Total Synthesis of Asperchalasines A, D, E, and H

Article abstract of DOI:10.1002/anie.201808481

The first total syntheses of the cytochalasan dimers asperchalasines A, D, E, and H have been accomplished. The key steps of the synthesis include a highly stereoselective intermolecular Diels–Alder reaction and a Horner–Wadsworth–Emmons macrocyclization to establish the key monomer aspochalasin B, and an intermolecular Diels–Alder reaction followed by a biomimetic oxidative heterodimerization by 5+2 cycloaddition to furnish asperchalasine A. The synthetic efforts provide insight into the biosynthetic pathway of cytochalasan dimers and enables the further study of their biological properties.

Full text of DOI:10.1002/anie.201808481

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Accepted Article
Title: Total Synthesis of Asperchalasines A, D, E and H
Authors: Xianwen Long, Yiming Ding, and Jun Deng
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201808481
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Angewandte Chemie International Edition
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COMMUNICATION
Title Total Synthesis of Asperchalasines A, D, E and H
+
,[a],[b]
+,[a]
*,[a]
Xianwen Long
, Yiming Ding
and Jun Deng
th
This paper is dedicated to the 80 anniversary celebration of Kunming Institute of Botany, Chinese Academy of Sciences.
Abstract: The first total syntheses of cytochalasan dimers
asperchalasines A, D, E and H have been accomplished. The key
steps of the synthesis include a highly stereoselective intermolecular
Diels-Alder reaction and a HWE macrocyclization to establish the
key monomer aspochalasin B and an intermolecular Diels-Alder
reaction followed by a biomimetic oxidative heterodimerization via
flaipes. Structurally, 1 possesses an unprecedented 13-
2.5 1.6
oxatetracyclo[7.2.1.1 .0 ]tride-8,12-dione core containing as
many as 20 stereogenic centers, which might be biosynthetically
generated by the fusion of two aspochalasins B (6) to an
epicoccine. Biologically, 1 selectively induces G1-phase cell
cycle arrest in fast-dividing cancner cells, making it a novel
cytoskeletal inhibitor against cancner cells. Herein, we report the
first asymmetric total synthesis of asperchalasine A (1).
5+2 cycloaddition to furnish asperchalasine A. The synthetic efforts
provide insight into the biosynthetic pathway of cytochalasan dimers
and enables the further study of their biological properties.
Cytochalasans are a large family of fungal metabolites (>
[
1]
3
00 members) with intriguing structures and bioactivity. They
exhibit broad 2r]ange of biological activities, including
immunomodulatory, cytotoxic, and nematicidal activities,
and has attracted considerable attention from the synthetic
a
[
[3]
[4]
[5]
community. In 2015, the first subclass cytochalasan dimers,
asperhalasines A, B, D, E and H（Figure 1）, were isolated by
Zhang and co-workers from the culture broth of Aspergillus
[6]
Figure 1. Asperchalasines A, B, D, E, H and epicocine.
Scheme 1. Retrosynthetic Analysis of Asperchalasine A.
[
a]
Mr. Xianwen Long, Mr. Yiming Ding, Prof. Dr. Jun Deng
Department State Key Laboratory of Phytochemistry and Plant
Resources in West China, and Yunnan Key Laboratory of Natural
Medicinal Chemistry, Kunming Institute of Botany, Chinese
Academy of Sciences, Kunming 650201, China.
We first undertook
a
retrosynthetic analysis of
asperchalasines A (1), as illustrated in Scheme 1. It’s likely that
asperchalasine A is formed biosynthetically through the union of
two aspochalasins B and one epicoccine. Inspired by this
biosynthetic hypothesis, the initial disconnection takes place at
the C19'–C4'' and C20'–C2'' bond to provide aspochalasin B (6)
and 5, which could be further disassembled in a retro-Diels-
Alder reaction to give aspochalasin B and hemi-acetal 7.
Aspochalasin B could be assembled from three fragments 8–10
through an intermolecular Diels-Alder reaction and a Horner-
Wadsworth-Emmons (HWE) macrocyclization. Previously, Trost
132 Lanhei Road, Kunming, China
E-mail: dengjun@mail.kib.ac.cn
Mr. Xianwen Long
University of Chinese Academy of Sciences, Beijing 100049, China.
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
[
[
b]
+
]
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Angewandte Chemie International Edition
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COMMUNICATION
[
5j]
and co-workers reported first total synthesis of aspochalasin B
the dienophile 8. The lactam 13 was readily prepared from N-
boc-L-leucine (5 steps, 57% yield). C-Acylation of 13 with
[5n]
[9]
in 1989 and Myers and co-workers reported their elegant total
synthesis of cytochalasin B using HWE macrocylization stragety
in 2004. Here, we report a concise and scalable approach to
aspochalasin B, which in turn enabled a rapid synthesis of
asperchalasine A and other dimers in this family.
methyl chloroformate provided methyl ester 14. After sequential
[10]
selenylation and oxidative elimination, 14 was converted into
the doubly activated dienophile 8 (88% yield for 2 steps), which
[11]
was unstable and was used immediately. With both 8 and 12
in hand, we examined variety of conditions for the
intermolecular Diels-Alder reaction. Lewis acid promoters such
a
1
2
) MeCOCHPPh3
) TBSOTf,
2,6-lutidine
[12]
Me
O
3
as: BF ·OEt
2
, Et
2
AlCl, TMSOTf, Eu(fod)
3
led to decomposition
Me
9
,
Me
O
of diene 12. To our delight, heating a mixture of 8 and 12 (neat,
100℃) furnished Diels-Alder products 15 and its C13-C14
isomer in 85% yield from 14 (E:Z = ~2:1,). The regioselectivity
was mainly induced by electron donating effect of 5, 6-dimethyl
groups and facial selectivity was controlled by a thermal endo
transition state with the triene approaching from the less
hindered face of the dienophile 8. The C13-C14 cis/trans
isomerization was mainly caused by thermodynamic
OH
3
) H2, Pd/C
KHMDS
Me
6
9% yield
TBSO
TBSO
8
2% yield
HO
OH
TBSO
OTBS
d.r. 7:1
OTBS
TBSO
1
1
10
12
5
steps,
ClCO2Me,
LiHMDS
CO2Me
O
O
Me
Me
5
7% yield
equilibration which was also observed by Thomas group in their
Me
Me
[5g-h]
OMe
O
Me
N
intramolecular Diels-Alder reaction.
dimethyl methylphosphonate
group of 15, followed
Addition of lithium
N
Me NHBoc
Bz
Bz
[13]
to the hindered methyl ester
by selectively deprotection
1
3
14
LiHMDS,
PhSeCl;
then H2O2
8
8% yield
for 2 steps
Me
Me
H
6
7
Me
CO2Me
O
5
14TBSO
OTBS
12 neat,
100°C
Me
8
Me
1
3
Me
BzN
N
Me
CO2Me
OTBS
85% yield
E:Z=2:1
Bz
O
8
1
5
1
) BuLi,
7
2% yield
MePO(OMe)2
2
3
for 3 steps
) HF Py
) DMP
Me
O
Me
Scheme 3. Construction of hemi-acetal 7 and 21.
1
) Zn(OTf)2,
Me
H
Me
H
Me
18
Me
Et3N, TMEDA
2) TBAF
TBSO
O
Me
Me
HN
Me
HN
79%
Me
PO(OMe)2
17
OTBS
O
O
and oxidation of the resultant primary alcohol with Dess-Martin
periodinane furnished aldehyde 16 (72% yield for 3 steps) as a
substrate for HWE macrocyclization. Various macrocylization
O
OH
HO
1
6
aspochalasin D (17)
[14a]
conditions, such as KHMDS, NaH, LiBr/Et
3
N,
2 3
K CO /18-
TsOH H2O,
TEMPO
[9b]
[5n]
9
2%
crown-6,
2
NaOCH CF3
were examined, which failed to
provide the resulting 11-membered enone and, in some cases,
led to epimerization of the C-18 stereogenic center. To our
Me
Me
Me
H
[15]
delight, the use of Zn(OTf)
2
,
a mild Lewis acid promoted
Me
macrocyclization in favor of intermolecular HWE olefination and
HN
Me
[16, 5n]
minimal epimerization at C-18.
After hydrolysis of the tert-
O
O
OH
O
butyldimethylsilyl ether with TBAF and selective oxidation of the
aspochalasin B (6)
[17]
2
allylic alcohol with TEMPO and p-TsOH·H O, we achieved the
syntheses of aspochalasin D (17) and aspochalasin B (6), in
overall 79% and 72% respectively.
Scheme 2. Total Synthesis of Aspochalasin B.
Subsequently, we prepared diene precursors 7 and 21
[18]
(
Scheme 3). Known compound 18
arising from eudesmic acid
Our synthesis commenced with
construction of the triene segment 12 (Sheme 2). Hemi-acetal
a
stereospcific
was subjected to a sequence of global demethylation, allylation
and partial reduction of lactone 19 with DIBAL-H, to give hemi-
acetal 7 as precursor of diene (71% yield for 3 steps). Another
hemi-acetal 21 was prepared similarly from mono-methylated
lactone 20 through allylation and partial reduction (54% yield
for 4 steps).
1
1 was obtained in 70% yield from L-Arabinose through a known
[7]
three-step sequence.
Wittig olefination (with reagent 1-
(
Triphenylphosphoranylidene)-2-propanone), followed by tert-
butyldimethylsilyl ethers protection of tri-ol and hydrogenation of
the resulting double bond furnished methyl-ketone 10 in 69%
yield. Coupling of this methyl-ketone to the dienyl phosphonate
[19]
[
8]
9
using KHMDS as base, gave the conjugated triene (12) with
good overall efficiency (82%, E:Z= ~7:1). We then constructed
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Angewandte Chemie International Edition
10.1002/anie.201808481
COMMUNICATION
Scheme 4. Total Synthesis of asperchalasines A, D, E and H.
Me
Me
Me
H
Me
H
Me
Me
Me
Me
H
H
H
H
HN
HN
Me
OAllyl
Me
OAllyl
Me
Me
O
+
O
O
AllylO
AllylO
AllylO
AllylO
O
OH
OH
HOAc,
120 °C
O
O
O
O
then 6
O
O
OH
78%
AllylO
Me
OAllyl
Me
OAllyl
AllylO
AllylO
OAllyl
7
22
1.2 : 1
23
Me
O
Me
Me
H
Me
HN
Pd/C,
HCO2NH4
Pd/C,
Me
75%
70%
HCO2NH4
O
OH
O
aspochalasin B (6)
Me
H
Me
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
H O
Me
Me
HN
O
H
H
H
Me
Me
Me
Me
O
O
then
NaHCO3,6
H
OH
H
H
H
H
H
H
O
HN
K3Fe(CN)6
HN
HN
Me
O
Me
Me
HO
HO
O
O
O
O
H
O
O
OH
OH
OH
49%
O
O
O
O
O
Me
O
O
O
H H
NH
Me
Me
HO
Me
HO
HO
Me
OH
Me
OH
OH
O
H
O
O
HO
Me
Me
Me
asperchalasine A (1)
2
asperchalasine H (4)
4
Me
Me
Me
Me
Me
Me
1
) 6, HOAc,
120 °C
) Pd(PPh3)4,
Et3SiH
H
H
Me
Me
OAllyl
Me
H
O
H
O
2
HN
H
HN
Me
H
MeO
Me
O
+
O
O
O
O
OH
OH
73%
O
O
AllylO
OH
HO
Me
OH
Me
OH
OMe
1.2 : 1
MeO
asperchalasine E (3)
HO
ORTEP of 22
21
asperchalasine D (2)
With a large quantity of aspochalasin B (6) and hemi-
acetal 7 in hand, we investigated the proposed biomimetic,
intermolecular Diels-Alder reaction. Upon treatment with HOAc,
hemi-acetal 7 underwent an 1, 4-elimination of water to generate
the active diene, which was trapped in situ by dienophile
underwent the same sequence used for asperchalasine H(4)
synthesis to render asperchalasines D (2) and E (3) in 73%
overall yield. The spectra and physical properties of 1, 2, 3, 4, 6,
17 were identical to those reported for their naturally occurring
counterparts, respectively.
[20]
aspochalasin B
to give exclusively endo-Diels-Alder adducts
In summary, we have accomplished the first total synthesis
of asperchalasines A, D, E and H. The monomer aspochalasin B
22 and its regioisomer 23 in 78% yield. No other diastereomeric
isomers were detected. The structure of adduct 22 was
determined by X-ray crystallographic analysis (Scheme 4). Both
(
6) was prepared through an intermolecular Diels-Alder
[
21]
cycloadducts were subjected to deallylation (Pd/C, HCO
2
4
NH )
cycloaddition and HWE macrocyclization. Acid promoted endo-
selective Diels-Alder reaction of 6 and 7 and subsequent
[22]
to furnish 24 and asperchalasine H (4) respectively. Then we
entered the final stage of the synthesis. Inspired by Zhang’s
oxidative heterodimerization of 24 and
6
furnished
[7a]
biosynthetic hypothesis
synthesis of epicolactone,
and Trauner’s elegant biomimetic
asperchalasines A, D, E and H. The reported synthetic strategy
is applicable to construct other structurally more complex
cytochalasan dimers, and in turn facilitate the investigation of
their mechanism of cell cycle arrest in cancer cell lines.
[19, 23]
we propose that asperchalasine
A is formed through a reaction cascade initiating with oxidation
of the electron-rich aromatic ring in 24, followed by an
intermolecular Michael addition of the resulting quinone to 6 and
intramolecular aldol cyclization. Treatment of 24 with potassium
ferricyanide led to facile oxidation of the electron-rich aromatic
ring to yield the corresponding o-quinone, which was unstable
and trapped by another molecule of aspochalasin B (6) in the
presence of sodium bicarbonate to furnish the formal [5+2]
adduct asperchalasine A (1) in 49% yield. Due to the poor
Acknowledgements
We thank Prof. Yonghui Zhang and Prof. Hucheng Zhu for
providing NMR spectra of asperchalasines E and H, Dr. Fan Liu
for helpful discussion and Dr. Xiaonian Li for X-ray
crystallographic analysis. Financial support was provided by the
selectivity of direct methylation (K
4) and 24, we turned to preinstalled mono-methylated hemi-
acetal 21. To our delight, mono-methylated hemi-acetal 21
2 3
CO /MeI) of asperchalasine H
(
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Angewandte Chemie International Edition
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COMMUNICATION
CAS Pioneer Hundred Talents Program (No. 2017-022) and Start
up funding of Kunming Institute of Botany.
5242; (d) G. Wei, C. Chen, Q. Tong, J. Huang, W. Wang, Z. Wu, J.
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[
7]
8]
M. Draskovits, C. Stanetty, I. R. Baxendale, M. D. Mihovilovic, J. Org.
Chem. 2018, 83, 2647.
Keywords: total synthesis • biomemitic synthesis •
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Entry for the Table of Contents (Please choose one layout)
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Xianwen Long, Yiming Ding, Jun Deng*
Page No. – Page No.
Title
Text for Table of Contents
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