Asymmetric total synthesis of talienbisflavan A

Article abstract of DOI:10.1039/c7ob02837g

The first asymmetric total syntheses of talienbisflavan A and bis-8,8′-epicatechinylmethane as well as a facile synthesis of bis-8,8′-catechinylmethane has been accomplished from readily available starting materials by using a newly developed direct regio

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Asymmetric total synthesis of talienbisflavan A
Deng-Ming Huang,a Hui-Jing Li,*a Jun-Hu Wanga and Yan-Chao Wu*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
The first asymmetric total syntheses of talienbisflavan A and bis-8,8´-epicatechinylmethane as well as a facile synthesis of
bis-8,8´-catechinylmethane has been accomplished from readily available starting materials by using a newly developed
direct regioselective methylenation of catechin derivatives as one of the key steps.
DOI: 10.1039/x0xx00000x
www.rsc.org/
OH
HO
Introduction
O
HO
OH
Flavan-3-ols and the oligomeric procyanidins constitute one of
the major families of polyphenols. These catechin-class
polyphenols possess potential health benefits as a result of
their antibacterial,1 anticancer,2 antioxidant3 and antiviral4
O
HO
HO
O
OH
O
OH
OH
H2C
HO
actions. Among them, dimeric flavanols are
a class of
O
OH
OH
OH
compounds that flavan-3-ol derivatives linked through a
methylene bridge. The typical natural products are
O
1: talienbisflavan A
OH
OH
talienbisflavan A (
1
), bis-8,8´-catechinylmethane (
2) and bis-
OH
5'
4'
HO
3'
HO
6'
7'
OH
8,8´-epicatechinylmethane
(
3), which were isolated from
HO
HO
HO
HO
Camellia taliensis,5 cacao liquor6 and Litchi chinensis,7
respectively. The preliminary studies showed that these
talienbisflavan A-type flavan-3-ol dimers with more catechol
and/or pyrogallol groups attached to the molecules led to
stronger radical scavenging activities.5,8 Unfortunately, these
talienbisflavan A-type natural products are difficult to obtain in
large quantities on account of the limited quantities
components from the natural sources, and thereby prevent
their clinical pharmacological research or development into
commercial products. To overcome this problem, development
of regioselective strategies for the efficient synthesis of these
bioactive natural products becomes a high priority. The
condensation of catechin with formaldehyde has been widely
studied as a model reaction to investigate the utilization of
condensed tannins as wood adhesive9 and HCHO scavenger10
to solve the problem of indoor air pollution caused by volatile
organic compounds. This strategy seems to be one of the
simplest and most straightforward methods for the synthesis
of methylene linked flavanol dimers. However, the goal is
difficult to achieve as the condensation of catechin with
formaldehyde is easy to form the complex higher oligomers
O
OH
O
O
1'
2'
8'
OH
OH
OH
OH
H2C
H2C
1
8
HO
HO
2
O
7
3
6
5
OH
OH
OH
4
OH
2: bis-8,8'-catechinylmethane
3: bis-8,8'-epicatechinylmethane
Fig. 1 Representatives of talienbisflavan A-type natural products.
mixtures.10 The poor C8-C8´/C8-C6´ regioselectivity makes this
endeavour even more Accordingly,
demanding.10
regioselective and concise synthesis of talienbisflavan A-type
flavan-3-ol dimers from catechin is still a challenge to date.
Ducrot reported an elegant synthesis of bis-8,8´-
catechinylmethane (
2) via the transformation of tetra-O-benzyl
catechin (4) to the corresponding penta-O-benzyl 8-formyl-
11,12
catechin (
hydrogenolysis conditions.11 Bis-8,8´-catechinylmethane
and bis-8,6´-catechinylmethane ( ) were obtained in 28% and
5
)
and subsequent reaction with catechin under
(2)
7
19% yields, respectively (Scheme 1). The result reflected that
the C8-C8´regioselectivity is poor when using catechin as the
nucleophile. Recently, Selenski developed a regioselective
synthesis of deca-O-benzyl bis-8,8´-catechinylmethane
from tetra-O-benzyl catechin ( ) in 5 steps via the key acid
intermediate
(Scheme 1).12 With the use of penta-
benzylated catechin instead of catechin as the nucleophile,
(9)
4
8
9
was obtained as a single diastereomer (Scheme 1).12 In
contrast to the C8 position of penta-benzylated catechin, the
C6 position suffers from severe steric congestion due to freely
rotating substituents,13 and thereby leads to a high C8-C8´
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OH
DIBAL-H, toluene
BnO
BnO
BnO
BnO
HO
-78 oC, 1 h
BnBr, K2CO3
OH
OH
HO
OBn
then 0 oC, 2 h
94%
OH
OH
acetone, reflux,
15 h, 90%
3'
HO
HO
6'
OH
O
11
12
13
montmorillonite
O
HO
HO
OH
O
O
3'
8'
H2C
OBn
OBn
OH
OH
CHO
8
8'
HO
14 K-10, CH2Cl2, rt,
8
BnO
O
HO
O
15 h, 60%
Pd/C, H2
catechin (6)
BnO
OBn
OH
O
3
6'
H2C
3
+
OH
OH
OBn
OBn
OBn
OBn
OH
1
O
8
8
OBn
5
HO
2
BnO
OH
BnO
OH
2 (28%)
5 steps
ref 15
(HCHO)n, Hf(OTf)4
OBn
7
6
3
3
CH2Cl2, rt, 0.3 h
95%
Ducrot's work11 2 steps
OH
7 (19%)
OH
5
4
OBn
6'
OBn
OH
OBn
4
OBn 15
3'
BnO
OBn
OBn
6'
BnO
1
O
8
HO
O
2
BnO
8'
H2C
5 steps
OBn Pd/C, H2
OBn
7
6
BnO
BnO
BnO
3
2 (30%)
8
O
Pd(OH)2/C, H2,
BnO
EtOAc
OBn
OBn
8'
H2C
O
Selenski's
work12
OH
5
4
2: bis-8,8'-catechinylmethane
OBn
OBn
OBn
3
4
THF/MeOH, rt,
10 h, 90%
8
OBn
BnO
O
OBn
9
this work 1 step
OBn
OH
OBn
DMP, CH2Cl2,
rt, 16 h, 87%
3'
HO
10
6'
1 step
OBn
OBn
OBn
CO2H
OBn
HO
2 (90%)
3 (59%)
1 (35%)
BnO
BnO
O
OBn
O
8
O
BnO
8'
C
8
O
OBn
OBn
H2
3 steps
4 steps
3
BnO
BnO
BnO
10
BnO
O
OBn
H2C
O
L-Selectride
OBn
O
OBn
OBn
OBn
OBn
OBn
3
OBn
H2C
THF, -78 oC, 4 h
75%
8
BnO
OH
BnO
O
BnO
OBn
O
OH
Scheme 1 Synthesis of methylene linked flavanol dimers.
OBn
OBn
16
17
OBn
OBn
BnO
BnO
BnO
BnO
O
O
Cl
OBn
regioselectivity (Scheme 1). Removal of the ten O-Bn functions
in deca-O-benzyl bis-8,8´-catechinylmethane ( ) under the
hydrogenolysis conditions afforded bis-8,8´-catechinylmethane
) in a quite low yield (30%, Scheme 1).12 Considering removal
of an aromatic O-Bn function is usually easier than that of an
aliphatic O-Bn function, we envisioned that might be
obtained in a higher yield with the use of octa-O-benzyl bis-
8,8´-catechinylmethane (10) instead of as the intermediate
18
O
9
BnO
BnO
DMAP, CH2Cl2,
rt, 16 h, 60%
O
OBn
O
Pd(OH)2/C, H2
,
OBn
OBn
H2C
THF/MeOH, rt,
10 h, 90%
BnO
(
2
O
OBn
19
3: bis-8,8'-epicatechinylmethane
Pd(OH)2/C, H2,
THF/MeOH, rt,
10 h, 84%
OBn
OBn
O
2
OBn
9
1: talienbisflavan A
(Scheme 1). In connection with our consistent interest towards
the development of concise strategies for the synthesis of
bioactive compounds,14 herein we would like to report the first
Scheme 2 Total synthesis of talienbisflavan A (1), bis-8,8´-catechinylmethane (2) and
bis-8,8´-epicatechinylmethane (3).
direct methylenation of tetra-O-benzyl catechin
(4) with
The direct methylenation of
4 with paraformaldehyde was
paraformaldehyde to afford the desired octa-O-benzyl bis-8,8´-
catechinylmethane (10) as a single diastereomer. The newly
developed strategy was then used for the efficient synthesis of
extensively investigated, and the representative results are
shown in Table 1. This methylenation reaction should be
performed as mild as possible to improve its C8-C8´/C8-C6´
regioselectivity (Schemes 1 and 2). By treating tetra-O-benzyl
bis-8,8´-catechinylmethane (
synthesis of bis-8,8´-epicatechinylmethane
talienbisflavan A ( , Scheme 1). The concise synthesis could be
2), as well as the first total
(3)
and
catechin (4) with paraformaldehyde in the presence of a
1
catalytic amount of montmorillonite K-10 (1 mol %) or acitic
acid (CH3CO2H, 1 mol %) in dichloromethane (CH2Cl2) at room
temperature for 12 hours, no reaction took place and the
used for the preparation of sufficient quantities of these
bioactive molecules for biological and medical studies.
starting material of
4
was recovered (Table 1, entries 1 and 2).
mol %), p-
Gratifyingly, trifluoroacetic acid (CF3CO2H,
1
Results and discussion
toluenesulfonic acid (p-TsOH, 1 mol %), aqueous hydrochloric
acid (HCl, 1 mol %) and concentrated sulfuric acid (H2SO4, 1
mol %) displayed some efficiency for this reaction. Treatment
As shown in Scheme 2, the synthesis of talienbisflavan A
commenced with commercially available and inexpensive caffic
acid (11). Treatment of caffic acid (11) with BnBr in acetone in
the presence of K2CO3 under reflux for 15 hours afforded ester
12 in 90% yield. Reduction of ester 12 with DIBAL-H occurred
smoothly to provide alcohol 13 in 94% yield. Friedel–Craft
alkylation of 3,5-bis(benzyloxy)phenol (14) with alcohol 13 in
the presence of montmorillonite K-10 generated phenol 15 in
60 % yield. Following Chan’s procedure,15 phenol 15 was
of
acids afforded octa-O-benzyl bis-8,8´-catechinylmethane (10),
in 30–32% yields, as single diastereomer at room
temperature within 12 hours (entries 3–6). When 1 mol % of
TiCl4, SnCl4 or CuCl2 was used, treatment of with
4 with paraformaldehyde in the presence of these Brønsted
a
4
paraformaldehyde afforded 10 in 20–23% yields under the
same conditions, albeit within a shorter reaction time (i.e., 5 h
converted to tetra-O-benzyl catechin (4) in five steps with 39%
versus 12 h, entries 3–9). The direct methylenation of
4 with
overall yield. The physical, spectroscopic, and spectrometric
data (1H NMR, 13C NMR, [α]D and HRMS) of the synthetic
material are identical to those reported in the literature.15
paraformaldehyde could be accomplished in 55–70% yields
with the use of BiCl3 (1 mol %), InCl3 (1 mol %), FeCl3 (1 mol %)
or BF3·Et2O (1 mol %) as the promoter (entries 10–13). Other
2 | J. Name., 2012, 00, 1-3
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Table 1 Survey of conditions for the direct methylenation of tetra-O-benzyl catechin (4)
with paraformaldehyde a
hydrogenolysis of
9
(i.e., 30% versus 90%),12 supporting our
previous anticipation (Schemes 1 and 2). On the other hand,
Dess–Martin oxidation of 10 gave ketone 16 in 87% yield,
which, in turn, was reduced by L-selectride to provide
exclusively the cis-substituted octa-O-benzyl bis-8,8´-
OBn
HO
BnO
O
OBn
O
OBn
OBn
OBn
OBn
H2C
BnO
BnO
O
(HCHO)n
epicatechinylmethane (17) in 75% yield. As in the case of 10
,
BnO
conditions
removal of the eight O-Bn functions in 17 under the
OH
OH
OBn
4
10
OBn
hydrogenolysis conditions did afford the desirable bis-8,8´-
epicatechinylmethane (3) in an excellent yield (Scheme 2).
Entry
1
Promoter
Equiv.
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.003
Time (h)
Yield (%)
0
Esterification of 17 with 3,4,5-tri-O-benzylgalloyl chloride (18),
prepared from 3,4,5-tri-O-benzylgalloyl acid and oxalyl chloride
in CH2Cl2, gave ester 19 in 85% yield. Finally, removal of the
fourteen O-Bn functions in 19 under the hydrogenolysis
montmorillonite K-10
CH3CO2H
CF3CO2H
p-TsOH
12
12
12
12
12
12
5
2
0
3
30
32
30
31
20
20
23
55
60
70
55
28
20
80
85
95
90
4
5
HCl (37%, H2O)
H2SO4
conditions afforded talienbisflavan A (1) in 84% yield (Scheme
2). The physical, spectroscopic, and spectrometric data (1H
6
NMR, 13C NMR, [α]D and HRMS) of the synthetic materials
are identical to those of natural products.5–7
1–3
7
TiCl4
8
SnCl4
5
9
CuCl2
5
Scheme
talienbisflavan A (
the newly developed regioselective methylenation strategy
mentioned above. The treatment of tetra-O-benzyl catechin (
3
illustrates an alternative synthesis of
10
11
12
13
14
15
16
17
18
19
BiCl3
5
1
) and bis-8,8´-epicatechinylmethane ( ) via
3
InCl3
5
FeCl3
5
4
)
BF3•Et2O
Yb(OTf)3
La(OTf)3
Al(OTf)3
Sc(OTf)3
Hf(OTf)4
Hf(OTf)4
5
with Dess–Martin periodinane followed by reduction with L-
selectride afforded exclusively the cis-substituted tetra-O-
benzyl epicatechin (20) in 75% overall yield (Scheme 3). The
direct methylenation of 20 with paraformaldehyde went
smoothly in the presence of Hf(OTf)4 (1 mol %) under mild
2
2
1
1
0.3
5
conditions
to
afford
octa-O-benzyl
bis-8,8´-
a
epicatechinylmethane (17) as a single diastereomer in 92%
yield. 17 underwent O-Bn deprotection to generate bis-8,8´-
General conditions: 4 (0.03 mmol, 1.0 equiv.), paraformaldehyde (0.03 mmol,
1.0 equiv.) and promoter (9×10-5–3×10-4 mmol, 0.003–0.01 equiv.) in CH2Cl2 (c =
1 M) at room temperature for 0.3–12 h.
epicatechinylmethane (3) in 90% yield (Scheme 3). On the
other hand, Acylation of 20 with 3,4,5-tris(benzyloxy)galloyl
chloride (18) gave ester 21 in 80% yield (Scheme 3). Treatment
Lewis acids were also investigated, reaction of
4 with
paraformaldehyde in the presence of various triflate salts (1
mol %) could be finished within 0.3–2 hours (entries 14–18).
The reaction was a little complex in the presence of Yb(OTf)3 (1
mol %) or La(OTf)3 (1 mol %) in CH2Cl2 at room temperature,
and the desirable octa-O-benzyl bis-8,8´-catechinylmethane
OBn
OBn
OBn
OBn
BnO
O
BnO
O
1) DMP, CH2Cl2, rt, 16 h
2) L-Selectride, THF, -78 oC,
4 h, 70% (2 steps)
OH
OH
OBn
OBn
4
20
OBn
OBn
(
10) was obtained in only 28% and 20% yields, respectively
OBn
BnO
BnO
O
(entries 14 and 15). Instead, Al(OTf)3 (1 mol %) or Sc(OTf)3 (1
mol %) was quite effective for this reaction, which afforded 10
in 80% and 85% yields, respectively (entries 16 and 17).
Fortuitously, 10 was obtained in 95% yield within only 0.3 h
when the reaction was performed in the presence of Hf(OTf)4
(1 mol %, entry 18). The reaction was still quite effective when
the loading of Hf(OTf)4 was decreased down to 0.3 mol %
(entry 19). These results are in good agreement with the
related reports in the literature that oxophilic Hf(OTf)4,
superior to the other selected Lewis acids and Brønsted
acids,16 is a mild and efficient catalyst for the promotion of
hydroxyl- or/and carbonyl-involved reactions.17
Cl
BnO
O
18
O
OBn
OBn
OBn
O
DMAP, CH2Cl2,
rt, 12 h, 80%
(HCHO)n, Hf(OTf)4
CH2Cl2, rt, 0.5 h
92%
21
OBn
(HCHO)n, Hf(OTf)4
CH2Cl2, rt, 2 h, 85%
OBn
OBn
BnO
BnO
HO
BnO
BnO
O
O
OBn
OBn
O
OBn
OBn
O
H2C
BnO
BnO
BnO
O
OBn
O
OBn
OBn
H2C
OH
OBn
17
BnO
O
With the desired octa-O-benzyl bis-8,8´-catechinylmethane
Pd(OH)2/C, H2,
OBn
Pd(OH)2/C, H2,
THF/MeOH, rt,
10 h, 84%
OBn
OBn
O
THF/MeOH, rt,
10 h, 90%
(
10) in hand, we turned our efforts towards the total synthesis
of talienbisflavan A ( ), bis-8,8´-catechinylmethane ( ) and bis-
8,8´-epicatechinylmethane ( , Scheme 2). Removal of the eight
O-Bn functions in 10 under the hydrogenolysis conditions
afforded bis-8,8´-catechinylmethane ( ) in 90% yield (Scheme
19
1
2
OBn
3: bis-8,8'-epicatechinylmethane
3
1: talienbisflavan A
Scheme An alternative synthesis of talienbisflavan
epicatechinylmethane (3).
3
A (1) and bis-8,8´-
2
2). This is an obviously higher yield in comparison to the
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of 21 with paraformaldehyde in the presence of Hf(OTf)4 (5
mol %) and subsequent O-Bn deprotection afforded
talienbisflavan A (1) in 71% overall yield (Scheme 3).
71.4, 71.3, 63.7; IR (film): νmax = 3294, 3063, 3033, 2924, 2861,
1653, 1599, 1581, 1510, 1454, 1425, 1380, 1342, 1318, 1260, 1235,
1221, 1163, 1134, 1197, 1080, 1043, 1007, 963 cm-1. HRMS (ESI)
m/z: calcd for C23H23O3 [M + H]+: 347.1647, found: 347.1650.
Synthesis of phenol 15. To
a well stirred mixture of 3,5-
Experimental
bis(benzyloxy)phenol (14, 480 mg, 1.57 mmol) in anhydrous
dichloromethane (20 mL) under nitrogen was added
montmorillonite K-10 (480 mg) at room temperature. Then, a
solution of alcohol 13 (181 mg, 0.52 mmol) in anhydrous
dichloromethane (10 mL) was added dropwise over 30 min. The
resulting purple mixture was stirred at room temperature for 15 h
and then filtered through a pad of Celite, which was rinsed with
ethyl acetate (200 mL). After evaporation, the residue was purified
by column chromatography over silica gel to afford phenol 15 as a
white amorphous foam (198 mg). Yield: 60%; 1 H NMR (400 MHz,
CDCl3): δ/ppm = 7.43–7.32 (m, 20H), 6.95 (d, 1H, J = 1.2 Hz), 6.84–
6.81 (m, 2H), 6.37 (d, 1H, J = 15.5 Hz), 6.27 (d, 1H, J = 1.7 Hz), 6.16
(d, 1H, J = 1.7 Hz), 6.14–6.10 (dd, 1H, J = 15.5, 5.8 Hz), 5.12 (s, 2H),
5.11 (s, 2H), 5.01 (s, 2H), 4.98 (s, 2H), 3.55 (d, 2H, J = 5.8 Hz); 13C
NMR (100 MHz, CDCl3): δ/ppm = 158.5, 157.6, 155.5, 148.7, 148.1,
137.0, 136.8, 136.6, 130.9, 129.8, 128.3, 128.2, 128.1, 127.7, 127.5,
127.4, 127.2, 127.1, 127.0, 126.4, 119.6, 114.8, 112.3, 106.7, 94.8,
93.4, 76.9, 71.1, 70.1, 69.8, 26.1; IR (film): νmax = 3492, 3029, 1621,
1506, 1374, 1116, 997 cm-1. HRMS (ESI) m/z: calcd for C43H38O5Na
[M+Na]+: 657.2617, found: 657.2631.
General methods
Common reagents and materials were purchased from
commercial sources and were used without further
purification. TLC plates were visualized by exposure to ultra
violet light (UV). Chemical shifts for protons are reported in
parts per million (δ scale) downfield from tetramethylsilane
and are referenced to residual protium in the NMR solvents
[CHCl3: δ 7.26, (CD3)2CO: δ 2.05, CD3OD: δ 3.31]. Chemical
shifts for carbon resonances are reported in parts per million
(δ scale) downfield from tetramethylsilane and are referenced
to the carbon resonances of the solvent (CDCl3: δ 77.0, CD3OD:
δ 49.05). Data are represented as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, br = broad), integration, and coupling constant in
Hertz (Hz).
Total synthesis of talienbisflavan A (1), bis-8,8´-catechinylmethane
(2) and bis-8,8´-epicatechinylmethane (3, Scheme 2)
Synthesis of ester 12. To a solution of caffeic acid (11, 1.5 g, 8.3
mmol) in acetone (20 mL) were added potassium carbonate (3.45 g,
25 mmol) and benzyl bromide (3.95 mL, 33.3 mmol). The resulting
mixture was stirred under reflux for 15 h, and was added with
water (20 mL). The mixture was extracted with ethyl acetate (3 × 20
mL), dried over sodium sulfate, filtered, and concentrated under
reduced pressure. The syrupy residue was purified by crystallization
in ethanol to afford ester 12 as a white solid (3.38 g). Yield: 90%;
Synthesis of tetra-O-benzyl catechin (4). Tetra-O-benzyl catechin
(4) was synthesized from phenol 15 according to the literature15
.
M.p. = 115–116°C (lit.,19 115–116 °C); [α]D +3 (c = 1.0, CH2Cl2); 1H
NMR (400 MHz, CDCl3): δ/ppm = 7.54–7.38 (m, 20H), 7.14 (s, 1H),
7.02 (s, 2H), 6.38 (s, 1H), 6.34 (s, 1H), 5.23 (s, 4H), 5.18–5.02 (m,
4H), 4.70 (d, 1H, J = 8.1 Hz), 4.05 (dd, 1H, J = 14.0, 7.9 Hz), 3.19 (dd,
1H, J =16.4, 5.5 Hz), 2.74 (dd, 1H, J = 16.4, 8.7 Hz,); 13C NMR (100
MHz,CDCl3): δ/ppm = 158.7, 157.6, 155.2, 149.1, 148.9, 137.0,
136.9, 136.8, 136.8, 131.0, 128.7, 128.4, 128.4, 128.3, 128.2, 128.0,
127.8, 127.7, 127.6, 127.4, 127.1, 127.0, 120.4, 114.8, 113.8, 102.2,
25
m.p. = 80–81 °C (lit.,18 80-82 °C); H NMR (400 MHz, CDCl3): δ/ppm
1
= 7.64 (d, 1H, J = 15.9 Hz), 7.48–7.34 (m, 15H), 7.15 (s, 1H), 7.09 (d,
1H, J = 8.3 Hz), 6.94 (d, 1H, J = 8.3 Hz), 6.32 (d, 1H, J = 15.9 Hz), 5.26
(s, 2H), 5.22 (s, 2H), 5.19 (s, 2H); 13C NMR (100 MHz, CDCl3): δ/ppm
= 166.9, 151.1, 149.0, 144.9, 136.8, 136.7, 136.2, 128.5, 128.2,
128.2, 127.9, 127.8, 127.3, 127.1, 122.9, 115.8, 114.3, 113.8, 71.3,
71.0, 66.2; IR (film): νmax = 3068, 3025, 2907, 2857, 1683, 1595,
1516, 1445, 1390, 1272, 1130, 1021, 946, 871, 840, 816 cm-1. HRMS
(ESI) m/z: calcd for C30H27O4 [M+H]+: 451.1909, found: 451.1913.
Synthesis of alcohol 13. To a solution of ester 12 (1.0 g, 2.22 mmol)
in toluene (10 mL) was added DIBAL-H (1.5 M in toluene, 3.7 mL,
5.55 mmol) at –78 °C. The mixture was stirred at –78 °C for 1 h,
warmed to 0 °C and stirred at this temperature for 2 h, then water
(5 mL) was added dropwise, and the resulting reaction mixture was
diluted with water (10 mL) and diethyl ether (10 mL). The aqueous
phase was extracted with diethyl ether (3 x 20 mL). The combined
organic phases were dried over sodium sulfate, filtered, and
concentrated under reduced pressure. Recrystallization of the
crude product from hexanes and dichloromethane provided alcohol
13 as a white solid (0.72 g). Yield: 94%; m.p. = 77–78 °C (lit.,15 75-
76 °C); 1H NMR (400 MHz, CDCl3): δ/ppm = 7.49–7.33 (m, 10H), 7.05
(s, 1H), 6.92 (s, 2H), 6.52 (d, 1H, J = 15.9 Hz), 6.21 (td, 1H, J = 15.9,
5.9 Hz), 5.19 (s, 2H), 5.18 (s, 2H), 4.69 (s, 1 H, OH), 4.30 (dd, 2H, J =
5.8 Hz, 1.3 Hz); 13C NMR (100 MHz, CDCl3): δ/ppm = 149.1, 148.9,
137.2, 130.5, 128.5, 127.8, 127.3, 127.2, 126.9, 120.3, 115.0, 113.1,
94.3, 93.7, 81.4, 71.1, 71.0, 69.9, 69.7, 67.9, 27.5. IR (film): νmax
=
3030, 1613, 1593, 1512, 1497, 1453, 1377, 1263, 1215, 1139, 1116,
744, 690 cm-1. HRMS (ESI) m/z: calcd for C43H39O6 [M + H]+:
651.2747, found: 651.2744.
Synthesis of octa-O-benzyl bis-8,8´-catechinylmethane (10). To a
solution of tetra-O-benzyl catechin (4, 100 mg, 0.15 mmol) in
anhydrous
dichloromethane
(0.15
mL)
were
added
paraformaldehyde (4.5 mg, 0.15 mmol) and Hf(OTf)4 (1.16 mg,
0.0015 mmol). The mixture was stirred at room temperature for 0.3
h. Water was poured into the solution, and the mixture was
extracted with ethyl acetate (3 × 20 mL), dried over sodium sulfate,
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography (50% ethyl acetate in petroleum
ether) over silica gel to afford octa-O-benzyl bis-8,8´-
25
catechinylmethane (10) as a yellow oil (95.9 mg). Yield: 95%; [α]D
-
1
5.0 (c = 1.0, CDCl3); H NMR (400 MHz, CDCl3): δ/ppm = 7.47–7.17
(m, 40H), 6.79 (dd, 4H, J = 9.1, 4.9 Hz), 6.59 (dd, 2H, J = 8.2, 1.5 Hz),
6.13 (s, 2H), 5.16–4.98 (m, 14H), 4.73 (d, 2H, J = 11.8 Hz), 4.57 (d,
2H, J = 11.8 Hz), 4.14 (d, 2H, J = 8.5 Hz), 4.05 (s, 2H), 3.14 (dd, 2H, J =
16.2, 5.7 Hz), 2.60 (dd, 2H, J = 16.2, 9.3 Hz); 13C NMR (100 MHz,
CDCl3): δ/ppm = 156.1, 154.6, 153.5, 148.9, 148.8, 137.8, 137.3,
137.3, 137.0, 131.7, 128.6, 128.5, 128.4, 128.3, 128.2, 127.8, 127.7,
4 | J. Name., 2012, 00, 1-3
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127.7, 127.6, 127.4, 127.3, 127.2, 127.1, 127.1, 120.6, 114.6, 113.8, dichloromethane (1 mL) was slowly added oxalyl chloride (0.1 mL)
111.2, 102.2, 91.1, 80.9, 71.3, 71.0, 70.0, 69.9, 68.5, 26.9, 17.4; IR in a nitrogen atmosphere. The resulting mixture was stirred under
(film): νmax = 3035, 1624, 1593, 1510, 1495, 1444, 1376, 1254, 1218, reflux for 3 h. The excess oxally chloride and solvent were removed
1128, 1113, 742, 695 cm-1. HRMS (ESI) m/z: calcd for C87H77O12 [M + by distillation and the residue was dried under vacuum for 3 h. To
H]+: 1313.5415, found: 1313.5418.
this mixture (3,4,5-tri-O-benzylgalloyl chloride, 18) was added octa-
Synthesis of ketone 16. To a solution of octa-O-benzyl bis-8,8´- O-benzyl bis-8,8´-epicatechinylmethane (17, 40 mg, 0.03 mmol) and
catechinylmethane (10, 90 mg, 0.068 mmol) in anhydrous DMAP (7.44 mg, 0.06 mmol) in dichloromethane (0.5 mL) at 0 °C.
dichloromethane (0.5 mL) were added Dess–Martin periodinane The mixture was stirred at room temperature for 16 h, and was
(87.18 mg, 0.21 mmol) under nitrogen atmosphere. The resulting then added with saturated aqueous NaHCO3. The organic layer was
mixture was stirred at room temperature for about 16 h until TLC separated, and the aqueous layer was extracted with
showed the absence of starting material. Subsequently, saturated dichloromethane (3 × 10 mL). The organic phases were combined,
aqueous NaHCO3 solution (1 mL) and 10% aqueous Na2S2O3 solution dried over magnesium sulfate, filtered, and concentrated under
(1 mL) were added to quench the reaction. The organic layer was reduced pressure. The residue was purified by flash
separated, and the aqueous layer was extracted with chromatography (20% ethyl acetate in petroleum ether) over silica
25
dichloromethane (3 × 20 mL). The combined organic phases were gel to afford ester 19 as a colourless oil (39.4 mg). Yield: 60%; [α]D
dried over magnesium sulfate, filtered, and concentrated under -105.0 (c = 1.0, CDCl3); 1H NMR (400 MHz, CDCl3): δ/ppm = 7.35–
reduced pressure. The residue was purified by flash 7.17 (m, 70H), 7.05 (d, 4H, J = 7.1 Hz), 6.84 (s, 2H), 6.69 (d, 2H, J =
chromatography (20% ethyl acetate in petroleum ether) over silica 8.1 Hz), 6.63 (d, 2H, J = 8.1 Hz), 6.19 (s, 2H), 5.38 (s, 2H), 5.08–4.94
25
gel to afford ketone 16 as a yellow oil (78.06 mg). Yield: 87%; [α]D
(m, 26H), 4.73–4.65 (m, 4H), 4.24–4.21 (m, 2H), 3.04–2.93 (m,
13C NMR (100 MHz, CDCl3): δ/ppm = 165.2, 156.3, 154.9, 153.7,
1
-5.8 (c = 1.0, CDCl3); H NMR (400 MHz, CDCl3): δ/ppm = 7.44–7.20 4H)
;
(m, 40H), 6.85 (s, 2H), 6.78 (d, 2H, J = 8.3 Hz), 6.67 (d, 2H, J = 8.2 152.3, 148.7, 148.5, 142.8, 137.4, 137.3, 137.1, 136.5, 131.8, 128.4,
Hz), 6.19 (s, 2H), 5.11 (s, 4H), 4.98 (s, 8H), 4.71 (d, 2H, J = 11.5 Hz), 128.3, 128.1, 127.9, 127.8, 127.7, 127.6, 127.4, 127.3, 127.3, 127.1,
4.60 (d, 2H, J = 11.4 Hz), 4.52 (s, 2H), 4.19 (s, 2H), 3.68 (d, 2H, J = 119.9, 114.5, 113.7, 111.7, 109.5, 101.1, 91.6, 75.0, 71.2, 71.2, 70.6,
20.3 Hz), 3.33 (d, 2H, J = 20.3 Hz); 13C NMR (100 MHz, CDCl3): δ/ppm 70.0, 68.6, 29.7, 17.4; IR (film): νmax = 3065, 3028, 2934, 2870, 1718,
= 206.5, 156.7, 154.1, 153.4, 149.0, 148.7, 137.2, 137.1, 137.0, 1614, 1590, 1499, 1446, 1428, 1371, 1322, 1269, 1119, 868, 813,
136.8, 128.6, 128.6, 128.5, 128.4, 128.3, 128.3, 128.2, 128.1, 128.0, 735, 694 cm-1. HRMS (ESI) m/z: calcd for C143H120O20Na [M + Na]+:
127.7, 127.7, 127.6, 127.4, 127.2, 127.2, 120.3, 114.5, 113.6, 112.8, 2179.8271, found: 2179.8268.
102.9, 92.7, 83.0, 71.1, 70.3, 70.1, 67.9, 26.9, 17.6; IR (film): νmax
=
Synthesis of talienbisflavan A (1). To a solution of ester 19 (21.6
3035, 1723, 1620, 1594, 1515, 1503, 1380, 1160, 736, 696 cm-1. mg, 0.01 mmol) in a solvent mixture of THF/MeOH (1:1, v/v, 1 mL)
HRMS (ESI) m/z: calcd for C87H73O12 [M + H]+: 1309.5102, found: were added Pd(OH)2/C (5%, 40 mg) in a hydrogen atmosphere. The
1309.5107.
resulting reaction mixture was stirred at room temperature for 10
Synthesis of octa-O-benzyl bis-8,8´-epicatechinylmethane (17). To h, and TLC showed that the reaction was completed. The reaction
a solution of ketone 16 (65 mg, 0.05 mmol) in dry THF (0.5 mL) was mixture was filtered to remove the catalyst. The filtrate was
added dropwise L-selectride (0.1 mL, 1.0 M solution in THF, 0.1 evaporated, and the residue was rapidly purified by flash
mmol) at –78 °C. The resulting solution was stirred at –78 °C for 4 h, chromatography (AcOH/MeOH/CH2Cl2 = 1:5:50) over silica gel to
and TLC showed the reaction was complete. Saturated aqueous afford talienbisflavan A (1) as a yellow amorphous powder (7.5 mg).
14
NaHCO3 (1 mL) was added to quench the reaction. The organic layer Yield: 84%; [α]D -105.4 (c = 0.1, methanol); 1H NMR (400 MHz,
was separated and the aqueous layer was extracted with ethyl CD3OD): δ/ppm = 6.92 (s, 4H), 6.84 (s, 2H), 6.69–6.65 (m, 4H), 6.01
acetate (3 × 10 mL). The combined organic phases were dried over (s, 2H), 5.40 (s, br, 2H), 4.81 (s, br, 2H), 3.92 (s, 2H), 2.93 (dd, 2H, J =
magnesium sulfate, filtered, and concentrated under reduced 17.9, 3.4 Hz), 2.77 (dd, 2H, J = 17.9, 3.4 Hz); 13C NMR (100 MHz,
pressure. The residue was purified by flash chromatography (25% CD3OD): δ/ppm = 167.6, 155.6, 155.3, 153.8, 146.2, 146.1, 145.8,
ethyl acetate in petroleum ether) over silica gel to afford octa-O- 140.0, 130.3, 121.6, 120.0, 116.1, 115.0, 110.3, 106.7, 99.9, 96.8,
benzyl bis-8,8´-epicatechinylmethane (17) as a colourless oil (48.9 79.0, 69.4, 26.4, 16.6; IR (film): νmax = 3407, 1695, 1615, 1451, 1229,
25
mg). Yield: 75%; [α]D -28.4 (c = 1.0, CDCl3); 1H NMR (400 MHz, 1038, 766 cm-1. HRMS (ESI) m/z: calcd for C45H35O20 [M - H]-:
CDCl3): δ/ppm = 7.46–7.11 (m, 40H), 6.93 (s, 2H), 6.84 (d, 2H, J = 8.2 895.1722, found: 895.1725.
Hz), 6.63 (d, 2H, J = 8.1 Hz), 6.21 (s, 2H), 5.22–5.11 (m, 14H), 4.75 (d, Synthesis of bis-8,8´-catechinylmethane (2). To a solution of octa-
2H, J = 13.1 Hz), 4.33 (s, 2H), 4.17 (s, 2H), 4.00 (s, 2H), 3.01 (d, 2H, J O-benzyl bis-8,8´-catechinylmethane (10, 13.1 mg, 0.01 mmol) in a
= 17.0 Hz), 2.82 (dd, 2H, J = 17.3, 3.9 Hz); 13C NMR (100 MHz,CDCl3): solvent mixture of THF/MeOH (1:1, v/v,
1 mL) were added
δ/ppm = 156.2, 155.3, 153.4, 148.6, 148.4, 137.7, 137.4, 137.4, Pd(OH)2/C (5%, 40 mg) under hydrogen atmosphere. The resulting
137.2, 132.1, 128.5, 128.4, 128.2, 127.8, 127.4, 127.3, 127.3, 127.2, reaction mixture was stirred at room temperature for 10 h, and TLC
119.6, 114.7, 113.6, 111.5, 101.0, 91.8, 77.8, 71.2, 71.1, 70.5, 70.0, showed that the reaction was completed. The reaction mixture was
66.1, 26.9, 17.6; IR (film): νmax = 3547, 1619, 1592, 1516, 1494, filtered to remove the catalyst. The filtrate was evaporated, and the
1460, 1441, 1379, 1261, 1219, 1146, 1110, 753, 699 cm-1. HRMS residue was purified by flash chromatography (AcOH/MeOH/CH2Cl2
(ESI) m/z: calcd for C87H77O12 [M
+
H]+: 1313.5415, found: = 1:5:50) over silica gel to afford bis-8,8´-catechinylmethane (2) as a
25
1313.5418.
yellow amorphous powder (5.3 mg). Yield: 90%; [α]D -104.7 (c =
Synthesis of ester 19. To a suspension of tri-O-benzyl gallic acid 1.5, MeOH); 1H NMR [400 MHz, (CD3)2CO]: δ/ppm = 6.94 (s, 2H),
(53.66 mg, 0.12 mmol) and one drop of DMF in anhydrous 6.80 (s, 4H), 5.98 (s, 2H), 4.69 (d, 2H, J = 7.2 Hz), 4.10–3.98 (m, 2H),
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3.61 (s, 2H), 2.91 (dd, 2H, J = 16.0, 8.1 Hz), 2.54 (dd, 2H, J = 16.0, 8.1 127.3, 127.2, 119.5, 115.3, 113.8, 101.0, 94.8, 94.1, 78.4, 71.5, 71.4,
Hz); 13C NMR (100 MHz, CD3OD): δ/ppm = 154.0, 153.8, 151.9, 70.2, 70.0, 66.3, 28.2; IR (film): νmax = 3030, 1617, 1592, 1512, 1498,
145.0, 144.8, 130.2, 118.8, 114.8, 114.0, 105.1, 99.9, 95.5, 81.9, 1455, 1441, 1377, 1260, 1217, 1144, 1112, 750, 697 cm-1. HRMS
67.0, 27.2, 15.4; IR (film): νmax = 3057, 3031, 2932, 2878,1612, 760 (ESI) m/z: calcd for C43H39O6 [M + H]+: 651.2747, found: 651.2749.
cm-1. HRMS (ESI) m/z: calcd for C31H27O12 [M - H]-: 591.1503, found: Synthesis of octa-O-benzyl bis-8,8´-epicatechinylmethane (17). To
591.1507.
a solution of tetra-O-benzyl epicatechin (20, 100 mg, 0.15 mmol) in
Synthesis of bis-8,8´-epicatechinylmethane (3). To a solution of dichloromethane (0.15 mL) were added paraformaldehyde (4.5 mg,
octa-O-benzyl bis-8,8´-epicatechinylmethane (17, 13.1 mg, 0.01 0.15 mmol) and Hf(OTf)4 (1.16 mg, 0.0015 mmol). The resulting
mmol) in a solvent mixture of THF/MeOH (1:1, v/v, 1 mL) were mixture was stirred at room temperature for 0.5 h. Water was
added Pd(OH)2/C (5%, 40 mg) under hydrogen atmosphere. The poured into the solution, and the mixture was extracted with ethyl
resulting reaction mixture was stirred at room temperature for 10 acetate (3 × 10 mL), dried over sodium sulfate, filtered, and
h, and TLC showed that the reaction was completed. The reaction concentrated under reduced pressure. The residue was purified by
mixture was filtered to remove the catalyst. The filtrate was flash chromatography (25% ethyl acetate in petroleum ether) over
evaporated, and the residue was rapidly purified by flash silica gel to afford octa-O-benzyl bis-8,8´-epicatechinylmethane
25
chromatography (AcOH/MeOH/CH2Cl2 = 1:5:50) over silica gel to (17) as a colourless oil (92.9 mg). Yield: 92%; [α]D -28.4 (c = 1.0,
afford bis-8,8´-epicatechinylmethane (3) as a white amorphous CDCl3); 1H NMR (400 MHz, CDCl3): δ/ppm = 7.46–7.11 (m, 40H), 6.93
25
powder (5.3 mg). Yield: 90%; [α]D -104.1 (c = 1.5, MeOH); 1H NMR (s, 2H), 6.84 (d, 2H, J = 8.2 Hz), 6.63 (d, 2H, J = 8.1 Hz), 6.21 (s, 2H),
(400 MHz, CD3OD): δ/ppm = 6.97 (s, br, 2H), 6.75 (s, br, 4H), 5.98 (s, 5.22–5.11 (m, 14H), 4.75 (d, 2H, J = 13.1 Hz), 4.33 (s, 2H), 4.17 (s,
2H), 4.78 (s, br, 2H), 4.12 (s, br, 2H), 3.90 (s, 2H), 2.85 (dd, 2H, J = 2H), 4.00 (s, 2H), 3.01 (d, 2H, J = 17.0 Hz), 2.82 (dd, 2H, J = 17.3, 3.9
16.6, 4.7 Hz), 2.70 (dd, 2H, J = 16.6, 4.7 Hz); 13C NMR (100 MHz, Hz); 13C NMR (100 MHz,CDCl3): δ/ppm = 156.2, 155.3, 153.4, 148.6,
CD3OD): δ/ppm = 155.8, 155.2, 153.6, 145.8, 131.6, 119.6, 116.0, 148.4, 137.7, 137.4, 137.4, 137.2, 132.1, 128.5, 128.4, 128.2, 127.8,
115.4, 106.5, 100.4, 96.8, 80.4, 67.0, 29.0, 16.5; IR (film): νmax
=
127.4, 127.3, 127.3, 127.2, 119.6, 114.7, 113.6, 111.5, 101.0, 91.8,
3065, 3033, 2919, 2873, 1606, 763 cm-1. HRMS (ESI) m/z: calcd for 77.8, 71.2, 71.1, 70.5, 70.0, 66.1, 26.9, 17.6; IR (film): νmax = 3541,
C31H27O12 [M - H]-: 591.1503, found: 591.1507.
1617, 1592, 1512, 1498, 1453, 1441, 1377, 1263, 1217, 1144, 1112,
750, 697 cm-1. HRMS (ESI) m/z: calcd for C87H77O12 [M + H]+:
1313.5410, found: 1313.5418.
Alternative synthesis of talienbisflavan
epicatechinylmethane (3, Scheme 3)
A (1) and bis-8,8´-
Synthesis of ester 21. To a suspension of tri-O-benzyl gallic acid
(135.38 mg, 0.31mol) and one drop of DMF in anhydrous
dichloromethane (3 mL) was added oxalyl chloride (0.5 mL) at room
temperature with agitation under nitrogen atmosphere. The
reaction mixture was stirred under reflux for 3 h. The excess oxalyl
chloride and solvent were removed by distillation. The residue was
dried under vacuum for 3 h, and was then added dropwise to a
solution of tetra-O-benzyl epicatechin (20, 100 mg, 0.15 mmol) and
DMAP (18.77 mg, 0.015 mmol) in dichloromethane (2 mL) at zero
temperature. The resulting mixture was stirred at room
temperature for 12 h, and was then added with saturated aqueous
NaHCO3. The organic layer was separated, and the aqueous layer
was extracted with dichloromethane (3 × 10 mL). The organic
phases were combined, dried over magnesium sulfate, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography (25% ethyl acetate in petroleum ether) over
silica gel to afford ester 21 as a white solid (131.9 mg). Yield: 80%;
Synthesis of tetra-O-benzyl epicatechin (20). To a solution of Bn4-
catechin 4 (325.4 mg, 0.5 mmol) in anhydrous dichloromethane (10
mL) were added Dess–Martin periodinane (318.1 mg, 0.75 mmol)
under nitrogen atmosphere. The resulting mixture was stirred at
room temperature for about 16 h until TLC showed the absence of
starting material. Subsequently, saturated aqueous NaHCO3
solution (4.2 mL) and 10% aqueous Na2S2O3 solution (4.2 mL) were
added to quench the reaction. The organic layer was separated, and
the aqueous layer was extracted with dichloromethane (3 × 10 mL).
The combined organic phases were dried over magnesium sulfate,
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography (15% ethyl acetate in petroleum
ether) over silica gel to afford the ketone as a yellow oil. To a
solution of this crude ketone in dry THF (5 mL) was added dropwise
L-selectride (0.6 mL, 1.0 M solution in THF, 0.60 mmol) at –78 °C.
The resulting mixture was stirred at –78 °C for 4 h, and TLC showed
the reaction was complete. Saturated aqueous NaHCO3 (5 mL) was
added to quench the reaction. The organic layer was separated and
the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The
combined organic phases were dried over magnesium sulfate,
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography (20% ethyl acetate in petroleum
ether) over silica gel to afford tetra-O-benzyl epicatechin (20) as a
white solid (244.1 mg). Yield: 70% (2 steps); m.p. = 129–130 °C
25
m.p. = 45–47 °C (lit.,20 45–47 °C); [α]D -87.0 (c = 3.45, CDCl3); 1H
NMR (400 MHz, CDCl3): δ/ppm = 7.36 (ddd, 35H, J = 7.7, 16.5 Hz, J =
25.1Hz), 7.23 (s, 2H), 7.08 (s, 1H), 6.95 (d, 1H, J = 8.0 Hz), 6.87 (d,
1H, J = 8.1 Hz), 6.41 (s, 1H), 6.37 (s, 1H), 5.65 (s, 1H), 5.12 (s, 4H),
5.05 (d, 8H, J = 11.4 Hz), 4.96 (s, 1H), 4.80 (d, 1H, J = 11.7 Hz), 4.69
(d, 1H, J = 11.7 Hz), 3.15 (m, 2H); 13C NMR (100 MHz, CDCl3): δ/ppm
= 165.0, 158.8, 158.0, 155.7, 152.3, 149.0, 148.9, 137.2, 137.0,
136.8, 136.5, 131.1, 128.6, 128.5, 128.4, 128.3, 128.3, 128.2, 128.0,
127.9, 127.9, 127.7, 127.5, 127.4, 120.0, 114.8, 113.7, 109.1, 100.9,
25
(lit.,19 129.5–130 °C); [α]D -27.7 (c = 2.16, EtOAc); 1H NMR (400
MHz, CDCl3): δ/ppm = 7.48–7.33 (m, 20H), 7.18 (s, 1H), 7.03–7.01
(m, 2H), 6.30 (s, 2H), 5.22 (s, 2H), 5.20 (s, 2H), 5.05 (s, 2H), 5.04 (s,
2H), 4.94 (s, 1H), 4.25 (s, br, 1H), 3.05–2.97 (m, 2H); 13C NMR (100
MHz, CDCl3): δ/ppm = 158.8, 158.3, 155.3, 149.1, 149.0, 137.3,
137.2, 137.0, 137.0, 128.5, 128.5, 128.4, 128.4, 127.9, 127.8, 127.5,
94.6, 93.9, 75.0, 71.2, 71.0, 70.2, 70.0, 68.5, 29.7; IR (film): νmax
=
3090, 3064, 3032, 2930, 2872, 1715, 1619, 1592, 1499, 1454, 1429,
1373, 1327, 1266, 1215, 1145, 1112, 1028, 910, 860, 812, 735, 696
cm-1. HRMS (ESI) m/z: calcd for C71H61O10 [M + H]+: 1073.4265,
found: 1073.4266.
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB02837G
Journal Name
ARTICLE
8
9
(a) D. F. Gao, Y. J. Zhang, C. R. Yang, K. K. Chen, H. J. Jiang, J.
Agric. Food Chem., 2008, 56, 7517; (b) D. F. Gao, M. Xu, C. R.
Synthesis of ester 19. To a solution of ester 21 (100 mg, 0.09
mmol) in anhydrous dichloromethane (0.09 mL) were added
paraformaldehyde (2.7 mg, 0.09 mmol) and Hf(OTf)4 (3.49 mg,
0.0045 mmol). The resulting mixture was stirred at room
temperature for 2 h, added with water, extracted with ethyl
acetate (3 × 10 mL), dried over sodium sulfate, filtered, and
concentrated under reduced pressure. The residue was purified
by flash chromatography (30% ethyl acetate in petroleum
ether) over silica gel to afford ester 19 as a yellow oil (87.2
Yang, M. Xu, Y. J. Zhang, J. Agric. Food Chem., 2010, 58
,
8820; (c) Q. Liu, Y. J. Zhang, C. R. Yang, M. Xu, J. Agric. Food
Chem., 2009, 57, 586.
(a) W. E. Hillis, U. Gerda, J. Appl. Chem., 1959,
Kiatgrajai, J. D. Wellons, L. Gollob, J. D. White, J. Org. Chem.,
1982, 47 2913; (c) M. Fechtal, B. Riedl, L. Calvé,
Holzforschung, 1993, 47, 419.
9, 474; (b) P.
,
10 (a) M. Watanabe, Kagaku, 1999, 54, 30; (b) A. Takagaki, K.
Fukai, F. Nanjo, Y. Hara, J. Wood Sci., 2000, 46, 334; (c) A.
Takagaki, K. Fukai, F. Nanjo, Y. Hara, M. Watanabe, S.
25
mg). Yield: 85%; [α]D -105.0 (c= 1.0, CDCl3); 1H NMR (400
Sakuragawa, Mokuzai Gakkaishi, 2000, 46, 231; (d) T.
Takano, T. Murakami, H. Kamitakahara, J. Wood Sci., 2008,
54, 329.
MHz, CDCl3): δ/ppm = 7.35
Hz), 6.84 (s, 2H), 6.69 (d, 2H, J = 8.1 Hz), 6.63 (d, 2H, J = 8.1 Hz),
6.19 (s, 2H), 5.38 (s, 2H), 5.08 4.94 (m, 26H), 4.73 4.65 (m,
4H), 4.24 (s, 2H), 2.99
2.96 (m, 4H); 13C NMR(100 MHz, CDCl3)
–7.17 (m, 70H), 7.05 (d, 4H, J = 7.1
–
–
11 F. D. Boyer, P. H. Ducrot, Tetrahedron Lett., 2005, 46, 5177.
12 M. Pariollaud, J. Cockrell, C. Selenski, Tetrahedron Lett.,
2014, 55, 2484.
13 G. Watanabe, K. Ohmori, K. Suzuki, Chem. Commun., 2014,
50, 14371.
(a) H. J. Li, M. L. Deinzer, Beer in Health and Disease Prevention,
ed. V. R. Preedy, Elsevier Inc., Burlington, England, 2009, pp.
333–348; (b) Y. C. Wu, H. J. Li, H. Z. Yang, Org. Biomol. Chem.,
–
:
δ/ppm = 165.2, 156.3, 154.9, 153.7, 152.3, 148.7, 148.5, 142.8,
137.4, 137.3, 137.1, 136.5, 131.8, 128.4, 128.3, 128.1, 127.9,
127.8, 127.7, 127.6, 127.4, 127.3, 127.3, 127.1, 119.9, 114.5,
113.7, 111.7, 109.5, 101.1, 91.6, 75.0, 71.2, 71.2, 70.6, 70.0,
68.6, 29.7; IR (film): νmax = 3065, 3028, 2934, 2870, 1718, 1614,
1590, 1499, 1446, 1428, 1371, 1322, 1269, 1119, 868, 813,
735, 694 cm-1. HRMS (ESI) m/z: calcd for C143H120O20Na [M +
2010,
Chen, Org. Biomol. Chem., 2011,
8, 3394; (c) Y. C. Wu, H. J. Li, L. Liu, Z. Liu, D. Wang, Y. J.
9, 2868; (d) H. J. Li, Y. Y. Wu,
Q. X. Wu, R. Wang, C. Y. Dai, Z. L. Shen, C. L. Xie, Y. C. Wu,
Na]+: 2179.8271, found: 2179.8268
.
Org. Biomol. Chem., 2014, 12, 3100; (e) Q. X. Wu, H. J. Li, H. S.
Wang, Z. G. Zhang, C. C. Wang, Y. C. Wu, Synlett, 2015, 26
,
243; (f) H. J. Li, R. Wang, J. Gao, Y. Y. Wang, D. H. Luo, Y.
C. Wu, Adv. Synth. Catal., 2015, 357, 1393; (g) H. J. Li, C. C.
Wang, S. Zhu, C. Y. Dai, Y. C. Wu, Adv. Synth. Catal.,
2015, 357, 583; (h) K. Deng, Q. Y. Huai, Z. L. Shen, H. J. Li, C.
Liu, Y. C. Wu, Org. Lett., 2015, 17, 1473; (i) Q. Wang, M.
Conclusions
In summary, we described a newly developed Hf(OTf)4-catalyzed
direct regioselective methylenation of catechin derivatives, which is
employed to the first asymmetric total syntheses of talienbisflavan
A and bis-8,8´-epicatechinylmethane as well as a facile synthesis of
bis-8,8´-catechinylmethane. This direct regioselective methylenation
reaction together with efficient hydrogenolysis of well-desighed
natural product precursors could facilitate the preparation of
sufficient quantities of these natural products for biological and
medical studies. Further applications of these strategies for the
synthesis of other bioactive natural products with related skeletons
are under investigation, and will be reported in due course.
Wang, H. J. Li, S. Zhu, Y. Liu, Y. C. Wu, Synthesis, 2016, 48
,
3985; (j) Y. Z. Ji, M. Wang, H. J. Li, Y. Liu, Y. C. Wu, Eur. J. Org.
Chem., 2016, 4077; (k) H. S. Wang, H. J. Li, X. Nan, Y. Y. Luo, Y.
C. Wu, J. Org. Chem., 2017, 82, 12914; (l) W. L. Mu, M. Wang,
H. J. Li, D. M. Huang, Y. Y. Zhang, C. Y. Li, Y. Liu, Y. C. Wu, Adv.
Synth. Catal., 2017, 359, 4250; (m) J. L. Wang, H. J. Li, H. S.
Wang, Y. C. Wu, Org. Lett., 2017, 19, 3811; (n) H. S. Wang, H.
J. Li, J. L. Wang, Y. C. Wu, Green Chem., 2017, 19, 2140.
14 S. B. Wan, D. Chen, Q. P. Dou, T. H. Chan, Bioorg. Med.
Chem., 2004, 12, 3521.
15 M. Noji, T. Ohno, K. Fuji, N. Futaba, H. Tajima, K. Ishii, J. Org.
Chem., 2003, 68, 9340.
16 (a) I. Hachiyai, M. Moriwaki, S. Kobayashi, Tetrahedron Lett.,
Acknowledgements
1995, 36, 409; (b) Y. C. Wu, J. P. Zhu, J. Org. Chem., 2008, 73
,
9522; (c) Y. C. Wu, M. Liron, J. P. Zhu, J. Am. Chem. Soc.,
2008, 130, 7148; (d) Y. C. Wu, G. Bernadat, G. Masson, C.
Couturier, T. Schlama, J. P. Zhu, J. Org. Chem., 2009, 74, 2046;
(e) N. Sakai, K. Shimamura, R. Ikeda, T. Konakahara, J. Org.
Chem., 2010, 75, 3923; (f) Y. C. Wu, H. J. Li, L. Liu, N.
Demoulin, Z. Liu, D. Wang, Y. J. Chen, Adv. Synth. Catal.,
2011, 353, 907; (g) H. Ishitani, H. Suzuki, Y. Saito, Y.
Yamashita, S. Kobayashi, Eur. J. Org. Chem., 2015, 5485.
17 M. Merlani, V. Barbakadze, L. Amiranashvili, L. Gogilashvili, E.
Yannakopoulou, B. Chankvetadze, Chirality, 2010, 22, 717.
18 J. Mustapha, R. Khan, I.A. Khan, D. Ferreira, Org. Prep.
Proced. Int., 2004, 36, 61.
This work was supported by the National Natural Science
Foundation of China (21372054) and the Fundamental
Research Funds for the Central Universities (HIT.NSRIF.201701).
Notes and references
1
(a) P. Erasto, G. Bojase-Moleta, R. T. Majinda,
Phytochemistry, 2004, 65, 875; (b) S. Tang, P. Bremner, A.
Kortenkamp, C. Schlage, A. I. Gray, S. Gibbons, M. Heinrich,
Planta Med., 2003, 69, 247.
2
V. Dumontet, N. V. Hung, M. T. Adeline, C. Riche, A. Chiaroni,
T. Sevenet, F. Gueritte, J. Nat. Prod., 2004, 67, 858.
D. Y. Xie, R. A. Dixon, Phytochemistry, 2005, 66, 2127.
J. S. Lee, H. J. Kim, Y. S. Lee, Planta Med., 2003, 69, 859.
L. F. Zhu, M. Xu, H. T. Zhu, D. Wang, S. X. Yang, C. R. Yang, Y.
J. Zhang, J. Agric. Food Chem., 2012, 60, 12170.
19 K. Ohmori, T. Yano, K. Suzuki, Org. Biomol. Chem., 2010, 8,
2693.
3
4
5
6
7
T. Hatano, H. Miyatake, M. Natsume, N. Osakabe, T.
Takizawa, H. Ito, T. Yoshida, Phytochemistry, 2002, 59, 749.
Q. Ma, H. Xie, S. Li, R. Zhang, M. Zhang, X. Wei, J. Agric. Food
Chem., 2014, 62, 1073.
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J. Name., 2013, 00, 1-3 | 7
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB02837G
Graphical Abstract
Asymmetric total synthesis of talienbisflavan A
Deng-Ming Huang, Hui-Jing Li, Jun-Hu Wang and Yan-Chao Wu
OH
OH
HO
HO
OH
OH
OH
HO
HO
OH
O
OH
O
HO
OH
OH
OH
H2C
HO
O
O
HO
HO
OH
O
O
OH
OH
OH
H2C
bis-8,8'-catechinylmethane
HO
OH
OH
HO
CO2H
HO
O
HO
HO
OH
HO
O
OH
O
O
O
OH
OH
OH
H2C
OH
HO
OH
(HCHO)n
HO
OH
OH
OH
OH
talienbisflavan A
bis-8,8'-epicatechinylmethane
The first asymmetric total syntheses of talienbisflavan A and bis-8,8´-
epicatechinylmethane as well as a facile synthesis of bis-8,8´-catechinylmethane has
been accomplished from readily available starting materials by using a newly
developed direct regioselective methylenation of catechin derivatives as one of the
key steps.