Convergent synthesis of the common FGHI-ring part of ciguatoxins

Article abstract of DOI:10.1016/j.tet.2006.05.014

Convergent synthesis of the common FGHI-ring part (54) of ciguatoxins was achieved via the following key steps: (i) the Nozaki-Hiyama-Kishi reaction connecting the F-ring part (6) with the I-ring part (7); (ii) regio- and stereoselective epoxidation; (iii) the 6-exo-epoxide opening reaction forming simultaneously the H-ring and the quaternary asymmetric center at C30; (iv) inversion of the C29 stereocenter by a two-step oxidation/reduction process, where the successful inversion depended on proper management of the steric environment of the substrate; and (v) final reductive cyclization constructing the G-ring.

Full text of DOI:10.1016/j.tet.2006.05.014

Tetrahedron 62 (2006) 7408–7435
Convergent synthesis of the common
FGHI-ring part of ciguatoxins
*
Ayumi Takizawa, Kenshu Fujiwara, Eriko Doi, Akio Murai,
Hidetoshi Kawai and Takanori Suzuki
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Received 15 April 2006; revised 28 April 2006; accepted 10 May 2006
Available online 5 June 2006
Abstract—Convergent synthesis of the common FGHI-ring part (54) of ciguatoxins was achieved via the following key steps: (i) the Nozaki–
Hiyama–Kishi reaction connecting the F-ring part (6) with the I-ring part (7); (ii) regio- and stereoselective epoxidation; (iii) the 6-exo-epoxide
opening reaction forming simultaneously the H-ring and the quaternary asymmetric center at C30; (iv) inversion of the C29 stereocenter
by a two-step oxidation/reduction process, where the successful inversion depended on proper management of the steric environment of
the substrate; and (v) final reductive cyclization constructing the G-ring.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
studied by many researchers from a variety of viewpoints
in order to prevent and treat ciguatera intoxication.4
Ciguatoxins (CTXs, Fig. 1)1 are the principal toxins respon-
sible for ciguatera,2 a form of sea food poisoning. More than
25,000 people suffer annually from this poisoning in the
Pacific and Indian Oceans as well as the Caribbean Sea.2b
In 1977, Yasumoto and co-workers identified an epiphytic
dinoflagellate, Gambierdiscus toxicus, as a causative organ-
ism.3 The dinoflagellate-produced toxins are first transferred
to herbivorous fish and accumulated most in carnivorous fish
through the marine food chain, thus causing human intoxi-
cation. The symptoms of ciguatera are characterized by
gastrointestinal and neurological disturbances. Since these
disturbances often last for months or years, ciguatera has
resulted in serious social problems. Thus, CTXs are now
CTXs have been isolated from both poisonous fish and
dinoflagellate G. toxicus with great effort over several years
and despite the extremely low content of CTXs in these
organisms. Ciguatoxin (CTX1B, 1) was first isolated from
the moray eel, Gymnothorax javanicus, by Scheuer and
co-workers in 1967, and characterized to be a polyether
compound in 1980.5 Determination of the relative structure
of 1 was achieved by Yasumoto and co-workers in 1989 with
only 0.35 mg of 1 isolated from 4000 kg of G. javanicus.
The absolute structure of 1 was determined by collaboration
of Yasumoto et al. in 1997.6 CTX3C (2) was isolated from
cultured G. toxicus by Yasumoto and co-workers in 1993.7
Me
H
H
Me
H
O
HO
Me
O
I
OH
H
J
H
O
K
H
G
H
H
O
H
H
H
O
O
M
H
O
H
H
O
55
L
H
O
H
O
D
H
Me
A
E
1
B
Me
I
5
C
F
OH
HO
O
O
Me
H
O
H
H
H
H
H
H
HO
H
H
OH
OH
Me
Me
O
H
O
Ciguatoxin CTX1B (1)
H
OH
H
J
H
H
G
O
H
O
H
K
H
H
H
O
O
B
E
O
H
O
O
H
O
F
L
52
H
C
D
A
O
H
O
M
H
O
H
1
Me
H
H
H
Me
OH
Ciguatoxin CTX3C (2)
Figure 1. Representative ciguatoxin congeners.
Keywords: Ciguatoxin; trans-Fused tetracyclic ether; Reductive etherification; The Nozaki–Hiyama–Kishi reaction; 6-exo Hydroxy epoxide opening.
* Corresponding author. Tel.: +81 11 706 2701; fax: +81 11 706 4924; e-mail: fjwkn@sci.hokudai.ac.jp
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.014

A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
7409
They elucidated the structure of 2 with only 0.70 mg of 2 iso-
lated from 1100 l of the culture. So far, more than 20 CTXs
have been isolated and structurally identified.
construction of three contiguous asymmetric centers from
C29 to C31 including a quaternary asymmetric center (C30)
at the junction between the G- and H-rings.15 We intended
to solve the issue based on the following scheme: (i) The
G-ring of 3 was envisioned to be constructed from hydroxy
ketone 4 by reductive etherification, which would generate
the O26–C31 bond and the C31 stereocenter,16,17 and inver-
sion of the C29 stereochemistry; (ii) In order to construct the
H-ring and the quaternary center at C30 concurrently, the
6-exo-epoxide-opening reaction of 5, whose product was in-
tended to be oxidized to 4, was planned; (iii) The epoxide 5
would be synthesized from E-iodoolefin 6 and aldehyde 7
via the Nozaki–Hiyama–Kishi (NHK) reaction18 followed
by regio- and diastereoselective epoxidation; (iv) Both 6
and 7 would be prepared from our previously reported
medium-ring ethers.10j,p Although the use of the cis-epoxide
(C29-epi-5) corresponding to 5 might be straightforward and
excludes the C29-inversion step, the cis-epoxide could not
be prepared so far because of the difficulty in the synthesis
of a Z-iodoolefin corresponding to E-iodoolefin 6.19 There-
fore, we decided to adopt the above synthetic plan that
employed the NHK reaction with an E-iodoolefin at the first
stage and C29 inversion at the final stage.
Pharmacological studies have disclosed that the potent neu-
rotoxicity of CTXs arises from the activation of voltage-sen-
sitive sodium channels (VSSCs) in neuron cells by the strong
binding to site-5 on the channel, and CTXs share the binding
site on VSSC with brevetoxins.8 However, further progress in
these studies has been prevented by the insufficient amounts
of CTXs from natural sources. Therefore, synthetic supply of
CTXs on a practical scale is desired for the advancement of
the above studies as well as the development of therapies
for ciguatera and methods for screening of ciguateric fish.
Structural features of CTXs, such as the stereochemical com-
plexity, huge molecular size, and ladder-shaped polyether
skeleton possessing five- to nine-membered cyclic ethers,
provide remarkable synthetic challenges. Therefore, CTXs
have been studied extensively by numerous chemists in the
synthetic viewpoint.9,10 To date, many convergent synthetic
strategies11,12 toward the total synthesis of CTXs have been
reported.9,10
In the course of our program toward the total synthesis of
CTXs,13 we have established a method for the convergent
construction of a trans-fused X/6/7/X cyclic ether system
based on the coupling reaction of an acyl anion equivalent
with an aldehyde followed by reductive cyclization reac-
tions.13g,i,k,14 So far, we reported the synthesis of the
ABCDE- and IJKLM-ring parts of 2 by the method13m,q as
well as by a new procedure for the addition of the F-ring
to the E-ring part of 1, which would also be available for
the CTX3C (2) synthesis.13n,o Accordingly, the remaining
issue is development of a synthetic method for the middle
(GH-ring) part of 2 from the left (ABCDEF-ring) and the
right (IJKLM-ring) segments. Here, a convergent synthesis
of the common FGHI-ring part of CTXs from F- and I-ring
segments is described.13r
3. Preparation of the F- and I-ring segments
The F-ring segment 6 was synthesized from known 813j
(Scheme 2). Removal of the TBS groups of 8 (98%) followed
O
O
OR1
OR2
RO
RO
BnO
BnO
O
O
Ph
c
8: R = TBS
9: R = H
10: R = Bn
11: R1 = R2 = H
a
b
d
12: R1 = Tf, R2 = TBS
Me
BnO
BnO
O
e
f
6
OTBS
13
Scheme 2. Reagents and conditions: (a) TBAF, THF, 25 ꢀC, 1 h, 98%; (b)
BnBr, NaH, TBAI, THF, 25 ꢀC, 23 h, 98%; (c) THF–3 M HCl (1:1), 21 h,
98%; (d) Tf2O, 2,6-lutidine, CH2Cl2, ꢁ78 ꢀC, 15 min, then TBSOTf,
0 ꢀC, 1 h, 95%; (e) propyne, BuLi, THF, ꢁ78 ꢀC, 10 min, then 12,
ꢁ78/24 ꢀC, 3 h, 99%; (f) Cp2ZrCl2, DIBAL, THF, 55 ꢀC, 30 min, then
I2, 0 ꢀC, 15 min, 86%.
2. Synthetic plan for the FGHI-ring part
Our synthetic plan for the FGHI-ring part 3 from the F- and
I-ring segments (6 and 7, respectively) is outlined in Scheme
1. A main issue of the synthesis of 3 was stereocontrolled
Inversion
6-exo-Epoxide-
opening reaction
HO
Me
29
G
Me
RO
H
H
Me
19
O
31
Me
H
H
BnO
BnO
BnO
BnO
O
F
O
I
H
29
OH
O
O
OPBB
OPBB
31
26
O
O
OPBB
OPBB
H
H
O
H
40
3
4
Reductive etherification
Nozaki-Hiyama-Kishi reaction
& Diastereoselective epoxidation
Me
BnO
BnO
19
Me
HO
Me
BnO
BnO
Me
PMBO
OHC
O
30
29
O
I
30 I
OTBS
F
OPBB
OPBB
+
O
OTBS
31
O
O
OTES
OPBB
OPBB
40
6
7
5
PBB: 4-bromobenzyl
Scheme 1. Synthetic plan for the FGHI-ring part (3).

7410
A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
by protection with BnBr (98%) provided 10, which was
hydrolyzed to give 11 (98%). The diol 11 was converted
to triflate 12 by a one-pot selective triflate formation/TBS-
protection process (95%).20 The subsequent reaction with
1-propynyllithium afforded 13 (99%),21 which was treated
first with a zirconium reagent, prepared from Cp2ZrCl2 and
DIBAL,22 and then with I2 to produce 6 regioselectively
(86%).
give 21 (45% from 7) and its C31-epimer 22 (40% from 7) in
good yield.26
Since the diastereoselective epoxidation in the next step
required S configuration at C31 of 21, inversion of the R con-
figuration at C31 of 22 was then examined. Although direct
inversion by an SN2 reaction, such as the Mitsunobu reaction,
was unsuccessful, a stepwise oxidation/selective reduction
process was found to be effective for the inversion after sev-
eral examinations (vide infra). Initial oxidation of 22 with
DMPI24 readily afforded a,b-unsaturated ketone 23 in quan-
titative yield (Scheme 5). Next, stereoselective reduction of
23 was investigated under several conditions (Table 1).
Aluminum reducing agents (DIBAL, DIBAL/BuLi,27 and
Red-AlÒ) exhibited low stereoselectivities (entries 1–3).
However, these results suggested that a bulkier reagent would
provide better selectivity. Then, boron-reducing agents were
examined. In order to avoid conjugate reduction, NaBH4 was
first used under the Luche conditions.28 Although the Luche
reduction of 23 at ꢁ40 to 0 ꢀC gave low selectivity
(21:22¼2:1), the reduction at ꢁ78 ꢀC showed enhanced
selectivity (4:1) (entries 4 and 5). It was notable that the
selectivity of NaBH4 at ꢁ78 ꢀC was higher than those of
aluminum reductants in spite of the small size of NaBH4.
Therefore, bulky L-SelectrideÒ was used instead of NaBH4
under Luche’s conditions at ꢁ78 ꢀC. As a result, the selectiv-
ity increased to 6:1 (entry 6). On the other hand, the reduction
with L-SelectrideÒ in the absence of CeCl3 displayed the
highest selectivity (>13:1) without side products by conju-
gate reduction (entry 7). Contrary to the above suggestion,
lithium trisiamylborohydride (LS-SelectrideÒ),29 a bulkier
reagent than L-SelectrideÒ, gave only moderate selectivity
independently of the presence of CeCl3 (entries 8 and 9).
Preparation of the I-ring segment 7 from known 1413j,p is
illustrated in Scheme 3. Although direct PMB-protection
of the hydroxy group at C34 of 14 was possible, the resulting
compound resisted the removal of the benzylidene acetal
without detachment of the PMB group. Therefore, the alco-
hol 14 was first transformed into pivalate 15 (100%), which
was converted to PMB ether 19 (overall 83%) by a five-step
process [(i) removal of the benzylidene acetal with Zn(OTf)2
and ethanedithiol,23 (ii) protection of the resulting diol with
p-bromobenzyl (PBB) bromide, (iii) detachment of the Piv
group, (iv) PMB-protection of the resulting alcohol, (v)
removal of the TBDPS group]. Oxidation of 19 with Dess–
Martin periodinane (DMPI)24 followed by Wittig reaction
afforded 20 (79%), which was hydrolyzed in the presence
of Hg(OAc)2 to produce 7 in good yield (99%).25
Me
Me
O
OR2
OR2
b
e, f
34
RO
a
R1O
Ph
O
O
O
OTBDPS
OTBDPS
16: R1 = Piv, R2 = H
17: R1 = Piv, R2 = PBB
18: R1 = H, R2 = PBB
14: R = H
15: R = Piv
c
d
Me
Me
PMBO
31
BnO
BnO
Me
i
g, h
OPBB
OPBB
OPBB
PMBO
HO
PMBO
Me
7
O
O
19
O
20
OPBB
b
O
O
MeO
22
OTBS
23
OPBB
OPBB
Scheme 3. Reagents and conditions: (a) PivCl, pyridine, 26 ꢀC, 14 h, 100%;
(b) Zn(OTf)2, HS(CH2)2SH, NaHCO3, CH2Cl2, 0 ꢀC, 4 h then 25 ꢀC, 1 h,
100%; (c) PBBBr, NaH, TBAI, THF, 25 ꢀC, 14 h, 100%; (d) DIBAL,
CH2Cl2, ꢁ78 ꢀC, 1.5 h, 88%; (e) PMBBr, NaH, TBAI, THF, 26 ꢀC, 21 h;
(f) TBAF, THF, 0 ꢀC, 1.5 h, 94% from 18; (g) DMPI, CH2Cl2, 0/23 ꢀC,
50 min; (h) Ph3P+CH2OMeClꢁ, NHMDS, 0 ꢀC, 30 min, then aldehyde,
ꢁ78/25 ꢀC, 17 h, 79%; (i) Hg(OAc)2, THF–H2O (10:1), 23 ꢀC, 1 h,
then TBAI, 1.5 h, 99%.
Scheme 5. Reagents and conditions: (a) DMPI, NaHCO3, CH2Cl2, 25 ꢀC,
2.5 h, 100%.
Table 1. Reduction of 23 with several reducing agents
PMBO
31
BnO
BnO
Me
Me
O
Conditions
21
+ 22
O
O
4. Construction of the H-ring
OTBS
23
OPBB
OPBB
Connection of 6 and 7 is depicted in Scheme 4. According to
the Nozaki–Hiyama–Kishi procedure,18 the segments 6 and
7 were treated with CrCl2 in the presence of NiCl2 (0.5 wt %
of CrCl2) in DMSO, and the reaction smoothly proceeded to
Entry Conditions
21:22a Yield
(%)b
1
2
3
4
5
6
7
8
9
DIBAL, CH2Cl2, ꢁ78 ꢀC, 0.5 h
1:1 w100
2:1 w100
3:1
2:1
4:1
DIBALÒ, BuLi, THF, ꢁ78 ꢀC, 1 h
PMBO
BnO
BnO
Me
Red-Al , THF, ꢁ78/ꢁ40 ꢀC, 8 h
92
75
35
Me
31
CeCl3$7H2O, NaBH4, MeOH, ꢁ40/0 ꢀC, 1.5 h
CeCl3$7H2O, NaBH4, MeOH, ꢁ78 ꢀC, 1.5 h
CeCl3, L-SelectrideÒ, THF, ꢁ78 ꢀC, 2 h
L-SelectrideÒ, THF, ꢁ78 ꢀC, 2 h
O
R1 R2
a
O
7
6:1 w100
OTBS
OPBB
>13:1 w100
OPBB
CeCl3, LS-SelectrideÒ, THF, ꢁ78/ꢁ40 ꢀC, 26 h
6:1
5:1 w100
67
21: R1 = H, R2 = OH
22: R1 = OH, R2 = H
LS-SelectrideÒ, THF, ꢁ40 ꢀC, 18 h
Determined by 1H NMR analysis.
Combined yield.
a
Scheme 4. Reagents and conditions: (a) 6, CrCl2, NiCl2, DMSO, 25 ꢀC,
25 h, 21: 45% from 7, 22: 40% from 7.
b

A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
7411
The low reactivity of LS-SelectrideÒ toward 23, suggested by
the fact that LS-SelectrideÒ needed higher temperature to
consume the substrate (23) than L-SelectrideÒ, was probably
due to its excessive bulkiness and might be attributable to
the moderate selectivity. Thus, the inversion of the stereo-
chemistry at C31 was efficiently achieved by a two-step
Dess–Martin oxidation/L-SelectrideÒ reduction process.
29-epi-FGHI-ring part, by diastereoselective reduction.
The reduction of 27 was expected to give 3 with high dia-
stereoselectivity because the methyl group adjacent to the
ketone would sterically hinder the approach of a reductant
to the ketone from the same side of the methyl group.
Accordingly, the construction of the 29-epi-FGHI-ring part
28 from 26 was first investigated.
Construction of the H-ring is illustrated in Scheme 6. The
VO(acac)2-catalyzed epoxidation of 21 with TBHP exclu-
sively afforded 24 (91%).30 Protection of the hydroxy group
at C31 of 24 by the TES group followed by removal of the
PMB group of 25 with DDQ produced 5 in good yield (over-
all 97%). The hydroxy epoxide 5 was smoothly cyclized
with catalytic CSA into 26 (80%). The stereochemistry at
C30 of 26 was confirmed by the presence of NOE between
H34 and the protons of the methyl group at C30. Thus, the
F–HI-ring part 26 was efficiently constructed from 6 and 7
in total seven steps, including the C31-inversion step, in
58% overall yield.
Protection of the hydroxy group at C29 of the F–HI-ring part
26 and the selective deprotection of the TES group at O31
were first examined in order to perform the oxidation at
C31 in the later step (Scheme 8). Although the hydroxy group
at C29 showed extremely low reactivity to AcCl, Ac2O, or
MsCl, which might be attributable to the steric hindrance
of the TES and the C31-methyl groups as well as the F-ring
part, the protection with highly reactive trifluoroacetic an-
hydride successfully afforded Tfa ester 29 in good yield.
Then the selective removal of the TES group under mild
conditions (THF–H2O–TFA) was examined. However, the
reaction proceeded very slowly with migration of the Tfa
group associated with the detachment of the TES group to
produce alcohol 30 having a Tfa group at O31 exclusively
(63% after three cycles) without the desired O29-protected
alcohol.
R2O
BnO
BnO
Me
O
Me
31
O
OR1
a
O
21
OTBS
OPBB
OPBB
R1O
29
OTBS 31
R2O
24: R1 = H, R2 = PMB
25: R1 = TES, R2 = PMB
5: R1 = TES, R2 = H
BnO
BnO
Me
b
c
Me
H
H
O
O
a
OPBB
OPBB
26
NOE
O
BnO
BnO
HO
Me
Me
H
34
29: R1 = Tfa, R2 = TES
30: R1 = H, R2 = Tfa
O
O
H
b
30
d
OTBS
OPBB
OPBB
O
H
TESO
26
Scheme 8. Reagents and conditions: (a) (CF3CO)2O, pyridine, CH2Cl2,
0 ꢀC, 1 h, 100%; (b) THF–H2O–TFA (4:1:0.1), 2 d, 63% after three cycles.
Scheme 6. Reagents and conditions: (a) VO(acac)2, TBHP, toluene, 0 ꢀC,
2 h, 91%; (b) TESOTf, 2,6-lutidine, CH2Cl2, 25 ꢀC, 10 min, 100%; (c)
DDQ, CH2Cl2–pH 7 buffer (10:1), 0 ꢀC, 1 h, 97%; (d) CSA, CH2Cl2,
0 ꢀC, 25 min, 80%.
Although selective deprotection of the O31-TES group
could not be achieved, this result suggested that the two
hydroxy groups at C29 and C31 were in close proximity.
Therefore, we next designed a stepwise route for the protec-
tion of the C29-hydroxy group via a cyclic acetal, which
would be facilely prepared from a 29,31-diol derivative
(31) of 26 due to close proximity of these two hydroxy
groups at C29 and C31 (Scheme 9).
5. Construction of the G-ring
5.1. First-generation approach to the construction of the
FGHI-ring part
The diol 31 was readily obtained from 26 by selective depro-
tection of the TES group under mild acidic conditions
(Scheme 9).31 Treatment of 31 with p-anisaldehyde under
acidic conditions gave a 1:1 mixture of 32a and 32b in excel-
lent yield. After the acetals were separated by HPLC, the
stereochemistry of 32a and 32b was determined from
NOE experiments on the basis of S configuration at C31 as
follows: for 32a, the presence of NOE between the acetal
proton and H29 as well as absence of NOEs between the
acetal proton and H31 and between H29 and H31 established
the S configuration at C29 and R at the acetal carbon; for
32b, the presence of NOE between the acetal proton and
H31 as well as the absence of NOEs between the acetal
proton and H29 and between H31 and H29 confirmed the
S configuration at C29 and S at the acetal carbon. The reduc-
tive cleavage reactions of acetals 32a and 32b with DIBAL
gave different results. While the cleavage of 32a showed
relatively high selectivity (33a:33b¼5:1), that of 32b gave
opposite but excellent selectivity (33b:33a>20:1). Although
At first, a plan for the construction of the G-ring part in-
cluding inversion of the stereochemistry at C29 at the final
stage, shown in Scheme 7, was examined. The target com-
pound 3 was envisioned to be constructed from ketone 27,
which would be prepared from 28 corresponding to the
Me
O
Me
H
H
19
O
H
H
BnO
BnO
29
O
F
I
G
31
3
OPBB
OPBB
26
O
O
H
27
H
40
Me
HO
29
Me
H
H
19
O
H
BnO
BnO
O
31
26
OPBB
OPBB
26
O
O
H
H
28
40
Scheme 7. First-generation plan for the construction of the FGHI-ring part
(3) from 26.

7412
A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
BnO
BnO
with HF$Py afforded 35 in overall 44% yield. Then, cycliza-
HO
29
OTBS 31
Me
Me
H
H
tion of 35 into a cyclic S,O-acetal or a cyclic acetal was at-
tempted. When the ketone 35 was treated with ethanethiol in
the presence of Zn(OTf)2,32 the desired cyclic S,O-acetal
was not produced, and decomposition of 35 due to detach-
ment of the PMB group followed by a retro aldol reaction
took place. On the other hand, treatment of 35 with trimethyl
orthoformate and catalytic PTS33 only resulted in recovery
of the starting material 35. These results showed that an
acid-labile group, such as PMB, was inappropriate for the
protection at O29 during the G-ring formation under acidic
conditions. Therefore, an alternative protective group at
O29 was then investigated.
O
O
a
26
OPBB
OPBB
O
HO
31
b
R2
BnO
BnO
R1
O
Me
Me
H
H
O
O
31
29
O
OTBS
OPBB
O
OPBB
32a: R1 = PMP, R2 = H
32b: R1 = H, R2 = PMP
Me
H
H
Me
H
29
Cyclization of the G-ring after protection of O29 as a benzyl
ether was performed as shown in Scheme 11. The F–HI-ring
part 33b possessing a PMB group at O31 was used as a start-
ing material. Protection of 33b with BnBr, which required
long reaction time (5 d) for the complete consumption of
33b, gave 38 in 71% yield. The PMB group of 38 was
smoothly deprotected with DDQ to provide 39 (85%). Oxi-
dation of 39 with DMPI24 followed by deprotection of the
TBS group afforded hydroxy ketone 41 in overall 75% yield.
The reductive cyclization of 41 with excess Et3SiH in the
presence of TMSOTf furnished the 29-epi-FGHI-ring part
42 stereoselectively.16 The G-ring closure and the desired
stereochemistry of C31 in 42 were proved by the presence
of NOE between H26 and H31 as well as the large JH31–H32ax
(12.4 Hz).
29
NOE
O
O
H
H
31
O 31
H
O
O
H
O
H
H
PMP
H
NOE
PMP
32a
32b
R3O
29
OTBS 31
R4O
BnO
BnO
Me
c
32a
32b
Me
H
H
O
O
d
OPBB
OPBB
O
33a: R3 = PMB, R4 = H
33b: R3 = H, R4 = PMB
Scheme 9. Reagents and conditions: (a) PPTS, MeOH–CH2Cl2 (4:1), 24 ꢀC,
40 min, 100%; (b) p-anisaldehyde, PPTS, benzene, reflux, 3 h, 100%
(32a:32b¼1:1); (c) DIBAL, CH2Cl2, ꢁ30 ꢀC, 1.5 h, 100% (33a:33b¼
5:1); (d) DIBAL, CH2Cl2, ꢁ20 ꢀC, 2 h, 100% (33b:33a>20:1).
R1O
29
OTBS 31
R2O
BnO
BnO
Me
Me
H
O
O
a
the reason for the regioselectivity of the reductive cleavage
with DIBAL cannot be clarified at present, it is suggested
that the stereochemistry of the acetal carbon would affect
the regioselectivity of the acetal fission. Thus, O29-pro-
tected compound 33a could be obtained though the overall
yield from 26 was moderate.
33b
OPBB
OPBB
O
H
38: R1 = Bn, R2 = PMB
b
39: R1 = Bn, R2 = H
c
BnO
BnO
BnO
29
Me
Me
H
H
O
O
Next, the construction of the G-ring from 33a via a two-step
cyclization/reductive etherification reaction of ketone 35
was examined (Scheme 10). The cyclization precursor 35
was readily synthesized in two steps. Oxidation of 33a
with DMPI24 followed by deprotection of the TBS group
31
OR
O
26
OPBB
OPBB
O
40: R = TBS
d
41: R = H
e
Me
BnO
Me
H
H
H
BnO
BnO
O
H
O
F
I
G
H
BnO
31
PMBO
29
Me
OPBB
OPBB
26
Me
H
H
O
O
32
O
BnO
O
31
H
NOE
a
OR
O
33a
26
OPBB
OPBB
J
H31-H32ax = 12.4 Hz
H31-H32eq = 4.3 Hz
O
42
J
34: R = TBS
35: R = H
b
Scheme 11. Reagents and conditions: (a) BnBr, NaH, TBAI, THF, 22 ꢀC,
5 d, 71%; (b) DDQ, CH2Cl2–pH 7 buffer (10:1), 0 ꢀC, 35 min, 85%; (c)
DMPI, NaHCO3, CH2Cl2, 25 ꢀC, 30 min; (d) THF–H2O–TFA (10:10:1),
25 ꢀC, 2 d, 75% from 39; (e) TMSOTf, Et3SiH–CH2Cl2 (1:10), 0 ꢀC,
30 min, 70%.
c or d
Me
PMBO
Me
H
H
H
BnO
BnO
O
O
Thus, the 29-epi-FGHI-ring part 42 was assembled from 26
in total eight steps in 15% overall yield. Although the syn-
thesis of a key compound (42) for the synthesis of the
FGHI-ring part 3 succeeded, it is still difficult to supply a rea-
sonable amount of 42 due to some problems, for example,
difficulty in the separation of acetals 32a and 32b, unusable
33a, and low reactivity of 33b in the protection step. On the
OPBB
OPBB
O
O
X
H
36: X = SEt
37: X = OMe
Scheme 10. Reagents and conditions: (a) DMPI, CH2Cl2, 24 ꢀC, 2 h, 70%;
(b) HF$Py, THF, 24 ꢀC, 2 d, 63%; (c) Zn(OTf)2, EtSH, NaHCO3, CH2Cl2,
25 ꢀC, 1 h; (d) HC(OMe)3, PTS, MeOH, 25 ꢀC, 4 d.

A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
7413
BnO
BnO
other hand, the synthesis of 3 from 42 would require four
more steps involving detachment of all Bn groups of 42,
selective protection of the 1,3-diol part, oxidation of the
hydroxy group at C29, and reduction of the resulting ketone
to 3. Accordingly, in order to overcome the above difficul-
ties, an alternative synthesis of the FGHI-ring part from
26, where the C29 configuration was inverted prior to the
G-ring cyclization, was designed as described in the next
section.
HO
Me
Me
H
H
O
O
29
OTBS
31
OPBB
OPBB
O
TESO
26
a
BnO
BnO
O
Me
Me
H
H
O
O
29
OTBS
31
OPBB
OPBB
O
RO
45: R = TES
46: R = H
5.2. Second-generation approach to the construction of
the FGHI-ring part
b
Scheme 13. Reagents and conditions: (a) (COCl)2, DMSO, CH2Cl2,
ꢁ45 ꢀC, 1 h, then Et3N, 0 ꢀC, 20 min, 61% after two cycles; (b) HF$Py,
THF–pyridine (2:1), 25 ꢀC, 6 d, 71%.
Next, a second plan for the synthesis of the FGHI-ring part
including inversion of the stereochemistry at C29 in advance
of the G-ring formation was investigated. In the plan, out-
lined in Scheme 12, O29-protected FGHI-ring part 43 was
selected as a target compound and envisaged to be synthe-
sized from 26 via the route including (i) inversion of the
stereochemistry at C29 providing 44 and (ii) formation of
the G ring from 44 through reductive etherification. Success
of the plane relied on the C29-inversion step.
Reduction with Red-AlÒ resulted in exclusive formation of
31 and low yield due to decomposition of the substrate and
the product (entry 1, Table 2). Combined use of DIBAL
and BuLi at ꢁ78 ꢀC also selectively gave 31 along with re-
covered 46 (entry 2).27 While reduction with LiBH4 in THF
afforded only 31 (entry 3), the reduction in MeOH produced
47 as a mixture with 31 (entry 4). The presence of MeOH in
the reaction with NaBH4 and KBH4 also effectively pro-
vided 47 though the selectivity was low (entries 5–8). While
use of Me4N(AcO)3BH35 afforded only 31 (entry 9), re-
duction with NaBH4 in the presence of Et2BOMe36 gave
a similar result as in entries 5–6 (entry 10). Among these
experiments, the reduction with NaBH4 in MeOH at 0 ꢀC
gave the best result (47:31¼2:1). Although L-SelectrideÒ
and Super-HydrideÒ were also examined, they were not
reacted with the ketone in THF at ꢁ20 ꢀC. The stereochem-
istry of the newly generated asymmetric center at C29 in 47
was elucidated at the later stage of the synthesis.
R1O
Me
Me
H
19
O
H
31
H
BnO
BnO
29
G
O
F
I
OPBB
OPBB
26
O
O
H
43
H
H
40
BnO
BnO
HO
Me
Me
H
34
O
O
H
30
26
OTBS
OPBB
OPBB
O
H
R2O
44
These results suggested that decrease of steric hindrance due
to unprotection of C31–OH contributed to increasing reac-
tivity of the ketone. The result from the reaction with
Me4N(AcO)3BH also suggested that coordination or com-
plexation of the unprotected hydroxyl group at C31 with
Scheme 12. Second-generation plan for the construction of the FGHI-ring
part (43) from 26.
At first, inversion of the stereochemistry at C29 of 26 was
examined. Since the hydroxy group at C29 of 26 showed
seriously low reactivity to electrophiles including several
protective groups and MsCl due to steric hindrance around
the hydroxy group, as mentioned in the previous section,
the inversion at C29 of 26 by an SN2 reaction was obviously
difficult. Therefore, we took an oxidation/reduction process
as a reasonable method for inversion of the stereochemistry
at C29. Although the alcohol 26 resisted several oxidation
reactions (DMPI,24 SO3$Py, TPAP, and PCC) owing to the
above steric hindrance, Swern oxidation34 of 26 at higher
temperature (ꢁ45 ꢀC) for prolonged reaction time (1 h)
was able to give the ketone 45 along with recovered 26.
In order to consume the substrate 26, when the mixture of
45 and 26 was subjected to the Swern oxidation again,
the ketone 45 was obtained in 61% yield without recovery
of 26 (Scheme 13). However, the reduction of the ketone
45 to C29-epi-26 was not achieved. While treatment of
45 with NaBH4 or LiAlH4 gave only decomposed com-
pounds due to the detachment of the TES and/or TBS
groups, DIBAL reduction of 45 regenerated exclusively
the original alcohol 26. Accordingly, we next examined
the reduction of 46, obtained selectively by treatment of
45 with HF$Py (71%), under several conditions as shown
in Table 2.
Table 2. Reduction of 46 with several reducing agents
1R2
BnO
BnO
R
Me
Me
H
O
O
29
Conditions
46
OPBB
OPBB
OTBS
O
H
HO
47: R1 = OH, R2 = H
31: R1 = H, R2 = OH
Entry Conditions
47:31a Yield
(%)b
1
2
3
4
5
6
7
8
9
10
Red-AlÒ, THF, ꢁ20 ꢀC, 3 h
0:1 50
DIBAL, BuLi, THF, ꢁ78 ꢀC, 1.5 h
LiBH4, THF, ꢁ20 ꢀC, 40 min
0:1 NDc
0:1 w100
0.3:1 w100
0.8:1 w100
2:1 w100
1.3:1 NDc
1.5:1 w100
0:1 w100
1:1 NDc
LiBH4, MeOH, ꢁ20 ꢀC, 22 h
NaBH4, MeOH, ꢁ20 ꢀC, 1 h
NaBH4, MeOH, 0 ꢀC, 15 min
KBH4, MeOH, 25 ꢀC, 21 h
KBH4, THF–MeOH (1:1), 0 ꢀC, 22 h
Me4N(AcO)3BH, AcOH, MeCN, 40 ꢀC, 2 d
Et2BOMe, NaBH4 THF–MeOH (5:1), 0 ꢀC, 15 h
Determined by 1H NMR analysis.
Combined yield.
Not determined.
a
b
c

7414
A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
BnO
BnO
the reducing agent did not participate the production of 47.
Since the reason for the solvent effect of MeOH producing
47 was unclear, we could only speculate the role of MeOH
as follows: (i) alteration of the conformation of 46 by hydro-
gen bonding between the ketone and MeOH, and/or (ii) pro-
hibition of the coordination or complexation of the reducing
agent with C31–OH, which would increase external attack
of the reagent to the ketone producing 47.
Np
O
Me
Me
H
H
O
H
O
a
29
47
O
31
OPBB
OPBB
OTBS
48
O
Me
Np: 2-naphthyl
NOE
29
H
O
H
31
O
b
O
H
H
Thus, the inversion of the stereochemistry at C29 was
achieved by the reduction of the b-hydroxy ketone 46 with
NaBH4 in MeOH at 0 ꢀC though the selectivity of the re-
duction was unsatisfactory. Hence, transformation of the un-
desired diol 31 into the desired 47 was examined. As a result,
the hydroxy group at C31 of 31 was simply and selectively
protected with TESOTf to provide 26 in excellent yield
(Scheme 14), thereby establishing the recycle route from
31 to 47 via 26.
Np
48
R1O
BnO
BnO
Me
Me
H
O
O
29
OTBS
R2O
31
OPBB
OPBB
O
H
NAP: 2-naphthylmethyl
49: R1 = H, R2 = NAP
50: R1 = Bn, R2 = NAP
51: R1 = Bn, R2 = H
c
d
e
BnO
BnO
BnO
29
Me
BnO
BnO
HO
Me
Me
H
Me
H
H
O
O
O
O
29
OTBS
31
OR
O
31
26
OPBB
OPBB
OPBB
OPBB
O
H
O
RO
31: R = H
26: R = TES
52: R = TBS
53: R = H
g
f
a
Me
BnO
G
Scheme 14. Reagents and conditions: (a) TESOTf, 2,6-lutidine, CH2Cl2,
ꢁ40 ꢀC, 1 h, 95%.
Me
H
H
H
BnO
BnO
O
H
O
F
I
31
OPBB
OPBB
26
O
O
32
Next, construction of the G-ring from 47 was investigated
(Scheme 15). At first, selective protection of the hydroxy
group at C29 of the diol 47 via a cyclic acetal was performed.
Treatment of 47 with 2-naphthaldehyde dimethyl acetal un-
der acidic conditions gave 2-(2-naphthyl)-1,3-dioxane 48 as
the sole product (89%). Stereochemistry of the acetal 48 in-
cluding the C29-stereocenter, whose formation is described
in the above section, was determined by NOE experiment on
the basis of S configuration at C31. The presence of NOEs
between the acetal proton and H31 and between the acetal
proton and H29 confirmed the R configuration at C29 as
well as the S configuration at the acetal carbon. Reduction
of 48 with DIBAL exclusively afforded 49 possessing the
NAP group35 at O31 in good yield. Protection of the re-
sultant hydroxy group at C29 of 49 with BnBr followed by
detachment of the NAP group at O31 provided 51 (overall
91%). Thus, the selective Bn-protection at O29 of 47 was ac-
complished by the four-step process. Next, G-ring formation
via reductive cyclization was executed. The alcohol 51 was
oxidized with DMPI,24 and the resulting 52 was desilylated
to give hydroxy ketone 53 quantitatively. The reductive
cyclization of 53 with excess Et3SiH in the presence of
TMSOTf at 0 ꢀC produced the FGHI-ring part 54 stereose-
lectively (78%).16 The stereochemistry of 54 was confirmed
by the presence of ROE between H26 and H31 as well as the
large JH31–H32ax (12.1 Hz). Thus, the FGHI-ring part 54 was
successfully constructed from the F–HI-ring part 26 in 18%
overall yield in 10 steps.
H
H
ROE
J
H31-H32ax = 12.1 Hz
H31-H32eq = 4.6 Hz
54
J
Scheme 15. Reagents and conditions: (a) NpCH(OMe)2, PPTS, benzene, re-
flux, 1.5 h, 89%; (b) DIBAL, CH2Cl2, 10 ꢀC, 3 h, 100%; (c) BnBr, NaH,
TBAI, THF, 25 ꢀC, 8 h, 100%; (d) DDQ, CH2Cl2–pH 7 buffer (10:1),
0 ꢀC, 20 min, 91%; (e) DMPI, NaHCO3, CH2Cl2, 25 ꢀC, 25 min; (f) HF$Py,
THF, 25 ꢀC, 2 d, 100% from 51; (g) TMSOTf, Et3SiH–CH2Cl2 (1:10), 0 ꢀC,
30 min, 78%.
for the conversion of the F–HI-ring part 26 to the alcohol
49 was investigated (Scheme 16).
The diol 31 prepared from 26 was treated with 2-naphthalde-
hyde dimethyl acetal in the presence of PPTS31 to give a
cyclic acetal 55a as a major product (89%) along with the
minor diastereomer 55b (11%). The stereochemistry of
55a and 55b was determined by similar NOE experiments
based on the S configuration at C31 as described in Section
5.1. The presence of NOE between the acetal proton and
H31 as well as the absence of NOEs between the acetal pro-
ton and H31 and between H29 and H31 in 55a confirmed its
stereochemistry. The stereochemistry of 55b was also veri-
fied by the presence of NOE between the acetal proton and
H29 as well as the absence of NOEs between the acetal pro-
ton and H31 and between H29 and H31. The reductive cleav-
age of the major Np-acetal 55a with DIBAL selectively
provided 56 (93%),37 where the regioselectivity agreed
with the case of 32b (Section 5.1). Oxidation of 56 with
DMPI smoothly afforded the ketone 57 in good yield
(90%). Prior to the reduction of 57, preliminary examina-
tions using ketone 58 (Fig. 2), derived from 33b, were per-
formed. When the ketone 58 was treated with NaBH4 in
MeOH, the starting ketone was only recovered due to
5.2.1. Refinement of the second-generation approach.
While construction of the FGHI-ring part was achieved,
the yield of b-hydroxy ketone 46 from the F–HI-ring part
26 was low (overall 43%) and the reduction of 46 gave
low stereoselectivity (w2:1). Therefore, an improved route

A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
7415
R2
an alternative method. In the first-generation approach, we
expected that the reduction of ketone 27 would produce 3
stereoselectively, but we could not prove the idea (Section
5.1). Since the above-mentioned acetal 55b, obtained as a
minor product, could be converted to 29-epi-FGHI-ring
part 28 via 59 (Scheme 17), we examined the initial idea
with 28. Reductive cleavage of 55b with DIBAL exclusively
gave 59 possessing an NAP-group at O29, which showed
similar stereoselectivity as that of 32b. Transformation of
59 to a tetracyclic 60, O29-NAP ether of 28, was readily per-
formed by the same procedure as that of 33b to 42. Depro-
tection of the NAP-group of 60 with DDQ followed by
Dess–Martin oxidation of the resulting hydroxy group
afforded the ketone 27. Contrary to our expectation, reduc-
tion of the ketone 27 with NaBH4, LiAlH4, or L-SelectrideÒ
provided 28 as a major product. Thus, we found that the first
generation-approach was unsuccessful, and the failure sug-
gested that the C29-stereocenter should be constructed at
the early stage of the synthesis.
BnO
BnO
R1
O
Me
Me
H
H
O
O
29
O
OTBS
a
31
31
OPBB
OPBB
O
55a: R1 = H, R2 = Np
55b: R1 = Np, R2 = H
Me
H
Me
H
H
H
29
29
H
NOE
H
O
O
H
31
31
O
O
O
O
H
H
NOE
Np
H
Np
55a
55b
BnO
BnO
HO
Me
Me
H
O
b
O
29
55a
OTBS
31
OPBB
OPBB
O
NAPO
H
56
c
BnO
BnO
O
Me
BnO
BnO
NAPO
29
OTBS 31
Me
H
Me
O
O
29
Me
H
H
O
O
OTBS 31
55b
OPBB
OPBB
O
NAPO
H
OPBB
OPBB
O
HO
57
d
59
BnO
BnO
HO
Me
Me
H
H
O
O
29
Me
RO
Me
H
H
OTBS 31
NAPO
49
O
H
BnO
BnO
OPBB
OPBB
29
O
O
31
OPBB
OPBB
26
O
O
H
H
Scheme 16. Reagents and conditions: (a) NpCH(OMe)2, PPTS, benzene,
reflux, 2 h, 55a: 89%, 55b: 11%; (b) DIBAL, CH2Cl2, 0/10 ꢀC, 2 h, 93%;
(c) DMPI, NaHCO3, CH2Cl2, 25 ꢀC, 8 h, 90%; (d) NaBH4, CeCl3$7H2O,
THF–H2O (3:1), 25 ꢀC, 8 d, 96% (49:56>5:1).
60: R = NAP
28: R = H
Me
O
Me
H
H
19
O
H
BnO
29
O
F
H
I
31
G
BnO
OPBB
OPBB
insolubility of the ketone to MeOH. The use of a THF–H2O
(5:1) mixed solvent system in the reduction, where the
ketone was soluble, produced alcohols 33b and 29-epi-33b
as a 1:2 mixture (preliminary data). Therefore, the reduction
of 57 with NaBH4 was performed in THF–H2O (3:1).
Although the mixed solvent system gave alcohols 49 and
56, significant decomposition was observed. After several
experiments, the reduction of 57 with NaBH4 in the presence
of CeCl3$7H2O28 in THF–H2O (3:1) was found to proceed
cleanly. Although long reaction time (8 d) was required in
order to consume the ketone 57, the reduction showed high
yield (96%) and selectivity (49:56>5:1). Thus, the improved
route from the F–HI-ring part 26 to alcohol 49 (overall 59%
yield in five steps; previous route: 26% yield in five steps)
based on selective protection of O31 and stereoselective
reduction of the C29-carbonyl group was developed.
26
O
O
H
27
H
40
Scheme 17. Synthesis of ketone 27 from 55b.
6. Conclusion
The aim of this study was the development of an efficient
method for the construction of the GH-ring part of ciguatox-
ins in a convergent manner, which was envisaged to be per-
formed at the final stage of the total synthesis of ciguatoxins.
Accordingly, we extensively explored a synthetic route for
the common FGHI-ring part (54) of ciguatoxins from the
F- and I-ring segments. As a result, the convergent synthesis
of 54 was achieved via the following key steps: (i) the
Nozaki–Hiyama–Kishi reaction connecting the F-ring (6)
with the I-ring (7); (ii) regio- and stereoselective epoxi-
dation; (iii) the 6-exo-epoxide opening reaction forming
simultaneously the H-ring and the quaternary asymmetric
center at C30; (iv) inversion of the C29 stereocenter by
a two-step oxidation/reduction process, where the successful
inversion depended on proper management of the steric
environment of the substrate; and (v) final reductive cycliza-
tion constructing the G-ring. Thus, the FGHI-ring part was
efficiently synthesized through a novel route in 17 steps in
24% overall yield from 6 and 7. Further studies toward the
Although it includes preliminary results, we also disclose
herein an assessment of the first-generation approach by
BnO
BnO
O
Me
Me
H
H
O
O
29
OTBS
31
OPBB
OPBB
O
PMBO
58
Figure 2.

7416
A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
total synthesis of the ciguatoxins are now under way in this
laboratory.
9: a colorless solid; mp 154.0–157.0 ꢀC; [a]D23 +29.3 (c
0.10, CHCl3); H NMR (300 MHz, CDCl3), d (ppm) 7.49–
1
7.31 (5H, m), 5.88–5.77 (2H, m), 5.43 (1H, s), 4.32 (1H,
dd, J¼3.9, 9.8 Hz), 3.87 (1H, dt, J¼8.6, 4.4 Hz), 3.73–
3.65 (3H, m), 3.63 (1H, dt, J¼3.9, 9.8 Hz), 3.57 (1H, t,
J¼9.8 Hz), 3.38 (1H, dt, J¼8.8, 4.4 Hz), 2.71–2.54 (4H,
m); IR (KBr), n (cmꢁ1) 3435, 3091, 2925, 2858, 1455,
1412, 1294, 1219, 1114, 1075, 1015, 963, 948, 916, 883,
759, 700; HR-EIMS, calcd for C17H22O5 [M]+: 306.1467,
found: 306.1446.
7. Experimental
7.1. General methods
All reactions involving air- or moisture-sensitive reagents
were carried out under an argon atmosphere in oven-dried
glasswares capped with septa, and sensitive liquids and
solutions were transferred by using syringe- or cannula-
techniques, unless otherwise stated. All commercially avail-
able reagents were used without further purification with the
following exceptions. Tetrahydrofuran (THF) was distilled
from sodium-benzophenone ketyl under argon. Dichloro-
methane (DCM), dimethylsulfoxide (DMSO), and benzene
(PhH) were distilled from CaH2 prior to use. Normal
reagent-grade solvents were used for flash chromatography
and extraction. Special reagent-grade solvents were used
for high-pressure liquid chromatography (HPLC). All reac-
tions were monitored by thin-layer chromatography (TLC)
with precoated silica gel (SiO2) plates (Merck, silica gel 60
F254). Plates were visualized by ultraviolet light and by treat-
ment with acidic anisaldehyde or phosphomolybdic acid
stain followed by heating. SiO2 (YMC, SIL-60-400/230W)
was utilized for flash chromatography. HPLC was run with
a JASCO Intelligent HPLC Pump PU-986, equipped with
a JASCO Intelligent UV–vis Detector UV-975 and a YMC-
Pack SIL-06 (250ꢂ10 or 20 mm ID) HPLC column. Melting
points were measured on Yanagimoto micro-melting appara-
tus without calibration. Optical rotations were recorded on
a JASCO P-1020 digital polarimeter. Infrared (IR) spectra
were measured on a JEOL JIR-WINSPEC100 infrared
7.1.2. (1R,3S,4R,6Z,9S)-4-Benzyloxy-3-benzyloxymethyl-
11-phenyl-2,10,12-trioxabicyclo[7.4.0]tridecan-6-ene
(10). To a solution of 9 (103 mg, 0.337 mmol) in THF
(4.0 ml) were added NaH (33.7 mg, 0.841 mmol) and
TBAI (12.4 mg, 0.0337 mmol) at 0 ꢀC and the mixture
was stirred for 10 min. Then, benzyl bromide (100 ml,
0.841 mmol) was added at 0 ꢀC, the reaction mixture was
warmed to 25 ꢀC, and stirred for 4.5 h. After that, extra
NaH (33.7 mg, 0.841 mmol) was added, and the stirring
was continued for further 18 h. Saturated aqueous NH4Cl
(4 ml) was added and the aqueous layer was extracted with
Et2O (3ꢂ20 ml). The combined organic layers were washed
with brine, dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo. The resultant residue was purified by col-
umn chromatography (silica gel, hexane/AcOEt¼15 to 5) to
give 10 (61.0 mg, 98%). 10: a colorless solid; mp 110.0–
113.0 ꢀC; [a]2D5 ꢁ12.8 (c 0.64, CHCl3); 1H NMR
(300 MHz, C6D6), d (ppm) 7.40–7.00 (10H, m), 5.86–5.70
(2H, m), 5.32 (1H, s), 4.71 (1H, br d, J¼6.4 Hz), 4.32 (1H,
d, J¼11.7 Hz), 4.31 (1H, d, J¼12.3 Hz), 4.25 (1H, d,
J¼12.3 Hz), 4.00 (1H, d, J¼11.7 Hz), 3.57–3.46 (4H, m),
3.48 (1H, br d, J¼9.7 Hz), 3.31 (1H, dd, J¼7.5, 9.7 Hz),
3.29–3.21 (1H, m), 2.85–2.78 (1H, m), 2.51–2.44 (2H, m),
2.31–2.25 (1H, m); IR (KBr), n (cmꢁ1) 3030, 2924, 2856,
1496, 1453, 1393, 1366, 1294, 1213, 1153, 1103, 1027,
976, 747, 697; HR-EIMS, calcd for C31H34O5 [M]+:
486.2406, found: 486.2420.
spectrometer. H and 13C NMR spectra were recorded on
1
JEOL JNM-AL300 (1H at 300 MHz, 13C at 75 MHz),
JNM-a-400 (1H at 400 MHz, 13C at 100 MHz), JNM-a-500
(13C at 125 MHz) or JNM-ECA600 (1H at 600 MHz, 13C
at 150 MHz) NMR spectrometers. 1H NMR spectra are
reported as chemical shifts (d) in parts per million (ppm)
based on tetramethylsilane (0.00 ppm), C6HD5 (7.15 ppm)
or CHD2C(]O)CD3 (2.04 ppm). Splitting patterns were
designated as ‘s, d, t, q, m, and br’ indicating ‘singlet,
doublet, triplet, quartet, multiplet, and broad’, respectively.
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 13C12C5D6 (128.0 ppm). High-
resolution mass spectra (HRMS) were measured on a JEOL
JMS-600H mass spectrometer under electron impact ioniza-
tion (EI) condition and a JEOL JMS-SX102A mass spec-
trometer under field desorption ionization (FD) condition.
7.1.3. (2R,3S,5Z,8R,9S)-8-Benzyloxy-9-benzyloxymethyl-
2-hydroxymethyl-2,3,4,7,8,9-hexahydrooxonin-3-ol (11).
To a solution of 10 (664 mg, 1.36 mmol) in THF (15.0 ml)
was added 3 M HCl (15.0 ml) at 25 ꢀC and the mixture
was stirred for 21 h. Then, H2O (15 ml) was added and the
aqueous layer was extracted with AcOEt (4ꢂ60 ml). The
combined organic layers were washed with saturated aque-
ous NaHCO3 and brine, dried over anhydrous MgSO4, fil-
tered, and concentrated in vacuo. The resultant residue was
purified by column chromatography (silica gel, hexane/
AcOEt¼5 to AcOEt) to give 11 (529 mg, 98%). 11: a color-
1
less oil; [a]2D5 ꢁ68.7 (c 1.04, CHCl3); H NMR (300 MHz,
CDCl3), d (ppm) 7.37–7.20 (10H, m), 5.87–5.73 (2H, m,
H5, 6), 4.62 (1H, d, J¼11.5 Hz), 4.52 (1H, d, J¼12.1 Hz),
4.46 (1H, d, J¼12.1 Hz), 4.28 (1H, d, J¼11.5 Hz), 3.87–
3.80 (2H, m, H3, 10), 3.68 (1H, dd, J¼5.0, 11.3 Hz, H10),
3.60–3.57 (1H, m, H1), 3.51–3.41 (4H, m, H1, 2, 8, OH),
3.25 (1H, ddd, J¼3.9, 5.0, 8.8 Hz, H9), 2.81 (1H, ddd,
J¼3.7, 9.9, 13.6 Hz, H4), 2.67–2.60 (1H, m, H7), 2.41–
2.36 (1H, m, H7), 2.15 (1H, ddd, J¼3.7, 4.8, 13.6 Hz, H4);
13C NMR (75 MHz, CDCl3), d (ppm) 137.9 (C), 137.2
(C), 128.5 (CHꢂ2), 128.4 (CHꢂ2), 128.1 (CHꢂ3), 127.9
(CH), 127.8 (CHꢂ2), 127.7 (CH), 127.2 (CH), 87.3 (CH),
84.0 (CH), 78.9 (CH), 73.3 (CH2), 72.0 (CH2), 71.2 (CH2),
7.1.1. (1R,3S,4R,6Z,9S)-3-Hydroxymethyl-11-phenyl-
2,10,12-trioxabicyclo[7.4.0]tridecan-6-en-4-ol (9). To a
solution of 8 (348 mg, 0.649 mmol) in THF (6.0 ml) was
added TBAF (1.95 ml, 1.0 M in THF, 1.95 mmol) at 25 ꢀC
and the mixture was stirred for 1 h. After that, saturated
aqueous NH4Cl (6 ml) was added and the aqueous layer was
extracted with AcOEt (3ꢂ30 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/AcOEt¼1 to AcOEt) to give 9 (196 mg, 98%).

A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
7417
70.3 (CH), 63.9 (CH2), 32.3 (CH2), 26.9 (CH2); IR (film),
n (cmꢁ1) 3407, 3063, 3027, 2919, 2860, 1496, 1453, 1367,
1310, 1260, 1207, 1098, 772, 698, 695; HR-EIMS, calcd
for C24H30O5 [M]+: 398.2093, found: 398.2112.
3.33 (1H, ddd, J¼2.4, 5.0, 8.6 Hz), 3.19 (1H, dt, J¼8.6,
3.3 Hz), 2.83 (1H, ddd, J¼3.3, 10.7, 13.5 Hz), 2.79–2.66
(2H, m), 2.39 (1H, ddq, J¼3.3, 16.9, 2.6 Hz), 2.31 (1H,
ddd, J¼3.3, 4.5, 13.6 Hz), 2.05 (1H, ddd, J¼3.3, 4.5,
13.5 Hz), 1.79 (3H, t, J¼2.6 Hz), 0.88 (9H, s), 0.11 (3H,
s), 0.094 (3H, s); 13C NMR (75 MHz, CDCl3), d (ppm)
138.4 (C), 138.3 (C), 128.24 (CHꢂ2), 128.19 (CHꢂ2),
128.1 (CH), 127.8 (CHꢂ2), 127.7 (CHꢂ2), 127.5
(CHꢂ2), 127.3 (CH), 85.0 (CH), 84.5 (CH), 78.9 (CH),
77.2 (C), 76.2 (C), 73.3 (CH2), 71.9 (CH), 71.8 (CH2),
71.3 (CH2), 32.1 (CH2), 26.8 (CH2), 25.7 (CH3ꢂ3), 22.3
(CH2), 17.8 (C), 3.8 (CH3), ꢁ4.5 (CH3), ꢁ5.0 (CH3); IR
(film), n (cmꢁ1) 3064, 3026, 2956, 2926, 2855, 1471,
1453, 1360, 1309, 1258, 1196, 1099, 1064, 1027, 836,
809, 776, 735, 697; HR-EIMS, calcd for C33H46O4Si
[M]+: 534.3165, found: 534.3209.
7.1.4. (2R,3S,5Z,8R,9S)-[8-Benzyloxy-9-benzyloxy-
methyl-3-(tert-butyldimethylsilyloxy)-2,3,4,7,8,9-hexa-
hydrooxonin-2-yl]methyl trifluoromethanesulfonate
(12). To a solution of 11 (11.4 mg, 28.6 mmol) in DCM
(0.70 ml) were added 2,6-lutidine (20.0 ml, 172 mmol) and
trifluoromethansulfonic anhydride (5.0 ml, 29.7 mmol) at
ꢁ78 ꢀC and the mixture was stirred for 15 min. Then,
TBSOTf (10.0 ml, 43.5 mmol) was added and the reaction
mixture was allowed to warm to 0 ꢀC and stirred for 1 h.
After that, H2O (1 ml) was added and the aqueous layer
was extracted with Et2O (4ꢂ5 ml). The combined organic
layers were washed with 1 M HCl, 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/AcOEt¼
30) to give 12 (17.5 mg, 95%). 12: a pale yellow oil; [a]D19
ꢁ36.5 (c 0.705, CHCl3); 1H NMR (300 MHz, C6D6),
d (ppm) 7.30–7.28 (2H, m), 7.20–7.07 (8H, m), 5.89–5.76
(2H, m), 5.43 (1H, dd, J¼1.5, 10.1 Hz), 4.54 (1H, d,
J¼12.1 Hz), 4.50 (1H, dd, J¼1.5, 10.1 Hz), 4.34 (1H, d,
J¼12.1 Hz), 4.30 (1H, d, J¼12.1 Hz), 4.09 (1H, dt, J¼3.3,
8.8 Hz), 4.00 (1H, d, J¼12.1 Hz), 3.64–3.61 (1H, m), 3.50–
3.40 (2H, m), 3.27 (1H, dt, J¼8.4, 3.1 Hz), 3.22 (1H, dt,
J¼8.8, 1.5 Hz), 2.72 (1H, ddd, J¼3.3, 10.1, 13.8 Hz), 2.56
(1H, ddd, J¼3.1, 10.1, 13.6 Hz), 2.34 (1H, dt, J¼13.6,
3.1 Hz), 2.02–1.95 (1H, m), 0.89 (9H, s), 0.03 (3H, s),
0.007 (3H, s); 13C NMR (75 MHz, C6D6), d (ppm) 138.7
(C), 138.5 (C), 128.8 (CH), 128.6 (CHꢂ2), 128.5 (CHꢂ2),
127.4 (CH), 86.4 (CH), 84.5 (CH), 79.0 (CH), 77.1 (CH2),
73.3 (CH2), 73.1 (CH2), 71.3 (CH2), 69.9 (CH), 32.0 (CH2),
26.9 (CH2), 25.8 (CH3ꢂ3), 17.9 (C), ꢁ4.3 (CH3), ꢁ5.3
(CH3) (The signals of seven carbons were undetected due
7.1.6. (2S,3R,5Z,8S,9R,20E)-3-Benzyloxy-2-benzyloxy-
methyl-8-(tert-butyldimethylsilyloxy)-9-(30-iodo-but-20-
enyl)-2,3,4,7,8,9-hexahydrooxonin (6). To a suspension of
Cp2ZrCl2 (1.47 g, 4.93 mmol) in degassed THF (4.0 ml)
were added DIBAL (5.0 ml, 0.94 M in hexane, 4.70 mmol)
and a solution of 13 (548 mg, 1.02 mmol) in degassed
THF (5.0 ml) at 25 ꢀC. The mixture was heated to 55 ꢀC
and stirred for 30 min in the dark. After the mixture was
cooled to 0 ꢀC, I2 (783 mg, 3.08 mmol) in THF (2.0 ml)
was added and the reaction mixture was stirred for 15 min.
Then, saturated aqueous Na2SO3 (5 ml) and saturated aque-
ous potassium sodium tartrate (10 ml) was added. The mix-
ture was diluted with Et2O and stirred at 25 ꢀC for 12 h. The
layers were separated and the aqueous layer was extracted
with Et2O (3ꢂ50 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/AcOEt¼
75 to 60) to give 6 (584 mg, 86%). 6: a colorless oil; [a]D21
ꢁ81.2 (c 0.46, CHCl3); 1H NMR (300 MHz, CDCl3),
d (ppm) 7.33–7.21 (10H, m), 6.30 (1H, tq, J¼6.6, 1.5 Hz),
5.81–5.70 (1H, m), 4.60 (1H, d, J¼11.4 Hz), 4.53 (1H, d,
J¼12.0 Hz), 4.43 (1H, d, J¼12.0 Hz), 4.29 (1H, d, J¼
11.4 Hz), 3.75 (1H, dt, J¼8.3, 3.4 Hz), 3.71 (1H, dt, J¼
8.6, 3.4 Hz), 3.56 (1H, dd, J¼2.6, 10.1 Hz), 3.47 (1H, dd,
J¼4.2, 10.1 Hz), 3.32 (1H, ddd, J¼2.6, 4.2, 8.6 Hz), 3.24
(1H, dt, J¼8.3, 4.2 Hz), 2.79 (1H, ddd, J¼3.4, 9.9,
13.4 Hz), 2.66 (1H, ddd, J¼3.4, 9.9, 13.6 Hz), 2.49 (1H,
dddq, J¼4.2, 6.6, 16.0, 1.7 Hz), 2.36–2.26 (5H, m), 2.05
(1H, dt, J¼13.4, 3.4 Hz), 0.88 (9H, s), 0.090 (3H, s), 0.023
(3H, s); 13C NMR (75 MHz, CDCl3), d (ppm) 138.3 (C),
138.2 (C), 137.7 (CH), 128.3 (CHꢂ4), 128.0 (CHꢂ3),
127.8 (CHꢂ2), 127.55 (CH), 127.51 (CH), 127.4 (CH),
94.4 (C), 85.4 (CH), 84.0 (CH), 78.3 (CH), 73.4 (CH),
73.3 (CH2), 71.3 (CH2), 71.0 (CH2), 33.5 (CH2), 32.0
(CH2), 28.0 (CH3), 26.9 (CH2), 25.8 (CH3ꢂ3), 17.9 (C),
ꢁ4.1 (CH3), ꢁ4.9 (CH3); IR (film), n (cmꢁ1) 3063, 3026,
1496, 1471, 1453, 1388, 1360, 1336, 1297, 1256, 1195,
1099, 1027, 939, 923, 835, 811, 775, 734, 697; HR-EIMS,
calcd for C33H47IO4Si [M]+: 662.2288, found: 662.2258.
to overlapping with solvent signal.); IR (film), n (cmꢁ1
)
3091, 3035, 2929, 2858, 1496, 1479, 1472, 1454, 1412,
1362, 1336, 1317, 1295, 1245, 1210, 1146, 1102, 1028,
998, 937, 836, 777, 749, 698; HR-EIMS, calcd for
t
C27H34O7F3SiS [Mꢁ Bu]+: 587.1746, found: 587.1745.
7.1.5. (2S,3R,5Z,8S,9R)-3-Benzyloxy-2-benzyloxymethyl-
8-(tert-butyldimethylsilyloxy)-9-(but-20-ynyl)-2,3,4,7,8,9-
hexahydrooxonin (13). To a solution of liquid propyne
(excess) in THF (1.0 ml) was added BuLi (0.60 ml, 1.56 M
in hexane, 0.936 mmol) at ꢁ78 ꢀC and the mixture was
stirred for 10 min. Then, a solution of 12 (123 mg,
0.191 mmol) in THF (2.0 ml) was added and the reaction
mixture was allowed to warm to 24 ꢀC and stirred for 3 h.
After that, H2O (3 ml) was added and the aqueous layer
was extracted with Et2O (3ꢂ15 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/AcOEt¼20) to give 13 (101 mg, 99%). 13: a col-
orless oil; [a]2D6 ꢁ78.4 (c 1.08, CHCl3); 1H NMR (300 MHz,
CDCl3), d (ppm) 7.38–7.23 (10H, m), 5.79 (1H, dt, J¼4.5,
10.7 Hz), 5.76 (1H, dt, J¼4.5, 10.7 Hz), 4.62 (1H, d,
J¼11.6 Hz), 4.54 (2H, s), 4.33 (1H, d, J¼11.6 Hz), 4.07
(1H, dt, J¼8.6, 3.3 Hz), 3.74 (1H, dt, J¼8.6, 3.3 Hz), 3.65
(1H, dd, J¼2.4, 10.3 Hz), 3.51 (1H, dd, J¼5.0, 10.3 Hz),
7.1.7. (10R,30S,40R,60R,80S)-30-(tert-Butyldiphenylsilyloxy-
methyl)-60-methyl-100-phenyl-20,90,110-trioxabicyclo[6.4.0]-
dodecan-40-yl 2,2-dimethylpropanoate (15). To a solution
of 14 (48.6 mg, 87.0 mmol) in pyridine (1.0 ml) was added
pivaloyl chloride (40.0 ml, 325 mmol) at 0 ꢀC. The reaction

7418
A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
mixture was allowed to warm to 26 ꢀC and stirred for 14 h.
Then, saturated aqueous NaHCO3 (1 ml) was added and
the aqueous layer was extracted with Et2O (4ꢂ5 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/AcOEt¼20 to 15) to give 15
(54.9 mg, w100%). 15: a colorless oil; [a]2D6 ꢁ13.3 (c
(8.5 mg, 23.0 mmol) in THF (0.50 ml) was added NaH
(6.2 mg, 155 mmol) at 0 ꢀC and the mixture was stirred for
10 min. Then, to the mixture was added p-bromobenzyl bro-
mide (33.0 mg, 132 mmol) at 0 ꢀC. The reaction mixture was
warmed to 25 ꢀC and stirred for 16 h. Saturated aqueous
NaHCO3 (1 ml) was added and the aqueous layer was
extracted with Et2O (4ꢂ5 ml). The combined organic layers
were washed with brine, dried over anhydrous MgSO4, fil-
tered, and concentrated in vacuo. The resultant residue was
purified by column chromatography (silica gel, hexane/
AcOEt¼20 to 15) to give 17 (11.4 mg,w100%). 17: a color-
1
0.755, CHCl3); H NMR (300 MHz, C6D6), d (ppm) 7.81–
7.76 (4H, m), 7.70–7.67 (2H, m), 7.28–7.11 (9H, m), 5.37
(1H, s), 4.95 (1H, dt, J¼2.8, 9.5 Hz), 4.51 (1H, dd, J¼4.2,
10.6 Hz), 3.68–3.56 (2H, m), 3.51–3.41 (3H, m), 1.94–
1.78 (3H, m), 1.73–1.65 (1H, m), 1.55 (1H, ddd, J¼6.4,
9.5, 14.7 Hz), 1.18 (9H, s), 1.02 (9H, s), 0.91 (3H, d,
J¼7.2 Hz); 13C NMR (75 MHz, CDCl3), d (ppm) 176.9
(C), 137.9 (C), 135.6 (CHꢂ2), 135.5 (CHꢂ2), 133.25 (C),
133.21 (C), 129.71 (CH), 129.67 (CH), 128.9 (CH), 128.3
(CHꢂ2), 127.7 (CHꢂ4), 126.2 (CHꢂ2), 100.9 (CH),
86.9 (CH), 80.7 (CH), 78.5 (CH), 72.5 (CH), 70.0 (CH2),
65.3 (CH2), 44.6 (CH2), 41.9 (CH2), 38.5 (C), 27.8 (CH),
27.0 (CH3), 26.9 (CH3ꢂ3), 26.8 (CH3ꢂ3), 19.1 (C); IR
(film), n (cmꢁ1) 3071, 3047, 2931, 1959, 1889, 1728,
1590, 1456, 1428, 1396, 1276, 1216, 1138, 975, 912, 823,
1
less oil; [a]2D5 +14.6 (c 1.08, CHCl3); H NMR (300 MHz,
C6D6), d (ppm) 7.87–7.76 (4H, m), 7.31–7.15 (10H, m),
6.88–6.81 (4H, m), 5.25 (1H, dt, J¼3.2, 9.4 Hz), 4.22 (1H,
d, J¼12.0 Hz), 4.20 (1H, d, J¼12.1 Hz), 4.10 (1H, d,
J¼12.1 Hz), 3.99 (1H, d, J¼12.0 Hz), 3.97–3.92 (1H, m),
3.85–3.80 (3H, m), 3.76 (1H, dd, J¼2.8, 9.7 Hz), 3.59
(1H, dd, J¼5.5, 9.7 Hz), 3.48 (1H, dt, J¼3.2, 8.4 Hz),
2.12–2.09 (1H, m), 1.96–1.84 (2H, m), 1.76 (1H, dt,
J¼14.2, 9.4 Hz), 1.59 (1H, dt, J¼8.4, 14.5 Hz), 1.18 (9H,
s), 1.07 (9H, s), 0.94 (3H, d, J¼7.2 Hz); 13C NMR
(75 MHz, CDCl3), d (ppm) 176.9 (C), 140.2 (Cꢂ2), 137.7
(CHꢂ2), 137.5 (CHꢂ2), 133.5 (C), 133.3 (C), 131.4
(CHꢂ2), 131.3 (CHꢂ2), 129.6 (CHꢂ2), 129.4 (CHꢂ2),
129.3 (CHꢂ2), 127.7 (CHꢂ2), 127.6 (CHꢂ2), 121.4 (C),
121.3 (C), 86.0 (CH), 85.6 (CH), 78.3 (CH), 72.6 (CH2),
72.0 (CH), 71.2 (CH2), 70.7 (CH2), 65.9 (CH2), 41.9
(CH2), 41.1 (CH2), 38.5 (C), 27.7 (CH), 26.93 (CH3),
26.88 (CH3ꢂ3), 26.85 (CH3ꢂ3), 19.2 (C); IR (film),
n (cmꢁ1) 3071, 2930, 2858, 1897, 1726, 1591, 1487, 1461,
1428, 1396, 1361, 1281, 1113, 1012, 823, 804, 739, 702;
t
754, 703, 615; HR-EIMS calcd for C34H41O6Si [Mꢁ Bu]+:
573.2627, found: 573.2672.
7.1.8. (20S,30R,50R,70S,80R)-20-(tert-Butyldiphenylsilyloxy-
methyl)-70-hydroxy-80-hydroxymethyl-50-methyl-oxo-
can-30-yl 2,2-dimethylpropionate (16). To a suspension
of 15 (1.95 g, 3.09 mmol), 1,2-ethanedithiol (2.60 ml,
31.0 mmol), and NaHCO3 (2.65 g, 3.15 mmol) in DCM
(30 ml) was added Zn(OTf)2 (1.13 g, 3.11 mmol) at 0 ꢀC
and the mixture was stirred for 4 h. After that, the mixture
was warmed to 25 ꢀC and stirred for 1 h. Saturated aqueous
NaHCO3 (30 ml) was added and the aqueous layer was
extracted with Et2O (2ꢂ150 ml) and AcOEt (150 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/AcOEt¼10 to 1) to give 16
(1.68 g, w100%). 16: a colorless oil; [a]2D6 ꢁ1.86 (c 0.850,
HR-FDMS, calcd for C45H Br2O6Si [M+H]+: 879.2286,
79
56
found: 879.2316.
7.1.10. (2S,3R,5S,7S,8R)-7-(4-Bromobenzyloxy)-8-(4-
bromobenzyloxymethyl)-2-(tert-butyldiphenylsilyloxy-
methyl)-5-methyloxocan-3-ol (18). To a solution of 17
(11.4 mg, 12.9 mmol) in DCM (0.60 ml) was added DIBAL
(0.14 ml, 0.95 M in hexane, 133 mmol) at ꢁ78 ꢀC and the
mixture was stirred for 2 h. After that, MeOH (0.10 ml)
and saturated aqueous potassium sodium tartrate (1 ml)
were added. The mixture was diluted with Et2O (5 ml) and
stirred at 25 ꢀC for 3 h. The layers were separated and the
aqueous layer was extracted with Et2O (3ꢂ5 ml). The com-
bined 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/AcOEt¼10 to 3) to give 18 (9.0 mg,
1
CHCl3); H NMR (300 MHz, C6D6), d (ppm) 7.80–7.76
(4H, m), 7.25–7.17 (6H, m), 4.66 (1H, dt, J¼2.8, 9.9 Hz),
4.19 (1H, ddd, J¼3.3, 9.5, 12.8 Hz), 4.02 (1H, dd, J¼2.9,
9.5 Hz), 3.94–3.83 (2H, m), 3.76 (1H, dd, J¼2.8, 10.6 Hz),
3.70 (1H, dd, J¼8.1, 10.6 Hz), 3.60 (1H, ddd, J¼3.3, 7.9,
9.0 Hz), 3.46–3.37 (1H, m), 1.85–1.76 (1H, m), 1.70 (1H,
dt, J¼14.3, 2.8 Hz), 1.62–1.55 (1H, m), 1.46 (1H, m),
1.42–1.31 (2H, m), 1.22 (9H, s), 0.93 (9H, s), 0.86 (3H, d,
J¼7.3 Hz); 13C NMR (75 MHz, CDCl3), d (ppm) 177.0
(C), 135.6 (CHꢂ2), 135.5 (CHꢂ2), 132.50 (C), 132.47 (C),
129.9 (CHꢂ2), 127.8 (CHꢂ4), 87.5 (CH), 85.9 (CH), 72.7
(CH), 72.0 (CH), 66.7 (CH2), 65.5 (CH2), 48.1 (CH2), 42.5
(CH2), 38.4 (C), 27.4 (CH), 27.3 (CH3), 26.8 (CH3ꢂ3),
26.7 (CH3ꢂ3), 19.0 (C); IR (film), n (cmꢁ1) 3447, 3072,
2932, 2859, 1728, 1473, 1461, 1428, 1395, 1363, 1282,
1154, 1113, 1034, 823, 740, 701; HR-EIMS, calcd for
1
88%). 18: a colorless oil; [a]2D6 +48.1 (c 1.26, CHCl3); H
NMR (300 MHz, C6D6), d (ppm) 7.81–7.74 (4H, m), 7.29–
7.16 (10H, m), 6.82 (2H, d, J¼8.3 Hz), 6.76 (2H, d,
J¼8.4 Hz), 4.18 (1H, d, J¼11.9 Hz), 4.11 (1H, dd, J¼5.2,
10.3 Hz), 4.09 (1H, d, J¼12.4 Hz), 4.02 (1H, dd, J¼5.9,
10.3 Hz), 3.99 (1H, d, J¼12.4 Hz), 3.91 (1H, d,
J¼11.9 Hz,), 3.85 (1H, dt, J¼9.0, 2.6 Hz), 3.68–3.61 (2H,
m), 3.58 (1H, dd, J¼2.6, 9.8 Hz), 3.35 (1H, dd, J¼6.4,
9.8 Hz), 3.30 (1H, dt, J¼3.3, 9.1 Hz), 2.69 (1H, d, J¼
2.6 Hz), 1.94–1.73 (4H, m), 1.54 (1H, ddd, J¼7.9, 9.1,
14.3 Hz), 1.13 (9H, s), 0.98 (3H, d, J¼7.0 Hz); 13C NMR
(75 MHz, CDCl3), d (ppm) 137.2 (C), 137.1 (C), 135.52
(CHꢂ2), 135.46 (CHꢂ2), 132.5 (C), 132.4 (C), 131.4
(CHꢂ2), 131.3 (CHꢂ2), 129.93 (CH), 129.91 (CH),
129.2 (CHꢂ2), 129.1 (CHꢂ2), 127.8 (CHꢂ4), 121.4 (C),
t
C27H37O6Si [Mꢁ Bu]+: 485.2359, found: 485.2359.
7.1.9. (20S,30R,50R,70S,80R)-70-(4-Bromobenzyloxy)-80-(4-
bromobenzyloxymethyl)-20-(tert-butyldiphenylsilyloxy-
methyl)-50-methyl-oxocan-30-yl 2,2-dimethylpropionate
(17). To a suspension of 16 (7.0 mg, 12.9 mmol) and TBAI

A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
7419
121.2 (C), 85.4 (CH), 85.1 (CH), 78.6 (CH), 74.8 (CH), 72.3
(CH2), 71.5 (CH2), 70.5 (CH2), 67.5 (CH2), 46.3 (CH2), 42.0
(CH2), 27.5 (CH), 27.4 (CH3), 26.7 (CH3ꢂ3), 19.0 (C); IR
(film), n (cmꢁ1) 3481, 3071, 2928, 2858, 1591, 1487,
1471, 1428, 1391, 1361, 1113, 1070, 1012, 823, 802, 740,
saturated aqueous Na2SO3 and brine, dried over anhydrous
MgSO4, filtered, and concentrated in vacuo. The resultant
crude aldehyde was used in the next reaction without puri-
fication. To a solution of Ph3P+CH2OMeClꢁ (748 mg,
2.18 mmol) in THF (2.0 ml) was added NHMDS (2.1 ml,
1.0 M in THF, 2.10 mmol) at 0 ꢀC and the mixture was
stirred for 30 min at the same temperature before cooling
to ꢁ78 ꢀC. After that, to the mixture was added a solution
of the above crude aldehyde in THF (4.0 ml) at ꢁ78 ꢀC
and the mixture was stirred for 20 min. The reaction mixture
was warmed to 23 ꢀC and stirred for 17 h. Then, brine (6 ml)
was added and the aqueous layer was extracted with Et2O
(3ꢂ30 ml). The combined organic layers were washed
with H2O, dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo. The resultant residue was purified by col-
umn chromatography (silica gel, hexane/AcOEt¼15 to 2) to
give 20 (241 mg, 79% from 19, E/Z¼1/1 from 1H NMR). 20:
a colorless oil; 1H NMR (300 MHz, CDCl3), d (ppm) 7.44–
7.39 (4H, m), 7.26–7.16 (4H, m), 7.08 (2H, d, J¼8.1 Hz),
6.86–6.82 (2H, m), 6.54 (0.5H, d, J¼12.7 Hz), 5.98 (0.5H,
d, J¼5.5 Hz), 4.82 (0.5H, dd, J¼7.3, 12.7 Hz), 4.57–4.35
(6H, m), 4.29–4.24 (1H, m), 3.94–3.83 (1.5H, m), 3.79
(3H), 3.74–3.67 (0.5H, m), 3.64–3.41 (5H, m), 3.36–3.24
(1H, m), 1.96–1.61 (5H, m), 1.05 (1.5H, d, J¼7.2 Hz),
1.02 (1.5H, d, J¼7.2 Hz); 13C NMR (75 MHz, CDCl3),
d (ppm) 159.1 (Cꢂ0.5), 159.0 (Cꢂ0.5), 149.5 (CHꢂ0.5),
148.2 (CHꢂ0.5), 137.8 (Cꢂ0.5), 137.5 (Cꢂ0.5), 137.4
(Cꢂ0.5), 137.3 (Cꢂ0.5), 131.41 (CH), 131.36 (CH), 131.3
(CH), 131.2 (CH), 130.8 (Cꢂ0.5), 130.5 (Cꢂ0.5), 129.5
(CH), 129.31 (CH), 129.25 (CHꢂ4), 121.4 (Cꢂ0.5),
121.32 (Cꢂ0.5), 121.27 (Cꢂ0.5), 121.1 (Cꢂ0.5), 113.7
(CH), 113.6 (CH), 107.4 (CHꢂ0.5), 103.4 (CHꢂ0.5), 84.5
(CHꢂ0.5), 83.91 (CHꢂ0.5), 83.86 (CHꢂ0.5), 81.5 (CHꢂ
0.5), 80.8 (CHꢂ0.5), 79.0 (CHꢂ0.5), 78.50 (CHꢂ0.5),
78.46 (CHꢂ0.5), 72.5 (CH2ꢂ0.5), 72.4 (CH2ꢂ0.5), 71.6
(CH2ꢂ0.5), 71.3 (CH2ꢂ0.5), 71.1 (CH2ꢂ0.5), 70.9 (CH2ꢂ
0.5), 70.6 (CH2ꢂ0.5), 70.5 (CH2ꢂ0.5), 59.7 (CH3ꢂ0.5),
55.8 (CH3ꢂ0.5), 55.27 (CH3ꢂ0.5), 55.25 (CH3ꢂ0.5), 42.1
(CH2), 41.2 (CH2), 27.9 (CHꢂ0.5), 27.7 (CHꢂ0.5), 27.3
(CH3ꢂ0.5), 27.2 (CH3ꢂ0.5); IR (film), n (cmꢁ1) 2926,
2862, 1657, 1612, 1586, 1513, 1487, 1462, 1358, 1302,
1248, 1201, 1172, 1088, 1037, 1011, 803; HR-FDMS, calcd
701; HR-FDMS, calcd for C40H Br2O5Si [M+H]+:
79
49
795.1711, found: 795.1718.
7.1.11. (2S,3R,5S,7S,8R)-[7-(4-Bromobenzyloxy)-8-(4-
bromobenzyloxymethyl)-3-(4-methoxybenzyloxy)-5-
methyloxocan-2-yl]methanol (19). To a suspension of 18
(85.4 mg, 0.107 mmol) and TBAI (17.8 mg, 0.0482 mmol)
in THF (0.70 ml) was added NaH (43.4 mg, 1.09 mmol) at
0 ꢀC and the mixture was stirred for 10 min. Then, to the
mixture was added a solution of p-methoxybenzyl bromide
(110 mg, 0.547 mmol) in THF (0.30 ml) at 0 ꢀC. The reac-
tion mixture was warmed to 25 ꢀC and stirred for 21 h. Sat-
urated aqueous NaHCO3 (1 ml) was added and the aqueous
layer was extracted with Et2O (4ꢂ5 ml). The combined
organic layers were washed with saturated aqueous Na2SO3
and brine, dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. The resultant residue was roughly
purified by column chromatography (silica gel, hexane/
AcOEt¼10) to give a crude product (100 mg), and it was
used in the next reaction without further purification. To a
solution of the above crude product in THF (1.0 ml) was
added TBAF (0.50 ml, 1.0 M in THF, 0.50 mmol) at 25 ꢀC
and the mixture was stirred for 2 h. The solvent was removed
in vacuo. The resultant residue was purified by column chro-
matography (silica gel, hexane/AcOEt¼5 to 1) to give 19
(68.3 mg, 94% from 18). 19: a colorless oil; [a]2D6 +12.2
1
(c 1.02, CHCl3); H NMR (300 MHz, CDCl3), d (ppm)
7.49–7.42 (4H, m), 7.21–7.17 (4H, m), 7.05 (2H, d,
J¼8.4 Hz), 6.85 (2H, d, J¼8.6 Hz), 4.52–4.48 (4H, m),
4.27 (1H, d, J¼11.0 Hz), 4.21 (1H, d, J¼11.6 Hz), 4.09–
4.03 (1H, m), 3.95–3.88 (1H, m), 3.80 (3H, s), 3.76–3.72
(2H, m), 3.67 (1H, dt, J¼3.1, 9.0 Hz), 3.43 (1H, dd, J¼
9.0, 11.1 Hz), 3.36 (1H, t, J¼8.8 Hz), 3.22 (1H, dt, J¼3.1,
9.5 Hz), 3.14 (1H, dt, J¼3.3, 10.5 Hz), 2.03–1.98 (1H, m),
1.93–1.88 (1H, m), 1.79–1.55 (3H, m), 1.07 (3H, d,
J¼7.0 Hz); 13C NMR (75 MHz, CDCl3), d (ppm) 159.2
(C), 136.9 (C), 136.2 (C), 131.6 (CHꢂ2), 131.5 (CHꢂ2),
130.1 (C), 129.6 (CHꢂ2), 129.4 (CHꢂ2), 129.3 (CHꢂ2),
121.9 (C), 121.6 (C), 113.8 (CHꢂ2), 87.6 (CH), 85.3 (CH),
79.5 (CH), 78.7 (CH), 72.7 (CH2), 72.6 (CH2), 71.1 (CH2),
70.2 (CH2), 65.6 (CH2), 55.2 (CH3), 42.7 (CH2), 41.8 (CH2),
27.39 (CH), 27.38 (CH3); IR (film), n (cmꢁ1) 3447, 3048,
2927, 1612, 1592, 1513, 1487, 1463, 1428, 1405, 1362,
1302, 1248, 1173, 1070, 1011, 804, 737, 703; HR-FDMS,
for C34H Br2O6 [M]+: 702.1192, found: 702.1213.
79
40
7.1.13. (2S,3R,5S,7S,8R)-[7-(4-Bromobenzyloxy)-8-(4-
bromobenzyloxymethyl)-3-(4-methoxybenzyloxy)-5-
methyloxocan-2-yl]ethanal (7). To a solution of 20
(21.9 mg, 31.1 mmol) in THF/H2O (10/1, v/v, 1.1 ml) was
added Hg(OAc)2 (47.3 mg, 148 mmol) at 24 ꢀC and the mix-
ture was stirred for 1 h. Then, TBAI (172 mg, 466 mmol) was
added at 24 ꢀC. After the mixture was stirred for 2 h, satu-
rated aqueous NH4Cl (1 ml) was added and the aqueous
layer was extracted with Et2O (3ꢂ5 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/AcOEt¼4 to 3) to give 7 (21.3 mg, 99%). 7:
calcd for C32H Br2O6 [M]+: 676.1035, found: 676.1042.
79
38
7.1.12. (2R,3S,5S,7R,8S,10E)-3-(4-Bromobenzyloxy)-
2-(4-bromobenzyloxymethyl)-7-(4-methoxybenzyloxy)-
8-(20-methoxyvinyl)-5-methyloxocane and (2R,3S,5S,
7R,8S,10Z)-3-(4-bromobenzyloxy)-2-(4-bromobenzyl-
oxymethyl)-7-(4-methoxybenzyloxy)-8-(20-methoxy-
vinyl)-5-methyloxocane (20). To a solution of 19 (295 mg,
0.435 mmol) in DCM (4.0 ml) was added DMPI (368 mg,
0.868 mmol) at 0 ꢀC. The reaction mixture was warmed to
23 ꢀC and stirred for 1 h. After the mixture was diluted
with Et2O (10 ml), saturated aqueous Na2SO3 (2 ml) was
added and the aqueous layer was extracted with Et2O
(2ꢂ5 ml). The combined organic layers were washed with
1
a colorless oil; [a]D26 +12.7 (c 0.803, CHCl3); H NMR
(300 MHz, CDCl3), d (ppm) 9.66 (1H, t, J¼2.4 Hz), 7.46–
7.41 (4H, m), 7.24–7.14 (4H, m), 7.07 (2H, d, J¼8.3 Hz),
6.86 (2H, d, J¼8.6 Hz), 4.51 (1H, d, J¼11.6 Hz), 4.50
(1H, d, J¼10.9 Hz), 4.44 (1H, d, J¼12.3 Hz), 4.38 (1H,
d, J¼12.3 Hz), 4.27 (1H, d, J¼10.9 Hz), 4.24 (1H, d,

7420
A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
J¼11.6 Hz), 4.04 (1H, ddd, J¼4.7, 7.5, 9.0 Hz), 3.80 (3H, s),
3.78–3.74 (1H, m), 3.59 (1H, dd, J¼2.4, 9.7 Hz), 3.39 (1H,
dd, J¼6.5, 9.7 Hz), 3.38–3.35 (1H, m), 3.23 (1H, dt, J¼2.7,
9.0 Hz), 2.77 (1H, ddd, J¼2.4, 4.7, 15.8 Hz), 2.54 (1H, ddd,
J¼2.4, 7.5, 15.8 Hz), 2.01–1.85 (3H, m), 1.77–1.64 (2H, m),
1.09 (3H, d, J¼7.0 Hz); 13C NMR (75 MHz, CDCl3),
d (ppm) 201.2 (CH), 159.3 (C), 137.2 (Cꢂ2), 131.44
(CHꢂ2), 131.43 (CHꢂ2), 129.8 (C), 129.7 (CHꢂ2), 129.4
(CHꢂ2), 129.2 (CHꢂ2), 121.5 (C), 121.4 (C), 113.9
(CHꢂ2), 84.6 (CH), 81.5 (CH), 80.8 (CH), 78.6 (CH),
72.6 (CH2), 71.8 (CH2), 70.7 (CH2), 70.6 (CH2), 55.3
(CH3), 48.8 (CH2), 41.0 (CH2), 40.1 (CH2), 28.1 (CH),
26.7 (CH3); IR (film), n (cmꢁ1) 2923, 2863, 1723, 1612,
1513, 1486, 1456, 1374, 1301, 1248, 1173, 1070, 1011,
(CH2), 72.2 (CH2), 71.3 (CH2), 71.0 (CH2), 70.6 (CH2),
70.3 (CH2), 55.2 (CH3), 39.8 (CH2), 38.9 (CH2), 38.0
(CH2), 32.0 (CH2), 30.4 (CH2), 28.4 (CH), 27.0 (CH2),
26.2 (CH3), 25.8 (CH3ꢂ3), 17.9 (C), 12.3 (CH3), ꢁ4.2
(CH3), ꢁ4.9 (CH3); IR (film), n (cmꢁ1) 3482, 2924, 2853,
1611, 1512, 1487, 1452, 1361, 1300, 1248, 1172, 1098,
79
86
1011, 775, 697; HR-FDMS, calcd for C66H Br2O10Si
[M]+: 1224.4357, found: 1224.4386. 22: a colorless oil;
[a]2D5 ꢁ29.4 (c 0.190, CHCl3); 1H NMR (400 MHz,
CDCl3), d (ppm) 7.42–7.39 (4H, m), 7.31–7.16 (14H, m),
7.05 (2H, d, J¼8.3 Hz), 6.81 (2H, d, J¼8.8 Hz), 5.78 (1H,
dt, J¼5.3, 10.6 Hz), 5.74 (1H, dt, J¼5.0, 10.6 Hz), 5.58
(1H, t, J¼6.2 Hz), 4.58 (1H, d, J¼11.5 Hz), 4.51 (1H, d,
J¼11.3 Hz), 4.48 (1H, d, J¼11.3 Hz), 4.46 (2H, d,
J¼11.5 Hz), 4.39 (1H, d, J¼11.3 Hz), 4.35 (2H, d,
J¼11.3 Hz), 4.22 (1H, d, J¼11.5 Hz), 4.23–4.21 (1H, m),
4.00–3.97 (1H, m), 3.85 (1H, t, J¼11.3 Hz), 3.83 (1H, dt,
J¼10.1, 3.9 Hz), 3.78–3.74 (2H, m), 3.75 (3H, s), 3.64
(1H, dd, J¼2.1, 9.6 Hz), 3.59 (1H, dd, J¼2.4, 10.0 Hz),
3.50–3.43 (3H, m), 3.34 (1H, dt, J¼8.4, 2.7 Hz), 3.28 (1H,
dt, J¼8.1, 3.9 Hz), 3.21–3.18 (1H, m), 2.83–2.77 (1H, m),
2.72–2.66 (1H, m), 2.48–2.45 (1H, m), 2.32–2.28 (2H,
m), 2.05–2.01 (2H, m), 1.91–1.71 (5H, m), 1.68–1.61 (1H,
m), 1.59 (3H, s), 1.06 (3H, d, J¼6.8 Hz), 0.87 (9H, s),
0.07 (3H, s), 0.01 (3H, s); 13C NMR (75 MHz, CDCl3),
d (ppm) 159.1 (C), 138.5 (Cꢂ3), 137.3 (C), 136.9 (C),
131.40 (CHꢂ2), 131.37 (CHꢂ2), 130.2 (C), 129.7
(CHꢂ2), 129.3 (CHꢂ2), 129.2 (CHꢂ2), 128.3 (CH),
128.23 (CHꢂ2), 128.16 (CHꢂ2), 127.8 (CHꢂ2), 127.7
(CHꢂ2), 127.4 (CH), 127.3 (CH), 127.2 (CH), 121.7
(CH), 121.5 (C), 121.4 (C), 113.7 (CHꢂ2), 86.2 (CH),
85.2 (CH), 83.5 (CH), 82.5 (CH), 81.9 (CH), 78.30 (CH),
78.25 (CH), 77.2 (CH), 73.7 (CH), 73.0 (CH2), 72.6
(CH2), 71.3 (CH2), 71.2 (CH2), 70.9 (CH2), 70.7 (CH2),
70.5 (CH2), 55.2 (CH3), 40.1 (CH2), 38.5 (CH2), 37.6
(CH2), 31.9 (CH2), 30.7 (CH2), 28.3 (CH), 27.0 (CH2),
26.0 (CH3), 25.8 (CH3ꢂ3), 17.9 (C), 12.4 (CH3), ꢁ4.2
(CH3), ꢁ4.8 (CH3); IR (film), n (cmꢁ1) 3505, 3026, 2926,
2856, 1612, 1513, 1487, 1454, 1381, 1349, 1249, 1172,
1098, 1012, 835, 805, 776, 698; HR-FDMS, calcd for
804; HR-FDMS, calcd for C33H Br2O6 [M]+: 688.1035,
79
38
found: 688.1044.
7.1.14. (2S,3E,20R,30S,50Z,80R,90S,200S,300R,500S,700S,800R)-
5-[80-Benzyloxy-90-benzyloxymethyl-30-(tert-butyldi-
methylsilyloxy)-20,30,40,70,80,90-hexahydrooxonin-20-yl]-
1-[700-(4-bromobenzyloxy)-800-(4-bromobenzyloxy-
methyl)-300-(4-methoxybenzyloxy)-500-methyloxocan-200-
yl]-3-methylpent-3-en-2-ol (21) and (2R,3E,20R,30S,50Z,
80R,90S,200S,300R,500S,700S,800R)-5-[80-benzyloxy-90-benzyl-
oxymethyl-30-(tert-butyldimethylsilyloxy)-20,30,40,70,80,90-
hexahydrooxonin-20-yl]-1-[700-(4-bromobenzyloxy)-800-
(4-bromobenzyloxymethyl)-300-(4-methoxybenzyloxy)-
500-methyloxocan-200-yl]-3-methylpent-3-en-2-ol (22). To
a suspension of CrCl2 (420 mg, 3.42 mmol) and NiCl2
(2.2 mg, 0.0174 mmol) in degassed DMSO (1.0 ml) was
added a solution of 6 (742 mg, 1.12 mmol) and 7 (226 mg,
0.327 mmol) in degassed DMSO (5.0 ml) at 25 ꢀC. The re-
action mixture was stirred for 25 h in the dark. Then, satu-
rated aqueous NH4Cl (6 ml) was added and the aqueous
layer was extracted with Et2O (2ꢂ30 ml) and AcOEt
(2ꢂ30 ml). The combined organic layers were washed
with brine, dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo. The resultant residue was purified by col-
umn chromatography (silica gel, benzene/AcOEt¼30 to 10)
to give 21 (181 mg, 45%) and 22 (160 mg, 40%). 21: a color-
less oil; [a]2D4 ꢁ40.4 (c 0.250, CHCl3); 1H NMR (400 MHz,
CDCl3), d (ppm) 7.43–7.41 (4H, m), 7.31–7.15 (14H, m),
7.04 (2H, d, J¼8.1 Hz), 6.84 (2H, d, J¼8.6 Hz), 5.78 (1H,
dt, J¼5.1, 10.1 Hz), 5.74 (1H, dt, J¼4.9, 10.1 Hz), 5.62
(1H, t, J¼5.7 Hz), 4.60 (1H, d, J¼11.5 Hz), 4.50 (2H,
d, J¼12.9 Hz), 4.49 (1H, d, J¼10.7 Hz), 4.46 (1H, d,
J¼12.9 Hz), 4.42 (1H, d, J¼10.9 Hz), 4.39 (1H, d, J¼
12.9 Hz), 4.33 (1H, d, J¼11.7 Hz), 4.30 (1H, d, J¼
11.7 Hz), 4.20 (1H, d, J¼11.5 Hz), 4.41–4.34 (1H, m),
3.91–3.79 (4H, m), 3.77 (3H, s), 3.65–3.58 (3H, m), 3.50
(1H, dd, J¼3.3, 10.1 Hz), 3.36–3.26 (5H, m), 2.81–2.76
(1H, m), 2.71–2.65 (1H, m), 2.52–1.48 (1H, m), 2.32–2.28
(2H, m), 2.04–1.93 (3H, m), 1.89–1.71 (4H, m), 1.60 (3H,
s), 1.55–1.49 (1H, m), 1.07 (3H, d, J¼7.0 Hz), 0.87 (9H,
s), 0.06 (3H, s), ꢁ0.01 (3H); 13C NMR (75 MHz, CDCl3),
d (ppm) 159.1 (C), 138.6 (C), 138.5 (C), 138.4 (C), 137.2
(C), 136.5 (C), 131.5 (CHꢂ2), 131.4 (CHꢂ2), 130.3 (C),
129.8 (CHꢂ2), 129.23 (CHꢂ2), 129.20 (CHꢂ2), 128.3
(CH), 128.23 (CHꢂ2), 128.21 (CHꢂ2), 127.8 (CHꢂ2),
127.7 (CHꢂ2), 127.44 (CH), 127.36 (CH), 127.2 (CH),
121.7 (C), 121.4 (C), 121.2 (CH), 113.7 (CHꢂ2), 86.1
(CH), 83.7 (CH), 82.7 (CH), 82.5 (CH), 81.4 (CH), 78.8
(CH), 78.2 (CH), 73.4 (CH), 73.1 (CH2), 72.8 (CH), 72.6
C66H Br2O10Si [M]+: 1224.4357, found: 1224.4386.
79
86
7.1.15. (1R,10R,20E,200R,300S,500Z,800R,900S,2000S,3000R,
5000S,7000S,8000R)-40-[800-Benzyloxy-900-benzyloxymethyl-300-
(tert-butyldimethylsilyloxy)-200,300,400,700,800,900-hexa-
hydrooxonin-200-yl]-10-[7000-(4-bromobenzyloxy)-8000-(4-
bromobenzyloxymethyl)-3000-(4-methoxybenzyloxy)-5000-
methyloxocan-2000-ylmethyl-20-methylbut-20-enyl]-1-
methoxy-1-trifluoromethyl-1-phenylacetate {(D)MTPA
ester}. To a solution of 22 (2.4 mg, 1.96 mmol) in DCM
(0.05 ml) was added triethylamine (16.0 ml, 115 mmol),
(+)MTPACl (10.0 ml, 53.4 mmol), and DMAP (3.0 mg,
24.6 mmol) at 0 ꢀC. The reaction mixture was warmed to
25 ꢀC and stirred for 7 h. Then, saturated aqueous NaHCO3
(0.5 ml) was added and the organic layer was extracted with
Et2O (4ꢂ3 ml). The combined organic layers were washed
with brine, dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo. The resultant residue was purified by col-
umn chromatography (silica gel, benzene/AcOEt¼50 to 10)
to give (+)MTPA ester of 22 (2.1 mg, 74%). (+)MTPA ester
of 22: a colorless oil; [a]2D6 ꢁ13.3 (c 0.110, CHCl3); 1H NMR
(400 MHz, CDCl3), d (ppm) 7.52–7.49 (2H, m), 7.40–7.34
(7H, m), 7.25–7.16 (14H, m), 7.03 (2H, d, J¼8.3 Hz), 6.81

A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
7421
(2H, d, J¼8.8 Hz), 5.85 (1H, dd, J¼5.9, 9.8 Hz), 5.83 (1H, t,
J¼6.4 Hz), 5.75 (1H, dt, J¼5.1, 10.7 Hz), 5.70 (1H, dt,
J¼5.1, 10.7 Hz), 4.58 (1H, d, J¼11.5 Hz), 4.59 (1H,
d, J¼11.7 Hz), 4.51 (1H, d, J¼11.2 Hz), 4.49 (1H, d,
J¼12.2 Hz), 4.47 (1H, d, J¼11.7 Hz), 4.44 (1H, d,
J¼11.2 Hz), 4.37 (1H, d, J¼11.7 Hz), 4.29 (1H, d, J¼
12.2 Hz), 4.23 (1H, d, J¼11.2 Hz), 4.22 (1H, d,
J¼11.7 Hz), 4.16 (1H, d, J¼11.2 Hz), 3.79 (1H, dt, J¼8.3,
3.4 Hz), 3.75 (3H, s), 3.64 (1H, dt, J¼8.1, 3.9 Hz),
3.56–3.53 (2H, m), 3.50 (3H, s), 3.49–3.46 (1H, m), 3.46–
3.29 (4H, m), 3.25–3.23 (1H, m), 3.15 (1H, dt, J¼2.4,
8.8 Hz), 2.71–2.66 (2H, m), 2.56 (1H, ddd, J¼2.9, 10.7,
14.2 Hz), 2.29–2.17 (2H, m), 2.12 (1H, ddd, J¼2.9, 9.8,
13.7 Hz), 1.97–1.93 (1H, m), 1.87–1.75 (3H, m), 1.70–
1.57 (3H, m), 1.53 (3H, s), 1.05 (3H, d, J¼6.8 Hz), 0.84
The reaction mixture was warmed to 25 ꢀC and stirred for
2.5 h. After the mixture was diluted with Et2O (5 ml), satu-
rated aqueous Na2SO3 (1 ml) was added and the aqueous
layer was extracted with Et2O (2ꢂ3 ml). The combined or-
ganic layers were washed with saturated aqueous Na2SO3
and brine, dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo. The resultant residue was purified by
column chromatography (silica gel, benzene/AcOEt¼20)
to give 23 (7.0 mg, w100%). 23: a colorless oil; [a]D19
ꢁ31.4 (c 0.195, CHCl3); 1H NMR (300 MHz, CDCl3),
d (ppm) 7.42–7.16 (16H, m), 7.10–7.03 (4H, m), 6.85–
6.79 (3H, m), 5.83 (2H, m), 4.60 (1H, d, J¼11.4 Hz), 4.50
(1H, d, J¼11.0 Hz), 4.47 (1H, d, J¼11.9 Hz), 4.43 (2H, d,
J¼12.5 Hz), 4.34–4.24 (5H, m), 4.17 (1H, dt, J¼2.9,
8.5 Hz), 3.83–3.77 (2H, m), 3.75 (3H, s), 3.64 (1H, dt,
J¼8.2, 3.4 Hz), 3.56 (1H, dd, J¼3.8, 10.2 Hz), 3.52–3.40
(3H, m), 3.39–3.34 (2H, m), 3.29 (1H, dt, J¼2.6, 8.5 Hz),
3.10 (1H, dd, J¼2.9, 16.3 Hz), 2.86 (1H, dd, J¼8.5,
16.3 Hz), 2.83–2.76 (1H, m), 2.74–2.69 (1H, m), 2.67–
2.61 (1H, m), 2.50 (1H, ddd, J¼2.8, 7.8, 17.1 Hz), 2.32
(1H, dt, J¼13.8, 3.4 Hz), 2.05 (1H, dt, J¼13.2, 3.4 Hz),
1.96–1.86 (3H, m), 1.78–1.72 (2H, m), 1.69 (3H, s), 1.06
(3H, d, J¼6.8 Hz), 0.86 (9H, s), 0.054 (3H, s), ꢁ0.055
(3H, s); 13C NMR (75 MHz, CDCl3), d (ppm) 199.7 (C),
159.1 (C), 139.4 (CH), 138.6 (C), 138.3 (C), 138.1 (C),
137.58 (C), 137.56 (C), 131.3 (CHꢂ4), 131.2 (CHꢂ2),
130.4 (C), 129.3 (CHꢂ2), 129.2 (CHꢂ2), 129.1 (CHꢂ2),
128.28 (CHꢂ2), 128.26 (CHꢂ2), 127.9 (CHꢂ2), 127.7
(CHꢂ2), 127.55 (CH), 127.53 (CH), 127.50 (CH), 121.18
(C), 121.15 (C), 113.7 (CHꢂ2), 85.2 (CH), 84.20 (CH),
84.15 (CH), 82.0 (CH), 80.8 (CH), 78.5 (CH), 78.1 (CH),
73.3 (CH), 73.1 (CH2), 72.4 (CH2), 71.7 (CH2), 71.3
(CH2), 70.8 (CH2), 70.5 (CH2), 70.4 (CH2), 55.2 (CH3),
42.6 (CH2), 40.9 (CH2), 40.4 (CH2), 32.1 (CH2), 31.8
(CH2), 28.0 (CH), 26.9 (CH2), 26.8 (CH3), 25.7 (CH3ꢂ3),
17.9 (C), 11.9 (CH3), ꢁ4.1 (CH3), ꢁ4.9 (CH3); IR (film),
n (cmꢁ1) 3026, 2925, 2856, 1665, 1612, 1513, 1487, 1462,
(9H, s), 0.03 (3H, s), ꢁ0.08 (3H, s); IR (film), n (cmꢁ1
)
2925, 2854, 1743, 1612, 1513, 1487, 1453, .1299, 1250,
1169, 1100, 1070, 1012, 836; HR-FDMS, calcd for
C76H Br2F3O12Si [M]+: 1440.4755, found: 1440.4736.
79
93
7.1.16. (1S,10R,20E,200R,300S,500Z,800R,900S,2000S,3000R,5000S,
7000S,8000R)-40-[800-Benzyloxy-900-benzyloxymethyl-300-(tert-
butyldimethylsilyloxy)-200,300,400,700,800,900-hexahydro-
oxonin-200-yl]-10-[7000-(4-bromobenzyloxy)-8000-(4-bromo-
benzyloxymethyl)-3000-(4-methoxybenzyloxy)-5000-methyl-
oxocan-2000-ylmethyl-20-methylbut-20-enyl]-1-methoxy-1-
trifluoromethyl-1-phenylacetate {(L)MTPA ester}. To
a solution of 22 (1.2 mg, 0.978 mmol) in DCM (0.05 ml)
was added triethylamine (16.0 ml, 115 mmol), (ꢁ)MTPACl
(10.0 ml, 52.8 mmol), and DMAP (3.0 mg, 24.6 mmol) at
0 ꢀC. The reaction mixture was warmed to 25 ꢀC and stirred
for 7 h. Then, saturated aqueous NaHCO3 (0.5 ml) was
added and the organic layer was extracted with Et2O
(4ꢂ3 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, benzene/AcOEt¼50 to 10) to
give (ꢁ)MTPA ester of 22 (1.1 mg, 78%). (ꢁ)MTPA ester
1453, 1361, 1301, 1249, 1207, 1172, 1099, 1012, 836,
805, 776, 698; HR-FDMS, calcd for C66H Br2O10Si
1
79
84
of 22: a colorless oil; [a]2D6 ꢁ22.6 (c 0.055, CHCl3); H
NMR (400 MHz, CDCl3), d (ppm) 7.52–7.48 (2H, m),
7.41–7.33 (7H, m), 7.30–7.16 (14H, m), 7.02 (2H, d,
J¼8.3 Hz), 6.79 (2H, d, J¼8.8 Hz), 5.85 (1H, dd, J¼5.1,
10.0 Hz), 5.82 (1H, t, J¼6.4 Hz), 5.75 (1H, dt, J¼4.9,
10.7 Hz), 5.69 (1H, dt, J¼4.9, 10.7 Hz), 4.60 (1H, d, J¼
12.7 Hz), 4.52–4.46 (4H, m), 4.39–420 (4H, m), 4.15 (1H,
d, J¼11.7 Hz), 3.82–8.76 (1H, m), 3.73 (3H, s), 3.68 (1H,
dd, J¼2.0, 9.3 Hz), 3.64–3.60 (2H, m), 3.56 (1H, dd, J¼
4.4, 9.3 Hz), 3.51 (3H, s), 3.49–3.29 (6H, m), 3.27–3.23
(2H, m), 2.72–2.65 (2H, m), 2.59–2.52 (1H, m), 2.33–2.18
(3H, m), 1.96–1.87 (4H, m), 1.81–1.64 (3H, m), 1.41
(3H, s), 1.08 (3H, d, J¼6.8 Hz), 0.85 (9H, s), 0.04 (3H, s),
ꢁ0.05 (3H, s); IR (film), n (cmꢁ1) 2918, 2849, 1744, 1612,
1487, 1462, .1250, 1168, 1100, 836; HR-FDMS, calcd for
[M]+: 1222.4200, found: 1222.4165.
7.1.18. Reduction of 23. To a solution of 23 (2.8 mg,
2.29 mmol) in THF (0.80 ml) was added L-SelectrideÒ
(0.10 ml, 1.0 M in THF, 0.10 mmol) at ꢁ78 ꢀC and the reac-
tion mixture was stirred for 2 h. After that, 5 M NaOH (1 ml)
and 30% aqueous H2O2 (1 ml) were added. The mixture was
diluted with Et2O (5 ml) and stirred at 25 ꢀC for 15 h. Then,
saturated aqueous Na2S2O3 (0.5 ml) was added at 0 ꢀC
and the mixture was stirred for 30 min. The layers were
separated and the aqueous layer was extracted with Et2O
(2ꢂ5 ml) and AcOEt (2ꢂ5 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, benz-
ene/AcOEt¼40 to 10) to give a mixture of 21 and 22
(2.8 mg,w100%, 21:22ꢃ13:1 from 1H NMR).
C76H Br2F3O12Si [M]+: 1440.4755, found: 1440.4752.
79
93
7.1.17. (3E,20R,30S,50Z,80R,90S,200S,300R,500S,700S,800R)-5-
[80-Benzyloxy-90-benzyloxymethyl-30-(tert-butyldi-
methylsilyloxy)-20,30,40,70,80,90-hexahydrooxonin-20-yl]-
1-[700-(4-bromobenzyloxy)-800-(4-bromobenzyloxy-
methyl)-300-(4-methoxybenzyloxy)-500-methyloxocan-200-
yl]-3-methylpent-3-en-2-one (23). To a solution of 22
(7.0 mg, 5.70 mmol) in DCM (0.50 ml) were added NaHCO3
(11.1 mg, 132 mmol) and DMPI (9.0 mg, 21.2 mmol) at 0 ꢀC.
7.1.19. (2S,3S,4S,20R,30S,50Z,80R,90S,200S,300R,500S,
700S,800R)-5-[80-Benzyloxy-90-benzyloxymethyl-30-(tert-
butyldimethysilyloxy)-20,30,40,70,80,90-hexahydrooxonin-
20-yl]-1-[700-(4-bromobenzyloxy)-800-(4-bromobenzyloxy-
methyl)-300-(4-methoxybenzyloxy)-500-methyloxocan-200-
yl]-3-methyl-3,4-epoxypentan-2-ol (24). To a solution of

7422
A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
21 (287 mg, 0.234 mmol) in toluene (2.0 ml) were added
VO(acac)2 (5.6 mg, 0.0211 mmol) and TBHP (0.10 ml,
7.2 M in toluene, 0.720 mmol) at 0 ꢀC. The reaction mixture
was stirred for 2.5 h at the same temperature. Then, to the re-
action mixture was added dimethylsulfide (0.1 ml) and the
mixture was stirred for 0.5 h at 24 ꢀC. After the mixture
was diluted with Et2O (10 ml), saturated aqueous NaHCO3
(2 ml) was added and the aqueous layer was extracted with
Et2O (2ꢂ10 ml). The combined organic layers were washed
with saturated aqueous Na2SO3 and brine, dried over anhy-
drous MgSO4, filtered, and concentrated in vacuo. The resul-
tant residue was purified by column chromatography (silica
gel, hexane/AcOEt¼5 to 3) to give 24 (263 mg, 91%). 24:
5.79 (1H, dt, J¼4.9, 10.3 Hz), 5.72 (1H, dt, J¼4.9,
10.3 Hz), 4.58 (1H, d, J¼11.5 Hz), 4.53–4.34 (6H, m),
4.33 (1H, d, J¼11.0 Hz), 4.25 (1H, d, J¼11.5 Hz), 4.24
(1H, d, J¼11.7 Hz), 4.12 (1H, dt, J¼8.4, 3.2 Hz), 3.87–
3.82 (2H, m), 3.76 (3H, s), 3.66 (1H, dd, J¼2.1, 9.3 Hz),
3.60–3.41 (7H, m), 3.38–3.33 (1H, m), 3.25 (1H, dt,
J¼2.9, 6.8 Hz), 3.11 (1H, dd, J¼1.1, 9.1 Hz), 2.75 (1H,
ddd, J¼3.2, 10.3, 13.2 Hz), 2.63 (1H, ddd, J¼3.0, 10.3,
13.6 Hz), 2.35–2.24 (2H, m), 2.05–1.98 (2H, m), 1.89–
1.60 (6H, m), 1.52 (1H, ddd, J¼2.4, 9.1, 14.8 Hz), 1.31
(3H, s), 1.06 (3H, d, J¼6.8 Hz), 0.93 (9H, t, J¼7.9 Hz),
0.87 (9H, s), 0.58 (6H, q, J¼7.9 Hz), 0.11 (3H, s), 0.058
(3H, s); 13C NMR (75 MHz, CDCl3), d (ppm) 158.9 (C),
138.4 (C), 138.3 (C), 137.7 (C), 137.6 (C), 131.35
(CHꢂ2), 131.29 (CHꢂ2), 130.9 (C), 129.4 (CHꢂ2), 129.1
(CHꢂ2), 128.8 (CHꢂ2), 128.3 (CH), 128.23 (CHꢂ2),
128.19 (CHꢂ2), 127.6 (CHꢂ4), 127.43 (CH), 127.37
(CH), 127.0 (CH), 121.3 (C), 121.2 (C), 113.6 (CHꢂ2),
85.4 (CH), 84.2 (CH), 82.6 (CH), 82.3 (CH), 80.7 (CH),
78.6 (CH), 78.4 (CH), 73.4 (CH), 73.1 (CH), 72.7 (CH2),
72.6 (CH2), 72.4 (CH2), 71.4 (CH2), 71.2 (CH2), 70.23
(CH2), 70.15 (CH2), 60.7 (C), 58.2 (CH), 55.2 (CH3), 39.6
(CH2), 38.7 (CH2), 38.3 (CH2), 32.1 (CH2), 30.7 (CH2),
28.3 (CH), 26.8 (CH2), 26.2 (CH3), 25.9 (CH3ꢂ3), 17.9
(C), 13.0 (CH3), 7.1 (CH3ꢂ3), 5.4 (CH2ꢂ3), ꢁ4.4 (CH3),
ꢁ4.5 (CH3); IR (film), n (cmꢁ1) 3063, 2957, 1612, 1586,
1
a colorless oil; [a]D23 ꢁ72.6 (c 0.370, CHCl3); H NMR
(400 MHz, CDCl3), d (ppm) 7.42–7.40 (4H, m), 7.32–7.21
(12H, m), 7.14 (2H, d, J¼8.3 Hz), 7.04 (2H, d, J¼8.3 Hz),
6.82 (2H, d, J¼8.8 Hz), 5.80 (1H, dt, J¼4.9, 10.7 Hz),
5.76 (1H, dt, J¼5.1, 10.7 Hz), 4.61 (1H, d, J¼11.5 Hz),
4.49 (1H, d, J¼11.6 Hz), 4.48–4.30 (6H, m), 4.29 (1H, d,
J¼11.5 Hz), 4.21 (1H, d, J¼11.6 Hz), 4.11–4.08 (1H, m),
3.86–3.81 (2H, m), 3.75 (3H, s), 3.66–3.63 (2H, m), 3.59–
3.55 (2H, m), 3.45 (1H, dd, J¼4.8, 10.1 Hz), 3.41–3.33
(5H, m), 3.29–3.24 (2H, m), 2.83 (1H, ddd, J¼2.8, 10.7,
13.2 Hz), 2.83 (1H, ddd, J¼3.2, 10.7, 13.7 Hz), 2.34–2.24
(2H, m), 2.07–2.02 (1H, m), 1.93–1.57 (8H, m), 1.17 (3H,
s), 1.06 (3H, d, J¼6.8 Hz), 0.87 (9H, s), 0.12 (3H, s),
0.079 (3H, s); 13C NMR (75 MHz, CDCl3), d (ppm) 159.0
(C), 138.4 (C), 138.2 (C), 137.3 (C), 136.6 (C), 131.4
(CHꢂ2), 131.3 (CHꢂ2), 130.4 (C), 129.6 (CHꢂ2), 129.3
(CHꢂ2), 129.2 (CHꢂ2), 128.3 (CH), 128.22 (CHꢂ2),
128.19 (CHꢂ2), 127.9 (CHꢂ2), 127.7 (CHꢂ2), 127.5
(CH), 127.4 (CH), 127.1 (CH), 121.6 (C), 121.3 (C), 113.6
(CHꢂ2), 85.1 (CH), 84.0 (CH), 82.9 (CH), 82.1 (CH),
81.3 (CH), 78.6 (CH), 78.5 (CH), 73.3 (CH), 73.0 (CH2),
72.5 (CH2), 71.7 (CH2), 71.6 (CH2), 71.2 (CH2), 70.8
(CH), 70.6 (CH2), 70.3 (CH2), 60.7 (C), 58.3 (CH), 55.1
(CH3), 39.8 (CH2), 39.0 (CH2), 35.9 (CH2), 32.1 (CH2),
30.7 (CH2), 28.3 (CH), 26.9 (CH2), 26.3 (CH3), 25.8
(CH3ꢂ3), 17.9 (C), 12.9 (CH3), ꢁ4.4 (CH3), ꢁ4.5 (CH3);
IR (film), n (cmꢁ1) 3490, 3028, 2931, 2858, 1612, 1514,
1513, 1487, 1454, 1360, 1301, 1249, 1172, 1108, 938,
79
100
836, 745, 697; HR-FDMS, calcd for C72H Br2O11Si2
[M]+: 1354.5171, found: 1354.5188.
7.1.21. (2S,3R,5S,7S,8R,2000S,30S,40S,200R,300S,500Z,800R,
900S)-2-{50-[800-Benzyloxy-9 -benzyloxymethyl-300-(tert-
butyldimethylsilyloxy)-200,300,400,700,800,900-hexahydrooxo-
nin-200-yl]-30-methyl-20-triethylsilyloxy-30,40-epoxypen-
tyl}-8-(4-bromobenzyloxy)-9-(4-bromobenzyloxy-
methyl)-5-methyloxocan-3-ol (5). To a solution of 25
(267 mg, 0.197 mmol) in DCM–pH 7 buffer (10:1, v/v,
2.0 ml) was added DDQ (50.0 mg, 0.220 mmol) at 0 ꢀC and
the mixture was stirred for 50 min. Then, to the mixture
was added DDQ (20.8 mg, 0.0916 mmol) at 0 ꢀC and the
stirring was continued for further 15 min. Saturated aqueous
NaHCO3 (2 ml) was added and the aqueous layer was
extracted with Et2O (4ꢂ10 ml). The combined organic layers
were washed with brine, dried over anhydrous MgSO4, fil-
tered, and concentrated in vacuo. The resultant residue was
purified by column chromatography (silica gel, hexane/
AcOEt¼10 to 4) to give 5 (236 mg, 97%). 5: a colorless
1488, 1454, 1360, 1302, 1251, 1211, 1173, 1011, 939,
836, 777, 698; HR-FDMS, calcd for C66H Br2O11Si
79
86
[M]+: 1240.4306, found: 1243.4263.
7.1.20. (2S,3R,5Z,8S,9R,20S,30S,40S,200S,300R,050 00S,
700S,800R)-3-Benzyloxy-2-benzyloxymethyl-9-{50-[7 -(4-
bromobenzyloxy)-800-(4-bromobenzyloxymethyl)-300-(4-
methoxybenzyloxy)-500-methyloxocan-200-yl]-30-methyl-
40-triethylsilyloxy-20,30-epoxypentyl}-8-(tert-butyldi-
methylsilyloxy)-2,3,4,7,8,9-hexahydrooxonin (25). To a
solution of 24 (4.5 mg, 3.62 mmol) in DCM (0.50 ml) were
added 2,6-lutidine (13.0 ml, 112 mmol) and TESOTf
(12.0 ml, 53.1 mmol) at 0 ꢀC. The reaction mixture was
warmed to 25 ꢀC and stirred for 10 min. Then, saturated
aqueous NaHCO3 (0.5 ml) was added and the aqueous layer
was extracted with Et2O (4ꢂ3 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/AcOEt¼15 to 10) to give 25 (4.9 mg,w100%).
25: a colorless oil; [a]2D3 ꢁ102.3 (c 1.07, CHCl3); 1H NMR
(300 MHz, CDCl3), d (ppm) 7.43–7.37 (4H, m), 7.31–7.15
(14H, m), 7.05 (2H, d, J¼8.4 Hz), 6.82 (2H, d, J¼8.8 Hz),
1
oil; [a]2D4 ꢁ22.3 (c 0.615, CHCl3); H NMR (300 MHz,
CD3COCD3), d (ppm) 7.53–7.45 (4H, m), 7.35–7.22 (14H,
m), 5.76 (1H, dt, J¼4.5, 10.7 Hz), 5.72 (1H, dt, J¼4.5,
10.7 Hz), 4.66 (1H, d, J¼11.9 Hz), 4.61 (1H, d, J¼
11.9 Hz), 4.59–4.47 (4H, m), 4.36 (2H, d, J¼11.9 Hz), 4.19
(1H, dt, J¼8.2, 3.3 Hz), 3.94 (1H, dd, J¼2.2, 9.5 Hz), 3.79
(1H, ddd, J¼2.2, 5.9, 8.3 Hz), 3.73 (1H, dt, J¼2.2, 8.7 Hz),
3.70–3.62 (3H, m), 3.57–3.48 (3H, m), 3.46–3.34 (4H, m),
3.22 (1H, dd, J¼1.1, 9.4 Hz), 2.73 (1H, ddd, J¼3.3, 10.7,
13.3 Hz), 2.60 (1H, ddd, J¼3.1, 10.7, 13.3 Hz), 2.48 (1H,
ddd, J¼1.1, 5.0, 14.7 Hz), 2.33 (1H, dt, J¼13.3, 4.5 Hz),
2.07–1.71 (5H, m), 1.64 (1H, ddd, J¼2.2, 8.7, 13.9 Hz),
1.50 (1H, ddd, J¼2.2, 8.7, 14.7 Hz), 1.13 (3H, s), 1.03 (3H,
d, J¼7.0 Hz), 0.96 (9H, t, J¼7.9 Hz), 0.89 (9H, s), 0.66
(6H, q, J¼7.9 Hz), 0.16 (3H, s), 0.12 (3H, s); 13C NMR
(75 MHz, CDCl3), d (ppm) 138.31 (C), 138.25 (C), 137.32

A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
7423
(C), 137.29 (C), 131.4 (CHꢂ4), 129.4 (CHꢂ2), 129.2 (CH),
128.2 (CHꢂ4), 128.1 (CH), 127.6 (CHꢂ4), 127.44 (CH),
127.41 (CH), 127.1 (CH), 121.37 (C), 121.35 (C), 85.2
(CH), 85.1 (CH), 84.9 (CH), 84.2 (CH), 78.9 (CH), 78.7
(CH), 75.2 (CH), 74.1 (CH), 73.1 (CH), 72.8 (CH2), 72.6
(CH2), 72.4 (CH2), 72.0 (CH2), 71.1 (CH2), 70.4 (CH2), 60.9
(C), 59.5 (CH), 47.3 (CH2), 41.2 (CH2), 41.1 (CH2), 32.1
(CH2), 30.5 (CH2), 28.0 (CH), 27.2 (CH3), 26.7 (CH2), 25.8
(CH3ꢂ3), 17.9 (C), 11.9 (CH3), 6.9 (CH3ꢂ3), 5.0 (CH2ꢂ3),
ꢁ4.3 (CH3), ꢁ4.5 (CH3); IR (film), n (cmꢁ1) 3447, 3063,
3026, 2927, 1593, 1487, 1453, 1360, 1311, 1250, 1210,
1095, 1012, 938, 836, 776, 744, 697; HR-FDMS, calcd for
(0.60 ml) was added trifluoroacetic anhydride (20.0 ml,
144 mmol) at 0 ꢀC and the mixture was stirred for 1 h.
Then, H2O (1 ml) was added and the aqueous layer was
extracted with Et2O (4ꢂ5 ml). The combined organic layers
were washed with 1 M HCl, saturated aqueous NaHCO3 and
brine, dried over anhydrous MgSO4, filtered, and concen-
trated in vacuo. The resultant residue was purified by column
chromatography (silica gel, benzene/AcOEt¼100 to 40) to
give 29 (11.0 mg,w100%). 29: a colorless oil; [a]2D5 ꢁ2.10
1
(c 0.660, CHCl3); H NMR (400 MHz, CDCl3/C6D6¼1:1),
d (ppm) 7.35–7.31 (6H, m), 7.26–7.11 (8H, m), 7.03 (2H,
d, J¼8.1 Hz), 6.90 (2H, d, J¼8.1 Hz), 5.84–5.76 (2H, m),
5.67 (1H, t, J¼6.1 Hz), 4.63 (1H, d, J¼12.4 Hz), 4.56 (1H,
d, J¼12.4 Hz), 4.47 (1H, d, J¼11.6 Hz), 4.32 (1H, d,
J¼12.6 Hz), 4.31 (1H, d, J¼11.5 Hz), 4.29 (1H, d, J¼
12.6 Hz), 4.20 (1H, d, J¼11.6 Hz), 3.99 (1H, d, J¼
11.5 Hz), 3.93 (1H, q, J¼6.1 Hz), 3.88 (1H, dd, J¼1.7,
10.0 Hz), 3.85–3.83 (1H, m), 3.80–3.70 (4H, m), 3.56 (1H,
dd, J¼2.0, 9.5 Hz), 3.54–3.48 (2H, m), 3.45 (1H, dt,
J¼2.6, 9.9 Hz), 3.34 (1H, dd, J¼6.6, 9.5 Hz), 3.24 (1H, dt,
J¼2.1, 9.4 Hz), 2.84–2.79 (1H, m), 2.74–2.69 (1H, m),
2.33 (1H, dt, J¼14.9, 6.1 Hz), 2.29–2.24 (1H, m), 2.18
(1H, dt, J¼13.7, 4.1 Hz), 2.09 (1H, dt, J¼13.7, 4.5 Hz),
1.86–1.78 (5H, m), 1.64–1.50 (2H, m), 1.16 (3H, s), 0.99
(3H, d, J¼7.1 Hz), 0.93 (9H, t, J¼7.9 Hz), 0.92 (9H, s),
0.59 (6H, q, J¼7.9 Hz), 0.084 (3H, s), 0.080 (3H, s); IR
(film), n (cmꢁ1) 3032, 2927, 1792, 1593, 1487, 1456,
1374, 1336, 1217, 1164, 1098, 1012, 960, 836, 775, 735,
C64H Br2O10Si2 [M]+: 1234.4596, found: 1234.4553.
79
92
7.1.22. (1S,20R,30S,50Z,80R,90S,100S,300R,400S,600S,800R,
1000R,1100S)-2-[80-Benzyloxy-90-benzyloxymethyl-30-(tert-
butyldimethylsilyloxy)-20,30,40,70,80,90-hexahydrooxonin-
20-yl]-1-{400-(4-bromobenzyloxy)-300-(4-bromobenzyloxy-
methyl)-600,1000-dimethyl-1100-triethylsilyloxy-200,900-dioxa-
bicyclo[6.4.0]dodecan-1000-yl}ethanol (26). To a solution
of 5 (233 mg, 0.188 mmol) in DCM (3.0 ml) was added
CSA (4.3 mg, 0.0185 mmol) at 0 ꢀC and the mixture was
stirred for 25 min. Then, Et3N (0.1 ml) was added at 0 ꢀC
and the mixture was warmed to 25 ꢀC and stirred for
30 min. The solvent was removed in vacuo. The resultant
residue was purified by column chromatography (silica
gel, hexane/AcOEt¼7 to 2) to give 26 (186 mg, 80%). 26:
1
a colorless oil; [a]D23 +12.2 (c 0.495, CHCl3); H NMR
79
91
(300 MHz, CD3COCD3), d (ppm) 7.52–7.47 (4H, m),
7.37–7.23 (14H, m), 5.70–5.64 (2H, m), 4.65 (1H, d,
J¼11.4 Hz), 4.63 (1H, d, J¼12.1 Hz), 4.53–4.49 (3H, m),
4.61 (1H, d, J¼11.4 Hz), 4.38 (1H, d, J¼11.4 Hz), 4.34
(1H, d, J¼11.7 Hz), 4.11–4.07 (1H, m), 4.04–4.01 (1H,
m), 3.92 (1H, t, J¼2.9 Hz), 3.86–3.81 (1H, m), 3.78–3.74
(2H, m), 3.70–3.67 (1H, m), 3.64–3.52 (4H, m), 3.44–3.35
(3H, m), 3.28 (1H, d, J¼4.0 Hz), 2.84–2.63 (2H, m), 2.35
(1H, dt, J¼12.8, 4.4 Hz), 2.11–2.09 (2H, m), 1.93–1.78
(5H, m), 1.69–1.67 (2H, m), 1.59–1.49 (1H, m), 1.09 (3H,
s), 1.03 (3H, d, J¼7.0 Hz), 0.93 (9H, t, J¼8.1 Hz), 0.89
(9H, s), 0.60 (6H, q, J¼8.1 Hz), 0.11 (3H, s), 0.10 (3H, s);
13C NMR (75 MHz, CDCl3), d (ppm) 138.5 (C), 138.3
(C), 137.5 (C), 137.3 (C), 131.4 (CHꢂ2), 131.3 (CHꢂ2),
129.31 (CHꢂ2), 129.30 (CHꢂ2), 129.0 (CH), 128.2
(CHꢂ4), 127.6 (CHꢂ4), 127.4 (CH), 127.3 (CH), 126.2
(CH), 121.4 (C), 121.3 (C), 85.4 (CH), 84.5 (CH), 80.9
(CH), 79.1 (CH), 78.6 (CH), 77.6 (C), 77.1 (CH),
76.6 (CH), 73.4 (CH), 73.1 (CH2), 72.5 (CH2), 71.7 (CH2),
71.6 (CH), 71.2 (CH2), 70.5 (CH2), 70.1 (CH), 69.4 (CH2),
45.4 (CH2), 40.2 (CH2), 36.1 (CH2), 34.6 (CH2), 29.2
(CH2), 28.3 (CH), 26.8 (CH3), 26.3 (CH2), 25.9 (CH3ꢂ3),
18.0 (C), 14.3 (CH3), 7.0 (CH3ꢂ3), 5.0 (CH2ꢂ3), ꢁ4.6
(CH3), ꢁ4.7 (CH3); IR (film), n (cmꢁ1) 3502, 3030, 2926,
697; HR-FDMS, calcd for C66H Br2F3O11Si2 [M]+:
1330.4419, found: 1330.4448.
7.1.24. (1S,3R,4S,6S,8R,10S,11S,10S,200R,300S,500Z,800R,
900S)-10-{20-[800-Benzyloxy-900-benzyloxymethyl-300-(tert-
butyldimethylsilyloxy)-200,300,400,700,800,900-hexahydrooxo-
nin-200-yl]-10-hydroxyethyl}-4-(4-bromobenzyloxy)-3-(4-
bromobenzyloxymethyl)-6,10-dimethyl-2,9-dioxabi-
cyclo[6.4.0]dodecan-11-yl trifluoroacetate (30). To a solu-
tion of 29 (11.0 mg, 8.23 mmol) in THF–H2O (4:1, v/v,
0.75 ml) was added TFA (15.0 ml) at 22 ꢀC and the mixture
was stirred for 2 d. Then, the solvent was removed in vacuo.
The resultant residue was purified by column chromato-
graphy (silica gel, hexane/AcOEt¼30 to 7) to give 30 and re-
covery of 29. For this recovered starting material, the above
procedure was repeated twice to give 30 (6.3 mg, 63%, after
three cycles). 30: a colorless oil; [a]1D9 +31.3 (c 0.265,
1
CHCl3); H NMR (400 MHz, C6D6), d (ppm) 7.37–7.28
(6H, m), 7.20–7.05 (8H, m), 6.92 (2H, d, J¼8.3 Hz), 6.82
(2H, d, J¼8.3 Hz), 5.87 (1H, dt, J¼6.1, 10.1 Hz), 5.80
(1H, dt, J¼6.1, 10.1 Hz), 4.52 (1H, d, J¼11.5 Hz), 4.33
(2H, d, J¼11.7 Hz), 4.24 (1H, d, J¼11.5 Hz), 4.20–4.16
(2H, m), 4.13 (1H, d, J¼12.2 Hz), 4.07 (1H, d, J¼
11.7 Hz), 3.98–3.91 (2H, m), 3.86 (1H, d, J¼12.2 Hz),
3.82–3.80 (1H, m), 3.75 (1H, dd, J¼1.8, 10.1 Hz), 3.70–
3.66 (1H, m), 3.65 (1H, dd, J¼3.3, 10.1 Hz), 3.61–3.47
(4H, m), 3.32 (1H, dd, J¼7.1, 9.8 Hz), 3.26 (1H, dt,
J¼2.9, 8.5 Hz), 2.78–2.69 (2H, m), 2.44 (1H, ddd, J¼3.0,
4.6, 14.9 Hz), 2.54–2.16 (2H, m), 2.09–2.06 (1H, m),
1.93–1.74 (5H, m), 1.64 (1H, dt, J¼14.1, 9.8 Hz), 1.55–
1.47 (1H, m), 1.04 (3H, s), 1.03 (3H, d, J¼6.6 Hz), 0.96
1594, 1488, 1456, 1362, 1256, 1206, 1099, 1012, 885,
79
92
836, 775, 735, 697; HR-FDMS, calcd for C64H Br2O10Si2
[M]+: 1234.4596, found: 1234.4587.
7.1.23. (1S,20R,30S,50Z,80R,90S,100S,300R,400S,600S,800R,1000R,
1100S)-2-[80-Benzyloxy-90-benzyloxymethyl-30-(tert-butyl-
dimethylsilyloxy)-20,30,40,70,80,90-hexahydrooxonin-20-
yl]-1-{400-(4-bromobenzyloxy)-300-(4-bromobenzyloxy-
methyl)-600,1000-dimethyl-1100-triethylsilyloxy-200,900-dioxa-
bicyclo[6.4.0]dodecan-1000-yl}ethyl trifluoroacetate (29).
To a solution of 26 (10.8 mg, 8.23 mmol) in pyridine
(9H, s), 0.036 (3H, s), 0.032 (3H, s); IR (film), n (cmꢁ1
)
3476, 3027, 2931, 1784, 1593, 1488, 1454, 1387, 1167,
1098, 939, 879, 837, 754, 698; HR-FDMS, calcd for
C60H Br2F3O11Si [M]+: 1216.3554, found: 1216.3586.
79
77

7424
A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
7.1.25. (1S,3R,4S,6S,8R,10R,11S,10S,200R,300S,500Z,800R,
900S)-10-{20-[800-Benzyloxy-900-benzyloxymethyl-300-(tert-
butyldimethylsilyloxy)-200,300,400,700,800,900-hexahydrooxo-
nin-200-yl]-10-hydroxyethyl}-4-(4-bromobenzyloxy)-3-(4-
bromobenzyloxymethyl)-6,10-dimethyl-2,9-dioxabi-
cyclo[6.4.0]dodecan-11-ol (31). To a solution of 26(60.2 mg,
48.7 mmol) in MeOH–DCM (4:1, v/v, 1.0 ml) was added
PPTS (11.3 mg, 45.0 mmol) at 24 ꢀC and the mixture was
stirred for 50 min. Then, saturated aqueous NaHCO3 (1 ml)
was added and the aqueous layer was extracted with Et2O
(4ꢂ5 ml) and AcOEt (5 ml). The combined organic layers
were washed with brine, dried over anhydrous MgSO4, fil-
tered, and concentrated in vacuo. The resultant residue was
purified by column chromatography (silica gel, hexane/
AcOEt¼7 to 3) to give 31 (54.7 mg,w100%). 31: a colorless
oil; [a]1D9 +14.5 (c 0.545, CHCl3); 1H NMR (400 MHz, C6D6),
d (ppm) 7.33–7.26 (5H, m), 7.20–7.05 (9H, m), 7.00 (2H, d,
J¼8.1 Hz), 6.84 (2H, d, J¼8.3 Hz), 5.96 (1H, dt, J¼6.0,
10.5 Hz), 5.87 (1H, dt, J¼5.6, 10.5 Hz), 4.40 (1H, d, J¼
11.8 Hz), 4.35 (1H, d, J¼11.8 Hz), 4.24 (1H, d, J¼12.7 Hz),
4.21–4.13 (5H, m), 4.12 (1H, d, J¼11.8 Hz), 3.97–3.88 (3H,
m), 3.87–3.82 (2H, m), 3.69 (1H, dt, J¼9.0, 3.3 Hz), 3.67–
3.65 (1H, m), 3.63–3.56 (3H, m), 3.54 (1H, dd, J¼2.3,
10.0 Hz), 3.43 (1H, dd, J¼6.6, 10.0 Hz), 3.34 (1H, dt,
J¼2.7, 8.5 Hz), 3.26–3.20 (1H, m), 2.87–2.75 (2H, m), 2.47
(1H, dt, J¼13.4, 3.9 Hz), 2.27 (1H, ddd, J¼3.3, 5.6,
13.8 Hz), 2.19 (1H, dt, J¼13.2, 6.0 Hz), 2.07–2.03 (1H, m),
2.00–1.79 (5H, m), 1.60 (1H, ddd, J¼6.1, 8.5, 14.6 Hz),
1.09 (3H, s), 1.05 (3H, d, J¼7.1 Hz), 0.99 (9H, s), 0.13
(3H, s), 0.086 (3H, s); 13C NMR (75 MHz, CDCl3),
d (ppm) 138.4 (C), 137.9 (C), 137.5 (C), 137.3 (C), 131.41
(CHꢂ2), 131.38 (CHꢂ2), 129.3 (CHꢂ4), 129.1 (CH),
128.33 (CHꢂ2), 128.29 (CHꢂ2), 127.8 (CHꢂ2), 127.7
(CHꢂ2), 127.65 (CH), 127.56 (CH), 126.1 (CH), 121.4
(C), 121.3 (C), 85.23 (CH), 85.15 (CH), 80.3 (CH), 79.8
(CH), 78.8 (CH), 77.2 (C), 76.3 (CH), 76.1 (CH), 74.7
(CH), 73.3 (CH), 73.2 (CH2), 72.5 (CH2), 71.7 (CH2), 71.3
(CH2), 70.5 (CH2), 70.3 (CH), 68.5 (CH2), 45.2 (CH2), 40.3
(CH2), 34.8 (CH2), 33.9 (CH2), 29.5 (CH2), 28.3 (CH), 26.9
(CH3), 26.4 (CH2), 25.8 (CH3ꢂ3), 18.0 (C), 15.8 (CH3),
ꢁ4.6 (CH3), ꢁ4.7 (CH3); IR (film), n (cmꢁ1) 3474, 3027,
2926, 2854, 1593, 1487, 1453, 1360, 1255, 1205, 1096,
1011, 939, 836, 804, 775, 751, 697; HR-FDMS, calcd for
MgSO4, filtered, and concentrated in vacuo. The resultant
residue was purified by column chromatography (silica
gel, hexane/AcOEt¼30 to 7) to give 32 (14.6 mg, w100%,
a 1:1 mixture of 32a and 32b from 1H NMR). This mixture
of 32a and 32b was separated by HPLC (hexane/AcOEt¼7)
to give 32a as less-polar eluate and 32b as polar eluate. 32a:
1
a colorless oil; [a]D24 +6.71 (c 0.235, CHCl3); H NMR
(400 MHz, C6D6), d (ppm) 7.51–7.49 (4H, m), 7.30–7.05
(12H, m), 6.97 (2H, d, J¼8.3 Hz), 6.90 (2H, d, J¼8.8 Hz),
6.82 (2H, d, J¼8.5 Hz), 6.07 (1H, s), 6.04 (1H, dt, J¼5.1,
10.6 Hz), 5.99 (1H, dt, J¼5.1, 10.6 Hz), 4.72 (1H, d,
J¼11.8 Hz), 4.54 (1H, dd, J¼4.1, 8.8 Hz), 4.52 (1H,
d, J¼11.8 Hz), 4.49 (1H, dt, J¼8.7, 3.2 Hz), 4.45 (1H, d,
J¼11.8 Hz), 4.21 (1H, d, J¼12.3 Hz), 4.19 (1H, d,
J¼11.8 Hz), 4.18 (1H, d, J¼11.5 Hz), 4.13 (1H, d, J¼
12.3 Hz), 3.98 (1H, dt, J¼8.5, 3.2 Hz), 3.93 (1H, t,
J¼4.8 Hz), 3.88 (1H, d, J¼11.5 Hz), 3.86–3.83 (2H, m),
3.76 (1H, dt, J¼4.8, 9.0 Hz), 3.64–3.53 (4H, m), 3.43–
3.40 (1H, m), 3.38 (1H, dd, J¼6.6, 9.8 Hz), 3.32 (3H, s),
3.27 (1H, dt, J¼2.4, 8.7 Hz), 3.07 (1H, ddd, J¼3.2, 10.6,
13.5 Hz), 2.80 (1H, ddd, J¼3.2, 10.6, 13.7 Hz), 2.46 (1H,
dt, J¼13.8, 4.8 Hz), 2.31–2.25 (1H, m), 2.17–2.14 (3H,
m), 1.98–1.75 (5H, m), 1.56 (1H, ddd, J¼6.1, 8.7,
14.6 Hz), 1.18 (3H, s), 1.05 (3H, d, J¼6.6 Hz), 1.04 (9H,
s), 0.22 (3H, s), 0.091 (3H, s); 13C NMR (125 MHz,
C6D6), d (ppm) 160.4 (C), 139.52 (C), 139.46 (C), 138.2
(C), 138.0 (C), 132.2 (C), 131.6 (CHꢂ4), 129.4 (CHꢂ2),
129.2 (CHꢂ2), 128.6 (CHꢂ2), 128.4 (CHꢂ2), 127.5
(CHꢂ2), 121.6 (C), 121.5 (C), 113.8 (CHꢂ2), 98.6 (CH),
85.1 (CH), 85.0 (CH), 84.9 (CH), 81.0 (CH), 79.8 (CH),
78.7 (CH), 77.4 (CH), 76.1 (C), 74.8 (CH), 73.4 (CH),
73.3 (CH2), 72.6 (CH2), 72.4 (CH2), 72.0 (CH2), 71.42
(CH), 71.35 (CH2), 70.3 (CH2), 54.8 (CH3), 45.2 (CH2),
33.0 (CH2), 32.7 (CH2), 31.9 (CH2), 30.2 (CH2), 28.9
(CH), 27.5 (CH2), 27.0 (CH3), 26.2 (CH3ꢂ3), 18.2 (C),
16.3 (CH3), ꢁ3.9 (CH3), ꢁ4.3 (CH3) (The signals of 10 car-
bons were undetected due to overlapping with solvent sig-
nal.); IR (film), n (cmꢁ1) 3063, 3026, 2925, 2853, 1614,
1588, 1513, 1487, 1453, 1360, 1301, 1249, 1213, 1170,
1095, 1011, 939, 833, 804, 776, 734, 697; HR-FDMS, calcd
for C66H Br2O11Si [M]+: 1238.4150, found: 1238.4125.
79
84
32b: a colorless oil; [a]2D3 ꢁ8.95 (c 0.200, CHCl3); 1H
NMR (400 MHz, C6D6), d (ppm) 7.75 (2H, d, J¼8.8 Hz),
7.35–7.21 (8H, m), 7.18–7.04 (6H, m), 6.98 (2H, d,
J¼8.5 Hz), 6.87 (2H, d, J¼8.8 Hz), 6.83 (2H, d,
J¼8.5 Hz), 5.96 (1H, dt, J¼5.4, 10.2 Hz), 5.90 (1H, s),
5.89 (1H, dt, J¼5.4, 10.2 Hz), 4.50 (1H, dd, J¼2.8,
11.3 Hz), 4.47 (1H, d, J¼11.8 Hz), 4.43 (1H, d,
J¼11.7 Hz), 4.42 (1H, d, J¼11.8 Hz), 4.22–4.14 (5H, m),
3.92–3.87 (1H, m), 3.86 (1H, d, J¼12.0 Hz), 3.73–3.58
(6H, m), 3.56–3.50 (3H, m), 3.40 (1H, dd, J¼6.8,
10.0 Hz), 3.31–3.26 (4H, m), 2.81 (1H, ddd, J¼2.6, 10.2,
13.6 Hz), 2.71 (1H, ddd, J¼2.3, 10.2, 12.7 Hz), 2.43 (1H,
ddd, J¼2.8, 4.6, 13.9 Hz), 2.31–2.25 (2H, m), 2.09 (1H,
dt, J¼13.6, 5.4 Hz), 2.02–1.90 (4H, m), 1.88–1.81 (2H,
m), 1.57–1.49 (1H, m), 1.04 (3H, s), 1.03 (3H, d,
J¼7.1 Hz), 1.00 (9H, s), 0.15 (3H, s), 0.084 (3H, s); 13C
NMR (125 MHz, C6D6), d (ppm) 160.5 (C), 139.3 (C),
139.2 (C), 138.2 (C), 138.1 (C), 132.1 (C), 131.7 (CHꢂ2),
131.6 (CHꢂ2), 129.22 (CHꢂ2), 129.16 (CHꢂ2), 128.54
(CHꢂ2), 128.50 (CHꢂ2), 128.45 (CHꢂ2), 127.5 (CH),
121.5 (C), 121.4 (C), 113.7 (CHꢂ2), 97.0 (CH), 84.8
(CH), 84.1 (CH), 83.8 (CH), 80.3 (CH), 79.7 (CH),
C58H Br2O10Si [M]+: 1120.3731, found: 1120.3763.
79
78
7.1.26. (1R,3R,4S,6R,8S,10S,12R,13S,15S,20R,30S,50Z,80R,
90S)-4-[80-Benzyloxy-90-benzyloxymethyl-30-(tert-
butyldimethylsilyloxy)-20,30,40,70,80,90-hexahydrooxonin-
20-yl]-13-(4-bromobenzyloxy)-12-(4-bromobenzyloxy-
methyl)-6-(4-methoxyphenyl)-3,15-dimethyl-2,5,7,11-
tetraoxatricyclo[8.6.0.03,8]hexadecane (32a) and (1R,3R,
4S,6S,8S,10S,12R,13S,15S,20R,30S,50Z,80R,90S)-4-[80-benz-
yloxy-90-benzyloxymethyl-30-(tert-butyldimethylsilyl-
oxy)-20,30,40,70,80,90-hexahydrooxonin-20-yl]-13-(4-bromo-
benzyloxy)-12-(4-bromobenzyloxymethyl)-6-(4-meth-
oxyphenyl)-3,15-dimethyl-2,5,7,11-tetraoxatricyclo-
[8.6.0.03,8]hexadecane (32b). To a solution of 31 (13.2 mg,
11.8 mmol) in benzene (2.0 ml) were added p-anisaldehyde
(30.0 ml, 247 mmol) and PPTS (3.2 mg, 12.7 mmol). The re-
action mixture was heated to 80 ꢀC and stirred for 3 h. Then,
saturated aqueous NaHCO3 (1 ml) was added and the aque-
ous layer was extracted with Et2O (4ꢂ5 ml). The combined
organic layers were washed with brine, dried over anhydrous

A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
7425
78.8 (CH), 75.3 (CH), 75.0 (CH), 74.8 (CH), 74.3 (C), 74.2
(CH), 73.3 (CH2), 72.8 (CH2), 72.7 (CH2), 72.4 (CH2), 71.3
(CH2), 70.2 (CH2), 54.8 (CH3), 45.1 (CH2), 33.9 (CH2), 32.3
(CH2), 31.2 (CH2), 30.2 (CH2), 28.9 (CH), 27.6 (CH2), 26.8
(CH3), 26.2 (CH3ꢂ3), 18.2 (C), 16.5 (CH3), ꢁ4.08 (CH3),
ꢁ4.14 (CH3) (The signals of seven carbons were undetected
3.55–3.49 (2H, m), 3.45 (1H, dd, J¼6.3, 10.0 Hz), 3.34
(1H, dt, J¼2.8, 8.8 Hz), 3.27 (3H, s), 2.96–2.89 (1H, m),
2.88–2.81 (1H, m), 2.47 (1H, dt, J¼13.4, 4.0 Hz), 2.34
(1H, ddd, J¼3.4, 5.1, 13.8 Hz), 2.14–1.79 (8H, m), 1.67
(1H, ddd, J¼5.6, 8.9, 14.4 Hz), 1.07–1.05 (6H, m), 1.01
(9H, s), 0.18 (3H, s), 0.038 (3H, s); 13C NMR (125 MHz,
C6D6), d (ppm) 159.8 (C), 139.3 (C), 139.1 (C), 138.2 (C),
138.1 (C), 131.7 (CHꢂ2), 131.64 (CHꢂ2), 131.60 (C),
130.1 (CHꢂ2), 129.3 (CHꢂ4), 129.2 (CH), 128.9 (CH),
128.54 (CHꢂ2), 128.50 (CHꢂ2), 121.6 (C), 121.5 (C),
114.1 (CHꢂ2), 85.5 (CH), 85.1 (CH), 84.6 (CH), 80.8
(CH), 79.8 (CHꢂ2), 78.5 (C), 78.1 (CH), 75.3 (CH), 74.3
(CH), 73.2 (CH2), 72.7 (CH2), 72.4 (CH2ꢂ2), 71.33
(CH2), 71.30 (CH2), 70.9 (CH), 70.3 (CH2), 54.7 (CH3),
45.9 (CH2), 36.1 (CH2), 32.5 (CH2), 31.9 (CH2), 30.4
(CH3), 30.2 (CH2), 28.9 (CH), 27.5 (CH2), 26.9 (CH3),
26.2 (CH3ꢂ3), 18.2 (C), ꢁ4.2 (CH3), ꢁ4.3 (CH3) (The sig-
nals of six carbons were undetected due to overlapping with
solvent signal.); IR (film), n (cmꢁ1) 3420, 3063, 3026, 2926,
2856, 1612, 1586, 1514, 1487, 1453, 1360, 1301, 1249,
1213, 1173, 1097, 1012, 939, 834, 804, 776, 750, 697;
due to overlapping with solvent signal.); IR (film), n (cmꢁ1
)
3063, 3026, 2927, 2855, 1614, 1589, 1514, 1487, 1453,
1360, 1301, 1249, 1214, 1170, 1098, 1011, 940, 834, 804,
79
84
775, 753, 697; HR-FDMS, calcd for C66H Br2O11Si
[M]+: 1238.4150, found: 1238.4172.
7.1.27. (1S,3R,4S,6S,8R,10R,11S,10S,200R,300S,500Z,800R,
900S)-10-{20-[800-Benzyloxy-900-benzyloxymethyl-300-(tert-
butyldimethylsilyloxy)-200,300,400,700,800,900-hexahydrooxo-
nin-200-yl]-10-(4-methoxybenzyloxy)ethyl}-4-(4-
bromobenzyloxy)-3-(4-bromobenzyloxymethyl)-6,10-di-
methyl-2,9-dioxabicyclo[6.4.0]dodecan-11-ol (33a) and
(1S,20R,30S,50Z,80R,90S,100S,300R,400S,600S,800R,1000S,1100S)-
2-[80-benzyloxy-90-benzyloxymethyl-30-(tert-butyl-
dimethylsilyloxy)-20,30,40,70,80,90-hexahydrooxonin-20-
yl]-1-{400-(4-bromobenzyloxy)-300-(4-bromobenzyloxy-
methy)-1100-(4-methoxybenzyloxy)-600,1000-dimethyl-
200,900-dioxabicyclo[6.4.0]dodecan-1000-yl}ethanol (33b).
7.1.27.1. Reaction of 32a. To a solution of 32a (3.8 mg,
3.06 mmol) in DCM (0.50 ml) was added DIBAL (0.10 ml,
0.94 M in hexane, 94.0 mmol) at ꢁ30 ꢀC and the mixture was
stirred for 1.5 h. Then, MeOH (0.1 ml) and saturated aqueous
potassium sodium tartrate (1 ml) were added. The mixture
was diluted with Et2O (5 ml) and stirred at 25 ꢀC for 2 h.
The layers were separated and the aqueous layer was ex-
tracted with Et2O (4ꢂ5 ml). The combined organic layers
were washed with brine, dried over anhydrous MgSO4, fil-
tered, and concentrated in vacuo. The resultant residue was
purified by column chromatography (silica gel, hexane/
AcOEt¼7 to 5) to give 33 (3.8 mg, w100%, 33a:33b¼5:1
from 1H NMR).
HR-FDMS, calcd for C66H Br2O11Si [M]+: 1240.4306,
79
86
found: 1240.4355. 33b: a colorless oil; [a]2D0 +15.6 (c
0.150, CHCl3); H NMR (400 MHz, C6D6), d (ppm) 7.36–
1
7.22 (8H, m), 7.18–7.04 (8H, m), 6.94 (2H, d, J¼8.5 Hz),
6.83 (2H, d, J¼8.3 Hz), 6.76 (2H, d, J¼8.8 Hz), 5.93 (1H,
dt, J¼6.2, 10.4 Hz), 5.85 (1H, dt, J¼5.7, 10.4 Hz), 4.66–
4.63 (1H, m), 4.60 (1H, d, J¼12.1 Hz), 4.51 (2H, s), 4.38
(1H, d, J¼11.7 Hz), 4.24 (1H, d, J¼12.1 Hz), 4.22–4.17
(3H, m), 4.15 (1H, d, J¼11.7 Hz), 4.06–4.03 (1H, m),
3.95–3.90 (3H, m), 3.87 (1H, d, J¼11.7 Hz), 3.84–3.79
(2H, m), 3.73–3.68 (3H, m), 3.65 (1H, dt, J¼2.7, 9.6 Hz),
3.61 (1H, d, J¼2.7 Hz), 3.59 (1H, dd, J¼2.3, 9.9 Hz), 3.41
(1H, dd, J¼7.0, 9.9 Hz), 3.32–3.27 (4H, m, H20), 2.90–
2.79 (2H, m), 2.45 (1H, ddd, J¼3.3, 4.5, 13.8 Hz), 2.26
(1H, ddd, J¼4.1, 5.7, 13.9 Hz), 2.25–2.17 (2H, m), 2.03–
1.74 (6H, m), 1.62 (1H, ddd, J¼5.5, 8.8, 14.8 Hz), 1.27
(3H, s), 1.08 (3H, d, J¼6.6 Hz), 0.96 (9H, s), 0.080 (3H,
s), 0.054 (3H, s); 13C NMR (125 MHz, C6D6), d (ppm)
159.6 (C), 139.4 (C), 139.1 (C), 138.2 (C), 138.0 (C),
131.73 (C), 131.66 (CHꢂ2), 131.6 (CHꢂ2), 129.3
(CHꢂ2), 129.2 (CHꢂ4), 128.44 (CHꢂ2), 128.37 (CHꢂ2),
127.54 (CH), 127.46 (CH), 126.8 (CH), 121.6 (C), 121.5
(C), 114.1 (CHꢂ2), 86.0 (CH), 85.4 (CH), 81.3 (CH), 80.0
(CH), 79.9 (CH), 78.1 (C), 77.3 (CH), 76.9 (CH), 76.6
(CH), 74.3 (CH), 73.3 (CH2), 73.0 (CH2), 72.5 (CH2), 72.1
(CH), 71.42 (CH2), 71.37 (CH2), 70.3 (CH2), 69.4 (CH2),
54.7 (CH3), 45.5 (CH2), 35.0 (CH2), 32.0 (CH2), 30.2
(CH2), 29.8 (CH2), 29.0 (CH), 26.9 (CH2), 26.7 (CH3),
26.1 (CH3ꢂ3), 18.2 (C), 15.0 (CH3), ꢁ4.5 (CH3), ꢁ4.6
(CH3) (The signals of five carbons were undetected due
7.1.27.2. Reaction of 32b. To a solution of 32b (4.0 mg,
3.22 mmol) in DCM (0.50 ml) was added DIBAL (0.10 ml,
0.94 M in hexane, 94.0 mmol) at ꢁ20 ꢀC and the mixture
was stirred for 2 h. Then, MeOH (0.1 ml) and saturated
aqueous potassium sodium tartrate (1 ml) were added. The
mixture was diluted with Et2O (5 ml) and stirred at 25 ꢀC
for 3 h. The layers were separated and the aqueous layer
was extracted with Et2O (4ꢂ5 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/AcOEt¼7 to 4) to give 33 (4.0 mg, w100%,
1
33b:33a>20:1 from H NMR). 33a: a colorless oil; [a]D21
ꢁ3.02 (c 0.150, CHCl3); 1H NMR (400 MHz, C6D6),
d (ppm) 7.40 (2H, d, J¼8.5 Hz), 7.35 (2H, d, J¼7.1 Hz),
7.29 (2H, d, J¼8.3 Hz), 7.25–7.05 (8H, m), 6.98 (2H, d,
J¼8.5 Hz), 6.84 (2H, d, J¼8.3 Hz), 6.81 (2H, d, J¼
8.5 Hz), 6.07 (1H, dt, J¼5.1, 10.7 Hz), 5.97 (1H, dt,
J¼5.1, 10.7 Hz), 5.20 (1H, d, J¼10.4 Hz), 4.73 (1H, d, J¼
10.4 Hz), 4.48 (1H, d, J¼11.7 Hz), 4.46 (1H, d,
J¼11.8 Hz), 4.41 (1H, dt, J¼7.8, 3.9 Hz), 4.31 (1H, dd, J¼
2.4, 10.2 Hz), 4.30 (1H, d, J¼11.8 Hz), 4.26–4.16 (4H, m),
4.10–4.04 (1H, m), 3.95–3.92 (1H, m), 3.91 (1H, d,
J¼12.2 Hz), 3.84 (1H, dt, J¼9.5, 3.4 Hz), 3.73–3.69 (2H,
m), 3.65–3.64 (2H, m), 3.57 (1H, dd, J¼2.4, 10.0 Hz),
to overlapping with solvent signal.); IR (film), n (cmꢁ1
)
3509, 3067, 3032, 2928, 2859, 1616, 1588, 1514, 1488,
1454, 1406, 1361, 1302, 1250, 1207, 1173, 1099, 1012,
940, 836, 805, 775, 735, 698; HR-FDMS, calcd for
C66H Br2O11Si [M]+: 1240.4306, found: 1240.4371.
79
86
7.1.28. (1S,3R,4S,6S,8R,10S,11S,10S,200R,300S,500Z,800R,
900S)-10-{20-[800-Benzyloxy-900-benzyloxymethyl-300-(tert-
butyldimethylsilyloxy)-200,300,400,700,800,900-hexahydrooxo-
nin-200-yl]-10-(4-methoxybenzyloxy)ethyl}-4-(4-bromo-
benzyloxy)-3-(4-bromobenzyloxymethyl)-6,10-dimethyl-
2,9-dioxabicyclo[6.4.0]dodecan-11-one (34). To a solution

7426
A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
of 33a (3.0 mg, 2.41 mmol) in DCM (0.80 ml) was added
DMPI (9.5 mg, 22.4 mmol) at 24 ꢀC and the reaction mixture
was stirred for 2 h. After the mixture was diluted with Et2O
(5 ml), saturated aqueous Na2SO3 (1 ml) was added and the
aqueous layer was extracted with Et2O (3ꢂ5 ml). The com-
bined organic layers were washed with saturated aqueous
Na2SO3 and brine, dried over anhydrous MgSO4, filtered,
and concentrated in vacuo. The resultant residue was puri-
fied by column chromatography (silica gel, benzene/
AcOEt¼15 to 5) to give 34 (2.1 mg, 70%). 34: a colorless
m), 6.92 (2H, d, J¼8.3 Hz), 6.82 (2H, d, J¼8.5 Hz), 6.79
(2H, d, J¼8.8 Hz), 5.97 (1H, dt, J¼5.7, 10.5 Hz), 5.89
(1H, dt, J¼5.7, 10.5 Hz), 4.86 (1H, d, J¼11.0 Hz), 4.81
(1H, d, J¼11.0 Hz), 4.54 (1H, d, J¼12.2 Hz), 4.41 (1H, d,
J¼11.7 Hz), 4.40 (1H, d, J¼12.2 Hz), 4.27 (1H, dd,
J¼2.0, 10.2 Hz, H11), 4.20–4.11 (4H, m), 4.02–3.99 (1H,
m), 3.87 (1H, d, J¼11.7 Hz), 3.80 (1H, dt, J¼9.1, 6.6 Hz),
3.70 (1H, dt, J¼7.9, 3.3 Hz), 3.63–3.62 (2H, m), 3.56–
3.43 (5H, m), 3.30 (1H, dd, J¼6.8, 10.2 Hz), 3.27 (3H, s),
3.26–3.20 (2H, m), 2.93 (1H, ddd, J¼3.9, 10.5, 13.4 Hz),
2.72 (1H, ddd, J¼3.3, 10.5, 13.1 Hz), 2.59 (1H, dd, J¼6.6,
16.8 Hz), 2.50 (1H, ddd, J¼1.1, 10.3, 14.6 Hz), 2.30 (1H,
ddd, J¼3.3, 5.7, 13.1 Hz), 2.14–2.08 (1H, m), 2.02 (1H,
ddd, J¼2.0, 7.4, 14.6 Hz), 1.99–1.95 (1H, m), 1.82–1.72
(3H, m), 1.55 (1H, ddd, J¼5.6, 9.0, 14.4 Hz), 1.30 (3H, s),
0.97 (3H, d, J¼6.8 Hz).
oil; [a]2D1 ꢁ14.4 (c 0.165, CHCl3); H NMR (400 MHz,
1
C6D6), d (ppm) 7.42–7.28 (8H, m), 7.25–7.09 (8H, m),
6.94 (2H, d, J¼8.5 Hz), 6.83–6.80 (4H, m), 6.07 (1H, dt,
J¼5.1, 10.6 Hz), 5.97 (1H, dt, J¼5.1, 10.6 Hz), 4.91 (2H,
s), 4.58 (1H, d, J¼11.7 Hz), 4.49–4.45 (2H, m), 4.35 (1H,
d, J¼11.7 Hz), 4.34 (1H, dd, J¼2.3, 11.0 Hz), 4.20–4.12
(4H, m), 3.87 (1H, d, J¼11.7 Hz), 3.85–3.80 (2H, m), 3.68
(1H, dd, J¼3.2, 10.2 Hz), 3.62 (1H, dd, J¼2.0, 10.2 Hz),
3.54 (1H, ddd, J¼2.1, 6.8, 8.8 Hz), 3.52–3.41 (4H, m),
3.33–3.27 (5H, m), 3.21 (1H, dt, J¼2.1, 8.8 Hz), 2.94–
2.87 (1H, m), 2.83–2.76 (1H, m), 2.62 (1H, dd, J¼6.1,
16.8 Hz), 2.34–2.27 (2H, m), 2.13–2.08 (1H, m), 2.04–
2.00 (1H, m), 1.89 (1H, ddd, J¼2.3, 7.2, 14.5 Hz), 1.82–
1.75 (3H, m), 1.61–1.53 (1H, m), 1.28 (3H, s), 1.05 (9H,
s), 0.99 (3H, d, J¼6.6 Hz), 0.25 (3H, s), 0.088 (3H, s); 13C
NMR (125 MHz, C6D6), d (ppm) 210.8 (C), 159.6 (C),
139.4 (C), 139.3 (C), 137.9 (C), 137.8 (C), 132.0 (C),
131.73 (CHꢂ2), 131.69 (CHꢂ2), 129.8 (CHꢂ2), 129.4
(CHꢂ4), 128.9 (CH), 128.5 (CH), 121.7 (C), 121.6 (C),
114.0 (CHꢂ2), 88.1 (C), 85.5 (CH), 85.4 (CH), 85.0 (CH),
83.1 (CH), 82.4 (CH), 79.7 (CH), 78.1 (CH), 75.1 (CH2),
74.7 (CHꢂ2), 73.1 (CH2), 72.6 (CH2), 72.2 (CH2), 71.4
(CH2), 71.3 (CH2), 70.4 (CH2), 54.8 (CH3), 46.8 (CH2),
44.6 (CH2), 39.4 (CH2), 31.3 (CH2), 30.2 (CH2), 28.7
(CH), 27.6 (CH2), 26.8 (CH3), 26.2 (CH3ꢂ3), 18.7 (CH3),
18.2 (C), ꢁ4.0 (CH3), ꢁ4.2 (CH3) (The signals of 10 carbons
were undetected due to overlapping with solvent signal.);
IR (film), n (cmꢁ1) 3062, 3026, 2925, 2855, 1593, 1716,
1613, 1586, 1513, 1487, 1454, 1360, 1301, 1249, 1213,
1173, 1071, 1012, 939, 834, 804, 777, 750, 698; HR-
7.1.30. (1S,3R,4S,6S,8R,10R,11S,10S,200R,300S,500Z,800R,
900S)-10-{10-Benzyloxy-20-[800-benzyloxy-900-benzyloxy-
methyl-300-(tert-butyldimethylsilyloxy)-200,300,400,700,800,900-
hexahydrooxonin-200-yl]ethyl}-4-(4-bromobenzyloxy)-3-
(4-bromobenzyloxymethyl)-11-(4-methoxybenzyloxy)-
6,10-dimethyl-2,9-dioxabicyclo[6.4.0]dodecane (38). To a
suspension of 33b (2.5 mg, 2.01 mmol) and TBAI (5.0 mg,
13.5 mmol) in THF (1.0 ml) was added NaH (15.0 mg,
375 mmol) at 0 ꢀC and the mixture was stirred for 10 min.
Then, to the mixture was added benzyl bromide
(20.0 mmol, 168 mmol) at 0 ꢀC and the reaction mixture
was warmed to 25 ꢀC. During 5 d, NaH was added several
times to the reaction mixture with stirring until the reaction
was complete. After that, H2O (1 ml) was added and the
aqueous layer was extracted with Et2O (4ꢂ5 ml). The com-
bined 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/AcOEt¼50 to 10) to give 38 (1.9 mg,
71%). 38: a colorless oil; [a]2D4 +8.71 (c 0.125, CHCl3); 1H
NMR (400 MHz, C6D6), d (ppm) 7.41–7.03 (17H, m), 6.94
(2H, d, J¼8.3 Hz), 6.83 (2H, d, J¼8.5 Hz), 6.72 (2H, d,
J¼8.8 Hz), 6.00 (1H, dt, J¼5.6, 10.6 Hz), 5.94 (1H, dt,
J¼5.6, 10.6 Hz), 5.03 (1H, d, J¼12.0 Hz), 4.79 (1H, d,
J¼12.0 Hz), 4.59–4.58 (1H, m), 4.55 (1H, d, J¼12.8 Hz),
4.48 (1H, d, J¼12.8 Hz), 4.44 (1H, d, J¼11.5 Hz), 4.43
(1H, d, J¼11.3 Hz), 4.24–4.20 (5H, m), 4.17 (1H, d,
J¼11.3 Hz), 3.93 (1H, dt, J¼8.9, 2.8 Hz), 3.87 (1H, d,
J¼12.0 Hz), 3.86–3.83 (1H, m), 3.82–3.73 (4H, m), 3.72–
3.62 (3H, m), 3.61 (1H, dd, J¼2.2, 9.9 Hz), 3.40 (1H, dd,
J¼7.4, 9.9 Hz), 3.28 (1H, dt, J¼2.6, 8.7 Hz), 3.26 (3H, s),
2.98–2.84 (2H, m), 2.53 (1H, dt, J¼14.4, 3.7 Hz), 2.35–
2.28 (2H, m), 2.21–2.12 (1H, m), 2.06–1.78 (6H, m),
1.68–1.56 (1H, m), 1.35 (3H, s), 1.08 (3H, d, J¼6.8 Hz),
1.00 (9H, s), 0.16 (3H, s), 0.048 (3H, s); 13C NMR
(125 MHz, C6D6), d (ppm) 159.6 (C), 140.6 (C), 139.9
(C), 139.5 (C), 138.1 (C), 138.0 (C), 131.69 (CHꢂ2),
131.65 (CHꢂ2), 131.2 (C), 129.7 (CHꢂ2), 129.4 (CHꢂ2),
129.3 (CHꢂ2), 128.5 (CH), 127.3 (CH), 127.23 (CH),
127.15 (CH), 121.63 (C), 121.60 (C), 114.1 (CHꢂ2), 85.7
(CH), 84.4 (CH), 82.5 (CH), 81.2 (CH), 79.9 (CH), 78.8
(C), 78.4 (CH), 77.3 (CH), 77.0 (CH), 75.7 (CH), 74.4
(CH), 73.3 (CH2), 73.1 (CH2), 72.54 (CH2), 72.46 (CH2),
71.5 (CH2), 71.1 (CH2), 70.4 (CH2), 70.3 (CH2), 54.7
(CH3), 45.6 (CH2), 39.4 (CH2), 33.3 (CH2), 31.4 (CH2),
30.9 (CH2), 29.0 (CH), 27.4 (CH2), 26.7 (CH3), 26.2
FDMS, calcd for C66H Br2O11Si [M]+: 1238.4150, found:
79
84
1238.4119.
7.1.29. (1S,3R,4S,6S,8R,10R,11S,10S,200R,300S,500Z,800R,
900S)-10-{20-[800-Benzyloxy-900-benzyloxymethyl-300-hy-
droxy-200,300,400,700,800,900-hexahydrooxonin-200-yl]-10-(4-
methoxybenzyloxy)ethyl}-4-(4-bromobenzyloxy)-3-(4-
bromobenzyloxymethyl)-6,10-dimethyl-2,9-dioxabi-
cyclo[6.4.0]dodecan-11-one (35). To a solution of 34
(2.1 mg, 1.69 mmol) in THF (0.80 ml) was added HF$Py at
0 ꢀC. The reaction mixture was warmed to 24 ꢀC and stirred
for 1 d. After the reaction mixture was diluted with Et2O and
cooling to 0 ꢀC, saturated aqueous NaHCO3 (1 ml) was
added and the mixture was stirred for 1 h. The layers were
separated and the aqueous layer was extracted with AcOEt
(3ꢂ5 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/AcOEt¼4 to 2) to give 35 (1.2 mg, 63%). 35
was immediately used for the next reaction. 35: a colorless
1
oil; H NMR (400 MHz, C6D6), d (ppm) 7.38–7.33 (4H,
m), 7.32–7.27 (4H, m), 7.21–7.15 (6H, m), 7.11–7.07 (2H,

A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
7427
(CH3ꢂ3), 18.2 (C), 15.6 (CH3), ꢁ4.1 (CH3), ꢁ4.4 (CH3)
(The signals of 13 carbons were undetected due to over-
lapping with solvent signal.); IR (film), n (cmꢁ1) 3063,
3028, 2926, 2855, 1612, 1586, 1513, 1487, 1454, 1367,
1301, 1249, 1206, 1172, 1097, 1012, 939, 835, 804, 775,
DCM (0.70 ml) were added NaHCO3 (5.0 mg, 59.5 mmol)
and DMPI (5.0 mg, 11.8 mmol) at 25 ꢀC and the reaction
mixture was stirred for 30 min. After the mixture was diluted
with Et2O (1 ml), saturated aqueous Na2SO3 (1 ml) was
added and the aqueous layer was extracted with Et2O
(4ꢂ5 ml). The combined organic layers were washed with
saturated aqueous Na2SO3 and brine, dried over anhydrous
MgSO4, filtered, and concentrated in vacuo. The resultant
residue was roughly purified by column chromatography
(silica gel, hexane/AcOEt¼5 to 4) to give a crude product
(3.4 mg), and it was used in the next reaction without further
purification. To a solution of the above crude product in
THF–H2O (1:1, v/v, 0.80 ml) was added TFA (40.0 ml) at
0 ꢀC. The reaction mixture was warmed to 25 ꢀC and stirred
for 2 d. Then, NaHCO3 (1 ml) was added and the aqueous
layer was extracted with AcOEt (4ꢂ5 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/AcOEt¼5 to 2) to give 41 (2.3 mg, 75% from
733, 697; HR-FDMS, calcd for C73H Br2O11Si [M]+:
79
92
1330.4776, found: 1330.4784.
7.1.31. (1S,3R,4S,6S,8R,10R,11S,10S,200R,030 00S,500Z,800R,
900S)-10-{10-Benzyloxy-20-[800-benzyloxy-9 -benzyloxy-
methyl-300-(tert-butyldimethylsilyloxy)-200,300,400,700,800,900-
hexahydrooxonin-200-yl]ethyl}-4-(4-bromobenzyloxy)-3-
(4-bromobenzyloxymethyl)-6,10-dimethyl-2,9-dioxabi-
cyclo[6.4.0]dodecan-11-ol (39). To a solution of 38 (4.4 mg,
3.30 mmol) in DCM–pH 7 buffer (10:1, v/v, 0.70 ml) was
added DDQ (5.0 mg, 22.0 mmol) at 0 ꢀC and the mixture
was stirred for 20 min. Then, saturated aqueous NaHCO3
(1 ml) was added and the aqueous layer was extracted with
Et2O (4ꢂ5 ml). The combined organic layers were washed
with brine, dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo. The resultant residue was purified by col-
umn chromatography (silica gel, hexane/AcOEt¼30 to 5) to
give 39 (3.4 mg, 85%). 39: a colorless oil; [a]2D2 ꢁ2.29
(c 0.170, CHCl3); 1H NMR (400 MHz, C6D6), d (ppm)
7.43 (2H, d, J¼7.1 Hz), 7.35 (2H, d, J¼6.8 Hz), 7.31–7.28
(4H, m), 7.24–7.08 (11H, m), 6.98 (2H, d, J¼8.3 Hz), 6.84
(2H, d, J¼8.3 Hz), 6.05 (1H, dt, J¼5.2, 10.9 Hz), 5.95
(1H, dt, J¼5.2, 10.9 Hz), 5.22 (1H, d, J¼10.7 Hz), 4.76
(1H, d, J¼10.7 Hz), 4.47 (1H, d, J¼11.7 Hz), 4.46 (1H, d,
J¼12.1 Hz), 4.38–4.34 (2H, m), 4.30 (1H, d, J¼12.1 Hz),
4.25 (1H, d, J¼12.7 Hz), 4.21 (1H, d, J¼11.9 Hz), 4.19
(1H, d, J¼12.7 Hz), 4.17 (1H, d, J¼11.7 Hz), 4.04–3.98
(1H, m), 3.92–3.89 (2H, m), 3.83 (1H, dt, J¼9.0, 3.0 Hz),
3.71–3.63 (4H, m), 3.57 (1H, dd, J¼2.1, 9.9 Hz), 3.54–
3.52 (1H, m), 3.50 (1H, dt, J¼9.0, 3.0 Hz), 3.44 (1H, dd,
J¼6.5, 9.9 Hz), 3.32 (1H, dt, J¼2.6, 8.9 Hz), 2.88–2.78
(2H, m), 2.43 (1H, dt, J¼13.4, 4.2 Hz), 2.32 (1H, ddd,
J¼3.0, 5.2, 13.7 Hz), 2.11–1.78 (8H, m), 1.64 (1H, ddd,
J¼6.1, 8.9, 14.6 Hz), 1.06 (3H, s), 1.05 (3H, d, J¼6.8 Hz),
1.01 (9H, s), 0.17 (3H, s), 0.024 (3H, s); 13C NMR
(125 MHz, C6D6), d (ppm) 139.6 (C), 139.3 (C), 139.1
(C), 138.2 (C), 138.1 (C), 131.7 (CHꢂ2), 131.6 (CHꢂ2),
129.33 (CHꢂ2), 129.32 (CHꢂ2), 128.9 (CH), 128.60
(CHꢂ2), 128.55 (CHꢂ2), 128.5 (CHꢂ2), 128.3 (CHꢂ2),
121.6 (C), 121.5 (C), 85.5 (CH), 85.1 (CH), 84.6 (CH),
80.7 (CH), 79.7 (CHꢂ2), 78.5 (C), 78.0 (CH), 75.3 (CH),
74.2 (CH), 73.2 (CH2), 72.7 (CH2), 72.4 (CH2ꢂ2), 71.3
(CH2), 71.2 (CH2), 70.9 (CH), 70.3 (CH2), 45.9 (CH2),
39.9 (CH2), 36.1 (CH2), 32.4 (CH2), 31.8 (CH2), 30.4
(CH3), 28.9 (CH), 27.5 (CH2), 26.9 (CH3), 26.2 (CH3ꢂ3),
18.2 (C), ꢁ4.3 (CH3ꢂ2) (The signals of eight carbons
were undetected due to overlapping with solvent signal.);
IR (film), n (cmꢁ1) 3584, 3433, 3063, 3028, 2923, 2857,
1593, 1487, 1454, 1405, 1359, 1298, 1256, 1207, 1096,
1012, 940, 836, 804, 776, 749, 698; HR-FDMS, calcd for
1
39). 41: a colorless oil; [a]2D1 ꢁ21.3 (c 0.115, CHCl3); H
NMR (400 MHz, C6D6), d (ppm) 7.41–7.35 (4H, m), 7.32–
7.27 (4H, m), 7.21–7.04 (11H, m), 6.92 (2H, d, J¼8.3 Hz),
6.82 (2H, d, J¼8.5 Hz), 5.94 (1H, dt, J¼5.5, 10.2 Hz),
5.87 (1H, dt, J¼5.5, 10.2 Hz), 4.90 (1H, d, J¼11.5 Hz),
4.85 (1H, d, J¼11.5 Hz), 4.53 (1H, d, J¼12.1 Hz), 4.40
(1H, d, J¼12.1 Hz), 4.39 (1H, d, J¼12.1 Hz), 4.28 (1H,
dd, J¼2.0, 10.4 Hz), 4.18 (1H, d, J¼11.7 Hz), 4.16 (1H, d,
J¼12.1 Hz), 4.12 (1H, d, J¼12.1 Hz), 3.98 (1H, dt, J¼8.8,
3.5 Hz), 3.86 (1H, d, J¼11.7 Hz), 3.76 (1H, dt, J¼9.0,
6.6 Hz), 3.69 (1H, dt, J¼8.7, 3.3 Hz), 3.62 (2H, d,
J¼2.4 Hz), 3.55–3.43 (5H, m), 3.30 (1H, dd, J¼7.1,
10.2 Hz), 3.23–3.17 (2H, m), 2.87 (1H, ddd, J¼3.5, 10.2,
13.4 Hz), 2.70 (1H, ddd, J¼3.3, 10.2, 13.4 Hz), 2.58 (1H,
dd, J¼6.6, 16.8 Hz), 2.50 (1H, ddd, J¼2.0, 10.4, 14.6 Hz),
2.28 (1H, ddd, J¼3.3, 5.5, 13.4 Hz), 2.07–1.95 (3H, m),
1.81–1.67 (3H, m), 1.53 (1H, ddd, J¼6.1, 8.8, 14.9 Hz),
1.28 (3H, s), 0.96 (3H, d, J¼6.6 Hz); 13C NMR (125 MHz,
C6D6), d (ppm) 210.5 (C), 139.5 (C), 139.3 (C), 139.2 (C),
137.9 (C), 137.8 (C), 133.0 (C), 131.74 (CHꢂ2), 131.70
(CHꢂ2), 129.4 (CHꢂ4), 128.6 (CHꢂ2), 128.50 (CHꢂ2),
128.47 (CHꢂ2), 127.6 (CHꢂ2), 121.74 (C), 121.69
(C), 87.8 (C), 85.2 (CH), 84.8 (CH), 84.7 (CH), 82.5
(CH), 82.2 (CH), 79.7 (CH), 78.4 (CH), 75.0 (CH2), 74.6
(CH), 74.4 (CH), 73.1 (CH2), 72.6 (CH2), 72.1 (CH2),
71.9 (CH2), 71.3 (CH2), 70.4 (CH2), 46.5 (CH2), 44.4
(CH2), 39.4 (CH2), 34.5 (CH2), 33.1 (CH2), 28.6 (CH),
27.7 (CH2), 26.8 (CH3), 18.5 (CH3) (The signals of nine
carbons were undetected due to overlapping with sol-
vent signal.); IR (film), n (cmꢁ1) 3465, 3063, 3027, 2924,
2858, 1716, 1592, 1487, 1453, 1405, 1366, 1305, 1256,
1215, 1098, 1027, 1012, 911, 839, 803, 753, 698; HR-
FDMS, calcd for C59H Br2O10 [M]+: 1094.3179, found:
79
68
1094.3176.
C65H Br2O10Si [M]+: 1210.4200, found: 1210.4218.
7.1.33. (1R,3S,5Z,8R,9S,11R,13S,14S,16R,18S,20S,
21R,23S)-8,13-Dibenzyloxy-9-benzyloxymethyl-20-(4-
bromobenzyloxy)-21-(4-bromobenzyloxymethyl)-14,18-
dimethyl-2,10,15,22-tetraoxatetracyclo[12.10.0.03,11.016,23]-
tetracos-5-ene (42). To a solution of 41 (2.3 mg, 2.10 mmol)
in DCM–Et3SiH (10:1, v/v, 0.70 ml) was added TMSOTf
(3.0 ml, 16.6 mmol) at 0 ꢀC and the mixture was stirred for
30 min. Then, saturated aqueous NaHCO3 (1 ml) was added
79
84
7.1.32. (1S,3R,4S,6S,8R,10S,11S,10S,200R,300S,500Z,800R,
900S)-10-[10-Benzyloxy-20-(800-benzyloxy-900-benzyloxy-
methyl-300-hydroxy-200,300,400,700,800,900-hexahydrooxonin-
200-yl)ethyl]-4-(4-bromobenzyloxy)-3-(4-bromobenzyl-
oxymethyl)-6,10-dimethyl-2,9-dioxabicyclo[6.4.0]dode-
can-11-one (41). To a solution of 39 (3.4 mg, 2.80 mmol) in

7428
A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
and the aqueous layer was extracted with Et2O (5 ml) and
AcOEt (3ꢂ5 ml). The combined organic layers were washed
with brine, dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo. The resultant residue was purified by col-
umn chromatography (silica gel, hexane/AcOEt¼10 to 4) to
give 41 (1.6 mg, 70%). 41: a colorless oil; [a]2D2 ꢁ60.8
stirred for 1 h. After Et3N (240 ml, 1.72 mmol) was added,
the reaction mixture was warmed to 0 ꢀC and stirred for
20 min. H2O (1 ml) was added and the aqueous layer was ex-
tracted with Et2O (4ꢂ5 ml). The combined organic layers
were washed with 1 M HCl, saturated aqueous NaHCO3
and brine, dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo. The resultant residue was purified by col-
umn chromatography (silica gel, hexane/AcOEt¼15 to 10)
to give 45 (19.8 mg, 61%). 45: a colorless oil; [a]2D3 +27.2
1
(c 0.080, CHCl3); H NMR (400 MHz, CDCl3), d (ppm)
7.45–7.41 (4H, m), 7.37–7.18 (17H, m), 7.07 (2H, d,
J¼8.5 Hz), 5.81 (1H, dt, J¼5.2, 10.7 Hz), 5.71 (1H, dt,
J¼5.2, 10.7 Hz), 4.621 (2H, s), 4.617 (1H, d, J¼11.3 Hz),
4.525 (1H, d, J¼12.8 Hz), 4.516 (1H, d, J¼11.5 Hz), 4.50
(1H, d, J¼12.1 Hz), 4.465 (1H, d, J¼12.1 Hz), 4.461 (1H,
d, J¼12.8 Hz), 4.30 (1H, d, J¼11.3 Hz), 4.23 (1H, d,
J¼11.5 Hz), 4.07–4.03 (1H, m), 3.88 (1H, dd, J¼4.3,
12.4 Hz), 3.72–3.68 (1H, m), 3.59 (1H, dd, J¼1.8, 9.8 Hz),
3.56–3.48 (3H, m), 3.45 (1H, dd, J¼5.7, 9.8 Hz), 3.41–
3.29 (4H, m), 3.27–3.21 (2H, m), 2.80–2.73 (1H, m),
2.68–2.61 (1H, m), 2.43 (1H, ddd, J¼5.5, 9.1, 15.4 Hz),
2.33–2.27 (1H, m), 2.18 (1H, dt, J¼12.4, 4.3 Hz), 2.12–
2.06 (1H, m), 1.98–1.90 (3H, m), 1.80–1.75 (1H, m),
1.71–1.51 (3H, m), 1.06 (3H, d, J¼7.1 Hz), 1.00 (3H, s);
13C NMR (125 MHz, CDCl3), d (ppm) 139.5 (C), 138.4
(C), 138.2 (C), 137.4 (C), 137.3 (C), 131.5 (CHꢂ4), 129.4
(CHꢂ2), 129.3 (CHꢂ2), 128.8 (CH), 128.33 (CHꢂ2),
128.29 (CHꢂ2), 128.1 (CHꢂ4), 127.8 (CHꢂ2), 127.6
(CHꢂ2), 127.5 (CHꢂ2), 127.13 (CH), 127.05 (CH), 121.5
(C), 121.4 (C), 85.8 (CH), 85.2 (CH), 84.8 (CH), 84.2 (CH),
82.5 (CH), 81.6 (CH), 79.7 (C), 79.0 (CH), 77.7 (CH), 73.6
(CH), 73.4 (CH2), 73.2 (CH2), 72.7 (CH2), 72.6 (CH), 71.9
(CH2), 71.4 (CH2), 71.1 (CH2), 70.5 (CH2), 45.3 (CH2),
40.6 (CH2), 37.2 (CH2), 34.6 (CH2), 32.1 (CH2), 28.1
1
(c 0.900, CHCl3); H NMR (400 MHz, C6D6), d (ppm)
7.35–7.23 (8H, m), 7.20–7.06 (6H, m), 6.95 (2H, d,
J¼8.3 Hz), 6.81 (2H, d, J¼8.3 Hz), 5.96–5.92 (2H, m),
4.51 (1H, d, J¼12.2 Hz), 4.48 (1H, d, J¼11.6 Hz), 4.45
(1H, d, J¼12.2 Hz), 4.39 (1H, ddd, J¼3.2, 5.4, 8.3 Hz),
4.30 (2H, d, J¼11.6 Hz), 4.28 (1H, dt, J¼9.0, 2.6 Hz),
4.21 (1H, d, J¼11.7 Hz), 4.20 (1H, s), 4.16 (1H, t,
J¼2.9 Hz), 3.98 (1H, dt, J¼9.0, 3.9 Hz), 3.96 (1H, dt,
J¼2.2, 5.4 Hz), 3.89–3.83 (2H, m), 3.80 (2H, d, J¼
2.6 Hz), 3.72 (1H, ddd, J¼2.1, 7.1, 9.0 Hz), 3.61 (1H, dd,
J¼2.1, 9.8 Hz), 3.55 (1H, dt, J¼3.0, 9.4 Hz), 3.38 (1H, dd,
J¼7.1, 9.8 Hz), 3.37 (1H, dd, J¼8.3, 18.8 Hz), 3.25 (1H,
dt, J¼2.6, 9.0 Hz), 3.03 (1H, dd, J¼3.2, 18.8 Hz), 2.97–
2.90 (1H, m), 2.83 (1H, ddd, J¼2.9, 9.0, 13.4 Hz), 2.34
(1H, dt, J¼13.4, 3.9 Hz), 2.25 (1H, dt, J¼13.4, 5.4 Hz),
2.22 (1H, dt, J¼13.7, 2.9 Hz), 2.05–2.02 (1H, m), 1.95–
1.87 (3H, m), 1.79 (1H, ddd, J¼2.9, 11.2, 13.7 Hz), 1.65
(1H, ddd, J¼5.2, 9.0, 14.5 Hz), 1.13 (3H, s), 1.07 (3H, d,
J¼6.3 Hz), 1.004 (9H, t, J¼7.9 Hz), 0.997 (9H, s), 0.62
(6H, q, J¼7.9 Hz), 0.19 (3H, s), 0.099 (3H, s); 13C NMR
(75 MHz, CDCl3), d (ppm) 212.2 (C), 138.75 (C), 138.68
(C), 137.4 (C), 137.2 (C), 131.5 (CHꢂ2), 131.4 (CHꢂ2),
129.4 (CHꢂ2), 129.3 (CHꢂ2), 128.2 (CHꢂ4), 127.9
(CHꢂ3), 127.8 (CHꢂ3), 127.7 (CH), 127.4 (CHꢂ2),
121.5 (C), 121.4 (C), 85.9 (CH), 83.4 (C), 82.0 (CH),
80.4 (CH), 80.2 (CH), 79.1 (CH), 77.9 (CH), 73.8 (CH),
73.7 (CH), 73.2 (CH2), 72.5 (CH2), 72.1 (CH), 72.0 (CH2),
71.7 (CH2), 71.4 (CH2), 70.6 (CH2), 70.1 (CH2), 45.6
(CH2), 44.4 (CH2), 40.7 (CH2), 35.7 (CH2), 32.0 (CH2),
28.1 (CH), 27.5 (CH2), 27.0 (CH3), 26.0 (CH3ꢂ3), 18.20
(CH3), 18.16 (C), 6.9 (CH3ꢂ3), 4.7 (CH2ꢂ3), ꢁ4.5 (CH3),
ꢁ4.6 (CH3); IR (film), n (cmꢁ1) 3026, 2926, 1719, 1593,
1487, 1453, 1361, 1337, 1257, 1202, 1098, 1070, 1012,
960, 836, 776, 733, 697; HR-FDMS, calcd for
(CH), 27.1 (CH2, CH3), 13.7 (CH3); IR (film), n (cmꢁ1
)
3062, 3027, 2923, 2854, 1593, 1495, 1487, 1454, 1376,
1330, 1315, 1259, 1204, 1096, 1027, 1012, 803, 778, 735,
697; HR-FDMS, calcd for C59H Br2O9 [M]+: 1078.3230,
79
68
found: 1078.3226.
7.1.34. (2R,3S,5Z,8R,9S,10S,30R,40S,60S,80R,100R,110S)-[8-
Benzyloxy-9-benzyloxymethyl-3-(tert-butyldimethylsilyl-
oxy)-2,3,4,7,8,9-hexahydrooxonin-2-yl]methyl 40-(4-
bromobenzyloxy)-30-(4-bromobenzyloxymethyl)-60,100-
dimethyl-110-triethylsilyloxy-20,90-dioxabicyclo[6.4.0]do-
decan-100-yl ketone (45). To a solution of oxalyl dichloride
(21.0 ml, 241 mmol) in DCM (0.30 ml) was added a solution
of DMSO (30.0 ml, 423 mmol) in DCM (0.30 ml) at ꢁ78 ꢀC
and the mixture was stirred for 10 min. Then, a solution of 26
(32.7 mg, 26.4 mmol) in DCM (0.90 ml) was added at
ꢁ78 ꢀC and the mixture was warmed to ꢁ45 ꢀC and stirred
for 1 h. After Et3N (120 ml, 861 mmol) was added, the reac-
tion mixture was warmed to 0 ꢀC and stirred for 15 min. H2O
(1 ml) was added and the aqueous layer was extracted with
Et2O (4ꢂ5 ml). The combined organic layers were washed
with 1 M HCl, saturated aqueous NaHCO3 and brine, dried
over anhydrous MgSO4, filtered, and concentrated in vacuo.
The resultant residue was roughly purified by column chro-
matography (silica gel, hexane/AcOEt¼5) to give a mixture
of 26 and 45 (31.6 mg). In order to consume 26 completely,
the process was repeated as follows: to a solution of oxalyl
dichloride (42.0 ml, 481 mmol) in DCM (0.30 ml) was added
a solution of DMSO (60.0 ml, 846 mmol) in DCM (0.40 ml)
at ꢁ78 ꢀC and the mixture was stirred for 10 min. Then, a so-
lution of the above mixture (31.6 mg) in DCM (0.90 ml) was
added at ꢁ78 ꢀC and the mixture was warmed to ꢁ45 ꢀC and
C64H Br2O10Si2 [M]+: 1232.4439, found: 1232.4431.
79
90
7.1.35. (2R,3S,5Z,8R,9S,10S,30R,40S,60S,80R,100R,110S)-[8-
Benzyloxy-9-benzyloxymethyl-3-(tert-butyldimethylsilyl-
oxy)-2,3,4,7,8,9-hexahydrooxonin-2-yl]methyl 40-(4-
bromobenzyloxy)-30-(4-bromobenzyloxymethyl)-110-hy-
droxy-60,100-dimethyl-20,90-dioxabicyclo[6.4.0]dodecan-
100-yl ketone (46). To a solution of 45 (19.8 mg, 16.0 mmol)
in THF–pyridine (2:1, v/v, 1.35 ml) was added HF$Py (ex-
cess) at 25 ꢀC. During 6 d, HF$Py was added several times
to the reaction mixture with stirring until the reaction was
complete. After the reaction mixture was diluted with
Et2O and cooled to 0 ꢀC, saturated aqueous NaHCO3
(1 ml) was added and the mixture was stirred for 1 h. The
layers were separated and the aqueous layer was extracted
with Et2O (3ꢂ5 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 chromato-
graphy (silica gel, hexane/AcOEt¼10 to 3) to give 46

A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
7429
(13.8 mg, 71%). 46: a colorless oil; [a]2D3 +36.0 (c 0.150,
CHCl3); H NMR (400 MHz, C6D6), d (ppm) 7.35–7.28
9.8 Hz), 3.33 (1H, dt, J¼2.4, 9.0 Hz), 2.79ꢁ2.67 (2H, m),
2.52 (1H, ddd, J¼2.9, 4.8, 13.3 Hz), 2.29ꢁ2.24 (1H, m),
2.15 (1H, dt, J¼13.5, 5.5 Hz), 2.04ꢁ1.77 (7H, m), 1.61
(1H, ddd, J¼6.1, 9.0, 15.0 Hz), 1.053 (3H, s), 1.050 (3H,
d, J¼6.6 Hz), 0.96 (9H, s), 0.056 (3H, s), 0.030 (3H, s);
13C NMR (100 MHz, CDCl3), d (ppm) 138.3 (C), 137.8
(C), 137.5 (C), 137.4 (C), 131.41 (CHꢂ2), 131.39 (CHꢂ2),
129.31 (CHꢂ2), 129.27 (CHꢂ2), 128.4 (CH), 128.3
(CHꢂ3), 128.2 (CHꢂ2), 127.8 (CHꢂ2), 127.7 (CH), 127.6
(CH), 126.9 (CH), 121.4 (C), 121.3 (C), 85.3 (CH), 83.9
(CH), 81.5 (CH), 80.4 (CH), 78.8 (CH), 77.2 (CH), 75.8
(C), 74.5 (CH), 74.0 (CH), 73.6 (CH), 73.2 (CH2),
72.9 (CH), 72.5 (CH2), 71.6 (CH2), 71.4 (CH2), 70.5
(CH2), 69.1 (CH2), 45.6 (CH2), 40.5 (CH2), 35.7 (CH2),
32.5 (CH2), 29.7 (CH2), 28.3 (CH), 27.0 (CH3), 26.8
(CH2), 25.8 (CH3ꢂ3), 18.0 (C), 17.5 (CH3), ꢁ4.2 (CH3),
ꢁ4.6 (CH3); IR (film), n (cmꢁ1) 3397, 3026, 2961, 2851,
1593, 1487, 1454, 1405, 1360, 1296, 1256, 1204, 1100,
1028, 1012, 947, 836, 804, 776, 751, 698; HR-FDMS,
1
(5H, m), 7.23–7.05 (9H, m), 6.96 (2H, d, J¼8.3 Hz), 6.82
(2H, d, J¼8.5 Hz), 5.99 (1H, dt, J¼4.9, 10.7 Hz), 5.95
(1H, dt, J¼4.9, 10.7 Hz), 4.48–4.41 (3H, m), 4.24 (1H, dt,
J¼7.6, 3.4 Hz), 4.22–4.14 (4H, m), 4.10 (1H, ddd, J¼3.4,
5.4, 8.2 Hz), 3.93 (1H, ddd, J¼2.4, 4.5, 8.3 Hz), 3.88 (1H,
d, J¼12.0 Hz), 3.85–3.73 (3H, m), 3.67 (1H, dd, J¼4.5,
10.5 Hz), 3.60 (1H, dd, J¼2.4, 10.5 Hz), 3.58–3.49 (4H,
m), 3.38 (1H, dd, J¼6.6, 10.0 Hz), 3.27 (1H, dt, J¼2.4,
9.0 Hz), 3.17 (1H, dd, J¼5.4, 19.5 Hz), 3.04 (1H, ddd,
J¼3.4, 10.7, 13.2 Hz), 2.77 (1H, ddd, J¼3.0, 10.7,
13.5 Hz), 2.29 (1H, dt, J¼13.5, 4.9 Hz), 2.23–2.16 (2H,
m), 2.00–1.96 (1H, m), 1.92–1.79 (3H, m), 1.70 (1H, ddd,
J¼2.8, 11.0, 13.7 Hz), 1.58 (1H, ddd, J¼5.4, 9.0,
14.8 Hz), 1.21 (3H, s), 1.04 (3H, d, J¼6.8 Hz), 0.97 (9H,
s), 0.12 (3H, s), 0.075 (3H, s); 13C NMR (75 MHz,
CDCl3), d (ppm) 213.3 (C), 138.5 (C), 138.3 (C), 137.4
(C), 137.3 (C), 131.44 (CHꢂ2), 131.41 (CHꢂ2), 129.3
(CHꢂ4), 128.31 (CHꢂ2), 128.26 (CHꢂ2), 127.94 (CHꢂ2),
127.88 (CH), 127.7 (CHꢂ3), 127.6 (CH), 127.5 (CH),
121.5 (C), 121.4 (C), 85.4 (CH), 83.2 (CH), 81.1 (CH), 79.8
(CH), 78.8 (CH), 78.3 (CH), 77.2 (C), 73.7 (CH), 73.1
(CH), 73.0 (CH2), 72.5 (CH2), 71.7 (CH2), 71.2 (CH2),
70.8 (CH), 70.6 (CH2), 70.5 (CH2), 45.3 (CH2), 41.9
(CH2), 40.4 (CH2), 34.5 (CH2), 32.0 (CH2), 28.1 (CH),
27.01 (CH2), 26.96 (CH3), 25.8 (CH3ꢂ3), 18.2 (CH3),
calcd for C58H Br2O10Si [M]+: 1120.3731, found:
79
78
1120.3730.
7.1.37. Conversion of 31 to 26. To a solution of 31 (2.1 mg,
1.87 mmol) in DCM (0.50 ml) were added 2,6-lutidine
(20 ml, 172 mmol) and TESOTf (3.0 ml, 13.3 mmol) at
ꢁ40 ꢀC. After the mixture was stirred for 25 min, TESOTf
(2.0 ml, 8.8 mmol) was added to the mixture at ꢁ40 ꢀC.
The mixture was stirred for 35 min. Then, saturated aqueous
NaHCO3 (0.5 ml) was added and the aqueous layer was ex-
tracted with Et2O (4ꢂ3 ml). The combined organic layers
were washed with brine, dried over anhydrous MgSO4, fil-
tered, and concentrated in vacuo. The resultant residue was
purified by column chromatography (silica gel, hexane/
AcOEt¼7) to give 26 (2.2 mg, 95%).
17.9 (C), ꢁ4.3 (CH3), ꢁ4.8 (CH3); IR (film), n (cmꢁ1
)
3463, 3026, 2926, 2854, 1715, 1593, 1487, 1453, 1361,
1257, 1204, 1099, 1069, 1011, 836, 803, 776, 735, 697;
HR-FDMS, calcd for C58H Br2O10Si [M]+: 1118.3574,
79
76
found: 1118.3552.
7.1.36. (1S,3R,4S,6S,8R,10R,11S,10R,200R,300S,500Z,800R,
900S)-10-{20-[800-Benzyloxy-900-benzyloxymethyl-300-(tert-
butyldimethylsilyloxy)-200,300,400,700,800,900-hexahydrooxo-
nin-200-yl]-10-hydroxyethyl}-4-(4-bromobenzyloxy)-3-(4-
bromobenzyloxymethyl)-6,10-dimethyl-2,9-dioxabi-
cyclo[6.4.0]dodecan-11-ol (47). To a solution of 46 (2.8 mg,
2.31 mmol) in MeOH (0.70 ml) was added NaBH4 (7.3 mg,
193 mmol) at 0 ꢀC and the reaction mixture was stirred for
15 min. Then, H2O (1 ml) was added and the aqueous layer
was extracted with Et2O (4ꢂ5 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/AcOEt¼15 to 10) to give a mixture of 47 and
7.1.38. (1R,3R,4R,6S,8S,10S,12R,13S,15S,20R,30S,50Z,80R,
90S)-4-[80-Benzyloxy-90-benzyloxymethyl-30-(tert-butyl-
dimethylsilyloxy)-20,30,40,70,80,90-hexahydrooxonin-20-
yl]-13-(4-bromobenzyloxy)-12-(4-bromobenzyloxy-
methyl)-3,15-dimethyl-6-(2-naphthyl)-2,5,7,11-tetraoxa-
tricyclo[8.6.0.03,8]hexadecane (48). To a solution of 47
(4.2 mg, 3.74 mmol) in benzene (1.0 ml) were added 2-naph-
thaldehyde dimethyl acetal (27.1 mg, 134 mmol) and PPTS
(4.3 mg, 17.1 mmol). The reaction mixture was heated to
80 ꢀC and stirred for 1.5 h. Then, saturated aqueous
NaHCO3 (1 ml) was added and the aqueous layer was ex-
tracted with Et2O (4ꢂ5 ml). The combined organic layers
were washed with brine, dried over anhydrous MgSO4, fil-
tered, and concentrated in vacuo. The resultant residue was
purified by column chromatography (silica gel, hexane/
AcOEt¼30 to 4) to give 48 (4.2 mg, 89%,). 48: a colorless
1
31 (2.8 mg, w100%, 47:31¼2:1 from H NMR). This mix-
ture of 47 and 31 was separated by HPLC (hexane/
AcOEt¼4) to give 47 (1.6 mg, 61%) as less-polar eluate
and 31 (0.7 mg, 27%) as polar eluate. 47: a colorless oil;
1
1
[a]2D0 +7.67 (c 0.225, CHCl3); H NMR (400 MHz, C6D6),
oil; [a]2D2 +39.4 (c 0.160, CHCl3); H NMR (400 MHz,
d (ppm) 7.40 (2H, d, J¼7.3 Hz), 7.31ꢁ7.05 (12H, m), 7.00
(2H, d, J¼8.3 Hz), 6.83 (2H, d, J¼8.3 Hz), 5.93 (1H, dt,
J¼5.5, 10.4 Hz), 5.87 (1H, dt, J¼5.5, 10.4 Hz), 4.82ꢁ4.79
(1H, m), 4.52 (1H, d, J¼11.6 Hz), 4.40 (1H, d, J¼
11.7 Hz), 4.30 (1H, d, J¼11.6 Hz), 4.25 (1H, d, J¼
12.3 Hz), 4.24ꢁ4.20 (2H, m), 4.19 (1H, d, J¼12.3 Hz),
4.13 (1H, d, J¼11.7 Hz), 4.04 (1H, dt, J¼4.8, 10.4 Hz),
4.02ꢁ3.99 (1H, m), 3.96 (1H, dt, J¼1.8, 5.5 Hz),
3.92ꢁ3.89 (2H, m), 3.84ꢁ3.82 (1H, m), 3.77ꢁ3.72 (3H,
m), 3.68 (1H, ddd, J¼2.2, 6.7, 9.0 Hz), 3.63ꢁ3.59 (2H,
m), 3.57 (1H, dd, J¼2.2, 9.8 Hz), 3.45 (1H, dd, J¼6.6,
C6D6), d (ppm) 8.28 (1H, s), 7.93 (1H, dd, J¼1.5, 8.4 Hz),
7.81–7.76 (2H, m), 7.62 (1H, J¼1.5, 7.7 Hz), 7.28–7.01
(16H, m), 6.94 (2H, d, J¼8.3 Hz), 6.78 (2H, d, J¼8.3 Hz),
5.99 (1H, dt, J¼6.7, 10.5 Hz), 5.89 (1H, dt, J¼6.0,
10.5 Hz), 5.75 (1H, s), 4.46 (1H, d, J¼12.0 Hz), 4.28–4.11
(8H, m), 4.08 (1H, dt, J¼9.1, 2.2 Hz), 4.02–4.00 (1H, m),
3.96 (1H, dt, J¼9.1, 2.9 Hz), 3.92–3.86 (2H, m), 3.83 (1H,
d, J¼12.0 Hz), 3.66 (1H, dd, J¼2.2, 10.1 Hz), 3.58 (1H, t,
J¼2.9 Hz), 3.55 (1H, dt, J¼2.8, 9.6 Hz), 3.48 (1H, ddd,
J¼2.2, 6.6, 8.8 Hz), 3.46 (1H, dd, J¼2.2, 10.1 Hz), 3.37
(1H, dd, J¼6.6, 10.1 Hz), 3.25 (1H, dt, J¼2.7, 8.8 Hz),

7430
A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
2.98 (1H, ddd, J¼2.9, 10.5, 13.3 Hz), 2.88–2.82 (1H, m),
2.44 (1H, ddd, J¼2.9, 4.8, 13.5 Hz), 2.40–2.26 (3H, m),
1.99–1.82 (5H, m), 1.77 (1H, dt, J¼14.6, 2.7 Hz), 1.46
(1H, ddd, J¼6.1, 8.8, 14.6 Hz), 1.01 (3H, d, J¼7.1 Hz),
0.99 (9H, s), 0.97 (3H, s), 0.14 (3H, s), 0.075 (3H, s); 13C
NMR (100 MHz, C6D6), d (ppm) 139.40 (C), 139.35 (C),
138.2 (C), 138.1 (C), 137.2 (C), 134.1 (C), 133.6 (C),
131.61 (CHꢂ2), 131.56 (CHꢂ2), 129.7 (CH), 129.2
(CHꢂ4), 128.6 (CHꢂ2), 127.3 (CHꢂ2), 126.4 (CH), 126.3
(CHꢂ2), 125.9 (CH), 124.8 (CH), 121.5 (C), 121.4 (C),
100.5 (CH), 85.0 (CH), 79.9 (CH), 79.80 (CH), 79.77 (CH),
79.6 (CH), 78.3 (CH), 78.23 (CH), 78.20 (CH), 76.1 (CH),
74.8 (CH), 73.2 (CH2), 72.7 (CH2), 72.3 (CH2), 71.3
(CH2), 70.0 (CH2), 69.6 (C), 68.7 (CH2), 45.2 (CH2), 39.5
(CH2), 34.9 (CH2), 34.1 (CH2), 30.4 (CH2), 29.0 (CH2),
28.8 (CH), 26.9 (CH3), 26.1 (CH3ꢂ3), 18.3 (C), 17.2
(CH3), ꢁ4.4 (CH3), ꢁ4.7 (CH3) (The signals of seven
carbons were undetected due to overlapping with solvent
signal.); IR (film), n (cmꢁ1) 3063, 3025, 2956, 2853, 1593,
1487, 1471, 1453, 1405, 1375, 1359, 1326, 1256, 1214,
1202, 1174, 1098, 1012, 954, 836, 804, 755, 698; HR-
(CHꢂ2), 129.2 (CHꢂ2), 129.1 (CH), 128.5 (CHꢂ4),
127.4 (CH), 126.8 (CH), 126.3 (CHꢂ2), 126.2 (CH),
126.0 (CHꢂ2), 121.6 (C), 121.5 (C), 85.7 (CH), 81.8
(CH), 81.2 (CH), 79.9 (CH), 79.5 (CH), 78.8 (C), 77.7
(CH), 77.5 (CH), 77.0 (CH), 74.2 (CH), 73.4 (CH2), 73.1
(CH2), 72.4 (CH2), 71.5 (CH), 71.3 (CH2), 71.0 (CH2),
70.2 (CH2), 70.1 (CH2), 45.4 (CH2), 39.7 (CH2), 36.1
(CH2), 31.6 (CH2), 29.8 (CH2), 28.8 (CH), 27.0 (CH2),
26.8 (CH3), 26.1 (CH3ꢂ3), 18.3 (C), 15.6 (CH3), ꢁ4.45
(CH3), ꢁ4.50 (CH3) (The signals of eight carbons were un-
detected due to overlapping with solvent signal.); IR (film),
n (cmꢁ1) 3584, 3503, 3061, 3025, 2925, 2854, 1593, 1509,
1487, 1454, 1404, 1375, 1360, 1337, 1298, 1256, 1203,
1100, 1012, 964, 946, 836, 804, 774, 751, 698; HR-
FDMS, calcd for C69H Br2O10Si [M+H]+: 1261.4430,
79
87
found: 1261.4440.
7.1.40. (1S,3R,4S,6S,8R,10S,11S,10R,200R,300S,500Z,800R,
900S)-10-{10-Benzyloxy-20-[800-benzyloxy-900-benzyloxy-
methyl-300-(tert-butyldimethylsilyloxy)-200,300,400,700,800,900-
hexahydrooxonin-200-yl]ethyl}-4-(4-bromobenzyloxy)-3-
(4-bromobenzyloxymethyl)-6,10-dimethyl-11-(2-naph-
thymethyl)-2,9-dioxabicyclo[6.4.0]dodecane (50). To a
suspension of 49 (3.8 mg, 3.01 mmol) and TBAI (3.0 mg,
8.12 mmol) in THF-DMF (5:1, v/v, 1.0 ml) was added NaH
(17.4 mg, 435 mmol) at 0 ꢀC and the mixture was stirred
for 10 min. Then, benzyl bromide (20.0 mmol, 168 mmol)
was added at 0 ꢀC, the reaction mixture was warmed to
25 ꢀC and stirred for 8 h. After that, H2O (1 ml) was added
and the aqueous layer was extracted with Et2O (4ꢂ5 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/AcOEt¼50 to 7) to give 50
(4.1 mg,w100%). 50: a colorless oil; [a]2D3 ꢁ7.61 (c 0.205,
FDMS, calcd for C69H Br2O10Si [M]+: 1285.4200, found:
79
84
1258.4218.
7.1.39. (1R,20R,30S,50Z,80R,90S,100S,300R,400S,600S,800R,1000S,
1100S)-2-[80-Benzyloxy-90-benzyloxymethyl-30-(tert-butyl-
dimethylsilyloxy)-20,30,40,70,80,90-hexahydrooxonin-20-
yl]-1-{400-(4-bromobenzyloxy)-300-(4-bromobenzyloxy-
methy)-600,1000-dimethyl-1100-(2-naphthylmethyl)-200,900-
dioxabicyclo[6.4.0]dodecan-1000-yl}ethanol(49). Toasolu-
tion of 48 (3.2 mg, 2.54 mmol) in DCM (0.70 ml) was added
DIBAL (0.15 ml, 0.94 M in hexane, 141 mmol) at 0 ꢀC. The
reaction mixture was warmed to 10 ꢀC and stirred for 3 h.
Then, MeOH (0.1 ml) and saturated aqueous potassium so-
dium tartrate (1 ml) were added. The mixture was diluted
with Et2O (5 ml) and stirred at 25 ꢀC for 18 h. The layers
were separated and the aqueous layer was extracted with
Et2O (4ꢂ5 ml). The combined organic layers were washed
with brine, dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo. The resultant residue was purified by col-
umn chromatography (silica gel, hexane/AcOEt¼4) to give
49 (3.2 mg, w100%,). 49: a colorless oil; [a]2D5 +7.40 (c
1
CHCl3); H NMR (400 MHz, C6D6), d (ppm) 7.95 (1H, s),
7.67–7.51 (6H, m), 7.35–7.03 (14H, m), 6.88 (2H, d,
J¼8.3 Hz), 6.82 (2H, d, J¼8.3 Hz), 5.88 (1H, dt, J¼6.8,
10.5 Hz), 5.77 (1H, dt, J¼5.7, 10.5 Hz), 5.50 (1H, d,
J¼12.2 Hz), 5.06 (1H, d, J¼12.2 Hz), 4.68 (1H, t, J¼
5.7 Hz), 4.59 (1H, d, J¼12.6 Hz), 4.48 (1H, d, J¼
12.6 Hz), 4.37–4.31 (2H, m), 4.22–4.16 (3H, m), 4.13 (2H,
s), 4.01 (1H, d, J¼12.0 Hz), 3.94 (1H, br d, J¼8.7 Hz),
3.93–3.89 (1H, m), 3.86 (1H, d, J¼12.0 Hz), 3.82 (1H, dd,
J¼1.7, 10.0 Hz), 3.76–3.69 (3H, m), 3.59 (2H, dd, J¼2.6,
10.0 Hz), 3.40 (1H, dd, J¼7.4, 10.0 Hz), 3.26 (1H, dt,
J¼2.4, 9.0 Hz), 3.14 (1H, br dd, J¼10.5, 12.6 Hz), 2.54–
2.44 (2H, m), 2.30 (1H, ddd, J¼6.8, 8.7, 12.6 Hz), 2.01–
1.90 (4H, m), 1.82 (1H, ddd, J¼2.9, 5.7, 13.4 Hz), 1.76
(1H, ddd, J¼2.6, 11.5, 13.9 Hz), 1.66 (1H, ddd, J¼5.1,
9.0, 14.3 Hz), 1.41 (1H, t, J¼5.7 Hz), 1.25 (3H, s), 1.00
(3H, d, J¼5.9 Hz), 0.95 (9H, s), 0.061 (3H, s), 0.060 (3H,
s); 13C NMR (100 MHz, C6D6), d (ppm) 141.5 (C), 139.8
(C), 139.4 (C), 138.1 (C), 137.9 (C), 136.9 (C), 133.9 (C),
133.3 (C), 131.64 (CHꢂ2), 131.60 (CHꢂ2), 129.4
(CHꢂ2), 129.1 (CHꢂ2), 128.5 (CH), 128.4 (CHꢂ4),
127.5 (CHꢂ2), 127.4 (CH), 127.2 (CHꢂ3), 127.0 (CH),
126.8 (CH), 126.2 (CH), 125.8 (CH), 125.5 (CHꢂ2),
121.6 (C), 121.5 (C), 85.8 (CH), 81.3 (CH), 81.0 (C), 80.7
(CH), 79.9 (CH), 79.3 (CH), 78.7 (CH), 78.1 (CH), 77.0
(CH), 76.1 (CH), 75.2 (CH2), 74.0 (CH), 73.1 (CH2ꢂ2),
72.3 (CH2), 71.1 (CH2), 70.8 (CH2), 70.2 (CH2), 69.7
(CH2), 45.7 (CH2), 39.9 (CH2), 37.5 (CH2), 31.4 (CH2),
1
0.160, CHCl3); H NMR (400 MHz, C6D6), d (ppm) 7.84
(1H, s), 7.72–7.62 (3H, m), 7.56 (1H, dd, J¼1.6, 8.4 Hz),
7.41–7.39 (2H, m), 7.30–7.05 (14H, m), 6.92 (2H, d,
J¼8.5 Hz), 6.82 (2H, d, J¼8.3 Hz), 5.96 (1H, dt, J¼6.5,
10.7 Hz), 5.84 (1H, dt, J¼5.7, 10.7 Hz), 4.65–4.62 (1H,
m), 4.58 (1H, d, J¼12.2 Hz), 4.474 (1H, d, J¼12.2 Hz),
4.472 (1H, d, J¼11.7 Hz), 4.284 (1H, d, J¼11.8 Hz),
4.279 (1H, d, J¼11.7 Hz), 4.20 (1H, d, J¼11.8 Hz), 4.17
(2H, s), 4.11 (1H, dt, J¼9.0, 3.5 Hz), 4.05 (1H, d,
J¼11.8 Hz), 3.96–3.87 (4H, m), 3.86 (1H, d, J¼11.8 Hz),
3.70 (1H, ddd, J¼2.1, 7.6, 9.1 Hz), 3.68–3.63 (2H, m),
3.61 (1H, dd, J¼2.1, 9.9 Hz), 3.53 (1H, dt, J¼9.0, 3.0 Hz),
3.39 (1H, dd, J¼7.6, 9.9 Hz), 3.35 (1H, t, J¼3.3 Hz), 3.25
(1H, dt, J¼2.4, 9.1 Hz), 3.05 (1H, br s), 2.81 (1H, ddd,
J¼1.3, 10.7, 12.7 Hz), 2.68 (1H, ddd, J¼3.0, 10.7,
13.4 Hz), 2.50 (1H, dt, J¼13.9, 3.3 Hz), 2.28–2.22 (1H,
m), 2.12 (1H, ddd, J¼3.0, 5.7, 13.4 Hz), 1.91–1.69 (6H,
m), 1.64–1.53 (2H, m), 1.22 (3H, s), 1.01 (3H, d, J¼
7.1 Hz), 0.97 (9H, s), 0.074 (6H, s); 13C NMR (100 MHz,
C6D6), d (ppm) 139.6 (C), 139.3 (C), 138.1 (C), 137.9 (C),
136.7 (C), 133.9 (C), 133.4 (C), 131.6 (CHꢂ4), 129.3

A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
7431
28.8 (CH), 27.9 (CH2), 26.9 (CH3), 26.2 (CH2), 26.0
(CH3ꢂ3), 18.3 (C), 14.7 (CH3), ꢁ4.6 (CH3), ꢁ4.8 (CH3)
(The signals of seven carbons were undetected due to over-
lapping with solvent signal.); IR (film), n (cmꢁ1) 3062, 3025,
2926, 2855, 1603, 1593, 1509, 1496, 1487, 1453, 1404,
1360, 1338, 1250, 1201, 1096, 1070, 1012, 946, 835, 774,
DCM (0.80 ml) were added NaHCO3 (21.8 mg, 259 mmol)
and DMPI (22.0 mg, 51.9 mmol) at 25 ꢀC and the reaction
mixture was stirred for 30 min. After the mixture was diluted
with Et2O (1 ml), saturated aqueous Na2SO3 (1 ml) was
added and the aqueous layer was extracted with Et2O
(4ꢂ5 ml). The combined organic layers were washed with
saturated aqueous Na2SO3 and brine, dried over anhydrous
MgSO4, filtered, and concentrated in vacuo. The resultant
residue was roughly purified by column chromatography
(silica gel, hexane/AcOEt¼4) 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 (0.80 ml)
was added HF$Py at 0 ꢀC. The reaction mixture was warmed
to 25 ꢀC and stirred for 2 d. After the reaction mixture was
diluted with Et2O and cooled to 0 ꢀC, saturated aqueous
NaHCO3 (1 ml) was added and the mixture was stirred for
1 h. The layers were separated and the aqueous layer was ex-
tracted with AcOEt (4ꢂ5 ml). The combined organic layers
were washed with brine, dried over anhydrous MgSO4, fil-
tered, and concentrated in vacuo. The resultant residue was
purified by column chromatography (silica gel, hexane/
AcOEt¼5 to 2) to give 53 (6.8 mg, w100% from 51). 53:
733, 697; HR-FDMS, calcd for C76H Br2O10Si [M]+:
79
92
1350.4826, found: 1350.4854.
7.1.41. (1S,3R,4S,6S,8R,10R,11S,10R,200R,300S,500Z,800R,
900S)-10-{10-Benzyloxy-20-[800-benzyloxy-900-benzyloxy-
methyl-300-(tert-butyldimethylsilyloxy)-200,300,400,700,800,900-
hexahydrooxonin-200-yl]ethyl}-4-(4-bromobenzyloxy)-3-
(4-bromobenzyloxymethyl)-6,10-dimethyl-2,9-dioxabi-
cyclo[6.4.0]dodecan-11-ol (51). To a solution of 50
(10.4 mg, 7.68 mmol) in DCM–pH 7 buffer (10:1, v/v,
0.90 ml) was added DDQ (10.7 mg, 47.1 mmol) at 0 ꢀC
and the mixture was stirred for 20 min. Then, saturated aque-
ous NaHCO3 (1 ml) was added and the aqueous layer was
extracted with Et2O (4ꢂ5 ml). The combined organic layers
were washed with brine, dried over anhydrous MgSO4, fil-
tered, and concentrated in vacuo. The resultant residue was
purified by column chromatography (silica gel, hexane/
AcOEt¼30 to 5) to give 51 (8.5 mg, 91%). 51: a colorless
1
a colorless oil; [a]D22 +15.6 (c 0.340, CHCl3); H NMR
(400 MHz, C6D6), d (ppm) 7.45–7.43 (2H, m), 7.31–7.28
(5H, m), 7.21–7.04 (12H, m), 6.92 (2H, d, J¼8.3 Hz), 6.81
(2H, d, J¼8.5 Hz), 5.95 (1H, dt, J¼5.9, 10.6 Hz), 5.88
(1H, dt, J¼5.9, 10.6 Hz), 4.79 (1H, d, J¼10.9 Hz), 4.60
(1H, d, J¼10.9 Hz), 4.41 (1H, d, J¼12.3 Hz), 4.39 (1H, d,
J¼11.7 Hz), 4.35 (1H, d, J¼12.3 Hz), 4.18–4.13 (4H, m),
4.10 (1H, d, J¼11.7 Hz), 3.85 (1H, d, J¼12.0 Hz), 3.83–
3.80 (2H, m), 3.74 (1H, dt, J¼6.8, 4.9 Hz), 3.70–3.65 (2H,
m), 3.58–3.54 (2H, m), 3.44 (1H, dd, J¼2.7, 9.8 Hz), 3.40
(1H, dt, J¼2.7, 6.8 Hz), 3.38 (1H, ddd, J¼2.0, 6.6,
9.0 Hz), 3.28 (1H, dd, J¼6.6, 9.8 Hz), 3.16 (1H, dt, J¼2.4,
9.0 Hz), 3.09 (1H, dd, J¼7.4, 16.8 Hz), 2.86 (1H, ddd,
J¼2.7, 10.6, 13.4 Hz), 2.75 (1H, ddd, J¼2.7, 10.6,
13.7 Hz), 2.52 (1H, dd, J¼6.6, 16.8 Hz), 2.34–2.24 (4H,
m), 1.92–1.88 (1H, m), 1.78–1.62 (3H, m), 1.47 (1H, ddd,
J¼5.6, 9.0, 15.6 Hz), 1.22 (3H, s), 0.95 (3H, d, J¼6.8 Hz);
13C NMR (100 MHz, C6D6), d (ppm) 211.2 (C), 139.1 (C),
139.0 (C), 138.8 (C), 138.0 (C), 137.8 (C), 131.73 (CHꢂ2),
131.67 (CHꢂ2), 129.4 (CHꢂ2), 129.3 (CHꢂ2), 128.64
(CHꢂ2), 128.60 (CHꢂ4), 128.5 (CHꢂ4), 121.69 (C),
121.66 (C), 86.6 (C), 85.1 (CH), 83.0 (CH), 82.7 (CH),
82.6 (CH), 81.7 (CH), 79.6 (CH), 78.7 (CH), 75.6 (CH),
74.8 (CH), 74.7 (CH2), 73.3 (CH2), 72.5 (CH2), 72.0
(CH2ꢂ2), 71.4 (CH2), 70.3 (CH2), 46.2 (CH2), 44.1 (CH2),
39.6 (CH2), 36.6 (CH2), 30.8 (CH2), 28.6 (CH), 26.9 (CH3,
CH2), 17.9 (CH3) (The signals of seven carbons were un-
detected due to overlapping with solvent signal.); IR
(film), n (cmꢁ1) 3454, 3063, 3027, 2926, 2865, 1717,
1592, 1487, 1453, 1405, 1367, 1321, 1300, 1215, 1099,
1027, 1012, 911, 838, 804, 755, 698; HR-FDMS, calcd for
1
oil; [a]1D8 +11.8 (c 0.425, CHCl3); H NMR (400 MHz,
C6D6), d (ppm) 7.48 (1H, d, J¼7.1 Hz), 7.37–7.21 (9H,
m), 7.15–7.01 (10H, m), 6.84 (2H, d, J¼8.3 Hz), 5.91–
5.82 (2H, m), 5.28 (1H, d, J¼12.0 Hz), 4.88 (1H, d, J¼
12.0 Hz), 4.40 (1H, d, J¼11.8 Hz), 4.37 (1H, d, J¼
11.7 Hz), 4.30–4.16 (7H, m), 4.13 (1H, d, J¼11.8 Hz),
4.04 (1H, ddd, J¼4.5, 9.8, 10.9 Hz), 3.90 (1H, d,
J¼12.0 Hz), 3.82–3.75 (4H, m), 3.72–3.60 (4H, m), 3.47
(1H, dd, J¼7.0, 10.0 Hz), 3.32 (1H, dt, J¼2.4, 9.0 Hz),
2.90–2.84 (1H, m), 2.61 (1H, br dd, J¼8.5, 13.2 Hz), 2.55
(1H, ddd, J¼3.5, 4.5, 13.3 Hz), 2.38 (1H, ddd, J¼3.8, 4.5,
13.5 Hz), 2.18 (1H, ddd, J¼5.6, 8.7, 13.2 Hz), 2.03–1.83
(5H, m), 1.67 (1H, ddd, J¼5.7, 9.0, 14.8 Hz), 1.45 (2H,
dd, J¼4.1, 6.1 Hz), 1.21 (3H, s), 1.03 (3H, d, J¼6.8 Hz),
0.94 (9H, s), 0.035 (3H, s), 0.027 (3H, s); 13C NMR
(100 MHz, C6D6), d (ppm) 140.9 (C), 139.2 (C), 139.0
(C), 138.3 (C), 138.1 (C), 131.6 (CHꢂ4), 129.4 (CHꢂ2),
129.3 (CHꢂ2), 129.2 (CH), 128.5 (CHꢂ2), 128.4
(CHꢂ2), 127.51 (CH), 127.47 (CH), 127.3 (CH), 126.4
(CH), 121.6 (C), 121.4 (C), 85.6 (CH), 82.1 (CH), 82.0
(CH), 80.5 (CH, C), 79.8 (CH), 77.0 (CH), 76.9 (CH),
76.5 (CH), 75.7 (CH2), 74.0 (CH), 73.3 (CH2), 72.9 (CH2),
72.3 (CH2), 71.54 (CH2), 71.48 (CH), 70.3 (CH2), 69.3
(CH2), 45.7 (CH2), 40.1 (CH2), 38.3 (CH2), 35.7 (CH2),
28.8 (CH), 27.6 (CH2), 27.0 (CH3), 26.4 (CH2), 26.0
(CH3ꢂ3), 18.3 (C), 13.8 (CH3), ꢁ4.77 (CH3), ꢁ4.84
(CH3) (The signals of eight carbons were undetected due
to overlapping with solvent signal.); IR (film), n (cmꢁ1
)
3475, 3063, 3027, 2927, 2857, 1593, 1487, 1470, 1453,
1405, 1372, 1360, 1339, 1298, 1250, 1215, 1088, 1028,
1012, 940, 888, 836, 804, 755, 697; HR-FDMS, calcd for
C59H Br2O10 [M]+: 1094.3179, found: 1094.3174.
79
68
C65H Br2O10Si [M]+: 1210.4200, found: 1210.4193.
7.1.43. (1R,3S,5Z,8R,9S,11R,13R,14S,16R,18S,20S,21R,
23S)-8,13-Dibenzyloxy-9-benzyloxymethyl-20-(4-bromo-
benzyloxy)-21-(4-bromobenzyloxymethyl)-14,18-di-
methyl-2,10,15,22-tetraoxatetracyclo[12.10.0.03,11.016,23]-
tetracos-5-ene (54). To a solution of 53 (6.0 mg, 5.47 mmol)
in DCM–Et3SiH (10:1, v/v, 0.80 ml) was added TMSOTf
(3.0 ml, 16.6 mmol) at 0 ꢀC and the mixture was stirred for
30 min. Then, saturated aqueous NaHCO3 (1 ml) was added
79
84
7.1.42. (1S,3R,4S,6S,8R,10S,11S,10R,200R,300S,500Z,800R,
900S)-10-[10-Benzyloxy-20-(800-benzyloxy-900-benzyloxy-
methyl-300-hydroxy-200,300,400,700,800,900-hexahydrooxonin-
200-yl)ethyl]-4-(4-bromobenzyloxy)-3-(4-bromobenzyl-
oxymethyl)-6,10-dimethyl-2,9-dioxabicyclo[6.4.0]dode-
can-11-one (53). To a solution of 51 (7.5 mg, 6.18 mmol) in

7432
A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
and the aqueous layer was extracted with Et2O (5 ml) and
AcOEt (3ꢂ5 ml). The combined organic layers were washed
with brine, dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo. The resultant residue was purified by col-
umn chromatography (silica gel, hexane/AcOEt¼10 to 4) to
give 54 (4.6 mg, 78%). 54: a colorless oil; [a]2D3 ꢁ4.96 (c
dd, J¼2.8, 11.3 Hz), 4.47 (1H, d, J¼12.0 Hz), 4.41 (1H, d,
J¼12.0 Hz), 4.38 (1H, d, J¼12.0 Hz), 4.22–4.15 (4H, m),
4.11 (1H, d, J¼12.0 Hz), 3.93 (1H, dt, J¼4.8, 9.5 Hz),
3.86 (1H, d, J¼12.2 Hz), 3.69–3.57 (7H, m), 3.53 (1H, dd,
J¼2.4, 10.0 Hz), 3.43–3.41 (1H, m), 3.40 (1H, dd, J¼6.7,
10.0 Hz), 3.30 (1H, dt, J¼2.6, 8.8 Hz), 2.71 (1H, ddd,
J¼2.8, 10.4, 13.2 Hz), 2.52–2.45 (2H, m), 2.30–2.24 (1H,
m), 2.17 (1H, dt, J¼13.2, 5.2 Hz), 2.05–1.82 (7H, m), 1.53
(1H, ddd, J¼5.4, 8.8, 14.5 Hz), 1.07 (3H, s), 1.03 (3H, d,
J¼6.3 Hz), 0.97 (9H, s), 0.13 (3H, s), 0.063 (3H, s); 13C
NMR (75 MHz, CDCl3), d (ppm) 138.6 (C), 138.4 (C),
137.5 (C), 137.4 (C), 136.3 (C), 133.6 (C), 133.0 (C),
131.41 (CHꢂ2), 131.39 (CHꢂ2), 129.2 (CHꢂ4), 128.4
(CH), 128.2 (CHꢂ5), 128.0 (CHꢂ2), 127.8 (CH), 127.7
(CHꢂ2), 127.6 (CH), 127.5 (CH), 127.4 (CH), 127.1
(CH), 125.9 (CH), 125.8 (CHꢂ2), 124.6 (CH), 121.4 (C),
121.3 (C), 95.7 (CH), 84.9 (CH), 83.2 (CH), 82.8 (CH),
80.3 (CH), 79.0 (CH), 78.2 (CH), 77.2 (C), 75.5 (CH),
75.2 (CH), 74.3 (CH), 73.4 (CH), 73.2 (CH2), 72.5 (CH2),
72.0 (CH2), 71.9 (CH2), 71.2 (CH2), 70.4 (CH2), 45.20
(CH2), 45.18 (CH2), 40.0 (CH2), 33.3 (CH2), 32.2 (CH2),
28.3 (CH), 27.0 (CH2), 26.9 (CH3), 25.9 (CH3ꢂ3), 17.9
(C), 16.4 (CH3), ꢁ4.3 (CH3), ꢁ4.4 (CH3); IR (film),
n (cmꢁ1) 3062, 3026, 2854, 1593, 1487, 1453, 1370, 1317,
1255, 1213, 1172, 1100, 941, 835, 776, 737, 697; HR-
1
0.025, CHCl3); H NMR (600 MHz, C6D6), d (ppm) 7.45
(2H, d, J¼7.3 Hz), 7.21–7.02 (17H, m), 6.94 (2H, d,
J¼8.1 Hz), 6.83 (2H, d, J¼8.1 Hz), 5.93 (1H, dt, J¼6.4,
10.0 Hz), 5.82 (1H, dt, J¼5.4, 10.0 Hz), 4.85 (1H, d, J¼
12.1 Hz), 4.71 (1H, d, J¼12.1 Hz), 4.39 (1H, d, J¼
12.3 Hz), 4.37 (2H, s), 4.25 (1H, d, J¼12.9 Hz), 4.22 (1H,
d, J¼12.9 Hz), 4.21 (1H, d, J¼11.7 Hz), 4.11 (1H, d,
J¼12.3 Hz), 3.87 (1H, d, J¼11.7 Hz), 3.70 (1H, t,
J¼6.0 Hz), 3.66–3.53 (6H, m), 3.52–3.50 (1H, m), 3.49–
3.47 (1H, m), 3.39 (1H, dd, J¼7.1, 9.9 Hz), 3.26–3.20
(2H, m), 3.07 (1H, dd, J¼4.6, 12.1 Hz), 2.94 (1H, ddd,
J¼5.0, 10.0, 13.9 Hz), 2.69–2.63 (2H, m), 2.40 (1H, dt,
J¼12.5, 4.6 Hz), 2.31–2.26 (3H, m), 2.00–1.84 (4H, m),
1.68–1.57 (2H, m), 1.44 (3H, s), 1.00 (3H, d, J¼7.3 Hz);
13C NMR (100 MHz, CDCl3), d (ppm) 139.5 (C), 138.3
(C), 138.2 (C), 137.4 (C), 137.2 (C), 131.5 (CHꢂ2), 131.4
(CHꢂ2), 129.4 (CHꢂ4), 128.3 (CHꢂ5), 128.1 (CHꢂ2),
128.0 (CHꢂ2), 127.8 (CHꢂ3), 127.62 (CH), 127.59 (CH),
127.5 (CHꢂ2), 127.1 (CH), 121.5 (C), 121.4 (C), 85.9
(CH), 84.7 (CH), 84.4 (CH), 83.7 (CH), 82.6 (CHꢂ2),
80.4 (C), 79.7 (CH), 79.0 (CH), 78.0 (CH), 73.3 (CH2),
73.1 (CH2), 72.7 (CH2), 72.1 (CH), 71.9 (CH2), 71.4
(CH2), 70.54 (CH2), 70.49 (CH2), 45.0 (CH2), 40.6
(CH2), 38.6 (CH2), 35.4 (CH2), 32.5 (CH2), 27.9 (CH),
FDMS, calcd for C69H Br2O10Si [M]+: 1258.4200, found:
79
84
1258.4202. 55b: a colorless oil; [a]2D1 +12.2 (c 0.105,
CHCl3); H NMR (400 MHz, C6D6), d (ppm) 8.05 (1H, s),
1
7.81 (1H, d, J¼8.1 Hz), 7.75 (1H, d, J¼8.5 Hz), 7.68–7.65
(2H, m), 7.51 (2H, d, J¼7.1 Hz), 7.35–6.95 (16H, m), 6.82
(2H, d, J¼8.3 Hz), 6.20 (1H, s), 6.07 (1H, dt, J¼5.0,
10.7 Hz), 6.00 (1H, dt, J¼5.0, 10.7 Hz), 4.74 (1H, d,
J¼11.7 Hz), 4.62 (1H, t, J¼7.0 Hz), 4.54 (1H, dt, J¼8.1,
3.3 Hz), 4.52 (1H, d, J¼11.7 Hz), 4.45 (1H, d, J¼
11.8 Hz), 4.20 (1H, d, J¼12.3 Hz), 4.190 (1H, d, J¼
11.8 Hz), 4.185 (1H, d, J¼12.1 Hz), 4.14 (1H, d,
J¼12.3 Hz), 4.00 (1H, dt, J¼8.4, 3.3 Hz), 3.93 (1H, t, J¼
4.8 Hz), 3.88 (1H, d, J¼12.1 Hz), 3.86 (2H, d, J¼2.4 Hz),
3.80 (1H, dt, J¼4.8, 9.1 Hz), 3.66–3.57 (3H, m), 3.53 (1H,
dd, J¼2.2, 10.0 Hz), 3.43–3.41 (1H, m), 3.39 (1H, dd,
J¼6.7, 10.0 Hz), 3.28 (1H, dt, J¼2.4, 9.0 Hz), 3.09 (1H,
ddd, J¼3.3, 10.7, 13.1 Hz), 2.81 (1H, ddd, J¼3.3, 10.7,
14.0 Hz), 2.48 (1H, dt, J¼13.8, 4.8 Hz), 2.32–2.26 (1H,
m), 2.21–2.14 (3H, m), 1.99–1.79 (5H, m), 1.61–1.55 (1H,
m), 1.19 (3H, s), 1.06 (3H, d, J¼7.6 Hz), 1.04 (9H, s),
0.24 (3H, s), 0.083 (3H, s); 13C NMR (100 MHz, CDCl3),
d (ppm) 138.61 (C), 138.56 (C), 137.4 (C), 137.3 (C),
136.5 (C), 133.4 (C), 132.9 (C), 131.44 (CHꢂ2), 131.41
(CHꢂ2), 129.3 (CHꢂ2), 129.2 (CHꢂ2), 128.3 (CHꢂ3),
128.2 (CHꢂ3), 127.9 (CHꢂ3), 127.8 (CHꢂ2), 127.7
(CH), 127.51 (CH), 127.47 (CH), 127.4 (CH), 126.09
(CH), 126.07 (CH), 125.0 (CH), 124.3 (CH), 121.5 (C),
121.3 (C), 97.9 (CH), 84.9 (CH), 84.5 (CH), 84.3 (CH),
81.0 (CH), 79.1 (CH), 78.3 (CH), 77.2 (CH), 75.4 (C),
74.8 (CH), 73.1 (CH2), 72.55 (CH2), 72.52 (CH), 71.8
(CH2), 71.4 (CH2), 71.3 (CH), 70.5 (CH2), 70.3 (CH2),
45.1 (CH2), 40.1 (CH2), 32.6 (CH2), 32.1 (CH2), 31.6
(CH2), 29.7 (CH2), 28.4 (CH), 26.9 (CH3), 26.0 (CH3ꢂ3),
18.0 (C), 16.1 (CH3), ꢁ4.2 (CH3), ꢁ4.4 (CH3); IR (film),
n (cmꢁ1) 3062, 3025, 2924, 2853, 1593, 1507, 1487, 1454,
27.6 (CH2), 27.0 (CH3), 11.5 (CH3); IR (neat), n (cmꢁ1
)
2954, 2923, 2853, 1594, 1487, 1462, 1376, 1287, 1260,
1204, 1096, 1070, 1027, 1012, 840, 803, 729, 697; HR-
79
68
FDMS, calcd for C59H Br2O9 [M]+: 1078.3230, found:
1078.3217.
7.1.44. (1R,3R,4S,6S,8S,10S,12R,13S,15S,20R,30S,50Z,80R,
90S)-4-[80-Benzyloxy-90-benzyloxymethyl-30-(tert-butyl-
dimethylsilyloxy)-20,30,40,70,80,90-hexahydrooxonin-20-
yl]-13-(4-bromobenzyloxy)-12-(4-bromobenzyloxy-
methyl)-3,15-dimethyl-6-(2-naphthyl)-2,5,7,11-tetraoxa-
tricyclo[8.6.0.03,8]hexadecane (55a) and (1R,3R,4S,6R,
8S,10S,12R,13S,15S,20R,30S,50Z,80R,90S)-4-[80-benzyloxy-
90-benzyloxymethyl-30-(tert-butyldimethylsilyloxy)-
20,30,40,70,80,90-hexahydrooxonin-20-yl]-13-(4-bromobenz-
yloxy)-12-(4-bromobenzyloxymethyl)-3,15-dimethyl-6-
(2-naphthyl)-2,5,7,11-tetraoxatricyclo[8.6.0.03,8]hexa-
decane (55b). To a solution of 31 (17.3 mg, 15.4 mmol) in
benzene (1.0 ml) were added 2-naphthaldehyde dimethyl
acetal (33.3 mg, 165 mmol) and PPTS (6.0 mg, 23.9 mmol).
The reaction mixture was heated to 80 ꢀC and stirred for
2 h. Then, saturated aqueous NaHCO3 (1 ml) was added
and the aqueous layer was extracted with Et2O (4ꢂ5 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/AcOEt¼30 to 4) to give 55a
(17.3 mg, 89%,) and 55b (2.1 mg, 11%). 55a: a colorless
1
oil; [a]2D4 ꢁ27.9 (c 0.750, CHCl3); H NMR (400 MHz,
C6D6), d (ppm) 8.29 (1H, s), 7.91 (1H, dd, J¼1.5, 8.5 Hz),
7.75–7.72 (2H, m), 7.62–7.58 (1H, m), 7.34–6.95 (18H,
m), 6.81 (2H, d, J¼8.5 Hz), 6.05 (1H, s), 5.88 (1H, dt,
J¼5.2, 10.4 Hz), 5.83 (1H, dt, J¼5.2, 10.4 Hz), 4.55 (1H,
1371, 1299, 1257, 1214, 1172, 1096, 1012, 940, 836, 803,
776, 752, 697; HR-FDMS, calcd for C69H Br2O10Si
79
84
[M]+: 1258.4200, found: 1258.4213.

A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
7433
7.1.45. (1S,20R,30S,50Z,80R,90S,100S,300R,400S,600S,800R,1000S,
1100S)-2-[80-Benzyloxy-90-benzyloxymethyl-30-(tert-butyl-
dimethylsilyloxy)-20,30,40,70,80,90-hexahydrooxonin-20-
yl]-1-{400-(4-bromobenzyloxy)-300-(4-bromobenzyloxy-
methy)-600,1000-dimethyl-1100-(2-naphthylmethyl)-200,900-
dioxabicyclo[6.4.0]dodecan-1000-yl}ethanol(56). Toasolu-
tion of 55a (26.4 mg, 20.9 mmol) in DCM (0.70 ml) was
added DIBAL (0.15 ml, 0.94 M in hexane, 141 mmol) at
0 ꢀC for 5.5 h. Then, MeOH (0.1 ml) and saturated aqueous
potassium sodium tartrate (1 ml) were added. The mixture
was diluted with Et2O (5 ml) and stirred at 25 ꢀC for 10 h.
The layers were separated and the aqueous layer was ex-
tracted with Et2O (4ꢂ5 ml). The combined organic layers
were washed with brine, dried over anhydrous MgSO4, fil-
tered, and concentrated in vacuo. Since the resultant residue
included 56 and unreacted 55a, the residue was dissolved in
DCM (0.80 ml) and treated again with DIBAL (0.25 ml,
0.94 M in hexane, 235 mmol) at 0 ꢀC for 4.5 h. Then, the
reaction was quenched with MeOH (0.1 ml) and saturated
aqueous potassium sodium tartrate (1 ml). After the same
work-up as described above, the resultant crude mixture
was roughly purified by column chromatography (silica
gel, hexane/AcOEt¼15 to 7) to give 56 (13.6 mg) and a mix-
ture of 55a and 56 (11.5 mg). The mixture of 55a and 56 was
dissolved in DCM (0.7 ml) and treated with DIBAL
(0.20 ml, 0.94 M in hexane, 188 mmol) at 0 ꢀC for 2 h.
Then the reaction mixture was warmed to 10 ꢀC and stirred
for 2 h. Then, the reaction was quenched with MeOH
(0.1 ml) and saturated aqueous potassium sodium tartrate
(1 ml). After the same work-up as described above, the resul-
tant crude mixture was purified by column chromatography
(silica gel, hexane/AcOEt¼15 to 7) to give 56 (11.0 mg).
Thus, total 24.6 mg (93%) of 56 was obtained. 56: a colorless
oil; [a]2D3 +17.0 (c 1.15, CHCl3); 1H NMR (400 MHz, C6D6),
d (ppm) 7.77 (1H, s), 7.66–7.58 (3H, m), 7.47 (1H, dd,
J¼1.6, 8.4 Hz), 7.30–7.00 (16H, m), 6.88 (2H, d,
J¼8.3 Hz), 6.82 (2H, d, J¼8.3 Hz), 5.92 (1H, dt, J¼6.2,
10.4 Hz), 5.84 (1H, dt, J¼5.7, 10.4 Hz), 4.72–4.69 (2H,
m), 4.66 (1H, d, J¼12.4 Hz), 4.49 (1H, d, J¼12.3 Hz),
4.36 (1H, d, J¼12.0 Hz), 4.20 (1H, d, J¼11.8 Hz), 4.17
(1H, d, J¼12.4 Hz), 4.13 (1H, d, J¼12.4 Hz), 4.12 (1H, d,
J¼12.0 Hz), 4.09 (1H, d, J¼12.3 Hz), 4.01–3.91 (4H, m),
3.87 (1H, d, J¼11.8 Hz), 3.82 (1H, d, J¼2.4 Hz), 3.80–
3.76 (3H, m), 3.71 (1H, ddd, J¼2.1, 7.1, 8.8 Hz), 3.70–
3.66 (1H, m), 3.64 (1H, dd, J¼2.6, 10.4 Hz), 3.55 (1H, dd,
J¼2.1, 9.9 Hz), 3.38 (1H, dd, J¼7.1, 9.9 Hz), 3.29 (1H, dt,
J¼2.6, 8.8 Hz), 2.88–2.79 (2H, m), 2.46 (1H, dt, J¼13.7,
3.9 Hz), 2.29–2.16 (3H, m), 2.04–1.74 (6H, m), 1.63 (1H,
ddd, J¼5.5, 8.8, 14.0 Hz), 1.28 (3H, s), 1.09 (3H, d,
J¼6.3 Hz), 0.94 (9H, s), 0.060 (3H, s), 0.036 (3H, s); 13C
NMR (75 MHz, CDCl3), d (ppm) 138.5 (C), 138.2 (C),
137.4 (C), 137.3 (C), 136.8 (C), 133.2 (C), 132.8 (C),
131.4 (CHꢂ2), 131.3 (CHꢂ2), 129.3 (CHꢂ3), 129.1
(CHꢂ2), 128.21 (CHꢂ2), 128.17 (CHꢂ2), 127.9 (CH),
127.8 (CH), 127.7 (CHꢂ2), 127.6 (CH), 127.5 (CHꢂ2),
127.4 (CH), 127.3 (CH), 126.1 (CH), 126.0 (CH), 125.8
(CHꢂ2), 125.7 (CH), 121.5 (C), 121.2 (C), 85.5 (CHꢂ2),
81.3 (CH), 79.0 (CH), 78.4 (CH), 77.6 (C), 77.2 (CH),
76.98 (CH), 75.9 (CH), 73.4 (CH), 72.9 (CH2), 72.4
(CH2ꢂ2), 72.3 (CH), 71.9 (CH2), 71.4 (CH2), 70.5
(CH2), 67.6 (CH2), 45.2 (CH2), 40.3 (CH2), 35.0 (CH2),
32.1 (CH2), 28.8 (CH2), 28.3 (CH), 26.9 (CH3), 26.4
(CH2), 25.9 (CH3ꢂ3), 18.0 (C), 14.6 (CH3), ꢁ4.67 (CH3),
ꢁ4.72 (CH3); IR (film), n (cmꢁ1) 3584, 3497, 3061, 3026,
2926, 2857, 1593, 1509, 1487, 1453, 1405, 1360, 1337,
1256, 1205, 1099, 1012, 940, 836, 774, 735, 698; HR-
FDMS, calcd for C69H Br2O10Si [M]+: 1260.4357, found:
79
86
1260.4365.
7.1.46. (2R,3S,5Z,8R,9S,10S,30R,40S,60S,80R,100R,110S)-[8-
Benzyloxy-9-benzyloxymethyl-3-(tert-butyldimethylsilyl-
oxy)-2,3,4,7,8,9-hexahydrooxonin-2-yl]methyl 40-(4-
bromobenzyloxy)-30-(4-bromobenzyloxymethyl)-60,100-
dimethyl-110-(2-naphthylmethyl)-20,90-dioxabi-
cyclo[6.4.0]dodecan-100-yl ketone (57). To a solution of 56
(24.6 mg, 19.5 mmol) in DCM (1.0 ml) were added NaHCO3
(24.6 mg, 293 mmol) and DMPI (28.3 mg, 117 mmol) at
0 ꢀC. The reaction mixture was warmed to 25 ꢀC and stirred
for 8 h. After the mixture was diluted with Et2O (5 ml), sat-
urated aqueous Na2SO3 (1 ml) was added and the aqueous
layer was extracted with Et2O (4ꢂ5 ml). The combined or-
ganic layers were washed with saturated aqueous Na2SO3
and brine, dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo. The resultant residue was purified by col-
umn chromatography (silica gel, benzene/AcOEt¼7 to 5) to
give 57 (22.1 mg, 90%). 57: a colorless oil; [a]1D9 +40.3 (c
1
1.11, CHCl3); H NMR (400 MHz, C6D6), d (ppm) 7.75
(1H, d, J¼8.1 Hz), 7.67 (1H, d, J¼8.3 Hz), 7.64 (1H, s),
7.59 (1H, d, J¼8.1 Hz), 7.43 (1H, dd, J¼1.5, 8.3 Hz),
7.33–7.06 (16H, m), 6.90 (2H, d, J¼8.3 Hz), 6.83 (2H, d,
J¼8.3 Hz), 5.99–5.91 (2H, m), 4.51 (1H, d, J¼12.3 Hz),
4.49–4.45 (3H, m), 4.44 (1H, d, J¼12.3 Hz), 4.36 (1H, dt,
J¼3.9, 6.3 Hz), 4.23 (1H, d, J¼12.0 Hz), 4.21 (1H,
d, J¼11.3 Hz), 4.18 (1H, dt, J¼8.7, 3.0 Hz), 4.17 (1H, d,
J¼12.4 Hz), 4.12 (1H, d, J¼12.4 Hz), 4.04 (1H, ddd,
J¼2.8, 4.9, 6.3 Hz), 3.89 (1H, dt, J¼8.7, 3.4 Hz), 3.86
(1H, d, J¼11.3 Hz), 3.84 (1H, dt, J¼4.4, 11.5 Hz), 3.73
(1H, t, J¼2.4 Hz), 3.72 (1H, d, J¼3.0 Hz), 3.71 (1H, ddd,
J¼2.0, 7.1, 9.3 Hz), 3.54 (1H, dd, J¼2.0, 9.8 Hz), 3.53–
3.50 (1H, m), 3.40–3.32 (3H, m), 3.24 (1H, dt, J¼2.3,
9.3 Hz), 2.98 (1H, ddd, J¼2.8, 9.4, 13.4 Hz), 2.85 (1H,
ddd, J¼3.4, 9.4, 13.4 Hz), 2.36–2.30 (2H, m), 2.14 (1H,
dt, J¼13.4, 4.9 Hz), 2.03–1.84 (4H, m), 1.63 (1H, ddd,
J¼5.2, 9.3, 14.3 Hz), 1.56 (1H, ddd, J¼2.4, 11.5,
13.9 Hz), 1.15 (3H, s), 1.06 (3H, d, J¼6.3 Hz), 0.89 (9H,
s), 0.12 (3H, s), 0.019 (3H, s); 13C NMR (75 MHz,
CDCl3), d (ppm) 212.6 (C), 138.8 (C), 138.6 (C), 137.4
(C), 137.2 (C), 135.8 (C), 133.1 (C), 132.9 (C), 131.5
(CHꢂ2), 131.4 (CHꢂ2), 129.3 (CHꢂ2), 129.2 (CHꢂ2),
128.22 (CHꢂ2), 128.19 (CHꢂ2), 128.1 (CH), 128.0 (CH),
127.9 (CH), 127.8 (CHꢂ2), 127.7 (CHꢂ4), 127.3 (CHꢂ2),
126.5 (CH), 126.01 (CH), 125.96 (CH), 125.8 (CH), 121.5
(C), 121.4 (C), 85.7 (CH), 83.0 (C), 82.5 (CH), 80.5 (CH),
80.4 (CH), 79.01 (CH), 78.97 (CH), 78.0 (CH), 73.79
(CH), 73.75 (CH), 73.1 (CH2), 72.5 (CH2), 71.9 (CH2ꢂ2),
71.3 (CH2), 70.5 (CH2), 70.2 (CH2), 45.3 (CH2), 44.3
(CH2), 40.6 (CH2), 31.7 (CH2), 31.1 (CH2), 28.1 (CH),
27.3 (CH2), 27.0 (CH3), 25.8 (CH3ꢂ3), 18.3 (CH3), 17.9
(C), ꢁ4.5 (CH3), ꢁ4.7 (CH3); IR (film), n (cmꢁ1) 3061,
3026, 2926, 2857, 1718, 1593, 1509, 1487, 1453, 1361,
1338, 1257, 1214, 1172, 1101, 1012, 948, 836, 775, 735,
697; HR-FDMS, calcd for C69H Br2O10Si [M]+:
79
84
1258.4200, found: 1258.4180.
7.1.47. Reduction of 57. To a solution of 57 (13.8 mg,
10.9 mmol) in THF–H2O (3:1, v/v, 1.2 ml) were added

7434
A. Takizawa et al. / Tetrahedron 62 (2006) 7408–7435
(b) Bidard, J.-N.; Vijverberg, H. P. M.; Frelin, C.; Chungue, E.;
Legrand, A.-M.; Bagnis, R.; Lazdanski, M. J. Biol. Chem.
1984, 259, 8353; (c) Lombet, A.; Bidard, J.-N.; Lazdanski,
M. FEBS Lett. 1987, 219, 355; (d) Dechraoui, M.-Y.; Naar,
J.; Pauillac, S.; Legrand, A.-M. Toxicon 1999, 37, 125. See
also references cited in Ref. 2.
CeCl3$7H2O (12.8 mg, 34.4 mmol) and NaBH4 (22.3 mg,
589 mmol) at 25 ꢀC. During 8 d, NaBH4 was added several
times to the reaction mixture with stirring until the reaction
was complete. After that, saturated aqueous NaHCO3 (1 ml)
was added and the aqueous layer was extracted with Et2O
(4ꢂ5 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/AcOEt¼4) to give a mix-
ture of 49 and 56 (13.3 mg, 96%, 49:56>5:1 from 1H NMR).
9. For the total synthesis of 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)
Maruyama, M.; Inoue, M.; Oishi, T.; Oguri, H.; Ogasawara,
Y.; Shindo, Y.; Hirama, M. Tetrahedron 2002, 58, 1835; (d)
Uehara, H.; Oishi, T.; Inoue, M.; Shoji, M.; Nagumo, Y.;
Kosaka, M.; Brazidec, J.-Y. L.; Hirama, M. Tetrahedron 2002,
58, 6493; (e) Inoue, M.; Yamashita, S.; Tatami, A.; Miyazaki,
K.; Hirama, M. J. Org. Chem. 2004, 69, 2797; (f) Kobayashi,
S.; Takahashi, Y.; Komano, K.; Alizadeh, B. H.; Kawada, Y.;
Oishi, T.; Tanaka, S.; Ogasawara, Y.; Sasaki, S.; Hirama, M.
Tetrahedron 2004, 60, 8375; (g) Inoue, M.; Hirama, M.
Synlett 2004, 577; (h) Inoue, M.; Hirama, M. Acc. Chem. Res.
2004, 37, 961; (i) Inoue, M.; Miyazaki, K.; Uehara, H.;
Maruyama, M.; Hirama, M. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 12013; (j) Hirama, M. Chem. Rec. 2005, 5, 240.
10. For recent synthetic studies on ciguatoxins from other groups,
see: (a) Takai, S.; Ploypradith, P.; Hamajima, A.; Kira, K.;
Isobe, M. Synlett 2002, 588; (b) Takai, S.; Isobe, M. Org.
Lett. 2002, 4, 1183; (c) Kira, K.; Hamajima, A.; Isobe, M.
Tetrahedron 2002, 58, 1875; (d) Sasaki, M.; Ishikawa, M.;
Fuwa, H.; Tachibana, K. Tetrahedron 2002, 58, 1889; (e)
Takakura, H.; Sasaki, M.; Honda, S.; Tachibana, K. Org.
Lett. 2002, 4, 2771; (f) Sasaki, M.; Noguchi, T.; Tachibana,
K. J. Org. Chem. 2002, 67, 3301; (g) Candenas, M. L.; Pinto,
Acknowledgements
We are grateful to Mr. Kenji Watanabe and Dr. Eri Fukushi
(GC–MS and NMR Laboratory, Graduate School of Agri-
culture, Hokkaido University) for the measurements of
mass spectra. We also thank Mr. Yasuhiro Kumaki (High
Resolution NMR Laboratory, Graduate School of Science,
Hokkaido University) for the measurements of NMR spec-
tra. 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.
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