A short synthesis of morachalcone A

Article abstract of DOI:10.1016/j.tetlet.2005.01.174

Advanced C-prenylated intermediates for three aromatase inhibitors, including morachalcone A, can be synthesized through a Claisen-Schmidt condensation followed by Florisil-catalyzed [1,3]-sigmatropic rearrangement of a prenyl phenyl ether.

Full text of DOI:10.1016/j.tetlet.2005.01.174

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2323–2326
A short synthesis of morachalcone A
Joseph J. Romanoa and Eduard Casillasb,*
aDepartment of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
bDepartment of Chemistry, Villanova University, Villanova, PA 19085, USA
Received 2 September 2004; revised 28 January 2005; accepted 31 January 2005
Abstract—Advanced C-prenylated intermediates for three aromatase inhibitors, including morachalcone A, can be synthesized
through a Claisen–Schmidt condensation followed by FlorisilÒ-catalyzed [1,3]-sigmatropic rearrangement of a prenyl phenyl ether.
Ó 2005 Elsevier Ltd. All rights reserved.
The growth of many breast cancers in postmenopausal
women is stimulated by estrogen at typical physiological
concentrations. One method for the treatment of breast
and prostate cancers relies on antiestrogens that bind to
an estrogen receptor within the tumor and block the ef-
fect of estrogen. Alternatively, tumor growth can be
slowed by reducing the circulating concentration of
estradiol and estrone by treatment with inhibitors of
estrogen biosynthesis.1 Aromatase, a key cytochrome
p450-dependent enzyme, catalyzes aromatization of the
androstenedione A ring which is the final and rate-limit-
ing step in the estrone biosynthetic pathway.2 Therefore,
aromatase inhibitors have become attractive breast can-
cer therapies for women beyond menopause.
aromatase inhibitors recently approved by the FDA in-
clude the nonsteroidals anastrazole and letrozole as well
as the steroidal exemestane that, like all aromatase
inhibitors, inhibit the synthesis of estrogen in tissues
other than the ovaries.4
There is a continuing search for new therapeutic leads
among botanical natural products. Aromatase inhibi-
tors of natural origin have been isolated from organic
extracts of the mulberry tree, Broussonetia papyrifera
(L.) LÕHer. Ex Vent (Moraceae),2 and the osage orange
tree, Machura pomifera. Fruits of M. pomifera have been
used for centuries in China to treat impotency and oph-
thalmic disorders.5 Several isolates from the mulberry
tree have demonstrated antifungal, antioxidant, and lens
aldose reductase inhibitory activities.2
Current therapies include the first FDA-approved aro-
matase inhibitor, aminogluthethimide [3-(4-aminophen-
yl)-3-ethylpiperidine-2,6-dione (AG)]. AG limits
estrogen synthesis by inhibiting adrenal steroid biosyn-
thesis and peripheral aromatase enzyme activity. How-
ever, it also inhibits glucocorticoids, leading to an
increased secretion of adrenocorticotropic hormone by
the pituitary that overpowers the drugÕs effect in the
adrenal gland. A strategy to avoid this deleterious side
activity is to identify drugs that will depress peripheral
aromatase activity while not affecting the pituitary
gland.3 AG has shown some clinical benefit in breast
cancer trials, but lack of selectivity and its weak aroma-
tase inhibitory activity has limited its usefulness.1 Other
The current study focuses on the synthesis of one of the
aforementioned isolates of the mulberry tree, morachal-
cone A (1). Morachalcone A is an attractive target,
exhibiting aromatase inhibitory activity greater than
that of the benchmark inhibitor AG (IC50 = 4.9 vs
6.4 lM for AG).1,2 Furthermore, morachalcone A has
potential synthetic utility as a precursor to isogemichal-
cone C (2) and its desmethoxy analog (3). The latter two
isolates from the same source demonstrate significant
aromatase activity with IC50Õs of 7.1 and 0.5 lM,
respectively.2
Disconnection of the prenyl group of morachalcone A
provides a potential precursor (4) that leads to all three
natural products. We envisioned subsequent disconnec-
tion at the bridging olefin, leading to common polyphe-
nolic starting materials (Fig. 1). To initiate the sequence,
aldehyde 5 was protected with MOMCl in 82% yield,
Keywords: [1,3]-Rearrangement; FlorisilÒ; Chalcone.
*
Corresponding author. Tel.: +1 610 519 5236; fax: +1 610 519
7167; e-mail: eduard.casillas@villanova.edu
0040-4039/$ - see front matter Ó 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.174

2324
J. J. Romano, E. Casillas / Tetrahedron Letters 46(2005) 2323–2326
HO
OHC
HO
MOMO
OH
O
OH
O
OMOM
5
R
HO
HO
HO
O
HO
HO
SEMO
4
Morachalcone A (1): R = H
6
HO
Isogemichalcone A (2): R =
O
O
MeO
HO
O
O
(3): R =
Figure 1. Retrosynthetic scheme of morachalcone A (1) and its aromatase inhibitor derivatives (2, 3).
while acetophenone 6 was selectively protected at the 4-
position as a SEM ether in 96% yield (Scheme 1).
Condensation of 7 and 8 under Claisen–Schmidt condi-
tions6 provides the desired enone (4) in 66% yield after
optimization without evidence of the undesired cis enone.
ether cleavage and numerous decomposition products.
Direct prenylation of the aromatic ring in 4 with prenyl
bromide using Friedel–Crafts conditions or aryl anionic
quench yielded no product.
Alternatively, numerous steps could be saved by directly
installing an O-prenyl group that could be converted to
the C-prenylated chalcone by 1,3-rearrangement (Scheme
2). Furthermore, installation of the unsubstituted prenyl
group on the aromatic ring would allow for synthesis of
all three natural products, instead of just 2 and 3. The
Claisen route would potentially provide the hydroxylated
prenyl group leading to 2 and 3, but would prohibit syn-
thesis of 10 as an intermediate through the same route.
The aldol condensation was very sensitive to modifica-
tion of reaction parameters. A significant excess of
KOH (150 equiv) was required to force the reaction to
completion. It was noted that the SEM ether was intol-
erant of prolonged reaction times, while the MOM ether
was sensitive to acidic workup. Numerous protection
strategies were attempted and the silylethoxymethyl
(SEM) and methoxymethyl (MOM) combination pro-
vided the best aldol reaction, most other combinations
failed to give any useful conversion.
Prior work has shown that 1,3-rearrangement of O-
prenylated phenols8,9 can be achieved with either mont-
morillonite clay, FlorisilÒ or silica gel. O-Prenylation
was achieved by reacting 4 with excess prenyl chloride
in refluxing acetone. This resulting prenyl ether (9) was
rearranged8 to 10 using a FlorisilÒ catalyzed [1,3]-sigma-
tropic shift to install the C-prenyl group [toluene,
100 °C, 10/1 w/w FlorisilÒ]. Some deprenylated (4) and
p-rearranged (11) products were also detected in a
2:1:1 ratio of 10:11:4 as reported by Talamas et al.8
Although FlorisilÒ catalysis did not prevent formation
of these byproducts, the desired isomer 10 was found
to be the major product, obtained in 23% isolated yield.
With the core chalcone established, all that remained
was the installation of the appropriately functionalized
prenyl group. Similarly protected phenols have been
prenylated in five steps from phenolic intermediates7
through O-allylation, Claisen rearrangement, ozonoly-
sis, Wittig olefination and reduction (Scheme 2). In
our case, ozonolysis was to be avoided due to the pres-
ence of the enone. Further, attempts at Claisen rear-
rangement of allyl ether 12 through heating with N,N-
dimethylaniline at 200 °C gave only a small amount of
the desired Claisen product (8% yield) accompanied by
HO
OHC
MOMO
OHC
a
MOMO
OH
OMOM
O
OMOM
HO
7
5
c
O
O
HO
HO
b
SEMO
4
HO
SEMO
6
8
Scheme 1. Synthetic sequence to enone 4. Reagents and conditions: (a) MOMCl, NaH, THF, 65 °C, 18 h, 82%; (b) SEMCl, DIPEA, CH2Cl2, 25 °C,
3 h, 96%; (c) KOH, EtOH, 25 °C, 18 h, 66%.

J. J. Romano, E. Casillas / Tetrahedron Letters 46(2005) 2323–2326
2325
MOMO
MOMO
MOMO
O
OMOM
e
O
OMOM
3 steps
O
OMOM
O
HO
HO
HO
HO
d
HO
SEMO
12
13
15
4
2 steps
HO
MOMO
MOMO
O
OMOM
O
OMOM
b
O
OH
HO
O
HO
a
c
10
9
1
SEMO
HO
SEMO
HO
+
MOMO
O
OMOM
11
SEMO
Scheme 2. [3,3] versus [1,3]-Rearrangement strategies to morachalcone A. Reagents and conditions: (a) prenyl chloride, K2 CO3, acetone, 65 °C, 18 h,
87%; (b) FlorisilÒ, toluene, 100 °C, 8 h, 23%; (c) HCl, 1:1 i-PrOH–THF, 25 °C, 18 h, 46%; (d) allyl bromide, K2CO3, acetone, 65 °C, 18 h, 78%; (e)
N,N-dimethylaniline, 200 °C, 18 h, 8%.
The Dauben protocol9 using montmorillonite clay in
benzene gave the desired product as well, but only pro-
vided a 1:1:2 ratio of 10:11:4 in 9% yield of 10. Silica
gel catalysis gave only deprenylated product (4). Mora-
chalcone A (1) was formed by simultaneous acid cata-
lyzed deprotection of the MOM and SEM ethers in
46% yield.
The described method of preparing intermediate 10 has
allowed for the synthesis of aromatase inhibitor mora-
chalcone A (1) in six steps with a 5.8% overall yield from
inexpensive, commercially available phenol reagents.
The sequence also has the potential to provide two other
potent aromatase inhibitors of natural origin in as little
as nine steps each for 2 and 3 from common intermedi-
ate 10. Further modifications in catalyst and reaction
conditions are currently being studied for the 1,3-rear-
rangement that would allow for better selectivity over
the undesired p-product (11) and increase the overall
yield significantly. Although the isolated yield of the
1,3-rearrangement is a modest 23%, this pathway has
the advantage of avoiding the longer and potentially
more problematic Claisen route (Scheme 2). This meth-
od also lends itself to the rapid analog synthesis of other
isogemichalcone C analogs through reaction with vari-
ous carboxylic acids.
Current investigations to prepare 2 and 3 from interme-
diate 10 are underway (Fig. 2). Oxidation10 with SeO2
provides the trans allylic alcohol (16). A unified syn-
thetic pathway consisting of ester formation with the
appropriate carboxylic acid and deprotection may allow
preparation of all three natural products. Acids could be
synthesized in three steps from commercially available
hydroxycinnamic acids via esterification, protection as
the SEM ethers, and hydrolysis of the ester to the car-
boxylic acid.
HO
MOMO
MOMO
O
OH
O
OMOM
O
OMOM
RO
HO
HO
HO
HO
1) esterify
t-BuOOH
SeO , THF
2
2) deprotect
15%
HO
SEMO
SEMO
HO
10
16
2: R =
MeO
HO
O
O
3: R =
Figure 2. Proposed synthesis of 2 and 3.

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J. J. Romano, E. Casillas / Tetrahedron Letters 46(2005) 2323–2326
3. Foye, W.; Lemke, T.; Williams, D. Principles of
Acknowledgements
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The authors wish to thank Merck & Co., Inc. for finan-
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Dr. John A. McCauley for advice and review.
5. Monache, G. D.; De Rosa, M.; Scurria, R.; Vitali, A.;
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Supplementary data
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Experimental data for compounds 1, 4, 7–10, and 16 are
included. Supplementary data associated with this arti-
cle can be found, in the online version at doi:10.1016/
j.tetlet.2005.01.174.
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