Biomimetic synthesis of equisetin and (+)-fusarisetin A

Article abstract of DOI:10.1002/chem.201302163

(+)-FusarisetinA belongs to a group of acyl tetramic acid natural products that show potential anticancer activity. Equisetin, a biogenetically related acyl tetramic acid, contains the basic skeleton of (+)-fusarisetinA. We proposed that equisetin and (+)-fusarisetinA share a biosynthetic pathway that starts with naturally occurring (S)-serine and an unsaturated fatty acid. In support of this hypothesis, we have demonstrated that a cyclization sequence involving an intramolecular Diels-Alder reaction followed by a Dieckmann cyclization of polyenoylamino acid yielded equisetin. The aerobic oxidation of equisetin, promoted by either Mn^III/O₂ or a reactive oxygen species (ROS) produced by visible-light chemistry, gave peroxyfusarisetin, which could be easily reduced to (+)-fusarisetinA. We report herein detailed information on the biogenetic synthesis of equisetin and (+)-fusarisetinA. Make the change to bio! Biomimetic synthesis of equisetin and (+)-fusarisetinA was achieved based on a biosynthetic hypothesis. An intramolecular Diels-Alder reaction followed by a Dieckmann cyclization of polyenoylamino ester furnished equisetin. The aerobic oxidation of equisetin to give (+)-fusarisetinA was mediated by a Mn^III/O₂ system or reactive oxygen species (ROS) (see scheme). Copyright

Full text of DOI:10.1002/chem.201302163

FULL PAPER
DOI: 10.1002/chem.201302163
Biomimetic Synthesis of Equisetin and (+)-Fusarisetin A
[
a]
[a]
[a]
[a]
[a]
Jun Yin, Lili Kong, Cheng Wang, Yingbo Shi, Shujun Cai, and
[
a, b]
Shuanhu Gao*
Abstract: (+)-Fusarisetin A belongs to
a group of acyl tetramic acid natural
products that show potential anticancer
activity. Equisetin, a biogenetically re-
lated acyl tetramic acid, contains the
basic skeleton of (+)-fusarisetin A. We
proposed that equisetin and (+)-fusari-
setin A share a biosynthetic pathway
that starts with naturally occurring (S)-
serine and an unsaturated fatty acid. In
support of this hypothesis, we have
demonstrated that a cyclization se-
quence involving an intramolecular
Diels–Alder reaction followed by a
Dieckmann cyclization of polyenoyla-
mino acid yielded equisetin. The aero-
bic oxidation of equisetin, promoted by
III
either Mn /O or a reactive oxygen
2
species (ROS) produced by visible-
light chemistry, gave peroxyfusarisetin,
which could be easily reduced to
(+)-fusarisetin A. We report herein de-
tailed information on the biogenetic
synthesis of equisetin and (+)-fusarise-
tin A.
Keywords: biomimetic synthesis ·
equisetin · fusarisetin A · radical re-
actions · total synthesis
Introduction
Tetramic acid based natural products typically contain a 2,4-
[1]
pyrrolidinedione motif, ubiquitous in nature. As shown in
Figure 1, most tetramic acids have an acyl-substituted group
at C3, which exists as a mixture of keto/enol tautomers. The
importance of the naturally occurring tetramic acids has at-
tracted considerable interest from the chemistry community
since the 1960s not only because of their unique structures
but also their potential biological activities. As a representa-
tive, equisetin (1), a fungal metabolite, was discovered from
[2]
the white mold Fusarium equiseti in 1974. Equisetin exhib-
its potent antibiotic and HIV inhibitory activity, as well as
selective cytotoxicity to mammalian cells.
In 2011, Ahn and co-workers reported the isolation of a
new acyl tetramic acid (+)-fusarisetin A ((+)-2; Figure 1)
[3]
from a soil fungus, Fusarium sp. FN080326. The compound
potently inhibits acinar morphogenesis, cell migration, and
cell invasion in MDAMB-231 cells without significant cyto-
[3]
toxicity. These biological tests suggest that (+)-2 holds
promise as a valuable anticancer agent. Structurally, it pos-
sesses an unusual pentacyclic ring system with several moiet-
ies based on trans-decalin (rings A and B), spiroskeleton (C,
Figure 1. Representative 3-acyl tetramic acid type natural products.
[
a] J. Yin, L. Kong, C. Wang, Y. Shi, S. Cai, Prof. Dr. S. Gao
Shanghai Key Laboratory of Green Chemistry
and Chemical Processes, Department of Chemistry
East China Normal University
E), and acyl tetramic acid (E). (+)-Fusarisetin A has 10
stereocenters that include two all-carbon quaternary centers
(C1, C16). The relative stereochemistry of fusarisetin A was
confirmed by using X-ray crystallographic analysis by Ahn
3
663N Zhongshan Road, Shanghai 200062 (P. R. China)
Fax : (+86)21-62604784
E-mail: shgao@chem.ecnu.edu.cn
[3]
et al. Its absolute configuration was previously determined
[3]
by the exciton chirality circular dichroism method, which
was revised by Li and co-workers through the chemical syn-
[
b] Prof. Dr. S. Gao
State Key Laboratory and Institute of Elemento-organic Chemistry
Nankai University, Tianjin 300071 (P. R. China)
[4a]
thesis. The unique chemical structure and potential anti-
cancer activity of (+)-fusarisetin A prompted us to explore
its laboratory synthesis and biological function. We aim to
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302163.
Chem. Eur. J. 2013, 00, 0 – 0
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develop an efficient synthetic approach to prepare acyl tet-
ramic acids that could enable structure–activity relationship
studies and facilitate further chemical biology studies.
We report herein the details of our synthetic studies of
both equisetin (1) and (+)-fusarisetin A (2) based on our
proposed biosynthetic hypothesis. We previously demon-
strated that oxidation of 1 with Mn CAHTUNGTRNEUNG( OAc) /O gave peroxy-
3 2
[4c]
fusarisetin, which could be easily reduced to 2. We now
provide evidence that 1 and 2 should derive from the same
biogenetic precursor: polyenoylamino acid 3. We further
found that oxygen played an important role in the aerobic
oxidation of 1, and this oxidation can be promoted by visible
light in the presence of a photoreactive catalyst. The reac-
tion conditions are physiologically relevant, which suggests
[5]
that a reactive oxygen species (ROS) may be involved in
the biosynthesis of 2 from 1.
Results and Discussion
Scheme 1. Biosynthetic hypothesis for the synthesis of equisetin (1) and
+)-fusarisetin A (2).
(
Biogenetic hypothesis and synthetic plan: Nature relies on
enzymatic and nonenzymatic processes to create complex
and diverse natural products from simple building blocks
with perfect selectivity and efficiency. The field of bio-
thetic approach to 1 that was based on pioneering studies
[6]
[4c]
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
mimetic organic synthesis, pioneered by Robert Robin-
(Scheme 2).
[
7]
son, aims to emulate biogenetic processes in the laborato-
ry. Over the past century, biomimetic synthesis of natural
products has achieved considerable successes, such as the bi-
ogenetic synthesis of terpenoids and steroids by using a pol-
By using a known two-step procedure, (+)-citronellal (6)
was converted to aldehyde 7 in large scale with good
[10]
yield. Reaction of 7 with ylide 9 gave unsaturated ester 8
in 91% yield (E/Z 16:1). Deprotection of ethylene glycol
provided aldehyde 10 which could be directly used in the
next transformation without purification. The Horner–Wads-
worth–Emmons (HWE) reaction of 10 with phosphonate
[8]
yene cyclization cascade. Biomimetic organic synthesis can
be said to have two aims: 1) propose and explore how
nature synthesizes the target molecule and 2) mimic the pro-
posed biosynthetic pathway in the laboratory to generate
the same target.
[9b]
12
lead the formation of 11 in 63% yield (E:Z>15:1).
Transformation of 11 to unsaturated aldehyde 14 was ach-
ieved by using a sequence of diisobutylaluminium hydride
(DIBAL) reduction and Dess–Martin periodinane (DMP)
oxidation. The intramolecular Diels–Alder (IMDA) reac-
Upon close inspection of natural sources and structural
properties of equisetin (1) and (+)-fusarisetin A (2), we
found that both molecules belong to fungal metabolites and
bear a similar basic skeleton (rings A, B, and E) but in dif-
ferent oxidation states. We questioned if equisetin (1) and
+)-fusarisetin A (2) are biogenetically related. We hypothe-
size that 1 and 2 share a biosynthetic pathway starting with
naturally occurring (S)-serine (4) and unsaturated fatty acid
[11]
tion,
promoted by Lewis acids BF ·OEt , Et AlCl, or
3 2 2
silica gel (during chromatography), effectively converted al-
[9a]
(
dehyde 14 to trans-decalin 15. We found that the follow-
ing Roskamp reaction, which was used to prepare a b-keto
ester from aldehyde, could also be promoted by BF ·OEt .
3
2
5
(Scheme 1). Coupling of 4 and 5 yields polyenoylamino
Thus, the IMDA reaction and Roskamp reaction could be
operated in one pot, and gave 16 in 47% yield over three
steps from 13. After application of the aminolysis and Die-
acid 3, which is cyclized to equisetin (1) through an intramo-
lecular Diels–Alder reaction followed by a Dieckmann cycli-
zation. We envisioned that the acyl tetramic acid moiety of
[9a]
ckmann cyclization sequence reported by Danishefsky, we
1
should be easily oxidized to a radical, which could be con-
completed the total synthesis of equisetin (1).
verted to 2 through aerobic oxidation. The chiral methyl
group of 5 could be induced from the (+)-citronellal (6)
through the classic chemical transformations.
Biomimetic synthesis of equisetin: Although the synthetic
route (Scheme 2) successfully delivered 1, it may not have
biosynthetic relevance to our biosynthetic hypothesis
(Scheme 1). We proposed polyenoylamino acid 3 to be a
key intermediate to both 1 and 2. We anticipated that 3,
which has all the required elements of 1 and 2, could be
transformed to 1 through a cyclization sequence. We there-
fore planed to develop a biomimetic synthesis of 1 based on
our biosynthetic hypothesis.
First-generation synthesis of equisetin: Our synthetic jour-
ney started from the preparation of equisetin (1) which
could be used as the biosynthetic precursor of (+)-fusarise-
ACHTUNGTRENNUNGt in A (2). The total synthesis of equisetin has been accom-
[
9a]
plished by several groups including Danishefsky,
Ley,
Dixon,
[
9b–c]
[9d]
and Shishido et al. We previously reported a syn-
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Biomimetic Synthesis of Equisetin and (+)-Fusarisetin A
FULL PAPER
Scheme 2. Preparation of equisetin (1): a) 9 (1.1 equiv), 258C, CH
2
Cl
2
, 12 h, E/Z 16:1, 91%; b) HCl (1.0n), 608C, 4 h, THF; c) 12 (1.3 equiv), LHMDS
(
1.4 equiv), 30 min, then 10 (1.0 equiv), ꢀ78!258C, 16 h, THF, E/Z>15:1, 63% in 2 steps; d) DIBAL (2.2 equiv), CH
Martin periodinane (1.5 equiv), H O (1.5 equiv), CH Cl , 10 min, 258C; f) BF ·OEt Cl , 20 min, then 17 (3.0 equiv), 08C, 1.5 h,
7% in 3 steps; g) 19 (2.0 equiv), DMAP (2.0 equiv), toluene, 1188C, 18 h, 68%; h) NaOMe (1.0 equiv), MeOH, 258C, 2 h, 72%, d.r.=3:1 (at C3); i) HF,
2
Cl
2
, ꢀ788C, 3 h, 94%; e) Dess–
2
2
2
3
2
(3.0 equiv), ꢀ788C, CH
2
2
4
3
CH CN, 258C, 2 h, 95%. DMAP=4-dimethylaminopyridine; LHMDS=lithium hexamethyl disilazide.
By starting from aldehyde 7, the HWE reaction of 7 and
phosphonate 20 converted 7 into unsaturated thioester
1 in 75% yield (Scheme 3). Deprotection of the ethylene
tively construct the C1ꢀC6 bond and oxidation of C5. In
[9b–c]
support of this hypothesis, we previously demonstrated that
2
oxidation of 1 with Mn ACHTUNGTNERGUN( OAc) /O gave peroxyfusarisetin,
3 2
[4c]
glycol yielded aldehyde 22, which was transformed into pol-
yene 23 by using a second HWE olefination in 65% yield
over two steps. We constructed 25, the methyl ester of 3, by
mimicking the biosynthetic coupling of 4 and 5. Aminolysis
of 23 with the (S)-serine derivative 24 promoted by silver
which could be reduced to 2 easily. Theodorakis and co-
workers recently also surveyed a series of metal oxidants for
the aerobic oxidative cyclization of the C-ring of 2 in a
model system. They found Ce ACTHUNGTERNNNU(G NH ) ACTHUNGTENRNUN(G NO ) to be an effec-
4 2 3 6
[4d]
tive oxidant.
Manganese
dant, especially for the enolizable carbonyl compounds.
To date, the Mn(III)-promoted radical reactions have been
extensively exploited and applied in the natural product syn-
[9b–c]
trifluoroacetate
gave polyenoylamino ester 25 in 85%
ACHTUNGTRENNU(GN III) acetate is an effective single-electron oxi-
[12]
yield. We next screened conditions of the intramolecular
Diels–Alder reaction (see details in the Supporting Informa-
AHCTUNGTRENNUNG
[11]
tion) and found that the IMDA
of 25 promoted by
[13]
BF ·Et O smoothly delivered the desired trans-decalin 27
thesis.
mally adopt Cu (Cu AHCTUNGTRNENUG( OAc) or Cu ACHTUNGTERNNNU(G OTf) ) as a co-oxidant
2 2
Under anaerobic conditions, these reactions nor-
3
2
II
[14]
with good diastereoselectivity (d.r.=17:1). We reasoned that
the stereoselectivity of this reaction was substrate-controlled
and involved the chair-like transition-state 26, such that the
activated dienophile reacted with the diene component and
adopted the endo approach. trans-decalin 27 could be easily
converted to equisetin (1) by Dieckmann cyclization under
to oxidize the radical to give a cation that eliminates to the
olefin. Notably, the radical intermediate could also be oxi-
dized by oxygen to form endoperoxides or hydroperoxides
under aerobic conditions. Nishino and co-workers carried
III
out systematic studies of the Mn /O -based peroxidation of
2
[4c]
[15]
basic conditions.
alkenes. We were intrigued by the possibilities to use the
Mn /O conditions in the oxidation of 1 to close the C ring
III
2
Biomimetic synthesis of (+)-fusarisetin A promoted by
as well as selective oxidation of C5 simultaneously.
We were pleased to find that oxidation of 1 with Mn-
III
Mn /O : We then turned our attention to the bioconversion
2
of 1 into (+)-fusarisetin A (2). The structural difference be-
tween 1 and 2 is the oxidation state, which relies on forma-
tion of rings C and D, that is, on formation of the C1ꢀC6
ACHTUNGTNERNGNU( OAc) (2.0 equiv) under air or 1 atm O in HOAc at room
3
2
temperature gave peroxyfusarisetin 28 and its C5-epimer 29
in 62% combined yield (d.r.=1.3:1) (Scheme 4). After opti-
mization of the reaction conditions, we found the reaction
could also be promoted by a catalytic amount of Mn ACHTUNGTRENNUNG( OAc)
3
(10 mol%) and provided 28 and 29 with a comparable 60%
yield (d.r.=1.1:1). A single crystal of 29 suitable for X-ray
bond and oxidation of C5. We envisioned that the acyl tetra-
mic acid moiety of 1, existing as a mixture of keto/enol tau-
tomers, should be easily oxidized to a radical intermediate,
which might undergo the aerobic radical cascade to effec-
Chem. Eur. J. 2013, 00, 0 – 0
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S. Gao et al.
Scheme 4. Aerobic oxidation of equisetin (1) promoted by Mn
a) Mn(OAc) ·2H O (2.0 equiv), air or 1 atm O , 258C, 1 h, d.r.=1.3:1 (at
C5), 62%; b) Mn(OAc) ·2H O (0.1 equiv), air or 1 atm O , 258C, 2 h,
d.r.=1.1:1 (at C5), 60%.
3 2
ACTHUNGTRENUNG( OAc) /O :
Scheme 3. Biomimetic synthesis of equisetin (1): a) KHMDS (2.2 equiv),
THF, ꢀ78 to 258C, 12 h, 75%; b) 1n HCl, THF, 608C, 4 h; c) LiHMDS
A
H
U
G
R
N
U
G
3
2
2
A
H
U
T
E
N
N
3
2
2
(
3.1 equiv), THF, ꢀ78 to 258C, 16 h, 65% over two steps; d) CF
3
COOAg
(2.0 equiv),
788C, DCM, 2 h; 63%, d.r.=17:1; f) MeONa (1.0 equiv), MeOH, 258C,
h, 100%, d.r.=1:1 (at C3).
(
ꢀ
1.0 equiv), Et
3
N, THF, ꢀ108C, 1 h; 85 %; e) BF
3 2
·Et O
1
sarisetin (28 and 29), but also regenerated the manganese
enolate 30 to form the catalytic cycle.
Ultimately, reductive cleavage of the peroxide bonds of
the mixture of 28 and 29 with Zn/HOAc furnished (+)-fu-
[4a]
sarisetin A (2) and 5-epi-2
in 75% combined yield
(
Scheme 5). The spectroscopic data of synthetic 2 were fully
Figure 2. X-ray structure of C5-epi-peroxyfusarisetin 29.
analysis was obtained, which allowed unambiguous determi-
nation of its relative configuration (Figure 2). The mecha-
nism of the reaction was proposed based on Sniderꢁs and
[13c,15a]
Nishinoꢁs mechanistic studies (Scheme 4).
ered that the reaction of the acyl tetramic acid moiety in 1
with Mn(OAc) formed the manganese enolate 30, which
We consid-
ACHTUNGTRENNUNG
3
then underwent a 5-exo cyclization to give the radical 31.
Under aerobic conditions, 31 was trapped by O2 and cy-
clized to yield 33 through 32. We believe that a hydrogen
abstraction from 1 not only terminated 33 to give peroxyfu-
Scheme 5. Synthesis of (+)-fusarisetin A (2): a) Zn (30.0 equiv), HOAc,
08C, 2 h, 75% combined yield; b) Mn(OAc) ·2H O (0.1 equiv), air or
1 atm O , 258C, HOAc, 2 h, then Zn (30.0 equiv), 508C, 2 h, 41 %.
5
A
H
U
G
R
N
U
G
3
2
2
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Biomimetic Synthesis of Equisetin and (+)-Fusarisetin A
FULL PAPER
consistent with the correspond- Table 1. Screening conditions for the ROS-mediated oxidative cyclization of equisetin (1) by using [Ru-
[
a]
3 2
AHCTUNGTRENNG(U bpy) ]Cl 34 as a photocatalyst.
ing data for the natural prod-
[
3]
uct. We further found that the
transformation of equisetin (1)
to (+)-Fusarisetin A (2) could
be operated in one-pot by
direct addition of Zn to the O2-
trapping oxidative radical se-
quence, and 2 was obtained in
4
1% yield over the reaction se-
[
b]
Entry
Photocat.
(mol%)
Base
(equiv)
Atmosphere
(1 atm)
Visible light
Ratio (28/29)
Total yield
(28+29) [%]
quence.
[d]
A
H
U
G
R
N
U
G
A
H
U
G
R
N
U
G
A
H
U
G
R
N
U
G
ACHTUNGTRENNUNG
1
2
3
4
5
6
7
8
9
5
0
5
5
5
0
5
5
5
–
air
air
air
air
air
air
air
yes
no
no
yes
no
yes
yes
yes
–
–
–
–
–
–
trace
n.r.
trace
trace
trace
n.r.
68
56
70
Biomimetic synthesis of (+)-fu-
sarisetin A mediated by ROS:
In parallel with these chemical
engineering considerations, we
also asked, how does nature ini-
tiate single-electron transfer
and oxidation? We found the
K
K
K
Et
Et
Et
Et
2
2
2
CO
CO
CO
3
3
3
(1.0)
(1.0)
(1.0)
3
3
3
3
N (4.0)
N (4.0)
N (4.0)
N (4.0)
2.0:1
1.9:1
1.8:1
O
2
[
c]
Et N (4.0)
3
air
sunlight
answer in photosynthesis,
a
ꢀ1
[
a] All the reactions were performed on a 20.0 mg scale at a substrate concentration of 0.02 molL at 258C
process vital for all aerobic for 4 h. [b] Irradiation with a 23 W household compact fluorescence lamp (CFL). [c] Irradiation with sunlight
[
16]
on the indoor windowsill. [d] Isolated yield. n.r.=no reaction.
life. In photosynthesis, chlor-
ophyll acts as a photosensitizer
and plays a key role in storing
solar energy in the form of chemical energy; during this
process, it efficiently initiates single-electron transfer. In-
spired by photosynthesis, we speculated that the desired bio-
oxidation of 1 to 2 might be initiated by visible light through
a radical cascade reaction. Given that equisetin (1) does not
absorb visible light, a photocatalyst would be required for
transferring photoenergy during this process.
Organometallic photocatalysts have been extensively
[
17]
studied recently.
ACHTUNGTRENNUNG( bpy) ]Cl
3 2
Among these complexes, [Ru-
(bpy=2,2’-bipyridine) is the most useful due to
its availability, chemical stability, and potent redox poten-
tials. The photoredox process using [Ru(bpy) ]Cl and
oxygen in the same system, which could generate superoxide
[18]
AHCTUNGTRENNUNG
3
2
2
ꢀ·
radical anion (O ), a common ROS, has been studied by
[19a]
[19b]
[19c–e]
[19f]
Zen,
Zhao,
Xiao,
and Jiao et al.
We envisioned
that this photoredox system could be used as a new initiator
for the formation of 2 by ROS-mediated oxidative cycliza-
tion of 1. To test this hypothesis, we irradiated a solution of
1
with a household compact fluorescence lamp (CFL) in the
presence of oxygen and a catalytic amount of [Ru(bpy) ]Cl
4. After a survey of the reaction conditions (shown in
AHCTUNGTRENNUNG
3
2
3
Scheme 6. Proposed mechanism for the ROS-mediated oxidative cycliza-
tion of equisetin (1).
Table 1), we found that irradiation of a solution of 1 in ace-
tonitrile with Et N (4.0 equiv) under air or oxygen produced
3
the desired peroxyfusarisetin 28 and its C5-epi-isomer 29
second SET. The superoxide radical anion initiates the radi-
cal cascade by abstracting hydrogen from equisetin (1). The
resulting radical intermediate 35 undergoes 5-exo cyclization
to yield 31, which is trapped by oxygen to give 33. A second
(
d.r.=2:1) in 68% combined yield. Similar results were ob-
tained when we performed the reaction with sunlight as the
photo source.
+
·
We suggest that ROS-mediated oxidative cyclization of 1
occurs through the following mechanism (Scheme 6). Irradi-
hydrogen abstraction from Et N or 1 terminates 33 and
3
provides peroxyfusarisetin 28 and 29. To the best of our
2
+
ation of [Ru
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(bpy) ]Cl gave the photoexcited [Ru
A
H
U
G
R
N
U
G
knowledge, this is the first case using the visible-light-in-
3
2
3
2ꢀ·
which Et N reductively quenched through single-electron
duced generation of ROS (O ) instead of metal oxidant to
3
+
transfer (SET). This generated [Ru
oxygen to the superoxide radical anion (O ) through a
A
H
U
G
R
N
N
(bpy) ] , which reduced
initiate an aerobic radical cascade in natural product synthe-
sis.
3
2ꢀ·
Chem. Eur. J. 2013, 00, 0 – 0
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S. Gao et al.
Table 2. Screening conditions for the ROS-mediated oxidative cyclization of equisetin (1) by using methylene serine and unsaturated fatty
[
a]
blue 35 as a photocatalyst.
acid. We believe that 3 under-
goes an intramolecular Diels–
Alder reaction followed by a
Dieckmann cyclization to yield
1
. The biosynthesis of (+)-fusar-
isetin A (2) may involve an
aerobic oxidation of equisetin
(
1). This process could be medi-
III
ated by a Mn /O system or
2
ROS. We demonstrated that
both the photolytically generat-
ed superoxide radical anion
[
b]
Entry
Photocat.
(mol%)
Base
(equiv)
Atmosphere
(1 atm)
Visible light
Ratio (28/29)
Total yield
(28+29) [%]
[
d]
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
A
H
U
G
E
N
N
A
H
U
G
R
N
U
G
ACHTUNGTRENNUNG
2ꢀ·
1
1
2
3
4
5
6
5
5
5
5
5
5
–
air
air
air
air
yes
yes
no
2.2:1
2.0:1
–
3.0:1
2.1:1
2.5:1
68
75
trace
70
55
69
ꢀ
(O ) and singlet oxygen ( O )
2
K
2
CO
3
(1.0)
can react with 1 to give peroxy-
fusarisetin 28. Reduction of per-
oxyfusarisetin gives 2. We are
currently studying the ROS-
mediated oxidative cyclization
Et
Et
Et
Et
3
3
3
3
N (4.0)
N (4.0)
N, (4.0)
N, (4.0)
yes
yes
sunlight
O
2
[
c]
air
1
[
a] All the reactions were performed on a 20.0 mg scale at a substrate concentration of 0.02 molL at 258C
for 4 h. [b] Irradiation with a 23 W household compact fluorescence lamp (CFL). [c] Irradiation with sunlight and utility of this method in re-
on the indoor windowsill. [d] Isolated yield.
lated natural product synthesis.
[20]
1
Singlet oxygen ( O ) is another reactive oxygen species
2
(
ROS) that can be generated by activation of triplet oxygen
by using dye-type photocatalysts. We questioned if the oxi-
dative cyclization of equisetin (1) could be promoted by sin-
glet oxygen. After an extensively survey of the catalysts and
reaction conditions (Table 2), we were pleased to find that
the oxidation of 1 using methylene blue (36) as the photoca-
talyst gave 28 and 29 (d.r.=3:1) in 70% yield. This reaction
worked under either neutral or basic conditions (K CO or
2
3
Scheme 7. Reduction of peroxyfusarisetin: P
08C, 3 h, 75% combined yield.
3
ACHTUNGENTRNUNG( OMe) , (40.0 equiv), MeCN,
8
Et N). We screened different dye-type photocatalysts that
3
could be used for the generation of singlet oxygen, including
Rose Bengal, eosin yellow, fluorescein, nile red, riboflavin
etc. (see details in the Supporting Information), and found
We believe this methodology potentially opens the door for
synthetic innovations in the biomimetic synthesis of natural
products.
that 36 is the most effective photocatalyst. Here, photoexcit-
1
ed 36* reacted with oxygen to yield singlet oxygen ( O )
2
(
singlet+triplet!triplet+singlet and triplet+triplet!sin-
glet+singlet are both viable), which reacted with the
C5ꢀC6 olefin to give 37. Rearrangement of 37 yielded 28
Acknowledgements
and 29.
We further investigated the reduction of the peroxide
bonds of peroxyfusarisetin and found that 28 and 29 could
Financial support was provided by the NSFC (21102045, 21272076), the
Shanghai “Pujiang Program” (11PJ1402800), RFDP (20110076120022) of
Higher Education of China and the program for professor of special ap-
pointment (Eastern Scholar) at Shanghai institutions of higher learning
be reduced with P
2) and C5-epi-2 in 75% combined yield (Scheme 7). Theo-
dorakis and co-workers reported that thiourea is also effec-
ACHTUNGTRENNUNG( OMe) and furnished (+)-fusarisetin A
3
(
(
no.1220000144). We also thank Prof. X. Zhao for X-ray analysis.
[4d]
tive for this reduction.
[
[
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[
(
&
6
&
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ÝÝ
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Biomimetic Synthesis of Equisetin and (+)-Fusarisetin A
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Received: June 6, 2013
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
7
&
ÞÞ
These are not the final page numbers!

S. Gao et al.
Biosynthesis
J. Yin, L. Kong, C. Wang, Y. Shi,
S. Cai, S. Gao* ................ &&&& — &&&&
Biomimetic Synthesis of Equisetin and
(
+)-Fusarisetin A
Make the change to bio! Biomimetic
synthesis of equisetin and (+)-fusarise-
tin A was achieved based on a biosyn-
thetic hypothesis. An intramolecular
Diels–Alder reaction followed by a
Dieckmann cyclization of polyenoyla-
mino ester furnished equisetin. The
aerobic oxidation of equisetin to give
(+)-fusarisetin A could be mediated
III
by a Mn /O system or reactive
2
oxygen species (ROS) (see scheme).
&
8
&
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!