Oxazoline chemistry. Part 12: A metal-mediated synthesis of DMU-212; X-ray diffraction studies of an important anti-cancer agent

Article abstract of DOI:10.1016/j.tetlet.2006.01.089

An improved synthesis of the anti-cancer agent DMU-212 (trans-3,4,5, 4′-tetramethoxystilbene) is described. The methodology involves the use of a Pd-oxazoline catalyst as a mediator of a regio-selective (Heck) C-C bond formation reaction. A simple isolation step is then used to obtain the title material. The compound has been further characterised in the solid-state by X-ray diffraction methods.

Full text of DOI:10.1016/j.tetlet.2006.01.089

Tetrahedron Letters 47 (2006) 2245–2247
Oxazoline chemistry. Part 12: A metal-mediated synthesis of
DMU-212; X-ray diffraction studies of an important
anti-cancer agent
q
a
a
a,
b,
*
Gordon G. Cross, Charles R. Eisnor, Robert A. Gossage and Hilary A. Jenkins
a
The Chester Woodleigh Small Laboratory of Organic Chemistry, Elliott Hall, Department of Chemistry, Acadia University,
Wolfville, Nova Scotia, Canada B4P 2R6
b
Department of Chemistry, Saint Mary’s University, Halifax, Nova Scotia, Canada B3H 3C3
Received 18 September 2005; revised 17 January 2006; accepted 18 January 2006
Available online 10 February 2006
This letter is dedicated to the memory of a friend, colleague and proud Cape Bretoner, Dr. Scott G. Foug e` re (1969–2005),
who left us all far too soon
0
Abstract—An improved synthesis of the anti-cancer agent DMU-212 (trans-3,4,5,4 -tetramethoxystilbene) is described. The meth-
odology involves the use of a Pd-oxazoline catalyst as a mediator of a regio-selective (Heck) C–C bond formation reaction. A simple
isolation step is then used to obtain the title material. The compound has been further characterised in the solid-state by X-ray
diffraction methods.
ꢀ
2006 Elsevier Ltd. All rights reserved.
Hydroxylated (E)-stilbenoids are a class of naturally
occurring polyphenolic compounds that are found in a
1
vast number of plant species throughout the world.
The discovery that these natural products act as anti-
cancer agents, in addition to possessing a variety of
other beneficial health properties, is a recent and impor-
tant realisation within medicinal and nutraceutical
2
Figure 1.
chemistry. Of the active compounds, Resveratrol (i.e.,
0
trans-3,5,4 -trihydroxystilbene: 1: Fig. 1) was one of
the first to be identified and has since been extensively
3
studied. Compound 1 has also been implicated in the
4
number of health benefits. O-Methylated stilbenes are
often also cytotoxic molecules and hence a number of
these derivatives have been explored as novel chemo-
so-called ‘French paradox’ in which components of
red wine, which includes 1, are thought to promote a
0
therapeutic agents. In particular, trans-3,4,5,4 -tetra-
methoxystilbene (2: Fig. 1), given the designation
Keywords: DMU-212; Resveratrol analogues; Palladium; Oxazoline;
C–C bond formation; trans-Stilbene; Chemotherapy agents; Heck
reaction; X-ray crystal structure.
DMU-212, has recently emerged as a strong candidate
5–7
for anti-tumour applications.
Compound 2 appears
to have broader and more potent anti-cancer activity
q
Part X: Berg, D. J.; Zhou, C.; Barclay, T.; Fei, X.; Feng, S.; Ogilvie,
K. A.; Gossage, R. A.; Twamley, B.; Wood, M. Can. J. Chem. 2005,
5–7
than the parent stilbene 1.
8
3, 449–459. Part XI. Eisnor, C. R.; Gossage, R. A.; Yadav, P. N.
The current synthesis of DMU-212 uses well-developed
Tetrahedron, 2006, 62, doi: 10.1016/j.tet.2006.01.046.
Corresponding author. Tel.: +1 902 585 1109; fax: +1 902 585 1114;
e-mail addresses: rgossage@acadiau.ca; hilary.jenkins@smu.ca
Author to whom queries concerning the crystallography should be
directed.
5
–7
chemistry (Scheme 1), but is hampered by poor atom
*
8
economy (Wittig). In addition, there are selectivity
issues, which force the removal of the by-product cis-iso-
9
mer (cis-2) from the desired product 2 (Scheme 1).
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.089

2246
G. G. Cross et al. / Tetrahedron Letters 47 (2006) 2245–2247
Scheme 2.
Scheme 1.
à
Hence, improvements in yield, ease of synthesis and
better regio-selectivity are still an issue in the production
of DMU-212. Obviously, investigations to circumvent
these problems will be necessary if large-scale applica-
tions of 2 as a therapeutic agent are to be undertaken.
We have recently reported that an air-stable Pd complex,
Figure 2. ORTEP of 2, with thermal ellipsoids shown at 50%
probability.
1
trans-[bis(2-ethyl-2-oxazoline-j N)palladium(II)dichlo-
1
0
ride] (3) is a robust pre-catalyst for a number of C–C
bond forming reactions (Heck, Miyaura–Suzuki, Ull-
man, etc.). In this letter, we disclose a simple ‘one-pot’
method (Scheme 2) to synthesise DMU-212, which
of 2 and significant decomposition of the starting mate-
rials was noted. Both polymeric palladium(II) chloride
1
0,11
employs 3 in Heck coupling chemistry.
The method-
and bis-(triphenyl-phosphine) palladium dichloride gave
§
ology suppresses the formation of cis-2 and allows for
the facile isolation of 2 in moderate yield. In addition,
2
in less than 20% yield (GC–MS) under the above
conditions.
2
is further characterised in the solid-state by single crys-
tal X-ray diffraction methods.
The solid-state structural properties of DMU-212 have
not previously been reported. These data can be very
useful in substrate-complex docking studies and related
investigations. We have therefore characterised 2 by sin-
A mixture of N,N-dimethylformamide (15 mL), 4-vinyl-
anisole (325 mg: 2.4 mmol; Sigma–Aldrich Chem. Co.),
1
3
3
,4,5-trimethoxy-1-bromobenzene (0.50 g: 2.0 mmol;
gle crystal X-ray diffraction methods. In the solid
phase, 2 exists as discrete monomeric units. The struc-
ture has closely related bond lengths and angles to that
Sigma–Aldrich Chem. Co.), potassium carbonate
1
0
(
330 mg: 2.4 mmol) and 3 (0.30 g: 0.8 mmol) was placed
1
4
into a round-bottomed flask (50 mL) equipped with a
reflux condenser (Scheme 2). The mixture was heated to
reflux temperature for a period of 24 h. The flask was
then cooled to room temperature, the mixture was
filtered and the solids were washed with acetone
of stilbene itself and a number of its derivatives, most
0
15
notably (E)-3,5,4 -trimethoxystilbene. An ORTEP of
the molecular structure of one of the molecules of 2 in
the unit cell is depicted in Figure 2.
(
10 mL). The organic layers were combined and all the
The internuclear bond distances and angles fall within
the range of expected values: C10–C11 bond distance
is 1.317(2) A and the C1–C10–C11–C12 torsion angle
is 177.8(2)ꢁ, indicating that there is only a slight devia-
tion from planarity about the styrene bond. This pro-
vides a slight twist to the molecule, so that the angle
between the planes of the two aromatic rings is 12.2ꢁ.
volatile components were removed in vacuo. The residue
was partitioned between dichloromethane (60 mL) and
water (60 mL). The organic layer was washed with water
˚
(
2 · 60 mL) and then isolated, dried (MgSO ) and evapo-
4
rated to give the crude brown oil. This product was
recrystallised from 95% EtOH to give light brown col-
oured crystals of trans-3,4,5,4 -tetramethoxystilbene (2:
0
DMU-212; 258 mg: 43%: Scheme 2). Characterisation
In conclusion, a new and simple route to the anti-cancer
1
7
of this material (mp, IR, H NMR) gave information
agent DMU-212 (2) has been detailed. This synthetic
1
2
1
0
that was fully consistent with the properties of 2.
protocol uses a simple, air-stable and readily available
Pd catalyst to facilitate a Heck coupling reaction
between two commercially available and inexpensive
aromatic precursors. DMU-212 has been further charac-
terised in the solid-state by single crystal X-ray
diffraction.
The above methodology was also used in which Pd cat-
alyst 3 was replaced by other typical Pd species. No
reaction was observed when Pd on Carbon was em-
ployed; [Pd(OAc) ] gave no evidence for the production
2
3
à
§
Numeric yields of compound 2 produced by the Wittig synthesis are
No attempt was made to determine the regio-isomer(s) of 2 produced
not disclosed, to our knowledge, in Ref. 5 or 6.
by these catalysts.

G. G. Cross et al. / Tetrahedron Letters 47 (2006) 2245–2247
2247
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Johnson-Matthey is also thanked for a generous loan
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2
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2
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˚
˚
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