A bio-inspired synthesis of hybrid flavonoids from 2-hydroxychalcone driven by visible light

Article abstract of DOI:10.1039/c9ra07198a

A bio-inspired synthesis of hybrid flavonoids from 2-hydroxylchalcone is described. Under the irradiation of 24 W CFL, 2-hydroxychalcone reacts with various nucleophiles to deliver structurally diverse hybrid flavonoids in good to excellent yields in the presence of a catalytic Br?nsted acid. Moreover, moderate enantioselectivities could be obtained using a catalytic chiral phosphoric acid via counter anion directed addition. Based on mechanistic studies, the reaction is proposed to proceed via tandem double-bond isomerization/dehydrated cyclization of 2-hydroxychalcone to form a transient flavylium cation, which is in situ captured by nucleophiles to afford hybrid flavonoids.

Full text of DOI:10.1039/c9ra07198a

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A bio-inspired synthesis of hybrid flavonoids from
2-hydroxychalcone driven by visible light†
Cite this: RSC Adv., 2019, 9, 29005
Yu-Qi Gao,a Yi Hou,a Liming Zhu,b Guzhou Chen,a Dongyang Xu,a
c
b
ad
*
*
*
Sheng-Yong Zhang, Yupeng He and Weiqing Xie
A bio-inspired synthesis of hybrid flavonoids from 2-hydroxylchalcone is described. Under the irradiation of
24 W CFL, 2-hydroxychalcone reacts with various nucleophiles to deliver structurally diverse hybrid
flavonoids in good to excellent yields in the presence of a catalytic Brønsted acid. Moreover, moderate
enantioselectivities could be obtained using a catalytic chiral phosphoric acid via counter anion directed
addition. Based on mechanistic studies, the reaction is proposed to proceed via tandem double-bond
isomerization/dehydrated cyclization of 2-hydroxychalcone to form a transient flavylium cation, which is
in situ captured by nucleophiles to afford hybrid flavonoids.
Received 8th September 2019
Accepted 9th September 2019
DOI: 10.1039/c9ra07198a
rsc.li/rsc-advances
Nature elegantly utilizes hybridization of different natural which reveals the equilibrium between those avonoids in
products to construct structurally diverse natural products by solution under the irradiation of UV or sunlight. As shown in
merging different biosynthetic pathways.1 Inspired by Fig. 1, this process is initiated with the E/Z isomerization to
nature's strategy, hybridization of natural products also deliver Z-enone I, which is transferred to avylium cation II
provides new opportunities for the development of medicinal via dehydrative cyclization in the presence of Brønsted acid.
and agrichemical molecules.2 Hybrid avonoids3 (Fig. 1, e.g. The in situ capture of this avylium cation has been proposed
yuremamine4 and diinsininol5 A) are widely present in to constitute the key step for the biosynthesis of some type of
natural and pharmaceutical molecules, and exhibit wide hybrid avonoids.7f
biological activities including antitumor, antioxidant, anti-
Synthesis of hybrid avonoids via nucleophilic addition
bacterial and anti-inammatory properties. According to the to avylium cation has been extensively explored,8 which
biosynthetic pathway of avonoids (Fig. 1, pathway 1),6 relies on the high electrophilicity on the C4 of avylium
hybrid avonoids (e.g. diinsininol5b) may be biogenetically cation.9 However, those protocols usually need base to act as
generated via nucleophilic addition of avanone IV to
anthocyanidin salt II, which is derived from avanol III
catalyzed by anthocyanidin synthase. Flavanol III is in turn
produced from chalcone 2 through a series of enzyme-
promoted transformations. However, an alternative biosyn-
thetic pathway has also been widely accepted, in which
sunlight plays a pivotal role (Fig. 1, pathway 2),7 In this
context, the photochemical interconversion of 2-hydrox-
ychone 1 and avylium salt II has been fully established,
aShaanxi Key Laboratory of Natural Products
Chemistry Pharmacy, Northwest A&F University, 22 Xinong Road, Yangling
& Chemical Biology, College of
&
712100, Shaanxi, China. E-mail: xiewq@nwafu.edu.cn
bCollege of Chemistry, Chemical Engineering and Environmental Engineering,
Liaoning Shihua University, Dandong Lu West 1, Fushun 113001, China. E-mail:
yupeng.he@lnpu.edu.cn
cDepartment of Chemistry, Fourth Military Medical University, Xi'an 710032, China.
E-mail: syzhang@fmmu.edu.cn
dKey Laboratory of Botanical Pesticide R&D in Shaanxi Province, Yangling, Shaanxi
712100, China
† Electronic supplementary information (ESI) available: General experimental
procedures, and spectroscopic date for the all new compounds. See DOI:
10.1039/c9ra07198a
Fig. 1 Previous protocols for the synthesis of hybrid flavonoids and
a bio-inspired synthesis of hybrid flavonoids form 2-hydrxoychalcone.
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acid scavenger or heating in protic solvent. Furthermore,
the avylium cation is sensitive to light in solution.7 The
other commonly employed strategy is the tandem Michael
addition/dehydrated cyclization of 2-hydroxylchalcone 1 to
deliver avonoids 3 or polycyclic avonoids 4.10 Different
catalysts such as I2, TfOH and NbCl5 have been discovered to
be effective for promoting this reaction. However, this
strategy is limited by its harsh reaction conditions (heating)
or need of precious metal catalysts. Drawn inspiration from
the light-driven biosynthetic pathway of hybrid avonoids
(Fig. 1, pathway 3),6,7 we proposed that if a suitable nucle-
ophile is exposed to 2-hydroxychalcone 1 in the presence of
catalytic Brønsted acid under the irradiation of 24 CFL,
hybrid avonoids 3 or 4 could be biomimetically obtained
via the in situ capture of the transient avylium salt. Herein,
we would like to describe our preliminary results on this bio-
inspired synthesis of hybrid avonoids driven by visible
light.
Scheme 1 Substrate scope with regard to indole as nucleophile.
To verify our hypothesis, the reaction of hydroxyl chalcone
1a with indole 5a was initially examined to establish the
optimal reaction conditions. To our delight, upon the irra-
diation of household 24 W compact uorescent lamp (CFL)
the desired avonoid 3aa could be obtained in 73% yield in
the presence of phosphoric acid CPA (Table 1, entry 1).
Subsequent survey of different kind of Brønsted acids
showed that biphenyl phosphate was the most efficient
promoter, affording desired product in 98% yield (Table 1,
entry 2–6 and ESI†). In sharp contrast, when the reaction was
run in the absence of Brønsted acid or in the dark (Table 1,
entry 7 and 8), no product could be detected, indicating that
the light-driven formation of avylium from 2-hydrox-
ychalcone might be involved. Subsequently, survey of
solvents revealed that THF was the optimal solvent, which
gave comparable yield and showed better solubility for 2-
hydroxylchalcone 1a (Table 1, entry 9 and ESI†).
Aer establishing the optimal reaction conditions, the
substrate scope was subsequently investigated. As shown in
Scheme 1, electron-withdrawing group (e.g. F, Cl and Br) on the
indole ring was compatible with the reaction conditions,
providing corresponding products in good isolated yields (3ab
to 3ag). Indoles with electron-donating groups (e.g. Me,
methoxy) were also well tolerated, affording 3ah to 3ak in good
yields. Substituents (e.g. phenyl and methyl) on the C-2 of indole
did not affect the outcomes of this reaction (3al and 3am).
Additionally, a variety of substituted 2-hydroxylchalcone was
prepared and subjected to the standard reaction conditions.
Satisfactorily, 2-hydroxylchalcones with electron-withdrawing
groups (Cl, Br) and electron-donating group (Me, methoxy)
could all be converted to hybrid avonoids in good to excellent
yields (3an to 3ar, 3at and 3au). Heterocycle such as furan was
also compatible with the reaction conditions to afford avonoid
3as in 85% yield.
Table 1 Optimization of the reaction conditionsa
Furthermore, this protocol was also applicable to other type
of bifunctional nucleophiles to give rise to polycyclic avonoids
resembling diinsininol. As listed in Scheme 2, cyclohexa-1,3-
dione, phloroglucinol, 4-hydroxycoumarin could all engage in
this type of reaction to give dioxabicyclo[3.3.1]nonane scaffold
Entry
Catalyst
Solvent
Time (h)
Yieldb (%)
via
tandem
cycloisomerization/nucleophilic
addition/
1
2
3
4
5
6
7
8c
9
CPA
CSA
HCl
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
18
18
18
30
42
42
42
42
19
73
42
40
98
45
43
ND
ND
98
cyclization process. For those substrates, employment of HCl
(for cyclohexa-1,3-dione and 4-hydroxycoumarin) or TsOH (for
phloroglucinol) was more benecial (see ESI† for details). When
cyclohexa-1,3-dione was employed as nucleophile, various
substituents on the aromatic ring of 2-hydroxyl chalcone were
well compatible excepting the Br on the aromatic ring A (4ag),
delivering the desired product in good to excellent yields
(Scheme 2, 4aa to 4aj). Phloroglucinol was also a suitable
nucleophile for this reaction, generating polycyclic avonoids
in acceptable yields. Different type of substitutes were tolerated
on the aromatic ring B of 2-hydryxoychalcone (Scheme 2, 4ba to
Biphenyl phosphate
TsOH
TFA
—
Biphenyl phosphate
Biphenyl phosphate
a
Reaction conditions: to a mixture of hydroxyl chalcone 1a (0.1 mmol)
and indole (0.12 mmol) was added solvent (3 mL). The reaction mixture
was stirred with irradiation by household 24 W compact uorescent
lamp (CFL). b Isolated yields. c The reaction was carried out in the dark.
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correspondent hybrid avonoids 3aa to 4ca in comparable isolated
yields with those using 24 W CFL as light source.
The enantioselective coupling of 2-hydroxychalcone was also
explored using chiral phosphoric acid as organocatalyst via
counter anion directed addition (Scheme 4).11 To our delight,
avonoid 3aa could be obtained in 99% yield with 45% ee
employing catalytic 8H-(R)-TRIP. Additionally, the enantiose-
lective coupling of cyclohexa-1,3-dione to 2-hydroxy chalcone 1a
could also be realized using (R)-TRIP as catalyst albeit in 67%
yield with 27% ee. When phloroglucinol was employed reaction
partner, avonoid 4ba could be obtained in 52% yield with 70%
ee using CPA1 as promoter (Scheme 4). Those initial results
paved a new way for the enantioselective synthesis of hybrid
avonoids via counter-anion directed enantioselective
addition.11
To gain in insights into the reaction pathway, a series of
experimental were executed (Scheme 5). When the reaction was
run in the dark, no product was detected with most of the
starting material being recovered (Scheme 4, eqn (1)). The hemi-
ketal 9 could be obtained in 62% yield when 2-hydroxylchalcone
was irradiated by visible-light (Scheme 4, eqn (2)), which was in
accordance with previous report.7 Treatment hemi-ketal 9 with
stoichiometric amount of HPF6, avylium salt 10 could be ob-
tained in 62% yield (Scheme 4, eqn (3)). Additionally, when
presence of stoichiometric amount of HPF6, 2-hydroxyl chal-
cone could also be converted to avylium salt 10 in 28% yield.
The low yield was ascribed to the instability of avylium cation
(Scheme 4, eqn (4)). In sharp contrast, only trace of product
could be observed when this reaction was run in the dark. We
also found that addition of cyclohexa-1,3-dione 6 to avylium 10
salt could smoothly proceeded in the dark, affording the
avonoid 4aa in 75% yield (Scheme 4, eqn (5)). All these
observations strongly supported the reaction proceeded
through the tandem isomerization/cyclization/dehydration of 2-
hydroxychalcone to produce a transient avylium ion, which
was in situ captured by the nucleophile to afford hybrid avo-
noids (Fig. 1).
Scheme 2 Substrate scope using bifunctional nucleophiles.
4bg), while the electron-donating groups on the aromatic ring A
were unfavorable for this reaction, resulting in much lower
yields (Scheme 2, 4bh). Finally, 4-hydroxycoumarin was evalu-
ated as the nucleophile to give access to coumarin hybrid
avonoids. For this specic substrate, the yields depended on
the substituents on the aromatic rings of 2-hydryxoychalcone.
Electron-withdrawing groups on the aromatic ring B of 2-
hydryxoychalcone were detrimental for reactions (4cb to 4cd),
affording much lower isolated yields than those with electron-
donating substituents (4ce and 4cf) and substituents on the
ring A were not well compatible with the reaction conditions
(4cg to 4cj).
To mimic the biosynthetic conditions, the sunlight-driven
coupling of 2-hydroxychalcone with different nucleophiles was
also carried out. As shown in Scheme 3, indole, cyclohexa-1,3-
dione, phloroglucinol and 4-hydroxycoumarin could all engage
in the tandem process under the irradiation of sunlight using the
same reaction conditions shown in Scheme 1 or 2, providing
Scheme 4 Chiral phosphoric acid catalyzed enantioselective addition
Scheme 3 Sunlight-driven synthesis of hybrid flavonoids.
of nucleophile to 2-hydroxychalcone.
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Conclusions
In conclusion, a bio-inspired synthesis of hybrid avonoids
from 2-hydroxychalcone was developed. This protocol provided
a facile entry to structurally diverse hybrid avonoids under the
irradiation of 24 W CFL. Based on the mechanistic studies, this
reaction was proposed to proceed via the cascade double bond
isomerization/dehydrated cyclization to afford a transient a-
vylium ion, which is in situ incepted by nucleophile. Further-
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enantioselective synthesis of hybrid avonoids.
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Conflicts of interest
There are no conicts to declare.
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We are grateful for nancial support from the National Natural
Science Foundation of China (grants. 21722206, 21672171) and
Shaanxi government. Financial support from Chinese Univer-
sities Scientic Fund and the Scientic Fund of Northwest A&F
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