Synthesis of a pericosine analogue with a bicyclo[2.2.2]octene skeleton

Article abstract of DOI:10.1016/j.tet.2009.07.084

A new analogue of the antitumor pericosines possessing a bicyclo[2.2.2]octene skeleton has been synthesized from methyl gallate using oxidative dearomatization and regio- and diastereoselective Diels-Alder reaction as the key steps.

Full text of DOI:10.1016/j.tet.2009.07.084

Tetrahedron 65 (2009) 8171–8175
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Tetrahedron
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Synthesis of a pericosine analogue with a bicyclo[2.2.2]octene skeleton
a
b
c
d
e
´
´
´
´
Zsolt Fejes , Attila Mandi , Istvan Komaromi , Attila Benyei , Lieve Naesens ,
f
g
a,
*
´
´
´
´
Ferenc Fenyvesi , Laszlo Szilagyi , Pal Herczegh
a Department of Pharmaceutical Chemistry, University of Debrecen, H-4032 Debrecen, Hungary
b Research Group for Carbohydrates of the Hungarian Academy of Sciences, University of Debrecen, H-4032 Debrecen, Hungary
c Thrombosis and Haemostasis Research Group of the Hungarian Academy of Sciences, University of Debrecen, H-4032 Debrecen, Hungary
d Institute of Physical Chemistry, University of Debrecen, H-4032 Debrecen, Hungary
e Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
f Department of Pharmaceutical Technology, University of Debrecen, H-4032 Debrecen, Hungary
g Department of Organic Chemistry, University of Debrecen, H-4032 Debrecen, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 April 2009
Received in revised form 29 June 2009
Accepted 28 July 2009
Available online 6 August 2009
A new analogue of the antitumor pericosines possessing a bicyclo[2.2.2]octene skeleton has been syn-
thesized from methyl gallate using oxidative dearomatization and regio- and diastereoselective Diels–
Alder reaction as the key steps.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Diels–Alder cycloaddition
Oxidative dearomatization
Houk rule violation
Bicyclo[2.2.2]octene
1. Introduction
gastrointestinal tract of the sea hare Aplysia kurodai.1,2 Pericosines
display in vitro antitumor activity, and 1 was shown to have in vivo
Pericosines A–E (1–5, Scheme 1) are natural compounds iso-
lated from the fungus Periconia byssoides OUPS-N133 found in the
antitumor activity.2
The synthesis of 1, 2, 3 and their stereoisomers has already been
established and all of these procedures start from (ꢀ)-quinic acid,
(ꢀ)-shikimic acid or other alicyclic compounds.3,4
In this study we report on the synthesis of a bridged analogue of
pericosines A–D and the evaluation of its biological activity.
2. Results and discussion
Masked ortho-benzoquinone (MOB) ketals5,6 are attractive
synthetic intermediates for obtaining complex chemical structures
since their Diels–Alder reaction is a versatile tool for the con-
struction of tricyclic compounds. MOBs can be obtained by oxida-
tion of o-alkoxyphenols in methanol and one of the most effective
reagents is diacetoxyiodobenzene.6–9 For the synthesis of the target
bridged pericosine analogue this dearomatization–Diels–Alder se-
quence has been chosen.
Methyl gallate (6), a cheap, commercially available aromatic
compound was selected as starting material. Since our target
molecule has five chiral centers an appropriate dearomatization of
the gallic ester was necessary as a key step of the synthesis. After
protection of two of the phenolic hydroxyl groups in the form of
a diphenylmethylene acetal (7)10, oxidative dearomatization with
Scheme 1. Structures of pericosines.
* Corresponding author. Tel.: þ36 52 512 900; fax: þ36 52 512 914.
E-mail address: herczeghp@gmail.com (P. Herczegh).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.084

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Z. Fejes et al. / Tetrahedron 65 (2009) 8171–8175
diacetoxyiodobenzene in methanol resulted in the dienone double
acetal 8. As this acetal is formed as a racemate, all of the products of
the following reactions are racemic, however, for the sake of sim-
plicity only one of the enantiomers is displayed in the schemes.
Thermal Diels–Alder reaction of 8 with benzyl vinyl ether11 gave
exclusively 9 with complete regio- and diastereoselectivity. The
exact structure of this compound was established by X-ray dif-
fraction (Fig. 1, Scheme 2).
observed selectivity. The HOMO and LUMO orbital energies, orbital
shapes, and the coefficients of the atomic orbital contributions to
the HOMO and LUMO at the diene and dienophile were calculated
(see Figs. S2 and S3 in Supplementary data). The cycloaddition
turned out to be an inverse electron demand reaction. Regarding
the coefficients of the atomic orbitals, the computationally pre-
dicted and experimentally observed products do not match, so the
reaction violates the Houk rule.12 Examining the TS geometry,
a non-negligible secondary interaction was obtained between the
carbonyl oxygen of COOMe and a H atom of the benzyl –CH2– group
(see Fig. S4 in Supplementary data), which stabilizes the TS and it
becomes the most favorable one even if it violates the Houk rule.
These facts clearly show the qualitative-only features of the
HOMO–LUMO interactions and the importance of the secondary
interactions.
For the temporary protection of the carbon–carbon double
bond, conjugate addition of thiophenol and oxidation of the so-
formed sulfide with m-chloroperbenzoic acid (m-CPBA) to sulfone
10 were performed in the next steps. The addition resulted in
a trans product, as shown by the value J2,3¼4.0 Hz. The long-range
coupling between H-3 and H-8b can be explained by a configura-
tion in which the H8b–C8–C4–C3–H3 bonds are in a nearly coplanar
W-arrangement. In this case the phenylsulfonyl group points to-
ward the C-8 atom. The configuration of 10 was confirmed by X-ray
diffraction (Fig. 2).
Figure 1. ORTEP view of cycloadduct 9.
Figure 2. ORTEP view of 10.
Reduction of the ketone 10 using NaBH4, LiBH4 or BH3$DMS
reagents resulted in 11 and 110 with low diastereoselectivity (w20%
de), while NaBH3CN and NaBH(OAc)3 did not even reduce the car-
bonyl group. However, application of the CeCl3/NaBH4 reagent13 in
methanol preformed prior to the reaction gave rise to a mixture of
11 and 110 in a 7.2:1 ratio. In this case the reducing agents should be
the methoxyborohydrides NaBH3OMe, NaBH2(OMe)2, and NaB-
H(OMe)3, the formation of which is facilitated by CeCl3. Steric effect
of these hydrides and the bonding of CeCl3 as a Lewis acid to the oxo
group of the ketone can contribute to the stereochemical outcome
of the reduction alike. However, the ratio of the diastereomers was
not adequately reproducible (the formation ratio of methoxybor-
ohydrides and the amount of NaBH4 formed by disproportion-
ation14 was largely dependent on the reaction time), therefore we
chose an alternative reducing agent, sodium tris(tri-
fluoroethoxy)borohydride. This reagent can be prepared from
NaBH4 and trifluoroethanol14, the de achieved by its use was 76%.
Separation of 11 and 110 was performed by column chromatography
Scheme 2. Route to the Diels–Alder adduct 9.
The dienophile has an electron releasing substituent, therefore
an inverse electron demand Diels–Alder reaction could be sus-
pected, but the presence of both electron releasing and electron
withdrawing substituents of the diene prompted us for a theoreti-
cal study of this reaction. For this reason we carried out various
quantum chemical calculations with the following results.
Upon examination of the possible transition states (TS) we
found that the lowest energy belongs to the TS leading to the only
product isolated from the Diels–Alder reaction (see Fig. S1 in
Supplementary data). Using model reactants (i.e., replacing the
phenyl and benzyl groups by hydrogen atoms, this way
distinguishing between the steric and electronic effects) gave the
same result. It suggests a strong electronic contribution to the

Z. Fejes et al. / Tetrahedron 65 (2009) 8171–8175
8173
and their relative stereochemistry was explored by NMR spec-
troscopy and X-ray diffraction (Fig. 3).
Scheme 3. Transformation of 9 to the perisocine analogue 14.
were made visible using UV light (254 nm) and/or spraying with
acidic (H2SO4) ammonium molybdate solution followed by heating.
Flash column chromatography was carried out under pressure using
Merck Kieselgel 60 silica (0.040–0.063 mm). NMR spectra were
recorded on a Bruker Avance DRX 500 or a Bruker Avance 360
spectrometer, at the given frequency and in the given solvent.
Chemical shifts are given in parts per million and coupling constants
in hertz. NMR assignments were based on 2D COSY and 2D HSQC
experiments. High resolution mass spectra were obtained on
a Bruker microTOF-Q (ESI-QqTOF) spectrometer. Melting points
were measured on a Bu¨chi Melting Point B-540 device and are un-
corrected. IR spectra were recorded on a Perkin Elmer 16 PC FT-IR
spectrometer. X-ray data were collected on a Bruker-Nonius MACH3
Figure 3. ORTEP view of 110.
Acid hydrolysis of the acetal 11 and subsequent stereoselective
reduction of the intermediary -hydroxyketone with NaBH4 in
a
methanol furnished triol 12. The coupling constant between H-2
and H-3 increased from w4 Hz (in 10, 11, and 110) to w8.5 Hz (in 12
and 13), which shows a change from the original trans stereo-
chemistry to cis. The epimerization can occur either at H-2 or at H-3
as both have acidic character, however, the change in the coupling
constant between H-1 and H-2 from w4 Hz (in 10, 11, and 110) to
w2 Hz (in 12 and 13) showed that it took place at C-2. After removal
of the benzyl group by catalytic hydrogenation, the phenylsulfonyl
group of 13 had to be eliminated to regenerate the carbon–carbon
double bond. Treating 13 with Et3N or DABCO did not lead to any
reaction, the use of DBU triggered lactone formation exclusively.
The suitable base was K2CO3 in methanol, which led to the for-
mation of the bridged pericosine analogue 14 (Scheme 3).
diffractometer at 293 K, Mo K
a
radiation
l¼0.71073 Å,
u motion. The
structure was solved using the SIR-92 software15 and refined on F2
using SHELX-97 program,16 publication material was prepared with
the WINGX-97 suite.17 All non-hydrogen atoms were refined aniso-
tropically. Hydrogen atoms were fixed into geometric position ex-
cept O–H, which could be found at the difference electron density
map. Further information on structure determination could be found
in Supplementary data (Table S2). Crystallographic data (excluding
structure factors) for the structures 9, 10, and 110 in this paper have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC 723534/723535/723536, re-
spectively. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
þ44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk). The
quantum chemical calculations were carried out by means of the
Gaussian ’03 quantum chemical software package.18 For visualiza-
tion the Molekel 5.219,20 and the Arguslab 4.0.121 suites of software
were used. The cytotoxicity assays were performeddaccording to
our previous work22din several human and animal cell lines, in
which the compound’s cytotoxicity was estimated from micro-
scopically visible alterations in cell morphology or from cell viability,
determined by the formazan-based MTS assay.
Unfortunately, 14 was found to have no cytotoxic activity in
several cell lines, i.e., Crandell-Rees feline kidney (CRFK), human
cervixcarcinoma (HeLa) cells, human embryonic lung (HEL) fibro-
blasts, Madin-Darby canine kidney (MDCK) cells and African green
monkey kidney (Vero) cells (maximum compound concentration
tested: 100 mM).
3. Summary
Starting from the achiral aromatic precursor 6 we performed the
stereoselective synthesis of 14 with 5 chiral centers in 10 synthetic
steps.
4. Experimental
4.1. General methods
Dry dichloromethane, dry methanol, and dry THF were distilled
from P2O5, Mg, and Na/Ph2CO (under N2), respectively. Solutions
were concentrated in vacuo at 40 ꢁC. Organic phases were dried over
Na2SO4. TLC was performed on Merck Kieselgel F254 plates, spots
4.2. Sodium tris(trifluoroethoxy)borohydride
Sodium tris(trifluoroethoxy)borohydride was prepared by the
method of Golden and co-workers14 with a few minor changes: the

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Z. Fejes et al. / Tetrahedron 65 (2009) 8171–8175
reaction time was longer (19 h) and after the initial cooling no
further cooling was applied. As the reaction mixture yet contained
some solid NaBH4, it was filtered off and the filtrate was used.
1153 (SO2) cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
8.27–6.90 (m, 20H,
4
Ar), 4.68 (dd, 1H, J2¼4.0, J8b¼2.0, H-3), 4.68 (d, 1H, Jgem¼11.9,
OCH2Ph), 4.36 (d, 1H, Jgem¼11.9, OCH2Ph), 4.31 (t, 1H, J1wJ3w4, H-
2), 3.76 (dd, 1H, J8b¼8.5, J1¼4.6, H-7), 3.67 (s, 3H, COOMe), 3.38 (t,
1H, J7wJ2w4, H-1), 3.07 (d, 1H, J8b¼15.6, H-8a), 2.73 (s, 3H, 5-OMe),
1.56 (ddd, 1H, J8a¼15.6, J7¼8.5, 4J3¼2.0, H-8b); 13C NMR (125 MHz,
4.3. Methyl 4,5-dihydroxy-4-methoxy-3-oxo-4,5-O-
diphenylmethylidenecyclohexa-1,5-dienecarboxylate (8)
CDCl3):
d 196.61 (C-6), 171.7 (COOMe), 143.2–124.6 (Ar), 114.8
To a stirred solution of 4,5-O-(diphenylmethylidene)methyl
gallate5 (14.0 g, 40.2 mmol) in dry MeOH (500 mL), PIDA (23.2 g,
72.1 mmol) was added in four portions at 20 ꢁC. The reaction
mixture was stirred for 15 min at 20 ꢁC and additional 45 min at
room temperature, then NaHCO3 (15 g) was added and the stirring
was continued for 15 min. The brown mixture was filtered, washed
with CH2Cl2, and the filtrate was evaporated in vacuo. The residue
was subjected to flash column chromatography (hexane/EtOAc 9:1)
to give 5.86 g (39%) 8 as a yellow solid. Mp: 115–118 ꢁC; HRMS m/z
calcd for C22H18O6Na (MþNaþ) 401.1001, found 401.0994; IR (KBr):
(CPh2), 102.7 (C-5), 86.1 (C-4), 69.9 (C-7), 69.9 (OCH2Ph), 63.7 (C-3),
52.8 (COOMe), 51.2 (C-1), 50.3 (5-OMe), 38.9 (C-2), 29.3 (C-8).
4.6. Methyl 7-benzyloxy-4,5,6-trihydroxy-5-methoxy-4,5-O-
diphenylmethylidene-3-phenylsulfonylbicyclo[2.2.2]-
octane-2-carboxylate (11, 110)
To a solution of 10 (2.01 g, 3.1 mmol) in dry THF (70 mL) at
ꢀ10 ꢁC a NaBH(OCH2CF3)3 solution (17 mL, ca. 0.9 mM in THF; ca.
15 mmol of hydride) was added in ca. 2 mL portions over 5 min
under argon. The solution was stirred for further 45 min at ꢀ10 ꢁC
then evaporated in vacuo. The residue was dissolved in EtOAc
(200 mL) and saturated NaHCO3 solution (30 mL) was added slowly
with vigorous stirring (rapid evolution of H2(g)!) to decompose the
excess reagent. Stirring was continued for 10 min and the mixture
was transferred to a separating funnel and shaked. The organic
phase were extracted with a further 30 mL of saturated NaHCO3
solution, then the combined aqueous phase was washed with
EtOAc (20 mL). The combined organic extract was dried (Na2SO4),
filtered, and evaporated in vacuo. The crude product was purified
by flash column chromatography (hexane/CH2Cl2/acetone 7:3:1) to
furnish 11 (1.43 g, 71%) as a white solid. After the elution of 11, the
eluent was changed to hexane/CH2Cl2/acetone 7:4:2 to afford 110
(0.20 g, 10%). Compound 11: mp: 194–196 ꢁC; HRMS: m/z calcd for
C37H36O9SNa (MþNaþ) 679.1978, found 679.1977; IR (KBr): 3479
1728, 1706 (C]O), 1555 (C]C) cmꢀ1 1H NMR (360 MHz, CDCl3):
;
d
2.99 (s, 3H, 4-OMe), 3.85 (s, 3H, COOMe), 5.87 (d, 1H, 4J¼1.0, H-2/
H-6), 6.44 (d, 1H, 4J¼1.0, H-2/H-6), 7.30–7.59 (m, 10H, Ar); 13C NMR
(90 MHz, CDCl3):
d 50.4, 52.8 (2C, 4-OMe, COOMe), 91.7 (C-6), 99.0
(C-4), 116.9 (CPh2), 121.5 (C-2), 125.8, 126.0, 128.0, 128.2 (10C, Ar),
128.7,129.3 (2C, C-2, C-6),139.6, 140.37, 143.4 (3C, C-5, Ar),159.4 (C-
1), 165.0 (COOMe), 191.2 (C-3).
4.4. Methyl 7-benzyloxy-4,5-dihydroxy-5-methoxy-6-oxo-4,5-
O-diphenylmethylidenebicyclo[2.2.2]oct-2-ene-2-
carboxylate (9)
A solution of 8 (3.01 g, 8.0 mmol) in benzyl vinyl ether6 (15.0 g,
111.8 mmol) was stirred at 90 ꢁC for 6 h. The reaction mixture was
subjected to flash column chromatography (hexane/EtOAc 92:8) to
furnish 3.22 g (79%) 9 as a slightly yellowish solid. Removal of the
remaining starting material by washing two times with cold eth-
anol afforded 2.94 g (72%) white solid. Mp: 151–153 ꢁC; HRMS: m/z
calcd for C31H28O7Na (MþNaþ) 535.1733, found 535.1730; IR (KBr):
(OH), 1745 (C]O), 1151 (SO2) cmꢀ1 1H NMR (500 MHz, CDCl3):
;
d
8.23–6.89 (m, 20H, Ar), 4.71 (d, 1H, Jgem¼11.9, OCH2Ph), 4.50 (dd,
1H, J2¼4.0, 4J8b¼2.1, H-3), 4.30 (d, 1H, Jgem¼11.9, OCH2Ph), 4.28 (dd,
1H, J3¼4.0, J1¼3.8, H-2), 4.17 (d, 1H, J6¼10.3, OH), 3.89 (d, 1H,
JOH¼10.3, H-6), 3.78 (dd, 1H, J8b¼8.4, J1¼4.6, H-7), 3.76 (s, 3H,
COOMe), 2.81 (d, 1H, J8b¼15.2, H-8a), 2.76 (t, 1H, J7wJ2w4, H-1),
2.71 (s, 3H, 5-OMe), 1.44 (ddd, 1H, J8a¼15.2, J7¼8.4, 4J3¼2.1, H-8b);
1747, 1716 (C]O), 1613 (C]C) cmꢀ1 1H NMR (360 MHz, CDCl3):
;
d
7.72 (dd, 1H, 4J1¼1.7, 4J8aw4J8bw0.9, H-3), 7.62–7.15 (m, 15H, Ar),
4.56 (d, 1H, Jgem¼11.3, OCH2Ph), 4.34 (ddd, J7¼3.5, 4J3¼1.7, 4J8b¼0.9,
1H, H-1), 4.28 (d, 1H, Jgem¼11.3, OCH2Ph), 3.90 (ddd, 1H, J8a¼8.0,
J1¼3.5, J8b¼1.6, H-7), 3.79 (s, 3H, COOMe), 2.81 (s, 3H, 5-OMe), 2.10
(ddd, 1H, J8a¼14.7, J7¼8.0, 4J3¼0.9, H-8b), 1.45 (ddd, 1H, J8b¼14.7,
13C NMR (125 MHz, CDCl3):
d 176.1 (COOMe), 144.3–124.8 (Ar),
113.4 (CPh2), 107.0 (C-5), 85.0 (C-4), 73.7 (C-6), 71.0 (C-7), 69.3
(OCH2Ph), 64.6 (C-3), 53.2 (COOMe), 52.8 (5-OMe), 42.4 (C-1), 38.6
(C-2), 27.5 (C-8). Compound 110: mp: 178–181 ꢁC; HRMS: m/z calcd
for C37H36O9SNa (MþNaþ) 679.1978, found 679.1975; IR (KBr):
4J7¼1.6, 4J3¼0.9, H-8a); 13C NMR (90 MHz, CDCl3):
d 194.3 (C-6),
164.3 (COOMe), 143.6, 143.0 (Ar), 140.7 (C-3), 137.0 (C-2), 128.3–
124.9 (Ar), 115.1 (CPh2), 99.7 (C-5), 89.3 (C-4), 73.5 (C-7), 70.5
(OCH2Ph), 53.0 (C-1), 52.0 (COOMe), 51.0 (5-OMe), 36.1 (C-8).
3491 (OH), 1736 (C]O), 1151 (SO2) cmꢀ1 1H NMR (500 MHz,
;
CDCl3):
d
8.23–6.89 (m, 20H, Ar), 4.75 (d, 1H, Jgem¼11.9, OCH2Ph),
4.62 (dd, 1H, J2¼4.2, 4J8b¼2.1, H-3), 4.27 (d, 1H, Jgem¼11.9, OCH2Ph),
4.25 (t, 1H, J1wJ3w4.5, H-2), 4.19 (dd, 1H, J1¼5.0, JOH¼2.4, H-6), 4.09
(dd, 1H, J8b¼8.2, J1¼4.6, H-7), 3.67 (s, 3H, COOMe), 3.10 (q, 1H,
J2wJ6wJ7w4.5, H-1), 2.88 (d, 1H, J8b¼14.8, H-8a), 2.53 (s, 3H, 5-
OMe), 2.13 (d, 1H, J6¼2.4, OH), 1.62 (ddd, 1H, J8a¼14.8, J7¼8.2,
4.5. Methyl 7-benzyloxy-4,5-dihydroxy-5-methoxy-6-oxo-4,5-
O-diphenylmethylidene-3-phenylsulfonylbicyclo-
[2.2.2]octane-2-carboxylate (10)
To a solution of 9 (2.85 g, 5.6 mmol) in CH3CN (100 mL, flushed
thoroughly with argon) thiophenol (0.80 mL, 7.8 mmol) and Et3N
(1.28 mL, 9.2 mmol) were added. The solution was stirred at room
temperature under argon for 1 h. Pre-dried (Na2SO4) solution of m-
CPBA (10.60 g in 150 mL CH2Cl2; max. 77% m-CPBA, ca. 47 mmol)
was added dropwise for 45 min at 20 ꢁC and the solution was
stirred for further 2 h, then evaporated in vacuo. The residue was
dissolved in EtOAc (300 mL) and washed with 10% Na2SO3 solution
(2ꢂ50 mL) and saturated NaHCO3 solution (2ꢂ50 mL). The com-
bined aqueous washings were extracted with EtOAc (20 mL). The
combined organic extract was dried (Na2SO4), filtered, and con-
centrated in vacuo. The crude product was purified by flash column
chromatography (hexane/acetone 7:3) to furnish 3.43 g (94%) 10 as
a white solid. Mp: 195–198 ꢁC; HRMS: m/z calcd for C37H34O9SNa
(MþNaþ) 677.1821, found 677.1829; IR (KBr): 1752, 1743 (C]O),
4J3¼2.1, H-8b); 13C NMR (125 MHz, CDCl3):
d 172.3 (COOMe), 143.8–
124.7 (Ar), 114.2 (CPh2), 105.0 (C-5), 85.6 (C-4), 69.7 (OCH2Ph), 69.3
(C-7), 66.5 (C-6), 63.3 (C-3), 52.4 (COOMe), 47.9 (5-OMe), 39.9 (C-1),
38.4 (C-2), 27.1 (C-8).
4.7. Methyl 7-benzyloxy-4,5,6-trihydroxy-3-phenyl-
sulfonylbicyclo[2.2.2]octane-2-carboxylate (12)
The solution of 11 (518 mg, 0.8 mmol) in trifluoroacetic acid
(25 mL) was stirred for 2 h at room temperature, diluted with dry
toluene (15 mL), and evaporated in vacuo at 35 ꢁC. The remaining
acid was removed by distilling a further 15 mL toluene from the
residue. The crude product was dissolved in methanol (20 mL) and
NaBH4 (120 mg, 3.2 mmol) was added in portions with stirring.
After 20 min the reaction mixture was neutralized with Serdolit-

Z. Fejes et al. / Tetrahedron 65 (2009) 8171–8175
8175
Red cation-exchanger, the resin was filtered off, washed with
methanol, and the filtrate was concentrated in vacuo. From the
residue methanol was evaporated four times. The crude triol was
subjected to flash column chromatography (CH2Cl2/MeOH 96:4) to
furnish 12 (150 mg, 41%) as an off-white solid. Mp: 164–167 ꢁC;
HRMS: m/z calcd for C23H26O8SNa (MþNaþ) 485.1246, found
(dd, 1H, J6¼7.8, 4J3¼1.4, H-5), 3.42 (m, 1H, H-1), 1.96 (ddd, 1H,
J8a¼13.5, J7¼8.4, 4J3¼1.0, H-8b), 1.23 (ddd, 1H, J8b¼13.5, J7¼2.9,
4J3¼1.0, H-8a); 13C NMR (125 MHz, CD3OD):
d 167.4 (COOMe),
147.1 (C-3), 132.1 (C-2), 76.6 (C-4), 74.5 (C-5), 67.9 (C-6), 66.2 (C-7),
52.3 (COOMe), 47.2 (C-1), 41.7 (C-8).
485.1233; IR (KBr): 3445 (OH), 1738 (C¼O), 1145 (SO2) cmꢀ1
;
1H
Acknowledgements
NMR (500 MHz, CDCl3):
d 7.97–7.29 (m, 10H, Ar), 4.59 (d, 1H,
Jgem¼11.9, OCH2Ph), 4.55 (d, 1H, Jgem¼11.9, OCH2Ph), 4.45 (s, 1H, 4-
This work was supported by the Hungarian National In-
frastructure Development Program (Grant: NIIF 1116) and the
Hungarian Scientific Research Funds (Grants: OTKA 68578, OTKA
79126).
4
OH), 4.37 (dd, 1H, J2¼8.6, J8b¼2.1, H-3), 3.93 (ddd, 1H, J1¼4.0,
J5¼8.8, J6-OH¼3.0, H-6), 3.80 (dd, 1H, J1¼2.0, J3¼8.6, H-2), 3.68 (ddd,
1H, J8b¼9.8, J8a¼4.4, J1¼2.6, H-7), 3.55 (d, 1H, J6¼8.8, J5-OHw1.0, H-
5), 3.53 (s, 3H, COOMe), 3.31 (d, 1H, J5w1.0, 5-OH), 3.14 (d, 1H,
J6¼3.0, 6-OH), 2.86 (ddd, 1H, J6¼4.0, J7¼2.6, J2¼2.0, H-1), 2.65 (dd,
1H, J8b¼14.1, J7¼4.4, H-8a), 1.82 (ddd, 1H, J8a¼14.1, J7¼9.8, 4J3¼2.1,
Supplementary data
H-8b); 13C NMR (125 MHz, CDCl3):
d 173.5 (COOMe), 140.4–127.7
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.07.084.
(Ar), 72.3 (C-4), 71.1 (C-5), 70.1 (OCH2Ph), 69.7 (C-7), 65.5 (C-6), 60.5
(C-3), 52.3 (COOMe), 40.8 (C-1), 37.2 (C-2), 35.2 (C-8).
References and notes
4.8. Methyl 4,5,6,7-tetrahydroxy-3-phenylsulfonyl-
bicyclo[2.2.2]octane-2-carboxylate (13)
1. Numata, A.; Iritani, M.; Yamada, T.; Minoura, K.; Matsumura, E.; Yamori, T.;
Tsuruo, T. Tetrahedron Lett. 1997, 38, 8215.
2. Yamada, T.; Iritani, M.; Ohishi, H.; Tanaka, K.; Minoura, K.; Doi, M.; Numata, A.
Org. Biomol. Chem. 2007, 5, 3979.
3. Usami, Y.; Ichikawa, H.; Arimoto, M. Int. J. Mol. Sci. 2008, 9, 401.
4. Usami, Y.; Suzuki, K.; Mizuki, K.; Ichikawa, H.; Arimoto, M. Org. Biomol. Chem.
2009, 7, 315.
5. Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. Rev. 2004, 104, 1383.
6. Liao, C.-C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35, 856.
7. Ku¨rti, L.; Herczegh, P.; Visy, J.; Simonyi, M.; Antus, S.; Pelter, A. J. Chem. Soc.,
Perkin Trans. 1 1999, 379.
8. Mal, D.; Roy, H. N.; Hazra, N. K.; Adhikari, S. Tetrahedron 1997, 53, 2177.
9. Mitchell, A. S.; Russell, R. A. Tetrahedron 1997, 53, 4387.
10. Jurd, L. J. Am. Chem. Soc. 1959, 81, 4606.
11. Nielsen, T. E.; Le Quement, S.; Juhl, M.; Tanner, D. Tetrahedron 2005, 61, 8013.
12. Houk, K. N. J. Am. Chem. Soc. 1973, 95, 4092.
13. Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.; John Wiley &
Sons: New York, NY, 1995; Vol. 2, pp 1031–1034.
14. Golden, J. H.; Schreier, C.; Singaram, B.; Williamson, S. M. Inorg. Chem. 1992, 31,
1533.
15. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A. J. Appl. Crystallogr.
1993, 26, 343.
To a solution of 12 (223 mg, 0.5 mmol) in the mixture of
methanol (5 mL) and ethyl acetate (5 mL) Pd(C) (99 mg, 10% Pd)
was added. After flushing with argon, the mixture was hydroge-
nated for 5 h. The reaction mixture was filtered through a pad of
Celite, then the Celite was washed with methanol and ethyl acetate.
Evaporation of the filtrate gave rise to 185 mg (quant.) white
powder, which was pure enough for the next reaction. Analytically
pure 13 was obtained by recrystallization from MeOH/CH2Cl2/
hexane. Mp: 181–185 ꢁC. HRMS: m/z calcd for C16H20O8SNa
(MþNaþ) 395.0777, found: 395.0764; IR (KBr): 3418 (OH), 1732
(C]O), 1141 (SO2) cmꢀ1
;
1H NMR (500 MHz, CD3OD):
d
7.99–7.55
4
(m, 5H, Ar), 4.51 (dd, 1H, J2¼8.7, J8b¼2.1, H-3), 4.00 (ddd, 1H,
J8b¼10.1, J8a¼4.1, J1¼3.1, H-7), 3.90 (dd, 1H, J1¼3.5, J5¼8.7, H-6), 3.69
(dd, 1H, J1¼2.1, J3¼8.7, H-2), 3.61 (s, 3H, COOMe), 3.44 (d, 1H, J6¼8.7,
H-5), 2.58 (dd, 1H, J8b¼14.1, J7¼4.1, H-8a), 2.53 (dd, 1H, J6wJ7w3.5,
J2¼2.1, H-1), 1.75 (ddd, 1H, J8a¼14.1, J7¼10.1, 4J3¼2.1, H-8b); 13C NMR
16. Sheldrick, G. M. Programs for Crystal Structure Analysis (Release 97-2); Institu¨t
fu¨ r Anorganische Chemie der Universita¨t: Tammanstrasse 4, D-3400 Go¨ttingen,
Germany, 1998.
(125 MHz, CD3OD):
d 175.6 (COOMe), 143.2, 134.6, 130.1, 130.0 (Ar),
73.6 (C-4), 73.0 (C-5), 66.7 (C-6), 64.6 (C-7), 61.5 (C-3), 52.8
17. Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837.
(COOMe), 46.4 (C-1), 37.3 (C-2), 37.1 (C-8).
18. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J.
R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar,
S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Pe-
tersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa,
J.;Ishida,M.;Nakajima, T.;Honda, Y.;Kitao,O.;Nakai, H.;Klene, M.;Li, X.; Knox, J.E.;
Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.;
Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V.
G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;
Cioslowski, J.;Stefanov, B.B.;Liu,G.;Liashenko,A.;Piskorz, P.;Komaromi, I.;Martin,
R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe,
M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
Gaussian 03, Revision C.02; Gaussian: Wallingford, CT, 2004.
4.9. Methyl 4,5,6,7-tetrahydroxybicyclo[2.2.2]oct-2-ene-
2-carboxylate (14)
To a solution of 13 (160 mg, 0.4 mmol) in dry methanol
(20 mL) K2CO3 (172 mg, 1.0 mmol) was added and the reaction
mixture was stirred at room temperature for 24 h. After neutral-
izing the solution with Serdolit-Red, the resin was filtered off and
washed with methanol. The filtrate was evaporated and the crude
product was purified by flash column chromatography (CH2Cl2/
MeOH 85:15) to obtain 59 mg (60%) 14 as a slightly yellowish
hygroscopic substance. HRMS: m/z calcd for C10H14O6Na (MþNaþ)
253.0688, found: 253.0698; IR (KBr): 3338 (OH), 1703 (C]O),
19. Flu¨kiger, P.; Lu¨thi, H. P.; Portmann, S.; Webere, J. MOLEKEL 5.2; Swiss Center for
Scientific Computing: Manno, Switzerland, 2000–2002.
20. Portmann, S.; Lu¨ thi, H. P. Chimia 2000, 54, 766.
21. Thompson M.A., ArgusLab 4.0.1, Planaria Software, Seattle, WA; http://www.
arguslab.com
1629 (C]C) cmꢀ1 1H NMR (500 MHz, CD3OD):
; d 7.12 (dd, 1H,
}
}
22. Naesens, L.; Vanderlinden, E.; Roth, E.; Jeko, J.; Andrei, G.; Snoeck, R.; Pan-
necouque, C.; Illye´s, E.; Batta, G.; Herczegh, P.; Sztaricskai, F. Antiviral Res. 2009,
82, 89.
4J1¼2.5, 4J5w4J8aw4J8bw1, H-3), 4.02 (dt, 1H, J8b¼8.4, J1wJ8aw2.9,
H-7), 3.93 (dd, 1H, J1¼2.7, J5¼7.8, H-6), 3.75 (s, 3H, COOMe), 3.57