Concise synthesis of fungal metabolite (+)-fusarochromanone via rhodium(III)-catalyzed oxidative sp2 C-H bond olefination

Article abstract of DOI:10.1246/cl.160530

The concise synthesis of a fungal metabolite, (+)-fusarochromanone (FC-101), was achieved via the oxidative sp² C-H bond olefination of an N-acetylaminochromanone with a chiral functionalized electron-rich alkene, catalyzed by an electron-deficient (η⁵-cyclopentadienyl)rhodium(III) complex, [Cp^ERhCl₂]₂, under ambient conditions as the key step. This protocol was applied to various acetanilides and functionalized electron-rich alkenes for the syntheses of fusarochromanone analogs.

Full text of DOI:10.1246/cl.160530

Advance Publication Cover Page
Concise Synthesis of Fungal Metabolite (+)-Fusarochromanone via
Rhodium(III)-Catalyzed Oxidative sp2 C–H Bond Olefination
Yuji Takahama, Yu Shibata,* and Ken Tanaka*
Advance Publication on the web July 16, 2016 by J-STAGE
doi:10.1246/cl.160530
© 2016 The Chemical Society of Japan
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1
Concise Synthesis of Fungal Metabolite (+)-Fusarochromanone via Rhodium(III)-Catalyzed
Oxidative sp2 C–H Bond Olefination
Yuji Takahama,1 Yu Shibata,*,2 and Ken Tanaka*,1,2
1 Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Koganei, Tokyo
184-8588
2 Department of Chemical Science and Engineering, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo
152-8550, Japan
(E-mail: ktanaka@apc.titech.ac.jp)
The concise synthesis of a fungal metabolite, (+)-
CO Et
2
Me
Me
Cl
Me
Me
Me
fusarochromanone (FC-101), was achieved via the oxidative
sp2 C−H bond olefination of an N-acetyl aminochromanone
with a chiral functionalized electron-rich alkene catalyzed by
Me
Cl
Rh
Rh
Me Cl
Me
EtO C Cl
2
2
2
η5-cyclopentadienyl)rhodium(III)
E
[Cp RhCl ] (1)
2 2
[Cp*RhCl ]
2 2
an
(electron-deficient
complex, [CpERhCl2]2, under ambient conditions as a key step.
This protocol was applied to various acetanilides and
functionalized electron-rich alkenes for the synthesis of
fusarochromanone analogs.
Figure 1. Structures of [CpERhCl2]2 (1) and [Cp*RhCl2]2.
Herein, we describe the concise synthesis of a fungal
metabolite, (+)-fusarochromanone (FC-101)16 [(+)-2] (Figure
2), via the acetamide-directed oxidative olefination of an N-
acetyl aminochromanone with an unactivated alkene catalyzed
by an electron-deficient rhodium(III) complex 1 as a key step.
The
transition-metal-catalyzed
direct
oxidative
(dehydrogenative) sp2 C−H bond olefination is a good
alternative to the well-known Mizoroki-Heck reaction for the
synthesis of styrene derivatives.1–6 This useful transformation
is catalyzed by palladium(II),2 rhodium(III),3 ruthenium(II),4
iridium(III),5 and cobalt(III)6 complexes. As no preactivation
or prefunctionalization of both coupling partners is required
and only water is generated as a byproduct, this process is
highly attractive from the viewpoint of atom-7 and step-
economy.8 In fact, a notable report for the highly efficient
synthesis of a biologically active natural product by using this
protocol was reported in 2011.9,10 The Yu group achieved the
highly efficient convergent total synthesis of (+)-Lithospermic
acid via the palladium(II)-catalyzed and carboxyl-directed
oxidative olefination of the aromatic sp2 C−H bond with a
densely functionalized acrylate.11 This report employed an
“activated” alkene as a coupling partner, while only a single
example of the synthetic application of the oxidative
olefination with an “unactivated” alkene has been reported. In
2013 the Jia group achieved the total synthesis of Clavicipitic
acid, however, the yield of the key olefination step was low
(31% yield, a mixture of olefinated and cyclized products) and
required harsh conditions (100 °C).11
NH2
O
NH2
O
HO
Me
Me
O
Figure 2. (+)-Fusarochromanone (FC-101) [(+)-2].
Fusarochromanone (2) is a mycotoxin, produced by the
symbiotic fungus, Fusarium equiseti. Its isolation16a and
structural determination16b were first accomplished by
Mirocha and co-workers. As this compound showed various
pharmaceutical activities, such as angiogenesis inhibitory
activity and anticancer activity, toxicological and
pharmacological studies of
2
have been extensively
performed.16c–e However, on the contrary, synthetic studies of
2 have been quite limited.17
(+)-fusarochromanone [(+)-2]
1. Wacker oxidation
2. deprotection
NH
O
O
O
O
Mizoroki-Heck
(ref 17)
2
NHCbz
I
R
AcO
NPG
NH
O
O
H
H
Me
Me
PGO
On the other hand, our research group recently reported
the oxidative sp2 C−H bond olefination of acetanilides with
“unactivated” alkenes catalyzed by an (electron-deficient η5-
cyclopentadienyl)rhodium(III) complex, [CpERhCl2]2 (1)12
(Figure 1).13,14 In sharp contrast, a commercially available
(electron-rich η5-cyclopentadienyl)rhodium(III) complex,
[Cp*RhCl2]2 (Figure 1), did not catalyze this reaction at all.
Thus tuning of cyclopentadienyl ligands frequently shows a
beneficial effect on reactivity and selectivity in the
rhodium(III)-catalyzed reactions.15 The mildness of our
reaction conditions (at room temperature under air) and the
expansive substrate scope including “unactivated” alkenes as
well as “activated” ones prompted us to apply this CpERh(III)-
catalyzed oxidative olefination to the synthesis of natural
products or biologically active compounds.
Me
Me
oxidative
olefination
(this work)
Ac
O
O
NH
R = H or Ac
NH
H
PG = protective group
Me
Me
Scheme 1. Synthetic strategies to (+)-fusarochromanone [(+)-2].
The key for the synthesis of (+)-2 is functionalization of
an aminochromanone skeleton with a chiral aminoalcohol side
chain, because the aminochromanone is a readily available
synthetic unit. In the previously reported synthesis, the
functionalization of the aminochromanone unit was
accomplished by the palladium(0)-catalyzed Mizoroki-Heck
reaction of an iodochromanone derivative with an acetyl- and

2
Cbz-protected chiral vinyl-aminoalcohol (Scheme 1, above).17
However, the yield of this step was very low (30%) and the
low-yielding regioselective prefunctionalization (iodination,
44%) of the aminochromanone was necessary. Therefore, the
direct introduction of the chiral aminoalcohol side chain to the
aminochromanone unit by our oxidative olefination protocol
using 1 as a precatalyst is highly attractive (Scheme 1,
bottom).
Ac
5 mol % 1
20 mol % AgSbF
40 mol % Cu(OAc) •H O
Ac
3
R
NH
NH
6
3
4
1
2
1
2
2
2
R
R
R
R
R
R
+
4
R
acetone, rt, 72 h
under air
4
6 (1 equiv)
7
a
entry
4
6
7 / yield (%)
O
Ac
NH
O
O
Ac
O
NH
NH
O
The concise synthesis of (+)-fusarochromanone [(+)-2]
via our oxidative olefination protocol as a key step was
accomplished as shown in Scheme 2. First, commercially
available aminochromanone 3 was acetylated with acetic
anhydride to give N-acetyl aminochromanone 4a in 80% yield,
O
NH
Me
O
Me
Me
Me
O
b
1
4a
4a
6b
7ab / 59%
7ab / 71%
2
6b
O
Ac
Ac
NH
O
in order to install
a
directive acetyl group for the
O
O
O
NH
O
O
O
regioselective sp2 C−H bond olefination. Commercially
available chiral vinyl-aminoalcohol (–)-5 (>97% ee) was
converted to vinyl-oxazolidinone (+)-6a in 82% yield by
treatment with triphosgene according to the literature
procedure.18 Vinyl-oxazolidinone (+)-6a was employed as a
coupling partner in place of the acetyl- and Cbz-protected
vinyl-aminoalcohol shown in Scheme 1, in order to avoid the
undesired olefination of the Cbz group and minimize steric
hindrance. The key oxidative olefination of 4a with (+)-6a
was conducted in the presence of a cationic rhodium(III)/CpE
catalyst, generated in situ from 1, AgSbF6, and
Cu(OAc)2•H2O, at room temperature under air. Fortunately,
the desired olefinated product (+)-7aa was obtained in 78%
yield with 99% ee without formation of regioisomers.19 Next,
the Wacker-type oxidation of the C−C double bond using
Pd(OAc)2, p-benzoquinone, and HClO4 afforded the desired
ketone (+)-8 in good yield (65%).20 Finally, deprotection of
oxazolidinone (+)-8 with aq HCl in 1,4-dioxane afforded free
aminoalcohol (+)-2 (fusarochromanone) in 74% yield with a
slight decrease of the ee value (97% ee). Thus, the concise
synthesis of (+)-fusarochromanone was completed in only 4
linear steps and 30 and 31% overall yields from commercially
available starting materials 3 and (–)-5, respectively.
O
Me
Me
Me
O
Me
3
4a
6c
7ac / <5%
O
Ac
Ac
Ac
NH
O
O
NH
NH
O
Me
Me
NH
6a
Me
4
4b
7ba / 77%
O
O
NH
Ac
O
NH
NH
O
NH
Me
Me
5
6
7
8
4b
6b
7bb / 73%
O
O
Ac
Ac
O
O
NH
O
NH
Me
O
4b
6c
7bc / 44%
O
O
Ac
Ac
NH
O
O
NH
NH
NH
4c
Ac
(+)-6a (>97% ee)
(+)-7ca / 79%, 87% ee
O
Ac
O
NH
O
NH
Ac
O
O
O
NH
O
NH
O
2
Ac O
2
Me
Me
Me
Me
O
O
O
Ac
6c
4c
7cc / 33%
O
NH
O
O
NH
a
3
4a / 80%
Me
Me
Figure 3. Oxidative olefination of acetanilides 4a–c with
functionalized electron-rich alkenes 6a–c. 4 (0.30 mmol), 6 (0.30
mmol), 1 (0.015 mmol), AgSbF6 (0.060 mmol), Cu(OAc)2•H2O (0.12
mmol), and acetone (1.5 mL) were used. Isolated yields. 1 (0.0075
mmol), AgSbF6 (0.030 mmol), and Cu(OAc)2•H2O (0.060 mmol) were
used.
O
triphosgene
NH •HCl
2
NH
O
(+)-7aa / 78%, 99% ee
HO
a
b
(–)-5 (>97% ee)
(+)-6a / 82%
Pd(OAc)
2
p-benzoquinone
aq HClO
4
O
O
NH
O
NH
O
O
Ac
2
2
NH
O
NH
O
O
analogs under the same reaction conditions as the synthesis of
7aa (Figure 3). Not only vinyl-oxazolidinone 6a (Scheme 2)
but also vinyl-oxazinone 6b was able to react with N-acetyl
aminochromanone 4a, while the reaction was slower than that
of 6a with 4a to give the corresponding olefinated products
7ab in moderate yield (59%, entry 1). Thus, increasing the
catalyst loading to double the amounts increased the yield of
7ab to 71% (entry 2). Unfortunately, dioxolanone 6c showed
poor reactivity toward 4a (entry 3).21 Not only N-acetyl
aminochromanone 4a but also 2-methylacetanilide (4b,
entries 4–6) and acetanilide (4c, entries 7 and 8) could be
employed for this process. Unfortunately, in the reaction of 4c
with (+)-6a (>97% ee), partial racemization was observed to
aq HCl
HO
Me
Me
Me
Me
(+)-fusarochromanone [(+)-2] / 74%, 97% ee
(30% from 3 and 31% from 5)
(+)-8 / 65%, 99% ee
Scheme 2. Concise synthesis of (+)-fusarochromanone [(+)-2]. a 4a (1
equiv), (+)-6a (1 equiv), 1 (2.5 mol %), AgSbF6 (10 mol %), and
Cu(OAc)2•H2O (20 mol %) in acetone under air at rt for 16 h.
The present oxidative olefination protocol was applied to
various acetanilides 4a–c and functionalized electron-rich
alkenes 6a–c, possessing protected aminoalcohol (6a and 6b)
and diol (6c) moieties, for the synthesis of fusarochromanone

3
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In conclusion, we have achieved the concise synthesis of
a fungal metabolite, (+)-fusarochromanone (FC-101), via the
oxidative sp2 C−H bond olefination of an N-acetyl
aminochromanone with a chiral functionalized electron-rich
4
alkene
catalyzed
by
an
(electron-deficient
η5-
cyclopentadienyl)rhodium(III) complex, [CpERhCl2]2, under
ambient conditions as a key step. This protocol was applied to
various acetanilides and functionalized electron-rich alkenes
for the synthesis of fusarochromanone analogs. Future work
will focus on further application of our CpERh(III)-catalyzed
oxidative sp2 C−H bond functionalization reactions to the key
step of the total synthesis of natural products or biologically
active compounds.
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This work was supported partly by ACT-C from the
Japan Science and Technology Agency (JST, Japan), Grants-
in-Aid for Scientific Research (Nos. 26102004 and 25105714)
from the Ministry of Education, Culture, Sports, Science and
Technology (MEXT, Japan), and a Grant-in-Aid for Research
Activity Start-up (No. 15H06201) from Japan Society for the
Promotion of Science (JSPS, Japan). We are grateful to
Umicore for generous support in supplying the rhodium
complex.
11
12
13
14
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In sharp contrast, no reaction was observed by using [Cp*RhCl2]2
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(<40%), and a mixture of by-products were observed other than a
trace amount of the desired olefinated product 7ac.
3
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