Total Synthesis of Mulberry Diels-Alder-Type Adducts Kuwanons G and H

Article abstract of DOI:10.1021/acs.joc.1c00229

Mulberry Diels-Alder-type adducts (MDAAs) are a group of rare natural polyphenols biosynthetically derived from [4 + 2]-cycloaddition of chalcones and dehydroprenylphenols. In this study, kuwanons G (1) and H (2), two bioactive MDAAs with unique dehydroprenylflavonoid dienes, were totally synthesized for the first time in a biomimetic manner. The key features of the convergent route include the use of the Baker-Venkataraman rearrangement, alkylation of β-diketone, intramolecular cyclization, and Suzuki-Miyaura coupling to achieve the subunit diene.

Full text of DOI:10.1021/acs.joc.1c00229

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Article
Total Synthesis of Mulberry Diels−Alder-Type Adducts Kuwanons G
and H
Si-Yuan Luo, Zhuo-Ya Tang, Qingjiang Li, Jiang Weng, Sheng Yin, and Gui-Hua Tang*
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ABSTRACT: Mulberry Diels−Alder-type adducts (MDAAs) are a
group of rare natural polyphenols biosynthetically derived from [4 +
2]-cycloaddition of chalcones and dehydroprenylphenols. In this
study, kuwanons G (1) and H (2), two bioactive MDAAs with
unique dehydroprenylflavonoid dienes, were totally synthesized for
the first time in a biomimetic manner. The key features of the
convergent route include the use of the Baker−Venkataraman
rearrangement, alkylation of β-diketone, intramolecular cyclization,
and Suzuki−Miyaura coupling to achieve the subunit diene.
INTRODUCTION
■
Mulberry Diels−Alder-type adducts (MDAAs), characteristic
constituents of Moraceous plants, are a group of structurally
rare natural phenolic compounds biosynthetically derived from
the intermolecular [4 + 2]-cycloaddition of chalcone
dienophiles and dehydroprenylphenol dienes. On the basis of
the phenol diene, MDAAs may be classified into four main
types1 (Figure 1): (I) dehydroprenyl-2-arylbenzofuran type
(mulberrofuran C and chalcomoracin); (II) dehydroprenyl-
stilbene type (kuwanon Y and kuwanon E); (III) dehydropre-
nylchalcone type (kuwanon J); and (IV) dehydroprenyl-
flavonoid type (kuwanon G and kuwanon H). Most of them
showed promising biological properties such as hypotensive,
antibacterial, anti-inflammation, anti-virus, antioxidation, and
antiphlogistic activities.1−5 To date, several natural MDAAs
have been synthesized by various methods, but all efforts
focused on types I−III,6−11 while the synthesis of the
corresponding type IV natural MDAAs has never been
reported. Presumably, the introduction of additional dehy-
droprenyl motif into the prenyledflavonoid makes synthesis of
the target diene a challenge.
In our previous investigation of the root bark of Morus alba,
two MDAAs kuwanons G (1) and H (2) (Figure 1) turned out
to be potent multi-targeted agents for Alzheimer’s disease
(AD), which exhibited strong inhibitory activity of tau
aggregation and good blood−brain barrier permeability,
respectively.12 As the representatives of type IV, kuwanons G
and H have been isolated and identified in 1981,13 but their
total synthesis has not been reported yet. In view of their
biological activities and peculiar structures, the total synthesis
of kuwanons G and H represents a meaningful task. Herein, we
report the first total synthesis of kuwanon G (1) and kuwanon
H (2).
Figure 1. Representative structures of four types of MDAAs.
Received: January 29, 2021
Published: March 10, 2021
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© 2021 American Chemical Society
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generate the dienophile 6.17 Subsequent prenylation of the
phenolic group of 6 with prenyl bromide under standard
conditions provided the prenyl ether 14 in 70% yield. The
product 14 was underwent sigmatropic rearrangement in the
presence of montmorillonite K10 in dichloromethane (DCM)
to form the desired [1,3]-rearrangement product 7 in 33%
yield,9 along with the corresponding [1,5]-rearranged isomer
in 21% yield as well as recovery of the dienophile 6.
RESULTS AND DISCUSSION
The retrosynthetic analysis for kuwanons G and H (1 and 2) is
depicted in Scheme 1. The target molecules 1 and 2 could be
■
Scheme 1. Retrosynthetic Analysis of 1 and 2
The synthesis of the key intermediate diene 5 commenced
with commercially available 2′,4′,6′-trihydroxyacetophenone
12 and 2,4-dimethoxybenzoic acid 13. As depicted in Scheme
3, treatment of 12 with 2.0 equiv of (CH3O)2SO2 in acetone
Scheme 3. Synthesis of β-Diketone 11
obtained from their heptamethyl ether precursors 3 and 4,
which might be prepared through Diels−Alder cycloaddition
of the synthetic diene 5 with 2′-hydroxychalcone dienophiles 6
or 7, respectively. Dienophile fragments 6 and 7 could be
synthesized from commercially available ketone 8 and
aldehyde 9 via the Claisen−Schmidt condensation reaction.14
The dehydroprenyl moiety of prenylated dehydroprenylflavo-
noid 5 could be introduced by the Suzuki−Miyaura coupling
reaction of the corresponding intermediate 10.15 Iodoflavonoid
10 could be sourced from 11 via alkylation of β-diketone and
intramolecular cyclization, while the β-diketone 11 could be
prepared from commercially available 12 and 13.16
As the dienophile of MDAAs, chalcone and its derivatives
could be easy furnished followed the established route.14 As
shown in Scheme 2, the Claisen−Schmidt condensation of 4′-
methoxy-2′-hydroxyacetophenone 8 and 2,4-dimethoxybenzal-
dehyde 9 occurred smoothly in the presence of NaOH to
provided the corresponding 2,4-dimethylate 15 in 95% yield.8
Regioselective iodination of 15 with KI/KIO3 in AcOH gave
iodobenzene 16 in 92% yield.18 Refluxing with thionyl
chloride, the acylation of 13 proceeded smoothly to afford
the crude product benzoyl chloride 17, which was immediately
conducted with 16 in the solution of pyridine to form an
acyloxy ketone 18. The base-catalyzed Baker−Venkataraman
rearrangement of 18 gave β-diketone 11 in an overall yield of
76% from 16. It was worth mentioning that the products of all
the above steps could be purified easily by recrystallization,
benefiting scale-up synthesis of the target product 11 in good
yield.
The preparation of iodoflavonoid 10 is summarized in
Scheme 4. We modified β-diketone 11 by treatment with
prenyl bromide but both the desired compound 20 and the
byproduct 19 were detected at the same time in all tried
conditions.19 To our delight, when the mixture stirred under
acidic condition, 19 could be completely hydrolyzed to 20 in a
Scheme 2. Synthesis of Dienophiles 6 and 7
Scheme 4. Preparation of Compound 10
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short time. Next, compound 20 was stirred in anhydrous
ethanol with concentrated sulfuric acid as dehydrant at 55 °C
for 60 h to give the target cyclic product 10 in 42% yield
together with an ethylated byproduct 21 in 35% yield.20,21
Notably, the byproduct 21 could be further converted to 10 in
28% yield under acidic conditions.
With iodoflavonoid 10 in hand, the Suzuki−Miyaura
coupling of 10 with pinacolboronate 24 was attempted to
furnish the key intermediate 5. As shown in Scheme 5,
(PCy3)2PdCl2 as the catalyst in toluene at 60 °C in the
presence of the base K3PO4 in 41% yield.22,23 It was found that
diene 5 was unstable and should be immediately used in the
next step after rapid purification.
For the construction of diene 5, other two reasonable
strategies have also been tried but failed. As shown in Scheme
S1 (see Supporting Information), the Suzuki−Miyaura
coupling reaction of iodide 16 with pinacolboronate 24 gave
compound 25 in a high yield. However, no reaction occurred
in the esterification reaction of 25 with acyl chloride 17. It may
be due to the electron-donating group formed by the
introduction of the isoprene chain hindered the progress of
the reaction. Then, we implemented another strategy by which
the desired compound 26 was obtained by the Suzuki−
Miyaura coupling reaction using the prepared 11 as the
substrate. Diene 26 was directly subjected to isopentenyl
bromide to furnish the precursor 27 with 27% yield. However,
both compounds 26 and 27 were particularly unstable, and
diene 5 was not obtained from the intramolecular cyclization
of 27 after many attempts. Therefore, these two strategies
suggested that the introduction of the diene motif in the early
stage may have detrimental effects on subsequent reactions.
With both diene (5) and dienophiles (6 and 7) in hand, we
investigated the key Diels−Alder cycloaddition (Scheme 6).
Scheme 5. Synthesis of Diene 5
compound 24 was easily prepared by hydroboration of
pinacolborane 22 and ennyne 23.9 A first attempt to carry
out the Suzuki−Miyaura coupling reaction with (PCy3)2PdCl2
as the catalyst in 1,4-dioxane at 60 °C using K3PO4 as the base
resulted in an unsatisfactory yield (10%, Table 1, entry 1). This
Scheme 6. Synthesis of ( )-Kuwanons G (1) and H (2)
Table 1. Optimization of the Suzuki−Miyaura Coupling
a
Reaction to Diene 5
T
b
entry
1
catalyst
base
additive
solvent
1,4-
dioxane
(°C)
yield
10%
(PCy3)2PdCl2
K3PO4
60
2
3
4
5
6
7
8
9
(PCy3)2PdCl2
(PCy3)2PdCl2
(PCy3)2PdCl2
(PCy3)2PdCl2
(PCy3)2PdCl2
(PCy3)2PdCl2
PdCl2
Pd(PPh3)4
Pd2(dba)3
Pd(OAc)2
K3PO4
K3PO4
K3PO4
K3PO4
KF
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
DMF
60
60
40
80
60
60
60
60
60
60
12%
41%
26%
11%
messy
33%
messy
messy
messy
8%
toluene
toluene
toluene
toluene
S-Phos toluene
The exo- and endo-adducts (3 and 3a, each in 23% yield) were
obtained by refluxing the substrates 5 and 6 at 180 °C for 40 h
in a sealed tube with toluene.7 Similarly, starting from diene 5
and dienophile 7, the target exo-adduct 4 was obtained in 28%
yield. By comparing the coupling constant of key proton with
that of related natural and synthetic MDAAs, the assignment of
the relative configuration for each adduct was unquestionably
determined.9,12 Typically, the coupling constant of H-3″ is
about 10 Hz in the exo-isomer (trans−trans) while the H-3″ of
the endo-isomer (cis−trans) has a small coupling constant.
In the next step, ( )-kuwanons G (1) and H (2) were
obtained after demethylation of the corresponding exo-isomers
( )-kuwanon G heptamethyl ether (3) and ( )-kuwanon H
heptamethyl ether (4), respectively.9 Subsequently, 1 was
subjected to HPLC with a chiral column to obtain a pair of
PCy3
toluene
toluene
toluene
toluene
10
11
a
The reactions were carried out with 10 (1 equiv) and 24 (1.5 equiv)
in solvent (1.0 mL/mmol). The catalyst was in 0.06 equiv, the base
was in 10.0 equiv, and the additive was in 0.1 equiv Isolated yield of
5.
b
prompted us to optimize the Suzuki−Miyaura coupling
reaction by variation of the solvent, temperature, catalyst,
base, and additive. As indicated in entries 1−3, toluene was the
optimal solvent. We subsequently investigated different
temperatures. The yield of the reaction decreased at higher
or lower temperatures (Table 1, entries 4 and 5), which may
be due to the low reactivity at 40 °C or the instability of the
product under the reaction condition with higher temperature.
With PdCl2, Pd(PPh3)4, Pd2(dba)3, and Pd(OAc)2 as the
palladium catalysts, either no expected product was detected or
the reactivity decreased in toluene. Eventually, careful
experimentation revealed that the reaction works best using
enantiomers, which had opposite specific rotations ([α]20
D
−94.2 for (−)-1 and [α]20 +87.1 for (+)-1) and mirror
D
image-like ECD curves (Figure S1 in Supporting Information).
Similarly, the enantiomers (−)-2 ([α]20 −116.4) and (+)-2
D
([α]20D +134.5) with mirror image-like ECD curves (Figure S2
in Supporting Information) were separated from 2. With the
authentic samples of kuwanons G and H previously isolated
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3H), 1.72 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 190.9, 163.8,
162.6, 160.1, 159.8, 138.3, 137.1, 133.0, 129.7, 125.6, 123.1, 119.7,
117.9, 105.5, 105.4, 99.9, 98.3, 65.8, 55.6, 55.56, 55.55, 25.9, 18.4.
(E)-3-(2,4-Dimethoxyphenyl)-1-(2-hydroxy-4-methoxy-3-(3-
methylbut-2-en-1-yl)phenyl)prop-2-en-1-one (7).9 To a cold
solution of 14 (1.2 g, 3.7 mmol, 1.0 equiv) in dry DCM (20 mL) was
added montmorillonite K10 (1.2 g). After stirring the mixture at 0 °C
for 6 h, the montmorillonite K10 was removed by filtration and
washed with DCM (3 × 10 mL). The DCM filtrate was concentrated
in vacuo to yield a yellow residue, which was purified by flash
chromatography (PE/EtOAc, 7:1) to obtain 7 (395 mg, 33%) as a
yellow solid. 1H NMR (400 MHz, CDCl3) δ 13.61 (s, 1H), 8.11 (d, J
= 15.5 Hz, 1H), 7.79 (d, J = 9.0 Hz, 1H), 7.63 (d, J = 15.5 Hz, 1H),
7.57 (d, J = 8.6 Hz, 1H), 6.54 (dd, J = 8.6 and 2.3 Hz, 1H), 6.49 (d, J
= 9.0 Hz, 1H), 6.48 (d, J = 2.3 Hz, 1H), 5.24 (tt, J = 7.0 and 1.3 Hz,
1H), 3.91 (s, 3H), 3.90 (s, 3H), 3.86 (s, 3H), 3.39 (d, J = 7.0 Hz,
2H), 1.80 (s, 3H), 1.68 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
193.0, 163.2, 163.1, 160.6, 140.0, 131.9, 131.3, 129.2, 122.3, 118.8,
117.5, 117.3, 115.0, 105.6, 102.0, 98.6, 55.9, 55.7, 55.6, 26.0, 21.9,
18.0.
from M. alba in hand, the synthetic compounds (−)-1 and
(−)-2 are identical to these two natural products by comparing
their specific rotations, respectively.
CONCLUSIONS
■
In summary, kuwanons G and H, the representative structures
of type IV natural MDAAs, were first totally synthesized via
intermolecular [4 + 2]-cycloaddition. The key features of this
approach included the use of the Baker−Venkataraman
rearrangement, alkylation of β-diketone, intramolecular cycli-
zation, and Suzuki−Miyaura coupling as the key steps for the
assembly of the unstable diene 5. In the process, we find that
the introduction of the diene motif may reduce the stability of
those synthetic flavonoids such as 5, 26, and 27, which might
explain why the corresponding natural MDAAs using these
common classes of compounds as dienes are rare. It also may
reflect the difficulty of the synthesis of the type IV natural
MDAAs. The results of this study offer an effective protocol for
the syntheses of a variety of potentially bioactive MDAAs and
analogs, which will provide more diversified and abundant
chemical entities for the study of their anti-AD activities and
multi-target mechanisms.
1-(2-Hydroxy-4,6-dimethoxyphenyl)ethan-1-one (15).24 To
a solution of 2′,4′,6′-trihydroxyacetophenone 12 (2.0 g, 11.9 mmol,
1.0 equiv) and K2CO3 (8.2 g, 59.5 mmol, 5.0 equiv) in acetone (100
mL) was added dropwise dimethylsulfate (2.0 mL, 23.8 mmol, 2.0
equiv). The reaction mixture was refluxed at 56 °C for 8 h and then
quenched by the addition of H2O (150 mL). After cooling the
resulting solution on an ice bath, a white solid product 15 in a
quantitative yield (2.2 g, 95%) was obtained by filtration and washing
with cold H2O (3 × 20 mL). 1H NMR (400 MHz, CDCl3) δ 14.02 (s,
1H), 6.04 (d, J = 2.4 Hz, 1H), 5.92 (d, J = 2.4 Hz, 1H), 3.83 (s, 3H),
3.80 (s, 3H), 2.60 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
203.3, 167.7, 166.2, 163.0, 106.1, 93.6, 90.8, 55.6, 33.0.
1-(2-Hydroxy-3-iodo-4,6-dimethoxyphenyl)ethan-1-one
(16).18 To a stirred solution of compound 15 (2.0 g, 10.2 mmol, 1.0
equiv) in AcOH (80 mL) was added KI (0.6 g, 3.6 mmol, 0.3 equiv)
and KIO3 (1.3 g, 6.1 mmol, 0.6 equiv) at rt. A solution of 1% HCl was
added after the reaction for 6 h and then stirred for another 2 h. The
reaction was then quenched with ice water, and the white precipitate
obtained by filtration was compound 16 (3.0 g, 92%). 1H NMR (400
MHz, CDCl3) δ 14.81 (s, 1H), 5.99 (s, 1H), 3.94 (s, 3H), 3.93 (s,
3H), 2.62 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 203.2, 165.0,
164.3 (two carbons), 106.5, 86.6, 66.9, 56.6, 55.9, 32.9.
1-(2,4-Dimethoxyphenyl)-3-(2-hydroxy-3-iodo-4,6-
dimethoxyphenyl)propane-1,3-dione (11). A solution of 2,4-
dimethoxybenzoic acid 13 (2.7 g, 14.8 mmol, 1.5 equiv) in thionyl
chloride (50 mL) was refluxed at 80 °C for 1 h, and then the excess
thionyl chloride was removed in vacuo to obtain the crude product
benzoyl chloride 17. The crude 17 was then dissolved in pyridine (10
mL), to which a solution of 16 (3.2 g, 9.9 mmol, 1.0 equiv) in
pyridine solution (60 mL) was added under a N2 atmosphere. The
reaction mixture was stirred at rt for 1 h and then quenched with
H2O. The mixture was neutralized with 1% HCl solution and
extracted with EtOAc (3 × 100 mL). The collected organic layers
were evaporated in vacuo to give the crude product 18, which was
dissolved in pyridine (100 mL) without purification. After adding
NaOH (1.6 mg, 40.0 mmol, 4.0 equiv) to the above solution, the
mixture was stirred at 50 °C for 1 h and then quenched with cold
H2O. A solution of HCl was added to neutralize the mixture, which
was then extracted with EtOAc (3 × 100 mL) to obtain the
corresponding organic phase. After removal of organic solvent under
reduced pressure, the crude product was successively washed by cold
water (3 × 50 mL) and MeOH (3 × 50 mL) to obtain the pure 11
(3.6 g, 76%) as a yellow solid. IR (neat) νmax 2924, 1593, 1553, 1455,
1255, 1210, 1123, 1018, 790, 587 cm−1. 1H NMR (400 MHz, CDCl3)
δ 14.51 (s, 1H), 7.93 (d, J = 8.8 Hz, 1H), 6.56 (dd, J = 8.8 and 2.3 Hz,
1H), 6.44 (d, J = 2.3 Hz, 1H), 5.95 (s, 1H), 4.53 (s, 2H), 3.93 (s,
3H), 3.87 (s, 3H), 3.78 (s, 3H), 3.66 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 200.1, 193.2, 165.1 (two carbons), 164.4, 163.5,
161.0, 133.1, 112.0, 106.4, 105.7, 98.4, 86.7, 67.2, 59.8, 56.6, 55.8,
EXPERIMENTAL SECTION
■
General Information. IR spectra were determined in neat on a
Bruker Tensor 37 infrared spectrophotometer. ECD spectra were
recorded on an Applied Photophysics Chirascan spectrometer. NMR
spectra were measured on Bruker AM-400 and AM-500 spectrom-
eters. HRESIMS were performed on a Waters Micromass Q-TOF
spectrometer (Waters, Milford, MA, USA). Semi-preparative HPLC
was performed with a Shimadzu LC-20AT equipped with an SPD-
M20A PDA detector. Purification by HPLC was obtained on a YMC-
pack ODS-A column (250 × 10 mm, S-5 μm, 12 nm). A chiral
column (Phenomenex Lux, cellulose-2, 250 × 4.6 mm, 5 μm) was
used for chiral analysis. Silica gels (100−200 and 300−400 mesh,
Qingdao Haiyang Chemical Co., Ltd.) were used for flash column
chromatography. All the chemical reagents were used directly without
further purification otherwise noted.
( E ) - 3 - (2 , 4 - D i me t h o x y p h eny l) - 1 - ( 2 - h y d r o x y - 4 -
methoxyphenyl)prop-2-en-1-one (6).7 To a solution of 4′-
methoxy-2′-hydroxyacetophenone 8 (1.6 g, 9.6 mmol, 1.0 equiv)
and 2,4-dimethoxybenzaldehyde 9 (1.8 g, 10.8 mmol, 1.1 equiv) in
EtOH (80 mL) was added NaOH (4.0 g, 100 mmol, 10.0 equiv) at rt.
The reaction mixture was stirred at rt for 16 h, and then H2O (100
mL) was added. After neutralization of the mixture by HCl on an ice
bath, the orange precipitate was filtered and washed with ice water to
1
obtain pure compound 6 as a yellow solid (2.8 g, 94%). H NMR
(400 MHz, CDCl3) δ 13.70 (s, 1H), 8.12 (d, J = 15.5 Hz, 1H), 7.81
(d, J = 9.3 Hz, 1H), 7.60 (d, J = 15.5 Hz, 1H), 7.56 (d, J = 8.6 Hz,
1H), 6.53 (dd, J = 8.6 and 2.3 Hz, 1H), 6.46 (m, 3H), 3.91 (s, 3H),
3.85 (s, 3H), 3.84 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
192.6, 166.7, 165.9, 163.3, 160.6, 140.3, 131.4, 131.3, 118.4, 117.1,
114.4, 107.5, 105.6, 101.1, 98.5, 55.7, 55.64, 55.62.
(E)-3-(2,4-Dimethoxyphenyl)-1-(4-methoxy-2-((3-methyl-
but-2-en-1-yl)oxy)phenyl)prop-2-en-1-one (14).7 To a solution
of compound 6 (1.6 g, 5.1 mmol, 1.0 equiv) in acetone (70 mL) was
added K2CO3 (6.9 g, 50.0 mmol, 10.0 equiv) and prenyl bromide (0.8
mL, 7.0 mmol, 1.4 equiv). After stirring the mixture at rt for 16 h, the
solvent acetone was removed in vacuo, and then the residue was
diluted with ice H2O and extracted with DCM (3 × 30 mL). The
combined organic phases were evaporated in vacuo and crystallized in
1
(PE/DCM, 1:1) to give pure 14 as a yellow solid (1.4 g, 70%). H
NMR (400 MHz, CDCl3) δ 7.96 (d, J = 15.9 Hz, 1H), 7.79 (d, J = 8.6
Hz, 1H), 7.58 (d, J = 15.9 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 6.55
(dd, J = 8.6 and 2.3 Hz, 1H), 6.49 (dd, J = 8.6 and 2.3 Hz, 1H), 6.48
(dd, J = 2.3 Hz, 1H), 6.44 (d, J = 2.3 Hz, 1H), 5.53 (t, J = 6.6 Hz,
1H), 4.59 (d, J = 6.6 Hz, 2H), 3.85 (s, 6H), 3.84 (s, 3H), 1.76 (s,
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55.7, 55.6. HRMS (ESI) m/z: [M + H]+ calcd for C19H20IO7
487.0248; found, 487.0249.
Hz, 1H), 6.47 (d, J = 2.3 Hz, 1H), 6.19 (1H, s), 4.86 (t, J = 7.4 Hz,
1H), 3.97 (3H, s), 3.94 (3H, s), 3.84 (3H, s), 3.80 (3H, s), 3.46 (t, J =
7.3 Hz, 1H), 3.25 (dq, J = 9.6 and 7.1 Hz, 1H), 3.14 (dq, J = 9.6 and
7.1 Hz, 1H), 1.94 (t, J = 7.3 Hz, 2H), 1.48 (s, 3H), 1.24 (s, 3H), 0.82
(t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 193.0,
163.5, 162.9, 161.6, 158.1, 157.9, 132.9, 131.3, 120.5, 117.6, 107.7,
105.8, 103.8, 99.0, 89.6, 66.4, 59.2, 56.6, 56.5, 55.50, 55.48, 54.9, 27.3,
25.8, 17.5, 15.1. HRMS (ESI) m/z: [M + H]+ calcd for C26H32IO7
583.1187; found, 583.1196.
(E)-4,4,5,5-Tetramethyl-2-(3-methylbuta-1,3-dien-1-yl)-
1,3,2-dioxaborolane (24).9 Compound 23 (0.4 mL, 4.2 mmol, 1.0
equiv), compound 22 (0.7 mL, 4.8 mmol, 1.15 equiv), Cp2ZrHCl (55
mg, 0.2 mmol, 0.05 equiv), and dry DCM were introduced in a tube
at 0 °C under a N2 atmosphere. After stirring in the dark for 20 h at rt,
the solution was diluted with water and extracted with DCM (3 × 15
mL). The organic layer was evaporated in vacuo and purified by flash
chromatography using PE as eluent to give compound 24 as a
colorless oil (650 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 7.08 (d, J
= 18.2 Hz, 1H), 5.53 (d, J = 18.2 Hz, 1H), 5.13 (s, 2H), 1.82 (s, 3H),
1.25 (s, 12H). 13C{1H} NMR (100 MHz, CDCl3) δ 152.3, 143.1,
120.2, 83.3, 24.9 (three carbons), 17.8.
(E)-2-(2,4-Dimethoxyphenyl)-5,7-dimethoxy-3-(3-methyl-
but-2-en-1-yl)-8-(3-methylbuta-1,3-dien-1-yl)-4H-chromen-4-
one (5). Compound 10 (540 mg, 1.0 mmol, 1.0 equiv), compound
24 (290 mg, 1.5 mmol, 1.5 equiv), (PCy3)2PdCl2 (45 mg, 0.06 mmol,
0.06 equiv), and K2CO3 (2120 mg, 10.0 mmol, 10.0 equiv) were
mixed in deoxygenated toluene (20 mL), which was stirred at 60 °C
for 4 h under a N2 atmosphere. After removal of insoluble substances
from the mixture by filtration, the organic solvent was evaporated in
vacuo. The crude was purified by flash column chromatography (PE/
EtOAc, 3:1) to give pure compound 5 (195 mg, 41%) as a yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 9.1 Hz, 1H), 7.23 (d, J =
16.6 Hz, 1H), 6.76 (d, J = 16.6 Hz, 1H), 6.55 (d, J = 9.1 Hz, 1H),
6.54 (d, J = 2.3 Hz, 1H), 6.39 (br. s, 1H), 5.21 (tt, J = 6.7 and 1.3 Hz,
1H), 4.94 (s, 1H), 4.86 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 3.87 (s,
3H), 3.78 (s, 3H), 3.06 (br. s, 2H), 1.89 (s, 3H), 1.60 (s, 3H), 1.43 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 177.8, 162.4, 160.9, 160.0,
158.5, 157.7, 156.7, 143.5, 134.7, 131.8, 131.2, 123.2, 122.5, 117.9,
116.3, 115.10, 108.7, 106.8, 104.3, 98.6, 91.0, 56.3, 55.9, 55.51, 55.48,
25.7, 25.0, 18.2, 17.7. HRMS (ESI) m/z: [M + H]+ calcd for
C29H33O6 477.2272; found, 477.2288.
(E)-1-(2-Hydroxy-4,6-dimethoxy-3-(3-methylbuta-1,3-dien-
1-yl)phenyl)ethan-1-one (25). After mixing compound 16 (320
mg, 1.0 mmol, 1.0 equiv), compound 24 (290 mg, 1.5 mmol, 1.5
equiv), (PCy3)2PdCl2 (45 mg, 0.06 mmol, 0.06 equiv), and K2CO3
(2120 mg, 10.0 mmol, 10.0 equiv) in deoxygenated toluene (20 mL),
the resulting solution was stirred at 60 °C for 4 h under a N2
atmosphere. After filtration, the insoluble substances in the mixture
were removed, and then the organic solvent was evaporated in vacuo
to obtain a crude, which was purified by flash column chromatography
(PE/DCM, 3:1) to give pure compound 25 (190 mg, 73%) as a
yellow solid. IR (neat) νmax 2941, 1613, 1592, 1415, 1273, 1213, 1120,
955, 794 cm−1. 1H NMR (400 MHz, CDCl3) δ 14.58 (s, 1H), 7.30 (d,
J = 16.5 Hz, 1H), 6.75 (d, J = 16.5 Hz, 1H), 5.93 (s, 1H), 5.04 (s,
1H), 5.00 (s, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 2.61 (s, 3H), 1.98 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 203.7, 164.7, 163.7, 162.4,
143.8, 134.0, 118.8, 115.8, 107.1, 105.8, 86.0, 55.7, 55.5, 33.3, 18.5.
HRMS (ESI) m/z: [M + H]+ calcd for C15H19O4 263.1278; found,
263.1264.
(E)-1-(2,4-Dimethoxyphenyl)-3-(2-hydroxy-4,6-dimethoxy-
3-(3-methylbuta-1,3-dien-1-yl)phenyl)propane-1,3-dione
(26). Compound 11 (485 mg, 1.0 mmol, 1.0 equiv), compound 24
(290 mg, 1.5 mmol, 1.5 equiv), (PCy3)2PdCl2 (45 mg, 0.06 mmol,
0.06 equiv), and K2CO3 (2120 mg, 10.0 mmol, 10.0 equiv) were
mixed in deoxygenated toluene (20 mL), which was stirred at 60 °C
under a N2 atmosphere for 4 h. After treating the mixture as the
progresses described above, the crude was purified by flash column
chromatography (PE/DCM, 1:1) to give pure compound 26 (145
mg, 34%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 13.95 (s,
1H), 7.96 (d, J = 8.8 Hz, 1H), 7.63 (s, 1H), 7.31 (d, J = 16.5 Hz, 1H),
1-(2,4-Dimethoxyphenyl)-3-(2-hydroxy-3-iodo-4,6-dime-
thoxyphenyl)-2-(3-methylbut-2-en-1-yl)propane-1,3-dione
(20). To a solution of compound 11 (240 mg, 0.49 mmol, 1.0 equiv)
in acetone was added K2CO3 (200 mg, 0.75 mmol, 1.5 equiv) and
prenyl bromide (140 μL, 0.6 mmol, 1.2 equiv) at rt. After stirring at rt
for 2 h, the reaction mixture was filtered to remove the base K2CO3,
and then the organic phase filtrate was concentrated in vacuo to yield
a crude product, which was purified by flash column chromatography
(PE/DCM, 2:1) to give compound 19 (150 mg, 49%) as a yellow oil
and compound 20 (98 mg, 36%) as a white solid. Subsequently, the
yellow oil of 19 (62 mg, 0.1 mmol, 1.0 equiv) was dissolved in EtOH
(20 mL), and then a drop of concentrated sulfuric acid was added at
rt. After stirring for 1 h, the white solid was filtered and washed with
EtOH (3 × 5 mL) as compound 20 (50 mg, 91%). Therefore, in the
subsequent large-scale reaction, the crude product was not further
separated, but directly dissolved in EtOH and stirred with sulfuric acid
at rt to yield compound 20.
Compound 19: [α]20D 0 (c 0.1, MeCN). IR (neat) νmax 2926, 1599,
1463, 1367, 1262, 1212, 1110, 1027, 706 cm−1. 1H NMR (400 MHz,
CDCl3) δ 7.48 (d, J = 8.7 Hz, 1H), 6.37 (dd, J = 8.7 and 2.3 Hz, 1H),
6.24 (d, J = 2.3 Hz, 1H), 5.99 (s, 1H), 5.48 (m, 2H), 5.10 (tt, J = 7.2
and 1.3 Hz, 1H), 4.41 (dd, J = 10.6 and 7.2 Hz, 1H), 4.29 (dd, J =
10.6 and 7.2 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.71 (s, 3H), 3.57
(s, 3H), 2.74 (dt, J = 14.9 and 7.7 Hz, 1H), 2.64 (dt, J = 14.9 and 6.8
Hz, 1H), 1.74 (s, 3H), 1.66 (s, 3H), 1.63 (s, 3H), 1.60 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 197.7, 195.5, 164.2, 160.6,
160.3, 158.4, 157.5, 138.3, 133.04, 132.95, 121.93, 121.90, 120.0,
119.4, 105.0, 97.8, 91.3, 74.2, 72.7, 66.1, 56.6, 55.7, 55.62, 55.57, 27.3,
25.92, 25.89, 18.4, 17.8. HRMS (ESI) m/z: [M + H]+ calcd for
C29H36IO7 623.1500; found, 623.1511.
Compound 20: [α]20D 0 (c 0.1, MeCN). IR (neat) νmax 2920, 1595,
1
1464, 1374, 1266, 1212, 1124, 1024, 832, 736 cm−1. H NMR (400
MHz, CDCl3) δ 14.7 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 6.52 (dd, J =
8.8 and 2.1 Hz, 1H), 6.43 (d, J = 2.1 Hz, 1H), 5.95 (s, 1H), 5.46 (dd,
J = 7.1 and 5.8 Hz, 1H), 5.07 (t, J = 6.8 Hz, 1H), 3.87 (s, 3H), 3.82
(s, 3H), 3.73 (s, 3H), 3.61 (s, 3H), 2.57 (dt, J = 14.0 and 7.1 Hz, 1H),
2.53 (dt, J = 14.0 and 5.8 Hz, 1H), 1.59 (s, 3H), 1.56 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 201.8, 194.6, 165.0, 164.9,
164.0, 163.1, 160.4, 133.5, 132.6, 122.4, 119.0, 106.0, 105.7, 98.0,
86.6, 67.1, 64.6, 56.5, 55.6, 55.5, 55.3, 27.2, 25.8, 17.7. HRMS (ESI)
m/z: [M + H]+ calcd for C24H27IO7 555.0874; found, 555.0864.
2-(2,4-Dimethoxyphenyl)-8-iodo-5,7-dimethoxy-3-(3-meth-
ylbut-2-en-1-yl)-4H-chromen-4-one (10). The white solid of
compound 20 (550 mg, 0.99 mmol, 1.0 equiv) was dissolved in
absolute ethanol (20 mL), and then five drops of concentrated
sulfuric acid was added at rt. After stirring at 55 °C for 60 h, the
reaction mixture was diluted with H2O and extracted with DCM (3 ×
15 mL). After removal of the solvent in vacuo, the crude residue was
purified by flash column chromatography (PE/EtOAc, 4:1) to give
two pure yellow oils 10 (223 mg, 42%) and 21 (200 mg, 35%). The
byproduct 21 (60 mg, 0.1 mmol, 1.0 equiv) was then dissolved in
ethanol (2 mL) with a drop of concentrated sulfuric acid. After
stirring for 24 h at rt, the mixture was diluted with H2O and extracted
with DCM (3 × 2 mL), and then 10 (16 mg, 28%) could be obtained
from the crude residue by flash column chromatography (PE/EtOAc,
4:1).
Compound 10: IR (neat) νmax 2927, 1590, 1464, 1393, 1336, 1211,
1161, 1029, 939, 808 cm−1. 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J
= 8.3 Hz, 1H), 6.57 (dd, J = 8.3 and 2.2 Hz, 1H), 6.55 (d, J = 2.2 Hz,
1H), 6.39 (s, 1H), 5.17 (t, J = 6.8 Hz, 1H), 4.01 (s, 3H), 3.99 (s, 3H),
3.87 (s, 3H), 3.81 (s, 3H), 3.04 (s, 2H), 1.59 (s, 3H), 1.42 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 177.4, 162.6, 162.4, 162.2,
158.7, 158.11, 158.09, 131.9, 131.5, 123.6, 122.4, 115.1, 109.6, 104.7,
98.9, 91.4, 64.8, 56.8, 56.6, 55.8, 55.6, 25.8, 25.2, 17.8. HRMS (ESI)
m/z: [M + H]+ calcd for C24H26IO6 537.0769; found, 537.0787.
Compound 21: [α]20D 0 (c 0.1, MeCN). IR (neat) νmax 2926, 1585,
1
1555, 1390, 1210, 1123, 1030, 938.9, 800, 733 cm−1. H NMR (400
MHz, CDCl3) δ 8.15 (d, J = 8.7 Hz, 1H), 6.58 (dd, J = 8.7 and 2.3
4790
https://dx.doi.org/10.1021/acs.joc.1c00229
J. Org. Chem. 2021, 86, 4786−4793

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
6.80 (d, J = 16.5 Hz, 1H), 6.59 (d, J = 8.8 and 2.2 Hz, 1H), 6.50 (d, J
= 2.2 Hz, 1H), 6.01 (s, 1H), 5.05 (s, 1H), 4.99 (s, 1H), 3.95 (s, 3H),
3.94 (s, 3H), 3.93 (s, 3H), 3.87 (s, 3H), 2.00 (s, 3H). HRMS (ESI)
m/z: [M + H]+ calcd for C24H27O7 427.1752; found, 427.1745.
(E)-1-(2,4-Dimethoxyphenyl)-3-(2-hydroxy-4,6-dimethoxy-
3-(3-methylbuta-1,3-dien-1-yl)phenyl)-2-(3-methylbut-2-en-
1-yl)propane-1,3-dione (27). To a solution of compound 26 (210
mg, 0.48 mmol, 1.0 equiv) in acetone was added K2CO3 (200 mg,
0.75 mmol, 1.6 equiv) and prenyl bromide (150 μL, 0.6 mmol, 1.3
equiv) at rt. After stirring at rt for 2 h, the reaction mixture was
filtered and concentrated, and then the product 27 (64 mg, 27%) as a
yellow oil was purified from the crude by flash column
(d, J = 8.5 Hz, 1H), 5.21 (s, 1H), 5.15 (t, J = 6.6 Hz, 1H), 5.04 (t, J =
6.9 Hz, 1H), 4.48 (t, J = 10.0 Hz, 1H), 4.31 (d, J = 9.3 Hz, 1H), 3.98
(s, 3H), 3.86 (s, 3H), 3.78 (s, 3H), 3.75 (s, 3H), 3.68 (s, 3H), 3.67 (s,
6H), 3.63 (s, 3H), 3.13 (t, J = 7.0 Hz, 2H), 3.09 (d, J = 6.9 Hz, 1H),
3.05 (d, J = 5.5 Hz, 1H), 1.97 (d, J = 16.5 Hz, 1H), 1.68 (s, 3H), 1.63
(s, 3H), 1.60 (s, 3H), 1.43 (s, 6H). 13C{1H} NMR (125 MHz,
MeOD) δ 210.1, 179.5, 164.3, 164.1, 162.5, 161.9, 161.1, 160.6,
159.7, 159.4, 158.8, 134.1, 132.5, 132.4, 132.0, 130.7, 128.5 (observed
in HSQC), 126.1, 124.6, 124.2, 123.4, 123.3, 117.1, 117.0, 116.3,
111.4, 109.3, 106.6, 105.5, 102.5, 99.8, 99.6, 92.2, 57.1, 56.5, 56.3,
56.2, 56.1, 55.8, 55.6, 48.7, 39.5, 38.8 (observed in HSQC), 26.0,
25.9, 25.5, 23.2, 22.3, 17.9, 17.7. HRMS (ESI) m/z: [M + H]+ calcd
for C52H59O11 859.4052; found, 859.4033.
chromatography (PE/DCM, 1:1). [α]20 0 (c 0.1, MeCN). 1H
D
( )-Kuwanon G (1).12 To a solution of compound 3 (80 mg, 0.11
mmol, 1.0 equiv) in dry DCM (10 mL) was added 1 M BBr3 in DCM
(2.2 mL, 1.65 mmol, 15.0 equiv) in a sealed tube, and then the
reaction mixture was stirred at −78 to 50 °C under a N2 atmosphere
for 120 h. After that, the reaction was quenched with H2O (20 mL)
and extracted with EtOAc (3 × 5 mL). The resultant dark red solid
was purified by HPLC (CH3CN/H2O, 3:1, 3 mL/min) to afford 1
NMR (400 MHz, CDCl3) δ 14.43 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H),
7.30 (d, J = 16.5 Hz, 1H), 6.77 (d, J = 16.5 Hz, 1H), 6.56 (d, J = 8.8
and 2.1 Hz, 1H), 6.43 (d, J = 2.1 Hz, 1H), 5.93 (s, 1H), 5.44 (t, J =
6.3 Hz, 1H), 5.11 (t, J = 6.9 Hz, 1H), 5.04 (s, 1H), 4.99 (s, 1H), 3.92
(s, 3H), 3.86 (s, 3H), 3.70 (s, 3H), 3.65 (s, 3H), 2.64 (m, 2H), 1.98
(s, 3H), 1.63 (s, 3H), 1.58 (s, 3H). HRESIMS m/z: [M + H]+ calcd
for C29H35O7 495.237; found, 495.2382.
1
(16 mg, tR 16.5 min, 21%) as a yellow solid. The H and 13C{1H}
( )-Kuwanon G Heptamethyl Ether (3). The solution of diene
5 (100 mg, 0.21 mmol, 1.0 equiv) and dienophile 6 (160 mg, 0.51
mmol, 2.4 equiv) in toluene was introduced in a sealed tube, which
was stirred at 180 °C for 40 h. Subsequently, the solvent was removed
in vacuo and then the corresponding crude products were separated
by flash column chromatography (DCM/MeOH, 300:1) to give two
pure yellow oils 3 (38 mg, 23%) and 3a (40 mg, 24%).
NMR data of 1 was consistent with that of kuwanon G.12
Subsequently, compound 1 (10 mg) was subjected to HPLC with a
chiral column (CH3CN/H2O, 3:1, 3 mL/min) to obtain the
enantiomers (+)-1 (3.5 mg, tR 17.2 min) and (−)-1 (4.2 mg, tR
18.0 min).
Compound (−)-1 (kuwanon G): [α]20 −94.2 (c 0.1, MeCN).
D
Compound 3 (exo): [α]20D 0 (c 0.1, MeCN). IR (neat) νmax 2955,
ECD (c 2.9 × 10−4 M, MeCN) λmax (Δε) 282 (−4.59), 267 (+2.28),
237 (−5.48), 209 (−15.85) nm. IR (neat) νmax 3349, 2916, 1654,
1
2918., 2851, 1611, 1459, 1210, 1159, 1083, 1034, 971, 814 cm−1. H
1
1612, 1439, 1378, 1226, 1162, 981, 833 cm−1. H NMR (400 MHz,
NMR (500 MHz, MeOD) δ 7.29 (br. s, 1H), 7.27 (br. s, 1H), 6.76
(d, J = 8.2 Hz, 1H), 6.71 (d, J = 7.7 Hz, 1H), 6.32 (s, 1H), 6.28 (s,
1H), 6.25 (d, J = 8.2 Hz, 1H), 6.11 (s, 1H), 5.99 (d, J = 8.8 Hz, 1H),
5.21 (br. s, 1H), 5.13 (t, J = 6.3 Hz, 1H), 4.50 (t, J = 10.1 Hz, 1H),
4.38 (d, J = 9.5 Hz, 1H), 4.32 (d, J = 9.4 Hz, 1H), 3.97 (s, 3H), 3.87
(s, 3H), 3.81 (s, 3H), 3.73 (s, 3H), 3.69 (s, 3H), 3.66 (br. s, 1H), 3.65
(s, 6H), 3.09 (br. s, 1H), 3.03 (br. s, 1H), 1.95(d, J = 16.0 Hz, 1H),
1.72 (s, 1H), 1.63 (s, 3H), 1.50 (s, 3H), 1.42 (s, 3H). 13C{1H} NMR
(125 MHz, MeOD) δ 209.8, 179.5, 167.2, 165.8, 164.4, 162.6, 161.2,
160.7, 159.6, 159.4, 158.8, 134.3, 132.8, 132.6, 132.4, 128.8 (observed
in HSQC), 124.6, 124.3, 123.3, 116.4, 116.3, 111.3, 109.2, 107.4,
106.6, 105.4, 101.2, 99.8, 99.5, 92.4, 57.0, 56.7, 56.4, 56.2, 56.0, 55.8,
55.6, 48.4 (observed in HSQC), 39.2, 38.7 (observed in HSQC),
25.9, 25.4, 23.2, 17.7. HRMS (ESI) m/z: [M + H]+ calcd for
C47H51O11 791.3426; found, 791.3472.
MeOD) δ 7.31 (br. s, 1H), 7.12 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 8.3
Hz, 1H), 6.48 (s, 1H), 6.45 (d, J = 8.1 Hz, 1H), 6.12 (s, 1H), 6.05
(dd, J = 8.3 and 2.4 Hz, 1H), 5.92 (s, 2H), 5.87 (d, J = 8.6 Hz, 1H),
5.15 (br. s, 1H), 5.14 (t, J = 7.0 Hz, 1H), 4.59 (br. s, 1H), 4.32 (d, J =
9.4 Hz, 1H), 3.66 (br. s, 1H), 3.15 (br. s, 2H), 1.93 (d, J = 14.0 Hz,
1H), 1.62 (s, 3H), 1.46 (s, 3H), 1.43 (s, 3H). 13C{1H} NMR (100
MHz, MeOD) δ 210.2, 183.9, 165.9, 165.8, 163.3, 162.5, 161.8, 161.1,
157.8, 156.9, 134.4, 134.1, 132.7, 132.7, 128.7 (observed in HSQC),
124.7, 123.0 (two carbons), 121.7, 115.9, 113.8, 108.6, 108.3, 107.9,
107.7, 105.7, 103.7, 103.6, 102.9, 98.5, 48.8 (observed in HSQC),
39.1, 39.0 (observed in HSQC), 25.9, 24.7, 23.2, 17.7. HRMS (ESI)
m/z: [M + H]+ calcd for C40H37O11 693.2330; found, 693.2331.
Compound (+)-1 ((+)-kuwanon G): [α]20D + 87.1 (c 0.1, MeCN).
ECD (c 2.9 × 10−4 M, MeCN) λmax (Δε) 283 (+2.73), 266 (−2.56),
237 (+2.75), 209 (+10.79) nm. IR, NMR, and HRMS data are the
same as those of (−)-1.
endo-( )-Kuwanon G Heptamethyl Ether (3a). [α]20 0 (c 0.1,
D
MeCN). IR (neat) νmax 2946, 2917, 2873, 1587, 1454, 1281, 1148,
1098, 1052, 977, 808 cm−1. 1H NMR (400 MHz, MeOD) δ 7.86 (br.
s, 1H), 6.86 (br. s, 1H), 6.65 (s, 1H), 6.62 (d, J = 8.3 Hz, 1H), 6.39
(overlapped, 1H), 6.37 (s, 1H), 6.32 (s, 1H), 6.27 (dd, J = 2.0 and 8.3
Hz, 1H), 6.24 (s, 1H), 5.41 (s, 1H), 5.10 (t, J = 6.2 Hz, 1H), 4.50 (s,
1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.80 (overlapped, 6H), 3.67 (s, 6H),
3.37 (br. s, 1H), 2.98 (br. s, 2H), 1.61 (s, 3H), 1.37 (s, 3H), 1.30 (s,
3H). 13C{1H} NMR (100 MHz, MeOD) δ 207.9, 179.7, 166.9, 165.8,
164.1, 163.2, 161.3, 160.5, 159.6, 159.4, 134.5, 133.1, 132.5, 132.0,
129.9, 126.7, 123.9, 123.3, 122.6, 116.2, 110.1, 109.1, 107.7, 105.9,
105.4, 101.6 (observed in HSQC), 99.7, 99.5, 92.1, 56.3, 56.2, 56.1,
56.0, 55.7, 55.6, 26.0, 25.9, 25.4, 23.5, 17.6. HRMS (ESI) m/z: [M +
H]+ calcd for C47H51O11 791.3426; found, 791.3472.
( )-Kuwanon H (2).12 Starting from compound 4 (85 mg, 0.10
mmol, 1.0 equiv), compound 2 was prepared following the same
procedures used for synthesis of 1. The resultant dark red solid was
purified by HPLC (CH3CN/H2O, 3:1, 3 mL/min) to afford 2 (19
1
mg, tR 22.5 min, 26%) as a yellow solid. The H and 13C{1H} NMR
data of 2 was consistent with that of kuwanon H.12 Subsequently,
compound 2 (10 mg) was subjected to HPLC with a chiral column
(CH3CN/H2O, 3:1, 3 mL/min) to obtain the enantiomers (+)-2 (4.6
mg, tR 24.3 min) and (−)-2 (3.8 mg, tR 25.0 min).
Compound (−)-2 (kuwanon H): [α]20 −116.4 (c 0.1, MeCN).
D
ECD (c 2.6 × 10−4 M, MeCN) λmax (Δε) 288 (−3.98), 269 (+2.96),
238 (−5.85), 208 (−10.92) nm. IR (neat) νmax 3356, 2913, 1651,
1
1619, 1432, 1370, 1241, 1162, 978, 841 cm−1. H NMR (400 MHz,
( )-Kuwanon G Heptamethyl Ether (4). Starting from diene 5
(120 mg, 0.25 mmol, 1.0 equiv) and dienophile 7 (165 mg, 0.5 mmol,
2.0 equiv), compound 4 were prepared following the same procedures
used for synthesis of 3. The crude products were purified by flash
column chromatography (DCM/MeOH, 300:1) to give a pure yellow
oil 4 (60 mg, 28%), while the endo-adduct 4a was not isolated in this
step.
MeOD) δ 7.18 (br. s, 1H), 7.13 (d, J = 8.2 Hz, 1H), 6.75 (d, J = 8.3
Hz, 1H), 6.49 (s, 1H), 6.45 (d, J = 8.2 and 1.8 Hz, 1H), 6.14 (s, 1H),
6.07 (dd, J = 8.3 and 2.4 Hz, 1H), 5.92 (s, 1H), 5.91 (d, J = 10.1 Hz,
1H), 5.18 (s, 1H), 5.16 (t, J = 7.0 Hz, 1H), 5.04 (d, J = 7.0 Hz, 1H),
4.57 (br. s, 1H), 4.32 (d, J = 9.2 Hz, 1H), 3.69 (br. s, 1H), 3.16 (m,
2H), 3.09 (d, J = 7.0 Hz, 2H), 1.95 (d, J = 13.3 Hz, 1H), 1.66 (s, 3H),
1.63 (s, 3H), 1.59 (s, 3H), 1.47 (br. s, 3H), 1.45 (s, 3H). 13C{1H}
NMR (100 MHz, MeOD) δ 210.3, 183.9, 163.6, 163.4, 163.0, 162.5,
161.8, 161.0, 157.8, 157.7, 156.9, 134.4, 132.7, 132.7 (observed in
HSQC), 131.6, 131.2 (observed in HSQC), 128.8 (observed in
HSQC), 124.6, 123.7, 123.0, 121.6, 115.8, 115.3, 113.8, 108.7, 107.9,
Compound 4 (exo): [α]20D 0 (c 0.1, MeCN). IR (neat) νmax 2956,
2923, 2851, 1607, 1507, 1463, 1332, 1201, 1158, 1132, 1032, 814
cm−1. 1H NMR (500 MHz, MeOD) δ 7.28 (d, J = 7.5 Hz, 1H), 7.23
(d, J = 8.5 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.78 (s, 1H), 6.70 (d, J =
7.5 Hz, 1H), 6.34 (s, 1H), 6.26 (d, J = 7.6 Hz, 1H), 6.14 (s, 1H), 6.03
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107.3, 105.7, 103.7, 103.6, 98.5, 48.7 (observed in HSQC), 39.2, 39.2
(observed in HSQC), 25.9, 24.7, 23.2, 22.3, 17.8, 17.7. HRMS (ESI)
m/z: [M + H]+ calcd for C45H45O11 761.2956; found, 761.2941.
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are the same as those of (−)-2.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00229.
■
sı
Comparison of the NMR data of isolated and synthetic
kuwanons G and H, ECD spectra of (+)-1/(−)-1 and
(+)-2/(−)-2, and NMR spectra of all synthetic
compounds (PDF)
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Intermolecular [4+2] Cycloaddition in Natural Product Biosynthesis.
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AUTHOR INFORMATION
Corresponding Author
Gui-Hua Tang − School of Pharmaceutical Sciences, Sun Yat-
sen University, Guangzhou 510006, People’s Republic of
China; orcid.org/0000-0002-8831-7154;
Email: tanggh5@mail.sysu.edu.cn
■
Authors
Si-Yuan Luo − School of Pharmaceutical Sciences, Sun Yat-sen
University, Guangzhou 510006, People’s Republic of China
Zhuo-Ya Tang − School of Pharmaceutical Sciences, Sun Yat-
sen University, Guangzhou 510006, People’s Republic of
China
Qingjiang Li − School of Pharmaceutical Sciences, Sun Yat-sen
University, Guangzhou 510006, People’s Republic of China;
orcid.org/0000-0001-5535-6993
(12) Xia, C. L.; Tang, G. H.; Guo, Y. Q.; Xu, Y. K.; Huang, Z. S.;
Yin, S. Mulberry Diels−Alder-Type Adducts from Morus alba as
Multi-Targeted Agents for Alzheimer’s Disease. Phytochemistry 2019,
157, 82−91.
Jiang Weng − School of Pharmaceutical Sciences, Sun Yat-sen
University, Guangzhou 510006, People’s Republic of China;
orcid.org/0000-0002-4117-4686
(13) Nomura, T.; Fukai, T.; Narita, T.; Terada, S.; Uzawa, J.; Iitaka,
Y.; Takasugi, M.; Ishikawa, S.-i.; Nagao, S.; Masamune, T.
Confirmation of the Structures of Kuwanons G and H (Albanins F
and G) by Partial Synthesis. Tetrahedron Lett. 1981, 22, 2195−2198.
(14) Talamás, F. X.; Smith, D. B.; Cervantes, A.; Franco, F.; Cutler,
S. T.; Loughhead, D. G.; Morgans, D. J.; Weikert, R. J. The Florisil®
Catalyzed [1,3]-Sigmatropic Shift of Allyl Phenyl Ethers  An
Entryway into Novel Mycophenolic Acid Analogues. Tetrahedron Lett.
1997, 38, 4725−4728.
Sheng Yin − School of Pharmaceutical Sciences, Sun Yat-sen
University, Guangzhou 510006, People’s Republic of China;
orcid.org/0000-0002-5678-6634
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00229
Notes
The authors declare no competing financial interest.
(15) Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-Coupling
Reactions of Organoboron Compounds. Chem. Rev. 1995, 95, 2457−
2483.
ACKNOWLEDGMENTS
■
The authors thank the National Natural Science Foundation of
China (nos. 81973203 and 81973195), the Guangdong Basic
and Applied Basic Research Foundation, China (no.
2020A1515010841), the Fundamental Research Funds for
the Central Universities (no. 20ykjc04), the Traditional
Chinese Medicine Bureau of Guangdong Province, China
(no. 20191058), and the Key-Area Research and Development
Program of Guangdong Province, China (no.
2020B1111110003) for providing financial support to this
work.
(16) Wu, D.; Zhang, T.; Chen, Y.; Huang, Y.; Geng, H.; Yu, Y.;
Zhang, C.; Lai, Z.; Wu, Y.; Guo, X.; Chen, J.; Luo, H. B. Discovery
and Optimization of Chromeno[2,3-c]pyrrol-9(2H)-ones as Novel
Selective and Orally Bioavailable Phosphodiesterase 5 Inhibitors for
the Treatment of Pulmonary Arterial Hypertension. J. Med. Chem.
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Dumontet, C. Antimitotic and Antiproliferative Activities of
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