Asymmetric Total Synthesis of Aglacins A, B, and E

Article abstract of DOI:10.1002/anie.202105395

An asymmetric photoenolization/Diels–Alder (PEDA) reaction between electron-rich 2-methylbenzaldehydes and unsaturated γ-lactones was developed to directly construct the basic tricyclic core of aryltetralin lactone lignans. This methodology enabled the first asymmetric total synthesis of aglacins A, B, and E and revision of the absolute configuration of these natural lignans. The strategy was also used to prepare the naturally occurring aryldihydronaphthalene-type lignans (?)-7,8-dihydroisojusticidin B and (+)-linoxepin in four and six steps, as well as 27 natural-product-like molecules containing a C8′ quaternary center. We believe that the synthetic aglacins and small-molecule library provide new opportunities to carry out the SAR studies of the podophyllotoxin family of natural products.

Full text of DOI:10.1002/anie.202105395

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Accepted Article
Title: Asymmetric Total Synthesis of Aglacins A, B and E
Authors: Mengmeng Xu, Min Hou, Haibing He, and Shuanhu Gao
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10.1002/anie.202105395
Angewandte Chemie International Edition
Research Article
Asymmetric Total Synthesis of Aglacins A, B and E
†
†
Mengmeng Xu,a Min Hou,a Haibing He,b Shuanhu Gao*a,b
Abstract: An asymmetric photoenolization/Diels–Alder (PEDA)
reaction, between electron-rich 2-methylbenzaldehydes and
unsaturated -lactones, was developed to directly construct the basic
tricyclic core of aryltetralin lactone lignans. The first asymmetric total
synthesis of aglacins A, B and E was achieved based on this newly
developed methodology, which enable us to revise the absolute
configuration of these natural lignans. This strategy was also used to
efficiently prepare naturally occurring aryl–dihydronaphthalene-type
lignans (–)-7,8-dihydroisojusticidine B and (+)-linoxepin in four and six
steps, as well as 27 members of natural product-like molecules
bearing an all-carbon quaternary center at C-8’. We believe that the
synthetic aglacins and small-molecule library provide new
opportunities to carry out the SAR studies of podophyllotoxin-family
natural products.
spectral data and X-ray crystallography, and their absolute
configuration were determined based on the modified Mosher’s
method. [7] Interestingly, the relative and absolute stereochemistry
of four chiral centers in aglacins were proposed different from
those of podophyllotoxin (1), which represents the most
commonly occurring configuration. Recently, Zhu and coworkers
reported an elegant radical-cation cascade under visible-light
photoredox catalysis to enable concise synthesis of aryltetralin
cyclic ether lignans, including aglacin B, with good yields and
excellent diastereoselectivity.[9]
Introduction
Podophyllotoxin (1) was mainly isolated from the rhizomes
and roots of Podophyllum species (Figure 1),[1] which belongs to
a naturally occurring aryltetralin lactone lignan.[2] This family of
natural lignans exhibit a broad spectrum of biological potentials,
[3]
such as anticancer, insecticidal, antifungal, antiviral anti-
inflammatory, neurotoxic, immunosuppressive activities. These
properties attracted considerable attentions from both
pharmaceutical industry and academic communities, and
significant efforts have been made regarding to the chemical
5]
synthesis,[4,
structure-activity relationships (SARs) and
mechanistic studies.[3] Structural modifications of podophyllotoxin
have successfully led to several commercially available
anticancer drugs as well as drug candidates. For instance,
etoposide (2, Figure 1) was developed as a topoisomerase II
inhibitor, which is clinically used in the treatment of small cell lung
cancer and multiform glioblastoma.[6]
Figure 1. Podophillotoxin, etopodside, originally proposed aglacins and
(+)-linoxepin.
Podophyllotoxin (1) contains a tetracyclic fused ring including
an aryltetralin (A-B ring), two highly oxygenated aromatic rings (A
and D rings), a -lactone (C ring), and four consecutive chiral
centers in B ring (C-7, 8, 7’ and 8’). Notabaly, biogenetically
related natural products in lower oxidation state were also
discovered in nature, such as aglacin A, B, E[7] and linoxepin[8] (3,
4, 5 and 6, Figure 1). Aglacins were isolated from the methanol
extract of the stem bark of Aglaia cordata collected in Indonesia
by Prokscha and coworkers, which belong to aryltetralin cyclic
ether lignans. The structures of aglacins were elucidated by NMR
Extensive structural modifications and structure–activity
relationships of podophyllotoxin have provided comprehensive
hints to discover new anticancer lead compounds. However,
limited information is available to identify the relationship between
the stereochemistry and the biological activities of this family of
lignans. We were attracted by the biological potential of natural
lignans, and report herein the development of an asymmetric
photoenolization/Diels–Alder (PEDA) reaction, between electron-
rich 2-methylbenzaldehyde and unsaturated -lactone, to directly
construct the basic tricyclic core of aryltetralin lactone lignans.
Using this strategy, we achieved the first asymmetric total
synthesis and absolute configuration revision of aglacins A, B and
E. Additionally, a small library of natural product-like lignans (27
examples) were generated for future bioactivity studies.
[a]
[b]
M. Xu, M. Hou, Prof. Dr. S. Gao
Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, School of Chemistry and Molecular Engineering
East China Normal University
E-mail: shgao@chem.ecnu.edu.cn
Dr. H. He, Prof. Dr. S. Gao
We envisioned that aglacins A and B might be derived from
aglacin E (5) by manipulation of the hydroxyl group at C-7
(Scheme 1A). Aryltetralin lactone lignan 7 was designed to serve
as a common precursor, which could be converted to aglacin E
through a late-stage selective oxidation reaction. In order to
construct the core skeleton of lignans, we proposed two pathways
based on a key photoenolization/Diels-Alder (PEDA) reaction.[10-
Shanghai Engineering Research Center of Molecular Therapeutics
and New Drug Development, East China Normal University
3663 North Zhongshan Road, Shanghai 200062, China
† These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
11]
Pathway A (Scheme 1B): a photo-induced cycloaddition
1
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10.1002/anie.202105395
Angewandte Chemie International Edition
Research Article
between a benzophenone substrate 9 and unsaturated -lactone
10 was devised to directly construct the tetracyclic 8 bearing the
basic core of aryltetralin lactone lignans. The challenge of this
pathway was how to activate the stereohindered hydroxy-o-
quinodimethane species, thus undergoing the following Diels-
Alder reaction with unsaturated -lactone 10. Pathway B (Scheme
1B): a stepwise approach was planned to form the core skeleton
unsaturated -lactone 10 by a combination of Lewis acid [Ti(Oi-
Pr)4] and a chiral ligand (Pathway B, Scheme 2B). When 10a was
used as a dienophine, the PEDA reactions with 13a and 13b gave
the desired product 12a and 12b in 89% and 65% yield,
respectively. However, the enantioselectivities of these reactions
were low (up to 45% ee) (see Table S2, S3 in the Supporting
Information). In order to improve the stereoselectivity and
suppress the background racemic reaction, we envisioned to
introduce a methyl group at the –position of lactone, namely 10b.
We reasoned that this substituted group might help to reduce the
rate of cycloaddition and facilitate the formation of chiral Ti-
complex. Indeed, we were pleased to observed that the APEDA
reaction proceeded smoothly in the presence of catalytic ligand L
(0.20.5 equiv.) and Ti(Oi-Pr)4 (0.41.0 equiv.), and yielded the
tricyclic adduct 12c and 12d in good yield (up to 91%) and
excellent enantioselectivity (up to 97% ee) (see Table S4 and S5
in the Supporting Information). The dosage of Lewis acid highly
influenced the efficiency of this reaction, using stoichiomertric
amount of Ti(Oi-Pr)4 gave best reaction yield. A chiral dinuclear
species Ti-TADDOLate II was proposed to serve as a bifunctional
catalyst, which induced an endo-cycloaddition in the chiral
environment.[12] 12c and 12d contain the tricyclic aryltetralin
lactone skeleton bearing an all-carbon quaternary center, which
differed from the previously reported lead compounds derived
from natural lignans.
7 through a metal-catalyzed cross coupling reaction of vinyl triflate
[12]
11 and phenylboronic acid. An asymmetric PEDA reaction
of
electron-rich 2-methylbenzaldehyde 13 and unsaturated -lactone
10 was designed to prepare tricyclic compound 12.
Scheme 1. Synthetic plan.
Results and Discussion
Our
research
commenced
with
the
key
photoenolization/Diels-Alder (PEDA) reaction between fragments
14 and 10 (Pathway A, Scheme 2A). We have disclosed that
Lewis acid [Ti(Oi-Pr)4] plays a key role in the PEDA reaction,
which activates inert dienophiles and controls the
diastereoselectivity.[12] Accordingly, we extensively investigated
the Lewis acid-promoted PEDA cycloaddition of 14 and 10a (see
Table S1 in the Supporting Information), and found that no desired
adduct 15 was obtained under the tested conditions. We then
explored the photolysis of 14 with the highly reactive dienophiles,
including maleic anhydride 16a, N-tert-butylmaleimide 16b and
dimethyl fumarate 17, and only found the formation of 15a in 32%
yield.[13] Principally, photoenolization of 14 would generate a
transient hydroxy-o-quinodimethane I bearing tetra-substituted
enol motif (Scheme 2A). It’s reasonable to predict the low
reactivity of this stereohindered diene species in the following
cycloaddition step, even with the highly reactive dienophiles and
in presence of the Lewis acid. We then tested the asymmetric
PEDA reaction of electron-rich 2-methylbenzaldehyde 13 and
Scheme 2. Construction of tricyclic core of aryltetralin lactone lignans
using asymmetric PEDA reactions.
2
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10.1002/anie.202105395
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Research Article
Table 1. Building a small library of aryltetralin lactones. Standard reaction conditions: aromatic aldehyde (0.30 mmol, 1.0 equiv.), dienophile (0.45 mmol,
1.5 equiv.), Ti(Oi-Pr)4 (0.30 mmol, 1.0 equiv.), L (0.15 mmol, 0.5 equiv.), toluene (30 mL, 0.01 M), 30 oC, 50 min. Isolated yields are shown. The ee
values were determined by chiral HPLC analys, a 0.05 mmol scale.
We were intrigued by the biological potentials of the
analogues like 12c and 12d, this also promoted us to prepare
a small library. As shown in Table 1, using electron rich
benzaldehydes (13a-d) and α-substituted -lactone (10b-n) as
sterically hindered dienophiles, 27 photo-induced adducts
(12c-f, 18-40) were efficiently prepared in good yield and
enantioselectivities (85%99% ee) under the standard reaction
condition. The products have good diastereoselectivity,
wherein the hydroxyl group on the benzylic position has the
cis-configuration with the electron-withdrawing groups. In order
to investigate the roles of substituents on aromatic aldehydes,
we carried out the following studies. When the methoxy group
at the ortho of the aldehyde group was absent or replaced by
acetoxy group, we found that no desired adduct was obtained
in the PEDA reaction. When the ortho-methyl was replaced by
benzyl group, the PEDA reaction didn’t occur (see Table S6 in
the Supporting Information). The aromatic ring contains an
electron withdrawing group, such as 13d, the asymmetric
PEDA reaction with lactone 10b gave 12f in 54% yield and
96% ee, which was comparable to 12e. The relative and
absolute configuration was determined and confirmed by the
X-ray crystallographic analysis of 30.[14] According to the
properties of the substituted groups, these newly formed
molecules could be divided into three groups: 1) adducts with
acyclic alkyl groups (12c-f, 18-23); 2) molecules bearing
electron-rich benzyl groups (24-30); and 3) molecules
containing electron-deficient benzyl groups (31-40).
We then turned our attention to the asymmetric total
synthesis of naturally occurring aglacins (Scheme 3). In order
to achieve a high enantioselectivity for APEDA reaction, a
removable group on the α-position of -lactone was necessary.
Accordingly, α-bromo lactone 41 was selected as the required
dienophile. We then investigated the key APEDA reaction by
irradiating a toluene solution of 13b and 41 in presence of
TADDOL-type ligand (L, 0.5 equiv.) and Ti(Oi-Pr)4 (1.0 equiv.)
under UV light (λmax = 366 nm), the cycloaddition smoothly
occurred and produced the desired tricyclic core 42 as a single
diastereomer in 72% yield and 92% ee. Its structure and
absolute configuration was confirmed by the X-ray
crystallographic analysis.[14] The hydroxyl group on C-7’ was
then oxidized by 2-Iodoxybenzoic acid and afforded 43 in 82%
yield. A regio- and stereoselective oxidation was required to
introduce a -hydroxyl group at C-7. This benzyl C−H oxidation
was accomplished through a sequence of radical bromination
(NBS/BPO) followed by the hydrolysis of the resulting labile
bromide, and produced 44 in 61% yield over 2 steps. After
protection of the hydroxyl group as its TIPS ether, we found
that bromine could be readily removed by adding sodium
thiosulfate during the work-up operation. Then, treatment of
the carbonyl group on C-7’ with trifluoromethylsulfonic
anhydride under basic conditioin furnished the desired triflate
45. A Pd-catalyzed Suzuki-Miyaura coupling of 45 with
aromatic boronic acid 46 led to 47 bearing the required aryl
substituent on C-7’. The tetra-substituted C7’=C8’ olefin in 47
3
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10.1002/anie.202105395
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Research Article
Scheme 3. Total synthesis of (–)-aglacins A, B and E. IBX = 2-iodoxybenzoic acid, DMSO = dimethyl sulfoxide, NBS = N-bromosuccinimide, BPO =
benzoyl peroxide, Py = pyridine, THF = tetrahydrofuran, TIPSOTf = triisopropylsilyl trifluoromethanesulfonate, Tf2O = trifluoromethanesulfonic anhydride,
DCM = dichloromethane, DCC = dicyclohexylcarbodiimide, DBAD = di-tert-butyl azodicarboxylate, TBAF = tetrabutyammonium fluoride.
was selectively hydrogenated at low temperature to give 48 as a
single diastereomer in 82% yield. In order to epimerize the C-8’
chiral center in 48, the lactone ring was hydrolyzed under
KOH/MeOH, then lactonization was achieved by means of DCC-
induced cyclization to construct the anti-B-C rings in 84% yield
based on the recovery of 48. Reduction of 49 with lithium
aluminum hydride gave diol 50 in 88% yield, and the cyclic ether
ring was formed by means of an intramolecular Mitsunobu
reaction. A final deprotection of the TIPS group produced aglacin
E (5) in 50% yield over 2 steps. We found that the NMR data (1H
and 13C spectra) of our synthetic aglacin E was in agreement with
those of the natural product.[7] However, the newly synthesized
APEDA reaction, which was successfully converted to the
desired (+)-aglacin A, B and E (Scheme 4). The NMR spectra,
5 ([α]2D0 = –21 (c 0.69, CHCl3)) holds an opposite optical rotation
20
to the natural aglacin E ([α]
= +17 (c 0.69, CHCl3)).
D
Transformation of (–)-aglacin E to (–)-aglacin A was achieved via
an intermolecular Mitsunobu reaction to give (–)-(3) ([α]2D0 = –40.3
(c 0.31, CHCl3)) in 65% yield based on the recovery of (–)-5.
Reductive dehydroxylation of (–)-5 was performed and
generated (–)-aglacin B (4) ([α]2D0 = –41.2 (c 0.46, CHCl3)) in 90%
yield.
Indeed, synthetic aglacin A and B from (–)-aglacin E also
possess opposite optical rotation to the natural ones, which
disclosed (–)-aglacins A, B and E to be the enantiomers of
natural aglacins. In order to confirm this proposal, we prepared
ent-42, its absolute configuration was determined by X-ray
crystallographic analysis,[14] using ent-L as a chiral ligand in the
Scheme 4. Total synthesis of (+)-aglacins A, B and E.
4
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10.1002/anie.202105395
Angewandte Chemie International Edition
Research Article
tricyclic core of aryltetralin lactone lignans. This strategy was
also applied to prepare naturally occurring aryl–
dihydronaphthalene-type lignans (–)-7,8-dihydroisojusticidine B
and (+)-linoxepin in four and six steps, as well as 27 members of
natural product-like molecules bearing a quaternary center at C-
8’. We are currently exploring the biological functions and SAR
studies of the synthetic aglacins and small-molecule library,
which will be disclosed in due course.
Acknowledgements
We thank the National Natural Science Foundation of China
(21971068,
21772044),
Program
of
Shanghai
Academic/Technology Research Leader (18XD1401500),
Program of Shanghai Science and Technology Committee
(18JC1411303), “Shuguang Program (19SG21)”, and “the
Fundamental Research Funds for the Central Universities” for
generous financial support.
Conflict of interest
Scheme 5. Total synthesis of (+)-linoxepin and 7,8-dihydroisojusticidine
B. DMP = Dess-Martin periodinane, DEAD = diethyl azodicarboxylate.
The authors declare no conflict of interest.
Keywords: lignans, aglacin, natural products, total synthesis,
The high-resolution mass spectrum, and optical rotation of
synthetic 3-5 (Table S7 in the Supporting Information) were fully
consistent with the corresponding data of the natural products.[7]
To further demonstrate the synthetic potentials of this
strategy (Pathway B, Scheme 1), we planned to prepare aryl–
APEDA reaction
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The synthesis started from the APEDA reaction with 13a and
dienophile 41 (Scheme 5), which gave the desired tricyclic core
51 in 76% isolated yield and good enantioselectivity (93% ee).
Using similar transformations as preparation of 45, the desired
triflate 52 was obtained through two steps of oxidation and
triflation. A Pd(0) catalyzed Suzuki-Miyaura coupling of 52 with
aryl boronic acid pinacol ester 53 afforded (–)-7,8-
dihydroisojusticidine B (54) in 70% yield.[8] The same cross
coupling reaction between 52 and 55 worked well to form the
desired coupling product 56 in 60% yield. To build the strained
dihydrooxepine ring, we first performed the acid-mediated
removal of the TBS and two methyl groups, then an
intramolecular Mitsunobu reaction was applied to close the
seven-membered cyclo-ether D ring. After introduction of an
additional methyl group, the total synthesis of (+)-linoxepin was
accomplished in 40% yield over 2 steps.[8, 15]
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In summary, the first asymmetric total synthesis of
aryltetralin cyclic ether lignans aglacins A, B and E were
achieved based on an asymmetric photoenolization/Diels–Alder
(APEDA) reaction. Both enantiomers of aglacins A, B and E were
prepared in 13-14 steps, which enable us to revise the absolute
configuration of these natural lignans. The APEDA reaction,
between electron-rich 2-methylbenzaldehyde and unsaturated -
lactone, provided a new approach to rapidly construct the basic
5
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Research Article
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This article is protected by copyright. All rights reserved.

10.1002/anie.202105395
Angewandte Chemie International Edition
Research Article
Natural Product Synthesis
Mengmeng Xu, Min Hou, Haibing He,
Shuanhu Gao*
__________ Page – Page
Asymmetric Total Synthesis of
Aglacins A, B and E
We report herein the first asymmetric total synthesis of aryltetralin cyclic ether lignans
aglacins A, B and E, based on a novel asymmetric photoenolization/Diels–Alder
(APEDA) reaction. This work also enables us: 1) revise the absolute configuration of
aglacins; 2) prepare aryl–dihydronaphthalene-type lignans (–)-7,8-dihydro-
isojusticidine B and (+)-linoxepin; 3) build a small library of lignans (27 members).
7
This article is protected by copyright. All rights reserved.