Radical-Cation Cascade to Aryltetralin Cyclic Ether Lignans Under Visible-Light Photoredox Catalysis

Article abstract of DOI:10.1002/anie.202007548

The development of concise, sustainable, and cost-effective synthesis of aryltetralin lignans, bearing either a fused lactone or cyclic ether, is of significant medicinal importance. Reported is that in the presence of Fukuzumi's acridinium salt under blue LED irradiation, functionalized dicinnamyl ether derivatives are converted into aryltetralin cyclic ether lignans with concurrent generation of three stereocenters in good to high yields with up to 20:1 diastereoselectivity. Oxidation of an alkene to the radical cation is key to the success of this formal Diels–Alder reaction of electronically mismatched diene and dienophile. Applying this methodology, six natural products, aglacin B, aglacin C, sulabiroin A, sulabiroin B, gaultherin C, and isoshonanin, are synthesized in only two to three steps from readily available biomass-derived monolignols. A revised structure is proposed for gaultherin C.

Full text of DOI:10.1002/anie.202007548

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Radical Cation Cascade to Aryltetralin Cyclic Ether Lignans
Enabled by Visible Light Photoredox Catalysis
Authors: Jia-Chen Xiang, Qian Wang, and Jieping Zhu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202007548
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10.1002/anie.202007548
Angewandte Chemie International Edition
Research Article
Radical Cation Cascade to Aryltetralin Cyclic Ether Lignans Under
Visible Light Photoredox Catalysis
Jia-Chen Xiang, Qian Wang, and Jieping Zhu*
a) Representative examples of aryltetralin lactone and aryltetralin cyclic ether lignans
Abstract: The development of concise, sustainable and cost-effective
HO
7
HO
H
synthesis of aryltetralin lignans bearing a fused lactone or cyclic ether
is of significant medicinal importance. We found that in the presence
of Fukuzumi’s acridinium salt under blue LEDs irradiation,
functionalized dicinnamyl ether derivatives are converted to
aryltetralin cyclic ether lignans with concurrent generation of three
stereocenters in good to high yields with up to 20:1
diastereoselectivity. Oxidation of alkene to radical cation is key to the
success of this formal Diels-Alder reaction of electronically mis-
matched diene and dienophile. Applying this methodology, six natural
products, viz, aglacin B, aglacin C, sulabiroin A, sulabiroin B,
gaultherin C and isoshonanin, are synthesized in only 2 to 3 steps
HO
7
H
H
H
H
H
MeO
MeO
O
O
O
O
H
O
O
8
H
7’
O
8’
O
H
MeO
O
MeO
OMe
MeO
OMe
MeO
OMe
OMe
OMe
OMe
3 C7-α-OH, aglacin E
4 C7-β-OH, aglacin F
H
1 podophyllotoxin
2 picropodophyllotoxin
H
MeO
MeO
MeO
H
MeO
H
O
H
O
H
O
HO
H
H
HO
MeO
R
H
MeO
MeO
OMe
OMe
OMe
from readily available biomass-derived monolignols.
structure is proposed for gaultherin C.
A revised
OH
8 isoshonanin
OMe
OH
5 R = OMe, aglacin B
6 R = H, aglacin C
7 gaultherin C
OH
HO
O
O
H
H
H
O
O
MeO
MeO
H
H
H
O
Introduction
O
O
O
O
H
O
H
H
MeO
O
MeO
Podophyllotoxin (1) and picropodophyllotoxin (2) bearing a
trans- and a cis-fused lactone ring, respectively, are two
prominent examples of aryltetralin lactone lignans,[1] while
O
OMe
OMe
O
O
O
MeO
OMe
OH
11 etoposide
aglacins (3-6),[2] gaultherin
C
(7),[3] isoshonanin (8)[4] and
9 sulabiroin A
10 sulabiroin B
sulabiroins A, B (9, 10)[5] are representatives of aryltetralin cyclic
ether lignans (Scheme 1a). Members of this family of natural
products display potent and diverse bioactivities and have served
successfully as lead compounds in searching for new medicines.
For instance, extensive structure-activity relationship (SAR) study
using 1 as a lead has led to the development of etoposide (11), a
semi-synthetic derivative of podophyllotoxin, as an anticancer
drug. Etoposide (11) has been clinically used for almost 40 years
and is on the WHO’s list of essential medicines.[6] Lignans are all
biosynthetically derived from (+)-pinoresinol (12), which is in turn
generated via phenoxy radical coupling of coniferyl alcohol in the
presence of dirigent proteins (DIR) (Scheme 1b).[7]
b) Biosynthesis of aryltetralin lignans via (+)-pinoresinol intermediate
OMe
OH
HO
O
DIR
Aryltetralin
lignans
MeO
O
HO
coniferyl alcohol
OH
OMe
12 (+)-pinoresinol
Scheme 1. Aryltetralin lactones and aryltetralin cyclic ethers: Occurrence and
biosynthesis: Abbreviation: DIR = Dirigent proteins.
has led to the loss of plant species at an alarming rate, alternative
sources of podophyllotoxin are therefore urgently needed in order
to solve the supply problem.[9]
In spite of the great progress recorded in the synthesis of
aryltetralin lactone lignans, a sustainable, general and cost-
effective chemical synthesis is still highly demanded in order to
fully exploit the potential of these natural products.[8] Indeed, no
total synthesis of aryltetralin cyclic ether lignans (3-10) has been
reported, whereas podophyllotoxin (1), obtained by extraction
from the rhizome of podophyllum species, is used in commercial
synthesis of etoposide (11). The increased demand of this drug
Oxidation of electron-rich alkenes by Weitz’ aminium salt to
radical cation (hole catalysis) followed by its pericyclic reaction
has been extensively studied by Bauld starting from 1980s.[10]
Recently, significant progress has been made using
electrocatalysis,[11] visible light photoredox catalysis,
iron
[12-16]
salts,[17] and hypovalent iodines[18] as oxidants. Different reactions
including [2+2],[10b,11b,12a,12c,12e,12f,17a-d,18] [4+2],[10a,11c,12b,13h-i,14a-
b,15b,17b-c]
[3+2][11d,14d]
cyclopropanation,[14c]
hydrocycloamination,[13c]
and
[2+2+2][12d]
cycloadditions,
hydrocycloetherifcation,[13a-b]
halolactonization,[13f]
[a]
Dr. J.-C. Xiang, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fédérale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
hydroacetoxylation,[13d] radical addition to carbonyl,[15a] olefin-
metathesis[11a] and polymerization,[19] etc, have been successfully
developed under hole catalysis conditions. In connection with our
interest in developing a concise synthesis of aforementioned
cyclolignans from easily available biomass-derived building
blocks, two reports are particularly inspiring. Nicewicz, Huang
and co-workers reported recently an intermolecular [4+2]
Homepage: http://lspn.epfl.ch
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.202007548
Angewandte Chemie International Edition
Research Article
cycloaddition of substituted styrenes to access tetralin derivatives
product 16 (step e). [13g, 23] We report herein the realization of this
endeavor and their application to the synthesis of aryltetralin
cyclic ether lignans. The mechanism of rearrangement from 15 to
16 is demonstrated to be indeed different from that of the
vinylcyclobutane counterpart. It proceeds most probably through
a stepwise C-C bond cleavage/re-cyclization sequence, rather
than a concerted 1,3-sigmatropic shift with a suprafacial/retention
stereoselectivity as proposed by Bauld for the rearrangement of
vinylcyclobutane.[21] We also document that the stereochemical
outcome is substrate-dependent and that two competitive
reaction pathways from radical cation A might be occurring
leading to 16 with either a cis- or a trans-fused B/C ring,
respectively.
13 (Scheme 2a),[13g]
while Yoon’s group developed
photooxidative intramolecular [2+2] cycloaddition of di(p-
methoxy)cinnamyl ether (14a) to generate 3-
a
oxabicyclo[3.2.0]heptane 15a (Scheme 2b).[12a,20] Both reactions
proceeded smoothly in the presence of a catalytic amount of
photoredox catalysts under visible light irradiation.
a) Nicewicz and Huang’s intermolecular [4+2] cycloaddition of substituted styrenes by
visible light photocatalysis
[Mes-Acr-Ph]+BF4- (5 mol%)
PhSSPh (20 mol%)
2 X
MeO
OMe
DCE, Blue LEDs, 77%
OMe 13
b) Yoon’s intramolecular [2+2] cycloaddition of diallyl ether by visible light photocatalysis
MeO
MeO
OMe
Ru(bpy)3(PF6)2 (5 mol%)
MV(PF6)2 (15 mol%)
H
O
Results and Discussion
visible light, MgSO4, MeNO2
O
H
MeO
14a
15a
The conversion of 14 to 16 represents formally a Diels-Alder
reaction of an electron-rich diene with an electron-rich dienophile
which is electronically mis-matched and is therefore difficult to
accomplish under mild conditions. A solution to this problem
consists of oxidizing one alkene unit to access a radical cation
intermediate in an umpolung strategy. To realize our planned
c) This work: formal intramolecular [4+2] cycloaddition of dicinnamyl ether derivatives to
aryltetralin lignans
*
FG1
B
C O
FG1
FG2
FG1
FG2
*
step a
step e
*
+
•
O
O
FG2
16
transformation, di(p-methoxy)cinnamyl ether (14a, E0 = + 1.05
A
14
1/2
step d
V) [24] was chosen as our test substrate for the survey of reaction
conditions. Given its high excited state oxidizing power
[E*red(Mes-Acr-Me)+/(Mes-Acr-Me)• = + 2.06 V], Fukuzumi’s
acridinium salt, 9-mesityl-10-methylacridinium tetrafluoroborate
+•
FG1
FG2
H
FG1
FG2
H
H
14, step b
O
O
step c
H
B
15
-
[(Mes-Acr-Me)+BF4 ], was chosen as a photosensitizer.[25] We
expect that the [2+2] cycloadduct 15a (E01/2 = + 1.15 V) [24] could
be oxidized back to cyclobutane radical cation B by Fukuzumi’s
catalyst (cf Scheme 2c), driving eventually to the
thermodynamically more stable [4+2] cycloadduct 16a. Inspired
by the work of Nicewicz and Huang on the visible light mediated
[4+2] cycloaddition of substituted styrenes,[13g] diphenyl disulfide
was used as a co-catalyst in our initial condition screening. As
shown in Table 1, irradiating a nitromethane (MeNO2) solution of
14a with 24W blue LEDs at 23 °C for 48 h afforded indeed the
desired tricyclic product 16a in 24% yield as a single diastereomer,
Scheme 2. Synthesis of aryltetralin cyclic ether lignans: [2+2] vs [4+2]
cycloaddition. Ru(bpy)3(PF6)2 Tris(2,2-bipyridine)ruthenium(II)
hexafluorophosphate; MV(PF6)2 = methyl viologen bis(hexafluorophosphate).
=
On the basis of these two seminal contributions, we reasoned
that it might be possible to access aryltetralin cyclic ether lignans
16 directly from diallyl ether 14 by fine-tuning the reaction
conditions. Our simplistic mechanistic rational is outlined in
Scheme 2c. Oxidation of 14 to radical cation A (step a) followed
by kinetically favored [2+2] cycloaddition would afford the fused
cyclobutane radical cation B. Single electron transfer from 14 to
B would afford product 15 with concurrent regeneration of
intermediate A ensuring therefore the chain process (step b). By
judicious choosing a photooxidant capable of oxidizing the
substrate 14, but not the cyclobutane adduct 15, Yoon was able
to successfully realize the [2+2] cycloaddition by inhibiting the
oxidation of 15 back to radical cation B (step c). Although aryl
together with two diastereomeric cyclobutanes 15a and 17a (E0
1/2
= + 1.41 V) [24] (entry 1). X-ray crystallographic analysis indicated
a
7’,8’-trans-8,8’-cis relative stereochemistry for 16a,
corresponding formally to an endo-DA adduct.[26]
Encouraged by these preliminary results, conditions were
further screened varying the solvent, the concentration and the
hydrogen atom transfer (HAT) co-catalyst. As shown in Table 1,
solvents impacted significantly the reaction outcome with
dichloromethane (DCM, entry 6) being the solvent of choice
(entries 1-6). Diminishing the reaction concentration increased
the yield of 16a (entries 7 vs 6). The experimental observation
could be accounted for by invoking the reduced electron-transfer
rate between radical cation B and the starting material 14a in a
diluted solution (cf step b, Scheme 2b) as well as increased
reactivity of B in an apolar solvent (DCM) towards fragmentation.
Similar impact of concentration on the product selectivity has
been observed in the related radical cation based
transformations.[12d, 20b-c, 23c] Replacing the diphenyl disulfide by
thiophenol as an HAT co-catalyst further augmented the reaction
substituted cyclobutane radical cation
B
can undergo
cycloreversion to A, the forward [2+2] cycloaddition is known to
be very fast. [20] Therefore, we reasoned that if we could promote
the step c by using a photocatalyst with a strong excited state
oxidation power, we might have chance to generate formally the
Diels-Alder (DA) adduct 16 (step d) in analogy to the known
rearrangement of vinylcyclobutane to cyclohexene,[21, 22] although
we were aware of the significant difference in reactivities between
vinylcyclobutane and phenylcyclobutane. Alternatively, radical
cation A could also undergo a stepwise radical addition followed
by electrophilic or radical cyclization to afford directly cyclic
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10.1002/anie.202007548
Angewandte Chemie International Edition
Research Article
efficiency to generate 16a in 91% isolated yield (entry 8). Without
HAT reagent under otherwise identical conditions, 16a was
formed in low yield together with 7,7’-cis and 7,7’-trans
disubstituted cyclobutanes 15a and 17a (entry 9).
With the optimum conditions in hands {DCM, c 0.025 M, [Mes-
-
Acr-Me]+BF4 (5 mol%), PhSH (20 mol%), blue LEDs, 23 °C, 48
h}, the generality of this reaction was next exploited (Scheme 3).
Symmetric di(p-alkoxy)cinnamyl ethers underwent a formal [4+2]
cycloaddition to afford the endo-adducts (16a-16e) with excellent
diastereoselectivity (d.r. > 20:1). Compound 16f with a thiomethyl
substituent was also accessible. Dissymmetric cinnamyl ether
afforded 16g as an only regio- and diastereoisomer in which the
p-methoxystyrene served as a diene. The reaction was not
sensitive to the nature of the tether. Thus, substrates with a
nitrogen tether and an all-carbon tether cyclized to aza-lignan 16h
and carba-lignan 16i in yields of 75% and 62%, respectively.
Finally, di(p-bromo)cinnamyl ether bearing an electron-
Table 1. Cyclization of di(p-methoxy)cinnamyl ether (14a): A survey of reaction
conditions.
7
H
MeO
H
H
8
H
O
MeO
OMe
8’
7
MeO
O
7’
+
H
Conditions [a]
7’
O
MeO
15a 7,7’-cis
17a 7,7’-trans
OMe
14a
16a
Entry
Solvent
MeNO2
MeCN
DMSO
Xylene
DCE
c (M)
0.1
Co-Catalyst
PhSSPh
PhSSPh
PhSSPh
PhSSPh
PhSSPh
PhSSPh
PhSSPh
PhSH
16a (%)[b]
15a, 17a (%)[b]
54, 19
withdrawing group [E0 E-1-(p-bromophenyl)propene = +1.75
1/2
1
2
3
4
5
6
7
8
9
24
23
0
V][27] was transformed to tricycle 16j, albeit with a moderate yield.
While both 8,8’-cis and 8,8’-trans stereomers are found in
aryltetralin lactone lignans, only 8,8’-trans diastereomer was
found in the aryltetralin cyclic ether lignans. The ready access to
the 8,8’-cis isomer is therefore of interesting for the SAR studies
of this family of lignans.
0.1
60, 14
0.1
0, 0
0.1
18
42
71
84
91[c]
14
33, 19
0.1
trace, 21
trace, 23
trace, 12
Trace, ~5%
20, 18
DCM
0.1
DCM
0.025
0.025
0.025
7
DCM
H
8
DCM
–
FG1
H
O
FG1
8’
FG2
Conditions [a]
7’
H
O
[a] 14a (0.05 mmol), [Mes-Acr-Me]+BF4- (5 mol%), co-catalyst (20 mol%), 24W
FG2
18
19
blue LEDs, 23 °C, 48 h; [b] 1H NMR yield using CH2Br2 as an internal standard;
-
[c] Isolated yield. Abbreviation: [Mes-Acr-Me]+BF4
methylacridinium tetrafluoroborate.
=
9-Mesityl-10-
H
H
MeO
RO
O
O
H
O
H
O
O
H
H
MeO
7 H
MeO
OMe
O
8
OR
H
Y
RX
XR
8’
5 R = Me, aglacin B, 51%[b]
19c R = MOM, 28%[b]
RX
19a 41%
Conditions [a]
7’
20 gaultherin C (revised)
H
[c]
H
20 R = H, gaultherin C, 81%
Y
MeO
H
MeO
MeO
H
H
O
OMe
H
MeO
H
14
16
O
XR
MeO
H
O
H
MeO
MeO
H
H
H
MeO
H
H
H
MeO
H
O
H
O
O
MeO
OMe
6 aglacin C, 42%[b]
RO
19d 30% [b]
O
19e 41%
H
H
H
R2
MeO
O
O
OMe
16a 91%
H
OR
16b R = iPr, 85%
16c R = cyclobutylmethyl, 76%
16d R = nC8H17, 53%
16e R = Ph, 79%
H
O
H
O
H
O
O
H
H
R1
+
H
O
MeO
O
H
H
H
O
O
OMe
OMe
OMe
O
MeS
MeO
19g-1 R1 = MeO, R2 = H, 34%
19g-2 R1 = H, R2 = MeO, 30%
H
O
O
9 sulabiroin A, 22%
19h 42%
H
H
H
16f 36%[b]
16g 57%
MeO
SMe
MeO
MeO
O
H
O
H
H
O
H
O
H
H
O
COOMe
COOMe
+
O
+
H
H
H
O
H
H
H
H
NTs
O
MeO
MeO
MeO
O
Br
MeO
MeO
H
H
MeO
OMe
OMe
OMe
OMe
OMe
O
19i-2 25%
10 sulabiroin B, 18%
19i-1 17%
Br
OMe
OMe
16i 62%, d.r. = 7:1
16j 28%, d.r. = 10:1
16h 75%, d.r. = 10:1
H
Scheme 3. Formation of 7’,8’-trans-8,8’-cis cycloadduct. [a] 14 (0.1 mmol),
[Mes-Acr-Me]+BF4- (5 mol%), PhSH (20 mol%), DCM (4 mL), 24W blue LEDs,
23 °C, 48 h, isolated yields, d.r. > 20:1 unless otherwise specified; [b] additional
[Mes-Acr-Me]+BF4- (5 mol%) was added after 48 h.
H
O
Conditions [a]
MeO
OMe
MeO
H
O
18j
19j 42%
OMe
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10.1002/anie.202007548
Angewandte Chemie International Edition
Research Article
Scheme 4. Formation of 7’,8’-trans-8,8’-trans cycloadduct. [a] 18 (0.1 mmol),
[Mes-Acr-Me]+BF4- (5 mol%), PhSH (20 mol%), DCM (4 mL), 24W blue LEDs,
23 °C, 48 h, isolated yields, d.r. > 20:1; [b] [Mes-Acr-Me]+BF4- (2.5 mol%) was
used; [c] 10% aqueous HCl, EtOH, 60 °C.
The relative stereochemistry of 19c is different from that of
assigned structure of gaultherin C (7, cf Scheme 1a). However,
we noticed that its 7’,8’-cis-8,8’-trans relative stereochemistry
assigned for 7 is unusual for aryltetralin cyclic ether lignans since
all other members possess the 7’,8’-trans-8,8’-trans
stereochemical triad (cf Scheme 1a). Therefore, we decided to
remove MOM ether for comparison purpose. Interestingly,
deprotection of the MOM ether from 19c under acidic conditions
afforded compound 20 whose spectroscopic data matched well
with those of gaultherin C (7). As the X-ray crystallographic
analysis of 20 indicated a 7’,8’-trans-8,8’-trans stereochemical
triad, we hypothesized that the 7’,8’-cis-8,8’-trans relative
stereochemistry initially assigned for gaultherin C (7)[3] should be
revised to 7’,8’-trans-8,8’-trans as shown in the structure of 20
(Scheme 4a).
Interestingly, the stereoselectivity of the reaction is substrate-
dependent. The reaction of dicinnamyl ether derivative 18 having
multiple alkoxy substituents on the aromatic rings afforded the
7’,8’-trans-8,8’-trans stereoisomer (19a, 5, 19c) with excellent
diastereoselectivity (Scheme 4). For instance, aglacin B (5) was
isolated in 51% yield as a single stereoisomer from the cyclization
of di(3,4,5-trimethoxycinnamyl) ether. With two electronically
different aryl units, the more electron-rich arene served as a diene
unit in this formal DA reaction (19d, 19e, 6). As expected, two and
three regioisomers were formed in the reactions leading to 19g,
19h and 19i, all having
a
7’,8’-trans-8,8’-trans relative
We have also encountered cases in which both 7’,8’-trans-
8,8’-cis and 7’,8’-trans-8,8’-trans cycloadducts were generated in
the same reaction (Scheme 5). Thus, cyclization of diallyl ethers
derived from cinnamyl alcohol, 4-alkyl, 2-methoxy and 3,4-
disubstituted cinnamyl alcohols afforded a mixture of two
diastereomers 16 and 19 as shown in Scheme 5. One of these
compounds (19m) was converted to isoshonanin (8)[4] by
selective deprotection of the MOM ether under acidic conditions.
stereochemistry. Finally, naphthyl substituted diallyl ether 18j also
afforded the 7’,8’-trans-8,8’-trans cycloadduct 19j selectively. This
switch of diastereoselectivity is a welcome surprise as most of the
aryltetralin cyclic ether lignans possess 7’,8’-trans-8,8’-trans
relative stereochemistry and their aromatic rings are all
polyoxygenated. By applying this reaction, four natural lignans,
namely, aglacin B (5), aglacin C (6), sulabiroin A (9), sulabiroin B
(10) were synthesized for the first time. The reaction leading to
aglacin B (5) has been performed at 1.4 mmol scale and the
desired natural product was isolated in a similar yield (52%).
Since the linear precursors were synthesized in one (for
symmetric ones) or two steps (for dissymmetric ones) from the
corresponding monolignols (see Supporting Information), the
present work represents a two or three-step synthesis of these
natural products from the biomass-derived building blocks. To the
best of knowledge, these are also the most complex structures
that have ever been made using monolignols as the only starting
material.[28]
14a
16a
15a
17a
100
90
80
70
60
50
40
30
20
10
0
(a)
0
1
2
3
4
5
6
7
8
9 1011 1213141516171819202122232425
time (h)
7
H
H
7 H
MeO
MeO
8
8
H
FG1
O
H
O
FG1
FG1
FG2
H
O
8’
Conditions [a]
8’
H
H
H
7
MeO
7
7’
H
7’
+
H
H
(b)
O
O
O
Standard
Conditions
67%
Standard
Conditions
78%
7’
FG2
FG2
7’
H
MeO
19
18
16
MeO
OMe
15a
16a
17a
H
H
H
H
H
H
H
MeO
RO
MeO
RO
MeO
HO
MeO
H
O
H
H
O
O
H
O
MeO
MeO
(c)
H
Standard
Conditions
87%
O
OMe
OMe
OMe
21
16a
OMe
OR
16l R = Me, 17%
16m R = MOM, 21%
OR
19l R = Me, 28%
19m R = MOM, 21%
OH
[b]
8 isoshonanin, 88%
Scheme 6. Reaction course of 14a by NMR monitoring using 1,3,5-
trimethylbenzene as an internal standard and results of control experiments.
H
H
OMe
OMe
H
H
H
H
O
H
O
R
R
H
O
H
H
O
H
The reaction course of 14a was monitored by 1H NMR
spectroscopy and the results are displayed in Scheme 6. The plot
revealed that cyclization of 14a displayed a high [2+2] vs [4+2]
periselectivity at the initial stage of the reaction with high
diastereoselectivity since 7,7’-cis-disubstituted cyclobutane 15a
was the only product formed after 1 h of reaction time (42% of 15a
with 58% of 14a remained, Scheme 6a). The rapid and exclusive
formation of cis-15a at the initial stage of the reaction was in
+
+
H
OMe
OMe
R
R
16n R = H, 34%
16o R = Me, 24% 19o R = Me, 18%
16p R = tBu, 23% 19p R = tBu, 23%
19n R = H, 29%
16q 31%
19q 26%
Scheme 5. Formation of both 7’,8’-trans-8,8’-cis and 7’,8’-trans-8,8’-trans
cycloadducts. [a] 18 (0.1 mmol), [Mes-Acr-Me]+BF4- (5 mol%), PhSH (20 mol%),
DCM (4 mL), 24W blue LEDs, 23 °C, 48 h, isolated yields, d.r. > 20:1; [b] 10%
aqueous HCl, EtOH, 60 °C.
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10.1002/anie.202007548
Angewandte Chemie International Edition
Research Article
Me
accord with the radical cation intermediate A, rather than the
triplet state of 14a.[29] Indeed, Fukuzumi’s acridinium salt with a
triplet energy (ET) of 44.7 kcal/mol[25b] was unlikely to sensitize
triplet energy transfer to 14a (ET 55 ~ 60 kcal/mol).[30] An
incubation time (about 1 h) was required before the formation of
7,7’-trans-disubstituted cyclobutane 17a, and tricyclic compound
16a. The initially formed cis-15a isomerized to both trans-17a and
endo-DA adduct 16a concurrently. After 2.5 h, all the starting
material was consumed affording a mixture of three-products, cis-
15a, trans-17a and 16a, in yields of 40%, 20% and 40%,
respectively. The amount of 16a increased rapidly until the
complete disappearance of cis-15a after about 3.5 h of reaction
time. It was also clear by examining the product ratios vs reaction
time that both 15a and 17a were precursors of tricyclic product
16a. Indeed, re-submitting a diastereomerically pure compounds
15a and 17a to our standard conditions for 12 h afforded 16a in
yields of 78% and 67%, respectively (Scheme 6b). The
isomerization of isolated 15a to 17a was also observed when the
former was resubmitted to the standard reaction conditions.
Finally, di(p-methoxy)cinnamyl ether (21) derived from (E)- and
(Z)-p-methoxycinnamyl alcohol was transformed to 16a in 87%
isolated yield indicating that (E)/(Z)-isomerization might be faster
than the [2+2] cycloaddition and that cycloaddition of diene to
cyclobutane was reversible in line with the aforementioned results
(Scheme 6c).
2Cl-
N
2+
N
N
Me
3+
Ir
N
N
N
Me
Ru
N
N
N
N
Me
-
BF4
[Mes-Acr-Me]+BF4- (P)
fac-Ir(ppy)3 (P1)
Ru(bpy)3Cl2 (P2)
F
F
CF3
Br
Br
N
N
N
HO
Br
O
O
N
N
3+
Ir
F3C
tBu
F
Br
N
N
N
COOH
N
N
F
PF6
-
tBu
Eosin Y (P3)
Me
Ir(dF-CF3-ppy)2(dtbpy)PF6 (P4)
4CzIPN (P5)
Me
MeO
Me
OMe
MeO
N
OMe
O
BF4
BF4
MeO
P6
OMe
Triphenylpyrylium (P7)
Figure 1. Structure of catalysts examined.
Table 2. Radical cation vs energy transfer mechanism
not be able to oxidize the substrate 14a (E0 = + 1.05 V) to
1/2
H
generate the corresponding radical cation. However, it’s triplet
energy (ET = 57.8 kcal/mol) is high enough to trigger the triplet
sensitization of 14a (ET = 55 ~ 60 kcal/mol), hence the formation
of the [2+2] cycloadducts. Conversely, Ru(bpy)3Cl2 (P2) and
Eosin Y (P3) with oxidation potential lower than 1.05 V and triplet
energy lower than 50 kcal/mol could not catalyze the
transformation (entries 2 and 3). The oxidation potential of Ir(dF-
CF3-ppy)2(dtbpy)PF6 (P4) and 4CzIPN (P5) were high enough to
lead a full conversion of 14a affording 17a as the major product,
albeit with moderate yield (entries 4 and 5). Acridinium salt P6
with an E* of + 1.65 V was also capable of catalyzing the
conversion of 14a to afford a mixture of three products.
Triphenylpyrylium (P7) led to the complete decomposition of the
starting material due probably to its strong oxidation power (E* =
+ 2.30 V). The acridinium salt (Mes-Acr-Me)+BF4- (P, E* = + 2.06
V, entry 8), identified as an optimum catalyst for this reaction, has
a triplet energy of 44.7 kcal/mol. It is therefore incapable of
undergoing energy transfer to 14a. Overall, it is reasonable to
conclude that the conversion of 14a to 16a in the presence of
MeO
H
H
O
MeO
OMe
MeO
Conditions [a]
7
O
+
H
7’
H
O
MeO
15a 7,7’-cis
17a 7,7’-trans
OMe
14a
16a
16a,15a,17a (%)[d]
7, 50, 30
Entry
Cat
E* (vs SCE)
ET (kcal/mol)
P1[b]
P2[b]
P3[c]
P4[b]
P5[c]
P6[c]
P7[c]
P
1
2
3
4
5
6
7
8
+ 0.31
+ 0.77
+ 0.79
+ 1.21
+ 1.35
+ 1.65
+ 2.30
+ 2.06
57.8
46.5
43.6
60.8
50.7
–
–, –, – [e]
–, –, –[f]
23, 5, 42
16, trace, 56
30, 12, 43
–, –, –[g]
–
44.7
91, trace, 5
-
(Mes-Acr-Me)+BF4 under visible light irradiation proceeded
[a] 14a (0.05 mmol), photocatalyst (1-5 mol%), PhSH (20 mol%), 24W blue
LEDs, 23 °C, 48 h; [b] 1 mol%; [c] 5 mol%; [d] 1H NMR yield using CH2Br2 as an
internal standard; [e] a trace amount of products, 14a was recovered in 82%
yield; [f] a trace amount of products, 14a was recovered in 53% yield; [g] a trace
amount of products, complete decomposition of 14a was observed.
through a radical cation mechanism. Finally, it is clear from these
experiments that reactions involving both energy transfer and
electron transfer mechanisms could lead to the formation of fused
cyclobutanes 15a and 17a. However, photoredox catalyst
capable of oxidizing trans cyclobutene 17a (E01/2 = + 1.41 V) to its
radical cation seemed to be essential to guarantee the efficient
formation of [4+2] cycloadduct 16a.
To further delineate the reaction mechanism, a series of
photocatalysts with different oxidation potential and triplet energy
were evaluated under optimized conditions (Table 2). Using fac-
Ir(ppy)3(P1) under otherwise standard conditions, 15a and 17a
were formed in yields of 50% and 30%, respectively (entry 1).
With its low oxidation potential (E* = + 0.31 V vs SCE), P1 would
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10.1002/anie.202007548
Angewandte Chemie International Edition
Research Article
via
RX
+
/
•
/
• +
O
H
H
RX
C’
H
H
Y
H
+
•
Blue LEDs
Z
*
Mes-Acr+
+
H
Y
Z
RX
•
Mes-Acr+
RX
H
D
Y
H
H
RX
PhS-
Z
SET
H
H
•
SET
H
Z
E
C
Y
Mes-Acr
SET
RX
Y
17
H
H
H
H
•
PhSH
[2+2] cycloaddition
Y
+
•
Z
H
Z
RX
RX
SET
Mes-Acr+
PhS
HAT
Y
B
Mes-Acr+
*
+
•
Z
RX
Blue LEDs
H
H
F
Y
A
H
H
Z
*
Mes-Acr+
Me
SET
Z
RX
Y
RX
H
Y
15
Me
Me
E*red(Mes-Acr-Me)+/(Mes-Acr-Me)• = +2.06 V
Eox(Mes-Acr-Me)•/ (Mes-Acr-Me)+ = -0.49 V
Ered(PhS•/ PhS-) = +0.16 V
Z
16
Y
N
Me
14
-
BF4
-
[Mes-Acr-Me]+BF4
Scheme 7. Proposed mechanism for the formation of endo-selective tricycle 16.
A concerted suprafacial/retention stereochemical mode has
been proposed to explain the hole-catalyzed vinylcyclobutane
rearrangement to DA adduct.[21] However, the stereochemical
convergency on the conversion of both 15a and 17a to the same
endo-DA adduct 16a in our case indicated that the isomerization
electrophilic or radical cyclization of C via transition state C’
would provide radical cation E. Deprotonation of by
thiophenolate would afford radical and thiophenol.
Intermolecular hydrogen atom abstraction between these two
species would provide endo-DA adduct 16 and thiyl radical PhS•.
Reduction of the latter by (Mes-Acr-Me)• would provide (Mes-Acr-
Me)+ and PhS- completing therefore the three catalytic cycles.
E
F
proceeded most probably through
a stepwise sequence
involving cleavage of a cyclobutane C-C bond followed by re-
cyclization via either a radical or a cationic process.
Interestingly, when 7,7’-cis-diphenyl substituted cyclobutane
15n derived from cinnamyl alcohol was re-submitted to the
standard conditions, the 7’,8’-trans-8,8’-cis tricyclic compound
16n and the trans cyclobutane 17n were isolated in yields of 27%
and 24%, respectively (Scheme 8a). Only a trace amount of 7’,8’-
trans-8,8’-trans isomer 19n was detected from the reaction
mixture. Indeed, in sharp contrast to 7,7’-trans-di-p-
methoxyphenyl substituted cyclobutane, 7,7’-trans-diphenyl
substituted cyclobutane 17n was found to be stable under our
standard reaction conditions (Scheme 8b). Since the
cycloaddition of 14n led to the formation of both 16n and 19n in
similar yields (Scheme 8c), we hypothesized that two
competitive reaction pathways were operating in the cyclization
of 14n. The intramolecular [2+2] cycloaddition followed by ring
opening and re-cyclization accounted for the formation of 16n
with a 7’,8’-trans-8,8’-cis relative stereochemistry. On the other
hand, radical cyclization via transition state TS-1 or TS-2
according to Beckwith-Houk model would provide trans-
disubstituted tetrahydrofuran radical cation intermediate G.[32]
Cyclization of the latter would then afford product 19n. In the
case of dicinnamyl ether derivatives whose aromatic rings were
di- and tri-methoxylated (cf Scheme 4), the cation would probably
locate mainly on the aromatic ring which reduced the propensity
of the radical cation to undergo the [2+2] cycloaddition and
On the basis of the aforementioned mechanistic studies, a
possible reaction pathway accounting for the stereoselective
formation of endo-cycloadduct 16 from 14 is shown in Scheme
7. Oxidation of styrene by excited acridinium salt [(Mes-Acr-
-
Me)+BF4 ]* would afford radical cation A and (Mes-Acr-Me)•.
Intramolecular [2+2] cycloaddition of A which is known to be very
fast (k ≃ 109 s-1)[20] would provide cyclobutane radical cation B.
At the beginning of the reaction, the concentration of starting
material 14 is relatively high, a SET process between B and 14
would occur to furnish the cis-cyclobutane 15 with concurrent
regeneration of intermediate A and an apparent accumulation of
compound 15. As the reaction proceeded, the concentration of
15 increased (≃ 42% after 1 h) and that of 14 decreased. The
SET process between 15 and [(Mes-Acr-Me)+]* became
competitive leading to the regeneration of intermediate B which
would afford, upon cleavage of the benzylic C-C bond, the
weakest cyclobutane bonds, to radical cation C.[31] Rotation of a
C-C bond followed by ring closure would afford
thermodynamically more stable trans-cyclobutane radical cation
D which was then converted to trans-17 after a SET process.
Intermediate 17 could also be oxidized by [(Mes-Acr-Me)+]* to
generate radical cation D and then transformed to product via
intermediate C. On the other hand, stereoselective aromatic
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10.1002/anie.202007548
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Research Article
stepwise cyclization became a competitive reaction manifold
leading to 7’,8’-trans-8,8’-trans stereoisomer as the only product.
Conflict of Interest
The authors declare no conflict of interest
H
H
H
H
H
H
H
H
H
Standard
Conditions
O
H
O
+
O
O
+
(a)
(b)
(c)
Keywords: Lignan • photoredox catalysis • radical cation •
natural product • organocatalysis • cycloaddition
15n
16n 27%
19n trace
17n 24%
[1]
[2]
X. Yu, Z. Che, H. Xu, Chem. Eur. J. 2017, 23, 4467-4526.
a) B. G. Wang, R. Ebel, B. W. Nugroho, D. Prijono, W. Frank, K. G.
Steube, X. J. Hao, P. Proksch, J. Nat. Prod. 2001, 64, 1521-1526; b)
B. G. Wang, R. Ebel, C. Y. Wang, V. Wray, P. Proksch, Tetrahedron
Lett. 2002, 43, 5783-5787.
H
H
Standard
Conditions
O
no conversion
17n
[3]
[4]
Z. Zhang, D. Guo, J. Zheng, K. Koike, Z. Jia, T. Nikaido, Heterocycles
2000, 53, 675-679.
H
H
H
H
O
H
O
Standard
Conditions
a) M. Nose, M. A. Bernards, M. Furlan, J. Zajicek, T. L. Eberhardt, N.
G. Lewis, Phytochemistry 1995, 39, 71-79; b) S. Z. Shang, H. Chen, C.
Q. Liang, Z. H. Gao, X. Du, R. R. Wang, Y. M. Shi, Y. T. Zheng, W. L.
Xiao, H. D. Sun, Arch. Pharm. Res. 2013, 36, 1223-1230.
R. Miyata, M. Sahlan, Y. Ishikawa, H. Hashimoto, S. Honda, S.
Kumazawa, J. Nat. Prod. 2019, 82, 205-210.These two natural products
were initially named as sulawesins A and B. They were however
renamed to sulabiroins A and B, see the correction by the same
authors: J. Nat. Prod. 2020, 83, 4, 1356.
H
+
O
16n 34%
19n 29%
14n
[5]
H
H
Ph
Ph
Ph
Ph
O
O
O
[6]
[7]
[8]
a) J. D. Sellars, P. G. Steel, Eur. J. Org. Chem. 2007, 3815-3828; b) X.
Zhang, K. P. Rakesh, C. S. Shantharam, H. M. Manukumar, A. M. Asiri,
H. M. Marwani, H. L. Qin, Bioorg. Med. Chem. 2018, 26, 340-355.
a) W. Lau, E. S. Sattely, Science 2015, 349, 1224-1228; b) L. B. Davin,
H.-B. Wang, A. L. Crowell, D. L. Bedgar, D. M. Martin, S. Sarkanen, N.
G. Lewis, Science 1997, 275, 362-367.
Ph
H
H
Ph
A
15n
G
Ph
or
Ph
O
O
Ph
Ph
Recent total syntheses, see: a) J. Li, X. Zhang, H. Renata, Angew.
Chem. Int. Ed. 2019, 58, 11657-11660; Angew. Chem. 2019, 131,
11783-11786; b) M. Lazzarotto, L. Hammerer, M. Hetmann, A. Borg, L.
Schmermund, L. Steiner, P. Hartmann, F. Belaj, W. Kroutil, K. Gruber,
M. Fuchs, Angew. Chem. Int. Ed. 2019, 58, 8226-8230; Angew. Chem.
2019, 131, 8310-8315; c) J. Xiao, X.-W Cong, G.-Z. Yang, Y.-W. Wang,
Y. Peng, Org. Lett. 2018, 20, 1651-1654; d) S. Hajra, S. Garai, S. Hazra,
Org. Lett. 2017, 19, 6530-6533; e) C. P. Ting, T. J. Maimone, Angew.
Chem. Int. Ed. 2014, 53, 3115-3119; Angew. Chem. 2014, 126, 3179-
3183.
TS-1
TS-2
Scheme 8. Cyclization of dicinnamyl ether 14n: A dual mechanistic pathways
leading to two diastereomers.
Conclusion
In conclusion, we have developed
a straightforward
[9]
M. Gordaliza, P. A. Garcia, J. M. Miguel del Corral, M. A. Castro, M. A.
Gomez-Zurita, Toxicon. 2004, 44, 441-459.
synthesis of aryltetralin cyclic ether lignans. In the presence of
Fukuzumi’s acridinium salt under blue LEDs irradiation,
dicinnamyl ether derivatives prepared in one step from the
corresponding allylic alcohols underwent double cyclization to
afford the tricyclic lignans with concurrent generation of three
stereocenters in good to high yields. In most cases, only one
among four possible stereoisomers was produced with excellent
diastereoselectivity. Six natural products, viz, aglacin B, aglacin
C, sulabiroin A, sulabiroin B, gaultherin C and isoshonanin have
been synthesized for the first time from the easily accessible
biomass-derived monolignols in only two or three steps. The
relative stereochemistry of gaultherin C was revised based on
comparison of NMR spectroscopic data and X-ray
crystallographic analysis of our synthetic compound.
[10] a) D. J. Bellville, D. W. Wirth, N. L. Bauld, J. Am. Chem. Soc. 1981, 103,
718-720; b) N. L. Bauld, R. Pabon, J. Am. Chem. Soc. 1983, 105, 633-
634; c) R. M. Wilson, J. G. Dietz, T. A. Shepherd, D. M. Ho, K. A.
Schnapp, R. C. Elder, J. W. Watkins II, L. S. Geraci, C. F. Campana, J.
Am. Chem. Soc. 1989, 111, 1749-1754; d) For a review, see: N. L.
Bauld, Tetrahedron 1989, 45, 5307-5363.
[11] a) T. Miura, S. Kim, Y. Kitano, M. Tada, K. Chiba, Angew. Chem. Int.
Ed. 2006, 45, 1461-1463; Angew. Chem. 2006, 118, 1489-1491; b) Y.
Okada, A. Nishimoto, R. Akaba, K. Chiba, J. Org. Chem. 2011, 76,
3470-3476; c) Y. Okada, Y. Yamaguchi, A. Ozaki, K. Chiba, Chem. Sci.
2016, 7, 6387-6393; d) K. J. Romero, M. S. Galliher, M. A. R. Raycroft,
J. R. Chauvin, I. Bosque, D. A. Pratt, C. R. J. Stephenson. Angew.
Chem. Int. Ed. 2018, 57, 17125-17129. Angew. Chem. 2018, 130,
17371-17375.
[12] a) M. A. Ischay, Z. Lu, T. P. Yoon, J. Am. Chem. Soc. 2010, 132, 8572-
8574; b) S. S. Lin, M. A. Ischay, C. G. Fry, T. P. Yoon, J. Am. Chem.
Soc. 2011, 133, 19350-19353; c) Z. Lu, T. P. Yoon, Angew. Chem. Int.
Ed. 2012, 51, 10329-10332. Angew. Chem. 2012, 124, 10475-10478;
d) J. D. Parrish, M. A. Ischay, Z. Lu, S. Guo, N. R. Peters, T. P. Yoon,
Org. Lett. 2012, 14, 1640-1643; e) M. A. Ischay, M. S. Ament, T. P.
Yoon, Chem. Sci. 2012, 3, 2807-2811; f) A. E. Hurtley, Z. Lu, T. P. Yoon,
Angew. Chem. Int. Ed. 2014, 53, 8991-8994; Angew. Chem. 2014, 126,
9137-9140.
Acknowledgements
We are thankful for financial support from EPFL (Switzerland)
and Swiss National Centers of Competence in Research NCCR-
Catalysis. We thank Dr. F.-T. Farzaneh and Dr. Rosario
Scopelliti for the X-ray structural analysis of compounds 16a and
20.
[13] a) D. S. Hamilton, D. A. Nicewicz, J. Am. Chem. Soc. 2012, 134, 18577-
18580; b) J. M. M. Grandjean, D. A. Nicewicz, Angew. Chem. Int. Ed.
2013, 52, 3967-3971; Angew. Chem. 2013, 125, 4059-4063; c) T. M.
Nguyen, D. A. Nicewicz, J. Am. Chem. Soc. 2013, 135, 9588-9591; d)
This article is protected by copyright. All rights reserved.

10.1002/anie.202007548
Angewandte Chemie International Edition
Research Article
A. J. Perkowski, D. A. Nicewicz, J. Am. Chem. Soc. 2013, 135, 10334-
10337; e) M. Riener, D. A. Nicewicz, Chem. Sci. 2013, 4, 2625-2629; f)
J. D. Griffin, C. L. Cavanaugh, D. A. Nicewicz, Angew. Chem. Int. Ed.
2017, 56, 2097-2100; Angew. Chem. 2017, 129, 2129-2132; g) L. F.
Wang, F. J. Wu, J. A. Chen, D. A. Nicewicz, Y. Huang, Angew. Chem.
Int. Ed. 2017, 56, 6896-6900; Angew. Chem. 2017, 129, 7000-7004; h)
F. Wu, L. Wang, J. A. Chen, D. A. Nicewicz, Y. Huang, Angew. Chem.
Int. Ed. 2018, 57, 2174-2178; Angew. Chem. 2018, 130, 2196-2200; i)
P. D. Morse, T. M. Nguyen, C. L. Cruz, D. A. Nicewicz, Tetrahedron
2018, 74, 3266-3272.
[20] The cyclization of 14a to 15a has been used as a radical cation probe,
see: a) T. Kim, G. A. Mirafzal, J. Liu, N. L. Bauld, J. Am. Chem. Soc.
1993, 115, 7653-7664; b) N. P. Schepp, D. Shukla, H. Sarker, N. L.
Bauld, L. J. Johnston, J. Am. Chem. Soc. 1997,119, 10325-10334; c) L.
J. Johnston, N. P. Schepp, Pure Appl. Chem. 1995, 67, 71-78.
[21] D. W. Reynolds, B. Harirchian, H.-S. Chiou, B. K. Marsh, N. L. Bauld, J.
Phys. Org. Chem. 1989, 2, 57-88.
[22] S. Kadota, K. Tsubono, K. Makino, M. Takeshita, T. Kikuchi,
Tetrahedron Lett. 1987, 28, 2857-2860.
[23] For earlier work on the photoinduced dimerization of 1,1-diarylethylene
involving a stepwise radical addition mechanism of the radical cation
intermediate, see: a) R. A. Neunteufel, D. R. Arnold, J. Am. Chem. Soc.
1973, 95, 4080-4081; b) S. L. Mattes, S. Farid, J. Am. Chem. Soc. 1983,
105, 1386-1387; c) S. L. Mattes, S. Farid, J. Am. Chem. Soc. 1986, 108,
7356-7361.
[14] a) S. M. Stevenson, M. P. Shores, E. M. Ferreira, Angew. Chem. Int.
Ed. 2015, 54, 6506-6510; Angew. Chem. 2015, 127, 6606-6610; b) S.
M. Stevenson, R. F. Higgins, M. P. Shores, E. M. Ferreira, Chem. Sci.
2017, 8, 654-660; c) F. J. Sarabia, E. M. Ferreira, Org. Lett. 2017, 19,
2865-2868; d) F. J. Sarabia, Q. Li, E. M. Ferreira, Angew. Chem. Int.
Ed. 2018, 57, 11015-11019; Angew. Chem. 2018, 130, 11181-11185.
[15] a) L. Pitzer, F. Sandfort, F. Strieth-Kalthoff, F. Glorius, J. Am. Chem.
Soc. 2017, 139, 13652-13655; b) Y. Zhao, M. Antonietti, Angew. Chem.
Int. Ed. 2017, 56, 9336-9340; Angew. Chem. 2017, 129, 9464-9468; c)
T. M. Monos, R. C. McAtee, C. R. J. Stephenson, Science 2018, 361,
1369-1373.
[24] The E°1/2 value was measured by cyclic voltammetry, see supporting
information.
[25] a) H. Kotani, K. Ohkubo, S. Fukuzumi, J. Am. Chem. Soc. 2004, 126,
15999-16006; b) A. C Benniston, A. Harriman, P. Li, J. P. Rostron, H.
J. van Ramesdonk, M. M. Groeneveld, H. Zhang, J. W. Verhoeven, J.
Am. Chem. Soc. 2005, 127, 16054−16064.
[16] For general reviews on photoredox catalysis, see: a) L. Buzzetti, G. E.
M. Crisenza, P. Melchiorre, Angew. Chem. Int. Ed. 2019, 58, 3730-
3747; Angew. Chem. 2019, 131, 3768-3786; b) D. Petzold, M. Giedyk,
A. Chatterjee, B. König, Eur. J. Org. Chem. 2019, 1193-1244; c) N. A.
Romero, D. A. Nicewicz, Chem. Rev. 2016, 116, 10075-10166; d) K. L.
Skubi, T. R. Blum, T. P. Yoon, Chem. Rev. 2016, 116, 10035-10074; e)
M. N. Hopkinson, A. Tlahuext-Aca, F. Glorius, Acc. Chem. Res. 2016,
49, 2261-2272; f) D. C. Fabry, M. Rueping, Acc. Chem. Res. 2016, 49,
1969-1979; g) T. Koike, M. Akita, Acc. Chem. Res. 2016, 49, 1937-
1945; h) J.-R. Chen, X.-Q. Hu, L.-Q. Lu, W.-J. Xiao, Chem. Soc. Rev.
2016, 45, 2044-2056; i) C. K. Prier, D. A. Rankic, D. W. C. MacMillan,
Chem. Rev. 2013, 113, 5322-5363; j) J. M. R. Narayanam, C. R. J.
Stephenson, Chem. Soc. Rev. 2011, 40, 102-113.
[26] CCDC 1954865 (16a) and CCDC 1954866 (20) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre.
[27] For a list of electrochemical potential of common organic molecules,
see: H. G. Roth, N. A. Romero, D. A. Nicewicz, Synlett 2016, 27, 714-
723.
[28] For a recent example, see: S. Elangovan, A. Afanasenko, J. Haupenthal,
Z. Sun, Y. Liu, A. K. H. Hirsch, K. Barta, ACS Cent. Sci. 2019, 5, 1707-
1716.
[29] T. Kim, H. Sarker, N. L. Bauld, J. Chem. Soc. Perkin Trans. 2, 1995,
577-580.
[30] T. Ni, R. A. Caldwell, L. A. Melton, J. Am. Chem. Soc. 1989, 111, 457-
464
[17] a) J. H. Shin, E. Y. Seong, H. J. Mun, Y. J. Jang, E. J. Kang, Org. Lett.
2018, 20, 5872-5876; b) Y. Yu, Y. Fu, F. Zhong, Green Chem. 2018, 20,
1743-1747; c) T. Horibe, S. Ohmura, K. Ishihara, J. Am. Chem. Soc.
2019, 141, 1877-1881; d) T. Horibe, K. Katagiri, K. Ishihara, Adv. Synth.
Catal. 2020, 362, 960-963.
[31] S. L. Mattes, H. R. Luss, S. Farid, J. Phys. Chem. 1983, 87, 4779-4781.
[32] a) A. L. J. Beckwith, C. H. Schiesser, Tetrahedron 1985, 41, 3925-3941;
b) D. C. Spellmeyer, K. N. Houk, J. Org. Chem. 1987, 52, 959-974; c)
T. V. RajnBabu, Acc. Chem. Res. 1991, 24, 139-145.
[18] I. Colomer, R. C. Barcelos, T. J. Donohoe, Angew. Chem. Int. Ed. 2016,
55, 4748-4752; Angew. Chem. 2016, 128, 4826-4830.
[19] A. J. Perkowski, W. You, D. A. Nicewicz, J. Am. Chem. Soc. 2015, 137,
7580-7583.
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10.1002/anie.202007548
Angewandte Chemie International Edition
Research Article
Entry for the Table of Contents (Please choose one layout)
Photoredox Catalysis
H
H
H
H
H
H
MeO
MeO
MeO
MeO
O
Jia-Chen Xiang, Qian Wang, and Jieping
Zhu*__________ Page – Page
H
O
H
O
H
O
H
O
RO
O
HO
H
H
MeO
R1
MeO
O
MeO
O
Radical Cation Cascade to Aryltetralin
Cyclic Ether Lignans by Visible Light
Photoredox Catalysis
OMe
OMe
OMe
OMe
OR
OH
O
O
aglacin B R = Me, R1 = OMe
aglacin C R = Me, R1 = H
sulabiroin A
sulabiroin B
isoshonanin
gaultherin C R = H, R1 = OMe
Complexity of simplicity under blue LEDs irradiation, dicinnamyl ether derivatives undergo
double cyclization to afford the tricyclic lignans. Six natural products are synthesized from the
corresponding monolignols in two or three steps.
This article is protected by copyright. All rights reserved.