High-yield total synthesis of (-)-strictinin through intramolecular coupling of gallates

Article abstract of DOI:10.1021/jo4003135

This paper describes a total synthesis of (-)-strictinin, an ellagitannin that is 1-O-galloyl-4,6-O-(S)-hexahydroxydiphenoyl (HHDP)-β-d-glucose. In the study, total efficiency of the synthesis was improved to produce a 78% overall yield in 13 steps from d-glucose. In the synthesis, formation of the 4,6-(S)-HHDP bridge including the 11-membered bislactone ring was a key step, in which intramolecular aryl-aryl coupling was adopted. The coupling was oxidatively induced by CuCl₂-n-BuNH₂ with perfect control of the axial chirality, and the reaction conditions of this coupling were optimized thoroughly to achieve the quantitative formation of the bridge.

Full text of DOI:10.1021/jo4003135

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Article
High Yield Total Synthesis of (–)-Strictinin
through Intramolecular Coupling of Gallates
Naoki Michihata, Yuki Kaneko, Yusuke Kasai, Kotaro Tanigawa,
Tsukasa Hirokane, Sho Higasa, and Hidetoshi Yamada
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4003135 • Publication Date (Web): 08 Apr 2013
Downloaded from http://pubs.acs.org on April 20, 2013
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High Yield Total Synthesis of (–)-Strictinin through Intramolecular Coupling of Gallates
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Naoki Michihata, Yuki Kaneko, Yusuke Kasai,§ Kotaro Tanigawa, Tsukasa Hirokane, Sho
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Higasa, Hidetoshi Yamada*
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School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda 669-1337,
Japan.
hidetosh@kwansei.ac.jp
HO
OH
100% de
HO
HO
OH
HO
S
HO
HO
O
78%
overall yield
OBn
BnO
HO
OH
O
O
O
O
OH
OH
HO
HO
HO
O
OH
SEt
O
O
O
O
O
BnO
O
HO
OH
HO
BnO
HO
(–)-strictinin
O
ABSTRACT: This paper describes a total synthesis of (–)-strictinin, an ellagitannin that is
1-O-galloyl-4,6-O-(S)-hexahydroxydiphenoyl (HHDP)-β-D-glucose. In the study, total efficiency
of the synthesis was improved to obtain 78% overall yield in 13 steps from D-glucose. In the
synthesis, formation of the 4,6-(S)-HHDP bridge including the eleven-membered bislactone ring
was a key step, in which intramolecular aryl–aryl coupling was adopted. The coupling was
oxidatively induced by CuCl2–n-BuNH2 with perfect control of the axial chirality, and the
reaction conditions of this coupling were optimized thoroughly to achieve the quantitative
formation of the bridge.
§ Present address: Center for Marine Biotechnology and Biomedicine, Scripps Institution of
Oceanography, University of California San Diego, 9500 Gilman Drive, La Jolla, California
92093-0212, USA
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Introduction
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(–)-Strictinin (1), 1-O-galloyl-4,6-O-(S)-hexahydroxydiphenoyl (HHDP)-β-D-glucopyranose
(Figure 1), is an ellagitannin that was first isolated from the leaves of Casuarina stricta
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hexahydroxydiphenoyl
HO
(HHDP) group
OH
HO
HO
HO
HO
OH
O
O
OH
OH
O
O
O
HO
O
HO
O
galloyl group
(–)-strictinin (1)
FIGURE 1. Structure of (–)-strictinin (1)
(Casuarinaceae) and whose structure was characterized by Okuda et al.1,2 Since then, many plant
species have been revealed to produce 1.3 In addition, 1 is a compound that has frequently
appeared in tea sciences.4 Because of its relatively good availability compared to general natural
ellagitannins, the biological activities of 1 have been extensively examined and found significant
in pharmaceutical utilization including anti-allergic and immunostimulating activities.5–12
Despite the investigations to find its biological activities and for where 1 can be isolated from,
the synthetic approach of 1 has only been reported by Khanbabaee et al.13 They achieved the total
synthesis of 1 through double esterification [Scheme 1, (A)]. The 4,6-(S)-HHDP compound 4 is
obtained as a single diastereomer via kinetic optical resolution of rac-2. The yield of this step is
24% because (R)-2 involves intermolecular esterification producing dimers (and perhaps larger
oligomers), production of which wastes 3.14 This disadvantage was avoided by the adoption of
axially chiral HHDP-diacid; thus double esterification with (S)-2 provided the 4,6-HHDP-bridge
in the synthesis of the proposed structure of roxbin B.15 However, the preparation of (S)-2
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SCHEME 1. Previous formation of the 4,6-HHDP-bridge
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BnO
BnO
BnO
OBn
BnO
BnO
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9
S
BnO
BnO
CO2H
CO2H
BnO
BnO
O
(o-NO2)Bn
(o-NO2)Bn
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11
12
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O
O
HO
HO
BnO
O
O
O
O
O
BnO
BnO
BnO
BnO
BnO
+
(A)
rac-2
3
4
DCC, DMAP, DMAP·HCl
24%
R1O
OR1
OR1
R1O
R1O
X
OR1
OR1
S
R1O
R1O
O
X
O
O
O
O
O
R1O
R1O
O
O
O
O
R2O
R2O
R2O
R2O
R3
R3
R1O
R1 = CPh2 and H
R2 = G(Bn)3
R3 = β-OBn
X = H
Pb(OAc)4
73%
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6
(B)
R1 = Me
Cu
R2 = G(Me)3
R3 = α-OMe
X = I
7
9
8
(C)
(D)
50%
R1 = Bn
i) Zn
ii) CuBr·SMe2
G(Bn)3 =
O
R2 = G(Bn)3
R3 = β-OBn
X = Br
10
OBn
OBn
O
iii)
O2N
N
N
OBn
CH3
> 68% NO2
requires extra synthetic steps.16 Improvements in efficiency of the synthesis would increase the
availability of not only 1 but also its analogues in pure form, which could help advance research
into the intended applications.17
For the formation of the 4,6-HHDP-bridge, intramolecular coupling of the galloyl groups on
the 4- and 6-oxygens of glucose have been the other strategy. The coupling was first employed by
Feldman et al. [Scheme 1, (B)] in the synthesis of tellimagrandin I,18 demonstrating that the axial
chirality in 6 could be completely controlled to be S. Similar complete diastereoselectivity in the
formation of the 4,6-HHDP-bridge was also exhibited by Dai and Martin with Ullmann coupling
of 7 (C).19 Most recently, Spring et al. applied their original method of aryl–aryl coupling to the
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4,6-HHDP formation (D),20 that is a three-step synthesis in one pot including halogen–zinc
exchange of 2-brominated gallates of 9, copper salt mediated transmetalation, and oxidation of
the resulting organocuprate.21 However, this coupling requires the 2-brominated gallates as the
substrate of the reaction, which slightly decreases the total efficiency of the synthesis due to the
additional steps required for the pre-installation of bromine. We here described the total synthesis
of 1 where we highlighted on the overall efficiency and the optimized formation of
4,6-(S)-HHDP-bridge.
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The retrosynthetic analysis of 1 is outlined in Scheme 2. We envisioned a β-selective
SCHEME 2. Retrosynthetic analysis of 1
BnO
OH
OH
HO
HO
OBn
OH
S
BnO
HO
HO
HO
O
O
O
O
O
O
BnO
SEt
O
O
O
BnO
O
BnO
SEt
BnO
11
BnO
12
1
1-β-O-galloylation
and deprotection
Intramolecular
Aryl–Aryl coupling
OBn
MOMO
OMOM
HO
HO
BnO
O
SEt
CO2H
13
BnO
+
14
esterification would install the required anomeric galloyl group at the final stage of the synthesis.
To construct the 4,6-HHDP group of 11, the bridge would be constructed by CuCl2–n-BuNH2
mediated aryl–aryl bond formation.16,22,23 The digallate 12 would be installed by simple
esterification of known carboxylic acid 1324,25 and diol 14.26 In the synthesis, we focused on high
overall yield and stable reproducibility. For this purpose, we improved the methods of
synthesizing the starting materials 13 and 14 although they are known compounds, which are
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described in the first half of this report. In the latter half, a new synthetic method for 1, starting
from 13 and 14, is described.
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Results and discussions
Preparation of protected gallic acid 13
The 4-O-selective benzylation of methyl gallate (15) was first reported by ElSohly et al. as in
Scheme 3 (eq 1).24 Later, Pearson and Bruhn reported the difficulty of reproducibility in this
SCHEME 3. Previous 4-O-selective benzylation and allylation of 15
OH
OBn
HO
HO
OH
OH
CO2Me
CO2Me
15
16
(1)
K2CO3, BnCl
KI (cat), acetone
50% yield
OBn
OBn
HO
BnO
OBn
OBn
CO2Me
CO2Me
18
15
15
(2)
(3)
16
16
+
16:17:18 = 2:2:1
17
+
K2CO3, acetone;
BnCl
1) Ac2O, py
O
2) K2CO3, KI
BnCl, acetone
3) K2CO3, MeOH
51% yield
HO
OH
(3 steps)
CO2Me
19
(4)
15
KHCO3, KI (cat)
allyl-Br, acetone
70% yield
method, along with inherent low regioselectivity in benzylation of 15 (eq 2).25 They therefore
developed the three-step sequence (eq 3) to improve the efficiency of 4-O-benzyl gallate (16). On
the other hand, Fréchet et al. allylated the 4-O-position selectively to give 19 (eq 4) by changing
the base from K2CO3 to KHCO3 and by the addition of KI as a catalyst.27
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On the basis of the above information, we improved the regioselective benzylation of 15
(Scheme 4). Thus, treatment of 15 with BnBr and KHCO3 in the presence of catalytic KI in DMF
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SCHEME 4. Preparation of 13
OBn
MOMO
OMOM
CO2Me
13
15
16
20
BnBr, KHCO3
KI (cat), DMF
83%
MOMCl
NaH, DMF
99%
LiOH
H2O, THF
99%
produced 16 as the major product along with 17 and 18 as the minor products. A
chromatographic separation provided pure 16 in 83% yield. Purification by washing the
powdered mixture of 16, 17, and 18 with toluene was also possible because of the higher
solubility of the byproducts 17 and 18 into toluene than 16. Transformation of 16 to carboxylic
acid 13 including MOM protection of the phenolic hydroxy groups followed by hydrolysis of the
ester proceeded in high yields.
High-yield synthesis of ethyl 1-thioglucoside 14
All approaches toward the synthesis of ethyl 1-thioglucoside 14 from D-glucose (21) have
been found in the literature.26,28–30 However, the reported yields are less satisfactory in several
steps; therefore we optimized each reaction condition to improve efficiency (Scheme 5).
Reported by Wolfrom and Juliano, per-acetylation of 21 is known to prepare the
β-pentaacetylglucose in moderate yield (73%). We found an optimized condition by slow
addition of powdered 21 into a gently refluxed Ac2O and NaOAc improved the yield
significantly.
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SCHEME 5. Synthesis of 14
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AcO
AcO
AcO
HO
HO
Ph
OAc
O
O
O
O
O
SEt
BnO
SEt
HO
AcO
22
HO
23
BnO
14
D-glc
9
1) BnBr, NaH
DMF, 99%
2)1 M aq HCl
1) EtSH, ZrCl4
2) NaOMe, MeOH
3) PhCH(OMe)2
CSA, DMF
Ac2O
NaOAc
100%
(21)
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acetone, 99%
92% (3 steps)
The three-step transformation of 22 to 23 includes (1) Lewis acid mediated β-selective
ethylthio glucosidation,31–39 (2) deacetylation,32 and (3) regioselective benzylidene formation.40
We improved the efficiency on the basis of Little's method for the first step,33 because we found
the cause of the reported moderate yield (74%), that is, decomposition of desired ethyl
2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranoside was induced by Zr-salts that remained despite
the workup procedures. Complete removal of the Zr-salts was difficult to achieve by
liquid–liquid extractions between organic and aqueous phases, and besides, the colorless crystal
of the desired ethylthioglucoside gradually changed to be blackish.41 Accordingly, the next
deacetylation soon after the workup of the first step made the decomposition insignificant. The
purity of the deacetylated product was excellent, and allowed the succeeding benzylidenation to
be carried out without purification. For the benzylidenation, the following efforts were effective,
using (±)-camphor-10-sulfonic acid (CSA) as the acid catalyst instead of p-TsOH as reported,
and carried out the reaction under reduced pressure (~15 mmHg) to remove the generated MeOH.
By these treatments the yield of the three steps increased to 92% overall.
Transformation from 23 to 14 including benzylation of the 2,3-diol followed by removal of the
benzylidene was quantitatively carried out by employing method developed by Crich and
Bowers26 with slight modification using 1 M HCl or aqueous AcOH as the hydrolytic agents for
the removal of benzylidene to provide 4,6-diol 14 in 99% and 95% yield, respectively.
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Total synthesis of 1
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The new synthetic steps for total synthesis of 1 commenced with acylation of 4,6-diol 14 with
carboxylic acid 13 using a modified Steglich's method42 (Scheme 6). This digalloylation
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SCHEME 6. Synthesis of 1
BnO
MOMO
OMOM
O
BnO
HO
OH
BnO
O
OH
HO
HO
S
BnO
HO
OBn
MOMO
O
MOMO
BnO
HO
BnO
O
O
O
O
OMOM
O
O
O
O
O
O
BnO
O
BnO
O
SEt
SEt
SEt
BnO
CO2H
13
MOMO
BnO
24
HO
BnO
BnO
11
+
14
12
EDCl·HCl, DMAP
CH2Cl2, py, 99%
CuCl2, n-BuNH2
i-PrOH/conc. HCl (50/1 v/v)
THF, 95%
MeOH, 100%
BnO
BnO
BnO
OBn
BnO
OBn
BnO
BnO
BnO
BnO
OBn
BnO
BnO
OBn
OBn
OBn
BnO
BnO
BnO
BnO
BnO
BnO
OBn
BnO
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
BnO
O
SEt
BnO
BnO
COCl
OH
O
BnO
β-28
BnO
BnO
26
27
25
1
BnBr, K2CO3
acetone, 98%
Et3N, CH2Cl2
97% (α/β = 2/98)
Pd(OH)2/C, H2
THF/MeOH, 99%
NIS, TfOH (cat), H2O
THF, CH2Cl2, 98%
successfully gave 4,6-digallate 24 in 99% yield. The four MOM groups of 24 were removed by
acidic hydrolysis using a mixture of 2-propanol and concentrated aqueous HCl (50/1 v/v) to
afford tetraol 12 in 95% yield. To perform this deprotection in high yield and with reliable
reproducibility, the following two points had to be noted: (1) the reaction temperature had to be
kept to 50 °C, and (2) the workup had to be started soon after the detection of the removal of all
MOM groups.
For the transformation of 12 to 11, we began by using our previously reported method for
CuCl2–n-BuNH2 catalyzed aryl–aryl coupling reaction (Table 1, entry 1). The coupling reaction
using 5 equiv of CuCl2 and 20 equiv of n-BuNH2 provided eleven-membered bislactone 11 in
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TABLE 1. Optimizations of Intramolecular Aryl–Aryl Coupling of 12
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6
7
8
BnO
OH
HO
HO
OH
OBn
HO
S
O
O
O
BnO
HO
BnO
HO
9
O
O
O
OH
SEt
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11
12
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15
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O
O
O
BnO
O
BnO
SEt
BnO
BnO
11
CuCl2, n-BuNH2
12
MeOH, rt
CuCl2
(equiv)
n-BuNH2
Time
Yield
(%)
Entry
(equiv)
(h)
1
2
3
4
5
6
5
20
4
34
3
2
2
2
2
12
8
13
26
70
65
12
20
30
2.5
0.5
0.25
89
99
100
34% yield, although these reaction conditions were previously used to construct the
twelve-membered 1,6- and 3,6-HHDP bridge.22,23 Similar diminished productivity due to ring
contraction has been observed in the construction of ten-membered HHDP-bislactone rings.16
The low yield was due to solvolytic degradation of galloyl and HHDP esters induced by
n-BuNH2. Accordingly, we reduced the quantity of the reagents, keeping the 1/4 ratio of CuCl2
and n-BuNH2 (entry 2), which enhanced the yield to 70%. However, further quantitative decrease
of the reagents (entry 3) prolonged the reaction time, which resulted in decline of the yield. The
1/4 ratio of CuCl2 and amine has been reported by Brussee et al. to be the optimized reaction
condition for intermolecular coupling of 2-naphthol.43
We then changed the ratio of CuCl2 and n-BuNH2. Application of the 1/6 ratio (Table 1, entry
4) shortened the reaction time to 2.5 h; in addition, the yield of 11 was increased to 89%.
Monitoring of this reaction indicated that the intramolecular coupling reaction was faster than the
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solvolytic cleavage of the ester bonds. These observations suggested that excessive amount of
n-BuNH2 might accelerate the rate of the coupling reaction in comparison to the rate of solvolytic
degradation. This hypothesis was confirmed by the reaction using 1/10 and 1/15 ratio of the
CuCl2 and n-BuNH2, the reaction conditions of which afforded 11 in 99% and 100% yield in 30
and 15 min, respectively (entries 5 and 6). The quick completion of the coupling reaction before
the solvolysis became conspicuous was the answer to achieving a successful transformation in
this case. A noteworthy feature was the excellent diastereoselectivity in the formation of the
axially chiral HHDP group; the derived 11 in each entry was obtained as a single diastereomer,
indicating that the sp3 chirality of the pyranose was completely transferred to the axial chirality of
the HHDP group.
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11
12
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The axial chirality of 11 was confirmed by the liberation of the HHDP group, introducing it to
a known compound. Thus, after benzylation of the phenolic hydroxy groups of 11 providing 25
(Scheme 6), the HHDP part was released by solvolysis to produce dimethyl diester 29 (Scheme
7). The optical rotation of 29 was in agreement with the S enantiomer.44
SCHEME 7. Solvolysis of 25
BnO
OBn
BnO
BnO
BnO
BnO
HO
HO
BnO
O
O
O
OMe
SEt
OMe
(+)-29
73%
BnO
+
25
14
76%
NaOMe, MeOH/THF
For the synthesis of 1-O-galloylated 28, we first attempted direct glycosyl ester formation
(Scheme 8) using 25 and carboxylic acid 30 because thioglycosides have commonly been used as
glycosyl donors in glycosylation reactions.45,46 Thus, treatment of thioglucoside 25 with MeOTf
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SCHEME 8. Glycosyl esterification of 25
5
6
7
BnO
OBn
BnO
BnO
BnO
BnO
8
9
OBn
BnO
OBn
OBn
BnO
O
O
OBn
O
10
11
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13
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15
16
17
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19
20
21
22
23
24
25
26
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28
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O
O
BnO
O
CO2H
BnO
O
+
25
30
28
MeOTf, 2,6-lutidine
MS 4A, CH2Cl2
87% (α/β = 83/17)
in the presence of 30 and MS 4A provided 28 in an α-selective manner (α/β = 83/17).
The α-preference of the glycosyl esterification was similar to the stereoselectivities in
glycosylation using a 2-O-benzylated glycosyl donor.47 Accordingly, we investigated the
acylation of pyranose 26 (Scheme 6) obtained by hydrolysis of the ethylthio group of 25.
Despite the seemingly facile transformation, the hydrolysis of the ethylthio group required
effort to find the optimal reaction conditions (Table 2). The hydrolysis with NBS48 was poor in
reproducibility (entry 1); the yield of 26 fluctuated in a range of 18–70%. Entries 2–4 present
results when general activating procedures of thioglycosides in glycosylations were applied. That
is, activation by MeOTf49 provided 26 in moderate yield (entry 2) along with an inseparable
byproduct, the structure of which was unidentified. The use of PhIO in combination with Lewis
acids50 produced no desired product (Entries 3 and 4). The employment of NIS resulted in
moderate yield (entry 5). Darko's reaction conditions using N-iodosaccharin (NISac) proceeded
rapidly, but the yield of 26 was moderate (entry 6).51 Mukhopadhyay's protocol using NIS and
H2SO4 immobilized on silica produced 26 along with many byproducts (entry 7).52 After these
attempts, we found that application of van Boom's method53 using NIS and a catalytic amount of
TfOH was quite effective; 26 was formed in 98% yield (entry 8). To obtain the excellent yield,
mixing of NIS and TfOH prior to the reaction with 25 was required. The addition of NIS and
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TABLE 2. Hydrolysis of Anomeric Ethylthio Group of 25
5
6
7
BnO
BnO
OBn
BnO
BnO
OBn
BnO
BnO
BnO
BnO
BnO
BnO
8
9
O
O
O
O
O
O
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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59
60
O
O
O
BnO
O
BnO
SEt
OH
BnO
BnO
26
Reagents, H2O
Solvent, Time, rt
25
Entr
y
Time
(h)
Yield
(%)
18–70 a
Reagents
NBS
Solvent
THF
1
2
3
4
5
6
7
8
0.25–4
MeOTf
THF
THF
2
2
65
Sn(OTf)2
PhIO
0
THF
2
0 a
Yb(OTf)3
PhIO
NIS
THF
9.5
0.08
36
0.5
57 a
NISac
NIS
MeCN
65 (55)a
N.D.b,c
98
CH2Cl2, THF
CH2Cl2, THF
H2SO4 silica
NIS
cat. TfOH
aReaction temperature was 0 °C. bN.D. = not determined.
cReaction temperature was 0 °C to rt.
TfOH into a solution of 25 resulted in a low yield. According to the armed-disarmed theory, as
stated by Mydock and Demchenko,54 thioglucoside 25 is classified as a disarmed glycosyl donor,
from which the generation of oxocarbenium intermediate is difficult. In addition, the
HHDP-bridge locked the conformation of the CH2O group to the tg-form, which also deactivates
the rate of hydrolysis.55 These inactivating effects would be the potential reasons for the
unexpected hydrolysis-resisting property of 25 at the anomeric position.
In the galloylation at the anomeric position (Scheme 6), acid chloride 2756 was employed in
the presence of Et3N to afford β-28 stereoselectively in 97% yield (α/β = 2/98).57,58 Both the
addition of a catalytic amount of DMAP to the reaction conditions and adoption of Steglich's
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condensation59 resulted in low anomeric stereoselectivity, to provide 28 as an α/β = 36/64 and
45/55 anomeric mixture, respectively. In general, an equatorially oriented anomeric hydroxy
group is more reactive than an axially oriented one in acylation.60 Acylation using acid chlorides
in the presence of Et3N have actualized this property by Bols and Hansen.57 In the presence of
DMAP, higher reactivity of galloylpyridinium ion intermediate 31 would allow the acylation of
the axial hydroxy group (α-OH in this case) to decrease the stereoselectivity.
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OBn
BnO
BnO
N
Cl
N
O
31
Finally, the hydrogenolytic cleavage of the eleven benzyl groups of β-28 provided 1 in 99%
yield (Scheme 6), and physical and spectral data (optical rotation, 1H and 13C NMR, IR, HRMS)
of which were identical to those of natural strictinin.2 For the final purification, successive
chromatography on ODS (Cosmosil 75C18-OPN) and then on TOYOPEARL HW-40C61 was
effective to afford 1 as a colorless amorphous solid.
Conclusion
We accomplished the total synthesis of (–)-strictinin in 13 steps and in a 78% overall yield
from D-glucose. All the synthetic steps were optimized to provide very good yields and stable
reproducibility including (1) improvements of the 4-O-selective benzylation of methyl gallate and
of the synthesis of ethyl 2,3-di-O-benzyl-1-thio-β-D-glucopyranoside (4 steps from D-glucose,
90% overall yield), (2) completely diastereoselective synthesis of the 4,6-(S)-HHDP in
quantitative yield, and (3) effective removal of the disarmed ethylthio group. This total synthesis
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demonstrates the possibility of the synthetic supply of strictinin and its analogues.
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Experimental section
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General methods. Anhydrous MgSO4 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.
1
The H NMR data are indicated by chemical shifts, with the multiplicity, the coupling
constants, and the integration 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 data are
reported as the chemical shift with the hydrogen multiplicity obtained from the DEPT spectra.
The multiplicities are abbreviated as s: C, d: CH, t: CH2, and q: CH3. When the number for
carbon was more than one, the number was added in parentheses.
For a full description of general methods, see Supporting Information.
Methyl 4-O-benzylgallate (16), (i) A procedure obtained the best yield. To a solution of
methyl gallate (15) (2.00 g, 10.9 mmol) in DMF (100 mL) were added KHCO3 (2.17 g, 21.7
mmol), KI (10.8 mg, 65.2 µmol) and BnBr (1.86 g, 10.9 mmol) at rt under Ar atmosphere. After
being stirred for 24 h at rt, the mixture was filtered through a cotton-Celite pad. The filtrate was
concentrated to remove DMF. After addition of H2O (30 mL) to the residue, the aqueous mixture
was extracted with EtOAc. The combined organic layer was successively washed with saturated
aq NH4Cl, H2O, and brine. After the general drying procedure, the resulting residue was
dissolved in EtOAc (50 mL). To the resulting solution was added silica gel (20 g). The mixture
was then concentrated to adsorb the products onto silica gel. The resulting silica gel adsorbed the
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products was brown, which was charged on the top of a column with 70 g of SiO2 (dry loading
method). Elution with n-hexane/EtOAc (7/1 to 1/1) produced purified 16 (2.47 g, 83% yield) as a
white powder, whose NMR data were identical to the literature data.24,25 (ii) A procedure for 50
g-scale synthesis. To a solution of methyl gallate (15) (53.3 g, 289 mmol) in DMF (700 mL)
were added KHCO3 (50.0 g, 499 mmol), KI (300 mg, 1.81 mmol), and BnBr (50.0 g, 292 mmol)
at rt under N2 atmosphere. After being stirred for 15 h at rt, the mixture was filtered through a
cotton-Celite pad. The filtrate was concentrated to remove DMF. To the resulting residue was
added 1 M aq HCl (100 mL). The aqueous mixture was extracted with EtOAc. The combined
organic layer was successively washed with saturated aq NaHCO3, H2O, and brine. After the
general drying procedure, white solid was obtained containing 15 (1.4%), 16 (78.3%), 17 (18.9%),
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1
and 18 (1.4%). The ratio was determined by H NMR spectra. The mixture was successively
washed with (1) saturated aq NaHCO3 to remove 15, (2) n-hexane to remove BnBr, and (3) cold
toluene to remove 17 and 18 because these two compounds dissolve into toluene more than 16.
Compound 16 (54.6 g, 69% yield) was afforded as a white powder.
Methyl 4-O-benzyl-3,5-di-O-methoxymethylgallate (20). To a solution of diol 16 (9.20 g,
33.5 mmol) in DMF (340 mL) were added 60% NaH in mineral oil (4.03 g, 101 mmol) and
chloromethyl methyl ether (8.10 g, 101 mmol) at 0 °C under Ar atmosphere, and the mixture was
stirred for 1 h at rt. The reaction was quenched by addition of saturated aq NH4Cl until the pH of
the mixture became ~6. After concentration of the mixture to remove most of DMF, H2O (50
mL) was added to the resulting mixture. The aqueous mixture was extracted with EtOAc. The
combined organic layer was successively washed with saturated aq NH4Cl, H2O, and brine. After
the general drying procedure, the mixture was purified by column chromatography (350 g of SiO2,
n-hexane/EtOAc = 5/1 to 1/1) to afford 20 (12.0 g, 99% yield) as a yellow syrup: IR (neat) 3090,
3066, 3033, 2953, 2907, 1721, 1593, 1499, 1435, 1395 1329, 1304, 1221, 1200, 1156, 1109,
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1084, 1048, 1011, 978, 924, 878, 855, 825, 762, 735, 698 cm–1; H NMR (400 MHz, CDCl3) δ
5
6
7
7.52 (s, 2H), 7.47–7.43 (m, 2H), 7.34–7.28 (m, 3H), 5.19 (s, 4H), 5.13 (s, 2H), 3.88 (s, 3H), 3.49
(s, 6H); 13C NMR (100 MHz, CDCl3) δ 166.6 (s), 151.1 (s, 2C), 143.1 (s), 137.4 (s), 128.5 (d, 2C),
128.4 (d, 2C), 128.3 (d), 125.8 (s), 112.1 (d, 2C), 95.6 (t, 2C), 75.3 (t), 56.5 (q, 2C), 52.4 (q);
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C19H22O7Na 385.1263, Found 385.1254.
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60
4-O-benzyl-3,5-di-O-methoxymethylgallic acid (13). To a solution of methyl ester 20 (12.0
g, 33.0 mmol) in THF (110 mL) and MeOH (220 mL) was added LiOH·H2O (6.93 g, 165 mmol)
in H2O (80 mL) at rt. The mixture was heated to reflux for 2 h. The reaction was quenched by
addition of 1 M aq HCl until the pH of the mixture became ~1. The aqueous mixture was
concentrated to remove most of THF and MeOH. H2O (20 mL) was added to the resulting
mixture. The aqueous mixture was extracted with EtOAc. The combined organic layer was
successively washed with H2O and brine. After the general drying procedure, the crude product
was purified by recrystallization (EtOAc/n-hexane) to afford 13 (11.4 g, 99% yield) as a white
powder, whose NMR data were identical to the literature data.23
Penta-O-acetyl-β-D-glucopyranose (22). To a gently refluxed Ac2O (28.4 g, 278 mmol)
containing NaOAc (1.14 g, 13.9 mmol) was slowly added powdered D-glucose (21) (5.00 g, 27.8
mmol) over a period of 15 min. After the mixture was heated to reflux for 5 min, the mixture was
cooled to rt. The reaction was then quenched by addition of ice under sonication. During this
treatment, 22 was precipitated. The precipitation (white powder) was filtered and washed with
H2O until the odor of the acetic acid disappeared. The crude product was purified by
recrystallization (EtOH) to afford pentaacetate 22 (10.81 g, 100% yield) as a white powder.
Because 22 has not adequately characterized (mp and optical rotation of 22 has been reported),28
25
we describe the data: mp 130–135 °C, lit.28 133.5–134 °C; [α]D +3.9 (c 1.00, CHCl3), lit.13
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[α]D22 +2 (c 0.9, CHCl3); IR (neat) 3029, 2969, 2951, 2907 1755, 1740, 1381, 1372, 1233, 1224,
5
6
7
8
1046, 914, 704, 642 cm–1; 1H NMR (400 MHz, CDCl3) δ 5.71 (d, J = 8.2 Hz, 1H), 5.24 (dd, J =
9.8, 9.4 Hz, 1H), 5.16–5.10 (m, 2H), 4.29 (dd, J = 12.6, 4.6 Hz, 1H), 4.11 (dd, J = 12.6, 2.3 Hz,
1H), 3.84 (ddd, J = 9.8, 4.6, 2.3 Hz, 1H), 2.11 (s, 3H), 2.09 (s, 3H), 2.03 (s, 6H), 2.01 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 170.7 (s), 170.2 (s), 169.5 (s), 169.4 (s) 169.1 (s), 91.8 (d), 72.9 (d),
72.8 (d), 70.3 (d), 67.9 (d), 61.6 (t), 20.9 (q), 20.8 (q), 20.7 (q, 3C); HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C16H22O11Na 413.1057, Found 413.1060.
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Ethyl 4,6-O-benzylidene-1-thio-β-D-glucopyranoside (23). To a solution of pentaacetate 22
(3.00 g, 7.69 mmol) in CH2Cl2 (80 mL) were added ethanethiol (573 mg, 9.22 mmol) and ZrCl4
(2.15 g, 9.22 mmol). The mixture was stirred for 2 h at 0 °C under Ar atmosphere. The reaction
was quenched by addition of ice water (50 mL). The aqueous mixture was extracted with CH2Cl2.
The combined organic layer was successively washed with 1 M aq HCl, saturated aq NaHCO3,
H2O, and brine. After the general drying procedure, the crude product was obtained as a white
powder.
A mixture of the crude product and NaOMe (125 mg, 2.31 mmol) in MeOH (80 mL) was
stirred for 1 h at rt. To the mixture was added protic ion-exchanger resin, IR-120 PLUS (H), until
the pH of the mixture became ~7. Then it was filtered through a cotton pad. The filtrate was
concentrated.
To a solution of the resulting residue in DMF (80 mL) were added PhCH(OMe)2 (1.40 g, 9.23
mmol) and CSA (536 mg, 2.31 mmol) at rt. The reaction was carried out using rotary evaporator
under reduced pressure (~15 mmHg) removing methanol for 2 h at rt; stirring of reaction mixture
was performed by rotation of the flask. Then the reaction mixture was concentrated to remove
most DMF at 80 °C. To the mixture was added saturated aq NaHCO3 until a white powder
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precipitated. It was cooled to 0 °C, and filtered by Hirsch funnel. The crude product was purified
by recrystallization (EtOAc/n-hexane) to afford 23 (2.21 g, 92% for 3 steps) as a white powder.
1H NMR data for 2,3-diol 23 was identical to the literature data.40
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Ethyl 2,3-di-O-benzyl-4,6-O-benzylidene-1-thio-β-D-glucopyranoside. To a solution of
2,3-diol 23 (1.00 g, 3.20 mmol) and 60% NaH in mineral oil (513 mg, 12.8 mmol) in DMF (30
mL) was added BnBr (2.19 g, 12.8 mmol) at 0 °C under Ar atmosphere. The mixture was stirred
for 2 h at 0 °C. To the reaction mixture was added saturated aq NH4Cl until the pH of the mixture
became ~7. The aqueous mixture was extracted with EtOAc. The combined organic layer was
successively washed with saturated aq NH4Cl, H2O, and brine. After the general drying
procedure, the resulting residue was purified by successive column chromatography (30 g of SiO2,
n-hexane/EtOAc = 6/1 to 2/1, followed by 30 g of SiO2, n-hexane/EtOAc = 10/1 to 2/1) to afford
ethyl 2,3-di-O-benzyl-4,6-O-benzylidene-1-thio-β-D-glucopyranoside (1.55 g, 99%) as a white
powder, 1H NMR data of which was identical to the literature data.62
Ethyl 2,3-di-O-benzyl-1-thio-β-D-glucopyranoside (14): Hydrolysis by using aq HCl. To
a solution of ethyl 2,3-di-O-benzyl-4,6-O-benzylidene-1-thio-β-D-glucopyranoside (50.0 mg, 105
µmol) in acetone (4 mL) was added 1 M aq HCl (0.1 mL). The mixture was refluxed for 1 h. The
reaction was quenched by addition of 1 M aq NaOH until the pH of the mixture became ~7. The
mixture was concentrated to remove acetone. The resulting aqueous mixture was extracted with
EtOAc. The combined organic layer was successively washed with saturated aq NaHCO3, H2O,
and brine. After the general drying procedure, the resulting residue was purified by column
chromatography (2 g of SiO2, n-hexane/EtOAc = 9/1 to 2/1) to afford 4,6-diol 14 (40.6 mg, 99%
1
yield) as a straw color amorphous solid, H NMR data of which was identical to the literature
data.29 Hydrolysis by using aqueous acetic acid.
A
solution of ethyl
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2,3-di-O-benzyl-4,6-O-benzylidene-1-thio-β-D-glucopyranoside (808 mg, 1.70 mmol) in aq
AcOH (AcOH: 40 mL, H2O: 10 mL) was refluxed for 30 min, then cooled to rt. Toluene (50 mL)
was added to the mixture, and the solution was concentrated to remove AcOH and H2O
azeotropically. This procedure was repeated five times. The resulting residue was purified by
column chromatography (20 g of SiO2, n-hexane/EtOAc = 2/1 to 0/1) to afford 4,6-diol 14 (628
mg, 95% yield).
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Ethyl 2,3-di-O-benzyl-4,6-O-bis(4-O-benzyl-3,5-di-O-methoxymethylgalloyl)-1-thio-β-D-
glucopyranoside (24). To a solution of 4,6-diol 14 (891 mg, 2.30 mmol) and carboxylic acid 13
(1.73 g, 4.95 mmol) in CH2Cl2 (15 mL) and pyridine (5 mL) were added EDCI·HCl (1.27 g, 6.60
mmol) and DMAP (134 mg, 1.10 mmol). The mixture was stirred for 14.5 h at rt under Ar
atmosphere. The reaction was quenched by addition of 1 M aq HCl until pH of the mixture
became ~1. The aqueous mixture was extracted with EtOAc. The combined organic layer was
successively washed with H2O and brine. After the general drying procedure, the mixture was
purified by column chromatography (30 g of SiO2, n-hexane/EtOAc = 4/1 to 2/1) to afford
4,6-digallate 24 (2.33 g, 99% yield) as a colorless amorphous solid: [α]D25 –14.6 (c 1.56, CHCl3);
IR (neat) 3095, 3065, 3030, 2950, 2923, 2851, 1723, 1592, 1497, 1433, 1393, 1327, 1302, 1217,
1194, 1156, 1109, 1048, 924, 865, 800, 756, 735, 698 cm–1; 1H NMR (400 MHz,
CDCl3) δ 7.50–7.28 (m, 19H), 7.13–7.08 (m, 5H), 5.27 (dd, J = 9.3, 9.8 Hz, 1H), 5.21–5.12 (m,
12H), 4.92 (d, J = 10.3 Hz, 1H), 4.79 (d, J = 11.0 Hz, 1H), 4.74 (d, J = 10.3 Hz, 1H), 4.66 (d, J =
11.2 Hz, 1H), 4.58 (d, J = 9.7 Hz, 1H), 4.54 (dd, J = 12.2, 2.5 Hz, 1H), 4.27 (dd, J = 12.2, 7.3 Hz,
1H), 3.90 (ddd, J = 9.8, 7.3, 2.5 Hz, 1H), 3.83 (dd, J = 8.9, 9.3 Hz, 1H), 3.56 (dd, J = 9.7, 8.9 Hz,
1H), 3.47 (s, 6H), 3.45 (s, 6H), 2.82–2.66 (m, 2H), 1.28 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 165.7 (s), 164.9 (s), 151.1 (s, 2C), 151.0 (s, 2C), 143.4 (s), 143.3 (s), 138.0 (s), 137.9
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(s), 137.4 (s), 137.4 (s), 128.6–127.8 (9 peaks were observed overlapping many doublets, 20C),
125.4 (s), 124.9 (s), 112.4 (d, 4C), 95.6 (t, 4C), 85.2 (d), 83.7 (d), 81.6 (d), 76.2 (d), 75.8 (t), 75.6
(t), 75.4 (t), 75.4 (t), 71.6 (d), 64.2 (t), 56.6 (q, 2C), 56.5 (q, 2C), 25.2 (t), 15.3 (q); HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C58H64O17SNa 1087.3762, Found 1087.3709.
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Ethyl 2,3-di-O-benzyl-4,6-O-bis(4-O-benzylgalloyl)-1-thio-β-D-glucopyranoside (12). To
a solution tetrakis(methoxymethyl ether) 24 (2.60 g, 2.44 mmol) in THF (6 mL) was added a
mixture of i-PrOH and concd aq HCl (50/1 v/v, 18 mL). The mixture was stirred for 13 h at 50 °C.
The eluent to check the reaction by TLC was CHCl3/MeOH/formic acid (10/1/0.01), which
improved the resolution performance of the spots. After cooling to rt, the reaction was quenched
by addition of saturated aq NaHCO3 until the pH of the mixture became ~7. After concentration
of the mixture to remove most of i-PrOH, the aqueous mixture was extracted with EtOAc. The
combined organic layer was successively washed with saturated aq NaHCO3, H2O, and brine.
After the general drying procedure, the resulting residue was purified by column chromatography
(60 g of SiO2, n-hexane/EtOAc = 6/1 to 0/1) to afford tetraol 12 (2.08 g, 95% yield) as a colorless
amorphous solid: mp 58–60 °C; [α] D26 +20.5 (c 1.30, CHCl3); IR (neat) 3393, 3112, 3090, 3065,
3033, 2963, 2932, 2882, 1717, 1707, 1601, 1522, 1455, 1356, 1267, 1217, 1183, 1092, 1057,
1
1030, 1005, 914, 872, 853, 754, 698 cm–1; H NMR (400 MHz, CDCl3) δ 7.40–7.29 (m, 15H),
7.18 (br s, 2H), 7.11–7.09 (m, 7H), 5.87 (br s, 4H), 5.36 (dd, J = 9.6, 9.6 Hz, 1H), 5.15–5.08 (m,
4H), 4.93 (d, J = 10.2 Hz, 1H), 4.76 (d, J = 11.1 Hz, 1H), 4.76 (d, J = 10.2 Hz, 1H) 4.62 (d, J =
11.1 Hz, 1H), 4.58 (d, J = 9.5 Hz, 1H), 4.45–4.44 (m, 2H), 3.82–3.76 (m, 2H), 3.60 (dd, J = 9.5,
13
9.2 Hz, 1H), 2.85–2.70 (m, 2H), 1.33 (t, J = 7.4 Hz, 3H); C NMR (100 MHz, CDCl3) δ 166.6
(s), 165.8 (s), 149.2 (s, 2C), 149.2 (s, 2C), 138.1 (s), 138.0 (s), 137.8 (s), 137.7 (s), 136.9 (s),
136.9 (s), 129.0–127.8 (11 peaks were observed overlapping many doublets, 20C), 125.0 (s),
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124.5 (s), 110.1 (d, 2C), 110.0 (d, 2C), 85.6 (d), 83.5 (d), 81.6 (d), 75.9 (t), 75.6 (d), 75.5 (t), 75.4
(t), 71.4 (d), 63.6 (t), 58.7 (t), 25.3 (t), 15.3 (q); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C50H48O13SNa 911.2713, Found 911.2670.
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Table 1: Ethyl 4,6-(aS)-[4,4’,6,6’-tetrahydroxy-5,5’-bisbenzyloxy-1,1’-biphenyl-2,2’-
dicarboxylate]-2,3-di-O-benzyl-1-thio-β-D-glucopyranoside (11).
Entry 1. A solution of CuCl2 (15.1 mg, 112 µmol) and n-BuNH2 (32.9 mg, 450 µmol) in
MeOH (1 mL) was stirred for 30 min at rt to prepare a blue solution of CuCl2–n-BuNH2 complex
under Ar atmosphere. Then a solution of digallate 12 (20.0 mg, 22.5 µmol) in MeOH (1 mL) was
added to the solution of CuCl2–n-BuNH2 complex. The mixture was stirred for 4 h at rt. The
reaction mixture was diluted with Et2O (3 mL) and added 5 M aq HCl (5 mL) and Et2O (3 mL).
After extraction of the aqueous mixture with Et2O, the combined organic layer was successively
washed with 3 M aq HCl, H2O, saturated aq NaHCO3, H2O, and brine. After the general drying
procedure, the resulting residue was purified by column chromatography (3 g of SiO2,
n-hexane/EtOAc = 6/1 to 2/1) to afford 11 (6.8 mg, 34% yield).
Entry 2. A solution of CuCl2 (9.1 mg, 68 µmol) and n-BuNH2 (19.8 mg, 270 µmol) in MeOH
(0.8 mL) was stirred for 30 min at rt. To this was added a solution of 12 (20.0 mg, 22.5 µmol) in
MeOH (1.2 mL). The mixture was stirred for 13 h at rt. The subsequent procedures were same
with those in Entry 1 to afford 11 (13.9 mg, 70% yield).
Entry 3. A solution of CuCl2 (7.6 mg, 56 µmol) and n-BuNH2 (16.4 mg, 225 µmol) in MeOH
(0.7 mL) was stirred for 30 min at rt. To this was added a solution of 12 (25.0 mg, 28.1 µmol) in
MeOH (0.7 mL). The mixture was stirred for 26 h at rt. The subsequent procedures were same
with those in entry 1 to afford 11 (16.2 mg, 65% yield).
Entry 4. A solution of CuCl2 (30.3 mg, 225 µmol) and n-BuNH2 (98.7 mg, 1.35 mmol) in
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MeOH (1 mL) was stirred for 1 h at rt. To this was added a solution of digallate 12 (100.0 mg,
112 µmol) in MeOH (3 mL). The mixture was stirred for 2.5 h at rt. The reaction mixture was
diluted with Et2O (5 mL) and added 5 M aq HCl (10 mL) and Et2O (5 mL). After extraction of
the aqueous mixture with Et2O, the combined organic layer was successively washed with 3 M aq
HCl, H2O, saturated aq NaHCO3, H2O, and brine. After the general drying procedure, the
resulting residue was purified by column chromatography (8 g of SiO2, n-hexane/EtOAc = 6/1 to
2/1) to afford 11 (88.4 mg, 89% yield).
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Entry 5. A solution of CuCl2 (30.3 mg, 225 µmol) and n-BuNH2 (165 mg, 2.25 mmol) in
MeOH (1 mL) was stirred for 1 h at rt. To this was added a solution of digallate 12 (100 mg, 112
µmol) in MeOH (3 mL). The mixture was stirred for 30 min at rt. The subsequent procedures
were same with those in entry 4 to afford 11 (98.3 mg, 99% yield) as a yellow syrup.
Entry 6. A solution of CuCl2 (30.3 mg, 225 µmol) and n-BuNH2 (247 mg, 3.38 mmol) in
MeOH (1 mL) was stirred for 1.25 h at rt. To this was added a solution of digallate 12 (100 mg,
112 µmol) in MeOH (3 mL). The mixture was stirred for 15 min at rt. The subsequent procedures
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were same with those in entry 4 to afford 11 (99.7 mg, 100% yield): [α]D −28.1 (c 1.60,
CHCl3); IR (neat) 3510, 3424, 3111, 3088, 3065, 3033, 3009, 2961, 2928, 2874, 1743, 1609,
1
1586, 1499, 1455, 1364, 1181, 1132, 1061, 1044, 974, 916, 845, 814, 752, 698 cm–1; H NMR
(400 MHz, CDCl3) δ 7.41–7.27 (m, 16H), 7.25–7.14 (m, 4H), 6.67 (s, 1H), 6.47 (s, 1H), 5.90 (br
s, 2H), 5.80 (br s, 1H), 5.71 (br s, 1H), 5.18–5.11 (m, 5H), 5.07 (dd, J = 9.9, 9.8 Hz, 1H), 4.87 (d,
J = 10.3 Hz, 1H), 4.78–4.67 (m, 3H), 4.46 (d, J = 9.7 Hz, 1H), 3.96 (br d, J = 13.0 Hz, 1H),
3.76–3.69 (m, 2H), 3.50 (dd, J = 9.7, 9.0 Hz, 1H), 2.83–2.68 (m, 2H), 1.32 (t, J = 7.4 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 168.0 (s), 167.2 (s), 149.2 (s), 149.2 (s), 147.4 (s), 147.4 (s),
138.0 (s), 137.9 (s), 136.7 (s, 2C), 136.3 (s), 135.8 (s), 130.6 (s), 129.7 (s), 129.0–128.0 (8 peaks
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were observed overlapping many doublets, 20C), 114.9 (s), 113.3 (s), 108.8 (d), 107.8 (d), 85.9
(d), 83.6 (d), 81.7 (d), 75.9 (t), 75.9 (d), 75.8 (t), 75.6 (t), 75.2 (t), 72.1 (d), 64.0 (t), 25.1 (t), 15.2
(q); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C50H46O13SNa 909.2557, Found 909.2516.
Ethyl 4,6-(aS)-[4,4’,5,5’,6,6’-hexakisbenzyloxy-1,1’-biphenyl-2,2’-dicaboxylate]-2,3-di-
O-benzyl-1-thio-β-D-glucopyranoside (25). A mixture of tetraol 11 (98.3 mg, 111 µmol),
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K2CO3 (122 mg, 885 µmol), and BnBr (151 mg, 885 µmol) in acetone (2.5 mL) was stirred for
13 h at rt under Ar atmosphere. The mixture was then filtered through a cotton-Celite pad to
remove excess K2CO3. Saturated aq NH4Cl (10 mL) was added to the filtrate. The aqueous
mixture was extracted with Et2O. The combined organic layer was successively washed with
saturated aq NH4Cl, H2O, and brine. After the general drying procedure, the resulting mixture
was purified by column chromatography (3 g of SiO2, n-hexane/EtOAc = 6/1 to 3/1) to afford 25
(137 mg, 98% yield) as a yellow syrup: [α]D23 −37.5 (c 1.00, CHCl3); IR (neat) 3088, 3063, 3032,
3009, 2928, 2874, 1746, 1593, 1497, 1482, 1455, 1431, 1368, 1333, 1271, 1188, 1145, 1096,
1
1050, 1045, 1025, 1010, 911, 843, 739, 696 cm–1; H NMR (400 MHz, CDCl3) δ 7.49–7.25 (m,
26H), 7.24–7.18 (m, 4H), 7.16–7.09 (m, 6H), 7.03–6.98 (m, 4H), 6.92 (s, 1H), 6.64 (s, 1H),
5.22–4.70 (m, 10H), 4.94–4.70 (m, 8H), 4.50 (d, J = 9.8 Hz, 1H), 3.99 (br d, J = 13.1 Hz, 1H),
3.79–3.73 (m, 2H), 3.56 (dd, J = 9.8, 8.5 Hz, 1H), 2.86–2.71 (m, 2H), 1.34 (t, J = 7.4 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 168.0 (s), 167.0 (s), 152.7 (s), 152.6 (s), 152.5 (s), 152.4 (s),
145.0 (s), 144.6 (s), 138.2 (s, 2C), 138.2 (s, 2C), 137.9 (s, 2C), 137.7 (s), 137.6 (s), 136.7 (s),
136.6 (s), 129.1–127.5 (14 peaks were observed overlapping many doublets, 40C), 124.5 (s),
123.7 (s), 108.1 (d), 108.1 (d), 85.9 (d), 83.7 (d), 82.0 (d), 76.2 (d), 76.0 (t), 75.7 (t), 75.7 (t), 75.2
(t, 2C), 75.2 (t), 72.1 (d), 71.5 (t), 71.4 (t), 63.9 (t), 25.2 (t), 15.2 (q); HRMS (ESI-TOF) m/z: [M
+ Na]+ Calcd for C78H70O13SNa 1269.4435, Found 1269.4393.
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Table 2: 4,6-(aS)-[4,4’,5,5’,6,6’-hexakisbenzyloxy-1,1’-biphenyl-2,2’-dicaboxylate]-2,3-
di-O-benzyl-D-gluco-pyranose (26).
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Entry 1. To a solution of thioglucoside 25 (25.2 mg, 20.2 µmol) in THF (1.1 mL) and H2O
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(300 µL) was added NBS (9.0 mg, 51 µmol) at 0 °C. The mixture was stirred for 10 min at 0 °C.
To the mixture was added 10% aq Na2S2O3. The aqueous mixture was extracted with EtOAc. The
combined organic layer was successively washed with H2O and brine. After the general drying
procedure, the resulting residue was purified by column chromatography (1.5 g of SiO2,
n-hexane/EtOAc = 4/1 to 0/1) to afford 26 (12.0 mg, 49% yield). This procedure was repeated 6
times using 25 and NBS (12.5 mg and 4.5 mg, 25.2 mg and 9.0 mg, 64.2 mg and 23 mg, 100 mg
and 29 mg, 115 mg and 41 mg, and 898 mg and 892 mg) to provide 26 in 40, 49, 68, 18, 70, and
22% yield, respectively.
Entry 2. To a solution of 25 (20 mg, 16 µmol) in THF (300 µL) were added MeOTf (26 mg,
160 µmol) and H2O (10 mg, 560 µmol) at rt. The mixture was stirred for 2 h at rt. To the mixture
was added Et3N (100 µL). The mixture was diluted with Et2O (10 mL) and washed with brine.
After the general drying procedure, the resulting residue was purified by column chromatography
(2 g of SiO2, n-hexane/EtOAc = 6/1 to 0/1) to afford 26 (12.5 mg, 65% yield).
Entry 3. To a solution of 25 (20 mg, 16 µmol) in THF (300 µL) were added Sn(OTf)2 (6.7
mg, 160 µmol), PhIO (4.6 mg, 20 µmol), and H2O (10 mg, 560 µmol) at rt. The mixture was
stirred for 2 h at rt. To the mixture was added saturated aq NaHCO3. The aqueous mixture was
extracted with Et2O. The combined organic layer was successively washed with brine. A mass
spectrum and TLC analysis of this extract indicated that none of 26 was produced.
Entry 4. To a solution of 25 (20 mg, 16 µmol) in THF (300 µL) were added Yb(OTf)3 (9.9
mg, 160 µmol), PhIO (4.6 mg, 20 µmol), and H2O (10 mg, 560 µmol) at 0 °C. The mixture was
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stirred for 2 h at 0 °C. To the mixture was added saturated aq NaHCO3. The aqueous mixture was
extracted with Et2O. The combined organic layer was successively washed with brine. A mass
spectrum and TLC analysis of this extract indicated that none of 26 was produced.
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Entry 5. To a solution of 25 (100 mg, 80 µmol) in a mixture of THF (1.2 ml) and H2O (200
µL) was added NIS (45.1 mg, 20 µmol) at 0 °C. The mixture was stirred for 1.5 h at 0 °C. To the
mixture was added further NIS (90 mg, 40 µmol). The mixture was stirred for additional 8 h. To
the mixture was added 10% aq Na2S2O3 solution. The aqueous mixture was extracted with EtOAc.
The combined organic layer was successively washed with H2O and brine. After the general
drying procedure, the resulting residue was purified by column chromatography (10 g of SiO2,
n-hexane/EtOAc = 6/1 to 2/1) to afford 26 (54.7 mg, 57% yield).
Entry 6. (1) To a solution of 25 (20 mg, 16 µmol) in a mixture of MeCN and H2O (10/1 v/v,
0.5 mL) was added NISac51 (9.9 mg, 32 µmol) at rt. The mixture was stirred for 5 min. To the
mixture was added 10% aq Na2S2O3. The aqueous mixture was extracted with Et2O, and the
combined organic layer was successively washed with H2O and brine. After the general drying
procedure, the resulting residue was purified by column chromatography (2.0 g of SiO2,
n-hexane/EtOAc = 6/1 to 1/1) to afford 26 (12.5 mg, 65% yield). (2) To a solution of 25 (20 mg,
16 µmol) in a mixture of MeCN and H2O (10/1 v/v, 0.5 mL) was added NISac (9.9 mg, 32 µmol)
at 0 °C. The mixture was stirred for 2 h at 0 °C. To the mixture was added 10% aq Na2S2O3. The
subsequent procedures were same with the above to afford 26 (10.7 mg, 55% yield).
Entry 7. To a solution of 25 (20 mg, 16 µmol) in a mixture of CH2Cl2 and H2O (10/1 v/v,
300 µL) were added H2SO4–silica52 (5 mg) and NIS (4.3 mg, 19 µmol) at 0 °C. The mixture was
stirred for 15 min at rt, Production of trace 26 was detected by a mass spectrum and TLC analysis.
To the reaction mixture were added THF (100 µL) and H2O (50 µL) at 0 °C. The mixture was
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stirred for 36 h at rt. Although 26 was detected, the reaction was not concluded. In addition, many
byproducts appeared during the reaction.
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Entry 8. To a stirred mixture of thioglucoside 25 (259 mg, 208 µmol) and H2O (1.0 mL) in
CH2Cl2 (10 mL) was added a solution of NIS (225 mg, 1.00 mmol) and TfOH (10.2 mg, 67.8
µmol) in THF/CH2Cl2 (40/1 v/v, 10 mL). The mixture was stirred for 30 min at rt. To the reaction
mixture was added 10% of aq Na2S2O3 until the mixture became colorless. The aqueous mixture
was extracted with Et2O. The combined organic layer was successively washed with H2O and
brine. After the general drying procedure, the resulting residue was purified by column
chromatography (15 g of SiO2, n-hexane/EtOAc = 1/0 to 1/1) to afford 26 (246 mg, 98% yield,
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α/β = 49/51) as a colorless syrup, whose NMR data were identical to the literature data:14 [α]D
−42.5 (c 1.24, CHCl3), lit.14 [α]D20 –48 (c 0.9, CHCl3); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C76H66O14Na 1225.4350, Found 1225.4290.
4,6-(aS)-[4,4’,5,5’,6,6’-hexakisbenzyloxy-1,1’-biphenyl-2,2’-dicaboxylate]-2,3-di-O-benzy
l-1-[3,4,5-trisbenzyloxybenzoyl]-D-glucopyranose (28). To a solution of hemiacetal 26 (246 mg,
204 µmol) in CH2Cl2 (5 mL) was added triethylamine (1 mL). The mixture was stirred for 5 min
at rt under Ar atmosphere. This mixture was added to a solution of 27 (376 mg, 819 µmol) in
CH2Cl2 (15 mL) at rt. The mixture was stirred for 17 h at rt under Ar atmosphere. The reaction
was quenched by addition of 3 M aq HCl until pH of the mixture became ~7. The aqueous
mixture was extracted with CH2Cl2. The combined organic layer was successively washed with
H2O and brine. Besides syrupy 28, 3,4,6-tri-O-benzylgallic acid and the corresponding acid
anhydride were produced as byproducts. These byproducts were easily crystallized. Therefore,
addition of cold EtOAc dissolved the desired 28 mainly, and filtration of the mixture removed the
byproducts. This procedure was repeated 3 times after the general drying procedure. Then the
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filtrate was concentrated. The obtained syrup was purified by column chromatography (30 g of
SiO2, n-hexane/EtOAc = 1/0 to 3/1) to afford 28 (324 mg, 97% yield, α/β = 2/98) as a yellow
syrup. The anomeric ratio was determined by the HPLC (column: YMC-Pack R&D SIL,
D-SIL-5-A, 250 × 20 mm, S-5 µm, 120A; eluent: n-hexane/EtOAc = 6/1).
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Data for α-28: [α]D −24.0 (c 0.15, CHCl3); IR (neat) 3108, 3088, 3063, 3031, 3007, 2955,
2923, 2872, 2851, 1748, 1732, 1592, 1497, 1482, 1455, 1431, 1416, 1369, 1329, 1260, 1229,
1211, 1188, 1150, 1100, 1078, 1028, 1003, 961, 911, 858, 843, 804, 739, 696 cm–1; H NMR
1
(400 MHz, CDCl3) δ 7.47–7.27 (m, 43H), 7.24–6.97 (m, 14H), 6.92 (s, 1H), 6.79 (s, 1H), 6.40 (d,
J = 3.8 Hz, 1H), 5.22–4.69 (m, 24H), 4.06–3.96 (m, 2H), 3.88 (dd, J = 3.8, 9.3 Hz, 1H), 3.77 (br
13
d, J = 13.0 Hz, 1H); C NMR (100 MHz, CDCl3) δ 167.9 (s), 167.0 (s), 164.4 (s), 152.8 (s),
152.8 (s), 152.7 (s), 152.7 (s, 2C), 152.5 (s), 145.2 (s), 144.7 (s), 143.3 (s), 138.5 (s), 138.3 (s),
137.9 (s), 137.8 (s), 137.6 (s), 137.5 (s, 3C), 136.9 (s, 2C), 136.7 (s), 136.6 (s, 2C), 129.1–127.5
(19 peaks were observed overlapping many doublets, 55C), 124.9 (s), 124.4 (s), 123.8 (s), 110.1
(d, 2C), 108.2 (d), 108.1 (d), 90.9 (d), 79.4 (d), 78.5 (d), 75.8 (t), 75.8 (t), 75.4 (t), 75.3 (t, 2C),
74.6 (t), 73.7 (t), 71.7 (t), 71.6 (t), 71.6 (d), 71.5 (t, 2C), 70.2 (d), 63.5 (t); HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C104H88O18Na 1648.5902, Found 1648.5962.
25
Data for β-28: [α]D −36.5 (c 0.23, CHCl3); IR (neat) 3090, 3065, 3033, 3007, 2923, 2872,
2853, 2361, 2342, 1746, 1736, 1592, 1499, 1455, 1429, 1370, 1335, 1188, 1144, 1098, 1057,
1028, 976, 910, 844, 825, 815, 739, 696 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.46–7.26 (m, 38H),
7.25–7.17 (m, 7H), 7.15–7.08 (m, 8H), 6.90 (s, 1H), 6.67 (s, 1H), 5.90 (d, J = 8.3 Hz, 1H), 5.20
(dd, J = 9.8, 9.7 Hz, 1H), 5.17–5.03 (m, 15H), 5.00 (d, J = 10.7, 1H), 4.90 (d, J = 10.8, 2H), 4.84
(d, J = 11.0 Hz, 1H), 4.82 (d, J = 11.7 Hz, 1H), 4.77 (d, J = 10.7 Hz, 1H), 4.71 (d, J = 11.7 Hz,
1H), 4.65 (d, J = 11.1 Hz, 1H), 4.55 (d, J = 11.1 Hz, 1H), 4.03–3.95 (m, 2H), 3.85 (dd, J = 9.4,
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9.8 Hz, 1H), 3.80 (dd, J = 8.3, 9.4 Hz, 1H); C NMR (100 MHz, CDCl3) δ 167.9 (s), 167.0 (s),
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164.5 (s), 152.8 (s, 2C), 152.8 (s), 152.7 (s), 152.6 (s), 152.5 (s), 145.2 (s), 144.6 (s), 143.3 (s),
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138.2 (s), 138.1 (s, 2C), 137.9 (s), 137.8 (s), 137.7 (s), 137.6 (s), 137.5 (s), 136.7 (s, 2C), 136.7 (s,
2C), 136.7 (s), 129.1–127.5 (19 peaks were observed overlapping many doublets, 55C), 124.6 (s),
123.9 (s), 123.7 (s), 109.7 (d, 2C), 108.3 (d), 108.0 (d), 94.8 (d), 81.7 (d), 81.4 (d), 75.7 (t), 75.4
(t), 75.3 (t, 2C), 75.2 (t), 75.2 (t), 75.0 (t), 72.3 (d), 71.9 (d), 71.6 (t), 71.4 (t, 3C), 63.6 (t); HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C104H88O18Na 1648.5902, Found 1648.5828.
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(−)-Strictinin (1). To a solution of undecabenzyl ether β-28 (61.2 mg, 34.6 µmol) in THF (1
mL) and MeOH (1 mL) was added Pd(OH)2 on carbon (20 wt. %, 26.4 mg, 188 µmol). The
mixture was stirred for 3 h at rt under H2 atmosphere. The mixture was filtered through a
cotton-Celite pad to remove Pd. The concentrated filtrate was purified by reverse phase column
chromatography and gel permeation chromatography (2 g of Cosmosil 140C18-PREP, acetone
only, followed by 2 g of TOYOPEARL HW-40C, MeOH only) to afford (−)-strictinin (1) (23.6
1
mg, 99% yield) as a white amorphous solid. H NMR data for 1 were identical to the literature
data (see SI):2 [α]D24 −2.94 (c 0.16, MeOH), lit.2 [α]D –3.1 (c 0.4, MeOH); 13C NMR (100 MHz,
acetone-d6) δ 168.5 (s), 168.3 (s), 165.5 (s), 146.1 (s, 2C), 145.0 (s, 2C), 144.8 (s), 144.7 (s),
139.4 (s), 136.5 (s), 136.2 (s), 127.0 (s), 126.6 (s), 120.9 (s), 116.3 (s), 116.0 (s), 110.4 (d, 2C),
108.2 (d), 107.9 (d), 96.0 (d), 75.6 (d), 74.6 (d), 73.3 (d), 72.8 (d), 63.7 (t); HRMS (ESI-TOF)
m/z: [M − H]— Calcd for C27H21O18 633.0728, Found 633.0685.
Dimethyl (aS)-4,4’,5,5’,6,6’-hexakisbenzyloxybiphenyl-6,6’-dicarboxylate (aS-29). To a
solution of 25 (50.0 mg, 40.1 µmol) in MeOH (2 mL) and THF (1 mL) was added NaOMe (5.4
mg, 0.10 mmol). The mixture was stirred at rt for 1 h, at 55 °C for 3 h, refluxed for 17 h, and
cooled to rt. To the mixture was added protic ion-exchanger resin, IR-120 PLUS (H) until the pH
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of the mixture became ~7. The mixture was filtered through a cotton pad. The filtrate was
concentrated and purified by column chromatography (5.0 g of SiO2, n-hexane/EtOAc = 7/1 to
1/3) to afford (aS)-29 (26.4 mg, 73% yield) and 14 (12.4 mg, 76% yield) both as a colorless oil.
1H NMR data and optical rotation for 29 were identical to the literature data.44
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Direct glycosyl ester formation of 25 with 30. To a solution of 25 (50.0 mg, 40.1 µmol) and
carboxylic acid 30 (52.9 mg, 120 µmol) in CH2Cl2 (4 mL) were added MeOTf (26.3 mg, 160
µmol) and MS 4A (30.0 mg) at rt under Ar atmosphere. The mixture was stirred for 1 h. Then, to
the mixture were added further MeOTf (26.3 mg, 160 µmol). The mixture was stirred for 7.5 h.
To the mixture was added 2,6-lutidine (1 mL). The mixture was refluxed for 9.5 h and cooled to
rt. To the mixture was added 1 M aq HCl until the pH of it became ~6. The aqueous mixture was
extracted with EtOAc. The combined organic layer was successively washed with H2O and brine.
After the general drying procedure, the resulting residue was purified by column chromatography
(15.0 g of SiO2, n-hexane/EtOAc = 7/1 to 0/1) to afford 28 (56.4 mg, 87% yield, α/β = 83/17) as
a colorless syrup. The anomeric ratio was determined on the basis of integration of anomeric
proton peak of the 1H NMR spectrum.
Acknowledgment. We thank Osaka Synthetic Chemical Laboratories, Inc. for provision of
EDCI. JSPS KAKENHI (Grant Number 22550047) and SUBOR grant partly supported this
work.
1
Supporting Information. Comparison of H NMR spectra of synthetic and natural strictinin,
the full description of General methods, and 1H and 13C NMR spectra for 1, 11–14, 16, 20, 22–26,
28, and 29. This material is available free of charge via the Internet at http://pubs.acs.org.
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