A Simple and Convenient Multigram Scale Synthesis of Hydroxyphenstatin: Potential Cancer Cell Growth Inhibitor

Article abstract of DOI:10.1081/SCC-120026308

A simple and convenient two-step synthesis of hydroxyphenstatin (2) is reported by condensing 3,4,5-trimethoxybenzoic acid with pyrogallol and subsequent selective methylation with dimethyl sulphate in presence of potassium carbonate.

Full text of DOI:10.1081/SCC-120026308

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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 22, pp. 3869–3873, 2003
A Simple and Convenient Multigram Scale
Synthesis of Hydroxyphenstatin: Potential
Cancer Cell Growth Inhibitor
*
Pedamallu Radha
A.V. Rama Rao Research Foundation, Habshiguda,
Hyderabad, India
ABSTRACT
A simple and convenient two-step synthesis of hydroxyphenstatin (2)
is reported by condensing 3,4,5-trimethoxybenzoic acid with
pyrogallol and subsequent selective methylation with dimethyl
sulphate in presence of potassium carbonate.
Key Words: Phenstatin; Hydroxyphenstatin; Benzophenone deriv-
atives; Friedel-Crafts benzoylation; Anticancer; Antineoplastic
activity.
*Correspondence: Pedamallu Radha, A.V. Rama Rao Research Foundation,
Habshiguda, Hyderabad 500 007, India; E-mail: avralab@hd2.vsnl.net.in.
3869
DOI: 10.1081/SCC-120026308
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3870
Radha
Recently, Pettit et al.[1–3] have reported the synthesis and cancer cell
growth inhibition of phenstatin (1) and hydroxyphenstatin (2). These two
compounds are derived from combining the features of two important
natural products combretastatin A-1 (3)[4] and podophyllotoxin (4),[5] the
latter being used in cancer therapy (Fig. 1). Along with its remarkable anti-
neoplastic activity, hydroxyphenstatin (2) also showed inhibition of tubu-
lin polymerization with IC50 comparable to that of combretastatin A-1.[1]
During the execution of a project dealing with the synthesis and
structure activity relation studies of hydroxyphenstatin derivatives, we
felt the need to synthesize reasonable quantity of hydroxyphenstatin
(2). The general procedure reported[1] (Sch. 1) for synthesis of 2 involves
about eight steps, starting from o-vanillin (5), and using addition of
suitably substituted aryllithium (6) to 3,4,5-trimethoxybenzaldehyde (7)
as key transformation. Subsequent oxidation of intermediate 8 and final
deprotection resulted in 2. Most of the steps are tedious and not suitable
for large-scale synthesis.
In this context, to have an alternative approach for gram scale
synthesis of 2, we attempted Friedel-Crafts[6] benzoylation of pyrogallol
(9) using 3,4,5-trimethoxybenzoic acid (10). After screening several Lewis
acids in this context, gratifyingly, we realized borontrifluoride:etherate
does serve our needs and gave the corresponding benzophenone (11) in
moderate yield. The adopted method involves the treatment of pyrogallol
with 3,4,5-trimethoxybenzoic acid in BF3:etherate at 90–100ꢀC for 2 h
under nitrogen. This method was found to be applicable even for scales
up to 200 g of 9. Resulting benzophenone (11) was then subjected
O
O
OH
H3CO
H3CO
H3CO
H3CO
OH
OH
OCH3
OCH3
OCH3
OCH3
Phenstatin (1)
Hydroxyphenstatin (2)
OH
O
O
O
O
H3CO
H3CO
OH
OH
OCH3
H3CO
OCH3
OCH3
OCH3
Podophyllotoxin (4)
Combretastatin A-1 (3)
Figure 1.

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Hydroxyphenstatin
3871
O
Li
CHO
OH
H3CO
H3CO
OMOM
OMOM
+
OCH3
OCH3
OCH3
o-vanillin
6
7
5
OH
OMOM
H3CO
OMOM
2
H3CO
OCH3
OCH3
8
Scheme 1.
to selective methylation with 1 equiv. of dimethyl sulphate in
acetone using potassium carbonate as base. As anticipated, the least
hindered and nonhydrogen bonded p-hydroxyl group was methylated
preferentially. The identity of the final compound was confirmed by
comparing the melting point as well the spectral data reported for 2.
In conclusion, we have developed an easy synthesis for hydroxy-
phenstatin through execution of Friedel-Crafts benzoylation on pyrogallol
and is characterized by considerable flexibility for the construction of
related analogues in a short way. Amenability of such methodology for
synthesis of small benzophenones library is currently progressing in our
laboratory.
EXPERIMENTAL SECTION
All solvents were redistilled over appropriate drying agents before
use. Merck Silica Gel plates were used to monitor the reactions. Column
Chromatography is performed using Silica Gel (ACME 100 mesh).
1H NMR spectra were measured on a Gemini 200 MHz instrument
using CDCl3 (TMS internal reference) as solvent.
2,3,4-Trihydroxy-30,40,50-trimethoxybenzophenone (11). A suspension
of pyrogallol (9, 200 g, 1.59 mol) 3,4,5-trimethoxybenzoic acid (10, 350 g,
1.65 mol) in freshly distilled BF3:Et2O (1.0 L) was heated at 90–100ꢀC in
an oil bath with stirring for a period of 2 h under nitrogen atmosphere.

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3872
Radha
O
OH
H3CO
H3CO
CO2H
H3CO
H3CO
OH
OH
OH
OH
a)
b)
+
2
OCH3
OCH3
OH
9
10
11
Scheme 2. Reagents and conditions. (a) BF3:etherate, 90–100ꢀC, 2 h, 25%;
(b) Me2SO4, K2CO3, acetone, reflux, 30 min, 61%.
The reaction was then allowed to come to room temperature and cooled
in an ice bath for a period of 30 min. The reaction mixture was filtered on
a Buchner funnel, and the precipitate was washed successively with
hexane (1.0 L), 10% sodium bicarbonate solution (1.5 L) and finally
with water (1.5 L). The resulting dark brown solid was dried in a
vacuum oven at 60ꢀ to give crude 11 (230 g). Repeated recrystallization
of the crude product from methanol–water gave 11 (120 g, 96% purity
was indicated by HPLC analysis) in a 25% final yield (Sch. 2).
M.p.: 154–155ꢀC. H NMR: ꢀ 7.26 (d, J ¼ 8.0 Hz, 1H), 6.92 (s, 2H),
1
6.54 (d, 8.0 Hz, 1H), 3.95 (s, 3H, -OCH3), 3.92 (s, 6H, 2x-OCH3). HRMS.
Calcd. for C16H16O7: 320.089603. Found: 320.088644.
Hydroxyphenstatin[(20,30-dihydroxy-40-methoxyphenyl)
(3,4,5-tri-
methoxyphenyl)methanone] (2). The above 2,3,4-trihydroxy-30,40,50-tri-
methoxybenzophenone (120 g, 0.37 mol) was taken in a 3 necked 2 L
flask fitted with a mechanical stirrer, a dropping funnel, and a reflux
condenser. To this acetone (1.2 L), anhydrous potassium carbonate
(150 g, 1.1 mol) were added and dimethyl sulphate (47.5 g, 0.37 mol)
was introduced slowly using dropping funnel over a period of 1 h
and the contents were refluxed with stirring for a period of 30 min after
completion of the addition. The reaction mixture was cooled to room
temperature, concentrated in vacuo, treated with water (1.0 L) and
allowed to settle at room temperature for overnight. The resulting
yellow solid was collected by filtration and dried. The crude product
was crystallized from acetone (400 mL) by heating initially to prepare a
homogeneous solution and then cooling to 0ꢀC. The crystallized product
(100 g) was subjected for recrystallization about two times to give 2 (75 g
of 96% purity by HPLC) in a final yield of 61%.
M.p.: 170–172ꢀC [Lit.[1] 171.1–171.9ꢀC]. H NMR: ꢀ 12.23 (s, 1H,
1
-OH), 7.27 (d, J ¼ 8.7 Hz, 1H, 60-ArH), 6.92 (s, 2H, 2,6-ArH), 6.51
(d, J ¼ 8.7 Hz, 1H, 50-ArH) 3.99 (s, 3H, -OCH3), 3.94 (s, 3H, -OCH3),
3.90 (s, 6H, 2x-OCH3).

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Hydroxyphenstatin
3873
REFERENCES
1. Pettit, G.R.; Grealish, M.P.; Herald, D.L.; Boyd, M.R.; Hamel, E.;
Pettit, R.K. J. Med. Chem. 2000, 43, 2731.
2. Pettit, G.R.; Toki, B.; Herald, D.L.; Verdier-Pinard, P.; Boyd, M.R.;
Hamel, E.; Pettit, R.K. J. Med. Chem. 1998, 41, 1688.
3. Pettit, G.R.; Singh, S.B.; Boyd, M.R.; Hamel, E.; Pettit, R.K.;
Schmidt, J.M.; Hogan, F. J. Med. Chem. 1995, 38, 1666.
4. Pettit, G.R.; Singh, S.B.; Niven, M.L.; Hamel, E.; Schmidt, J.M.
J. Nat. Prod. 1987, 50, 119.
5. King, L.; Sullivan, M. Science 1946, 104, 244.
6. Olah, G.A. Friedel-Crafts Chemistry; Wiley-Interscience: New York,
1973.

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