1002
Published on the web August 14, 2010
Synthetic Studies on the Natural Multidrug Resistance Modulator, Irciniasulfonic Acid B
Chisato Emura, Ryuichi Higuchi, and Tomofumi Miyamoto*
Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582
(Received June 21, 2010; CL-100577; E-mail: miyamoto@phar.kyushu-u.ac.jp)
Synthetic studies on the natural multidrug resistance (MDR)
O
O
2'
1
-
modulator irciniasulfonic acid (ISA)-B utilizing cross metathesis
and the Horner-Wadsworth-Emmons olefination is described.
The key intermediate, 7-hydroxy-2-nonanone was optically
resolved using a cyclopenta[b]furan derivative (ALBO-V).
SO3
-
SO3
N
O
1'
H
OR
3
8R
10
11
9R
OR
Irciniasulfonic acid (ISA)
R=H: deacyl ISA
Irciniasulfonic acid B (ISA-B: 1)
R=H: deacyl ISA-B (2)
In our continuing research for bioactive compounds from
marine invertebrates, we isolated novel fatty acid analogs, ISA1
and ISA-B (1)2 from the Japanese marine sponge Ircinia sp.
(Figure 1). These compounds reversed multidrug resistance
(MDR) against a membrane glycoprotein (termed P-glycoprotein
or P-gp) overexpressing cancer cells. In this letter, we report on
the synthesis of deacyl ISA-B (2), which is a deacyl derivative
of ISA-B. First, the total synthesis of ISA, via a nucleophilic
ring-opening reaction with racemic epoxide and hex-1-yne, and
a cuprate addition to ¡,¢-unsaturated alkynyl ester was reported
by Dobbs’s group.3 Because deacyl ISA-B (2) consists of a
regioisomeric hydroxy fatty acid, (2Z,8R)-8-hydroxy-3-methyl-
2-decenoic acid (18), we opted to synthesize 2 utilizing cross
metathesis (CM) reactions4 and the Horner-Wadsworth-
Emmons (HWE) olefination.5
Treatment of commercially available 1-penten-3-ol (3) with
1 equiv of 5-hexen-2-one (4) and 0.6 mol % of the Hoveyda-
Grubbs catalyst 2nd generation 56 in refluxing CH2Cl2 provided
the desired CM product 6 in a yield of 48%. However, the
reaction was not carried out efficiently because a self-metathesis
of 3 and 4 occurred. It was reported that a two-step CM
procedure provided CM products selectively.4 According to this
method, 1-penten-3-ol (3) was first self-metathesized with
catalyst 5 to provide the homodimer 7. Then treatment of
compound 7 with 0.5 equiv of 4 and 0.1 mol % of 5 provided the
7-hydroxy-5-nonen-2-one (6)7 in a 72% yield (Scheme 1).
The racemic alcohol 8, which was prepared by the catalytic
reduction of 6 was optically resolved using (R)-3a-allyl-3,3a,4,5-
tetrahydro-2H-cyclopenta[b]furan (ALBO-V).8 Treatment of 8
with ALBO-V gave diastereomeric acetal, and this was easily
separated into 9 and 10 by silica gel column chromatography
[¦Rf value of 9/10 on TLC 0.05 (n-hexane/EtOAc = 2/1)]. Part
of the acetals 9 and 10 were treated with PPTS in MeOH to
obtain optically active alcohols 11 and 12, and their specific
rotations were [¡]D = ¹11.4° for 11, and +11.4° for 12,
respectively. The absolute configuration at C-7 of 12 was
determined to be an S-configuration by the application of a
modified Mosher’s method,9 so that 9 and 11 have R-
configuration at C-7 in the same way as the natural product.
Optically pure acetal 9 reacted with t-butyl diethoxyphosphor-
ylacetate (14) and KOt-Bu to give unsaturated ester 15, which
was a mixture of an E/Z (5.5/1) isomer. Because the natural
ISA-B has trisubstituted Z-olefin, we attempted Z-selective
HE olefination using trifluoroethoxyphosphoryl ester and
KN(TMS)2/18-crown-6,10 however, the reactivity to ketone
O
O
O
5''
9''
24''
22''
15''
R =
23''
(found only in ISA)
Figure 1. Structures of ISAs.
O
0.6 mol % 5
O
+
OH
CH2Cl2, ∆, 48%
6
OH
4
3
OH
4, 5
5, rt
OH
7
CH2Cl2, ∆, 72%
Scheme 1. Cross metathesis reactions using Hoveyda-Grubbs
catalyst 2nd generation.
was poor, so that 2Z,8R (15a) and 2E,8R (15b) olefin was
separated by silica gel column chromatography. The structures
of 15a and 15b were confirmed by the characteristic allylic
1
methyl and methylene proton signals in H NMR [15a: ¤H 1.81
(3H, d, J = 1.3 Hz), 2.57 (2H, m)]. Before the deprotection of the
t-butyl group of 15a, cyclopenta[b]furanoacetal was replaced
with the acetyl group to avoid hydroxy elimination. Compound
15a was treated with PPTS to give hydroxy derivative 16. Next,
the hydroxy group was protected with Ac2O/pyridine to give
acetyl derivative 17. The t-butyl group in 17 was removed using
TFA, and then the acetyl group was removed using NaOMe to
afford (2Z,8R)-8-hydroxy-3-methyl-2-decenoic acid (18),11 suc-
cessively.
Finally, direct condensation of hydroxy fatty acid 18 and
taurine using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmor-
pholinium chloride (DMT-MM)12 gave deacyl ISA-B (2)
(Scheme 2). The spectroscopic data of 2 was in full agreement
with those of the deacyl derivative of natural ISA-B.13
In conclusion, we have developed a synthesis of optically
pure deacyl ISA-B using a CM reaction followed by HWE
olefination via chiral resolution with ALBO-V. This method
is applicable for obtaining stereoisomer of deacyl ISA-B. The
reversing MDR activities of the ISA-B analogs will be reported
elsewhere.
Chem. Lett. 2010, 39, 1002-1003
© 2010 The Chemical Society of Japan
Emura, Chisato
