10.1016/j.tet.2005.05.073

Tetrahedron 61 (2005) 7392–7419
Synthesis of the EF-ring segment of ciguatoxin CTX1B based
on novel regioselective reduction of unsaturated cyanohydrins
and ring-closing olefin metathesis
†
Atsushi Takemura, Kenshu Fujiwara, Ken Shimawaki, Akio Murai, Hidetoshi Kawai
and Takanori Suzuki
*
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Received 22 January 2005; revised 23 May 2005; accepted 24 May 2005
Available online 15 June 2005
Abstract—Aiming at a convergent total synthesis of ciguatoxin CTX1B, its EF-ring segment has been synthesized. During the synthesis, a
novel method for the construction of branched ethers, based on regioselective reduction of g-alkoxy b,g-unsaturated a-silyloxy nitriles with
borontrifluoride etherate and trialkyl silane or tributyltin hydride, has been developed. Combination use of the method and ring-closing olefin
metathesis successfully provided medium-sized cyclic ethers. Efficient site-selective reduction of vinyl epoxides into homoallyl alcohols has
also been developed.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
CTX1B consisted of 12 trans-fused cyclic ethers, ranging
from six- to nine-membered, and a five-membered
spirocyclic ether at one end. Moreover, the absolute
configuration of CTX1B was determined in 1997 as
shown in Figure 1 by collaboration of Yasumoto, Hirama
and Harada.6
Ciguatoxin CTX1B is a causative toxin of ciguatera fish
poisoning,1,2 which afflicts more than 20,000 people in
tropical and subtropical areas annually. The toxin is
produced originally by the epiphytic dinoflagellate,
Gambierdiscus toxicus, transferred to herbivorous fish,
and accumulated subsequently in carnivorous fish through
the food chain, thus causing human intoxication.3 The
symptoms of ciguatera are represented by diarrhea,
vomiting, joint pain, prostration and unusual temperature
perception disturbance called ‘dry-ice sensation’. Gener-
ally, patients need several months to recover completely
from these symptoms, which has resulted in serious social
problems.
The potent bioactivity of CTX1B is thought to result from
the activation of voltage-sensitive sodium channels
(VSSCs) in neuron cells by the strong binding of CTX1B
to site 5 on the channel.7 While it is known that the binding
site on VSSC was shared by brevetoxins or another class
of structurally related marine toxins,8 the precise location of
the receptor site for these toxins and the binding mode of
CTX1B to the channel protein has not yet been elucidated.9
However, the studies of ciguatoxin in neurology and
hygiene have been impeded by the extremely limited
availability of CTX1B from natural sources. Therefore, a
synthetic supply of CTX1B on a practical scale is essential
in order to solve the problem.
CTX1B was first isolated from the moray eel, Gymnothorax
javanicus, by Scheuer and co-workers in 1967 and
characterized as a polycyclic ether compound in 1980.4
The whole structure of CTX1B, except for the absolute
configuration and the relative configuration at C2, was
elucidated from a purified sample of only 0.35 mg of
CTX1B isolated from 4 t of G. javanicus by Yasumoto and
co-workers in 1989.5 They reported that the structure of
From the synthetic viewpoint, its unique trans-fused
polycyclic ether structure and strong bioactivity have
attracted the attention of synthetic chemists. The convergent
construction of such large fused polyether structure has been
a significant challenge. Intensive efforts by synthetic
chemists aiming at the concise construction of the polyether
framework as well as completion of the total synthesis of
CTX1B and its congeners are ongoing.10–13 In the course of
Keywords: Ciguatoxin CTX1B; Fused medium-ring ether; Ring-closing
olefin metathesis; Branched ether synthesis; Site-selective reduction.
*
Corresponding author. Tel.: C81 11 706 2701; fax: C81 11 706 4924;
e-mail: fjwkn@sci.hokudai.ac.jp
† Present address: 6-14-44, Asabu-cho, Kita-ku, Sapporo 001-0045, Japan.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.05.073

A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
7393
Figure 1.
our synthetic studies on CTX1B and its congeners,14 we
have established a method based on the coupling reaction of
an acyl anion equivalent with an aldehyde for the
convergent construction of a trans-fused 6/6 or 6/7 cyclic
ether system in the middle part.14g,i,k,15 Therefore, we
designed the synthetic segments of CTX1B corresponding
to the AB-, EF-, I-, and LM-ring parts, and planned to
connect them at the CD-,14i,k GH-, and JK-ring14i parts at
the later stage of total synthesis. So far, the AB-,14l I-,14j and
LM-ring14e segments have been constructed. Here, syn-
thesis of the remaining EF-ring segment based on a novel
branched ether formation using regioselective reduction of
unsaturated cyanohydrins and ring-closing olefin metathesis
(RCM) is described.14n An efficient transformation reaction
of a vinyl epoxide into a homoallyl alcohol, developed
during the synthesis, is also disclosed.
butenoate part of 4 and (iv) hetero-Michael addition of
2-butynoate ester 6 with the F-ring part 5 according to
Paintner’s procedure.18
Grubbs’ RCM has now become one of the most reliable
methods among a number of approaches for the construction
of medium-sized cyclic ethers, because it realizes efficient
ring-closure under mild catalytic conditions and tolerates a
wide variety of functional groups in its substrates.10,16
Accordingly, we applied Grubbs’ RCM to the construction
of the E-ring in the process (i). On the other hand,
preparation of the precursors for RCM involves a serious
difficulty of the stereoselective construction of an acyclic
branched ether part in each substrate. Recently, several
successful methods based on an alkylation or an aldol
reaction of a glycolate ester derivative,11q,r,19 allyl11a,f,t,y or
hydride11e,w addition to an acetal group, an addition reaction
of an a-alkoxy carbon radical to a b-alkoxy propenoate
ester,11h,j,v or ring cleavage of C-glycosides,14j,20 have been
developed to solve the problem. However, the number of
methods is insufficient to meet the requirements for the
synthesis of a variety of complex natural cyclic ethers.
Therefore, a reductive transformation reaction shown in
Scheme 2 was newly designed for the process (iii).14n,21 We
expected that g-alkoxy b,g-unsaturated a-silyloxy nitrile 7
would be activated by an appropriate Lewis acid to generate
oxonium ion 8, which would be selectively reduced at the
g-position into g-alkoxy a,b-unsaturated nitrile 9 by a
proper reducing agent. The nitrile group of 9 would be
available for the synthesis of 2 (process (ii)).
2. First generation synthesis of the EF-ring segment
First, we planned to synthesize the EF-ring segment 1 from
the F-ring part 5 (Scheme 1). The synthetic route consisted
of the following four processes: (i) construction of the
E-ring in 1 from precursor diene 2 by Grubbs’ RCM;16,17
(ii) introduction of a hydroxy group to the b-position of the
branched ether part of 3; (iii) reduction of the 3-alkoxy-2-
Scheme 2. Lewis-acid-promoted g-position selective reduction of a g-
alkoxy b,g-unsaturated a-silyloxy nitrile system.
First, g-position selective reduction of simple acyclic
cyanohydrin derivatives 10, 11, and 12 was examined. We
selected Et3SiH as a reducing agent because of its efficient
reducing ability toward the oxonium ion intermediate. After
extensive exploration for effective activators of the
cyanohydrins, BF3$OEt2 was found to give the best result.
Selected successful examples are shown in Table 1. Every
Scheme 1. Retrosynthetic analysis for the EF-ring segment 1.

7394
A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
Table 1. BF3$OEt2 promoted g-position selective reduction of model
compounds
for further construction of a trans-fused ether ring, from
1914g and 20 according to the above strategy. Reduction
precursor 24 was synthesized according to Scheme 4.
Hetero-Michael addition of 19 to butynoate 20 in the
presence of Me3P afforded 21 in 95% yield.22 Reduction of
the ester 21 with DIBAH followed by oxidation with TPAP
gave the aldehyde 23 in 88% yield. Treatment of 23 with
TMSCN (2.5 equiv) in the presence of Me3Al in benzene at
ambient temperature gave 24 as a 1:1 mixture of
diastereomers in 74% yield.
The regioselective reduction of 24 under the same
conditions as the case of acyclic models produced a mixture
of 25a,b, and 26 (3.6:6.4:1.0) in 49% yield along with
alcohol 25c in 14% yield (entry 1, Table 2).23 Although the
by-production of 25c was reduced by lowering reaction
temperature to K18 8C, the ratio of diene 26 increased
(25a:25b:26Z1.9:3.8:1.0, entry 2). In order to suppress the
diene, we examined several organometallic hydrides.
Trialkyl silanes (Et3SiH, Et2MeSiH, EtMe2SiH, and
Me2PhSiH) gave almost the same result, and changing the
bulkiness of their alkyl substituents did not affect the diene-
formation (entries 2–5). On the other hand, Bu3SnH
provided a good result, where no production of 26 was
observed, and the ratio of 25a to 25b slightly increased
(entry 6). The stereochemistry at the newly formed
stereocenters of 25a and 25b was determined after
transformation of 25b into bicyclic ether 31 (vide infra).
Thus, efficient conditions for the g-selective reduction of
a-silyloxy nitrile 24 were found.
Entry
R
Yield (%)
1
2
3
H
Me
CH2OTBS
64% (E:ZZ6.2:1.0)
62% (only E)
64% (only E)
reaction was carried out in a 1:1 (v/v) mixture of Et3SiH and
CH2Cl2 in the presence BF3$OEt2 (3.0 equiv) at 0 8C and
afforded the corresponding g-alkoxy a,b-unsaturated nitrile
(13, 14, or 15) in good yield. On the other hand, simple and
easily available 3-alkoxy-2-propenyl acetate 16 did not
produce the corresponding allyl or vinyl ether (17 or 18)
under the same conditions. It only resulted in decomposition
of the substrate. Thus, the g-alkoxy b,g-unsaturated a-silyl-
oxy nitrile was found to be a good substrate (Scheme 3).
Table 2. BF3$OEt2 promoted reduction of 24 with several reducing
reagents
Scheme 3. An attempt to reduce 3-alkoxy-2-propenyl acetate 16.
Next, encouraged by the results, we planned to synthesize a
trans-fused 6/8 cyclic ether model, which has a side chain
and a hydroxyl group with proper stereochemistry available
Entry
R3MH
Temp.
25a:25b:26 (Yield) 25c
1
Et3SiH
Et3SiH
Et2MeSiH
EtMe2SiH
Me2PhSiH
Bu3SnH
0 8C
3.6:6.4:1.0 (49%) 14%
1.9:3.8:1.0 (71%)
1.8:3.9:1.0 (65%)
1.4:3.5:1.0 (74%)
2.0:4.2:1.0 (61%)
1.0:1.3:0 (64%)
2a
3
K18 8C
K18 8C
K18 8C
K18 8C
K18 8C
4
5
6
a Reaction period was 17 min.
Synthesis of a 6/8 bicyclic system from 25a and 25b is
shown in Scheme 5. A ca. 1:2 mixture of 25a and 25b was
converted to a mixture of allyl alcohols 28a and 28b (68%)
by repeated reduction with DIBAH. The Katsuki-Sharpless
asymmetric epoxidation24 of the allyl alcohols using
Scheme 4. Preparation of reduction precursor 24. Reagents and conditions:
(a) PMe3 (1.1 equiv), 20 (1.7 equiv), CH2Cl2, 0 8C, /24 8C, 1 h, 95%
(only E); (b) DIBAH (4.0 equiv), CH2Cl2, K78 8C, 10 min, w100%;
(c) TPAP (0.1 equiv), NMO (2.0 equiv), MS 4A, CH2Cl2, 24 8C, 50 min,
88%; (d) Me3Al (1.1 equiv), TMSCN (2.5 equiv), benzene, 24 8C, 1 h, 74%.

A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
7395
(K)-DET stereoselectively produced a mixture of epoxides
29a and 29b (w100%), which was treated with PPh3 and I2
in the presence of imidazole at ambient temperature to give
allyl alcohols 30a and 30b (61%) as a 1:2 mixture.25,26 Ring
closure of dienes 30a and 30b in refluxing CH2Cl2 by
Grubbs’ second-generation catalyst27 gave a mixture of
products, in which only 31 was isolated as a bicyclic product
(44%), and the desired trans-fused 6/8 bicyclic ether was
not detected.28 Stereochemistry of 31 was confirmed by the
presence of NOE between H4 and H11 as well as the small J
value between H9 and H10 (4.6 Hz). From the fact that the
1:2 ratio of the diastereomers was maintained throughout
the transformation process from 25 to 30, and that the yield
of 31 (44%) was apparently higher than the ideal yield
(33%) of the cyclization product from minor diastereomer
30a, it was concluded that 31 was produced from 30b and
originated from 25b.
Scheme 6. Synthesis of trans-fused bicyclic ether 34. Reagents and
conditions: (a) TBAF (2.0 equiv), THF, 24 8C, 20.5 h, 99%; (b) 2,2-
dimethoxypropane (10 equiv), CSA (0.5 equiv), CH2Cl2, 24 8C, 7.5 h, 33a:
24%, 33b: 60%; (c) (H2IMes)(PCy3)Cl2Ru]CHPh (10 mol%), CH2Cl2
(4 mM), reflux, 4.5 h, 83%; (d) THF–H2O–TFA (10:10:1), 23 8C, 11.5 h,
71%.
compound was determined by the J value between H9 and
H10. RCM27 of desired 33a with Grubbs’ second-
generation catalyst in refluxing CH2Cl2 expectedly gave
the desired trans-fused 6/8 cyclic ether 34 in 83% yield.
Since the structure of 34 was difficult to be confirmed, the
acetonide 34 was converted to diol 35. The stereochemistry
of 35 was verified by the presence of NOE between H4 and
H10 as well as the large J value between H9 and H10
(8.8 Hz). Thus, a bicyclic precursor was proved to promote
efficient ring closure by RCM.
Scheme 5. Synthesis of bicyclic ether 31. Reagents and conditions:
(a) DIBAH (2.5 equiv), CH2Cl2, K78 8C, 10 min, 68%; (b) DIBAH
(3.0 equiv), CH2Cl2, K78 8C, 8 min, w100%; (c) D-(K)-DET (0.8 equiv),
Ti(OiPr)4 (0.7 equiv), TBHP (5.0 equiv), MS 4A, CH2Cl2, K40 8C,
30 min/K25 8C, 24 h, w100%; (d) Ph3P (5.0 equiv), imidazole
(5.0 equiv), I2 (4.0 equiv), THF, 25 8C, 45 min, 61%; (e) (H2IMes)(PCy3)-
Cl2Ru]CHPh (10 mol%), CH2Cl2 (5 mM), reflux, 6 h, 44%.
Then, according to the above results, we examined the
synthesis of the EF-ring segment 50 from the F-ring part
3614j (Scheme 7). Treatment of 36 with TFA gave primary
alcohol 37 selectively in 68% yield along with 36 in 24%
recovery. Swern oxidation of the primary alcohol and Wittig
reaction followed by removal of benzylidene acetal afforded
the diol 38 in 58% yield for three steps. The benzyl (Bn)
protection of the diol and removal of the TBS group gave
the alcohol 5 in 100% yield. Hetero-Michael addition of the
alcohol to 2-butynoate ester 20 produced 39 in good yield
(90%),18 which was converted to a-silyloxy nitrile 42
through reduction, oxidation, and addition of TMSCN. The
reduction of 42 with Bu3SnH in CH2Cl2 in the presence of
BF3$OEt2 (3.0 equiv) at K18 8C smoothly afforded nitrile
43 as a 1:1 mixture of diastereomers in 55% yield along with
42 in 18% recovery. Conversion of nitrile 43 to allyl alcohol
45 followed by a three-step transformation [(i) Katsuki-
Sharpless asymmetric epoxidation24 using (C)-DET;
(ii) iodation of the hydroxy group25 and (iii) reduction of
the resulting epoxy iodide with Zn] gave the corresponding
The results from the final RCM step suggested that the vinyl
groups of 30a were apart from each other in the stable
conformation of 30a, and such orientation of the vinyl
groups was inappropriate for the cyclization of 30a.
Therefore, we decided to prepare bicyclic RCM precursor
33a, of which the vinyl groups would be placed in close
proximity to each other, for successful ring closure in the
synthesis of trans-fused-bicyclic ether 34 (Scheme 6).
A ca. 1:2 mixture of 30a and 30b was converted to a mixture
of diols 32a and 32b by removal of the TBS group (99%).
The acetonide protection of the diols under the standard
conditions produced bicyclic RCM precursor 33a (24%) and
33b (60%), which were easily separated by silica gel
column chromatography. The stereochemistry of each

7396
A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
Scheme 7. Synthesis of the EF-ring segment 50. Reagents and conditions: (a) THF–H2O–TFA (10:10:1), 0 8C, 4 h, 68%, 24% recovery of 36; (b) (COCl)2
(3.0 equiv), DMSO (5.0 equiv), CH2Cl2, K78 8C, 15 min then NEt3 (10 equiv), K20 8C, 10 min; (c) Ph3PCH3Br (5.0 equiv), NaHMDS (4.8 equiv), THF,
K78 8C, 2.5 h/ 24 8C, 2.5 h; (d) 1,2-ethanedithiol (20 equiv), NaHCO3 (10 equiv), Zn(OTf)2 (1.0 equiv), CH2Cl2, 0 8C, 2.5 h, 58% for three steps; (e) NaH
(12 equiv), BnBr (6.0 equiv), TBAI (0.1 equiv), THF, 24 8C, 15 h; (f) TBAF (9.0 equiv), THF, 25 8C, 18 h, 100% for two steps; (g) PMe3 (1.5 equiv), 20
(3.0 equiv), CH2Cl2, 0 8C, /24 8C, 1 h, 90% (only E); (h) DIBAH (4.0 equiv), CH2Cl2, K78 8C, 10 min, 99%; (i) TPAP (0.2 equiv), NMO (2.0 equiv), MS
4A, CH2Cl2, 24 8C, 1.5 h, 76%; (j) Me3Al (1.1 equiv), TMSCN (5.0 equiv), benzene, 24 8C, 1 h, 79%; (k) BF3$OEt2 (3.0 equiv), CH2Cl2–Bu3SnH (1:1),
K18 8C, 15 min, 55%, 18% recovery of 42; (l) DIBAH (2.5 equiv), CH2Cl2, K78 8C, 10 min; (m) DIBAH (6.0 equiv), CH2Cl2, K78 8C, 20 min, 72% for two
steps; (n) L-(C)-DET (1.5 equiv), Ti(OiPr)4 (1.3 equiv), TBHP (10 equiv), MS 4A, CH2Cl2, K40 8C, 30 min/K25 8C, 26 h; (o) Ph3P (5.0 equiv), imidazole
(5.0 equiv), I2 (4.0 equiv), THF, 25 8C, 35 min; (p) Zn (7.0 equiv), EtOH-satd. NH4Claq. (40:1), 25 8C, 2.5 h, 68% for three steps; (q) TBAF (1.5 equiv), THF,
25 8C, 11.5 h, 68%; (r) 2,2-dimethoxypropane (4.0 equiv), CSA (0.5 equiv), CH2Cl2, 24 8C, 3 h then acetone (5.0 equiv), 11.5 h, 49a: 50%, 49b: 46%; (s)
(Cy3P)2Cl2Ru]CHPh (25 mol%), CH2Cl2 (3 mM), 24 8C, 15 h, 49a:50:51Z1:1:0.5; (Cy3P)2Cl2Ru]CHPh (30 mol%), CH2Cl2 (3 mM), 24 8C, 24 h, 50:
67%, 51: 24%, after two cycles.
allyl alcohol 47 as a 1:1 mixture of diastereomers in 68%
yield. In order to facilitate the closure of the trans-fused
medium ring by RCM and to confirm the stereochemistry of
each diastereomer, acetonides 49a and 49b were synthe-
sized from 47 through removal of the TBS group followed
by protection of the resulting diol. Diastereomers 49a and
49b were easily separated by silica gel column chroma-
tography, and the stereochemistry of each compound was
determined by the J value between H2 and H3. RCM16,17 of
49a with Grubbs’ first-generation catalyst in CH2Cl2 at
ambient temperature successfully produced the desired
trans-fused EF-ring segment 50 of CTX1B in 67% yield
along with 51 in 24% yield. The stereochemistry of 50 was
confirmed by the presence of NOE between H2 and H7 as
well as the large J value between H2 and H3 (9.4 Hz).
Although the synthesis of 50 was thus achieved, two
problems arose at the final RCM stage. One was the low
reactivity of 49a under the RCM conditions using Grubbs’
first-generation catalyst. The reaction often stopped before
completion, and had to be repeated in order to consume
49a completely. The other problem was a significant

A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
7397
by-production of 51. It meant that the desired RCM between
the terminal vinyl groups making the E-ring was a slow
process, and that the metathesis at the olefin part of the
F-ring competed with the RCM. These problems would be
caused by the severe strain of the E-ring part. In order to
solve the problems, we decided to design an alternative
improved synthesis of the EF-ring segment.
In the revised plan, site-selective reduction of vinyl epoxide
54 to the corresponding homoallyl alcohol was a key step.
Tsuji and Shimizu reported efficient site-selective hydro-
genolysis of epoxides adjacent to an alkene group using a
Pd-catalyst and formic acid.29,30 Therefore, we decided to
apply the Pd-catalyzed reduction to our synthesis. Although
many trisubstituted epoxides were successfully reduced
under the conditions,29 there were few applications to
simple vinyl epoxides.29a,30 In order to optimize the
reduction conditions, epoxide 66 was first examined as a
model substrate.
3. Second generation synthesis of the EF-ring segment
The revised plan for the synthesis of the EF-ring segment of
CTX1B is shown in Scheme 8. We intended to cyclize the
F-ring by RCM16,17 at the final stage of the synthesis, and to
use the E-ring part as a Michael donor in the initial stage.
Therefore, the EF-ring segment 52 was planned to be
constructed from the bicyclic diene 53 by RCM.16,17 The
diene would be synthesized via site-selective reduction
of vinyl epoxide 54, which would be prepared from
a,b-unsaturated nitrile 55. According to our established
process, the nitrile was designed to be synthesized through
hetero-Michael reaction of the E-ring part 58 with 20,18
cyanohydrin synthesis from 57, and regioselective reduction
of 56.14n
Model compound 66 was synthesized from propargyl
alcohol 59, shown in Scheme 9. Protection of 59 as
p-methoxy benzyl (PMB) ether (99%) followed by lithiation
and addition to ethyl chloroformate produced 2-butynoate
ester 61 (79%), which was reduced with DIBAH to give
alcohol 63 (26%) and aldehyde 62 (74%). The aldehyde 62
was reduced again with DIBAH to 63 (100%). Reduction of
63 with LAH in THF provided trans-allyl alcohol 64, which
was subjected to Katsuki-Sharpless asymmetric epoxida-
tion24 using (K)-DET to give epoxide 65 (71% yield, 93%
ee). Oxidation of 65 followed by Wittig reaction
synthesized the desired vinyl epoxide 66 (overall yield
78%).
With the model compound 66 in hand, we examined the
site-selective reduction of 66 into homoallyl alcohol 67 in
the presence of a Pd-catalyst. First, according to the Tsuji–
Shimizu procedure,29 we attempted the reduction of 66 with
formic acid in the presence of triethylamine (entry 1).
Although the epoxide 66 was selectively cleaved at the
desired site, over-reduced alcohol 69 was mainly produced
Scheme 9. Synthesis of model compound 66. Reagents and conditions:
(a) NaH (1.8 equiv), PMBCl (1.5 equiv), TBAI (0.13 equiv), THF, 24 8C,
16 h, 99%; (b) n-BuLi (1.5 equiv), EtOCOCl (1.5 equiv), THF, K78 8C,
1 h/0 8C, 15 min, 79%; (c) DIBAH (2.5 equiv), CH2Cl2, K78 8C, 45 min,
62: 74%, 63: 26%; (d) DIBAH (2.5 equiv), CH2Cl2, K78 8C, 10 min,
100%; (e) LAH (4.0 equiv), THF, K78 8C, 13 min/K20 8C, 26 h, 64%,
24% recovery of 63; (f) D-(K)-DET (0.20 equiv), Ti(OiPr)4 (0.15 equiv),
TBHP (2.5 equiv), MS 4A, CH2Cl2, K40 8C, 30 min/K20 8C, 2.5 d,
71%, 93% ee; (g) SO3$pyridine (10 equiv), DMSO–NEt3–CH2Cl2
(1:1.4:6), 0 8C/24 8C, 1 h; (h) Ph3PCH3Br (5.0 equiv), NaHMDS
(4.7 equiv), THF, K78 8C, 2 h/24 8C, 17 h, 78% for two steps.
Scheme 8. Retrosynthetic analysis for the EF-ring segment 52.

7398
A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
Table 3. The site-selective reduction of vinyl epoxide 66
Entry
Conditions
Product
1
2
3
4
Pd2(dba)3$CHCl3 (0.1 equiv), n-Bu3P (0.1 equiv), HCOOH (5.0 equiv), NEt3 (2.0 equiv), THF, 24 8C, 2.5 h 69 (83%), 70 (13%)
Pd(PPh3)4 (0.1 equiv), Me2NH$BH3 (1.1 equiv), AcOH (3.0 equiv), CH2Cl2, 23 8C, 1.5 h
Pd(PPh3)4 (0.1 equiv), Et3SiH (1.1 equiv), CH2Cl2, 24 8C, 1 h
Pd(PPh3)4 (0.1 equiv), Bu3SnH (1.1 equiv), CH2Cl2, 24 8C, 20 min
67:68Z5.6: 1.0 (97%)
71 (75%)
67 (95%)
31
´
along with ketone 70. Next, as described by Guibe, who
reported an improved version of the Tsuji–Shimizu
procedure,29 vinyl epoxide 66 was treated with a catalytic
amount of Pd(PPh3)4 and Me2NH$BH3 in the presence of
acetic acid to give an inseparable 5.6:1.0 mixture of the
desired 67 and the isomer 68 (entry 2). On the other hand,
when the site-selective reduction was examined with Et3SiH
instead of Me2NH$BH3 in the absence of acetic acid, not
only the desired site selective reduction but also silylation
occurred to afford TES ether 71 in 75% yield (entry 3).
Eventually, the site-selective reduction with 1.1 equiv of
Bu3SnH gave the best result, where the desired homoallyl
alcohol 67 was afforded as the sole product in 95% yield
(entry 4). Thus, we found the effective conditions in the site-
selective reduction of vinyl epoxide (Table 3).
compound was determined by the J value between H12 and
H13. RCM16,17 of 53a with Grubbs’ first-generation catalyst
in CH2Cl2 at ambient temperature smoothly produced the
desired 52 as the sole product in 97% yield.
Stereochemical confirmation of 52 by 1H NMR was difficult
because the signals of 52 at ambient temperature were
extremely broadened due to the slow conformational
changes of the F-ring part, as reported for natural
CTX1B5 and other model compounds.11f,j,o,s,v Although
the spectrum of 52 in pyridine-d5 at K30 8C exhibited sharp
signals of a ca. 1:1 mixture of two conformers, stereo-
chemistry of 52 could not be confirmed due to overlapping
signals of both conformers. In order to solve the
conformational problem, acetonide 52 was converted to
diol 83. The diol 83 was flexible enough to give a set of
sharp and clear signals at ambient temperature. Eventually,
the stereochemistry of 52 was proved by the detailed NMR
analysis of 83, which showed the presence of NOE between
H6 and H13 as well as the large J value (8.8 Hz) between
H12 and H13.
The synthesis of 52 is illustrated in Scheme 10. The Michael
donor 58 was prepared from known oxepan alcohol 72.32
Swern oxidation of alcohol 72 followed by Wittig reaction
gave enol ether 73 (overall yield 70%). Hydrolysis of 73
with Hg(OAc)2 and TBAI in THF–H2O33 afforded aldehyde
74 (95%), which was subjected to Wittig reaction and the
subsequent removal of the PMB group to provide 58
(overall yield 92%). According to the procedure described
in the synthesis of 50, the alcohol 58 was transformed into
a-silyloxy nitrile 56 in four steps ((i) hetero-Michael
addition of 58 with 20;18 (ii) reduction of ester 57;
(iii) oxidation of the resulting 76 into aldehyde 77;
(iv) addition of TMSCN) (overall yield 57%). The reduction
of 56 with Bu3SnH in CH2Cl2 in the presence of BF3$OEt2
(3.0 equiv) at 0 8C gave nitrile 55 as an inseparable 1:1
mixture of diastereomers in 63% yield with the complete
consumption of 56. The nitrile 55 was reduced to allyl
alcohol 79 by a DIBAH reduction–hydrolysis–DIBAH
reduction sequence (overall 76%). The allyl alcohol was
subjected to Katsuki-Sharpless asymmetric epoxidation24
using (K)-DET to produce epoxide 80 (76%), which was
converted to vinyl epoxide 54 by oxidation with SO3–
pyridine/DMSO34 and the subsequent Wittig reaction
(overall yield 59%). The reduction of vinyl epoxide 54
with Bu3SnH/Pd(PPh3)4 under the same conditions
described above gave 81 selectively in 88% yield. Removal
of the TBS group of 81 followed by protection of the
resulting diol afforded acetonides 53a and 53b. The
diastereomers at C13 were facilely separated by silica gel
chromatography at this stage. Stereochemistry of each
Thus, the F-ring was efficiently cyclized at the final stage
whereby the improved synthesis of the EF-ring segment of
CTX1B was accomplished.
4. Conclusion
Aiming at the convergent total synthesis of CTX1B,
construction of its EF-ring segment has been investigated.
During the study, a novel method for the construction of
branched ethers based on regioselective reduction of
g-alkoxy b,g-unsaturated a-silyloxy nitriles with
BF3$OEt2 and R3SiH or Bu3SnH has been developed.
Combined use of the branched ether synthesis and RCM
successfully provided medium-sized cyclic ether 34, and
also contributed to the synthesis of the EF-ring segment 50.
Although a difficulty in the cyclization of the E-ring by
RCM arose in the synthesis of 50, it was solved in a revised
synthetic route to the EF-ring part 52, where the F-ring was
cyclized at the final stage. In the course of the synthesis of
52, efficient site-selective reduction of vinyl epoxides into
homoallyl alcohols mediated by Bu3SnH and Pd(PPh3)4 was
also developed. Thus, a novel route to the EF-ring segment
of CTX1B has been established. Further studies toward the

A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
7399
Scheme 10. Synthesis of the EF-ring segment 52. Reagents and conditions: (a) (COCl)2 (3.0 equiv), DMSO (5.0 equiv), CH2Cl2, K78 8C, 15 min then NEt3
(10 equiv), K18 8C, 10 min; (b) Ph3PCH2OMeCl (5.1 equiv), NaHMDS (4.9 equiv), THF, K78 8C, 1.5 h/24 8C, 17.5 h, 70% for two steps; (c) Hg(OAc)2
(3.0 equiv), THF–H2O (10:1), 24 8C, 1.5 h then TBAI (9.0 equiv), 1 h, 95%; (d) Ph3PCH3Br (3.5 equiv), NaHMDS (3.2 equiv), THF, K78 8C, 2 h/22 8C,
18 h, 100%; (e) DDQ (2.5 equiv), CH2Cl2—pH 7 buffer (4:1), 0 8C, 3 h, 92%; (f) PMe3 (1.5 equiv), 20 (3.0 equiv), CH2Cl2, 0 8C, /24 8C, 30 min, 98% (only
E); (g) DIBAH (3.5 equiv), CH2Cl2, K78 8C, 1 h, 94%; (h) TPAP (0.2 equiv), NMO (2.0 equiv), MS 4A, CH2Cl2, 23 8C, 1.5 h, 84%; (i) Me3Al (1.1 equiv),
TMSCN (2.5 equiv), benzene, 25 8C, 1 h, 74%; (j) BF3$OEt2 (3.0 equiv), CH2Cl2–Bu3SnH (1:1), 0 8C, 10 min, 63%; (k) DIBAH (4.0 equiv), CH2Cl2, K78 8C,
1 h; (l) 0.5 M HCl, CH2Cl2, 24 8C, 20 min, 83% for two steps; (m) DIBAH (3.0 equiv), CH2Cl2, K78 8C, 30 min, 91%; (n) D-(K)-DET (2.0 equiv), Ti(OiPr)4
(1.5 equiv), TBHP (20 equiv), MS 4A, CH2Cl2, K40 8C, 30 min/K25 8C, 2.5 d, 76%; (o) SO3$pyridine (25 equiv), DMSO–NEt3–CH2Cl2 (1:1.4:3), 0 8C/
24 8C, 3 h; (p) Ph3PCH3Br (28 equiv), NaHMDS (23 equiv), THF, K78 8C, 2 h/24 8C, 2.5 d, 59% for two steps; (q) Pd(PPh3)4 (0.1 equiv), Bu3SnH
(1.1 equiv), CH2Cl2, 24 8C, 25 min, 88%; (r) TBAF (2.0 equiv), THF, 23 8C, 1.5 h, 100%; (s) 2,2-dimethoxypropane (10 equiv), CSA (0.5 equiv), CH2Cl2,
24 8C, 3 h, 53a: 47%, 53b: 50%; (t) (Cy3P)2Cl2Ru]CHPh (20 mol%), CH2Cl2 (3 mM), 23 8C, 4 h, 97%; (u) THF–H2O–TFA (10:10:1), 23 8C, 3 h, 88%.
total synthesis of CTX1B are currently under way in our
laboratory.
syringe-septum and cannula techniques. All commercially
available reagents were used without further purification
with the following exceptions. THF was distilled from
sodium-benzophenone ketyl under argon. CH2Cl2, benzene
were distilled from CaH2 prior to use. All reactions were
monitored by TLC with precoated SiO2 plates (Merck, silica
gel 60 F254). Plates were visualized by ultraviolet light and
by treatment with acidic anisaldehyde or phosphomolybdic
acid stain followed by heating. Flash chromatography was
performed on YMC Silica Gel 60 (230–400 mesh) as a
stationary phase. Melting points were measured on
YANAGIMOTO micro-melting apparatus without
5. Experimental
5.1. General methods
All reactions sensitive to air or moisture were carried out
under an argon atmosphere in dry, freshly distilled solvents
under anhydrous conditions, unless otherwise noted.
Sensitive liquids and solutions were transferred by

7400
A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
calibration. Optical rotations were recorded on a JASCO
P-1020 digital polarimeter. Infrared spectra (IR) were
measured on a JEOL JIR-WINSPEC100 infrared spectro-
meter in noted states and are reported in wave numbers
(cmK1). 1H NMR and 13C NMR spectra were recorded on a
JEOL JNM-AL300 (1H at 300 MHz, 13C at 75 MHz), JNM-
a-400 (1H at 400 MHz), and/or JNM-a-600 (13C at
150 MHz) magnetic resonance spectrometer. 1H NMR
spectra are reported as chemical shifts (d) in parts-per-
million (ppm) based on tetramethylsilane (0 ppm), C6HD5
(7.15 ppm), CHD2C(]O)CD3 (2.04 ppm) or C5HD4N
(8.71 ppm). The following abbreviations are used to
describe spin multiplicity: sZsinglet, dZdoublet, tZ
triplet, qZquartet, mZmultiplet, brZbroad, ddZdouble
doublets, dtZdouble triplets, dqZdouble quartets, and
dddZdouble double doublets; other combination is derived
from those listed. Coupling constants (J) are reported in
Hertz (Hz). 13C NMR spectra are reported as chemical shifts
(d) in ppm based on 13CDCl3 (77.0 ppm) or 13C6D6
(128.0 ppm). Low and high resolution mass spectra were
measured on a JEOL JMS-600H mass spectrometer under
electron ionization (EI) condition and a JEOL JMS-SX102A
mass spectrometer under field desorption (FD) condition.
6.4 Hz), 2.69 (2H, brt, JZ7.7 Hz), 1.95–1.86 (2H, m), 1.26
(3H, d, JZ6.6 Hz); LR-EIMS, m/z 215 (42.5%, [M]C), 91
(bp); HR-EIMS, calcd for C14H17NO [M]C: 215.1310,
found: 215.1336.
5.1.3. (2E)-5-(tert-Butyldimethylsilyloxy)-4-(3-phenyl-
propoxy)pent-2-enenitrile (15). To a solution of 12
(82.2 mg, 0.190 mmol) in CH2Cl2–Et3SiH (1:1, v/v,
3.0 ml) was added BF3$OEt2 (70 ml, 0.570 mmol) at 0 8C
and the mixture was stirred for 10 min. Then, saturated
aqueous NaHCO3 (7 ml) was added and the mixture was
extracted with Et2O (3!5 ml). The combined organic
layers were washed with brine, dried over anhydrous
MgSO4, filtered and concentrated in vacuo. The resultant
residue was purified by column chromatography (silica gel,
hexane/EtOAcZ20/10) to give 15 (41.8 mg, 64%). 15: a
colorless oil; IR (film), nmax 3085, 3063, 3027, 2953, 2929,
2858, 2739, 2225, 1629, 1603, 1497, 1471, 1462, 1455,
1406, 1389, 1361, 1343, 1306, 1254, 1222, 1111, 1006, 965,
939, 837, 814, 779, 747, 700, 670 cmK1 1H NMR
;
(300 MHz, CDCl3), d 7.31–7.16 (5H, m), 6.72 (1H, dd,
JZ16.4, 4.7 Hz), 5.61 (1H, dd, JZ16.4, 1.7 Hz), 3.91 (1H,
dddd, JZ6.2, 5.9, 4.7, 1.7 Hz), 3.70 (1H, dd, JZ10.2,
5.9 Hz), 3.55 (1H, dd, JZ10.2, 6.2 Hz), 3.49 (2H, t, JZ
6.4 Hz), 2.72–2.67 (2H, m), 1.95–1.86 (2H, m), 0.89 (9H, s),
0.06 (6H, s); LR-EIMS, m/z 288 (21.9%, [MKt-Bu]C), 91
(bp); HR-EIMS, calcd for C16H22NO2Si [MKt-Bu]C:
288.1420, found: 288.1417.
5.1.1. 4-(3-Phenylpropoxy)but-2-enenitrile (13). To a
solution of 10 (50.6 mg, 0.175 mmol) in CH2Cl2–Et3SiH
(1:1, v/v, 3.2 ml) was added BF3$OEt2 (65 ml, 0.524 mmol)
at 0 8C and the mixture was stirred for 10 min. Then,
saturated aqueous NaHCO3 (5 ml) was added and the
mixture was extracted with Et2O (3!5 ml). The combined
organic layers were washed with brine, dried over
anhydrous MgSO4, filtered and concentrated in vacuo.
The resultant residue was purified by column chroma-
tography (silica gel, hexane/EtOAcZ10) to give 13
(22.6 mg, 64%) as a inseparable mixture of E and Z-isomers
5.1.4. Methyl (2E,20R,30S)-3-{(20-allyloxan-30-yl)oxy}-4-
(tert-butyldimethylsilyloxy)-2-butenoate (21). A solution
of butynoate 20 (1.29 g, 5.65 mmol) in CH2Cl2 (10 ml) was
slowly added dropwise to a solution of 19 (479.0 mg,
3.37 mmol) and PMe3 (3.7 ml, 1.0 M in THF, 3.71 mmol) in
CH2Cl2 (24 ml) at 0 8C by means of a syringe. The mixture
was warmed to 24 8C and stirred for 1 h. The mixture was
cooled to 0 8C and diluted with Et2O (20 ml) and hexane
(20 ml). Then, saturated aqueous NH4Cl (15 ml) was added
and the mixture was extracted with Et2O (3!15 ml). The
combined organic layers were washed with brine, dried over
anhydrous MgSO4, filtered and concentrated in vacuo. The
resultant residue was purified by column chromatography
(silica gel, hexane/EtOAcZ20) to give 21 (1.19 g, 95%).
21: a colorless oil; [a]D26 C58.1 (c 0.75, CHCl3); IR (film),
nmax 3077, 2951, 2856, 1716, 1626, 1472, 1436, 1434, 1389,
1361, 1342, 1310, 1295, 1252, 1189, 1147, 1098, 1051,
1
(E/ZZ6.2:1 from H NMR). 13: a colorless oil; IR (film),
nmax 3063, 3026, 2943, 2861, 2795, 2224, 1693, 1602, 1496,
1477, 1454, 1365, 1264, 1180, 1135, 1047, 1029, 952, 913,
1
748, 701 cmK1; H NMR (300 MHz, CDCl3), d 7.32–7.15
(5H, m), 6.73 (0.86H, dt, JZ16.3, 3.7 Hz), 6.57 (0.14H, dt,
JZ11.4, 5.9 Hz), 5.64 (0.86H, dt, JZ16.3, 2.4 Hz), 5.45
(0.14H, dt, JZ11.4, 1.8 Hz), 4.29 (0.28H, dd, JZ5.9,
1.8 Hz), 4.08 (1.72H, dd, JZ3.7, 2.4 Hz), 3.48 (2H, t, JZ
6.4 Hz), 2.70 (2H, t, JZ7.7 Hz), 1.98–1.88 (2H, m); LR-
EIMS, m/z 201 (43.5%, [M]C), 118 (bp); HR-EIMS, calcd
for C13H15NO [M]C: 201.1154, found: 201.1162.
1
1005, 939, 914, 837, 778, 675 cmK1; H NMR (300 MHz,
CDCl3), d 5.92–5.78 (1H, m), 5.11–5.09 (2H, m), 5.05 (1H,
s), 4.90 (1H, d, JZ13.6 Hz), 4.65 (1H, d, JZ13.6 Hz),
3.98–3.92 (1H, m), 3.91–3.83 (1H, m), 3.68 (3H, s), 3.45–
3.33 (2H, m), 2.59–2.50 (1H, m), 2.34–2.30 (1H, m), 2.25–
2.15 (1H, m), 1.75–1.66 (2H, m), 1.52–1.37 (1H, m), 0.90
(9H, s), 0.09 (6H, s); 13C NMR (75 MHz, CDCl3), d 170.4
(C), 167.3 (C), 134.2 (CH), 117.1 (CH2), 91.6 (CH), 79.4
(CH), 74.8 (CH), 67.7 (CH2), 60.0 (CH2), 50.8 (CH3), 36.0
(CH2), 27.8 (CH2), 25.7 (CH3!3), 24.9 (CH2), 18.2 (C),
K5.35 (CH3), K5.38 (CH3); LR-EIMS, m/z 313 (82.4%,
[MKt-Bu]C), 189 (bp); HR-EIMS, calcd for C15H25O5Si
[MKt-Bu]C: 313.1471, found: 313.1466.
5.1.2. (2E)-4-(3-Phenylpropoxy)pent-2-enenitrile (14).
To a solution of 11 (27.3 mg, 0.0900 mmol) in CH2Cl2–
Et3SiH (1:1, v/v, 1.8 ml) was added BF3$OEt2 (33 ml,
0.270 mmol) at 0 8C and the mixture was stirred for 10 min.
Then, saturated aqueous NaHCO3 (5 ml) was added and the
mixture was extracted with Et2O (3!5 ml). The combined
organic layers were washed with brine, dried over
anhydrous MgSO4, filtered and concentrated in vacuo.
The resultant residue was purified by column chromato-
graphy (silica gel, hexane/EtOAcZ20/10) to give 14
(12.1 mg, 62%). 14: a colorless oil; IR (film), nmax 3062,
3026, 2978, 2932, 2856, 2224, 1636, 1602, 1584, 1496,
1476, 1454, 1370, 1340, 1246, 1178, 1150, 1102, 963, 748,
1
700 cmK1; H NMR (300 MHz, CDCl3), d 7.32–7.16 (5H,
5.1.5. (2E,20R,30S)-3-{(20-Allyloxan-30-yl)oxy}-4-(tert-
butyldimethylsilyloxy)-2-butenol (22). To a solution of
21 (115.6 mg, 0.312 mmol) in CH2Cl2 (5.0 ml) was added
m), 6.64 (1H, dd, JZ16.3, 5.0 Hz), 5.54 (1H, dd, JZ16.3,
1.7 Hz), 3.96 (1H, qdd, JZ6.6, 5.0, 1.7 Hz), 3.41 (2H, t, JZ

A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
7401
DIBAH (1.3 ml, 0.95 M in n-hexane, 1.25 mmol) at K78 8C
and the mixture was stirred for 10 min. Then, saturated
aqueous potassium sodium tartrate (5 ml) was added and the
mixture was stirred at 24 8C for 3 h. The layers were
separated and the aqueous layer was extracted with EtOAc
(3!10 ml). The combined organic layers were washed with
brine, dried over anhydrous MgSO4, filtered and concen-
trated in vacuo. The resultant residue was purified by
column chromatography (silica gel, hexane/EtOAcZ5/
3/1) to give 22 (106.6 mg, w100%). 22: a colorless oil;
[a]2D6 C45.1 (c 0.65, CHCl3); IR (film), nmax 3417, 3075,
2930, 2857, 2725, 1661, 1472, 1463, 1436, 1389, 1361,
1340, 1306, 1276, 1252, 1184, 1098, 1004, 913, 837, 814,
washed with brine, dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The resultant residue was
purified by column chromatography (silica gel, hexane/
EtOAcZ30/10) to give 24 (42.1 mg, 74%) as an
inseparable 1:1 mixture of diastereomers. The nitrile 24
was unstable and immediately used for the next reaction. 24:
1
a colorless oil; H NMR (300 MHz, CDCl3), d 5.92–5.78
(1H, m), 5.58 (0.5H, d, JZ9.1 Hz), 5.57 (0.5H, d, JZ
9.1 Hz), 5.12–5.04 (2H, m), 4.75–4.70 (1H, m), 4.20–4.08
(2H, m), 3.97–3.87 (1H, m), 3.79–3.65 (1H, m), 3.42–3.28
(2H, m), 2.54–2.43 (1H, m), 2.37–2.25 (1H, m), 2.23–2.12
(1H, m), 1.74–1.65 (2H, m), 1.41–1.30 (1H, m), 0.92 (9H,
s), 0.21 (9H, s), 0.11 (6H, s); 13C NMR (75 MHz, CDCl3), d
156.8 (C), 134.5 (CH), 119.9 (C!0.5), 117.2 (C!0.5),
117.0 (CH2), 98.4 (CH), 79.6 (CH), 74.2 (CH), 67.8 (CH2),
62.2 (CH2), 57.6 (CH), 36.3 (CH2), 28.1 (CH2), 25.8
(CH3!3), 25.0 (CH2), 18.3 (C), K0.10 (CH3!3), K5.38
(CH3), K5.53 (CH3).
1
777, 674 cmK1; H NMR (300 MHz, CDCl3), d 5.93–5.79
(1H, m), 5.12–5.04 (2H, m), 4.95 (1H, t, JZ7.9 Hz), 4.20–
4.15 (4H, m), 3.94 (1H, dtd, JZ11.0, 3.3, 1.8 Hz), 3.74 (1H,
ddd, JZ10.3, 9.0, 4.2 Hz), 3.42–3.29 (2H, m), 2.58–2.49
(1H, m), 2.38–2.29 (1H, m), 2.24–2.13 (1H, m), 1.72–1.63
(2H, m), 1.43–1.21 (1H, m), 0.91 (9H, s), 0.10 (6H, s); 13C
NMR (75 MHz, CDCl3), d 155.9 (C), 134.6 (CH), 116.5
(CH2), 100.3 (CH), 79.8 (CH), 73.1 (CH), 67.5 (CH2), 60.6
(CH2), 57.6 (CH2), 36.0 (CH2), 28.0 (CH2), 25.5 (CH3!3),
24.8 (CH2), 17.9 (C), K5.52 (CH3), K5.56 (CH3); LR-
EIMS, m/z 285 (19.1%, [MKt-Bu]C), 227 (bp); HR-EIMS,
calcd for C14H25O4Si [MKt-Bu]C: 285.1522, found:
285.1518.
5.1.8. (2E,4S,20R,30S)-4-{(20-Allyloxan-30-yl)oxy}-5-(tert-
butyldimethylsilyloxy)pent-2-enenitrile (25a) and (2E,
4R,20R,30S)-4-{(20-allyloxan-30-yl)oxy}-5-(tert-butyldi-
methylsilyloxy)pent-2-enenitrile (25b). Silane reduction.
The reduction of 24 with organosilanes in entries 1–4 in
Table 2 followed the procedure described in the synthesis of
model compounds 13, 14 and 15.
5.1.6. (2E,20R,30S)-3-{(20-Allyloxan-30-yl)oxy}-4-(tert-
butyldimethylsilyloxy)-2-butenal (23). To a mixture of
Stannane reduction. To a solution of 24 (14.7 mg,
0.0334 mmol) in CH2Cl2–Bu3SnH (1:1, v/v, 0.60 ml) was
added BF3$OEt2 (12 ml, 0.100 mmol) at K18 8C and the
mixture was stirred for 10 min. Then, saturated aqueous
NaHCO3 (5 ml) was added and the aqueous layer was
extracted with Et2O (3!5 ml). The combined organic
layers were washed with brine, dried over anhydrous
MgSO4, filtered and concentrated in vacuo. The resultant
residue was purified by column chromatography (silica gel,
hexane/EtOAcZ30/10) to give 25 (7.5 mg, 64%) as an
inseparable mixture of two diastereomers (25a:25bZ
1.0:1.3). 25: a colorless oil; IR (film), nmax 3074, 2954,
2930, 2857, 2225, 2211, 1628, 1472, 1463, 1434, 1389,
1361, 1341, 1255, 1222, 1178, 1099, 1005, 965, 913, 837,
779 cmK1; 1H NMR (300 MHz, CDCl3), d 6.78 (0.57H, dd,
JZ16.3, 4.6 Hz), 6.69 (0.43H, dd, JZ16.3, 5.4 Hz), 5.95–
5.80 (1H, m), 5.66 (0.57H, dd, JZ16.3, 1.8 Hz), 5.63
(0.43H, dd, JZ16.3, 1.6 Hz), 5.13–5.07 (2H, m), 4.11–4.02
(1H, m), 3.92–3.87 (1H, m), 3.72–3.63 (1H, m), 3.54–3.47
(1H, m), 3.39–3.08 (3H, m), 2.67–2.61 (0.57H, m), 2.58–
2.50 (0.43H, m), 2.26–2.05 (2H, m), 1.67–1.57 (2H, m),
1.29–1.26 (1H, m), 0.89 (9H, s), 0.06 (6H, s); 13C NMR
(75 MHz, CDCl3) (A 1:2 mixture of 25a and 25b was
measured), d 153.6 (CH!0.67), 152.8 (CH!0.33), 135.0
(CH!0.67), 134.7 (CH!0.33), 117.1 (C!0.67), 116.9
(CH2!0.33), 116.8 (C!0.33), 116.6 (CH2!0.67), 101.2
(CH!0.33), 100.4 (CH!0.67), 80.2 (CH!0.33), 80.1
(CH!0.67), 77.6 (CH!0.67), 77.4 (CH!0.33), 76.6
(CH!0.33), 76.2 (CH!0.67), 67.6 (CH2!0.67), 67.5
(CH2!0.33), 65.3 (CH2!0.33), 64.6 (CH2!0.67), 36.41
(CH2!0.33), 36.37 (CH2!0.67), 30.2 (CH2!0.67), 29.7
(CH2!0.33), 25.8 (CH3!2), 25.7 (CH3), 25.23 (CH2!
0.67), 25.19 (CH2!0.33), 18.14 (C!0.67), 18.09 (C!
0.33), K5.45 (CH3!0.33), K5.53 (CH3), K5.59 (CH3!
0.67); LR-EIMS, m/z 294 (23.7%, [MKt-Bu]C), 125 (bp);
˚
22 (158.2 mg, 0.462 mmol) and MS 4 A (158.2 mg,
100 wt%) in CH2Cl2 (5.0 ml) was added NMO (108.2 mg,
0.924 mmol) at 24 8C and the mixture was stirred for
10 min. Then, TPAP (16.2 mg, 0.0462 mmol) was added to
the reaction mixture at 24 8C and the mixture was stirred for
50 min. The mixture was filtered through Celite and
concentrated in vacuo. The resultant residue was purified
by column chromatography (silica gel, hexane/EtOAcZ
10/5) to give 23 (139.0 mg, 88%). 23: a colorless oil; [a]D25
C49.0 (c 1.01, CHCl3); IR (film), nmax 3075, 2954, 2930,
2857, 2764, 1665, 1615, 1472, 1463, 1438, 1389, 1361,
1323, 1279, 1254, 1209, 1164, 1099, 1041, 1005, 974, 957,
1
947, 939, 914, 837, 778, 680 cmK1; H NMR (300 MHz,
CDCl3), d 9.98 (1H, d, JZ7.7 Hz), 5.91–5.77 (1H, m), 5.41
(1H, d, JZ7.7 Hz), 5.09–5.04 (2H, m), 4.52 (1H, d, JZ
13.2 Hz), 4.46 (1H, d, JZ13.2 Hz), 3.98–3.86 (2H, m),
3.45–3.35 (2H, m), 2.52–2.44 (1H, m), 2.32–2.16 (1H, m),
1.73–1.65 (2H, m), 1.52–1.37 (1H, m), 0.91 (9H, s), 0.11
(6H, s); 13C NMR (75 MHz, CDCl3), d 189.9 (CH), 173.7
(C), 133.7 (CH), 117.1 (CH2), 105.7 (CH), 78.9 (CH), 75.1
(CH), 67.4 (CH2), 61.1 (CH2), 35.9 (CH2), 27.6 (CH2), 25.5
(CH3!3), 24.6 (CH2), 17.9 (C), K5.58 (CH3!2); LR-
EIMS, m/z 283 (73.8%, [MKt-Bu]C), 159 (bp); HR-EIMS,
calcd for C14H23O4Si [MKt-Bu]C: 283.1365, found:
283.1362.
5.1.7. (3E,20R,30S)-4-{(20-Allyloxan-30-yl)oxy}-5-(tert-
butyldimethylsilyloxy)-2-(trimethylsilyloxy)pent-3-ene-
nitrile (24). To a solution of 23 (43.9 mg, 0.129 mmol) and
TMSCN (43 ml, 0.323 mmol) in benzene (1.3 ml) was added
Me3Al (0.14 ml, 1.03 M in n-hexane, 0.142 mmol) at 24 8C
and the mixture was stirred for 1 h. Then, saturated aqueous
NaHCO3 (5 ml) was added and the mixture was extracted
with Et2O (3!5 ml). The combined organic layers were

7402
A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
HR-EIMS, calcd for C15H24NO3Si [MKt-Bu]C: 294.1525,
found: 294.1523.
m), 5.68 (0.67H, dt, JZ7.0, 1.5 Hz), 5.62 (0.33H, dt, JZ
6.6, 1.5 Hz), 5.14–5.05 (2H, m), 4.17 (2H, brs), 3.96–3.86
(2H, m), 3.68–3.59 (1H, m), 3.56–3.49 (1H, m), 3.36–3.10
(3H, m), 2.78–2.69 (0.67H, m), 2.66–2.57 (0.33H, m), 2.22
(1H, dt, JZ15.0, 7.7 Hz), 2.14–2.07 (1H, m), 1.64–1.57
(2H, m), 1.43–1.25 (1H, m), 0.89 (9H, s), 0.05 (6H, s); 13C
NMR (75 MHz, CDCl3), d 135.54 (CH!0.67), 135.45
(CH!0.33), 133.1 (CH!0.33), 131.9 (CH!0.67), 130.2
(CH!0.67), 129.3 (CH!0.33), 116.4 (CH2), 80.8 (CH!
0.67), 80.5 (CH!0.33), 80.4 (CH!0.67), 78.1 (CH!0.33),
76.7 (CH!0.67), 74.2 (CH!0.33), 67.71 (CH2!0.33),
67.68 (CH2!0.67), 66.4 (CH2!0.33), 66.2 (CH2!0.67),
62.83 (CH2!0.67), 62.81 (CH2!0.33), 36.4 (CH2), 31.0
(CH2!0.67), 29.3 (CH2!0.33), 25.85 (CH3!2), 25.83
(CH3), 25.5 (CH2!0.67), 25.3 (CH2!0.33), 18.29 (C!
0.67), 18.27 (C!0.33), K5.21 (CH3!0.33), K5.33 (CH3),
K5.43 (CH3!0.67); LR-EIMS, m/z 299 (2.1%, [MKt-
Bu]C), 125 (bp); HR-EIMS, calcd for C15H27O4Si [MKt-
Bu]C: 299.1678, found: 299.1674.
5.1.9. (2E,4S,20R,30S)-4-{(20-Allyloxan-30-yl)oxy}-5-(tert-
butyldimethylsilyloxy)-2-pentenal (27a) and (2E,4R,20R,
30S)-4-{(20-allyloxan-30-yl)oxy}-5-(tert-butyldimethyl-
silyloxy)-2-pentenal (27b). To a solution of 25 (25a:25bZ
1:2, 24.0 mg, 0.0683 mmol) in CH2Cl2 (1.0 ml) was added
DIBAH (0.18 ml, 0.95 M in n-hexane, 0.171 mmol) at
K78 8C and the mixture was stirred for 10 min. Then,
saturated aqueous potassium sodium tartrate (3 ml) was
added and the mixture was stirred at 24 8C for 12 h. The
layers were separated and the aqueous layer was extracted
with Et2O (3!5 ml). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The resultant residue was puri-
fied by column chromatography (silica gel, hexane/EtOAcZ
10/5) to give 27 (16.5 mg, 68%) as an inseparable mixture
of two diastereomers (27a:27bZ1.0:2.0). 27: a yellow oil;
IR (film), nmax 3074, 2953, 2929, 2857, 2723, 1697, 1641,
1472, 1463, 1437, 1389, 1361, 1339, 1279, 1254, 1214,
5.1.11. (2R,3S,4R,20R,30S)-4-{(20-Allyloxan-30-yl)oxy}-5-
(tert-butyldimethylsilyloxy)-2,3-epoxypentanol (29a)
and (2R,3S,4S,20R,30S)-4-{(20-allyloxan-30-yl)oxy}-5-
(tert-butyldimethylsilyloxy)-2,3-epoxypentanol (29b). To
a mixture of D-(K)-DET (14.4 ml, 0.0840 mmol) and pre-
1186, 1099, 1005, 978, 939, 912, 838, 814, 778, 669 cmK1
;
1H NMR (300 MHz, CDCl3), d 9.58 (1H, d, JZ7.7 Hz),
6.84 (0.67H, dd, JZ15.8, 5.1 Hz), 6.73 (0.33H, dd, JZ15.8,
5.9 Hz), 6.38–6.26 (1H, m), 5.97–5.80 (1H, m), 5.15–5.07
(2H, m), 4.28–4.15 (1H, m), 3.92–3.87 (1H, m), 3.78–3.70
(1H, m), 3.62–3.55 (1H, m), 3.36–3.10 (3H, m), 2.72–2.56
(1H, m), 2.27–2.18 (1H, m), 2.12–2.07 (1H, m), 1.68–1.54
(2H, m), 1.44–1.31 (1H, m), 0.89 (9H, s), 0.06 (6H, s); 13C
NMR (75 MHz, CDCl3), d 193.3 (CH!0.67), 193.1 (CH!
0.33), 155.7 (CH!0.67), 154.6 (CH!0.33), 135.2 (CH!
0.67), 135.0 (CH!0.33), 133.3 (CH!0.33), 132.5 (CH!
0.67), 116.7 (CH2!0.33), 116.6 (CH2!0.67), 80.30 (CH!
0.33), 80.26 (CH!0.67), 78.1 (CH!0.67), 77.5 (CH!
0.67), 77.2 (CH!0.33), 75.9 (CH!0.33), 67.6 (CH2), 65.6
(CH2!0.33), 64.9 (CH2!0.67), 36.44 (CH2!0.67), 36.40
(CH2!0.33), 30.4 (CH2!0.67), 29.6 (CH2!0.33), 25.77
(CH3!2), 25.75 (CH3), 25.29 (CH2!0.67), 25.25 (CH2!
0.33), 18.2 (C), K5.37 (CH3!0.33), K5.46 (CH3), K5.52
(CH3!0.67); LR-EIMS, m/z 354 (14.0%, [M]C), 125 (bp);
HR-EIMS, calcd for C15H25O4Si [MKt-Bu]C: 297.1522,
found: 297.1540.
˚
dried MS 4 A (49.7 mg, 133 wt%) in CH2Cl2 (0.5 ml) was
added Ti(OiPr)4 (21.6 ml, 0.0735 mmol) at K40 8C and the
mixture was stirred for 30 min. Then, TBHP (0.14 ml,
3.7 M in toluene, 0.525 mmol) was added and the mixture
was stirred at K40 8C for 30 min. To the mixture was added
dropwise a solution of 28 (28a:28bZ1:2, 37.5 mg,
0.105 mmol) in CH2Cl2 (1.5 ml). The reaction mixture
was stirred at K40 8C for 30 min. Then, the reaction
mixture was warmed to K25 8C and stirred for 24 h. DMS
(38.6 ml, 0.525 mmol) was added at K25 8C and the mixture
was stirred for 2 h until unreacted TBHP was consumed. To
the mixture was added 10% DL-tartaric acid (43.2 ml) and
NaF (18.5 mg) at K25 8C. The suspension was warmed to
26 8C and stirred for 24 h. The mixture was filtered through
Celite and concentrated in vacuo. To the resultant residue
was added Et2O (3.0 ml) and 30% aqueous NaOH in brine
(1.0 ml) at 0 8C and the mixture was stirred for 1 h. The
layers were separated and the aqueous layer was extracted
with Et2O (3!5 ml). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The resultant residue was
purified by column chromatography (silica gel, hexane/
EtOAcZ5/3) to give 29 (39.2 mg, w100%) as an
inseparable mixture of two diastereomers (29a:29bZ
1.0:2.0). 29: a colorless oil; IR (film), nmax 3468, 3075,
2930, 2857, 1642, 1472, 1463, 1389, 1368, 1257, 1130,
5.1.10. (2E,4S,20R,30S)-4-{(20-Allyloxan-30-yl)oxy}-5-
(tert-butyldimethylsilyloxy)-2-pentenol (28a) and
(2E,4R,20R,30S)-4-{(20-allyloxan-30-yl)oxy}-5-(tert-butyl-
dimethylsilyloxy)-2-pentenol (28b). To a solution of 27
(27a:27bZ1:2, 16.5 mg, 0.0465 mmol) in CH2Cl2 (1.0 ml)
was added DIBAH (0.15 ml, 0.95 M in n-hexane,
0.140 mmol) at K78 8C and the mixture was stirred for
8 min. Then, saturated aqueous potassium sodium tartrate
(3 ml) was added and the mixture was stirred at 24 8C for
12 h. The layers were separated and the aqueous layer was
extracted with EtOAc (3!5 ml). The combined organic
layers were washed with brine, dried over anhydrous
MgSO4, filtered and concentrated in vacuo. The resultant
residue was purified by column chromatography (silica gel,
hexane/EtOAcZ5) to give 28 (16.6 mg, w100%) as an
inseparable mixture of two diastereomers (28a:28bZ
1.0:2.0). 28: a pale yellow oil; IR (film), nmax 3345, 3076,
2931, 2858, 1642, 1472, 1463, 1443, 1378, 1342, 1321,
1279, 1256, 1213, 1098, 1004, 974, 948, 912, 837, 814, 778,
1
1097, 1027, 939, 910, 837, 815, 778, 669 cmK1; H NMR
(300 MHz, CDCl3), d 5.96–5.82 (1H, m), 5.15–5.05 (2H,
m), 3.96 (1H, brddd, JZ12.8, 5.1, 2.2 Hz), 3.92–3.86 (1H,
m), 3.73–3.61 (2H, m), 3.60 (1H, dd, JZ10.3, 7.3 Hz),
3.36–3.27 (1H, m), 3.24–3.17 (3H, m), 3.12 (1H, dt, JZ4.4,
2.2 Hz), 3.03 (1H, dd, JZ6.8, 2.2 Hz), 2.67–2.58 (1H, m),
2.33–2.28 (1H, m), 2.25–2.15 (1H, m), 1.71–1.61 (3H, m),
0.90 (3H, s), 0.89 (6H, s), 0.07 (2H, s), 0.06 (4H, s); 13C
NMR (75 MHz, CDCl3), d 135.33 (CH!0.67), 135.29
(CH!0.33), 116.5 (CH2!0.33), 116.4 (CH2!0.67), 80.5
(CH!0.33), 80.4 (CH!0.67), 80.2 (CH), 77.3 (CH!0.67),
76.8 (CH!0.33), 67.7 (CH2!0.67), 67.6 (CH2!0.33),
1
666 cmK1; H NMR (300 MHz, CDCl3), d 5.96–5.83 (2H,

A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
7403
64.3 (CH2!0.33), 63.0 (CH2!0.67), 61.4 (CH2!0.33),
61.2 (CH2!0.67), 56.9 (CH), 56.3 (CH!0.67), 54.5 (CH!
0.33), 36.5 (CH2!0.67), 36.3 (CH2!0.33), 30.6 (CH2!
0.67), 29.9 (CH2!0.33), 25.79 (CH3), 25.77 (CH3!2),
25.5 (CH2!0.67), 25.3 (CH2!0.33), 18.2 (C!0.33), 18.1
(C!0.67), K5.41 (CH3!0.33), K5.49 (CH3!0.33),
K5.59 (CH3!1.34); LR-EIMS, m/z 315 (12.4%, [MKt-
Bu]C), 125 (bp); HR-EIMS, calcd for C15H27O5Si [MKt-
Bu]C: 315.1628, found: 315.1626.
1376, 1361, 1323, 1256, 1217, 1179, 1146, 1089, 1057,
1
1026, 993, 972, 956, 939, 838, 777, 664 cmK1; H NMR
(300 MHz, C6D6), d 5.88–5.73 (2H, m), 4.53–4.52 (1H, m),
4.10 (1H, dt, JZ7.9, 4.6 Hz), 4.04 (1H, dd, JZ10.8,
4.6 Hz), 3.97 (1H, dd, JZ10.8, 7.9 Hz), 3.90–3.80 (1H, m),
3.71–3.65 (1H, m), 3.28 (1H, ddd, JZ8.8, 5.1, 2.4 Hz),
3.06–2.97 (1H, m), 2.68 (1H, ddd, JZ13.7, 8.4, 5.1 Hz),
2.42–2.34 (1H, m), 2.21–2.04 (1H, m), 1.77–1.75 (1H, m),
1.54–1.42 (2H, m), 1.32–1.16 (1H, m), 0.95 (9H, s), 0.04
(3H, s), 0.03 (3H, s); 13C NMR (75 MHz, C6D6), d 135.8
(CH), 127.8 (CH), 84.8 (CH), 80.3 (CH), 71.1 (CH), 69.2
(CH), 68.1 (CH2), 60.7 (CH2), 32.4 (CH2), 32.0 (CH2), 26.6
(CH2), 26.0 (CH3!3), 18.4 (C), K5.43 (CH3), K5.46
(CH3); LR-EIMS, m/z 271 (36.4%, [MKt-Bu]C), 71 (bp);
HR-EIMS, calcd for C13H23O4Si [MKt-Bu]C: 271.1365,
found: 271.1355.
5.1.12. (3S,4R,20R,30S)-4-{(20-Allyloxan-30-yl)oxy}-5-
(tert-butyldimethylsilyloxy)pent-1-en-3-ol (30a) and
(3S,4S,20R,30S)-4-{(20-allyloxan-30-yl)oxy}-5-(tert-butyl-
dimethylsilyloxy)pent-1-en-3-ol (30b). To a solution of 29
(29a:29bZ1:2, 23.0 mg, 0.0617 mmol), PPh3 (80.9 mg,
0.309 mmol), and imidazole (21.0 mg, 0.309 mmol) in THF
(1.0 ml) was added I2 (62.6 mg, 0.247 mmol) at 25 8C and
the mixture was stirred for 45 min. Then, saturated aqueous
Na2S2O3 (5 ml) was added and the mixture was extracted
with Et2O (3!5 ml). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The resultant residue was
purified by column chromatography (silica gel, hexane/
EtOAcZ30/10/5) to give 30 (13.4 mg, 61%) as an
inseparable mixture of two diastereomers (30a:30bZ
1.0:2.0). 30: a colorless oil; IR (film), nmax 3457, 3075,
2929, 2857, 1642, 1472, 1463, 1434, 1389, 1361, 1340,
5.1.14. (2R,3S,20R,30S)-2-{(20-Allyloxan-30-yl)oxy}pent-
4-en-1,3-diol (32a) and (2S,3S,20R,30S)-2-{(20-allyloxan-
30-yl)oxy}pent-4-en-1,3-diol (32b). To a solution of 30
(30a:30bZ1:2, 48.4 mg, 0.136 mmol) in THF (2.0 ml) was
added TBAF (0.27 ml, 1.0 M in THF, 0.272 mmol) at 24 8C
and the mixture was stirred for 20.5 h. Then, the solvent was
removed in vacuo. The resultant residue was purified by
column chromatography (silica gel, hexane/EtOAcZ3/
1/2/1/5) to give 32 (32.7 mg, 99%) as an inseparable
mixture of two diastereomers (32a:32bZ1.0:2.0). 32: a pale
yellow oil; IR (film), nmax 3423, 3074, 2938, 2855, 1641,
1479, 1463, 1433, 1375, 1340, 1280, 1213, 1099, 995, 918,
869, 856, 681 cmK1; 1H NMR (300 MHz, CDCl3), d 5.99–
5.84 (2H, m), 5.42–5.36 (1H, m), 5.25 (1H, dt, JZ10.6,
1.5 Hz), 5.16–5.07 (2H, m), 4.36 (0.33H, dd, JZ5.5,
4.0 Hz), 4.22 (0.67H, t, JZ5.5 Hz), 3.90 (1H, ddd, JZ
11.4, 4.2, 1.8 Hz), 3.79 (1H, dd, JZ11.7, 4.4 Hz), 3.71
(0.33H, dd, JZ10.6, 5.5 Hz), 3.66 (0.67H, dd, JZ11.7,
4.4 Hz), 3.50 (0.33H, dt, JZ5.5, 4.0 Hz), 3.43 (0.67H, dt,
JZ5.5, 4.4 Hz), 3.34 (1H, td, JZ11.4, 2.9 Hz), 3.28–3.21
(2H, m), 2.69–2.57 (1H, m), 2.46 (1H, brs) 2.34–2.21 (2H,
m), 1.99 (1H, brs), 1.74–1.53 (2H, m), 1.43–1.26 (1H, m);
13C NMR (75 MHz, CDCl3), d 137.0 (CH!0.67), 136.6
(CH!0.33), 135.24 (CH!0.33), 135.19 (CH!0.67), 117.1
(CH2), 116.7 (CH2!0.67), 116.6 (CH2!0.33), 80.1 (CH!
0.33), 79.8 (CH!0.67), 79.2 (CH!0.33), 78.7 (CH!0.67),
76.4 (CH!0.33), 75.7 (CH!0.67), 72.9 (CH!0.33), 72.7
(CH!0.67), 67.6 (CH2!0.33), 67.5 (CH2!0.67), 62.0
(CH2!0.33), 61.4 (CH2!0.67), 36.7 (CH2!0.33), 36.5
(CH2!0.67), 30.1 (CH2!0.33), 29.6 (CH2!0.67), 25.3
(CH2!0.33), 25.2 (CH2!0.67); LR-EIMS, m/z 242 (1.6%,
[M]C), 185 (35.3%, [MKC3H5O]C), 125 (bp); HR-EIMS,
calcd for C10H17O3 [MKC3H5O]C: 185.1178, found:
185.1200.
1279, 1257, 1186, 1098, 1030, 995, 919, 837, 814, 777 cmK1
;
1H NMR (300 MHz, CDCl3), d 5.97–5.82 (2H, m), 5.36
(0.67H, dt, JZ17.3, 1.5 Hz), 5.35 (0.33H, dt, JZ17.3,
1.5 Hz), 5.21 (1H, dt, JZ10.3, 1.5 Hz), 5.15–5.06 (2H, m),
4.32–4.17 (1H, m), 3.92–3.87 (1H, m), 3.77–3.69 (1H, m),
3.67–3.61 (1H, m), 3.51–3.41 (1H, m), 3.36–3.26 (1H, m),
3.24–3.13 (2H, m), 2.78–2.65 (2H, m), 2.30–2.13 (2H, m),
1.68–1.53 (2H, m), 1.40–1.23 (1H, m), 0.90 (9H, s), 0.06
(6H, s); 13C NMR (75 MHz, CDCl3), d 137.5 (CH!0.67),
136.9 (CH!0.33), 135.4 (CH!0.33), 135.3 (CH!0.67),
116.5 (CH2!0.33), 116.44 (CH2!0.67), 116.36 (CH2!
0.33), 116.26 (CH2!0.67), 80.34 (CH!0.33), 80.31
(CH!0.67), 79.8 (CH!0.33), 78.7 (CH!0.67), 76.7
(CH!0.33), 76.0 (CH!0.67), 73.7 (CH!0.33), 72.3
(CH!0.67), 67.7 (CH2!0.67), 67.5 (CH2!0.33), 63.8
(CH2!0.33), 62.1 (CH2!0.67), 36.6 (CH2), 30.2 (CH2!
0.33), 29.8 (CH2!0.67), 25.8 (CH3!3), 25.32 (CH2!
0.67), 25.28 (CH2!0.33), 18.1 (C), K5.47 (CH3!0.33),
K5.57 (CH3!0.33), K5.62 (CH3!0.67), K5.64 (CH3!
0.67); LR-EIMS, m/z 299 (24.8%, [MKt-Bu]C), 125 (bp);
HR-EIMS, calcd for C15H27O4Si [MKt-Bu]C: 299.1678,
found: 299.1692.
5.1.13. (1S,3S,4S,5Z,8R)-3-(tert-Butyldimethylsilyloxy-
methyl)-2,9-dioxabicyclo[6.4.0]dodec-5-en-4-ol (31). To
a solution of 30 (30a:30bZ1:2, 13.4 mg, 0.0376 mmol) in
CH2Cl2 (6.0 ml) was added a solution of (H2IMes)(PCy3)-
Cl2Ru]CHPh (3.2 mg, 3.76 mmol) in CH2Cl2 (6.0 ml). The
resultant solution was stirred at 45 8C for 6 h. The mixture
was cooled to 25 8C and stirred for 24 h under O2
atmosphere. The reaction mixture was filtered through
Celite-Florisil and concentrated in vacuo. The resultant
residue was purified by column chromatography (silica gel,
hexane/EtOAcZ15/7/3) to give 31 (5.4 mg, 44%). 31:
a yellow oil; [a]D24 K14.3 (c 0.27, CHCl3); IR (film), nmax
3610, 3428, 3025, 2928, 2856, 1471, 1462, 1439, 1388,
5.1.15. (2R,3S,40S,50R)-2-Allyl-3-{(20,20-dimethyl-40-
vinyl-10,30-dioxan-50-yl)oxy}oxane (33a) and (2R,3S,40S,
50S)-2-allyl-3-{(20,20-dimethyl-40-vinyl-10,30-dioxan-50-
yl)oxy}oxane (33b). To a solution of 32 (32a:32bZ1:2,
32.7 mg, 0.135 mmol) and 2,2-dimethoxypropane (83 ml,
0.675 mmol) in CH2Cl2 (1.5 ml) was added CSA (15.7 mg,
0.0675 mmol) at 24 8C and the mixture was stirred for 3.5 h.
Then, to the mixture was added 2,2-dimethoxypropane
(83 ml, 0.675 mmol) and stirred at 24 8C for 4 h. Then,
saturated aqueous NaHCO3 (3 ml) was added and the
mixture was extracted with Et2O (3!5 ml). The combined

7404
A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
organic layers were washed with brine, dried over
anhydrous MgSO4, filtered and concentrated in vacuo.
The resultant residue was purified by column chromato-
graphy (silica gel, hexane/EtOAcZ10/5) to give 33a
(9.0 mg, 24%) and 33b (22.8 mg, 60%). 33a: a colorless oil;
[a]2D3 C17.2 (c 0.45, CHCl3); IR (film), nmax 3074, 2991,
2939, 2852, 2726, 1641, 1462, 1433, 1409, 1372, 1340,
1261, 1225, 1201, 1167, 1097, 1022, 993, 926, 870,
JZ13.6, 7.7, 2.2 Hz), 1.67–1.64 (1H, m), 1.49 (3H, s), 1.35–
1.11 (3H, m), 1.13 (3H, s); 13C NMR (75 MHz, CDCl3), d
134.4 (CH), 126.7 (CH), 98.2 (C), 83.1 (CH), 77.2 (CH),
75.2 (CH), 72.2 (CH), 68.3 (CH2), 63.0 (CH2), 31.24 (CH2),
31.17 (CH2), 29.0 (CH3), 26.3 (CH2), 18.8 (CH3); LR-
EIMS, m/z 254 (4.1%, [M]C), 239 (38.5%, [MKCH3]C),
196 (bp); HR-EIMS, calcd for C13H19O4 [MKCH3]C:
239.1283, found: 239.1269.
1
655 cmK1; H NMR (300 MHz, C6D6), d 6.21–5.99 (2H,
m), 5.49 (1H, dd, JZ17.3, 1.3 Hz), 5.22 (1H, dd, JZ17.3,
1.8 Hz), 5.15 (1H, dd, JZ10.6, 1.3 Hz), 5.13–5.09 (1H, m),
4.15 (1H, dd, JZ9.2, 5.9 Hz), 3.79 (1H, dd, JZ11.4,
5.5 Hz), 3.66–3.64 (1H, m), 3.59 (1H, dd, JZ11.4, 9.2 Hz),
3.20 (1H, td, JZ9.2, 5.5 Hz), 3.10 (1H, td, JZ8.4, 2.9 Hz),
2.98–2.87 (2H, m), 2.82–2.74 (1H, m), 2.36–2.27 (1H, m),
1.64–1.54 (1H, m), 1.49 (3H, s), 1.35–0.89 (3H, m), 1.28
(3H, s); 13C NMR (75 MHz, CDCl3), d 135.8 (CH), 135.4
(CH), 118.4 (CH2), 116.6 (CH2), 98.5 (C), 80.5 (CH), 77.6
(CH), 74.2 (CH), 73.5 (CH), 67.6 (CH2), 64.0 (CH2), 36.5
(CH2), 31.0 (CH2), 28.7 (CH3), 25.2 (CH2), 19.3 (CH3); LR-
EIMS, m/z 267 (17.1%, [MKCH3]C), 140 (bp); HR-EIMS,
calcd for C16H26O4 [M]C: 282.1831, found: 282.1831. 33b:
a colorless oil; [a]2D4 C106.4 (c 1.14, CHCl3); IR (film),
nmax 3076, 2990, 2937, 2854, 2725, 1641, 1453, 1434, 1380,
1371, 1270, 1240, 1199, 1133, 1096, 1049, 1029, 993, 950,
5.1.17. (1S,3R,4S,5Z,8R)-3-Hydroxymethyl-2,9-dioxa-
bicyclo[6.4.0]dodec-5-en-4-ol (35). To a solution of 34
(2.9 mg, 0.0114 mmol) in THF–H2O (1:1, v/v, 0.80 ml) was
added TFA (40 ml) at 0 8C. The mixture was warmed to
23 8C and stirred for 11.5 h. After the mixture was diluted
with Et2O (3 ml), saturated aqueous NaHCO3 (5 ml) was
added. The mixture was extracted with EtOAc (4!5 ml).
The combined organic layers were washed with brine, dried
over anhydrous MgSO4, filtered and concentrated in vacuo.
The resultant residue was purified by column chromato-
graphy (silica gel, hexane/EtOAcZ1/1/5) to give 35
(1.7 mg, 71%). 35: a colorless oil; [a]2D3 K38.5 (c 0.085,
CHCl3); IR (film), nmax 3413, 3023, 2932, 2856, 1678, 1439,
1377, 1334, 1308, 1281, 1264, 1205, 1144, 1117, 1085,
1033, 979, 959, 918, 909, 855, 844, 760, 699, 647 cmK1; 1H
NMR (400 MHz, C5D5N), d 6.23 (1H, dd, JZ11.0, 5.9 Hz),
5.90–5.82 (1H, m), 4.85 (1H, ddd, JZ8.8, 5.9, 2.0 Hz), 4.45
(1H, dd, JZ11.5, 3.4 Hz), 4.24 (1H, dd, JZ11.5, 5.9 Hz),
3.80–3.77 (1H, m), 3.77 (1H, ddd, JZ8.8, 5.9, 3.4 Hz), 3.60
(1H, td, JZ9.3, 4.4 Hz), 3.31 (1H, ddd, JZ9.3, 4.4, 2.0 Hz),
3.17 (1H, td, JZ11.2, 2.9 Hz), 2.91 (1H, ddd, JZ13.7, 9.8,
4.4 Hz), 2.34 (1H, ddd, JZ13.7, 6.8, 2.0 Hz), 2.06–2.04
(1H, m), 1.50–1.39 (3H, m); 13C NMR (75 MHz, CDCl3), d
136.7 (CH), 127.0 (CH), 83.1 (CH), 82.8 (CH), 77.5 (CH),
70.8 (CH), 68.3 (CH2), 64.2 (CH2), 31.0 (CH2), 29.7 (CH2),
26.2 (CH2); LR-EIMS, m/z 214 (20.0%, [M]C), 71 (bp);
HR-EIMS, calcd for C11H18O4 [M]C: 214.1205, found:
214.1232.
1
920, 886, 857, 811 cmK1; H NMR (300 MHz, C6D6), d
6.32–6.18 (1H, m), 6.08 (1H, ddd, JZ17.3, 10.3, 6.2 Hz),
5.37–5.32 (1H, m), 5.23 (1H, dt, JZ17.3, 1.8 Hz), 5.18–
5.13 (1H, m), 5.08 (1H, ddd, JZ10.3, 1.8, 1.1 Hz), 4.11
(1H, ddt, JZ6.2, 1.8, 1.1 Hz), 3.74 (1H, dd, JZ12.8,
1.8 Hz), 3.73–3.69 (1H, m), 3.45 (1H, dd, JZ12.8, 1.8 Hz),
3.25 (1H, ddd, JZ8.8, 7.3, 3.3 Hz), 3.05–2.96 (1H, m), 3.03
(1H, td, JZ11.6, 2.5 Hz), 2.87 (1H, ddd, JZ10.3, 8.8,
4.4 Hz), 2.64 (1H, q, JZ1.8 Hz), 2.56 (1H, dt, JZ14.3,
7.3 Hz), 1.75–1.71 (1H, m), 1.50 (3H, s), 1.37–1.01 (3H, m),
1.26 (3H, s); 13C NMR (75 MHz, CDCl3), d 135.9 (CH),
135.5 (CH), 117.0 (CH2), 116.5 (CH2), 98.6 (C), 80.1 (CH),
74.9 (CH), 73.3 (CH), 70.5 (CH), 67.8 (CH2), 61.7 (CH2),
36.4 (CH2), 29.3 (CH3), 29.1 (CH2), 25.4 (CH2), 19.0
(CH3); LR-EIMS, m/z 282 (1.9%, [M]C), 267 (52.4%, [MK
CH3]C), 125 (bp); HR-EIMS, calcd for C16H26O4 [M]C:
282.1831, found: 282.1824.
5.1.18. (1R,3S,4R,6Z,9S,11R)-4-(tert-Butyldimethylsilyl-
oxy)-3-hydroxymethyl-11-phenyl-2,10,12-trioxabicyclo-
[7.4.0]tridec-6-ene (37). To a solution of 36 (87.0 mg,
0.160 mmol) in THF–H2O (1:1, v/v, 2.0 ml) was added TFA
(100 ml) at 0 8C and the mixture was stirred for 4 h. After the
mixture was diluted with Et2O (5 ml), saturated aqueous
NaHCO3 (5 ml) was added and the mixture was extracted
with EtOAc (3!5 ml). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The resultant residue was
purified by column chromatography (silica gel, hexane/
EtOAcZ10/3) to give 37 (46.5 mg, 68%) along with
recovered 36 (21.2 mg, 24%). 37: a colorless oil; [a]2D1 K2.2
(c 0.34, CHCl3); IR (film), nmax 3478, 3018, 2955, 2929,
2857, 1471, 1462, 1455, 1390, 1360, 1340, 1294, 1252,
1213, 1139, 1104, 1074, 1041, 1028, 971, 940, 889, 777,
5.1.16. (1S,3R,8S,9Z,12R)-6,6-Dimethyl-2,5,7,13-tetra-
oxatricyclo[10.4.0.03,8]hexadeca-9-ene (34). To a solution
of 33a (3.9 mg, 0.0138 mmol) in CH2Cl2 (2.5 ml) was
added a solution of (H2IMes)(PCy3)Cl2Ru]CHPh (1.2 mg,
1.38 mmol) in CH2Cl2 (1.0 ml). The resultant solution was
stirred at 45 8C for 4.5 h. The mixture was cooled to 24 8C
and stirred for 14 h under O2 atmosphere. The reaction
mixture was filtered through Celite-Florisil and concen-
trated in vacuo. The resultant residue was purified by
column chromatography (silica gel, hexane/EtOAcZ10/
5) to give 34 (2.9 mg, 83%). 34: a colorless oil; [a]2D2 K79.9
(c 0.15, CHCl3); IR (film), nmax 3032, 2991, 2924, 2851,
2722, 1462, 1439, 1372, 1333, 1305, 1298, 1285, 1265,
1223, 1198, 1163, 1147, 1102, 1088, 1050, 1032, 987, 959,
943, 866, 843, 758, 645 cmK1; 1H NMR (300 MHz, C6D6),
d 5.95 (1H, dd, JZ10.6, 4.8 Hz), 5.87–5.77 (1H, m), 4.54–
4.49 (1H, m), 3.92 (1H, dd, JZ11.2, 5.7 Hz), 3.65 (1H, dd,
JZ11.2, 10.1 Hz), 3.65–3.60 (1H, m), 3.32–3.22 (2H, m),
3.15 (1H, ddd, JZ9.2, 4.8, 2.2 Hz), 2.95 (1H, td, JZ11.6,
2.6 Hz), 2.72 (1H, ddd, JZ13.6, 8.8, 4.8 Hz), 2.33 (1H, ddd,
1
697, 673 cmK1; H NMR (300 MHz, CDCl3), d 7.37–7.22
(5H, m), 5.73–5.62 (2H, m), 5.31 (1H, s), 4.25 (1H, dd, JZ
9.3, 3.4 Hz), 3.74–3.70 (1H, m), 3.59–3.52 (3H, m), 3.49–
3.42 (2H, m), 3.27–3.22 (1H, m), 2.67–2.61 (1H, m), 2.44–
2.40 (3H, m), 0.78 (9H, s), 0.11 (3H, s), 0.08 (3H, s); LR-
EIMS, m/z 363 (53.8%, [MKt-Bu]C), 75 (bp); HR-EIMS,
calcd for C19H27O5Si [MKt-Bu]C: 363.1628, found:
363.1650.

A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
7405
5.1.19. (2R,3S,5Z,8R,9S)-8-(tert-Butyldimethylsilyloxy)-
2-hydroxymethyl-9-vinyl-2,3,4,7,8,9-hexahydrooxonin-
3-ol (38). To oxalyl chloride (157 ml, 1.80 mmol) in CH2Cl2
(2.0 ml) was added DMSO (0.21 ml, 3.00 mmol) in CH2Cl2
(1.0 ml) dropwise at K78 8C and the mixture was stirred for
10 min. Then, 37 (259.1 mg, 0.599 mmol) in CH2Cl2
(0.9 ml) was added dropwise at K78 8C and the mixture
was stirred for 15 min. Et3N (0.83 ml, 5.99 mmol) was
added dropwise at K78 8C. The mixture was warmed to
K20 8C and stirred for 10 min. Then, saturated aqueous
NaHCO3 (5 ml) was added and the mixture was extracted
with Et2O (3!8 ml). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The resultant crude aldehyde
was used immediately in the next reaction without
purification. To a stirred suspension of Ph3PCCH3BrK
(1.07 g, 3.00 mmol) in THF (4.0 ml) was added NaHMDS
(2.88 ml, 1.0 M in THF, 2.88 mmol) and the mixture was
stirred at 24 8C. After 1 h, the resulting yellow suspension
was allowed to stand at K78 8C. To the mixture was added
dropwise a solution of the above crude aldehyde in THF
(4.0 ml) at K78 8C and the mixture was stirred for 2.5 h.
Then, the reaction mixture was warmed to 25 8C and stirred
for 2.5 h. After the mixture was diluted with hexane (10 ml)
and Et2O (5 ml), saturated aqueous NH4Cl (10 ml) was
added and the mixture was extracted with Et2O (3!10 ml).
The combined organic layers were washed with brine, dried
over anhydrous MgSO4, filtered and concentrated in vacuo.
The resultant residue was roughly purified by column
chromatography (silica gel, hexane/EtOAcZ20) to give a
crude olefin compound, and it was used in the next reaction
without further purification. To a suspension of the above
olefin compound, 1,2-ehtanedithiol (0.79 ml, 9.40 mmol)
and NaHCO3 (394.8 mg, 4.70 mmol) in CH2Cl2 (7.0 ml)
was added Zn(OTf)2 (170.8 mg, 0.470 mmol) at 0 8C and
the mixture was stirred for 2.5 h. After the mixture was
diluted with Et2O (5 ml), saturated aqueous NaHCO3 (5 ml)
and H2O (5 ml) were added and the mixture was extracted
with Et2O–EtOAc (1:1, v/v, 3!10 ml). The combined
organic layers were washed with brine, dried over
anhydrous MgSO4, filtered and concentrated in vacuo.
The resultant residue was purified by column chromato-
graphy (silica gel, hexane/EtOAcZ3/1) to give 38
(113.5 mg, 58% from 37). 38: a colorless oil; [a]2D4 K46.9
(c 0.21, CHCl3); IR (film), nmax 3584, 3382, 3018, 2955,
2928, 2858, 1472, 1462, 1449, 1256, 1098, 1051, 933, 833,
811, 775, 664 cmK1; 1H NMR (300 MHz, CDCl3), d 5.91–
5.78 (3H, m), 5.25 (1H, dt, JZ17.3, 1.1 Hz), 5.19 (1H, dt,
JZ10.3, 1.1 Hz), 4.02–3.94 (1H, m), 3.74–3.69 (3H, m),
3.52 (1H, brtd, JZ8.4, 1.1 Hz), 3.23 (1H, dt, JZ8.8,
4.4 Hz), 2.83–2.73 (2H, m), 2.23–1.99 (4H, m), 0.87 (9H, s),
0.06 (3H, s), 0.01 (3H, s); 13C NMR (75 MHz, CDCl3), d
139.5 (CH), 128.6 (CH), 127.2 (CH), 117.2 (CH2), 89.0
(CH), 86.7 (CH), 74.5 (CH), 71.6 (CH), 63.8 (CH2), 32.9
(CH2), 32.5 (CH2), 25.7 (CH3!3), 17.9 (C), K4.44 (CH3),
K4.59 (CH3); LR-EIMS, m/z 271 (15.3%, [MKt-Bu]C), 73
(bp); HR-EIMS, calcd for C13H23O4Si [MKt-Bu]C:
271.1365, found: 271.1360.
0 8C and the mixture was stirred for 20 min. Then, to the
mixture was added benzyl bromide (0.25 ml, 2.07 mmol)
and TBAI (12.7 mg, 0.0345 mmol) at 0 8C. The reaction
mixture was warmed to 24 8C and stirred for 15 h. After the
mixture was cooled to 0 8C and diluted with Et2O (5 ml),
saturated aqueous NH4Cl (10 ml) was added and the
mixture was extracted with Et2O (3!5 ml). The combined
organic layers were washed with brine, dried over
anhydrous MgSO4, filtered and concentrated in vacuo.
The resultant residue was roughly purified by column
chromatography (silica gel, hexane/EtOAcZ20) to give a
crude product, and it was used in the next reaction without
further purification. To a solution of the above crude product
in THF (3.0 ml) was added TBAF (0.69 ml, 1.0 M in THF,
0.690 mmol) at 25 8C and the mixture was stirred for 4 h.
Since TLC analysis showed the starting material remained,
TBAF (2.41 ml, 1.0 M in THF, 2.41 mmol) was added, and
the stirring was continued for further 14 h. The solvent was
removed in vacuo. The resultant residue was purified by
column chromatography (silica gel, hexane/EtOAcZ5/3)
to give 5 (135.8 mg, 100% from 38) 5: a colorless oil; [a]D27
C28.3 (c 0.33, CHCl3); IR (film), nmax 3439, 3087, 3063,
3027, 2913, 2864, 1495, 1453, 1364, 1338, 1317, 1274,
1257, 1207, 1097, 1070, 1043, 1027, 928, 773, 736,
697 cmK1 1H NMR (300 MHz, CDCl3), d 7.37–7.20
;
(10H, m), 5.96–5.77 (3H, m), 5.28–5.22 (1H, m), 5.19–
5.15 (1H, m), 4.59 (1H, d, JZ11.4 Hz), 4.54 (1H, d, JZ
12.5 Hz), 4.41 (1H, d, JZ12.5 Hz), 4.29 (1H, d, JZ
11.4 Hz), 3.93 (1H, dt, JZ8.4, 3.7 Hz), 3.72 (1H, ddd, JZ
8.8, 4.0, 2.9 Hz), 3.53 (1H, dd, JZ10.3, 2.9 Hz), 3.49 (1H,
dd, JZ10.3, 2.9 Hz), 3.44 (1H, brt, JZ8.8 Hz), 3.28 (1H, dt,
JZ8.4, 2.9 Hz), 2.95–2.86 (1H, m), 2.74–2.65 (1H, m), 2.35
(1H, brdt, JZ13.9, 4.0 Hz), 2.21–2.17 (1H, m); 13C NMR
(75 MHz, CDCl3), d 139.0 (CH), 138.4 (C), 138.2 (C), 128.7
(CH), 128.3 (CH!2), 128.2 (CH!2), 128.0 (CH!2),
127.8 (CH!2), 127.5 (CH!2), 127.3 (CH), 117.7 (CH2),
88.7 (CH), 84.3 (CH), 78.1 (CH), 73.2 (CH2), 72.7 (CH),
71.6 (CH2), 69.3 (CH2), 31.3 (CH2), 27.4 (CH2); LR-EIMS,
m/z 394 (11.4%, [M]C), 92 (bp); HR-EIMS, calcd for
C25H30O4 [M]C: 394.2144, found: 394.2145.
5.1.21. Methyl (2E,20S,30R,50Z,80S,90R)-3-{(80-benzyloxy-
90-benzyloxymethyl-20-vinyl-20,30,40,70,80,90-hexahydro-
oxonin-30-yl)oxy}-4-(tert-butyldimethylsilyloxy)-2-
butenoate (39). A solution of butynoate 20 (148.0 mg,
0.648 mmol) in CH2Cl2 (2.0 ml) was slowly added dropwise
to a solution of 5 (85.4 mg, 0.216 mmol) and PMe3
(0.32 ml, 1.0 M in THF, 0.324 mmol) in CH2Cl2 (3.0 ml)
at 0 8C by means of a syringe. The mixture was warmed to
24 8C and stirred for 1 h. The mixture was cooled to 0 8C
and diluted with hexane (5 ml) and Et2O (5 ml). Then,
saturated aqueous NH4Cl (5 ml) was added and the mixture
was extracted with Et2O (3!8 ml). The combined organic
layers were washed with brine, dried over anhydrous
MgSO4, filtered and concentrated in vacuo. The resultant
residue was purified by column chromatography (silica gel,
hexane/EtOAcZ30/20/10) to give 39 (121.5 mg, 90%).
39: a colorless oil; [a]D23 C24.8 (c 0.91, CHCl3); IR (film),
nmax 3027, 2949, 2928, 2857, 1716, 1626, 1471, 1453, 1434,
1389, 1360, 1297, 1253, 1206, 1138, 1096, 1048, 837, 776,
5.1.20. (2S,3R,5Z,8S,9R)-8-Benzyloxy-9-benzyloxy-
methyl-2-vinyl-2,3,4,7,8,9-hexahydrooxonin-3-ol (5). To
a solution of 38 (113.5 mg, 0.345 mmol) in THF (4.0 ml)
was added NaH (165.7 mg, 60 wt% in oil, 4.14 mmol) at
1
735, 697 cmK1; H NMR (300 MHz, CDCl3), d 7.34–7.19
(10H, m), 5.94–5.80 (2H, m), 5.70 (1H, td, JZ10.8, 5.5 Hz),
5.32 (1H, dt, JZ17.2, 1.4 Hz), 5.07 (1H, dt, JZ10.5,

7406
A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
1.4 Hz), 4.99 (1H, s), 4.80 (1H, d, JZ13.3 Hz), 4.68 (1H, d,
JZ13.3 Hz), 4.59 (1H, d, JZ11.2 Hz), 4.54 (1H, d, JZ
12.2 Hz), 4.40 (1H, d, JZ12.2 Hz), 4.29 (1H, d, JZ
11.2 Hz), 4.23–4.20 (1H, m), 3.98 (1H, dt, JZ8.8, 3.0 Hz),
3.80–3.76 (1H, m), 3.66 (3H, s), 3.59 (1H, dd, JZ10.1,
2.4 Hz), 3.53 (1H, dd, JZ10.1, 2.4 Hz), 3.28 (1H, brdt, JZ
8.8, 2.4 Hz), 2.86–2.76 (1H, m), 2.74–2.65 (1H, m), 2.39–
2.30 (2H, m), 0.89 (9H, s), 0.07 (6H, s); 13C NMR (75 MHz,
CDCl3), d 170.5 (C), 167.4 (C), 138.3 (C), 138.1 (C), 137.8
(CH), 129.1 (CH), 128.3 (CH!2), 128.2 (CH!2), 128.1
(CH!2), 127.8 (CH!2), 127.6 (CH!2), 126.6 (CH),
116.4 (CH2), 92.6 (CH), 84.9 (CH), 84.7 (CH), 79.6 (CH),
77.5 (CH), 73.3 (CH2), 71.7 (CH2), 68.9 (CH2), 60.1 (CH2),
50.9 (CH3), 27.4 (CH2), 27.0 (CH2), 25.8 (CH3!3), 18.3
(C), K5.26 (CH3), K5.28 (CH3); LR-EIMS, m/z 565 (2.3%,
[MKt-Bu]C), 91 (bp); HR-EIMS, calcd for C32H41O7Si
[MKt-Bu]C: 565.2621, found: 565.2660.
(16.7 mg, 0.144 mmol) at 24 8C and the mixture was stirred
for 10 min. Then, TPAP (5.1 mg, 0.0144 mmol) was added
to the reaction mixture at 24 8C and the mixture was stirred
for 1.5 h. The mixture was filtered through Celite and
concentrated in vacuo. The resultant residue was purified by
column chromatography (silica gel, hexane/EtOAcZ10/
5) to give 41 (32.5 mg, 76%). 41: a colorless oil; [a]D26
C33.2 (c 0.52, CHCl3); IR (film), nmax 3087, 3064, 3027,
2953, 2928, 2885, 2857, 2766, 1663, 1615, 1496, 1471,
1462, 1389, 1361, 1321, 1295, 1255, 1207, 1144, 1097,
1037, 1006, 921, 837, 777, 736, 698 cmK1 1H NMR
;
(300 MHz, CDCl3), d 9.98 (1H, d, JZ7.3 Hz), 7.35–7.20
(10H, m), 5.91–5.79 (2H, m), 5.66 (1H, td, JZ10.7, 5.9 Hz),
5.35 (1H, d, JZ7.3 Hz), 5.28 (1H, dt, JZ17.3, 1.3 Hz), 5.08
(1H, dt, JZ10.3, 1.3 Hz), 4.60 (1H, d, JZ11.0 Hz), 4.53
(1H, d, JZ12.1 Hz), 4.51 (1H, d, JZ13.2 Hz), 4.41 (1H, d,
JZ12.1 Hz), 4.39 (1H, d, JZ13.2 Hz), 4.29 (1H, d, JZ
11.0 Hz), 4.25–4.20 (1H, m), 4.00–3.94 (1H, m), 3.79–3.74
(1H, m), 3.58 (1H, dd, JZ9.9, 2.8 Hz), 3.52 (1H, dd, JZ9.9,
2.4 Hz), 3.29 (1H, brdt, JZ8.8, 2.8 Hz), 2.88–2.79 (1H, m),
2.73–2.63 (1H, m), 2.40–2.26 (2H, m), 0.90 (9H, s), 0.09
(3H, s), 0.08 (3H, s); 13C NMR (75 MHz, CDCl3), d 190.5
(CH), 174.2 (C), 138.2 (C), 138.1 (C), 137.5 (CH), 129.6
(CH), 128.32 (CH!2), 128.26 (CH!2), 128.1 (CH!2),
127.8 (CH!2), 127.6 (CH!2), 126.0 (CH), 117.1 (CH2),
106.6 (CH), 84.8 (CH), 84.6 (CH), 79.9 (CH), 77.6 (CH),
73.3 (CH2), 71.7 (CH2), 68.9 (CH2), 61.6 (CH2), 27.4 (CH2),
27.0 (CH2), 25.7 (CH3!3), 18.2 (C), K5.33 (CH3), K5.36
(CH3); LR-EIMS, m/z 535 (29.5%, [MKt-Bu]C), 50 (bp);
HR-EIMS, calcd for C31H39O6Si [MKt-Bu]C: 535.2516,
found: 535.2514.
5.1 .22. (2E,20S,30R,50Z,80S,90R)-3-{(80-Benzyloxy-90-ben-
zyloxymethyl-20-vinyl-20,30,40,70,80,90-hexahydrooxonin-
30-yl)oxy}-4-(tert-butyldimethylsilyloxy)-2-butenol (40).
To a solution of 39 (50.2 mg, 0.0806 mmol) in CH2Cl2
(1.5 ml) was added DIBAH (0.34 ml, 0.94 M in n-hexane,
0.322 mmol) at K78 8C and the mixture was stirred for
10 min. Then, saturated aqueous potassium sodium tartrate
(5 ml) was added and the mixture was stirred at 24 8C for
3 h. The layers were separated and the aqueous layer was
extracted with EtOAc (3!5 ml). The combined organic
layers were washed with brine, dried over anhydrous
MgSO4, filtered and concentrated in vacuo. The resultant
residue was purified by column chromatography (silica gel,
hexane/EtOAcZ10/5/3) to give 40 (47.4 mg, 99%). 40:
a colorless oil; [a]D22 C14.4 (c 0.39, CHCl3); IR (film), nmax
3584, 3416, 3087, 3064, 3027, 2952, 2927, 2857, 1660,
1496, 1471, 1462, 1454, 1389, 1360, 1337, 1319, 1295,
1274, 1253, 1203, 1183, 1145, 1096, 1027, 1004, 960, 929,
5.1.24. (3E,20S,30R,50Z,80S,90R)-4-{(80-Benzyloxy-90-ben-
zyloxymethyl-20-vinyl-20,30,40,70,80,90-hexahydrooxonin-
30-yl)oxy}-5-(tert-butyldimethylsilyloxy)-2-(trimethyl-
silyloxy)pent-3-enenitrile (42). To a solution of 41
(5.2 mg, 8.77 mmol) and TMSCN (5.8 ml, 0.0439 mmol) in
benzene (0.40 ml) was added Me3Al (9.6 ml, 1.01 M in
n-hexane, 9.65 mmol) at 24 8C and the mixture was stirred
for 1 h. Then, saturated aqueous NaHCO3 (5 ml) was added
and the mixture was extracted with Et2O (3!5 ml). The
combined organic layers were washed with brine, dried over
anhydrous MgSO4, filtered and concentrated in vacuo. The
resultant residue was purified by column chromatography
(silica gel, hexane/EtOAcZ20/10) to give 42 (4.8 mg,
79%) as an inseparable 1:1 mixture of diastereomers. The
nitrile 42 was unstable and immediately used for the next
reaction. 42: a colorless oil; 1H NMR (300 MHz, CDCl3), d
7.31–7.20 (10H, m), 5.91–5.78 (2H, m), 5.72–5.62 (1H, m),
5.60 (0.5H, d, JZ9.0 Hz), 5.58 (0.5H, d, JZ9.0 Hz), 5.29–
5.23 (1H, m), 5.10–5.03 (1H, m), 4.68–4.65 (1H, m), 4.60
(1H, d, JZ11.2 Hz), 4.56–4.52 (1H, m), 4.41 (0.5H, d, JZ
12.3 Hz), 4.40 (0.5H, d, JZ12.3 Hz), 4.30 (0.5H, d, JZ
11.2 Hz), 4.29 (0.5H, d, JZ11.2 Hz), 4.19–4.04 (3H, m),
4.00–3.94 (1H, m), 3.68–3.60 (1H, m), 3.57–3.49 (2H, m),
3.29–3.26 (1H, m), 2.82–2.64 (1H, m), 2.39–2.27 (2H, m),
0.91 (4.5H, s), 0.90 (4.5H, s), 0.20 (4.5H, s), 0.18 (4.5H, s),
0.10 (1.5H, s), 0.09 (1.5H, s), 0.08 (3H, s); 13C NMR
(75 MHz, CDCl3), d 157.3 (C!0.5), 156.9 (C!0.5), 138.3
(C), 138.18 (CH!0.5), 138.16 (C), 138.0 (CH!0.5), 129.0
(CH!0.5), 128.9 (CH!0.5), 128.33 (CH!2), 128.26
(CH!2), 128.1 (CH!2), 127.9 (CH!2), 127.6 (CH!2),
126.9 (CH!0.5), 126.8 (CH!0.5), 120.0 (C!0.5), 119.9
1
836, 815, 776, 735, 697, 673 cmK1; H NMR (300 MHz,
CDCl3), d 7.33–7.20 (10H, m), 5.94–5.77 (2H, m), 5.69 (1H,
td, JZ10.6, 5.4 Hz), 5.28 (1H, dt, JZ17.3, 1.7 Hz), 5.05
(1H, ddd, JZ10.5, 1.7, 1.1 Hz), 4.88 (1H, t, JZ8.1 Hz),
4.59 (1H, d, JZ11.2 Hz), 4.54 (1H, d, JZ12.3 Hz), 4.40
(1H, d, JZ12.3 Hz), 4.29 (1H, d, JZ11.2 Hz), 4.19 (1H, d,
JZ12.3 Hz), 4.16–4.09 (2H, m), 4.11 (1H, d, JZ12.3 Hz),
4.11–4.08 (1H, m), 3.99–3.94 (1H, m), 3.70–3.65 (1H, m),
3.59 (1H, dd, JZ10.1, 2.8 Hz), 3.53 (1H, dd, JZ10.1,
2.2 Hz), 3.30–3.26 (1H, m), 2.78–2.66 (1H, m), 2.40–2.31
(2H, m), 0.90 (9H, s), 0.09 (3H, s), 0.08 (3H, s); 13C NMR
(75 MHz, CDCl3), d 157.4 (C), 138.4 (CH), 138.3 (C),
138.2 (C), 128.5 (CH), 128.3 (CH!2), 128.2 (CH!2),
128.1 (CH!2), 127.8 (CH!2), 127.6 (CH!2), 127.4
(CH), 115.9 (CH2), 101.0 (CH), 85.5 (CH), 84.5 (CH),
78.0 (CH), 77.6 (CH), 73.3 (CH2), 71.6 (CH2), 69.0 (CH2),
61.5 (CH2), 58.2 (CH2), 27.4 (CH2), 26.8 (CH2), 25.8
(CH3!3), 18.2 (C), K5.30 (CH3), K5.33 (CH3);
LR-EIMS, m/z 537 (3.0%, [MKt-Bu]C), 91 (bp); HR-
EIMS, calcd for C31H41O6Si [MKt-Bu]C: 537.2672, found:
537.2698.
5.1.23. (2E,20S,30R,50Z,80S,90R)-3-{(80-Benzyloxy-90-ben-
zyloxymethyl-20-vinyl-20,30,40,70,80,90-hexahydrooxonin-
30-yl)oxy}-4-(tert-butyldimethylsilyloxy)-2-butenal (41).
˚
To a mixture of 40 (42.8 mg, 0.0720 mmol) and MS 4 A
(42.8 mg, 100 wt%) in CH2Cl2 (1.2 ml) was added NMO

A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
7407
(C!0.5), 116.6 (CH2!0.5), 116.3 (CH2!0.5), 99.3 (CH!
0.5), 99.1 (CH!0.5), 85.4 (CH!0.5), 85.3 (CH!0.5), 84.6
(CH!0.5), 84.5 (CH!0.5), 78.7 (CH!0.5), 78.5 (CH!
0.5), 77.6 (CH), 73.3 (CH2), 71.6 (CH2!0.5), 71.3 (CH2!
0.5), 69.0 (CH2), 62.4 (CH2!0.5), 62.2 (CH2!0.5), 57.7
(CH!0.5), 57.6 (CH!0.5), 27.4 (CH2), 26.9 (CH2), 25.8
(CH3!3), 18.3 (C), 0.02 (CH3!1.5), K0.05 (CH3!1.5),
K5.38 (CH3!0.5), K5.40 (CH3!0.5), K5.51 (CH3!
0.5), K5.54 (CH3!0.5).
10 min. Then, saturated aqueous potassium sodium tartrate
(5 ml) was added and the mixture was stirred at 24 8C for
10 h. The layers were separated and the aqueous layer was
extracted with Et2O (3!5 ml). The combined organic
layers were washed with brine, dried over anhydrous
MgSO4, filtered and concentrated in vacuo. The resultant
residue was purified by column chromatography (silica gel,
hexane/EtOAcZ20/10/5) to give 44 (39.6 mg,
w100%) as an inseparable 1:1 mixture of diastereomers
at C2.35 44: a colorless oil; IR (film), nmax 3064, 3027,
2953, 2927, 2858, 2736, 1694, 1496, 1471, 1462, 1454,
1377, 1361, 1329, 1294, 1254, 1206, 1099, 1069, 1027,
5.1.25. (2E,20S,30R,50Z,80S,90R)-4-{(80-Benzyloxy-90-ben-
zyloxymethyl-20-vinyl-20,30,40,70,80,90-hexahydrooxonin-
30-yl)oxy}-5-(tert-butyldimethylsilyloxy)pent-2-ene-
nitrile (43). To a solution of 42 (58.8 mg, 0.0850 mmol) in
CH2Cl2–Bu3SnH (1:1, v/v, 1.0 ml) was added BF3$OEt2
(31 ml, 0.255 mmol) at K18 8C and the mixture was stirred
for 15 min. Then, saturated aqueous NaHCO3 (5 ml) was
added and the mixture was extracted with EtOAc (3!5 ml).
The combined organic layers were washed with brine, dried
over anhydrous MgSO4, filtered and concentrated in vacuo.
The resultant residue was purified by column chromato-
graphy (silica gel, hexane/EtOAcZ50/10/5) to give 43
(28.3 mg, 55%) as an inseparable 1:1 mixture of dia-
stereomers at C235 along with recovered 42 (10.7 mg, 18%).
43: a colorless oil; IR (film), nmax 3064, 3027, 2954, 2927,
2858, 2225, 1496, 1471, 1462, 1454, 1388, 1361, 1331,
1294, 1254, 1204, 1098, 1027, 1005, 967, 928, 837, 814,
1
1005, 981, 928, 837, 814, 776, 736, 698 cmK1; H NMR
(300 MHz, CDCl3), d 9.58 (0.5H, d, JZ8.1 Hz), 9.52 (0.5H,
d, JZ8.1 Hz), 7.31–7.20 (10H, m), 6.88 (0.5H, dd, JZ15.8,
4.8 Hz), 6.66 (0.5H, dd, JZ15.8, 5.5 Hz), 6.35 (0.5H, ddd,
JZ15.8, 8.1, 1.5 Hz), 6.29 (0.5H, ddd, JZ15.8, 8.1,
1.5 Hz), 6.03–5.69 (3H, m), 5.33–5.28 (1H, m), 5.11–5.06
(1H, m), 4.58 (1H, d, JZ11.4 Hz), 4.53 (0.5H, d, JZ
12.1 Hz), 4.52 (0.5H, d, JZ12.1 Hz), 4.39 (1H, d, JZ
12.1 Hz), 4.28 (0.5H, d, JZ11.4 Hz), 4.27 (0.5H, d, JZ
11.4 Hz), 4.19–4.18 (1H, m), 3.96 (1H, brdt, JZ8.6,
3.1 Hz), 3.76–3.44 (6H, m), 3.24–3.21 (1H, m), 2.82–2.62
(2H, m), 2.36–2.29 (1H, m), 2.25–2.19 (0.5H, m), 2.12–2.10
(0.5H, m), 0.88 (4.5H, s), 0.87 (4.5H, s), 0.06 (1.5H, s), 0.05
(1.5H, s), 0.04 (3H, s); LR-EIMS, m/z 606 (12.9%, [M]C),
213 (bp); HR-EIMS, calcd for C32H41O6Si [MKt-Bu]C:
549.2672, found: 549.2669.
1
776, 736, 698, 670 cmK1; H NMR (300 MHz, CDCl3), d
7.39–7.20 (10H, m), 6.81 (0.5H, dd, JZ16.5, 4.4 Hz), 6.62
(0.5H, dd, JZ16.5, 4.8 Hz), 5.99–5.70 (3H, m), 5.68 (0.5H,
dd, JZ16.5, 1.8 Hz), 5.65 (0.5H, dd, JZ16.5, 1.5 Hz),
5.32–5.21 (1H, m), 5.12 (0.5H, dd, JZ10.3, 1.8 Hz), 5.08
(0.5H, dd, JZ10.3, 1.8 Hz), 4.59 (1H, d, JZ11.4 Hz), 4.53
(0.5H, d, JZ12.1 Hz), 4.52 (0.5H, d, JZ12.5 Hz), 4.40
(0.5H, d, JZ12.5 Hz), 4.38 (0.5H, d, JZ12.1 Hz), 4.28 (1H,
d, JZ11.4 Hz), 4.08–3.93 (2H, m), 3.69–3.46 (5H, m), 3.38
(1H, dd, JZ9.9, 7.3 Hz), 3.24–3.20 (1H, m), 2.82–2.74 (1H,
m), 2.67 (1H, ddd, JZ13.9, 10.6, 3.3 Hz), 2.36–2.29 (1H,
m), 2.21–2.17 (0.5H, m), 2.08–2.02 (0.5H, m), 0.88 (4.5H,
s), 0.87 (4.5H, s), 0.05 (1.5H, s), 0.04 (1.5H, s), 0.03 (3H, s);
13C NMR (75 MHz, CDCl3), d 153.7 (CH!0.5), 152.7
(CH!0.5), 138.9 (CH!0.5), 138.8 (CH!0.5), 138.4 (C),
138.3 (C), 128.8 (CH!0.5), 128.5 (CH!0.5), 128.32
(CH!2), 128.26 (CH!2), 128.1 (CH!2), 127.8 (CH!2),
127.6 (CH!2), 127.4 (CH!0.5), 127.1 (CH!0.5), 117.4
(CH2!0.5), 117.2 (C!0.5), 117.1 (C!0.5), 116.1 (CH2!
0.5), 101.1 (CH!0.5), 100.2 (CH!0.5), 86.4 (CH!0.5),
85.9 (CH!0.5), 84.6 (CH!0.5), 84.5 (CH!0.5), 82.7
(CH!0.5), 81.6 (CH!0.5), 78.4 (CH!0.5), 78.2 (CH!
0.5), 77.7 (CH!0.5), 77.4 (CH!0.5), 73.3 (CH2), 71.6
(CH2), 68.8 (CH2), 65.2 (CH2!0.5), 64.2 (CH2!0.5), 28.9
(CH2), 28.7 (CH2), 25.8 (CH3!3), 18.23 (C!0.5), 18.19
(C!0.5), K5.41 (CH3!0.5), K5.50 (CH3!0.5), K5.52
(CH3!0.5), K5.63 (CH3!0.5); LR-EIMS, m/z 546 (6.0%,
[MKt-Bu]C), 91 (bp); HR-EIMS, calcd for C32H40NO5Si
[MKt-Bu]C: 546.2675, found: 546.2678.
5.1.27. (2E,20S,30R,50Z,80S,90R)-4-{(80-Benzyloxy-90-ben-
zyloxymethyl-20-vinyl-20,30,40,70,80,90-hexahydrooxonin-
30-yl)oxy}-5-(tert-butyldimethylsilyloxy)-2-pentenol (45).
To a solution of 44 (39.6 mg, 0.0652 mmol) in CH2Cl2
(1.5 ml) was added DIBAH (0.21 ml, 0.94 M in n-hexane,
0.196 mmol) at K78 8C and the mixture was stirred for
20 min. Then, saturated aqueous potassium sodium tartrate
(5 ml) was added and the mixture was stirred at 24 8C for
2 h. The layers were separated and the aqueous layer was
extracted with EtOAc (3!5 ml). The combined organic
layers were washed with brine, dried over anhydrous
MgSO4, filtered and concentrated in vacuo. The resultant
residue was purified by column chromatography (silica gel,
hexane/EtOAcZ10/3) to give 45 (28.5 mg, 72% from 43)
as an inseparable 1:1 mixture of diastereomers at C2.35 45: a
colorless oil; IR (film), nmax 3584, 3443, 3087, 3064, 3027,
2952, 2927, 2857, 1496, 1471, 1454, 1388, 1360, 1336,
1294, 1256, 1206, 1098, 1068, 1027, 1005, 928, 836, 815,
775, 736, 697 cmK1; 1H NMR (300 MHz, CDCl3), d 7.32–
7.19 (10H, m), 6.09–5.76 (4H, m), 5.74–5.66 (0.5H, m),
5.46 (0.5H, ddt, JZ15.4, 7.3, 1.5 Hz), 5.36–5.27 (1H, m),
5.05 (1H, ddd, JZ10.5, 5.0, 1.7 Hz), 4.58 (1H, d, JZ
11.0 Hz), 4.54 (0.5H, d, JZ12.5 Hz), 4.53 (0.5H, d, JZ
12.5 Hz), 4.38 (1H, d, JZ12.5 Hz), 4.27 (1H, d, JZ
11.0 Hz), 4.17–4.10 (2H, m), 3.98–3.92 (1H, m), 3.91–3.81
(1H, m), 3.64 (1H, dd, JZ13.2, 5.9 Hz), 3.62–3.50
(4H, m), 3.45 (1H, dd, JZ10.3, 5.9 Hz), 3.24–3.20
(1H, m), 2.78–2.65 (2H, m), 2.34–2.29 (1H, m), 2.25–2.21
(0.5H, m), 2.17–2.12 (0.5H, m), 0.88 (4.5H, s), 0.87
(4.5H, s), 0.05 (1.5H, s), 0.04 (1.5H, s), 0.03 (3H, s); LR-
EIMS, m/z 551 (5.0%, [MKt-Bu]C), 215 (bp); HR-EIMS,
calcd for C32H43O6Si [MKt-Bu]C: 551.2829, found:
551.2819.
5.1.26. (2E,20S,30R,50Z,80S,90R)-4-{(80-Benzyloxy-90-ben-
zyloxymethyl-20-vinyl-20,30,40,70,80,90-hexahydrooxonin-
30-yl)oxy}-5-(tert-butyldimethylsilyloxy)-2-pentenal (44).
To a solution of 43 (39.4 mg, 0.0652 mmol) in CH2Cl2
(1.0 ml) was added DIBAH (0.17 ml, 0.94 M in n-hexane,
0.163 mmol) at K78 8C and the mixture was stirred for

7408
A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
5.1.28. (2S,3R,20S,30R,50Z,80S,90R)-4-{(80-Benzyloxy-90-
benzyloxymethyl-20-vinyl-20,30,40,70,80,90-hexahydro-
oxonin-30-yl)oxy}-5-(tert-butyldimethylsilyloxy)-2,3-
epoxypentanol (46). To a mixture of L-(C)-DET (12 ml,
(film), nmax 3488, 3064, 3027, 2953, 2927, 2857, 1496,
1471, 1462, 1454, 1388, 1361, 1337, 1295, 1256, 1206,
1
1098, 1027, 1004, 925, 837, 814, 776, 735, 697 cmK1; H
NMR (300 MHz, CDCl3), d 7.32–7.19 (10H, m), 6.05–5.85
(2H, m), 5.83–5.71 (2H, m), 5.42–5.05 (4H, m), 4.59 (0.5H,
d, JZ11.4 Hz), 4.58 (0.5H, d, JZ11.4 Hz), 4.53 (0.5H, d,
JZ12.5 Hz), 4.52 (0.5H, JZ12.5 Hz), 4.40 (0.5H, d, JZ
12.5 Hz), 4.38 (0.5H, d, JZ12.5 Hz), 4.28 (0.5H, d, JZ
11.4 Hz), 4.27 (0.5H, d, JZ11.4 Hz), 4.26–4.19 (1H, m),
3.99–3.93 (1H, m), 3.70–3.38 (7H, m), 3.26–3.19 (1H, m),
2.80–2.64 (2H, m), 2.66 (0.5H, d, JZ7.0 Hz), 2.61 (0.5H, d,
JZ5.5 Hz), 2.35–2.17 (2H, m), 0.88 (9H, s), 0.05 (3H, s),
0.04 (3H, s); LR-FDMS, m/z 608 (bp, [M]C); HR-FDMS,
calcd for C36H52O6Si [M]C: 608.3533, found: 608.3512.
˚
0.0702 mmol) and pre-dried MS 4 A (28.5 mg, 100 wt%) in
CH2Cl2 (0.5 ml) was added Ti(OiPr)4 (18 ml, 0.0608 mmol)
at K40 8C and the mixture was stirred for 30 min. Then,
TBHP (0.13 ml, 3.7 M in toluene, 0.468 mmol) was added
and the mixture was stirred at K40 8C for 30 min. To the
mixture was added dropwise a solution of 45 (28.5 mg,
0.0468 mmol) in CH2Cl2 (1.0 ml). The reaction mixture was
stirred at K40 8C for 30 min. Then, the reaction mixture
was warmed to K25 8C and stirred for 26 h. DMS (34 ml,
0.463 mmol) was added at K25 8C and the mixture was
stirred for 2 h until unreacted TBHP was consumed. To the
mixture was added 10% DL-tartaric acid (36 ml) and NaF
(15.3 mg) at K25 8C. The suspension was warmed to 24 8C
and stirred for 24 h. The mixture was filtered through Celite
and concentrated in vacuo. To the resultant residue was
added Et2O (4.0 ml) and 30% aqueous NaOH in brine
(2.0 ml) at 0 8C and the mixture was stirred for 1 h. The
layers were separated and the aqueous layer was extracted
with Et2O (3!5 ml). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The resultant residue was
purified by column chromatography (silica gel, hexane/
EtOAcZ5/3/1) to give 46 (29.2 mg, w100%) as an
inseparable 1:1 mixture of diastereomers at C2.35 46: a
colorless oil; IR (film), nmax 3454, 3064, 3027, 2927, 2858,
1496, 1471, 1454, 1389, 1361, 1256, 1096, 1027, 930, 901,
5.1.30. (3R,20S,30R,50Z,80S,90R)-2-{(80-Benzyloxy-90-ben-
zyloxymethyl-20-vinyl-20,30,40,70,80,90-hexahydrooxonin-
30-yl)oxy}pent-4-en-1,3-diol (48). To a solution of 47
(19.3 mg, 0.0317 mmol) in THF (1.0 ml) was added TBAF
(48 ml, 1.0 M in THF, 0.0476 mmol) at 25 8C and the
mixture was stirred for 11.5 h. Then, the solvent was
removed in vacuo. The resultant residue was purified by
column chromatography (silica gel, hexane/EtOAcZ3/
1/2/EtOAc) to give 48 (10.7 mg, 68%) as an inseparable
1:1 mixture of diastereomers at C2.35 48: a colorless oil; IR
(film), nmax 3357, 3087, 3063, 3028, 2911, 1498, 1453,
1425, 1422, 1402, 1361, 1337, 1294, 1257, 1207, 1146,
1096, 1070, 1027, 994, 930, 774, 735, 697 cmK1; 1H NMR
(300 MHz, CDCl3), d 7.34–7.20 (10H, m), 6.03–5.87 (1H,
m), 5.86–5.69 (3H, m), 5.44–5.17 (4H, m), 4.59 (1H, d, JZ
11.4 Hz), 4.52 (1H, d, JZ12.5 Hz), 4.41 (0.5H, d, JZ
12.5 Hz), 4.41 (0.5H, JZ12.5 Hz), 4.33–4.23 (1H, m), 4.28
(1H, d, JZ11.4 Hz), 3.95 (1H, brdqn, JZ8.9, 3.0 Hz), 3.73–
3.63 (2H, m), 3.60–3.46 (5H, m), 3.28–3.25 (1H, m), 2.85–
2.75 (1H, m), 2.73–2.64 (1H, m), 2.54 (0.5H, d, JZ3.3 Hz),
2.46 (0.5H, d, JZ2.9 Hz), 2.31–2.22 (2H, m), 1.99–1.90
(1H, m); LR-EIMS, m/z 494 (7.7%, [M]C), 91 (bp); HR-
EIMS, calcd for C30H38O6 [M]C: 494.2668, found:
494.2666.
1
837, 776, 737, 698 cmK1; H NMR (300 MHz, CDCl3), d
7.31–7.19 (10H, m), 6.03–5.89 (1H, m), 5.84–5.74 (2H, m),
5.31–5.26 (1H, m), 5.06 (1H, ddd, JZ10.3, 4.8, 1.8 Hz),
4.60–4.51 (3H, m), 4.41–4.25 (3H, m), 3.98–3.90 (2H, m),
3.66–3.43 (6H, m), 3.29–3.20 (1H, m), 3.18–3.05 (2H, m),
2.84–2.64 (2H, m), 2.34–2.20 (2H, m), 0.89 (4.5H, s), 0.87
(4.5H, s), 0.06 (3H, s), 0.03 (3H, s); LR-EIMS, m/z 624
(14.6%, [M]C), 92 (bp); HR-EIMS, calcd for C36H52O7Si
[M]C: 624.3482, found: 624.3487.
5.1.29. (3R,20S,30R,50Z,80S,90R)-4-{(80-Benzyloxy-90-ben-
zyloxymethyl-20-vinyl-20,30,40,70,80,90-hexahydrooxonin-
30-yl)oxy}-5-(tert-butyldimethylsilyloxy)pent-1-en-3-ol
(47). To a solution of 46 (29.2 mg, 0.0468 mmol), PPh3
(59.8 mg, 0.228 mmol), and imidazole (15.5 mg,
0.228 mmol) in THF (1.0 ml) was added I2 (46.3 mg,
0.182 mmol) at 25 8C and the mixture was stirred for
35 min. Then, saturated aqueous Na2S2O3 (8 ml) was added
and the mixture was extracted with Et2O (3!5 ml). The
combined organic layers were washed with brine, dried over
anhydrous MgSO4, filtered and concentrated in vacuo. The
resultant residue was roughly purified by column chroma-
tography (silica gel, hexane/EtOAcZ10/5/3) to give
the corresponding crude epoxy iodide, and it was used in the
next reaction without further purification. To a solution of
the above crude epoxy iodide in EtOH (0.80 ml) was added
Zn (17.8 mg, 0.272 mmol) and saturated aqueous NH4Cl
(20 ml) at 25 8C and the mixture was stirred for 2.5 h. The
mixture was filtered through Celite-anhydrous MgSO4 and
concentrated in vacuo. The resultant residue was purified by
column chromatography (silica gel, hexane/EtOAcZ20/
10/5) to give 47 (19.3 mg, 68% from 45) as an inseparable
1:1 mixture of diastereomers at C2.35 47: a colorless oil; IR
5.1.31. (2R,3S,5Z,8R,9S,40R,50S)-3-Benzyloxy-2-benzyl-
oxymethyl-8-{(20,20-dimethyl-40-vinyl-10,30-dioxan-50-yl)
oxy}-9-vinyl-2,3,4,7,8,9-hexahydrooxonin (49a) and
(2R,3S,5Z,8R,9S,40R,50R)-3-benzyloxy-2-benzyloxy-
methyl-8-{(20,20-dimethyl-40-vinyl-10,30-dioxan-50-yl)-
oxy}-9-vinyl-2,3,4,7,8,9-hexahydrooxonin (49b). To a
solution of 48 (10.7 mg, 0.0216 mmol) and 2,2-dimethoxy-
propane (11 ml, 0.0864 mmol) in CH2Cl2 (0.5 ml) was
added CSA (2.5 mg, 0.0108 mmol) at 24 8C and the mixture
was stirred for 3 h. Then, to the mixture was added acetone
(7.9 ml, 0.108 mmol) and stirred at 24 8C for 11.5 h. Then,
saturated aqueous NaHCO3 (3 ml) was added and the
mixture was extracted with Et2O (3!5 ml). The combined
organic layers were washed with brine, dried over
anhydrous MgSO4, filtered and concentrated in vacuo.
The resultant residue was purified by column chromato-
graphy (silica gel, hexane/EtOAcZ10/5) to give 49a
(5.8 mg, 50%) and 49b (5.3 mg, 46%). 49a: a colorless oil;
[a]1D9 C39.4 (c 0.27, CHCl3); IR (film), nmax 3065, 3026,
2992, 2914, 2865, 1453, 1372, 1262, 1201, 1146, 1099,
1
1027, 696 cmK1; H NMR (300 MHz, C6D6), d 7.29–7.15
(10H, m), 6.14–5.90 (2H, m), 5.89–5.81 (1H, m), 5.79–5.74
(1H, m), 5.52 (1H, dt, JZ17.3, 1.7 Hz), 5.42 (1H, ddd, JZ

A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
7409
17.3, 2.0, 1.1 Hz), 5.15 (1H, dt, JZ10.6, 1.7 Hz), 5.06 (1H,
ddd, JZ10.3, 2.6, 1.1 Hz), 4.43 (1H, d, JZ11.7 Hz), 4.37
(1H, d, JZ11.7 Hz), 4.27 (1H, d, JZ11.7 Hz), 4.22 (1H, d,
JZ11.7 Hz), 4.19–4.16 (1H, m), 3.99 (1H, dt, JZ7.7,
3.1 Hz), 3.89 (1H, dd, JZ11.2, 5.5 Hz), 3.68–3.63 (1H, m),
3.65 (1H, dd, JZ11.2, 9.5 Hz), 3.58 (2H, d, JZ2.9 Hz),
3.43–3.36 (2H, m), 3.23 (1H, td, JZ9.5, 5.5 Hz), 2.77–2.71
(1H, m), 2.69–2.63 (1H, m), 2.29–2.22 (1H, m), 1.93–1.85
(1H, m), 1.49 (3H, s), 1.27 (3H, s); LR-FDMS, m/z 534 (bp,
[M]C); HR-FDMS, calcd for C33H42O6 [M]C: 534.2981,
found: 534.2957. 49b: a colorless oil; [a]1D9 K15.5 (c 0.27,
CHCl3); IR (film), nmax 3065, 3012, 2921, 2866, 2803, 1453,
1373, 1365, 1335, 1272, 1241, 1198, 1183, 1152, 1120,
1095, 1063, 1044, 1028, 989, 978, 935, 915, 857, 773, 752,
(1H, m), 6.01–5.86 (2H, m), 5.77–5.63 (1H, m), 4.69 (1H, d,
JZ11.5 Hz), 4.53–4.49 (3H, m), 4.42 (1H, d, JZ11.5 Hz),
4.10–4.07 (1H, m), 3.96 (1H, dd, JZ11.0, 5.5 Hz), 3.84–
3.68 (4H, m), 3.67–3.61 (1H, m), 3.58–3.52 (1H, m), 3.40
(1H, td, JZ9.5, 5.5 Hz), 3.00–2.90 (1H, m), 2.76–2.67 (1H,
m), 2.44–2.36 (1H, m), 2.19–2.09 (1H, m), 1.47 (3H, s),
1
1.44 (3H, s); H NMR (300 MHz, (CD3)2C]O), d 7.34–
7.24 (10H, m), 6.00 (1H, dt, JZ12.4, 2.6 Hz), 5.78–5.67
(2H, m), 5.40 (1H, dt, JZ12.4, 2.6 Hz), 4.68 (1H, d, JZ
11.6 Hz), 4.49 (2H, s), 4.41 (1H, d, JZ11.6 Hz), 4.30 (1H,
brdqn, JZ9.4, 2.6 Hz), 3.88–3.83 (1H, m), 3.72 (1H, dd,
JZ11.3, 5.7 Hz), 3.70–3.61 (3H, m), 3.58–3.50 (1H, m),
3.55 (1H, dd, JZ11.3, 9.4 Hz), 3.29 (1H, ddd, JZ8.5, 5.7,
2.6 Hz), 3.18 (1H, td, JZ9.4, 5.7 Hz), 2.89–2.78 (1H, m),
2.66–2.58 (1H, m), 2.39–2.32 (1H, m), 2.07–1.98 (1H, m),
1.42 (3H, s), 1.28 (3H, s); 13C NMR (150 MHz, CDCl3), d
138.4 (C), 138.1 (C), 136.5 (CH), 131.2 (CH), 128.44
(CH!2), 128.42 (CH!2), 128.3 (CH!2), 128.2 (CH!2),
127.93 (CH), 127.91 (CH), 127.8 (CH), 127.7 (CH), 98.3
(C), 85.8 (CH), 85.5 (CH), 83.3 (CH), 77.7 (CH), 75.0 (CH),
73.4 (CH2), 73.3 (CH), 71.6 (CH2), 69.6 (CH2), 62.9 (CH2),
31.8 (CH2), 29.8 (CH2), 29.0 (CH3), 18.9 (CH3); LR-FDMS,
m/z 506 (22.4%, [M]C), 491 (47.9%, [MKMe]C), 91 (bp);
HR-FDMS, calcd for C31H38O6 [M]C: 506.2669, found:
506.2650. 51: a colorless oil; [a]2D4 C3.5 (c 0.065, CHCl3);
IR (film), nmax 3063, 3029, 2991, 2922, 2854, 1496, 1495,
1454, 1434, 1371, 1301, 1267, 1199, 1161, 1102, 1028, 737,
1
697 cmK1; H NMR (300 MHz, C6D6), d 7.28–7.15 (10H,
m), 6.48 (1H, ddd, JZ17.3, 10.6, 4.4 Hz), 6.12 (1H, ddd,
JZ17.3, 10.6, 6.2 Hz), 6.03–5.97 (2H, m), 5.75 (1H, ddd,
JZ17.3, 2.2, 1.5 Hz), 5.25 (1H, dt, JZ17.3, 1.5 Hz), 5.18
(1H, ddd, JZ10.6, 2.2, 1.5 Hz), 5.09 (1H, dt, JZ10.6,
1.5 Hz), 4.44 (1H, d, JZ11.7 Hz), 4.37 (1H, d, JZ11.7 Hz),
4.23 (2H, d, JZ11.7 Hz), 4.11–4.05 (2H, m), 3.80–3.76
(1H, m), 3.70 (1H, dd, JZ12.8, 1.8 Hz), 3.61 (2H, d, JZ
2.6 Hz), 3.40 (1H, dd, JZ12.8, 1.8 Hz), 3.35 (1H, dt, JZ
8.4, 2.6 Hz), 3.26 (1H, dt, JZ8.8, 2.9 Hz), 2.86–2.70 (2H,
m), 2.55 (1H, brqn, JZ1.8 Hz), 2.36–2.28 (1H, m), 2.07–
2.00 (1H, m), 1.52 (3H, s), 1.24 (3H, s); LR-FDMS, m/z 534
(bp, [M]C), 519 (22.0, [MKMe]C); HR-FDMS, calcd for
C33H42O6 [M]C: 534.2981, found: 534.2964.
1
697 cmK1; H NMR (300 MHz, C6D6), d 7.25–7.05 (10H,
m), 5.95 (1H, ddd, JZ11.4, 2.8, 1.7 Hz), 5.79–5.74 (1H, m),
5.71–5.61 (2H, m), 4.54–4.47 (2H, m), 4.34 (1H, d, JZ
11.7 Hz), 4.26 (1H, d, JZ11.7 Hz), 4.22 (1H, d, JZ
12.1 Hz), 4.12–3.99 (4H, m), 3.96 (1H, dd, JZ11.4,
5.5 Hz), 3.70 (1H, dd, JZ11.4, 9.4 Hz), 3.62–3.51 (3H,
m), 2.76–2.67 (1H, m), 2.52–2.41 (3H, m), 1.48 (3H, s),
1.26 (3H, s); LR-FDMS, m/z 507 (64.2%, [MCH]C), 506
(bp, [M]C); HR-FDMS, calcd for C31H38O6 [M]C:
506.2669, found: 506.2657.
5.1.32. (1R,3S,8R,9Z,11S,13R,14S,16Z)-14-Benzyloxy-
13-benzyloxymethyl-6,6-dimethyl-2,5,7,12-tetraoxatri-
cyclo[9.7.0.03,8]octadeca-9,16-diene (50) and (1S,3R,5Z,
7R,20S,30Z,60S,70R)-3-(60-benzyloxy-70-benzyloxymethyl-
20,50,60,70-tetrahydrooxepin-20-yl)-9,9-dimethyl-2,8,10-
trioxabicyclo[5.4.0]undec-5-ene (51). To a solution of 49a
(5.8 mg, 0.0108 mmol) in degassed CH2Cl2 (3.0 ml) was
added a solution of (Cy3P)2Cl2Ru]CHPh (0.9 mg,
1.08 mmol) in degassed CH2Cl2 (1.0 ml). The resultant
solution was stirred at 24 8C for 3 h. Then, extra (Cy3P)2-
Cl2Ru]CHPh (1.3 mg, 1.62 mmol) in degassed CH2Cl2
(2.0 ml) was added, and the stirring was continued for
further 12 h. After that, the mixture was stirred for 2 h under
O2 atmosphere, and the solvent was removed in vacuo. The
resultant residue was purified by column chromatography
(silica gel, benzene/EtOAcZ40/10) to give the 1:1:0.5
mixture of 49a, 50 and 51. In order to consume 49a
completely, the process was repeated as follows. To a
solution of the above mixture in degassed CH2Cl2 (2.0 ml)
was added a solution of (Cy3P)2Cl2Ru]CHPh (0.60 ml,
1.64mM in degassed CH2Cl2, 0.984 mmol). The resultant
solution was stirred at 26 8C for 8 h. Then, extra (Cy3P)2-
Cl2Ru]CHPh (0.80 ml, 1.21 mM in degassed CH2Cl2,
0.968 mmol) was added, and the stirring was continued for
further 16 h. After that, the mixture was stirred for 2 h under
O2 atmosphere, and the solvent was removed in vacuo. The
resultant residue was purified by column chromatography
(silica gel, benzene/EtOAcZ50/40/10) to give 50
(3.7 mg, 67%, after 2 cycles) and 51 (1.3 mg, 24%, after 2
cycles). 50: a colorless oil; [a]2D3 C13.0 (c 0.20, CHCl3); IR
(film), nmax 3087, 3063, 3027, 2991, 2922, 2855, 1496,
1454, 1372, 1336, 1311, 1292, 1267, 1221, 1200, 1100,
1027, 988, 945, 893, 866, 779, 767, 735, 697, 680 cmK1; 1H
NMR (300 MHz, C5D5N), d 7.46–7.27 (10H, m), 6.29–6.23
5.1.33. 1-(4-Methoxybenzyloxy)-2-propyne (60). To a
solution of propargyl alcohol 59 (1.50 ml, 25.8 mmol) in
THF (70 ml) was added NaH (1.86 g, 60 wt% in oil,
46.4 mmol) at 0 8C and the mixture was stirred for 15 min.
Then, p-methoxy benzyl chloride (PMBCl) (5.20 ml,
38.7 mmol) and TBAI (1.24 g, 3.35 mmol) was added at
0 8C. The reaction mixture was warmed to 24 8C and stirred
for 16 h. After the mixture was cooled to 0 8C and diluted
with Et2O (30 ml), saturated aqueous NH4Cl (50 ml) was
added and the mixture was extracted with Et2O (3!30 ml).
The combined organic layers were washed with brine, dried
over anhydrous MgSO4, filtered and concentrated in vacuo.
The resultant residue was purified by column chromato-
graphy (silica gel, hexane/Et2OZ15/10/5) to give 60
(4.50 g, 99%). 60: a colorless oil; IR (film), nmax 3289, 3001,
2937, 2907, 2837, 2754, 2115, 1612, 1586, 1513, 1464,
1441, 1422, 1387, 1352, 1302, 1249, 1174, 1078, 1034, 927,
1
848, 819, 759, 647 cmK1; H NMR (300 MHz, CDCl3), d
7.30–7.26 (2H, m), 6.90–6.87 (2H, m), 4.54 (2H, s), 4.14
(2H, d, JZ2.4 Hz), 3.81 (3H, s), 2.45 (1H, t, JZ2.4 Hz);
LR-EIMS, m/z 176 (61.6, [M]C), 121 (bp); HR-EIMS, calcd
for C11H12O2 [M]C: 176.0837, found: 176.0822.
5.1.34. Ethyl 4-(4-methoxybenzyloxy)-2-butynoate (61).
To a solution of 60 (2.85 g, 16.2 mmol) in THF (40 ml) was

7410
A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
added n-BuLi (15.4 ml, 1.58 M in n-hexane, 24.3 mmol) at
K78 8C and the mixture was stirred for 10 min. Then,
ethylchloroformate (2.30 ml, 24.3 mmol) was added at
K78 8C and the mixture was stirred for 1 h. The reaction
mixture was warmed to 0 8C and stirred for 15 min. After
the mixture was diluted with Et2O (20 ml), H2O (30 ml) was
added and the mixture was extracted with Et2O (3!30 ml).
The combined organic layers were washed with brine, dried
over anhydrous MgSO4, filtered and concentrated in vacuo.
The resultant residue was purified by column chromato-
graphy (silica gel, hexane/Et2OZ20/15/10/5/3) to
give 61 (3.18 g, 79%). 61: a pale yellow oil; IR (film), nmax
2983, 2939, 2907, 2869, 2838, 2235, 1713, 1613, 1586,
1513, 1465, 1443, 1388, 1366, 1302, 1248, 1174, 1091,
and concentrated in vacuo. The resultant residue was
purified by column chromatography (silica gel, hexane/
EtOAcZ2/1/2) to give 63 (1.83 g, w100%).
5.1.37. (2E)-4-(4-Methoxybenzyloxy)-2-butenol (64). To
a mixture of LAH (2.05 g, 43.3 mmol) in THF (25 ml) was
added dropwise a solution of 63 (2.23 g, 10.8 mmol) in THF
(15 ml) at K78 8C and the mixture was stirred for 13 min.
Then, the reaction mixture was warmed to K20 8C and
stirred for 26 h. The mixture was warmed to 0 8C and
diluted with Et2O (30 ml). Then, H2O (2.1 ml), 4N aqueous
NaOH (2.1 ml) and H2O (6.3 ml) were added in turn. The
resultant suspension was filtered with Celite-anhydrous
MgSO4 and concentrated in vacuo. The resultant residue
was purified by column chromatography (silica gel, hexane/
EtOAcZ3/2/1/2) to give 64 (1.43 g, 64%) along with
63 (0.54 g, 24%). 64: a colorless oil; IR (film), nmax 3583,
3377, 3003, 2933, 2854, 1612, 1586, 1513, 1463, 1442,
1421, 1404, 1386, 1360, 1302, 1247, 1174, 1093, 1033,
1055, 1034, 820, 751, 626 cmK1 1H NMR (300 MHz,
;
CDCl3), d 7.29–7.26 (2H, m), 6.90–6.87 (2H, m), 4.54 (2H,
s), 4.25 (2H, q, JZ7.2 Hz), 4.25 (2H, s), 3.81 (3H, s), 1.32
(3H, t, JZ7.2 Hz); LR-EIMS, m/z 248 (37.4, [M]C), 121
(bp); HR-EIMS, calcd for C14H16O4 [M]C: 248.1048,
found: 248.1051.
1009, 972, 847, 819, 757 cmK1 1H NMR (300 MHz,
;
CDCl3), d 7.28–7.25 (2H, m), 6.89–6.86 (2H, m), 5.96–5.79
(2H, m), 4.46 (2H, s), 4.22–4.16 (2H, m), 4.01 (2H, d, JZ
5.1 Hz), 3.81 (3H, s); LR-EIMS, m/z 208 (21.2%, [M]C),
121 (bp); HR-EIMS, calcd for C12H16O3 [M]C: 208.1099
found: 208.1106.
5.1.35. 4-(4-Methoxybenzyloxy)-2-butynal (62) and 4-(4-
methoxybenzyloxy)-2-butynol (63). To a solution of 61
(2.96 g, 11.9 mmol) in CH2Cl2 (35 ml) was added DIBAH
(25.6 ml, 0.93 M in n-hexane, 23.8 mmol) at K78 8C and
the mixture was stirred for 30 min. Then, extra DIBAH
(6.40 ml, 0.93 M in n-hexane, 5.95 mmol) was added at
K78 8C and the mixture was stirred for 45 min. Then,
saturated aqueous potassium sodium tartrate (50 ml) was
added and the mixture was stirred at 23 8C for 14 h. The
layers were separated and the aqueous layer was extracted
with CH2Cl2 (3!30 ml). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The resultant residue was
purified by column chromatography (silica gel, hexane/
EtOAcZ3/1/1/2) to give 63 (635.5 mg, 26%) along
with 62 (1.80 g, 74%). 62: a yellow oil; IR (film), nmax 3004,
2973, 2838, 2248, 2182, 1728, 1671, 1612, 1586, 1578,
1513, 1465, 1442, 1428, 1388, 1349, 1302, 1250, 1175,
5.1.38. (2R,3R)-2,3-Epoxy-4-(4-methoxybenzyloxy)-1-
butanol (65). To a mixture of D-(K)-DET (0.22 ml,
˚
1.29 mmol) and pre-dried MS 4 A (1.35 g, 100 wt%) in
CH2Cl2 (15 ml) was added Ti(OiPr)4 (0.29 ml, 0.97 mmol)
at K40 8C and the mixture was stirred for 30 min. Then,
TBHP (4.6 ml, 3.5 M in toluene, 16.2 mmol) was added and
the mixture was stirred at K40 8C for 30 min. To the
mixture was added dropwise a solution of 64 (1.35 g,
6.47 mmol) in CH2Cl2 (15 ml). The reaction mixture was
stirred at K40 8C for 30 min, warmed to K20 8C and stirred
for 2.5 d. Then, DMS (1.2 ml, 16.2 mmol) was added at
K20 8C and the mixture was stirred for 2 h until unreacted
TBHP was consumed. To the mixture was added 10%
DL-tartaric acid (0.58 ml) and NaF (244.4 mg) at K25 8C.
The suspension was warmed to 23 8C and stirred for 24 h.
The mixture was filtered through Celite and concentrated in
vacuo. To the resultant residue was added Et2O (30 ml) and
30% aqueous NaOH in brine (10 ml) at 0 8C and the mixture
was stirred for 1 h. The layers were separated and the
aqueous layer was extracted with Et2O (3!20 ml). The
combined organic layers were washed with brine, dried over
anhydrous MgSO4, filtered and concentrated in vacuo. The
resultant residue was purified by column chromatography
(silica gel, hexane/EtOAcZ3/2/1/1/2/1/4) to give
65 (1.03 g, 71%, 93% ee). 65: a colorless solid (EtOAc),
mp 62.0–63.0 8C; [a]2D5 C13.9 (c 1.01, CHCl3); IR (KBr),
nmax 3442, 3020, 2967, 2937, 2869, 1613, 1585, 1514,
1480, 1459, 1444, 1424, 1369, 1325, 1303, 1250, 1212,
1177, 1145, 1090, 1061, 1030, 1005, 987, 974, 932, 866,
1
1160, 1112, 1075, 1032, 817 cmK1; H NMR (300 MHz,
CDCl3), d 9.25 (1H, d, JZ0.55 Hz), 7.29–7.26 (2H, m),
6.92–6.88 (2H, m), 4.56 (2H, s), 4.32 (2H, d, JZ0.55 Hz),
3.81 (3H, s); LR-EIMS, m/z 204 (75.5%, [M]C), 121 (bp);
HR-EIMS, calcd for C12H12O3 [M]C: 204.0786 found:
204.0747. 63: a yellow oil; IR (film), nmax 3629, 3394, 3000,
2935, 2859, 1612, 1586, 1513, 1464, 1442, 1422, 1386,
1351, 1302, 1248, 1175, 1122, 1072, 1031, 942, 920, 819,
756, 709, 603 cmK1; 1H NMR (300 MHz, CDCl3), d 7.30–
7.26 (2H, m), 6.91–6.87 (2H, m), 4.53 (2H, s), 4.33 (2H, dt,
JZ6.2, 1.8 Hz), 4.18 (2H, t, JZ1.8 Hz), 3.81 (3H, s), 1.62
(1H, t, JZ6.2 Hz); LR-EIMS, m/z 206 (21.5%, [M]C), 121
(bp); HR-EIMS, calcd for C12H14O3 [M]C: 206.0943 found:
206.0904.
5.1.36. 4-(4-Methoxybenzyloxy)-2-butynol (63). To a
solution of 62 (1.80 g, 8.81 mmol) in CH2Cl2 (25 ml) was
added DIBAH (23.5 ml, 0.93 M in n-hexane, 21.9 mmol) at
K78 8C and the mixture was stirred for 10 min. Then,
saturated aqueous potassium sodium tartrate (50 ml) was
added and the mixture was stirred at 24 8C for 10 h. The
layers were separated and the aqueous layer was extracted
with Et2O (3!20 ml). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered
850, 816, 759, 728, 709, 642, 636 cmK1 1H NMR
;
(300 MHz, CDCl3), d 7.29–7.24 (2H, m), 6.91–6.86
(2H, m), 4.53 (1H, d, JZ11.6 Hz), 4.48 (1H, d, JZ
11.6 Hz), 3.94 (1H, ddd, JZ12.7, 5.3, 2.6 Hz), 3.81 (3H, s),
3.73 (1H, dt, JZ11.5, 2.6 Hz), 3.65 (1H, ddd, JZ12.7, 7.5,
4.0 Hz), 3.50 (1H, dt, JZ11.5, 5.4 Hz), 3.22 (1H, dt, JZ5.4,
2.6 Hz), 3.09 (1H, dt, JZ4.0, 2.6 Hz), 1.71 (1H, brdd, JZ
7.5, 5.3 Hz); LR-EIMS, m/z 224 (20.6%, [M]C), 121 (bp);

A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
7411
HR-EIMS, calcd for C12H16O4 [M]C: 224.1048, found:
224.1044.
[M]C), 121 (bp); HR-EIMS, calcd for C13H18O3 [M]C:
222.1256, found: 222.1250.
5.1.41. (2S,3R,4Z,6S,7R,10E)-3-Benzyloxy-2-benzyloxy-
methyl-6-(4-methoxybenzyloxy)-7-(20-methoxyvinyl)-
2,3,6,7-tetrahydrooxepin and (2S,3R,4Z,6S,7R,10Z)-3-
benzyloxy-2-benzyloxymethyl-6-(4-methoxybenzyloxy)-
7-(20-methoxyvinyl)-2,3,6,7-tetrahydrooxepin (73). To
oxalyl chloride (0.19 ml, 2.18 mmol) in CH2Cl2 (6.0 ml)
was added DMSO (0.28 ml, 3.91 mmol) in CH2Cl2 (3.0 ml)
dropwise at K78 8C and the mixture was stirred for 10 min.
Then, 72 (383.4 mg, 0.782 mmol) in CH2Cl2 (6.0 ml) was
added dropwise at K78 8C and the mixture was stirred for
15 min. Et3N (1.10 ml, 7.82 mmol) was added dropwise at
K78 8C. The mixture was warmed to K18 8C and stirred
for 10 min. Then, saturated aqueous NaHCO3 (10 ml) was
added and the mixture was extracted with EtOAc (3!
10 ml). The combined organic layers were washed with
brine, dried over anhydrous MgSO4, filtered and concen-
trated in vacuo. The resultant crude aldehyde was used in
the next reaction without purification. To a stirred
suspension of Ph3PCCH2OMeClK (1.37 g, 3.99 mmol) in
THF (8.0 ml) was added NaHMDS (3.8 ml, 1.0 M in THF,
3.83 mmol) and the mixture was stirred at 0 8C. After
30 min, the resulting red solution was allowed to stand at
K78 8C. To the mixture was added dropwise a solution of
the above crude aldehyde in THF (5.0 ml) at K78 8C and
the mixture was stirred for 1.5 h. Then, the reaction mixture
was warmed to 24 8C and stirred for 17.5 h. Et2O (10 ml)
and brine (10 ml) were added and the mixture was extracted
with Et2O (3!10 ml). The combined organic layers were
washed with H2O, dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The resultant residue was
purified by column chromatography (silica gel, hexane/
EtOAcZ15/10/5/3) to give 73 (282.6 mg, 70% from
72, E/ZZ2:1 from 1H NMR). 73: a colorless oil; IR (film),
nmax 3062, 3029, 2862, 1657, 1612, 1586, 1513, 1496, 1454,
1365, 1301, 1247, 1210, 1172, 1089, 1029, 938, 820, 736,
698 cmK1; 1H NMR (300 MHz, CDCl3), d 7.36–7.22 (12H,
m), 6.90–6.79 (2H, m), 6.61 (0.67H, d, JZ12.8 Hz), 6.04
(0.33H, dd, JZ6.2, 0.7 Hz), 5.87 (2H, s), 4.84 (0.67H, dd,
JZ12.8, 7.3 Hz), 4.71–4.47 (4.33H, m), 4.59 (1H, d, JZ
11.2 Hz), 4.43 (1H, d, JZ11.2 Hz), 4.22–4.17 (1H, m),
4.08–4.03 (1H, m), 3.99–3.91 (1H, m), 3.87 (1H, ddd, JZ
8.8, 5.1, 3.7 Hz), 3.79 (3H, s), 3.68–3.59 (2H, m), 3.58 (1H,
s), 3.53 (2H, s); 13C NMR (75 MHz, CDCl3), d 159.3 (C!
0.67), 159.1 (C!0.33), 150.3 (CH!0.67), 148.8 (CH!
0.33), 138.6 (C!0.33), 138.4 (C!0.67), 138.2 (C!0.33),
138.0 (C!0.67), 132.0 (CH!0.33), 131.9 (CH!0.67),
131.7 (CH!0.33), 131.6 (CH!0.67), 130.5 (C!0.33),
130.1 (C!0.67), 129.6 (CH!0.66), 129.5 (CH!1.34),
128.33 (CH!1.34), 128.29 (CH!0.66), 128.27 (CH!
1.34), 128.21 (CH!0.66), 127.82 (CH!0.66), 127.78
(CH!1.34), 127.65 (CH!1.34), 127.55 (CH!0.66),
127.48 (CH!1.34), 127.37 (CH!0.66), 113.8 (CH!
1.34), 113.6 (CH!0.66), 106.2 (CH!0.33), 102.5 (CH!
0.67), 81.7 (CH!0.67), 81.6 (CH!0.33), 81.4 (CH3!
0.67), 80.3 (CH!0.67), 79.6 (CH!0.33), 77.1 (CH), 76.7
(CH), 76.5 (CH3!0.33), 73.3 (CH2!0.67), 73.2 (CH2!
0.33), 71.3 (CH2), 71.1 (CH2!0.33), 71.0 (CH2!0.67),
70.8 (CH2!0.67), 70.5 (CH2!0.33), 55.8 (CH3!0.33),
55.2 (CH3!0.67); LR-EIMS, m/z 516 (6.0%, [M]C), 395
5.1.39. (2R,3R)-2,3-Epoxy-1-(4-methoxybenzyloxy)-4-
pentene (66). To a solution of 65 (78.0 mg, 0.348 mmol)
in CH2Cl2–NEt3–DMSO (6:1.4:1, v/v/v, 3.36 ml) was
added SO3$pyridine (553.9 mg, 3.48 mmol) at 0 8C. The
mixture was warmed to 24 8C and stirred for 1 h. After the
mixture was diluted with Et2O (5 ml), the mixture was
washed with H2O (2!10 ml). The layers were separated
and the aqueous layer was extracted with Et2O (3!8 ml).
The combined organic layers were washed with brine, dried
over anhydrous MgSO4, filtered and concentrated in vacuo.
The resultant crude aldehyde was used immediately in the
next reaction without purification. To a stirred suspension of
Ph3PCCH3BrK (621.6 mg, 1.74 mmol) in THF (4.0 ml) was
added NaHMDS (1.64 ml, 1.0 M in THF, 1.64 mmol) and
the mixture was stirred at 24 8C. After 1 h, the resulting
yellow suspension was allowed to stand at K78 8C. To the
mixture was added dropwise a solution of the above crude
aldehyde in THF (2.0 ml) at K78 8C and the mixture was
stirred for 2 h. Then, the reaction mixture was warmed to
24 8C and stirred for 17 h. After the mixture was diluted
with hexane (10 ml) and Et2O (5 ml), saturated aqueous
NH4Cl (10 ml) was added and the mixture was extracted
with Et2O (3!10 ml). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The resultant residue was
purified by column chromatography (silica gel, hexane/
EtOAcZ20/10) to give 66 (59.8 mg, 78% from 65). 66: a
colorless oil; [a]D24 C10.0 (c 0.68, CHCl3); IR (film), nmax
3086, 3062, 2995, 2934, 2909, 2855, 2836, 1642, 1612,
1586, 1512, 1464, 1442, 1422, 1405, 1387, 1359, 1302,
1247, 1209, 1173, 1099, 1058, 1033, 987, 928, 877,
1
849, 820, 757, 681 cmK1; H NMR (300 MHz, CDCl3),
d 7.27 (2H, d, JZ8.8 Hz), 6.88 (2H, d, JZ8.8 Hz), 5.59
(1H, ddd, JZ17.3, 9.8, 7.2 Hz), 5.48 (1H, dd, JZ17.3,
2.0 Hz), 5.29 (1H, dd, JZ9.8, 2.0 Hz), 4.53 (1H, d, JZ
11.6 Hz), 4.48 (1H, d, JZ11.6 Hz), 3.80 (3H, s), 3.72 (1H,
dd, JZ11.6, 3.3 Hz), 3.49 (1H, dd, JZ11.6, 5.3 Hz), 3.26
(1H, dd, JZ7.2, 2.2 Hz), 3.09 (1H, ddd, JZ5.3, 3.3,
2.2 Hz); LR-EIMS, m/z 220 (4.2%, [M]C), 121 (bp); HR-
EIMS, calcd for C13H16O3 [M]C: 220.1099, found:
220.1082.
5.1.40. (2S)-1-(4-Methoxybenzyloxy)pent-4-en-2-ol (67).
To a solution of Pd(PPh3)4 (6.5 mg, 5.63 mmol) in CH2Cl2
(0.5 ml) was added Bu3SnH (16.5 ml, 0.0619 mmol) at
24 8C. To the mixture was added dropwise a solution of 66
(12.4 mg, 0.0563 mmol) in CH2Cl2 (1.0 ml) at 24 8C and the
mixture was stirred for 20 min. The solvent was removed in
vacuo. The resultant residue was purified by column
chromatography (silica gel, hexane/EtOAcZ10/3) to
give 67 (11.9 mg, 95%). 67: a colorless oil; [a]2D6 C2.8 (c
0.76, CHCl3); IR (film), nmax 3447, 3074, 3001, 2910, 2859,
1641, 1612, 1586, 1513, 1465, 1442, 1419, 1363, 1302,
1
1249, 1209, 1173, 1101, 1035, 997, 916, 820 cmK1; H
NMR (300 MHz, CDCl3), d 7.26 (2H, d, JZ8.7 Hz), 6.88
(2H, d, JZ8.7 Hz), 5.82 (1H, ddt, JZ17.2, 10.1, 7.1 Hz),
5.15–5.07 (2H, m), 4.49 (2H, s), 3.90–3.82 (1H, m), 3.81
(3H, s), 3.49 (1H, dd, JZ9.5, 3.5 Hz), 3.34 (1H, dd, JZ9.5,
7.3 Hz), 2.25 (2H, t, JZ7.1 Hz); LR-EIMS, m/z 222 (7.0%,

7412
A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
(bp); HR-EIMS, calcd for C32H36O6 [M]C: 516.2511,
found: 516.2504.
d 159.2 (C), 138.3 (C), 137.9 (C), 135.2 (CH), 131.6 (CH),
131.5 (CH), 129.9 (C), 129.4 (CH!2), 128.2 (CH!2),
128.1 (CH!2), 127.7 (CH!2), 127.5 (CH!2), 127.3
(CH!2), 116.6 (CH2), 113.7 (CH!2), 83.1 (CH), 82.3
(CH), 79.4 (CH), 76.9 (CH), 73.2 (CH2), 71.2 (CH2), 70.7
(CH2), 70.5 (CH2), 55.1 (CH3), 37.4 (CH2); LR-EIMS, m/z
500 (5.0%, [M]C), 122 (bp); HR-EIMS, calcd for C32H36O5
[M]C: 500.2562, found: 500.2572.
5.1.42. (2R,3S,4Z,6R,7S)-{6-Benzyloxy-7-benzyloxy-
methyl-3-(4-methoxybenzyloxy)-2,3,6,7-tetrahydro-
oxepin-2-yl}ethanal (74). To a solution of 73 (282.6 mg,
0.547 mmol) in THF–H2O (10:1, v/v, 11.0 ml) was added
Hg(OAc)2 (523.0 mg, 1.64 mmol) at 24 8C and the mixture
was stirred for 1.5 h. Then, TBAI (1.82 g, 4.92 mmol) was
added at 24 8C and the mixture was stirred for 1 h. Then,
saturated aqueous NH4Cl (20 ml) was added and the
mixture was extracted with Et2O (3!10 ml). The combined
organic layers were washed with brine, dried over
anhydrous MgSO4, filtered and concentrated in vacuo.
The resultant residue was purified by column chromato-
graphy (silica gel, hexane/EtOAcZ5/3) to give 74
(262.1 mg, 95%). 74: a colorless oil; [a]2D6 C22.5 (c 1.35,
CHCl3); IR (film), nmax 3063, 3030, 2862, 2735, 1725, 1612,
1586, 1513, 1496, 1454, 1372, 1301, 1248, 1174, 1087,
1029, 821, 737, 698 cmK1; 1H NMR (300 MHz, CDCl3), d
9.73 (1H, t, JZ2.0 Hz), 7.36–6.85 (14H, m), 5.92 (1H, d,
JZ14.5 Hz), 5.86 (1H, d, JZ14.5 Hz), 4.63–4.34 (6H, m),
4.21 (1H, d, JZ8.8 Hz), 4.11 (1H, td, JZ8.8, 4.0 Hz), 3.92
(1H, d, JZ8.8 Hz), 3.80 (3H, s), 3.74 (1H, dt, JZ8.8,
3.5 Hz), 3.61 (2H, d, JZ3.5 Hz), 2.79 (1H, ddd, JZ16.5,
4.0, 2.0 Hz), 2.54 (1H, ddd, JZ16.5, 8.8, 2.0 Hz); 13C NMR
(75 MHz, CDCl3), d 200.6 (CH), 159.3 (C), 138.0 (C), 137.7
(C), 132.3 (CH), 131.1 (CH), 129.6 (CH!2), 129.2 (C),
128.2 (CH!2), 128.1 (CH!2), 127.6 (CH!2), 127.5
(CH!2), 127.4 (CH!2), 113.7 (CH!2), 82.8 (CH), 79.0
(CH), 78.6 (CH), 76.7 (CH), 73.2 (CH2), 71.4 (CH2), 70.7
(CH2), 70.3 (CH2), 55.0 (CH3), 47.4 (CH2); LR-EIMS, m/z
502 (6.2%, [M]C), 258 (bp); HR-EIMS, calcd for C31H34O6
[M]C: 502.2355, found: 502.2353.
5.1.44. (2R,3S,4Z,6R,7S)-2-Allyl-6-benzyloxy-7-benzyl-
oxymethyl-2,3,6,7-tetrahydrooxepin-3-ol (58). To a solu-
tion of 75 (69.6 mg, 0.139 mmol) in CH2Cl2—pH 7 buffer
(4:1, v/v, 2.0 ml) was added DDQ (47.3 mg, 0.208 mmol) at
0 8C and the mixture was stirred for 2 h. Then, to the
mixture was added DDQ (31.6 mg, 0.139 mmol) at 0 8C and
the stirring was continued for further 1 h. After the mixture
was diluted with Et2O (3 ml), saturated aqueous NaHCO3
(10 ml) was added. The mixture was extracted with Et2O
(2!5 ml) and EtOAc (5 ml). The combined organic layers
were washed with brine, dried over anhydrous MgSO4,
filtered and concentrated in vacuo. The resultant residue was
purified by column chromatography (silica gel, hexane/
EtOAcZ5) to give 58 (48.5 mg, 92%). 58: a colorless oil;
[a]2D5 K33.7 (c 0.90, CHCl3); IR (film), nmax 3426, 3065,
3029, 2866, 1818, 1769, 1641, 1496, 1454, 1365, 1208,
1097, 913, 736, 697 cmK1; 1H NMR (300 MHz, CDCl3), d
7.35–7.24 (10H, m), 5.98 (1H, ddt, JZ17.1, 10.1, 7.0 Hz),
5.81 (1H, dt, JZ12.8, 2.2 Hz), 5.74 (1H, dt, JZ12.8,
2.0 Hz), 5.16–5.09 (1H, m), 5.08–5.04 (1H, m), 4.61 (1H, d,
JZ11.4 Hz), 4.60 (1H, d, JZ12.3 Hz), 4.55 (1H, d, JZ
12.3 Hz), 4.46 (1H, d, JZ11.4 Hz), 4.18 (1H, ddd, JZ8.0,
4.2, 2.0 Hz), 4.15–4.09 (1H, m), 3.74–3.68 (1H, m), 3.62
(2H, d, JZ3.3 Hz), 3.49 (1H, td, JZ8.5, 3.5 Hz), 2.60–2.51
(1H, m), 2.37–2.26 (1H, m); 13C NMR (75 MHz, CDCl3), d
138.2 (C), 137.7 (C), 135.1 (CH), 134.1 (CH), 130.0 (CH),
128.3 (CH!2), 128.2 (CH!2), 127.8 (CH!2), 127.6
(CH), 127.5 (CH!2), 127.4 (CH), 116.7 (CH2), 84.2 (CH),
82.7 (CH), 76.8 (CH), 73.3 (CH), 73.2 (CH2), 71.4 (CH2),
70.4 (CH2), 37.7 (CH2); LR-FDMS, m/z 381 (bp, [MC
H]C), 380 (21.8%, [M]C); HR-FDMS, calcd for C24H29O4
[MCH]C: 381.2066, found: 381.2081.
5.1.43. (2R,3S,4Z,6R,7S)-2-Allyl-6-benzyloxy-7-benzyl-
oxymethyl-3-(4-methoxybenzyloxy)-2,3,6,7-tetrahydro-
oxepin (75). To a stirred suspension of Ph3PCCH3BrK
(51.8 mg, 0.145 mmol) in THF (0.5 ml) was added
NaHMDS (0.13 ml, 1.0 M in THF, 0.132 mmol) and the
mixture was stirred at 20 8C. After 1 h, the resulting yellow
suspension was allowed to stand at K78 8C. To the mixture
was added dropwise
a
solution of 74 (20.8 mg,
5.1.45. Methyl (2E,20R,30S,40Z,60R,70S)-3-{(20-allyl-60-
benzyloxy-70-benzyloxymethyl-20,30,60,70-tetrahydrooxe-
pin-30-yl)oxy}-4-(tert-butyldimethylsilyloxy)-2-buteno-
ate (57). A solution of butynoate 20 (462.4 mg, 2.03 mmol)
in CH2Cl2 (6.0 ml) was slowly added dropwise to a solution
of 58 (256.8 mg, 0.675 mmol) and PMe3 (1.0 ml, 1.0 M in
THF, 1.01 mmol) in CH2Cl2 (7.0 ml) at 0 8C by means of a
syringe. The mixture was warmed to 24 8C and stirred for
30 min. The mixture was cooled to 0 8C and diluted with
hexane (10 ml) and Et2O (10 ml). Then, saturated aqueous
NH4Cl (10 ml) was added and the mixture was extracted
with Et2O (3!10 ml). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The resultant residue was
purified by column chromatography (silica gel, hexane/
EtOAcZ30/20/10) to give 57 (401.6 mg, 98%). 57: a
colorless oil; [a]D21 C17.3 (c 0.90, CHCl3); IR (film), nmax
3065, 3030, 2953, 2929, 2885, 2857, 1716, 1629, 1497,
1472, 1462, 1454, 1435, 1389, 1361, 1346, 1313, 1288,
1253, 1207, 1188, 1141, 1051, 1005, 939, 916, 837,
0.0414 mmol) in THF (1.5 ml) at K78 8C and the mixture
was stirred for 2 h. Then, the reaction mixture was warmed
to 22 8C and stirred for 18 h. After the mixture was diluted
with hexane (5 ml) and Et2O (3 ml), saturated aqueous
NH4Cl (5 ml) was added. The aqueous layer was extracted
with Et2O (3!5 ml). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The resultant residue was
purified by column chromatography (silica gel, hexane/
EtOAcZ10) to give 75 (20.6 mg, 100%). 75: a colorless oil;
[a]2D5 C12.7 (c 1.0, CHCl3); IR (film), nmax 3064, 3029,
2864, 1641, 1612, 1586, 1513, 1496, 1454, 1382, 1300,
1248, 1209, 1173, 1074, 1035, 914, 821, 735, 698 cmK1; 1H
NMR (300 MHz, CDCl3), d 7.34–6.85 (14H, m), 5.93 (1H,
ddt, JZ17.1, 10.3, 6.8 Hz), 5.86 (2H, s), 5.07 (1H, d, JZ
17.1 Hz), 5.02 (1H, d, JZ10.3 Hz), 4.62–4.38 (6H, m), 4.19
(1H, d, JZ8.8 Hz), 3.91 (1H, d, JZ8.4 Hz), 3.80 (3H, s),
3.71 (1H, ddd, JZ8.8, 4.6, 2.0 Hz), 3.64 (2H, m), 3.60 (1H,
td, JZ8.4, 3.1 Hz), 2.54 (1H, ddd, JZ14.7, 6.8, 3.1 Hz),
2.21 (1H, dt, JZ14.7, 6.8 Hz); 13C NMR (75 MHz, CDCl3),
1
779, 735, 697, 674 cmK1; H NMR (300 MHz, CDCl3), d

A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
7413
7.36–7.23 (10H, m), 5.99–5.85 (1H, m), 5.91 (1H, dt, JZ
13.0, 2.4 Hz), 5.59 (1H, dt, JZ13.0, 2.4 Hz), 5.11–5.02 (2H,
m), 4.97 (1H, d, JZ13.6 Hz), 4.95 (1H, s), 4.62 (1H, d, JZ
11.2 Hz), 4.61 (1H, d, JZ13.6 Hz), 4.60 (1H, d, JZ
12.5 Hz), 4.56 (1H, d, JZ12.5 Hz), 4.54–4.51 (1H, m), 4.46
(1H, d, JZ11.2 Hz), 4.28–4.23 (1H, m), 3.75–3.65 (5H, m),
3.67 (3H, s), 2.58–2.50 (1H, m), 2.28–2.19 (1H, m), 0.90
(9H, s), 0.08 (3H, s), 0.07 (3H, s); 13C NMR (75 MHz,
CDCl3), d 170.0 (C), 167.1 (C), 138.3 (C), 137.6 (C), 134.1
(CH), 133.6 (CH), 128.9 (CH), 128.3 (CH!2), 128.2
(CH!2), 127.7 (CH!2), 127.6 (CH), 127.5 (CH!2),
127.3 (CH), 117.2 (CH2), 92.7 (CH), 83.2 (CH), 82.9 (CH),
77.6 (CH), 76.8 (CH), 73.3 (CH2), 71.6 (CH2), 70.4 (CH2),
60.1 (CH2), 50.9 (CH3), 36.9 (CH2), 25.8 (CH3!3), 18.2
(C), K5.36 (CH3!2); LR-FDMS, m/z 609 (55.5%, [MC
H]C), 608 (34.0%, [M]C), 551 (bp, [MKt-Bu]C); HR-
FDMS, calcd for C35H49O7Si [MCH]C: 609.3247, found:
609.3228.
concentrated in vacuo. The resultant residue was purified by
column chromatography (silica gel, hexane/EtOAcZ10/
5) to give 77 (155.3 mg, 84%). 77: a colorless oil; [a]D20
C22.2 (c 0.90, CHCl3); IR (film), nmax 3065, 3030, 2954,
2928, 2885, 2857, 2766, 1666, 1615, 1497, 1471, 1462,
1454, 1389, 1361, 1328, 1292, 1255, 1206, 1100, 1043,
1
1005, 916, 837, 779, 735, 697 cmK1; H NMR (300 MHz,
CDCl3), d 9.98 (1H, d, JZ7.7 Hz), 7.36–7.24 (10H, m),
5.98–5.84 (1H, m), 5.92 (1H, dt, JZ13.2, 2.6 Hz), 5.55 (1H,
dt, JZ13.2, 2.6 Hz), 5.32 (1H, d, JZ7.7 Hz), 5.10–5.02
(2H, m), 4.63–4.43 (7H, m), 4.22 (1H, dqn, JZ8.4, 2.2 Hz),
3.78–3.61 (4H, m), 2.51–2.43 (1H, m), 2.29–2.19 (1H, m),
0.90 (9H, s), 0.10 (3H, s), 0.09 (3H, s); 13C NMR (75 MHz,
CDCl3), d 189.9 (CH), 173.3 (C), 138.2 (C), 137.5 (C),
134.0 (CH), 133.9 (CH), 128.3 (CH!2), 128.2 (CH!2),
128.1 (CH), 127.8 (CH!2), 127.7 (CH), 127.5 (CH!2),
127.4 (CH), 117.4 (CH2), 106.7 (CH), 83.1 (CH), 82.3 (CH),
78.0 (CH), 76.7 (CH), 73.3 (CH2), 71.7 (CH2), 70.3 (CH2),
61.2 (CH2), 37.0 (CH2), 25.6 (CH3!3), 18.1 (C), K5.43
(CH3), K5.46 (CH3); LR-FDMS, m/z 579 (51.5%, [MC
H]C), 578 (47.2, [M]C), 363 (bp); HR-FDMS, calcd for
C34H47O6Si [MCH]C: 579.3142, found: 579.3120.
5.1.46. (2E,20R,30S,40Z,60R,70S)-3-{(20-Allyl-60-benzyl-
oxy-70-benzyloxymethyl-20,30,60,70-tetrahydrooxepin-30-
yl)oxy}-4-(tert-butyldimethylsilyloxy)-2-butenol (76). To
a solution of 57 (401.6 mg, 0.660 mmol) in CH2Cl2 (7.0 ml)
was added DIBAH (2.50 ml, 0.94 M in n-hexane,
2.31 mmol) at K78 8C and the mixture was stirred for 1 h.
Then, saturated aqueous potassium sodium tartrate (10 ml)
was added and the mixture was stirred at 23 8C for 12 h. The
layers were separated and the aqueous layer was extracted
with EtOAc (3!10 ml). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The resultant residue was
purified by column chromatography (silica gel, hexane/
EtOAcZ10/3/1) to give 76 (361.4 mg, 94%). 76: a
colorless oil; [a]D25 C11.7 (c 0.78, CHCl3); IR (film), nmax
3423, 3065, 3030, 2953, 2928, 2857, 1659, 1497, 1471,
1462, 1454, 1389, 1361, 1294, 1274, 1252, 1187, 1094,
5.1.48. (3E,20R,30S,40Z,60R,70S)-4-{(20-Allyl-60-benzyl-
oxy-70-benzyloxymethyl-20,30,60,70-tetrahydrooxepin-30-
yl)oxy}-5-(tert-butyldimethylsilyloxy)-2-(trimethylsilyl-
oxy)pent-3-enenitrile (56). To a solution of 77 (155.3 mg,
0.268 mmol) and TMSCN (89 ml, 0.670 mmol) in benzene
(5.5 ml) was added Me3Al (0.29 ml, 1.01 M in n-hexane,
0.295 mmol) at 25 8C and the mixture was stirred for 1 h.
Then, saturated aqueous NaHCO3 (5 ml) was added and the
mixture was extracted with Et2O (3!8 ml). The combined
organic layers were washed with brine, dried over
anhydrous MgSO4, filtered and concentrated in vacuo.
The resultant residue was purified by column chromato-
graphy (silica gel, hexane/EtOAcZ30/10) to give 56
(134.6 mg, 74%) as an inseparable 1:1 mixture of
diastereomers. The nitrile 56 was unstable and immediately
1028, 1004, 914, 837, 778, 735, 697 cmK1 1H NMR
;
(300 MHz, CDCl3), d 7.36–7.24 (10H, m), 6.00–5.86 (1H,
m), 5.85 (1H, dt, JZ13.2, 2.2 Hz), 5.66 (1H, dt, JZ13.2,
2.2 Hz), 5.11–5.00 (2H, m), 4.83 (1H, t, JZ7.9 Hz), 4.61
(1H, d, JZ11.2 Hz), 4.59 (2H, s), 4.45 (1H, d, JZ11.2 Hz),
4.42–4.39 (1H, m), 4.26–4.22 (1H, m), 4.20 (2H, s), 4.17–
4.15 (2H, m), 3.73–3.60 (4H, m), 2.54–2.46 (1H, m), 2.27–
2.17 (1H, m), 1.86–1.84 (1H, m), 0.90 (9H, s), 0.10 (6H, s);
13C NMR (75 MHz, CDCl3), d 156.4 (C), 138.3 (C), 137.7
(C), 134.7 (CH), 132.3 (CH), 130.3 (CH), 128.2 (CH!2),
128.1 (CH!2), 127.7 (CH!2), 127.5 (CH), 127.4 (CH),
127.2 (CH!2), 116.7 (CH2), 101.3 (CH), 83.2 (CH), 83.1
(CH), 76.9 (CH), 76.3 (CH), 73.2 (CH2), 71.5 (CH2), 70.4
(CH2), 61.0 (CH2), 57.8 (CH2), 37.1 (CH2), 25.7 (CH3!3),
18.1 (C), K5.38 (CH3), K5.43 (CH3); LR-FDMS, m/z 581
(44.9%, [MCH]C), 580 (bp, [M]C); HR-FDMS, calcd for
C34H48O6Si [M]C: 580.3220, found: 580.3203.
1
used for the next reaction. 56: a colorless oil; H NMR
(300 MHz, CDCl3), d 7.36–7.24 (10H, m), 5.99–5.84 (2H,
m), 5.64 (1H, dt, JZ12.8, 2.4 Hz), 5.58 (0.5H, d, JZ
8.8 Hz), 5.56 (0.5H, d, JZ8.8 Hz), 5.11–5.00 (2H, m),
4.67–4.54 (4H, m), 4.46 (1H, d, JZ11.4 Hz), 4.41–4.36
(1H, m), 4.25–4.21 (1H, m), 4.18 (2H, m), 3.72–3.60 (4H,
m), 2.48–2.42 (1H, m), 2.28–2.15 (1H, m), 0.92 (4.5H, s),
0.91 (4.5H, s), 0.21 (4.5H, s), 0.20 (4.5H, s), 0.11 (3H, s),
0.10 (3H, s); 13C NMR (75 MHz, CDCl3), d 156.6 (C!0.5),
156.4 (C!0.5), 138.4 (C!0.5), 138.3 (C!0.5), 137.75
(C!0.5), 137.70 (C!0.5), 134.4 (CH!0.5), 134.3 (CH!
0.5), 133.2 (CH!0.5), 133.1 (CH!0.5), 129.6 (CH!0.5),
129.5 (CH!0.5), 128.31 (CH), 128.30 (CH), 128.2 (CH!
2), 127.83 (CH), 127.79 (CH), 127.69 (CH!0.5), 127.60
(CH!0.5), 127.5 (CH!2), 127.4 (CH), 119.8 (C!0.5),
119.6 (C!0.5), 117.2 (CH2!0.5), 117.0 (CH2!0.5), 99.55
(CH!0.5), 99.52 (CH!0.5), 83.2 (CH!0.5), 83.1 (CH!
0.5), 82.8 (CH), 77.0 (CH!0.5), 76.93 (CH!0.5), 76.92
(CH!0.5), 76.85 (CH!0.5), 73.34 (CH2!0.5), 73.32
(CH2!0.5), 71.7 (CH2), 70.51 (CH2!0.5), 70.46 (CH2!
0.5), 62.0 (CH2!0.5), 61.9 (CH2!0.5), 57.6 (CH!0.5),
57.5 (CH!0.5), 37.23 (CH2!0.5), 37.15 (CH2!0.5), 25.8
(CH3!1.5), 25.7 (CH3!1.5), 18.2 (C), K0.08 (CH3!1.5),
K0.10 (CH3!1.5), K5.44 (CH3!0.5), K5.47 (CH3!
0.5), K5.53 (CH3!0.5), K5.61 (CH3!0.5).
5.1.47. (2E,20R,30S,40Z,60R,70S)-3-{(20-Allyl-60-benzyl-
oxy-70-benzyloxymethyl-20,30,60,70-tetrahydrooxepin-30-
yl)oxy}-4-(tert-butyldimethylsilyloxy)-2-butenal (77). To
˚
a mixture of 76 (185.2 mg, 0.319 mmol) and MS 4 A
(185.2 mg, 100 wt%) in CH2Cl2 (4.0 ml) was added NMO
(74.7 mg, 0.638 mmol) at 23 8C and the mixture was stirred
for 10 min. Then, TPAP (22.4 mg, 0.0638 mmol) was added
to the reaction mixture at 23 8C and the mixture was stirred
for 1.5 h. The mixture was filtered through Celite and

7414
A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
5.1.49. (2E,20R,30S,40Z,60R,70S)-4-{(20-Allyl-60-benzyl-
oxy-70-benzyloxymethyl-20,30,60,70-tetrahydrooxepin-30-
yl)oxy}-5-(tert-butyldimethylsilyloxy)pent-2-enenitrile
(55). To a solution of 56 (220.0 mg, 0.324 mmol) in
CH2Cl2–Bu3SnH (1:1, v/v, 3.4 ml) was added BF3$OEt2
(0.12 ml, 0.972 mmol) at 0 8C and the mixture was stirred
for 10 min. Then, saturated aqueous NaHCO3 (5 ml) was
added and the mixture was extracted with Et2O (3!5 ml).
The combined organic layers were washed with brine, dried
over anhydrous MgSO4, filtered and concentrated in vacuo.
The resultant residue was purified by column chromato-
graphy (silica gel, hexane/EtOAcZ50/20/10/5) to
give 55 (119.8 mg, 63%) as an inseparable 1:1 mixture of
diastereomers at C13.36 55: a colorless oil; IR (film), nmax
3065, 3030, 2954, 2928, 2858, 2225, 1641, 1496, 1471,
1462, 1454, 1388, 1361, 1294, 1253, 1207, 1103, 1028,
EtOAcZ10/5) to give 78 (100.2 mg, 83% from 55) as an
inseparable 1:1 mixture of diastereomers at C13.36 78: a
colorless oil; IR (film), nmax 3066, 3030, 2954, 2928, 2857,
1694, 1641, 1497, 1471, 1462, 1454, 1389, 1361, 1294,
1253, 1207, 1110, 1028, 1005, 979, 939, 913, 837, 778, 735,
1
698 cmK1; H NMR (300 MHz, CDCl3), d 9.57 (0.5H, d,
JZ7.7 Hz), 9.55 (0.5H, d, JZ7.7 Hz), 7.35–7.24 (10H, m),
6.81 (0.5H, dd, JZ15.8, 5.5 Hz), 6.71 (0.5H, dd, JZ15.8,
6.2 Hz), 6.31 (0.5H, ddd, JZ15.8, 7.7, 1.5 Hz), 6.30 (0.5H,
ddd, JZ15.8, 7.7, 1.3 Hz), 6.01–5.78 (2.5H, m), 5.68 (0.5H,
dt, JZ12.9, 2.4 Hz), 5.13–5.01 (2H, m), 4.60 (1H, d, JZ
11.2 Hz), 4.59 (1H, d, JZ12.5 Hz), 4.54 (1H, d, JZ
12.5 Hz), 4.45 (1H, d, JZ11.2 Hz), 4.26–4.15 (2H, m), 3.98
(0.5H, brdqn, JZ8.4, 2.4 Hz), 3.92 (0.5H, brdqn, JZ8.4,
2.4 Hz), 3.80–3.52 (6H, m), 2.62–2.48 (1H, m), 2.27–2.15
(1H, m), 0.89 (4.5H, s), 0.88 (4.5H, s), 0.06 (1.5H, s), 0.05
(1.5H, s), 0.04 (3H, s); 13C NMR (75 MHz, CDCl3), d 193.1
(CH!0.5), 192.9 (CH!0.5), 154.8 (CH!0.5), 153.8
(CH!0.5), 138.4 (C), 137.9 (C), 135.1 (CH!0.5), 135.0
(CH!0.5), 133.7 (CH!0.5), 132.9 (CH!0.5), 132.4
(CH!0.5), 132.0 (CH!0.5), 131.7 (CH!0.5), 131.5
(CH!0.5), 128.3 (CH!2), 128.2 (CH!2), 127.80 (CH),
127.78 (CH), 127.6 (CH), 127.58 (CH!2), 127.4 (CH),
116.8 (CH2!0.5), 116.7 (CH2!0.5), 83.2 (CH!0.5), 82.9
(CH!0.5), 82.4 (CH!0.5), 82.3 (CH!0.5), 80.3 (CH!
0.5), 79.2 (CH!0.5), 78.6 (CH!0.5), 78.4 (CH!0.5), 76.8
(CH!0.5), 76.7 (CH!0.5), 73.3 (CH2), 71.53 (CH2!0.5),
71.46 (CH2!0.5), 70.4 (CH2), 65.2 (CH2!0.5), 64.5
(CH2!0.5), 37.42 (CH2!0.5), 37.37 (CH2!0.5), 25.8
(CH3!3), 18.2 (C), K5.36 (CH3!0.5), K5.44 (CH3!
0.5), K5.47 (CH3!0.5), K5.49 (CH3!0.5); LR-FDMS,
m/z 592 (bp, [M]C), 535 (43.7, [MKt-Bu]C); HR-FDMS,
calcd for C35H48O6Si [MKt-Bu]C: 592.3220, found:
592.3230.
1
1005, 967, 939, 914, 837, 778, 735, 697 cmK1; H NMR
(300 MHz, CDCl3), d 7.36–7.24 (10H, m), 6.75 (0.5H, dd,
JZ16.3, 4.6 Hz), 6.66 (0.5H, dd, JZ16.3, 5.7 Hz), 6.00–
5.84 (2H, m), 5.75 (0.5H, dt, JZ12.8, 2.2 Hz), 5.67–5.59
(1.5H, m), 5.12–5.04 (2H, m), 4.60 (1H, JZ11.8 Hz), 4.56
(2H, s), 4.45 (1H, d, JZ11.8 Hz), 4.20–4.15 (1H, m), 4.12–
4.04 (1H, m), 3.98–3.89 (1H, m), 3.75–3.47 (6H, m), 2.56–
2.41 (1H, m), 2.27–2.15 (1H, m), 0.89 (4.5H, s), 0.88 (4.5H,
s), 0.05 (3H, s), 0.04 (3H, s); 13C NMR (75 MHz, CDCl3), d
152.9 (CH!0.5), 152.3 (CH!0.5), 138.3 (C), 137.9 (C!
0.5), 137.8 (C!0.5), 134.9 (CH!0.5), 134.8 (CH!0.5),
132.5 (CH!0.5), 132.2 (CH!0.5), 131.5 (CH!0.5), 130.8
(CH!0.5), 128.4 (CH), 128.3 (CH), 128.2 (CH!2), 127.85
(CH), 127.79 (CH), 127.72 (CH!0.5), 127.69 (CH!0.5),
127.6 (CH!2), 127.4 (CH), 117.03 (C!0.5), 116.96 (C!
0.5), 116.8 (CH2!0.5), 116.7 (CH2!0.5), 101.7 (CH!
0.5), 101.0 (CH!0.5), 82.9 (CH!0.5), 82.5 (CH!0.5),
82.4 (CH!0.5), 82.1 (CH!0.5), 80.3 (CH!0.5), 79.5
(CH!0.5), 78.4 (CH!0.5), 78.2 (CH!0.5), 76.76 (CH!
0.5), 76.66 (CH!0.5), 73.4 (CH2!0.5), 73.3 (CH2!0.5),
71.59 (CH2!0.5), 71.57 (CH2!0.5), 70.4 (CH2), 64.9
(CH2!0.5), 64.1 (CH2!0.5), 37.5 (CH2!0.5), 37.4
(CH2!0.5), 25.8 (CH3!3), 18.2 (C), K5.43 (CH3!0.5),
K5.49 (CH3!0.5), K5.52 (CH3!0.5), K5.53 (CH3!
0.5); LR-EIMS, m/z 589 (5.5%, [M]C), 91 (bp); HR-EIMS,
calcd for C31H38NO5Si [MKt-Bu]C: 532.2519, found:
532.2510.
5.1.51. (2E,20R,30S,40Z,60R,70S)-4-{(20-Allyl-60-benzyl-
oxy-70-benzyloxymethyl-20,30,60,70-tetrahydrooxepin-30-
yl)oxy}-5-(tert-butyldimethylsilyloxy)-2-pentenol (79).
To a solution of 78 (100.2 mg, 0.169 mmol) in CH2Cl2
(3.0 ml) was added DIBAH (0.54 ml, 0.94 M in n-hexane,
0.507 mmol) at K78 8C and the mixture was stirred for
30 min. Then, saturated aqueous potassium sodium tartrate
(5 ml) was added and the mixture was stirred at 24 8C for
15 h. The layers were separated and the aqueous layer was
extracted with EtOAc (3!5 ml). The combined organic
layers were washed with brine, dried over anhydrous
MgSO4, filtered and concentrated in vacuo. The resultant
residue was purified by column chromatography (silica gel,
hexane/EtOAcZ5/3) to give 79 (91.2 mg, 91%) as an
inseparable 1:1 mixture of diastereomers at C13.36 79: a
colorless oil; IR (film), nmax 3584, 3451, 3065, 3029, 2953,
2927, 2857, 1496, 1471, 1462, 1454, 1388, 1361, 1295,
1252, 1207, 1099, 1028, 1005, 913, 836, 815, 777, 734,
5.1.50. (2E,20R,30S,40Z,60R,70S)-4-{(20-Allyl-60-benzyl-
oxy-70-benzyloxymethyl-20,30,60,70-tetrahydrooxepin-30-
yl)oxy}-5-(tert-butyldimethylsilyloxy)-2-pentenal (78).
To a solution of 55 (119.8 mg, 0.203 mmol) in CH2Cl2
(3.5 ml) was added DIBAH (0.86 ml, 0.94 M in n-hexane,
0.812 mmol) at K78 8C and the mixture was stirred for 1 h.
Then, saturated aqueous potassium sodium tartrate (5 ml)
was added and the mixture was stirred at 24 8C for 10 h. The
layers were separated and the aqueous layer was extracted
with Et2O (3!5 ml). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered
and concentrated in vacuo. To a mixture of the resultant
imine in CH2Cl2 (3.0 ml) was added 0.5 M aqueous HCl
(1.5 ml) at 24 8C and the mixture was stirred for 20 min. The
mixture was extracted with Et2O (3!5 ml). The combined
organic layers were washed with saturated aqueous
NaHCO3 and brine, dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The resultant residue was
purified by column chromatography (silica gel, hexane/
1
697 cmK1; H NMR (300 MHz, C6D6), d 7.33–7.01 (10H,
m), 6.30–6.12 (1H, m), 6.03–5.88 (1.5H, m), 5.78 (0.5H, dt,
JZ13.0, 2.6 Hz), 5.66–5.47 (2H, m), 5.30–5.09 (2H, m),
4.50–4.35 (3H, m), 4.31 (1H, d, JZ11.7 Hz), 4.30–4.23
(1H, m), 4.10–4.05 (1H, m), 4.00–3.94 (1H, m), 3.89–3.83
(2H, m), 3.81–3.63 (5H, m), 3.55 (1H, ddd, JZ10.6, 9.0,
4.6 Hz), 2.92–2.74 (1H, m), 2.51–2.34 (1H, m), 1.00 (4.5H,
s), 0.98 (4.5H, s), 0.10 (1H, s), 0.08 (2.5H, s), 0.07 (2.5H, s);
13C NMR (75 MHz, CDCl3), d 138.4 (C), 138.00 (C!0.5),
137.98 (C!0.5), 135.5 (CH), 133.9 (CH!0.5), 133.2

A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
7415
(CH!0.5), 132.8 (CH!0.5), 132.5 (CH!0.5), 131.5
(CH!0.5), 130.6 (CH!0.5), 129.47 (CH!0.5), 129.46
(CH!0.5), 128.3 (CH!2), 128.2 (CH!2), 127.80 (CH),
127.79 (CH), 127.6 (CH!3), 127.4 (CH), 116.43 (CH2!
0.5), 116.40 (CH2!0.5), 83.8 (CH!0.5), 83.6 (CH!0.5),
82.7 (CH!0.5), 82.5 (CH!0.5), 81.0 (CH!0.5), 79.7
(CH!0.5), 79.5 (CH!0.5), 77.6 (CH!0.5), 77.0 (CH!
0.5), 76.9 (CH!0.5), 73.3 (CH2), 71.43 (CH2!0.5), 71.35
(CH2!0.5), 70.5 (CH2), 66.1 (CH2!0.5), 65.9 (CH2!0.5),
62.8 (CH2!0.5), 62.7 (CH2!0.5), 37.31 (CH2!0.5),
37.26 (CH2!0.5), 25.86 (CH3!1.5), 25.84 (CH3!1.5),
18.29 (C!0.5), 18.27 (C!0.5), K5.19 (CH3!0.5), K5.32
(CH3!0.5), K5.36 (CH3!0.5), K5.41 (CH3!0.5); LR-
FDMS, m/z 595 (bp, [MCH]C), 594 (25.1%, [M]C); HR-
FDMS, calcd for C35H51O6Si [MCH]C: 595.3455 found:
595.3467.
0.5), 77.9 (CH!0.5), 76.9 (CH), 73.3 (CH2), 71.4 (CH2!
0.5), 71.3 (CH2!0.5), 70.5 (CH2), 63.9 (CH2!0.5), 62.7
(CH2!0.5), 61.3 (CH2!0.5), 61.1 (CH2!0.5), 56.7 (CH!
0.5), 56.6 (CH!0.5), 56.4 (CH!0.5), 53.9 (CH!0.5), 37.3
(CH2!0.5), 37.2 (CH2!0.5), 25.8 (CH3!1.5), 25.7
(CH3!1.5), 18.2 (C!0.5), 18.1 (C!0.5), K5.43 (CH3!
0.5), K5.54 (CH3!0.5), K5.61 (CH3!0.5), K5.63
(CH3!0.5); LR-FDMS, m/z 611 (bp, [MCH]C), 610
(51.7, [M]C); HR-FDMS, calcd for C35H51O7Si [MC
H]C: 611.3404, found: 611.3384.
5.1.53. (2R,3S,4Z,6R,7S,30S,40R)-2-Allyl-6-benzyloxy-7-
benzyloxymethyl-3-{10-(tert-butyldimethylsilyloxy)-30,
40-epoxyhex-50-en-20-yl}oxy-2,3,6,7-tetrahydrooxepin
(54). To a solution of 80 (3.4 mg, 5.57 mmol) in CH2Cl2–
NEt3–DMSO (3:1.4:1, v/v/v, 0.27 ml) was added SO3$
pyridine (22.2 mg, 0.139 mmol) at 0 8C. The mixture was
warmed to 24 8C and stirred for 3 h. After the mixture was
diluted with Et2O (5 ml), the mixture was washed with H2O
(2!5 ml). The layers were separated and the aqueous layer
was extracted with Et2O (3!5 ml). The combined organic
layers were washed with brine, dried over anhydrous
MgSO4, filtered and concentrated in vacuo. The resultant
crude aldehyde was used in the next reaction without
purification. To a stirred suspension of Ph3PCCH3BrK
(55.7 mg, 0.156 mmol) in THF (0.90 ml) was added
NaHMDS (0.13 ml, 1.0 M in THF, 0.128 mmol) and the
mixture was stirred at 24 8C. After 1 h, the resulting yellow
suspension was allowed to stand at K78 8C. To the mixture
was added dropwise a solution of the above crude aldehyde
in THF (0.60 ml) at K78 8C and the mixture was stirred for
2 h. Then, the reaction mixture was warmed to 24 8C and
stirred for 2.5 d. After the mixture was diluted with hexane
(5 ml) and Et2O (3 ml), saturated aqueous NH4Cl (5 ml) was
added and the mixture was extracted with Et2O (3!5 ml).
The combined organic layers were washed with brine, dried
over anhydrous MgSO4, filtered and concentrated in vacuo.
The resultant residue was purified by column chromato-
graphy (silica gel, hexane/EtOAcZ20) to give 54 (2.0 mg,
59% from 80) as an inseparable 1:1 mixture of dia-
stereomers at C13.36 54: a colorless oil; IR (film), nmax 3065,
2926, 2856, 1473, 1462, 1454, 1361, 1293, 1252, 1097,
5.1.52. (2R,3S,20R,30S,40Z,60R,70S)-4-{(20-Allyl-60-benzyl-
oxy-70-benzyloxymethyl-20,30,60,70-tetrahydrooxepin-30-
yl)oxy}-5-(tert-butyldimethylsilyloxy)-2,3-epoxypentanol
(80). To a mixture of D-(K)-DET (12 ml, 0.0696 mmol) and
˚
pre-dried MS 4 A (20.7 mg, 100 wt%) in CH2Cl2 (0.3 ml)
was added Ti(OiPr)4 (15.4 ml, 0.0522 mmol) at K40 8C and
the mixture was stirred for 30 min. Then, TBHP (0.14 ml,
4.9 M in toluene, 0.696 mmol) was added and the mixture
was stirred at K40 8C for 30 min. To the mixture was added
dropwise a solution of 79 (20.7 mg, 0.0348 mmol) in
CH2Cl2 (1.2 ml). The reaction mixture was stirred at
K40 8C for 30 min. Then, the reaction mixture was warmed
to K25 8C and stirred for 2.5 d. Then, DMS (52 ml,
0.708 mmol) was added at K25 8C and the mixture was
stirred for 2 h until unreacted TBHP was consumed. To the
mixture was added 10% DL-tartaric acid (31 ml) and NaF
(13.2 mg) at K25 8C. The suspension was warmed to 24 8C
and stirred for 24 h. The mixture was filtered through Celite
and concentrated in vacuo. To the resultant residue was
added Et2O (1.0 ml) and 30% aqueous NaOH in brine
(1.0 ml) at 0 8C and the mixture was stirred for 1 h. The
layers were separated and the aqueous layer was extracted
with Et2O (3!5 ml). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The resultant residue was
purified by column chromatography (silica gel, hexane/
EtOAcZ10/7/5/3) to give 80 (16.2 mg, 76%) as an
inseparable 1:1 mixture of diastereomers at C13.36 80: a
colorless oil; IR (film), nmax 3458, 3065, 3029, 2953, 2927,
2857, 1496, 1471, 1462, 1454, 1388, 1361, 1295, 1253,
1028, 837, 777, 733, 697 cmK1 1H NMR (300 MHz,
;
CDCl3), d 7.35–7.21 (10H, m), 6.03–5.81 (3H, m), 5.78–
5.42 (2H, m), 5.29 (1H, dt, JZ9.5, 2.2 Hz), 5.13–5.00 (2H,
m), 4.61 (1H, d, JZ11.2 Hz), 4.60 (1H, d, JZ13.2 Hz), 4.54
(1H, d, JZ13.2 Hz), 4.44 (1H, d, JZ11.2 Hz), 4.23–4.16
(1H, m), 4.03–3.93 (1H, m), 3.75–3.58 (5H, m), 3.50 (1H,
ddd, JZ17.5, 8.9, 2.9 Hz), 3.41–3.34 (0.5H, m), 3.33 (0.5H,
dd, JZ6.8, 1.8 Hz), 3.27 (0.5H, dd, JZ7.3, 1.8 Hz), 3.21–
3.14 (0.5H, m), 2.93 (0.5H, dd, JZ7.2, 1.8 Hz), 2.88 (0.5H,
dd, JZ5.7, 1.8 Hz), 2.61–2.53 (1H, m), 2.32–2.27 (1H, m),
0.90 (4.5H, s), 0.88 (4.5H, s), 0.06 (3H, s), 0.05 (1.5H, s),
0.04 (1.5H, s); 13C NMR (75 MHz, CDCl3), d 138.5 (C!
0.5), 138.4 (C!0.5), 138.1 (C!0.5), 138.0 (C!0.5), 135.4
(CH), 134.9 (CH), 132.7 (CH!0.5), 132.3 (CH!0.5),
131.5 (CH!0.5), 131.1 (CH!0.5), 128.33 (CH), 128.31
(CH), 128.2 (CH!2), 127.8 (CH!2), 127.6 (CH!3),
127.41 (CH!0.5), 127.40 (CH!0.5), 119.81 (CH2!0.5),
119.77 (CH2!0.5), 116.6 (CH2), 83.6 (CH!0.5), 83.2
(CH!0.5), 82.7 (CH), 81.2 (CH!0.5), 80.6 (CH!0.5),
80.3 (CH!0.5), 78.6 (CH!0.5), 76.98 (CH!0.5), 76.96
(CH!0.5), 73.4 (CH2), 71.5 (CH2!0.5), 71.4 (CH2!0.5),
1208, 1096, 1028, 1005, 911, 837, 814, 778, 735, 697 cmK1
;
1H NMR (300 MHz, CDCl3), d 7.35–7.24 (10H, m), 6.02–
5.78 (3H, m), 5.13–5.01 (2H, m), 4.60 (1H, d, JZ11.4 Hz),
4.59 (1H, d, JZ12.5 Hz), 4.54 (1H, d, JZ12.5 Hz), 4.45
(1H, d, JZ11.4 Hz), 4.21–4.15 (1H, m), 4.02–3.91 (2H, m),
3.74–3.42 (8H, m), 3.24–3.15 (1H, m), 3.04 (1H, ddd, JZ
10.8, 5.5, 2.2 Hz), 2.60–2.52 (1H, m), 2.27–2.15 (1H, m),
0.90 (4.5H, s), 0.88 (4.5H, s), 0.06 (3H, s), 0.05 (3H, s); 13C
NMR (75 MHz, CDCl3), d 138.4 (C!0.5), 138.3 (C!0.5),
138.0 (C!0.5), 137.9 (C!0.5), 135.3 (CH!0.5), 135.2
(CH!0.5), 132.5 (CH!0.5), 132.3 (CH!0.5), 131.5
(CH!0.5), 131.1 (CH!0.5), 128.23 (CH!2), 128.16
(CH!2), 127.8 (CH!2), 127.5 (CH!3), 127.34 (CH!
0.5), 127.32 (CH!0.5), 116.6 (CH2!0.5), 116.5 (CH2!
0.5), 83.4 (CH!0.5), 83.2 (CH!0.5), 82.6 (CH!0.5), 82.5
(CH!0.5), 80.8 (CH!0.5), 80.5 (CH!0.5), 80.0 (CH!

7416
A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
70.6 (CH2!0.5), 70.5 (CH2!0.5), 64.0 (CH2!0.5), 62.8
(CH2!0.5), 61.2 (CH!0.5), 58.5 (CH!0.5), 57.0 (CH!
0.5), 56.6 (CH!0.5), 37.42 (CH2!0.5), 37.38 (CH2!0.5),
25.9 (CH3!3), 18.3 (C!0.5), 18.2 (C!0.5), K5.33
(CH3!0.5), K5.45 (CH3!0.5), K5.50 (CH3!0.5),
K5.58 (CH3!0.5); LR-FDMS, m/z 606 (bp, [M]C), 549
(29.9, [MKt-Bu]C); HR-FDMS, calcd for C36H50O6Si
[M]C: 606.3377, found: 606.3369.
4.61 (1H, d, JZ11.6 Hz), 4.59 (1H, d, JZ12.7 Hz), 4.53
(1H, d, JZ12.7 Hz), 4.45 (1H, d, JZ11.6 Hz), 4.16–3.98
(2H, m), 3.89–3.79 (2H, m), 3.77–3.60 (4H, m), 3.54 (1H,
dd, JZ10.5, 4.6 Hz), 3.46–3.42 (1H, m), 2.54–2.14 (4H, m);
13C NMR (75 MHz, CDCl3), d 138.4 (C), 137.8 (C!0.5),
137.7 (C!0.5), 135.1 (CH!0.5), 134.9 (CH!0.5), 134.5
(CH!0.5), 134.3 (CH!0.5), 132.6 (CH!0.5), 132.4
(CH!0.5), 130.65 (CH!0.5), 130.60 (CH!0.5), 128.4
(CH), 128.35 (CH), 128.26 (CH!2), 128.1 (CH), 128.0
(CH), 127.9 (CH!0.5), 127.7 (CH!0.5), 127.67 (CH),
127.65 (CH), 127.5 (CH), 118.2 (CH2!0.5), 117.6 (CH2!
0.5), 117.0 (CH2!0.5), 116.8 (CH2!0.5), 82.6 (CH!0.5),
82.3 (CH!0.5), 81.6 (CH!0.5), 81.1 (CH!0.5), 80.0
(CH!0.5), 79.0 (CH!0.5), 78.6 (CH!0.5), 78.2 (CH!
0.5), 76.6 (CH!0.5), 76.2 (CH!0.5), 73.3 (CH2), 71.9
(CH2!0.5), 71.7 (CH2!0.5), 70.9 (CH!0.5), 70.7 (CH2!
0.5), 70.60 (CH2!0.5), 70.56 (CH!0.5), 61.2 (CH2!0.5),
61.0 (CH2!0.5), 37.9 (CH2!0.5), 37.7 (CH2!0.5), 37.6
(CH2!0.5), 37.5 (CH2!0.5); LR-FDMS, m/z 495 (80.0%,
[MCH]C), 494 (11.2%, [M]C), 91 (bp); HR-FDMS, calcd
for C30H39O6 [MCH]C: 495.2747, found: 495.2754.
5.1.54. (3S,20R,30S,40Z,60R,70S)-2-{(20-Allyl-60-benzyl-
oxy-70-benzyloxymethyl-20,30,60,70-tetrahydrooxepin-30-
yl)oxy}-1-(tert-butyldimethylsilyloxy)hex-5-en-3-ol (81).
To a solution of Pd(PPh3)4 (11.8 mg, 0.0102 mmol) in
CH2Cl2 (0.5 ml) was added Bu3SnH (30 ml, 0.112 mmol) at
24 8C. To the mixture was added dropwise a solution of 54
(62.2 mg, 0.102 mmol) in CH2Cl2 (1.5 ml) at 24 8C and the
mixture was stirred for 25 min. The solution was passed
through a short silica gel column, and the filtrate was
concentrated in vacuo. The resultant residue was purified by
column chromatography (silica gel, hexane/EtOAcZ30/
20/10) to give 81 (54.6 mg, 88%) as an inseparable 1:1
mixture of diastereomers at C13.36 81: a colorless oil; IR
(film), nmax 3583, 3491, 3067, 3030, 2927, 2856, 1462,
5.1.56. (2R,3S,4Z,6R,7S,40S,50R)-2-Allyl-3-{(40-allyl-
20,20-dimethyl-10,30-dioxan-50-yl)oxy}-6-benzyloxy-7-
benzyloxymethyl-2,3,6,7-tetrahydrooxepin (53a) and
(2R,3S,4Z,6R,7S,40S,50S)-2-allyl-3-{(40-allyl-20,20-di-
methyl-10,30-dioxan-50-yl)oxy}-6-benzyloxy-7-benzyloxy-
methyl-2,3,6,7-tetrahydrooxepin (53b). To a solution of
82 (44.4 mg, 0.0897 mmol) and 2,2-dimethoxypropane
(55 ml, 0.449 mmol) in CH2Cl2 (1.5 ml) was added CSA
(10.5 mg, 0.0449 mmol) at 24 8C and the mixture was
stirred for 2 h. Then, 2,2-dimethoxypropane (55 ml,
0.449 mmol) was added, and the stirring was continued
for further 1 h. After that, saturated aqueous NaHCO3 (5 ml)
was added and the mixture was extracted with Et2O (3!
5 ml). The combined organic layers were washed with
brine, dried over anhydrous MgSO4, filtered and concen-
trated in vacuo. The resultant residue was purified by
column chromatography (silica gel, hexane/EtOAcZ15/
5/3) to give 53a (22.4 mg, 47%) and 53b (23.7 mg, 50%).
53a: a colorless oil; [a]2D0 K17.1 (c 1.12, CHCl3) IR (film),
nmax 2924, 2855, 1466, 1461, 1457, 1453, 1446, 1434, 1378,
1454, 1257, 1101, 1028, 1005, 914, 837, 776, 734, 697 cmK1
;
1H NMR (300 MHz, CDCl3), d 7.38–7.24 (10H, m), 6.03–
5.78 (4H, m), 5.17–5.00 (4H, m), 4.60 (1H, d, JZ11.4 Hz),
4.58–4.52 (2H, m), 4.45 (1H, d, JZ11.4 Hz), 4.20–4.14
(1H, m), 4.03–3.98 (1H, m), 3.86–3.53 (7H, m), 3.46–3.35
(1H, m), 2.61–2.51 (1H, m), 2.37–2.16 (3H, m), 0.90 (4.5H,
s), 0.89 (4.5H, s), 0.07 (6H, s); 13C NMR (75 MHz, CDCl3),
d 138.44 (C!0.5), 138.41 (C!0.5), 138.0 (C!0.5), 137.9
(C!0.5), 135.31 (CH!0.5), 135.29 (CH!0.5), 135.0
(CH!0.5), 134.8 (CH!0.5), 132.8 (CH!0.5), 132.0
(CH!0.5), 131.4 (CH!0.5), 131.0 (CH!0.5), 128.3
(CH!2), 128.2 (CH!2), 127.9 (CH), 127.8 (CH), 127.7
(CH!0.5), 127.64 (CH!2), 127.61 (CH!0.5), 127.42
(CH!0.5), 127.41 (CH!0.5), 117.7 (CH2!0.5), 117.1
(CH2!0.5), 116.64 (CH2!0.5), 116.59 (CH2!0.5), 83.4
(CH!0.5), 83.2 (CH!0.5), 82.4 (CH!0.5), 82.1 (CH!
0.5), 81.0 (CH!0.5), 79.8 (CH!0.5), 79.0 (CH!0.5), 78.5
(CH!0.5), 76.9 (CH!0.5), 76.7 (CH!0.5), 73.3 (CH2),
71.6 (CH2!0.5), 71.54 (CH!0.5), 71.45 (CH2!0.5), 70.8
(CH!0.5), 70.6 (CH2!0.5), 70.5 (CH2!0.5), 62.9 (CH2!
0.5), 61.5 (CH2!0.5), 37.62 (CH2), 37.58 (CH2), 25.83
(CH3!1.5), 25.80 (CH3!1.5), 18.2 (C!0.5), 18.1 (C!
0.5), K5.43 (CH3!0.5), K5.56 (CH3), K5.61 (CH3!0.5);
LR-FDMS, m/z 609 (bp, [MCH]C), 608 (36.3%, [M]C),
551 (45.2%, [MKt-Bu]C); HR-FDMS, calcd for
C36H53O6Si [MCH]C: 609.3611, found: 609.3585.
1
1372, 1362, 1360, 1261, 1199, 1165, 1092, 697 cmK1; H
NMR (300 MHz, C6D6), d 7.41–7.05 (10H, m), 6.16–5.99
(2H, m), 5.77–5.70 (1H, m), 5.59–5.55 (1H, m), 5.19–5.05
(4H, m), 4.46 (1H, d, JZ11.4 Hz), 4.44 (1H, d, JZ
12.3 Hz), 4.38 (1H, d, JZ12.3 Hz), 4.30 (1H, d, JZ
11.4 Hz), 4.18–4.15 (1H, m), 3.99–3.91 (1H, m), 3.92 (1H,
dd, JZ11.2, 5.1 Hz), 3.84–3.73 (2H, m), 3.70–3.59 (3H, m),
3.63 (1H, dd, JZ11.2, 8.8 Hz), 3.31 (1H, td, JZ8.8,
5.1 Hz), 2.68–2.53 (2H, m), 2.41–2.24 (2H, m), 1.45 (3H, s),
1.26 (3H, s); 13C NMR (75 MHz, CDCl3), d 138.4 (C),
138.0 (C), 135.0 (CH), 134.4 (CH), 131.9 (CH), 131.8 (CH),
128.4 (CH!2), 128.3 (CH!2), 127.9 (CH!2), 127.69
(CH), 127.65 (CH!2), 127.5 (CH), 116.94 (CH2), 116.92
(CH2), 98.6 (C), 83.0 (CH), 81.8 (CH), 80.1 (CH), 76.7
(CH), 74.4 (CH), 73.4 (CH2), 72.4 (CH), 71.5 (CH2), 70.5
(CH2), 63.6 (CH2), 37.6 (CH2), 36.4 (CH2), 28.4 (CH3), 19.5
(CH3); LR-FDMS, m/z 535 (bp, [MCH]C), 534 (50.1,
[M]C); HR-FDMS, calcd for C33H43O6 [MCH]C:
535.3059, found: 535.3038. 53b: a colorless oil; [a]D22
C38.0 (c 1.19, CHCl3) IR (film), nmax 3065, 2925, 2855,
1496, 1455, 1419, 1377, 1295, 1278, 1245, 1230, 1198,
5.1.55. (3S,20R,30S,40Z,60R,70S)-2-{(20-Allyl-60-benzyl-
oxy-70-benzyloxymethyl-20,30,60,70-tetrahydrooxepin-30-
yl)oxy}hex-5-en-1,3-diol (82). To a solution of 81 (2.5 mg,
4.11 mmol) in THF (0.4 ml) was added TBAF (8.2 ml, 1.0 M
in THF, 8.22 mmol) at 23 8C and the mixture was stirred for
1.5 h. The solvent was removed in vacuo. The resultant
residue was purified by column chromatography (silica gel,
hexane/EtOAcZ1/1/2/EtOAc) to give 82 (2.0 mg,
100%) as an inseparable 1:1 mixture of diastereomers at
C13.36 82: a colorless oil; IR (film), nmax 3583, 3420, 3065,
3028, 2924, 2855, 1641, 1454, 1377, 1294, 1207, 1073,
1028, 914, 735, 697 cmK1; 1H NMR (300 MHz, CDCl3), d
7.34–7.24 (10H, m), 6.01–5.75 (4H, m), 5.19–5.01 (4H, m),

A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
7417
1092, 1074, 1028, 995, 984, 912, 733, 697 cmK1; 1H NMR
(300 MHz, (CD3)2C]O), d 7.38–7.22 (10H, m), 6.12–5.72
(4H, m), 5.11–4.94 (4H, m), 4.66 (1H, d, JZ11.7 Hz), 4.59
(1H, d, JZ12.5 Hz), 4.53 (1H, d, JZ12.5 Hz), 4.49 (1H, d,
JZ11.7 Hz), 4.14–4.09 (1H, m), 4.03–4.00 (1H, m), 4.01
(1H, dd, JZ12.8, 1.5 Hz), 3.91–3.87 (1H, m), 3.88 (1H, dd,
JZ12.8, 1.5 Hz), 3.75–3.60 (3H, m), 3.57–3.48 (1H, m),
3.29 (1H, brqn, JZ1.5 Hz), 2.87–2.68 (2H, m), 2.35–2.13
(2H, m), 1.41 (3H, s), 1.28 (3H, s); 13C NMR (75 MHz,
CDCl3), d 138.5 (C), 138.0 (C), 135.6 (CH), 134.3 (CH),
131.8 (CH), 131.3 (CH), 128.34 (CH!2), 128.26 (CH!2),
127.8 (CH!2), 127.3 (CH!3), 127.4 (CH), 117.3 (CH2),
116.5 (CH2), 98.5 (C), 83.8 (CH), 82.9 (CH), 77.2 (CH),
77.0 (CH), 73.4 (CH2), 71.6 (CH2), 71.2 (CH), 70.5 (CH2),
69.0 (CH), 60.8 (CH2), 37.3 (CH2), 35.6 (CH2), 29.3 (CH3),
18.9 (CH3); LR-FDMS, m/z 535 (bp, [MCH]C), 534
(58.2%, [M]C); HR-FDMS, calcd for C33H43O6 [MCH]C:
535.3059, found: 535.3066.
1377, 1292, 1231, 1214, 1092, 1071, 1027, 934, 730,
1
695 cmK1; H NMR (400 MHz, C6D6), d 7.36–7.05 (10H,
m), 5.99 (1H, td, JZ10.7, 5.9 Hz), 5.85–5.81 (1H, m), 5.80
(1H, dt, JZ12.7, 2.4 Hz), 5.70 (1H, dt, JZ12.7, 2.4 Hz),
4.50 (1H, d, JZ11.7 Hz), 4.48 (1H, d, JZ11.7 Hz), 4.45
(1H, d, JZ11.7 Hz), 4.33 (1H, d, JZ11.7 Hz), 4.20 (1H,
dqn, JZ8.8, 2.4 Hz), 4.20 (1H, dqn, JZ8.8, 2.4 Hz), 3.79–
3.70 (3H, m), 3.63 (1H, dd, JZ11.0, 3.7 Hz), 3.59 (1H, ddd,
JZ8.8, 4.4, 2.4 Hz), 3.55–3.51 (1H, m), 3.53 (1H, dd, JZ
11.0, 5.2 Hz), 2.99 (1H, ddd, JZ8.8, 5.2, 3.7 Hz), 2.78 (1H,
brddd, JZ12.8, 10.7, 3.8 Hz), 2.67–2.59 (1H, m), 2.26–2.21
(1H, m), 1.99 (1H, brddd, JZ13.9, 5.4, 3.9 Hz); 13C NMR
(75 MHz, CDCl3), d 138.5 (C), 137.8 (C), 136.2 (CH), 131.8
(CH), 128.8 (CH), 128.4 (CH!2), 128.3 (CH!2), 127.8
(CH!2), 127.7 (CH), 127.6 (CH!2), 127.5 (CH), 127.2
(CH), 87.1 (CH), 85.7 (CH), 84.0 (CH), 82.9 (CH), 77.6
(CH), 73.4 (CH2), 71.7 (CH2), 71.3 (CH), 70.9 (CH2), 63.5
(CH2), 32.5 (CH2), 32.3 (CH2); LR-FDMS, m/z 467 (66.6%,
[MCH]C), 466 (44.3%, [M]C), 91 (bp); HR-FDMS, calcd
for C28H35O6 [MCH]C: 467.2434, found: 467.2455.
5.1.57. (1S,3R,8S,10Z,13R,15S,16R,17Z)-16-Benzyloxy-
15-benzyloxymethyl-6,6-dimethyl-2,5,7,14-tetraoxatri-
cyclo[11.5.0.03,8]octadeca-10,17-diene (52). To a solution
of 53a (22.4 mg, 0.0419 mmol) in degassed CH2Cl2 (12 ml)
was added a solution of (Cy3P)2Cl2Ru]CHPh (6.9 mg,
8.38 mmol) in degassed CH2Cl2 (2 ml). The resultant
solution was stirred at 23 8C for 4 h. The mixture was
stirred for 15.5 h under O2 atmosphere, and the solvent was
removed in vacuo. The resultant residue was purified by
column chromatography (silica gel, benzene/EtOAcZ50/
10) to give 52 (20.5 mg, 97%). 52: a colorless oil; [a]D23
K22.3 (c 0.050, CHCl3); IR (film), nmax 2924, 2854, 1496,
1457, 1454, 1434, 1378, 1267, 1206, 1097, 1028, 732,
Acknowledgements
We thank Mr. Kenji Watanabe and Dr. Eri Fukushi (GC–
MS and NMR Laboratory, Graduate School of Agriculture,
Hokkaido University) for the measurements of mass
spectra. We thank Dr. Yasuhiro Kumaki (High-Resolution
NMR Laboratory, Graduate School of Science, Hokkaido
University) for the 13C NMR measurement of 50. This work
was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science,
and Technology of Japanese Government.
697 cmK1 1H NMR (400 MHz, C5D5N, K30 8C, a 1:1
;
mixture of conformers), d 7.52–7.22 (10H, m), 5.99–5.92
(0.5H, m), 5.89–5.63 (2.5H, m), 5.60–5.49 (1H, m) 4.71
(0.5H, d, JZ11.2 Hz), 4.67 (0.5H, d, JZ11.2 Hz), 4.61–
4.51 (2.5H, m), 4.47 (0.5H, d, JZ11.2 Hz), 4.36–4.31 (1H,
m), 4.28–4.23 (0.5H, m), 3.99–3.92 (1H, m), 3.90–3.81
(2.5H, m), 3.90–3.47 (1H, m), 3.77–3.61 (2.5H, m), 3.56–
3.47 (1H, m), 3.34 (0.5H, td, JZ9.6, 5.9 Hz), 3.01–3.05
(0.5H, m), 2.92–2.78 (1.5H, m), 2.38–2.32 (0.5H, m), 2.19–
2.11 (1H, m), 2.04–1.99 (0.5H, m), 1.46 (1.5H, s), 1.39
(1.5H, s), 1.14 (1.5H, s), 1.13 (1.5H, s); 13C NMR data of 52
is not shown because the spectrum of 52 exhibited
extremely broadened signals that gave only unclear
chemical shifts.; LR-FDMS, m/z 507 (64.5%, [MCH]C),
506 (bp, [M]C), 491 (22.9%, [MKMe]C); HR-FDMS,
calcd for C31H38O6 [M]C: 506.2668, found: 506.2648.
References and notes
1. For reviews of ciguatera, see (a) Lehane, L.; Lewis, R. J. Int.
J. Food Microbiol. 2000, 61, 91. (b) Lewis, R. J. Toxicon 2001,
39, 97.
2. For reviews of ciguatoxins and related marine toxins, see
(a) Shimizu, Y. Chem. Rev. 1993, 93, 1685. (b) Yasumoto, T.;
Murata, M. Chem. Rev. 1993, 93, 1897. (c) Scheuer, P. J.
Tetrahedron 1994, 50, 3. (d) Yasumoto, T.; Murata, M. Nat.
Prod. Rep. 2000, 17, 293. (e) Yasumoto, T. Chem. Rec. 2001,
3, 228.
5.1.58. (1S,3R,4S,6Z,9R,11S,12R,13Z)-12-Benzyloxy-11-
benzyloxymethyl-3-hydroxymethyl-2,10-dioxabicyclo-
[7.5.0]tetradeca-6,13-dien-4-ol (83). To a solution of 52
(20.5 mg, 0.0405 mmol) in THF–H2O (1:1, v/v, 0.80 ml)
was added TFA (40 ml) at 0 8C. The mixture was warmed to
23 8C and stirred for 3 h. After the mixture was diluted with
Et2O (3 ml), saturated aqueous NaHCO3 (5 ml) was added.
The mixture was extracted with EtOAc (5!5 ml). The
combined organic layers were washed with brine, dried over
anhydrous MgSO4, filtered and concentrated in vacuo. The
resultant residue was purified by column chromatography
(silica gel, hexane/EtOAcZ2/1/3) to give 83 (16.6 mg,
88%). 83: a colorless oil; [a]2D3 K34.9 (c 0.045, CHCl3); IR
(film), nmax 3586, 3411, 2953, 2923, 2853, 1456, 1419,
3. Yasumoto, T.; Nakajima, R.; Bagnis, R.; Adachi, R. Bull.
Jpn. Soc. Sci. Fish. 1977, 43, 1021.
4. (a) Scheuer, P. J.; Takahashi, W.; Tsutsumi, J.; Yoshida, T.
Science 1967, 155, 1267. (b) Tachibana, K. PhD Thesis,
University of Hawaii, 1980. (c) Nukina, M.; Koyanagi, L. M.;
Scheuer, P. J. Toxicon 1984, 22, 169. (d) Tachibana, K.;
Nukina, M.; Joh, Y. G.; Scheuer, P. J. Biol. Bull. 1987, 172,
122.
5. (a) Murata, M.; Legrand, A.-M.; Ishibashi, Y.; Fukui, M.;
Yasumoto, T. J. Am. Chem. Soc. 1989, 111, 8929. (b) Murata,
M.; Legrand, A.-M.; Ishibashi, Y.; Fukui, M.; Yasumoto, T.
J. Am. Chem. Soc. 1990, 112, 4380. (c) Murata, M.; Legrand,
A.-M.; Scheuer, P. J.; Yasumoto, T. Tetrahedron Lett. 1992,
33, 525.

7418
A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
6. Satake, M.; Morohashi, A.; Oguri, H.; Oishi, T.; Hirama, M.;
68, 3225. (b) Baba, T.; Isobe, M. Synlett 2003, 547. (c) Tatami,
A.; Inoue, M.; Uehara, H.; Hirama, M. Tetrahedron Lett. 2003,
44, 5229. (d) Baba, T.; Huang, G.; Isobe, M. Tetrahedron
2003, 59, 6851. (e) Kobayashi, S.; Alizadeh, B. H.; Sasaki,
S.-y.; Oguri, H.; Hirama, M. Org. Lett. 2004, 6, 751. (f) Baba,
T.; Takai, S.; Sawada, N.; Isobe, M. Synlett 2004, 603.
(g) Inoue, M.; Yamashita, S.; Tatami, A.; Miyazaki, K.;
Hirama, M. J. Org. Chem. 2004, 69, 2797. (h) Inoue, M.;
Yamashita, S.; Hirama, M. Tetrahedron Lett. 2004, 45, 2053.
(i) Inoue, M. Org. Biomol. Chem. 2004, 1811. (j) Fuwa, H.;
Fujikawa, S.; Tachibana, K.; Takakura, H.; Sasaki, M.
Tetrahedron Lett. 2004, 45, 4795. (k) Kobayashi, S.;
Takahashi, Y.; Komano, K.; Alizadeh, B. H.; Kawada, Y.;
Oishi, T.; Tanaka, S.-i.; Ogasawara, Y.; Sasaki, S.-y.; Hirama,
M. Tetrahedron 2004, 8375 and references therein.
Harada, N.; Yasumoto, T. J. Am. Chem. Soc. 1997, 119, 11325.
7. For bioactivity of ciguatoxins and related compounds, see
(a) Bidard, J.-N.; Vijverberg, H. P. M.; Frelin, C.; Chungue, E.;
Legrand, A.-M.; Bagnis, R.; Lazdanski, M. J. Biol. Chem.
1984, 259, 8353. (b) Lombet, A.; Bidard, J.-N.; Lazdanski, M.
FEBS Lett. 1987, 219, 355. For a review, see (c) Dechraoui,
M.-Y.; Naar, J.; Pauillac, S.; Legrand, A.-M. Toxicon 1999, 37,
125. See also the references cited in Ref. 1.
8. Catterall, W. A.; Risk, M. Mol. Pharmacol. 1981, 19, 345. See
also Ref. 7b.
9. (a) Trainer, V. L.; Thomsen, W. J.; Catterall, W. A.; Baden,
D. G. Mol. Pharmacol. 1991, 40, 988. (b) Trainer, V. L.;
Baden, D. G.; Catterall, W. A. J. Biol. Chem. 1994, 269,
19904.
10. Recent reviews for the synthesis of medium cyclic ethers and
´
polycyclic ethers, see (a) Alvarez, E.; Candenas, M.-L.; Perez,
13. For the total synthesis of ciguatoxin CTX3C, see (a) Hirama,
M.; Oishi, T.; Uehara, H.; Inoue, M.; Maruyama, M.; Oguri,
H.; Satake, M. Science 2001, 294, 1904. (b) Inoue, M.; Uehara,
H.; Maruyama, M.; Hirama, M. Org. Lett. 2002, 4, 4551.
(c) Inoue, M.; Hirama, M. Synlett 2004, 577. (d) Inoue, M.;
Hirama, M. Acc. Chem. Res. 2004, 37, 961.
´
R.; Ravero, J. L.; Martın, J. D. Chem. Rev. 1995, 95, 1953.
(b) Mori, Y. Chem. Eur. J. 1997, 3, 849. (c) Hoberg, J. O.
Tetrahedron 1998, 54, 12631. (d) Yet, L. Chem. Rev. 2000,
100, 2963. (e) Elliot, M. C.; Williams, E. J. Chem. Soc., Perkin
Trans. 1 2001, 2303. (f) Elliot, M. C. J. Chem. Soc., Perkin
Trans. 1 2002, 2301. (g) Nakamura, I.; Yamamoto, Y. Chem.
Rev. 2004, 104, 2127. (h) Fujiwara, K.; Murai, A. Bull. Chem.
Soc. Jpn. 2004, 77, 2129.
14. For synthetic studies of ciguatoxins in our laboratory, see
(a) Oka, T.; Murai, A. Chem. Lett. 1994, 1611. (b) Oka, T.;
Fujiwara, K.; Murai, A. Tetrahedron 1996, 52, 12091.
(c) Atsuta, H.; Fujiwara, K.; Murai, A. Synlett 1997,
307. (d) Oka, T.; Fujiwara, K.; Murai, A. Tetrahedron Lett.
1997, 38, 8053. (e) Oka, T.; Murai, A. Tetrahedron 1998, 54,
1. (f) Oka, T.; Fujiwara, K.; Murai, A. Tetrahedron 1998, 54,
21. (g) Fujiwara, K.; Saka, K.; Takaoka, D.; Murai, A. Synlett
1999, 1037. (h) Fujiwara, K.; Tanaka, H.; Murai, A. Chem.
Lett. 2000, 610. (i) Fujiwara, K.; Takaoka, D.; Kusumi, K.;
Kawai, K.; Murai, A. Synlett 2001, 691. (j) Fujiwara, K.;
Koyama, Y.; Doi, E.; Shimawaki, K.; Ohtaniuchi, Y.;
Takemura, A.; Souma, S.-i.; Murai, A. Synlett 2002, 1496.
(k) Fujiwara, K.; Koyama, Y.; Kawai, K.; Tanaka, H.; Murai,
A. Synlett 2002, 1835. (l) Tanaka, H.; Kawai, K.; Fujiwara, K.;
Murai, A. Tetrahedron 2002, 58, 10017. (m) Fujiwara, K.;
Goto, A.; Sato, D.; Ohtaniuchi, Y.; Tanaka, H.; Murai, A.;
Kawai, H.; Suzuki, T. Tetrahedron Lett. 2004, 45, 7011.
(n) Takemura, A.; Fujiwara, K.; Murai, A.; Kawai, H.; Suzuki,
T. Tetrahedron Lett. 2004, 45, 7567.
11. For convergent approaches to polycyclic ether systems, see
´
´
(a) Alvarez, E.; Dıaz, M. T.; Hanxing, L.; Martın, J. D. J. Am.
Chem. Soc. 1995, 117, 1437. (b) Nicolaou, K. C. Angew.
Chem., Int. Ed. 1996, 35, 589. (c) Ravelo, J. L.; Regueiro, A.;
´ ´
Rodrıguez, E.; de Vera, J.; Martın, J. D. Tetrahedron Lett.
´
1996, 37, 2869. (d) Alvarez, E.; Perez, R.; Rico, M.;
´
´
Rodrıguez, R. M.; Martın, J. D. J. Org. Chem. 1996, 61,
3003. (e) Oishi, T.; Nagumo, Y.; Hirama, M. Synlett 1997,
980. (f) Inoue, M.; Sasaki, M.; Tachibana, K. Tetrahedron
Lett. 1997, 38, 1611. (g) Oishi, T.; Nagumo, Y.; Hirama, M.
Chem. Commun. 1998, 1041. (h) Sasaki, M.; Inoue, M.;
Noguchi, T.; Takeichi, A.; Tachibana, K. Tetrahedron Lett.
1998, 39, 2783. (i) Sasaki, M.; Fuwa, H.; Inoue, M.;
Tachibana, K. Tetrahedron Lett. 1998, 39, 9027. (j) Sasaki,
M.; Noguchi, T.; Tachibana, K. Tetrahedron Lett. 1999, 40,
1337. (k) Fujiwara, K.; Morishita, H.; Saka, K.; Murai, A.
Tetrahedron Lett. 2000, 41, 507. (l) Matsuo, G.; Hinou, H.;
Koshino, H.; Suenaga, T.; Nakata, T. Tetrahedron Lett. 2000,
41, 903. (m) Mori, Y.; Mitsuoka, S.; Furukawa, H.
Tetrahedron Lett. 2000, 41, 4161. (n) Kadowaki, C.; Chan,
P. W. H.; Kadota, I.; Yamamoto, Y. Tetrahedron Lett. 2000,
41, 5769. (o) Imai, H.; Uehara, H.; Inoue, M.; Oguri, H.; Oishi,
15. (a) Ogura, K.; Tsuchihashi, G. Tetrahedron Lett. 1972, 13,
2681. (b) Herrmann, J. L.; Richman, J. E.; Wepplo, P. J.;
Schlessinger, R. H. Tetrahedron Lett. 1973, 14, 4707.
16. Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH:
Weinhem, 2003.
17. (a) FuS, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc.
1993, 9856. (b) Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H.
J. Am. Chem. Soc. 1996, 118, 6634.
´
T.; Hirama, M. Tetrahedron Lett. 2001, 42, 6219. (p) Dıaz,
´
´
´
M. T.; Perez, R. L.; Rodrıguez, L.; Ravelo, J. L.; Martın, J. D.
Synlett 2001, 345. (q) Oishi, T.; Tanaka, S.-i.; Ogasawara, Y.;
Maeda, K.; Oguri, H.; Hirama, M. Synlett 2001, 952.
(r) Maruyama, M.; Inoue, M.; Oishi, T.; Oguri, H.; Ogasawara,
Y.; Shindo, Y.; Hirama, M. Tetrahedron 2002, 58, 1835.
(s) Sasaki, M.; Noguchi, T.; Tachibana, K. J. Org. Chem.
2002, 67, 3301. (t) Kadota, I.; Ohno, A.; Matsuda, K.;
Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 3562. (u) Suzuki,
K.; Nakata, T. Org. Lett. 2002, 4, 2739. (v) Inoue, M.; Wang,
G. X.; Wang, J.; Hirama, M. Org. Lett. 2002, 4, 3439.
(w) Oishi, T.; Watanabe, K.; Murata, M. Tetrahedron Lett.
2003, 44, 7315. (x) Sasaki, M.; Fuwa, H. Synlett 2004, 1851.
(y) Kadota, I.; Yamamoto, Y. Acc. Chem. Res. 2005, 38, 423.
12. For recent synthetic studies on ciguatoxins from other groups,
see (a) Takai, S.; Sawada, N.; Isobe, M. J. Org. Chem. 2003,
18. (a) Paintner, F. F.; Metz, M.; Bauschke, G. Synthesis 2002,
869. (b) Inanaga, J.; Baba, Y.; Hanamoto, T. Chem. Lett. 1993,
241.
19. Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121,
5653.
20. Fujiwara, K.; Souma, S.-i.; Mishima, H.; Murai, A. Synlett
2002, 1493.
21. Several attempts to reduce selectively the a,b-unsaturated
ester part of 21 were unsuccessful.
22. Hetero-Michael addition of 19 to butynoate 20 with a catalytic
amount of Me3P according to Paintner’s procedure18 often
stopped before completion. The incomplete reaction was due
to the oligomerization of 20. A stoichiometric amount of Me3P

A. Takemura et al. / Tetrahedron 61 (2005) 7392–7419
7419
and excess 20 (1.7 equiv) were required to accelerate the
reaction rate and to improve the yield.
28. In the RCM reaction, 30a was not recovered, and an oligomer
that would result from 30a was detected.
23. When TMSOTf was used instead of BF3$OEt2, complex
products were obtained. On the other hand, Me3Al was
ineffective in activating the substrate.
29. (a) Tsuji, J.; Shimizu, I.; Minami, I. Chem. Lett. 1984, 1017.
(b) Oshima, M.; Yamazaki, H.; Shimizu, I.; Nisar, M.; Tsuji, J.
J. Am. Chem. Soc. 1989, 111, 6280. (c) Nagasawa, K.;
Shimizu, I.; Nakata, T. Tetrahedron Lett. 1996, 37,
6881–6885.
24. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974.
25. Classon, B.; Liu, Z.; Samuelsson, B. J. Org. Chem. 1988, 53,
6126.
30. See also: Kakei, H.; Nemoto, T.; Ohshima, T.; Shibasaki, M.
Angew. Chem., Int. Ed. 2004, 43, 317.
´
31. David, H.; Dupuis, L.; Guillerez, M.-G.; Guibe, F.
Tetrahedron Lett. 2000, 41, 3335.
26. Under the reaction conditions, epoxides 29a and 29b were
directly converted to allyl alcohols 30a and 30b, respectively.
There were several reports for conversion of 2,3-epoxy-
propanol derivatives to the corresponding 1-propen-3-ol
derivatives under Classon–Samuelsson conditions. For
examples, (a) Aziz, M.; Rouessac, F. Tetrahedron 1988, 44,
101. (b) Hayashi, N.; Mine, T.; Fujiwara, K.; Murai, A. Chem.
32. Oxepan alcohol 72 was facilely available from the known
E-ring segment.14j
33. (a) Crimmins, M. T.; Tabet, E. A. J. Am. Chem. Soc. 2000,
122, 5473. (b) Sawada, D.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2000, 122, 10521.
´
Lett. 1994, 2143. (c) Dorta, R. L.; Rodrıguez, M. S.; Salazar,
´
J. A.; Suarez, E. Tetrahedron Lett. 1997, 38, 4675.
34. Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89,
5505.
27. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
35. The position number is corresponding to that of Scheme 7.
36. The position number is corresponding to that of Scheme 10.