Baker’s yeast: An efficient, green, and reusable biocatalyst for the one-pot synthesis of biologically important N-substituted decahydroacridine-1,8-dione derivatives

Article abstract of DOI:10.1080/00397911.2016.1266501

A green approach for one-pot three-component synthesis of N-substituted decahydroacridine-1,8-diones is offered for the first time using baker’s yeast (Saccharomyces cerevisiae) as a biocatalyst under ultrasonication. Due to growing safety and environment

Full text of DOI:10.1080/00397911.2016.1266501

Baker’s yeast: An efficient, green and reusable biocatalyst for the one-pot synthesis
of biologically important N-substituted decahydroacridine-1,8-dione derivatives
Asha V. Chate1, Shital B. Sukale1, Reshma S. Ugale1, Charansingh H. Gill1
1Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad, India
Corresponding author: E-mail: chgill16@gmail.com
Abstract
A green approach for one-pot three-component synthesis of N-substituted
decahydroacridine-1,8-diones is offered for the first time using baker’s yeast
(Saccharomyces cerevisiae) as a biocatalyst under ultrasonication. Due to growing safety
and environmental concerns, enzymatic methods were constantly investigated as an
attractive alternative to toxic and non-specific chemical approaches. This method is
relatively simple, efficient, inexpensive, and environment-friendly. The catalyst was
recovered and reused and also the recyclability of baker’s yeast resulted in excellent
yields of products without loss of any catalytic activity.
GRAPHICAL ABSTRACT
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KEYWORDS: Baker’s yeast, Acridine-1,8-diones, Tandem reaction, Biocatalyst,
Ultrasonication.
INTRODUCTION
Modern industries necessarily need to exploit renewable resources in a sustainable
manner, promoting bio-based environmentally friendly or beneficial technologies in order
to keep competitive market positions[1] and create high-performing materials for a range
of application.[2,3] Now a day’s steps are being taken, mainly due to increasing economic,
social, legal, and environmental pressures, to avoid further degradation of ecological
balance. Therefore, the so-called Green Chemical Processes where the “best available
technology” not entailing excessive cost and aspiring to “performance without pollution”
can be used in industrial processes.[4-6]
In the last decade, biocatalysis has been integrated into mainstream organic
synthesis, [7, 8] particularly in the pharmaceutical industry.[9] This can be largely attributed
to its numerous environmental and economic benefits. The catalyst (an enzyme) is
derived from renewable resources and is biocompatible, biodegradable, and essentially
nonhazardous and nontoxic. Biocatalysis avoids the use of scarce precious metals and the
associated, often prohibitive, costs of removing traces of noble metal catalysts from the
end product.
Also the impression that biocatalytic based processes are per se more ecological
or sustainable than their chemical alternatives. Nevertheless, the environmental
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friendliness and the economic feasibility of the whole process must be clarified and
evaluated for every single procedure.[10] Baker’s yeast (Saccharomyces cerevisiae) is the
first and most popular whole cell biocatalyst, economical and neither toxic nor
pathogenic, which has been used for different organic transformations. Here the focus lies
on reaction types that are of high interest for the industry.
Many biologically important molecular scaffolds can easily be synthesized from
readily available starting materials with the help of multi-component reactions
(MCRs).[11-14] Multicomponent reactions (MCRs) allow for rapid synthesis of drug-like
compound libraries by combining three or more reagents into a single product in one
step.[14c]
The acridine and acridine-1,8-dione derivative are an important class of nitrogen
heterocycles that can be converted into biologically important compounds exhibiting
favorable biological and pharmaceutical properties, such as anti-malaria,[15] anti-tumor,[16]
anti-cancer,[17] fungicidal,[18] cytotoxic,[19] anti-multidrug-resistant,[20] antimicrobial,[21]
and are widely prescribed as calcium β-blockers.[22,23] Additionally, 1,8-dioxo-
decahydroacridines were created to act as laser dyes,[24,25] and used as photo initiators.[26]
Thus, the synthesis of 1,8-dioxo-decahydroacridine derivatives is currently of
great importance. Some new methods have been developed to improve the reaction
efficiency in the synthesis of 1,8-dioxo-decahydroacridine using catalysts such as urea,[27]
hydroxylamine,[28] ammonium acetate on basic alumina,[29] ammonium bicarbonate,[30]
3

ammonium hydroxide and various appropriate amines or ammonium acetate.[31]
Additional methods have included conventional heating of organic solvents in the
presence of Amberlyst-15,[32] benzyl triethyl ammonium chloride (TEBAC),[33] the use of
microwave irradiation,[34,35] and using ionic liquids.[36,37] Furthermore, 9,10-
diarylacridine-1,8-diones have also been prepared using p-dodecylbenzenesulfonic acid
(DBSA),[38] Zn(OAc)2.2H2O, ammonium chloride or L-proline/proline [39], CAN [40] and
the sulfonated organic heteropoly acid salts, [MIMPS]3PW12O40 and
[TEAPS]3PW12O40.[41] However, these methodologies suffer from one or more
shortcomings, such as low yield, prolonged reaction time, use of toxic organic solvents
and employ costly and hazardous catalysts as well as cumbersome work-up procedures.
Therefore, introducing clean processes and utilizing eco-friendly catalysts, which can be
easily recycled at the end of the reaction, have received increasing attention.
Conversely, in comparison with conventional thermal heating, Ultrasound
irradiation is a powerful technique, which is being used frequently to accelerate organic
transformations.[42-45] It is one of the most widely used laboratory methods for the
disruption of cells of baker’s yeast for the fast release of enzymes.[46] The ability of
ultrasonic irradiation methods to accelerate and, occasionally, to increase the chemical
reactions yield have attracted the scientific community for its use over the last decades.
Despite the widespread use of ultrasonic energy in various research disciplines, only
recently the synergetic use of ultrasonication and enzymes to enhance reactions has been
described. [47-50]
4

The demand for an environmentally benign procedure utilizing a heterogeneous
and reusable catalyst led our investigations to develop a safe alternative method for the
synthesis of acridine-1,8-dione derivatives. Bearing the above points in mind, we believe
this to be the first ever report on a sonically enhanced one-pot multicomponent reaction
in organic media using the environmentally benign baker’s yeast (Saccharomyces
cerevisiae) as a whole cell biocatalyst.
RESULT AND DISCUSSION
In this study, we describe for the first time, a sustainable one-pot synthesis of N-
substituted 1,8-dioxo-decahydroacridines 4a–4t (Scheme 1) under ultrasonication at
room temperature in organic media using baker’s yeast (Saccharomyces cerevisiae) as a
whole cell biocatalyst.
There is scanty information on the use of enzymes for the acceleration of tandem
condensation. Isolated lipases have been found to catalyze this type of condensation.[51,52]
The use of isolated pure enzymes to accelerate organic transformations has several
drawbacks such as high cost, narrow substrate specificities and in some cases low
performance under nonnatural conditions.
Here, we have attempted the tandem condensation using a cheaper whole cell
biocatalyst, baker’s yeast (Saccharomyces cerevisiae). The cell of baker’s yeast acts as a
mini reactor and produces a variety of enzymes and is known to provide specific enzyme
for specific reaction. Baker’s yeast has the ability to catalyze various organic
5

transformations.[53] It is also used in the formation of CQC double bonds via acyloin
condensation,[54,55] and Michael addition reaction.[56] Due to this important aspect, baker’s
yeast is gaining much importance in organic synthesis.[57]
Initially, our investigations started with an optimization study of model reaction
by allowing cyclocondensation of dimedone (1), benzaldehyde (2a) and aniline (3a) in
presence of baker’s yeast (Saccharomyces cerevisiae) (Scheme 1). To see the effect of
reaction medium on the rate and yield of the reaction we carried model reaction in
various solvents under stirring at room temperature.
The optimization study was started by screening of various solvents for model
reaction. The releative activity of the baker’s yeast (Saccharomyces cerevisiaes)
immobilized was higher than the free baker’s yeast (Saccharomyces cerevisiaes).
Immobilized cells were more resistant to organic solvents than free cells. Therefore,
during the whole-cell biocatalyzing process in organic media the immobilization of
microorganisms not only has the advantage of easy separation but also can enhance the
tolerance of cells. Despite the ideal environmental profile of water, its use in organic
reactions is limited due to the low dissolving ability of most organic substrates, a
characteristic that reduces the reaction rate. Moreover, as the enantioselectivity in water
could be reduced by the side effects of the different enzymes in the yeast cell, organic
solvents can alter the enantioselectivity to an even greater degree when compared to the
corresponding transformations in water.[58] Therefore, the quest for a solvent with a
minimal impact on the environment, e.g., a green solvent, is of the utmost importance.
6

Their greenness is attributed mainly to their unique physical properties, such as low
volatility and high stability, and to their recyclability and reusability. However, the
advantages of better substrate solubility or improved enzyme stability should be balanced
against the price of solvent and additional efforts for downstream processing. Inspired by
this, The screening of the solvent was initiated from natural solvent i.e water (H2O),
dimedone (1), benzaldehyde (2a) and aniline (3a) in water was stirred for 28 h but there
was formation of desired product observed in trace amount (Table 1, entry 1). It might be
due to sparingly solubility of substrates in aqueous medium. To overcome this problem
we turned our attention towards the use of various organic solvents. Although there were
earlier reports of the use of enzymes in organic media,[59] it was the seminal paper by
Zaks and Klibanov in 1984,[60] describing enzymatic catalysis at 100 ˚C in organic media,
that heralded the era of “nonaqueous enzymology”.[61] They observed that many
enzymes were actually more thermally stable in organic solvents, than in water, leading
to the realization that biocatalysis had a much broader scope than was previously thought
possible. Additional benefits of biocatalysis in nonaqueous media include easier product
recovery from low-boiling organic solvents and elimination of microbial
contamination.[62] so we turned our attention towards the use of various organic solvents
e.g. protic, aprotic, polar and nonpolar solvents. Then the model reaction was run in
water-ethanol (H2O-EtOH). Interestingly within 22 h of the reaction 30 % yield of
desired product was isolated (Table 1, entry 2). Inspired by this result model recation was
carried out in ethanol (EtOH), surprisingly 47% yield of desired product was obtained in
20 hr of reaction time (Table 1, entry 3). Then other solvents like methanol (CH3OH),
1,4-dioxane, dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane
7

(DCM) and acetonitrile (ACN), were screened for model reaction, even after 25 h less
yield of product 4a was obtained as compared to yield obtained in acetonitrile (Table 1,
entry 4–8). It varied from 47% to 60% in different solvents. The model reaction proceeds
in all organic solvents but it was interesting to observe that the yield of product 4a
obtained was highest in acetonitrile within 22 h of stirring (Table 1, entry 9). Therefore
acetonitrile was selected as a solvent for such reaction.
It is clear from (Table 1) that the reaction performed without ultrasound afforded
comparatively lower yields even after longer reaction time under ambient condition. In
order to verify the effect of ultrasound, we performed the same transformations under
ultrasonication, were this transformation successfully carried out under ultrasound
irradiation at room temperature in comparatively short duration (3–5 h) with moderate to
good yield (65–84%) (Table 1). It is apparent that the ultrasound can accelerate the
reaction significantly. After having these results we decided to carry all reaction by using
ultrasonic irradiation, compare to the other cell disruption method, the release of product
by ultrasound has certain selectivity, which makes ultrasound more attractive in organic
synthesis, Therefore, in the present system; ultrasound was found to have beneficial
effect on the synthesis of title compounds.
To examine the catalytical efficiency of baker’s yeast (Saccharomyces
cerevisiaes), reaction of dimedone (1), benzaldehyde (2a) and aniline (3a) in acetonitrile
was performed in the absences of yeast as the control experiment where we found that
8

there was no formation of the product. The result indicates that the baker’s yeast
(Saccharomyces cerevisiaes) is necessary to catalyze the reaction.
After obtaining the optimized reaction conditions, thereafter the investigation
studied the reaction between a series of aromatic aldehydes and aromatic amines or
isoniazide with 1,3-cyclohexanediones. To assess the general applicability of this method
under the given optimized reaction conditions, a wide range of divergent aldehydes and
anilines possessing varying substituent’s, in the presence of two equivalents of 1,3-
cyclohexanediones, were allowed to undergo this three-component condensation. The
nature of the functional group on the aldehyde/aniline aromatic rings exerted a slight
influence on the reaction time. -Cl, -F, -Me, -OMe and -NO2 were found to be compatible
under the optimized reaction conditions. Heteroaromatic aldehydes, such as 2-Furan-2-
carbaldehyde and 2-thiophene-2-carbaldehyde was equally amenable to these conditions
(Table 2, entry 15,16). An attempt was made to synthesize 1,8-dioxo-decahydroacridine
by reacting the aliphatic aldehyde, instead of arylaldehyde, aliphatic aldehyde was less
reactive than arylaldehyde, no product was obtained when aliphatic aldehyde was used, It
seems that this protocol has its limitations. Also, both hydrazine hydrate and phenyl
hydrazine similarly underwent well to the conversion (Table 2, entry 25). The active site
of baker’s yeast (Saccharomyces cerevisiae) forms an enzyme substrate complex with the
aldehyde and dimedone more effectively and enhances the rate of reaction resulting in an
increase in the product yield and a decrease in reaction time. The ultrasound irradiation
technique was also established to be compatible with all listed substrates (Table 2).
9

Representative results are summarized in (Table 2). Product formation was confirmed by
1H NMR, 13C NMR, elemental analysis and melting point data.
Catalyst Recycles
Reusability is one attractive advantage of biocatalyst, which could decrease the cost of
enzyme in practical application. The reusability of the baker’s yeast was also evaluated.
The reusability were studied by three cycles including the use of fresh catalyst for the
synthesis of 1,8-dioxo-decahydroacridines. In every cycle, the catalyst was almost
quantitatively recovered and after second and third use of catalyst decreasing yield is not
much more significant as shown in Figure 1.
Reaction Mechanism
Baker’s yeast is a known source of oxidoreductase and lipases.[63] Among these enzymes
oxidoreductases have been found to be utilized in organic synthesis. However, the use of
lipases produced by baker’s yeast has not been explored to undergo knovengel
condensation or similar type of condensation. In this route the lipase, produced by
baker’s yeast might be for enhancing electrophilic character of aldehydic carbon forming
hydrogen bonding with carbonyl oxygen, thereby accelerating the rate of addition of
aldehyde to dimedone to generate intermediate, This probably expedites the Michael
addition of second dimedone on the first intermediate and then cyclocondensation with
aniline leading to the desired N-substituted decanhydroacridine-1,8-diones.
EXPERIMENTAL
10

General Information
All chemicals were purchased and used by further purification. Melting points were
determined on a open capillary tube and are uncorrected. Progress of the reaction was
monitored by thin layer chromatography on Merck’s silica plates. 1H NMR spectra were
recorded on Bruker Avance 300 MHz instruments using TMS as internal standard, 13C
NMR spectra were recorded on Bruker AvII- 400 MHz instruments, and elemental
analysis recorded on elemental analyzers Euro-E 3000.
Ultrasound Instrumentation
All the reactions were carried out in Bandelin Sonorex (with a frequency of 35 kHz and a
nominal power 200 W) ultrasonic bath was used for ultrasonic irradiation. Built-in
heating, 30–80 ˚C there-mostatically adjustable. The reaction vessel placed inside the
ultrasonic bath containing water.
Ultrasound Promoted General Synthesis Of N-Substituted 1,8-Dioxo-
Decahydroacridines (4a-Q)
A mixture of 5,5-dimethylcyclohexane-1,3-dione 1a (1.31 gm, 2 mmole), benzaldehyde
2a (500 mg, 1 mmole) and aniline 3a (650 mg,1 mmole) was dissolve in acetonitrile (20
mL). To this stirred solution active dry baker’s yeast (1 gm) was added. The resulting
reaction mass was further irradiated at room under ultrasonication for stipulated time
mentioned in (Table 2) at room temerature. The progress of the reaction was monitored
by thin layer chromatography (TLC) by using pet ether: ethyl acetate (18:2) as the eluent.
After 3 h, the reaction mass was filtered through the bed of Celite. The filtrate was
11

concerted under reduced pressure to get the solid product and crystallized from hot
ethanol to get pure product. The compound was characterized by melting point, 1H NMR,
and Mass spectrum, and the results obtained are summarized in (Table 2).
Ultrasound Promoted General Synthesis Of N-Substituted 1,8-Dioxo-
Decahydroacridines (4r-Y)
The mixture of 5,5-dimethylcyclohexane-1,3-dione 1a (1.31 gm, 2 mmol), aldehyde 2a
(500 mg, 1 mmol) and isoniazid 3a (640 mg, 1 mmol) was dissolve in acetonitrile (20
mL). To this stirred solution active dry baker’s yeast (1 gm) was added. The resulting
reaction mass was further irradiated at room under ultrasonication for stipulated time
mentioned in (Table 2) at room temperature. The progress of the reaction was monitored
by thin layer chromatography (TLC) by using pet ether: ethyl acetate (18:2) as the eluent.
After 3 h, the reaction mass was filtered through the bed of Celite. The filtrate was
concerted under reduced pressure to get the solid product and crystallized from hot
ethanol to get pure product. The recovered baker’s yeast was reused for 3-4 consecutive
runs in this reaction without any significant loss in yield and activity. The product was
confirmed by melting point, 1H NMR, 13C NMR, elemental analysis and the results
obtained are summarized in (Table 2).
CONCLUSION
In conclusion, non-aqueous solvent with one-pot three component condensation of
pharmaceutically important precursor N-substituted decanhydroacridine-1,8-dione was
demonstrated to be a suitable support for baker’s yeast. The baker’s yeast played key
12

roles in achieving high stability and reusability without significant lose in enzyme
activity and enantioselectivity. The developed protocol might be useful for the synthesis
of N-substituted 1,8-dioxo-decahydroacridines derivatives. Exploring the use of baker’s
yeast within the sustainable chemistry concept, this protocol covers waste minimization;
the use of alternative solvents and energies; the use of renewable resources and
biocatalysts recycling. It is valuable resource for researchers and industrialists working in
green chemistry and sustainability.
ACKNOWLEDGEMENTS
This work was supported by Special Assistance Programme (SAP), University Grants
Commission, New Delhi, India, intended to encourage the pursuit of excellence and
teamwork in advanced teaching and research to accelerate the realization of international
standards in specific fields, and also Sophisticated Analytical Instrumentation Facility,
Chandigarh, for providing characterization facility for this work.
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18

Table 1. Screening of solvent on the synthesis of 4a.a
Sr. No
Solvent
Time (h)
Yield (%)b
With US
Without US
With US
44
Without US
1.
2.
3.
4.
5.
6.
7.
8.
9.
Water
7
5
5
5
4
3
5
7
3
28
22
20
27
21
26
24
23
22
22
30
47
49
55
52
60
50
65
Water/Ethanol
Ethanol
Methanol
1,4-dioxane
DMF
48
58
60
62
63
THF
71
DCM
56
CH3CN
88
aReaction conditions: dimedone (2 mmole), benzaldehyde (1 mmole), and aniline (1
mmole), baker’s yeast (1gm) and solvent (10 mL) at rt,
bIsolated yield
19

Table 2. Baker’s yeast catalyzed synthesis of N-substituted decanhydroacridine-1,8-
diones 4 (a-y) under ultrasonic irradiation.a
Sr. No.
Product Aldehyde
Aniline/INH Time
(h:min)
M.P. (˚C) [29,64]
Yield (%)b
1.
04:10
270-273
83
4a
2.
3.
4.
03:35
03:50
04:00
184-187
177-180
188-190
80
76
73
4b
4c
4d
5.
03:50
175-178
84
4e
6.
7.
03:40
03:35
>300
74
78
4f
242-244
4g
8.
9.
02:55
04:20
219-223
263-267
76
72
4h
4i
20

10.
03:15
252-254
75
4j
11.
12.
03:40
03:45
278-281
280-285
70
75
4k
4l
13.
14.
04:00
03:30
110-113
261-263
76
73
4m
4n
15.
16.
05:10
03:00
278-280
242-244
71
75
4o
4p
17.
18.
04:10
03:45
281-283
160-163
78
75
4q
4r
19.
20.
03:40
04:20
240-243
217-221
71
79
4s
4t
21

21.
22.
23.
03:50
03:35
04:15
217-220
92-94
77
72
73
4u
4v
4w
85-87
24.
25.
03:45
04.15
153-155
167-169
71
72
4x
4y
aReaction conditions: dimedone (2 mmole), benzaldehyde (1 mmole), and aniline (1
mmole), baker’s yeast (1gm) and solvent (20 mL) at rt, bIsolated yield
22

Scheme 1. General scheme for the synthesis of N-substituted 1,8-dioxo-
decahydroacridines.
23

Scheme 2. Standard model reaction
24

Scheme 3. Plausible mechanism for the synthesis of N‐substituted-
1,8‐dioxo‐decahydroacridines.
25

Figure 1. Reuse and recovery of baker’s yeast and its effect on yield.
26