Ruthenium-catalyzed C-H oxygenation of quinones by weak O-coordination for potent trypanocidal agents

Article abstract of DOI:10.1039/c8cc07572g

Ruthenium-catalysis enabled the C-5 selective C-H oxygenation of naphthoquinones, and also sets the stage for the site-selective introduction of a hydroxyl group into anthraquinones. A-ring modified naphthoquinoidal compounds represent an important class of bioactive quinones for which the present study encompasses the first C-H oxygenation strategy by weak O-coordination.

Full text of DOI:10.1039/c8cc07572g

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Ruthenium-catalyzed C–H oxygenation of
quinones by weak O-coordination for potent
trypanocidal agents†
Cite this: Chem. Commun., 2018,
54, 12840
Received 18th September 2018,
Accepted 16th October 2018
c
Gleiston G. Dias,ab Torben Rogge,b Rositha Kuniyil,b Claus Jacob,
Rubem F. S. Menna-Barreto,d Eufranio N. da Silva Junior *a and
ˆ
´
b
DOI: 10.1039/c8cc07572g
Lutz Ackermann
*
rsc.li/chemcomm
Ruthenium-catalysis enabled the C-5 selective C–H oxygenation of
naphthoquinones, and also sets the stage for the site-selective
introduction of a hydroxyl group into anthraquinones. A-ring
modified naphthoquinoidal compounds represent an important class
of bioactive quinones for which the present study encompasses the
first C–H oxygenation strategy by weak O-coordination.
Among the versatile scaffolds studied in Medicinal Chemistry,
quinones represent a privileged class of substance.1 Thus,
quinoidal compounds are involved in biologically relevant pro-
cesses, such as in the electron transport chain, redox mediators,
and as alkylating agents in a broad spectrum of biological
processes.2 For example, nocardiones A are notable bioactive
naphthoquinoidal molecules. (À)-Nocardione A is a Cdc25B
tyrosine phosphatase inhibitor, while (+)-nocardione A presents
antifungal and cytotoxic activity with the ability to kill human
myeloid leukemia cell lines via a mechanism of action associated
with apoptosis.3 Remarkable 1,4-naphthoquinones (1,4-NQs)
include crassiflorone,4 a natural product isolated from the stem
bark of the African ebony (persimmon) tree Diospyros crassiflora
with anti-mycobacterial and anti-gonorrhoeal properties,5 among
others. Furthermore, juglomycin A,6 (R)-8-hydroxy-R-dunnione7
and kidamycinone8 are examples of important quinoidal com-
pounds with diverse bioactivity9 (Scheme 1A).
The quinones depicted in Scheme 1A bear a hydroxyl group
as a recurring structural motif in the benzenoid A-ring, which is
Scheme 1 Overview.
a Institute of Exact Sciences, Department of Chemistry, Federal University of Minas
Gerais, Belo Horizonte, MG, 31270-901, Brazil. E-mail: eufranio@ufmg.br
usually installed in the first steps of their previously reported
respective syntheses.3,4,8 The preparation of such molecules via
late-stage functionalization by C–H activation logic has thus far
not been addressed.10 This C–H activation strategy can be an
instrument to maximize the synthesis process with the pre-
paration of the target molecules in a reduced number of steps
with overall significantly improved yields. Late-stage function-
alization of quinones is not easily achieved due to the following
aspects, including: (a) generally deactivated quinoidal systems
present low nucleophilicity at the benzenoid A-ring; (b) the
b
¨
¨
Institut fur Organische und Biomolekulare Chemie, Georg-August-Universitat,
¨
¨
Gottingen, Tammannstraße 2, 37077 Gottingen, Germany.
E-mail: lutz.ackermann@chemie.uni-goettingen.de
c Division of Bioorganic Chemistry, School of Pharmacy, University of Saarland,
D-66123 Saarbruecken, Germany
d Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, RJ, 21045-900, Brazil
† Electronic supplementary information (ESI) available: Experimental procedures
and characterisation data for all compounds. CCDC 1859287 (2i), 1859288 (2f),
1859289 (2c), 1859290 (2d), 1859453 (2j), 1859454 (2e) and 1859455 (2h). For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c8cc07572g
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Table 1 Optimization of C–H oxygenationa
C–H oxygenations of quinonoid compounds have been proven to
be elusive. Given our recent success in terms of ruthenium-
catalyzed C–H oxygenations with weakly coordinating ketones,
amides and aldehydes12 (Scheme 1C), herein, we describe an
efficient process for the direct, site-selective installation of a
hydroxyl group in a broad range of naphthoquinones and anthra-
quinones. For the first time, a C–H bond oxygenation strategy was
thus established for the synthesis of quinonoid derivatives with
unique bioactivity (Scheme 1D).
Preliminary studies involved the reaction of 1,4-naphtho-
quinone (1a) with PhI(CF3CO2)2 (PIFA) as an oxidant and
[RuCl2(p-cymene)]2 as the catalyst (Table 1, entry 1). Here,
juglone (2a) and naphthazarin (2b) were obtained in 53 and
42% yield, respectively. Further refinement aiming at minimizing
the amount of the ruthenium-based catalyst afforded products 2a
and 2b in 87 and 5% yield when 2 mol% of [RuCl2(p-cymene)]2
and 1.2 equivalents of PIFA were used (entry 2). Despite the
efficiency of the catalyst, we continued our efforts towards
alternative oxidation sources. Hence, PIDA and NH4S2O8 were
also evaluated as oxygenation agents, albeit with limited suc-
cess (entries 3 and 4). We also tested alternative sources of
catalysts with the use of rhodium, cobalt and palladium com-
Entry [Ru]-Source (mol%)
Oxidant
Y
Temp (1C) 2a 2b
1
2
3
[RuCl2(p-cymene)]2 (5) PIFA
[RuCl2(p-cymene)]2 (2) PIFA
[RuCl2(p-cymene)]2 (2) PIDA
2.0 110
1.2 80
1.2 80
53 42
87
5
71 Traces
NR NR
NR NR
NR NR
NR NR
NR NR
NR NR
4
5
6
7
[RuCl2(p-cymene)]2 (2) NH4S2Os 1.2 80
RuCl3ÁH20 (5)
[RhCp*Cl2]2 (5)
CoCp*(CO)I2(5)
Pd(OAc)2 (5)
—
PIFA
PIFA
PIFA
PIFA
PIFA
1.2 80
1.2 80
1.2 80
1.2 80
1.2 80
1.2 80
8
9b
10b
[RuCl2(p-cymene)]2 (2) PIFA
92
3
a
General reaction conditions: (1a) (0.4 mmol), PIFA (0.5 mmol),
[RuCl2(p-cymene)]2 (5.0 or 2.0 mol%); (TFAA) (1 mL) and TFA (0.02 mL),
b
18 h. 12 h. PIFA = PhI(CF3CO2)2. PIDA = PhI(CH3CO2)2. NR = for all cases
starting material 1a was recovered, with the exception of the reaction
with Pd(OAc)2, here degradation of the products was observed. Yields of
isolated products.
weakly coordinating ability of the B-ring carbonyls towards plexes, but promising results were not observed (entries 5–8).
transition metal catalysts and (c) the difficulty in developing A control experiment confirmed the essential role of the ruthenium
general reaction protocols capable of providing favorable results catalyst (entry 9). Fine tuning of the reaction temperature enabled
with the use of different classes of quinonoid systems.10
the formation of juglone (2a) in 92% yield (entry 10). Viable
In this context, Sun and Zhang, Kakiuchi, Bower and da Silva substrates for the new C–H oxygenation strategy are outlined in
Ju´nior groups11 have recently developed useful methods for Scheme 2.
C–H functionalization of naphthoquinones and anthraquinones
Structural assignments were based on detailed NMR analysis
(Scheme 1B). Despite the recent development in the area, direct and X-ray diffraction analysis of products 2c–2f, 2h, 2i and 2j.
Scheme 2 Scope of the naphthoquinone C-5 oxygenation protocol.
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In general, quinones were prepared in moderate to high
Communication
yields, tolerating the presence of electron withdrawing and
donating groups. In most cases, the dihydroxylated product was
not formed or was observed in only 3% yield (2b and 2d). Our
method proved effective even for the preparation of the hydroxyl-
ated derivative of a-lapachone (2l), a natural product related to
the lapachol family with remarkable antitumor activity.13
Subsequently, the synthetic utility of the ruthenium(II)-
catalyzed C–H oxygenation was reflected by the chemo-selective
diversification of anthraquinones 3. Here, a slight modification of
the reaction conditions featured the use of PIDA, allowing for the
C–H oxygenations with excellent levels of positional and chemo-
selectivities in terms of mono-functionalization, fully tolerating,
inter alia, chloro and bromo functional groups (Scheme 3).
Based on our previous reports, a plausible catalytic cycle is
initiated by carboxylate-assisted C–H ruthenation,12,14 along with
subsequent oxidation-induced reductive elimination (Scheme 4).14,15
Neglected tropical diseases (NTDs) comprehend a group of
seventeen illnesses that affect more than one billion people.
Among NTDs, Chagas disease caused by the hemoflagellate
protozoa Trypanosoma cruzi presents significant mortality and
morbidity, especially in low-income populations in Latin America
endemic countries.16,17 Recently, the intense flux of immigration
due to globalization has changed the distribution of Chagas disease
patients, resulting in the presence of infected people in non-endemic
countries such as European countries, the United States, Japan
or Australia, where the transmission is sustained by blood
transfusion or congenital routes.18,19 Since the 1960s up to
now, the clinical chemotherapy for Chagas disease has been
based on two nitroderivatives, benznidazole and nifurtimox,
that present important side effects and debatable anti-T. cruzi
activity in chronic patients.20 The absence of alternatives for the
most severe phase of this illness leads to the continuous search
for novel trypanocidal drugs.21 In this context, in the last
few years, we have evaluated diverse naphthoquinones against
the parasite and proved the potential trypanocidal effect of
Scheme 4 Proposed mechanism.
these compounds.11f To understand the biological importance
of A-ring modified quinoidal compounds and to continue our
efforts towards the development of potent trypanocidal agents,
we herein disclose the evaluation of 1,4-NQs against T. cruzi.
Thus, compounds 2c, 2e, 2k and 2l were not active against the
parasite with IC50/24 h 4 1000.0 mM. To our delight, six com-
pounds showed activity against T. cruzi with IC50 in the range of
176.1 to 29.5 mM (Table S1), highlighting 2h (IC50 = 32.9 mM)
and 2i (IC50 = 29.5 mM). In comparison with the standard drug
benznidazole (IC50 = 103.6 mM), 2h and 2i are 3.1 and 3.5-fold
more active, respectively (Fig. 1).
In conclusion, we have reported on an efficient C–H oxygen-
ation strategy for naphthoquinones and anthraquinones. Thus,
carboxylate-assisted22 ruthenium(II) catalysis enabled the step-
economical synthesis of potent bioactive compounds with ample
scope. The obtained C–H hydroxylated naphthoquinones dis-
played unique trypanocidal activities.
E. N. S. J. acknowledges funding from CNPq 404466/2016-8
and PQ 305741/2017-9, CAPES and DAAD for exchange PROBRAL
Fig. 1 Most active naphthoquinones on trypomastigote forms of T. cruzi.
Benznidazole, a standard drug for the treatment of chagasic patients, was
used as a control. IC50/24 h values in mM.
Scheme 3 Synthesis of anthraquinone derivatives.
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Chem. Rev., 2012, 112, 5879–5918; (m) O. Daugulis, H.-Q. Do and
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program (99999.008126/2015-01) and Capes-Humboldt research
fellowship programme for experienced researchers (Proc. No.
88881.145517/2017-01). L. A. acknowledges funding from the
DFG (Gottfried-Wilhelm-Leibniz prize).
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Conflicts of interest
There are no conflicts to declare.
˜
M. O. F. Goulart, C. A. de Simone, J. M. C. Barbosa, K. Salomao,
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