Synthesis of an ellagitannin component, the macaranoyl group with a tetra-ortho-substituted diaryl ether structure

Article abstract of DOI:10.1021/acs.orglett.0c02066

Herein, a practical synthesis of the macaranoyl group contained in ellagitannins, i.e., a C-O digallate structure with a tetra-ortho-substituted diaryl ether bond, is described. The methodology involved an oxa-Michael addition/elimination reaction between a brominated ortho-quinone monoketal and a phenol with a hexahydroxydiphenoyl moiety in the presence of 18-crown-6 under dark conditions, followed by reductive aromatization. The existence of rotamers originating from the constructed ether moiety is discussed as well.

Full text of DOI:10.1021/acs.orglett.0c02066

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Letter
Synthesis of an Ellagitannin Component, the Macaranoyl Group
with a Tetra-ortho-Substituted Diaryl Ether Structure
Hajime Hashimoto, Takayuki Ishimoto, Hayato Konishi, Tsukasa Hirokane, Shinnosuke Wakamori,
Kazutada Ikeuchi,* and Hidetoshi Yamada
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ABSTRACT: Herein, a practical synthesis of the macaranoyl
group contained in ellagitannins, i.e., a C−O digallate structure
with a tetra-ortho-substituted diaryl ether bond, is described. The
methodology involved an oxa-Michael addition/elimination
reaction between a brominated ortho-quinone monoketal and a
phenol with a hexahydroxydiphenoyl moiety in the presence of 18-
crown-6 under dark conditions, followed by reductive aromatiza-
tion. The existence of rotamers originating from the constructed
ether moiety is discussed as well.
llagitannins are a class of natural polyphenols. To date,
1
Emore than a thousand ellagitannins have been isolated.
Their general structure comprises D-glucose esterified with
galloyl and axially chiral hexahydroxydiphenoyl (HHDP)
groups, biosynthesized via C−C coupling of two galloyl groups
in pentagalloyl-D-glucose.2 Ellagitannins additionally contain
C−O digallate moieties, comprising a diaryl ether structure
wherein two galloyl groups are connected via a C−O bond.
Ethereal linkages between a galloyl group and other
components, e.g. an HHDP group, have also been found in
nature and form more complicated C−O digallate structures.3
Dehydrodigalloyl (DHDG), valoneoyl, tergalloyl, and macar-
anoyl groups are representative components (Figure 1). As
exemplified by eumaculin B, these components can oligo-
merize a monomeric ellagitannin via esterification of a carboxyl
group in the motif with a hydroxy group of a glucose moiety in
another ellagitannin, resulting in the broad structural diversity
of the ellagitannins.4
C−O digallate structures have previously been constructed
by three groups. Feldmann et al. and Abe et al. synthesized the
DHDG group using independent strategies,5,6 and Abe et al.
additionally prepared the valoneoyl group.7 Recently, we
reported a unified synthetic strategy for DHDG, valoneoyl, and
tergalloyl groups.8 Nevertheless, their synthetic application to
the macaranoyl group has not been explored as yet.
Nishioka and co-workers have previously synthesized a
methylated macaranoyl analogue 1, for the structural
determination of this component of natural ellagitannins.
They achieved this via Ullmann coupling between an aryl
bromide, prepared from 2, and a second aryl bromide 3
(Scheme 1a).9 However, the yield was low, and two isomers of
1, derived from the undesired bromination products of 2, were
also generated. Herein, we describe a practical synthesis of the
Figure 1. Ellagitannins with C−O digallate structures.
macaranoyl group achieved by adaption of our synthetic
procedure for the C−O digallate structures.
Received: June 22, 2020
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© XXXX American Chemical Society
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Scheme 1. (a) Reported Method for Synthesizing the
Macaranoyl Group; (b) Our Synthetic Method for C−O
Digallate Structures
Scheme 2. Attempt To Synthesize the Macaranoyl Group
Using o-Qk 10
prepared in 97% yield via phenyliodine(III) bis-
(trifluoroacetate) (PIFA)-mediated oxidation11 of phenol
1210 in the presence of excess benzyl alcohol (BnOH).
Although the synthesis of 7 also provided its regioisomer,8b 13,
the corresponding regioisomer of 10, was not formed. The
reaction of 10 with 11 proceeded smoothly to furnish the
desired product 14 in 91% yield. However, subsequent
reductive aromatization using Et3SiH and catalytic Pd(PPh3)4
to obtain 15 failed, instead affording 11 as the major product.
Other reaction conditions such as Luche reduction12 and
hydrogenolysis were also attempted; while no desired product
was obtained, 11 was generated (Supporting Information (SI)-
S2). Hydride reduction failure may be explained by the high
electrophilicity of the α,β-unsaturated aldehyde moiety of 14,
which preferred an attack by H− on the β-carbon to eliminate
11. Under hydrogenolysis conditions, in addition to reductive
aromatization of 14 and removal of two Bn groups in 15, the
aldehyde function is likely being reduced. Thus, we assumed
that the production of 11 was attributed to the oxidation of the
1-aryloxy-2,3,4-trihydroxy-6-methylbenzene ring in air.
Therefore, we conducted experiments using o-Qk 7, the
reactivity of which was enhanced owing to the mesomeric
effects between the ketone and ester. The oxa-Michael
addition/elimination reaction between 7 and 11 gave the
coupling product 16 in 47% yield (Scheme 3a).13 However,
the reaction required over 5 days and various byproducts were
detected by TLC and MS analysis. One of the major
byproducts was identified as 17; its structure was confirmed
by comparing its spectral data with those of 17, synthesized in
97% yield via oxa-Michael addition/elimination reaction of 7
and phenol 18.8b Because the isolated yield of 17 was 32%, it
was expected that suppressing this side reaction would increase
the yield of 16. We established that 17 was generated via self-
aromatization of 7 under light irradiation. The 1H NMR
spectrum of 7 in chloroform-d, after irradiation with a
fluorescent light (Panasonic, FL20SS·EX-N/18) for 24 h,
displayed signals corresponding to benzaldehyde and phenol
18 along with those attributed to 7 (SI-S3). The amounts of
these two products increased continually over time, with a
disappearance of 7 observed after 4 days. The production of 17
involved the generation of 18 in situ, followed by its reaction
with the remaining 7. This side reaction was not detected in
the previous study that utilized 7 because those reactions were
complete within a shorter time (≤10 h).8b Thus, prolonged
reactions with 7 should be conducted under dark conditions.
We further hypothesized that the addition of 18-crown-6
would enhance the reactivity of 11 because of the formation of
the salt-free phenolate anion.14 Based on this consideration, we
conducted the following experiment. To a suspension of 11
Our unified synthetic method for DHDG, valoneoyl, and
tergalloyl groups is described in Scheme 1b.8 Orthoquinone
monoketal (o-Qk) 48a was used as an electrophile, and the oxa-
Michael addition of a phenol bearing a galloyl or HHDP
moiety to 4, followed by elimination of the bromine atom, gave
5. Subsequent treatment of 5 with Et3SiH and a catalytic
amount of Pd(PPh3)4 resulted in reductive aromatization of 5
to form 6. We further developed a novel o-Qk 7,8b wherein the
ketone and ketal locations in 4 were reversed. Thus, the
electrophilic carbon of 7 was more reactive than that of 4 by
acquiring an additional conjugation effect from the ketone,
which allowed the oxa-Michael/elimination reaction despite
the replacement of the aldehyde at the 1-position of 4 with a
methyl ester. This modification had further positive effects on
the subsequent reaction; in addition to reductive conditions
involving Et3SiH and Pd(PPh3)4, NaBH4 reduction followed
by acidic workup, as well as hydrogenolysis, could both induce
the reductive aromatization of 8 to supply 9. As these two
electrophiles enabled the formation of a tetra-ortho-substituted
diaryl ether structure in the tergalloyl group, wherein the
ethereal bond is located at the 5-oxygen of the HHDP group,
this method may also form the corresponding bond in the
macaranoyl group. However, this transformation appears
challenging because the C−O bond must be constructed at a
more crowded position (6-O), implying that steric repulsion
may be problematic for the synthesis.
To construct the macaranoyl group, we initially used
electrophile 10, wherein the methyl ester of 7 was replaced
with an aldehyde (Scheme 2). o-Qk 10 is more electrophilic
than 7 owing to the strong inductive effect of the aldehyde and
is hence expected to realize the desired reaction. To minimize
steric hindrance at the reaction site, phenol 1110 was selected
as the nucleophile, wherein all the oxygen atoms of the HHDP
group, except for 6−O, were methylated. o-Qk 10 was
B
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moiety of 7 because selective hydrolysis of the methyl ester in
the presence of other esters, formed between D-glucose and
HHDP/galloyl groups, is difficult. Replacement with a benzyl
ester would facilitate the release of the carboxylic group, which
expedites the synthesis of oligomeric ellagitannins containing
the macaranoyl group.16 Thus, we focused on the oxa-Michael
addition/elimination reaction of phenol 2010 and o-Qk 21.
The synthetic method of 21 is shown in Scheme 4a.
Transformation of alcohol 228b into carboxylic acid 23 via
2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO)-mediated oxi-
dation with PhI(OAc)2 and NaClO2,17 benzylation of 23, and
removal of the allyl group provided phenol 24. PIFA-mediated
oxidation of 24 into 21 was performed in the presence of 2.0
equiv of BnOH to generate a crude product mixture of 21 and
25 in a 5.8:1 ratio. Undesired 25 was decomposed during
purification by silica gel chromatography, and 21 was isolated
exclusively in 73% yield, suggesting that 25 possesses similar
properties to the regioisomer of o-Qk 7.8b Similar to 7, o-Qk
21 underwent light-mediated self-aromatization to afford 24
and benzaldehyde (SI-S4).
Scheme 3. (a) Formation of Byproduct 17 in the Reaction
of 11 with 7; (b) Optimized oxa-Michael Addition/
Elimination Reaction Using 7 and Transformation into
Phenol 19
The oxa-Michael addition/elimination reaction of 20 and 21
proceeded under conditions analogous to those of the reaction
between 11 and 7 (Scheme 4b). Even though the reaction site
of 20 is more hindered than that of 11, owing to the
surrounding Bn groups, the reaction was completed within 43
h and gave the desired product 26 in 64% yield, illustrating the
robust reactivity of 21. While 26 also underwent self-
aromatization under light to slowly degrade into phenol 27
and benzaldehyde, it remained stable for a month when kept in
the dark (SI-S5). Interestingly, the 1H and 13C NMR spectra of
26 in acetonitrile-d3 at 24 °C displayed signal duplication. For
example, the proton and carbon signals for the 5′′- and 2′′-
positions were detected at δ 6.22/5.94 and 98.3/95.9,
respectively. The four substituents located adjacent to the
formed ether bond impart rigidity to it and impede bond
rotation, appearing to generate a C−O chiral axis.18 Although
26 also contains a C−C chiral axis in the biphenyl structure, no
examples exist of C−C chiral axis rotation in protected HHDP
groups. Thus, we rationalized that the duplication of signals is
attributed to the presence of rotamers, arising from the C−O
chiral axis.19 No coalescence of the signals pairs was observed
in the 1H NMR spectrum despite elevating the temperature to
75 °C, which suggested that the rotation energy barrier was
sufficiently high. As self-aromatization of 26 was observed in
and K2CO3 in acetonitrile in a reaction flask wrapped with
aluminum foil, 7 and 18-crown-6 were added, and the mixture
was stirred at 71 °C. The desired reaction was complete within
49 h, which was 83 h shorter than the time required for
reaction in Scheme 3a; 16 was obtained in 66% yield (Scheme
3b). Subsequent reductive aromatization of 16 proceeded
smoothly under Luche reduction conditions12 to supply
phenol 19 with a macaranoyl structure in 98% yield.
We next attempted a practical synthesis of the macaranoyl
group. Because removal of methyl protecting groups of
phenolic hydroxy groups is difficult, benzyl (Bn)-protecting
groups are frequently used in ellagitannin synthesis owing to
their tolerance of various reaction conditions and ease of
removal via hydrogenolysis.8a,15 Thus, an oxa-Michael
addition/elimination reaction using an analogue of 11, wherein
its methyl groups were substituted by Bn groups, would be
more practical. Additionally, we decided to change the ester
Scheme 4. (a) Synthesis of Novel o-Qk 21; (b) Synthesis of the Macaranoyl Group
C
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1
this experiment (SI-S6), we did not measure the H NMR
spectra at higher temperatures.
suppressed. NaBH4-mediated reductive aromatization of 26
provided diaryl ether 27, which was readily transformed to 29.
We additionally discovered that 26 and 27 existed as rotational
mixtures owing to the presence of the C−O chiral axis. This
observation demonstrates the robustness of our method and
suggests the possibility of its application to the synthesis of
other C−O digallate structures. We intend to report the
synthesis of ellagitannins with a macaranoyl group in the near
future.
We next transformed 26 into the unprotected macaranoyl
derivative (Scheme 4b). Treatment of 26 with NaBH4
followed by 1 M aqueous HCl induced reductive aromatiza-
tion, affording 27 in 91% yield. Selective hydrolysis of diester
moieties bearing the propane tether, followed by the
hydrogenolysis of obtained 28, provided the desired
compound 29. The macaranoyl structure of 29 was confirmed
via the transformation of 26 into known compound 1.
Following the reductive aromatization of 26, and removal of
all the Bn groups via hydrogenolysis, the treatment of obtained
30 with TMS diazomethane20 gave a nona-methylated
compound 31. Methanolysis to cleave the propane tether of
31 using NaOMe in MeOH produced 1 and the product of
partial hydrolysis, resulting from the presence of a small
amount of water contained in the reaction mixture. Thus, the
crude product was exposed to MeI and K2CO3 to afford 1. The
1H NMR spectrum of synthesized 1 was identical to the
literature data for 1,9 confirming the macaranoyl structure of
27−31.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02066.
Experimental procedures, analytical data, and copies of
1
the H and 13C NMR spectra for all new products
(PDF)
AUTHOR INFORMATION
■
Diaryl ether 27 was also isolated as a rotameric mixture
(Figure 2). The H NMR spectrum of 27 in acetonitrile-d3 at
Corresponding Author
1
Kazutada Ikeuchi − School of Science and Technology, Kwansei
Gakuin University, Sanda, Hyogo 669-1337, Japan;
Department of Chemistry, Faculty of Science, Hokkaido
University, Sapporo 060-0810, Japan; orcid.org/0000-
0001-5343-3502; Email: ikeuchi@sci.hokudai.ac.jp
Authors
Hajime Hashimoto − School of Science and Technology,
Kwansei Gakuin University, Sanda, Hyogo 669-1337, Japan
Takayuki Ishimoto − School of Science and Technology,
Kwansei Gakuin University, Sanda, Hyogo 669-1337, Japan
Hayato Konishi − School of Science and Technology, Kwansei
Gakuin University, Sanda, Hyogo 669-1337, Japan
Tsukasa Hirokane − School of Science and Technology, Kwansei
Gakuin University, Sanda, Hyogo 669-1337, Japan;
orcid.org/0000-0001-5727-1731
1
Figure 2. H NMR spectra of 27 in acetonitrile-d3 (500 MHz) at
Shinnosuke Wakamori − School of Science and Technology,
Kwansei Gakuin University, Sanda, Hyogo 669-1337, Japan;
orcid.org/0000-0002-0544-9486
various temperatures.
Hidetoshi Yamada − School of Science and Technology,
Kwansei Gakuin University, Sanda, Hyogo 669-1337, Japan;
orcid.org/0000-0003-2272-319X
24 °C contained signal pairs, which appeared broadened in the
3.6−5.3 ppm region. While some of the broad signals became
sharp at 0 °C, almost all signals in that range were broadened
at 50 °C. Coalescence of a pair of the broad signals was
detected at 75 °C,21 indicating that the rotation barrier of 27
was lower than that of 26. This difference was attributed a
decrease in steric hindrance resulting from the transformation
of the ketal moiety of 26 to the benzyloxy moiety of 27.
Although tri- or tetra-o-substituted diaryl ethers can exhibit
atropisomerism,22 this feature was not observed in previously
synthesized diaryl ether compounds.8 Rotamers of 28 were
also detected in the 1H/13C NMR spectra at 22 °C, indicating
that the presence of rotamers is specific to the macaranoyl
structure.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02066
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are very grateful to Prof. Hidetoshi Yamada, who passed
away on November 23, 2019, for his dedication. We thank
Prof. Takashi Tanaka at Nagasaki University for providing H
1
In summary, we succeeded in a practical synthesis of the
macaranoyl group by expanding our established synthetic
procedures for the C−O digallate structure. The oxa-Michael
addition/elimination reaction using phenol 20 and o-Qk 21
gave a satisfactory yield of 26 upon addition of 18-crown-6,
which enhanced the reactivity of 20, and by performing the
reaction in the dark, the self-aromatization of 21 was
NMR spectrum data of 1. We also thank Osaka Synthetic
Chemical Laboratories, Inc. for their provision of EDCI·HCl.
We also acknowledge support from the MEXT-supported
program for the Strategic Research Foundation at Private
Universities (S1311046), and JSPS KAKENHI (Grant
Number JP16H01163 in Middle Molecular Strategy, and
JP16KT0061).
D
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(b) Wakimoto, T.; Asakawa, T.; Akahoshi, S.; Suzuki, T.; Nagai, K.;
Kawagishi, H.; Kan, T. Angew. Chem., Int. Ed. 2011, 50, 1168−1170.
(18) Kumarasamy, E.; Raghunathan, R.; Sibi, M. P.; Sivaguru, J.
Chem. Rev. 2015, 115, 11239−11300.
(19) Although 16 also appeared to be a rotameric mixture at 24 °C,
14 was not, suggesting that the ester moieties on the o-Qk ring of 16
and 26 are required to establish the C−O chiral axis. Dicarboxylic
acid 28 was also isolated as a rotameric mixture, indicating that the
propane tether of 26 was not involved in the generation of the
rotamers.
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