Convergent synthesis of the BCDEFGHIJ-ring polyether core of gambieric acids, potent antifungal polycyclic ethers

Article abstract of DOI:10.1016/j.tet.2007.02.039

A convergent synthesis of the nonacyclic BCDEFGHIJ-ring polyether core of gambieric acids, potent antifungal polycyclic ether marine natural products, has been achieved. The present synthesis involved as key features: (i) convergent union of the BCD- and GHIJ-ring fragments through esterification, (ii) construction of the E-ring as a lactone form via reductive acetylation, (iii) stereoselective allylation to establish the C26 stereocenter, and (iv) ring-closing metathesis reaction to form the nine-membered F-ring.

Full text of DOI:10.1016/j.tet.2007.02.039

Tetrahedron 63 (2007) 5977–6003
Convergent synthesis of the BCDEFGHIJ-ring polyether core
of gambieric acids, potent antifungal polycyclic ethers
*
Kazushi Sato and Makoto Sasaki
Laboratory of Biostructural Chemistry, Graduate School of Life Sciences, Tohoku University, 1-1 Tsutsumidori-amamiya,
Aoba-ku, Sendai 981-8555, Japan
Received 25 January 2007; accepted 9 February 2007
Available online 14 February 2007
Abstract—A convergent synthesis of the nonacyclic BCDEFGHIJ-ring polyether core of gambieric acids, potent antifungal polycyclic ether
marine natural products, has been achieved. The present synthesis involved as key features: (i) convergent union of the BCD- and GHIJ-ring
fragments through esterification, (ii) construction of the E-ring as a lactone form via reductive acetylation, (iii) stereoselective allylation to
establish the C26 stereocenter, and (iv) ring-closing metathesis reaction to form the nine-membered F-ring.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
configurations were subsequently determined by combining
the modified Mosher method, NMR conformational analysis,
and chiral fluorometric HPLC analysis.2c
Marine organisms provide an important source of structur-
ally diverse secondary metabolites with unique molecular
architecture and significant biological properties. Among
these marine natural products, ladder-shaped polycyclic
ethers have attracted considerable attention of chemists and
biologists because of their complex and huge molecular
structures coupled with exceptionally potent biological
activities.1 Gambieric acids A–D (1–4, Fig. 1) were isolated
in 1992 by Nagai and co-workers from the culture media of
the marine dinoflagellate, Gambierdiscus toxicus, which is
well-known as the causative organism responsible for cigua-
tera seafood poisoning.2 Their gross structures including the
relativestereochemistry of the polycyclic ether skeleton were
determined based on extensive 2D-NMR experiments.2a,b
Structurally, gambieric acids consist of a nonacyclic fused
polyether system (BCDEFGHIJ-ring) and one isolated tetra-
hydrofuran ring (A-ring) in the terminal chain. Their absolute
These polycyclic ethers exhibited potent antifungal activity
against filamentous fungi.3 Especially, their growth inhibi-
tory activity against Aspergillus niger by the paper disk
method was 2000 times greater than that of amphotericin
B, whereas they did not show either toxicity or abnormal
reaction in mice up to the dose of 1 mg/kg (intraperitoneal
injection).2b,3 These useful biological aspects make them
potential lead compounds for the discovery of antifungal
agents. Interestingly, it has been reported that gambieric acid
A enhances the cell concentration of G. toxicus in a dose-
dependent manner with inhibition at higher concentration,
suggesting the potential biological function of gambieric
acid A to be an endogenous growth regulator of G. toxicus.4
Moreover, Inoue et al. recently described that gambieric acid
A inhibits the binding of tritiated brevetoxin-B derivative
Me
H
1: gambieric acid A R1 = R2 = H
30
H
Me Me
H
O
F
O
C
R1
HO
HO
20
O
Me
35
H
OH
H
2: gambieric acid B R1 = Me, R2 = H
B 15
D
25
E
G
O
3: gambieric acid C R1 = H, R2
=
H
O
H
O
O
H
J
CO2H
H
H
H
5
Me
H
10
H
4: gambieric acid D R1 = Me, R2
=
O
I40
O
Me
A
H
H
O
H
Me
O
Me
HO2C
Me
H
Me
OR2
45
1
49
Figure 1. Structures of gambieric acids.
* Corresponding author. Tel.: +81 22 717 8828; fax: +81 22 717 8897; e-mail: masasaki@bios.tohoku.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.039

5978
K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
Me
BnO
Me
H
H
Me
H
H
H
H
Me Me
H
O
C
OTBS
O
G
O
F
O
C
+
O
Me
H
OBn
H
D
O
NAPO
B
D
O
E
G
O
CO2H
HO
H
5
H
O
H
O
H
J
H
H
8
H
7
H
O
I
NAPO
OBn
H
CO2Me
OBn
OBn
Me
H
Me
O
H
Me
H
H
H
Me
F
O
H
O
C
H
O
C
Me
O
O
SPh
D
O
E
O
G
O
D
G
H
H
O
H
H
O
6
H
H
9
RCM
Figure 2. BCDEFGHIJ-ring polyether core 5 and CDEFG-ring system 6 of
gambieric acids.
Me
H
H
Me
H
H
F
O
O
C
O
([3H]PbTx-3) to site 5 of voltage-sensitive sodium channels
of excitable membranes, although its binding affinity is sig-
nificantly lower than those of brevetoxins and ciguatoxins.5
D
O
E
G
O
H
H
H
6
radical cyclization
Scheme 1. First synthetic plan for CDEFG-ring system 6.
These intriguing biological properties and the molecular
complexity of gambieric acids have generated considerable
interest within the synthetic community, and several syn-
thetic approaches toward the total synthesis of these poly-
cyclic ether compounds have been reported to date.6–8 In this
paper, we describe the details of the synthesis of the nonacy-
clic BCDEFGHIJ-ring polyether core 5 (Fig. 2) of gambieric
acids A and C.
olefin 14 in 77% yield for the three steps. Hydroboration
using 9-BBN-H followed by oxidative workup gave an
alcohol, which was then oxidized by a two-step procedure
(Parikh–Doering oxidation14 and NaClO2) to provide the
desired CD-ring carboxylic acid 7 in 88% yield for the three
steps.
2. Results and discussion
H
H
H
O
C
O
C
Me
O
C
Me
g
a-d
e,f
O
O
2.1. Synthesis of the CDEFG-ring system
OTBS
O
O
TBS
10
11
12
We have previously reported a convergent route to the FGH-
ring system ciguatoxins.9 The synthesis features a stereo-
selective intramolecular radical cyclization to construct the
seven-membered G-ring and closure of the nine-membered
F-ring by a ring-closing metathesis (RCM) reaction. This
remarkable approach was further modified and refined by
the Hirama and Inoue’s group,10 culminating in the total syn-
thesis of ciguatoxin and its congeners.11 We envisioned this
strategy being applied to the total synthesis of gambieric
acids and selected the CDEFG-ring system 6 (Fig. 2) as a
prime synthetic target. Retrosynthetically, the CDEFG-ring
6 can be dissected into the CD- and G-ring segments (7
and 8, respectively, Scheme 1). We expected successful
union of these segments and further transformations to give
the desired mixed thioacetal 9, a key intermediate, which
upon radical cyclization would form the seven-membered
E-ring. Finally, construction of the nine-membered F-ring
by RCM would lead to the CDEFG-ring system 6.
CO2Et
Me
NOE
Me
OTBS
k-m
Me
OH
H
H
H
H
H
O
C
O
O
C
OTBS
h-j
D
O
C
D
O
D
O
H
H
H
14
H
CO2Et
CO2H
13
7
Scheme 2. Synthesis of CD-ring 7. Reagents and conditions: (a) 9-BBN-H,
THF; aq NaOH, H2O2; (b) SO3$pyr, Et3N, DMSO/CH2Cl2; ꢀ(c) MeMgBr,
˚
THF; (d) TPAP, NMO, 4 A molecular sieves, CH2Cl2, 0 C/rt, 82%
(four steps); (e) TBAF, THF, 94%; (f) ethyl propiolate, NMM, CH2Cl2,
87%; (g) SmI2, MeOH, THF, 0 ꢀC, 99%; (h) TBSOTf, 2,6-lutidine,
CH2Cl2, 0 ꢀC/rt; (i) DIBALH, CH2Cl2, ꢁ78 ꢀC; (j) NaHMDS,
Ph3PCH3Br, THF, 77% (three steps); (k) 9-BBN-H, THF; aq NaOH,
H2O2; (l) SO3$pyr, Et3N, DMSO/CH2Cl2; (m) NaClO2, KH2PO4, 2-methyl-
2-butene, t-BuOH/H2O, 88% (three steps).
The synthesis of alcohol 8 started with the known alcohol
1512 (Scheme 3). Protection as the TBS ether (90%) and
oxidative cleavage of the double bond (OsO4, NMO; then
NaIO4), followed by Wittig reaction, afforded a,b-unsatu-
rated ester 16 in 91% overall yield. Treatment of 16 with
MeMgBr and TMSCl in the presence of bis(N-isopropyl-
salicylaldimine) copper(II) complex 1715 (THF, ꢁ45 ꢀC)
gave the desired 1,4-adduct 18 as the sole product in 90%
yield.16 The stereochemistry of the newly generated methyl
stereocenter was confirmed by conversion to lactone 19 by
deprotection of the TBS group followed by acid-catalyzed
lactonization (81%, two steps) and its NMR analysis as
shown. DIBALH reduction of 18 produced primary alcohol
20 (95%), which was protected as the benzyl ether and then
desilylated with TBAF to give alcohol 8 in 90% yield for the
two steps. Alcohol 20 was converted to a terminal olefin via
The synthesis of carboxylic acid 7 commenced with the
known TBS ether 10,12 which was converted to methyl
ketone 11 by a standard four-step sequence in 82% overall
yield (Scheme 2). After desilylation with TBAF (94%),
treatment of the resultant alcohol with ethyl propiolate
in the presence of 4-methylmorpholine (NMM) produced
b-(E)-alkoxyacrylate 12 in 87% yield. Treatment of 12
with SmI2 in the presence of methanol (THF, 0 ꢀC) effected
reductive cyclization13 to form the D-ring, giving bicyclic
ether 13 as the sole product in excellent yield. After pro-
tection as the TBS ether, DIBALH reduction of the ester
moiety to the aldehyde followed by Wittig reaction afforded

K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
5979
the corresponding o-nitrophenyl selenide by the Grieco/
Nishizawa protocol (1. 2-NO2C6H4SeCN, Bu3P; 2. m-CPBA,
92% for the two steps).17 Subsequent desilylation afforded
alcohol 21 in 94% yield.
the tertiary alcohol by treatment with methyl propiolate and
Me3P20 to provide 9 albeit in modest yield (47%, 82% yield
based on recovered 24). However, radical cyclization of 9
(Bu3SnH, AIBN, toluene, 80 ꢀC) was sluggish and yielded a
complex mixture of the desired O-linked oxepane 25, its
diastereomer 26, and reduction product 27 (25/26/27¼ca.
1:4:3), along with recovered 9. Stereostructure of compound
25 was assigned by NOE between 21-Me21 and 26-H and
H
H
O
G
MeO2C
TBSO
O
G
a-c
d
i-Pr
HO
3
N
Cu
N
a small coupling constant, J25,26¼3.5 Hz. The outcome of
O
15
16
this radical cyclization can be explained as indicated in
Figure 3. Severe steric repulsion between the tertiary methyl
group at C21 and b-hydrogen on the acrylate unit in the
transition state structure A resulted in a preference for the
structure B, which leads to 26. A similar result has been
reported by Nakata and co-workers in their SmI2-mediated
reductive cyclization.22
O
i-Pr
Me
Me
17
H
H
MeO2C
O
G
O
G
g
HO
TBSO
TBSO
h,i
18
20
j-l
e,f
NOE
H
O
Accordingly, we next investigated an alternative route as
summarized in Scheme 5. Alcohol 21 and carboxylic acid
7 were coupled through esterification under Yamaguchi con-
ditions18 to afford 28 in 91% yield. Reductive acetylation19
proceeded smoothly to give an a-acetoxy ether as a 3:1 mix-
ture of diastereomers, which was subsequently treated with
TMSCN and TMSOTf in the presence of DTBMP to gener-
ate a-cyano ether 29. Removal of the TBS group with TBAF
(MeCN, 70 ꢀC) afforded alcohol 30 in 61% yield for the
three steps. The nitrile group was hydrolyzed under alkaline
conditions (KOH, ethylene glycol, 150 ꢀC) to give carboxy-
lic acid 31 in high yield as a 1:1 mixture of isomers. Sub-
sequent Yamaguchi lactonization18 produced a mixture of
seven-membered lactones, which was separated by flash col-
umn chromatography to give 32a and 32b in 38% and 40%
yield, respectively. All attempts to isomerize 32b to the
Me
Me
Me
H
H
H
H
O
O
G
O
G
NOE
BnO
O
HO
HO
19
8
21
Scheme 3. Synthesis of G-rings 8 and 21. Reagents and conditions: (a)
TBSCl, imidazole, DMAP, DMF, 90%; (b) cat OsO4, NMO, THF/H2O;
NaIO4; (c) Ph3P]CHCO2Me, CH2Cl2, 91% (two steps); (d) MeMgBr,
17, TMSCl, THF, ꢁ45 ꢀC, 90%; (e) aq HCl, MeOH; (f) PPTS, toluene,
110 ꢀC, 81% (two steps); (g) DIBALH, CH2Cl2, ꢁ78 ꢀC, 95%; (h) KOt-Bu,
BnBr, THF, 90%; (i) TBAF, THF, quant.; (j) 2-NO2C6H4SeCN,
Bu3P, CH2Cl2; (k) m-CPBA, CH2Cl2, 0 ꢀC, 92% (two steps); (l) TBAF,
THF, 94%.
With the desired fragments 7 and 8 in hand, we next turned
our attention to their coupling. Yamaguchi esterification18 of
7 with 8 proceeded smoothly to afford ester 22 in quantita-
tive yield (Scheme 4). Conversion to the a-acetoxy ether
23 was performed by the procedure of Rychnovsky.19 Thus,
reduction of 22 with DIBALH (CH2Cl2, ꢁ78 ꢀC) followed
by treatment of the resulting hemiacetal intermediate with
Ac2O, DMAP, and pyridine (ꢁ78 ꢀC/room temperature)
provided the desired acetate 23 in 98% yield. Subsequent
treatment with phenylthiotrimethylsilane (TMSSPh) and
TMSOTf in the presence of 2,6-di-tert-butyl-4-methylpyri-
dine (DTBMP) afforded the corresponding mixed thioacetal
(88%), which was desilylated with TBAF to give alcohol 24
in 94% yield. The b-(E)-alkoxyacrylate unit was attached to
Me
H
Me
21
H
OR
CO2Me
O
O
O
O
CO2Me
OR
H
H
H
H
A
B
25
26
Figure 3. Possible rationale for radical cyclization.
MeO2C
BnO
Me
BnO
BnO
SPh
Me
H
Me
H
a
b
e
TBS
O
7 + 8
H
H
Me
H
H
H
H
Me
H
H
H
Me
O
C
O
O
C
OR
O
C
O
X
O
O
O
21
D
O
D
O
D
O
G
G
G
O
O
O
H
H
H
H
22
9
23: R = TBS, X = OAc
24: R = H, X = SPh
c,d
MeO2C
BnO
BnO
BnO
MeO2C
Me
H
Me
H
MeO2C
Me
H
H
H
Me
21 E
H
H
Me
H
f
H
H
Me
O
26
25
O
C
O
C
O
26
25
O
C
O
E
+
+
O
O
O
D
D
O
G
G
D
O
O
O
G
O
H
O
H
H
H
H
H
H
H
H
25
26
27
Scheme 4. Attempted synthesis of O-linked oxepane 25. Reagents and conditions: (a) 2,4,6-Cl3C6H2COCl, Et3N, THF, 40 ꢀC; DMAP, toluene, 40 ꢀC, quant.;
(b) DIBALH, CH2Cl2, ꢁ78 ꢀC; Ac2O, DMAP, pyr, ꢁ78 ꢀC/rt, 98%; (c) TMSSPh, TMSOTf, DTBMP, CH2Cl2, 0 ꢀC/rt, 88%; (d) TBAF, MeCN, 70 ꢀC,
94%; (e) methyl propiolate, Me3P, CH2Cl2, 47% (82% based on recovered 24); (f) Bu3SnH, AIBN, toluene, 80 ꢀC, 74% (25/26/27¼ca. 1:4:3).

5980
K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
Me
H
Me
H
a
b,c
e
TBS
Me
H
7 + 21
H
H
Me
H
H
H
Me
H
H
H
Me
H
O
C
O
O
C
OR
CN
O
OH
O
C
O
O
CO2H
O
O
D
O
D
O
G
G
D
O
O
O
G
H
H
H
28
31
29: R = TBS
30: R = H
d
NOEs
Me
H
Me
H
g
Me
f
O
H
O
H OAc
H
H
Me
H
Me
32a
+
Me
H
H
H
O
E
O
E
O
C
O
C
O
O
C
26
25
O
O
O
D
O
D
O
G
G
D
O
E
G
O
O
O
H
H
H
H
H
H
H
H
H
J
25,26 = 0 Hz
32a
32b
33
NOE
NOE
h
Me
H
i
Me
H
Mes-N N-Mes
H
O
H
H
Me
H
H
Me
26
O
C
26
25
Cl
Cl
O
O
C
F
Ru
PCy3
O
O
35
D
O
21 E
D
O
E
Ph
G
G
O
O
H
H
H
H
H
H
H
J
25,26 = 10.5 Hz
34
6
NOEs
Scheme 5. Synthesis of CDEFG-ring system 6. Reagents and conditions: (a) 2,4,6-Cl3C6H2COCl, Et3N, THF, 40 ꢀC; DMAP, toluene, 40 ꢀC, 91%; (b) DIBALH,
CH2Cl2, ꢁ78 ꢀC; Ac2O, DMAP, pyr, ꢁ78/0 ꢀC; (c) TMSCN, TMSOTf, DTBMP, CH2Cl2, ꢁ78/0 ꢀC; (d) TBAF, MeCN, 70 ꢀC, 61% (three steps); (e) KOH,
ethylene glycol, 150 ꢀC, 95%; (f) 2,4,6-Cl3C6H2COCl, Et3N, THF/toluene; DMAP, toluene, reflux, 38% for 32a, 40% for 32b; (g) DIBALH, CH2Cl2, ꢁ78 ꢀC;
ꢀ
ꢀ
ꢀ
˚
Ac2O, DMAP, pyr, ꢁ78/0 C, 96%; (h) CH2]CHCH2TMS, BF3$OEt2, 4 A molecular sieves, MeCN, ꢁ40/0 C, 66%; (i) 35, CH2Cl2, 40 C, 98%.
desired 32a under various basic conditions were unsuccess-
ful. Reductive acetylation (DIBALH, CH2Cl2, ꢁ78 ꢀC; then
Ac2O, DMAP, pyridine, ꢁ78/0 ꢀC)19 of lactone 32a
produced acetate 33 in 96% yield as the sole product. The
stereochemistry at C26 of 33 was assigned on the basis of
NOEs and the coupling constant, J25,26¼0 Hz, as shown.
Upon treatment of 33 with allyltrimethylsilane in the pres-
ence of BF3$OEt2 (MeCN, ꢁ40/0 ꢀC), stereoselective
allylation took place from the opposite side of the angular
methyl group at C21 to afford the requisite diene 34 in
66% yield. Stereochemistry at the C26 position was deter-
mined by NOE between 21-Me and 26-H. Finally, construc-
tion of the nine-membered F-ring was achieved by RCM
using the second-generation Grubbs catalyst 3523 (CH2Cl2,
40 ꢀC) to furnish the CDEFG-ring system 6 in 98% yield.
The stereostructure of 6 was unequivocally established by
NOE experiments and the coupling constant as shown in
Scheme 5.
alcohol was subjected to Sharpless asymmetric epoxidation
using (+)-diethyl tartrate (DET). Oxidation of the derived
epoxy alcohol and Wittig methylenation, followed by re-
moval of the TBS group, gave hydroxy epoxide 40 in 81%
overall yield. Upon treatment of 40 with PPTS, 6-endo
cyclization24 proceeded smoothly to afford the C-ring tetra-
hydropyran 41 after TBS protection (93%, two steps). The
terminal olefin of 41 was then converted to methyl ketone
42 by a standard four-step sequence, and the secondary TBS
group of 42 was changed to b-(E)-alkoxyacrylate in two
13
steps to give 43. Reductive cyclization of 43 with SmI2
in the presence of methanol (THF, 0 ꢀC/room tempera-
ture) afforded the CD-ring 44 in high yield as a single diaste-
reomer. After protection of the tertiary alcohol as the TMS
ether (93%), the ethyl ester was reduced with DIBALH and
the resulting aldehyde was subjected to Wittig reaction to
give olefin 45 in 93% yield for the two steps. Subsequent
treatment with 1,3-propanedithiol in the presence of TMSOTf
(MeCN, 0 ꢀC) effected ring-opening of the methyl acetal and
2.2. Synthesis of the BCDEFGHIJ-ring core
OBn
Me
Having successfully developed a convergent synthetic route
to the CDEFG-ring system 6, we next applied this strategy to
construct the nonacyclic BCDEFGHIJ-ring polyether core 5
of gambieric acids A and C from two complex fragments, the
BCD-ring carboxylic acid 36 and the GHIJ-ring alcohol 37,
as illustrated in Scheme 6.
Me
H
H
Me
Me
H
H
H
O
G
O
I
OBn
OBn
OTBS
CO2H
O
C
H
O
J
O
NAPO
NAPO
B
D
HO
O
O
H
H
Me
H
H
H
H
36
37
coupling + EF-ring
The synthesis of the BCD-ring fragment 36 started with
the known alcohol 38, which is available in four steps from
tri-O-acetyl-D-glucal.16a Parikh–Doering oxidation14 and
Wittig olefination, followed by hydroboration with 9-
BBN-H, produced a homologated alcohol in 75% overall
yield (Scheme 7). The resultant primary alcohol was sub-
jected to a second oxidation/Wittig reaction to afford a,b-
unsaturated ester 39 in 90% yield for the two steps. Ester
39 was reduced with DIBALH, and the resulting allylic
Me
H
H
Me
H
Me
F
O
C
O
E
O
Me
H
OBn
H
NAPO
NAPO
B
D
G
O
H
O
H
O
O
I
H
J
H
H
H
H
H
O
5
H
OBn
OBn
Me
O
H
Scheme 6. Synthetic plan for BCDEFGHIJ-ring polyether core 5.

K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
5981
OTBS
OH
OTBS
OH
f-j
CO2Et
The synthesis of the GHIJ-ring fragment 37 was performed
by the union of the G- and J-rings (49 and 50, respectively)
followed by the HI-ring formation according to the acet-
ylide–aldehyde coupling/hetero-Michael cyclization strategy
developed by the Nakata group with some modifications.26
The synthesis of the G-ring aldehyde 49 began with the
known alcohol 51,27 which was protected as the benzyl ether
to afford 52 in quantitative yield (Scheme 8). Oxidative
cleavage of the double bond (OsO4, NMO; then NaIO4) fol-
lowed by Wittig reaction gave a,b-unsaturated ester 53 in
80% yield for the three steps. Treatment of 53 with MeMgBr
(TMSCl, Cu(II) complex 17,15 THF, ꢁ45 ꢀC) gave the ex-
pected 1,4-adduct 54 in 96% yield. DIBALH reduction,
benzyl protection, and hydrolysis of the benzylidene acetal
provided diol 55 in 91% yield for the three steps. The second-
ary hydroxy group of 55 was selectively protected as the TBS
ether by bis-TBS protection followed by selective deprotec-
tion of the primary TBS group (95%, two steps). The result-
ing primary alcohol was oxidized under Parikh–Doering
conditions14 to furnish the G-ring aldehyde 49 in 94% yield.
a-e
MeO
O
MeO
O
O
MeO
O
H
H
H
Me
Me
38
39
40
H
Me
H
H
Me
O
O
m-p
k,l
MeO
O
C
Me
s
C
O
OTBS
MeO
O
OR
42: R = TBS
H
41
q,r
43: R = (E)-CH=CHCO2Et
H
H
Me Me
OH
H
Me Me
O
O
OTMS
t-v
CO2Et
w
C
D
O
C
D
O
MeO
S
O
MeO
O
H
H
H
H
45
H
44
S
H
Me Me
OH
H
Me Me
O
OHC
O
OTBS
x-z
aa
C
D
O
C
D
EtO2C
HO
O
O
H
H
H
H
46
47
H
Me
H
Me
O
G
MeO2C
O
G
b-d
e
H
H
Me Me
H
H
Me Me
O
O
bb-ff
O
C
OTBS
O
C
OTBS
H
O
NAPO
B
D
O
B
D
O
RO
O
Ph
BnO
BnO
O
Ph
H
H
CO2H
O
O
51: R = H
H
H
H
H
O
53
H
H
a
NAPO
36
52: R = Bn
48
NOEs
Me
Me
H
Me
O
H
Me
MeO2C
O
G
O
G
f-h
i-k
BnO
OH
Scheme 7. Synthesis of BCD-ring 36. Reagents and conditions: (a)
SO3$pyr, Et3N, DMSO/CH2Cl2; (b) NaHMDS, Ph3PCH3Br, THF, 95%
(two steps); (c) 9-BBN-H, THF; aq NaOH, H2O2, 79%; (d) SO3$pyr,
Et3N, DMSO/CH2Cl2; (e) Ph3P]C(Me)CO2Et, toluene, 100 ꢀC, 90%
(two steps); (f) DIBALH, CH2Cl2, ꢁ78 ꢀC, 99%; (g) t-BuOOH, (+)-DET,
BnO
O
Ph
OH
H
54
55
Me
H
Me
CHO
ꢀ
˚
Ti(Oi-Pr)4, 4 A molecular sieves, CH2Cl2, ꢁ20 C; (h) SO3$pyr, Et3N,
DMSO/CH2Cl2; (i) NaHMDS, Ph3PCH3Br, THF, 88% (three steps); (j)
TBAF, THF, 93%; (k) PPTS, CH2Cl2, 96%; (l) TBSOTf, 2,6-lutidine,
CH2Cl2, 97%; (m) BH3$SMe2, 2-methyl-2-butene, THF; aq NaOH, H2O2,
98%; (n) SO3$pyr, Et3N, DMSO/CH2Cl2, 0 ꢀC; (o) MeMgBr, THF, 88%
O
G
BnO
OTBS
BnO
49
˚
(two steps); (p) TPAP, NMO, 4 A molecular sieves, CH2Cl2, 92%; (q)
Scheme 8. Synthesis of G-ring 49. Reagents and conditions: (a) NaH, BnBr,
Bu4NI, DMF, quant.; (b) cat OsO4, NMO, THF/H2O; (c) NaIO4, THF/H2O;
(d) Ph3P]CHCO2Me, THF, 80% (three steps); (e) MeMgBr, 17, TMSCl,
THF, ꢁ45 ꢀC, 96%; (f) DIBALH, CH2Cl2, ꢁ78 ꢀC, quant.; (g) NaH,
BnBr, Bu4NI, DMF, 0 ꢀC/rt; (h) TsOH, MeOH, 40/70 ꢀC, 91% (two
steps); (i) TBSOTf, 2,6-lutidine, CH2Cl2; (j) CSA, MeOH/CH2Cl2, 0 ꢀC,
95% (two steps); (k) SO3$pyr, Et3N, DMSO/CH2Cl2, 94%.
TBAF, THF, 99%; (r) ethyl propiolate, NMM, CH2Cl2; (s) SmI2, MeOH,
THF, 0 ꢀC/rt, 83% (two steps); (t) TMSOTf, 2,6-lutidine, CH2Cl2, 0 ꢀC,
93%; (u) DIBALH, toluene, ꢁ78 ꢀC; (v) NaHMDS, Ph3PCH3Br, THF,
93% (two steps); (w) 1,3-propanedithiol, TMSOTf, MeCN, 0 ꢀC, 92%;
(x) ethyl propiolate, NMM, CH2Cl2, 94%; (y) TBSOTf, 2,6-lutidine,
CH2Cl2, 0 ꢀC, 97%; (z) MeI, NaHCO3, MeCN/H2O, 98%; (aa) SmI2,
MeOH, THF; (bb) LiAlH4, THF, 0 ꢀC, 89% (two steps); (cc) NaH, NAPBr,
Bu4NI, DMF, 0 ꢀC/rt, 96%; (dd) 9-BBN-H, THF; aq NaOH, H2O2;
(ee) SO3$pyr, Et3N, DMSO/CH2Cl2; (ff) NaClO2, 2-methyl-2-butene,
KH2PO4, t-BuOH/H2O, 88% (three steps).
The synthesis of the J-ring alkyne 50 is summarized in
Scheme 9. Protection of the known alcohol 5628 as the p-
methoxybenzyl (PMB) ether and removal of the benzylidene
acetal, followed by benzylation of the resultant diol, pro-
vided 57 in 81% yield for the three steps. Hydroboration
of the terminal olefin with 9-BBN-H (71%) and subsequent
oxidation of the derived alcohol with tetra-n-propylammo-
nium perruthenate (TPAP)/NMO29 led to aldehyde 58 in
77% yield. Treatment of aldehyde 58 with Ohira–Bestmann
reagent 5930 (Cs2CO3, i-PrOH, 92%) completed the synthe-
sis of the J-ring alkyne 50.
desilylation to provide dithiane diol 46 in 92% yield. Upon
exposure of 46 to ethyl propiolate and NMM, selective het-
ero-Michael reaction of the secondary alcohol took place
and the remaining tertiary alcohol was protected as the
TBS ether. The thioacetal was hydrolyzed (MeI, NaHCO3,
MeCN/H2O) to produce aldehyde 47 in 89% yield from 46.
SmI2-promoted reductive cyclization of 47 proceeded again
smoothly to form the seven-membered B-ring, giving g-lac-
tone 48 as the sole product. The stereostructure of 48 was
confirmed by NOE experiments as shown in Scheme 7. After
reduction of the lactone moiety with LiAlH4, the resultant
diol was protected as the 2-naphthylmethyl (NAP) ethers
(85% yield from 47).11b,25 Finally, the terminal olefin was
converted to the carboxylic acid in a three-step sequence in-
volving hydroboration with 9-BBN-H and a two-step oxida-
tion of the resultant primary alcohol (88%, three steps),
completing the synthesis of the BCD-ring fragment 36.
Reaction of the lithium acetylide, generated from alkyne 50
(t-BuLi, THF/HMPA, ꢁ78 ꢀC), with aldehyde 49 provided
propargyl alcohol 60 in 95% yield as a mixture of diastereo-
mers (Scheme 10). Swern oxidation afforded ynone 61
(93%), which was treated with NaOMe (MeOH/THF, room
temperature) to afford vinylogous ester 62 in 98% yield.
Subsequent removal of the TBS group from 62 was best
carried out by treatment with HF$pyridine/pyridine/THF

5982
K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
H
HO
O
Ph
PMBO
OBn
d,e
OBn
a-c
J
O
J
O
O
Me
H
56
Me
H
O
O
57
P OMe
Me
59
OMe
PMBO
OHC
OBn
OBn
PMBO
OBn
OBn
N2
f
J
O
J
O
Me
H
Me
H
58
50
Figure 4. Stereochemical confirmation of GHIJ-ring 71.
Scheme 9. Synthesis of J-ring 50. Reagents and conditions: (a) NaH,
PMBCl, Bu4NI, DMF, 0 ꢀC/rt; (b) CSA, MeOH, 86% (two steps); (c)
NaH, BnBr, Bu4NI, DMF, 0 ꢀC/rt, 94%; (d) 9-BBN-H, THF; aqꢀNaOH,
yield. The use of large excess amounts of Et3SiH was neces-
sary to attain high yield of 70 in this reductive etherification;
stoichiometric amounts of Et3SiH resulted in variable yield
(28–62%). The stereochemistry of 70 was established based
˚
H2O2, 71%; (e) TPAP, NMO, 4 A molecular sieves, CH2Cl2, 0 C/rt,
77%; (f) 59, Cs2CO3, i-PrOH, 92%.
1
(2:1:4) at 0 ꢀC/room temperature to give alcohol 63 in
93% yield. The use of TBAF resulted in moderate yield of
63 with recovery of 62. The resultant alcohol 63 was treated
with PPTS (toluene, 100 ꢀC) to induce an intramolecular
hetero-Michael reaction, leading to the desired dihydropyr-
anone 64 in 87% yield. Subsequent reduction of 64 with
DIBALH proceeded stereoselectively to afford equatorial-
oriented b-alcohol 65 in 92% yield as the sole product. Hy-
droboration of the enol ether with BH3$THF led exclusively
to diol 66 (91%), which was protected as the bis-TES ether
67 (quant.). After removal of the PMB group from 67 with
DDQ, oxidation of the resultant alcohol with TPAP/NMO29
provided ketone 68, which was then desilylated with TBAF/
HOAc to afford dihydroxy ketone 69 in 81% yield (three
steps). Treatment of 69 with Et3SiH and TMSOTf (MeCN,
ꢁ10 ꢀC) furnished the desired tetracyclic ether 70 in 83%
on the H NMR analysis of the corresponding acetate 71
(Ac2O, DMAP, Et3N, room temperature, 86%) as shown in
Figure 4. A four-step sequence of standard protecting group
manipulations was performed on 70 to afford diol 73 via 72
in 65% overall yield. The resulting diol 73 was then con-
verted to primary alcohol 74 in a further three-step sequence.
Alcohol 74 was then transformed to terminal olefin 75 via
the corresponding o-nitrophenyl selenide.17 After removal
of the TIPS and acetonide groups from 75, the resultant triol
was protected as the tris-benzyl ether 76 and the PMB group
was selectively removed (BF3$OEt2, Et3SiH/MeCN, 0 ꢀC)31
to complete the synthesis of the GHIJ-ring fragment 37.
With the requisite key fragments 36 and 37 in hand, the stage
was now set for the union of these complex fragments fol-
lowed by formation of the EF-ring. Acid 36 and alcohol
BnO
Me
BnO
Me
R
BnO
Me
O
PMB
O
H
Me
H
Me PMBO
OBn
OBn
H
Me
O
G
CHO PMBO
OBn
OBn
O
G
O
G
OBn
OBn
J
O
+
a
c
J
O
J
O
BnO
OTBS
BnO
OTBS
Me
H
BnO
OR
Me
H
OMe Me
H
60: R = H, OH
61: R = O
62: R = TBS
63: R = H
49
50
b
d
OR
BnO
Me
R
PMB
O
BnO
Me
OR1 R1
BnO
Me
H
Me
H
Me
H
Me
H
H
O
G
OBn
OBn
O
G
OR2
OBn
OBn
O
G
O
I
OBn
OBn
g
e
l
J
O
J
O
J
O
H
O
H
O
H
BnO
BnO
BnO
O
H
Me
H
H
H
Me
H
H
H
Me
H
64: R = O
65: R = α-H, β-OH
66: R1 = H, R2 = α-OPMB, β-H
67: R1 = TES, R2 = α-OPMB, β-H
68: R1 = TES, R2 = O
69: R1 = H, R2 = O
70: R = H
72: R = TIPS
f
h
i,j
m
k
OTIPS
OTIPS
OBn
R1O
Me
Me
Me
H
Me
H
H
H
H
H
Me
H
H
H
H
H
Me
H
H
O
G
O
I
O
O
G
O
I
O
O
G
O
I
OBn
OBn
n-p
v-x
t,u
J
O
J
O
J
O
H
H
H
O
O
R2O
q-s
O
PMBO
O
RO
O
H
H
Me
H
H
Me
H
H
Me
H
73: R1 = R2 = H
74: R1 = H, R2 = PMB
76: R = PMB
37: R = H
75
y
Scheme 10. Synthesis of GHIJ-ring 37. Reagents and conditions: (a) 50, t-BuLi, THF/HMPA, ꢁ78 ꢀC; then 49, ꢁ78 ꢀC, 95%; (b) (COCl)2, DMSO, Et3N,
CH2Cl2, ꢁ78 ꢀC/rt, 93%; (c) NaOMe, MeOH/THF, 98%; (d) HF$pyr/pyr/THF (2:1:4), 93%; (e) PPTS, toluene, 100 ꢀC, 87%; (f) DIBALH, toluene,
ꢁ78 ꢀC, 92%; (g) BH3$THF, THF, 0 ꢀC/rt; aq NaOH, H2O2, 91%; (h) TESOTf, 2,6-lutidine, CH2Cl2, quant.; (i) DDQ, CH2Cl2/pH 7 buffer, 0 ꢀC; (j)
ꢀ
ꢀ
˚
TPAP, NMO, 4 A molecular sieves, CH2Cl2, 0 C/rt; (k) TBAF, HOAc, THF, 81% (three steps); (l) TMSOTf, Et3SiH/MeCN (1:4), ꢁ10 C, 83%; (m) TIP-
SOTf, 2,6-lutidine, CH2Cl2; (n) H2, Pd/C, MeOH; (o) 2,2-dimethoxypropane, CSA, DMF, 30 ꢀC; (p) PPTS, MeOH/CH2Cl2, 0 ꢀC, 65% (four steps); (q) PivCl,
pyr, 0 ꢀC, 85%; (r) NaH, PMBCl, Bu4NI, DMF, 0 ꢀC/rt, 78%; (s) DIBALH, CH2Cl2, ꢁ78 ꢀC, 72%; (t) 2-NO2C6H4SeCN, Bu3P, THF; (u) m-CPBA, Et3N,
CH2Cl2, 0/35 ꢀC, 94% (two steps); (v) TBAF, THF, 92%; (w) TsOH, MeOH, 0 ꢀC; (x) NaH, BnBr, Bu4NI, DMF, 0 ꢀC/rt, 89% (two steps); (y) BF3$OEt2,
Et3SiH, MeCN, 0 ꢀC, quant.

K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
5983
37 were coupled by Yamaguchi esterification18 to afford 77
in 92% yield (Scheme 11). Ester 77 was then subjected to re-
ductive acetylation (DIBALH, CH2Cl2, ꢁ78 ꢀC; then Ac2O,
DMAP, pyridine, ꢁ78/0 ꢀC).19 The desired a-acetoxy
ether 78 was obtained albeit in moderate yield (55%) as an
approximately 1:1 mixture of diastereomers. Subsequent
treatment of 78 with TMSCN and TMSOTf in the presence
of DTBMP afforded the corresponding a-cyano ether, which
was desilylated with TBAF (MeCN, 70 ꢀC) to give alcohol
79 in 87% yield for the two steps. The nitrile group was
hydrolyzed under alkaline conditions (KOH, ethylene glycol,
150 ꢀC) to provide carboxylic acid 80 in 86% yield as a 1:1
mixture of diastereomers. Yamaguchi lactonization18 of
80 provided a mixture of seven-membered lactones, which
Figure 5. Stereochemical confirmation of BCDEFGHIJ-ring 5.
Me
was separated by flash column chromatography to afford
the desired 81 and its C25 diastereomer 82 in 36% and
32% yield for the two steps, respectively. The C25 stereo-
chemistry of 81 was unambiguously determined by NOE be-
tween 22-H and 25-H as shown in Scheme 11. Attempted
isomerization of 82 to the desired 81 under basic conditions
was unsuccessful as was the case with 32b. Reductive acet-
ylation of lactone 81 produced acetate 83 in 68% yield and
ca. 10:1 diastereomeric ratio. Stereochemistry at the C26 po-
sition of 83 was tentatively assigned on the basis of the fore-
going model studies (see Scheme 5). Upon treatment of 83
H
H
Me Me
OR
H
O
C
X
a
O
Me
H
OBn
H
36 + 37
NAPO
B
D
O
G
O
H
O
O
H
J
H
H
H
H
O
I
NAPO
77: R = TBS, X = O
b
H
OBn
78: R = TBS, X = H, OAc
79: R = H, X = H, CN
80: R = H, X = H, COOH
Me
O
c,d
e
H
OBn
O
f
Me
H
O
E
Me
O
25
+
H
H
Me Me
H
O
O
O
C
H
O
˚
Me
25
O
OBn
H
with allyltrimethylsilane in the presence of BF3$OEt2 (4 A
NAPO
B
D
O
22E
G
82
molecular sieve, MeCN, ꢁ40/ꢁ30 ꢀC), stereoselective
allylation took place from the less hindered a-side of the
molecule to afford diene 84 in 58% yield. Finally, RCM
reaction of 84 with second Grubbs catalyst 3523 (CH2Cl2,
40 ꢀC) led to the formation of the nine-membered F-ring,
furnishing the targeted nonacyclic BCDEFGHIJ-ring poly-
ether core 5 in 67% yield. The stereostructure of nonacycle
5 was unequivocally established by extensive NMR experi-
ments as shown in Figure 5.
H
H
O
H
O
H
J
H
H
H
H
O
I
81
NAPO
NOE
H
OBn
OBn
g
Me
O
Me
H
H
OAc
26
H
H
Me Me
O
O
C
O
Me
H
OBn
H
NAPO
B
D
O
E
G
O
H
H
O
O
H
J
H
H
H
H
O
I
83
NAPO
H
OBn
OBn
Me
h
O
H
Me
H
H
H
H
Me Me
3. Conclusion
O
O
C
O
Me
OBn
H
NAPO
B
D
O
E
G
O
We have accomplished the synthesis of the nonacyclic
BCDEFGHIJ-ring polyether core 5 of gambieric acids A
and C in a convergent fashion. The synthesis involved as
key features: (i) convergent union of the BCD- and GHIJ-
ring fragments through esterification; (ii) construction of
the seven-membered E-ring as a lactone form via reductive
acetylation; (iii) stereoselective allylation to establish the
C26 stereocenter; and (iv) cyclization of the nine-membered
F-ring by utilizing ring-closing metathesis reaction. Further
studies toward the total synthesis of gambieric acids A and C
and their analogues along these lines are in progress and will
be reported in due course.
H
H
H
O
H
O
H
J
H
H
H
H
O
I
NAPO
84
H
OBn
OBn
Me
O
i
35
H
Me
H
H
H
H
Me Me
O
F
O
C
O
Me
H
OBn
H
NAPO
B
D
O
E
G
O
H
O
O
H
J
H
H
H
H
O
I
5
NAPO
H
OBn
OBn
Me
O
H
Scheme 11. Synthesis of BCDEFGHIJ-ring polyether core 5. Reagents and
conditions: (a) 2,4,6-Cl3C6H2COCl, Et3N, THF, 40 ꢀC; DMAP, toluene,
40 ꢀC, 92%; (b) DIBALH, CH2Cl2, ꢁ78 ꢀC; Ac2O, DMAP, pyr, ꢁ78/
0 ꢀC, 55%; (c) TMSCN, TMSOTf, DTBMP, CH2Cl2, ꢁ78/0 ꢀC; (d)
TBAF, MeCN, 70 ꢀC, 87% (two steps); (e) KOH, ethylene glycol, 150 ꢀC,
86%; (f) 2,4,6-Cl3C6H2COCl, Et3N, THF/toluene; DMAP, reflux, 36% for
81, 32% for 82; (g) DIBALH, CH2Cl2, ꢁ78 ꢀC; Ac2O, DMAP, pyr,
4. Experimental
4.1. General methods
ꢀ
˚
All reactions sensitive to air or moisture were performed
under an atmosphere of argon in dry, freshly distilled
ꢁ78/0 C, 68%; (h) CH2]CHCH2TMS, BF3$OEt2, 4 A molecular
sieves, MeCN, ꢁ40/ꢁ30 ꢀC, 58%; (i) 35, CH2Cl2, 40 ꢀC, 67%.

5984
K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
solvents under anhydrous conditions, unless otherwise
noted. Anhydrous dichloromethane (CH2Cl2) was purchased
from Kanto Chemical Co., Inc. and used directly without
further drying. N,N-Dimethylformamide (DMF) was dried
saturated aqueous NH4Cl. The mixture was diluted with
EtOAc, washed with water and brine, dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. Purification
by column chromatography on silica gel (40% EtOAc/hex-
anes) afforded alcohol (3.04 g), which was used directly in
the subsequent reaction.
˚
over active 4 A molecular sieves. Acetonitrile (MeCN) and
toluene were freshly distilled from calcium hydride under
an atmosphere of argon. Tetrahydrofuran (THF) was freshly
distilled over sodium/benzophenone ketyl under an atmo-
sphere of argon. Hexamethylphosphoramide (HMPA) was
distilled from calcium hydride under reduced pressure. Tri-
methylsilyl chloride (TMSCl) was distilled from calcium
hydride. All other reagents were used as supplied unless oth-
erwise stated. Analytical thin-layer chromatography (TLC)
was performed using E. Merck silica gel 60 F254 pre-coated
plates (0.25-mm thickness). Column chromatography was
performed using Kanto Chemical silica gel 60 N (40–100
mesh, spherical, neutral), and for flash column chromato-
graphy Fuji Silysia silica gel BW-300 (200–400 mesh) was
used. Optical rotations were recorded on a JASCO DIP-
370 or P-1020 digital polarimeter. IR spectra were recorded
˚
To a suspension of the above alcohol and 4 A molecular
sieves in CH2Cl2 (36 mL) were added NMO (2.50 g,
21.3 mmol) and TPAP (0.31 g, 0.88 mmol). The resulting
mixture was stirred at 0 ꢀC for 2 h and then at room temper-
ature for 1 h. The mixture was concentrated under reduced
pressure, and the residue was purified by column chromato-
graphy on silica gel (20% EtOAc/hexanes) to afford methyl
ketone 11 (2.89 g, 82% for the four steps) as a colorless oil:
[a]2D1 +72.1 (c 0.18, CHCl3); IR (film) 2929, 1359, 1253,
1
1098, 837, 775, 669 cmꢁ1; H NMR (500 MHz, CDCl3)
d 3.82–3.79 (m, 1H), 3.51 (ddd, J¼9.5, 9.5, 3.0 Hz, 1H),
3.35–3.33 (m, 2H), 2.79 (dd, J¼15.5, 2.5 Hz, 1H), 2.42
(dd, J¼15.5, 9.5 Hz, 1H), 2.16 (s, 3H), 2.00–1.97 (m, 1H),
1.66–1.54 (m, 2H), 1.48–1.39 (m, 1H), 0.84 (s, 9H), 0.033
(s, 3H), 0.025 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 207.9, 79.4, 71.0, 67.8, 46.9, 33.4, 30.6, 25.7 (ꢂ3), 25.5,
17.9, ꢁ4.0, ꢁ4.8; HRMS (FAB) calcd for C14H29O3Si
[(M+H)+] 273.1886, found 273.1886.
1
on a JASCO FT/IR-4100 spectrometer. H and 13C NMR
spectra were recorded on a Varian Unity INOVA 500 or
INOVA 600 spectrometer. Chemical shifts are reported in
d (ppm) from tetramethylsilane with reference to internal re-
sidual solvent [1H NMR: CHCl3 (7.24), C6HD5 (7.15); 13
C
NMR: CDCl3 (77.0), C6D6 (128.0)]. Coupling constants
(J) are reported in hertz (Hz). The following abbreviations
are used to designate the multiplicities: s¼singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet, br¼broad
peak. FAB mass spectra were recorded on a JEOL JMS-
700 spectrometer and ESI-TOF mass spectra were measured
on a Bruker microTOFfocus spectrometer.
4.1.2. b-Alkoxyacrylate 12. To a solution of methyl ketone
11 (2.89 g, 10.6 mmol) in THF (54 mL) at 0 ꢀC was added
TBAF (1.0 M in THF, 21.2 mL, 21.2 mmol). The resulting
mixture was stirred at room temperature for 14 h before it
was concentrated under reduced pressure. Purification by
column chromatography on silica gel (70% EtOAc/hexanes)
afforded alcohol (1.58 g, 94%), which was used directly in
the subsequent reaction.
4.1.1. Methyl ketone 11. To a solution of olefin 10 (3.12 g,
12.9 mmol) in THF (43 mL) at 0 ꢀC was added 9-BBN-H
(0.5 M in THF, 103 mL, 51.5 mmol). The resulting mixture
was stirred at room temperature for 20 h. The solution was
cooled to 0 ꢀC and treated with 10% aqueous NaOH
(72 mL) followed by 30% H2O2 (58 mL). The resulting
mixture was stirred at room temperature for 9 h before it
was diluted with EtOAc. The organic layer was separated,
washed with saturated aqueous Na2SO3 and brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification by column chromatography on silica gel (30%
EtOAc/hexanes) afforded alcohol (3.16 g), which was used
directly in the subsequent reaction.
To a solution of the above alcohol (1.58 g, 10.0 mmol) in
CH2Cl2 (48 mL) at 0 ꢀC were added 4-methylmorpholine
(1.48 mL, 13.5 mmol) and ethyl propiolate (3.19 mL,
31.5 mmol). The resulting mixture was stirred at room tem-
perature for 14 h before it was concentrated under reduced
pressure. Purification by column chromatography on silica
gel (30% EtOAc/hexanes) afforded b-alkoxyacrylate 12
(2.22 g, 87%) as a pale yellow oil: [a]2D1 +15.8 (c 1.87,
1
CHCl3); IR (film) 2941, 1709, 1643, 1137, 835 cmꢁ1; H
NMR (500 MHz, CDCl3) d 7.43 (d, J¼12.0 Hz, 1H), 5.24
(d, J¼12.0 Hz, 1H), 4.12 (dd, J¼11.0, 4.0 Hz, 2H), 3.86–
3.83 (m, 1H), 3.72 (ddd, J¼9.5, 9.5, 3.5 Hz, 1H), 3.63
(ddd, J¼10.5, 10.5, 4.5 Hz, 1H), 3.36 (ddd, J¼11.5, 11.5,
3.5 Hz, 1H), 2.68 (dd, J¼16.0, 3.0 Hz, 1H), 2.52 (dd,
J¼15.5, 9.0 Hz, 1H), 2.21 (m, 1H), 2.15 (s, 3H), 1.72–1.62
(m, 2H), 1.50 (dddd, J¼12.5, 12.5, 12.5, 5.5 Hz, 1H), 1.23
(t, J¼7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 206.3,
167.6, 160.8, 98.4, 79.9, 76.1, 67.6, 59.8, 45.9, 31.0, 29.4,
25.0, 14.3; HRMS (FAB) calcd for C13H21O5 [(M+H)+]
257.1389, found 257.1394.
To a solution of the above alcohol in CH2Cl2/DMSO (1:1,
v/v, 48 mL) at 0 ꢀC were added Et3N (8.0 mL, 57.4 mmol)
and SO3$pyridine (7.63 g, 47.9 mmol). The resulting
mixture was stirred at room temperature for 2.5 h before it
was quenched with water. The solution was diluted with
EtOAc, washed with 1 M aqueous HCl, saturated aqueous
NaHCO3 and brine, dried over Na2SO4, filtered, and concen-
trated under reduced pressure. Purification by column chro-
matography on silica gel (30% EtOAc/hexanes) afforded
aldehyde, which was used directly in the subsequent
reaction.
4.1.3. Bicyclic ether 13. To a solution of b-alkoxyacrylate
12 (0.15 g, 0.59 mmol) in THF (6.3 mL) at 0 ꢀC were added
MeOH (60 mL) and SmI2 (0.1 M in THF, 18.9 mL,
1.89 mmol). The resulting mixture was stirred at 0 ꢀC for
15 min before it was quenched with 50% aqueous
Na2S2O3 and saturated aqueous NaHCO3. The mixture
was diluted with EtOAc, washed with brine, dried over
To a solution of the above aldehyde in THF (40 mL) at 0 ꢀC
was added methylmagnesium bromide (3.0 M in Et2O,
4.0 mL, 12.0 mmol). The resulting mixture was stirred at
room temperature for 3 h before it was quenched with

K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
5985
Na2SO4, filtered, and concentrated under reduced pressure.
Purification by column chromatography on silica gel (30%
EtOAc/hexanes) afforded bicyclic ether 13 (0.15 g, 99%)
as a colorless solid: [a]2D1 +28.9 (c 2.26, CHCl3); IR (film)
4.1.5. Carboxylic acid 7. To a solution of olefin 14 (1.82 g,
5.58 mmol) in THF (84 mL) at 0 ꢀC was added 9-BBN-H
(0.5 M in THF, 44 mL, 22.0 mmol). The reaction mixture
was stirred at room temperature for 4 h. The mixture was
cooled to 0 ꢀC, and treated with 10% aqueous NaOH
(33 mL) followed by 30% H2O2 (26 mL). The resulting mix-
ture was stirred at room temperature for 12 h before it was
diluted with EtOAc. The mixture was washed with saturated
aqueous Na2SO3 and brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. Purification by column
chromatography on silica gel (30% EtOAc/hexanes) af-
forded alcohol (1.74 g), which was used directly in the sub-
sequent reaction.
3437, 2940, 1736, 1298, 1105, 947 cmꢁ1
;
1H NMR
(500 MHz, CDCl3) d 4.19–4.09 (m, 2H), 3.89–3.84 (m,
1H), 3.69 (dd, J¼9.5, 4.0 Hz, 1H), 3.34 (ddd, J¼11.5,
11.5, 7.0 Hz, 1H), 3.05 (ddd, J¼9.5, 9.5, 4.5 Hz, 1H), 2.96
(ddd, J¼12.0, 12.0, 4.5 Hz, 1H), 2.68 (dd, J¼15.0, 3.0 Hz,
1H), 2.37 (dd, J¼15.5, 9.0 Hz, 1H), 2.12 (dd, J¼12.0,
4.5 Hz, 1H), 2.02 (ddd, J¼8.0, 8.0, 3.5 Hz, 1H), 1.73–1.66
(m, 3H), 1.60–1.51 (m, 1H), 1.44–1.36 (m, 1H), 1.24 (t,
J¼7.0 Hz, 3H), 1.21 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 172.2, 81.0, 79.0, 76.7, 70.8, 67.9, 60.7, 46.0, 34.9, 29.2,
25.5, 21.4, 14.2; HRMS (FAB) calcd for C13H23O5
[(M+H)+] 259.1545, found 259.1547.
To a solution of the above alcohol in CH2Cl2/DMSO (1:1,
v/v, 50 mL) at 0 ꢀC were added Et3N (3.48 mL, 25.0 mmol)
and SO3$pyridine (3.18 g, 20.0 mmol). The resulting mix-
ture was stirred at room temperature for 4 h before it was
quenched with water. The mixture was diluted with Et2O,
washed with water and brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure. The crude alde-
hyde was used directly in the subsequent reaction without
purification.
4.1.4. Olefin 14. To a solution of bicyclic ether 13
(0.63 g, 2.44 mmol) in CH2Cl2 (12 mL) at 0 ꢀC were added
2,6-lutidine (0.72 mL, 6.18 mmol) and TBSOTf (0.78 mL,
3.40 mmol). The resulting mixture was stirred at 0 ꢀC for
1 h and at room temperature for 12 h before it was quenched
with saturated aqueous NaHCO3. The mixture was diluted
with EtOAc, washed with brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure. The residue was
filtered through a plug of silica gel (20% EtOAc/hexanes)
to give TBS ether, which was used directly in the subsequent
reaction.
To a solution of the above aldehyde in t-BuOH/water (4:1,
v/v, 50 mL) at 0 ꢀC were added 2-methyl-2-butene (2.43 mL,
22.9 mmol), KH2PO4 (0.69 g, 5.07 mmol), and NaClO2
(1.61 g, 17.8 mmol). The resulting mixture was stirred at
room temperature for 2 h before it was diluted with
CHCl3. The mixture was washed with 1 M aqueous HCl,
dried over Na2SO4, filtered, and concentrated under reduced
pressure. Purification by column chromatography on silica
gel (10% MeOH/CHCl3) afforded carboxylic acid 7
(1.75 g, 88% for the three steps) as a colorless oil: [a]D21
+37.8 (c 2.69, CHCl3); IR (film) 2951, 1709, 1256, 1107,
To a solution of the above TBS ether in CH2Cl2 (20 mL) at
ꢁ78 ꢀC was added DIBALH (0.95 M in hexane, 2.9 mL,
2.76 mmol). The resulting mixture was stirred at ꢁ78 ꢀC
for 1.5 h before it was quenched with saturated aqueous
potassium sodium tartrate. The mixture was diluted with
EtOAc and vigorously stirred until the layers became clear.
The organic layer was separated, washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pres-
sure. The obtained crude aldehyde was used directly in the
subsequent reaction without purification.
1
1071, 835, 774, 667 cmꢁ1; H NMR (500 MHz, CDCl3)
d 3.88–3.86 (m, 1H), 3.34 (ddd, J¼15.5, 8.5, 6.0 Hz, 1H),
3.08 (dd, J¼10.5, 1.5 Hz, 1H), 2.99–2.90 (m, 2H), 2.53
(ddd, J¼16.5, 8.5, 6.5 Hz, 1H), 2.40 (ddd, J¼15.5, 7.5,
7.5 Hz, 1H), 2.12–1.99 (m, 3H), 1.73–1.16 (m, 9H), 0.82
(s, 9H), 0.07 (s, 6H); 13C NMR (125 MHz, CDCl3)
d 199.1, 84.5, 78.8, 76.7, 73.4, 67.9, 46.1, 31.6, 29.2, 25.7
(ꢂ3), 25.5, 23.6, 22.1, 17.9, ꢁ2.02, ꢁ2.07; HRMS (FAB)
calcd for C18H35O5Si [(M+H)+] 359.2254, found 359.2255.
To a solution of Ph3PCH3Br (2.5 g, 7.00 mmol) in CH2Cl2
(5 mL) at 0 ꢀC was added NaHMDS (1.0 M in THF,
4.62 mL, 4.62 mmol). The resulting ylide solution was
stirred at 0 ꢀC for 30 min. A solution of the above crude
aldehyde in THF (5.0 mL) was added and the mixture was
stirred at room temperature for 9 h before it was quenched
with saturated aqueous NH4Cl. The mixture was diluted
with Et2O, washed with brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure. Purification by
column chromatography on silica gel (20% EtOAc/hexanes)
afforded olefin 14 (0.61 g, 77% for the three steps) as a color-
less oil: [a]2D1 +48.4 (c 1.11, CHCl3); IR (film) 2953, 1256,
4.1.6. a,b-Unsaturated ester 16. To a solution of alcohol 15
(0.75 g, 5.86 mmol) in DMF (12 mL) at 0 ꢀC were added
imidazole (1.24 g, 18.2 mmol), DMAP (70.9 mg,
0.58 mmol), and TBSCl (2.20 g, 14.6 mmol). The resulting
solution was stirred at room temperature for 5 h before it
was quenched with saturated aqueous NH4Cl. The mixture
was diluted with Et2O, washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification by column chromatography on silica gel (20%
EtOAc/hexanes) afforded TBS ether (1.28 g, 90%), which
was used directly in subsequent reaction.
1139, 1105, 836, 774, 668 cmꢁ1 1H NMR (500 MHz,
;
CDCl3) d 5.94–5.85 (m, 1H), 5.06 (d, J¼17.0 Hz, 1H),
5.00 (d, J¼10.5 Hz, 1H), 3.88–3.86 (m, 1H), 3.37–3.31
(m, 1H), 3.15–3.13 (m, 1H), 3.00–2.91 (m, 2H), 2.43 (dd,
J¼15.0, 7.5 Hz, 1H), 2.10 (dd, J¼11.5, 4.5 Hz, 1H), 2.05–
1.96 (m, 2H), 1.71–1.60 (m, 3H), 1.45–1.37 (m, 1H), 1.20
(s, 3H), 0.83 (s, 9H), 0.07 (s, 6H); 13C NMR (125 MHz,
CDCl3) d 136.8, 115.7, 85.2, 78.8, 76.8, 73.5, 67.9, 46.1,
33.0, 29.3, 25.7, 25.6 (ꢂ3), 22.2, 18.0, ꢁ2.0, ꢁ2.1; HRMS
(FAB) calcd for C18H34O3SiNa [(M+Na)+] 349.2175, found
349.2177.
To a solution of the above TBS ether (1.28 g, 5.29 mmol) in
THF/H2O (1:1, v/v, 20 mL) were added NMO (50 wt % in
water, 2.4 mL, 10.2 mmol) and OsO4 (0.039 M in t-BuOH,
6.67 mL, 0.26 mmol). The resulting solution was stirred
at room temperature for 23 h before NaIO4 (3.38 g,
15.8 mmol) was added. The mixture was stirred at room

5986
K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
temperature for further 8 h. The reaction mixture was diluted
with EtOAc, washed with water, saturated aqueous Na2SO3,
and brine, dried over Na2SO4, filtered and concentrated un-
der reduced pressure. The crude aldehyde was used directly
in the subsequent reaction without purification.
with saturated aqueous NaHCO3. The mixture was diluted
with EtOAc, washed with brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure. Purification by
column chromatography on silica gel (30% EtOAc/hexanes)
afforded lactone 19 (1.0 mg, 81% for the two steps) as a col-
orless oil: [a]2D0 +105.6 (c 0.07, CHCl3); IR (film) 2920,
To a solution the above aldehyde in CH2Cl2 (53 mL) was
added Ph3P]CHCO2Me (2.30 g, 6.88 mmol). The resulting
mixture was stirred at room temperature for 12 h before it
was diluted with Et2O. The organic layer was washed with
brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure. Purification by column chromatography
on silica gel (30% EtOAc/hexanes) afforded a,b-unsaturated
ester 16 (1.44 g, 91% for the two steps) as a colorless oil:
[a]2D0 ꢁ40.8 (c 0.81, CHCl3); IR (film) 2951, 1726, 1265,
1727, 1383, 1075, 778, 661 cmꢁ1 1H NMR (500 MHz,
;
CDCl3) d 4.12 (ddd, J¼10.5, 10.5, 5.0 Hz, 1H), 3.98–3.95
(m, 1H), 3.47 (ddd, J¼11.5, 11.5, 3.5 Hz, 1H), 3.36 (dd,
J¼9.0, 5.0 Hz, 1H), 2.75 (dd, J¼18.0, 7.5 Hz, 1H), 2.45
(dd, J¼17.5, 3.5 Hz, 1H), 2.34 (ddd, J¼13.0, 6.5, 4.0 Hz,
1H), 2.25 (m, 1H), 1.73–1.54 (m, 3H), 1.07 (d, J¼7.5 Hz,
3H); 13C NMR (125 MHz, CDCl3) d 197.1, 72.9, 68.4,
37.5, 31.2, 30.1, 29.0, 25.1, 14.7; HRMS (EI) calcd for
C9H14O3 (M+) 170.0943, found 170.0951.
1
1099, 838, 777 cmꢁ1; H NMR (500 MHz, CDCl3) d 7.10
(dd, J¼15.5, 4.5 Hz, 1H), 6.03 (dd, J¼15.5, 1.5 Hz, 1H),
3.95–3.92 (m, 1H), 3.71 (s, 3H), 3.68–3.65 (m, 1H), 3.39–
3.34 (m, 1H), 3.32–3.27 (m, 1H), 2.04–2.01 (m, 1H),
1.68–1.64 (m, 2H), 1.55–1.47 (m, 1H), 0.86 (s, 9H), 0.02
(s, 6H); 13C NMR (125 MHz, CDCl3) d 167.0, 146.5,
120.4, 81.1, 71.2, 67.6, 51.5, 33.8, 25.7 (ꢂ3), 25.3, 17.9,
ꢁ4.3, ꢁ4.9; HRMS (FAB) calcd for C15H28O4SiNa
[(M+Na)+] 323.1655, found 323.1660.
4.1.9. Alcohol 20. To a solution of ester 18 (1.04 g,
3.29 mmol) in CH2Cl2 (16 mL) at ꢁ78 ꢀC was added
DIBALH (0.94 M in hexane, 10.5 mL, 9.87 mmol). The
resulting mixture was stirred at ꢁ78 ꢀC for 2 h before it
was quenched with saturated aqueous potassium sodium
tartrate. The mixture was vigorously stirred until the layers
became clear. The organic layer was separated, washed with
brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure. Purification by column chromatography
on silica gel (40% EtOAc/hexanes) afforded alcohol 20
(0.90 g, 95%) as a colorless oil: [a]2D1 ꢁ25.1 (c 1.34,
1H NMR (500 MHz, C6D6) d 3.70–3.55 (m, 5H), 3.00–
2.95 (m, 2H), 2.34–2.31 (m, 1H), 2.02 (br, 1H), 1.84–1.82
(m, 1H), 1.76 (ddd, J¼14.0, 14.0, 7.5 Hz, 1H), 1.70–1.64
(m, 1H), 1.41–1.32 (m, 1H), 1.29–1.18 (m, 1H), 1.10 (d,
J¼7.5 Hz, 3H), 0.95 (s, 9H), 0.08 (s, 3H), 0.04 (s, 3H);
13C NMR (125 MHz, C6D6) d 87.2, 68.1, 68.1, 59.9, 34.3,
33.0, 30.0, 26.0 (ꢂ3), 25.8, 18.1, 17.2, ꢁ3.6, ꢁ4.6; HRMS
(FAB) calcd for C15H33O3Si [(M+H)+] 289.2199, found
289.2204.
4.1.7. Ester 18. To a solution of bis(N-isopropylsalicylald-
imine) copper(II) complex 17 (5 mg, 12.9 mmol) and TMSCl
(0.49 mL, 3.86 mmol) in THF (3.2 mL) at ꢁ45 ꢀC was
added enoate 16 (0.39 g, 1.30 mmol) in THF (3.2 mL).
Methylmagnesium bromide (3.0 M in Et2O, 0.64 mL,
1.92 mmol) was added and the resulting mixture was stirred
at ꢁ45 ꢀC for 1.5 h before it was quenched with 1 M aque-
ous HCl. The mixture was diluted with Et2O, washed with
saturated aqueous NaHCO3 and brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. Purifica-
tion by column chromatography on silica gel (30% EtOAc/
hexanes) afforded ester 18 (0.37 g, 90%) as a colorless oil:
[a]2D0 ꢁ2.12 (c 0.24, CHCl3); IR (film) 2953, 1740, 1259,
CHCl3); IR (film) 2934, 1251, 1100, 836, 775, 669 cmꢁ1
;
1
1094, 837, 775, 669 cmꢁ1; H NMR (500 MHz, CDCl3)
4.1.10. Alcohol 8. To a solution of alcohol 20 (0.50 g,
1.74 mmol) in THF (17 mL) at 0 ꢀC was added KOt-Bu
(0.78 g, 6.95 mmol). The resulting solution was stirred at
room temperature for 10 min before benzyl bromide
(0.62 mL, 5.21 mmol) and Bu4NI (44 mg 0.12 mmol) were
added. The reaction mixture was stirred at room temperature
for 1 h before it was quenched with MeOH. The mixture was
diluted with Et2O, washed with brine, dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. Purification
by column chromatography on silica gel (40% EtOAc/hex-
anes) afforded benzyl ether (0.59 g, 90%) as a yellow oil:
[a]1D7 ꢁ42.3 (c 1.18, CHCl3); IR (film) 2930, 2855, 1099,
d 3.84–3.82 (m, 1H), 3.63 (s, 3H), 3.38 (ddd, J¼10.0,
10.0, 4.5 Hz, 1H), 3.25 (m, 1H), 2.93–2.91 (m, 1H), 2.44–
2.37 (m, 2H), 2.12 (dd, J¼15.0, 10.5 Hz, 1H), 2.02–1.99
(m, 1H), 1.59–1.51 (m, 2H), 1.43–1.35 (m, 1H), 1.02 (d,
J¼7.5 Hz, 3H), 0.86 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H);
13C NMR (125 MHz, CDCl3) d 174.2, 86.2, 68.0, 68.0,
51.3, 35.0, 33.9, 29.9, 25.8 (ꢂ3), 25.6, 17.9 (ꢂ2), ꢁ3.9,
ꢁ4.9; HRMS (FAB) calcd for C16H33O4Si [(M+H)+]
317.2148, found 317.2150.
4.1.8. Lactone 19. To a solution of ester 18 (2.3 mg,
7.3 mmol) in MeOH (0.07 mL) was added 1% HCl in
MeOH (0.35 mL). The resulting mixture was stirred at room
temperature for 2 h before being quenched with saturated
aqueous NaHCO3. The mixture was diluted with EtOAc,
washed with brine, dried over Na2SO4, filtered, and concen-
trated under reduced pressure. The crude alcohol was used
directly in the subsequent reaction without purification.
1
835, 775, 697 cmꢁ1; H NMR (500 MHz, CDCl3) d 7.31–
7.30 (m, 4H), 7.25 (m, 1H), 4.51–4.43 (m, 2H), 3.84 (m,
1H), 3.55–3.47 (m, 2H), 3.42 (m, 1H), 3.24 (m, 1H), 2.90
(dd, J¼8.5, 2.0 Hz, 1H), 2.1–2.0 (m, 2H), 1.79 (m, 1H),
1.75–1.54 (m, 2H), 1.46 (m, 1H), 1.37 (m, 1H), 0.96 (d,
J¼6.5 Hz, 3H), 0.84 (s, 9H) 0.04 (s, 3H), 0.03 (s, 3H); 13C
NMR (125 MHz, CDCl3) d 128.2 (ꢂ3), 127.5 (ꢂ2), 127.3,
87.3, 72.7, 69.2, 68.0, 67.8, 34.0, 29.51, 29.48, 25.8 (ꢂ3),
25.7, 17.9, 17.4, ꢁ3.7, ꢁ4.7; HRMS (ESI) calcd for
C22H38NaO3Si [(M+Na)+] 401.2488, found 401.2487.
To a solution the above alcohol in benzene (0.54 mL) was
added PPTS (0.9 mg, 3.6 mmol). The resulting mixture was
stirred at 80 ꢀC for 10 h. Toluene (1.0 mL) was added and
the mixture was stirred at 110 ꢀC for further 5 h. The reac-
tion mixture was cooled to room temperature and quenched
To a solution of the above benzyl ether (0.56 g, 1.48 mmol)
in THF (15 mL) at 0 ꢀC was added TBAF (1.0 M in THF,

K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
5987
4.5 mL, 4.5 mmol). The resultant mixture was stirred at
room temperature for 2 h and concentrated under reduced
pressure. Purification by column chromatography on silica
gel (30% EtOAc/hexanes) afforded alcohol 8 (0.39 g,
quant.) as a colorless oil: [a]1D7 ꢁ28.0 (c 1.00, CHCl3); IR
NH4Cl. The reaction mixture was diluted with EtOAc,
washed with brine and saturated aqueous NaHCO3, dried
over Na2SO4, filtered, and concentrated under reduced pres-
sure. Purification by column chromatography on silica gel
(20% EtOAc/hexanes) afforded ester 22 (0.85 g, quant.) as
a colorless oil: [a]1D7 +4.0 (c 1.76, CHCl3); IR (film) 2952,
1
(film) 3397, 2933, 2851, 1453, 1091, 737, 697 cmꢁ1; H
1
NMR (500 MHz, CDCl3) d 7.24–7.14 (m, 5H), 4.43–4.36
(m, 2H), 3.77 (m, 1H), 3.48 (m, 1H), 3.39–3.32 (m, 2H),
3.16 (m, 1H), 2.81 (dd, J¼8.5, 1.5 Hz, 1H), 2.47 (m, 1H),
2.00–1.92 (m, 2H), 1.87–1.80 (m, 1H), 1.54–1.49 (m, 2H),
1.31–1.16 (m, 2H), 0.90 (d, J¼7.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 128.5 (ꢂ2), 128.3, 127.8 (ꢂ2),
127.7, 86.8, 73.2, 69.4, 68.0, 67.1, 32.5, 30.1, 30.0, 25.8,
17.9; HRMS (ESI) calcd for C16H24NaO3 [(M+Na)+]
287.1623, found 287.1603.
2854, 1736, 1251, 1107, 835, 774, 697 cmꢁ1; H NMR
(500 MHz, CDCl3) d 7.31–7.24 (m, 5H), 4.73 (ddd,
J¼10.5, 10.5, 5.0 Hz, 1H), 4.48–4.42 (m, 2H), 3.89–3.85
(m, 2H), 3.50–3.41 (m, 2H), 3.36–3.28 (m, 2H), 3.15–3.13
(m, 1H), 3.03 (m, 1H), 2.94–2.88 (m, 2H), 2.49–2.43 (ddd,
J¼16.0, 9.5, 5.0 Hz, 1H), 2.28–2.22 (m, 1H), 2.16–2.08
(m, 2H), 2.02–1.96 (m, 2H), 1.87–1.82 (m, 2H), 1.69–1.47
(m, 6H), 1.44–1.36 (m, 3H), 1.18 (s, 3H), 0.96 (d,
J¼6.5 Hz, 3H), 0.83 (s, 9H), 0.07 (m, 6H); 13C NMR
(125 MHz, CDCl3) d 198.8, 128.3 (ꢂ2), 127.5 (ꢂ2), 127.3
(ꢂ2), 84.5, 83.8, 78.8, 76.8, 73.4, 72.5, 68.8, 68.7, 67.9,
67.7, 46.2, 32.0, 30.5, 30.2, 29.6, 29.3, 25.7 (ꢂ3), 25.5,
25.1, 23.9, 22.2, 18.0, 16.8, ꢁ2.0, ꢁ2.1; HRMS (ESI) calcd
for C34H56NaO7Si [(M+Na)+] 627.3693, found 627.3688.
4.1.11. Alcohol 21. To a solution of alcohol 20 (0.89 g,
3.09 mmol) in THF (15 mL) were added o-nitrophenyl
selenocyanate (1.05 g, 4.62 mmol) and Bu3P (1.53 mL,
6.13 mmol). The resulting mixture was stirred at room tem-
perature for 30 min before it was concentrated under
reduced pressure. The residue was filtered through a plug
of silica gel (10% EtOAc/hexanes) to give o-nitrophenyl
selenide, which was used directly in the subsequent reaction.
4.1.13. a-Acetoxy ether 23. To a solution of ester 22 (0.40 g,
0.66 mmol) in CH2Cl2 (13 mL) at ꢁ78 ꢀC was added DI-
BALH (0.94 M in hexane, 2.81 mL, 2.64 mmol). The resul-
tant mixture was stirred at ꢁ78 ꢀC for 20 min. A solution
of Ac2O (0.75 mL, 7.93 mmol) and DMAP (1.05 g,
8.59 mmol) in CH2Cl2 (13 mL) was added over 80 min,
and then a solution of pyridine (0.64 mL, 7.91 mmol) in
CH2Cl2 (6 mL) was added dropwise over 40 min. The mix-
ture was stirred at ꢁ78 ꢀC for 19 h and allowed to warm to
0 ꢀC. After being stirred at 0 ꢀC for 1 h, the reaction was
quenched with saturated aqueous NH4Cl and saturated aque-
ous potassium sodium tartrate. The mixture was vigorously
stirred until the layers became clear. The solution was di-
luted with EtOAc, washed with brine, dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. The residue
was filtered through a plug of silica gel (20% EtOAc/hex-
anes containing 1% Et3N) to afford a-acetoxy ether 23
(0.42 g, 98%) as a 4:1 mixture of diastereomers; [a]D17
ꢁ6.3 (c 1.39, CHCl3); IR (film) 2936, 2854, 1737, 1247,
To a solution the above selenide in CH2Cl2 (31 mL) at 0 ꢀC
was added m-CPBA (77%, 1.39 g, 6.20 mmol). The result-
ing mixture was stirred at 0 ꢀC for 30 min before it was
quenched with Et3N. The mixture was stirred at 35 ꢀC for
further 12 h and concentrated under reduced pressure. Puri-
fication by column chromatography on silica gel (10%
EtOAc/hexanes) afforded olefin (0.77 g, 92% for the two
steps), which was used directly in the subsequent reaction.
To a solution of the above olefin (0.77 g, 2.85 mmol) in THF
(28 mL) at 0 ꢀC was added TBAF (1.0 M in THF, 5.6 mL,
5.6 mmol). The resulting mixture was stirred at room tem-
perature for 15 h before it was quenched with saturated
aqueous NH4Cl. The organic layer was separated, washed
with brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. Purification by column chromato-
graphy on silica gel (40% EtOAc/hexanes) afforded
alcohol 21 (0.42 g, 94%) as a yellow oil: [a]2D1 ꢁ18.9 (c
3.83, CHCl3); IR (film) 3397, 2935, 1085, 1054, 1004,
1089, 836, 774, 698 cmꢁ1 1H NMR (500 MHz, C6D6)
;
d 7.32–7.30 (m, 2H), 7.19–7.17 (m, 2H), 7.08 (m, 1H),
6.29 (dd, J¼7.0, 4.0 Hz, 1H), 4.35 (m, 2H), 3.73–3.65 (m,
3H), 3.56–3.47 (m, 2H), 3.18–2.99 (m, 4H), 2.94–2.85 (m,
2H), 2.45 (m, 1H), 2.21–2.00 (m, 5H), 1.96–1.60 (m, 8H),
1.56–1.30 (m, 4H), 1.25–1.12 (m, 8H), 0.95 (s, 9H), 0.07
(s, 3H), 0.06 (s, 3H); 13C NMR (125 MHz, C6D6) d 168.6,
137.6, 126.5 (ꢂ2), 126.44, 126.0, 125.4, 92.9, 83.8, 83.2,
77.3, 75.3, 72.1, 70.8, 69.8, 67.5, 65.6, 65.7, 44.8, 31.3,
28.6, 28.5, 27.8, 27.7, 24.0 (ꢂ3), 23.9, 23.6, 21.5, 20.4,
18.8, 14.3, 15.3, ꢁ3.88, ꢁ3.93; HRMS (ESI) calcd for
C36H60NaO8Si [(M+Na)+] 671.3955, found 671.3976.
1
914, 717 cmꢁ1; H NMR (500 MHz, CDCl3) d 5.88 (ddd,
J¼17.0, 10.0, 8.0 Hz, 1H), 5.09–5.03 (m, 2H), 3.91–3.88
(m, 1H), 3.47–3.42 (m, 1H), 3.31–3.23 (m, 1H), 2.95 (dd,
J¼9.0, 2.5 Hz, 1H), 2.66 (ddd, J¼14.5, 7.5, 6.0 Hz, 1H),
2.05 (m, 1H), 1.64–1.56 (m, 2H), 1.45 (d, J¼4.0 Hz, 1H),
1.42–1.34 (m, 1H), 1.10 (d, J¼7.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 139.9, 115.1, 85.5, 67.9, 67.8, 38.6,
32.9, 25.6, 16.9; HRMS (FAB) calcd for C9H17O2
[(M+H)+] 157.1229, found 157.1231.
4.1.14. Alcohol 24. To a solution of a-acetoxy ether 23
(0.21 g, 0.32 mmol) in CH2Cl2 (0.4 mL) at 0 ꢀC were added
2,6-di-tert-butyl-4-methylpyridine (0.26 g, 1.27 mmol),
TMSSPh (0.12 mL, 0.63 mmol) and TMSOTf (0.17 mL,
0.94 mmol). The resultant mixture was stirred at 0 ꢀC
for 5 min and allowed to warm to room temperature.
After being stirred at room temperature for 2 h, the mixture
was quenched with Et3N, filtered, and concentrated under
reduced pressure. The residue was filtered through a
plug of silica gel (20% EtOAc/hexanes) to afford crude
4.1.12. Ester 22. To a solution of carboxylic acid 7 (0.70 g,
1.96 mol) in THF (14 mL) at 0 ꢀC were added Et3N
(0.70 mL, 5.02 mmol) and 2,4,6-trichlorobenzoyl chloride
(0.55 mL, 3.52 mmol). The resultant mixture was stirred at
room temperature for 1.5 h and concentrated under reduced
pressure. The mixture was added to a solution of alcohol 8
(0.37 g, 1.40 mmol) and DMAP (0.35 g, 2.86 mmol) in
THF (14 mL). The mixture was stirred at room temperature
for 2 h before it was quenched with saturated aqueous

5988
K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
mixed thioacetal (0.20 g, 88%) as a 1.5:1 mixture of
diastereomers.
(0.40 mL, 2.56 mmol). The reaction mixture was stirred at
40 ꢀC for 1.5 h before it was concentrated under reduced
pressure. The mixture was dissolved in toluene (20 mL)
and treated with alcohol 21 (0.31 g, 1.98 mmol) and
DMAP (0.48 g, 3.93 mmol). The resulting mixture was
stirred at 40 ꢀC for 2.5 h before it was quenched with satu-
rated aqueous NH4Cl. The mixture was diluted with EtOAc,
washed with brine and saturated aqueous NaHCO3, dried
over Na2SO4, filtered, and concentrated under reduced pres-
sure. Purification by column chromatography on silica gel
(20% EtOAc/hexanes) afforded ester 28 (0.90 g, 91%) as
a pale yellow oil: [a]D21 +21.7 (c 1.47, CHCl3); IR (film)
To a solution of the above mixed thioacetal (0.14 g,
0.20 mmol) in MeCN (2 mL) was added TBAF (0.54 g,
2.07 mmol). The resultant mixture was stirred at 70 ꢀC for
7 h before it was concentrated under reduced pressure. Puri-
fication by column chromatography on silica gel (EtOAc)
afforded alcohol 24 (0.11 g, 94%) as a ca. 1.25:1 mixture of
diastereomers: [a]1D6 ꢁ5.2 (c 1.49, CHCl3); IR (film) 3438,
1
2950, 2850, 1732, 1638, 1258, 1104, 750, 697 cmꢁ1; H
NMR (500 MHz, C6D6) d 7.69–7.67 (m, 0.88H), 7.61–
7.60 (m, 1.12H), 7.36–7.34 (m, 0.88H), 7.31–7.29 (m,
1.12H), 7.26 (m, 0.44H), 7.22–6.94 (m, 5.56H), 5.27 (m,
0.44H), 5.04 (m, 0.56H), 4.45–4.23 (m, 2H), 3.97 (ddd,
J¼9.5, 4.0, 4.0 Hz, 0.44H), 3.74–3.59 (m, 3.56H), 3.44–
3.29 (m, 2H), 3.18–3.14 (m, 1H), 3.04–2.96 (m, 3.44H),
2.92 (m, 0.44H), 2.88–2.73 (m, 2.56H), 2.49–2.45 (m,
1.44H), 2.45–2.35 (m, 2.56H), 2.17–1.99 (m, 3.24H),
1.94–1.82 (m, 2.88H), 1.73–1.64 (m, 1H), 1.60–1.09 (m,
10.44H); 13C NMR (125 MHz, C6D6) d 133.5 (ꢂ2), 133.3
(ꢂ2), 129.1 (ꢂ2), 129.0 (ꢂ2), 128.6 (ꢂ2), 128.53 (ꢂ2),
128.45 (ꢂ2), 128.3 (ꢂ3), 128.0 (ꢂ2), 127.7 (ꢂ2), 127.4,
127.3 (ꢂ2), 90.0, 86.6, 85.9, 85.5, 85.2, 84.8, 79.13, 79.10,
77.4, 77.3, 74.4 (ꢂ2), 73.1, 72.9, 71.1, 70.7, 69.6, 68.4,
67.7, 67.6 (ꢂ3), 46.7 (ꢂ2), 35.3, 34.5, 31.7, 30.6, 30.5,
30.3, 29.7, 29.2, 28.5, 27.6, 25.9 (ꢂ3), 25.8, 25.5 (ꢂ2),
21.64, 21.60, 17.6, 17.5; HRMS (ESI) calcd for
C34H48NaO6S [(M+Na)+] 607.3069, found 607.3077.
2953, 1737, 1107, 835, 774, 667 cmꢁ1
;
1H NMR
(500 MHz, CDCl3) d 5.78 (ddd, J¼18.5, 17.5, 10.5 Hz,
1H), 4.99 (dd, J¼11.0, 1.5 Hz, 1H), 4.90 (d, J¼17.5 Hz,
1H), 4.60 (dd, J¼12.5, 4.5 Hz, 1H), 3.93–3.86 (m, 2H),
3.38–3.27 (m, 2H), 3.17 (dd, J¼9.5, 2.5 Hz, 1H), 3.05 (dd,
J¼10.5, 1.5 Hz, 1H), 2.97–2.90 (m, 2H), 2.50 (ddd,
J¼15.5, 10.0, 5.5 Hz, 1H), 2.41 (ddd, J¼13.5, 7.0, 7.0 Hz,
1H), 2.27 (ddd, J¼15.5, 10.0, 6.5 Hz, 1H), 2.18–2.15 (m,
1H), 2.11 (dd, J¼11.5, 4.0 Hz, 1H), 2.04–1.98 (m, 2H),
1.71–1.50 (m, 6H), 1.43–1.33 (m, 2H), 1.20 (s, 3H) 1.08
(d, J¼7.0 Hz, 3H), 0.83 (s, 9H), 0.074 (s, 3H), 0.072 (s,
3H); 13C NMR (125 MHz, CDCl3) d 172.4, 138.9, 115.4,
84.5, 83.1, 78.9, 76.8, 73.4, 69.5, 68.0, 67.9, 46.2, 38.5,
32.1, 29.5, 29.3, 25.7 (ꢂ3), 25.6, 25.1, 24.0, 22.2, 18.0,
17.0, ꢁ2.0, ꢁ2.1; HRMS (FAB) calcd for C27H49O6Si
[(M+H)+] 497.3298, found 497.3300.
4.1.17. Alcohol 30. To a solution of ester 28 (0.29 g,
0.58 mmol) in CH2Cl2 (12 mL) at ꢁ78 ꢀC was added
DIBALH (0.95 M in hexane, 2.55 mL, 2.42 mmol). The re-
sulting mixture was stirred at ꢁ78 ꢀC for 1 h. A solution
of Ac2O (0.68 mL, 7.19 mmol) and DMAP (0.96 g,
7.86 mmol) in CH2Cl2 (12 mL) was added dropwise over
1 h, and then a solution of pyridine (0.57 mL, 7.37 mmol)
in CH2Cl2 (6 mL) was added over 0.5 h. The mixture was
stirred at ꢁ78 ꢀC for 8 h and allowed to warm to 0 ꢀC. After
being stirred at 0 ꢀC for 1 h, the reaction mixture was
quenched with saturated aqueous NH4Cl and saturated aque-
ous potassium sodium tartrate. The mixture was vigorously
stirred until the layers became clear. The solution was di-
luted with EtOAc, washed with brine, dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. The residue
was filtered through a plug of silica gel (20% EtOAc/
hexanes containing 1% Et3N) to afford a-acetoxy ether
(0.32 g) as a 3:1 mixture of diastereomers, which was used
directly in the subsequent reaction.
4.1.15. b-Alkoxyacrylate 9. To a solution of alcohol 24
(62.1 mg, 0.106 mmol) in CH2Cl2 (0.1 mL) at 0 ꢀC were
added Me3P (1.0 M in THF, 3.0 mL, 3.0 mmol) and methyl
propiolate (0.15 mL, 1.69 mmol). The resultant mixture was
stirred at room temperature for 11 h before it was concen-
trated under reduced pressure. Purification by column chro-
matography on silica gel (30% EtOAc/hexanes) afforded
b-alkoxyacrylate 9 (33.4 mg, 47%) as a ca. 1.2:1 mixture of
diastereomers, along with recovered 24 (26.3 mg, 42%) 9:
[a]1D7 ꢁ6.7 (c 0.62, CHCl3); IR (film) 2945, 2852, 1714,
1638, 1135, 1105, 748, 696 cmꢁ1 1H NMR (500 MHz,
;
C6D6) d 7.82–7.79 (m, 1H), 7.69–7.68 (m, 0.9H), 7.59–
7.58 (m, 1.1H), 7.35–6.93 (m, 8H), 5.67–5.64 (m, 1H),
5.25–5.18 (m, 0.55H), 4.96 (m, 0.45H), 4.44–4.36 (m,
2H), 3.95 (m, 0.45H), 3.73–3.67 (m, 1.9H), 3.62–3.58 (m,
2.65H), 3.51–3.20 (m, 5.55H), 3.17–3.12 (m, 2.1H), 3.05–
2.86 (m, 3.35H), 2.61–2.48 (m, 3.25H), 2.42–2.33 (m,
1.55H), 2.24 (m, 0.55H), 2.15–1.86 (m, 5.45H), 1.72–1.04
(m, 7.2H), 0.98 (s, 1.65H), 0.96 (s, 1.35H); 13C NMR
(125 MHz, C6D6) d 198.9, 196.9, 156.7, 156.6, 133.7
(ꢂ2), 133.5 (ꢂ2), 129.1 (ꢂ2), 129.0, 128.6, 128.5, 128.4
(ꢂ2), 128.3 (ꢂ6), 127.8 (ꢂ2), 127.7, 127.6, 127.5, 127.4
(ꢂ2), 127.3, 100.4, 100.3, 86.3 (ꢂ2), 85.5 (ꢂ2), 82.5,
82.3, 80.5 (ꢂ2), 78.9, 78.8, 76.5 (ꢂ2), 73.1, 72.9, 71.2,
69.6 (ꢂ2), 68.3, 67.7, 67.6 (ꢂ2), 50.6 (ꢂ2), 42.4 (ꢂ2),
34.6, 33.9, 31.9, 30.5 (ꢂ2), 30.3, 29.4 (ꢂ2), 29.3 (ꢂ2),
28.5, 25.6 (ꢂ3), 25.5 (ꢂ2), 18.5 (ꢂ2), 17.7, 17.6; HRMS
(ESI) calcd for C38H52NaO8S [(M+Na)+] 691.3281, found
691.3276.
To a solution of the above a-acetoxy ether (0.32 g) in
CH2Cl2 (11 mL) at ꢁ78 ꢀC were added 2,6-di-tert-butyl-4-
methylpyridine (0.46 g, 2.24 mmol), TMSCN (0.15 mL,
1.20 mmol), and TMSOTf (0.30 mL, 1.66 mmol). The
resulting mixture was stirred at ꢁ78 ꢀC for 30 min and
allowed to warm to 0 ꢀC. After being stirred at 0 ꢀC for 1 h,
the mixture was quenched with Et3N, filtered, and concen-
trated under reduced pressure. The residue was filtered
through a plug of silica gel (30% EtOAc/hexanes) to afford
crude a-cyano ether 29 (0.32 g) as a ca. 3:1 mixture of
diastereomers: [a]2D1 +5.2 (c 0.96, CHCl3); IR (film) 3074,
1
4.1.16. Ester 28. To a solution of carboxylic acid 7 (0.71 g,
1.98 mmol) in THF (20 mL) at 0 ꢀC were added Et3N
(0.41 mL, 2.94 mmol) and 2,4,6-trichlorobenzoyl chloride
2934, 1462, 1250, 1106, 836, 774, 667 cmꢁ1; H NMR
(500 MHz, CDCl3) d 5.87–5.75 (m, 1H), 5.14–4.89 (m, 2H),
4.31 (dd, J¼8.5, 5.0 Hz, 0.75H), 4.22–4.19 (m, 0.25H),

K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
5989
3.92–3.86 (m, 2H), 3.49–3.44 (m, 0.75H), 3.37–3.32 (m,
1.25H), 3.30–3.22 (m, 1H), 3.07–3.05 (m, 1H), 2.99–2.90
(m, 3H), 2.67 (ddd, J¼6.5, 6.5, 6.5 Hz, 0.75H), 2.55 (ddd,
J¼6.5, 6.5, 6.5 Hz, 0.25H), 2.44–2.41 (m, 0.25H), 2.22–
2.19 (m, 0.75H), 2.12–2.01 (m, 4H), 1.94–1.89 (m, 1H),
1.86–1.76 (m, 1H), 1.72–1.55 (m, 4H), 1.43–1.29 (m, 2H),
1.27–1.18 (m, 4H), 1.09–1.06 (m, 3H), 0.83 (m, 9H),
0.078 (s, 3H), 0.073 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 138.7, 118.5, 116.1, 109.7, 85.2, 83.9, 78.8, 76.7, 73.6,
73.4, 67.9, 64.3, 46.1, 38.0, 32.2, 29.3, 28.2, 25.69 (ꢂ3),
25.66, 25.5, 24.9, 24.0, 22.2, 17.7, ꢁ2.0, ꢁ2.1 (major iso-
mer); HRMS (FAB) calcd for C28H49NO5SiNa [(M+Na)+]
530.3278, found 530.3284.
(ꢂ2), 26.5, 26.2, 25.6, 25.4, 21.6, 21.5, 18.9, 18.6; HRMS
(FAB) calcd for C22H36O7Na [(M+Na)+] 435.2359, found
435.2365.
4.1.19. Lactones 32a and 32b. To a solution of hydroxy
acid 31 (0.44 g, 1.07 mol) in THF/toluene (1:1, v/v,
22 mL) at 0 ꢀC were added Et3N (0.30 mL, 2.15 mmol)
and 2,4,6-trichlorobenzoyl chloride (0.25 mL, 1.60 mmol).
The resulting mixture was stirred at room temperature for
2 h before it was diluted with toluene (44 mL). This mixture
was added dropwise to a refluxing solution of DMAP
(0.65 g, 5.32 mmol) in toluene (107 mL) over a period of
1.5 h. The reaction mixture was cooled to room temperature
and concentrated under reduced pressure. Purification by
column chromatography on silica gel (10–20% EtOAc/hex-
anes) afforded lactones 32a (0.16 g, 38%) as a colorless oil
and 32b (0.17 g, 40%) as a solid. 32a: [a]2D1 ꢁ49.5 (c 0.55,
To a solution of the above a-cyano ether 29 (0.32 g) in
MeCN (11 mL) was added TBAF (1.35 g, 5.16 mmol).
The resulting mixture was stirred at 70 ꢀC for 29 h before
it was concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel
(EtOAc) to afford alcohol 30 (0.14 g, 61% for the three
steps) as a ca. 1.5:1 mixture of diastereomers: [a]2D1 ꢁ5.4
(c 0.81, CHCl3); IR (film) 3443, 2938, 1455, 1383, 1105,
1
CHCl3); IR (film) 2940, 1720, 1076, 947, 705 cmꢁ1; H
NMR (500 MHz, CDCl3) d 5.80 (ddd, J¼18.5, 10.5,
9.0 Hz, 1H), 5.07 (d, J¼16.5 Hz, 1H), 5.05 (d, J¼10.5 Hz,
1H), 4.40 (d, J¼4.0 Hz, 1H), 3.91–3.85 (m, 2H), 3.43–
3.31 (m, 3H), 3.24 (ddd, J¼11.0, 11.0, 2.5 Hz, 1H), 3.04–
2.95 (m, 3H), 2.65 (ddd, J¼14.0, 7.0, 7.0 Hz, 1H), 2.28
(dd, J¼12.5, 8.5 Hz, 1H), 2.17 (m, 1H), 2.11–2.02 (m,
2H), 1.95–1.89 (m, 1H), 1.80–1.76 (m, 2H) 1.73–1.66 (m,
5H), 1.63–1.49 (m, 3H), 1.45–1.34 (m, 2H), 1.07 (d,
J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 171.1,
138.9, 116.1, 84.1, 82.9, 82.4, 79.0, 78.5, 76.5, 76.4, 67.9,
67.6, 45.1, 37.7, 30.1, 29.1, 27.7, 25.4, 25.1, 24.8, 20.2,
18.1; HRMS (FAB) calcd for C22H35O6 [(M+H)+]
395.2434, found 395.2434. 32b: [a]2D1 ꢁ13.9 (c 0.83,
1
967, 930, 680 cmꢁ1; H NMR (500 MHz, CDCl3) d 5.89–
5.78 (m, 1H), 5.15–4.95 (m, 2H), 4.34 (dd, J¼7.0, 6.0 Hz,
0.6H), 4.22 (dd, J¼6.5, 6.5 Hz, 0.4H), 3.92–3.87 (m, 2H),
3.47 (ddd, J¼11.0, 9.5, 4.5 Hz, 0.6H), 3.38–3.32 (m, 1H),
3.31–3.23 (m, 1.4H), 3.13–3.10 (m, 1H), 3.02–2.92
(m, 3H), 2.68 (ddd, J¼15.0, 7.0, 7.0 Hz, 0.6H), 2.56 (ddd,
J¼14.0, 7.0, 7.0 Hz, 0.4H), 2.43 (m, 0.4H), 2.20 (m,
0.6H), 2.11–2.02 (m, 3.6H), 1.91–1.81 (m, 2H), 1.74–1.35
(m, 9.4H), 1.29–1.18 (m, 3H), 1.09 (d, J¼6.5 Hz, 1.8H),
1.07 (d, J¼7.5 Hz, 1.2H); 13C NMR (125 MHz, CDCl3)
d 140.1, 138.7, 119.7, 118.5, 116.2, 115.4, 84.4, 84.3,
83.8, 83.7, 78.9, 78.9, 77.6, 76.7 (ꢂ2), 73.7, 71.14, 71.12,
68.1, 67.9 (ꢂ3), 67.8, 64.5, 46.0, 45.9, 38.4, 38.0, 31.8,
31.7, 30.0, 29.24, 29.23, 28.17, 25.5 (ꢂ2), 25.3, 24.9, 24.0,
23.6, 21.7, 21.6, 18.1, 17.7; HRMS (FAB) calcd for
C22H36NO5 [(M+H)+] 394.2593, found 394.2594.
CHCl3); IR (film) 3070, 2943, 1743, 1098, 941, 681 cmꢁ1
;
1H NMR (500 MHz, CDCl3) d 5.95 (ddd, J¼19.0, 9.0,
9.0 Hz, 1H), 5.05 (dd, J¼10.0, 1.5 Hz, 1H), 5.02 (d,
J¼17.0 Hz, 1H), 4.12 (dd, J¼11.0, 1.5 Hz, 1H), 3.91–3.85
(m, 2H), 3.37–3.32 (m, 2H), 3.25 (ddd, J¼13.5, 11.5,
2.5 Hz, 1H), 3.11–3.01 (m, 3H), 2.96 (ddd, J¼12.0, 9.5,
4.0 Hz, 1H), 2.63 (ddd, J¼15.0, 7.5, 7.5 Hz, 1H), 2.37–
2.35 (m, 1H), 2.26 (dd, J¼12.0, 3.5 Hz, 1H), 2.04–2.02
(m, 3H), 1.85–1.76 (m, 3H) 1.73–1.69 (m, 2H), 1.64–1.61
(m, 1H), 1.58–1.45 (m, 5H), 1.43–1.35 (m, 1H), 1.09 (d,
J¼6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 172.8,
140.7, 115.2, 84.5, 80.9, 80.8, 79.1, 79.0, 77.6, 76.3, 68.0,
67.9, 45.1, 38.6, 30.4, 29.03, 29.01, 27.7, 25.7, 25.4, 19.8,
18.7; HRMS (FAB) calcd for C22H35O6 [(M+H)+]
395.2434, found 395.2433.
4.1.18. Hydroxy acid 31. To a solution of alcohol 30 (0.14 g,
0.36 mmol) in ethylene glycol (3.5 mL) was added KOH
(0.20 g, 3.56 mmol). The resulting mixture was stirred at
150 ꢀC for 14 h. The solution was cooled to room tempera-
ture and quenched with 1 M aqueous HCl. The mixture was
diluted with CHCl3, washed with 1 M aqueous HCl and
brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure. Purification by column chromatography
on silica gel (20% MeOH/CHCl3) afforded hydroxy acid
31 (0.14 g, 95%) as a 1:1 mixture of diastereomers: [a]D21
+0.89 (c 1.12, CHCl3); IR (film) 3416, 2938, 1728, 1105,
4.1.20. Acetate 33. To a solution of lactone 32a (0.15 g,
0.38 mmol) in CH2Cl2 (7.7 mL) at ꢁ78 ꢀC was added
DIBALH (0.95 M in hexane 1.64 mL, 1.56 mmol). The
resulting mixture was stirred at ꢁ78 ꢀC for 1 h. A solution
of Ac2O (0.44 mL, 4.65 mmol) and DMAP (0.61 g,
4.99 mmol) in CH2Cl2 (7.7 mL) was added dropwise over
40 min, and then a solution of pyridine (0.38 mL,
4.70 mmol) in CH2Cl2 (3.9 mL) was added over 20 min.
The resulting mixture was stirred at ꢁ78 ꢀC for 13 h and
allowed to warm to 0 ꢀC. After being stirred at 0 ꢀC for 1 h,
the reaction mixture was quenched with saturated aqueous
NH4Cl and saturated aqueous potassium sodium tartrate,
and vigorously stirred until the layers became clear. The
mixture was diluted with CH2Cl2, washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pres-
sure. Purification by column chromatography on silica gel
1
921, 680 cmꢁ1; H NMR (500 MHz, CD3OD) d 5.90–5.81
(m, 1H), 5.09–4.95 (m, 2H), 4.05 (dd, J¼7.5, 4.5 Hz,
0.5H), 3.90 (dd, J¼5.5, 5.5 Hz, 0.5H), 3.85–3.82 (m, 2H),
3.40–3.23 (m, 4.5H), 3.18 (ddd, J¼9.0, 4.0 Hz, 0.5H),
3.12–2.91 (m, 4H), 2.84 (ddd, J¼14.5, 7.0, 7.0 Hz, 0.5H),
2.74 (ddd, J¼14.0, 7.0, 7.0 Hz, 0.5H), 2.28–2.26 (m,
0.5H), 2.17–2.14 (m, 0.5H), 2.02–1.92 (m, 3.5H), 1.86–
1.76 (m, 1.5H), 1.69–1.26 (m, 8H), 1.14 (s, 3H), 1.08 (d,
J¼6.5 Hz, 1.5H), 1.06 (d, J¼6.0 Hz, 1.5H); 13C NMR
(125 MHz, CD3OD) d 178.5, 176.9, 141.1, 141.0, 116.1,
115.8, 86.2, 86.0, 85.8, 85.5, 80.2, 80.2, 79.8, 78.3 (ꢂ2),
77.9, 77.4, 75.4, 71.6, 71.6, 68.8 (ꢂ2), 68.8, 68.6, 46.7,
46.7, 39.5, 38.9, 32.2, 32.2, 31.1, 30.5, 30.33, 30.31, 26.7

5990
K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
(30% EtOAc/hexanes) afforded acetate 33 (0.16 g, 96%) as
a colorless oil: [a]2D1 ꢁ26.4 (c 0.73, CHCl3); IR (film) 2939,
4.1.23. a,b-Unsaturated ester 39. To a solution of alcohol
38 (22.8 g, 82.6 mmol) in CH2Cl2/DMSO (1/2, v/v, 309 mL)
at 0 ꢀC were added Et3N (34.0 mL, 244 mmol) and
SO3$pyridine (26.2 g, 165 mmol). The resulting mixture
was stirred at room temperature for 3 h before water was
added. The mixture was diluted with Et2O, washed with wa-
ter and brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. Purification by column chromato-
graphy on silica gel (30% EtOAc/hexanes) afforded alde-
hyde, which was used directly in the subsequent reaction.
1
1752, 1234, 1085, 1020, 943 cmꢁ1; H NMR (500 MHz,
CDCl3) d 5.96–5.89 (m, 2H), 5.02–4.98 (m, 2H), 3.88–
3.86 (m, 2H), 3.77–3.56 (m, 1H), 3.36–3.30 (m, 2H),
3.27–3.21 (m, 2H), 3.06 (dd, J¼9.5, 1.0 Hz, 1H), 3.01–
2.98 (m, 2H), 2.89 (ddd, J¼7.5, 7.5, 7.5 Hz, 1H), 2.07–
2.00 (m, 8H), 1.97–1.85 (m, 2H), 1.72–1.50 (m, 4H),
1.47–1.37 (m, 3H), 1.33 (s, 3H), 1.08 (d, J¼7.5 Hz, 3H);
13C NMR (125 MHz, CDCl3) d 169.2, 140.2, 115.2, 91.7,
85.2, 83.2, 79.9, 77.2, 76.7, 76.2, 74.3, 67.90, 67.85, 43.0,
37.2, 31.4, 29.4, 28.9, 25.6, 25.5, 24.4, 21.2, 20.8, 18.1;
HRMS (FAB) calcd for C24H38O7Na [(M+Na)+] 461.2515,
found 461.2519.
To a suspension of Ph3PCH3Br (42.0 g, 118 mmol) in THF
(137 mL) at 0 ꢀC was added NaHMDS (1.9 M in THF,
45.0 mL, 85.5 mmol). The resulting ylide solution was
stirred at 0 ꢀC for 30 min. A solution of the above crude
aldehyde in THF (5.0 mL) was added, and the mixture was
stirred at room temperature for 12.5 h before saturated aque-
ous NH4Cl was added. The reaction mixture was diluted
with Et2O, washed with brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure. Purification by
column chromatography on silica gel (30% EtOAc/hexanes)
afforded olefin (21.4 g, 95% for the two steps) as a color-
less oil.
4.1.21. Diene 34. To a suspension of acetate 33 (50.0 mg,
˚
0.114 mmol) and 4 A molecular sieves in MeCN (1.2 mL)
at ꢁ40 ꢀC was added allyltrimethylsilane (55.0 mL,
0.35 mmol). After 5 min, BF3$OEt (4 mL, 32 mmol) was
added. The resulting mixture was stirred at ꢁ40 ꢀC for 2 h
and allowed to warm to 0 ꢀC. After being stirred at 0 ꢀC
for 2 h, the reaction mixture was quenched with Et3N, fil-
tered, and concentrated under reduced pressure. Purification
by column chromatography on silica gel (10% EtOAc/hex-
anes) afforded diene 34 (31.6 mg, 66%) as a colorless oil:
[a]2D1 +2.9 (c 1.30, CHCl3); IR (film) 3072, 2938, 1454,
To a solution of the above olefin (4.49 g, 16.5 mmol) in THF
(163 mL) at 0 ꢀC was added 9-BBN-H (0.5 M in THF,
130 mL, 65.0 mmol). The resulting mixture was stirred at
room temperature for 18 h. The reaction mixture was cooled
to 0 ꢀC and treated with 10% aqueous NaOH (40 mL) fol-
lowed by 30% H2O2 (73 mL). The resulting mixture was
stirred at room temperature for 15 h before being diluted
with EtOAc. The organic layer was separated, washed
with saturated aqueous Na2SO3 and brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification by column chromatography on silica gel (30%
EtOAc/hexanes) afforded primary alcohol (3.80 g, 79%) as
a colorless oil.
1
1436, 1086, 912, 679 cmꢁ1; H NMR (500 MHz, CDCl3)
d 5.91–5.76 (m, 2H), 5.05–4.99 (m, 4H), 3.89–3.84 (m,
2H), 3.77 (ddd, J¼7.5, 7.5, 2.0 Hz, 1H), 3.51 (dd, J¼2.5,
2.5 Hz, 1H), 3.34 (ddd, J¼11.5, 11.5, 4.0 Hz, 1H), 3.23
(ddd, J¼11.0, 11.0, 2.5 Hz, 1H), 3.11–2.95 (m, 5H), 2.66
(ddd, J¼15.0, 5.0, 5.0 Hz, 1H), 2.23–2.21 (m, 2H), 2.10–
2.02 (m, 2H), 1.94 (dd, J¼11.0, 3.5 Hz, 1H) 1.84 (m, 1H),
1.78–1.67 (m, 3H), 1.58–1.51 (m, 5H), 1.46–1.38 (m, 1H),
1.35–1.27 (m, 4H), 1.08 (d, J¼7.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 139.7, 135.4, 116.8, 115.2, 85.6,
84.8, 80.5, 79.2, 77.6, 77.2, 76.0, 74.3, 68.0, 67.9, 45.1,
41.2, 37.7, 31.1, 29.5, 27.1, 25.7, 25.4, 23.7, 18.4, 16.0;
HRMS (FAB) calcd for C25H41O5Si [(M+H)+] 421.2954,
found 421.2959.
To a solution of the above alcohol (3.75 g, 12.9 mmol) in
CH2Cl2/DMSO (1:1, v/v, 130 mL) at 0 ꢀC were added
Et3N (8.9 mL, 63.9 mmol) and SO3$pyridine (8.20 g,
51.5 mmol). The resulting mixture was stirred at room tem-
perature for 1 h before water was added. The mixture was di-
luted with Et2O, washed with water and brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure
to give the crude aldehyde, which was used directly in the
subsequent reaction without purification.
4.1.22. CDEFG-ring model 6. To a solution of diene 34
(6.7 mg, 16.0 mmol) in CH2Cl2 (3.2 mL) was added Grubbs’
catalyst 35 (3.4 mg, 4.0 mmol). The resulting mixture was
stirred at 40 ꢀC for 20 h. The reaction mixture was cooled
to 0 ꢀC, quenched with Et3N (one drop), and concentrated
under reduced pressure. Purification by column chromato-
graphy on silica gel (10% EtOAc/hexanes) afforded
CDEFG-ring model 6 (6.1 mg, 98%) as a colorless oil:
[a]2D1 ꢁ54.3 (c 1.00, CHCl3); IR (film) 3090, 2937, 1462,
To a solution the above aldehyde in toluene (65 mL) was
added Ph3P]C(CH3)CO2Et (9.33 g, 25.7 mmol). The re-
sulting mixture was stirred at 100 ꢀC for 11 h before being
concentrated under reduced pressure. The residue was puri-
fied by column chromatography on silica gel (30% EtOAc/
hexanes) to afford a,b-unsaturated ester 39 (4.34 g, 90% for
the two steps) as a colorless oil: [a]3D1 +84.4 (c 1.50, CHCl3);
IR (film) 2953, 2931, 2894, 2857, 1712, 1257, 1129, 1091,
1376, 1095, 1039, 791, 678 cmꢁ1 1H NMR (500 MHz,
;
CDCl3) d 5.71 (ddd, J¼11.0, 5.0, 5.0 Hz, 1H), 5.42 (dd,
J¼11.0, 11.0 Hz, 1H), 3.86 (m, 2H), 3.80 (ddd, J¼10.5,
3.0, 3.0 Hz, 1H), 3.34 (ddd, J¼11.0, 11.0, 4.5 Hz, 1H),
3.24–3.12 (m, 3H), 3.10–3.05 (m, 2H), 3.03–2.98 (m, 2H),
2.93 (ddd, J¼11.0 ,11.0, 3.5 Hz, 1H), 2.78 (ddd, J¼14.5,
14.5, 3.5 Hz, 1H), 2.14–1.92 (m, 5H), 1.79–1.65 (m, 4H),
1.63–1.50 (m, 4H), 1.45–1.34 (m, 2H), 1.18 (s, 3H), 1.00
(d, J¼6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 134.0,
126.6, 84.8, 84.0, 83.9, 82.2, 79.1, 77.0, 75.4, 75.3, 68.7,
67.9, 45.0, 32.3, 32.2, 32.1, 31.4, 29.4, 26.2, 25.6, 24.5,
16.6, 15.5; HRMS (FAB) calcd for C23H37O5 [(M+H)+]
393.2641, found 393.2644.
1
1058, 8337, 775, 668 cmꢁ1; H NMR (500 MHz, CDCl3)
d 6.88 (dd, J¼7.0, 7.0 Hz, 1H), 4.59 (d, J¼2.5 Hz, 1H),
4.16 (dd, J¼14.0, 6.5 Hz, 2H), 3.56 (ddd, J¼9.5, 9.5,
3.0 Hz, 1H), 3.37 (m, 1H), 3.29 (m, 3H), 2.66 (dd, J¼15.0,
6.5 Hz, 1H), 2.19 (m, 1H), 1.87–1.66 (m, 7H), 1.25 (dd,
J¼7.0, 7.0 Hz, 3H), 0.86 (s, 9H), 0.04 (s, 6H); 13C NMR
(125 MHz, CDCl3) d 163.3, 139.3, 129.3, 97.5, 72.8, 71.1,

K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
5991
60.6, 54.6, 31.5, 29.6, 28.5, 26.0 (ꢂ3), 18.2, 14.5, 12.8,
ꢁ3.7, ꢁ4.5; HRMS (FAB) calcd for C19H36O5SiNa
[(M+Na)+] 395.2230, found 395.2231.
chromatography on silica gel (40% EtOAc/hexanes contain-
ing 1% Et3N) afforded hydroxy epoxide 40 (2.11 g, 93%) as
a colorless oil: [a]3D2 +111.3 (c 0.91, CHCl3); IR (film) 3415,
2937, 1441, 1383, 1127, 1053, 940, 875, 763, 665 cmꢁ1; 1H
NMR (500 MHz, CDCl3) d 5.64 (dd, J¼17.5, 10.5 Hz, 1H),
5.32 (dd, J¼15.0, 1.0 Hz, 1H), 5.17 (dd, J¼11.0, 1.0 Hz,
1H), 4.64 (d, J¼2.0 Hz, 1H), 3.65 (ddd, J¼10.0, 7.0, 3.0 Hz,
1H), 3.54 (m, 1H), 3.31 (s, 3H), 3.07 (dd, J¼7.5, 4.5 Hz,
1H), 2.06 (m, 1H), 1.87–1.71 (m, 6H), 1.41 (s, 3H); 13C
NMR (125 MHz, CDCl3) d 140.7, 128.3, 116.2, 97.4, 71.4,
69.5, 62.0, 54.4, 30.9, 29.5, 27.3, 15.0; HRMS (ESI) calcd
for C12H20O4Na [(M+Na)+] 251.1259, found 251.1234.
4.1.24. Hydroxy epoxide 40. To a solution of a,b-unsatu-
rated ester 39 (4.2 g, 11.3 mmol) in CH2Cl2 (113 mL) at
ꢁ78 ꢀC was added DIBALH (0.95 M in hexane, 59.5 mL,
56.5 mmol). The resulting solution was stirred at ꢁ78 ꢀC
for 1 h before it was quenched with saturated aqueous potas-
sium sodium tartrate. The mixture was vigorously stirred un-
til the layers became clear. The organic layer was separated,
washed with brine, dried over Na2SO4, filtered, and concen-
trated under reduced pressure. Purification by column chro-
matography on silica gel (30% EtOAc/hexanes) afforded
allylic alcohol (3.70 g, 99%) as a colorless oil.
4.1.25. TBS ether 41. To a solution of alcohol 40 (2.11 g,
9.25 mmol) in CH2Cl2 (92 mL) at 0 ꢀC was added pyridi-
nium p-toluenesulfonate (1.16 g, 4.62 mmol). The resulting
mixture was stirred at room temperature for 14.5 h before
being quenched with Et3N. The solution was filtered and
concentrated under reduced pressure. Purification by column
chromatography on silica gel (30% EtOAc/hexanes) af-
forded bicyclic ether (2.02 g, 96%) as a colorless oil.
To a solution of the allylic alcohol (3.70 g, 11.2 mmol) and
˚
activated powdered 4 A molecular sieves in CH2Cl2
(110 mL) at ꢁ20 ꢀC was added D-(+)-diethyl tartrate
(0.58 mL, 3.39 mmol). The mixture was stirred at ꢁ20 ꢀC
for 15 min before Ti(Oi-Pr)4 (0.66 mL, 2.23 mmol) was
added. The solution was stirred at the same temperature
for further 30 min. t-BuOOH (5.5 M in isooctane,
4.08 mL, 22.4 mmol) was added, and the reaction mixture
was stirred at ꢁ20 ꢀC for 17 h before Et2O and aqueous
Na2SO4 were added. The resulting mixture was vigorously
stirred at room temperature for 2 h before being filtered
through a pad of Celite. The filtrate and washings were com-
bined and concentrated, and the residue was filtered through
a plug of silica gel (40% EtOAc/hexanes) to afford the crude
epoxy alcohol, which was used directly in the subsequent
reaction.
To a solution of the above bicyclic ether (2.02 g, 8.86 mmol)
in CH2Cl2 (45 mL) at 0 ꢀC were added 2,6-lutidine
(3.09 mL, 26.5 mmol) and TBSOTf (2.99 mL, 13.0 mmol).
The resulting solution was stirred at room temperature for
2 h before it was quenched with saturated aqueous NH4Cl.
The mixture was diluted with EtOAc, washed with brine,
dried over Na2SO4, filtered, and concentrated under reduced
pressure. Purification by column chromatography on silica
gel (30% EtOAc/hexanes) afforded TBS ether 41 (2.94 g,
97%) as a colorless oil: [a]3D2 +72.0 (c 0.61, CHCl3); IR
(film) 3408, 2952, 2886, 1643, 1105, 1031, 837,
To a solution of the epoxy alcohol in CH2Cl2/DMSO (4:1,
v/v, 70 mL) at 0 ꢀC were added Et3N (6.7 mL, 48.1 mmol)
and SO3$pyridine (5.34 g, 33.6 mmol). The resulting mix-
ture was stirred at room temperature for 1.5 h before it was
quenched with water. The solution was diluted with Et2O,
washed with water and brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure to give the crude
aldehyde, which was used directly in the subsequent reaction
without purification.
775 cmꢁ1 1H NMR (500 MHz, CDCl3) d 5.89 (dd,
;
J¼17.5, 10.5 Hz, 1H), 5.26 (dd, J¼17.5, 1.5 Hz, 1H), 5.07
(dd, J¼10.5, 1.5 Hz, 1H), 4.62 (d, J¼1.5 Hz, 1H), 3.56
(dd, J¼11.5, 5.0 Hz, 1H), 3.40 (ddd, J¼13.5, 9.5, 4.5 Hz,
1H), 3.35–3.27 (m, 4H), 1.92 (ddd, J¼11.5, 4.5, 4.5 Hz,
1H), 1.87–1.84 (m, 1H), 1.79–1.69 (m, 3H), 1.63 (m, 1H),
1.55 (s, 3H), 0.84 (s, 9H), 0.03, (s, 3H), 0.00 (s, 3H); 13C
NMR (125 MHz, CDCl3) d 143.5, 113.6, 98.0, 78.0, 73.1,
70.3, 68.2, 54.9, 35.4, 29.8, 26.0 (ꢂ3), 25.0, 18.1, 15.0,
ꢁ3.9, ꢁ4.6; HRMS (ESI) calcd for C18H34O4SiNa
[(M+Na)+] 365.2124, found 365.2130.
To a suspension of Ph3PCH3Br (8.4 g, 23.5 mmol) in THF
(18.7 mL) at 0 ꢀC was added NaHMDS (1.0 M in THF,
5.89 mL, 5.89 mmol). The resulting ylide solution was
stirred at 0 ꢀC for 30 min. A solution of the above crude al-
dehyde in THF (18.7 mL) was added, and the reaction mix-
ture was stirred at room temperature for 1.5 h before being
quenched with saturated aqueous NH4Cl. The mixture was
diluted with Et2O, washed with brine, dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. Purification
by column chromatography on silica gel (5% EtOAc/hex-
anes) afforded olefin (3.39 g, 88% for the three steps) as
a colorless oil.
4.1.26. b-Alkoxyacrylate 43. To a solution of 2-methyl-2-
butene (4.5 mL, 42.5 mmol) in THF (21 mL) at 0 ꢀC was
added BH3$SMe2 (2.0 M in Me2S, 21.0 mL, 42.0 mmol).
The resulting solution was added to a solution of TBS ether
41 (2.84 g, 8.30 mmol) in THF (28 mL) at 0 ꢀC. The reaction
mixture was stirred at room temperature for 4 h. The solution
was then cooled to 0 ꢀC and treated with 10% aqueous
NaOH (50 mL) followed by 30% H2O2 (39 mL). The result-
ing mixture was stirred at room temperature for 17 h before
it was diluted with EtOAc. The organic layer was separated,
washed with saturated aqueous Na2SO3 and brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification by column chromatography on silica gel (40%
EtOAc/hexanes) afforded alcohol (2.94 g, 98%) as a color-
less oil.
To a solution of the olefin (3.39 g, 9.91 mmol) in THF
(50 mL) at 0 ꢀC was added TBAF (1.0 M in THF,
19.8 mL, 19.8 mmol). The resulting mixture was stirred at
room temperature for 3 h before it was quenched with satu-
rated aqueous NH4Cl. The organic layer was separated,
washed with brine, dried over Na2SO4, filtered, and con-
centrated under reduced pressure. Purification by column
To a solution of the alcohol in CH2Cl2/DMSO (1:1, v/v,
54 mL) at 0 ꢀC were added Et3N (5.58 mL, 40.0 mmol)

5992
K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
and SO3$pyridine (5.12 g, 32.2 mmol). The resulting mix-
ture was stirred at 0 ꢀC for 3 h before water was added.
The solution was diluted with Et2O, washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced
pressure to give the crude aldehyde, which was used directly
in the subsequent reaction without purification.
NaHCO3. The mixture was diluted with EtOAc, washed with
brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure. Purification by column chromatography
on silica gel (80% EtOAc/hexanes) afforded ester 44
(1.58 g, 83% for the two steps) as a colorless oil: [a]D30
+45.4 (c 0.55, C6H6); IR (film) 3454, 2947, 2891, 1736,
1383, 1303, 1194, 1111, 1051, 1045, 924, 859, 620 cmꢁ1
;
To a solution of the aldehyde in THF (80 mL) at 0 ꢀC was
added methylmagnesium bromide (3.0 M in Et2O,
11.0 mL, 33.0 mmol). The resulting mixture was stirred at
room temperature for 1 h before it was quenched with satu-
rated aqueous NH4Cl. The mixture was diluted with EtOAc,
washed with water and brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure. Purification by
column chromatography on silica gel (30–50% EtOAc/hex-
anes) afforded alcohol (2.69 g, 88% for the two steps) as a
colorless oil.
1H NMR (500 MHz, CDCl3) d 4.61 (d, J¼3.0 Hz, 1H),
4.20–4.11 (m, 2H), 3.76 (dd, J¼9.0, 3.5 Hz, 1H), 3.70 (m,
1H), 3.41 (m, 1H), 3.32 (s, 3H), 3.23 (dd, J¼12.5, 3.5 Hz,
1H), 2.66 (dd, J¼14.5, 4.0 Hz, 1H), 2.43 (dd, J¼15.5,
9.0 Hz, 1H), 2.07 (d, J¼12.5 Hz, 1H), 1.98 (ddd, J¼12.0,
4.0, 4.0 Hz, 1H), 1.85 (m, 1H), 1.73–1.68 (m, 6H), 1.28 (s,
3H) 1.27 (s, 3H), 1.25 (t, J¼7.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 172.1, 97.8, 84.0, 81.1, 73.0, 70.3,
69.9, 69.1, 60.8, 54.5, 54.4, 34.9, 30.2, 29.8, 25.0, 24.0,
15.9, 14.2; HRMS (ESI) calcd for C18H30O7Na [(M+Na)+]
381.1889, found 381.1857.
To a suspension of the alcohol (6.58 g, 17.6 mmol) and
4 A molecular sieves in CH2Cl2 (76 mL) at 0 ꢀC were
˚
4.1.28. Diol 46. To a solution of ester 44 (1.56 g, 4.36 mmol)
in CH2Cl2 (50 mL) at 0 ꢀC were added 2,6-lutidine (1.20 mL,
10.3 mmol) and TMSOTf (1.18 mL, 6.52 mmol). The re-
sulting mixture was stirred at 0 ꢀC for 1 h before it was
quenched with saturated aqueous NaHCO3. The mixture
was diluted with EtOAc, washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification by column chromatography on silica gel (30%
EtOAc/hexanes) afforded TMS ether (1.75 g, 93%) as a
colorless oil.
added NMO (5.10 g, 43.5 mmol) and TPAP (0.54 g,
1.54 mmol). The resulting mixture was allowed to warm to
room temperature over 5 h before it was concentrated under
reduced pressure. The residue was purified by column chro-
matography on silica gel (20% EtOAc/hexanes) to afford
methyl ketone 42 (6.03 g, 92%) as a colorless oil.
To a solution of methyl ketone 42 (6.03 g, 16.2 mmol) in
THF (81 mL) at 0 ꢀC was added TBAF (1.0 M in THF,
32.4 mL, 32.4 mmol). The resulting solution was stirred at
room temperature for 7 h before it was concentrated under
reduced pressure. The residue was purified by column chro-
matography on silica gel (50% EtOAc/hexanes) to afford
alcohol (4.16 g, 99%) as a colorless oil.
To a solution of the TMS ether (1.75 g, 4.07 mmol) in tolu-
ene (40 mL) at ꢁ78 ꢀC was added DIBALH (1.01 M in
toluene, 4.74 mL, 4.79 mmol). The resulting mixture was
stirred at ꢁ78 ꢀC for 10 min before it was quenched with sat-
urated aqueous potassium sodium tartrate. The mixture was
diluted with EtOAc and vigorously stirred until the layers
became clear. The organic layer was separated, washed
with brine, dried over Na2SO4, filtered, and concentrated un-
der reduced pressure to give the crude aldehyde, which was
used directly in the subsequent reaction.
To a solution of the alcohol (1.37 g, 5.31 mmol) in CH2Cl2
(27 mL) at 0 ꢀC were added 4-methylmorpholine
(0.87 mL, 7.91 mmol) and ethyl propiolate (1.63 mL,
16.1 mmol). The resulting solution was stirred at room tem-
perature for 4.5 h before it was concentrated under reduced
pressure. The residue was purified by column chromato-
graphy on silica gel (30% EtOAc/hexanes) to afford b-
alkoxyacrylate 43 (1.96 g), which was used directly in the
subsequent reaction: [a]3D2 +60.3 (c 0.81, CHCl3); IR (film)
2946, 2898, 1707, 1643, 1624, 1384, 1322, 1198, 1125,
To a solution of Ph3PCH3Br (6.08 g, 17.0 mmol) in THF
(6.75 mL) at 0 ꢀC was added NaHMDS (1.0 M in THF,
15.8 mL, 15.8 mmol). The resulting ylide solution was
stirred at 0 ꢀC for 30 min. A solution of the crude aldehyde
in THF (6.75 mL) was added, and the reaction mixture was
stirred at room temperature for 1 h before it was quenched
with saturated aqueous NH4Cl. The mixture was diluted
with Et2O, washed with brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure. Purification by
column chromatography on silica gel (30% EtOAc/hexanes)
afforded olefin 45 (1.45 g, 93% for the two steps) as a color-
less oil.
1
1084, 1051, 1020, 845 cmꢁ1; H NMR (500 MHz, CDCl3)
d 7.52 (d, J¼12.0 Hz, 1H), 5.31 (d, J¼12.0 Hz, 1H), 4.61
(d, J¼3.0 Hz, 1H), 4.20 (dd, J¼11.5, 4.5 Hz, 1H), 4.14
(ddd, J¼7.5, 7.5, 7.5 Hz, 2H), 3.39–3.33 (m, 4H), 3.25
(ddd, J¼10.0, 10.0, 5.0 Hz, 1H), 2.65 (d, J¼12.5 Hz, 1H),
2.43 (d, J¼12.5 Hz, 1H), 2.17–2.11 (m, 4H), 1.84 (m, 1H),
1.76–1.62 (m, 4H), 1.28 (s, 3H), 1.25 (d, J¼6.0 Hz, 3H);
13C NMR (125 MHz, CDCl3) d 207.8, 167.6, 161.3, 98.8,
97.7, 79.8, 76.0, 70.4, 67.2, 59.9, 54.7, 51.3, 33.5, 30.5,
30.9, 24.4, 17.0, 14.3; HRMS (ESI) calcd for C18H28O7Na
[(M+Na)+] 379.1733, found 379.1759.
To a solution of olefin 45 (166 mg, 0.432 mmol) in MeCN
(4.8 mL) at 0 ꢀC were added 1,3-propanedithiol (53.0 mL,
0.53 mmol) and TMSOTf (86.8 mL, 0.48 mmol). The result-
ing mixture was stirred at 0 ꢀC for 10 min before it was
quenched with saturated aqueous NaHCO3. The mixture
was diluted with EtOAc, washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification by column chromatography on silica gel (80%
EtOAc/hexanes) afforded diol 46 (154 mg, 92%) as a
4.1.27. Ester 44. To a solution of the above b-alkoxyacrylate
43 (1.96 g) in THF (53 mL) at 0 ꢀC were added MeOH
(0.12 mL) and SmI2 (0.1 M in THF, 160 mL, 16.0 mmol).
The resulting mixture was stirred at 0 ꢀC for 1 h and then
at room temperature for 1 h. The reaction mixture was
quenched with 50% aqueous Na2S2O3 and saturated aqueous

K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
5993
colorless oil: [a]3D0 ꢁ23.2 (c 2.25, C6H6); IR (film) 3398,
temperature for 1 h before it was quenched with saturated
aqueous Na2S2O3 and saturated aqueous NaHCO3. The mix-
ture was diluted with EtOAc, washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification by column chromatography on silica gel (25%
EtOAc/hexanes) afforded lactone 48 (3.52 g), which was
used directly in the subsequent reaction.
2947, 1641, 1423, 1384, 1088, 1035, 910, 754, 665 cmꢁ1
;
1H NMR (500 MHz, CDCl3) d 5.90 (m, 1H), 5.11 (dd,
J¼17.0, 1.5 Hz, 1H), 5.05 (d, J¼10.0 Hz, 1H), 4.02 (dd,
J¼7.0, 7.0 Hz, 1H), 3.36 (d, J¼5.5 Hz, 2H), 3.25 (dd,
J¼10.0, 4.0 Hz, 1H), 3.04 (dd, J¼13.0, 3.5 Hz, 1H), 2.87–
2.79 (m, 4H), 2.39 (ddd, J¼11.0, 7.0, 3.5 Hz, 1H), 2.20–
2.06 (m, 4H), 2.04–1.93 (m, 3H), 1.89–1.81 (m, 1H),
1.79–1.73 (m, 1H), 1.63–1.51 (m, 4H), 1.28 (s, 3H), 1.21
(s, 3H); 13C NMR (125 MHz, CDCl3) d 135.9, 116.6, 87.0,
80.0, 73.1, 71.8, 71.1, 70.9, 54.2, 47.6, 33.6, 33.5, 31.2,
30.3 (ꢂ2), 29.4, 26.0, 24.1, 15.7; HRMS (ESI) calcd for
C19H32O4S2Na [(M+Na)+] 411.1640, found 411.1651.
To a solution of lactone 48 (3.52 g) in THF (88 mL) at 0 ꢀC
were added LiAlH4 (0.41 g, 10.8 mmol). The resulting mix-
ture was stirred at 0 ꢀC for 1 h before it was quenched with
saturated aqueous potassium sodium tartrate. The mixture
was diluted with EtOAc and vigorously stirred until the
layers became clear. The organic layer was separated,
washed with brine, dried over Na2SO4, filtered, and concen-
trated under reduced pressure. Purification by column chro-
matography on silica gel (80% EtOAc/hexanes) afforded
diol (3.70 g, 89% for the two steps) as a colorless oil.
4.1.29. Aldehyde 47. To a solution of diol 46 (4.09 g,
10.5 mmol) in CH2Cl2 (105 mL) at 0 ꢀC were added
4-methylmorpholine (1.94 mL, 17.6 mmol) and ethyl pro-
piolate (1.82 mL, 18.0 mmol). The resulting mixture was
stirred at room temperature for 13 h before it was concen-
trated under reduced pressure. The residue was purified by
column chromatography on silica gel (30–50% EtOAc/
hexanes) to afford b-alkoxyacrylate (4.80 g, 94%).
To a solution of the diol (0.39 g, 0.83 mmol) in DMF
(8.30 mL) at 0 ꢀC was added NaH (50% in oil, 0.16 g,
3.33 mmol). The resulting solution was stirred at 0 ꢀC for
1 h before 2-naphthylmethyl bromide (0.55 g, 2.48 mmol)
and Bu4NI (91.5 mg, 0.25 mmol) were added. The reaction
mixture was stirred at room temperature for 12 h before it
was quenched with saturated aqueous NH4Cl. The mixture
was diluted with Et2O, washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification by column chromatography on silica gel (30%
EtOAc/hexanes) afforded bis-naphthylmethyl ether (0.60 g,
96%) as a colorless oil.
To a solution of the b-alkoxyacrylate (4.80 g, 9.88 mmol) in
CH2Cl2 (99 mL) at 0 ꢀC were added 2,6-lutidine (5.45 mL,
46.8 mmol) and TBSOTf (6.88 mL, 30.0 mmol). The result-
ing mixture was stirred at 0 ꢀC for 14 h before saturated
aqueous NH4Cl was added. The mixture was diluted with
EtOAc, washed with brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure. Purification by
column chromatography on silica gel (10% EtOAc/hexanes)
afforded TBS ether (5.72 g, 97%) as a colorless oil.
To a solution of the bis-naphthylmethyl ether (0.60 g,
0.81 mmol) in THF (4.1 mL) at 0 ꢀC was added 9-BBN-H
(0.5 M in THF, 3.30 mL, 1.65 mmol). The resulting solution
was stirred at room temperature for 2 h. The mixture was
cooled to 0 ꢀC and treated with 10% aqueous NaOH
(2.5 mL) followed by 30% H2O2 (1.7 mL). The reaction
mixture was stirred at room temperature for 12 h before it
was diluted with EtOAc. The mixture was washed with
saturated aqueous Na2SO3 and brine, dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. Purification
by column chromatography on silica gel (30% EtOAc/hex-
anes) afforded alcohol (0.62 g), which was used directly in
the subsequent reaction.
To a solution of the TBS ether (5.72 g, 9.53 mmol) in
MeCN/H2O (1:1, v/v, 98 mL) were added NaHCO3
(16.4 g, 0.20 mol) and methyl iodide (12.3 mL, 0.20 mol).
The resulting mixture was stirred at room temperature for
19 h before it was diluted with EtOAc. The mixture was
washed with saturated aqueous Na2S2O3 and brine, dried
over Na2SO4, filtered, and concentrated under reduced pres-
sure. Purification by column chromatography on silica gel
(25% EtOAc/hexanes) afforded aldehyde 47 (4.76 g, 98%)
as a pale yellow oil: [a]D32 +64.6 (c 0.62, CHCl3); IR (film)
2953, 2892, 1740, 1623, 1382, 1303, 1253, 1114, 1058,
1028, 840, 757, 670 cmꢁ1 1H NMR (500 MHz, C6D6)
;
d 9.27 (s, 1H), 7.53 (d, J¼13.0 Hz, 1H), 6.15 (m, 1H),
5.56 (d, J¼12.5 Hz, 1H), 5.23 (d, J¼12.5 Hz, 1H), 5.15 (d,
J¼10.0 Hz, 1H), 4.12 (dd, J¼14.0, 7.0 Hz, 2H), 3.33–3.28
(m, 2H), 3.02 (ddd, J¼10.0, 10.0, 5.5 Hz, 1H), 2.69 (dd,
J¼12.5, 3.5 Hz, 1H), 2.47 (dd, J¼14.0, 8.0 Hz, 1H), 2.14
(ddd, J¼15.5, 10.5, 6.5 Hz, 1H), 2.03–1.87 (m, 3H), 1.81–
1.73 (m, 2H), 1.44–1.29 (m, 3H), 1.10 (s, 3H), 1.04 (d,
J¼7.5 Hz, 3H), 0.93–0.90 (m, 12H), 0.07 (s, 3H) 0.04 (s,
3H); 13C NMR (125 MHz, C6D6) d 200.0, 199.1, 160.1,
136.9, 116.4, 99.3, 88.3, 81.1, 79.3, 73.7, 72.1, 69.9, 59.8,
54.7, 39.8, 33.8, 30.7, 25.9 (ꢂ3), 25.2, 24.9, 18.2, 15.6,
14.5, ꢁ1.8, ꢁ1.9; HRMS (ESI) calcd for C27H46O7SiNa
[(M+Na)+] 533.2911, found 533.2919.
To a solution of the alcohol in CH2Cl2/DMSO (1:1, v/v,
8.1 mL) at 0 ꢀC were added Et3N (0.56 mL, 4.02 mmol)
and SO3$pyridine (0.52 g, 3.27 mmol). The resulting mix-
ture was stirred at room temperature for 45 min before water
was added. The mixture was diluted with Et2O, washed with
water and brine, dried over Na2SO4, filtered, and concen-
trated under reduced pressure to give the crude aldehyde,
which was used directly in the subsequent reaction.
To a solution of the aldehyde in t-BuOH/water (4:1, v/v,
8 mL) at 0 ꢀC were added 2-methyl-2-butene (0.39 mL,
3.68 mmol), KH2PO4 (0.11 g, 0.81 mmol), and NaClO2
(0.26 g, 2.87 mmol). The resulting mixture was stirred at
room temperature for 2 h before it was diluted with CHCl3.
The organic layer was separated, washed with 1 M aqueous
HCl, dried over Na2SO4, filtered, and concentrated under re-
duced pressure. Purification by column chromatography on
4.1.30. BCD-ring fragment 36. To a solution of aldehyde
47 (4.49 g, 8.80 mmol) in THF (88 mL) were added
MeOH (0.25 mL) and SmI2 (0.1 M in THF, 264 mL,
26.4 mmol). The resulting mixture was stirred at room

5994
K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
silica gel (10% MeOH/CHCl3) afforded BCD-ring fragment
36 (0.55 g, 88% for the three steps) as a colorless oil: [a]D29
ꢁ2.0 (c 4.47, CHCl3); IR (film) 3374, 3055, 2929, 2856,
CDCl3) d 7.48–7.46 (m, 2H), 7.39–7.27 (m, 8H), 7.10 (dd,
J¼15.5, 4.5 Hz, 1H), 6.11 (dd, J¼11.5, 1.5 Hz, 1H), 5.54
(s, 1H), 4.61 (d, J¼11.0 Hz, 1H), 4.48 (d, J¼12.0 Hz, 1H),
4.25 (ddd, J¼9.5, 4.0, 1.0 Hz, 1H), 3.97 (d, J¼10.0 Hz,
1H), 3.75 (s, 3H), 3.65 (d, J¼10.5 Hz, 1H), 3.56 (dd,
J¼13.0, 4.0 Hz, 1H), 3.32 (ddd, J¼10.0, 5.5, 5.5 Hz, 1H),
2.40 (ddd, J¼12.5, 4.5, 4.5 Hz, 1H), 1.85 (ddd, J¼12.0,
12.0, 12.0 Hz, 1H), 1.51 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 166.8, 145.2, 137.4, 137.3, 129.2, 128.5 (ꢂ2),
128.4 (ꢂ2), 128.0, 127.9 (ꢂ2), 126.2 (ꢂ2), 121.3, 102.8,
78.4, 76.8, 76.2, 71.9, 71.4, 69.2, 51.6, 36.5, 14.6; HRMS
(ESI) calcd for C25H28O6Na [(M+Na)+] 447.1784, found
447.1787.
1710, 1383, 1252, 1149, 836, 774 cmꢁ1
;
1H NMR
(500 MHz, CDCl3) d 7.81–7.74 (m, 8H), 7.46–7.43 (m,
6H), 4.70 (d, J¼12.5 Hz, 1H), 4.64 (d, J¼11.5 Hz, 1H),
4.60 (d, J¼12.0 Hz, 1H), 4.51 (d, J¼11.5 Hz, 1H), 3.82
(ddd, J¼8.5, 7.5, 3.5 Hz, 1H), 3.82–3.54 (m, 3H), 3.42–
3.31 (m, 2H), 3.12 (d, J¼9.5 Hz, 1H), 3.00 (dd, J¼13.0,
3.5 Hz, 1H), 2.59–2.54 (m, 1H), 2.43–2.36 (m, 2H), 2.06–
1.95 (m, 3H), 1.89–1.77 (m, 3H), 1.73–1.47 (m, 4H),
1.38–1.23 (m, 5H), 1.20 (s, 3H), 0.82 (s, 9H), 0.09 (s, 3H),
0.07 (s, 3H); 13C NMR (125 MHz, CDCl3) d 178.4, 136.0,
135.9, 133.24, 133.21, 132.9 (ꢂ2), 128.1 (ꢂ2), 127.84,
127.83, 127.68, 127.67, 126.2 (ꢂ2), 126.09, 126.05,
125.82, 125.78, 125.73, 125.71, 87.0, 81.6, 81.2, 80.2,
79.8, 73.7, 73.3, 71.9, 70.6, 67.2, 54.4, 41.9, 35.3, 32.0,
31.4, 26.6, 25.7 (ꢂ3), 24.7, 23.7, 23.4, 17.9, 16.0, ꢁ1.9,
ꢁ2.0; HRMS (ESI) calcd for C47H62O8SiNa [(M+Na)+]
805.4112, found 805.4114.
4.1.32. Ester 54. To a solution of a,b-unsaturated ester 53
(1.23 g, 2.90 mmol), bis(N-isopropylsalicylaldimine) cop-
per(II) complex 17 (11.0 mg, 28.4 mmol), and TMSCl
(1.14 mL, 8.98 mmol) in THF (15 mL) at ꢁ45 ꢀC was added
methylmagnesium bromide (3.0 M in Et2O, 1.51 mL,
4.53 mmol). The resulting solution was stirred at ꢁ45 ꢀC
for 3 h before it was quenched with 1 M aqueous HCl. The
mixture was diluted with Et2O, washed with saturated aque-
ous NaHCO3 and brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. Purification by column
chromatography on silica gel (20% EtOAc/hexanes) af-
forded ester 54 (1.23 g, 96%) as a colorless oil: [a]D31
ꢁ114.5 (c 0.14, CHCl3); IR (film) 2951, 2867, 1725, 1384,
4.1.31. a,b-Unsaturated ester 53. To a solution of alcohol
51 (9.78 g, 35.4 mmol) in DMF (118 mL) at 0 ꢀC was added
NaH (50% in oil, 2.85 g, 59.4 mmol). The resulting mixture
was stirred at 0 ꢀC for 1 h before benzyl bromide (8.65 mL,
72.7 mmol) and Bu4NI (1.31 g, 3.55 mmol) were added. The
mixture was stirred at room temperature for 16 h before it
was quenched with saturated aqueous NH4Cl. The mixture
was diluted with Et2O, washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification by column chromatography on silica gel (30%
EtOAc/hexanes) afforded benzyl ether 52 (13.0 g, quant.)
as a colorless oil.
1
1107, 1007, 747, 698 cmꢁ1; H NMR (500 MHz, CDCl3)
d 7.63 (d, J¼7.5 Hz, 2H), 7.33 (d, J¼7.5 Hz, 2H) 7.22–
7.19 (m, 4H), 7.15–7.09 (m, 2H), 5.37 (s, 1H), 4.46 (d,
J¼12.5 Hz, 1H), 4.25 (d, J¼11.5 Hz, 1H), 3.81 (d,
J¼10.0 Hz, 1H), 3.52 (dd, J¼10.0, 2.0 Hz, 1H), 3.39–3.35
(m, 4H), 3.23 (ddd, J¼10.0, 5.0, 5.0 Hz, 1H), 3.07 (dd,
J¼12.0, 3.5 Hz, 1H), 2.79 (m, 1H), 2.41 (dd, J¼16.0,
4.0 Hz, 1H), 2.26–2.20 (m, 2H), 1.66 (m, 1H), 1.34 (s,
3H), 1.12 (d, J¼6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 171.5, 136.7, 136.6, 127.0, 126.7 (ꢂ2), 126.5, 126.31
(ꢂ2), 126.26 (ꢂ2), 124.8 (ꢂ2), 100.6, 76.9, 74.6, 74.5,
71.5, 68.2, 66.8, 49.0, 33.5, 28.9, 28.3, 16.1, 12.7; HRMS
(ESI) calcd for C26H32O6Na [(M+Na)+] 463.2097, found
463.1761.
To a solution of the benzyl ether 52 (1.98 g, 5.41 mmol)
in THF/H2O (1:1, v/v, 21 mL) were added NMO (50 wt %
in water, 3.84 mL, 16.4 mmol) and OsO4 (0.039 M in t-
BuOH, 8.03 mL, 0.31 mmol). The resulting mixture was
stirred at room temperature for 11 h before it was diluted
with EtOAc. The organic layer was separated, washed
with brine, dried over Na2SO4, filtered, and concentrated un-
der reduced pressure to give the crude diol.
4.1.33. Diol 55. To a solution of ester 54 (1.23 g, 2.80 mmol)
in CH2Cl2 (7.3 mL) at ꢁ78 ꢀC was added DIBALH (0.95 M
in hexane, 9.19 mL, 8.73 mmol). The resulting mixture was
stirred at ꢁ78 ꢀC for 1 h before being quenched with satu-
rated aqueous potassium sodium tartrate. The mixture was
vigorously stirred until the layers became clear. The organic
layer was separated, washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. Purifica-
tion by column chromatography on silica gel (20% EtOAc/
hexanes) afforded alcohol (1.16 g, quant.) as a colorless oil.
To a solution of the crude diol in THF/H2O (1:1, v/v, 21 mL)
was added NaIO4 (3.49 g, 16.3 mmol). The resulting mix-
ture was stirred at room temperature for 1 h before it was di-
luted with EtOAc. The mixture was washed with H2O,
saturated aqueous Na2SO3 and brine, dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. The residue
was filtered through a plug of silica gel (50% EtOAc/hex-
anes) to give the crude aldehyde, which was used directly
in the subsequent reaction.
To a solution the aldehyde in THF (18.2 mL) was added
Ph3P]CHCO2Me (1.91 g, 5.71 mmol). The resulting mix-
ture was stirred at room temperature for 26 h before it was
diluted with Et2O. The mixture was washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pres-
sure. Purification by column chromatography on silica gel
(30% EtOAc/hexanes) afforded a,b-unsaturated ester 53
(1.83 g, 80% for the three steps) as a colorless oil: [a]D31
ꢁ65.9 (c 0.28, CHCl3); IR (film) 2950, 2865, 1723, 1384,
To a solution of the alcohol (4.33 g, 10.5 mmol) in DMF
(35 mL) at 0 ꢀC was added NaH (50% in oil, 0.76 g,
15.8 mmol). The resulting solution was stirred at 0 ꢀC for
1.5 h before benzyl bromide (2.29 mL, 19.3 mmol) and
Bu4NI (0.19 g, 0.51 mmol) were added. The reaction mix-
ture was stirred at room temperature for 15 h before it was
quenched with saturated aqueous NH4Cl. The mixture was
diluted with Et2O, washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The
residue was filtered through a plug of silica gel (20%
1306, 1278, 1108, 747, 698 cmꢁ1 1H NMR (500 MHz,
;

K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
5995
EtOAc/hexanes) to give bis-benzyl ether, which was used
directly in the subsequent reaction.
75.3, 71.1, 70.7, 69.0, 66.9, 64.6, 33.3, 28.3, 27.7, 23.8
(ꢂ3), 16.0, 15.2, 8.8, ꢁ4.2, ꢁ4.9; HRMS (ESI) calcd for
C31H46O5SiNa [(M+Na)+] 549.3012, found 549.3020.
To a solution of the bis-benzyl ether in MeOH (35 mL) at
0 ꢀC was added p-TsOH$H2O (1.99 g, 10.5 mmol). The re-
sulting mixture was stirred at 40–70 ꢀC for 3 h. The reaction
mixture was cooled to room temperature and quenched with
Et3N. The mixture was concentrated under reduced pressure,
and the residue was purified by column chromatography on
silica gel (80% EtOAc/hexanes) to afford diol 55 (3.95 g,
91% for the two steps) as a colorless oil: [a]3D0 ꢁ58.0
(c 0.10, CHCl3); IR (film) 3417, 2933, 2873, 1455, 1383,
4.1.35. p-Methoxybenzyl ether 57. To a solution of alcohol
56 (2.00 g, 7.25 mmol) in DMF (24 mL) at 0 ꢀC was added
NaH (50% in oil, 0.97 g, 20.2 mmol). The resulting solution
was stirred at 0 ꢀC for 1 h before p-methoxybenzyl chloride
(2.95 mL, 21.8 mmol) and Bu4NI (0.54 g, 1.46 mmol) were
added. The reaction mixture was stirred at room temperature
for 15.5 h before being quenched with saturated aqueous
NaHCO3. The mixture was diluted with Et2O, washed with
brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was filtered through a plug
of silica gel (20% EtOAc/hexanes) to give p-methoxybenzyl
ether, which was used directly in the subsequent reaction.
1065, 735, 548 cmꢁ1
;
1H NMR (500 MHz, CDCl3)
d 7.31–7.20 (m, 10H), 4.56 (d, J¼11.0 Hz, 1H), 4.47 (m,
3H), 3.73 (ddd, J¼12.0, 5.0, 5.0 Hz, 1H), 3.51–3.45 (m,
2H), 3.41 (dd, J¼11.0, 3.5 Hz, 1H), 3.36 (dd, J¼7.5,
7.5 Hz, 1H), 3.31–3.30 (m, 2H), 2.31 (ddd, J¼8.0, 4.0,
4.0 Hz, 1H), 2.28 (d, J¼5.0 Hz, 1H), 2.09–2.06 (m, 2H),
1.70 (m, 1H), 1.54 (m, 1H), 1.33 (m, 1H), 1.06 (s, 3H),
0.91 (d, J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 138.5, 138.0, 128.4 (ꢂ2), 128.3 (ꢂ2), 127.9 (ꢂ2), 127.8,
127.6 (ꢂ2), 127.5, 76.8, 75.9, 73.2, 73.0, 70.8, 68.9, 68.3,
67.1, 33.8, 29.8, 29.6, 17.2, 12.9; HRMS (ESI) calcd for
C25H34O5Na [(M+Na)+] 437.2304, found 437.2311.
To a solution of the p-methoxybenzyl ether in MeOH
(36 mL) at 0 ꢀC was added CSA (0.17 g, 0.73 mmol). The
resulting mixture was stirred at room temperature for 0.5 h
before it was quenched with Et3N. The mixture was concen-
trated under reduced pressure, and the residue was purified
by column chromatography on silica gel (100% EtOAc) to
afford diol (1.91 g, 86% for the two steps) as a colorless oil.
4.1.34. Aldehyde 49. To a solution of diol 55 (3.93 g,
9.49 mmol) in CH2Cl2 (32 mL) at 0 ꢀC were added 2,6-
lutidine (2.34 mL, 20.1 mmol) and TBSOTf (3.92 mL,
17.1 mmol). The resulting solution was stirred at room tem-
perature for 1.5 h before it was concentrated under reduced
pressure. The residue was filtered through a plug of silica gel
(50% EtOAc/hexanes) to give bis-TBS ether, which was
used directly in the subsequent reaction.
To a solution of the diol (1.91 g, 6.20 mmol) in DMF
(20 mL) at 0 ꢀC was added NaH (50% in oil, 1.20 g,
25.0 mmol). The resulting solution was stirred at 0 ꢀC for
1 h before benzyl bromide (3.79 mL, 31.9 mmol) and
Bu4NI (0.69 g, 1.87 mmol) were added. The reaction mixture
was stirred at room temperature for 16 h before it was
quenched with saturated aqueous NH4Cl. The mixture was
diluted with Et2O, washed with brine, dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. Purification
by column chromatography on silica gel (20% EtOAc/hex-
anes) afforded p-methoxybenzyl ether 57 (2.85 g, 94%) as
a colorless oil: [a]D32 +24.9 (c 0.33, CHCl3); IR (film)
To a solution of the bis-TBS ether in CH2Cl2/MeOH (1:1,
v/v, 47 mL) at 0 ꢀC was added CSA (1.09 g, 4.69 mmol). The
resulting solution was stirred at 0 ꢀC for 2 h before it was
quenched with Et3N. The mixture was concentrated under
reduced pressure, and the residue was purified by column
chromatography on silica gel (80% EtOAc/hexanes) to
afford primary alcohol (4.77 g, 95% for the two steps) as a
colorless oil.
1
2938, 2869, 1513, 1352, 1248, 1074, 736, 698 cmꢁ1; H
NMR (500 MHz, CDCl3) d 7.34–7.19 (m, 12H), 6.85 (d,
J¼9.0 Hz, 2H), 6.02 (dd, J¼17.5, 10.5 Hz, 1H), 5.34 (dd,
J¼17.5, 1.0 Hz, 1H), 5.08 (dd, J¼11.0, 1.5 Hz, 1H), 4.62
(d, J¼13.0 Hz, 1H), 4.57–4.54 (m, 2H), 4.48 (d,
J¼11.5 Hz, 1H), 4.41–4.37 (m, 2H), 3.79 (s, 3H), 3.69–
3.68 (m, 2H), 3.65–3.62 (m, 1H) 3.43 (ddd, J¼11.5,
5.0 Hz, 1H), 3.25 (dd, J¼11.5, 4.5 Hz, 1H), 2.41 (ddd,
J¼12.0, 4.5, 4.5 Hz, 1H), 1.57 (m, 1H), 1.29 (s, 3H); 13C
NMR (125 MHz, CDCl3) d 143.0 (ꢂ2), 138.7, 138.2,
129.1 (ꢂ2), 128.4 (ꢂ2), 128.3 (ꢂ2), 127.8 (ꢂ2), 127.69
(ꢂ2), 127.67, 127.4, 113.7 (ꢂ2), 113.1, 109.7, 78.3, 76.1,
73.4, 73.1, 72.8, 71.4, 71.1, 69.7, 55.3, 31.1, 15.2; HRMS
(ESI) calcd for C31H36O5Na [(M+Na)+] 511.2460, found
511.2448.
To a solution of the alcohol (0.16 g, 0.30 mmol) in CH2Cl2/
DMSO (3:5, v/v, 0.74 mL) at 0 ꢀC were added Et3N
(0.19 mL, 1.36 mmol) and SO3$pyridine (0.18 g, 1.13 mmol).
The resulting mixture was stirred at room temperature
for 2.5 h before it was quenched with water. The mixture
was diluted with Et2O, washed with water and brine, dried
over Na2SO4, filtered, and concentrated under reduced
pressure. Purification by column chromatography on silica
gel (80% EtOAc/hexanes) afforded aldehyde 49 (0.15 g,
94%) as a colorless oil: [a]3D2 ꢁ64.1 (c 0.13, CHCl3); IR
1
(film) 2928, 2856, 1754, 1384, 777, 736, 698 cmꢁ1; H
4.1.36. Alkyne 50. To a solution of p-methoxybenzyl ether
57 (2.85 g, 5.84 mmol) in THF (12 mL) at 0 ꢀC was added
9-BBN-H (0.5 M in THF, 46.7 mL, 23.4 mmol). The result-
ing solution was stirred at room temperature for 2 h. The
mixture was cooled to 0 ꢀC and treated with 10% aqueous
NaOH (18.0 mL) followed by 30% H2O2 (12.0 mL). The
reaction mixture was stirred at room temperature for 18 h
before it was diluted with EtOAc. The mixture was washed
with saturated aqueous Na2SO3 and brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure.
NMR (500 MHz, C6D6) d 9.33 (s, 1H), 7.32–7.28 (m, 4H),
7.18–7.08 (m, 6H), 4.44 (d, J¼12.0 Hz, 1H), 4.39–4.31
(m, 3H), 3.65 (dd, J¼11.0, 4.5 Hz, 1H), 3.49–3.45 (m,
1H), 3.41–3.36 (m, 2H), 3.30 (ddd, J¼11.0, 4.5, 4.5 Hz,
1H), 2.39 (m, 1H), 2.20 (ddd, J¼12.0, 5.0, 5.0 Hz, 1H),
1.95 (m, 1H), 1.65–1.52 (m, 2H), 1.26 (s, 3H), 1.01 (d,
J¼7.5 Hz, 3H), 0.92 (s, 9H), ꢁ0.00 (s, 3H), ꢁ0.02 (s, 3H);
13C NMR (125 MHz, C6D6) d 197.4, 137.4, 136.9, 126.6,
126.5 (ꢂ3), 126.1 (ꢂ2), 125.9, 125.7 (ꢂ2), 125.6, 78.8,

5996
K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
Purification by column chromatography on silica gel (40%
EtOAc/hexanes) afforded primary alcohol (2.1 g, 71%) as
a colorless oil.
EtOAc, washed with brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure. Purification by
column chromatography on silica gel (20% EtOAc/hexanes)
afforded propargyl ketone 61 (7.63 g, 93%) as a colorless
oil: [a]2D0 ꢁ20.8 (c 1.44, CHCl3); IR (film) 2929, 1681,
To a suspension of the primary alcohol (2.70 g, 5.33 mmol)
˚
and 4 A molecular sieves in CH2Cl2 (26 mL) were added
1
1513, 1454, 1250, 1091, 837, 736, 698 cmꢁ1; H NMR
NMO (1.25 g, 10.7 mmol) and TPAP (150 mg, 0.427 mmol).
The resulting mixture was stirred at 0 ꢀC for 5 min and
then at room temperature for 12 h. The reaction mixture was
concentrated under reduced pressure, and the residue was
purified by column chromatography on silica gel (30%
EtOAc/hexanes) to afford aldehyde 58 (2.06 g, 77%) as a
colorless oil.
(500 MHz, CDCl3) d 7.41 (d, J¼7.5 Hz, 2H), 7.31–7.08
(m, 20H), 6.82 (d, J¼9.0 Hz, 2H), 4.62 (d, J¼13.0 Hz,
1H), 4.54 (d, J¼12.0 Hz, 1H), 4.48–4.45 (m, 2H), 4.40–
4.30 (m, 6H), 4.23 (d, J¼11.5 Hz, 1H), 3.80–3.74 (m, 2H),
3.67 (m, 1H), 3.50–3.41 (m, 7H), 3.32 (s, 3H), 2.68 (d,
J¼17.0 Hz, 1H), 2.60 (d, J¼17.5 Hz, 1H), 2.47–2.32 (m,
3H), 2.08 (m, 1H), 1.75–1.70 (m, 2H), 1.52 (s, 3H), 1.27
(s, 3H), 1.09 (d, J¼7.0 Hz, 3H), 0.97 (s, 9H), 0.20 (s, 3H),
0.12 (s, 3H); 13C NMR (125 MHz, CDCl3) d 186.9, 159.8,
157.2, 139.5, 139.3, 139.14 (ꢂ2), 139.08 (ꢂ2), 130.8,
129.4 (ꢂ2), 128.6 (ꢂ4), 128.3 (ꢂ3), 127.99 (ꢂ2), 127.97
(ꢂ2), 127.80 (ꢂ2), 127.77 (ꢂ2), 127.70 (ꢂ2), 127.6,
127.5, 114.1 (ꢂ2), 93.0, 82.7, 82.0, 77.8, 77.0, 76.0, 74.4,
73.6, 73.2, 73.1, 72.9, 71.10, 71.06 (ꢂ2), 70.1, 69.2, 68.7,
54.8, 35.7, 31.4, 31.0, 30.6, 30.0, 26.0, 18.1, 17.5, 15.8,
12.3, ꢁ4.1, ꢁ4.6; HRMS (ESI) calcd for C63H80O10SiNa
[(M+Na)+] 1047.5418, found 1047.5491.
To a solution of aldehyde 58 (0.83 g, 1.65 mmol) in i-PrOH
(20 mL) at 0 ꢀC were added dimethyl (1-diazo-2-oxopro-
pyl)phosphonate (0.66 g, 3.44 mmol) and Cs2CO3 (1.53 g,
4.70 mmol). The resulting mixture was stirred at room tem-
perature for 20 h before it was quenched with saturated aque-
ous NH4Cl. The mixture was diluted with Et2O, washed with
brine, dried over Na2SO4, filtered, and concentrated under re-
duced pressure. Purification by column chromatography on
silica gel (30% EtOAc/hexanes) afforded alkyne 50
(0.76 g, 92%) as a colorless oil: [a]3D0 +8.9 (c 3.57, C6H6);
IR (film) 3290, 2939, 2870, 1612, 1513, 1249, 1085, 737,
4.1.38. Vinylogous ester 62. To a solution of ketone 61
(7.58 g, 7.40 mmol) in MeOH/THF (10:1, v/v, 74 mL) was
added NaOMe (4.00 g, 74.0 mmol). The resulting solution
was stirred at room temperature for 11 h before it was con-
centrated under reduced pressure. The residue was purified
by column chromatography on silica gel (20% EtOAc/hex-
anes) to afford vinylogous ester 62 (7.63 g, 98%) as a color-
less oil: [a]3D2 ꢁ41.5 (c 0.08, CHCl3); IR (film) 2926, 2855,
1
698 cmꢁ1; H NMR (500 MHz, CDCl3) d 7.25–7.11 (m,
12H), 6.76 (d, J¼8.0 Hz, 2H), 4.58 (d, J¼12.5 Hz, 1H), 4.48
(d, J¼12.5 Hz, 1H), 4.47 (d, J¼11.0 Hz, 1H), 4.45 (d, J¼
11.5 Hz, 1H), 4.33 (d, J¼11.5 Hz, 1H), 4.30 (d, J¼11.0 Hz,
1H), 3.69 (s, 3H), 3.62–3.58 (m, 2H), 3.52–3.47 (m, 1H),
3.40 (dd, J¼12.0, 4.5 Hz, 1H), 3.34 (ddd, J¼11.5, 11.5,
5.0 Hz, 1H), 2.43 (dd, J¼17.0, 2.5 Hz, 1H), 2.38–2.33 (m,
2H), 1.85 (dd, J¼2.5, 2.5 Hz, 1H), 1.43 (ddd, J¼11.5, 11.5,
11.5 Hz, 1H), 1.13 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 159.2, 138.9, 138.2, 130.4, 129.2 (ꢂ2), 128.4 (ꢂ2), 128.2
(ꢂ2), 127.71 (ꢂ2), 127.65, 127.62 (ꢂ2), 127.3, 113.7
(ꢂ2), 81.0, 76.2, 75.5, 73.8, 73.3, 72.8, 71.2, 70.9, 70.3,
69.4, 55.2, 30.5, 30.4, 15.6; HRMS (ESI) calcd for
C32H36O5Na [(M+Na)+] 523.2460, found 523.2467.
1
1584, 1512, 1453, 1383, 1247, 1094, 837, 697 cmꢁ1; H
NMR (500 MHz, CDCl3) d 7.45 (d, J¼7.5 Hz, 2H), 7.35
(d, J¼9.0 Hz, 2H), 7.30–7.07 (m, 18H), 6.88 (d, J¼8.0 Hz,
2H), 6.22 (s, 1H), 4.69 (d, J¼12.5 Hz, 1H), 4.58 (d,
J¼12.5 Hz, 1H), 4.51–4.42 (m, 4H), 4.38–4.27 (m, 5H),
3.97 (dd, J¼11.5, 5.0 Hz, 1H), 3.82–3.76 (m, 4H), 3.55
(dd, J¼10.0, 1.5 Hz, 1H), 3.50–3.38 (m, 3H), 3.34 (m,
4H), 3.26 (s, 3H), 2.68 (d, J¼12.5 Hz, 1H), 2.48–2.39 (m,
3H), 2.29 (m, 1H), 2.03 (m, 1H), 1.77 (m, 1H), 1.63–1.56
(m, 4H), 1.54 (s, 3H), 1.05 (d, J¼7.0 Hz, 3H), 1.00 (s,
9H), 0.15 (s, 3H), 0.08 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 197.8, 174.5, 159.5, 140.0, 139.43, 139.35,
139.1, 131.6, 129.3 (ꢂ2), 129.2 (ꢂ2), 128.5 (ꢂ5), 128.33,
128.26, 127.98, 127.97, 127.89, 127.77, 127.75, 127.65,
127.57, 127.56, 127.4 (ꢂ2), 113.9 (ꢂ4), 83.2, 78.3, 78.0,
77.7, 73.6, 73.3, 73.1 (ꢂ2), 71.0, 70.8, 70.1, 69.2, 54.82,
54.79, 54.75, 54.69, 42.8, 35.8, 31.2, 30.8, 30.1, 26.1 (ꢂ3),
18.2 (ꢂ2), 17.6, 16.4, 13.1, ꢁ4.3, ꢁ4.7; HRMS (ESI)
calcd for C64H84O11SiNa [(M+Na)+] 1079.5681, found
1079.5741.
4.1.37. Propargyl ketone 61. To a solution of alkyne 50
(8.89 g, 17.8 mmol) and HMPA (5.6 mL) in THF
(42.1 mL) was added t-BuLi (1.56 M in pentane, 10.3 mL,
16.1 mmol) at ꢁ78 ꢀC. The resulting mixture was stirred
at ꢁ78 ꢀC for 20 min before a solution of aldehyde 49
(4.43 g, 8.42 mmol) in THF (34 mL) at ꢁ78 ꢀC was added.
The reaction mixture was stirred at ꢁ78 ꢀC for 1.5 h before
being quenched with saturated aqueous NH4Cl. The mixture
was diluted with EtOAc, washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification by column chromatography on silica gel (20%
EtOAc/hexanes) afforded propargyl alcohol 60 (8.23 g,
95%) as a colorless oil.
4.1.39. Alcohol 65. To a solution of vinylogous ester 62
(0.23 g, 0.22 mmol) in pyridine/THF (1:4, v/v, 2.8 mL) at
0 ꢀC was added HF/pyridine complex (70% solution,
1.10 mL). The resulting mixture was stirred at room temper-
ature for 15 h before it was quenched with saturated aqueous
NaHCO3. The mixture was diluted with Et2O, washed with
brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure. Purification by column chromatography
on silica gel (40% EtOAc/hexanes) afforded alcohol 63
(0.19 g, 93%) as a colorless oil.
To a solution of CH2Cl2/DMSO (1:2, v/v, 80 mL) at ꢁ78 ꢀC
was added dropwise (COCl)2 (2.08 mL, 24.6 mmol). After
the resulting mixture was stirred at ꢁ78 ꢀC for 15 min, a so-
lution of alcohol 60 (8.23 g, 8.02 mmol) in CH2Cl2
(13.4 mL) was added. The reaction mixture was stirred at
ꢁ78 ꢀC for 30 min before Et3N (1.1 mL, 7.9 mmol) was
added. The resulting mixture was allowed to warm to
room temperature over 3 h before it was quenched with
saturated aqueous NH4Cl. The mixture was diluted with

K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
5997
To a solution of alcohol 63 (5.91 g, 6.27 mmol) in toluene
(63 mL) was added pyridinium p-toluenesulfonate (1.58 g,
6.29 mmol). The resulting mixture was stirred at 100 ꢀC
for 3.5 h. The reaction mixture was cooled to room temper-
ature and quenched with Et3N. The mixture was concen-
trated under reduced pressure, and the residue was purified
by column chromatography on silica gel (30% EtOAc/hex-
anes) to afford dihydropyranone 64 (4.95 g, 87%) as a color-
less oil.
138.7, 138.1, 138.0, 137.9, 130.4, 129.6 (ꢂ2), 128.35
(ꢂ2), 128.33 (ꢂ2), 128.28 (ꢂ2), 128.24, 128.23 (ꢂ2),
127.90 (ꢂ2), 127.86 (ꢂ2), 127.70, 127.66 (ꢂ3), 127.5
(ꢂ2), 127.3, 113.6 (ꢂ2), 80.2, 77.2 (ꢂ2), 76.1, 75.9, 74.5,
74.2, 73.7, 73.6, 73.4, 72.8, 72.8, 72.0, 71.3, 70.7, 70.0,
69.0, 68.5, 55.3, 44.2, 30.08, 30.05, 30.02, 29.99, 17.7,
17.1, 9.8; HRMS (ESI) calcd for C57H70O11Na [(M+Na)+]
953.4816, found 953.4787.
4.1.41. Bis-TES ether 67. To a solution of diol 66 (4.12 g,
4.43 mmol) in CH2Cl2 (44 mL) at 0 ꢀC were added 2,6-
lutidine (1.55 mL, 13.3 mmol) and TESOTf (2.96 mL,
13.1 mmol). The resulting mixture was stirred at room tem-
perature for 1.5 h before it was diluted with EtOAc. The
mixture was washed with brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure. Purification by
column chromatography on silica gel (20–50% EtOAc/hex-
anes) afforded bis-TES ether 67 (5.13 g, quant.) as a color-
less oil: [a]2D9 +3.28 (c 3.11, CHCl3); IR (film) 2951, 2874,
To a solution of dihydropyranone 64 (0.13 g, 0.14 mmol) in
toluene (1.4 mL) at ꢁ78 ꢀC was added DIBALH (1.01 M in
toluene, 0.54 mL, 0.55 mmol). The resulting mixture was
stirred at ꢁ78 ꢀC for 2 h before it was quenched with satu-
rated aqueous potassium sodium tartrate. The mixture was
vigorously stirred until the layers became clear. The organic
layer was separated, washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. Purifica-
tion by column chromatography on silica gel (30% EtOAc/
hexanes) afforded alcohol 65 (0.12 g, 92%) as a colorless
oil: [a]3D2 ꢁ34.1 (c 1.47, CHCl3); IR (film) 3425, 2940,
1H NMR (500 MHz, C6D6) d 7.44 (d, J¼7.5 Hz, 1H),
7.33–7.07 (m, 21H), 6.82 (d, J¼10.0 Hz, 2H), 4.76 (m,
1H), 4.65 (d, J¼12.5 Hz, 1H), 4.55 (d, J¼12.0 Hz, 1H),
4.50 (d, J¼11.5 Hz, 1H), 4.45 (d, J¼11.5 Hz, 1H), 4.40–
4.30 (m, 5H), 4.23–4.21 (m, 2H), 3.83–3.71 (m, 2H),
3.55–3.46 (m, 3H), 3.41–3.29 (m, 6H), 3.17 (ddd, J¼10.5,
10.5, 4.5 Hz, 1H), 2.51–2.44 (m, 2H), 2.36 (m, 1H), 2.29
(ddd, J¼9.5, 4.0, 4.0 Hz, 1H), 1.89 (m, 1H), 1.76 (m, 1H),
1.63 (m, 1H), 1.56–1.51 (m, 2H), 1.39 (s, 3H), 1.35–1.27
(m, 2H), 1.24 (s, 3H), 1.05 (d, J¼6.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 159.7, 152.4, 139.7, 139.5, 139.3,
139.0, 131.2, 129.2 (ꢂ2), 128.57 (ꢂ2), 128.55 (ꢂ2),
128.53 (ꢂ4), 128.0 (ꢂ2), 127.82 (ꢂ2), 127.78 (ꢂ2),
127.71 (ꢂ4), 127.6 (ꢂ2), 114.1 (ꢂ2), 104.3, 77.9, 77.6,
76.2, 75.0, 74.0, 73.9, 73.8, 73.5, 73.1, 73.0, 72.8, 71.0,
70.7, 70.5, 70.3, 69.2, 54.8, 44.4, 30.9, 30.7, 30.4, 30.1,
17.4, 16.3, 9.6; HRMS (ESI) calcd for C57H68O10Na
[(M+Na)+] 935.4710, found 935.4751.
1
1513, 1455, 1247, 1091, 1007, 735, 697 cmꢁ1; H NMR
(500 MHz, C6D6) d 7.56–7.54 (m, 2H), 7.49–7.46 (m, 2H),
7.43–7.13 (m, 18H), 6.94 (d, J¼10.0 Hz, 2H), 4.84 (d,
J¼12.5 Hz, 1H), 4.72 (m, 1H), 4.64 (dd, J¼10.5, 2.5 Hz,
1H), 4.61–4.57 (m, 2H), 4.47–4.36 (m, 4H), 4.22 (d,
J¼11.5 Hz, 1H), 4.12 (m, 1H), 4.06–4.03 (m, 2H), 3.85–
3.83 (m, 2H), 3.77–3.73 (m, 2H), 3.67 (m, 1H), 3.60–3.49
(m, 3H), 3.41 (s, 3H), 3.28 (m, 1H), 2.96 (m, 1H), 2.68
(m, 1H), 2.45 (m, 1H), 2.31–2.11 (m, 4H), 1.86–1.73
(m, 3H), 1.46 (s, 3H), 1.32 (s, 3H), 1.23 (m, 21H),
1.08–0.92 (m, 12H); 13C NMR (125 MHz, C6D6) d 157.7,
138.0, 137.5, 137.4, 137.1, 129.8, 127.7 (ꢂ2), 126.6
(ꢂ2), 126.5 (ꢂ5), 126.3, 125.8 (ꢂ2), 125.7 (ꢂ2), 125.7
(ꢂ2), 125.6, 125.6, 125.6, 125.5, 125.4, 112.0 (ꢂ2), 81.2,
76.1, 75.4, 75.0, 74.6, 74.0, 73.7, 73.6, 72.3, 72.2, 71.6,
71.1, 71.0, 69.3, 69.1, 68.7, 67.9, 67.2, 52.8 (ꢂ2), 40.1,
30.7, 29.8, 29.5, 28.9, 16.1, 15.2, 8.1, 5.48 (ꢂ2), 5.46,
5.36, 5.0, 4.9, 4.3 (ꢂ2), 4.2, 3.6 (ꢂ2), 2.9; HRMS (ESI)
calcd for C69H98O11Si2Na [(M+Na)+] 1181.6545, found
1181.6541.
2872, 1612, 1512, 1454, 1248, 1092, 1029, 737, 698 cmꢁ1
;
4.1.42. Dihydroxy ketone 69. To a solution of bis-TES
ether 67 (5.13 g, 4.43 mmol) in CH2Cl2/pH 7 phosphate
buffer (10:1, v/v, 89 mL) at 0 ꢀC was added DDQ (3.02 g,
13.3 mmol). The resulting mixture was stirred at 0 ꢀC for
1 h before it was quenched with saturated aqueous NaHCO3.
The mixture was diluted with EtOAc, washed with brine,
dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was filtered through a plug of silica gel
(20% EtOAc/hexanes) to give alcohol, which was used di-
rectly in the subsequent reaction.
4.1.40. Diol 66. To a solution of alcohol 65 (4.46 g,
4.89 mmol) in THF (50 mL) at 0 ꢀC was added BH3$THF
(0.98 M in THF, 20.2 mL, 19.8 mmol). The resulting solu-
tion was stirred at 0 ꢀC for 30 min and then at room temper-
ature for 2.5 h. The reaction mixture was cooled to 0 ꢀC and
treated with 10% aqueous NaOH (31 mL) followed by 30%
H2O2 (63 mL). The solution was stirred at room temperature
for 3.5 h before it was diluted with EtOAc. The organic layer
was separated, washed with brine, dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. Purification
by column chromatography on silica gel (50% EtOAc/
hexanes) afforded diol 66 (4.12 g, 91%) as a colorless oil:
[a]3D0 ꢁ24.9 (c 0.49, C6H6); IR (film) 3435, 2873, 1612,
˚
To a suspension of the alcohol and 4 A molecular sieves in
CH2Cl2 (44 mL) were added NMO (1.04 g, 8.88 mmol)
and TPAP (77.7 mg, 0.22 mmol). The resulting mixture
was stirred at 0 ꢀC for 5 min and then at room temperature
for 6 h. The mixture was concentrated under reduced pres-
sure, and the residue was filtered through a plug of silica
gel (20% EtOAc/hexanes) to give ketone 68, which was
used directly in the subsequent reaction.
1513, 1454, 1248, 1070, 737, 698 cmꢁ1
;
1H NMR
(500 MHz, CDCl3) d 7.37–7.27 (m, 22H), 6.89 (d,
J¼8.5 Hz, 2H), 4.64–4.41 (m, 9H), 4.37 (d, J¼11.5 Hz,
1H), 3.27 (d, J¼3.0 Hz, 1H), 3.82–3.74 (m, 4H), 3.65–
3.54 (m, 5H), 3.49–3.42 (m, 3H), 3.30–3.24 (m, 2H), 3.03
(ddd, J¼8.0, 8.0, 4.0 Hz, 1H), 2.71 (m, 1H), 2.55 (m, 1H),
2.37 (m, 1H), 2.26 (m, 1H), 2.18–2.16 (m, 2H), 1.85–1.79
(m, 2H), 1.63 (m, 3H), 1.26 (s, 3H), 1.17 (m, 3H), 1.02 (d,
J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 159.2,
To a solution of the above ketone 68 in THF (44 mL) at 0 ꢀC
were added TBAF (1.0 M in THF, 26.6 mL, 26.6 mmol) and
acetic acid (0.76 mL, 13.3 mmol). The resulting solution

5998
K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
was stirred at room temperature for 7.5 h before it was
quenched with saturated aqueous NH4Cl. The mixture was
diluted with EtOAc, washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification by column chromatography on silica gel (50%
EtOAc/hexanes) afforded dihydroxy ketone 69 (2.89 g,
81% for the three steps) as a colorless oil: [a]3D2 +68.1
(c 1.06, CHCl3); IR (film) 3454, 2952, 2887, 2857, 1462,
(500 MHz, C6D6) d 7.34–7.26 (m, 9H), 7.20–7.08 (m,
11H), 4.52–4.47 (m, 3H), 4.44–4.30 (m, 7H), 3.78–3.76
(m, 2H), 3.73–3.69 (m, 2H), 3.58–3.56 (m, 2H), 3.49 (m,
1H), 3.42 (m, 1H), 3.33 (m, 1H), 3.13 (m, 1H), 2.94 (m,
1H), 2.82 (m, 1H), 2.67 (m, 1H), 2.41 (m, 1H), 2.34 (m,
1H), 2.26–2.24 (m, 2H), 1.97 (m, 1H), 1.73–1.60 (m, 2H),
1.39–1.24 (m, 24H), 1.14 (m, 6H); 13C NMR (125 MHz,
C6D6) d 139.5, 139.3, 138.9 (ꢂ2), 128.6 (ꢂ4), 128.5 (ꢂ2),
128.3 (ꢂ3), 128.2 (ꢂ3), 128.1 (ꢂ2), 127.9 (ꢂ2), 127.7
(ꢂ2), 127.60, 127.57, 84.1, 79.5, 79.2, 78.3, 77.3, 77.0,
76.7, 73.6, 73.4, 73.3, 73.13, 73.08, 72.8, 71.2, 70.5, 70.3,
69.2, 43.8, 30.9, 30.5, 30.3, 18.83 (ꢂ3), 18.77 (ꢂ3), 17.8,
15.9, 13.3, 13.26 (ꢂ3), 10.2; HRMS (ESI) calcd for
C58H80O9SiNa [(M+Na)+] 971.5469, found 971.5493.
1
1360, 1253, 1107, 1031, 838, 776, 672 cmꢁ1; H NMR
(500 MHz, C6D6) d 7.36–7.24 (m, 20H), 4.66–4.57 (m,
3H), 4.53–4.41 (m, 4H), 4.35 (m, 1H), 4.13 (dd, J¼7.5,
3.5 Hz, 1H), 4.06 (m, 1H), 3.73 (dd, J¼11.5, 4.0 Hz, 1H),
3.65–3.49 (m, 3H), 3.43 (m, 1H), 3.37–3.30 (m, 2H), 3.26
(m, 1H), 2.92 (dd, J¼14.5, 4.5 Hz, 1H), 2.79 (dd, J¼12.5,
3.5 Hz, 1H), 2.57 (dd, J¼15.0, 4.5 Hz, 1H), 2.43–2.40 (m,
2H), 2.12–2.04 (m, 4H), 1.75 (m, 1H), 1.55 (m, 1H), 1.45–
1.39 (m, 5H), 1.08 (m, 3H), 0.96 (d, J¼6.5 Hz, 3H); 13C
NMR (125 MHz, CDCl3) d 212.0, 138.6, 138.1, 137.9,
137.7, 128.4 (ꢂ2), 128.33 (ꢂ5), 128.26 (ꢂ2), 127.8 (ꢂ2),
127.7 (ꢂ3), 127.53 (ꢂ2), 127.50 (ꢂ2), 127.4 (ꢂ2), 80.7,
80.6, 76.5, 76.2, 75.9, 75.1, 74.7, 73.9, 73.7, 73.5, 73.2,
72.9, 71.0, 70.9, 70.4, 68.9, 53.7, 43.2, 41.0, 30.1, 29.9,
29.7, 28.9, 9.8; HRMS (ESI) calcd for C49H60O10Na
[(M+Na)+] 831.4084, found 831.4075.
4.1.45. Diol 73. To a solution of the TIPS ether 72 (3.14 g) in
MeOH (18 mL) was added 10% Pd/C (2.5 g). The resulting
mixture was stirred at room temperature under an atmo-
sphere of hydrogen for 17 h before it was filtered through
a pad of Celite. The filtrate and washings were combined
and concentrated under reduced pressure to give tetraol,
which was used directly in the subsequent reaction.
To a solution of the tetraol in DMF (26.8 mL) at room
temperature were added 2,2-dimethoxypropane (3.55 mL,
28.9 mmol) and CSA (3.75 g, 16.1 mmol). The resulting
mixture was stirred at 30 ꢀC for 6.5 h before being quenched
with Et3N. The mixture was concentrated under reduced
pressure, and the residue was filtered through a plug of silica
gel (20% EtOAc/hexanes) to give a mixture of monoaceto-
nide and bis-acetonide, which was used directly in the sub-
sequent reaction.
4.1.43. Tetracyclic ether 70. To a solution of dihydroxy
ketone 69 (52.8 mg, 65.3 mmol) in MeCN/Et3SiH (4:1,
v/v, 1.3 mL) at ꢁ10 ꢀC was added TMSOTf (14.1 mL,
77.9 mmol). The resulting solution was stirred at ꢁ10 ꢀC
for 15 min before being quenched with Et3N. The mixture
was concentrated under reduced pressure, and the residue
was purified by column chromatography on silica gel
(40% EtOAc/hexanes) to afford tetracyclic ether 70
(42.8 mg, 83%) as a colorless oil: [a]2D9 ꢁ10.1 (c 1.07,
CHCl3); IR (film) 3475, 2950, 2875, 1454, 1380, 1087,
To a solution of the mixture of monoacetonide and bis-aceto-
nide in CH2Cl2/MeOH (4:1, v/v, 21.8 mL) at 0 ꢀC was added
PPTS (0.27 g, 1.07 mmol). The resulting mixture was stirred
at 0 ꢀC for 1 h before being quenched with Et3N. The mixture
was concentrated under reduced pressure, and the residue
was purified by column chromatography on silica gel (50%
EtOAc/hexanes) to afford diol 73 (1.09 g, 65% for the four
steps) as a colorless oil: [a]3D1 ꢁ17.1 (c 1.41, CHCl3); IR
(film) 3397, 2944, 2866, 1463, 1329, 1063, 1035, 757,
1
1065, 738, 698 cmꢁ1; H NMR (500 MHz, C6D6) d 7.34–
7.15 (m, 16H), 7.12–7.08 (m, 4H), 4.52–4.46 (m, 2H),
4.45–4.33 (m, 4H), 4.31–4.28 (m, 2H), 3.79 (m, 1H),
3.76–3.71 (m, 2H), 3.55–3.46 (m, 4H), 3.39 (ddd, J¼8.0,
8.0, 5.5 Hz, 1H), 3.33 (ddd, J¼10.5, 5.0 Hz, 1H), 3.17 (m,
1H), 3.09 (d, J¼9.5 Hz, 1H), 2.81 (dd, J¼12.5, 3.5 Hz,
1H), 2.71 (dd, J¼13.0, 4.0 Hz, 1H), 2.37 (m, 1H), 2.28–
2.15 (m, 4H), 1.95 (m, 1H), 1.74–1.55 (m, 4H), 1.28 (s,
3H), 1.18 (s, 3H), 1.08 (d, J¼6.5 Hz, 3H); 13C NMR
(125 MHz, C6D6) d 139.5, 139.4, 138.9, 138.9, 128.6
(ꢂ3), 128.5 (ꢂ2), 128.5 (ꢂ2), 128.3 (ꢂ3), 128.1 (ꢂ2),
127.9 (ꢂ2), 127.8 (ꢂ2), 127.7 (ꢂ2), 127.6 (ꢂ2), 83.1,
79.4, 78.2, 77.9, 76.7, 76.6, 76.2, 73.6, 73.5, 73.3, 73.1
(ꢂ2), 73.1, 72.8, 70.8, 70.6, 70.3, 69.1, 43.8, 30.6, 30.4,
30.3, 17.6, 15.9, 10.1; HRMS (ESI) calcd for C49H60O9Na
[(M+Na)+] 815.4135, found 815.4413.
1
679 cmꢁ1; H NMR (500 MHz, C6D6) d 3.79 (dd, J¼10.0,
4.5 Hz, 1H), 3.71 (ddd, J¼5.0, 5.0, 5.0 Hz, 1H), 3.67–3.63
(m, 2H), 3.61–3.50 (m, 5H), 3.32–3.28 (m, 2H), 3.12 (dd,
J¼12.0, 3.5 Hz, 1H), 3.04–3.01 (m, 2H), 2.11–2.01 (m,
4H), 1.72–1.59 (m, 4H), 1.55–1.45 (m, 4H), 1.39 (s, 3H),
1.33–1.26 (m, 4H), 1.19 (s, 3H), 1.12–0.97 (m, 24H); 13C
NMR (125 MHz, CDCl3) d 99.5, 84.2, 80.4, 78.6, 78.4,
77.8, 76.6, 74.4, 70.8, 67.4, 66.5, 63.5, 60.6, 42.9, 33.1,
31.9, 30.3, 29.2, 29.0, 27.6, 19.2, 18.34 (ꢂ3), 18.28 (ꢂ3),
17.2, 16.4, 12.8 (ꢂ3), 10.2; HRMS (ESI) calcd for
C33H61O9Si [(M+H)+] 629.4085, found 629.4116.
4.1.44. TIPS ether 72. To a solution of tetracyclic ether 70
(2.12 g, 2.68 mmol) in CH2Cl2 (27 mL) at 0 ꢀC were added
2,6-lutidine (0.62 mL, 5.32 mmol) and TIPSOTf (1.41 mL,
5.25 mmol). The resulting mixture was stirred at room tem-
perature for 2.5 h before it was quenched with saturated
aqueous NaHCO3. The mixture was diluted with EtOAc,
washed with brine, dried over Na2SO4, filtered, and concen-
trated under reduced pressure. The residue was filtered
through a plug of silica gel (20% EtOAc/hexanes) to give
TIPS ether 72 (3.14 g): [a]3D0 ꢁ8.81 (c 1.91, CHCl3); IR
4.1.46. Olefin 75. To a solution of diol 73 (1.00 g,
1.59 mmol) in pyridine (16 mL) at 0 ꢀC was added pivaloyl
chloride (1.56 mL, 12.7 mmol). The resulting solution was
stirred at 0 ꢀC for 40 min before saturated aqueous NH4Cl
was added. The mixture was diluted with EtOAc, washed
with brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. Purification by column chromato-
graphy on silica gel (40% EtOAc/hexanes) afforded pivalate
ester (0.96 g, 85%) as a colorless oil: [a]2D9 ꢁ15.7 (c 1.22,
1
(film) 2943, 2864, 1455, 1100, 736, 679 cmꢁ1; H NMR

K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
5999
CHCl3); IR (film) 3410, 2944, 2867, 1725, 1463, 1384, 1157,
1064, 1036, 882, 759, 677 cmꢁ1 1H NMR (500 MHz,
J¼12.5, 4.0 Hz, 1H), 3.03 (dd, J¼9.0, 9.0 Hz, 1H), 2.97
(dd, J¼12.5, 3.0 Hz, 1H), 2.63 (ddd, J¼15.0, 7.5, 7.5 Hz,
1H), 2.27 (ddd, J¼11.0, 4.5, 4.5 Hz, 1H), 2.10 (dd, J¼11.0,
4.5 Hz, 1H), 2.04 (m, 1H), 1.64 (m, 2H), 1.56–1.47 (m,
4H), 1.40 (s, 3H), 1.27 (s, 3H), 1.19 (s, 3H), 1.13–1.03 (m,
24H); 13C NMR (125 MHz, CDCl3) d 159.3, 140.0, 130.1,
129.6 (ꢂ2), 115.3, 113.8 (ꢂ2), 99.5, 84.1, 80.3, 78.4, 78.3,
76.5, 75.7, 74.4, 74.0, 70.8, 70.3, 67.4, 63.5, 55.2, 42.9,
38.7, 30.3, 29.9, 29.2, 19.1, 18.37, 18.34 (ꢂ3), 18.28
(ꢂ3), 18.19, 16.4, 12.8 (ꢂ3), 9.9; HRMS (ESI) calcd for
C41H66O9SiNa [(M+Na)+] 753.4374, found 753.4415.
;
CDCl3) d 4.11 (m, 1H), 4.00 (m, 1H), 3.79 (dd, J¼10.5,
5.0 Hz, 1H), 3.67–3.50 (m, 5H), 3.34–3.25 (m, 2H), 3.13
(dd, J¼12.0, 3.5 Hz, 1H), 3.04–3.01 (m, 2H), 2.15–2.08
(m, 2H), 2.02 (m, 1H), 1.96 (m, 1H), 1.87–1.77 (m, 2H),
1.71–1.59 (m, 2H), 1.55–1.37 (m, 8H), 1.27 (s, 3H), 1.19
(s, 3H), 1.16 (s, 9H), 1.10–0.98 (m, 24H); 13C NMR
(125 MHz, CDCl3) d 178.8, 99.5, 84.1, 80.4, 78.4, 78.3,
77.6, 76.6, 74.4, 70.8, 67.4, 67.0, 63.5, 63.4, 42.9, 38.7, 33.8,
30.3, 30.0, 29.2, 29.1, 27.2 (ꢂ3), 19.2, 18.4, 18.3 (ꢂ3), 18.3
(ꢂ3), 17.2, 16.4, 12.8 (ꢂ3), 10.1; HRMS (ESI) calcd for
C38H68O10SiNa [(M+Na)+] 735.4479, found 735.4478.
4.1.47. Tris-benzyl ether 76. To a solution of olefin 75
(0.18 g, 0.25 mmol) in THF (2.4 mL) at 0 ꢀC was added
TBAF (1.0 M in THF, 0.99 mL, 0.99 mmol). The resulting
solution was stirred at room temperature for 16 h before it
was concentrated under reduced pressure. Purification by
column chromatography on silica gel (30% EtOAc/hexanes)
afforded alcohol (0.13 g, 92%) as a colorless oil.
To a solution of the pivalate ester (0.24 g, 0.34 mmol) in
DMF (6.6 mL) at 0 ꢀC was added NaH (50% in oil,
32.0 mg, 0.67 mmol). The resulting solution was stirred at
0 ꢀC for 1 h before p-methoxybenzyl chloride (44.7 mL,
0.33 mmol) and Bu4NI (36.0 mg, 97.5 mmol) were added.
The reaction mixture was stirred at room temperature for
6 h before it was quenched with saturated aqueous NH4Cl.
The mixture was diluted with Et2O, washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pres-
sure. Purification by column chromatography on silica gel
(20% EtOAc/hexanes) afforded p-methoxybenzyl ether
(0.22 g, 78% for two cycles) as a colorless oil.
To a solution of the alcohol (0.20 g, 0.35 mmol) in MeOH
(3.6 mL) at 0 ꢀC was added p-TsOH$H2O (67.8 mg,
0.36 mmol). The reaction mixture was stirred at 0 ꢀC for
1 h before being quenched with Et3N. The mixture was
concentrated under reduced pressure, and the residue was
filtered through a plug of silica gel (10% MeOH/CHCl3)
to give triol, which was used directly in the subsequent
reaction.
To a solution of p-methoxybenzyl ether (0.20 g, 0.24 mmol)
in CH2Cl2 (2.5 mL) at ꢁ78 ꢀC was added DIBALH (0.95 M
in hexane, 0.48 mL, 0.46 mmol). The resulting mixture was
stirred at ꢁ78 ꢀC for 30 min before it was quenched with
saturated aqueous potassium sodium tartrate. The mixture
was vigorously stirred until the layers became clear. The
organic layer was separated, washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification by column chromatography on silica gel (30%
EtOAc/hexanes) afforded alcohol 74 (0.13 g, 72%) as a
colorless oil.
To a solution of the triol in DMF (3.5 mL) at 0 ꢀC was added
NaH (50% in oil, 0.10 g, 2.08 mmol). The resulting solution
was stirred at 0 ꢀC for 1 h before benzyl bromide (0.22 mL,
1.85 mmol) and Bu4NI (39.4 mg, 0.107 mmol) were added.
The reaction mixture was stirred at room temperature for
17.5 h before it was quenched with saturated aqueous
NH4Cl. The mixture was diluted with Et2O, washed with
brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure. Purification by column chromatography
on silica gel (30% EtOAc/hexanes) afforded tris-benzyl
ether 76 (0.25 g, 89% for the two steps) as a colorless oil:
[a]3D0 ꢁ51.2 (c 0.04, CHCl3); IR (film) 2944, 2866, 1513,
To a solution of alcohol 74 (0.12 g, 0.16 mmol) in THF
(1.6 mL) were added o-nitrophenyl selenocyanate (79.0 mg,
0.35 mmol) and Bu3P (0.79 mL, 3.2 mmol). The resulting
mixture was stirred at room temperature for 45 min before
it was concentrated under reduced pressure. The residue
was filtered through a plug of silica gel (10% EtOAc/hex-
anes) to give o-nitrophenyl selenide, which was used directly
in the subsequent reaction.
1465, 1383, 1086, 882, 673 cmꢁ1 1H NMR (500 MHz,
;
CDCl3) d 7.34–7.32 (m, 2H), 7.25–7.11 (m, 15H), 6.79 (d,
J¼10.0 Hz, 2H), 5.67 (ddd, J¼17.0, 9.5, 9.5 Hz, 1H), 4.91
(dd, J¼10.5, 2.0 Hz, 1H), 4.88–4.84 (m, 2H), 4.66 (d,
J¼12.0 Hz, 1H), 4.53–4.42 (m, 4H), 4.27 (d, J¼11.5 Hz,
1H), 4.26 (d, J¼10.5 Hz, 1H), 3.71 (s, 3H), 3.63 (m, 1H),
3.55 (m, 2H), 3.38–3.32 (m, 3H), 3.28–3.14 (m, 3H), 3.02
(dd, J¼13.0, 4.0 Hz, 1H), 2.95 (dd, J¼12.5, 3.5 Hz, 1H),
2.60 (m, 1H), 2.32 (ddd, J¼11.5, 4.0, 4.0 Hz, 1H), 2.24
(ddd, J¼11.5, 4.5, 4.5 Hz, 1H), 2.10 (dd, J¼11.0, 4.0 Hz,
1H), 1.61–1.50 (m, 3H), 1.19 (s, 3H), 1.18 (s, 3H), 1.05 (d,
J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 159.3,
139.8, 139.1, 138.4, 137.8, 130.0, 129.6 (ꢂ2), 128.4 (ꢂ2),
128.3 (ꢂ2), 128.2 (ꢂ2), 127.8 (ꢂ2), 127.8 (ꢂ3), 127.7
(ꢂ2), 127.5, 127.3, 115.7, 113.9 (ꢂ2), 84.2, 82.5, 79.1,
78.0, 77.7, 75.6, 74.2, 74.0, 73.3, 73.2, 72.8, 72.6, 71.0,
70.4, 69.6, 55.3 (ꢂ2), 43.2, 38.6, 30.1, 29.7, 18.8, 15.9,
10.5; HRMS (ESI) calcd for C50H60O9Na [(M+Na)+]
827.4135, found 827.4141.
To a solution the above selenide in CH2Cl2 (3.2 mL) at 0 ꢀC
was added m-CPBA (77%, 40.0 mg, 0.18 mmol). The result-
ing solution was stirred at 0 ꢀC for 45 min before it was
quenched with Et3N. The mixture was stirred at 35 ꢀC for
further 12 h and concentrated under reduced pressure. Puri-
fication by column chromatography on silica gel (10%
EtOAc/hexanes) afforded olefin 75 (0.11 g, 94% for the
two steps) as a colorless oil: [a]3D2 ꢁ51.2 (c 0.04, CHCl3);
IR (film) 2945, 2866, 1513, 1465, 1383, 1249, 1079,
882, 673 cmꢁ1 1H NMR (500 MHz, C6D6) d 7.22 (d,
;
J¼8.5 Hz, 2H), 6.85 (d, J¼9.0 Hz, 2H), 5.74 (ddd,
J¼17.5, 10.0, 10.0 Hz, 1H), 4.95 (dd, J¼10.5, 2.5 Hz, 1H),
4.88 (dd, J¼17.5, 2.0 Hz, 1H) 4.49 (d, J¼11.0 Hz, 1H),
4.32 (d, J¼11.5 Hz, 1H), 3.82–3.76 (m, 4H), 3.68–3.51
(m, 4H), 3.37 (m, 1H), 3.34–3.23 (m, 2H), 3.14 (dd,
4.1.48. GHIJ-ring fragment 37. To a solution of tris-benzyl
ether 76 (0.21 g, 0.26 mmol) in MeCN (5.3 mL) at 0 ꢀC were

6000
K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
added Et3SiH (0.13 mL, 0.81 mmol) and BF3$OEt2 (33 mL,
0.27 mmol). The resulting solution was stirred at 0 ꢀC for
45 min before being quenched with Et3N. The mixture was
concentrated under reduced pressure, and the residue was
purified by column chromatography on silica gel (40%
EtOAc/hexanes) to afford GHIJ-ring fragment 37 (0.18 g,
quant.) as a colorless oil: [a]3D1 +53.1 (c 0.23, CHCl3); IR
(film) 3407, 2876, 1642, 1383, 1066, 1029, 737,
73.1, 72.8, 72.6, 71.9, 71.0, 70.6, 69.6, 68.6, 67.2, 54.5,
43.1, 38.7, 35.3, 32.1, 32.0, 30.1, 29.7, 26.6, 25.7 (ꢂ3),
24.8, 23.9, 23.3, 18.0, 17.9, 16.1, 15.9, 10.5, ꢁ1.9, ꢁ2.0;
HRMS (FAB) calcd for C89H112O15SiNa [(M+Na)+]
1471.7668, found 1471.7606.
4.1.50. Alcohol 79. To a solution of ester 77 (0.23 g,
0.16 mmol) in CH2Cl2 (3.2 mL) at ꢁ78 ꢀC was added
DIBALH (0.94 M in hexane, 0.34 mL, 0.32 mmol). The
resulting solution was stirred at ꢁ78 ꢀC for 1 h. A solution
of Ac2O (0.18 mL, 1.90 mmol) and DMAP (0.26 g,
2.13 mmol) in CH2Cl2 (3.2 mL) was added dropwise over
1 h, and then a solution of pyridine (0.16 mL, 1.98 mmol)
in CH2Cl2 (1.6 mL) was added over 0.5 h. The reaction mix-
ture was stirred at ꢁ78 ꢀC for 20 h and allowed to warm to
0 ꢀC. After being stirred at 0 ꢀC for 1 h, the reaction mixture
was quenched with saturated aqueous NH4Cl and saturated
aqueous potassium sodium tartrate. The mixture was vigor-
ously stirred until the layers became clear. The solution was
diluted with EtOAc, washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The resi-
due was filtered through a plug of silica gel (20% EtOAc/
hexanes containing 1% Et3N) to afford a-acetoxy ether 78
(0.13 g, 55%) as an approximately 1:1 mixture of diastereo-
mers, which was used directly in the subsequent reaction.
697 cmꢁ1
; d 7.58 (d,
1H NMR (500 MHz, C6D6)
J¼7.5 Hz, 2H), 7.31 (d, J¼7.0 Hz, 2H), 7.26–7.07 (m,
11H), 5.95 (ddd, J¼17.0, 10.0, 10.0 Hz, 1H), 5.11–5.06
(m, 3H), 4.91 (d, J¼12.5 Hz, 1H), 4.49 (d, J¼12.5 Hz,
1H), 4.43 (d, J¼11.5 Hz, 1H), 4.40 (d, J¼12.5 Hz, 1H),
4.24 (d, J¼12.0 Hz, 1H), 3.79 (m, 1H), 3.75–3.69 (m, 2H),
3.50 (ddd, J¼7.0, 7.0, 5.5 Hz, 1H), 3.39 (d, J¼9.5 Hz,
1H), 3.34 (m, 1H), 3.27 (dd, J¼10.5, 10.5 Hz, 1H), 3.19
(dd, J¼9.5, 1.5 Hz, 1H), 3.15 (ddd, J¼12.0, 12.0, 4.5 Hz,
1H), 2.89 (dd, J¼12.5, 3.0 Hz, 1H), 2.79 (dd, J¼12.5,
3.5 Hz, 1H), 2.69 (dd, J¼7.0, 7.0 Hz, 1H), 2.30 (ddd,
J¼11.0, 4.0, 4.0 Hz, 1H), 2.26 (dd, J¼11.0, 3.5 Hz, 1H),
2.01 (ddd, J¼11.0, 4.5, 4.5 Hz, 1H), 1.73 (dd, J¼12.0,
12.0 Hz, 1H), 1.68–1.54 (m, 3H), 1.31 (s, 3H), 1.22 (d,
J¼7.0 Hz, 3H), 1.16 (s, 3H); 13C NMR (125 MHz, C6D6)
d 138.2, 138.1, 137.4, 137.0, 126.54 (ꢂ2), 126.46 (ꢂ2),
126.43 (ꢂ2), 126.3, 125.9 (ꢂ2), 125.84, 125.80 (ꢂ2),
125.76, 125.54, 125.48, 113.6, 82.5, 81.6, 77.6, 76.2, 75.9,
75.3, 74.9, 72.5, 71.5, 71.4, 71.3, 70.8, 68.9, 68.3, 65.6,
41.9, 37.0, 31.9, 28.7, 16.6, 13.9, 8.8; HRMS (ESI) calcd
for C42H52O8Na [(M+Na)+] 707.3560, found 707.3535.
To a solution of the a-acetoxy ether 78 (0.12 g, 80.4 mmol) in
CH2Cl2 (1.60 mL) at ꢁ78 ꢀC were added 2,6-di-tert-butyl-
4-methylpyridine (65.6 mg, 0.32 mmol), TMSCN (21.3 mL,
0.17 mmol), and TMSOTf (43.4 mL, 0.24 mmol). The result-
ing mixture was stirred at ꢁ78 ꢀC for 5 min and allowed to
warm to 0 ꢀC. The reaction mixture was stirred at 0 ꢀC for
1 h before it was quenched with Et3N. The mixture was
filtered and concentrated under reduced pressure. The resi-
due was filtered through a plug of silica gel (30% EtOAc/
hexanes) to afford a-cyano ether (0.12 g) as a 1:1 mixture
of diastereomers.
4.1.49. Ester 77. To a solution of carboxylic acid 36 (0.21 g,
0.27 mmol) in THF (2.6 mL) at 0 ꢀC were added Et3N
(54.0 mL, 0.39 mmol) and 2,4,6-trichlorobenzoyl chloride
(52 mL, 0.33 mmol). The resulting mixture was stirred at
40 ꢀC for 1 h before it was concentrated under reduced pres-
sure. The mixture was dissolved in toluene (2.6 mL) and
treated with alcohol 37 (0.18 g, 0.26 mmol) and DMAP
(65.9 mg, 0.54 mmol). The reaction mixture was stirred at
40 ꢀC for 1.5 h before being quenched with saturated aque-
ous NH4Cl. The mixture was diluted with EtOAc, washed
with brine and saturated aqueous NaHCO3, dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification by column chromatography on silica gel (30%
EtOAc/hexanes) afforded ester 77 (0.35 g, 92%) as a solid:
[a]2D6 +15.4 (c 0.55, CHCl3); IR (film) 2926, 2855, 1738,
To a solution of the a-cyano ether (0.12 g, 79.8 mmol) in
MeCN (3.2 mL) was added TBAF (0.21 g, 0.80 mmol).
The reaction mixture was stirred at 70 ꢀC for 20 h before it
was concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (50%
EtOAc/hexanes) to afford alcohol 79 (93.7 mg, 87% for
the two steps) as a 1:1 mixture of diastereomers: [a]D25
+1.0 (c 0.98, CHCl3); IR (film) 3465, 3060, 2944, 1455,
1383, 1251, 1068, 774, 658 cmꢁ1 1H NMR (500 MHz,
;
1
CDCl3) d 7.82–7.75 (m, 8H), 7.46–7.40 (m, 8H), 7.34–
7.26 (m, 11H), 7.21–7.19 (m, 2H), 5.71 (ddd, J¼17.5, 9.5,
9.5 Hz, 1H), 5.01 (d, J¼11.5 Hz, 1H), 4.92–4.90 (m, 2H),
4.78–4.51 (m, 9H), 4.35 (d, J¼11.0 Hz, 1H), 3.85–3.82
(m, 1H), 3.71–3.54 (m, 7H), 3.48–3.30 (m, 5H), 3.23 (dd,
J¼8.0, 8.0 Hz, 1H), 3.13–3.08 (m, 3H), 3.00 (dd, J¼12.0,
3.0 Hz, 1H), 2.57–2.51 (m, 1H), 2.40–2.24 (m, 4H), 2.17
(dd, J¼11.5, 4.5 Hz, 1H), 2.07–1.78 (m, 7H), 1.73–1.50
(m, 8H), 1.28–1.23 (m, 9H), 1.21 (s, 3H), 1.11 (d,
J¼7.0 Hz, 3H), 0.83 (s, 9H), 0.08 (m, 6H); 13C NMR
(125 MHz, CDCl3) d 172.1, 139.0, 138.5, 138.4, 137.8,
136.0, 135.8, 133.23, 133.19, 132.9, 128.4 (ꢂ2), 128.3
(ꢂ2), 128.2 (ꢂ2), 128.1 (ꢂ2), 127.8 (ꢂ2), 127.7 (ꢂ2),
127.5, 127.3, 126.24 (ꢂ2), 126.21 (ꢂ2), 126.10 (ꢂ2),
126.06 (ꢂ2), 125.83 (ꢂ2), 125.78 (ꢂ2), 125.72 (ꢂ2),
125.6 (ꢂ2), 116.2, 87.2, 84.1, 82.6, 81.6, 81.2, 80.3, 79.8,
79.2, 77.8, 77.4, 76.8, 74.3, 74.2, 73.6, 73.4, 73.3, 73.2,
1382, 1093, 753, 698 cmꢁ1; H NMR (500 MHz, CDCl3)
d 7.81–7.72 (m, 10H), 7.46–7.40 (m, 10H), 7.35–7.20 (m,
9H), 5.84–5.70 (m, 1H), 5.21–4.90 (m, 3H), 4.77–4.51 (m,
8H), 4.37–4.35 (m, 1H), 4.30 (dd, J¼5.5, 5.5 Hz, 0.5H),
4.20 (dd, J¼6.0, 6.0 Hz, 0.5H), 3.87–3.85 (m, 1H), 3.72–
3.53 (m, 7H), 3.49–3.30 (m, 6H), 3.26–3.22 (m, 1H),
3.12–2.97 (m, 4H), 2.65–2.63 (m, 1H), 2.54–2.48 (m, 1H),
2.42–2.40 (m, 1H), 2.29–2.27 (m, 1H), 2.19–2.17 (m, 1H),
2.09–2.01 (m, 4H), 1.89–1.69 (m, 7H), 1.66–1.43 (m, 6H),
1.27–1.23 (m, 12H), 1.16–1.13 (m, 3H); 13C NMR
(125 MHz, CDCl3) d 139.7, 138.93 (ꢂ2), 138.91 (ꢂ2),
138.4 (ꢂ3), 138.3 (ꢂ2), 137.82, 137.79 (ꢂ2), 136.0,
135.9, 135.8, 133.20 (ꢂ2), 133.16 (ꢂ2), 132.88 (ꢂ2),
132.86 (ꢂ2), 128.4 (ꢂ4), 128.3 (ꢂ4), 128.2 (ꢂ2), 128.14
(ꢂ2), 128.09 (ꢂ2), 128.07 (ꢂ2), 127.8 (ꢂ5), 127.73 (ꢂ4),
127.66 (ꢂ3), 127.65 (ꢂ3), 127.61, 127.5, 127.4, 127.34,
127.32, 126.23, 126.22, 126.16, 126.14, 126.07 (ꢂ2),

K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
6001
1
126.05, 126.04, 125.81, 125.77, 125.76, 125.69 (ꢂ2),
125.68, 125.63, 125.61, 119.1, 118.1, 117.0, 116.1, 86.9,
86.8, 84.2, 84.0, 82.54, 82.46, 81.6 (ꢂ2), 81.20, 81.15,
80.31, 80.25, 79.7, 79.6, 79.2 (ꢂ2), 77.69, 77.66, 77.59,
77.55, 77.33, 77.31, 77.2, 77.0, 76.8 (ꢂ2), 75.0, 74.8, 74.3,
73.6, 73.3 (ꢂ2), 73.19, 73.15, 73.0 (ꢂ2), 72.73, 72.71,
72.58, 72.55, 71.72, 71.70, 71.0, 70.9, 70.75, 70.74, 70.6,
69.6, 68.3, 67.17, 67.12, 65.0, 60.4, 54.51, 54.47, 43.14,
43.10, 38.7, 38.3, 35.28, 35.26, 32.02, 31.96, 31.6, 31.5,
30.3, 30.0 (ꢂ2), 28.69, 28.68, 26.5, 24.2, 24.04, 24.00,
23.8, 23.3, 23.2, 21.0, 18.8, 18.6, 15.9, 15.8, 15.72, 15.69,
14.2, 14.1, 10.5, 10.4; HRMS (ESI) calcd for
C84H99NO14Na [(M+Na)+] 1368.6963, found 1368.7057.
2927, 2871, 1739, 1453, 1382, 1093, 750, 698 cmꢁ1; H
NMR (500 MHz, C6D6) d 7.71–7.58 (m, 12H), 7.47–7.44
(m, 2H), 7.34–7.09 (m, 15H), 6.12 (ddd, J¼17.5, 9.5,
9.5 Hz, 1H), 5.13–5.01 (m, 3H), 4.92 (d, J¼12.0 Hz, 1H),
4.55–4.41 (m, 7H), 4.32 (d, J¼12.5 Hz, 1H), 4.25 (d,
J¼11.5 Hz, 1H), 4.18–4.15 (m, 2H), 3.81–3.71 (m, 3H),
3.63–3.47 (m, 8H), 3.40 (m, 1H), 3.34–3.26 (m, 2H), 3.18
(m, 1H), 3.02 (ddd, J¼11.0, 3.5, 3.5 Hz, 1H), 2.93 (m,
1H), 2.88 (dd, J¼13.0, 3.5 Hz, 1H), 2.78 (dd, J¼12.5,
4.0 Hz, 1H), 2.73 (m, 1H), 2.68–2.64 (m, 1H), 2.31–2.28
(m, 2H), 2.18–2.01 (m, 5H), 1.90–1.54 (m, 10H), 1.33 (s,
3H), 1.27 (d, J¼7.0 Hz, 3H), 1.21 (s, 3H), 1.20 (s, 3H),
1.08 (s, 3H); 13C NMR (125 MHz, C6D6) d 171.3, 141.3,
140.1, 139.4, 139.0, 136.8, 136.4, 133.8 (ꢂ2), 133.5 (ꢂ2),
128.53 (ꢂ4), 128.46 (ꢂ2), 128.41 (ꢂ2), 128.2 (ꢂ2),
128.07, 128.05, 127.9 (ꢂ2), 127.81 (ꢂ2), 127.78 (ꢂ2),
127.72, 127.5, 127.4, 126.7, 126.5, 126.4, 126.3, 126.1,
126.04, 126.00, 125.97, 115.6, 84.8, 83.8, 83.7, 81.8, 81.3,
80.8, 80.1, 80.0, 79.6, 79.5, 78.5, 77.9, 77.3, 76.9, 76.4,
74.5, 74.1, 73.5 (ꢂ2), 73.4, 73.2, 72.8, 71.7, 70.9 (ꢂ2),
70.3, 67.7, 54.0, 43.9, 39.5, 35.9, 32.4, 31.9, 31.6, 30.7,
29.6, 27.1, 23.3, 22.2, 19.7, 16.0, 15.9, 10.8; HRMS (ESI)
calcd for C84H98O15Na [(M+Na)+] 1369.6803, found
1369.6848.
4.1.51. Lactones 81 and 82. To a solution of alcohol 79
(66.5 mg, 49.4 mmol) in ethylene glycol (5 mL) was added
KOH (0.39 g, 6.95 mmol). The resulting mixture was stirred
at 150 ꢀC for two days. The reaction mixture was cooled to
room temperature and quenched with 3 M aqueous HCl. The
mixture was diluted with CHCl3, and washed with 1 M
aqueous HCl and brine. The organic layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification by column chromatography on silica gel (20%
MeOH/CHCl3) afforded hydroxy acid 80 (58.0 mg, 86%)
as a 1:1 mixture of diastereomers, which was used directly
in the subsequent reaction.
4.1.52. Acetate 83. To a solution of lactone 81 (15.5 mg,
11.5 mmol) in CH2Cl2 (0.23 mL) at ꢁ78 ꢀC was added
DIBALH (0.95 M in hexane, 49.0 mL, 46.6 mmol). The re-
sulting mixture was stirred at ꢁ78 ꢀC for 1 h. A solution
of Ac2O (13.0 mL, 0.14 mmol) and DMAP (18.0 mg,
0.15 mmol) in CH2Cl2 (0.12 mL), and then a solution of pyr-
idine (11.0 mL, 0.14 mmol) in CH2Cl2 (0.12 mL) were
added over 30 min. The reaction mixture was stirred at
ꢁ78 ꢀC for 12 h and allowed to warm to 0 ꢀC. The reaction
mixture was stirred at 0 ꢀC for further 1 h before it was
quenched with saturated aqueous NH4Cl and saturated aque-
ous potassium sodium tartrate. The resulting mixture was
vigorously stirred until the layers became clear. The mixture
was diluted with CH2Cl2, washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Purification by column chromatography on silica gel (30%
EtOAc/hexanes containing 1% Et3N) afforded acetate 83
(10.8 mg, 68%) as a colorless oil: [a]2D5 +1.56 (c 1.08,
CHCl3); IR (film) 2922, 2871, 1747, 1383, 1068, 750,
To a solution of hydroxy acid 80 (58.0 mg, 42.5 mmol) in
THF/toluene (1:1, v/v, 1.8 mL) at 0 ꢀC were added Et3N
(25.6 mL, 0.18 mmol) and 2,4,6-trichlorobenzoyl chloride
(21.5 mL, 0.14 mmol). The resulting mixture was stirred at
room temperature for 3 h before it was diluted with toluene
(4.6 mL). This mixture was added dropwise to a refluxing
solution of DMAP (28.1 mg, 0.23 mmol) in toluene
(4.6 mL) over a period of 1 h. The reaction mixture was
cooled to room temperature and concentrated under reduced
pressure. Purification by column chromatography on silica
gel (20–30% EtOAc/hexanes) afforded lactones 81
(20.7 mg, 36%) and 82 (18.4 mg, 32%). 81: [a]2D5 ꢁ4.2
(c 1.55, CHCl3); IR (film) 2946, 2872, 2357, 1714, 1455,
1
1274, 1097, 751, 698 cmꢁ1; H NMR (500 MHz, C6D6)
d 7.71–7.58 (m, 12H), 7.47–7.45 (m, 2H), 7.33–7.07 (m,
15H), 5.99 (ddd, J¼18.0, 10.5, 10.5 Hz, 1H), 5.47 (d,
J¼17.5 Hz, 1H), 5.28 (d, J¼12.0 Hz, 1H), 5.06 (d,
J¼12.0 Hz, 1H), 4.90 (d, J¼12.0 Hz, 1H), 4.55–4.41 (m,
7H), 4.33–4.31 (m, 2H), 4.25 (d, J¼11.5 Hz, 1H), 4.16 (m,
1H), 3.82 (m, 1H), 3.78–3.72 (m, 3H), 3.62–3.39 (m, 8H),
3.27 (m, 1H), 3.17 (m, 1H), 3.01 (m, 1H), 2.93–2.81 (m,
3H), 2.66 (dd, J¼12.5, 3.5 Hz, 1H), 2.31–2.25 (m, 3H),
2.17–2.07 (m, 4H), 1.99 (m, 1H), 1.89–1.48 (m, 14H),
1.31 (s, 3H), 1.27 (d, J¼7.5 Hz, 3H), 1.23 (s, 3H), 1.13 (s,
3H); 13C NMR (125 MHz, C6D6) d 169.9, 140.0, 139.3,
139.2, 139.0, 136.8, 136.4, 133.9, 133.8, 133.51, 133.49,
128.6, 128.54 (ꢂ2), 128.52, 128.47 (ꢂ2), 128.45, 128.44,
128.2 (ꢂ2), 128.1 (ꢂ2), 127.9 (ꢂ4), 127.81 (ꢂ2), 127.78,
127.55, 127.54, 126.7, 126.5, 126.4, 126.3, 126.09,
126.05, 125.98 (ꢂ2), 117.3, 85.4, 84.5, 83.5, 82.3, 81.9,
81.3, 81.1, 79.7, 79.6, 79.2, 77.7, 77.5, 76.9, 76.1, 75.9,
74.6, 74.1, 73.53, 73.46, 73.3, 73.2, 72.8, 71.9, 70.9, 70.8,
70.4, 67.2, 53.9, 44.0, 38.7, 35.9, 32.5, 30.71, 30.69, 28.4,
27.1, 25.0, 23.3, 22.9, 19.2, 16.1, 16.0, 10.5; HRMS (ESI)
calcd for C84H99O15 [(M+H)+] 1347.6984, found
1347.7243. 82: [a]2D5 +16.8 (c 1.35, CHCl3); IR (film)
698 cmꢁ1 1H NMR (500 MHz, C6D6) d 7.71–7.55 (m,
;
12H), 7.46–7.43 (m, 2H), 7.32–7.08 (m, 15H), 6.31 (s,
1H), 6.08 (m, 1H), 5.40 (m, 1H), 5.20 (dd, J¼10.5, 2.0 Hz,
1H), 5.09 (d, J¼12.5 Hz, 1H), 4.92 (d, J¼12.0 Hz, 1H),
4.53–4.40 (m, 6H), 4.30 (d, J¼12.0 Hz, 1H), 4.25 (d,
J¼11.5 Hz, 1H), 4.15 (m, 1H), 3.82–3.72 (m, 4H), 3.67–
3.19 (m, 14H) 3.07–3.01 (m, 2H), 2.91 (m, 1H), 2.81 (m,
1H), 2.34–2.24 (m, 4H), 2.22–2.09 (m, 4H), 1.91–1.53 (m,
13H), 1.50 (s, 3H), 1.32 (s, 3H), 1.29 (d, J¼7.0 Hz, 3H),
1.23 (s, 3H), 1.21 (s, 3H); 13C NMR (125 MHz, C6D6)
d 168.7, 140.3, 140.0, 139.3, 139.0, 136.8, 136.5, 133.88,
133.85, 133.5, 128.55 (ꢂ2), 128.53 (ꢂ3), 128.46 (ꢂ2),
128.44, 128.41, 128.2 (ꢂ2), 128.06, 128.05, 127.89 (ꢂ2),
127.87, 127.82 (ꢂ2), 127.77, 127.55 (ꢂ2), 127.50, 126.6,
126.5, 126.34, 126.29 (ꢂ2), 126.1, 126.03, 125.98, 125.95,
114.3, 93.7, 84.7, 84.5, 83.5, 82.0, 81.6, 81.4, 80.1, 79.6,
78.0, 77.80, 77.76, 77.0, 76.6, 76.3, 75.4, 74.5, 74.2,
73.53, 73.46, 73.3, 73.2 (ꢂ2), 72.8, 72.1, 70.9, 70.7, 70.4,
67.3, 53.6, 44.0, 38.3, 36.0, 32.8, 28.7, 27.2, 23.5, 23.3,

6002
K. Sato, M. Sasaki / Tetrahedron 63 (2007) 5977–6003
Yasumoto, T. Nat. Prod. Rep. 2000, 17, 293; (c) Yasumoto,
T. Chem. Rec. 2001, 1, 228.
21.0, 19.3, 16.6, 16.0 (ꢂ2), 10.6; HRMS (ESI) calcd for
C86H102O16Na [(M+Na)+] 1413.7066, found 1413.6857.
2. (a) Nagai, H.; Torigoe, K.; Satake, M.; Murata, M.; Yasumoto,
T.; Hirota, H. J. Am. Chem. Soc. 1992, 114, 1102; (b) Nagai, H.;
Murata, M.; Torigoe, K.; Satake, M.; Yasumoto, T. J. Org.
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Nagai, H.; Oshima, Y.; Yasumoto, T. Tetrahedron 2000, 56,
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3. Nagai, H.; Mikami, Y.; Yazawa, K.; Gonoi, T.; Yasumoto, T.
J. Antibiot. 1993, 46, 520.
4. Sakamoto, B.; Nagai, H.; Hokama, Y. Phycologia 1996, 35, 350.
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6. (a) Sato, K.; Sasaki, M. Org. Lett. 2005, 7, 2441; (b) Sato, K.;
Sasaki, M. Angew. Chem., Int. Ed., in press; (c) Fuwa, H.;
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2001, 42, 3645; (b) Kadota, I.; Takamura, H.; Yamamoto, Y.
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10. (a) Imai, H.; Uehara, H.; Inoue, M.; Oguri, H.; Oishi, T.;
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1853.
4.1.53. BCDEFGHIJ-ring polyether core 5. To a suspen-
sion of acetate 83 (4.00 mg, 2.88 mmol) and 4 A molecular
˚
sieves in MeCN (0.3 mL) at ꢁ40 ꢀC was added allyltri-
methylsilane (23.0 mL, 0.14 mmol). After 5 min, BF3$OEt2
(one drop) was added. The resulting mixture was stirred at
ꢁ40 ꢀC and allowed to warm to ꢁ30 ꢀC over 1 h before it
was quenched with Et3N. The mixture was filtered and con-
centrated under reduced pressure. Purification by column
chromatography on silica gel (10% EtOAc/hexanes) af-
forded diene 84 (2.30 mg, 58%), which was used directly
in the subsequent reaction.
To a solution of diene 84 (3.04 mg, 2.22 mmol) in CH2Cl2
(1.11 mL) was added the second-generation Grubbs catalyst
35 (2.81 mg, 3.31 mmol). The resulting solution was stirred
at 40 ꢀC for two days. The mixture was cooled to room tem-
perature, quenched with Et3N, and concentrated under re-
duced pressure. Purification by column chromatography on
silica gel (10% EtOAc/hexanes) afforded BCDEFGHIJ-
ring 5 (1.99 mg, 67%) as a colorless oil: [a]2D8 ꢁ2.5
(c 0.28, CHCl3); IR (film) 2925, 2872, 1632, 1454, 1384,
1
1069, 739, 698 cmꢁ1; H NMR (500 MHz, C6D6) d 7.69–
7.56 (m, 14H), 7.45–7.41 (m, 3H), 7.33–7.07 (m, 12H),
6.12 (ddd, J¼11.0, 11.0, 5.0 Hz, 1H), 5.63 (dd, J¼10.5,
10.5 Hz, 1H), 5.12 (d, J¼12.5 Hz, 1H), 4.92 (d,
J¼12.5 Hz, 1H), 4.53–4.41 (m, 6H), 4.29 (d, J¼12.0 Hz,
1H), 4.24 (d, J¼11.5 Hz, 1H), 4.14 (m, 1H), 3.81 (m, 1H),
3.78–3.70 (m, 2H), 3.67–3.66 (m, 2H), 3.62–3.59 (m, 2H),
3.51–3.46 (m, 4H), 3.32–3.20 (m, 5H), 3.22 (dd, J¼12.0,
3.0 Hz, 1H), 2.98 (m, 1H), 2.92–2.89 (m, 2H), 2.34–2.12
(m, 8H), 1.94–1.53 (m, 15H), 1.32 (s, 3H), 1.28 (s, 3H),
1.22 (s, 3H), 1.20 (d, J¼7.0 Hz, 3H), 1.09 (s, 3H); 13C
NMR (125 MHz, C6D6) d 140.2, 139.4, 139.0, 136.8,
136.5, 134.4, 133.9 (ꢂ2), 133.5 (ꢂ2), 128.54 (ꢂ3), 128.46
(ꢂ2), 128.43 (ꢂ2), 128.3, 128.2 (ꢂ2), 128.1 (ꢂ2), 127.9
(ꢂ2), 127.80 (ꢂ3), 127.75, 127.54 (ꢂ2), 127.48, 126.5
(ꢂ2), 126.31, 126.27, 126.0 (ꢂ3), 125.94 (ꢂ2), 85.1, 85.0,
84.9, 84.7, 83.7, 83.6, 82.0, 81.4, 81.2, 79.9, 79.7, 79.2,
78.6, 77.4, 75.7, 74.6, 74.2, 74.1, 73.53 (ꢂ2), 73.48, 73.36,
73.2, 72.8, 70.9, 70.8, 70.4, 67.3, 54.5, 44.1, 35.9, 33.0,
32.9, 32.6, 32.3, 31.2, 30.7, 27.3, 24.0, 23.4, 18.3, 16.7,
16.3, 16.0, 11.2; HRMS (ESI) calcd for C85H100O14Na
[(M+Na)+] 1367.7011, found 1367.7224.
Acknowledgements
This work was financially supported in part by the Sumitomo
Foundation and Grants-in-Aid for Scientific Research from
the Japan Society for Promotion of Science (JSPS) and Min-
istry of Education, Science, Sports, Culture and Technology,
Japan (Scientific Research (B) 16310145 and Priority Area
16073202). A research fellowship for K.S. from JSPS is
acknowledged.
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