The First Racemic Total Syntheses of the Antiplasmodials Watsonianones A and B and Corymbone B

Article abstract of DOI:10.1021/acs.jnatprod.8b01077

The first biomimetic total syntheses of three biologically meaningful acylphloroglucinols, watsonianones A and B and corymbone B, with potent antiplasmodial activity, were performed. Their total syntheses were carried out through a diversity-oriented synthetic strategy from congener 2,2,4,4-tetramethyl-6-(3-methylbutylidene)cyclohexane-1,3,5-trione with high step efficiency. The spontaneous enolization/air oxidation of the precursor 2,2,4,4-tetramethyl-6-(3-methylbutylidene)cyclohexane-1,3,5-trione through a singlet O₂-induced Diels-Alder reaction pathway to assemble the key biosynthetic peroxide intermediate is also discussed.

Full text of DOI:10.1021/acs.jnatprod.8b01077

Communication
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Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX
The First Racemic Total Syntheses of the Antiplasmodials
Watsonianones A and B and Corymbone B
Xiao Zhang,†,‡,∥ Guiyun Wu,†,‡,∥ Luqiong Huo,‡ Xueying Guo,‡ Shengxiang Qiu,‡ Hongxin Liu,*,§
Haibo Tan,*,‡ and Yingjie Hu*,†
†Institute of Tropical Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, People’s Republic of China
‡Key Laboratory of Plant Resources Conservation and Sustainable Utilization, Guangdong Provincial Key Laboratory of Applied
Botany, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, People’s Republic of China
§State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture
Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology,
Guangzhou 510070, People’s Republic of China
S
* Supporting Information
ABSTRACT: The first biomimetic total syntheses of three biologically
meaningful acylphloroglucinols, watsonianones A and B and corymbone B,
with potent antiplasmodial activity, were performed. Their total syntheses
were carried out through a diversity-oriented synthetic strategy from congener
2,2,4,4-tetramethyl-6-(3-methylbutylidene)cyclohexane-1,3,5-trione with high
step efficiency. The spontaneous enolization/air oxidation of the precursor
2,2,4,4-tetramethyl-6-(3-methylbutylidene)cyclohexane-1,3,5-trione through a
singlet O2-induced Diels−Alder reaction pathway to assemble the key
biosynthetic peroxide intermediate is also discussed.
potential of a diversity-oriented synthetic strategy, which
olycyclic polymethylated phloroglucinols (PPPs) contain-
Ping a tetramethylcyclohexenedione moiety have emerged would permit efficient access to the biomimetic total syntheses
of watsonianones A and B and corymbone B (1−3),
respectively, with the aim of revealing their potential in drug
discovery and biosynthesis. Herein, we report experimental
details for the first racemic total syntheses of compounds 1−3
with the use of a bioinspired synthetic strategy, using 2,2,4,4-
tetramethyl-6-(3-methylbutylidene)cyclohexane-1,3,5-trione
(9) as the mutual synthetic precursor.
Regarding their characteristic structures, it could be
speculated that these novel natural products might biosyntheti-
cally originate from the precursors syncarpic acid (7) and
isovaleraldehyde (8) through a series of intriguing biotrans-
formations. Therefore, the retrosynthetic analysis of watsonia-
nones A and B and corymbone B (1−3) is summarized in
Scheme 1. Watsonianone A (1) and corymbone B (3) could be
formed through a Michael addition from intermediate 9.
Intermediate 9 could be formed from the common
intermediates syncarpic acid (7) and isovaleraldehyde (8) by
an organocatalyzed Knoevenagel condensation. Watsonianone
B (2) could be formed by incorporation of intermediate 10
and 2,4,6-trihydroxy-4-methydihydrochalcone via a sequential
dehydroxylation/Michael addition/Kornblum−DeLaMare per-
as attractive targets for total synthesis in recent years due to
their structural diversity, architectural complexity, and wide-
ranging biological activities.1−5 Among them, watsonianones A
and B (1 and 2) possess the first naturally occurring bis-
tetramethylcyclohexatrione skeleton and an intriguing fused
bisfurano β-triketone scaffold, respectively. Corymbone B (3)
has been disclosed to be a novel acyclic acylphloroglucinol
(Figure 1).4 All of these compounds exhibited highly
significant antiplasmodial activity against chloroquine-resistant
(Dd2) and chloroquine-sensitive strains (3D7) of Plasmodium
falciparum, which are responsible for serious malarial
infections.4,5 Specifically, watsonianone B showed the most
potent inhibitory effect with an IC50 value as low as 0.3 μM
against P. falciparum 3D7, and it demonstrated significant
selectivity versus the human cell line HEK 293 (>400-fold).4a
The remarkable biological activities and novel structural
features of the synthesized compounds render them appealing
targets for total synthesis and structure−activity relationship
studies.
In our ongoing research to discover biologically meaningful
and structurally diverse acylphloroglucinols from Chinese
medicinal plants and their chemical syntheses,6 the bio-
activities and novel structures of compounds 1−3 captured our
attention. Their structures prompted the exploration of the full
Received: December 20, 2018
© XXXX American Chemical Society and
American Society of Pharmacognosy
A
DOI: 10.1021/acs.jnatprod.8b01077
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Communication
Figure 1. Representative Polycyclic Polymethylated Phloroglucinols.
Scheme 1. Retrosynthetic Analysis of Watsonianones A and B (1 and 2) and Corymbone B (3)
Scheme 2. Synthetic Route to Watsonianone A
oxide rearrangement cascade reaction.7 Chemically, intermedi-
ate 10 could be envisioned from compound 9 through a
putative sequential transformation, which could include a
spontaneous enolization/singlet O2 Diels−Alder cycloaddition
as the key reaction.7,8
tophenone (11). Compound 11 was converted into the
precursor syncarpic acid (7) by our previously established two-
step protocol involving the selective C-methylation and
thermally promoted retro-Friedel−Crafts acylation reactions.9
Proline-catalyzed Knoevenagel condensation10 with excess
isovaleraldehyde (8) was applied to directly install the
isopentyl chain to afford precursor 9 in 95% yield. Compound
The total synthesis of watsonianone A (1), as shown in
Scheme 2, began with the commercially available phloroace-
B
DOI: 10.1021/acs.jnatprod.8b01077
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Journal of Natural Products
Communication
Scheme 3. Synthesis of Corymbone B (3) and Derivative 16
9 was transformed into the target watsonianone A (1) in 97%
yield by a proline-mediated Michael addition. Moreover, the
exploration of different catalytic condensation conditions with
the aim of directly transforming syncarpic acid (7) and
isovaleraldehyde (8) into watsonianone A (1) in one step was
also performed. Satisfyingly, when 2.0 equiv of syncarpic acid
(7) was used, the Knoevenagel condensation/Michael addition
cascade reaction11 proceeded smoothly and afforded product
watsonianone A (1) in one step in 93% yield. Therefore, the
first racemic total synthesis of watsonianone A (1) was
successfully established, and it provided a concise synthetic
route to rapidly access this bioactive molecule and its structural
derivatives.
catalyzed peroxidation seemed to be incompatible with
substrate 9 under the conditions of a 300 W medium-pressure
mercury lamp, providing peroxide 10 in 29% yield (entry 1 in
Table 1). Serendipitously, the treatment of substrate 9 under
Table 1. Partial Optimization of the Reaction Conditions
a
for the Synthesis of Peroxide 10
photo
condition
t
time
(h)
yield
b
With the synthesis of precursor 9 in place, the total
syntheses of watsonianone B (2) and corymbone B (3) were
attempted. The requisite acylphloroglucinol 15 was synthe-
sized from the commercially available aldehyde 13 in two
steps. The selective reduction of 13 with NaBH3CN under
acidic conditions afforded methylphloroglucinol (14).12
Compound 14 afforded key intermediate 15 in moderate
yield via the treatment with dihydrocinnamoyl chloride in the
presence of MSA (methylsulfonic acid) through an acid-
catalyzed Friedel−Crafts acylation. When precursor 9 was
subjected to a NaH/tetrahydrofuran (THF) solution of
dihydrochalcone 15, the Michael addition reaction afforded
corymbone B (3) in 91% yield.
entry solvent
catalyst
(°C)
(%)
c
1
2
3
4
5
6
7
8
DCM
DCM
DCM
DCM
DCM
DCM
CHCl3
THF
MeCN
MeOH
toluene
toluene
−
−
hν
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
60
rt
rt
60
6
6
29
13
10
13
<10
<10
13
12
18
<10
13
<10
35
<10
11
hν
hν
hν
hν
hν
hν
hν
hν
hν
hν
hν
hν
TFA
HOAc
PTSA
ET3N
−
−
−
−
−
−
−
−
−
12
12
12
12
12
12
12
12
12
12
24
24
12
9
10
11
12
13
14
15
1
d
−
The H NMR spectrum of corymbone B (3) in CDCl3
showed the presence of a pair of keto/enol tautomers.4b
Although its NMR and HRESIMS data (for details, see
Supporting Information) matched those of the natural isolate,
its spectroscopic assignments were difficult. Hence, corymbone
B (3) was cyclized with p-toluenesulfonic acid (PTSA) to
afford the racemic product 16, which could be readily
characterized via NMR data to confirm its structure.
Compound 16 closely resembled the known compound 6,8-
dihydroxy-9-isobutyl-2,2,4,4-tetramethyl-5-(3-phenylpropano-
yl)-4,9-dihydro-1H-xanthene-1,3(2H)-dione13 and was suc-
cessfully produced in 91% yield. The NMR spectra of
compound 16 shared close similarity (except for the lack of
a methyl moiety) with those of the aforementioned known
compound, thus confirming the structure of corymbone B (3).
The total synthesis of watsonianone B (2) commenced with
the preparation of racemic peroxide intermediate 10 according
to the previously reported protocol,7 in which the photo-
e
−
d
−
hν
a
Reaction conditions: compound 9 (0.5 mmol), solvent (3 mL), hν
b
(house light), rt, 6−12 h. Combined yield of the isolated product.
c
d
hν (300 W medium-pressure mercury lamp). Neat (solvent free).
Neat (solvent free), in the dark. DCM: dichloromethane; TFA:
e
trifluoroacetic acid; PTSA: p-toluenesulfonic acid.
ambient light conditions in an air atmosphere for 6 h led to
peroxide 10 in 13% yield (entry 2). Although the yield was
unsatisfactory, it showed promising potential because of the
mild reaction conditions. In an attempt to improve the yield of
this spontaneous enolization/air oxidation cascade sequence
under similar conditions, variables such as solvent, catalyst, and
lighting sources were screened.
The addition of catalytic Bronsted acid or base failed to
promote the transformation, whereas the solvents did influence
C
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the reaction efficiency (entries 7−12). In this way, the product
was obtained in 18% yield in MeCN. The exposure of neat 9 in
thin-film form proved to be the most effective conditions,
yielding product 10 in a 35% yield, as shown in entry 13. As
expected, no reaction occurred in the absence of light (entry
14), which strongly suggested that the reaction should take
place through a singlet O2 Diels−Alder reaction pathway.14
Normally, the singlet O2-induced Diels−Alder reaction would
require the presence of a photosensitizer; thus, these results
also indicated that the α,β-unsaturated intermediate 9 might
act as a self-photosensitizer because of its extensive conjugated
system.14,15 Elevated temperatures seemed to be detrimental
for spontaneous transformation (entry 15). Notably, the
spontaneous oxidation process coupled with the mild reaction
conditions present in the wild plant suggests a strong
possibility for the process to be biomimetic in nature, and it
may in fact mimic the actual biosynthetic generation of 10 and
its derivatives downstream.4,16
watsonianone B (2) in both the structural skeleton and
spectroscopic data. Compound 19 was purified as a solid and
1
possessed the same molecular formula as 2. The H and 13C
NMR spectroscopic data (Supporting Information) of 19 were
similar to those of 2, suggesting that the two compounds were
regioisomers. This conclusion was confirmed by the HMBC
correlations from H3-14 to C-4b, C-5, and C-6; HO-6 to C-5,
C-6, and C-7; and HO-8 to C-8 and C-8a, as well as the
correlations from H2-2′ to C-1′ and C-7, which indicated that
the phenylpropanoyl group in 19 was located at C-7. A single
crystal of 19 suitable for X-ray crystallography analysis (Cu Kα
radiation) was obtained from a CDCl3 solution, which
unequivocally confirmed the structure of 19 (Supporting
Information). Based on the aforementioned results, the
structure of compound 19 was defined and given the trivial
name iso-watsonianone B.
Scheme 5. HMBC Correlations and ORTEP Drawing of iso-
Having established the optimal conditions to access the key
intermediate 10, our efforts were focused on constructing the
bisfurano β-triketone scaffold of watsonianone B (2) through
the sequential dehydroxylation/Michael addition/Kornblum−
DeLaMare peroxide rearrangement cascade sequence.7 As
shown in Scheme 4, the acid-promoted elimination of the
Watsonianone B (19)
Scheme 4. Biomimetic Total Syntheses of Watsonianone B
(2) and iso-Watsonianone B (19)
Compounds 2 and 19 were thus shown to be regioisomers,
as expected from the two phenolic groups that may participate
in the cyclization process. A similar regioisomeric cyclization
has been reported in rhodomyrtone and rhodomyrtosone B
natural products.17 Compound 19 was stable at room
temperature and could be separated by silica gel column
chromatography. iso-Watsonianone B (19) and watsonianone
B (2) could be tautomerized in refluxing HOAc. The
equilibrium between iso-watsonianone B (19) and watsonia-
none B (2) could be attributed to the reversibility of ketal
formation under acidic conditions. In this regard, it is possible
that the series of natural products belonging to the bisfurano β-
triketone family might also exist as complex mixtures of
regioisomers, although compelling evidence from a naturally
occurring source has not been confirmed.
In summary, the biosynthetic hypothesis of these natural
products inspired us to explore a diversity-oriented synthetic
strategy, subsequently leading to the first biomimetic total
syntheses of antiplasmodial watsonianones A (1) and B (2)
and corymbone B (3). The results revealed the spontaneous
enolization/air oxidation of precursor 9 through a singlet O2-
induced Diels−Alder reaction pathway for the generation of
peroxide 10. The mild reaction conditions strongly suggests
the possibility of a biomimetic process in nature and may in
fact mimic the actual biosynthetic processes for the related
downstream natural products. Complementing the efficiency
and simplicity of the developed synthetic route, this method-
ology also provides a route for the rapid assembly of similar
phloroglucinol-derived products in a practical fashion and
sufficient quantities to facilitate drug discovery. Further
hydroxy group of 10 would lead to the in situ generated α,β-
unsaturated oxonium ion. Trapping of this active electrophile
with 2,4,6-trihydroxy-4-methydihydrochalcone (15) via a
Michael addition reaction afforded intermediate 17. The
subsequent Kornblum−DeLaMare peroxide rearrangement of
17 would afford the bisfurano-β-triketone scaffold via
intermediate 18. Gratifyingly, this cascade proceeded in an
efficient manner in refluxing HOAc, leading to the formation
1
of watsonianone B (2) in 27% yield. The H and 13C NMR
spectra as well as the HRESIMS data of synthetic
watsonianone B (2) fully matched those of the isolate reported
by Carroll and his co-workers (for details, see the Supporting
Information).4a
The formation of compound 19 accounted for the remaining
14% yield, and 19 showed close similarity with the product
D
DOI: 10.1021/acs.jnatprod.8b01077
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.8b01077.
■
S
Experiment procedures, NMR spectra, MS data for new
compounds, and X-ray crystallography data for com-
pound 19 (PDF)
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X. Org. Lett. 2015, 17, 4050−4053. (c) Tan, H. B.; Liu, H. X.; Chen,
X. Z.; Chen, H. Y.; Qiu, S. X. Org. Biomol. Chem. 2015, 13, 9977−
9983. (d) Zou, Z. X.; Tan, G. S.; Huang, Q.; Sun, H. H.; Huo, L. Q.;
Zhong, W. Q.; Zhao, L. Y.; Liu, H. X.; Tan, H. B. Fitoterapia 2018,
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AUTHOR INFORMATION
Corresponding Authors
*Tel/Fax: +86 20 87688612. E-mail: liuhx@gidm.cn (H.-X.
Liu).
*Tel/Fax: +86 20 37652958. E-mail: tanhaibo@scbg.ac.cn
(H.-B. Tan).
*Tel/Fax: +86 20 37652958. E-mail: yjhu01@126.com (Y.-J.
Hu).
■
(7) Gervais, A.; Lazarski, K. E.; Porco, J. A. J. Org. Chem. 2015, 80,
9584−9591.
ORCID
(8) Gavrilan, M.; Andre-Barres, C.; Baltas, M.; Tzedakis, T.;
Gorrichon, L. Tetrahedron Lett. 2001, 42, 2465−2468.
(9) Tan, H. B.; Liu, H. X.; Zhao, L. Y.; Yuan, Y.; Li, B. L.; Jiang, Y.
M.; Gong, L.; Qiu, S. X. Eur. J. Med. Chem. 2017, 125, 492−499.
(10) This Knoevenagel condensation reaction could also be
promoted by an achiral promoter like pyrrolidine with the addition
of trifluoroacetic acid; we chose proline as the catalyst because of its
better catalytic efficiency.
Haibo Tan: 0000-0002-1652-5544
Author Contributions
∥X. Zhang and G. Wu contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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5056−5068. (b) Jiang, L.; Wang, B.; Li, R. R.; Shen, S.; Yu, H. W.; Ye,
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■
We thank the National Natural Science Foundation of China
(NSFC) (Nos. 81773602, 81502949), Natural Science
Foundation of Guangdong Province (2016A030313149,
2016A010105015), Strategic Resources Service Network
Program on Plant Genetic Resources Innovation of the
Chinese Academy of Sciences (No. ZSZC-005), Pearl River
Science and Technology New Star Fund of Guangzhou
(201605120849569), and the Foundation of Key Laboratory
of Plant Resources Conservation and Sustainable Utilization,
South China Botanical Garden, Chinese Academy of Sciences.
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