Total synthesis of brevenal

Article abstract of DOI:10.1016/j.tet.2010.05.069

The convergent total synthesis of brevenal, a non-toxic brevetoxin antagonist, has been achieved.The ABC ring segment and the E ring precursor were connected by the intramolecular allylation followed by ring-closing metathesis to furnish the pentacyclic e

Full text of DOI:10.1016/j.tet.2010.05.069

Tetrahedron 66 (2010) 5329e5344
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of brevenal
Hiroyoshi Takamura a, Yuji Yamagami a, Takayuki Kishi a, Shigetoshi Kikuchi b, Yuichi Nakamura a,
,
b
Isao Kadota a , Yoshinori Yamamoto
*
a Department of Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushimanaka, Kitaku, Okayama 700-8530, Japan
b Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The convergent total synthesis of brevenal, a non-toxic brevetoxin antagonist, has been achieved. The ABC
ring segment and the E ring precursor were connected by the intramolecular allylation followed by ring-
closing metathesis to furnish the pentacyclic ether compound. An alternative route to the key synthetic
intermediate, a pentacyclic ether core, was also examined. The right- and left-hand side chains were in-
troduced by Wittig and HornereWadswortheEmmons reactions, respectively, to furnish brevenal (1).
Ó 2010 Elsevier Ltd. All rights reserved.
Received 23 April 2010
Received in revised form 15 May 2010
Accepted 17 May 2010
Available online 9 June 2010
Keywords:
Brevenal
Marine polycyclic ether
Total synthesis
Intramolecular allylation
Ring-closing metathesis
1. Introduction
In recent years there has been an explosion of interest in bi-
ologically active natural products of marine origin.1 Due to their
structural novelty and toxicity, polycyclic ethers are particularly
attractive targets for synthetic chemists.2 Brevenal (1) was isolated
from Karenia brevis in 2004, as a new family of marine polycyclic
ether (Fig. 1).3 This compound inhibits the binding of tritiated
dihydrobrevetoxin B to voltage-sensitive sodium channels in
a concentration dependent manner without showing toxicity.3
Moreover, a significant improvement of tracheal mucus velocity
was observed in an animal model of asthma.4 The novel biological
activities and the unique structural features have attracted atten-
tion of synthetic chemists. In 2006, the first total synthesis and
structural revision of 1 was reported by Sasaki and co-workers.5 In
this paper, we wish to describe a full detail of our total synthesis of
brevenal (1).6
Figure 1. Structures of brevenal (1).
HornereWadswortheEmmons reactions, respectively, at a later
stage. A key synthetic intermediate, the pentacyclic ether core 2,
would be synthesized from 3 via the intramolecular allylation fol-
lowed by ring-closing metathesis.7 The substrate 3 was retro-
synthetically broken down into the ABC ring segment 4 and the E ring
precursor 5. The tricycle 4 would be prepared from 6 and 7.
2. Results and discussion
2.2. Synthesis of the ABC ring segment
2.1. First generation retrosynthetic analysis
Scheme 2 describes the synthesis of the ABC ring. Protection of
the known alcohol 88 with TBSCl/imidazole, reductive cleavage of
the benzylidene acetal with DIBAL-H, and protection of the
resulting primary alcohol with BnBr/KH gave the bis-benzyl ether
9 in 71% yield over three steps. Ozonolysis of the olefin 9 followed
by Brown’s asymmetric allylboration provided 10 as a single
Our retrosynthetic analysis of 1 is illustrated in Scheme 1. The
right- and left-hand side chains would be constructed by Wittig and
* Corresponding author. Tel./fax: þ81 86 251 7836; e-mail address: kadota-i@cc.
okayama-u.ac.jp (I. Kadota).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.069

5330
H. Takamura et al. / Tetrahedron 66 (2010) 5329e5344
Scheme 1. Retrosynthetic analysis of 1.
Scheme 2. Synthesis of the mixed thioacetal 17.
stereoisomer in 95% yield over two steps.9 Protection of the alcohol
10 with MOMCl/i-Pr2NEt followed by hydroborationeoxidation
afforded the corresponding alcohol. The alcohol obtained was
subjected to the stepwise oxidation leading to the carboxylic acid
11. Removal of the TBS group with TBAF, followed by the Yama-
guchi lactonization provided 7 in 64% yield over six steps.10 The
lactone 7 was converted to the enol phosphate 12 with (PhO)2
-
POCl/KHMDS. The SuzukieMiyaura coupling of 12 and an alkyl
borate, prepared from the iodide 65c by known procedure,11 was
carried out with PdCl2(dppf) to furnish the enol ether 13 in 81%
yield over two steps.12 Unfortunately, hydroboration of 13 with
BH3 followed by oxidative workup gave the undesired stereoiso-
mer 14 as the sole product. Although the detailed conformational
analysis of 13 was not carried out, the MOM group at C14 position
Figure 2. A plausible conformation for 13 composed by Chem 3D. The protective
groups and side chain were replaced by methyl and ethyl groups for clarity.
seems to prevent the reagent approaching from the b-face of the
olefin (Fig. 2). Since several attempts failed to obtain the desired
product from 13 directly, stereoinversion at the C11 position was
carried out. Oxidation of 14 with TPAP/NMO followed by treatment
of the resulting ketone with DBU in toluene at 110 ꢀC provided 15
as a single stereoisomer. Deprotection of the PMB group of 15 using
DDQ furnished the alcohol 16 in 89% yield over four steps. Treat-
ment of the hydoxy ketone 16 with EtSH/Zn(OTf)2 gave the mixed
thioacetal 17 in 89% yield.5,13
We next examined the construction of an angular methyl
group at the C12 position based on a reported procedure (Scheme
3). Thus, oxidation of 17 with m-CPBA followed by treatment of
the resulting sulfoxide intermediate 18 with AlMe3 provided 19 as
a single stereoisomer in 69% yield.5,14 Although, the desired
product 19 was obtained in a reasonable yield, formation of sig-
nificant amount of unidentified by-products was observed.

H. Takamura et al. / Tetrahedron 66 (2010) 5329e5344
5331
Scheme 3. Synthesis of the ABC ring segment 4.
Furthermore the reproducibility of this reaction was not satis-
2.3. Coupling of the segments
factory in large-scale experiments, presumably, because of the
low stability of the intermediate 18. After several examinations,
we found that the reaction of 17 with Me2Zn/Zn(OTf)2 furnished
19, directly, in quantitative yield. The MOM protection was totally
inert under the reaction conditions. Debenzylation of 19 with H2/
Pd(OH)2eC, protection of the resulting diol with TESCl/imidazole,
and selective cleavage of the primary TES ether under acidic
conditions afforded 20 in 89% yield over three steps. TPAP oxi-
dation of the alcohol 20 followed by Wittig reaction with Ph3P]
CHCO2Me gave the unsaturated ester 21 in 96% yield over two
steps. The ester obtained was subjected to hydrogenation and
saponification leading to the ABC ring segment 4, which was used
for the next reaction directly.
We next examined the key segment coupling (Scheme 4). Thus,
esterification of the carboxylic acid 4 and the known alcohol 515
under the Yamaguchi conditions gave the ester 22. The TES pro-
tection was cleaved with CSA, selectively, to provide 23 in 74% yield
over four steps. Reaction of 23 with g-methoxyallylstannane 24 in
the presence of CSA provided the acetal 25 as a mixture of di-
astereoisomers in 88% yield. Treatment of 25 with TMSI/HMDS gave
allylic stannane 26 in 91% yield.16 Since the MOM protection was
cleaved under the reaction conditions, the resulting hydroxy group
of 26 was protected as a TBS ether to furnish 27 in 95% yield.
Modified Rychnovsky acetylation of the ester 27 provided the
a-
chloroacetoxy ether 3.17,18 The cyclization precursor 3 was then
Scheme 4. Coupling of the segments 4 and 5.

5332
H. Takamura et al. / Tetrahedron 66 (2010) 5329e5344
subjected to the intramolecular allylation with MgBr2$OEt2 to give
28 as a single stereoisomer in 52% yield over two steps. Ring-closing
metathesis of the diene 28 was carried out with the Grubbs’ catalyst
29 leading to the pentacyclic ether 30 in 69% yield.19 At this stage,
the trans relationship between H22 and H23 was confirmed by the
coupling constant, JH22eH23¼9.0 Hz. Having synthesized the pen-
tacyclic ether core, we next examined the deprotection of the 2,4,6-
trichlorobenzyl (TCBn) group before constructing the left-hand side
chain. However, the direct conversion of 30 to the alcohol 2 resulted
in failure. Cleavage of the TCBn ether was very slow under the
standard hydrogenation conditions such as H2 and Pd catalysts, and
decomposition of the substrate was observed when a prolonged
reaction time was employed.20
2.4. Removal of the TCBn group
Scheme 6. Second generation retrosynthesis of 2.
After several attempts, removal of the TCBn group was per-
formed via the Sajiki’s dechlorination procedure as shown in
Scheme 5. Thus, the reaction of 30 with H2/PdeC in the presence of
Et3N afforded the corresponding benzyl ether 31 in quantitative
yield.21 Although the direct conversion to 2 under the hydrogena-
tion conditions was unsatisfactory, reduction of the E ring olefin
with diimide proceeded smoothly to furnish 32, a synthetic in-
termediate of Sasaki’s total synthesis,5a,b,22 in 84% yield over two
steps. Finally, debenzylation of 32 was carried out with H2/Pd
(OH)2eC leading to 2 in 89% yield.
in 93% yield over two steps (Scheme 7). Debenzylation of 36, fol-
lowed by protection of the resulting diol with TESCl/imidazole and
selective desilylation of the primary TES ether provided 37 in 65%
yield over three steps. TPAP oxidation of the alcohol 37, Wittig re-
action, and selective removal of the TES protection furnished the
ABC ring segment 34 in 86% yield over three steps.
Scheme 5. Synthesis of the key intermediate 2.
2.5. Second generation retrosynthesis of 2
We next examined an alternative, more convergent approach to
the key synthetic intermediate 2. The retrosynthesis for the new
strategy is shown in Scheme 6. The intramolecular allylation would
be employed for the synthesis of the E ring, and the D ring moiety
would be constructed by the ring-closing metathesis. The cycliza-
tion precursor 33 was retrosynthetically broken down into the ABC
ring segment 34 and the E ring precursor 35, which has an allylic
stannane moiety.
Scheme 7. Synthesis of the ABC ring segment 34.
2.7. Preparation of the E ring precursor
Scheme 8 describes the synthesis of the E ring precursor 35
having an allylic stannane moiety. Protection of the alcohol 38,
prepared by the known procedure,15 with TBSOTf/2,6-lutidine
followed by hydroborationeoxidation afforded 39 in 85% yield
over two steps. Protection of the alcohol 39 with MOMCl/i-
2.6. Preparation of the ABC ring segment
The MOM protection of 19 was removed by TMSI/HMDS, and the
resulting alcohol was protected with TBSOTf/2,6-lutidine to give 36

H. Takamura et al. / Tetrahedron 66 (2010) 5329e5344
5333
Pr2NEt, deprotection of the Bn and MPM groups with H2/Pd
(OH)2eC, and selective protection of the primary alcohol with
TBSCl/imidazole afforded 40 in 94% yield over three steps.
Treatment of 40 with allyl bromide/KH followed by deprotection
of the MOM group with TMSI/HMDS and protection of the
resulting alcohol with TESCl/imidazole provided the allyl ether
41 in 92% yield over three steps. Treatment of 41 with s-BuLi/
TMEDA followed by trapping the resulting allylic anion with
n-Bu3SnCl gave the allylic stannane 42 in 64% yield.23,24 Selective
removal of the TES group with PPTS gave 43 in 65% yield. The
primary alcohol 43 was subjected to the two-step oxidation
leading to the carboxylic acid 35, which was used for the next
reaction without purification.
yield. Conversion of 44 to the cyclization precursor 33 was per-
formed by the same procedure described in Scheme 4. Intra-
molecular allylation of 33 was carried out with MgBr2$OEt2 to
give 45 as a single stereoisomer in 57% yield over two steps.
Ring-closing metathesis of the diene 45 with the Grubbs’ catalyst
29, diimide reduction of the resulting olefin 46, and selective
removal of the primary TBS group of 47 with CSA furnished the
AeE ring system 2 in 76% yield over three steps.
2.9. Construction of the right-hand side chain
Having the pentacyclic ether core 2 in hand, we next exam-
ined the synthesis of the diene side chains. Construction of the
Scheme 8. Synthesis of the E ring precursor 35.
2.8. Synthesis of the pentacycle 2
right-hand (Z)-diene moiety was carried out according to the
Nicolaou’s procedure (Scheme 10).25 Thus, oxidation of 2 with
SO3$py/DMSO followed by Wittig reaction using a ylide gener-
ated from the phosphonium salt 48 and NaHMDS, and sub-
Synthesis of the key synthetic intermediate 2 is described in
Scheme 9. Esterification of the carboxylic acid 35 and the alcohol
34 under the Yamaguchi conditions gave the ester 44 in 85%
sequent oxidation with H2O2 provided 49 as
a
single
Scheme 9. Coupling of the segments 34 and 35.

5334
H. Takamura et al. / Tetrahedron 66 (2010) 5329e5344
stereoisomer in 90% yield over three steps. Selective removal of
the TBDPS group was carried out with TBAF/AcOH to give the
alcohol 50 in 94% yield.
2.11. Completion of the total synthesis of brevenal
Encouraged by the results obtained above, we faced up to the
final stage of the total synthesis. Thus, after oxidation of 50 with
SO3$py/DMSO, the resulting aldehyde was treated with the enolate
generated from 52 and n-BuLi to provide 54 as a single stereoiso-
mer in 88% yield over two steps. Reduction of the ester 54 with
DIBAL-H followed by desilylation with TBAF afforded the triol 55 in
98% yield over two steps. Finally, selective oxidation of the allylic
alcohol 55 with MnO2 furnished brevenal (1) in quantitative yield.
The synthetic 1 exhibited physical and spectroscopic data identical
with those reported previously.
3. Conclusion
In conclusion, we have achieved a stereocontrolled total syn-
thesis of brevenal (1). Key features of the synthetic strategy in-
cluded the intramolecular allylation of an
a-chloroacetoxy ether
and ring-closing metathesis. In the first generation synthesis, the
longest linear sequence leading to 1 was 57 steps with 1.2% overall
yield. The second generation strategy provided 1 in 1.8% overall
yield over 53 steps (the longest liner sequence). Novel methods for
the direct methylation of a mixed thioacetal (Scheme 2) and the
stereoselective synthesis of the left-hand (E,E)-diene system
(Scheme 11) are also deserving of attention.
Scheme 10. Construction of the right-hand side chain.
2.10. Model studies for the construction of the (E,E)-diene
side chain
Next task was the synthesis of the left-hand side chain. As well
as the synthesis of the pentacyclic ether framework, the stereo-
selective construction of the left-hand side chain, highly
substituted (E,E)-diene moiety, was one of the challenging prob-
lems inherent in the total synthesis of brevenal (1). We chose
a HornereWadswortheEmmons reaction as a possible route to the
diene system, and tested the reaction using aldehyde 51 as a model
substrate. Table 1 summarizes the results of the reaction of 51 with
the phosphonate 526,26 under various conditions. The best result
was obtained from the reaction using n-BuLi as a base in the ab-
sence of any additives (entry 1). The desired product 53 was
obtained in 92% yield as a single stereoisomer. The stereochemistry
of 53 was determined by NOE experiments. None of the other
olefinic isomer was detected in this reaction. The use of DMPU as an
additive decreased the stereoselectivity (entries 2, 4, and 5). The
reaction with LiHMDS gave the product in moderate yield although
the high stereoselectivity was observed (entry 3). On the other
hand, poor selectivity was obtained in the reaction with NaHMDS
(entry 6).
Table 1
HornereWadswortheEmmons reaction with phosphonate 52a
NOEs
Me
MeO2C
P(OEt)2
O
H
Me
H
Me
52
MeO2C
OR
OHC
OR
R = TBDPS
Base
Me
H
Scheme 11. Completion of the total synthesis of brevenal (1).
base
53
51
Yieldb (%)
E/Zc
4. Experimental section
4.1. General
Entry
Additive
Solvent
1
2
3
4
5
6
n-BuLi
n-BuLi
LiHMDS
LiHMDS
LDA
d
THF
THF
THF
THF
THF
THF
92
96
41
61
87
91
>95:5
93:7
>95:5
93:7
89:11
75:25
DMPU
d
DMPU
DMPU
DMPU
All reactions involving air- and/or moisture-sensitive materials
were carried out under argon with dry solvents purchased from
Wako or Kanto chemicals. On workup, extracts were dried over
MgSO4. Reactions were monitored by thin-layer chromatography
carried out on 0.25 mm Merck silica gel plates (60F-254). Column
chromatography was performed with Kanto Chemical silica gel 60N
NaHMDS
a
Reactions were carried out with 5.0 equiv of 52 and 5.0 equiv of base at ꢁ78 ꢀ
C
to rt.
b
c
Isolated yields.
The ratio was determined by 1H NMR analysis.

H. Takamura et al. / Tetrahedron 66 (2010) 5329e5344
5335
(40e100 mesh, spherical, neutral) or Fuji Silysia silica gel BW-300
(200e400 mesh). Yields refer to chromatographically and spec-
troscopically homogeneous materials. The NMR spectra were
recorded on JEOL JNM-AL400 (1H, 13C NMR). Chemical shifts were
warm to room temperature with stirring. Concentration gave the
corresponding crude aldehyde, which was used for the next re-
action directly.
To a solution of (ꢁ)-Ipc2BOMe (3.77 g, 11.9 mmol) in Et2O
(15 mL) at 0 ꢀC was added allylmagnesium bromide (11.9 mL,
11.9 mmol, 1.0 M solution in Et2O). After stirring for 70 min at room
temperature, the mixture was cooled to ꢁ78 ꢀC. To this mixture was
added a solution of the crude aldehyde in Et2O (15 mL). After stir-
ring for 1 h at ꢁ78 ꢀC, the reaction mixture was allowed to warm to
room temperature over 1.5 h with stirring before quenching with
MeOH at 0 ꢀC. To the mixture were added 3 M NaOH (7.0 mL) and
30% H2O2 (7.0 mL) at the same temperature, and the reaction
mixture was stirred for 40 min at 30 ꢀC. The reaction mixture was
quenched with saturated Na2SO3 at 0 ꢀC and then stirred for 20 min
at room temperature. The mixture was diluted with EtOAc, then
washed with water and brine. Concentration and chromatography
reported in delta units (d) relative to chloroform (7.24) or benzene
(7.15). IR spectra were recorded on a JASCO FT/IR-460 Plus. Optical
rotations were measured by a JASCO DIP-1000. Mass spectra were
measured by Micromass LCT (ESI TOF-MS).
4.2. Bis-benzyl ether 9
To a solution of 8 (11.3 g, 40.8 mmol) in DMF (200 mL) at room
temperature were added imidazole (5.56 g, 81.6 mmol) and TBSCl
(9.24 g, 61.2 mmol). After stirring for 2 h at 50 ꢀC, the reaction
mixture was quenched with MeOH. The mixture was diluted with
EtOAc, then washed with water and brine. After concentration, the
residue was passed through a short silica gel column (hexane/
EtOAc, 10:1) to give the crude silyl ether, which was used for the
next reaction directly.
To a solution of the crude silyl ether in CH2Cl2 (180 mL) at
ꢁ78 ꢀC was added DIBAL-H (168 mL, 163.3 mmol, 0.97 M solution
in hexane). The mixture was allowed to warm to room temperature
over 5.5 h. The reaction mixture was quenched with MeOH, filtered
through a Celite pad, and concentrated. The residue was purified by
chromatography (hexane/EtOAc, 25:1 to 10:1 to 6:1 to 2:1) to give
the corresponding primary alcohol (11.6 g, 72% for the 2 steps) and
(hexane/EtOAc, 5:1) gave 10 (2.99 g, 95% for the 2 steps) as a single
23
stereoisomer: colorless oil; Rf¼0.30 (hexane/EtOAc, 4:1); [
a]
D
ꢁ36.2 (c 1.00, CHCl3); IR (neat) 3492, 2980, 1087 cmꢁ1
;
1H NMR
(400 MHz, CDCl3)
d
7.32e7.25 (m, 10H), 5.92 (dddd, J¼17.1, 9.8, 7.1,
7.1 Hz, 1H), 5.10 (dd, J¼17.1, 1.5 Hz, 1H), 5.06 (ddd, J¼9.8, 1.5, 1.0 Hz,
1H), 4.59 (d, J¼12.4 Hz, 1H), 4.54 (d, J¼12.4 Hz, 1H), 4.52
(d, J¼11.7 Hz, 1H), 4.47 (d, J¼11.7 Hz, 1H), 3.82 (m, 1H), 3.68 (dd,
J¼12.0, 4.6 Hz, 1H), 3.58e3.52 (m, 1H), 3.53 (d, J¼10.5 Hz, 1H), 3.40
(d, J¼10.5 Hz, 1H), 3.36 (dd, J¼9.0, 5.4 Hz, 1H), 2.41e2.32 (m, 1H),
2.30e2.22 (m, 1H), 2.12 (ddd, J¼12.0, 4.6, 4.6 Hz, 1H), 1.59
(q, J¼12.0 Hz, 1H), 1.13 (s, 3H), 0.86 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H);
unreacted starting material (3.22 g, 20% recovery): colorless oil;
28
Rf¼0.38 (hexane/EtOAc, 4:1); [
a
]
ꢁ32.4 (c 1.00, CHCl3); IR (neat)
13C NMR (100 MHz, CDCl3)
d 138.6, 138.5, 135.3, 128.2 (4C), 127.5
D
3466, 3033, 1072 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
7.33e7.26
(2C), 127.4 (2C), 127.3 (2C), 116.8, 77.2, 75.6, 74.6, 73.5, 73.4, 72.2,
71.7, 70.5, 36.6, 35.2, 25.8 (3C), 17.9, 13.6, ꢁ3.6, ꢁ4.6; HRMS (ESI
TOF) calcd for C31H46O5SiNa (MþNa)þ 549.3012, found 549.2993.
(m, 5H), 5.78 (ddd, J¼17.1, 10.5, 6.0 Hz, 1H), 5.29 (ddd, J¼17.1, 1.6,
1.6 Hz, 1H), 5.17 (ddd, J¼10.5, 1.6, 1.0 Hz, 1H), 4.58 (d, J¼11.7 Hz, 1H),
4.51 (d, J¼11.7 Hz, 1H), 3.78 (dd, J¼9.0, 6.0 Hz, 1H), 3.68 (dd, J¼12.0,
4.4 Hz, 1H), 3.62e3.48 (m, 2H), 3.25 (ddd, J¼11.2, 9.3, 4.9 Hz, 1H),
2.17 (ddd, J¼9.3, 4.6, 4,6 Hz, 1H), 2.02 (dd, J¼9.5, 3.7 Hzw, 1H), 1.62
(q, J¼12.0 Hz, 1H), 1.17 (s, 3H), 0.85 (s, 9H), 0.02 (s, 3H), 0.00 (s, 3H);
4.4. Lactone 7
To a solution of 10 (7.23 g, 13.7 mmol) in CH2Cl2 (60 mL) at room
temperature were added diisopropylethylamine (14.1 mL,
82.3 mmol) and MOMCl (4.1 mL, 54.9 mmol). After stirring for 1 h,
the reaction mixture was quenched with MeOH, diluted with
EtOAc, then washed with saturated NH4Cl, saturated NaHCO3, and
brine. Concentration and chromatography (hexane/EtOAc, 20:1 to
13C NMR (100 MHz, CDCl3)
d 138.4 (2C), 136.4, 128.3, 127.6, 127.5
(2C), 116.9, 76.5, 75.7, 73.2, 71.5, 70.8, 67.7, 34.8, 25.8 (3C), 18.1, 13.7,
ꢁ4.1, ꢁ4.4; HRMS (ESI TOF) calcd for C22H36O4SiNa (MþNa)þ
415.2281, found 415.2275.
To a stirred suspension of KH (5.81 g, 72.4 mmol, 50%, pre-
washed with hexane) in THF (100 mL) at 0 ꢀC were added a solution
of the alcohol (19.0 g, 48.3 mmol) in THF (100 mL) and BnBr
(8.6 mL, 72.4 mmol). After stirring for 1 h at room temperature, the
reaction mixture was quenched with MeOH, diluted with EtOAc,
then washed with water and brine. Concentration and chroma-
10:1 to 5:1) gave the corresponding MOM ether (7.43 g, 95%):
24
colorless oil; Rf¼0.60 (hexane/EtOAc, 4:1); [
a]
ꢁ46.9 (c 1.00,
D
CHCl3); IR (neat) 3030, 2929, 1641 cmꢁ1; 1H NMR (400 MHz, CDCl3)
7.31e7.23 (m, 10H), 5.93 (dddd, J¼17.1, 10.0, 7.1, 7.1 Hz, 1H), 5.07
d
(dd, J¼17.1, 2.0 Hz, 1H), 5.01 (dd, J¼10.0, 2.0 Hz, 1H), 4.71 (d,
J¼6.9 Hz, 1H), 4.63 (d, J¼12.0 Hz, 1H), 4.61 (d, J¼6.9 Hz, 1H), 4.55 (d,
J¼11.5 Hz, 1H), 4.52 (d, J¼12.0 Hz, 1H), 4.49 (d, J¼11.5 Hz, 1H), 3.87
(ddd, J¼9.5, 3.7, 1.0 Hz, 1H), 3.72 (dd, J¼12.0, 4.4 Hz, 1H), 3.60e3.56
(m, 1H), 3.58 (d, J¼10.5 Hz, 1H), 3.47 (d, J¼10.5 Hz, 1H), 3.43 (ddd,
J¼9.0, 4.8, 4.8 Hz, 1H), 3.35 (s, 3H), 2.49e2.40 (m, 1H), 2.29e2.20
(m, 1H), 2.12 (ddd, J¼12.0, 4.6, 4.6 Hz, 1H), 1.57 (q, J¼12.0 Hz, 1H),
1.14 (s, 3H), 0.86 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR
tography (hexane/EtOAc, 100:1 to 50:1) gave 9 (23.1 g, 99%): light
23
yellow oil; Rf¼0.53 (hexane/EtOAc, 10:1); [
CHCl3); IR (neat) 3030, 1093 cmꢁ1
7.34e7.23 (m, 10H), 5.85 (ddd, J¼17.1, 10.5, 6.1 Hz, 1H), 5.31 (ddd,
a
]
ꢁ29.6 (c 1.00,
D
;
1H NMR (400 MHz, CDCl3)
d
J¼17.1, 2.0, 2.0 Hz, 1H), 5.16 (ddd, J¼10.5, 2.0, 1.0 Hz, 1H), 4.64
(d, J¼12.6 Hz, 1H), 4.54 (d, J¼12.6 Hz, 1H), 4.53 (d, J¼11.8 Hz, 1H),
4.43 (d, J¼11.8 Hz, 1H), 3.77 (dd, J¼9.0, 6.1 Hz, 1H), 3.72 (dd, J¼12.2,
4.6 Hz, 1H), 3.55 (d, J¼10.6 Hz, 1H), 3.44 (d, J¼10.6 Hz, 1H), 3.30
(ddd, J¼11.0, 9.2, 4.6 Hz, 1H), 2.15 (ddd, J¼12.0, 4.9, 4,9 Hz, 1H), 1.62
(q, J¼12.0 Hz, 1H), 1.17 (s, 3H), 0.85 (s, 9H), 0.01 (s, 3H), ꢁ0.01
(100 MHz, CDCl3)
d 138.9, 138.7, 136.3, 128.2 (2C), 128.1 (2C), 127.5
(2C), 127.4 (2C), 127.3, 127.2, 116.4, 95.9, 77.2, 76.5, 76.4, 74.7, 73.6,
73.3, 71.6, 67.3, 55.6, 35.1, 33.9, 25.8 (3C), 17.9, 13.3, ꢁ3.7, ꢁ4.6;
HRMS (ESI TOF) calcd for C33H50O6SiNa (MþNa)þ 593.3275, found
593.3295.
To a solution of 2-methyl-2-butene (0.5 mL, 4.55 mmol) in THF
(2 mL) at 0 ꢀC was added BH3$SMe2 (0.2 mL, 2.28 mmol) and stirred
for 15 min at the same temperature. To the mixture was added
a solution of the MOM ether (260 mg, 0.455 mmol) in THF (2.5 mL),
and the resulting mixture was stirred for 1 h at room temperature.
To the mixture were added 3 M NaOH (1 mL) and 30% H2O2 (1 mL)
at 0 ꢀC, and the reaction mixture was stirred for 10 min at room
temperature. To the mixture at 0 ꢀC was added saturated Na2SO3,
and the stirring was continued for additional 20 min at room
(s, 3H); 13C NMR (100 MHz, CDCl3)
d 138.7, 138.6, 136.8, 128.2 (2C),
127.6 (2C), 127.5 (2C), 127.4 (2C), 127.3 (2C), 116.8, 77.2, 76.0, 74.7,
73.6, 73.5, 71.4, 70.7, 34.9, 25.9 (3C),18.1, 13.7, ꢁ4.1, ꢁ4.4; HRMS (ESI
TOF) calcd for C29H42O4SiNa (MþNa)þ 505.2750, found 505.2739.
4.3. Homoallylic alcohol 10
Ozone was passed through a solution of 9 (2.88 g, 5.96 mmol) in
MeOH/CH2Cl2 (6.0 mL/4.5 mL) at ꢁ78 ꢀC until the solution turned
to blue. After removal of excess ozone with an oxygen stream, the
mixture was treated with Me2S (1.32 mL,17.9 mmol) and allowed to

5336
H. Takamura et al. / Tetrahedron 66 (2010) 5329e5344
temperature. The mixture was diluted with EtOAc, then washed
with water and brine. Concentration gave the crude alcohol, which
was used for the next reaction directly.
(18 mL), and the mixture was stirred for 40 min at room tempera-
ture. To the reaction mixture were added 3 M NaOH (5 mL) and 30%
H2O2 (5 mL) at 0 ꢀC, and stirred for 20 min at room temperature.
The mixture was quenched with saturated Na2SO3 at 0 ꢀC and
stirred for 0.5 h at room temperature. The resulting mixture was
diluted with EtOAc, then washed with water and brine. Concen-
tration and chromatography (hexane/EtOAc, 10:1 to 8:1 containing
To a solution of the crude alcohol in CH2Cl2 (2 mL) and DMSO
(0.5 mL) at 0 ꢀC were added Et3N (0.3 mL, 2.28 mmol) and SO3$py
(217 mg, 1.37 mmol), and the mixture was stirred for 1 h at room
temperature. The mixture was diluted with EtOAc, then washed
with saturated NH4Cl, water, and brine. Concentration gave the
crude aldehyde, which was used for the next reaction directly.
To a solution of the crude aldehyde in t-BuOH (1.5 mL) and 2-
methyl-2-butene (1.5 mL) at 0 ꢀC were added 5% NaH2PO4 (3.0 mL)
and NaClO2 (412 mg, 4.55 mmol), and the mixture was stirred
vigorously at the same temperature for 3 h. The mixture was
diluted with Et2O, then washed with water and brine. Concentra-
tion gave the crude carboxylic acid 11, which was used for the next
reaction directly.
To a solution of the crude carboxylic acid 11 was added TBAF
(2.3 mL, 2.30 mmol, 1.0 M solution in THF), and the mixture was
stirred for 7 h at 50 ꢀC. The mixture was diluted with Et2O, then
washed with saturated NH4Cl, water, and brine. Concentration gave
the crude hydroxy carboxylic acid, which was used for the next
reaction directly.
0.5% Et3N) gave 13 (1.13 g, 81% for the 2 steps): yellow oil; Rf¼0.34
25
(hexane/EtOAc, 4:1); [
a]
þ17.5 (c 1.00, CHCl3); IR (neat) 3028,
D
2933, 1109 cmꢁ1 1H NMR (400 MHz, C6D6)
; d 7.82e7.76 (m, 4H),
7.34e7.03 (m, 18H), 6.81 (d, J¼8.8 Hz, 2H), 4.94 (d, J¼6.4 Hz, 1H),
4.73 (dd, J¼8.3, 3.4 Hz, 1H), 4.71 (d, J¼6.4 Hz, 1H), 4.52 (d,
J¼12.0 Hz, 1H), 4.49e4.37 (m, 4H), 4.27 (d, J¼12.0 Hz, 1H),
4.02e3.93 (m, 2H), 3.83 (dd, J¼12.0, 4.6 Hz, 1H), 3.76e3.66 (m, 2H),
3.57 (d, J¼10.5 Hz, 1H), 3.53 (dd, J¼9.5, 2.2 Hz, 1H), 3.42 (d,
J¼10.5 Hz, 1H), 3.35e3.25 (m, 1H), 3.31 (s, 3H), 3.30 (s, 3H), 2.56
(dd, J¼12.0, 2.7 Hz, 1H), 2.52 (ddd, J¼11.7, 5.0, 5.0 Hz, 1H), 2.33e2.12
(m, 3H), 1.99e1.61 (m, 6H), 1.18 (s, 9H), 1.18 (s, 3H), 1.13 (d, J¼6.8 Hz,
3H); 13C NMR (100 MHz, C6D6)
d 159.5, 158.2 (2C), 139.4, 139.3,
136.0 (4C), 134.5 (4C), 131.9 (2C), 129.9 (2C), 129.4 (2C), 128.5 (2C),
128.4 (2C), 127.9 (4C), 127.6 (2C), 114.0 (2C), 105.2, 96.7, 82.2, 78.3,
77.4, 75.2, 74.1, 73.8, 73.4, 71.8, 71.6, 71.5, 64.5, 55.3, 54.9, 39.8, 33.6,
32.5, 29.6, 28.2, 27.3 (3C), 27.2, 19.6,15.4,13.4; HRMS (ESI TOF) calcd
for C58H74O9SiNa (MþNa)þ 965.0000, found 965.0001.
To a solution of the crude hydroxy carboxylic acid in THF
(3.0 mL) were added Et3N (0.13 mL, 0.910 mmol) and 2,4,6-tri-
chlorobenzoyl chloride (0.11 mL, 0.675 mmol). After stirring for
1.5 h at room temperature, the reaction mixture was concentrated
under reduced pressure and diluted with toluene (10 mL). To the
mixture was added DMAP (111 mg, 0.910 mmol) in toluene (7 mL),
and stirred for 40 min at room temperature. The mixture was di-
luted with EtOAc and filtered through a Celite pad. The filtrate was
concentrated, and the residue was purified by chromatography
(hexane/EtOAc, 5:1 to 2.5:1) to give 7 (144 mg, 67% for the 5 steps):
4.6. Hydroxy ketone 16
To a solution of 13 (332 mg, 0.352 mmol) in THF (1.5 mL) at 0 ꢀC
was added BH3$THF (3.5 mL, 3.50 mmol, 1.0 M solution in THF).
After stirring for 40 min at the same temperature, the mixture was
quenched with MeOH at 0 ꢀC. The mixture was then treated with
3 M NaOH (2 mL) and 30% H2O2 (2 mL), and the resulting mixture
was stirred for 20 min at the same temperature. The mixture was
quenched with saturated Na2SO3 at 0 ꢀC and stirred for 0.5 h at
room temperature. The mixture was diluted with EtOAc, then
washed with water and brine. Concentration gave the crude alcohol
14, which was used for the next reaction directly.
yellow oil; Rf¼0.53 (hexane/EtOAc, 1:1); [
a
]
22 þ3.2 (c 1.00, CHCl3);
D
IR (neat) 3031, 1739, 1038 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
7.32e7.22 (m, 10H), 4.84 (d, J¼6.6 Hz, 1H), 4.62e4.55 (m, 1H), 4.61
(d, J¼6.6 Hz, 1H), 4.57 (d, J¼12.0 Hz, 1H), 4.53 (d, J¼12.0 Hz, 1H),
4.45 (d, J¼12.0 Hz, 1H), 4.44 (d, J¼12.0 Hz, 1H), 4.03e3.98 (m, 1H),
3.72 (dd, J¼12.0, 4.4 Hz, 1H), 3.57e3.52 (m, 1H), 3.52 (d, J¼10.5 Hz,
1H), 3.40 (d, J¼10.5 Hz, 1H), 3.32 (s, 3H), 3.03 (t, J¼13.0 Hz, 1H),
2.45e2.35 (m, 2H), 2.11e2.02 (m, 1H), 1.90e1.76 (m, 2H), 1.15
ꢀ
To a stirred solution of the crude alcohol 14 and MS4 A in CH2Cl2
(3 mL) at 0 ꢀC were added TPAP (14.1 mg, 40.1
mmol) and NMO
(82.5 mg, 0.704 mmol). After stirring for 1.5 h at room temperature,
the mixture was filtered through a short silica gel column (hexane/
EtOAc, 2:1) to give the crude ketone, which was used for the next
reaction directly.
A mixture of the crude ketone and DBU (0.11 mL, 0.704 mmol) in
toluene (3 mL) was heated at 110 ꢀC with stirring. After 3 h, the
mixture was filtered through a short silica gel column (hexane/
EtOAc, 2:1) to give ketone 15, which was used for the next reaction
without further purification.
To a solution of the ketone 15 in CH2Cl2 (7.5 mL) and saturated
NaHCO3 (1.5 mL) was added DDQ (160 mg, 0.704 mmol). After
stirring for 0.5 h at room temperature, the reaction mixture was
diluted with CH2Cl2, then washed with water and brine. Con-
centration and chromatography (hexane/EtOAc, 7:1 to 4:1 to 2:1)
(s, 3H); 13C NMR (100 MHz, CDCl3)
d 174.6, 138.3, 138.2, 128.3 (2C),
128.2 (2C), 127.6 (2C), 127.5 (2C), 127.4 (2C), 97.2, 77.2, 74.6, 74.0,
73.4, 73.2, 72.4, 71.5, 70.0, 55.6, 30.3, 27.6, 27.1,13.1; HRMS (ESI TOF)
calcd for C27H34O7Na (MþNa)þ 493.2202, found 493.2216.
4.5. Enol ether 13
To a solution of 7 (699 mg, 1.48 mmol), DMPU (0.98 mL,
3.70 mmol), and (PhO)2POCl (0.55 mL, 2.67 mmol) in THF (10 mL)
at ꢁ78 ꢀC was added KHMDS (5.9 mL, 2.95 mmol, 0.5 M solution in
toluene). After stirring for 0.5 h at ꢁ78 ꢀC, the reaction mixture was
quenched with a 1:1 mixture of saturated NaHCO3 and MeOH
(3 ml), and the resultant mixture was allowed to warm to room
temperature. The mixture was diluted with Et2O, then washed with
water and brine, and concentrated. The residue was passed through
a short pad of silica gel column (hexane/EtOAc, 2:1) to give the
crude enol phosphate 12, which was used for the next reaction
without further purification.
gave 16 (263 mg, 89% for the 4 steps): light yellow oil; Rf¼0.33
26
(hexane/EtOAc, 2:1);
[
a
]
ꢁ32.8 (c 0.97, CHCl3); IR (neat)
D
3686e3243, 2940, 1715 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
7.67e7.63 (m, 4H), 7.40e7.20 (m, 16H), 4.74 (d, J¼6.8 Hz, 1H),
4.57 (d, J¼11.5 Hz, 1H), 4.57 (d, J¼6.8 Hz, 1H), 4.53 (d, J¼12.0 Hz,
1H), 4.45 (d, J¼12.0 Hz, 1H), 4.40 (d, J¼11.5 Hz, 1H), 4.09 (br d,
J¼7.8 Hz, 1H), 3.84 (dd, J¼10.1, 3.4 Hz, 1H), 3.72e3.63 (m, 3H),
3.58 (br d, J¼3.9 Hz, 2H), 3.53e3.46 (m, 1H), 3.51 (d, J¼10.3 Hz,
1H), 3.41 (d, J¼10.3 Hz, 1H), 3.33 (s, 3H), 2.99 (d, J¼12.9 Hz, 1H),
2.73 (dd, J¼12.9, 7.8 Hz, 1H), 2.35 (ddd, J¼11.7, 3.9, 3.9 Hz, 1H),
2.22 (br s, 1H), 1.81e1.40 (m, 8H), 1.17 (s, 3H), 1.03 (s, 9H), 0.90 (d,
To a solution of 6 (1.63 g, 2.64 mmol) in Et2O (15 mL) at ꢁ78 ꢀC
was added t-BuLi (4.4 mL, 5.28 mmol, 1.2 M solution in pentane).
After stirring for 3 min at ꢁ78 ꢀC a mixture of 9-BBNeOMe (6.6 mL,
6.60 mmol, 1.0 M solution in hexane) in THF (12 mL) was in-
troduced, and the mixture was allowed to warm to room temper-
ature over 1.5 h. To the mixture were added 3 M K3PO4 (2.2 mL,
6.60 mmol) and a solution of the crude enol phosphate 12 and
PdCl2(dppf) (122 mg, 0.149 mmol) in a 5:1 mixture DMF and THF
J¼6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 212.7, 138.5, 138.4,
135.5 (4C), 133.7 (2C), 129.5 (2C), 128.2 (4C), 127.6 (2C), 127.5

H. Takamura et al. / Tetrahedron 66 (2010) 5329e5344
5337
(6C), 127.4 (2C), 96.2, 85.9, 77.5, 77.2, 74.8, 74.7, 74.4, 73.5 (2C),
71.6, 71.3, 64.1, 55.6, 43.7, 36.0, 35.5, 31.7, 30.6, 29.5, 26.9 (3C),
19.3, 13.6, 13.4; HRMS (ESI TOF) calcd for C50H66O9SiNa (MþNa)þ
861.4374, found 861.4376.
the mixture was stirred for 30 min at room temperature. The
mixture was quenched with MeOH, diluted with Et2O, then washed
with water and brine. Concentration gave the crude bis-silyl ether,
which was used for the next reaction directly.
To a solution of the crude bis-silyl ether in MeOH (2 mL) and
4.7. Mixed thioacetal 17
CH2Cl2 (2 mL) at 0 ꢀC was added PPTS (11.0 mg, 43.6
mmol). After
stirring for 1 h at the same temperature, the reaction mixture was
quenched with Et3N (0.5 mL). Concentration and chromatography
To a solution of 16 (182 mg, 0.217 mmol) in THF (2 mL) were
added EtSH (0.32 mL, 4.35 mmol) and Zn(OTf)2 (115 mg,
0.326 mmol). After stirring for 15 min at room temperature, the
mixture was quenched with Et3N, and the insoluble material was
filtered off through a Celite pad. The filtrate was concentrated and
(hexane/EtOAc, 20:1 to 5:1) gave 20 (148 mg, 89% for the 3 steps):
23
colorless oil; Rf¼0.37 (hexane/EtOAc, 4:1); [
a]
ꢁ13.7 (c 0.97,
D
CHCl3); IR (neat) 3655e3299, 2953, 1087 cmꢁ1; 1H NMR (400 MHz,
CDCl3)
7.64 (dd, J¼8.0, 1.6 Hz, 4H), 7.42e7.31 (m, 6H), 4.71 (d,
d
purified by chromatography (hexane/EtOAc, 15:1) to give 17
J¼6.7 Hz, 1H), 4.66 (d, J¼6.7 Hz, 1H), 4.12 (dd, J¼11.1, 5.0 Hz, 1H),
3.88 (dd, J¼11.8, 4.8 Hz, 1H), 3.84 (t, J¼3.7 Hz, 1H), 3.69e3.56 (m,
3H), 3.50e3.34 (m, 3H), 3.37 (s, 3H), 3.28 (d, J¼9.0 Hz, 1H), 2.56 (dd,
J¼9.8, 2.7 Hz, 1H), 2.18 (dd, J¼15.9, 3.8 Hz, 1H), 2.08 (ddd, J¼12.0,
4.6, 4.6 Hz, 1H), 1.91 (dd, J¼15.9, 3.8 Hz, 1H), 1.79e1.20 (m, 8H), 1.16
(s, 3H),1.03 (s, 3H),1.02 (s, 9H), 0.95e0.90 (m, 9H), 0.92 (d, J¼7.8 Hz,
27
(171 mg, 89%): colorless oil; Rf¼0.53 (hexane/EtOAc, 4:1); [
a]
D
ꢁ38.9 (c 1.00, CHCl3); IR (neat) 3030, 2931 cmꢁ1
;
1H NMR
(400 MHz, CDCl3) d 7.66e7.61 (m, 4H), 7.42e7.32 (m, 6H), 7.32e7.20
(m, 10H), 4.72 (d, J¼6.6 Hz, 1H), 4.65 (d, J¼6.6 Hz, 1H), 4.57 (d,
J¼11.8 Hz, 1H), 4.54 (d, J¼12.2 Hz, 1H), 4.48 (d, J¼12.2 Hz, 1H), 4.39
(d, J¼11.8 Hz, 1H), 4.15 (dd, J¼11.8, 5.0 Hz, 1H), 4.00e3.95 (m, 1H),
3.93 (d, J¼9.5 Hz, 1H), 3.85e3.78 (m, 1H), 3.75e3.57 (m, 4H), 3.48
(d, J¼10.5 Hz, 1H), 3.41 (d, J¼10.5 Hz, 1H), 3.33 (s, 3H), 2.68 (dd,
J¼15.8, 5.1 Hz, 1H), 2.41e2.21 (m, 4H), 2.03 (ddd, J¼12.4, 12.4,
4.5 Hz, 1H), 1.83e1.75 (m, 1H), 1.72e1.35 (m, 6H), 1,19 (t, J¼7.6 Hz,
3H), 1.16 (s, 3H), 1.02 (s, 9H), 0.90 (d, J¼7.1 Hz, 3H); 13C NMR
3H), 0.58 (q, J¼7.8 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 135.5 (4C),
134.0 (2C), 129.4 (2C), 127.5 (4C), 97.3, 79.0, 77.4, 75.7, 73.6, 73.0,
71.0, 67.3, 66.5, 63.9, 55.5, 46.5, 36.0, 34.8, 32.7, 32.6, 29.2, 29.1, 26.9
(3C), 20.5, 19.3, 13.0, 12.4, 6.9 (3C), 5.1 (3C); HRMS (ESI TOF) calcd
for C43H70O8Si2Na (MþNa)þ 793.4507, found 793.4514.
(100 MHz, CDCl3)
d
138.7, 138.6, 135.5 (4C), 134.0 (2C), 129.5 (2C),
4.10. Unsaturated ester 21
128.2 (4C), 127.5 (4C), 127.4 (2C), 127.3 (2C), 127.2 (2C), 96.4, 93.0,
77.2, 75.9, 75.1, 74.4, 73.9, 73.7, 73.4 (2C), 72.7, 71.7, 70.9, 63.9, 55.4,
46.0, 35.5, 31.9, 31.6, 29.5, 28.7, 26.9 (3C),19.3,14.4,13.3,12.9; HRMS
(ESI TOF) calcd for C52H70O8SSiNa (MþNa)þ 905.4459, found
905.4427.
ꢀ
To a solution of 20 (270 mg, 0.345 mmol) and MS4 A (30 mg) in
CH2Cl2 (3.5 mL) at 0 ꢀC were added TPAP (12.1 mg, 34.5
mmol) and
NMO (80.8 mg, 0.690 mmol), and the mixture was stirred for 0.5 h
at room temperature. The mixture was filtered through a short
silica gel column (hexane/EtOAc, 2:1) to give the crude aldehyde,
which was used for the next reaction directly.
4.8. Tricycle 19
A mixture of the crude aldehyde and Ph3P]CHCO2Me (346 mg,
1.04 mmol) in benzene (3.5 mL) was refluxed for 4 h. The mixture
was subjected directly to a column chromatography (hexane/
EtOAc, 20:1 to 5:1) to give the unsaturated ester 21 (141 mg, 96% for
To a solution of 17 (171 mg, 0.194 mmol) in CH2Cl2 (2 mL) at 0 ꢀC
were added Me2Zn (1.9 mL, 1.90 mmol, 1.0 M solution in hexane)
and Zn(OTf)2 (2.6 mg, 0.58 mmol), and the reaction mixture was
allowed to warm to room temperature over 1 h with stirring. After
quenching with a 1:1 mixture of MeOH and Et3N (1 mL), the mix-
ture was diluted with Et2O and filtered through a Celite pad. Con-
the 2 steps): colorless oil; Rf¼0.48 (hexane/EtOAc, 4:1); [
a
]
22 ꢁ21.8
D
(c 0.76, CHCl3); IR (neat) 2952, 1727, 1661 cmꢁ1; 1H NMR (400 MHz,
CDCl3)
d
7.64 (dd, J¼6.3, 1.6 Hz, 4H), 7.42e7.32 (m, 6H), 7.05 (d,
centration and chromatography (hexane/EtOAc, 10:1) gave 19
J¼15.6 Hz, 1H), 5.98 (d, J¼15.6 Hz, 1H), 4.77 (d, J¼6.7 Hz, 1H), 4.69
(d, J¼6.7 Hz, 1H), 4.16 (dd, J¼11.6, 5.0 Hz, 1H), 3.95 (t, J¼3.8 Hz, 1H),
3.71e3.57 (m, 3H), 3.71 (s, 3H), 3.50 (dd, J¼11.6, 4.8 Hz, 1H),
3.45e3.39 (m, 1H), 3.40 (s, 3H), 3.32 (d, J¼8.8 Hz, 1H), 2.21 (dd,
J¼16.0, 3.8 Hz, 1H), 2.07 (ddd, J¼12.0, 4.8, 4.8 Hz, 1H), 1.89 (dd,
J¼16.0, 3.8 Hz, 1H), 1.75e1.21 (m, 8H), 1.22 (s, 3H), 1.16 (s, 3H), 1.02
(s, 9H), 0.92 (t, J¼8.1 Hz, 9H), 0.91 (d, J¼7.6 Hz, 3H), 0.56 (q,
24
(163 mg, quant.): colorless oil; Rf¼0.50 (hexane/EtOAc, 4:1); [
a]
D
ꢁ18.7 (c 0.97, CHCl3); IR (neat) 3030, 2931 cmꢁ1
;
1H NMR
(400 MHz, CDCl3)
d
7.65 (dd, J¼7.8, 1.4 Hz, 4H), 7.42e7.32 (m, 6H),
7.32e7.20 (m, 10H), 4.73 (d, J¼6.6 Hz, 1H), 4.70 (d, J¼6.6 Hz, 1H),
4.58 (d, J¼11.7 Hz, 1H), 4.56 (d, J¼12.2 Hz, 1H), 4.49 (d, J¼12.2 Hz,
1H), 4.41 (d, J¼11.7 Hz, 1H), 4.17 (dd, J¼11.5, 5.1 Hz, 1H), 3.98e3.93
(m, 1H), 3.75e3.57 (m, 4H), 3.50 (d, J¼10.5 Hz, 1H), 3.43 (d,
J¼10.5 Hz, 1H), 3.36 (s, 3H), 3.46e3.31 (m, 2H), 2.35 (ddd, J¼11.9,
4.6, 4.6 Hz,1H), 2.20 (dd, J¼16.1, 3.7 Hz, 1H),1.90 (dd, J¼15.9, 3.9 Hz,
1H), 1.77e1.24 (m, 8H), 1.18 (s, 3H), 1.14 (s, 3H), 1.04 (s, 9H), 0.90 (d,
J¼8.1 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 167.2, 152.2, 135.5 (4C),
134.0 (2C), 129.4 (2C), 127.5 (4C), 118.1, 96.3, 77.2, 76.8, 75.9, 73.5,
72.6, 71.5, 71.0, 63.9, 55.5, 51.5, 46.1, 36.2, 34.8, 32.7, 29.2, 29.1, 26.9
(3C), 22.7, 20.5, 19.3, 14.8, 12.4, 6.9 (3C), 5.0 (3C); HRMS (ESI TOF)
calcd for C46H72O9Si2Na (MþNa)þ 847.4612, found 847.4606.
J¼7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 138.7, 138.6, 135.5 (4C),
134.0 (4C), 129.4 (2C), 128.2 (4C), 127.5 (4C), 127.4 (2C), 127.3 (2C),
127.2 (2C), 96.0, 77.4, 77.1, 76.5, 76.1, 75.0, 73.9, 73.5, 73.3, 72.9, 71.0,
63.9, 55.3, 46.1, 34.9, 32.7, 31.9, 29.8, 29.2, 29.1, 26.9 (3C), 20.5, 19.3,
13.3, 12.4; HRMS (ESI TOF) calcd for C51H68O8SiNa (MþNa)þ
859.4581, found 859.4512.
4.11. Hydroxy ester 23
A mixture of 21 (278 mg, 0.332 mmol) and PdeC (55.0 mg) in
EtOAc (5 mL) was stirred under H2 atmosphere at room tempera-
ture. After 3 h, the catalyst was filtered off through a short silica gel
column (EtOAc), and the filtrate was concentrated to give the crude
saturated ester, which was used for the next reaction directly.
To a solution of the crude ester in THF (2 mL) and H2O (2 mL)
was added LiOH$H2O (41.8 mg, 0.996 mmol). After stirring for 10 h
at 75 ꢀC, an additional amount of LiOH$H2O (41.8 mg, 0.996 mmol)
was added, and the reaction mixture was stirred for further 6.5 h.
The reaction mixture was cooled to 0 ꢀC, diluted with Et2O, and
then neutralized carefully with 0.5 M HCl. The resulting mixture
was diluted with EtOAc, then washed with water and brine. The
4.9. Alcohol 20
A mixture of 19 (181 mg, 0.216 mmol) and Pd(OH)2eC (60.0 mg)
in THF (2 mL) was stirred under H2 atmosphere at room tempera-
ture. After 4 h, the catalyst was filtered off, and the filtrate was
concentrated to give the crude diol, which was used for the next
reaction directly.
To a solution of the crude diol in DMF (1 mL) were added im-
idazole (148 mg, 2.18 mmol) and TESCl (0.18 mL, 1.09 mmol), and

5338
H. Takamura et al. / Tetrahedron 66 (2010) 5329e5344
aqueous layer was extracted with EtOAc (two times). The combined
organic layer was concentrated to give the crude carboxylic acid 4,
which was used for next reaction directly.
d
7.83e7.77 (m, 4H), 7.26e7.21 (m, 6H), 6.93 (s, 2H), 5.84 (dd, J¼17.4,
10.7 Hz,1H), 5.17 (dd, J¼17.4,1.2 Hz,1H), 5.08 (dd, J¼9.9, 2.3 Hz,1H),
4.98 (dd, J¼10.7, 1.2 Hz, 1H), 4.68 (ddd, J¼9.0, 9.0, 6.0 Hz, 1H), 4.44
(s, 2H), 4.14 (dd, J¼9.6, 7.2 Hz, 1H), 3.97 (br s, 1H), 3.79e3.65 (m,
2H), 3.60 (ddd, J¼10.7, 10.7, 4.4 Hz, 1H), 3.45e3.25 (m, 5H),
2.54e2.42 (m, 3H), 2.37 (dd, J¼15.9, 2.9 Hz, 1H), 2.33e2.21 (m, 2H),
2.13e1.99 (m, 2H), 1.97e1.85 (m, 2H), 1.84e1.48 (m, 20H), 1.45e1.33
(m, 8H), 1.29 (s, 3H), 1.20 (s, 3H), 1.19 (s, 9H), 1.01 (s, 9H), 1.01e0.96
(m, 18H), 0.16 (s, 3H), 0.12 (s, 3H); HRMS (ESI TOF) calcd for
C73H115Cl3O10Si2SnNa (MþNa)þ 1455.6014, found 1455.6338.
To a solution of the crude 4 in THF (1.5 mL) were added Et3N
(0.21 mL, 1.49 mmol) and 2,4,6-trichlorobenzoyl chloride (0.13 mL,
0.830 mmol). After stirring for 40 min at room temperature, the
mixture was concentrated under reduced pressure, then diluted
with toluene (5 mL). To the resulting mixture was added a solution
of 5 (310.7 mg, 0.644 mmol) and DMAP (142.0 mg, 1.16 mmol) in
toluene (5 mL). After stirring for 1.5 h at room temperature, the
mixture was diluted with EtOAc and filtered through a Celite pad.
Concentration and chromatography (hexane/EtOAc, 4:1) gave
a mixture of ester 22 and unreacted 5. The mixture was used for the
next reaction without further purification.
4.14. Silyl ether 27
To a solution of 26 (170 mg, 0.119 mmol) in CH2Cl2 (3 mL) at 0 ꢀC
were added 2,6-lutidine (0.14 mL, 1.19 mmol) and TBSOTf (0.08 mL,
0.348 mmol). After stirring for 0.5 h at 0 ꢀC, an additional amount of
TBSOTf (0.04 mL, 0.174 mmol) was added, and the reaction mixture
was stirred for 0.5 h. The reaction mixture was quenched with
MeOH, diluted with EtOAc, then washed with saturated NaHCO3
and brine. Concentration and chromatography (hexane/EtOAc, 1:0
to 50:1 to 20:1 containing 0.5% Et3N) gave 27 (175 mg, 95%): col-
To a crude mixture of 22 and 5 in MeOH (2 mL) and CH2Cl2
(2 mL) at 0 ꢀC was added CSA (15.4 mg, 66.4
mmol). After stirring for
1 h at the same temperature, the reaction mixture was quenched
with Et3N. Concentration and chromatography (hexane/EtOAc, 20:1
to 4:1 to 2:1) gave 23 (281 mg, 74% for the 4 steps): colorless oil;
25
Rf¼0.41 (hexane/EtOAc, 2:1); [
a]
ꢁ23.7 (c 0.83, CHCl3); IR (neat)
D
3637e3243, 2929, 1737 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 7.64 (dd,
J¼7.9, 1.6 Hz, 4H), 7.42e7.32 (m, 6H), 7.31 (s, 2H), 5.81 (dd, J¼17.3,
10.7 Hz, 1H), 5.16 (dd, J¼17.3, 1.2 Hz, 1H), 5.08 (dd, J¼10.7, 1.2 Hz,
1H), 4.82e4.76 (m,1H), 4.70 (d, J¼6.6 Hz,1H), 4.63 (d, J¼6.6 Hz,1H),
4.65 (s, 2H), 4.11 (dd, J¼11.5, 4.9 Hz, 1H), 3.88 (t, J¼3.6 Hz, 1H),
3.69e3.56 (m, 3H), 3.48 (t, J¼6.1 Hz, 2H), 3.44e3.32 (m, 2H), 3.36 (s,
3H), 3.24 (d, J¼9.3 Hz,1H), 2.46 (ddd, J¼17.4, 7.0, 7.0 Hz,1H), 2.39 (d,
J¼5.4 Hz, 1H), 2.31 (ddd, J¼17.4, 7.0, 7.0 Hz, 1H), 2.17 (dd, J¼16.0,
3.5 Hz, 1H), 2.10 (ddd, J¼11.7, 4.5, 4.5 Hz, 1H), 1.94e1.84 (m, 3H),
1.83e1.42 (m, 10H), 1.39e1.28 (m, 2H), 1.24 (s, 3H), 1.15 (s, 3H), 1.11
(s, 3H), 1.02 (s, 9H), 0.89 (d, J¼6.8 Hz, 3H), 0.84 (s, 9H), 0.06 (s, 3H),
orless oil; Rf¼0.56 (hexane/EtOAc, 7:1); [
a
]
D
23 ꢁ1.6 (c 0.75, C6D6); IR
(neat) 2928, 1738, 1089 cmꢁ1; 1H NMR (400 MHz, C6D6)
d
7.83e7.76
(m, 4H), 7.28e7.21 (m, 6H), 6.93 (s, 2H), 5.88 (dd, J¼17.3, 10.7 Hz,
1H), 5.68 (d, J¼5.9 Hz, 1H), 5.19 (dd, J¼17.3, 1.5 Hz, 1H), 5.14 (dd,
J¼10.1, 2.1 Hz,1H), 5.01 (dd, J¼10.7, 1.2 Hz, 1H), 4.65 (ddd, J¼9.0, 9.0,
6.0 Hz, 1H), 4.44 (s, 2H), 4.45e4.40 (m, 1H), 3.99 (br s, 1H),
3.88e3.79 (m, 1H), 3.79e3.62 (m, 2H), 3.49e3.32 (m, 4H), 3.23 (d,
J¼9.3 Hz, 1H), 2.76e2.58 (m, 2H), 2.42e2.32 (m, 2H), 2.22 (dd,
J¼16.0, 3.0 Hz, 1H), 2.10e2.01 (m, 1H), 2.01e1.90 (m, 2H), 1.89e1.49
(m,19H), 1.45e1.33 (m, 6H), 1.31 (s, 3H), 1.23 (s, 3H), 1.22 (s, 3H), 1.19
(s, 9H), 1.09 (s, 9H), 1.05 (d, J¼7.1 Hz, 3H), 1.02e0.97 (m, 15H), 1.01
(s, 9H), 0.21 (s, 3H), 0.19 (s, 3H), 0.18 (s, 3H), 0.13 (s, 3H); HRMS
(ESI TOF) calcd for C79H129Cl3O10Si3SnNa (MþNa)þ 1569.6881,
found 1569.6549.
0.04 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 174.7, 142.9, 137.2 (2C),
135.5 (4C), 134.6, 134.0 (2C), 132.3, 129.4 (2C), 128.2 (2C), 127.5 (4C),
114.3, 95.9, 78.8, 77.4, 76.9, 76.5, 75.8, 75.6, 73.4, 73.2, 70.9, 70.4,
69.4, 66.5, 63.9, 55.2, 46.0, 34.9, 34.8, 33.9, 32.6, 29.2, 29.1, 27.7, 26.9
(3C), 26.4, 25.9 (3C), 25.6, 22.3, 20.5, 19.3, 18.3, 15.5, 12.4, ꢁ2.0 (2C);
HRMS (ESI TOF) calcd for C60H89Cl3O11Si2Na (MþNa)þ 1171.4899,
found 1171.4878.
4.15. Diene 28
To a stirring solution of 27 (24.6 mg, 15.9
m
mol) in CH2Cl2
4.12. Mixed acetal 25
(1.5 mL) at ꢁ78 ꢀC was added DIBAL-H (32
mL, 32.6 mol, 1.02 M
m
solution in hexane). To this mixture, pre-cooled (ꢁ40 ꢀC) solutions
To a mixture of 23 (214 mg, 0.186 mmol) and 24 (0.18 mL,
0.559 mmol) in CH2Cl2 (3 mL) was added CSA (8.6 mg, 0.037 mmol).
After stirring for 15 min at room temperature, the reaction mixture
was quenched with Et3N. Concentration and chromatography
(hexane/EtOAc, 100:1 to 50:1 to 15:1 to 4:1 containing 0.5% Et3N)
gave 25 (245 mg, 88%) and unreacted 23 (25.1 mg, 12% recovery):
colorless oil; Rf¼0.54 (hexane/EtOAc, 4:1); IR (neat) 2928, 1737,
of pyridine (8 mL, 98.9 mmol) and DMAP (7.8 mg, 63.6 mmol) in
CH2Cl2 (0.3 mL) and (clCH2CO)2O (22 mg, 0.129 mmol) in CH2Cl2
(0.7 mL) were introduced immediately. The reaction mixture was
allowed to warm to ꢁ10 ꢀC over 1 h with stirring, and quenched
with H2O. The mixture was diluted with Et2O, then washed with
saturated potassium sodium tartrate, saturated CuSO4, water, sat-
urated NaHCO3, and brine. Concentration gave the crude a-chlor-
1101 cmꢁ1; 1H NMR (400 MHz, C6D6)
d
7.82e7.77 (m, 4H), 7.27e7.09
oacetoxy ether 3, which was used for the next reaction directly.
To the stirring suspension of MgBr2$OEt2 (41.1 mg, 0.159 mmol)
(m, 6H), 6.94e6.91 (m, 2H), 5.93e5.83 (m, 1H), 5.21e5.11 (m, 2H),
5.04e4.97 (m,1H), 4.80e4.74 (m, 2H), 4.50e4.34 (m, 4H), 4.02e3.94
(m, 1H), 3.89e3.59 (m, 3H), 3.48e3.10 (m, 11H), 2.80e2.55 (m, 2H),
2.46e2.02 (m, 3H), 2.00e1.46 (m,18H),1.45e1.33 (m, 6H),1.30e1.16
(m, 21H), 1.04e0.84 (m, 30H), 0.18e0.11 (m, 6H).
and MS5 A (30 mg) in CH2Cl2 (1.5 mL) at ꢁ78 ꢀC was added a pre-
ꢀ
ꢀ
ꢀ
cooled (ꢁ40 C) solution of 3 (dried over MS5 A) in CH2Cl2 (1.5 mL).
The mixture was allowed to warm to 0 ꢀC over 50 min, and
quenched with Et3N. The mixture was filtered through a short silica
gel column (EtOAc) and concentrated. The residue was purified by
chromatography (hexane/EtOAc, 1:0 to 40:1 to 20:1 to 10:1) to give
4.13. Allylic stannane 26
28 (10.2 mg, 52% for the 2 steps): colorless oil; Rf¼0.42 (hexane/
23
To a mixture of 25 (89.3 mg, 59.1
m
mol) in CH2Cl2 (4 mL) at
EtOAc, 7:1); [
a
]
ꢁ8.6 (c 0.63, CHCl3); IR (neat) 2929, 1471, 1428,
D
ꢁ15 ꢀC were added HMDS (0.39 ml, 1.77 mmol) and TMSI (84
ml,
1081 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
7.64 (dd, J¼7.4, 1.5 Hz, 4H),
0.59 mmol), and the mixture was stirred for 1.5 h at the same
temperature. The reaction mixture was quenched with saturated
NaHCO3, diluted with AcOEt, then washed with water and brine.
Concentration and chromatography (hexane/EtOAc, 100:1 to 20:1
to 10:1 to 8:1 containing 2% Et3N) gave 26 (76.8 mg, 91%): colorless
7.42e7.31 (m, 6H), 7.31 (s, 2H), 5.90 (dd, J¼17.6, 10.7 Hz, 1H), 5.63
(ddd, J¼17.1, 10.7, 5.1 Hz, 1H), 5.20 (dd, J¼17.1, 1.5 Hz, 1H), 5.18 (d,
J¼17.6 Hz, 1H), 5.15 (d, J¼10.7 Hz, 1H), 5.01 (dd, J¼10.7, 1.5 Hz, 1H),
4.66 (s, 2H), 4.29 (d, J¼4.6 Hz, 1H), 4.21 (dd, J¼11.3, 5.0 Hz, 1H), 3.95
(br s, 1H), 3.70e3.36 (m, 8H), 3.17 (d, J¼9.3 Hz, 1H), 3.07 (dd, J¼7.1,
2.7 Hz, 1H), 2.05e1.20 (m, 19H), 1.26 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H),
1.03 (s, 9H), 0.92e0.88 (m, 12H), 0.83 (s, 9H), 0.06 (s, 3H), 0.05 (s,
oil; Rf¼0.51 (hexane/EtOAc, 4:1); [
a
]
D
23 ꢁ8.6 (c 0.78, C6D6); IR (neat)
3668e3280, 2929, 1736 cmꢁ1
;
1H NMR (400 MHz, C6D6)

H. Takamura et al. / Tetrahedron 66 (2010) 5329e5344
5339
6H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
145.6, 137.9, 137.2
(s, 3H), 1.19 (s, 9H), 1.15 (s, 3H), 1.13 (s, 3H), 1.09 (s, 9H), 1.05 (d,
(2C), 135.5 (4C), 134.5, 134.1 (2C), 132.4, 129.4 (2C), 128.2 (2C), 127.5
(4C), 114.4, 114.1, 87.3, 82.7, 82.2, 77.6, 77.5, 77.2, 76.2, 75.2, 72.7,
72.5, 71.4, 70.8, 66.6, 64.0 (2C), 49.5, 35.0, 34.9, 34.4, 32.5, 29.3, 29.1,
28.2, 27.5, 26.9 (3C), 26.1 (3C), 26.0 (3C), 23.3, 20.9, 20.2, 19.3, 18.3,
18.2, 15.5, 12.4, ꢁ1.9 (2C), ꢁ3.9, ꢁ5.0; HRMS (ESI TOF) calcd for
C67H103Cl3O9Si3Na (MþNa)þ 1265.5868, found 1265.6018.
J¼7.1 Hz, 3H), 0.94 (s, 9H), 0.20 (s, 3H), 0.17 (s, 3H), 0.07 (s, 3H), 0.06
(s, 3H); 13C NMR (100 MHz, CDCl3)
d 138.6, 135.5 (4C), 134.1 (2C),
129.4 (2C), 128.2 (2C), 127.6 (2C), 127.5 (4C), 127.4, 88.2, 86.6, 85.0,
82.2, 77.6, 77.2, 76.1, 75.5, 73.1, 72.9, 72.8, 72.6, 70.8, 70.7, 64.0, 49.5,
37.8, 37.7, 35.0, 33.9, 32.6, 29.6, 29.5, 29.3, 29.1, 28.9, 27.3, 27.0 (3C),
26.0 (3C), 25.8 (3C), 24.0, 20.9, 19.3, 18.3, 18.1, 16.2, 12.4, ꢁ2.0, ꢁ2.2,
ꢁ4.2, ꢁ4.8; (100 MHz, C6D6)
d 139.5, 136.0 (4C), 134.5 (2C), 129.9
4.16. Pentacycle 30
(2C), 128.5(2C), 127.9 (4C), 127.5 (3C), 88.7, 86.6, 85.0, 83.0, 78.1,
77.7, 76.6, 76.2, 73.8, 73.4, 73.3, 73.1, 71.2, 71.0, 64.4, 50.0, 38.1 (2C),
35.6, 34.8, 33.3, 30.3, 30.0, 29.6, 29.5, 27.9 (2C), 27.3 (3C), 26.5 (3C),
26.2 (3C), 24.1, 21.4, 19.6, 18.7, 18.5, 16.1, 13.0, ꢁ1.8, ꢁ1.9, ꢁ3.8, ꢁ4.6;
HRMS (ESI TOF) calcd for C65H104O9Si3Na (MþNa)þ 1135.6886,
found 1135.6899.
To a solution of 28 (10.9 mg, 8.77
added the Grubbs’ catalyst 29 (22 mg, 26
was stirred at 100 ꢀC. After 15 min, an additional amount of 29
(3.6 mg, 4.37
mol) was added. After stirring for 15 min at 100 ꢀC,
mmol) in toluene (2.9 mL) was
mmol), and the mixture
m
the reaction was quenched with Et3N at room temperature, diluted
with EtOAc, filtered through a short silica gel column (EtOAc).
Concentration and chromatography (cH2Cl2/EtOAc, 1:0 to 100:1 to
4.18. Alcohol 2
50:1, hexane/EtOAc, 40:1 to 30:1 to 20:1) gave 30 (7.4 mg, 69%):
A mixture of 32 (5.6 mg, 5.03 mmol) and Pd(OH)2eC (7.2 mg) in
24
colorless oil; Rf¼0.46 (hexane/EtOAc, 7:1); [
CHCl3); IR (neat) 2929, 1090 cmꢁ1
7.67e7.61 (m, 4H), 7.42e7.31 (m, 6H), 7.31 (s, 2H), 5.63 (dd, J¼13.3,
a
]
ꢁ11.0 (c 0.67,
EtOAc (1.2 mL) was stirred under H2 atmosphere at room temper-
ature. After 45 min, the catalyst was filtered off through a short
silica gel column (EtOAc) and concentrated. The residue was puri-
fied by chromatography (hexane/EtOAc, 10:1 to 7:1 to 4:1) to give 2
D
;
1H NMR (400 MHz, CDCl3)
d
2.3 Hz, 1H), 5.41 (dd, J¼13.3, 1.5 Hz, 1H), 4.67 (s, 2H), 4.16 (dd,
J¼11.3, 4.8 Hz, 1H), 3.95 (br s, 1H), 3.89 (br d, J¼9.3 Hz, 1H),
3.75e3.46 (m, 5H), 3.39 (dd, J¼6.1, 6.1 Hz, 1H), 3.31 (d, J¼10.7 Hz,
1H), 3.28e3.18 (m, 3H), 2.06 (ddd, J¼11.5, 4.3, 4.3, 1H), 2.03e1.95
(m, 1H), 1.94e1.21 (m, 17H), 1.17 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.02
(s, 9H), 0.89 (s, 9H), 0.88 (d, J¼6.6 Hz, 3H), 0.81 (s, 9H), 0.07 (s, 6H),
(4.6 mg, 89%): colorless oil; Rf¼0.20 (hexane/EtOAc, 4:1); [
a]
22 ꢁ9.1
D
(c 0.87, CHCl3); IR (neat) 3606e3144, 2928, 1731, 1085 cmꢁ1
;
1H
NMR (400 MHz, CDCl3) d 7.66e7.61 (m, 4H), 7.41e7.31 (m, 6H), 4.17
(dd, J¼11.6, 5.0 Hz, 1H), 3.94 (dd, J¼3.7, 3.7 Hz, 1H), 3.73e3.56 (m,
5H), 3.41e3.22 (m, 3H), 3.22e3.16 (m, 2H), 3.10 (dd, J¼12.1, 3.7 Hz,
1H), 2.17e1.20 (m, 23H), 1.14 (s, 3H), 1.12 (s, 3H), 1.08 (s, 3H), 1.02 (s,
9H), 0.89 (s, 9H), 0.88 (d, J¼6.3 Hz, 3H), 0.81 (s, 9H), 0.06 (s, 3H),
0.04 (s, 3H), 0.03 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3)
0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 138.8, 137.2
(2C), 135.5 (4C), 134.5, 134.1 (2C), 132.4, 129.9, 129.4 (2C), 128.2 (2C),
127.5 (4C), 88.2, 86.3, 83.9, 80.2, 78.3, 77.6, 77.2, 76.0, 75.7, 73.1,
72.6, 71.2, 70.8, 66.6, 64.0, 49.5, 38.1, 35.0, 33.7, 32.6, 30.4, 29.3, 29.1,
27.2, 26.9 (3C), 26.7, 26.0 (3C), 25.8 (3C), 21.9, 20.9, 19.3, 18.3, 18.2,
17.7, 12.3, ꢁ1.9, ꢁ2.1, ꢁ4.1, ꢁ4.9; HRMS (ESI TOF) calcd for
C65H99Cl3O9Si3Na (MþNa)þ 1237.5554, found 1237.5496.
d
135.5 (4C), 134.1 (2C), 129.4 (2C), 127.5 (4C), 88.3, 86.5, 84.8, 82.3,
77.6, 77.2, 76.0, 75.5, 73.1, 72.9, 72.5, 70.8, 64.0, 63.0, 49.5, 37.7, 37.5,
35.0, 33.9, 32.5, 30.3, 29.8, 29.6, 29.3, 28.8, 26.9 (3C), 26.5, 26.0 (3C),
25.8 (3C), 24.0, 20.9,19.3,18.3,18.1,16.1,12.4, ꢁ2.0, ꢁ2.2, ꢁ4.2, ꢁ4.8;
HRMS (ESI TOF) calcd for C58H98O9Si3Na (MþNa)þ 1045.6416,
found 1045.6412.
4.17. Benzyl ether 32
A mixture of 30 (5.7 mg, 4.69
mmol) and PdeC (5.6 mg) and Et3N
4.19. TBS ether 36
(50 L) in EtOH (1 mL) was stirred under H2 atmosphere. After
m
1.5 h, the catalyst was filtered off through a short silica gel column
(EtOAc), and the filtrate was concentrated to give the crude benzyl
ether 31, which was used for the next reaction directly.
To a stirred solution of 18 (215 mg, 0.257 mmol) in CH2Cl2
(7.0 mL) were added HMDS (0.86 mL, 5.14 mmol) and TMSI
(0.36 mL, 2.53 mmol) at 0 ꢀC. After 30 min, the reaction mixture was
quenched with saturated NaHCO3, and diluted with Et2O. The or-
ganic layer was washed with water and brine. After concentration,
the residue was dissolved in MeOH (4.0 mL) and CH2Cl2 (4.0 mL). To
this solution at 0 ꢀC was added CSA (26 mg, 0.112 mmol), and the
mixture was stirred for 40 min at the same temperature. The re-
action mixture was quenched with Et3N, diluted with EtOAc, then
washed with water and brine. Concentration gave the crude alcohol,
which was used for the next reaction directly.
To a stirred solution of the crude benzyl ether, pyridine (85
1.06 mmol) and KO2CN]NCO2K (68.3 mg, 0.352 mmol) in MeOH
(1 mL) at room temperature was added a solution of AcOH (40 L,
mL,
m
0.704 mmol) in MeOH (0.3 mL) over 75 min via a syringe pomp. The
reaction mixture was the quenched with saturated NH4Cl, diluted
with Et2O. The organic layer was washed with saturated CuSO4,
water, saturated NaHCO3, and brine. After concentration, the resi-
due was subjected to the same procedure described above to
complete the reaction. The crude product obtained was purified by
chromatography (hexane/EtOAc, 40:1 to 20:1 to 15:1) to give 32
(4.4 mg, 84% for the 2 steps): colorless oil; Rf¼0.39 (hexane/EtOAc,
To a stirred solution of the alcohol in CH2Cl2 (5.0 mL) at 0 ꢀC
were added 2,6-lutidine (0.15 mL, 1.28 mmol) and TBSOTf (0.14 mL,
0.789 mmol). After stirring for 1 h at room temperature, the re-
action mixture was cooled to 0 ꢀC, and quenched with MeOH. The
mixture was diluted with Et2O, and washed with water and brine.
Concentration and chromatography (hexane/EtOAc, 50:1 to 30:1)
7:1); [
(400 MHz, CDCl3)
a
]
24 ꢁ13.1 (c 0.21, CHCl3); IR (neat) 2929, 1090 cmꢁ1; 1H NMR
D
d
7.64 (dd, J¼7.8, 1.5 Hz, 4H), 7.41e7.20 (m, 11H),
4.49 (s, 2H), 4.17 (dd, J¼11.5, 5.1 Hz, 1H), 3.94 (dd, J¼3.7, 3.7 Hz, 1H),
3.73e3.56 (m, 3H), 3.51e3.43 (m, 2H), 3.42e3.36 (m,1H), 3.34e3.15
(m, 4H), 3.10 (dd, J¼12.2, 3.9 Hz, 1H), 2.13e1.20 (m, 23H), 1.14 (s,
3H), 1.10 (s, 3H), 1.06 (s, 3H), 1.02 (s, 9H), 0.89 (s, 9H), 0.88 (d,
J¼6.3 Hz, 3H), 0.81 (s, 9H), 0.05 (s, 3H), 0.03 (s, 6H), 0.03 (s, 3H);
gave 36 (218 mg, 93% for the 2 steps): colorless oil; Rf¼0.70 (hex-
27
ane/EtOAc, 4:1); [
a
]
ꢁ10.2 (c 0.95, CHCl3); IR (neat) 3434, 3069,
D
1079 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
7.64 (dd, J¼7.8, 1.7 Hz, 4H),
7.42e7.31 (m, 6H), 7.31e7.19 (m, 10H), 4.56 (d, J¼12.0 Hz, 1H), 4.48
(s, 2H), 4.36 (d, J¼12.0 Hz, 1H), 4.25 (dd, J¼11.3, 5.0 Hz, 1H),
4.04e3.97 (m, 1H), 3.73e3.57 (m, 2H), 3.48 (d, J¼7.1 Hz, 1H),
3.47e3.35 (m, 3H), 3.44 (d, J¼7.1 Hz,1H), 3.25 (d, J¼9.5 Hz,1H), 2.34
(ddd, J¼12.2, 4.1, 4.1 Hz, 1H), 2.01 (dd, J¼14.8, 3.6 Hz, 1H), 1.90 (dd,
J¼15.6, 3.9 Hz, 1H), 1.74e1.44 (m, 5H), 1.38e1.22 (m, 3H), 1.16 (s,
3H), 1.15 (s, 3H), 1.03 (s, 9H), 0.90e0.84 (m, 12H), 0.06 (s, 3H), 0.03
(400 MHz, C6D6)
d
7.83e7.73 (m, 4H), 7.33 (d, J¼7.6 Hz, 2H),
7.26e7.06 (m, 9H), 4.42 (dd, J¼11.4, 5.7 Hz, 1H), 4.36 (s, 2H), 4.03 (br
s, 1H), 3.92 (ddd, J¼11.7, 9.3, 4.9 Hz, 1H), 3.78e3.60 (m, 2H),
3.59e3.27 (m, 6H), 3.23 (ddd, J¼8.9, 8.9, 3.7 Hz, 1H), 3.17 (dd,
J¼12.0, 4.0 Hz, 1H), 2.34 (ddd, J¼12.0, 4.0, 4.0 Hz, 1H), 2.25e2.15 (m,
2H), 2.10e1.65 (m, 13H), 1.65e1.42 (m, 5H), 1.40e1.25 (m, 2H), 1.24

5340
H. Takamura et al. / Tetrahedron 66 (2010) 5329e5344
(s, 3H); 13C NMR (100 MHz, CDCl3)
d
138.7, 138.6, 135.5 (4C), 134.1
4.6 Hz, 1H), 2.03 (dd, J¼16.6, 3.4 Hz, 1H), 1.92 (dd, J¼16.6, 4.2 Hz,
1H), 1.77e1.45 (m, 5H), 1.43e1.18 (m, 3H), 1.23 (s, 3H), 1.17 (s, 3H),
1.03 (s, 9H), 0.92e0.87 (m, 12H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR
(2C), 129.4 (2C), 128.1 (4C), 127.6 (2C), 127.5 (4C), 127.3 (2C), 127.2
(2C), 77.6, 76.7, 75.9, 75.0, 73.5, 72.6, 72.1, 71.0, 70.8, 65.8, 64.0, 49.4,
35.1, 32.6, 31.8, 29.3, 29.1, 27.0 (3C), 26.0 (3C), 20.9, 19.3, 18.2, 15.3,
13.1, 12.4, ꢁ4.4, ꢁ4.9; HRMS (ESI) calcd for C55H78O7Si2Na (MþNa)þ
929.5184, found 929.5189.
(100 MHz, CDCl3)
d 143.0, 135.5 (4C), 134.1 (2C), 129.4 (2C), 127.5
(4C), 114.2, 77.6, 76.7, 75.6, 72.8, 72.6, 72.2, 70.8 (2C), 64.0, 49.4,
35.0, 34.7, 32.6, 29.3, 29.1, 26.9 (3C), 26.0 (3C), 20.9, 19.3, 18.2, 13.4,
12.4, ꢁ4.3, ꢁ4.7; HRMS (ESI) calcd for C42H66O6Si2Na (MþNa)þ
745.4296, found 745.4297.
4.20. Alcohol 37
A mixture of 36 (218 mg, 0.240 mmol) and Pd(OH)2eC (75.0 mg)
in THF (4.0 mL) was stirred vigorously under hydrogen atmosphere.
After 4 h, the catalyst was filtered off through a short silica gel
column (EtOAc). The filtrate was concentrated to give the corre-
sponding diol, which was used for next reaction directly.
To a solution of the crude diol in DMF (7.0 mL) at room tem-
perature were added imidazole (163 mg, 2.39 mmol) and TESCl
(0.20 mL, 1.19 mmol). After stirring for 20 min, the reaction mixture
was quenched with MeOH, diluted with EtOAc, then washed with
water and brine. Concentration gave the crude bis-TES ether, which
was used for the next reaction directly.
4.22. Alcohol 39
To a mixture of 38 (678 mg, 1.76 mmol) in CH2Cl2 (12 mL) at 0 ꢀC
were added 2,6-lutidine (0.62 mL, 5.29 mmol) and TBSOTf
(0.81 mL, 3.53 mmol), and the mixture was stirred for 2.5 h at room
temperature. The reaction mixture was quenched with MeOH at
0 ꢀC, diluted with Et2O, then washed with saturated NaHCO3 and
brine. Concentration gave the corresponding silyl ether, which was
used for next reaction directly.
To a stirred solution of 2-methyl-2-butene (1.87 mL, 17.6 mmol)
in THF (15 mL) at ꢁ15 ꢀC was added BH3$SMe2 (0.84 mL,
8.82 mmol), and the mixture was stirred for 0.5 h at the same
temperature. To this mixture at ꢁ15 ꢀC was introduced a solution of
the silyl ether in THF (20 mL). After stirring for 1 h at the same
temperature, the reaction mixture was quenched with MeOH, then
3 M NaOH (5.0 mL) and 30% H2O2 (5.0 mL), and was stirred for 0.5 h
at room temperature. The mixture was quenched with saturated
Na2SO3, diluted with Et2O, then washed with water and brine.
Concentration and chromatography (hexane/EtOAc, 6:1 to 4:1) gave
To a stirred solution of the bis-TES ether in CH2Cl2 (2.4 mL) and
MeOH (2.4 mL) at 0 ꢀC was added PPTS (12.0 mg, 47.8
mmol). After
25 min, the reaction mixture was quenched with Et3N, then washed
with water and brine. Concentration and chromatography (hexane/
EtOAc, 20:1 to 10:1) gave 37 (135 mg, 67% for the 3 steps): colorless
27
oil; Rf¼0.45 (hexane/EtOAc, 10:1); [
a
;
]
ꢁ20.9 (c 0.63, CHCl3); IR
D
(neat) 3553e3273, 2953, 1087 cmꢁ1
1H NMR (400 MHz, CDCl3)
d
7.65 (dd, J¼7.8, 1.5 Hz, 4H), 7.42e7.22 (m, 6H), 4.22 (dd, J¼11.5,
8.1 Hz, 1H), 4.01e3.97 (m, 1H), 3.75 (dd, J¼11.8, 4.6 Hz, 1H),
3.71e3.57 (m, 4H), 3.48e3.37 (m, 3H), 3.23 (d, J¼9.3 Hz, 1H), 2.07
(ddd, J¼12.0, 4.7, 4.7 Hz, 1H), 2.03 (dd, J¼15.3, 3.4 Hz, 1H), 1.94e1.86
(m, 2H), 1.76e1.20 (m, 7H), 1.16 (s, 3H), 1.06 (s, 3H), 1.03 (s, 9H),
0.96e0.88 (m, 21H), 0.58 (q, J¼7.9 Hz, 6H), 0.07 (s, 3H), 0.04 (s, 3H);
39 (774 mg, 85% for the 2 steps): colorless oil; Rf¼0.16 (hexane/
25
EtOAc, 4:1); [
a
]
D
þ6.4 (c 1.14, CHCl3); IR (neat) 3730e3141, 2953,
2855 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 7.36e7.19 (m, 7H), 6.85 (d,
J¼8.8 Hz, 2H), 4.55 (d, J¼10.7 Hz,1H), 4.51 (d, J¼10.7 Hz,1H), 4.49 (s,
2H), 3.78 (s, 3H), 3.57 (t, J¼6.3 Hz, 2H), 3.53e3.42 (m, 2H), 3.25 (dd,
J¼8.7, 2.6 Hz,1H),1.95e1.30 (m, 9H),1,21 (s, 3H), 0.86 (s, 9H), 0.08 (s,
13C NMR (100 MHz, CDCl3)
d 135.5 (4C), 134.1 (2C), 129.4 (2C), 127.5
(4C), 77.5, 77.2, 75.9, 72.9, 72.6, 72.2, 70.9, 68.1, 67.5, 64.0, 49.3, 36.1,
34.9, 32.6, 29.3, 29.1, 27.0 (3C), 25.9 (3C), 20.8, 19.3, 18.2, 12.7, 12.5,
6.9 (3C), 5.1 (3C), ꢁ4.4, ꢁ4.6; HRMS (ESI) calcd for C47H80O7Si3Na
(MþNa)þ 863.5110, found 863.5104.
6H); 13C NMR (100 MHz, CDCl3)
d 158.9, 138.6, 131.2, 128.9 (2C),
128.2 (2C), 127.5 (2C), 127.4, 113.6 (2C), 84.2, 78.1, 73.6, 72.8, 70.8,
63.6, 55.3, 36.5, 27.9, 27.2, 27.1, 26.1 (3C), 23.6,18.5, ꢁ1.7, ꢁ1.8; HRMS
(ESI) calcd for C30H48O5SiNa (MþNa)þ 539.3169, found 539.3166.
4.21. Alcohol 34
4.23. Alcohol 40
ꢀ
To a mixture of 37 (135 mg, 0.160 mmol) and MS4 A (16 mg) in
CH2Cl2 (3.2 mL) at room temperature were added TPAP (16.0 mg,
45.5 mmol) and NMO (112 mg, 0.956 mmol). After stirring for 2.5 h,
the mixture was filtered through a short silica gel column (hexane/
EtOAc, 4:1) to give the corresponding aldehyde, which was used for
the next reaction directly.
To a solution of 39 (384 mg, 0.742 mmol) in CH2Cl2 (7.4 mL) at
room temperature were added diisopropylethylamine (1.30 mL,
7.42 mmol) and MOMCl (0.28 mL, 3.71 mmol). After stirring for 1 h,
the reaction mixture was quenched with MeOH at 0 ꢀC, diluted
with EtOAc, then washed with saturated NH4Cl, saturated NaHCO3,
and brine. Concentration gave the crude MOM ether, which was
used for next reaction directly.
A mixture of the MOM ether and Pd(OH)2eC (112 mg) in THF
(7.4 mL) was stirred under hydrogen atmosphere. After 1 h, the
catalyst was filtered off, and concentrated. The crude diol obtained
was used for next reaction directly.
To a suspension of Ph3PþCH3Brꢁ (340 mg, 0.952 mmol) in THF
(2.0 mL) at 0 ꢀC was added NaHMDS (0.80 mL, 0.80 mmol, 1.0 M
solution in THF), and the mixture was stirred for 10 min. A solution
of the crude aldehyde in THF (2.0 mL) was introduced, and the
mixture was allowed to warm to room temperature. After 1.5 h, the
reaction mixture was quenched with H2O, diluted with EtOAc, then
washed with water and brine. After concentration, the crude
product was used for next reaction directly.
To a mixture of the diol in DMF (7.4 mL) at ꢁ15 ꢀC were added
imidazole (253 mg, 3.72 mmol) and TBSCl (340 mg, 2.26 mmol),
and the mixture was stirred for 0.5 h at the same temperature. The
reaction mixture was quenched with MeOH, diluted with EtOAc,
then washed with water and brine. Concentration and chroma-
To a stirred solution of the olefin in CH2Cl2 (1.6 mL) and MeOH
(1.6 mL) at 0 ꢀC was added CSA (11.0 mg, 47.4
mmol). After 25 min,
the reaction mixture was quenched with Et3N. Concentration and
chromatography (hexane/EtOAc, 10:1 to 8:1) gave 34 (99.8 mg, 86%
tography (hexane/EtOAc,10:1 to 6:1) gave 40 (324 mg, 94% for the 3
24
24
for the 3 steps): amorphous; Rf¼0.20 (hexane/EtOAc, 4:1); [
a
;
]
steps): colorless oil; Rf¼0.41 (hexane/EtOAc, 4:1); [
(c 1.09, CHCl3); IR (neat) 3735e3102, 2954, 1109 cmꢁ1
(400 MHz, CDCl3)
6.3, 2.5 Hz, 2H), 3.38e3.31 (m, 1H), 3.32 (s, 3H), 2.58 (d, J¼3.9 Hz,
1H), 1.84e1.50 (m, 6H), 1.48e1.34 (m, 1H), 1.34e1.24 (m, 1H), 1,19
(s, 3H), 0.86 (s, 9H), 0.85 (s, 9H), 0.09 (s, 6H), 0.02 (s, 6H); 13C NMR
a
]
þ12.9
D
ꢁ31.5 (c 1.00, CHCl3); IR (neat) 3564e3145, 2931, 1071 cmꢁ1
1DH
;
1H NMR
NMR (400 MHz, CDCl3)
d
7.65 (dd, J¼7.8, 1.5 Hz, 4H), 7.43e7.32 (m,
d
4.58 (s, 2H), 3.70e3.57 (m, 2H), 3.47 (ddd, J¼6.3,
6H), 5.89 (dd, J¼17.7, 11.0 Hz, 1H), 5.27 (dd, J¼17.7, 1.2 Hz, 1H), 5.15
(dd, J¼11.0, 1.2 Hz, 1H), 4.24 (dd, J¼11.3, 5.3 Hz, 1H), 4.06e4.00 (m,
1H), 3.79 (ddd, J¼11.7, 9.3, 4.9 Hz, 1H), 3.69e3.57 (m, 2H),
3.46e3.37 (m, 2H), 3.29 (d, J¼9.3 Hz, 1H), 2.18 (ddd, J¼11.7, 4.6,
(100 MHz, CDCl3)
d 96.3, 78.3, 77.5, 68.3, 63.2, 55.1, 34.7, 30.3, 27.8,

H. Takamura et al. / Tetrahedron 66 (2010) 5329e5344
5341
26.0 (6C), 24.1, 23.9, 18.4 (2C), ꢁ1.9 (2C), ꢁ5.2 (2C); HRMS (ESI)
calcd for C23H52O5Si2 (MþNa)þ 487.3251, found 487.3257.
SO3$py (242 mg, 0.846 mmol), and the mixture was stirred at room
temperature. After 2 h, the mixture was diluted with EtOAc, then
washed with saturated NH4Cl, water, and brine. Concentration gave
the crude aldehyde, which was used for the next reaction directly.
To a mixture of the aldehyde in t-BuOH (2.2 mL), 5% NaH2PO4
(2.2 mL), and 2-methyl-2-butene (3.3 mL) was added NaClO2
(46.5 mg, 0.514 mmol) at 0 ꢀC. After stirring at same temperature
for 0.5 h, the mixture was diluted with EtOAc, then washed with
water and brine. Concentration gave the crude carboxylic acid 35,
which was used for the next reaction directly.
To a solution of the crude 35 in THF (1 mL) were added Et3N
(0.11 mL, 0.756 mmol) and 2,4,6-trichlorobenzoyl chloride (66 mL,
0.422 mmol). After stirring for 2.5 h at room temperature, the
mixture was concentrated under reduced pressure, then diluted
with toluene (0.6 mL). To the resulting mixture was added a solu-
4.24. Allyl ether 41
To a stirred suspension of KH (475 mg, 3.55 mmol, 30%, pre-
washed with hexane) in THF (7 mL) at 0 ꢀC were added allyl bro-
mide (0.30 mL, 3.54 mmol) and
a solution of 40 (329 mg,
708 mmol) in THF (7 mL), and the mixture was stirred for 1 h at
room temperature. The reaction mixture was cooled to 0 ꢀC, and
quenched with MeOH, diluted with Et2O, then washed with water
and brine. Concentration gave the crude allylic ether, which was
used for next reaction directly.
To a mixture of the allylic ether in CH2Cl2 (7 mL) at 0 ꢀC were
added HMDS (1.48 mL, 7.08 mmol) and TMSI (0.50 mL, 3.54 mmol).
After stirring for 1 h, the reaction mixture was quenched with
MeOH (7 mL), and stirred with K2CO3 (300 mg) for 1 h at room
temperature. The reaction mixture was diluted with EtOAc, then
washed with water and brine. Concentration gave the crude alco-
hol, which was used for next reaction directly.
To a mixture of the alcohol in DMF (7 mL) were added imidazole
(243 mg, 3.56 mmol) and TESCl (0.36 mL, 2.12 mmol). After stirring
for 20 min at room temperature, the reaction mixture was
quenched with MeOH, diluted with EtOAc, then washed with water
and brine. Concentration and chromatography (hexane/EtOAc,
tion of 34 (29.4 mg, 54.5 mmol) and DMAP (73.3 mg, 0.594 mmol) in
toluene (1.2 mL). After stirring for 2.5 h at room temperature, the
mixture was diluted with EtOAc and filtered through a Celite pad.
Concentration and chromatography (hexane/EtOAc, 80:1 to 40:1 to
15:1, containing 0.5% Et3N) gave 44 (68.0 mg, 85%): colorless oil;
23
Rf¼0.60 (hexane/EtOAc, 7:1); [
a
]
D
ꢁ39.7 (c 1.46, CHCl3); IR (neat),
2955, 1743, 1102 cmꢁ1
;
1H NMR (400 MHz, C6D6)
d 7.82e7.75 (m,
4H), 7.27e7.21 (m, 6H), 6.06 (dd, J¼17.5, 11.0 Hz, 1H), 5.81 (d,
J¼6.1 Hz, 1H), 5.41 (dd, J¼17.5, 1.2 Hz, 1H), 5.12 (dd, J¼11.0, 1.2 Hz,
1H), 5.12e5.02 (m, 1H), 4.52 (ddd, J¼8.8, 8.8, 6.2 Hz, 1H), 4.39 (dd,
11.7, 5.4 Hz, 1H), 4.12e4.06 (m, 1H), 4.06e3.96 (m, 1H), 3.80e3.55
(m, 4H), 3.43 (d, J¼9.3 Hz, 1H), 3.37e3.25 (m, 2H), 2.68e2.40 (m,
3H), 2.27e2.13 (m, 2H), 2.13e1.47 (m, 22H), 1.47e1.37 (m, 6H), 1.27
(s, 3H),1.23 (s, 3H),1.18 (s, 9H),1.06e0.93 (m, 48H), 0.28 (s, 3H), 0.16
(s, 3H), 0.15 (s, 3H), 0.14 (s, 3H), 0.10 (s, 6H); HRMS (ESI) calcd for
C78H140O10Si4SnNa (MþNa)þ 1491.8462, found 1491.8472.
200:1 to 40:1) gave 41 (373 mg, 92% for the 3 steps): colorless oil;
25
Rf¼0.31 (hexane/EtOAc, 20:1); [
a
]
D
þ5.6 (c 1.35, CHCl3); IR (neat)
3081, 1098 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
5.88 (dddd, J¼17.1,
10.5, 5.4, 5.4 Hz, 1H), 5.22 (dd, J¼17.1, 1.2 Hz, 1H), 5.08 (dd, J¼10.5,
1.2 Hz, 1H), 4.11e4.01 (m, 2H), 3.67e3.50 (m, 4H), 3.10 (dd, J¼8.8,
1.7 Hz, 1H), 1.90e1.29 (m, 8H), 1,17 (s, 3H), 0.94 (t, J¼7.9 Hz, 9H),
0.88 (s, 9H), 0.85 (s, 9H), 0.58 (q, J¼7.9 Hz, 6H), 0.08 (s, 6H), 0.03
(s, 6H); 13C NMR (100 MHz, CDCl3)
d
135.4, 115.6, 84.6, 78.1, 73.2,
4.27. Diene 45
63.8, 63.4, 36.8, 31.0, 27.3, 27.0, 26.1 (6C), 23.5,18.5 (2C), 6.9 (3C), 4.5
(3C), ꢁ1.7, ꢁ1.8, ꢁ5.2 (2C); HRMS (ESI) calcd for C30H66O4Si3Na
(MþNa)þ 597.4167, found 597.4169.
To a stirring solution of 44 (22.1 mg, 15.0
m
mol) in CH2Cl2 (2 mL)
at ꢁ78 ꢀC was added DIBAL-H (30
mL, 31 mmol, 1.02 M solution in
hexane). To this mixture, pre-cooled (ꢁ40 ꢀC) solutions of pyridine
4.25. Allyl stannane 43
(10 mL, 120 mmol) and DMAP (15.0 mg, 123 mmol) in CH2Cl2
(0.5 mL), and (clCH2CO)2O (31 mg, 181 mmol) in CH2Cl2 (0.5 mL)
To a stirred solution of 41 (164 mg, 0.285 mmol) in THF (2.8 mL)
at ꢁ78 ꢀC was added s-BuLi (1.35 mL, 1.43 mmol. 1.06 M solution in
hexane), and the mixture was stirred for 3 h at the same temper-
ature. To the resulting yellow solution was added Bu3SnCl (0.39 mL,
1.44 mmol), and the mixture was allowed to warm to 0 ꢀC with
stirring. The reaction mixture was diluted with Et2O, then washed
with water and brine. Concentration gave the crude allylic stannane
42, which was used for next reaction directly.
were introduced immediately. The reaction mixture was allowed to
warm to 0 ꢀC over 1 h with stirring, and quenched with H2O. The
mixture was diluted with Et2O, then washed with saturated po-
tassium sodium tartrate, saturated CuSO4, water, saturated
NaHCO3, and brine. Concentration gave the crude a-chloroacetoxy
ether 33, which was used for the next reaction directly.
To the stirring suspension of MgBr2$OEt2 (102 mg, 395
m
mol)
and MS5 A (5ꢀ0 mg) in CH2Cl2 (1.5 mL) at ꢁ78 ꢀC was added a pre-
ꢀ
ꢀ
To a mixture of 42 in CH2Cl2 (1.5 mL) and MeOH (3.0 mL) at
cooled (ꢁ40 C) solution of 33 (dried over MS5 A) in CH2Cl2
ꢁ15 ꢀC was added PPTS (13.4 mg, 53.3
m
mol), and the mixture was
(2.5 mL). The mixture was allowed to warm to 0 ꢀC over 1 h, and
quenched with Et3N. The mixture was filtered through a short silica
gel column (EtOAc) and concentrated. The residue was purified by
chromatography (hexane/EtOAc, 50:1 to 30:1, containing 0.5%
stirred for 0.5 h, at the same temperature. The reaction mixture was
quenched with Et3N, diluted with Et2O, then washed with water
and brine. Concentration and chromatography (hexane/EtOAc, 40:1
to 30:1 to 20:1, containing 0.5% Et3N) gave 43 (88.4 mg, 41% for the
Et3N) to give 45 (10.0 mg, 57% for the 2 steps): colorless oil; Rf¼0.20
23
27
2 steps): colorless oil; Rf¼0.26 (hexane/EtOAc, 7:1); [
(c 1.41, CHCl3); IR (neat) 3599e3114, 2955, 1098 cmꢁ1
(400 MHz, C6D6)
6.1 Hz, 1H), 3.76e3.62 (m, 2H), 3.49e3.37 (m, 3H), 2.09e1.96
(m, 2H), 1.96e1.49 (m, 14H), 1.42 (sex, J¼7.3 Hz, 6H), 1.31 (s, 3H),
1.05e0.95 (m,15H),1.02 (s, 9H),1.00 (s, 9H), 0.19 (s, 3H), 0.16 (s, 3H),
0.10 (s, 6H); HRMS (ESI) calcd for C36H78O4Si2SnNa (MþNa)þ
773.4365, found 773.4362.
a
;
]
ꢁ36.9
(hexane/EtOAc, 20:1); [
a
]
ꢁ13.7 (c 0.73, CHCl3); IR (neat), 3071,
D
D
1H NMR
5.86 (d, J¼6.1 Hz, 1H), 4.49 (ddd, J¼8.9, 8.9,
2851, 1086 cmꢁ1 1H NMR (400 MHz, C6D6)
; d 7.83e7.75 (m, 4H),
d
7.27e7.21 (m, 6H), 6.21 (dd, J¼17.4, 10.9 Hz, 1H), 5.97 (ddd, J¼17.2,
10.6, 5.1 Hz, 1H), 5.51 (dd, J¼17.4, 1.7 Hz, 1H), 5.46 (ddd, J¼17.2, 1.7,
1.7 Hz, 1H), 5.17 (dd, J¼10.9, 1.8 Hz, 1H), 5.10 (dd, J¼10.6, 1.8 Hz, 1H),
4.52 (dd, J¼11.5, 5.4 Hz, 1H), 4.14e4.08 (m, 1H), 3.99 (ddd, J¼11.7,
9.3, 4.6 Hz, 1H), 3.89 (dd, J¼6.6, 5.4 Hz, 1H), 3.76e3.55 (m, 4H),
3.45e3.24 (m, 5H), 2.36 (ddd, J¼12.2, 4.6, 4.6 Hz, 1H), 2.24 (dd,
J¼15.7, 3.0 Hz, 1H), 1.98e1.68 (m, 9H), 1.68e1.43 (m, 8H), 1.34 (s,
3H), 1.25 (s, 3H), 1.10 (s, 12H), 1.07 (s, 9H), 1.06 (d, J¼7.1 Hz, 3H), 1.00
(s, 9H), 0.99 (s, 9H), 0.22 (s, 3H), 0.18 (s, 3H), 0.13 (s, 3H), 0.11 (s, 3H),
4.26. Ester 44
To a mixture of 43 (126 mg, 0.168 mmol), DMSO (1.1 mL), and
0.01 (s, 6H); 13C NMR (100 MHz, C6D6)
134.5 (2C), 129.9 (2C), 127.9 (4C), 114.7, 113.3, 88.1, 86.3, 83.2, 79.1,
d 143.6, 138.5, 136.0 (4C),
Et3N (0.23 mL, 1.68 mmol) in CH2Cl2 (4.4 mL) at 0 ꢀC was added

5342
H. Takamura et al. / Tetrahedron 66 (2010) 5329e5344
78.1, 77.7, 76.6, 76.4, 73.4, 73.1, 72.6, 71.2, 64.4, 63.9, 49.9, 37.7, 35.7,
34.8, 33.3, 30.8, 30.0, 29.6, 27.7, 27.3 (3C), 27.2, 26.4 (6C), 26.3 (3C),
23.3, 21.3, 19.6, 18.7, 18.6, 18.5, 15.7, 13.1, ꢁ1.6, ꢁ1.7, ꢁ4.0, ꢁ4.4, ꢁ4.9
(2C); HRMS (ESI) calcd for C66H114O9Si4Na (MþNa)þ 1185.7438,
found 1185.7432.
21H),1.14 (s, 3H),1.10 (s, 3H),1.06 (s, 3H),1.02 (s, 9H), 0.89 (s, 9H), 0.88
(d, J¼6.3 Hz, 3H), 0.82 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H),
0.03 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 135.5 (4C), 134.1 (2C), 132.7,
132.1,129.6,129.4(2C),127.5(4C),117.0, 86.9, 86.3, 85.2,82.1, 77.6, 77.2,
76.1, 75.5, 73.1, 72.9, 72.6, 70.8, 64.0, 49.5, 37.8, 37.7, 35.0, 34.0, 32.6,
30.2, 29.8, 29.3, 29.1, 28.8, 27.0 (3C), 25.9 (3C), 25.8 (3C), 24.8, 24.1,
20.9,19.3,18.3,18.1,16.3,12.4, ꢁ2.0, ꢁ2.2, ꢁ4.2, ꢁ4.8; HRMS (ESI TOF)
calcd for C61H100O8Si3Na (MþNa)þ 1067.6624, found 1067.6631.
4.28. Pentacycle 2
To a mixture of 45 (6.9 mg, 5.9
added the Grubbs’ catalyst 29 (4.8 mg, 5.8
45 min at 80 ꢀC, an additional amount of 29 (16.1 mg, 19.6
m
mol) in toluene (1.0 mL) was
mol). After stirring for
mol)
m
4.30. Alcohol 50
m
was added. After stirring for 1 h at 80 ꢀC, the reaction mixture
was quenched with Et3N at room temperature, diluted with EtOAc,
filtered through a short silica gel column (hexane/EtOAc, 2:1,
containing 0.5% Et3N). The filtrate was concentrated to give the
crude 46, which was used for next reaction without further
purification.
To a mixture of 49 (3.3 mg, 3.16
temperature was added a solution of TBAF/AcOH (0.1 mL, prepared
from 0.5 mL of TBAF (1.0 M solution in THF) and 30 L of AcOH).
After stirring for 11 h, the mixture was diluted with EtOAc, then
washed with saturated NaHCO3, water, and brine. Concentration
mmol) in THF (0.1 mL) at room
m
and chromatography (hexane/EtOAc, 7:1 to 4:1 to 3:1) gave 50
23
To a stirred solution of the crude 46, pyridine (0.16 mL,
1.98 mmol) and KO2CN]NCO2K (126 mg, 0.646 mmol) in MeOH
(2.4 mg, 94%): colorless oil; Rf¼0.10 (hexane/EtOAc, 4:1); [
a]
D
ꢁ22.3 (c 0.12, CHCl3); IR (neat) 3661e3120, 2928, 1737, 1643,
(1 mL) at room temperature was added a solution of AcOH (74
mL,
1089 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
6.63 (ddd, J¼16.8, 11.0,
1.29 mmol) in MeOH (0.3 mL) over 1 h via a syringe pump. The
reaction mixture was quenched with saturated NH4Cl, diluted with
Et2O. The organic layer was washed with saturated CuSO4, water,
saturated NaHCO3, and brine. After concentration, the residue was
filtered through a short silica gel column (hexane/Et2O,10:1) to give
the crude 47, which was used for next reaction without further
purification.
9.8 Hz, 1H), 6.01 (dd, J¼11.0, 10.2 Hz, 1H), 5.41 (ddd, J¼10.2, 7.1,
7.1 Hz, 1H), 5.17 (d, J¼16.8 Hz, 1H), 5.07 (d, J¼9.8 Hz, 1H), 4.22 (dd,
J¼11.6, 5.0 Hz, 1H), 3.95 (dd, J¼3.7, 3.7 Hz, 1H), 3.74e3.59 (m, 2H),
3.59e3.46 (m, 2H), 3.30e3.14 (m, 4H), 3.11 (dd, J¼12.2, 3.9 Hz, 1H),
2.92 (br s, 1H), 2.38e2.20 (m, 2H), 2.18e1.95 (m, 3H), 1.91e1.20 (m,
18H), 1.23 (s, 3H), 1.10 (s, 3H), 1.06 (s, 3H), 0.93 (d, J¼6.8 Hz, 3H),
0.90 (s, 9H), 0.82 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H), 0.03
To a stirred mixture of the crude TBS ether 47 in CH2Cl2 (0.4 mL)
(s, 3H); 13C NMR (100 MHz, CDCl3)
d 132.7, 132.1, 129.6, 117.0, 86.9,
and MeOH (0.80 mL) at 0 ꢀC was added CSA (2.4 mg, 10
mmol). After
86.3, 85.2, 82.0, 78.5, 77.2, 76.2, 75.5, 73.2, 72.6, 72.5, 72.3, 62.8,
49.3, 37.8, 37.7, 34.9, 33.9, 33.6, 30.6, 30.5, 30.1, 29.8, 28.8, 26.0 (3C),
25.8 (3C), 24.8, 24.0, 20.7, 18.3, 18.1, 16.3, 12.6, ꢁ2.0, ꢁ2.2, ꢁ4.2,
ꢁ4.8; HRMS (ESI TOF) calcd for C45H82O8Si2Na (MþNa)þ 829.5446,
found 829.5440.
stirring for 1 h at the same temperature, the reaction mixture was
quenched with Et3N. Concentration and chromatography (hexane/
EtOAc, 20:1 to 10:1 to 5:1) gave 2 (4.6 mg, 76% for the 3 steps).
4.29. (Z)-Diene 49
4.31. Reaction of 51 and 52
To a mixture of 2 (4.8 mg, 4.69
m
mol) in CH2Cl2 (0.4 mL) and
DMSO (0.1 mL) at 0 ꢀC was added Et3N (65
m
L, 0.469 mmol) and
To a mixture of phosphate 52 (120 mg, 0.46 mmol) in THF
(1.2 mL) ꢁ78 ꢀC was added n-BuLi (0.22 mL, 0.37 mmol, 1.65 M
solution in hexane), and the mixture was stirred for 10 min at the
same temperature. After stirring for additional 50 min at 0 ꢀC, the
mixture was cooled to ꢁ78 ꢀC. To this mixture was added a pre-
cooled (ꢁ78 ꢀC) solution of the aldehyde 51 (30 mg, 0.0191 mmol)
in THF (0.8 mL). The reaction mixture was allowed to warm to room
temperature over 1 h with stirring. The reaction was quenched
with saturated NH4Cl, diluted with EtOAc, and washed with water
and brine. Concentration and chromatography (hexane/EtOAc,
100:1 to 70:1 to 40:1 to 20:1) gave 53 (37 mg, 92%): colorless oil;
SO3$py (37.3 mg, 0.235 mmol). After stirring for 1 h at room tem-
perature, the mixture was diluted with EtOAc, then washed with
saturated NH4Cl, water, and brine. Concentration gave the crude
aldehyde, which was used for the next reaction directly.
To a stirring suspension of 48 (126.7 mg, 0.235 mmol) in THF
(0.3 mL) at ꢁ30 ꢀC was added NaHMDS (0.19 mL, 0.190 mmol, 1.0 M
solution in THF). After stirring for 15 min at the same temperature,
the mixture was cooled to ꢁ78 ꢀC. To this solution was added a pre-
cooled (ꢁ78 ꢀC) solution of the crude aldehyde in THF (0.7 mL), and
the mixture was allowed to warm to room temperature over 1 h
with stirring. The reaction mixture was quenched with saturated
NaHCO3, diluted with EtOAc, then washed with water and brine.
After concentration, the residue was filtered through a short silica
gel column (hexane/EtOAc, 10:1) to give the crude phenylselenide,
which was used for next reaction without further purification.
To a mixture of the crude phenylselenide in THF (0.6 mL) at room
Rf¼0.72 (hexane/EtOAc, 4:1); IR (neat) 3071, 2931, 1609 cmꢁ1
;
1H
NMR (400 MHz, CDCl3) d 7.66e7.63 (m, 4H), 7.42e7.33 (m, 6H), 5.88
(t, J¼7.2 Hz, 1H), 5.83 (s, 1H), 3.70 (s, 3H), 3.66 (t, J¼6.3 Hz, 2H), 2.28
(s, 3H), 2.27e2.23 (m, 2H), 1.79 (s, 3H), 1.68e1.61 (m, 2H), 1.05 (s,
9H); 13C NMR (100 MHz, CDCl3)
d 156.5,135.5 (4C),135.4,133.8 (2C),
132.9, 129.5, 129.4 (2C), 127.5 (4C), 113.9, 63.2, 50.9, 32.2, 26.9 (3C),
25.3, 19.3, 15.5, 14.1; HRMS (ESI TOF) calcd for C27H36O3SiNa
(MþNa)þ 459.2332, found 459.2312.
temperature were added NaHCO3 (7.9 mg, 93.8 mL) and 30% H2O2
(0.2 mL), and the mixture was stirred for 21 h at 30 ꢀC. The reaction
mixture was quenched with saturated Na2SO3 at 0 ꢀC, then diluted
with EtOAc, washed with water and brine. Concentration and chro-
matography (hexane/EtOAc, 100:1 to 70:1 to 40:1 to 20:1) gave 49
4.32. Unsaturated ester 54
(4.4 mg, 90% for the 3 steps): colorless oil; Rf¼0.38 (hexane/EtOAc,
To a solution of 50 (2.4 mg, 2.97
m
mol) in CH2Cl2 (0.3 mL) and
24
10:1); [
a
]
ꢁ14.3 (c 0.20, CHCl3); IR (neat) 2930, 1737, 1643,
DMSO (0.1 mL) at 0 ꢀC were added Et3N (41
mL, 0.297 mmol) and
1087 cmꢁ1D; 1H NMR (400 MHz, CDCl3)
d
7.64 (dd, J¼7.8, 1.5 Hz, 4H),
SO3$py (23.6 mg, 0.149 mmol), and the mixture was stirred for
45 min at room temperature. The mixture was diluted with EtOAc,
then washed with saturated NH4Cl, water, and brine. After con-
centration, the residue was filtered through a short silica gel col-
umn (Et2O) to give the crude aldehyde, which was used for the next
reaction directly.
7.41e7.31 (m, 6H), 6.63 (ddd, J¼16.8,11.1,10.0 Hz,1H), 6.01 (dd, J¼11.1,
10.0 Hz, 1H), 5.41 (ddd, J¼10.0, 6.6, 6.6 Hz,1H), 5.18 (d, J¼16.8 Hz,1H),
5.07 (d, J¼10.0 Hz, 1H), 4.17 (dd, J¼11.6, 5.0 Hz, 1H), 3.94 (dd, J¼3.7,
3.7 Hz,1H), 3.74e3.56 (m, 3H), 3.39 (dd, J¼6.8, 6.8,1H), 3.30e3.15 (m,
4H), 3.11 (dd, J¼12.1, 3.8 Hz, 1H), 2.36e2.19 (m, 2H), 2.19e1.20 (m,

H. Takamura et al. / Tetrahedron 66 (2010) 5329e5344
5343
To a solution of 52 (92.3 mg, 0.349 mmol) in THF (0.2 mL)
ꢁ78 ꢀC was added n-BuLi (0.19 mL, 0.297 mmol, 1.59 M solution in
hexane), and the mixture was stirred for 10 min at the same tem-
perature. After stirring for additional 50 min at 0 ꢀC, the mixture
was cooled to ꢁ78 ꢀC. To this mixture was added a pre-cooled
(ꢁ78 ꢀC) solution of the crude aldehyde in THF (0.7 mL). The re-
action mixture was allowed to warm to room temperature over 1 h
with stirring. After stirring the mixture for additional 26 h at room
temperature, the reaction mixture was quenched with saturated
NH4Cl, diluted with EtOAc, then washed with water and brine.
Concentration and chromatography (hexane/EtOAc, 100:1 to 70:1
ꢁ27.7 (c 0.05, benzene); IR (neat) 3655e3163, 2935, 1657, 1619,
1087 cmꢁ1; 1H NMR (400 MHz, C6D6)
10.08 (d, J¼7.6 Hz, 1H), 6.76
d
(ddd, J¼16.8, 10.2, 10.0 Hz, 1H), 6.14 (d, J¼7.6 Hz, 1H), 6.08 (dd,
J¼10.7, 10.2 Hz, 1H), 5.81 (t, J¼7.2 Hz, 1H), 5.45 (ddd, J¼10.7, 7.8,
7.8 Hz, 1H), 5.16 (d, J¼16.8 Hz, 1H), 5.06 (d, J¼10.0 Hz, 1H),
4.10e4.04 (m, 1H), 4.01 (dd, J¼10.7, 6.3 Hz, 1H), 3.71 (ddd, J¼10.5,
9.5, 5.1 Hz, 1H), 3.45 (dd, J¼9.5, 2.4 Hz, 1H), 3.39e3.31 (m, 1H), 3.28
(ddd, J¼9.0, 2.9, 2.9 Hz, 1H), 3.21e3.13 (m, 2H), 2.94 (dd, J¼12.3,
4.0 Hz, 1H), 2.38e1.97 (m, 9H), 1.97e1.38 (m, 14H), 1.79 (s, 3H), 1.55
(s, 3H), 1.18 (s, 3H), 1.14 (s, 3H), 1.13e1.06 (m, 1H), 0.97 (s, 3H), 0.96
(d, J¼7.3 Hz, 3H), 0.55 (br s, 1H); 13C NMR (100 MHz, C6D6)
d 190.5,
to 40:1 to 20:1) gave 54 (2.4 mg, 88% for the 2 steps): colorless oil;
156.1, 135.9, 134.5, 132.9, 132.6, 130.1, 126.0, 117.2, 87.4, 86.2, 84.8,
82.0, 77.3, 76.8, 76.5, 75.1, 74.0, 73.3, 70.9, 70.0, 47.5, 38.6, 37.8, 35.4,
34.6, 33.6, 32.8, 30.8, 30.0, 29.5, 26.6, 25.3, 23.7, 19.4, 16.3, 14.0, 13.9,
12.9; HRMS (ESI TOF) calcd for C39H60O8Na (MþNa)þ 679.4186,
found 679.4190.
23
Rf¼0.59 (hexane/EtOAc, 4:1); [
a
]
ꢁ22.4 (c 0.12, CHCl3); IR (neat)
D
2929,1719,1609,1086 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 6.63 (ddd,
J¼17.1, 10.9, 10.2 Hz, 1H), 6.01 (dd, J¼10.9, 10.0 Hz, 1H), 5.93 (t,
J¼7.1 Hz, 1H), 5.82 (s, 1H), 5.41 (ddd, J¼10.0, 7.3, 7.3 Hz, 1H), 5.18
(d, J¼17.1 Hz, 1H), 5.07 (d, J¼10.2 Hz, 1H), 4.19 (dd, J¼11.5, 5.1 Hz,
1H), 3.95 (dd, J¼3.4, 3.4 Hz, 1H), 3.74e3.62 (m, 1H), 3.69 (s, 3H),
3.45e3.39 (m, 1H), 3.30e3.15 (m, 4H), 3.11 (dd, J¼12.2, 4.1 Hz, 1H),
2.37e1.20 (m, 23H), 2.29 (s, 3H), 1.78 (s, 3H), 1.17 (s, 3H), 1.10 (s, 3H),
1.06 (s, 3H), 0.91 (d, J¼7.1 Hz, 3H), 0.90 (s, 9H), 0.82 (s, 9H), 0.06 (s,
3H), 0.05 (s, 3H), 0.04 (s, 3H), 0.04 (s, 3H); 13C NMR (100 MHz,
Acknowledgements
This work was financially supported by the Nagase Science and
Technology Foundation, the Wesco Scientific Promotion Founda-
tion, the Naito Foundation, the Sumitomo Foundation, and the
Grant-in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
CDCl3) d 156.7, 135.8, 133.5, 132.7, 132.1, 129.6 (2C), 117.0, 113.8, 86.9,
86.3, 85.2, 82.1, 77.7, 77.2, 76.1, 75.5, 73.1, 72.8, 72.6, 70.7, 50.9, 49.5,
37.8, 37.7, 35.0, 34.0, 32.9, 32.5, 30.2, 29.8 (2C), 28.8, 25.9 (3C), 25.8
(3C), 24.8, 24.0, 20.9, 18.3, 18.1, 16.3, 15.5, 14.1, 12.6, ꢁ2.0, ꢁ2.2, ꢁ4.2,
ꢁ4.8; HRMS (ESI TOF) calcd for C52H90O9Si2Na (MþNa)þ 937.6021,
found 937.6024.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.05.069. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
4.33. Triol 55
To a solution of 54 (2.4 mg, 2.62
m
mol) in CH2Cl2 (0.7 mL) at
m
ꢁ78 ꢀC was added DIBAL-H (10
m
L, 10.2 mol, 1.02 M solution in
References and notes
hexane). After stirring for 15 min, the reaction mixture was
quenched with MeOH, diluted with Et2O, then filtered through
a short silica gel column (Et2O to EtOAc). Concentration gave the
crude alcohol, which was used for the next reaction directly.
A mixture of the crude alcohol obtained and TBAF (0.2 mL,
0.2 mmol, 1.0 M solution in THF) was stirred for 32 h at 75 ꢀC in
a sealed tube. The mixture was diluted with EtOAc, then washed
with water and brine. Concentration and chromatography (hexane/
1. For reviews, see: (a) Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93, 1897e1909;
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Prod. Rep. 2000, 17, 293e314; (d) Yasumoto, T. Chem. Rec. 2001, 1, 228e242.
2. For recent reviews of the total synthesis of polycyclic ethers, see: (a)
€
Marmsater, F. P.; West, F. G. Chem.dEur. J. 2002, 8, 4347e4353; (b) Evans, P. A.;
Delouvrie, B. Curr. Opin. Drug Discovery Dev. 2002, 5, 986e999; (c) Inoue, M.
Org. Biomol. Chem. 2004, 2, 1811e1817; (d) Nakata, T. Chem. Rev. 2005, 105,
4314e4347; (e) Inoue, M. Chem. Rev. 2005, 105, 4379e4405.
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Jacocks, H. M.; Wright, J. L. C.; Bigwarfe, P. M., Jr.; Baden, D. G. J. Nat. Prod. 2005,
68, 2e6.
4. Abraham, W. M.; Bourdelais, A. J.; Sabater, J. R.; Ahmed, A.; Lee, T. A.;
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Fuwa, H.; Ebine, M.; Bourdelais, A. J.; Baden, D. G.; Sasaki, M. J. Am. Chem. Soc.
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7. Kadota, I.; Ohno, A.; Matsuda, K.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124,
3562e3566.
8. (a) Nicolaou, K. C.; Nugiel, D. A.; Couladouros, E.; Hwang, C.-K. Tetrahedron Lett.
1990, 46, 4517e4552; (b) Kadota, I.; Kadowaki, C.; Park, C.-H.; Takamura, H.;
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1799e1816.
9. Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401e404.
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1979, 52, 1989e1993.
11. Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885e7892.
12. Sasaki and co-workers have reported the same CeC bond formation with this
alkyl borate: see Ref. 5c.
13. Nicolaou, K. C.; Veale, C. A.; Hwang, C.-K.; Hutchinson, J.; Prasad, C. V. C.;
Ogilvie, W. W. Angew. Chem., Int. Ed. Engl. 1991, 30, 299e303.
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EtOAc, 1:1 to 1:2 to 0:1) gave 55 (1.7 mg, 98% for the 2 steps):
25
colorless oil; Rf¼0.19 (hexane/EtOAc, 1:1); [
a
]
ꢁ22.4 (c 0.08,
1H NMR
6.76 (ddd, J¼16.8, 10.9, 10.5 Hz, 1H), 6.08 (dd,
D
benzene); IR (neat) 3649e3114, 2929, 1643, 1087 cmꢁ1
(400 MHz, C6D6)
;
d
J¼10.9, 10.5 Hz, 1H), 5.70 (t, J¼6.3 Hz, 1H), 5.65 (t, J¼7.3 Hz, 1H),
5.45 (ddd, J¼10.5, 7.3, 7.3 Hz, 1H), 5.16 (d, J¼16.8 Hz, 1H), 5.06 (d,
J¼10.5 Hz, 1H), 4.10e4.05 (m, 3H), 4.01 (dd, J¼11.4, 5.5 Hz, 1H), 3.70
(ddd, J¼11.2, 9.7, 5.2 Hz, 1H), 3.45 (dd, J¼9.6, 2.8 Hz, 1H), 3.44e3.39
(m, 1H), 3.34 (ddd, J¼8.4, 8.4, 7.5 Hz, 1H), 3.20e3.12 (m, 2H), 2.93
(dd, J¼12.3, 4.0 Hz, 1H), 2.39e2.07 (m, 9H), 1.95e1.23 (m, 17H), 1.81
(s, 3H), 1.71 (s, 3H), 1.22 (s, 3H), 1.12 (s, 3H), 0.99 (d, J¼7.1 Hz, 3H),
0.97 (s, 3H); 13C NMR (100 MHz, C6D6)
d 138.2, 136.1, 132.9, 132.6,
130.1, 127.5, 125.5, 117.2, 87.4, 86.2, 84.7, 82.0, 77.3, 77.2, 76.7, 75.1,
74.1, 73.7, 70.8, 69.9, 60.1, 48.0, 38.6, 37.8, 35.5, 34.6, 33.6, 33.4, 30.8,
30.0, 29.4, 26.1, 25.3, 23.7, 19.4, 16.3, 14.4, 14.3, 13.0; HRMS (ESI TOF)
calcd for C39H62O8Na (MþNa)þ 681.4343, found 681.4343.
4.34. Brevenal (1)
To a mixture of 55 (1.0 mg,1.52
mmol) in CH2Cl2 (0.2 mL) at room
temperature was added MnO2 (4.0 mg, 46.0
mmol). After stirring for
1 h, the mixture was filtered through a short silica gel column
(EtOAc), and the filtrate was concentrated. The residue was purified
by chromatography (hexane/EtOAc, 2:1 to 1:1 to 1:2) to give 1
23
(1.0 mg, quant.): colorless oil; Rf¼0.30 (hexane/EtOAc, 1:1); [
a]
D

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H. Takamura et al. / Tetrahedron 66 (2010) 5329e5344
18. For the original conditions, see: (a) Dahanukar, V. H.; Rychnovsky, S. D. J. Org.
Chem. 1996, 61, 8317e8320; (b) Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem.
2000, 65, 191e198; (c) Kopecky, D. J.; Rychnovsky, S. D. Org. Synth. 2003, 80,
177e183.
19. (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2039e2041; (b) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem.
Soc. 1996, 118, 100e110.
22. 1H and 13C NMR spectra of 32 were identical with those reported previously.
23. (a) Yamamoto, Y.; Saito, Y.; Maruyama, K. Tetrahedron Lett. 1982, 23,
4959e4962; (b) Keck, G. E.; Abbott, D. E.; Wiley, M. R. Tetrahedron Lett. 1987, 28,
139e142; (c) Koreeda, M.; Tanaka, Y. Tetrahedron Lett. 1987, 28, 143e146.
24. Acetalization of the sterically hindered alcohol 40 with the enol ether 24
resulted in failure.
25. (a) Nicolaou, K. C.; Reddy, K. R.; Skokotas, G.; Sato, F.; Xiao, X.-Y. J. Am. Chem. Soc.
1992, 114, 7935e7936; (b) Nicolaou, K. C.; Reddy, K. R.; Skokotas, G.; Sato, F.;
Xiao, X.-Y.; Hwang, C.-K. J. Am. Chem. Soc. 1993, 115, 3558e3575.
20. For successful examples of the deprotection of TCBn group in similar cases, see
Ref. 15.
21. Sajiki, H.; Kume, A.; Hattori, K.; Hirota, K. Tetrahedron Lett. 2002, 43, 7247e7250.
26. Fadeyi, O. O.; Lindsley, C. W. Org. Lett. 2009, 11, 3950e3952.