A dual-protein cascade reaction for the regioselective synthesis of quinoxalines

Article abstract of DOI:10.1021/acs.orglett.0c01186

In this work, an efficient dual-protein (lipase and hemoglobin) system was successfully constructed for the regioselective synthesis of quinoxalines in water. A set of quinoxalines were obtained in high yields under optimal reaction conditions. This dual-protein method exhibited a regioselectivity higher than those of previously reported methods. This study not only provides a green and mild strategy for the synthesis of quinoxalines but also expands the application of lipase and hemoglobin in organic synthesis.

Full text of DOI:10.1021/acs.orglett.0c01186

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Letter
A Dual-Protein Cascade Reaction for the Regioselective Synthesis of
Quinoxalines
Fengxi Li, Xuyong Tang, Yaning Xu, Chunyu Wang, Zhi Wang, Zhengqiang Li,* and Lei Wang*
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ABSTRACT: In this work, an efficient dual-protein (lipase and hemoglobin) system was successfully constructed for the
regioselective synthesis of quinoxalines in water. A set of quinoxalines were obtained in high yields under optimal reaction
conditions. This dual-protein method exhibited a regioselectivity higher than those of previously reported methods. This study not
only provides a green and mild strategy for the synthesis of quinoxalines but also expands the application of lipase and hemoglobin in
organic synthesis.
uinoxaline derivatives are important structural motifs
mentally benign and sustainable chemical processes. Numer-
ous attempts have been made to produce novel compounds
and natural products by multienzymatic cascade reactions.22,23
Recently, researchers have shown an increased level of
interest in mining non-natural reactions of proteins, and many
studies on this topic have been reported.24−30 Lipases and
hemoglobins are ideal candidates because of their low cost,
commercial availability, broad catalytic abilities, and good
stability. Herein, we designed a novel lipase−hemoglobin
cascade reaction for the efficient synthesis of quinoxalines via a
three-component reaction of 1,3-dicarbonyl compounds,
sulfonyl azides, and 1,2-diamines (Scheme 1). In such a
dual-protein system, lipase was used to catalyze the in situ
generation of diazodicarbonyls by a diazo transfer reaction to
1,3-dicarbonyl compounds with sulfonyl azides. Then, the in
situ-generated α-diazo carbonyl compounds were reacted with
1,2-diamines via a condensation catalyzed by hemoglobin to
Q that exhibit a wide range of biological activities, such as
antitumor, antiviral, antibacterial, anti-inflammatory, and anti-
HIV activities.1−6 Moreover, quinoxalines have been widely
used for the synthesis of dyes, organic semiconductors,
dehydroannulenes, solar cells, cavitands, etc.7−12 Many
chemical methods, including double condensation of aromatic
1,2-diamine with 1,2-dicarbonyl compounds, cascade oxida-
tion−condensation of 1,2-ketoalcohols with aromatic 1,2-
diamine, deoxidation of quinoxaline N-oxides, oxidative
cyclization of terminal or internal alkynes or ketones with
1,2-diamines, coupling of epoxides with ene-1,2-diamines, and
tandem annulation of o-phenylenediamines with diazocarbon-
yls, have been developed for the construction of quinoxa-
lines.13−20 However, most of these methods suffer from
expensive and detrimental metal catalysts, unsatisfactory
product yields, low regioselectivity, harsh reaction conditions,
and volatile or hazardous solvents, thereby limiting their wide
application. Thus, developing a more efficient, regioselective,
and environmentally benign synthetic route is the primary
challenge in constructing quinoxalines.
Scheme 1. Lipase−Hemoglobin System for the Synthesis of
Quinoxalines
Biocatalysis has become increasingly attractive for the
development of more efficient and cleaner chemical
processes.21 High regio- and stereoselectivity and the use of
mild reaction conditions provide an excellent “green” profile
for reactions catalyzed by enzymes. These enzymatic systems
can involve one enzyme that catalyzes one specific reaction or
multiple enzymes that catalyze cascade reactions. Multi-
enzymatic cascade reactions in one pot can offer many
considerable advantages: they are not time-consuming, the
costs and chemicals for product recovery may be reduced,
reversible reactions can be driven to completion, and the
concentration of harmful or unstable compounds can be kept
to a minimum. Therefore, multienzymatic cascade reactions
are considered important strategies for establishing environ-
Received: April 2, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01186
© XXXX American Chemical Society
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afford quinoxalines. This dual-protein system is an environ-
mentally benign, efficient, and regioselective system for the
synthesis of quinoxalines. To the best of our knowledge, this is
the first report of a dual-protein system containing lipase and
hemoglobin, and no report on the regioselective synthesis of
quinoxalines using proteins as catalysts has been published.
Initially, ethyl acetoacetate, p-toluenesulfonyl azide (TsN3),
and 1,2-diaminobenzene were used as the model substrates for
this lipase−hemoglobin-catalyzed cascade reaction. By using
this model reaction, we investigated the effect of the type of
proteins. As shown in Table 1, all of the used lipases and heme
catalytic conformations of proteins are necessary for this dual-
protein-catalyzed reaction. The commercial ferric chloride
hemes [hemin and Fe(TPP)Cl] afforded poor yields of 4a in
this reaction even when the heme concentration was increased
to 1 mol % (entries 14 and 15). We also used Et3N and
Fe(OTf)3 as the chemical catalysts (dosage of ≤1 mol %), and
an only 14% yield was obtained after reaction for 48 h (entry
16). The combination of Et3N and HbBv was investigated to
clarify the necessity of lipase, and the yield was obviously lower
than that of the combination of PPL and HbBv (entry 17). An
excessive dosage of Et3N could lead to a decrease in the
catalytic activity of HbBv (data listed in Table S1).
Furthermore, the optimum operational ratio of PPL and
HbBv is also important for this dual-protein cascade reaction.
We fixed the dosage of HbBv at 16 mg (0.1 mol %) and
investigated the effects of the ratio of PPL and HbBv (data
listed in Table S2). The quinoxaline yield (4a) increased as the
amount of PPL increased to 4 mg. However, further increasing
the amount of PPL did not improve the yield. Considering the
high efficiency, mild condition, and low catalyst dosage, the
dual-protein strategy is a more practical method for the
synthesis of quinoxalines.
Table 1. Synthesis of Quinoxaline (4a) by a Dual-Protein
a
System (lipase and hemoglobin)
entry
lipase
hemoglobin
HbBv
HbBv
HbBv
HbBv
HbSv
Mb
isolated yield (%)
1
2
3
4
5
6
7
8
PPL
90
76
41
35
61
47
28
ND
ND
ND
ND
Cal-B
PSL
CRL
PPL
PPL
PPL
PPL
−
HP
−
Using environmentally friendly solvents as the ideal
alternative to hazardous organic solvents has attracted
considerable interest in organic synthesis.35 In this dual-
protein system, we used water as the reaction medium because
of its nontoxic characteristics. However, the yield was not very
satisfactory due to the poor solubility or dispersibility of
substrates in water (Table 2, entry 1). Generally, surfactants
b
b
9
HbBv
HbBv
denatured HbBv
apo-HbBv
−
b
10
11
12
13
14
15
16
17
denatured PPLc
c
b
PPL
PPL
−
PPL
PPL
b
ND
ND
b
d
hemin
26
31
14
67
d
Fe(TPP)Cl
Fe(OTf)3
Table 2. Effects of Surfactants on the Dual-Protein-
e
e
a
Et3N
Et3N
Catalyzed Synthesis of Quinoxaline (4a)
f
HbBv
a
surfactant concentration isolated yield
Reaction conditions: ethyl acetoacetate (1a, 1.0 mmol), TsN3 (2, 1.2
entry solvent
surfactant
(mol %)
(%)
equiv), 1,2-diaminobenzene (3a, 1.0 equiv), hemoprotein (heme
concentration of 0.1 mol %), lipase (protein content of 4 mg), water
(2 mL), Triton X-100 (5% mol), 55 °C, 6 h. Abbreviations: PPL,
porcine pancreas lipase; Cal-B, lipase B from Candida antarctica; PSL,
Pseudomonas sp. lipase; CRL, Candida rugosa lipase; HbBv,
hemoglobin from bovine blood; HbSv, hemoglobin from swine
blood; Mb, myoglobin from equine heart; HP, horseradish
1
2
3
4
5
6
7
water
water
water
water
water
water
water
−
−
5
5
5
5
45
90
72
34
29
77
81
Triton X-100
Tween 80
SDS
AOT
Triton X-100
Triton X-100
2.5
10
b
c
peroxidase; hemin, chloroprotoferriheme. Not detected. Denatured
d
e
by heating. Heme concentration of 1 mol %. Using 1% mol, 48 h.
a
f
Reaction conditions: ethyl acetoacetate (1.0 mmol), TsN3 (1.2
Using 1% mol, 6 h.
equiv), 1,2-diaminobenzene (1.0 equiv), PPL (protein content of 4
mg), HbBv (heme concentration of 0.1 mol %), water, 2 mL,
surfactant, 55 °C, 6 h.
proteins could catalyze the reaction (entries 1−7), and the
combination of porcine pancreas lipase (PPL) and hemoglobin
from bovine blood (HbBv) achieved the highest yield of
quinoxaline (4a). Accordingly, PPL always exhibits a
satisfactory catalytic ability in many lipase-catalyzed promis-
cuous reactions.31−33 The higher catalytic performance of
hemoglobin compared with those of other heme proteins may
be due to the synergistic effect of hemoglobin, which is
composed of four subunits.34 Therefore, we selected these two
proteins as the catalysts for further studies. No corresponding
product was observed when PPL or HbBv was used
independently in this reaction (entry 8 or 9, respectively),
whereas one of the proteins combined with the other
denatured one could not catalyze this reaction (entries 10
and 11). When Apo-HbBv replaced HbBv as the catalyst in
this dual-protein-catalyzed reaction, the reaction did not occur
(entry 12). These control experiments were the same as the
blank experiment (entry 13). These results suggest that both
proteins are involved in this catalytic process and their active
not only can enhance the biocatalytic efficiency and stability of
proteins but also can substantially increase the degree of
dispersion of the organic substrate in aqueous media.36,37 In
the study presented here, the effects of four types of
surfactants, namely, sodium di-2-ethylhexylsulfosuccinate
(AOT, anionic surfactant), sodium dodecyl sulfate (SDS,
anionic surfactant), Triton X-100 (non-ionic surfactant), and
Tween 80 (non-ionic surfactant), on the dual-protein-catalyzed
synthesis of quinoxalines were investigated. The non-ionic
surfactants (entries 2 and 3) were remarkably more effective in
accelerating the reaction, whereas the anionic surfactants
(entries 4 and 5) decreased the reaction rate. The highest yield
was obtained when Triton X-100 was adopted. These results
are consistent with the findings of other researchers who
reported that anionic surfactants can interact strongly with
proteins and cause their denaturation.38−40 Furthermore, the
B
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effect of the amount of Triton X-100 was also examined, and
the optimal concentration was 5 mol %. Triton X-100
markedly decreased the yield of quinoxaline.
Scheme 2. Dual-Protein-Catalyzed Synthesis of
Quinoxalines
a
Temperature is another key factor that affects enzymatic
reactions. Our results (Figure 1) demonstrated that the yield
Figure 1. Effect of temperature on the dual-protein-catalyzed
synthesis of quinoxalines. Reaction conditions: ethyl acetoacetate
(1a, 1.0 mmol), TsN3 (2, 1.2 equiv), 1,2-diaminobenzene (3a, 1.0
equiv), HbBv (heme concentration of 0.1 mol %), PPL (protein
content of 4 mg), water (2 mL), Triton X-100 (5% mol), 6 h.
a
Reaction conditions: (a) β-ketoester (1.0 mmol), TsN3 (1.2 equiv),
1,2-diamine (1.0 equiv), PPL (protein content of 4 mg), HbBv (heme
concentration of 0.1 mol %), water, Triton X-100 (5 mol %), 55 °C, 6
1
h, isolated yield; (b) ratio determined by H NMR; (c) catalyzed by
hemin (1 mol %) and PPL; (d) catalyzed by Et3N and Fe(OTf)3.
increased as the temperature increased from 30 to 55 °C, and
the maximum yield was achieved at 55 °C. The catalytic
performance of the dual-protein system gradually declined as
the temperature was further increased. Generally, higher
temperatures can increase the frequency of the collision
between protein and substrate molecules and improve the
catalytic efficiency. However, the temperature beyond 55 °C
may destroy the active conformation of the protein, which may
decrease the catalytic activity. Under the optimum conditions,
we scaled up the biocatalytic process by 100-fold [water (2 L),
ethyl acetoacetate (100 mmol), TsN3 (120 mmol), 1,2-
diaminobenzene (100 mmol), lipase (0.4 g), HbBv (heme
concentration of 0.1 mol %), and Triton X-100 (5 mol %) at
55 °C]. The yield of quinoxaline reached 93% (20.06 g, 92.9
mmol) after 6 h. This result implies that this green method has
high potential for industrial production.
Scheme 3. Control Experiments
To test the robustness of this reaction, various substituted
1,2-diaminobenzenes and β-ketoesters were used for the
synthesis of quinoxalines. As shown in Scheme 2, all of the
used 1,2-diamines and β-ketoesters can react with TsN3 in one
pot and afford the desired quinoxalines with satisfactory yields
(81−95%). It was noteworthy that hemoglobin exhibited
moderate regioselectivity when monosubstituted 1,2-diamino-
benzenes were used as the substrates (4i−4l). To prove that
this regioselectivity was derived from hemoglobin, hemin and
PPL were combined to catalyze the reaction, and a poor
regioselectivity was achieved as expected. Compared with the
result catalyzed by Et3N and Fe(OTf)3, HbBv also exhibited
obviously higher regioselectivity. The regioselectivity of the
protein can be improved by the current tools of enzyme
engineering or directed evolution. Further study of the directed
evolution of hemoglobin for the synthesis of quinoxalines is
now in progress in our laboratory.
carbonyl compound 5a was isolated with 60% yield (eq 1).
Compound 5a was reacted with 1,2-diaminobenzene to
generate quinoxaline 4a in 84% yield in the presence of
hemoglobin (eq 2). Only compound 5a was obtained when
PPL was used for this three-component reaction (eq 3),
whereas no reaction occurred when HbBv was applied as the
catalyst (eq 4), suggesting that the diazotization reaction
cannot proceed in the presence of 1,2-diaminobenzene and
this dual-protein-catalyzed reaction comprises two sequential
steps: (1) lipase-catalyzed diazo transfer reaction and (2)
hemoglobin-catalyzed annulation. No quinoxaline 4a was
obtained when the reaction was conducted under a nitrogen
atmosphere in a closed system (eq 5). This result confirmed
that an oxidative aromatization was involved in the process of
hemoglobin-catalyzed annulation.
To understand the dual-protein-catalyzed reaction, control
experiments were conducted, and the results are presented in
Scheme 3. Diazo transfer reaction to ethyl acetoacetate with p-
toluenesulfonyl azide could be catalyzed by lipase, and α-diazo
On the basis of our experimental results and previous
reports,41−45 a reasonable mechanism of this cascade reaction
is proposed in Scheme 4. First, ethyl acetoacetate (1a) is
deprotonated by the catalytic triad of lipase forming an enolate
C
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Scheme 4. Mechanism of the Dual-Protein-Catalyzed
Synthesis of Quinoxalines
AUTHOR INFORMATION
Corresponding Authors
■
Lei Wang − Key Laboratory of Molecular Enzymology and
Engineering of Ministry of Education, School of Life Sciences,
Jilin University, Changchun 130023, P. R. China; orcid.org/
0000-0002-9728-0613; Email: w_lei@jlu.edu.cn
Zhengqiang Li − Key Laboratory of Molecular Enzymology and
Engineering of Ministry of Education, School of Life Sciences,
Jilin University, Changchun 130023, P. R. China; Email: lzq@
jlu.edu.cn
Authors
Fengxi Li − Key Laboratory of Molecular Enzymology and
Engineering of Ministry of Education, School of Life Sciences,
Jilin University, Changchun 130023, P. R. China
Xuyong Tang − Key Laboratory of Molecular Enzymology and
Engineering of Ministry of Education, School of Life Sciences,
Jilin University, Changchun 130023, P. R. China
Yaning Xu − Key Laboratory of Molecular Enzymology and
Engineering of Ministry of Education, School of Life Sciences,
Jilin University, Changchun 130023, P. R. China
Chunyu Wang − State Key Laboratory of Supramolecular
Structure and Materials, Jilin University, Changchun 130023,
P. R. China
Zhi Wang − Key Laboratory of Molecular Enzymology and
Engineering of Ministry of Education, School of Life Sciences,
Jilin University, Changchun 130023, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01186
Notes
ion that is necessary for the diazo transfer reaction. Second,
TsN3 can be reacted with the enolate ion to produce the α-
diazo carbonyl compound 5a. Third, 5a is catalyzed by heme
in hemoglobin to generate an iron carbenoid with N2
elimination, which can be attacked by the NH2 group of 1,2-
diaminobenzene (3a) to produce the zwitterion intermediate.
The regioselective product could be formed in this step, and
the regioselectivity observed might be due to the steric
hindrance in the active center of hemoglobin. Then, 2H-
quinoxaline intermediate 6 is formed by proton transfer and
intramolecular dehydration, which is similar to Lee’s work.20
Finally, an oxidative aromatization of intermediate 6 is
catalyzed by oxyhemoglobin (HbO2) to afford target quinoxa-
line 4a.
In conclusion, we have demonstrated that a dual-protein
(lipase and hemoglobin) system can be applied for the
regioselective synthesis of quinoxalines in water. This green
and efficient method not only can be easily scaled up but also
exhibits a moderate regioselectivity in the synthesis of
quinoxalines. Therefore, this novel dual-protein system has
high potential for the development of new synthetic
approaches and green technology in organic synthesis.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authots gratefully acknowledge the National Natural
Science Foundation of China (31670797) and the National
Defense Science and Technology Innovation Zone Foundation
of China.
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