Discovery and Biomimetic Synthesis of a Phloroglucinol-Terpene Adduct Collection from Baeckea frutescens and Its Biogenetic Origin Insight

Article abstract of DOI:10.1002/chem.202001111

A phloroglucinol-terpene adduct (PTA) collection consisting of twenty-four molecules featuring three skeletons was discovered from Baeckea frutescens. Inspired by its biosynthetic hypothesis, we synthesized this PTA collection by reductive activation of s

Full text of DOI:10.1002/chem.202001111

Accepted Article
Accepted Article
Title: Discovery and Biomimetic Synthesis of a Phloroglucinol-Terpene
Adduct Collection from Baeckea frutescens and Its Biogenetic
Origin Insight
Authors: Shi-Lin Luo, Li-Jun Hu, Xiao-Jun Huang, Jun-Cheng Su, Xue-
Hua Shao, Lei Wang, Han-Hong Xu, Chuang-Chuang Li, Ying
Wang, and Wen-Cai Ye
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To be cited as: Chem. Eur. J. 10.1002/chem.202001111
Link to VoR: https://doi.org/10.1002/chem.202001111
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Discovery and Biomimetic Synthesis of a Phloroglucinol-Terpene
Adduct Collection from Baeckea frutescens and Its Biogenetic
Origin Insight
Shi-Lin Luo†, Li-Jun Hu†, Xiao-Jun Huang, Jun-Cheng Su, Xue-Hua Shao, Lei Wang, Han-Hong Xu,
Chuang-Chuang Li*, Ying Wang*, and Wen-Cai Ye*
[] Dr. S.-L. Luo,[†] Dr. L.-J. Hu,[†] Dr. X.-J. Huang, Dr. J.-C. Su, Dr. L. Wang, Prof. Dr. Y. Wang, Prof. Dr. W.-C. Ye
Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, P. R. China
E-mail: wangying_cpu@163.com
chywc@aliyun.com
Dr. S.-L. Luo,[†] Dr. L.-J. Hu,[†] Dr. X.-J. Huang, Dr. J.-C. Su, Dr. L. Wang, Prof. Dr. Y. Wang, Prof. Dr. W.-C. Ye
Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, P. R.
China
Prof. Dr. C.-C. Li
Department of Chemistry, South University of Science &Technology of China, Shenzhen 518055, P. R. China
E-mail: ccli@sustc.edu.cn
Dr. X.-H. Shao
Institute of Fruit Tree Research, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, P. R. China
Prof. Dr. H.-H. Xu
State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, South China Agricultural University, Guangzhou 510642, P. R. China
[†] These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document.
Abstract:
A
phloroglucinol-terpene adduct (PTA) collection
consisting of twenty-four molecules featuring three skeletons was
discovered from Baeckea frutescens. Inspired by its biosynthetic
hypothesis, we synthesized this PTA collection by reductive
activation of stable phloroglucinol precursors into highly reactive
ortho-quinone methide (o-QM) intermediates and subsequently
Diels-Alder cycloaddition. We also demonstrated for the first time the
generation process of the active o-QM by performing dynamic
nuclear magnetic resonance (NMR) and HPLC-MS monitoring
experiments. Moreover, the PTA collection showed significant
antifeedant effect toward the Plutella xylostella larvae.
Introduction
The diverse specialized metabolites generated by plants are
probably the consequence of adaptive evolution to allow plants
to protect themselves against herbivory, pathogenic microbes,
and various abiotic stresses.[1,2] The phloroglucinol-terpene
adducts (PTAs) are a class of hybrid natural products with
structural features that phloroglucinol derivatives incorporated
mono- or sesqui-terpenoid units via various coupling patterns.[3]
So far, over 300 PTAs have been discovered from natural
sources, most of which came from the plants belonging to
families Myrtaceae and Guttiferae.[3–5] Due to their intriguing
chemical structures and remarkably biological activities, PTAs
have received increasing attention from both chemical and
biological communities in recent years.[3–5]
Biogenetically, PTAs are commonly hypothesized to form via
a crucial Diels-Alder cycloaddition between terpene precursors
and putative ortho-quinone methide (o-QM) intermediates.[3b,4]
Recently, several biomimetic approaches involving Diels-Alder
cycloaddition have been reported for the synthesis of a series of
PTAs, employing in situ-generated o-QMs as key
intermediates.[4a,4c,4e,6–8] In those reported synthetic strategies,
the desired o-QM intermediates were commonly generated
through oxidative activation of the benzyl sites of phloroglucinol
precursors or Knoevenagel condensation between aldehydes
and phloroglucinols. However, the generation process of o-QMs
Figure 1. Chemical structures of PTAs from B. frutescens.
1
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in plants has received much less attention, to the best of our
knowledge, no experimental evidence was reported to explain
how stable phloroglucinol precursors convert into highly reactive
o-QM intermediates. Actually, little progress was made in
understanding the underlying biosynthesis mechanism of this
intriguing group of natural products. Further work is needed to
demonstrate how, and perhaps why, plants apply combinatorial
strategy to create those diverse PTAs.
predicted in Scheme 1. First, the construction of the
phloroglucinol moiety involved a polyketide pathway utilizing
isobutyryl-CoA as the starting unit. Subsequent carbon chain
extension, cyclization, and methylation modification led to the
generation of two pairs of acylphloroglucinol tautomerisms,
tasmanone and agglomerone. The phloroglucinol precursors
were further reduced and dehydrated to generate the active o-
QM intermediates, A1/A2 and B1/B2. As enophiles, both A1/A2
and B1/B2 could incorporate different monoterpene precursors
[(+)/(−)-sabinene and (+)/(−)-α-thujene] through hetero-Diels-
In our current study, a PTA collection consisting of twenty-four
molecules featuring three skeletons, including twelve new ones,
was obtained from the leaves and twigs of Baeckea frutescens L. Alder cycloaddition to generate 2–17 featuring a heterocyclic
(Myrtaceae). Based on the identification of key phloroglucinol
and terpene precursors in the same plant material, a plausible
biogenetic route for the PTA collection was proposed. Inspired
chroman ring system. Meanwhile, A1/A2 could also act as
dienophiles to couple with β-myrcene via Diels-Alder
cycloaddition to form (+)/(−)-1, which have a rare all-carbon
spirocyclic ring system. Meanwhile, all proposed phloroglucinol
and monoterpene precursors were detected in the crude extract
of title plant (Figures S17–S19).
by this hypothetical biogenetic pathway, we designed
a
biomimetic synthesis strategy for the PTA collection involving
the in situ generation of active o-QM intermediates via the
reductive activation of coexisting phloroglucinol precursors and
subsequent Diels-Alder cycloaddition with corresponding
monoterpenes. The activation process for conversion of stable
phloroglucinol precursors into reactive o-QM intermediates was
1
revealed for the first time by using dynamic H NMR and HPLC-
MS monitoring experiments. Moreover, the quantum chemical
calculation of the Diels-Alder cycloaddition and the antifeedant
property of the PTA collection toward larvae of Plutella xylostella
were studied. Herein, we report the discovery, plausible
biogenetic
pathway,
biomimetic
synthesis,
generation
mechanism, and feeding deterrent activity of the PTA collection.
Results and Discussion
The PTA-containing extract of B. frutescens was obtained and
further fractionated following our early procedure.[5] The PTA-rich
fraction was then selected based on the result of HPLC-MS
analysis, which revealed typical UV profiles and ion peaks for
PTAs. Further UV-guided chiral chromatography isolation was
performed to obtain twenty-four optically pure compounds, (+)-
frutescone
Q Q
(1),[4f] (−)-frutescone (1),[4f] (+)-(2), (−)-
baeckfrutone Q (2),[9b] (+)-3, (−)-3, (+)-baeckfrutone I (4),[9a] (−)-
baeckfrutone I (4),[9a] (+)-5, (+)-baeckfrutone B (6),[9a] (+)-
baeckfrutone
C
(7),[9a] (−)-baeckfrutone
C
(7),[9a] (−)-
baeckfrutone D (8),[9a] (−)-baeckfrutone N (9),[9a] (+)-10, (−)-10,
(+)-baeckfrutone J (11),[9a] (−)-11, (−)-12, (−)-13, (−)-14, (+)-
baeckfrutone M (15),[9a] (+)-16, and (−)-17 (Figure 1). Their
structures with absolute configurations were elucidated on the
basis of comprehensive spectroscopic and single crystal X-ray
diffraction analyses, as well as computational calculations.
Among them, (+)-2, (+)-3, (−)-3, (+)-5, (+)-10, (−)-10, (−)-11, (−)-
12, (−)-13, (−)-14, (+)-16, and (−)-17 are twelve new structures.
These molecules constituted a PTA collection comprising three
types of carbon skeletons: (A) 1 contains a spiro[5.5]undecane
ring system; (B) 2–11 possess a polymethylated chroman-spiro-
bicyclo[3.1.0]hexane backbone structure; (C) 12–17 bear a
polymethylated chroman-fused-bicyclo[3.1.0]hexane skeleton.
Among these isolates, (+/−)-1, (+/−)-2, (+/−)-3, (+/−)-4, (+/−)-7,
(+/−)-10, and (+/−)-11 are seven pairs of enantiomers.
Interestingly, chiral HPLC analysis showed that 1 occurs as a
racemic mixture, 2–4, 7, 10, and 11 exist as scalemic mixtures,
and other PTAs (5, 6, 8, 9, and 12–17) present as optically pure
compounds in plant (see the Supporting Information for details).
Scheme 1. Hypothetical biogenetic pathway of the PTA collection.
To support our biosynthetic hypothesis, we designed a
biomimetic synthesis approach to create the PTA collection.
Following the similar strategy to those employed by our recent
work,[10] we firstly synthesized tasmanone and agglomerone in
gram quantities via the concise routes shown in Scheme 2. With
the acylphloroglucinol precursors in hand, we then turned our
attention to conversion of them into reactive o-QMs. After
screening various reductants, diisobutylaluminium hydride
(DIBAL-H) was proved to be the best option because it could
efficiently and chemoselectively reduce the exocyclic carbonyl
group in tasmanone and agglomerone. However, the expected
alcohol products were too unstable to separate, and would
spontaneously dehydrate to afford the desired o-QMs. Thus,
PTAs were then formed via direct cycloaddition between the
reductive products, without further purification, and the
Based on the structural features of these PTAs,
a
hypothetical biogenetic pathway for the PTA collection is
2
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corresponding monoterpenes (commercial availability) through
Diels-Alder cycloaddition. Actually, the o-QMs (A1/A2 and B1/B2)
were so highly reactive that the cycloaddition could proceed
even at room temperature without any catalyst. Nevertheless,
the yield could be improved by enhancing the reaction
temperature. HPLC-MS analyses of the synthetic compounds
and natural products indicated that we obtained not only all the
desired natural PTAs in the collection but also some pseudo-
natural stereoisomers (Figures S4–S5 and Table S1). The
structures of synthetic compounds were further confirmed by
comparing their NMR data with those of natural products (Tables
S2–S5).
sequential generation of four compounds (24, 25, A1, and A2)
with the corresponding Ha1, Ha2, Hb1, and Hb2 signals, followed by
their conversion into 26 with Hc, which finally yielded the stable
product 27 with Hd. Compound 27 was further isolated and
elucidated as a known naturally occurring endoperoxide, which
had been isolated from the same plant species by other
groups[11,12] and us in the present study. HPLC-MS analysis of
the reductive products provided supplementary evidence to
support aforementioned dynamic processes (Figures S21–S22).
Notably, the above findings provided the first experimental
evidence for revealing the dynamic generation process of how
the stable acylphloroglucinol precursors converted into reactive
o-QMs via reductive activation. Thus, the reductive activation
and cycloaddition processes are illustrated in Figure 2B. The
selective reduction of the exocyclic carbonyl group of tasmanone
resulted in the ready formation of the corresponding alcohols 24
and 25, which in turn spontaneously dehydrated to afford the o-
QMs A1/A2. Next, combinatorial cycloaddition between o-QMs
A1/A2 and monoterpenes could efficiently result in the creation of
PTA collection. Meanwhile, o-QMs A1/A2 could also undergo an
isomerization process to generate the corresponding stable
compound 26, which was spontaneously oxidized to form the
endoperoxide 27 by trapping oxygen from environment.
Because all putative biogenetic precursors (tasmanone,
agglomerone, and monoterpenes) and final stable products
(PTAs and 27) were present in the original plant, the entire
chemical synthetic route was highly in line with the plausible
biosynthetic pathway.
Scheme 2. Biomimetic synthesis of PTAs. a) ClCOCH(CH3)2 (1.1 equiv.),
AlCl3 (3.0 equiv.), PhNO2, 65 ºC, 82%; b) MeI (3.1 equiv.), NaOMe (4 equiv.),
MeOH, 55 ºC, 63%; c) CH2N2 (2.5 equiv.), AcOEt-MeOH (5:1), −78 ºC, 91%; d)
ClCOCH(CH3)2 (2.1 equiv.), AlCl3 (4.0 equiv.), PhNO2, 65 ºC,76%; e) MeI (2.0
equiv.), NaOMe (2.0 equiv.), MeOH, 55 ºC, 91%; f) conc. H2SO4, 70 ºC, 70%; g)
CH2N2 (3.0 equiv.), AcOEt-MeOH (5:1), −78 ºC, 95%; h) Diisobutylaluminium
hydride (2.0 equiv.),THF, −78 ºC ; l) Toluene, 110 oC.
Due to the rapid reactivity of the o-QMs, we failed to identify
these proposed intermediates in plants. To gain insight into the
biogenetic process of reactive o-QMs via reductive activation of
the stable acylphloroglucinol precursors, we designed an in vitro
experiment to monitor the dynamic process of the reductive
products of tasmanone by using 1H NMR and HPLC-MS. 1H
NMR spectra of the reductive products revealed the presence of
six characteristic proton signals (Ha1, Ha2, Hb1, Hb2, Hc, and Hd;
Figures 2 and S20), which were used as the probes to monitor
different compounds. The changing trend indicated the
Figure 2. A) Dynamic 1H NMR spectra of the reductive products of tasmanone.
B) Generation process for A1/A2, 27, and PTAs.
Considering the fact that the o-QMs and terpene precursors
could hybridize spontaneously without any catalyst in vitro, we
wonder whether the Diels-Alder cycloaddition involved in PTA
3
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biosynthesis is a non-enzyme-mediated process in plants. With
this question, we investigated the reactivity of this process
computationally by employing PWPB95-D3(BJ)/def2-QZVPP
model chemistry. Because all these PTAs were generated in a
similar manner, the Diels-Alder cycloadditions between A1/A2
and (+)/(−)-sabinene were selected as the studying model. All
twenty-four plausible transition structures (TSs) and twelve
possible products (nine of which were isolated as natural
products in this study, see the Supporting Information for details)
of the cycloaddition reactions were located using toluene as the
solvent condition. The computed free-energy profile of (+)-6 is
shown in Figure 3, and those of other products are shown in
Figure S41. As results, the activation energies of all favoured
TSs (ΔG‡) were estimated ranging 21–29 kcal/mol, and the
heats of reaction (ΔG) for all cycloaddition reactions were
computed to be 4.5–13.5 kcal/mol, indicating that the
cycloaddition processes between o-QMs and terpenes were
exergonic reactions in toluene. The above data indicated that
the Diels-Alder cycloaddition could proceed entirely and
irreversibly in toluene, even at room temperature without
enzymatic assistance, which was consistent with the result of
biomimetic synthesis. Interestingly, the activation energies of all
preferred TSs in water were predicted to be much lower than
those in toluene (ΔΔG‡ = 3–13 kcal/mol), suggesting that these
Diels-Alder cycloadditions might proceed more easily and rapidly
in plants.
data suggested that the PTA collection likely play an important
role in plant defense.
Conclusions
Phytochemical investigation of B. frutescens led to the discovery
of
a PTA collection comprising of twenty-four molecules
featuring three skeletons. Inspired by the proposed biosynthetic
pathway, we successfully generated highly reactive o-QM
intermediates by reducing the corresponding stable
phloroglucinol precursors and completed the biomimetic
synthesis of the PTA collection. Further investigation of the
reductive activation of the phloroglucinol precursor revealed the
o-QMs generation process. Computational studies of the Diels-
Alder cycloaddition between o-QMs and monoterpenes indicated
the combinatorial cycloaddition process could spontaneously
proceed in the absence of catalyst. The PTA collection showed
significant feeding deterrent effect toward the larvae of Plutella
xylostella.
Throughout the present study, we proved that reductive
activation could convert stable biogenetic phloroglucinol
precursors into highly reactive o-QMs using only a chemical
reductant, implying endogenous reductases may perform this
key transformation step during PTA collection biosynthesis in
plants. Interestingly, plant aldo-keto reductases (a protein
superfamily of NAD[P]H-dependent oxidoreductases) were
reported to play a crucial role in diverse plant metabolic
processes and biotic/abiotic stress defense.[14] An attractive idea
was raised that attacked by potential enemies may induce the
enhancement of activities of aldo-keto reductases in plants,
which in turn trigger the formation of active o-QMs. The resulting
PTA collection is believed to play an important defensive role
against insect herbivores toward plants.
Acknowledgements
We thank Dr. Hai-Yan Tian and Prof. Dr. Ren-Wang Jiang for X-
ray crystal structure analysis. This work was financially
supported by the National Key R&D Program of China (No.
2017YFC1703800), the National Mega-Project for Innovative
Drugs (No. 2019ZX09735002), the National Natural Science
Foundation of China (Nos. 81630095, 81622045, and
81903493), and the Local Innovative and Research Teams
Project of Guangdong Pearl River Talents Program (No.
2017BT01Y036), the Natural Science Foundation of Guangdong
Province (No. 2019A1515011478). This work was also
supported by the high-performance computing platform of Jinan
University.
Figure 3. DFT-simulated process for the Diels-Alder cycloaddition of (+)-6.
PTAs are highly frequent occurrence in Myrtaceae species,
however, the role of these specialized metabolites in plants
remains unclear. To probe the potential ecological function of
the PTAs, the antifeedant activities of the natural PTA collection
as well as several selected PTAs [(±)-1, (−)-4, (+)-6, (+)-7, (−)-10,
(+)-11, and (−)-17] against third-instar larvae of Plutella
xylostella (Linnaeus) were tested by using leaf disc no-choice
method.[13] As shown in Table S25, the natural PTA collection
showed comparable feeding deterrent effect (AFC50 = 50.23 ±
Conflict of interest
The authors declare no conflict of interest.
Keywords: biosynthetic pathways
• phloroglucinol-terpene
adduct • biomimetic synthesis • natural products • Baeckea
7.19 μg/g) to that of the positive control azadirachtin A (AFC50
=
frutescens L.
43.69 ± 5.91 μg/g), while most of the individual PTAs only
displayed moderate to modest antifeedant activities. The above
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Entry for the Table of Contents
Insight of Nature: A phloroglucinol-terpene adduct (PTA) collection was discovered from Baeckea frutescens. The plausible
biogenetic pathway, biomimetic synthesis, generation mechanism, and feeding deterrent activity of the PTA collection were also
investigated. The current study first provided experimental evidences to explain how, and perhaps why, plants apply combinatorial
strategy to create the PTA collection.
6
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