Asymmetric synthesis and biosynthetic implications of (+)-fusarisetin A

Article abstract of DOI:10.1002/anie.201202455

Starting from equisetin, the asymmetric synthesis of (+)-fusarisetin A has been accomplished in a one-pot transformation including a biomimetic oxidation and an intramolecular Diels-Alder/Roskamp reaction. Peroxyfusarisetin is proposed as a plausible biosynthetic intermediate based on studies of the oxidation of equisetin. Copyright

Full text of DOI:10.1002/anie.201202455

Angewandte
Chemie
DOI: 10.1002/anie.201202455
Natural Products
Asymmetric Synthesis and Biosynthetic Implications of
(+)-Fusarisetin A**
Jun Yin, Cheng Wang, Lili Kong, Shujun Cai, and Shuanhu Gao*
The fungal metabolite (+)-fusarisetin A [(+)-1; Figure 1],
produced by the soil fungus Fusarium sp. FN080326, potently
inhibits acinar morphogenesis, cell migration, and cell inva-
sion in MDAMB-231 cells.[1] Tests of cell growth and cell
death using the same cell line showed that (+)-1 does not
exhibit significant cytotoxicity. These findings suggest that
(+)-1 holds promise as a valuable anticancer agent. We aim to
develop an efficient synthetic route to enable structure–
activity relationship studies of this compound and facilitate
the target identification studies. As a first step, we report
herein a concise synthesis of (+)-1 and its potential biosyn-
thetic pathway.
Equisetin (3) is another secondary metabolite isolated
from Fusarium sp. and contains the basic skeleton (A,B, and E
rings) of (+)-1 but is at a lower oxidation state.[2] It is
reasonable to assume that (+)-1 is derived from 3 through an
oxidative cascade sequence (Scheme 1).[8] According to this
proposed biosynthetic pathway, single-electron oxidation of 3
would give the radical intermediate 5, which would undergo
Figure 1. Fusarisetin A [(+)-1] and its proposed biosynthetic precursors
peroxyfusarisetin (2) and equisetin (3).
(+)-Fusarisetin A (1) possesses unique structural charac-
teristics: 1) a fused pentacyclic ring system (A,B,C,D,E)
which contains a trans decalin (A,B), a spiroskeleton (C,E),
and a tetramic acid moiety fused with a tetrahydrofuran ring
(D,E); and 2) 10 stereocenters, including two all-carbon
quaternary centers (C1, C16). Structurally related natural
products possessing tetramic acid rings include equisetin
(3),[2] diaporthichalasin,[3] integramycin,[4] tirandamycin,[5] and
others.[6] Recently, Li and co-workers reported the first
synthesis of (ꢀ)-1 and revised its absolute configuration.[7]
Theodorakis and co-workers later proposed 3 to be the
biosynthetic precursor of 1 and accomplished a biomimetic
synthesis of (ꢀ)-1.[8]
Scheme 1. Proposed biosynthetic pathway of (+)-fusarisetin A [(+)-1]
and equisetin (3).
a 5-exo cyclization to yield 6.[9] Under anaerobic conditions
(Pathway A), a second single-electron oxidation would afford
1 via cation 7. Under aerobic conditions (Pathway B), the
radical 6 may trap oxygen to give peroxyfusarisetin (2), which
could then be reduced to (+)-1. The trans-decalin unit of 3 is
likely produced from the polyene tetramic acid 4 by an
intramolecular Diels–Alder reaction (IMDA).[10] This IMDA
strategy was first used by Dixon, Ley, and co-workers to
synthesize 3 in 2000,[2e] and also adopted by Li and co-
workers,[7] as well as Theodorakis and co-workers[8] to
synthesize (ꢀ)-1.
[*] J. Yin,[+] C. Wang,[+] L. Kong, S. Cai, Prof. Dr. S. Gao
Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, Department of Chemistry, East China Normal University
3663N Zhongshan Road, Shanghai 200062 (China)
E-mail: shgao@chem.ecnu.edu.cn
[+] These authors contributed equally to this work.
Guided by this biosynthetic analysis, we developed the
synthetic strategy outlined in Scheme 2. We envisioned that
preparation of (+)-1 could be achieved using either the
biosynthetic Pathway A or B. The tetramic acid moiety of 3
could be installed through the aminolysis/Dieckmann cycli-
zation of b-keto ester 8 and the (S)-serine derivative 9.[2d] An
[**] Financial support was provided by the “Yingcai Program” of East
China Normal University, the NSFC (21102045), and the Shanghai
“Pujiang Program” (11PJ1402800).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202455.
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Scheme 2. Retrosynthetic analysis of (+)-fusarisetin A [(+)-1] and
equisetin (3).
IMDA/Roskamp reaction could be used to construct the
trans-decalin 8 from the polyene 10 and ethyl diazoacetate
11.[2e,d] In turn, 10 could be easily prepared through Wittig and
Horner–Wadsworth–Emmons (HWE) olefinations of 12 with
the ylide 13 and phosphonate 14.
Scheme 3. Preparation of equisetin (3). Reagents and Conditions:
a) 13 (1.1 equiv), 258C, CH2Cl2, 12 h, E/Z=16:1, 91%. b) HCl (1.0n),
608C, 4 h, MeOH. c) 14 (1.3 equiv), LHMDS (1.4 equiv), 30 min, then
16 (1.0 equiv), ꢀ788C!258C, 16 h, THF, E/Z>15:1, 63% in 2 steps.
d) DIBAL (2.2 equiv), CH2Cl2, ꢀ788C, 3 h, 94%. e) Dess–Martin per-
iodinane (1.5 equiv), H2O (1.5 equiv), CH2Cl2, 10 min, 258C.
f) BF3·OEt2 (3.0 equiv), ꢀ788C, CH2Cl2, 20 min, then 11 (3.0 equiv),
08C, 1.5 h, 47% in 3 steps. g) 9 (2.0 equiv), DMAP (2.0 equiv),
toluene, 1188C, 18 h, 68%; h) NaOMe (1.0 equiv), MeOH, 258C, 2 h,
72%. i) HF, CH3CN, 258C 2 h, 95%. DIBAL=diisobutylaluminum
hydride, DMAP=4-(dimethylamino)pyridine, LHMDS=lithium hexa-
methyldisilazide, THF=tetrahydrofuran.
Our synthesis commenced with the preparation of 12 from
(+)-citronellal using a previously described two-step proce-
dure (Scheme 3).[11] Treating 12 with the ylide 13 provided 15
in 91% yield (E/Z = 16:1). Removal of the ethylene glycol
gave 16, which was used directly without purification. The
HWE olefination of 16 and phosphonate 14[2e] converted 16
into triene 17 in 63% yield. The reduction of 17 with DIBAL
yielded the allylic alcohol 18, which was easily oxidized to
polyene 10 using Dess–Martin periodinane (DMP). To
construct the trans-decalin moiety, we extensively surveyed
the reaction conditions and found that BF3·OEt2, Et2AlCl, or
silica gel (during chromatography) promoted the IMDA
reaction of 10 with good selectivity (d.r. = 9:1). We further
found that the Roskamp reaction of the resulting aldehyde 19
and 11 could also be promoted by BF3·OEt2 in one pot, thus
giving 8 in 47% yield over three steps from 18. Finally, the
total synthesis of 3 was completed using the aminolysis and
Dieckmann cyclization sequence reported by Danishefsky.[2d]
We anticipated that 3 would be readily oxidized by single-
electron oxidants as it contains a tricarbonyl system which
exists as a mixture of keto/enol tautomers. Manganese(III)
acetate has been shown to be an effective oxidant for
enolizable carbonyl compounds.[12] The initial application of
manganese(III) to oxidative radical cyclizations was reported
by Corey and Kang,[13] Ernst and Fristad,[14] and Snider and
co-workers[12a,c–g] in the 1980s. To date, radical reactions
promoted by manganese(III) have been widely used in
organic synthesis, especially natural product synthesis.[15] We
therefore expected that the biomimetic oxidation of 3 could
be realized with Mn(OAc)3 to give (+)-fusarisetin A by either
Pathway A or Pathway B.
We first found that, under anaerobic conditions, the C ring
can be successfully formed by oxidizing 3 with Mn(OAc)3, but
all attempts to induce the formation of the D ring to yield
(+)-1 or trap 6 as an acetate failed (Scheme 4A). The
elimination product was obtained as the major product even
in the presence of Cu(OAc)2 or Yb(OTf)3. For example,
oxidation of 3 with Mn(OAc)3 (2.0 equiv) and Cu(OAc)2
(5.0 equiv) in degassed HOAc at room temperature gave 21
in 62% yield (d.r. = 3.3:1).[16] On the basis of Sniderꢀs
mechanistic studies,[12c–g] we believe that the highly acidic 3
first complexes with Mn(OAc)3 to form the manganese
enolate, which then cyclizes directly to give the radical 6
without the formation of 5. Oxidation of 6 proceeded through
the copper(III) intermediate 7ꢀ to give 21 through a Hofmann
elimination with loss of CuOAc and HOAc.[12c,h-j]
We next found that, under aerobic conditions,[17] both the
C ring and “D ring” can be formed by oxidizing 3 with
Mn(OAc)3 (Scheme 4B). Oxidation of 3 with Mn(OAc)3
(2.0 equiv) in either air or 1 atm O2 in HOAc at room
temperature gave peroxyfusarisetin (2) and 5-epi-2 as insep-
arable diastereomers in 62% yield (d.r. = 1.3:1).[18] Reduction
of 2 and 5-epi-2 with Zn/HOAc furnished (+)-fusarisetin A
(1) and 5-epi-1[7] in a 75% combined yield. The spectroscopic
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Scheme 4. Key transformations in the synthesis of (+)-fusarisetin A [(+)-1] from equisetin (3) and mechanistic analyses. Reagents and
Conditions: a) Mn(OAc)3·2H2O (2.0 equiv), Cu(OAc)2 (5.0 equiv), 258C, degassed HOAc, 2 h, 258C, d.r.=3.3:1, 62%. b) Mn(OAc)3·2H2O
(0.1 equiv), air or 1 atm O2, 258C, HOAc, 2 h, then Zn (30.0 equiv), 508C, 2 h, 41%.
data (1H and 13C NMR spectra, as well as HRMS, and optical
rotation) of synthetic (+)-1 were fully consistent with the
corresponding data for the natural product.[1]
allows us to easily access the natural product(s) for future
biological studies. We are particularly interested in examining
the antimalarial activity of 2.
Mechanistically, this reaction should also proceed through
the radical 6, which is trapped by O2 instead of Cu(OAc)2 to
give 23 via 22.[17] A hydrogen abstraction from 3 then yielded
2 and the radical 5, which underwent a 5-exo cyclization to
provide 6 again, thus creating a catalytic cycle. Indeed, we
found that oxidation of 3 with 10 mol% Mn(OAc)3 in either
air or O2 also gave 2 and 5-epi-2 with a comparable 60% yield
(d.r. = 1.1:1).[18] The zinc reduction can be performed in situ to
give (+)-1 directly from 3 in 41% yield. While the enolate of 3
was also involved in the radical initiation step, this aerobic
oxidation proceeded mainly through radical 5, which was not
formed in the anaerobic oxidation of 3. The observation of
different diastereoselectivity in the MnIII/CuII and MnIII/O2
oxidation reactions is explained by the different intermediates
involved in the diastereoselectivity determining step.[19]
Our synthetic work suggests that the biosynthesis[20] of
(+)-1 may involve a single-electron transfer (SET) oxidation
of 3 to generate 5 and lead to the formation of 2. The labile
peroxy group has been found in the antimalarial natural
products artemisinin (Qinghaosu)[21] and yingzhaosu A[22]
(Figure 2). We suggest that peroxyfusarisetin (2) is the
biosynthetic intermediate of (+)-1 and question if the
reductive cleavage of the peroxide occurred during its
isolation. This one-pot, biomimetic synthesis of (+)-fusarise-
tin A ((+)-1) and peroxyfusarisetin (2) from equisetin (3)
In summary, we have accomplished the first asymmetric
synthesis of (+)-fusarisetin A ((+)-1). This efficient strategy
relies on our proposed biosynthetic pathway involving 1) a
one-pot IMDA/Roskamp reaction to construct the trans-
decalin skeleton, and 2) biosynthetic oxidation of equisetin
(3) promoted by MnIII/O2. Our synthetic approach has
verified the absolute configuration of naturally occurring
(+)-1, which matches that of its biosynthetic precursor 3.
Received: March 29, 2012
Revised: May 2, 2012
Published online: && &&, &&&&
Keywords: biosynthesis · natural products · peroxides ·
.
radical reactions · total synthesis
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Chemie
Communications
Natural Products
J. Yin, C. Wang, L. Kong, S. Cai,
S. Gao*
&&&& — &&&&
Asymmetric Synthesis and Biosynthetic
Implications of (+)-Fusarisetin A
Starting from equisetin, the asymmetric
synthesis of (+)-fusarisetin A has been
accomplished in a one-pot transforma-
tion including a biomimetic oxidation and
an intramolecular Diels–Alder/Roskamp
reaction. Peroxyfusarisetin is proposed as
a plausible biosynthetic intermediate
based on studies of the oxidation of
equisetin.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!