Laccase from basidiomycetous fungus catalyzes the synthesis of substituted 5-deaza-10-oxaflavins via a domino reaction

Article abstract of DOI:10.1002/adsc.200800611

The present investigation provides a simple and convenient route for the synthesis of substituted 5-deaza-10-oxaflavins owing to their importance as probable redox coenzymes. The reaction of α,β-unsaturated derivatives of barbituric acid and dimedone with

Full text of DOI:10.1002/adsc.200800611

FULL PAPERS
DOI: 10.1002/adsc.200800611
Laccase from Basidiomycetous Fungus Catalyzes the Synthesis of
Substituted 5-Deaza-10-oxaflavins via a Domino Reaction
Mazaahir Kidwai,a,* Roona Poddar,a Sarika Diwaniyan,b
and Ramesh Chander Kuhadb
a
Green Research Laboratory, Department of Chemistry, University of Delhi, North Campus, New Delhi 110007, India
Fax : (+91)-112-2766-6235; e-mail: kidwai.chemistry@gmail.com
Lignocellulose Biotechnology Laboratory, Department of Microbiology, University of Delhi, South Campus, New Delhi
b
110021, India
Received: October 8, 2008; Revised: February 17, 2009; Published online: March 4, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800611.
Abstract: The present investigation provides
a
generated in situ by the oxidation of the correspond-
simple and convenient route for the synthesis of sub- ing catechol or 1,4-hydroquinones, underwent a
stituted 5-deaza-10-oxaflavins owing to their impor- domino reaction with chalcones to produce 5-deaza-
tance as probable redox coenzymes. The reaction of 10-oxaflavins and tetrahydroxanthen-1-ones.
a,b-unsaturated derivatives of barbituric acid and di-
medone with catechol or 1,4-hydroquinones was cat- Keywords: aqueous medium; 5-deaza-10-oxaflavins;
alyzed using laccase in aqueous medium. Quinones, domino reactions; laccase; tetrahydroxanthen-1-ones
Introduction
of the benzopyrano
5, led to the formation of several lead compounds
ACHTUNGTRENN[UNG 2,3-d]pyrimidines, especially at C-
Extensive research has been carried out to explore with very similar pharmacological profiles as the 5-
the functions of 5-deazaflavin derivatives 1 in biologi- deazaflavin-based derivatives.[3]
cal system and to develop a biomimetic model pos-
Some synthetic work on derivatives in this catagory
sessing the same basic skeleton since the discovery of has been reported, but these precedents did not meet
these derivatives 1 (Figure 1) as one of the naturally our requirements. In 1980, one of the authors (F. Y.)
occurring essential redox coenzymes.[1] In this context, first reported a method for the synthesis of 5-deaza-
5-deaza-10-oxaflavin
[2,3-d]pyrimi- 10-oxaflavin,[4] which involved three steps including
2 [2H-chromenoCAHTUNTGNRUEGN
dine-2,4(3H)-dione] was considered (Figure 1), in condensation of a phenol to 6-chlorouracil, Vilsmei-
which the nitrogen atom was replaced by an oxygen er–Haack reaction and dehydrative cyclization with
thus resulting in a substantial oxidation potential due polyphosphoric acid (Figure 2). However, isolation of
to the stronger electronegativity of oxygen atom.[2] 5- the final product was somewhat troublesome and the
Deaza-10-oxaflavin 2 possesses both isoelectronic and overall yield was very low. Blythin and co-workers
isosteric structures with 5-deazaflavin. It exhibits a published a one-step synthesis of a 5-deaza-10-oxafla-
strong function of oxidizing alcohols to the corre- vin derivative,[5] but this approach was not considered
sponding carbonyl compounds. Further derivatisation attractive because the starting material used, N-cya-
noacetylurethane, is not easy to prepare (Figure 2).
This necessitated the search for an alternative ap-
proach.
The use of biocatalysts is being explored in new
millennium industries because they are stable and
remain functional in diverse physiological environ-
ments including aqueous medium.[6] The unique prop-
erties of water in aqueous medium like high dielectric
constant and cohensive energy density showed an ex-
traordinary effect on reaction rates. Moreover, its
Figure 1. 5-Deazaflavin derivatives 1 and 5-deaza-10-oxafla-
vin 2.
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The reaction conditions were optimized for the en-
zymatic synthesis of 5a (Scheme 1) and 7a (Scheme 2)
from 3a. An experiment was carried using 1 mmole of
3a and 1.5 mmole of 5a/7a in 15 mL of solvent with-
out the addition of laccase or H2O2. There was no
product formation. The same was also observed when
0.5 mL of 30% of H2O2 and heat killed laccase were
also added. In another experiment, when 400 U lac-
case were added without H2O2, then only traces of
product formation were observed on TLC. The yield
of 5a was significantly improved with the addition of
0.5 mL of 30% H2O2 along with 400 U of laccase.
Excess of chalcone was required for the reaction; qui-
nones may undergo competing decomposition, dime-
rization or polymerization due to their intrinsic unsta-
bility. Quinones and a,b-unsaturated derivatives of
barbituric acid were used in a 1:1.5 ratio to tackle the
problem.
Figure 2. Synthetic approach to 5-deaza-10-oxaflavin 2.
cost-effectiveness, high abundance, non-inflammabili-
ty and non-toxic nature increased its applicability.[7]
The enzymes have been immobilized using several
methodologies for their biocatalytic applicability af-
In course of our search for an effective biomimetic fecting their activity, effectiveness of utilization, deac-
model compound, 5-deaza-10-oxaflavin, and to ex- tivation, regeneration kinetics and cost too[11] without
plore chemo-enzymatic reactions in aqueous medium, considering the toxicity of the immobilization re-
an efficient laccase-catalyzed synthesis of derivatives agents and the waste disposal problem. In this study,
of 5-deaza-10-oxaflavin was investigated. This reac- the laccase-catalyzed synthesis was carried out in
tion also required H2O2, a stoichiometric oxidant.
aqueous medium for three consecutive runs and
monitored by TLC. Table 1 depicts the yield of the
products 5-deaza-10-oxaflavin 5a and 7a from the re-
action catalyzed by laccase in three consecutive runs.
The yield was observed to decrease slightly after each
Result and Discussion
There has been a great deal of interest in the synthe- run.
sis of 5-deaza-10-oxaflavin {2H-chromeno[2,3-d]pyri- Table 2 shows the effect of different solvent systems
midine-2,4(3H)-dione} owing to its biological impor- on product yield. In DMSO, DMF and MeCN no re-
tance and function as essential redox coenzymes.[8]
action was observed due to denaturation of laccase.
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
A
successful synthesis of 5-deaza-10-oxaflavin through The reaction in aqueous buffer proceeded in higher
fusion of quinones with chalcones was endeavored. yield using buffer tablets of NaH2PO4, Na2HPO4, and
Here the action of the laccase, for the in situ genera- potassium phthalate (pH 4). The lower percentage
tion of quinones, is reported.
yields in other solvent systems were due to a decrease
Laccase, a multicopper oxidase, which reduces in laccase activity in non-inter miscible organic and
oxygen (source of O2 is from the disproportionation aqueous phases. Moreover, the domino reaction was
redox reaction of H2O2 in acidic medium) to water shown to exhibit higher reactivity and selectivity in
and simultaneously performs one-electron oxidation aqueous medium rather than in organic solvents.
of many aromatic substrates such as phenol and aro-
Furthermore, the effect of reaction temperature
matic amines. Catechol/hydroquinones have more was studied by varying it from 58C to 608C. The opti-
electron density at the ortho-position, so they undergo mal reaction temperature was found to be room tem-
1,4-addition reaction with a,b-unsaturated derivatives perature (258C). This could be attributed to the in-
of barbituric acids leading to non-isolable 8 followed crease in the rate of decomposition and polymeri-
by its oxidation via laccase to give 9 which further un- zation of the in situ generated quinones when a
dergo intramolecular 1,4-addition reaction to form 10. higher temperature was employed while the insolubil-
The intermediate 10 is oxidized by laccase to give 10a ity of the a,b-unsaturated derivatives of barbituric
followed by 1,4 addition to give an intermediate that acids was observed at lower temperature.
exists in a resonance form consisting of structure 11
The reaction was observed with diverse a,b-unsatu-
in acidic medium.[9] Upon protonation 10a undergoes rated derivatives of barbituric acids under the opti-
transformation to its resonance structure 11. Due to mized conditions (Scheme 3 and Scheme 4). The
acidic medium, 11 again gets protonated and leads to choice of aldehyde was important based on its biolog-
the formation of the final 5-deaza-10-oxaflavins (5a– ical activity. For example, in chlorobenzaldehyde and
h/7a–h) (Figure 3).[10]
2-chloroquinolin-3-ylaldehyde, the chloro group en-
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Laccase from Basidiomycetous Fungus Catalyzes the Synthesis
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Figure 3. Proposed mechanism pathway.
Scheme 1.
hances the biological activity whereas heteroaromatic out the synthesis.[12] The reactivity of the a,b-unsatu-
aldehydes like thiophenecarboxaldehyde, benzo- rated derivatives of barbituric acids with the in situ
ACHTUNGTRENNUNG
side, nitro and methoxy groups were also found to the scope of this process to the chalcone of dimedone,
possess activity. These aldehydes were chosen to carry which result in the xanthene moiety, an important
Adv. Synth. Catal. 2009, 351, 589 – 595
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Mazaahir Kidwai et al.
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Scheme 2. R=phenyl, 4-methoxyphenyl, benzoACTHNUTRGENUG[N 1,3]dioxol-5-yl, 2-thienyl, 3-nitrophenyl, 4-chlorophenyl, 2H-indol-3-yl, 2-
chloroquinolin-3-yl.
Table 1. 5-Deaza-10-oxaflavin derivatives 5a and 7a: synthe-
Table 2. Solvent optimization for the synthesis of 5-deaza-
sis by catalysis of laccase using the optimized conditions.[a]
10-oxaflavin.[a]
Runs
5a Yield [%][b]
7a Yield [%][b]
Entry Solvent
5a Yield
7a Yield
[%][b]
[%][b]
I (Fresh)
II
III
72
68
62
76
69
61
1
2
3
4
5
1M Acetate buffer pH 4
Water
THF
Ethanol
1M Phosphate/Citrate
buffer pH 5.5
1M Buffer tablet of
pH 4+THF
Methanol
DMSO
25
–
53
40
–
29
–
57
46
–
[a]
Reaction conditions: 1 mmole 4 or 6 and 1.5 mmoles of
3a were taken in 15 mL of buffer solution and THF was
added to dissolve the reactants. 400 U of laccase and
0.5 mL of 30% H2O2 were added and the resultant solu-
tion was stirred well for 4 h.
6
72
76
[b]
Yield refers to the isolated and unoptimized yield.
7
8
23
–
27
–
9
MTBE
MeCN
1,4-Dioxane
DMF
t-BuOH
15
–
37
–
23
–
35
–
10
11
12
13
synthon for the synthesis of various heterocyclic com-
pounds. Xanthene-based fluorescent dyes are widely
used in chemical biology to detect biological substan-
ces, such as proteins, DNA and sugars with high sensi-
tivity and selectivity.[13] The classical synthetic ap-
proaches are numerous with the use of harsh organic
solvents such as p-TSA, polyaniline-p-toluenesulfo-
nate salt, sulfamic acid, glacial acetic acid,[14] AcOH-
H2SO4 and Amberlyst-15 etc. under acidic conditions.
39
42
[a]
[b]
Reaction conditions: 1 mmole 4 or 6 and 1.5 mmoles of
3a were taken in 15 mL of solvents. 400 U of laccase and
0.5 mL of 30% H2O2 were added and the resultant solu-
tion was stirred well for 4 h.
Yield refers to the isolated and unoptimized yield.
Here, the desired derivatives of 9-aryl-7,8-dihydroxy- obtained in a reduced reaction time period and with
3,3-dimethyl-2,3,4,9-tetrahydro-xanthen-1-one
were improved yield.
Scheme 3.
Scheme 4. R=phenyl, 4-methoxyphenyl, benzoACTHUNTGRNEUNG[1,3]dioxol-5-yl, thiophen-2-yl.
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Laccase from Basidiomycetous Fungus Catalyzes the Synthesis
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Table 3. Laccase-catalyzed synthesis of 5-deaza-10-oxaflavin derivatives 5a–h and 7a–h.[a]
S. No.
Entry No.
R
5a–h
7a–h
Yield [%][b]
Time [h]
Yield [%][b]
Time [h]
1
2
3
4
5
6
7
8
a
b
c
d
e
f
Phenyl
4-Methoxyphenyl
BenzoACTHNUGRTENUNG[1,3]dioxol-5-yl
Thiophen-2-yl
3-Nitrophenyl
4-Chlorophenyl
2H-Indol-3-yl
72
63
65
55
25
43
52
64
4
76
26
57
24
48
9.5
65
58
4.5
6.5
5
4.5
8.5
6
4.5
5.5
3.5
7.5
6
g
h
4
4.5
5
4
2-Chloroquinolin-3-yl
[a]
Reaction conditions: 1 mmole 4 or 6 and 1.5 mmoles of 3a–d were taken in 15 mL of solvents. 400 U of laccase and
0.5 mL of 30% H2O2 were added and the resultant solution was stirred well for 4 h.
Yield refers to the isolated and unoptimized yield.
[b]
Table 4. Laccase-catalyzed synthesis of 5-deaza-10-oxaflavin derivatives 13a–d and 14a–d.[a]
S. No.
Entry No.
R
13a–d
Yield [%][b]
14a–d
Yield [%][b]
Time [h]
Time [h]
1
2
3
4
a
b
c
Phenyl
4-Methoxyphenyl
68
55
57
42
4
56
47
43
37
4.5
6.5
5
4.5
5.5
3.5
Benzo
ACHTUNGTREN[NUGN 1,3]dioxol-5-yl
d
Thiophen-2-yl
4.5
[a]
Reaction conditions: 1 mmole 4 or 6 and 1.5 mmoles of 11a-d were taken in 15 mL of solvents. 400 U of laccase and
0.5 mL of 30% H2O2 were added and the resultant solution was stirred well for 4 h.
Yield refers to the isolated and unoptimized yield.
[b]
Laccase Production
Conclusions
Static cultivation was carried out at 308C in 250-mL Erlen-
meyer flasks with 50 mL malt extract broth (MEB) contain-
ing (gLÀ1): malt extract 20.0, KH2PO4 0.5, MgSO4·7H2O 0.5,
In the present work, the simple reaction conditions,
easy work-up procedure and product yield in consecu-
tive runs made our methodology a valid contribution
to the existing organic synthesis approach of 5-deaza-
10-oxaflavin.
CaACHTUNRTGNEU(GN NO3)2·4H2O 0.5 (pH 7.0). The flasks were inoculated
with two fungal discs (8 mm diameter each) from the pe-
riphery of 4-day-old fungal culture and incubated at 308C.
After 96 h of growth, 50 mL copper sulphate (1M) were
added to the MEB. The cultures were harvested by filtering
through Whatman No. 1 filter paper after 264 h of growth.
The culture filtrate was centrifuged at 12,000ꢁg for 20 min
at 48C and the supernatant obtained was assayed for laccase
activity.
Experimental Section
The chalcone was prepared according to the literature pro-
cedure.[15] Guaiacol was purchased from Hi Media Labora-
tories Pvt. Ltd. (Mumbai, India). All media components and
chemicals used were of analytical grade.
Purification of Laccase
The culture filtrate (900 mL) containing laccase enzyme was
precipitated by addition of ammonium sulphate (80% cut-
off) and centrifuged at 10,000ꢁg for 20 min 48C. The pre-
cipitate was resuspended in 50 mM citrate phosphate buffer
(pH 5.5) and dialyzed at 48C against the same buffer. This
partially purified enzyme (78 mL) was concentrated to
20 mL using 10 kDa filter membrane (Vivaspin, Vivascience,
Sartorius Group, Stone house, UK) at 48C and thereafter,
the concentrated enzyme sample was loaded to an anion-ex-
change DEAE-sepharose (Amersham Pharmacia Biotech,
Freiburg, Germany) column (25ꢁ2 cm2), equilibrated with
10 mM Tris HCl buffer (pH 7.5). The proteins were eluted
Microorganism
The basidiomycetous fungus, RCK-1, isolated from deterio-
rated sugarcane bagasse, collected from Sugar Mill Industry,
Sonipat, Haryana, India, was grown and maintained on malt
extract agar (MEA) containing (gLÀ1): malt extract 20.0,
KH2PO4 0.5, MgSO4·7H2O 0.5, CaACHTUNGTRENUNG(NO3)2·4H2O 0.5, agar
20.0 (pH 7.0) at 308C.[16] Pure cultures were stored at 48C
and sub-cultured every fortnight.
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Mazaahir Kidwai et al.
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by NaCl gradient (0–1M dissolved in equilibrating buffer) at
a flow rate of 0.5 mLminÀ1 with each 1 mL fraction. Frac-
tions with laccase activity were pooled, desalted and assayed
for laccase activity.
1673.83 cmÀ1 (C=C); 1H NMR (DMSO-d6, 300 MHz): d=
0.96 (s, 3H, CH3), 1.16 (s, 3H, CH3), 4.86 (1H, s, C9-H),
6.66–9.20 (m, 17H, Ar), 9.97 (s, 2H. OH); 13C NMR
(DMSO-d6, 75 MHz): d=25.14, 29.13, 50.14, 111.64, 117.25,
122.43, 123.12, 123.96, 125.35, 126.39, 127.46, 127.53, 127.93,
128.78, 129.35, 130.38, 131.46, 148.35, 154.43, 164.56, 195.71.
Enzyme Assay
Supporting Information
Guaiacol was used as a substrate for assaying laccase activi-
ty.[16] One unit (U) of laccase was defined as the change in
absorbance of 0.01 mLÀ1 minÀ1 at 470 nm.
Additional experimental procedures and spectral data are
available as Supporting Information.
General Procedure for the Synthesis of 2H-
ChromenoACHTUNGTRENNUNG[2,3-d]pyrimidine-2,4(3H)-dione and
Tetrahydroxanthen-1-one
Acknowledgements
The authors (M. Kidwai and R. Poddar) are thankful to
CSIR New Delhi for providing finance assistance. The au-
thors (S. Diwaniyan and R.C. Kuhad) acknowledge the finan-
cial support from Department of Biotechnology, New Delhi,
India.
Catechol or hydroquinone (1 mmole) and chalcone (1.5
mmoles) were taken in 15 mL of buffer solution where THF
was added to dissolve the reactants. Then, purified laccase
(400U) was added to the resultant solution and stirred well.
0.5 mL of 30% H2O2 was added to oxygenate the reaction
mixture. The progress of the reaction was checked by TLC
examination at an interval of every 30 min. Upon comple-
tion of reaction, the reaction mixture was extracted with References
ethyl acetate (3ꢁ15). The organic layer was dried over
Na2SO4. The product was purified by column chromatogra-
phy using a mobile phase of hexane:ethyl acetate (80:20)
and recrystallized with ethanol. The aqueous phase was fur-
ther used for another run without any pre-treatment.
5,6-Dihydroxy-10-phenyl-9-oxa-1,3-diaza-anthracene-2,4-
dione (5a): HR-MS: m/z=324.2322 (M+); anal. calcd for
C17H10N2O5: C 62.96, N 8.64, H 3.73%; found: C 62.85, N
8.59, H 3.86%; IR (KBr pellet): n=3322.44 (OH), 3205.54
(NH), 1733.56 (C=O), 1672.34 cmÀ1 (C=O); 1H NMR
(DMSO-d6, 300 MHz): d=6.38–7.54 (m, 7H, Ar), 8.81 (s,
2H. OH), 9.85 (s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz):
d=113.41,114.42, 115.68, 119.39, 128.39, 129.59, 131.47,
133.48, 135.82, 137.06, 143.25, 144.77, 164.18, 165.51, 166.99,
168.77, 191.20.
5,8-Dihydroxy-5-phenyl-9-oxa-1,3-diaza-anthracene-2,4-
dione (7a): HR-MS: m/z=324.1452 (M+); anal. calcd. for
C17H10N2O5: C 62.96, N 8.64, H 3.73%; found: C 62.75, N
8.69, H 3.76%; IR (KBr pellet): n=3312.24 (OH), 3203.45
(NH), 1730.65 (C=O), 1673.42 cmÀ1 (C=O); 1H NMR
(DMSO-d6, 300 MHz): d=6.38–8.20 (m, 7H, Ar), 8.90 (s,
2H. OH), 10.25 (s, 1H, NH); 13C NMR (DMSO-d6,
75 MHz): d=113.41, 114.42, 115.68, 119.39, 128.39, 129.59,
131.47, 133.48, 135.82, 137.06, 143.25, 144.77, 164.18, 165.51,
166.99, 168.77, 191.20.
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Laccase from Basidiomycetous Fungus Catalyzes the Synthesis
FULL PAPERS
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