Improved synthesis of natural isomeric naphthoxanthenones

Article abstract of DOI:10.1016/j.tetlet.2019.151359

5-methoxy-1H-naphtho[2,1,8-mna]xanthen-1-one (1) and 5-methoxy-3H-naphtho[2,1,8-mna]xanthen-3-one (musafluorone 2), a pair of positional isomers isolated from Wachendorfia thyrsiflora and Musa acuminata, were synthesized in six steps in an overall yield o

Full text of DOI:10.1016/j.tetlet.2019.151359

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Improved Synthesis of Natural Isomeric Naphthoxanthenones
Julian Barrera, Edwin Patiño, Felipe Otálvaro
PII:
S0040-4039(19)31150-5
DOI:
https://doi.org/10.1016/j.tetlet.2019.151359
TETL 151359
Reference:
Tetrahedron Letters
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Accepted Date:
2 October 2019
29 October 2019
2 November 2019
Please cite this article as: Barrera, J., Patiño, E., Otálvaro, F., Improved Synthesis of Natural Isomeric
Naphthoxanthenones, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151359
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Improved Synthesis of Natural Isomeric Naphthoxanthenones
Julian Barreraa, Edwin Patiñob, and Felipe Otálvaroa,*
aInstituto de Química, Síntesis y Biosíntesis de Metabolitos Naturales, Universidad de Antioquia, AA 1226 Medellín, Colombia
bInstituto de Química, Grupo de Bioquímica Estructural de Macromoléculas, Universidad de Antioquia, AA 1226 Medellín, Colombia
ABSTRACT: 5-methoxy-1H-naphtho[2,1,8-mna]xanthen-1-one (1) and 5-methoxy-3H-
naphtho[2,1,8-mna]xanthen-3-one (musafluorone 2), a pair of positional isomers isolated
from Wachendorfia thyrsiflora and Musa acuminata, were synthesized in six steps in an
overall yield of 53 % and 59 % starting from the corresponding methoxyphenalenones and
employing an acid mediated cyclocondensation strategy. Preliminary assays demonstrated
the intercalation ability of compounds 1 and 2 into DNA.
Keywords: Naphthoxanthenones, phenylphenalenones, cyclocondensation
1

Introduction
In 2002 Opitz and coworkers reported on the occurrence of 5-methoxy-1H-naphtho[2,1,8-
mna]xanthen-1-one (1) and 5-methoxy-3H-naphtho[2,1,8-mna]xanthen-3-one (2) in plants
of Wachendorfia thyrsiflora and Musa acuminata respectively[1]. Apart from their
chemotaxonomic interest, these isomers encompass some structural features of biological
and chemical relevance. For instance, their intrinsic push-pull (donor--acceptor)
chromophore (Fig. 1) represents a desirable feature in chemical gap engineering [2].
Moreover, their “bay” region (C-10 through C-11, Fig. 1) in conjunction with their
phenalenone core stimulates questions concerning their biological potential in
photochemotherapy [3-5].
OMe
5
OMe
5
6
6
O
O
O
3
10
10
11
11
donor--aceptor
chromophore
bay
region
phenalenone
core
1
1
O
1
2
Figure 1. Some salient features of compounds 1 and 2.
Unfortunately, because of their minute occurrence in phenylphenalenone-producing plants
[1,6], these naphthoxanthenones seem to be accessible only by total synthesis.
Historically, the dominant strategy for the generation of the heterocyclic ring of
naphthoxanthenones has been the cyclisation of a properly substituted phenylphenalenone
(Scheme 1). Such a cyclization can be performed in two different ways, namely,
photocyclization and cyclocondensation [7-9]. In the former case, the carbonyl group of the
2

excited molecule interacts with the peri-located phenyl ring [10]. In contrast, the
cyclocondensation process employs an ortho-phenolic group in the peri-located phenyl ring
to engage the carbonyl group of the phenalenone core (Scheme 1) [9]. Although
comparative studies are scarce, it seems that the cyclocondensation strategy offers
advantages in terms of yield and scalability at least for the synthesis of naphthoxanthenium
salts [11].
Compound 1 has been prepared previously employing both strategies (Scheme 1). The first
one, a semisynthetic preparation via photocyclization of lachnanthocarphone (2,6-
dihydroxy-9-phenylphenalen-1-one), was reported without yield (Scheme 1 part A) [7].
The second one employed a sequence of demethylation, decarboxylative-cyclocondensation
and methylation using 2-hydroxy-6-methoxy-9-(2-methoxyphenyl)-1-oxo-1H-phenalene-7-
carboxylic acid as substrate (Scheme 1 part B) but again, no yield was reported for the
entire sequence [9]. For the synthesis of compound 2, a photocyclization strategy was
employed culminating in a 3% overall yield after nine steps [12]. Here we wish to report
our synthetic efforts aimed at the improvement of the synthesis of compounds 1 and 2.
3

A
1(n*)
OH
2
OH
OH
OMe
H
O
O
O
O
1) h
2) [O], -H2
3) CH2N2
9
6
1
OH
OH
OH
O
B
OH
OH
H2O OH
O
OH
OH
OMe
2
O
H O
O
O
O
1) HCl / AcOH
-MeCl
~H
-H3O
OH
MeO
2) Cu2O / Quinoline
3) CH2N2
7
6
1
OMe
OH
OH
O
O
O
HO
HO
HO
O
HO
O
H
HO
O
O
O
Scheme 1. Synthetic strategies reported in the preparation of 5-methoxy-1H-naphtho[2,1,8-mna]xanthen-1-one (1). A)
Photocyclization [7]. B) Cyclocondensation [9].
4

Our synthetic strategy, illustrated with compound 1, adopted the cyclocondensation for the
generation of the heterocyclic ring of the target molecules with concomitant generation of
the carbonyl group (Fig. 2). The precursor for this step could be generated by the well-
known conjugated addition of Grignard reagents to position C-9 of a suitable substituted
phenalenone [13-14] which in turn can be prepared via annulation or cyclization of a
naphthalene substrate (Fig. 2) [12, 15-16].
Buchwald
cyclocondensation
Grignard
OMe
O
OMe
O
O
HO
OMe
1
O
OMe
OMe
OH
Skraup like
annulation
Figure 2: Synthetic strategy adopted for the generation of compound 1.
Results and discussion
Initial efforts towards 1 commenced from 6-methoxyphenalenone (1c) which was generated
via microwave assisted Skraup-like annulation between 2,7-dihydroxynaphthalene and
glycerol [15-16] (Scheme 2 part A). Treatment of the crude product with dimethylsulphate
afforded the desired starting material in 38% yield. This protocol, although far from
optimum, represents a significant improvement over previous methods [16]. Bromination
of 1c by means of NBS afforded 2-bromo-6-methoxyphenalenone (1b) in 78%. Treatment
of compound 1b with 2-methoxyphenylmagnesium bromide followed by DDQ
5

dehydrogenation
afforded
the
desired
2-bromo-6-methoxy-9-(2-
methoxyphenyl)phenalenone (1a) in 84% yield (Scheme 2). Although somewhat risky due
to the possibility of halogen-metal exchange, this order of events proved experimentally
more convenient in terms of yield and ease of purification than the conjugated addition-
bromination sequence. Aromatic substitution of (1a) was achieved by adapting the
Stradiotto modification to the Buchwald hydroxylation [17-18]. Thus, microwave
irradiation of (1a) with KOH under Pd2(dba)3/bippyphos catalysis afforded the phenolic
analog of (1a). The sensitivity of the hydroxylated compound prompted the execution of
the next steps without extensive purification. Hence, demethylation by means of
HBr/AcOH caused the desired cyclocondensation and the reaction crude was immediately
methylated to afford 5-methoxy-1H-naphtho[2,1,8-mna]xanthen-1-one (1) in a gratifyingly
81% from (1a) (Scheme 2 part A).
The use of the Buchwald reaction in this sequence bypassed the long standing problem of
methoxyperinaphthenone hydroxylation for which only partial solutions via Jacobsen
epoxidation were previously reported [12, 16, 19].
Extrapolation of these methods towards compound
2
commenced with 4-
methoxyphenalenone (2c) which was obtained in four steps from 2-naphthol according to
our previous report [12]. Treatment of 2c with NBS afforded the corresponding 2-bromo-
4-methoxyphenalenone (2b) in 82% yield. Grignard addition proceeded smoothly to
provide the corresponding 2-bromo-4-methoxy-9-(2-methoxyphenyl)-1H-phenalen-1-one
(2a) in 91% yield after DDQ treatment. Buchwald hydroxylation, demethylation
(cyclocondensation) and methylation sequence afforded compound 2 in 79% yield (Scheme
2 part B).
6

A
Br
Br
OMe
OMe
O
O
O
O
1) Pd2(dba)3.CHCl3, bippyphos,
Dioxane, H2O, KOH,
80 oC, 15 min, w
1)
HO
OH
NBS, CH3CN
60 oC, 10 min, w
1)
, H2SO4
, THF, -78 o
C
OH
HO
OH
MgBr
OMe
FeSO4.7H2O, B(OH)3,
2) DDQ, CH2Cl2, r.t
84% overall yield
2) HBr, AcOH
160 oC, 15 min, w
OMe
OMe
OMe
O
sodium 3-nitrobenzenesulphonate
80 oC, 10 min, w
1c
1b
1a
1
3) Me2SO4, K2CO3, acetone
reflux, 1h
2) Me2SO4, K2CO3, acetone
reflux, 1h
38% overall yield
78%
81% overall yield
B
OMe
Br
Br
OMe
1) Pd2(dba)3.CHCl3, bippyphos,
Dioxane, H2O, KOH,
80 oC, 15 min, w
NBS, CH3CN
60 oC, 10 min, w
O
O
O
O
1)
4 steps
, THF, -78 o
C
MgBr
OH
OMe
OMe
OMe
O
OMe
2) HBr, AcOH
160 oC, 15 min, w
2) DDQ, CH2Cl2, r.t
2c
2b
2a
2
3) Me2SO4, K2CO3, acetone
reflux, 1h
27 % global yield [12]
82%
91% overall yield
79% overall yield
Scheme 2: Synthesis of compounds 1 (part A) and 2 (part B) starting from the corresponding methoxyphenalenones 1c and 2c.
7

With compounds 1 and 2 at hand, we proceeded to test their DNA intercalation ability by
adding an ethanolic solution of 1 or 2 instead of ethidium bromide in the well of a typical
DNA electrophoresis. Figure S1 (supporting information) shows the electrophoretic
mobility of compounds 1 and 2 in conjunction with DNA ladder samples but not by
themselves. This result argues in favor of the DNA intercalation ability of the title
compounds. Moreover, if such intercalation occurs in the cell, a hampering effect on DNA
replication must be expected which should result in smaller genomic-DNA degradation
products. This behavior was demonstrated by means of a comet-assay on HaCaT human
keratinocytes which displayed significant genomic-DNA damage with a 22 ± 2 and 33 ± 5
percentage of DNA in “tail” for compounds 1 and 2 respectively at concentrations of 50
g/mL (Fig. S2-S3, supporting information). These comet-values are contrasted against
ethidium bromide (a well-known DNA intercalator) for which a value of 19 ± 9 was found
in the same assay at the same concentration (supplementary information).
Conclusions
In conclusion, a synthesis of 5-methoxy-1H-naphtho[2,1,8-mna]xanthen-1-one (1) and 5-
methoxy-3H-naphtho[2,1,8-mna]xanthen-3-one (2) was achieved in five steps starting from
the corresponding methoxyphenalenone in a 53% and 59% global yield respectively using a
cyclocondensation as the key step. The employment of the Buchwald hydroxylation for the
substitution of a bromomethoxyphenalenone significantly improved the yields by avoiding
the difficult epoxidation of methoxyphenalenones. The synthesis is suitable for the
8

preparation of the title compounds in the 1 mmol scale. Initial explorations demonstrated
the DNA-intercalation properties of compounds 1 and 2.
References
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(2002) 335-338.
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9

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47 (2004) 147-159.
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(2006) 10694-10695.
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Acknowledgements
The authors acknowledge the assistance of Dr. Gloria Santa and Ms. Katherine Montoya in
obtaining the comet assay and electrophoresis data respectively. Prof. Mauricio Camargo is
gratefully acknowledged for providing the HaCaT cell line. This research was financially
supported by Universidad de Antioquia (grant CODI 2017-16205).
10

Graphycal Abstract
phenalenone
core
donor- -aceptor
chromophore

OMe
5
OMe
5
6
6
O
O
O
3
10
10
bay11
region
11
1
12
1
O
2
1
six steps
59 %
six steps
53 %
O
O
OMe
OMe
Graphycal Abstract
11

phenalenone
core
donor- -aceptor
chromophore

OMe
5
OMe
5
6
6
O
O
O
3
10
10
bay11
region
11
1
12
1
O
2
1
six steps
59 %
six steps
53 %
O
O
OMe
OMe
Highlights:

A pair of natural isomeric naphthoxanthenones were prepared with efficiency and in the
mmol scale


Cyclocondensation and Buchwald hydroxylation were implemented as key steps
The compounds show DNA-intercalation ability
Declaration of interests
12

☒ The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be
considered as potential competing interests:
13