Synthesis of new carbonyl and fluoroalkyl o-quinone methides from β-lapachone

Article abstract of DOI:10.1016/j.tetlet.2007.06.145

The synthesis of new carbonyl and fluoroalkyl o-quinone methides from β-lapachone is reported.

Full text of DOI:10.1016/j.tetlet.2007.06.145

Tetrahedron Letters 48 (2007) 6171–6173
Synthesis of new carbonyl and fluoroalkyl o-quinone
methides from b-lapachone
a
b
a
Milton N. da Silva, Sabrina B. Ferreira, Alessandra Jorqueira,
a
c
b
a,
*
Maria C. B. V. de Souza, Antonio V. Pinto, Carlos R. Kaiser and Vitor F. Ferreira
a
Universidade Federal Fluminense, Instituto de Qu ı´ mica, Departamento de Qu ı´ mica Org aˆ nica, CEG,
Campus do Valonguinho, 24210-150, Niter o´ i—RJ, Brazil
b
Universidade Federal do Rio de Janeiro, Instituto de Qu ı´ mica, Ilha do Fund a˜ o, 21949-900, Rio de Janeiro- RJ, Brazil
c
Universidade Federal do Rio de Janeiro, NPPN-CCS, bloco H, Ilha do Fund a˜ o, 21949-900, Rio de Janeiro, Brazil
Received 20 April 2007; revised 23 June 2007; accepted 26 June 2007
Available online 4 July 2007
Abstract—The synthesis of new carbonyl and fluoroalkyl o-quinone methides from b-lapachone is reported.
Ó 2007 Elsevier Ltd. All rights reserved.
o-Quinones (o-Qs) and o-quinone methides (o-QMs) are
related sub-structural moieties present in several bio-
active compounds with high interest due to several
related biological activities. For example, quinones have
b-Lapachone (1a) is an o-naphthoquinone that can be
isolated from plant extracts of Tabebuia avellanedae. It
had been intensely investigated for clinical use as try-
1
3
panocidal, HIV-1 replication suppression in both
acute and chronic infection and, topoisomerases inhibi-
tion that has potential clinical utility for human leuke-
1
2
been studied for antitumor, molluscicidal, leischmani-
3
4
5
cidal, anti-inflammatory, antifungic, and trypanoci-
6
14
dal activities. This group generally accepts one and/or
mia and prostate cancer chemotherapy.
two electrons (redox cycling) to form the corresponding
radical anion or dianion species in situ. In such a way,
the semi-quinone radicals accelerate the intracellular
Since the transformation of o-quinones into o-quinone
methides adds new biological possibilities, it seems that
an interesting starting point is to transform bioactive
naphthoquinones, such as 1a, into new lead compounds.
Two recent studies have been carried out (Scheme 1).
7
hypoxic conditions by producing a superoxide anion.
Quinone methides, on the other hand, are reactive
intermediates involved in a large number of chemical
reactions and biological processes such as enzyme inhi-
bition, reaction with phosphodiester, DNA alkylation,
and cross-linking.8 Their electrophilicity towards
amines, thiols, water, amino acids and peptides has also
O
9
HO
been used for interactions with DNA bases. Several
CO Et
2
important clinical anti-cancer drugs (e.g., cisplatin,
psoralens, and mitomycin C) are known to induce
DNA ISC formation, which can disrupt cell mainte-
nance and replication by a mechanism that involve o-
QMs intermediates. Since o-QMs are unstable interme-
diates, they must be generated in situ by processes that
involve photolysis of o-, m- and p-hydroxybenzyl alco-
NaOH 1%
EtOH
1a
Ph P=CHCO Et
O
4, 85%
3
2
CH Cl
2
2
EtO C
O
2
O
hols,1 thermal reactions,
0
11
and anionic triggering
1
2
reactions.
O
5
, 74%
*
Corresponding author. Tel.: +55 21 26292345; fax: +55 21
6292362; e-mail: cegvito@vm.uff.br
2
Scheme 1. Recent reports involving the transformations of 1a.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.145

6172
M. N. da Silva et al. / Tetrahedron Letters 48 (2007) 6171–6173
O
O
O
14
1
R1
3
11 R2
2
1
3
7a, R1 = CH , R2 = H, 80%
I2
6
5
7
b, R1 = R2 = CH3, 66%
7c, R1 = cyclopropyl, R2 = H, 26%
d, R1 = CH3, R2 = CO2Et, 36%
7e, R1 = EtO CCH ,R = H, 9%
O
O
7
6a
10a
8
9
1a
O
7
1
0
4a
R2
2
2
2
R1
4
10b
CH2N2
Et O
6
a-d
3
O
O
H C
3
O
2
2
O
15
16
DAST
R2
R3 R4
R1
9, 94%
AlCl3 or I2
O
CH2Cl2
O
R O
2
R1
7b', 30%
O
O
1
1
1
0a, R = Cl, R = H, 84%
1 2
Ac2O
Py
0b, R = I, R = OH, 87%
1
2
O
0c, R = Cl, R = OAc, 87%
8a, R = CH , R = H, R = R = F, 80%
1 3 2 3 4
1
2
8
b, R = R = CH , R = R = F, 75%
1 2 3 3 4
Scheme 2. o-QMs and fluorinated o-QMs obtained from b-lapachone (1a).
Pinto and co-workers15 studied the aldol condensation
using NaOH 1%/EtOH isolating a dihydro-cyclopenta-
none (4) adduct in 85% yield. It is worthy to note that
compound 4 upon acid treatment led to cyclopentanone.
Nicolaides and co-workers16 have studied the Wittig
reactions of o-quinones, as 1a and derivatives, with alk-
oxy-carbonyl-methylene (triphenyl)-phosphoranes.
The confirmation of such frameworks behavior was
1
13
done by H and C NMR including 2D NMR tech-
niques as COSY, HSQC, HMBC and NOESY. For
example, in 7a it is possible to clearly confirm that the
exocyclic olefin was formed at the C-6 carbonyl due to
correlations between H-13 and H-7 in the NOESY spec-
trum. This result also confirms that its configuration can
be securely assigned as E.
In this Letter, we present our efforts on the preparation
of stable o-QMs and fluorinated o-QMs from b-lapach-
one (1a), as well as three halogenated derivatives (8a–c),
which might be a source of non-substituted o-QM of 1a.
In order to perform these transformations chemoselec-
tive reactions between b-lapachone (1a) with several ke-
tones catalyzed by iodine were done to produce o-QMs
Treatment of o-QMs 7a–b with DAST in dry dichloro-
methane at room temperature for 24 h gave the alkyl-
fluorinated o-QMs 8a–b in 80% and 75% yields,
respectively. The NOESY spectra in the same way as
above, show the H-13 and H-7 correlations and confirm
the E configuration for these compounds.
7
a–e, in moderate to good yields. o-QMs 7a–b was also
reacted with DAST to produce fluorinated o-QMs 10a–
b, as outlined in Scheme 2.
Since non-substituted o-QMs were never isolated, we
also studied an alternative route that could lead to
unsubstituted o-QMs of 1a. As shown in Scheme 2,
the synthesis of 10a–b was carried out in two steps.
The first involved the preparation of lapachone-oxyran
derivative 9, which was obtained in high yield from
The preparation of o-QMs 7a–e was carried out in one
step by aldol condensation reactions between b-lapach-
one 1a with ketones 6a–d at room temperature. The
reaction of ketones 6a and 6c with 1a lead exclusively
to products 7a and 7c with the configuration E in exocy-
clic double bond. The reaction of ketone 6b should fur-
nish two o-QMs products, but only o-QM 7b with the
configuration E was isolated, since the Z isomer under-
went a second aldol condensation producing cyclopenta-
1
9
the reaction of 1a with diazomethane in ether. In the
second step oxyran 9 was reacted with AlCl and iodine
3
in DCM at room temperature. Both these Lewis acids
catalyzed the opening of the oxyran ring furnishing sub-
stances 10a–b in high yield. Additionally, compound 10a
was transformed into the acetate derivative 10c to pro-
duce a compound with a better leaving group for the
generation of o-QM. However, all the attempts to gener-
ate and isolate o-QMs from 10a–c were unsuccessful.
0
none 7b . The reaction with ketone 6d gave a complex
mixture, from which was possible to isolate the o-QMs
0
7
d and 7d in low yields.
The chemoselectivities found in the reactions of 1a were
not surprising, since there are several reports in the liter-
ature indicating that the carbonyl nearest to the aro-
In summary, a novel method for the synthesis of stable
o-quinone methides from b-lapachone (1a) is described.
The aldol condensation under iodine-catalyzed process
forming the o-QMs 7a–e occurs chemoselectively and
diastereoselectively at the 6-carbonyl groups. Two of
these o-QMs were transformed into alkyl-fluorinated
1
7
matic ring is the more reactive.
The formation
mainly of the E diastereoisomer products observed in
1
8
these reactions was governed by steric effects.

M. N. da Silva et al. / Tetrahedron Letters 48 (2007) 6171–6173
6173
o-QMs 8a–b, which turns also to be stable. Additionally,
three new compounds (10a–c) that can generate in situ
7. (a) Santos, E. V. M.; Carneiro, J. W. M.; Ferreira, V. F.
Bioorg. Med. Chem. 2004, 12, 87–93; (b) Silva, M. N.;
Ferreira, V. F.; de Souza, M. C. B. V. Quim. Nova 2003,
2
3
o-QMs were prepared from the oxyran 7 in high yields.
To the best of our knowledge, the preparation of the
presented o-QMs represents the first example of the
chemoselective and diastereoselective formation of sta-
ble o-quinone methides from b-lapachone (1a). Full
2
6, 407–416.
8
9
. Wang, P.; Song, Y.; Zhang, L. X.; He, H. P.; Zhou, X.
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. Freccero, M.; Gandolfi, R.; Sarzi-Amad e` , M. J. Org.
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experimental details and H, C NMR spectra data
are available in the supporting informations. See Sup-
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