Stilbenophane analogues of deoxycombretastatin A-4

Article abstract of DOI:10.1021/jo0508393

A new family of polyoxygenated stilbenophanes has been synthesized as conformationally restricted analogues of antimitotic combretastatins. By means of the McMurry olefination process, compounds derived from diethyleneglycol and 1,6-hexanediol were obtain

Full text of DOI:10.1021/jo0508393

Stilbenophane Analogues of
Deoxycombretastatin A-4
Carmen Mateo, Concepci o´ n P e´ rez-Melero,
Rafael Pel a´ ez,* and Manuel Medarde*
Laboratorio de Qu ı´ mica Org a´ nica y Farmac e´ utica,
Universidad de Salamanca, Facultad de Farmacia, Campus
“
Miguel de Unamuno”, E-37007, Salamanca, Spain
FIGURE 1. Structure of combretastatin A-1 (CA1), combre-
tastatin A-4 (CA4), its 3′-deoxyanalogue (DCA4), and designed
stilbenophane 4a.
pelaez@usal.es; medarde@usal.es
Received April 26, 2005
FIGURE 2. Retrosynthetic analysis of synthesized stil-
benophanes. Ring-closing metathesis (Y ) CH ) or McMurry
2
olefination (Y ) O) was the methodology selected for the
A new family of polyoxygenated stilbenophanes has been
synthesized as conformationally restricted analogues of
antimitotic combretastatins. By means of the McMurry
olefination process, compounds derived from diethyleneglycol
and 1,6-hexanediol were obtained, whereas Grubbs’ catalyst
failed in producing the ring-closing metathesis to this kind
of macrocyclic products.
macrocyclization process.
cellular transport agents.8 The combination of cyclo-
9
phanes and crown ethers is known as crownophanes.
During our research directed at the synthesis and
evaluation of new cytotoxic agents based on natural
10
products, we designed several macrocyclic derivatives
of the antimitotic agents combretastatin A-4 and related
compounds (Figure 1).11
Diversely substituted paracyclophane derivatives are
compounds of interest due to their structural features
These compounds are polyoxygenated stilbenophanes
macrocyclized through a polymethylene(polyether) chain
sharing in part the structure of crownophanes. The
presence of hexamethylene or 3-oxapentamethylene link-
ers restrict the conformational freedom of combreta-
statins, because they occupy the space between the two
rings. This fact prevents the adoption of conformations
in which the phenyl rings could be close to the coplanarity
with the double bond. The synthesis of these derivatives
and the study of the effect on their particular conforma-
tions and biological activities are very interesting in the
search for new bioactive compounds. We planned the
synthesis of title compounds as depicted in Figure 2. For
synthetic simplicity and versatility, we selected the
formation of the stilbenic double bond as the macrocy-
1
and properties. Among the paracyclophanes, the so-
2
called stilbenophanes have two aromatic systems linked
by an olefinic bridge. Polyether linkages between aro-
matic systems are found in interesting organic com-
pounds such as the crown ethers, their main use being
3
as complexing agents for cations (coronands and other
4
supramolecular hosts ). They have also been used as
5
6
catalysts, polymeric materials, and molecular machines
7
and switches. However, less frequent are those display-
ing biological activity as in the use of rotaxanes as
(1) (a) V o¨ gtle, F.; Neumann, P. Tetrahedron 1970, 26, 5847. (b)
Keehn, P. M., Rosenfeld, S. M., Eds. Cyclophanes; Academic Press:
New York, 1983; Vols. 1 and 2. (c) V o¨ gtle, F. Cyclophane Chemistry;
Wiley: Chichester, UK, 1993.
(
2) (a) Rajakumar, P.; Murali, V. Tetrahedron 2004, 60, 2351-2360.
(
b) Gierschner, J.; Mack, H. G.; Oelkrug, D.; Waldner, I.; Rau, H. J.
(8) Dvornikovs, V.; House, B. E.; Kaetzel, M.; Dedman, J. R.;
Smithrud, D. B. J. Am. Chem. Soc. 2003, 125, 8290-8301.
Phys. Chem. A 2004, 108, 257-263. (c) Ernst, L. Prog. Nucl. Magn.
Reson. Spectrosc. 2000, 37, 47-190. (d) Tanner, D.; Wennerstrom, O.
Tetrahedron Lett. 1981, 22, 2313-2316.
(9) (a) Furstner, A.; Seidel, G.; Kopiske, C.; Kruger, C.; Mynott, R.
Liebigs Ann. 1996, 655-662. (b) Hiratani, K.; Sakamoto, N.; Kameta,
N.; Karikomia, M.; Nagawa, Y. E. Chem. Commun. 2004, 1474-1475.
(c) Inokuma, S.; Sakai, S.; Nishimura, J. In Cyclophanes; 1994; Vol.
172, pp 87-118. (d) Inokuma, S.; Funaki, T.; Hara, D.; Nishimura, J.
Heterocycles 2004, 63, 333-346. (e) Lukyanenko, N. G.; Kirichenko,
T. I.; Lyapunov, A. Y.; Kulygina, C. Y.; Siminov, Y. A.; Fonari, M. S.;
Botoshansky, M. M. Tetrahedron Lett. 2004, 45, 2927-2930.
(10) (a) Lignans: Madrigal, B.; Puebla, P.; Pel a´ ez, R.; Caballero, E.;
Medarde, M. J. Org. Chem. 2003, 68, 854-864. (b) Indolocarbazole
alkaloids: Adeva, M.; Sahagun, H.; Caballero, E.; Pel a´ ez, R..; Medarde,
M.; Tom e´ , F. J. Org. Chem. 2000, 65, 3387-3394. (c) Combretast-
atins: P e´ rez-Melero, C.; Maya, A. B. S.; del Rey, B.; Pel a´ ez, R.;
Caballero, E.; Medarde, M. Bioorg. Med. Chem. Lett. 2004, 14, 3771-
3774. Maya, A. B. S.; P e´ rez-Melero, C.; Mateo, C.; Alonso, D.;
Fern a´ ndez, J. L.; Gajate, C.; Mollinedo, F.; Pel a´ ez, R.; Caballero, E.;
Medarde, M. J. Med. Chem. 2005, 48, 556-568.
(
3) Marquis, D.; Desvergne, J. P.; Bouas-Laurent, H. J. Org. Chem.
1
995, 60, 7984-7996.
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R. M. J. Org. Chem. 1996, 61, 7270-7275.
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6, 7287-7293. (b) Sharghi, H.; Massah, A. R.; Eshghi, H.; Niknam,
K. J. Org. Chem. 1998, 63, 1455-1461.
6) (a) Pearson, A. J.; Gelormini, A. M. J. Org. Chem. 1995, 60, 281-
84. (b) Komura, K.; Itsuno, S.; Ito, K. Chem. Commun. 1999, 35-36.
7) (a) Ashton, P. R.; Baldoni, V.; Balzani, V.; Credi, A.; Hoffmann,
(
(
6
(
2
(
H. D. A.; Mart ´ı nez-D ´ı az, M. V.; Raymo, F. M.; Stoddart, J. F.; Venturi,
M. Chem. Eur. J. 2001, 7, 3482-3493. (b) Badjic J. D.; Balzani, V.;
Credi, A.; Lowe, J. N.; Silvi, S.; Stoddart, J. F. Chem. Eur. J. 2004.
1
0, 1926-1935. (c) Ashton, P. R.; Balzani, V.; Becher, J.; Credi, A.;
Fyfe, M. C. T.; Mattersteig, G.; Menzer, S.; Nielsen, M. B.; Raymo, F.
M.; Stoddart, J. F.; Venturi, M.; Williams, D. J. J. Am. Chem. Soc.
1
(11) Lin, C. M.; Singh, S. B.; Chu, P. S.; Dempcy, R. O.; Schmidt, J.
M.; Pettit, G. R.; Hamel, E. Mol. Pharm. 1988, 34, 200-208.
999, 121, 3951-3957.
10.1021/jo0508393 CCC: $30.25 © 2005 American Chemical Society
6544
J. Org. Chem. 2005, 70, 6544-6547
Published on Web 07/14/2005

SCHEME 1. Preparation of Synthetic
SCHEME 2. Synthesis of 4a and 4ba
Intermediates for Planned RCM and McMurry
a
Macrocyclizations
a
Conditions (1 equiv ) 1 mol/mol): (a) Grubb’s catalyst (0.05
3
equiv to excess) in CHCl3 or CH3OH, 12-4.5 × 10 h, rt to 80 °C
(
(
eventually ultrasound). (b) TiCl4-Zn (5 equiv/10 equiv) in THF
dry) stirred for 30 min under reflux, then 2 in THF added
a
Conditions (1 equiv ) 1 mol/mol): (a) Diethyleneglycol or 1,6-
dropwise and reacted 3-5 h (5-15% yield of 4 after purification).
hexanediol (2-10 equiv), DBAD (1.5-2 equiv), Ph3P-resin (2
equiv), CH2Cl2 (dry), 48 h (70-80%); (b) 4-hydroxybenzaldehyde
We started by investigating the ring-closing meta-
thesis approach (Scheme 2). Under reaction conditions
(
1 equiv), DBAD (1 equiv), Ph3P-resin (1 equiv), 70 h (55-80%);
+
-
n
14
(
3
8
c) CH3PPh3 I (4-7 equiv), THF, -40 °C, BuLi (1.6 M in hexane,
.5-6 equiv), 50 min, then dialdehyde, -40 °Cf rt, 24 h (75-
that demonstrated their utility for related macrocycliza-
5%).
15
tions, neither compound 3a nor 3b produced the
expected stilbenophanes 4a or 4b. Chloroform, methanol,
or benzene at either room temperature or reflux and the
addition of catalyst up to equimolecular amounts and
clization step, avoiding the formation of Z/E stereoiso-
mers if the formation of the double bond was selected as
the first step.
16
long periods of time were assayed, but in no case was
Ring-closing metathesis (RCM) of divinyl derivatives
Figure 2, Y ) CH ) was initially chosen due to its
2
transformation of the starting material to cyclization
products observed (no dimerization is produced under
diluted conditions). As the activity of the catalyst had
been checked with model compounds, we conclude that
the tension required to approach both ends of the
molecule is responsible for this lack of reactivity. The
rigidity of the benzenic systems and the steric and
torsional hindrance of the polymethylene bridge arising
upon folding to the reaction intermediates seem to be the
origin of such tension.
(
experimental simplicity and general utility for this kind
of transformations. The McMurry reaction was envisaged
as an alternative procedure, which could be directly
applied to intermediate dialdehydes (Figure 2, Y ) O) in
a shorter synthetic sequence. However, the harsh condi-
tions required, the low tolerance to functional groups, and
the possibility of formation of undesired sideproducts
(
e.g., the dihydroxyderivatives) kept us from selecting it
as our initial choice. Following this plan, the first results
obtained during the synthesis of those stilbenophanes
containing the diethyleneglycol bridge (Z ) O) and the
Once the RCM approach was discarded, we turned to
17
the McMurry reaction as an alternative procedure.
Following the literature, several conditions were assayed.
The reactions were carried out by slow addition of a
solution of the dialdehyde to the reagent, under highly
hexamethylene bridge (Z ) (CH
2 2
) ) are now presented.
Compounds 1a and 1b were obtained in high yields
1
2
by Mitsunobu reaction of syringaldehyde with a large
excess of either diethyleneglycol or 1,6-hexanediol (Scheme
18
diluted conditions. Reactions carried out at room tem-
perature led to spectroscopically complex mixtures of
polar compounds, which we believe correspond to the
macrocyclic glycols. Reactions in refluxing THF favored
the formation of olefinic products but had to be carefully
controlled, as extended reaction times greatly reduced
the reaction yields. In any case, the reactions produced
1
), to prevent the appearance of the dialkylation products
that could result from the double Mitsunobu reaction of
the diol. Subsequently, 4-hydroxybenzaldehyde was
coupled to these compounds by a second Mitsunobu
reaction, producing dialdehydes 2a and 2b. When they
were to be used in the McMurry reaction, the use of solid-
supported triphenylphosphine greatly improved the over-
all outcome of the synthetic route.13 Divinyl derivatives
(
14) (a) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997,
36, 2037-2056. (b) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1
1
3
1
998, 371-388. (c) Furstner, A. Angew. Chem., Int. Ed. 2000, 39,
013-3043. (d) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
8-29. (e) Grubbs, R. H. Tetrahedron 2004, 60, 7117-7140.
(15) Dyker, G.; Korning, J.; Stirner, W. Eur. J. Org. Chem. 1998,
3a and 3b were prepared by Wittig olefination.
(
12) (a) Mitsunobu, O. Synthesis 1981, 1-28. (b) Hughes, D. L. Org.
React. 1992, 42, 335-656. (c) Hughes, D. L. Org. Prep. 1996, 28, 127-
64.
13) Absence of triphenyl phosphine or its oxide is an absolute
149, 9-154.
1
(16) An NMR sample was maintained for three months under
catalytic conditions and additionally for nine months using equimo-
lecular amounts of the catalyst without any observable change in the
spectrum.
(17) McMurry, J. E. Chem. Rev. 1989, 89, 1513-1524.
(18) Kawase, T.; Ueda, N.; Tanaka, K.; Seirai, Y.; Oda, M. Tetra-
hedron Lett. 2001, 42, 5509-5511.
(
requirement in the McMurry reaction, which did not work if minor
amounts of this product were present. Due to the coelution of triphenyl
phosphine oxide during the chromatographic purification of the Mit-
sunobu reaction products, use of the resin-supported reagent fully
avoids this problem.
J. Org. Chem, Vol. 70, No. 16, 2005 6545

Once these compounds were prepared, we assayed
them for their antimitotic activity, to check if the
structural relationship between 4a, 4b, and combre-
tastatin A-4 (CA4) or its deoxyanalogue DCA4 is also
reflected in their biological properties. Following the
known methodology,21 the inhibition of tubulin poly-
merization (ITP) IC50 values were >40 µM (4a) and about
4
0 µM (4b), far from the value (3 µM) obtained for CA4
1
9
(
and that described for DCA4, IC50 (ITP) ) 2.2 µΜ ).
The decrease in antimitotic activity, despite the struc-
tural similarity, could be attributed to either the presence
of three (4a) or four (4b) additional atoms, in comparison
to DCA4, or the conformational restrictions imposed on
the phenyl rings by the bridge. Taking into consideration
the relatively small increase of the molecular volume
produced by these additional atoms, as well as the
orthogonality between both aromatic rings in the related
FIGURE 3. Ortep representation of the X-ray structure of
compound 4b, showing two molecules in the asymmetric unit.
1
TABLE 1. Comparison of H NMR Shifts for
Representative Protons of 4a,b and DCA4
22
active compounds when bound to the target protein, the
second explanation is the most feasible.
DCA4
4a
4b
3
2
2
3
,5-OMe
,6
3.69
3.62
3.63
In conclusion, the synthesis of a family of new stil-
benophanes (crownophanes) has been completed and
their activity as inhibitors of tubulin polymerization
investigated. After these results, new members of this
type of compound are being obtained in order to deduce
the structure-activity relationships.
6.51
5.93
6.09
′,6′
7.25
6.80
6.44/6.53
6.69
6.67
6.92/6.95
6.80
6.63
6.88/6.88
′,5′
olefinic
mixtures containing new olefinic and hydroxylated mac-
rocyclic products. Careful separation by CC allowed us
to isolate the final products 4a or 4b, although not in
very high yields.
Compounds 4a and 4b showed simple NMR spectra,
with a single signal for each chemically equivalent set
of protons or carbons such as both methoxy groups, the
Experimental Section
General Procedure for the Mitsunobu Reactions
Producing Hydroxyaldehydes 1 and Dialdehydes
2
. A mixture of the PPh
hyde (11.0 mmol), and a large excess of the diol (55.0
mmol) in dry CH Cl (125 mL) was stirred for 1 h before
3
-resin (11.0 mmol), syringalde-
2
2
2
,6, the 2′,6′, and the 3′,5′ aromatic proton pairs, or the
the slow addition of DBAD or DIAD (12.1 mmol) at rt.
After 48 h, the reactions were filtered, and the resin was
washed with EtOAc. The combined organic layers were
evaporated, dissolved in EtOAc, and washed with NaOH
potentially diastereotopic hydrogens of the methylene
groups. The symmetry of the benzene rings and the
absence of highly severe restrictions on the interconver-
sion of both of the most stable (enantiomeric) conforma-
tions in the NMR spectra account for this fact. The NOEs
between the 2,6 proton pair and 2′,6′ and 3′,5′ and the
methylene bridge are the only ones observed. A compari-
son of the proton chemical shifts of the macrocycles with
(
4%) and water to neutrality. Once dried and evaporated,
the crude reaction products were used in the next
Mitsunobu reaction or purified by flash chromatography
(
Hex/EtOAc mixtures) for characterization purposes.
Using the same procedure, the reaction products were
reacted with an excess of 4-hydroxybenzaldehyde (1.1
mol/mol of 1) to produce the dialdehydes (2).
1
9
those described for their noncyclized analogue deoxy-
combretastatin A-4 (DCA4, Figure 1) shows significant
upfield shifting of all the aromatic protons and a down-
field shift of the olefinic ones (Table 1), suggesting
different conformational spaces for the macrocycles and
the open analogues.
4-[2-(2-Hydroxyethoxy)ethoxy]-3,5-dimethoxyben-
zaldehyde (1a). Oily compound. Yield: 73%. FTIR:
3
-
1 1
401, 2736, 1683 cm . H NMR (200 MHz) δ: 3.60 (2H,
m), 3.70 (2H, m), 3.80 (2H, m), 3.92 (6H, s), 4.20 (2H,
The structure of compound 4b was confirmed by X-ray
diffraction studies (Figure 3). The observed conformation
in the solid state is the same calculated and in full
agreement with the NMR data. We have compared this
conformation with that obtained for the related combre-
m), 7.14 (2H, s), 9.86 (1H, s). 13C NMR (50.3 MHz) δ: 56.3
(
2)(CH
06.7 (2)(CH), 131.8 (C), 142.5 (C), 153.7 (2)(C), 191.1
3 2 2 2 2
), 61.5 (CH ), 70.2 (CH ), 72.4 (CH ), 72.5 (CH ),
1
+
(
CHO). GC-MS, m/z: 270 (M , 11%).
-{2-[2-(4-Formylphenoxy)ethoxy]ethoxy}-3,5-di-
methoxybenzaldehyde (2a). Oily compound. Yield:
4
20
tastatin A-1. The most noticeable difference is the close
to parallel disposition of both aromatic rings, shifted to
a situation that maintains the 2,6 (2′,6′) protons over the
other aromatic ring, thus producing the strong shielding
observed in 4a,b. Combretastatin A-1, without the re-
strictions imposed by the bridge between positions 4 and
-1 1
7
0%. FTIR: 2738, 1693 cm . H NMR (200 MHz) δ: 3.80
(
(
(
(
2H, m), 3.91 (6H, s), 4.00 (2H, m), 4.20 (4H, m), 7.01
2H, d, J ) 8.4), 7.12 (2H, s), 7.82 (2H, d, J ) 8.4), 9.86
1H, s), 9.88 (1H, s). 13C NMR (50.3 MHz) δ: 56.2 (2)
CH
3 2 2 2 2
), 67.9 (CH ), 69.5 (CH ), 70.8 (CH ), 72.4 (CH ),
4
′, has a nearly orthogonal disposition of both aromatic
1
06.7 (2)(CH), 114.9 (2)(CH), 130.0 (C), 130.9 (C), 131.9
rings.
(
21) S a´ nchez Maya, A. B.; P e´ rez-Melero, C.; Salvador, N.; Pel a´ ez,
(
19) Cushman, M.; Nagarathnam, D.; Gopal, D.; Chakraborti, A. K.;
R.; Caballero, E.; Medarde, M. Bioorg. Med. Chem. 2005, 13, 2097-
2107.
Lin, C. M.; Hamel, E. J. Med. Chem. 1991, 34, 2579-2588.
(
20) Pettit, G. R.; Singh, S. B.; Niven, M. L.; Hamel, E.; Schmidt, J.
(22) Ravelli, R. B. G.; Gigant, B.; Curmi, P. A.; Jourdain, I.; Lachkar,
S.; Sobel, A.; Knossow, M. Nature 2004, 428, 198-202.
M. J. Nat. Prod. 1987, 50, 119-131.
6546 J. Org. Chem., Vol. 70, No. 16, 2005

(
1
2)(CH), 142.6 (C), 153.7 (2)(C), 163.9 (C), 190.9 (CHO),
91.1 (CHO). GC-MS, m/z: 374 (M , 32%).
General Procedure for Wittig Reactions Produc-
General Procedure for McMurry Reactions Yield-
ing Stilbenophanes 4. A mixture of TiCl ‚2THF 97%
+
4
(32.0 mmol) and Zn (64.0 mmol) in dry THF (200 mL)
was prepared at 0 °C and refluxed for 30 min; then, a
solution of the dialdehyde 2 (6.4 mmol) in dry THF (30
mL) was added and maintained at reflux for 3 h. The
reaction was poured onto a mixture of EtOAc and 2 M
HCl; the aqueous layer was extracted, and the combined
ing Diolefins 3. To a solution of methyltriphenylphos-
phonium iodide (5.8 mmol) in dry THF (80 mL) at -40
°
C was added nBuLi 1.6 M in hexane (2,5 mL; 4.0 mmol),
and the bright red solution was stirred for 30 min. After
the addition of the dialdehyde 2 (0.6 mmol in dry THF,
2
0 mL), a pale yellow solution was obtained that was
2
organic layers were worked up. By chromatography (SiO ,
hexane/EtOAc mixtures), the olefinic products 4 were
allowed to heat to room temperature and to react
overnight. The reaction mixture was added to an am-
monium chloride solution, extracted with EtOAc and
separated from the mixture of hydroxylated products.
4,7
(
2Z)-8,11,14-Trioxatricyclo[13.2.2.2 ]henicosa-1-
purified by chromatography (SiO
tures) to give the pure diolefins 3 in high yields.
,3-Dimethoxy-5-vinyl-2-{2-[2-(4-vinylphenoxy)-
ethoxy]ethoxy}benzene (3a). Oily compound. Yield:
2
, hexane/EtOAc mix-
(
17),2,4,6,15,18,20-heptaene (4a). Oily compound. Iso-
lated yield: 5% (plus 30-40% polyhydroxylated prod-
ucts). FTIR: 1603, 1578, 1505 cm . H NMR (400 MHz)
1
-1 1
δ: 3.56 (2H, t, J ) 3.9), 3.62 (2H, m, overlapped), 3.62
-
1 1
8
3%. FTIR: 1606, 1582, 1509 cm . H NMR: 3.78 (6H,
(
6H, s), 4.13 (2H, t, J ) 4.3), 4.26 (2H, dd, J ) 5.3, J )
s), 3.80 (2H, m), 3.90 (2H, m), 4.10 (4H, m), 5.05 (1H, d,
J ) 11.4), 5.14 (1H, d, J ) 11.2), 5.53 (1H, d, J ) 16.7),
5
3
8
.9), 5.93 (2H, s), 6.67 (2H, d, J ) 8.8), 6.69 (2H, d, J )
1
3
.8), 6.92 (1H, d, J ) 9.9), 6.95 (1H, d, J ) 9.9). C NMR
), 67.0 (CH ), 73.2 (CH ), 73.3
), 107.1 (2)(CH), 114.5 (2)(CH), 130.0 (2)
CH), 131.1 (C), 134.0 (CH), 134.3 (CH), 134.8 (C), 136.2
C), 152.2 (2)(C), 156,9 (C). HRMS: calcd for C20
42.1467, found 342.1421. Anal. Calcd. for C20
70.16; H, 6.48. Found: C, 70.47; H, 6.74.
.58 (1H, d, J ) 17.6), 6.55 (2H, s), 6.57 (1H, dd, J )
7.6, J ) 11.2), 6.58 (1H, dd, J ) 16.7, J ) 11.4), 6.80
(
(
(
(
100.6 MHz) δ: 55.7 (2)(CH
3
2
2
1
CH ), 73.4 (CH
2
2
(
(
2H, d, J ) 8.4), 7.20 (2H, d, J ) 8.4). 13C NMR: 56.2
2)(CH
3
), 67.7 (CH
03.4 (2)(CH), 111.7 (CH
2
), 69.8 (CH
2
), 70.8 (CH
2 2
), 72.4 (CH ),
22 5
H O
H O : C,
22 5
1
1
1
3
2
), 113.3 (CH
2
), 114.7 (2)(CH),
3
27.4 (2)(CH), 130.6 (C), 132.1 (C), 133.5 (C), 136.3 (CH),
+
36.8 (CH), 153.5 (2)(C), 158.7 (C). GC-MS, m/z: 370 (M ,
4%).
Acknowledgment. We thank the “Junta de Castilla
y Le o´ n” (Ref 073/02), Spanish MCyT (Ref PPQ-2001-
General Procedure for Ring-Closing Metathesis.
The failed ring-closing metatheses were carried out in
different solvents, under variable conditions (inert at-
mosphere, temperature from rt to reflux, time from
overnight to several months) using Grubbs’ catalyst
1
977), and MEC (Ref CTQ2004-00369/BQU) and the EU
(
Structural Funds) for financial support.
(
benzylidene-bis(tricyclohexylphosphine)dichlororuthen-
ium; from 0.05 to 1.0 mol/mol). The reaction was checked
by evaporation of the solvent, dissolution in CH Cl , and
Supporting Information Available: Analytical and spec-
1
tral characterization data of all compounds (1a-4b), H and
1
3
C NMR spectra of 1a-3b, and a crystallographic information
2
2
1
file for 4b (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
stirring in the presence of carbon black followed by H
NMR of the crude product. No transformation was
detected in any of the assayed conditions.
JO0508393
J. Org. Chem, Vol. 70, No. 16, 2005 6547