Total synthesis of peumusolide A, NES non-antagonistic inhibitor for nuclear export of MEK

Article abstract of DOI:10.1016/j.tet.2010.08.025

The first total synthesis of peumusolide A (1) has been achieved by combination of regio- and stereo-selective aluminum-mediated hydroiodination to 2-yn-1-ol and enantioselective reduction of 4-en-1-yn-3-one with the chiral oxazaborolidine as the key reactions. This total synthesis has unequivocally established our proposed absolute structure of 1.

Full text of DOI:10.1016/j.tet.2010.08.025

Tetrahedron 66 (2010) 8476e8480
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of peumusolide A, NES non-antagonistic inhibitor for nuclear
export of MEK
*
Satoru Tamura, Shunsuke Doke, Nobutoshi Murakami
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 July 2010
Received in revised form 6 August 2010
Accepted 10 August 2010
Available online 14 August 2010
The first total synthesis of peumusolide A (1) has been achieved by combination of regio- and stereo-
selective aluminum-mediated hydroiodination to 2-yn-1-ol and enantioselective reduction of 4-en-1-yn-
3-one with the chiral oxazaborolidine as the key reactions. This total synthesis has unequivocally
established our proposed absolute structure of 1.
Ó 2010 Published by Elsevier Ltd.
Keywords:
Peumusolide A
Total synthesis
Hydroiodination
Asymmetric reduction
MEK-export inhibitor
1. Introduction
synthetic route involved strict geometrical limitation giving rise to
only (2E)-isomers. To examine structureeactivity relationship of
In many kinds of tumor cells, the mitogen-activated protein
kinase (MAPK) cascade, one of the important signal pathways for
cell proliferation, was reported to be significantly activated as
compared with that in normal cells. Export of MAPK/ERK kinase
(MEK) from the nucleus to the cytoplasm was established as an
essential process for the cell proliferation by this cascade.1 Hence,
inhibitors for nuclear export of MEK have been intensively antici-
pated to be attractive scaffolds toward new antitumor agents.2
Previously, we disclosed peumusolide A (1) as the first MAPK/ERK
kinase (MEK)-export inhibitor with nuclear export signal (NES)3
non-antagonistic mode from the Southern American medicinal
plant Peumus boldus Molina. Furthermore, peumusolide A (1) was
verified to be the promising anti-tumor scaffold by demonstrating
selective growth-inhibition for the MEK-activated tumor cells.4
In addition to peumusolide A (1), several congenic polyketides
with interesting biological activities have been revealed very re-
cently.5,6 Despite such attractive biological properties, the
peumusolide A (1) in detail, we developed the stereo-controlled
construction of the core structure of 1 by utilizing regio- and ste-
reo-selective hydroiodination to 2-yn-1-ol and enantioselective
reduction of 4-en-1-yn-3-one as the key reactions.8 By application
of this protocol, we have accomplished the total synthesis of (S)-
peumusolide A (1). This paper describes the first total synthesis of 1
leading to impregnable confirmation of our proposed absolute
structure for 1 isolated from the medicinal plant (Fig. 1).
Figure 1. Chemical structures of peumusolide A (1).
asymmetric synthesis of the core structure,
a-alkylidene-b-hy-
2. Results and discussion
droxy-g-methylenebutyrolactone, in these polyketides was only
achieved by using the sulfoxide as a chiral auxiliary.7 However, the
2.1. Retrosynthetic analysis
Our retrosynthetic approach to peumusolide A (1) is illustrated
in Figure 2. Namely, the lactone moiety in 1 would be furnished by
silver-mediated alkyne-lactonization of optically active 4-carboxy-
1-yn-3-ol 2 in the last stage. The carboxylic acid 2 will be provided
by asymmetric reduction of 4-en-1-yn-3-one 3. The conjugated
* Corresponding author. Present address. Kyoto Pharmaceutical University. 1
Shichono-cho, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan. Tel.: þ81 75 595
4634; fax: þ81 75 595 4768; e-mail address: murakami@poppy.kyoto-phu.ac.jp (N.
Murakami).
0040-4020/$ e see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tet.2010.08.025

S. Tamura et al. / Tetrahedron 66 (2010) 8476e8480
8477
ketone 3 was envisioned to be obtained by C3-elongation of (Z)-
iodoalkene 4 using protected 2-propyn-1-al. The (Z)-iodoalkene 4
will be accessible from 2-yn-1-ol 5 by regio- and trans-selective
hydroiodination. The 2-yn-1-ol 5 was planned to be prepared by
coupling of phenyl alkenyl sulfone and protected 4-bromo-2-
butyn-1-ol.
desulfonation with 5% sodium-amalgam and removal of the THP
group in 10 with p-toluenesulfonic acid (p-TsOH) provided primary
alcohol 5 bearing an en-yne functionality in 55% yield for two steps.
Sequential treatment of 5 with n-BuLi, i-Bu2AlH (DIBAL), and
iodine induced trans-selective hydroiodination to give (Z)-iodoal-
kene 4 in 50% yield for three steps.9 Coupling of the iodoalkene 4
and 3-trimethylsilyl-2-propyn-1-al (11) using MeLi and t-BuLi10
provided en-yne-diol 12 in 80% yield. After protection of the pri-
mary hydroxyl group in 12 as pivaloyl ester, the resulting ester was
converted to conjugated ketone 3 by MnO2 oxidation in 74% yield
for two steps. The Z-configuration of the trisubstituted olefin in 3
was unequivocally confirmed by the NOE correlations between the
olefinic proton and the methylene protons adjacent to the piv-
aloyloxy function in the NOESY spectrum.
2.3. Transformation from 4-en-1-yn-3-one into peumusolide
A (1)
Subsequently, transformation from the conjugated ketone 3 into
peumusolide A (1) was conducted as illustrated in Scheme 2. Pre-
viously, McDonald et al. presented that optical active 2-methyl-
CBS-oxazaborolidine11 enabled to distinguish from the ene and yne
function in reduction of 3-en-1-yn-2-one to furnish an optically
active 3-en-1-yn-2-ol in high enantiomeric excess.12 Furthermore,
we demonstrated that application of this asymmetric reduction to
unprecedented 4-substituted 4-en-1-yn-3-one also afforded an
optical alcohol with predicted stereochemical outcome in high
enantioselectivity.8 Thus, asymmetric center at C-3 was introduced
by reduction with the CBS catalyst. Asymmetric reduction of the
ketone 3 with the complex of (S)-2-methyl-CBS-oxazaborolidine
and BH3 provided optical active secondary alcohol 13 in 82% yield
with 94% ee.
Introduction of triethylsilyl (TES) protection to the secondary
hydroxyl group in 13 using triethylsilyl chloride (TESCl) and imid-
azole followed by reductive removal of the pivaloyl protection with
LiBH4 gave primary alcohol 14 quantitatively. The alcohol 14 was
treated with MnO2 to provide aldehyde, which was submitted to
NaClO2 oxidation to generate carboxylic acid 2 concomitant with
removal of the TES group in 71% yield for two steps. Removal of the
TMS group in 2 with K2CO3 and subsequent Ag(I)-mediated alkyne-
Figure 2. Retrosynthetic analysis of peumusolide A (1).
2.2. Construction of 4-en-1-yn-3-one framework
In the first instance, construction of 4-en-1-yn-3-one frame-
work was executed as shown in Scheme 1. Reduction of commer-
cially available (Z)-11-hexadecen-1-al (6) with NaBH4 followed by
treatment with diphenyldisulfide and tri-n-butylphosphine affor-
ded phenylsulfide in 98% yield for two steps. The resulting phe-
nylsulfide was subjected to oxidation with Oxone to give phenyl
sulfone 7 in 92% yield. On the other hand, preparation of the
counterpart bromoalkyne 9 commenced with purchased 2-butyne-
1,4-diol (8). In brief, protection of either hydroxyl group in 8 was
conducted with dihydropyran (DHP) and pyridinium p-toluene-
sulfonate (PPTS) to provide tetrahydropyranyl (THP) ether in 67%
yield. Treatment of the THP ether with CBr4 and triphenylphos-
phine afforded the bromoalkyne 9 in 71% yield. Coupling of 7 and 9
proceeded with t-BuLi in the presence of hexamethylphosphor-
amide (HMPA) to afford alkynyl sulfone 10 in 56% yield. Successive
lactonization furnished the desired g-lactone in 78% yield for two
steps. After chiral HPLC separation of the resulting lactone, the total
synthesis of (S)-peumusolide A (1) has been accomplished. The ab-
solute configuration of 1 was unambiguously confirmed by the CD
Scheme 1. Construction of 4-en-1-yn-3-one framework. Reagents and conditions: (a) (i) NaBH4, MeOH, rt; (ii) PhSSPh, n-Bu3P, benzene, rt, 98% for two steps; (iii) Oxone, THF/
MeOH/H2O, rt, 92%; (b) (i) DHP, PPTS, CH2Cl2, rt, 67%; (ii) PPh3, CBr4, THF, rt, 71%; (c) t-BuLi, HMPA, THF, ꢀ78 ꢁC/ꢀ50 ꢁC, 56%; (d) (i) 5% Na/Hg, Na2HPO4, MeOH, ꢀ10 ꢁC, 61%; (ii)
p-TsOH, MeOH, rt, 90%; (e) (i) t-BuLi, THF, ꢀ20 ꢁC; (ii) DIBAL, THF, reflux; (iii) I2, rt, 50% for three steps; (f) MeLi, t-BuLi, Et2O, ꢀ78 ꢁC, 80%; (g) (i) PivCl, pyridine, (CH2Cl)2, reflux, 81%;
(ii) MnO2, (CH2Cl)2, rt, 91%.

8478
S. Tamura et al. / Tetrahedron 66 (2010) 8476e8480
Scheme 2. Transformation from 4-en-1-yn-3-one into peumusolide A (1). Reagents and conditions: (a) (S)-2-methyl-CBS-oxazaborolidine, BH3$THF, THF, ꢀ40 ꢁC, 82%, 94% ee; (b)
(i) TESCl, imidazole, CH2Cl2, rt; (ii) LiBH4, THF, reflux, quant. for two steps; (c) (i) MnO2, (CH2Cl)2, reflux; (ii) NaClO2, 2-methyl-2-butene, NaH2PO4, t-BuOH/H2O, 40 ꢁC, 71% for two
steps; (d) (i) K2CO3, MeOH/THF, rt; (ii) Ag2CO3, benzene, 80 ꢁC, 78% for two steps; (iii) chiral HPLC separation, 90%.
spectra described in our previous report.8 In addition, the physico-
chemical data as well as the biological potency of 1 are in entire
accordance with those of the isolated peumusolide A from the me-
dicinal plant, this verifying our proposed absolute structure of 1.
pressure gave alcohol. To a solution of the alcohol in benzene
(30.4 mL) were successively added PhSSPh (1.38 g, 6.31 mmol) and
n-Bu3P (1.56 mL, 6.31 mmol), then the reaction mixture was stirred
at rt for 2 h. Removal of the solvent from the reaction mixture under
reduced pressure gave a residue, which was purified by column
chromatography (SiO2 70 g, n-hexane/EtOAc¼15:1) to afford sulfide
(681.3 mg, 98% for two steps). A solution of the sulfide (681.3 mg,
2.05 mmol) in THF/MeOH/H2O (3:1:1, 37.5 mL) was treated with
Oxone (3.78 g, 6.15 mmol) at rt for 2 h. After the reaction mixture
was treated with aq satd Na2SO3 for 10 min, the whole was
extracted with EtOAc. The EtOAc extract was washed with aq satd
NaCl and dried over MgSO4. Removal of the solvent from the EtOAc
extract under reduced pressure gave a residue, which was purified
by column chromatography (SiO2 20 g, n-hexane/EtOAc¼7:1) to
afford 7 (687.5 mg, 92%) as colorless oil: IR nmax (KBr) 1654, 1305,
3. Conclusion
In summary, the first total synthesis of peumusolide A (1) has
been achieved by combination of regio- and stereo-selective alu-
minum-mediated hydroiodination to 2-yn-1-ol and enantiose-
lective reduction of 4-en-1-yn-3-one with the chiral
oxazaborolidine as the key reactions. This synthesis has un-
equivocally established our proposed absolute structure of 1. Ad-
ditionally, it is noteworthy that the present study opens an avenue
to synthesize naturally occurring congeneric
a-(E)-alkylidene-b-
hydroxy-
g
-methylenebutyrolactones bearing olefin moieties in the
1145, 1113 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
7.91 (2H, d, J¼7.5 Hz),
side chains.13,14
7.60 (3H, m), 5.34 (2H, m), 3.07 (2H, t, J¼8.1 Hz), 2.01 (4H, m), 1.70
(2H, tt, J¼7.5, 7.5 Hz), 1.23e1.33 (18H, m), 0.89 (3H, t, J¼7.0 Hz); MS
(FAB) m/z 365 [MþH]þ; HRMS (FAB) m/z calcd for C22H37O2S:
365.2514, found: 365.2508.
4. Experimental
4.1. General procedures
4.2.2. 4-Bromo-1-O-(2-tetrahydropyranyl)-2-butyn-1-ol (9). To a so-
lution of the alcohol 8 (500 mg, 5.80 mmol) in CH2Cl2 (11.6 mL)
were successively added dihydropyran (0.53 mL, 6.30 mmol) and
pyridinium p-toluenesulfonate (PPTS) (146.0 mg, 0.63 mmol), then
the reaction mixture was stirred at 40 ꢁC for 1 h. After the reaction
mixture was poured into aq satd NaCl, the whole was extracted
with EtOAc. The EtOAc extract was successively washed with aq
satd NaHCO3 and aq satd NaCl and dried over MgSO4. Removal of
the solvent from the EtOAc extract under reduced pressure gave
a residue, which was purified by column chromatography (SiO2
20 g, n-hexane/EtOAc¼5:1) to afford THP ether (661.2 mg, 67%). A
solution of the THP ether (450.7 mg, 2.65 mmol) in THF (13.3 mL)
was treated with CBr4 (1.76 g, 5.30 mmol) and Ph3P (1.39 g,
5.30 mmol) at rt for 1 h. After the reaction mixture was poured into
H2O, the whole was extracted with EtOAc. The EtOAc extract was
washed with aq satd NaCl and dried over MgSO4. Removal of the
solvent from the EtOAc extract under reduced pressure gave a res-
idue, which was purified by column chromatography (SiO2 50 g, n-
hexane/EtOAc¼10:1) to afford 9 (438.2 mg, 71%) as colorless oil. The
chemical structure of 9 was confirmed by comparison of the
spectral data with those reported in the literature.15
1H NMR spectra were recorded on a JEOL JNM LA-500 (500 MHz)
and NOESY spectra were recorded on a Varian Unity Inova 600
(600 MHz) spectrometer. The chemical shifts are given in parts per
million (ppm) on the delta (d) scale, and signal patterns are in-
dicated as follows. All 1H NMR data were referenced to the residual
solvent signal (dH 7.26 ppm) as an internal standard. Optical rota-
tions were obtained on a JASCO DIP-370 digital polarimeter. IR
spectra were recorded on a JASCO FT/IR-5300 infrared spectrome-
ter. FABMS and HR FABMS data were acquired on a JEOL JMS SX-102
mass spectrometer. HPLC was performed on a JASCO PU2080 pump
equipped with a JASCO UV2070 UV detector. Silica gel (Fuji Silysia
Chemical, BW-200) and pre-coated thin-layer chromatography
(TLC) plates (Merck, Kiesel gel 60 F254) were used for column
chromatography and TLC, respectively. Spots on TLC plates were
detected by spraying Ce(SO4)2/H2SO4 [Ce(SO4)2$nH2O 10 g in 6.3%
aqueous H2SO4 1.0 L] or acidic para-anisaldehyde solution (para-
anisaldehyde 25 mL, c-H2SO4 25 mL, AcOH 5 mL, EtOH 425 mL)
with subsequent heating. Tetrahydrofuran (THF), diethyl ether, and
benzene were freshly distilled from sodiumebenzophenon ketyl.
Dichloromethane and dichloroethane were freshly distilled from
CaH2. Hexamethylphosphoramide (HMPA) was distilled in vacuo
from CaH2 and stored with 4 Å molecular sieves. Pyridine was dried
over KOH pellets.
4.2.3. (Z)-5-Phenylsulfonyl-1-O-(2-tetrahydropyranyl)-15-icosen-2-
yn-1-ol (10). To a solution of the alcohol 7 (502.4 mg, 1.38 mmol) in
THF (13.8 mL) and HMPA (1.38 mL) was added t-BuLi (1.73 mL,
2.76 mmol,1.6 M in n-pentane) at ꢀ78 ꢁC, then the reaction mixture
was stirred at ꢀ78 ꢁC for 15 min. After a solution of 9 (385.8 mg,
1.66 mmol) in THF/HMPA (10:1, 2.76 mL) was added to the mixture
at ꢀ78 ꢁC, the whole was stirred at ꢀ50 ꢁC for 1 h. The reaction
mixture was poured into aq satd NH4Cl, then the whole was
extracted with EtOAc. The EtOAc extract was washed with aq satd
NaCl and dried over MgSO4. Removal of the solvent from the EtOAc
extract under reduced pressure gave a residue, which was purified
4.2. Construction of 4-en-1-yn-3-one framework
4.2.1. (Z)-11-Hexadecenyl phenyl sulfone (7). A solution of
6
(500 mg, 2.10 mmol) in MeOH (12.5 mL) was treated with NaBH4
(95.3 mg, 2.53 mmol) at rt for 1 h. After the reaction mixture was
poured into aq satd NaCl, the whole was extracted with EtOAc. The
EtOAc extract was washed with aq satd NaCl and dried over MgSO4.
Removal of the solvent from the EtOAc extract under reduced

S. Tamura et al. / Tetrahedron 66 (2010) 8476e8480
8479
by column chromatography (SiO2 15 g, n-hexane/EtOAc¼15:1) to
afford 10 (400.7 mg, 56%) as colorless oil: IR nmax (KBr) 2238, 1660,
a residue, which was purified by column chromatography (SiO2 8 g,
n-hexane/EtOAc¼5:1) to afford 12 (64.0 mg, 80%) as colorless oil: IR
1305, 1148, 1114 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
7.89 (2H, d,
nmax (KBr) 3314, 2172, 1668 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d 5.60
J¼7.5 Hz), 7.64 (3H, m), 5.37 (2H, m), 4.70 (1H, br s), 4.04 (2H, m),
3.79 (1H, ddd, J¼18.7, 7.9, 3.0 Hz), 3.52 (1H, ddd, J¼18.7, 4.0, 2.5),
3.09 (1H, quint-like, J¼ca. 8 Hz), 2.73 (1H, dd, J¼17.8, 7.8 Hz), 2.64
(1H, dd, J¼17.8, 10.5 Hz), 2.02 (4H, m), 1.25e1.33 (26H, m), 0.90 (3H,
t, J¼6.8 Hz); MS (FAB) m/z 517 [MþH]þ; HRMS (FAB) m/z calcd for
C31H49O4S: 517.3352, found: 517.3340.
(1H, t, J¼7.4 Hz), 5.30e5.38 (3H, m), 4.57 (1H, dd, J¼12.1, 5.7 Hz),
4.17 (1H, dd, J¼12.1, 5.7 Hz), 2.88 (1H, d, J¼5.7 Hz, CHOH), 2.11 (2H,
dt, J¼7.4, 7.7 Hz), 2.02 (5H, m, CH2(CH]CH)CH2, CH2OH), 1.26e1.39
(22H, m), 0.89 (3H, t, J¼6.8 Hz), 0.18 (9H, s); MS (FAB) m/z 443
[MþH]þ; HRMS (FAB) m/z calcd for C26H48O2SiNa: 443.3321, found:
443.3326.
4.2.4. (Z)-15-Icosen-2-yn-1-ol (5). A solution of 10 (392.7 mg,
0.76 mmol) in MeOH (7.6 mL) was treated with sodium mercury
amalgam (2.84 g, 30.4 mmol) and Na2HPO4 (1.08 g, 7.61 mmol) at rt
for 10 h. After the reaction mixture was poured into H2O, the whole
was extracted with EtOAc. The EtOAc extract was washed with aq
satd NaCl and dried over MgSO4. Removal of the solvent from the
EtOAc extract under reduced pressure gave a residue, which was
purified by column chromatography (SiO2 10 g, n-hexane/
EtOAc¼15:1) to afford desulfonated alkyne (174.5 mg, 61%). A so-
lution of the alkyne (174.5 mg, 0.46 mmol) in MeOH (4.7 mL) was
treated with p-TsOH$H2O (17.4 mg, 0.093 mmol) at rt for 1 h. After
the reaction mixture was poured into aq satd NaCl, the whole was
extracted with EtOAc. The EtOAc extract was successively washed
with aq satd NaHCO3 and aq satd NaCl and dried over MgSO4. Re-
moval of the solvent from the EtOAc extract under reduced pres-
sure gave a residue, which was purified by column chromatography
(SiO2 10 g, n-hexane/EtOAc¼15:1/7:1) to afford 5 (122.0 mg, 90%)
4.2.7. (4Z,17Z)-4-Pivaloyloxymethyl-1-trimethylsilyl-4,17-docosa-
dien-1-yn-3-one (3). A solution of 12 (59.6 mg, 0.14 mmol) was
treated with pyridine (34.0
mL, 0.42 mmol) and pivaloyl chloride
(19.2 L, 0.31 mmol) in (CH2Cl)2 (6.3 mL) under reflux for 2 h. After
m
the reaction mixture was poured into aq satd NaCl, the whole was
extracted with EtOAc. The EtOAc extract was washed with aq satd
NaCl and dried over MgSO4. Removal of the solvent from the EtOAc
extract under reduced pressure gave a residue, which was purified
by column chromatography (SiO2 8 g, n-hexane/EtOAc¼8:1) to af-
ford pivaloyl ester (57.9 mg, 81%) as colorless oil. A solution of the
pivaloyl ester in (CH2Cl)2 (1.68 mL) was heated under reflux in the
presence of MnO2 (100.0 mg, 1.15 mmol) for 5 h. After the reaction
mixture was filtered with Celite, the filtrate was concentrated un-
der reduced pressure to give a residue. The residue was purified by
column chromatography (SiO2 6 g, n-hexane/EtOAc¼25:1) to afford
3 (52.5 mg, 91%) as colorless oil: IR nmax (KBr) 2172, 1734, 1662,
1616 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
6.37 (1H, t, J¼7.6 Hz),
as colorless oil: IR nmax (KBr) 3372, 2208, 1654 cmꢀ1
(500 MHz, CDCl3)
;
1H NMR
5.30e5.40 (2H, m), 4.82 (2H, s), 2.66 (2H, td, J¼7.6, 7.6 Hz), 2.00 (4H,
m), 1.23e1.53 (22H, m), 1.19 (9H, s), 0.91 (3H, t, J¼6.8 Hz), 0.24 (9H,
s); MS (FAB) m/z 503 [MþH]þ; HRMS (FAB) m/z calcd for
C31H55O3Si: 503.3921, found: 503.3930.
d
5.40e5.33 (2H, m), 4.25 (2H, t, J¼2.2 Hz), 2.21
(2H, tt, J¼7.1, 2.2 Hz), 2.01 (4H, m), 1.26e1.53 (22H, m), 0.89 (3H, t,
J¼6.8 Hz); MS (FAB) m/z 293 [MþH]þ; HRMS (FAB) m/z calcd for
C20H37O: 293.2844, found: 293.2851.
4.3. Transformation from 4-en-1-yn-3-one into peumusolide
A (1)
4.2.5. (2Z,15Z)-2-Iodo-2,15-icosadien-1-ol (4). To a solution of 5
(117.5 mg, 0.40 mmol) in THF (1.33 mL) was added t-BuLi (0.30 mL,
0.47 mmol,1.6 M in n-pentane) at ꢀ20 ꢁC, then the reaction mixture
was stirred at ꢀ20 ꢁC for 10 min. After DIBAL (0.81 mL, 1.21 mmol,
1.5 M in toluene) was added to the mixture at ꢀ20 ꢁC, the whole
was heated under reflux for 20 h. The reaction mixture was cooled
to rt, then dehydrated EtOAc (0.082 mL) and iodine (307.1 mg,
1.21 mmol) were successively added. After the whole was stirred at
rt for 30 min, the mixture was treated with aq satd Na2S2O3, aq satd
K2CO3, and aq satd Rochelle salt at rt for 10 min. The whole was
extracted with EtOAc, then the EtOAc extract was washed with H2O
and dried over MgSO4. Removal of the solvent from the EtOAc ex-
tract under reduced pressure gave a residue, which was purified by
column chromatography (SiO2 10 g, benzene/EtOAc¼30:1) to afford
4 (84.8 mg, 50% for three steps) as colorless oil: IR nmax (KBr) 3462,
4.3.1. (S)-(4Z,17Z)-4-Pivaloyloxymethyl-1-trimethylsilyl-4,17-docosa-
dien-1-yn-3-ol (13). To a solution of 3 (48.7 mg, 0.097 mmol) in THF
(1.50 mL) were successively (S)-2-methyl-CBS-oxazaborolidine
(0.58 mL, 0.58 mmol, 1.0 M in toluene) and BH3$THF (0.49 mL,
0.49 mmol, 1.0 M in THF) at ꢀ78 ꢁC, then the reaction mixture was
stirred at ꢀ40 ꢁC for 3 h. After gradual addition of MeOH and aq
satd Rochelle salt, the whole was stirred at rt for 5 min. The mixture
was poured into H2O, then the whole was extracted with EtOAc.
The EtOAc extract was successively washed with aq satd Rochelle
salt and aq satd NaCl and dried over MgSO4. Removal of the solvent
from the EtOAc extract under reduced pressure gave a residue,
which was purified by column chromatography (SiO2 5 g, n-hex-
ane/EtOAc¼8:1) to afford 13 (40.5 mg, 82%, 94% ee) as colorless oil:
24
1665 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
5.89 (1H, t, J¼6.7 Hz),
[
a
]
þ58.9 (c 0.98, MeOH); IR nmax (KBr) 3456, 2172, 1732,
D
5.33e5.37 (2H, m), 4.24 (2H, d, J¼6.0 Hz), 2.16 (2H, dt, J¼7.5, 7.5 Hz),
2.01 (4H, m), 1.87 (1H, t, J¼6.0 Hz, OH), 1.27e1.57 (22H, m), 0.89
(3H, t, J¼6.8 Hz); MS (FAB) m/z 443 [MþNa]þ; HRMS (FAB) m/z calcd
for C20H37IONa: 443.1787, found: 443.1787.
1664 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
5.70 (1H, t, J¼7.5 Hz),
5.30e5.40 (2H, m), 5.24 (1H, d, J¼7.5 Hz), 4.85 (1H, d, J¼12.5 Hz),
4.61 (1H, d, J¼12.5 Hz), 2.70 (1H, d, J¼7.5 Hz, 3-OH), 2.16 (2H, dt,
J¼7.5, 7.5 Hz), 2.00 (4H, m), 1.26e1.43 (22H, m), 1.22 (9H, s), 0.89
(3H, t, J¼6.8 Hz), 0.15 (9H, s); MS (FAB) m/z 527 [MþNa]þ; HRMS
(FAB) m/z calcd for C31H56O3SiNa: 527.3896, found: 527.3897. Op-
tical purity of 13 was determined by chiral HPLC analysis under the
following condition; column: Chiralcel OD 4.6ꢂ250 mm (DAICEL
Chemical Industries), mobile phase: n-hexane/EtOAc¼10:1, flow
rate: 1.0 mL, detection: UV¼220 nm, retention time: (S)-13;
5.5 min, (R)-13; 10.6 min.
4.2.6. (4Z,17Z)-4-Hydroxymethyl-1-trimethylsilyl-4,17-docosadien-
1-yn-3-ol (12). To a solution of the alcohol 4 (79.8 mg, 0.19 mmol)
in Et2O (1.0 mL) was added MeLi (0.19 mL, 0.19 mmol, 1.0 M in Et2O)
at ꢀ30 ꢁC, then the reaction mixture was stirred at ꢀ30 ꢁC for
15 min. After t-BuLi (0.24 mL, 0.38 mmol, 1.6 M in n-pentane) was
added to the mixture at ꢀ78 ꢁC, the whole was stirred at ꢀ78 ꢁC for
15 min. To the reaction mixture was added a solution of 11 (71.8 mg,
0.57 mmol) in Et2O (3.7 mL) at ꢀ78 ꢁC, then the whole was stirred
at ꢀ78 ꢁC for 1 h. After the reaction mixture was poured into aq satd
NH4Cl, the whole was extracted with EtOAc. The EtOAc extract was
washed with aq satd NaCl and dried over MgSO4. Removal of the
solvent from the EtOAc extract under reduced pressure gave
4.3.2. (S)-(4Z,17Z)-4-Hydroxymethyl-1-trimethylsilyl-3-O-tri-
ethylsilyl-4,17-docosadien-1-yn-3-ol (14). A solution of 13 (36.2 mg,
0.072 mmol) in CH2Cl2 (2.4 mL) was treated with imidazole
(24.6 mg, 0.36 mmol) and TESCl (0.050 mL, 0.29 mmol) at rt for 1 h.
After the reaction mixture was poured into H2O, the whole was

8480
S. Tamura et al. / Tetrahedron 66 (2010) 8476e8480
extracted with EtOAc. The EtOAc extract was successively washed
with aq 5% HCl, aq satd NaHCO3, and aq satd NaCl and dried over
MgSO4. Removal of the solvent from the EtOAc extract under re-
duced pressure gave crude TES ether. A solution of the crude TES
ether in THF (2.4 mL) was heated under reflux in the presence of
LiBH4 (15.9 mg, 0.73 mmol) for 1 h. After gradual addition of EtOAc,
the mixture was poured into H2O. The whole was extracted with
EtOAc, then the EtOAc extract was washed with aq satd NaCl and
dried over MgSO4. Removal of the solvent from the EtOAc extract
under reduced pressure gave a residue, which was purified by
extract was washed with aq satd NaCl and dried over MgSO4. Re-
moval of the solvent from the EtOAc extract under reduced pres-
sure gave a residue, which was purified by column chromatography
(SiO2 2 g, n-hexane/EtOAc¼12:1) to afford the lactone (10.7 mg, 78%
for two steps) as colorless oil. The resulting lactone was purified by
HPLC [column: Chiralcel OD 10.0ꢂ250 mm, mobile phase: n-hex-
ane/EtOAc¼9:1, flow rate: 4.0 mL/min, detection: UV 220 nm,
retention time: (S)-1; 5.8 min, (R)-1; 11.1 min] to furnish (S)-peu-
25
musolide A (1, 9.6 mg, 90%) as colorless oil: [
a
]
D
ꢀ23.4 (c 0.4,
MeOH); IR nmax (KBr) 3418, 1770, 1672 cmꢀ1; MS (FAB) m/z 363
[MþH]þ; HRMS (FAB) m/z calcd for C23H39O3: 363.2899, found:
column chromatography (SiO2 5 g, n-hexane/EtOAc¼15:1) to afford
24
14 (38.5 mg, quant. for two steps) as colorless oil: [
a
]
þ41.2 (c
363.2904; CD lMeOH
(
De): 226 nm (ꢀ3.2). 1H and 13C NMR data
D
0.65, MeOH); IR nmax (KBr) 3343, 2170, 1668 cmꢀ1
(500 MHz, CDCl3)
;
1H NMR
entirely coincided with those for the enantiomeric mixture repor-
d
5.53 (1H, t, J¼7.3 Hz), 5.38 (1H, t, J¼3.7 Hz),
ted in our literature.4
5.33e5.36 (2H, m), 4.45 (1H, dd, J¼11.6, 3.7 Hz), 4.05 (1H, dt, J¼11.6,
3.7 Hz), 2.67 (1H, d, J¼3.7 Hz, OH), 1.97e2.09 (6H, m), 1.26e1.39
(22H, m), 0.98 (9H, t, J¼7.9 Hz), 0.89 (3H, t, J¼6.8 Hz), 0.68 (6H, m),
0.15 (9H, s); MS (FAB) m/z 557 [MþNa]þ; HRMS (FAB) m/z calcd for
C32H62O2Si2Na: 557.4186, found: 557.4181.
(S)-peumusolide A (1) from the natural resource: colorless oil;
25
[a
]
ꢀ23.7 (c 0.4, MeOH); HRMS (FAB) m/z calcd for C23H39O3:
D
363.2899, found: 363.2878; CD lMeOH
(
De): 226 nm (ꢀ3.3). 1H and
13C NMR, IR, and FABMS spectra were superimposable on those of
the synthesized (S)-peumusolide A (1). The synthesized and iso-
lated (S)-peumusolide A (1), respectively, inhibited nuclear-export
4.3.3. (S)-(4Z,17Z)-4-Carboxy-1-trimethylsilyl-4,17-docosadien-1-
yn-3-ol (2). A solution of 14 (35.0 mg, 0.066 mmol) in (CH2Cl)2
(4.20 mL) was heated under reflux in the presence of MnO2
(46.9 mg, 0.66 mmol) for 6 h. After the reaction mixture was filtered
with Celite, the filtrate was concentrated under reduced pressure to
give crude aldehyde. To a solution of the crude aldehyde in t-BuOH/
H2O (2:1, 5.66 mL) were successively added 2-methyl-2-butene
(0.70 mL, 6.6 mmol), NaH2PO4$H2O (91.1 mg, 0.66 mmol), and
NaClO2 (29.7 mg, 0.33 mmol), then the reaction mixture was stirred
at 40 ꢁC for 5 h. After the mixture was treated with aq satd Na2S2O3
at rt for 5 min, the whole was poured into aq satd NH4Cl. The
mixture was extracted with EtOAc, then the EtOAc extract was
washed with aq satd NaCl and dried over MgSO4. Removal of the
solvent from the EtOAc extract under reduced pressure gave a res-
idue, which was purified by column chromatography [SiO2 3 g,
of MEK with IC50 of 3.9
mM and 3.7 mM according to our procedure
described previously.4
Acknowledgements
This work was supported in part by Grants-in-Aid for Scientific
Research from the Japan Society for the Promotion of Science.
References and notes
1. Hoshino, R.; Chatani, Y.; Yamori, T.; Tsuruo, T.; Oka, H.; Yoshida, O.; Shimada, Y.;
Ari-i, S.; Wada, H.; Fujimoto, J.; Kohno, M. Oncogene 1999, 18, 813.
2. Kudo, N.; Wolff, B.; Sekimoto, T.; Schreiner, E. P.; Yoneda, Y.; Yanagida, M.;
Horinouchi, S.; Yashida, M. Exp. Cell Res. 1998, 242, 540.
3. Asano, S.; Nakamura, T.; Adachi, M.; Yoshida, M.; Yanagida, M.; Nishida, E.
Nature (London) 1997, 390, 308 MEK is exported from the nucleus to the cy-
toplasm with the aid of the carrier protein, chromosomal region maintenance 1
(CRM1), which is the receptor for the nuclear export signal (NES) sequence in
MEK.
4. Tamura, S.; Hattori, Y.; Kaneko, M.; Shimizu, N.; Tanimura, S.; Khono, M.;
Murakami, N. Tetrahedron Lett. 2010, 51, 1678.
5. Chen, C.-Y.; Chen, C.-H.; Lo, Y.-C.; Wu, B.-N.; Wang, H.-M.; Lo, W.-L.; Yen, C.-M.;
Lin, R.-J. J. Nat. Prod. 2008, 71, 933.
CHCl3/MeOH/H2O¼50:3:1 (lower layer)] to afford 2 (20.2 mg, 71%
24
for two steps) as colorless oil: [
a
]
þ27.6 (c 0.34, CHCl3); IR nmax
D
(KBr) 3324, 3000, 2174, 1693, 1662 (sh) cmꢀ1
CDCl3)
;
1H NMR (500 MHz,
d
6.97 (1H, t, J¼7.3 Hz), 5.30e5.38 (3H, m), 2.32e2.37 (2H,
m), 1.97e2.02 (4H, m), 1.26e1.64 (22H, m), 0.90 (3H, t, J¼6.8 Hz),
0.15 (9H, s); MS (FAB) m/z 457 [MþNa]þ; HRMS (FAB) m/z calcd for
C26H46O3SiNa: 457.3114, found: 457.3108.
6. Kuo, P.-L.; Chen, C.-Y.; Tzeng, T.-F.; Lin, C.-C.; Hsu, Y.-L. Toxicol. Appl. Pharmacol.
2008, 229, 215.
7. Nokami, J.; Ohtsuki, H.; Sakamoto, Y.; Mitsuoka, M.; Kunieda, N. Chem. Lett.
1992, 21, 1647.
4.3.4. (S)-Peumusolide A (1). A solution of 2 (16.4 mg, 0.038 mmol)
in MeOH/THF (1:1, 1.82 mL) was treated with K2CO3 (52.4 mg,
0.38 mmol) at rt for 1 h. After the reaction mixture was neutralized
with Amberlyst-15, the whole was filtered. The filtrate was con-
centrated under reduced pressure to give free alkyne. A solution of
the free alkyne in benzene (0.83 mL) was treated with Ag2CO3
8. Tamura, S.; Tonokawa, M.; Murakami, N. Tetrahedron Lett. 2010, 51, 3134.
9. Piers, E.; Coish, D. P. Synthesis 1995, 47.
10. Commeiras, L.; Santelli, M.; Parrain, J.-L. Tetrahedron Lett. 2003, 44, 2311.
11. Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K. J. Am. Chem. Soc.
1987, 109, 7925.
12. McDonald, E. F.; Reddy, K. S.; Diaz, Y. J. Am. Chem. Soc. 2000, 122, 4304.
13. Niwa, M.; Iguchi, M.; Yamamura, S. Tetrahedron Lett. 1975, 16, 4395.
14. Martinez, J. C.; Yoshida, M.; Gottlieb, O. R. Tetrahedron Lett. 1979, 20, 1021.
15. Nicolaus, N.; Strauss, S.; Neudorfl, J. M.; Prokop, A.; Schmalz, H. G. Org. Lett.
2009, 11, 341.
(2.1 mg, 7.6
poured into H2O, the whole was extracted with EtOAc. The EtOAc
m
mol) at 80 ꢁC for 1 h. After the reaction mixture was