Synthesis of diaryl ether components of ellagitannins using: Ortho -quinone with consonant mesomeric effects

Article abstract of DOI:10.1039/d0cc00889c

Methods for synthesizing C-O digallate structures, the basic unit of diaryl ether components of natural ellagitannins, are described. In the designed building block derived from gallic acid, consonantly overlapped mesomeric effects enhanced its electrophi

Full text of DOI:10.1039/d0cc00889c

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DOI: 10.1039/D0CC00889C
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Synthesis of Diaryl Ether Components of Ellagitannins Using
Ortho-quinone with Consonant Mesomeric Effects
Hayato Konishi, Tsukasa Hirokane,‡ Hajime Hashimoto, Kazutada Ikeuchi,§ Shintaro Matsumoto,
Received 00th January 20xx,
Accepted 00th January 20xx
Shinnosuke Wakamori,* Hidetoshi Yamada*,†
DOI: 10.1039/x0xx00000x
Methods for synthesizing C–O digallate structures, the basic unit of
diaryl ether components of natural ellagitannins, are described. In
the designed building block derived from gallic acid, consonantly
overlapped mesomeric effects enhanced its electrophilicity. This
building block demonstrated substantial reactivity to improve
synthesis of dehydrodigalloyl, tergalloyl, and valloneoyl groups.
Ellagitannins are a class of natural polyphenols, whose basic
structure includes glucose with esterified galloyl and
hexahydroxydiphenoyl (HHDP) groups whose contains C–C
bond by coupling between galloyl groups (Figure 1).1 Since
glucose contains multiple hydroxy groups, the flexibility of the
positions and numbers of the esterified galloyl and HHDP
groups impart significant structural diversity.2 Moreover, the
formation of diaryl ether components enhances this diversity
because formation of these components oligomerizes mono-
mers.3 Each diaryl ether component contains a C–O digallate
structure with two galloyl groups connected via a C–O bond, the
Figure 1. Examples of dimeric natural ellagitannins and diaryl ether-components of
ellagitannins
dehydrodigalloyl (DHDG) group being
a representative
both tergalloyl and valoneoyl groups. In this method9, a
example.4 Other diaryl ether components, such as tergalloyl and
valoneoyl groups,4 also contain the C–O digallate structure.
Oligomeric ellagitannins and their monomers exhibit a variety
of biological activities.5 However, the unavailability of
systematically modified analogues from nature has impeded
the understanding of their structure-activity relationships. A
promising strategy to solve the problem is the customizable
syntheses of oligomeric ellagitannins.3,6
derivative of gallic acid
corresponding brominated aldehyde
the phenolic moiety provides the ortho-(o-) quinone monoketal
. The oxa-Michael addition of a phenolate ion to and
simultaneous elimination of bromide forms a C–O bond to
1
(Scheme 1) is transformed to the
2
, and then oxidation of
3
3
afford
obtain
digallate
4
5
. Subsequently,
and oxidation of the aldehyde produces the C–O
. In this route, relying on the use of bypasses the
4 requires reductive aromatization to
6
To date, three methods have been reported for the
synthesis of the most basic diaryl ether component, the DHDG
group.7–9 However, only one method9 enables the syntheses of
aldehyde is advantageous for discrimination of the carboxylate
moieties of the diaryl ether components. Since the carboxylate
moieties are unequally modified in most ellagitannins, as in
both the natural products shown in Figure 1,10 an aldehyde is
convenient for constructing unequally esterified carboxylates.
School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda,
Hyogo 669-1337, Japan. E-mail: shinnosuke1010@kwansei.ac.jp
† Deceased on 23th November 2019. This paper is dedicated to the memory of
Prof. Dr. Hidetoshi Yamada.
‡ Present Address: Faculty of Pharmaceutical Sciences, Tokushima Bunri
University, 180 Nishihamaboji, Yamashiro-cho, Tokushima 770-1337, Japan
§ Present Address: Department of Chemistry, Faculty of Science, Hokkaido
University, West 8, North 10, Kita-ku, Sapporo, Hokkaido 060-0810, Japan.
Electronic Supplementary Information. See DOI: 10.1039/x0xx00000x
Another reason for installing aldehyde in
oxa-Michael addition to the corresponding ester
3
is the unsuccessful
, making the
7
aldehyde indispensable for the successful addition of
phenolate. Consequently, the synthetic route demands
oxidation-state adjustments of the carboxyl group, the innate
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state of galloyl group, aldehyde must be oxidized to a carboxyl the increased reactivity of
8 was attributed to the enhanced
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g
r
o
u
p
,
electrophilicity induced by the mesomeDriOcI:e1f0fe.1c0t3s9/aDr0isCinCg00f8r8o9mC
t
h
e
k
e
t
o
n
e
a
n
d
Scheme 2. Preparation of 8, an improved building block for synthesizing the C–O digallate
structure
ester groups.
Reductive aromatization of 17 can be achieved using several
methods. Tetrakis(triphenylphosphine)palladium(0)-catalysedred-
uctive aromatization, using triethylsilane as a reductant, is a
unique method for preparing the aldehyde type C–O digallate
like 20.9 Application of this method to 17 afforded the desired
compound 22 and the corresponding triethylsilyl ether 23
(Table 1, entry 1; ESI-17), with unreproducible yields of the two
compounds. Regardless, the addition of tetrabutylammonium
fluoride (TBAF) after completion of the reductive aromatization
provided only 22 steadily (Table 1, entry 2; ESI-18). In contrast,
the ketone in 17 was selectively reduced by sodium borohydride
in methanol (Table 1, entry 3; ESI-19). Alternatively,
hydrogenolysis of 17 using a Pearlman catalyst18 can be used
for reductive aromatization to furnish the pentaphenol 24 in
excellent yields (Table 1, entry 4; ESI-20). The use of
hydrogenolytic benzyl group removal accompanied by
reductive aromatization of an aldehyde-equipped o-quinone
monoketal moiety (20 for example) is unrealistic in the previous
Scheme 1. Comparison of the previous (yellow background) and improved (blue
background) methods for synthesizing the C–O digallate structure. [Br]:
bromination, [Ox]: oxidation, [Rd]: reduction.
which increases the number of required steps. Herein, we
describe a novel building block
to remove extra redox steps in the currently used method.
The brominated o-quinone monoketal was prepared in
8 (Scheme 1, blue background),
8
four steps from 1011 (Scheme 2). Bromination of 10 using 1,3-
dibromo-5,5-dimethylhydantoin (DBDMH)12 yielded a mixture
of unreacted 10, monobrominated 11, and dibrominated 12
(ESI-3). After separation of 10, benzylation of a mixture of 11
and 12 furnished 13 and 14, and chromatographic separation
provided pure 13 in 48% yield from 10 (ESI-4). Successive
removal of the allyl group13 from 13 generated
9 (ESI-5) and
oxidation of the corresponding phenol moiety using
phenyliodine bis(trifluoroacetate) (PIFA)14 in the presence of
benzyl alcohol afforded
(40% yield; ESI-6). Isolated
8
in 54% yield and its regioisomer 15
was stable in air at 25 °C, while 15
8
decomposed at the same temperatures.
Consecutive addition of phenolate to
8
and release of
bromide via elimination afforded good to excellent yields
(Scheme 3). Starting with phenol 16
15 reaction of equimolar
amounts of in the presence of potassium carbonate in
acetonitrile provided 17 in 83% yield (ESI-7), while the use of
1.3 equiv of and the heating to 70 °C improved the yield to
95% (ESI-8). From phenol 18 16
in which the hydroxy group was
more sterically hindered than in 16 19 was obtained in 73%
yield with 1.0 equiv of (ESI-9). When 1.3 equiv of was
,
8
8
,
,
8
8
applied, the yield was improved and the reaction time was
halved (ESI-10). Comparison of the newly obtained results to
those of the previous method utilizing 39 indicated the
enhanced reactivity of
8. In contrast, replacement of the keto-
"ester" with keto-"ether" 21 (ESI-11–15) did not produce the
8
corresponding C–O connected compound (ESI-16). Therefore,
2 | J. Name., 2012, 00, 1-3
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Scheme 3. The addition/elimination reactions of phenolate ions to 8 and consonant
mesomeric effects in 8. The products 17 and 19 are equipped with the skeleton of the
DHDG group.
corresponding less sterically hindered tri o-substituted
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7
analogue, as reported by Feldman et al (DEOSII-:2106.)1.039/D0CC00889C
Table 1. Reductive aromatization of the o-quinone monoketal moiety.
Entry Reagents
Solvents
DMF
Products Yield (%)
22
23
37–83
17–60
1
2
Pd(PPh3)4, Et3SiH
i) Pd(PPh3)4, Et3SiH DMF
ii) TBAF (one pot)
i) NaBH4
22
80
THF, DMF
MeOH, Et2O
3
4
22
24
93
99
ii) HCl aq (one pot) IPA
H2, Pd(OH)2/C acetone
method. This is because phenolic hydroxy groups would be
generated by the hydrogenolysis, which aldehyde oxidation to
the corresponding carboxylic acid is difficult with the hydroxyl
groups intact.
The one pot transformation of oxa-Michael addition/eli-
mination followed by reductive aromatization was possible
without work up process (Scheme 4, a). Specifically, after
addition/elimination using 18 and 8, the directly addition of
sodium borohydride to the reaction mixture reduced the
quinone monoketal. Subsequent workup with 1 M hydrochloric
acid and purification afforded 25 in 65% yield (ESI-21).
The newly developed method for constructing the C–O digallate
structure was applied to valoneoyl and tergalloyl group
syntheses. Thus, the use of phenol 269 (Scheme 4, b) as a
nucleophile for
8 afforded C–O connected 27 (ESI-22). The
structure of 27 was confirmed by transformation to the known
2919 via reductive aromatization accompanied by debenzylation
and full methylation of the phenolic hydroxy groups (ESI-23).
The 1H NMR data of 29 were identical to those derived from the
natural product containing the valoneoyl group.19 Although the
previous method allowed for the synthesis of the tergalloyl
group using 30 and
required to compensate for the low reactivity of
3
(Scheme 4, c),9 two treatments were
and construct
Scheme 4. One pot synthesis of the DHDG skeleton and improved synthesis of the
valoneoyl and tergalloyl groups.
3
the sterically hindered tetra o-substituted diaryl ether. The first
was the adoption of the methoxymethyl (MOM) as protecting
groups of the nucleophilic phenol 30 to reduce steric hindrance
around the reaction point. The other was the use of DMSO as
the reaction solvent. Acetonitrile is a standard solvent when
synthesizing DHDG and valoneoyl groups from
higher volatility; however, the reaction in acetonitrile decreases
the yield of 31 drastically. In contrast, allowed nucleophilic
attack of 32 (Scheme 4, d; ESI-24), where the benzyl groups
protected the phenols in acetonitrile to furnish C–O connected
33 in 84% yield (ESI-25). The use of trimethylsilyldiazomethane
for the methylation of 34 prevented Similes rearrangement,
transforming tetra o-substituted C–O digallate compound to the
The improved method for preparing the C–O digallate
structure using building block
ellagitannin syntheses containing diaryl ether components. The
previous method requires aldehyde in building block (Scheme
8 may provide novel routes for
3
3 thanks to its
5, a), limiting the pathway to esterification of 'sugar B' after C–
O digallate structure formation containing 'sugar A'. The
improved method may enable the oxa-addition of a phenolate
containing 'sugar A' (Scheme 5, b) to a brominated o-quinone
monoketal derivative furnished with 'sugar B' as a converged
synthetic route.
8
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5
S. Quideau, Chemistry and biology of ellagitannins—an
In conclusion, the newly prepared o-quinone monoketal
was sufficiently stable to be isolated and exhibited high
reactivity in the synthesis of the diaryl ether components of
8
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underestimated class of bioactive plant polyphenols, World
DOI: 10.1039/D0CC00889C
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8
9
Scheme 5. Possibility convergent synthesis of ellagitannins containing diaryl ether
components. [Bn]: benzylation.
T. Hirokane, Y. Hirata, T. Ishimoto, K. Nishii and H. Yamada,
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in the
8
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elimination of the repeated redox steps required in the
previously developed method; (2) increased method tolerance
for the reductive aromatization of the o-quinone monoketal to
form the C–O digallate structure; and (3) plausible adoption of
a convergent route for ellagitannin synthesis composed of the
diaryl ether components. These advantages shorten the
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ellagitannins.
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This work was partly supported by JSPS KAKENHI (Grant No.
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Conflicts of interest
There are no conflicts to declare.
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