Palladium-Catalzyed Atroposelective 16-Membered Macrocyclization: Total Synthesis of Isoplagiochin D?

Article abstract of DOI:10.1002/cjoc.202000051

Isoplagiochin D is a ring-strained macrocyclic bisbibenzylis, which showed stable axial chirality in one biaryl structure, and semistable axial chirality in the other biaryl moiety. We reported here an unprecedented example for the catalytically asymmetri

Full text of DOI:10.1002/cjoc.202000051

Chinese Journal
of Chemistry
CJC 中 国 化 学 - An International Journal
Accepted Article
Title: Palladium-Catalzyed Atroposelective 16-Membered Macrocyclization: Total
Synthesis of Isoplagiochin D
Authors: Junwei Xi, and Zhenhua Gu*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.202000051.
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Chinese Journal
of Chemistry
中 国 化 学 - An International Journal
Atroposelective, Macrocyclization, Asymmetric Synthesis, Axial Chirality,
Palladium Catalysis, Bisbibenzylis, Natural Product
Report
CJC
Palladium-Catalzyed Atroposelective 16-Membered Macrocyclization:
Total Synthesis of Isoplagiochin D
a
,a,b
Junwei Xi, and Zhenhua Gu*
a
Hefei National Laboratory for Physical Sciences at the Microscale, and Department of Chemistry, University of Science and Technology of China, 96 Jinzhai
Road, Hefei, Anhui Province, 230026, P. R. China
b
Center for Excellence in Molecular Synthesis of CAS, Hefei, 230026, P. R. China
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Summary of main observation and conclusion Isoplagiochin D is a ring-strained macrocyclic bisbibenzylis, which showed stable axial chirality in one biaryl
structure, and semistable axial chirality in the other biaryl moiety. We reported here an unprecedented example for the catalytically asymmetric synthesis
of ring-strained atropisomers via Pd-catalyzed macrocyclization between benzyl halides and carbenes. This newly developed Pd-catalyzed asymmetric
macrocyclization protocol enabled us a quick synthesis of isoplagiochin D in a highly enantioselective manner.
Background and Originality Content
-
cyclophane like bis bipbenzyls and analogue
(
)
Biaryl natural products bearing strong strain bridged-rings
usually showed atropisomerism, whose rotation around the aryl-
aryl single bond was inhibited. Many representatives of these
natural products, such haouamine A and vancomycin, exhibit
remarkable bioactivities. The macrocyclic bisbibenzylis
isoplagiochin C (1a) and isoplagiochin D (1b) were isolated from the
liverwort Plagiochila fruticosa in 1996 by Asakawa and co-workers
Cl
OH
OH
OH
a
OH
*
OH
OH
OH
HO
OH
HO
b
*
(
)
HO
O
OH
configuration stable
OH
OH
*
Cl
O
H
*
configuration semistable
bazzanin J (2)
riccardin C (3)
i
soplagiochin C 1a
(
)
( )
isoplagiochin D (1b)
1
2
(
Figure 1). The chlorinated analogue bazzanin J (2), diaryl ether
3
,4
riccardin C (3) have been isolated by Asakawa et al. It was found
the existence of chirality in isoplagiochin C (1a) and isoplagiochin D
Figure 1 Structure of Isoplagiochins and Analogues
2,5-7
(
1b) by the analysis of CD spectra and optical rotation.
The 16-
membered macrocycle bearing two linear biaryls displayed
potential axial chirality of biaryl systems: bond a in isoplagiochin D
displayed stable axial chirality while bond b bearing less hindered
two ortho-hydroxy substituents was semistable. Becker, Speicher
and Bringmann et al. discussed the atropisomerism and ring strain
for these compounds, and determined the energy of racemization
7
of isoplagiochin C to be 101.6 kJ/mol, approximately. Markedly,
the optical rotation of natural isoplagiochins C and D varied from
1,3
the plant source and the isolation protocol. These compounds
8
,9
also exhibit anti-MRSA,
antimycotic activities.
antitumoural, antibacterial and
The interesting twisted structure, along
with the remarkable biological activities attracted considerable
10,11
12-16
attentions from synthetic and bio-chemists.
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through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1002/cjoc.202000051
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Report
First author et al.
Scheme 1 Approaches for Asymmetric Synthesis of Isoplagiochins
and insertion. The β-elimination of 14 afforded the key
intermediate 15. The axial chirality determining-step may either be
the carbene coordination Step A or ring contraction Step B.
Alternatively, the benzylic chloride and aldehyde hydrazone
moieties can be switched, such as compound 10 vs 11.
.
a
Catalytically Asymmetric Heck Macrocyclization Speicher et al
)
(
)
possible atropostable
ortho bulky group
M or P
MeO
M or P
OMe
OM
e
MeO
OMe
OM
e
*
*
P
Pd(BINAP)
conditions
2
*
Scheme 2 Synthetic Plan for Asymmetric Macrocyclization
OTf
Pd
,
ee
X
P
22% 37%
a
Two Key Precursors
)
OMe
Cl
OMe
OMe
MeO
OMe
MeO
MeO
MeO
MeO OM
e
4
5
6
Cl
NNHSO
2
A
r
.
N
b) Chiral Sulfinyl Auxilary Strategy (Speicher et al )
T
s
HN
-
p Tol
O
OMe
OMe
OM
e
S
*
M
MeO OMe
MeO OMe
3,
Pd
2
(dba) PMP
I
I
Pd
O
,
d
r
:
99 1
10
11
,
o
,
80%
DMF 70
C
70 h
S
-
S
-
o
O
p Tol
p T
l
b) P d K y A
ro ose
e
s
mme r c acroc
c
li ti
za on
p
y
t i
M
-
y
flexiable Ar Ar bond
OMe
MeO
MeO
OMe
OMe
OMe
L
MeO
OM
e
M
e
O
OM
e
MeO
M
e
O
7
8
9
L
Pd
Cl
NNHSO
Ar
Pd(0)
L
X
N
2
Pd
X
2
conditions
base
St p A
e
The asymmetric synthesis of atropo-active natural products
have caught significant attentions.
macrocyclization for atropisomers construction is challenging,
and diastereo-controlled approach was the general strategy.
The syntheses of the cyclophane-like bis(bipbenzyls) were almost
1
7-22
The catalytically asymmetric
OMe
MeO OMe
2
2
3,24
5,26
MeO OMe
Me
O
12
1
1
13
OMe
OM
e
O
Me
*
OMe
*
(
M
or
P)
(M or P)
27-29
in racemic form,
until in 2012 Speicher and co-workers started
Step B
2
PdL X
1
b
the first trial for catalytically asymmetric synthesis of Isoplagiochins
D (Scheme 1a). In this study, they controlled the axial chirality of
OMe
OMe
OMe
OMe
30
Isoplagiochin D via a palladium-catalysed Heck macrocyclization.
14
15
(
0)
2
It was proposed that the oxidative addition of Pd (BINAP) with 4
We started our studies by the synthesis of cyclization precursor
0 (Scheme 3). The reduction of ester 16 with DIBAL-H gave alcohol
7, which was transferred to Wittig reagent 18 with Ph PHBr. The
3
possibly afforded an atropostable arylpalladium species due to the
large size of ortho Pd group. It might account for the low
enantioselectivity (37% ee), where the Ar-Ar bond bearing ortho Pd
group cannot undergo dynamical isomerization freely to adopt
proper conformation during the macrocyclization; furthermore, to
avoid possible “ligand-free” background reactions, complex
1
1
palladium-catalyzed borylation of 19 gave 20, which would furnish
the biaryl 22 via the cross-coupling with the bromide 21. The Wittig
olefination of 22 with 18 provided a pair of Z/E isomers 26 in 85%
overall yield. The subsequent palladium-catalyzed Suzuki coupling
with 25 furnished 27 in excellent yield. Three-step manipulation,
hydrogenation, hydrolysis and chlorination gave benzyl chloride 28.
Unfortunately, the electron-donating property of the para-
methoxy group made this benzyl chloride 10 unstable, which was
quickly decomposed in the next step.
2
[Pd(M)-BINAP] had to be prepared independently before use. Six
years later, the same group developed an elegant chiral sulfinyl
group induced diastereoselective Heck macrocyclization of iodide
31-34
7
(Scheme 1b).
Pleasingly, high yield (80%) and high
diastereoselectivity (de 98%) have been achieved, although the
modification of sulfinyl group to hydroxyl group required a very
Subsequently, hydrazone 11, whose methoxy group is at the
meta-position of benzyl chloride, was going to be prepared
Scheme 4). The aldehyde 19 was treated with ethylene glycol to
careful three-step manipulation with 34% overall yield at as low as
o
-
100 C.
(
give ketal 29, which successfully delivered 30 via palladium-
catalyzed cross-coupling with 20. The olefination of 30 with 18
furnished 31 in 90% yield (Z/E ~ 1:1), which was further transferred
to 35 via Suzuki-coupling with boronic ester 32. The same three-
step manipulation provided 34 in 81% overall yield. Compound 34
was stable enough and readily condensed with hydrazines bearing
different steric and electronic properties in good yields.
Results and Discussion
In continuation our research interests in transition-metal-
3
5-38
catalyzed atropisomer synthesis
Speicher’s work,
and with the inspiration of
30-32
herein we report a catalytically asymmetric
macrocyclization of benzyl chlorides and N-Ts hydrazones. Due to
the high ring-strain, the atroposelective ring closure was obviously
considered as the most challenging step. It was reasoned that the
benzylic palladium species (12) (one-carbon extension in
comparison with arylpalladium 5), was atropo-unstable at ambient
temperature, which could adopt proper configuration to achieve
high enantioselectivity during the macrocyclization (Scheme 2).
Thus, the Pd-catalyzed styrenes synthesis between benzyl chloride
3
9-51
and arylhydrazones became an ideal reaction for our strategy.
The key cyclic palladium complex 13 would give 14 via migration
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Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
Scheme 3 Synthesis of Precursor 10
WingPhos (L12) displayed best performance, and the reaction
afforded the cyclization product in excellent ee value (entries 10-
O
r
,
M CN
e
DIBAL H 0 o
-
,
C
O
HB PPh
reflux, 12 h
3
O
PPh3Br
54,55
o
O
OH
12).
The reaction conducted at 70 C gave 15 in 93% ee, while
C resulted in the rate of
O
9
8%
Br
96%
Br
further decreasing the temperature to 60
o
Br
1
6
17
18
this reaction becoming very sluggish (entries 13-14). It was found
that the yield of this reaction was very sensitive to moisture. Finally,
the combination of LiOtBu and LiOH (1:2) gave reliable yield while
maintained high enantioselectivity (entry 15). Increasing the
O
,
c
2
PdCl dppf KOA
Br
O
O
n2, dioxane
O
B
2
pi
OTBS
21
)
(
3,
CHO
OHC
Br
92%
OHC
Bpin
Pd
2
dba SPh
os
OTBS
9
1%
O
O
1
9
20
22
loading of Pd(TFA) only slightly improved the yield (entry 16).
2
,
c
Furthermore, the reaction with a stoichiometric amount of
palladium catalyst gave only a trace amount of product. In all these
reactions, the hydrolysis of hydrazone to aldehyde, as well as the
dimerization of carbene intermediate to C=C bond are the main
byproducts.
CHO
O
O
PdCl
2
dppf KOA
n2
112 o
O
Br
HOCH
o
2
CH
,
2
OH
B
pi
2
1
60
C
24 h
Br
oxane,
Bpin
di
C
O
94%
O
99%
O
2
3
24
25
O
O
O
Br
25, Pd2dba3
CO3,
-
-
,
O
K
2
18 C 6
re ux
SPhos
K
CO
100 o
,
2
3
O
CH
2
Cl
2
fl
o uene,
a
1
8
+
22
O
t
l
C
O
Table 1 Optimization of Reaction Conditions
,
=
:
8
5% Z/E 1 1
9
1%
O
OMe
O
M
e
O
OMe
O
M
e
OTBS
OTBS
O
O
27
m
,
ga
g
n
d
.
P
P
d
d
t
t
(
T
T
B
F
F
2
2
) (
A) (20 mo
A 2
0
, o uene, em
O
Li
t
uOLi oluene, temp
o
l
l
%
%
t
)
)
, l
l
i
i
a. nd
2
6
Cl
l
u
, t
l
p
O
O
O
O
O
O
N
N
N
NHTs
HT
s
a
Pd/C, H , NEt , 40
o
C
Me
M
e
OMe
O
M
e
15
15
)
2
3
,
O
O
M
M
e
e
O
O
,
o
s e
p
s
NNHT
s
b) 2N HCl 50
C
71% (2
t
)
O
TsNHNH
1
11
1
a
a
2
c
MsCl, NEt , LiCl, 62%
O
MeOH, 50 oC
O
The Screened Chiral Phosphines
S C
d p
Th hi l Ph hi
e c ee e a os es
r n r n
)
3
Me H
M H
e
Ph
Ph
Cl
Cl
O
O
M
M
e
e
P
P
C
C
y
2
2
P
O
O
PPh
PPh
2
2
O
O
10
P
P
P
P
P
P
P
h
h
2
2
P
P
P
Ph
h
PPh
PPh
2
2
2
8 (unstable)
F
F
e
e
O
O
O
O
Ph
O
O
L
1
1
L
L
2
2
L
L
3
3
L4
L
4
Scheme 4 Synthesis of Precursor 11
O
O
PPh
PPh
2
2
O
O
P
P
(
(
X
X
y
y
l
l
)
)
( )
P(Tol)
P T l
o
2
2
2
2
( )
P(Xyl)
y
P X l
2
2
P
P
(
(
T
T
o
o
l
l
)
)
2
O O
O O
O
O
O
,
a ,
SPh
os
PPh
PPh
2
2
O
HOCH
2
CH
2
OH
O
20 Pd db
2
3
2
2
PPh Ph P
PPh Ph P
o
,
o uene
CHO
O
O
2
2
1
60
C
K
3
PO
4
t
l
O
O
L
5
5
L
L
6
6
L
L
7
7
L8
L
8
OHC
Br
Br
93%
96%
O
H
H
H
H
O
O
O
O
O
O
O
O
O
O
O
1
9
29
30
P
P
P
P
P
P
P
P
P
t
t
B
B
u
u
tB
t
B
u
u
t
t
B
B
u
u
tBu tBu
B B
t t
u u
O
O
O
O
O
Br
O
O
TB
S
, 3,
-
-
L
L
9
9
L
L
1
1
0
0
L
L
1
1
1
1
L12
L
12
1
8
K CO 18 C 6
2
,
fl
re ux
O
O
Bpin
32)
OTBS
CH
2
Cl
,
2
O
(
=
:
9
0% Z/E 1 1
O
O
Pd
o .,
2
dba
,
3
SPh
os
O
100 oC, 90%
.
t
l
O
O
3
1
33
O
O
O
O
a
Pd/C, H , 40
o
C
ArS(O
)NHNH
2 2
o
)
2
,
o
,
95% (2
t
p
s e s
)
,
b) 2N HCl 50
C
MeOH 50
-
C
c
MsCl, NEt , LiCl, 90%
Cl
)
3
O
11a, r =
ol,
p T 92%
-
O
Cl
A
,
,
,
r =
,
,
e
C
)
3
O
11b
A
2 4 6 (M
r = -na
phthyl
6
H
2
N
O
1
1
1
1c
A
A
2
NH
r =
-
e
1d
p M OC
6
H
4
S O
O
e, Ar =
-
O
Ar
1
3 6
C
p CF H
4
3
4
11
With the hydrazone 11a in hand, we tried to study the
asymmetric macrocyclization (Table 1). Primary screening found
that Pd(TFA) was the optimal pre-catalyst. The monodentate
2
ligand MOP gave 6% yield with 7% ee, while bidentate ligands L2
and L3 only produced trace amount of desired product (entries 1-
3
). DIOP (L4) gave an increased yield of 15, while the
enantioselectivity was still low (entry 4). The reactions by using
axially chiral phosphine L5 or L6, or the Ding’s Ph-SKP (L7) as the
52
ligand did not achieve better results (entries 5-7). The planar
chiral biphosphine L8 dramatically improved the efficacy of this
macrocyclization (43% yield), however, the enantioselectivity was
still dissatisfied (entry 8). Pleasingly, the chirality at P-center ligand
L9, developed by Tang and co-workers showed significantly
53
improved enantioselectivity (entry 9). Thus, the corresponding
analogous have been investigated. It was found that 9-anthracenyl
group was critical for the stereoselectivity, and the bidentate ligand
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Report
First author et al.
Scheme 5 Other Effects for Macrocyclization
CONC.
Yield of 15
ee of
entry
Ligand
T/oC
O
O
OM
e
15 (%)
OMe
(mol/L)
(%)
.
,
Pd(TFA)
2
(0 10 equiv) L12
X
tBuOLi
,
o uene
(0 02 M) 70 o
C
.
,
t
l
O
1
2
L1
L2
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
80
80
80
80
80
80
80
80
80
80
80
80
70
60
70
70
6
trace
trace
27
7
7
-
N
NHSO
2
Ar
OMe
OM
e
O
Me
Substituent Effect
O
O
3
L3
-
O
O
4
L4
<2
<2
20
<2
5
X
Me
O
Me
X
O
O
O
5
L5
N
S
N
S
O
N
N
H
O
Me
H
OMe
89%
11b)
OMe
(11
c
,
ee
11% 91%
(
ee
)
6
L6
11
19
43
18
5
,
9
%
O
O
O
7
L7
O
X
R
8
9[b]
L8
O
B
r
Me
O
O
N
S
O
L9
61
10
10
85
92
-
N
N
S
O
H
O
N
OM,
e
H
=
=
OMe 11d trace
,
OM (11f)
4% 63% ee
e
0[b]
R
R
1
1
1
1
1
L10
L11
L12
L12
L12
L12
L12
,
,
,
CF
3
11e trace
1[b]
2[b]
3[b]
4[b]
9
eome r c
Eff t
ec
G
t
i
O
O
O
O
13
11
-
a
2N HCl 50 oC, 95%
,
Cl
TsNHNH
2
Cl
)
O
b) MsCl, NEt LiCl 90%
3,
,
O
e
OH 50 oC
,
M
O
O
O
9
2%
O
Z) 33
O
35
-
(
5[c]
OMe
1
18
22
93
93
O
OMe
O
1
6[c,d]
Cl
O
conditions
a
Reaction Conditions: 11a (0.04 mmol) tBuOLi (3.0 equiv), Pd(TFA)
mol%), ligand (24 mol%) in toluene at indicated temperature. 10 mol% of
2
(20
Ts
N
N
b
H
M
e
O
OMe
37, no orme
d
O
36
c
d
Pd(TFA)
mol% Pd(TFA)
2
was used. tBuOLi (1.5 equiv) and LiOH (3.0 equiv) was used. 30
t f
2
was used. After 15 being converted to 1b, the absolute
configuration of the product was assigned as S by comparison of the optical
rotation of the natural product.
With 15 in hand, two-step manipulation smoothly furnished
the synthesis of isoplagiochin D (1b) in 71% overall yield (Scheme
6
). Notably, partial racemization was observed during Pd/C-
Additionally, the substituent effect of arylsulfonyl moiety was
studied (Scheme 5). The 2,4,6-trimethylphenyl derivative 11b gave
a slight decreased yield and enantioselectivity. The β-naphthyl
analogue 11c spontaneously degraded to diazo compound partially,
and mixture of 11c and diazo showed almost same efficacy as 11a.
Unfortunately, strong electron-donating (11d) or electron-
withdrawing group (11e) at arylsulfonyl moiety was deleterious for
this palladium-catalyzed cyclization. The benzyl bromide 11f only
produced 6% of yield of the macrocycle possible due to its less
stability than the benzyl chloride analogue 11a.
Finally, an alkene derivative 36 was prepared from (Z)-33 in the
same manner as above (Figure 6). We anticipated that the fixed
geometry of Z-isomer would improve the cyclization yield.
Disappointedly, the reaction of 36 did not produce any desired
product under the standard conditions.
catalyzed hydrogenation of 15 to 38. No racemization was observed
by independent submitting compound 38 to standard
hydrogenation conditions at room temperature. Thus, it is
necessary to perform the hydrogenation reaction at -10 C to
minimize the racemization (93% ee to 91% ee). The rotational
barrier [G(373.15K) ] of compound 15 was determined to be 129
kJ/mol by analysing the racemization rate at 90, 100, 110 C,
respectively. The calculated rotational barrier at 298.15 K was 119
kJ/mol, approximately. These data indicated that compound 15 is
more stable than isoplagiochin C.
o
ǂ
o
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Running title
Chin. J. Chem.
Scheme 6 The Synthesis of Isoplagiochins D
Sakuraii and Mastigophora Diclados, Tetrahedron 2000, 56, 3153-3159.
Asakawa, Y.; Toyota, M.; Tori, M.; Hashimoto, T.; Chemical Structures
of Macrocyclic Bis(bibenzyls) Isolated from Liverworts (Hepaticae),
Spectroscopy 2000, 14, 149-175.
Bringmann, G.; Gulder, T. A.; Reichert, M.; Gulder, T.; The Online
Assignment of the Absolute Configuration of Natural Products: HPLC-
CD in Combination with Quantum Chemical CD Calculations, Chirality
OMe
OM
e
e
OH
OMe
OM
OH
*
P
,
a
oon
,
Pd/C
H
2
(b ll
)
BBr
3
,
-
o
DCM, rt 3 h
,
a
EtOAc 10
C
1 h
,
ee
uantitative
9
71% 91%
q
1% ee
OMe
OMe
OMeOMe
OH OH
( ) isoplagiochin D (1b)
-
-
1
5 (93% ee)
38
-
2008, 20, 628-642.
∗
∗
∆
∆
.
=
mo
mo
1
compound 15
G(298 15K) 119 kJ
l-
=
1
G(373 15K) 129 kJ
.
l
Speicher, A.; Backes, T.; Hesidens, K.; Kolz, J.; Ring Strain and Total
Syntheses of Modified Macrocycles of the Isoplagiochin Type,
Beilstein J. Org. Chem. 2009, 5, No. 71. doi:10.3762/bjoc.5.71.
Bringmann, G.; Mühlbacher, J.; Reichert, M.; Dreyer, M.; Kolz, J.;
Speicher, A.; Stereochemistry of Isoplagiochin C, a Macrocyclic
Bisbibenzyl from Liverworts, J. Am. Chem. Soc. 2004, 126, 9283-9290.
Sawada, H.; Onoda, K.; Morita, D.; Ishitsubo, E.; Matsuno, K.; Tokiwa,
H.; Kuroda, T.; Miyachi, H.; Structure–anti-MRSA Activity Relationship
of Macrocyclic Bis(bibenzyl) Derivatives, Bioorg. Med. Chem. Lett.
2
013, 23, 6563-6568.
Onoda, K.; Sawada, H.; Morita, D.; Fujii, K.; Tokiwa, H.; Kuroda, T.;
Miyachi, H.; Anti-MRSA Activity of Isoplagiochin-type Macrocyclic
Bis(bibenzyls) is Mediated Through Cell Membrane Damage, Biorg.
Med. Chem. 2015, 23, 3309-3316.
Dodo, K.; Aoyama, A.; Noguchi-Yachide, T.; Makishima, M.; Miyachi,
H.; Hashimoto, Y.; Co-existence of α-Glucosidase-inhibitory and Liver
X Receptor-Regulatory Activities and Their Aeparation by Structural
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Keserű, G.; Nógrádi, M.; The Chemistry of Macrocyclic Bis(bibenzyls),
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Harrowven, D. C.; Kostiuk, S. L.; Macrocylic Bisbibenzyl Natural
Products and Their Chemical Synthesis, Nat. Prod. Rep. 2012, 29, 223-
Conclusions
We reported a palladium-catalyzed highly enantioselective
macrocyclization for the preparation of bisbibenzylis isoplagiochin
D. It represented the first example for palladium-catalyzed
enantioselective macrocyclization of benzyl halides and carbenes.
In this Pd-catalyzed strain ring construction, WingPhos displayed
unique stereo-induction activity. It showcased a new way for
catalytically asymmetric construction of macrocycle, which might
be applicable for other strained natural product synthesis.
2
42.
Supporting Information
Speicher, A.; Backes, T.; Grosse, S.; Syntheses of Macrocyclic
Bisbibenzyls on Solid Support, Tetrahedron 2005, 61, 11692-11696.
Harrowven, D. C.; Woodcock, T.; Howes, P. D.; Total Synthesis of
Cavicularin and Riccardin C: Addressing the Synthesis of an Arene that
Adopts a Boat Configuration, Angew. Chem. Int. Ed. 2005, 44, 3899-
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Acknowledgement (optional)
3
901.
This work was financially supported by National Natural
Science Foundation of China (21871241), and the
Fundamental Research Funds for the Central Universities
Harada, K.; Makino, K.; Shima, N.; Okuyama, H.; Esumi, T.; Kubo, M.;
Hioki, H.; Asakawa, Y.; Fukuyama, Y.; Total Synthesis of Riccardin C and
(±)-Cavicularin via Pd-Catalyzed Ar–Ar Cross Couplings, Tetrahedron
2
013, 69, 6959-6968.
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Chin. J. Chem. 2019, 37, XXX－XXX
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www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.

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Running title
Chin. J. Chem.
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
(
The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Chin. J. Chem. 2019, 37, XXX－XXX
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Entry for the Table of Contents
Page No.
Palladium-Catalzyed
Atroposelective
16-
OMe
O
OH
OH
Membered Macrocyclization: Total Synthesis of
Isoplagiochin D
O
OMe
2,
Pd(TFA) Wi
ngPhos
,
.,
tBuOLi LiOH tol 70 oC
,
Cl
O
9
3% ee
N
NHTs
OMe
OMe
HO
OH
OMe
-
-
) i
soplagiochin D
(
A catalytically asymmetric macrocyclization via palladium-catalyzed intramolecular coupling
between benzyl chloride and arylhydrazone was reported. This method enabled the asymmetric
total synthesis of bisbibenzylis isoplagiochin D.
Junwei Xi, and Zhenhua Gu*
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© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.