A green and one-pot synthesis of benzo[g] chromene derivatives through a multi-component reaction catalyzed by lipase

Article abstract of DOI:10.1039/c4ra13272f

The synthesis of benzo[g]chromene derivatives through a multicomponent reaction catalyzed by lipase is reported for the first time. This novel efficient method has the advantages of environmental friendliness, high yield and simple work-up. Moreover, this

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Lipase-catalyzed synthesis of benzo[g]chromene derivatives

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A green and one-pot synthesis of benzo[g]chromene derivatives through
a multi-component reaction catalyzed by lipase
Fengjuan Yang,a,b Haoran Wang,a,b Liyan Jiang,a,b Hong Yue,a,b Hong Zhang,a,c Zhi Wang*a,b and Lei
Wang*a,b
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Initial studies were undertaken using benzaldehyde,
malononitrile and 2ꢀhydroxyꢀ1,4ꢀnaphthoquinone as a model
45 reaction. Several kinds of lipases were selected to catalyze this
multiꢀcomponent reaction and the results are listed in Table 1. It
could be found that all the selected lipases can catalyze this
multiꢀcomponent reaction and the catalytic activities depend
mainly on the lipase origin. When the denatured lipase or bovine
50 serum albumin (BSA) was used as the catalyst, almost no product
could be detected which suggested a special active conformation
of enzyme play a crucial role in this multiꢀcomponent reaction.
Among of the selected lipases, Candida sp. lipase (CSL)
exhibited the highest catalytic activity. Therefore, we chose CSL
55 as the catalyst for the multiꢀcomponent reaction. ‡
The synthesis of benzo[g]chromene derivatives through a
multi-component reaction catalyzed by lipase was reported in
the first time. This novel efficient method has the advantages
10 of environmental friendliness, high yield and simple work-up.
Moreover, this protocol extends the phenomenon of enzyme
promiscuity.
A multiꢀcomponent reaction is generally defined as a reaction
in which three or more reactants combine in one pot to form a
15 single product that contains essentially all of the atoms of the
starting materials (with the exception of condensation products,
such as H2O, HCl, or MeOH) [1ꢀ2]. Compared with the
conventional chemical reactions, the multiꢀcomponent reaction
strategies can offer the advantage of simplicity and synthetic
20 efficiency [3ꢀ4].
Table 1 The catalytic activities of different lipases in the synthesis of
benzo[g]chromene derivatives a
Enzyme catalytic promiscuity is the ability of an enzyme to
catalyze more than one type of chemical transformation. As a
“hidden skill” of enzyme, it can provide novel synthesis pathway
that are currently not available [5,6] and can widen the
25 application of enzyme. In this area, lipase is the most used
enzyme due to its broad specificity and excellent stability in
various media. Many elegant works of lipase catalytic
promiscuity in the carbon–carbon bondꢀforming reactions (Aldol
condensation, Morita–Baylis–Hillman reaction, Michael addition,
30 Markovnikov addition, and Knoevenagel reaction, et al.) have
been reported in the past few years [7ꢀ14]. As a part of our
interest to explore the applications of lipase in this new area, we
are focusing on the multiꢀcomponent reaction of synthesis of
benzo[g]chromene derivatives catalyzed by lipase in this study.
35 Benzo[g]chromene derivatives have extensive bioactivities, such
as antibacterial, antiproliferation and antitumor activities [15ꢀ20].
To the best of our knowledge, it is reported for the first time that
the synthesis of benzo[g]chromene derivatives can be catalyzed
by lipase (Scheme 1).
Entry
1
Enzyme
Candida antarctica Lipase B
(CALB)
Porcine pancreas Lipase
(PPL)
Candida sp. Lipase
(CSL)
Pseudomonas fluorescens Lipase
(PFL)
Isolated yield (%)
57
2
3
79
88
4
54
5
Pseudomonas sp. Lipase
(PSL)
Bacillus subtillus Lipase
(BSL2)
C. rugosa Lipase
(CRL)
Bovine serum albumin
(BSA)
66
6
70
7
61
8
Trace
Trace
9
Candida sp. Lipase
(denatured) b
10
No enzyme
Trace
a
Reaction condition:
malononitrile (1 mmol) and benzaldehyde (1 mmol), ethanol (2mL),
60 enzyme (20 mg, protein content), 55 C, 12h. CSL was denatured by
heating it to 100 oC for 6 h in water before lyophilization.
2ꢀhydroxyꢀ1,4ꢀnaphthoquinone (1 mmol),
o
b
Choosing a suitable solvent is of crucial importance for the
enzyme catalytic performance [21]. Thus, seven organic solvents
65 were screened for this reaction and the results are presented in
Figure 1. Compared with other solvents, the highest yield (88%)
could be obtained while ethanol was used as the reaction media.
It's believed that the solvent can lead to a conformational change
40
Scheme 1 Lipaseꢀcatalyzed synthesis of benzo[g]chromene
derivatives
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Fig. 2 Temperature effect on the synthesis of benzo[g]chromene
of the enzyme and then affect the enzyme activity [22].
derivatives catalyzed by lipase
Reaction condition: 2ꢀhydroxyꢀ1,4ꢀnaphthoquinone (1 mmol),
malononitrile (1 mmol) and benzaldehyde (1 mmol), ethanol (2mL), CSL
25 (20 mg, protein content), 12h at different temperature.
80
60
40
20
0
To explore the scope and feasibility of this multiꢀcomponent reaction,
a series of benzo[g]chromene derivatives were synthesized under the
optimum reaction conditions. The results in Table 2 demonstrated that the
protocol could be applied to aromatic aldehydes either with electronꢀ
30 withdrawing groups (Entry 2ꢀ6) or electronꢀdonating groups (Entry 7ꢀ9)
with satisfied yields (from 81% to 93%). It is noteworthy that the
electronic nature of substituents of the aromatic aldehyde has no distinct
effect on the multiꢀcomponent reaction.
The lipaseꢀcatalyzed Knoevenagel condensation and Michael addition
35 have been reported previously [10, 24]. According to these reports and
our results in this study, a plausible mechanism was proposed in Scheme
Solvent
Fig. 1 Solvent effect on the synthesis of benzo[g]chromene derivatives
2. The synthesis of benzo[g]chromene derivatives involves
a
catalyzed by lipase
Knoevenagel condensation, Michael addition, cyclization and
isomerization, respectively. As shown in Scheme 2, lipase could catalyze
40 the steps of Knoevenagel condensation and Michael addition during the
reaction process. Firstly, enzymatic Knoevenagel condensation of the
aldehyde 1 to malononitrile 2 was occurred to produce an intermediate 5.
Secondly, Michael addition of the 2ꢀHydroxyꢀ1,4ꢀnaphthoquinone 3 on
the intermediate 5 could be catalyzed by lipase to produce an intermediate
45 6. Finally, intramolecular cyclization and isomerization formed the
product 4 automatically. It’s important to note that the benzo[g]chromene
derivatives obtained in this study were racemic when all the screened
lipases were used as catalyst, which indicated that lipase didn't exhibit the
stereoselectivity in the Michael addition of this reaction. This
50 phenomenon was in accordance with the recent reported literatures [25,
26].
5
Reaction condition: 2ꢀhydroxyꢀ1,4ꢀnaphthoquinone (1 mmol),
malononitrile (1 mmol) and benzaldehyde (1 mmol), solvent (2mL), CSL
(20 mg, protein content), 55 oC, 12h.
It’s generally believed that reaction temperature is another
10 vital influence factor for all enzymatic reactions [23]. In this
o
study, the reaction temperature was varied from 25 to 75 C to
investigate its effect. As shown in Figure 2, the yield increased as
temperature was enhanced from 25 to 55 oC and dropped
dramatically at higher temperature. The increased collision
15 chance between the enzyme and substrate at the elevated
temperature may improve the reaction rate. Further increasing
temperature may disrupt the enzyme conformation and decrease
the enzyme activity. Since the yield was found to be the highest
at 55 oC, the optimum temperature for this reaction was 55 oC.
100
90
80
70
60
50
40
Scheme 2 Mechanism of the lipase-catalyzed synthesis of
20
30
40
50
60
70
80
Temperature (oC)
benzo[g]chromene derivatives
20
2
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Table 2 Lipaseꢀcatalyzed synthesis of benzo[g]chromene derivatives with
different aromatic aldehydes a
Notes and references
Entry
Aromatic
aldehyde
Product
Isolated yield (%)
35 a Key Laboratory of Molecular Enzymology and Engineering of Ministry
of Education, Jilin University, Changchun 130023, P R China;Email:
wangzhi@jlu.edu.cn, w_lei@jlu.edu.cn
1
2
3
4
4a
4b
4c
4d
88
90
91
93
b School of life sciences, Jilin University, Changchun 130023, P R China;
c College of Chemistry, Jilin University, Changchun 130023, P R China;
40
Cl
CHO
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
5
6
4e
4f
89
85
‡ A typical enzymatic procedure of the reaction: CSL (20 mg, protein
45 content) was added to a 25 mL roundꢀbottom flask containing aromatic
aldehyde (1 mmol), malononitrile (1 mmol) and ethanol (2 mL). The
suspension was maintained at 55 oC for 10 min. Then, 2ꢀhydroxyꢀ1,4ꢀ
naphthoquinone (1 mmol) was added to the reaction mixture. After
completion of the reaction (after 12 h, monitored by TLC), the reaction
50 mixture was concentrated under vacuum. The residue was washed with
water and cold diethyl ether three times to remove unreacted starting
materials and other organic contaminations, and then the filter cake was
recrystallized from 95% ethanol to give products 4 with high purity. The
experiments were performed triplicate, and all data were obtained based
55 on the average values. The products were characterized by NMR and
ESIꢀMS experiments.
7
8
4g
4h
86
83
9
4i
81
a
Reaction condition: 2ꢀHydroxyꢀ1,4ꢀnaphthoquinone (1 mmol),
malononitrile (1 mmol) and aromatic aldehyde (1 mmol), ethanol (2mL),
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In summary, an efficient and simple method for the synthesis
of benzo[g]chromene derivatives catalyzed by lipase was reported
for the first time. After thorough optimization of reaction
10 conditions, all the products could be obtained in high yields (from
81% to 93%). Compared with the reported methods [27ꢀ33], the
notable features of this new synthetic route are not only atom
economy, environmental friendliness and simple operational
process, but more importantly, this work significantly expands
15 the utility of lipase in organic synthesis and encourages us to use
the current tools of enzyme engineering and directed evolution to
increase the catalytic performance of lipase. It's known that
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a powerful tool to avoid the enzyme
aggregation in organic solvent and recover and reuse of the
20 enzyme with high remnant activity [34ꢀ37]. Further study of the
immobilization enzyme on the lipaseꢀcatalyzed synthesis of
benzo[g]chromene derivatives is now in progress in our
laboratory.
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We gratefully acknowledge the National Natural Science
Foundation of China (No. 21172093 and 31070708), the Natural
Science Foundation of Jilin Province of China (No.
20140101141JC) and the Scientific Research Fund of Jilin
30 University (No. 450060326007 and 450060491559) for the
financial support.
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