First bovine serum albumin-promoted synthesis of enones, cinnamic acids and coumarins in ionic liquid: An insight into the role of protein impurities in porcine pancreas lipase for olefinic bond formation

Article abstract of DOI:10.1002/adsc.201000870

During studies on exploiting the catalytic promiscuity of crude porcine pancreas lipase (PPL) in ionic liquid for C=C bond formations, bovine serum albumin (BSA) was found to be competing for these reactions. After a detailed investigation, we establish that these transformations are possible by unspecific protein catalysis rather than catalytic promiscuity of "PPL" - a first insight into the role of protein impurities in crude enzyme. Thus, a novel and highly efficient, environmentally friendly approach involving synergistic catalysis by bovine serum albumin-1-butyl-3- methylimidazolium bromide (BSA-[bmim]Br) has been developed for the synthesis of (E)-α,β-unsaturated compounds including a one-pot cascade synthesis of cinnamic acids and coumarins via aldol, Knoevenagel and Knoevenagel-Doebner condensations.

Full text of DOI:10.1002/adsc.201000870

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DOI: 10.1002/adsc.201000870
First Bovine Serum Albumin-Promoted Synthesis of Enones,
Cinnamic Acids and Coumarins in Ionic Liquid: An Insight into
the Role of Protein Impurities in Porcine Pancreas Lipase for
Olefinic Bond Formation
Nandini Sharma,a Upendra K. Sharma,a Rajesh Kumar,a Nidhi Katoch,a
Rakesh Kumar,a and Arun K. Sinhaa,*
a
Natural Plant Products Division, Institute of Himalayan Bioresource Technology, Council of Scientific and Industrial
Research (CSIR), Post Box No. 6, Palampur – 176061 HP, India
Fax : (+91)-1894-230433; e-mail: aksinha08@rediffmail.com
Received: November 19, 2010; Revised: January 14, 2011; Published online: April 14, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000870.
Abstract: During studies on exploiting the catalytic
promiscuity of crude porcine pancreas lipase (PPL)
in ionic liquid for C=C bond formations, bovine
serum albumin (BSA) was found to be competing
for these reactions. After a detailed investigation,
we establish that these transformations are possible
by unspecific protein catalysis rather than catalytic
promiscuity of “PPL” – a first insight into the role
of protein impurities in crude enzyme. Thus, a
novel and highly efficient, environmentally friendly
approach involving synergistic catalysis by bovine
serum albumin-1-butyl-3-methylimidazolium bro-
mide (BSA-[bmim]Br) has been developed for the
synthesis of (E)-a,b-unsaturated compounds includ-
ing a one-pot cascade synthesis of cinnamic acids
and coumarins via aldol, Knoevenagel and Knoeve-
nagel–Doebner condensations.
mental sustainability, operational simplicity, broad
substrate scope, selectivity and involving novel cas-
cade strategies is of significant concern.
Since the past decade, dynamic efforts to exploit
the biological potential of enzymes for catalyzing or-
ganic reactions is on the rise due to their simple proc-
essing requirements and high selectivity.[4] Among all
enzymes, lipases top the list due to their remarkable
versatility for the range of substrates and biotransfor-
mations they catalyze.[5] Recently, a new frontier,
termed as biocatalytic promiscuity, has attracted
À
much attention and several lipase-catalyzed C C
bond forming reactions[6] have been developed.
On the other hand, for C=C bond formations, very
few enzymatic systems are reported. However, these
procedures are hampered by the use of organic sol-
vents or additives,[6c] lower product yields, prolonged
reaction times and limited substrate scope. Accord-
ingly, the development of new biocatalytic procedures
might help to improve the existing catalytic condi-
tions.
Keywords: aldol condensation; bovine serum albu-
min; ionic liquids; Knoevenagel condensation;
Knoevenagel–Doebner condensation
In addition, due to environmental concerns, “green
solvents” are becoming an ideal medium for organic
reactions. One such group of promising green solvents
is “ionic liquids (IL)” because of their unique proper-
The formation of the olefinic (C=C) bond, a funda- ties of non-volatility, non-flammability, recyclability,
mental transformation in organic synthesis, is well and ability to dissolve a wide range of materials.[7] In
represented by aldol and Knoevenagel condensations. our previous study, we have observed promiscuous
This transformation is generally achieved in the pres- behaviour of Candida antarctica lipase in IL as H2O2
ence of a strong acid/base[1] or metal ions as cata- activator for alcohol oxidation under neutral condi-
lyst;[2] thus raising serious environmental concerns. tions.[8] This case and other relevant reports encour-
Recently some alternative approaches[3] using organic aged us to explore the catalytic promiscuity of lipase
and heterogeneous catalysts for the aldol condensa- for olefinic bond formation in IL.
tion have been reported; still the development of new
Initially, we screened different commercially avail-
cross-coupling methods beneficial in terms of environ- able lipases for the condensation of 0.12 mmol of 4-
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Table 1. Optimization study of aldol condensation of 4-methoxybenzaldehyde
with different ketones.[a]
[a]
Reaction conditions: 0.12 mmol 1a, 50 mg catalyst, 0.5 mL IL, 0.5 mL ketone,
6 h. CAL-B=Candida antarctica lipase B; CCL=C. cylindracea lipase; CRL=
C. rugosa lipase; PPL=porcine pancreas lipase; PCL=Pseudomonas cepacia
lipase; MJL=Mucor javanicus lipase; TLL=Thermomyces lanuginosus lipase.
Yield on the basis of HPLC against reference standard.
Pre-treated with urea and thiourea (7:1) at 1008C for 2 h.
[b]
[c]
[d]
Conversion after 48 h; nc=no conversion.
methoxybenzaldehyde (1a) with acetone using 1-
To exclude any background activity, control experi-
butyl-3-methylimidazolium bromide ([bmim]Br) as a ments carried out in the absence of IL (Table 1,
representative IL. Under the optimized conditions entry 14) or lipase (Table 1, entry 15) provided 1b
(see Supporting Information, Table SI), “PPL” pro- only in traces even after 72 h. Similarly, a reaction
vided best results (83% yield) with all other lipases carried out with 1-methylimidazole (MIm) (precursor
failing to provide any significant yield of 4-methoxy- for [bmim]Br) provide a trace yield; ruling out cata-
phenylprop-2-en-1-one (1b) (Table 1, entries 1–7). Re- lytic activity from residual MIm (Table 1, entry 16), if
placement of [bmim]Br with other ILs provided 1b in any. Further experiments carried out for the conden-
low yield (Table 1, entries 8–13).
sation of 1a with different ketones (Table 1, en-
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First Bovine Serum Albumin-Promoted Synthesis of Enones, Cinnamic Acids and Coumarins
Figure 1. SDS page analysis of different fractions prepared from PPL and photographs of reaction mixture at different time
intervals; F1, F2, F3, F4, F5 as mentioned in Scheme S1 (see Supporting Information), M=marker.
tries 17–23) indicated that the above reaction prefers
acetone over other ketones.
To investigate the catalytic potential of BSA-
[bmim]Br under the optimized conditions for aldol
Amazingly, replacement of “PPL” with “off-the- condensation, we studied the substrate scope for wide
shelf’ꢁ protein that is, bovine serum albumin, resulted range of aldehydes (Table 2).
in 89% yield (Table 1, entry 24) although BSA alone
Good to excellent product yields were observed in
provided a trace yield (Table 1, entry 25). In addition, all cases. In particular, the catalyst exhibited remark-
a moderate yield was also obtained with denatured able activity even for halogen-, nitrogen- or N,N-di-
lipase (Table 1, entry 26). These anomalous results (in methyl-containing compounds ensuing the exclusive
comparison to a previous report by Li et al.[6f]) togeth- formation of the enone product[11] (Table 2, entries 9,
er with the crude nature of “PPL” made us sceptical 17, 19, 20). In addition, the above biocatalytic ap-
about the involvement of the enzyme in the reaction. proach provided a facile access towards the synthesis
There are reports that crude preparations of “PPL”, of hydroxy-substituted enones (Table 2, entries 4–7)
apart from true lipase (protein band at 50 kDa), con- that otherwise requires protection-deprotection
tain a significant number of other proteins as impuri- strategies.[12]
ties.[9] Thus, we decided to enrich “true PPL” by frac-
In order to take the advantage of the developed ap-
tionation and to explore its exact role as catalyst. Ac- proach, we successfully extended it towards citral for
cordingly, five different fractions from the crude the synthesis of E-pseudoionone,[13] a key starting ma-
enzyme were prepared and tested for the aldol con- terial for the synthesis of vitamin A and carotenoids
densation. Interestingly, fractions F4 and F5 contain- etc. (Scheme 1).
ing peptides and residual amino acids of molecular
The next important aspect was examination of the
weight less than 10 kDa provided best results while possibility for catalyst reuse in subsequent reactions
the “PPL”-containing fractions (F1 and F2) gave sig- (examined for up to four cycles). The recovered cata-
nificantly lower yields; suggesting the role of protein lyst showed complete conversion for first two cycles
catalysis in the above reaction (Figure 1).
and a slight decrease in activity was recorded for the
To further validate our hypothesis of protein cataly- third and fourth cycles (80% conversion) which was
sis and the nature of catalysis (specific or unspecific), compensated by adding few mg of fresh BSA.
we performed experiments using BSA, lysine and egg
To obtain more insight into the catalytic possibili-
albumin as catalyst under the optimized conditions. ties of BSA, we investigated the product formation
Almost similar yields were observed in all cases for a series of aldehydes with active methylene
(Table 1, entries 27 and 28) confirming the role of groups. This reaction, known as the Knoevenagel con-
non-specific protein catalysis for the aldol condensa- densation, occurs in the presence of acid/base catalyst
tion. Since the completion of this work, a protein-cat- or a heterogeneous support.[14] Of late, the use of gua-
alyzed Henry reaction[10] was reported which corrobo- nidine-based task-specific ionic liquids,[15] and amino
rated our findings.
acids as a promoter in ionic liquids[16] has also been
established.
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Table 2. BSA-catalyzed aldol condensation in [bmim]Br.[a]
[a]
[b]
Reaction conditions: 0.12 mmol substrate, 50 mg BSA, 0.5 mL IL, 0.5 mL ace-
tone.
On HPLC basis and product confirmation by ESI-MS/MS and NMR (with E-
selectivity).
Isolated yield in parentheses.
In 72 h.
[c]
[d]
excellent yields. Reactions with ethyl acetoacetate
and ethyl cyanoacetate took 4 to 8 h for conversion
providing products with (E) selectivity.
Interestingly, the condensation of malonic acid with
aldehydes was followed by decarboxylation (a case of
Knoevenagel–Doebner condensation); furnishing the
corresponding cinnamic acids in high yields (Table 4).
Thus, the developed approach offers a remarkable
improvement over classical conditions and results in
an efficient, mild and base-free synthesis of several
Scheme 1. BSA-IL-catalyzed synthesis of pseudoionone.
As expected, quantitative conversion was observed substituted cinnamic acids with high selectivity.
with BSA, PPL as well as lysine for the condensation Another, important utility of the BSA-catalyzed ap-
of 4-methoxybenzaldehyde (1a) and diethyl malonate proach surfaced in the case of reactions of o-hydroxy
under optimized conditions (Table 3, entries 1–3). substituted benzaldehydes with malonic acid, diethyl
strengthening our perception of protein catalysis malonate and ethyl acetoacetate. Here the condensa-
rather than lipase promiscuity. These results were in tion was accompanied by decarboxylation and subse-
contrast to a recent report by Lai et al.[17] where the quently cyclization furnishing coumarins in good
possibility of protein catalysis has been ruled out. To yields (Table 5). Coumarins constitute one of the bio-
substantiate our findings, we decided to perform two logically important class of heterocyclic compounds
set of experiments with BSA at 608C employing our and numerous methodologies have been reported for
optimized conditions (in [bmim]Br) and the condi- their synthesis; however, these generally involve
tions reported by Lai et al. (in DMSO).[17] Surprising- harsh conditions (acidic or basic), multiple-step syn-
ly, we observed significant conversion (up to 70%) in thesis, lengthy work-up procedures and sometimes
both cases. Thereafter, we studied the scope of the elevated temperatures or specialized instruments.[18]
BSA-catalyzed Knoevenagel reaction towards various Thus, the present study provides a new perspective
active methylene groups. As evident from Table 3, for the direct synthesis of cinnamic acids and coumar-
condensation of aromatic aldehydes with malononi- ins (Knoevenagel–Doebner condensations) under
trile occurred at a very fast rate (within 1 h) providing mild and neutral reaction conditions.
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First Bovine Serum Albumin-Promoted Synthesis of Enones, Cinnamic Acids and Coumarins
Table 3. BSA mediated Knoevenagel condensation in [bmim]Br.[a]
[a]
Reaction conditions: 0.12 mmol substrate, 50 mg catalyst, 0.5 mL IL, 1 equiv.
active methylene compound.
On the basis of HPLC and product confirmation by ESI-MS/MS and NMR.
Isolated yield.
[b]
[c]
A plausible mechanism suggested the probable role
of some amino acid side chain in BSA as the catalytic
base[19] and IL acting as co-catalyst in above reaction.
Firstly, the basic amino group removes an acidic hy-
drogen from active methylene compound generating
a carbanion. Next, the nucleophilic attack of the carb-
anion on an aldehyde results in the formation of a b-
hydroxy carbonyl compound. Interaction of the b-hy-
droxy group with ionic liquid,[20] facilitated by BSA,
results in concurrent dehydration–decarboxylation–
cyclization through a concerted mechanism; thus pro-
viding coumarin as the final product (Figure 2).
Table 4. Direct catalytic synthesis of cinnamic acids by
Knoevenagel–Doebner condensation.[a]
To probe the practical applicability of our catalytic
system for aldol condensation, preparative scale reac-
tions (1 g batch) of some substituted benzaldehydes
were effectively accomplished. Furthermore, two of
the isolated condensates 4b and 5b (Table 2) were
subjected to chemoselective hydrogenation,[21] provid-
ing raspberry ketone and zingerone, respectively, in
good yields (Scheme 2).
In summary we have, for the first time, uncovered
the role of protein impurities in “PPL” (rather than
catalytic promiscuity) for olefinic bond formations, by
realizing the ability of BSA to catalyze these transfor-
mations. Accordingly, a simple, mild, inexpensive and
[a]
Reaction conditions: 0.12 mmol substrate, 1 equiv. of
active methylene group, 50 mg catalyst, 0.5 mL IL.
On the basis of HPLC and product identification against
reference standard and ESI-MS/MS.
[b]
[c]
Isolated yield.
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Table 5. One-pot, four steps cascade synthesis of coumarins via Knoevenagel–
Doebner condensation.[a]
[a]
Reaction conditions: 0.12 mmol substrate, 1 equiv. of active methylene
group, 50 mg catalyst, 0.5 mL of IL.
On the basis of HPLC and product identification by HPLC against refer-
[b]
ence standard and ESI-MS/MS.
Isolated yields in parenthesis.
[c]
Figure 2. Proposed mechanism for the synthesis of coumarins.
case of chloro-, nitro- and N,N-dimethylbenzalde-
hydes; (iii) decarboxylation and/or cyclization under
neutral conditions leading to the formation of cin-
namic acids and coumarins in good yields. Moreover,
catalyst recyclability and practical scale synthesis have
been demonstrated to enhance the practical utility of
process.
Experimental Section
General Procedure for the Aldol Condensations
(Table 1, Table 2, Scheme 1 and Scheme 2)
Scheme 2. Preparative scale synthesis of hydroxy enones.
Substrate (0.12 mmol), catalyst (50 mg), ketone (0.5 mL)
and IL [bmim]Br (0.5 mL) were taken in a flask and the re-
action mixture was incubated at 608C for 6 h. After the
completion of the reaction, the reaction mixture was cooled,
evaporated under vacuum to remove acetone and taken into
ethyl acetate (4ꢂ3 mL). The combined organic layer was
washed with water and dried over anhydrous Na2SO4 and
green synthetic methodology was developed using a
synergistic combination of BSA-[bmim]Br for aldol
and Knoevenagel–Doebner condensations. Other sig-
nificant features of the developed protocol are: (i) it
offers a promising platform for the synthesis of hy-
droxy enones; (ii) no dual activation of the ketone in evaporated under reduced pressure using
a rotavapor
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First Bovine Serum Albumin-Promoted Synthesis of Enones, Cinnamic Acids and Coumarins
(Bꢃchi, Switzerland). The product was analyzed by HPLC in
comparison with a reference standard and further confirmed
by ESI-MS/MS. For determination of isolated yield, the
crude product was purified by column chromatography on
silica gel with a mixture of ethyl acetate-hexane (10: 90 v/v).
1H and 13C NMR spectra were recorded and matched with
reported values.
For, preparative scale experiments, reactions with 1 g of
substrate were carried out as stated below. Substrate (1 g),
BSA 2 g, ketone (35 mL) and [bmim]Br (8 mL) were taken
in a flask and the reaction mixture was incubated at 608C
for 6–8 h. After the completion of reaction, the reaction
mixture was worked up as described above.
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General Procedure for Knoevenagel Condensation
(Table 3, Table 4 and Table 5)
Substrate (0.12 mmol), active methylene group (1 equiv.),
catalyst 50 mg and IL [bmim]Br (0.5 mL) were taken in a
round-bottom flask and the reaction mixture was incubated
at 608C for 0.5–72 h. After the completion of the reaction,
the reaction mixture was worked up as described above.
Fractionation of Crude “PPL”
Crude lipase from porcine pancreas was dissolved to a final
concentration of 25 mgmLÀ1 in 5 mM sodium phosphate
buffer at pH 7. This suspension was centrifuged for 30 min
at 12000 rpm, 48C and the pellet was discarded.[22] Further,
this solution was also filtered and then passed through a
50 kDa, 30 kDa and 10 kDa cutoff Amicon Filters (Milli-
pore) for further fractionation (F1-F5) as described in
Scheme S1, see the Supporting Information).
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Acknowledgements
[11] During the synthesis of reference enone standards of
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NS, UKS, RK are indebted to CSIR, New Delhi, for the
award of research fellowships. The authors gratefully ac-
knowledge the Director, IHBT Palampur, for providing nec-
essary laboratory facilities and funding under MLP0025. The
authors also acknowledge Mr. Rahul M. Singh and Mr. Arun
Kumar of IHBT Palampur for help in SDS PAGE experi-
ments. IHBT Communication No. is 2016.
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