Studies on the laccases catalyzed oxidation of norbelladine like acetamides

Article abstract of DOI:10.1016/j.mcat.2020.110788

Herein, we study for the first time, the Laccase catalyzed oxidation of Norbelladine like amides 1 and 2. It was determined that the Laccases/ABTS and Laccases alone were able to catalyze the dimerization and trimerization reaction of the amides 1 and 2 i

Full text of DOI:10.1016/j.mcat.2020.110788

MolecularCatalysis485(2020)110788
Contents lists available at ScienceDirect
Molecular Catalysis
journal homepage: www.elsevier.com/locate/mcat
Studies on the laccases catalyzed oxidation of norbelladine like acetamides
Viviane Marques de Aguiar, Rodrigo Esquinelato Silva, Raquel A.C. Leão,
Rodrigo Octávio Mendonça Alves de Souza, Raoni Schroeder B. Gonçalves,
Leandro Soter de Mariz e Miranda*
Universidade Federal do Rio de Janeiro, Biocatalysis and Organic Syntheis Group, Av. Athos da Silveira Ramos 149, Centro de Tecnologia, Bloco A, 21941909, Ilha do
Fundão, Rio de Janeiro, Brazil
A R T I C L E I N F O
A B S T R A C T
Keywords:
Herein, we study for the first time, the Laccase catalyzed oxidation of Norbelladine like amides 1 and 2. It was
determined that the Laccases/ABTS and Laccases alone were able to catalyze the dimerization and trimerization
reaction of the amides 1 and 2 in high conversions, respectively. The synthesis of the selectively deuterated
substrates D-1 and D-2 and the analysis of their reaction products by HPLC-ESI-TOF MS allowed the determi-
nation of the bond (CeCe or CeO) formed between the monomers.
Biocatalysis
Laccase Norbelladine
Phenol
1. Introduction
through the Cys-His pathway to the trinuclear copper cluster (T2 and
T3) which then accomplishes the four electron reduction of oxygen.
Phenolic compounds are largely distributed in nature, especially in
the plant kingdom where they are considered to play important roles in
the defense of such organisms against infection. So, it does not come as
a surprise that phenolic compounds are reported to display different
biological activities [1] such as anti-inflammatory [2–7], anti-oxidant
[6,8–12], antithrombotic [13–15], anti-atherogenic [16–19] and anti-
microbial [20–24]. Additionally, these compounds have also found
application in catalysis [25–28] and functional materials [29,30]. Such
characteristics of phenolic compounds promoted a great amount of
work in the synthesis of their derivatives in the search for bioactive and
catalytic active ligands.
This oxidation occurs through an outer-sphere mechanism on T1, where
the first- and second-sphere residues surrounding the T1 control both
the intermolecular ET to the T1 from the substrate, and the in-
tramolecular ET from the T1 to the T2-T3 cluster [31].
Laccases are reported to perform the oxidation of structurally di-
verse compounds such as 2,2′-Azino-bis(3-ethylbenzothiazoline-6-sul-
fonic acid) diammonium salt (ABTS) [32–34], 2,2,6,6-Tetramethyl-1-
piperidinyloxy free radical (TEMPO) [35–39], N-hydroxyphtalimide
[39–41], 1-Hydroxybenzotriazole [42–46] and hydroquinone [47]. It is
proposed that many of these compounds once oxidized by the laccases
(with concomitant reduction of molecular oxygen) reacts further oxi-
dizing other compounds leading to the reaction product formation. In
such cases these compounds are called mediators and this process is
present in Figs. 1 and 2. These mediators present electrochemical po-
tential that varies from 0.8 to 1.2 mV. The structure of mediators is
show in Fig. 1.
Laccasess (EC 1.10.3.2 p-diphenol: dioxygen oxidoreductase) are a
multicopper oxidases (MCO) containing four copper atoms distributed
in three different redox sites. In nature, these enzymes catalyze the
synthesis and degradation of lignin with the concomitant four electron
reduction of O2 to H2O while bypassing a stage of H2O2 production.
These enzymes are common from fungal and vegetal origin. The en-
zyme contain four copper atoms that can be classified into three types
based on their unique spectroscopic features. In the oxidized state, the
Type 1 copper (T1) exhibits an intense absorption 600 nm, while the
Type 2 (T2) Cu (II) shows no significant absorbance feature. The
Binuclear Type 3 (T3) copper sites are EPR silent due to anti-
ferromagnetic (AF) coupling resulting from a bridging hydroxo ligand
between the coppers in the resting oxidized state. From the mechanistic
point of view, the substrate is oxidized at T1, which transfers electrons
The structural diversity of the mediators and the different me-
chanisms by which they oxidize the substrate, may allow the oxidation
of structurally divergent compounds. Under these circumstances, the
substrate non-specificity of Laccasess/mediator system is vastly ex-
plored in the literature [48–50], leading to its application in different
fields such as pollutant and dye removal [33,39–41,51], clarification of
beverages and paper bleaching [52–55].
Intramolecular phenolic coupling is a reaction present in the bio-
synthetic pathways of many important natural products. One
⁎ Corresponding author.
E-mail address: leandrosoter@iq.ufrj.br (L.S. de Mariz e Miranda).
https://doi.org/10.1016/j.mcat.2020.110788
Received 14 November 2019; Received in revised form 23 January 2020; Accepted 24 January 2020
2468-8231/©2020ElsevierB.V.Allrightsreserved.

V.M. de Aguiar, et al.
MolecularCatalysis485(2020)110788
Fig. 1. Structure of mediators used in Laccases catalyzed reactions.
Fig. 2. The proposed coupling of the Laccase/mediator system with oxygen as the terminal oxidant.
Scheme 1. Norbelladine as intermediate in the biosynthesis of Amaryllidaceae alkaloids.
interesting group of substances where oxidative dearomative coupling
of phenol plays a key role is the synthesis of Amaryllidaceae alkaloids
[56] where Norbelladine is cyclized leading to the synthesis of Ga-
lantamine, Narwedine, Haemanthamine, Crinine and Lycorine, for ex-
ample [57,58] as depicted in Scheme 1.
In cases where intra vs intermolecular phenol coupling reactions are
concerned, studies report that its outcome is dependent on the oxidant
and on the substitution pattern of the coupling phenols. According to
Swartz and others [59–62], monophenolic compounds may not go in-
tramolecular reaction trough the intermediacy of phenoxy radicals,
2

V.M. de Aguiar, et al.
MolecularCatalysis485(2020)110788
Fig. 3. Structure of the amides used in the present study.
where a more electrophilic intermediate such as the phenoxenium ca-
tion is necessary. The easy of formation of such phenoxenium cation is
pH dependent where at neutral or weakly acidic conditions, a two
electron oxidation process can be achieved with a 1200 mV potential
[63,64]. On the other hand, at higher pH, the phenolate anion in oxi-
dized to the same cation at much lower potential (800 mV). Such values
are in the range of those compounds that are reported to be oxidized by
Laccases or a Laccases/mediator system.
K2CO3 (6.4 mmol) at 45 °C for 3 h. The mixture was filtered over celite
and concentrated. After this, the residue was taken up in ethyl acetate
and washed with HCl 3 M and brine. The organic phase was dried over
anhydrous Na2SO4, filtered and the crude oil obtained after con-
centration was purified by column chromatography on silica gel (40 →
100 % AcOEt – Hex) to afford the respective products.
2.3. General procedure for the synthesis of the deuterated substrates (d-1
and d-2)
On the other hand, when a phenol is present on both rings under-
going the intramolecular reaction, cyclization may occur through the
intermediacy of a phenoxy diradical. Additionally, in cases where non
phenolic electron rich arenes are anodically oxidized the cyclization
products are the result of the intermediacy of the dication radical [65].
Finally, if the oxidation leads to a radical, instead of a phenoxyca-
tion or a diradical where intramolecular reaction is expected, the ob-
served product may be the result of an intermolecular reaction that
leads to a complex mixture of products from constitutional and re-
gioisomeric dimers, trimers or even polymers [66] [67] [68]. Such
approach is used in the synthesis of phenol derived polymers, anti-
oxidants, metal ligands as well as (pseudo)symmetric alkaloids [69]
[70] [71].
In a Schlenk flask under an inert atmosphere, the tyramine (5.6
mmol) and 5 mL of water were added, followed by 2.6 mmol of metallic
sodium. The reaction mixture was stirred at 100 °C for 48 h. The re-
actions was then cooled to room temperature and the solution was
acidified to pH = 6 when a slight precipitation occurred. Because of
this, the supernatant was transfer and extracted with diethyl ether.
GC–MS analysis indicated the product was in the aqueous phase. So, the
aqueous phase was lyophilized getting a brown solid.
This solid was used without any additional purification in the
synthesis of the abovementioned substrates (1 and 2) following the
same protocol as the previous section, getting 19 % d-1 and 17 % d-2
after purification.
Herein, we study for the first time the Laccase catalyzed oxidation of
Norbelladine like amides 1 and 2 (Fig. 3). According to the previous
discussion, if the laccases or a laccases/mediator system is able to
perform the oxidation of 1 to the phenoxenium cation, cyclization
would occur through the attack of the electron rich ring B, with the
formation of the four ring system present in alkaloids such as Ga-
lantamine. On the other hand, in the case of amide 2, the presence of
the two phenolic rings, cyclization would occur if the enzymatic system
could lead to the formation of a phenoxy diradical. Finally, in both
cases, If radical coupling is faster than the formation of the cation or the
diradical, intermolecular dimerization and trimerization are to be ex-
pected as the reaction products.
2.4. General procedure for the laccase catalyzed reactions
For both substrates, two reaction medium were studied:
I Phosphate buffer (0.1 M, pH = 6.4) : acetonitrile – 6:1
II Acetate buffer (0.02 M, pH = 5.4 : ethyl acetate – 1:1
When ABTS was used, this was added in 10 % mol of the substrate.
Laccase fromTrametes versicolor (30U) was dissolved in the corre-
sponding buffer and then the substrate was added dissolved in the or-
ganic solvent and stirred at room temperature for 24h in an open vial.
When acetonitrile was the solvent, the reaction medium was con-
centrated before its extraction with ethyl acetate. When ethyl acetate
was the solvent, the phases were separated and aqueous phase was
extracted with ethyl acetate. Lastly, the organic phases were combined,
dried over anhydrous Na2SO4, filtered and evaporated.
2. Experimental section
2.1. General information
All chemicals and solvents were purchased from commercial sources
and used without further purification. All solvents used in Liquid
Chromatography-Mass Spectrometry (LC–MS) analysis were HPLC
grade (HPLC/Spectro) and were purchased from Tedia (USA).
The same protocol was used with d-1 and d-2
3. Results and discussion
2.2. General procedure for the synthesis of the substrates 1 and 2
Compounds 1 and 2 were obtained through the reductive amination
between Tyramine and the corresponding aldehyde, 2,3,4-trimethox-
ybenzaldehyde 3 for the synthesis of 1 and 3-hydroxybenzaldehylde 4
for the synthesis of 2, respectively. The secondary amines were then
acylated lending to the desired amides. Compounds 1 and 2 were ob-
tained in 56 % and 44 % overall yield respectively, and observed as a
pair of rotamers (scheme 2 ) in the NMR analysis.
A solution of the respective aldehyde (7 mmol) and the tyramine (7
mmol) in 42 mL of methanol was stirred for 4 h at room temperature,
under inert atmosphere. The reaction was then cooled with an Ice bath,
and sodium triacetoxyborohydride (9.7 mmol) and 7 mL of glacial
acetic acid were added and the mixture was stirred overnight at room
temperature. After removal of the solvent, 12 mL of acetic anhydride
was added on the residue and stirred in the presence of DMAP (0.38
mmol) at 45 °C for 4 h. Then, 12 mL of methanol was added and stirred
for additional 30 min. After removal the solvent, the residue was taken
up in ethyl acetate and washed with HCl 1 M. The organic phase was
dried over anhydrous Na2SO4, filtered and concentrated. The residue
was dissolved in 15 mL of methanol and stirred in the presence of
The laccases catalyzed reactions of 1 and 2 were conducted with the
Laccase from T. versicolor (30 U) in a phosphate (pH = 6.4) : acet-
onitrile or acetate (pH = 5.4) : Ethyl Acetate buffer solvent mixture and
in the presence or absence of ABTS as mediator as depicted in Table 1.
As can be seen in Table 1, the conversion was highly sensitive to the
reaction conditions. For both compounds, the higher conversions were
observed at higher pH. In the case of the reaction of 1, the presence of
3

V.M. de Aguiar, et al.
MolecularCatalysis485(2020)110788
Scheme 2. Synthesis of substrates 1 and 2.
Table 1
S15). The D-1 and D-2 were also analyzed through ESI-TOF MS. For
compound D-1 the deuterated compound presented the exact mass of
362.1944 Da for its proton adduct (Theoretical [M+H]+ =362.1937
Da) and for D-2 a mass of 288.1556 also for its proton adduct
(Theoretical [M+H]+=288.1569 Da), two units higher then the non-
deuterated compounds
The laccases catalyzed reaction of 1 and 2 under different conditions.
Entry Substrate Buffer pH Mediator Conversion (%) Selectivity
(C-C):
(C-O)
Dimer/
Trimer
1
2
3
4
5
6
7
8
1
2
6,4a
5,4b
–
5
ND
ND
The deuterated amides D-1 and D-2 were submitted to the reaction
condition presented in Table 1 entries 2 and 6, respectively, where
higher conversion was obtained. Important to note that the reaction
with the deuterated compounds afforded the same profile as for the
non-deuterated (Figures S46 and S51). This identical reaction outcome,
allowed the determination of the structure of the dimers and trimers
formed.
ABTSc
–
98
33
38
93
91
61
68
3.23
3.80
4.52
1.24
1.43
3.85
4.41
10:90
64:36
62:38
55:45d
3:97d
67:33d
62:38d
ABTSc
–
a
6,4
5,4
ABTSc
–
b
ABTSc
a
b
Conditions: [substrate] 20 mM, 30U of laccase T. versicolor. Solvent mixture
For the substrate D-1, dimeric compounds with molecular mass two
([M+H]+ = 719.3496) and three units ([M+H]+ = 720.3558) hea-
Phosphate buffer 100 mM (pH = 6.4) : acetonitrile (6:1) Solvent mixture
Acetate 50 mM (pH = 5.4) : Ethyl Acetate (1:1) 10 % mol ABTS d-these
c
vier than that of the dimer of the non-deuterated ([M+H]+
=
selectivities are relative to the C-C linked dimer detected., see discussion.
ND: Not Determined.
717.3373) compound could be observed. These results are consistent
with the presence of two and three deuterium atoms, respectively. In
the present case, that dimer that contain two deuterium atoms may
have the monomers linked through a carbon-carbon bond, and that
with three deuterium atoms may be linked through a carbon-oxygen
bond, as depicted in, Fig. 4.
ABTS had profound influence in the reaction outcome where only at pH
= 6.4 complete conversion was observed. The same reaction conditions
yielded 91 % of conversion for substrate 2. However, in the case of
substrate 2 the presence of the mediator did not impacted the conver-
sion as compared to substrate 1, once 93 % conversion was observed in
the absence of the mediator.
Concerning the region corresponding to the molecular mass of the
trimers, compounds containing the presence of two, three and four
deuterium atoms were detected corresponding to the presence of tri-
mers linked by two carbon-carbon bonds one carbon-carbon and one
carbon-oxygen bond one carbon-carbon and two carbon-oxygen bonds,
respectively. The respective structures of these products are depicted in
Fig. 4.
As can be seen in Figures S5-S-8, all the reactions presented the
same product profile through HPLC-UV analysis of the crude isolated
reaction. Unfortunately, in order to get structural information con-
cerning the reaction products, all the attempts to obtain a fraction with
adequate purity for spectroscopic characterization after chromato-
graphy were deemed with failure. To get insight into the type of pro-
ducts formed, the reactions were then analyzed by hyphenated HPLC-
UV-ESI-TOF-MS.
In the case of compound 2, three peaks with the molecular mass
corresponding to the dimers were detected; one with molecular mass
two units higher than the non deuterated counterpart and two with
three units higher. While the dimer containing two units higher can be
attributed to the CeC bonded dimer. The elucidation of the structures
of the dimers with molecular mass three units higher is more compli-
cated since the coupling between the phenolic ring from the aldehyde
derived portion of 2 with the tyramine portion through a carbon-carbon
(or oxygen-carbon bond) bond would also present three deuterium
atoms in its structure, being isobaric with the product obtained from the
formation of a carbon-oxygen bond between the two tyramine portion
of the molecule, Fig. 5.
For the reaction of 1 and 2, products with the mass correspondent to
the proton adduct of dimers and trimers could be detected. In the case
of substrate 1 the dimers were the major products as can be seen in
table Table 1. In the case of substrate 2 the amount of dimers and trimer
were almost the same at higher pH, where the phenolic compounds are
more reactive due to higher concentration of the phenolate species. This
issue associated with the presence of two phenols in the structure can
be responsible for this selectivity.
These dimers and trimers can be built up through the formation of a
carbon-carbon or a carbon-oxygen bond. The above presented analysis
do not shed any light into the nature of the bond formed, and con-
sequentially, into the structure of these products. Once no pure com-
pound could be obtained, and in order to elucidate this issue, the
synthesis of selectively deuterium labeled derivatives D-1 and D-2 was
pursued, as depicted in Scheme 3. Tyramine was deuterated through its
reflux in a solution of NaOD in D2O (formed by diluting Na(0) in D2O,
see SI). The subsequent reductive amination and acylation afforded the
desired deuterium labeled compounds in 19 % and 17 % yields for D-1
and D-2, respectively.
In an attempt to obtain information on the structure of the other two
dimers detected, i. e. to differentiate between these isobaric dimers 11-
13, these two peaks observed on the HPLC-UV-ESI-TOF-MS were frag-
mented and their Ms/Ms fragmentogram were recorded. In these frag-
mentograms, the ion with m/z = 392.1827 Da was used as a diag-
+
nostic. This ion presents the molecular formula of C24H22D2NO4
theoretical = 3,921,825 Da and is compatible only with structure 11,
as depicted in Fig. 5. For a discussion and structure of the other ions
present in these fragmentograms see supporting information Figure
S58-S60. Concerning the structure of the third dimer, the data did not
allow the distinction between structures 12 an 13 in Fig. 6.
To confirm that the deuterium atoms were introduced at the desired
position, 2D NMR of the substrates were obtained, confirming the in-
corporation only at the ortho positions relative to the phenol (see figure
In relation to the trimers, three different were detected, where two
contains molecular mass two units higher and one three units higher
4

V.M. de Aguiar, et al.
MolecularCatalysis485(2020)110788
Scheme 3. Synthesis of D-1 and D-2.
then their non deuterated counterparts. These results demonstrate that
there is at least two carbon-carbon bond linked through the tyramine
moiety.
small selectivity favoring the CeC linked dimer. The case of entry 2 is
interesting once it presented high selectivity for the CeO linked dimer.
The same selectivity is also observed for the reaction with the deuter-
ated substrate.
Concerning the selectivity of the bond formed, in the case of sub-
strate 1 it is interesting that, with the exception of the reaction with
ABTS at pH 6.4, entry 2 and Table 1, all reaction conditions presented a
In the case of substrate 2, the determination of such selectivity is
difficult due the ambiguity in stablishing the reaction products, once
Fig. 4. The attributed structure for the dimers and trimers for the reaction of D-1 with the laccases of T.versicolor.
5

V.M. de Aguiar, et al.
MolecularCatalysis485(2020)110788
Fig. 5. Structure 10, 11 and 12 (or 13) of the dimers detected with two or three deuterium atoms.
Fig. 6. Fragmentogram of the ion m/z 572.2829 Da, and the proposed structure of the fragment ion with m/z 392.1827 Da, for the peak eluting at 19.5 min in Figure
S40.
6

V.M. de Aguiar, et al.
MolecularCatalysis485(2020)110788
Scheme 4. The proposed events for the dimerization of 1 and 2.
only the CeC and one C-Oe bonded products could be elucidated. Then
a selectivity toward this CeC linked product was calculated (Table 1),
and interestingly the selectivity for this CeC linked dimer is smaller at
pH 6.4 in the presence of ABTS, Table 1 entry 6, as analogous to sub-
strate 1. The different outcome of the Laccase catalyzed oxidation of
phenols concerning the bond formed is reported in the literature,
however rarely discussed [72–75]. Lahtinen and co-workers have re-
ported [72] an increase formation of CeO bond in the case of the di-
merization of vannilyl alcohol with increasing pH (7.0). However the
influence of the mediator in such selectivity remains to be elucidated.
The abovementioned results demonstrate that the laccases catalyzed
reaction of substrates 1 and 2 lead mainly to the dimers and trimers
once no other type of product could be detected. From the mechanistic
point of view, the data make it clear that the laccases catalyzed reaction
of phenols occurs through a one electron oxidation reaction even in the
presence of the mediator ABTS. The dimerization of the herein studied
phenolic compounds is believed to occur through a phenoxy radical-
radical coupling. as depicted in Scheme 4 [73] [74].
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
Acknowledgements
The authors acknowledge financial support and fellowships from
FAPERJ, CAPES, and CNPq.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.mcat.2020.110788.
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In conclusion, it was determined that the Laccases/ABTS and
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