Expediently Scalable Synthesis and Antifungal Exploration of (+)-Yahazunol and Related Meroterpenoids

Article abstract of DOI:10.1021/acs.jnatprod.8b00310

The efficient synthesis and antifungal exploration of (+)-yahazunol and related natural products are described. Central to this strategy is the Barton decarboxylative coupling, comprising a one-pot radical decarboxylation and quinone addition cascade. The scalable synthesis of (+)-yahazunol was accomplished in five longest linear sequences (LLS) starting from commercially available and inexpensive (-)-sclareol. The divergent translational potential of (+)-yahazunol was demonstrated by the expedient preparation of (-)-zonarone, (-)-isozonarone, (-)-zonarol, (-)-isozonarol, (+)-chromazonarol, and (+)-yahazunone. This approach also enables the formal synthesis of puupehenol, puupehedione, and hongoquercin A. Antifungal evaluation was performed, and this represents the first biological profiles for (+)-yahazunone, (+)-8-O-acetylyahazunone, and (+)-8-O-acetylyahazunol. (+)-Chromazonarol and (+)-yahazunone are promising candidates against Sclerotinia scleotiorum, with EC₅₀ values of 24.1 and 28.7 μM, respectively, demonstrating advantages over the original model (DM) and synthesized heterocyclic mimic (3a) of meroterpenoids. This will favor the establishment of a chemical repertoire in the management of different plant diseases.

Full text of DOI:10.1021/acs.jnatprod.8b00310

Article
Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX
pubs.acs.org/jnp
Expediently Scalable Synthesis and Antifungal Exploration of
+)-Yahazunol and Related Meroterpenoids
(
†
†
†
‡
§
,†
Shasha Zhang, Xia Wang, Jin Hao, Dangdang Li, Rene Csuk, and Shengkun Li*
́
†Department of Pesticide Science, College of Plant Protection, Nanjing Agricultural University, Weigang 1, Xuanwu District,
Nanjing 210095, People’s Republic of China
‡
R & D Center, Jiangsu New Energy Crop Protection Co., Ltd., 5 Xinmofan Road, Nanjing 210009, People’s Republic of China
§
Organic Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Straße 2, D-06120 Halle (Saale), Germany
*
S Supporting Information
ABSTRACT: The efficient synthesis and antifungal exploration of (+)-yahazunol and related natural products are described.
Central to this strategy is the Barton decarboxylative coupling, comprising a one-pot radical decarboxylation and quinone
addition cascade. The scalable synthesis of (+)-yahazunol was accomplished in five longest linear sequences (LLS) starting from
commercially available and inexpensive (−)-sclareol. The divergent translational potential of (+)-yahazunol was demonstrated
by the expedient preparation of (−)-zonarone, (−)-isozonarone, (−)-zonarol, (−)-isozonarol, (+)-chromazonarol, and
(
+)-yahazunone. This approach also enables the formal synthesis of puupehenol, puupehedione, and hongoquercin A.
Antifungal evaluation was performed, and this represents the first biological profiles for (+)-yahazunone, (+)-8-O-
acetylyahazunone, and (+)-8-O-acetylyahazunol. (+)-Chromazonarol and (+)-yahazunone are promising candidates against
Sclerotinia scleotiorum, with EC50 values of 24.1 and 28.7 μM, respectively, demonstrating advantages over the original model
(
DM) and synthesized heterocyclic mimic (3a) of meroterpenoids. This will favor the establishment of a chemical repertoire in
the management of different plant diseases.
o-evolving with biological systems for millions of years,
natural products often feature biologically relevant
Minor modifications of the decoration on either the
hydroquinone or the drimane subunits will lead to a number
of meroterpenoid natural products. More interestingly, some
related enantiomers exist naturally or can be produced
artificially, exemplified by (−)-yahazunol and (+)-yahazunol
(Figure 1B), which were isolated from the brown seaweed
C
pharmacophores that have resulted in preferred ligand−protein
1
binding motifs. A range of uncharted chemotypes were
discovered and developed as chemical probes and drugs from
2
natural products or their intricate frameworks. Natural
9
products also occupy a privileged space in novel agrochemical
Dictyopteris undulata Okamura in 1979 and a sponge of the
10
discovery, with up to 50% of pesticide sales (in 2012) and
genus Dysidea in 2005, respectively. (−)-Yahazunol showed a
strong antimicrobial activity against some yeasts, and
(+)-yahazunol demonstrated modest inhibition against
human tumor cell lines MDA-MB-231 and A-549. (−)-Yaha-
zunol-related natural products, including zonarol, isozonarol,
3
>
60% of all action mechanisms of pesticides inspired by them.
Biologically important natural products have been serving as
powerful weapons for human beings in the competition with
various pests. Meroterpenoids are an assembly of sesquiterpene
and phenolic or quinone moieties. They possess versatile
bioactivities ranging from anticancer and anti-HIV to
11,12
zonarone, and isozonarone, were isolated,
some of which
are fungitoxic toward Phytophthora cinnamomic, Rhizoctonia
solani, and Sclerotinia sclerotiorum. Feeding-deterrent activity
4
antifungal potentials. In continuing efforts to discover novel
13
5
−8
was reported for cyclozonarone. There are no reports
agrochemicals based on natural products,
we are interested
documenting the agrochemically antifungal potential of
in hydroquinone sesquiterpenes with a drimane skeleton
among different meroterpenoids not only for their versatile
biological activities but also for the diverse structures with a
constant scaffold as shown in Figure 1A serving as potential
respiration regulators.
(
+)-yahazunol and related enantiomers of natural products
Received: April 17, 2018
©
XXXX American Chemical Society and
American Society of Pharmacognosy
A
DOI: 10.1021/acs.jnatprod.8b00310
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Article
Figure 1. Drimane meroterpenoid model and yahazunol-related products.
Scheme 1. Versatile Protocols for the Synthesis of Drimane Meroterpenoids
Scheme 2. Retrosynthetic Analysis of (+)-Yahazunol
(
(
Figure 1C), including (+)-chromazonarol, (−)-zonarone, and
−)-isozonarone. Considering the importance of chirality in
RESULTS AND DISCUSSION
■
Retrosynthetic Analysis and Tactic Development.
1
4
agrochemical exploration and medicinal chemistry, we
previously conceived “carbon assimilation” and applied it for
the rapid and divergent construction of (+)-yahazunol mimics
from readily available materials, whereby drimanyl isoxazoline
and drimanyl pyrimidine mimics are presented as potent
antifungal leads. Herein, we document the efficient synthesis
and antifungal exploration of (+)-yahazunol and related natural
products and analogues.
15
Besides biomimetic cyclizations of polyprenoids and
16,17
catalyzed epoxypolyene cyclization
for the construction
of drimanyl meroterpenoids (Scheme 1A), applying a semi-
synthesis protocol is powerful when starting from the readily
18
available labdane-type diterpenes, including sclareol, sclar-
eolide, labdanolic acid, abietic acid, larixol, and ozic acid. This
protocol is well developed for the efficient synthesis of drimane
meroterpenoids by the coupling of a drimanyl or drimenyl
8
B
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Scheme 3. Synthesis of 8-O-Acetyl Derivatives of (+)-Yahazunol and (+)-Yahazunone
aldehyde with an organolithium compound derived from
The synthesis of the required photolabile and redox-active
1
9−22
26,28
arenes
(Scheme 1B). Recently, a seminal and divergent
thiohydroxamic ester 3 (Barton ester)
was efficiently
synthesis of bioactive meroterpenoids has been developed by
obtained from the condensation of 8-O-acetylhomodrimanic
acid (2) with 2-mercaptopyridine N-oxide applying Steglich-
esterification conditions. Shielding the reaction is necessary in
the case of the decomposition of the photosensitive
intermediate 3. Light-induced (250 W) decarboxylative
coupling of 3 with the electron-deficient benzoquinone was
achieved at 0 °C in a tandem one-pot reaction. A drimanic
radical was produced in the presence of light and trapped by
the quinone through a radical-chain process to yield semi-
quinone 4. This sequence constructs the C-11−C-16 bond in
only three steps from sclareol. In contrast, there are usually
more than six steps required for the coupling of a drimanyl
aldehyde with an organolithium compound or in the Suzuki
coupling approach with “borono-sclareolide”. In addition, the
former approach often suffers from an ensuing post-
deoxygenation of 11-hydroxymeroterpenoids under the rather
harsh conditions. Compound 4 tautomerizes to the pyridylthio
hydroquinone meroterpenoid 5, preventing further attack by a
drimanyl radical to the second dienone moiety of 4. The
pyridylthioquinone meroterpenoid 6 was obtained in good
yield (85%) by in situ oxidation of 5 with an excess of the
quinone. ESIMS analysis showed two ions at m/z 482.22 [M +
the Baran group through the invention of “borono-
2
3
sclareolide” (Scheme 1C). This allowed the synthesis of
+)-chromazonarol in six steps from (+)-sclareolide, which
(
also served as a node for (+)-yahazunol and related natural
products. Dethe and co-workers utilized Lewis-acid-catalyzed
Friedel−Crafts alkylations for the establishment of (+)-chro-
24,25
mazonarol (Scheme 1D).
Biosynthetically, the generation of (+)-yahazunol presum-
ably involves the coupling of farnesyl pyrophosphate and
hydroquinone followed by stereoselective polyene cyclization.
The generated tertiary carbocation is captured by H O
2
enantioselectively to afford (+)-yahazunol (Scheme 2A).
Inspired by this biosynthetic pathway and the elegant synthesis
26−28
of rearranged drimane meroterpenoids,
we envisioned
that the Barton ester of homodrimanic acid might be an ideal
synthon or equivalent to replace farnesyl pyrophosphate for
coupling.
From a structural standpoint and proposed biosynthesis, the
relatively “simple” (+)-yahazunol or its derivative was chosen
as the starting point for potential divergent transformations to
other related drimane meroterpenoids. The global retrosyn-
thetic analysis is depicted in Scheme 2B featuring the
connection of the drimane unit with a hydroquinone by the
establishment of the C-11−C-16 bond, through a radical
decarboxylative coupling. The starting materials for this
approach may be traced back to (−)-sclareol and quinone,
which are both commercially available and inexpensive.
Synthesis of Precursors or Analogues of (+)-Yahazu-
nol. As shown in Scheme 3, the synthetic approach started
from optically pure and bulk feedstock, (−)-sclareol (1), which
is a well-known fragrance diterpenoid isolated mainly from the
plant Salvia sclarea. This diterpenoid is used in the perfume
+
+
13
H] and 504.19 [M + Na] . The C NMR and DEPT spectra
showed the presence of 28 carbons, including five methyls, six
methylenes, eight methines, and nine nonprotonated carbons.
Two carbonyl resonances at δ 182.0 and 185.5 corroborated
C
the presence of a 1,4-benzoquinone moiety. The resonance at
1
δC 169.5 represented the acetate carbonyl carbon. The H
NMR spectrum indicated the presence of four protons in the
pyridine ring (δH 7.02, 7.34, 7.55, and 8.26), two quinone
hydrogens (δ 6.82), and five methyl singlets (δ 0.80, 0.87,
H
H
0.92, 1.60, and 1.75).
Treatment of compound 6 with Raney-nickel in EtOH at
room temperature for a few minutes (5−10 min) afforded the
acetate of (+)-yahazunol (7) in excellent yield (91%), which is
otherwise hard to achieve by regioselective esterification of
(+)-yahazunol. The ESIMS data correlated well with the
(+)-8-O-acetylyahazunol by showing two ions at m/z 397.29
2
9
industry and can be purchased even in kilogram quantities.
30
Oxidative degradation of (−)-sclareol (1) with potassium
permanganate in the presence of Ac O gave the 8-O-
2
acetylhomodrimanic acid (2) directly in moderate yield
(
42%), with sclareolide as the other major product (yield
+
+
13
3
5%). The latter can be used as a starting material in the
[M + Na] and 315.31 [M − HOAc + H] . The C NMR and
DEPT spectra showed the presence of 23 carbons, including
seven nonprotonated carbons, five methines, six methylenes,
18
synthesis of complex natural products or be hydrolyzed to
homodrimanic acid.
C
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and five methyls. The carbonyl resonance at δ 170.1 verified
at room temperature (rt) afforded (+)-chromazonarol (13) in
C
1
the preservation of the ester moiety during Raney-nickel
up to 94% yield. The structure was confirmed by ESIMS, H
1
13
23
reduction. The H NMR spectrum showed three aromatic
and C NMR, and DEPT data (vide infra). Other acid-
mediated cyclizations with BF −Et O, ion-exchange resin
H
H
3
2
(Amberlyst15), p-TsOH, and Eaton reagent (7.7 wt % P O
2 5
solution in methanesulfonic acid) afforded unwanted by-
(
7) with MnO produced (+)-8-O-acetylyahazunone (8) in
products or led to decomposition.
Oxidation of diphenol 9 with MnO afforded (+)-yahazu-
2
practical yield (50%). Other oxidation systems were also
explored for this transformation, and no improvements could
be achieved (see Supporting Information for more details).
Thus, the successful preparation of (+)-8-O-acetylyahazunol
2
none (10) in 83% yield. Notably, (+)-yahazunone (10) is
supposed to be a new natural product along with
(+)-yahazunol. Treatment of (+)-yahazunone (10) with
SOCl /Et N gave the inseparable exo- and endo-cyclic olefins
(7) was established, representing the core scaffold of the
2
3
drimane meroterpenoids in Figure 1. This method served as a
good alternative to the aforementioned available protocols
11a and 11b in 86% combined yield. The reaction temperature
definitively influenced the ratio of (−)-zonarone (11a) to
(−)-isozonarone (11b) (Scheme 4). Increased temperature
favored the formation of isomer 11b, which may be more
stable than the disubstituted alkene 11a. Decomposition of
(+)-yahazunone (10) was also detectable when the temper-
ature was increased.
(
Scheme 1) by avoiding the air/moisture-sensitive organo-
metallic reagents, ensuing manipulation for dehydroxylation,
stoichiometric transition metal reagent mediation, isomer-
ization, etc.
Synthesis of (+)-Yahazunol and Related Meroterpe-
noids. Attempted hydrolysis of (+)-8-O-acetylyahazunol (7)
with LiOH or NaOH did not provide the target (+)-yahazunol
Reduction of (−)-zonarone (11a) and its isomer 11b with
sodium dithionite in CH Cl afforded (−)-zonarol (12a) and
2
2
(
9), although full conversion was observed. Adding LiAlH to a
(−)-isozonarol (12b) in 50% combined yield, but avoided the
formation of the tetrasubstituted cyclic olefin isomer of
(−)-zonarol from the direct treatment of (+)-chromazonarol
4
solution of acetate 7 in anhydrous THF at 0 °C afforded
(
H O + H] was observed in the ESIMS spectrum. Resonances
for the ester group were absent in the C NMR spectrum, and
+)-yahazunol (9) in 93% yield. The ion at m/z 315.47 [M −
+
23
(13) by BCl . Usage of LiAlH is to be avoided, since its
2
3
4
13
usage invariably led to the decomposition of (−)-zonarone
(11a) and (−)-isozonarone (11b).
the resonance at δ 75.1 was consistent with the presence of an
C
oxygenated tertiary carbon. With the assistance of DEPT
spectra, we speculated compound 9 comprised six non-
protonated carbons, five methines, six methylenes, and four
Formal Synthesis of (+)-Chromazonarol-Related Mer-
oterpenoids. With (+)-chromazonarol (13) in hand,
attention turned to the synthesis of other bioactive
meroterpenoids (Scheme 5). Synthesis of puupehenol (14)
and (+)-8-epi-puupehedione (15) was accomplished via
1
methyls. The H NMR spectrum verified the presence of three
aromatic hydrogens (δ 6.49, 6.53, and 6.63), two phenolic
H
23
protons (δ 7.45 and 8.76), a tertiary hydroxy group (δ 4.89),
oxidation by IBX, followed by redox manipulation. Formal
H
H
and four methyl singlets (δ 0.82, 0.86, 0.97, and 1.30). The
synthesis of antibacterial (+)-hongoquercin A (16) was
realized through a C−H functionalization over four steps.
H
31
structure of (+)-yahazunol (9) was confirmed by X-ray
diffraction (Figure 2) and was deposited at the CCDC with
the number 1827163.
Antifungal Exploration of (+)-Yahazunol (9) and
Related Meroterpenoids. Keeping in mind the importance
of natural products in medicinal and agrochemical exploration,
the diverse bioactivities of (−)-yahazunol and related natural
products prompted us to explore the agrochemical potential of
the synthesized naturally occurring meroterpenoids [(+)-ya-
1
0
23
20
hazunol, (+)-yahazunone, (+)-chromazonarol, and
1
0,32
33
(
(
[
−)-isozonarol
−)-isozonarone,
(+)-8-O-acetylyahazunol, (+)-8-O-acetylyahazunone] as anti-
] and enantiomers [(−)-zonarone,
12,19 23
and (−)-zonarol ] or analogues
fungal agents.
Synthetic (+)-yahazunol (9) and (+)-chromazonarol (13)
were initially evaluated against seven agriculturally important
plant pathogens (see Supporting Information for more details).
(
+)-Yahazunol (9) showed modest activity against all the
Figure 2. Scalable synthesis and crystal structure of (+)-yahazunol
tested fungi, while the antifungal activities were enhanced
when the structure comprised the tetracyclic counterpart
(9).
(
+)-chromazonarol (13). This structure features decalin-fused
As shown in Scheme 4, a scalable synthesis of (+)-yahazunol
9) can be conducted successfully (4 g prepared), and this
dihydrobenzopyran, displaying excellent activity against
Sclerotinia scleotiorum. The enhancement in the effect against
Rhizoctonia solani is also impressive. Oxidation of (+)-yahazu-
nol (9) to the quinone 10 can lead to an increased antifungal
effect, likely due to the formation of a Michael acceptor, which
may interact with amino acid residues in the active site. It is
noteworthy that the location of the olefinic bond (11a vs 11b)
is crucial for antifungal effect against R. solani. (+)-Chroma-
zonarol (13) was recognized as the most potent compound
against S. scleotiorum, with an EC50 value of 24.1 μM in vitro
(
route constitutes the shortest sequences (5 LLS) to date
starting from sclareol. The novel acetate 7 was obtained
successfully as a precursor for (+)-yahazunol (9). Acetate 7 is
not readily available through the regioselective esterification of
the tertiary hydroxy group of 9. (+)-Yahazunol (9) was
enlisted in the preparation of other drimane meroterpenoid-
derived natural products (Scheme 4). Treatment of
(
+)-yahazunol (9) with trifluoroacetic acid (TFA) in CH Cl
2 2
D
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Scheme 4. Synthesis of (+)-Yahazunol (9) and Its Transformation into Related Analogues
Scheme 5. Formal Synthesis of (+)-Chromazonarol (13)-Related Meroterpenoids
Figure 3. Antifungal activity of (+)-yahazunol (9) and related compounds.
Figure 4. Relationship between ubiquinol and (+)-chromazonarol (13).
8
(
Figure 3). Notably, the in vivo assessment of 13 on rape
reported heterocyclic mimics, 3a (Figure 3). This biologically
complementary effect against different plant pathogens will
favor the establishment of the chemical repertoire in the
management of different plant diseases. This represents the
first biological profiles reported for (+)-yahazunone (10),
(+)-8-O-acetylyahazunone (8), and (+)-8-O-acetylyahazunol
(7).
leaves (Brassica napus) showed both curative and preventative
effects. Furthermore, the presumed natural product, yahazu-
none (10), also showed prominent activity in vitro against S.
scleotiorum with an EC50 value of 28.7 μM. Both
(
+)-yahazunone (10) and (+)-chromazonarol (13) showed
advantages in the inhibition of S. scleotiorum compared to the
original model, (1R,2R,4aS,8aS)-1-benzyl-2,5,5,8a-tetramethyl-
decahydronaphthalen-2-ol (DM), and one of the previously
On the other hand, coenzyme Qn are present in respiring
eukaryotic cells and participate in aerobic cellular respiration
E
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and energy generation in the form of ATP. The precursor of
was complete. A solution of Na
2
CO
3
(10 g) in H
2
O (150 mL) was
added to quench the reaction, and the mixture was stirred for 15 min.
The resulting mixture was extracted with EtOAc (3 × 100 mL) and
combined. The organic phases were washed sequentially with a
saturated aqueous solution of Na S O (2 × 50 mL) and brine (50
mL) and then dried over anhydrous Na SO , filtered, and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel, affording homodrimanic acid (2) as a
(
+)-yahazunol (9) was proposed as one kind of analogue of
coenzyme Qn (n = 3), and the synthesized natural products
can be regarded as conformational restricted congeners of
ubiquinol (Figure 4). The preferred conformation may be
forged and adopted to minimize the entropic loss in the
binding interaction with the pharmacological target, leading to
enhanced potency and improved selectivity.
2
2
3
2
4
white solid (42% yield). Note: Sclareolide was isolated in 35% yield
1
In summary, the scalable and efficient synthesis of
+)-yahazunol (9) was accomplished in five longest linear
from this residue. H NMR (400 MHz, CDCl ) for homodrimanic
3
(
acid, δ 0.79 (s, 3H, CH ), 0.83 (s, 3H, CH ), 0.98 (s, 3H, CH ), 1.03−
3 3 3
1
.12 (m, 2H), 1.17 (m, 1H), 1.26 (m, 1H), 1.36−1.47 (m, 2H), 1.51
sequences (LLS) starting from commercially available and
inexpensive (−)-sclareol (1), with a Barton decarboxylative
coupling as the key step. This is the shortest approach to
(
(
(
s, 3H, CH ), 1.53 (m, 1H), 1.59 (m, 1H), 1.66−1.77 (m, 2H), 1.88
3
s, 3H, CH ), 2.21 (m, 1H), 2.34−2.44 (m, 2H), 2.77 (m, 1H), 3.50
3
s, br, 1H).
(
+)-yahazunol (9) employing (−)-sclareol (1) as starting
26,28
Synthesis of Barton Ester of Homodrimanic Acid (3).
To a
material. The divergent translational potential of (+)-yahazu-
solution of homodrimanic acid (2) (143 mg, 0.46 mmol) in
anhydrous CH Cl (5 mL) was added 2-mercaptopyridine N-oxide
nol (9) was demonstrated by the expedient preparation of
2
2
(
(
(
+)-yahazunone (10), (−)-zonarone (11a), (−)-isozonarone
11b), (−)-zonarol (12a), (−)-isozonarol (12b), and
+)-chromazonarol (13). This radical decarboxylation and
(
60 mg, 0.47 mmol), followed by the addition of 1-Ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl) (115
mg, 0.6 mmol) and dimethylaminopyridine (12 mg, 0.10 mmol) in an
ice bath. The mixture was stirred in the dark and allowed to warm to
ambient temperature until it was complete as monitored by TLC. The
mixture was diluted with CH Cl (30 mL), and the combined organic
quinone addition cascade should also enable the formal
synthesis of puupehenol (14), 8-epi-puupehedione (15), and
2
2
(
+)-hongoquercin A (16). The antifungal screening of the
phases were washed with water (3 × 15 mL) and brine (15 mL), then
synthesized natural products and analogues showed (+)-chro-
mazonarol (13) and (+)-yahazunone (10) as promising
candidates against S. scleotiorum with EC50 values of 24.1 and
dried over anhydrous Na SO , filtered, and concentrated under
2
4
reduced pressure to give crude products. The resultant residue was
purified by flash chromatography on silica gel (200−300 m) with
petroleum ether/EtOAc (4:1, v/v) as eluent to give the Barton ester 3
in 80% yield, which was used without any further purification for the
next step.
Synthesis of the Pyridylthioquinone Meroterpenoid (6). To a
solution of Barton ester 3 (122 mg, 0.29 mmol) in anhydrous CH Cl
2
8.7 μM, respectively. This is beneficial to the structure
optimization for the discovery of novel agrochemicals. Further
exploration of the mechanism of action will also be facilitated
by the scalable synthesis of (+)-yahazunol (9) and analogues
reported herein.
2
2
(5 mL) was added p-benzoquinone (94 mg, 0.87 mmol), and the
reaction mixture was cooled at 0 °C followed by irradiation with a
high-pressure mercury lamp (250 W). The reaction process was
monitored by TLC until full conversion of compound 3 was observed.
The concentrated mixture was subjected to chromatography on silica
EXPERIMENTAL SECTION
■
General Experimental Procedures. Unless otherwise stated, all
solvents and reagents were purchased from commercial sources
Energy or Meryer Chemicals etc.); they were analytically pure and
used without further purification. Anhydrous solvents were dried and
distilled by standard techniques before use. Silica gel GF254 and
column chromatography silica gel for isolation (200−300 mesh) were
both purchased from Qingdao Broadchem Industrial Co., Ltd.
Reaction progress was monitored by TLC on silica gel GF2 with
phosphomolybdic acid and ultraviolet (UV nm) detection. H and
gel (200−300 mesh) with petroleum ether/EtOAc (5:1, v/v) to
(
1
afford compound 6 in 85% yield: H NMR (400 MHz, CDCl ) δ 0.80
3
(
s, 3H, CH ), 0.87 (s, 3H, CH ), 0.92 (s, 3H, CH ), 1.04 (dd, J = 12.2,
3 3 3
2
1
3
.0 Hz, 1H), 1.16−1.26 (m, 2H), 1.35−1.44 (m, 2H), 1.48 (m, 1H),
.51−1.57 (m, 2H), 1.58−1.63 (m, 1H), 1.60 (s, 3H, CH ), 1.75 (s,
3
H, CH ), 1.86 (ddd, J = 12.6, 3.1, 3.1 Hz, 1H), 2.21 (dd, J = 10.7, 2.9
3
54
1
Hz, 1H), 2.72 (ddd, J = 12.4, 3.3, 2.9 Hz, 1H), 2.87 (dd, J = 13.8, 2.9
Hz, 1H), 3.14 (dd, J = 13.8, 10.7 Hz, 1H), 6.82 (d, J = 1.3 Hz, 2H),
2
54
13
C NMR spectra were recorded on a Bruker AV 400 or 600
7
.02 (dd, J = 4.92, 4.92 Hz, 1H), 7.34 (m, 1H), 7.55 (m 1H), 8.26
spectrometer with CDCl or acetone-d as solvent and tetramethylsi-
3
6
1
3
(dd, J = 4.9, 1.0 Hz, 1H); C NMR (100 MHz, CDCl ) δ 15.5, 18.7,
lane as the internal standard. The chemical shifts (δ) were recorded in
parts per million (ppm). ESIMS data were obtained with a Waters
Xevo TQ-S micro-spectrometer. The single-crystal X-ray diffraction
study was carried out on a Bruker SMART APEX CCD
diffractometer. The fungi were provided by the College of Plant
Protection, Nanjing Agricultural University (Nanjing, China).
Antifungal Assay. The in vitro and in vivo antifungal activities of
the synthesized natural products and analogues were carried out
3
1
5
1
4
5
9.7, 20.10, 21.6, 23.3, 26.4, 33.4, 33.5, 39.4, 39.8, 40.0, 41.6, 55.7,
7.8, 87.6, 120.7, 122.8, 136.7, 137.1, 137.4, 139.2, 149.8, 155.1,
+
57.3, 169.5, 182.0, 185.5; ESIMS calcd for C H NO S [M + H]
28 36
4
+
82.24, found 482.22; C H NNaO S [M + Na] 504.22; found
28 35
4
04.19.
Synthesis of (+)-8-O-Acetylyahazunol (7). To a solution of
pyridylthioquinone meroterpenoid 6 (192 mg, 0.40 mmol) in
anhydrous EtOH was added Raney-nickel (1.40 g, excess). The
reaction mixture was stirred for 5 min at ambient temperature for full
conversion. The heterogeneous system was filtered, and the solvent
was removed under reduced pressure to give the crude products,
which were purified by flash column chromatography on silica gel
5
according to the published method. All the tested compounds were
dissolved in DMSO at a given concentration, and the in vitro activity
against the plant pathogens was tested by virtue of the mycelium
growth rate. The in vivo biotest was conducted on rape leaves
Brassica napus). All experiments were replicated three times, and the
statistical analyses of the antifungal bioassay were performed using
SPSS software version 20.0.
(
(
(
200−300 m) with petroleum ether/EtOAc (4:1, v/v) to afford
1
+)-8-O-acetylyahazunol (7) in 91% yield: H NMR (400 MHz,
CDCl ) δ 0.66 (td, J = 13.0, 3.7 Hz, 1H), 0.78 (s, 3H, CH ), 0.84 (s,
Synthesis of Pyridylthioquinone Meroterpenoid (Inter-
mediate 6). Synthesis of Homodrimanic Acid through Oxidative
Degradation of (−)-Sclareol (1). Homodrimanic acid (2) was
synthesized in a one-pot reaction following the procedure of Alvarez-
3
3
3H, CH
), 0.98 (s, 3H, CH ), 1.04 (dd, J = 14.3, 4.8 Hz, 1H), 1.25−
3
3
1.35 (m, 4H), 1.51 (m, 1H), 1.60 (s, 3H, CH ), 1.64−1.70 (m, 2H),
1.77 (m, 1H), 1.93 (s, 3H, CH ), 2.03 (dd, J = 7.1, 2.9 Hz, 1H), 2.56
3
3
30
Manzaneda. To a solution of (−)-sclareol (5.00 g, 16.23 mmol) in
(dd, J = 15.4, 7.0 Hz, 1H), 2.74−2.82 (m, 2H), 5.71 (s, br, 1H, OH),
6.56 (s, br, 1H, OH), 6.58 (dd, J = 8.5, 3.1 Hz, 1H, aromatic H), 6.65
(d, J = 3.1 Hz, 1H, aromatic H), 6.67 (d, J = 8.5 Hz, 1H, aromatic H);
acetone (120 mL) and Ac O (30 mL) was added slowly KMnO
2
4
(
16.00 g, 101.27 mmol) in portions in an ice bath. The reaction
mixture was stirred at 0 °C and monitored by TLC until the reaction
1
3
C NMR (100 MHz, CDCl ) δ 15.6, 18.2, 19. 9, 20.0, 21.5, 22.6,
3
F
DOI: 10.1021/acs.jnatprod.8b00310
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
+
+
2
1
7.1, 33.0, 33.4, 38.9, 40.3, 40.3, 41.4, 55.5, 58.1, 90.1, 113.9, 116.3,
18.4, 129.5, 148.1, 148.8, 170.1; ESIMS calcd for C H NaO [M +
[M − H O + H] 313.22, found 313.24; C H NaO [M + Na]
2
21 30
3
353.21, found 353.25.
Synthesis of (−)-Zonarone (11a) and (−)-Isozonarone (11b).
To a stirred solution of (+)-yahazunone (10) (330 mg, 1.00 mmol)
2
3
34
4
+
+
Na] 397.24, found 397.29; C H O [M − HOAc + H] 315.23,
found 315.31.
2
1
31
2
Synthesis of (+)-8-O-Acetylyahazunone (8). To a solution of
and Et
added a solution of SOCl
−78 °C. The reaction mixture was stirred for full conversion before it
was quenched by the addition of a saturated aqueous NaHCO
solution (10 mL). The resulting mixture was separated and extracted
with CH Cl (3 × 10 mL). The combined organic phases were
washed with brine (10 mL) and dried over anhydrous Na SO
3
N (417 μL, 3.00 mmol) in anhydrous CH
2
Cl
2
(8 mL) was
Cl (2 mL) at
(
+)-8-O-acetylyahazunol (7) (374 mg, 1.00 mmol) in Et O (20 mL)
2
(106 μL, 1.50 mmol) in CH
2
2
2
was added MnO (348 mg, 4.00 mmol). The reaction mixture was
stirred at ambient temperature until the full conversion of 7 as
monitored by TLC. The mixture was filtered through Celite and
rinsed by Et O (2 × 10 mL). The filtrate was concentrated and
subjected to flash column chromatography on silica gel (200−300 m)
with petroleum ether/EtOAc (5:1, v/v) to afford (+)-8-O-
2
3
2
2
2
,
4
2
filtered, and evaporated under reduced pressure. The residue was
purified by flash column chromatography on silica gel (200−300 m)
with petroleum ether/EtOAc (8:1, v/v) to afford (−)-zonarone (11a)
1
acetylyahazunone (8) in 50% yield: H NMR (400 MHz, CDCl ) δ
0
3
.80 (s, 3H, CH ), 0.88 (s, 3H, CH ), 0.91 (s, 3H, CH ), 0.98−1.04
3
3
3
and (−)-isozonarone (11b) in the ratio of 3.7:1 as a yellow solid, in
(
m, 2H), 1.15 (td, J = 12.9, 3.9 Hz, 1H), 1.27 (dd, J = 12.5, 3.1 Hz,
1
8
6% combined yield. Zonarone: H NMR (400 MHz, CDCl ) δ 0.77
1
1
1
2
2
H), 1.37−1.45 (m, 2H), 1.55 (m, 1H), 1.57 (s, 3H, CH ), 1.61 (m,
3
3
(
s, 3H, CH ), 0.83 (s, 3H, CH ), 0.90 (s, 3H, CH ), 1.11−1.22 (m,
H), 1.64−1.71 (m, 2H), 1.74 (s, 3H, CH ), 1.94 (dd, J = 6.9, 4.2 Hz,
3
3
3
3
2
1
H), 1.31−1.37 (m, 2H), 1.41 (m, 1H), 1.44 (m, 1H), 1.46 (m, 1H),
H), 2.48 (dd, J = 15.7, 6.8 Hz, 1H), 2.63 (dd, J = 15.7, 4.4 Hz, 1H),
.76 (m, 1H), 6.68 (d, J = 2.4 Hz, 1H, quinone H), 6.71 (d, J = 10.1,
.4 Hz, 1H, quinone H), 6.78 (d, J = 10.1 Hz, 1H, quinone H);
.54 (m, 1H), 1.75 (m, 1H), 1.79 (m, 1H), 2.04 (m, 1H), 2.38 (m,
1
3
1H), 2.63−2.55 (m, 2H, quinone-CH ), 4.33 (s, 1H, CH ), 4.78 (s,
C
2
2
1
6
H, CH ), 6.47 (d, J = 2.1 Hz, 1H), 6.68 (dd, J = 10.0, 2.5 Hz, 1H),
NMR (100 MHz, CDCl ) δ 15.5, 18. 5, 19.7, 20.2, 21.5, 22.9, 23.8,
2
3
1
3
.75 (d, J = 10.0 Hz, 1H); C NMR (100 MHz, CDCl ) δ 14.5, 19.4,
3
1
3
3.2, 33.4, 39.2, 39.5, 39.9, 41.6, 55.7, 59.0, 87.3, 132.7, 136.1, 136.9,
52.0, 169.5, 187.3, 187.8; ESIMS calcd for C H O [M + H]
3
+
21.7, 23.1, 24.2, 33.6 (2 × C), 37.9, 39.2, 39.9, 42.0, 54.1, 55.6, 108.0,
132.9, 136.0, 136.9, 147.2, 149.4, 187.7, 187.8. Selected signals for
2
3
33
4
+
73.24, found 373.20; C H NaO [M + Na] 395.22; found 395.18.
2
3
32
4
1
(
−)-isozonarone (11b): H NMR (400 MHz, CDCl3) δ 0.85 (s, 3H,
Synthesis of (+)-Yahazunol (9). To a solution of (+)-8-O-
acetylyahazunol (7) (375 mg, 1.00 mmol) in anhydrous tetrahy-
drofuran (THF) (10 mL) was added LiAlH (40 mg, 1.00 mmol) at 0
CH ), 0.87 (s, 3H, CH ), 0.90 (s, 3H, CH ), 5.43 (s, br, 1H, CH−),
3
3
3
6
.79 (d, J = 9.5 Hz, 1 H), 6.68 (d, J = 9.5 Hz, 1H, H in quinone ring).
4
13
The other signals overlap with the (−)-zonarone signals): C NMR
°C. The reaction mixture was stirred at this temperature until the full
(
100 MHz, CDCl ) δ 13.9, 18.8, 21.9, 22.7, 23.7, 25.7, 33.0, 33.2,
3
conversion of (+)-8-O-acetylyahazunol (7) monitored by TLC. An
aqueous solution of HCl (1 M, 5 mL) was added at 0 °C to quench
the reaction, and the reaction mixture was extracted with EtOAc (3 ×
3
1
3
6.8, 39.7, 42.1, 50.1, 52.9, 123.4, 132.7, 133.5, 136.1, 137.0, 151.5,
87.4, 187.6; ESIMS calcd for C H O [M + H] 313.22, found
13.32; C H NaO [M + Na] 335.20, found 335.29; C H NaO
2M + Na] 647.41, found 647.55.
Synthesis of (−)-Zonarol (12a) and (−)-Isozonarol (12b). To
a solution of the mixture of (−)-zonarone (11a) and (−)-isozonarone
11b) (63 mg, 0.2 mmol) in CH Cl (5 mL) was added sodium
dithionite (208 mg, 1.20 mmol). The resulting suspension was stirred
for 24 h at 30 °C, and the solvent was removed under reduced
pressure. The residue was subjected to column chromatography on
silica gel (200−300 m) with petroleum ether/EtOAc (6:1, v/v) to
afford a mixture of (−)-zonarol (12a) and (−)-isozonarol (12b) as a
white solid in 50% combined yield. (−)-Zonarol (12a) signals: H
NMR (400 MHz, CDCl ) δ 0.81 (s, 3H, CH ), 0.83 (s, 3H, CH ),
.89 (s, 3H, CH ), 1.38−1.44 (m, 4H), 1.56−1.67 (m, 4H), 1.73−
.78 (m, 2H), 2.16 (dd, J = 5.5, 5.5 Hz, 1H), 2.40 (m, 1H), 2.70 (d, J
+
2
1
29
2
+
2
1
28
2
42 56
4
1
0 mL). The organic layers were collected and washed sequentially
+
[
with 5% NaHCO (2 × 10 mL), H O (2 × 10 mL), and brine (10
mL), dried over anhydrous Na SO , filtered, and concentrated under
reduced pressure to give the crude product. The resultant residue was
3
2
2
4
(
2
2
purified by chromatography on silica gel (200−300 m) to afford
1
(
+)-yahazunol (9) in 93% yield: H NMR (600 MHz, acetone-d ) δ
6
0
.72 (td, J = 13.2, 3.8 Hz, 1 H), 0.82 (s, 3 H, CH ), 0.86 (s, 3 H,
3
CH ), 0.95 (m, 1 H), 0.97 (s, 3 H, CH ), 1.10 (td, J = 13.4, 4.4 Hz, 1
3
3
H), 1.30 (s, 3H, CH ), 1.31−1.38 (m, 3H), 1.55−1.65 (m, 4H), 1.83
3
(
m, 1H), 1.92 (ddd, J = 12.7, 3.3, 3.3 Hz, 1H), 2.39 (dd, J = 15.0, 6.2
1
Hz, 1H, Ph-CH), 2.85 (dd, J = 15.0, 2.2 Hz, 1H, Ph-CH), 4.89 (s, br,
OH), 6.49 (dd, J = 8.5, 2.9 Hz, 1H, aromatic H), 6.53 (d, J = 8.5 Hz,
3
3
3
0
3
1
H, aromatic H), 6.63 (d, J = 2.9 Hz, 1H, aromatic H), 7.45 (s, br, 1H,
1
=
1
3
OH), 8.76 (s, br, 1H, OH); C NMR (150 MHz, acetone-d ) δ 15.8,
6
6.3 Hz, 2H), 4.42 (s, br, 1H, OH), 4.54 (s, br, 1H, OH), 4.69 (d, J =
1
9.0, 21.1, 21.8, 24.5, 27.9, 33.7, 33.7, 40.5, 41.3, 42.4, 44.4, 56.8,
1
.6 Hz, 1H, CH ), 4.81 (d, J = 1.6 Hz, 1H, CH ), 6.52 (d, J = 3.1
2
2
6
2.2, 75.1, 114.2, 117.4, 118.8, 131.1, 149.6, 150.3; ESIMS calcd for
13
Hz, 1H), 6.59−6.61 (m, 2H, H); C NMR (100 MHz, CDCl ) δ
3
+
C H O [M − H O + H] 315.23, found 315.47. The pale yellow
solid was redissolved in EtOAc, and the crystals obtained from this
solution were subjected to X-ray single-crystal diffraction analysis
21
31
2
2
14.8, 19.7, 21.9, 23.8, 24.6, 33.8 (2 × C), 38.3, 39.5, 40.4, 42.2, 55.7,
5
6.3, 107.7, 113.2, 116.1, 116.7, 130.2, 147.6, 148.9, 149.3.
1
(
(
3
−)-Isozonarol (12b) signals: H NMR (400 MHz, CDCl ) δ 0.88
3
(
CCDC: 1569963).
s, 6H, 2 × CH ), 0.91 (s, 3H, CH ), 1.12 (m, 1H), 1.32−1.36 (m,
3
3
Synthesis of (+)-Yahazunone (10). A solution of (+)-yahazunol
H), 1.34−1.40 (m, 2H), 1.47 (s, 3H, CH ), 1.53 (m, 1H), 1.85−1.94
3
(9) (332 mg, 1.00 mmol) in anhydrous Et O (10 mL) was treated
2
(m, 2H), 2.40 (m, 1H), 2.57−2.61 (m, 2H), 4.32 (s, br, 1H, OH),
4.40 (s, br, 1H, OH), 5.39 (s, br, 1H, CH), 6.49 (d, J = 2.8 Hz, 1H,
aromatic H), 6.59 (m, 1H, aromatic H), 6.74 (d, J = 2.8 Hz, 1H,
with MnO (348 mg, 4.00 mmol) at 25 °C. The reaction mixture was
stirred until full conversion of (+)-yahazunol (9). The heterogeneous
system was filtered through Celite and rinsed with Et O (2 × 10 mL).
The filtrate was concentrated and subjected to flash column
chromatography on silica gel (200−300 m) with petroleum ether/
EtOAc (4:1, v/v) to afford (+)-yahazunone (10) as a yellow wax in
2
+
2
aromatic H); ESIMS calcd for C H KO [M + K] 353.19, found
2
1
30
2
3
53.22.
Synthesis of (+)-Chromazonarol (13). To a solution of
+)-yahazunol (9) (332 mg, 1.00 mmol) in anhydrous CH Cl (10
mL) was added TFA (75.00 μL, 1.00 mmol) at ambient temperature.
The reaction mixture was stirred until full conversion as monitored by
TLC. A saturated NaHCO aqueous solution (15 mL) was added to
quench the reaction. The separated aqueous phase was extracted with
(
2
2
1
8
3% yield: H NMR (400 MHz, CDCl ) δ 0.80 (s, 3H, CH ), 0.87 (s,
3
3
3
H, CH ), 0.88 (s, 3H, CH ), 0.93 (dd, J = 11.9, 2.3 Hz, 1H), 1.12
3
3
(
1
td, J = 13.3, 4.3 Hz, 1H), 1.21 (s, 3H, CH ), 1.26 (m, 1H), 1.45−
3
3
.31 (m, 2H), 1.61−1.53 (m, 3H), 1.72−1.62 (m, 2H), 1.81−1.73
(
m, 1H), 1.89 (dt, J = 12.2 Hz, J = 3.2 Hz, 1H), 2.48 (ddd, J = 15.2,
CH Cl (3 × 10 mL). The combined organic phases were washed
2
2
2
5
.2, 1.3 Hz, 1H, Ph-CH), 2.63 (ddd, J = 15.2, 6.0, 1.5 Hz, 1H, Ph-
CH), 6.6 (d, J = 1.4 Hz, 1H), 6.7 (dd, J = 10.0, 2.4 Hz, 1H), 6.75 (d, J
10.0 Hz, 1 H); 13C NMR (100 MHz, CDCl ) δ 15.3, 18.5, 20.4,
with H O (3 × 10 mL) and brine (10 mL), dried over anhydrous
2
Na SO , filtered, and concentrated under reduced pressure to give a
2
4
=
2
1
crude product. The resultant residue was purified by chromatography
on silica gel (200−300 m) with petroleum ether/EtOAc (8:1, v/v) to
yield (+)-chromazonarol (13) as a white solid in 94% yield: H NMR
3
1.5, 23.7, 24.6, 33.3, 33.4, 39.4, 40.4, 41.6, 44.7, 56.1, 61.6, 73.9,
32.9, 136.2, 137.0, 152.6, 187.8, 188.1; ESIMS calcd for C H O
1
2
1
29
2
G
DOI: 10.1021/acs.jnatprod.8b00310
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
(
600 MHz, CDCl ) δ 0.84 (s, 3H, CH ), 0.87 (s, 3H, CH ), 0.90 (s,
(14) Lamberth, C.; Jeanmart, S.; Luksch, T.; Plant, A. Science 2013,
341, 742−746.
3
3
3
3
1
H, CH ), 0.96 (dd, J = 12.4, 3.2 Hz, 1H), 1.02 (dd, J = 12.0, 2.1 Hz,
3
H), 1.16 (m, 1H), 1.17 (s, 3H, CH ), 1.33−1.50 (m, 3H), 1.61−1.70
(15) Ishibashi, H.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc.
2004, 126, 11122−11123.
3
(
m, 4H), 1.75 (m, 1H), 2.04 (m, 1H), 2.55−2.57 (m, 2H, Ph-CH ),
2
4
.60 (s, br, 1H, OH), 6.54−6.58 (m, 2H, aromatic H), 6.62 (d, J = 8.4
(16) Gansaeuer, A.; Justicia, J.; Rosales, A.; Worgull, D.; Rinker, B.;
Cuerva, J. M.; Oltra, J. E. Eur. J. Org. Chem. 2006, 2006, 4115−4127.
(17) Barrett, T. N.; Barrett, A. G. M. J. Am. Chem. Soc. 2014, 136,
17013−17015.
1
3
Hz, 1H, aromatic H); C NMR (150 MHz, CDCl ) δ 14.8, 18.5,
3
1
7
9.7, 20.7, 21.6, 22.5, 33.2, 33.4, 36.8, 39.2, 41.1, 41.8, 52.0, 56.1,
6.7, 114.2, 115.8, 117.5, 123.3, 147.1, 148.5; ESIMS calcd for
+
C H O [M + H] 315.23, found 315.26.
(18) Frija, L. M.; Frade, R. F.; Afonso, C. A. Chem. Rev. 2011, 111,
4418−4452.
21
31
2
The reader is referred to the Supporting Information for the
comparison of observed and reported data of (+)-yahazunol,
(
(19) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Herrador, M. M.;
Chahboun, R.; Galera, P. Bioorg. Med. Chem. Lett. 1999, 9, 2325−
+)-yahazunone, (−)-zonarone, (−)-zonarol, and (+)-chromazonarol.
2328.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.8b00310.
(20) Huang, J. H.; Lei, X. G. Sci. China: Chem. 2013, 56, 349−353.
21) Takao, K.-i.; Sasaki, T.; Kozaki, T.; Yanagisawa, Y.; Tadano, K.-
i.; Kawashima, A.; Shinonaga, H. Org. Lett. 2001, 3, 4291−4294.
22) Markwell-Heys, A. W.; Kuan, K. K. W.; George, J. H. Org. Lett.
015, 17, 4228−4231.
23) Dixon, D. D.; Lockner, J. W.; Zhou, Q.; Baran, P. S. J. Am.
Chem. Soc. 2012, 134, 8432−8435.
24) Dethe, D. H.; Murhade, G. M.; Dherange, B. D.; Sau, S. K. Eur.
J. Org. Chem. 2017, 7, 1143−1150.
25) Alvarez-Manzaneda, E.; Chahboun, R.; Cabrera, E.; Alvarez, E.;
■
(
S
(
2
(
X-ray crystallographic data (CIF)
Synthetic details, comparison of observed and reported
data, antifungal data, and NMR spectra (PDF)
(
(
Haidour, A.; Ramos, J. M.; Alvarez-Manzaneda, R.; Tapia, R.; Es-
Samti, H.; Fernandez, A.; Barranco, I. Eur. J. Org. Chem. 2009, 2009,
AUTHOR INFORMATION
■
1
(
1
(
139−1143.
26) Ling, T.; Xiang, A. X.; Theodorakis, E. A. Angew. Chem., Int. Ed.
999, 38, 3089−3091.
27) Ling, T.; Poupon, E.; Rueden, E. J.; Kim, S. H.; Theodorakis, E.
A. J. Am. Chem. Soc. 2002, 124, 12261−12267.
28) Marcos, I. S.; Conde, A.; Moro, R. F.; Basabe, P.; Diez, D.;
Urones, J. G. Tetrahedron 2010, 66, 8280−8290.
29) Caniard, A.; Zerbe, P.; Legrand, S.; Cohade, A.; Valot, N.;
Magnard, J.-L.; Bohlmann, J.; Legendre, L. BMC Plant Biol. 2012, 12,
19−131.
30) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R.;
Corresponding Author
*E-mail (S. Li): SKL505@outlook.com.
ORCID
Shengkun Li: 0000-0001-5458-0811
Notes
The authors declare no competing financial interest.
(
(
ACKNOWLEDGMENTS
■
1
(
This work was financially supported by National Natural
Science Foundation of China (No. 21772094) and the
Fundamental Research Funds for the Central Universities
Arteaga, A. F. Synth. Commun. 2004, 34, 3631−3643.
(31) Rosen, B. R.; Simke, L. R.; Thuy-Boun, P. S.; Dixon, D. D.; Yu,
J.-Q.; Baran, P. S. Angew. Chem., Int. Ed. 2013, 52, 7317−7320.
(
KYZ201706, Y0201700151). We are grateful to the reviewers
(
32) Welch, S. C.; Rao, A. S. C. P. J. Org. Chem. 1978, 43, 1957−
and Editor for their valuable advice.
1
961.
33) Schroder, J.; Magg, C.; Seifert, K. Tetrahedron Lett. 2000, 41,
469−5473.
(
5
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DOI: 10.1021/acs.jnatprod.8b00310
J. Nat. Prod. XXXX, XXX, XXX−XXX