Stereo-controlled synthesis of analogs of peumusolide A, NES non-antagonistic inhibitor for nuclear export of MEK

Article abstract of DOI:10.1016/j.tetlet.2010.04.027

Stereo-controlled construction of the core structure of peumusolide A (1), α-alkylidene-β-hydroxy-γ-methylenebutyrolactone, was developed by a combination of regio- and stereo-selective hydroiodination of 2-yn-1-ol and asymmetric reduction of 1-yn-4-en-3-one as the key reactions. By using this protocol, all the four stereoisomers of the analog of 1 were synthesized from the common starting material.

Full text of DOI:10.1016/j.tetlet.2010.04.027

Tetrahedron Letters 51 (2010) 3134–3137
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereo-controlled synthesis of analogs of peumusolide A, NES
non-antagonistic inhibitor for nuclear export of MEK
Satoru Tamura a, Masayuki Tonokawa a, Nobutoshi Murakami a,b,
*
a Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
b PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereo-controlled construction of the core structure of peumusolide A (1),
a-alkylidene-b-hydroxy-c-
Received 2 April 2010
Accepted 9 April 2010
Available online 13 April 2010
methylenebutyrolactone, was developed by a combination of regio- and stereo-selective hydroiodination
of 2-yn-1-ol and asymmetric reduction of 1-yn-4-en-3-one as the key reactions. By using this protocol, all
the four stereoisomers of the analog of 1 were synthesized from the common starting material.
Ó 2010 Elsevier Ltd. All rights reserved.
Export of MAPK/ERK kinase (MEK) from the nucleus to the cyto-
plasm was found to be essential process for cell proliferation in
many kinds of MEK-activated tumor cells.1 Thus, inhibitors for nu-
clear export of MEK have been anticipated to be highly attractive
seed principles toward new anti-tumor agents. In this context,
we have been engaged in search for nuclear export inhibitors of
MEK to disclose peumusolide A (1) as the first MEK-export inhibi-
tor with NES non-antagonistic mode. In addition, peumusolide A
(1) was found to be a promising anti-tumor scaffold with the novel
mechanism of action by demonstrating selective growth inhibition
for the MEK-activated tumor cells by 1.2 Besides peumusolide A
(1), several congenic polyketides with interesting biological activ-
ities have been revealed very recently.3,4 Despite such attractive
biological properties, the asymmetric synthesis of the core struc-
ducted by alkyne-lactonization of 4-carboxy-1-yn-3-ol i at the last
stage. The carboxylic acid i was planned to be prepared from opti-
cally active secondary alcohol ii, which would be provided by
asymmetric reduction of 4-en-1-yn-3-one iii. The ketone iii was
envisioned to be obtained by coupling of iodoalkene 5a and
protected 2-yn-1-al iv. The (E)-iodoalkene 5a is accessible from
decyn-1-ol (4) by cis-selective hydroiodination. In addition, (Z)-
iodoalkene 5b is afforded by trans-selective hydroiodination of
the common starting material 4. Application of the same synthetic
procedure of (S)-3 to 5b enables to facilely provide the (E)-isomer,
(S)-2. Obviously, both (R)-enantiomers of (S)-2 and (S)-3 will be
readily furnished by alternation of the chirality of a reagent for
asymmetric reduction.
ture in these polyketides, a-alkylidene-b-hydroxy-c-methylenebu-
tyrolactone, was only achieved by using the sulfoxide as a chiral
auxiliary.5 However, the synthetic route involved strict geometri-
cal limitation giving only (2E)-isomers.
In the structural elucidation of 1, we synthesized a pair of enan-
tiomers of 2 with 2E-configuration according to the reported
procedure to establish the configuration at C-3. To elucidate partic-
ipation of the stereochemistry of the C2–C6 double bond in the
biological activity of peumusolide A (1), we embarked on the
development of stereo-selective construction procedure providing
(2Z)-isomers as well as (2E)-isomers of a-alkylidene-b-hydroxy-c-
methylenebutyrolactones. This letter describes the synthesis of the
four stereoisomers of the analog of peumusolide A (1) (Fig. 1).
Our retrosynthetic approach to (S)-3, illustrated in Figure 2, in-
cludes regio- and stereo-selective hydroiodination of 2-yn-1-ol and
enantioselective reduction of 4-en-1-yn-3-one as the key reactions.
In brief, construction of the lactone framework would be con-
* Corresponding author. Present address: Kyoto Pharmaceutical University,
Japan. Tel.: +81 75 595 4634; fax: +81 75 595 4768.
E-mail address: murakami@poppy.kyoto-phu.ac.jp (N. Murakami).
Figure 1. Chemical structures of peumusolide A (1) and targeted analogs.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.027

S. Tamura et al. / Tetrahedron Letters 51 (2010) 3134–3137
3135
Figure 2. Retrosynthetic analysis of targeted analogs.
The synthesis of (S)-3 was executed as shown in Scheme 1.
Palladium (0)-catalyzed hydrostannylation of 2-decyn-1-ol (4) by
(Ph3P)4Pd and n-Bu3SnH followed by direct iododestannylation
regio- and stereo-selectively proceeded to afford (E)-2-iodo-2-de-
cen-1-ol (5a).6 Coupling of the iodoalkene 5a and 3-trimethyl-
silyl-2-propyn-1-al (6) using MeLi and t-BuLi gave en-yne-diol
7a. After protection of the primary hydroxyl group in 7a as pivaloyl
ester, the resulting ester was converted to conjugated ketone 8a by
MnO2 oxidation. Asymmetric reduction of the ketone 8a with the
complex of (S)-2-methyl-CBS-oxazaborolidine and BH3 [(S)-CBS
catalyst]7 provided the optically active secondary alcohol (S)-9a
in 83% yield with 93% ee. Because of the absence of precedented
reduction of 4-substituted 4-en-1-yn-3-one by the CBS catalyst,
the absolute configuration of (S)-9a was determined by modified
Sequential reductive cleavage of the pivaloyl group with LiBH4
and selective oxidation of the primary hydroxyl group with
MnO2 provided aldehyde (S)-10, which was further oxidized with
NaClO2 to give alkynyl carboxylic acid (S)-11. Removal of the tri-
methylsilyl group with K2CO3 in MeOH followed by Ag (I)-medi-
ated alkyne-lactonization furnished the desired
c-lactone. After
chiral HPLC separation of the lactone, the absolute configuration
at C-3 of (S)-39 was unambiguously confirmed by the CD spectra
described in our previous report.2
Next, we examined the synthesis of (S)-2, the geometrical
isomer of (S)-3, by application of the above-mentioned protocol
(Scheme 2). Successive treatment of 4 with n-BuLi, i-Bu2AlH
(DIBAL), and iodine induced trans-selective hydroiodination to
provide (Z)-iodoalkene 5b. The iodoalkene 5b was transformed to
the optically active alcohol (S)-9b in the same manner for the prep-
aration of (S)-9a. In contrast to the synthesis of (S)-10, MnO2 oxi-
dation of diol, prepared by removal of the pivaloyl group in (S)-
Mosher’s method.8 As depicted in Figure 3, distributions of
Dd
values from the corresponding (S)- and (R)-MTPA esters (9b and
9c) revealed (S)-9a to bear the predicted S-configuration.
Scheme 1. Synthesis of (Z)-analog, (S)-3 and (R)-3. Reagents and conditions: (a) Bu3SnH, (Ph3P)4Pd, benzene, rt; (b) I2, CH2Cl2, rt, 75% (two steps); (c) MeLi, t-BuLi, 6, Et2O,
ꢀ30 °C to ꢀ78 °C, 75%; (d) PivCl, pyridine, (CH2Cl)2, reflux, 67%; (e) MnO2, CH2Cl2, rt, 82%; (f) (S)- or (R)-2-methyl-CBS-oxazaborolidine, BH3ꢁTHF, THF, ꢀ40 °C, 85% (93% ee) for
(S)-9a, 84% (92% ee) for (R)-9a; (g) LiBH4, THF, 0 °C, 76% for S-isomer, 74% for R-isomer; (h) MnO2, CH2Cl2, rt, quant. for (S)- and (R)-10; (i) NaClO2, 2-methyl-2-butene,
NaH2PO4, t-BuOH–H2O, rt, 60% for (S)-11, 61% for (R)-11; (j) K2CO3, MeOH–THF, rt, 93% for S-isomer, 92% for R-isomer; (k) Ag2CO3, C6H6, 80 °C, 89% for (S)-3, 88% for (R)-3.

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S. Tamura et al. / Tetrahedron Letters 51 (2010) 3134–3137
Table 1
Inhibitory activity for MEK export of peumusolide A (1) and four analogs
Configuration of C3
Geometry of C2–C6
IC50 (lM)
(S)-1
(R)-1
(S)-2
(R)-2
(S)-3
(R)-3
S
R
S
R
S
R
E
E
E
E
Z
Z
3.7
17.4
3.5
16.2
3.8
18.7
HPLC separation. By utilization of (R)-CBS catalyst, both 3R enanti-
omers [(R)-2 and (R)-39] were also synthesized in the same
manner.
Figure 3. Establishment of stereochemistry in (S)-9a. Reagents and conditions: (a)
(R)- or (S)-a-methoxy-a-(trifluoromethyl)phenylacetic acid, EDCIꢁHCl, DMPA,
CH2Cl2, rt, 59% for 9c, 58% for 9d.
Finally, we evaluated inhibitory effect of peumusolide A (1) and
the synthesized four analogs for nuclear export of MEK in HeLa
cells by an indirect fluorescent antibody technique.2 Table 1 sum-
marizes IC50 values of all compounds for nuclear export of MEK.
Comparison of the biological activity in the three pairs of enantio-
mers indicated that the configuration at C-3 is crucial for the inhib-
itory activity for MEK export. On the other hand, the geometry of
the C2–C6 double bond was found to have little influence on the
biological potency.
9b, afforded the corresponding ketoalcohol as a sole product,
therefore the protection of the secondary hydroxyl group in (S)-
9b was revealed to be necessary. Introduction of the triethylsilyl
(TES) group followed by removal of the pivaloyl protection affor-
ded primary alcohol, which was oxidized with MnO2 to give alde-
hyde (S)-12. After NaClO2 oxidation of (S)-12 concomitant with
removal of the TES group, the resulting hydroxycarboxylic acid
was converted to (S)-2 by the same procedure to (S)-3.10 The C-3
configuration of (S)-2 was confirmed by the CD spectra after chiral
In conclusion, we developed the stereo-controlled construction
of the optically active
a-alkylidene-b-hydroxy-c-methylenebuty-
rolactone, the core structure of peumusolide A (1) with MEK-ex-
port inhibitory activity. This protocol comprises both regio- and
stereo-selective hydroiodination of 2-yn-1-ol and enantioselective
reduction of 1-yn-4-en-3-one as the key reactions to furnish all
types of stereoisomers. Evaluation of MEK-export activity of the
synthesized analogs clarified 3R configuration to be curial for the
biological efficacy of the congers of peumusolide A (1), while the
geometry of the C2–C6 double bond was shown to have little influ-
ence of inhibition for nuclear export of MEK. It is noteworthy that
the present study opens an avenue to the synthesis of (2Z)-a-alkyl-
idene-b-hydroxy-c-methylenebutyrolactones coexisting with the
E-congeners in the nature.11,12 Our synthetic protocol enables to
assemble peumusolide A (1) analogs, thereby exploration of more
potent analogs than 1 is currently underway in our group.
Acknowledgments
This work was supported in part a Grant-in-Aid for Scientific
Research from the Japan Society for the Promotion of Science.
The authors are grateful to the Shorai Foundation for Science and
Technology for financial support.
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. Tamura, S.; Hattori, Y.; Kaneko, M.; Shimizu, N.; Tanimura, S.; Khono, M.;
Murakami, N. Tetrahedron Lett. 2010, 51, 1678.
3. 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.
4. Kuo, P.-L.; Chen, C.-Y.; Tzeng, T.-F.; Lin, C.-C.; Hsu, Y.-L. Toxicol. Appl. Pharmacol.
2008, 229, 215.
5. Nokami, J.; Ohtsuki, H.; Sakamoto, Y.; Mitsuoka, M.; Kunieda, N. Chem. Lett.
1992, 1647.
6. Piers, E.; Coish, D. P. Synthesis 1995, 47.
7. Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K. J. Am. Chem. Soc.
1987, 109, 7925.
Scheme 2. Synthesis of (E)-analog, (S)-2 and (R)-2. Reagents and conditions: (a) n-
BuLi, Et2O, ꢀ20 °C; (b) DIBAL, Et2O, 35 °C; (c) I2, Et2O, rt, 71% (three steps); (d) MeLi,
t-BuLi, 6, Et2O, ꢀ30 °C to ꢀ78 °C, 76%; (e) PivCl, pyridine, (CH2Cl)2, reflux; (f) MnO2,
CH2Cl2, rt, 53% (two steps); (g) (S)- or (R)-2-methyl-CBS-oxazaborolidine, BH3ꢁTHF,
THF, ꢀ40 °C, 82% (83% ee) for (S)-9b, 83% (82% ee) for (R)-9b; (h) TESCl, pyridine,
CH2Cl2, rt; (i) LiBH4, THF, rt; (j) MnO2, CH2Cl2, reflux, 97% for (S)-12, 98% for (R)-12
(three steps); (k) NaClO2, 2-methyl-2-butene, NaH2PO4, t-BuOH–H2O, 40 °C, 90% for
S-isomer, 86% for R-isomer; (l) K2CO3, MeOH–THF, rt; (m) Ag2CO3, C6H6, 80 °C, 87%
for (S)-2, 88% for (R)-2 (two steps).
8. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
4092.
9. (S)-3: colorless oil, ½a D24
ꢂ
ꢀ32.5 (c 0.90, MeOH), CD kMeOH
(De): 226 nm (ꢀ3.5), IR
mmax (KBr) cmꢀ1: 3442, 1768, 1670, 1H NMR (500 MHz, CDCl3) d: 6.69 (1H, td,
J = 7.9, 2.0 Hz, 6-H), 5.12 (1H, br s, 3-H), 4.89 (1H, dd, J = 2.4, 2.4 Hz, 5-Ha), 4.67
(1H, br s, 5-Hb), 2.77 (2H, m, 7-H), 1.49 (2H, m, 8-H), 1.25–1.30 (8H, m, 9, 10,
11, 12-H), 0.88 (3H, t, J = 6.6 Hz, 13-H), FAB-MS (m/z): 225 [M+H]+, HR FAB-MS
(m/z): calcd for C13H20O3+H; 225.1491, found; 225.1496. (R)-3: colorless oil,

S. Tamura et al. / Tetrahedron Letters 51 (2010) 3134–3137
3137
½
a 2D4
ꢂ
+32.2 (c 0.90, MeOH), CD kMeOH
(
D
e
): 226 nm (+3.5), FAB-MS (m/z): 225
analog (S)-3 was synthesized without protecting the secondary hydroxyl group
in (S)-9a.
11. Niwa, M.; Iguchi, M.; Yamamura, S. Tetrahedron Lett. 1975, 4395.
12. Martinez, J. C.; Yoshida, M.; Gottlieb, O. R. Tetrahedron Lett. 1979, 1021.
[M+H]+, HR FAB-MS (m/z): calcd for C13H20O3+H; 225.1491, found; 225.1493.
The IR and 1H NMR spectra were superimposable on those of (S)-3.
10. In the synthesis of (S)-3, MnO2 oxidation to the Z-isomer of (S)-12 was
unsuccessful because of extreme lability of the reactants. Therefore, the Z-