The biomimetic synthesis of balsaminone A and ellagic acid via oxidative dimerization

Article abstract of DOI:10.3762/BJOC.16.169

The application of oxidative dimerization for the biomimetic synthesis of balsaminone A and ellagic acid is described. Balsaminone A is synthesized via the oxidative dimerization of 1,2,4-trimethoxynaphthalene under anhydrous conditions using CAN, PIDA in BF₃·OEt₂ or PIFA in BF₃·OEt₂ in 7–8% yields over 3 steps. Ellagic acid is synthesized from its biosynthetic precursor gallic acid, in 83% yield over 2 steps.

Full text of DOI:10.3762/BJOC.16.169

The biomimetic synthesis of balsaminone A and ellagic acid
via oxidative dimerization
Sharna-kay Daley and Nadale Downer-Riley*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 2026–2031.
Department of Chemistry, The University of the West Indies, Mona,
Jamaica
doi:10.3762/bjoc.16.169
Received: 27 April 2020
Accepted: 06 August 2020
Published: 18 August 2020
Email:
Nadale Downer-Riley* - nadale.downer02@uwimona.edu.jm
*
Corresponding author
Associate Editor: J. Aubé
Keywords:
© 2020 Daley and Downer-Riley; licensee Beilstein-Institut.
License and terms: see end of document.
balsaminone A; biomimetic synthesis; ellagic acid; oxidative
dimerization
Abstract
The application of oxidative dimerization for the biomimetic synthesis of balsaminone A and ellagic acid is described. Balsaminone
A is synthesized via the oxidative dimerization of 1,2,4-trimethoxynaphthalene under anhydrous conditions using CAN, PIDA in
BF3·OEt2 or PIFA in BF3·OEt2 in 7–8% yields over 3 steps. Ellagic acid is synthesized from its biosynthetic precursor gallic acid,
in 83% yield over 2 steps.
Introduction
Over the last century, the formation of an aryl to aryl bond has (PIDA) and phenyliodine bis(trifluoroacetate) (PIFA), have
garnered considerable synthetic attention due to the applica- been utilized for oxidative dimerization reactions [14,15]. The
tions of biaryls as pharmaceutical agents, as well as chiral auxil- use of these one-electron oxidants, as well as non-metallic
iaries in asymmetric synthesis [1-3]. Methods such as the reagents, plays an important role in accessing symmetrical and
Ullman coupling, Suzuki–Miyaura coupling and Stille coupling asymmetrical biaryls and polyaryls [1]. There are many impor-
have dominated the field for the synthesis of biaryls [1,4]. tant applications of oxidative dimerization reactions, one of
Throughout the years, the exploration of oxidative dimerization which is the direct synthesis of natural product scaffolds
reactions of electron-rich aromatic compounds, such as thio- [1,7,16-18]. Examples of this application include the
phenes, anilines and alkoxyarenes, in an attempt to establish biomimetic synthesis of the bioactive natural products bismur-
high-yielding and selective oxidative coupling reactions, has rayaquinone A (1) [16], parvistemin A (2) [17] and violet-
afforded new and greener synthetic protocols for biaryls [5-7]. quinone (3) [18] (Figure 1).
Several oxidants, such as the salts of Ag(I&II) [8], Ti(III&IV)
[
9], Mn(III) [10], Ce(IV) [11], Sn(IV) [12] and Fe(III) [13], as Similar to those natural products, the biomimetic synthesis of
well as the hypervalent iodine reagents phenyliodine diacetate balsaminone A (4) and ellagic acid (5) can be attained using ox-
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Figure 1: Selected natural products synthesized via oxidative dimerization.
idative dimerization reactions, based on their proposed biosyn- arenol 9, which, following intramolecular cyclization, affords
thesis (Scheme 1 and Scheme 2) [19,20]. These pathways, balsaminone A (4, Scheme 1). Similarly, the biosynthetic pre-
which start with shikimic acid, feature the dimerization of cursor of ellagic acid (5), gallic acid (10), undergoes dimeriza-
monomeric phenolic precursors by a laccase enzyme, a single- tion to the dimeric polyphenolic acid 11, followed by intramo-
electron enzyme complex within macro-organisms which facili- lecular cyclization to yield ellagic acid (5, Scheme 2) [20].
tates oxidative dimerization through phenolic coupling [19]. In
the case of balsaminone A (4), lawsone (6) is methylated to Because of the bioactivity of both natural products, there have
ether 7 which undergoes reduction to the dihydroxynaphthalene been previous investigations of the synthesis of balsaminone A
8
. This is then dimerized by the copper-rich enzyme to quinone (4) [21,22] and ellagic acid (5) [23]. In our previous synthesis
Scheme 1: Proposed biosynthesis of balsaminone A (4) [19].
Scheme 2: Proposed biosynthesis of ellagic acid (5) [20].
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of balsaminone A (4) [22] (Scheme 3), silver oxide was used as methanolic solution of 2-methoxy-1,4-dihydroxynaphthalene
the oxidative dimerizing agent for the formation of the binaph- (8), obtained from the reduction of lawsone (6), was subjected
thoquinone intermediate 13. This was followed by photolytic to the oxidants activated carbon (Act-C), potassium ferri-
cyclisation and ortho-formylation to give carbaldehyde 14. cyanide (K3[Fe(CN)6]), p-benzoquinone and stannic chloride
Conversion to balsaminone A (4) could then be achieved in (SnCl4). As shown in Scheme 4, with the exception of SnCl4,
5
7% yield over 5 steps. The synthesis of ellagic acid (5) on the all oxidants resulted in the re-oxidation of the hydroxylated sub-
other hand featured an o-chloranil-mediated dimerization of strate to naphthoquinone 7. SnCl4, however, while not success-
methyl gallate (15), which yielded the natural product in 48% ful for the synthesis of the desired biomimetic precursor 9,
yield over 5 steps, as reported by Tsuboi et al. (Scheme 3) [23]. afforded the binaphthylquinone 16 in 22% yield.
Results and Discussion
Given the initial unsuccessful attempt at the synthesis of the
Biomimetic synthesis of balsaminone A
biomimetic precursor of balsaminone A (4), it was evident that
With the initial focus being the biomimetic synthesis of alternative oxidative dimerization conditions needed to be
balsaminone A (4), well-established methods for the dimeriza- explored. The oxidants cerium(IV) ammonium nitrate (CAN),
tion of phenolic compounds were explored [8,9]. As such, a ferric chloride hexahydrate (FeCl3·6H2O), vanadium pentoxide
Scheme 3: Previous syntheses of balsaminone A (4) [22] and ellagic acid (5) [23].
Scheme 4: Attempted synthesis of the biomimetic precursor 9. [O]: Act-C, K3[Fe(CN)6], or p-benzoquinone.
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(
V2O5), PIFA, and PIDA, in addition to SnCl4, were consid- verted quantitatively to binaphthyl 16 in the presence of an
ered. Also investigated were 2-iodoxybenzoic acid (IBX) aqueous solution of CAN at 0 °C. Alternatively, the binaph-
because of its implication in single-electron oxidation [24], and thylquinone 16 was synthesized through the oxidation of
chromium trioxide (CrO3), which, based on its Cr(VI) oxida- lawsone (6), in the presence of sodium persulfate, followed by
tion state, should be able to facilitate single-electron transfer in methylation [25]. The cyclization of binaphthyl 16 was then
the presence of electron-rich arenes.
attempted taking into consideration the photolytic cyclization of
binaphthyls to form pentacyclic furan derivatives [8,18,22].
The dimerization of 1,2,4-trimethoxynaphthalene (17) in the However, the photolytic cyclization of binaphthyl 16 using a
presence of the metal oxidants CAN, V2O5, and CrO3, afforded 100 W bulb was attempted without success, due to degradation
binaphthyl 16 in 29, 34, and 19% yields, respectively (Table 1). of the starting material. This led to a different approach employ-
As anticipated, the reaction of naphthalene 17 with CAN under ing a reductive, base-mediated cyclization using alkaline
aqueous conditions resulted in preferential oxidative demethyla- aqueous sodium dithionite. Interestingly, the typical conditions
tion to give quinone 7, as opposed to oxidative dimerization. for reduction using dithionite proved too harsh for the substrate,
The elimination of water from the reaction posed a few chal- and like the photolysis of the binaphthyl 16, degradation
lenges since the solubility of CAN in organic solvents deter- occurred. However, the use of triethylamine instead of aqueous
mines the likelihood of nitration or oxidative dimerization [1]. It sodium hydroxide resulted in the isolation of balsaminone A (4)
was found that dry acetonitrile was more conducive to nitration, in 13% yield, an overall 7–8% yield over 3 steps, completing
whereas methanol afforded the desired biaryl in 55% yield. In the biomimetic synthesis of the natural product as shown in
contrast to CAN, both V2O5 and CrO3 required aqueous condi- Scheme 5.
tions to prevent complexation of the reagent and the starting
material. Of the Lewis acids used, stannic chloride proved to be Synthesis of ellagic acid
the most effective oxidant for dimerization (Table 1). However, With the synthesis of balsaminone A (4) accomplished, the
the hypervalent iodine reagents PIFA and PIDA gave better direct biomimetic synthesis of ellagic acid (5) was targeted.
results overall, affording dimer 18 in 63% and 59% yields, re- While the synthesis of ellagic acid (5) has been achieved
spectively (Table 1).
in 48% yield over four steps by Alam et al. [23], starting
from methyl gallate (15), it was anticipated that a more
Following the successful oxidative dimerization of 1,2,4- concise and efficient synthesis could be attained. Methyl
trimethoxynaphthalene 17 to biaryl 18, the biaryl was con- gallate (15), which may be obtained commercially or from the
Table 1: Reagents and products in the oxidative dimerization of 1,2,4-trimethoxynaphthalene (17).
16 (%)
18 (%)
7 (%)
CANa
29b
34
19
15
–
55c
–
67b
–
V2O5a,b
CrO3a,b
–
62
–
FeCl3·SiO2a,c
FeCl3·6H2Oa,c
SnCl4d
43
8
–
22
21
12
13
48d
59
63
–
–
PIDA, BF3·OEt2e,f
PIFA, BF3·OEt2e,f
IBX, BF3·OEt2e,f
–
–
45
aReaction of naphthalene 17 (0.5 mmol) with oxidant (1.65 mmol) at rt. bAddition of oxidant in H2O (1 mL, dropwise) to substrate in CH3CN or CH3OH
1 mL). cAddition of oxidant (neat) in thirds, to substrate dissolved in CH3CN. dReaction was carried out in CH2Cl2 at 100 °C in a sealed tube.
eReaction of naphthalene 17 (0.5 mmol) with oxidant (0.65 mmol). fReaction carried out under N2.
(
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Scheme 5: Biomimetic synthesis of balsaminone A (4).
methylation of gallic acid (10) [23], was subjected to the one-step synthesis of ellagic acid (5) from methyl gallate (15) in
oxidants CAN, PIDA, FeCl3·6H2O, and FeCl3·SiO2. Treatment 83% yield is described. These biosynthetically-driven synthe-
of the polyphenol with PIDA (1.5 equiv) in boron trifluoride ses represent the most efficient routes to these bioactive natural
etherate (1.5 mL) at room temperature proved to be the most products to date.
successful dimerization protocol, as the dimeric precursor 19
was formed in 80% yield after 16 hours. The biaryl 19 was con-
verted quantitatively to the natural product when heated at
reflux in aqueous methanol (1:1) for 24 hours. However,
allowing the PIFA reaction mixture to stir at room temperature
for 24 hours resulted in complete cyclization, affording the
natural product 5 in 83% yield directly from methyl gallate (15,
Scheme 6), an improvement for the synthesis of the bioactive
natural product.
Supporting Information
Supporting Information File 1
Experimental part.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-16-169-S1.pdf]
Conclusion
Funding
The synthesis of balsaminone A (4) is reported in 7–8% yield The authors thank the Department of Chemistry, The Univer-
over 3 steps from 1,2,4-trimethoxynaphthalene (17). Also, the sity of the West Indies, Mona, Jamaica for support of this work.
Scheme 6: Concise and efficient biomimetic synthesis of ellagic acid (5).
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Beilstein J. Org. Chem. 2020, 16, 2026–2031.
ORCID® iDs
Nadale Downer-Riley - https://orcid.org/0000-0002-2850-1726
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