Synthesis of (-)-pericosine B, the antipode of the cytotoxic marine natural product

Article abstract of DOI:10.1039/b813072h

The stereoselective synthesis of (-)-pericosine B, which is the antipode of the cytotoxic metabolite of the fungus Periconia byssoides OUPS-N133 separated from the sea hare, was accomplished in 9 steps in 12% total yield from (-)-quinic acid, together wit

Full text of DOI:10.1039/b813072h

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of (-)-pericosine B, the antipode of the cytotoxic marine
natural product†
Yoshihide Usami,* Kentaro Suzuki, Koji Mizuki, Hayato Ichikawa and Masao Arimoto
Received 29th July 2008, Accepted 15th October 2008
First published as an Advance Article on the web 13th November 2008
DOI: 10.1039/b813072h
The stereoselective synthesis of (-)-pericosine B, which is the antipode of the cytotoxic metabolite of
the fungus Periconia byssoides OUPS-N133 separated from the sea hare, was accomplished in 9 steps in
12% total yield from (-)-quinic acid, together with the synthesis of its epimer. Every crucial step of this
total synthesis, including ring opening of a b-epoxide and NaBH4 reduction of an unstable
b,g-unsaturated enone, proceeded with excellent stereoselectivity.
spite of extensive effort by other groups including ours to date.11–13
Introduction
However, the only successful synthesis had problems in terms
of the use of expensive starting materials and a stoichiometric
amount of toxic osmium tetroxide. Recently, we reported the
determination of the absolute configuration of pericosine D by
a synthetic approach.8 Unfortunately, the total yield of desired
product 4 was quite low when relatively inexpensive (-)-quinic
acid was used. Nevertheless, that work gave us a hint for a
short synthesis of 2. Following several years of failed attempts
at synthesizing 2,11 we describe herein a short synthesis of the
antipode of 2 and its epimer.
The isolation and structure determination of highly functionalized
C-7 cyclohexenoid natural products pericosines A–E 1–5 (Fig. 1),
which are cytotoxic metabolites of the fungus Periconia byssoides
OUPS-N133 originally separated from the sea hare Aplysia
kurodai, were reported in 1997 and 2007 by Numata and co-
workers.1,2 The absolute configuration of pericosines A–D 1–4
was elucidated by total syntheses.3–9 Compound 1 was reported
to exhibit significant inhibitory activity against protein kinase
EGFR and human topoisomerase II, but similar biological tests
on 2–4 were not reported. We were therefore interested in the
biological activity of 2 against human cancer cell lines. In addition
to their significant bioactivity, it is noteworthy that pericosines C
3 and E 5 exist as a mixture of enantiomers. X-ray analysis by
Numata and co-workers2 established the relative stereochemistry
of pericosine E 5 to originate from two monomeric pericosines 1
and 2 having different chirality. As we pointed out previously, their
finding meant that the presence of the antipode of monomeric 1
or 2 in nature is possible.10 Therefore, synthesis of the antipode of
1–3 is significant. We have already reported the synthesis of the
antipode of 16,7 and 33 but not that of 2.
Results and discussion
From the results of our previous work that dealt with the deter-
mination of pericosine D 4, we suspected that the introduction of
a 6a-methoxy group into the pericosine core 6-membered ring is
possible when MeOH is used as solvent in the stereoselective ring
opening of intermediate b-epoxide 8.8
The synthesis of (-)-pericosine B is summarized in Scheme 1
followed by Scheme 2. Methyl quinate derivative 6 was prepared
from commercially available (-)-quinic acid in 78% according to
the literature.14 Compound 6 was converted into unstable diene 7
in 2 steps. Then, without purification, crude 7 was oxidized with
The total synthesis of (+)-2, a naturally occurring enantiomer,
was reported only once in 1998 by Donohoe and co-workers9 in
◦
mCPBA at 40 C to afford an inseparable mixture of epoxides 8
and 9 in 40% yield in 3 steps.
Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki,
Osaka, 569-1094, Japan. E-mail: usami@gly.oups.ac.jp; Fax: +81 72 690
1005; Tel: +81 72 690 1083
Ring opening of a mixture of 8 and 9 with a catalytic
amount of HCl in MeOH gave the desired 6a-methoxypericosine
derivative 10 in 54% yield, with small amount of 118 (1%) and 1-
methoxylated alcohol 12 (1%) (whose configuration at C-1 could
not be determined), with the recovery of 9 (32%). The relative
† Electronic supplementary information (ESI) available: 1H- and 13C-
NMR spectra of synthetic (-)-pericosine B, compounds 10, 14, natural
pericosine B, and its acetonide. NOESY spectrum of compound 10. See
DOI: 10.1039/b813072h
Fig. 1 Structures of naturally occurring pericosines.
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conformation, as illustrated in Fig. 2, that inhibits SN2-type attack
of the nucleophile from inside the pericosine core 6-membered
ring, which is in a fixed conformation due to the cyclohexylidene
bridge.
Fig. 2 Plausible conformation of 10.
Then, the inversion of stereochemistry of C-5 in 10 was
attempted by means of Dess–Martin oxidation followed by
stereoselective reduction with NaBH4. Methoxy alcohol 10 was
oxidized with Dess–Martin periodinane, albeit very slowly, to give
crude b,g-unsaturated enone 13. Without purification, 1315 was
reduced with NaBH4 at 0 ◦C to give the desired diastereomer 14
as the sole product in 86% yield in 2 steps.
This total synthesis was completed by deprotection of the
cyclohexylidene moiety in 14 with TFA in MeOH to afford (-)-
pericosine B 2 in 82% yield. All spectral data except specific
rotation agreed with those of reported natural pericosine B. The
25
specific rotation ([a]D -32.6) of synthesized compound showed
almost the same value as previously synthesized (+)-2 ([a]D21 +30.6
(c 0.8 in EtOH)) but with the opposite sign.
Scheme 1 Stereoselective synthesis of 6a-methoxyalchohol 10.
Fig. 3 Structures of undesired compounds.15
The overall yield of this total synthesis of 2 was 12% in 9 steps
starting from (-)-quinic acid. Similarly, epimer 15 was prepared in
57% yield from 10.
Conclusions
We have accomplished the stereoselective total synthesis of (-)-
pericosine B 2, which has opposite chirality to the natural product,
in 9 steps in 12% total yield. Its epimer 15 was also prepared.
The second synthesis of pericosine B described herein is a toxic-
reagent-free method and is also applicable to the synthesis of (+)-
pericosine B, which was obtained as a minor component in nature
and has significant biological activity, since either enantiomer of
unstable diene 716 could be prepared from (-)-quinic acid. This
synthetic route toward 2 is also a divergent one, as the common
intermediate yielded pericosine D 4.8
Scheme 2 Completion of total synthesis of (-)-pericosine B 2.
stereochemistry of major product 10 was confirmed by NOESY
analysis as shown in Scheme 1. Cross-peaks of H-4/H-6 and H-
5/6-methoxy group were observed.
In next step, it was difficult to promote the SN2-type Walden
inversion by Mitsunobu reaction at C-5 in 10. Close inspection of
1
the H-NMR spectra of 10, which had relatively large coupling
constants of J4,5 = 7.3 Hz and J5,6 = 6.6 Hz, suggested a half-chair
316 | Org. Biomol. Chem., 2009, 7, 315–318
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(10H, m), 3.60 (3H, s, 6-OMe), 3.80 (3H, s, COOMe), 3.94 (1H,
dd, J = 7.3, 6.6 Hz, H-5), 4.00 (1H, dt, J = 6.6, 1.4 Hz, H-6),
4.17 (1H, dd, J = 7.3, 6.4 Hz, H-4), 4.66 (1H, ddd, J = 6.4,
3.9, 1.4 Hz, H-3), 6.68 (1H, dd, J = 3.9, 1.4 Hz, H-2); 13C-NMR
(125.6 MHz; CDCl3; Me4Si) d 23.6 (t), 24.0 (t), 25.0 (t), 35.3
(t), 37.8 (t), 52.0 (q), 60.5 (q), 70.7 (d), 72.6 (d), 75.9 (d), 78.0
(d), 111.7 (s), 132.3 (d), 134.7 (s), 166.4 (s); EIMS m/z 298 (M+,
76%); HREIMS m/z calcd for C15H22O6 (M)+ 298.1416, found
298.1415.
Experimental section
General information
IR spectra were obtained with a JEOL FT/IR-680 Plus spec-
trometer. HRMS was determined with a JEOL JMS-700 (2)
mass spectrometer. NMR spectra were recorded at 27 ◦C on
Varian UNITY INOVA-500 and Mercury-300 spectrometers in
CDCl3 with tetramethylsilane (TMS) as internal standard. Melting
points were determined on a Yanagimoto micromelting point
apparatus and are uncorrected. Specific rotations were measured
on a JASCO DIP-1000 polarimeter and [a]D values are given in
10-1 deg cm2 g-1. Liquid column chromatography was conducted
over silica gel (Nacalai, silica gel 60, mesh 70–230 or 230–400).
Analytical TLC was performed on precoated Merck glass plates
(silica gel 60 F254), and compounds were detected by dipping an
ethanol solution of phosphomolybdic acid, followed by heating.
Dry THF was distilled over sodium benzophenone ketyl under
argon atmosphere.
25
12 : Colorless oil; [a]D +146.8 (c 0.5 in CHCl3); IR nmax
1
(liquid film)/cm-1 3553 (OH), 1724 (C O), 1660 (C C); H-NMR
(500 MHz; CDCl3; Me4Si) d 1.35–1.77 (10H, m), 2.63 (1H, d, J =
3.4 Hz, 6-OH), 3.45 (3H, s, -OMe), 3.78 (3H, s, COOMe), 3.91
(1H, dd, J = 8.4, 3.4 Hz, H-4), 4.45 (1H, dd, J = 8.4, 7.1 Hz,
H-5), 4.78 (1H, ddd, J = 7.1, 3.4, 1.1 Hz, H-6), 5.86 (1H, dd,
J = 10.1, 1.1 Hz, H-1), 6.17 (1H, dd, J = 10.1, 3.4 Hz, H-2);
13C-NMR (125.6 MHz; CDCl3; Me4Si) d 23.5 (t), 24.0 (t), 25.1 (t),
34.5 (t), 37.6 (t), 52.2 (q), 52.8 (q), 71.9 (d), 73.1 (d), 76.5 (d), 83.3
(s), 111.2 (s), 127.7 (d), 129.9 (d), 170.0 (s); EIMS m/z 298 (M+,
85%); HREIMS m/z calcd for C15H22O6 (M)+ 298.1416, found
298.1416.
=
=
Synthesis of a mixture of epoxides 8 and 9 from 6
To a solution of diol 6 (552 mg, 1.93 mmol) in CH2Cl2 (25 mL)
were added pyridine (780.5 mL, 9.65 mmol) and catalytic DMAP
(30.0 mg). A solution of Tf2O (729 mL, 4.25 mmol) in CH2Cl2
(25 mL) was added dropwise to the mixture at 0 ◦C with stirring.
After stirring overnight at rt, the reaction mixture was treated with
aqueous NaHCO3 and then extracted with CH2Cl2. The organic
layer was dried over MgSO4, filtered, and evaporated to give a
crude residue containing triflates and diene 7. The mixture was
dissolved in DMF (3 mL), and CsOAc (1.99 mmol) was added to
the solution with stirring at rt. After 3 hr, the reaction mixture
was extracted with t-butylmethylether and H2O. The organic layer
was washed with brine twice, dried over MgSO4, filtered, and
evaporated to afford crude diene 7. To a solution of crude diene 7 in
CH2Cl2 (10 mL), mCPBA (518.8 mg, max 77%, calcd ca. 2.3 mmol)
was added and the reaction mixture was kept at 40 ◦C overnight.
The reaction mixture was treated with aqueous NaHCO3 and then
extracted with CH2Cl2. The organic layer was separated, dried over
MgSO4, filtered, and evaporated to afford a crude residue that was
purified by column chromatography (eluent: hexane:EtOAc = 4:1)
to give a mixture of 8 and 9 (204.9 mg, 40% from 6, ratio: 8:9 =
3:2 from 1H-NMR spectrum).
Methyl (3R,4R,5R,6S)-3,4-O-cyclohexylidene-3,4,5-trihydroxy-6-
methoxy-1-cyclohexene-1-carboxylate 14
To a solution of 10 (13.8 mg, 0.046 mmol) in CH2Cl2 (2 mL) was
added Dess–Martin periodinane (99.1 mg, 0.23 mmol) at rt with
stirring. After 24 hr, the reaction mixture was diluted with tert-
butylmethylether and treated with aq. Na2S2O4 and aq. NaHCO3.
The organic layer was separated, dried over MgSO4, and filtered
and the solvent was removed under reduced pressure to afford
crude ketone 13. Data of crude 13: IR nmax (liquid film)/cm-1 1726
1
=
=
(C O), 1612 (C C); H-NMR (300 MHz; CDCl3; Me4Si) d 1.25–
1.70 (10H, m), 3.60 (3H, s, 6-OMe), 3.80 (3H, s, COOMe), 3.94
(1H, dd, J = 7.3, 6.6 Hz, H-5), 4.00 (1H, dt, J = 6.6, 1.4 Hz,
H-6), 4.17 (1H, dd, J = 7.3, 6.4 Hz, H-4), 4.66 (1H, ddd, J = 6.4,
3.9, 1.4 Hz, H-3), 6.68 (1H, dd, J = 3.9, 1.4 Hz, H-2); 13C-NMR
(75.5 MHz; CDCl3; Me4Si) d 24.1 (t), 25.2 (t), 30.0 (t), 35.8 (t),
37.2 (t), 52.6 (q), 59.6 (q), 74.5 (d), 77.1 (d), 113.3 (s), 133.0 (d),
134.3 (s), 164.6 (s), 200.9 (s); EIMS m/z 296 (M+, 94%); HREIMS
m/z calcd for C15H20O6 (M)+ 296.1260, found 296.1262
To a suspension of NaBH4 in MeOH (0.5 mL) was added crude
ketone 13 dissolved in CH2Cl2 (2 mL) at 0 ◦C with stirring. After
1 hr, the reaction mixture was treated with aq. NH4Cl and ex-
tracted with CH2Cl2. The organic layer was dried over MgSO4 and
filtered. The solvent was removed under reduced pressure to afford
a crude residue that was purified by column chromatography
(eluent: EtOAc: hexane = 1: 1) to give 14 (11.9 mg, 86% in
Methyl (3R,4R,5S,6S)-3,4-O-cyclohexylidene-3,4,5-trihydroxy-6-
methoxy-1-cyclohexene-1-carboxylate 10
Methyl (4S,5R,6R)-4,5-O-cyclohexylidene-4,5,6-trihydroxy-1-
methoxy-2-cyclohexene-1-carboxylate 12
25
2 steps). 14: Colorless oil; [a]D +25.1 (c 0.12 in CHCl3); IR nmax
1
(liquid film)/cm-1 3497 (OH), 1720 (C O), 1656 (C C); H-NMR
(300 MHz; CDCl3; Me4Si) d 1.25–1.70 (10H, m), 3.17 (1H, d, J =
11.5 Hz, 5-OH), 3.58 (3H, s, 6-OMe), 3.81 (3H, s, COOMe), 3.83
(1H, m, H-5), 4.28 (1H, dd, J = 4.9, 0.6 Hz, H-6), 4.48 (1H, ddd,
J = 5.7, 3.4, 0.7 Hz, H-3), 4.66 (1H, dd, J = 5.7, 3.2 Hz, H-4),
6.82 (1H, br d, J = 3.4 Hz, H-2); 13C-NMR (75.5 MHz; CDCl3;
Me4Si) d 24.1(t), 24.3 (t), 25.3 (t), 36.0 (t), 37.5 (t), 52.3 (q), 61.3
(q), 68.1 (d), 72.1 (d), 73.0 (d), 74.2 (d), 111.5 (s), 129.7 (s), 137.3
(d), 166.0 (s); EIMS m/z 298 (M+, 69%); HREIMS m/z calcd for
C15H22O6 (M)+ 298.1416, found 298.1419.
=
=
To a mixture of 8 and 9 (ca. 3:2) (73.9 mg, combined amount)
in MeOH (5 mL) was added 1 drop of 1.0 M HCl in Et2O
with a microsyringe. After stirring overnight at rt, the reaction
mixture was condensed under reduced pressure to afford a crude
residue that was purified by column chromatography (eluent:
hexane:EtOAc = 5:3) to give 10 (44.9 mg, 54%), 11 (0.8 mg,
1%), and 12 (0.9 mg, 1%) with recovery of 9 (23.6 mg, 32%).
10: Colorless crystals (CH2Cl2); mp 132–135 ◦C; [a]D -55.2 (c
25
0.165 in CHCl3); IR nmax (KBr)/cm-1 3395 (OH), 1719 (C O),
=
1
=
1660 (C C); H-NMR (500 MHz; CDCl3; Me4Si) d 1.25–1.70
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(-)-Pericosine B: Methyl (3R,4R,5R,6R)-6-methoxy-3,4,5-
trihydroxy-1-cyclohexene-1-carboxylate 2
References
1 A. Numata, M. Iritani, T. Yamada, K. Minoura, E. Matsumura, T.
Yamori and T. Tsuruo, Tetrahedron Lett., 1997, 38, 8215–8218.
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and A. Numata, Org. Biomol. Chem., 2007, 5, 3979–3986.
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Chem. Pharm. Bull., 2004, 52, 1130–1133 (Erratum: Chem. Pharm.
Bull. 2005, 53, 271.).
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6 Y. Usami, Y. Horibe, I. Takaoka, H. Ichikawa and M. Arimoto, Synlett,
2006, 1598–1600.
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Otsuka, Y. Imanishi and M. Arimoto, J. Org. Chem., 2007, 68, 6127–
6134.
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Asymmetry, 2008, 19, 1460–1463.
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Newcombe, Tetrahedron Lett., 1998, 39, 8755–8758.
10 Y. Usami, H. Ichikawa and M. Arimoto, Int. J. Mol. Sci., 2008, 9,
401–421.
11 Y. Usami and A. Numata, Chem. Pharm. Bull., 2004, 52, 1125–1129.
12 H. Okamura, Y. Nakamura, K. Morishige, R. Ohura, H. Shimizu, T.
Iwakawa, M. Nakatani, Proceedings of the 40th Tennen Yuki Kagobutsu
Toronkai Koen Yoshisyu, 1988, Fukuoka, Japan, pp. 187–192.
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and J. H. Rogriguez, Ramos, Phosphorus, Sulfur and Silicon and the
Related Elements, 2005, 180, 1493–1494.
To a solution of alcohol 14 (13.2 mg) in MeOH (0.5 mL) was
added TFA (0.5 mL, excess) at 0 ◦C and the reaction mixture was
stirred for 1 hr. After stirring for another 4 hr at rt, the reaction
mixture was condensed under reduced pressure to afford a crude
residue that was purified by silica gel chromatography (eluent: 3–
5% MeOH in CH2Cl2) to give (-)-2 (7.9 mg, 82%). (-)-2: Colorless
crystals (hexane-EtOAc); mp 69–71 ◦C; [a]D -32.6 (c 0.35 in
25
-1
=
EtOH); IR nmax (liquid film)/cm 3433 (OH), 1713 (C O), 1651
1
=
(C C); H-NMR (500 MHz; acetone-d6; Me4Si) d 3.60 (3H, s, 6-
OMe), 3.78 (3H, s, COOMe), 3.85 (1H, dd, J = 4.1, 2.0 Hz, H-5),
3.98 (1H, m, H-4), 4.20 (1H, m, H-3), 4.26 (1H, ddd, J = 4.1,
1.1, 0.9 Hz, H-6), 6.74 (1H, dd, J = 2.5, 1.1 Hz, H-2); 13C-NMR
(125.6 MHz; acetone-d6; Me4Si) d 52.2 (q), 61.5 (q), 69.5 (d), 70.0
(d), 72.8 (d), 77.0 (d), 130.5 (s), 141.9 (d), 166.9 (s); EIMS m/z
219 (M+, 0.8%), 186 (M+-MeOH, 8%); HREIMS m/z calcd for
C9H15O6 (M + H)+ 219.0868, found 219.0860.
Methyl (3R,4R,5S,6S)-6-methoxy-3,4,5-trihydroxy-1-
cyclohexene-1-carboxylate 15
Alcohol 10 (11.4 mg) was converted to (-)-15 (4.7 mg, 57%) by
the same process as above. (-)-15: Colorless crystals (hexane-
14 G. Ulibarri, W. Nadler, T. Skrydstrup, H. Audrain, A. Chianori, C.
Riche and A. A. Grierson, J. Org. Chem., 1995, 60, 2753–2761.
15 b,g-Unsaturated enone 13 was so unstable that purification by silica
gel chromatography afforded a complex mixture including more stable
16 shown in Fig. 3 formed by double bond migration. Therefore,
other oxidizing agents could not be used in the preparation of 13.
Dess–Martin oxidation at 40 ◦C to accelerate the reaction resulted in
the formation of 16 and aromatized product 17. Methyl (4R,5R)-4,5-
cyclohexylidene-2-methoxy-3-oxo-1-cyclohexene-1-carboxylate 16: Col-
EtOAc); mp 94–97 ◦C; [a]D -75.6 (c 0.23 in EtOH); IR nmax
25
(KBr)/cm-1 3418 (OH), 1716 (C O), 1651 (C C); 1H-NMR
(500 MHz; acetone-d6; Me4Si) d 3.51 (3H, s, 6-OMe), 3.676 (1H,
dd, J = 7.3, 4.1 Hz, H-4), 3.76 (3H, s, COOMe), 3.98 (1H, ddd,
J = 4.8, 0.9, 0.7 Hz, H-6), 4.11 (1H, dd, J = 7.3, 4.8 Hz, H-5),
4.32 (1H, br dd, J = 4.1, 3.9 Hz, H-3), 6.69 (1H, ddd, J = 3.9,
0.9, 0.5 Hz, H-2); 13C-NMR (125.6 MHz; acetone-d6; Me4Si) d
52.0 (q), 59.7 (q), 66.7 (d), 70.5 (d), 71.2 (d), 79.3 (d), 132.3 (s),
139.2 (d), 167.2 (s); EIMS m/z 219 (M+, 0.4%), 186 (M+-MeOH,
6%); HREIMS m/z calcd for C9H15O6 (M + H)+ 219.0868, found
219.0861.
=
=
orless crystals (CH2Cl2); mp 60–62 ◦C; [a]D -1.8 (c 0.085 in CHCl3);
25
-1
1
=
=
=
IR nmax (KBr)/cm 1732 (C O), 1693 (C O), 1617 (C C); H-NMR
(500 MHz; CDCl3; Me4Si) d 1.35–1.70 (10H, m), 2.91 (1H, dd, J = 9.2,
4.8 Hz, H-6A), 3.09 (1H, dd, J = 9.2, 2.1 Hz, H-6B), 3.79 (3H, s, -OMe),
3.85 (3H, s, COOMe), 4.36 (1H, d, J = 5.3 Hz, H-4), 4.62 (1H, ddd, J =
5.3, 4.8, 2.1 Hz, H-5);13C-NMR (125.6 MHz; CDCl3; Me4Si) d 23.7 (t),
23.8 (t), 24.9 (t), 26.4(t), 35.2 (t), 37.1 (t), 52.4 (q), 60.6 (q), 71.4 (d), 76.3
(d), 76.5 (d), 110.5 (s), 127.4 (s), 151.2 (s), 166.4 (s), 193.1 (s); EIMS
m/z 296 (M+, 76%); HREIMS m/z calcd for C15H20O6 (M)+ 296.1260,
found 296.1259. Methyl 3,4-dihydroxy-2-methoxybenzoate 17: Yellow
Acknowledgements
oil; IR nmax (liquid film)/cm-1 3538 (OH), 1714 (C O), 1604 (C C);
1H-NMR (CDCl3) d 3.89 (3H, s, -OMe), 3.93 (3H, s, COOMe), 5.87
(2H, br s, -OH), 6.74 (1H, d, J = 8.9 Hz), 7.46 (1H, d, J = 8.9 Hz);
13C-NMR (CDCl3) d 51.9 (q), 62.3 (q), 110.9 (d), 115.2 (s), 123.9 (d),
136.7 (s), 148.1 (s), 148.6 (s), 165.4 (s); EIMS m/z 198 (M+, 76%), 166
(M+-MeOH, 88%); HREIMS m/z calcd for C9H10O5 (M)+ 198.0520,
found 198.0524.
=
=
We are grateful to Dr. K. Minoura and Ms. M. Fujitake of this
University for NMR and MS measurements, respectively. We also
thank Dr. T. Yamada of this Unversity for providing copies of 1H-
and 13C-NMR spectra of natural pericosine B and its acetonide,
which appear in the ESI†. This work was supported in part
by a Grant-in-Aid from “Dousoukai” of Osaka University of
Pharmaceutical Sciences awarded to Y. Usami.
16 Y. Usami, K. Mizuki, K. Suzuki, E. Sakamoto, H. Ichikawa, M.
Arimoto, Proceedings of the 50th Tennen Yuki Kagobutsu Toronkai Koen
Yoshisyu, 2008, Fukuoka, Japan, pp. 547–552.
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