A one-pot, efficient and facile synthesis of 4β -arylaminopodophyllotoxins: Synthesis of NPF and GL-331 as DNA topoisomerase II inhibitors

Article abstract of DOI:10.1016/j.tetlet.2003.09.110

A series of 4β-arylamino-4′-O-demethylepipodophyllotoxins and 4β-arylaminopodophyllotoxins have been synthesized with significant stereoselectivity and improved yields by employing the BF₃· OEt₂/NaI reagent system. Compounds NPF, GL-331 and other DNA topoisomerase II inhibitors have been prepared in good to excellent yields by employing this methodology.

Full text of DOI:10.1016/j.tetlet.2003.09.110

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8457–8459
A one-pot, efficient and facile synthesis of
4b-arylaminopodophyllotoxins: synthesis of NPF and GL-331 as
DNA topoisomerase II inhibitors
Ahmed Kamal,* B. Ashwini Kumar and M. Arifuddin
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
Received 21 July 2003; revised 5 September 2003; accepted 12 September 2003
Abstract—A series of 4b-arylamino-4%-O-demethylepipodophyllotoxins and 4b-arylaminopodophyllotoxins have been synthesized
with significant stereoselectivity and improved yields by employing the BF3·OEt2/NaI reagent system. Compounds NPF, GL-331
and other DNA topoisomerase II inhibitors have been prepared in good to excellent yields by employing this methodology.
© 2003 Elsevier Ltd. All rights reserved.
The biological activity of podophyllotoxin has led to
extensive structure modifications resulting in several
clinically useful compounds. Etoposide1 and teniposide2
developed in the late 1960s and early 1970s are two
epipodophyllotoxins3 in clinical use as anticancer
agents. With a view to improving the clinical efficacy
and to overcoming the problems of drug resistance and
myelosuppression various 4b-substituted congeners of
epipodophyllotoxin have been synthesized and evalu-
ated for their biological properties.4 Podophyllotoxin is
known as an antimicrotubule agent while the epipodo-
phyllotoxin and its 4b-congeners are potent DNA
topoisomerase II inhibitors. A large number of 4b-
amino substituted congeners have been prepared and
some of these derivatives (e.g. NPF and GL-331)5,6
have displayed a better pharmacological profile than
those of etoposide. One of them, 4%-O-demethyl-4b-(4%%-
nitroanilino)-4-desoxypodophyllotoxin (GL-331) is cur-
rently in phase-II of the clinical trials against gastric
carcinoma, colon cancer, non-small cell carcinoma and
etoposide resistant malignancies.7
In the literature, 4b-amino substituted congeners such
as 4%-O-demethyl-4b-(4%%-fluoroanilino)-4-desoxypodo-
phyllotoxin (NPF) have been synthesized by Lee’s8
approach, which involves the following reactions start-
ing from podophyllotoxin: (i) one-pot C-4 epimeriza-
tion and 4%-O-demethylation, (ii) C-4 bromination
(100% crude yield) via a modified Khun’s method and
nucleophilic displacement with 4-fluoroaniline (45%
* Corresponding author. Tel.: +91-40-27193157; fax: +91-40-27193189; e-mail: ahmedkamal@iict.ap.nic.in
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.110

8458
A. Kamal et al. / Tetrahedron Letters 44 (2003) 8457–8459
congeners such as NPF and GL-331. The reaction of
podophyllotoxin with the BF3·OEt2/NaI reagent system
followed by the addition of the corresponding aryl-
amines in the presence of mild bases like BaCO3 or
K2CO3 or CsCO3 affords the arylamino substituted
podophyllotoxins. Similarly, in these reactions the pro-
cess of 4%-O-demethylation has been controlled by
employing the required solvents that is CH2Cl2 to give
4b-arylamino 4%-O-demethylpodophyllotoxins (4a–d in
40–55% yields)14 and CH3CN to give 4b-aryl-
aminopodophyllotoxins (4e–g in 80–85% yield)15 as
shown in Scheme 2.
Scheme 1. Reagents and conditions: (i) BF3·OEt2/NaI,
CH2Cl2, 5 h, rt; (ii) BF3·OEt2/NaI, MeCN, 15 min, rt; (iii)
BaCO3, CH3COCH3–H2O, 2 h, rt.
yield) to afford NPF in 23% overall yield together with
minor amounts of the 4a-substituted product. Later,
Monneret9 and co-workers reported a method employ-
ing TMSI to afford NPF in 52% yield. This method has
recently been improved in our laboratory by the addi-
tion of tetrabutylammonium iodide10 to afford the
target compound in higher yields. We have also
reported the synthesis of this compound by employing
the methanesulfonic acid/NaI reagent system11 and by
reduction of the azido functionality by employing bak-
er’s yeast.12 In continuation of these efforts, we herein
report the synthesis of 4b-arylaminopodophyllotoxin
derivatives including NPF and GL-331 by employing
the BF3·OEt2/NaI reagent system. This reagent system
has recently been utilized for the iodination of alcohols
but the present procedure describes the preparation of
aminoaryl derivatives via the iodo intermediates. More-
over, iodination of allylic and benzylic alcohols by the
use of the BF3·OEt2/KI reagent system13 is also known.
Scheme 2. Reagents and conditions: (i) BF3·OEt2/NaI,
CH2Cl2, 5 h, rt; (ii) BF3·OEt2/NaI, MeCN, 15 min, rt; (iii)
THF, RNH2, BaCO3, 8 h, rt.
In summary, we have demonstrated a convenient and
practical one-pot process for the synthesis of 4b-aryl-
aminopodophyllotoxin analogues. This procedure also
exhibits selectivity in 4%-O-demethylation by using the
appropriate solvent thus demonstrating the application
of this methodology for the selective preparation of
4%-O-demethyl or epipodophyllotoxin congeners in high
yields. Moreover, this procedure has been extended to
the efficient synthesis of DNA topoisomerase II
inhibitors such as NPF and GL-331 and hence it has
potential for the preparation of other related amino
substituted podophyllotoxin analogues.
In view of our interest in the preparation of new
podophyllotoxin congeners, we have investigated the
use of the BF3·OEt2/NaI reagent system in CH2Cl2
for iodination of the benzylic alcohol in the C-ring of
the podophyllotoxin system followed by hydrolysis
(water:acetone, BaCO3) to afford 4%-O-demethyl
epipodophyllotoxin. Interestingly, carrying out this iodi-
nation process in CH3CN followed by hydrolysis pro-
vides the epipodophyllotoxin without 4%-O-demethyla-
tion. In this methodology 4%-O-demethylation could be
maneuvered by using the required solvent (Scheme 1).
Acknowledgements
This procedure has been further extended towards the
preparation of potential 4b-arylaminopodophyllotoxin
One of the author’s B.A.K is thankful to CSIR, New
Delhi for the award of senior research fellowship.

A. Kamal et al. / Tetrahedron Letters 44 (2003) 8457–8459
8459
References
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1619, 1513 and 1473 (aromatic CꢀC) cm−1; 1H NMR (200
MHz, CDCl3) l 6.90 (m, 2H, 3%%, 5%%-H), 6.75 (s, 1H, 5-H),
6.53 (s, 1H, 8-H), 6.49 (m, 2H, 2%%, 6%%-H), 6.29 (s, 2H, 2%,
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exchangeable NH), 3.15 (dd, J=4.8, 13.7 Hz, 1H, 2-H),
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’
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without further purification. To the above crude product,
anhydrous BaCO3 (395 mg, 2 mmol) and then the appro-
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toxin (414 mg, 1 mmol) in dry CH2Cl2 (10 mL), NaI (447
mg, 3 mmol) was added and stirred for 5 min. To this
suspension BF3·OEt2 (425 mg, 3 mmol) was added drop-
wise by syringe at 0°C and stirring was continued for
another 5 h at room temperature. This solution was then
evaporated in vacuo and used for the next reaction
without further purification. To the above crude product,
anhydrous BaCO3 (395 mg, 2 mmol) and then the appro-
priate arylamine (1.2 mmol) in 10 mL of dry THF under
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3388 (NH), 1772 (lactone), 1619, 1513 and 1473 (aro-
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6.49 (m, 2H, 2%%, 6%%-H), 6.29 (s, 2H, 2%, 6%-H), 5.97 and
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J=8.0 Hz, 1H, 11-H), 3.90 (s, 3H, 4%-OCH3), 3.80 (s, 6H,
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+
’
507 [M] ; HRMS (FAB): calcd for C28H26O7NF
507.5114, found: 507.1693.