An Improved Synthesis of Balsaminone A

Article abstract of DOI:10.1055/s-0037-1611975

A short and efficient synthesis of balsaminone A, a dinaphthofuran-1,4-dione, is described. The eight-step synthesis features two alternate pathways including a base-induced coupling reaction of 4-methoxy-1-naphthol and 2,3-dichloro-1,4-naphthoquinone, as well as a light-mediated cyclization of 1,1'-binaphthoquinone to afford the dinaphthofurandione core. Subsequent ortho formylation yielded a known precursor to balsaminone A, affording the natural product in 20-27% yield. This represents a moderate increase from the previous synthesis of 7.4% yield.

Full text of DOI:10.1055/s-0037-1611975

SYNLETT
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©
Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
letter
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Synlett
S.-k. A. Daley, N. K. Downer-Riley
Letter
An Improved Synthesis of Balsaminone A
Sharna-kay A. Daley
Nadale K. Downer-Riley*
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Department of Chemistry, The University of the West Indies,
Mona Kingston 7, Jamaica, West Indies
nadale.downer02@uwimona.edu.jm
Received: 01.11.2018
Accepted after revision: 11.12.2018
Published online: 10.01.2019
activity towards the cancer cell lines A549, Bel7402, and
HeLa. These findings indicate the pharmaceutical potential
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DOI: 10.1055/s-0037-1611975; Art ID: st-2018-v0713-l
of the natural product.
Abstract A short and efficient synthesis of balsaminone A, a dinaph-
thofuran-1,4-dione, is described. The eight-step synthesis features two
alternate pathways including a base-induced coupling reaction of 4-me-
thoxy-1-naphthol and 2,3-dichloro-1,4-naphthoquinone, as well as a
light-mediated cyclization of 1,1'-binaphthoquinone to afford the di-
naphthofurandione core. Subsequent ortho formylation yielded a
known precursor to balsaminone A, affording the natural product in
MeO
OR
O
O
OH
OH
1
R = H, 2 R =
O
OH
O
O
HO
O
OH
O
O
O
20–27% yield. This represents a moderate increase from the previous
O
OMe
synthesis of 7.4% yield.
Key words balsaminone A, Liebermann coupling, light-mediated cy-
clization, naphthofurandione, natural products
O
O
3
4
Polycyclic compounds containing oxygen, particularly
naphthofuran derivatives, have garnered considerable at-
tention in organic synthesis. Several methods for the con-
Figure 1 Compounds isolated from I. balsamina
1
struction of the dinaphthofurandione nucleus have been
The first total synthesis of balsaminone A (1) was re-
ported by Padwal and co-workers in 2011. The synthesis
8
reported. These include the light-mediated cyclization of
2
2
,2'-biquinones, the base-induced coupling reaction of di-
was accomplished in 7.4% yield over nine steps from 2-bro-
mo-1,4-dimethoxynaphthalene. It utilized a base-induced
coupling reaction, referred to as the Liebermann approach,
as the key step to the naphthofurandione carbaldehyde 7,
which was subjected to a series of functional group trans-
formations to yield balsaminone A (1) (Scheme 1).8
Given the insight obtained from the work conducted by
Padwal et al., an alternative synthesis of the pentacyclic nu-
cleus of balsaminone A (1), also using the Liebermann ap-
proach, was considered. This involved the use of 1,4-dihy-
droxynaphthalene (8a) as the phenolic precursor. It was en-
visaged that a direct ortho methoxylation of the resultant
dinaphthofurandione (9a), would afford an attractive two-
step synthesis of the natural product. Alternatively, the core
scaffold of 9a could also undergo halogenation, followed by
3
chloroquinones and phenols, as well as metal-mediated
4,5
cyclization of benzene derivatives. The interest in these
polycyclic compounds arises from the reported biological
activities of both the synthetic and natural compounds.1
One such naturally occurring compound with the naphtho-
furandione motif is balsaminone A (1). Balsaminone A,
along with balsaminone B (2) and 2-methoxy-1,4-naphtho-
quinone (3), were isolated from the aerial portion of Impa-
6
tiens balsamina in 1998 by Ishiguro and co-workers, and in
2
012 from the seeds of the same plant, along with balsami-
7
none C (4), by Pei and co-workers (Figure 1). Both parts of
the plant containing balsaminone A have been used in tra-
ditional Chinese and Japanese medicine as remedies for
bruises, beriberi, articular rheumatism, stomach ulcers, and
6
urticaria. More recently, balsaminone A showed cytotoxic
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

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Synlett
S.-k. A. Daley, N. K. Downer-Riley
Letter
O
Prior to attempts at the synthesis of balsaminone A (1),
the base-induced coupling of selected, substituted dihy-
droxynaphthalenes 8a–c with 2,3-dichloronaphthoquinone
6 was conducted. This was done in an attempt to optimize
the yield of the dinaphthofurandione 9a, given that the
base-induced coupling reaction was the only low-yielding
step in Padwal’s synthesis. To commence the coupling reac-
tions, 2-bromo-1,4-naphthoquinone (10b) and 2-chloro-
OH
CHO
Cl
+
Cl
2 3
K CO , pyr., 90 °C
(
20%)
OH
O
5
6
OH
OHC
O
O
1
,4-naphthoquinone (10c) were synthesized from 1-naph-
57% over 5 steps
9,10
1
thol as previously reported,
hydrogenation (Scheme 3).
and subjected to catalytic
Padwal et al.
O
As expected, the reaction of the 1,4-dihydroxynaphtha-
lene derivatives upon treatment with 2,3-dichloronaphtho-
quinone (6) in the presence of base, resulted in the synthe-
sis of the respective dinaphthofurandiones 9a–c (Scheme
7
Scheme 1 Previous synthesis of balsaminone A (1)
3). However, fair amounts of the unstable diethers 11a–c,
substitution with a methoxide source. Also anticipated was
the synthesis of key intermediate 7, following the ortho
formylation of dinaphthofurandione 9a. This would allow
access to the natural product, as reported by Padwal et al.
confirmed by using high-resolution mass spectrometry,
were also obtained. It was expected that formation of the
ethers would be negligible in comparison to the pentacyclic
derivatives, since it was considered that following the initial
substitution, intramolecular cyclization would occur at a
faster rate than the Michael-type substitution. Unfortunate-
ly, this was not observed, primarily for 1,4-dihydroxynaph-
thalene, where the ratio of the pentacyclic compound to
that of the diether was greater than 1:2. The bromo- and
chloro-substituted arenes, however, were marginally more
favorable to cyclization (Scheme 3).
(Scheme 2).
OH
O
Cl
Cl
+
OH
O
8a
6
O
base
OH
R
R
H2, Pd/C, MeOH
OH
O
O
6
, K2CO3, pyr.,
O
90 °C
OH
1
1
1
0a R= H
0b R = Br
0c R = Cl
O
8a–c
O
OH
9a
R
halogenation
Cl
formylation
O
O
O
O
O
OHC
OH
methoxylation
R
O
OH
+
O
O
9
9
9
a (25%)
b (37%)
c (48%)
R
O
O
O
O
O
O
9
9
b R = Br
c R = Cl
7
Cl
1
1a (60%)
substitution
5
(
7% over 5 steps
Padwal et al.)
11b (28%)
11c (17%)
MeO
OH
O
Scheme 3 Base-induced coupling reactions
O
To circumvent the challenges of di-substitution, 4-me-
thoxy-1-naphthol (12) was considered for the base-induced
coupling reaction with 2,3-dichloronaphthoquinone 6, and
the synthesis of 5-methoxydinaphthofurandione 13 was
O
1
Scheme 2 Approaches to balsaminone A (1)
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

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Synlett
S.-k. A. Daley, N. K. Downer-Riley
Letter
achieved in 75% yield. Subsequent demethylation with 50%
aqueous HBr afforded the desired dinaphthofurandione 9a
in 83% yield (Scheme 4).
tained proved otherwise. Despite the naphthalene moiety
of dinaphthofurandione 9a having a high electron density,
it was postulated that a nucleophilic attack by a methoxy
source ortho to the hydroxyl substituent in the presence of
PIFA or PIDA, would occur. Initial failed attempts indicated
the need for carbon 6 to be more activated towards the nuc-
leophilic attack. However, activation using boron trifluoride
diethyl etherate also proved futile (Scheme 6). With the un-
favorable outcomes from the attempts at direct methoxyl-
ation of 5-hydroxydinaphthofuran-7,12-dione (9a), it was
envisaged that methoxy substitution on a halogenated di-
naphthofurandione such as dinaphthofurandione 9b was a
more practical approach towards balsaminone A (1).
OMe
O
OH
6, K2CO3, pyr., 90 °C
O
(
75%)
O
OMe
13
12
aq. HBr (50%),
reflux (83%)
9a
Scheme 4 Synthesis of the dinaphthofurandione (9a) core through a
base-induced cyclization
OH
O
6
5
4
3
An alternate route to dinaphthofurandione 9a was also
O
2
1
attempted (Scheme 5). As mentioned, it was reported that
O
9a
binaphthyl 14 can be converted into dinaphthofurandione
(
COCl)2, DMF
NBS, DMF
r.t. (74%)
2
reflux, (55%)
9
a in the presence of light or high temperatures. For the
preparation of the binaphthyl from 1,4-naphthoquinone
10a), the quinone was dissolved in carbon disulfide and al-
(
uminium chloride and 2-methoxynaphthalene were added.
The mixture was stirred for 72 hours at room temperature,
affording a 16% conversion to the binaphthyl 14. Given the
low yield obtained, oxidative coupling of 4-methoxy-1-
naphthol (12) was attempted by using silver oxide and 40%
PIDA or PIFA
MeOH
X
Br
OH
OHC
O
OH
O
O
O
O
11
nitric acid and provided binaphthyl 14 in quantitative
yield. Having accomplished the high-yielding synthesis of
the binaphthyl, we attempted light-mediated intramolecu-
lar cyclization and the dinaphthofurandione 9a intermedi-
ate was synthesized in 87% yield over two steps.
O
9b
7
X
5
7% over 5 steps
NaOMe, MeOH
CuI
MeO
OH
(
Padwal et al.)
O
O
O
O
O
AlCl3, CS2
AgO, HNO3 (40%)
r.t. (quant.)
12
reflux (16%)
1
2
O
O
Scheme 6 Synthesis of balsaminone A (1)
10a
14
hν, CHCl3
87%)
(
Although dinaphthofurandione 9b was previously syn-
thesized through the base-induced coupling reaction
(Scheme 2), a more efficient route to the compound from
9a
9
a was employed. The bromination was straightforward
and provided bromodinaphthofurandione 9b in 74% yield
Scheme 6). Initial attempts to effect substitution of the
Scheme 5 Synthesis of dinaphthofurandione 9a through a light-medi-
ated cyclization
(
bromide substituent with the use of 0.5 M sodium methox-
ide in methanol were futile. As such, sodium methoxide
was generated in situ, and copper iodide was added as cata-
lyst to effect the transformation. Interestingly, NMR spec-
troscopic analysis of the crude reaction mixture revealed
the presence of the natural product; however, similarities in
the retention factors prevented isolation of the pure natural
product. A similar attempt with use of chlorodinaphthofu-
Having successful approaches to the dinaphthofurandi-
one core 9a in hand, we targeted the modification of posi-
tion 6. To effect the direct transformation to balsaminone A
(
1), the methoxylation of 9a, in the presence of a hyperva-
12
lent iodine reagent and methanol, was considered. Al-
though it is reported that phenyliodine diacetate (PIDA) or
phenyliodine bis(trifluoroacetate) (PIFA) in methanol serve
12
as a useful tool for ortho methoxylation, the results ob-
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Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

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Synlett
S.-k. A. Daley, N. K. Downer-Riley
Letter
randione 9c as the substrate, with anticipation of a higher
conversion to the natural product and subsequently more
favorable conditions for purification, also proved futile.
Despite the unsuccessful attempts at direct methoxyl-
ation, it was recognized that ortho formylation of dinaph-
thofurandione 9a would yield a known precursor to the
natural product, as previously indicated (Scheme 2). The
first attempts at the ortho formylation of dinaphthofurandi-
one 9a to access carbaldehyde 7, by using triethylformate in
the presence of AlCl with conc. HCl, as well as MgCl with
References
(
1) Kirilmis, C.; Koca, M.; Servi, S.; Gur, S. Turk. J. Chem. 2009, 33,
75.
2) Buchan, R.; Musgrave, O. C. J. Chem. Soc., Perkin Trans. 1 1980,
0.
3
(
9
(3) Liebermann, C. Chem. Ber. 1899, 32, 916.
(4) Martínez, A.; Fernández, M.; Estévez, J. C.; Estévez, R. J.; Castedo,
L. Tetrahedron 2005, 61, 1353.
(5) del Coral, J. M. M.; Castro, M. A.; Gordaliza, M.; Martín, M. L.;
Gamito, A. M.; Cuevas, C.; San Feliciano, A. Bioorg. Med. Chem.
3
2
2006, 14, 2816.
paraformaldehyde in triethylamine, did not show any con-
version to the desired product. However, much to our de-
light, upon subjecting the dinaphthofuran derivative to
modified Vilsmeier–Haack ortho formylation conditions,
conversion to carbaldehyde 7 was accomplished in 55%
yield, with identical spectral data to those reported previ-
(
(
6) Ishiguro, K.; Ohira, Y.; Oku, H. J. Nat. Prod. 1998, 61, 1126.
7) Pei, H.; Lei, J.; Qian, S. A. Journal of Chinese Medicinal Materials
2012, 35, 407.
(8) Padwal, W.; Lewis, W.; Moody, C. J. J. Org. Chem. 2011, 76, 8082.
9) Brimble, M. A.; Bachu, P.; Sperry, J. Synthesis 2007, 2887.
(
(
10) Bhatkhande, B. S.; Adhikari, M. V.; Samant, S. D. Ultrason.
Sonochem. 2002, 9, 31.
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8,13
ously.
Further functional group transformation of carbal-
(
dehyde 7 as reported by Padwal et al. could then afford the
60, 3941.
8
natural product.
(12) Zhdankin, V.; Stang, P. J. Chem. Rev. 2008, 108, 5299.
(13) Synthesis of Carbaldehyde 7
In summary, a concise, efficient approach towards bal-
saminone A (1) in 20–27% yield over eight steps has been
developed. This represents an improvement over the previ-
ous synthesis of 7.4% yield over nine steps.
DMF (5 mL, 64.85 mmol) in acetonitrile (5 mL) was added drop-
wise to a solution of oxalyl chloride (5 mL, 58.24 mmol) in ace-
tonitrile (5 mL). The mixture was stirred at –10 °C for 1 h, after
which a solution of 5-hydroxy-dinaphthofuran-7,12-dione (9a)
(100.6 mg, 0.320 mmol) in acetonitrile (5 mL) and DMF (2 mL)
was added, followed by CuI (10 mg, 0.056 mmol). The reaction
mixture was stirred to reach r.t. and then heated at reflux over-
night. After cooling to r.t., the solvent was removed in vacuo.
The remaining residue was dissolved in ethyl acetate (40 mL),
washed with water (3 x 10 mL) and brine (2 x 20 mL), and dried
with magnesium sulfate. Evaporation of the solvent yielded a
brown orange solid (107 mg), which was purified by column
chromatography (ethyl acetate/hexane). The desired product
was obtained as a pale-orange solid (60.1 mg, 55% yield). Mp
Funding Information
The authors thank the Department of Chemistry, The University of
West-Indies for grants received towards this work.()
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611975.
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295–298 °C (methylene chloride) (ref. 302 °C); IR: 3678, 1728,
–
1 1
1
1
330 cm ; H NMR (MeOH): δ = 14.44 (s, 1 H, H-C=O), 11.17 (s,
H, OH), 8.26 (m, 4 H, H-2,3,9,10), 7.43 (m, 4 H, H-1,4,8,11); 13
C
NMR (MeOH): δ = 108.1, 116.9, 121.4, 125.0, 125.9, 126.1,
1
1
26.8, 127.7, 128.5, 132.0, 132.1, 133.4, 134.4, 148.0, 153.6,
64.0, 174.4, 180.9, 198.9.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D