One-pot green synthesis of 1,3,5-triarylpentane-1,5-dione and triarylmethane derivatives as a new class of tyrosinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2015.12.092

A new method was developed for one-pot green synthesis 1,3,5-triarylpentane-1,5-dione, triarylmethane, and flavonoid derivatives from the reaction between 2,4-dihydroxybenzaldehyde and hydroxyacetophenones via Aldol, Michael, and Friedel-Crafts additions

Full text of DOI:10.1016/j.bmcl.2015.12.092

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
One-pot green synthesis of 1,3,5-triarylpentane-1,5-dione and
triarylmethane derivatives as a new class of tyrosinase inhibitors
b
a
a,c
Zong-Ping Zheng a, , Yi-Nan Zhang , Shuang Zhang , Jie Chen
⇑
a State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu 214122, People’s Republic of China
b College of Pharmacy, University of Kentucky, Lexington, KY 40536, United States
c Synergetic Innovation Center of Food Safety and Nutrition, Jiangnan University, Wuxi, Jiangsu 214122, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new method was developed for one-pot green synthesis 1,3,5-triarylpentane-1,5-dione, triaryl-
methane, and flavonoid derivatives from the reaction between 2,4-dihydroxybenzaldehyde and hydrox-
yacetophenones via Aldol, Michael, and Friedel–Crafts additions using boric acid as catalyst in
polyethylene glycol 400. The synthetic compounds demonstrated significant tyrosinase inhibitory activ-
ities much stronger than that of kojic acid. More important, 1,3,5-triarylpentane-1,5-dione and triaryl-
methane derivatives were found to be a new class of tyrosinase inhibitors.
Received 29 September 2015
Revised 17 December 2015
Accepted 25 December 2015
Available online xxxx
Keywords:
One-pot green synthesis
Boric acid
Ó 2015 Elsevier Ltd. All rights reserved.
1,5-Dione derivative
Triarylmethane derivative
Tyrosinase inhibitors
Tyrosinase plays a key role in enzymatic browning in vegetables
and fruits and the formation of skin melanin.1,2 Enzymatic brown-
ing causes great loss in fruits and vegetables.3 On the other hand,
excessive secretion of melanin in the skin may also cause serious
aesthetic problems in human beings.4 Inhibition of tyrosinase
activity will contribute to reduce these adverse effects in vegeta-
bles and fruits and in the skin. Application of tyrosinase inhibitors
therefore gets a lot of attention due to its capable to inhibit the
activity of tyrosinase and possess the great potential market profits
and enormous application prospects. Up to now, numerous tyrosi-
nase inhibitors identified from natural or synthetic origins have
been reported.5,6 However, only a few of them are sufficiently
potent for practical use due to poor inhibitory activity, solubility,
instability, and safety concerns. Therefore, finding a novel, stron-
ger, and safer tyrosinase inhibitor remains challenge in food and
medicinal chemistry.
Flavonoids have a variety of biological activities, such as antity-
rosinase, antimicrobial, anticancer, and antioxidants.7–10 Many fla-
vonoid derivatives have been found to be strong inhibitory activity
against tyrosinase in the course of our searching potent inhibitors
from natural sources, such as 2,4,20,40-tetrahydroxychalcone,
morachalcone A, norartocarpetin, and steppogenin.11–14 However,
the low isolated yields from natural source greatly restrict the
application of these flavonoids. Therefore, a robust synthetic
method would be better to developed to obtain these tyrosinase
inhibitors. Although many methods have been developed to syn-
thetize flavonoids, their application are still suffered from harsh
reaction conditions, toxic reagents and metal catalysts, strong
acidic/basic conditions, prolonged reaction time, oily product,
and tedious extraction procedure.15–19 More worse, most synthetic
methods to polyhydroxy flavonoids require extra protection/
deprotection steps for the hydroxyl, leading to a waste of effort
and unnecessary expense of chemical reagents. Recently, some
green methods focused on tackling these problems on the basis
of an increasing economic and ecological pressure.20–22 However,
lack of production and tedious manipulation did not only urgent
an eco-friendly approach, but also an easy handling procedures
with short reaction time and economic reaction.
Herein, we reported one-pot green synthesis of one 1,3,5-tri-
arylpentane-1,5-dione and one triarylmethane derivative, together
with four flavonoid derivatives by Aldol, Michael, and Friedel–
Crafts additions between 2,4-dihydroxybenzaldehyde and hydrox-
yacetophenones using boric acid as catalyst in polyethylene glycol
400 (Scheme 1). Meanwhile, the products were also subjected to
tyrosinase inhibitory activity tests.
Scheme 1 depicted the synthetic route of new 1,3,5-triarylpen-
tane-1,5-dione (3a), triarylmethane derivatives (3b), and four
known flavonoids (4a, 5a, 4b, 5b). In Scheme 1(1), substrates 1
and 2a were chosen as the starting materials. The reaction was
conducted with the mixture of 2,4-dihydroxybenzaldehyde (1),
⇑
Corresponding author. Tel./fax: +86 510 85327850.
E-mail address: zzpsea@jiangnan.edu.cn (Z.-P. Zheng).
http://dx.doi.org/10.1016/j.bmcl.2015.12.092
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Zheng, Z.-P.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2015.12.092

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Z.-P. Zheng et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
Scheme 1. One pot synthesis of 1,3,5-triarylpentane-1,5-dione, triarylmethane, and flavonoid derivatives.
Figure 1. The key 1H–1H COSY and HMBC correlations of 3a and 3b.
Scheme 2. Proposed mechanism for the synthesis of 1,3,5-triarylpentane-1,5-dione and flavonoid derivatives.
Please cite this article in press as: Zheng, Z.-P.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2015.12.092

Z.-P. Zheng et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
3
Scheme 3. Proposed mechanism for the synthesis of triarylmethane and flavonoid derivatives.
2-hydroxyacetophnone (2a), and boric acid dissolved in PEG-400
Table 1
and then stirred to react for 6 hours at 130 °C. A major 1,5-dione
derivative 3-(2,4-dihydroxy-phenyl)-1,5-bis-(2-hydroxy-phenyl)-
pentane-1,5-dione (3a) and two minor products, one chalcone
2,4,20-trihydroxychalcone (4a) and one flavonone 20,40-dihydrox-
yflavonone (5a), were isolated by chromatographic purification
and their structures were characterized by NMR and mass spectra
(Supplementary material).23 The structure of the new 1,3,5-tri-
arylpentane-1,5-dione derivative 3a was finally determined on
the base of the 2D-NMR (1H–1H COSY, HSQC, HMBC, Fig. 1).
The plausible mechanism of the formation of 3-(2,4-dihydroxy-
phenyl)-1,5-bis-(2-hydroxy-phenyl)-pentane-1,5-dione could be
explained by the successive Aldol and Michael addition of ketone
Tyrosinase inhibition activities of substrates (1, 2a, 2b) and products 3a–5b (n = 3)
Compounds
IC50
M) SD
(
l
2,4-Dihydroxybenzaldehyde (1)
2-Hydroxyacetophenone (2a)
>200
>300
2,6-Dihydroxyacetophenone (2b)
3-(2,4-Dihydroxy-phenyl)-1,5-bis-(2-hydroxy-phenyl)-
pentane-1,5-dione(3a)
>300
1.67 0.01
2,4,20-Trihydroxychalcone(4a)
0.029 0.001
0.970 0.001
16.17 0.26
20,40-Dihydroxyflavonone (5a)
1-{3-[(3-Acetyl-2,4-dihydroxy-phenyl)-(2,4-dihydroxy-
phenyl)-methyl]-2,6-dihydroxy-phenyl}-ethanone (3b)
5,20,40-Trihydroxyflavonone (4b)
5,20,40-Trihydroxyflavone (5b)
1.96 0.14
2.72 0.07
49.30 1.75
on
a
,b-unsaturated ketones (Scheme 2).24 The initial step was
Kojic acid
Aldol condensation catalyzed by boric acid between 2,4-dihydrox-
ybenzaldehyde and 2-hydroxyacetophenone and firstly led to the
product of 2,4,20-trihydroxychalcone (4a). Then the 2-hydroxyace-
tophenone underwent Michael addition on 2,4,20-trihydroxychal-
cone (4a) to offer the product 3-(2,4-dihydroxy-phenyl)-1,5-bis-
(2-hydroxy-phenyl)-pentane-1,5-dione (3a). On the other way,
the carbonyl oxygen of 2,4,20-trihydroxychalcone (4a) accepted
proton from boric acid to produce canonical product 20,40-trihy-
droxyflavonone (5a) by intramolecular ring closure.25
In Scheme 1(2), substrates 1 and 2b reacted to produce a new
triarylmethane derivative 1-{3-[(3-Acetyl-2,4-dihydroxy-phenyl)-
(2,4-dihydroxy-phenyl)-methyl]-2,6-dihydroxy-phenyl}-ethanone
(3b) and two flavonoids, one main product 5,20,40-trihydrox-
yflavonone (4b) and the other minor product 5,20,40-trihydrox-
droxyflavone (5b) follows the same mechanism the same as the
Scheme 1(1).
The synthetic products 3a–5b showed much stronger tyrosi-
nase inhibitory activities than kojic acid (Table 1). The new product
3a showed a little weaker tyrosinase inhibitory activity than other
two products 4a and 5a, but its tyrosinase inhibitory activity had
about 30-fold stronger than kojic acid. Among them, product 4a
showed the strongest tyrosinase inhibitory activity in six products,
whereas the new product 3b exhibited the weakest tyrosinase
inhibitory activity. It seemed that the intramolecular ring closure
of chalcone to flavonone, the double bond at position 2 and 3 in
C ring of flavone, and hydroxyl substituent at position 5 in A ring
of flavonone were detrimental to their tyrosinase inhibitory
activities.
In summary, a robust and one-pot green synthesis method of
1,3,5-triarylpentane-1,5-dione, triarylmethane, and flavonoid
derivatives had been developed in this study. The method provides
an inexpensive, safe, simple, and eco-friendly way to synthetize
1,3,5-triarylpentane-1,5-dione, triarylmethane, and flavonoid
derivatives. To our knowledge, this is the first report on one-pot
green synthesis of 1,3,5-triarylpentane-1,5-dione, triarylmethane,
and 20,40-dihydroxyflavonoids following this strategy. More impor-
tant, this study developed a new class of 1,3,5-triarylpentane-1,5-
dione and triarylmethane derivatives which may serve as a new
lead structure for novel tyrosinase inhibitor discovery.
yflavone (5b), which was obtained probably from
a
dehydrogenation under high temperature and atmosphere. Their
structures were characterized by NMR (1D-NMR and 2D-NMR)
and mass spectra (Supplementary material). The plausible mecha-
nism of the formation of 1-{3-[(3-Acetyl-2,4-dihydroxy-phenyl)-
(2,4-dihydroxy-phenyl)-methyl]-2,6-dihydroxy-phenyl}-ethanone
could be explained by Friedel–Crafts addition (Scheme 3). 2,6-
Dihydroxyacetophenone firstly attacked 2,4-dihydroxybenzalde-
hyde in the initial step and led to produce diphenyl carbinol
(1b). Then the 2,6-dihydroxyacetophenone further attacked
diphenyl carbinol (1b) under the catalysis by boric acid to offer
the product 1-{3-[(3-Acetyl-2,4-dihydroxy-phenyl)-(2,4-dihy-
droxy-phenyl)-methyl]-2,6-dihydroxy-phenyl}-ethanone
(3b).
The formation of 5,20,40-trihydroxyflavonone (4b) and 5,20,40-trihy-
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This work was supported by Grants from the Natural Science
Foundation of Jiangsu Province of China (BK20141110), the
National Basic Research Program of China (973 Program,
2012CB720801), and the Independent Research Program of State
Key Laboratory of Food Science and Technology of China (SKLF-
ZZA-201510).
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2015.12.
092.
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