An improved synthesis of (-)-brevisamide, a marine monocyclic ether amide of dinoflagellate origin

Article abstract of DOI:10.1016/j.tet.2010.06.074

An improved synthesis of (-)-brevisamide a marine cyclic ether isolated from the red-tide dinoflagellate Karenia brevis was achieved. The ether ring portion was constructed from an unsaturated lactone, which was prepared enantioselectively via an Evans aldol reaction and one-pot lactonization in the presence of excessive base after an Ando reaction. The ether ring and a dienol side chain fragment were connected via Suzuki-Miyaura coupling.

Full text of DOI:10.1016/j.tet.2010.06.074

Tetrahedron 66 (2010) 6775e6782
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An improved synthesis of (ꢀ)-brevisamide, a marine monocyclic ether amide
of dinoflagellate origin
Ryosuke Tsutsumi a, Takefumi Kuranaga a, Jeffrey L.C. Wright b, Daniel G. Baden b, Emiko Ito c,
,
a,
*
Masayuki Satake a , Kazuo Tachibana
*
a Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 Japan
b Center for Marine Science, University of North Carolina, Wilmington, Marvin K. Moss Lane, Wilmington, NC 28409, USA
c Medical Mycology Research Center, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8673, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 April 2010
Received in revised form 23 June 2010
Accepted 23 June 2010
Available online 3 July 2010
An improved synthesis of (ꢀ)-brevisamide a marine cyclic ether isolated from the red-tide dinoflagellate
Karenia brevis was achieved. The ether ring portion was constructed from an unsaturated lactone, which
was prepared enantioselectively via an Evans aldol reaction and one-pot lactonization in the presence of
excessive base after an Ando reaction. The ether ring and a dienol side chain fragment were connected
via SuzukieMiyaura coupling.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Cyclic ether
One-pot lactonization
SuzukieMiyaura coupling
Dinoflagellate origin
1. Introduction
18
17
Me
OH
10
Me
15
Me
H
Ladder-frame polyethers represent a characteristic group of
secondary metabolites produced by numerous marine di-
noflagellates.1 Many of these compounds are potent toxins, which
were initially identified as the causative agents in massive fish kills
or seafood poisoning events. As a group the ladder-frame polyethers
are fascinating not only to chemists for the structural and synthetic
challenges they provide, but also to biochemists interested in their
biogenesis and potent and selective biological activities. To date,
enormous efforts have been conducted to synthesize those com-
plicated molecules,2 and as a result several synthetic approaches to
these ether ring systems have been reported. In contrast, the bio-
synthetic mechanism leading to formation of the ladder-frame
polyethers has been less thoroughlystudied and consequently is less
well understood, though a general biosynthetic process is beginning
to emerge.3 It is hypothesized that a polyepoxide precursor probably
derived from E-polyolefin is converted to a ladder-frame polyether
via an enzyme mediated cascade of epoxide openings.4
O
14
N
O
13
H
H
1
Me
O
16
brevisamide (1)
Figure 1. Structure of (ꢀ)-brevisamide (1).
determined based on extensive 2D NMR studies, and was charac-
terized as a single tetrahydropyran ring with a 3,4-dimethylhepta-
2,4-dienal side chain and an acetylated terminal amine. This cyclic
ether amide is the first nitrogen-containing cyclic ether from
K. brevis and can be regarded as a truncated analog of brevenal and
brevisin containing the A-ring portion and the dienal side chain. In
addition to our first total synthesis of 1,9 the compound has also been
synthesized by 4 independent groups.10e12 Our original synthesis
established the absolute configuration of brevisamide, which has
recently been confirmed by a modified Mosher’s method.3 Some
steps in our original synthesis resulted in low product yields and it
was determined that in order to obtain sufficient material for more
extensive biological testing, an improved synthesis was essential.
In our original synthetic approach of a putative biosynthetic
precursor of 1, we reported a concise synthesis of a bromodienol
side chain moiety, which was used in a coupling reaction.13 In this
latest study we focused on improving two aspects of the synthesis,
The monocyclic ether amide, brevisamide (1, Fig. 1)5 was isolated
from the red-tide dinoflagellate Karenia brevis, which also produces
brevetoxins,6 brevenal,7 and brevisin.8 The structure of 1 was
* Corresponding authors. Tel.: þ81 3 5841 4357; fax: þ81 3 5841 8380; e-mail
address: msatake@chem.s.u-tokyo.ac.jp (M. Satake).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.074

6776
R. Tsutsumi et al. / Tetrahedron 66 (2010) 6775e6782
namely more efficient synthesis of the ether ring fragment and
improving the yield of the key SuzukieMiyaura coupling reaction.14
To this end, the ether ring fragment was synthesized using an Evans
aldol reaction15 followed by one-pot lactonization in the presence
of excessive base after an Ando reaction.16 The low yield of the
SuzukieMiyaura coupling step was attributed to reduction of the
acetamide by 9-BBN-H. In this latest approach, the ether ring
fragment contains instead a protected primary alcohol function and
following addition of the dienol side chain fragment by Suzu-
kieMiyaura coupling, the primary alcohol group can be converted
to the acetamide. Herein we report an improved total synthesis of 1
via stereo-controlled ether ring construction and a key Suzu-
kieMiyaura cross coupling reaction.
a
BnO
OH
OH
BnO
O
N
5
6
b
O
OH
O
O
c
Me
BnO
N
BnO
O
Me OMe
8
Me
Bn
7
d
OH
OH
O
e
2. Results and discussion
2.1. Retrosynthetic analysis
BnO
BnO
BnO
Me CO2Me
f
Me
10
9
Our synthetic strategy is summarized in Scheme 1. The bro-
modienol fragment 2 was prepared from methyl methacrylate (4),
and the ether ring fragment 3 was prepared from 3-benzyloxy-
propan-1-ol (5). The fragments 2 and 3 could be linked by the
SuzukieMiyaura cross coupling.
Me
g
O
O
H
11
Scheme 2. Reagents and conditions: (a) TEMPO, PhI(OAc)2, CH2Cl2, rt, 94%; (b) (R)-4-
benzyl-N-propionyl-2-oxazolidinone, n-Bu2BOTf, Et3N, CH2Cl2, ꢀ78 to 0 ꢁC; then
MeOH/30% H2O2 aq, rt, 92%; (c) NH(OMe)Me$HCl, AlMe3, CH2Cl2, ꢀ15 to 0 ꢁC; (d)
LiAlH4, THF, 0 ꢁC, 85%; (e) (PhO)2P(O)CH2COOMe (1.4 equiv), NaH (1.3 equiv), THF,
ꢀ78 ꢁC, 69%; (f) PPTS, benzene, reflux, 97%; (g) (PhO)2P(O)CH2COOMe (1.2 equiv), NaH
(1.5 equiv), THF, ꢀ78 to 0 ꢁC, 71%.
Me
OH
Me
H
O
N
Me
O
H
H
Me
O
1
Me
Me
OTBS
OTBS
Me
Me
a
TBDPSO
Br
+
I
O
BnO
O
O
BnO
O
O
Me
2
H
H
H
12
H
11
3
b,c
Me
Me
Me
Me
d
MeO
BnO
OH
OH
BnO
BnO
CO2Me
OTBS
O
13
BnO
BnO
O
O
H
H
H
5
4
14
e
Scheme 1. Retrosynthetic analysis of 1.
Me
OH
OH
10
f
6
2.2. Synthesis of the ether ring fragment
A synthesis of an -unsaturated lactone 11, a key intermediate
OTBS
O
O
13
H
H
H
a,b
16
15
of 3 started from 3-benzyloxypropan-1-ol (5) (Scheme 2). The al-
cohol was oxidized to an aldehyde 6 with TEMPO. An aldol addition
of the enolborate derived from (R)-4-benzyl-N-propionyl-2-oxa-
zolidinone to the aldehyde 6 gave a syn aldol adduct 7 in 92%
yield.15 The aldol adduct 7 was converted to a Weinreb amide 8
with NH(OMe)Me$HCl and AlMe3 in 93% yield. The amide 8 was
g
Me
OTBS
OTBS
Me
OTBS
h
OTBS
I
O
HO
O
H
H
H
H
3
17
reduced to a b
-hydroxyaldehyde 9 with LiAlH4 in 85% yield.17 Then
9 was treated with (PhO)2P(O)CH2COOMe16 (1.2 equiv) and exces-
sive amounts of NaH (1.5 equiv) in THF. In this operation, when
Scheme 3. Reagents and conditions: (a) H2, Pd/C, EtOAc, rt, 98%; (b) PhNTf2, KHMDS,
DMPU, THF, ꢀ78 to 0 ꢁC; (c) CO, Et3N, Pd(PPh3)4, DMF/MeOH, rt, 88% for two steps; (d)
DIBALH, CH2Cl2, ꢀ78 to 0 ꢁC, 88%; (e) BH3$SMe2, THF, 0 ꢁC; then 3 M NaOH aq, 30%
H2O2 aq, 45 ꢁC, 86%; (f) TBSCl, imidazole, DMF, rt, 95%; (g) LiDBB, THF, ꢀ78 ꢁC, 82%; (h)
I2, PPh3, imidazole, toluene, rt, 91%.
reaction temperature was elevated from ꢀ78 to 0 ꢁC, an
a,b-un-
saturated six-membered lactone 11 was obtained in 71% yield. Al-
though this annulation can be ordinarily carried out via two steps (e
and f), the one-pot method is obviously superior to the two-step
method because of time savings and comparable yields.
afforded an oxene carboxylate 13 in 88% yield after two steps. The
methyl ester 13 was reduced with DIBALH, and subsequent
hydroboration gave a diol 15 as a single isomer in 86% yield. Steric
interaction between BH3$SMe2 and the C-9 axial methyl group
generated the desired stereoselectivity of hydroboration. The ster-
eostructure of the ether ring was assigned at this stage by NOE
Following successful lactone formation, we focused next on
conversion of 11 to the ether ring moiety 3 (Scheme 3).
After hydrogenation of 11 in 98% yield, treatment of 12 with
PhNTf2, KHMDS, and DMPU gave a ketene acetal triflate, followed
by Pd(0)-catalyzed carbonylation with CO, Et3N, and MeOH
3
correlations and JH,H coupling constants. NOE correlations

R. Tsutsumi et al. / Tetrahedron 66 (2010) 6775e6782
6777
between the C-9 methyl and H-11, and the C-9 methyl and H-10
Me
OTBS
OTBS
Me
suggested an axial orientation of the C-9 methyl and H-11 and an
equatorial orientation of H-10. An NOE correlation and small cou-
pling constant (J¼3 Hz) between H-9 and H-8 confirmed an axial
direction of H-8. The resultant diol 15 was protected with TBSCl and
followed by treatment with LiDBB to generate primary alcohol 17.
The primary alcohol 17 was converted to iodide with I2, PPh3, and
imidazole to give rise to the ether ring fragment 3 in 91% yield.
TBDPSO
Br
+
I
O
H
H
Me
2
3
a
Me
OTBS
OTBS
Me
TBDPSO
O
2.3. Synthesis of the bromodienol side chain fragment
H
H
Me
20
21
22
In this approach, the dienol fragment 2 was prepared from
methyl methacrylate (4) (Scheme 4). Bromination of 4, followed by
dehydrobromination and concomitant hydrolysis of the ester
afforded a carboxylic acid, which was then reduced to an allylic
alcohol.18 The allylic alcohol was oxidized to an aldehyde, and
subsequent addition of Grignard reagent, followed by oxidation of
the resultant secondary alcohol gave the known bromoenone.19
HornereWadswortheEmmons reaction of this bromoenone with
(EtO)2P(O)CH2CO2Et in the presence of n-BuLi gave (E,E)-bromo-
dienoate 18a and undesired (Z,E)-bromodienoate 18b in a highly
stereoselective fashion (5:1). It should be noted that 18a was
obtained in a good yield (31% from 4) without purification until
HWE reaction. Reduction of the desired (E,E)-dienoate 18a with
DIBALH, followed by protection of the resultant hydroxy group with
TBDPS afforded the bromodienol side chain fragment 2 in 99% yield.
b
Me
OTBS
OH
Me
TBDPSO
TBDPSO
HO
O
O
H
H
H
H
Me
c
Me
OTBS
I
Me
Me
d,e,f,g
Me
OH
Me
Me
H
Me
a,b
N
Me
O
MeO
O
HO
HO
Br
Br
H
H
Me
O
23
O
4
h
c
Me
Me
Me
OH
Me
d,e,f
O
H
O
O
Br
O
N
Me
O
O
Me
H
H
Me
1
g
Scheme 5. Reagents and conditions: (a) 3, B-OMe-9-BBN, t-BuLi, ether/THF, ꢀ78 ꢁC to
rt; then 2, Pd(dppf)Cl2, 3 M Cs2CO3 aq, DMF, 64%; (b) CSA, CH2Cl2/MeOH, 0 ꢁC, 85%
brsm; (c) I2, PPh3, imidazole, toluene, rt, 90%; (d) NaN3, DMF, rt; (e) PPh3, THF, rt; then
H2O, 50 ꢁC; (f) Ac2O, pyridine, rt; (g) TBAF, THF, 0 ꢁC to rt, 89% for four steps; (h)
TEMPO, PhI(OAc)2, CH2Cl2, rt, 88%.
EtO
Me
Me
EtO
HO
Br
+
Br
18b
Me
18a
Me
Cl2 to give rise to a cross-coupled product 20 in 64% yield. The
primary TBS group on the ether ring was selectively deprotected
with CSA to give a primary alcohol 21, which was converted to an
iodide 22 using I2, PPh3, and imidazole. The iodide 22 was con-
verted to an azide with NaN3 and then reduced to an amine, which
was acetylated with acetic anhydride to give an amide. This amide
was treated with TBAF to give a dienol 23 in 89% yield over four
steps. Finally, chemoselective oxidation of the allylic alcohol at C-1
with TEMPO and PhI(OAc)2 in CH2Cl2 gave rise to 1 in 88% yield.
Brevisamide showed weak cytotoxicity against mouse lymphoid
h
Me
Me
i
Br
TBDPSO
Br
Me
19
Me
2
Scheme 4. Reagents and conditions: (a) Br2, CCl4, 0 ꢁC to rt; (b) NaOH, THF/H2O, 0 ꢁ
C
to rt; (c) LiAlH4, ether, 0 ꢁC to rt; (d) MnO2, ether, rt, (e) MeMgBr, ether, 0 ꢁC; (f) MnO2,
ether, rt; (g) (EtO)2P(O)CH2COOEt, n-BuLi, THF, 0 ꢁC to rt, 18a 31%, 18b 6% for seven
steps; (h) DIBALH, CH2Cl2, ꢀ78 ꢁC, 98%; (i) TBDPSCl, imidazole, DMF, 0 ꢁC to rt, 99%.
P388 cells at more than 30 m
g/mL20 but did not induce any symp-
toms against mice even at 3 mg/kg.
2.4. Total synthesis of (L)-brevisamide
3. Conclusion
Linkage of the bromodienol side chain fragment 2 and the ether
ring fragment 3 was accomplished by a SuzukieMiyaura cross
coupling (Scheme 5).
Treatment of 3 with t-BuLi and B-OMe-9-BBN produced a borate
intermediate, which was reacted in situ with the bromodienol 2 in
the presence of aqueous Cs2CO3 and a catalytic amount of Pd(dppf)
We accomplished the improved synthesis of 1. The longest lin-
ear sequence leading to 1 was 21 steps with overall yield 8.6% and
the overall yield of this synthesis was five times as high as that of
our previous synthesis (1.6%). In particular, one-pot lactonization in
the existence of excessive base after an Ando reaction was found to
be an effective method.

6778
R. Tsutsumi et al. / Tetrahedron 66 (2010) 6775e6782
4. Experimental section
The combined organic phase was washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. The crude
oil was purified by silica gel chromatography (70/30 to 60/40
4.1. General methods
hexane/acetone) to afford 8 as a colorless oil (547 mg, 1.94 mmol,
26
All reactions sensitive to air and/or moisture were carried out in
an oven-dried (>100 ꢁC) glassware under argon atmosphere, and
under anhydrous conditions otherwise noted. Anhydrous
dichloromethane (CH2Cl2), diethyl ether (Et2O), and tetrahydrofu-
ran (THF) were purchased from Kanto Chemical Co. Inc and used
without further drying. All other reagents and solvents were pur-
chased at highest commercial grade and used as supplied unless
otherwise noted. Analytical thin-layer chromatography (TLC) was
performed using E. Merck silica gel 60 F254 plates (0.25-mm
thickness). Column chromatography was performed using Kanto
Chemical silica gel 60N (40e100 mesh, spherical, neutral). Optical
rotations were recorded on a JASCO DIP-350 digital polarimeter. IR
spectra were recorded on a JASCO FT/IR-420 spectrometer. 1H and
13C NMR spectra were measured on a JEOL ECA-500 and ECX-400
spectrometer, and chemical shift values are reported in parts per
93%). [
d
a
]
ꢀ14.5 (c 0.235 in CHCl3); 1H NMR (500 MHz, CDCl3)
D
7.33e7.29 (m, 4H), 7.27e7.25 (m, 1H), 4.50 (s, 2H), 3.69e3.61 (m,
2H), 3.64 (s, 3H), 3.16 (s, 3H),1.82 (dddd, J¼14.3, 9.2, 6.3, 5.5 Hz,1H),
1.71e1.65 (m, 1H), 1.18 (d, J¼6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
177.7, 138.1, 128.3, 127.6, 127.6, 73.2, 70.3, 68.3, 61.5, 39.4, 33.9,
31.8, 11.1; IR (film) nmax cmꢀ1 3447 (br), 2933, 2868, 1651, 1636,
1456, 1419, 1387, 1098, 988, 738, 699; HRMS (FAB) calcd for [MþH]þ
(C15H24NO4) 282.1700, found 282.1713.
4.1.3.
b-Hydroxyaldehyde (9). To a suspension of LiAlH4 (463 mg,
12.2 mmol) in THF (10 mL) was added a solution of 8 (1.68 g,
5.97 mmol) in THF (50 mL) dropwise via cannula at 0 ꢁC. The re-
action mixture was stirred for 1 h before quenching with EtOAc.
After aqueous saturated potassium sodium tartrate was added, the
reaction mixture was warmed to room temperature and stirred for
50 min. The layers were separated, and the aqueous layer was
extracted with EtOAc. The combined organic phase was washed
with brine, dried over anhydrous MgSO4, filtered, and concentrated
in vacuo. The crude oil was purified by silica gel chromatography
million (d
) with reference to internal residual solvent [1H NMR,
CDCl3 (7.24), C6D6 (7.16); 13C NMR, CDCl3 (77.0), C6D6 (127.0)].
Coupling constants (J) are reported in hertz (Hz). The following
abbreviations are used to designate the multiplicities: s¼singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet, br¼broad. Low- and
high-resolution mass spectra were recorded on a JEOL JMS-700P
mass spectrometer under fast atom bombardment (FAB) conditions
using m-nitrobenzyl alcohol (NBA) as a matrix and a JEOL JMS-
T100TD mass spectrometer under direct analysis in real time
(DART) conditions.
(60/40 hexane/EtOAc) to afford
5.09 mmol, 85%). [
9 as a colorless oil (1.13 g,
a
]
18 ꢀ20.7 (c 0.508 in CHCl3); 1H NMR (500 MHz,
D
CDCl3)
d
9.75 (s, 1H), 7.36e7.28 (m, 5H), 4.51 (s, 2H), 4.27 (dddd,
J¼9.6, 4.2, 2.5, 2.5 Hz, 1H), 3.73 (ddd, J¼9.2, 5.9, 4.6 Hz, 1H), 3.66
(ddd, J¼9.2, 9.2, 3.8 Hz, 1H), 2.46 (qd, J¼7.1, 4.2 Hz, 1H),1.85 (dddd,
J¼14.3, 9.6, 9.2, 4.2 Hz, 1H), 1.68 (dddd, J¼14.3, 5.9, 3.8, 2.5 Hz, 1H),
1.11 (d, J¼7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 204.8, 137.6,
4.1.1. Aldol adduct (7). To a solution of (R)-4-benzyl-3-propionyl-2-
oxazolidinone (4.81 g, 20.6 mmol) in CH2Cl2 (100 mL) was added n-
Bu2BOTf (1.0 M in CH2Cl2, 22.7 mL, 23 mmol) and Et3N (3.4 mL)
slowly at 0 ꢁC. The reaction mixture was stirred for 1 h and cooled
to ꢀ78 ꢁC. A solution of 6 (3.38 g, 20.6 mmol) in CH2Cl2 (30 mL) was
added dropwise, and the reaction mixture was stirred for 1.5 h then
for 2 h at 0 ꢁC. The reaction was quenched with phosphate buffer
(pH 7, 40 mL). MeOH/30% aqueous H2O2 (60 mL, 30 mL) was added,
and the reaction mixture was stirred at room temperature for 1 h.
Two layers were separated and the aqueous layer was extracted
with CHCl3. The combined organic phase was washed with satu-
rated aqueous NaHCO3, dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. The crude oil was purified by silica gel
128.4,127.8,127.6, 73.3, 70.2, 68.9, 51.5, 33.5, 7.7; IR (film) nmax cmꢀ1
3454 (br), 2926, 2863, 2721, 1719, 1454, 1364, 1090, 1024, 741, 696;
HRMS (FAB) calcd for [MþNa]þ (C13H18NaO3) 245.1154, found
245.1146.
4.1.4.
a,b-Unsaturated lactone (11). To a solution of NaH (354 mg,
8.9 mmol, 60% dispersion in oil) in THF (40 mL) was added a solu-
tion of (PhO)2P(O)CH2COOMe (2.27 g, 7.41 mmol) in THF (10 mL)
dropwise at 0 ꢁC, and the reaction mixture was stirred for 10 min.
The solution was cooled to ꢀ78 ꢁC, and a solution of 9 (1.43 g,
6.11 mmol) in THF (10 mL) was added dropwise via cannula. After
80 min the reaction mixture was warmed to 0 ꢁC and stirred for
10 min before quenching with saturated aqueous NH4Cl. The mix-
ture was concentrated and extracted twice with EtOAc. The organic
phase was washed twice with water then with brine, dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. The crude
chromatography (70/30 to 60/40 hexane/EtOAc) to afford 7 as
26
a pale yellow oil (7.52 g, 18.9 mmol, 92%). [
a
]
ꢀ51.2 (c 0.144 in
D
CHCl3); 1H NMR (500 MHz, CDCl3)
d
7.33e7.30 (m, 8H), 7.19 (d,
J¼6.7 Hz, 2H), 4.67 (dddd, J¼10.1, 6.7, 3.4, 3.4 Hz, 1H), 4.50 (s, 2H),
3.80 (td, J¼7.1, 3.8 Hz, 1H), 3.69 (ddd, J¼9.2, 6.3, 5.0 Hz, 1H), 3.64
(ddd, J¼9.2, 7.5, 5.0 Hz, 1H), 3.28 (d, J¼2.5 Hz, 1H), 3.24 (dd, J¼13.4,
3.4 Hz, 1H), 2.76 (dd, J¼13.4, 9.6 Hz, 1H), 2.02 (s, 1H), 1.86 (dddd,
J¼14.3, 9.6, 7.1, 5.0 Hz, 1H), 1.75e1.70 (m, 1H), 1.26 (d, J¼7.1 Hz, 3H);
oil was purified by silica gel chromatography (95/5 CHCl3/EtOAc) to
22
afford 11 as a colorless oil (1.07 g, 4.34 mmol, 71%). [
a
]
ꢀ106 (c
D
0.408 in CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.35e7.25 (m, 5H),
6.92 (dd, J¼9.6, 6.4 Hz, 1H), 5.94 (d, J¼9.6 Hz, 1H), 4.64 (ddd, J¼9.2,
3.7, 3.7 Hz, 1H), 4.51 (d, J¼11.9 Hz, 1H), 4.48 (d, J¼11.9 Hz, 1H), 3.68
(ddd, J¼9.2, 9.2, 5.0 Hz, 1H), 3.62 (ddd, J¼9.6, 5.0, 5.0 Hz, 1H),
2.39e2.31 (m, 1H), 2.04 (dddd, J¼14.2, 9.6, 5.0, 5.0 Hz, 1H), 1.83
(dddd, J¼14.2, 8.7, 5.9, 4.1 Hz, 1H), 1.03 (d, J¼7.3 Hz, 3H); 13C NMR
13C NMR (100 MHz, CDCl3)
d 176.6, 153.0, 138.0, 135.1, 129.4, 128.9,
128.3, 127.7, 127.4, 73.2, 70.4, 68.3, 66.1, 55.2, 42.5, 37.8, 33.7, 11.1; IR
(film) nmax cmꢀ1 3512 (br), 2921, 2868, 1778, 1695, 1451, 1386, 1208,
1108, 969, 744, 700; HRMS (FAB) calcd for [MþNa]þ (C15H20NO3Na)
271.1305, found 271.1301.
(100 MHz, CDCl3) d 164.5,151.6,138.0, 128.3, 127.6,127.6, 119.8, 76.9,
73.1, 65.7, 32.1, 31.9, 11.3; IR (film) nmax cmꢀ1 2872, 1721, 1454, 1381,
1250, 1094, 985, 823, 739, 698; HRMS (FAB) calcd for [MþH]þ
(C15H19O3) 247.1329, found 247.1331.
4.1.2. Weinreb amide (8). To
a solution of NH(OMe)Me$HCl
(412 mg, 4.22 mmol) in CH2Cl2 (15 mL) was added AlMe3 (2.0 M in
heptane, 2.1 mL, 4.2 mmol) slowly at 0 ꢁC. The reaction mixture was
stirred at room temperature for 1 h then cooled to ꢀ15 ꢁC. A so-
lution of 7 (833 mg, 2.10 mmol) in CH2Cl2 (5 mL) was added
dropwise, and the reaction mixture was warmed to 0 ꢁC and stirred
for 40 min. Saturated aqueous potassium sodium tartrate was
added, and the reaction mixture was stirred for 1 h. Two layers
were separated and the aqueous layer was extracted with CHCl3.
4.1.5. Lactone (12). To a solution of 11 (1.04 g, 4.22 mmol) in EtOAc
(30 mL) was added a suspension of Pd/C (0.06 g, 5%) in EtOAc
(10 mL). The flask was flushed with H2 and the mixture was stirred
for 14 h at room temperature before it was filtered through CeliteÒ.
The filtrate was concentrated in vacuo to give 12 as a colorless oil
22
(1.03 g, 4.15 mmol, 98%). [
(400 MHz, CDCl3)
a
]
ꢀ98.4 (c 0.606 in CHCl3); 1H NMR
D
d
7.35e7.26 (m, 5H), 4.52 (ddd, J¼9.6, 3.2, 3.2 Hz,

R. Tsutsumi et al. / Tetrahedron 66 (2010) 6775e6782
6779
1H), 4.50 (d, J¼11.9 Hz, 1H), 4.48 (d, J¼11.9 Hz, 1H), 3.66 (ddd, J¼9.2,
9.2, 5.0 Hz, 1H), 3.61 (ddd, J¼9.2, 6.0, 4.6 Hz, 1H), 2.52 (dd, J¼7.8,
6.9 Hz, 1H), 2.07e1.98 (m, 1H), 1.91 (dddd, J¼14.2, 10.6, 5.0, 5.0 Hz,
1H), 1.80 (dddd, J¼14.2, 8.7, 6.0, 3.7 Hz, 1H), 1.64 (ddd, J¼9.2, 6.9,
6.9 Hz, 1H), 0.95 (d, J¼6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3)
1367, 1207, 1104, 1077, 1014, 737, 696; HRMS (FAB) calcd for
[MþNa]þ (C16H22O3Na) 285.1461, found 285.1461.
4.1.8. Diol (15). To a solution of 14 (145 mg, 0.553 mmol) in THF
(5.0 mL) was added BH3$SMe2 (2.0 M in THF, 0.55 mL, 1.1 mmol) at
0 ꢁC, and the solution was stirred for 4 h. Aqueous 3 M NaOH
(0.7 mL) and aqueous 30%H2O2 (0.4 mL) was added, andthe reaction
mixture was stirred for 30 min at 45 ꢁC. The mixture was extracted
twicewith EtOAc, and the combined organic phasewas washed with
brine, dried over anhydrous MgSO4, filtered, and concentrated in
vacuo. The crude oil was purified by silica gel chromatography (2/8
to 1/9 hexane/EtOAc) to afford 15 as a white solid (133 mg,
d
171.8, 138.1, 127.7, 127.7, 79.4, 73.2, 66.2, 32.6, 29.5, 26.7, 26.1, 12.6;
IR (film) nmax cmꢀ1 2965, 2875, 1734, 1454, 1364, 1239, 1203, 1076,
991, 741, 696; HRMS (FAB) calcd for [MþNa]þ (C15H20O3Na)
271.1305, found 271.1301.
4.1.6. Oxene carboxylate (13). To
a solution of 12 (340 mg,
1.37 mmol) in THF (24 mL) was added DMPU (0.21 mL, 1.8 mmol),
KHMDS (0.5 M in toluene, 3.6 mL, 1.8 mmol), a solution of PhNTf2
(698 mg, 1.95 mmol) in THF (3.0 mL) at ꢀ78 ꢁC, and the mixture
was stirred for 30 min. The reaction mixture was warmed to 0 ꢁC
and stirred for further 40 min before hexane and phosphate buffer
(pH 7) was added. The layers were separated and the aqueous layer
was extracted with hexane. The combined organic phase was dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo to af-
ford an oil. The product was employed in the next reaction without
further purification.
The above enoltriflate was dissolved in DMF (15 mL), MeOH
(5.2 mL) at room temperature. Et3N (0.77 mL, 5.5 mmol), Pd
(PPh3)4 77 mg (0.067 mmol) was added. The flask was flushed
with CO, and the reaction mixture was stirred for 16 h. Additional
Pd(PPh3)4 (86 mg, 0.074 mmol) was added, and the reaction
mixture was warmed to 40 ꢁC. After 10 h the reaction mixture was
cooled to room temperature, and EtOAc and brine was added. Two
layers were separated, and the aqueous layer was extracted with
EtOAc. The combined organic phase was dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. Purification on silica
0.476 mmol, 86%). [
a
]
22 ꢀ33.3 (c 0.255 in CHCl3); 1H NMR (500 MHz,
D
CDCl3)
d
7.34e7.24 (m, 5H), 4.50 (d, J¼11.7 Hz,1H), 4.46 (d, J¼11.7 Hz,
1H), 3.79e3.75 (m, 2H), 3.63 (ddd, J¼9.2, 4.2, 2.5 Hz, 1H), 3.59e3.48
(m, 2H), 3.11 (ddd, J¼9.2, 4.6, 4.6 Hz,1H), 2.49 (dd, br, J¼18.9, 4.6 Hz,
2H),1.93 (ddd, J¼12.6, 4.6, 2.5 Hz,1H),1.85e1.79 (m,1H),1.75 (dddd,
J¼14.3, 9.2, 5.4, 5.4 Hz,1H),1.65e1.58 (m, 2H), 0.93 (d, J¼7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3)
d 138.3,128.3,127.6,127.6, 81.9, 76.4, 72.9,
67.0, 63.8, 63.4, 40.0, 33.0, 32.7, 12.6; IR (film) nmax cmꢀ1 3392 (br),
2921, 2861,1454,1387, 1361, 1100,1065, 738, 696; HRMS (FAB) calcd
for [MþNa]þ (C16H24O4Na) 281.1748, found 281.1761.
4.1.9. Bis-TBS ether (16). To a solution of 15 (133 mg, 0.473 mmol)
in DMF (2.5 mL) was added imidazole (184 mg, 1.72 mmol) and
TBSCl (337 mg, 1.27) at room temperature, and the reaction mixture
was stirred for 1.5 h before water was added at 0 ꢁC. The mixture
was extracted twice with EtOAc. The combined organic phase was
washed twice with water, then brine, dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The crude oil was purified by
silica gel chromatography (93/7 hexane/EtOAc) to afford 16 as
22
gel with hexane/EtOAc/Et3N (90/10/0.5 to 80/20/0.5) gave 13 as
a colorless oil (230 mg, 0.452 mmol, 95%). [
a]
þ8.23 (c 0.417 in
D
22
a colorless oil (349 mg, 1.20 mmol, 88% for two steps). [
a
]
ꢀ77.8
CHCl3); 1H NMR (500 MHz, CDCl3)
d 7.35e7.31 (m, 4H), 7.29e7.24
D
(c 0.445 in benzene); 1H NMR (400 MHz, C6D6)
d
7.44e7.15 (m,
(m, 1H), 4.49 (d, J¼12.2 Hz, 1H), 4.48 (d, J¼12.2 Hz, 1H), 3.76e3.68
(m, 3H), 3.60e3.53 (m, 3H), 3.02 (ddd, J¼9.2, 4.6, 2.1 Hz, 1H), 1.83
(ddd, J¼12.6, 4.6, 2.5 Hz, 1H), 1.80e1.73 (m, 2H), 1.65e1.56 (m, 2H),
1.93 (ddd, J¼12.6, 4.6, 2.5 Hz,1H), 0.93 (d, J¼7.1 Hz, 3H), 0.88 (s, 9H),
0.86 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H); 13C
5H), 6.11 (dd, J¼4.1, 4.1 Hz, 1H), 4.39 (d, J¼12.8 Hz, 1H), 4.38 (d,
J¼12.8 Hz, 1H), 4.10 (ddd, J¼9.6, 2.7, 2.7 Hz, 1H), 3.70 (ddd, J¼9.2,
9.2, 5.5 Hz, 1H), 3.55 (ddd, J¼9.2, 5.5, 5.5 Hz, 1H), 3.48 (s, 3H), 1.99
(ddd, J¼18.7, 6.4, 3.2 Hz, 1H), 1.92 (ddd, J¼14.2, 5.0, 5.0 Hz, 1H),
1.68e1.56 (m, 1H), 1.48 (ddd, J¼18.3, 4.6, 4.6 Hz, 1H), 0.75 (d,
NMR (100 MHz, CDCl3)
d 138.6, 128.3, 127.6, 127.5, 83.5, 75.9, 73.0,
J¼6.9 Hz, 3H); 13C NMR (100 MHz, C6D6)
d
163.1, 144.0, 139.3,
67.5, 63.0, 62.9, 41.1, 33.2, 33.1, 25.9, 25.8, 18.4, 17.9, 12.8, ꢀ4.3, ꢀ4.9,
ꢀ5.3; IR (film) nmax cmꢀ1 2959, 2929, 2882, 2857, 1461, 1387, 1361,
1252, 1136, 1103, 1017, 866, 836, 776, 731, 696; HRMS (FAB) calcd for
[MþNa]þ (C16H24O4Na) 531.3297, found 531.3309.
128.5, 127.7, 127.5, 109.6, 75.8, 73.0, 67.0, 51.3, 31.6, 29.0, 29.0, 13.4;
IR (film) nmax cmꢀ1 2954, 1732, 1649, 1437, 1371, 1287, 1253, 1102,
739, 698; HRMS (FAB) calcd for [MþNa]þ (C17H22O4Na) 313.1416,
found 313.1425.
4.1.10. Primary alcohol (17). To
a solution of 16 (25.9 mg,
4.1.7. Allylic alcohol (14). To a solution of 13 (258 mg, 0.888 mmol)
in CH2Cl2 (10 mL) was added DIBALH (1.0 M in hexane, 2.2 mL,
2.2 mmol) dropwise at ꢀ78 ꢁC. The reaction mixture was warmed
to 0 ꢁC and stirred for 20 min before the reaction was quenched
with EtOAc and water. Saturated aqueous potassium sodium tar-
trate was added, and the mixture was stirred additional 1 h at room
temperature. The layers were separated, and the aqueous layer was
extracted with EtOAc. The combined organic phase was washed
with brine, dried over anhydrous Na2SO4, filtered, and concentrated
in vacuo. The crude oil was purified by silica gel chromatography
0.0509 mmol) in THF (1 mL) was added a pre-made 0.5 M solution
of LiDBB in THF (ca. 6 mL) dropwise at ꢀ78 ꢁC. The reaction mixture
was stirred for 3 h before MeOH and saturated aqueous NH4Cl was
added. The reaction mixture was extracted three times with EtOAc,
and the combined organic phase was dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. Purification on silica gel chro-
matography (9/1 to 8/2 hexane/EtOAc) afforded 17 as a colorless oil
22
(17.5 mg, 0.0418 mmol, 82%). [
a
]
þ26.5 (c 0.243 in CHCl3); 1H
D
NMR (500 MHz, CDCl3),
d
3.81e3.72 (m, 3H), 3.68e3.59 (m, 3H),
3.16 (ddd, J¼8.4, 6.3, 2.1 Hz, 2H), 1.87e1.77 (m, 3H), 1.73e1.66 (m,
1H), 1.62 (td, J¼11.8, 4.6 Hz, 1H), 1.41 (dddd, J¼14.7, 4.6, 2.1, 2.1 Hz,
1H), 0.96 (d, J¼6.7 Hz, 3H), 0.87 (s, 9H), 0.84 (s, 9H), 0.03 (s, 3H),
(75/25/0.5 to 50/50/0.5 heane/EtOAc/Et3N) to afford 14 as a color-
22
less oil (205 mg, 0.781 mmol, 88%). [
a
]
D
ꢀ66.6 (c 0.322 in ben-
zene); 1H NMR (400 MHz, C6D6)
d
7.38e7.16 (m, 5H), 4.64 (s, 1H),
0.02 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 83.6, 81.3, 63.2, 62.8, 40.9,
4.42 (d, J¼12.4 Hz, 1H), 4.41 (d, J¼12.4 Hz, 1H), 4.12 (ddd, J¼9.6, 3.2,
3.2 Hz, 1H), 3.96 (s, 2H), 3.59 (ddd, J¼8.7, 8.7, 5.5 Hz, 1H), 3.50 (ddd,
J¼8.7, 5.5, 5.5 Hz, 1H), 2.07 (ddd, J¼4.6, 3.2, 1.4 Hz, 1H), 1.92 (dddd,
J¼14.6, 10.1, 5.0, 5.0 Hz, 1H), 1.80e1.71 (m, 1H), 1.64 (dddd, J¼14.6,
8.7, 6.4, 3.7 Hz, 1H), 1.56 (ddd, J¼16.9, 4.6, 4.6 Hz, 1H), 0.84 (d,
34.4, 33.5, 25.9, 25.7, 18.3, 17.9, 13.0, ꢀ4.2, ꢀ5.0, ꢀ5.3, ꢀ5.4; IR (film)
nmax cmꢀ1 3422 (br), 2959, 2930, 2882, 2857, 1469, 1387, 1253, 1104,
1018, 976, 866, 836, 776, 670; HRMS (FAB) calcd for [MþNa]þ
(C21H46O4Si2Na) 441.2827, found 441.2834.
J¼7.3 Hz, 3H); 13C NMR (100 MHz, C6D6)
d
152.5, 139.2, 128.5, 127.8,
4.1.11. Ether ring fragment (3). To a solution of 17 (159 mg,
0.379 mmol) in toluene (4 mL) was added imidazole (46.0 mg,
0.675 mmol), PPh3 (132 mg, 0.503 mmol), I2 (173 mg, 0.682 mmol)
127.6, 95.2, 75.4, 73.1, 67.2, 63.2, 30.9, 29.7, 28.1, 13.9; IR (film)
nmax cmꢀ1 3409 (br), 2959, 2908, 2868, 2367, 2342, 1683, 1451, 1381,

6780
R. Tsutsumi et al. / Tetrahedron 66 (2010) 6775e6782
at room temperature. The flask was wrapped in aluminum foil, and
the mixture was stirred for 1 h before aqueous Na2S2O3 was added
at 0 ꢁC. The reaction mixture was extracted twice with EtOAc, and
the combined organic phase was dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. Purification on silica gel with
To a solution of (EtO)2P(O)CH2CO2Et (17 mL, 85.2 mmol) in THF
(140 mL) at 0 ꢁC was added dropwise n-BuLi (1.6 M in hexane,
35.5 mL, 57 mmol). After being stirred at 0 ꢁC for 30 min, a solution
of the above crude bromoenone in THF (27 mL) was added. The
reaction mixture was stirred at room temperature for 12 h, and
then quenched with saturated aqueous NH4Cl. The organic layer
was separated, and the aqueous layer was extracted twice with
ether. The combined organic layer was washed with brine, dried
over anhydrous MgSO4, filtered, and concentrated in vacuo. The
residue was subjected to column chromatography (99/1 to 98/2
hexane/EtOAc) to give the mixture of 18a and 18b (4.00 g,
17.2 mmol, 37% for seven steps) as a colorless oil. The ratio of 18a
and 18b was calculated to be 5:1 based on the 1H NMR integration
values. Pure 18a obtained after repetitive column chromatography
was used in the next reaction. Spectroscopic data for 18a. 1H NMR
(98/2 hexane/EtOAc) afforded
3 as a colorless oil (183 mg,
24
0.346 mmol, 91%). [
(500 MHz, CDCl3)
a
]
ꢀ4.24 (c 0.471 in CHCl3); 1H NMR
D
d
3.79e3.68 (m, 3H), 3.49 (ddd, J¼9.2, 2.5, 2.5 Hz,
1H), 3.30e3.21 (m, 2H), 3.05 (ddd, J¼9.2, 4.6, 2.1 Hz,1H),1.97 (dddd,
J¼14.3, 9.6, 6.7, 5.0 Hz, 1H), 1.83 (ddd, J¼12.6, 5.0, 2.5 Hz, 1H),
1.79e1.69 (m, 2H), 1.63 (td, J¼12.2, 4.6 Hz, 1H), 0.93 (d, J¼7.2 Hz,
3H), 0.87 (s, 9H), 0.85 (s, 9H), 0.03 (s, 3H), 0.02 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 83.6, 78.8, 62.8, 40.9, 36.8, 32.8, 25.9, 25.8, 18.4,
17.9, 13.0, 4.0, ꢀ4.3, ꢀ4.9, ꢀ5.0, ꢀ5.3; IR (film) nmax cmꢀ1 2959,
2930, 2882, 2856, 1462, 1387, 1251, 1108, 1016, 866, 836, 776, 667;
HRMS (FAB) calcd for [MþNa]þ (C21H45IO3Si2Na) 551.1845, found
551.1841.
(500 MHz, CDCl3)
d
6.61 (s, 1H), 5.89 (s, 1H), 4.15 (q, J¼7.2 Hz, 2H),
2.28 (s, 3H), 1.98 (s, 3H), 1.26 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3)
d 166.8, 153.1, 142.5, 116.9, 110.8, 60.0, 17.5, 15.6, 14.2; IR
4.1.12. Bromodienoate (18a). To a solution of 4 (5.0 mL, 46.6 mmol)
in CCl4 (60 mL) at 0 ꢁC was added dropwise bromine (2.4 mL,
46.6 mmol) in CCl4 (30 mL). After being stirred at room tempera-
ture for 80 min, the reaction mixture was quenched with saturated
aqueous Na2S2O3 and diluted with ether. The organic layer was
separated, and the aqueous layer was extracted with ether. The
combined organic layer was washed with brine, dried over anhy-
drous MgSO4, filtered, and concentrated in vacuo. The residual
crude dibromide was used in the next reaction without further
purification.
(film) nmax cmꢀ1 3100, 2980,1715,1617,1444,1375,1345,1302,1227,
1165, 1096, 1050, 1020, 978, 871, 792, 732; HRMS (DART) calcd for
[MþH]þ (C9H1479BrO2) 233.0177, found 233.0174. Spectroscopic
data for 18b. 1H NMR (500 MHz, CDCl3)
d 5.93 (s, 1H), 5.63 (d,
J¼1.2 Hz, 1H), 4.07 (q, J¼7.2 Hz, 2H), 1.92 (s, 3H), 1.90 (d, J¼1.2 Hz,
3H), 1.21 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 165.4, 154.8,
141.8, 139.9, 118.2, 103.3, 60.0, 24.3, 18.7, 14.1; IR (film) nmax cmꢀ1
3077, 2980,1720,1643,1617,1443,1373,1347,1274,1216,1154,1095,
1051, 984, 868, 793, 716.
To a solution of the above dibromide in THF (40 mL) was added
NaOH (7.46 g, 186 mmol) in water (40 mL) at 0 ꢁC. After being
stirred at room temperature for 24 h, the reaction mixture was
acidified with 1 M HCl aq and diluted with ether. The organic layer
was separated, and the aqueous layer was extracted four times with
ether. The combined organic layer was dried over MgSO4, filtered,
and concentrated in vacuo. The residual crude carboxylic acid,
obtained as a white solid, was used in the next reaction without
further purification.
4.1.13. Bromodienol (19). To a solution of 18a (1.13 g, 4.85 mmol) in
CH2Cl2 45 mL at ꢀ78 ꢁC was added DIBALH (1.03 M in hexane,
11.3 mL,11.6 mmol). After being stirred for 1 h, the reaction mixture
was quenched with MeOH, allowed to warm to room temperature,
and diluted with EtOAc and saturated aqueous potassium sodium
tartrate. The resultant mixture was stirred at room temperature
until the layers became clear. The organic layer was separated, and
the aqueous layer was extracted with EtOAc. The combined organic
layer was washed with brine, dried over MgSO4, filtered, and con-
centrated in vacuo. The residue was subjected to column chroma-
tography (75/25 hexane/EtOAc) to give the bromodienol 19
(910 mg, 4.76 mmol, 98%) as a colorless oil. 1H NMR (500 MHz,
To a suspension of LiAlH4 (2.46 g, 65.0 mmol) in ether (150 mL)
was slowly added above crude carboxylic acid in ether (45 mL) at
0 ꢁC. After being stirred at room temperature for 1.5 h, the reaction
mixture was quenched with water (2.5 mL), 3 M NaOH aq (2.5 mL),
and water (7.5 mL) at 0 ꢁC. The mixture was allowed to warm to
room temperature and stirred for 24 h. To the mixture was added
anhydrous Na2SO4, and the salt was filtered through CeliteÒ. The
solution was concentrated in vacuo. The residual crude allylic al-
cohol was used in the next reaction without further purification.
To a solution of the above crude alcohol in ether (100 mL) was
added MnO2 (59 g) at room temperature. After being stirred for 3 h,
additional MnO2 (29.5 g) was added, and the reaction mixture was
CDCl3)
d
6.32 (s, 1H), 5.77 (t, J¼6.3 Hz, 1H), 4.25 (d, J¼6.3 Hz, 2H),
1.97 (s, 3H), 1.79 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 142.2, 136.6,
126.9, 106.2, 59.7, 17.4, 14.3; IR (film) nmax cmꢀ1 3319, 2924, 2862,
1442, 1377, 1287, 1205, 1116, 1079, 1003, 764, 732; HRMS (DART)
calcd for [MꢀH2OþH]þ (C7H1079Br) 172.9966, found 172.9970.
4.1.14. Bromodienol fragment (2). To a solution of 19 (357 mg,
1.86 mmol) in DMF (20 mL) at 0 ꢁC were added imidazole (201 mg,
2.95 mmol) and TBDPSCl (0.74 mL, 2.8 mmol). After being stirred at
room temperature for 3.5 h, the reaction mixture was quenched
with water at 0 ꢁC. The mixture was extracted twice with EtOAc.
The combined organic layer was washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. The residue
was subjected to column chromatography (97/3 hexane/EtOAc) to
give 2 (789 mg, 99%) as a colorless oil. 1H NMR (500 MHz, CDCl3)
stirred for a further 1 h. The mixture was filtered through CeliteÒ
.
The filtrate containing the resultant aldehyde was used in the next
reaction as obtained.
To a solution of the above crude aldehyde in ether was added
MeMgBr (3 M in ether, 16.9 mL, 50.8 mmol) at 0 ꢁC. After being
stirred for 1 h, the reaction mixture was quenched with saturated
aqueous NH4Cl. The organic layer was separated, and the aqueous
layer was extracted three times with ether. The combined organic
layer was washed with brine, dried over anhydrous MgSO4, filtered,
and concentrated in vacuo. The residual crude secondary alcohol
was used in the next reaction without further purification.
To a solution of the above alcohol in ether (56 mL) was added
MnO2 (47.2 g) at room temperature. After being stirred for 9 h,
additional MnO2 (47.2 g) was added, and the reaction mixture was
stirred for a further 10 h. The mixture was filtered through CeliteÒ
and concentrated in vacuo. The residual crude bromoenone was
used in the next reaction without further purification.
d
7.66 (m, 4H), 7.43e7.35 (m, 6H), 6.21 (s, 1H), 5.75 (t, J¼5.9 Hz, 1H),
4.30 (d, J¼5.9 Hz, 2H), 1.92 (s, 3H), 1.56 (s, 3H), 1.03 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 142.4, 135.6, 134.7, 133.7,129.6, 127.7, 105.5, 61.4,
26.8, 19.1, 17.4, 14.3; IR (film) nmax cmꢀ1 3319, 2924, 2862, 1442,
1377, 1287, 1205, 1116, 1079, 1003, 764, 732; HRMS (DART) calcd for
(C23H2879BrOSi) [MþNa]þ 427.1090, found 427.1093.
4.1.15. Cross-coupled product (20). The ether ring fragment 3
(36.4 mg, 0.0688 mmol) was dissolved in ether (1 mL) and the so-
lution was cooled to ꢀ78 ꢁC. To this solution was added a B-OMe-9-
BBN (1.0 M, 0.19 mL in hexane, 0.19 mol) and t-BuLi (1.58 M, 0.17 mL

R. Tsutsumi et al. / Tetrahedron 66 (2010) 6775e6782
6781
in pentane, 0.27 mol). After 15 min, THF (1 mL) was added, and the
solution was stirred for 5 min at ꢀ78 ꢁC then for 1 h at room tem-
perature. Aqueous Cs2CO3 (3 M aqueous solution, 0.3 mL, 0.9 mmol)
was then added followed by addition of 2 (50.0 mg, 0.116 mmol) in
DMF (1 mL). Pd(dppf)Cl2 (9.9 mg, 0.012 mmol) was added and the
resulting mixture was warmed to 45 ꢁC and stirred for 17 h. The
reaction was quenched with saturated NH4Cl at 0 ꢁC. The organic
layer was extracted twice with ether. The combined organic layers
were washed with brine, dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. Purification on silica gel chromatography
126.5, 125.2, 81.3, 79.2, 68.0, 61.9, 40.9, 33.2, 32.6, 26.8, 25.2, 19.2,
17.8, 14.2, 14.0, 13.0, 9.6, ꢀ4.0, ꢀ4.5; IR (film) nmax cmꢀ1 3512 (br),
2959, 2930, 2882, 2856, 1469, 1429, 1384, 1253, 1108, 1043, 863,
776, 740, 703; HRMS (FAB) not detected.
4.1.18. Dienol (23). To a solution of 22 (25.0 mg, 0.0335 mmol) in
DMF (0.60 mL) was added NaN3 (21.6 mg, 0.332 mmol) at room
temperature, and the solution was stirred for 7 h. NaN3 (24.2 mg,
0.372 mmol) was added, and the solution was stirred for 3.5 h.
NaN3 (38.9 mg, 0.598 mmol) was added, and the solution was
stirred for 12 h before adding water and ether. Two layers were
separated, and the aqueous layer was extracted with ether. The
combined organic phase was dried over anhydrous MgSO4, filtered,
and concentrated in vacuo. The crude product was used in the next
step without further purification.
(99/1 to 96/4 hexane/ether) gave 20 as a colorless oil (32.9 mg,
25
0.0438 mmol, 64%). [
(500 MHz, CDCl3)
a
]
D
þ8.01 (c 0.220 in CHCl3); 1H NMR
d
7.69 (dd, J¼8.0, 1.7 Hz, 4H), 7.42e7.35 (m, 6H),
5.65 (t, J¼5.9 Hz, 1H), 5.48 (t, J¼7.1 Hz, 1H), 4.36 (d, J¼5.9 Hz, 2H),
3.81e3.71 (m, 3H), 3.32 (ddd, J¼8.8, 4.2, 2.5 Hz,1H), 3.01 (ddd, J¼9.2,
4.6, 2.1 Hz,1H), 2.24e2.13 (m, 2H),1.83 (ddd, J¼12.6, 4.2, 2.5 Hz,1H),
1.75 (s, 3H),1.63e1.55(m, 2H),1.58 (s, 3H),1.29 (dddd, J¼13.0, 8.8, 7.6,
4.6 Hz, 1H), 1.04 (s, 9H), 0.93 (d, J¼7.2 Hz, 3H), 0.89 (s, 9H), 0.86 (s,
9H), 0.06 (s, 3H), 0.05 (s, 6H), 0.04 (s, 3H); 13C NMR (100 MHz, CDCl3)
The above obtained azide was dissolved in THF (1.0 mL) and PPh3
(11.0 mg, 0.0419 mmol) was added at 0 ꢁC. The reaction mixture was
warmed to room temperature and stirred for 17 h before water
(50 mL) was added. The reaction mixture was stirred for 72 h before
d
136.8, 136.0, 135.6, 129.5, 127.6, 126.6, 125.1, 83.6, 78.5, 63.0, 61.9,
PPh3 (10.6 mg, 0.0404 mmol) and THF (0.50 mL) were added. The
reaction mixture was stirred for 1 h before water (0.10 mL) was
added. Then the reaction mixture was warmed to 50 ꢁC and stirred
for 9 h. The reaction mixture was cooled to room temperature and
saturated NaHCO3 was added. The mixture was extracted twice with
EtOAc, and the combined organic phases were dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. The crude product was
used in the next step without further purification.
The above obtained amine was dissolved in Ac2O (1.0 mL) and
pyridine (1.0 mL), and the reaction mixture was stirred for 15 h at
room temperature. The mixture was concentrated in vacuo and
subjected to silica gel column chromatography (99/1 to 98/2 CHCl3/
MeOH) to afford crude acetamide as a colorless oil. The crude
product was used in the next step without further purification.
The above obtained acetamide was dissolved in THF (2.0 mL)
and TBAF (1 M, 2.0 mL in THF 20 mmol) was added at 0 ꢁC. The
reaction mixture was warmed to room temperature and stirred for
4.5 h before the reaction was quenched with saturated NH4Cl
aqueous at 0 ꢁC. The mixture was extracted three times with EtOAc,
and the combined organic phases were dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. Purification on silica
gel with CHCl3/MeOH (93/7 to 9/1) gave 23 as a colorless amor-
phous (8.9 mg, 0.0273 mmol, 89% for four steps). Spectroscopic
data were identified with reported compound.
41.1, 33.0, 32.8, 26.8, 25.9, 25.8, 25.2, 19.2, 18.4, 18.0, 14.2, 13.8, 12.8,
ꢀ4.3, ꢀ4.9, ꢀ5.0, ꢀ5.2; IR nmax cmꢀ1 2959, 2930, 2882, 2856, 1462,
1387, 1251, 1108, 1016, 866, 836, 776, 667; HRMS (FAB) calcd for
[MþNa]þ (C44H74NaO4Si3) 773.4787, found 773.4777.
4.1.16. Primary alcohol (21). To
a solution of 20 (17.0 mg,
0.0226 mmol) in CH2Cl2 (1 mL), MeOH (1 mL) under air was added
CSA (2.1 mg, 0.0090 mmol) at 0 ꢁC. After 1 h, the reaction was
quenched with Et3N, and the mixture was concentrated in vacuo
and purified by silica gel column chromatography (96/4 to 90/10
hexane/EtOAc) to afford 21 as a colorless oil (9.1 mg, 0.014 mmol,
63%). The starting material was recovered (4.2 mg, 0.0056 mmol,
25%). [
d
25
a
]
þ5.90 (c 0.420 in CDCl3); 1H NMR (500 MHz, CHCl3)
D
7.69 (dd, J¼8.0, 1.7 Hz, 4H), 7.42e7.35 (m, 6H), 5.66 (t, J¼5.9 Hz,
1H), 5.47 (t, J¼7.1 Hz, 1H), 4.36 (d, J¼5.9 Hz, 2H), 3.81 (d, J¼10.9 Hz,
1H), 3.69 (ddd, J¼10.9, 9.2, 5.0 Hz, 1H), 3.60 (dd, J¼10.9, 5.5 Hz, 1H),
3.42 (ddd, J¼8.8, 4.6, 2.5 Hz, 1H), 3.15 (ddd, J¼9.2, 5.9, 2.9 Hz, 1H),
2.18 (dt, J¼7.5, 7.5 Hz, 2H), 2.08 (br, 1H), 1.87 (ddd, J¼12.6, 4.6,
2.5 Hz, 1H), 1.81 (ddd, J¼9.6, 4.6, 2.5 Hz, 1H), 1.75 (s, 3H), 1.66e1.60
(m, 2H),1.58 (s, 3H),1.39e1.32 (m,1H),1.05 (s, 9H), 0.94 (d, J¼7.1 Hz,
3H), 0.87 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (100 MHz,
CDCl3)
d 136.6, 136.2, 134.8, 133.9, 129.5, 128.3, 127.6, 126.2, 125.4,
82.5, 78.9, 64.2, 63.2, 61.9, 40.9, 32.8, 32.6, 26.8, 26.5, 25.7, 25.2,
19.2, 17.9, 14.1, 13.9, 12.7, ꢀ4.2, ꢀ4.9; IR (film) nmax cmꢀ1 3512 (br),
2930, 2856, 1470, 1458, 1425, 1387, 1252, 1107, 1039, 866, 836, 776,
738, 703; HRMS (FAB) calcd for [MþNa]þ (C38H60NaO4Si2)
659.3923, found 659.3929.
4.1.19. (ꢀ)-Brevisamide (1). To
a
solution of 23 (8.9 mg,
0.0273 mmol) in CH2Cl2 (1.5 mL) was added PhI(OAc)2 (19.0 mg,
0.0590 mmol) and TEMPO (1.9 mg, 0.012 mmol) at room temper-
ature. After 3 h the reaction was quenched with saturated Na2S2O3
aqueous at 0 ꢁC, and the mixture was extracted twice with EtOAc.
The combined organic phases were dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. Purification on silica gel column
chromatography (95/5 CHCl3/MeOH) gave brevisamide (1) as
a yellow oil (7.8 mg, 0.0241 mmol, 88%). Spectroscopic data were
identified with reported compound.
4.1.17. Iodide (22). To a solution of 21 (37.0 mg, 0.0581 mmol) in
toluene (2 mL) were added imidazole (31.3 mg, 0.460 mmol), PPh3
(68.8 mg, 0.262 mmol), and I2 (107 mg, 0.422 mmol) at room
temperature, and the reaction mixture was stirred for 50 min be-
fore saturated aqueous Na2S2O3 was added. The layers were sepa-
rated and the aqueous layer was extracted with EtOAc. The
combined organic phases were dried over anhydrous MgSO4, fil-
tered, and concentrated in vacuo. Purification on silica gel with
Acknowledgements
hexane/EtOAc (96/4) gave 22 as
a colorless oil (39.0 mg,
þ11.8 (c 0.309 in CHCl3); 1H NMR
We are grateful to Mr. T. Shirai for significant contribution to the
synthesis of 2. This work was financially supported by KAKENHI
(No. 2061102) and the Global COE Program for Chemistry In-
novation, the University of Tokyo. T.K. is grateful for a SUNBOR
Scholarship. The natural brevisamide was isolated from the cul-
tures maintained under grants P01 ES 10594 (NIEHS, DHHS) and
MARBIONC, Marine Biotechnology in North Carolina. J.L.C.W. ac-
knowledges funding from NOAA-ECOHAB (MML-106390A) and
NCDHHS (01515-04).
26
0.0522 mmol, 90%). [
(500 MHz, CDCl3)
a
]
D
d
7.69 (dd, J¼8.0, 1.7 Hz, 4H), 7.43e7.35 (m, 6H),
5.66 (t, J¼5.9 Hz, 1H), 5.51 (t, J¼7.1 Hz, 1H), 4.37 (d, J¼5.9 Hz, 2H),
3.57 (ddd, J¼10.9, 8.8, 5.0 Hz, 1H), 3.52 (dd, J¼10.1, 2.5 Hz, 1H), 3.43
(ddd, J¼9.2, 4.2, 2.1 Hz, 1H), 3.26 (dd, J¼10.5, 6.7 Hz, 1H), 2.31e2.18
(m, 2H), 2.08 (br, 1H), 1.84 (ddd, J¼12.6, 4.6, 2.5 Hz, 1H), 1.78 (s, 3H),
1.68e1.61 (m, 2H), 1.59 (s, 3H), 1.37e1.31 (m, 1H), 1.05 (s, 9H), 0.97
(d, J¼7.1 Hz, 3H), 0.87 (s, 9H), 0.10 (s, 3H), 0.07 (s, 3H); 13C NMR
(100 MHz, CDCl3)
d 136.7, 136.2, 135.6, 133.9, 129.5, 128.3, 127.6,

6782
R. Tsutsumi et al. / Tetrahedron 66 (2010) 6775e6782
9. Kuranaga, T.; Shirai, T.; Baden, D. G.; Wright, J. L. C.; Satake, M.; Tachibana, K.
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