Synthesis of the ABCDEF-ring of ciguatoxin 3C

Article abstract of DOI:10.1016/j.tet.2016.12.041

The synthesis of the ABCDEF-ring of ciguatoxin 3C was achieved via a route that included anion coupling of a dimethyldithioacetal mono-S-oxide derivative corresponding to the AB-ring and an aldehyde corresponding to the EF-ring, followed by cyclization us

Full text of DOI:10.1016/j.tet.2016.12.041

Accepted Manuscript
Synthesis of the ABCDEF-ring of ciguatoxin 3C
Takuto Sato, Kenshu Fujiwara, Keisuke Nogoshi, Akiyoshi Goto, Daisuke Domon,
Natsumi Kawamura, Yoshitaka Nomura, Daisuke Sato, Hideki Tanaka, Akio Murai,
Yoshihiko Kondo, Uichi Akiba, Ryo Katoono, Hidetoshi Kawai, Takanori Suzuki
PII:
S0040-4020(16)31327-8
10.1016/j.tet.2016.12.041
TET 28333
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 November 2016
Revised Date: 15 December 2016
Accepted Date: 19 December 2016
Please cite this article as: Sato T, Fujiwara K, Nogoshi K, Goto A, Domon D, Kawamura N, Nomura
Y, Sato D, Tanaka H, Murai A, Kondo Y, Akiba U, Katoono R, Kawai H, Suzuki T, Synthesis of the
ABCDEF-ring of ciguatoxin 3C, Tetrahedron (2017), doi: 10.1016/j.tet.2016.12.041.
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Synthesis of the ABCDEF-ring of ciguatoxin 3C
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Takuto Sato,a Kenshu Fujiwara,*b Keisuke Nogoshi,a
Akiyoshi Goto,a Daisuke Domon,a Natsumi Kawamura,a
Yoshitaka Nomura,a Daisuke Sato,a Hideki Tanaka,a Akio
Murai,a Yoshihiko Kondo,b Uichi Akiba,b Ryo Katoono,a
Hidetoshi Kawai,a and Takanori Suzukia
a Department of Chemistry, Faculty of Science, Hokkaido
University, Sapporo 060-0810, Japan
b Department of Life Science, Graduate School of
Engineering Science, Akita University, Akita 010-8502,
Japan

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of the ABCDEF-ring of ciguatoxin 3C
Takuto Sato,a Kenshu Fujiwara,*b Keisuke Nogoshi,a Akiyoshi Goto,a Daisuke Domon,a Natsumi
Kawamura,a Yoshitaka Nomura,a Daisuke Sato,a Hideki Tanaka,a Akio Murai,a Yoshihiko Kondo,b Uichi
Akiba,b Ryo Katoono,a Hidetoshi Kawai,a and Takanori Suzukia
a Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
b Department of Life Science, Graduate School of Engineering Science, Akita University, Akita 010-8502, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The synthesis of the ABCDEF-ring of ciguatoxin 3C was achieved via a route that included
anion coupling of a dimethyldithioacetal mono-S-oxide derivative corresponding to the AB-ring
and an aldehyde corresponding to the EF-ring, followed by cyclization using reductive
etherification. The AB-ring was synthesized from a known D-glucose derivative based on ring-
closing olefin metathesis, and the EF-ring was prepared by a process employing chirality-
transferring Ireland-Claisen rearrangement and ring-closing olefin metathesis.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved
.
Natural product synthesis
Fused polycyclic ethers
Ireland-Claisen rearrangement
Ring closing olefin metathesis
Stereoselective Synthesis
1. Introduction
The potent toxicity of 1 (MLD = 1.3 µg/kg, ip, in mice) and
other ciguatoxin congeners is attributed to strong activation of
voltage-gated sodium channels of nerve cells by their firm
binding to the channels (1: Ki = 0.81 × 10–4 µM).6 This strong
effect on sodium channels has potential for the application of
ciguatoxins as biological tools. However, the supply of
ciguatoxins from natural sources is insufficient to meet the
demand for biological studies. Therefore, a synthetic supply of
ciguatoxins is a practical solution.
Ciguatoxin 3C (CTX3C, 1) is a causative toxin of ciguatera
fish poisoning,1,2 which often breaks out in tropical coral reef
regions and affects more than 20,000 patients annually. The
symptoms of ciguatera, represented by nausea, emesis, fatigue,
arthralgia, and reversal of temperature sensation, are developed
when people eat fish poisoned by ciguatera toxins. The toxins are
originally produced by dinoflagellates,3 and are transferred up the
food chain to herbivorous fish and then to carnivorous fish. In
1993, Yasumoto and co-workers isolated 1 from cultured
dinoflagellates, Gambierdiscus toxicus, providing strong
evidence that ciguatoxins are produced by the dinoflagellate.
They also determined the relative structure of 1 by NMR analysis
using only 0.7 mg of the sample, obtained from 1100 L of the
culture.4 The framework of 1 consists of twelve trans-fused ether
rings with ring sizes ranging from six to nine members, a
terminal five-membered spirocyclic acetal, and thirty asymmetric
centers. The absolute structure of 1 was determined by the total
synthesis achieved by the Hirama group in 2001.5a
In the total synthesis of ciguatoxins, the large molecular size
and complexity of the structure are challenges that have been
tackled by many research groups,7,8 including our own,9 since the
first publication of the structure of ciguatoxin 1B by Yasumoto.
After many years of effort, the Hirama and Isobe groups
independently achieved the total synthesis of ciguatoxins with
their respective methodologies.5,8 However, to date, only these
two groups have completed the total synthesis of any ciguatoxins.
Thus, further studies toward the development of a new synthetic
methodology for ciguatoxins have been continued by our and
other research groups.
In the course of our program toward the total synthesis of 1,
we established a convergent method for constructing X/6/7/X
polycyclic trans-fused ethers via a coupling reaction between an
acyl anion equivalent and an aldehyde.10,11 So far, we have
synthesized the ABCDE-ring9a and the IJKL-ring9b of 1 by this
method in preliminary studies. Since another convergent method
for connecting the F- and the I-ring to afford the FGHI-ring has
been developed,9c the next challenge is the construction of the
Figure 1. Structure of ciguatoxin 3C (1).
──
* Corresponding author. e-mail: fjwkn@gipc.akita-u.ac.jp

2
Tetrahedron
ABCDEF-ring as the counterpart of the IJKL-ring. Although the
stereochemistry, intermediate 9 would be prepared from known
ACCEPTED MANUSCRIPT
attachment of the F-ring to the ABCDE-ring failed,12 the
convergent synthesis of the ABCDEF-ring from the AB-ring and
the EF-ring was achieved. Here, the details of this achievement
are described. The preparation of the AB-ring from a known D-
glucose derivative and the construction of the EF-ring by a
process including Ireland-Claisen rearrangement and ring-closing
olefin metathesis are also described.
D-glucose derivative 10.15
2. Synthetic plan for ABCDEF-ring 3
Our final goal is the achievement of the total synthesis of 1
from IJKL-ring 2 and ABCDEF-ring 3 through a process
previously developed by our group (Scheme 1). Since the
synthetic methodology for 2 was established previously,9b the
completion of the synthesis of 3 is the subject of this paper.
Although the attachment of a ring to the previously synthesized
ABCDE-ring segment would have been the ideal access to 3, the
difficulty in manipulating protective groups of the ABCDE-ring
prevented the formation of 3.12 Therefore, we planned to
synthesize 3 from AB-ring 5 and EF-ring 6 in a convergent
manner using our previously developed method.9a The
construction of the C- and D-rings of 3 would employ a stepwise
process, including intramolecular reductive etherification
reactions,13 via α,ε-dihydroxy ketone 4, which would be
constructed by a coupling reaction of an acyl anion equivalent,
generated from dimethyldithioacetal mono-S-oxide 5, with
aldehyde 6 followed by hydrolysis.10 The convergent route would
provide rapid access to 3 from 5 and 6.
Scheme 2. Retrosynthesis of AB-ring 5.
Based on the above retrosynthesis, synthesis of 5 began with
10 (Scheme 3). Diol 10 was first transformed to 1,1,3,3-
tetraisopropyldisiloxane-1,3-diyl (TIPDS) derivative 11 (95%),
which was subjected to the removal of the allyl group with
NiCl2(dppp) and Et3Al to give hemiacetal 12.16 After Swern
oxidation of 12,17 the resulting lactone was converted to 9 with
allylmagnesium bromide (88% from 11). Treatment of 9 with
EtSH and BF3·OEt2 induced the formation of a thioacetal and the
removal of the benzylidene acetal to produce S,O-acetal 13
(88%). Oxidation of the ethylthio group of 13 followed by
reductive etherification with Et3SiH and BF3·OEt2 gave oxane 14
(89%), which was subjected to protection as
a
2-
naphthylmethylidene acetal. Removal of the TIPDS group
afforded 1,2-diol 15 (86% from 14). Selective protection of the
hydroxy group at C7 of 15 with tert-butyldimethylsilyl
trifluoromethanesulfonate (TBSOTf) and 2,6-lutidine at –78 ºC
produced 16 (93%). Alcohol 16 was reacted with allyl bromide
under Williamson conditions to afford diene 8 (100%).
Me
Me
OPMP
OPBB
H
H
O
J
H
O
L
I
K
CTX3C ( )
HO
HO
1
O
O
H
H
H
Me
Me
2
+
In the RCM reaction of 8, 10 mol% of the first generation
Grubbs catalyst18 was first used in CH2Cl2 under high dilution
conditions (5 mM) to give cyclized compound 18 in 80% yield.9a
However, the conditions were inappropriate for large-scale
synthesis. Therefore, after optimizing the amounts of catalyst and
solvent, we found that using 1 mol% of the second generation
Grubbs catalyst (17)19 in CH2Cl2 at a higher concentration (20
mM) gave 18 in 82% yield.
NAP: 2ꢀNaphthylmethyl
PBB: 4ꢀBromobenzyl
PMP: 4ꢀMethoxyphenyl
Reductive Etherification
28
OH
H
H
O
H
H 10
C
H
H
O
O
B
E
OH
15O
H
O
F
A
O
D
SMe
SMe
H
H
H
O
B
O
1
10
H
H
A
O
3
OPBB
ONAP
OPBB
1
Reductive Etherification
5
The TBS group of 18 was removed with tetrabutylammonium
fluoride (TBAF) to afford alcohol 19 (85%). After the protection
+
,
Dihydroxy
Ketone Formation
TESO
of 19 as
a
4-bromobenzyl (PBB) ether, the 2-
H
HO
H
O
O
E
28
naphthylmethylidene acetal was reductively cleaved to produce
alcohol 7 (87% from 19).20 Alcohol 7 was then reacted with
trifluoromethanesulfonyl anhydride (Tf2O) to give triflate 21. In
our preliminary study, triflate 21 was purified before use in the
next reaction.9a However, we found that the instability of 21
during silica gel column chromatography resulted in decreased
yield on large scale preparation. Therefore, triflate 21 was used
immediately in the next reaction without purification. As a result,
the reaction of 21 with deprotonated formaldehyde dimethyl
dithioacetal mono-S-oxide cleanly afforded AB-ring 5 (96% from
7). Thus, AB-ring 5 was furnished from D-glucose derivative 10
in 16 steps in 34% overall yield.
15
O
OHC
H
O
ONAP
ONAP
O
HO
O
H
F
ONAP
ONAP
O
H
PBBO
ONAP
H
6
4
Scheme 1. Retrosynthesis of ciguatoxin 3C (1).
3. Synthesis of AB-ring 5
Retrosynthesis of AB-ring 5 is shown in Scheme 2. It was
planned to introduce the dimethyldithioacetal mono-S-oxide
group of 5 to 7 at the final stage of the synthesis. The A-ring of 7
would be formed by Grubbs’ ring-closing olefin metathesis
(RCM)14 from diene 8, which would be prepared from 9 via allyl
ether formation and reductive etherification of the hemiacetal.
Because of the similarity of 9 to D-glucose in structure and

3
O
OMe
Et Al
OH
OH
ACCEPTED MANUSCRIPT
H
H
3
O
O
Cl(iPr)2SiO(iPr)2SiCl
imidazole, THF, 25 ºC
O
27
NiCl2(dppp) (cat.)
H
H
O
O
OPMP
26
PhMe, 0
Ph
24 ºC
H
O
H
O
O
O
TIPDS
10
6
24
tBu
tBu
tBu
tBu
O
95%
O
O
Si
Si
H
H
11
O
O
RCM
22
21
1) (COCl)2, DMSO
CH2Cl2, –78 ºC
then Et3N, 0 ºC
Ireland-Claisen Rearrangement
H
H
HO
O
EtSH, BF3—OEt2
CH2Cl2, –20 ºC
O
PCP: 4ꢀchlorophenyl
9
O
Ph
O
TIPDS
MgBr
2)
88%
O
O
O
27
Z
O
Et2O, –78 ºC
24
12
R
O
24R
O
27
88% from
Z
11
OSiR3
OPMP
H
O
H
O
PMPO
tBu
tBu
tBu
26 Z
O
O
EtS
Si
Si
H
H
mCPBA, CH2Cl2, 0 ºC
then Et3SiH
O
O
tBu
O
O
OH
OH
OH
23
OH
O
TIPDS
BF3—OEt2, –20 ºC
O
TIPDS
O
O
RCM
89%
Me
Me
14
13
Me
Me
O
H
H
O
O
PCP
O
O
1) 2ꢀnaphthaldehyde
PPTS, PhH, reflux
2) TBAF, THF, 24 ºC
OPMP
OPMP
PMPO
MeO
O
86%
OH
OH
25
O
Mes N N Mes
Cl
R
R
from
14
28
(1 mol%)
O
Ru
Cl
H
H
24
Ph
allylbromide, NaH
O
PCy3
Z 16
O
TBAI (cat), THF, 27 ºC
6
17
OPMP
15O
O
7
HO
O
Np
8
R
PCP
100%
Ireland-Claisen
Rearrangement
RO
O
O
CH2Cl2 (20 mM)
reflux
TBSOTf, 2,6ꢀlutidine
: R=H
15
O
27
CH2Cl2, –78 ºC, 93%
: R=TBS
16
82%
18
16
O
PCP
OPMP
Z
1) PBBBr, NaH
PMPO
MeO
O
R3SiO
15O
O
TBAI, THF, 23 ºC
2) LiAlH4, AlCl3
H
H
H
H
R 18
O
O
PCP
Tf2O, 2,6ꢀlutidine
CH2Cl2, –78 ºC
O
O
O
15
O
Z
CH2Cl2ꢀEt2O, 23 ºC
26
O
Np
O
7
Scheme 4. Retrosynthesis of EF-ring 6.
RO
87% from
19
: R=TBS
: R=H
18
TBAF, THF, 20 ºC, 95%
The preparation of (Z)-aryloxyallyl alcohols 25 and 28 is
shown in Scheme 5. 4-Methoxyphenol (29) was treated with
NaH, KI, and trichloroethylene to afford 4-methoxyphenyl
(PMP) ether 30 (96%).25 Exposure of 30 with 2 equivalents of
BuLi generated a lithium acetylide,26 which was reacted with (R)-
2,3-O-isopropylidene glyceraldehyde (31)24 in situ to give
alcohol 32 as a 1:1 mixture of diastereomers (66% from 31).
Lindlar hydrogenation of 32 produced a 1:1 mixture of 25 (48%
from 31) and 28 (41% from 31), which were separated by HPLC.
While the (R)-2,2-dimethyl-1,3-dioxolan-4-yl group did not
influence the stereoselectivity at the addition step, it acted as a
"chiral resolving agent" to achieve efficient chromatographic
separation of homochiral diastereomers 25 and 28. The
stereochemistry of 25 and 28 was confirmed by X-ray
crystallographic analysis of 33 (Figure 2), which was obtained
from 25 by Pd/C-catalyzed hydrogenation.
19
H
O
O
MeSCH2S(O)Me
BuLi, THF, –20 ºC
SMe
SMe
H
O
OTf
A
B
ONAP
OPBB
21
O
H
then , –20 0 ºC
7
ONAP
O
H
OPBB
96% from
7
5
Scheme 3. Synthesis of AB-ring 5.
4. Synthesis of EF-ring 6
The retrosynthesis of EF-ring 6 is illustrated in Scheme 4. It
was planned to construct the α,β-unsaturated aldehyde moiety of
6 from 21 at the final stage. The F-ring of 21 would be formed by
RCM from divinyl compound 22. Bond formation between
asymmetric centers C26 and C27 would be performed by the
Ireland-Claisen rearrangement of (Z)-3-aryloxyallyl ester 23.21,22
The chirality at C24 of 23 was anticipated to be transferred to
C27 and C26 of 22 via a chair-form transition state after
formation of a (Z)-ketene silyl acetal.22,23 Ester 23 would be
prepared from 24 and 25. It was intended to construct the E-ring
of 24 by the same process as the F-ring. Therefore, the eight-
membered ring of 24 would be constructed from 26 by RCM, and
the C15-C16 bond of 26 would be formed stereoselectively by
the Ireland-Claisen rearrangement of (Z)-3-aryloxyallyl ester 27.
(Z)-3-Aryloxyallyl alcohol 28, which is a constituent of 27, is a
diastereomer of 25 having the same (4R)-2,2-dimethyl-1,3-
dioxolan-4-yl group. Both 25 and 28 would be synthesized
simultaneously from the known (R)-2,3-O-isopropylidene
glyceraldehyde24 in a non-stereoselective manner.
Scheme 5. Synthesis of alcohols 25 and 28.

4
Tetrahedron
rearrangement via a chair-form transition state (TS-I) under the
ACCEPTED MANUSCRIPT
reaction conditions.
Table 1. Ireland-Claisen rearrangement of 27.
27
Me
O
Me
O
R=
1) Reagent 1 (5 equiv)
THF, –78 ºC, Time
then Reagent 2 (5 equiv), 15 min
then diethyl malonate, 15 min
Figure 2. ORTEP diagram of 33.
OPMP
Ester 27 was synthesized from carboxylic acid 39 and alcohol
OPMP
TMSO
Z
TMSO
O
28 (Scheme 6). Carboxylic acid 39 was prepared from 4-
chlorobenzylidene dimethyl acetal (34) and D-glucose via a 4-
step process similar to the previously reported procedure (55%
from 34).27 Thus, selective protection of the 1,3-diol at C4 and
Z
O
O
O
R
R
O
O
O
PCP
E
O
PCP
Z
TS-I
TS-II
–78 → 0 ºC, 30 min
C6 of D-glucose as
a
4-chlorobenzylidene acetal,
2) TMSCHN2
oxidativecleavage by NaIO4, Wittig methylenation, and
formation of a carboxymethyl ether constructed 39. Carboxylic
acid 39 was then condensed with 28 using 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride (EDCI·HCl)
and 4-dimethylaminopyridine (DMAP) to afford ester 2728 (94%
from 28).
MeOH-PhH, R.T.
R
R
O
PCP
O
PCP
16
15O
16
15O
PMPO
MeO
O
PMPO
MeO
O
O
O
40
15-epi-40
desired
undesired
HO
HO
O
OH
OH
Entry Reagent 1 Time
Reagent 2 Yield (2 steps) 40:15-epi-40
H
MeO
MeO
HO
HO
O
OH
O
1
2
3
KHMDS
KHMDS
TMSCl
2 min
10 min
3 min
TMSCl
TMSCl
KHMDS
65%
32%
96%
>20 : 1
>20 : 1
>20 : 1
D-glucose (35)
O
PCP
PTS·H2O (cat.), DMF
60 ºC, 200 mmHg
75%
H
Cl
HO
34
36
NaIO4, pH 7 buffer
MeOH, 50 ºC
bromoacetic acid
1,4-dioxane
OH
OH
MePPh3Br
tBuOK, THF, 21 ºC
O
O
PCP
O
PCP
NaH, 65 ºC
then 37, 21 ºC
0.5 M HCl-MeCN
0 ºC
O
PCP
O
O
HO
HO
40
97%
77% from 36
PMPO
MeO
O
38
37
(40:15-epi-40 > 20:1)
O
92%
O
41
O
PCP
28, EDCI·HCl
DMAP, CH2Cl2
22 ºC
OPMP
IPNBSH, PPh3
DIAD, 1-hexene
THF, 17 ºC
O
PCP
O
O
O
O
Me
Me
1) NaIO4, THF
O
O
O
HO
pH 7 buffer, 25 ºC
2) NaBH4, CeCl3·7H2O
MeOH, –78 ºC
HO2C
94% from 28
O
then H2O
39
27
CF3CH2OH, 17 ºC
O
PCP
Scheme 6. Synthesis of ester 27.
PMPO
MeO
O
84%
91% from 41
O
O
Next, we examined the Ireland-Claisen rearrangement of 27
(Table 1). Ester 27 was initially treated with potassium
bis(trimethylsilyl)amide (KHMDS) (5 equiv) in tetrahydrofuran
(THF) at –78 °C for 2 min, and the resulting enolate was reacted
with trimethylsilyl chloride (TMSCl) (5 equiv) for 15 min.29
After the treatment with diethyl malonate (8 equiv) to scavenge
the unreacted base, the resulting ketene silyl acetal was warmed
to 0 °C to complete the rearrangement. After methylation with
TMSCHN2,30 15,16-anti diether 40 was obtained exclusively in
65% yield (40:15-epi-40 > 20:1) (Entry 1). Because the
prolonged exposure of 27 with KHMDS (10 min) resulted in
decreased yield due to decomposition of 27 (Entry 2), the time of
the deprotonation of 27 was minimized. Thus, we found that the
treatment of 27 with KHMDS in the presence of TMSCl
improved the yield (96%) with high selectivity (40:15-epi-40 >
20:1) (Entry 3). The stereochemistry of 40, which was confirmed
at a later stage of the synthesis, was rationalized by the selective
formation of a (Z)-ketene silyl acetal intermediate and its
42
Mes
N
N Mes
H
Cl
Ru
Cl
O
PCP
21
(cat.)
16
PMPO
MeO
O
Ph
PCy3
15
O
H
H
17
26
CH2Cl2, 23 ºC
O
NOE
24 (single diastereomer)
JH15-H16
= 9.5 Hz
75%
Scheme 7. Synthesis of eight-membered ring ether 24.
The construction of the E-ring is outlined in Scheme 7. The
isopropylidene acetal of 40, which included a small amount of
15-epi-40 (40:15-epi-40 > 20:1), was selectively hydrolyzed
upon treatment with 0.5 M aqueous HCl in MeCN without
removal of the 4-chlorobenzylidene acetal to afford diol 41
(92%).31 Oxidative cleavage of diol 41 followed by Luche
reduction gave allyl alcohol 42 (91% from 41).32 Reductive
rearrangement of allyl alcohol 42 was performed with N-
isopropylidene-N'-2-nitrobenzenesulfonyl hydrazine (IPNBSH)

5
according to Movassaghi's procedure with a slight modification,
ACCEPTED MANUSCRIPT
in which an excess amount of 1-hexene was used as a scavenger
of free diimide generated during the reaction, to furnish diene 26
successfully (84%).33 Diene 26 was then transformed to eight-
membered ring ether 24 (75%) by RCM using the second
generation Grubbs catalyst (17). Although diene 26 included a
trace amount of 15-epi-26, the RCM reaction gave no cyclized
product from 15-epi-26, which was easily separated from 24 by
column chromatography. The stereochemistry of 24 was
determined by the presence of a nuclear Overhauser effect (NOE)
between H15 and H21, a large JH15-H16 value (9.5 Hz), and
absence of an NOE between H15 and H16, thereby also
confirming the stereochemistry of the major product (40) from
the Ireland-Claisen rearrangement step.
Toward the F-ring formation, protected cyclic ether 24 was
converted to ester 23 (Scheme 8). After removal of the PMP
group of 24 with cerium ammonium nitrate (CAN) (93%),34 the
resulting β-hydroxy ester 43 was reduced with NaBH4 to produce
1,3-diol 44 (95%), which was converted to 1,3,2-dioxasilinane 45
(90%). The 4-chlorobenzylidene acetal group of 45 was removed
with 1,2-ethanedithiol and BF3·OEt2 to afford diol 46 (97%).35
One-pot selective triflation/triethylsilyl (TES) protection of 46
followed by vinylation of the triflate ester gave alkene 47 (98%
from 46),36 which was treated with pyridinium p-toluenesulfonate
(PPTS) in EtOH to produce alcohol 48 (93%). Etherification of
48 with tert-butyl bromoacetate under phase-transfer conditions
and subsequent one-pot hydrolysis by simple addition of
methanol as a solvent afforded glycolic acid 49 (97%).
Condensation of 49 with alcohol 25 afforded (Z)-3-aryloxyallyl
ester 23 (92%).28
Scheme 9. Ireland-Claisen rearrangement of 23 using KHMDS.
Table 2. Ireland-Claisen rearrangement of 23.
O
O
O
Me
Me
O
PMPO
O
H
O
tBu
tBu
Z
O
R
Si
H
O
23
1) Base, Time
THFꢀPhCH3, –78 ºC,
then TMSCl, 15 min
then diethyl malonate, 15 min
H
O
PCP
Z
CAN
O
O
E
O
NaBH4
HO
O
R
MeCNꢀH2O
0 ºC
O
O
Z
H
R
MeOH, 22 ºC
OSiMe3
OPMP
O
MeO
Z
O
24
OSiMe3
OPMP
O
93%
95%
43
–78 0 ºC, 30 min
2) TMSCHN2
H
H
O
O
PCP
PCP
MeOHꢀPhH, R.T.
(tBu)2Si(OTf)2
H
HO
HO
O
O
pyridine, DMF, 19 ºC
tBu
tBu
O
Si
O
H
O
H
H
O
O
OMe
OMe
90%
O
44
45
O27
O27
OPMP
OPMP
26
26
H
H
O
1) Tf2O, 2,6ꢀlutidine
CH2Cl2, –78 ºC
HS(CH2)2SH
BF3—OEt2
OH
OH
O
Si
H
tBu
tBu
tBu
tBu
O
O
Si
R
R
H
H
tBu
O
Si
then TESOTf, 0 ºC
2) tetravinyltin, BuLi
CH2Cl2, –40 ºC
97%
O
O
O
H
tBu
27ꢀepiꢀ50
undesired
O
50
desired
CuCN, –78
98% from
0 ºC
46
46
BrCH2CO2tBu, Bu4NHSO4
50% aq NaOH, PhH, 25 ºC
then MeOH, 25 ºC
Entry
Base
Time Yield (2 steps)
:27ꢀepiꢀ
50
50
OR
H
1 min
4 min
2 min
1 min
1
2
3
4
LDA
No Reaction
28%
tBu
O
O
Si
2.0:1
1.7:1
13:1
KHMDS
97%
H
tBu
O
PPTS (cat.)
: R=TES
: R=H
LDA ꢀ KHMDS (1:1)
93%
47
EtOH, 25 ºC
93%
48
Et2NLi ꢀ KHMDS (1:1)
87%
O
OH
ꢀ
N Li KHMDS (1:1)
6.5 min
89%
> 20:1
5
, EDCI—HCl
25
O
DMAP, CH2Cl2, 27 ºC
H
23
tBu
O
Si
O
92%
H
tBu
O
49
At the initial stage of the F-ring formation, rearrangement of
23 was first examined under the same conditions as that of 27
(Scheme 9). However, the desired 26,27-anti diether from 23 was
produced with low stereoselectivity (50:27-epi-50 = 1.3:1, 74%
combined yield). Upon optimization of the reaction conditions,
we found that the selectivity of 50 was improved by modification
of the procedure for the enolate formation (Table 2). The enolate
Scheme 8. Synthesis of ester 23.

6
Tetrahedron
ACCEPTED MANUSCRIPT
formation from 23 by the treatment with lithium
diisopropylamide (LDA) for 1 min and then with TMSCl for 15
min, which was followed by the rearrangement step under the
same conditions as above, resulted in recovery of 23 (Entry 1).
However, the use of KHMDS instead of LDA produced 50 in
low yield with improved stereoselectivity (50:27-epi-50 = 2.0:1,
28% combined yield) (Entry 2). Exposure of 23 to the
combination of KHMDS (6 equiv) and LDA (6 equiv) as a base
in toluene-THF (3.4:1) at –78 °C for 2 min produced 50
somewhat selectively in improved yield (50:27-epi-50 = 1.7:1,
93% combined yield) (Entry 3). Interestingly, small lithium
amide bases in place of LDA displayed good results: KHMDS-
LiNEt2 (6 equiv/6 equiv) showed a ratio of 50:27-epi-50 = 13:1
(Entry 4) and KHMDS-lithium pyrrolidinide (6 equiv/6 equiv)
gave a ratio of 50:27-epi-50 > 20:1 (Entry 5).37,38 Thus, we
optimized conditions for the stereoselective Ireland-Claisen
rearrangement of 23 to 50, and established the chiral centers at
C26 and C27.
Figure 3. ORTEP diagram of 54: one of the two
crystallographically independent molecules is shown.
EF-ring segment 6, a key synthetic intermediate for 3, was
prepared from 21 as shown in Scheme 11. After the 1,3-diol
group of 21 was protected with 2-naphthylmethyl bromide
(NAPBr) (72%), the cyclic silylene group of resulting 56 was
removed with TBAF to give diol 57 (99%), which was converted
to bis-TES ether 58 upon treatment with TESOTf and 2,6-
lutidiene (100%). The regioselective oxidation of 58 under Swern
conditions generated an aldehyde,39 which was alkynylated using
Ohira-Bestmann’s reagent to afford alkyne 60 (64% from 58).40
The treatment of 60 with MeLi generated a lithium acetylide,
which was reacted in situ with paraformaldehyde to give alcohol
61 (94%). While partial hydrogenation of 61 with Lindlar
catalyst was sluggish and afforded only a trace amount of 62, Au
nanoparticles (AuNPs) catalyzed the hydrogenation of 61 to
cleanly provide (Z)-alkene 62 in 93% yield.41 Finally, Swern
oxidation of 62 produced aldehyde 6 (100%).17 Thus, we
achieved the synthesis of EF-ring 6 from carboxylic acid 39 over
36 steps by a sequential process including Ireland-Claisen
rearrangement and RCM.
O
OMe
OPMP
HS(CH2)2SH
BF3·OEt2
O
50:27-epi-50
CH2Cl2, –40 ºC
H
> 20:1
tBu
tBu
O
O
H
95%
Si
O
OH
HO
51
O
O
OMe
OPMP
1) NaIO4, THF
pH 7 buffer, 18 ºC
H
O
Si
O
tBu
2) NaBH4, CeCl3·7H2O
O
H
MeOH, –78 ºC
92% from 50
tBu
OH
PCy3
ONAP
52
IPNBSH, PPh3
DIAD, 1-hexene
THF, 18 ºC
Cl
O
H
H
ONAP
NAPBr, NaH
KI, THF-DMF
0 ºC
O
OMe
OPMP
Ru
H
O
Si
O
TBAF
27
(cat.)
Ph
H
H
Cl
O
26
tBu
tBu
THF, 23 ºC
PCy3
O
H
H
O
Si
O
53
21
then H2O
tBu
tBu
99%
72%
CH2Cl2, 0 ºC
O
H
CF3CH2OH, 18 ºC
92%
56
22
O
O
82%
54
(single diastereomer)
P OMe
OMe
1) (COCl)2, DMSO
Me
ONAP
ONAP
N2
59
CH2Cl2, –78 → –40 ºC
then Et3N –78 → 0 ºC
2) 59, K2CO3
O
H
O
OMe
OH
CAN, MeCN-
NaBH4
H
O
CH2Cl2-water
0 ºC
RO
RO
MeOH, 0 ºC
THF, MeOH, 16 ºC
O
H
H
tBu
tBu
21
O
Si
O
O
96%
97%
H
57: R=H
H
TESOTf, CH2Cl2
0 ºC, 100%
64% from 58
58: R=TES
55
Scheme 10. Synthesis of EF-ring diol 21.
MeLi
then
ONAP
ONAP
ONAP
ONAP
H
O
H
O
(CH2O)n, THF
Synthesis of EF-ring diol 21 is outlined in Scheme 10. The
second ring was constructed using a procedure similar to that
described above. The acetonide group of 50 was removed by
BF3·OEt2/1,2-ethanedithiol (95%). The oxidative cleavage of 1,2-
diol 51 followed by Luche reduction gave allyl alcohol 52 (92%
from 51), which was transformed to 22 by reductive
rearrangement (92%). The divinyl compound 22 was cyclized by
RCM with the first generation Grubbs catalyst (53)18 at 0 °C to
produce bicyclic ether 54 (82%). When the RCM was conducted
at higher temperature (> room temperature), significant
production of byproducts was observed. The stereochemistry at
C26 and C27, generated by the Ireland-Claisen rearrangement,
was determined at this stage by X-ray crystallographic analysis
TESO
HO
–78 → 19 ºC
TESO
O
H
O
H
94%
60
Au NPs: Au nano particles
61
H2, Lindlar cat.
ONAP
ONAP
H
H
O
Au NPs (cat.)
Me2NH·BH3 (100 equiv)
EtOH, 19 ºC
TESO
HO
O
93%
62
TESO
(Figure 3). The PMP group of 54 was removed with CAN to
Bookmark not defined.34
afford alcohol 55 (97%),Error!
which was
H
E
(COCl)2, DMSO
CH2Cl2, –78 ºC
then Et3N, 0 ºC
O
OHC
ONAP
ONAP
O
H
reduced with NaBH4 to give EF-ring diol 21 (96%).
F
6
Scheme 11. Synthesis of EF-ring 6.

7
5. Synthesis of ABCDEF-ring 3
reductive cyclization to produce hexacyclic ether 3 (73%). The
ACCEPTED MANUSCRIPT
stereochemistry of C11 and C12, generated in the reductive
etherification steps, was confirmed by the presence of NOEs
between H11 and H16, and between H8 and H12. Moreover,
after extensive attempts at recrystallization, we obtained a single
crystal of 3, which was subjected to X-ray crystallographic
analysis to determine the stereochemistry of 3 as shown in Figure
4. Thus, we achieved the convergent synthesis of ABCDEF-ring
3 in 6.9% yield over 7 steps from EF-ring 6.
With the AB-ring 5 and EF-ring 6 in hand, we next undertook
the completion of the synthesis of ABCDEF-ring 3. First, we
investigated the coupling reaction of 5 with 6 followed by the
transformation of resulting adduct 63 into α,ε-dihydroxy ketone 4
(Table 3). Treatment of dimethyldithioacetal mono-S-oxide 5
with lithium bis(trimethylsilyl)amide (LiHMDS) in THF at –78
°C for 15 min and then with aldehyde 6 for 15 min only resulted
in decomposition of aldehyde 6 with almost complete recovery of
5 (Entry 1). After extensive optimization of the reaction
conditions using model compounds, we found that the
TMSOTf
11-epi-64
deprotonation of
5
with sodium bis(trimethylsilyl)amide
Et3SiH
(NaHMDS) gave the corresponding anion species and that the
hydrolysis of the dimethyldithioacetal mono-S-oxide group of the
adduct proceeded smoothly with p-toluenesulfonic acid
monohydrate (PTS·H2O) in CH2Cl2-MeOH. Thus, the anion
generated from AB-ring 5 and NaHMDS reacted with aldehyde 6
to give 63 cleanly. However, the hydrolysis of 63 with PTS·H2O
in CH2Cl2-MeOH gave 4 only in 19% yield from alcohol 62
along with unknown byproducts (Entry 2). After further
optimization of the solvent in the hydrolysis, we found that the
treatment of 63 with PTS·H2O in CF3CH2OH-H2O produced α,ε-
dihydroxy ketone 4 in an acceptable yield (40% from 62, Entry
3). Thus, we ensured a sufficient supply of α,ε-dihydroxy ketone
4.
+
ONAP
ONAP
CH2Cl2, 0 ºC
H
H
4
H
H
10
H
O
O
O
64%
11
O
HO
ONAP
H
H
O
PBBO
64
(1:1 epimer mixture)
HPLC separation
(COCl)2, DMSO
CH2Cl2, –78 ºC
then Et3N, 0 ºC
28
ONAP
ONAP
H
H
H
H
H
O
10
O
O
O
11
26
8
O
64
H
H
O
79%
ONAP
PBBO
65
DDQ
Table 3. Coupling between AB-ring 5 and EF-ring 6 and
hydrolysis of adduct 63.
O
H
H
Np
H
O
H
H
O
CH2Cl2-H2O
17 ºC
O
O
H
O
O
O
H
H
Base, THF
SMe
SMe
6, THF
O
H
H
PBBO
OH
O
–78 ºC, 15 min
–78 ºC, 15 min
5
66
ONAP
OPBB
OH
OH
O
H
H
H
EtOH-1 M HCl
19 ºC
H
H
H
O
O
O
O
O
OH
H
H
O
93% from 65
OTES
PBBO
O
H
SMe
67
O
Acid, Solvent
R.T., 30 min
SMe
H
O
HO
NOE
TMSOTf
ONAP
ONAP
4
O
H
O
OH
OH
H
ONAP
Et3SiH
H
H
H
PBBO
O
H
H
H
CH2Cl2, 0 ºC
O
E
B8 C 12D
O
16
11
63
F
A
O
73%
O
H
H
O
H
H
PBBO
Entry Base
Acid
TFA
Solvent
THF-H2O
Yield from 62
NOE
3
1
2
LiHMDS
decomp
19%
NaHMDS
PTS·H2O CH2Cl2-MeOH
PTS·H2O CF3CH2OH-H2O
Scheme 12. Synthesis of ABCDEF-ring 3.
3
NaHMDS
40%
The completion of the synthesis of ABCDEF-ring 3 from α,ε-
dihydroxy ketone 4 is illustrated in Scheme 12. Intramolecular
reductive etherification of 4 with Et3SiH and TMSOTf afforded a
1:1 mixture of 64 and 11-epi-64 (64%), and the desired 64 was
separated from 11-epi-64 by HPLC. Swern oxidation of 64 gave
ketone 65 (79%).17 Alcohol 11-epi-64 also oxidized into the
corresponding ketone 11-epi-65, which was isomerized with 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) in CH2Cl2 to produce a
3:1 mixture of 65 and 11-epi-65 in a small scale experiment.42
Ketone 65 was treated with 2,3-dichloro-5,6-dicyano-p-
benzoquinone (DDQ) in order to detach the NAP groups at O8,
O26, and O28.43 However, the formation of a 2-naphthylidene
acetal between O26 and O28 occurred even though the NAP
group at O8 was removed. Therefore, the resulting acetal 66 was
then hydrolyzed under acidic conditions to afford trihydroxy
ketone 67 (93% from 64),44 which was finally subjected to
Figure 4. ORTEP diagram of 3.

8
Tetrahedron
6. Conclusion
7.1.1.
(5aS,5bR,7R,9aR,11aR)-11-(Allyloxy)-2,2,4,4-
ACCEPTED MANUSCRIPT
tetraisopropyl-7-
The synthesis of the ABCDEF-ring (3) of ciguatoxin 3C (1)
was achieved via a route including anion coupling of a
dimethyldithioacetal mono-S-oxide derivative (5) corresponding
to the AB-ring and an aldehyde (6) corresponding to the EF-ring,
followed by cyclization using reductive etherification. AB-ring 5
was synthesized from known D-glucose derivative 10 based on
ring-closing olefin metathesis, and EF-ring 6 was prepared by a
phenylhexahydro[1,3]dioxino[4',5':5,6]pyrano[3,4-f]
[1,3,5,2,4]trioxadisilepine (11). To a solution of 10 (43.23 g,
0.1402 mol) in DMF (280 ml) were added imidazole (22.91 g,
0.3365 mol) and ClSi(iPr)2O(iPr)2SiCl (55.0 mL, 0.172 mol) at 25
ºC, and the mixture was stirred for 13 h. Then, the reaction was
quenched with saturated aq. NaHCO3, and the mixture was
extracted with EtOAc several times. The combined organic layers
were washed with brine, dried over anhydrous MgSO4, filtered
and concentrated under reduced pressure. The resulting residue
was purified by column chromatography (silica gel,
hexane/EtOAc = 50 → 20 → 10) to give 11 (73.12 g, 0.1327 mol,
95%, α-anomer:β-anomer = 2:1) as a colorless oil.
process
employing
chirality-transferring
Ireland-Claisen
rearrangement and ring-closing olefin metathesis. Further studies
toward the total synthesis of 1 are currently underway in our
laboratory.
7. Experimental
11: colorless oil; IR (film) ν 2944, 2867, 1464, 1382, 1248, 1212,
1176, 1142, 1091, 1048, 990, 923, 886, 847, 746, 697 cm–1; H
1
All air sensitive reactions were carried out under argon or
nitrogen in oven-dried glassware using standard syringe, cannula
and septa techniques. Anhydrous tetrahydrofuran (THF) was
prepared by Glass Contour Solvent Dispensing System (Nikko
Hansen & Co., Ltd.) or purchased from commercial source. Other
dry solvents were purchased from commercial sources. All
reactions were monitored by thin-layer chromatography (TLC)
with precoated silica gel plates (Merck, silica gel 60 F254). Plates
were visualized by ultraviolet light and by treatment with acidic
anisaldehyde or phosphomolybdic acid stain followed by heating.
Column chromatography was performed on YMC Silica Gel 60
(63-40 ꢀm for flash chromatography, 230-63 ꢀm for gravity
chromatography) as a stationary phase. High-performance liquid
chromatography (HPLC) was performed on a JASCO 880-PU
HPLC pump equipped with a pre-packed column (YMC-Pack
SIL-06, 5 µm, 150 mm × 4.6 mm ID [for normal-phase
chromatography], or YMC-Pack SIL-06, 5 µm, 500 mm × 20
mm ID [for normal-phase chromatography]) and a JASCO UV-
975 UV detector (UV 254 nm detection). Optical rotations were
recorded on a JASCO P-1020 digital polarimeter at 589 nm.
NMR (500 MHz, CDCl3) δ 0.90-1.17 (28H, m), 3.39 (1/3H, dt, J
= 4.5, 9.5 Hz), 3.49 (2/3H, t, J = 9.5 Hz), 3.54 (1/3H, t, J = 9.5
Hz), 3.63 (1/3H, t, J = 7.8 Hz), 3.73 (2/3H, t, J = 10.2 Hz), 3.76-
3.83 (1H, m), 3.85-3.93 (1H, m), 4.06 (2/3H, tdd, J = 1.5, 5.6,
13.5 Hz), 4.13-4.18 (4/3H, m), 4.21 (1/3H, tdd, J = 1.7, 4.9, 13.6
Hz), 4.28 (2/3H, dd, J = 4.7, 10.0 Hz), 4.32-4.39 (2/3H, m), 4.45
(1/3H, d, J = 7.5 Hz), 4.86 (2/3H, d, J = 3.8 Hz), 5.18 (1H, qd, J
= 1.4, 10.5 Hz), 5.35 (1/3H, qd, J = 1.7, 17.3 Hz), 5.36 (2/3H, qd,
J = 1.7, 17.3 Hz), 5.55 (1H, s), 5.85-5.94 (1H, m), 7.30-7.37 (3H,
m), 7.46-7.51 (2H, m); 13C NMR (125 MHz, CDCl3) δ 12.3 (CH),
12.46 (CH×2/3), 12.53 (CH×1/3), 12.9 (CH×1/3), 13.0 (CH),
13.2 (CH×2/3), 17.18 (CH3×2/3), 17.21 (CH3×1/3), 17.23
(CH3×1/3), 17.28 (CH3), 17.33 (CH3), 17.35 (CH3×2/3), 17.37
(CH3×1/3), 17.40 (CH3×2/3H), 17.42 (CH3×1/3), 17.45 (CH3),
17.47 (CH3×1/3), 17.6 (CH3×2/3), 17.7 (CH3×2/3), 62.5
(CH×2/3), 66.3 (CH×1/3), 68.8 (CH2×2/3), 68.9 (CH2×1/3), 69.3
(CH2×2/3), 70.9 (CH2×1/3), 73.3 (CH×2/3), 76.0 (CH×2/3), 76.8
(CH×1/3), 77.9 (CH×1/3), 80.6 (CH×1/3), 81.7 (CH×2/3), 98.9
(CH×2/3), 101.1 (CH×1/3), 101.2 (CH×2/3), 103.1 (CH×1/3),
117.0 (CH2.×2/3), 117.1 (CH2×1/3), 126.0 (CH×2), 128.2 (CH×2),
128.78 (CH×2/3), 128.83 (CH×1/3), 134.11 (CH×1/3), 134.13
(CH×2/3), 137.2 (C×1/3), 137.9 (C×2/3); EI-HRMS (m/z) calcd
for C25H39O7Si2 [M – iPr]+: 507.2234, found: 507.2232.
Infrared spectra (IR) were measured on
a JEOL JIR-
WINSPEC100 infrared spectrometer in noted states and are
reported in wave numbers (cm–1). 1H NMR and 13C NMR spectra
were recorded on a JEOL JNM-AL300 (1H at 300 MHz, 13C at 75
MHz), a JEOL JNM-α-400 (1H at 400 MHz, 13C at 100 MHz), a
JEOL JNM-ECA500 (1H at 500 MHz, 13C at 125 MHz), a Bruker
AVANCE III 400 (1H at 400 MHz, 13C at 100 MHz), or a Bruker
AMX500 (1H at 500 MHz, 13C at 125 MHz) magnetic resonance
spectrometer. Chemical shifts (δ) are reported in ppm based on
the resonance of the residual solvent (3.30 ppm in CD3OD or
7.15 ppm in C6D6, 13C NMR: 49.0 ppm in CD3OD or 128.0 ppm
in C6D6) as the internal standard. The following abbreviations are
used to describe spin multiplicity: s= singlet, d= doublet, t=
triplet, q= quartet, m= multiplet, br= broad, dd= double doublets,
dt= double triplets, td= triple doublets and ddd= double double
doublets; other combination is derived from those listed.
Coupling constants (J) are reported in Hz. High resolution mass
spectra (HRMS) were measured on a JEOL JMS-600H (under
electron impact ionization [EI] conditions), a JEOL JMS-
SX102A (under field desorption [FD] conditions), a JEOL JMS-
700TZ (under field desorption [FD] conditions), or a JEOL JMS-
T100GCV (under field desorption [FD] conditions) double
focusing magnetic sector mass spectrometer. Several HRMS data
were recorded under electrospray ionization (ESI) or atmospheric
pressure chemical ionization (APCI) conditions on a Thermo
Scientific Exactive Fourier transform ion cyclotron resonance
mass spectrometer.
7.1.2. (5aS,5bR,7R,9aR,11aR)-11-Allyl-2,2,4,4-tetraisopropyl-
7-phenylhexahydro[1,3]dioxino[4',5':5,6]pyrano[3,4-
f][1,3,5,2,4]trioxadisilepin-11-ol (9). To a solution of 11 (50.90
g, 92.41 mmol) and NiCl2(dppp) (1.008 g, 1.860 mmol) was
added Et3Al (0.92 mol/L in PhCH3, 200 mL, 0.184 mol) at 0 ºC,
and the mixture was stirred for 3 h at 28 ºC. Then, the reaction
was quenched with saturated aq. potassium sodium tartrate, and
the mixture was stirred for 13 h at 28 ºC. The mixture was
extracted with Et2O several times. The combined organic layers
were washed with brine, dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure to give crude 12, which
was used in the next reaction without purification.
To a solution of (COCl)2 (25.0 mL, 0.291 mol) in CH2Cl2 (240
mL) was added a solution of DMSO (33.0 mL, 0.465 mol) in
CH2Cl2 (240 mL) dropwise at –78 ºC, and the mixture was stirred
for 15 min. Then, to the mixture was added a solution of the
above crude 12 in CH2Cl2 (50 mL) at –78 ºC, and the mixture
was stirred for 30 min. To the mixture was added Et3N (130 mL,
0.925 mol) at –78 ºC, and the mixture was warmed to 0 ºC. After
being stirred for 30 min, the reaction was quenched with
saturated aq. NH4Cl, and the mixture was extracted with Et2O
several times. The combined organic layers were washed with 0.2
mol/L aq. HCl, H2O, and brine, dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure to give a crude
product, which was used in the next reaction without purification.

9
To a solution of the above crude product in Et2O (1.9 L) was
added dropwise allylmagnesium bromide (1.0 mol/L in Et2O, 186
mL, 186 mmol) at –78 ºC, and the mixture was stirred for 30
min. Then, the reaction was quenched with saturated aq. NH4Cl,
and the mixture was extracted with EtOAc several times. The
combined organic layers were washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography
(silica gel, hexane/EtOAc = 15) to give 9 (44.83 g, 81.39 mmol,
88% from 11) as a colorless oil.
Celite pad. The filtrate was extracted with EtOAc several times.
ACCEPTED MANUSCRIPT
The combined organic layers were washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography
(silica gel, hexane/EtOAc = 5) to give 14 (34.86 g, 78.03 mmol,
89%) as a colorless oil.
30
14: [α]D –21.8 (c 1.67, CHCl3); IR (neat) ν 3418, 3076, 2944,
2867, 2758, 2725, 1643, 1464, 1432, 1413, 1387, 1366, 1287,
1248, 1140, 990, 915, 886, 841, 701, 606, 564, 444 cm–1; H
1
NMR (400 MHz, CDCl3) δ 1.05 (28H, m), 2.14-2.23 (1H, m),
2.41 (1H, brs), 2.63 (1H, brdd, J = 1.4, 6.5 Hz), 3.28-3.38 (2H,
m), 3.40 (1H, t, J = 9.4 Hz), 3.48 (1H, t, J = 9.4 Hz), 3.61 (1H, t,
J = 8.4 Hz), 3.73 (1H, dd, J = 5.4, 11.6 Hz), 3.89 (1H, brdd, J =
3.2, 11.6 Hz), 5.08 (2H, dt, J = 1.8, 17.2 Hz), 5.88 (1H, tdd, J =
6.8, 10.2, 17.2 Hz); 13C NMR (100 MHz, CDCl3) δ 12.1 (CH),
12.2 (CH), 12.79 (CH), 12.82 (CH), 17.2 (CH3), 17.25 (CH3),
17.31 (CH3), 17.32 (CH3), 17.36 (CH3), 17.43 (CH3×3), 36.1
(CH2), 63.0 (CH2), 71.6 (CH), 76.1 (CH), 78.1 (CH), 79.5 (CH),
81.4 (CH), 116.9 (CH2), 134.8 (CH); EI-HRMS (m/z) calcd for
C18H35O6Si2 [M – iPr]+: 403.1972, found: 403.1961.
30
9: [α]D –17.3 (c 1.50, CHCl3); IR (neat) ν 3552, 3075, 3036,
2945, 2894, 2867, 1464, 1386, 1247, 1179, 1137, 1092, 991, 919,
886, 861, 817, 749, 698, 653, 520 cm–1; 1H NMR (400 MHz,
CDCl3) δ 1.06 (28H, m), 2.43 (1H, dd, J = 5.5, 14.2 Hz), 2.56
(1H, dd, J = 7.2, 14.2 Hz), 3.12 (1H, s), 3.49 (1H, t, J = 9.6 Hz),
3.69 (1H, d, J = 8.3 Hz), 3.71 (1H, t, J = 10.2 Hz), 3.97-4.02 (1H,
m), 4.05 (1H, dd, J = 8.3, 9.6 Hz), 4.31 (1H, dd, J = 4.9, 10.2
Hz), 5.16 (1H, dd, J = 1.7, 17.2 Hz), 5.20 (1H, dd, J = 1.7, 10.2
Hz), 5.55 (1H, s), 5.89 (1H, tdd, J = 7.2, 10.2, 17.2 Hz), 7.29-
7.37 (3H, m), 7.48 (2H, dd, J = 2.8, 7.8 Hz); 13C NMR (100
MHz, CDCl3) δ 12.1 (CH), 12.3 (CH), 12.7 (CH), 13.0 (CH),
17.0 (CH3), 17.1 (CH3), 17.2 (CH3), 17.26 (CH3), 17.34 (CH3),
17.4 (CH3), 17.46 (CH3), 17.51 (CH3), 43.2 (CH2), 63.1 (CH),
69.0 (CH2), 74.2 (CH), 78.2 (CH), 80.7 (CH), 98.5 (C), 101.0
(CH), 119.6 (CH2), 125.9 (CH×2), 128.0 (CH×2), 128.6 (CH),
131.9 (CH), 137.6 (C); EI-HRMS (m/z) calcd for C25H39O7Si2 [M
7.1.5.
(2R,4aR,6S,7R,8R,8aS)-6-Allyl-2-(naphthalen-2-
yl)hexahydropyrano[3,2-d][1,3]dioxine-7,8-diol (15). To
a
solution of 14 (23.08 g, 51.66 g) in PhH (300 mL) were added 2-
naphthaldehyde (16.16 g, 103.4 mmol) and PPTS (1.300 g, 5.173
mmol) at 24 ºC, and the mixture was stirred and heated to reflux
with removal of H2O by a Dean-Stark apparatus. After being
stirred for 3 h, the mixture was cooled to 24 ºC, and the reaction
was quenched with saturated aq. NaHCO3. Then, the mixture was
extracted with EtOAc several times. The combined organic layers
were washed with brine, dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure to give a crude product,
which was used in the next reaction without purification.
To a solution of the above crude product in THF (260 mL) was
added TBAF (1.0 mol/L in THF, 130 mL, 129 mmol) at 0 ºC, and
the mixture was stirred for 40 min at 24 ºC. Then, the reaction
was quenched with H2O, and the mixture was extracted with
EtOAc several times. The combined organic layers were washed
with brine, dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, hexane/EtOAc = 10 → 2 →
1) to give 15 (15.18 g, 44.34 mmol, 86% from 14) as a colorless
solid.
–
iPr]+: 507.2234, found: 507.2281.
7.1.3. (5aR,8R,9R,9aS)-6-Allyl-6-(ethylthio)-8-
(hydroxylmethyl)-2,2,4,4-tetraisopropyltetrahydro-6H-
pyrano[3,4-f][1,3,5,2,4]trioxadisilepin-9-ol (13). To a solution
of 9 (55.61 g, 100.9 mmol) and EtSH (37.4 mL, 505 mmol) in
CH2Cl2 (500 mL) was added BF3·OEt2 (25.3 mL, 202 mmol) at –
20 ºC, and the mixture was stirred for 20 min. Then, the reaction
was quenched with saturated aq. NaHCO3, and the mixture was
extracted with EtOAc several times. The combined organic layers
were washed with brine, dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, hexane/EtOAc =
5 → 3) to give 13 (45.12 g, 89.02 mmol, 88%) as a colorless
solid.
30
13: mp 69-71 ºC; [α]D +56.0 (c 0.980, CHCl3); IR (KBr) ν
3576, 3431, 2943, 2886, 1465, 1378, 1250, 1165, 1120, 1086,
1051, 1003, 986, 931, 885, 855, 823, 693, 632, 620, 586 cm–1; 1H
NMR (400 MHz, CDCl3) δ 1.06 (30H, m), 1.23 (3H, t, J = 7.5
Hz), 1.94 (1H, dd, J =5.5, 7.9 Hz), 2.34-2.55 (3H, m), 2.78 (2H,
brd, J = 6.6 Hz), 3.49 (1H, dt, J = 2.2, 9.4 Hz), 3.75-3.92 (4H,
m), 4.11 (1H, t, J = 8.5 Hz), 5.10 (1H, brs), 5.14 (1H, brdd, J =
1.6, 3.4 Hz), 5.82-5.93 (1H, m); 13C NMR (100 MHz, CDCl3) δ
12.20 (CH), 12.22 (CH), 12.6 (CH), 12.9 (CH), 14.3 (CH3), 17.0
(CH3), 17.1 (CH3), 17.3 (CH3), 17.40 (CH3), 17.41 (CH3), 17.5
(CH3), 17.57 (CH3), 17.59 (CH3), 19.9 (CH2), 43.6 (CH2), 62.8
(CH2), 71.3 (CH), 72.5 (CH), 76.8 (CH), 77.9 (CH), 91.5 (C),
118.4 (CH2), 133.0 (CH); EI-HRMS (m/z) calcd for C21H41O6Si2
[M – SEt]+: 445.2441, found: 445.2446.
19
15: mp 144-146 ºC; [α]D –27.8 (c 0.270, CHCl3); IR (KBr) ν
3447, 3071, 2976, 2867, 1641, 1476, 1435, 1377, 1345, 1328,
1272, 1213, 1179, 1128, 1094, 1078, 1009, 982, 951, 922, 900,
861, 823, 809, 798, 748, 608, 561, 502, 477 cm-1; H NMR (400
1
MHz, CDCl3) δ 2.26 (1H, brtd, J = 6.0, 13.5 Hz), 2.57 (1H, brdd,
J = 6.6, 14.6 Hz), 2.72 (1H, brs), 3.07 (1H, brs), 3.35-3.51 (4H,
m), 3.68-3.76 (2H, m), 4.34 (1H, dd, J = 5.0, 10.9 Hz), 5.11 (2H,
dt, J = 1.4, 17.1 Hz), 5.65 (1H, s), 5.87 (1H, tdd, J =7.0, 10.2,
17.2 Hz), 7.47-7.52 (2H, m), 7.59 (1H, dd, J = 1.5, 8.5 Hz), 7.81-
7.87 (3H, m), 7.96 (1H, s); 13C NMR (100 MHz, CDCl3) δ 36.0
(CH2), 68.9 (CH2), 70.2 (CH), 73.9 (CH), 75.3 (CH), 79.2 (CH),
81.1 (CH), 101.9 (CH), 117.5 (CH2), 123.7 (CH), 125.8 (CH),
126.3 (CH), 126.5 (CH), 127.7 (CH), 128.29 (CH), 128.33 (CH),
132.9 (C), 133.7 (C), 134.0 (CH), 134.3 (C); EI-HRMS (m/z)
calcd for C20H22O5 [M]+: 342.1467, found: 342.1460.
7.1.4. (5aS,6S,8R,9R,9aS)-6-Allyl-8-(hydroxymethyl)-2,2,4,4-
tetraisopropyltetrahydro-6H-pyrano[3,4-f][1,3,5,2,4]trioxa-
disilepin-9-ol (14). To a solution of 13 (44.27 g, 87.35 mmol) in
CH2Cl2 (440 mL) was added mCPBA (30.16 g, 174.5 mmol) at 0
ºC, and the mixture was stirred for 1 h. Then, to the mixture were
added Et3SiH (84.0 mL, 526 mmol) and BF3·OEt2 (66.0 mL, 525
mmol) at –20 ºC, and the mixture was stirred for 30 min. Then,
the reaction was quenched with 2.0 mol/L aq. NaOH and
saturated aq. Na2S2O3, and the mixture was filtered through a
7.1.6.
(2R,4aR,6S,7S,8R,8aR)-6-Allyl-8-((tert-
butyldimethylsilyl)oxy)-2-(naphthalen-2-
yl)hexahydropyrano[3,2-d][1,3]dioxin-7-ol (16). To a solution
of 15 (318.0 mg, 0.9288 mmol) and 2,6-lutidine (0.325 mL, 2.81
mmol) in CH2Cl2 (5 mL) was added TBSOTf (0.320 mL, 1.39

10
Tetrahedron
mmol) at –78 ºC, and the mixture was stirred for 30 min. The
and stirred for 1 h under O2 atmosphere. Then, the mixture was
concentrated under reduced pressure, and the residue was
purified by column chromatography (silica gel + Florisil®, PhH)
to give 18 (767.8 mg, 1.638 mmol, 82%) as a colorless solid.
ACCEPTED MANUSCRIPT
reaction was quenched with saturated aq. NaHCO3, and the
mixture was extracted with EtOAc several times. The combined
organic layers were washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel,
hexane/EtOAc = 10) to give 16 (392.6 mg, 0.8597 mmol, 93%)
as a colorless solid.
22
18: mp 133-136 ºC; [α]D –96.9 (c 0.0350, CHCl3); IR (neat) ν
3481, 3023, 2927, 2855, 1725, 1510, 1472, 1387, 1247, 1175,
1108, 1011, 970, 855, 770, 740, 669, 623 cm–1; H NMR (400
1
MHz, CDCl3) δ 0.08 (3H, s), 0.11 (3H, s), 0.90 (9H, s), 2.29-2.38
(1H, m), 2.67 (1H, ddd, J = 4.4, 8.0, 16.4 Hz), 3.24 (1H, t, J = 8.4
Hz), 3.40 (1H, dt, J = 4.4, 9.8 Hz), 3.47 (1H, dd, J = 5.1, 9.8 Hz),
3.55 (1H, t, J = 9.3 Hz), 3.74 (1H, t, J = 10.1 Hz), 3.82 (1H, t, J =
7.7 Hz), 3.99 (1H, brddd, J = 2.7, 5.7, 15.8 Hz), 4.31 (1H, dd, J =
5.7, 15.8 Hz), 4.36 (1H, dd, J = 5.1, 10.1 Hz), 5.70 (1H, s), 5.73-
5.80 (1H, m), 5.85-5.90 (1H, m), 7.47-7.51 (1H, m), 7.60 (1H,
dd, J = 1.7, 8.7 Hz), 7.82-7.85 (3H, m), 8.01 (1H, s); 13C NMR
(100 MHz, CDCl3) δ –4.53 (CH3), –4.46 (CH3), 18.4 (C), 25.9
(CH3×3), 34.8 (CH2), 68.8 (CH2), 69.0 (CH2), 69.9 (CH), 74.9
(CH), 77.2 (CH), 82.0 (CH), 88.3 (CH), 101.4 (CH), 123.9 (CH),
125.5 (CH), 126.0 (CH), 126.2 (CH), 126.3 (CH), 127.7 (CH),
127.9 (CH), 128.4 (CH), 131.3 (CH), 132.9 (C), 133.6 (C), 134.9
(C); EI-HRMS (m/z) calcd for C25H31O5 Si [M]+: 411.1628,
found: 411.1653.
16: mp 87-88 ºC; [α]D20 –65.9 (c 0.210, CHCl3); IR (KBr) ν 3573,
3064, 2951, 2931, 2901, 2855, 1640, 1472, 1388, 1248, 1174,
1128, 1101, 1075, 1020, 911, 857, 778, 670, 473 cm–1; H NMR
1
(400 MHz, CDCl3) δ 0.04 (3H, s), 0.11 (3H, s), 0.88 (9H, s), 2.27
(1H, d, J = 2.5 Hz), 2.32 (1H, quin, J = 7.5 Hz), 2.64 (1H, brd, J
= 14.2 Hz), 3.35-3.51 (4H, m), 3.71-3.78 (2H, m), 4.36 (1H, dd, J
= 4.4, 13.2 Hz), 5.11 (1H, dd, J = 1.0, 10.2 Hz), 5.16 (1H, dd, J =
1.7, 17.3 Hz), 5.65 (1H, s), 5.92 (1H, tdd, J = 6.8, 10.2, 17.3 Hz),
7.47-7.52 (2H, m), 7.59 (1H, dd, J = 1.6, 8.6 Hz), 7.85 (3H, brd,
J = 8.6 Hz), 7.97 (1H, s); 13C NMR (100 MHz, CDCl3) δ –4.8
(CH3), –4.0 (CH3), 18.2 (C), 25.9 (CH3×3), 36.2 (CH2), 69.0
(CH2), 70.7 (CH), 75.0 (CH), 76.7 (CH), 79.2 (CH), 81.5 (CH),
101.7 (CH), 117.3 (CH2), 123.9 (CH), 125.7 (CH), 126.1 (CH),
126.3 (CH), 127.7 (CH), 128.0 (CH), 128.3 (CH), 132.9 (C),
133.6 (C), 134.2 (CH), 134.7 (C); EI-HRMS (m/z) calcd for
C22H27O5Si [M – tBu]+: 399.1628, found: 399.1637.
7.1.9.
(2R,4aR,5aS,10aR,11R,11aS)-2-(Naphthalen-2-yl)-
4,4a,5a,6,9,10a,11,11a-octahydro-
[1,3]dioxino[4',5':5,6]pyrano[3,2-b]oxepin-11-ol (19). To
a
7.1.7.
(((2R,4aR,6S,7S,8R,8aR)-6-Allyl-7-(allyloxy)-2-
solution of 18 (10.5 g, 22.4 mmol) in THF (120 mL) was added
TBAF (1.0 mol/L in THF, 90 mL, 90 mmol) at 20 ºC, and the
mixture was stirred for 5 h. Then, the mixture was concentrated
under reduced pressure, and the residue was purified by
recrystallization (PhH + H2O) to give 19 (7.50 g, 21.2 mmol,
95%) as a colorless needle.
(naphthalen-2-yl)hexahydropyrano[3,2-d][1,3]dioxin-8-
yl)oxy)tert-butyldimethylsilane (8). To a solution of 16 (17.77
g, 38.91 mmol), TBAI (1.470 g, 3.979 mmol), and allylbromide
(6.7 mL, 78 mmol) in THF (200 mL) was added NaH (60% in
mineral oil, 7.7619 g, 194.13 mmol) at 0 ºC, and the mixture was
stirred for 10 h. Then, the reaction was quenched with saturated
aq. NH4Cl, and the mixture was extracted with EtOAc several
times. The combined organic layers were washed with brine,
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by column
chromatography (silica gel, hexane/EtOAc = 10) to give 8 (19.15
g, 38.55 mmol, 100%) as a colorless solid.
24
19: mp 217-219 ºC; [α]D –39.7 (c 0.0350, CHCl3); IR (KBr) ν
3484, 3054, 3026, 2891, 1436, 1380, 1265, 1103, 1031, 861, 828,
1
801, 744, 678, 549, 476 cm–1; H NMR (400 MHz, CDCl3) δ
2.36-2.45 (1H, m), 2.66 (1H, ddd, J = 3.6, 8.3, 15.9 Hz), 2.80
(1H, s), 3.34 (1H, t, J = 8.5 Hz), 3.39 (1H, ddd, J = 4.0, 9.7, 19.4
Hz), 3.53 (1H, dt, J = 5.2, 9.7 Hz), 3.65 (1H, t, J = 9.3 Hz), 3.77
(1H, t, J = 10.5 Hz), 3.89 (1H, t, J = 8.8 Hz), 4.07 (1H, brqd, J =
2.9, 15.3 Hz), 4.35-4.40 (2H, m), 5.73 (1H, s), 5.82-5.88 (1H, m),
5.92-5.98 (1H, m), 7.46-7.50 (2H, m), 7.62 (1H, d, J = 8.5 Hz),
7.82-7.88 (3H, m), 7.99 (1H, s); 13C NMR (100 MHz, CDCl3) δ
34.3 (CH2), 68.5 (CH2), 68.9 (CH2), 69.9 (CH), 73.6 (CH), 76.4
(CH), 80.9 (CH), 87.8 (CH), 101.9 (CH), 123.8 (CH), 125.8
(CH), 126.1 (CH), 126.4 (CH), 127.3 (CH), 127.7 (CH), 128.2
(CH), 128.4 (CH), 131.7 (CH), 132.9 (C), 133.7 (C), 134.4 (C);
EI-HRMS (m/z) calcd for C21H22O5 [M]+: 354.1467, found:
354.1464.
8: mp 65-67 ºC; [α]D21 –65.6 (c 0.390, CHCl3); IR (KBr) ν 3075,
2924, 2854, 1644, 1472, 1388, 1256, 1176, 1081, 1031, 856, 776,
671, 473 cm–1; H NMR (400 MHz, CDCl3) δ 0.01 (3H, s), 0.08
1
(3H, s), 0.85 (9H, s), 2.29 (1H, quin, J = 7.9 Hz), 2.60 (1H, brd, J
= 13.9 Hz), 3.12 (1H, t, J = 8.5 Hz), 3.38-3.47 (3H, m), 3.72 (1H,
t, 9.6 Hz), 3.86 (1H, t, J = 8.5 Hz), 4.10 (1H, dd, J = 6.0, 11.9
Hz), 4.34 (1H, dd, J = 4.6, 10.4 Hz), 4.41 (1H, dd, J = 6.0, 11.9
Hz), 5.09-5.20 (3H, m), 5.28 (1H, dd, J = 1.5, 17.2 Hz), 5.62
(1H, s), 5.86-5.98 (2H, m), 7.47-7.51 (2H, m), 7.59 (1H, dd, J =
1.8, 8.7 Hz), 7.81-7.87 (3H, m), 7.97 (1H, s); 13C NMR (100
MHz, CDCl3) δ –4.4 (CH3), –4.1 (CH3), 18.2 (C), 25.9 (CH3×3),
36.0 (CH2), 69.1 (CH2), 70.4 (CH), 74.5 (CH2), 76.3 (CH), 79.3
(CH), 82.2 (CH), 82.4 (CH), 101.9 (CH), 117.2 (CH2), 117.3
(CH2), 124.0 (CH), 125.8 (CH), 126.0 (CH), 126.3 (CH), 127.7
(CH), 127.9 (CH), 128.3 (CH), 132.8 (C), 133.6 (C), 134.49
(CH), 134.52 (CH), 134.7 (C); EI-HRMS (m/z) calcd for
C25H31O5 Si [M – tBu]+: 439.1941, found: 439.1940.
7.1.10.
((2R,3R,4R,4aS,9aS)-4-((4-Bromobenzyl)oxy)-3-
(naphthalen-2-ylmethoxy)-3,4,4a,6,9,9a-hexahydro-2H-
pyrano[3,2-b]oxepin-2-yl)methanol (7). To a solution of 19
(11.98 g, 33.80 mmol), PBBBr (14.46 g, 57.84 mmol), and TBAI
(1.255 g, 3.398 mmol) in THF (350 mL) was added NaH (60% in
mineral oil, 4.995 g, 124.9 mmol) at 0 ºC, and the mixture was
stirred for 27 h at 23 ºC. Then, the reaction was quenched with
saturated aq. NH4Cl, and the mixture was extracted with EtOAc
several times. The combined organic layers were washed with
brine, dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure to give a crude product, which was used
immediately in the next reaction.
7.1.8.
tert-Butyldimethyl(((2R,4aR,5aS,10aS,11R,11aR)-2-
(naphthalen-2-yl)-4,4a,5a,6,9,10a,11,11a-octahydro-
[1,3]dioxino[4',5':5,6]pyrano[3,2-b]oxepin-11-yl)oxy)silane
(18). To a solution of 8 (1.006 g, 2.026 mmol) in degassed
CH2Cl2 (100 mL) was added a solution of the second generation
Grubbs catalyst (17) (18.3 mg, 0.0216 mmol) in degassed CH2Cl2
(1 mL) at 24 ºC, and the mixture was refluxed with stirring. After
2 h from the start of the reaction, the mixture was cooled to 24 ºC
To a solution of the above crude product in CH2Cl2-Et2O (240
mL : 240 mL) were added LiAlH4 (7.769 g, 204.7 mmol) and a
solution of AlCl3 (9.030 g, 67.72 mmol) in Et2O (70 mL) at 23

11
ºC, and the mixture was stirred for 3 h. Then, to the mixture was
added saturated aq. potassium sodium tartrate, and the mixture
was stirred for 20 h at 23 ºC. Then, the mixture was extracted
with EtOAc several times. The combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, hexane/EtOAc = 5 → 2) to
give 7 (15.44 g, 29.39 mmol, 87% from 19) as a colorless solid.
7: mp 101-103 ºC; [α]D24 –32.4 (c 1.30, CHCl3); IR (KBr) ν 3587,
3438, 3059, 3020, 2959, 2899, 2861, 2827, 1595, 1484, 1402,
1352, 1237, 1160, 1121, 1071, 1011, 813, 746, 620, 482 cm–1; 1H
NMR (400 MHz, CDCl3) δ 1.84 (1H, t, J = 6.0 Hz), 2.30-2.41
(1H, m), 2.65 (1H, ddd, J = 4.0, 8.0, 16.1 Hz), 3.28 (1H, td, J =
4.0, 9.2 Hz), 3.36-3.41 (1H, m), 3.37 (1H, t, J = 9.2 Hz), 3.55
(1H, t, J = 9.2 Hz), 3.65-3.71 (1H, m), 3.66 (1H, t, J = 9.2 Hz),
3.87 (1H, ddd, J = 2.8, 6.0, 11.6 Hz), 3.99 (1H, ddd, J = 2.4, 6.0,
15.4 Hz), 4.27 (1H, dd, J = 6.0, 15.4 Hz), 4.76 (1H, d, J = 11.5
Hz), 4.80 (1H, d, J = 11.5 Hz), 4.91 (1H, d, J = 11.5 Hz), 4.98
(1H, d, J = 11.5 Hz), 5.80 (1H, m), 5.90 (1H, m), 7.22 (2H, d, J =
8.5 Hz), 7.38 (1H, dd, J = 1.6, 8.5 Hz), 7.42 (2H, dt, J = 2.4, 8.5
Hz), 7.45-7.50 (2H, m), 7.69 (1H, s), 7.80 (3H, dd, J = 7.4, 15.9
Hz); 13C NMR (100 MHz, CDCl3) δ 34.5 (CH2), 62.4 (CH2), 67.9
(CH2), 74.7 (CH2), 75.1 (CH2), 75.8 (CH), 77.6 (CH), 78.5 (CH),
85.6 (CH), 88.2 (CH), 121.3 (C), 125.9 (CH), 126.0 (CH), 126.2
(CH), 126.7 (CH), 127.1 (CH), 127.7 (CH), 128.0 (CH), 128.3
(CH), 129.5 (CH×2), 131.4 (CH×2), 131.6 (CH), 133.0 (C),
133.3 (C), 135.6 (C), 138.1 (C); FD-HRMS (m/z) calcd for
C28H29O579Br [M]+: 524.1198, found: 524.1206.
(CH2×1/2), 74.4 (CH×1/2), 74.9 (CH×1/4), 74.95 (CH2×1/2),
ACCEPTED MANUSCRIPT
75.02 (CH2×1/2), 75.8 (CH), 81.5 (CH×1/2), 81.6 (CH×1/2),
85.69 (CH×1/2), 85.74 (CH×1/2), 88.1 (CH), 121.13 (C×1/2),
121.14 (C×1/2), 125.7 (CH×1/2), 125.83 (CH×1/2), 125.84
(CH×1/2), 125.9 (CH×1/2), 126.1 (CH×1/2), 126.3 (CH×1/2),
126.5 (CH×1/4), 126.56 (CH×1/2), 126.58 (CH×1/4), 127.7
(CH), 127.86 (CH×1/2), 127.89 (CH×1/2), 127.97 (CH×2),
128.04 (CH×1/2), 128.1 (CH×1/2), 129.17 (CH), 129.19 (CH),
131.3 (CH), 131.5 (CH), 133.1 (C×1/2), 133.16 (C×1/4), 133.18
(C×1/4), 133.5 (C), 136.08 (C×1/2), 136.12 (C×1/2), 138.5
(C×1/2), 138.6 (C×1/2); FD-HRMS (m/z) calcd for
C31H35O579BrS2Si [M]+: 630.1091, found: 630.1100.
7.1.12. (E)-1-((1,2-Dichlorovinyl)oxy)-4-methoxybenzene (30).
To a stirred solution of 4-methoxyphenol (29) (40.06 g, 0.3227
mol) in THF (650 mL) were added NaH (60% in mineral oil,
25.45 g, 0.6361 mol) and KI (2.741 g, 16.51 mmol) at 0 °C. After
the effervescence of hydrogen was completed, trichloroethylene
(69.6 mL, 773 mmol) was added, and the mixture was heated to
40 °C. After being stirred for 14 h, the reaction was quenched
with saturated NH4Cl aq. at 0 °C and the mixture was filtered
through a Celite pad. Then, the filtrate was extracted with EtOAc
several times. The combined organic layers were washed with
brine, dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure. The residue was purified by column
chromatography (silica gel, hexane/EtOAc = 50) to give 30
(67.83 g, 0.3096 mol, 96% from 29) as a colorless oil.
30: IR (neat) ν 3104, 3003, 2953, 2927, 2852, 2837, 1630, 1596,
1503, 1463, 1442, 1298, 1275, 1248, 1193, 1162, 1103, 1073,
7.1.11.
(2R,3R,4R,4aS,9aS)-4-((4-Bromobenzyl)oxy)-2-(2-
1
1036, 833, 793, 730, 695 cm–1; H NMR (400 MHz, CDCl3) δ
(methylsulfinyl)-2-(methylthio)ethyl)-3-(naphthalen-2-
ylmethoxy)-3,4,4a,6,9,9a-hexahydro-2H-pyrano[3,2-b]oxepine
(5). To a solution of 7 (14.21 g, 27.04 mmol) and 2,6-lutidine
(9.40 mL, 81.1 mmol) in CH2Cl2 (150 mL) was added Tf2O (9.20
mL, 54.8 mmol) at –78 ºC, and the mixture was stirred for 30
min. The reaction was quenched with saturated aq. NaHCO3, and
the mixture was extracted with Et2O several times. The combined
organic layers were washed with 0.5 mol/L aq. HCl, H2O, and
brine, dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure to give a crude 21, which was used
immediately in the next reaction.
3.80 (3H, s), 5.88 (1H, s), 6.88 (2H, d, J = 9.4 Hz), 7.01 (2H, d, J
= 9.4 Hz); 13C NMR (100 MHz, CDCl3) δ 55.7 (CH3), 102.5
(CH), 114.8 (CH×2), 110.6 (CH×2), 140.8 (C), 147.6 (C), 156.6
(C); FD-HRMS (m/z) calcd for 217.9901, found: 217.9912.
7.1.13
1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-(4-
methoxyphenoxy)prop-2-yn-1-ol (32). To a solution of 30
(37.13 g, 0.1695 mmol) in Et2O (500 mL) was added dropwise
BuLi (1.65 mol/L in hexane, 210 mL, 0.347 mmol) over 10 min
at 0 ºC, and the mixture was stirred for 1 h 40 min. Then, a
solution of 31 (14.68 g, 0.1128 mmol) was added dropwise to the
mixture, and the mixture was stirred and allowed to return to
ambient temperature (25 ºC) for 15 h. Then, the reaction was
quenched with H2O, and the mixture was extracted with Et2O
several times. The combined organic layers were washed with
brine, dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by column
chromatography (silica gel, eluent:* hexane/EtOAc = 25: *the
eluent contained 10% Et3N) to give 32 (colorless oil, 20.80 g,
74.74 mmol, 66% from 30) as a 1:1 mixture of diastereomer.
32 (a 1:1 mixture of diastereomers): [α]D24 +18.3 (c 1.14, CHCl3),
IR (neat) ν 3439, 3114, 3076, 2987, 2936, 2903, 2837, 2273,
1501, 1463, 1455, 1443, 1382, 1372, 1297, 1239, 1215, 1173,
To a solution of MeSCH2S(O)Me (8.80 mL, 86.5 mmol) in THF
(170 mL) was added BuLi (1.60 mol/L in hexane, 51.0 mL, 81.6
mmol) at –20 ºC, and the mixture was stirred for 20 min. Then, to
the mixture was added a solution of the above crude 21 in THF
(100 mL), and the mixture was stirred for 40 min. The reaction
was quenched with saturated aq. NaHCO3, and the mixture was
extracted with CHCl3 several times. The combined organic layers
were washed with brine, dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, hexane/EtOAc =
1 → 0.5) to give 5 (brown oil, 16.3448 g, 25.88 mmol, 96% from
7) as an inseparable mixture of 4 diastereomers.
1
5: IR (neat) ν 3034, 2888, 1593, 1479, 1091, 815, 678 cm–1; H
1
1146, 1104, 1069, 1035, 829, 729 cm–1; H NMR (300 MHz,
NMR (500 MHz, C6D6) δ 1.74-1.78 (2H, m), 1.89 (1H, s), 1.95
(1H, s), 2.13 (2H, s), 2.15-2.29 (2H, m), 2.34-2.52 (2H, m), 3.14-
3.38 (4H, m), 3.57-3.67 (2H, m), 3.74-3.82 (1H, m), 3.94 (1H,
dd, J = 5.1, 14.9 Hz), 4.54 (1/2H, d, J = 11.9 Hz), 4.61-4.66 (1H,
m), 4.81-4.87 (1H, m), 4.90 (1/4H, d, J = 11.8 Hz), 4.93 (1/4H, d,
J = 11.5 Hz), 5.46-5.59 (2H, m), 6.98-7.06 (2H, m), 7.20-7.35
(5H, m), 7.57-7.68 (4H, m); 13C NMR (100 MHz, C6D6) δ 11.7
(CH3×1/2), 14.1 (CH3×1/4), 15.1 (CH3×1/4), 28.8 (CH2×1/2),
29.2 (CH2×1/2), 32.9 (CH3×1/4), 34.5 (CH2), 35.4 (CH3×1/4),
36.4 (CH3×1/2), 61.2 (CH×1/2), 63.2 (CH×1/2), 65.5 (CH2×1/4),
67.5 (CH2×3/4), 71.9 (CH×1/4), 74.27 (CH2×1/2), 74.32
CDCl3) δ 1.40 (3H, s), 1.48 (3/2H, s), 1.49 (3/2H, s), 2.25 (1/2H,
brd, J = 2.4 Hz), 2.41 (1/2H, brd, J = 2.4 Hz), 3.79 (3H, s), 3.94
(1/2H, dd, J = 5.3, 8.6 Hz), 4.06-4.17 (3/2H, m), 4.23 (1/2H, dt, J
= 5.3, 6.7 Hz), 4.29 (1/2H, dt, J = 4.1, 6.7 Hz), 4.47 (1/2H, brdd,
J = 4.1, 7.0 Hz), 4.65 (1/2H, brt, J = 4.1 Hz), 6.87 (2H, d, J = 9.3
Hz), 7.17 (1H, d, J = 9.3 Hz), 7.18 (1H, d, J = 9.3 Hz); 13C NMR
(75 MHz, CDCl3) δ 25.1 (CH3×1/2), 25.20 (CH3×1/2), 26.3
(CH3×1/2), 26.8 (CH3×1/2), 41.36 (C×1/2), 41.45 (C×1/2), 55.7
(CH3), 62.3 (CH×1/2), 64.1 (CH×1/2), 65.4 (CH2×1/2), 66.3
(CH2×1/2), 78.3 (CH×1/2), 79.3 (CH×1/2), 89.1 (C×2), 110.1

12
Tetrahedron
ACCEPTED MANUSCRIPT
(C×1/2), 110.4 (C×1/2), 114.58 (CH×1/2), 114.60 (CH×1/2),
ρcalcd(Z = 2) = 1.302 g cm–3. A total 1799 unique data (2θmax
=
115.77 (CH×1/2), 115.79 (CH×1/2), 149.44 (C×1/2), 149.49
(C×1/2), 156.40 (C×1/2), 156.43 (C×1/2); FD-HRMS (m/z) calcd
for C15H18O5 [M]+: 278.1154, found: 278.1155.
55°) were measured at T = 153 K by Rigaku Mercury CCD
apparatus (Mo Kα radiation, λ = 0.71070 Å). Numerical
absorption correction was applied (µ = 0.97 cm–1). The structure
was solved by the direct method (SIR92) and refined by the full-
matrix least-squares method of F2 with anisotropic temperature
factors for non-hydrogen atoms. All the hydrogen atoms were
located at the calculated positions. The final wR value is 0.0916
(all data) for 1799 reflections and 182 parameters. CCDC 906654.
7.1.14.
(R,Z)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-(4-
methoxyphenoxy)prop-2-en-1-ol (25) and (S,Z)-1-((R)-2,2-
dimethyl-1,3-dioxolan-4-yl)-3-(4-methoxyphenoxy)prop-2-en-
1-ol (28). To a solution of 32 (12.25 g, 44.02 mmol) in PhH (300
mL) was added Lindlar catalyst (300 mg) at 27 ºC, and the
mixture was stirred for 22 h under H2 atmosphere. Then, the
mixture was filtered through a Celite pad, and the filtrate was
concentrated under reduced pressure. The residue was purified by
HPLC (eluent:* hexane/EtOAc = 1.33: *the eluent contained 5%
Et3N, flow rate: 20 mL/min) to give 25 (brown solid, 5.09 g,
18.16 mmol, 41% from 32, Rt = 12.8 min) as a less-polar
component and 28 (brown oil, 5.93 g, 21.15 mmol, 48% from 30,
Rt = 15.2 min) as a polar component.
7.1.16.
(2R,4aR,7R,8R,8aS)-2-(4-
Chlorophenyl)hexahydropyrano[3,2-d][1,3]dioxine-6,7,8-triol
(36). PTS·H2O (7.90 g, 41.5 mmol) in DMF (1.5 L) is stirred for
70 min at 80 °C in vacuo (200 mmHg) to remove H2O
azeotropically. Then, to the solution were added D-glucose (35)
(246.0 g, 1.365 mol) and p-chlorobenzaldehyde dimethylacetal
34 (127.3 g, 0.6821 mol), and the mixture was stirred at 60 °C for
6 h in vacuo (200 mmHg). After the reaction mixture was cooled
and returned to atmospheric pressure, the reaction was quenched
with Et3N, and concentrated under reduced pressure. Then, to the
residue was added H2O, and the mixture was extracted with
EtOAc several times. The combined organic layers were washed
with brine, dried over anhydrous MgSO4, filtered and
concentrated under reduced pressure. After the resulting residue
was recrystallized with CH2Cl2 several times, all volatiles were
removed in vacuo at 80 °C to give 36 (156.0 g, 0.5153 mol, 75%
from p-chlorobenzaldehyde dimethylacetal 34, α-anomer:β-
anomer = 3:2) as a colorless solid.
23
25: mp 48-49 ºC; [α]D –20.0 (c 1.39, CHCl3); IR (neat) ν 3465,
3046, 2986, 2936, 2904, 2836, 1667, 1505, 1466, 1443, 1381,
1371, 1227, 1216, 1182, 1157, 1103, 1065, 1009, 993, 853, 827
cm–1; H NMR (300 MHz, CDCl3) δ 1.39 (3H, s), 1.48 (3H, s),
1
2.55 (1H, s), 3.78 (3H, s), 3.87 (1H, dd, J = 6.0, 8.3 Hz), 4.03
(1H, dd, J = 6.2, 8.3 Hz), 4.11 (1H, q, J = 6.2 Hz), 4.70 (1H, brdt,
J = 3.1, 7.0 Hz), 4.76 (1H, dd, J = 6.0, 8.6 Hz), 6.44 (1H, dd, J =
0.8, 6.0 Hz), 6.85 (2H, d, J = 9.2 Hz), 6.94 (2H, d, J = 9.2 Hz);
13C NMR (75 MHz, CDCl3) δ 25.3 (CH3), 26.8 (CH3), 55.6
(CH3), 65.9 (CH2), 67.3 (CH), 79.2 (CH), 108.7 (CH), 109.8 (C),
114.7 (CH×2), 117.9 (CH×2), 144.6 (CH), 151.0 (C), 155.7 (C);
EI-HRMS (m/z) calcd for C15H20O5 [M]+: 280.1311, found:
280.1311.
24
36: mp 162-165 °C; [α]D +2.34 (c 0.820, CH3OH); IR (KBr), ν
3361, 2926, 2872, 1605, 1496, 1468, 1380, 1303, 1270, 1220,
1083, 1016, 819, 758, 730, 681, 659, 559, 532, 488, 449 cm–1; 1H
NMR (300 MHz, CD3OD) δ 3.23 (2/5H, t, J = 8.0 Hz), 3.37-3.49
(2H, m), 3.61 (2/5H, t, J = 8.5 Hz), 3.73 (1H, q, J = 9.9 Hz), 3.85
(3/5H, t, J = 9.0 Hz), 3.95 (3/5H, dt, J = 4.9, 9.9 Hz), 4.16 (3/5H,
dd, J = 4.9, 9.9 Hz), 4.25 (2/5H, dd, J = 4.3, 10.5 Hz), 4.58 (2/5H,
d, J = 7.7 Hz), 5.12 (3/5H, d, J = 3.9 Hz), 5.55 (1H, d, J = 3.2
Hz), 7.34 (2H, d, J = 8.5 Hz), 7.48 (2H, d, J = 8.5 Hz); 13C NMR
(75 MHz, CD3OD) δ 63.5 (CH×3/5), 67.7 (CH×2/5), 69.8
(CH2×2/5), 70.2 (CH2×3/5), 71.8 (CH×3/5), 74.4 (CH×3/5), 74.7
(CH×2/5), 77.2 (CH×2/5), 82.4 (CH×2/5), 83.1 (CH×3/5), 94.7
(CH×3/5), 99.0 (CH×2/5), 102.0 (CH×2/5), 102.1 (CH×3/5),
129.16 (CH×2), 129.20 (CH×2), 135.65 (C×3/5), 135.68 (C×2/5),
138.0 (C×2/5), 138.1 (C×3/5); EI-HRMS (m/z) calcd for
C13H15O635Cl [M]+: 302.0557, found: 302.0563.
24
28: [α]D +45.4 (c 0.595, CHCl3); IR (neat) ν 3453, 3046, 2986,
2936, 2907, 1667, 1504, 1466, 1456, 1443, 1381, 1371, 1294,
1229, 1182, 1157, 1125, 1104, 1065, 1011, 847, 827 cm–1; H
1
NMR (300 MHz, CDCl3) δ 1.38 (3H, s), 1.46 (3H, s), 2.24 (1H,
s), 3.78 (3H, s), 3.95 (1H, dd, J = 6.6, 8.3 Hz), 4.05 (1H, dd, J =
6.6, 8.3 Hz), 4.26 (1H, dt, J = 4.4, 6.6 Hz), 4.80 (1H, dd, J = 5.8,
8.1 Hz), 4.86 (1H, brdd, J = 4.4, 8.1 Hz), 6.45 (1H, d, J = 5.8
Hz), 6.85 (2H, d, J = 9.1 Hz), 6.93 (2H, d, J = 9.1 Hz); 13C NMR
(75 MHz, CDCl3) δ 25.1 (CH3), 26.3 (CH3), 55.5 (CH3), 65.3
(CH2), 65.7 (CH), 78.0 (CH), 108.8 (CH), 109.2 (C), 114.6
(CH×2), 117.7 (CH×2), 144.2 (CH), 150.9 (C), 155.6 (C); EI-
HRMS (m/z) calcd for C15H20O5 [M]+: 280.1311,
found:280.1310.
7.1.15.
(R)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-(4-
methoxyphenoxy)propan-1-ol (33). To a solution of 25 (29.6
mg, 0.106 mmol) in methanol (1.2 mL) was added 10% Pd/C
catalyst (3.0 mg) at 23 °C, and the mixture was stirred for 2 h
under H2 atmosphere. The mixture was filtered through a Celite
pad and concentrated under reduced pressure to give almost pure
33 (27.4 mg, 97 .0 ꢀmol, 92%) as a colorless solid.
7.1.17. (2R,4S,5R)-2-(4-Chlorophenyl)-4-vinyl-1,3-dioxan-5-ol
(38). To a solution of 36 (30.05 g, 99.26 mmol) in MeOH (500
mL) were added pH 7 phosphate buffer (250 mL) and NaIO4
(44.76 g, 209.3 mmol) at 21 ºC, and the mixture was stirred for
30 min. Then, the mixture was heated to 50 ºC and stirred for 1 h.
The mixture was cooled to 21 ºC, and the reaction was quenched
with 2.0 mol/L aq. NaOH. Then, the mixture was extracted with
EtOAc several times. The combined organic layers were dried
over anhydrous MgSO4, filtered, and concentrated under reduced
pressure to give crude 37, which was used immediately in the
next reaction.
To a solution of CH3PPh3Br (106.4 g, 297.7 mmol) in THF (300
mL) was added t-BuOK (33.36 g, 297.3 mmol) at 21 ºC, and the
mixture was stirred for 1 h. Then, the mixture was cooled to 0 ºC,
and a solution of the above crude 37 in THF (200 mL) was added
dropwise to the mixture. The mixture was wormed to 21 ºC and
stirred for 17 h. The reaction was quenched with saturated aq.
NH4Cl, and the mixture was extracted with EtOAc several times.
The combined organic layers were washed with brine, dried over
24
33: mp 97-99 °C; [α]D +17.8 (c 0.120, CHCl3); IR (KBr), ν
3461, 2926, 1512, 1473, 1374, 1231, 1160, 1132, 1055, 1033,
1
973, 929, 857, 823, 730 cm–1; H NMR (300 MHz, CDCl3), δ
1.38 (3H, s), 1.45 (3H, s), 1.89 (2H, q, J = 5.9 Hz), 2.40 (1H, brd,
J = 3.4 Hz), 3.77 (3H, s), 3.78-3.87 (2H, m), 4.02-4.17 (4H, m),
6.83 (4H, s); 13C NMR (75 MHz, CDCl3), δ 25.2 (CH3), 26.6
(CH3), 33.3 (CH2), 55.7 (CH3), 65.2 (CH2), 66.0 (CH2), 69.7
(CH), 78.9 (CH), 109.5 (C), 114.7 (CH×2), 115.5 (CH×2), 152.8
(C), 153.9 (C); EI-HRMS calcd for C15H22O5 [M]+: 282.1467,
found: 282.1475; Crystal Data: Crystals were obtained by
recrystallizing from Et2O/hexane. C15H22O5,
M = 282.34,
colorless platelet, 0.50 × 0.20 × 0.05 mm3, monoclinic P21 (No.
4), a = 8.741(3) Å, b = 5.523(2) Å, c = 15.366(5) Å, α =
90.000(1)°, β = 103.967(1)°, γ = 90.000(1)°, V = 719.9(4) Å3,

13
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography
(silica gel, hexane/EtOAc = 5 → 2.5) to give 38 (18.41 g, 76.49
mmol, 77% from 36) as a colorless solid.
s), 1.45 (3H, s), 3.38 (1H, dt, J = 5.1, 13.3 Hz), 3.69 (1H, t, J
ACCEPTED MANUSCRIPT
= 10.7 Hz), 3.76-3.84 (2H, m), 3.78 (3H, s), 4.07-4.15 (2H, m),
4.21 (2H, d, J = 6.7 Hz), 4.38 (1H, dt, J = 3.8, 6.7 Hz), 4.51 (1H,
dd, J = 5.1, 10.7 Hz), 4.80 (1H, dd, J = 6.2, 8.9 Hz), 5.32 (1H,
brddd, J = 1.0, 1.3, 10.7 Hz), 5.49 (1H, brtd, J = 1.3, 17.3 Hz),
5.49 (1H, s), 6.00-6.11 (2H, m), 6.51 (1H, dd, J = 0.8, 6.2 Hz),
6.84 (2H, d, J = 9.2 Hz), 6.94 (2H, d, J = 9.2 Hz), 7.33 (2H, d, J
= 8.5 Hz), 7.43 (2H, d, J = 8.5 Hz); 13C NMR (75 MHz, CDCl3) δ
24.9 (CH3), 26.0(CH3), 55.3 (CH3), 65.3 (CH2), 68.0 (CH2), 68.5
(CH), 69.0 (CH2), 74.2 (CH), 76.2 (CH), 77.2 (C), 80.8 (CH),
99.5 (CH), 103.4 (CH), 114.4 (CH×2), 117.8 (CH×2), 118.0
(CH2), 127.5 (CH×2), 128.1 (CH×2), 134.3 (C), 134.4 (CH),
136.0 (C), 145.9 (CH), 150.6 (C), 155.6 (C), 168.9 (C); EI-
HRMS (m/z) calcd for C29H33O935Cl [M]+: 560.1813, found:
560.1817.
23
38: mp 78-80 °C; [α]D –48.6 (c 0.975, CHCl3); IR (KBr), ν
3388, 3091, 3059, 2987, 2926, 2865, 1600, 1496, 1408, 1383,
1
1270, 1215, 1081, 1015, 981, 967, 930, 814, 730, 636 cm–1; H
NMR (300 MHz, CDCl3) δ 1.73 (1H, brd, J = 3.3 Hz), 3.58-3.70
(2H, m), 4.02 (1H, t, J = 8.0 Hz), 4.29-4.41 (1H, m), 5.38 (1H,
brdd, J = 1.1, 10.4 Hz), 5.49 (1H, dd, J = 1.1, 18.0 Hz), 5.52 (1H,
s), 5.97 (1H, ddd, J = 6.8, 10.4, 18.0 Hz), 7.34 (2H, d, J = 8.6
Hz), 7.45 (2H, d, J = 8.6 Hz); 13C NMR (75 MHz, CDCl3) δ 65.1
(CH), 70.7 (CH2), 83.4 (CH), 100.1 (CH), 119.4 (CH2), 127.6
(CH × 2), 128.4 (CH×2), 134.4 (CH), 134.8 (C), 136.1 (C); EI-
HRMS (m/z) calcd for C12H13O335Cl [M]+: 240.0553, found:
240.0551.
7.1.20. Methyl (2R,3R,E)-2-(((2R,4S,5R)-2-(4-chlorophenyl)-4-
vinyl-1,3-dioxan-5-yl)oxy)-5-((S)-2,2-dimethyl-1,3-dioxolan-4-
yl)-3-(4-methoxyphenoxy)pent-4-enoate (40). To a solution of
27 (41.05 g, 73.17 mmol) in THF (370 mL) was added TMSCl
(18.5 mL, 146 mmol) at –78 ºC, and the mixture was stirred for 5
min. Then, KHMDS (0.5 mol/L in PhCH3, 290 mL, 146 mmol)
was added dropwise, and the mixture was stirred for 40 min. To
the mixture was added diethyl malonate (22.0 mL, 146 mmol)
and the mixture was stirred for 15 min. Then, the mixture was
warmed to 0 ºC, and stirred for 4 h. The reaction was quenched
with 0.5 mol/L aq. HCl, and the mixture was extracted with
EtOAc several times. The combined organic layers were washed
with brine, dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure to give a crude product,
which was used in the next reaction without purification.
7.1.18. 2-(((2R,4S,5R)-2-(4-Chlorophenyl)-4-vinyl-1,3-dioxan-
5-yl)oxy)acetic acid (39). To a solution of 38 (315.6 mg, 1.311
mmol) in 1,4-dioxane (5 mL) was added NaH (60% in mineral
oil, 230.3 mg, 5.760 mmol) at 22 ºC, and heated to 60 ºC. After
being stirred for 30 min, bromoacetic acid (220.0 mg, 1.583
mmol) was added, and the mixture was stirred for 11 h. Then, the
mixture was cooled to 22 ºC, and the reaction was quenched with
H2O. To the mixture was added Et2O, and the mixture was
extracted with H2O several times. The combined aqueous layers
were acidified to pH 2 with 2.0 mol/L aq. HCl and extracted with
Et2O several times. The combined organic layers were dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure to give 39 (colorless solid, 378.9 mg, 1.268 mmol, 97%)
in an almost pure form.
24
39: [α]D –30.4 (c 0.850, CHCl3); IR (KBr) ν 3300-2400 (br),
To a solution of the above crude product in PhH-MeOH (185
mL:185 mL) was added TMSCHN2 (73.0 mL, 146 mmol) at 21
ºC, and the mixture was stirred for 12 h. Then, the mixture was
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, hexane/EtOAc = 5 → 2) to
give 40 (39.93 g, 69.44 mmol, 95% from 27, containing 15-epi-
40 [40:15-epi-40 = > 20:1]) as a colorless oil.
3044, 2985, 2963, 2927, 2861, 2763, 2668, 2571, 1737, 1709,
1600, 1495, 1420, 1388, 1380, 1360, 1300, 1292, 1270, 1252,
1213, 1142, 1121, 1094, 1080, 1042, 1017, 1003, 992, 983, 965,
938, 930, 885, 878, 817, 808, 692, 644 cm–1; 1H NMR (300 MHz,
CDCl3) δ 1.26 (1H, brs), 3.43 (1H, dt, J = 5.4, 9.6 Hz), 3.71 (1H,
t, J = 10.7 Hz), 4.15 (1H, brdd, J = 1.2, 8.8 Hz), 4.24 (1H, d, J =
2.7 Hz), 4.47 (1H, dd, J = 5.4, 10.7 Hz), 5.38 (1H, d, J = 10.7
Hz), 5.51 (1H, s), 5.52 (1H, d, J = 17.9 Hz), 6.03 (1H, ddd, J =
6.8, 10.7, 17.9 Hz), 7.33 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8.6
Hz); 13C NMR (75 MHz, CDCl3) δ 67.7 (CH2), 69.0 (CH2), 74.6
(CH), 81.3 (CH), 100.1 (CH), 119.1 (CH2), 127.6 (CH×2), 128.4
(CH×2), 134.4 (CH), 134.9 (C), 135.9 (C), 174.1 (C); EI-HRMS
(m/z) calcd for C14H15O535Cl [M]+: 298.0608, found: 298.0609.
23
40: [α]D –42.8 (c 1.75, CHCl3); IR (neat) ν 3043, 2987, 2952,
2934, 2905, 2869, 2836, 1750, 1603, 1505, 1463, 1439, 1416,
1381, 1371, 1279, 1226, 1180, 1147, 1109, 1090, 1061, 1038,
1
1016, 976, 937, 824 cm–1; H NMR (300 MHz, CDCl3) δ 1.37
(3H, s), 1.40 (3H, s), 3.40 (1H, ddd, J = 5.6, 9.3, 10.0 Hz), 3.53
(1H, t, J = 7.7 Hz), 3.67-3.75 (1H, m), 3.75 (3H, s), 3.77 (3H, s),
4.06 (1H, dd, J = 6.2, 8.1 Hz), 4.11-4.22 (1H, brdd, 5.6, 8.9 Hz),
4.32 (1H, d, J = 4.8 Hz), 4.38 (1H, dd, J = 5.0, 10.7 Hz), 4.52
(1H, q, J = 6.8 Hz), 4.81 (1H, t, J = 5.6 Hz), 5.25 (1H, brd, J =
10.6 Hz), 5.44-5.50 (1H, m), 5.49 (1H, s), 5.76 (1H, dd, J = 6.2,
15.6 Hz), 5.88 (1H, dd, J = 6.2, 15.6 Hz), 6.07 (1H, ddd, J = 5.6,
10.7, 17.1 Hz), 6.81 (4H, d, J = 2.1 Hz), 7.32 (2H, d, J = 8.4 Hz),
7.42 (2H, d, J = 8.4 Hz); 13C NMR (75 MHz, CDCl3) δ 25.8
(CH3), 26.6 (CH3), 52.4 (CH3), 55.7 (CH3), 69.3 (CH2), 69.4
(CH2), 74.7 (CH), 76.0 (CH), 79.5 (CH), 80.9 (CH), 81.3 (CH),
90.9 (CH), 109.5 (C), 114.6 (CH×2), 117.5 (CH×2), 118.4 (CH2),
127.6 (CH×2), 128.2 (CH), 128.4 (CH×2), 133.0 (CH), 134.5
(CH), 134.8 (C), 136.1 (C), 151.2 (C), 154.6 (C), 170.7 (C); EI-
HRMS (m/z) calcd for C30H35O935Cl [M]+: 574.1969, found:
574.1977.
7.1.19.
(S,Z)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-(4-
methoxyphenoxy)allyl2-(((2R,4S,5R)-2-(4-chlorophenyl)-4-
vinyl-1,3-dioxan-5-yl)oxy)acetate (27). To a solution of 39
(33.67 g, 112.7 mmol) in CH2Cl2 (600 mL) were added DMAP
(1.0670 g, 8.7337 mmol), EDCI·HCl (31.56 g, 165.1 mmol), and
a solution of 28 (23.14 g, 82.55 mmol) in CH2Cl2 (200 mL) at 22
ºC, and the mixture was stirred for 18 h. The reaction was
quenched with 0.2 mol/L aq. HCl, and the mixture was extracted
with EtOAc several times. The combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, eluent:* hexane/EtOAc = 10
→ 5: *the eluent contained 5% Et3N) to give 27 (43.41 g, 77.38
mmol, 94%) as a colorless oil.
7.1.21.
Methyl
(2R,3R,6S,E)-2-(((2R,4S,5R)-2-(4-
24
27: [α]D –0.229 (c 1.91, CHCl3); IR (neat) ν 3045, 2987, 2934,
chlorophenyl)-4-vinyl-1,3-dioxan-5-yl)oxy)-6,7-dihydroxy-3-
(4-methoxyphenoxy)hept-4-enoate (41). To a solution of 40
(21.68 g, 37.70 mmol) in MeCN (900 mL) was added 0.5 mol/L
aq. HCl (150 mL) at 0 ºC, and the mixture was stirred for 47 h.
2908, 2837, 1759, 1668, 1603, 1504, 1465, 1457, 1443, 1410,
1382, 1373, 1297, 1214, 1141, 1110, 1090, 1062, 1039, 1016,
977, 942, 827, 758 cm–1; 1H NMR (300 MHz, CDCl3) δ 1.37 (3H,

14
Tetrahedron
The reaction was quenched with saturated aq. NaHCO3, and the
136.0 (C), 151.1 (C), 154.3 (C), 170.7 (C); EI-HRMS (m/z) calcd
ACCEPTED MANUSCRIPT
mixture was extracted with EtOAc several times. The combined
organic layers were washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel,
hexane/EtOAc = 5 → 3 → 1 → EtOAc) to give 41 (18.57 g,
34.71 mmol, 92%, containing 15-epi-41 [41:15-epi-41 = > 20:1])
as a colorless oil.
for C26H29O835Cl [M]+: 504.1551, found: 504.1552.
7.1.23. Methyl (2R,3R)-2-(((2R,4S,5R)-2-(4-chlorophenyl)-4-
vinyl-1,3-dioxan-5-yl)oxy)-3-(4-methoxyphenoxy)hex-5-
enoate (26). To a solution of 42 (27.99 g, 55.43 mmol) in THF-
1-hexene (450 mL: 90 mL) were added PPh3 (29.09 g, 110.9
mmol) and IPNSBH (28.60 g, 111.2 mmol) at 17 ºC, and the
mixture was cooled to 0 ºC with stirring. Then, to the mixture
was added DIAD (22.0 mL, 112 mmol), and the mixture was
warmed to 17 ºC. After being stirred for 10 h, to the mixture were
added 2,2,2-trifluoroethanol (200 mL) and H2O (200 mL), and
the mixture was stirred for 19 h. The reaction was quenched with
0.5 mol/L aq. HCl, and the mixture was extracted with EtOAc
several times. The combined organic layers were washed with
brine, dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by column
chromatography (silica gel, hexane/EtOAc = 20 → 5) to give 26
(22.87 g, 46.77 mmol, 84%, containing 15-epi-26 [26:15-epi-26
= > 20:1]) as a colorless oil.
22
41: [α]D –49.3 (c 0.620, CHCl3); IR (neat) ν 3404, 3042, 3002,
2953, 2928, 2865, 2837, 1751, 1646, 1603, 1506, 1465, 1457,
1437, 1419, 1387, 1362, 1297, 1230, 1180, 1109, 939, 877, 823,
761, 733 cm–1; H NMR (300 MHz, CDCl3) δ 3.36-3.48 (2H, m),
1
3.61 (1H, dd, J = 3.6, 11.3 Hz), 3.68-3.75 (1H, m), 3.76 (3H, s),
3.78 (3H, s), 4.18 (1H, brdd, J = 6.0, 8.9 Hz), 4.27 (1H, brq, J =
5.2 Hz), 4.35-4.41 (2H, m), 4.83 (1H, t, J = 5.2 Hz), 5.26 (1H,
dd, J = 1.2, 10.6 Hz), 5.48 (1H, dd, J = 1.2, 17.3 Hz), 5.49 (1H,
s), 5.72 (1H, dd, J = 5.6, 15.9 Hz), 5.90 (1H, dd, J = 6.6, 15.9
Hz), 6.09 (1H, ddd, J = 5.6, 10.6, 17.3 Hz), 6.78-6.85 (4H, m),
7.32 (2H, d, J = 8.4 Hz), 7.42 (2H, d, J = 8.4 Hz); 13C NMR (75
MHz, CDCl3) δ 52.4 (CH3), 55.5 (CH3), 65.9 (CH2), 69.1 (CH2),
71.9 (CH), 74.8 (CH), 79.5 (CH), 80.6 (CH), 81.2 (CH), 99.7
(CH), 114.5 (CH×2), 117.3 (CH×2), 118.1 (CH2), 126.8 (CH),
127.6 (CH×2), 128.2 (CH×2), 133.8 (CH), 134.3 (CH), 134.6
(C), 136.0 (C), 151.0 (C), 154.4 (C), 170.8 (C); EI-HRMS (m/z)
calcd for C27H31O935Cl [M]+: 534.1656, found: 534.1657.
25
26: [α]D –21.7 (c 1.14, CHCl3); IR (neat) ν 3078, 3044, 2998,
2953, 2932, 2911, 2858, 2835, 1753, 1642, 1603, 1506, 1464,
1437, 1416, 1385, 1360, 1340, 1280, 1227, 1180, 1146, 1110,
1089, 1038, 1016, 989, 929, 825 cm–1; 1H NMR (300 MHz,
CDCl3) δ 2.40-2.61 (2H, m), 3.35 (1H, dt, J = 5.2, 10.0 Hz),
3.68-3.73 (1H, m), 3.75 (3H, s), 3.77 (3H, s), 4.16 (1H, brdd, J =
5.9, 9.2 Hz), 4.33 (1H, d, J = 4.1 Hz), 4.40 (1H, dd, J = 5.2, 11.2
Hz), 4.44-4.48 (1H, m), 5.10 (1H, d, J = 9.2 Hz), 5.19 (1H, d, J =
11.2 Hz), 5.43 (1H, d, J = 17.2 Hz), 5.49 (1H, s), 5.82 (1H, tdd, J
= 7.1, 10.0, 17.2 Hz), 6.01 (1H, ddd, J = 5.9, 10.5, 17.2 Hz),
6.80-6.89 (4H, m), 7.32 (2H, d, J = 8.4 Hz), 7.42 (2H, d, J = 8.4
Hz); 13C NMR (75 MHz, CDCl3) δ 34.2 (CH2), 52.2 (CH3), 55.5
(CH3), 69.3 (CH2), 74.5 (CH), 79.0 (CH), 79.5 (CH), 80.9 (CH),
99.7 (CH), 114.6 (CH×2), 117.2 (CH×2), 118.1 (CH2), 118.4
(CH2), 127.6 (CH×2), 128.2 (CH×2), 133.3 (CH), 134.3 (CH),
134.6 (C), 136.0 (C), 151.3 (C), 154.3 (C), 171.2 (C); EI-HRMS
(m/z) calcd for C26H29O735Cl [M]+: 488.1601, found: 488.1603.
7.1.22. Methyl (2R,3R,E)-2-(((2R,4S,5R)-2-(4-chlorophenyl)-4-
vinyl-1,3-dioxan-5-yl)oxy)-6-hydroxy-3-(4-methoxyphenoxy)
hex-4-enoate (42). To a solution of 41 (464.4 mg, 0.8681 mmol)
in THF (4.3 mL) were added pH 7 phosphate buffer (1.0 mL) and
NaIO4 (928.4 mg, 4.341 mmol) at 25 ºC, and the mixture was
stirred for 1.5 h. Then, the reaction was quenched with saturated
aq. NaHCO3 and the mixture was concentrated under reduced
pressure to remove organic solvent. The residual aqueous
mixture was extracted with EtOAc several times. The combined
organic layers were washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure to give
a crude product, which was used immediately in the next
reaction.
To a solution of the above crude product in MeOH (18 mL) were
added CeCl3·7H2O (970.7 mg, 2.603 mmol) and NaBH4 (98.5
mg, 2.60 mmol) at –78 ºC, and the mixture was stirred for 20
min. Then, the reaction was quenched with 0.2 mol/L aq. HCl,
and the mixture was extracted with EtOAc several times. The
combined organic layers were washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography
(silica gel, hexane/EtOAc = 2) to give 42 (400.3 mg, 0.7927
mmol, 91% from 41, containing 15-epi-42 [42:15-epi-42 = >
20:1]) as a colorless oil.
7.1.24. Methyl (2R,4aR,6R,7R,10aS,Z)-2-(4-chlorophenyl)-7-
(4-methoxyphenoxy)-4,4a,6,7,8,10a-
hexahydro[1,3]dioxino[5,4-b]oxocine-6-carboxylate (24). To a
solution of 26 (469.1 mg, 0.9594 mmol) in degassed CH2Cl2 (50
mL) was added a solution of the second generation Grubbs
catalyst (17) (46.8 mg, 0.0551 mmol) in degassed CH2Cl2 (2 mL)
at 23 ºC, and the mixture was stirred for 14 h. Then, the mixture
was stirred under O2 atmosphere for 2 h. The mixture was
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel + Florisil®, hexane/EtOAc =
10 → 5) to give 24 (colorless solid, 329.5 mg, 0.7149 mmol,
75%) as a single diastereomer. Under the reaction conditions, 15-
epi-26 was not reactive. Unreacted 15-epi-26 was easily
separable from 24 by column chromatography.
24
42: [α]D –54.4 (c 1.85, CHCl3); IR (neat) ν 3493, 3043, 2998,
2953, 2930, 2911, 2860, 2836, 1747, 1603, 1509, 1504, 1464,
1455, 1439, 1420, 1416, 1385, 1359, 1280, 1227, 1180, 1109,
25
24: mp 128-130 ºC; [α]D –125 (c 1.03, CHCl3); IR (KBr) ν
1090, 1038, 1016, 980, 941, 825, 733 cm–1; H NMR (300 MHz,
1
3017, 2951, 2931, 2868, 2846, 1752, 1509, 1463, 1436, 1381,
1344, 1319, 1292, 1280, 1265, 1251, 1244, 1218, 1196, 1178,
1162, 1119, 1102, 1085, 1055, 1036, 1024, 1010, 978, 837, 818,
CDCl3) δ 3.42 (1H, dt, J = 4.8, 9.8 Hz), 3.72 (1H, t, J = 10.5 Hz),
3.76 (3H, s), 3.78 (3H, s), 4.13-4.21 (3H, m), 4.34 (1H, d, J = 4.8
Hz), 4.39 (1H, dd, J = 4.8, 11.2 Hz), 4.84 (1H, t, J = 5.8 Hz),
5.26 (1H, dd, J = 1.1, 10.5 Hz), 5.47 (1H, d, J = 16.1 Hz), 5.49
(1H, s), 5.81 (1H, dd, J = 6.4, 16.1 Hz), 5.92 (1H, td, J = 4.4,
16.1 Hz), 6.09 (1H, ddd, J = 5.8, 10.5, 17.2 Hz), 6.78-6.85 (4H,
m), 7.32 (2H, d, J = 8.4 Hz), 7.42 (2H, d, J = 8.4 Hz); 13C NMR
(75 MHz, CDCl3) δ 52.3 (CH3), 55.5 (CH3), 62.2 (CH2), 69.2
(CH2), 74.6 (CH), 79.4 (CH), 80.6 (CH), 81.3 (CH), 99.7 (CH),
114.5 (CH×2), 117.2 (CH×2), 118.0 (CH2), 125.4 (CH), 127.5
(CH×2), 128.2 (CH×2), 134.3 (CH), 134.47 (CH), 134.53 (C),
767, 662 cm–1; H NMR (300 MHz, C6D6) δ 2.32-2.48 (2H, m),
1
3.28 (3H, s), 3.31 (3H, s), 3.39 (1H, t, J = 10.4 Hz), 3.52 (1H,
brdt, J = 5.0, 9.9 Hz), 4.14 (1H, brt, J = 7.2 Hz), 4.22 (1H, dd, J
= 5.0, 10.4 Hz), 4.26 (1H, d, J = 9.6 Hz), 4.91 (1H, td, J = 2.7,
9.6 Hz), 5.04 (1H, s), 5.69 (1H, brdq, J = 1.6, 9.0 Hz), 5.89 (1H,
dd, J = 5.0, 10.4 Hz), 6.73 (2H, d, J = 8.7 Hz), 6.95 (2H, d, J =
8.7 Hz), 7.17 (2H, d, J = 8.5 Hz), 7.35 (2H, d, J = 8.5 Hz); 13C
NMR (75 MHz, C6D6) δ 28.1 (CH2), 51.8 (CH3), 55.1 (CH3),

15
69.3 (CH2), 77.0 (CH), 79.5 (CH), 80.2 (CH), 80.4 (CH), 100.0
(CH), 115.1 (CH×2), 119.0 (CH×2), 126.4 (CH), 128.2 (CH×2),
128.5 (CH×2), 134.0 (CH), 134.9 (C), 136.8 (C), 151.7 (C),
155.5 (C), 170.6 (C); EI-HRMS (m/z) calcd for C24H25O735Cl
[M]+: 460.1288, found: 460.1289.
solution of 44 (172.7 mg, 0.5285 mmol) and pyridine (0.130
t
ACCEPTED MANUSCRIPT
mL, 1.62 mmol) in DMF (2.6 mL) was added Bu2Si(OTf)2
(0.260 mL, 0.803 mmol) at 0 ºC, and the mixture was stirred for
3 h at 19 ºC. Then the reaction was quenched with H2O, and the
mixture was extracted with Et2O several times. The combined
organic layers were washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel,
hexane/EtOAc = 20) to give 45 (222.2 mg, 0.4757 mmol, 90%)
as a colorless solid.
7.1.25. Methyl (2R,4aR,6R,7R,10aS,Z)-2-(4-chlorophenyl)-7-
hydroxy-4,4a,6,7,8,10a-hexahydro[1,3]dioxino[5,4-b]oxocine-
6-carboxylate (43). To a solution of 24 (15.43 g, 33.48 mmol) in
CH2Cl2-DMF (120 mL: 120 mL) was added a solution of CAN
(73.41 g, 134.1 mmol) in H2O (60 mL) dropwise at 0 ºC, and the
mixture was stirred for 16 h. Then, the mixture was diluted with
H2O, and extracted with Et2O several times. The combined
organic layers were washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel,
hexane/EtOAc = 3 → 1) to give 43 (11.02 g, 31.06 mmol, 93%)
as a colorless solid.
25
45: mp 118-120 ºC; [α]D –93.0 (c 0.560, CHCl3); IR (KBr) ν
3036, 2961, 2933, 2889, 2860, 1495, 1474, 1386, 1365, 1295,
1282, 1272, 1213, 1151, 1110, 1091, 1063, 1046, 1016, 987, 972,
951, 933, 902, 826, 795, 765, 653 cm–1; H NMR (400 MHz,
1
CDCl3) δ 0.96 (9H, s), 1.02 (9H,s), 2.40-2.51 (1H, m), 2.64-2.74
(1H, m), 3.48 (1H, ddd, J = 4.1, 8.4, 10.2 Hz), 3.55 (1H, brt, J =
10.2 Hz), 3.66 (1H, ddd, J = 4.4, 8.9, 10.7 Hz), 3.74 (1H, dd, J =
9.4, 10.7 Hz), 4.03 (1H, dd, J = 4.4, 9.4 Hz), 4.13 (1H, ddd, J =
2.8, 3.6, 8.9 Hz), 4.22 (1H, dd, J = 4.1, 9.9 Hz), 4.42 (1H, brdd, J
= 2.8, 8.4 Hz), 5.42 (1H, s), 5.82-5.95 (2H, m), 7.33 (2H, d, J =
8.5 Hz), 7.42 (2H, d, J = 8.5 Hz); 13C NMR (75 MHz, CDCl3) δ
20.1 (C), 22.5 (C), 27.1 (CH3×3), 27.4 (CH3×3), 32.7 (CH2), 67.0
(CH2), 69.3 (CH2), 74.7 (CH), 76.6 (CH), 77.7 (CH), 79.8 (CH),
99.9 (CH), 127.1 (CH), 127.6 (CH×2), 128.3 (CH×2), 133.1
(CH), 134.6 (C), 136.1 (C); APCI-HRMS (m/z) calcd for
C24H35O535Cl2Si [M + Cl]-: 501.1636, found: 501.1642.
43: mp 95-96 ºC; [α]D23 –64.4 (c 0.925, CHCl3); IR (KBr) ν 3492,
3034, 2953, 2930, 2902, 2857, 1744, 1603, 1495, 1461, 1440,
1384, 1350, 1293, 1274, 1240, 1203, 1176, 1128, 1110, 1065,
1
1016, 815, 751, 661 cm–1; H NMR (300 MHz, CDCl3) δ 2.40-
2.51 (1H, m), 2.63-2.74 (1H, m), 2.93 (1H, brs), 3.54 (1H, dt, J =
5.1, 9.6 Hz), 3.66 (1H, brt, J = 10.4 Hz), 3.80 (3H, s), 4.00 (1H,
d, J = 9.6 Hz), 4.15-4.23 (1H, m), 4.37 (1H, dd, J = 5.1, 10.4 Hz),
4.67 (1H, brdd, J = 2.7, 8.8 Hz), 5.46 (1H, s), 5.83-5.96 (2H, m),
7.34 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8.6 Hz); 13C NMR (75
MHz, CDCl3) δ 31.4 (CH2), 52.6 (CH3), 69.1 (CH2), 72.4 (CH),
76.5 (CH), 79.3 (CH), 80.5 (CH), 100.1 (CH), 126.8 (CH), 127.6
(CH×2), 128.4 (CH×2), 133.2 (CH), 134.9 (C), 135.9 (C), 173.4
(C); ESI-HRMS (m/z) calcd for C17H19O635ClNa [M + Na]+:
377.0762, found: 377.0765.
7.1.28.
(4aS,6R,7S,10aR,Z)-2,2-Di-tert-butyl-6-
(hydroxymethyl)-4,4a,6,7,10,10a-
hexahydro[1,3,2]dioxasilino[5,4-b]oxocin-7-ol (46). To
a
solution of 45 (222.2 mg, 0.4757 mmol) and 1,2-ethanedithiol
(0.164 mL, 1.95 mmol) in CH2Cl2 (5.0 mL) was added BF3·OEt2
(0.120 mL, 0.972 mmol) at –40 ºC, and the mixture was stirred
for 3 h. Then, the reaction was quenched with saturated aq.
NaHCO3, and the mixture was extracted with EtOAc several
times. The combined organic layers were washed with brine,
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by column
chromatography (silica gel, hexane/EtOAc = 3 → 1) to give 46
(158.8 mg, 0.4609 mmol, 97%) as a colorless oil.
7.1.26.
(2R,4aR,6S,7R,10aS,Z)-2-(4-Chlorophenyl)-6-
(hydroxymethyl)-4,4a,6,7,8,10a-hexahydro[1,3]dioxino[5,4-
b]oxocin-7-ol (44). To a solution of 43 (11.02 g, 31.06 mmol) in
MeOH (160 mL) was added NaBH4 (2.379 g, 62.88 mmol) at 0
ºC, and the mixture was stirred for 1 h at 22 ºC. Then, to the
mixture was added extra NaBH4 (1.182 g, 31.23 mmol) at 0 ºC,
and the mixture was stirred for 1 h at 22 ºC. The reaction was
quenched with NaHCO3 and the mixture was filtered through a
Celite pad. The filtrate was evaporated to remove organic
solvent, and the aqueous mixture was extracted with EtOAc
several times. The combined organic layers were washed with
brine, dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by column
chromatography (silica gel, hexane/EtOAc = 1) to give 44 (9.69
g, 29.6 mmol, 95%) as a colorless solid.
23
46: [α]D –56.0 (c 0.350, CHCl3); IR (neat) ν 3396, 3025, 2962,
2933, 2860, 1474, 1440, 1387, 1364, 1213, 1200, 1146, 1104,
1
1075, 1011, 1004, 990, 940, 826, 794, 767, 753, 652 cm–1; H
NMR (300 MHz, CDCl3) δ 0.96 (9H, s), 1.02 (9H, s), 2.06 (2H,
brs), 2.39 (1H, brddd, J = 2.4, 6.3, 13.4 Hz), 2.66 (1H, ddd, J =
3.9, 8.9, 13.4 Hz), 3.40 (1H, ddd, J = 3.9, 5.3, 8.9 Hz), 3.62 (1H,
ddd, J = 5.0, 9.1, 10.6 Hz), 3.69-3.81 (2H, m), 3.85 (1H, brdd, J
= 4.1, 11.6 Hz), 4.05 (1H, dd, J = 5.0, 9.9 Hz), 4.11 (1H, ddd, J =
2.4, 3.9, 9.1 Hz), 4.47 (1H, brdd, J = 3.9, 8.9 Hz), 5.74-5.89 (2H,
m); 13C NMR (75 MHz, CDCl3) δ 20.1 (C), 22.5 (C), 27.0
(CH3×3), 27.4 (CH3×3), 32.6 (CH2), 64.0 (CH2), 67.0 (CH2), 69.7
(CH), 76.8 (CH), 77.5 (CH), 83.9 (CH), 126.6 (CH), 136.7 (CH);
ESI-HRMS (m/z) calcd for C17H32O5SiNa [M + Na]+: 367.1911,
found: 367.1912.
44: mp 54-56 ºC; [α]D26 –96.2 (c 0.910, CHCl3); IR (KBr) ν 3396,
3033, 2928, 2859, 1603, 1495, 1462, 1442, 1417, 1403, 1383,
1351, 1293, 1276, 1217, 1114, 1091, 1069, 1042, 1015, 875, 816,
760, 735, 660, 617, 521 cm–1; 1H NMR (300 MHz, CDCl3) δ 2.14
(2H, brs), 2.32-2.42 (1H, m), 2.66-2.77 (1H, m), 3.46-3.56 (2H,
m), 3.63 (1H, t, J = 10.4 Hz), 3.70 (1H, dd, J = 5.5, 11.5 Hz),
3.78 (1H, dd, J = 5.5, 11.5 Hz), 4.00 (1H, brtd, J = 3.1, 9.2 Hz),
4.28 (1H, dd, J = 5.0, 10.4 Hz), 4.45 (1H, dd, J = 3.1, 8.8 Hz),
5.44 (1H, s), 5.81-5.94 (2H, m), 7.34 (2H, d, J = 8.6 Hz), 7.43
(2H, d, J = 8.6 Hz); 13C NMR (75 MHz, CDCl3) δ 32.7 (CH2),
64.0 (CH2), 69.4 (CH2), 72.6 (CH), 75.7 (CH), 79.7 (CH), 81.8
(CH), 99.9 (CH), 126.4 (CH), 127.6 (CH×2), 128.4 (CH×2),
133.4 (CH), 134.8 (C), 135.9 (C); ESI-HRMS (m/z) calcd for
C16H18O535Cl [M + H]+: 325.0848, found: 325.0856.
7.1.29.
(4aS,6R,7S,10aR,Z)-6-Allyl-2,2-di-tert-butyl-7-
((triethylsilyl)oxy)-4,4a,6,7,10,10a-
hexahydro[1,3,2]dioxasilino [5,4-b]oxocine (47). To a solution
of 46 (385.2 mg, 1.118 mmol) and 2,6-lutidine (0.660 mL, 5.70
mmol) in CH2Cl2 (10 mL) was added Tf2O (0.190 mL, 1.13
mmol) at –78 ºC, and the mixture was stirred for 15 min. Then, to
the mixture was added TESOTf (0.380 mL, 1.68 mmol) at –78
ºC. Then, the mixture was warmed to 0 ºC, and stirred for 45
min. The reaction was quenched with saturated aq. NaHCO3, and
the mixture was extracted with EtOAc several times. The
combined organic layers were washed with 0.5 mol/L aq. HCl
7.1.27.
(4aS,5aR,8R,9aS,12aR,Z)-2,2-Di-tert-butyl-8-(4-
chlorophenyl)-4a,5a,6,9a,12,12a-hexahydro-4H-
[1,3,2]dioxasilino[5,4-b][1,3]dioxino[4,5-g]oxocine (45). To a

16
Tetrahedron
and brine, dried over anhydrous MgSO4, filtered, and
mmol) in PhH (3.0 mL) were added 50% aq. NaOH (3.0 mL),
tert-butyl bromoacetate (0.510 mL, 3.77 mmol), and Bu4NHSO4
(13.0 mg, 0.0383 mmol), at 25 ºC, and the mixture was stirred for
2 h. Then, the mixture was diluted with H2O (20 mL) and PhH
(10 mL). To the mixture was added MeOH (40 mL) until the
solution became homogeneous, and the mixture was stirred for 4
h. After the mixture was evaporated to remove organic solvent,
the resulting aqueous mixture was diluted with Et2O and
extracted with H2O several times. The combined aqueous layers
were acidified to pH 4 with 2.0 mol/L aq. HCl and extracted with
CH2Cl2 several times. The combined organic layers were washed
with brine, dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, hexane/EtOAc = 3) to give
49 (150.4 mg, 0.3645 mmol, 97%) as a colorless oil.
A
CCEPTED MANUSCRIPT
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, hexane/EtOAc = 20 → 1 →
EtOAc) to give a trifluoromethanesulfonate ester, which was
used immediately in the next reaction.
To a solution of tetravinyltin (0.995 mL, 5.48 mmol) in THF (27
mL) was added BuLi (1.60 mol/L in hexane, 13.7 mL, 21.9
mmol) at –78 ºC, and the mixture was stirred for 1 h. To the
resulting vinyllithium solution was added a suspension of CuCN
(990.5 mg, 11.06 mmol) in THF (27 mL) dropwise at –78 ºC, and
the mixture was stirred for 45 min. Then, to the mixture was
added a solution of the above trifluoromethanesulfonate ester in
THF (10 mL) at –78 ºC. Then, the mixture was warmed to –20 ºC
and stirred for 18 h. The reaction quenched with a mixture of
saturated aq. NH4Cl and 25% aq. NH3 (v/v = 9/1), and the
mixture was extracted with EtOAc several times. The combined
organic layers were washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel,
hexane → hexane/EtOAc = 50) to give 47 (503.5 mg, 1.075
mmol, 98%) as a colorless oil.
21
49: [α]D -7.35 (c 0.785, CHCl3); IR (neat) ν 3500-2400 (br),
3076, 3022, 2962, 2933, 2860, 2773, 2738, 2710, 2667, 2573,
1764, 1732, 1643, 1474, 1439, 1435, 1393, 1387, 1364, 1307,
1296, 1248, 1213, 1200, 1101, 1074, 1056, 1011, 1000, 970, 938,
919, 825, 794, 755, 652, 634 cm–1; 1H NMR (300 MHz, CDCl3) δ
0.95 (9H, s), 1.01 (9H, s), 2.12-2.25 (1H, m), 2.40 (1H, brddd, J
= 2.5, 6.8, 13.4 Hz), 2.57-2.71 (2H, m), 3.42 (1H, dt, J = 2.8, 8.8
Hz), 3.55 (1H, ddd, J = 5.0, 9.1, 10.6 Hz), 3.74 (1H, t, J = 10.2
Hz), 3.97-4.05 (2H, m), 4.06 (1H, d, J = 16.8 Hz), 4.06-4.13 (1H,
m), 4.21 (1H, d, J = 16.8 Hz), 5.05 (1H, brd, J = 10.2 Hz), 5.08
21
47: [α]D –30.4 (c 1.20, CHCl3); IR (neat) ν 3077, 3027, 2959,
2933, 2876, 2860, 1642, 1474, 1439, 1414, 1386, 1364, 1307,
1241, 1200, 1147, 1102, 1058, 1006, 941, 844, 826, 794, 752,
727, 652, 632 cm–1; 1H NMR (300 MHz, CDCl3) δ 0.60 (6H, q, J
= 7.9 Hz), 0.94 (9H, s), 0.95 (9H, t, J = 7.9 Hz), 1.01 (9H, s),
1.91-2.04 (1H, m), 2.30-2.39 (1H, m), 2.55-2.72 (2H, m), 3.29
(1H, ddd, J = 2.5, 8.7, 10.0 Hz), 3.54 (1H, ddd, J = 5.0, 9.1, 10.6
Hz), 3.71 (1H, t, J = 10.6 Hz), 4.00 (1H, dd, J = 5.0, 10.0 Hz),
4.08 (1H, ddd, J = 2.5, 4.0, 9.1 Hz), 4.14 (1H, dd, J = 3.3, 8.7
Hz), 5.00-5.11 (2H, m), 5.67-5.87 (3H, m); 13C NMR (75 MHz,
CDCl3) δ 4.9 (CH2×3), 6.8 (CH3×3), 20.1 (C), 22.5 (C), 27.1
(CH3×3), 27.4 (CH3×3), 32.7 (CH2), 36.9 (CH2), 67.1 (CH2), 72.9
(CH), 76.9 (CH), 77.6 (CH), 85.6 (CH), 116.5 (CH2), 125.7
(CH), 135.5 (CH), 138.5 (CH); APCI-HRMS (m/z) calcd for
C25H49O4Si2 [M + H]+: 469.3164, found: 469.3167.
(1H, brd, J = 17.2 Hz), 5.69-5.89 (2H, m), 5.91-6.03 (1H, m); 13
C
NMR (75 MHz, CDCl3) δ 20.1 (C), 22.5 (C), 27.0 (CH3×3), 27.4
(CH3×3), 32.8 (CH2), 36.8 (CH2), 65.6 (CH2), 66.9 (CH2), 76.9
(CH), 77.4 (CH), 79.9 (CH), 83.6 (CH), 117.0 (CH2), 130.1
(CH), 134.0 (CH), 134.9 (CH), 175.2 (C); ESI-HRMS (m/z)
calcd for C21H36O6SiNa [M + Na]+: 435.2173, found: 435.2171.
7.1.32.
(R,Z)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-(4-
methoxyphenoxy)allyl 2-(((4aS,6R,7S,10aR,Z)-6-allyl-2,2-di-
tert-butyl-4,4a,6,7,10,10a-hexahydro[1,3,2]dioxasilino[5,4-
b]oxocin-7-yl)oxy)acetate (23). To a solution of 25 (3.46 g, 12.3
mmol), DMAP (1.0776 g, 8.8205 mmol), and EDCI·HCl (3.951
g, 20.61 mmol) in CH2Cl2 (70 mL) was added a solution of 49
(2.816 g, 6.825 mmol) at 27 ºC, and the mixture was stirred for
15 h. Then, the reaction was quenched with 0.5 mol/L aq. HCl,
and the mixture was extracted with EtOAc several times. The
combined organic layers were washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography
(silica gel, eluent:* hexane → hexane/EtOAc = 5; the eluent
contained 5% Et3N) to give 23 (4.213 g, 6.243 mmol, 92% from
49) as a colorless oil.
7.1.30.
(4aS,6R,7S,10aR,Z)-6-Allyl-2,2-di-tert-butyl-
4,4a,6,7,10,10a-hexahydro[1,3,2]dioxasilino[5,4-b]oxocin-7-ol
(48). To a solution of 47 (260.6 mg, 0.5559 mmol) in EtOH (7.0
mmol) was added PPTS (17.6 mg, 0.0700 mmol) at 25 ºC, and
the mixture was stirred for 3.5 h. The reaction was quenched with
Et3N, and the mixture was concentrated under reduced pressure.
The residue was purified by column chromatography (silica gel,
hexane/EtOAc = 50 → 40 → 20) to give 48 (184.2 mg, 0.5195
mmol, 93%) as a colorless oil.
22
48: [α]D –56.7 (c 1.33, CHCl3); IR (neat) ν 3455, 3077, 3023,
22
2961, 2933, 2860, 1642, 1473, 1439, 1393, 1387, 1364, 1306,
1250, 1212, 1199, 1147, 1104, 1072, 1056, 995, 939, 917, 825,
794, 768, 754, 652, 617 cm–1; 1H NMR (300 MHz, CDCl3) δ 0.95
(9H, s), 1.01 (9H, s), 1.79 (1H, brs), 2.11-2.23 (1H, m), 2.36 (1H,
ddd, J = 2.4, 6.6, 13.5 Hz), 2.53-2.63 (1H, m), 2.68 (1H, ddd, J =
4.0, 8.8, 13.5 Hz), 3.32 (1H, dt, J = 3.0, 8.9 Hz), 3.55 (1H, ddd, J
= 5.0, 9.1, 10.6 Hz), 3.74 (1H, t, J = 10.6 Hz), 4.01 (1H, dd, J =
1H, dd, J = 5.0, 10.0 Hz), 4.10 (1H, ddd, J = 2.4, 4.0, 9.1 Hz),
4.18-4.26 (1H, m), 5.06 (1H, brd, J = 10.0 Hz), 5.11 (1H, brd, J =
17.1 Hz), 5.71-5.93 (3H, m); 13C NMR (75 MHz, CDCl3) δ 20.2
(C), 22.5 (C), 27.1 (CH3×3), 27.4 (CH3×3), 32.8 (CH2), 37.0
(CH2), 67.1 (CH2), 72.2 (CH), 76.9 (CH), 77.5 (CH), 84.5 (CH),
117.1 (CH2), 127.0 (CH), 135.0 (CH), 136.8 (CH); APCI-HRMS
(m/z) calcd for C19H34O435ClSi [M + Cl]-: 389.1920, found :
389.1929.
23: [α]D +10.1 (c 1.85, CHCl3); IR (neat) ν 3075, 2961, 2933,
2860, 1762, 1740, 1669, 1506, 1473, 1442, 1394, 1382, 1371,
1365, 1231, 1214, 1103, 1072, 1044, 1011, 971, 938, 826, 795,
652 cm–1; H NMR (300 MHz, CDCl3) δ 0.94 (9H, s), 1.01 (9H,
1
s), 1.36 (3H, s), 1.45 (3H, s), 2.12-2.24 (1H, m), 2.36 (1H, ddd, J
= 2.7, 6.6, 13.4 Hz), 2.59-2.75 (2H, m), 3.39 (1H, dt, J = 2.7, 9.0
Hz), 3.54 (1H, ddd, J = 5.0, 9.3, 10.6 Hz), 3.73 (1H, t, J = 10.6
Hz), 3.78 (3H, s), 3.85 (1H, dd, J = 6.2, 8.7 Hz), 3.97-4.11 (5H,
m), 4.21 (1H, d, J = 16.3 Hz), 4.28 (1H, q, J = 6.6 Hz), 4.70 (1H,
dd, J = 6.2, 8.7 Hz), 5.02 (1H, brd, J = 10.2 Hz), 5.07 (1H, brd, J
= 17.2 Hz), 5.72-5.99 (4H, m), 6.45 (1H, dd, J = 0.9, 6.2 Hz),
6.84 (2H, d, J = 9.2 Hz), 6.95 (2H, d, J = 9.2 Hz); 13C NMR (75
MHz, CDCl3) δ 20.1 (C), 22.5 (C), 25.5 (CH3), 26.4 (CH3), 27.1
(CH3×3), 27.4 (CH3×3), 32.8 (CH2), 36.9 (CH2), 55.6 (CH3), 65.8
(CH2), 66.3 (CH2), 67.1 (CH2), 69.8 (CH), 76.8 (CH), 76.9 (CH),
77.5 (CH), 79.9 (CH), 83.9 (CH), 104.5 (CH), 110.1 (C), 114.7
(CH×2), 116.8 (CH2), 118.2 (CH×2), 129.7 (CH), 134.6 (CH),
135.3 (CH), 146.0 (CH), 150.9 (C), 155.9 (C), 169.2 C); ESI-
7.1.31.
2-(((4aS,6R,7S,10aR,Z)-6-Allyl-2,2-di-tert-butyl-
4,4a,6,7,10,10a-hexahydro[1,3,2]dioxasilino[5,4-b]oxocin-7-
yl)oxy) acetic acid (49). To a solution of 48 (133.6 mg, 0.3768

17
24
HRMS (m/z) calcd for C36H54O10SiNa [M + Na]+: 697.3379,
found: 697.3374.
51: [α]D –3.33 (c 0.535, CHCl3); IR (neat) ν 3440, 3075,
ACCEPTED MANUSCRIPT
3000, 2958, 2933, 2859, 1747, 1507, 1474, 1440, 1386, 1364,
1286, 1226, 1181, 1103, 1072, 1055, 1041, 1011, 977, 939, 921,
825, 795, 755, 653, 627 cm–1; 1H NMR (300 MHz, CDCl3) δ 0.93
(9H, s), 1.00 (9H, s), 2.00 (1H, brs), 2.06-2.18 (1H, m), 2.23 (1H,
brs), 2.34 (1H, brddd, J = 2.5, 6.5, 13.4 Hz), 2.61 (1H, ddd, J =
3.9, 9.2, 13.4 Hz), 2.72 (1H, brdd, J = 6.5, 13.7 Hz), 3.38-3.64
(4H, m), 3.72 (1H, t, J = 10.1 Hz), 3.756 (3H, s), 3.760 (3H, s),
4.00 (1H, dd, J = 5.0, 10.1 Hz), 4.04-4.15 (2H, m), 4.21-4.30
(1H, m), 4.24 (1H, d, J = 4.5 Hz), 4.89 (1H, dd, J = 4.5, 6.5 Hz),
5.04 (1H, brd, J = 10.2 Hz), 5.07 (1H, brd, J = 17.2 Hz), 5.70-
5.93 (5H, m), 6.76-6.86 (4H, m); 13C NMR (75 MHz, CDCl3) δ
20.1 (C), 22.5 (C), 27.0 (CH3×3), 27.4 (CH3×3), 32.6 (CH2), 36.9
(CH2), 52.3 (CH3), 55.6 (CH3), 66.0 (CH2), 67.0 (CH2), 72.1
(CH), 76.9 (CH), 77.4 (CH), 79.9 (CH), 80.3 (CH), 82.1 (CH),
83.8 (CH), 114.6 (CH×2), 117.0 (CH2), 117.4 (CH×2), 127.3
(CH), 129.3 (CH), 134.0 (CH), 134.2 (CH), 135.1 (CH), 151.0
(C), 154.5 (C), 170.9 (C); ESI-HRMS (m/z) calcd for
C34H52O10SiNa [M + Na]+: 671.3222, found: 671.3220.
7.1.33. Methyl (2S,3S,6S,E)-2-(((4aS,6R,7S,10aR,Z)-6-allyl-
2,2-di-tert-butyl-4,4a,6,7,10,10a-
hexahydro[1,3,2]dioxasilino[5,4-b]oxocin-7-yl)oxy)-5-((S)-2,2-
dimethyl-1,3-dioxolan-4-yl)-3-(4-methoxyphenoxy)pent-4-
enoate (50). To a solution of pyrrolidine (0.120 mL, 1.40 mmol)
in THF (3.0 mmol) were added KHMDS (0.5 mol/L in PhCH3,
2.80 mL, 1.40 mmol) and BuLi (1.65 mol/L in hexane, 0.848 mL,
1.40 mmol) dropwise at –78 ºC, and the mixture was stirred for
15 min. To the solution was added a solution of 23 (157.8 mg,
0.234 mmol) in PhCH3 (7.5 mL) at –78 ºC. Then, to the solution
was added TMSCl (0.354 mL, 2.80 mmol) immediately at –78
ºC, and the mixture was stirred for 15 min. To the mixture was
added diethyl malonate (0.425 mL, 2.80 mmol) at –78 ºC, and the
mixture was warmed to 0 ºC. After being stirred for 30 min, the
reaction was quenched with 0.2 mol/L aq. HCl, and the mixture
was extracted with CHCl3 several times. The combined organic
layers were washed with brine, dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure to give a crude
product.
7.1.35. Methyl (2S,3S,E)-2-(((4aS,6R,7S,10aR,Z)-6-allyl-2,2-
di-tert-butyl-4,4a,6,7,10,10a-hexahydro[1,3,2]dioxasilino[5,4-
b]oxocin-7-yl)oxy)-6-hydroxy-3-(4-methoxyphenoxy)hex-4-
enoate (52). To a solution of 51 (1.665 g, 2.567 mmol) in THF
(20 mL) were added pH 7 phosphate buffer (4.0 mL) and NaIO4
(1.113 g, 5.205 mmol) at 18 ºC, and the mixture was stirred for 1
h. Then, to the mixture was added extra NaIO4 (544.9 mg, 2.548
mmol) at 18 ºC, and the mixture was stirred for 1 h. Then, the
mixture was diluted with H2O and extracted with EtOAc several
times. The combined organic layers were washed with brine,
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure to give a crude product, which was used
immediately in the next reaction.
To a solution of the above crude product in THF-MeOH (12 mL:
12 mL) were added CeCl3·7H2O (4.7850 g, 12.843 mmol) and
NaBH4 (484.4 mg, 12.80 mmol) at –78 ºC, and the mixture was
stirred for 30 min. Then, the reaction was quenched with
saturated aq. NH4Cl, and the mixture was evaporated to remove
organic solvent. The resulting aqueous mixture was extracted
with EtOAc several times. The combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, hexane/EtOAc = 5 → 1) to
give 52 (1.463 g, 2.364 mmol, 92% from 52, containing 27-epi-
52 [52:27-epi-52 = > 20:1]) as a colorless oil.
To a solution of the above crude product in PhH-MeOH (1.0 mL:
1.0 mL) was added TMSCHN2 (2.0 mol/L in Et2O, 0.20 mL, 0.40
mmol) at 24 ºC, and the mixture was stirred for 10 min. Then, the
mixture was concentrated under reduced pressure. The residue
was purified by column chromatography (silica gel,
hexane/EtOAc = 10 → 5) to give 50 (142.9 mg, 0.207 mmol,
89% from 23, containing a trace of 27-epi-50 [50:27-epi-50 = >
20:1]) as a colorless oil.
24
50: [α]D +4.83 (c 0.470, CHCl3); IR (neat) ν 3075, 2961, 2934,
2861, 1751, 1643, 1506, 1472, 1465, 1457, 1437, 1380, 1371,
1226, 1180, 1148, 1103, 1071, 1011, 974, 942, 921, 825, 795,
1
767, 754 cm–1; H NMR (300 MHz, CDCl3) δ 0.93 (9H, s), 1.00
(9H, s), 1.36 (3H, s), 1.38 (3H, s), 2.04-2.17 (1H, m), 2.34 (1H,
brddd, J = 2.4, 6.5, 13.6 Hz), 2.61 (1H, ddd, J = 3.9, 9.7, 13.6
Hz), 2.71 (1H, brdd, J = 7.2, 15.1 Hz), 3.38-3.47 (1H, m), 3.48
(1H, t, J = 7.9 Hz), 3.47-3.57 (1H, m), 3.72 (1H, t, J = 10.4 Hz),
3.74 (3H, s), 3.75 (3H, s), 3.96-4.14 (4H, m), 4.20 (1H, d, J = 5.0
Hz), 4.51 (1H, q, J = 6.5 Hz), 4.87 (1H, t, J = 5.8 Hz), 5.04 (1H,
brd, J = 10.4 Hz), 5.07 (1H, brd, J = 17.2 Hz), 5.70-5.96 (5H, m),
6.76-6.85 (4H, m); 13C NMR (75 MHz, CDCl3) δ 20.1 (C), 22.5
(C), 25.8 (CH3), 26.6 (CH3), 27.0 (CH3×3), 27.4 (CH3×3), 32.6
(CH2), 37.0 (CH2), 52.2 (CH3), 55.6 (CH3), 67.0 (CH2), 69.3
(CH2), 75.9 (CH), 76.9 (CH), 77.5 (CH), 79.9 (CH), 80.3 (CH),
82.1 (CH), 83.8 (CH), 109.5 (C), 114.6 (CH×2), 117.0 (CH2),
117.4 (CH×2), 128.4 (CH), 129.2 (CH), 132.9 (CH), 134.3 (CH),
135.1 (CH), 151.2 (C), 154.5 (C), 170.8 (C); ESI-HRMS (m/z)
calcd for C37H56O10SiNa [M + Na]+: 711.3535, found: 711.3533.
23
52: [α]D –6.54 (c 1.75, CHCl3); IR (neat) ν 3483, 3075, 3007,
2959, 2934, 2892, 2860, 1748, 1507, 1473, 1440, 1387, 1364,
1285, 1227, 1181, 1146, 1104, 1055, 1040, 1011, 1001, 978, 941,
920, 826, 795, 756, 653, 629 cm–1; 1H NMR (300 MHz, CDCl3) δ
0.93 (9H, s), 1.00 (9H, s), 2.06-2.19 (1H, m), 2.34 (1H, ddd, J =
2.4, 6.6, 13.2 Hz), 2.61 (1H, ddd, J = 4.0, 9.4, 13.2 Hz), 2.73
(1H, brdd, J = 6.6, 14.7 Hz), 3.43 (1H, dt, J = 2.7, 9.5 Hz), 3.52
(1H, ddd, J = 5.0, 9.3, 10.5 Hz), 3.72 (1H, brt, J = 10.3 Hz), 3.75
(3H, s), 3.76 (3H, s), 4.00 (1H, dd, J = 5.0, 10.0 Hz), 4.04-4.18
(3H, m), 4.21 (1H, d, J = 4.9 Hz), 4.89 (1H, brt, J = 5.8 Hz), 5.04
(1H, brd, J = 10.2 Hz), 5.07 (1H, brd, J = 17.2 Hz), 5.73-5.98
(5H, m), 6.76-6.86 (4H, m); 13C NMR (75 MHz, CDCl3) δ 20.1
(C), 22.5 (C), 27.0 (CH3×3), 27.4 (CH3×3), 32.6 (CH2), 37.0
(CH2), 52.2 (CH3), 55.6 (CH3), 62.5 (CH2), 67.0 (CH2), 76.9
(CH), 77.4 (CH), 79.9 (CH), 80.4 (CH), 82.1 (CH), 83.8 (CH),
114.6 (CH×2), 116.9 (CH2), 117.4 (CH×2), 126.0 (CH), 129.2
(CH), 134.3 (CH), 134.7 (CH), 135.2 (CH), 151.1 (C), 154.5 (C),
170.9 (C); ESI-HRMS (m/z) calcd for C33H50O9SiNa [M + Na]+:
641.3116, found: 641.3113.
7.1.34. Methyl (2S,3S,6S,E)-2-(((4aS,6R,7S,10aR,Z)-6-allyl-
2,2-di-tert-butyl-4,4a,6,7,10,10a-
hexahydro[1,3,2]dioxasilino[5,4-b]oxocin-7-yl)oxy)-6,7-
dihydroxy-3-(4-methoxyphenoxy)hept-4-enoate (51). To
a
solution of 50 (68.1 mg, 0.0989 mmol) and 1,2-ethanedithiol
(0.042 mL, 0.50 mmol) in CH2Cl2 (5.0 mL) was added BF3·OEt2
(0.025 mL, 0.20 mmol) at –40 ºC, and the mixture was stirred for
4 h. Then, the reaction was quenched with saturated aq. NaHCO3,
and the mixture was extracted with CHCl3 several times. The
combined organic layers were washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography
(silica gel, hexane/EtOAc = 3 → 1 → 0.5) to give 51 (60.7 mg,
0.0935 mmol, 95%, containing 27-epi-51 [51:27-epi-51 = >
20:1]) as a colorless oil.

18
Tetrahedron
7.1.36. Methyl (2S,3S)-2-(((4aS,6R,7S,10aR,Z)-6-allyl-2,2-di-
= 8.808(3) Å, b = 9.111(3) Å, c = 19.458(6) Å, α = 83.231(6)°, β
= 89.474(9)°, γ = 89.004(10)°, V = 1550.4(8) Å3, ρcalcd(Z = 2) =
1.231 g cm–1. A total 6463 unique data (2θmax = 55°) were
measured at T = 150 K by Rigaku Mercury CCD apparatus (Mo
Kα radiation, λ = 0.71070 Å). Numerical absorption correction
was applied (µ = 1.23 cm–1). The structure was solved by the
direct method (SIR92) and refined by the full-matrix least-
squares method of F2 with anisotropic temperature factors for
non-hydrogen atoms. All the hydrogen atoms were located at the
calculated positions. The final wR value is 0.2161 (all data) for
6448 reflections and 718 parameters. CCDC 906653.
ACCEPTED MANUSCRIPT
tert-butyl-4,4a,6,7,10,10a-hexahydro-[1,3,2]dioxasilino[5,4-
b]oxocin-7-yl)oxy)-3-(4-methoxyphenoxy)hex-5-enoate
To a solution of 52 (1.357 g, 2.192 mmol), PPh3 (1.154 g, 4.400
mmol), and IPNBSH (1.129 g, 4.390 mmol) in THF-1-hexene
(20 mL: 4.0 mL) was added DIAD (0.860 mL, 4.38 mmol) at 0
ºC, and the mixture was stirred for 6 h at 18 ºC. Then, to the
mixture were added CF3CH2OH (6.0 mL) and H2O (6.0 mL) at
18 ºC, and the mixture was stirred for 22 h. The mixture was
diluted with brine and extracted with EtOAc several times. The
combined organic layers were washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography
(silica gel, hexane/EtOAc = 10) to give 22 (1.218 g, 2.021 mmol,
92%, containing 27-epi-22 [22:27-epi-22 = > 20:1]) as a colorless
oil.
(22)
7.1.38. Methyl (4aS,5aR,7Z,10S,11S,12aS,13Z,15aR)-2,2-di-
tert-butyl-10-hydroxy-4,4a,5a,6,9,10,11,12a,15,15a-
decahydro[1,3,2]dioxasilino[4',5':7,8]oxocino[3,2-b]oxonine-
11-carboxylate (55). To a solution of 54 (647.7 mg, 1.127
mmol) in MeCN-CH2Cl2 (10 mL: 5 mL) was added a solution of
CAN (3.102 g, 5.658 mmol) in H2O (10 mL) at 0 ºC, and the
mixture was stirred for 30 min. Then, the mixture was diluted
with H2O and extracted with EtOAc several times. The combined
organic layers were washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel,
hexane/EtOAc = 5 → 3) to give 55 (510.4 mg, 1.089 mmol,
97%) as a colorless oil.
25
22: [α]D –28.6 (c 0.310, CHCl3); IR (neat) ν 3075, 2933, 2859,
1753, 1642, 1507, 1474, 1439, 1227, 1103, 1073, 1055, 1042,
825 cm–1; H NMR (300 MHz, CDCl3) δ 0.93 (9H, s), 1.00 (9H,
1
s), 2.06-2.18 (1H, m), 2.26-2.35 (1H, m), 2.41-2.63 (3H, m), 2.74
(1H, brdd, J = 6.6, 13.9 Hz), 3.43 (1H, dt, J = 2.5, 9.3 Hz), 3.51
(1H, ddd, J = 5.0, 9.3, 10.6 Hz), 3.62-3.75 (1H, m), 3.73 (3H, s),
3.76 (3H, s), 3.96-4.09 (3H, m), 4.19 (1H, d, J = 4.1 Hz), 4.52
(1H, brtd, J = 4.4, 7.0 Hz), 5.02-5.18 (4H, m), 5.74-5.92 (4H, m),
6.77-6.91 (4H, m); 13C NMR (75 MHz, CDCl3) δ 20.1 (C), 22.5
(C), 27.0 (CH3×3), 27.4 (CH3×3), 32.6 (CH2), 34.2 (CH2), 36.9
(CH2), 52.0 (CH3), 55.6 (CH3), 67.0 (CH2), 77.0 (CH), 77.4 (CH),
78.2 (CH), 79.4 (CH), 81.9 (CH), 83.9 (CH), 114.7 (CH×2),
116.9 (CH2), 117.4 (CH×2), 118.0 (CH2), 129.0 (CH), 133.5
(CH), 134.2 (CH), 135.1 (CH), 151.3 (C), 154.4 (C), 171.3 (C);
ESI-HRMS (m/z) calcd for C33H50O8SiNa [M + Na]+: 625.3167,
found: 625.3174.
24
55: [α]D –144 (c 1.02, CHCl3); IR (neat) ν 3473, 3023, 2959,
2932, 2891, 2859, 1745, 1665, 1474, 1439, 1386, 1364, 1308,
1278, 1249, 1214, 1199, 1173, 1123, 1099, 1048, 1011, 1001,
942, 825, 795, 754, 652 cm–1; 1H NMR (300 MHz, CDCl3) δ 0.94
(9H, s), 1.02 (9H, s), 2.07-2.25 (2H, m), 2.32 (1H, ddd, J = 2.2,
6.7, 13.6 Hz), 2.57 (1H, ddd, J = 3.9, 9.9, 13.6 Hz), 2.74-2.94
(2H, m), 2.76 (1H, brs), 3.47 (1H, ddd, J = 5.0, 9.4, 10.4 Hz),
3.56-3.63 (2H, m), 3.69-3.85 (1H, m), 3.79 (3H, s), 3.89 (1H, brt,
J = 7.9 Hz), 4.02 (1H, dd, J = 5.1, 10.0 Hz), 4.04-4.14 (1H, m),
5.70-5.92 (3H, m), 5.96 (1H, dd, J = 6.1, 11.1 Hz); 13C NMR (75
MHz, CDCl3) δ 20.2 (C), 22.5 (C), 27.1 (CH3×3), 27.4 (CH3×3),
30.9 (CH2), 32.2 (CH2), 32.6 (CH2), 52.3 (CH3), 67.4 (CH2), 72.3
(CH), 77.6 (CH), 78.0 (CH), 84.3 (CH), 85.4 (CH), 85.7 (CH),
126.2 (CH), 127.3 (CH), 128.9 (CH), 135.6 (CH), 174.1 (C);
ESI-HRMS (m/z) calcd for C24H41O7Si [M + H]+: 469.2616,
found: 469.2612.
7.1.37. Methyl (4aS,5aR,7Z,10S,11S,12aS,13Z,15aR)-2,2-di-
tert-butyl-10-(4-methoxyphenoxy)-
4,4a,5a,6,9,10,11,12a,15,15a-
decahydro[1,3,2]dioxasilino[4',5':7,8]oxocino[3,2-b]oxonine-
11-carboxylate (54). To a solution of 22 (118.7 mg, 0.1969
mmol) degassed CH2Cl2 (37 mL) was added a solution of the first
generation Grubbs catalyst (53) (32.4 mg, 0.03938 mmol) in
degassed CH2Cl2 (3.0 mL) at 0 ºC, and the mixture was stirred
for 11 h. Then, the mixture was stirred under O2 atmosphere for 1
h. The mixture was concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel +
Florisil®, hexane/EtOAc = 20 → 10) to give 54 (colorless
platelets, 92.7 mg, 0.161 mmol, 82%) as a single diastereomer.
7.1.39. (4aS,5aR,7Z,10S,11S,12aS,13Z,15aR)-2,2-Di-tert-butyl-
11-(hydroxymethyl)-4,4a,5a,6,9,10,11,12a,15,15a-
decahydro[1,3,2]dioxasilino[4',5':7,8]oxocino[3,2-b]oxonin-
10-ol (21). To a solution of 55 (510.4 mg, 1.089 mmol) in MeOH
(10 mL) was added NaBH4 (609.2 mg, 16.10 mmol) at 0 ºC, and
the mixture was stirred for 30 min. Then, the reaction was
quenched with saturated aq. NH4Cl, and the mixture was
extracted with EtOAc several times. The combined organic layers
were washed with brine, dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, hexane/EtOAc =
2 → 1) to give 21 (459.2 mg, 1.042 mmol, 96%) as a colorless
oil.
25
54: mp 137-139 ºC; [α]D –88.5 (c 0.750, CHCl3); IR (KBr) ν
3014, 2961, 2932, 2872, 2858, 1742, 1509, 1475, 1466, 1439,
1294, 1253, 1235, 1200, 1181, 1134, 1122, 1109, 1092, 1068,
1047, 1017, 1001, 946, 934, 829, 796, 786, 753, 654 cm–1; H
1
NMR (400 MHz, C6D6) δ 1.08 (9H, s), 1.10 (9H, s), 2.06 (1H,
brd, J = 12.7 Hz), 2.27-2.38 (2H, m), 2.61 (1H, ddd, J = 4.1, 9.8,
13.8 Hz), 2.69 (1H, ddd, J = 3.8, 10.3, 14.1 Hz), 2.83 (1H, brt,
11.4 Hz), 3.25-3.36 (1H, m), 3.29 (3H, s), 3.32 (3H, s), 3.51 (1H,
ddd, J = 5.1, 9.1, 10.5 Hz), 3.82 (1H, t, J = 10.5 Hz), 3.99-4.17
(4H, m), 4.89 (1H, brtd, J = 3.3, 8.6 Hz), 5.74-5.99 (4H, m), 6.69
(2H, d, J = 9.2 Hz), 6.89 (2H, d, J = 9.2 Hz); 13C NMR (100
MHz, C6D6) δ 20.4 (C), 22.7 (C), 27.4 (CH3×3), 27.6 (CH3×3),
27.8 (CH2), 32.7 (CH2), 33.0 (CH2), 51.5 (CH3), 55.1 (CH3), 67.7
(CH2), 78.3 (CH), 78.4 (CH), 79.7 (CH), 84.3 (CH), 84.6 (CH),
85.3 (CH), 115.1 (CH×2), 118.5 (CH×2), 126.6 (CH), 127.7
(CH), 129.1 (CH), 136.5 (CH), 151.9 (C), 155.3 (C), 171.8 (C);
ESI-HRMS (m/z) calcd for C31H46O8SiNa [M + Na]+: 597.2854,
found: 597.2853; Crystal data: Crystals were obtained by
recrystallizing from Et2O/hexane. C31H46O8Si, M = 574.79,
colorless platelet, 0.70 × 0.20 × 0.01 mm3, triclinic P1 (No. 1), a
25
21: [α]D –100 (c 1.37, CHCl3); IR (neat) ν 3396, 3020, 2960,
2932, 2893, 2860, 1474, 1463, 1450, 1443, 1386, 1364, 1214,
1199, 1145, 1123, 1099, 1067, 1056, 1011, 941, 825, 795, 777,
1
755, 652 cm–1; H NMR (300 MHz, CDCl3) δ 0.94 (9H, s), 1.02
(9H, s), 2.08-2.22 (3H, m), 2.29-2.42 (2H, m), 2.62 (1H, ddd, J =
4.0, 8.2, 13.3 Hz), 2.72-2.90 (2H, m), 3.14 (1H, ddd, J = 3.7, 4.9,
8.6 Hz), 3.45 (1H, ddd, J = 5.1, 9.2, 10.5 Hz), 3.53 (1H, brtd, J =
3.7, 8.7 Hz), 3.64-3.82 (2H, m), 3.76 (1H, t, J = 10.5 Hz), 3.90
(1H, dd, J = 3.7, 8.7 Hz), 3.98-4.05 (2H, m), 4.09 (1H, ddd, J =
2.3, 4.0, 9.2 Hz), 5.71-5.90 (4H, m); 13C NMR (75 MHz, CDCl3)
δ 20.1 (C), 22.5 (C), 27.1 (CH3×3), 27.4 (CH3×3), 32.3 (CH2×2),

19
32.7 (CH2), 63.7 (CH2), 67.4 (CH2), 71.6 (CH), 77.7 (CH), 78.0
(CH), 84.0 (CH), 84.7 (CH), 86.8 (CH), 126.8 (CH), 127.6 (CH),
128.5 (CH), 136.7 (CH); ESI-HRMS (m/z) calcd for C23H41O6Si
[M + H]+: 441.2667, found: 441.2667.
brddd, J = 4.0, 10.0, 13.9 Hz), 2.97 (1H, brt, J = 9.5 Hz), 3.22
ACCEPTED MANUSCRIPT
(1H, brd, J = 8.8 Hz), 3.31 (1H, td, J = 5.0, 10.2 Hz), 3.52-3.70
(4H, m), 3.76 (1H, dd, J = 5.0, 11.7 Hz), 3.84-3.92 (2H, m), 3.96
(1H, brtd, J = 2.9, 8.8 Hz), 4.36 (1H, d, J = 11.5 Hz), 4.55 (1H, d,
J = 12.3 Hz), 4.67 (1H, d, J = 12.3 Hz), 4.73 (1H, d, J = 11.5
Hz), 5.60 (1H, brq, J = 10.5 Hz), 5.75-5.87 (2H, m), 5.92 (1H,
dd, J = 5.9, 10.9 Hz), 7.20 (1H, dd, J = 1.7, 8.6 Hz), 7.41-7.48
(5H, m), 7.52 (1H, s), 7.62-7.69 (2H, m), 7.70 (1H, s), 7.74-7.81
(4H, m); 13C NMR (100 MHz, CDCl3) δ 27.41 (CH2),27.43
(CH2), 32.5 (CH2), 64.5 (CH2), 69.1 (CH2), 71.7 (CH2), 73.3
(CH), 73.4 (CH2), 77.7 (CH), 83.0 (CH), 83.7 (CH), 85.0 (CH),
86.2 (CH), 124.5 (CH), 125.8 (CH), 125.85 (CH), 125.89 (CH),
126.0 (CH), 126.1 (CH), 126.2 (CH), 126.4 (CH), 127.0 (CH),
127.6 (CH), 127.7 (CH), 127.8 (CH×2), 127.9 (CH), 128.0 (CH),
128.1 (CH), 128.4 (CH), 132.9 (C), 133.0 (C), 133.2 (C×2),
135.6 (C), 135.7 (C), 138.1 (CH); FD-HRMS (m/z) calcd for
C37H40O6 [M]+: 580.2825, found: 580.2838.
7.1.40. (4aS,5aR,7Z,10S,11S,12aS,13Z,15aR)-2,2-Di-tert-butyl-
10-(naphthalen-2-ylmethoxy)-11-((naphthalen-2-
ylmethoxy)methyl)-4,4a,5a,6,9,10,11,12a,15,15a-decahydro-
[1,3,2]dioxasilino[4',5':7,8]oxocino[3,2-b]oxonine (56). To a
solution of 21 (388.1 mg, 0.8807 mmol) in THF-DMF (8.0 mL:
16 mL) were added KI (17.5 mg, 0.105 mmol), NAPBr (589.2
mg, 2.665 mmol), and NaH (60% in mineral oil, 297.9 mg, 7.448
mmol) at 0 ºC, and the mixture was stirred for 75 min. Then, the
reaction was quenched with saturated aq. NH4Cl, and the mixture
was extracted with EtOAc several times. The combined organic
layers were washed with brine, dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The residue
was purified by column chromatography (silica gel,
hexane/EtOAc = 50 → 20) to give 56 (459.5 mg, 0.6373 mmol,
72%) as a colorless oil.
7.1.42.
Triethyl(((2S,3R,5Z,6aS,8R,9S,11Z,13aR)-9-
(naphthalen-2-ylmethoxy)-8((naphthalen-2-
ylmethoxy)methyl)-2-(((triethylsilyl)oxy)methyl)-
21
56: [α]D –28.5 (c 1.12, CHCl3); IR (neat) ν 3059, 3020, 2971,
2932, 2861, 2806, 1953, 1914, 1853, 1743, 1633, 1605, 1512,
1473, 1445, 1390, 1365, 1351, 1308, 1295, 1274, 1249, 1214,
1196, 1168, 1097, 1014, 947, 902, 855, 821, 796, 750, 655 cm–1;
1H NMR (400 MHz, CDCl3) δ 0.95 (9H, s), 1.00 (9H, s), 2.08
(1H, brd, J = 13.0 Hz), 2.26 (1H, ddd, J = 2.1, 6.7, 13.5 Hz), 2.34
(1H, brtd, J = 3.1, 13.5 Hz), 2.56 (1H, ddd, J = 3.8, 10.5, 13.5
Hz), 2.70 (1H, ddd, J = 2.9, 10.0, 13.5 Hz), 2.93 (1H, brt, J =
10.5 Hz), 3.20 (1H, brd, J = 9.1 Hz), 3.45 (1H, dt, J = 5.6, 11.3
Hz), 3.53-3.64 (3H, m), 3.75 (1H, t, J = 11.3 Hz), 3.84 (1H, brt, J
= 7.3 Hz), 3.94-4.09 (3H, m), 4.36 (1H, d, J = 11.5 Hz), 4.55
(1H, d, J = 12.5 Hz), 4.68 (1H, d, J = 12.5 Hz), 4.72 (1H, d, J =
11.5 Hz), 5.61 (brq, J = 10.5 Hz), 5.71-5.84 (2H, m), 5.88 (1H,
dd, J = 5.9, 10.5 Hz), 7.20 (1H, dd, J = 1.8, 8.7 Hz), 7.40-7.48
(5H, m), 7.51 (1H, s), 7.62-7.68 (2H, m), 7.70 (1H, s), 7.73-7.81
(4H, m); 13C NMR (100 MHz, CDCl3) δ 20.2 (C), 22.5 (C), 27.1
(CH3×3), 27.4 (CH3×3), 32.25 (CH2), 32.27 (CH2), 32.6 (CH2),
67.4 (CH2), 69.1 (CH2), 71.6 (CH2), 73.4 (CH2), 77.7 (CH), 77.8
(CH), 77.9 (CH), 83.8 (CH), 84.7 (CH), 84.9 (CH), 125.6 (CH),
125.8 (CH), 125.85 (CH), 125.86 (CH), 126.0 (CH), 126.1 (CH),
126.2 (CH), 126.4 (CH), 126.9 (CH), 127.6 (CH), 127.7 (CH),
127.8 (CH×2), 128.0 (CH), 128.09 (CH), 128.12 (CH), 128.2
(CH), 132.9 (C), 133.0 (C), 133.2 (C×2), 135.6 (C), 135.8 (C),
137.4 (CH); FD-HRMS (m/z) calcd for C45H56O6Si [M]+:
720.3846, found: 720.3856.
3,4,6a,8,9,10,13,13a-octahydro-2H-oxocino[3,2-b]oxonin-3-
yl)oxy)silane (58). To a solution of 57 (19.6 mg, 0.0338 mmol)
and 2,6-lutidine (50.0 µL, 0.432 mmol) was added TESOTf (33.0
µL, 0.146 mmol) at 0 ºC, and the mixture was stirred for 35 min.
Then, the reaction was quenched with H2O, and the mixture was
extracted with EtOAc several times. The combined organic layers
were washed with brine, dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, hexane/EtOAc =
20) to give 58 (27.9 mg, 0.0344 mmol, 100%) as a colorless oil.
22
58: [α]D –62.7 (c 0.740, CHCl3); IR (neat) ν 3056, 3021, 2953,
2919, 2872, 2802, 2731, 1735, 1636, 1605, 1509, 1457, 1415,
1379, 1355, 1340, 1308, 1291, 1270, 1242, 1210, 1196, 1098,
1060, 1014, 983, 951, 933, 884, 855, 817, 774, 746, 687, 644,
627 cm–1; 1H NMR (500 MHz, CDCl3, measured at 50 ºC) δ 0.58
(6H, q, J = 8.0 Hz), 0.60 (6H, q, J = 8.0 Hz), 0.94 (9H, t, J = 8.0
Hz), 0.96 (9H, t, J = 8.0 Hz), 2.04 (1H, ddd, J = 3.3, 6.6, 13.3
Hz), 2.27-2.39 (2H, m), 2.55 (1H, ddd, J = 2.9, 10.4, 13.3 Hz),
2.72 (1H, ddd. J = 3.4, 10.9, 14.2 Hz), 2.89 (1H, brddd, J = 4.2,
10.9, 14.2 Hz), 3.26-3.31 (2H, m), 3.51 (1H, dd, J = 7.2, 10.3
Hz), 3.56-3.64 (3H, m), 3.77-3.81 (2H, m), 3.87 (1H, brt, J = 7.6
Hz), 3.92 (1H, brtd, J = 3.4, 8.7 Hz), 4.43 (1H, d, J = 11.7 Hz),
4.56 (1H, d, J = 12.3 Hz), 4.67 (1H, d, J = 12.3 Hz), 4.74 (1H, d,
J = 11.7 Hz), 5.54 (1H, ddd, J = 1.6, 6.6, 10.4 Hz), 5.75-5.89
(3H, m), 7.26 (1H, dd, J = 1.4, 8.3 Hz), 7.39-7.45 (5H, m), 7.58
(1H, s), 7.64-7.69 (2H, m), 7.71 (1H, s), 7.73-7.79 (4H, m); 13C
NMR (125 MHz, CDCl3, measured at 50 ºC) δ 4.7 (CH2×3), 5.1
(CH2×3), 6.8 (CH3×6), 27.7 (CH2), 32.1 (CH2), 33.1 (CH2), 65.0
(CH2), 70.1 (CH2), 71.8 (CH2), 72.8 (CH), 73.5 (CH2), 78.3 (CH),
84.3 (CH), 85.1 (CH), 85.6 (CH), 86.3 (CH), 125.3 (CH), 125.8
(CH×2), 126.0 (CH), 126.06 (CH), 126.09 (CH), 126.2 (CH),
126.5 (CH), 126.9 (CH), 127.7 (CH), 127.78 (CH), 127.82 (CH),
128.0 (CH×2), 128.08 (CH), 128.12 (CH), 129.0 (CH), 133.1
(C), 133.2 (C), 133.5 (C×2), 136.0 (C), 136.1 (C), 137.6 (CH);
FD-HRMS (m/z) calcd for C49H68O6Si2 [M]+: 808.4554, found:
808.4544.
7.1.41. (2S,3R,5Z,6aS,8R,9S,11Z,13aR)-2-(Hydroxymethyl)-9-
(naphthalen-2-ylmethoxy)-8-((naphthalen-2-
ylmethoxy)methyl)-3,4,6a,8,9,10,13,13a-octahydro-2H-
oxocino[3,2-b]oxonin-3-ol (57). To a solution of 56 (459.5 mg,
0.6373 mmol) in THF (6.0 mL) was added TBAF (1.0 mol/L in
THF, 1.95 mL, 1.95 mmol) at 23 ºC, and the mixture was stirred
for 10 h. Then, the reaction mixture was diluted with H2O, and
extracted with EtOAc several times. The combined organic layers
were washed with brine, dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, hexane/EtOAc =
1 → EtOAc) to give 57 (364.8 mg, 0.6282 mmol, 99%) as a
colorless solid.
7.1.43. Triethyl(((2S,3R,5Z,6aS,8R,9S,11Z,13aR)-2-ethynyl-9-
(naphthalen-2-ylmethoxy)-8-((naphthalen-2-
22
57: mp 115 ºC; [α]D –41.2 (c 0.930, CHCl3); IR (KBr) ν 3296,
3056, 3014, 2975, 2926, 2912, 2891, 2855, 1735, 1601, 1509,
1449, 1365, 1355, 1340, 1306, 1274, 1245, 1127, 1098, 1088,
1060, 1049, 1025, 986, 955, 895, 855, 821, 778, 753, 699, 651,
627, 606, 550, 518, 489, 475 cm–1; 1H NMR (400 MHz, CDCl3) δ
1.92 (1H, brs), 2.01 (1H, brs), 2.08-2.21 (2H, m), 2.36 (1H, brd, J
= 13.9 Hz), 2.57 (1H, ddd, J = 2.6, 10.5, 13.5 Hz), 2.71 (1H,
ylmethoxy)methyl)-3,4,6a,8,9,10,13,13a-octahydro-2H-
oxocino[3,2-b]oxonin-3-yl)oxy)silane (60). To a solution of
(COCl)2 (26.0 µL, 0.303 mmol) in CH2Cl2 (1.0 mL) was added
DMSO (35.0 µL, 0.493 mmol) at -78 ºC, and the mixture was
stirred for 10 min. Then, to the mixture was added a solution of
58 (39.2 mg, 0.0484 mmol) in CH2Cl2 (1.0 mL) at –78 ºC, and

20
Tetrahedron
ACCEPTED MANUSCRIPT
1
the mixture was stirred for 5 min. The mixture was warmed to –
40 ºC, and stirred for 30 min. Then, to the solution was added
Et3N (0.140 mL, 1.00 mmol) at –78 ºC, and the mixture was
warmed to 0 ºC. After being stirred for 30 min, the reaction was
quenched with saturated aq. NH4Cl, and the mixture was
extracted with EtOAc several times. The combined organic layers
were washed with 0.5 mol/L aq. HCl and brine, dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure to give a crude product, which was used immediately in
the next reaction.
To a solution of the above crude product in THF-MeOH (0.5 mL:
0.5 mL) were added Ohira-Bestmann reagent 59 (19.0 µL, 0.126
mmol) and K2CO3 (16.7 mg, 0.121 mmol) at 16 ºC, and the
mixture was stirred for 4 h. Then, the reaction was quenched with
saturated NH4Cl, and the mixture was extracted with EtOAc
several times. The combined organic layers were washed with
brine, dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by column
chromatography (silica gel, hexane/EtOAc = 20 → 10) to give 60
(21.2 mg, 0.0308 mmol, 64% from 57) as a colorless oil.
685, 667, 621 cm–1; H NMR (500 MHz, CDCl3, measured at 50
ºC) δ 0.62 (6H, q, J = 7.9 Hz), 0.96 (9H, t, J = 7.9 Hz), 1.40 (1H,
t, J = 6.3 Hz), 2.08 (1H, dd, J = 6.4, 12.7 Hz), 2.25 (1H, brd, J =
13.1 Hz), 2.34 (1H, brtd, J = 4.2, 14.0 Hz), 2.55 (1H, brt, J = 12.7
Hz), 2.70 (1H, ddd, J = 3.4, 10.2, 14.0 Hz), 2.93 (1H, brddd, J =
4.7, 9.7, 13.1 Hz), 3.26 (1H, brtd, J = 2.9, 9.0 Hz), 3.54-3.63 (3H,
m), 3.86 (1H, brt, J = 7.5 Hz), 3.91 (1H, brtd, J = 3.3, 9.0 Hz),
3.95 (2H, brs), 4.27 (2H, d, J = 6.3 Hz), 4.42 (1H, d, J = 11.7
Hz), 4.56 (1H, d, J = 12.3 Hz), 4.65 (1H, d, J = 12.3 Hz), 4.73
(1H, d, J = 11.7 Hz), 5.52 (1H, dddd, J = 1.9, 6.4, 8.7, 10.5 Hz),
5.77-5.84 (2H, m), 5.86 (1H, dd, J = 6.0, 11.7 Hz), 7.25 (1H, dd,
J = 1.7, 8.1 Hz), 7.39-7.45 (5H, m), 7.57 (1H, s), 7.65-7.70 (3H,
m), 7.73-7.79 (4H, m); 13C NMR (125 MHz, CDCl3, measured at
50 ºC) δ 5.1 (CH3×3), 6.8 (CH2×3), 27.6 (CH2), 32.4 (CH2), 33.1
(CH2), 51.5 (CH2), 70.0 (CH2), 71.8 (CH2), 73.5 (CH2), 74.6
(CH), 75.8 (CH), 78.3 (CH), 83.4 (C), 83.6 (CH), 85.2 (CH),
85.6 (CH), 86.3 (C), 124.8 (CH), 125.88 (CH), 125.91 (CH),
125.94 (CH), 126.09 (CH), 126.14 (CH), 126.2 (CH), 126.5
(CH), 126.9 (CH), 127.7 (CH), 127.8 (CH), 128.0 (CH×2), 128.1
(CH), 128.16 (CH), 128.22 (CH), 128.4 (CH), 133.1 (C), 133.2
(C), 133.4 (C×2), 135.9 (C), 136.1 (C), 137.7 (CH); FD-HRMS
(m/z) calcd for C45H54O6Si [M]+: 718.3690, found: 718.3695.
22
60: [α]D –59.5 (c 0.990, CHCl3); IR (neat) ν 3307, 3058, 3019,
2955, 2917, 2878, 1729, 1634, 1603, 1507, 1454, 1447, 1413,
1362, 1310, 1290, 1273, 1241, 1217, 1199, 1174, 1104, 1083,
1058, 1015, 977, 945, 900, 857, 815, 776, 751, 628 cm–1; H
7.1.45. (Z)-3-((2S,3R,5Z,6aS,8R,9S,11Z,13aR)-9-(Naphthalen-
2-ylmethoxy)-8-((naphthalen-2-ylmethoxy)methyl)-3-
1
NMR (500 MHz, CDCl3, measured at 50 ºC) δ 0.62 (6H, q, J =
8.0 Hz), 0.96 (9H, t, J = 8.0 Hz), 2.08 (1H, ddd, J = 2.7, 6.2, 13.3
Hz), 2.25 (1H, brd, J = 13.7 Hz), 2.34 (1H, brtd, J = 3.9, 13.8
Hz), 2.38 (1H, d, J = 2.2 Hz), 2.55 (1H, ddd, J = 3.1, 10.6, 13.3
Hz), 2.69 (1H, ddd, J = 3.2, 10.2, 13.8 Hz), 2.93 (1H, brddd, J =
4.4, 10.2, 13.7 Hz), 3.26 (1H, brtd, J = 2.7, 9.2 Hz), 3.54-3.64
(3H, m), 3.84-3.93 (3H, m), 3.97 (1H, td, J = 3.1, 9.2 Hz), 4.42
(1H, d, J = 11.3 Hz), 4.56 (1H, d, J = 12.2 Hz), 4.65 (1H, d, J =
12.2 Hz), 4.73 (1H, d, J = 11.3 Hz), 5.52 (1H, ddd, J = 1.4, 6.2,
10.6 Hz), 5.77-5.89 (3H, m), 7.25 (1H, d, J = 8.0 Hz), 7.39-7.45
(5H, m), 7.57 (1H, s), 7.64-7.71 (3H, m), 7.72-7.79 (4H, m); 13C
NMR (125 MHz, CDCl3, measured at 50 ºC) δ 5.1 (CH2×3), 6.84
(CH3×3), 27.6 (CH2), 32.4 (CH2), 33.0 (CH2), 70.0 (CH2), 71.8
(CH2), 73.3 (C), 73.5 (CH2), 74.6 (CH), 75.8 (CH), 78.3 (CH),
83.6 (CH), 84.3 (CH), 85.2 (CH), 85.8 (CH), 124.8 (CH), 125.87
(CH), 125.90 (CH), 125.94 (CH), 126.09 (CH), 126.14 (CH),
126.2 (CH), 126.5 (CH), 126.9 (CH), 127.7 (CH), 127.8 (CH),
128.0 (CH × 2), 128.1 (CH), 128.2 (CH), 128.27 (CH), 128.31
(CH), 133.1 (C), 133.2 (C), 133.4 (C×2), 135.9 (C), 136.1 (C),
137.7 (CH); FD-HRMS (m/z) calcd for C44H52O5Si [M]+:
688.3584, found: 688.3602.
((triethylsilyl)oxy)-3,4,6a,8,9,10,13,13a-octahydro-2H-
oxocino[3,2-b]oxonin-2-yl)prop-2-en-1-ol (62). To a solution of
61 (137.8 mg, 0.1917 mmol) in EtOH (10 mL) were added Au
nanoparticles (1% on TiO2, 214.1 mg) and Me2NH·BH3 (1.148 g,
19.48 mmol) at 19 ºC, and the mixture was stirred for 3 days. The
reaction mixture was filtered through a Celite pad, and the
mixture was diluted with H2O. Then, the mixture was evaporated
to remove organic solvent, and the residue was extracted with
EtOAc several times. The combined organic layers were washed
with brine, dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, hexane/EtOAc = 5 → 3) to
give 62 (128.1 mg, 0.1777 mmol, 93%) as a colorless oil.
23
62: [α]D –74.2 (c 0.690, CHCl3); IR (neat) ν 3454, 3056, 3020,
2953, 2918, 2875, 2802, 1727, 1635, 1604, 1511, 1458, 1416,
1373, 1353, 1307, 1292, 1271, 1243, 1219, 1173, 1127, 1102,
1060, 1017, 947, 898, 859, 817, 778, 750, 687, 669, 627 cm–1; 1H
NMR (500 MHz, CDCl3, measured at 50 ºC) δ 0.58 (6H, q, J =
8.0 Hz), 0.93 (9H, t, J = 8.0 Hz), 2.08-2.15 (2H, m), 2.34 (1H,
brtd, J = 3.4, 13.9 Hz), 2.61 (1H, ddd, J = 2.9, 10.5, 13.4 Hz),
2.70 (1H, brddd, J = 3.8, 10.0, 13.9 Hz), 2.90 (1H, ddd, J = 4.3,
10.1, 13.9 Hz), 3.28 (1H, brtd, J = 2.8, 8.9 Hz), 3.52-3.63 (3H,
m), 3.72 (1H, td, J = 2.9, 9.2 Hz), 3.88-3.94 (2H, m), 4.07-4.17
(3H, m), 4.44 (1H, d, J = 11.3 Hz), 4.57 (1H, d, J = 12.2 Hz),
4.66 (1H, d, J = 12.2 Hz), 4.74 (1H, d, J = 11.3 Hz), 5.49-5.58
(2H, m), 5.73-5.84 (3H, m), 5.90 (1H, dd, J = 5.9, 11.2 Hz), 7.27
(1H, dd, J = 1.6, 8.5 Hz), 7.40-7.45 (5H, m), 7.58 (1H, s), 7.65-
7.71 (3H, m), 7.73-7.80 (4H, m); 13C NMR (125 MHz, CDCl3,
measured at 50 ºC) δ 5.0 (CH2×3), 6.7 (CH3×3), 27.6 (CH2), 32.5
(CH2), 33.0 (CH2), 59.5 (CH2), 70.2 (CH2), 71.8 (CH2), 73.6
(CH2), 75.6 (CH), 78.4 (CH), 79.6 (CH), 83.9 (CH), 84.7 (CH),
65.1 (CH), 124.9 (CH), 125.9 (CH×2), 126.0 (CH), 126.09 (CH),
126.12 (CH), 126.2 (CH), 126.5 (CH), 126.9 (CH), 127.74 (CH),
127.78 (CH), 128.0 (CH×2), 128.1 (CH), 128.2 (CH), 128.3
(CH×2), 130.8 (CH), 132.9 (CH), 133.1 (C), 133.2 (C), 133.4
(C×2), 136.0 (C), 136.1 (C), 137.9 (CH); FD-HRMS (m/z) calcd
for C45H56O6Si [M]+: 720.3846, found: 720.3838.
7.1.44. 3-((2S,3R,5Z,6aS,8R,9S,11Z,13aR)-9-(Naphthalen-2-
ylmethoxy)-8-((naphthalen-2-ylmethoxy)methyl)-3-
((triethylsilyl)oxy)-3,4,6a,8,9,10,13,13a-octahydro-2H-
oxocino[3,2-b]oxonin-2-yl)prop-2-yn-1-ol (61). To a solution of
60 (21.2 mg, 0.0308 mmol) in THF (1.0 mL) was added MeLi
(1.17 mol/L in Et2O, 0.260 mL, 0.304 mmol) at –78 ºC, and the
mixture was stirred for 15 min. Then, to the solution was added a
suspension of (CH2O)n (22.2 mg) in THF (0.5 mL) at –78 ºC, and
the mixture was rapidly warmed to 19 ºC. After being stirred for
40 min, the reaction was quenched with saturated aq. NH4Cl, and
the mixture was extracted with EtOAc several times. The
combined organic layers were washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography
(silica gel, hexane/EtOAc = 5 → 3) to give 61 (20.9 mg, 0.0291
mmol, 94%) as a colorless oil.
23
61: [α]D –76.7 (c 0.660, CHCl3); IR (neat) ν 3443, 3056, 3020,
2953, 2915, 2875, 2805, 2732, 1949, 1914, 1731, 1635, 1604,
1509, 1456, 1414, 1379, 1354, 1308, 1287, 1273, 1241, 1217,
1199, 1171, 1107, 1051, 1015, 977, 949, 903, 857, 815, 776, 748,
7.1.46. (Z)-1-((2R,3R,4R,4aS,9aS)-4-((4-bromobenzyl)oxy)-3-
(naphthalen-2-ylmethoxy)-3,4,4a,6,9,9a-hexahydro-2H-
pyrano[3,2-b]oxepin-2-yl)-3-hydroxy-5-

21
((2S,3R,5Z,6aS,8R,9S,11Z,13aR)-3-hydroxy-9-(naphthalen-2-
ylmethoxy)-8-((naphthalen-2-ylmethoxy)methyl)-
(C), 136.2 (C), 136.4 (C), 136.6 (CH), 138.0 (CH), 138.5 (C),
ACCEPTED MANUSCRIPT
207.4 (C); FD-HRMS (m/z) calcd for C68H6979BrO11 [M]+:
1140.4023, found: 1140.4029.
3,4,6a,8,9,10,13,13a-octahydro-2H-oxocino[3,2-b]oxonin-2-
yl)pent-4-en-2-one (4). To a solution of (COCl)2 (46.5 µL, 0.542
mmol) in CH2Cl2 (2 mL) was added DMSO (64.1 µL, 0.903
mmol) at –78 ºC, and the mixture was stirred for 15 min. Then, to
the mixture was added a solution of 62 (130.2 mg, 0.1806 mmol)
in CH2Cl2 (2 mL) at –78 ºC, and the mixture was stirred for 15
min. Then, to the mixture was added Et3N (0.252 mL, 1.81
mmol) at –78 ºC, and the mixture was stirred for 30 min at 0 ºC.
The reaction was quenched with saturated aq. NH4Cl, and the
mixture was extracted with EtOAc several times. The combined
organic layers were washed with 0.5 mol/L aq. HCl and brine,
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure to give a crude 6, which was used immediately
in the next reaction.
7.1.47.
(2S,5aS,6aR,8Z,11S,12R,13aS,14Z,16aR)-2-
(((2R,3R,4R,4aS,9aS)-4-((4-Bromobenzyl)oxy)-3-
(naphthalene-2-ylmethoxy)-3,4,4a,6,9,9a-hexahydro-2H-
pyrano[3,2-b]oxepin-2-yl)methyl)-11-(naphthalen-2-
ylmethoxy)-12-((naphthalen-2-ylmethoxy)methyl)-
3,5a,6a,7,10,11,12,13a,16,16a-decahydro-3H-
oxepino[2',3':7,8]oxocino[3,2-b]oxonin-3-ol
(2R,5aS,6aR,8Z,11S,12R,13aS,14Z,16aR)-2-
(64)
and
(((2R,3R,4R,4aS,9aS)-4-((4-Bromobenzyl)oxy)-3-(naphthalen-
2-ylmethoxy)-3,4,4a,6,9,9a-hexahydro-2H-pyrano[3,2-
b]oxepin-2-yl)methyl)-11-(naphthalen-2-ylmethoxy)-12-
((naphthalene-2-ylmethoxy)methyl)-
To a solution of 5 (356.2 mg, 0.5418 mmol) in THF (2 mL) was
added NHMDS (1.10 mol/L in THF, 0.490 mL, 0.539 mmol) at -
78 ºC, and the mixture was stirred for 20 min. Then, to the
solution was added a solution of the above crude 6 in THF (2
mL) at –78 ºC, and the mixture was stirred for 30 min. The
reaction was quenched with saturated aq. NaHCO3, and the
mixture was extracted with EtOAc several times. The combined
organic layers were washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel,
hexane/EtOAc = 2 → 1) to give 63 (brown oil, diastereomer
mixture), which was used immediately in the next reaction.
To a solution of the above 63 in CF3CH2OH-H2O (3.0 mL: 0.3
mL) was added PTS·H2O (20.5 mg, 0.107 mmol) at 19 ºC, and
the suspension was stirred for 1 h. Then, the reaction was
quenched with saturated aq. NaHCO3, and the mixture was
extracted with EtOAc several times. The combined organic layers
were washed with brine, dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, hexane/EtOAc =
2 → 1 → 0.5) to give 4 (81.0 mg, 0.0709 mmol, 40% from 62) as
a colorless oil.
3,5a,6a,7,10,11,12,13a,16,16a-decahydro-3H-
oxepino[2',3':7,8]oxocino[3,2-b]oxonin-3-ol (11-epi-64). To a
solution of 4 (11.4 mg, 9.98 µmmol) in CH2Cl2-Et3SiH (0.4 mL:
0.2 mL) was added TMSOTf (4.0 µL, 0.022 mmol) at 0 ºC, and
the mixture was stirred for 15 min. Then, the reaction was
quenched with saturated aq. NaHCO3, and the mixture was
extracted with EtOAc several times. The combined organic layers
were washed with brine, dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, hexane/EtOAc =
3 → 2) to give a 1:1 diastereomer mixture of 64 and 11-epi-64
(7.2 mg, 64%). The mixture of 64 and 11-epi-64 was separated
by HPLC (hexane/EtOAc = 2) to give 64 (colorless oil) as a less-
polar component and 11-epi-64 (colorless solid) as a polar
component.
23
64: [α]D –30 (c 0.41, CHCl3); IR (neat) ν 3464, 3056, 3024,
2956, 2922, 2854, 1727, 1632, 1601, 1512, 1484, 1467, 1449,
1361, 1308, 1290, 1266, 1209, 1171, 1093, 1012, 987, 962, 896,
1
853, 815, 779, 755, 741, 702, 667 cm–1; H NMR (400 MHz,
CDCl3, measured at 50 ºC) δ 1.80 (1H, td, J = 6.4, 14.1 Hz),
2.07-2.19 (2H, m), 2.22 (1H, ddd, J = 2.1, 6.4, 13.1 Hz), 2.27-
2.39 (3H, m), 2.55-2.65 (2H, m), 2.66-2.74 (1H, m), 2.89-2.99
(1H, m), 3.21 (1H, dt, J = 4.1, 9.7 Hz), 3.26 (1H, brtd, J = 2.6,
9.0 Hz), 3.36 (1H, t, J = 8.8 Hz), 3.38 (1H, t, J = 8.8 Hz), 3.40-
3.46 (1H, m), 3.52-3.66 (5H, m), 3.71-3.78 (2H, m), 3.88 (1H,
brt, J = 6.6 Hz), 3.93 (1H, brtd, J = 3.2, 8.8 Hz), 3.98 (1H, brdd,
J = 2.3, 15.4 Hz), 4.15 (1H, brd, J = 8.1 Hz), 4.25 (1H, dd, J =
5.9, 15.4 Hz), 4.43 (1H, d, J = 11.7 Hz), 4.56 (1H, d, J = 12.4
Hz), 4.66 (1H, d, J = 12.4 Hz), 4.726 (1H, d, J = 11.5 Hz), 4.732
(1H, d, J = 11.7 Hz), 4.83 (1H, d, J = 11.3 Hz), 4.88 (1H, d, J =
11.3 Hz), 4.97 (1H, d, J = 11.5 Hz), 5.61 (1H, brq, J = 9.4 Hz),
5.72-5.91 (7H, m), 7.19 (2H, d, J = 8.3 Hz), 7.25 (1H, dd, J =
1.6, 8.3 Hz), 7.36-7.47 (10H, m), 7.57 (1H, s), 7.64-7.82 (11H,
m); 13C NMR (100 MHz, CDCl3, measured at 50 ºC) δ 27.5
(CH2), 32.58 (CH2), 32.64 (CH2), 34.6 (CH2), 35.4 (CH2), 67.9
(CH2), 69.4 (CH), 69.8 (CH2), 71.6 (CH2), 73.4 (CH2), 74.6
(CH2), 75.1 (CH2), 75.6 (CH), 75.9 (CH), 78.1 (CH), 80.2 (CH),
81.5 (CH), 81.8 (CH), 83.7 (CH), 85.0 (CH), 85.1 (CH), 85.3
(CH), 85.7 (CH), 88.2 (CH), 121.3 (C), 125.1 (CH), 125.71
(CH), 125.74 (CH), 125.78 (CH), 125.83 (CH×2), 125.9 (CH),
126.00 (CH), 126.02 (CH), 126.04 (CH), 126.3 (CH), 126.5
(CH), 126.7 (CH), 127.0 (CH), 127.58 (CH), 127.63 (CH×2),
127.79 (CH), 127.80 (CH), 127.89 (CH), 127.94 (CH), 128.0
(CH), 128.06 (CH), 128.14 (CH), 128.2 (CH), 129.4 (CH×2),
131.3 (CH×2), 131.4 (CH), 132.97 (C), 133.04 (C), 133.28 (C),
133.34 (C), 135.8 (C), 135.85 (C), 135.94 (C), 137.6 (CH), 138.3
(C), 139.5 (CH); FD-HRMS (m/z) calcd for C68H6979BrO10 [M]+:
1124.4074, found: 1124.4068.
23
4: [α]D +7.5 (c 1.11, CHCl3); IR (neat) ν 3438, 3052, 3021,
2920, 2889, 2862, 2727, 1953, 1915, 1719, 1655, 1634, 1605,
1511, 1488, 1447, 1396, 1362, 1271, 1244, 1092, 893, 859, 818,
774, 750, 737, 703 cm–1; 1H NMR (400 MHz, C6D6, measured at
50 ºC) δ 2.13 (1H, ddd, J = 2.5, 6.5, 13.3 Hz), 2.20-2.34 (3H, m),
2.35-2.43 (1H, m), 2.61-2.78 (3H, m), 2.88 (1H, dd, J = 3.2, 14.8
Hz), 3.05-3.13 (2H, m), 3.30 (1H, t, J = 9.1 Hz), 3.35 (1H, t, J =
9.1 Hz), 3.46-3.54 (2H, m), 3.58 (1H, t, J = 9.1 Hz), 3.63-3.71
(3H, m), 3.77 (1H, brtd, J = 2.9, 8.6 Hz), 3.85-3.98 (3H, m), 4.14
(1H, brddd, J = 1.6, 5.6, 8.6 Hz), 4.30 (1H, t, J = 8.7 Hz), 4.39
(1H, d, J = 11.9 Hz), 4.45 (1H, d, J = 12.3 Hz), 4.52 (1H, d, J =
12.3 Hz), 4.59 (1H, d, J = 11.9 Hz), 4.62 (1H, d, J = 11.9 Hz),
4.70 (1H, d, J = 11.9 Hz), 4.81 (1H, d, J = 11.9 Hz), 4.89 (1H,
dd, J = 1.0, 8.6 Hz), 4.97 (1H, d, J = 11.9 Hz), 5.39 (1H, ddd, J =
0.8, 8.6, 11.1 Hz), 5.43-5.56 (2H, m), 5.63 (1H, brddd, J = 1.0,
8.7, 11.1 Hz), 5.89-6.07 (2H, m), 6.10 (1H, dd, J = 5.6, 11.2 Hz),
7.02 (2H, d, J = 8.1 Hz), 7.22-7.40 (10H, m), 7.57-7.70 (13H, m);
13C NMR (100 MHz, C6D6) δ 27.3 (CH2), 32.0 (CH2), 32.7
(CH2), 34.3 (CH2), 40.9 (CH2), 67.4 (CH2), 71.1 (CH2), 71.3
(CH2), 73.1 (CH2), 74.2 (CH2), 74.59 (CH), 74.61 (CH2), 75.0
(CH), 75.4 (CH), 75.8 (CH), 78.7 (CH), 79.8 (CH), 81.0 (CH),
83.3 (CH), 84.9 (CH), 85.1 (CH), 85.6 (CH), 88.0 (CH), 121.1
(C), 125.0 (CH), 125.58 (CH×2), 125.64 (CH), 125.72 (CH),
125.74 (CH), 125.8 (CH), 125.9 (CH×2), 126.1 (CH), 126.2
(CH), 126.3 (CH), 126.4 (CH), 126.6 (CH), 127.4 (CH), 127.65
(CH×2), 127.67 (CH), 127.76 (CH), 127.79 (CH×2), 127.9 (CH),
128.08 (CH), 128.14 (CH×2), 128.5 (CH), 129.2 (CH×2), 131.2
(CH×2), 131.3 (CH), 133.2 (C×2), 133.5 (C×2), 133.6 (C), 135.9
23
11-epi-64: mp 143-144 ºC; [α]D –36 (c 0.39, CHCl3); IR (neat)
ν 3393, 3056, 3027, 2922, 2900, 2875, 1727, 1601, 1510, 1489,

22
Tetrahedron
1450, 1394, 1359, 1348, 1309, 1274, 1260, 1218, 1172, 1126,
5.87 (5H, m), 5.94 (1H, dd, J = 5.8, 10.8 Hz), 6.42 (1H, dd, J =
2.3, 12.8 Hz), 7.19 (2H, d, J = 8.3 Hz), 7.25 (1H, dd, J = 1.6, 8.3
Hz), 7.35-7.47 (10H, m), 7.57 (1H, s), 7.64-7.82 (11H, m); 13C
NMR (100 MHz, CDCl3, measured at 50 ºC) δ 27.6 (CH2), 31.6
(CH2), 32.5 (CH2), 34.4 (CH2), 36.1 (CH2), 68.1 (CH2), 70.0
(CH2), 71.8 (CH2), 73.6 (CH2), 74.3 (CH), 74.6 (CH2), 75.1
(CH2), 76.1 (CH), 78.2 (CH), 80.8 (CH), 81.8 (CH), 83.1 (CH),
83.5 (CH), 83.7 (CH), 85.2 (CH), 85.3 (CH), 85.9 (CH), 88.3
(CH), 121.3 (C), 125.2 (CH), 125.85 (CH), 125.86 (CH), 125.89
(CH), 125.92 (CH), 126.0 (CH), 126.06 (CH), 126.10 (CH),
126.14 (CH), 126.2 (CH), 126.4 (CH), 126.6 (CH), 126.8 (CH),
127.0 (CH×2), 127.7 (CH), 127.8 (CH×2), 127.86 (CH), 127.90
(CH×2), 128.0 (CH), 128.1 (CH), 128.15 (CH), 128.18 (CH),
128.5 (CH), 129.5 (CH×2), 131.2 (CH), 131.4 (CH×2), 133.1
(C), 133.2 (C), 133.4 (C×2), 133.5 (C), 135.8 (C), 135.9 (C),
136.0 (C), 138.3 (CH), 138.4 (C), 146.1 (CH), 203.7 (C); FD-
HRMS (m/z) calcd for C68H6779BrO10 [M]+: 1122.3918, found:
1122.3933.
ACCEPTED MANUSCRIPT
1109, 1091, 1031, 1013, 996, 950, 932, 907, 890, 858, 816, 770,
753 cm–1; 1H NMR (400 MHz, CDCl3, measured at 50 ºC) δ 1.53
(1H, m), 2.08-2.22 (3H, m), 2.27-2.38 (2H, m), 2.52 (1H, ddd, J
= 3.6, 10.7, 13.8 Hz), 2.60 (1H, ddd, J = 4.1, 8.2, 16.4 Hz), 2.70
(1H, brtt, J = 3.6, 9.7 Hz), 2.94 (1H, brdd, J = 4.0, 9.7, 13.6 Hz),
3.20-3.29 (2H, m), 3.26 (1H, t, J = 9.5 Hz), 3.37 (1H, t, J = 8.8
Hz), 3.47 (1H, dt, J = 1.5, 9.9 Hz), 3.54-3.61 (3H, m), 3.63 (1H,
t, J = 8.8 Hz), 3.76-3.87 (2H, m), 3.90-4.02 (3H, m), 4.20-4.29
(2H, m), 4.43 (1H, d, J = 11.7 Hz), 4.55 (1H, d, J = 12.4 Hz),
4.66 (1H, d, J = 12.4 Hz), 4.74 (1H, d, J = 11.7 Hz), 4.75 (1H, d,
J = 11.8 Hz), 4.78 (1H, d, J = 11.3 Hz), 4.90 (1H, d, J = 11.8
Hz), 5.00 (1H, d, J = 11.3 Hz), 5.52-5.60 (2H, m), 5.72-5.91 (6H,
m), 7.22 (2H, d, J = 8.3 Hz), 7.26 (1H, dd, J = 1.7, 8.3 Hz), 7.35-
7.47 (10H, m), 7.57 (1H, s), 7.64-7.81 (11H, m); 13C NMR (100
MHz, CDCl3, measured at 50 ºC) δ 27.5 (CH2), 32.4 (CH2), 32.6
(CH2), 34.5 (CH2), 35.1 (CH2), 67.8 (CH2), 69.8 (CH2), 71.7
(CH2), 71.9 (CH), 73.4 (CH2), 74.7 (CH2), 75.2 (CH2), 75.3 (CH),
75.6 (CH), 75.8 (CH), 76.2 (CH), 78.1 (CH), 79.5 (CH), 81.8
(CH), 83.6 (CH), 85.0 (CH), 85.2 (CH), 85.8 (CH), 88.1 (CH),
131.3 (C), 124.9 (CH), 125.7(CH), 125.76 (CH), 125.77 (CH),
125.92 (CH×2), 125.94 (CH), 125.99 (CH), 126.02 (CH), 126.1
(CH), 126.3 (CH), 126.6 (CH), 126.7 (CH), 127.0 (CH), 127.58
(CH), 127.63 (CH), 127.7 (CH), 127.8 (CH×2), 127.9 (CH),
128.0 (CH), 128.05 (CH), 128.12 (CH), 128.14 (CH), 128.2
(CH), 129.3 (CH), 129.4 (CH×2), 131.37 (CH×2), 131.44 (CH),
132.98 (C), 133.04 (C), 133.1 (C), 133.28 (C×2), 133.33 (C),
135.5 (CH), 135.75 (C), 135.76 (C), 135.9 (C), 137.8 (CH),
138.2 (C); FD-HRMS (m/z) calcd for C68H6979BrO10 [M]+:
1124.4074, found: 1124.4096.
7.1.49.
(2R,5aS,6aR,8Z,11S,12R,13aS,14Z,16aR)-2-
(((2R,3R,4R,4aS,9aS)-4-((4-Bromobenzyl)oxy)-3-(naphthalen-
2-ylmethoxy)-3,4,4a,6,9,9a-hexahydro-2H-pyrano[3,2-
b]oxepin-2-yl)methyl)-11-(naphthalen-2-ylmethoxy)-12-
((naphthalen-2-ylmethoxy)methyl)-
3,5a,6a,7,10,11,12,13a,16,16a-decahydro-3H-
oxepino[2',3':7,8]oxocino[3,2-b]oxonin-3-one (11-epi-65). To a
solution of (COCl)2 (14.0 µL, 0.150 mmol) in CH2Cl2 (0.5 mL)
was added DMSO (19.0 µL, 0.267 mmol) at –78 ºC, and the
mixture was stirred for 10 min. Then, to the mixture was added a
solution of 11-epi-64 (10.0 mg, 8.88 µmol) in CH2Cl2 (0.5 mL) at
–78 ºC, and the mixture was stirred for 10 min. Then, to the
solution was added Et3N (70.0 µL, 0.502 mmol) at –78 ºC, and
the mixture was stirred for 30 min at 0 ºC. The reaction was
quenched with saturated aq. NH4Cl, and the mixture was
extracted with EtOAc several times. The combined organic layers
were washed with 0.5 mol/L aq. HCl and brine, dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography
(silica gel, hexane/EtOAc = 5 → 3) to give 11-epi-65 (7.4 mg,
6.6 µmol, 74%) as a colorless oil.
7.1.48.
(2S,5aS,6aR,8Z,11S,12R,13aS,14Z,16aR)-2-
(((2R,3R,4R,4aS,9aS)-4-((4-Bromobenzyl)oxy)-3-(naphthalen-
2-ylmethoxy)-3,4,4a,6,9,9a-hexahydro-2H-pyrano[3,2-
b]oxepin-2-yl)methyl)-11-(naphthalen-2-ylmethoxy)-12-
((naphthalen-2-ylmethoxy)methyl)-
3,5a,6a,7,10,11,12,13a,16,16a-decahydro-3H-
oxepino[2',3':7,8]oxocino[3,2-b]oxonin-3-one (65). To
solution of (COCl)2 (14.0 µL, 0.150 mmol) in CH2Cl2 (0.5 mL)
was added DMSO (18.0 µL, 0.253 mmol) at –78 ºC, and the
mixture was stirred for 15 min. Then, to the mixture was added a
solution of 64 (10.3 mg, 9.15 µmol) in CH2Cl2 (1.0 mL) at –78
ºC, and the mixture was stirred for 10 min. Then, to the solution
was added Et3N (70.0 µL, 0.502 mmol) at –78 ºC, and the
mixture was stirred for 30 min at 0 ºC. The reaction was
quenched with saturated aq. NH4Cl, and the mixture was
extracted with EtOAc several times. The combined organic layers
were washed with 0.5 mol/L aq. HCl and brine, dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography
(silica gel, hexane/EtOAc = 5 → 3) to give 65 (8.1 mg, 7.2 µmol,
79%) as a colorless oil.
a
23
11-epi-67: [α]D –34 (c 0.37, CHCl3); IR (neat) ν 3059, 3026,
2916, 2899, 2849, 1727, 1666, 1600, 1512, 1490, 1445, 1358,
1281, 1099, 901, 857, 819, 758, 736, 703 cm-1; H NMR (400
1
MHz, CDCl3, measured at 50 ºC) δ 2.00 (1H, ddd, J = 2.6, 10.5,
15.0 Hz), 2.34 (5H, m), 2.47 (1H, ddd, J = 4.1, 10.5, 14.2 Hz),
2.59 (1H, ddd, J = 3.8, 7.5, 16.1 Hz), 2.69 (1H, ddd, J = 3.4,
10.5, 13.8 Hz), 2.97 (1H, ddd, J = 4.1, 11.6, 14.2 Hz), 3.23 (2H,
m), 3.29 (1H, t, J = 9.2 Hz), 3.39 (1H, t, J = 9.0 Hz), 3.53 (3H,
m), 3.63 (2H, m), 3.64 (1H, t, J = 8.6 Hz), 3.79 (1H, ddd, J = 1.6,
6.1, 8.6 Hz), 3.93 (1H, td, J = 3.0, 8.6 Hz), 4.01 (1H, ddd, J =
2.6, 5.1, 15.0 Hz), 4.16 (1H, t, J = 2.6, 9.0 Hz), 4.25 (1H, dd, J =
6.1, 15.7 Hz), 4.37 (1H, dd, J = 2.5, 11.4 Hz), 4.43 (1H, d, J =
11.7 Hz), 4.54 (1H, d, J = 12.4 Hz), 4.64 (1H, d, J = 12.4 Hz),
4.735 (1H, d, J = 11.4 Hz), 4.740 (1H, d, J = 11.7 Hz), 4.75 (1H,
d, J = 11.7 Hz), 4.91 (1H, d, J = 11.4 Hz), 5.01 (1H, d, J = 11.4
Hz), 5.57 (1H, m), 5.82 (6H, m), 6.53 (1H, dd, J = 2.6, 12.4 Hz),
7.21 (2H, d, J = 8.6 Hz), 7.29 (1H, ddd, J = 1.3, 8.0, 16.0 Hz),
7.41 (9H, m), 7.59 (1H, s), 7.71 (12H, m); 13C NMR (100 MHz,
CDCl3, measured at 50 ºC) δ 27.6 (CH2), 31.7 (CH2), 32.5 (CH2),
33.2 (CH2), 34.6 (CH2), 68.0 (CH2), 69.9 (CH2), 71.8 (CH2), 73.5
(CH2), 74.6 (CH), 74.7 (CH2), 75.4 (CH2), 75.8 (CH), 78.2 (CH),
79.3 (CH), 80.4 (CH), 80.5 (CH), 82.2 (CH), 83.5 (CH), 85.2
(CH), 85.4 (CH), 86.1 (CH), 88.3 (CH), 121.4 (C), 124.9 (CH),
125.8 (CH), 125.86 (CH × 2), 125.91 (CH), 126.0 (CH), 126.08
(CH), 126.10 (CH), 126.2 (CH), 126.39 (CH), 126.43 (CH),
126.9 (CH), 127.0 (CH), 127.3 (CH), 127.7 (CH), 127.75 (CH),
26
65: [α]D –16 (c 0.41, CHCl3); IR (neat) ν 3056, 3024, 2960,
2918, 2847, 2724, 1953, 1914, 1727, 1667, 1632, 1604, 1512,
1488, 1460, 1403, 1389, 1358, 1333, 1277, 1160, 1096, 1012,
1
959, 896, 857, 811 cm–1; H NMR (400 MHz, CDCl3, measured
at 50 ºC) δ 1.89 (1H, ddd, J = 4.6, 8.7, 13.7 Hz), 2.14-2.39 (5H,
m), 2.54 (1H, ddd, J = 4.2, 7.5, 16.2 Hz), 2.62 (1H, brddd, J =
3.7, 10.4, 14.1 Hz), 2.70 (1H, brddd, J = 3.3, 10.4, 13.3 Hz), 2.98
(1H, brddd, J = 4.2, 10.4, 14.1 Hz), 3.15 (1H, dt, J = 4.2, 9.9 Hz),
3.23-3.33 (3H, m), 3.51 (1H, dt, J = 3.1, 9.1 Hz), 3.54-3.68 (6H,
m), 3.88-3.99 (3H, m), 4.06 (1H, brtd, J = 2.3, 9.2 Hz), 4.19-4.31
(2H, m), 4.43 (1H, d, J = 11.6 Hz), 4.57 (1H, d, J = 12.5 Hz),
4.67 (1H, d, J = 12.5 Hz), 4.73 (1H, d, J = 11.6 Hz), 4.74 (1H, d,
J = 11.6 Hz), 4.77 (1H, d, J = 11.3 Hz), 4.87 (1H, d, J = 11.6
Hz), 4.95 (1H, d, J = 11.3 Hz), 5.65 (1H, brq, J = 9.5 Hz), 5.69-

23
127.77 (CH), 127.8 (CH), 127.85 (CH), 127.91 (CH × 2), 128.1
(C); FD-HRMS (m/z) calcd for C35H4379BrO10 [M]+: 702.2040,
found: 702.2042.
ACCEPTED MANUSCRIPT
(CH), 128.15 (CH), 128.18 (CH), 128.6 (CH), 129.4 (CH × 2),
131.45 (CH), 131.46 (CH × 2), 133.1 (C × 2), 133.2 (C), 133.38
(C), 133.40 (C × 2), 135.8 (C), 135.9 (C), 136.0 (C), 138.35
(CH), 138.37 (C), 148.0 (CH), 202.9 (C); FD-HRMS (m/z) calcd
for C68H67BrO10 [M]+: 1122.3918, found: 1122.3904.
7.1.52.
(5aS,6aR,7aS,8aR,10Z,11aS,13R,14S,16Z,18aR,19aS,21aR,22a
R,23R,23aS)-23-((4-bromobenzyl)oxy)-13-(hydroxymethyl)-
5,5a,6a,7,7a,8a,9,11a,13,14,15,18,18a,19a,21a,22a,23,23a-
octadecahydro-2H-
7.1.50. Isomerization of 11-epi-65.
To a solution of 11-epi-65 (3.0 mg, 2.7 µmol) in CH2Cl2 (0.5
mL) was added DBU (2 drops) at 24 ºC, and the mixture was
stirred for 7 h. Then, the reaction was quenched with 0.5 mol/L
aq. HCl, and the mixture was extracted with EtOAc several
times. The combined organic layers were washed with brine,
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by column
chromatography (silica gel, hexane/EtOAc = 5 → 3) to give a 3:1
mixture of 65 and 11-epi-65 (1.6 mg, 1.4 µmol, 53%) as a
colorless oil.
oxepino[2'''',3'''':5''',6''']pyrano[2''',3''':5'',6'']pyrano[2'',3'':
6',7']oxepino[2',3':7,8]oxocino[3,2-b]oxonin-14-ol (3). To a
solution of 67 (1.4 mg, 2.0 µmol) in CH2Cl2-Et3SiH (0.2 mL: 0.1
mL) was added TMSOTf (3.0 µL, 0.017 mmol) at 0 ºC, and the
mixture was stirred for 15 min. Then, the reaction was quenched
with saturated aq. NaHCO3, and the mixture was extracted with
EtOAc several times. The combined organic layers were washed
with brine, dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, hexane/EtOAc = 1 → 0.8 →
0.5) to give 3 (1.0 mg, 1.5 µmol, 73% ) as a colorless solid.
3: mp 168-169 ºC; [α]D24 –22 (c 0.050, CHCl3); IR (KBr) ν 3418,
3024, 2953, 2925, 2879, 2858, 2823, 1724, 1660, 1632, 1445,
1386, 1294, 1262, 1135, 1086, 1072, 1051, 1015, 804, 769, 687,
670 cm–1; 1H NMR (400 MHz, C6D6) δ 1.67 (1H, q, J = 11.6 Hz),
1.95 (1H, brd, J = 13.5 Hz), 2.15 (1H, ddd, J = 2.5, 6.3, 13.1 Hz),
2.17-2.27 (2H, m), 2.32 (1H, td, J = 4.7, 11.6 Hz), 2.52 (1H, ddd,
J = 1.0, 2.4, 6.6 Hz), 2.56 (1H, dd, J = 3.7, 7.5 Hz), 2.64 (1H,
ddd, J = 4.3, 10.9, 13.8 Hz), 2.72 (1H, brddd, J = 3.2, 9.4, 13.5
Hz), 2.83-2.94 (2H, m), 3.00-3.08 (2H, m), 3.11 (1H, t, J = 9.2
Hz), 3.22-3.26 (1H, m), 3.27 (1H, t, J = 9.2 Hz), 3.37 (1H, brtd, J
= 2.8, 8.4 Hz), 3.48-3.57 (3H, m), 3.61-3.69 (1H, m), 3.70-3.75
(2H, m), 3.80 (1H, brd, J = 6.9 Hz), 3.91 (1H, brt, J = 8.4 Hz),
4.00-4.07 (2H, m), 4.81 (1H, d, J = 12.7 Hz), 4.88 (1H, d, J =
12.7 Hz), 5.44-5.56 (2H, m), 5.63 (1H, dd, J = 5.6, 10.8 Hz),
5.71-5.77 (2H, m), 5.87-6.03 (3H, m), 7.17 (2H, m), 7.36 (2H, d,
J = 8.4 Hz); 13C NMR (125 MHz, CDCl3, measured at 50 ºC) δ
31.9 (CH2), 32.5 (CH2), 32.9 (CH2), 34.7 (CH2), 37.0 (CH2), 63.9
(CH2), 68.4 (CH2), 71.8 (CH), 73.3 (CH), 74.2 (CH), 76.9 (CH),
78.1 (CH), 80.7 (CH), 81.0 (CH), 82.3 (CH), 82.4 (CH), 84.0
(CH), 85.0 (CH), 86.1 (CH), 87.4 (CH), 121.2 (C), 126.6 (CH),
126.7 (CH), 127.6 (CH), 128.6 (CH), 129.3 (CH×2), 130.5 (CH),
130.9 (CH), 131.2 (CH), 131.3 (CH×2), 136.2 (CH), 136.5 (CH),
138.5 (C); FD-HRMS (m/z) calcd for C35H4379BrO9 [M]+:
686.2090, found: 686.2117; Crystal data: Crystals were obtained
by recrystallizing from EtOAc/benzene. C43H53O10Br, M =
809.79, colorless needle, 0.50 × 0.02 × 0.01 mm3, monoclinic P21
(No. 4), a = 16.716(12) Å, b = 5.985(4) Å, c = 19.98(2) Å, β =
100.006(13)°, V = 1968(3) Å3, ρcalcd(Z = 2) = 1.366 g cm–3. A
total 744 unique data (2θmax = 55°) were measured at T = 150 K
by Rigaku Mercury 70 apparatus (Mo Kα radiation, λ = 0.71070
Å). Numerical absorption correction was applied (µ = 11.056 cm–
1). The structure was solved by the direct method (SIR2004) and
refined by the full-matrix least-squares method of F2. Some non-
hydrogen atoms were refined anisotropically, while the rest were
refined isotropically. Hydrogen atoms were included but not
refined. The final wR value is 0.2301 (all data) for 5928
reflections and 480 parameters. CCDC 1517386.
7.1.51.
(2S,5aS,6aR,8Z,11S,12R,13aS,14Z,16aR)-2-
(((2R,3R,4S,4aS,9aS)-4-((4-Bromobenzyl)oxy)-3-hydroxy-
3,4,4a,6,9,9a-hexahydro-2H-pyrano[3,2-b]oxepin-2-
yl)methyl)-11-hydroxy-12-(hydroxymethyl)-
3,5a,6a,7,10,11,12,13a,16,16a-decahydro-3H-
oxepino[2',3':7,8]oxocino[3,2-b]oxonin-3-one (67). To
a
solution of 65 (2.3 mg, 2.1 µmmol) in CH2Cl2-H2O (1.0 mL: 0.5
mL) was added DDQ (6.2 mg, 0.027 mmol) at 17 ºC, and the
mixture was stirred for 1 h. Then, the reaction was quenched with
saturated aq. NaHCO3 and saturated aq. Na2S2O3, and the mixture
was extracted with CH2Cl2 several times. The combined organic
layers were washed with brine, dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The residue
was purified by column chromatography (silica gel,
hexane/EtOAc = 3 → 2) to give 66, which was used immediately
in the next reaction.
To a solution of the above 66 in EtOH (0.2 mL) was added 1.0
mol/L aq. HCl (0.1 mL) at 17 ºC, and the mixture was stirred for
2 h. Then, the reaction was quenched with saturated aq. NaHCO3,
and the mixture was extracted with EtOAc several times. The
combined organic layers were washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography
(silica gel, hexane/EtOAc = 1 → 0.5 → 0.2) to give 67 (1.4 mg,
1.9 µmol, 93% from 65) as a colorless oil.
25
67: [α]D –23 (c 0.12, CHCl3); IR (neat) ν 3429, 3024, 2956,
2918, 2854, 1741, 1724, 1664, 1597, 1486, 1468, 1446, 1405,
1380, 1359, 1331, 1284, 1126, 1088, 1013, 943, 911, 873, 845,
1
802, 781, 739, 700 cm–1; H NMR (400 MHz, CDCl3, measured
at 50 ºC) δ 1.80-1.86 (1H, m), 1.86-1.94 (1H, m), 2.15 (1H, brd, J
= 14.2 Hz), 2.21-2.31 (3H, m), 2.40 (1H, brddd, J = 2.0, 6.1, 13.8
Hz), 2.53 (1H, ddd, J = 4.0, 8.1, 16.2 Hz), 2.69 (1H, ddd, J = 4.1,
9.4, 13.8 Hz), 2.81 (1H, brddd, J = 3.6, 10.1, 13.8 Hz), 2.91 (1H,
brddd, J = 4.0, 9.7, 13.8 Hz), 3.11-3.19 (2H, m), 3.26 (1H, t, J =
8.5 Hz), 3.31 (1H, t, J = 8.5 Hz), 3.33 (1H, t, J = 8.5 Hz), 3.41
(1H, dt, J = 2.0, 8.5 Hz), 3.61-3.80 (4H, m), 3.89-4.06 (3H, m),
4.11 (1H, td, J = 2.9, 8.9 Hz), 4.22 (1H, dd, J = 5.7, 15.8 Hz),
4.26-4.32 (1H, m), 4.69 (1H, d, J = 12.0 Hz), 4.89 (1H, d, J =
12.0 Hz), 5.70-5.89 (7H, m), 6.46 (1H, dd, J = 2.9, 13.3 Hz), 7.22
(2H, d, J = 8.4 Hz), 7.46 (2H, d, J = 8.4 Hz); 13C NMR (125
MHz, CDCl3, measured at 50 ºC) δ 31.5 (CH2), 32.5 (CH2), 34.4
(CH2), 36.2 (CH2), 63.8 (CH2), 65.5 (CH2), 67.9 (CH2), 71.7
(CH), 73.7 (CH), 74.2 (CH2), 74.5 (CH), 76.1 (CH), 80.7 (CH),
83.0 (CH), 83.7 (CH), 85.2 (CH), 85.3 (CH), 87.2 (CH), 87.6
(CH), 121.5 (C), 126.3 (CH), 126.97 (CH), 127.03 (CH), 127.9
(CH), 128.2 (CH), 128.8 (CH), 129.3 (CH×2), 130.9 (CH), 131.2
(CH), 131.6 (CH×2), 137.6 (CH), 138.2 (C), 146.1 (CH), 203.5
Acknowledgments
We thank Dr. Eri Fukushi (GC-MS and NMR Laboratory,
Faculty of Agriculture, Hokkaido University) for the
mesurements of mass and NMR spectra. We are also grateful to
Mr. Yusuke Takata, Mr. Kenji Watanabe (GC-MS and NMR
Laboratory, Faculty of Agriculture, Hokkaido University), Ms.
Seiko Oka, and Ms. Ai Tokumitsu (Equipment Management
Center, Creative Research Institution, Hokkaido University) for

24
Tetrahedron
the measurements of mass spectra. We thank Mr. Wataru Nojo
9. (a) Fujiwara, K.; Goto, A.; Sato, D.; Ohtaniuchi, Y.; Tanaka, H.;
Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2004, 45,
7011; (b) Domon, D.; Fujiwara, K.; Murai, A.; Kawai, H.; Suzuki,
T. Tetrahedron Lett. 2005, 46, 8285; (c) Takizawa, A.; Fujiwara,
K.; Doi, E.; Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron 2006,
62, 7408; (d) Goto, A.; Fujiwara, K.; Kawai, H.; Suzuki, T. Org.
Lett. 2007, 9, 5373; (e) Nogoshi, K.; Domon, D.; Fujiwara, K.;
Kawamura, N.; Katoono, R.; Kawai, H.; Suzuki, T. Tetrahedron
Lett. 2013, 54, 676.
ACCEPTED MANUSCRIPT
(Graduate School of Chemical Science and Engineering,
Hokkaido University) for assistance in X-ray crystallographic
analysis. This work was supported by Grants-in-Aid for
Scientific Research from MEXT, Japan.
Supplementary Data
Supplementary data associated with this article can be found
in the online version, at http://dx.doi.org/#####/#####.
10. (a) Fujiwara, K.; Saka, K.; Takaoka, D.; Murai, A. Synlett 1999,
1037; (b) Fujiwara, K.; Takaoka, D.; Kusumi, K.; Kawai, K.;
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Kawai, K.; Tanaka, H.; Murai, A. Synlett 2002, 1835.
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(b) Herrmann, J. L.; Richman, J. E.; Wepplo, P. J.; Schlessinger,
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