Studies toward the total synthesis of gambieric acids, potent antifungal polycyclic ethers: Convergent synthesis of a fully elaborated GHIJ-ring fragment

Article abstract of DOI:10.1016/j.tet.2011.05.082

A stereocontrolled synthesis of a fully elaborated GHIJ-ring fragment of gambieric acids, which are potent antifungal polycyclic ether natural products, has been accomplished. The synthesis features convergent assembly of the tetracyclic polyether skeleto

Full text of DOI:10.1016/j.tet.2011.05.082

Tetrahedron 67 (2011) 6600e6615
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Studies toward the total synthesis of gambieric acids, potent antifungal polycyclic
ethers: convergent synthesis of a fully elaborated GHIJ-ring fragment
*
Koichi Tsubone, Keisuke Hashizume, Haruhiko Fuwa, Makoto Sasaki
Laboratory of Biostructural Chemistry, Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 April 2011
Received in revised form 17 May 2011
Accepted 18 May 2011
Available online 26 May 2011
A stereocontrolled synthesis of a fully elaborated GHIJ-ring fragment of gambieric acids, which are potent
antifungal polycyclic ether natural products, has been accomplished. The synthesis features convergent
assembly of the tetracyclic polyether skeleton through aldol coupling/cyclodehydration/reductive
etherification processes and stereoselective construction of the J-ring side chain by a CeCl3-promoted
JuliaeKocienski olefination.
Ó 2011 Elsevier Ltd. All rights reserved.
This paper is dedicated to Professor Satoshi
Omura on the occasion of his receiving the
ꢀ
Tetrahedron Prize
Keywords:
Convergent synthesis
Gambieric acids
JuliaeKocienski olefination
Polycyclic ethers
1. Introduction
NMR studies,1 and the complete stereostructure was subsequently
proposed on the basis ofdegradation experiments, applicationof the
Gambieric acids AeD (1e4, Fig. 1) are marine polycyclic ether
natural products isolated from the culture medium of the ciguatera
causative dinoflagellate Gambierdiscus toxicus by Nagai and co-
workers.1 The gross structure, including the relative stereochemis-
try of the polycyclic ether domain, was determined by extensive 2D
modified Mosher method, and chiral HPLC analysis.2 Structurally,
gambieric acids are characterized by the nonacyclic polyether core
arranged with complex side chains appended to the B- and J-rings,
respectively. Recently, we synthesized the A/B-ring domain of
gambieric acid B and their possible diastereomers, and a comparison
Me
H
H
H
Me Me
H
OTES
O
R1
HO
HO
F
O
C
H
H
Me
H
H
O
Me
H
OH
H
O
G
O
I
B
D
O
E
G
O
t-Bu Si
t-Bu
Me Me
O
H
J
O
H
H
O
OTBS
O
H
H
H
Me
H
O
O
H
O
I
H
H
Me
H
A
H
J
H
O
5
H
Me
Me
O
gambieric acid A (1): R1 = R2 = H
gambieric acid B (2): R1 = Me, R2 = H
gambieric acid C (3): R1 = H, R2
gambieric acid D (4): R1 = Me, R2
Me
Me
HO2C
H
=
OR2
CO2H
=
O
Me
Fig. 1. Structures of gambieric acids AeD (1e4) and the GHIJ-ring fragment 5.
of their NMR data with those of the natural product led to stereo-
chemical reassignment of the absolute configuration of the non-
acyclic polyether core as shown in Fig. 1.3
* Corresponding author. Tel.: þ81 22 217 6212; fax: þ81 22 217 6213; e-mail
address: masasaki@bios.tohoku.ac.jp (M. Sasaki).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.082

K. Tsubone et al. / Tetrahedron 67 (2011) 6600e6615
6601
These polycyclic ethers exhibit extremely potent antifungal
activity against filamentous fungi. Especially, the growth inhibitory
activity against Aspergillus niger by the paper disk method was
2,000 times greater than that of amphotericin B, whereas they
show only moderate toxicity against mice at a dose of 1 mg/kg
given by intraperitoneal injection.4 It has also been reported that
gambieric acid A inhibits the binding of brevetoxin-B derivative
(PbTx-3) to the voltage-gated sodium channels of excitable mem-
branes, although its affinity is significantly lower than those of
brevetoxins and ciguatoxins.5 In addition to their remarkable range
of biological activities, gambieric acid A was shown to possess
a possible role as an endogenous growth regulator of G. toxicus.6
The complex molecular architecture of gambieric acids, coupled
with their promising biological properties and lack of natural ma-
terials make these polycyclic ethers attractive candidates for total
synthesis.3,7ꢀ11 However, no total synthesis of these natural prod-
ucts has been reported to date. Herein, we describe the details of
a convergent synthesis of a fully elaborated GHIJ-ring fragment 5
(Fig. 1) of gambieric acids.12
from diketone 8 through cyclodehydration.14 The diketone 8, in
turn, would be constructed by an aldol union of the G-ring alde-
hyde 9 and the J-ring methyl ketone 10.
2.2. Synthesis of the G- and J-rings
The synthesis of the G-ring aldehyde 9 is shown in Scheme 2.
The known alcohol 1115 was protected as its triethylsilyl (TES) ether,
and subsequent ozonolysis of the double bond afforded aldehyde 9
in 96% yield for the two steps.
H
Me
H
Me
CHO
O
O
G
a,b
O
O
Ph
O
OH
Ph
O
OTES
H
H
11
9
Scheme 2. Synthesis of the G-ring. Reagents and conditions: (a) TESCl, imidazole,
CH2Cl2, rt; (b) O3, CH2Cl2, ꢀ78 ꢁC; then PPh3, ꢀ78 ꢁC to rt, 96% (two steps).
The synthesis of the J-ring methyl ketone 10 started with the
known epoxy alcohol 12.16 Regioselective epoxide ring-opening
with Ti(OBn)4 afforded diol 13 in 79% yield (Scheme 3). Selec-
2. Results and discussion
17
2.1. Synthetic plan of the GHIJ-ring skeleton
tive sulfonylation of the primary alcohol followed by base treat-
ment gave epoxide 14 in 91% yield for the two steps. Exposure of
14 to dimethylsulfonium methylide (Me3SI, n-BuLi)18 afforded
allylic alcohol 15 in 94% yield. Protection as its PMB ether using
We have previously described a convergent synthesis of the
GHIJ-ring fragment in its antipodal form based on acetylide-
aldehyde coupling,9b,c which was originally developed by the
Nakata group.13 The present synthesis of the GHIJ-ring skeleton 6
relied on an alternative convergent strategy outlined in Scheme 1.
19
PMBOC(]NH)CCl3 in the presence of La(OTf)3 was followed by
hydroboration with disiamylborane to afford alcohol 16 in 81% yield
(two steps). Benzylation and removal of the tert-butyldiphenylsilyl
(TBDPS) group provided primary alcohol 17 (77%, two steps), which
was then converted into (E)-enoate 18 via a one-pot Swern oxida-
tion20/Wittig reaction (95%). DIBALH reduction followed by
Sharpless asymmetric epoxidation21 gave epoxy alcohol 19 as
a single stereoisomer (76%, two steps). This was oxidized with
2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO)/NaClO22 and sub-
sequently methylenated to afford vinyl epoxide 20 (93%, two steps).
Upon treatment with DDQ, cleavage of the PMB group with con-
comitant 6-endo cyclization23 took place to afford tetrahydropyran
21 in 72% yield.24 The stereochemistry of 21 was confirmed by an
NOE as shown. Protection of 21 as its PMB ether and hydroboration
of the terminal olefin afforded primary alcohol 22 (98%, two steps).
Oxidation of 22 under ParihkeDoering conditions25 gave aldehyde
23, which was reacted with MeMgBr and then oxidized with tetra-
n-propylammonium perruthenate (TPAP)/NMO26 to afford the de-
sired methyl ketone 10 (83%, three steps).
The I-ring of
6 was to be constructed by reductive ether-
ification.9b,c,13 The precursor dihydropyrone 7 would be available
reductive etherification
OH
H
H
Me
H
H
H
O
G
O
I
OBn
O
t-Bu Si
t-Bu
H
J
O
O
O
O
OBn
H
Me
H
6
O
PMB
O
H
H
Me
O
G
OBn
O
t-Bu Si
t-Bu
H
J
O
O
OBn
H
Me
H
7
cyclodehydration
2.3. Aldol coupling of the G- and J-rings
aldol
PMB
O
With the two desired fragments in hand, their aldol union was
next investigated (Table 1). We first examined Mukaiyama aldol
reaction using silyl enol ether.27,28 Thus, methyl ketone 10 was
converted to the corresponding trimethylsilyl enol ether (TMSOTf,
i-Pr2NEt, CH2Cl2, 0 ꢁC), which was reacted with aldehyde 9 in the
presence of MgBr2$OEt2.29 Under these conditions, however, the
starting ketone 10 was only recovered (Table 1, entry 1). While
reaction of the lithium enolate derived from 10 (LDA, THF, ꢀ78 ꢁC)
with aldehyde 9 also led to no reaction (entry 2), the addition of the
zinc enolate generated from 10 (LiHMDS, ZnCl2, THF, ꢀ78 ꢁC) to 9
O
H
Me
O
G
OBn
J
O
O
Ph
O
O
TES
8
O
OBn
H
Me
H
PMB
H
H
Me
O
G
CHO
O
OBn
gave the expected b-hydroxy ketone 24 albeit in moderate yield as
O
O
+
J
O
an inconsequential 2.6:1 mixture of diastereomers at the C36
stereogenic center (entry 3).30 Finally, it was found that the best
result could be obtained by treatment of the dibutylboron enolate
derived from 10 (n-Bu2BOTf, i-Pr2NEt, Et2O, 0 ꢁC)28,31 with aldehyde
9 (1.5 equiv) at ꢀ78 to ꢀ20 ꢁC. Under these conditions, the desired
Ph
O
OTES
Me
OBn
Me
H
9
10
Scheme 1. Synthetic plan of the GHIJ-ring skeleton 6.

6602
K. Tsubone et al. / Tetrahedron 67 (2011) 6600e6615
OBn
OH
OBn
OBn
a
b,c
d
e,f
n
O
TBDPSO
HO
13
TBDPSO
14
TBDPSO
HO
15
TBDPSO
OH
O
12
OBn
OBn
OBn
OBn
l,m
i
j,k
O
O
R1O
O
PMB
HO
OR2
EtO2C
O
OBn
O
PMB
OBn
O
PMB
20
OBn
Me
Me
Me
PMB
18
16: R1 = TBDPS, R2 = H
17: R1 = H, R2 = Bn
19
g,h
PMB
HO
OBn
o,p
PMBO
HO
OBn
PMBO
OHC
OBn
O
OBn
q
r,s
O
J
O
O
OBn
O
OBn
O
OBn
Me
OBn
Me
NOE
H
Me
H
Me
23
H
Me
H
21
22
10
Scheme 3. Synthesis of the J-ring. Reagents and conditions: (a) Ti(OBn)4, toluene, 85 ꢁC, 79%; (b) MesSO2Cl, pyridine, rt; (c) K2CO3, MeOH, rt, 91% (two steps); (d) Me3SI, n-BuLi, THF,
ꢀ30 ꢁC to rt, 94%; (e) PMBOC(]NH)CCl3, La(OTf)3, toluene, rt; (f) (Sia)2BH, THF, 0 ꢁC to rt; then 3 M aq NaOH, H2O2, 0 ꢁC to rt, 81% (two steps); (g) KOt-Bu, BnBr, THF, rt; (h) 10% aq
KOH, THF/MeOH, 70 ꢁC, 77% (two steps); (i) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 ꢁC to rt; then Ph3P]C(Me)CO2Et, rt, 95%; (j) DIBALH, CH2Cl2, ꢀ78 ꢁC, 96%; (k) (þ)-DET, Ti(Oi-Pr)4,
TBHP, 4 A molecular sieves, CH2Cl2, ꢀ40 ꢁC, 79%; (l) TEMPO, aq NaClO, KBr, aq NaHCO3, CH2Cl2, 0 ꢁC; (m) Ph3PCH3Br, NaHMDS, THF, 0 ꢁC, 93% (two steps); (n) DDQ, CH2Cl2/H2O, rt,
ꢁ
72%; (o) KOt-Bu, PMBCl, TBAI, DMF, rt, 98%; (p) (Sia)2BH, THF, 0 ꢁC to rt; then 3 M aq NaOH, H2O2, rt, 100%; (q) SO3$pyridine, Et3N, DMSO/CH2Cl2, 0 ꢁC; (r) MeMgBr, Et2O, ꢀ78 ꢁC; (s)
ꢁ
TPAP, NMO, 4 A molecular sieves, CH2Cl2, rt, 83% (three steps).
Table 1
Aldol coupling of the G- and J-rings
PMB
PMB
O
O
OH
H
Me
CHO
H
H
Me
aldol reaction
O
G
O
OBn
O
G
OBn
36
O
O
O
+
J
O
J
O
Ph
O
OTES
Me
OBn
Ph
O
O
TES
OBn
H
Me
H
Me
H
24
9
10
Entry
Reagents and conditions
Yield (%)
dra
1
2
3
4
10, TMSOTf (5.0 equiv), i-Pr2NEt (10 equiv), CH2Cl2, 0 ꢁC; then 9 (1.5 equiv), MgBr2$OEt2 (5 equiv), CH2Cl2, 0 ꢁ
10 (1.2 equiv), LDA (1.2 equiv), THF, ꢀ78 ꢁC; then 9, ꢀ78 ꢁC to rt
C
0
0
62
74
d
d
10, LiHMDS (3.0 equiv), ZnCl2 (3.0 equiv), THF, ꢀ78 ꢁC; then 9 (1.5 equiv), ꢀ78 ꢁC to rt
2.6:1
4:1
10, n-Bu2BOTf (1.5 equiv), i-Pr2NEt (2.0 equiv), Et2O, 0 ꢁC; then 9 (1.5 equiv), ꢀ78 to ꢀ20 ꢁ
C
a
dr¼diastereomer ratio at C36.
aldol adduct 24 was obtained in 74% yield (dr¼4:1) after purifica-
decomposed products, probably due to overoxidation of the C37
position during extended reaction times (entry 2).33 Treatment of
24 with DesseMartin periodinane (DMP)34 gave 8 only in low yield
(entry 3). Under these conditions, the reaction stopped before the
starting material was consumed completely, and only de-
composition of 24 was observed after prolonged reaction times. In
contrast, the use of t-BuOH as an additive34 accelerated the
DesseMartin oxidation, thereby leading to the desired 8 in 91%
yield (entry 4).
tion by preparative HPLC (entry 4).
2.4. Cyclodehydration to form the H-ring
Conversion of hydroxy ketone 24 to diketone 8 turned out to be
unexpectedly nontrivial and required optimization experiments
(Table 2). Swern oxidation of 24 resulted only in decomposition of
the material (Table 2, entry 1). In contrast, oxidation of 24 by using
2-iodoxybenzoic acid (IBX)32 in DMSO gave the desired diketone 8
in 62% yield, along with recovered starting 24 (13%) and
The synthesis of 1,3-diketone 8 could also be realized by an al-
ternative aldol reaction between the G-ring methyl ketone 25 and
Table 2
Oxidation of hydroxy ketone 24
OH PMB
O
PMB
O
O
H
H
Me
H
H
Me
O
O
O
OBn
O
OBn
37
oxidation
O
O
Ph
O
O
TES
O
OBn
Ph
O
O
TES
O
OBn
Me
H
Me
H
24
8
Entry
Reagents and conditions
Yield (%)
1
2
3
4
(COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 ꢁC to rt
Decomposition
IBX,a DMSO, rt
62b
27
DMP,c CH2Cl2, rt
DMP,c CH2Cl2/t-BuOH, rt
91
a
IBX¼2-iodoxybenzoic acid.
b
c
Hydroxy ketone 24 was recovered in 13% yield.
DMP¼DesseMartin periodinane.

K. Tsubone et al. / Tetrahedron 67 (2011) 6600e6615
6603
O
PMB
O
O
the J-ring aldehyde 23 (Scheme 4). Methyl ketone 25 was synthe-
H
Me
O
OBn
H
sized from aldehyde 9 in a two-step sequence involving methyla-
tion with MeMgBr (74%) and Swern oxidation (84%) (Scheme 5).
Addition of the lithium enolate of methyl ketone 25 to aldehyde 23
led to the expected aldol adduct 26 in 67% yield as an in-
consequential 1.7:1 mixture of diastereomers. Subsequent oxida-
b
O
Ph
O
OR
O
OBn
H
Me
H
8 : R = TES
27: R = H
O
PMB
O
a
Me
O
OBn
HO
tion of
b-hydroxy ketone 26 by using DesseMartin periodinane
H
O
(CH2Cl2/t-BuOH) provided diketone 8 in 92% yield. Importantly, this
aldol sequence efficiently provided diketone 8 without complicated
HPLC purification.
HO
O
OBn
H
Me
H
28
Scheme 6. Synthesis of dihydropyrone 28. Reagents and conditions: (a) TBAF, AcOH,
THF, rt, 75%; (b) PPTS, MeOH, 80 ꢁC, 88% from 27; 95% from 8.
O
PMB
O
O
H
H
Me
O
OBn
O
protected as its di-tert-butylsilylene to afford 7 in 93% yield
(Scheme 7). Reduction of enone 7 under Luche conditions (NaBH4,
CeCl3$7H2O)35 gave the corresponding allylic alcohol with the de-
sired stereochemistry at the C36 stereogenic center in 97% yield (dr
>20:1), and ensuing hydroboration of the enol ether moiety gave
diol 29 as a single stereoisomer in 80% yield. The observed high
stereoselectivity of the hydroboration can be explained by consid-
ering the steric hindrance of the angular methyl group at the C35
stereogenic center.36 Protection as the bis-TES ether and oxidative
removal of the PMB group, followed by oxidation of the resultant
alcohol, provided ketone 30 (80%, three steps). After cleavage of the
TES ethers (93%), treatment of the resultant ketodiol with Et3SiH/
TMSOTf (EtCN, ꢀ78 ꢁC) led to the desired GHIJ-ring skeleton 6 as
a single stereoisomer in 74% yield.37 The stereochemistry of 6 was
unambiguously established based on NMR analysis after de-
rivatization to the corresponding acetate 31 as shown.
Ph
O
O
TES
O
OBn
OBn
H
Me
aldol
H
8
O
H
H
Me
O
G
PMBO
OHC
O
Me
OTES
J
+
Ph
O
O
OBn
Me
23
H
25
Scheme 4. Alternative aldol route to diketone 8.
O
H
H
Me
CHO
H
H
Me
O
O
G
2.6. Construction of the J-ring side chain
a,b
c
O
O
Me
Ph
O
OTES
Ph
O
OTES
OBn
Having constructed the tetracyclic GHIJ-ring skeleton, we next
turned our attention to introduction of the side chain to the J-ring.
Stereocontrolled construction of the (E)-trisubstituted alkene in the
J-ring side chain poses a significant synthetic challenge. The only
synthesis of the J-ring side chain has been reported by the Kadota/
Yamamoto group,7b which relied on the coupling of aldehyde 32
and alkenyl lithium 33 (Scheme 8). However, removal of the re-
sultant hydroxy group within the coupling product 34 by means of
BartoneMcCombie deoxygenation38 resulted only in a low yield of
the desired trisubstituted alkene 35. It was deemed that the de-
velopment of a more efficient method for synthesis of the side
chain would be indispensable for a successful total synthesis.
Initially, we planned to introduce the J-ring side chain by
a Wittig or related olefination of methyl ketone 36 with a four-
carbon unit 37 (Scheme 9). Exploratory experiments performed
25
9
+
PMBO
OHC
J
O
O
Me
PMB
O
OH
OBn
H
H
Me
H
O
OBn
OBn
O
O
23
Ph
Ph
O
O
O
TES
O
OBn
Me
H
26
d
O
PMB
O
O
H
H
Me
O
on ketone 38 as
nereWadswortheEmmons reaction39 using phosphonium salt 37a
or phosphonate 37b under variety of conditions (n-BuLi,
a model substrate by Wittig or Hor-
O
TES
O
OBn
Me
H
8
a
NaHMDS, or LiHMDS as a base, THF, DME, or THF/HMPA as a sol-
vent) proved fruitless; the desired product 39 was not isolated at all
and the starting material 38 remained unchanged.
Scheme 5. Second synthesis of diketone 8. Reagents and conditions: (a) MeMgBr, THF,
ꢀ78 to 0 ꢁC, 74%; (b) (COCl)2, Et3N, DMSO, CH2Cl2, ꢀ78 ꢁC to rt, 84%; (c) 25 (1.3 equiv),
LDA, THF, ꢀ78 ꢁC; then 23, ꢀ78 to ꢀ20 ꢁC, 67%; (d) DMP, CH2Cl2/t-BuOH, rt, 92%.
We next investigated JuliaeLythgoe olefination40 of ketone 38
using phenyl sulfone 40 (Table 3). Reaction of ketone 38 with the
lithium anion of sulfone 40a,41 followed by the addition of BzCl,
afforded neither benzoate 41a nor hydroxy sulfone 42a at all (Table
3, entries 1 and 2). Under these conditions, only the undesired enol
benzoate 43 was detected as a byproduct. Since the problem as-
sociated with the JuliaeLythgoe olefination reaction stemmed
mainly from the enolizable nature of methyl ketone 38, it was
reasoned that the use of a cerium reagent might suppress the ex-
cessive basicity of the sulfone anion.42 Gratifyingly, a far more
promising result was obtained when the lithium anion of sulfone
40b43 (n-BuLi, THF, ꢀ78 ꢁC) was added to ketone 38 in the presence
of CeCl3 in THF at ꢀ78 ꢁC. This afforded the expected hydroxy
Removal of the TES group within 1,3-diketone 8 thus prepared
with TBAF/AcOH provided alcohol 27 (75%), which upon treatment
with PPTS in MeOH at 80 ꢁC underwent cyclodehydration14 with
concomitant removal of the benzylidene acetal group to afford
dihydropyrone 28 in 88% yield (Scheme 6). More conveniently,
direct treatment of TES ether 8 under the same conditions afforded
the desired 28 in 95% yield.
2.5. Construction of the GHIJ-ring skeleton
Construction of the I-ring was carried out without incident
following the previously described route.9b,c,13 Diol 28 was

6604
K. Tsubone et al. / Tetrahedron 67 (2011) 6600e6615
OH
Me
O
PMB
O
O
PMB
O
H PMB
O O
H
Me
H
H
Me
H
H
36
a
b,c
OBn
O
OBn
TES
O
OBn
O
OBn
HO
HO
O
t-Bu Si
t-Bu
O
t-Bu Si
t-Bu
O
O
OBn
O
O
O
O
O
O
OBn
H
Me
H
H
Me
H
H
H
Me
H
28
7
29
NOEs
O
OR
TES
O O
H
H
Me
H
H
Me
H
36H
g,h
d-f
O
OBn
O
G
O
OBn
6 : R = H
31: R = Ac
(J
O
O
H 38 37 I
J
O
i
t-Bu Si
t-Bu
t-Bu Si
t-Bu
O
O
O
OBn
O
O
OBn
J
37,38 = 10.0 Hz)
36,37 =
H
H
Me
H
H
H
Me
H
30
Scheme 7. Synthesis of the GHIJ-ring skeleton 6. Reagents and conditions: (a) t-Bu2Si(OTf)2, 2,6-lutidine, DMF, rt, 93%; (b) NaBH4, CeCl3$7H2O, MeOH/CH2Cl2, 0 ꢁC, 97%; (c) BH3$THF,
THF, rt; then 3 M aq NaOH, H2O2, 0 ꢁC to rt, 80%; (d) TESOTf, 2,6-lutidine, CH2Cl2, rt, 94%; (e) DDQ, CH2Cl2/H2O, 0 ꢁC; (f) TPAP, NMO, 4 A molecular sieves, CH2Cl2, 0 ꢁC to rt, 85% (two
ꢁ
steps); (g) TsOH$H2O, CH2Cl2/MeOH, rt, 93%; (h) Et3SiH, TMSOTf, EtCN, ꢀ78 ꢁC, 74%; (i) Ac2O, pyridine, rt, 95%.
Me Me
sulfone 44 (LDA, THF, ꢀ78 ꢁC) proceeded in the presence of CeCl3 to
OTBDPS
Li
TBS
afford trisubstituted alkene 46 as an inseparable 1.6:1 mixture of
33
BnO
O
BnO
OTBS
Me Me
E/Z isomers in 80% combined yield (Table 4, entry 1). In contrast, the
absence of CeCl3 resulted in lower yield of 46 (entry 2). The ste-
reochemistry of the trisubstituted olefin within 46E and 46Z was
assigned in each case by an NOE experiment as shown. To the best
of our knowledge, this is the first use of an organocerium derivative
for the JuliaeKocienski olefination.
OTBDPS
O
O
CHO
Me
34
H
Me
32
H
BnO
OH
BnO
TBS
Barton–McCombie
deoxygenation
BnO
O
Me Me
BnO
OTBDPS
25% (2 steps)
O
Me
35
H
2.7. Completion of the synthesis of a fully elaborated GHIJ-
ring fragment
Scheme 8. Synthesis of the J-ring side chain by Kadota and co-workers7b
.
Having developed an efficient method for the introduction of
the J-ring side chain, we proceeded to complete the synthesis of
a fully elaborated GHIJ-ring fragment 5. Protection of alcohol 6 as its
TES ether, hydrogenolysis of the benzyl ethers, and selective pro-
tection of the primary alcohol as its pivaloate ester provided alcohol
47 in 80% yield for the three steps (Scheme 11). DesseMartin oxi-
dation followed by Wittig methylenation, and removal of the piv-
aloyl group with DIBALH afforded primary alcohol 48 in 64% yield
for the three steps. Alcohol 48 was then converted into the requisite
methyl ketone 36 by a three-step sequence involving oxidation to
the aldehyde, methylation with MeMgBr, and a second oxidation
(51%, three steps). Finally, introduction of the J-ring side chain was
successfully performed under the optimized conditions described
before. Thus, lithiation of phenyltetrazolyl sulfone 44 with LDA
followed by addition to methyl ketone 36 in the presence of CeCl3
(THF, ꢀ78 to 0 ꢁC) furnished the desired trisubstituted (E)-alkene 5
in 58% yield, along with the corresponding (Z)-isomer 49 in 18%
yield. The stereochemistry of 5 was unequivocally established by an
NOE experiment as shown.
OTES
H
H
Me
H
H
O
G
O
I
O
t-Bu Si
t-Bu
Me Me
H
J
O
OTBS
O
O
O
H
O
H
Me
H
O
5
OTES
H
H
Me
H
H
Me
O
Me
O
+
X
OBn
t-Bu Si
t-Bu
O
O
H
H
Me
H
37a: X = PPh3I
37b: X = P(O)(OMe)2
36
Me
TBS
O
TBS
X
OBn
37
O
Me
Me Me
OBn
O
O
O
H
H
Wittig or
Horner–Wadsworth–Emmons
38
39
Scheme 9. Attempts at Wittig-type olefination.
3. Conclusion
We have synthesized a fully elaborated GHIJ-ring fragment of
gambieric acids through a convergent strategy. Key reactions of the
synthesis include: (i) aldol reaction to couple the G- and J-rings; (ii)
acid-catalyzed cyclodehydration to form the H-ring; and (iii)
a CeCl3-promoted JuliaeKocienski reaction for stereoselective in-
troduction of the J-ring side chain. Further studies toward the total
synthesis of gambieric acids are currently underway and will be
reported in due course.
sulfone 42b in 95% yield as a mixture of four diastereomers (entry
3). Unfortunately, an attempted in situ trapping of the
JuliaeLythgoe adduct by quenching the reaction with BzCl was
unsuccessful (entry 4). Likewise, benzoylation of the isolated hy-
droxy sulfone 42b was examined under several conditions but did
not proceed at all.44 The low reactivity of the sterically hindered
tertiary alcohol within 42b precluded the way to trisubstituted
olefin 39.
We next investigated CeCl3-promoted JuliaeKocienski olefina-
tion45 using phenyltetrazolyl sulfone 44. The required sulfone 44
was synthesized from the known alcohol 45 (Scheme 10).46 Thus,
the primary alcohol of 45 was displaced with 1-phenyl-1H-tetra-
zole-5-thiol under Mitsunobu conditions47 to generate a sulfide
(88%), which was oxidized with m-CPBA to give sulfone 44 (89%).
We were delighted to find that olefination of methyl ketone 38 with
4. Experimental
4.1. General methods
All reactions sensitive to moisture and/or air were carried out
under an atmosphere of argon in dry, freshly distilled solvents under

K. Tsubone et al. / Tetrahedron 67 (2011) 6600e6615
6605
Table 3
Model JuliaeLythgoe olefination
Me
TBS
O
TBS
PhSO2
OR
O
OTBS
OBz
Me
Me
40
Me OP
OR
O
O
O
O
a: R = Bn b: R = TBS
H
H
H
SO2Ph
38
41: P = Bz
43
42: P = H
Entry
Sulfone
Regents and conditions
Yield (%)
41
42
1a
2a
3
40a
40a
40b
40b
n-BuLi, THF/HMPA, ꢀ78 ꢁC to rt; then BzCl, rt
LiHMDS, THF, ꢀ78 ꢁC; then BzCl, ꢀ78 ꢁC to rt
0
0
d
0
0
95
83
n-BuLi, CeCl3, THF, ꢀ78 ꢁ
C
4
n-BuLi, CeCl3, THF, ꢀ78 ꢁC; then BzCl, ꢀ78 ꢁC to rt
0
a
Enol benzoate 43 was detected as an only isolable byproduct.
Me
O
O
Me
OH
Me
a,b
S
OTBS
H
H
H
H
H
H
N
N
HO
OTBS
O
O
O
OBn
a-c
d-f
N
O
t-Bu Si
t-Bu
N
45
44
Ph
O
O
O
O
OBn
OPiv
H
H
Me
H
Scheme 10. Synthesis of phenyltetrazolyl sulfone 44. Reagents and conditions: (a) 1-
phenyl-1H-tetrazole-5-thiol, DIAD, Ph3P, THF, rt, 88%; (b) m-CPBA, CH2Cl2, rt, 89%.
6
OTES
Me
H
H
O
OH
O
t-Bu Si
t-Bu
Table 4
JuliaeKocienski olefination of methyl ketone 38
O
O
H
H
Me
H
H
H
TBS
47
O
Me
O
Me Me
O
OTES
S
OTBS
N
N
OTBS
H
H
Me
H
TBS
O
H
O
N
O
O
O
H
g-i
N
H
O
t-Bu Si
t-Bu
H
H
44
Ph
Me
46E
O
O
O
O
OH
+
NOEs
O
O
LDA, additive
THF
H
H
Me
TBS
H
48
38
O
–78 to 0 °C
Me
H
OTES
O
H
H
Me
H
H
H
O
OTBS
j
O
t-Bu Si
t-Bu
Me
Me
46Z
O
O
O
H
H
Me
Entry
Additive
Yield (%)
E/Z
36
1
2
CeCl3
None
80
38
1.6:1
1:1
OTES
Me
H
O
Me
H
H
O
G
O
I
+
Me Me
H
J
O
t-Bu Si
t-Bu
OTBS
OTBS
anhydrous conditions using oven-dried glassware unless otherwise
noted. Anhydrous dichloromethane (CH2Cl2) was purchased from
Kanto Chemical Co. Inc. and used directly without further drying.
Anhydrous tetrahydrofuran (THF), diethyl ether (Et2O), and toluene
were purchased from Wako Pure Chemical Industries, Ltd. and fur-
ther purified bya Glass Contoursolvent purification systemunderan
atmosphere of argon immediately prior to use. Diisopropylamine (i-
Pr2NH), triethylamine (Et3N), 2,6-lutidine, 1,2-dichloroethane, and
methanol (MeOH) were distilled from calcium hydride under an
atmosphere of argon. Hexamethylphosphoramide (HMPA) was
distilled from calcium hydride under reduced pressure. N,N-Dime-
thylformamide (DMF) and dimethyl sulfoxide (DMSO) were distilled
from magnesium sulfate under reduced pressure. All other chem-
icals were purchased at the highest commercial grade and used di-
rectly. Analytical thin-layer chromatography (TLC) was performed
using E. Merck silica gel 60 F254 plates (0.25-mm thickness). Flash
column chromatographywas carriedout using KantoChemicalsilica
gel 60N (40e100 mesh, spherical, neutral) or Fuji Silysia silica gel
BW-300 (200e400 mesh). Preparative HPLC was carried out using
a Japan Analytical Industry Co., Ltd. LC-9201 HPLC system. Optical
rotations were recorded on a JASCO P-1020 digital polarimeter. IR
O
O
Me
H
H
H
Me
H
H
H
H
5
49
NOE
Scheme 11. Completion of the synthesis of fully elaborated GHIJ-ring fragment 5.
Reagents and conditions: (a) TESOTf, 2,6-lutidine, CH2Cl2, rt, 97%; (b) H2, Pd(OH)2/C,
EtOAc, rt, 97%; (c) PivCl, pyridine, 0 ꢁC, 85%; (d) DMP, CH2Cl2, rt, 80%; (e) Ph3PCH3Br,
NaHMDS, THF, 0 ꢁC, 83%; (f) DIBALH, CH2Cl2, ꢀ78 ꢁC, 96%; (g) DMP, CH2Cl2, rt; (h)
MeMgBr, Et2O, ꢀ78 ꢁC; (i) DMP, CH2Cl2, rt, 51% (three steps); (j) 44, LDA, CeCl3, THF,
ꢀ78 to 0 ꢁC, 5: 58%, 49: 18%.
spectra were recorded on a JASCO FT/IR-4100 spectrometer. 1H and
13C NMR spectrawererecorded on a Varian Unity INOVA-500 or JEOL
JNM-ECA-600 spectrometer, and chemical shift values are reported
in parts per million (d) downfield from tetramethylsilane with ref-
erence to internal residual solvent [1H NMR, CHCl3 (7.24), C6HD5
(7.15); 13C NMR, CDCl3 (77.0), C6D6 (128.0)] unless otherwise noted.
Coupling constants (J) are reported in hertz (Hz). The following ab-
breviations were used to designate the multiplicities: s¼singlet;
d¼doublet; t¼triplet; m¼multiplet; br¼broad. ESI-TOF mass spec-
tra were measured on a Bruker microTOFfocus spectrometer.

6606
K. Tsubone et al. / Tetrahedron 67 (2011) 6600e6615
4.1.1. Aldehyde 9. To a solution of alcohol 1115 (1.35 g, 4.92 mmol)
in CH2Cl2 (50 mL) were added imidazole (600 mg, 6.39 mmol) and
TESCl (1.07 mL, 6.39 mmol). The resultant solution was stirred at
room temperature for 5 h before it was diluted with EtOAc. The
mixture was washed with saturated aqueous NH4Cl solution and
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was filtered through a short pad of silica gel to
give a crude material, which was used in the next reaction without
further purification.
residue was diluted with H2O and EtOAc. The organic layer was
washed with saturated aqueous NH4Cl solution and brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by column chromatography (silica gel,
10% EtOAc/hexanes) gave epoxide 14 (11.9 g, 91% for the two steps)
25
as a colorless oil: [
a]
þ5.4 (c 1.0, CHCl3); IR (film) 2929, 2856,
D
1472, 1427, 1360, 1190, 997 cmꢀ1
;
1H NMR (600 MHz, CDCl3)
d
7.66e7.64 (m, 4H), 7.42e7.39 (m, 2H), 7.37e7.28 (m, 4H),
7.31e7.28 (m, 2H), 7.26e7.24 (m, 3H), 4.64 (d, J¼11.3 Hz, 1H), 4.45
(d, J¼11.3 Hz, 1H), 3.86 (ddd, J¼10.0, 8.6, 4.8 Hz, 1H), 3.80 (ddd,
J¼10.3, 6.2, 4.4 Hz, 1H), 3.63 (ddd, J¼9.3, 4.1, 3.8 Hz, 1H), 2.97 (m,
1H), 2.75 (dd, J¼5.2, 3.8 Hz,1H), 2.72 (dd, J¼5.2, 2.8 Hz,1H),1.93 (m,
1H), 1.78 (dddd, J¼8.9, 8.9, 5.2, 4.8 Hz, 1H), 1.04 (s, 9H); 13C NMR
Ozone was bubbled through a solution of the above TES ether in
CH2Cl2 (50 mL) at ꢀ78 ꢁC for 15 min. After oxygen was then bub-
bled through the solution to remove excess ozone, Ph3P (3.87 g,
14.8 mmol) was added to the solution at ꢀ78 ꢁC. The resultant
solution was allowed to warm to room temperature overnight. The
mixture was concentrated under reduced pressure, and the residue
was purified by flash column chromatography (silica gel, 5e50%
EtOAc/hexanes) to give aldehyde 9 (1.86 g, 96% for the two steps) as
(125 MHz, CDCl3)
d 135.5 (3C), 129.6 (3C), 128.3 (3C), 127.62 (6C),
127.55 (3C), 74.7, 72.7, 59.8, 53.7, 45.3, 35.5, 26.8 (3C), 19.2; HRMS
(ESI) calcd for C28H34O3SiNa [(MþNa)þ] 469.2169, found 469.2162.
a colorless oil: [
a]
24 þ2.1 (c 0.9, CHCl3); IR (film) 2954, 2876, 1746,
4.1.4. Allylic alcohol 15. To a suspension of trimethylsulfonium
iodide (22.1 g, 109 mmol) in THF (220 mL) at ꢀ30 ꢁC was added
n-BuLi (2.6 M solution in hexane, 52.2 mL, 136 mmol). After stirring
at ꢀ30 ꢁC for 30 min, a solution of epoxide 14 (24.2 g, 54.3 mmol) in
THF (50 mL) was introduced to the mixture, producing a milky
suspension. The resultant mixture was allowed to warm to room
temperature over 1 h 45 min before it was treated with saturated
aqueous NH4Cl solution. The mixture was extracted with EtOAc,
and the organic layer was washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. Purification of
D
1456, 1128, 1094, 1028, 828, 747 cmꢀ1
;
1H NMR (600 MHz, CDCl3)
d
9.44 (s, 1H), 7.48e7.46 (m, 2H), 7.38e7.32 (m, 3H), 5.51 (s, 1H),
4.27 (dd, J¼10.3, 4.5 Hz, 1H), 3.97 (dd, J¼11.3, 4.8 Hz, 1H), 3.71 (dd,
J¼11.2, 10.0 Hz, 1H), 3.62 (ddd, J¼10.3, 9.2, 4.8 Hz, 1H), 3.53 (m, 1H),
2.28 (ddd, J¼11.7, 4.4, 4.4 Hz, 1H), 1.89 (ddd, J¼11.6, 11.6, 11.6 Hz,
1H), 1.39 (s, 3H), 0.91 (t, J¼7.8 Hz, 9H), 0.54 (q, J¼7.8 Hz, 6H); 13C
NMR (150 MHz, CDCl3)
d 199.3, 137.2, 129.2, 128.4, (2C), 126.1 (2C),
101.8, 82.0, 76.5, 69.6, 67.2, 66.3, 34.5, 11.1, 6.7 (3C), 4.9 (3C); HRMS
(ESI) calcd for C21H32O5SiNa [(MþNa)þ] 415.1911, found 415.1897.
the residue by column chromatography (silica gel, 10% EtOAc/hex-
24
4.1.2. Diol 13. A mixture of benzyl alcohol (125 mL, 1.21 mol) and
Ti(Oi-Pr)4 (42.6 mL, 182 mmol) was heated at 100 ꢁC for 1 h. The
mixture was cooled to room temperature and concentrated under
reduced pressure. The residue was azeotropically dried with tolu-
ene twice. To the residual Ti(OBn)4 was added a solution of epoxy
alcohol 1216 (43.1 g, 121 mmol) in toluene (121 mL), and the re-
sultant solution was stirred at 85 ꢁC for 2 h. The mixture was cooled
to room temperature, and the reaction was quenched with 5%
aqueous H2SO4 solution. The mixture was diluted with EtOAc and
stirred at room temperature for 3 h. The mixture was extracted
with EtOAc, and the organic layer was washed with saturated
aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure. After removal of benzyl
alcohol by vacuum distillation (5 Torr, 70 ꢁC), the residue was pu-
rified by column chromatography (silica gel, 10e30% EtOAc/hex-
anes) gave allylic alcohol 15 (23.5 g, 94%) as a colorless oil: [a]
D
ꢀ0.9 (c 1.0, CHCl3); IR (film) 3454, 3070, 2957, 2930, 2857, 1471,
1427, 1111, 1088, 822, 738, 701 cmꢀ1 1H NMR (600 MHz, CDCl3)
7.65e7.62 (m, 4H), 7.43e7.38 (m, 2H), 7.38e7.32 (m, 4H),
;
d
7.32e7.25 (m, 5H), 5.85 (ddd, J¼17.2, 10.7, 5.5 Hz, 1H), 5.31 (ddd,
J¼17.2, 1.7, 1.4 Hz, 1H), 5.20 (ddd, J¼13.8, 1.7, 1.4 Hz, 1H), 4.60 (d,
J¼11.5 Hz,1H), 4.52 (d, J¼11.5 Hz,1H), 4.35 (m,1H), 3.78 (apparent t,
J¼5.9 Hz, 2H), 3.73 (ddd, J¼6.8, 5.5, 3.8 Hz, 1H), 1.79e1.74 (m, 2H),
1.03 (s, 9H), one proton missing due to H/D exchange of the hy-
droxyl group; 13C NMR (125 MHz, CDCl3)
d 138.3, 136.7, 135.5 (3C),
133.6, 133.5, 129.62, 129.60, 128.4 (3C), 127.7, 127.6 (6C), 116.3, 79.1,
73.3, 72.1, 60.2, 32.0, 26.8 (3C), 19.1; HRMS (ESI) calcd for
C29H36O3SiNa [(MþNa)þ] 483.2326, found 483.2325.
4.1.5. Alcohol 16. To
a solution of allylic alcohol 15 (34.6 g,
anes) to give diol 13 (44.3 g, 79%) as a colorless oil: [
a
]
23 ꢀ8.2 (c 1.0,
75.1 mmol) in toluene (200 mL) at room temperature were added
PMBOC(]NH)CCl3 (42.4 g, 150 mmol) and La(OTf)3 (2.20 g,
3.76 mmol). The resultant mixture was stirred at 50 ꢁC for 35 h
before it was concentrated under reduced pressure. The residue
was filtered through a short pad of silica gel, and the crude material
was used in the next reaction without further purification.
D
CHCl3); IR (film) 3407, 3069, 2930, 2857, 1471, 1427, 1389, 1361, 1111,
1087, 737, 701 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 7.65e7.36 (m,
4H), 7.44 (m, 6H), 7.32e7.24 (m, 5H), 4.53 (d, J¼12.0 Hz,1H), 4.48 (d,
J¼12.0 Hz, 1H), 3.86e3.70 (m, 6H), 3.19 (m, 1H), 2.19 (m, 1H),
1.92e1.74 (m, 2H), 1.04 (s, 9H); 13C NMR (125 MHz, CDCl3)
d 135.6,
135.5 (2C), 129.8 (3C), 128.5 (3C), 127.80 (3C), 127.77 (6C), 78.4, 72.8,
72.4, 63.6, 60.2, 33.0, 26.8 (3C), 14.2; HRMS (ESI) calcd for
C28H36O4SiNa [(MþNa)þ] 487.2275, found 487.2292.
To a solution of 2-methyl-2-butene (31.8 mL, 300 mmol) in THF
(275 mL) at 0 ꢁC was added BH3$SMe2 (1.9 M solution in THF,
79.0 mL, 150 mmol). The resultant solution was stirred at 0 ꢁC for
1 h. To this solution was added a solution of the above crude ma-
terial in THF (50 mL). After being stirred at room temperature for
90 min, the mixture was cooled to 0 ꢁC and treated with 3 M
aqueous NaOH solution (150 mL) and 30% aqueous H2O2 solution
(150 mL). The resultant mixture was stirred at 0 ꢁC for 30 min and
then at room temperature for 3 h. The mixture was extracted with
EtOAc, and the organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. Purifi-
cation of the residue by column chromatography (silica gel, 20e40%
EtOAc/hexanes) gave alcohol 16 (36.2 g, 81% for the two steps) as
4.1.3. Epoxide 14. To a solution of diol 13 (13.7 g, 29.3 mmol) in
pyridine (100 mL) at 0 ꢁC was added 2-mesitylenesulfonyl chloride
(7.68 g, 35.1 mmol). The resultant solution was stirred at room
temperature overnight before it was diluted with EtOAc. The mix-
ture was washed successively with saturated aqueous CuSO4 so-
lution, saturated aqueous NaHCO3 solution, and brine. The organic
layer was dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residual crude sulfonate was used in the next
reaction without further purification.
To a solution of the above material in MeOH (100 mL) at 0 ꢁC
was added K2CO3 (4.85 g, 35.1 mmol). The resultant solution was
stirred at room temperature for 4 h before it was concentrated to
approximately one-fifth of its volume under reduced pressure. The
a colorless oil: [
a
]
D
25 ꢀ6.2 (c 1.0, CHCl3); IR (film) 3069, 2930, 2857,
1612, 1587, 1513, 1471, 1248, 1111, 1086, 822 cmꢀ1
;
1H NMR
(600 MHz, CDCl3)
d 7.67e7.64 (m, 4H), 7.43e7.40 (m, 2H), 7.38e7.34
(m, 4H), 7.32e7.24 (m, 7H), 6.87e6.85 (m, 2H), 4.76 (d, J¼11.3 Hz,

K. Tsubone et al. / Tetrahedron 67 (2011) 6600e6615
6607
1H), 4.67 (d, J¼11.3 Hz, 1H), 4.51 (d, J¼11.3 Hz, 1H), 4.48 (d,
J¼11.3 Hz, 1H), 3.95 (ddd, J¼10.0, 2.4, 2.0 Hz, 1H), 3.84 (m, 1H),
3.81e3.68 (m, 4H), 3.79 (s, 3H), 2.46 (br s, 1H), 1.88 (dddd, J¼15.1,
12.0, 8.5, 4.1 Hz, 1H), 1.80 (dddd, J¼14.1, 8.9, 4.8, 4.4 Hz, 1H), 1.75 (m,
J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d
167.9, 159.1, 138.6, 138.4,
138.3,130.5,129.5 (2C),129.1,128.3 (2C),128.2 (2C),127.8 (2C),127.6
(2C), 127.49, 127.46, 113.6 (2C), 79.3, 76.8, 72.9, 72.14, 72.13, 66.7,
60.3, 55.1, 31.1, 30.1, 14.2, 12.6; HRMS (ESI) calcd for C33H40O6Na
[(MþNa)þ] 555.2717, found 555.2741.
1H), 1.70 (m, 1H), 1.07 (s, 9H); 13C NMR (125 MHz, CDCl3)
d 159.2,
138.6, 135.51, 135.49 (2C), 133.72, 133.71, 130.3, 129.6, 129.5 (2C),
129.0, 128.3 (2C), 128.2, 127.7 (2C), 127.6 (4C), 127.5 (2C), 113.8 (2C),
79.5, 72.8, 71.6, 60.44, 60.36, 55.2, 34.0, 32.6, 26.8 (3C), 19.2; HRMS
(ESI) calcd for C37H46O5SiNa [(MþNa)þ] 621.3007, found 621.3034.
4.1.8. Epoxy alcohol 19. To a solution of (E)-enoate 18 (4.91 g,
9.23 mol) in CH2Cl2 (90 mL) at ꢀ78 ꢁC was added DIBALH (0.97 M
solution in hexane, 20.9 mL, 20.3 mmol). The resultant solution was
stirred at ꢀ78 ꢁC for 30 min before it was quenched with MeOH.
The mixture was diluted with saturated aqueous potassium sodium
tartrate solution and EtOAc, and stirred at room temperature
overnight. The organic layer was separated, washed with brine,
dried over Na2SO4, filtered, and concentrated under reduced pres-
sure. Purification of the residue by column chromatography (silica
4.1.6. Alcohol 17. To a solution of alcohol 16 (2.03g, 3.39 mmol) in
THF (34 mL) at 0 ꢁC was added KOt-Bu (571 mg, 5.09 mmol), and
the resultant mixture was stirred at room temperature for 15 min.
The mixture was cooled to 0 ꢁC and treated with benzyl bromide
(806 mL, 6.78 mmol). The resultant solution was stirred at room
temperature overnight before it was quenched with saturated
aqueous NH4Cl solution. The mixture was extracted twice with
EtOAc, and the organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
residual crude benzyl ether was used in the next reaction without
further purification.
gel, 10e30% EtOAc/hexanes) gave an allylic alcohol (4.36 g, 96%) as
22
a pale yellow oil: [
a]
ꢀ7.6 (c 1.0, CHCl3); IR (film) 3435, 2905,
D
2860, 1611, 1513, 1454, 1247, 1092, 1030, 820.6, 739, 698 cmꢀ1
;
1H
NMR (500 MHz, CDCl3) 7.33e7.25 (m, 10H), 7.19e7.17 (m, 2H),
d
6.83e6.81 (m, 3H), 5.40 (ddd, J¼6.5, 6.5, 1.0 Hz, 1H), 4.64 (d,
J¼12.0 Hz, 1H), 4.55 (d, J¼11.0 Hz, 1H), 4.53 (d, J¼12.0 Hz, 1H), 4.46
(d, J¼12.0 Hz, 1H), 4.40 (d, J¼12.0 Hz, 1H), 4.38 (d, J¼11.0 Hz, 1H),
3.93 (s, 2H), 3.76 (s, 3H), 3.68 (ddd, J¼6.5, 4.0, 3.5 Hz,1H), 3.58e3.53
(m, 3H), 2.35 (ddd, J¼15.0, 7.5, 6.5 Hz, 1H), 2.24 (ddd, J¼15.0, 7.0,
6.0 Hz, 1H), 1.88e1.84 (m, 2H), 1.61 (s, 3H); 13C NMR (150 MHz,
To a solution of the above benzyl ether in THF/MeOH (1:2, v/v,
45 mL) at room temperature was added 10% aqueous KOH solution
(5.0 mL). After being stirred at 70 ꢁC overnight, the mixture was
cooled to room temperature and neutralized with 1 M aqueous HCl
solution. The mixture was extracted with EtOAc and washed with
brine. The aqueous layer was extracted with EtOAc. The combined
organic layer was dried over Na2SO4, filtered, and concentrated
under reduced pressure. Purification of the residue by column
chromatography (silica gel, 20e60% EtOAc/hexanes) gave alcohol
CDCl3)
d 159.1, 138.8, 138.5, 136.5, 130.8, 129.6 (2C), 128.33 (2C),
128.26 (2C), 127.8 (2C), 127.7 (2C), 127.53, 127.49, 122.3, 113.7 (2C),
80.4, 76.9 72.9, 72.2, 72.0, 68.9, 66.9, 55.3, 30.9, 29.1, 13.9; HRMS
(ESI) calcd for C31H38O5Na [(MþNa)þ] 513.2611, found 513.2587.
To a suspension of the above allylic alcohol (4.36 g, 8.90 mmol)
23 ꢀ7.1 (c 1.0,
and 4 A molecular sieves (4.0 g) in CH2Cl2 (80 mL) at room tem-
ꢁ
17 (1.17 g, 77% for the two steps) as a colorless oil: [
a
]
D
CHCl3); IR (film) 3436, 2862, 1611, 1513, 1453, 1359, 1302, 1247, 1173,
perature was added a solution of (þ)-DET (2.74 g, 13.3 mmol) in
CH2Cl2 (10 mL). The resultant mixture was cooled to ꢀ40 ꢁC and
treated with Ti(Oi-Pr)4 (3.13 mL, 10.7 mmol). After being stirred
at ꢀ40 ꢁC for 30 min, the reaction mixture was treated with TBHP
(4.64 M solution in isooctane, 5.75 mL, 26.7 mmol). The reaction
mixture was stirred at ꢀ40 ꢁC for 1 h before it was diluted with 1 M
aqueous NaOH solution and Et2O. After being stirred at room tem-
perature for 2 h, the mixture was filtered through a pad of Celite. The
filtrate was diluted with EtOAc, washed with H2O and brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by column chromatography (silica gel,
20e40% EtOAc/hexanes) gave epoxy alcohol 19 (3.56 g, 79%) as
1092, 737 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 7.34e7.25 (m, 10H),
7.21e7.17 (m, 2H), 6.84e6.80 (m, 2H), 4.70 (d, J¼12.0 Hz, 1H), 4.66
(d, J¼11.0 Hz, 1H), 4.52 (d, J¼11.0 Hz, 1H), 4.46 (d, J¼12.0 Hz, 1H),
4.43 (d, J¼10.5 Hz, 1H), 4.41 (d, J¼12.0 Hz, 1H), 3.83 (ddd, J¼9.0, 3.5,
2.0 Hz, 1H), 3.77e3.67 (m, 3H), 3.76 (s, 3H), 3.59e3.49 (m, 2H), 2.08
(d, J¼1.5 Hz, 1H), 1.91e1.70 (m, 4H); 13C NMR (125 MHz, CDCl3)
d
159.1, 138.33, 138.27, 130.5, 129.5 (2C), 128.4 (2C), 128.3 (2C), 127.8
(2C), 127.68, 127.66 (2C), 127.5, 113.7 (2C), 79.8, 76.8, 72.9, 72.5, 72.0,
66.7, 60.0, 55.2, 32.5, 31.3; HRMS (ESI) calcd for C28H34O5Na
[(MþNa)þ] 473.2298, found 473.2295.
4.1.7. (E)-Enoate 18. To a solution of DMSO (13.8 mL, 194 mmol) in
CH2Cl2 (200 mL) at ꢀ78 ꢁC was added oxalyl chloride (8.46 mL,
97.0 mmol), and the resultant solution was stirred at ꢀ78 ꢁC for
15 min. To this solution was added a solution of alcohol 17 (21.8 g,
48.5 mmol) in CH2Cl2 (40 mL), and the resultant solution was stir-
red at ꢀ78 ꢁC for 45 min before Et3N (40.6 mL, 291 mmol) was in-
troduced. The mixture was allowed to warm to room temperature
over 1 h, and then treated with Ph3P]C(Me)CO2Et (20.3 g,
58.2 mmol). After being stirred at room temperature for 3 h, the
mixture was concentrated to approximately one-fifth of its volume.
The mixture was diluted with EtOAc, washed successively with H2O
and brine, dried over Na2SO4, filtered, and concentrated under re-
duced pressure. Purification of the residue by column chromatog-
a colorless oil: [
a
]
D
23 ꢀ15.0 (c 1.0, CHCl3); IR (film) 3449, 2927, 2861,
1611,1513,1454,1247,1092,1034, 740, 698 cmꢀ1; 1H NMR (500 MHz,
CDCl3)
d 7.34e7.24 (m, 10H), 7.20e7.18 (m, 2H), 6.83e6.81 (m, 2H),
4.65 (d, J¼11.5 Hz,1H), 4.59 (d, J¼11.0 Hz,1H), 4.55 (d, J¼11.5 Hz,1H),
4.45 (d, J¼12.5 Hz, 1H), 4.40 (d, J¼11.5 Hz, 1H), 4.40 (d, J¼12.5 Hz,
1H), 3.77 (m, 1H), 3.76 (s, 3H), 3.62 (ddd, J¼6.5, 4.5, 4.5 Hz, 1H),
3.59e3.53 (m, 3H), 3.45 (dd, J¼12.0, 8.0 Hz, 1H), 3.11 (dd, J¼6.5,
6.0 Hz,1H),1.95 (ddd, J¼14.5, 7.0, 7.0 Hz,1H),1.85e1.82 (m, 2H),1.74
(ddd, J¼14.5, 5.0, 5.0 Hz, 1H), 1.58 (m, 1H), 1.20 (s, 3H); 13C NMR
(150 MHz, CDCl3)
d 159.1, 138.4 (2C), 130.7, 129.6 (2C), 128.3 (4C),
127.9 (2C),127.7 (2C),127.61,127.56,113.7 (2C), 78.8, 76.8, 73.0, 72.2,
71.9, 66.7, 65.4, 60.5, 57.7, 55.2, 31.1, 29.5, 14.3; HRMS (ESI) calcd for
C31H38O6Na [(MþNa)þ] 529.2561, found 529.2570.
raphy (silica gel, 0e20% EtOAc/hexanes) gave (E)-enoate 18 (24.6 g,
24
95%) as a pale yellow oil: [
a
]
ꢀ1.6 (c 1.0, CHCl3); IR (film) 2862,
4.1.9. Vinyl epoxide 20. To a solution of epoxy alcohol 19 (822 mg,
D
1706, 1652, 1613, 1513, 1456, 1248, 1094, 1031, 821 cmꢀ1
;
1H NMR
1.62 mmol) in CH2Cl2 (16 mL) at 0 ꢁC were added KBr (0.5 M solu-
(500 MHz, CDCl3) 7.34e7.25 (m, 10H), 7.18e7.16 (m, 2H),
d
tion in H2O, 324
To this mixture were added dropwise a freshly prepared mixture of
NaOCl (1.80 M solution in H2O, 900 L, 1.62 mmol) and saturated
aqueous NaHCO3 solution (900 L). The resultant mixture was
mL, 0.162 mmol) and TEMPO (12.7 mg, 81.0 mmol).
6.85e6.80 (m, 3H), 4.62 (d, J¼12.0 Hz, 1H), 4.56 (d, J¼11.0 Hz, 1H),
4.53 (d, J¼12.0 Hz, 1H), 4.45 (d, J¼12.0 Hz, 1H), 4.40 (d, J¼12.0 Hz,
1H), 4.40 (d, J¼11.0 Hz, 1H), 4.18 (q, J¼7.0 Hz, 2H), 3.76 (s, 3H), 3.71
(m, 1H), 3.60 (ddd, J¼8.0, 4.5, 3.5 Hz, 1H), 3.55 (dd, J¼5.5, 5.5 Hz,
1H), 3.55 (m, 1H), 2.50 (ddd, J¼16.0, 8.0, 7.0 Hz, 1H), 2.36 (ddd,
J¼14.5, 6.5, 5.5 Hz, 1H), 1.86e1.82 (m, 2H), 1.78 (s, 3H), 1.28 (t,
m
m
vigorously stirred at 0 ꢁC for 10 min before it was quenched with
saturated aqueous Na2S2O3 solution. The mixture was extracted
with EtOAc, and the organic layer was washed with H2O and brine.

6608
K. Tsubone et al. / Tetrahedron 67 (2011) 6600e6615
The aqueous layers were combined and extracted with EtOAc. The
combined organic layer was dried over Na2SO4, filtered, and con-
centrated under reduced pressure to give a crude aldehyde, which
was used in the next reaction without further purification.
concentrated under reduced pressure. Purification of the residue by
column chromatography (silica gel, 5e20% EtOAc/hexanes) gave
25
a PMB ether (1.45 g, 98%) as a colorless oil: [
a
]
D
ꢀ40.7 (c 1.0,
CHCl3); IR (film) 2866,1612, 1513, 1455,1351, 1302, 1248,1091, 1032,
To a suspension of Ph3PCH3Br (1.74 g, 4.86 mmol) in THF (10 mL)
at 0 ꢁC was added NaHMDS (1.0 M solution in THF, 4.54 mL,
4.54 mmol), and the resultant mixture was stirred at 0 ꢁC for
30 min. To this suspension was added a solution of the above crude
aldehyde in THF (6.0 mL), and the resultant solution was stirred at
0 ꢁC for 1 h before it was quenched with saturated aqueous NH4Cl
solution. The mixture was extracted twice with EtOAc. The organic
layer was washed with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. Purification of the residue by
column chromatography (silica gel, 10e20% EtOAc/hexanes) gave
vinyl epoxide 20 (760 mg, 93% for the two steps) as a colorless oil:
922, 821, 736, 697 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
7.35e7.24 (m,
10H), 7.23e7.20 (m, 2H), 6.88e6.84 (m, 2H), 6.00 (dd, J¼17.5,
11.0 Hz, 1H), 5.26 (d, J¼17.5 Hz, 1H), 5.03 (d, J¼11.0 Hz, 1H), 4.60 (d,
J¼11.5 Hz, 1H), 4.50 (d, J¼12.0 Hz, 1H), 4.50 (d, J¼11.5 Hz, 1H), 4.46
(d, J¼12.0 Hz, 1H), 4.43 (d, J¼11.5 Hz, 1H), 4.38 (d, J¼11.0 Hz, 1H),
3.79 (s, 3H), 3.66e3.54 (m, 3H), 3.21 (dd, J¼11.5, 4.5 Hz, 1H), 3.11
(ddd, J¼10.5, 10.0, 4.5 Hz, 1H), 2.41 (ddd, J¼11.5, 5.0, 4.5 Hz, 1H),
2.24 (m, 1H),1.65 (m, 1H),1.54 (ddd, J¼11.5,11.5, 11.5 Hz,1H),1.23 (s,
3H); 13C NMR (125 MHz, CDCl3)
d 159.1, 143.2, 138.7, 138.1, 130.5,
129.1 (2C), 128.4 (2C), 128.3 (2C), 127.8 (2C), 127.7, 127.6 (2C), 127.4,
113.7 (2C), 112.5, 78.5, 76.8, 75.6, 72.9, 71.3, 70.9, 69.8, 67.0, 55.3,
32.4, 31.0, 15.8; HRMS (ESI) calcd for C32H38O5Na [(MþNa)þ]
525.2611, found 525.2608.
[
a]
23 ꢀ8.5 (c 1.0, CHCl3); IR (film) 2927, 2858,1509,1456,1247,1092,
D
736, 697 cmꢀ1
;
1H NMR (500 MHz, C6D6)
d
7.35e7.34 (m, 2H),
7.28e7.24 (m, 4H), 7.18e7.15 (m, 4H), 7.10e7.07 (m, 2H), 6.80e6.79
(m, 2H), 5.61 (dd, J¼17.5, 11.0 Hz, 1H), 5.24 (d, J¼17.5 Hz, 1H), 4.99
(d, J¼11.0 Hz, 1H), 4.64 (d, J¼11.0 Hz, 1H), 4.56 (d, J¼12.0 Hz, 1H),
4.50 (d, J¼11.0 Hz, 1H), 4.47 (d, J¼11.0 Hz, 1H), 4.30 (d, J¼12.0 Hz,
1H), 4.26 (d, J¼12.0 Hz, 1H), 3.88 (ddd, J¼7.0, 4.5, 4.0 Hz, 1H), 3.66
(m, 1H), 3.58 (m, 1H), 3.48 (ddd, J¼9.0, 5.5, 5.0 Hz, 1H), 3.28 (s, 3H),
3.01 (dd, J¼6.0, 6.0 Hz, 1H), 2.06 (ddd, J¼14.5, 7.0, 6.5 Hz, 1H),
1.98e1.91 (m, 2H), 1.78 (ddd, J¼14.5, 5.0, 5.0 Hz, 1H), 1.22 (s, 3H);
To a solution of 2-methyl-2-butene (921 mL, 8.67 mmol) in THF
(20 mL) at 0 ꢁC was added BH3$SMe2 (1.9 M solution in THF,
4.34 mL, 2.28 mmol), and the resultant solution was stirred at 0 ꢁC
for 1 h. To this solution was added a solution of the above PMB
ether (1.45 g, 2.89 mmol) in THF (9.0 mL). After being stirred at
room temperature for 3 h, the mixture was cooled to 0 ꢁC and
treated with 3 M aqueous NaOH solution (15 mL) and 30% aqueous
H2O2 solution (15 mL). The resultant mixture was stirred at 0 ꢁC for
30 min and then at room temperature for 5 h. The mixture was
extracted twice with EtOAc, and the organic layer was washed with
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. Purification of the residue by column chromatography
13C NMR (125 MHz, CDCl3)
d 159.1, 140.8, 138.41, 138.39, 130.7, 129.6
(2C), 128.3 (4C), 127.8 (2C), 127.7 (2C), 127.5 (2C), 115.9, 113.7 (2C),
78.9, 76.8, 73.0, 72.2, 71.9, 66.7, 62.6, 59.1, 55.2, 31.1, 29.9, 15.0;
HRMS (ESI) calcd for C32H38O5Na [(MþNa)þ] 525.2611, found
525.2601.
(silica gel, 20e40% EtOAc/hexanes) gave primary alcohol 22 (1.50 g,
25
100%) as a colorless oil: [
a]
ꢀ16.4 (c 1.0, CHCl3); IR (film) 2867,
D
4.1.10. Secondary alcohol 21. To a solution of vinyl epoxide 20
(711 mg, 1.41 mmol) in CH2Cl2/H2O (20:1, v/v, 15 mL) at 0 ꢁC was
added DDQ (337 mg, 1.49 mmol), and the resultant mixture was
stirred at room temperature overnight before it was quenched with
saturated aqueous NaHCO3 solution. The mixture was extracted
with EtOAc, and the organic layer was washed with saturated
aqueous NaHCO3 solution and brine. The aqueous layers were
combined and extracted with EtOAc. The combined organic layer
was dried over Na2SO4, filtered, and concentrated under reduced
pressure. Purification of the residue by column chromatography
(silica gel, 10e30% EtOAc/hexanes) gave secondary alcohol 21
1611,1513,1454,1248,1173,1088,1030, 821, 737, 698 cmꢀ1; 1H NMR
(500 MHz, CDCl3) 7.35e7.24 (m, 10H), 7.20e7.19 (m, 2H),
d
6.87e6.85 (m, 2H), 4.60 (d, J¼11.5 Hz, 1H), 4.55 (d, J¼11.0 Hz, 1H),
4.49 (d, J¼12.5 Hz, 1H), 4.44 (d, J¼11.5 Hz, 1H), 4.43 (d, J¼11.5 Hz,
1H), 4.33 (d, J¼11.5 Hz, 1H), 3.79 (s, 3H), 3.70 (ddd, J¼11.5, 8.0,
3.5 Hz, 1H), 3.63 (ddd, J¼11.0, 7.0, 3.5 Hz, 1H), 3.57 (ddd, J¼9.5, 9.5,
2.0 Hz, 1H), 3.49 (apparent t, J¼6.3 Hz, 2H), 3.32 (dd, J¼11.5, 5.5 Hz,
1H), 3.09 (ddd, J¼10.0, 9.5, 4.5 Hz,1H), 2.47 (ddd, J¼12.5, 5.0, 4.0 Hz,
1H), 2.20 (dddd, J¼14.5, 7.5, 7.5, 2.5 Hz, 1H), 1.87 (ddd, J¼15.5, 6.5,
3.5 Hz, 1H), 1.72 (ddd, J¼15.0, 8.0, 3.5 Hz, 1H), 1.56 (m, 1H), 1.52
(ddd, J¼12.0, 12.0, 11.5 Hz, 1H), 1.21 (s, 3H), one proton missing due
to H/D exchange of the hydroxy group; 13C NMR (125 MHz, CDCl3)
(390 mg, 72%) as a colorless oil: [
a
]
24 ꢀ80.9 (c 1.0, CHCl3); IR (film)
D
3438, 2868, 1496, 1454, 1362, 1454, 1362, 1096, 1028, 923,
d 159.2, 138.4, 138.0, 130.1, 129.2 (2C), 128.4 (2C), 128.3 (2C), 127.8
736 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
7.34e7.24 (m,10H), 5.90 (dd,
(2C), 127.8 (3C), 127.5, 113.8 (2C), 78.1, 77.1, 76.5, 72.9, 70.9, 70.7,
70.6, 66.9, 59.1, 55.2, 41.1, 32.3, 30.0, 15.9; HRMS (ESI) calcd for
C32H40O6Na [(MþNa)þ] 543.2717, found 543.2695.
J¼17.5, 11.0 Hz, 1H), 5.26 (d, J¼17.5 Hz, 1H), 5.13 (d, J¼11.0 Hz, 1H),
4.61 (d, J¼12.0 Hz, 1H), 4.50 (d, J¼12.0 Hz, 1H), 4.48 (d, J¼12.0 Hz,
1H), 4.45 (d, J¼12.0 Hz, 1H), 3.62e3.54 (m, 3H), 3.44 (s, 1H), 3.18
(ddd, J¼10.0, 10.0, 4.0 Hz, 1H), 2.34 (ddd, J¼12.5, 4.5, 4.0 Hz, 1H),
2.23 (dddd, J¼14.0, 8.0, 8.0, 5.0 Hz, 1H), 1.66 (m, 1H), 1.61 (ddd,
J¼11.5, 11.5, 11.5 Hz, 1H), 1.23 (s, 3H), one proton missing due to H/D
4.1.12. Methyl ketone 10. To a solution of alcohol 22 (590 mg,
1.13 mmol) in CH2Cl2/DMSO (1:1, v/v, 12 mL) at 0 ꢁC were added
Et3N (630 mL, 4.52 mmol) and SO3$pyridine (542 mg, 3.40 mmol).
exchange of the hydroxy group; 13C NMR (125 MHz, CDCl3)
d
143.0,
The resultant mixture was stirred at 0 ꢁC for 1 h before it was di-
luted with Et2O. The mixture was washed successively with satu-
rated aqueous NH4Cl solution, H2O, and brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The crude al-
dehyde 23 thus obtained was used in the next reaction without
further purification.
138.6, 138.1,128.4 (2C),128.3 (2C),127.8 (2C),127.7,127.6 (2C),127.4,
114.0, 76.8, 76.6, 72.9, 70.94, 70.92, 69.8, 66.9, 33.3, 32.4, 14.0;
HRMS (ESI) calcd for C24H30O4Na [(MþNa)þ] 405.2036, found
405.2031.
4.1.11. Primary alcohol 22. To a solution of alcohol 21 (1.13 g,
2.96 mmol) in DMF (10 mL) at 0 ꢁC was added KOt-Bu (498 mg,
4.44 mmol), and the resultant mixture was stirred at room tem-
perature for 15 min. To the mixture at 0 ꢁC were added PMBCl
To a solution of the above crude aldehyde 23 in Et2O (11 mL) at
ꢀ78 ꢁC was added MeMgBr (3.0 M solution in Et2O, 1.88 mL,
5.65 mmol), and the resultant solution was stirred at ꢀ78 ꢁC for
20 min before it was quenched with saturated aqueous NH4Cl so-
lution. The mixture was extracted twice with EtOAc, and the or-
ganic layer was washed with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was filtered
through a short pad of silica gel to give a crude material, which was
used in the next reaction without further purification.
(480 mL, 3.55 mmol) and TBAI (219 mg, 0.592 mmol), and the re-
sultant solution was stirred at room temperature for 1 h. The re-
action was quenched with saturated aqueous NH4Cl solution at
0 ꢁC. The mixture was extracted with EtOAc, and the organic layer
was washed with brine, dried over Na2SO4, filtered, and

K. Tsubone et al. / Tetrahedron 67 (2011) 6600e6615
6609
ꢁ
To a suspension of the above crude alcohol, 4 A molecular sieves
The mixture was extracted with EtOAc, and the organic layer was
washed with brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. Purification of the residue by flash column
chromatography (silica gel, 20% EtOAc/hexanes) gave diketone 8
(500 mg), and NMO (265 mg, 2.26 mmol) in CH2Cl2 (11 mL) at room
temperature was added TPAP (19.9 mg, 56.5 mmol). The resultant
mixture was stirred at room temperature for 1 h before it was
concentrated to approximately one-fifth of its volume under re-
duced pressure. Purification of the residue by column chromatog-
raphy (silica gel, 0e10% EtOAc/hexanes) gave methyl ketone 10
(119 mg, 91%) as a colorless oil: [
a
]
25 ꢀ12.0 (c 1.5, CHCl3); IR (film)
D
2952, 2874, 1612, 1514, 1455, 1364, 1248, 1093, 1028, 830, 771 cmꢀ1
;
1H NMR (600 MHz, CDCl3)
d
7.49e7.25 (m, 17H), 6.88 (d, J¼8.5 Hz,
(500 mg, 83% for the three steps) as a colorless oil: [
a
]
D
22 ꢀ41.1 (c 4.3,
2H), 5.96 (br s, 1H), 5.43 (s, 1H), 4.62 (d, J¼10.0 Hz, 1H), 4.55 (d,
J¼11.0 Hz, 1H), 4.50 (d, J¼12.0 Hz, 1H), 4.46 (d, J¼12.0 Hz, 1H), 4.42
(d, J¼11.0 Hz, 1H), 4.42 (d, J¼10.0 Hz, 1H), 4.21 (ddd, J¼10.0, 10.0,
5.5 Hz, 1H), 3.92 (dd, J¼11.0, 4.4 Hz, 1H), 3.80 (s, 3H), 3.65e3.54 (m,
5H), 3.49 (m, 1H), 3.36 (dd, J¼11.7, 4.1 Hz, 1H), 3.06 (ddd, J¼11.3, 9.3,
4.4 Hz, 1H), 2.55 (d, J¼13.4 Hz, 1H), 2.49 (d, J¼12.7 Hz, 1H), 2.45 (m,
1H), 2.27e2.19 (m, 2H), 1.87 (ddd, J¼12.0, 12.0, 11.3 Hz, 1H), 1.58 (m,
1H), 1.51 (ddd, J¼12.0, 12.0, 11.3 Hz, 1H), 1.43 (s, 3H), 1.23 (s, 3H),
0.89 (t, J¼7.9 Hz, 9H), 0.51 (q, J¼7.9 Hz, 6H), one proton missing due
to H/D exchange of the enol form; 13C NMR (150 MHz, CDCl3)
CHCl3); IR (film) 3031, 2937, 2867, 1704, 1612, 1514, 1455, 1354,
1249, 1173, 1098, 1030, 822, 739, 699 cmꢀ1
;
1H NMR (500 MHz,
7.34e7.21 (m, 12H), 6.86e6.84 (m, 2H), 4.57 (d, J¼11.5 Hz,
CDCl3)
d
1H), 4.53 (d, J¼11.0 Hz, 1H), 4.48 (d, J¼12.0 Hz, 1H), 4.44 (d, J¼12.0,
Hz, 1H), 4.40 (d, J¼11.5 Hz, 1H), 4.39 (d, J¼11.0 Hz, 1H), 3.79 (s, 3H),
3.54e3.47 (m, 3H), 3.36 (dd, J¼11.5, 5.0 Hz, 1H), 3.03 (ddd, J¼11.5,
9.5, 5.0 Hz, 1H), 2.61 (d, J¼12.0 Hz, 1H), 2.45 (d, J¼12.0 Hz, 1H), 2.39
(ddd, J¼12.5, 4.5, 4.0 Hz, 1H), 2.21 (m, 1H), 2.07 (s, 3H), 1.55 (m, 1H),
1.47 (ddd, J¼12.0, 11.5, 11.5 Hz, 1H), 1.19 (s, 3H); 13C NMR (150 MHz,
CDCl3)
d
208.7, 159.2, 138.5, 138.1, 130.5, 129.3 (2C), 128.4 (2C), 128.3
d 196.1, 189.0, 159.2, 138.6, 138.1, 137.3, 130.5, 129.2 (2C), 129.1, 128.5
(2C), 127.8 (2C), 127.7 (2C), 127.6 (2C), 127.5, 113.7, 76.8, 76.7, 76.3,
72.9, 70.9 (2C), 70.0, 66.7, 55.3, 52.6, 33.2, 32.4, 30.4, 16.4; HRMS
(ESI) calcd for C33H40O6Na [(MþNa)þ] 555.2717, found 555.2686.
(2C), 128.3 (3C), 127.8 (4C), 127.5 (3C), 126.1 (2C), 113.7 (2C), 101.7,
99.0, 81.7, 77.1, 76.9, 76.0, 72.9, 70.9, 70.5, 69.9, 69.8, 66.9, 66.4, 55.3
(2C), 47.7. 35.0, 32.7, 30.4, 16.5, 14.1, 12.4, 6.8 (3C), 4.7 (3C); HRMS
(ESI) calcd for C54H70O11SiNa [(MþNa)þ] 945.4580, found 945.4600.
4.1.13.
(198 mg, 0.372 mmol) and i-Pr2NEt (130
(3.0 mL) at 0 ꢁC was added n-Bu2BOTf (141
b
-Hydroxy ketone 24. To a solution of methyl ketone 10
L, 0.744 mmol) in Et2O
L, 0.559 mmol, freshly
m
4.1.15. Methyl ketone 25. To a solution of aldehyde 9 (594 mg,
1.51 mmol) in THF (7.5 mL) at ꢀ78 ꢁC was added MeMgBr (3.0 M
solution in Et2O, 1.51 mL, 4.53 mmol), and the resultant solution
was allowed to warm to 0 ꢁC over 1.5 h before it was quenched with
saturated aqueous NH4Cl solution. The mixture was extracted with
EtOAc, and the organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. Purifi-
cation of the residue by flash column chromatography (silica gel,
10e15% EtOAc/hexanes) gave a secondary alcohol (465 mg, 74%) as
a colorless oil, which was used in the next reaction without further
purification.
m
prepared from n-Bu3B and TfOH31). The resultant solution was
stirred at 0 ꢁC for 1 h and then cooled to ꢀ78 ꢁC. To this solution
was added a solution of aldehyde 9 (219 mg, 0.558 mmol) in Et2O
(0.7 mL), and the resultant solution was allowed to warm to ꢀ20 ꢁC
over 2 h before it was quenched with pH 7 buffer (0.5 mL) and
MeOH (1 mL). The resultant mixture was treated with 30% aqueous
H2O2 solution (0.5 mL) and MeOH (1 mL) at 0 ꢁC and stirred at room
temperature for 1 h. The mixture was extracted with EtOAc, and the
organic layer was washed with brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure. Purification of the resi-
due by flash column chromatography (silica gel, 10e30% EtOAc/
To a solution of DMSO (221 mL, 3.11 mmol) in CH2Cl2 (5 mL) at
ꢀ78 ꢁC was added oxalyl chloride (135
mL, 1.55 mmol), and the re-
hexanes) gave
b
-hydroxy ketone 24, which was contaminated with
sultant solution was stirred at ꢀ78 ꢁC for 15 min. To this solution
was added a solution of the above alcohol (317 mg) in CH2Cl2
(3 mL), and the resultant solution was stirred at ꢀ78 ꢁC for 45 min
a small amount of 9 and some impurities. Further purification by
preparative HPLC gave pure hydroxy ketone 24 (254 mg, 74%, a 4:1
23
mixture of diastereomers) as a colorless oil: [
a]
ꢀ36.7 (c 0.98,
before Et3N (650 mL, 4.66 mmol) was introduced. The mixture was
D
CHCl3); IR (film) 3503, 3031, 2953, 2874, 1708, 1611, 1513, 1455,
allowed to warm to room temperature and stirred for 1 h before it
was quenched with saturated aqueous NaHCO3 solution. The mix-
ture was extracted twice with EtOAc, and the organic layer was
washed with brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. Purification of the residue by flash column
chromatography (silica gel, 10% EtOAc/hexanes) gave methyl ke-
1364, 1248, 1092, 1028, 825 cmꢀ1; 1H NMR (600 MHz, CDCl3, major
diastereomer) d 7.49e7.25 (m, 17H), 6.87e6.85 (m, 2H), 5.44 (s, 1H),
4.57 (d, J¼11.3 Hz, 1H), 4.55 (d, J¼11.0 Hz, 1H), 4.50 (d, J¼12.0 Hz,
1H), 4.45 (d, J¼11.3 Hz, 1H), 4.45 (d, J¼12.0 Hz, 1H), 4.39 (d,
J¼11.0 Hz, 1H), 4.14 (m, 1H), 4.09 (dd, J¼8.9, 2.8 Hz, 1H), 3.95 (dd,
J¼11.3, 4.9 Hz, 1H), 3.79 (s, 3H), 3.58e3.52 (m, 5H), 3.45 (dd, J¼11.7,
4.5 Hz, 1H), 3.38 (m, 1H), 3.23 (br s, 1H), 3.02 (ddd, J¼10.3, 5.2,
4.8 Hz, 1H), 2.73 (dd, J¼14.1, 2.8 Hz, 1H), 2.67 (m, 1H), 2.66 (d,
J¼12.4 Hz, 1H), 2.57 (d, J¼12.4 Hz, 1H), 2.38 (ddd, J¼12.1, 4.8, 4.4 Hz,
1H), 2.24e2.17 (m, 2H), 1.85 (ddd, J¼11.7, 11.6, 11.3 Hz, 1H),
1.56e1.45 (m, 2H), 1.23 (s, 3H), 1.22 (s, 3H), 0.94 (t, J¼7.9 Hz, 9H),
0.60 (q, J¼7.9 Hz, 6H); 13C NMR (150 MHz, CDCl3, major di-
tone 25 (265 mg, 84%) as a colorless oil: [
a]
24 þ11.2 (c 0.9, CHCl3.); IR
D
(film) 2954, 2876, 1724, 1365, 1094, 1008, 825, 747 cmꢀ1
;
1H NMR
(600 MHz, CDCl3)
d 7.48e7.46 (m, 2H), 7.38e7.32 (m, 3H), 5.52 (s,
1H), 4.25 (dd, J¼10.3, 4.5 Hz, 1H), 3.98 (dd, J¼11.0, 4.8 Hz, 1H), 3.68
(dd, J¼10.0, 10.0 Hz, 1H), 3.60 (ddd, J¼9.3, 8.9, 4.4 Hz, 1H), 3.53 (m,
1H), 2.24 (ddd, J¼12.0, 4.5, 4.5 Hz,1H), 2.18 (s, 3H),1.84 (ddd, J¼11.7,
11.7,11.3 Hz,1H),1.40 (s, 3H), 0.90 (t, J¼7.9 Hz, 9H), 0.54 (q, J¼7.9 Hz,
6H); 13C NMR (150 MHz, CDCl3) 206.9, 137.3, 129.2, 128.4 (2C), 126.1
(2C), 101.8, 84.2, 76.7, 69.9, 68.4, 66.4, 34.9, 24.5, 12.5, 6.7 (3C), 4.9
(3C); HRMS (ESI) calcd for C22H34O5SiNa [(MþNa)þ] 429.2068,
found 429.2066.
astereomer)
d 209.4, 159.1, 138.5, 138.0, 137.3, 130.6, 129.3 (2C),
129.1, 128.4 (2C), 128.3 (4C), 127.8 (2C), 127.7, 127.5 (2C), 127.4, 126.1
(2C), 113.7 (2C), 101.7, 78.8, 76.8, 76.6, 76.4, 76.3, 74.1, 72.9, 72.3,
71.0, 70.7, 70.0, 69.7, 66.9, 66.1, 55.2, 52.2, 47.2, 34.6, 32.5, 30.4, 16.8,
11.6, 6.8 (3C), 5.3 (3C); HRMS (ESI) calcd for C54H72O11SiNa
[(MþNa)þ] 947.4736, found 947.4738.
4.1.16. Aldehyde 23. To
1.47 mmol) in CH2Cl2 (8 mL) at 0 ꢁC were added KBr (0.5 M solution
in H2O, 294 L, 0.147 mmol) and TEMPO (11.5 mg, 73.5 mol). To
this mixture were added dropwise a freshly prepared mixture of
NaOCl (1.73 M solution in H2O, 850 L, 1.47 mmol) and saturated
L). The resultant mixture was
a solution of alcohol 22 (766 mg,
4.1.14. Diketone 8. To a solution of hydroxy ketone 24 (132 mg,
0.142 mmol) in CH2Cl2/t-BuOH (10:1, v/v, 1.4 mL) at room temper-
ature was added DesseMartin periodinane (90.3 mg, 0.213 mmol).
The resultant solution was stirred at room temperature for 90 min
before it was quenched with a 1:1 mixture of saturated aqueous
NaHCO3 solution and saturated aqueous Na2S2O3 solution (2 mL).
m
m
m
aqueous NaHCO3 solution (850
m
vigorously stirred at 0 ꢁC for 20 min before it was quenched with
saturated aqueous Na2S2O3 solution. The mixture was extracted

6610
K. Tsubone et al. / Tetrahedron 67 (2011) 6600e6615
twice with EtOAc, and the organic layer was washed with H2O and
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. Purification of the residue by flash column chromatog-
10e15% EtOAc/hexanes) gave diketone 8 (68.2 mg, 92%), which was
identical in all aspects to that prepared by oxidation of 24.
raphy (silica gel, 20% EtOAc/hexanes) gave aldehyde 23 (722 mg,
4.1.19. Dihydropyrone 28. To a solution of diketone 8 (50.4 mg,
22
95%) as a colorless oil: [
a]
ꢀ28.7 (c 1.4, CHCl3); IR (film) 2939,
0.546 mmol) in MeOH (1 mL) at room temperature was added PPTS
D
2862, 1718, 1611, 1513, 1248, 1087, 1030, 821, 736, 697 cmꢀ1
;
1H
(4.2 mg, 16
6 h. The mixture was cooled to room temperature, treated with
Et3N (4.6 L, 33 mol), and concentrated under reduced pressure.
m
mol), and the resultant solution was stirred at 80 ꢁC for
NMR (600 MHz, CDCl3)
d
9.68 (dd, J¼3.4, 2.7 Hz, 1H), 7.35e7.24 (m,
10H), 7.19e7.18 (m, 2H), 6.87e6.84 (m, 2H), 4.60 (d, J¼11.3 Hz, 1H),
4.50 (d, J¼11.0 Hz, 1H), 4.50 (d, J¼12.1 Hz, 1H), 4.44 (d, J¼11.3 Hz,
1H), 4.42 (d, J¼12.1 Hz,1H), 4.30 (d, J¼11.3 Hz,1H), 3.79 (s, 3H), 3.59
(dd, J¼9.3, 9.3 Hz, 1H), 3.54e3.51 (m, 2H), 3.24 (dd, J¼12.0, 4.8 Hz,
1H), 3.08 (ddd, J¼11.0, 9.6, 4.8 Hz, 1H), 2.52 (dd, J¼14.4, 3.4 Hz, 1H),
2.44 (ddd, J¼12.0, 4.8, 4.8 Hz, 1H), 2.37 (dd, J¼14.5, 2.7 Hz, 1H), 2.22
(ddd, J¼13.7, 7.9, 2.4 Hz, 1H), 1.56 (m, 1H), 1.49 (ddd, J¼11.7, 11.7,
m
m
Purification of the residue by flash column chromatography (silica
gel, 10% MeOH/EtOAc) gave dihydropyrone 28 (36.3 mg, 95%) as
a colorless oil: [
a]
25 þ79.8 (c 1.47, CHCl3); IR (film) 3380, 2871, 1668,
D
1595, 1514, 1454, 1454, 1371, 1073, 1030, 772 cmꢀ1
;
1H NMR
(600 MHz, CDCl3)
d
7.34e7.23 (m, 10H), 7.18 (d, J¼8.6 Hz, 2H), 6.86
(m, 2H), 5.21 (s, 1H), 4.60 (d, J¼11.3 Hz, 1H), 4.54 (J¼11.0 Hz, 1H),
4.48 (d, J¼12.1 Hz, 1H), 4.44 (d, J¼11.3 Hz, 1H), 4.40 (d, J¼12.1 Hz,
1H), 4.25 (d, J¼11.0 Hz, 1H), 3.87e3.84 (m, 2H), 3.79 (s, 3H), 3.74
(dd, J¼12.7, 4.8 Hz, 1H), 3.58e3.44 (m, 5H), 3.20 (dd, J¼11.7, 4.4 Hz,
1H), 3.06 (ddd, J¼11.0, 9.6, 4.4 Hz,1H), 2.49 (ddd, J¼12.4, 4.4, 4.4 Hz,
1H), 2.42 (d, J¼13.7 Hz, 1H), 2.33 (d, J¼13.7 Hz, 1H), 2.25 (ddd,
J¼12.1, 4.8, 4.4 Hz, 1H), 2.20 (ddd, J¼13.7, 7.9, 2.4 Hz, 1H), 1.93 (ddd,
J¼12.1, 12.0, 11.6 Hz, 1H), 1.52 (m, 1H), 1.48 (ddd, J¼11.7, 11.6, 9.0 Hz,
1H), 1.27 (s, 3H), 1.19 (s, 3H), two protons missing due to H/D ex-
11.7 Hz, 1H), 1.27 (s, 3H); 13C NMR (150 MHz, CDCl3)
d 202.3, 159.3,
138.5, 138.0, 129.9, 129.4 (2C), 128.4 (2C), 128.3 (2C), 127.81 (2C),
127.78, 127.7 (2C), 127.5, 113.8 (2C), 77.8, 76.6, 75.6, 72.9, 71.0, 70.6,
69.9, 66.6, 55.3, 53.6, 32.3, 30.2, 16.4; HRMS (ESI) calcd for
C32H38O6Na [(MþNa)þ] 541.2561, found 541.2575.
4.1.17.
0.911 mmol) in THF (0.3 mL) at 0 ꢁC was added n-BuLi (2.6 M so-
lution in hexane, 303
L, 0.788 mmol). After being stirred at 0 ꢁC for
b-Hydroxy ketone 26. To a solution of i-Pr2NH (128 mL,
m
change of the hydroxy groups; 13C NMR (150 MHz, CDCl3)
d 173.6,
15 min, the resultant solution was cooled to ꢀ78 ꢁC. To the solution
was added a solution of methyl ketone 25 (308 mg, 0.789 mmol) in
THF (0.7 mL), and the resultant solution was stirred at ꢀ78 ꢁC for
1 h. To this cold solution was added a solution of aldehyde 23
(314 mg, 0.606 mmol) in THF (0.7 mL). The reaction mixture was
gradually allowed to warm to ꢀ20 ꢁC over 2 h before it was
quenched with saturated aqueous NH4Cl solution. The mixture was
extracted twice with EtOAc, and the organic layer was washed with
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. Purification of the residue by column chromatography
159.3, 138.6, 138.0, 130.1, 129.3 (2C), 128.4 (2C), 128.3 (2C), 127.8
(3C), 127.5 (3C), 127.4, 113.9 (2C), 105.2, 77.6, 77.5, 76.8, 75.8, 75.3,
73.4, 72.8, 71.1, 70.3, 69.9, 66.7, 66.0, 62.6, 55.3, 44.8, 32.4, 32.1, 30.1,
16.2, 12.8; HRMS (ESI) calcd for C41H50O10Na [(MþNa)þ] 725.3296,
found 725.3294.
4.1.20. Silylene 7. To a solution of diol 28 (151 mg, 0.215 mmol) and
2,6-lutidine (75.3
added t-Bu2Si(OTf)2 (83.6
m
L, 0.645 mmol) in DMF (2.2 mL) at 0 ꢁC was
mL, 0.258 mmol), and the resultant solu-
tion was stirred at room temperature for 2 h before it was diluted
with EtOAc. The mixture was washed successively with H2O, sat-
urated aqueous NaHCO3 solution, and brine. The organic layer was
dried over Na2SO4, filtered, and concentrated under reduced pres-
sure. Purification of the residue by flash column chromatography
(silica gel, 10e20% EtOAc/hexanes) gave silylene 7 (168 mg, 93%) as
(silica gel, 0e20% EtOAc/hexanes) gave
mg, 67%) as a 1.7:1 mixture of diastereomers: [
CHCl3); IR (film) 3485, 2952, 2909, 2875, 1719, 1612, 1514, 1456,
1365, 1094, 1029, 824, 750 cmꢀ1 1H NMR (600 MHz, CDCl3, major
diastereomer) 7.48e7.45 (m, 2H), 7.37e7.24 (m, 13H), 7.22e7.20
b-hydroxy ketone 26 (365
23
a]
ꢀ15.4 (c 1.3,
D
;
d
(m, 2H), 6.87e6.85 (m, 2H), 5.47 (s, 1H), 4.58 (d, J¼11.7 Hz, 1H), 4.52
(d, J¼11.3 Hz, 1H), 4.48 (d, J¼12.0 Hz, 1H), 4.44 (d, J¼12.0 Hz, 1H),
4.41 (d, J¼11.3 Hz, 1H), 4.37 (d, J¼11.7 Hz, 1H), 4.23 (dd, J¼13.7,
4.1 Hz, 1H), 3.99 (dd, J¼11.0, 4.8 Hz, 1H), 3.79 (s, 3H), 3.65e3.55 (m,
3H), 3.51e3.46 (m, 3H), 3.24 (dd, J¼11.7, 4.5 Hz, 1H), 3.06 (ddd,
J¼11.0, 9.7, 7.5 Hz, 1H), 2.94 (dd, J¼17.5, 6.5 Hz, 1H), 2.54 (dd, J¼17.5,
5.9 Hz, 1H), 2.40 (ddd, J¼12.4, 4.5, 4.5 Hz, 1H), 2.23 (ddd, J¼11.7, 4.4,
4.4 Hz, 1H), 2.19 (dddd, J¼12.0, 6.9, 6.9, 4.9 Hz, 1H), 1.96 (dd, J¼14.1,
1.7 Hz, 1H), 1.83 (ddd, J¼11.7, 11.6, 11.6 Hz, 1H), 1.59e1.47 (m, 3H),
1.40 (s, 3H), 1.28 (s, 3H), 0.89 (t, J¼7.9 Hz, 9H), 0.53 (q, J¼7.9 Hz, 6H),
one proton missing due to H/D exchange of the hydroxy group; 13C
a white foam: [
a]
23þ43.0 (c 1.05, CHCl3); IR (film) 3535, 2933, 2855,
D
1685, 1604, 1514, 1472, 1364, 1249, 1075, 827 cmꢀ1
;
1H NMR
(600 MHz, CDCl3)
d 7.34e7.23 (m, 10H), 7.20e7.18 (m, 2H),
6.87e6.85 (m, 2H), 5.22 (s, 1H), 4.60 (d, J¼11.3 Hz, 1H), 4.54 (d,
J¼11.0 Hz, 1H), 4.49 (d, J¼12.4 Hz, 1H), 4.44 (d, J¼11.3 Hz, 1H), 4.40
(d, J¼12.4 Hz, 1H), 4.26 (d, J¼11.0 Hz, 1H), 4.20 (dd, J¼10.5, 5.2 Hz,
1H), 3.91 (dd, J¼12.4, 4.1 Hz, 1H), 3.83 (dd, J¼10.3, 10.0 Hz, 1H), 3.79
(s, 3H), 3.70 (ddd, J¼11.0, 9.6, 4.8 Hz, 1H), 3.58e3.48 (m, 4H), 3.21
(dd, J¼11.6, 2.8 Hz, 1H), 3.05 (ddd, J¼11.3, 9.2, 4.8 Hz, 1H), 2.49 (ddd,
J¼12.1, 4.4, 4.4 Hz, 1H), 2.42 (d, J¼13.7 Hz, 1H), 2.34 (d, J¼13.7 Hz,
1H), 2.31 (ddd, J¼12.4, 4.4, 4.4 Hz, 1H), 2.20 (dddd, J¼13.7, 7.9, 7.9,
2.8 Hz, 1H), 1.92 (ddd, J¼12.0, 11.7, 11.7 Hz, 1H), 1.53 (m, 1H), 1.48
(ddd, J¼11.7, 11.7, 11.6 Hz, 1H), 1.31 (s, 3H), 1.20 (s, 3H), 1.01 (s, 9H),
NMR (150 MHz, CDCl3, major diastereomer)
d 207.4, 159.2, 138.4,
138.0, 137.3, 130.5, 129.3, 129.1, 129.0 (2C), 128.4 (2C), 128.32 (2C),
128.27 (2C), 127.80, 127.76 (2C), 127.6, 127.4, 126.1 (2C), 113.7 (2C),
101.8, 83.6, 79.1, 77.6, 76.6, 76.4, 72.9, 70.9, 70.80, 70.77, 69.8, 68.3,
67.0, 66.3, 64.6, 55.2, 46.4, 44.2, 35.0, 32.2, 30.2, 15.2, 12.8, 6.8 (3C),
4.9 (3C); HRMS (ESI) calcd for C54H72O11SiNa [(MþNa)þ] 947.4736,
found 947.4744.
0.98 (s, 9H); 13C NMR (150 MHz, CDCl3)
d 193.7, 173.0, 159.3, 138.6,
138.0, 130.0, 129.3 (2C), 128.4 (2C), 128.3 (2C), 127.8 (3C), 127.5 (2C),
127.4, 113.8 (2C), 105.4, 77.60, 77.56, 77.2, 75.8, 74.2, 72.9, 72.5,
71.12, 71.08, 70.3, 69.9, 67.2, 66.7, 55.3, 44.8, 32.8, 32.5, 30.1, 27.4
(3C), 27.0 (3C), 22.6, 19.9, 16.2, 12.9; HRMS (ESI) calcd for
C49H66O10SiNa [(MþNa)þ] 865.4317, found 865.4295.
4.1.18. Diketone 8. To a solution of
b-hydroxy ketone 26 (74.6 mg,
80.7 mol) in CH2Cl2/t-BuOH (9:1, v/v, 1.0 mL) was added
m
4.1.21. Diol 29. To a solution of silylene 7 (289 mg, 0.343 mmol) in
MeOH/CH2Cl2 (1:1, v/v, 4.0 mL) at 0 ꢁC was added CeCl3$7H2O
(141 mg, 0.378 mmol), and the resultant mixture was stirred at 0 ꢁC
for 15 min. NaBH4 (14.3 mg, 0.378 mmol) was added to the mixture,
and the resultant mixture was stirred at 0 ꢁC for 2 h before it was
quenched with pH 7 phosphate buffer. The mixture was extracted
twice with EtOAc, and the organic layer was washed with brine,
dried over Na2SO4, filtered, and concentrated under reduced
DesseMartin periodinane (51.3 mg, 0.121 mmol), and the resultant
solution was stirred at room temperature for 105 min before it was
quenched with a 1:1 mixture of saturated aqueous NaHCO3 solution
and saturated aqueous Na2S2O3 solution. The mixture was extracted
with EtOAc, and the organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. Purifi-
cation of the residue by flash column chromatography (silica gel,

K. Tsubone et al. / Tetrahedron 67 (2011) 6600e6615
6611
pressure. Purification of the residue by flash column chromatog-
1H), 3.62e3.45 (m, 5H), 3.34 (d, J¼8.5 Hz, 1H), 3.19 (dd, J¼8.5,
8.5 Hz, 1H), 3.09 (ddd, J¼10.5, 10.0, 4.0 Hz, 1H), 2.93 (dd, J¼12.5,
7.5 Hz, 1H), 2.44 (ddd, J¼12.0, 5.0, 4.0 Hz,1H), 2.22 (ddd, J¼12.0, 8.0,
8.0 Hz, 1H), 2.12 (ddd, J¼12.0, 5.0, 4.0 Hz, 1H), 1.84 (d, J¼14.0 Hz,
1H), 1.72 (dd, J¼14.5, 9.5 Hz, 1H), 1.66e1.56 (m, 2H), 1.48 (ddd,
J¼12.0, 11.5, 11.0 Hz,1H), 1.13 (s, 3H),1.09 (s, 3H),1.03 (s, 9H), 0.98 (s,
9H), 0.94 (t, J¼8.0 Hz, 18H), 0.63 (q, J¼8.0 Hz, 12H); 13C NMR
raphy (silica gel, 10% EtOAc/hexanes) gave an allylic alcohol
23
(280 mg, 97%) as a white foam: [
a
]
ꢀ1.0 (c 1.14, CHCl3); IR (film)
D
3457, 2933, 2859,1514,1471,1248,1173,1109,1085,1030, 826 cmꢀ1
1H NMR (600 MHz, C6D6)
7.39 (d, J¼7.2 Hz, 2H), 7.30 (d, J¼6.8 Hz,
;
d
2H), 7.21e7.09 (m, 8H), 6.79 (d, J¼8.6 Hz, 2H), 4.67 (d, J¼1.7 Hz, 1H),
4.54 (d, J¼12.4 Hz, 1H), 4.50 (d, J¼12.4 Hz, 1H), 4.46 (d, J¼12.1 Hz,
1H), 4.41 (d, J¼11.3 Hz, 1H), 4.27 (d, J¼12.1 Hz, 1H), 4.27 (br s, 1H),
4.22 (dd, J¼10.3, 4.8 Hz, 1H), 4.19 (d, J¼11.3 Hz, 1H), 3.87 (dd, J¼9.6,
9.6 Hz, 1H), 3.78e3.70 (m, 5H), 3.47 (dd, J¼12.4, 4.5 Hz, 1H), 3.31 (s,
3H), 3.23 (dd, J¼11.7, 4.8 Hz, 1H), 3.06 (ddd, J¼11.0, 9.6, 4.4 Hz, 1H),
2.48 (d, J¼13.7 Hz, 1H), 2.46 (m, 1H), 2.41 (ddd, J¼12.0, 4.8, 4.4 Hz,
1H), 2.37 (ddd, J¼12.0, 4.5, 4.4 Hz, 1H), 2.32 (d, J¼13.7 Hz, 1H), 1.96
(ddd, J¼12.0, 12.0, 11.0 Hz, 1H), 1.76 (m, 1H), 1.58 (ddd, J¼11.7, 11.7,
11.7 Hz, 1H), 1.35 (s, 3H), 1.29 (s, 3H), 1.11 (s, 9H), 1.02 (s, 9H), one
proton missing due to H/D exchange of the hydroxy group; 13C NMR
(125 MHz, CDCl3)
d 159.0, 138.8, 138.3, 131.2, 129.3 (2C), 128.4 (2C),
128.3 (2C), 127.8 (2C), 127.6, 127.5 (2C), 127.4, 113.6 (2C), 82.1, 78.1,
77.14, 77.06, 76.3, 75.6, 74.9, 73.6, 72.9, 70.83, 70.78, 69.8, 69.5, 67.6,
67.3, 55.3 (2C), 41.2, 33.6, 32.5, 30.6, 27.5 (3C), 27.1 (3C), 22.6, 19.9,
17.6, 10.0, 7.1 (6C), 5.6 (3C), 5.1 (3C); HRMS (ESI) calcd for
C61H98O11Si3 [(MþNaþ)] 1113.6309, found 1113.6284.
To a solution of the above bis-TES ether (182 mg, 0.167 mmol) in
CH2Cl2/H2O (9/1, v/v, 8.8 mL) at 0 ꢁC was added DDQ (39.7 mg,
0.175 mmol) in five portions over 50 min. The resultant mixture
was stirred at 0 ꢁC for 2 h before it was quenched with saturated
aqueous NaHCO3 solution. The mixture was extracted with EtOAc,
and the organic layer was washed with saturated aqueous NaHCO3
solution and brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was filtered through a short
pad of silica gel to give a crude material, which was used in the next
reaction without further purification.
(150 MHz, C6D6) d 159.7, 152.7, 139.7, 139.1, 131.0, 129.4, 128.6, 128.5,
128.3 (3C), 127.8 (4C), 127.7, 127.5, 114.1 (2C), 104.2, 78.3, 77.4, 75.8,
75.0, 74.4, 73.8, 73.5, 73.0, 71.2, 70.8, 70.5, 70.0, 68.0, 67.1, 54.8, 44.1,
33.9, 33.2, 30.7, 27.6 (3C), 27.5 (3C), 22.8, 20.1, 16.0, 9.8; HRMS (ESI)
calcd for C49H68O10SiNa [(MþNa)þ] 867.4474, found 867.4484.
To a solution of the above allylic alcohol (140 mg, 0.166 mmol) in
THF (1.7 mL) at 0 ꢁC was added BH3$THF (1.0 M solution in THF,
ꢁ
332
mL, 0.332 mmol), and the resultant solution was stirred at room
To a solution of the above crude material, 4 A molecular sieves
temperature for 2 h. The mixture was cooled to 0 ꢁC and treated
with 3 M aqueous NaOH solution (1.7 mL) and 30% H2O2 solution
(1.7 mL). The resultant mixture was stirred at 0 ꢁC for 30 min and
then at room temperature for 4 h. The mixture was extracted twice
with EtOAc, and the organic layer was washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by column chromatography (silica gel,
30e40% EtOAc/hexanes) gave diol 29 (114 mg, 80%) as a white
(140 mg), and NMO (39.0 mg, 0.334 mmol) in CH2Cl2 (1.7 mL) at
0 ꢁC was added TPAP (2.9 mg, 8.4
mmol). After being stirred at room
temperature for 2 h, the mixture was filtered through a short pad of
silica gel. The filtrate was concentrated and purified by column
chromatography (silica gel, 0e10% EtOAc/hexanes) to give ketone
30 (137 mg, 85% for the two steps) as a colorless oil: [
a
]
25 ꢀ24.9 (c
D
0.13, CHCl3); IR (film) 2955, 1737, 1462, 1092, 1010, 827, 779,
736 cmꢀ1; 1H NMR (600 MHz, CDCl3)
d 7.33e7.24 (m, 10H), 4.55 (d,
foam: [
a]
25 ꢀ13.9 (c 0.30, CHCl3); IR (film) 3442, 2933, 2859, 1613,
J¼12.0 Hz, 1H), 4.50 (d, J¼11.7 Hz, 1H), 4.45 (d, J¼12.0 Hz, 1H), 4.40
(d, J¼11.7 Hz, 1H), 4.04 (dd, J¼10.0, 4.5 Hz, 1H), 3.90 (ddd, J¼7.3, 5.5,
3.8 Hz, 1H), 3.74e3.67 (m, 3H), 3.62e3.56 (m, 2H), 3.52e3.45 (m,
2H), 3.30 (d, J¼8.3 Hz, 1H), 3.18 (dd, J¼8.9, 8.6 Hz, 1H), 2.92e2.88
(m, 2H), 2.44 (dd, J¼15.5, 5.2 Hz, 1H), 2.08 (m, 1H), 1.96 (ddd, J¼11.7,
4.4, 4.4 Hz, 1H), 1.93e1.92 (m, 2H), 1.80 (m, 1H), 1.26 (s, 3H), 1.02 (s,
3H), 1.02 (s, 9H), 0.98 (s, 9H), 0.93 (t, J¼7.9 Hz, 9H), 0.91 (t, J¼7.9 Hz,
D
1514, 1470, 1363, 1248, 1092, 1069, 826, 760 cmꢀ1
;
1H NMR
(500 MHz, CDCl3)
d
7.35e7.23 (m, 12H), 6.87 (d, J¼8.5 Hz, 2H), 4.60
(d, J¼11.0 Hz, 1H), 4.52 (d, J¼11.5 Hz, 1H), 4.50 (d, J¼12.0 Hz, 1H),
4.43 (d, J¼12.0 Hz, 1H), 4.43 (d, J¼11.0 Hz, 1H), 4.34 (d, J¼11.5 Hz,
1H), 4.10 (dd, J¼9.5, 6.5 Hz, 1H), 3.95 (br s, 1H), 3.79 (s, 3H),
3.79e3.73 (m, 2H), 3.66 (dd, J¼9.5, 7.5 Hz, 1H), 3.55e3.47 (m, 4H),
3.30 (d, J¼9.0 Hz, 1H), 3.21 (dd, J¼9.0, 8.5 Hz, 1H), 3.10e3.01 (m,
2H), 2.86 (dd, J¼12.5, 4.0 Hz, 1H), 2.49 (m, 1H), 2.48 (br s, 1H), 2.25
(ddd, J¼12.5, 7.5, 7.5 Hz, 1H), 2.13 (ddd, J¼12.0, 4.5, 4.0 Hz, 1H), 2.10
(dd, J¼15.5, 4.0 Hz, 1H), 1.78 (dd, J¼15.5, 6.0 Hz, 1H), 1.65 (ddd,
J¼11.5, 11.5, 11.5 Hz, 1H),1.52 (m, 1H), 1.19 (s, 3H), 1.19 (s, 3H), 1.04 (s,
9H), 0.98 (s, 9H), one proton missing due to H/D exchange of the
9H), 0.65e0.55 (m, 12H); 13C NMR (150 MHz, CDCl3)
d 212.2, 138.4,
137.8, 128.5 (2C), 128.4 (2C), 127.8 (3C), 127.62 (2C), 127.57, 81.9,
80.1, 77.4, 76.19, 76.17, 73.6, 73.1, 71.1, 70.5, 69.5, 67.5, 66.6, 43.3,
41.4, 34.0, 33.2, 27.5 (3C), 27.1 (3C), 22.6, 22.5, 20.0, 10.0, 7.1 (3C), 7.0
(3C), 5.6 (3C), 5.1 (3C), two carbons missing presumably due to
solvent overlapping; HRMS (ESI) calcd for C53H88O10Si3 [(MþNa)þ]
991.5577, found 991.5583.
hydroxy group; 13C NMR (125 MHz, CDCl3)
d 159.3, 138.5, 138.0,
130.3, 130.0 (2C), 128.4 (2C), 128.3 (2C), 127.8 (3C), 127.7 (2C), 127.5,
113.7 (2C), 79.9, 76.7, 76.3, 76.1 (2C), 74.5, 74.4, 73.5, 72.9, 71.0, 70.6,
70.4, 69.8, 67.8, 66.4, 60.4, 55.3, 43.6, 33.2, 32.2, 30.2, 27.4 (3C), 27.1
(3C), 22.6, 19.9, 17.9, 10.1; HRMS (ESI) calcd for C49H70O11Si
[(MþNa)þ] 885.4580, found 885.4571.
4.1.23. Alcohol 6. To a solution of ketone 30 (70.5 mg, 72.8
CH2Cl2/MeOH (1:1, v/v, 2 mL) at 0 ꢁC was added TsOH$H2O (1.2 mg,
7.1 mol). The resultant solution was stirred at room temperature
for 3 h before it was quenched with Et3N (2.0 L, 14 mol). The
mixture was concentrated under reduced pressure. Purification of
the residue by flash column chromatography (silica gel, 20e30%
mmol) in
m
m
m
4.1.22. Ketone 30. To a solution of diol 29 (110 mg, 0.128 mmol) and
2,6-lutidine (44.7
m
L, 0.384 mmol) in CH2Cl2 (1.3 mL) at 0 ꢁC was
EtOAc/hexanes) gave a ketodiol (50.3 mg, 93%) as a colorless oil:
25
added TESOTf (72.3
mL, 0.319 mmol). The resultant solution was
[a
]
ꢀ37.0 (c 0.2, CHCl3); IR (film) 2859, 1069, 826, 757 cmꢀ1
;
1H
D
stirred at room temperature for 2 h before it was diluted with
EtOAc. The mixture was washed with saturated aqueous NH4Cl
solution and brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. Purification of the residue by column
chromatography (silica gel, 10e20% EtOAc/hexanes) gave a bis-TES
NMR (500 MHz, CDCl3)
d
7.33e7.25 (m, 10H), 4.55 (d, J¼11.5 Hz,1H),
4.52 (d, J¼11.5 Hz, 1H), 4.45 (d, J¼12.5 Hz, 1H), 4.41 (d, J¼12.5 Hz,
1H), 4.05 (dd, J¼10.0, 5.0 Hz, 1H), 3.95 (ddd, J¼8.5, 5.5, 4.5 Hz, 1H),
3.74e3.70 (m, 3H), 3.60e3.58 (m, 2H), 3.56e3.50 (m, 2H), 3.35 (d,
J¼9.0 Hz, 1H), 3.24 (dd, J¼9.5, 8.5 Hz, 1H), 2.97 (dd, J¼12.5, 4.0 Hz,
1H), 2.90 (dd, J¼15.5, 5.0 Hz, 1H), 2.73 (br s, 1H), 2.51 (br s, 1H), 2.48
(dd, J¼15.5, 6.0 Hz, 1H), 2.12e2.00 (m, 4H), 1.80 (m, 1H), 1.65 (ddd,
J¼12.0, 11.5, 11.5 Hz, 1H),1.30 (s, 3H),1.13 (s, 3H), 1.02 (s, 9H), 0.97 (s,
ether (132 mg, 94%) as a white foam: [
a
]
D
24 ꢀ38.3 (c 0.6, CHCl3); IR
(film) 2952, 2360, 1093, 775 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
7.33e7.25 (m, 12H), 6.88e6.83 (m, 2H), 4.62 (d, J¼11.5 Hz, 1H),
4.51 (d, J¼12.0 Hz, 1H), 4.46 (d, J¼10.5 Hz, 1H), 4.45 (d, J¼11.5 Hz,
1H), 4.42 (d, J¼12.0 Hz,1H), 4.38 (d, J¼10.5 Hz,1H), 4.08 (dd, J¼10.0,
5.0 Hz, 1H), 3.79 (s, 3H), 3.77e3.70 (m, 2H), 3.69 (dd, J¼11.5, 4.5 Hz,
9H); 13C NMR (125 MHz, CDCl3)
d 211.9, 138.3, 137.7, 128.5 (2C),
128.4 (2C), 127.8, 127.7 (2C), 127.6 (2C), 127.6, 80.4, 80.3, 77.3, 76.6,
76.4, 76.3, 73.8, 73.5, 73.0, 71.4, 70.6, 69.8, 67.6, 66.5, 43.0, 41.3, 33.8,

6612
K. Tsubone et al. / Tetrahedron 67 (2011) 6600e6615
33.0, 27.4 (3C), 27.0 (3C), 22.6, 22.2, 19.9, 10.1; HRMS (ESI) calcd for
for 25 h before it was treated with 3 M aqueous NaOH solution
(20 mL). The mixture was extracted with EtOAc, and the organic
layer was washed with 3 M aqueous NaOH solution and brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by column chromatography (silica gel,
0e20% EtOAc/hexanes) gave phenyltetrazolyl sulfone 44 (520 mg,
C41H60O10SiNa [(MþNa)þ] 763.3848, found 763.3838.
To a solution of the above ketodiol (43.6 mg, 45.0 mmol) in EtCN/
Et3SiH (4:1, v/v, 0.5 mL) at ꢀ78 ꢁC was added TMSOTf (61
mL,
0.34 mmol). The resultant solution was stirred at ꢀ78 ꢁC for
100 min before it was quenched with saturated aqueous NaHCO3
solution. The mixture was extracted with EtOAc, and the organic
layer was washed with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. Purification of the residue by
89%) as a colorless oil: [
a
]
24 þ4.2 (c 0.4, CHCl3); IR (film) 3069, 2929,
D
2884, 2857, 1596, 1498, 1463, 1391, 1254, 1103, 1027, 841, 763, cmꢀ1
;
1H NMR (600 MHz, CDCl3)
d 7.68e7.66 (m, 2H), 7.62e7.57 (m, 3H),
flash column chromatography (silica gel, 10e30% EtOAc/hexanes)
4.03 (dd, J¼14.8, 4.8 Hz, 1H), 3.70 (dd, J¼10.0, 4.8 Hz, 1H), 3.53 (dd,
J¼14.8, 7.9 Hz, 1H), 3.48 (dd, J¼10.0, 5.5 Hz, 1H), 2.45 (m, 1H), 1.14
(d, J¼6.9 Hz, 3H), 0.87 (s, 9H), 0.03 (s, 6H); 13C NMR (150 MHz,
25
gave alcohol 6 (24.1 mg, 74%) as a solid: mp: 216e217 ꢁC; [
a]
D
ꢀ41.1 (c 0.26, CHCl3); IR (film) 2933, 2859, 1472, 1363, 1084, 827,
757 cmꢀ1; 1H NMR (600 MHz, CDCl3)
7.33e7.24 (m, 10H), 4.58 (d,
d
CDCl3) d 154.0, 133.1, 131.4, 129.7 (2C), 125.1 (2C), 66.1, 58.6, 31.2,
J¼11.7 Hz, 1H), 4.50 (d, J¼12.0 Hz, 1H), 4.44 (d, J¼12.0 Hz, 1H), 4.42
(d, J¼12.0 Hz, 1H), 4.11 (dd, J¼10.0, 4.8 Hz, 1H), 3.80e3.74 (m, 2H),
3.63 (ddd, J¼9.3, 9.1, 2.7 Hz, 1H), 3.53 (dd, J¼10.0, 4.9 Hz, 1H),
3.58e3.50 (m, 3H), 3.32 (ddd, J¼11.7, 10.0, 4.5 Hz, 1H), 3.20e3.12
(m, 3H), 3.03 (dd, J¼12.4, 3.8 Hz, 1H), 2.43 (br s, 1H), 2.36 (ddd,
J¼11.7, 4.4, 4.1 Hz, 1H), 2.21 (ddd, J¼12.0, 4.4, 4.1 Hz, 1H), 2.18 (m,
1H), 2.08 (dd, J¼11.7, 4.1 Hz, 1H), 1.71 (ddd, J¼12.0, 11.7, 11.7 Hz, 1H),
1.64e1.59 (m, 1H), 1.57 (ddd, J¼11.7, 11.7, 11.7 Hz, 1H), 1.49 (dd,
J¼11.7, 11.6 Hz, 1H), 1.27 (s, 3H), 1.21 (s, 3H), 1.02 (s, 9H), 0.98 (s, 9H);
25.8 (3C), 18.2, 16.8, ꢀ5.5, ꢀ5.6; HRMS (ESI) calcd for
C17H28N4O3SSiNa [(MþNa)þ] 419.1544, found 419.1524.
4.1.26. Trisubstituted olefin 46. To a solution of i-Pr2NH (76
0.54 mmol) in THF (300
L) at 0 ꢁC was added n-BuLi (2.6 M solu-
tion in hexane, 188
mL,
m
m
L, 0.490 mmol). After being stirred at 0 ꢁC for
30 min, the solution was cooled to ꢀ78 ꢁC. To the solution was
added
a solution of phenyltetrazolyl sulfone 44 (215 mg,
0.544 mmol) in THF (500 mL). The resultant solution was stirred at
13C NMR (150 MHz, CDCl3)
d
138.6, 137.8, 128.4 (2C), 128.3 (2C),
ꢀ78 ꢁC for 30 min and then transferred to a suspension of methyl
127.9 (2C), 127.8, 127.6 (2C), 127.4, 82.5, 79.7, 78.0, 77.25, 77.15,
77.12, 76.6, 73.5, 72.8, 72.4, 70.8, 70.0, 69.5, 67.7, 66.8, 43.0, 33.0,
32.5, 30.2, 27.4 (3C), 27.0 (3C), 22.6, 19.9,16.1, 10.2; HRMS (ESI) calcd
for C41H61O9Si [(MþH)þ] 725.4079, found 725.4108.
ketone 38 (14.8 mg, 54.4 mmol) and anhydrous CeCl3 (134 mg,
0.545 mmol) in THF (800
m
L) at ꢀ78 ꢁC. The resultant mixture was
gradually allowed to warm to 0 ꢁC over 70 min before it was
quenched with saturated aqueous NH4Cl solution. The mixture was
filtered through a pad of Celite, and the filtrate was extracted twice
with EtOAc. The organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. Purifi-
cation of the residue by column chromatography (silica gel, 0e5%
Et2O/hexanes) gave olefin 45 (19.2 mg, 80%, an inseparable 1.6:1
mixture of (E)- and (Z)-isomers) as a colorless oil: IR (film) 2955,
4.1.24. Acetate 31. To a solution of alcohol 6 (1.4 mg, 1.9
mmol) in
pyridine (100 L) was added Ac2O (50 L). The resultant solution
m
m
was stirred at room temperature for 2 h before it was diluted with
EtOAc. The mixture was washed successively with 1 M aqueous HCl
solution, saturated aqueous NaHCO3 solution, and brine. The or-
ganic layer was dried over Na2SO4, filtered, and concentrated under
reduced pressure. Purification of the residue by flash column
2929, 2856, 1471, 1255,1126, 1255, 836, 774, cmꢀ1; [
a
]
22 þ16.9 (c 1.4
D
CHCl3); 1H NMR (600 MHz, CDCl3, (E)-isomer)
d
4.91 (d, J¼8.6 Hz,
chromatography (silica gel, 20% EtOAc/hexanes) gave acetate 31
1H), 3.83 (m, 1H), 3.45 (dd, J¼9.6, 3.8 Hz, 1H), 3.31e3.22 (m, 3H),
3.11 (dd, J¼9.6, 9.6 Hz, 1H), 2.61e2.51 (m, 2H), 1.97 (m, 1H), 1.86 (dd,
J¼14.4, 9.6 Hz, 1H), 1.64 (s, 3H), 1.64e1.56 (m, 2H), 1.41 (m, 1H), 0.92
(d, J¼6.5 Hz, 3H), 0.87 (s, 9H), 0.87 (s, 9H), 0.04 (s, 6H), 0.01 (s, 6H);
22
(1.4 mg, 95%) as a colorless oil: [
a]
ꢀ33.7 (c 0.5, CHCl3); IR (film)
D
2939, 2858, 2360, 1750, 1457, 1221, 1084, 1056, 772, 669 cmꢀ1
;
1H
NMR (600 MHz, CDCl3)
d
7.34e7.24 (m, 10H), 4.98 (d, J¼10.0 Hz,
1H), 4.59 (d, J¼11.3 Hz, 1H), 4.50 (d, J¼12.0 Hz, 1H), 4.43 (d,
J¼12.0 Hz, 1H), 4.39 (d, J¼11.3 Hz, 1H), 3.97 (dd, J¼10.0, 4.8 Hz, 1H),
3.76 (ddd, J¼11.0, 11.0, 4.9 Hz, 1H), 3.73 (dd, J¼10.0, 10.0 Hz, 1H),
3.63 (ddd, J¼9.3, 9.3, 2.8 Hz, 1H), 3.57e3.49 (m, 3H), 3.38 (ddd,
J¼12.0, 9.7, 4.5 Hz, 1H), 3.23 (dd, J¼12.4, 3.8 Hz, 1H), 3.19 (dd,
J¼10.0, 10.0 Hz, 1H), 3.17 (ddd, J¼10.6, 10.6, 5.1 Hz, 1H), 2.96 (dd,
J¼12.7, 3.8 Hz, 1H), 2.26e2.15 (m, 3H), 2.10 (s, 3H), 2.08 (m, 1H) 1.69
(ddd, J¼11.7, 11.6, 11.6 Hz, 1H), 1.64e1.46 (m, 4H), 1.27 (s, 3H), 1.19 (s,
1H NMR (600 MHz, CDCl3, (Z)-isomer)
d
5.00 (d, J¼9.7 Hz, 1H), 3.83
(m, 1H), 3.43 (dd, J¼9.6, 5.8 Hz, 1H), 3.30 (dd, J¼9.6, 7.6 Hz, 1H),
3.27e3.23 (m, 2H), 3.10 (ddd, J¼11.0, 8.9, 2.0 Hz, 1H), 2.59 (m, 1H),
2.49 (d, J¼13.7 Hz, 1H), 2.07 (dd, J¼13.7, 10.3 Hz, 1H) 1.98 (m, 1H),
1.73 (s, 3H), 1.69e1.58 (m, 2H), 1.42 (m, 1H), 0.91 (d, J¼6.8 Hz, 3H),
0.88 (s, 9H), 0.88 (s, 9H), 0.06 (s, 6H), 0.02 (s, 3H), 0.02 (s, 3H); 13C
NMR (150 MHz, CDCl3, (E)-isomer)
d 133.3, 129.0, 81.6, 71.3, 68.1,
67.7, 42.4, 35.5, 33.7, 26.0 (3C), 25.8 (3C), 25.7, 18.4, 18.0, 17.5, 16.7,
ꢀ3.9, ꢀ4.7, ꢀ5.3, ꢀ5.4; HRMS (ESI) calcd for C24H50O3Si2Na
[(MþNa)þ] 465.3191, found 465.3217.
3H), 1.00 (s, 9H), 0.96 (s, 9H); 13C NMR (150 MHz, CDCl3)
d 170.1,
138.7,137.9,128.4 (2C),128.3 (2C),127.9 (2C),127.8,127.6 (2C),127.4,
81.0, 79.8, 78.3, 77.4, 77.2, 76.5,76.3, 73.4, 72.8, 72.4, 70.8, 69.9, 69.5,
67.6, 66.8, 43.2, 32.9, 32.6, 30.2, 27.4 (3C), 27.1 (3C), 22.6, 21.1, 19.9,
16.2, 11.0; HRMS (ESI) calcd for C43H63O10Si [(MþH)þ] 767.4185,
found 767.4184.
4.1.27. Pivaloate ester 47. To a solution of alcohol 6 (10.8 mg,
14.9
m
mol) and 2,6-lutidine (12
m
L, 0.10 mmol) in CH2Cl2 (0.5 mL) at
mol). The resultant solution was
0 ꢁC was added TESOTf (17
mL, 75
m
stirred at room temperature for 2 h before it was diluted with
EtOAc. The mixture was washed with saturated aqueous NH4Cl
solution and brine. The organic layer was dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. Purification of the
residue by column chromatography (silica gel, 0e10% EtOAc/hex-
4.1.25. Phenyltetrazolyl sulfone 44. To a solution of alcohol 4546
(340 mg, 1.68 mmol), 1-phenyl-1H-tetrazole-5-thiol (330 mg, 1.85
mmol), and PPh3 (485 mg, 1.85 mmol) in THF (8.4 mL) at 0 ꢁC was
added DIAD (1.9 M solution in toluene, 0.97 mL, 1.8 mmol). The
resultant solution was stirred at room temperature overnight and
concentrated under reduced pressure. Purification by flash column
chromatography (silica gel, 2e5% Et2O/hexanes) gave a sulfide
(540 mg, 88%), which was used in the next reaction without further
purification.
anes) gave a TES ether (12.1 mg, 97%) as a white foam: [
a
]
24 ꢀ36.7 (c
D
1.5, CHCl3); IR (film) 2952, 2875, 1472, 1385, 1363, 1107, 1082, 1027,
827, 739 cmꢀ1 1H NMR (600 MHz, CDCl3)
; d 7.33e7.25 (m, 10H),
4.59 (d, J¼11.3 Hz, 1H), 4.50 (d, J¼12.0 Hz, 1H), 4.44 (d, J¼12.0 Hz,
1H), 4.43 (d, J¼11.3 Hz, 1H), 4.03 (dd, J¼10.3, 4.8 Hz, 1H), 3.75e3.70
(m, 2H), 3.64 (ddd, J¼9.3, 8.7, 2.8 Hz, 1H), 3.58 (m, 3H), 3.42 (d,
J¼9.3 Hz, 1H), 3.25 (ddd, J¼9.6, 7.9, 5.9 Hz, 1H), 3.16 (ddd, J¼12.2,
10.6, 5.2 Hz, 1H), 3.07 (dd, J¼12.4, 3.8 Hz, 1H), 3.02 (dd, J¼9.7,
To a solution of the above phenyltetrazolyl sulfide (540 mg,
1.48 mmol) in CH2Cl2 (8.0 mL) at 0 ꢁC was added m-CPBA (639 mg,
3.70 mmol). The resultant solution was stirred at room temperature

K. Tsubone et al. / Tetrahedron 67 (2011) 6600e6615
6613
9.6 Hz, 1H), 2.97 (dd, J¼12.4, 3.5 Hz, 1H), 2.23e2.13 (m, 3H), 2.04
(dd, J¼11.3, 4.4 Hz, 1H), 1.70 (ddd, J¼12.0, 11.7, 11.7 Hz, 1H), 1.62 (m,
1H),1.50 (ddd, J¼12.0,11.7,11.6 Hz,1H),1.46 (dd, J¼11.7,11.6 Hz,1H),
1.20 (s, 3H), 1.18 (s, 3H), 1.02 (s, 9H), 0.98 (s, 9H), 0.91 (t, J¼7.9 Hz,
30% EtOAc/hexanes) gave a ketone (31.6 mg, 80%) as a colorless oil:
24
[a
]
ꢀ2.9 (c 0.27, CHCl3); IR (film) 3444, 2957, 2875, 2070, 1726,
D
1633, 1472, 1136, 1083, 826 cmꢀ1
;
1H NMR (600 MHz, CDCl3)
d
4.16e4.10 (m, 2H), 4.07 (dd, J¼7.2, 4.1 Hz, 1H), 4.02 (dd, J¼10.0,
9H), 0.56 (q, J¼7.9 Hz, 6H); 13C NMR (150 MHz, CDCl3)
d
138.7,138.0,
4.8 Hz, 1H), 3.73 (ddd, J¼10.7, 9.6, 4.8 Hz, 1H), 3.71 (dd, J¼10.0,
10.0 Hz, 1H), 3.54 (ddd, J¼9.6, 9.6, 4.9 Hz, 1H), 3.47 (dd, J¼12.7,
5.5 Hz, 1H), 3.43 (d, J¼9.3 Hz, 1H) 3.29 (ddd, J¼12.0, 9.7, 4.1 Hz, 1H),
3.07 (d, J¼9.2 Hz, 1H), 3.00 (dd, J¼14.0, 4.0 Hz, 1H), 2.75 (dd, J¼17.2,
5.5 Hz, 1H), 2.42 (dd, J¼17.2, 12.7 Hz, 1H), 2.22e2.13 (m, 3H), 1.95
(ddd, J¼14.1, 13.7, 6.5 Hz, 1H), 1.71 (ddd, J¼11.7, 11.7, 11.6 Hz, 1H),
1.65 (dd, J¼12.0, 11.7 Hz, 1H), 1.29 (s, 3H), 1.20 (s, 3H), 1.15 (s, 9H),
1.01 (s, 9H), 0.97 (s, 9H), 0.88 (t, J¼7.9 Hz, 9H), 0.52 (q, J¼7.9 Hz, 6H);
128.4 (2C), 128.3 (2C), 127.9 (2C), 127.7, 127.6 (2C), 127.4, 83.4, 79.5,
78.3, 77.9, 77.43, 77.37, 73.8, 72.8, 72.5, 71.0, 69.7, 69.5, 67.7, 66.8,
60.4, 43.3, 33.2, 32.6, 30.1, 27.5 (3C), 27.1 (3C), 22.6, 19.9, 16.2, 10.3,
6.8 (3C), 5.1 (3C); HRMS (ESI) calcd for C47H74O9Si2Na [(MþNaþ)]
861.4764, found 861.4781.
To a solution of the above TES ether (16.3 mg, 19.4 mmol) in
EtOAc (0.5 mL) was added 20 wt % Pd(OH)2/C (1.6 mg). The re-
sultant mixture was stirred at room temperature under an atmo-
sphere of H2 (balloon) for 27 h before it was filtered through a pad
of Celite. The filtrate was concentrated under reduced pressure, and
the residue was purified by flash column chromatography (silica
13C NMR (150 MHz, CDCl3)
d 207.1, 178.5, 83.2, 78.5, 78.0, 77.8, 77.4,
76.6, 74.4, 73.8, 72.8, 69.8, 67.7, 60.6, 42.9, 41.0, 38.8, 33.3, 30.2, 27.6
(3C), 27.24 (3C), 27.18 (3C), 22.7, 20.1, 15.6, 10.4, 6.8 (3C), 5.0 (3C);
HRMS (ESI) calcd for C38H68O10Si2Na [(MþNaþ)] 763.4243, found
763.4235.
gel, 30e100% EtOAc/hexanes) to give a diol (12.4 mg, 97%) as
22
a colorless oil: [
a]
ꢀ14.8 (c 0.74, CHCl3); IR (film) 3363, 2952,
To a suspension of Ph3PCH3Br (56.6 mg, 0.158 mmol) in THF
D
2876, 1472, 1386, 1106, 1080, 1058, 1010, 826, 759 cmꢀ1
;
1H NMR
(300 m mL,
L) at 0 ꢁC was added NaHMDS (1.0 M solution in THF, 153
(600 MHz, CDCl3)
d
4.02 (dd, J¼10.0, 4.8 Hz, 1H), 3.82e3.69 (m, 4H),
0.153 mmol), and the resultant mixture was stirred at 0 ꢁC for
30 min. To this suspension was added a solution of the above ke-
3.57 (m, 1H), 3.53 (ddd, J¼9.6, 9.6, 4.9 Hz, 1H), 3.44 (m, 1H), 3.42 (d,
J¼9.7 Hz, 1H), 3.26 (ddd, J¼12.0, 9.6, 4.1 Hz, 1H), 3.07 (ddd, J¼11.7,
3.4, 2.4 Hz, 1H), 3.07 (d, J¼11.7 Hz, 1H), 3.04 (d, J¼9.6 Hz, 1H), 2.68
(br s, 1H), 2.18 (ddd, J¼12.0, 4.4, 4.4 Hz, 1H), 2.15 (ddd, J¼12.0, 4.1,
4.1 Hz, 1H), 2.09 (dd, J¼11.3, 4.4 Hz, 1H), 1.95 (m, 1H), 1.76 (dddd,
J¼14.8, 7.2, 6.9, 3.4 Hz, 1H), 1.69 (ddd, J¼11.7, 11.7, 11.6 Hz, 1H), 1.58
(ddd, J¼12.0, 12.0, 11.3 Hz, 1H), 1.52 (dd, J¼11.6, 11.3 Hz, 1H), 1.24 (s,
3H), 1.19 (s, 3H), 1.01 (s, 9H), 0.97 (s, 9H), 0.90 (t, J¼7.9 Hz, 9H), 0.54
tone (39.1 mg, 0.158 mmol) in THF (230 mL). The resultant solution
was stirred at 0 ꢁC for 1 h before it was quenched with saturated
aqueous NH4Cl solution. The mixture was extracted twice with
EtOAc, and the organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. Purifi-
cation of the residue by column chromatography (silica gel, 0e10%
EtOAc/hexanes) gave an exo-olefin (32.5 mg, 83%) as a colorless oil:
25
(q, J¼7.9 Hz, 6H); 13C NMR (150 MHz, CDCl3)
d
83.5, 79.3, 78.4, 77.8,
[a
]
ꢀ23.6 (c 0.26, CHCl3); IR (film) 2955, 2360, 1731, 1474, 1161,
D
77.4, 76.8, 74.8, 73.8, 73.1, 70.6, 69.7, 67.7, 61.1, 43.2, 35.4, 33.2 (2C),
27.5 (3C), 27.1 (3C), 22.6, 20.0, 16.2, 10.3, 6.8 (3C), 4.9 (3C); HMRS
(ESI) calcd for C33H63O9Si2 [(MþH)þ] 659.4005, found 659.3996.
1082, 827 cmꢀ1 1H NMR (600 MHz, CDCl3)
; d 4.85 (s, 1H), 4.80 (s,
1H), 4.21e4.14 (m, 3H), 4.02 (dd, J¼10.0, 4.8 Hz, 1H), 3.72 (m, 1H),
3.71 (dd, J¼10.0, 10.0 Hz, 1H), 3.53 (ddd, J¼9.7, 9.6, 4.9 Hz, 1H), 3.42
(d, J¼9.3 Hz, 1H), 3.26 (ddd, J¼12.1, 9.6, 4.1 Hz, 1H), 3.09 (dd, J¼10.7,
4.4 Hz, 1H), 3.07 (dd, J¼10.3, 4.4 Hz, 1H), 3.04 (dd, J¼9.7, 9.7 Hz, 1H),
2.43 (dd, J¼13.7, 4.5 Hz, 1H), 2.30 (dd, J¼13.7, 13.1 Hz,1H), 2.18 (ddd,
J¼15.8, 4.1, 4.1 Hz, 1H), 2.08 (m, 1H), 2.08 (dd, J¼13.0, 4.5 Hz, 1H),
1.80 (ddd, J¼17.2, 10.6, 5.8 Hz, 1H), 1.70 (ddd, J¼11.7, 11.7, 11.6 Hz,
1H),1.51 (dd, J¼11.7,11.3 Hz,1H),1.23 (s, 3H),1.19 (s, 3H),1.17 (s, 9H),
1.01 (s, 9H), 0.97 (s, 9H), 0.91 (t, J¼7.9 Hz, 9H), 0.55 (q, J¼7.9 Hz, 6H);
To a solution of the above diol (22.7 mg, 34.5
mmol) in pyridine
(0.5 mL) at 0 ꢁC was added PivCl (4.5
mL, 36 mmol). The resultant
solution was stirred at 0 ꢁC for 1 h before it was treated with H2O
and EtOAc. The mixture was stirred at room temperature for 1 h
and then extracted with EtOAc. The organic layer was washed with
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. Purification of the residue by column chromatography
(silica gel, 10e20% EtOAc/hexanes) gave pivaloate ester 47 (21.8 mg,
13C NMR (150 MHz, CDCl3)
d 178.5, 144.9, 109.9, 83.2, 81.9, 78.3,
24
85%) as a colorless oil: [
a
]
ꢀ28.2 (c 0.16, CHCl3); IR (film) 2955,
77.9, 77.4, 77.0, 73.8, 73.0, 69.7, 67.7, 67.1, 61.3, 43.3, 38.7, 34.7, 33.2,
30.8, 27.5 (3C), 27.2 (3C), 27.1 (3C), 22.6, 20.0, 15.8, 10.3, 6.8 (3C), 4.9
(3C); HRMS (ESI) calcd for C39H70O9Si2Na [(MþNa)þ] 761.4451,
found 761.4468.
D
2876, 1729, 1463, 1385, 1287, 1080, 826 cmꢀ1
;
1H NMR (600 MHz,
CDCl3)
d
4.19 (ddd, J¼10.6, 6.9, 5.2 Hz, 1H), 4.13 (dd, J¼7.9, 6.2 Hz,
1H), 4.02 (dd, J¼10.0, 4.8 Hz, 1H), 3.72 (m, 1H), 3.71 (dd, J¼10.3,
10.0 Hz,1H), 3.54 (ddd, J¼10.0, 9.6, 4.9 Hz,1H), 3.45 (ddd, J¼9.0, 9.0,
3.1 Hz, 1H), 3.42 (d, J¼9.3 Hz, 1H), 3.39 (ddd, J¼11.0, 10.7, 5.2 Hz,
1H), 3.26 (ddd, J¼12.0, 11.7, 4.4 Hz, 1H), 3.07 (dd, J¼12.4, 3.4 Hz,1H),
3.06 (m, 2H), 2.18 (ddd, J¼12.0, 4.5, 4.1 Hz, 1H), 2.14 (ddd, J¼12.0,
5.0, 4.4 Hz, 1H), 2.13e2.06 (m, 2H), 1.73e1.65 (m, 2H), 1.56 (ddd,
J¼11.7, 11.7, 11.6 Hz, 1H), 1.49 (dd, J¼11.7, 11.7 Hz, 1H), 1.22 (br s, 1H),
1.19 (s, 3H), 1.19 (s, 3H), 1.17 (s, 9H), 1.00 (s, 9H), 0.97 (s, 9H), 0.89 (t,
J¼7.9 Hz, 9H), 0.54 (q, J¼7.9 Hz, 6H); 13C NMR (150 MHz, CDCl3)
To a solution of the above exo-olefin (22.0 mg, 29.8 mmol) in
CH2Cl2 (0.5 mL) at ꢀ78 ꢁC was added DIBALH (1.04 M solution in
hexane, 143 mL, 0.149 mmol). The resultant solution was stirred at
ꢀ78 ꢁC for 2 h before it was quenched with MeOH. The mixture was
diluted with saturated aqueous potassium sodium tartrate solution
and EtOAc, and stirred at room temperature overnight. The layers
were separated, and the organic layer was washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by column chromatography (silica gel,
10e30% EtOAc/hexanes) gave alcohol 48 (18.7 mg, 96%) as a color-
d
178.6, 83.4, 79.4, 78.4, 77.9, 77.4, 77.0, 73.8, 72.8, 71.0, 70.8, 69.7,
67.7, 61.3, 43.1, 38.7, 33.6, 33.2, 31.6, 27.5 (3C), 27.2 (3C), 27.1 (3C),
22.6, 19.9, 16.0, 10.3, 6.8 (3C), 4.9 (3C); HRMS (ESI) calcd for
C38H70O10Si2 [(MþNa)þ] 765.4400, found 765.4394.
less oil: [
a
]
D
25 ꢀ22.7 (c 0.67, CHCl3); IR (film) 3565, 2950, 2875, 2351,
1472, 1136, 1081, 1062, 826 cmꢀ1; 1H NMR (600 MHz, CDCl3)
d 4.86
(s, 1H), 4.79 (s, 1H), 4.32 (d, J¼7.9 Hz, 1H), 4.02 (dd, J¼10.3, 4.8 Hz,
1H), 3.81e3.68 (m, 3H), 3.70 (dd, J¼10.3, 10.0 Hz, 1H), 3.54 (ddd,
J¼9.8, 9.7, 4.8 Hz, 1H), 3.43 (d, J¼9.3 Hz, 1H), 3.27 (ddd, J¼11.6, 9.7,
4.1 Hz, 1H), 3.12 (dd, J¼12.7, 4.5 Hz, 1H), 3.07 (dd, J¼12.4, 3.8 Hz,
1H), 3.05 (dd, J¼9.6, 9.3 Hz, 1H), 2.76 (br s, 1H), 2.43 (dd, J¼13.4,
4.5 Hz, 1H), 2.30 (dd, J¼13.1, 12.7 Hz, 1H), 2.18 (ddd, J¼9.2, 4.4,
4.1 Hz, 1H), 2.10 (dd, J¼11.3, 4.4 Hz, 1H), 1.97 (m, 1H), 1.86 (dddd,
J¼9.3, 9.1, 7.9, 4.5 Hz, 1H), 1.69 (ddd, J¼11.7, 11.7, 11.6 Hz, 1H), 1.56
(dd, J¼11.7, 11.3 Hz, 1H), 1.29 (s, 3H), 1.19 (s, 3H), 1.01 (s, 9H), 0.97 (s,
9H), 0.91 (t, J¼7.9 Hz, 9H), 0.55 (q, J¼7.9 Hz, 6H); 13C NMR
4.1.28. Primary alcohol 48. To a solution of alcohol 47 (39.8 mg,
53.6 mmol) in CH2Cl2 (0.5 mL) was added DesseMartin periodinane
(68.0 mg, 0.161 mmol), and the resultant solution was stirred at
room temperature for 50 min before it was quenched with a 1:1
mixture of saturated aqueous NaHCO3 solution and saturated
aqueous Na2S2O3 solution (2 mL). The mixture was extracted with
EtOAc, and the organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. Purifi-
cation of the residue by flash column chromatography (silica gel,

6614
K. Tsubone et al. / Tetrahedron 67 (2011) 6600e6615
(150 MHz, CDCl3)
d
144.4, 110.5, 83.2, 81.4, 78.3, 77.8, 77.4, 76.8,
hexanes) gave (E)-olefin 5 (2.9 mg, 58%) and (Z)-olefin 49 (0.9 mg,
73.8, 73.5, 71.7, 69.7, 67.7, 61.4, 43.4, 34.4, 33.6, 33.2, 27.5 (3C), 27.1
(3C), 22.6, 20.0, 16.0. 10.3, 6.8 (3C), 4.9 (3C); HRMS (ESI) calcd for
C34H63O8Si2 [(MþH)þ] 655.4056, found 655.4069.
18%) as colorless oils, respectively. Data for (E)-olefin 5: [
a
]
24 ꢀ23.1
D
(c 0.3, CHCl3); IR (film) 3441, 2954, 1645, 1471, 1083, 835 cmꢀ1
;
1H
NMR (600 MHz, C6D6)
d
5.09 (d, J¼8.2 Hz, 1H), 4.82 (s, 1H), 4.77 (s,
1H), 4.26 (dd, J¼10.0, 4.8 Hz, 1H), 4.14 (dd, J¼8.6, 3.4 Hz, 1H), 3.90
(dd, J¼10.0, 10.0 Hz, 1H), 3.79 (ddd, J¼11.0, 9.6, 4.4 Hz, 1H), 3.73
(ddd, J¼10.0, 9.6, 4.8 Hz, 1H), 3.56 (d, J¼9.3 Hz, 1H), 3.51 (dd, J¼9.6,
5.9 Hz, 1H), 3.39 (dd, J¼9.6, 7.2 Hz, 1H), 3.21 (ddd, J¼11.6, 9.6,
4.4 Hz, 1H), 3.14 (dd, J¼12.7, 4.5 Hz, 1H), 3.09 (dd, J¼9.6, 9.3 Hz, 1H),
2.82 (dd, J¼12.4, 3.8 Hz, 1H), 2.68 (m, 1H), 2.58 (dd, J¼13.1, 4.5 Hz,
1H), 2.45 (dd, J¼13.4, 3.4 Hz, 1H), 2.37 (dd, J¼13.1, 12.7 Hz, 1H), 2.32
(dd, J¼13.4, 8.6 Hz, 1H), 2.25 (ddd, J¼11.7. 4.4, 3.8 Hz, 1H), 2.18 (dd,
J¼11.4, 4.4 Hz,1H),1.85 (ddd, J¼12.4,11.7,11.0 Hz,1H),1.69e1.65 (m,
4H),1.27 (s, 3H),1.21 (s, 3H),1.14 (s, 9H),1.13 (t, J¼7.9 Hz, 9H),1.08 (s,
9H), 1.05 (d, J¼6.9 Hz, 3H), 0.99 (s, 9H), 0.78 (q, J¼7.9 Hz, 6H), 0.07
4.1.29. Methyl ketone 36. To a solution of alcohol 48 (9.2 mg,
14
mmol) in CH2Cl2 (0.5 mL) was added DesseMartin periodinane
(17.9 mg, 42.3
mmol). The resultant mixture was stirred at room
temperature for 25 min before it was quenched with a 1:1 mixture
of saturated aqueous NaHCO3 solution and saturated aqueous
Na2S2O3 solution (2 mL). The mixture was extracted with EtOAc,
and the organic layer was washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The crude al-
dehyde thus obtained was used in the next reaction without further
purification.
To a solution of the above crude aldehyde in Et2O (0.5 mL) at
(s, 3H), 0.07 (s, 3H); 13C NMR (150 MHz, C6D6)
d 146.0, 132.8, 130.1,
ꢀ78 ꢁC was added MeMgBr (3.0 M solution in Et2O, 47
m
L,
110.0, 83.8, 82.3, 78.5, 78.4, 77.9, 77.2, 74.4, 72.9, 70.3, 69.4, 68.4,
68.2, 43.9, 42.5, 35.9, 35.5, 33.8, 27.7 (3C), 27.3 (3C), 26.1 (3C), 22.8,
20.1, 18.5, 17.7, 16.9, 15.9, 10.5, 7.2 (3C), 5.5 (3C), ꢀ5.1, ꢀ5.2; HRMS
(ESI) calcd for C45H84O8Si3Na [(MþNa)þ] 859.5366, found
0.14 mmol), and the resultant solution was stirred at ꢀ78 ꢁC for
15 min before it was quenched with saturated aqueous NH4Cl so-
lution. The mixture was extracted twice with EtOAc, and the or-
ganic layer was washed with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was filtered
through a short pad of silica gel to give a crude alcohol, which was
used in the next reaction without further purification.
859.5388. Data for (Z)-olefin 49: [
a]
24 ꢀ12.4 (c 0.1, CHCl3); IR (film)
D
2951, 2361, 1698, 1507, 1220, 1082, 841, 773 cmꢀ1
;
1H NMR
(600 MHz, C6D6)
d
5.12 (d, J¼9.6 Hz, 1H), 4.78 (s, 1H), 4.74 (s, 1H),
4.26 (dd, J¼10.3, 4.8 Hz, 1H), 4.11 (d, J¼8.9 Hz, 1H), 3.89 (dd, J¼10.0,
10.0 Hz, 1H), 3.78 (ddd, J¼9.6, 9.3, 5.2 Hz, 1H), 3.73 (dd, J¼9.7,
4.5 Hz, 1H), 3.69 (dd, J¼9.7, 5.2 Hz, 1H), 3.56 (d, J¼8.9 Hz, 1H), 3.35
(dd, J¼9.3, 7.9 Hz, 1H), 3.18 (ddd, J¼11.7, 9.6, 4.1 Hz, 1H), 3.14e3.10
(m, 2H), 2.79 (dd, J¼12.4, 3.4 Hz, 1H), 2.75 (m, 1H), 2.57 (dd, J¼13.1,
4.5 Hz, 1H), 2.45 (dd, J¼13.7, 10.0 Hz, 1H), 2.39e2.34 (m, 2H), 2.22
(ddd, J¼12.8, 4.4, 4.4 Hz, 1H), 2.18 (dd, J¼11.3. 4.1 Hz, 1H), 1.84 (ddd,
J¼11.7, 11.7, 11.3 Hz, 1H), 1.77 (d, J¼1.4 Hz, 3H), 1.70 (dd, J¼12.1,
11.6 Hz, 1H), 1.31 (s, 3H), 1.18 (s, 3H), 1.14 (s, 9H), 1.13 (d, J¼6.5 Hz,
3H), 1.12 (t, J¼7.9 Hz, 9H), 1.08 (s, 9H), 1.00 (s, 9H), 0.78 (q, J¼7.9 Hz,
To a solution of the above alcohol (9.2 mg, 14
(0.5 mL) was added DesseMartin periodinane (12.4 mg, 29.2
m
mol) in CH2Cl2
mol).
m
The resultant solution was stirred at room temperature for 25 min
before it was quenched with a 1:1 mixture of saturated aqueous
NaHCO3 solution and saturated aqueous Na2S2O3 solution (2 mL).
The mixture was extracted with EtOAc, and the organic layer was
washed with brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. Purification of the residue by column
chromatography (silica gel, 0e15% EtOAc/hexanes) gave methyl
23
ketone 36 (4.8 mg, 51% for the three steps) as a colorless oil: [
a
]
6H), 0.11 (s, 3H), 0.11 (s, 3H); 13C NMR (150 MHz, C6D6)
d 146.2,
D
ꢀ12.4 (c 0.48, CHCl3); IR (film) 2951, 1721, 1471, 1083, 1011, 826,
132.8, 130.3, 109.9, 83.9, 82.3, 78.5, 78.3, 77.8, 77.2, 74.4, 72.9,
70.3, 69.0, 68.3, 68.2, 44.0, 35.7, 35.3, 34.9, 33.7, 27.7 (3C), 27.3
(3C), 26.2 (3C), 24.3, 22.9, 20.1, 18.6, 17.9, 15.8, 10.4, 7.2 (3C), 5.5
(3C), ꢀ5.0, ꢀ5.3; HRMS (ESI) calcd for C45H84O8Si3Na [(MþNa)þ]
859.5366, found 859.5392.
744 cmꢀ1 1H NMR (600 MHz, C6D6)
;
d
4.66 (s, 1H), 4.57 (dd, J¼7.6,
4.1 Hz, 1H), 4.45 (s, 1H), 4.26 (dd, J¼10.0, 4.9 Hz, 1H), 3.89 (dd,
J¼10.0, 10.0 Hz, 1H), 3.79 (ddd, J¼10.7, 10.1, 4.8 Hz, 1H), 3.73 (ddd,
J¼9.6, 9.6, 4.8 Hz, 1H), 3.50 (d, J¼9.3 Hz, 1H), 3.14 (ddd, J¼11.7, 9.6,
4.1 Hz, 1H), 3.07 (dd, J¼9.2, 9.2 Hz, 1H), 3.05 (dd, J¼12.4, 4.4 Hz, 1H),
2.78 (dd, J¼12.4, 3.8 Hz, 1H), 2.51 (dd, J¼13.0, 4.4 Hz, 1H), 2.44 (dd,
J¼15.5, 8.3 Hz, 1H), 2.32 (dd, J¼13.0 Hz, 1H), 2.27 (dd, J¼15.5, 4.1 Hz,
1H), 2.24 (ddd, J¼11.7, 4.5, 4.1 Hz, 1H), 2.14 (dd, J¼11.3, 4.1 Hz, 1H),
1.84 (ddd, J¼12.0, 11.7, 11.3 Hz, 1H), 1.75 (s, 3H), 1.60 (dd, J ¼ 11.7 Hz,
11.3 Hz, 1H), 1.28 (s, 3H), 1.18 (s, 3H), 1.14 (s, 9H), 1.12 (t, J¼7.9 Hz,
9H), 1.08 (s, 9H), 0.78 (q, J¼7.9 Hz, 6H); 13C NMR (150 MHz, C6D6)
Acknowledgements
We thank Dr. Y. Kasai (Tohoku University) for measurement of
NMR spectra. This work was supported by a Grant-in-Aid for Sci-
entific Research (A) (No. 21241050) from the Japan Society for the
Promotion of Science (JSPS). A research fellowship for K.T. from JSPS
is thankfully acknowledged.
d
204.5, 145.1, 109.6, 83.8, 82.2, 78.5, 78.4, 77.9, 77.1, 74.4, 73.3, 70.3,
68.2, 68.0, 45.8, 43.8, 35.1, 33.7, 30.6, 27.7 (3C), 27.3 (3C), 22.8, 20.1,
15.7, 10.5, 7.2 (3C), 5.5 (3C); HRMS (ESI) calcd for C35H62O8Si2Na
[(MþNa)þ] 689.3875, found 689.3885.
Supplementary data
4.1.30. Trisubstituted olefin 5. To a solution of i-Pr2NH (25
0.18 mmol) in THF (300
L) at 0 ꢁC was added n-BuLi (2.6 M in
hexane, 62
mL,
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.05.082.
m
m
L, 0.16 mmol). After being stirred at 0 ꢁC for 30 min, the
solution was cooled to ꢀ78 ꢁC. To the solution was added a solution
References and notes
of phenyltetrazolyl sulfone 44 (71.3 mg, 0.180 mmol) in THF
(300
m
L), and the resultant solution was stirred at ꢀ78 ꢁC for
1. (a) Nagai, H.; Torigoe, K.; Satake, M.; Murata, M.; Yasumoto, T.; Hirota, H. J. Am.
Chem. Soc. 1992, 114, 1102e1103; (b) Nagai, H.; Murata, M.; Torigoe, K.; Satake,
M.; Yasumoto, T. J. Org. Chem. 1992, 57, 5448e5453.
2. Morohashi, A.; Satake, M.; Nagai, H.; Oshima, Y.; Yasumoto, T. Tetrahedron 2000,
56, 8995e9001.
3. (a) Fuwa, H.; Goto, T.; Sasaki, M. Org. Lett. 2008, 10, 2211e2214; (b) Fuwa, H.;
Ishigai, K.; Goto, T.; Suzuki, A.; Sasaki, M. J. Org. Chem. 2009, 74, 4024e4040.
4. Nagai, H.; Mikami, Y.; Yazawa, K.; Gonoi, T.; Yasumoto, T. J. Antibiot. 1993, 46,
520e522.
5. Inoue, M.; Hirama, M.; Satake, M.; Sugiyama, K.; Yasumoto, T. Toxicon 2003, 41,
469e474.
30 min. This cold solution was then transferred to a suspension of
methyl ketone 36 (4.0 mg, 6.0
0.180 mmol) in THF (600
mmol) and anhydrous CeCl3 (44.3 mg,
m
L) at ꢀ78 ꢁC. The reaction mixture was
gradually allowed to warm to 0 ꢁC over 2 h before it was quenched
with saturated aqueous NH4Cl solution. The mixture was filtered
through a pad of Celite, and the filtrate was extracted twice with
EtOAc. The organic layer was washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. Purification of
the residue by column chromatography (silica gel, 0e5% Et2O/
6. Sakamoto, B.; Nagai, H.; Hokama, Y. Phycologia 1996, 35, 350e353.

K. Tsubone et al. / Tetrahedron 67 (2011) 6600e6615
6615
7. (a) Kadota, I.; Oguro, N.; Yamamoto, Y. Tetrahedron Lett. 2001, 42, 3645e3647;
(b) Kadota, I.; Takamura, H.; Yamamoto, Y. Tetrahedron Lett. 2001, 42,
3649e3651.
30. For stereochemical assignment of the newly generated secondary alcohol of the
major aldol adduct 24, see Supplementary data.
31. (a) Mukaiyama, T.; Inoue, T. Chem. Lett. 1976, 559e562; (b) Inoue, T.;
8. (a) Clark, J. S.; Fessard, T. C.; Wilson, C. Org. Lett. 2004, 6, 1773e1776; (b) Clark, J.
S.; Kimber, M. C.; Robertson, J.; McErlean, C. S. P.; Wilson, C. Angew. Chem., Int.
Ed. 2005, 44, 6157e6162.
9. (a) Sato, K.; Sasaki, M. Org. Lett. 2005, 7, 2441e2444; (b) Sato, K.; Sasaki, M.
Angew. Chem., Int. Ed. 2007, 46, 2518e2522; (c) Sato, K.; Sasaki, M. Tetrahedron
2007, 63, 5977e6003; (d) Fuwa, H.; Suzuki, A.; Sato, K.; Sasaki, M. Heterocycles
2007, 72, 139e144; (e) Fuwa, H.; Noji, S.; Sasaki, M. Chem. Lett. 2009, 38,
866e867; (f) Fuwa, H.; Noji, S.; Sasaki, M. J. Org. Chem. 2010, 75, 5072e5082.
10. Roberts, S. W.; Rainier, J. D. Org. Lett. 2007, 9, 2227e2230.
11. Saito, T.; Nakata, T. Org. Lett. 2009, 11, 113e116.
Mukaiyama, T. Bull. Chem. Soc. Jpn. 1980, 53, 174e178.
32. (a) Frigero, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019e8022; (b) De
Munari, S.; Frigero, M.; Santagostino, M. J. Org. Chem. 1996, 61, 9272e9279.
33. (a) Moriarty, R. M.; Prakash, O. Org. React. 1999, 54, 273e418; (b) Meyer, S. D.;
Schreiber, S. L. J. Org. Chem. 1994, 59, 7549e7552; (c) Hubbs, J. L.; Heathcock, C.
H. J. Am. Chem. Soc. 2003, 125, 12836e12843.
34. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155e4156; (b) Dess, D. B.;
Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277e7287.
35. (a) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226e2227; (b) Gemal, A. L.; Luche, J.
L. J. Am. Chem. Soc. 1981, 103, 5454e5459.
12. For a preliminary communication see: Tsubone, K.; Hashizume, K.; Fuwa, H.;
Sasaki, M. Tetrahedron Lett. 2011, 52, 548e551.
13. Suzuki, K.; Nakata, T. Org. Lett. 2002, 4, 2739e2741.
36. For similar stereoselective hydroboration see: (a) Sasaki, M.; Tsukano, C.; Ta-
chibana, K. Org. Lett. 2002, 4, 1747e1750; (b) Tsukano, C.; Ebine, M.; Sasaki, M. J.
Am. Chem. Soc. 2005, 127, 4326e4335.
14. For a related example see: Kawamura, K.; Hinou, H.; Matsuo, G.; Nakata, T.
37. Direct treatment of 30 with Et3SiH/TMSOTf in EtCN at ꢀ78 ꢁC afforded 6 as
Tetrahedron Lett. 2003, 44, 5259e5261.
a single diastereomer in a somewhat lower yield (72%).
15. Nicolaou, K. C.; Nugiel, D. A.; Couladouros, E.; Hwang, C.-K. Tetrahedron 1990,
46, 4517e4552.
16. Furstner, A.; Kattnig, E.; Lepage, O. J. Am. Chem. Soc. 2006, 128, 9194e9204.
17. Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1557e1560.
18. Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.; Le Gall, T.; Shin, D.-S.;
Flack, J. R. Tetrahedron Lett. 1994, 35, 5449e5452.
19. Rai, A. N.; Basu, A. Tetrahedron Lett. 2003, 44, 2267e2269.
20. (a) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480e2482; (b)
Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651e1660.
21. (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974e5976; (b) Gao,
Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko, S. Y.; Sharpless, K. B. J. Am.
Chem. Soc. 1987, 109, 5765e5780.
22. Anelli, P. L.; Bifli, C. B.; Montanari, F.; Quici, S. J. Org. Chem. 1987, 52, 2559e2562.
23. Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J. Am. Chem. Soc.
1989, 111, 5330e5334.
24. (a) Uehara, H.; Oishi, T.; Inoue, M.; Shoji, M.; Nagumo, Y.; Kosaka, M.; Le Bra-
zidec, J.-M.; Hirama, M. Tetrahedron 2002, 58, 6493e6512; (b) Fuwa, H.; Ebine,
M.; Bourdelais, A. J.; Baden, D. G.; Sasaki, M. J. Am. Chem. Soc. 2006, 128,
16989e16999.
25. Parikh, J. P.; Doering, W. E. J. Am. Chem. Soc. 1967, 84, 5505e5507.
26. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639e666.
27. (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011e1014; (b)
Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974, 96, 7503e7509.
28. For reviews see: (a) Mukaiyama, T.; Matsuo, J. In Modern Aldol Reactions;
Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004; Vol. 1, pp 127e160; (b)
Mukaiyama, T. Angew. Chem., Int. Ed. 2004, 43, 5590e5614.
38. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574e1585.
39. For reviews see: (a) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863e927;
(b) Nicolaou, K. C.; Harter, M. W.; Gunzner, J. L.; Nadin, A. Eur. J. Org. Chem. 1997,
1283e1301.
40. (a) Julia, M.; Paris, J. M. Tetrahedron Lett. 1973, 4833e4836; (b) Kocienski, P. J.;
Lythgoe, B.; Ruston, S. J. Chem. Soc., Perkin Trans. 1 1978, 829e834; (c) Kocienski,
P. Phosphorus and Sulfur 1985, 24, 97e127.
41. For the synthesis of ent-40a see: (a) Deng, L.-S.; Huang, X.-P.; Zhao, G. J. Org.
Chem. 2006, 71, 4625e4635; (b) White, J. D.; Kawasaki, M. J. Org. Chem. 1992, 57,
5292e5300.
€
42. (a) Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita, T.; Hatanaka,
Y.; Yokoyama, M. J. Org. Chem. 1984, 49, 3904e3912; (b) Imamoto, T.; Takiyama,
N.; Nakamura, K.; Hatajima, T.; Kamiya, Y. J. Am. Chem. Soc. 1989, 111,
4392e4398; (c) Imamoto, T. Pure Appl. Chem. 1990, 62, 747e752; (d) Bartoli, G.;
Marcantoni, E.; Marcolini, M.; Sambri, L. Chem. Rev. 2010, 110, 6104e6143.
ꢂ
ꢃ
43. For the synthesis of ent-40b see: Pospísil, J.; Marko, I. E. J. Am. Chem. Soc. 2007,
129, 3516e3517.
44. Treatment of 42b with Bz2O and DMAP in pyridine resulted only in recovery of
the material, while 42b decomposed upon reaction with Bz2O and Sc(OTf)3 in
MeCN.
45. (a) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 26e28;
(b) For reviews see: Aïssa, C. Eur. J. Org. Chem. 2009, 1831e1844; (c) Blakemore,
P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563e2585.
46. (a) Jones, T. K.; Reamer, R. A.; Mills, S. G. J. Am. Chem. Soc. 1990, 112, 2998e3017;
(b) For the synthesis of ent-45 see: Brandl, T.; Hoffmann, R. W. Eur. J. Org. Chem.
2004, 4373e4378.
29. For an example see: Evans, D. A.; Kværnø, L.; Dunn, T. B.; Beauchemin, A.;
Raymer, B.; Mulder, J. A.; Olhava, E. J.; Juhl, M.; Kagechika, K.; Favor, D. A. J. Am.
Chem. Soc. 2008, 130, 16295e16309.
47. For reviews see: (a) Mitsunobu, O. Synthesis 1981, 1e28; (b) Swamy, K. C. K.;
Kumar, N. N. B.; Balaraman, E.; Kumar, K. V. P. P. Chem. Rev. 2009, 109,
2551e2651.