Bio-Catalytic Bis-Michael Reaction for Generating Cyclohexanones with a Quaternary Carbon Center Using Glucoamylase

Article abstract of DOI:10.1007/s10562-016-1964-6

Abstract: Bio-catalytic bis-Michael reaction for the construction of quaternary carbon centers is reported. Glucoamylase from Aspergillus niger (AnGA) was used as a sustainable and eco-friendly catalyst. Various highly substituted trans-cyclohexanones wit

Full text of DOI:10.1007/s10562-016-1964-6

Catal Lett
DOI 10.1007/s10562-016-1964-6
Bio-Catalytic Bis-Michael Reaction for Generating
Cyclohexanones with a Quaternary Carbon Center Using
Glucoamylase
1
1
1
1
Yong Zhang · Rui Li · Yan-Hong He · Zhi Guan
Received: 13 November 2016 / Accepted: 26 December 2016
©
Springer Science+Business Media New York 2017
Abstract Bio-catalytic bis-Michael reaction for the con-
struction of quaternary carbon centers is reported. Glu-
coamylase from Aspergillus niger (AnGA) was used as a
sustainable and eco-friendly catalyst. Various highly substi-
tuted trans-cyclohexanones with a quaternary carbon center
were obtained with yields of up to 92%. As a novel case
of enzyme promiscuity, this work provides a bio-catalytic
alternative for construction of quaternary carbon centers.
Keywords Bis-Michael reaction · Glucoamylase ·
Enzyme catalysis · Quaternary carbon center
1 Introduction
Enzymes as sustainable, practical, eco-friendly, economic
and biodegradable catalysts have attracted increasing atten-
tion from organic chemists [1, 2]. Enzymatic methods
as part of green technologies for organic synthesis were
considered to possess great potential and were exploited
increasingly in organic synthesis [3–5]. Primitively,
enzyme catalytic reactions had a narrow scope of applica-
tion since reactions were restricted to natural substrates
and aqueous reaction media [5, 6]. Since Klibanov discov-
ered that enzymes can maintain their activities in organic
solvents in the early 1980s [7–9], enzymatic reactions in
organic media have drawn significant attraction. Nowa-
days, more and more enzymes have been found to have the
ability to catalyze chemical transformations that vary from
their natural reactions [4, 10–12]. This phenomenon is
called enzymatic promiscuity which brings novel enzyme
activities for organic synthesis [13]. Many reactions were
reported with enzyme catalytic promiscuity by catalyzing
the formation of C–C and C–heteroatom bonds [4, 14–16].
These reactions included the Markovnikov additions
Graphical Abstract Glucoamylase from Aspergil-
lus niger (AnGA) catalyzed the bis-Michael addition of
(
1E,4E)-1,5-diarylpenta-1,4-dien-3-ones with active meth-
ylene compounds to form various highly substituted trans-
cyclohexanones with a quaternary carbon center
O
O
AnGA
Ar1
Ar2
Z1 Z2
Ar1
Ar2
o
4
0 C, MeCN
Z1 Z2
1
2
up to 92%, Dr >99:1
examples, yields
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-016-1964-6) contains supplementary
material, which is available to authorized users.
[17], aldol reactions [18, 19], Mannich reactions [20, 21],
Michael additions [22–25], multi-component cascade or
domino reactions [26, 27], and the asymmetric synthesis of
α-aminonitrile amides [28, 29] The study of enzyme prom-
iscuity not only provided novel research methods and tools
for organic synthesis, but also formed a bond that led to
developments on interdisciplinary sciences between biol-
ogy and organic chemistry [5, 30–38]. Thus, it is necessary
*
Yan-Hong He
heyh@swu.edu.cn
*
Zhi Guan
guanzhi@swu.edu.cn
1
Key Laboratory of Applied Chemistry of Chongqing
Municipality, School of Chemistry and Chemical
Engineering, Southwest University, 400715 Chongqing,
People’s Republic of China
Vol.:(0
1
123456789)
3

Y. Zhang et al.
1
to study enzyme catalytic promiscuity, especially for those
enzymes that are well-known and widely used in industries.
Synthesis of carbon atoms with four nonhydrogen sub-
stituents has become a hot topic because of their proper-
ties of stereochemistry and biological activities [5, 39, 40].
The synthesis of quaternary carbons is a challenge because
of the extreme steric congestion. Conjugate addition of
nucleophilic reagents to Michael acceptors is one of the
most powerful methods for constructing the quaternary car-
bon centers. A few catalysts have been reported for the bis-
Michael additions to construct the quaternary carbon cent-
ers, such as ruthenium(II) complexes [41, 42], basic ionic
liquid [bmIm]OH [43, 44], silica nanoparticles (NPs) [45],
KF/basic alumina under ultrasound irradiation [46]. Asym-
metric double-conjugate additions have also been reported
to form the quaternary carbon centers using 9-amino-
trans-cyclohexanone (determined by H NMR) was
obtained for the model reaction in all the tested solvents.
Unfortunately, there was no enantiomeric excess of the
products observed by the chiral HPLC analysis. There-
fore, MeCN was chosen as the optimal solvent for the fol-
lowing studies.
In order to further improve the yield of the AnGA-cat-
alyzed bis-Michael reaction, effects of molar ratio of sub-
strates on the model reaction were investigated (Table 2).
When increasing the ratio of (1E, 4E)-1,5-diphenylpenta-
1,4-dien-3-one (1a) to malononitrile (2a) from 1:1 to 5:1,
a good yield of 71% was obtained at a ratio of 4:1 (1a:2a)
(Table 2, entry 4), while other ratios only got moderate
Table 1 Effects of solvents on the AnGA-catalyzed bis-Michael reac-
tion
9
-deoxyepiquinine [47], cinchona-based primary amines/
O
(
S)-BINOL-phosphoric acid [48] and quinine [49] as chiral
organocatalysts. Although some elegant synthetic meth-
ods have been reported in this field, the exploration of bio-
catalysts for the bis-Michael additions to construct quater-
nary carbon centers that are safe, environmentally benign
and operationally simple is still desirable. We found that
glucoamylase from Aspergillus niger (AnGA) as a green
catalyst could catalyze the bis-Michael addition of (1E,4E)-
O
AnGA
NC
CN
Ph
Ph
Ph
Ph
0 oC, solvent
3
NC CN
1
a
2a
3a
(+)
a
Drb
Entry
Solvent
Yield (%)
1
,5-diarylpenta-1,4-dien-3-ones (1) with active methyl-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
Cyclohexane
Hexane
Methyl tert-butyl ether
Toluene
DMSO
Anisole
N-methylpyrrolidone
Isopropanol
EtOH
MeOH
DMF
trace
trace
trace
trace
6
–
ene compounds (2) to form trans-cyclohexanones with a
quaternary carbon center (Scheme 1). Herein, we wish to
report this work as a complement for existing methods, and
a novel case of enzymatic promiscuity.
–
–
–
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
14
15
17
18
20
22
22
26
2
Results and Discussion
In initial research, (1E,4E)-1,5-diphenylpenta-1,4-dien-
0
1
2
3
4
5
3
-one (1a) and malononitrile (2a) was used as a model
reaction. The solvent screening was performed to find the
favorable solvent for this bio-transformation (Table 1).
It can be seen that only trace amounts of product were
observed for the reactions in non- or low-polar solvents
1,2-Dichloroethane
Butylacetate
1,4-dioxane
MeCN
30
42
(
such as cyclohexane, hexane, methyl tert-butyl ether
and toluene) (Table 1, entries 1–4). The model reaction
gave a moderate yield of 42% in MeCN (Table 1, entry
Reaction conditions: 1a (0.25 mmol), 2a (0.25 mmol) and AnGA (3.6
kU) in solvent (1.0 mL) at 30°C stirring for 60 h
a
1
6). Many other solvents were also screened, which
Isolated yield
b
1
gave yields of 6–30% (Table 1, entries 5–15). Only
Diastereomeric ratio (dr): determined by H NMR analysis
Scheme 1 Bis-Michael addi-
O
tion
O
Ar1
Ar2
Ar1
Ar2
Z1 Z2
2
Z1 Z2
3
1
1
3

Bio-Catalytic Bis-Michael Reaction for Generating Cyclohexanones with a Quaternary Carbon…
Table 2 Effects of molar ratio of substrates on the AnGA-catalyzed
(1a:2a) was selected as the optimal condition for the fur-
bis-Michael reaction
ther investigation. Excess 1a can be easily removed dur-
ing the purification of product 3a by flash column chro-
matography on silica gel.
O
O
Considering about that the enzyme loading and concen-
tration of the reactants and catalysts in the reaction also
play key roles, their effects on this AnGA-catalyzed model
bis-Michael reaction were tested next. The optimized reac-
tion conditions consist of the following: 4.8 kU of enzyme
loading (One unit corresponds to the amount of enzyme
which liberates 1 μmole of glucose per minute at pH 4.8
and 60°C with starch as substrate.) and 2.0 mL of MeCN
AnGA
0 oC, MeCN
NC
CN
Ph
Ph
Ph
Ph
3
NC CN
1a
2a
3a ( +– )
a
Drb
Entry
Molar ratio (1a:2a) Yield (%)
1
2
3
4
5
6
7
1:1
2:1
3:1
4:1
5:1
1:2
1:3
42
59
66
71
61
5
>99:1
(
for details, please see Supplementary Information Tables
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
S1 and S2).
Since enzymes come from organisms, their work tem-
perature is mild. Therefore, the environmental temperature
is very important for their stability and activity. To find a
suitable temperature for the AnGA-catalyzed bis-Michael
reaction, a temperature screening was conducted from 25
to 60°C at 5°C intervals (Table 3). Among the results, 92%
yield was exhibited at 40°C which was also proven to be
the best choice accordingly (Table 3, entry 4). Tempera-
ture higher than 40°C caused a decrease in the yield, prob-
ably due to the partial denaturation of the enzyme at higher
temperature.
3
Reaction conditions: 1a, 2a and AnGA (3.6 kU) in MeCN (1.0 mL) at
3
0°C stirring for 60 h
a
Isolated yield
b
1
Determined by H NMR analysis
Table 3 Effects of temperature on the AnGA-catalyzed bis-Michael
With the optimized conditions in hand, several sub-
strates were tested to expand upon this novel enzymatic
bis-Michael reaction (Table 4). (1E, 4E)-1,5-Diarylpenta-
reaction
O
1
,4-dien-3-one (1) with different substituents on the ben-
O
zene ring were applied to react with malononitrile, ethyl
cyanoacetate and ethyl nitroacetate. When there are Cl- or
Br- on the ortho or para position of benzene ring substitu-
AnGA
NC
CN
Ph
Ph
Ph
Ph
MeCN
NC CN
2a
3a +
1
2
1a
( )
–
ents (as Ar and Ar ), the yields are not as good as expected
(
Table 4, entries 3, 4, 9 and 10). But, when Cl- is on the
meta position of benzene ring, there were good yields
from 74 to 76% (Table 4, entries 2, 8 and 12). The high-
est yield of 92% was obtained with the reaction of 1a and
o
a
Drb
Entry
Temperature ( C)
Yield (%)
1
2
3
4
5
6
7
8
25
30
35
40
45
50
55
60
67
71
74
92
85
84
79
68
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
2
a (Table 4, entry 1). However, the lowest yield of 24%
1 2
was achieved when both benzene rings (Ar and Ar ) were
substituted by CH - on the para position (Table 4, entry
3
5
). In general, the reactivity of malononitrile is higher than
ethyl cyanoacetate and ethyl nitroacetate (Table 4, entries
1
, 7 and 11). All the products obtained are trans-cyclohex-
1
anones (determined by H NMR). Unfortunately, there was
no enantiomeric excess of the products observed by the chi-
ral HPLC analysis. To further confirm the configuration of
the products, product 3h as a representative example was
determined by single-crystal X-ray analysis (Fig. 1).
Reaction conditions: 1a (1.00 mmol), 2a (0.25 mmol) and AnGA (4.8
kU) in MeCN (2.0 mL) stirring for 60 h
a
Isolated yield
Determined by H NMR analysis
b
1
To verify the catalytic effect of AnGA on the bis-
Michael addition, some control experiments were per-
formed with the model reaction of 1a and 2a (Table 5). In
the absence of the enzyme, only trace amount of product
was observed (Table 5, entry 1), while in the presence of
yields (Table 2, entries 1–3 and 5). But, when changing
the ratio of 1a to 2a into 1:2 and 1:3, the yields decreased
rapidly (Table 2, entries 6 and 7). Thus, molar ratio of 4:1
1
3

Y. Zhang et al.
Table 4 Substrate scope of the AnGA-catalyzed bis-Michael addition
O
O
AnGA
Ar1
Ar2
Z1 Z2
Ar1
Ar2
o
4
0 C, MeCN
Z1 Z2
2
3
a
Drb
Entry
Ar1
Ph
m-ClC H
o-ClC H
p-ClC H
p-CH C H
p-CH C H
Ph
m-ClC H
p-ClC H
p-BrC H
Ph
Ar2
Z1
Z2
Product
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
Ph
m-ClC H
o-ClC H
p-ClC H
p-CH C H
Ph
Ph
m-ClC H
p-ClC H
CN
CN
CN
CN
CN
CN
CO Et
CO Et
CO Et
CO Et
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
NO2
NO2
3a
3b
3c
3d
3e
3f
3g
3h
3i
48
36
48
40
36
36
48
40
48
40
48
48
92
76
44
50
24
90
66
76
30
40
74
74
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
6
4
6
4
6
4
6
4
6
4
6
4
3
6
4
4
3 6 4
3
6
2
6
4
6
4
2
6
4
6
4
2
1
1
1
0
1
2
p-BrC H
Ph
m-ClC H
3j
3k
3l
6
4
6
4
2
CO Et
CO Et
2
m-ClC H
6
4
6
4
2
Reaction conditions: 1a (1.00 mmol), 2a (0.25 mmol) and AnGA (4.8 kU) in MeCN (2.0 mL) at 40°C
a
Isolated yield
Determined by H NMR analysis
b
1
O
Cl
Cl
O
CN
O
Fig. 1 X-ray crystal structure of 3h
AnGA, product 3a was obtained in an excellent yield of
amounts of product was observed (Table 5, entries 3 and 4).
The fact that metal ions completely destroyed the activity
of AnGA on the model reaction indicated that the specific
natural fold of AnGA is responsible for its catalytic activity
in the bis-Michael addition. Moreover, miglitol (Fig. 2) is
structurally similar to glucose, it has been frequently used
as a competitive inhibitor of glucoamylase [50–52]. Thus,
9
2% (Table 5, entry 2), indicating that AnGA indeed had
a catalytic effect on the bis-Michael addition. Since metal
ions can change the conformation of enzymes, disrupt the
active site and ultimately denature enzymes, AnGA was
+
2+
pretreated with Ag and Cu . Metal-denatured AnGA was
then used to catalyze the model reaction, and only trace
1
3

Bio-Catalytic Bis-Michael Reaction for Generating Cyclohexanones with a Quaternary Carbon…
Table 5 Control experiments for the AnGA-catalyzed bis-Michael
of AnGA includes Glu179 and Glu400 [53, 54], 1,1-Car-
addition
bonyldiimidazole (CDI) can irreversibly react with carbox-
ylic acids [55]. Thus, CDI was used as an inhibitor to pre-
treat AnGA, and the model reaction with the CDI-inhibited
AnGA only gave a trace amount of product (Table 5, entry
7). At the same time, CDI alone had no detectable effect
on the model reaction (Table 5, entry 8). Based on the con-
trol experiments with miglitol and CDI, it can be inferred
that the natural active center of AnGA is responsible for its
activity in the bis-Michael addition.
O
O
catalyst
0 oC, MeCN
NC
CN
Ph
Ph
Ph
Ph
4
NC CN
1a
2a
3a ( +– )
a
Entry Catalyst
Yield (%) Drb
Finally, based on the above control experiments and the
previous literature [53, 54], we attempted to propose the
possible mechanism of the AnGA-catalyzed bis-Michael
reaction (Scheme 2). The catalytic site of AnGA consists
of Glu179 and Glu400 located at the bottom of a pocket.
Based on the widely accepted mechanism of hydrolysis
of AnGA, we hypothesized the possible mechanism with
the model reaction of 1a and 2a as an example. Glu400,
as a base, deprotonates malononitrile (2a), and the formed
nucleophile attacks one of the double bonds of 1a. And at
the same time, Glu179, as an acid, donates a proton, form-
ing the first Michael adduct I. Then in the same way Glu179
deprotonates adduct I and an intramolecular Michael addi-
tion occurs in which Glu400 as an acid, donates a proton, to
get the final product 3a.
1
2
3
4
5
6
7
8
None
AnGA (4.8 kU)
AnGA (4.8 kU) pretreated with Ag
trace
92
trace
trace
–
>99:1
+
c
–
–
2
+d
AnGA (4.8 kU) pretreated with Cu
e
AnGA (4.8 kU) pretreated with miglitol 11
>99:1
>99:1
–
–
miglitolf
85
trace
trace
g
AnGA (4.8 kU) pretreated with CDI
CDIh
Reaction conditions: 1a (1.00 mmol), 2a (0.25 mmol) and catalyst in
MeCN (2.0 mL) at 40°C stirring for 60 h
a
Isolated yield
Determined by H NMR analysis
The mixture of AnGA (4.8 kU), deionized water (1 mL) and silver
b
c
1
nitrate (0.25 mmol) was stirred at 40°C for 24 h, then water was
removed by lyophilization
d
The mixture of AnGA (4.8 kU), deionized water (1 mL) and cop-
3
Materials
per sulfate (0.25 mmol) was stirred at 40°C for 24 h, then water was
removed by lyophilization
e
Amyloglucosidase from Aspergillus niger [glucoamylase,
The mixture of AnGA (4.8 kU), deionized water (1 mL) and miglitol
(
1.0 mmol) was stirred at 40°C for 12 h, then water was removed by
1,4-α-D-glucan glucohydrolase, EC 3.2.1.3, 120 U/mg
lyophilization
(One unit corresponds to the amount of enzyme which lib-
f
Miglitol (1.0 mmol) was used instead of AnGA
erates 1 μmole of glucose per minute at pH 4.8 and 60°C
with starch as substrate.)] was purchased from Sigma-
Aldrich. (1E, 4E)-1,5-Diarylpenta-1,4-dien-3-ones were
prepared according to literature [56, 57]. All reagents were
purchased from commercial suppliers and used without
further purification unless otherwise noted.
g
The mixture of AnGA (4.8 kU), dichloromethane (1 mL) and CDI
(
1.85 mmol) was stirred at 40°C for 4 h, and dichloromethane was
removed by vacuum rotary evaporation. The excess CDI was removed
by dialysis against water and the enzyme solution was lyophilized
h
CDI (1.85 mmol) was used instead of AnGA
Fig. 2 Structure of miglitol
OH
3.1 General Procedure for the AnGA-Catalyzed
OH
OH
Bis-Michael Addition
N
HO
A mixture of (1E,4E)-1,5-diarylpenta-1,4-dien-3-one (1)
(1.00 mmol), active methylene compound (2) (0.25 mmol)
OH
and AnGA (40 mg, 4.8 kU) in MeCN (2.0 mL) was stirred
at 40°C for the specified reaction time and monitored by
TLC. The reaction was terminated by filtering out the
enzyme (with 40 mm Buchner funnel and qualitative filter
paper), and the filter cake was washed with ethyl acetate
(3×10 mL). The solvents were removed under reduced
pressure. The crude products were purified by column
chromatography on a silica gel (petroleum ether/EtOAc:
20/1–4/1) and gave the desired products.
miglitol was used to pretreat AnGA. Miglitol alone can
catalyze the model bis-Michael addition very well, giving a
good yield of 85% (Table 5, entry 6), while the model reac-
tion with miglitol-pretreated AnGA only gave the product
with a low yield of 11% (Table 5, entry 5), suggesting that
miglitol strongly inhibited the enzyme activity in the bis-
Michael addition. In addition, it is known that catalytic site
1
3

Y. Zhang et al.
Scheme 2 Proposed mecha-
nism for the AnGA-catalyzed
bis-Michael reaction
Glu400
O
H
O
O
Ph
CN
Ph
H
O
CN
Glu179
H
H
O
O
CN
CN
H
Ph
Ph
O
Glu400
O
O
Ph
Ph
H
Glu179
NC
O
CN
O
3
a
O
Glu400
H
Ph
O
O
CN
NC
Ph
H
O
O
Glu179
I
4
Conclusion
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