Lipase-Catalyzed Highly Efficient 1,6-Conjugated Addition for Synthesis of Triarylmethanes

Article abstract of DOI:10.1007/s10562-019-03043-8

Lipase from porcine pancreas (PPL) is first reported to catalyze direct 1,6-conjugated addition for synthesis of triarylmethanes using p-quinonemethides (p-QMs) and 2-naphthols. The catalytic activity of PPL was evaluated through investigating the solvent, the ratio of substrates, the enzyme loading and the temperature of the enzyme-catalyzed reactions. The present method proves to be environmentally friendly and efficient in terms of high yield, green catalyst and simple synthesis method. GraphicAbstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s10562-019-03043-8

Catalysis Letters
https://doi.org/10.1007/s10562-019-03043-8
Lipase‑Catalyzed Highly Efcient 1,6‑Conjugated Addition
ꢀor Synthesis oꢀ Triarylmethanes
1
1
1
1
1
1
Zeng‑Jie Yang · Na Wang · Wei‑Xun He · Yuan Yu · Qing‑Tian Gong · Xiao‑Qi Yu
Received: 29 August 2019 / Accepted: 15 November 2019
©
Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract
Lipase from porcine pancreas (PPL) is ꢀrst reported to catalyze direct 1,6-conjugated addition for synthesis of triarylmeth-
anes using p-quinonemethides (p-QMs) and 2-naphthols. The catalytic activity of PPL was evaluated through investigating
the solvent, the ratio of substrates, the enzyme loading and the temperature of the enzyme-catalyzed reactions. The present
method proves to be environmentally friendly and eꢁcient in terms of high yield, green catalyst and simple synthesis method.
GraphicAbstract
OH
O
R2
OH
PPL
R2
R1
R1
HO
2
2 examples
yield up to 98%
3
1
2
Keywords Lipase · Biocatalysis · 1,6-Conjugated addition · Triarylmethanes · One-pot synthesis · Ecofriendly
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s10562-019-03043-8) contains
supplementary material, which is available to authorized users.
1
Introduction
As a kind of versatile structural skeleton, triarylmethanes
plays an important role not only in the dye industry but
also in the neighborhood of organic functional materials
*
Na Wang
wnchem@scu.edu.cn
*
Xiao-Qi Yu
[
1, 2]. In addition, triarylmethane compounds have been
xqyu@scu.edu.cn
found to be part of some naturally occurring molecules, and
such symmetrical and asymmetric compounds have been
observed in drug discovery and screening with many inter-
esting biological and medicinal properties [3, 4]. For exam-
ple, 4,4′-dihydroxy-triphenylmethane (Fig. 1a) is a class
of antiviral agents that show high activity against HSV-1.
Bis-(4-acetoxypheny1)-2-pyridyl methane (Fig. 1b) is the
main component of the bisacodyl enteric-coated tablets. The
thiophene-containing triarylmethane (Fig. 1c) is an antitu-
bercular agent having signiꢀcant inhibitory activity against
the proliferation of mycobacterium tuberculosis in mouse
Zeng-Jie Yang
1
56888003@qq.com
Wei-Xun He
12840936@qq.com
4
Yuan Yu
45416315@qq.com
7
Qing-Tian Gong
qingtian-gong@qq.com
1
Key Laboratory of Green Chemistry & Technology, Ministry
of Education, College of Chemistry, Sichuan University,
Chengdu 610064, People’s Republic of China
Vol.:(0
1
123456789)
3

Z.-J. Yang et al.
Fig. 1 Selected examples of
triarylmethanes embodied with
biological and pharmacological
activity
OAc
N
OMe
HO
X
OH
X
R1
R3
S
AcO
HO
R2
X=H, Br
R , R , R =H, OMe, OPh, OCH O
1
2
3
2
B
C
A
and human macrophages [5–8]. Therefore, it is becoming
more and more important to seek an eꢂective synthetic route
for triarylmethane and its derivatives. The most common
method for the synthesis of triarylmethanes includes the
Lewis acid or Brønsted acid catalyzed Friedel–Crafts type
reaction of diarylmethanol or its derivatives with arenes or
heteroarenes [9–12]. Lewis acid-surfactant combined cata-
lyst developed by Kobayashi has gained much attention in
catalysis during the past decades because of its dual behav-
ior. Common Brønsted acids like MeSO H, CF SO H were
this novel catalytic promiscuity is enantioselective and can
especially tolerate a wide range of substrates, it not only
could extend the enzymatic reaction speciꢀcity, but also
might be practically utilized in organic synthesis. In 2009,
we described the ꢀrst MML-catalyzed direct, three-com-
ponent Mannich reaction with ketone, aldehyde and amine
(under aqueous conditions) to form β-amino-ketone com-
pounds. Interestingly, these promiscuous reactions can be
greatly promoted by water and generally require aromatic
aldehydes. A series of substrates have been explored, result-
ing in moderate to good yields.
3
3
3
also found eꢂective for the transformation. Although the
above synthetic strategy can exhibit a wide range of sub-
strates and excellent functional group tolerance, the atomic
economy is poor and harsh reaction conditions are required.
Therefore, it is meaningful and necessary to develop a mild
and atomic economic method for the synthesis of triaryl-
methane compounds.
Continuing our interests in lipase-catalyzed organic syn-
thesis, we herein used lipase from porcine pancreas as a
biocatalyst to catalyze the 1,6-conjugated addition reaction
of a substrate to p-quinonemethides and 2-naphthol under
mild reaction conditions to synthesize triarylmethanes. After
several optimizations of the reaction conditions, the yield of
the template reaction reached 95% and had good substrate
tolerance (Scheme 1).
In recent years, lipases have received extensive attention
as biocatalysts due to their attractive properties, such as
exhibited stability in organic solvents, no cofactors required,
broad substrate tolerance, commercial availability and high
chemo-, regio- and stereo-selectivity [13, 14]. Lipase (EC
2 Experimental
3
.1.1.3) is a class of enzymes ubiquitous in all organisms
and plays an important role in the food, beverage, biodiesel
production and biopolymer industries [15, 16]. Recently,
enzymes with promiscuous catalytic activity have been iden-
tiꢀed, and several new examples of catalytic promiscuity
of hydrolases have been reported for their ability to cata-
lyze carbon–carbon or carbon-heteroatom bond formations,
such as aldol reaction, Michael addition, Mannich reaction,
Henry reaction, Knoevenagel reaction, Hantzsch reaction
and Biginelli reaction [17–26]. In our previous work, we
have reported a variety of enzymatic promiscuous reactions
PPL (lipase from porcine pancreas, 6.8 U/mg), BPL (Lipase
from Bovine pancreas, 15–35 u/g), MJL (Amano Lipase M
from Mucor javanicus, 10,000 U/mg), PFL(Amano Lipase
AK from Pseudomonas fuorescens, ≥600 U/g), α-BSA(α-
Amylase from Bacillus subtilis, 50 U/mg), AOA (α-Amylase
from Aspergillus oryzae, 28.7 U/mg), CAL-B (Lipase from
Candida antarctia B, 2 U/mg) were purchased from Sigma-
Aldrich. BSA (Bovine serum albumin), Trypsin from Bovine
pancreas, 2500 U/mg were purchased from Aladdin. Unless
otherwise mentioned, all reagents were obtained from com-
1
[
27–34], such as in 2008, we ꢀrst reported that lipase from
mercial suppliers and used without further puriꢀcation. H
1
3
porcine pancreas have a promiscuous ability to catalyze
asymmetric aldol reactions between acetones and aldehydes
in the presence of water. To clarify the enzymatic process,
we performed some experiments to tentatively hypothesize
the mechanism of the new biocatalytic promiscuity. Since
NMR, C NMR spectra were measured on Bruker AM400
NMR spectrometer (400 MHz or 100 MHz, respectively)
with CDCl as solvent and recorded in ppm relative to tetra-
3
methylsilane (TMS). Thin layer chromatography (TLC)
experiments were performed on glass-backed silica plates
1
3

Lipase-Catalyzed Highly Eꢀcient 1,6-Conjugated Addition for Synthesis of Triarylmethanes
Scheme 1 Lipase-catalyzed
OH
highly eꢁcient 1,6-conjugated
addition
O
R2
OH
Lipase
R2
R1
HO
R1
1
2
3
and visualized with UV-detection. HPLC was performed on
an Agilent instrument (LC 1200 UV/Vis Detector) by using
a chiral column (4.6 mm, 250 mm). HRMS were performed
on Bruker Daltonics BIO TOF mass spectrometer. Column
chromatography was carried on silica gel (200–300 mesh)
using ethyl acetate-petroleum ether as mobile phase.
3 Results and Discussion
Initially, we chose the reaction of the substrate methylene
benzoquinone (1a) and 2-naphthol (2a) in dichloromethane
as a model reaction. In order to select a suitable biocatalyst
to catalyze the synthesis of triarylmethane compounds, the
catalytic eꢂects of diꢂerent commercial enzymes on the
model reaction were ꢀrst investigated. The results are shown
in Table 1. The catalytic activities of lipases from diꢂerent
sources are quite diꢂerent, compared with the poorer activity
of lipase from Bovine pancreati(BPL), and the diꢂerence in
source and the diꢂerence between the sources of lipase from
Mucor jaranicus and lipase from Candida antarctia B (MJL
and CAL-B) showed moderate activity, and lipase from
porcine pancreas (PPL) showed signiꢀcant catalytic ability,
yielding the highest yield of 95% (entries 2–4, 6, Table 1).
Trypsin from Bovine pancreas also exhibited poor catalytic
activity (entry 5, Table 1). The catalytic activity of diꢂerent
amylase sources is similar to that of lipase. α-Amylase from
Aspergillus oryzao (AOA) has lower activity in this tem-
plate reaction, while α-amylase from Bacillus subtilis exhib-
its high catalytic activity (entries 8, 9, Table 1). Under the
same experimental conditions, pepsin and α-chymotrypsin
were used as catalysts to obtain a moderately low yield
(entries 10–11, Table 1). In addition, almost no target prod-
uct was produced under the conditions of no catalyst (entry
2
.1 General Procedure for the Preparation
of p‑Quinonemethides
2
, 6-Di-tert-butylphenol (0.2 mmol) and the correspond-
ing aromatic aldehyde (25 mmol) were added to toluene
100 mL), and then the mixture was heated to reꢃux. Piperi-
(
dine (50 mmol, 4.94 mL) was added drop wise over 1 h then
the reaction mixture was reꢃuxed for 6–15 h. After this step,
drop temperature, and when it was just below the boiling
point of the reaction mixture, acetic anhydride (50 mmol,
2
.55 g) was added and stirring was continued for 15 min.
The reaction was detected by TLC (observed under a UV
lamp), and after the reaction was completed, the reaction
mixture was cooled to room temperature, and the organic
phase was removed under reduced pressure. The crude prod-
uct was puriꢀed by silica gel rapid column chromatogra-
phy and recrystallized with n-hexane to obtain the desired
product.
1, Table 1). When the PPL is deactivated at 120 °C, no prod-
uct could be obtained.(entry 12, Table 1).The similar result
has been found when PPL was pretreated with urea as a
denaturing agent (entry 14, Table 1). The results show that
the denatured PPL loses its natural activity as well as its
catalytic ability of non-natural reactions. In order to deter-
mine the eꢂect of urea on the model reaction, only urea was
used to catalyze the model reaction, and no catalysis activ-
ity was observed (entry 13, Table 1). Heavy metal ions can
also be used to deactivate enzymes because they can react
with some structural groups (such as sulfhydryl groups) and
cause irreversible damage, or they can interact with some
amino acid residues, causing changes in tertiary structure.
2
.2 General Procedure for the Preparation
of Triarylmethanes(3a‑v)
Add p-methyl compound (0.2 mmol), 2-naphthol
0.4 mmol), 60 mg PPL, 1 mL of dichloromethane to a
0 mL Erlenmeyer ꢃask and shaken at 40 °C, 200 rpm.
(
1
The TLC traces the detection reaction (observed under
ultraviolet light), and after the reaction is completed, the
enzyme is removed by ꢀltration and the solvent in the reac-
tion is removed by a rotary evaporator. Finally, the target
product was obtained by column chromatography (silica
gel: 200–300 mesh, mobile phase: petroleum ether/ethyl
acetate=40:1–20:1).
2+
Therefore, Cu was used for pretreatment of PPL. Metal ion
pretreated PPL lost the ability to catalyze model reactions
1
3

Z.-J. Yang et al.
Table 1 The catalytic activities of diꢂerent enzymes for 1,6-addition reaction
O
OH
OH
Enzyme
o
DCM, 40 C
O
O
HO
3a
1a
2a
a
Entry
Catalysts
No enzyme
Yield (%)
1
2
3
4
5
6
7
8
9
2
95
29
50
11
64
75
21
71
45
30
Lipase from Porcine pancreas (PPL)
Lipase from Bovine pancreatic (BPL)
Lipase from Mucor jaranicus (MJL)
Trypsin from Bovine pancreas
Lipase from Candida antarctia B (CAL-B)
Amano lipase from Pseudomonas fuorescens
α-Amylase from Aspergillus oryzao (AOA)
α-Amylase from Bacillus subtilis
Pepsin
α-Chymotrypsin
Denatured PPL
Urea (200 mg)
PPL (pretreated with urea)
1
1
1
1
1
1
1
0
1
2
3
4
5
6
d
0
0
1b
0
CuSO (39.9 mg)
4
PPL (pretreated with 250 mM Cu2+)
0c
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), enzyme (30 mg), DCM (1000 μL) were added to10 mL Erlenmeyer ꢃask, and shaken at
2
00 rpm at 40 °C for 48 h
a
All yields were determined by HPLC
b
PPL (30 mg) in urea solution (6.7 M) [urea (400 mg) in deionized water (1 mL)] was stirred at 25 °C for 24 h, and then water was removed by
lyophilization before use
c
2+
PPL (30 mg) in Cu solution (250 mM) [CuSO4 (39.9 mg) in deionized water (1 mL)] was stirred at 25 °C for 24 h, and then water was
removed by lyophilization before use
d
PPL (30 mg) at 120 °C for 48 h
with yields of only 0% (entry 16, Table 1). Metal ion treat-
ment also results in a severe decrease in the natural activity
to which diꢂerent types of solvents aꢂect the reaction var-
ies widely. When acetonitrile, tetrahydrofuran, dimethyl
sulfoxide, N, N-dimethylformamide, water, 1, 4-dioxane,
ethanol and ethyl acetate were used as the reaction sol-
vent, almost no target product was formed (Table 2, entries
1–8). The yields obtained with n-hexane, isopropyl ether
and dichloroethane as solvents were all lower (Table 2,
entries 9, 10, 13). Comparing the three similar chlorin-
ated hydrocarbon solvents of dichloroethane, chloroform
and dichloromethane, it can be found that the yields of
the target products obtained by the three are signiꢀcantly
diꢂerent, and the highest yield of 95% can be obtained
in dichloromethane. When dichloroethane was used as a
solvent, only a yield of 19% was obtained. This may be
2
+
of PPL. The blank reaction using only Cu as a catalyst
failed to give the product (entry 15, Table 1). The above
control experiments show that the PPL catalyzes the model
reaction, and its speciꢀc three-dimensional structure is cru-
cial for the catalytic activity. Thus, we ꢀnally chose PPL as
the best biocatalyst to catalyze this 1,6-addition reaction.
Since the reaction medium can directly or indirectly
aꢂect the enzyme activity, the choice of the solvent for the
enzymatic reaction is also one of the key factors for the
reaction to be eꢂective. We selected a series of solvents
with diꢂerent polarities to examine their eꢂect on the tem-
plate reaction. The results are shown in Table 2. The extent
1
3

Lipase-Catalyzed Highly Eꢀcient 1,6-Conjugated Addition for Synthesis of Triarylmethanes
Table 2 The eꢂect of solvents on the 1,6-addition reaction
O
OH
OH
PPL
0oC
4
O
O
HO
3a
1a
2a
a
Entry
Solvents
Log P
Yield (%)
1
2
3
4
5
6
7
8
9
H O
Ethanol
–
Trace
3
Trace
Trace
Trace
2
2
−0.24
−0.33
−1
−1.1
−1.3
0.49
0.68
1.3
1.9
2
3.4
3.5
CH CN
3
DMF
1,4-Doxane
DMSO
THF
Ethyl acetate
Dichloroethane
Isopropyl ether
Chloroform
Dichloromethane
n-Hexane
1
Trace
19
19
54
95
1
1
1
1
0
1
2
3
16
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), PPL (30 mg), Solvents (1000 μL) were added to a 10 mL Erlenmeyer ꢃask, and shaken at
2
00 rpm at 40 °C for 48 h
a
All yields were determined by HPLC
due to the fact that the polarity of methylene chloride is
relatively larger than that of the former two, and the solvat-
ing ability is stronger than the former two, it is precisely
the suitable polarity that makes the conformation of the
enzyme satisꢀed with the catalytic reaction, which means
that it can interact better with PPL to increase the reac-
tivity of the enzyme to the template. Therefore, we used
dichloromethane as the optimal reaction solvent for the
1
,6-addition reaction.
Next, we further explored the eꢂect of the molar ratio
between p-quinonemethides and 2-naphthol on the reaction.
The results are shown in Fig. 2. It can be observed that the
relative excess of the p-quinonemethide (1a) and the rela-
tive excess of 2-naphthol (2a) have a noticeable eꢂect on
the eꢂect of the reaction. The yield obtained by the relative
excess of 1a is signiꢀcantly higher than the relative excess of
a
a
2
a. When 2a is excessive, the yield decreases directly (rela-
Fig. 2 The eꢂect of molar ratio on the 1,6-addition reaction . Reac-
tion conditions: In this ꢀgure, 1 is equiv 0.1 mmol, such as 3:1=2a
tive to 1:1). When the molar ratio between the p-quinonem-
ethide and 2-naphthol is 2:1, the highest yield of 93% can
be obtained, as the ratio increases further, the yield begins
(
0.3 mmol):1a (0.1 mmol); 1:2=2a (0.1 mmol):1a (0.2 mmol). PPL
(
30 mg), DCM (1000 μL) were added to a 10 mL Erlenmeyer ꢃask, and
b
shaken at 200 rpm at 40 °C for 48 h. All yields were determined by
HPLC
1
3

Z.-J. Yang et al.
3
0 °C and 40 °C was investigated. In order to increase the
authenticity of the experiment, we performed three paral-
lel reactions at the same time. The standard deviation was
taken as the error bar and the average of the three time points
as the ꢀnal yield value. It can be seen from Fig. 4 that the
yield of the target product obtained at 40 °C as the reaction
temperature at the same reaction time is generally higher
than that obtained at 30 °C. In the initial period of time, the
reaction yields not only at 40 °C increased with the gradual
increase of the reaction time, but also at 30 °C. Under the
condition of 40 °C as the reaction temperature, the yield of
the target product was 95% when the reaction time reached
4
8 h, and then reached a plateau.
Based on the optimal reaction conditions for the above the
template, a series of studies including a variety of 2-naph-
thols and p-quinones on the conversion of the reaction has
been executed to investigate the scope of substrates. The
results are shown in Table 3. It can be seen from the table
that the electronic eꢂect on the aryl substituent on the meth-
ylene benzoquinone has a great inꢃuence on the reaction.
Although most of the p-methylene benzoquinone compounds
derived from electron-deꢀcient or electron-rich aromatic
aldehydes can be smoothly converted into the correspond-
ing triarylmethane products, the yields obtained are greatly
diꢂerent. It can be observed from the table that compounds
composed of p-quinonederivatives containing electron-rich
like 3(a, d, g–l) can be obtained a good yield of 69–95%.
However, p-quinoneswith electron-deꢀcient like 3p yields
only a 14% yield. In general, this enzymatic method is more
suitable for the reaction of a p-quinonemethides substrate
derived from an electron-rich aromatic aldehyde. However,
compound 3f, which has a methyl in the ortho position of
the aryl group, is a special case, and the yield obtained is
only 19%, and the methoxy group is also in the ortho posi-
tion of the aryl group. A yield of 80% can be obtained for
the methylene benzoquinone substrate 3i. The reason for this
disparity may be that, besides the diꢂerence in the electron
donating ability of the two groups, it is also possible that the
hydroxyl group on the naphthol interacts with the methoxy
group in the ortho position of the aryl group in the 1i sub-
strate. This facilitates the attack of carbon atoms on the sub-
strate 2-naphthol. The substrate 1f plays a leading role due
to steric hindrance, which makes the reaction more inclined
to the attack direction of the hydroxyl group on the substrate
2-naphthol, and other by-products are formed, resulting in
a decrease in the yield of the target product. The steric hin-
drance eꢂect is prominent in such reactions. For example,
the yield obtained by participating in the reaction of p-qui-
nonemethide 1 m with a relatively large naphthyl group as
a substrate is low, and the aryl group is investigated. When
the benzene ring of 1a was altered to naphthalene ring, the
yield plunged from 69 to 22%. Also, no product could be
obtained when the benzene ring was altered to anthracene
Fig. 3 The eꢂect of enzyme loading on the 1,6-addition reaction.
a
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), PPL (0–40 mg),
DCM (1000 μL) were added to 10 mL Erlenmeyer ꢃask, and shaken
b
at 200 rpm at 40 °C for 48 h. All yields were determined by HPLC
a
Fig. 4 The eꢂect of temperature on the 1,6-addition reaction. Reac-
tion conditions: 1a (0.1 mmol), 2a (0.2 mmol), PPL (30 mg), DCM
(
1000 μL) were added to a 10 mL Erlenmeyer ꢃask, and shaken at
b
2
00 rpm at 40 °C or 30 °C for 6–48 h. All yields were determined
by HPLC
to decrease, so we used 2a:1a=2:1 as the best molar ratio
for subsequent studies.
Subsequently, we studied the eꢂects of the amount of
enzyme, reaction temperature and time on the reaction, and
the results are shown in Figs. 3 and 4, respectively. It can be
observed from Fig. 3 that when the amount of the enzyme
is increased from 0 mg to 30 mg, the yield of the target
product is increased from 2 to 91%. However, as the amount
of enzyme loading is further increased, the yield remains
substantially unchanged. Based on the amount of 30 mg of
enzyme loading, the reaction yield as a function of time at
1
3

Lipase-Catalyzed Highly Eꢀcient 1,6-Conjugated Addition for Synthesis of Triarylmethanes
Table 3 Substrate scope of the
OH
1
,6-addition reaction
O
R
2
OH
PPL
R
2
DCM
R
1
R
1
HO
1
2
3
OH
OH
OH
OH
O
HO
HO
3b, 69%
OH
F
HO
Cl
HO
3a, 95%
3c, 74%
OH
3d, 52%
OH
OH
Br
HO
HO
HO
HO
3e, 52%
3f, 19%
3g, 69%
3h, 85%
OH
OH
OH
OH
O
O
O
HO
i, 80%
OH
HO
N
HO
3l, 92%
OH
O
HO
3
3j, 70%
3k, 88%
OH
OH
OH
HO
m, 22%
OH
HO
F
3
C
HO
3
3n, 0%
OH
3o, 76%
OH
3p, 14%
OH
OH
O
S
N
HO
HO
3t, 85%
HO
HO
3q, 98%
3r, 82%
OH
3s, 36%
OH
N
Br
O
HO
u, 83%
O
HO
3
3v, 62%
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), PPL (60 mg), DCM (1000 uL) were
added to a 10 mL Erlenmeyer ꢃask, and shaken at 200 rpm at 40 °C for 48 h
b
Column chromatography to obtain isolated yield
1
3

Z.-J. Yang et al.
ring. Moreover, the larger side groups of 1a also reduced
the yield. The reaction of the p-quinonemethide substrates
I undergoes aromatization to form intermediate II, the lat-
ter followed by accepting protons on the imidazole of His
ultimately leads to the formation of the product 3a.
3
c, 3d and 3e containing a halogen group was found to give
a moderate yield. In addition, p-quinonemethides prepared
from 2-thenaldehyde, 2-furaldehyde and 2-pyridinecarbox-
aldehyde is also used as a substrate to participate in the reac-
tion, and triarylmethane 3q, 3r and 3 s containing heteroaryl
groups can be obtained, respectively. It can be observed that
the yield obtained is sequentially decreased, which may be
attributed to the sequential decrease in electron density on
thiophene, furan and pyridine. To further explore the range
of substrates, we simply selected two substituted 2-naphthols
and 1a for the 1,6-conjugated addition reactions. It can be
seen from the table that the method is also eꢂective for the
two 2-naphthol derivatives as substrates, and a moderate to
good yield can be obtained. The relatively electron-deꢀcient
4
Conclusions
In the present work, the PPL-catalyzed synthesis of triar-
ylmethanes by 1,6-conjugated addition reaction between a
p-quinonemethide compounds and 2-naphthols is reported
for the ꢀrst time. The optimal reaction conditions were
obtained by investigating factors such as enzyme source,
reaction solvent, molar ratio, enzyme amount and tempera-
ture, and reaction time. A series of substrates were extended
based on the ꢀnal reaction conditions, and although the yield
of the individual target compounds was low, the overall
performance was moderate to good, and the highest yield
was 98%. The method for synthesizing triarylmethane com-
pounds is atomic economical and the reaction conditions
are mild, which expands the application of lipase in organic
synthesis.
2
-naphthol derivative 2v gave a lower yield of the corre-
sponding product than the other 2-naphthol derivative 2u.
Based on the results of the reaction and similar transfor-
mations reported in the literature, we have reasonably specu-
lated about the possible mechanism of action of this reaction,
as shown in Fig. 5. First, p-quinonemethide 1a enters the
binding pocket of the enzyme, was stabilized by three hydro-
gen bonds. A proton is then transferred from 2-naphthol 2a
to imidazolylofHis, 2-naphthalene oxide anion immediately
attacks the p-quinonemethide to produce intermediate I, and
a transition state is formed. Subsequently the intermediate
Acknowledgements This work was financially supported by the
National Key R&D Program of China (Grant No. 2018YFA0901600).
We also thank the Comprehensive Training Platform of Specialized
Laboratory, College of Chemistry, Sichuan University.
Compliance with Ethical Standards
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Conꢀlict oꢀ interest The authors declare that they have no conꢃict of
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interest.
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