Peroxygenase-Catalyzed Enantioselective Sulfoxidations

Article abstract of DOI:10.1002/ejoc.201701390

The performances of the unspecific peroxigenase from Agrocybe aegerita (AaeUPO) in the asymmetric sulfoxidation of substituted aryl alkyl sulfides were here investigated. A small library of differently substituted aryl alkyl sulfoxides was successfully synthesized from the corresponding sulfides in the presence of AaeUPO and H₂O₂. All the sulfoxides were obtained as (R)-enantiomers, regardless the substitution pattern both on the aromatic ring and the alkyl chain, in up to > 99 % conversion and > 99 % ee. An overview about the biocatalytic entries to chiral sulfoxides is also presented here in form of a comparison between the results obtained with AaeUPO and performances of the chloroperoxidase from Caldariomyces fumago, and three different Baeyer–Villiger monooxygenases. To the best our knowledge, this is the first example of a systematic investigation of the AaeUPO synthetic potential in the asymmetric oxidation of hetero atoms, i.e., the pro-stereogenic sulfur of sulfides.

Full text of DOI:10.1002/ejoc.201701390

A Journal of
Accepted Article
Title: Peroxygenase-catalyzed enantioselective sulfoxidations
Authors: Ivan Bassanini, Erica Elisa Ferrandi, Marta Vanoni, Gianluca
Ottolina, Sergio Riva, Michele Crotti, Elisabetta Brenna, and
Daniela Monti
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701390
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701390
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10.1002/ejoc.201701390
European Journal of Organic Chemistry
COMMUNICATION
Peroxygenase-catalyzed enantioselective sulfoxidations
Ivan Bassanini,[a,b] Erica Elisa Ferrandi,[a] Marta Vanoni,[a] Gianluca Ottolina,[a] Sergio Riva,[a] Michele
Crotti,[c] Elisabetta Brenna,[c] and Daniela Monti*[a]
Abstract: The performances of the unspecific peroxigenase from
Agrocybe aegerita (AaeUPO) in the asymmetric sulfoxidation of
substituted aryl alkyl sulfides were here investigated. A small library
of differently substituted aryl alkyl sulfoxides was successfully
synthesized from the corresponding sulfides in the presence of
AaeUPO and H2O2. All the sulfoxides were obtained as (R)-
enantiomers, regardless the substitution pattern both on the
aromatic ring and the alkyl chain, in up to >99% conversion and
>99% ee. An overview about the biocatalytic entries to chiral
sulfoxides is also presented here via a comparison between the
results obtained with AaeUPO and performances of the
chloroperoxidase from Caldariomyces fumago, and three different
Baeyer-Villiger monooxygenases. To the best our knowledge, this is
the first example of a systematic investigation of the AaeUPO
synthetic potential in the asymmetric oxidation of hetero atoms, i.e.
the pro-stereogenic sulfur of sulfides.
dependent monooxygenase activity resulting e.g., in the
hydroxylation of different alkane and aromatic compounds, in
alkene epoxidation and O- and N-dealkylation reactions.
The best characterized UPO (AaeUPO) has been identified
in 2004 from the edible mushroom Agrocybe aegerita[6] and its
structural and functional features have been largely investigated
in the last years.[5,7] Moreover, the practical application of
AaeUPO in useful synthetic biotransformations has been
recently implemented by developing improved systems for
enzyme production/optimization[8] and for the efficient set-up of
preparative-scale reactions.[9]
In recent reviews of the current state-of-the-art on
applications of peroxygenases,[3c,5] sulfoxidations are commonly
listed among the wide number of possible reactions catalyzed by
UPOs. However, to the best of our knowledge, only preliminary
information is available so far about the exploitation of UPOs,
including AaeUPO, in the (enantioselective) oxyfunctionalisation
of sulfides to sulfoxides.[10] Specifically, the enantioselective
oxidation of thioanisole (1, Scheme 1 and Table 1) to the
corresponding (R)-1a sulfoxide has been previously reported.[10a]
However, neither the conversion nor the enantiomeric excess
(ee) of the obtained product were shown in this conference
communication. The only other example has been reported a
couple of years later about the S-oxidation of the heterocyclic
compound dibenzothiophene by using both whole cells
basidiomycetes and purified UPOs.[10b] Although investigated to
a deeper extent, this reaction was not suitable to get information
about the enantioselectivity of AaeUPO given the symmetrical
nature of the substrate.
Chiral sulfoxides are valuable compounds that find several
applications as synthons in the preparation of biologically active
molecules as well as chiral auxiliaries in asymmetric synthesis.[1]
Among the different methods aimed at the efficient preparation
of optically pure sulfoxides, enzyme-catalyzed enantioselective
oxidation of prochiral sulfides has been widely investigated in
the last decades.[1a,c,2] In particular, the best results, in terms of
both enantioselectivity and conversions, have been obtained
with the chloroperoxidase (CPO) from Caldariomyces fumago,
[2a-b,3]
and different monooxygenases,[4] in particular Baeyer-
[2b,4a-e]
Villiger monooxygenases (BVMOs),
in the presence of
either H2O2 or O2 as oxidant, respectively.
Unspecific peroxygenases (UPOs, EC 1.11.2.1) represent
an emerging class of biocatalysts with a wide range of potential
applications in different oxyfunctionalization reactions.[3c,5] They
are extracellular heme-thiolate enzymes produced by several
fungi with no significant sequence homology to cytochrome
P450s and only distantly related to CPO (~ 30% sequence
similarity). Based on a catalytic mechanism resembling the
"peroxide shunt" pathway of P450s, they show a peroxide-
Scheme 1. UPO-catalyzed sulfoxidation of aryl alkyl sulfides 1-10 (see Table
1 for structure details).
[a]
Dr. I. Bassanini, Dr. E. E. Ferrandi, Dr. M. Vanoni, Dr. G. Ottolina,
Dr. S. Riva, Dr. D. Monti*
Istituto di Chimica del Riconoscimento Molecolare,
Consiglio Nazionale delle Ricerche
Via Mario Bianco 9, Milano, 20131, Italy.
E-mail: daniela.monti@icrm.cnr.it
Dr. I. Bassanini
Dipartimento di Chimica,
Università degli Studi di Milano,
Via Golgi 19, Milano, 20133, Italy.
Dr. M. Crotti, Prof. E. Brenna
Politecnico di Milano, Dipartimento di Chimica, Materiali, Ingegneria
Chimica,
The aim of this work was to assess the performances of
AaeUPO in the asymmetric synthesis of different chiral
sulfoxides, thus filling this gap in the knowledge of the
biocatalytic potential of the unspecific peroxygenases.
[b]
[c]
The ability of AaeUPO of catalyzing the sulfoxidation of the
model substrate
1 was further investigated by testing a
peroxygenase preparation easily obtained from the wild-type
Agrocybe aegerita TM-A1 (DSM 22459) strain[6] as described in
the literature (see Supporting information for details). In a first
set of reactions, the starting concentration of both the substrate
1 and the oxidant H2O2 were kept at 1 mM to avoid the well-
Via Mancinelli 7, Milano, 20131, Italy.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701390
European Journal of Organic Chemistry
COMMUNICATION
described peroxide-dependent inactivation of the enzyme.[5b,9c,11]
Reactions with AaeUPO were carried out at 20°C in citrate
phosphate buffer (10 mM, pH 7.0), in the presence of 20% (v/v)
CH3CN as cosolvent, and stopped at scheduled times by
extraction with ethyl acetate to analyze the obtained crude
mixtures by means of HPLC on a chiral column (see Supporting
Information for further details). Control reactions were performed
in the absence of the enzyme or the oxidant. Under these
reaction conditions, the (R)-sulfoxide 1a could be obtained after
20 min in quantitative yields and 80% ee (Table 1, Fig. S1 in
Supporting Information). AaeUPO showed a good operative
stability, retaining >90% of the starting activity for at least 2 h (as
assayed by spectrophotometric measurement of the activity with
2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) as
substrate). No formation of by-products, and in particular of the
corresponding over-oxidation sulfone product, was observed,
even when performing a control reaction with the racemic
mixture of 1a sulfoxides as substrates. The same result was
previously reported also for CPO-catalyzed sulfoxidations,[3]
while, differently from CPO, AaeUPO showed negligible activity
(<1% conversion) in the oxidation of 1 when using tert-butyl
hydroperoxide (t-BuOOH) as oxidant. However, this finding is
not surprising since the use of t-BuOOH as an alternative to
H2O2 showed to be challenging also in other oxyfunctionalization
reactions catalyzed by AaeUPO.[9a] Additionally, the apparent KM
(21 mM) and kcat (4.2  105 s-1) kinetic parameters, estimated by
interpolating with the Michealis-Menten equation the initial
reaction rate data obtained at fixed (1 mM) H2O2 concentration
and increasing concentration of 1 (1-50 mM, see Supporting
Information for details), look compatible with further practical
application of this biocatalyst by process development.
To confirm this, the concentration of 1 was increased to 10
mM (35 μmol in 3.5 mL final volume). As mentioned before, the
in situ H2O2 concentration is the critical point in the operative
stability of peroxygenases. Among the several options described
in the literature to face this issue,[3c,9c] we opted for a simple
step-wise addition of a concentrated H2O2 solution (35 μmol
added in 10 aliquots at 30 min intervals in the first 4.5 h, then the
reaction was maintained for additional 2.5 h without further
oxidant addition). The residual AaeUPO activity in the reaction
solution, conversion of substrate 1 and ee value of the formed
product were monitored at scheduled times.
As shown in Figure 1, the controlled supplementation of
H2O2 allowed to obtain a >95% conversion of 1 into 1a without
observing dramatic drops of enzyme activity during oxidant
addition (~60% residual activity after the first 5 h). In agreement
with previous studies,[11] the application of an optimized starting
substrate/H2O2/enzyme ratio allowed a minimization of the
catalase side-activity, which has been suggested as the main
responsible of UPOs inactivation. In fact, only one equivalent of
oxidant was required to obtain an almost complete conversion of
the target substrate, thus suggesting the lack of significant H2O2
time. The scalability of AaeUPO-catalyzed sulfoxidations was
further demonstrated in the semi-preparative scale synthesis of
1a performed on 0.2 mmol of substrate 1 (see Supporting
Information for further details).
Figure 1. Sulfoxidation of 1 (10 mM) catalyzed by Agrocybe aegerita UPO in
the presence of H2O2 as oxidant. Green bars, residual UPO activity; red line,
conversion of 1 into 1a.
In addition to thioanisole 1, the versatility of AaeUPO in
promoting enantioselective sulfoxidations was further studied by
testing a panel of differently substituted aryl alkyl sulfides (2-10,
Table 1). The obtained conversions and ee values of sulfoxide
products were compared with those available in the literature for
CPO and three different BVMOs (CHMO, PAMO and HAPMO)
for the biooxidation of the same compounds.
In general, AaeUPO converted the tested aryl alkyl sulfides
into the corresponding sulfoxides with good conversions, with
the exception of the o-substituted substrate 2 (35%) and the p-
cyanophenyl methyl sulfide 6 (<5%). The formation of the (R)
enantiomer of the sulfoxide products was always observed (the
(S) product was obtained only in the case of 10a due to a
change in the CIP priority rules) with good to excellent
enantioselectivity (70->99% ee).
Electron donating groups in the para position of the aromatic
ring seemed to be well tolerated (entry 4, 5 and 7), as well as
substitution on the meta carbon atom (entry 3), while the
presence of an electron withdrawing substituent in para
dramatically affected the biocatalytic oxidation (entry 6). The
best results in terms of enantiomeric excess were obtained
when a substituent was introduced on the R-group: the vinyl
thioanisole 8, as well as the cyclopropyl derivative 9, were
converted into the corresponding (R)-sulfoxides with >99% ee.
However, a decrease of both conversion and ee value was
observed with compound 10. This fact could be possibly
ascribed to the presence of a flexible CH2-OMe R substituent
allowing a higher conformational freedom and more than one
energetically equivalent conformations during the binding with
consumption by dismutation to O2 and H2O.
A possible
protective effect of the substrate toward peroxide-induced
inactivation, previously investigated by Karich and coauthors for
UPO-catalyzed hydroxylation reactions,[11] was suggested also
in this case by the superior operative stability shown by AaeUPO
at low (<50%) conversion degrees. The ee value of the formed
(R)-sulfoxide 1a was unaltered (80%) during the whole reaction
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10.1002/ejoc.201701390
European Journal of Organic Chemistry
COMMUNICATION
the active site, or, alternatively, to the presence of a coordinating
oxygen atom on the R substituent.
compound 4. The strict (S)-selectivity previously shown by
HAPMO is herein well complemented by the preference toward
the formation of the (R)-sulfoxides demonstrated by AaeUPO,
thus enabling a fully biocatalytic access to both the enantiomers
of sulfoxides 1a-10a. However, while different BVMOs have
been successfully used to produce chiral sulfoxides by kinetic
resolutions of racemic sulfoxides,[4] this was not true for
AaeUPO as we have shown that this peroxygenase catalyzes
the asymmetric S-oxidation of sulfides, but do not accept
sulfoxides as substrates.
Interestingly, during the biocatalytic sulfoxidation of 8 only
the (R) enantiomer of sulfoxide 8a was recovered, suggesting a
faster kinetic for the sulfoxidation in comparison with olefin
epoxidation, another example of UPO-catalyzed reactions
largely reported in the literature.[3c,5]
Coming to the comparison with other biocatalyzed
sulfoxidations, it is not surprising to observe pretty similar results
in terms of conversions and enantioselectivity with CPO, as it is,
as mentioned before, an enzyme structurally related to UPOs.
With the exception of 5, AaeUPO usually achieved better
conversions, but slight lower ee values than CPO, the
stereoselectivity being in both cases toward the formation of the
(R) enantiomer.
As far as BMVOs concern, only few data are available about
our panel of substrates for the enzymes from Acinetobacter
calcoaceticus (CHMO)[4a] and Thermobifida fusca (PAMO),[4c] in
most cases showing less impressive performances than UPO
(and CPO), both in terms of conversion and enantiomeric
excesses. Instead, a full set of data was reported on the
asymmetric sulfoxidation of 1-10 catalyzed by the HAPMO
enzyme from Pseudomonas fluorescens.[4d] Interestingly,
satisfactory results were obtained with HAPMO in most cases,
the formation of the (S)-enantiomers of sulfoxides 1a-10a being
achieved with good conversion (except for substrates 3 and 4)
and very good enantiomeric excesses, with the only exception of
In conclusion, a small library of differently substituted aryl
alkyl sulfoxides was successfully synthesized from the
corresponding sulfides in the presence of AaeUPO and H2O2
with up to >99% ee and conversion. All the obtained sulfoxides
were (R)-enantiomers, regardless the substitution pattern both
on the aromatic ring and the alkyl chain. As previously shown for
other oxyfunctionalization reactions, the preparative exploitation
of AaeUPO (and likely also of other UPOs) in asymmetric
sulfoxidations requires a very careful control of the in situ
concentration of the oxidant H2O2 to avoid enzyme inactivation.
However, both the lack of over-oxidation side-activities and the
stereocomplementarity with other biocatalysts suggest that
UPOs may have a good potential as useful tools in the
obtainment of chiral sulfoxides.
Table 1. Comparison of UPO-catalyzed sulfoxidations with literature data for CPO and the Baeyer-Villiger monooxygenases CHMO, PAMO, and HAPMO.
Substrate
R
R'
UPO[a]
CPO[b]
CHMO[c]
PAMO[d]
HAPMO[e]
c [%][f]
ee [%][f]
c [%]
ee [%]
c [%]
ee [%]
c [%]
ee [%]
c [%]
ee [%]
1
2
3
4
5
6
7
8
9
10
CH3
H
>99
35
80 (R)
74 (R)
90 (R)
93 (R)
90 (R)
n.d.[h]
>99
33
98 (R)
85 (R)
n.a.
88
99 (R)
32 (R)
n.a.
94
44 (R)
n.a.
96
76
42
37
77
64
78
78
74
63
99 (S)
96 (S)
93 (S)
44 (S)
99 (S)
96 (S)
99 (S)
98 (S)
97 (S)
98 (R)[i]
CH3
o-Cl
m-Cl
p-Cl
p-CH3
p-CN
p-OCH3
H
35
n.a.[g]
n.a.
n.a.
68
CH3
>99
>99
83
n.a.
77
n.a.
78
n.a.
CH3
90 (R)
91 (R)
n.a.
51 (S)
37 (S)
n.a.
n.a.
CH3
98
94
10 (R)
n.a.
CH3
<5
n.a.
72
n.a.
81
n.a.
47
CH3
87
70 (R)
>99 (R)
>99 (R)
81 (S)[i]
90 (R)
n.a.
51 (S)
n.a.
25 (R)
n.a.
CH=CH2
C3H5
CH2OCH3
85
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
67
H
95
n.a.
n.a.
48 (R)
n.a.
H
50
n.a.
n.a.
n.a.
[a] substrate, 1 mM; H2O2, 1 mM, UPO, 0.15 U mL-1, 0.166 M ; 10 mM citrate phosphate buffer, pH 7.0, 2% (v/v) CH3CN; 20°C; 20 min. [b] substrate, 9 mM; H2O2,
2 eq. (added portionwise in 13 aliquots), CPO, 0.144 μM; 50 mM citrate buffer, pH 5.0; 25°C; 1 h. [3b] [c] substrate, 40 mM; NADP+, 0.15 mM; glucose-6-phosphate
(G6P), 0.1 M; CHMO, 0.3 U mL-1; glucose-6-phosphate dehydrogenase (G6PDH), 2.5 U mL-1; 50 mM Tris/HCl buffer, pH 8.6; 25°C; 24 h. [4a] [d] substrate, 20 mM;
NADP+, 0.02 mM; G6P, 2 eq.; PAMO, 1 U mL-1; G6PDH, 10 U mL-1; 50 mM Tris/HCl buffer, pH 9.0; 25°C; 24 h. [4c] [e] substrate, 20 mM; NADP+, 0.02 mM; G6P,
1.5 eq.; HAPMO, 1 U mL-1; G6PDH, 10 U mL-1; 50 mM Tris/HCl buffer, pH 9.0; 25°C; 24 h. [4d] [f] Conversions and enantiomeric excesses calculated on the basis
of chiral HPLC analysis (see Supporting Information for details). [g] n.a.: not available from literature data. [h] n.d.: not determined. [i] Absolute configuration is
reversed due to a change in the substituent priority according to the sequence rules.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701390
European Journal of Organic Chemistry
COMMUNICATION
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Experimental Section
Agrocybe aegerita strain TM-A1 (DSM 22459) was grown in 2 L-shaken
flasks containing 0.5 L of 30 g L-1 soybean peptone. The culture was
maintained at 25°C and monitored daily for accumulation of UPO activity,
as well as of possible contaminant laccase activities, in the culture
medium. After 14-15 days, the mycelium was filtrated and the UPO was
recovered from the culture medium by ammonium sulfate precipitation.
Detailed methods are reported in the Supporting Information. The
analytical scale biooxidation of aryl alkyl sulfides was performed by
adding each substrate (1 mmol) to a 20% solution of CH3CN in citrate
phosphate buffer (10 mM, pH 7.0, 1 mL final volume) containing H2O2 (1
eq, 1 mM) and UPO (0.15 U mL-1, 0.166 M). Extraction with AcOEt
allowed the recovery of the desired oxidized product to be analysed by
HPLC on chiral column. The absolute configurations of the obtained
products were determined by comparing the tR reported in literature for
the (R) and (S) enantiomers of compounds 1a-10a in the same analytic
conditions. Suitable racemic mixtures of sulfoxides to be used as NMR
and HPLC standards were prepared by chemical sulfoxidations by
adding dropwise mCPBA (1.2 eq, 0.5 M in CHCl3) to a CHCl3 solution of
the desired aryl alkyl sulfide at 0°C (substrates 1-10, 1 eq, 50 mM, 2 mL
final volume). After stirring the mixture for 30-60 min, racemic sulfoxides
1a-10a were obtained by extraction with AcOEt, drying over sodium
sulfate and in vacuum concentration. Product were obtained in good
isolated yields (70-90%) and characterized by 1H NMR and HPLC
analysis on chiral column.
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This work was supported by Fondazione Cariplo, grant n. 2014-
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Keywords: unspecific peroxigenase •enantioselectivity • chiral
sulfoxides • biocatalysis • asymmetric oxidation
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10.1002/ejoc.201701390
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
The biocatalytic enantioselective
oxidation of prochiral sulfides in the
presence of a fungal unspecific
peroxygenase from Agrocybe
aegerita and hydrogen peroxide as
oxidant was investigated. The
synthesis of differently substituted
(R)-aryl alkyl sulfoxides was
achieved with up to >99% conversion
and >99% ee.
Ivan Bassanini, Erica E. Ferrandi,
Marta Vanoni, Gianluca Ottolina,
Sergio Riva, Michele Crotti Elisabetta
Brenna, Daniela Monti*
Page No. – Page No.
Peroxygenase-catalyzed
enantioselective sulfoxidations
This article is protected by copyright. All rights reserved.