Laccase-catalysed biotransformation of collismycin derivatives. A novel enzymatic approach for the cleavage of oximes

Article abstract of DOI:10.1039/c5gc02220g

Analogues of the natural product collismycin bearing a carboxylic acid moiety has been efficiently synthesised from several collismycin precursors through a laccase-catalysed oxidation under mild conditions with TEMPO (2,2,6,6-tetramethylpiperidin-1-oxyl) as a mediator and aerial O₂ as an oxidant in aqueous medium. The biotransformations proceeded with excellent yields (85-95%) and involved, depending on the precursor, the oxidation of a benzylic hydroxyl group or the bioconversion of an aldoxime group into carboxylic acid. Since the latter is herein reported for the first time, we explored the potential of this novel oxime cleavage with several synthetic aldo- and ketoximes. Thus, the laccase/TEMPO system proved to be an efficient and green alternative for the deprotection of both aromatic and aliphatic ketoximes into the corresponding ketones. On the other hand, the reaction with aldoximes leads to dimeric species generated by coupling reactions.

Full text of DOI:10.1039/c5gc02220g

View Article Online
View Journal
Green
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: J. González-
Sabín, N. Ríos Lombardía, I. Garcia, N. M. Vior, A. F. Brana, C. Mendez, J. A. Salas and F. Moris, Green
Chem., 2015, DOI: 10.1039/C5GC02220G.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/greenchem

Green Chemistry
Page 1 of 7Journal Name
Dynamic Article Links ►
View Article Online
DOI: 10.1039/C5GC02220G
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
ARTICLE TYPE
Laccase-catalysed biotransformation of collismycin derivatives. A novel
enzymatic approach for the cleavage of oximes†
Javier González-Sabín,a,* Nicolás Ríos-Lombardía,a Ignacio García,b Natalia M. Vior,b Alfredo F. Braña,b
Carmen Méndez,b José A. Salasb and Francisco Morísa,*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
neuroprotective activity against oxidative stress in a zebra fish
model.8
Analogues of the natural product collismycin bearing a
carboxylic acid moiety has been efficiently synthesised from
several collismycin precursors through a laccase-catalysed
10 oxidation under mild conditions with TEMPO (2,2,6,6-
tetramethylpiperidin-1-oxyl) as mediator and aerial O2 as
oxidant in aqueous medium. The biotransformations
proceeded with excellent yields (85-95%) and involved,
depending on the precursor, the oxidation of a benzylic
15 hydroxyl group or the bioconversion of an aldoxime group
into a carboxylic acid. Since the latter is herein reported for
the first time, we explored the potential of this novel oxime
cleavage with several synthetic aldo- and ketoximes. Thus, the
laccase/TEMPO system proved to be an efficient and green
20 alternative for the deprotection of both aromatic and
aliphatic ketoximes into the corresponding ketones. On the
other hand, the reaction with aldoximes leads to dimeric
species generated by coupling reactions.
50
Figure 1 Chemical structure of collismycin A (1a).
55
Laccases are copperꢀcontaining enzymes belonging to the
group of oxidoreductases. In nature, laccases are involved in
biological processes such as lignification in plants or lignin
degradation in fungi, and catalyse oxidation of substrates such as
60 phenols, polyphenols and anilines by means of fourꢀelectron
transfer processes while reducing O2 to water.9 Typically, these
molecules are preliminary oxidised to reactive radical
intermediates which can undergo coupling to provide complex
mixtures of dimeric, oligomeric or polymeric derivatives, or can
65 be further oxidised. At first, applications of laccases were aimed
at the field of bioremediation and pulp/textile bleaching due to
their ability to degrade many recalcitrant pollutants in soil and
water. However, recent improvements in protein engineering
enable today easy access to these enzymes, which have moved
70 from mere antiꢀpollutant reagents to smart biocatalysts for
biooxidation processes. Thus, the employment of chemical
(natural or artificial) mediators has allowed to oxidise not only
phenolic compounds but also benzylic, aliphatic, allylic or
propargylic alcohols, and the radical species triggered in these
75 processes can led to very complex molecules via tricky
cyclisation or coupling reactions.10 Additionally, the laccaseꢀ
mediated biooxidations proceed in water, demand O2 as oxidant
and generate only water as byꢀproduct, which perfectly fits the
present requirements of the chemical industry in its quest for ecoꢀ
80 friendly processes. Taking in mind these considerations and our
ongoing interest in the discovery of novel collismycins, we wish
to report herein our findings regarding the laccaseꢀmediated
biooxidation of 1a and some analogues. Moreover, a novel
enzymatic protocol for the deprotection of both aromatic and
85 aliphatic ketoximes under mild reaction conditions is also
reported.
Introduction
25
The group of the 2,2´ꢀbipyridylꢀcontaining natural products is
constituted by compounds sharing a bipyridine ring system which
is further modified with some tailoring modifications. Members
of this family include SF2738AꢀF,1 pyrisulfoxins,2
30 caerulomycins3 and collismycins.4 Particularly, the latter were
isolated for the first time by Gomi et al. from Streptomyces
species. The biological activities displayed by this family of
compounds comprise antibacterial, antifungal and cytotoxic
activities3ꢀ5 and collismycin A (1a, Figure 1) is also an inhibitor
35 of dexamethasoneꢀglucocorticoid receptor binding and therefore a
potential antiꢀinflammatory agent.3 Structurally, collismycin
derivatives belong to the hybrid polyketidesꢀnonribosomal
peptides. Recently, the isolation and characterisation of the gene
cluster of 1a has been described,6 enabling the expansion of the
40 chemical space of this natural product by genetic engineering.
Thus, insertional inactivation allowed the isolation of seven novel
analogues modified in the second ring of collismycin7 whereas a
mutasynthesis approach led to two more analogues modified in
the first pyridine ring.8 Although the cytotoxicity of the parental
45 1a was not improved, some of them exhibited enhanced
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

Green Chemistry
Page 2 of 7
View Article Online
DOI: 10.1039/C5GC02220G
to improve isolation, the biotransformations were performed in
water to avoid salts in the reaction medium. All oxidations
proceeded well and the products were isolated in excellent
60 isolated yield without chromatographic purification (see
Experimental Section).
Results and Discussion
Laccase-catalysed oxidation of collismycins 1a-6a
From the plethora of reported analogues, a panel of six
collysmicins was selected,7,8 the parental 1a and the compounds
2aꢀ6a (Figure 2), attending to criteria such as its neuroprotectant
activity and the diversity of the functional groups present. In fact,
laccases have provided to effectively oxidise hydroxyl groups in
benzylic positions, like those contained in 4aꢀ6a, to aldehydes
5
Table 1 Laccaseꢀcatalysed oxidation of collismycins 1aꢀ6a in the
a
presence of TEMPO and aerial O2
10 and carboxylic acids.11 Moreover, there are some examples of
laccaseꢀcatalysed biotransformations involving pyridylic
compounds through oxidative or coupling reactions.12
15
Entry
1
Substrate
t (h)
Conv./Yieldb
100 / 85
Product
1a
24
20
2
3
2a
3a
24
24
100 / 90
100 / 88
25 Figure 2 Collismycin derivatives selected for the laccaseꢀcatalysed
biooxidation.
The screening biotransformation conditions were attempted
with the most commonly used laccase/mediator system, that is,
laccase from Trametes versicolor and TEMPO (Table 1). First,
30 the reaction with 1a was conducted at room temperature, in
citrate buffer (pH 5.0), in an open vessel under vigorous stirring.
Monitoring by reversedꢀphase HPLC showed 1a totally converted
after 24 h into a single new compound (1b). Additionally, control
experiments performed respectively in the absence of laccase or
35 mediator revealed that the biotransformation could not proceed
without the presence of both components. MS analysis of 1b
showed a molecular weight of 276 versus 275 mass units for
collismycin A. Once isolated, the structure of 1b was
unambiguously identified by NMR spectroscopy as 4ꢀmethoxyꢀ5ꢀ
40 (methylthio)ꢀ[2,2'ꢀbipyridine]ꢀ6ꢀcarboxylic acid. This compound,
which was previously reported by us and named collismycin C,7
differs from 1a in the presence of a carboxylic group instead of
the aldoxime group. Similarly, the aldoximeꢀbased derivatives 2a
and 3a led to the corresponding carboxylic acids 2b and 3b in
45 excellent yields and purity. Regarding collismycins 4aꢀ6a bearing
4
5
4a
5a
12
12
100 / 95
100/ 90
6
6a
12
100/ 95
a
Reaction conditions: 1a-6a (0.04 mmol), laccase (1.84 U), TEMPO (15% mol),
water (1 mL) and acetonitrile (100 µL), stirring in an open vessel at rt. b Conversion
measured by HPLC. Isolated yields after lyophilisation.
65
a
benzylic alcohol, we performed the biotransformation
foreseeing in this case the oxidation of the hydroxyl group. This
was indeed the result, and the corresponding carboxylic acid
derivative was the only isolated product in each case. It is also
50 noteworthy that despite monitoring the process (MSꢀHPLC) at
short reaction time, only traces of the expected aldehydeꢀ
intermediate were detected, which suggests fast kinetics of the
full bioconversion. Also interestingly, although the collysmicin
derivatives 1aꢀ6a were very soluble in slightly acid solutions like
55 the citrate buffer used herein (pH 5.0), the presence of acid and
basic groups in 1b-3b made challenging their isolation. In order
Mechanism insights
Conventional chemical transformations of oximes (aldoximes
and ketoximes) comprise hydrolyses catalysed by inorganic salts
to yield aldehydes or ketones,13 reductions with metals or
70 hydrides to produce amines14 and the Beckmann rearrangement
into amides,15 which can be subsequently transformed into acids
by hydrolysis under harsh conditions. Regarding enzymatic
processes, oximes are often found in several metabolic pathways,
being converted by the action of enzymes. Thus, there have been
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 3 of 7
Green Chemistry
View Article Online
DOI: 10.1039/C5GC02220G
characterised aldoxime dehydratases able to produce nitriles from
complete conversion in just 2 h. However, the process was not as
the corresponding aldoximes.16 Moreover, Kroutil and coꢀ 60 clean as the TEMPOꢀmediated biotransformation and several byꢀ
workers17 reported
a
promiscuous activity of alcohol
products proved detrimental for the yield. Next, we prepared a set
of aldoximes and ketoximes starting from the corresponding
carbonyl compounds. While in the first case the oxidative bioꢀ
deoximation would led to acid derivatives, in the second a ketone
dehydrogenases which reduces aldoximes to alcohols through an
initial reduction to the unstable imine (which hydrolyses
spontaneously) and a second reduction of the resulting aldehyde.
5
The unexpected biocatalytic activity ─namely the conversion of 65 would be obtained.
an aldoxime into a carboxylic acid occurred in entries 1ꢀ3 (Table
Table 2 Laccaseꢀcatalysed bioꢀdeoximation of 7 in the presence of
TEMPO and aerial O2
1)─ would imply two steps: i) oxime disproportionation into the
a
10 corresponding aldehyde and hydroxylamine; ii) oxidation of the
triggered aldehyde to carboxylic acid (Scheme 1). The initial
aldoxime hydrolysis has been previously assumed in
biotransformations involving baker’s yeast and whole cell
biocatalysts18 and was supported by the detection of the aldehyde
15 by HPLC/MS in selected experiments.19 So far in the literature
there are four main pathways for the deoximation, including
hydrolytic, reductive, oxidative pathways as well as
transoximation. In general, the oxidative and reductive pathways
only need weak acid conditions, since oximes are reduced or
20 oxidised to form unstable intermediates which are much more
susceptible to hydrolysis than oximes themselves. Herein, our
enzymatic system gives an oxidative environment under mild
acid conditions which could transform the oxime into a more
readily hydrolysable species. Likewise, deconvolution
25 experiments demonstrated that both enzyme and mediator must
be present for the reaction to happen. Although the role of
TEMPO cannot be ensured at this point, we postulate that it
transforms the oxime into a radical compound which, after some
evolution, can be easily hydrolysed.20 In Scheme 1 is formally
30 depicted the loss of hydroxylamine although another species
could be released. Then, the oxidation of the resulting aldehyde to
render the carboxylic acid would be easily accomplished by the
oxidizing system as in literature reports.10,11,21 In the case of
derivatives 4aꢀ6a, the benzylic hydroxyl group is particularly
35 activated and prone to undergo oxidation to acid through the
reactive aldehyde intermediate. Accordingly, the oxidative bioꢀ
deoximation presented herein to convert oximes into acids could
be a green alternative to the conventional chemical processes and
also expands the biocatalysis toolbox for chemists.
Entry
Laccase
Mediator
TEMPO
TEMPO
TEMPO
TEMPO
ABTS
t (h)
14
24
24
24
2
c (%)b
100
ꢀꢀꢀ
1
2
3
4
5
6
7
8
T. versicolor
R. vernicifera
A. bisporus
ꢀꢀꢀ
C. versicolor
T. versicolor
T. versicolor
T. versicolor
T. versicolor
100
100
60
HOBT
24
24
24
NHPI
25
AZADO
80
a Reaction conditions: 7 (0.04 mmol), laccase (2 mg; 1.84 U for T. versicolor, 100
U for R. vermicifera, 8 U for A. bisporus, 0.6 U for C. versicolor), mediator (15%
mol), citrate buffer 50 mM pH 5.0 (1 mL) and acetonitrile (100 µL), stirring in an
open vessel at rt. b Conversion measured by HPLC.
First, ketoximes from acetophenone (7), 1ꢀphenylbutanꢀ2ꢀone
(8) and benzophenone (9) were chosen to cover examples with
70 the oxime moiety in both benzylic and nonꢀbenzylic positions as
well as a sterically hindered substrate. As can be seen in Table 3,
deoximation of ketoximes with the laccaseꢀTEMPO system
(entries 1ꢀ3) took place efficiently and the corresponding ketones
were isolated in excellent yields (>90%). Furthermore, the
75 reaction rate decreased in the following order: 9 > 7 > 8,
presumably caused by the activation of the benzylic positions. In
contrast to the previous biotransformations with 1aꢀ6a, reactions
exhibited herein certain turbidity despite using 10% of
acetonitrile. However, this percentage of cosolvent enabled a
80 partial solution of the starting products, without inactivation of
the laccase, and led to excellent conversions. Regarding
aldoximes, we selected those coming from benzaldehyde (10),
pyridineꢀ2ꢀcarboxaldehyde (11) and 2ꢀphenylpropanal (12).
However, in this occasion the expected acids were not formed as
85 in the case of the collismycin derivatives. Instead, mainly we
detected by HPLC/MS far more apolar compounds, which are
attributable to dimeric species. Actually, this kind of reaction
products is very common since laccaseꢀmediated systems
typically generate radicals, which are subsequently involved in
90 either oxidative coupling (i.e., bond formation) or bond cleavage.
Further efforts to promote the oxidative deoximation against the
coupling reaction consisted of experiments performed with a 10ꢀ
and 100ꢀfold dilution, but were unsuccessful in both cases.
Finally, by changing the mediator to ABTS (Table 3, entries 4ꢀ6),
95 the target acids 16ꢀ18 were obtained although in very low yields
40 Laccase-catalysed cleavage of aldoximes and ketoximes
The previous findings with collismycins bearing an oxime
moiety (1a-3a) prompted us to study the scope of this
unprecedented enzymatic transformation. First, the laccaseꢀ
catalysed biotransformation of acetophenone oxime (7) was taken
45 as a benchmark reaction and the catalytic activity of several
laccases explored in the presence of TEMPO as mediator (Table
2, entries 1ꢀ4). Thus, it was found that the bioꢀdeoximation
happened exclusively with laccases from Trametes versicolor and
Coriolus versicolor (entries 1 and 4, respectively), the reaction
50 being slightly faster in the first case. Specifically, complete
conversion was reached after 14 h with Trametes versicolor
laccase in citrate buffer 50 mM at pH 5.0 and rt. Once identified
the optimal laccase, the reaction was also tested in presence of
mediators
such
as
Nꢀhydroxyphthalimide
(NHPI),
55 hydroxybenzotriazole (HOBT), 2ꢀazaadamantane Nꢀoxyl
(AZADO) or 2,2’ꢀazinoꢀbis(3ꢀethylbenzothiazolineꢀ6ꢀsulphonic
(ABTS). Although the first three showed incomplete reaction
after 24 h, ABTS turned out to be particular effective and reached
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

Green Chemistry
Page 4 of 7
View Article Online
DOI: 10.1039/C5GC02220G
due to byꢀproducts. This evidence, taken together with the
reaction described above for collismycin, supports the hypothesis
that the 2,2’ꢀbipyridyl moiety in collismycin stabilizes the
Although most of these methods work well, they suffer from
several drawbacks: for example, use of toxic and hazardous
transition metal oxidants such as Mn,24 Cr,25 Ti,26 Th,27 Hg,28 and
intermediate radical, avoiding thus the coupling reaction and 20 problems associated with waste disposal, use of strong Lewis29
5
enabling the attack of a water molecule to render, after reꢀ
oxidation, a carboxylic acid.
Although the chemical scope of laccases for synthetic purposes
has been significantly broaden in recent years, it is worth noting
and Bronsted acids,30 moderate yields and difficulties in the
downstream and isolation of products.31 Additionally, other
strategies involve microwave irradiation and photosensitization25
or drastic conditions of pressure and temperature.32 Our
that most applications are aimed to oxidative processes. In fact, 25 methodology fits some of the key requirements to be considered
10 there are only two examples of laccases involved in the cleavage
of protecting groups, namely the pꢀmethoxyphenyl and the benzyl
group, both in amines.22,23 Hence, the enzymatic cleavage of
ketoximes disclosed herein represents a new contribution to
biocatalytic deprotecting strategies.
as a catalytic green chemical process.33,34 Thus, the absence of
tedious intermediate downstream and purification steps improves
the ecological footprint and the efficiency of the process.35,36
Additionally, to deliver truly greener processes the use of a safe,
30 nonꢀtoxic, biorenewable and cheap solvent such as water is
highly desirable.37
15 The number of reported methodologies to regenerate carbonyl
compounds from the corresponding oximes is impressive.
35
40
Scheme 1. Pathways for the laccaseꢀcatalysed biotransformation of collismycins.
a
Table 3 Laccaseꢀcatalysed biotransformation of ketoximes and aldoximes in the presence of TEMPO or ABTS and aerial O2
Entry
1
Substrateb
t (h)
Conv./Yield
100 / 95
Product
Entry
4
Substrateb
t (h)
Conv./Yield
Product
14
12
100 / 20c
100 / 25c
2
30
100 / 92
5
12
4
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 5 of 7
Green Chemistry
View Article Online
DOI: 10.1039/C5GC02220G
3
10
100 / >95
6
12
100 / 20c
a Reaction conditions: 7-12 (0.5 mmol), laccase (16.6 U), TEMPO or ABTS (10% mol), citrate buffer 50 mM pH 5.0 (10 mL) and acetonitrile (1 mL), stirring in an
open vessel at rt. b Z/E mixtures of different ratio depending on the substrate. c Yieldꢀdrop due to the formation of dimeric species and byꢀproducts.
10 a) S. Riva, Trends Biotechnol. 2006, 24, 219ꢀ226; b) S. Witayakran,
A. J. Ragauskas, Adv. Synth. Catal. 2009, 351, 1187ꢀ1209; c) M.
Mogharabi, M. A. Faramarzi, Adv. Synth. Catal. 2014, 356, 897ꢀ927.
55 11 F. Hong, L. J. Jönsson, K. Lundquist, Y. Wei, Appl. Biochem.
Biotechnol. 2006, 129-132, 303ꢀ319.
12 A. Wells, M. Teria, T. Eve, Biochem. Soc. Trans. 2006, 34, 304ꢀ308.
13 Science of Synthesis: Houben-Weyl Methods of Molecular
Transformations Vol. 26: Ketones, Georg Thieme Verlag, 2014.
60 14 F. George, B. Saunders (1960). Practical Organic Chemistry, 4th Ed.
London: Longman. P. 93 & 226.
15 a) C. L. Allen, R. Lawrence, L. Emmett, J. M. J. Williams, Adv.
Synth. Catal. 2011, 353, 3262ꢀ3268; b) P. Crochet, V. Cadierno,
Chem. Commun. 2015, 51, 2495ꢀ2505.
Conclusion
To summarise, an unprecedented and ecoꢀfriendly method for the
deprotection of ketoximes with laccase as catalyst, TEMPO as
mediator and aerial O2 as the oxidant has been developed. Their
simplicity, mildness and efficiency turn this enzymatic approach
into a valuable alternative to the existing methods. On the other
hand, although the oxidative system suffered from low yields
10 when applied to aldoximes, the presence of an intramolecular
stabilising motiff, in this case the 2,2´ꢀbipiridyl unit found in
collismycin, makes possible the efficient conversion into the
corresponding carboxylic acid.
5
65 16 a) K. Oinuma, Y. Hashimoto, K. Konishi, M. Goda, T. Noguchi, H.
Higashibata, M. Kobayashi, J. Biol. Chem. 2003, 278, 29600ꢀ29608;
b) J. Nomura, H. Hashimoto, T. Ohta, Y. Hashimoto, K. Wada, Y.
Naruta, K. Oinuma, M. Kobayashi, Proc. Natl. Acad. Sci. USA 2013,
110, 2810ꢀ2815.
Acknowledgements
70 17 B. FerreiraꢀSilva, I. Lavandera, A. Kern, K. Faber, W. Kroutil,
Tetrahedron 2010, 66, 3410ꢀ3414.
18 a) O. Kreutz, P. J. S. Moran, J. A. R. Rodrigues, Tetrahedron:
Asymmetry 1997, 8, 2649ꢀ2653; b) H. Korbekandi, P. Mather, J.
Gardiner, G. Stephens, Enzyme Microb. Technol. 2008, 42, 308ꢀ314.
75 19 See Supporting Information (section 3.6).
20 X. Zhu, Y.ꢀF. Wang, W. Ren, F.ꢀL. Zhang, S. Chiba, Org. Lett. 2013,
15, 3214ꢀ3217.
21 For a study about the mechanism of the laccaseꢀcatalysed oxidation
of alcohols, see: S. A. Tromp, I. Matijosyte, R. A. Sheldon, I. W.C.
15 The authors would like to thank Iván Lavandera for assistance
with the EATOS tool and helpful discussions.
Notes and references
a
EntreChem SL, Edificio Científico Tecnológico, Campus El Cristo,
33006 Oviedo, Spain. E-mail: fmv@entrechem.com
b
20
Departamento de Biología Funcional e Instituto Universitario de
Oncología del Principado de Asturias (I.U.O.P.A), Universidad de
Oviedo, 33006 Oviedo, Spain
80
E. Arends, G. Mul, M. T. Kreutzer, J.A. Moulijn, S. de Vries,
ChemCatChem 2010, 2, 827ꢀ833.
† Electronic Supplementary Information (ESI) available: Experimental
procedures, substrate characterization, Eꢀfactor calculation, analytical
25 data and NMR spectra.
22 J. M. M. Verkade, L. J. C. van Hemert, P. J. L. M. Quaedflieg, H. E.
Schoemaker, M. Schürmann, F. L. van Delft, F. P. J. Rutjes, Adv.
Synth. Catal. 2007, 349, 1332ꢀ1336.
85 23 L. MartínezꢀMontero, A. DíazꢀRodríguez, V. Gotor, V. Gotorꢀ
Fernández, I. Lavandera, Green Chem. 2015, 17, 2794ꢀ2798.
24 G. H. Imanzadeh, A. R. Hajipour, S. E. Mallakpour, Synth. Commun.
2003, 33, 735ꢀ740.
1
2
3
S. Gomi, S. Amano, E. Sato, S. Miyadoh, Y. Kodama, J. Antibiot.
(Tokyo) 1994, 47, 1385ꢀ1394.
N. Tsuge, K. Furihata, K. ShinꢀYa, Y. Hayakawa, H. Seto, J.
Antibiot. (Tokyo) 1999, 52, 505ꢀ507.
a) A. Funk, P. V. Divekar, Can. J. Microbiol. 1959, 5, 317ꢀ321; b) A.
McInnes, D. Smith, J. Wright, L. Vining, Can. J. Chem. 1977, 55,
4159ꢀ4165; c) A. McInnes, D. Smith, J. Walter, J. Wright, L. Vining,
G. Arsenault, Can. J. Chem. 1978, 56, 1836ꢀ1842.
30
35
40
45
50
25 S. Sahu, S. Sahu, S. Patel, S. Dash, B. K. Mishra, Indian J. Chem.
90
2008, 47B, 259ꢀ271.
26 G. H. Timms, E. Wildsmith, Tetrahedron Lett. 1971, 195ꢀ198.
27 A. McKillop, J. D. Hunt, R. D. Naylor, E. C. Taylor, J. Am. Chem.
Soc. 1971, 93, 4918ꢀ4919.
28 S. K. De, Synth. Commun. 2004, 34, 2289ꢀ2294.
95 29 M. P. Doyle, M. A. Zaleta, J. E. Deboer, W. Wierenga, J. Org. Chem.
1973, 38, 1663ꢀ1667.
30 E. J. Corey, P. B. Hopkins, S. Kim, S. Yoo, K. P. Nambiar, J. R.
Falck, J. Am. Chem. Soc. 1979, 101, 7131ꢀ7134.
31 a) J. Drabowicz, Synthesis 1980, 125ꢀ126; b) D. H. R. Barton, D. J.
Lester, S. V. Ley, J. Chem. Soc., Chem. Commun. 1977, 445ꢀ446.
32 B. R. Kim, H.ꢀG. Lee, E. J. Kim, S.ꢀG. Lee, Y.ꢀJ. Yoon, J. Org.
Chem. 2010, 75, 484ꢀ486.
33 The 12 Principles of Green Chemistry have become a widely
accepted set of criteria for the rapid assessment of the greenness of a
given chemical reaction: P. T. Anastas and J. C. Warner, in Green
Chemistry Theory and Practice, Oxford University Press, Oxford,
1998, p 30.
4
5
K. Shindo, Y. Yamagishi, Y. Okada, H. Kawai, J. Antibiot. (Tokyo)
1994, 47, 1072ꢀ1074.
M. Stadler, F. Bauch, T. Henkel, A. Muhlbauer, H. Muller, F.
Spaltmann, K. Weber, Arch. Pharm. (Weinheim) 2001, 334, 143ꢀ
147.
6
The gene cluster for 1a biosynthesis was isolated from Streptomyces
sp. CS40, a strain isolated from the leafꢀcutting ant Acromyrmex
octospinosus: I. García, N. M. Vior, A. F. Braña, J. GonzálezꢀSabín,
J. Rohr, F. Morís, C. Méndez, J. A. Salas, Chem. Biol. 2012, 19, 399ꢀ
413.
100
7
8
9
I. García, N. M. Vior, J. GonzálezꢀSabín, A. F. Braña, J. Rohr, F.
Morís, C. Méndez, J. A. Salas, Chem. Biol. 2013, 20, 1022ꢀ1032.
C. Sialer, I. García, J. GonzálezꢀSabín, A. F. Braña, C. Méndez, F.
Morís, J. A. Salas, Bioorg. Med. Chem. Lett. 2013, 23, 5707ꢀ5709.
a) P. Giardina, V. Faraco, C. Pezzella, A. Piscitelli, S. Vanhulle, G.
Sannia, Cell. Mol. Life Sci. 2010, 67, 369ꢀ385; b) J.ꢀR. Jeon, Y.ꢀS.
Chang, Trends Biotechnol. 2013, 31, 335ꢀ341.
105
34 I. W. C. E. Arends, R. A. Sheldon and U. Henefeld, in Green
Chemistry and Catalysis, WileyꢀVCH, Weinheim, 2007.
110 35 Y. Ni, D. Holtmann, F. Hollmann, ChemCatChem 2014, 6, 930ꢀ943.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 5

Green Chemistry
Page 6 of 7
View Article Online
DOI: 10.1039/C5GC02220G
36 See the Supporting Information for a simplified environmental
impact analysis using the Eꢀfactor for the laccaseꢀmediated system.
37 a) C.ꢀJ. Li and T. H. Chan, in Organic Reactions in Aqueous Media,
John Wiley & Sons, New York, 1997; b) U. M. Lindström, Chem.
Rev., 2002, 102, 2751ꢀ2772.
5
6
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 7 of 7
Green Chemistry
View Article Online
DOI: 10.1039/C5GC02220G
An unprecedented and eco-friendly method for the deprotection of oximes with a laccase/TEMPO system was
developed
80x18mm (150 x 150 DPI)