Total Synthesis of Mallotusinin

Article abstract of DOI:10.1002/chem.202002753

The total synthesis of mallotusinin, which bears a tetrahydroxydibenzofuranoyl (THDBF) bridge between the 2-oxygen and 4-oxygen of glucose on corilagin with a 3,6-O-(R)-hexahydroxydiphenoyl (HHDP) bridge, is described. The key features of the total synthesis are: 1) improvements of our previously reported method to synthesize corilagin; 2) establishment of the THDBF skeleton via an unusual intramolecular S_NAr reaction of an HHDP analogue, and 3) the application of a two-step bislactonization strategy for a HHDP bridge construction into the 2,4-O-THDBF bridge. Oxidative phenol coupling of 1,2,4-orthoacetyl-3,6-di-(4-O-benzylgalloyl)-α-d-glucopyranose and the orthoester cleavage of the coupling product without the pyranose-furanose ring transformation are key reactions for the improved synthesis of corilagin, which enabled the adequate supply of a corilagin precursor that was required to develop the mallotusinin synthesis. These established methods are expected to help develop the synthesis of other ellagitannins with a bridge between the two oxygens of corilagin.

Full text of DOI:10.1002/chem.202002753

Accepted Article
Accepted Article
Title: Total Synthesis of Mallotusinin
Authors: Kohei Yamashita, Yuji Kume, Seiya Ashibe, Cicilia A. D.
Puspita, Kotaro Tanigawa, Naoki Michihata, Shinnosuke
Wakamori, Kazutada Ikeuchi, and Hidetoshi Yamada
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202002753
Link to VoR: https://doi.org/10.1002/chem.202002753
01/2020

10.1002/chem.202002753
Chemistry - A European Journal
FULL PAPER
Total Synthesis of Mallotusinin
Kohei Yamashita,[a] Yuji Kume,[a] Seiya Ashibe,[a] Cicilia A. D. Puspita,[a] Kotaro Tanigawa,[a] Naoki
Michihata,[a] Shinnosuke Wakamori,[a] Kazutada Ikeuchi,*[a],[b] and Hidetoshi Yamada[a]
[a]
K. Yamashita, Y. Kume, S. Ashibe, C. A. D. Puspita, K. Tanigawa, N. Michihata, Prof. Dr. S. Wakamori, Prof. Dr. K. Ikeuchi, Prof. Dr. H. Yamada
School of Science and Technology, Kwansei Gakuin University
2-1 Gakuen, Sanda 669-1337 Japan
E-mail: ikeuchi@sci.hokudai.ac.jp
[b]
Department of Chemistry, Faculty of Science, Hokkaido University
Kita 10, Nishi 8, Kita-ku, Sapporo 060-0810 Japan
Supporting information for this article is given via a link at the end of the document.
Abstract: We describe the total synthesis of mallotusinin that bears a
tetrahydroxydibenzofuranoyl (THDBF) bridge between the 2-oxygen
HO
HO
HO
OH
O
HO
OH
O
OH
OH
and 4-oxygen of glucose on corilagin with
a
3,6-O-(R)-
OH
HO
HO
R
hexahydroxydiphenoyl (HHDP) bridge. The key features of the total
synthesis are: (1) improvements of our previously reported method to
synthesize corilagin; (2) an establishment of forming the THDBF
skeleton via an unusual intramolecular SNAr reaction of an HHDP
analog, and (3) the application of two-step bislactonization strategy
for an HHDP bridge construction into the 2,4-O-THDBF bridge
construction. Oxidative phenol coupling of 1,2,4-orthoacetyl-3,6-di-(4-
O-benzylgalloyl)-α-D-glucopyranose and the orthoester cleavage of
the coupling product without the pyranose–furanose ring
transformation are key reactions for the improvement synthesis of
corilagin, which enabled the adequate supplement of a corilagin
precursor for developing the mallotusinin synthesis. These
established methods are expected to development of the synthesis of
other ellagitannins with a bridge between the two oxygens of corilagin.
OH
O
O
O
O
O
O
O
OH
OH
O
OH
OH
O
O
O
O
OH
OH
HO
OH
O
O
O
O
corilagin (2)
galloyl group
HexaHydroxyDiPhenoyl (HHDP) group
TetraHydroxyDiBenzoFuranoyl (THDBF) group
HO
OH
O
HO
OH
mallotusinin (1)
Figure 1. Structures of mallotusinin (1) and corilagin (2).
The task for the synthesis of mallotusinin (1) is the formation
of the 2,4-O-THDBF bridge. The bridge construction appears
difficult because no examples of constructing a bridge other than
an HHDP bridge on D-glucose have been reported to date.
Because the bridge is formed by the two ester bonds, double
esterification or two-step bislactonization strategy for constructing
an HHDP bridge has the potential for constructing the THDBF
bridge.[6] The double esterification strategy is used to form two
ester bonds of HHDP bridged compound 3 in one-pot using chiral
Introduction
Mallotusinin (1) is one of the monomeric ellagitannins,
usually comprising D-glucose, galloyl group(s), and one or more
axial chiral hexahydroxydiphenoyl (HHDP) groups (Figure 1). The
Nishioka and Nonaka group isolated 1 in 1989, along with 18
other ellagitannins from the bark of Mallotus japonicus.[1] The
remarkable structural features of 1 include the pyranose ring of D-
glucose exhibiting a flipped chair conformation and further
or racemic HHDP-derived dicarboxylic acid
4
or the
corresponding diacyl halide and diol 5 with a glucose moiety
(Scheme 1a). The 4,6-O-(S)-HHDP bridge has often been
constructed by this method using (S)-4.[7–9] The use of racemic 4
proceeds via kinetic resolution to provide only the (S)-HHDP
bridged compound.[10] This strategy has also been applied into
synthesizing 2,3-O-(R)-HHDP- and 2,3-O-(S)-HHDP-bridged
glucoses.[8, 9c, 11–13] The reaction using racemic 4 provides both
diastereomers, the ratio of which varies under reaction
conditions.[13] On the other contrary, the two-step bislactonization
strategy entails mono-acylation of diol 5 with HHDP-derived acid
anhydride 6, followed by intramolecular lactonization of produced
seco acid 7 (Scheme 1b). This method enabled to form 1,2-O-(S)-,
[9d] 1,2-O-(R)-,[9a,9c] 4,6-O-(S)-,[9c] and 4,6-O-(R)-HHDP bridges,[14]
the construction of which was difficult via double esterification
strategy. We expected that either of the two strategies would allow
the formation of the 2,4-O-THDBF bridge of 1. Therefore, the
fragments requisite for the synthesis of 1 are 2,4-diol 8, where the
phenolic hydroxy groups of corilagin (2) are protected, and
dicarboxylic acid 9 with a THDBF moiety (Scheme 1c). Although
the synthesis of 9 has not been reported, use of methodology for
component,
a tetrahydroxydibenzofuranoyl (THDBF) group
bridging between the 2-oxygen and 4-oxygen (2-O and 4-O) of
the glucose. Ellagitannins with a 3,6-O-(R)-HHDP bridge, as
corilagin (2),[2] possess such pyranose conformation owing to the
lock by the bridge. The 3,6-O-(R)-HHDP bridged ellagitannins
often contain an additional bridge between the 2-O and 4-O of the
glucose via esterification,[3] and mallotusinin (1) is
a
representative ellagitannin. These ellagitannins exhibit a variety
of biological activities,[4] e.g., 1 shows antioxidant activity and
antiproliferative activity against MCF-7 breast cancer cell lines,[5]
which are expected to lead to the development of medicinal
chemistry. However, no published reports of these synthesis
exist; thus, their total syntheses are one of the most important
challenges of ellagitannin chemistry.
1
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10.1002/chem.202002753
Chemistry - A European Journal
FULL PAPER
constructing a dibenzofuran skeleton[15] will allow the synthesis.
The selection of HHDP-derived compound 10, where the function
at the 6-position is replaced into a triflate group or its analog, will
be suitable as the precursor of 10 because 10 can be prepared
through derivatization of a carboxyl-group protected compound of
4. Thus, we plan to use palladium catalyzed intramolecular C–O
coupling of 10 for synthesizing 9.[16]
impossible. Here we report improvements in the synthesis of 2,
and the first total synthesis of 1 via the construction of the 2,4-O-
THDBF bridge on 2. An unique reaction encountered in forming
the THDBF moiety is also described.
BnO
HO
OH
OBn
HO
HO
R
O
O
O
O
BnO
HO
OH
O
CuCl2
BuNH2
a)
OH
OPMB
O
HO
BnO
3 steps
2 steps
OP
OP
glucose moiety
OPMB
OBn
BnO
O
PO
PO
BnO
HO
OPMB
OBn
O
O
MeOH
76%
40%
application
HO
OBn
12
O
·2,3-O-(S)-HHDP bridge
·2,3-O-(R)-HHDP bridge
·4,6-O-(S)-HHDP bridge
O
O
HO
HO
PO
PO
CO2H
CO2H
PO
PO
BnO
+
*
*
13
11
single isomer
5
PO
PO
BnO
BnO
BnO
BnO
OBn
O
OBn
OP
OP
OBn
OBn
OBn
BnO
O
BnO
4
3
OBn
OBn
OBn Cl
15
O
O
O
O
O
H2
OBn
O
OBn
OBn
b)
O
OP
OP
OP
OP
Pd(OH)2/C
DMAP
O
O
PO
PO
OH
2
O
O
O
O
O
THF/MeOH
90%
CH2Cl2
73%
α/β =33/67
then separation
·1,2-O-(S)-HHDP bridge
·1,2-O-(R)-HHDP bridge
·4,6-O-(S)-HHDP bridge
·4,6-O-(R)-HHDP bridge
application
CO2H
HO
O
5
OBn
PO
PO
PO
PO
BnO
OBn
BnO
OBn
*
*
3
14
16
O
PO
PO
6
7
Scheme 2. Previously established route for synthesizing corilagin (2). Ph =
phenyl, Bn = benzyl, PMB = p-methoxybenzyl, Bu = butyl, Me =methyl, DMAP
= 4-dimethylaminopyridine, THF = tetrahydrofuran.
PO2C
CO2P
c)
PO
PO
O
PO
PO
OP
OP
O
6
OP
OP
PO
intramolecular
C–O coupling
XO OH
10
OP
Results and Discussion
O
O
HO2C
CO2H
double
O
OP
OP
O
esterificaiton
+
1
O
PO
OP
or
Considering the abovementioned methods, we designed a
new synthetic route of 2 as shown in Scheme 3. The most
important task for the efficient synthesis of 2 was to establish a
method for constructing a 3,6-O-(R)-HHDP bridge on the glucose
moiety. Recently, we succeeded in construction of 3,6-O-(R)-
HHDP bridge via oxidative phenol coupling of penta-(4-
benzylgalloyl)-β-glucose; however, the adoption is unreasonable
due to low yields.[9a] Flipping the pyranose ring from the inherent
equatorial-rich conformation to an axial-rich conformation is
unfavorable due to 1,3-diaxial repulsion, causing the difficulty in
formation of the 3,6-O-(R)-HHDP bridge on D-glucose. We
expected that the use of 1,2,4-orthoacetylglucose (17),[19] where
the 3-O and 6-O are locked in an axial conformation by the ortho
ester bridge, would result in a solution. The two galloyl moieties
of the digalloylated compound 18 are proximal; thus, we expect
progress toward oxidative phenol coupling. Stereoselective
O
two-step
OP
HO
OH
8
PO
OP
bislactonization
9
Scheme 1. (a) Double esterification strategy. (b) Two-step bislactonization
strategy. (c) Synthetic strategy of the 2,4-O-THDBF bridge of 1. P = protecting
group. X = trifluoromethanesulfonyl (Tf) or its analog.
We have previously reported the total synthesis of corilagin
(2) (Scheme 2).[17] The 3,6-O-(R)-HHDP bridge of 2 was
constructed via CuCl2/BuNH2 mediated oxidative phenol coupling
of acyclic tetra-ol 11, which was prepared from glucose-derived
compound 12[18] in two steps, providing 13 as a single isomer.
After reconstruction of the pyranose ring in three steps, treatment
of 14 with tri-O-benzylgalloyl chloride 15 and 4-
dimethylaminopyridine (DMAP) gave an anomeric mixture of
galloyl ester 16, β-isomer being the major isomer. Following
separation of diastereomeric-mixture, β-16 was subjected to
hydrogenolysis, which produced corilagin (2).
This method is inapplicable to the synthesis of mallotusinin
(1) due to inefficient transformation into 2 and the benzyl (Bn)
protections of the 2-O and 4-O of 16. The established route
requires the pyranose ring opening-closing sequence for
constructing the 3,6-O-(R)-HHDP bridge, resulting in an increase
in the total steps for 2 and decrease in the overall yield. Fair yield
and stereoselectivity for anomeric galloylation of 14 also
increases the inefficiency of the synthesis. Our goal is to achieve
the total synthesis of 1; thus, supplying adequate amount of 2 and
its precursor is essential. Further, the two Bn groups on the
glucose of 16 disadvantage the development. Because the
phenolic hydroxy groups of the HHDP and galloyl group are also
benzylated, selective cleavage of the two protections is required
for the synthesis of 1. However, owing to less reactivity, removal
of the two Bn groups without affecting other Bn groups is
OBn
OBn
HO
BnO
BnO
OBn
OH
oxidative
phenol
HO
R
OH
BnO
BnO
HO
BnO
cleavage of
orthoester
O
O
O
O
galloylation
coupling
O
O
O
HO
OO
O
O
O
O
O
CH3
OO
OO
1,2,4-orthoacetyl
glucose (17)
O
O
18
20
CH3
CH3
BnO
BnO
BnO
2,4-O-THDBF
bridge
formation
BnO
OBn
OBn
OBn
OBn
OBn
OBn
BnO
BnO
mallotusinin (1)
corilagin (2)
O
O
O
O
O
glycosyl
esterification
O
O
O
deprotection
OBn
OBn
O
O
LG
O
O
OBn
PO
OP
HO
OH
19
21
Scheme 3. Synthetic strategy of mallotusinin (1) and corilagin (2).
2
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10.1002/chem.202002753
Chemistry - A European Journal
FULL PAPER
incorporation of a galloyl group at the anomeric position is
attainable via glycosyl esterification[20] of 19 derived from the (R)-
HHDP bridged compound 20 through the orthoester cleavage.
The use of the acyl group is suitable for the two hydroxy group
protection of 19 because the neighboring group participation of
the 2-O acyl group drives β-selective glycosylation.[21] Finally,
chemoselective removal of the two acyl groups could provide 2,4-
diol 21 of a precursor of mallotusinin (1).
mirrors our previous findings for acid hydrolysis of 1,2,4-O-
orthoacetyl-3,6-O-(o-xylylene)glucose,[19b] and suggests that
furanoside 25 is more thermodynamically stable than pyranoside
26. Transformation of the pyranose ring into the furanose ring
arises through intramolecular attack by releasing the hydroxy
group at 4-position on a generated oxocarbenium ion.[23] The
following two successful methods for obtaining 3,6-O-(o-
xylylene)glucopyranoside were attempted next: thioglycosylation
using thiophenol and trimethylsilyl triflate[23] and thermal
Based on the synthesis strategy, we first constructed the
3,6-O-(R)-HHDP bridge (Scheme 4a). The coupling precursor 18
was prepared via condensation of the two hydroxy group of 1,2,4-
orthoacetylglucose (17) with 3,5-di-O-allyl-4-O-benzylgallic acid
glycosylation
using
p-methoxyphenol.[19b]
Although
20
decomposed in the former method, the latter method provided the
desired product, but resulted in unacceptable yields with low
reproducibility. These modified reaction conditions were also
examined, but the results were unsatisfactory [See Supporting
Information (SI)-S-1]. In contrast, recently reported reaction
conditions for cleaving the orthoester of 1,2,4-O-orthoacetyl-3,6-
O-(1,1'-(ethane-1,2-diyl)dibenzene-2,2'-bis(methylene)glucose
caused the desired conversion smoothly.[19a] Thus, treatment of
20 in benzotrifluoride containing molecular sieves 4A with
thiophenol and indium bromide induced anomeric phenylthiolation
along with the cleavage of the orthoester to furnish pyranoside 27
in high yield in a highly stereoselective manner (Scheme 4a). The
β-configuration of the anomeric proton was assumed by the fact
22[9d]
using
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDCI·HCl) and DMAP, followed by removal of the
four allyl groups. As expected, CuCl2/BuNH2 mediated
intramolecular oxidative phenol coupling[17] of 18 proceeded
smoothly to give the 3,6-O-(R)-HHDP bridged compound 23 in
76% yield as a single isomer. The axial chirality was ensured by
comparing the optical rotation value of the derived methyl ester
24 with that of reported (R)-24.[22] Benzylation of the four phenolic
hydroxy groups of 23 provided 20, which was then subjected to
methanolysis to deliver 24. The optical rotation value was
approximate to the literature value, showing that the axial chirality
produced by the oxidative phenol coupling of 18 was (R).
3
that JHH value of anomeric proton of 27 was 6.9 Hz, which was
Cleavage of the orthoester moiety on benzylated compound
20 required detailed examination. Treatment of 20 with 1 M HCl
allyl alcohol solution provided only furanoside 25 without the
production of pyranoside 26 (Scheme 4b). The HMBC spectrum
detected correlation between the anomeric proton and the carbon
at 4-position, which identified the furanose structure. This result
2.1 Hz higher than that of 20. Because the pyranose conformation
of 27 was not determined, the pyranose ring was purposely
illustrated as a plane structure. Establishment of this conversion
allowed us to supply adequate amounts of 27 to enable the
development to the synthesis of 1.
OBn
OBn
a)
OAllyl
R1O
R1O
OR1
pyranose conformation
unclear
HO
HO
OH
O
22
BnO
1)
OBn
OBn
BnO
BnO
R
HO
BnO
R1O
BnO
HO
OH
O
AllylO
O
O
O
O
O
OH
29
O
O
OBn
HO
O
Ar
EDCI•HCl, DMAP
CH2Cl2/pyridine, 99%
O
O
R2O
SPh
O
HO
O
O
PhSH, InBr3
NIS, TfOH
CuCl2, BuNH2
O
BnO
BnO
O
O
O
O
O
O
MSv 4A
BTF
97%
MSv 4A
CH2Cl2
O
OAc
MeOH
76%
single isomer
OO
CH3
O
2) morpholine
Pd(PPh3)4
CH2Cl2, 89%
O
OO
AcO
OO
CH3
2 °C to rt
O
O
BnO
BnO
30
CH3
23: R1 = H
27: R2 = H
28: R2 = Ac
17
18
Ac2O
pyridine
100%
BnBr, K2CO3
DMF, 78%
82%
20: R1 = Bn
20
b)
1 M HCl
in allyl alcohol
NaOMe
MeOH/THF
50 °C, 79%
R3O
BnO
92%
BnO
R3O
BnO
OR3
OBn
OR3
OR3
OBn
OBn
R3O
BnO
OBn
NH2NH2
in THF
O
O
O
O
O
O
OBn
OBn
O
BnO
OR3
OR3
O
OBn
OBn
O
BnO
O
O
O
O
O
HMBC
MeCN
70%
O
BnO
BnO
CO2Me
CO2Me
O
O
O
R
BnO
BnO
OH
O
HO
OAllyl
BnO
BnO
OR3
O
OBn
AcO
OAc
H
HO
OH
21: R3 = Bn
corilagin (2): R3 = H
O
O 4
O
OH
O
OAllyl
BnO
31
H2, Pd(OH)2/C
THF/MeOH
100%
BnO
single isomer
BnO
OH
24
BnO
OBn
OBn
[α]D24 –34 (c 0.75, CHCl3)
lit. [α]D20 –45 (c 0.63, CHCl3)
total 9 steps from 17
29% overall yield
pyranoside (26)
furanoside (25)
c)
method A:
Pd(PPh3)4
Cs2CO3, MeCN
100 °C, 99%
A
A
1) Tf2O, Et3N
CH2Cl2
0 °C
O
O
O
O
O
O
O
O
O
1) K2CO3
MeOH
1) K2CO3
MeOH
O
O
O
O
O
O
O
32
4
4'
2) Cs2CO3
DMF, 80 °C
94% (2 steps)
R4O
OR4
R7O
OR7
method Β:
Cs2CO3, DMF
100 °C, 99%
2) BnBr , K2CO3, KI
DMF/toluene, 60 °C
72% (2 steps)
2) OcBnBr
K2CO3
DMF/toluene
86% (2 steps)
BnO
BnO
OBn
OcBnO
OOcBn
R8O OR8
BnO OBn
O
R4O OR4
R5O OR6
BnO
OBn
OBn
BnO
OBn
34: R5 = R6 = Ac
35: R5 = R6 = H
36: R5 = Tf, R6 = H
37: R7 = Bn, A = -(CH2)4-
42: R7 = OcBn, A = -(CH2)4-
38: R7 = Bn, A = H
40: R8 = Ac
41: R8 = H
33: R4 = H
32: R4 = Ac
3 M LiOH aq.
DMSO
90 °C, 100%
Ac2O
pyridine
94%
NH2NH2•H2O
CH2Cl2, 96%
NH2NH2•H2O
MeCN, 100%
3 M LiOH aq.
DMSO, 80 °C
89%
Tf2O, Et3N, CH2Cl2
0 °C, 97%
39: R7 = OcBn, A = H
Scheme 4. (a) The second-generation synthetic route of corilagin (2). (b) The result of acid hydrolysis of orthoester 20. (c) Synthesis of dicarboxylic acid 38 and 39
possessing a THDBF moiety. EDCI·HCl =1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, DMF = N,N-dimethylformamide, Msv = molecular sieves,
BTF = benzotrifluoride, Ac = acetyl, NIS = N-iodosuccinimide, Et = ethyl, DMSO = dimethyl sulfoxide, OcBn =p-octylbenzyl.
3
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10.1002/chem.202002753
Chemistry - A European Journal
FULL PAPER
Transforming β-thioglycoside 27 into corilagin (2) was
achieved in four steps (Scheme 4a). After acetylation of the
remaining hydroxy group of 27, the resulting compound 28 was
subjected to glycosyl esterification with tri-O-benzylgallic acid (29)
using N-iodosuccinimide and triflic acid.[24] The reaction
proceeded in high β-selectivity via the formation of oxocarbenium
ion 30, where the 2-O acetyl group probably involves the
neighboring group participation, to provide galloyl ester 31 in 82%
yield as a single isomer. The multiplicity of the proton signals in
the pyranose ring of 31 were broad singlet or doublet with 1.7 Hz
of the spin coupling constant, showing that the pyranose
conformation of 31 was a flipped chair form.[17] Subsequently,
chemoselective removal of two Ac groups at 2-O and 4-O of 31 in
the presence of the galloyl and HHDP ester was examined.
Several experiments showed that treatment of 31 in acetonitrile
with a solution of hydrazine in tetrahydrofuran (THF) gave the best
outcome, resulting in diol 21 in 70% yield (See SI-S-2). Removal
of all Bn groups of 21 via hydrogenolysis completed the total
synthesis of corilagin (2). The overall yield from 1,2,4-
orthoacetylglucose (17) was 29%, completed in nine steps.
Toward synthesis of mallotusinin (1), we next turned our
attention to the preparation of the THDBF unit of 1 using the
strategy as shown in Scheme 1c (Scheme 4c). Methanolysis of
the tetra-acetylated compound of 32 derived from tetra-ol 33[17]
removed the two Ac groups at the 4- and 4'-position selectively.[9b]
After Bn protection of the resulting two hydroxy groups,
hydrazinolysis of the two Ac group of 34 provided diol 35. Mono-
triflation of 35 provided the desired precursor 36 for constructing
the THDBF moiety. Aimed intramolecular C–O coupling of 36
proceeded smoothly via treatment of 36 with catalytic
tetrakistriphenylphosphine palladium (0) and cesium carbonate in
N,N-dimethylformamide (DMF) at 100 °C to provide 37 in 99%
yield (method A). Unexpectedly, 37 was also obtained in the same
yield under the basic conditions without the palladium catalyst
(method B). This interesting reaction is discussed further below.
Hydrolysis of obtained 37 in dimethyl sulfoxide at 100 °C provided
the desired dicarboxylic acid 38.
The insolubility of 38 meant that changing the protecting
groups on the dibenzofuran skeleton was necessary. Hard
solubility in dichloromethane made conducting the esterification
reaction required for next step in the synthesis difficult. The
insolubility would be attributed to intermolecular robust π-stacking
interactions among the Bn groups and the THDBF moiety of 38.
We hypothesized that the attachment of alkyl groups to the
benzene ring of the Bn groups would decrease the interactions by
steric hindrance of the alkyl groups, resulting in an improvement
in the solubility of the corresponding dicarboxylic acid in organic
solvents. Hence, we designed 39 where the 4-O- and 4’-O- Bn
groups of 38 were replaced by the p-octylbenzyl (OcBn) group.[25]
The synthesis of 39 followed that of 38 except for a step to protect
the 4- and 4’-oxygens of 33. Thus, OcBnBr[26] rather than BnBr
was used in the second step to transform 32 into 34, providing 40.
The 4-step conversion of 40 into 39 proceeded similarly to that of
34 into 38. The dicarboxylic acid 39 easily dissolved in
dichloromethane, allowing us to proceed with the next reaction to
construct the 2,4-O-THDBF bridge.
the reaction suggested degradation of diol 21. Nucleophilic attack
by DMAP on the galloyl ester appeared to induce the
decomposition because the m/z ion peak of 44, which lost the
galloyl moiety of 21, was detected in the MS analysis of the
reaction. To suppress the side reaction, other additives were then
used. Although 2-dimethylaminopyridine[27] and 9-azajulolidine[28]
did not produce 43 (entries 2–3), 4-morpholinopyridine[29]
increased the yield to 15% (entry 4). In contrast, the reaction with
4-pyrrolidinopyridine (PPY)[30] produced seco acid 45 in 73% yield
(entry 5). The structure was confirmed by using NMR analysis
because the proton signal of the 2-O of 45 was observed in a 1.35
ppm lower field than that of 21 detected at 4.19 ppm. A compound
esterified between the 4-O of 21 and 39 was not detected. This
result suggested that PPY should be used as the optimized
additive in subsequent experiments. To obtain 43 in an
acceptable yield, other condensation reagents were screened.
Although the use of N,N’-dicyclohexylcarbodiimide (DCC)[31] gave
a similar result for entry 5 (entry 6), the Shina reagent (6-methyl-
2-nitro benzoic acid anhydride; MNBA)[32] supplied bislactone 43;
however, the isolated yield remained at 23% (entry 7). We also
examined the use of a condensation reagent under absence of
PPY, such as pentafluoroanilinium trifluoromethane sulfonate,[33]
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chlo-
ride,[34] 1-methyl-2-fluoropyridinium tosylate,[35] and 1-[bis(di-
methyl-amino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
Table 1. Esterification of diol 21 with dicarboxylic acid 39.
BnO
BnO
BnO
BnO
OBn
OBn
O
OBn
OBn
OBn
OBn
BnO
BnO
or
O
O
O
O
O
O
O
OBn
OBn
O
OBn
OBn
reagent
additive
21
+
O
O
O
O
O
CH2Cl2
rt
OBn
OBn
39
O
O
HO
O
O
O
O
HO2C
OOcBn
OBn
OcBnO
OOcBn
OBn
O
O
OcBnO
BnO
43
45
BnO
BnO
N
BnO
OBn
A =
NMe2
4-dimethylaminopyridine
(DMAP)
OBn
OBn
BnO
A
N
O
O
9-azajulolidine
4-morpholinopyridine
N
N
O
O
N
O
OH
44
O
Me2
N
N
4-pyrrolidinopyridine
(PPY)
2-dimethylaminopyridine
HO
OH
entry
reagent
additive
product (%)[a]
1
2
3
4
5
6
7
EDCI·HCl
EDCI·HCl
EDCI·HCl
EDCI·HCl
EDCI·HCl
DCC
DMAP
43 (4%)
not detected
not detected
43 (15%)
2-(dimethylamino)pyridine
9-azajulolidine
4-morpholinopyridine
4-pyrrolidinopyridine (PPY)
45 (73%)
PPY
PPY
45 (72%)
The results of the double esterification reaction of diol 21
with dicarboxylic acid 39 are summarized in Table 1. We first
treated the two reactants with EDCI·HCl in the presence of
DMAP.[9] Although desired bislactone 43 was obtained, the
isolated yield was only 4% yield (entry 1). The TLC monitoring in
MNBA
45 (23%)
[a]Isolated yield.DCC = N,N’-dicyclohexylcarbodiimide, MNBA = 6-methyl-2-nitro
benzoic acid anhydride.
4
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10.1002/chem.202002753
Chemistry - A European Journal
FULL PAPER
HO
3-oxide hexafluorophosphate;[36] however, all reactions did not
give the desired product (See SI-S-3). Therefore, we shifted to
using two-step bislactonization strategy for constructing the 2,4-
O-THDBF bridge efficiently.
HO
OH
BnO
OH
BnO
OBn
O
HO
OBn
OBn
BnO
OH
O
O
O
O
O
O
O
OH
OH
H2
O
O
O
OBn
OBn
Pd(OH)2/C
O
O
The intramolecular lactonization of 45 proceeded under the
Yamaguchi and Shina reaction conditions (Table 2). Treatment of
45 with 2,4,6-trichlorobenzoyl chloride (TCBCl)[37] and PPY in
toluene at 70 °C provided 43 in 36% yield (entry 1). The yield of
43 increased by replacing toluene into acetonitrile (entry 2),
indicating that selection of the solvent is crucial for the reaction.
Although the use of DMF caused 45 to be decomposed (entry 3),
the reaction in THF under reflux gave the best outcome to give 43
in 69% yield (entry 4). The treatment with MNBA in the presence
of PPY also supplied 45 (entry 5), but the isolated yield was in
48% yield. We also attempted the intramolecular lactonization of
an acyl chloride, prepared from 45 and oxalyl chloride; however,
no production of 43 occurred (entry 6).
O
THF
56%
OH
O
O
OBn
O
O
O
O
O
O
HO
OH
total 18 steps
from 17 and 33
5.6% overall yield
OcBnO
OOcBn
OBn
O
HO
OH
O
BnO
mallotusinin (1)
43
Scheme 5. Total synthesis of mallotusinin (1).
The unusual reaction of 36 to construct the dibenzofuran
skeleton 37 (Table 3, entry 1) led us to examine this reaction
further. We found that this reaction proceeded via the
intramolecular aromatic nucleophilic substitution (SNAr) reaction.
However, the SNAr reaction appeared disfavored because of the
presence of two benzyl ethers of the electrophilic benzene ring of
36. Additionally, the inductive effect of the ester substituted into
the benzene ring was inefficient because the ester is in a meta-
position relative to the triflate group. To identify the key factors for
the reaction, we synthesized analogs 46a–d, with partly changed
substituents at the 2- and 2’-positions (See SI-S-6), and treated
these compounds with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
in DMF at 70 °C (Table 3). To exclude metal-cation effects of a
base in the reaction, DBU was selected as the base. We also
Table 2. Optimization of the intramolecular lactonization of 45.
O
O
O
O
O
O
O
O
reaction conditions
HO
O
O
O
O
O
O
HO2C
OOcBn
OBn
OcBnO
BnO
OOcBn
OBn
O
OcBnO
O
BnO
45
43
entry
reaction conditions
product (%)[a]
Table 3. Trial to form a dibenzofuran skeleton by using alcohol 46a–d.
TCBCl, PPY, toluene, 70 °C
TCBCl, PPY, MeCN, 70 °C
TCBCl, PPY, DMF, 70 °C
TCBCl, PPY, THF, reflux
MNBA, PPY, CH2Cl2, rt
36
1
2
3
4
5
A
B
A
B
2
2’
56
DBU
BnO
BnO
OBn
OBn
BnO
BnO
OBn
OBn
6
6’
DMF, 70 ºC
O
decomposed
TfO OH
36, 46a–d
37, 47a–d
69
entry
1[a]
reactant
time
product
A
B
48
1) oxayl chloride, DMF, toluene, 70 °C
2) triethylamine, CH2Cl2, rt
decomposed
6
37
(99%[c]
O
O
36
20 h
1 h
O
O
)
)
)
[a]Isolated yield. TCBCl = 2,4,6-trichlorobenzoyl chloride.
37
(86%[c]
2[b]
36
O
O
O
O
O
O
O
Scheme 5 shows the final step for the synthesis of
mallotusinin (1). Obtained bislactone 43 was subjected to
hydrogenolysis to remove all Bn and OcBn groups, which
47a
(52%[c]
O
3
46a
46b
46c
8 h
1
produced 1 in 56% yield. The H NMR and 13C NMR spectra of
O
synthetic 1 were similar, but not identical, to those of natural 1
(See SI-S-4). The reason for this disagreement is probably
differences in the aggregation state of 1 caused by the phenolic
hydroxyl groups. Pleasingly, the respective signals of synthesized
47b = 47a
(47%[c]
O
4
6 h
)
O
1 and natural1 coalesced in the H and 13C NMR spectra of the
1
47c
O
5
21 h
(not detected)
mixture. (See SI-S-5) Therefore, we concluded that the structures
of synthesized 1 and natural 1 were the same. The overall yields
of 1 from 1,2,4-orthoacetylglucose (17) and the known compound
33 was 5.6%, completed in 18 steps.
OMe
MeO
47d
6
46d
4 h
O
(not detected)
[a]Cesium carbonate was used as the base, and the reaction was performed at
100 °C. [b]The reaction was performed at 100 °C. [c]Isolated yield. DBU = 1,8-
diazabicyclo[5.4.0]undec-7-ene.
5
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10.1002/chem.202002753
Chemistry - A European Journal
FULL PAPER
treated 36 with DBU to confirm the production of 37 in 86% yield
(entry 2). The reaction of 46a and 46b, reducing one ester moiety
of 36 to ether, provided desired compound 47a in 52% yield and
47% yield, respectively (entries 3 and 4). Cyclic diether compound
46c did not provide the desired compound, indicating that one
carbonyl moiety at the 2 or 2’ position was essential for the SNAr
reaction (entry 5). Notably, no reaction proceeded when using
mono-ester 46d (entry 6), which showed that the butane tether
was crucial for inducing the SNAr reaction of 36. The tether
restricts the rotation of the aryl-aryl bond, allowing the biphenyl
structure to form a configuration, where the location between the
hydroxy group of 36 and the carbon at 6-position was proximal.
Furthermore, the generated complex A via the intramolecular
attack by the oxygen on the carbon can form another complex B
through a mesomeric effect of the ester at the 2’-postion (Scheme
6). This stabilizing effect contributed to allow the production of the
Meisenheimer complex in situ, inducing the intramolecular SNAr
We succeeded in the total synthesis of mallotusinin (1) by
improving our previously established synthetic route of corilagin
(2). The key steps in the second-generation synthesis of 2
involved (1) construction of the 3,6-O-(R)-HHDP bridge via
oxidative phenol coupling without opening the pyranose ring and
(2) efficient cleavage of the orthoester of 20 without the pyranose–
furanose ring transformation. The highly β-selective glycosyl
esterification of 28 also facilitated the supply diol 21 as the
precursor of 1 and 2. The THDBF unit 39 requisite for synthesis
of 1 was prepared from the mono-triflate compound of the HHDP
derivative 41 using the unique intramolecular SNAr reaction. We
also accomplished the construction method of the 2,4-O-THDBF
bridge of 1 via two-step bislactonization entailing mono-acylation
of 21 with 39 using EDCI·HCl and PPY, followed by intramolecular
lactonization of obtained seco acid 45 under optimized
Yamaguchi lactonization conditions. The established method is
applicable to the synthesis of other ellagitannins with a bridge
reaction. Because the reaction of mono-ester 46a also proceeded, between 2-O and 4-O of corilagin (2). Furthermore, provision of
the formation of the Meisenheimer complex C prepared from
phenolate anion 48a would be favored because it enables the
formation of the more stable complex D. In contrast, the
generation of Meisenheimer complex E from 48b is disfavored
because another considerable complex F is instable due to lack
of ester at the 2-position; nevertheless, the reaction of 46b
occurred. The reason will be isomerization of the phenolate anion
48b into 48a via intramolecular migration of the Tf group in situ
these ellagitannins will advance the development of medicinal
chemistry.
Experimental Section
General information: All commercially available reagents were used as
received. All moisture and air sensitive reactions were carried out in
glassware equipped with rubber septa (or a septum) under the positive
pressure of argon or nitrogen after degassing using sonic wave. When
necessary, the glassware was dried under reduced pressure by heating
with a heat-gun and solvents were distilled prior to use. The substrates
were azeotropically dried if needed by evaporation of their acetonitrile or
toluene solution several times to remove trace water that may be contained
to the substrates. Molecular sieves (Msv) were dried under reduced
pressure by heating with a heat-gun before use. The reaction mixture was
magnetically stirred. Concentration was performed under reduced
pressure. The reactions were monitored by TLC and mass spectra (MS).
Anhydrous MgSO4 or Na2SO4 was used to dry organic layers after
extraction, and it was removed by filtration through a cotton pad. The
filtrate was concentrated and subjected to further purification protocols if
necessary. This sequence was represented as “the general drying
procedure” in the following experimental methods. TLC was performed on
Merck pre-coated silica gel 60 F-254 plates or Merck RP-19 F-254 plates.
Spots were visualized by exposure to UV light, or by immersion into a
solution of 2% anisaldehyde, 5% H2SO4 in ethanol or a solution of 10%
phosphomolybdic acid in ethanol, followed by heating at ca. 200 °C.
Column chromatography was performed on Merck silica gel 60 (63–200 or
40–63 μm) and Kanto Chemical silica gel 60 N (Spherical, neutral, 40–50
or 63–210 μm), for ordinary phase or Nacalai Tesque Cosmosil 140C18-
PREP for reverse phase. The other carrier materials were noted in each
case. Gel permeation chromatography (GPC) measurement was
performed on a Japan Analytical Industrial Co., Ltd. (JAI) LC-9260IINEXT
equipped with a JAI RI-700NEXT refractive index detector and JAI
JAIGEL-1H-40 and JAI JAIGEL-2H-40 columns using chloroform (CHCl3)
as an eluent (14 mL/min). The melting points were determined using a
Yanagimoto micro-melting point apparatus and uncorrected. Optical
rotations were determined using a JASCO DIP-370 polarimeter with a 100
mm cell with transmitting the sodium D-line. IR spectra were recorded on
JASCO FT/IR-4200, or Shimazu IRAffinity-1S, and the major absorbance
bands are all reported in wavenumbers (cm–1). HRMS were recorded on a
JEOL JMS-T100LC spectrometer at School of Science and Technology,
Kwansei Gakuin University, a JEOL JMS-SX102A at Global Facility Center,
Hokkaido University, and JEOL JMS-700 and Waters SYNAPT G2-Si
HDMS mass spectrometers at Tokushima Bunri University. The data are
reported in units of mass to charge. NMR spectra were recorded on JNM-
ECX-500, and ECA-500 instruments at 400, and 500 MHz for 1H and 101,
126 MHz for 13C, respectively, with either TMS or residual proton of
(Scheme 6). An intramolecular SNAr reaction to form
a
dibenzofuran skeleton has been developed;[38] but, no examples
using electron-rich compounds such as 36 and 46a exist. The
Ullmann coupling is an alternative method in the construction;
however, the reaction often requires harsh conditions.[39] Our
established reaction conditions proceed at 70–100 °C, indicating
that this reaction will be used in a new synthetic method to create
dibenzofuran compounds from biphenyl compounds.
O
O
O
O
O
37
from 36
O
X
stable
X
2
2’
2’
DBU
36
BnO
BnO
OBn
6
BnO
BnO
OBn
OBn
A: X = C=O
C: X = CH2
47a
from
46a/46b
6’
TfO
O
TfO
O
OBn
Β: X = C=O
D: X = CH2
O
O
O
O
O
DBU
DBU
O
46a
46b
BnO
BnO
OBn
OBn
BnO
BnO
OBn
O
O
O
O
OBn
48b
Tf
Tf
48a
disfavored
O
O
O
O
unstable
O
O
BnO
BnO
OBn
OBn
BnO
BnO
OBn
O
O
O
O
OBn
Tf
Tf
F
E
Scheme 6. Proposed mechanism of production of 37/47a from 36/46a/46b.
Conclusion
6
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10.1002/chem.202002753
Chemistry - A European Journal
FULL PAPER
a yellow amorphous solid. [α]D23 +21 (c 0.81, CHCl3). 1H NMR (400 MHz,
CDCl3, 25 °C) δ 7.40–7.36 (m, 10H, Bn), 6.89 (s, 1H, HHDP), 6.66 (s, 1H,
HHDP), 5.89 (s, 1H, OH), 5.81 (d, J = 4.6 Hz, 1H, H-1), 5.73 (s, 1H, OH),
5.52 (s, 1H, OH), 5.27 (s, 1H, OH), 5.24 (dd, J = 4.1, 2.3 Hz, 1H, H-3),
5.19–5.12 (m, 4H, Bn), 4.88 (dd, J = 8.5, 3.2 Hz, 1H, H-5), 4.69 (dd, J =
12.4, 8.5 Hz, 1H, H-6), 4.55 (dd, J = 4.1, 3.9 Hz, 1H, H-4), 4.54 (ddd, J =
4.6, 3.9, 2.3 Hz, 1H, H-2), 3.96 (dd, J = 12.4, 3.2 Hz, 1H, H-6), 1.66 (s, 3H,
orthoester). 13C NMR (101 MHz, CDCl3, 25 °C) δ 167.8 (s, HHDP), 166.1
(s, HHDP), 149.3 (s, HHDP), 149.2 (s, HHDP), 147.7 (s, HHDP), 147.6 (s,
HHDP), 136.5 (s, HHDP or Bn), 136.4 (s, HHDP or Bn), 136.2 (s, HHDP
or Bn), 135.5 (s, HHDP or Bn), 129.3 (s, HHDP), 129.1 (d, 2C, Bn), 129.0
(d, 2C, Bn), 128.9 (d, 2C, Bn), 128.8 (d, 4C, Bn), 128.4 (s, HHDP), 119.7
(s, orthoester), 113.8 (s, HHDP), 111.9 (s, HHDP), 109.1 (d, HHDP), 109.0
(d, HHDP), 97.2 (d, C-1), 75.7 (t, Bn), 75.5 (t, Bn), 73.5 (d, C-5), 72.8 (d,
C-2), 69.4 (d, C-4), 65.2 (t, C-6), 64.3 (d, C-3), 20.3 (q, orthoester). IR
(ZnSe thin film) 3424, 3033, 1736, 1586, 1499, 1453, 1368, 1235, 1136,
1051, 758, 700 cm-1. HRMS (ESI) m/z [M + Na]+ calcd for C36H30O14Na,
709.1533, found 709.1509.
deuterated solvent as internal reference in the indicated solvent in each
parenthesis. The 1H NMR spectroscopic data are indicated by a chemical
shift (δ), with the multiplicity, the coupling constants, the integration, and
the assignments in parentheses in this order. The multiplicities are
abbreviated as s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, and
br: broad. The 13C NMR spectroscopic data are reported as the chemical
shift (δ), with the hydrogen multiplicity obtained from the DEPT spectra and
the assignments in parentheses. The multiplicities are abbreviated as s: C,
d: CH, t: CH2, and q: CH3. When the number of the carbon was more than
one, the number was added in the parentheses.
Synthesis of 3,6-di-O-(3,5-di-O-allyl-4-O-benzyl)galloyl-1,2,4-O-ortho-
acetyl-α-D-glucopyranose (49): To a stirred solution of 17 (362 mg, 1.77
mmol) in CH2Cl2 (21 mL) and pyridine (14 mL) were added EDCI·HCl (1.09
g, 5.69 mmol), DMAP (382 mg, 3.12 mmol), and 22[9d] (1.71 g, 5.02 mmol)
at rt. After stirring for 9 h at rt, to the mixture was added H2O (100 mL).
The mixture was extracted with CH2Cl2 (40 mL × 3). The combined organic
layer was successively washed with H2O (100 mL) and brine (100 mL).
After the general drying procedure, the residue was purified by column
chromatography (30 g of SiO2, hexane/EtOAc = 7/3) to give 49 (1.49 g,
1.76 mmol, 99% yield) as a white amorphous solid. [α]D25 –6.6 (c 1.55,
CHCl3). 1H NMR (500 MHz, CDCl3, 23 °C) δ 7.48–7.44 (m, 4H, Bn), 7.34–
7.27 (m, 6H, Bn), 7,25 (s, 2H, galloyl), 7.25 (s, 2H, galloyl), 6.03 (ddt, J =
17.2, 10.3, 5.2 Hz, 2H, allyl), 6.02 (ddt, J = 17.2, 10.3, 5.2 Hz, 2H, allyl),
5.83 (br d, J = 4.6 Hz, 1H, H-1), 5.43 (dd, J = 4.6, 1.7 Hz, 1H, H-3), 5.41
(ddt, J = 17.2, 1.7, 1.2 Hz, 2H, allyl), 5.40 (ddt, J = 17.2, 1.7, 1.2 Hz, 2H,
allyl), 5.28 (ddt, J = 10.3, 1.7, 1.2 Hz, 2H, allyl), 5.26 (ddt, J = 10.3, 1.7, 1.2
Hz, 2H, allyl), 5.13 (s, 2H, Bn), 5.12 (s, 2H, Bn), 4.82 (dd, J = 6.9, 6.3 Hz,
1H, H-5), 4.67–4.61 (m, 2H, H-2, H-6), 4.60 (ddd, J = 5.2, 1.7, 1.2 Hz, 4H,
allyl), 4.58 (ddd, J = 5.2, 1.7, 1.2 Hz, 4H, allyl), 4.47 (dd, J = 11.2, 6.9 Hz,
Synthesis of benzylated compound 20: To a stirred solution of 23 (732
mg, 1.07 mmol) in DMF (11 mL) were added K2CO3 (1.55 g, 11.2 mmol)
and BnBr (1.87 g, 10.9 mmol) at rt. After stirring for 10 h at rt, to the mixture
was added H2O (20 mL). The reaction mixture was extracted with EtOAc
(40 mL × 3). The combined organic layer was successively washed with
H2O (40 mL) and brine (40 mL). After the general drying procedure, the
residue was purified by column chromatography (30
g of SiO2,
hexane/EtOAc = 3/1 to 2/1) to give 20 (877 mg, 0.837 mmol, 78% yield)
as a yellow amorphous solid. [α]D24 +34 (c 0.68, CHCl3). 1H NMR (400 MHz,
CDCl3, 23 °C) δ 7.47–7.27 (m, 16H, Bn), 7.25–7.21 (m, 4H, Bn), 7.16–7.08
(m, 7H, Bn, HHDP), 7.02 (s, 1H, HHDP), 6.95–6.90 (m, 4H, Bn), 5.84 (d,
J = 4.8 Hz, 1H, H-1), 5.27 (dd, J = 4.6, 1.8 Hz, 1H, H-3), 5.22 (d, J = 11.7
Hz, 1H, Bn), 5.16 (d, J = 11.5 Hz, 1H, Bn), 5.14 (d, J = 11.7 Hz, 1H, Bn),
5.12 (d, J = 11.5 Hz, 1H, Bn), 5.02 (d, J = 11.0 Hz, 1H, Bn), 5.00 (d, J =
10.4 Hz, 1H, Bn), 4.95 (d, J = 11.0 Hz, 1H, Bn), 4.94 (d, J = 11.5 Hz, 1H,
Bn), 4.92 (d, J = 10.4 Hz, 1H, Bn), 4.90 (d, J = 11.0 Hz, 1H, Bn), 4.86 (dd,
J = 8.2, 2.8 Hz, 1H, H-5), 4.85 (d, J = 11.0 Hz, 1H, Bn), 4.80 (dd, J = 12.4,
8.2 Hz, 1H, H-6), 4.66 (d, J = 11.0 Hz, 1H, Bn), 4.57 (ddd, J = 4.8, 2.1, 1.8
Hz, 1H, H-2), 4.53 (dd, J = 4.6, 2.1 Hz, 1H, H-4), 3.92 (dd, J = 12.4, 2.8
Hz, 1H, H-6), 1.67 (s, 3H, orthoester). 13C NMR (126 MHz, CDCl3, 22 °C)
δ 167.6 (s, HHDP), 165.8 (s, HHDP), 152.4 (s, HHDP), 152.3 (s, HHDP),
152.1 (s, HHDP), 152.1 (s, HHDP), 145.4 (s, HHDP), 144.6 (s, HHDP),
137.9 (s, Bn), 137.5 (s, Bn), 137.4 (s, Bn), 137.1 (s, Bn), 136.5 (s, Bn),
136.4 (s, Bn), 128.6–127.4 (overlapping 30 doublets and 1 singlet: 14
peaks were observed, 31C, Bn, HHDP), 127.3 (s, HHDP), 124.8 (s, HHDP),
123.4 (s, HHDP), 119.6 (s, orthoester), 109.8 (d, HHDP), 109.0 (d, HHDP),
97.1 (d, C-1), 75.4 (t, 2C, Bn), 74.9 (t, Bn), 74.7 (t, Bn), 73.5 (d, C-5), 72.7
(d, C-2), 71.5 (t, Bn), 71.2 (t, Bn), 69.3 (d, C-4), 64.7 (t, C-6), 64.2 (d, C-3),
20.2 (q, orthoester). IR (ATR) 3088, 3064, 3030, 3016, 2951, 2880, 1738,
1591, 1497, 1454, 1433, 1409, 1366, 1215, 1190, 1094, 1055, 746, 696
cm–1. HRMS (ESI) m/z [M + Na]+ calcd for C64H54O14Na 1069.3411, found
1069.3411.
1H, H-6), 4.42 (dd, J = 4.6, 1.7 Hz, 1H, H-4), 1.69 (s, 3H, orthoester). 13
C
NMR (126 MHz, CDCl3, 25 °C) δ 165.7 (s, galloyl), 165.2 (s, galloyl), 152.7
(s, 2C, galloyl), 152.6 (s, 2C, galloyl), 142.8 (s, galloyl), 142.5 (s, galloyl),
137.5 (s, 2C, Bn), 133.1 (d, 2C, allyl), 133.0 (d, 2C, allyl), 128.6 (d, 2C, Bn),
128.6 (d, 2C, Bn), 128.3 (d, 4C, Bn), 128.2 (d, 2C, Bn), 124.5 (s, galloyl),
123.7 (s, galloyl), 119.6 (s, orthoester), 118.0 (t, 2C, allyl), 117.9 (t, 2C,
allyl), 109.1 (d, 2C, galloyl), 109.0 (d, 2C, galloyl), 97.7 (d, C-1), 75.3 (d,
C-5), 75,1 (t, Bn), 75.1 (t, Bn), 72.4 (d, C-2), 71.1 (d, C-4), 70.2 (t, 2C, allyl),
70.1 (t, 2C, allyl), 65.5 (d, C-3), 64.5 (t, C-6), 20.3 (q, orthoester). IR (ATR)
3087, 3017, 2923, 2872, 1717, 1422, 1332, 1200, 1130, 757 cm-1. HRMS
(MALDI) m/z [M + Na]+ calcd for C48H48O14Na 871.2936, found 871.2919.
Synthesis of coupling precursor 18: To a stirred solution of 49 (14.5 g,
17.1 mmol) in CH2Cl2 (170 mL) were added morpholine (7.44 g, 85.4
mmol) and Pd(PPh3)4 (370 mg, 0.320 mmol) at rt. After stirring for 10 h at
rt, to the mixture was added H2O (100 mL). The mixture was extracted with
CH2Cl2 (200 mL × 4). The combined organic layer was successively
washed with H2O (100 mL) and brine (100 mL). After the general drying
procedure, the residue was purified by column chromatography (90 g of
SiO2, hexane/EtOAc = 2/1) to give 18 (10.5 g, 15.2 mmol, 89% yield) as a
24
yellow amorphous solid. [α]D –1.2 (c 0.49, CHCl3). 1H NMR (400 MHz,
Synthesis of diester 24: To a stirred solution of 20 (35.0 mg, 33.4 μmol)
in MeOH (3.0 mL) and THF (1.5 mL) was added NaOMe (18.1 mg, 16.7
μmol) at rt. After stirring for 19 h at 50 °C, to the mixture was added
amberlite IR-120. The reaction mixture was filtered through a cotton pad,
and concentrated. The residue was purified by silica gel chromatography
(13 g of SiO2, hexane/EtOAc = 5/1, then EtOAc/MeOH = 1/1) to give 24
(24.0 mg, 26.5 μmol, 79% yield) as yellow syrup. The NMR spectral data
was identical to the literature data.[22a] The optical rotation was [α]D24 −34
CDCl3, 25 °C) δ 7.39–7.32 (m, 10H, Bn), 7,29 (s, 2H, galloyl), 7.18 (s, 2H,
galloyl), 6.43 (br s, 2H, OH), 5.83 (d, J = 4.6 Hz, 1H, H-1), 5.81 (br s, 2H,
OH), 5.43 (dd, J = 4.6, 1.7 Hz, 1H, H-3), 5.18 (s, 2H, Bn), 5.17 (dd, J =
11.5, 9.2 Hz, 1H, H-6), 5.12 (s, 2H, Bn), 4.91 (dd, J = 9.2, 4.6 Hz, 1 H, H-
5), 4.59 (ddd, J = 4.6, 2.3, 1.7 Hz, 1H, H-2), 4.31 (dd, J = 4.6, 2.3 Hz, 1H,
H-4), 4.21 (dd, J = 11.5, 4.6 Hz, 1H, H-6), 1.69 (s, 3H, orthoester). 13C
NMR (126 MHz, CDCl3, 25 °C) δ 166.9 (s, galloyl), 164.9 (s, galloyl), 149.4
(s, 2C, galloyl), 149.2 (s, 2C, galloyl), 138.2 (s, galloyl), 138.1 (s, galloyl),
136.8 (s, Bn), 136.4 (s, Bn), 129.3 (d, Bn), 129.2 (d, Bn), 129.0 (d, 3C, Bn),
128.8 (d, 2C, Bn), 128.8 (d, 2C, Bn), 125.2 (s, galloyl), 124.2 (s, galloyl),
119.7 (s, orthoester), 110.3 (d, 2C, galloyl), 110.2 (d, 2C, galloyl), 97.8 (d,
C-1), 75.9 (t, Bn), 75.4 (t, Bn), 75.1 (d, C-5), 72.3 (d, C-2), 70.8 (d, C-4),
64.9 (d, C-3), 64.8 (t, C-6), 20.3 (q, orthoester). IR (ATR) 3064, 3014, 2966,
2916, 2870, 1716, 1597, 1521, 1454, 1406, 1300, 1269, 1213, 1198, 800,
748, 696 cm–1. HRMS (ESI) m/z [M – H]– calcd for C36H32O14 687.1714,
found 687.1714.
25
(c 0.75, CHCl3), the sign of which was agreed with the literature data {[α]D
–45 (c 1.00, CHCl3)},[22b] showing that the axial chirality of 24 was R.
Synthesis of β-thioglycoside 27: To a stirred suspension of 20 (876 mg,
0.836 mmol) in BTF (16.8 mL) and Msv 4A (2.50 g) was added PhSH (109
mg, 0.989 mmol) at rt. After stirring for 30 min at rt, InBr3 (88.9 mg, 0.251
mmol) was added to the mixture. After stirring for 9 h at rt, the mixture was
filtered through a Celite pad to remove Msv 4A. 1 M NaOH aq. (30 mL)
was added to the filtrate, then the mixture was extracted with EtOAc (50
mL × 3). The combined organic layer was successively washed with 1 M
NaOH aq. (50 mL), H2O (50 mL), and brine (50 mL). After the general
drying procedure, the residue was purified by column chromatography (15
g of SiO2, hexane/EtOAc = 5/1 to 3/1) to give 27 (942 mg, 0.813 mmol,
97% yield) as a yellow amorphous solid. [α]D24 +7.6 (c 1.00, CHCl3). 1H
NMR (500 MHz, CDCl3, 23 °C) δ 7.52–7.49 (m, 4H, Bn), 7.46–7.30 (m,
15H, Bn), 7.27–7.22 (m, 6H, Bn), 7.16 (s, 1H, HHDP), 7.13–7.07 (m, 6H,
Bn), 7.04 (s, 1H, HHDP), 6.94–6.90 (m, 4H, Bn), 5.42 (d, J = 6.9 Hz, 1H,
H-1), 5.28 (ddd, J = 6.9, 1.7, 1.0 Hz, 1H, H-2), 5.21 (d, J = 11.5 Hz, 1H,
Bn), 5.16 (d, J = 11.5 Hz, 1H, Bn), 5.11 (d, J = 11.5 Hz, 1H, Bn), 5.10 (d,
J = 11.5 Hz, 1H, Bn), 5.02 (d, J = 10.9 Hz, 1H, Bn), 5.01 (d, J = 10.9 Hz,
1H, Bn), 4.98 (d, J = 10.9 Hz, 1H, Bn), 4.97 (d, J = 10.9 Hz, 1H, Bn), 4.95
Synthesis of 3,6-O-(R)-HHDP bridged compound 23: To a stirred
solution of CuCl2 (314 mg, 2.33 mmol) in MeOH (20 mL) was added BuNH2
(703 mg, 9.61 mmol) at rt. After stirring for 1 h at rt, to the mixture was
added a solution of 18 (540 mg, 0.784 mmol) in MeOH (60 mL) via cannula.
After stirring for 1.5 h at rt, Et2O (150 mL), H2O (50 mL), and saturated
NH4Cl aq. (50 mL) were added to the reaction mixture. The aqueous
mixture was extracted with Et2O (100 mL) and EtOAc (100 mL × 2). The
combined organic layer was successively washed with saturated NH4Cl aq.
(100 mL), H2O (50 mL), and brine (50 mL). After the general drying
procedure, the residue was purified by column chromatography (10 g of
SiO2, hexane/EtOAc = 3/1) to give 23 (410 mg, 0.597 mmol, 76% yield) as
7
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10.1002/chem.202002753
Chemistry - A European Journal
FULL PAPER
(d, J = 10.9 Hz, 1H, Bn), 4.90 (d, J = 10.9 Hz, 1H, Bn), 4.84 (dd, J = 3.4,
1.7 Hz, 1H, H-3), 4.82 (d, J = 10.9 Hz, 1H, Bn), 4.71 (d, J = 10.9 Hz, 1H,
Bn), 4.61–4.53 (m, 3H, H-5, H-6, H-6), 4.51 (ddd, J = 6.9, 3.4, 1.0 Hz, 1H,
H-4), 2.56 (d, J = 6.9 Hz, 1H, 4-OH), 2.13 (s, 3H, Ac). 13C NMR (126 MHz,
CDCl3, 23 °C) δ 169.5 (s, Ac), 167.2 (s, HHDP), 166.1 (s, HHDP), 152.6
(s, HHDP), 152.5 (s, HHDP), 152.5 (s, HHDP), 152.1 (s, HHDP), 145.4 (s,
HHDP), 145.0 (s, HHDP), 137.9 (s, Bn), 137.7 (s, Bn), 137.6 (s, Bn), 137.4
(s, Bn), 136.6 (s, 2C, Bn), 133.4 (s, SPh), 132.2 (d, 2C, SPh), 129.2 (d, 2C,
SPh), 128.8–127.6 (overlapping 31 doublets and 1 singlet: 16 peaks were
observed, 32C, SPh, Bn, HHDP), 127.4 (s, HHDP), 124.8 (s, HHDP),
124.0 (s, HHDP), 110.1 (d, HHDP), 109.0 (d, HHDP), 81.9 (d, C-1), 77.6
(d, C-5), 75.5 (t, 2C, Bn), 74.9 (t, Bn), 74.9 (t, Bn), 72.8 (d, C-3), 71.6 (d,
C-2), 71.5 (t, Bn), 71.3 (t, Bn), 64.4 (t, C-6), 62.6 (d, C-4), 21.1 (q, Ac). IR
(ATR) 3618–3322, 3088, 3063, 3030, 2945, 2878, 1738, 1589, 1454, 1365,
1215, 1188, 1093, 908, 746, 694 cm–1. HRMS (ESI) m/z [M + Na]+ calcd
for C70H60O14SNa 1179.3601, found 1179.3599.
92.8 (d, C-1), 75.5 (t, Bn), 75.2 (t, Bn), 75.1 (t, 2C, Bn), 74.4 (t, Bn), 72.3
(d, C-5), 71.4 (t, Bn), 71.3 (t, 2C, Bn), 71.0 (t, Bn), 67.2 (d, C-2), 66.4 (d,
C-3), 63.8 (t, C-6), 62.1 (d, C-4), 21.1 (q, Ac), 21.0 (q, Ac). IR (ATR) 3063,
3030, 2933, 2876, 1745, 1589, 1498, 1454, 1335, 1215, 1093, 1057, 910,
842, 750, 696. HRMS (ESI) m/z [M + Na]+ calcd for C94H80O20Na
1551.5152, found 1551.5141.
Synthesis of diol 21: To a stirred solution of 31 (627 mg, 0.410 mmol) in
MeCN (4.1 mL) was added 1.0 M of hydrazine in THF (1.6 mL, 1.6 mmol)
at rt. After stirring for 14 h at rt, to the mixture was added 1 M hydrochloric
acid (20 mL). The mixture was extracted with EtOAc (80 mL × 3). The
combined organic layer was successively washed with 1 M hydrochloric
acid (30 mL), H2O (30 mL), and brine (30 mL). After the general drying
procedure, the residue was purified by column chromatography (10 g of
SiO2, hexane/EtOAc =7/2 to 3/1) to give 21 (414 mg, 0.286 mmol, 70%
yield) as a yellow amorphous solid. [α]D22 –26 (c 0.75, CHCl3). 1H NMR
(500 MHz, CDCl3, 23 °C) δ 7.45 (d, J = 6.9 Hz, 2H, Bn), 7.41–7.32 (m, 12H,
Bn, galloyl), 7.27–7.04 (m, 29H, Bn), 6.97 (dd, J = 7.6, 1.7 Hz, 2H, Bn),
6.94 (s, 1H, HHDP), 6.74 (s, 1H, HHDP), 6.74 (dd, J = 7.2, 1.7 Hz, 2H, Bn),
6.53 (s, 1H, H-1), 5.19 (dd, J = 11.5, 11.2 Hz, 1H, H-6), 5.17 (d, J = 11.5
Hz, 1H, Bn), 5.09 (d, J = 11.5 Hz, 1H, Bn), 5.03 (d, J = 11.5 Hz, 1H, Bn),
4.98 (br s, 1H, H-3), 4.97 (d, J = 10.9 Hz, 2H, Bn), 4.96 (d, J = 10.9 Hz,
1H, Bn), 4.95 (d, J = 11.5 Hz, 1H, Bn), 4.93 (d, J = 10.9 Hz, 1H, Bn), 4.89
(d, J = 11.5 Hz, 1H, Bn), 4.87 (d, J = 10.9 Hz, 3H, Bn), 4.74 (d, J = 11.5
Hz, 1H, Bn), 4.73 (d, J = 10.9 Hz, 1H, Bn), 4.72–4.68 (m, 2H, H-4, 2-OH),
4.48 (d, J = 11.5 Hz, 1H, Bn), 4.42 (dd, J = 11.2, 8.0 Hz, 1H, H-6), 4.36 (d,
J = 10.9 Hz, 1H, Bn), 4.36 (dd, J = 11.5, 8.0 Hz, 1H, H-5), 4.35 (d, J = 10.9
Hz, 1H, Bn), 4.19 (br d, J = 6.9 Hz, 1H, H-2), 4.73 (d, J = 11.5 Hz, 1H, Bn),
3.68 (br d, J = 7.5 Hz, 1H, 4-OH). 13C NMR (126 MHz, CDCl3, 23 °C) δ
167.7 (s, HHDP), 165.9 (s, HHDP), 165.2 (s, galloyl), 153.1 (s, 2C, galloyl),
152.9 (s, HHDP), 152.5 (s, HHDP), 152.4 (s, HHDP), 152.3 (s, HHDP),
145.4 (s, HHDP), 144.5 (s, HHDP), 143.5 (s, galloyl), 137.9 (s, Bn), 137.9
(s, Bn), 137.7 (s, Bn), 137.6 (s, Bn), 137.5 (s, Bn), 136.7 (s, 2C, Bn), 136.5
(s, Bn), 136.1 (s, Bn), 129.1 (s, HHDP), 128.7–127.2 (overlapping 45
doublets: 17 peaks were observed, 45C, Bn), 126.8 (s, HHDP), 125.4 (s,
HHDP), 123.7 (s, galloyl), 123.4 (s, HHDP), 109.4 (d, HHDP), 108.8 (d, 2C,
galloyl), 107.5 (d, HHDP), 96.5 (d, C-1), 75.7 (t, Bn), 75.2 (t, Bn), 75.1 (t,
2C, Bn), 74.5 (d, C-5), 74.4 (t, Bn), 71.4 (t, Bn), 71.2 (t, 2C, Bn), 70.5 (t,
Bn), 68.3 (d, C-3), 67.0 (d, C-2), 64.0 (t, C-6), 61.3 (d, C-4). IR (ATR) 3600–
3000, 3032, 2943, 2932, 1738, 1709, 1589, 1499, 1454, 1213, 1192, 1097,
1022, 734, 696 cm–1. HRMS (ESI) m/z [M + Na]+ calcd for C90H76O18Na
1467.4929, found 1467.4926.
Synthesis of acetylated compound 28: To a stirred solution of 27 (136
mg, 0.118 mmol) in pyridine (0.8 mL) was added Ac2O (0.4 mL) at rt. After
stirring for 4 h at rt, to the mixture was added 1 M hydrochloric acid (15
mL). The mixture was extracted with EtOAc (20 mL × 3). The combined
organic layer was successively washed with 1 M hydrochloric acid (20 mL),
H2O (20 mL), and brine (20 mL). After the general drying procedure, the
residue was purified by column chromatography (10
g of SiO2,
hexane/EtOAc =7/3) to give 28 (141 mg, 0.118 mmol, 100% yield) as a
24
yellow amorphous solid. [α]D +8.1 (c 0.84, CHCl3). 1H NMR (500 MHz,
CDCl3, 24 °C) δ 7.52 (d, J = 7.5 Hz, 4H, Bn), 7.48–7.31 (m, 16H, Bn), 7.29–
7.20 (m, 5H, Bn), 7.15 (s, 1H, HHDP), 7.14 (s, 1H, HHDP), 7.12–7.08 (m,
6H, Bn), 6.92–6.90 (m, 4H, Bn), 5.51 (d, J = 3.4 Hz, 1H, H-4), 5.23 (d, J =
9.2 Hz, 1H, H-2), 5.21 (d, J = 10.9 Hz, 1H, Bn), 5.17 (d, J = 11.5 Hz, 1H,
Bn), 5.11 (d, J = 11.5 Hz, 1H, Bn), 5.09 (d, J = 10.9 Hz, 1H, Bn), 5.06 (d,
J = 9.2 Hz, 1H, H-1), 5.01 (d, J = 10.9 Hz, 2H, Bn), 4.97 (d, J = 10.9 Hz,
1H, Bn), 4.97 (d, J = 3.4 Hz, 1H, H-3), 4.96 (d, J = 10.9 Hz, 1H, Bn), 4.92
(d, J = 10.9 Hz, 1H, Bn), 4.90 (d, J = 10.9 Hz, 1H, Bn), 4.80 (d, J = 10.9
Hz, 1H, Bn), 4.72 (dd, J = 10.9, 5.2 Hz, 1H, H-6), 4.69 (d, J = 10.9 Hz, 1H,
Bn), 4.40 (ddd, J = 5.2, 4.6 Hz, 1H, H-5), 4.36 (dd, J = 10.9, 4.6 Hz, 1H, H-
6), 2.14 (s, 3H, Ac), 2.10 (s, 3H, Ac). 13C NMR (126 MHz, CDCl3, 24 °C) δ
169.4 (s, Ac), 169.3 (s, Ac), 167.4 (s, HHDP), 165.3 (s, HHDP), 152.5 (s,
HHDP), 152.4 (s, HHDP), 152.2 (s, HHDP), 152.0 (s, HHDP), 145.4 (s,
HHDP), 145.0 (s, HHDP), 137.9 (s, Bn), 137.6 (s, Bn), 137.6 (s, Bn), 137.3
(s, Bn), 136.6 (s, Bn), 136.5 (s, Bn), 132.6 (s, SPh), 132.4 (d, 2C, SPh),
129.1 (d, 2C, SPh), 128.7–127.3 (overlapping 30 doublets and 2 singlets:
18 peaks were observed, 32C, Bn, HHDP), 124.6 (s, HHDP), 123.6 (s,
HHDP), 110.2 (d, HHDP), 109.7 (d, HHDP), 81.9 (d, C-1), 77.4 (d, C-5),
75.5 (t, Bn), 75.4 (t, Bn), 74.9 (t, Bn), 74.8 (t, Bn), 71.6 (t, Bn), 71.2 (t, Bn),
71.0 (d, C-2), 70.8 (d, C-3), 65.2 (t, C-6), 64.7 (d, C-4), 20.9 (q, 2C, Ac).
IR (ATR) 3064, 3030, 3016, 2943, 2878, 1742, 1589, 1454, 1368, 1215,
1096, 1028, 746, 694, 667 cm–1. HRMS (ESI) m/z [M + Na]+ calcd for
C72H62O15SNa 1221.3707, found 1221.3711.
Synthesis of corilagin (2): A mixture of 21 (106 mg, 73.4 μmol) and
Pd(OH)2/C (20 wt. %, 58.9 mg, 39.0 μmol) in THF (2.0 mL) and methanol
(2.0 mL) was stirred under H2 atmosphere at rt. After stirring for 15 h at rt,
the mixture was filtered through a cotton-Celite pad to remove the catalyst.
After the filtrate was concentrated, the residue was purified by column
chromatography (5 g of Sephadex G-25, CHCl3/MeOH = 6/1) to give 2
(46.4 mg, 73.1 μmol, 100% yield). The 1H and 13C NMR spectral data were
in agreement with that of our previously synthesized 2.[17] Please see SI-
S-7 for details. 1H NMR (400 MHz, acetone-d6, 24 °C) δ 8.02–7.41 (br s,
9H, OH), 7.14 (s, 2H, galloyl), 6.86 (s, 1H, HHDP), 6.70 (s, 1H, HHDP),
6.38 (s, 1H, H-1), 5.14 (br s, 2H, OH), 4.96 (dd, J = 11.0, 10.8 Hz, 1H, H-
6), 4.84 (br s, 1H, H-3), 4.53 (br dd, J = 10.8, 8.9 Hz, 1H, H-5), 4.47 (br s,
1H, H-4), 4.11 (dd, J = 11.0, 8.9 Hz, 1H, H-6), 4.10 (br s, 1H, H-2). 13C
NMR (101 MHz, acetone-d6, 24 °C) δ 168.5 (s, HHDP), 167.2 (s, HHDP),
165.1 (s, galloyl), 145.9 (s, 2C, galloyl), 145.4 (s, HHDP), 145.0 (s, HHDP),
144.9 (s, HHDP), 144.8 (s, HHDP), 139.2 (s, galloyl), 137.1 (s, HHDP),
136.6 (s, HHDP), 125.8 (s, HHDP), 125.5 (s, HHDP), 120.8 (s, galloyl),
116.4 (s, HHDP), 115.9 (s, HHDP), 110.9 (d, 2C, galloyl), 110.0 (d, HHDP),
108.1 (d, HHDP), 94.1 (d, C-1), 75.6 (d, C-5), 70.5 (d, C-3), 68.9 (d, C-2),
64.3 (t, C-6), 62.2 (d, C-4). HRMS (ESI) m/z [M + Na]+ calcd for
C27H22O18Na 657.0701, found 657.0704.
Synthesis of galloyl ester 31: To a stirred suspension of 28 (601 mg,
0.501 mmol) in CH2Cl2 (25.0 mL) and Msv 4A (1.0 g) was added 3,4,5-
tris(benzyloxy)benzoic acid (29) (338 mg, 0.768 mmol) at 2 ºC. After
stirring for 30 min at 2 ºC, NIS (228 mg, 1.01 mmol) and TfOH (102 mg,
0.680 mmol) were added to the mixture. After stirring for additional 40 min
at rt, to the mixture was added 10% Na2S2O3 aq. (100 mL). The reaction
mixture was extracted with CH2Cl2 (100 mL × 3). The combined organic
layer was successively washed with H2O (100 mL) and brine (100 mL).
After the general drying procedure, the mixture was dissolved in EtOAc,
then the solution was filtered through a SiO2 on cotton pad. After the filtrate
was evaporated, the residue was purified by GPC (1.4 MPa, 3 cycles, 50
min for 1 cycle) to give 31 (627 mg, 0.410 mmol, 82% yield) as a yellow
20
amorphous solid. [α]D –27 (c 1.20, CHCl3). 1H NMR (500 MHz, CDCl3,
23 °C) δ 7.48 (d, J = 7.5 Hz, 2H, Bn), 7.42–7.33 (m, 13H, Bn, galloyl),
7.29–7.15 (m, 21H, Bn), 7.11–7.06 (m, 8H, Bn, HHDP), 6.97 (br dd, J =
6.9, 2.3 Hz, 2H, Bn), 6.92 (s, 1H, HHDP), 6.78 (d, J = 6.9 Hz, 2H, Bn), 6.49
(br s, 1H, H-1), 5.65 (br d, J = 1.7 Hz, 1H, H-4), 5.29 (br s, 1H, H-2), 5.20
(d, J = 11.5 Hz, 1H, Bn), 5.16 (dd, J = 10.9, 10.3 Hz, 1H, H-6), 5.12 (d, J =
11.5 Hz, 1H, Bn), 4.98 (d, J = 10.9 Hz, 1H, Bn), 5.02 (d, J = 1.7 Hz, 1H, H-
3), 5.00 (d, J = 11.5 Hz, 2H, Bn), 4.96–4.90 (m, 5H, Bn), 4.84 (d, J = 11.5
Hz, 1H, Bn), 4.79 (d, J = 11.5 Hz, 1H, Bn), 4.77–4.72 (m, 3H, Bn, H-5),
4.46 (dd, J = 10.9, 5.7 Hz, 1H, H-6), 4.45 (d, J = 10.9 Hz, 1H, Bn), 4.40 (d,
J = 10.9 Hz, 1H, Bn), 4.36 (d, J = 10.9 Hz, 1H, Bn), 2.20 (s, 3H, Ac), 2.16
(s, 3H, Ac). 13C NMR (101 MHz, CDCl3, 23 °C) δ 169.3 (s, 2C, Ac), 167.5
(s, HHDP), 165.3 (s, HHDP), 164.6 (s, galloyl), 153.0 (s, 3C, galloyl,
HHDP), 152.5 (s, 2C, HHDP), 152.3 (s, HHDP), 145.4 (s, HHDP), 144.8
(s, HHDP), 143.6 (s, galloyl), 138.0 (s, Bn), 137.9 (s, Bn), 137.7 (s, 2C,
Bn), 137.5 (s, Bn), 136.7 (s, 2C, Bn), 136.7 (s, Bn), 136.2 (s, Bn), 128.7–
127.4 (overlapping 45 doublets and 1 singlet : 17 peaks were observed,
46C, Bn, HHDP), 126.9 (s, HHDP), 125.4 (s, HHDP), 123.6 (s, HHDP),
123.5 (s, galloyl), 109.4 (d, HHDP), 109.0 (d, 2C, galloyl), 108.1 (d, HHDP),
Synthesis of tetra-acetylated compound 32: To a stirred solution of
33[17] (600 mg, 1.08 mmol) in pyridine (10 mL) was added Ac2O (4 mL).
After stirring for 15 min at rt, 1 M hydrochloric acid (20 mL) was added to
the mixture. The aqueous mixture was extracted with EtOAc (20 mL × 3).
The combined organic layer was successively washed with
1 M
hydrochloric acid (10 mL), H2O (10 mL), and brine (10 mL). After the
general drying procedure, the residue was purified by column
chromatography (28 g of SiO2, hexane/EtOAc = 10/1 to 0/1) to give 32
(752 mg, 1.02 mmol, 94% yield) as a colorless syrup. 1H NMR (400 MHz,
CDCl3, 24 °C) δ 7.43 (s, 2H, HHDP), 7.42–7.30 (m, 10H, Bn), 5.11 (d, J =
11.5 Hz, 2H, Bn), 4.98 (d, J = 11.5 Hz, 2H, Bn), 4.46–4.37 (m, 2H, butane
linker), 4.23–4.13 (m, 2H, butane linker), 2.19 (s, 6H, Ac), 1.99–1.91 (m,
2H, butane linker), 1.90 (s, 6H, Ac), 1.80–1.72 (m, 2H, butane linker). 13
C
NMR (101 MHz, CDCl3, 24 °C) δ 168.3 (s, 2C, Ac), 167.6 (s, 2C, Ac), 165.8
(s, 2C, HHDP), 146.0 (s, 2C, HHDP), 143.7 (s, 2C, HHDP), 143.4 (s, 2C,
HHDP), 136.9 (s, 2C, Bn), 129.0 (s, 2C, HHDP), 128.6 (d, 4C, Bn), 128.3
8
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10.1002/chem.202002753
Chemistry - A European Journal
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(d, 2C, Bn), 127.7 (d, 4C, Bn), 126.7 (s, 2C, HHDP), 121.5 (d, 2C, HHDP),
75.6 (t, 2C, Bn), 65.7 (t, 2C, butane linker), 25.9 (t, 2C, butane linker), 20.8
(q, 2C, Ac), 20.2 (q, 2C, Ac). IR (ATR) 3065, 3032, 2982, 2954, 2911, 1775,
1737, 1606, 1569, 1410, 1371, 1286, 1241, 1184, 1049, 1013, 974, 859,
786, 700 cm–1.HRMS (ESI) m/z [M + Na]+ calcd for C40H36O14Na 763.2003,
found 763.1982.
1084, 914, 792, 734 cm–1. HRMS (ESI) m/z [M + Na]+ calcd for
C47H39F3O12SNa 907.2012, found 907.2002. *The CF3 signal was not
detected.
Synthesis of dibenzofuran 37: Method A: To a stirred suspension of 36
(20.0 mg, 22.6 μmol) and Cs2CO3 (14.7 mg, 45.1 μmol) in MeCN (1 mL)
was added Pd(PPh3)4 (0.2 mg, 0.2 μmol) at rt. After stirring for 8 h at 100 °C,
the reaction mixture was then diluted with Et2O (5 mL) and filtered through
a cotton-Celite pad to remove Pd catalyst and Cs salt. The filtrate was
concentrated under reduced pressure. The residue was purified by column
chromatography (2 g of SiO2, hexane/EtOAc = 4/1) to give 37 (20.0 mg,
22.4 μmol, 99%) as a white solid. Method B: A mixture of 36 (20.0 mg, 22.6
μmol) and Cs2CO3 (14.7 mg, 45.1 μmol) in DMF (1 mL) was stirred for 20
h at 100 °C. The reaction mixture was diluted with Et2O (5 mL) and filtered
through a cotton-Celite pad to remove Cs salt. After H2O (5 mL) was added
to the filtrate, the aqueous mixture was extracted with EtOAc (10 mL × 3).
The combined organic layer was successively washed with H2O (10 mL ×
2) and brine (10 mL). The general drying procedure afforded 37 (20.0 mg,
22.4 μmol, 99% yield) as a white solid. mp 121–122 °C. 1H NMR (400 MHz,
CDCl3, 25 °C) δ 7.51–7.45 (m, 8H, Bn), 7.44 (s, 2H, THDBF), 7.42–7.28
(m, 12H, Bn), 5.39 (s, 4H, Bn), 5.21 (s, 4H, Bn), 4.48 (m, 4H, butane linker),
2.08 (m, 4H, butane linker). 13C NMR (101 MHz, CDCl3, 22 °C) δ 168.3 (s,
2C, THDBF), 150.4 (s, 2C, THDBF), 150.1 (s, 2C, THDBF), 137.2 (s, 2C,
THDBF), 136.6 (s, 2C, Bn), 136.5 (s, 2C, Bn), 128.8 (d, 4C, Bn), 128.6 (d,
4C, Bn), 128.4 (d, 4C, Bn), 128.4 (d, 2C, Bn), 128.3 (d, 2C, Bn), 127.8 (d,
4C, Bn), 122.1 (s, 2C, THDBF), 117.4 (s, 2C, THDBF), 112.9 (d, 2C,
THDBF), 75.5 (t, 2C, Bn), 72.3 (t, 2C, Bn), 65.6 (t, 2C, butane linker), 26.9
(t, 2C, butane linker). IR (ATR) 3088, 3066, 3029, 2966, 2928, 1779, 1735,
1707, 1635, 1541, 1455, 1320, 1285, 1093, 1028, 983, 778 cm–1. HRMS
(ESI) m/z [M + Na]+ calcd for C46H38O9Na 757.2414, found 757.2404.
Synthesis of diacetate 34: A mixture of K2CO3 (305 mg, 2.21 mmol) and
32 (711 mg, 0.961 mmol) in MeOH (10 mL) was stirred for 30 min at rt.
After 1 M hydrochloric acid (20 mL) was added to the stirred mixture, the
aqueous mixture was extracted with EtOAc (30 mL × 3). The combined
organic layer was successively washed with 1 M hydrochloric acid (30 mL),
H2O (30 mL), and brine (30 mL). After the general drying procedure, the
residue was purified by column chromatography (23
g of SiO2,
hexane/EtOAc = 5/1 to 1/1) to give diol. To a stirred solution of the obtained
product in a mixture of DMF and toluene (v/v = 5/1, 10 mL) were added
K2CO3 (389 mg, 2.35 mmol), KI (10.0 mg, 60.2 μmol), and BnBr (402 mg,
2.35 mmol) at rt. The mixture was stirred at 60 °C for 3 h. After cooling to
rt, to the mixture was added 1 M hydrochloric acid (10 mL). The aqueous
mixture was extracted with EtOAc (40 mL × 2). The combined organic layer
was successively washed with 1 M hydrochloric acid (40 mL), H2O (40 mL),
and brine (40 mL). After the general drying procedure, the residue was
purified by recrystallization from EtOAc/hexane to give 34 (576 mg, 0.689
mmol, 72% yield in 2 steps) as a white solid. mp 205.1–206.2 °C. 1H NMR
(400 MHz, CDCl3, 23 °C) δ 7.49–7.27 (m, 20H, Bn), 7.23 (s, 2H, HHDP),
5.20 (d, J = 11.1 Hz, 4H, Bn), 5.13 (d, J = 11.1 Hz, 2H, Bn), 5.03 (d, J =
11.1 Hz, 2H, Bn), 4.50–4.42 (m, 2H, butane linker), 4.16–4.09 (m, 2H,
butane linker), 2.03–1.95 (m, 2H, butane linker), 1.89 (s, 6H, Ac), 1.83–
1.76 (m, 2H, butane linker). 13C NMR (101 MHz, CDCl3, 23 °C) δ 168.0 (s,
2C, Ac), 166.9 (s, 2C, HHDP), 151.8 (s, 2C, HHDP), 143.4 (s, 2C, HHDP),
142.8 (s, 2C, HHDP), 137.5 (s, 2C, Bn), 136.3 (s, 2C, Bn), 129.1 (s, 2C,
HHDP), 128.8 (d, 4C, Bn), 128.5 (d, 4C, Bn), 128.4 (d, 2C, Bn), 128.3 (d,
4C, Bn), 128.1 (d, 2C, Bn), 127.9 (d, 4C, Bn), 121.8 (s, 2C, HHDP), 111.5
(d, 2C, HHDP), 74.8 (t, 2C, Bn), 71.3 (t, 2C, Bn), 65.6 (t, 2C, butane linker),
26.1 (t, 2C, butane linker), 20.5 (q, 2C, Ac). IR (ATR) 3065, 3032, 2937,
2873, 1734, 1605, 1577, 1455, 1417, 1357, 1196, 1139, 1084, 1069, 914,
820, 793 cm–1. HRMS (ESI) m/z [M + Na]+ calcd for C50H44O12Na 859.2730,
found 859.2760.
Synthesis of dicarboxylic acid 38: To a solution of 37 (11.3 mg, 15.4
μmol) in DMSO (0.75 mL) was added 3 M LiOH aq. (0.25 mL) at rt. After
stirred at 90 °C for 19 h, the mixture was cooled to rt, and 1 M hydrochloric
acid (5 mL) was added to the mixture. The aqueous mixture was extracted
with EtOAc (10 mL × 3). The combined organic layer was successively
washed with H2O (10 mL × 4) and brine (10 mL). After the general drying
procedure, the residue was purified by trituration with acetone to give 38
(10.4 mg, 15.4 μmol, 100% yield) as a white solid. mp 275.0–275.5 °C. 1H
NMR (500 MHz, DMSO-d6, 25 °C) δ 12.9 (br s, 2H, CO2H), 7.52–7.46 (m,
8H, Bn), 7.45–7.40 (m, 6H, Bn, THDBF), 7.38–7.30 (m, 8H, Bn), 5.37 (s,
4H, Bn), 5.30 (s, 4H, Bn). 13C NMR (126 MHz, DMSO-d6, 26 °C) δ 168.5
(s, 2C, THDBF), 150.0 (s, 2C, THDBF), 149.8 (s, 2C, THDBF), 137.5 (s,
2C, Bn), 137.3 (s, 2C, Bn), 135.4 (s, 2C, THDBF), 129.0 (d, 4C, Bn), 128.9
(d, 4C, Bn), 128.8 (d, 2C, Bn), 128.7 (d, 4C, Bn), 128.6 (d, 2C, Bn), 128.2
(d, 4C, Bn), 124.1 (s, 2C, THDBF), 117.4 (s, 2C, THDBF), 112.5 (d, 2C,
THDBF), 75.2 (t, 2C, Bn), 71.6 (t, 2C, Bn). IR (ATR) 3504, 3065, 3031,
2942, 1733, 1603, 1417, 1333, 1197, 1084, 981, 735, 696 cm–1. HRMS
(unanalyzable due to impossibility of ionization).
Synthesis of diol 35: To a stirred mixture of 34 (550 mg, 0.657 mmol) in
CH2Cl2 (6.5 mL) was added N2H4·H2O (132 mg, 2.63 mmol). After stirring
for 20 min at rt, the mixture was concentrated under reduced pressure.
The residue was diluted with EtOAc (40 mL), and the organic solution was
successively washed with H2O (20 mL) and brine (20 mL). After the
general drying procedure, the residue was purified by recrystallization from
acetone/hexane to give 35 (477 mg, 0.634 mmol, 96% yield) as a white
solid. mp 87.2–88.0 °C. 1H NMR (400 MHz, CDCl3, 23 °C) δ 7.48–7.28 (m,
20H, Bn), 6.91 (s, 2H, HHDP), 5.8 (s, 2H, OH), 5.2 (d, J = 11.0 Hz, 4H,
Bn), 5.12 (d, J = 11.0 Hz, 2H, Bn), 5.12 (d, J = 11.0 Hz, 2H, Bn), 4.41–4.48
(m, 2H, butane linker), 4.15–4.08 (m, 2H, butane linker), 2.04–1.93 (m, 2H,
butane linker), 1.88–1.76 (m, 2H, butane linker). 13C NMR (101 MHz,
CDCl3, 23 °C) δ 167.8 (s, 2C, HHDP), 150.7 (s, 2C, HHDP), 148.3 (s, 2C,
HHDP), 137.1 (s, 2C, Bn), 136.9 (s, 2C, HHDP), 136.6 (s, 2C, HHDP),
129.3 (s, 2C, HHDP), 128.8 (d, 4C, Bn), 128.7 (d, 4C, Bn), 128.6 (d, 4C,
Bn), 128.5 (d, 2C, Bn), 128.3 (d, 2C, Bn), 127.8 (d, 4C, Bn), 115.4 (s, 2C,
HHDP), 105.5 (d, 2C, HHDP), 75.6 (t, 2C, Bn), 71.0 (t, 2C, Bn), 65.4 (t, 2C,
butane linker), 26.2 (t, 2C, butane linker). IR (ATR) 3509, 3065, 3032, 2945,
2871, 1733, 1716, 1603, 1577, 1454, 1334, 1217, 1196, 1087, 911, 739,
695 cm–1. HRMS (ESI) m/z [M + Na]+ calcd for C46H40O10Na 775.2519,
found 775.2506.
Synthesis of OcBn-protected compound 40: To a stirred solution of 32
(1.07 g, 1.44 mmol) in MeOH (16.0 mL) was added K2CO3 (790 mg, 5.72
mmol) at rt. After stirring for 20 min at rt, to the mixture was added 1 M
hydrochloric acid (15 mL). The mixture was extracted with EtOAc (40 mL
× 3). The combined organic layer was successively washed with H2O (40
mL) and brine (40 mL). The general drying procedure gave diol. To a
stirred solution of the crude product in DMF (25.0 mL) and toluene (3.0
mL) were added K2CO3 (597 mg, 4.34 mmol) and OcBnBr[26] (1.22 g, 4.31
mmol) at rt. After stirring for 2 h at rt, to the mixture was added 1 M
hydrochloric acid (50 mL). The reaction mixture was extracted with EtOAc
(50 mL × 3). The combined organic layer was successively washed with
H2O (50 mL) and brine (50 mL). After the general drying procedure, the
Synthesis of triflate 36: To a stirred solution of 35 (1.29 g, 1.71 mmol) in
CH2Cl2 (120 mL) were added Et3N (223 mg, 2.20 mmol) and Tf2O (621 mg,
2.20 mmol) at 0 °C. After stirring for 20 min at 0 °C, to the mixture was
added 1 M hydrochloric acid (100 mL). The aqueous mixture was extracted
with EtOAc (150 mL × 3). The combined organic layer was successively
washed with H2O (100 mL) and brine (100 mL). After the general drying
procedure, the residue was purified by recrystallization from acetone/
hexane to give 36 (1.47 g, 1.66 mmol, 97% yield) as a white solid. mp
100.3–101.5 °C: 1H NMR (400 MHz, CDCl3, 26 °C) δ 7.52–7.27 (m, 21H,
Bn, HHDP), 7.01 (s, 1H, HHDP), 5.88 (s, 1H, OH), 5.33–5.06 (m, 8H, Bn),
4.50–4.40 (m, 2H, butane linker), 4.20–4.11 (m, 2H, butane linker), 2.03–
1.95 (m, 2H, butane linker), 1.84–1.76 (m, 2H, butane linker). 13C NMR*
(101 MHz, CDCl3, 24 °C) δ 166.8 (s, 2C, HHDP), 151.7 (s, HHDP), 150.9
(s, HHDP), 150.7 (s, HHDP), 148.1 (s, HHDP), 142.4 (s, HHDP), 142.1 (s,
2C, Bn), 137.3 (s, Bn), 137.0 (s, Bn), 136.3 (s, 1H, HHDP), 135.8 (s, 1H,
HHDP), 129.3 (s, HHDP), 129.3–127.8 (overlapping 20 doublets: 14 peaks
were observed, Bn), 122.3 (s, HHDP), 113.3 (s, HHDP), 112.7 (d, HHDP),
106.2 (d, HHDP), 75.9 (t, Bn), 75.4 (t, Bn), 71.6 (t, Bn), 71.1 (t, Bn), 65.9
(t, butane linker), 65.5 (t, butane linker), 25.9 (t, 2C, butane linker). IR
(ATR) 3522, 3066, 3033, 2942, 2867, 1735, 1605, 1578, 1454, 1334, 1197,
residue was purified by column chromatography (10
g of SiO2,
hexane/EtOAc = 6/1) to give 40 (1.32 g, 1.24 mmol, 86% yield in 2 steps)
as a yellow amorphous solid. 1H NMR (500 MHz, CDCl3, 24 °C) δ 7.37 (d,
J = 8.0 Hz, 4H, OcBn), 7.32 (dd, J = 7.7, 2.3 Hz, 4H, Bn), 7.33–7.25 (m,
6H, Bn), 7.23 (s, 2H, HHDP), 7.20 (d, J = 8.0 Hz, 4H, OcBn), 5.21 (d, J =
10.9 Hz, 2H, Bn), 5.15 (d, J = 11.5 Hz, 2H, OcBn), 5.09 (d, J = 11.5 Hz,
2H, OcBn), 5.03 (d, J = 10.9 Hz, 2H, Bn), 4.45 (br dd, J = 11.5, 7.5 Hz, 2H,
butane linker), 4.11 (br dd, J = 11.5, 5.2 Hz, 2H, butane linker), 2.62 (t, J =
7.5 Hz, 4H, OcBn), 1.96 (m, 2H, butane linker), 1.89 (s, 6H, Ac), 1.79 (m,
2H, butane linker), 1.66 (quintet, J = 7.5 Hz, 4H, OcBn), 1.38–1.24 (m, 20H,
OcBn), 0.88 (t, J = 6.8 Hz, 6H, OcBn). 13C NMR (126 MHz, CDCl3, 24 °C)
δ 167.9 (s, 2C, Ac), 166.8 (s, 2C, HHDP), 151.7 (s, 2C, HHDP), 143.3 (s,
2C, OcBn), 143.2 (s, 2C, HHDP), 142.7 (s, 2C, HHDP), 137.5 (s, 2C, Bn),
133.4 (s, 2C, OcBn), 129.0 (s, 2C, HHDP), 128.7 (d, 4C, OcBn), 128.3 (d,
6C, Bn), 128.3 (d, 4C, Bn), 128.0 (d, 4C, OcBn), 121.6 (s, 2C, HHDP),
111.4 (d, 2C, HHDP), 74.7 (t, 2C, Bn), 71.2 (t, 2C, OcBn), 65.5 (t, 2C,
butane linker), 35.8 (t, 2C, OcBn), 32.0 (t, 2C, OcBn), 31.6 (t, 2C, OcBn),
29.6 (t, 2C, OcBn), 29.4 (t, 2C, OcBn), 29.3 (t, 2C, OcBn), 26.0 (t, 2C,
butane linker), 22.7 (t, 2C, OcBn), 20.4 (q, 2C, Ac), 14.2 (q, 2C, OcBn). IR
9
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10.1002/chem.202002753
Chemistry - A European Journal
FULL PAPER
(ATR) 3032, 3030, 2953, 2924, 2855, 1773, 1734, 1601, 1487, 1454, 1412,
1366, 1323, 1192, 1082, 858, 810, 750 cm–1. HRMS (ESI) m/z [M + Na]+
calcd for C66H76O12Na 1083.5234, found 1083.5230.
CO2H), 150.4 (s, 2C, THDBF), 150.3 (s, 2C, THDBF), 143.3 (s, 2C, OcBn),
137.4 (s, 2C, THDBF), 137.2 (s, 2C, Bn), 133.6 (s, 2C, OcBn), 128.8 (d,
4C, OcBn), 128.6 (d, 4C, Bn), 128.4 (d, 6C, Bn), 127.9 (d, 4C, OcBn),
121.0 (s, 2C, THDBF), 117.7 (d, 2C, THDBF), 112.4 (s, 2C, THDBF), 75.5
(t, 2C, Bn), 72.5 (t, 2C, OcBn), 35.9 (t, 2C, OcBn), 32.0 (t, 2C, OcBn), 31.6
(t, 2C, OcBn), 29.6 (t, 2C, OcBn), 29.5 (t, 2C, OcBn), 29.4 (t, 2C, OcBn),
22.8 (t, 2C, OcBn), 14.3 (q, 2C, OcBn). IR (ATR) 3300–2800, 3063, 3030,
2954, 2853, 2629, 1701, 1626, 1597, 1454, 1261, 1179, 1111, 864, 814,
696 cm–1. HRMS (FAB) m/z [M]+ calcd for C58H64O9 904.4550, found
904.4559.
Synthesis of diol 41: To a stirred solution of 40 (1.65 g, 1.55 mmol) in
MeCN (31.0 mL) was added N2H4·H2O (340 mg, 6.79 mmol) at rt. After
stirring for 30 min at rt, to the mixture was added 1 M hydrochloric acid (60
mL). The mixture was extracted with EtOAc (100 mL × 3). The combined
organic layer was successively washed with 1 M hydrochloric acid (60 mL),
H2O (60 mL), and brine (60 mL). After the general drying procedure, the
residue was purified by column chromatography (20
g of SiO2,
hexane/EtOAc = 3/1) to give 41 (1.52 g, 1.55 mmol 100% yield) as a white
amorphous solid. 1H NMR (500 MHz, CDCl3, 24 °C) δ 7.35 (d, J = 8.0 Hz,
4H, OcBn), 7.33 (dd, J = 6.0, 2.9 Hz, 4H, Bn), 7.30–7.26 (m, 6H, Bn), 7.19
(d, J = 8.0 Hz, 4H, OcBn), 6.90 (s, 2H, HHDP), 5.87 (br s, 2H, OH), 5.17
(d, J = 11.5 Hz, 2H, Bn), 5.11 (d, J = 10.9 Hz, 2H, OcBn), 5.09 (d, J = 11.5
Hz, 2H, Bn), 5.04 (d, J = 10.9 Hz, 2H, OcBn), 4.43 (br dd, J = 9.7, 9.5 Hz,
2H, butane linker), 4.08 (br dd, J = 9.7, 4.0 Hz, 2H, butane linker), 2.62 (t,
J = 7.7 Hz, 4H, OcBn), 1.94 (m, 2H, butane linker), 1.78 (m, 2H, butane
linker), 1.61 (quintet, J = 7.7 Hz, 4H, OcBn), 1.38–1.22 (m, 20 H, OcBn),
0.87 (t, J = 7.5 Hz, 6H, OcBn). 13C NMR (126 MHz, CDCl3, 24 °C) δ 167.7
(s, 2C, HHDP), 150.7 (s, 2C, HHDP), 148.2 (s, 2C, HHDP), 143.0 (s, 2C,
OcBn), 137.2 (s, 2C, Bn), 136.9 (s, 2C, HHDP), 133.7 (s, 2C, OcBn), 129.2
(s, 2C, HHDP), 128.6 (d, 4C, OcBn), 128.6 (d, 4C, Bn), 128.5 (d, 4C, Bn),
128.3 (d, 2C, Bn), 127.8 (d, 4C, OcBn), 115.3 (s, 2C, HHDP), 105.5 (d, 2C,
HHDP), 75.4 (t, 2C, Bn), 70.9 (t, 2C, OcBn), 65.3 (t, 2C, butane linker),
35.8 (t, 2C, OcBn), 31.9 (t, 2C, OcBn), 31.6 (t, 2C, OcBn), 29.5 (t, 2C,
OcBn), 29.4 (t, 2C, OcBn), 29.3 (t, 2C, OcBn), 26.1 (t, 2C, butane linker),
22.7 (t, 2C, OcBn), 14.2 (q, 2C, OcBn). IR (ATR) 3680–3040, 3061, 3013,
2926, 2855, 1726, 1717, 1603, 1578, 1497, 1335, 1234, 1142, 1096, 997,
752, 696 cm–1. HRMS (ESI) m/z [M + Na]+ calcd for C62H72O10Na 999.5023,
found 999.5020.
Synthesis of seco acid 45 (Table 1, entry 5): To a stirred solution of 21
(64.5 mg, 44.6 μmol) and 39 (56.5 mg, 62.4 μmol) in CH2Cl2 (4.5 mL) were
added EDCI·HCl (26.2 mg, 137 μmol) and PPY (8.2 mg, 55 μmol) at rt.
After stirring for 45 min at rt, to the mixture was added 1 M hydrochloric
acid (7 mL). The separated organic layer was successively washed with
H2O (20 mL) and brine (20 mL). After the general drying procedure, the
residue was purified by column chromatography (10
g of SiO2,
hexane/EtOAc = 4/1 to 2/1) to give 45 (75.8 mg, 32.5 μmol, 73% yield) as
22
a yellow syrup. [α]D –17 (c 0.76, CHCl3). 1H NMR (500 MHz, CDCl3,
24 °C) δ 7.52 (s, 1H, THDBF), 7.49–7.35 (m, 19H, Bn, OcBn, THDBF,
galloyl), 7.35–7.02 (m, 44H, Bn, OcBn, H-1), 7.01 (d, J = 7.5 Hz, 2H, Bn),
7.00 (s, 1H, HHDP), 6.93 (s, 1H, HHDP), 6.77 (d, J = 6.9 Hz, 2H, Bn), 5.54
(s, 1H, H-2), 5.42 (s, 2H, Bn), 5.42 (s, 2H, Bn), 5.31 (s, 1H, H-3), 5.28 (dd,
J = 10.9, 8.0 Hz, 1H, H-6), 5.22–5.12 (m, 6H, OcBn, Bn), 5.07 (d, J = 11.5
Hz, 1H, Bn), 5.03–4.88 (m, 10H, Bn), 4.82 (dd, J = 10.9, 10.0 Hz, 1H, H-
5), 4.75 (d, J = 10.9 Hz, 2H, Bn), 4.69 (s, 1H, H-4), 4.48 (dd, J = 10.0, 8.0
Hz, 1H, H-6), 4.39 (d, J = 10.9 Hz, 1H, Bn), 4.33 (br d, J = 10.9 Hz, 1H,
Bn), 4.32 (br d, J = 10.9 Hz, 1H, Bn), 2.61 (br t, J = 7.5 Hz, 2H, OcBn),
2.58 (br t, J = 7.5 Hz, 2H, OcBn), 1.63–1.56 (m, 4H, OcBn), 1.38–1.26 (m,
20H, OcBn), 0.87 (t, J = 7.5 Hz, 3H, OcBn), 0.86 (t, J = 7.5 Hz, 3H, OcBn).
13C NMR (126 MHz, CDCl3, 24 °C) δ 169.3 (s, CO2H), 167.5 (s, HHDP),
166.0 (s, HHDP), 166.0 (s, THDBF), 165.5 (s, galloyl), 153.2 (s, 2C,
galloyl), 152.9 (s, HHDP), 152.6 (s, 2C, HHDP), 152.4 (s, HHDP), 150.6
(s, THDBF), 150.6 (s, THDBF), 150.2 (s, THDBF), 150.1 (s, THDBF),
145.4 (s, HHDP), 144.7 (s, HHDP), 144.1 (s, galloyl), 143.3 (s, OcBn),
143.3 (s, OcBn), 137.9 (s, 2C, Bn), 137.6 (s, Bn), 137.6 (s, 2C, Bn), 137.2
(s, THDBF), 137.2 (s, Bn), 137.1 (s, THDBF), 137.1 (s, Bn), 136.7 (s, 2C,
Bn), 136.5 (s, Bn), 136.2 (s, Bn), 133.7 (s, OcBn), 133.6 (s, OcBn), 128.9–
127.3 (overlapping 63 doublets and 1 singlet: 22 peaks were observed,
64C, Bn, OcBn, HHDP), 127.0 (s, HHDP), 125.3 (s, HHDP), 123.7 (s,
galloyl), 123.2 (s, HHDP), 121.1 (s, THDBF), 120.3 (s, THDBF), 118.0 (s,
THDBF), 117.7 (s, THDBF), 112.6 (d, THDBF), 112.3 (d, THDBF), 109.3
(d, 3C, galloyl, HHDP), 107.9 (d, HHDP), 93.2 (d, C-1), 75.7 (t, Bn), 75.5
(t, Bn), 75.5 (t, Bn), 75.2 (t, Bn), 75.2 (t, Bn), 75.1 (t, Bn), 74.8 (d, C-5),
74.4 (t, Bn), 72.4 (t, 2C, OcBn), 71.5 (t, 2C, Bn), 71.4 (t, Bn), 71.1 (t, Bn),
67.9 (d, C-3), 67.6 (d, C-2), 64.0 (t, C-6), 60.5 (d, C-4), 35.9 (t, 2C, OcBn),
32.0 (t, 2C, OcBn), 31.6 (t, OcBn), 31.6 (t, OcBn), 29.6 (t, 2C, OcBn), 29.5
(t, OcBn), 29.5 (t, OcBn), 29.4 (t, 2C, OcBn), 22.8 (t, 2C, OcBn), 14.2 (q,
2C, OcBn). IR (ATR) 3600–3050, 3032, 2924, 2854, 1737, 1589, 1498,
1454, 1369, 1190, 1096, 1015, 732, 694 cm–1. HRMS (unanalyzable due
to instability under ionization conditions).
Synthesis of dibenzofuran 42: To a stirred solution of 41 (1.19 g, 1.21
mmol) in CH2Cl2 (25.0 mL) were added Et3N (146 mg, 1.44 mmol) and
Tf2O (361 mg, 1.28 mmol) at 0 ºC. After stirring for 15 min at 0 ºC, to the
mixture was added H2O (50 mL). The mixture was extracted with CH2Cl2
(60 mL × 3). The combined organic layer was successively washed with
H2O (60 mL) and brine (60 mL). The general drying procedure gave mono-
triflate. To a solution of the crude product in DMF (40.5 mL) were added
Cs2CO3 (808 mg, 2.48 mmol) at 80 ºC. After stirring for 7 h at 80 ºC, to the
mixture was added 1 M hydrochloric acid (40 mL). The mixture was
extracted with EtOAc (60 mL × 3). The combined organic layer was
successively washed with 1 M hydrochloric acid (60 mL), H2O (60 mL),
and brine (60 mL). After the general drying procedure, the residue was
purified by column chromatography (35 g of SiO2, hexane/EtOAc = 4/1) to
give 42 (1.09 g, 1.14 mmol, 94% yield in 2 steps) as a yellow syrup. 1H
NMR (500 MHz, CDCl3, 23 °C) δ 7.49 (dd, J = 6.9, 2.9 Hz, 4H, Bn), 7.47
(s, 2H, THDBF), 7.39 (d, J = 8.0 Hz, 4H, OcBn), 7.34–7.31 (m, 6H, Bn),
7.23 (d, J = 8.0 Hz, 4H, OcBn), 5.41 (s, 4H, Bn), 5.20 (s, 4H, OcBn), 4.51
(br s, 4H, butane linker), 2.65 (t, J = 7.7 Hz, 4H, OcBn), 2.10 (br s, 4H,
butane linker), 1.67 (quintet, J = 7.7 Hz, 4H, OcBn), 1.35–1.30 (m, 20H,
OcBn), 0.91 (t, J = 6.9 Hz, 6H, OcBn). 13C NMR (126 MHz, CDCl3, 23 °C)
δ 168.3 (s, 2C, THDBF), 150.4 (s, 2C, THDBF), 150.1 (s, 2C, THDBF),
143.2 (s, 2C, OcBn), 137.2 (s, 2C, Bn), 136.6 (s, 2C, THDBF), 133.8 (s,
2C, OcBn), 128.8 (d, 4C, OcBn), 128.5 (d, 4C, Bn), 128.4 (d, 4C, Bn),
128.3 (d, 2C, Bn), 127.9 (d, 4C, OcBn), 122.0 (s, 2C, THDBF), 117.4 (s,
2C, THDBF), 113.0 (d, 2C, THDBF), 75.5 (t, 2C, Bn), 72.3 (t, 2C, OcBn),
65.5 (t, 2C, butane linker), 35.9 (t, 2C, OcBn), 32.0 (t, 2C, OcBn), 31.6 (t,
2C, OcBn), 29.6 (t, 2C, OcBn), 29.5 (t, 2C, OcBn), 29.4 (t, 2C, OcBn), 26.9
(t, 2C, butane linker), 22.8 (t, 2C, OcBn), 14.2 (q, 2C, OcBn). IR (ATR)
3062, 3030, 2924, 2853, 1824, 1717, 1627, 1590, 1516, 1454, 1378, 1317,
1209, 1093, 997, 815, 732, 696 cm–1. HRMS (ESI) m/z [M + Na]+ calcd for
C62H70O9Na 981.4918, found 981.4918.
Synthesis of 2,4-O-THDBF bridged compound 43 (Table 2, entry 4):
To a stirred solution of 45 (37.3 mg, 16.0 μmol) in THF (0.76 mL) was
added TCBCl (7.8 mg, 32 μmol). After stirring for 1 h at reflux, to the
mixture was added PPY (ca. 4.7 mg, ca. 32 μmol) at reflux. After stirring
for 14 min at reflux, to the mixture was add 1 M hydrochloric acid (5 mL).
The mixture was extracted with EtOAc (20 mL × 3). The combined organic
layer was successively washed with H2O (20 mL) and brine (20 mL). After
the general drying procedure, the residue was purified by column
chromatography (10 g of SiO2, hexane/EtOAc = 9/1 to 5/1) to give 43 (25.6
24
mg, 11.1 μmol, 69% yield) as a yellow syrup. [α]D +14 (c 0.26, CHCl3).
1H NMR (500 MHz, CDCl3, 25 °C) δ 7.54 (s, 1H, THDBF), 7.51–7.06 (m,
62 H, Bn, OcBn, galloyl, THDBF), 7.03 (s, 1H, HHDP), 7.01–6.98 (m, 2H,
Bn), 6.97 (s, 1H, HHDP), 6.82 (br s, 1H, H-3), 6.78 (d, J = 7.5 Hz, 2H, Bn),
6.49 (s, 1H, H-1), 5.56 (br s, 2H, H-2, H-4), 5.41 (s, 2H, Bn), 5.35 (s, 2H,
Bn), 5.23–5.12 (m, 6H, Bn, OcBn), 5.05 (dd, J = 10.9, 9.9 Hz, 1H, H-6),
5.04 (d, J = 10.9 Hz, 1H, Bn), 5.00–4.92 (m, 7H, Bn, H-5), 4.89 (d, J = 10.9
Hz, 1H, Bn), 4.88 (d, J = 11.5 Hz, 2H, Bn), 4.76 (d, J = 10.9 Hz, 1H, Bn),
4.74 (d, J = 10.9 Hz, 1H, Bn), 4.73 (d, J = 10.9 Hz, 1H, Bn), 4.67 (dd, J =
10.9, 8.0 Hz, 1H, H-6), 4.45 (d, J = 10.9 Hz, 1H, Bn), 4.36 (d, J = 10.9 Hz,
1H, Bn), 4.29 (d, J = 10.9 Hz, 1H, Bn), 2.66–2.60 (m, 4H, OcBn), 1.67–
1.60 (m, 4H, OcBn), 1.38–1.26 (m, 20H, OcBn), 0.91–0.87 (m, 6H, OcBn).
13C NMR (126 MHz, CDCl3, 24 °C) δ 168.6 (s, THDBF), 167.8 (s, HHDP),
166.7 (s, THDBF), 165.3 (s, HHDP), 164.6 (s, galloyl), 153.1 (s, 2C,
galloyl), 153.0 (s, HHDP), 152.7 (s, HHDP), 152.6 (s, HHDP), 152.5 (s,
HHDP), 150.7 (s, THDBF), 150.5 (s, THDBF), 150.5 (s, THDBF), 150.3 (s,
THDBF), 145.7 (s, HHDP), 144.9 (s, HHDP), 143.7 (s, galloyl), 143.4 (s,
OcBn), 143.4 (s, OcBn), 138.0 (s, Bn), 137.9 (s, Bn), 137.7 (s, Bn), 137.7
(s, Bn), 137.5 (s, THDBF), 137.2 (s, Bn), 137.1 (s, Bn), 137.1 (s, Bn), 136.7
Synthesis of dicarboxylic acid 39: To a stirred solution of 42 (267 mg,
0.278 mmol) in DMSO (28 mL) was added 3 M LiOH aq. (1.0 mL) at 80 ºC.
After stirring for 2 d at 80 ºC, to the mixture was further added 3 M LiOH
aq. (1.0 mL) at 80 ºC. After stirring for 2 d at 80 ºC, to the mixture was
added 1 M hydrochloric acid (100 mL). The mixture was extracted with
EtOAc (100 mL × 3). The combined organic layer was successively
washed with 1 M hydrochloric acid (50 mL), and then diluted with hexane
(100 mL). The organic layer was successively washed with H2O (50 × 4
mL) and brine (50 mL). After the general drying procedure, the residue was
purified by trituration with MeOH to give 39 (224 mg, 0.247 mmol, 89%
yield) as a white solid. mp 249.0–250.9 °C. 1H NMR (500 MHz, CDCl3,
23 °C) δ 7.49 (dd, J = 6.6, 4.0 Hz, 4H, Bn), 7.46 (s, 2H, THDBF), 7.36 (d,
J = 8.0 Hz, 4H, OcBn), 7.33–7.30 (m, 6H, Bn), 7.20 (d, J = 8.0 Hz, 4H,
OcBn), 5.42 (s, 4H, Bn), 5.16 (s, 4H, OcBn), 2.62 (t, J = 7.5 Hz, 4H, OcBn),
1.62 (quintet, J = 7.5 Hz, 4H, OcBn), 1.38–1.23 (m, 20H, OcBn), 0.87 (t, J
= 7.5 Hz, 6H, OcBn). 13C NMR (126 MHz, CDCl3, 23 °C) δ 175.2 (s, 2C,
10
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10.1002/chem.202002753
Chemistry - A European Journal
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(s, Bn), 136.7 (s, 2C, Bn), 136.2 (s, Bn), 135.9 (s, THDBF), 133.5 (s, OcBn),
133.5 (s, OcBn), 128.9–127.4 (overlapping 63 doublets and 1 singlets: 11
peaks were observed, 64C, Bn, OcBn, HHDP), 126.5 (s, HHDP), 125.6 (s,
HHDP), 123.5 (s, THDBF), 123.4 (s, HHDP), 122.9 (s, galloyl), 118.9 (s,
THDBF), 116.4 (s, THDBF), 115.7 (s, THDBF), 114.8 (d, THDBF), 109.8
(d, HHDP), 109.5 (d, THDBF), 108.9 (d, 2C, galloyl), 108.0 (d, HHDP),
93.3 (d, C-1), 75.7 (t, Bn), 75.6 (t, Bn), 75.6 (t, Bn), 75.3 (t, Bn), 75.3 (t,
Bn), 75.1 (t, Bn), 74.5 (t, Bn), 73.5 (d, C-5), 72.5 (t, Bn), 72.3 (t, Bn), 71.6
(t, Bn), 71.3 (t, 2C, Bn), 71.0 (t, Bn), 70.4 (d, C-2), 67.0 (d, C-4), 64.3 (t, C-
6), 61.5 (d, C-3), 35.9 (t, 2C, OcBn), 32.1 (t, 2C, OcBn), 31.7 (t, OcBn),
31.6 (t, OcBn), 29.6 (t, 2C, OcBn), 29.5 (t, 2C, OcBn), 29.4 (t, 2C, OcBn),
22.8 (t, 2C, OcBn), 14.3 (q, 2C, OcBn). IR (ATR) 3063, 3032, 2924, 2855,
1744, 1711, 1589, 1499, 1369, 1209, 1182, 1094, 1013, 959, 906, 729,
694 cm–1. HRMS (ESI) m/z [M + Na]+ calcd for C148H136O25Na 2336.9302,
found 2336.9280.
MS spectra of partial compounds, and Osaka Synthetic Chemical
Laboratories, Inc. for their provision of EDCI·HCl. MEXT-
supported the program for the Strategic Research Foundation at
Private Universities (S1311046), and JSPS KAKENHI (Grant
Number JP16H01163 in Middle Molecular Strategy, and
JP16KT0061, JP19K15549) partly supported this work.
Keywords: mallotusinin • corilagin • intramolecular SNAr
reaction• two-step bislactonization • total synthesis
[1]
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R. Saijo, G. Nonaka, I. Nishioka, Chem. Pharm. Bull. 1989, 8, 2063–2070.
a) O. T. Schmidt, R. Lademann, Liebigs Ann. Chem. 1951, 571, 232–237.
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2561–2564.
Synthesis of mallotusinin (1): A mixture of 43 (9.0 mg, 3.9 μmol) and
Pd(OH)2/C (20 wt. %, 13.6 mg, 19.4 μmol) in THF (0.8 mL) was stirred
under H2 atmosphere at rt. After stirring for 1.5 h at rt, the mixture was
filtered through a Celite pad to remove the catalyst and carbon. After the
filtrate was concentrated, the residue was purified by column
chromatography (3 g of Sephadex G-25, MeOH/water = 3/2) to give 1 (2.0
mg, 2.2 μmol, 56% yield) as a brown amorphous solid. [α]D24 –15 (c 0.21,
CHCl3). 1H NMR (500 MHz, acetone-d6, 24 °C) δ 7.35 (s, 1H, THDBF),
7.13 (s, 2H, galloyl), 7.10 (s, 1H, THDBF), 7.09 (s, 1H, HHDP), 6.69 (s, 1
H, HHDP), 6.69 (br d, J = 4.0 Hz, 1H, H-3), 6.32 (d, J = 3.4 Hz, 1H, H-1),
5.43 (ddd, J = 3.4, 1.7, 1.2 Hz, 1H, H-2), 5.33 (br d, J = 4.0 Hz, 1H, H-4),
4.86 (br dd, J = 8.0, 6.3 Hz, 1H, H-5), 4.66 (br dd, J = 12.0, 8.0 Hz, 1H, H-
6), 4.34 (dd, J = 12.0, 6.3 Hz, 1H, H-6). 13C NMR (126 MHz, acetone-d6,
24 °C) δ 169.2 (s, THDBF), 168.5 (s, HHDP), 167.2 (s, THDBF), 166.5 (s,
HHDP), 165.0 (s, galloyl), 147.2 (s, THDBF or HHDP), 147.0 (s, THDBF
or HHDP), 146.1 (s, 2C, galloyl), 145.4 (s, THDBF or HHDP), 145.4
(HHDP), 145.2 (s, THDBF or HHDP), 145.0 (s, HHDP or THDBF), 145.0
(s, HHDP or THDBF), 144.6 (s, THDBF), 139.8 (s, 2C, galloyl), 137.6 (s,
HHDP), 136.5 (s, HHDP), 136.0 (s, THDBF), 133.3 (s, THDBF), 125.5 (s,
HHDP), 125.0 (s, HHDP), 120.4 (s, galloyl or THDBF), 120.2 (s, galloyl or
THDBF), 116.5 (s, THDBF), 116.5 (s, HHDP), 116.1 (d, THDBF), 115.8 (s,
THDBF), 115.4 (d, THDBF), 115.2 (s, HHDP), 111.1 (s, THDBF), 110.5 (d,
2C, galloyl), 110.0 (d, HHDP), 108.4 (d, HHDP), 92.1 (d, C-1), 75.8 (d, C-
5), 74.1 (d, C-2), 68.6 (d, C-4), 64.8 (t, C-6), 63.4 (d, C-3). IR (ATR) 3545–
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2965, 2881, 1733, 1716, 1699, 1616, 1541, 1362, 1219, 1036, 772 cm–1
.
HRMS (ESI) m/z [M – H]– calcd for C41H25O25 917.0685, found 917.0681.
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T. D. Nelson, A. I. Meyers, J. Org. Chem. 1994, 59, 2577–2580.
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Synthesis of dibenzofuran 47a (Table 3, entry 3): To a stirred solution
of 46a (11.6 mg, 13.3 μmol) in DMF (0.5 mL) was added DBU (4.5 mg, 30
μmol) at 70 ºC. After stirring for 8 h at 70 ºC, to the mixture was added 1
M hydrochloric acid (1 mL). The mixture was extracted with EtOAc (10 mL
× 4). The combined organic layer was successively washed with 1 M
hydrochloric acid (1 mL), H2O (30 mL), and brine (30 mL). After the general
drying procedure, the residue was purified by column chromatography (3
g of SiO2, hexane/EtOAc = 6/1 to 5/1) to give 47a (5.0 mg, 6.9 μmol, 52%
yield) as a yellow syrup. 1H NMR (500 MHz, CDCl3, 22 °C) δ 7.52–7.49
(m, 4H, Bn), 7.47–7.43 (m, 4H, Bn), 7.41–7.28 (m, 12H, Bn), 7.17 (s, 1H,
dibenzofuran), 6.83 (s, 1H, dibenzofuran), 5.36 (s, 2H, Bn), 5.29 (s, 2H,
Bn), 5.19 (s, 2H, Bn), 5.19 (s, 2H, Bn), 4.65–4.62 (m, 4H, benzylic, butane
linker), 3.69–3.65 (m, 2H, butane linker), 2.00–1.94 (m, 2H, butane linker),
1.87–1.82 (m, 2H, butane linker). 13C NMR (126 MHz, CDCl3, 25 °C) δ
168.9 (s, ester), 151.4 (s, dibenzofuran), 150.5 (s, dibenzofuran), 150.1 (s,
dibenzofuran), 149.4 (s, dibenzofuran), 137.6 (s, Bn), 137.4 (s, Bn), 137.1
(s, Bn), 136.9 (s, Bn), 135.8 (s, dibenzofuran), 133.6 (s, dibenzofuran),
128.7–127.6 (d, overlapping 20 doublets and 1 singlet: 7 peaks were
observed, 21C, Bn, dibenzofuran), 124.0 (s, dibenzofuran), 118.2 (s,
dibenzofuran), 117.2 (s, dibenzofuran), 112.6 (d, dibenzofuran), 110.6 (d,
dibenzofuran), 75.7 (t, Bn), 75.5 (t, Bn), 74.3 (t, benzylic), 72.4 (t, Bn), 72.4
(t, Bn), 71.8 (t, butane linker), 63.3 (t, butane linker), 28.7 (t, butane linker),
25.2 (t, butane linker). IR (ATR) 3017, 2926, 2855, 1713, 1605, 1514,
1454, 1416, 1215, 1099, 748, 696, 667 cm–1. HRMS (ESI) m/z [M + Na]+
calcd for C46H40ONa 743.2621, found 743.2610.
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We are very grateful to Prof. Hidetoshi Yamada who deceased on
November 23, 2019 for his dedicated education provided to us.
We thank Prof. Takashi Tanaka at Nagasaki University for
provision of natural mallotusinin. We also thank Dr. Yasuko
Okamoto at Tokushima Bunri University for measurements of the
11
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Entry for the Table of Contents
OBn
HO
BnO
HO
HO
OH
HO
O
OH
BnO
OBn
OH
OH
OBn
OBn
HO
BnO
BnO
HO
R
2. orthoester
O
cleavage using
PhSH/InBr3
4. two-step
bislactonization
mallotusinin
O
O
O
O
O
O
O
A =
O
O
OH
O
O
OBn
OBn
O
O
O
O
O
O
1. oxidative
phenol
coupling
O
3. glycosyl
HO2
C
CO2H
O
OH HO
OH
esterification
O
O O
CH3
OH
OBn
HO
OH
O
O
O
HO
OH
OcBn = p-octylbenzyl
OcBnO
OOcBn
OBn
corilagin: A = H
O
A
A
BnO
We describe the total synthesis of mallotusinin via the second-generation synthesis of corilagin. The key steps are as follows: (1)
oxidative phenol coupling of 1,2,4-orthoacetyl-3,6-di-(4-O-benzylgalloyl)-α-D-glucopyranose; (2) orthoester cleavage along with
thioglycosylation followed by β-selective glycosyl esterification; (3) two-step bislactonization to construct
tetrahydroxydibenzofuranoyl bridge on corilagin.
a
2,4-O-
13
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