Biomimetic Total Synthesis of Scabellone B

Article abstract of DOI:10.1055/s-0037-1610178

A biomimetic total synthesis of scabellone B is described. Through sequential regioselective introduction of a geranyl group by means of silyl protection, oxidative dimerization, and biomimetic oxo-6π electrocyclization with good cyclization selectivity,

Full text of DOI:10.1055/s-0037-1610178

SYNLETT
0
9
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6
-
5
2
1
4
1
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2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
A
en
T. Yu et al.
Letter
Synlett
Biomimetic Total Synthesis of Scabellone B
Tao Yu
O
Xin Shu
O
Kewu Yang
O
O
O
Xiangdong Hu*
O
O
biomimetic oxo-6π
O
O
O
O
4 steps
33%
electrocyclization
+
Department of Chemistry and Material Science,
Key Laboratory of Synthetic and Natural Functional
Molecule Chemistry of Ministry of Education of
China, Northwest University, Xi’an 710127, P. R. of
China
excellent cyclization
selectivity & yield
O
Br
O
O
OH
xiangdonghu@nwu.edu.cn
scabellone B
Received: 03.03.2018
Accepted after revision: 15.05.2018
Published online: 18.06.2018
We proposed a divergent biosynthetic hypothesis for
scabellones A–D (Scheme 2). Biquinone 6 might be the
common starting point for the biosyntheses of these natu-
ral products. The oxo-6π electrocyclization of 6 could
proceed by three different pathways. In Path A, intermedi-
ate I might be formed under basic conditions, generating
scabellone B (2) through cyclization between the two
quinone rings. In Path B, intermediate II might be formed.
Oxo-6π electrocyclization of the bottom portion would
then lead to the formation of scabellone A (1). For the
DOI: 10.1055/s-0037-1610178; Art ID: st-2018-b0134-l
Abstract A biomimetic total synthesis of scabellone B is described.
Through sequential regioselective introduction of a geranyl group by
means of silyl protection, oxidative dimerization, and biomimetic oxo-
6π electrocyclization with good cyclization selectivity, a biomimetic
approach to scabellone B was achieved in five steps and 32% overall
yield.
Key words total synthesis, protecting groups, dimerization, electro-
cyclic reactions, natural products
Scabellones A–D (1–4; Figure 1) are four meroter-
penoids isolated from the New Zealand ascidian Aplidium
scabellum by Copp and co-workers1 during their explora-
tions on anti-inflammatory and antimalarial natural prod-
ucts.2 Notably, during biological evaluations, scabellone B
(2) exhibited selective antimalarial activity toward Plasmo-
dium falciparum (IC50 4.8 μM), and no detectable apoptosis
toward human neutrophils, indicating its potential as a
novel lead compound for the development of new treat-
ments for malaria. Furthermore, the molecular structures
of 1–4 contain a benzo[c]chromene-7,10-dione skeleton
rarely found in natural products.
O
O
O
O
O
O
OH
O
O
O
O
OH
scabellone A (1)
scabellone B (2)
Their interesting biological feature and molecular struc-
tures make these natural products interesting targets for
synthetic chemists. The first synthesis was reported by
Copp and co-workers.3 This pioneering work, based on an
oxidative dimerization/oxo-6π electrocyclization of hydro-
quinone 5 (Scheme 1), proved the feasibility of biomimetic
synthetic pathways, albeit with a low yield. To facilitate fur-
ther biological evaluations of these compounds, especially
scabellone B, new synthetic routes with better efficiency
are required.
O
O
O
O
O
O
O
O
O
O
O
O
Me
Me
scabellone C (3)
scabellone D (4)
Figure 1 Structures of scabellones A–D
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
T. Yu et al.
Letter
Synlett
generation of scabellones C and D (Path C), a successive
oxo-6π electrocyclization/cyclization/aerial oxidation pro-
cess of 6 might be involved, as demonstrated later (see
Scheme 4 below). Therefore, attaining good selectivity of
these cyclization pathways could be pivotal, but might be
difficult.
Our synthesis started with the preparation of biquinone
6 (Scheme 3). The symmetric biquinone skeleton is a core
structure that is also present in other natural products,
including parvistemin A,4 diperezone,5 and popolohuanone
E.6 Oxidative dimerization of the corresponding phenol
compounds has been verified as a facile strategy.7 The
preparation of phenol 10 was first carried out. To attain
good regioselectivity for the introduction of the geranyl
group in 10, we used a silyl-protecting approach. Silyl
derivative 8, readily prepared by TMS protection of 1,2,4-
trimethoxybenzene (7), was treated with butyllithium and
geranyl bromide to give diene 9 in 81% yield. Subsequent
deprotection afforded the desilylated product 10 in excel-
lent yield. Oxidative dimerization of 10 was attempted by
using various oxidants: DDQ, PhI(OAc)2, K3Fe(CN)6, Ag2O,
Pb(OAc)4, and CAN.8 The expected biquinone 6 was ob-
tained only upon treatment with CAN. Decreasing the reac-
tion temperature slightly improved the yield of 6.
O
O
OH
OH
O
oxidative dimerization/
oxo-6π electrocyclization
O
O
O
OH
scabellone A (1, 11%)
5
O
O
O
O
O
O
O
+
+
We then moved on to the biomimetic oxo-6π electro-
cyclization9 process, with the hope of attaining a good
cyclization selectivity among the three plausible reaction
pathways (Scheme 2). Various bases were used in the
cyclization of 6 (Table 1). With pyridine as the base, scabel-
lone B and scabellone A were formed in 40% and 22% yield,
O
O
O
OH
O
scabellone B (2, 3%)
scabellone C (3, 1%)
Scheme 1 The pioneering syntheses of scabellones A–C
O
O
O
O
O
O
O
O
O
OH
O
O
O
O
O
O
OH
O
Me
scabellone C (3)
scabellone D (4)
scabellone B (2)
scabellone A (1)
Path C
O
O
O
O
O
O
O
O
O
O
O
Path A
Path B
O
O
O
O
O
O
O
I
6
II
Scheme 2 Proposed biosynthetic pathways to scabellones A–D starting from biquinone 6
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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T. Yu et al.
Letter
Synlett
Table 1 Oxo-6π Electrocyclization of 6 and Synthesis of Scabellone B
O
O
O
O
O
O
OH
O
+
O
O
O
OH
O
scabellone B (2)
scabellone A (1)
O
O
conditions
O
O
O
O
O
O
O
O
O
+
+
6
O
O
O
O
O
O
scabellone C (3)
scabellone D (4)
Entry
Conditionsa
Yieldb (%)
2
40
10
0
1
3
0
4
0
1
2
3
4
5
6
7
8
pyridine, CH2Cl2
CuCl, pyridinec
22
0
42
0
21
0
1,10-phenanthroline, CH2Cl2
K2CO3, CH3OH, H2O
0
23
18
36
62
95
0
0
0
2,6-lutidine, CH2Cl2
0
0
0
4-methylpiperidine, CH2Cl2
2-methylpiperidine, CH2Cl2
Et3N, CH2Cl2
0
0
0
0
0
0
0
0
0
a Reactions were carried out at room temperature with 2.5 equivalents of the base.
b Isolated yields.
c 0.5 equivalents of CuCl were used.
respectively (Table 1, entry 1). When Copp’s conditions
were tested for the oxo-6π electrocyclization (entry 2),
scabellone C was obtained as the major product, together
with low yields of scabellones B and D. As a result, our
hypothesis that scabellones A–D might be formed through
three different oxo-6π electrocyclization pathways from bi-
quinone 6 is reasonable. To our delight, scabellone B was
obtained as the sole product under other basic conditions
(entries 4–7). Furthermore, treatment of 6 with triethyl-
amine led to the formation of scabellone B in almost quan-
titative yield (entry 8).10 The spectroscopic data for synthet-
ic scabellone B matched the reported values for the natural
sample.
facilitating this process, affording scabellones C and D in
56% and 15% yield, respectively. We proposed that interme-
diate 11 is initially generated through isomerization of
scabellone A. Subsequent cyclization furnishes intermedi-
ate 12, and scabellones C and D are finally formed through
an aerial oxidation process.
In summary, a biomimetic synthetic route to scabellone
B has been developed. Biquinone 6 was readily prepared by
regioselective introduction of a geranyl group through silyl
protection and subsequent oxidative dimerization. Selec-
tive oxo-6π electrocyclization of
6 was successfully
achieved in the presence of triethylamine, facilitating the
synthesis of scabellone B with good synthetic efficiency,
which should promote further biological studies on scabel-
lone B.
Later, we found that scabellone A (1) could be trans-
formed into scabellones C and D in deuterated chloroform
(Scheme 4). Furthermore, CuCl was proved to be capable of
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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Letter
Synlett
Funding Information
OMe
OMe
MeO
TMS
MeO
n-BuLi, TMEDA, 0 °C
n-BuLi, TMEDA, –78 °C
The project is supported by the National Natural Science Foundation
of China (21772153, 21642006), the Key Science and Technology
Innovation Team of Shaanxi Province (2017KCT-37), and the China
TMSCl, THF 96%
geranyl bromide, 81%
OMe
OMe
OMe
Postdoctoral Science Foundation (334100041).
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Supporting Information
MeO
TMS
MeO
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610178.
KI, TMSCl
EtOAc, r.t.. 87%
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References and Notes
conditions
(1) Chan, S. T. S.; Pearce, A. N.; Januario, A. H.; Page, M. J.; Kaiser, M.;
McLaughlin, R. J.; Harper, J. L.; Webb, V. L.; Barker, D.; Copp, B. R.
J. Org. Chem. 2011, 76, 9151.
O
(2) (a) Pearce, A. N.; Chia, E. W.; Berridge, M. V.; Clark, G. R.; Harper,
J. L.; Larsen, L.; Maas, E. W.; Page, M. J.; Perry, N. B.; Webb, V. L.;
Copp, B. R. J. Nat. Prod. 2007, 70, 936. (b) Pearce, A. N.; Chia, E.
W.; Berridge, M. V.; Maas, E. W.; Page, M. J.; Harper, J. L.; Webb,
V. L.; Copp, B. R. Tetrahedron 2008, 64, 5748. (c) Appleton, D. R.;
Chuen, C. S.; Berridge, M. V.; Webb, V. L.; Copp, B. R. J. Org. Chem.
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Kaiser, M.; Copp, B. R. Eur. J. Med. Chem. 2013, 69, 22. (f) Harper,
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Valentin, A.; Barker, D.; Copp, B. R. Mar. Drugs 2015, 13, 5102.
(g) Cadelis, M.; Bourguet-Kondracki, M.-L.; Dubois, J.; Valentin,
A.; Barker, D.; Copp, B. R. Bioorg. Med. Chem. 2016, 24, 3102.
conditions
isolated yield of 6
O
O
DDQ, CH3CN, r.t.
0%
0%
0%
0%
0%
PhI(OAc)2, CH3CN, r.t.
K3Fe(CN)6, KOH, CH3OH, r.t.
Ag2O, AcOH, CH3CN, r.t.
Pb(OAc)4, CH2Cl2, 0 °C
CAN, CH3CN,H2O, r.t.
CAN, CH3CN,H2O, –40 °C
O
O
32%
49%
O
6
Scheme 3 Synthesis of biquinone 6
O
O
O
O
O
O
O
O
O
O
OH
CuCl
+
CDCl3
O
O
O
O
O
O
O
scabellone A (1)
scabellone C (3) 56%
scabellone D (4) 15%
aerial oxidation
O
OH
O
O
OH
cyclization
O
O
OH
OH
O
O
O
11
12
Scheme 4 Transformation of scabellone A into scabellones C and D
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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Letter
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(10) Scabellone B
Et3N (47 mg, 0.54 mmol) was added to solution of biquinone 6
(100 mg, 0.18 mmol) in CH2Cl2 (5 mL), and the mixture was
stirred for 5 min. The mixture was then concentrated by
vacuum and purified by column chromatography (silica gel) to
give a purple oil; yield: 95 mg (95%); Rf = 0.3 (EtOAc–PE, 1:5). IR
(CCl4): 3467, 2922, 1684, 1594, 1221, 750 cm–1 1H NMR (400
.
MHz, CDCl3): δ = 6.40 (s, 1 H), 6.00 (d, J = 8 Hz, 1 H), 5.79 (s, 1 H),
5.50 (s, 1 H), 5.27 (d, J = 8 Hz, 1 H), 5.05 (m, 1 H), 5.00 (t, J = 4 Hz,
1 H), 4.93 (t, J = 4 Hz, 1 H), 3.88 (s, 3 H), 3.79 (s, 3 H), 3.57 (m, 1
H), 3.36 (dd, J = 12 Hz, 1 H), 1.94–1.98 (m, 4 H), 1.92–1.94 (m, 2
H), 1.92 (s, 3 H), 1.85–1.87 (m, 2 H), 1.62 (s, 3 H), 1.59 (s, 3 H),
1.56 (s, 3 H), 1.50 (s, 3 H), 1.49 (s, 3 H). 13C NMR (100 MHz,
CDCl3): δ = 182.7, 178.9, 158.0, 151.5, 150.2, 144.5, 139.3, 137.7,
137.2, 131.9, 131.8, 130.9, 127.0, 124.4, 124.0, 123.7, 117.0,
111.2, 107.4, 98.5, 67.8, 56.3, 56.2, 40.0, 39.9, 26.7, 26.5, 26.3,
25.7, 25.7, 17.7, 17.6, 17.4, 16.7. HRMS (ESI+): m/z [M + H]+ calcd
for C34H43O6, 547.3054; found: 547.3041.
(9) (a) Linn, B. O.; Shunk, C. H.; Wong, E. L.; Folkers, K. J. Am. Chem.
Soc. 1963, 85, 239. (b) Schudel, P.; Mayer, H.; Metzger, J.; Rüegg,
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E