Synthesis of chiloscyphones and the biological activities of their synthetic intermediates against methicillin-resistant Staphylococcus aureus (MRSA)

Article abstract of DOI:10.1002/ejoc.200500928

The total syntheses of chiloscyphone (1) and isochiloscyphone (2) have been achieved. Furthermore, the synthetic intermediate 5 shows biological activity against methicillin-resistant Staphyrococcus aureus, and compounds 5, 17, and 18, display imipenem-ty

Full text of DOI:10.1002/ejoc.200500928

FULL PAPER
DOI: 10.1002/ejoc.200500928
Synthesis of Chiloscyphones and the Biological Activities of Their Synthetic
Intermediates Against Methicillin-Resistant Staphylococcus aureus (MRSA)
Junichi Shiina,[a] Rika Obata,[a] Hiroshi Tomoda,[b] and Shigeru Nishiyama*[a]
Keywords: Antimicrobial activity / Bioorganic chemistry / Cyclization / Medicinal chemistry / MRSA / Natural products
The total syntheses of chiloscyphone (1) and isochiloscy-
phone (2) have been achieved. Furthermore, the synthetic
intermediate 5 shows biological activity against methicillin-
resistant Staphyrococcus aureus, and compounds 5, 17, and
18, display imipenem-type activity. The tricyclic lactone
framework, which includes an α,β-unsaturated ketone moi-
ety, might play a crucial role in the anti-MRSA activity.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
have attractive and important dispositions from the view-
point of biological evaluation and organic synthesis.[7]
However, the structure–activity relationship studies of these
natural products and their derivatives have been limited ow-
ing to the difficulty of functional-group arrangement, even
though their congeners would provide a considerable
amount of information. Against such a background, we
have constructed potent intermediates possessing the bicy-
clo[4.3.0]nonane framework towards the total synthesis of
1 and 2, and submitted them to assessment for a variety of
antimicrobial activities (Gram-positive and Gram-negative
bacteria). We describe herein a practical synthesis, as well
as the biological activities, of these synthetic intermediates.
Introduction
It has been known for a long time that liverwort extracts
show a variety of antimicrobial activities,[1] and many natu-
ral products with attractive biological activities, such as an-
ticancer, fish-killing, and antifeedant properties, have been
isolated from the liverwort.[2] In addition, a bicyclo[4.3.0]-
nonane framework is shared by such members as chiloscy-
phone (1),[3] isochiloscyphone (2),[4] acutifolone A (3),[5]
and pinguisenol (4; Figure 1).[6] These natural products
Results and Discussion
Synthesis
We have recently reported the construction of a bicy-
clo[4.3.0]nonane structure carrying cis-oriented continuous
substitution by the intramolecular Diels–Alder reaction.[8]
In this previous paper, we revealed that our synthetic route
towards natural products from the liverwort is more effec-
tive than the conventional methodologies[9] from the view-
points of not only being able to construct the bicyclo[4.3.0]-
nonane framework but also to introduce a variety of func-
tional groups into desired positions. In a retrosynthetic
analysis, 1 and 2 would be obtained from the synthetic in-
termediate 5, which proved to be a practical common inter-
mediate and could be readily obtained from the triene 6.
Synthesis of the Diels–Alder precursors 6 and 14 com-
menced by treatment of 7[10] with butadienyllithium[11] to
give 8, which, upon protection with a TBDPS group, fur-
nished 9 (Scheme 1). Selective removal of the TBS group
produced 10, which was sequentially oxidized with SO3·py,
DMSO, and Et3N, and then PDC to provide the carboxylic
Figure 1. Sesquiterpenoids isolated from the liverwort.
[a] Department of Chemistry, Faculty of Science and Technology,
Keio University,
Hiyoshi 3-14-1, Kohoku-ku, Yokohama 223-8522, Japan
Fax: +81-45-566-1717
E-mail: nisiyama@chem.keio.ac.jp
[b] Laboratory of Microbial Chemistry, School of Pharmaceutical
Sciences, Kitasato University,
Shirokane 5-9-1, Minato-ku, Tokyo 108-8641, Japan
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Synthesis of Chiloscyphones and Biological Activities Against MRSA
FULL PAPER
Scheme 1. Reagents and conditions: (a) (E)-nBu3SnCH=CHCH=CH2, nBuLi, THF, –78 °C, 93%; (b) TBDPSCl, Imid, DMF, room
temp., 100%; (c) PPTS, EtOH, room temp., 95%; (d) SO3·py, DMSO, Et3N, CH2Cl2, 0 °C; (e) PDC, DMF, room temp., 82% in two
steps; (f) K2CO3, MeI, DMF, 0 °C, 99%; (g) LDA, THPOCH2CHO, THF, –78 °C, 95%; (h) PPTS, MeOH, room temp.; (i) Et3N, MeOH,
room temp.; (j) Ac2O, py, room temp.; (k) DBU, PhMe, 0 °C, 87% in four steps; (l) TBAF, AcOH, THF, room temp., 92%.
acid 11. After esterification, ester 12 was submitted to an
aldol reaction with THPOCH2CHO to give 13. Removal
of the THP group, followed by cyclization under the basic
conditions, afforded the corresponding five-membered lac-
tone, a secondary alcohol of which was acetylated, followed
by elimination to give the triene 14. Subsequent removal of
the TBDPS group furnished the triene 6.
The trienes 6 and 14 were subjected to an intramolecular
Diels–Alder reaction (Scheme 2, Table 1), and triene 14 was
studied first under a variety of Lewis acidic conditions.
With Et2AlCl, ZnCl2, or LiClO4 as Lewis acid the desired
tricyclic 15 was not obtained (entries 1, 3, and 4). Reaction
with a stronger Lewis acid such as EtAlCl2 was also unsuc-
cessful due to removal of the TBDPS group and concomi-
tant undesired rearrangement (entry 2). Heating 14 at
180 °C in toluene in a sealed tube in the presence of BHT,
however, provided the expected product 15 (entry 5). The
reason for the low yield in this reaction might be due to its
slow reaction rate, which causes considerable amounts of
unreacted 14 to remain. Ultimately, use of the triene 6,
which contains a free hydroxy group, gave the desired tricy-
clic compound 16 in high yield as a diastereomeric mixture
(1:1.1:0.6, entry 6). Other solvents and radical inhibitors
had no effect on the high yield of this procedure (entries 7
and 8).
Scheme 2. Intramolecular Diels–Alder reaction.
Table 1. Intramolecular Diels–Alder reaction.
Entry Substrate Reagents and conditions
Results
1
2
3
14
Et2AlCl, CH2Cl2, r.t.
EtAlCl2, CH2Cl2, –78 °C
ZnCl2, PhMe, 70 °C
no reaction
dec.
no reaction
no reaction
15 (13%)[b]
16 (83%)[b]
16 (72%)[b]
16 (24%)[b]
4
LiClO4, CH3NO2, 80 °C
BHT, PhMe, 180 °C
BHT, PhMe, 180 °C
BHT, PhH, 180 °C
methylene blue, PhMe, 180 °C
5[a]
6[a]
7[a]
8[a]
6
[a] Reactions were carried out in a sealed tube. [b] A diastereomeric
mixture was obtained (1:1.1:0.6).
The tricyclic compound 16 was then oxidized, followed of 19 with a TBDPS group, selective epoxidation of the tri-
by isomerization with DBU to afford the important inter- substituted olefin and reductive opening by LiEt3BH gave
mediate 5, which was converted under the Ito–Saegusa con- 21. In this process, the β-epoxide is obtained by attack of
ditions[12] into the dienone 17. Modification of the adjacent the reagent at the convex face. Oxidative cleavage of the
β-face lactone moiety by selective Michael addition of a terminal olefin furnished an aldehyde, which, upon re-
vinyl group furnished 18 as a single product. Selective re- duction, afforded the diol 22. Compound 22 was protected
duction of the unsaturated ketone, mesylation, and elimi- as an MPM ether to give 23, which was treated with SOCl2
nation provided a tri-substituted olefin, which was further at –30 °C, followed by removal of the TBDPS group, to
reduced with DIBAL-H to give the diol 19. After protection afford a mixture of chromatographically separable 24 and
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J. Shiina, R. Obata, H. Tomoda, S. Nishiyama
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Scheme 3. Reagents and conditions: (a) TFAA, DMSO, Et3N, CH2Cl2, –60 °C; (b) DBU, PhMe, 0 °C, 87% in two steps; (c) TMSOTf,
Et3N, CH2Cl2, 0 °C; (d) Pd(OAc)2, CH3CN, room temp., 98% in two steps; (e) CH2=CHMgBr, CuI, THF, –78 °C, 75%; (f) NaBH4,
MeOH, 0 °C; (g) MsCl, py, room temp.; (h) AcOK, DMF, H2O, 80 °C; (i) DIBAL-H, CH2Cl2, 0 °C, 75% in four steps; (j) TBDPSCl,
Imid, DMF, 0 °C, 97%; (k) mCPBA, NaH2PO4, CH2Cl2, –20 °C; (l) LiEt3BH, THF, room temp., 74% in two steps; (m) OsO4, Me3NO,
acetone, H2O, room temp., then NaIO4, NaH2PO4, room temp.; (n) NaBH4, MeOH, 0 °C, 58% in two steps; (o) MPMCl, NaH, nBu4NI,
DMF, 0 °C, 70%; (p) SOCl2, py, –30 °C; (q) TBAF, THF, 50 °C, 94 % (24: 18%, 25: 76%) in two steps; (r) TBDPSCl, Imid, DMF, 0 °C;
(s) DDQ, CH2Cl2, H2O, 0 °C; (t) IBX, DMSO, THF, room temp.; (u) Ph3PCH3Br, NaHMDS, THF, –40 °C, 65% in four steps.
25. The regioisomer of the olefin was confirmed by trans- Evaluation of the Antimicrobial Activity
formation of 25 into the precursor 20. Compounds 24 and
25 were then used for synthesis of 1 and 2 (Scheme 3).
The obtained synthetic intermediates 5, 6, and 17–19,
Deoxygenation of the diol moiety of 24 was examined were assessed for various antimicrobial activities against
first (Scheme 4). Compound 24 was converted into the thio- Bacillus subtilis PCI 219, Staphylococcus aureus FDA 209P,
ester 26, which was treated with nBu3SnH to afford an un- methicillin-resistant Staphyrococcus aureusK-24 (a clinical
known compound that is probably produced by intramolec- isolate, MRSA), Micrococcus luteus PCI 1001, Mycobacte-
ular radical coupling. Alternatively, 24 was mesylated to rium smegmatis ATCC 607, Escherichia coli NIHJ, Escher-
give 27, which was deoxygenated under hydride reduction ichia coli NIHJJ-2 IFO 12734, Pseudomonas aeruginosa P-3,
conditions with LiAlH4 in Et2O, LiEt3BH in THF, or Xanthomonas campestris pv. oryzae KB 88, Bacteroides fra-
NaBH4 in DMSO to furnish the undesired cyclic com- gilis ATCC 23745, Acholeplasma laidlawii PG 8, Pyricularia
pound 28 by cleavage of the S–O bond and successive cycli- oryzae KF 180, Aspergillus niger ATCC 6275, Mucor ra-
zation. The dimesylated derivative 27 was converted into cemosus IFO 4581, Candida albicans ATCC 64548, and
the cyclic sulfide 29, which was desulfurized with Raney Ni Saccharomyces cerevisiae.[14] Among these, methicillin-re-
W-4[13] to afford the desired deoxygenated product 30.
sistant Staphyrococcus aureus (MRSA) is a drug-resistant
To complete the total synthesis of chiloscyphone 1 and bacteria that cause serious infections, therefore chemicals
isochiloscyphone 2, removal of the MPM group of 30 gave with significant potential as leads for the development of
the alcohol 31, which was oxidized, followed by alkylation anti-bacterial drugs are urgently required. As shown in
and further oxidation, to afford 1 (Scheme 5). The yields of Table 2, compound 17 shows antimicrobial activity against
the desired product were improved by using the mild oxi- B. subtilis, S. aureus, M. luteus, E. coli NIHJ, X. oryzae, and
dation conditions with IBX. Compound 25 was converted A. liadlawii, as well as anti-MRSA activity. It is thought
into 2 in a similar way. The spectroscopic data of the syn- that the two unsaturated ketone groups of 17 strongly affect
thetic 1 and 2 were superimposable with those of the natu- these bacterial pathogens. Furthermore, 17 potentiates the
ral products.[4,5]
imipenem activity, and 5 and 18 also showed selective po-
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Synthesis of Chiloscyphones and Biological Activities Against MRSA
FULL PAPER
Scheme 5. Reagents and conditions: (a) DDQ, CH2Cl2, H2O, 0 °C,
92%; (b) IBX, DMSO, THF, room temp.; (c) CH2=C(Me)MgBr,
THF, 0 °C; (d) IBX, DMSO, THF, room temp., 75% in three steps;
(e) MsCl, py, room temp.; (f) Na2S·9H2O, DMF, 50 °C; (g) Raney
Ni W-4, THF, room temp., 60% in three steps; (h) DDQ, CH2Cl2,
H2O, 0 °C, 85%; (i) IBX, DMSO, THF, room temp.; (j)
CH2=C(Me)MgBr, THF, 0 °C; (k) IBX, DMSO, THF, room temp.,
73% in three steps.
Scheme 4. Reagents and conditions: (a) DBU, CS2, MeI, DMF,
room temp.; or (Imid)2CS, pyr, room temp.; (b) nBu3SnH, AIBN,
benzene, reflux; (c) MsCl, py, room temp.; (d) LiAlH4, Et2O, reflux;
or LiEt3BH, THF, reflux; or NaBH4, DMSO, 100 °C; (e)
Na2S·9H2O, DMF, 50 °C; (f) Raney Ni W-4, THF, room temp.,
66% in three steps.
Table 2. Antimicrobial activity.[a]
tentiation of imipenem activity. A tricyclic lactone structure
including an α,β-unsaturated ketone might therefore be ef-
fective in potentiating imipenem activity against MRSA.
6
5
17 18 19
Bacillus subtilis
–
–
–
–
–
–
–
–
10
–
–
–
–
–
–
–
11 44
–
–
–
14
–
25 22
–
–
–
–
–
–
–
–
–
–
–
–
–
12
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
Staphylococcus aureus
Micrococcus luteus
19
23
15
–
Conclusions
Esherichia coli[b]
Esherichia coli[c]
We have achieved the total synthesis of chiloscyphone (1)
and isochiloscyphone (2) from the key intermediate 5,
which was synthesized effectively by an intramolecular Di-
els–Alder reaction. The synthetic intermediates 5, 17, and
18 exhibit biological activity against MRSA and/or potenti-
ation of imipenem activity. The tricyclic derivatives might
be essential for anti-MRSA activity. It is expected that these
results will contribute to the development of new anti-
MRSA drugs. A detailed structure–activity relationship
study is now in progress.
Pseudomonas aeruginosa
Xanthomonas campestris pv. oryzae
Bacteroides fragilis
Acholeplasma laidlawii
Pyricularia oryzae
Aspergillus niger
Mucor racemosus
–
–
21
–
–
–
–
–
–
16
Candida albicans
Saccharomyces cerevisiae
Mycobacterium smegmatis
Methicillin-resistant Staphylococcus
aureus
Potentiation of imipenem
–
15 30 20
–
Experimental Section
[a] The values indicate the diameter of the inhibitory zone on the
plates in mm. [b] Escherichia coli NIHJ. [c] Escherichia coli NIHJJ-2
IFO 12734.
General: IR spectra were recorded with a JASCO Model A-202
spectrophotometer. 1H NMR spectra were recorded at 400 MHz,
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J. Shiina, R. Obata, H. Tomoda, S. Nishiyama
FULL PAPER
and 13C NMR spectra were recorded at 100 MHz with JEOL JNM
GX-400 spectrometers with CDCl3 as solvent and tetramethylsilane
as internal standard. High-resolution mass spectra were obtained
with a Hitachi M-80 B GC-MS spectrometer operating at an ion-
ization energy of 70 eV. Silica gel column chromatography was car-
ried out using Kanto Chemical silica 60 N (spherical, neutral, 63–
210 µm). Thin-layer chromatography (TLC) was carried out on
0.25-mm precoated silica gel plates of silica gel 60 F254 (E. Merck,
Darmstadt) and visualized with either UV (254 nm) or 5% phos-
phomolybdic acid in ethanol.
(6E)-5-(tert-Butyldiphenylsiloxy)nona-6,8-dienoic Acid (11): SO3·py
(25.0 g, 157 mmol) was added to a solution of 10 (20.7 g, 53 mmol)
in DMSO (50 mL), CH2Cl2 (50 mL), and Et3N (50 mL) at 0 °C;
the resulting solution was stirred at the same temperature for
30 min. After the addition of 1  HCl at 0 °C, the resulting slurry
was partitioned between EtOAc and H2O. The combined organic
layers were washed with saturated aq. NaHCO3, brine, dried
(Na2SO4), and concentrated in vacuo. A mixture of the crude resi-
due and PDC (40.0 g, 106 mmol) in DMF (110 mL) was stirred at
room temperature for 8 h. After the addition of H2O at 0 °C, the
resulting slurry was partitioned between EtOAc/hexane and H2O,
the combined organic layers were dried (Na2SO4), and concen-
trated in vacuo. Purification by silica gel column chromatography
(hexane/EtOAc, 20:1Ǟ1:1) gave 11 (17.6 g, 82% in two steps) as a
(3E)-9-(tert-Butyldimethylsiloxy)nona-1,3-dien-5-ol
(8):
nBuLi
(1.58  solution in hexane; 21 mL, 33 mmol) was added dropwise
to a solution of (E)-nBu3SnCH=CHCH=CH2 (11.7 g, 34 mmol) in
THF (40 mL) at –78 °C; the resulting solution was stirred at the
same temperature for 20 min. A solution of 7 (8.09 g, 37 mmol) in
THF (10 mL) was then added dropwise at the same temperature
and the mixture stirred for another 10 min. After the addition of
saturated aq. NH4Cl at 0 °C, the resulting slurry was partitioned
between EtOAc and H2O. The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated in vacuo. Pu-
rification by silica gel column chromatography (hexane/EtOAc,
colorless oil. IR (film): ν = 2931, 2858, 1709 cm–1 1H NMR: δ =
˜
7.68–7.62 (complex, 4 H), 7.42–7.33 (complex, 6 H), 6.21 (m, 1 H),
5.89 (m, 1 H), 5.61 (dd, J = 6.6, 15.3 Hz, 1 H), 5.05 (d, J = 16.2 Hz,
1 H), 5.02 (d, J = 9.7 Hz, 1 H), 4.19 (m, 1 H), 2.21 (t, J = 6.6 Hz,
2 H), 1.63–1.49 (complex, 4 H), 1.06 (s, 9 H) ppm. 13C NMR: δ =
180.8, 136.3, 135.8, 134.1, 133.9, 130.9, 129.5, 129.4, 127.4, 127.3,
116.8, 73.4, 37.0, 33.7, 27.1, 19.8, 19.4 ppm. HRMS: calcd. for
C25H32O3Si [M+] 408.2121; found 408.2110.
20:1Ǟ10:1) gave 8 (8.33 g, 93%) as a colorless oil. IR (film): ν =
˜
3359, 2931, 2858 cm–1. 1H NMR: δ = 6.40–6.17 (complex, 2 H),
5.71 (dd, J = 6.8, 14.6 Hz, 1 H), 5.20 (d, J = 15.7 Hz, 1 H), 5.09
Methyl (6E)-5-(tert-Butyldiphenylsiloxy)nona-6,8-dienoate (12): A
mixture of 11 (11.5 g, 28 mmol) and K2CO3 (15.6 g, 113 mmol) in
(d, J = 9.2 Hz, 1 H), 4.15 (m, 1 H), 3.61 (t, J = 6.1 Hz, 2 H), 1.61– DMF (100 mL) was stirred at 0 °C for 5 min. MeI (5.3 mL,
1.36 (complex, 6 H), 0.89 (s, 9 H), 0.05 (s, 6 H) ppm. 13C NMR: δ
85 mmol) was added dropwise to this mixture at the same tempera-
= 136.4, 136.2, 130.9, 117.4, 72.5, 63.1, 48.7, 37.0, 32.7, 26.1, 21.8, ture and stirred for another 2 h. After the addition of 1  HCl at
–5.1 ppm. HRMS: calcd. for C15H30O2Si [M+] 270.2015; found
270.2033.
0 °C, the resulting slurry was partitioned between EtOAc/hexane
and H2O. The combined organic layers were washed with saturated
aq. Na2S2O3, saturated aq. NaHCO3, brine, dried (Na2SO4), and
concentrated in vacuo. Purification by silica gel column chromatog-
(3E)-5-(tert-Butyldimethylsiloxy)-9-(tert-butyldiphenylsiloxy)nona-
1,3-diene (9): A mixture of 8 (7.89 g, 29 mmol), imidazole (5.20 g,
76 mmol), and TBDPSCl (10 mL, 38 mmol) in DMF (50 mL) was
stirred at room temperature for 12 h. After the addition of 1  HCl
at 0 °C, the resulting slurry was partitioned between EtOAc/hexane
and H2O. The combined organic layers were washed with saturated
aq. NaHCO3, brine, dried (Na2SO4), and concentrated in vacuo.
Purification by silica gel column chromatography (hexane/EtOAc,
raphy (hexane/EtOAc, 15:1) gave 12 (11.8 g, 99%) as a colorless
1
oil. IR (film): ν = 2952, 2858, 1741 cm–1. H NMR: δ = 7.67–7.62
˜
(complex, 4 H), 7.44–7.33 (complex, 6 H), 6.21 (m, 1 H), 5.88 (dd,
J = 10.6, 15.2 Hz, 1 H), 5.61 (dd, J = 6.8, 15.2 Hz, 1 H), 5.05 (d,
J = 16.8 Hz, 1 H), 5.00 (d, J = 10.0 Hz, 1 H), 4.19 (m, 1 H), 3.63
(s, 3 H), 2.17 (t, J = 7.0 Hz, 2 H), 1.62–1.46 (complex, 4 H), 1.05
(s, 9 H) ppm. 13C NMR: δ = 173.8, 136.4, 135.9, 135.8, 134.2,
134.0, 130.9, 129.5, 129.4, 127.4, 127.3, 116.8, 73.5, 51.4, 37.2, 34.0,
27.1, 20.1, 19.4 ppm. HRMS: calcd. for C26H34O3Si [M+] 422.2277;
found 422.2297.
30:1) gave 9 (14.8 g, 100%) as a colorless oil. IR (film): ν = 2931,
˜
2864 cm–1 1H NMR: δ = 7.68–7.63 (complex, 4 H), 7.41–7.32
.
(complex, 6 H), 6.21 (m, 1 H), 5.87 (dd, J = 10.0, 15.4 Hz, 1 H),
5.61 (dd, J = 7.0, 15.4 Hz, 1 H), 5.03 (d, J = 16.8 Hz, 1 H), 4.99
(d, J = 10.0 Hz, 1 H), 4.17 (m, 1 H), 3.50 (t, J = 6.6 Hz, 2 H),
1.55–1.27 (complex, 6 H), 1.06 (s, 9 H), 0.88 (s, 9 H), 0.02 (s, 6 H)
ppm. 13C NMR: δ = 136.5, 135.9, 135.8, 134.4, 134.2, 130.6, 129.4,
127.4, 127.3, 116.4, 73.9, 63.1, 37.7, 32.8, 27.1, 26.0, 21.0, 19.4,
18.4, –5.2 ppm. HRMS: calcd. for C31H48O2Si2 [M+] 508.3193;
found 508.3186.
Methyl (6E)-5-(2,2-Dimethyl-1,1-diphenyl-1-silapropoxy)-2-[1-
hydroxyethyl-2-(2H-3,4,5,6-tetrahydropyran-2-yloxy)]nona-6,8-dien-
oate (13): nBuLi (1.58  solution in hexane; 24 mL, 38 mmol) was
added dropwise to a solution of diisopropylamine (6.0 mL,
43 mmol) in THF (50 mL) at –10 °C and the resulting solution was
stirred at the same temperature for 30 min. A solution of 12 (14.6 g,
35 mmol) in THF (20 mL) was then added dropwise to this solu-
tion at –78 °C and the resulting solution was stirred at the same
temperature for another 30 min. A solution of THPOCH2CHO
(5.70 g, 40 mmol) in THF (3 mL) was added dropwise at –78 °C
and the resulting solution was stirred at the same temperature for
another 3 h. After the addition of 1  HCl at 0 °C, the resulting
slurry was partitioned between EtOAc and H2O. The combined
organic layers were washed with saturated aq. NaHCO3, brine,
dried (Na2SO4), and concentrated in vacuo. Purification by silica
gel column chromatography (hexane/EtOAc, 15:1Ǟ1:1) gave 12
(5.11 g, 35 % recovery) and 13 (12.0 g, 95 % conv.) as a dia-
stereomeric mixture.
(6E)-5-(tert-Butyldiphenylsiloxy)nona-6,8-dien-1-ol (10): A mixture
of 9 (28.6 g, 56 mmol) and PPTS (697 mg, 2.8 mmol) in EtOH
(100 mL) was stirred at room temperature for 18 h. After the ad-
dition of pyridine (1 mL) at 0 °C, the resulting mixture was concen-
trated in vacuo. Purification by silica gel column chromatography
(hexane/EtOAc, 5:1) gave 10 (21.1 g, 95%) as a colorless oil. IR
1
(film): ν = 3340, 2933, 2858 cm–1. H NMR: δ = 7.69–7.62 (com-
˜
plex, 4 H), 7.44–7.33 (complex, 6 H), 6.23 (m, 1 H), 5.90 (dd, J =
10.6, 15.2 Hz, 1 H), 5.63 (dd, J = 6.8, 15.2 Hz, 1 H), 5.05 (d, J =
16.8 Hz, 1 H), 5.00 (d, J = 10.0 Hz, 1 H), 4.18 (m, 1 H), 3.51 (t, J
= 6.4 Hz, 2 H), 1.55–1.37 (complex, 6 H), 1.07 (s, 9 H) ppm. 13C
NMR: δ = 136.5, 136.3, 135.9, 135.8, 134.4, 134.0, 130.7, 129.5,
129.4, 127.4, 127.3, 116.6, 73.8, 62.8, 37.6, 32.7, 27.1, 20.8,
2-[(4E)-3-(tert-Butyldiphenylsiloxy)-4,6-heptadienyl]-2-buten-4-olide
19.4 ppm. HRMS: calcd. for C21H25O2Si [M – C4H9+] 337.1624; (14): A mixture of 13 (12.0 g, 21 mmol) and PPTS (504 mg,
found 337.1654.
2.0 mmol) in MeOH (60 mL) was stirred at room temperature for
2366
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Eur. J. Org. Chem. 2006, 2362–2370

Synthesis of Chiloscyphones and Biological Activities Against MRSA
FULL PAPER
12 h. After the addition of saturated aq. NaHCO3 at 0 °C, the re-
sulting slurry was partitioned between EtOAc and H2O. The com-
bined organic layers were washed with brine, dried (Na2SO4), and
concentrated in vacuo. A mixture of the crude residue and Et3N
due and DBU (1.2 mL, 8.0 mmol) in PhMe (90 mL) was stirred at
0 °C for 2 h. After the addition of 1  HCl at 0 °C, the resulting
slurry was partitioned between EtOAc and H2O. The combined
organic layers were washed with NaHCO3, brine, dried (Na2SO4),
(40 mL) in MeOH (400 mL) was stirred at room temperature for and concentrated in vacuo. Purification by silica gel column
24 h, then the mixture was concentrated in vacuo. A mixture of this
crude residue and Ac2O (10 mL) in pyridine (20 mL) was stirred at
room temperature for 12 h, then the mixture was concentrated in
vacuo. The crude residue and DBU (6.4 mL, 43 mmol) in PhMe
(200 mL) was stirred at 0 °C for 2 h. After the addition of 1  HCl
at 0 °C, the resulting slurry was partitioned between EtOAc and
H2O. The combined organic layers were washed with saturated aq.
NaHCO3, brine, dried (Na2SO4), and concentrated in vacuo. Puri-
fication by silica gel column chromatography (hexane/EtOAc, 5:1)
chromatography (hexane/EtOAc, 1:1) gave 5 (790 mg, 87% in two
steps) as a colorless oil. IR (film): ν = 2912, 1761, 1722, 1651 cm–1.
˜
1H NMR: δ = 6.84 (t, J = 3.8 Hz, 1 H), 4.56 (dd, J = 5.0, 9.2 Hz,
1 H), 4.09 (d, J = 9.2 Hz, 1 H), 2.80–2.71 (m, 1 H), 2.49 (dd, J =
8.8, 12.4 Hz, 1 H), 2.39–2.22 (complex, 4 H), 1.96–1.90 (m, 1 H),
1.84–1.78 (m, 1 H), 1.66–1.56 (m, 1 H) ppm. 13C NMR: δ = 203.1,
177.6, 136.1, 134.4, 70.9, 49.2, 39.1, 35.2, 31.1, 24.4, 24.0 ppm.
HRMS: calcd. for C11H12O3 [M+] 192.0786; found 192.0766.
(1S,5S)-3-Oxatricyclo[7.3.0.01,5]dodec-8,11-diene-2,10-dione (17):
Et3N (2.5 mL, 18 mmol) was added dropwise to a solution of 5
(523 mg, 2.7 mmol) in CH2Cl2 (25 mL) at 0 °C and the resulting
solution was stirred at the same temperature for 5 min. A solution
of TMSOTf (1.5 mL, 8.3 mmol) in CH2Cl2 (1 mL) was then added
dropwise to this solution at the same temperature and the mixture
was stirred at the same temperature for another 30 min. After the
addition of saturated aq. NaHCO3 at 0 °C, the resulting slurry was
partitioned between CHCl3 and H2O. The combined organic layers
were dried (Na2SO4), and concentrated in vacuo. The crude residue
and Pd(OAc)2 (702 mg, 3.1 mmol) in CH3CN (50 mL) was stirred
at room temperature for 1 h. The reaction mixture was then filtered
through a Celite pad and washed with EtOAc. The filtrate was
concentrated in vacuo. Purification by silica gel column chromatog-
raphy (hexane/EtOAc, 1:1) gave 17 (508 mg, 98% in two steps) as
gave 14 (7.98 g, 87% in four steps) as a colorless oil. IR (film): ν
˜
1
= 2931, 2858, 1759 cm–1. H NMR: δ = 7.69–7.62 (complex, 4 H),
7.44–7.33 (complex, 6 H), 6.79 (t, J = 1.6 Hz, 1 H), 6.23 (m, 1 H),
5.93 (dd, J = 10.4, 15.2 Hz, 1 H), 5.63 (dd, J = 6.8, 15.2 Hz, 1 H),
5.08 (d, J = 17.2 Hz, 1 H), 5.03 (d, J = 10.4 Hz, 1 H), 4.65 (d, J =
1.6 Hz, 2 H), 4.23 (m, 1 H), 2.28–2.20 (complex, 2 H), 1.77–1.70
(complex, 2 H), 1.07 (s, 9 H) ppm. 13C NMR: δ = 173.9, 143.7,
136.1, 135.9, 135.8, 135.3, 134.1, 134.0, 133.7, 131.3, 129.6, 129.5,
127.5, 127.3, 117.2, 73.0, 70.0, 35.2, 27.1, 20.6, 19.4 ppm. HRMS:
calcd. for C23H23O3Si [M – C4H9+] 375.1416; found 375.1391.
2-(3-Hydroxy-4,6-heptadienyl)-2-buten-4-olide (6): A solution of
AcOH (0.80 mL, 14 mmol) and TBAF (1  solution in THF;
16 mL, 16 mmol) was added dropwise to a solution of 14 (2.34 g,
5.4 mmol) in THF (15 mL) at 0 °C and the resulting solution was
stirred at room temperature for 15 h. After the addition of satu-
rated aq. NaHCO3 at 0 °C, the resulting slurry was partitioned be-
tween EtOAc and H2O. The combined organic layers were washed
with brine, dried (Na2SO4), and concentrated in vacuo. Purification
by silica gel column chromatography (hexane/EtOAc, 3:1Ǟ1:1)
a colorless powder. IR (KBr): ν = 2916, 1761, 1703, 1658 cm–1. 1H
˜
NMR: δ = 7.41 (d, J = 5.8 Hz, 1 H), 6.83 (t, J = 4.2 Hz, 1 H), 6.56
(d, J = 5.8 Hz, 1 H), 4.69 (dd, J = 5.2, 9.6 Hz, 1 H), 4.22 (d, J =
9.6 Hz, 1 H), 2.60–2.55 (m, 1 H), 2.40–2.28 (complex, 2 H), 2.04–
1.96 (m, 1 H), 1.84–1.74 (m, 1 H) ppm. 13C NMR: δ = 193.4, 174.2,
151.7, 138.1, 135.9, 133.4, 71.4, 55.1, 36.4, 26.2, 23.8 ppm. HRMS:
calcd. for C11H10O3 [M+] 190.0630; found 190.0656.
gave 6 (966 mg, 92%) as a colorless oil. IR (film): ν = 3421, 2931,
˜
1747 cm–1. 1H NMR: δ = 7.15 (t, J = 1.6 Hz, 1 H), 6.39–6.19 (com-
plex, 3 H), 5.71 (dd, J = 6.5, 14.3 Hz, 1 H), 5.21 (d, J = 15.7 Hz,
1 H), 5.11 (d, J = 10.0 Hz, 1 H), 4.78 (d, J = 1.6 Hz, 2 H), 4.19
(m, 1 H), 2.46–2.38 (complex, 2 H), 1.85–1.77 (complex, 2 H) ppm.
13C NMR: δ = 174.3, 144.6, 136.0, 135.5, 133.8, 131.4, 117.9, 71.4,
70.2, 34.9, 21.5 ppm. HRMS: calcd. for C11H14O3 [M+] 194.0943;
found 194.0915.
(1S,5S,12R)-12-Vinyl-3-oxatricyclo[7.3.0.01,5]dodec-8-ene-2,10-di-
one (18): CH2=CHMgBr (1.32  solution in THF; 4.3 mL,
5.7 mmol) was added dropwise to a mixture of CuI (216 mg,
1.1 mmol) in THF (6 mL) at –25 °C and the resulting mixture was
stirred at –20 °C for 30 min. A solution of 17 (359 mg, 1.9 mmol)
in THF (7 mL) was then added dropwise to this mixture at –78 °C
and the mixture was stirred at the same temperature for another
30 min. After the addition of saturated aq. NH4Cl at 0 °C, the re-
sulting slurry was partitioned between EtOAc and H2O. The com-
bined organic layers were washed with brine, dried (Na2SO4), and
concentrated in vacuo. Purification by silica gel column chromatog-
raphy (hexane/EtOAc, 2:1) gave 18 (309 mg, 75%) as a colorless
(1S,5S)-10-Hydroxy-3-oxatricyclo[7.3.0.01,5]dodec-7-en-2-one (16):
A solution of 6 (874 mg, 4.5 mmol) and BHT (99 mg, 0.45 mmol)
in dry PhMe (45 mL) was heated at 180 °C for 48 h in a sealed
tube. After being cooled to room temperature, the tube was opened
and the mixture was concentrated in vacuo. The crude products
were purified by silica gel column chromatography (hexane/EtOAc,
1:1) to give 16 (725 mg, 83 %) as a diastereomeric mixture. IR powder. IR (KBr): ν = 2939, 1759, 1724, 1651 cm–1. 1H NMR: δ =
˜
(film): ν = 3419, 2939, 1747 cm–1. HRMS: calcd. for C11H14O3 6.94 (t, J = 3.8 Hz, 1 H), 5.47 (m, 1 H), 5.19–5.14 (complex, 2 H),
˜
[M+] 194.0943; found 194.0917.
4.45 (dd, J = 5.2, 9.2 Hz, 1 H), 4.04 (dd, J = 0.8, 5.2 Hz, 1 H),
3.16–3.09 (complex, 2 H), 2.46–2.18 (complex, 3 H), 1.91–1.65
(complex, 3 H) ppm. 13C NMR: δ = 202.3, 177.3, 135.9, 134.3,
118.0, 114.5, 70.3, 44.6, 41.9, 40.6, 35.2, 24.1, 23.9 ppm. HRMS:
calcd. for C13H14O3 [M+] 218.0943; found 218.0928.
(1S,5S)-3-Oxatricyclo[7.3.0.01,5]dodec-8-ene-2,10-dione (5): A solu-
tion of DMSO (2.0 mL, 28 mmol) in CH2Cl2 (2 mL) was added
dropwise to a solution of TFAA (2.0 mL, 14 mmol) in CH2Cl2
(35 mL) at –60 °C and the resulting solution was stirred at the same
temperature for 15 min. A solution of 16 (917 mg, 4.7 mmol) in
CH2Cl2 (8 mL) was then added dropwise to this mixture at the
same temperature and stirred for another hour. Et3N (8.0 mL,
58 mmol) was added to this reaction mixture and stirred at 0 °C
for another 15 min. After the addition of 1  HCl at 0 °C, the re-
sulting slurry was partitioned between EtOAc and H2O. The com-
bined organic layers were washed with saturated aq. NaHCO3,
brine, dried (Na2SO4), and concentrated in vacuo. The crude resi-
{(1S,2S,9R)-1-Hydroxymethyl-9-vinylbicyclo[4.3.0]non-6-en-2-
yl}methan-1-ol (19): A mixture of 18 (259 mg, 1.2 mmol) and
NaBH4 (151 mg, 4.0 mmol) in MeOH (10 mL) was stirred at 0 °C
for 10 min. After the addition of 1  HCl at 0 °C, the resulting
slurry was partitioned between EtOAc and H2O. The combined
organic layers were washed with saturated aq. NaHCO3, brine,
dried (Na2SO4), and concentrated in vacuo. The crude residue and
MsCl (0.50 mL, 6.5 mmol) in pyridine (3 mL) was stirred at room
Eur. J. Org. Chem. 2006, 2362–2370
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2367

J. Shiina, R. Obata, H. Tomoda, S. Nishiyama
FULL PAPER
temperature for 4 h. After the addition of 1  HCl at 0 °C, the
resulting slurry was partitioned between EtOAc and H2O. The
combined organic layers were washed with saturated aq. NaHCO3,
brine, dried (Na2SO4), and concentrated in vacuo. The crude resi-
due and AcOK (1.17 g, 12 mmol) in DMF (14 mL) and H2O
(7 mL) was stirred at 80 °C for 24 h. After the addition of 1  HCl
at 0 °C, the resulting slurry was partitioned between EtOAc/hexane
and H2O. The combined organic layers were washed with saturated
aq. NaHCO3, brine, dried (Na2SO4), and concentrated in vacuo.
DIBAL-H (1.0  solution in PhMe; 12 mL, 12 mmol) was added
to the crude residue in CH2Cl2 (6 mL) at 0 °C. The mixture was
stirred at the same temperature for 1 h. After the addition of 3 
HCl at 0 °C, the resulting slurry was partitioned between EtOAc
and H2O. The combined organic layers were washed with saturated
aq. NaHCO3, brine, dried (Na2SO4), and concentrated in vacuo.
Purification by silica gel column chromatography (CHCl3/MeOH,
40:1) gave 19 (185 mg, 75% in four steps) as a colorless oil. IR
H), 2.96 (m, 1 H), 2.83 (m, 1 H), 2.31–2.27 (complex, 2 H), 1.71–
1.43 (complex, 5 H), 1.31–1.17 (complex, 3 H), 1.03 (s, 9 H), 0.80
(s, 9 H) ppm. 13C NMR: δ = 143.7, 136.0, 135.7, 135.6, 135.5,
134.2, 133.1, 132.7, 129.6, 129.5, 129.2, 127.7, 127.5, 127.4, 127.3,
113.9, 82.7, 66.5, 63.2, 54.6, 53.2, 44.6, 40.0, 37.0, 30.9, 27.0, 26.9,
26.6, 24.9, 20.5, 19.3, 19.0 ppm. HRMS: calcd. for C45H58O3Si2
[M+] 702.3924; found 702.3919.
(1S,5S,6R,7S)-5,6-Bis[(tert-butyldiphenylsiloxy)methyl]-7-(hydroxy-
methyl)bicyclo[4.3.0]nonan-1-ol (22): To a solution of 21 (361 mg,
0.51 mmol) and Me3NO (170 mg, 1.5 mmol) in acetone (5.0 mL)
and H2O (1.5 mL) was added OsO4 0.04  solution in tBuOH
(0.65 mL, 0.026 mmol) at 0 °C. The mixture was stirred at room
temperature for 12 h. To this mixture were added NaH2PO4
(310 mg, 2.6 mmol) and NaIO4 (551 mg, 2.6 mmol) at 0 °C. The
mixture was stirred at room temperature for another hour. After
the addition of saturated aq. Na2SO3, the resulting slurry was parti-
tioned between EtOAc and H2O. The combined organic layers were
washed with saturated aq. Na2S2O3, brine, dried (Na2SO4), and
concentrated in vacuo. The crude residue and NaBH4 (101 mg,
2.6 mmol) in MeOH (5.0 mL) was stirred at 0 °C for 20 min. After
the addition of 1  HCl, the resulting slurry was partitioned be-
tween EtOAc and H2O. The combined organic layers were washed
with saturated aq. NaHCO3, brine, dried (Na2SO4), and concen-
trated in vacuo. Purification by silica gel column chromatography
(film): ν = 3296, 2927, 2856 cm–1. 1H NMR: δ = 5.78 (m, 1 H),
˜
5.34 (br. s, 1 H), 5.05–4.93 (complex, 2 H), 3.74 (d, J = 11.6 Hz, 1
H), 3.69 (dd, J = 4.4, 11.2 Hz, 1 H), 3.60 (dd, J = 4.8, 11.2 Hz, 1
H), 3.33 (d, J = 11.6 Hz, 1 H), 3.10 (m, 1 H), 2.67 (m, 1 H), 2.38
(m, 1 H), 1.93 –1.76 (complex, 3 H), 1.62–1.55 (complex, 3 H), 1.27
(m, 1 H) ppm. 13C NMR: δ = 144.4, 141.4, 121.7, 113.6, 64.2,
63.3, 56.4, 48.1, 42.6, 37.2, 27.1, 26.3, 25.5 ppm. HRMS: calcd. for
C13H20O2 [M+] 208.1463; found 208.1452.
(hexane/EtOAc, 3:1) gave 22 (212 mg, 58% in two steps) as a color-
1
less oil. IR (film): ν = 3221, 2931, 2858 cm–1. H NMR: δ = 7.72–
(1S,5S,6R,7R)-5,6-Bis[(tert-butyldiphenyl)siloxymethyl]-7-
vinylbicyclo[4.3.0]nonan-1-ol (20): A mixture of 19 (162 mg,
0.78 mmol), imidazole (0.52 g, 7.6 mmol), and TBDPSCl (1.0 mL,
3.9 mmol) in DMF (4 mL) was stirred at 0 °C for 3 h. After the
addition of 1  HCl at 0 °C, the resulting slurry was partitioned
between EtOAc/hexane and H2O. The combined organic layers
were washed with saturated aq. NaHCO3, brine, dried (Na2SO4),
and concentrated in vacuo. Purification by silica gel column
˜
7.24 (complex, 20 H), 3.95 (d, J = 9.2 Hz, 1 H), 3.83–3.77 (complex,
2 H), 3.54 (dd, J = 2.0, 11.2 Hz, 1 H), 3.39 (dd, J = 4.4, 11.2 Hz,
2 H), 2.81 (d, J = 10.8 Hz, 1 H), 2.51 (m, 1 H), 2.31–2.23 (complex,
2 H), 1.80–1.68 (complex, 3 H), 1.55–1.34 (complex, 3 H), 1.22–
1.16 (complex, 2 H), 1.05 (s, 9 H), 0.83 (s, 9 H) ppm. 13C NMR: δ
= 135.7, 135.6, 135.5, 134.2, 133.9, 133.0, 132.7, 129.6, 129.4, 129.3,
127.7, 127.6, 127.5, 80.3, 67.8, 63.7, 62.2, 60.4, 54.4, 41.2, 40.0,
37.2, 30.2, 27.0, 26.9, 25.6, 21.8, 20.4, 19.3, 19.0, 14.3 ppm. HRMS:
calcd. for C44H58O4Si2 [M+] 706.3874; found 706.3871.
chromatography (hexane/EtOAc, 50:1) gave 20 (516 mg, 97%) as a
1
colorless oil. IR (film): ν = 2929, 2856 cm–1. H NMR: δ = 7.72–
˜
7.24 (complex, 20 H), 5.78 (m, 1 H), 5.22 (br. s, 1 H), 4.85–4.79
(complex, 2 H), 3.87 (dd, J = 3.0, 9.8 Hz, 1 H), 3.72–3.55 (complex,
2 H), 3.24 (dd, J = 3.0, 9.8 Hz, 1 H), 2.82 (m, 1 H), 2.36–2.32
(complex, 2 H), 2.21 (m, 1 H), 1.90–1.78 (complex, 5 H), 1.38 (m,
1 H), 1.00 (s, 9 H), 0.88 (s, 9 H) ppm. 13C NMR: δ = 145.2, 140.8,
135.7, 135.6, 135.5, 134.0, 133.4, 133.3, 129.4, 129.3, 129.2, 127.5,
127.4, 127.3, 120.7, 113.3, 65.3, 65.1, 55.8, 55.2, 48.3, 44.4, 37.1,
27.8, 26.9, 26.8, 26.4, 26.1, 19.3, 19.1 ppm. HRMS: calcd. for
C45H56O2Si2 [M+] 684.3819; found 684.3811.
(1S,5S,6R,7S)-5,6-Bis[(tert-butyldiphenylsiloxy)methyl]-7-[(4-meth-
oxyphenyl)methoxy]bicyclo[4.3.0]nonan-1-ol (23): To a solution of
22 (212 mg, 0.30 mmol) in DMF (5 mL) was added NaH 60% dis-
persion in oil (250 mg, 6.3 mmol) at 0 °C. The mixture was stirred
at the same temperature for 10 min. To this mixture were added
MPMCl (0.40 mL, 3.0 mmol) and TBAI (11 mg, 0.03 mmol) at
0 °C. The mixture was stirred at the same temperature for another
20 min. After the addition of MeOH, the resulting slurry was parti-
tioned between EtOAc/hexane and H2O. The combined organic
layers were washed with 1  HCl, saturated aq. NaHCO3, brine,
dried (Na2SO4), and concentrated in vacuo. Purification by silica
gel column chromatography (hexane/EtOAc, 20:1Ǟ5:1) gave 23
(1S,5S,6R,7R)-5,6-Bis[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]-7-
vinylbicyclo[4.3.0]nonan-1-ol (21): A mixture of 20 (474 mg,
0.69 mmol), NaH2PO4 (610 mg), and mCPBA (601 mg, 2.3 mmol)
in CH2Cl2 (7 mL) was stirred at –20 °C for 2 h. After the addition
of saturated aq. Na2S2O3, the resulting slurry was partitioned be-
tween CHCl3 and H2O. The combined organic layers were washed
with saturated aq. NaHCO3, brine, dried (Na2SO4), and concen-
trated in vacuo. LiEt3BH (1.0  solution in THF; 3.5 mL,
3.5 mmol) was added dropwise to the crude residue in THF
(3.5 mL) at 0 °C and the mixture was stirred at room temperature
for 3 h. After the addition of 1  HCl, the resulting slurry was
partitioned between EtOAc and H2O. The combined organic layers
were washed with saturated aq. NaHCO3, brine, dried (Na2SO4),
and concentrated in vacuo. Purification by silica gel column
chromatography (hexane/EtOAc, 40:1) gave 21 (361 mg, 74% in
(174 mg, 70%) as a colorless powder. IR (KBr): ν = 3396, 2931,
˜
2858 cm–1. 1H NMR: δ = 7.71–7.24 (complex, 22 H), 6.89–6.86
(complex, 2 H), 4.79 (br. s, 1 H), 4.51 (d, J = 11.6 Hz, 1 H), 4.36
(d, J = 11.6 Hz, 1 H), 3.98 (d, J = 9.7 Hz, 1 H), 3.88–3.73 (complex,
2 H), 3.78 (s, 3 H), 3.53 (dd, J = 2.2, 9.7 Hz, 1 H), 3.37 (dd, J =
4.5, 9.7 Hz, 1 H), 2.82 (d, J = 9.7 Hz, 1 H), 2.61 (m, 1 H), 2.43 (m,
1 H), 2.23 (m, 1 H), 1.92–1.38 (complex, 9 H), 1.09 (s, 9 H), 0.78
(s, 9 H) ppm. 13C NMR: δ = 159.1, 135.6, 135.5, 135.4, 134.2,
133.9, 133.0, 132.7, 129.5, 129.4, 129.3, 129.2, 127.6, 127.5, 127.4,
113.8, 79.5, 73.1, 70.3, 68.0, 63.9, 60.4, 55.2, 54.5, 40.2, 39.8, 37.2,
29.9, 27.1, 26.9, 26.1, 22.7, 20.5, 19.4, 19.0, 14.3 ppm. HRMS:
calcd. for C52H66O5Si2 [M+] 826.4449; found 826.4440.
two steps) as a colorless oil. IR (film): ν = 3585, 2931, 2856 cm–1.
˜
1H NMR: δ = 7.68–7.25 (complex, 20 H), 6.18 (m, 1 H), 4.87–4.83 [(3S,4S,3aR)-3a-(Hydroxymethyl)-3-{[(4-methoxyphenyl)methoxy]-
(complex, 2 H), 4.06 (dd, J = 2.4, 10.4 Hz, 1 H), 3.78 (d, J =
10.4 Hz, 1 H), 3.73 (d, J = 10.4 Hz, 1 H), 3.71 (d, J = 10.4 Hz, 1
methyl}-2,3,4,5,6,3a-hexahydroinden-4-yl]methan-1-ol (24).
[(2S,9S,1R)-1-(Hydroxymethyl)-9-{[(4-methoxyphenyl)methoxy]-
2368
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Eur. J. Org. Chem. 2006, 2362–2370

Synthesis of Chiloscyphones and Biological Activities Against MRSA
FULL PAPER
methyl}bicyclo[4.3.0]non-6-en-2-yl]methan-1-ol (25): A mixture of
23 (108 mg, 0.13 mmol) and SOCl2 (0.20 mL, 2.7 mmol) in pyridine
NaHCO3, the resulting slurry was partitioned between CHCl3 and
H2O. The combined organic layers were washed with brine, dried
(1.2 mL) was stirred at –30 °C for 20 min. After the addition of (Na2SO4), and concentrated in vacuo. Purification by silica gel col-
MeOH, the resulting slurry was partitioned between EtOAc and
H2O. The combined organic layers were washed with 1  HCl, sat-
urated aq. NaHCO3, brine, dried (Na2SO4), and concentrated in
vacuo. The crude residue in THF (1.5 mL) was added TBAF 1 
solution in THF (1.5 mL, 1.5 mmol) at 0 °C. The mixture was
stirred at 50 °C for 3 h. After the addition of H2O, the resulting
slurry was partitioned between EtOAc and H2O. The combined
organic layers were washed with brine, dried (Na2SO4), and con-
centrated in vacuo. Purification by silica gel column chromatog-
raphy (hexane/EtOAc, 1:1) gave 24 (8.0 mg, 18% in two steps) and
25 (33.0 mg, 76% in two steps) as a colorless oil.
umn chromatography (PhMe/EtOAc, 10:1) gave 31 (3.3 mg, 92%)
as a colorless oil. IR (film): ν = 3334, 2954, 2922, 2852 cm–1. 1H
˜
NMR: δ = 5.34 (m, 1 H), 3.63 (dd, J = 4.8, 10.0 Hz, 1 H), 3.32
(dd, J = 7.2, 10.0 Hz, 1 H), 2.47 (m, 1 H), 2.30 (m, 1 H), 2.04–1.42
(complex, 8 H), 0.94 (d, J = 6.4 Hz, 3 H), 0.91 (s, 3 H) ppm. 13C
NMR: δ = 147.5, 117.3, 63.8, 49.3, 46.0, 32.6, 27.8, 26.6, 25.7, 23.1,
20.2, 16.9 ppm. HRMS: calcd. for C12H20O [M+] 180.1514; found
180.1518.
Chiloscyphone (1): A mixture of 31 (3.3 mg, 0.018 mmol) and IBX
(20 mg, 0.073 mmol) in DMSO (0.3 mL) and THF (0.6 mL) was
stirred at room temperature for 1 h. The mixture was concentrated
and through a silica gel short column, and washed with EtOAc/
hexane. The filtrate was concentrated in vacuo The crude residue
in THF (0.5 mL) was added isopropenylmagnesium bromide 0.5 
solution in THF (0.5 mL, 0.25 mmol) at 0 °C. The mixture was
stirred at the same temperature for 30 min. After the addition of
1  HCl, the resulting slurry was partitioned between EtOAc and
H2O. The combined organic layers were washed with saturated aq.
NaHCO3, brine, dried (Na2SO4), and concentrated in vacuo. The
crude residue and IBX (21 mg, 0.073 mmol) in THF (0.6 mL) and
DMSO (0.3 mL) was stirred at room temperature for 12 h. The
mixture was concentrated and purified by silica gel column
chromatography (hexane/EtOAc, 20:1) to give 1 (3.0 mg, 75% in
1
24: IR (film): ν = 3330, 2929, 2856 cm–1. H NMR: δ = 7.22 (d, J
˜
= 8.8 Hz, 2 H), 6.88 (d, J = 8.8 Hz, 2 H), 5.57 (m, 1 H), 4.40
(complex, 2 H), 3.80 (s, 3 H), 3.72 (dd, J = 5.4, 11.8 Hz, 2 H), 3.40
(m, 1 H), 3.34 (m, 1 H), 3.24 (complex, 2 H), 2.91 (m, 1 H), 2.33
(m, 1 H), 2.12–1.99 (complex, 4 H), 1.83 (m, 1 H), 1.40–1.35 (com-
plex, 3 H) ppm. 13C NMR: δ = 159.4, 141.9, 129.5, 129.1, 122.5,
122.4, 113.8, 72.9, 72.3, 66.0, 61.8, 55.3, 51.7, 42.1, 38.9, 27.3, 25.2,
25.1, 21.6 ppm. HRMS: calcd. for C20H28O4 [M+] 332.1988; found
332.1984.
1
25: IR (film): ν = 3348, 2929, 2856 cm–1. H NMR: δ = 7.25–7.23
˜
(complex, 2 H), 6.89–6.87 (complex, 2 H), 5.31 (m, 1 H), 4.43 (s, 2
H), 3.93 (d, J = 10.8 Hz, 1 H), 3.80 (s, 3 H), 3.67 (dd, J = 5.2,
10.8 Hz, 1 H), 3.61 (m, 1 H), 3.43 (m, 1 H), 3.33 (dd, J = 4.0,
10.8 Hz, 1 H), 3.22 (d, J = 10.8 Hz, 1 H), 2.87 (m, 1 H), 2.56 (m,
1 H), 2.32 (m, 1 H), 1.84–1.80 (complex, 3 H), 1.49–1.11 (complex,
4 H) ppm. 13C NMR: δ = 159.4, 145.2, 129.6, 129.0, 121.9, 121.8,
113.9, 73.0, 71.9, 65.4, 64.0, 55.7, 55.3, 44.0, 41.1, 34.5, 27.6, 26.1,
25.9 ppm. HRMS: calcd. for C20H28O4 [M+] 332.1988; found
332.1986.
three steps) as a colorless oil. IR (film): ν = 2952, 2856, 1665 cm–1.
˜
1H NMR: δ = 5.94 (br. s, 1 H), 5.73 (br. s, 1 H), 5.42 (m, 1 H),
3.58 (dd, J = 7.6, 1.6 Hz, 1 H), 2.53 (m, 2 H), 2.10–1.84 (complex,
6 H), 1.70–1.25 (complex, 4 H), 0.98 (s, 3 H), 0.85 (d, J = 6.4 Hz,
3 H) ppm. 13C NMR: δ = 206.5, 146.5, 146.0, 123.7, 117.1, 52.6,
49.8, 33.1, 29.1, 27.1, 26.1, 25.5, 20.6, 17.8, 17.5 ppm. HRMS:
calcd. for C15H22O [M+] 218.1671; found 218.1666.
{[(1S,7S,7aS)-7,7a-Dimethyl(2,4,5,6,7,7a-hexahydroindenyl)]meth-
oxy}(4-methoxyphenyl)methane (32): A mixture of 25 (12.0 mg,
0.036 mmol) and MsCl (0.1 mL) in pyridine (0.5 mL) was stirred
at room temperature for 1 h. After the addition of 1  HCl, the
resulting slurry was partitioned between EtOAc and H2O. The
combined organic layers were washed with saturated aq. NaHCO3,
brine, dried (Na2SO4), and concentrated in vacuo. The crude resi-
due and Na2S·9H2O (120 mg, 0.50 mmol) in DMF (3.6 mL) was
stirred at 50 °C for 12 h. After the addition of H2O, the resulting
slurry was partitioned between EtOAc/hexane and H2O. The com-
bined organic layers were washed with brine, dried (Na2SO4), and
concentrated in vacuo. The crude residue and Raney Ni W-4
(ca.100 mg) in THF (3.6 mL) was stirred at room temperature for
3 h. The reaction mixture was filtered through a Celite pad, and
washed with EtOAc. The filtrate was concentrated in vacuo. Purifi-
cation by silica gel column chromatography (hexane/EtOAc, 10:1)
{[(1S,7S,7aS)-7,7a-Dimethyl-2,3,5,6,7,7a-hexahydroindenyl]meth-
oxy}(4-methoxyphenyl)methane (30): A mixture of 24 (10.0 mg,
0.030 mmol) and MsCl (0.1 mL) in pyridine (0.5 mL) was stirred
at room temperature for 1 h. After the addition of 1  HCl, the
resulting slurry was partitioned between EtOAc and H2O. The
combined organic layers were washed with saturated aq. NaHCO3,
brine, dried (Na2SO4), and concentrated in vacuo. The crude resi-
due and Na2S·9H2O (71 mg, 0.50 mmol) in DMF (3.0 mL) was
stirred at 50 °C for 12 h. After the addition of H2O, the resulting
slurry was partitioned between EtOAc/hexane and H2O. The com-
bined organic layers were washed with brine, dried (Na2SO4), and
concentrated in vacuo. The crude residue and Raney Ni W-4
(ca.100 mg) in THF (3.0 mL) was stirred at room temperature for
3 h. The reaction mixture was filtered through a Celite pad, and
washed with EtOAc. The filtrate was concentrated in vacuo. Purifi-
cation by silica gel column chromatography (hexane/EtOAc, 10:1)
gave 32 (6.5 mg, 60% in three steps) as a colorless oil. IR (film): ν
˜
gave 30 (6.0 mg, 66% in three steps) as a colorless oil. IR (film): ν
˜
1
= 2924, 2852 cm–1. H NMR: δ = 7.26 (d, J = 8.6 Hz, 2 H), 6.87
1
= 2954, 2922, 2852 cm–1. H NMR: δ = 7.25 (d, J = 8.8 Hz, 2 H),
(d, J = 8.6 Hz, 2 H), 5.09 (m, 1 H), 4.45 (d, J = 11.2 Hz, 1 H), 4.39
(d, J = 11.2 Hz, 1 H), 3.81 (s, 3 H), 3.51 (dd, J = 4.4, 8.8 Hz, 1 H),
3.20 (dd, J = 8.8, 10.2 Hz, 1 H), 2.43 (m, 1 H), 2.30–2.17 (complex,
2 H), 1.93 (m, 1 H), 1.68 (m, 1 H), 1.45–1.12 (complex, 5 H), 0.91
(s, 3 H), 0.85 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR: δ = 158.9, 149.0,
130.8, 129.1, 128.9, 118.2, 118.1, 113.6, 72.7, 71.1, 55.3, 50.2, 47.3,
35.1, 33.0, 30.8, 26.4, 26.2, 18.0, 17.9 ppm. HRMS: calcd. for
C20H28O2 [M+] 300.2089; found 300.2085.
6.87 (d, J = 8.8 Hz, 2 H), 5.31 (m, 1 H), 4.39 (complex, 2 H), 3.80
(s, 3 H), 3.43 (dd, J = 5.2, 9.2 Hz, 1 H), 2.96 (t, J = 9.2 Hz, 1 H),
2.41 (m, 1 H), 2.22–1.42 (complex, 9 H), 0.90 (d, J = 7.6 Hz, 3 H),
0.89 (s, 3 H) ppm. 13C NMR: δ = 159.0, 147.2, 130.9, 129.1, 129.0,
117.4, 116.3, 113.7, 72.6, 70.8, 55.3, 47.0, 46.2, 32.4, 27.4, 26.6,
25.7, 23.4, 20.2, 17.0 ppm. HRMS: calcd. for C20H28O2 [M+]
300.2089; found 300.2081.
[(1S,7S,7aS)-7,7a-Dimethyl-2,3,5,6,7,7a-hexahydroindenyl]-
methan-1-ol (31): A mixture of 30 (6.0 mg, 0.020 mmol) and DDQ [(1S,7S,7aS)-7,7a-Dimethyl-2,4,5,6,7,7a-hexahydroindenyl]-
(21 mg, 0.090 mmol) in CH2Cl2 (0.5 mL) and H2O (0.025 mL) was methan-1-ol (33): A mixture of 32 (15.0 mg, 0.050 mmol) and DDQ
stirred at 0 °C for 10 min. After the addition of saturated aq.
(28 mg, 0.12 mmol) in CH2Cl2 (1.0 mL) and H2O (0.05 mL) was
Eur. J. Org. Chem. 2006, 2362–2370
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2369

J. Shiina, R. Obata, H. Tomoda, S. Nishiyama
FULL PAPER
stirred at 0 °C for 10 min. After the addition of saturated aqueous
NaHCO3, the resulting slurry was partitioned between CHCl3 and
H2O. The combined organic layers were washed with brine, dried
(Na2SO4), and concentrated in vacuo. Purification by silica gel col-
umn chromatography (PhMe/EtOAc, 10:1) gave 33 (7.7 mg, 85%)
24 h. Yeasts and X. oryzae were incubated at 27 °C for 24 h. Fungi
were incubated at 27 °C for 48 h. Antimicrobial activity was ex-
pressed as diameter [mm] of the inhibitory zone.
In vitro Assay for Potential of Imipenem Activity Against Methicil-
lin-Resistant Staphylococcus Aureus: MRSA (2.0 × 107 CFU) was
spread on the HMA medium in a plastic plate (10 × 14 cm, Eikiken
Kizai Co) containing Mueller–Hinton broth and 1.5% agar plate
with or without imipenem at 10 µg/mL (HMA+IMP plate or HMA
plate, respectively), which concentration has no effect on MRSA
growth. Paper disks (Advantec) containing a sample (10 µg) were
placed on the HMA+IMP and HMA plate, and incubated at 37 °C
for 20 h. Anti-MRSA activity was expressed as diameter [mm] of
the inhibitory zone on the plates. If the sample potentiates the im-
ipenem activity, larger inhibitory zone is observed on the
HMA+IMP plate than on the HMA plate.
as a colorless oil. IR (film): ν = 3334, 2956, 2925, 2852 cm–1. 1H
˜
NMR: δ = 5.15 (m, 1 H), 3.70 (dd, J = 4.0, 10.0 Hz, 1 H), 3.49
(dd, J = 8.0, 10.0 Hz, 1 H), 2.50 (m, 1 H), 2.30 (m, 1 H), 2.18 (m,
1 H), 2.05–1.91 (complex, 2 H), 1.73–1.15 (complex, 5 H), 0.92 (s,
3 H), 0.89 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR: δ = 150.2, 118.2,
64.1, 50.1, 49.6, 34.9, 32.5, 30.7, 26.4, 26.2, 18.0, 17.8 ppm. HRMS:
calcd. for C12H20O [M+] 180.1514; found 180.1514.
Isochiloscyphone (2): A mixture of 33 (3.6 mg, 0.020 mmol) and
IBX (21 mg, 0.073 mmol) in DMSO (0.3 mL) and THF (0.6 mL)
was stirred at room temperature for 1 h. The mixture was concen-
trated and through a silica gel short column, and washed with
EtOAc/hexane. The filtrate was concentrated in vacuo. The crude
residue in THF (0.5 mL) was added isopropenylmagnesium bro-
mide 0.5  solution in THF (0.5 mL, 0.25 mmol) at 0 °C. The mix-
ture was stirred at the same temperature for 30 min. After the ad-
dition of 1  HCl, the resulting slurry was partitioned between
EtOAc and H2O. The combined organic layers were washed with
saturated aq. NaHCO3, brine, dried (Na2SO4), and concentrated
in vacuo. The crude residue and IBX (20 mg, 0.073 mmol) in THF
(0.6 mL) and DMSO (0.3 mL) was stirred at room temperature for
12 h. The mixture was concentrated and purified by silica gel col-
umn chromatography (hexane/EtOAc, 20:1) to give 2 (3.2 mg, 73%
Acknowledgments
This work was supported by Grant-in-Aid for the 21st Century
COEprogram “Keio Life Conjugated Chemistry” from the Minis-
try of Education, Culture, Sports, Science, and Technology, Ja-
pan. J. S. was financially supported by the same program.
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in three steps) as a colorless oil. IR (film): ν = 2925, 2854,
˜
1662 cm–1 1H NMR: δ = 6.02 (br. s, 1 H), 5.77 (br. s, 1 H), 5.19
(m, 1 H), 3.71 (m, 1 H), 2.45 (complex, 2 H), 2.31 (m, 1 H), 1.90
(br. s, 3 H), 1.68–1.25 (complex, 6 H), 1.10 (s, 3 H), 0.60 (d, J =
6.8 Hz, 3 H) ppm. 13C NMR: δ = 205.1, 149.1, 140.5, 124.0, 118.0,
52.3, 35.4, 35.3, 31.3, 29.7, 27.1, 26.2, 19.9, 18.2, 17.9 ppm. HRMS:
calcd. for C15H22O [M+] 218.1671; found 218.1677.
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Antimicrobial Activity against 15 Species of Microorganisms: Anti-
microbial activity against 15 species of microorganisms was mea-
sured by the agar diffusion method using paper disks (i.d 6 mm,
ADVANTEC). The microorganisms were as follows; Bacillus subti-
lis PCI 219, Staphylococcus aureus FDA 209P, methicillin-resistant
Staphyrococcus aureus K-24 (a clinica isolate, MRSA), Micrococcus
luteus PCI 1001, Mycobacterium smegmatis ATCC 607, Escherichia
coli NIHJ, Escherichia coli NIHJJ-2 IFO 12734, Pseudomonas aeru-
ginosa P-3, Xanthomonas campestris pv. oryzae KB 88, Bacteroides
fragilis ATCC 23745, Acholeplasma laidlawii PG 8, Pyricularia ory-
zae KF 180, Aspergillus niger ATCC 6275, Mucor racemosus IFO
4581, Candida albicans ATCC 64548 and Saccharomyces cerevisiae.
Media for microorganisms were as follows: GAM agar (Nissui Sei-
yaku Co.) for B. fragilis; Bacto PPLO agar (Difco) supplemented
with 15% horse serum, 0.1% glucose, 0.25% phenol red (5 mg/mL)
and 1.5% agar for A. laidlawii; Mueller–Hinton broth (Difico) and
1.5% agar (Shimizu Shokuhin Co.) for MRSA; Taiyo agar (Shim-
izu Syokuhin Kaisya Ltd.) for the other bacteria; a medium com-
posed of 1.0% yeast extract, and 0.8% agar for fungi and yeasts.
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plate. Bacteria except for X. oryzae were incubated at 37 °C for
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Received: November 28, 2005
Published Online: March 16, 2006
2370
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2362–2370