Catalytic asymmetric synthesis of (-)-E-δ-viniferin via an intramolecular C-H insertion of diaryldiazomethane using Rh2(S-TFPTTL)4

Article abstract of DOI:10.1016/j.tetlet.2015.05.072

An asymmetric synthesis of (-)-E-δ-viniferin, a trans-resveratrol dimer natural product containing a dihydrobenzofuran ring, has been achieved by exploiting a Rh(II)-catalyzed intramolecular C-H insertion reaction of a diaryldiazomethane derivative as a k

Full text of DOI:10.1016/j.tetlet.2015.05.072

Tetrahedron Letters 56 (2015) 4324–4327
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Catalytic asymmetric synthesis of (À)-E-d-viniferin via an
intramolecular C–H insertion of diaryldiazomethane using
Rh2(S-TFPTTL)4
⇑
Yoshihiro Natori, Motoki Ito, Masahiro Anada, Hisanori Nambu, Shunichi Hashimoto
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060–0812, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An asymmetric synthesis of (À)-E-d-viniferin, a trans-resveratrol dimer natural product containing a
dihydrobenzofuran ring, has been achieved by exploiting a Rh(II)-catalyzed intramolecular C–H insertion
reaction of a diaryldiazomethane derivative as a key step. The C–H insertion under catalysis by
dirhodium(II) tetrakis[N-tetrafluorophthaloyl-(S)-tert-leucinate], Rh2(S-TFPTTL)4, provided the 2,3-di-
aryl-2,3-dihydrobenzofuran core structure with perfect cis diastereoselectivity and 96% ee.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 16 April 2015
Revised 14 May 2015
Accepted 19 May 2015
Available online 5 June 2015
Keywords:
Chiral dirhodium(II) complex
C–H insertion
Diaryldiazomethane
trans-Resveratrol dimer
E-d-Viniferin
E-d-Viniferin, a trans-resveratrol dimer containing a 2,3-diaryl-
The Rh(II)-catalyzed asymmetric intramolecular C–H insertion
reaction of aryldiazoacetates bearing an arylmethyloxy group at
the ortho position represents one of the most powerful methods
for constructing enantioenriched 2,3-dihydrobenzofurans.9–18 In
this context, we have provided a protocol for the asymmetric syn-
thesis of 2-aryl-3-methoxycarbonyl-2,3-dihydrobenzofurans 5 via
intramolecular C–H insertion of phenyldiazoacetates 4 catalyzed
by dirhodium(II) tetrakis[N-phthaloyl-(S)-tert-leucinate], Rh2(S-
PTTL)4 (2a), in which high enantioselectivity (up to 94% ee) and
perfect cis diastereoselectivity are achieved (Scheme 1).9,10,13,14
Using this catalytic method, we recently achieved the asymmetric
synthesis of dihydrobenzofuran neolignans, (À)-epi-conocarpan,
(+)-conocarpan,10a and (À)-trans-blechnic acid.10b As an extension
of our studies in this field, we herein report an asymmetric
synthesis of (À)-E-d-viniferin (1) by exploiting a Rh(II)-catalyzed
2,3-dihydrobenzofuran ring,1 was obtained in racemic form by
treatment of trans-resveratrol with horseradish peroxidase and
2a,b
H2O2
prior to its isolation from nature. In 2001, (À)-E-d-
viniferin (1), which is also referred to as (À)-maximol A, was
isolated from the roots of Rheum maximowiczii by Takaishi and
co-workers.2d,3 E-d-Viniferin exhibits modest cytotoxicity against
human lymphoblastoid cells4a and inhibitory activities for
a
diverse array of enzymes including cyclooxygenase I and II,
lipoxygenase, and
a
-glucosidase.4b–d Although racemic E-d-
viniferin can be easily synthesized by an oxidative dimerization
of trans-resveratrol under enzymatic2a,b,5 or non-enzymatic
conditions,6 asymmetric synthesis of 1 has remained a major
challenge due to the difficulty in constructing an enantioenriched
2,3-diaryl-2,3-dihydrobenzofuran core structure.7,8
X
O
N
O
N
X
HO
X
HO
HO
OH
H
O
H
O
X
O
O
O
O
HO
Rh Rh
Rh Rh
HO
OH
X = H: Rh2(S-PTTL)4 (2a)
X = F: Rh2(S-TFPTTL)4 (2b)
X = Cl: Rh2(S-TCPTTL)4 (2c)
Rh2(S-PTAD)4 (3)
O
OH
)-E- -viniferin (1)
)-maximol A]
trans-resveratrol
intramolecular C–H insertion of a diaryldiazomethane derivative19
as
key step,20 which comprises an uncommon class of
rhodium(II)–carbene precursors.21–23
a
⇑
Corresponding author. Tel.: +81 11 706 3236; fax: +81 11 706 4981.
E-mail address: hsmt@pharm.hokudai.ac.jp (S. Hashimoto).
http://dx.doi.org/10.1016/j.tetlet.2015.05.072
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

Y. Natori et al. / Tetrahedron Letters 56 (2015) 4324–4327
4325
CO2Me
N2
Ph
1. MnO2 (400 wt%)
CH2Cl2, 0.5 h
CO2Me R2
Rh2(S-PTTL)4
NH2
Ph
(1 mol %)
N
R1
R2
R1
O
O
toluene
C
O
10
4
5
Ph
Ph
89%
R1 = H, Cl, OMe, OTBS
>99:1 cis selectivity
Rh2(S-PTTL)4 (1 mol %)
up to 94% ee
R2 = H, OTBS
N2
Ph
Ph
O
CH2Cl2,
C, 0.5 h
O
12
97% ee
>99:1 cis selectivity
Scheme 1. Diastereo- and enantioselective intramolecular C–H insertion reaction
of aryldiazoacetates catalyzed by Rh2(S-PTTL)4.
11
88% (2 steps)
Scheme 3. Diastereo- and enantioselective intramolecular C–H insertion reaction
of diaryldiazomethane 11 catalyzed by Rh2(S-PTTL)4.
HO
HO
OH
HO
RO
deprotection
epimerization
MeO
OMe MeO
OMe
NH2
5
OH
Br
CHO
OH
2
O
Br
Br
d
c
O
N
(–)-E- -viniferin (1)
RO
O
O
MeO
13
Mizoroki–Heck
reaction
14
15
OMe
OMe
OMe
RO
5
Scheme 4. Reagents and conditions: (a) para-methoxybenzyl bromide, K2CO3, DMF,
93%; (b) 1-bromo-3,5-dimethoxybenzene, n-BuLi, THF, À78 °C to rt, 96%; (c) MnO2,
CH2Cl2, 99%; (d) N2H4ÁH2O, AcOH, EtOH, reflux, 90%.
OMe
2
O
RO
6
7
MeO
OMe
MeO
OMe
Table 1
C–H
insertion
Diastereo- and enantioselective intramolecular C–H insertion of diaryldiazomethane
Br
9 catalyzed by dirhodium(II) carboxylatesa
Br
N2
OMe
O
O
MeO
OMe
NH2
Rh(II)
8
9
OMe
1. MnO2 (400 wt%)
CH2Cl2, 0.5 h
Scheme 2. Retrosynthetic analysis of 1.
Br
N
O
15
OMe
Our retrosynthetic analysis of 1 is outlined in Scheme 2.
Following an instructive precedent in the reaction of aryldiazoac-
etates,9 we envisaged that a Rh2(S-PTTL)4-catalyzed intramolecular
C–H insertion reaction of diaryldiazomethane 9 would preferen-
MeO
MeO
OMe
OMe
Rh(II) catalyst
(1 mol %)
5
Br
Br
N2
OMe
tially provide cis-2,3-diaryl-2,3-dihydrobenzofuran 8,
a key
O
O
intermediate in this synthesis. It was anticipated that an
E-arylethenyl group at the C5 position would be introduced by a
Mizoroki–Heck reaction24 of 8 with 3,5-disubstituted styrene 7. It
has been documented that cis-2-(4-alkoxyphenyl)-2,3-dihy-
drobenzofurans can be readily epimerized to thermodynamically
more stable trans-isomers with the aid of a Lewis acid.14,25 Thus,
we expected that 1 would be obtained from 6 by epimerization
at the C2 stereocenter and removal of protecting groups.26
9
8
OMe
Entry Rh(II) catalyst
Solvent
CH2Cl2
Temp
(°C)
Time
(h)
Yieldb
(%)
eec
(%)
1
2
3
4
Rh2(S-PTTL)4
(2a)
Rh2(S-PTTL)4
(2a)
Rh2(S-TFPTTL)4
(2b)
Rh2(S-TCPTTL)4
(2c)
À60
3
85
92
80
96
72
Toluene À60
24
0.5
2.5
95
87
78
CH2Cl2
CH2Cl2
À60
À40
Toward this end, we selected diaryldiazomethane 1119c as a
model system for the C–H insertion reaction (Scheme 3). Since
19
11 prepared from hydrazone 10 by oxidation with MnO2 was
instantly decomposed upon column chromatography on silica
gel, alumina, or Florisil,Ò the crude mixture was used after filtra-
tion and evaporation without purification for the C–H insertion
reaction. The reaction in CH2Cl2 using 1 mol % of Rh2(S-PTTL)4
proceeded smoothly at À60 °C to completion in less than 0.5 h,
giving cis-2,3-diphenyl-2,3-dihydrobenzofuran (12)19c as the sole
a
All reactions were carried out as follows: MnO2 (400 wt%) was added to a
solution of 15 (0.2 mmol) in CH2Cl2 (2 mL) at 0 °C and stirred at room temperature
for 0.5 h. After filtration through a Celite pad and evaporation, Rh(II) catalyst
(1 mol %) was added to a solution of crude 9 in the indicated solvent (2 mL) at the
indicated temperature.
b
Isolated yield based on hydrazone 15.
Determined by HPLC (Chiralcel OD-H).
c
product in 88% yield with no trace of the formation of
a
trans-isomer. The enantioselectivity of this reaction was
determined to be 97% ee by HPLC analysis (Chiralcel OD-H).27
Encouraged by this result, we next examined the C–H insertion
reaction of diaryldiazomethane 9 derived from hydrazone 15,
which was prepared as shown in Scheme 4. O-alkylation of com-
mercially available 5-bromosalicylaldehyde (13) followed by addi-
tion of 3,5-dimethoxyphenyllithium and oxidation with MnO2
provided ketone 14 in 88% yield for the three steps. Treatment of
14 with hydrazine monohydrate in the presence of acetic acid
gave hydrazone 15 in 90% yield. The C–H insertion of 9 derived
from 15 using Rh2(S-PTTL)4 under the same conditions as those
for the reaction with 11 provided cis-5-bromo-2,3-diaryl-2,3-
dihydrobenzofuran 8 in 85% yield and 92% ee (Table 1, entry 1).
The reaction required a significantly longer time (3 h) to reach
completion than that with 11. Again, no evidence of the formation
of trans-isomer 16 was detected.10a,28 Switching the solvent from
CH2Cl2 to toluene at À60 °C resulted in a marked decrease in the
rate and enantioselectivity (entry 2). Using CH2Cl2 as a solvent,
we next evaluated the performance of Rh2(S-TFPTTL)4 (2b)29 and
Rh2(S-TCPTTL)4 (2c),30 fluorinated and chlorinated analogues of
Rh2(S-PTTL)4. While perfect cis selectivity was observed in each
case, Rh2(S-TFPTTL)4 exhibited the highest enantioselectivity of
96% ee (entry 3).26 It is also notable that Rh2(S-TFPTTL)4 displayed

4326
Y. Natori et al. / Tetrahedron Letters 56 (2015) 4324–4327
higher reactivity than that of Rh2(S-PTTL)4 in this system as mani-
fested by a shorter reaction time for full conversion (0.5 h vs 3 h).31
Rh2(S-TCPTTL)4 was the least effective in terms of both reactivity
and enantioselectivity (entry 4). Clearly, Rh2(S-TFPTTL)4 proved
to be the catalyst of choice for this transformation in terms of
the rate and enantioselectivity. While the superiority of
Rh2(S-TFPTTL)4 has been demonstrated in enantiotopically selec-
tive aromatic C–H insertion29a and aromatic cycloaddition
(Buchner reaction)29d as well as enantioselective [2,3]-sigmatropic
rearrangement via oxonium ylide generation,29c this is the first
successful example of enantioselective aliphatic C–H insertion
catalyzed by Rh2(S-TFPTTL)4.33e
application of this method to asymmetric synthesis of biologically
active stilbene dimers and oligomers containing a 2,3-dihydroben-
zofuran skeleton is currently in progress.
Acknowledgments
This research was supported, in part, by a Grant-in-Aid for
Scientific Research from the Japan Society for the Promotion of
Science (JSPS). We thank Ms. S. Oka and M. Kiuchi of Center for
Instrumental Analysis at Hokkaido University for mass measure-
ments and elemental analysis.
With efficient construction of the 2,3-diaryl-2,3-dihydrobenzo-
furan core structure realized, the stage was now set for completion
Supplementary data
of the asymmetric synthesis of 1 as illustrated in Scheme 5. A sin-
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.05.
072.
23
gle recrystallization of 8 [96% ee, mp 105.5–106.5 °C, [
(c 1.16, CHCl3)] from hexane–EtOAc produced enantiomerically
a
]
À51.2
D
23
pure material [mp 109.0–110.0 °C, [
a]
À57.6 (c 1.16, CHCl3)] in
D
68% yield. Mizoroki–Heck reaction of 8 (>99% ee) with 3,5-diace-
toxystyrene (7) in the presence of Pd(OAc)2 and P(o-tolyl)3 pro-
vided the coupling product 6 in 81% yield.32 Finally, a one-pot
sequential epimerization at the C2 position14,25,28 and global
deprotection with BBr3 in CH2Cl2 furnished (À)-E-d-viniferin (1).
The spectroscopic data (IR, 1H NMR, 13C NMR, HRMS) of this pro-
References and notes
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duct were consistent with those reported for natural product 1.2
21
Although optical rotation of the synthetic material 1, [
a
]
À3.0
D
(c 0.71, MeOH), was much lower than that reported for natural 1
[lit.2d
[a]
À16.3 (c 0.75, MeOH)],35 the enantiomeric purity of
25
D
synthetic 1 was confirmed to be >99% by comparison of HPLC
(Chiralpak IA) retention time with a racemic sample of 1 prepared
with the aid of dirhodium(II) tetrakis(triphenylacetate),
36
Rh2(TPA)4 (see the Supplementary data).
In summary, we have achieved the asymmetric synthesis of
(À)-E-d-viniferin in 8 steps37 and 27% overall yield from commer-
cially available 5-bromosalicylaldehyde (13). The key feature of
the synthesis includes
a
novel, Rh2(S-TFPTTL)4-catalyzed
intramolecular C–H insertion reaction of a diaryldiazomethane
derivative to construct the 5-bromo-2,3-diaryl-2,3-dihydrobenzo-
furan core structure with perfect cis diastereoselectivity and
96% ee. Furthermore, enantiomeric enrichment of 8 by recrystal-
lization enabled access to (À)-E-d-viniferin of >99% ee that is amor-
phous. While Rh2(S-PTTL)4 has proven to be optimal in a wide
range of asymmetric C–H insertion reactions,9,10b,14,17,33,34 Rh2(S-
TFPTTL)4 has been found to display even higher enantioselectivity
and reactivity than those of Rh2(S-PTTL)4 in this system. Further
AcO
MeO
MeO
OMe
OMe
AcO
Br
b
OMe
OMe
2
O
O
8
6
96% ee
a
>99% ee
HO
HO
OH
HO
c
OH
2
O
(–)-E- -viniferin (1)
[
]
21 –3.0 (c 0.71, MeOH)
D
lit.2d
[ ]
25 –16.3 (c 0.75, MeOH)
D
Scheme 5. Reagents and conditions: (a) recrystallization from hexane/EtOAc, 68%;
(b) 3,5-diacetoxystyrene (7), Pd(OAc)2 (5 mol %), P(o-tolyl)3 (12.5 mol %), i-Pr2NEt,
DMF, 100 °C, 81%; (c) BBr3, CH2Cl2, À78 °C to rt, 72%.
13. For the effective use of an immobilized catalyst based on Rh2(S-PTTL)4 for
intramolecular C–H insertion of aryldiazoacetate, see: Takeda, K.; Oohara, T.;

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isomer 16 in 91% yield with no erosion in enantioselectivity. This observation
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via the p-quinonemethide intermediate generated by the Lewis acid BBr3. In
addition, no evidence of deprotection of methyl ethers was observed at this
temperature. See Ref. 14.
MeO
OMe
BBr3
Br
OMe
CH2Cl2
2
O
C
8
96% ee
MeO
MeO
OMe
OMe
Br
Br
O+
Me
OMe
2
O
O
91%
16
96% ee
BBr2
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without an electron-withdrawing substituent on the diazo carbon, see: (a)
Fulton, J. R.; Aggarwal, V. K.; de Vicente, J. Eur. J. Org. Chem. 2005, 1479–1492;
(b) López-Sánchez, C.; Álvarez-Corral, M.; Jiménez-González, L.; Muñoz-
Dorado, M.; Rodríguez-García, I. Tetrahedron 2013, 69, 5511–5516; (c) Li, Y.;
Huang, Z.; Wu, X.; Xu, P.-F.; Jin, J.; Zhang, Y.; Wang, J. Tetrahedron 2012, 68,
5234–5240.
23. For ruthenium(II)-catalyzed intramolecular C–H insertion reaction of diazo
compounds without an electron-withdrawing substituent on the diazo carbon,
see: (a) Cheung, W.-H.; Zheng, S.-L.; Yu, W.-Y.; Zhou, G.-C.; Che, C.-M. Org. Lett.
2003, 5, 2535–2538; (b) Zhou, C.-Y.; Huang, J.-S.; Che, C.-M. Synlett 2010,
2681–2700; (c) Reddy, A. R.; Zhou, C.-Y.; Guo, Z.; Wei, J.; Che, C.-M. Angew.
Chem., Int. Ed. 2014, 53, 14175–14180.
29. (a) Tsutsui, H.; Yamaguchi, Y.; Kitagaki, S.; Nakamura, S.; Anada, M.;
Hashimoto, S. Tetrahedron: Asymmetry 2003, 14, 817–821; (b) Anada, M.;
Tanaka, M.; Washio, T.; Yamawaki, M.; Abe, T.; Hashimoto, S. Org. Lett. 2007, 9,
4559–4562; (c) Shimada, N.; Nakamura, S.; Anada, M.; Shiro, M.; Hashimoto, S.
Chem. Lett. 2009, 38, 488–489; (d) Liu, Y.; Deng, Y.; Zavalij, P. Y.; Liu, R.; Doyle,
M. P. Chem. Commun. 2015, 565–568.
30. (a) Yamawaki, M.; Tsutsui, H.; Kitagaki, S.; Anada, M.; Hashimoto, S.
Tetrahedron Lett. 2002, 43, 9561–9564; (b) Shimada, N.; Anada, M.;
Nakamura, S.; Nambu, H.; Tsutsui, H.; Hashimoto, S. Org. Lett. 2008, 10,
3603–3606; (c) Shimada, N.; Oohara, T.; Krishnamurthi, J.; Nambu, H.;
Hashimoto, S. Org. Lett. 2011, 13, 6284–6287; (d) Krishnamurthi, J.; Nambu,
H.; Takeda, K.; Anada, M.; Yamano, A.; Hashimoto, S. Org. Biomol. Chem. 2013,
11, 5374–5382; (e) Lindsay, V. N. G.; Lin, W.; Charette, A. B. J. Am. Chem. Soc.
2009, 131, 16383–16385; (f) Fu, L.; Wang, H.; Davies, H. M. L. Org. Lett. 2014,
16, 3036–3039.
31. In stark contrast to the reaction of 9, the reaction of model substrate 11 with
Rh2(S-TFPTTL)4 at À60 °C required a significantly longer reaction time (10 h)
than that with Rh2(S-PTTL)4, even though the highest enantioselectivity of 99%
ee was achieved.
32. Mizoroki–Heck reaction of 8 with 3,5-dimethoxystyrene provided a coupling
product in only 19% yield.
33. (a) Watanabe, N.; Ogawa, T.; Ohtake, Y.; Ikegami, S.; Hashimoto, S. Synlett 1996,
85–86; (b) Anada, M.; Hashimoto, S. Tetrahedron Lett. 1998, 39, 79–82; (c)
Takahashi, T.; Tsutsui, H.; Tamura, M.; Kitagaki, S.; Nakajima, M.; Hashimoto, S.
Chem. Commun. 2001, 1604–1605; (d) Minami, K.; Saito, H.; Tsutsui, H.;
Nambu, H.; Anada, M.; Hashimoto, S. Adv. Synth. Catal. 2005, 347, 1483–1487;
(e) Ito, M.; Kondo, Y.; Nambu, H.; Anada, M.; Takeda, K.; Hashimoto, S.
Tetrahedron Lett. 2015, 56, 1397–1400; (f) Taber, D. F.; Tian, W. J. Org. Chem.
2007, 72, 3207–3210; (g) Xu, X.; Deng, Y.; Yim, D. N.; Zavalij, P. Y.; Doyle, M. P.
Chem. Sci. 2015, 6, 2196–2201.
24. Heck, R. F. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 4, pp 833–865.
25. Kurihara, H.; Kawabata, J.; Ichikawa, S.; Mizutani, J. Agric Biol. Chem. 1990, 54,
1097–1099.
26. Very recently, Shaw et al. reported the first example of enantioselective
intramolecular C–H insertion reaction of donor–donor metal carbenes with no
pendant electron-withdrawing groups. This process under catalysis by Rh2(S-
PTAD)4 (3)15 enabled the synthesis of densely substituted dihydrobenzofurans
with high levels of diastereo- and enantioselectivity (up to 98% ee). As an
application of this method, they accomplished the first asymmetric synthesis
of (À)-E-d-viniferin using a similar approach to ours, which also established the
absolute stereochemistry of natural E-d-viniferin as shown in 1. While
intramolecular C–H insertion reaction of 9 in CH2Cl2 using 1 mol % of Rh2(S-
PTAD)4 (3)15 at À20 °C provided 8 in 90% yield and with perfect cis selectivity,
the enantioselectivity was 86% ee: Soldi, C.; Lamb, K. N.; Squitieri, R. A.;
González-López, M.; Di Maso, M. J.; Shaw, J. T. J. Am. Chem. Soc. 2014, 136,
15142–15145.
27. Although a one-pot sequential oxidation/Rh2(S-PTTL)4-catalyzed C–H insertion
reaction of 10 at À60 °C provided 12 in virtually the same product yield and
enantioselectivity (92% yield, 97% ee), much longer reaction time (12 h) was
required.
34. DeAngelis, A.; Dmitrenko, O.; Yap, G. P. A.; Fox, J. M. J. Am. Chem. Soc. 2009, 131,
7230–7231.
23
35. Shaw et al. reported optical rotation of 1 of 86% ee, [
a
]
À13 (c 0.098,
D
MeOH).26
Ph
Ph
MnO2 (400 wt%)
CH2Cl2, rt, 0.5 h
36. (a) Hashimoto, S.; Watanabe, N.; Ikegami, S. Tetrahedron Lett. 1992, 33, 2709–
2712; (b) Hashimoto, S.; Watanabe, N.; Ikegami, S. J. Chem. Soc., Chem. Commun.
1992, 1508–1510.
NH2
Ph
N
Ph
O
O
then
37. By taking advantage of
a one-pot sequential epimerization and global
Rh2(S-PTTL)4 (1 mol %)
10
12
97% ee
>99:1 cis selectivity
deprotection at the final stage, 2 steps are shortened in the route from the
C, 12 h
92%
same intermediate 8 as compared to Shaw’s synthesis.26