Total synthesis of penipanoid C, 2-(4-hydroxybenzyl)quinazolin-4(3H)-one and NU1025

Article abstract of DOI:10.1016/j.tetlet.2016.08.018

The first total synthesis of penipanoid C and 2-(4-hydroxybenzyl)quinazolin-4(3H)-one is reported using a greener mild deep eutectic solvent mediated cyclization strategy with good overall yields. NU1025 drug is also synthesized using the similar protocol.

Full text of DOI:10.1016/j.tetlet.2016.08.018

Accepted Manuscript
Total synthesis of penipanoid C, 2-(4-hydroxybenzyl)quinazolin-4(3H)-one and
NU1025
Suman Kr Ghosh, Rajagopal Nagarajan
PII:
S0040-4039(16)31005-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.08.018
TETL 47989
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
12 July 2016
4 August 2016
5 August 2016
Please cite this article as: Ghosh, S.K., Nagarajan, R., Total synthesis of penipanoid C, 2-(4-
hydroxybenzyl)quinazolin-4(3H)-one and NU1025, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/
j.tetlet.2016.08.018
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Total synthesis of penipanoid C, 2-(4-
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NU1025
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Suman Kr Ghosh and Rajagopal Nagarajan

1
Tetrahedron Letters
Total synthesis of penipanoid C, 2-(4-hydroxybenzyl)quinazolin-4(3H)-one and
NU1025
a
a
Suman Kr Ghosh and Rajagopal Nagarajan 
a
School of chemistry, University of Hyderabad, Hyderabad- 500046, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The first total synthesis of penipanoid C and 2-(4-hydroxybenzyl)quinazolin-4(3H)-one is
reported using a greener mild deep eutectic solvent mediated cyclization strategy with good
overall yields. NU1025 drug is also synthesized using the similar protocol.
Available online
Keywords:
Penipanoid C
Quinazolinone
Alkaloids
Total synthesis
Deep Eutectic Solvent
Nitrogen containing heterocyclic cores always remained as an
1
important building block among naturally occurring alkaloids.
Due to their versatile pharmacological and biological properties
there is always an urge for synthesis of nitrogen containing
2
natural products. Among these heterocyclic cores, quinazolinone
is one of the important core that is present in a variety of
naturally occurring alkaloids. The distinctive biological
properties of quinazolinones like, protein tyrosine kinase
inhibition,
cholecystokinin
inhibiton,
anti-microbial,
anticonvulsant, sedative, hypotensive, anti-depressant, anti-
inflammatory, and anti-allergy fascinates chemists to synthesize
3
various quinazolinone alkaloids.
In 2011, Wang group isolated four new alkaloids; penipanoid
A (1), penipanoid B (2), penipanoid C (3) and 2-(4-
hydroxybenzyl) quinazolin-4(3H)-one (4) from the marine
Figure 1. Structure of alkaloids isolated from the marine sediment derived
fungus Penicillium paneum SD-44 & NU1025 drug.
4
sediment-derived fungus penicillium paneum SD-44 (Figure 1).
Among them penipanoid B and C (2 and 3) were newly isolated
quinazolinone alkaloids whereas alkaloid 4 was already known in
literature, as Che et al. isolated this compound 4 along with other
six alkaloids from the Cordyceps-colonizing fungus Isaria
Penipanoid C shows moderate inhibitory activity against TMV
4, 5, 6
and human gastric cancer cell SGC-7901.
Penipanoid C was
extracted in a small amount and thus tested only for antimicrobial
activity against two bacteria and five plant-pathogenic fungi
where it showed no activity. Hence, synthesis of these natural
alkaloids were necessary due to their low abundance and wide
5
farinose in 2011 itself. Later, Penipanoid C and compound 4
was again isolated from marine fungus Penicillium oxalicum
6
4
0
312F
1
. Compound 4 was reported for its significant cytotoxic
biological spectrum.
activity against the A-549 and BEL-7402 cell lines cell with IC50
NU1025 [8-hydroxyl-2-methyl-4(3H)-quinazoline] (5, Figure
) is known as a potent inhibitor of poly(ADP ribose)
values of 17.5 and 19.8 μM, and also exhibits strong inhibitory
4,6
1
activity on the replication of tobacco mosaic virus (TMV).
polymerase. NU1025 potentiate the cytotoxicity of a panel of
mechanistically diverse anti-cancer agents was evaluated in
7
L1210 cells. However; in literature no synthetic report are
—
——

Corresponding author. Tel.: (+) 91 40 23012460; e-mail: nagaindole@gmail.com

2
available till today for these molecules. As our group is working
on the synthesis of various natural products especially on
quinazolinones, These alkaloids fascinated us as they are
Scheme 2: Synthesis of 2-(4-hydroxybenzyl)quinazolin-
4(3H)-one and penipanoid C
8
structurally related and contains the quinazolinone core (Fig. 1).
Recently, we reported, synthesis of various quinazolinones using
9
Deep Eutectic Solvent (DES). From an environmental
perspective, use of deep eutectic solvent mediated cyclization as
a key step for total synthesis of alkaloids would open new
directions for the scientific community. Thus, in this letter, we
report the first total synthesis of penipanoid C and 2-(4-
hydroxybenzyl)quinazolin-4(3H)-one via deep eutectic solvent
mediated cyclization strategy.
Scheme 1: Retrosynthesis of penipanoid C
Scheme 1 shows the retrosynthetic approach for penipanoid C
which can be obtained from compound 9 via benzylic oxidation
and deprotection in consecutive steps. Compound 9 can be
stemmed using a cyclization reaction of commercially available
anthranilimide and appropriately protected phenylacetaldehyde.
We prepared 2-(4-(benzyloxy)phenyl)acetaldehyde (11) in
three steps from 4-hydroxyphenylacetic acid. Next, Compound
1 and anthranilamide (6) were added to the L-(+) tartaric acid-
1
DMU mixture (3:7) at 90 corresponding
C,
dihydroquinazolinone (12’) was obtained in 80% yield.
Our investigation began with the preparation of 4-
methoxyphenylacetaldehyde (7) from 4-hydroxylphenylacetic
acid by following three consecutive steps. Next, this aldehyde (7)
was treated with anthranilamide (6) in the L-(+)-tartaric acid-
DMU mixture (3:7) at 90 C to obtain the 2-(4-methoxybenzyl)-
Scheme 3: Revised synthesis of 2-(4-
hydroxybenzyl)quinazolin-4(3H)-one and penipanoid C
2,3-dihydroquinazolin-4(1H)-one (9’) which was further
converted to the aromatized product 2-(4-
methoxybenzyl)quinazolin-4(3H)-one (9) with DDQ at rt. We
could acquire compound 9 directly if the cyclization reaction was
continued for 10h. Next, methoxy deprotection of compound 9
3
with BBr gave the alkaloid 2-(4-hydroxybenzyl) quinazolin-
4(3H)-one (4) with a good overall yield. We envisaged that the
benzylic oxidation of compound 4 could have been able to
furnish the penipanoid C but unfortunately direct benzylic
oxidation strategy was a failure. It was the free phenolic –OH
which might be the reason for this termination. Thus, we first
carried out the oxidation step at the benzylic position of
compound 9 with KBr/ Oxone in DCM-MeNO
2
solvents to
obtain compound 10 in 75% yields. Next, deprotection of
methoxy group of compound 10 with BBr to obtain penipanoid
C, was a failure again. Coordination of BBr with the carbonyl
10
3
3
group might be the probable reason for this failure. Thus we
modified the strategy with a different protecting group, from
methoxy to tert-butyldimethylsilyl ether (-OTBDMS) (8).
Unfortunately, when the anthranilamide (1a) and compound 8
was subjected to our standard cyclization condition, we obtained
the corresponding TBDMS deprotected dihydroquinazolinone
(4’) and quinazolinone (4) product. The acidic nature of the
reaction media might be the reason for this deprotection of
TBDMS group. Protection of compound 4 with TBDMS was
again attempted using TBDMSCl and imidazole in dry DMF but
it again went in vain. After failing for two times with two
different protecting groups, we opted for a neutral and easy
leaving group like benzyl.
It was further aromatized to 2-(4-(benzyloxy)benzyl)quinazolin-
4(3H)-one (12) in 82% yield using DDQ in dry DCM. The
benzylic oxidation of Compound 12 was achieved with
KBr/Oxone in DCM-MeNO
73% yields. Next, the deprotection of the benzyl group with H
on Pd/C not only deprotected the benzyl group but unfortunately
2
solvent to obtain compound 13 in
2

3
also reduced the benzylic carbonyl to secondary alcohol (14,
scheme 5). Hence, that benzylic hydroxy of compound 14 was
again oxidised with Pyridinium chlorochromate (PCC) in DCM
Chem. Rev. 2014, 114, 10369−10428. c) AlQathamaab, A.; Prieto, J.
M. Nat. Prod. Rep. 2015, 32, 1170–1182.
3
.
a) Mhaske, S. B.; Argade, N. P. Tetrahedron 2006, 62, 9787–9826. b)
He, L.; Li, H.; Chen, J.; Wu, X- F. RSC Adv. 2014, 4, 12065. c) Khan,
I.; Ibrar, A.; Ahmed, W.; Saeed, A. Eur. J. Med. Chem. 2015, 90, 124-
169. e) Kshirsagar, U. A. Org. Biomol. Chem. 2015, 13, 9336–9352.
Li, C- S.; An, C –Y.; Li, X –M.; Gao, S –S.; Cui, C –M.; Sun, H –F.;
Wang, B –G. J. Nat. Prod. 2011, 74, 1331–1334.
to obtain penipanoid
C
(3) in 85% yield. 2-(4-
Hydroxybenzyl)quinazolin-4(3H)-one (4) was also obtained via
debenzylation of compound 12 with hydrogen in Pd/C. We have
accomplished the first total syntheses of penipanoid C and 2-(4-
hydroxybenzyl)quinazolin-4(3H)-one in overall 36.6% and 57%
yield respectively.
4.
5
.
Ma, C.; Li, Y.; Niu, S.; Zhang, H.; Liu, X.; Che, Y. J. Nat. Prod. 2011,
7
4, 32–37.
6
7
.
.
Shen, S.; Li W.; Wang, W. J. Nat. Prod. Res. 2013, 27, 2286.
a) Bowman, K. J.; White, A.; Golding, B. T.; Griffin, R. J.; Curtin, N. J.
Br. J. Cancer 1998, 78, 1269-1277. b) Boulton, S.; Kyle, S.; Durkacz,
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a) Ghosh, S. K.; Nagarajan, R. RSC Adv. 2014, 4, 63147-63149. b)
Ghosh, S. K.; Nagarajan, R. RSC Adv. 2014, 4, 20136-20144. c) Viji,
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Further, we were eager to synthesize NU1025 [8-hydroxyl-2-
methyl-4(3H)-quinazoline] (Scheme 4) using this green deep
eutectic solvent mediated cyclization strategy due to its diverse
pharmacological properties (vide supra). In the beginning, 2-
amino-3-methoxybenzamide (15) was synthesized from 3-
methoxy-2-aminobenzoic acid via two steps which on treatment
8.
9
1
.
Ghosh, S. K.; Nagarajan, R. RSC Adv. 2016, 6, 27378–27387.
0
with acetaldehyde solution in low melting mixtures at 90 C
0. Moriyama, K.; Nakamura, Y.; Togo, H. Org. Lett. 2014, 16,
furnished 8-methoxy-2-methyl-2,3-dihydroquinazolin-4(1H)-one
3812−3815.
(
16’) in 87% yield in 2h. It was further aromatized to
quinazolionone product 16 with 10% Pd/C at rt. Treatment of
compound 16 with BBr in dry DCM in reflux condition,
3
deprotected the methoxy group that led to NU1025(5) in 73%
yield and we have completed the synthesis of NU1025 with
51.4% overall yield.
Scheme 4: Synthesis of 8-hydroxyl-2-methyl-4(3H)-
quinazoline (NU1025)
In conclusion, we have utilized a milder and economical
strategy for the synthesis of dihydroquinazolinones to synthesize
naturally occurring alkaloids penipanoid
C
and 2-(4-
hydroxybenzyl)quinazolin-4(3H)-one have synthesized for the
first time with overall good yields. NU1025 drug also been
synthesized using this DES protocol.
Acknowledgments
We thank DST for financial support. S.K.G. thanks UGC for
senior research fellowship.
Supplementary Material
NMR, CHN, LCMS and HRMS spectra are available in
supporting information
References and notes
1
.
a) Ishikura, M.; Abe, T.; Choshi, T.; Hibino, S. Nat. Prod. Rep. 2013,
0, 694−752. b) Bharate, B. S.; Sawant, S. D.; Singh, P. P.;
3
Vishwakarma R. A. Chem. Rev. 2013, 113, 6761−6815. c) Iranshahy,
M.; Quinn, R. J.; Iranshahi, M. RSC Adv. 2014, 4, 15900–15913.d)
Blunt, J. W.; Copp, B. R.; Keyzers, R. A.; Munroa, M. H. G.; Prinsep,
M. R. Nat. Prod. Rep. 2015, 32, 116–211.
2
.
a) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104−6155. b)
Hussain, H; Al-Harrasi, A.; Al-Rawahi, A.; Green, I. R.; Gibbons, S.

Highlights:



The first total synthesis of penipanoid C and 2-(4-hydroxybenzyl)quinazolin-4(3H)-one is
reported.
A greener mild deep eutectic solvent mediated cyclization strategy was used with good
overall yields.
NU1025 drug is also synthesized using the similar protocol.