Rhodomentosones A and B: Two Pairs of Enantiomeric Phloroglucinol Trimers from Rhodomyrtus tomentosa and Their Asymmetric Biomimetic Synthesis

Article abstract of DOI:10.1021/acs.orglett.1c01616

Rhodomentosones A and B (1 and 2), two pairs of novel enantiomeric phloroglucinol trimers featuring a unique 6/5/5/6/5/5/6-fused ring system were isolated from Rhodomyrtus tomentosa. Their structures with absolute configurations were elucidated by NMR spe

Full text of DOI:10.1021/acs.orglett.1c01616

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Letter
Rhodomentosones A and B: Two Pairs of Enantiomeric
Phloroglucinol Trimers from Rhodomyrtus tomentosa and Their
Asymmetric Biomimetic Synthesis
Lu-Ming Deng,⊥ Li-Jun Hu,⊥ Yang-Ting-Zhi Bai, Jie Wang, Guan-Qiu Qin, Qiao-Yun Song,
Jun-Cheng Su, Xiao-Jun Huang, Ren-Wang Jiang, Wei Tang, Yao-Lan Li, Chuang-Chuang Li,*
Wen-Cai Ye,* and Ying Wang*
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ABSTRACT: Rhodomentosones A and B (1 and 2), two pairs of
novel enantiomeric phloroglucinol trimers featuring a unique 6/5/
5/6/5/5/6-fused ring system were isolated from Rhodomyrtus
tomentosa. Their structures with absolute configurations were
elucidated by NMR spectroscopy, X-ray crystallography, and ECD
calculation. The bioinspired syntheses of 1 and 2 were achieved in
six steps featuring an organocatalytic asymmetric dehydroxylation/
Michael addition/Kornblum−DeLaMare rearrangement/ketaliza-
tion cascade reaction. Compounds 1 and 2 exhibited promising
antiviral activities against respiratory syncytial virus (RSV).
olycyclic polymethylated phloroglucinols (PPPs) are an
emerging group of plant specialized metabolites mainly
P
derived from species of the Myrtaceae and Guttiferae
families.1,2 Structurally, PPPs are characterized by incorporat-
ing polymethylated phlorogulcinol core with terpenoid or
acylphloroglucinol unit(s) via various coupling patterns, which
usually resulted in the construction of highly functionalized
polycyclic scaffolds with complex stereochemistry. Besides
their intriguing structural features, PPPs exhibited diverse
biological activities such as antibacterial, anti-inflammatory,
and antiplasmodial activities, which made PPPs attractive
targets for total synthesis.1 In the past few years, a number of
impressive synthetic studies based on a variety of elegant
strategies for constructing their fascinating architectures has
been reported.3 However, strategies for the asymmetric total
syntheses of PPPs are still rarely reported.
The plant Rhodomyrtus tomentosa (Ait.) Hassk. (Myrtaceae)
is an evergreen shrub native to tropical and subtropical area of
Asia. In the southern region of China, the leaves of R.
tomentosa have been used as a folk medicine for the treatment
of cold, fever, and inflammation for a long time. As an ongoing
research interest of our group in recent years, we had reported
the discovery and biomimetic synthesis of a series of novel
PPPs from medicinal plants of family Myrtaceae.4,5 In the
current study, guided by the UPLC−UV−QTOF/HRMS
technique, two pairs of novel enantiomeric phloroglucinol
trimers, rhodomentosones A (1) and B (2) (Figure 1), along
with their biogenetically related dimers (6 and 7)2c,m and
monomer (4a)2p were isolated from the leaves of the title
plant. Structurally, compounds 1 and 2 possess an
Figure 1. Chemical structures of 1 and 2.
unprecedented highly functionalized 6/5/5/6/5/5/6-fused
heptacyclic ring system with a striking tetrafuran-di-β-triketone
core. Sharing the identical planar structure but with a different
Received: May 12, 2021
Published: May 25, 2021
https://doi.org/10.1021/acs.orglett.1c01616
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4499−4504
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configurational relationship between the two independent
stereoclusters, C-9−C-1″ (cluster A) and C-7‴−C-8‴ (cluster
B), made it a difficult task to establish their stereostructures. A
combination of X-ray crystallography and ECD methods
allowed the definite determination of the absolute config-
urations of all optically pure stereoisomers (+)-1, (−)-1, (+)-2,
and (−)-2. A plausible biosynthetic pathway for 1 and 2 was
proposed, in which the coexisting phloroglucinol dimers 6 and
7 and monomer 4a served as the putative precursors. Inspired
by this biogenetic hypothesis, the biomimetic syntheses of 1
and 2 were completed by developing a unique organocatalytic
asymmetric dehydroxylation/Michael addition/Kornblum−
DeLaMare rearrangement/ketalization cascade reaction. Here-
in, we report the isolation, structural determination, biogenetic
hypothesis, and asymmetric biomimetic synthesis of 1 and 2.
Moreover, the in vitro antiviral activities of the two novel PPPs
were also evaluated.
each other, the NOE experiment could not provide any useful
information for relative configurational determination between
clusters A and B.
To establish the whole three-dimensional structure of 1, we
tried to obtain the crystals of 1. After several attempts, a
qualified crystal suitable for a single-crystal X-ray diffraction
experiment was crystallized from a binary solvent system
(MeOH/CHCl3, 5:1). As a result, the structure with a relative
configuration of 1 was unambiguously determined as shown in
Figure 3. However, the presence of symmetric space group
The molecular formula of 1 was established to be C41H50O10
on the basis of its HR-ESI-MS data at m/z 725.3297 [M +
Na]+ (calcd for C41H50O10Na: 725.3296). The IR spectrum
suggested the presence of hydroxyl (3194 cm−1) and carbonyl
(1667 and 1717 cm−1) functional groups. Comprehensive
analyses of the 1D and 2D NMR spectroscopic data of 1 led to
the full assignment of its proton and carbon resonances (Table
S1). Further detailed analysis of its 2D NMR spectra resulted
in the establishment of two 1,1,3,3-tetramethyl-β-triketone
moieties (rings A and G) and a fully substituted benzene ring
(ring D) bearing an isovaleryl group in 1. In the HMBC
spectrum, the correlations between H-9 and C-4a/C-4b/C-2″,
between H-7‴ and C-5‴/C-6/C-8/C-9‴, between H3-3″/H3-
4″ and C-1″, and between H3-10‴/H3-11‴ and C-8‴ were
observed, indicating that both of the two β-triketone motifs
were incorporated with the benzene ring via fused bisfuran
rings (rings B/C and E/F). In addition, the HMBC
correlations between H2-2′ and C-5/C-1′ suggested that the
isovaleryl group was linked to the C-5 position of the benzene
ring. In addition, the two isopropyl groups were assigned to
attach to the quaternary carbons C-1″ and C-8‴, respectively,
on the basis of the HMBC cross peaks between H-3″/H-4″
and C-1″, as well as between H-10‴/H-11‴ and C-8‴. Thus,
the planar structure of 1 was determined to be a novel
tetrafuran-di-β-triketone phloroglucinol with an unprecedented
6/5/5/6/5/5/6-fused heptacyclic ring system (Figure 2).
Figure 3. X-ray ORTEP drawings of 1 and 2 (the C and O atoms are
drawn as 50% thermal ellipsoids).
̅
(P1) in its crystal structure as well as its barely measured
specific rotation suggested that 1 was a racemic mixture
(Figure S20 and Table S16). Two optically pure enantiomers,
in a ratio of 1:1, were then successfully separated by HPLC on
a chiral column. Finally, the absolute configurations of the two
enantiomers (+)-1 and (−)-1 were, respectively, established as
9R,1″R,7‴S,8‴S and 9S,1″S,7‴R,8‴R by comparing their
experimental and calculated ECD spectra (Figure S1).
Compound 2 was determined to possess the molecular
formula identical to that of 1 by its HR-ESI-MS data. The
NMR spectroscopic data of 2 highly resembled those of 1,
suggesting the structural similarity of these two compounds.
The significant differences in their NMR spectra were observed
at the signals of the methyl protons (H3-10‴, H3-11‴, and H3-
4″) and the methine protons (H-9, H-7‴, and H-9‴). Detailed
analyses of its 1D and 2D NMR spectral data revealed that 2
possessed the planar structure identical to that of 1 (Figure
S2). Similar to 1, the relative stereochemistries of chiral centers
within clusters A and B of 2 were established by the NOESY
experiment, in which both rings B/C and rings E/F were cis-
conjugated (Figure S3). Subsequently, the structure of 2,
including its relative configuration, was definitely established
by single-crystal X-ray analysis (Figure 3). As shown in Figure
3, compound 2 was a diastereoisomer of 1 with an opposite
configurational relationship between the two stereoclusters.
Similar to 1, the following chiral resolution experiment led to
the separation of a pair of enantiomers of 2. By using the ECD
method similar to that described for 1, the absolute
configurations of (+)-2 and (−)-2 were defined as
9R,1″R,7‴R,8‴R and 9S,1″S,7‴S,8‴S, respectively (Figure S4).
On the basis of their structural feature, the hypothetical
biogenetic pathways of 1 and 2 were proposed employing
leptospermone (3),2a a natural and abundant monomeric
phloroglucinol existing in plants of Myrtaceae, as the putative
precursor (Scheme 1). First, reduction, dehydration, and olefin
migration of 3 could generate the active intermediate I, which
could be further oxidized to afford endoperoxides 4a and 4b.5d
Subsequently, assembling of the endoperoxides and acylphlor-
Figure 2. Key 1H−1H COSY, HMBC, and NOESY correlations of 1.
In the NOESY spectrum, NOE correlations between H-9
and H-2″/H3-3″/H3-4″, and between H-7‴ and H3-9‴/H3-
10‴/H3-11‴, were observed, indicating that rings B/C as well
as rings E/F both adopted a cis conjunction pattern in 1
(Figure 2). Thus, the relative configurations of stereogenic
centers within stereoclusters A and B were established.
However, because the two stereoclusters are too distant from
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photoenolization condition (455 nm blue LEDs) in toluene
as solvent,3e,m followed by [4 + 2] cycloaddition with O2 at
room temperature, generated a mixture of a pair of separable
diastereomers 4a and 4b in a combined yield of 80% on a gram
scale (Scheme 2).
Scheme 1. Hypothetical Biogenetic Pathways of 1 and 2
Next, we turned our attention to investigate the asymmetric
synthesis of dimers 6 and 7. Recently, Porco and co-workers
reported the pioneer racemic synthesis of 6 and 7 by treating
the endoperoxide precursors 4a or 4b with 5 in acetic acid
conditions through a dehydroxylation/Michael addition/
Kornblum−DeLaMare rearrangement/ketalization tandem
reaction.3e,m We then envisioned that chiral phosphoric acids
(CPAs),6 which have been used as powerful organocatalysts
for numerous reactions over the past several decades, might
facilitate this transformation with enantiocontrol. We initially
conducted the tandem reaction of 5 and 4a in toluene at 50 °C
in the presence of phosphoric acid (R)-C1. Encouragingly,
despite the multistep sequence, this transformation proceeded
smoothly to give a separable mixture of (−)-6 and (+)-7 in a
combined yield of 49% and a ratio of 2:1, as well as −74% and
−53% ee, respectively. Subsequently, in order to improve the
enantioselectivity of the above transformation, we investigated
the influences of substituents and axial chiral backbones of the
catalysts. As listed in Table 1, the electron-donating/with-
drawing properties and steric bulk of the aromatic ring
substituents of the catalysts, as well as the nature of their
backbones, could considerably affect the enantioselectivity of
the transformation. We then optimized the reaction conditions
oglucinol 5 via a dehydroxylation/Michael addition/Korn-
blum−DeLaMare rearrangement/ketalization cascade reaction
could result in the generation of 6/5/5/6-fused phloroglucinol
dimers 6 and 7. Finally, endoperoxides 4a/4b and
phloroglucinol dimers 6/7 could further couple and form the
trimers 1 and 2 with the 6/5/5/6/5/5/6-fused tetrafuran-di-β-
triketone scaffold.
To support our biosynthetic hypothesis and provide
sufficient samples for further biological investigation, we
designed a biomimetic approach to synthesize 1 and 2 in
line with their proposed biogenetic pathways. Following the
strategy similar to those employed by our recent works,5 our
present synthetic study began with preparation of the putative
monomeric phloroglucinol precursors 3 and 4 (Scheme 2).
Table 1. Optimization of Enantioselective Dehydroxylation/
Michael Addition/Kornblum−DeLaMare Rearrangement/
Ketalization Cascade Reaction
Scheme 2. Syntheses of Phloroglucinol Monomers 5, 3, 4a,
and 4b
a
b
c
entry
cat.
yield (%)
ee (%) (6, 7)
rr (6:7)
1
2
3
4
5
6
7
8
9
(R)-C1
(S)-C2
(S)-C3
(S)-C4
(S)-C5
(R)-C5
(S)-C6
(S)-C7
49
73
70
72
73
73
74
71
69
70
−74, −53
58, 21
1, 56
70, 74
90, 76
−87, −70
0, 0
23, 19
68, 41
90, 75
2.0:1.0
2.0:1.0
2.0:1.0
1.9:1.0
2.0:1.0
2.2:1.0
2.0:1.0
1.7:1.0
2.0:1.0
2.0:1.0
d
(S)-C5
(S)-C5
The commercially available 1,3,5-trihydroxybenzene 8, serving
as the starting material, was readily converted to acylphlor-
oglucinol 5 through Friedel−Crafts acylation. Then, methyl-
ation of 5 with iodomethane under basic conditions gave the
desired common precursor 3. Treatment of 3 with DIABAL-H
in THF resulted in the chemoselective reduction of the
exocyclic carbonyl group, followed by in situ elimination of the
resulting hydroxyl group, which afforded the active dearom-
atized ortho-quinone methide (o-QM) intermediate in 90%
yield.5d Subjection of the intermediate to a modified
e
10
a
Unless otherwise stated, the reactions of entries 1−10 were
performed with 5 (0.15 mmol), 4a (0.1 mmol), and CPA (0.01
b
c
mmol) in toluene (2 mL) at 40−60 °C. Isolated yield. Determined
by HPLC analysis on a Phenomenex Lux Cellulose-2 chiral column
(4.6 mm × 250 mm, MeOH/H2O, 85:15, 1.0 mL/min). 4b was
added. The reaction of entry 10 was performed with 5 (1.1 g, 5.25
mmol), 4a (1 g, 3.5 mmol), and CPA (0.35 mmol) in toluene (70
mL) at 50 °C.
d
e
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by changing the solvents and adding Lewis acids (Table S22).
After extensive experimentations, we identified the following
protocol to be optimal (entry 10): when 5 was treated with 4a
in the presence of catalytic (S)-C5 (10 mol %) and AlF3 (100
mol %) in toluene at 50 °C for 7 days, (+)-6 and (−)-7 were
obtained in a combined yield of 70% and a ratio of 2:1, as well
as 90% and 75% ee, respectively (1.0 g scale). Moreover, we
also achieved the highly enantioselective synthesis of (−)-6 by
using (R)-C5 as the catalyst under the same procedure as
described above (entry 6). However, when replacing 4a with
4b as the endoperoxide, the enantioselectivity of the above
catalytic cascade reaction decreased slightly (entry 9), which
was presumed to undergo a different mechanism from that of
4a.3m
Subsequently, we tried to complete the synthesis of
phloroglucinol trimers 1 and 2 by assembling the above
obtained phloroglucinol dimers and monomers together.
Initially, we treated phloroglucinol dimer (+)-6 (90% ee)
with monomer 4a under the optimized catalytic condition
(Scheme 3). However, this reaction gave no conversion to the
heptacyclic ring system. Inspired by their proposed bio-
synthetic pathway, we achieved the asymmetric biomimetic
synthesis of the two unusual trimers in only six steps without
the protecting groups, which not only enabled the further
verification of their absolute configurations but also gave
evidence from a chemistry perspective to support our
biogenetic hypothesis. The present synthetic strategy featured
a unique organocatalytic asymmetric dehydroxylation/Michael
addition/Kornblum−DeLaMare rearrangement/ketalization
cascade reaction. An antiviral assay revealed that both 1 and
2 showed good in vitro anti-RSV activities, suggesting that
these PPPs might be a new class of antiviral substance.
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01616.
Detailed descriptions of isolation, structural elucidation,
and synthesis experimental procedures, and UV, IR, MS,
and NMR spectra for all compounds (PDF)
Scheme 3. Asymmetric Syntheses of 1 and 2
Accession Codes
CCDC 2043060−2043061 and 2043066−2043069 contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Ying Wang − Center for Bioactive Natural Molecules and
Innovative Drugs Research, College of Pharmacy and
Guangdong Province Key Laboratory of Pharmacodynamic
Constituents of TCM & New Drugs Research, Jinan
University, Guangzhou 510632, People’s Republic of China;
orcid.org/0000-0003-4524-1812;
desired trimers (+)-1 and (+)-2. After several attempts, this
transformation proceeded smoothly by enhancing the reaction
temperature to give a mixture of trimers (+)-1 and (+)-2 in a
combined yield of 45% and a ratio of 1:2 with 90% ee. The
NMR spectra, HR-ESI-MS data, and specific rotations of the
synthesized trimers (+)-1 and (+)-2 were in good agreement
with those of the isolated compounds. The absolute
configurations of 1 and 2 were therefore further confirmed
by the asymmetric total synthesis results.
Our previous investigations demonstrated that some PPPs
from medicinal plants of the Myrtaceae family showed
promising antiviral activities.4c,d In the present study,
compounds 1 and 2 were tested for their in vitro antiviral
activities against simplex virus type-1 (HSV-1) and respiratory
syncytial virus (RSV) by using a cytopathic effect (CPE)
reduction assay. As a result, compounds 1 and 2 exhibited
good anti-RSV activities with IC50 values of 12.50 1.42 and
15.00 1.36 μM, respectively. However, the two compounds
did not show obvious anti-HSV-1 activity at the tested
concentrations (Table S25).
Email: wangying_cpu@163.com
Wen-Cai Ye − Center for Bioactive Natural Molecules and
Innovative Drugs Research, College of Pharmacy and
Guangdong Province Key Laboratory of Pharmacodynamic
Constituents of TCM & New Drugs Research, Jinan
University, Guangzhou 510632, People’s Republic of China;
orcid.org/0000-0002-2810-1001; Email: chywc@
aliyun.com
Chuang-Chuang Li − Department of Chemistry, Southern
University of Science & Technology, Shenzhen 518055,
People’s Republic of China; orcid.org/0000-0003-4344-
0498; Email: ccli@sustech.edu.cn
Authors
Lu-Ming Deng − Center for Bioactive Natural Molecules and
Innovative Drugs Research, College of Pharmacy and
Guangdong Province Key Laboratory of Pharmacodynamic
Constituents of TCM & New Drugs Research, Jinan
University, Guangzhou 510632, People’s Republic of China
Li-Jun Hu − Center for Bioactive Natural Molecules and
Innovative Drugs Research, College of Pharmacy and
Guangdong Province Key Laboratory of Pharmacodynamic
Constituents of TCM & New Drugs Research, Jinan
University, Guangzhou 510632, People’s Republic of China
In summary, our phytochemical investigation on the
medicinal plant Rhodomyrtus tomentosa led to the discovery
of two pairs of unprecedented enantiomeric phloroglucinol
trimers 1 and 2 featuring a unique 6/5/5/6/5/5/6-fused
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Yang-Ting-Zhi Bai − Center for Bioactive Natural Molecules
and Innovative Drugs Research, College of Pharmacy and
Guangdong Province Key Laboratory of Pharmacodynamic
Constituents of TCM & New Drugs Research, Jinan
University, Guangzhou 510632, People’s Republic of China
Jie Wang − Center for Bioactive Natural Molecules and
Innovative Drugs Research, College of Pharmacy and
Guangdong Province Key Laboratory of Pharmacodynamic
Constituents of TCM & New Drugs Research, Jinan
University, Guangzhou 510632, People’s Republic of China
Guan-Qiu Qin − Center for Bioactive Natural Molecules and
Innovative Drugs Research, College of Pharmacy and
Guangdong Province Key Laboratory of Pharmacodynamic
Constituents of TCM & New Drugs Research, Jinan
University, Guangzhou 510632, People’s Republic of China
Qiao-Yun Song − Center for Bioactive Natural Molecules and
Innovative Drugs Research, College of Pharmacy and
Guangdong Province Key Laboratory of Pharmacodynamic
Constituents of TCM & New Drugs Research, Jinan
University, Guangzhou 510632, People’s Republic of China
Jun-Cheng Su − Center for Bioactive Natural Molecules and
Innovative Drugs Research, College of Pharmacy and
Guangdong Province Key Laboratory of Pharmacodynamic
Constituents of TCM & New Drugs Research, Jinan
University, Guangzhou 510632, People’s Republic of China;
orcid.org/0000-0002-1458-5383
Xiao-Jun Huang − Center for Bioactive Natural Molecules and
Innovative Drugs Research, College of Pharmacy and
Guangdong Province Key Laboratory of Pharmacodynamic
Constituents of TCM & New Drugs Research, Jinan
University, Guangzhou 510632, People’s Republic of China;
orcid.org/0000-0002-3636-4813
Ren-Wang Jiang − Guangdong Province Key Laboratory of
Pharmacodynamic Constituents of TCM & New Drugs
Research, Jinan University, Guangzhou 510632, People’s
Republic of China
Wei Tang − Center for Bioactive Natural Molecules and
Innovative Drugs Research, College of Pharmacy and
Guangdong Province Key Laboratory of Pharmacodynamic
Constituents of TCM & New Drugs Research, Jinan
University, Guangzhou 510632, People’s Republic of China
Yao-Lan Li − Guangdong Province Key Laboratory of
Pharmacodynamic Constituents of TCM & New Drugs
Research, Jinan University, Guangzhou 510632, People’s
Republic of China
(2020B1111110004). This work was also supported by the
high-performance computing platform of Jinan University.
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01616
Author Contributions
⊥L.-M.D. and L.-J.H. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Mega-
Project for Innovative Drugs (2019ZX09735002), the National
Natural Science Foundation of China (81630095 and
81903493), the Local Innovative and Research Teams Project
of Guangdong Pearl River Talents Program (2017BT01Y036),
the Natural Science Foundation of Guangdong Province
(2019A1515011478), and the Key-Area Research and
Development Program of Guangdong Province
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