Total synthesis of murisolins and evaluation of tumor-growth inhibitory activity

Article abstract of DOI:10.1002/chem.200500462

Convergent total syntheses of murisolin (1), natural 16,19-cis-murisolin 2, and unnatural 16,19-cis-murisolin 3 were accomplished by asymmetric alkynylation of α-tetrahydrofuranic aldehyde with a diyne and Sonogashira coupling with a γ-lactone segment as

Full text of DOI:10.1002/chem.200500462

FULL PAPER
DOI: 10.1002/chem.200500462
Total Synthesis of Murisolins and Evaluation of Tumor-Growth Inhibitory
Activity
Naoyoshi Maezaki,[a] Hiroaki Tominaga,[a] Naoto Kojima,[a] Minori Yanai,[a]
Daisuke Urabe,[a] Risa Ueki,[a] Tetsuaki Tanaka,*[a] and Takao Yamori[b]
Abstract: Convergent total syntheses of murisolin (1), natural 16,19-cis-murisolin
2, and unnatural 16,19-cis-murisolin 3 were accomplished by asymmetric alkynyla-
tion of a-tetrahydrofuranic aldehyde with a diyne and Sonogashira coupling with a
Keywords: acetogenins · antitumor
g-lactone segment as the key steps.Stereoisomers of a-tetrahydrofuranic aldehyde
agents · murisolin · natural prod-
were synthesized with high optical purity and the asymmetric alkynylation of these
ucts · total synthesis
with 1,6-heptadiyne proceeded in good yield and with high diastereoselectivity.
The cell-growth inhibition profile and COMPARE analysis of the synthetic com-
pounds 1–3 were also investigated.
Introduction
plex I (NADH=reduced nicotinamide adenine dinucleo-
tide).[1,2]
Acetogenins are polyketides featuring one to three tetrahy-
drofuran (THF) ring(s) with various stereoconfigurations
connected with a butenolide moiety by a long hydrocarbon
chain, which often contains oxygenated moieties.More than
400 annonaceous acetogenins have been isolated from
nature so far.They have attracted worldwide attention due
to a broad range of biological activities, such as cytotoxic,
antitumor, immunosuppressive, pesticidal, antifeedant, and
antimalarial effects.In particular, their potent and selective
cytotoxicity against human cancer cell lines makes them at-
tractive lead compounds for new types of antitumor drugs.
Furthermore, it is known that some acetogenins inhibit mul-
tidrug-resistant cancer cells with an adenosine triphosphate
(ATP) driven transporter system.The mode of action is as-
sumed to be based on inhibitory activity against the
NADH:ubiquinone oxidoreductase of mitochondrial com-
Murisolin (1)[3] is a mono-THF acetogenin isolated from
the seed of Annona muricata by the Cortes group in 1990.
After five years, the diastereoisomer 16,19-cis-murisolin 2[4]
was isolated, along with murisolin, from the seed of Asimina
triloba by McLaughlinꢀs group.Biological evaluation of
these compounds revealed that murisolin is one million
times more potent against human lung (A-549), kidney (A-
498), and colon (HT-29) cancer cells than adriamycin and
that 16,19-cis-murisolin shows activity greater than or equal
to that of adriamycin against human breast (MCF-7) and
lung (A-549) cancer cells.In spite of the comparatively
simple structure and interesting biological activity, there was
no total synthesis of these compounds for a long time.In
2004, Curran and co-workers[5] and our group[6] accomplish-
ed the first total syntheses of murisolin.At the same time,
Curran and co-workers reported the first total synthesis of a
16,19-cis-murisolin in a communication.[5] However, the syn-
thetic reports of these compounds are restricted to these ex-
amples.
[a] Dr.N.Maezaki, H.Tominaga, Dr.N.Kojima, M.Yanai, D.Urabe,
R.Ueki, Prof.Dr.T.Tanaka
We were interested in the relationship between the ster-
eochemistry of the THF moiety and the cytotoxicity against
various cancer cell lines.So we synthesized murisolin conge-
ners 2 and 3, in addition to murisolin (1), for evaluation of
our methodology and the biological activity of these com-
pounds.Herein, we describe in detail the total syntheses of
1–3 (Scheme 1).The comparison of growth inhibition
against various cancer cells and the results of the COM-
PARE analysis are also described.
Graduate School of Pharmaceutical Sciences
Osaka University
1–6 Yamadaoka, Suita, Osaka 565–0871 (Japan)
Fax : (+81)6-6879-8214
E-mail: t-tanaka@phs.osaka-u.ac.jp
[b] Prof.Dr.T.Yamori
Division of Molecular Pharmacology
Cancer Chemotherapy Center
Japanese Foundation for Cancer Research
3–10–6 Ariake, Koto-ku, Tokyo 135–8550 (Japan)
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conditions of Carreira and co-workers.[10] The results are
summarized in Table 1.
Table 1.Asymmetric alkynylation of a-oxyaldehyde with diyne 7.
Scheme 1.Structure of the murisolins.
Results and Discussion
[a]
Conditions
7[a]
Zn(OTf)2
NME[a]
Et3N[a]
Yield [%]
9
10
We have developed a methodology of systematic and stereo-
selective construction of the THF ring moiety for acetoge-
nins.The library of mono- and bis-THF ring moieties was
synthesized by applying this method.[7] Next, we focused on
the synthesis of murisolin congeners and the evaluation of
their biological activity.
A
B
C
D
1.2
2.0
2.0
4.0
1.3
2.2
1.3
1.3
1.4
2.4
1.4
1.4
1.4
2.4
1.4
1.4
58
71
72
84
27
24
20
12
[a] Values given are equivalents of reagents.TBS =tert-butyldimethylsilyl,
Tf=trifluoromethanesulfonyl, NME=(1R,2S)-N-methylephedrine.
Scheme 2 shows a retrosynthetic analysis for the muriso-
lins.Murisolins are bisected at the C7 and C8 carbons into
THF-ring segment 4 and g-lactone segment 5.[8,9] Segment 4
According to the protocol of Carreira and co-workers,
(R)-8 was treated with the diyne 7 (1.2 equiv), Zn(OTf)2
(1.3 equiv), (1R,2S)-NME (1.4 equiv), and Et3N (1.4 equiv)
in toluene.Although the desired syn adduct 9 was obtained
in 58% yield, a considerable amount of byproduct 10 was
produced (conditions A).When about twice the amount of
diyne and reagents were used, the yield of 9 was improved
to 71% (conditions B).However, this improved yield was
not changed when the amounts of the reagents were re-
duced if the amount of diyne remained the same (condi-
tions C).Finally, the yield of 9 was improved to 84% by
using 4 equivalents of the diyne 7 (conditions D).The alky-
nylation proceeded with excellent diastereoselectivity to
give adducts 9 and 10, each as a single isomer.
Next, we conducted an asymmetric alkynylation of the a-
tetrahydrofuranic aldehyde 11 with diyne 7 under the opti-
mized conditions (Scheme 3).The a-tetrahydrofuranic alde-
hyde 11 was synthesized from a-oxyaldehyde (R)-8 by asym-
metric alkynylation with (1R,2S)-NME followed by THF-
ring formation.[7b] Upon treatment of the a-tetrahydrofuran-
Scheme 2.Retrosynthetic analysis of murisolins.PG =protecting group.
is synthesized by an asymmetric alkynylation of THF-ring
segment 6 with diyne 7.The a-tetrahydrofuranic aldehyde 6
can be prepared stereoselectively from a-oxyaldehyde by
the previously established method.[7] In this project, we plan-
ned an unprecedented asymmetric alkynylation of 6 with un-
protected 1,6-heptadiyne (7) to eliminate the steps of pro-
tection and deprotection.
In order to establish suitable reaction conditions for the
partial reaction of the diyne 7, a model study was carried
out with a-oxyaldehyde (R)-8[7b] as a substrate under the
Scheme 3.Asymmetric alkynylation of a-tetrahydrofuranic aldehyde 11
with diyne 7: a) Zn(OTf)2, Et3N, (1R,2S)-NME, toluene, RT, 84% (a-
OH:b-OH 3:>97) for 12 and 12% (b-OH/b-OH:other isomer >97:3)
for 13.
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Murisolin Synthesis and Evaluation
FULL PAPER
ic aldehyde 11 with the diyne 7 (4 equiv), alcohol 12 was ob-
tained in 84% yield, along with 12% of diol 13.Even in the
functionalized aldehyde 11, the alkynylation proceeded with
very high diastereoselectivity (>97:3 d.r.). Thus, the THF
moiety did not affect either the diastereoselectivity or the
ratio of monool and diol.The absolute configuration of
adduct 12 was confirmed to be the desired R configuration
by the modified Mosher method.[11] Interestingly, the by-
product 13 was also a single isomer and is assumed to be a
syn/syn adduct since the compound has C2 symmetry.
The a,b-unsaturated g-lactone segment 5 (PG=TBS) was
synthesized by Marshall and co-workersꢀ from a-sulfenyl g-
lactone 16 through oxidation of the sulfide followed by ther-
molysis of the sulfoxide.[8] In their work, a coupling reaction
of triflate 14 and g-lactone 15 with lithium diisopropylamide
(LDA) in the presence of hexamethyl phosphoramide
(HMPA) proceeded in a moderate yield (54%).In the pre-
vious synthesis of mosin B, we reported that potassium
1,1,1,3,3,3-hexamethyldisilazanide (KHMDS) was a suitable
base for the alkylation of the g-lactone with the triflate.
Therefore, we employed KHMDS in the alkylation of 15
with 14 (E:Z=4.6:1) (Scheme 4); however, the adduct 16
Scheme 5.Synthesis of murisolin ( 1): a) H2, [Rh(PPh3)3Cl] (0.4 equiv),
benzene, RT, 41%; b) H2, [Rh(PPh3)3Cl] (1.0 equiv), benzene/MeOH
(1:1), RT, 47%; c) TsNHNH2, NaOAc, 1,2-dimethoxyethane/H2O (1:1),
reflux, 71%; d) 48% aq.HF, CH 3CN, THF, RT, 91%.Ts =toluene-4-sul-
fonyl.
red in the g-lactone without a proximal C4 substituent.For-
tunately, diimide reduction was also effective to retard the
formation of the unidentified byproduct in the case of cou-
pling product 17, to give 18 in 71% yield.Finally, global de-
protection with HF in MeCH/THF afforded murisolin (1) in
excellent yield.
The spectroscopic and physical data (1H NMR, 13C NMR,
IR, and MS spectra and m.p.) of synthetic 1 were in good
agreement with those reported.On the other hand, the spe-
cific rotation of synthetic 1 ([a]2D3 =+20.7 (c=0.39, MeOH);
[a]2D2 =+21.5 (c=0.36, CHCl3)) was consistent with the high-
est values reported in the literature ([a]D =++14.8 (c=0.1,
MeOH); [a]D =+16.0 (c=0.1, CHCl3); [a]1D4:5 =+19.05 (c=
0.84, CHCl3); [a]1D8:5 =+20.44 (c=5.92, CHCl3)).[3,4,16] Our
synthetic sample was also compared with Professor Curranꢀs
sample by HPLC analysis in his laboratory.
To demonstrate the stereodivergency of our methodology,
we synthesized the two stereoisomers of 16,19-cis-murisolin,
2 and 3 (Scheme 6).The unnatural 16,19- cis-murisolin 3 has
Scheme 4.Construction of the murisolin framework ( 17) through Sonoga-
shira coupling: a) KHMDS, THF, 08C!RT, 19%; b) KHMDS, HMPA,
THF, 08C!RT, 77%; c) [(Ph3P)2PdCl2], CuI, Et3N, RT, 72 %.
was produced in poor yield (19%).This problem was over-
come by the addition of HMPA, to give 16 in 77% yield.
Assembly of the THF-ring segment 12 and the g-lactone
Scheme 6.Stereodivergent syntheses of 1–3.
segment
5 was carried out by Sonogashira coupling
(Scheme 4) to give the coupling product 17 in 72% yield.[12]
Next, we examined the selective reduction of enediyne 17
by using catalytic[13] or stoichiometric[14] amounts of Wilkin-
son catalyst, but compound 18 was obtained in moderate
yields (Scheme 5).Marshall and Chen employed diimide in-
stead of the Wilkinson catalyst for the selective reduction of
an enyne.[15] They employed these conditions, instead of
using the Wilkinson catalyst, to prevent overreduction of
the a,b-unsaturated g-lactone moiety, a problem that occur-
a THF moiety that is a mirror image to that of 2.We were
also interested in the biological activity of these compounds.
The stereocenters at the C15 and C19 positions can be con-
structed stereodivergently by changing the N-methylephe-
drine configuration in the asymmetric alkynylation.On the
other hand, stereoselective construction of the C16 and C20
stereocenters can be accomplished by changing the mode of
THF-ring formation and by choosing an appropriate enan-
tiomer of Jacobsenꢀs catalyst,[17] respectively (Scheme 6).
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T.Tanaka et al.
16,19-cis-Murisolin 2 was synthesized from a-oxyaldehyde
(S)-8, which was prepared through kinetic resolution of (ꢀ)-
tetradecene oxide with an antipode of Jacobsenꢀs salen-
cobalt catalyst (Scheme 7).Asymmetric alkynylation of ( S)-
Scheme 8.Asymmetric alkynylation of a-tetrahydrofuranic aldehyde 25
or ent-25 with diyne 7: a) Zn(OTf)2, Et3N, (1R,2S)-NME, toluene, RT,
79% (a-OH:b-OH 6:94); b) Zn(OTf)2, Et3N, (1S,2R)-NME, toluene, RT,
79% (a-OH:b-OH 94:6).
Scheme 7.Preparation of aldehyde 25: a) ZnO(Tf)2, (1S,2R)-NME, Et3N,
toluene, RT, 92% (a-OH:b-OH >97:3); b) H2, Pd/C, EtOAc, RT, 84%;
c) TrisCl, pyridine, CH2Cl2, 08C!RT, 86 %; d) K2CO3, MeOH, 08C!RT,
70%; e) Dess–Martin periodinane, pyridine, CH2Cl2, 08C!RT, 65 %.
Tris=2,4,6-triisopropylbenzenesulfonyl.
8 with alkyne 19[7b] by using (1S,2R)-NME afforded syn-
propargyl alcohol 20 in 92% yield with excellent diastereo-
selectivity.Hydrogenation of 20 on Pd/C in EtOAc gave
triol 21 in 84% yield.After conversion of the primary alco-
hol into the leaving group, one-pot THF-ring formation was
carried out by treatment with K2CO3 in MeOH, through an
epoxide intermediate, to provide a-tetrahydrofuranic alco-
hol 24.Finally, Dess–Martin oxidation of the primary alco-
hol gave the aldehyde 25[7b] in 65% yield.
a-Tetrahydrofuranic aldehyde ent-25 was synthesized
from (R)-8 according to the procedure described in referen-
ce [7b].
Scheme 9.Syntheses of 16,19- cis-murisolin 2 and unnatural 16,19-cis-mur-
isolin 3: a) [(Ph3P)2PdCl2], CuI, Et3N, RT, 73% for 27 and 78% for 29;
b) TsNHNH2, NaOAc, 1,2-dimethoxyethane, H2O, reflux, 60% for 28
and 61% for 30; c) 48% aq.HF, CH 3CN, THF, RT, 85% for 2 and 82%
for 3.
Asymmetric alkynylation with 1,6-heptadiyne (7) was con-
ducted on the a-tetrahydrofuranic aldehydes 25 and ent-25
in a similar manner to that performed in the murisolin syn-
thesis.By using the appropriate NME, both ( R)- and (S)-
propargyl alcohols 26 and ent-26 were synthesized with ex-
cellent diastereoselectivity and in 79% yield without being
influenced by the three internal stereogenic centers in the
aldehydes (Scheme 8).[18]
give enediynes 27 and 29 in 73 and 78% yield, respectively.
Subsequent diimide reduction delivered 28 and 30 and re-
moval of the protecting groups yielded 16,19-cis-murisolin 2
and the unnatural isomer 3.
With both enantiomers 26 and ent-26 in hand, the Sonoga-
shira coupling with g-lactone segment 5 was examined
(Scheme 9).The coupling reaction proceeded smoothly to
The spectroscopic data (1H NMR, 13C NMR, IR, and MS
spectra and [a]D) of synthetic 2 were in good agreement
with those reported.However, the melting point of the syn-
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Murisolin Synthesis and Evaluation
FULL PAPER
thetic 2 (76.5–77.58C) was higher than that of the natural
product (67–688C).[4] The data (1H NMR, 13C NMR, IR, and
MS spectra) of 3 were almost identical to those of 2.Fur-
thermore, the value of specific rotation of 3 ([a]2D9 =+9.1
(c=0.50 in CH2Cl2)) was relatively close to that of 2 ([a]2D7 =
+11.3 (c=0.62 in CH2Cl2)).Interestingly, the value of the
melting point of 3 (65.0–66.08C) was closer to the reported
value of 2.Since the natural product is not available at the
present time, the difference in melting points cannot be ex-
plained clearly.However, we suggest that great care is nec-
essary in identification of 16,19-cis-murisolins since both the
specific rotation and spectral data for 2 and 3 are very
close.[19]
significant effects against some lung and stomach cancer cell
lines.In particular, these compounds inhibited the growth of
DMS114 lung cancer cells very potently (log GI50 =ꢁ7.53
(3.0”10ꢁ8 m) to ꢁ8.00 (1.0”10ꢁ8 m)).Among 1–3, the natural
16,19-cis-murisolin 2 exhibited the highest growth inhibition
against MKN28 stomach cancer cells (log GI50 =ꢁ8.00). The
activity was considerably influenced by the stereochemistry
of the THF-ring moiety (order of activity (log GI50): 2
(ꢁ8.00)>3 (ꢁ5.89)>1 (ꢁ5.56)). An effect of the stereo-
chemistry on the growth inhibition was also found against
NCI-H23 cells (order of activity (log GI50): 3 (ꢁ6.76)>1
(ꢁ6.67)>2 (ꢁ4.97)) and MKN7 cells (order of activity (log
GI50): 1 (ꢁ6.15)>2 (ꢁ5.83)>3 (ꢁ4.72)). Moderate inhibi-
tion was observed against some breast cancer cells (BSY-1
and MCF-7), CNS cancer cells (SF-295), lung cancer cells
(NCI-H522), melanoma cells (LOX-IMVI), and stomach
cancer cells (MKN74).
Biological evaluation of 1–3: The growth inhibitory activity
of 1–3 was evaluated against a panel of human cancer cell
lines.[20,21] Figure 1 shows the mean graphs for murisolin (1),
16,19-cis-murisolin 2, and unnatural 16,19-cis-murisolin 3.
The graphs were drawn based on a set of GI50 values for
each compound against 39 cancer cell lines, where the GI50
value indicates the concentration that induces 50% inhibi-
tion of cell growth.These compounds commonly showed
COMPARE analysis[20,21] is a tool to examine a pair of
compounds in terms of their mean graphs, and it was re-
vealed here that compounds 1–3 were different from any of
the present anticancer drugs (r<0.5). This result suggests
that they have unique modes of action.In addition, the
Figure 1.Growth inhibition of 1–3 against a panel of 39 human cancer cell lines.Columns extending to the right indicate the degree of the sensitivity of a
cell line to the compound; columns extending to the left indicate the degree of resistance of a cell line to the compound.For details of the procedure fo r
the assay, see reference [20].GI 50 =concentration that induces 50% growth inhibition, Br=breast, CNS=central nervous system (brain), Co=colon,
Lu=lung, Me=melanoma, Ov=ovarian, Re=renal, St=stomach, xPg=prostate.MG-MID =the mean of the log GI50 values.
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T.Tanaka et al.
2H), 2.34 (td, J=7.3, 1.8 Hz, 2H), 2.45 (brd, J=6.1 Hz, 1H), 3.68 (q, J=
5.5 Hz, 1H), 4.19 ppm (brs, 1H); 13C NMR d=ꢁ4.5, ꢁ4.4, 14.1, 17.6,
17.8, 18.1, 22.6, 24.9, 25.8 (3C), 27.4, 29.3, 29.48, 29.53, 29.59 (2C), 29.63,
29.7, 31.9, 33.7, 65.0, 68.8, 75.8, 80.4, 83.3, 84.4 ppm; IR (KBr): n˜ =3552,
COMPARE analysis indicated that compounds 1–3 were
very like each other (1 versus 2: r=0.768; 1 versus 3: r=
0.889; 2 versus 3: r=0.762), as shown in Figure 1. This may
indicate that these three compounds share the same mode
of action, albeit one that is unknown at present.
3464, 3313, 2119, 636 cmꢁ1 MS (FAB): m/z: 441 [M+Li]+; HRMS
;
(FAB): m/z calcd for C27H50LiO2Si: 441.3740; found: 441.3752 [M+Li]+.
10: [a]2D6 =ꢁ1.59 (c=1.32 in CHCl3); 1H NMR: d=0.10 (s, 6H), 0.12 (s,
6H), 0.88 (t, J=7.0 Hz, 6H), 0.91, (s, 18H), 1.26–1.34 (m, 40H), 1.48–
1.55 (m, 2H), 1.58–1.65 (m, 2H), 1.71 (qn, J=7.0 Hz, 2H), 2.31 (td, J=
7.0, 1.8 Hz, 4H), 2.45 (d, J=6.7 Hz, 2H), 3.68 (q, J=5.5 Hz, 2H), 4.17–
4.20 ppm (m, 2H); 13C NMR: d=ꢁ4.5 (2C), ꢁ4.4 (2C), 14.1 (2C), 18.07
(2C), 18.15 (2C), 22.7 (2C), 24.9 (2C), 25.9 (6C), 27.5, 29.3 (2C), 29.55
(2C), 29.58 (2C), 29.64 (4C), 29.7 (2C), 29.8 (2C), 31.9 (2C), 33.7 (2C),
65.0 (2C), 75.8 (2C), 80.4 (2C), 84.5 ppm (2C); IR (KBr): n˜ =3559,
3463 cmꢁ1; MS (FAB): m/z: 800 [M+Na]+; HRMS (FAB): m/z calcd for
C47H92NaO4Si2: 799.6432; found: 799.6404 [M+Na]+.
Conclusion
We have accomplished the total syntheses of murisolin con-
geners 1–3 by employing our systematic synthesis of the
THF-ring moiety, asymmetric alkynylation with the diyne,
and Sonogashira coupling as the key steps.Evaluation of
cell-growth inhibition of these compounds indicated that
they commonly have strong inhibitory activity against lung
(8R,9R,12R,13R)-13-(tert-Butyldimethylsilyloxy)-9,12-epoxy-pentacosa-
1,6-diyn-8-ol (12) and (13R,14R,17R,18R,26R,27R,30R,31R)-13,31-bis-
(tert-butyldimethylsilyloxy)-14,17:27,30-diepoxytritetraconta-19,24-diyne-
18,26-diol (13): The procedure was the same as that used for the prepara-
tion of 9 and 10.Compounds 12 (129 mg, 84%, a-OH:b-OH 3:>97) and
13 (14.1 mg, 12%) were prepared as colorless oils from 11 (126 mg,
0.305 mmol). 12: [a]2D4 =+11.2 (c=1.10 in CHCl3); 1H NMR: d=0.06 (s,
3H), 0.08 (s, 3H), 0.88 (t, J=7.0 Hz, 3H), 0.89 (s, 9H), 1.23–1.49 (m,
22H), 1.65–1.79 (m, 2H), 1.73 (qn, J=6.7 Hz, 2H), 1.89–1.94 (m, 1H),
1.95 (t, J=2.4 Hz, 1H), 2.02–2.08 (m, 1H), 2.30 (td, J=6.7, 2.4 Hz, 2H),
2.35 (td, J=6.7, 1.8 Hz, 2H), 2.47 (d, J=4.3 Hz, 1H), 3.57 (td, J=6.1,
3.7 Hz, 1H), 3.91 (dt, J=7.3, 6.1 Hz, 1H), 4.01 (q, J=6.7 Hz, 1H), 4.14–
4.18 ppm (m, 1H); 13C NMR: d=ꢁ4.7, ꢁ4.2, 14.1, 17.5, 17.7, 18.2, 22.6,
25.5, 25.9 (3C), 27.3, 27.6, 28.3, 29.3, 29.55, 29.59 (3C), 29.63, 29.8, 31.9,
32.9, 65.5, 68.8, 74.9, 78.9, 82.3, 82.7, 83.3, 84.9 ppm; IR (KBr): n˜ =3450,
3313, 2233, 2119 cmꢁ1; MS (FAB): m/z: 505 [M+H]+; HRMS (FAB): m/z
cancer cells (DMS114).16,19- cis-murisolin
2 exhibited
potent activity against stomach cancer cells (MKN28) and
the effect of the compounds was affected by the stereo-
chemistry of the THF moiety.COMPARE analysis of 1–3
indicated that they may share a mode of action that is differ-
ent from those of currently used anticancer drugs.
Experimental Section
Melting points are uncorrected.Optical rotations were measured by
using a JASCO DIP-360 digital polarimeter. 1H NMR spectra were re-
calcd for C31H57O3Si: 505.4077; found: 505.4084 [M+H]+. 13: [a]D24
=
corded in CDCl3 solution with
a JEOL JNM-GX-500 spectrometer
+12.4 (c=1.74 in CHCl3); 1H NMR: d=0.06 (s, 6H), 0.08 (s, 6H), 0.88
(t, J=7.0 Hz, 6H), 0.89 (s, 18H), 1.23–1.47 (m, 44H), 1.64–1.78 (m, 6H),
1.89–1.94 (m, 2H), 2.02–2.08 (m, 2H), 2.31 (td, J=7.0, 1.8 Hz, 4H), 2.51
(brd, J=3.1 Hz, 2H), 3.57 (td, J=6.7, 3.1 Hz, 2H), 3.91 (dt, J=7.9,
6.1 Hz, 2H), 4.00 (q, J=6.7 Hz, 2H), 4.15 ppm (brd, J=6.7 Hz, 2H);
13C NMR: d=ꢁ4.6 (2C), ꢁ4.2 (2C), 14.1 (2C), 17.9 (2C), 18.2 (2C), 22.7
(2C), 25.5 (2C), 25.9 (6C), 27.4, 27.6 (2C), 28.3 (2C), 29.3 (2C), 29.58
(2C), 29.62 (6C), 29.7 (2C), 29.8 (2C), 31.9 (2C), 32.9 (2C), 65.5 (2C),
74.8 (2C), 78.7 (2C), 82.3 (2C), 82.6 (2C), 85.0 ppm (2C); IR (KBr): n˜ =
3429, 2233 cmꢁ1; MS (FAB): m/z: 940 [M+Na]+; HRMS (FAB): m/z
calcd for C55H104NaO6Si2: 939.7269; found: 939.7256 [M+Na]+.
(500 MHz). 13C NMR spectra were recorded in CDCl3 solution with a
JEOL JNM-AL300 spectrometer (75 MHz).All signals are expressed as
d values in ppm downfield from the tetramethylsilane internal standard.
The following abbreviations are used: br=broad, s=singlet, d=doublet,
tr=triplet, q=quartet, qn=quintet, sep=septet, and m=multiplet.IR
absorption spectra (FT=diffuse reflectance spectroscopy) were recorded
with KBr powder by using a Horiba FT-210 IR spectrophotometer, and
only noteworthy absorptions (in cmꢁ1) are listed.Mass spectra were ob-
tained with JEOL JMS-600H and JEOL JMS-700 mass spectrometers.
Column chromatography was carried out by using Kanto Chemical silica
gel 60N (spherical, neutral, 63–210 mm).All air- or moisture-sensitive re-
actions were carried out in flame-dried glassware under an atmosphere
of Ar or N2.All solvents were dried and distilled according to standard
procedures.All organic extracts were dried over anhydrous MgSO 4, fil-
tered, and concentrated under reduced pressure with rotary evaporator.
(3RS,5S)-3-Phenylthio-3-[(EZ,2R)-2-(tert-butyldimethylsiloxy)-5-iodo-4-
pentenyl]-5-methyl-2(5H)-2,3-dihydrofuranone (16): Method without
HMPA: KHMDS (0.5m in toluene, 0.422 mL, 0.211 mmol) was added to
a solution of 15 (43.9 mg, 0.211 mmol) in THF (0.2 mL) with stirring at
08C.After 5 min, a solution of 14 (100 mg, 0.211 mmol) in THF (0.2 mL)
was added to the mixture with stirring at 08C.After being stirred for 2 h
at room temperature, the reaction was quenched with saturated NH4Cl
and the mixture was extracted with EtOAc.The combined organic layers
were washed with brine prior to drying and solvent evaporation.Purifica-
tion by column chromatography on silica gel (hexane/EtOAc 20:1!10:1)
yielded 16 (20.8 mg, 19%).
(8R,9R)-9-(tert-Butyldimethylsilyloxy)heneicosa-1,6-diyn-8-ol (9) and
(13R,14R,22R,23R)-13,23-bis-(tert-butyldimethylsilyloxy)pentatriaconta-
15,20-diyne-14,22-diol (10): A flask was charged with Zn(OTf)2 (138 mg,
0.379 mmol). Vacuum (5 mmHg) was applied and the flask was heated to
1258C overnight.The vacuum was released and the flask was cooled to
room temperature.(1 R,2S)-N-Methylephedrine (73.2 mg, 0.409 mmol),
toluene (0.7 mL), and Et3N (0.057 mL, 0.409 mmol) were added to the
flask with stirring at room temperature for 2.75 h. A solution of 1,6-hep-
tadiyne (7; 111 mg, 11.7 mmol) in toluene (0.3 mL) was added to the mix-
ture.After the mixture had been stirred at room temperature for 02. 5 h,
a solution of (R)-8 (100 mg, 0.292 mmol) in toluene (0.3 mL) was added
with stirring at room temperature for 1.5 h. The reaction was quenched
with saturated NH4Cl and the mixture was extracted with EtOAc.The
combined organic layers were washed with brine prior to drying and sol-
vent evaporation.Purification by column chromatography on silica gel
(hexane/EtOAc 20:1!10:1) yielded 9 (106 mg, 84%, anti:syn 3:>97)
and 10 (13.1 mg, 12%), both as colorless oils. 9: [a]2D5 =ꢁ3.56 (c=1.03 in
CHCl3); 1H NMR: d=0.10 (s, 3H), 0.13 (s, 3H), 0.88 (t, J=7.0 Hz, 3H),
0.92, (s, 9H), 1.26–1.34 (m, 20H), 1.49–1.56 (m, 1H), 1.59–1.66 (m, 1H),
1.73 (qn, J=7.0 Hz, 2H), 1.95 (t, J=2.4 Hz, 1H), 2.30 (td, J=6.7, 2.4 Hz,
Method with HMPA: HMPA (0.668 mL, 3.84 mmol) was added to a solu-
tion of 15 (159 mg, 0.767 mmol) in THF (1.1 mL) with stirring at room
temperature and then KHMDS (0.5m in toluene, 1.53 mL, 0.767 mmol)
was added to the solution at 08C.After the mixture had been stirred for
5 min at the same temperature, a solution of 14 (364 mg, 0.767 mmol) in
THF (1.1 mL) was added with stirring. After being stirred for 1 h at
room temperature, the reaction was quenched with saturated NH4Cl and
the mixture was extracted with EtOAc.The combined organic layers
were washed with saturated NH4Cl, water, and brine prior to drying and
solvent evaporation.Purification by column chromatography on silica gel
(hexane/EtOAc 20:1!10:1) yielded 16 (315 mg, 77%).The spectral data
(1H NMR, 13C NMR spectra) were identical to those reported previous-
ly.[8]
6242
www.chemeurj.org
ꢁ 2005 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
Chem. Eur. J. 2005, 11, 6237 – 6245

Murisolin Synthesis and Evaluation
FULL PAPER
(5S)-3-[(E,2R,13R)-2-(tert-Butyldimethylsilyloxy)-13-hydroxy-13-
[(2R,5R)-5-[(1R)-1-(tert-butyldimethylsilyloxy)tridecyl]tetrahydrofuran-
2-yl]tridec-4-ene-6,11-diynyl]-5-methyl-2,5-dihydrofuran-2-one (17): Pd-
(PPh3)2Cl2 (6.4 mg, 0.0092 mmol) and CuI (7.0 mg, 0.037 mmol) were
added to a solution of 5 (77.3 mg, 0.183 mmol) in Et3N (1.0 mL) with stir-
(2RS,4S)-4-[(3’S,4’S)-4’-tert-Butyldimethylsilyloxy-3’-hydroxy-1’-hexadec-
ynyl]-2-phenyl-1,3-dioxolane (20): A flask was charged with Zn(OTf)2
(3.49 g, 9.60 mmol). Vacuum (15 mmHg) was applied and heated to
1258C for 8 h.The vacuum was released and the flask was cooled to
room temperature.(1 S,2R)-N-Methylephedrine (1.84 g, 10.3 mmol), tolu-
ene (9.0 mL), and Et3N (1.44 mL, 10.3 mmol) were added to the flask
with stirring at room temperature.A solution of 19 (1.54 g, 8.86 mmol) in
toluene (3.0 mL) was added to the mixture with stirring at room temper-
ature.After 02.5 h, a solution of ( S)-8 (2.53 g, 7.38 mmol) in toluene
(3.0 mL) was added to the mixture with stirring at room temperature.
After being stirred for 18 h, the reaction was quenched with saturated
NH4Cl and extracted with EtOAc.The combined organic layers were
washed with brine prior to drying and solvent evaporation.Purification
by column chromatography on silica gel (hexane/EtOAc 30:1!20:1!
10:1!4:1) yielded 20 (3.52 g, 92%, anti:syn 3:>97) as a yellow oil.
[a]1D7 =+32.6 (c=1.09 in CHCl3); 1H NMR: d=0.10 (s, 1.2H), 0.12 (s,
3H), 0.15 (s, 1.8H), 0.88 (t, J=7.0 Hz, 3H), 0.91 (s, 3.6H), 0.93 (s, 5.4H),
1.26–1.34 (m, 20H), 1.47–1.57 (m, 1H), 1.58–1.69 (m, 1H), 2.53 (d, J=
7.3 Hz, 0.4H), 2.58 (d, J=7.3 Hz, 0.6H), 3.72 (td, J=6.1, 4.3 Hz, 0.4H),
3.76 (td, J=5.5, 4.9 Hz, 0.6H), 3.98 (dd, J=7.9, 6.1 Hz, 0.6H), 4.06 (dd,
J=7.9, 6.1 Hz, 0.4H), 4.18 (dd, J=7.9, 6.1 Hz, 0.4H), 4.28 (ddd, J=7.3,
4.3, 1.2 Hz, 0.4H), 4.30 (ddd, J=7.3, 4.3, 1.8 Hz, 0.6H), 4.36 (dd, J=7.9,
6.1 Hz, 0.6H), 4.89 (td, J=6.1, 1.2 Hz, 0.4H), 4.94 (td, J=6.1, 1.8 Hz,
0.6H), 5.85 (s, 0.4H), 5.95 (s, 0.6H), 7.37–7.39 (m, 3H), 7.46–7.48 (m,
1.2H), 7.51–7.53 ppm (m, 0.8H); 13C NMR: d=ꢁ4.49 (0.4C), ꢁ4.46
(0.6C), ꢁ4.44 (0.4C), ꢁ4.41 (0.6C), 14.1, 18.0 (0.4C), 18.1 (0.6C), 22.6,
24.9 (0.4C), 25.0 (0.6C), 25.8 (3C), 29.3, 29.46, 29.50, 29.57 (2C), 29.60,
29.7, 31.9, 33.57 (0.4C), 33.62 (0.6C), 64.68 (0.6C), 64.70 (0.4C), 65.8
(0.6C), 66.4 (0.4C), 70.5 (0.4C), 71.0 (0.6C), 75.17 (0.4C), 75.20 (0.6C),
81.5 (0.4C), 81.9 (0.6C), 86.1 (0.4C), 86.5 (0.6C), 103.6 (0.6C), 104.8
(0.4C), 126.5 (1.2C), 126.8 (0.8C), 128.2 (0.8C), 128.3 (1.2C), 129.3
(0.4C), 129.4 (0.6C), 136.6 (0.6C), 137.0 ppm (0.4C); IR (KBr): n˜ =3478,
3037, 2360, 1068 cmꢁ1; MS (FAB): m/z: 539 [M+Na]+; HRMS (FAB):
m/z calcd for C31H52NaO4Si: 539.3533; found: 539.3535 [M+Na]+.
ring at room temperature.After 05.h,
a
solution of
12 (92.4 mg,
0.183 mmol) in Et3N (0.5 mL) was added to the reaction mixture. The re-
action mixture was stirred at room temperature for 6.5 h and concentrat-
ed.Purification by column chromatography on silica gel (hexane/EtOAc
10:1!5:1) yielded 17 (112 mg, 72%) as a yellow oil.[ a]2D4 =+0.50 (c=
0.96 in CHCl3); 1H NMR: d=0.02 (s, 3H), 0.06 (s, 6H), 0.08 (s, 3H),
0.86–0.90 (m, 3H), 0.88 (s, 9H), 0.89 (s, 9H), 1.23–1.35 (m, 21H), 1.36–
1.46 (m, 1H), 1.42 (d, J=6.7 Hz, 3H), 1.66–1.79 (m, 4H), 1.89–1.95 (m,
1H), 2.02–2.08 (m, 1H), 2.24–2.29 (m, 2H), 2.33 (td, J=7.3, 1.8 Hz, 2H),
2.39 (td, J=6.7, 1.2 Hz, 2H), 2.42 (d, J=6.1 Hz, 2H), 2.47 (d, J=4.3 Hz,
1H), 3.56–3.59 (m, 1H), 3.91 (dt, J=7.9, 6.1 Hz, 1H), 4.00 (q, J=6.7 Hz,
1H), 4.05 (qn, J=6.1 Hz, 1H), 4.14–4.17 (m, 1H), 5.00 (qd, J=6.7,
1.2 Hz, 1H), 5.47 (dt, J=15.9, 1.8 Hz, 1H), 6.03 (dt, J=15.9, 7.3 Hz, 1H),
7.10 ppm (brs, 1H); 13C NMR: d=ꢁ4.6 (2C), ꢁ4.5, ꢁ4.2, 14.0, 17.87,
17.95, 18.2, 18.5, 18.8, 22.6, 25.5, 25.8 (3C), 25.9 (3C), 27.6, 27.7, 28.3,
29.3, 29.5, 29.57 (3C), 29.60, 29.8, 31.9, 32.8, 32.9, 40.7, 65.6, 69.3, 74.9,
77.4, 78.8, 79.5, 82.4, 82.7, 85.1, 88.1, 112.7, 130.6, 138.4, 151.7, 173.7 ppm;
IR (KBr): n˜ =3456, 2219, 1759, 1653 cmꢁ1; MS (FAB): m/z: 800 [M+H]+;
HRMS (FAB): m/z calcd for C47H83O6Si2: 799.5728; found: 799.5720
[M+H]+.
(5S)-3-[(2R,13R)-2-(tert-Butyldimethylsilyloxy)-13-hydroxy-13-[(2R,5R)-
5-[(1R)-1-(tert-butyldimethylsilyloxy)tridecyl]tetrahydrofuran-2-yl]tridec-
yl]-5-methyl-2,5-dihydrofuran-2-one (18): A solution of NaOAc (811 mg,
9.89 mmol) in water (13 mL) was added to a stirred solution of 17
(101 mg, 0.126 mmol) and p-toluenesulfonylhydrazine (1.62 g, 8.67 mmol)
in dimethoxyethane (13 mL) at reflux over 5 h.The mixture was then
cooled to room temperature, poured into water, and extracted with
CH2Cl2.The combined organic layers were dried and concentrated.Puri-
fication by column chromatography on silica gel (hexane/EtOAc 6:1)
yielded 18 (72.8 mg, 71%) as a colorless oil. [a]2D4 =+15.8 (c=1.49 in
CHCl3); 1H NMR: d=0.02 (s, 3H), 0.05 (s, 3H), 0.06 (s, 3H), 0.08 (s,
3H), 0.85–0.90 (m, 3H), 0.87 (s, 9H), 0.89 (s, 9H), 1.25–1.46 (m, 42H),
1.42 (d, J=6.7 Hz, 3H), 1.56–1.68 (m, 2H), 1.90–1.96 (m, 2H), 2.424 (d,
J=4.3 Hz, 1H), 2.425 (d, J=5.5 Hz, 2H), 3.35–3.40 (m, 1H), 3.55 (td, J=
6.1, 3.7 Hz, 1H), 3.77 (dt, J=7.9, 6.1 Hz, 1H), 3.85 (dt, J=7.9, 6.1 Hz,
1H), 3.95 (qn, J=5.5 Hz, 1H), 5.01 (qd, J=6.7, 1.2 Hz, 1H), 7.13 ppm (d,
J=1.2 Hz, 1H); 13C NMR: d=ꢁ4.6, ꢁ4.49, ꢁ4.48, ꢁ4.1, 14.1, 18.0, 18.3,
18.9, 22.7, 25.1, 25.4, 25.6, 25.8 (3C), 25.9 (3C), 28.5, 28.6, 29.3, 29.57
(4C), 29.63 (3C), 29.67 (2C), 29.68, 29.71, 29.8, 31.9, 32.7, 33.1, 33.4, 36.9,
70.1, 74.1, 75.2, 77.5, 82.2, 82.4, 130.8, 151.6, 174.1 ppm; IR (KBr): n˜ =
3597, 1759, 1653 cmꢁ1; MS (FAB): m/z: 832 [M+Na]+; HRMS (FAB):
m/z calcd for C47H92NaO6Si2: 831.6330; found: 831.6331 [M+Na]+.
(2S,5S,6S)-6-(tert-Butyldimethylsilyloxy)octadecane-1,2,5-triol (21): A so-
lution of 20 (1.20 g, 2.13 mmol) in EtOAc (15 mL) was hydrogenated on
10% Pd/C (60.0 mg) with stirring at room temperature for 14.5 h. The
Pd/C was filtered off and the filtrate was concentrated under reduced
pressure.Purification by column chromatography on silica gel (hexane/
EtOAc 10:1!1:1) yielded 21 (842 mg, 84%) as a colorless waxy oil.
[a]1D9 =+3.0 (c=1.01 in CHCl3); 1H NMR: d=0.08 (s, 3H), 0.09 (s, 3H),
0.88 (t, J=7.0 Hz, 3H), 0.90 (s, 9H), 1.26–1.33 (m, 20H), 1.39–1.44 (m,
1H), 1.49–1.70 (m, 5H), 2.12 (brs, 1H), 2.22 (brs, 1H), 2.68 (brs, 1H),
3.44–3.53 (m, 3H), 3.61–3.65 (m, 1H), 3.70–3.74 ppm (m, 1H); 13C NMR:
d=ꢁ4.6, ꢁ4.2, 14.1, 18.0, 22.6, 25.0, 25.8 (3C), 29.3, 29.56 (2C), 29.60
(2C), 29.64 (2C), 29.9, 30.3, 31.9, 33.4, 66.8, 72.4, 73.3, 75.4 ppm; IR
(KBr): n˜ =3311 cmꢁ1; MS (FAB): m/z: 433 [M+H]+; HRMS (FAB): m/z
calcd for C24H53O4Si: 433.3713; found: 433.3726 [M+H]+.
(5S)-3-[(2R,13R)-2,13-Dihydroxy-13-[(2R,5R)-5-[(1R)-1-hydroxytride-
cyl]tetrahydrofuran-2-yl]tridecyl]-5-methyl-2,5-dihydrofuran-2-one (muri-
solin, 1): Two drops of 48% aqueous HF was added to a stirred solution
of 18 (27.5 mg, 0.034 mmol) in MeCN/THF (1.6:1, 0.55 mL) at room tem-
perature.After being stirred at room temperature for 135. h, the reaction
mixture was partitioned between CH2Cl2 and brine.The organic layer
was separated and the aqueous layer was extracted with CH2Cl2.The
combined organic layers were washed with brine prior to drying and sol-
vent evaporation.Purification by column chromatography on silica gel
(hexane/EtOAc 1:1) yielded 1 (17.9 mg, 91%) as a colorless waxy solid.
M.p.=72.5–73.58C; [a]D23 =+20.7 (c=0.39 in MeOH), [a]2D2 =+21.5 (c=
0.36 in CHCl3); 1H NMR: d=0.88 (t, J=7.0 Hz, 3H), 1.25–1.57 (m,
42H), 1.44 (d, J=6.7 Hz, 3H), 1.63–1.71 (m, 2H), 1.94–2.02 (m, 2H),
2.40 (dd, J=15.3, 8.6 Hz, 1H), 2.47–2.58 (m, 3H), 2.51–2.55 (m, 1H),
3.41 (td, J=6.7, 4.9 Hz, 2H), 3.80 (q, J=6.7 Hz, 2H), 3.82–3.87 (m, 1H),
5.07 (qd, J=6.7, 1.2 Hz, 1H), 7.20 ppm (d, J=1.2 Hz, 1H); 13C NMR:
d=14.1, 19.1, 22.7, 25.5 (2C), 25.6, 28.7 (2C), 29.3, 29.4, 29.5 (4C), 29.57,
29.62 (4C), 29.65, 29.69, 31.9, 33.3, 33.4 (2C), 37.4, 70.0, 74.0 (2C), 78.0,
82.6 (2C), 131.2, 151.8, 174.6 ppm; IR (KBr): n˜ =3435, 3419, 2916, 2848,
1751, 1470, 1319, 1201, 1119, 1074, 1028, 960, 847, 721 cmꢁ1; MS (FAB):
m/z: 582 [M+H]+; HRMS (FAB): m/z calcd for C35H65O6: 581.4781;
found: 581.4786 [M+H]+.
(2S,5S,6S)-6-tert-Butyldimethylsilyloxy-2,5-dihydroxyoctadecanyl 2’,4’,6’-
triisopropylbenzenesulfonate (22): 2,4,6-Triisopropylbenzenesulfonyl
chloride (1.77 g, 5.83 mmol) was added to a solution of 21 (842 mg,
1.94 mmol) in pyridine (6.3 mL) and CH2Cl2 (11 mL) at 08C with stirring
for 0.25 h. After the mixture had been left for 34 h at room temperature,
water (6.3 mL) was added. The mixture was then extracted with EtOAc.
The combined organic layers were washed with brine prior to drying and
solvent evaporation.Purification by column chromatography on silica gel
(hexane/EtOAc 5:1!2:1) yielded 22 (1.17 g, 86%) as a colorless waxy
oil.[ a]2D4 =+1.2 (c=1.00 in CHCl3); 1H NMR: d=0.06 (s, 3H), 0.08 (s,
3H), 0.87–0.90 (m, 3H), 0.89 (s, 9H), 1.23–1.31 (m, 38H), 1.37–1.44 (m,
1H), 1.49–1.66 (m, 4H), 1.74–1.79 (m, 1H), 2.54 (brs, 1H), 2.91 (sep, J=
6.7 Hz, 1H), 3.44–3.51 (m, 3H), 3.87–3.92 (m, 1H), 3.97 (dd, J=9.8,
6.1 Hz, 1H), 4.00 (dd, J=9.8, 4.9 Hz, 1H), 4.14 (sep, J=6.7 Hz, 2H),
7.19 ppm (s, 2H); 13C NMR: d=ꢁ4.7, ꢁ4.2, 14.1, 18.0, 22.6, 23.5 (2C),
24.69 (2C), 24.72 (2C), 24.8, 25.8 (3C), 29.3, 29.52, 29.54, 29.59 (3C),
29.63 (2C), 29.8, 30.2, 30.4, 31.9, 33.7, 34.2, 69.6, 72.76, 72.80, 75.4, 123.8
(2C), 129.1, 150.8 (2C), 153.8 ppm; IR (KBr): n˜ =3300, 1463, 1178 cmꢁ1
;
MS (FAB): m/z: 699 [M+H]+; HRMS (FAB): m/z calcd for C39H75O6SSi:
699.5054; found: 699.5041 [M+H]+.
Chem. Eur. J. 2005, 11, 6237 – 6245
ꢁ 2005 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
www.chemeurj.org
6243

T.Tanaka et al.
(2R,5S,6S)-6-(tert-Butyldimethylsiloxy)-2,5-epoxyoctadecan-1-ol
(24):
29.74, 29.8, 31.9, 32.7, 34.0, 34.3, 36.9, 70.2, 74.2, 74.6, 77.4, 81.5, 82.1,
130.8, 151.4, 174.0 ppm; IR (KBr): n=3509, 1761, 1657 cmꢁ1; MS (FAB):
m/z: 810 [M+H]+; HRMS (FAB): m/z calcd for C47H93O6Si2: 809.6511;
found: 809.6546 [M+H]+.
K2CO3 (730 mg, 5.28 mmol) was added to a mixture of 22 (739 mg,
1.06 mmol) with stirring at 08C.After 2 h at the same temperature, the
whole mixture was stirred for 66.5 h at room temperature. Water was
added to the reaction mixture.The mixture was extracted with EtOAc
and the combined organic layers were washed with brine prior to drying
and solvent evaporation.Purification by column chromatography on
silica gel (hexane/EtOAc 10:1) yielded 24 (307 mg, 70%) as a colorless
(5S)-3-[(2R,13R)-2,13-Dihydroxy-13-[(2R,5S)-5-[(1S)-1-hydroxytridecyl]-
tetrahydrofuran-2-yl]tridecyl]-5-methyl-2,5-dihydrofuran-2-one
(16,19-
cis-murisolin, 2): The procedure was the same as that used for the prepa-
ration of 1.Compound 2 (20.9 mg, 85%) was prepared from 28 (34.3 mg,
0.0424 mmol) as a colorless waxy solid. M.p.=76.5–77.58C; [a]2D7 =+11.3
(c=0.62 in CH2Cl2); 1H NMR: d=0.88 (t, J=7.0 Hz, 3H), 1.23–1.53 (m,
42H), 1.43 (d, J=6.7 Hz, 3H), 1.71–1.78 (m, 2H), 1.90–1.97 (m, 2H),
2.40 (dd, J=15.3, 8.5 Hz, 1H), 2.48 (brs, 1H), 2.52 (ddd, J=15.3, 1.8,
1.2 Hz, 1H), 2.66 (brs, 2H), 3.42 (dt, J=7.3, 4.9 Hz, 2H), 3.80–3.86 (m,
3H), 5.06 (qd, J=6.7, 1.2 Hz, 1H), 7.19 ppm (d, J=1.2 Hz, 1H);
13C NMR: d=14.1, 19.1, 22.7, 25.5, 25.6, 25.7, 28.1 (2C), 29.3, 29.4, 29.5
(2C), 29.59 (3C), 29.60 (3C), 29.64 (2C), 29.7, 31.9, 33.3, 34.03, 34.04,
37.4, 69.9, 74.3 (2C), 78.0, 82.7 (2C), 131.1, 151.8, 174.7 ppm; IR (KBr):
n˜ =3438, 3342, 2918, 2848, 1747, 1649, 1469, 1315, 1203, 1120, 1074, 1028,
968, 849, 721 cmꢁ1; MS (FAB): m/z: 581 [M+H]+; HRMS (FAB): m/z
calcd for C35H65O6: 581.4781; found: 581.4763 [M+H]+.
1
oil.[ a]2D3 =+3.2 (c=0.95, CHCl3).The spectral data ( H NMR, 13C NMR,
and MS spectra) were identical to those reported for the enantiomer of
24.[7b]
(2R,5S,6S)-6-(tert-Butyldimethylsiloxy)-2,5-epoxyoctadecanal (25): Dess–
Martin periodinane (1.16 g, 2.74 mmol) was added to a solution of 24
(284 mg, 0.685 mmol) in pyridine (0.62 mL) and CH2Cl2 (7.5 mL) with
stirring at 08C.After 05. h at the same temperature, the whole mixture
was stirred for 3 h at room temperature.The mixture was filtered through
silica gel and the filtrate was concentrated under the reduced pressure.
Purification by flash column chromatography (hexane/EtOAc 30:1) yield-
ed 25 (183 mg, 65%) as colorless oil.The aldehyde was unstable and was
therefore used immediately in the next step.
(8S,9S,12R,13R)-13-(tert-Butyldimethylsilyloxy)-9,12-epoxy-pentacosa-
1,6-diyn-8-ol (ent-26): The procedure was the same as that used for the
preparation of 12.The compound ent-26 (105 mg, 79%) was prepared
from ent-25 (109 mg, 0.265 mmol) as a pale yellow oil. [a]2D7 =ꢁ8.0 (c=
1.06 in CHCl3).The spectral data ( 1H NMR, 13C NMR, and MS spectra)
were identical to those of 26.
(8R,9R,12S,13S)-13-(tert-Butyldimethylsilyloxy)-9,12-epoxy-pentacosa-
1,6-diyn-8-ol (26): The procedure was the same as that used for the prep-
aration of 9.Compound 26 (160 mg, 79%) was prepared from 25
(166 mg, 0.401 mmol) as
a
pale yellow oil. [a]2D5 =+6.8 (c=1.02 in
CHCl3); 1H NMR: d=0.078 (s, 3H), 0.081 (s, 3H), 0.88 (t, J=7.0 Hz,
3H), 0.90 (s, 9H), 1.23–1.45 (m, 21H), 1.60–1.67 (m, 1H), 1.73 (qn, J=
7.0 Hz, 2H), 1.77–1.91 (m, 3H), 1.95 (t, J=2.4 Hz, 1H), 1.99 (dq, J=
12.8, 7.9 Hz, 1H), 2.30 (td, J=7.0, 2.4 Hz, 2H), 2.35 (td, J=7.0, 1.8 Hz,
2H), 2.90 (d, J=4.3 Hz, 1H), 3.58 (td, J=6.1, 3.7 Hz, 1H), 3.98–4.02 (m,
2H), 4.16 ppm (brs, 1H); 13C NMR: d=ꢁ4.6, ꢁ4.4, 14.1, 17.5, 17.8, 18.2,
22.6, 25.4, 25.9 (3C), 27.0, 27.4, 28.1, 29.3, 29.55, 29.59 (3C), 29.62, 29.8,
31.9, 33.9, 65.5, 68.7, 74.3, 79.6, 82.10, 82.12, 83.4, 84.3 ppm; IR (KBr):
n˜ =3450, 3313, 2231, 2119 cmꢁ1; MS (FAB): m/z: 505 [M+H]+; HRMS
(FAB): m/z calcd for C31H57O3Si: 505.4077; found: 505.4091 [M+H]+.
(5S)-3-[(E,2R,13S)-2-(tert-Butyldimethylsilyloxy)-13-hydroxy-13-
[(2S,5R)-5-[(1R)-1-(tert-butyldimethylsilyloxy)tridecyl]tetrahydrofuran-2-
yl]tridec-4-ene-6,11-diynyl]-5-methyl-2,5-dihydrofuran-2-one (29): The
procedure was the same as that used for the preparation of 17.Com-
pound 29 (170 mg, 78%) was prepared from ent-26 (138 mg, 0.273 mmol)
and 5 (115 mg, 0.273 mmol) as a yellow oil. [a]2D6 =ꢁ9.2 (c=0.95 in
CHCl3); 1H NMR: d=0.01 (s, 3H), 0.05 (s, 3H), 0.068 (s, 3H), 0.072 (s,
3H), 0.86–0.90 (m, 3H), 0.87 (s, 9H), 0.90 (s, 9H), 1.22–1.46 (m, 21H),
1.41 (d, J=6.7 Hz, 3H), 1.59–1.65 (m, 1H), 1.69–1.90 (m, 5H), 1.95–2.02
(m, 1H), 2.20–2.30 (m, 2H), 2.33 (td, J=7.0, 1.8 Hz, 2H), 2.37–2.42 (m,
4H), 2.89 (brd, J=3.7 Hz, 1H), 3.58 (td, J=6.1, 4.3 Hz, 1H), 3.97–4.01
(m, 2H), 4.04 (qn, J=5.5 Hz, 1H), 4.15 (brs, 1H), 5.00 (qd, J=6.7,
1.2 Hz, 1H), 5.46 (dt, J=15.9, 1.8 Hz, 1H), 6.03 (dt, J=15.9, 7.3 Hz, 1H),
7.11 ppm (d, J=1.2 Hz, 1H); 13C NMR: d=ꢁ4.7, ꢁ4.6, ꢁ4.5, ꢁ4.3, 14.1,
17.9, 18.0, 18.2, 18.5, 18.9, 22.6, 25.4, 25.8 (3C), 25.9 (3C), 27.0, 27.7, 28.1,
29.3, 29.55, 29.59 (3C), 29.62, 29.8, 31.9, 32.8, 33.9, 40.7, 65.5, 69.2, 74.3,
77.5, 79.4, 79.5, 82.1, 82.2, 84.6, 88.2, 112.7, 130.6, 138.4, 151.8, 173.7 ppm;
IR (KBr): n˜ =3480, 2222, 1759, 1655 cmꢁ1; MS (FAB): m/z: 800 [M+H]+;
HRMS (FAB): m/z calcd for C47H83O6Si2: 799.5728; found: 799.5700
[M+H]+.
(5S)-3-[(E,2R,13R)-2-(tert-Butyldimethylsilyloxy)-13-hydroxy-13-
[(2R,5S)-5-[(1S)-1-(tert-butyldimethylsilyloxy)tridecyl]tetrahydrofuran-2-
yl]tridec-4-ene-6,11-diynyl]-5-methyl-2,5-dihydrofuran-2-one (27): The
procedure was the same as that used for the preparation of 17.Com-
pound 27 (98.7 mg, 73%) was prepared from 26 (85.6 mg, 0.170 mmol)
and 5 (71.6 mg, 0.170 mmol) as a yellow oil. [a]2D4 =ꢁ3.0 (c=0.75 in
CHCl3); 1H NMR: d=0.01 (s, 3H), 0.06 (s, 3H), 0.07 (s, 3H), 0.08 (s,
3H), 0.86–0.90 (m, 3H), 0.87 (s, 9H), 0.90 (s, 9H), 1.23–1.47 (m, 21H),
1.42 (d, J=6.7 Hz, 3H), 1.58–1.65 (m, 1H), 1.70–1.91(m, 5H), 1.94–2.03
(m, 1H), 2.23–2.31 (m, 2H), 2.33 (td, J=7.3, 1.8 Hz, 2H), 2.38–2.43 (m,
2H), 2.42 (d, J=6.1 Hz, 2H), 2.87 (d, J=4.9 Hz, 1H), 3.58 (td, J=6.1,
4.3 Hz, 1H), 3.97–4.01 (m, 2H), 4.05 (qn, J=6.1 Hz, 1H), 4.15–4.17 (m,
1H), 5.01 (qd, J=6.7, 1.2 Hz, 1H), 5.47 (d, J=15.9 Hz, 1H), 6.03 (dt, J=
15.9, 7.9 Hz, 1H), 7.11 ppm (brs, 1H); 13C NMR: d=ꢁ4.7, ꢁ4.6, ꢁ4.5,
ꢁ4.3, 14.1, 17.92, 17.95, 18.2, 18.5,18.8, 22.6, 25.4, 25.8 (3C), 25.9 (3C),
27.0, 27.7, 28.1, 29.3, 29.5, 29.57 (3C), 29.61, 29.8, 31.9, 32.7, 33.9, 40.7,
65.5, 69.2, 74.3, 77.4, 79.4, 79.5, 82.1, 82.2, 84.6, 88.2, 112.7, 130.6, 138.4,
151.7, 173.7 ppm; IR (KBr): n˜ =3484, 2222, 1759, 1653 cmꢁ1; MS (FAB):
m/z: 800 [M+H]+; HRMS (FAB): m/z calcd for C47H83O6Si2: 799.5728;
found: 799.5710 [M+H]+.
(5S)-3-[(2R,13S)-2-(tert-Butyldimethylsilyloxy)-13-hydroxy-13-[(2S,5R)-
5-[(1R)-1-(tert-butyldimethylsilyloxy)tridecyl]tetrahydrofuran-2-yl]tridec-
yl]-5-methyl-2,5-dihydrofuran-2-one (30): The procedure was the same as
the diimide reduction used for the preparation of 18.Compound 30
(37.0 mg, 61%) was prepared from 29 (60.0 mg, 0.0751 mmol) as a color-
less oil.[ a]2D8 =+2.1 (c=1.09 in CHCl3); 1H NMR: d=0.01 (s, 3H), 0.04
(s, 3H), 0.06 (s, 3H), 0.07 (s, 3H), 0.86–0.89 (m, 3H), 0.86 (s, 9H), 0.89
(s, 9H), 1.22–1.48 (m, 41H), 1.41 (d, J=6.7 Hz, 3H), 1.60 (dq, J=14.0,
6.7 Hz, 1H), 1.71–1.92 (m, 4H), 2.41 (d, J=5.5 Hz, 2H), 3.36 (ddd, J=
7.9, 5.5, 4.3 Hz, 1H), 3.57 (td, J=6.1, 3.7 Hz, 1H), 3.77 (dt, J=6.7,
5.5 Hz, 1H), 3.89–3.97 (m, 2H), 5.00 (qd, J=6.7, 1.2 Hz, 1H), 7.12 ppm
(s, 1H); 13C NMR: d=ꢁ4.53, ꢁ4.49, ꢁ4.48, ꢁ4.3, 14.1, 18.0, 18.2, 18.9,
22.7, 25.1, 25.4, 25.8, 25.85 (3C), 25.93 (3C), 27.4, 28.2, 29.3, 29.58 (3C),
29.59 (3C), 29.62 (2C), 29.65, 29.69, 29.74, 29.8, 31.9, 32.7, 34.0, 34.3,
36.9, 70.2, 74.2, 74.6, 77.4, 81.5, 82.1, 130.8, 151.4, 174.0 ppm; IR (KBr):
n˜ =3510, 1761, 1658 cmꢁ1; MS (FAB): m/z: 810 [M+H]+; HRMS (FAB):
m/z calcd for C47H93O6Si2: 809.6511; found: 809.6536 [M+H]+.
(5S)-3-[(2R,13R)-2-(tert-Butyldimethylsilyloxy)-13-hydroxy-13-[(2R,5S)-
5-[(1S)-1-(tert-butyldimethylsilyloxy)tridecyl]tetrahydrofuran-2-yl]tridec-
yl]-5-methyl-2,5-dihydrofuran-2-one (28): The procedure was the same as
the diimide reduction used for the preparation of 18.Compound 28
(45.5 mg, 60%) was prepared from 27 (73.7 mg, 0.0922 mmol) as a yellow
oil.[ a]2D6 =+14.1 (c=0.95 in CHCl3); 1H NMR: d=0.01 (s, 3H), 0.04 (s,
3H), 0.06 (s, 3H), 0.07 (s, 3H), 0.86–0.89 (m, 3H), 0.86 (s, 9H), 0.89 (s,
9H), 1.25–1.51 (m, 41H), 1.41 (d, J=6.7 Hz, 3H), 1.56–1.63 (m, 1H),
1.70–1.93 (m, 4H), 2.41 (d, J=5.5 Hz, 2H), 2.65 (brd, J=2.4 Hz, 1H),
3.35–3.37 (m, 1H), 3.57 (td, J=5.5, 4.3 Hz, 1H), 3.77 (dt, J=7.3, 5.5 Hz,
1H), 3.91 (td, J=6.7, 4.3 Hz, 1H), 3.94 (qn, J=5.5 Hz, 1H), 5.00 (qd, J=
6.7, 1.2 Hz, 1H), 7.11 ppm (d, J=1.2 Hz, 1H); 13C NMR: d=ꢁ4.53,
ꢁ4.49, ꢁ4.47, ꢁ4.3, 14.1, 18.0, 18.2, 19.0, 22.7, 25.1, 25.4, 25.8, 25.85 (3C),
25.93 (3C), 27.4, 28.2, 29.3, 29.57 (4C), 29.61 (3C), 29.65 (2C), 29.69,
(5S)-3-[(2R,13S)-2,13-Dihydroxy-13-[(2S,5R)-5-[(1R)-1-hydroxytridecyl]-
tetrahydrofuran-2-yl]tridecyl]-5-methyl-2,5-dihydrofuran-2-one (unnatu-
ral 16,19-cis-murisolin, 3): The procedure was the same as that used for
the preparation of 1.Compound 3 (21.1 mg, 82%) was prepared from 30
(36.1 mg, 0.0446 mmol) as a colorless waxy solid. M.p.=65.0–66.08C;
6244
www.chemeurj.org
ꢁ 2005 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
Chem. Eur. J. 2005, 11, 6237 – 6245

Murisolin Synthesis and Evaluation
FULL PAPER
[a]2D9 =+9.1 (c=0.50 in CH2Cl2); 1H NMR: d=0.88 (t, J=7.0 Hz, 3H),
1.26–1.51 (m, 42H), 1.43 (d, J=6.7 Hz, 3H), 1.72–1.79 (m, 2H), 1.88–1.97
(m, 2H), 2.33–2.64 (m, 3H), 2.40 (dd, J=15.3, 8.5 Hz, 1H), 2.52 (ddd, J=
15.3, 1.8, 1.2 Hz, 1H), 3.42 (dt, J=7.3, 5.5 Hz, 2H), 3.80–3.87 (m, 3H),
5.06 (qd, J=6.7, 1.2 Hz, 1H), 7.19 ppm (d, J=1.2 Hz, 1H); 13C NMR:
d=14.1, 19.1, 22.7, 25.5, 25.6, 25.7, 28.1 (2C), 29.3, 29.40, 29.43, 29.5
(3C), 29.62 (3C), 29.64 (3C), 29.7, 31.9, 33.3, 34.0, 34.1, 37.4, 70.0, 74.3
(2C), 78.0, 82.7 (2C), 131.2, 151.8, 174.6 ppm; IR (KBr): n˜ =3444, 3340,
2918, 2850, 1747, 1716, 1651, 1464, 1321, 1205, 1120, 1093, 1030, 971, 850,
721 cmꢁ1; MS (FAB): m/z: 581 [M+H]+; HRMS (FAB): m/z calcd for
C35H65O6: 581.4781; found: 581.4795 [M+H]+.
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We thank Prof.D.Cortes, University of Valencia, for providing us with
13C NMR spectroscopic data of murisolin and Prof.D.P.Curran, Univer-
sity of Pittsburgh, for identification of our murisolin by comparison with
their synthetic sample by 1H NMR spectroscopy and HPLC.We also
thank the Screening Committee of New Anticancer Agents supported by
a Grant-in-Aid for Scientific Research on Priority Area “Cancer” from
The Ministry of Education, Culture, Sports, Science and Technology,
Japan, for biological evaluation of compounds 1–3.Financial support was
provided by a Grant-in-Aid for Scientific Research (C) from the Japan
Society for the Promotion of Science (no.16590006) and a Grant-in-Aid
for Scientific Research on Priority Areas (no.17035052) from The Minis-
try of Education, Culture, Sports, Science and Technology (MEXT).We
also thank the Research Foundation for Pharmaceutical Sciences and the
Suntory Institute for Bioorganic Research for financial support.NK. .is
grateful for a Research Fellowship of the Japan Society for the Promo-
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[19] Prof.Curran reported that two 16,19- cis-murisolins, 2 and 3, were
distinguished by HPLC analysis with Daicel Chiralcel OD.[5] The re-
sults were confirmed in our laboratory.
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Received: April 23, 2005
Casiraghi, F.Zanardi, L.Battistini, G.Rassu,
Chemtracts: Org.
Published online: August 1, 2005
Chem. Eur. J. 2005, 11, 6237 – 6245
ꢁ 2005 Wiley-VCH Verlag GmbH & Co.KGaA, Weinheim
www.chemeurj.org
6245